@article {pmid42999280, year = {2026}, author = {Maita, N and Kim, SY and Kajino, Y and Kato, M}, title = {ALS-associated mutations reveal a conserved C-terminal self-assembly module in the TDP-43 low-complexity domain.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.10.09.756561}, pmid = {42999280}, issn = {2692-8205}, abstract = {TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein whose low-complexity domain (LCD) mediates self-assembly, liquid-liquid phase separation, and pathological aggregation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies have established the central ultraconserved region (UCR) of the LCD as a major determinant of TDP-43 self-association. However, the contribution of the evolutionarily conserved C-terminal region remains poorly understood. To identify LCD residues required for self-assembly, we systematically analyzed 47 ALS-associated substitutions distributed throughout the TDP-43 LCD using hydrogel-binding and thioflavin T (ThT) assays. Several ALS-associated substitutions within the C-terminal conserved region (CCR) markedly reduced hydrogel incorporation and impaired fibrillization. Similar assembly defects were observed for methionine-to-serine substitutions at two conserved CCR residues, M405 and M414. Furthermore, CCR-containing C-terminal fragments encompassing residues 360-414 or 379-414 formed ThT-positive fibrillar assemblies in vitro . The assembly kinetics exhibited a characteristic lag phase followed by rapid fluorescence growth, consistent with the formation of cross-β-rich assemblies. These findings identify the CCR as an additional conserved self-assembly module within the TDP-43 LCD and expand the prevailing UCR-centered model of TDP-43 assembly. The observation that multiple ALS-associated substitutions reduce rather than enhance self-association further raises the possibility that disruption of normal TDP-43 assembly contributes to disease pathogenesis.}, } @article {pmid42999738, year = {2026}, author = {Wang, D and Xu, L and Liu, W and Xie, Z and Sun, Y and Fan, M and Wang, L and Ren, Q and Liu, Y and Liang, J and Wang, R}, title = {Muscle Organoids Frontier: Construction Strategies and Applications of Multi-lineage Muscle Organoids and Multi-organoid Systems.}, journal = {Phenomics (Cham, Switzerland)}, volume = {6}, number = {5}, pages = {757-772}, pmid = {42999738}, issn = {2730-5848}, abstract = {In recent years, multi-lineage muscle organoids have rapidly emerged as transformative research tools, providing high-fidelity models for deciphering skeletal muscle development and the pathological mechanisms of muscle diseases such as sarcopenia, amyotrophic lateral sclerosis, and myasthenia gravis. Primarily derived from pluripotent stem cells, these organoids integrate multiple functional lineages, such as skeletal muscle, neural, vascular, and skeletal components, thereby addressing the limitations of conventional single-tissue muscle models. In parallel, multi-organoid systems, such as assembloids and organ-on-a-chip platforms, further integrate distinct organoids (e.g., muscle, skeletal tissue, tendon, and hindbrain/cervical spinal cord) to reconstruct inter-organ communication and systemic physiology under physiologically relevant conditions. By recapitulating in vivo-like multi-tissue interactions, they serve as critical platforms for drug screening and therapeutic development. This review summarizes recent advances in multi-lineage muscle organoids and multi-organoid systems, outlining their cellular sources, construction strategies, and major applications in basic research, disease modeling, and drug discovery, and discusses current challenges and future directions to enhance their potential in muscle research.}, } @article {pmid43000537, year = {2026}, author = {Montanera, KN and Lee, AJ and Yun, W and Ialongo Del Prete, A and Yeh, SY and Jung, I and Rhee, HS}, title = {CREST functions as a molecular bridge between neuron-specific enhancers and epigenetic regulators in mature motor neurons.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {43000537}, issn = {2041-1723}, support = {202203PJT-183582//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; RGPIN-2018-0604//Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology)/ ; CFI37547//Canada Foundation for Innovation (Fondation canadienne pour l'innovation)/ ; }, mesh = {Animals ; *Motor Neurons/metabolism/cytology ; *Epigenesis, Genetic ; Mice ; *Enhancer Elements, Genetic ; *Transcription Factors/metabolism/genetics ; Cell Differentiation/genetics ; Histones/metabolism ; Neurogenesis/genetics ; Gene Expression Regulation, Developmental ; Embryonic Stem Cells/cytology/metabolism ; Nerve Tissue Proteins/metabolism/genetics ; DNA Helicases/metabolism/genetics ; }, abstract = {Motor neuron development requires precise transcriptional regulation mediated in part by BAF (BRG1/BRM-associated factor) chromatin remodeling complexes. The neuron-specific BAF subunit CREST is critical for neuronal function and is mutated in some cases of amyotrophic lateral sclerosis (ALS), yet its underlying genomic mechanisms remain unclear. Using mouse embryonic stem cell differentiation, we show that CREST is essential for motor neuron maturation by activating mature neuronal genes and repressing progenitor genes. Mechanistically, CREST interacts with the neuronal transcription factors ONECUT1 and NGN2, and the BRM ATPase to target pre-existing accessible enhancers of neuronal genes. CREST deletion selectively prevents CBP histone acetyltransferase recruitment, reducing histone H3K27 acetylation at these enhancers and downregulating target gene expression, without disrupting BRM binding, enhancer accessibility, or long-range chromatin architecture. Overall, our findings identify CREST as a crucial epigenetic mediator bridging lineage-specific transcription factors, BAF complexes, and CBP to activate enhancers and promote proper motor neuron development.}, } @article {pmid43001128, year = {2026}, author = {AlRuwaili, R and Alenzi, MH and Alenzi, MH and Alali, AOA and Aljohani, SN and Alenzi, RF and Abu Alsel, B and Fawzy, MS}, title = {Community awareness and knowledge of amyotrophic lateral sclerosis: a cross-sectional study in the Northern Border Region of Saudi Arabia.}, journal = {PeerJ}, volume = {14}, number = {}, pages = {e21710}, pmid = {43001128}, issn = {2167-8359}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Saudi Arabia ; Female ; Cross-Sectional Studies ; *Health Knowledge, Attitudes, Practice ; Middle Aged ; Adult ; Male ; Surveys and Questionnaires ; Young Adult ; Aged ; *Awareness ; Logistic Models ; }, abstract = {BACKGROUND: Public awareness of amyotrophic lateral sclerosis (ALS) is limited worldwide, with potential implications for timely recognition, care seeking, and social support. Data from the Northern Border Region of Saudi Arabia are lacking. This study aims to assess community awareness and knowledge of ALS and identify predictors of good awareness among adults in the Northern Border Region of Saudi Arabia.

METHODS: A cross-sectional survey of 1,277 adults used a structured self-administered questionnaire covering sociodemographic characteristics, general awareness, knowledge, attitudes, personal experience, and information sources. Awareness was scored from 16 knowledge items and categorized as good (≥ 60%) or poor (<60%). Descriptive statistics, chi-square tests with Cramér's V, and multivariable logistic regression were applied; model performance was assessed using the Hosmer-Lemeshow test and area under the receiver operating characteristic (ROC) curve (AUC).

RESULTS: Participants were mainly young to middle-aged, female, and university-educated, and most worked outside the health field. Although 45.2% had heard of ALS, 90.8% showed poor awareness, while only 9.2% showed good awareness. Uncertainty predominated regarding prognosis, risk groups, neuroanatomical involvement, non-motor symptoms, curability, and diagnostic difficulty. Age and occupation were associated with awareness in bivariate analyses but lost significance after adjustment. Never having heard of ALS markedly reduced the odds of good awareness (adjusted odds ratio (AOR) = 0.167, 95% confidence interval (CI) [0.097-0.288], p < 0.001), while using the internet and healthcare sources was associated with higher awareness. The model showed good calibration (Hosmer-Lemeshow p = 0.891) and discrimination (AUC = 0.820).

CONCLUSIONS: Community awareness and knowledge of ALS in this region are poor, underscoring the need for targeted digital and healthcare-based educational initiatives to improve ALS literacy.}, } @article {pmid42993774, year = {2026}, author = {Demeyere, M and Dufourni, A and Verhaeghe, LM and Paulussen, E and Heirman, L and De Baere, S and Croubels, S and De Backer, T and van Loon, G and Decloedt, A}, title = {Blood serotonin, ionized magnesium, cardiac troponin I, N-terminal pro-brain natriuretic peptide concentrations, and mitral valve billowing in horses with mitral valve regurgitation.}, journal = {Journal of veterinary internal medicine}, volume = {40}, number = {6}, pages = {}, pmid = {42993774}, issn = {1939-1676}, support = {1SA2225N//Research Foundation Flanders/ ; FWO.HMZ.2022.0008.01//Research Foundation Flanders/ ; D25EQ-039//Morris Animal Foundation/ ; 01B05818//Special Research Fund Ghent University/ ; //Nova Biomedical/ ; }, mesh = {Animals ; Horses ; *Magnesium/blood ; *Troponin I/blood ; *Natriuretic Peptide, Brain/blood ; *Mitral Valve Insufficiency/veterinary/blood/diagnostic imaging ; *Serotonin/blood ; *Horse Diseases/blood/diagnostic imaging/pathology ; Female ; *Peptide Fragments/blood ; Male ; Cross-Sectional Studies ; Biomarkers/blood ; Prospective Studies ; Echocardiography/veterinary ; Mitral Valve Prolapse/veterinary/blood ; }, abstract = {BACKGROUND: Serotonin, ionized magnesium (iMg), cardiac biomarkers, and mitral valve prolapse are extensively investigated in humans and dogs with mitral valve regurgitation (MR), but not in horses.

HYPOTHESIS/OBJECTIVES: To investigate serotonin, iMg, cardiac troponin I (cTnI), and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations and degree of mitral valve billowing (MVB) in horses with MR.

ANIMALS: Eighty controls (no/trivial MR), 122 horses with MR (92 mild, 24 moderate, 6 severe).

METHODS: Prospective cross-sectional observational study. All horses underwent echocardiography with MVB distance assessment and MR classification. Platelet-poor plasma serotonin and serum iMg, cTnI, and NT-proBNP concentrations were determined. Controls and horses with different MR grades, biomarker concentrations, and MVB distance were compared using (non-)parametric tests.

RESULTS: Ionized magnesium concentration was lower in MR compared to controls (mean difference, 0.03 mmol/L; 95% CI, 0.01-0.05; P = .01), but showed no correlation with billowing distance. The billowing distance was higher in horses with MR than in controls (septal: median difference, 0.2 cm; 95% CI, 0.1-0.3; P < .001; parietal: median difference, 0.3 cm; 95% CI, 0.2-0.3; P < .001), and in horses with a crescendo compared to a holosystolic MR jet (septal: median difference, 0.2 cm; 95% CI, 0.1-0.3; P = .003; parietal: median difference, 0.1 cm; 95% CI, 0.0-0.2; P = .01). No differences in serotonin, cTnI, and NT-proBNP concentrations were detected.

Mitral valve billowing is to some extent likely physiological. The association of serotonin and iMg in MVB and MR requires further investigation. Both cTnI and NT-proBNP showed limited use as biomarkers of MR severity.

ABSTRACT (DUTCH): Achtergrondinformatie: Serotonine, geïoniseerd magnesium (iMg), cardiale biomarkers en mitraalklep prolaps werden reeds uitgebreid onderzocht bij mensen en honden met mitraalklep regurgitatie (MR), in tegenstelling tot paarden met MR. Hypothese/Doelstelling: Het onderzoeken van de serotonine, iMg, cardiaal troponine I (cTnI) en N-terminal pro-brain natriuretic peptide (NT-proBNP) concentraties en de mate van bolling van de mitraalklep naar het linker atrium (MVB) bij paarden met MR. Studiepopulatie: Tachtig controle paarden (geen/triviaal MR), 122 paarden met MR (92 mild, 24 matig, 6 erg). Materiaal en methoden: Prospectieve cross-sectionele observationele studie. Alle paarden ondergingen echocardiografie, waarna de mate van MVB gemeten werd en MR classificatie uitgevoerd werd. De concentraties van serotonine in bloedplaatjesarm plasma en van iMg, cTnI en NT-proBNP in serum werden bepaald. Controle paarden en paarden met verschillende MR graden, biomarker concentraties en de mate van MVB werden onderling vergeleken aan de hand van (non-)parametrische testen. Resultaten: De concentratie iMg was lager bij paarden met MR in vergelijking met controle paarden (gemiddeld verschil, 0.03 mmol/L; 95% BI, 0.01-0.05; P = 0.01), maar vertoonde geen correlatie met de mate van MVB. De mate van MVB was hoger bij paarden met MR dan bij controle paarden (septaal: mediaan verschil, 0.2 cm; 95% BI, 0.1-0.3; P < 0.001; pariëtaal: mediaan verschil, 0.3 cm; 95% BI, 0.2-0.3; P < 0.001), en bij paarden met een crescendo MR jet in vergelijking met paarden met een holosystolische MR jet (septaal: mediaan verschil, 0.2 cm; 95% BI, 0.1-0.3; P = 0.003; pariëtaal: mediaan verschil, 0.1 cm; 95% BI, 0.0-0.2; P = 0.01). Er werden geen verschillen gedetecteerd in de concentraties van serotonine, cTnI en NT-proBNP. Conclusies en klinisch belang: De mate van MVB is tot op een bepaalde hoogte waarschijnlijk fysiologisch. De rol van serotonine en iMg in MVB en MR vergt verder onderzoek. Zowel cTnI als NT-proBNP vertoonden een beperkte meerwaarde als biomarkers bij het bepalen van de ernst van MR.}, } @article {pmid42995649, year = {2026}, author = {Howard, JM and Tuite, M and Mueth, T and Varela, MC and Lazzaro, M and Lieber, L and Liu, S and Rai, KM and Chopra, R}, title = {Discovery and Deployment of Herbicide Tolerance in Domesticated Pennycress (Thlaspi arvense L.) to Enable Modern Agronomic Integration.}, journal = {Plant biotechnology journal}, volume = {}, number = {}, pages = {}, pmid = {42995649}, issn = {1467-7652}, abstract = {Modern agronomic systems for large-scale oilseed production rely heavily on chemical weed control, presenting a barrier to the adoption of newly domesticated crops that lack herbicide tolerance. Pennycress (Thlaspi arvense L.), a domesticated winter oilseed developed to increase land productivity and support sustainable biofuel production, is highly sensitive to commonly used herbicides targeting acetolactate synthase (ALS) and 4-hydroxyphenylpyruvate dioxygenase (HPPD). Here, we report complementary strategies for identifying and deploying herbicide-tolerant alleles in pennycress. ALS inhibitor tolerance was identified through Ethyl methanesulfonate (EMS)-derived chemical mutagenesis, whereas HPPD inhibitor tolerance was explored using a microbial-based rational enzyme design platform as proof of concept. Selected alleles were introduced into advanced germplasm via homology-directed repair (HDR) and evaluated across developmental stages. Plants carrying the P187S mutation in the ALS gene exhibited robust tolerance at both seedling and rosette stages without detectable penalties to growth or seed yield. In contrast, the G419A allele in the HPPD gene conferred tolerance to residual herbicide activity when overexpressed but showed limited efficacy when expressed from its native locus, indicating context-dependent functionality. Collectively, this study demonstrates the feasibility of integrating herbicide tolerance into a newly domesticated oilseed crop and highlights the utility of combining mutagenesis-based discovery, rational enzyme engineering, and precision genome editing to support agronomic compatibility and crop deployment.}, } @article {pmid42995797, year = {2026}, author = {Haizel, SA and Ceballos, AV and Ko, AN and Lyu, L and Manning, L and Ge, X and Park, V and Zou, H and Cheng, C and Afful, R and Kher, S and Widjaja, A and Jean-Baptiste, J and Khazhinsky, S and Spealman, P and Jones, AN and Valasek, LS and Vogel, C}, title = {Multi-level repression ensures tight translation control of C9ORF72.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.08.09.669471}, pmid = {42995797}, issn = {2692-8205}, abstract = {C9ORF72 is involved in multiple neuronal functions and a major factor in Amyotrophic Lateral Sclerosis, a fatal neurodegenerative disease. Pathogenicity is implemented through an intronic repeat expansion in the gene's mRNA leader that produces long, repetitive RNA and dipeptides when translated through repeat associated non-canonical translation. The expanded repeat also suppresses transcription of the major transcript variant (Variant 2) which comprises 90% of the C9ORF72 levels in healthy cells, leading to an additional loss-of-function effect. Examining the sequence, structure, and ribosome occupancy of Variant 2's mRNA leader in detail, we found that translation of C9ORF72 is tightly regulated through a multi-layered system. To deconvolute this system, we conducted a mutant screen and developed a method to evaluate the results quantitatively. We found that near-cognate start codons in all three frames, a start-stop element in frame 2, a uTranslon in frame 1, and secondary structures cooperate to keep baseline C9ORF72 translation low. Further, initiation at upstream near-cognate start codons reduces the impact of both the start-stop and the uTranslon, effectively buffering their repressive function and creating a feedforward loop. A strong secondary structure in the Variant 2-specific sequence further modulates initiation at all the elements. We hypothesize that this buffered repressor system has evolved to ensure reliable, noise-insensitive expression of this critical regulator of neuronal function. Finally, we used ADAR-based RNA editing of specific sites in Variant 2's mRNA leader, increasing translation of the gene and providing a novel avenue to rescue the loss-of-function phenotype in disease.}, } @article {pmid42995867, year = {2026}, author = {Amoros, MA and Ekambaram, S and Iskandar, RM and Simmons, Z and Dokholyan, NV}, title = {ALSmiR: a curated evidence resource for ALS-associated microRNAs for biomarker discovery.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.10.16.759728}, pmid = {42995867}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis is a multifactorial, late-onset neurodegenerative disease with incompletely understood pathogenesis. Limited survival after symptom onset creates an urgent need for biomarkers to support diagnosis, prognosis, and patient stratification. MicroRNAs are among the candidate biomarkers investigated in this disease. Although reviews have synthesized microRNA expression findings, differences in patient populations, biospecimens, and methods complicate comparisons. In the age of data-driven research, we need an updated, searchable resource that links each finding to its context and incorporates growing evidence. Here, we present ALSmiR, a public, manually curated database of polymerase chain reaction-based microRNA expression findings from human biological fluids and their components. ALSmiR currently contains 1,620 expression records from 49 publications comparing patients with amyotrophic lateral sclerosis with healthy controls, covering 816 microRNA names across 13 biospecimen categories. We link publication, cohort, and microRNA-result tables to preserve each finding's clinical and experimental context. We retain significant and non-significant results and provide searchable records and comma-separated values exports for independent analysis. We update ALSmiR annually and verify author submissions against source publications before inclusion. Researchers can use ALSmiR to assess candidate biomarkers, formulate hypotheses, and design independent validation studies. ALSmiR is freely accessible worldwide without registration at https://alsmir.dokhlab.org/ .}, } @article {pmid42998121, year = {2026}, author = {Propes, C and Montgomery, T and Cheung, K and Kass, N and Morain, S and Alexander, GC}, title = {Public Participation in U.S. Food and Drug Administration (FDA) Advisory Committees: A Qualitative Analysis.}, journal = {Therapeutic innovation & regulatory science}, volume = {}, number = {}, pages = {}, pmid = {42998121}, issn = {2168-4804}, abstract = {IMPORTANCE: The FDA frequently solicits public input to inform advisory committee meetings reviewing new drug applications. Although intended to enhance transparency and incorporate patient perspectives, the content of these submissions has not been well described.

OBJECTIVE: To characterize public comments to FDA advisory committee meetings and examine the values and considerations expressed.

DESIGN: Qualitative study using inductive content analysis with an iterative coding framework. Comments were coded by one reviewer and independently double-coded for a random subset; disagreements were resolved through discussion (Light's kappa = 0.81).

SETTING: Public comments associated with FDA advisory committee meetings for five new drug applications reviewed between January 2020 and December 2024.

PARTICIPANTS: A random sample of 600 public comments from the five products with the highest public engagement: (1) sodium phenylbutyrate-taurursodiol for ALS; (2) teplizumab for type 1 diabetes; (3) midomafetamine (MDMA-assisted therapy) for PTSD; (4) delandistrogene moxeparvovec for Duchenne muscular dystrophy; and (5) eflornithine tablets for pediatric neuroblastoma.

MAIN OUTCOME MEASURES: Stakeholder role, stance regarding drug approval, and thematic content.

RESULTS: Submissions were most commonly from caregivers or immediate family members (31.5%), individuals without disclosed roles (20.0%), friends or extended family (18.5%), and patients (17.2%). Most comments supported approval (90.2%), with few neutral (7.8%) or opposing (1.3%) views. Four themes emerged: (1) experiential considerations; (2) evidentiary considerations, including clinical trial data and personal observations; (3) regulatory and policy considerations, such as urgency of access; and (4) values-based considerations, such as therapeutic hope and autonomy.

CONCLUSIONS AND RELEVANCE: Public comments were overwhelmingly supportive of approval, reflecting experiential, evidentiary, policy, and values-based considerations. Strengthening mechanisms for synthesizing public input may enhance transparency and confidence in the FDA regulatory process.}, } @article {pmid42999187, year = {2026}, author = {Aliya, B and Liu, S and Mansfield, A and Yao, SX and Mouhi, S and Wariyar, SS and Tenkorang, JS and Smith, NE and Chung, M and Rachel Yu, AJ and Pio, T and Smith, NEJ and Zhu, SH and Trautwig, AN and Parameswaran, J and Yin, L and Watson, CM and Hub, BO and Jiang, J and Seyfried, NT and McEachin, ZT and Yao, B and Andersen, J}, title = {Temporal RNA splicing dysregulation in a human multicellular model of C9orf72 ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.10.13.755334}, pmid = {42999187}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and heterogenous disease, comprising of familial and sporadic forms, numerous genetic mutations, and a wide range of affected cell types and proposed dysregulated processes. While the usage of in vitro cell cultures, mouse models, and postmortem patient tissue have advanced our understanding of ALS disease mechanisms, the temporal progression of the disease and how early molecular changes evolve remain poorly understood. Here, we establish human spinal cord organoids (hSpO) derived from C9orf72 patient induced pluripotent stem cells (C9-ALS hiPSCs) as a platform to model longitudinal changes across the disease trajectory. We show that C9-ALS hSpO recapitulate hallmark C9orf72 -related pathologies, increased cell death, and progressive neuronal dysfunction. We further identify RNA splicing dysregulation as an early and persistent feature of C9-ALS, with splicing signatures in hSpO closely mirroring those observed in postmortem patient tissue. Finally, prediction of RNA binding proteins (RBPs) that induce early splicing changes in C9-ALS reveals signatures consistent with a broad RBP network dysfunction. Together, this work establishes hSpO as an in vitro system for investigating early disease mechanisms of ALS in a human multicellular context and highlights dysregulated events that precede cell death.}, } @article {pmid42990966, year = {2026}, author = {Herrmann, C and Jagodzinski, L and Elmas, Z and Herschmann, T and Fröhlich, E and Bachhuber, F and Ruschitzka, T and Willkomm, F and Parlak, Ö and Weiland, U and Becker, F and Richter, L and Wiesenfarth, M and Uzelac, Z and Michels, S and Witzel, S and Tumani, H and Weishaupt, JH and Maier, L and Mayer, B and Dreyhaupt, J and Schuster, J and Dorst, J}, title = {Efficacy and tolerability of D-β-hydroxybutyrate ester in patients with amyotrophic lateral sclerosis (KETO-ALS)-a randomised, placebo-controlled, double-blind study.}, journal = {EClinicalMedicine}, volume = {101}, number = {}, pages = {104272}, pmid = {42990966}, issn = {2589-5370}, abstract = {BACKGROUND: Hypermetabolism and weight loss are prominent features of amyotrophic lateral sclerosis (ALS). Here, we sought to target the energy deficit in ALS by applying oral ketone bodies as high-energetic substrates.

METHODS: Patients with probable or definite ALS were enrolled to this randomised, placebo-controlled, parallel-group, double-blind, monocentre phase 2 trial. Eligible patients had a decline of ALS functional rating scale revised (ALSFRS-R) of at least 0.33 points/month. They were randomly assigned (1:1) to receive D-β-hydroxybutyrate ester (βHB, 30 g/day) or placebo. Primary endpoint was change of neurofilament light chain (NfL) per month, measured as slope over 6 months. Multiple linear regressions models were applied to adjust for NfL, age, BMI, and slow vital capacity (SVC) at baseline. The trial is registered with clinicaltrials.gov, number NCT04820478.

FINDINGS: Between April 5, 2022, and February 12, 2025, 81 patients were randomly assigned to receive βHB (n = 40) or placebo (n = 41) and included in the intention-to-treat analysis. In the unadjusted analysis, the primary endpoint NfL slope was negative, showing a decline of -0.5 pg/mL/month (IQR -3.2 to 2.0, minimum -11.2, maximum 10.4) in the βHB group and a stable course of 0.0 pg/mL/month (IQR -1.7 to 3.3, minimum -6.2, maximum 49.0) in the placebo group (p = 0.094). In the adjusted analysis, the NfL slope showed a benefit for the βHB group (-1.5 pg/ml/month in βHB vs. +2.8 pg/ml/month in placebo, mean difference -4.2 pg/ml/month, 95% CI - ∞ to -1.1, p = 0.014). When using a mixed effect model, this effect was not statistically different (-0.4 pg/ml/month in βHB vs. +0.3 pg/ml/month in placebo, mean difference -0.7 pg/ml, month, p = 0.30). In the unadjusted analysis, ALSFRS-R showed a faster decline in the verum group (-1.4 points/month (IQR -2.1 to -0.6) vs. -0.8 points/month (IQR -1.2 to -0.2), p = 0.020). No significant difference between βHB and placebo was found regarding clinical endpoints such as ALSFRS-R or BMI in the adjusted analysis. βHB was well tolerated, with similar frequency of adverse events across both groups.

INTERPRETATION: Whether the effects on NfL can be confirmed and translated into meaningful clinical effects, remains to be clarified by a larger phase 3 trial with extended treatment duration. βHB was well tolerated.

FUNDING: This was an investigator-initiated study, funded by a private donation.}, } @article {pmid42991605, year = {2026}, author = {Hauser, W and Keller, JE and Pasnoor, M and Wright, DE}, title = {Small-fiber degeneration, sensory dysfunction, and nociception comorbidity in central neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1854989}, pmid = {42991605}, issn = {1663-4365}, support = {P20 GM103418/GM/NIGMS NIH HHS/United States ; R01 NS043314/NS/NINDS NIH HHS/United States ; }, abstract = {Progressive neurodegenerative disease typically calls for clinical effort to improve cognitive and motor deficits. It is also focused on improving patients' quality of life. However, across these dementias and other diseases, the underlying causes and potential mechanisms remain unclear. Most experimental and clinical research focuses on the central nervous system, examining pathogenic proteins such as tau and amyloid beta, as well as the potential cascade following mitochondrial damage and neuroinflammation. Although peripheral involvement, including gut microbiome influences and other visceral organs, is well-documented, the peripheral nervous system remains an understudied component of these progressive diseases. As peripheral terminals of primary afferent neurons are exposed to inflammatory or toxic mediators, these neurons respond to these threats via neuron-specific phenotypic changes, including the generation of pain. Although normal peripheral sensitization is protective, exposure to damage in a chronic disease state can have long-term detrimental effects. Diseases that lead to central neurodegeneration often also feature peripheral neuropathy and chronic pain. We provide an overview of the incidence of peripheral neuropathy within these diseases, the contribution of changes in sensation to disease, and secondary neuropathic phenotypes resulting from disease. Woven in are discussions of the intersection of degeneration and toxic protein aggregation, briefly touching on resulting inflammatory signaling. Altogether, this review aims to synthesize current understanding of sensory peripheral nerve involvement across these neurodegenerative diseases.}, } @article {pmid42992452, year = {2026}, author = {Wang, B and Wang, I and Park, C and Barkhaus, PE and Shirilla, D}, title = {Leuprorelin Acetate for Spinal and Bulbar Muscular Atrophy: A Systematic Review of Clinical Efficacy, Long-Term Outcomes, and Safety Considerations.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70454}, pmid = {42992452}, issn = {1097-4598}, abstract = {Spinal and bulbar muscular atrophy (SBMA; Kennedy disease) is a rare X-linked neuromuscular disorder caused by a CAG repeat expansion in the androgen receptor gene. Leuprorelin acetate, a luteinizing hormone-releasing hormone agonist, suppresses androgen signaling and is approved for SBMA-associated dysphagia in Japan; however, evidence regarding efficacy remains heterogeneous. PubMed and Embase were searched from inception through June 18, 2026, for studies evaluating leuprorelin in genetically confirmed SBMA. Randomized trials, observational cohorts, natural history-controlled studies, extension studies, and safety case reports were included, and findings were synthesized narratively because of substantial heterogeneity. Eleven studies met inclusion criteria, including eight efficacy studies (460 patients) and three safety-focused case reports. Leuprorelin reduced pathogenic androgen receptor accumulation and improved biochemical markers, including serum creatine kinase and creatinine decline. Although neither pivotal randomized trial demonstrated significant short-term functional improvement at 48 weeks, longer-term studies showed slower decline in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), Limb Norris, and Norris Bulbar scores and improved event-free survival from pneumonia and death. Benefits were greatest with earlier treatment, particularly disease duration < 10 years. Leuprorelin was generally well tolerated; common adverse effects included hot flushes, sexual dysfunction, and decreased bone mineral density. Leuprorelin may slow long-term functional deterioration in SBMA, with greater benefit following early initiation and prolonged treatment.}, } @article {pmid42990340, year = {2026}, author = {Kaufhold, R and Dong, W and Purwar, I and Saladin, B and Wieland, CM and Krans, A and Laimon, E and Malik, I and Leskaj, S and Havilio, T and Sokabe, M and Fraser, CS and Todd, PK and Querido, JB}, title = {Structural basis for repeat-associated non-AUG translation initiation on C9orf72 mRNA.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.10.25.761709}, pmid = {42990340}, issn = {2692-8205}, abstract = {A GGGGCC (G 4 C 2) hexanucleotide repeat expansion in the first intron of C9orf72 is the most common monogenic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). This element serves as a template for repeat-associated non-AUG (RAN) translation, which generates neurotoxic dipeptide repeat (DPR) proteins that aggregate in patient brains and contribute to neurodegeneration in model systems. To understand the mechanisms underlying RAN translation initiation, we used cryo-electron microscopy to determine the structure of an in vitro assembled human late-stage C9orf72 translation initiation complex at 3.2 Å resolution and a near-native complex purified from human cell lysate at 3.5 Å resolution. RAN translation on C9orf72 mRNA initiates predominantly at a near-cognate CUG codon that is located 24 nucleotides upstream of the G 4 C 2 repeat and is flanked by a strong endogenous Kozak sequence. The structures further reveal a direct interaction between the G 4 C 2 repeat and 18S ribosomal RNA expansion segment 9 (ES9S) on the 40S small ribosomal subunit through a kissing-loop interaction. Preventing this RNA-RNA interaction using complementary antisense oligonucleotides significantly reduces RAN translation in vitro and in patient-derived iNeurons, indicating that this structural interaction is functionally important. These findings provide mechanistic insights into RAN translation initiation and highlight a novel potential therapeutic approach to mitigate toxic DPR production in C9orf72-associated neurodegenerative disease.}, } @article {pmid42990486, year = {2026}, author = {Obara, K and Mastrangelo, A and Ranieri, A and Janelidze, S and Ito, D and Yamamoto, M and Vacchiano, V and Liguori, R and Caldera, S and Riku, Y and Iwasaki, Y and Tran, S and Kawase, T and Mori, Y and Hiraga, K and Yamada, S and Tsujikawa, K and Nishio, Y and Ogi, T and Nakamura, R and Atsuta, N and Sobue, G and Stomrud, E and Palmqvist, S and Hansson, O and Parchi, P and Katsuno, M and Mattsson-Carlgren, N}, title = {Cerebrospinal fluid α-synuclein seed amplification assay positivity identifies a prognostically distinct subgroup in amyotrophic lateral sclerosis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.10.23.26366349}, pmid = {42990486}, abstract = {BACKGROUND: α-synuclein (Lewy body-type) co-pathology has been identified at autopsy in a subset of patients with amyotrophic lateral sclerosis (ALS). However, its prevalence and prognostic relevance in vivo remain poorly characterized.

METHODS: We analyzed baseline cerebrospinal fluid (CSF) α-synuclein seed amplification assay (αSyn SAA) status in 443 patients with ALS from two cohorts (Nagoya, Japan, n = 248; Bologna, Italy, n = 195). Samples were classified as strong-positive, weak-positive, or negative based on RT-QuIC reactivity across replicate wells, using the assay's established a priori criteria at initial and repeat testing; classifications were corroborated by quantitative kinetic parameters. We compared age- and sex-adjusted odds of positivity in ALS with those in cognitively unimpaired (CU; n = 999; stratified by amyloid-β [Aβ] status), Aβ-positive mild cognitive impairment (n = 224), and Alzheimer's disease dementia (n = 319) groups from the Swedish BioFINDER cohort. In ALS, we examined tracheostomy-free survival and longitudinal functional decline using cohort-stratified Cox and linear mixed-effects models, respectively. We also assessed interactions between αSyn SAA status and baseline CSF neurofilament light chain (NfL). Prognostic analyses were performed in sporadic ALS and repeated after including familial or genetic cases.

RESULTS: Strong αSyn SAA positivity was detected in 24/443 patients with ALS (5.4%); overall positivity, including weak-positive samples, was 37/443 (8.4%). Patients with ALS did not have significantly higher odds of SAA positivity than Aβ-negative CU participants (age- and sex-adjusted odds ratio [OR] 1.33, 95% CI [0.82, 2.14]) and had significantly lower odds than patients with Alzheimer's disease dementia (OR 0.44, [0.27, 0.70]). Among patients with sporadic ALS, strong αSyn SAA positivity was associated with shorter tracheostomy-free survival after adjustment for established predictors including NfL (adjusted HR 2.08 [1.25, 3.45]), whereas weak positivity showed no clear survival association. In linear mixed-effects models, strong αSyn SAA positivity modified the association between NfL and ALSFRS-R decline (NfL × αSyn SAA × time interaction β-0.70 points/month [-1.26, -0.14] per SD NfL). These findings persisted in analyses including familial or genetic ALS cases and in those restricted to Aβ-negative patients. Neuropathological findings (n = 5) were concordant with the CSF αSyn SAA classification.

CONCLUSIONS: A strong α-synuclein seeding profile was uncommon in ALS but identified a subgroup with shorter survival and a stronger association between NfL and functional decline. These findings provide ante-mortem evidence that α-synuclein co-pathology may contribute to prognostic heterogeneity in ALS.}, } @article {pmid42990777, year = {2026}, author = {Huang, J and Li, H and Zhou, H and Li, T and Li, J and Liu, D and Yan, K}, title = {Pathological separation utility of plasma neurofilament light chain (NfL) detected by a single-molecule immunoassay platform in neurodegenerative diseases.}, journal = {BMJ neurology open}, volume = {8}, number = {2}, pages = {e001715}, pmid = {42990777}, issn = {2632-6140}, abstract = {BACKGROUND: To establish age-stratified plasma neurofilament light chain (NfL) reference intervals using a domestic Digital Single-Molecule Sensing (DiSMS) platform and to explore neuropathological profiles across amyotrophic lateral sclerosis (ALS), inflammatory demyelinating diseases (IDD) and healthy individuals.

METHODS: We enrolled 719 participants (510 healthy controls, 121 ALS, 88 IDD). Age-specific reference intervals defining the healthy boundary were established using the 2.5th-97.5th percentile method. Pathological separation utility was evaluated via age-stratified subgroup comparisons and receiver operating characteristic (ROC) analysis.

RESULTS: Plasma NfL levels in healthy individuals increased significantly with age (p<0.0001), with reference intervals of 2.68-17.09 pg/mL (20-49 years), 7.14-61.95 pg/mL (50-69 years) and 14.20-104.71 pg/mL (≥70 years). Out-of-boundary NfL elevation rates demonstrated prominent age-dependent fluctuations. In ALS, out-of-boundary elevation rates were 98.3% (57/58) for the 20-49 age group, 68.4% (39/57) for the 50-69 group and 50.0% (3/6) for the ≥70 group, capturing the aggressive tempo of primary motor neuron degeneration. In IDD-which primarily comprised patients in early, clinically stable phases-out-of-boundary rates were 17.0% (8/47) in the 20-49 group and 2.6% (1/38) in the 50-69 group. Age-stratified ROC analysis demonstrated exceptional separation capacity for ALS against healthy controls (area under the curve (AUC): 20-49 years=0.999; 50-69 years=0.964; ≥70 years=0.981) and against IDD (AUC: 20-49 years=0.910; 50-69 years=0.976). Intriguingly, in the 20-49 group where physiological ageing noise was minimal, the platform retained a modest capability to distinguish stable IDD from healthy controls (AUC=0.607).

CONCLUSION: Age-stratified plasma NfL mapping provides a rigorous normative framework for defining population-specific healthy boundaries in China. Rather than functioning as a standalone differential classifier, the dramatic cross-sectional variance in peripheral NfL magnitude successfully maps the distinct pathological spaces separating primary, continuous neurodegeneration (ALS) from quiescent neuroinflammation (IDD) across the adult lifespan, validating the analytical utility of domestic DiSMS platforms.}, } @article {pmid42990859, year = {2026}, author = {Benech, H and Krebs-Drouot, L and Viardot, G and Bertaina-Anglade, V and Lhotellier, C and Flament, V and Roucairol, C and Mabondzo, A and Pinquier, JL and Joudinaud, T}, title = {Intranasal CBT101 demonstrates favorable safety and neurophysiological evidence of central activity in healthy male volunteers.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1940627}, pmid = {42990859}, issn = {1664-2295}, mesh = {Humans ; Male ; Administration, Intranasal ; Adult ; Double-Blind Method ; Electroencephalography ; Young Adult ; *Evoked Potentials/drug effects ; Healthy Volunteers ; *Prodrugs/administration & dosage/adverse effects/pharmacology ; Dose-Response Relationship, Drug ; Middle Aged ; }, abstract = {OBJECTIVES: CBT101 is a creatine prodrug under development for disorders driven by impaired neuronal energy homeostasis, with initial development focused on creatine transporter deficiency and amyotrophic lateral sclerosis. This first-in-human study aimed to assess the safety and tolerability of single and repeated ascending intranasal doses of CBT101 in healthy male volunteers and explored neurophysiological evidence of central pharmacodynamic activity using quantitative EEG (qEEG) and event-related potentials (ERPs).

METHODS: This was a randomized, double-blind, single-center, placebo-controlled phase 1 trial including single ascending dose (SAD) and multiple ascending dose (MAD) parts. Forty-eight healthy male volunteers were randomized 3:1 to CBT101 or placebo. CBT101 was administered intranasally at 4.2, 8.4, or 12.6 mg in the SAD part and at 4.2, 8.4, or 12.6 mg/day for 14 days in the MAD part. The primary objective was safety and tolerability. Secondary analyses assessed quantitative EEG (qEEG) and event-related potentials (ERPs) as pharmacodynamic evaluations.

RESULTS: No serious or severe treatment-emergent adverse events occurred, no dose-limiting toxicity was observed, and no clinically relevant safety findings were reported. As expected, plasma CBT101 concentrations were below the limit of quantification in all analyzed samples. qEEG analyses identified an acute post-dose increase in relative beta activity after single dosing. After repeated dosing, the qEEG profile evolved toward a more sustained pattern characterized by beta-1 modulation and early gamma-band changes. ERP/P300 analyses showed a transient decrease in P300 latency, with no statistically significant change in P300 amplitude.

CONCLUSION: Intranasal CBT101 was safe and well tolerated across the evaluated SAD and MAD dose ranges in healthy male volunteers. Convergent qEEG and ERP findings provided early neurophysiological evidence of central pharmacodynamic engagement. These findings support continued clinical development of CBT101 for disorders associated with impaired neuronal energy homeostasis.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT07050316.}, } @article {pmid42982035, year = {2026}, author = {Lee, K and Kwak, T and Park, W}, title = {Retraction to "Integrative ALS therapy: gene targeted therapy by base editing and potential exercise rehabilitation as synergistic strategies for functional recovery".}, journal = {Physical activity and nutrition}, volume = {}, number = {}, pages = {}, doi = {10.20463/pan.2026.0045.r1}, pmid = {42982035}, issn = {2733-7545}, } @article {pmid42983429, year = {2026}, author = {Bubphachat, P and Majumder, P and Wang, IF and Huang, JK and Kao, TJ and Lee, YC and Shen, CJ and Chen, GC and Chen, PC and Huang, CS}, title = {The TNKS/PI31-proteasome axis as a central node in TDP-43 neuropathies.}, journal = {Journal of biomedical science}, volume = {33}, number = {1}, pages = {}, pmid = {42983429}, issn = {1423-0127}, support = {NSTC110-2320-B-038-067-MY3//National Science and Technology Council/ ; }, mesh = {Animals ; *Proteasome Endopeptidase Complex/metabolism/genetics ; Mice ; *DNA-Binding Proteins/genetics/metabolism ; *Tankyrases/metabolism/genetics ; Humans ; Mice, Transgenic ; *TDP-43 Proteinopathies/genetics ; }, abstract = {BACKGROUND: Pathological aggregation of Tar DNA-binding protein 43 (TDP-43) and disruption of neuronal protein homeostasis are defining features of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and related TDP-43 proteinopathies. Efficient axonal transport of proteasomes is essential for maintaining local protein quality control in neurons. Proteasome inhibitor 31 (PI31) regulates both 26S proteasome assembly and dynein-mediated transport of 20S proteasomes. Although Tankyrase 1/2 (TNKS)-mediated ADP-ribosylation of PI31 promotes 26S proteasome assembly, its role in proteasome transport and its contribution to TDP-43 pathology remain unclear.

METHODS: Live-cell imaging was performed to examine 20S proteasome transport in primary cortical and motor neurons from wild-type and Prp-TDP-43[A315T] transgenic mice. Protein interactions among TDP-43, TNKS, and PI31 were analyzed by immunoprecipitation and Förster resonance energy transfer (FRET). Insoluble protein accumulation and colocalization were assessed by RIPA/urea fractionation, Western blotting, and immunofluorescence. Proteasome assembly and activity were evaluated using native gel electrophoresis and a 20S proteasome-specific fluorogenic substrate. TDP-43 aggregation was examined by semi-denaturing detergent agarose gel electrophoresis (SDD-AGE).

RESULTS: In cell models expressing TDP-43-FL, TDP-43-A315T, or TDP-25 and in Prp-TDP-43[A315T] transgenic mice, pathological TDP-43 species formed distinct aggregates, ranging from oligomers to prominent cytoplasmic aggregates, yet all reduced proteasome activity, impaired axonal proteasome transport, and caused the accumulation of polyubiquitinated proteins, PI31, 20S proteasomes, and TDP-43 in the proximal axon and cell body. Pathological TDP-43 sequestered TNKS and proteasome components into insoluble fractions, thereby limiting the availability of free and soluble TNKS for interaction with PI31 and subsequent PI31 ADP-ribosylation, ultimately impairing 19S/20S proteasome assembly. Notably, disruption of the TNKS-PI31 interaction or inhibition of TNKS activity recapitulated the proteasome dysfunction induced by pathological TDP-43, supporting a role for the aberrant TNKS-TDP-43 interaction and consequent impairment of TNKS-mediated PI31 ADP-ribosylation in TNKS/PI31/proteasome axis dysfunction.

CONCLUSIONS: Pathological TDP-43 disrupts proteasome function by impairing the TNKS/PI31/proteasome axis, suggesting that this axis may represent a potential therapeutic target for TDP-43 proteinopathies. Selectively restoring this pathway may enhance pathological TDP-43 clearance while minimizing nonspecific proteasome activation, thereby providing a more precise and safer therapeutic strategy for ALS and FTLD.}, } @article {pmid42983584, year = {2026}, author = {Xiong, M and Huang, Y and Jiang, H and Zhang, Z}, title = {Brain clearance of protein aggregates in degenerative diseases: the role of microglia and astrocytes.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {42983584}, issn = {2047-9158}, support = {82501688//National Natural Science Foundation of China/ ; 82525025//National Natural Science Foundation of China/ ; 2025AFB243//Natural Science Foundation of Hubei Province/ ; }, mesh = {Humans ; *Astrocytes/metabolism/pathology ; *Microglia/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; *Protein Aggregates/physiology ; *Protein Aggregation, Pathological/metabolism/pathology ; Phagocytosis/physiology ; Proteotoxic Stress ; }, abstract = {Protein aggregation and impaired clearance constitute central pathological hallmarks of numerous neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Misfolded proteins, both extracellular and intracellular, disrupt proteostasis and contribute to synaptic dysfunction, neuroinflammation, and neuronal loss. Within the central nervous system, glial cells serve as the primary mediators of pathological protein clearance. Microglia detect, phagocytose, and degrade aggregated proteins. However, under chronic pathological stress, microglial function turns from clearing pathological proteins to paradoxically facilitating their spread. Astrocytes, which provide metabolic and homeostatic support for neurons, also participate in the clearance of aggregates through phagocytosis and glymphatic drainage. Critically, crosstalk between astrocytes and microglia enhances the clearance: microglia can recruit and process aggregates internalized by astrocytes, while astrocyte-derived signals modulate the microglial phagocytic activity. Aging, genetic risk factors, or sustained neuroinflammation may reduce the efficiency of glial removal of aggregates and accelerate disease progression. Understanding the cellular and molecular underpinnings of microglial and astrocytic clearance pathways is essential for developing therapies aimed at restoring proteostasis and mitigating neurodegeneration.}, } @article {pmid42983872, year = {2026}, author = {Kiryu-Seo, S}, title = {[Damage response mechanisms for evading neurodegeneration: mitochondrial supply driven by logistics gate disassembly].}, journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica}, volume = {161}, number = {6}, pages = {422-426}, doi = {10.1254/fpj.26064}, pmid = {42983872}, issn = {0015-5691}, mesh = {Animals ; *Mitochondria/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Axons/pathology/metabolism ; Motor Neurons/pathology/metabolism ; }, abstract = {Mature neurons are highly vulnerable to trauma and neurodegenerative diseases. Conversely, certain peripheral neurons exhibit remarkable survival and regenerative capacities by synchronously activating damage responses to undergo a transient "rejuvenation." Identifying and elucidating these unresolved mechanisms is essential for understanding disease pathogenesis and developing fundamental therapies. Because these responses are driven by complex intercellular interactions, in vivo investigations are indispensable. To address this, we developed the Atf3:BAC Tg mice, a powerful tool that enables damaged neuron-specific genetic manipulation coupled with mitochondrial visualization. Tracking mitochondrial dynamics-which sensitively reflect neuronal states-revealed a novel damage response: injured motor neurons actively disassemble the axon initial segment (AIS), a structural hallmark of mature neurons, via the proteasome to evade axonal degeneration. The AIS functions as a logistical gate restricting axonal transport between the soma and the axon. Strikingly, dismantling this gate allows healthy mitochondria to surge from the soma into the distal axon, successfully preventing energy depletion. In contrast, in amyotrophic lateral sclerosis (ALS) motor neurons, this disassembly switch malfunctions from the early stages of the disease; the gate remains closed under pathological insults, leading to energetic starvation and subsequent degeneration. Intriguingly, ALS-resistant sensory neurons inherently lack this logistical gate, allowing unrestricted mitochondrial supply to axons even under proteasomal dysfunction. This review outlines these cutting-edge findings and introduces the forefront of fundamental research aiming to uncover the pathogenesis of neurodegenerative diseases through the lens of neuronal damage responses.}, } @article {pmid42983891, year = {2026}, author = {Ikegami, I and Hongo, S and Koyama, A and Hayakawa-Yano, Y and Yano, M and Sugai, A and Ishihara, T and Tada, M and Kakita, A and Onodera, O and Koike, YM}, title = {TDP-43-related cryptic splicing reflects pathological heterogeneity in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42983891}, issn = {2051-5960}, support = {24K10506//the Japan Society for the Promotion of Science (JSPS)/ ; Program for Forming Japan's Peak Research Universities (J-PEAKS) JPJS00420240016//the Japan Society for the Promotion of Science (JSPS)/ ; 24K10635//the Japan Society for the Promotion of Science (JSPS)/ ; MoonShot 7 Program JP24zf0127012//the Japan Agency for Medical Research and Development (AMED)/ ; 23ek0109641h0001//the Japan Agency for Medical Research and Development (AMED)/ ; PRESTO, Sakigake, JPMJPR248A//the Japan Science and Technology Agency (JST)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Female ; Male ; Aged ; Middle Aged ; Retrospective Studies ; *Nerve Tissue Proteins/genetics/metabolism ; *Motor Cortex/pathology/metabolism ; Aged, 80 and over ; }, abstract = {Amyotrophic lateral sclerosis (ALS) involves TAR DNA-binding protein 43 (TDP-43) dysfunction, leading to cryptic splicing, including UNC13A cryptic exon inclusion and truncated STMN2 production. Pathologically, ALS is classified into three phosphorylated TDP-43 subtypes (Types 1, 2a, and 2b) based on the distribution of neuronal and glial cytoplasmic inclusions and the density of dystrophic neurites. However, the relationship between these pathological subtypes and TDP-43-associated cryptic splicing remains unclear. This retrospective postmortem study aimed to analyze motor cortex tissue from sporadic ALS cases (Type 1, n = 12; Type 2a, n = 12; Type 2b, n = 11) with previously described subtype-specific morphological features. UNC13A cryptic RNA and truncated STMN2 RNA levels were quantified using quantitative real-time PCR (qRT-PCR). Compared with Types 1 and 2a, Type 2b, characterized by abundant thread-, dot-, and grain-like dystrophic neurites, exhibited significantly higher levels of UNC13A cryptic RNA and truncated STMN2 RNA. Droplet digital PCR revealed a similar subtype-dependent trend and showed strong correlations with qRT-PCR measurements, providing partial support for the primary findings. UNC13A cryptic RNA and truncated STMN2 RNA levels were positively correlated (Spearman's ρ = 0.58), indicating coordinated dysregulation of multiple TDP-43-dependent splicing targets. Our results demonstrate that the burden of TDP-43-associated cryptic splicing differs across ALS pathological subtypes. Additional analyses indicated that these subtype-dependent differences were not readily accounted for by disease duration, RNA quality, normalization strategy, or semiquantitative neuronal loss scores. These findings suggest that molecular heterogeneity parallels pathological heterogeneity in ALS and provide additional insight into the biological diversity of TDP-43 proteinopathy.}, } @article {pmid42986019, year = {2026}, author = {Deng, X and Mitchison, T}, title = {STMN2: Membrane-Binding Microtubule Regulator or Tubulin Effector?.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {48}, number = {11}, pages = {}, doi = {10.1002/bies.70200}, pmid = {42986019}, issn = {1521-1878}, support = {R35GM131753/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Tubulin/metabolism ; Animals ; *Microtubules/metabolism ; *Stathmin/metabolism/genetics ; Signal Transduction ; }, abstract = {STMN2, a protein implicated in motor neuron degeneration, is widely viewed as a membrane-associated microtubule inhibitor, but emerging evidence challenges whether this activity defined its cellular function. Three alternative models integrates available evidence to offer perspectives beyond microtubule regulation. The vesicle cargo adaptor model proposes that STMN2 recruits diverse cargos to transport vesicles for axonal delivery. The membrane-bound signaling messenger model links STMN2 turnover to local signaling, effector, degradation, or effector release. The traffic director model proposes that STMN2 regulates cargo routing between delivery and degradative pathways. These models are not mutually exclusive and position tubulin binding as a regulator of STMN2 function rather than its defining activity.}, } @article {pmid42987653, year = {2026}, author = {Bilgorai, J and Rafferty, GF and Carobin, A and Scott, J and Chen, M and Zhou, P and Shaw, CE and Vanhoestenberghe, A and Bashford, J}, title = {A revised motor unit number estimate detects presymptomatic motor neuron loss in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {194}, number = {}, pages = {2112448}, doi = {10.1016/j.clinph.2026.2112448}, pmid = {42987653}, issn = {1872-8952}, abstract = {OBJECTIVE: To assess the feasibility and sensitivity of a revised stimulation-free motor unit number estimate (REMUNE) for detecting motor unit (MU) loss in amyotrophic lateral sclerosis (ALS).

METHODS: Eighteen ALS patients and twelve healthy controls underwent up to six assessments over one year. High-density surface EMG was recorded bilaterally from clinically relevant hand and lower-leg muscles during stable contractions across ten force levels. MU decomposition used blind source separation, following a novel REMUNE algorithm. In ALS patients, ALS functional rating scale-revised scores and motor unit number index were recorded in parallel.

RESULTS: REMUNE was lower in ALS than controls after adjusting for age and gender (24.9 vs. 52.1, p=0.006; -52%). This difference persisted when only strong ALS muscles were analysed (26.0 vs. 56.1, p=0.027; -54%; strength data available only at first visits). Within ALS, weak muscles produced lower REMUNE values than strong ones (15.5 vs 26.0, p=0.003; -40%). An age-related decline in REMUNE was observed across all participants (-0.85 units/year, p=0.014). REMUNE remained stable over time in ALS muscles (p=0.997).

CONCLUSIONS: REMUNE distinguished ALS from healthy muscles and captured strength-dependent MU loss.

SIGNIFICANCE: REMUNE's sensitivity to presymptomatic MU loss highlights its potential as an early diagnostic aid and trial stratification tool.}, } @article {pmid42988481, year = {2026}, author = {Vila-Trias Jover, E and Alcántara Souza, R and Moncusí Armengol, A and Vernet Tomás, MM and Comerma Blesa, L and Maiques Llácer, JM and Azcona Sáenz, J}, title = {Diagnostic value of contrast-enhanced mammography versus magnetic resonance imaging in invasive lobular carcinomas: Correlation with pathological assessment and detection of additional lesions.}, journal = {Radiologia}, volume = {68}, number = {6}, pages = {501753}, doi = {10.1016/j.rxeng.2025.501753}, pmid = {42988481}, issn = {2173-5107}, mesh = {Humans ; Female ; *Carcinoma, Lobular/diagnostic imaging/pathology ; *Breast Neoplasms/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; Retrospective Studies ; *Mammography/methods ; *Contrast Media ; Middle Aged ; Aged ; Sensitivity and Specificity ; Neoplasm Invasiveness ; Adult ; Aged, 80 and over ; }, abstract = {OBJECTIVE: To compare the diagnostic performance of contrast-enhanced mammography (CEM) with magnetic resonance imaging (MRI) in the preoperative assessment of invasive lobular carcinoma (ILC).

MATERIALS AND METHODS: This was a single-centre, retrospective observational study including women with histologically confirmed ILC who underwent both preoperative CEM and MRI between January 2018 and June 2022. The detection sensitivity of ILC was evaluated using low-energy images (LEI), recombined images (RCI), CEM (LEI + RCI), and MRI. We analysed the correlation of tumour size estimated by each imaging modality and pathology, and the correlation between lesion conspicuity and tumour grade. We also assessed the detection of additional lesions (AL).

RESULTS: Fifty-eight patients with 60 ILCs were included. LEIs showed a sensitivity of 83.3% compared to 100% for RCI, CEM and MRI. MRI demonstrated the strongest correlation with tumour size on HP (r = 0.792). High conspicuity was observed in 68% of ILCs and strongly correlated with MRI enhancement level (ρ = 0.81; P < .001). No significant association was found between conspicuity and tumour grade (P = .074). Of the 53 ALs detected, 39 were malignant. MRI identified all malignant lesions, whereas CEM failed to detect five.

CONCLUSION: CEM may be a comparable alternative to MRI in the detection and size estimation of ILC; however, MRI appears to be superior in identifying malignant additional lesions.}, } @article {pmid42988796, year = {2026}, author = {Long, A and Currey, HN and Goldberg, M and Eck, RJ and Han, M and Kow, RL and Kraemer, BC and Liachko, NF}, title = {Shared and distinct gain-of-function consequences from pathologic cytoplasmic versus nuclear TDP-43.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {}, pmid = {42988796}, issn = {2041-4889}, support = {R01AG066729//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; F31AG082391//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01NS064131//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; I01BX005762//U.S. Department of Veterans Affairs (Department of Veterans Affairs)/ ; IK6BX006467//U.S. Department of Veterans Affairs (Department of Veterans Affairs)/ ; }, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Cytoplasm/metabolism ; *Cell Nucleus/metabolism ; Caenorhabditis elegans/metabolism/genetics ; Humans ; Nuclear Localization Signals/metabolism ; Caenorhabditis elegans Proteins/metabolism/genetics ; Unfolded Protein Response ; Neurons/metabolism/pathology ; Phosphorylation ; }, abstract = {While predominantly nuclear localized in healthy cells, TDP-43 can transit between the nucleus and cytoplasm. In frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), TDP-43 accumulates in hyperphosphorylated cytoplasmic aggregates. However, a subset of patients develops nuclear aggregates. Expression of wild-type TDP-43 in C. elegans neurons results in nuclear protein accumulation and toxic gain of function. To enable comparative study of nuclear and cytoplasmic TDP-43 phenotypes, we generated new models with inactivating mutations in the nuclear localization sequence (NLS) of TDP-43. When compared to nuclear TDP-43 strains, similar protein levels of cytoplasmic TDP-43 cause less neuronal dysfunction in C. elegans. Using RNA sequencing, we determine that transcriptomes are largely unchanged in these models. However, we identify innate immune pathway increases in response to cytoplasmic but not nuclear TDP-43. We find phosphorylation-mediated neurotoxicity of both cytoplasmic and nuclear localized TDP-43 is controlled by the phosphatase calcineurin. We also find that overexpression of the unfolded protein response (UPR) transcription factor XBP-1s worsens outcomes for wild-type TDP-43 animals but improves TDP-43 ΔNLS, suggesting different pathways controlling toxicity and clearance of nuclear versus cytoplasmic TDP-43. Taken together, these data support shared and distinct cellular responses to nuclear versus cytoplasmic TDP-43 localization in an intact animal nervous system. This comparative approach supports a better understanding of human disease and informs therapeutic development for pathological subtypes of TDP-43 proteinopathies.}, } @article {pmid42989888, year = {2026}, author = {Ruisinger, MM}, title = {Ansichtssache. Ein menschliches Herz als Fragengenerator und Exponat.}, journal = {Berichte zur Wissenschaftsgeschichte}, volume = {}, number = {}, pages = {}, doi = {10.1002/bewi.70053}, pmid = {42989888}, issn = {1522-2365}, abstract = {Ideally, provenance research concerning a human specimen leads from its extracorporeal fate back to its intracorporeal location within a living individual and its biography. This article traces the history of a paraffinated heart from the collection of the German Museum of the History of Medicine in Ingolstadt all the way back to its former owner. Furthermore, it discusses whether and how the research findings obtained in this manner can be incorporated into a public exhibition as part of the museum's science communication efforts.}, } @article {pmid42989982, year = {2026}, author = {Cimmino, FA and Comandini, G and Bigliazzi, C and D'Alessandro, M and Salvadori, E and Pianigiani, T and De Stefano, N and Ginanneschi, F and Casali, S and Bargagli, E}, title = {The decline of respiratory function in amyotrophic lateral sclerosis patients and the role of non-invasive ventilation.}, journal = {Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace}, volume = {}, number = {}, pages = {}, doi = {10.4081/monaldi.2026.3644}, pmid = {42989982}, issn = {2532-5264}, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by a poor prognosis, with an average survival of 3 to 5 years from symptom onset. Respiratory failure is the main cause of death, and non-invasive ventilation (NIV) is a cornerstone in the management of ALS patients. This single-center retrospective study was conducted at Siena University Hospital between 2010 and 2024 to analyze respiratory function parameters in ALS patients undergoing NIV, stratified by disease severity and followed over one year, to assess the relationship between lung function decline and the timing of NIV initiation. A total of 49 patients (29 males, 20 females; mean age 67±12 years) were enrolled, and 31 (63%) received NIV. Clinical and functional parameters, including forced vital capacity (FVC), pCO2, respiratory symptoms at baseline, and longitudinal measurements of sitting FVC (FVCsit%), supine FVC (FVCsup%), and pCO2, were collected and analyzed over time. Differences in FVC decline were observed according to the timing of NIV initiation. Among non-severe patients, those starting NIV at T0 showed a 22.5% reduction in FVC over a mean follow-up of 12.8±4.8 months. Patients initiating NIV at T2 exhibited a reported FVCsit decline of 26% (p=0.0488) and a survival of 51.3±50 months from NIV initiation, whereas those starting later (T3-T6) showed a greater decline (FVCsit decline 34%, p=0.0002) and shorter survival duration (15.7±28.6 months). These findings describe differences in respiratory function trajectories and observed survival among patients initiating NIV at different follow-up time points. However, the retrospective design, small sample size, baseline differences between groups, and potential confounding and survival-related selection bias limit causal interpretation. Further studies are needed to clarify the relationship between NIV initiation timing and clinical outcomes in ALS.}, } @article {pmid42977507, year = {2026}, author = {Li, M and Xu, D and Li, Y and Zhao, Q}, title = {Mitochondria-Associated Membranes as a Convergent Hub of Brain Aging: From Neurodegeneration to Cerebral Ischemia.}, journal = {The European journal of neuroscience}, volume = {64}, number = {9}, pages = {}, doi = {10.1111/ejn.70746}, pmid = {42977507}, issn = {1460-9568}, support = {CY2024-MS-A05//Lanzhou University Second Hospital/ ; CY2023-MS-A01//Lanzhou University Second Hospital/ ; 82660095//National Natural Science Foundation of China/ ; GSWSQNPY2024-13//Major Scientific and Technological Innovation Project of the Gansu Provincial Health Sector/ ; 2022RCCX0023//Science and Technology Planning Project of Chengguan District/ ; 2025B-017//Gansu Provincial Department of Education/ ; }, mesh = {Humans ; *Aging/metabolism/pathology ; *Mitochondria Associated Membranes/metabolism ; *Brain Ischemia/metabolism/pathology ; Animals ; *Brain/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; }, abstract = {Brain aging is the principal risk factor for both neurodegenerative diseases (NDDs) and cerebral ischemic disorders, yet the subcellular mechanisms linking these conditions remain incompletely defined. Mitochondria-associated membranes (MAMs)-specialized contact sites between the endoplasmic reticulum (ER) and mitochondria-sit at the intersection of two well-established hallmarks of aging, mitochondrial dysfunction, and loss of proteostasis, making them an attractive mechanistic node for understanding age-related brain decline. In this review, we propose a MAM-centered framework that unifies neurodegenerative and ischemic brain pathology under the broader paradigm of brain aging. We first summarize the molecular architecture of MAMs and their core functions in neuronal Ca[2+] transfer, mitochondrial dynamics, lipid metabolism, inflammasome assembly, and autophagic quality control, together with emerging evidence from non-neuronal brain cells. We then examine how MAM dysfunction intersects with five hallmarks of aging-mitochondrial dysfunction, loss of proteostasis, disabled macroautophagy, chronic inflammation (inflammaging), and altered intercellular communication-drawing on evidence from physiological aging and cellular senescence models. Next, we discuss disease-specific roles of MAMs in cerebral ischemia and in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. A central theme emerges: Rather than a unidirectional decline of MAMs, brain aging is associated with a loss of MAM homeostasis, in which both insufficient and excessive ER-mitochondria coupling can be pathological and the shared deficit is the failure to maintain contact-site function within an optimal range. Finally, we consider age-relevant therapeutic and biomarker strategies targeting MAMs and their potential translation into geriatric neurology. To our knowledge, this is the first review to integrate MAM biology across physiological brain aging, cerebral ischemia, and the four major NDDs within a single homeostatic framework, offering a unified perspective on the mechanisms of age-related brain decline.}, } @article {pmid42978072, year = {2026}, author = {Zhao, J and Jin, W and Hu, L and Yang, L and Wang, Y and Li, Z and Bai, L}, title = {Multi-omics dissection of interactive cross-stress tolerance to Penoxsulam and salinity in Echinochloa crus-galli.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71436}, pmid = {42978072}, issn = {1526-4998}, support = {32472586//Natural Science Foundation of China/ ; 2024RC2015//Yuelushan Laboratory Talent Program/ ; 2024JJ2036//Natural Science Foundation of Hunan Province/ ; 2024JJ1005//Natural Science Foundation of Hunan Province/ ; YLS-2025-ZY01003//Yuelushan Laboratory Breeding Program/ ; //Hunan Agriculture Research System (HARS-02)/ ; 2026CX20//Agricultural Science and Technology Innovation Fund Project of Hunan Province/ ; }, abstract = {BACKGROUND: Herbicide resistance and soil salinization increasingly co-occur in rice paddies, yet how evolved penoxsulam resistance shapes the fitness of barnyardgrass (Echinochloa crus-galli) under combined salt and herbicide stress remains poorly understood. This study aimed to resolve the physiological and molecular basis of such cross-stress tolerance.

RESULTS: Using a fully factorial design contrasting a penoxsulam-resistant (AH-225, RI = 4.21) and a susceptible (HN-232) biotype under 100 mm NaCl, 25 g a.i. ha[-1] penoxsulam, and their combination, integrated phenotyping, untargeted metabolomics and RNA-seq revealed that the two biotypes were equally suppressed by salinity alone but diverged under penoxsulam exposure; under combined dual stress, resistant plants maintained 3.78-fold greater aboveground biomass, corresponding to an antagonistic buffering interaction quantified by Bliss independence modelling. Sequencing of eight ALS codons associated with target-site resistance detected no mutation in either biotype, indicating a nontarget-site (metabolic) basis of resistance. Metabolome-wide profiling showed that susceptible plants mounted a costly defensive burst of flavonoids and anthocyanins (Group 9), whereas resistant plants preferentially sustained lignin precursors and accumulated rosin-type diterpenoids (Group 15). Weighted gene co-expression network analysis resolved two antagonistic transcriptional programs: a damage-responsive module marked by the DNA-repair gene MSH4, and a growth-homeostasis module enriched in lipid transfer proteins.

CONCLUSION: Penoxsulam resistance in E. crus-galli operates through constitutive homeostasis maintenance and targeted carbon partitioning rather than amplified defence, providing a mechanistic framework for integrated resistance management in saline paddy fields. © 2026 Society of Chemical Industry.}, } @article {pmid42979863, year = {2026}, author = {Choudhury, AK and Rani, P and Gupta, R and Gulati, M and Kapoor, B}, title = {Liposomal Delivery of a Riluzole-Butyric Acid Mutual Prodrug Enhances Neuroprotection and Cognitive Recovery in Experimental Alzheimer's Disease.}, journal = {Journal of drug targeting}, volume = {}, number = {}, pages = {1-21}, doi = {10.1080/1061186X.2026.2759730}, pmid = {42979863}, issn = {1029-2330}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, impaired synaptic signaling, and persistent neuroinflammation. Current therapies primarily provide symptomatic relief and have limited effects on disease progression. Riluzole, approved for amyotrophic lateral sclerosis, exhibits neuroprotective effects through modulation of glutamatergic signaling, but its poor oral bioavailability limits its therapeutic potential. Butyric acid, a short-chain fatty acid postbiotic produced by gut microbial fermentation, possesses well-established anti-inflammatory and neuroprotective properties. In this study, a mutual prodrug of riluzole and butyric acid was synthesized and encapsulated into liposomes to investigate its effects on drug distribution and preclinical efficacy. The prodrug-loaded liposomes exhibited an average particle size of 322 nm, zeta potential of -7.95 mV, and entrapment efficiency of 43.49%. Oral administration significantly improved cognitive performance and attenuated neuroinflammation and oxidative stress in an AlCl3-induced AD-like rat model. Administration of prodrug-loaded liposomes led to the highest concentrations of riluzole in brain homogenates among the relevant treatment groups. Overall, the prodrug-loaded liposomes demonstrated better therapeutic efficacy than the prodrug suspension, individual drug-loaded liposomes, and their respective conventional formulations. The enhanced therapeutic performance is attributed to the complementary pharmacological actions of riluzole and butyric acid, combined with the ability of the liposomal system to improve drug bioavailability and facilitate cerebral delivery.}, } @article {pmid42980086, year = {2026}, author = {Yardimci, BI and Zurel, AG and Biterge, B}, title = {Protein Isoaspartate Repair in Amyotrophic Lateral Sclerosis: An Integrative Bioinformatic Analysis of the PCMT Gene Family.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {21}, pages = {3526-3537}, doi = {10.1021/acschemneuro.6c00479}, pmid = {42980086}, issn = {1948-7193}, support = {THD-2025-47488//Bilimsel Arastirma Projeleri Birimi, Istanbul Teknik ?niversitesi/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Computational Biology/methods ; *Protein D-Aspartate-L-Isoaspartate Methyltransferase/genetics/metabolism ; *Isoaspartic Acid/metabolism ; Animals ; }, abstract = {Protein homeostasis is a fundamental determinant of neuronal survival, and its disruption contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). Protein L-isoaspartate O-methyltransferases (PCMTs) are evolutionarily conserved proteins involved in the recognition and processing of damaged proteins through the repair of isoaspartyl residues and protein quality-control pathways; however, their potential involvement in ALS remains largely unexplored. Here, we performed a comprehensive in silico characterization of the PCMT family (PCMT1, PCMTD1, and PCMTD2) by integrating structural, transcriptomic, single-cell, genetic, and protein modeling analyses. Domain analysis demonstrated that all three proteins share a conserved PCMT domain, while predicted S-adenosylmethionine-binding motifs were identified in PCMT1 and PCMTD2 but not PCMTD1, indicating evolutionary conservation with functional divergence. Expression profiling revealed that PCMT family genes are expressed in ALS-relevant tissues and broadly distributed across neuronal, glial, vascular, and immune cell populations in both healthy and ALS-associated brain single-cell data sets. Analysis of multiple independent ALS transcriptomic cohorts identified consistent upregulation of PCMT family members, with PCMTD1 exhibiting the most reproducible disease-associated expression changes across nervous system tissues and peripheral blood. Gene set correlation analyses further revealed distinct relationships between PCMT expression and neuronal pathways, with PCMT1 showing positive associations with axonal transport and synaptic signaling, whereas PCMTD1 and PCMTD2 displayed largely inverse correlation patterns. Rare missense variants identified in ALS patients were predicted to impair protein function and decrease protein stability, while structural modeling suggested that several substitutions may disrupt conserved residues and the local protein architecture. Collectively, these findings identify the PCMT family as previously underexplored candidates associated with ALS and provide a comprehensive framework for future mechanistic studies investigating their roles in neuronal protein homeostasis and neurodegeneration.}, } @article {pmid42980369, year = {2026}, author = {Kumar, N and Paruchuri, N and Punshon, T and Jackson, B and Cornell, K and Stommel, E and Deosthali, H and Ravikumar, V and Mostafa, E and Palisoul, S and Vaickus, L and Ho, S and Levy, J}, title = {Integrative spatial metallomics: a tutorial review of multimodal elemental imaging workflows, challenges and opportunities.}, journal = {Analytical methods : advancing methods and applications}, volume = {}, number = {}, pages = {}, doi = {10.1039/d6ay01718e}, pmid = {42980369}, issn = {1759-9679}, abstract = {Spatially resolved molecular assays are increasingly used to study human health and disease, revealing complex tissue organization beyond what is accessible through bulk analyses. While spatial transcriptomic, metabolomic, and proteomic approaches have rapidly matured, quantitative mapping of metals and trace elements in biological tissues and biominerals through elemental imaging remains comparatively nascent. Elemental distributions alone often provide limited biological interpretation without contextualization within the tissue microenvironment. Here, we summarize themes and computational strategies for integrating spatial elemental data with histopathology and complementary spatial molecular assays. We highlight multimodal approaches for tissue alignment, pixel-wise clustering, and correlative analysis, illustrated through limited use cases involving amyotrophic lateral sclerosis (ALS) and kidney stone formation. In the ALS cohort, pixel-level elemental profiles were clustered and compared with annotated tissue structures. In the kidney stone cohort, spatial gradients and correlations in elemental and biomolecular features from the renal papilla through the medulla to cortex were examined. Finally, we discuss key challenges for cross-sample, cohort-level analyses, including differences in spatial resolution, normalization, tissue architecture, and mechanistic inference. Addressing these challenges will require interdisciplinary collaboration, enhanced biobanking practices, and development of computational and statistical frameworks.}, } @article {pmid42980747, year = {2026}, author = {He, BH and Yang, W and Yang, M and Lv, X and Zhao, JJ}, title = {Advances in plant polysaccharide research for neurodegenerative diseases therapy.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42980747}, issn = {1573-4978}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Polysaccharides/therapeutic use/pharmacology/chemistry ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Oxidative Stress/drug effects ; *Plants/chemistry ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), represent a growing global public health burden with limited therapeutic options. Plant polysaccharides are natural, biocompatible, and multi-target bioactive macromolecules that have emerged as promising candidates for ND intervention. This review systematically summarizes recent progress in elucidating the structural characteristics, structure-activity relationships, and neuroprotective mechanisms of plant polysaccharides. Key structural features such as molecular weight, monosaccharide composition, glycosidic bond configuration, and spatial conformation critically modulate the biological activity of these molecules. Furthermore, we summarize the numerous protective effects of plant polysaccharides against NDs, including inhibiting abnormal protein aggregation, alleviating oxidative stress via the Nrf2/HO-1 pathway, suppressing neuroinflammation through the NF-κB and MAPK signaling pathways, regulating neuronal apoptosis, and modulating the gut-brain axis. Clinical translation challenges, primarily blood-brain barrier penetration, structural heterogeneity, and insufficient clinical validation, are discussed. Future directions include developing advanced delivery systems, conducting large-scale randomized controlled trials, and exploring synergistic combination therapies. Collectively, plant polysaccharides show considerable promise as potential multi-target candidates for the intervention of NDs, although further studies are needed to clarify their therapeutic potential and facilitate clinical translation.}, } @article {pmid42981879, year = {2026}, author = {Sanchez-Santos, C and Madruga, E and Recio, J and Diaz-Palacios, K and Aledavood, E and Lietha, D and Gil, C and Martinez, A}, title = {Targeting the DFG-out conformation of TTBK1 enables the discovery of selective type II neuroprotective inhibitors.}, journal = {European journal of medicinal chemistry}, volume = {321}, number = {Pt 3}, pages = {119468}, doi = {10.1016/j.ejmech.2026.119468}, pmid = {42981879}, issn = {1768-3254}, abstract = {Tau Tubulin Kinase 1 (TTBK1) is an emerging therapeutic target for neurodegenerative diseases because it promotes the pathological phosphorylation of tau and TDP-43, key drivers of Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). However, the development of selective TTBK1 inhibitors is hindered by the high structural similarity between TTBK1 and the essential paralog TTBK2, making ATP-competitive strategies challenging. Here, we report the discovery of computationally supported type II TTBK1 inhibitors by targeting the inactive DFG-out kinase conformation. A druggable DFG-out model was generated using metadynamics and molecular dynamic simulations and employed for virtual screening of the MBC chemical library. This approach identified novel chemotypes that were validated as selective TTBK1 inhibitors with improved discrimination over TTBK2. The most promising compounds also displayed neuroprotective activity in SH-SY5Y neuroblastoma cells. These findings demonstrate that targeting the inactive TTBK1 conformation is a viable strategy to achieve isoform selectivity and establish a new framework for developing disease-modifying therapies for ALS, AD, and other TTBK1-driven neurodegenerative disorders.}, } @article {pmid42933032, year = {2026}, author = {Arabinour, M and Sultani, N and Zhou, X and Tayebi, L}, title = {From prediction to design rules: explainable machine learning analysis of cryoprotectant effects in GelMA-based cryobioprinting bioinks.}, journal = {Biomedical physics & engineering express}, volume = {12}, number = {6}, pages = {}, doi = {10.1088/2057-1976/aeb94c}, pmid = {42933032}, issn = {2057-1976}, mesh = {*Cryoprotective Agents/pharmacology/chemistry ; *Machine Learning ; *Cryopreservation/methods ; Random Forest ; }, abstract = {Machine learning has been used to predict cryoprotective-agent (CPA) effects in cryobioprinting, but prediction accuracy alone does not yield experimentally usable formulation rules. Here, we performed a secondary explainable analysis of Qiaoet al's GelMA-HUVEC dataset using formulation-grouped validation, SHAP interpretation, stability metrics, and multi-objective ranking. A compact Random Forest model using permeable CPA identity, sugar CPA identity, permeable CPA concentration, sugar concentration, and storage day achieved MAE = 4.842%, RMSE = 6.106%, andR[2]= 0.649, with bootstrap 95% confidence intervals of 4.418-5.274% for MAE and 0.585-0.710 forR[2]. SHAP analysis identified permeable CPA concentration and storage day as the strongest viability drivers, with directional patterns favoring balanced 15% permeable CPA and 15% sugar CPA rather than simple concentration maximization. Multi-objective ranking identified GL_15_RA_15 as the strongest individual formulation, whereas EG + trehalose showed the highest average CPA-family performance. Cross-domain tests showed limited transfer between EG and GL formulations, indicating that the extracted rules should be treated as local, data-supported design hypotheses rather than universal cryoprotectant principles. Together, these results show that explainable secondary analysis can convert small cryobioprinting datasets into experimentally testable CPA hypotheses while explicitly defining their transferability limits.}, } @article {pmid42974963, year = {2026}, author = {Libonati, L and Cambieri, C and Ceccanti, M and Moret, F and Petrucci, A and Carbone, A and Suppa, A and Inghilleri, M}, title = {Urinary Dysfunction in ALS Patients: Assessment With the Overactive Bladder Awareness Tool.}, journal = {Neurourology and urodynamics}, volume = {}, number = {}, pages = {}, doi = {10.1002/nau.70527}, pmid = {42974963}, issn = {1520-6777}, abstract = {AIMS: To compare urinary symptom bother and overactive bladder screening positivity between patients with amyotrophic lateral sclerosis (ALS) and controls using the Overactive Bladder Awareness Tool (OAB-V8).

METHODS: This retrospective study included 101 patients with definite ALS and 324 controls. OAB-V8 scores were compared using Welch's t-test and multiple linear regression adjusted for age and sex with HC3 robust standard errors. Screening positivity (OAB-V8 ≥ 8) was evaluated using Firth's logistic regression adjusted for age and sex.

RESULTS: Mean OAB-V8 scores were 14.0 ± 6.8 in ALS patients and 12.40 ± 5.10 in controls (unadjusted p = 0.026). The adjusted mean difference was 1.65 points (95% confidence interval [CI] 0.20-3.10; p = 0.026). Screening positivity was observed in 101/101 ALS patients (100%) and 272/324 controls (84.0%). The adjusted odds ratio was 41.03 (95% penalized profile-likelihood CI 5.75-5205.66; p < 0.001), indicating substantial uncertainty in its magnitude.

CONCLUSIONS: ALS patients reported modestly greater urinary symptom burden than controls after adjustment for age and sex. These findings support clinical attention to urinary symptoms in ALS but do not establish their underlying urodynamic mechanism.}, } @article {pmid42975030, year = {2026}, author = {Ayoubi, R and MacDougall, EJ and McDowell, I and Biddle, MS and Ferreira, BT and Zha, C and Dorion, MF and Ross, JP and Bolivar, SG and Ruiz Moleon, V and Alende, C and Francis, V and Fotouhi, M and Chaineau, M and Chen, CX and Piscopo, VEC and Soubannier, V and Shlaifer, I and You, Z and Nicouleau, M and Keates, T and Lee, WH and Marsden, BD and Koukouflis, L and Wigren, E and Marks, CA and Healy, LM and Dion, PA and Rouleau, GA and Fon, EA and Virk, HS and Gräslund, S and Gileadi, O and Edwards, AM and Durcan, TM and McPherson, PS and Laflamme, C}, title = {A validated antibody toolbox for ALS research.}, journal = {eLife}, volume = {15}, number = {}, pages = {}, pmid = {42975030}, issn = {2050-084X}, support = {ALS-RAP//Motor Neurone Disease Association, Amyotrophic Lateral Sclerosis Association and ALS Society of Canada/ ; OGI-210//Genome Canada, Genome Quebec and Genome Ontario/ ; YCharOS: A platform enabling neuroscience target validation//Québec Consortium for Drug Discovery/ ; NC/NAM0019/1//National Centre for the Replacement Refinement and Reduction of Animals in Research/ ; MRC UKRI076/MRC_/Medical Research Council/United Kingdom ; OGI-196//Genome Canada and Ontario Genomics/ ; grant no. 875510//EUbOPEN/ ; PJT-195804/CAPMC/CIHR/Canada ; Tier 1//Canada Research Chairs/ ; ALS Scholars//Sean M. Healey & AMG Center for ALS/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/genetics/metabolism ; Humans ; *Antibodies/immunology ; *C9orf72 Protein/immunology/genetics ; Induced Pluripotent Stem Cells/metabolism ; }, abstract = {A substantial fraction of amyotrophic lateral sclerosis (ALS)-associated proteins remains poorly characterized, in part because of the limited availability of validated research antibodies. We established knockout (KO)-based antibody characterization workflows and demonstrated that widely used antibodies against the major ALS-associated protein C9orf72 lacked specificity (Laflamme et al., 2019). We subsequently scaled this framework to systematically benchmark research antibodies, revealing that up to 61% fail to perform as recommended by manufacturers (Ayoubi et al., 2023b). Here, we extend this approach by establishing the ALS-Reproducible Antibody Platform (ALS-RAP), a comprehensive effort to generate a publicly available dataset of KO-validated antibodies targeting proteins encoded by ALS risk genes. In total, we characterized 303 antibodies against 33 ALS-associated proteins to identify high-quality reagents for use in western blot, immunoprecipitation, and immunofluorescence. Using these antibodies, we profiled protein levels across human induced pluripotent stem cell-derived and primary neurological cell types. These analyses revealed diverse cellular distributions and higher levels of several ALS-associated proteins in glial populations, consistent with emerging evidence for immune contributions to ALS. Together, ALS-RAP provides a validated antibody toolbox and protein expression resource to support the study of ALS-associated proteins.}, } @article {pmid42975041, year = {2026}, author = {Kuiper, MM and Kruithof, WJ and Broekman-Peters, N and Visser-Meily, JMA and Beelen, A}, title = {Personalizing nutritional care in amyotrophic lateral sclerosis (ALS): a multi-perspective qualitative focus group study of experiences and challenges.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2750614}, pmid = {42975041}, issn = {2167-9223}, abstract = {Background: Proactive, timely nutritional care is important for people living with amyotrophic lateral sclerosis (plwALS), as weight loss and malnutrition are associated with faster disease progression and shorter survival. However, previous studies have shown that there is considerable practice variation in nutritional care, and that care is not always delivered proactively. Objectives: To gain insight into how healthcare professionals (HCPs), plwALS and their primary caregiver experience nutritional care. Methods: A generic qualitative study was conducted using semi-structured focus group discussions. Five focus group discussions were organized: two with HCPs and three with plwALS and their primary caregivers. Data were transcribed verbatim and analyzed inductively using thematic analysis. Results: In total, 14 HCPs, 19 plwALS, and three primary caregivers participated. Analyses resulted in four major themes: (1) A gap between knowing and acting, (2) balancing providing and withholding care, (3) sufficiently informed to participate in shared decision-making? and (4) opportunities for improvement. Conclusion: Findings suggest that improving nutritional care in ALS requires clear and transparent communication to ensure that plwALS and caregivers are well-informed about the importance of nutrition and monitoring of nutritional status, and more involved in clinical decision-making. Clear explanations about the dietitian's role and nutritional care process may improve patient engagement and facilitate shared decision-making.}, } @article {pmid42975618, year = {2026}, author = {Xu, Z and Fan, T and Xu, R}, title = {Current findings, application, and diagnosis of magnetic resonance imaging in amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {}, number = {}, pages = {}, pmid = {42975618}, issn = {2191-0200}, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disorder within the motor neuron disease (MND) spectrum, characterized by progressive degeneration of upper and lower motor neurons. The clinical phenotype ranges from pure motor syndromes to forms with cognitive and behavioral impairment, and the pathological burden extends beyond the motor system. Diagnosis remains primarily clinical, supported by electrophysiology and exclusion of mimics. Therefore, objective imaging biomarkers are urgently needed. Magnetic resonance imaging (MRI) is widely used as an auxiliary and differential diagnostic tool in ALS. T1- and T2-weighted imaging can assess cortical thickness, gray matter atrophy, and signal changes. Diffusion tensor imaging probes white matter microstructure. Magnetic resonance spectroscopy detects neurochemical alterations. Resting-state functional MRI assesses functional connectivity and network organization. Susceptibility-weighted imaging is sensitive to iron and calcium deposition. Ultra-high-field MRI provides higher resolution and improved metabolite quantification. This critical review summarizes current findings on MRI in ALS, but importantly organizes the evidence by the specific question being addressed: pathological/histological correlates, diagnostic or discriminatory performance, and clinical associations with phenotype, severity, progression, and prognosis. We also discuss major limitations, including methodological heterogeneity, limited standardization, small and clinically heterogeneous cohorts, frequent use of healthy rather than disease controls, and scarce multicenter validation. Although advanced MRI has revealed robust group-level alterations, none of these techniques has yet become established in routine clinical diagnosis of ALS. We, therefore, distinguish promising research findings from validated clinical biomarkers and outline priorities for future translation.}, } @article {pmid42975660, year = {2026}, author = {Yin, Y and Tu, Y and Wang, B and Chen, Y and Zhao, Y and Tang, J and Zhang, M and Zhang, J}, title = {Subtype and stage inference of tract-level diffusion abnormalities in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {11}, pages = {}, pmid = {42975660}, issn = {1432-1459}, support = {No.82471967//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/classification/pathology ; Female ; *Diffusion Tensor Imaging ; Male ; Middle Aged ; Retrospective Studies ; Anisotropy ; Aged ; *White Matter/diagnostic imaging/pathology ; Adult ; Severity of Illness Index ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) shows substantial heterogeneity in clinical presentation and white matter involvement, but conventional diffusion tensor imaging analyses provide limited information on whether tract-level abnormalities follow distinct patient level patterns.

METHODS: This retrospective secondary analysis included 73 patients with ALS and 30 healthy controls. Fractional anisotropy (FA) and mean diffusivity (MD) from 11 predefined tracts were used as SuStaIn biomarkers, with healthy controls providing the normative reference for Z-score standardization. SuStaIn subtypes and stages were examined against Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), King's stage, and peak width of skeletonized mean diffusivity (PSMD).

RESULTS: The three-subtype model classified patients into cingulate callosal motor mixed subtype (n = 34), hippocampal cingulum posterior projection subtype (n = 32), and posterior callosal projection, MD predominant subtype (n = 7). Exploratory comparisons showed lower PSMD in subtype 0 than subtypes 1 and 2 (both p = 0.026), lower ALSFRS-R in subtype 2 than subtype 1 (p = 0.026), and higher SuStaIn stage in subtype 2 than subtype 0 (p = 0.025). Higher SuStaIn stage correlated with higher King's stage (rho = 0.318, p = 0.006) and lower ALSFRS-R (rho = - 0.289, p = 0.013). After adjustment, higher SuStaIn stage remained associated with lower ALSFRS-R (β = - 0.333, p = 0.013) and more advanced King's stage (odds ratio = 1.181, p < 0.001).

CONCLUSION: Tract-level diffusion SuStaIn identified anatomically interpretable patterns of white matter involvement in ALS and provided patient-level stage estimates associated with clinical disease burden.}, } @article {pmid42976580, year = {2026}, author = {Jiménez-Villegas, J and Carnicero-Senabre, D and Sicart, A and Van Den Bosch, L and Cuadrado, A and Rojo, AI}, title = {Lack of NRF2 expression alters the dynamics of stress granules promoting the aggregation of ALS disease-associated proteins.}, journal = {Redox biology}, volume = {98}, number = {}, pages = {104462}, doi = {10.1016/j.redox.2026.104462}, pmid = {42976580}, issn = {2213-2317}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron death. Although ALS pathogenesis is multifactorial, increasing evidence highlights a close interplay between dysfunction of RNA metabolism and redox imbalance in disease progression. Redox perturbation converges with RNA dysregulation at the level of the dynamics of stress granules, transient ribonucleoprotein assemblies implicated in protein aggregation, in ALS. The redox-sensitive transcription factor NRF2 (Nuclear factor erythroid 2-related factor 2) plays a pivotal role in cellular homeostasis, yet its function and regulation remain poorly defined in ALS. In this study, we explore how NRF2 modulates stress granule dynamics under oxidative and non-oxidative stress conditions. Using live-cell imaging, we reveal that NRF2 deficiency enhances the formation of stress granules in response to oxidative and non-oxidative stressors, facilitates their persistence, and promotes increased stress granule recruitment of ALS-linked proteins such as TDP-43 and FUS. Likewise, we uncover a protective role of pharmacological NRF2 activation in limiting exacerbated stress granule responses in iPSC-derived motor neurons from C9orf72-ALS patients and show how NRF2 activation can impact TDP-43 aggregation and loss of function in SH-SY5Y cells. Together, these findings position NRF2 as a crucial integrator of redox signalling and RNA metabolism in ALS pathogenesis. Targeting NRF2 may offer novel therapeutic avenues to counteract the vicious cycle of oxidative stress, dysfunctional stress granule dynamics, and protein aggregation in motor neuron disease.}, } @article {pmid42977228, year = {2026}, author = {Mercadante, S and Travia, M and Scimone, P and Dabbene, M and Cascio, AL}, title = {Cancer versus Non-Cancer Patients Admitted to Hospice: a comparison study.}, journal = {Journal of pain and symptom management}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpainsymman.2026.10.030}, pmid = {42977228}, issn = {1873-6513}, abstract = {CONTEXT: Malignant disease remains the leading reason for hospice admission, and direct, patient-level comparisons of cancer and non-cancer patients within the same residential hospice are scarce.

OBJECTIVES: To compare sociodemographic and clinical characteristics, symptom burden, nutritional support, length of stay and outcome between oncological and non-oncological patients admitted to a single hospice.

METHODS: Prospective observational cohort study of 175 consecutive admissions over one year, after removal of duplicate records. Patients were classified as oncological (n=151, 86.3%) or non-oncological (n=24, 13.7%) based on structured case report form fields. Sociodemographic, functional (Karnofsky Performance Status, KPS), nutritional, symptom (Edmonton Symptom Assessment System, ESAS) and cognitive (Memorial Delirium Assessment Scale, MDAS) data were collected at admission (T0); ESAS completion was also examined at 1 week (T7). Categorical variables were compared with the chi-square or Fisher's exact test, continuous variables (reported as median and interquartile range, including ESAS and MDAS scores) with the Mann-Whitney U test; p-values were adjusted for multiple comparisons with the Benjamini-Hochberg procedure (q).

RESULTS: Most non-oncological patients had a neurological disease (21/24), mainly neurodegenerative diseases, amyotrophic lateral sclerosis and dementia. Non-oncological patients were older (median 78.5 vs 72 years, P=0.002, q=0.012) and had worse performance status at admission (median KPS 20 vs 30, P<0.001, q=0.006). Artificial nutrition was more frequent among non-oncological patients (37.5% vs 14.9%, P=0.018), although not after correction for multiple comparisons (q=0.060). MDAS scores were higher in non-oncological patients (median 13 vs 4, P=0.021). ESAS data were missing in about half of oncological and three quarters of non-oncological patients; no ESAS item differed between groups after correction for multiple comparisons, and the non-oncological group's valid ESAS sample fell to a single patient by T7. Length of stay (11 vs 8 days, P=0.518) and in-hospice mortality (80.0% vs 70.8%, P=0.455) did not differ significantly.

CONCLUSION: In this single-centre series, non-oncological patients, mostly affected by neurological diseases, were admitted older, more functionally compromised and with higher MDAS scores than oncological patients, despite comparable length of stay and mortality. Apparent differences in symptom burden are confounded by substantial, likely informative, missing data and should be interpreted with caution. Whether these differences reflect later referral or the age profile of the underlying diseases cannot be determined from these data.}, } @article {pmid42967168, year = {2026}, author = {Cao, S and Liu, T and Cheng, X and Tian, X and Wei, J}, title = {The "Invisible Killer" of Neurodegeneration: Mitochondrial Dysfunction in Neurodegenerative Disorders, Mechanisms, Emerging Pathways and Therapeutic Strategies.}, journal = {Journal of inflammation research}, volume = {19}, number = {}, pages = {653025}, pmid = {42967168}, issn = {1178-7031}, abstract = {Neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) place substantial burden on global public health. Mounting evidence identifies mitochondrial dysfunction as a central contributor to neuronal damage and progressive brain functional decline. As a narrative review, this work aims to dissect mitochondrial‑associated pathological features across these major neurodegenerative disorders, summarize under‑recognized emerging mechanisms, and highlight translational bottlenecks for mitochondrial‑targeted therapies. Mitochondria sustain neuronal survival by mediating oxidative‑phosphorylation‑driven energy production, biomolecule biosynthesis, calcium homeostasis, reactive oxygen species (ROS) metabolism, and apoptotic regulation. In PD, aggregated α‑synuclein (α‑syn) damages respiratory‑chain complex I, perturbs mitochondrial dynamics and blocks PINK1/Parkin‑dependent mitophagy. In AD, amyloid‑β together with hyper‑phosphorylated tau (p-Tau) impairs respiratory complex activity, axonal mitochondrial trafficking and mitophagic clearance. Mutant huntingtin induces multiple mitochondrial lesions in HD, while inflammation‑triggered oxidative stress secondarily compromises mitochondrial function in MS. Pathogenic mutations in ALS disrupt respiratory‑chain assembly, mitochondrial dynamics and mitophagy. Beyond classic mitochondrial defects including respiratory‑chain impairment, dynamic imbalance and defective mitophagy, emerging mechanisms such as mitocytosis, mitochondrial aminoacyl‑tRNA synthetase (mt‑aaRS) dysfunction and mitochondria‑associated membrane (MAM) disruption are discussed. Mitochondrial dysfunction drives neurodegeneration via energy exhaustion, aggravated oxidative stress, pathological protein aggregation and excessive neuronal apoptosis. We further recapitulate mitochondrial‑oriented therapeutic approaches including small‑molecule regulators, mitophagy activators, mitochondrial biogenesis promoters, gene‑editing strategies and mitochondrial transplantation. Notable translational obstacles remain, including limited blood‑brain‑barrier penetration of candidate drugs, narrow therapeutic time‑window post‑symptom onset, and prominent disease heterogeneity. By synthesizing basic experimental findings and pre‑clinical and clinical trial progress, this review provides updated insights into the pathogenesis of neurodegenerative diseases and facilitates the development of precise mitochondrial‑targeted therapeutic regimens.}, } @article {pmid42969635, year = {2026}, author = {Bannwarth, S and Paquis-Flucklinger, V}, title = {[Mitochondria in sporadic amyotrophic lateral sclerosis: actor or initiator?].}, journal = {Medecine sciences : M/S}, volume = {42}, number = {10}, pages = {797-799}, doi = {10.1051/medsci/2026146}, pmid = {42969635}, issn = {1958-5381}, } @article {pmid42970317, year = {2026}, author = {Pourhadi, M and LeWitt, PA and Todi, SV}, title = {Ceruloplasmin in Disorders of the Nervous System.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2026.0988}, pmid = {42970317}, issn = {2152-5250}, abstract = {Ceruloplasmin (Cp) is a multicopper ferroxidase that links copper handling, iron export, and redox homeostasis. Within the nervous system, these functions are critical because disruption of iron and copper balance can amplify oxidative stress, neuroinflammation, and neuronal vulnerability. Although Cp has long been studied as a circulating biomarker, most reports characterize it only by protein concentration, leaving its enzymatic and structural status comparatively unexplored. Here, we synthesize human literature on Cp across major neurological disorders, with attention to studies that assess Cp's ferroxidase activity, oxidation, fragmentation, and copper-binding state alongside its circulating levels. The evidence is by far most extensive in Alzheimer's and Parkinson's diseases, which together account for the majority of the reviewed literature: reduced ferroxidase activity, increased Cp oxidation, and altered non-Cp-bound copper are repeatedly linked to disease severity, regional iron accumulation, and biomarker-defined patient subgroups; in several studies, these alterations were independent of total Cp concentration. A smaller but growing body of evidence in amyotrophic lateral sclerosis, multiple sclerosis, essential tremor, and the cerebellar ataxias points to a related pattern of Cp-linked iron mishandling contributing to neuronal vulnerability. Preliminary findings from a few small studies in schizophrenia and a single study in obsessive-compulsive disorder further suggest that circulating Cp levels track systemic inflammatory and oxidative states in these conditions. From these investigations, a picture emerges where Cp's functional and structural integrity, rather than its abundance alone, is the more informative correlate of disease-relevant metal dyshomeostasis, most clearly demonstrated in Alzheimer's and Parkinson's diseases. Based on this body of work, we propose that future studies adopt combined assessments of Cp quantity and function to clarify disease-specific Cp signatures and to evaluate whether correcting Cp activity or copper/iron imbalance can improve outcomes.}, } @article {pmid42970788, year = {2026}, author = {Poppe, A and Gruen, E and Butz, C and Meenen, B and Lampe, D and Schmidt, J and Greiner, W and Köberlein-Neu, J and Meyer, I and , }, title = {Using a Living Lab to Refine an Electronic Prescribing Workflow: Insights From the eRIKA Project.}, journal = {JMIR formative research}, volume = {10}, number = {}, pages = {e100362}, doi = {10.2196/100362}, pmid = {42970788}, issn = {2561-326X}, mesh = {*Workflow ; *Electronic Prescribing/standards ; Humans ; Germany ; Digital Health ; }, abstract = {BACKGROUND: The integration of eHealth solutions into routine health care remains challenging despite their potential to improve care quality and efficiency. Living labs (LLs) have emerged as an approach to addressing these challenges by enabling co-design and iterative testing of eHealth tools. LLs promote collaboration among patients, health care professionals, developers, and policy makers. However, systematic insights into their practical implementation remain limited.

OBJECTIVE: This study explores the use of an LL approach to dynamically create and adapt project workflows, as well as its potential as a methodological framework for developing an implementation plan for a digital prescribing workflow (eRIKA [eRezept als Element Interprofessioneller Versorgungspfade für Kontinuierliche Arzneimitteltherapiesicherheit]). The analysis focuses on intervention-level insights identified throughout the LL process. The study also reflects on the limitations of the approach.

METHODS: The co-design process was structured into 4 thematic sprints conducted across 3 regions in Germany (Saarland, Berlin, and Westphalia-Lippe) between November 2022 and September 2024. Workshops were held with general practitioners (GPs), pharmacists (PHs), medical assistants, and pharmacy technicians recruited from 6 GP practices, 6 pharmacies, and 1 hospital (n=17). Audio-recorded workshop data were analyzed using reflexive thematic analysis.

RESULTS: Three themes were identified: (1) Workflow Efficiency, encompassing demands for filtering and prioritization mechanisms to manage information volume, direct digital communication channels, and concerns about workload; (2) Technical Implementation, addressing the need for seamless system integration, data integrity of the medication history, and interoperability with existing practice management systems; and (3) A New Way of Working, reflecting interprofessional negotiations around roles and responsibilities and regulatory requirements, including data privacy. Notably, strongly divergent views emerged between GPs and PHs regarding what data PHs require to conduct effective medication safety reviews.

CONCLUSIONS: Consistent with previous research, the results highlight concerns about workload, system interoperability, roles and responsibilities, and regulatory barriers to implementation. Beyond these established challenges, the results also reveal interprofessional tensions between GPs and PHs regarding the extent of data sharing required for effective pharmaceutical counseling. These findings inform the subsequent phase 1 and phase 2 evaluation studies and contribute to the growing evidence base on LL methodology in digital health implementation.

RR2-10.2196/87277.}, } @article {pmid42970872, year = {2026}, author = {Wang, XC and Wen, YJ and Huang, YJ and Wu, HX and Zhang, XJ and Cui, JY and Yu, YJ and Fu, HY and She, Y}, title = {Roasting-time dependent aroma development in sesame oil: time-resolved VOCs evolution revealed by deconvolution-assisted HS-SPME-GC-MS.}, journal = {Food chemistry}, volume = {532}, number = {Pt 4}, pages = {151826}, doi = {10.1016/j.foodchem.2026.151826}, pmid = {42970872}, issn = {1873-7072}, abstract = {Roasting is essential for developing sesame oil's color, aroma, and texture. This study investigated the effects of roasting time on key volatile organic compounds (VOCs) and sensory profiles. An optimized HS-SPME-GC-MS coupled with DEMCR-ALS-based deconvolution (AntDAS-GCMS) was established to profile VOC dynamics during roasting at 150 °C for 0-40 min. Among 731 resolved differential features, 94 VOCs changed significantly across 30 samples. Volatile composition changed markedly during the first 20 min, when the characteristic roasted aroma emerged. However, odor activity values (OAVs) of key aroma-active compounds continued to change with prolonged roasting, particularly those associated with caramel-sweet and smoky notes. Hydrocarbon-associated signals progressively decreased, whereas nitrogen-containing heterocyclic compounds increased. Sensory and OAV-based analyses showed a shift from fresh, seed-like profile toward a thermally derived flavor system. Roasting for 20-30 min enhanced desirable aromas, whereas longer roasting increased smoky notes and reduced aroma balance.}, } @article {pmid42972546, year = {2026}, author = {Zhuang, SP and Cai, ZW and Huang, ZY and Lin, LY and Chen, S and Zou, ZY and Ding, H and Qin, W and Chen, HJ}, title = {Voxel-based texture similarity networks reveal abnormal brain network topology linked to molecular signatures in amyotrophic lateral sclerosis.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {42972546}, issn = {1741-7015}, support = {No. 82572160//National Natural Science Foundation of China/ ; Nos. 2023CXA009//Fujian Provincial Health Technology Project/ ; No.2024J01625//Fujian Provincial Natural Science Foundation of China/ ; Nos. 2024Y9253//Fujian Province Joint Funds for the Innovation of Science and Technology/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/genetics ; Female ; Male ; *Brain/diagnostic imaging/physiopathology/pathology ; Magnetic Resonance Imaging/methods ; Middle Aged ; *Nerve Net/diagnostic imaging/physiopathology ; Aged ; Adult ; Case-Control Studies ; }, abstract = {BACKGROUND: While amyotrophic lateral sclerosis (ALS) is characterized by disrupted brain network function, the abnormal patterns of structural similarity networks and their biological underpinnings remain poorly understood. This study employed voxel-based texture similarity network (vTSN) analysis to identify complex brain network disruptions in ALS, aiming to advance the pathophysiological understanding of the disease.

METHODS: Individual vTSNs were constructed based on structural T1-weighted magnetic resonance imaging data from 113 patients with ALS and 144 healthy controls. We first explored the vTSN disruption patterns in ALS patients and compared their sensitivity with two other popular structural similarity networks: morphometric similarity networks (MSN) and morphometric inverse divergence (MIND). We then linked vTSN abnormalities with molecular signatures. Finally, we explored the potential of vTSN in predicting the clinical traits and states of ALS patients.

RESULTS: ALS patients demonstrated bidirectional patterns of both increased and decreased connectivity in vTSN (P < 0.05, Bonferroni correction), particularly involving sensorimotor network (SMN), default mode network (DMN), frontoparietal network (FPN) and subcortical network (SN). vTSN showed the highest sensitivity in detecting abnormal connectivity (N = 137) compared to the two well-known approaches, MSN (N = 0) and MIND (N = 30) (P < 0.05, Bonferroni correction), and revealed unique disruption patterns (r < 0.02, P > 0.05). Notably, vTSN alterations were linked to ALS risk genes; representative genes CHMP2B and SOD1 showed distinct developmental profiles and significant regional correlations. Furthermore, vTSN changes mirrored neuroreceptor distributions (notably M1, 5-HT6, and MOR), with M1 showing coupling in the SN and FPN, linking network decay to neurochemical imbalances. Finally, the network-based vTSN model achieved robust diagnostic power (AUC = 0.757), which was statistically equivalent to edge-level or whole-brain models (DeLong's test, P > 0.05).

CONCLUSIONS: vTSN exhibits excellent performance for detecting network abnormality in ALS and reveals potential molecular signatures of the pathophysiology of disease. These findings underscore the potential of vTSN-derived network measure as a biologically meaningful biomarker for ALS.}, } @article {pmid42972606, year = {2026}, author = {Bedarf, L and Neuhaus, D and Bauer, M and Berger, C and Wendebourg, MJ and Schlaeger, R and Birkl, C and Scheurer, E and Lenz, C}, title = {Evidence of White Matter R2* Homogenization After Formalin Fixation.}, journal = {Magnetic resonance in medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/mrm.70646}, pmid = {42972606}, issn = {1522-2594}, support = {//Stiftung zur Foerderung der gastroenterologischen und allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung/ ; 219548//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; //Neuromuscular Research Association Basel/ ; }, abstract = {PURPOSE: Disentangling intrinsic susceptibility-driven R2* characteristics in white matter (WM) from fixation-related effects using in vivo, postmortem (PM) in situ, and formalin-fixed PM ex situ MRI.

METHODS: DTI and multi-echo gradient-echo MRI were acquired in vivo, PM in situ and PM ex situ. PM cases included neurologically healthy individuals and patients with amyotrophic lateral sclerosis (ALS). Voxel-wise R2* values were obtained using a mono-exponential fit and evaluated both as whole WM averages and according to WM fiber-to-field orientation. For the PM ex situ orientation-dependency analysis, PM ex situ R2* data were registered to the corresponding in situ DTI acquisition. Averaged as well as orientation-dependent R2* profiles were pooled across WM and compared across conditions.

RESULTS: Whole WM averaged and orientation-dependent R2* values differed across in vivo, PM in situ, and PM ex situ conditions. No differences were observed between PM in situ healthy and PM in situ ALS cases. Compared with in vivo measurements, both PM conditions showed elevated whole WM averaged R2* values and reduced orientation dependency, with the strongest R2* anisotropy in vivo and nearly absent orientation dependency in the PM ex situ condition.

CONCLUSION: While orientation-dependent R2* is reduced but preserved in unfixed PM in situ tissue, it is largely eliminated after prolonged formalin fixation without rehydration, likely due to microstructural reorganization and protein cross-linking. Collectively, these findings indicate that orientation-dependent R2* measured in fixed tissue has limited translational validity, while underscoring its sensitivity to intact microstructural organization in vivo and in unfixed PM tissue.}, } @article {pmid42974031, year = {2026}, author = {Wang, M and Yang, J and Gao, C and Qu, S and Mi, H and Guo, Y and Gui, T and Gai, Z}, title = {Utility of extracellular vesicles in the diagnosis of central nervous system diseases.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1959745}, pmid = {42974031}, issn = {1664-2295}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Central Nervous System Diseases/diagnosis/metabolism ; Biomarkers/metabolism/cerebrospinal fluid ; Animals ; Parkinson Disease/diagnosis ; Alzheimer Disease/diagnosis/metabolism ; }, abstract = {Central nervous system (CNS) disorders encompass a diverse spectrum of conditions characterized by intricate pathological mechanisms, and the presence of the blood-brain barrier (BBB) has long impeded early diagnosis. Extracellular vesicles (EVs) are lipid bilayer nanoparticles released by living cells that can encapsulate and transport bioactive molecules such as proteins and nucleic acids across the BBB. EVs can be detected in biofluids such as blood and cerebrospinal fluid (CSF) through non-invasive or minimally invasive assays, and have emerged as highly promising vehicles for CNS liquid biopsies. Recent studies demonstrate that specific EV-associated protein cargoes (e.g., phosphorylated tau, α-syn) and non-coding RNAs (e.g., miR-422a, miR-409-3p) exhibit distinct differential expression profiles across various pathologies. These molecular signatures hold promise for early detection, differential diagnosis, and disease staging, with some biomarker panels showing high diagnostic accuracy. However, whether they outperform conventional CSF biomarkers still requires direct comparison and validation within the same cohorts. This review highlights recent research advances in the use of EVs for the diagnosis of Alzheimer's disease and Parkinson's disease, briefly touches upon other CNS disorders including stroke, glioma, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis, and discusses the clinical translational potential and remaining challenges of EV-based diagnostics.}, } @article {pmid42974758, year = {2026}, author = {Xue, L and Ma, J and Wan, G and Long, B and Mao, Y and Wang, F and Bai, S}, title = {A Wavelet-ALS-Assisted CNN-BiGRU Method for Peak Recognition in CCD-Based Capillary Electrophoresis Fluorescence Detection.}, journal = {Electrophoresis}, volume = {}, number = {}, pages = {}, doi = {10.1002/elps.70177}, pmid = {42974758}, issn = {1522-2683}, support = {62163006//National Natural Science Foundation of China/ ; 61605153//National Natural Science Foundation of China/ ; }, abstract = {Capillary electrophoresis (CE) is an efficient, rapid, and sensitive separation and analysis technique that has been widely applied in biochemistry, pharmaceutical research, and environmental monitoring. However, charge-coupled device (CCD)-based CE fluorescence signals are susceptible to baseline drift, random noise, and channel crosstalk, which reduce the accuracy of peak recognition. To meet the demand for high-precision signal analysis, this study proposes a convolutional neural network (CNN)-bidirectional gated recurrent unit (BiGRU) peak recognition algorithm on the basis of wavelet transform and one-dimensional asymmetric least squares (ALS). In the proposed system, an FPGA-based platform is used for real-time signal acquisition and data transmission, whereas the host computer performs subsequent processing of the received spectral data. Experimental results show that the proposed method achieves high-accuracy peak recognition on the spectral dataset, with Precision, Recall, and F1-score reaching 98.44%, 99.93%, and 99.18%, respectively. These results demonstrate its good robustness and practical applicability, providing technical support for the miniaturization and intelligent development of portable gene sequencers.}, } @article {pmid42974926, year = {2026}, author = {Gangfuß, A and Gowda, VK and Natera-de Benito, D and Munot, P and Vanegas, M and Darling, A and Reutlinger, C and Carrera-Garcia, L and Wunderlich, G and Kölbel, H and Stüve, B and Muhmann, D and Monfort Belenguer, L and Barca, DG and Reddy C, VS and Srinivasan, VM and Anguita, CM and Jungbluth, H and Dafsari, HS and Rossor, T and Böhm, J and Schara-Schmidt, U and Roos, A}, title = {Clinical Variability and Genotype Driven Outcomes in an International Cohort of 14 Pediatric FIG4 Patients.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70561}, pmid = {42974926}, issn = {2328-9503}, support = {//Mediment/ ; //Josepha und Charlotte von Siebold Habilitandinnen-Förderprogramm/ ; //German Society of Muscular Diseases (DGM)/ ; CP22/00141//Miguel Servet program from Instituto de Salud Carlos III, Spain/ ; B2B-RARE//European Regional Development Fund (ERDF)/ ; }, abstract = {BACKGROUND: Biallelic FIG4 variants classically cause distinct conditions characterized by peripheral neuropathy (Charcot-Marie-Tooth disease type 4J) or skeletal dysplasia (Yunis-Varón syndrome). However, central nervous system involvement is increasingly recognized. The prevalence and specific characteristics of movement disorders within FIG4-related disease remain poorly characterized, prompting a need to redefine its clinical continuum.

OBJECTIVE: To delineate the phenotypic spectrum of FIG4-related disorders beyond established entities (Yunis-Varón syndrome, Charcot-Marie-Tooth disease type 4J, bilateral temporooccipital polymicrogyria, and amyotrophic lateral sclerosis type 11) using an international multicentre cohort.

METHODS: We retrospectively analyzed clinical, genetic, and neurophysiological data from patients with biallelic FIG4 variants to redefine genotype-phenotype correlations, focusing on motor development, cognitive status, and movement disorders.

RESULTS: Evaluating 14 pediatric FIG4 patients revealed a continuous phenotypic spectrum rather than the clinical entities previously described in the literature. Instead of the typical peripheral neuropathy classically associated with pathogenic FIG4 variants, the predominant clinical picture in this age group was a severe neurodevelopmental disorder. Patients showed profound motor and cognitive delay, with a subset additionally displaying distinct movement abnormalities such as dystonia and bradykinesia.

CONCLUSION: Loss of functional FIG4 causes a broader and more severe disease spectrum with central nervous system involvement, including intellectual disability and movement abnormalities such as dystonia and bradykinesia. Recognizing these features should prompt clinicians to consider FIG4-associated disorders, allowing for optimized patient care and tailored therapeutic strategies.}, } @article {pmid42963097, year = {2026}, author = {Hald, K and Fagerström, M and Thomsen, JL and Johnsen, SP and Nilsen, P}, title = {Implementation of artificial intelligence in healthcare: a protocol for a phased mixed-methods multiple case study in the North Denmark Region.}, journal = {BMJ open}, volume = {16}, number = {10}, pages = {e124097}, pmid = {42963097}, issn = {2044-6055}, abstract = {BACKGROUND: Artificial intelligence (AI) is increasingly being implemented across healthcare systems with the potential to improve diagnostic accuracy, support clinical decision-making and enhance healthcare delivery. Despite growing investments in AI, evidence on how AI innovations are successfully implemented, adopted and sustained in routine clinical practice remains limited. Existing research has predominantly focused on technical performance and clinical effectiveness, while implementation-related factors have received less attention. This study aims to evaluate the implementation of AI innovations across multiple healthcare settings over time.

METHODS AND ANALYSIS: This study applies a phased mixed-methods multiple case study design to evaluate the implementation of 11 AI innovations introduced across hospital-based and cross-sectoral healthcare settings in the North Denmark Region. Each AI innovation is conceptualised as an individual case. The study consists of three sequential phases: (1) exploratory cross-case mapping of implementation processes and contextual determinants. (2) In-depth longitudinal case studies of selected cases. (3) Cross-case synthesis and programme-level evaluation. Data collection includes interviews, observations, document analysis, questionnaires and regional register data. The study is informed by the Consolidated Framework for Implementation Research, Proctor et al’s Implementation Outcomes Taxonomy, the Quality Implementation Framework and the WHO’s Health System Performance Assessment framework. Qualitative and quantitative data will be analysed separately and integrated through triangulation at case and cross-case levels.

ETHICS AND DISSEMINATION: According to Danish legislation, this study does not require approval from a regional research ethics committee. The study has been assessed by the Aalborg University Research Ethics Committee and registered as a research project involving the processing of personal data at Aalborg University. All participants will provide informed consent prior to participation. Findings will be disseminated through peer-reviewed publications, conference presentations and reports targeting relevant stakeholders.}, } @article {pmid42963841, year = {2026}, author = {Xu, J and Guo, B and Li, B and Qi, Z and Liu, X and Wang, G and Chen, S and Xu, X}, title = {Ala-205-met mutation in acetolactate synthase (ALS) of Bromus japonicus confers resistance to ALS-inhibiting herbicides.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71450}, pmid = {42963841}, issn = {1526-4998}, support = {2024060203//Basic Research Funds of Hebei Academy of Agriculture and Forestry Sciences/ ; 2023LYS03//HAAFS Youth Innovation Fund Project/ ; }, abstract = {BACKGROUND: Acetolactate synthase (ALS)-inhibitor-resistant Bromus japonicus populations are widespread in wheat fields in China. A novel population BD-R has evolved resistance to flucarbazone-sodium, whereas its underlying resistance mechanism remains unclear. The objectives of this study were to (i) determine the resistance and cross-resistance levels to ALS inhibitors; (ii) investigate the resistance mechanisms; (iii) evaluate response to herbicides with other modes of action; and (iv) develop a CAPS molecular marker for rapid resistance detection.

RESULTS: The resistant index (RI) value of BD-R to flucarbazone-sodium was 62.4, and the cross RI values to mesosulfuron-methyl and pyroxsulam were 62.5 and 142.4. A novel Ala-205-Met substitution was found in BD-R. ALS activity bioassays showed the I50 values of BD-R and HS-S to flucarbazone-sodium were 7753.82 and 144.12 nm. 3D modelling and molecular docking results revealed the Ala-205-Met mutation reduced the binding affinity between ALS and the three ALS inhibitors. Homozygous transgenic Arabidopsis thaliana lines harboring ALS from BD-R exhibited resistance to flucarbazone-sodium, with FW inhibition merely 4.93%. Haloxyfop-P-methyl and quizalofop-P-ethyl showed excellent control of BD-R, whereas topramezone and mesotrione exhibited no efficacy. A CAPS-ALS marker with the primers CAPS-ALS-F (5'-TCATCACCAACCATCTCTTCC-3') and CAPS-ALS-R (5'-ATCAGAGTAGTTGTAACTGGAATC-3') was developed and could reliably identify the resistant BD-R plants.

CONCLUSION: BD-R conferred high-level resistance and cross-resistance levels to ALS-inhibitors. Haloxyfop-P-methyl and quizalofop-P-ethyl can be used for effective control BD-R. This study is the first report of the Ala-205-Met mutation conferring resistance to ALS inhibitors in weeds, indicating the complexity of the evolution of herbicide resistance in weeds. © 2026 Society of Chemical Industry.}, } @article {pmid42964735, year = {2026}, author = {Ghiasvand, K and Meftahi, GH}, title = {Black Myrobalan (Terminalia chebula) as a potential multitarget neuroprotective agent: Translational insights and future directions in neurodegenerative diseases.}, journal = {Biochemistry and biophysics reports}, volume = {48}, number = {}, pages = {102850}, pmid = {42964735}, issn = {2405-5808}, abstract = {Myrobalan or Haritaki (Terminalia chebula Retz.) has been integrated into Ayurvedic, Unani, and even Tibetan medicine systems for over 2000 years. The "King of Medicines" has traditionally been used for diverse ailments such as digestive issues, wound healing, and general body strengthening. Now, modern medicine is focusing on the myrobalan's potential neuroprotective properties and its use in Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis (ALS) neurodegenerative disorders. These ailments are characterized by some combination of enduring oxidative damage, mitochondrial dysfunction, neuroinflammation, irregular protein aggregation, and progressive neuron cell death. Most of the current treatment options revolve around addressing the symptoms of the diseases, which is insufficient as the underlying disease continues to progress. There is an urgent need to devise therapies that work simultaneously on multiple disease pathways. Some of the noted secondary metabolites in T. chebula include hydrolyzable tannins like chebulinic and chebulagic acid as well as corilagin. Others occur as phenolic acids such as gallic and ellagic acid and flavonoids quercetin and kaempferol. Moreover, glycosides, sterols, and a wide range of alkaloids are also present. A number of these compounds are known to possess multifunctional biological properties like scavenging ROS, activating Nrf2/ARE signaling, downregulating pro-inflammatory mediators through blockade of NF-κB, and exerting protective effects on the mitochondria, as well as modulating apoptosis via Bcl-2 and caspases. T. chebula extracts and some isolated compounds have also been shown to improve cognitive function, reduce neuroinflammation, and protect dopaminergic neurons, and ameliorate neurotoxic effects of amyloid-β or α-synuclein through in vitro and in vivo animal studies. A review of the contributions from the phytochemistry, mechanism of action, preclinical, translational, and adjunctive applications of Terminalia chebula in neurodegenerative disease therapy is presented here.}, } @article {pmid42966163, year = {2026}, author = {Gao, C and Shi, R and Jiang, X and Chai, H and He, X}, title = {Immunometabolic dysregulation of reactive microglia and astrocytes in neurodegenerative diseases: Mechanistic insights and therapeutic implications.}, journal = {Journal of the neurological sciences}, volume = {491}, number = {}, pages = {126237}, doi = {10.1016/j.jns.2026.126237}, pmid = {42966163}, issn = {1878-5883}, abstract = {Neurodegenerative diseases (NDDs) are increasingly understood as multifactorial disorders characterized by intertwined pathological processes, in which metabolic dysfunction may act as a critical and potentially disease-amplifying contributor to the proteinopathy-driven pathological cascade. Despite growing recognition that microglial and astrocytic metabolism governs central nervous system tissue damage-repair homeostasis, intercellular metabolic crosstalk between glia and neurons remains insufficiently synthesized across major NDDs. This review delineates how core metabolic pathways, including glycolysis, mitochondrial respiration, lipid processing, and amino acid transport, shape glial reactivity in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We highlight glial metabolic reprogramming, a proposed theoretical framework arising from severe glial metabolic dysregulation. Within this framework, persistent pathological stress may drive reactive glia to sequester local energy substrates in excess, which is hypothesized to trigger bioenergetic failure in neighboring neurons. Broad-spectrum anti-inflammatory agents show poor clinical performance because they only block cytokine outputs rather than reverse glial metabolic exhaustion. Therapeutic efforts should therefore shift toward restoring glial metabolic flexibility. Cell-type-specific metabolic reprogramming, instead of pan-metabolic suppression, may circumvent systemic adverse effects. Precision strategies targeting such intercellular metabolic imbalance could provide promising cell-resolved metabolic avenues to retard NDD progression.}, } @article {pmid42966271, year = {2026}, author = {D'Antoni, L and Viccaro, F and D'Andria, M and Sanna, A and Cardini, ME and Tomsa, C and Flore, R and Di Meo, F and Fabozzi, A and Baccolini, V and Siena, L and Palange, P and Ceccanti, M}, title = {The impact of diagnostic criteria on the detection of nocturnal hypoventilation in adult amyotrophic lateral sclerosis patients.}, journal = {Sleep medicine}, volume = {149}, number = {}, pages = {109344}, doi = {10.1016/j.sleep.2026.109344}, pmid = {42966271}, issn = {1878-5506}, abstract = {BACKGROUND: Nocturnal hypoventilation (NH) is an early manifestation of respiratory muscle weakness in amyotrophic lateral sclerosis (ALS) and plays a key role in determining the optimal timing for non-invasive ventilation (NIV). However, several diagnostic definitions of NH have been proposed, and their impact on NH prevalence remains unclear.

METHODS: In this cross-sectional study, 56 non-ventilated ALS patients underwent home-based overnight monitoring with transcutaneous carbon dioxide (TcCO2) and pulse oximetry. NH prevalence was assessed using seven definitions derived from daytime arterial blood gases, nocturnal oximetry, and TcCO2 parameters. Agreement between definitions was evaluated using Cohen's and Light's kappa coefficients.

RESULTS: NH prevalence varied widely depending on the definition used, ranging from approximately 5% with daytime arterial criteria to 36.7% using peak TcCO2 ≥49 mmHg. Overall concordance among definitions was low (Light's κ = 0.27), indicating that current NH definitions are not interchangeable.

CONCLUSIONS: Currently used definitions of NH in ALS show substantial heterogeneity and identify different patient subsets. These findings highlight the need for ALS-specific consensus definitions of NH.}, } @article {pmid42963796, year = {2026}, author = {Hirayama, T and Shibukawa, M and Morioka, H and Ogawa, M and Yorimoto, K and Ebihara, S and Sakano, T and Iguchi, Y and Katsuno, M and Aoki, M and Fujita, K and Izumi, Y and Morita, M and Nakamura, R and Atsuta, N and Yamanaka, K and Kobayakawa, Y and Bokuda, K and Iwata, I and Sakushima, K and Imamura, K and Tsuda, H and Nakayama, Y and Urushitani, M and Shimizu, T and Nagano, S and Kano, O}, title = {Patient and public involvement in amyotrophic lateral sclerosis research in Japan: a survey through nationally advertised ALS Café events and a pilot advocacy training program.}, journal = {Research involvement and engagement}, volume = {12}, number = {1}, pages = {}, pmid = {42963796}, issn = {2056-7529}, support = {JP23K10515//Japan Society for the Promotion of Science/ ; JP25K22608//Japan Society for the Promotion of Science/ ; JP24wm0625301//Japan Agency for Medical Research and Development/ ; JP24mk0121294//Japan Agency for Medical Research and Development/ ; JPMH23FC1008//Ministry of Health, Labour and Welfare/ ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) remains an incurable, progressive neurodegenerative disease. Patient and public involvement (PPI) has been increasingly recognized as a means to enhance the relevance, quality, and efficiency of research; however, its implementation in intractable neurological disease research remains limited in Japan. This webinar-based study, conducted through nationally advertised ALS Café events, aimed to clarify current PPI awareness among the Japanese ALS community and to explore strategies for promoting patient advocacy. Data were collected during the "ALS Café" held in September 2024 and a subsequent patient advocacy training program organized in October 2025. Among 79 respondents (42 patients with ALS and 37 caregivers), approximately 80% reported being unfamiliar with the concept of PPI, yet 72.2% expressed willingness to participate once the concept was explained. Among the 57 respondents willing to participate, interest was highest for involvement in translating research findings into practice (56.1%) and in identifying research themes (47.4%), and most (93%) stated that they expected no remuneration beyond reimbursement of expenses. The subsequent training program was well received, with mean evaluation scores exceeding 8.0 on a 0-10 scale, indicating high comprehensibility among participants (changes in knowledge or willingness to participate were not assessed). Respondents were a self-selected group of ALS Café participants with limited demographic characterization who may not represent patients and caregivers who do not participate in such events, and the training program evaluation lacked a pre-training baseline; these limitations should be considered when interpreting our findings.

CONCLUSIONS: These findings reveal substantial stated willingness among Japanese patients with ALS and their caregivers to contribute to research despite low baseline awareness of PPI. This gap between limited awareness and high stated willingness suggests that targeted educational efforts could meaningfully expand patient engagement in ALS research. Systematic awareness-building initiatives, structured and accessible engagement opportunities, and sustained collaborative relationships between researchers and the patient community are essential for strengthening patient advocacy and accelerating drug development for ALS in Japan.}, } @article {pmid42957098, year = {2026}, author = {Kuo, YC and Ting, CH and Lai, HJ and Huang, PY and Shih, YA and Yang, CC and Cheng, LF and Tai, ST and Chao, CC and Chang, HY and Wang, IF and Tsai, LK}, title = {Characterization of plasma misfolded superoxide dismutase 1 in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107669}, doi = {10.1016/j.nbd.2026.107669}, pmid = {42957098}, issn = {1095-953X}, abstract = {OBJECTIVE: To characterize the dynamics of plasma misfolded superoxide dismutase 1 (mSOD1) and evaluate its utility as a state-dependent biomarker for patient stratification and therapeutic monitoring in amyotrophic lateral sclerosis (ALS).

METHODS: We utilized an SOD1/G93A mouse model and a cohort of 160 ALS patients, including four with SOD1 mutations, 12 with non-SOD1 mutations (C9orf72, TARDBP, FUS, OPTN), and 144 with nongenetic ALS. Chemical precipitation and enzyme-linked immunosorbent assay were used to quantify mSOD1 levels in plasma, spinal cord extracts, and cerebrospinal fluid (CSF). Clinical outcomes were assessed by the annual reduction in the revised ALS Functional Rating Scale (ALSFRS-R) score and ventilator-free survival.

RESULTS: In mice, plasma mSOD1 increased at the late symptomatic stage with subsequent numerical decline at the humane endpoint, accompanied by progressive motor neuron loss and increasing mSOD1-associated pathology. In humans, mSOD1 was elevated in 100% of SOD1-mutant, 25% of non-SOD1-mutant, and 22.2% of nongenetic ALS patients. Elevation was state-dependent, enriched in patients with moderate disability (ALSFRS-R 17-45). Plasma and CSF mSOD1 levels were correlated across the overall ALS cohort, but this association was no longer significant after exclusion of SOD1-mutant ALS cases. In one tofersen-treated patient, plasma mSOD1 showed rapid, parallel, and sustained reduction with CSF levels. No significant differences in clinical outcomes were observed in nongenetic ALS based on mSOD1 status.

INTERPRETATION: Approximately 22% of nongenetic ALS patients exhibit elevated plasma mSOD1, primarily during the moderate disease stage. Plasma mSOD1 is a candidate state-dependent biomarker for biological stratification and may have potential for treatment monitoring.}, } @article {pmid42958460, year = {2026}, author = {Keskin, I and Sigfridsson, I and Skagerberg Ekhtiari, E and Marklund, M and Mattson, S and Brännström, T and Marklund, SL and Nordström, U and Andersen, PM}, title = {Strain-specific morphology and CNS propagation of template-directed SOD1 aggregation following peripheral nerve inoculation.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42958460}, issn = {2051-5960}, support = {VR-MH 2012-3167; 2015-02804; 2017-03100; 2019-01707//Swedish Research Council/ ; 2012.0091; 2014.0305; 2020.0232//Knut and Alice Wallenberg Foundation/ ; 2015-0234; 2016-0303; 2018-0310; 2019-0320; 2020-0353//Hjärnfonden, Sweden/ ; }, mesh = {Animals ; Mice, Transgenic ; *Superoxide Dismutase-1/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Disease Models, Animal ; *Spinal Cord/pathology/metabolism ; *Sciatic Nerve/pathology/metabolism ; Mice ; Species Specificity ; Female ; Humans ; Mice, Inbred C57BL ; Male ; *Protein Aggregation, Pathological/pathology/genetics/metabolism ; }, abstract = {Accumulation of misfolded SOD1 protein into intracellular aggregates, in the spinal cord (SpC) and brainstem, is a hallmark of amyotrophic lateral sclerosis caused by mutations in the SOD1 gene (SOD1-ALS). Two distinct aggregate conformations, denoted strain A and strain B, were identified in the CNS of SOD1[G85R] and SOD1[D90A] transgenic (Tg) ALS mouse models, respectively. Both strains transmit templated SOD1 aggregation and ALS-like disease in Tg mouse models when inoculated into the SpC, whereas muscle or intraperitoneal inoculations, of up to 300 times more inoculate, did not. Here, we used strain A and strain B aggregate seeds, prepared from SpCs of the Tg mice, to investigate strain-specific differences in transmission of templated aggregation and ALS phenotype via a peripheral nerve. We show that both strains can transmit templated aggregation to the CNS via the sciatic nerve in SOD1[G85R] Tg mice. Strain A resulted in shorter time to disease onset and earlier end-stage disease compared to strain B, and these strain-specific differences were accentuated in the sciatic nerve inoculation model compared to direct SpC inoculations. To further analyse the differences between strain A and strain B, we developed an immunohistochemical method that distinguishes the two SOD1 aggregate strains in tissue sections. This method revealed that strain B adopts an elongated, skein-like morphology, whereas strain A aggregates appear as accumulations of rounded, bead-like structures. These findings suggest that SOD1 aggregates forming in a peripheral nerve might transmit disease to the CNS and that different SOD1 aggregate strains can influence disease onset and progression. Our results warrant further exploratory studies of SOD1 aggregate conformations and their potential role in the manifestation of SOD1 mutant-specific disease phenotypes.}, } @article {pmid42959461, year = {2026}, author = {Dorça, AC and Rocha, EMSS and Marra, MB and Morais, LA and Andersen, TM}, title = {Beyond the Larynx: New Insights Into Upper Airway Responses to Mechanical Insufflation-Exsufflation.}, journal = {Respirology case reports}, volume = {14}, number = {11}, pages = {e70792}, pmid = {42959461}, issn = {2051-3380}, abstract = {This case report describes a 44-year-old man with amyotrophic lateral sclerosis (ALS) and ineffective secretion clearance despite home use of mechanical insufflation-exsufflation (MI-E). He reported upper airway obstruction, respiratory discomfort and recurrent aerophagia during therapy. Dynamic assessments using transnasal flexible laryngoscopy and videofluoroscopy under different MI-E settings showed that upper airway responses were strongly influenced by inspiratory flow, pressure levels, expiratory time and cervical positioning. Higher inspiratory flow and pressure induced supraglottic closure and airflow diversion to the oesophagus. In contrast, lower inspiratory flow combined with reduced expiratory pressure and shorter expiratory time improved glottic opening, maintained airway patency and enhanced cough mechanics. Spontaneously adopted cervical extension optimized airflow and minimized oesophageal insufflation, whereas neutral alignment impaired cough efficiency. These findings emphasize the importance of individualized MI-E settings and patient-specific biomechanics in optimizing therapy in ALS.}, } @article {pmid42959522, year = {2026}, author = {Matta, C and Cheon, YH and Vágó, J and Mészár, Z and Kim, EH and Jiang, S and Balogh, A and Zana, M and Dinnyés, A and Jin, EJ}, title = {Engineered peroxisomes and patient-derived iPSC models as potential biomaterial platforms for precision neuroprotection in oxidative stress-driven central nervous system disorders.}, journal = {Materials today. Bio}, volume = {41}, number = {}, pages = {103752}, pmid = {42959522}, issn = {2590-0064}, abstract = {Peroxisomes couple hydrogen peroxide metabolism to lipid homeostasis, making their functions relevant to neurological disease and to the design of intracellular catalytic biomaterials. However, the strength of disease-specific evidence and the functions reproduced by current materials vary substantially. This narrative review distinguishes modified biological peroxisomes from artificial and biomimetic platforms and evaluates how patient-derived induced pluripotent stem cell (iPSC) models could support their development. We examine membrane chemistry, substrate permeability, enzyme retention, catalytic activity, cell targeting, blood-brain barrier transport, three-dimensional tissue penetration, and intracellular fate. We separate the established causal role of peroxisomal defects in primary peroxisomal disorders from associative or unresolved findings in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Kleefstra syndrome is discussed as a hypothesis-generating neurodevelopmental model, without assuming a primary peroxisomal defect. Published artificial-organelle studies establish selected catalytic and delivery capabilities, but do not validate the integrated patient-specific CNS therapeutic strategy proposed here. We therefore outline a staged evaluation framework that combines materials characterization with mechanistic controls, differentiated neural cultures, multicellular models, animal pharmacology, safety, and manufacturing assessment. Comparison with conventional antioxidant carriers, plasmalogen supplementation, and PPAR agonists should determine whether compartmentalized catalysis offers a measurable advantage. We provide a platform classification, a disease-resolved evidence hierarchy, and a set of controls and measurable endpoints intended to make peroxisome-inspired constructs comparable across studies. Clinical development will require evidence of disease-relevant benefit beyond ROS reduction and an acceptable therapeutic window.}, } @article {pmid42960175, year = {2026}, author = {}, title = {Corrigendum to From Vision to Validation: The Journey of Tofersen in Superoxide Dismutase 1Gene-Associated Amyotrophic Lateral Sclerosis [Mayo Clinic Proceeding: Innovations, Quality & Outcomes 10(5) (2026) PIQO_100755].}, journal = {Mayo Clinic proceedings. Innovations, quality & outcomes}, volume = {10}, number = {6}, pages = {100775}, doi = {10.1016/j.mayocpiqo.2026.100775}, pmid = {42960175}, issn = {2542-4548}, abstract = {[This corrects the article DOI: 10.1016/j.mayocpiqo.2026.100755.].}, } @article {pmid42955216, year = {2026}, author = {Oria, RS and Esomonu, UG and Sunday, KI and Oge, PA}, title = {Microglial perturbation in heavy metal-induced neuroinflammation and neurodegeneration: mechanisms, phenotypic plasticity, and therapeutic prospects.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {}, number = {}, pages = {}, pmid = {42955216}, issn = {1572-8773}, abstract = {Heavy metal exposure has emerged as a significant environmental contributor to neurodegenerative disease, and a substantial body of mechanistic evidence implicates microglia in the pathological cascades that follow. Lead, cadmium, arsenic, manganese, copper, cobalt, mercury, and zinc disrupt central nervous system homeostasis through multiple cellular targets, but the resident innate immune cells of the brain are well placed to translate these insults into sustained neuroinflammation. Evidence for this critical narrative review was assembled through a purposive search of PubMed, MEDLINE, and Google Scholar for mechanistically informative studies reporting glial endpoints, with reference lists searched by hand and no systematic protocol applied. This review synthesizes current understanding of how individual metals engage microglial signaling networks, with particular attention to oxidative stress, NF-κB activation, NLRP3 inflammasome assembly, MAPK cascades, and suppression of the Nrf2 antioxidant axis. We examine the phenotypic spectrum that extends well beyond the classical M1/M2 dichotomy, including disease-associated microglia, lipid-droplet-accumulating microglia, and interferon-responsive states, and consider how metal-specific signatures map onto these transcriptional programs. Manganese-driven inflammasome assembly, cadmium-induced mitochondrial impairment, lead-mediated disruption of calcium homeostasis, and mercury-evoked autophagic dysfunction are discussed as illustrative examples of mechanistic divergence within a common neuroinflammatory framework. Glial responses to metal mixtures, which better represent real exposure than single-element designs, are considered separately, and the evidence for greater-than-additive effects is appraised. Downstream consequences for astrocyte reactivity, blood-brain barrier integrity, synaptic remodeling, and neuronal viability are placed in the context of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Therapeutic avenues are appraised, including chelation, natural antioxidants, NLRP3 inhibitors, TREM2 modulation, and microglial replacement strategies. Methodological constraints, particularly the overreliance on BV-2 cells and acute high-dose exposure paradigms, are critically considered. The review concludes by identifying priorities for translational research, including longitudinal human cohort studies, single-cell transcriptomic profiling of metal-exposed microglia, and the development of region-specific exposure models that better reflect chronic environmental realities.}, } @article {pmid42955945, year = {2026}, author = {Setti, A and Stufera Mecarelli, L and Santini, T and D'Angelo, A and Padovano, V and Vitiello, E and Castagnetti, F and Martone, J and Mariani, D and Bozzoni, I}, title = {ALS-linked FUS mutation impairs GEMIN5-dependent mRNA recruitment to neuronal late endosomes.}, journal = {Cell reports}, volume = {45}, number = {11}, pages = {118206}, doi = {10.1016/j.celrep.2026.118206}, pmid = {42955945}, issn = {2211-1247}, abstract = {Neurons depend on tightly regulated positioning of cellular components to maintain long-distance signaling, but the mechanisms guiding specific mRNAs to distant regions remain unclear. Here, we show that late endosomes function as selective RNA carriers in human motor neurons and uncover the molecular logic guiding their loading. Using APEX2-mediated proximity labeling, we identify the external transcriptome of RAB7A-positive endosomes and find a specific population of mRNAs enriched for endosomal, axonal, and synaptic functions. We find that mRNAs enriched in RAB7A endosomes contain evolutionarily conserved 5'UTRs that act as localization signals, and that the RNA-binding protein GEMIN5 interacts with these regions to promote endosomal RNA recruitment. Finally, we show that there is a conspicuous loss of endosome-associated transcripts in amyotrophic lateral sclerosis-associated conditions, accompanied by the mislocalization of GEMIN5 from endosomes. These findings uncover fundamental principles of RNA compartmentalization and highlight endosomal mRNA loading as a vulnerable axis in neuronal homeostasis.}, } @article {pmid42955954, year = {2026}, author = {Longo, F and La Spada, AR}, title = {Ataxin-2 loss flips a metabolic switch for neuron health.}, journal = {Cell reports}, volume = {45}, number = {11}, pages = {118128}, doi = {10.1016/j.celrep.2026.118128}, pmid = {42955954}, issn = {2211-1247}, abstract = {Gastaldo et al.[1] report that lowering ataxin-2 protects neurons from TDP-43 toxicity in amyotrophic lateral sclerosis by activating neuronal glycolysis and astrocytic cholesterol synthesis, not by reversing TDP-43-dependent molecular pathology. The downstream effectors, IDH1 and HMGCS1, thus emerge as candidate therapeutic targets.}, } @article {pmid42956091, year = {2026}, author = {Helbig, J}, title = {Wissenschaftsgeschichte als Objektarbeit am Museum für Naturkunde Berlin: Lehrtafeln bewahren und erforschen*.}, journal = {Berichte zur Wissenschaftsgeschichte}, volume = {}, number = {}, pages = {}, doi = {10.1002/bewi.70047}, pmid = {42956091}, issn = {1522-2365}, abstract = {Historical teaching charts are often overlooked in museum collections, despite their potential as valuable sources for the history of science. This article examines how the documentation and contextualisation of such objects can generate new perspectives on scientific practice and knowledge production. It presents a collaborative university seminar at the Museum für Naturkunde Berlin in which students from different disciplines systematically documented a dispersed collection of 267 historical teaching charts and developed a documentation framework through object-based research. Using the teaching chart Anatomie von Helix pomatia as an exemplary case study, the article demonstrates how close examination of a single object reveals connections between scientific illustration, institutional practices, teaching, and the material production of knowledge. Rather than serving merely as visual aids, historical teaching charts emerge as material witnesses to scientific work, preserving traces of their production, use, and historical context. The project illustrates how the systematic documentation of neglected museum objects can provide a foundation for future research, collection management, and preservation. More broadly, it argues that the history of science begins with recognising, documenting, and interpreting material evidence as historical sources.}, } @article {pmid42947858, year = {2026}, author = {Cerami, C and Panzavolta, A and Faltracco, V and Dalla Bella, E and Riva, N and Telesca, A and Ferrara, F and Dodich, A and Lunetta, C and Consonni, M}, title = {The cost of mentalizing: executive contributions to social cognition performance in amyotrophic lateral sclerosis.}, journal = {Frontiers in psychology}, volume = {17}, number = {}, pages = {1960658}, pmid = {42947858}, issn = {1664-1078}, abstract = {BACKGROUND: Mentalizing deficits are common in amyotrophic lateral sclerosis (ALS). Performance at high-level socio-cognitive tasks may be particularly vulnerable to integrity of basic cognitive processes. However, the extent to which non-social functioning contributes to socio-cognitive impairment in ALS remains poorly understood. In this study, we addressed this question in a large cohort of patients.

METHODS: We assessed 257 ALS patients and 120 healthy controls using the Story-based Empathy Task (SET), which dissociates intention attribution (IA), emotion attribution (EA), and basic causal inference (CI). Vectorial analyses were applied to quantify overall performance and imbalance between social and non-social components. Mediation analyses were conducted to evaluate the contribution of executive system integrity to social cognition performance in ALS.

RESULTS: Patients showed significantly reduced performance across all SET conditions compared to controls, with imbalance between mentalizing and basic causal inference. Distinct profiles emerged across ALS phenotypes. ALS patients with behavioral changes exhibited predominant deficits in emotion attribution, whereas cognitively unimpaired ALS showed selective impairment in intention attribution. Executive functioning was significantly associated with SET performances and mediated the relationship between basic inference and both intention and emotion attribution.

DISCUSSION: Mentalizing impairment in ALS reflects an interaction between executive processes and specialized socio-cognitive systems. The identification of dissociable profiles supports a dual-route, network-based model of ALS, involving socio-affective and inferential pathways, and underscores the importance of integrated cognitive assessment and more targeted interventions addressing both social and non-social cognitive domains.}, } @article {pmid42948861, year = {2026}, author = {Lin, H and Li, C and Wu, J and Yin, J}, title = {Longitudinal coagulation-fibrinolysis dynamics are associated with survival in amyotrophic lateral sclerosis: a prospective cohort study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2026.2750602}, pmid = {42948861}, issn = {2167-9223}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) has been associated with thromboembolic risk. However, whether dynamic coagulation-fibrinolysis markers provide prognostic information in ALS remains insufficiently defined. Methods: We conducted a prospective cohort study of 151 patients with ALS, including repeated coagulation measurements in a longitudinal subset (n = 58), and assessed directional validation in the independent Answer ALS (AALS) cohort (n = 270). Survival analyses, longitudinal modeling, and plasma proteomic analyses were used to examine associations between coagulation-fibrinolysis dynamics, functional decline, and survival. Results: Higher baseline fibrinogen (FIB) was independently associated with shorter survival (HR = 2.19; 95% confidence interval (CI), 1.40-3.44). In the longitudinal subset, a steeper increase in D-dimer (DD) was associated with shorter survival (HR = 1.012; 95% CI, 1.001-1.024) and lower ALSFRS-R scores over time (β = -0.013; 95% CI, -0.016 to -0.009). Directionally consistent validation was observed in AALS using rescaled SomaScan-derived DD trajectories (HR = 1.0002; 95% CI, 1.0000-1.0004). Plasma proteomics showed reduced tetranectin, a fibrinolysis-related protein, in ALS; slower tetranectin decline was associated with longer survival using rescaled SomaScan-derived tetranectin trajectories (HR = 0.996; 95% CI, 0.993-0.998). Conclusions: These findings suggest that longitudinal coagulation-fibrinolysis markers may help identify a survival-related biomarker profile in ALS, involving higher baseline FIB, steeper rising DD, and reduced or more rapidly declining tetranectin.}, } @article {pmid42949499, year = {2026}, author = {Poddar, K and Wahi, C}, title = {Deep learning models to detect neurodegenerative diseases across different modalities, datasets, and stages: A systematic review.}, journal = {Technology and health care : official journal of the European Society for Engineering and Medicine}, volume = {}, number = {}, pages = {9287329261502060}, doi = {10.1177/09287329261502060}, pmid = {42949499}, issn = {1878-7401}, abstract = {BackgroundNeurodegenerative diseases like Alzheimer's and Parkinson's pose significant diagnostic challenges because they are incurable. Their symptoms often overlap with those of normal ageing and involve progressive neuronal loss. This makes early prediction, proper diagnosis, and ongoing monitoring crucial at every stage of the disease. Deep learning has become a useful tool for handling different types of data. However, the performance of these models relies heavily on the availability and variety of data, making it important to characterize datasets.ObjectiveThis PRISMA-based systematic review looks at 111 studies from 2019 to April 2026, organized into three clinical stages of neurodegenerative diseases: early prediction, diagnosis, and progression.MethodsEach study is assessed across four dimensions: data type (neuroimaging or non-neuroimaging), datasets (open-access, self-created, or hybrid), deep learning model architecture, and the use of explainable AI.ResultsMRI is the only imaging modality that spans all three stages. Speech is the most common non-neuroimaging method for diagnosis, while gait is used only for diagnosis and progression. The ADNI and PPMI datasets are the most commonly used. Self-created datasets introduce new modalities such as ECG and iPSCs, which are not found in open-access datasets. CNNs are the leading models for neuroimaging tasks, while LSTMs and RNNs capture temporal patterns in longitudinal datasets. Survival models are exclusively used for ALS and LATE. Fewer than 6% of the studies used confirmed XAI. Only 2 of the 111 studies validated their results on an independent external cohort.ConclusionThis review is the only one that covers all three disease stages across multiple neurodegenerative diseases.}, } @article {pmid42951561, year = {2026}, author = {Pellacani, S and Strani, L and Tanzilli, D and Barbieri, R and Marabottini, R and Martone, F and Napolitano, A and Cocchi, M and Durante, C}, title = {A multiway approach to overcome the peak resolution challenges in gas-chromatography coupled to ion mobility spectrometry.}, journal = {Analytica chimica acta}, volume = {1425}, number = {}, pages = {346326}, doi = {10.1016/j.aca.2026.346326}, pmid = {42951561}, issn = {1873-4324}, abstract = {BACKGROUND: Gas-chromatography coupled to ion mobility spectrometry (GC-IMS) is a powerful platform for untargeted analysis of volatile compounds, combining high sensitivity and short analysis times. However, its practical implementation still presents several analytical and computational challenges. From the instrumental perspective, the high sensitivity of isothermal GC-IMS makes it prone to signal saturation and memory effects, which can compromise the reproducibility of measurements. On the data-analysis side, the nature of GC-IMS outputs produce large and collinear datasets, in which baseline drift, shift in ion mobility and retention time modes, and peak overlap hinder the reliable extraction of relevant chemical information.

RESULTS: This work proposes a comprehensive workflow from the analytical strategy to the data analysis using as benchmark a data set of honey samples of different origin. Analysing the GC-IMS data, obtained with an instrument operating in isothermal condition, a prominent and marked memory effect was observed; it could be contained only through the systematic use of frequent blanks. Notably, most papers in the literature do not adopt blanks at such frequency. Attention was then devoted to the preprocessing, to improve data quality prior to modelling while limiting the number of preprocessing steps. A multiway approach, i.e. Parallel Factor Analysis 2 (PARAFAC2) applied interval wise, was adopted, for the first time, to resolve overlapping peaks and extract chemically meaningful components from the GC-IMS landscape. The results obtained were also compared with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and recent improved PARAFAC2 algorithms.

SIGNIFICANCE: A complete pipeline for the GC-IMS analysis was carefully developed and validated. PARAFAC2, was successfully applied for the deconvolution of GC-IMS data. This approach provided comparable results with previous methods and indicated that the same grade of automation reached in the analysis of GC-MS data with the same approach is feasible.}, } @article {pmid42951629, year = {2026}, author = {Inoue, H}, title = {[Disease modeling with iPSCs for pathophysiological elucidation and therapeutic research: establishment of an iPSC-based drug discovery platform centered on drug repositioning].}, journal = {[Rinsho ketsueki] The Japanese journal of clinical hematology}, volume = {67}, number = {9}, pages = {1145-1149}, doi = {10.11406/rinketsu.67.1145}, pmid = {42951629}, issn = {0485-1439}, mesh = {*Induced Pluripotent Stem Cells/cytology ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/genetics ; *Drug Repositioning ; *Drug Discovery/methods ; Animals ; *Models, Biological ; }, abstract = {Advances in induced pluripotent stem cell (iPSC) technology have enabled the establishment of patient-derived disease models, greatly accelerating research on disease mechanisms and drug discovery. Drug repositioning, which applies existing drugs to new indications, has emerged as an efficient therapeutic development strategy that reduces both development time and cost. This review summarizes recent progress in disease modeling and therapeutic research using iPSCs, focusing on amyotrophic lateral sclerosis (ALS). Motor neurons differentiated from ALS patient-derived iPSCs successfully recapitulated disease phenotypes and enabled compound screening. Using this platform, the Src/c-Abl inhibitor bosutinib was identified as a promising therapeutic candidate. Bosutinib promoted autophagy, reduced abnormal protein accumulation, and suppressed motor neuron degeneration in vitro and in vivo. Based on these findings, investigator-initiated clinical trials were conducted, demonstrating acceptable safety and suggesting potential efficacy in ALS patients. Furthermore, integration of iPSC-based analyses with biomarkers such as neurofilament light chain enabled patient stratification and suggested the feasibility of personalized therapeutic approaches. Future integration of iPSC models with artificial intelligence, genomic analysis, and real-world clinical data is expected to further enhance predictive precision and accelerate translational research. iPSC-based drug discovery therefore represents a promising platform for developing novel therapies for neurodegenerative diseases.}, } @article {pmid42952031, year = {2026}, author = {Lee, SH and Blecha, J and Kim, JM and Nillo, RM and Flavell, RR and Chao, CK and Forsayeth, JR and Gerdes, JM and VanBrocklin, HF and Wilson, DM}, title = {Copper-Mediated Radiofluorination of the Excitatory Amino Acid Transporter 2 (EAAT2)-Targeted PET Tracer [[18]F]RP-115: Alternate Synthetic Method.}, journal = {Journal of labelled compounds & radiopharmaceuticals}, volume = {69}, number = {13-14}, pages = {}, doi = {10.1002/jlcr.70044}, pmid = {42952031}, issn = {1099-1344}, support = {RC-201810-2017455//Alzheimer's Drug Discovery Foundation/ ; 1R01AG072743-01A1/AG/NIA NIH HHS/United States ; }, mesh = {*Fluorine Radioisotopes/chemistry ; *Positron-Emission Tomography ; *Copper/chemistry ; *Radiopharmaceuticals/chemical synthesis/chemistry ; *Excitatory Amino Acid Transporter 2/metabolism ; Chemistry Techniques, Synthetic ; Halogenation ; }, abstract = {Excitatory amino acid transporter 2 (EAAT2) is a key regulator of extracellular glutamate in the central nervous system. Dysregulated EAAT2 is implicated in neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), highlighting EAAT2 as a potential target for PET imaging. We previously reported a multistep radiosynthesis of [[18]F]RP-115, a CNS-permeable prodrug that undergoes esterase-mediated hydrolysis in the CNS to yield the active EAAT2-binding carboxylate. Motivated by recent advances in copper-mediated radiofluorination (CMRF), we sought to develop a more efficient late-stage radiosynthesis of [[18]F]RP-115. A two-step radiosynthesis of [[18]F]RP-115 using CMRF provided [[18]F]RP-115 in high radiochemical yield (52.8% ± 2.1 %, decay-corrected from starting [[18]F]fluoride ion, n = 4), high molar activity (355 ± 61 GBq/μmol), and high radiochemical purity (> 99%) with a total synthesis time of 70 min. Chiral HPLC analysis demonstrated that the configuration of the aspartic acid residue remained intact without racemization during both the CMRF and trifluoroacetic acid mediated deprotection. We developed an efficient radiosynthesis of [[18]F]RP-115 via CMRF, achieving high radiochemical yield and molar activity. This efficient synthesis may serve as a basis for the future implementation of a CMRF-based automated radiosynthesis of [[18]F]RP-115.}, } @article {pmid42952702, year = {2026}, author = {Morioka, H and Hirayama, T and Shibukawa, M and Sugisawa, T and Nagasawa, J and Hanashiro, S and Ebina, J and Okamoto, R and Ogawa, M and Okuni, I and Murakami, Y and Kano, O}, title = {Impact of hybrid assistive limb on gait ability and quality of life in patients with amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1823485}, pmid = {42952702}, issn = {1664-2295}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/complications/physiopathology ; *Quality of Life ; Female ; Male ; Middle Aged ; Aged ; *Gait/physiology ; *Gait Disorders, Neurologic/rehabilitation/etiology ; Robotics ; }, abstract = {OBJECTIVE: Hybrid Assistive Limb (HAL) is a cyborg-type wearable robot that supports gait training based on the wearer's intended motion. This study aimed to evaluate the effects of HAL treatment on gait ability and quality of life (QoL) in patients with amyotrophic lateral sclerosis (ALS).

METHODS: Patients with an unsteady gait with the ability to walk ≥10 m with assistance from a caregiver and/or walker were included in this study. Patients underwent nine HAL treatment sessions (20-40 min per session), with no more than one session per day, over a period of at least 4 weeks. Gait ability was evaluated using the distance of the 2-min walk test (2MWT), and the speed (m/s), step length (m/step), and cadence (step/s) of the 10-m walk test. Both tests were performed without HAL assistance. QoL was evaluated using the 36-Item Short Form Health Survey.

RESULTS: We evaluated 30 patients who completed one course of treatment. To evaluate the effectiveness of HAL, a paired t- test was used for the results of one course. With one course of treatment, the 2MWT improved from 92.27 m (40.46) at baseline to 104.16 m (41.73) (p < 0.001). Regarding QoL, the mental component summary score was 55.35 (8.27) before HAL treatment, indicating relatively preserved mental QoL. There were no significant changes in QoL before and after treatment.

CONCLUSION: Although no curative treatment exists for ALS, HAL treatment may provide short-term improvement in gait ability in patients with ALS. However, no significant changes in QoL were observed after one course of treatment.}, } @article {pmid42952712, year = {2026}, author = {Guha, R and Kim, S and Bandaru, A and Vivek, N}, title = {Biophysics-informed computational framework for predicting antisense oligonucleotide knockdown efficacy under small-data constraints.}, journal = {Frontiers in systems biology}, volume = {6}, number = {}, pages = {1921636}, pmid = {42952712}, issn = {2674-0702}, abstract = {A central strategy in treating neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), is lowering levels of disease-driving proteins. Antisense oligonucleotides (ASOs) offer a direct RNA-targeted approach to reduce protein expression, but experimental discovery and optimization are constrained by small, heterogeneous datasets and target-specific variability. Computational models that predict ASO knockdown efficacy directly from sequence and context could improve candidate selection, yet generalization across gene families and experimental settings remains challenging. In this study, we present a biophysics-based computational framework for predicting RNase H-active ASO knockdown efficacy under small-data constraints. We curate and integrate heterogeneous literature-derived ASO efficacy measurements into a unified dataset and evaluate model transfer using independently generated experimental ASOs targeting ALS-relevant genes DAZAP1 and FAM69C. Knockdown efficacy is defined at the transcript level (%KD), providing a mechanistic measure of RNase H-mediated activity. To our knowledge, this is the first framework that combines ASO feature engineering with one-shot family calibration for prediction under realistic small-data conditions. We integrate sequence representations with physics-based features capturing RNA-DNA hybridization thermodynamics, targeting RNA accessibility. Compared to sequence-only baselines, this mechanistic feature augmentation reduces external wet-lab prediction error, improving generalization to independent experimental data. Despite these gains, uncalibrated predictions exhibit systematic target-family-specific scale bias. We address this challenge by using a minimal one-shot family calibration strategy that applies an additive offset derived from a single experimentally measured reference ASO per new target family. We further assess the model's behavior using a leave-one-family-out simulation on literature-derived ASO families, repeatedly applying one-shot calibration to quantify its expected benefit and variability under controlled small-n conditions. One-shot calibration markedly improves absolute prediction accuracy while preserving within-family ranking, without retraining or increasing model complexity. Out-of-distribution evaluation shows stable performance for DAZAP1 and increased uncertainty for FAM69C, consistent with the expected effects of very small sample sizes. Permutation-based interpretability analyses show that predictive signal is dominated by global sequence architecture, with thermodynamic and accessibility features providing correlated, secondary contributions. Together, these results establish a computational workflow in which literature-trained models can be transferred to new target genes using minimal experimental input, supporting systematic ASO prioritization in small-data models.}, } @article {pmid42953394, year = {2026}, author = {Turra, GM and Angonese, PS and Rudell, EC and Tasca, VF and Markus, C and Merotto Junior, A}, title = {Legacy of Recurrent Gene Flow and Evidence of Independent Evolution of ALS Resistance Mutations in Weedy Rice.}, journal = {Evolutionary applications}, volume = {19}, number = {11}, pages = {e70342}, pmid = {42953394}, issn = {1752-4571}, abstract = {Weedy rice (Oryza spp.) provides a unique model for studying adaptive evolution because herbicide resistance can arise through both crop-to-weed gene flow and independent mutational events. In Brazil, nearly two decades of cultivation of imidazolinone (IMI)-resistant rice have imposed intense selection for acetolactate synthase (ALS) inhibitors resistance. This study investigated how historical gene flow and independent evolution have shaped the contemporary landscape of ALS resistance mutations in Brazilian weedy rice. Specifically, we characterized the diversity and distribution of ALS resistance mutations and developed rapid allele-specific molecular markers for major resistance alleles. A total of 200 weedy rice accessions collected from the major rice-growing region of Brazil were screened for IMI resistance and genotyped using newly developed SNAP (single nucleotide amplified polymorphism) qPCR markers targeting the IMI rice-derived mutations Ala122Thr, Ser653Asn, and Gly654Glu. Samples negative for these mutations were sequenced, and dose-response assays were conducted with imazethapyr, penoxsulam, nicosulfuron, and cloransulam-methyl. Ninety-three percent of the accessions were resistant to IMI herbicides. The ALS mutation Gly654Glu, present in rice cultivars used until 2006, was found in 15.5% of weedy rice resistant accessions, Ala122Thr became the dominant mutation (54.5%), whereas Ser653Asn occurred at an intermediate frequency (16.0%), indicating a temporal shift in the genetic basis of ALS resistance. Sequencing further identified the ALS substitutions Ala205Val, Trp574Leu, and Ser653Thr, which were not associated with commercial IMI-resistant rice cultivars, indicating ongoing independent evolution of target-site resistance. Trp574Leu conferred broad cross-resistance to all ALS-inhibiting herbicides evaluated, whereas the remaining mutations displayed mutation-specific resistance spectra. The SNAP markers showed high specificity and sensitivity, enabling reliable high-throughput detection of resistance alleles. Together, our findings demonstrate that the contemporary ALS resistance landscape in Brazilian weedy rice has been shaped mainly by repeated crop-to-weed gene flow, but also ongoing independent mutational events that continue to diversify resistance under herbicide selection.}, } @article {pmid42953823, year = {2026}, author = {Chen, HW}, title = {Bypassing the Blood-Central Nervous System (CNS) Barrier: A Dual-Axis Framework for Amyotrophic Lateral Sclerosis (ALS) Utilizing Glymphatic-Lymphatic Clearance and In Situ Chaperone Synthesis.}, journal = {Cureus}, volume = {18}, number = {9}, pages = {e117043}, pmid = {42953823}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by prion-like propagation of misfolded TAR DNA-binding protein 43 (TDP-43) and superoxide dismutase 1 (SOD1) across motor neuron pools. Because any circulating pharmacological agent must cross the blood-brain and blood-spinal cord barriers (BBB and BSCB), this review proposes active craniospinal tensioning (ACT) as a mechanical, non-pharmacological route to disease modification that acts on cerebrospinal fluid (CSF) and venous pressure dynamics rather than requiring penetration of these barriers. ACT is proposed to engage a single Monro-Kellie/Queckenstedt pressure continuity through two concurrent mechanisms: suboccipital venous occlusion-rebound, hypothesized to transiently raise and release craniospinal CSF pressure via venous compression and thereby accelerate venous-side glymphatic efflux; and dural pull-recoil, hypothesized to generate a reciprocal CSF pressure gradient via spinal elongation, agitating perivascular CSF directly while inducing a coupled venous pressure gradient. Because both mechanisms act concurrently on a shared venous-side target, the combined maneuver is proposed to be more potent than either delivered alone, as in prior work on pelvis-stabilized axial spinal traction (PSAST), which lacks the occlusion-rebound component. A secondary, hypothesis-generating micro-biochemical axis, cerebral venous preconditioning (CVPC), proposes that the same occlusion-rebound cycle produces capillary/venule wall strain sufficient to activate heat shock factor 1 (HSF-1) across the neurovascular unit, independent of oxygen tension, with a possible but uncharacterized contribution from hypoxia-inducible factor 1-alpha (HIF-1α). The two routes are non-exclusive, with the macro-fluidic axis alone proposed as sufficient. This framework is entirely theoretical, requires preclinical and clinical validation, and is intended as a template for related proteinopathy-driven neurodegenerative diseases, including Parkinson's disease, Huntington's disease, spinocerebellar ataxia, and fatal familial insomnia, addressed in forthcoming work.}, } @article {pmid42953977, year = {2026}, author = {Zhang, J and Wang, D and Chen, J and Lu, Y and Deng, D and Xu, B and Xu, Y and Jin, K and Xu, J and Liu, B and Ruan, J and Wang, X}, title = {The TBK1-OTUB2-IRF3 signalling complex promotes neuroinflammation and neurodegeneration.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag378}, pmid = {42953977}, issn = {1460-2156}, abstract = {The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway-mediated chronic inflammation drives neurodegeneration in natural aging and various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we identify Otubain-2 (OTUB2) as a pivotal regulator that orchestrates the STING signalosome to amplify inflammatory responses. The function of OTUB2 in neuroinflammation and neurodegeneration was investigated through genetic deletion and pharmacological inhibition of OTUB2 in hTARDBP transgenic mice , adeno-associated virus-mediated TDP43 overexpression mice, and aged mice. Biochemical assays were performed to dissect underlying molecular mechanisms. OTUB2 inhibited K63 ubiquitination of TANK-binding kinase 1 (TBK1), thereby suppressing TBK1 kinase activity and promoting cell death mediated by hyperactivated receptor-interacting serine/threonine-protein kinase 1 (RIPK1). Additionally, OTUB2 functioned as a scaffold facilitating assembly of the TBK1-interferon regulatory factor 3 (IRF3) signalling complex, a prerequisite for IRF3 phosphorylation, and enhanced IRF3 dimerization by reducing its K11 ubiquitination. Genetic deletion or pharmacological inhibition of OTUB2 significantly ameliorated neuroinflammation and neurodegeneration in both ALS and aged mouse models. This study establishes OTUB2 as a critical regulator of cGAS-STING signalling and a potential therapeutic target for neuroinflammation and neurodegeneration.}, } @article {pmid42954000, year = {2026}, author = {Geronimo, A and Cao, Q and Elman, L and Simmons, Z and Ackrivo, J}, title = {Feasibility of Longitudinal Home Monitoring of Nocturnal Transcutaneous CO2 and Relationship to Standard Respiratory Measures in Patients With ALS: A Pilot Cohort Study.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70432}, pmid = {42954000}, issn = {1097-4598}, support = {MDA874016//Muscular Dystrophy Association/ ; UL1 TR002014/TR/NCATS NIH HHS/United States ; UL1 TR00045/TR/NCATS NIH HHS/United States ; K23 HL-151879/HL/NHLBI NIH HHS/United States ; //Sentec AG/ ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) results in respiratory muscle weakness causing hypoventilation, retention of carbon dioxide (CO2), and chronic hypercapnic respiratory failure. In this pilot study, we performed a 12-month assessment of daytime and home nocturnal CO2 to track respiratory progression, determine relationships with surrogate respiratory measures, and assess the impact of non-invasive ventilatory support.

METHODS: Adults with forced vital capacity (FVC) less than 90% predicted secondary to ALS were recruited from two sites in the northeast US. Participants were followed up at standard visits every 3 months for up to five visits. Spirometry, functional scores, and patient-reported outcomes of dyspnea were recorded. Each visit included a 15-min, seated measurement of transcutaneous CO2 (PtcCO2) while in clinic, followed by 3 nights of home overnight PtcCO2 monitoring. Linear mixed-effects models were employed to describe the changes that occurred longitudinally and resulting from the initiation of non-invasive ventilation (NIV).

RESULTS: Sixteen subjects were enrolled, with nine completing the full study. Strength and FVC declined over time, while daytime PtcCO2 remained stable. Five individuals demonstrated nocturnal hypercapnia that preceded FVC < 50% predicted normal. Transition to NIV was associated with a 7 mmHg decrease in nocturnal PtcCO2.

DISCUSSION: Home nocturnal PtcCO2 assessment in ALS may identify respiratory insufficiency prior to FVC. Transcutaneous CO2 may play a role in the respiratory management of patients as a biomarker for hypoventilation risk and NIV titration. However, equipment availability and data quality limitations would benefit from professional assistance rather than independent in-home use.}, } @article {pmid42954893, year = {2026}, author = {Young, MJ}, title = {Consciousness in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2026.2739759}, pmid = {42954893}, issn = {2167-9223}, } @article {pmid42942116, year = {2026}, author = {Ramadan, S and Panza, E and Orlacchio, A}, title = {Beyond Monogenic Inheritance: Emerging Genetic Architecture of Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {20}, pages = {}, pmid = {42942116}, issn = {1422-0067}, support = {JALSDGC project to A.O.//Italian research Foundation for ALS/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genetic Predisposition to Disease ; C9orf72 Protein/genetics ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by marked genetic and phenotypic heterogeneity. Although pathogenic variants in major ALS genes, including C9ORF72, SOD1, TARDBP, and FUS, have provided fundamental insights into disease pathogenesis, many familial and most sporadic cases remain without a molecular diagnosis, suggesting a genetic architecture extending beyond coding variants and monogenic inheritance. Advances in genomic technologies have revealed contributions from deep-intronic and regulatory variants, structural rearrangements, repeat expansions, and other forms of genomic variation incompletely captured by standard diagnostic approaches. Evidence also indicates that combinations of rare variants with moderate or incomplete penetrance may contribute to disease susceptibility and clinical variability, supporting a multilayer model of ALS genetics. Population-specific variation and convergence of genetically diverse defects on common molecular pathways further complicate variant interpretation and disease classification. This review examines emerging components of ALS genetic architecture, including non-coding variation, structural variants, repeat expansions, oligogenic burden, ancestry-related gaps, and convergent neurodegenerative pathways. Integrating these genomic layers with functional and transcriptomic evidence may improve variant interpretation, diagnostic yield, patient stratification, and the development of mechanism-based precision therapies.}, } @article {pmid42944613, year = {2026}, author = {Abbasi Dezfouli, S and Heidenreich, E and Shahrbaf, M and Khajeh, E and Ramouz, A and Klauss, M and Hellbach, K and Öcal, O and Loos, M and Mehrabi, A}, title = {Novel algorithm for the diagnosis and treatment of different types of bile leakage following liver surgery.}, journal = {BJS open}, volume = {10}, number = {5}, pages = {}, pmid = {42944613}, issn = {2474-9842}, mesh = {Humans ; *Anastomotic Leak/diagnosis/therapy/etiology ; *Hepatectomy/adverse effects ; *Algorithms ; Female ; Male ; Bilirubin/analysis/blood ; Aged ; Middle Aged ; Bile ; Anastomosis, Surgical/adverse effects ; Retrospective Studies ; Bile Ducts/surgery ; Drainage ; Postoperative Complications/diagnosis ; }, abstract = {BACKGROUND: Posthepatectomy bile leakage (PHBL) after liver resection with bilioenteric anastomosis may originate from the anastomosis (anastomotic leak (AL)) or the transection surface (surface leak), including leakage from isolated bile ducts (IBDLs). Differentiating these sources remains challenging, and standardized management guidelines are lacking.

METHODS: All patients undergoing liver resection with bilioenteric anastomosis from 2008-2023 were analysed. PHBL was classified by origin (AL, surface leak, IBDL) and timing (early versus late onset). Drain fluid bilirubin concentration, drain-to-serum bilirubin ratio, and daily bilirubin loss were evaluated by leak type. Outcomes of conservative, interventional, and surgical management were compared.

RESULTS: Among 2936 liver resections, 229 involved bilioenteric anastomosis. PHBL occurred in 96 patients, including 44 ALs (46%), 47 surface leaks (49%), and 5 IBDLs (5%). AL showed higher peak drain bilirubin than surface leak/IBDL (38.3 versus 18.6 mg/dl; P < 0.001). Receiver operating characteristic analysis identified cut-offs for AL diagnosis: drain bilirubin > 20.85 mg/dl, drain-to-serum ratio > 10.57, and bilirubin loss > 160.93 mg/day. Management success varied by type and timing: AL and IBDL responded best to reoperation (success rates 78% and 100%), whereas surface leak was more effectively managed without surgery (65%). In AL specifically, reoperation was more successful in early-onset leaks (65% versus 38% in late-onset; P = 0.069), whereas interventional therapy was more successful in late-onset leaks (58% versus 15% in early-onset; P = 0.003).

CONCLUSIONS: Distinct diagnostic thresholds help differentiate AL from other PHBL types. AL and IBDL benefit from reoperation, whereas surface leak is better managed without surgery. Timing influences therapeutic success, supporting a novel type- and timing-based management algorithm for PHBL.}, } @article {pmid42945473, year = {2026}, author = {Salmon, K and de Majo, M and Basak, N and Crook, A and Cummings, C and Dratch, L and França, MC and Heckmann, J and Higgins, P and Knight, D and Koo, A and Nalini, A and Rouleau, G and Shahrizaila, N and Sokhi, DS and Son, B and Thomas, P and Trefiak, P and Van Damme, P and , and Roggenbuck, J and Harms, M and Al-Chalabi, A}, title = {Global best practice recommendations for genetic counselling and testing in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag375}, pmid = {42945473}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with substantial clinical and genetic heterogeneity. Advances in ALS genomics, emerging gene-targeted therapies, and genotype-specific clinical trials have increased the importance of genetic counselling and testing for individuals with ALS and their families. However, access to these services remains highly variable globally due to disparities in healthcare infrastructure, laboratory capacity, specialist availability, and funding. Existing guidance has largely been developed in high-resource settings and may not be feasible or equitable worldwide. The International Alliance of ALS/MND Associations convened an international, multidisciplinary Genetics Task Force to develop expert consensus recommendations for genetic counselling, genetic testing, and laboratory practice in ALS across diverse geographic and resource settings. Recommendations were developed through a structured, iterative consensus process incorporating clinical expertise, lived experience perspectives, published evidence, and global representation. Final recommendations were reviewed and approved through anonymous voting at an in-person consensus meeting. The resulting recommendations establish both minimum and aspirational best practices, emphasizing equitable access, informed decision-making, culturally responsive counselling, tiered genetic testing approaches, and context-appropriate laboratory standards. These globally informed recommendations provide a pragmatic framework to support clinicians, laboratories, policymakers, and advocacy organizations in improving access to high-quality ALS genetics services worldwide.}, } @article {pmid42946239, year = {2026}, author = {Dale, A and Sattler, R}, title = {TDP-43 dysfunction destabilizes glial homeostatic identity in ALS/FTD.}, journal = {Brain research}, volume = {}, number = {}, pages = {150618}, doi = {10.1016/j.brainres.2026.150618}, pmid = {42946239}, issn = {1872-6240}, abstract = {TAR DNA-binding protein 43 (TDP-43) pathology is a defining feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 dysfunction has traditionally been studied through a neuron-centric framework, increasing evidence demonstrates that astrocytes, microglia, and oligodendrocytes are also directly affected and actively contribute to disease progression. In this review, we examine how TDP-43 dysfunction disrupts lineage-specific glial homeostatic programs and promotes distinct pathological state transitions across major glial populations. In astrocytes, TDP-43 dysfunction impairs neurotransmitter regulation, metabolic and neuronal support, RNA homeostasis, and secretory signaling while promoting inflammatory and antiviral-like states. In microglia, altered TDP-43 disrupts inflammatory regulation, phagocytosis, lysosomal function, lipid metabolism, and stage-dependent protective responses. In oligodendrocytes, TDP-43 dysfunction compromises RNA processing, lineage maintenance, lipid metabolism, myelin integrity, and long-term axonal support. Together, these findings suggest that glial TDP-43 dysfunction cannot be reduced to a single generalized form of reactivity but instead reflects the breakdown of distinct cell type-specific identities required to maintain central nervous system homeostasis. A cross-glial framework integrating cell-autonomous dysfunction, non-cell-autonomous signaling, disease stage, and genetic context may therefore provide a more complete understanding of TDP-43 proteinopathy and its contribution to neurodegeneration across the ALS-FTD spectrum.}, } @article {pmid42946847, year = {2026}, author = {Raina, GS and Mehan, S and Das Gupta, G}, title = {Combined melatonin and edaravone therapy attenuates methylmercury-induced amyotrophic lateral sclerosis-like neurodegeneration through GLP-1 modulation and myelin preservation.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {42946847}, issn = {1432-1912}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons, resulting in progressive muscle weakness, paralysis, and respiratory failure. Despite the availability of disease-modifying therapies, current treatment options provide only modest clinical benefits, highlighting the need for novel therapeutic strategies targeting multiple pathological mechanisms. Melatonin, a pleiotropic neuroprotective molecule with antioxidant, anti-inflammatory, and anti-apoptotic properties, has emerged as a promising candidate; however, its influence on glucagon-like peptide-1 (GLP-1)-associated neuroprotective signaling and related molecular events in ALS remains poorly understood. Therefore, the present study investigated the neuroprotective efficacy of melatonin in a methylmercury (MTMR)-induced rat model of ALS and explored its effects on GLP-1-associated molecular alterations, neuroinflammation, oxidative stress, apoptosis, neurotransmitter homeostasis, demyelination, and neuronal injury. Molecular docking analysis was performed to predict the interaction of melatonin with proteins implicated in ALS pathology. Adult Wistar rats were exposed to MTMR (5 mg/kg, p.o.) for 21 days to induce ALS-like neurodegeneration, followed by treatment with melatonin (5 or 10 mg/kg, i.p.), edaravone (3 mg/kg, i.p.), or their combination for an additional 21 days. Neurobehavioral performance, biochemical alterations, hematological parameters, molecular biomarkers, and histopathological changes were subsequently evaluated. MTMR administration produced profound motor deficits accompanied by reduced GLP-1 levels, neurotransmitter imbalance, increased neuroinflammatory and apoptotic markers, elevated neurofilament light chain (NEFL), skeletal muscle injury, methylmercury accumulation, and extensive myelin and neuronal damage. Melatonin treatment significantly attenuated these pathological alterations in a dose-dependent manner by increasing GLP-1 levels, improving antioxidant status, reducing inflammatory and apoptotic responses, restoring neurotransmitter balance, preserving myelin integrity, and improving neuronal morphology across multiple brain regions and the spinal cord. Molecular docking further predicted favorable interactions between melatonin and several proteins associated with ALS pathophysiology, supporting its potential as a multitarget therapeutic agent. In most outcome measures, combined treatment with melatonin and edaravone produced greater neuroprotective effects than either intervention alone. Collectively, these findings demonstrate that melatonin substantially attenuates methylmercury-induced ALS-like neuropathology through coordinated modulation of multiple pathological processes associated with neurodegeneration. Although the precise molecular mechanisms require further experimental validation, the observed restoration of GLP-1 levels together with improvements in oxidative stress, neuroinflammation, apoptosis, neurotransmitter homeostasis, and myelin integrity suggests that melatonin may represent a promising adjunctive therapeutic strategy for ALS.}, } @article {pmid42946878, year = {2026}, author = {Chen, Z and Mansikkaviita, J and Seitz, C and Yazdani, S and Lehikoinen, J and Deeba, E and Lovik, A and Keszei, M and Grönlund, H and Laaksovirta, H and Fang, F and Tienari, PJ and Ingre, C and Andersson, J}, title = {Persistent and compartmentalized T cell immunity in ALS.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {42946878}, issn = {1546-170X}, support = {802091//EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))/ ; 2023-02428//Vetenskapsrådet (Swedish Research Council)/ ; 2024-02262//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; FS-2023-ESC-S5//Target ALS (Target ALS Foundation)/ ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease increasingly linked to T cell responses, although the mechanisms driving T cell activation and disease progression remain unclear. Here we used single-cell RNA and T cell receptor sequencing, longitudinal immune profiling and imaging flow cytometry to identify long-lived intrathecal clonotypes and antigen-presenting cell-T cell complexes displaying features of immunological synapse formation, consistent with intrathecal antigen presentation. Higher frequencies of CD4[+] effector, CD4[+] regulatory and CD8[+] T cells in cerebrospinal fluid (CSF) were associated with slower disease progression, whereas increased circulating CD4[+] effector and regulatory T cells were associated with faster progression. T cell clonotypes shared between blood and CSF exhibited distinct transcriptional states. Finally, frequencies of cytomegalovirus-specific T cells in CSF and anticytomegalovirus serum antibodies were correlated with faster progression and shorter survival in sporadic amyotrophic lateral sclerosis. These findings reveal compartmentalized immune dynamics, largely contrasting protective intrathecal responses with harmful systemic activation.}, } @article {pmid42946883, year = {2026}, author = {Lillini, D and Basili, T and Migliorelli, L and Aironi, C and Gabrielli, L and Squartini, S}, title = {Improving dysarthric speech classification with generative AI-based data augmentation.}, journal = {Medical & biological engineering & computing}, volume = {}, number = {}, pages = {}, pmid = {42946883}, issn = {1741-0444}, abstract = {Dysarthria is a neurological speech disorder characterized by impaired motor control of speech production, resulting in reduced intelligibility. It commonly arises in the context of neurodegenerative conditions, including amyotrophic lateral sclerosis and cerebral palsy. The development of deep learning systems for dysarthria assessment is hindered by the scarcity of annotated data, which restricts the ability of models to generalize to unseen speakers. This study proposes a cross-corpus diffusion-based data augmentation strategy for improving automatic speech intelligibility classification from dysarthric speech. A Grad-TTS model is trained on dysarthric speakers from the TORGO dataset and used to synthesize the vocabulary of UA-Speech, producing speaker-conditioned samples intended to transfer pathological acoustic traits across corpora. The proposed strategy is evaluated both independently and in combination with conventional signal-level augmentation using ResNet-50 and ResNet-152 classifiers in binary and four-class intelligibility classification tasks. The results indicate that cross-corpus synthetic augmentation improves average performance and that, in most settings, its integration with conventional augmentation yields further gains, suggesting that the two strategies introduce complementary forms of variability.}, } @article {pmid42947273, year = {2026}, author = {Sigfridsson, I and Marklund, M and Andersen, PM and Zetterström, P and Marklund, SL and Brännström, T}, title = {Intracisternal injection of two human SOD1 aggregate strains induces templated aggregation and ALS in transgenic mouse model.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42947273}, issn = {2051-5960}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Mice, Transgenic ; *Superoxide Dismutase-1/administration & dosage/metabolism/genetics ; Humans ; Disease Models, Animal ; Spinal Cord/pathology/metabolism ; Mice ; *Protein Aggregation, Pathological/pathology ; Female ; Mutation ; Mice, Inbred C57BL ; }, abstract = {Cytosolic aggregates containing misfolded superoxide dismutase-1 (SOD1) protein is an established hallmark of ALS caused by mutations in the SOD1 gene. We have previously identified two structurally distinct strains of human (h) SOD1 aggregates (denoted A and B) in mice transgenic (Tg) for hSOD1. Strain A and B have both been shown to transmit templated aggregation and induce early-onset of fatal ALS-like disease when injected directly into the spinal cord or peripheral nerve of hSOD1 Tg mice. In contrast, peripheral administration of hSOD1 aggregates into the intraperitoneal cavity or skeletal muscle did not induce disease. Collectively, these studies provide insight on the spreading mechanism of SOD1. However, the complete map of propagation routes and underlying mechanisms utilized by SOD1 aggregates in ALS is not fully charted. Here, we investigated whether hSOD1 aggregates may spread to the central nervous system (CNS) via the cerebrospinal fluid (CSF). Mutant hSOD1 aggregate seeds or control samples prepared from spinal cords of hSOD1 Tg mice or non-Tg mice, respectively, were inoculated into the cisterna magna of adult 100-day-old Tg mice expressing the G85R mutated hSOD1 protein. Disease phenotyping as well as biochemical and immunohistochemical analyses were performed and compared across the experimental groups. The mice inoculated with hSOD1 seeds developed early signs of ALS by 90 days after inoculation and reached terminal stage approximately 180 days earlier than mice receiving control seeds. Additionally, both strain A and B were observed to initiate templated aggregation along the neuroaxis. The results show that hSOD1 aggregates are capable of transmitting from the CSF to the CNS where they induce ALS-like pathology and concomitant phenotype. Unraveling the propagation pathways utilized by SOD1 opens new avenues to assess treatment strategies against ALS.}, } @article {pmid42947290, year = {2026}, author = {Meyer, T and Grehl, T and Schumann, P and Weyen, U and Rödiger, A and Smesny, U and Ilse, B and Weydt, P and Bernsen, S and Fabian, R and Göricke, B and Petri, S and Lumi, R and Bjelica, B and Großkreutz, J and Cetin, H and Keritam, O and Haimberger, F and Korsukewitz, C and Löscher, W and Kohl, Z and Regensburger, M and Baum, P and Metelmann, M and Kettemann, D and Norden, J and Steinbach, R and Körtvélyessy, P and Lingor, P and McFarlane, R and Münch, C and Boentert, M and Maier, A}, title = {Anatomically Defined Motor Phenotypes Reveal Dissociated Trajectories of Progression, Neurofilament Profiles, and Survival in ALS.}, journal = {European journal of neurology}, volume = {33}, number = {11}, pages = {}, doi = {10.1111/ene.70798}, pmid = {42947290}, issn = {1468-1331}, support = {//Boris Canessa ALS Stiftung/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/blood/pathology/physiopathology/classification ; Disease Progression ; *Neurofilament Proteins/blood ; Female ; Phenotype ; Male ; Middle Aged ; *Motor Neurons/pathology ; Aged ; Cohort Studies ; }, abstract = {BACKGROUND: Clinical heterogeneity in amyotrophic lateral sclerosis (ALS) may reflect structured disease trajectories. This study investigated whether anatomically defined motor phenotypes capture reproducible patterns associated with progression, serum neurofilament light chain (NfL), and survival.

METHODS: In a multicenter cohort of 1307 ALS patients, motor phenotypes were classified by region of onset, timing of propagation to a vertically distant body region (early ≤ 12 months vs. later), and the degree of upper (UMN) and lower motor neuron (LMN) dysfunction. Intercenter consistency was assessed using the Friedman test and Kendall's W. Associations with ALS progression rate (ALSPR), NfL, and survival were analyzed using group comparisons and Cox regression models.

RESULTS: Phenotype classification was consistent across centers (Kendall's W 0.75-0.89). Onset phenotypes were significantly associated with ALSPR, NfL, and survival (p < 0.001). Trunk onset showed the lowest log(NfL/ALSPR), indicating dissociation between rapid progression and relative NfL elevation. Early propagation was the strongest marker of disease aggressiveness, with higher ALSPR, elevated NfL, and reduced survival (HR 2.93, p < 0.001). In early propagation, NfL disproportionally increased with progression indicating a relative uncoupling of NfL from functional decline. Phenotypes with balanced UMN/LMN and predominant LMN involvement were associated with shorter survival (HR 2.51, p < 0.001).

CONCLUSIONS: Anatomically defined motor phenotypes identify reproducible ALS trajectories with distinct clinical and neurofilament profiles. Early propagation provides an actionable risk marker of disease aggressiveness, while combined upper and lower motor neuron dysfunction or lower motor neuron predominance is prognostically unfavorable. These findings support integrating structured phenotyping into prognostic models and clinical trial stratification.}, } @article {pmid42947405, year = {2026}, author = {Agarwal, S and Rehman, SAA and Muñoz, IM and Knebel, A and Hop, PJ and Gourlay, R and Brown, F and Macartney, T and Squires, I and Veldink, JH and Kenna, KP and Rouse, J and Mehta, AR}, title = {NEK1 autophosphorylation is disrupted by amyotrophic lateral sclerosis-associated missense variants: activity biomarkers and structural insights.}, journal = {Open biology}, volume = {16}, number = {10}, pages = {}, doi = {10.1098/rsob.260209}, pmid = {42947405}, issn = {2046-2441}, support = {//Greater Houston Community Foundation/ ; //UK Medical Research Council/ ; //National Institute for Health and Care Research/ ; MR/Z505535/1//Dementias Platform UK/ ; RGS/R2/252027//Royal Society/ ; }, mesh = {*NIMA-Related Kinase 1/genetics/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Mutation, Missense ; Phosphorylation ; Humans ; Biomarkers/metabolism ; Models, Molecular ; }, abstract = {Rare variants in NEK1, encoding a serine/threonine kinase, are among the most consistently implicated genetic contributors to amyotrophic lateral sclerosis (ALS), reported in approximately 2-3% of cases. Yet, while recent studies have characterized the cell biological consequences of NEK1 loss-of-function, the biochemical effects of ALS-associated missense variants on kinase activity have not been directly investigated. This distinction is mechanistically important, because missense alleles encode mutant proteins rather than simply reducing protein dosage. Here, we provide the most comprehensive cell-based phosphoproteomic map of NEK1 phosphorylation to date, identifying 10 recurrent phosphorylation sites across independent expression and acquisition conditions. We experimentally assign pSer14, pThr156 and pSer418 as NEK1 autophosphorylation sites using kinase-dead controls, targeted extracted ion chromatogram analysis, phosphosite mutagenesis and phosphospecific antibodies. Leveraging activation-loop pThr156 as a read-out of NEK1 activity, we assessed nine ALS-associated missense variants spanning the major functional regions of the protein. Among catalytic-domain variants, R261C produced the most robust reduction in pThr156 autophosphorylation, R232C produced a smaller reduction, and R232H increased pThr156; the basic-region variant, A313T, also showed a smaller reduction. Structural modelling provides a mechanistic framework for understanding these variant-specific effects. Our study establishes the first activity-based framework for functional classification of NEK1 missense variants, and provides direct evidence that ALS-associated missense variants can alter NEK1 autophosphorylation through a mechanism distinct from simple haploinsufficiency. The phosphospecific antibodies, isogenic cell lines and curated phosphoproteomic datasets generated here provide a community resource for future studies of NEK1 regulation, variant interpretation and therapeutic target validation.}, } @article {pmid42947411, year = {2026}, author = {Duffy, K and Gwathmey, K and Schneck, D and Arguedas, A and Xenopoulos-Oddsson, A and Heiman-Patterson, T and Ajroud-Driss, S and Arcila-Londono, X and Wymer, J and Olney, N and Hayat, G and Lunetta, C and Cerri, F and Al-Lahham, T and Sherman, A and Ghasemi, M and Cui, E and Fiecas, M and Walk, D}, title = {Time-to-Event Analysis of Clinical Milestones in the ALS Natural History Consortium Dataset.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70440}, pmid = {42947411}, issn = {1097-4598}, support = {FD-R01-007630/FD/FDA HHS/United States ; //Department of Neurology, University of Minnesota/ ; }, abstract = {INTRODUCTION/AIMS: Study of clinical milestones, particularly intermediate events like loss of ambulation, in large amyotrophic lateral sclerosis (ALS) cohorts is limited. Here, we leverage the ALS Natural History Consortium dataset to evaluate the time-to-event for several outcomes and prognostic factors that predict risk.

METHODS: Longitudinal data from 1950 participants were used in time-to-event analyses based on time from diagnosis. Outcomes were gastrostomy, loss of ambulation, loss of useful speech, non-invasive ventilation (NIV) usage, and death equivalent (death or mechanical ventilation). Median times-to-event were calculated along with Kaplan-Meier curves. Cox proportional hazards models for each outcome estimated (through adjusted hazard ratios [HR]) the impact of several prognostic factors, including sex, region of onset, age at diagnosis, and the initial rate of change (delta-FRS) in ALS Functional Rating Scale-Revised (ALSFRS-R) scores.

RESULTS: Estimated median times-to-event for clinical outcomes ranged from 1.44 to 6.21 years, with a median time to death equivalent of 2.12 years. A higher delta-FRS was the greatest risk factor for all outcomes (HRs between 2.01 and 3.05). Limb onset decreased risk of loss of speech, NIV use, gastrostomy, and death equivalent (HRs 0.41-0.78). Older age at diagnosis increased risk of gastrostomy, NIV use, and death equivalent (HRs 1.08-1.27).

DISCUSSION: These findings further inform expectations of time to various outcomes, especially rarely investigated intermediate events, and their risk factors. The importance of progression rate supports other recent findings, highlighting delta-FRS as a key prognostic factor with potential utility in clinical trial designs.}, } @article {pmid42947522, year = {2026}, author = {Sanghai, N and Vuong, B and Afridi, MSK and Leggett, S and Roghzai, H and Tranmer, GK}, title = {The Boron-Neuron Connection: The Potential of Boron-Containing Molecules for Treating Incurable Amyotrophic Lateral Sclerosis.}, journal = {ChemMedChem}, volume = {21}, number = {21}, pages = {}, doi = {10.1002/cmdc.70554}, pmid = {42947522}, issn = {1860-7187}, support = {202210PJT-495295//Canadian Institutes of Health Research (CIHR)/ ; RGPIN-2017-05938//Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Reactive Oxygen Species/metabolism ; Animals ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; *Boron Compounds/chemistry/pharmacology/therapeutic use ; *Neurons/drug effects/metabolism ; Blood-Brain Barrier/metabolism/drug effects ; *Boron/chemistry/pharmacology ; Molecular Structure ; Oxidative Stress/drug effects ; }, abstract = {BACKGROUND: Boron (B), a group 13 metalloid, has emerged as a versatile element at the intersection of chemistry, biology, and medicine. Its electron-deficient nature and ability to reversibly interconvert between trigonal planar (sp[2]) and tetrahedral (sp[3]) geometries enable dynamic covalent interactions with biological nucleophiles, making boron-containing compounds (BCCs) attractive pharmacophores that selectively interact with reactive oxygen species (ROS) and are ROS-responsive for therapeutic development. BCCs possess antioxidant, anti-inflammatory, and metal-chelating properties that make them attractive candidates for neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS), a fatal and multifactorial motor neurodegenerative disorder, is characterized by oxidative stress, neuroinflammation, mitochondrial dysfunction, and metal dyshomeostasis, providing a strong rationale for exploring boron-based therapeutics.

METHODS: This review examines current literature on B chemistry, pharmacology, and translational applications, with emphasis on mechanisms relevant to ALS pathogenesis. This review focuses on ROS-responsive B scaffolds, blood-brain barrier (BBB) permeability, neuroprotective mechanisms, hormonal modulation, metal chelation, and emerging preclinical evidence supporting boron-based interventions.

CONCLUSIONS: BCCs represent a promising yet underexplored therapeutic platform for ALS and related neurodegenerative disorders. Their ROS-responsive, redox-modulating, and neuroprotective properties, combined with favorable CNS drug-like pharmacokinetics, offer a mechanistically distinct approach to disease modification. Emerging preclinical evidence strongly supports further translational investigation.}, } @article {pmid42933233, year = {2026}, author = {Lehrer, S}, title = {ALS-associated cytoskeletal and glial gene expression: evidence consistent with developmental pathway re-engagement.}, journal = {Journal of the neurological sciences}, volume = {491}, number = {}, pages = {126231}, doi = {10.1016/j.jns.2026.126231}, pmid = {42933233}, issn = {1878-5883}, abstract = {BACKGROUND: We examined whether amyotrophic lateral sclerosis (ALS) is associated with cytoskeletal and glial transcriptional patterns compatible with developmental pathway re-engagement, while recognizing that similar patterns may arise from injury responses and altered cell composition.

METHODS: Postmortem RNA-sequencing data from the Target ALS Postmortem Tissue Core were analyzed using linear mixed-effects models accounting for repeated tissue samples within subjects. Models were adjusted for tissue source, age at death, sex, and postmortem interval. Composite scores represented Arp2/3 activity, SOX9/MEGF10 developmental-glial expression, and MYH10-associated transport imbalance.

RESULTS: ALS was associated with increased Arp2/3 expression (β = 0.399, P = 8.26 × 10[-9]), SOX9/MEGF10 expression (β = 0.643, P = 4.28 × 10[-6]), MYH10 expression (β = 0.308, P = 0.000801), and MYH10-KIF5C transport mismatch (β = 0.121, P = 0.00537); all remained significant after false-discovery-rate correction. The MYH10-Arp2/3 contractility index was not significant (β = -0.0909, P = 0.107).

CONCLUSIONS: ALS was associated with higher expression of selected cytoskeletal and glial genes in bulk postmortem tissue. These cross-sectional associations are compatible with, but do not demonstrate, developmental program reactivation, altered protein activity, or causation. Cell-resolved and functional studies are needed.}, } @article {pmid42933234, year = {2026}, author = {Cappelli, J and Hundal, S}, title = {Cost-effectiveness of multidisciplinary care compared with standard neurology care in Amyotrophic Lateral Sclerosis: A model-based cost-utility analysis.}, journal = {Journal of the neurological sciences}, volume = {491}, number = {}, pages = {126235}, doi = {10.1016/j.jns.2026.126235}, pmid = {42933234}, issn = {1878-5883}, abstract = {OBJECTIVE: To evaluate the cost-effectiveness of multidisciplinary clinic (MDC) care compared with standard general neurology care for adults with amyotrophic lateral sclerosis (ALS).

METHODS: A cost-utility analysis was conducted using a state-transition Markov model with monthly cycles over a 10-year horizon from the U.S. payer perspective. Health states comprised King's stages 1, 2, 3, 4 A, 4B, and death. Disease progression, mortality, utility, and cost inputs were derived from published literature (2005-2026). Transition probabilities were based on longitudinal data from the Pooled Resource Open-Access ALS Clinical Trials and permitted non-sequential progression. MDC-associated survival benefit was applied to stage-specific mortality across all King's stages. No additional utility benefit was assigned to MDC, while MDC-specific multipliers were applied to outpatient, inpatient, and emergency department costs. Outcomes included quality-adjusted life-years (QALYs), costs, cost per life-year gained, and incremental cost-effectiveness ratios (ICERs). Uncertainty intervals (UIs) were derived from sensitivity analyses.

RESULTS: MDC increased costs ($523,170 vs $378,171) and QALYs (0.73 vs 0.60), yielding 0.13 incremental QALYs (95% UI, 0.06-0.20) at an incremental cost of US$144,999 (95% UI, $53,784-$257,504). The ICER was US$1,158,673/QALY and cost per life-year gained was US$149,483. MDC was cost-effective in 0.1% of simulations at a willingness-to-pay threshold of $150,000/QALY.

CONCLUSION: MDC improved survival and quality-adjusted survival but at substantially higher cost. Its ICER remained well above commonly used U.S. willingness-to-pay thresholds across sensitivity analyses, including alternative utility valuations. These findings highlight the distinction between clinical benefit and cost-effectiveness and quantify the long-term economic consequences of survival gains associated with multidisciplinary ALS care.}, } @article {pmid42933736, year = {2026}, author = {Chakraborty, W and Anand, A and Kumar, S and Roy, KK}, title = {Circadian aging and neurodegeneration: the emerging role of the melatonin-cortisol axis in brain homeostasis, disease progression, and precision chronomedicine.}, journal = {Frontiers in neuroendocrinology}, volume = {83}, number = {}, pages = {101292}, doi = {10.1016/j.yfrne.2026.101292}, pmid = {42933736}, issn = {1095-6808}, abstract = {Circadian aging may promote neurodegenerative illnesses by dysregulating the melatonin-cortisol axis. Low nighttime melatonin synthesis, blunted cortisol circadian cycles, abnormal clock-gene oscillation patterns, and sleep-wake architecture undermine central and peripheral circadian equilibrium with age. Neuroendocrine alterations produce oxidative stress, mitochondrial failure, pervasive neuroinflammation (CNS immune function loss), and proteostasis. Increasing Alzheimer's, Parkinson's, ALS, Huntington's, frontotemporal dementia, Lewy body disease, PTSD, and vascular cognitive impairment due to impaired glymphatic axonal clearance/blood-brain barrier dysregulation/synaptic degeneration/pathoproteopathic protein We examine how clock genes, melatonin signaling, hypothalamic-pituitary-adrenal axis administration, microglia reactivity, and immune-mediated metabolic dysregulation affect dementia. New endocrine, transcriptomic, multi-omics, and wearable-derived digital biomarkers, chronopharmacology (including melatonin receptor agonists), bright-light therapy, time-restricted eating with exercise chronotherapy guidance/synchronization, sleep optimization, and gut microbiota modulation This study addressed inter-individual circadian variability, genetic susceptibility to therapy timing, biomarker standardization, and clinical trial design. The melatonin-cortisol axis may identify and treat age-related neurodegenerative diseases with tailored treatment.}, } @article {pmid42933747, year = {2026}, author = {Gray, EL and McGuiness, O and Menadue, C and Piper, A and Wong, K and Kiernan, MC and Yee, BJ}, title = {Diaphragm reserve utilisation in motor neurone disease: A novel ultrasound-derived physiological index.}, journal = {Respiratory physiology & neurobiology}, volume = {347}, number = {}, pages = {104667}, doi = {10.1016/j.resp.2026.104667}, pmid = {42933747}, issn = {1878-1519}, abstract = {INTRODUCTION: Respiratory involvement is a major determinant of prognosis in motor neurone disease (MND; or amyotrophic lateral sclerosis), yet conventional static respiratory measures provide limited information about how much available diaphragm thickening capacity is recruited during quiet breathing. We evaluated diaphragm reserve utilisation (RU), an ultrasound-derived ratio of tidal diaphragm thickening relative to maximal diaphragm thickening, as a novel physiological descriptor in MND.

METHODS: In a prospective observational study, 38 patients with MND and 20 healthy controls underwent right hemidiaphragm ultrasound to measure thickness at end-tidal expiration, peak tidal inspiration and peak maximal inspiration. Thickening fractions and RU were calculated. Between-group differences in diaphragm ultrasound indices were assessed. Secondary analyses examined relationships between RU, respiratory function and survival.

RESULTS: Tidal diaphragm thickening fraction was similar between patients with MND and controls, whereas maximal thickening fraction was lower in MND, resulting in higher RU in MND than controls. This pattern indicates that patients with MND maintained tidal diaphragm thickening while using a greater proportion of their available maximal thickening capacity. Higher RU was also associated with shorter survival, supporting its potential physiological and clinical relevance.

CONCLUSION: Diaphragm reserve utilisation describes the proportion of measured diaphragm thickening capacity recruited during tidal breathing. Patients with MND demonstrated preserved tidal thickening despite reduced maximal thickening capacity, resulting in higher RU than healthy controls. This supports RU as a novel physiological index of relative diaphragm thickening reserve utilisation. The relationship between RU and survival warrants validation in larger prospective cohorts.}, } @article {pmid42934257, year = {2026}, author = {Okoshi, K and Aoki, Y}, title = {Neuromuscular junction pathology in amyotrophic lateral sclerosis and emerging molecular therapeutic strategies.}, journal = {Journal of human genetics}, volume = {}, number = {}, pages = {}, pmid = {42934257}, issn = {1435-232X}, abstract = {Traditionally conceptualized as a soma-centric pathology, amyotrophic lateral sclerosis (ALS) is a fatal, heterogeneous neurodegenerative disease. The suboptimal outcomes of central nervous system (CNS)-directed therapeutic strategies have necessitated a shift in focus toward the dying-back hypothesis. This hypothesis contends that synaptic disconnection and axonal retraction at the distal neuromuscular junction (NMJ) are early pathological events that may antedate overt motor neuron loss. This review systematically examines the NMJ as an early vulnerable and therapeutically tractable peripheral niche in ALS pathogenesis, rather than merely a downstream consequence of proximal proteinopathy. Evidence from human clinical samples and ALS mouse models, particularly SOD1-G93A mice, collectively supports the early vulnerability of the NMJ, with the temporal precedence of denervation, synaptic retraction, and mitochondrial dysfunction most clearly demonstrated in experimental models. We highlight how the breakdown of the tripartite synapse-comprising the motor terminal, skeletal muscle, and terminal Schwann cells (tSCs)-may disrupt essential neurotrophic signaling and local metabolic homeostasis. Furthermore, we discuss how advancements in humanized in vitro NMJ models and spatial transcriptomics provide unprecedented resolution into localized RNA dysmetabolism and bioenergetic failure. Finally, we evaluate emerging therapeutic strategies specifically designed to stabilize or restore the NMJ, including MuSK agonists and other NMJ-directed approaches. By recontextualizing the NMJ as a critical early site of vulnerability, we propose that targeting the peripheral synaptic microenvironment may offer a promising strategy for modifying the progression of ALS.}, } @article {pmid42934377, year = {2026}, author = {Wu, Y and Zhang, X and Gao, C and Zhang, Z and Liao, X and Kang, Y}, title = {The cGAS-STING Pathway in Neuroinflammation and Neurological Disease: Mechanisms, Disease Contexts, and Periphery-to-Brain Communication.}, journal = {Cellular and molecular neurobiology}, volume = {46}, number = {1}, pages = {}, pmid = {42934377}, issn = {1573-6830}, support = {2024MZFS007//Research Grant of Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education/ ; 82272199//National Natural Science Foundation of China/ ; 2022YFC2504500//Key Technologies Research and Development Program/ ; }, mesh = {Humans ; Animals ; cGAS-STING Signaling Pathway ; *Nucleotidyltransferases/metabolism ; *Nervous System Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism/pathology ; *Membrane Proteins/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; Signal Transduction ; Inflammation/metabolism/pathology ; }, abstract = {Neurodegenerative disorders involve a strong inflammatory component, yet the underlying inflammatory mechanisms may be heterogeneous across disease stage, cell type, and systemic context. A key unresolved question is how cellular and systemic stress is converted into sustained neuroinflammation. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an innate DNA-sensing hub that translates mislocalized self-DNA - derived from mitochondrial stress and mtDNA leakage, nuclear envelope instability, micronuclei formation, or impaired nucleic-acid disposal - into type I interferon, NF-kB, autophagy-related, and senescence-associated inflammatory programs. Rather than treating cGAS-STING as a universal disease-defining pathway, this review frames it as a context-dependent amplifier that becomes pathogenic when DNA-DAMP burden, defective mitochondrial quality control, neurovascular "leakage", and glial priming converge. We synthesize cell-type-specific evidence in microglia, astrocytes, neurons, and the neurovascular unit; compare mechanistic involvement across Alzheimer's disease, Parkinson's disease dementia and Lewy body disease, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), vascular and acute brain injury, and systemic inflammatory encephalopathies; and organize periphery-to-brain communication axes using an explicit evidence-grading framework. A distinctive contribution of this review is a two-hit model in which systemic inflammatory stressors and barrier dysfunction first lower cognitive resilience, followed by brain-resident mitochondrial/DNA damage programs that lock in complement-linked synaptopathy. We also evaluate pharmacological and lifestyle-based modulation, emphasizing biomarker-enriched trial design, CNS exposure, compartment-specific target engagement, and immune-safety constraints. This framework aims to clarify when, where, and in whom cGAS-STING modulation may preserve synapses and cognition without unacceptable immune trade-offs.}, } @article {pmid42934615, year = {2026}, author = {Bakhshi, F and Ashkezari, AD and Heydari, S}, title = {Design and protocol of a randomized assessor-blinded controlled trial evaluating an educational escape room for individual and team cardiopulmonary resuscitation skills among nursing students.}, journal = {BMC nursing}, volume = {25}, number = {1}, pages = {}, pmid = {42934615}, issn = {1472-6955}, support = {18765//Shahid Sadoughi University of Medical Sciences/ ; }, abstract = {BACKGROUND: High-quality cardiopulmonary resuscitation (CPR) depends not only on technical competence but also on effective communication, role clarity, leadership, and coordinated team performance under pressure. However, conventional CPR instruction may not adequately reproduce the collaborative and time-sensitive demands of real resuscitation. Educational escape rooms (EERs), as simulation-based gamified learning strategies, may provide a more immersive and learner-centered approach to strengthening both cognitive and teamwork-related aspects of CPR training. This study protocol was developed to evaluate the effect of a team-based CPR educational escape room (CPR-EER) integrated into advanced life support (ALS) training for undergraduate nursing students.

METHODS: This study was designed as a two-arm, parallel-group, assessor-blinded randomized controlled trial with a 1:1 allocation ratio. Participants were seventh-semester undergraduate nursing students at Shahid Sadoughi University of Medical Sciences, Yazd, Iran. All participants first received a standardized 8-hour CPR refresher workshop to establish a common educational baseline. The intervention group then participated in a structured CPR-EER delivered in fixed six-member teams in a simulated in-hospital cardiac arrest environment, whereas the control group continued with the routine curriculum during the primary comparison phase and received the intervention after post-test assessment. The primary outcome was team coordination during CPR, assessed using a Team Objective Structured Clinical Examination (TOSCE). Secondary outcomes included role-specific performance, CPR knowledge, and learner satisfaction. Outcomes were assessed at baseline and one month after the intervention. Data analysis was prespecified using a per-protocol framework and distribution-appropriate statistical tests.

DISCUSSION: This protocol provides a methodologically explicit and pedagogically grounded model for evaluating a gamified, team-based CPR-EER training strategy in undergraduate nursing education. By aligning intervention design, educational objectives, and outcome assessment, it may contribute to the development of more immersive, competency-oriented, and reproducible approaches to resuscitation training.

TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT), registered on 16 October 2024, IRCT20240815062770N1. Available at: https://irct.behdasht.gov.ir/ .}, } @article {pmid42934968, year = {2026}, author = {Seyam, M and Thompson, R and Luo, J and Skelly, J and Waheed, W and van den Berg, L and Tandan, R}, title = {Respiratory Phenotypes for Stratifying and Predicting Survival in ALS.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70443}, pmid = {42934968}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Phenotypic heterogeneity in amyotrophic lateral sclerosis (ALS) is an obstacle to stratification and survival prediction and is not sufficiently accounted for in clinical practice or trial design. We aimed to identify respiratory phenotypes to allow stratification and survival prediction in ALS.

METHODS: We retrospectively analyzed 292 ALS patients. Data included demographics, disease-related characteristics, and respiratory measurements (initial predicted forced vital capacity [FVC] and 3-month decline slope). Survival analysis was performed using Kaplan-Meier estimates and Cox regression. We defined four respiratory phenotypes based on dichotomized predicted FVC at the initial visit and its 3-month decline slope: (1) initial high, slow decline (IHSD), (2) initial high, fast decline (IHFD), (3) initial low, slow decline (ILSD), and (4) initial low, fast decline (ILFD).

RESULTS: Patients with an initial predicted FVC above the median had a median survival of 33 months, compared to 15 months for those below the median (p < 0.0001). The highest quartile had an almost threefold survival advantage over the lowest quartile (37 vs. 13 months, p < 0.0001). A 3-month slope at or above the median predicted longer survival (33 vs. 14 months, p < 0.0001). Survival varied across respiratory phenotypes, ranging from 41 months in IHSD to 11 months in ILFD-with all comparisons being significant (p ≤ 0.0012) except for ILSD vs. IHFD.

DISCUSSION: Defining respiratory phenotypes in ALS may allow tailored research within those subgroups, biomarker correlations, more accurate prognostication, and stratification in clinical trials based on phenotype-specific disease progression.}, } @article {pmid42937037, year = {2026}, author = {Calvo, A and Moglia, C and Canosa, A and Manera, U and Zucchi, E and Gianferrari, G and Martinelli, I and Mora, G and Cabras, S and Palumbo, F and Matteoni, E and Pellegrino, G and Minerva, E and Pascariu, D and Callegaro, S and D'Ovidio, F and Vasta, R and Mazzini, L and De Marchi, F and Mandrioli, J and Chiò, A}, title = {Rate and Shape of Functional Decline in Amyotrophic Lateral Sclerosis Identify Clinically Distinct Amyotrophic Lateral Sclerosis Phenotypes.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78394}, pmid = {42937037}, issn = {1531-8249}, abstract = {OBJECTIVE: The ALS Functional Rating Scale-Revised decline rate compresses trajectory shape into a single number, potentially missing distinct phenotypes. We tested whether shape identifies phenotypes that rate does not distinguish, and whether post-hoc analysis recovers a hidden ultrarapid subgroup.

METHODS: From the Piemonte and Valle d'Aosta register (2000-2022), we applied 2 models to 1,686 amyotrophic lateral sclerosis patients: a Gaussian mixture model (GMM; rate axis) and a latent-class mixed model (LCMM) with cubic splines (shape axis). Concordance, prognostic performance, calibration, and clinical utility were assessed at 24 months. External validation used the Emilia-Romagna register.

RESULTS: The rate model identified 4 classes (GMM-Slow 31%, GMM-Inter-slow 46%, GMM-Inter-fast 17%, GMM-Catastrophic 6%; slopes -0.44 to -3.52 points/month); the shape model 4 (LCMM-SlowLinear 46%, LCMM-PlateauFall 23%, LCMM-LateDecline 15%, LCMM-RapidEarly 16%). Concordance was modest (kappa = 0.273). Adding shape to rate changed discrimination negligibly (C-index 0.761 vs 0.755), but separated subgroups within rate classes (within GMM-Catastrophic, 30.1 vs 12.0 months). LCMM-LateDecline combined moderate early decline with reduced respiratory reserve (median forced vital capacity 83.5%) and 22.7-month median survival. The combined model gave the greatest net benefit for the composite outcome. Of 945 patients excluded for sparse sampling, 367 were ultrarapid progressors with shorter survival than LCMM-RapidEarly; findings replicated in the Emilia-Romagna register.

INTERPRETATION: Rate and shape describe partially overlapping aspects of the disease. LCMM-LateDecline, with moderate early decline yet occult respiratory compromise, is clinically challenging, and the 3-visit criterion hides over half of ultrarapid patients. Rate predicts the overall burden of progression, whereas shape predicts the timing of deterioration. ANN NEUROL 2026.}, } @article {pmid42938002, year = {2026}, author = {Huang, Z and Zhang, X and Song, WL and Wang, M and Yu, Z and Jiao, S}, title = {Deciphering Electrocatalytic Sulfur Reduction Reactions in Al-S Batteries via Single-Particle Electrodes.}, journal = {Journal of the American Chemical Society}, volume = {148}, number = {37}, pages = {39638-39646}, doi = {10.1021/jacs.6c08648}, pmid = {42938002}, issn = {1520-5126}, support = {52304318//National Natural Science Foundation of China/ ; 2023M740225//China Postdoctoral Science Foundation/ ; BX20230038//National Postdoctoral Program for Innovative Talents/ ; 24RCKA004//Science and Technology Program of Gansu Province/ ; }, abstract = {The kinetically sluggish sulfur reduction reaction (SRR) governs the performance of ultrahigh-capacity aluminum-sulfur batteries, while deciphering the SRR process is critical for rationally electrocatalyzing reaction kinetics to unlock their full energy output. To overcome this challenge, a single-particle electrochemical methodology has been developed to investigate the SRR process on a cobalt/nickel and nitrogen codoped graphene (CoNi-NG) electrocatalyst. The SRR process involves a major route of S8 → Al2S8 → Al2S4 → Al2S3 with a minor route of Al2S8 → Al2S6 → Al2S4, where Al2S4 conversion governs the overall SRR kinetics and Al2S4 contributes the most to the shuttle effect owing to its fastest generation and slowest consumption. The CoNi-NG raises the Co d-orbital energy level via Ni-to-Co electron transfer to accelerate cleavage of polysulfides, which doubles the exchange current density of rate-determining Al2S4 conversion. Consequently, the sulfur composite (S@CoNi-NG) electrode delivers a specific capacity of ∼1480 mAh gsulfur-1. Such a single-particle methodology for quantitatively deciphering electrocatalytic SRRs offers mechanistic guidance for rationally enhancing battery performance.}, } @article {pmid42939346, year = {2026}, author = {Alfaro-Rodríguez, A and Cortes-Altamirano, JL and Reyes-Long, S and Bonilla-Jaime, H and Avila-Camacho, FJ and Moreno-Villalba, LM and Herrera-López, ME and González-Maciel, A and Pérez-Guille, B and Soriano-Rosales, RE and Calderon-Guzman, D and Juaréz-Olguín, H}, title = {Glial Contributions to Pain in Neurodegenerative Disease Models: A Systematic Review of Microglial and Astrocytic Evidence.}, journal = {Brain sciences}, volume = {16}, number = {10}, pages = {}, pmid = {42939346}, issn = {2076-3425}, abstract = {Background/Objectives: Pain is a common and disabling non-motor manifestation of neurodegenerative disorders, but the contribution of glial cells to nociceptive processing remains incompletely understood. This systematic review evaluated evidence from preclinical models of neurodegenerative diseases linking microglial and astrocytic activity to pain. Methods: The protocol was prospectively registered in PROSPERO (CRD420251084310), and reporting followed PRISMA 2020. We conducted the original electronic search in PubMed/MEDLINE; during major revision, we conducted supplementary searches in Scopus and Web of Science Core Collection. Across the three sources, we identified 2248 records. After hierarchical deduplication by DOI, PMID, and normalized title, 1567 unique records were screened. Eligible in vivo studies assessed microglial and/or astrocytic alterations together with pain- or nociception-related outcomes. Risk of bias was independently evaluated by two investigators using the SYRCLE tool, and findings were synthesized qualitatively. Results: Twenty-six studies met the eligibility criteria: sixteen examined multiple sclerosis/experimental autoimmune encephalomyelitis (61.5%), seven Parkinson's disease (26.9%), two Alzheimer's disease-related models (7.7%), and one Huntington's disease model (3.8%); no eligible amyotrophic lateral sclerosis study was identified. Pain-related alterations involved inflammatory, neuroimmune, synaptic, and astrocyte-associated pathways, but the evidence was strongly model-dependent. Findings based on individual studies, including early astrocytic contributions in experimental autoimmune encephalomyelitis and altered inflammatory allodynia in an Alzheimer's disease model, are interpreted as study-specific observations requiring replication. Conclusions: The available evidence supports context-dependent associations between glial responses and nociceptive processing; however, marker specificity, EAE predominance, sex and age imbalance, and incomplete reporting of bias control procedures limit causal and cross-disease generalization.}, } @article {pmid42939372, year = {2026}, author = {Swindell, WR and Ali, A and Iacoangeli, A and Bhai, S}, title = {Meta-Analysis of ALS Post-Mortem Cerebral Cortex Transcriptome Studies Identifies Robust Shifts in Gene Expression Despite Significant Between-Study Heterogeneity.}, journal = {Brain sciences}, volume = {16}, number = {10}, pages = {}, pmid = {42939372}, issn = {2076-3425}, abstract = {Background: ALS is characterized by motor neuron failure with potential neurocognitive comorbidity. Cortical neurons, and their support cells, exhibit pathologic features, some of which have been identified in post-mortem transcriptome studies of the cortex from ALS patients and control subjects. These studies, however, have utilized varying technologies with few attempts to reconcile findings. Methods: This study used meta-analysis to evaluate differential gene expression (ALS vs. control) from 16 prior transcriptome studies utilizing multiple technologies (microarray, bulk RNA-seq or snRNA-seq). Normalization with GC content correction was used to mitigate downstream biases impacting differential expression. Results: Approximately one-third of protein-coding genes (5930 of 16,579) exhibited significant between-study effect size heterogeneity (FDR < 0.05), which was frequently associated with variation in average post-mortem interval. Nonetheless, we identified 269 and 273 differentially expressed genes (DEGs) with relatively consistent increased or decreased expression in the ALS cortex, respectively (FDR < 0.05 with SMD ≥ 0.20 or SMD ≤ -0.20). ALS-increased DEGs were associated with transcription (RNA polymerase), cell signaling (TGF-beta, PI3K), interneurons, microglia, endothelial cells, and deep laminar layers (L5, L6). ALS-decreased DEGs were associated with transcription (RNA polymerase), glial cells (astrocytes, oligodendrocytes) and the L1 layer. There was significant overlap between DEGs from the ALS cortex and those previously identified from ALS spinal cord and blood. Conclusions: These findings highlight signaling pathways, cell types and cortical layers associated with robust changes in ALS cortex gene expression. Our results illustrate the importance of meta-analysis as a tool for understanding between-study heterogeneity and identifying repeatable findings across technologies.}, } @article {pmid42939724, year = {2026}, author = {Hutchison, LL and Parkes, MM and Pioro, EP}, title = {Serotonergic Dysfunction and the Interacting Role of TAR DNA-Binding Protein 43 in the Progression of Amyotrophic Lateral Sclerosis: A Scoping Review.}, journal = {Biomolecules}, volume = {16}, number = {10}, pages = {}, pmid = {42939724}, issn = {2218-273X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology ; *DNA-Binding Proteins/metabolism ; *Serotonin/metabolism ; Animals ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons and widespread neural dysfunction. Loss of serotonin (5-HT) signaling and TAR DNA-binding protein 43 (TDP-43) dysfunction have both been identified as contributing factors to disease progression, although their relationship has yet to be fully defined. The objective of this review was to assess whether any mechanistic links exist between serotonergic dysfunction and TDP-43 proteinopathy in ALS. A scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Databases were queried for the peer-reviewed literature concerning ALS pathophysiology, 5-HT, and TDP-43 (1946 to January 2026). Articles were screened and data independently extracted by two reviewers, which were subsequently synthesized qualitatively (n = 14). The current literature suggests that serotonergic dysfunction can be identified early in ALS pathology, indicated by decreased 5-HT concentration, degeneration of raphe projections, and changes in receptor activity. TDP-43 proteinopathy is a defining characteristic of ALS progression, characterized by cytoplasmic mislocalization and aggregation of TDP-43. Additionally, studies have identified bidirectional links between these dysfunctions: TDP-43 impairs serotonergic transmission, and 5-HT deficiency may drive pathological TDP-43 aggregation. Many mechanisms affected by both serotonergic and TDP-43 dysfunction are associated with disease progression including excitotoxicity, metabolic disturbances, and network hyperexcitability. Despite this, there is a lack of direct experimental evidence elucidating connections between these pathologies. Serotonergic dysfunction and TDP-43 proteinopathy may be linked by shared mechanisms in ALS, though specific causality has not been identified. Further research should aim to clarify the connection between these processes and discover therapeutic targets.}, } @article {pmid42939744, year = {2026}, author = {Mohamed, YK and Yan, LJ}, title = {Edaravone for Potential Mitigation of Oxidative Stress and Inflammation in Kidney Disease.}, journal = {Biomolecules}, volume = {16}, number = {10}, pages = {}, pmid = {42939744}, issn = {2218-273X}, mesh = {Humans ; *Oxidative Stress/drug effects ; *Edaravone/therapeutic use/pharmacology ; Animals ; *Inflammation/drug therapy/metabolism ; *Kidney Diseases/drug therapy/metabolism/pathology ; Anti-Inflammatory Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Free Radical Scavengers/therapeutic use/pharmacology ; }, abstract = {Edaravone (EDA) is a synthetic free-radical scavenger FDA-approved for amyotrophic lateral sclerosis (ALS) treatment in the United States and is used clinically for treatment of acute ischemic stroke in Japan and other countries. While its antioxidant activity has been the primary focus of investigation in the mitigation of oxidative-stress-related injury, EDA exhibits anti-inflammatory, anti-fibrotic, anti-apoptotic, and anti-necrotic effects in animal models. These properties make it a potentially attractive therapeutic agent for kidney disease, where oxidative stress and inflammation contribute to renal cell injury, mitochondrial dysfunction, and progression of disease. In this review, we cover the underlying mechanisms of oxidative stress and inflammation in renal injury, and pharmacological and free-radical-scavenging mechanisms of EDA. Preclinical evidence in several kidney diseases, including ischemic/reperfusion injury, nephrotoxin-induced disease, and diabetic kidney disease, has been used to assess EDA for efficacy. In addition, we explore the modulatory roles of key signaling pathways, such as Nrf2 and NF-κB, in protective effects of EDA against oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, necrosis, and fibrosis. Finally, we highlight the potential of EDA as a therapy in future clinical applications for various kidney diseases such as acute kidney injury (AKI) and chronic kidney disease (CKD). It should also be emphasized that as EDA's renal efficacy evidence described in this review is largely limited to animal studies, robust human clinical data are lacking. Therefore, additional clinical studies are still needed to fully elucidate the efficacy, safety, and benefits of EDA for prevention and treatment of human kidney disease.}, } @article {pmid42940139, year = {2026}, author = {Carata, E and Mariano, S and Tenuzzo, BA and Panzarini, E}, title = {Advancing the Translational Pipeline: From In Vivo and In Vitro 2D Models to Next-Generation Cell Culture Models for Amyotrophic Lateral Sclerosis Modelling and Drug Discovery.}, journal = {Biomedicines}, volume = {14}, number = {10}, pages = {}, pmid = {42940139}, issn = {2227-9059}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is still a global health challenge, as there is no effective treatment due to the inadequacy of conventional experimental platforms for comprehending pathogenic mechanisms and developing therapy. Objectives: This review details the recent progress and clinical utility of next-generation iPSC-derived 3D in vitro systems integrated with microfluidics, CRISPR-Cas9 gene editing, multi-omics readouts, and AI-based machine learning, which are emerging as transformative platforms for recapitulating key ALS pathological hallmarks. Methods: A literature search was performed using PubMed and Web of Science, including only English-language publications. All the published papers collected covered the period from January 2015 to June 2026. Results: Human induced pluripotent stem cell (iPSC) cerebral organoids, assembloids, and organ-on-a-chip technologies are revolutionizing research into ALS by providing a way to model the complex spatial organization, cellular heterogeneity, and neural network dynamics of the human brain. Moreover, recent bioengineering advancements enable the inclusion of functional neurovascular units, the integration of resident immune cells (microglia), and the use of 3D bioprinting to accelerate the functional maturation of age-related phenotypes. CRISPR-Cas9 genome editing, OMICS, and machine learning improve tools for studying ALS and identifying therapeutic targets. Conclusions: Novel cell culture models may bridge the gap between preclinical animal models and human clinical trials and reduce the duration and costs of translation. Future work is likely to integrate bioprinting with organ-on-chip microfluidics, CRISPR-based genetic editing, and multi-omics readouts to build increasingly faithful, patient-specific ALS models for both basic research and precision therapeutics.}, } @article {pmid42941452, year = {2026}, author = {Gołąb-Janowska, M and Wełnicka-Wesołowska, A and Baumert, B and Machowska-Sempruch, K and Meller, A and Sobuś, A and Paczkowska, E and Kotlęga, D and Nowacki, P and Machaliński, B}, title = {Functional Status, Quality of Life and Survival After Repeated Intrathecal Administration of Autologous Lineage-Negative Cells in Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical medicine}, volume = {15}, number = {20}, pages = {}, pmid = {42941452}, issn = {2077-0383}, support = {STRATEGMED1/234261/2/NCBR/2014//National Centre for Research and Development/ ; }, abstract = {Background/Objectives: Adjuvant cell-based strategies are still being explored in amyotrophic lateral sclerosis (ALS). Materials and Methods: In this open-label, single-arm study of intrathecal autologous bone marrow-derived lineage-negative (LIN[-]) cells, we report functional status, quality of life, and survival after three administrations at six-week intervals. A total of 45 patients with sporadic ALS were qualified: 42 received all three administrations and 23 completed the 24-week assessment schedule, while 19 stopped attending because of deterioration. Results: In the 23 completers, Norris scale scores were stable until week 13 and then declined (p = 0.00004), and the Amyotrophic Lateral Sclerosis Assessment Questionnaire 40 (ALSAQ-40) followed the same pattern (p = 0.0019), whereas the ALS Functional Rating Scale-Revised (ALSFRS-R) declined at a constant 0.5 points per month. In all 42 treated patients the Norris score fell during treatment (0.95 points per month; 95% CI 0.52-1.38), so the plateau was confined to completers, who had milder baseline disease. Dose-related differences in quality of life were confounded by baseline imbalance; survival analyses were exploratory. Cell number did not correlate with cerebrospinal fluid brain-derived neurotrophic factor (BDNF) after the third administration in the 39 patients with paired samples (ρ = 0.14). No adverse event was recorded in 126 procedures, but harms were not graded systematically. Conclusions: These exploratory findings do not demonstrate efficacy; a sham-controlled trial with blinded raters is required.}, } @article {pmid42941856, year = {2026}, author = {Gómez-Pérez, CA and Ramírez-García, MÁ and Yescas-Gómez, P}, title = {The Role of SOD1 and Oxidative Stress in Amyotrophic Lateral Sclerosis: An Overview.}, journal = {International journal of molecular sciences}, volume = {27}, number = {20}, pages = {}, pmid = {42941856}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; *Oxidative Stress ; Animals ; Reactive Oxygen Species/metabolism ; Mutation ; Motor Neurons/metabolism/pathology ; Signal Transduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder that selectively affects motor neurons. The median survival time after diagnosis is 2 to 5 years. Oxidative stress (OS), driven mainly by reactive oxygen species (ROS), plays a central role in motor neuron (MN) degeneration. In this narrative review, we analyse the pathogenic role of SOD1 variants and their contribution to OS in ALS. SOD1 mutations alter the Cu/Zn superoxide dismutase enzyme, thereby promoting oxidative damage and triggering neuroinflammatory cascades via the MAPK, NF-κB and Nrf2/ARE signalling pathways. We also discuss emerging proteomic and machine-learning biomarkers, as well as the current therapeutic landscape. Riluzole and edaravone are approved treatments, while AMX0035 was approved in 2022 but withdrawn in 2024. Masitinib and EPI-589 remain investigational. In the realm of genetic therapies, the antisense oligonucleotide tofersen received accelerated FDA approval in 2023 for SOD1-ALS, primarily due to its ability to reduce plasma neurofilament light chain levels. However, the clinical benefit remains modest. RNA interference has reached human trials, while CRISPR/Cas9 remains in the preclinical stage. Both approaches have shown promising results in experimental models. Further research into ALS pathogenesis is needed to develop treatments that integrate antioxidant, anti-inflammatory, and gene-editing strategies.}, } @article {pmid42941925, year = {2026}, author = {Gómez-Pérez, CA and Ramírez-García, MÁ and Ruiz-Sánchez, E and Romero-Hidalgo, S and Ochoa-Morales, A and Jara-Prado, A and Méndez-Armenta, M and Nava-Ruiz, C and Yescas-Gómez, P}, title = {Identification of SOD1 Gene Variants in Mexican Patients with Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {20}, pages = {}, pmid = {42941925}, issn = {1422-0067}, support = {262111//Secretariat of Science, Humanities, Technology, and Innovation (SECIHTI)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *Superoxide Dismutase-1/genetics ; Mexico/epidemiology ; Female ; Mutation ; Male ; Middle Aged ; Aged ; Gene Frequency ; Genetic Variation ; Adult ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressing, fatal neurodegenerative disorder that selectively affects motor neurons. Clinical manifestations include progressive muscle weakness, amyotrophy, fasciculations, dysphagia, and fatal respiratory failure. The median survival after symptom onset is typically 2 to 5 years. Despite its severity, the epidemiological profile and genetic landscape of ALS in Latin American populations, particularly in Mexico, remain unclear. In this study, we evaluated the mutational spectrum of the SOD1 gene in a Mexican cohort of 156 ALS patients. Using high-resolution melting (HRM) analysis and Sanger sequencing, we identified 22 SOD1 variants in 42 of 156 patients (overall variant carrier frequency, 26.92%). Pathogenic or likely pathogenic (P/LP) variants were found in 21 patients (13.5%). Notably, 5 of the 22 variants were novel, expanding the spectrum of SOD1 variants. The variant carrier frequency identified in this study is higher than that reported for European populations but similar to frequencies observed in Asian populations. Our results highlight the distinct genetic heterogeneity of ALS in Mexico and demonstrate that HRM is a rapid and effective method for identifying SOD1 gene variants.}, } @article {pmid42942089, year = {2026}, author = {Lv, X and Huang, M and Long, W and Li, X and Hu, Z and Feng, Y and Du, J and Long, Q and Chen, Y and Shi, M and Qin, D}, title = {Epigenetic Mechanisms in Neurodegenerative Diseases: From Genetic Regulation to Therapeutic Potential.}, journal = {International journal of molecular sciences}, volume = {27}, number = {20}, pages = {}, pmid = {42942089}, issn = {1422-0067}, support = {YPKLS2025-029//Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Dis-ease in Prevention and Treatment/ ; KUST-KH2022017Y//Kunming University of Science and Technology & the First People's Hospital of Yunnan Province Joint Special Project on Medical Research/ ; 202401AY070001-135//Yunnan Provincial Department of Science and Technology-Kunming Medical University Joint Special Project/ ; }, mesh = {Humans ; *Epigenesis, Genetic ; *Neurodegenerative Diseases/genetics/therapy/metabolism ; Animals ; DNA Methylation ; Gene Expression Regulation ; RNA Methylation ; Biomarkers/metabolism ; Histones/metabolism ; Epitranscriptome ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are multifactorial disorders in which genetic susceptibility alone cannot account for sporadic onset, clinical diversity, or age-dependent progression. Epigenetic mechanisms-DNA methylation, histone modifications, non-coding RNAs, and m6A RNA methylation-bridge environmental and intracellular cues to stable gene expression changes. Emerging evidence associates epigenetic dysregulation with amyloid-β/tau pathology in AD, α-synuclein pathology in PD, and TDP-43/C9orf72-associated toxicity in ALS, while functional studies suggest that selected epigenetic alterations may contribute to these processes. In this narrative review, we distinguish associative, functional, and mechanistic evidence using claim-specific criteria based on experimental perturbation, direct molecular assessment, and pathway-dependence or rescue testing, while considering the study system. We further evaluate the translational promise of epigenetic biomarkers in liquid biopsies, while emphasizing the major barriers that separate bench findings from bedside application, including poor target specificity, limited blood-brain barrier penetration, and the absence of biomarker-guided patient stratification. By integrating pathological mechanisms, biomarker development, and therapeutic strategies, this review argues that future epigenetic research in neurodegeneration must prioritize causal validation, CNS-penetrant drug development, and prospective trials integrating epigenetic profiling to achieve meaningful clinical impact.}, } @article {pmid42927744, year = {2026}, author = {Mishchenko, TA and Grechukhina, AA and Kulikov, SS and Olajide, OJ and Mitroshina, EV and Krysko, DV and Vedunova, MV}, title = {When the Brain Signals Danger: Roles of Calreticulin and HMGB1 in Cell Death Mechanisms in Neurooncology and Neurodegeneration.}, journal = {Biochemistry. Biokhimiia}, volume = {91}, number = {10}, pages = {1822-1841}, doi = {10.1134/S0006297926601565}, pmid = {42927744}, issn = {1608-3040}, mesh = {Humans ; *HMGB1 Protein/metabolism ; *Calreticulin/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; Cell Death ; Signal Transduction ; Alarmins/metabolism ; }, abstract = {Contrary to the classical paradigm of brain immune privilege, damage-associated molecular patterns (DAMPs) act as key mediators in the dialogue between CNS cells and the immune system, determining pathways of immune response development. This review examines the role of key DAMPs - calreticulin (CRT) and high-mobility group box 1 protein (HMGB1) - in the functioning of CNS under normal conditions and during the development of neuropathologies, particularly oncological and neurodegenerative processes. Under normal conditions, CRT and HMGB1 ensure functioning of the brain, acting as necessary effectors of neurogenesis and homeostatic plasticity. In neurooncology, exposure of CRT on the surface of dying cells and release of HMGB1 serve as powerful adjuvant signals for antigen-presenting cells, inducing immunogenic cell death (ICD). Particular attention is given to the mechanisms of passive HMGB1 release during various types of regulated cell death (apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis), as well as to the role of redox modifications of the protein, which determine its pro-inflammatory, immunogenic, or tolerogenic properties. In neurodegeneration (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), excessive DAMP release exacerbates the development of chronic neuroinflammation, disrupts integrity of the blood-brain barrier (BBB), and forms a vicious cycle of pathological changes. Detection of CRT and HMGB1 in biological fluids or brain tissues has important prognostic potential, and regulation of their signaling pathways opens promising approaches for overcoming tumor resistance or inhibiting progressive neurodegenerative changes in the brain.}, } @article {pmid42927931, year = {2026}, author = {Luan, J and Yun, Y and Jiao, Y and Wang, Y and Ma, M and Shan, D and Wang, H and Ji, X and Tang, Y and Li, J and Zhan, Z and Sun, X and Gao, N and Lin, P and Yan, C and Sun, X and Yu, D and Liu, S and Liu, F}, title = {Cortical Motor Hierarchy Disruption Is Associated With Functional Status in Early Amyotrophic Lateral Sclerosis.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {17}, number = {5}, pages = {}, doi = {10.1002/jcsm.70411}, pmid = {42927931}, issn = {2190-6009}, support = {2025CXPT133//the Key R&D Program of Shandong Province/ ; 2022ZLGX03//the Key R&D Program of Shandong Province/ ; ZR2023MH180//the Natural Science Foundation of Shandong Province/ ; 20201125//the Qilu Young Scholarship of Shandong University/ ; ZR2023ZD14//the Shandong Provincial Natural Science Foundation Major Basic Research Project/ ; 2025M782111//the China Postdoctoral Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Female ; Male ; Middle Aged ; Magnetic Resonance Imaging ; *Motor Cortex/physiopathology/pathology ; Aged ; Cross-Sectional Studies ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterised by progressive muscle wasting and functional decline. Although cortical motor network disruption is a hallmark of ALS, the large-scale functional hierarchy alterations and their underlying molecular mechanisms in the early stage of the disease (ALS-ES) remain poorly understood. We aimed to characterise cortical gradient changes in early-stage ALS and to examine their neurochemical and transcriptomic correlates, as well as their cross-sectional associations with clinical functional status.

METHODS: We recruited 97 patients with early-stage ALS, all at King's stage 1 and 94 healthy controls with comparable age and sex distributions. The ALS-ES group included 65 women and had a median ALSFRS-R score of 40 (IQR, 37-44). Resting-state fMRI was used to construct the principal functional gradient. We integrated neurochemical maps of 19 neurotransmitter receptors/transporters, and transcriptomic data from the Allen Human Brain Atlas. Partial least squares (PLS) regression and cell-type enrichment analysis were employed to identify molecular correlates of gradient alterations.

RESULTS: Compared with HCs, ALS-ES patients exhibited a significant spatial contraction of the principal gradient. Specifically, gradient values significantly increased in the somatomotor network (SMN; t = 3.670, pFDR = 0.001) and decreased in the default mode network (DMN; t = -4.124, pFDR < 0.001). Within the ALS-ES group, higher SMN gradient values were associated with lower ALSFRS-R scores, whereas higher DMN gradient values were associated with higher ALSFRS-R scores. These macroscale alterations showed spatial correspondence with normative 5-HT4 receptor and norepinephrine transporter maps. PLS analysis identified a primary gene set (PLS1+) enriched in oligodendrocytes and mitochondrial functions (pFDR < 0.05), whereas the negative set (PLS1-) was associated with astrocytes, GABAergic neurons and RNA splicing pathways. Chromosome-level analysis revealed significant enrichment of PLS1- genes on chromosomes 5 and 16 (p < 0.05).

CONCLUSIONS: Early-stage ALS is characterised by a collapsed cortical functional hierarchy centred on the motor-somatosensory axis. These alterations were spatially associated with normative neurochemical maps and distinct transcriptomic annotations related to energy metabolism and RNA processing. These findings identify cross-sectional cortical functional-hierarchy alterations associated with functional status in early-stage ALS and provide a multi-scale framework for investigating their neurochemical and transcriptomic correlates.}, } @article {pmid42927993, year = {2026}, author = {Clarysse, M and Korsos, S and Cuypers, C and Raes, E and Vlaminck, L}, title = {Chirurgische behandeling van unilateraal geïmpacteerde maaltanden in de bovenkaak bij een paard.}, journal = {Journal of veterinary dentistry}, volume = {}, number = {}, pages = {8987564261493278}, doi = {10.1177/08987564261493278}, pmid = {42927993}, issn = {2470-4083}, abstract = {Impactie van permanente maaltanden bij het paard wordt voornamelijk gerapporteerd ter hoogte van de mandibula, terwijl betrokkenheid van de maxilla zeldzaam is. Dit rapport beschrijft een ongewone presentatie van congenitale impactie van drie opeenvolgende maxillaire molaren bij een 4-jarige merrie. Computertomografie toonde complexe ruimtelijke verhoudingen tussen de geïmpacteerde elementen, de sinusbodem en de aangrenzende structuren, deze werden op conventionele radiografie niet volledig onderkend en waren essentieel voor de chirurgische planning. Chirurgische extractie via een botflap van de sinus maxillaris liet gecontroleerde sectionering en aansluitende verwijdering van alle aangetaste elementen toe. Histopathologisch onderzoek van botstalen uit de sinusbodem toonde reactieve osteosclerose, wat veroorzaakt kan worden door chronische druk en/of sinusitis. Als postoperatieve complicaties ontstonden een oromaxillaire communicatie en een secundaire sinusitis na verlies van de polysiloxaanplug; deze werden behandeld door herhaardelijk debrideren en sinoscopische lavage. Op lange termijn resulteerde de behandeling in een bevredigend functioneel herstel en behoud van oraal comfort, niettegenstaande het verlies van meerdere maaltanden in de bovenkaak.}, } @article {pmid42929812, year = {2026}, author = {Zhang, N and Freeman, DD and Polster, BM}, title = {BAX, VDAC, Gasdermin, and Permeability Transition Pores in Inflammatory Mitochondrial DNA Release: Is This the "Hole" Story?.}, journal = {Cells}, volume = {15}, number = {20}, pages = {}, doi = {10.3390/cells15201839}, pmid = {42929812}, issn = {2073-4409}, support = {R01NS112212/NS/NINDS NIH HHS/United States ; R21NS133527/NS/NINDS NIH HHS/United States ; R21 NS133527 (B.M.P.)./NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *DNA, Mitochondrial/metabolism ; Animals ; *bcl-2-Associated X Protein/metabolism ; *Mitochondrial Permeability Transition Pore/metabolism ; *Voltage-Dependent Anion Channels/metabolism ; Mitochondria/metabolism ; *Inflammation/metabolism ; }, abstract = {Disease-modifying neuroprotective therapies for traumatic brain injury (TBI), stroke, and age-related neurodegenerative disorders have proven elusive. Interest in mitochondrial outer membrane permeabilization mechanisms as a drug target evolved from the 1990s discovery of BAX/BAK-mediated mitochondrial cytochrome c release as an apoptotic cell death trigger. However, enthusiasm waned as subsequent findings revealed that apoptosis is not the dominant cell death mechanism in the mature brain. The more recent discovery of mitochondrial DNA (mtDNA) as an inflammatory trigger produced renewed interest in mitochondrial permeability pathways. In particular, the DNA-sensing molecule cGAS and its downstream effector STING were implicated in the pathogenesis of several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and TBI. Nevertheless, these findings raised a puzzling question: how does mtDNA, which resides in the mitochondrial matrix surrounded by double membranes, escape to initiate inflammatory responses without triggering cytochrome c-dependent cell death? Here, we review the many proposed mechanisms for mtDNA release, including several that do not require mitochondrial membrane holes, and discuss advances toward pharmacological targeting of these pathways. Identification of the specific mtDNA efflux pathway(s) proximal to maladaptive neuroinflammatory responses may yield new treatment strategies for AD, TBI, and other neurological diseases.}, } @article {pmid42929861, year = {2026}, author = {Gong, X and Wei, H and Shen, L and Wang, Q and Wu, J and Wang, W and Xu, T}, title = {Single-Dose Intrathecal rAAV2-Retro Delivering Anti-hSOD1 miRNA Confers Robust Neuroprotection in Adult ALS Mice.}, journal = {Cells}, volume = {15}, number = {20}, pages = {}, doi = {10.3390/cells15201890}, pmid = {42929861}, issn = {2073-4409}, support = {22ZR1414500//Natural Science Foundation of Shanghai/ ; 21ZR1407700//Natural Science Foundation of Shanghai/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology ; *MicroRNAs/genetics/metabolism/administration & dosage ; *Superoxide Dismutase-1/genetics/metabolism ; Injections, Spinal ; *Dependovirus/genetics/metabolism ; Mice ; Humans ; Insulin-Like Growth Factor I/metabolism ; *Neuroprotection ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Gene Silencing ; Genetic Vectors ; Spinal Cord/metabolism/pathology ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) kills within a few years of onset, and the drugs licensed for treatment change that course only marginally. Silencing SOD1 has become a credible treatment route, but two gaps hold this approach back: an efficient vector platform for spinal cord transduction with limited peripheral transduction and evidence on whether adding neurotrophic support to gene silencing has any effect. We built an rAAV2-retro platform for intrathecal delivery. One intrathecal dose of an eGFP-expressing vector transduced all spinal cord segments and several brain regions, with a clear preference for spinal motor neurons and low expression in the liver and heart. Side by side in adult mice, we then used this platform to compare miRNA-mediated silencing of human SOD1, overexpression of IGF1, and the two together in SOD1[G93A] animals. A single injection of rAAV2-retro carrying an anti-hSOD1 miRNA extended median survival by 25 days, improved motor performance, protected neuromuscular junctions, spared α-motor neurons, and damped gliosis and apoptosis. IGF1 on its own also lengthened survival and limited neuronal loss, but it left motor performance unchanged. The benefit of IGF1 over miRNA alone was observed on most endpoints under the conditions tested; a modest, nominally significant improvement in hindlimb clasping was observed, which should be interpreted as exploratory given the number of comparisons performed. Silencing of hSOD1 therefore accounts for most of the benefit, and no statistically detectable additional benefit was observed for IGF1 on top of hSOD1 silencing under the conditions tested. A single intrathecal dose of rAAV2-retro-miRNA is thus an effective gene silencing approach in the SOD1[G93A] mouse model, with limited peripheral transduction in the liver and heart observed in C57BL/6J mice. However, these data also show the difficulty of achieving additional benefit by adding IGF1 under the conditions tested.}, } @article {pmid42930312, year = {2026}, author = {Nguyen, TT and Wang, L and Dao, TK}, title = {Biomimetic Coverage Optimization in WSNs via an Enhanced Spider-Wasp Optimizer with Adaptive Learning and Dual-Median-Point Guidance.}, journal = {Biomimetics (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, doi = {10.3390/biomimetics11100760}, pmid = {42930312}, issn = {2313-7673}, support = {FITGR20250//Fuzhou Institute of Technology/ ; }, abstract = {Coverage optimization in wireless sensor networks (WSNs) is a non-convex deployment problem on which population-based optimizers often converge prematurely and lose diversity. This paper proposes the Enhanced Spider-Wasp Optimizer (ESWO), an extension of the Spider-Wasp Optimizer (SWO) conceptually inspired by the foraging and nesting behavior of Pompilidae wasps. ESWO integrates (i) an Adaptive Learning Strategy (ALS) that uses four types of positional gaps among individuals to sustain diversity, (ii) a dual-median-point guidance (DMPG) mechanism that steers exploitation towards the midpoint of two elite solutions, and (iii) a position-update rule with nest-overlap avoidance. Coverage is evaluated on a discretized target grid with a Euclidean binary-disk sensing model and an energy-penalized fitness. In four scenarios (25-65 nodes; 50 × 50 to 165 × 165 m[2]), ESWO was compared with seven algorithms, including SWO. It achieved coverage rates of 81%, 88%, 92% and 85%, the highest in every scenario (tied with MGWO at 81% in the smallest). In the 100 × 100 m[2] scenario it reached 85% coverage after 523 iterations, against 601-698 for the competitors, although final convergence iteration counts were not uniformly the lowest. Over 15 runs, ESWO obtained a mean coverage of 90.2% (SD 1.2), a 95% success rate and the lowest estimated energy consumption (175.3 J).}, } @article {pmid42931148, year = {2026}, author = {Giecko, M and Bossowski, F and Bossowska, M and Moniuszko-Malinowska, A and Chorąży, M and Sarnowska, M and Grygorczuk, S}, title = {Amyotrophic Lateral Sclerosis in a Patient Treated for Neurosyphilis: A Case Report.}, journal = {Neurology international}, volume = {18}, number = {10}, pages = {}, doi = {10.3390/neurolint18100193}, pmid = {42931148}, issn = {2035-8385}, abstract = {BACKGROUND/OBJECTIVES: Neurosyphilis is a recognized treatable mimic of amyotrophic lateral sclerosis (ALS); syphilis serology is commonly included in the work-up of suspected motor neuron disease. We describe the converse situation: neurosyphilis that delayed recognition of coexisting ALS.

METHODS: A 46-year-old man with type 2 diabetes mellitus and degenerative spine disease presented with a six-month history of progressive limb weakness and gait disturbance. Serum syphilis serology was reactive (Venereal Disease Research Laboratory [VDRL] titer 1:32; Treponema pallidum hemagglutination assay [TPHA] titer 1:20,480), and cerebrospinal fluid (CSF) showed a mild mononuclear pleocytosis with raised protein and immunoglobulin G. Neurosyphilis was diagnosed and treated with a 14-day course of intravenous penicillin. The subsequent course was followed with neuroimaging and electrodiagnostic studies.

RESULTS: Despite treatment and resolution of the CSF pleocytosis, weakness and wasting progressed and bulbar involvement developed. Examination showed combined upper and lower motor neuron signs, electromyography showed an anterior horn cell pattern with widespread fasciculations, and cervical spine imaging showed degenerative changes without spinal cord compression. ALS was diagnosed at a later neurological admission.

CONCLUSIONS: Identifying a treatable mimic does not close the diagnostic process. Combined upper and lower motor neuron signs that continue to progress despite adequate treatment of neurosyphilis should prompt early electrodiagnostic evaluation for ALS, even though the relative contribution of each condition may remain uncertain.}, } @article {pmid42907117, year = {2026}, author = {Blinker, EJ and Amoh, GKA and Ankamah, S and Agyemang, C and Omech, B and Beune, E and Wekesah, FM and Azumah, M and Munneke, W}, title = {Implementation strategies, outcomes and determinants of integrated care for cardiometabolic conditions and mental, neurological and substance use disorders: protocol for a mixed-methods systematic review.}, journal = {BMJ open}, volume = {16}, number = {10}, pages = {e125828}, pmid = {42907117}, issn = {2044-6055}, abstract = {ΙNTRODUCTION: The co-occurrence of cardiometabolic diseases and mental, neurological and substance use disorders health conditions represents a growing global health burden, particularly in low- and middle-income countries. Although integrated, people-centred multimorbidity care is increasingly recognised as essential across settings, evidence remained limited on how these models are operationalised in routine practice and which implementation strategies are most effective to support their delivery. This protocol outlines the methods for a systematic review aiming to identify implementation strategies used to integrate care for cardiometabolic conditions and mental, neurological and substance use (MNS) disorders, examine associated implementation outcomes and explore contextual determinants influencing implementation across settings.

METHODS AND ANALYSIS: This protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines. A comprehensive search will be conducted in PubMed, CINAHL, APA PsycINFO, Scopus and Web of Science and relevant grey literature sources. Eligible studies include randomised controlled trials, quasi-experimental studies, mixed-methods studies, qualitative studies and implementation evaluations reporting on integrated care models addressing both cardiometabolic conditions and MNS disorders. To be included in this Systematic Review, studies must detail strategies or models integrating care for at least one cardiometabolic condition and one MNS disorder and provide data on implementation outcomes or contextual determinants. Title/abstract screening, full-text screening, data extraction and data synthesis will be conducted independently by at least two researchers following pilot testing. A formal risk of bias assessment will be performed using the Mixed Methods Appraisal Tool. A mixed-method, framework-based synthesis will be undertaken. Implementation strategies will be coded using the Expert Recommendations for Implementing Change taxonomy, implementation outcomes using Proctor et al’s taxonomy, and contextual determinants using the Consolidated Framework for Implementation Research. Quantitative data will be summarised descriptively using frequencies, proportions and summary tables, with findings stratified by country income level, setting and type of integrated care model where possible. Qualitative data will be analysed using inductive coding and deductive mapping to implementation science frameworks.

ETHICS AND DISSEMINATION: Ethical approval is not required as no primary data will be collected. The findings of this study will be disseminated through peer-reviewed publications, conference presentations, and stakeholders’ engagement in the field.

REGISTRATION DETAILS: The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 6 April 2026 (registration number CRD420261321825).}, } @article {pmid42919527, year = {2026}, author = {Jiang, M and Ning, J and Wang, J and Hu, W and Sun, P and Zhao, N and Cao, H and Liao, M}, title = {Metabolic nontarget-site mechanism confers dual resistance to cyhalofop-butyl and imazamox in Leptochloa chinensis from China.}, journal = {Pesticide biochemistry and physiology}, volume = {224}, number = {}, pages = {107324}, doi = {10.1016/j.pestbp.2026.107324}, pmid = {42919527}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology/toxicity ; *Imidazoles/pharmacology/toxicity ; *Herbicide Resistance/genetics ; *Poaceae/drug effects/genetics/metabolism ; China ; *Nitriles/pharmacology/toxicity ; *Oximes/pharmacology ; *Butanes/pharmacology ; Plant Proteins/genetics/metabolism ; }, abstract = {Chinese sprangletop (Leptochloa chinensis (L.) Nees) has emerged as a dominant grass weed in rice fields, representing a serious risk to crop productivity because of its rapidly increasing resistance to herbicides. A putative resistant population, MASHS7 (R), was collected from an imidazolinone-tolerant rice field, where it had survived applications of cyhalofop-butyl (CYB) and imazamox (IMA) at the field-recommended rates. Dose-response assays indicated that compared with the susceptible (S) population, the R population developed resistance to CYB (26.29-fold) and IMA (5.50-fold). Additionally, both the cytochrome P450 (P450) inhibitor malathion and the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) partially reversed the resistance of the R population to CYB and IMA. Target-site resistance mechanism analysis revealed that the R plants carried a Trp-to-Cys mutation at codon 1999 of ACCase, with no mutations in the ALS gene, and exhibited no overexpression of any target gene. Compared with the S plants, the R plants metabolized CYB, cyhalofop acid (CYA) and IMA faster. RNA sequencing analysis and quantitative real-time PCR (qPCR) validation confirmed that two P450s (CYP709B2 and CYP81Q32b) and one GST (GST4) gene were constitutively upregulated in the R plants. Molecular docking results predicted favorable binding interactions of these enzymes with CYA and IMA.}, } @article {pmid42919989, year = {2026}, author = {Rossini, E and Garibaldi, M and Hanna, MG and Pitceathly, RDS and Pizzamiglio, C}, title = {Mitochondrial dysfunction in neurology: biomarkers and clinical implications.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {42919989}, issn = {1759-4766}, abstract = {Mitochondrial dysfunction is increasingly recognized as a shared downstream pathogenic mechanism across a wide spectrum of neurological disorders, ranging from primary mitochondrial diseases to conditions including amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, multiple sclerosis, hereditary ataxias and idiopathic inflammatory myopathies. This Review examines the role of mitochondrial biomarkers in improving diagnostic accuracy, patient stratification and monitoring of disease progression and therapeutic response. Primary mitochondrial diseases are presented as proof-of-concept models of impaired oxidative phosphorylation, providing a framework for biomarker identification and validation with translational relevance to other neurological diseases. Mitochondrial biomarkers can be broadly categorized into four domains: fluid biomarkers, reflecting metabolic alterations and stress signalling; genetic biomarkers, capturing mitochondrial DNA integrity and dynamics; multi-omics approaches, integrating transcriptomic, proteomic and metabolomic signatures; and imaging biomarkers, enabling in vivo assessment of structural and functional consequences of mitochondrial dysfunction. Across disorders, these biomarkers reveal shared disturbances in bioenergetics, redox homeostasis, mitochondrial genome maintenance and inflammatory signalling. However, clinical implementation remains limited by methodological heterogeneity, biological variability and reduced disease specificity. Integrated, multimodal biomarker strategies, combined with longitudinal validation, will be essential for supporting precision medicine and guiding the development of therapies to target mitochondrial pathways in neurology.}, } @article {pmid42920457, year = {2026}, author = {Malik, A and Ferdousi, M and Azmi, S and Malik, RA}, title = {Corneal Confocal Microscopy (CCM) in Patients With Central Neurodegenerative Disease.}, journal = {Cureus}, volume = {18}, number = {9}, pages = {e116756}, pmid = {42920457}, issn = {2168-8184}, abstract = {Corneal confocal microscopy (CCM) is a rapid, non-invasive ophthalmic imaging technique that enables detailed visualization and quantification of small corneal nerve fibres. Although initially developed for the assessment of diabetic neuropathy, its application has broadened substantially, with increasing evidence supporting its value in a range of central neurodegenerative diseases. This narrative review synthesizes current findings on the use of CCM in dementia, multiple sclerosis, stroke, burning mouth syndrome, amyotrophic lateral sclerosis, trigeminal neuralgia, migraine and Parkinson's disease. Across these conditions, CCM consistently identifies measurable alterations in corneal nerve fibre density, length, branching and morphology, as well as changes in corneal immune cell populations. These structural abnormalities frequently correlate with disease severity, functional decline and clinical progression. In some disorders, CCM demonstrates diagnostic performance comparable to or exceeding existing biomarkers, and offers distinct advantages as a non-invasive, repeatable and objective measure that can detect early or subclinical neurodegeneration. Corneal confocal microscopy also shows potential as a prognostic and monitoring tool, particularly in conditions with limited reliable biomarkers. It may help stratify risk, track therapeutic response, and provide surrogate endpoints for clinical trials. Despite these strengths, several limitations remain, including modest sample sizes in some studies, variability in image interpretation, and difficulties differentiating between neurodegenerative conditions with overlapping patterns of nerve loss. Emerging automated analysis methods and artificial intelligence-based algorithms may help address these challenges by improving accuracy, reproducibility, and scalability. Overall, CCM represents a promising technique that bridges ophthalmology and neurology. A growing body of literature supports its utility across multiple neurodegenerative diseases, and further large-scale, longitudinal studies may help establish its role within routine clinical assessment and research.}, } @article {pmid42921272, year = {2026}, author = {He, Z and Zeng, J and Wang, G and Li, Y and Zhang, F}, title = {Neurodegenerative Diseases: Epidemiology, Risk Factors, Classification, Pathophysiology, Clinical Features, Diagnosis, and Therapeutic Strategies.}, journal = {MedComm}, volume = {7}, number = {11}, pages = {e71090}, pmid = {42921272}, issn = {2688-2663}, abstract = {Neurodegenerative diseases are a growing cause of disability worldwide, particularly as populations age. Although these disorders differ in etiology and clinical presentation, advances in genetics, neuropathology, and biomarker research have identified shared disturbances in protein homeostasis, mitochondrial function, and immune regulation. These processes may contribute to selective neuronal vulnerability and neural circuit dysfunction. These findings are refining disease classification and diagnosis, yet effective disease-modifying therapies remain limited. Disease-specific abnormalities remain essential to clinical interpretation and treatment selection. Existing reviews often focus on individual disorders or isolated mechanisms, leaving the links between shared biology and disease-specific phenotypes insufficiently clear. We synthesize evidence on the epidemiology, risk factors, classification, and pathophysiology of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, frontotemporal dementia, Friedreich's ataxia, and multiple sclerosis. We compare their clinical manifestations and diagnostic approaches, including the evolving role of biomarkers, and critically assess established and emerging therapies. By distinguishing shared mechanisms from disease-specific abnormalities, we identify key translational gaps and explore how common biological disturbances may lead to distinct clinical trajectories. This cross-disease perspective may inform diagnostic reasoning, treatment development, and future comparative research.}, } @article {pmid42922081, year = {2026}, author = {Adorinni, S and Grieco, I and Morasso, S and Fornasier, M and Novello, G and Salmaso, V and Martínez-González, L and Cescon, E and Bassani, D and Bassan, GA and Gianferrara, T and Prencipe, F and Kost, V and Da Ros, T and Storici, P and Martinez, A and Spalluto, G and Moro, S and Federico, S}, title = {Riluzole-Derived Benzo[d]thiazoles as CK1δ Inhibitors for Amyotrophic Lateral Sclerosis-Related Neurodegeneration.}, journal = {ChemMedChem}, volume = {21}, number = {20}, pages = {}, pmid = {42922081}, issn = {1860-7187}, support = {PRIN 20227K7YJS//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Humans ; *Riluzole/chemistry/pharmacology ; Structure-Activity Relationship ; *Casein Kinase Idelta/antagonists & inhibitors/metabolism ; *Protein Kinase Inhibitors/chemistry/pharmacology/chemical synthesis ; Animals ; *Benzothiazoles/chemistry/pharmacology/chemical synthesis ; Molecular Docking Simulation ; *Neuroprotective Agents/chemistry/pharmacology/chemical synthesis ; Molecular Structure ; }, abstract = {Riluzole-derived benzo[d]thiazoles were investigated as metabolite-inspired CK1δ inhibitors, a kinase involved in TDP-43 phosphorylation and therefore relevant to amyotrophic lateral sclerosis (ALS). Starting from the known CK1δ activity of riluzole, we examined whether its major hydroxylamine metabolite could preserve target recognition and provide a rational entry point for scaffold optimisation. The metabolite retained CK1δ inhibition, but its limited chemical stability and toxicity in neuronal cells identified the hydroxylamine group as a critical liability. Replacement of this functionality with a hydrazine converted the fragile metabolite-derived structure into a more potent and tractable CK1δ inhibitor series. Structure-activity relationship studies revealed that the hydrazine moiety accommodates broader substitution than the hydroxylamine counterparts, with branched alkyl and benzyl groups giving the most balanced profiles. Docking and molecular dynamics suggested that the improvement could be attributed to an additional hydrogen-bond with Gly86 in the hinge region. The best derivative combined submicromolar CK1δ inhibition with passive blood-brain barrier permeability, short-term cellular tolerance, ATP competitive inhibition, direct target engagement, and preliminary selectivity over GSK3β. Although this compound did not result neuroprotective in an oxidative stress model, it paves the way for a focused benzo[d]thiazole platform for probing CK1δ biology in ALS.}, } @article {pmid42922691, year = {2026}, author = {Grycz, K and Jan, C and Zawistowski, P and Wasicki, B and Özkan, B and Aousji, O and Sirtori, R and Fallini, C and Caron, G and Danner, SM and Roselli, F and Zytnicki, D and Bączyk, M}, title = {Defective synapto-nuclear signaling contributes to motoneuron vulnerability in SOD1-ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.09.01.748568}, pmid = {42922691}, issn = {2692-8205}, abstract = {Glutamatergic excitatory synapses not only shape spiking activity and neuronal communication but also initiate activity-dependent signaling pathways that trigger transcriptional programs. Since glutamatergic excitatory synapses onto spinal motoneurons (MNs) are impaired presymptomatically in Amyotrophic Lateral Sclerosis, we investigated whether synapto-nuclear coupling is disrupted in MNs from mSOD1 mice and whether restoring it mitigates pathology. We developed an in vivo approach to selectively investigate the coupling between synaptic excitation and nuclear CREB phosphorylation in spinal MNs. Specific activation of Ia-MN synapses induces CREB phosphorylation in wild-type MNs but not in mSOD1 MNs at P50, indicating presymptomatic synapto-nuclear uncoupling. Enhancing cAMP/PKA signaling by pharmacological inhibition of cAMP degradation restored synapto-nuclear coupling, reduced misfolded SOD1, and slowed neuromuscular-junction denervation. Thus, activity-dependent synapto-nuclear signaling is impaired yet pharmacologically rescuable in mSOD1 MNs, supporting synapto-nuclear signaling as a determinant of MN resilience.}, } @article {pmid42922848, year = {2026}, author = {Gorenshtein, A and Omar, M and Jia, E and Adiniaev, Y and Daniel, O and Kruskal, J and Ahmed, M and Brook, O and Klang, E and Barash, Y}, title = {Limits of Trial-Adaptive Neural-Language Fusion Across Large Language Models in P300 Brain-Computer Interfaces.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.08.30.26361777}, pmid = {42922848}, abstract = {OBJECTIVE: Published P300-speller fusion schemes fix prior trust regardless of trial reliability; we tested whether a reliability estimate improves on it.

METHODS: We reanalyzed 3,373 archived P300-speller selections from 47 people with ALS (BigP3BCI). A fair, matched-search-space comparison, tuning both a fixed weight and an adaptive policy out-of-fold, was evaluated across 22 evaluable language-model priors up to 46.7B parameters. Two representative priors, GPT-2 and a classical 5-gram, additionally received detailed naive and mechanistic analyses.

RESULTS: No prior's 95% CI favored adaptive fusion under the fair comparison, despite unexploited oracle headroom at every scale. Under GPT-2, the naive comparison was significantly worse for adaptive fusion; both anchors converged to a degenerate or near-degenerate fair-comparison solution. For the representative anchors, three further controllers failed to convert that headroom into benefit; the fixed-fused posterior's output probability outperformed the best controller for flagging errors (2.8- to 3.8-fold enrichment).

CONCLUSION: A tuned fixed weight is a difficult-to-beat default across the tested scale range; reliability estimation gave no deployable adaptive advantage.

SIGNIFICANCE: Adaptive weighting should be validated against a fairly tuned baseline across model families and scales; in this dataset, the fused output's confidence identified high-risk selections better than the tested purpose-built ranker.}, } @article {pmid42922986, year = {2026}, author = {Yang, SH and Han, SK and Koo, Y}, title = {CRISPR/Cas9-mediated editing of SlALS1 enhances fruit sweetness in tomato.}, journal = {Frontiers in plant science}, volume = {17}, number = {}, pages = {1927332}, pmid = {42922986}, issn = {1664-462X}, abstract = {Fruit sweetness is a primary determinant of consumer preference and market value in tomato (Solanum lycopersicum), yet increasing sugar content without negatively affecting plant performance remains a major challenge in breeding programs. In this study, we targeted Acetolactate synthase 1 (SlALS1), a key enzyme in branched-chain amino acids (BCAAs) biosynthesis, to investigate whether modulation of primary metabolism could enhance fruit sugar accumulation. Tomato contains two ALS homologs, SlALS1 and SlALS2. Using CRISPR/Cas9-mediated genome editing, we generated SlALS1 knock-out lines in the Micro-Tom background. Loss of SlALS1 function led to a significant reduction in the levels of valine, leucine, and isoleucine in fruit tissues, confirming disruption of the BCAA biosynthetic pathway. Notably, soluble sugar content was markedly increased in the mutant lines, with glucose and fructose levels elevated by approximately 1.3-fold compared with wild-type fruits, resulting in a significantly higher Brix index. Metabolic profiling indicates that reduced BCAA biosynthesis may influence carbon allocation toward soluble sugar accumulation in fruit tissues, revealing an association between amino acid metabolism and carbohydrate accumulation during fruit development. Our findings demonstrate that precise editing of a central metabolic enzyme can enhance tomato fruit sweetness and suggest that SlALS1 may represent a promising target for genome editing aimed at improving fruit quality traits. However, further evaluation of agronomic traits, including plant growth and fruit yield, will be necessary to assess its potential for practical breeding applications.}, } @article {pmid42923269, year = {2026}, author = {Shen, C and Wu, XT and Yin, H and Zuo, JL and Zhang, CH and Cao, F and Zhang, Y and Tian, ZY and Robinson, N and Liu, JP}, title = {Selected traditional Chinese medicines for treating amyotrophic lateral sclerosis: a Bayesian network meta-analysis based on randomised controlled trials.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1706211}, pmid = {42923269}, issn = {1663-9812}, abstract = {OBJECTIVE: To assess the effectiveness of specific Traditional Chinese Medicine (TCM) therapies for Amyotrophic Lateral Sclerosis (ALS) using Bayesian network meta-analysis.

METHODS: PubMed, the Cochrane Library, EMBASE, Web of Science, and four Chinese databases up to 15th December 2024 was searched, including RCTs on adult Amyotrophic Lateral Sclerosis patients treated with TCM therapies (Chinese herbal medicine, preparations, non-pharmacological treatments) alone or combined with conventional treatments. Controls included no intervention, placebo, conventional treatments, or combinations. Primary outcomes were functional status (ALSFRS, ALSFRS-R, AALSS, m-Norris scales). Bayesian network meta-analysis compared treatment effects and calculated SUCRA values.

RESULTS: Thirty-five RCTs involving 27 TCM therapies were included. No significant differences in functional status or quality of life were found among TCM therapies, ICT, Riluzole alone, and Riluzole plus placebo. For functional status, Shenmai injection + ICT (SUCRA 0.735 for ALSFRS, 0.870 for ALSFRS-R), Jiweiling injection + placebo (SUCRA 0.868 for ALSFRS), Jiawei Sijunzi decoction alone (SUCRA 0.739 for ALSFRS-R), Acupuncture + rehabilitation exercises + Riluzole (SUCRA 0.928 for AALSS, 0.863 for m-Norris) and Shenzhe Jiangqi powder + placebo (SUCRA 0.860 for m-Norris) had the highest probabilities of being superior treatment. For quality of life, Thunder fire moxibustion + Riluzole and Jiweiling injection + placebo for ALSAQ-40 were favorable.

CONCLUSION: Despite no significant differences in functional status among TCM therapies, ICT, Riluzole alone, and Riluzole plus placebo, Jiweiling injection, Shenmai injection, Jiawei Sijunzi decoction, and Shenzhe Jiangqi powder may be regarded as candidate preparations for ALS patients. Future research should focus on real-world data to explore long-term effects and practical benefits.

https://inplasy.com/inplasy-2024-8-0050/, identifier INPLASY202480050.}, } @article {pmid42924413, year = {2026}, author = {Vornetti, G and Punzetti, F and Vacchiano, V and Rochat, MJ and Cantoni, E and Rizzo, G and D'Angeli, D and Morandi, L and Manners, DN and Liguori, R and Lodi, R and Tonon, C}, title = {Cerebellar involvement in sporadic amyotrophic lateral sclerosis: a magnetic resonance spectroscopy study.}, journal = {Brain communications}, volume = {8}, number = {5}, pages = {fcag382}, pmid = {42924413}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is increasingly recognized as a multisystem neurodegenerative disorder, and recent evidence suggests that the cerebellum may contribute to disease pathology, although cerebellar metabolic alterations have not previously been demonstrated in vivo. This study investigated cerebellar metabolic and structural changes using proton magnetic resonance spectroscopy ([1]H-MRS) and volumetric imaging. Thirty patients with amyotrophic lateral sclerosis (21 M, mean age 59.7 ± 7.6 years), 22 healthy controls (HC, 10 M, mean age 59.8 ± 9.6 years) and 16 individuals with hereditary spastic paraplegia type 4 (8 M, mean age 50.8 ± 12.5 years), a potential clinical mimic, underwent 3T MRI and [1]H-MRS with a single-voxel positioned in the left cerebellar hemisphere. Patients with amyotrophic lateral sclerosis showed significant reductions in myo-inositol/creatinine (P = 0.01) and glutathione/creatinine (P = 0.005), compared with HC, together with selective volume loss in cerebellar lobules I-IV, V, VI, and Crus I. Among metabolites, glutathione/creatinine had the highest discriminative accuracy for amyotrophic lateral sclerosis versus both HC and spastic paraplegia type 4, with areas under the curve of 0.80 and 0.71, respectively. These findings reveal distinct cerebellar metabolic alterations in amyotrophic lateral sclerosis, providing further evidence for cerebellar involvement in disease pathology and highlighting cerebellar [1]H-MRS as a potential adjunct to diagnostic evaluation.}, } @article {pmid42924853, year = {2026}, author = {Regazzetti, M and Kiper, P and Merico, A and Rossi, S and Bulcão Visco, D and Luque Moreno, C and Baba, A}, title = {Feasibility and apparent safety of functional electrical stimulation-assisted cycling in amyotrophic lateral sclerosis and primary lateral sclerosis: a single-arm longitudinal pilot feasibility study.}, journal = {European journal of translational myology}, volume = {}, number = {}, pages = {}, doi = {10.4081/ejtm.2026.16025}, pmid = {42924853}, issn = {2037-7452}, abstract = {Functional electrical stimulation-assisted cycling may be relevant in motor neuron disease, but its feasibility and safety in amyotrophic lateral sclerosis and primary lateral sclerosis remain unclear. The authors aimed to assess feasibility, apparent safety, and exploratory pre-post clinical changes of a three-week functional electrical stimulation-assisted cycling protocol in ambulatory inpatients with amyotrophic lateral sclerosis or primary lateral sclerosis. Fifteen patients were assessed; 11 were enrolled (5 ALS, 6 PLS) and received 15 supervised 30-minute FES-cycling sessions over three weeks in addition to conventional neuromotor rehabilitation. Bilateral eight-channel stimulation targeted quadriceps, tibialis anterior, hamstrings, and gastrocnemius during active or active-assisted cycling. Feasibility outcomes were enrollment, completion, tolerance, adverse events, and pre-post data availability. Clinical outcomes were analyzed descriptively. Eleven of 15 assessed patients were enrolled (73.3%; 5 ALS, 6 PLS). All enrolled participants completed the protocol, no adverse events were documented, and complete pre-post data were available. Exploratory outcomes showed favorable short-term changes in mobility, walking, strength, and spasticity. This protocol appears feasible and apparently safe in selected ambulatory inpatients. Findings are hypothesis-generating and support a prospective controlled feasibility trial before efficacy is tested.}, } @article {pmid42925434, year = {2026}, author = {Shah, A and Godad, A and Bagwe Parab, S}, title = {Unlocking therapeutic potential of Wnt signaling pathway in neurodegenerative diseases.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42925434}, issn = {1573-7365}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Wnt Signaling Pathway/drug effects/physiology ; Animals ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {The Wnt Signaling pathway is a regulatory network that is highly conserved in the central nervous system and is essential for the survival of neurons, synaptic plasticity, and the blood-brain barrier's integrity. The pathophysiology of major neurodegenerative and neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), is highly influenced by canonical and non-canonical Wnt Signaling dysregulation, according to increasingly compelling evidence. In addition to emphasising common molecular events such as GSK-3β overactivation, β-catenin destabilisation, neuroinflammation, synaptic dysfunction, and BBB disruption, this study offers a comparative and mechanistic overview of Wnt pathway changes across various illnesses. This article identifies overlapping treatment targets, such as GSK-3β, DKK1, LRP5/6, and Wnt ligands, by integrating common and disease-specific Wnt-associated pathways, in contrast to traditional disease-specific reviews. Furthermore, new translational approaches involving natural substances, Wnt modulators, and pathway-targeted treatments are critically examined. All things considered, this study presents Wnt Signaling as a potential neuroprotective and regenerative target for upcoming precision-based treatments in neurodegenerative disorders.}, } @article {pmid42925563, year = {2026}, author = {Niu, Y and Zhang, D and Gong, T and Guo, G and Zhang, H and Gao, C and Yang, J}, title = {Constructing functional neural circuits to model amyotrophic lateral sclerosis with induced pluripotent stem cell-derived brain organoids.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRRONLINE-D-26-00781}, pmid = {42925563}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons. Recent advances in human-induced pluripotent stem cell-derived brain organoids offer an innovative platform to model amyotrophic lateral sclerosis in a human-specific context. These three-dimensional organoid systems allow for the study of neuronal circuit-level dysfunction, which is central to amyotrophic lateral sclerosis pathogenesis, by incorporating multiple neuronal subtypes and supporting glial populations. In particular, the integration of region-specific brain organoids into assembloid models has enabled the reconstruction of functional long-range projections and cortico-motor circuits, closely resembling human neural connectivity. This review summarizes the generation and application of human induced pluripotent stem cell-derived brain organoids for amyotrophic lateral sclerosis research, with a focus on the reconstruction of neural circuits, multi-omics profiling, and functional assays. We also discuss how organoid systems can be leveraged for drug discovery and personalized medicine in amyotrophic lateral sclerosis, highlighting their potential to unveil human-specific disease mechanisms. Lastly, we address the current challenges and future directions for improving the physiological relevance of organoid models in amyotrophic lateral sclerosis research.}, } @article {pmid42925619, year = {2026}, author = {Moreira, JVA and Pinheiro, CVA and de Souza, RF and Chiappa, GR and Ramos, SC and da Silva de Magalhães, MJ and de Aguiar, DR and Dos Santos, DF}, title = {The clinical spectrum of suicide-related outcomes in amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {General hospital psychiatry}, volume = {103}, number = {}, pages = {204-212}, doi = {10.1016/j.genhosppsych.2026.10.002}, pmid = {42925619}, issn = {1873-7714}, abstract = {OBJECTIVE: To synthesize clinically distinct suicide-related outcomes in amyotrophic lateral sclerosis (ALS) and comparative suicide risk without pooling non-equivalent constructs.

METHODS: We searched MEDLINE, Embase, Scopus, PsycINFO, the Virtual Health Library, and SciELO through March 17, 2026, and updated all searches for March 18 through October 9, 2026. We included observational reports of predefined suicide-related outcomes. Outcomes with at least 3 independent studies were pooled using random-effects generalized linear mixed models for proportions and a Hartung-Knapp model for comparative estimates. We used Joanna Briggs Institute tools and adapted GRADE.

RESULTS: Twenty-eight reports representing 26 independent cohorts were included; 21 cohorts contributed quantitative data. Active suicidal ideation was 43% (23/53; 95% CI, 30%-58%) in an end-stage cohort and 14% (10/71; 95% CI, 7%-24%) in a general clinic cohort; these estimates were not pooled. Hypothetical consideration of assisted dying was 50% (95% CI, 41%-59%; I[2] = 49%; 95% prediction interval, 21%-79%; 4 studies). Crude suicide mortality rates were 0.16 and 0.36 per 100 person-years in 2 cohorts. Three registry or administrative cohorts yielded a relative suicide-risk estimate of 4.6 (95% CI, 2.5-8.5; 95% prediction interval, 0.4-53.6). Certainty was low or very low.

CONCLUSIONS: Suicide-related experiences in ALS are clinically distinct. Clinicians should clarify meaning, assess intent and immediacy, evaluate decision-making capacity and treatable psychiatric symptoms, and address palliative and psychosocial needs. A death wish or assisted-dying preference should not be assumed to indicate active suicidal intent.}, } @article {pmid42925692, year = {2026}, author = {Ocampo, DEM and Martínez, SS}, title = {Dynamic UV-Vis monitoring of ternary pharmaceutical photodegradation using multivariate curve resolution and predictive modeling.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {367}, number = {Pt 2}, pages = {129014}, doi = {10.1016/j.saa.2026.129014}, pmid = {42925692}, issn = {1873-3557}, abstract = {Ultraviolet (UV) photodegradation of multicomponent pharmaceutical systems generates complex spectral signals due to overlapping absorption bands and transient intermediates, limiting conventional quantitative approaches. To address this challenge, an integrated chemometric strategy was developed to predict concentration profiles in dynamic ternary mixtures of paracetamol (PAR), naproxen sodium (NPX), and diclofenac sodium (DIC) in spiked river water using Ultraviolet-visible (UV-Vis) spectroscopy. UV-Vis spectra from individual photolysis experiments were analyzed by Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to estimate concentration profiles of the parent pharmaceuticals. These profiles were associated with ternary mixture spectra reconstructed by linear combination of the spectral data obtained from the individual photolysis experiments. The combined spectral data, together with experimentally acquired calibration data, served as input to develop a linear Partial Least Squares (PLS) and non-linear Artificial Neural Network (ANN) models, enabling simultaneous prediction of component concentrations. The degree of nonlinearity in the calibration datasets was first assessed using the Non-Linearity Degree (NLD), yielding values of 0.248, 0.398, and 0.214 for PAR, NPX, and DIC, respectively. These results exceeded the 0.05 threshold, indicating significant non-linear behavior in the calibration datasets. Accordingly, the linear PLS model showed limited predictive performance, particularly for DIC. In contrast, the non-linear ANN model achieved higher predictive accuracy, demonstrating its superior suitability for the dynamically evolving multicomponent systems.}, } @article {pmid42926444, year = {2026}, author = {Bennett, A and Johnson, EK and Benjamin, KJM}, title = {IsoGraph resolves coordinated transcript choice and gene abundance in the aging human brain.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.10.04.756439}, pmid = {42926444}, issn = {2692-8205}, abstract = {Relative transcript usage can change without a corresponding change in total gene expression, but resolving coordinated transcript choice across genes while separating it from abundance remains challenging. We present IsoGraph, a gene-centered framework that represents isoform usage and abundance as paired network channels, identifies gene modules, and quantifies their channel-specific contributions. In synthetic benchmarks, IsoGraph preferentially recovered network structure when coordinated transcript usage carried the planted signal, whereas abundance-based representations were more informative in abundance-dominated and RNA-degradation settings. Applied to BrainSEQ and GTEx adult brain transcriptomes, IsoGraph identified age-associated transcript-usage signals that persisted after conditioning on gene abundance and, in a region-dependent manner, after adjustment for estimated cellular composition. Modules were stable across donor subsets, and frozen module axes retained age associations across cohorts even when exact gene partitions differed. IsoGraph module context captured predictive information about held-out differential transcript usage beyond gene-wise evidence and conventional co-expression. Convergent evidence from structural annotation, short-read junction usage, independent long-read sequencing, and within-donor allelic analyses supported constituent transcript events. Disease colocalization further prioritized candidate isoform events at neurological and psychiatric disease loci, including an alternative terminal-exon event at PRDM2 associated with amyotrophic lateral sclerosis. Together, these results establish coordinated transcript usage as a reproducible component of transcriptomic organization and provide a framework for resolving its contribution alongside gene abundance and for tracing network-level signals to candidate transcript events.}, } @article {pmid42926625, year = {2026}, author = {Bhandary, P and Wang, Y and Omar, M and Moore, JH and Wang, ZP}, title = {CCT2 expression marks a translation-activated state in sporadic ALS motor neurons and is associated with functional decline.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.10.06.757033}, pmid = {42926625}, issn = {2692-8205}, abstract = {Sporadic disease accounts for about 90% of amyotrophic lateral sclerosis (ALS) cases, and its biological heterogeneity is a major contributor to the failure of trials that enroll patients under a single diagnosis. Because sporadic ALS lacks a shared genetic anchor, identifying biological signals is critical for effective patient stratification. We analyzed induced pluripotent stem cell-derived motor neurons from 619 AnswerALS participants using transcriptomics, proteomics, and whole-genome sequencing and identified CCT2 as the first single-gene marker of a molecular state within sporadic ALS, providing a measurable basis for trial enrollment according to biology. We first anchored the analysis in known ALS genotypes. C9orf72 and SOD1 motor neurons did not converge on a common signature but retained genotype-specific differences that bulk postmortem tissue compresses. Scoring 391 sporadic patients along three transcriptomic axes (bioenergetic stress, cell cycle, and inflammation) resolved three states. One state was marked by CCT2, a TRiC chaperonin subunit, which distinguished it from the quiescent state with an area under the curve of 0.892. CCT2 was also elevated at the protein level and associated with the rate of ALSFRS-R decline, although this association weakened after adjustment for culture composition. Upstream regulator analysis placed this state downstream of MYC and mTORC1 activation. No germline test across 360 whole genomes explained these states. Validation using Target ALS data showed that the relationship between CCT2 and the cell cycle program was also present in postmortem cortex enriched for layer 5b projection neurons.}, } @article {pmid42926632, year = {2026}, author = {Barbier, M and Ichalalen, M and Amador, MD and De Houwer, JFH and Suh, E and Lejeune, FX and Bieth, T and Reyes, C and Henry, E and Hinks, AE and Martin-Hardy, P and Rinaldi, D and Araktingi, L and Seelaar, H and Roué-Jagot, C and , and Lagarde, J and Sarazin, M and Salachas, F and Bruneteau, G and Teichmann, M and Levy, R and Bernard, E and Kaat, LD and Van Deerlin, V and Haase, G and van Swieten, J and Rapinat, A and Gentien, D and Le Ber, I}, title = {Somatic instability of the C9orf72 repeat expansion in blood differs between patients with amyotrophic lateral sclerosis or frontotemporal dementia.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.10.06.26364580}, pmid = {42926632}, abstract = {Individuals carrying a G4C2 repeat expansion in C9orf72 can develop amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD), at various and unpredictable ages. The contribution of the expansion to this extreme clinical variability remained a matter of debate. In this work, we validated the use of optical genome mapping to efficiently size this expansion from blood and applied this method to a cohort of 54 repeat expansion carriers including patients with FTD (n = 23), ALS (n = 22) and presymptomatic individuals (n = 9). Despite the high variability in expansion profiles, distinct groups can be inferred. Although consensus repeat profiles were similar between FTD and ALS patients, relationships between repeat number, indexes of repeat instability, and the age at sampling differed between clinical conditions. An age at sampling-dependent increase of repeat instability in blood was observed in presymptomatic carriers and FTD patients (p = 0.01 and p = 0.04 respectively), in contrast to patients with ALS (p = 0.9). The proportion of shorter repeats ([500-1500 repeats]) increased with the age at sampling in ALS patients but decreased in presymptomatic and FTD cohorts, while the proportion of larger repeats (>2000 G4C2), in particular those exceeding 4000 repeats, increased along with the age at sampling in presymptomatic carriers and FTD cases (p <1.10 [-e4] and p = 0.006 respectively) conversely to patients with ALS (p = 0.98). In conclusion, this work strongly supports different dynamics of repeat instability of the C9orf72 pathogenic expansion in blood linked to the clinical evolution. These findings provide new insights into the relationship between expansion profiles and clinical variability.}, } @article {pmid42926777, year = {2026}, author = {Ding, YN and Bahati, M and Li, MQ and Guan, PP and Wang, P}, title = {A CNS-targeted atovaquone nanotherapy mitigates complement activation and neuromuscular degeneration in ALS.}, journal = {Materials today. Bio}, volume = {41}, number = {}, pages = {103738}, pmid = {42926777}, issn = {2590-0064}, abstract = {Complement-mediated glial inflammation and synaptic injury are increasingly implicated in amyotrophic lateral sclerosis (ALS), but clinically translatable complement-modulating therapies remain limited. Atovaquone (ATQ) is an approved, poorly water-soluble small molecule with reported immunomodulatory activity. We investigated whether ATQ could modulate C1qb or C5aR1-associated pathology and whether lactoferrin (Lf)-derived nanomicelles could improve delivery to the spinal cord. ALS spinal-cord single-cell transcriptomic and pathway-enrichment analyses were combined with screening of an FDA-approved drug library, molecular docking and surface plasmon resonance (SPR). Lf-ATQ nanomicelles were characterised by dynamic light scattering, transmission electron microscopy and fluorescence distribution studies. Complement/inflammasome responses were examined in microglial and motor-neuron-microglia models. Therapeutic effects were evaluated in mice expressing the human superoxide dismutase 1 G93A variant (SOD1[G93A]) by motor testing, compound muscle action potential recording, histology, immunostaining, western blotting and proteomics. Complement genes, particularly C1qb and C5aR1, were enriched in microglia, whereas glutamatergic-synapse and axon-guidance programmes were negatively enriched. In cellular models and SOD1[G93A] spinal cord, Lf-ATQ reduced C1qb, NLRP3 and multiple inflammatory mediators, attenuated glial reactivity and altered autophagy-related proteins. Treatment preserved rotarod performance, grip strength, gait parameters, compound muscle action potential amplitude and gastrocnemius morphology. Proteomic analysis indicated remodelling of complement/coagulation, vesicular-transport and synaptic modules. These findings support Lf-ATQ as a central nervous system (CNS) -oriented, complement-regulating nanotherapy candidate for ALS. Direct functional target-inhibition assays, quantitative ATQ pharmacokinetics, long-term safety assessment and validation in non-SOD1 models remain necessary before translational conclusions can be drawn.}, } @article {pmid42926935, year = {2026}, author = {Celier, A and Lanore, A and Hesters, A and Hussein, S and Benchikh, R and Bruneteau, G and Morélot-Panzini, C and Parfait, M and Piljan, M and Le Guennec, L and Weiss, N and Demeret, S and Mayaux, J and Marois, C}, title = {Outcomes of patients with amyotrophic lateral sclerosis admitted to the ICU for acute respiratory failure.}, journal = {Annals of intensive care}, volume = {16}, number = {}, pages = {100183}, pmid = {42926935}, issn = {2110-5820}, abstract = {BACKGROUND: Data on patients with amyotrophic lateral sclerosis (ALS) admitted to the intensive care unit (ICU) for acute respiratory failure are scarce, and early prognostic markers are lacking.

METHODS: We conducted a retrospective cohort study of consecutive patients with ALS admitted for acute respiratory failure to two ICUs of a tertiary referral center between 2016 and 2022. The primary outcome was 3-month mortality. Factors associated with 3-month mortality were assessed using multivariable Cox proportional hazards regression. Survival and functional outcomes were evaluated up to 12 months.

RESULTS: Among 139 patients [median age 66 (IQR 57-73) years, 61.2% being men], 109 (78.4%) patients presented with hypercapnia and 82 (59.0%) with hypoxemia (defined as PaO₂/FiO₂ ratio < 300) at ICU admission, with frequent overlap between both conditions. Non-invasive ventilation was used in 79.9% of patients, while 13.7% were intubated, and 2.2% underwent tracheostomy. Three-month mortality was 48.2%, increasing to 61.2% and 74.1% at 6 and 12 months respectively. In multivariable analysis, hypoxemia at ICU admission was independently associated with increased 3-month mortality (HR = 2.27, 95% CI: 1.28-4.01; P = 0.005), along with older age (HR=1.03 per year, 95% CI: 1.00-1.06; P = 0.035). Among patients alive at 3 months, a majority (79.2%) were living at home.

CONCLUSION: ICU admission for acute respiratory failure in ALS is associated with substantial short-term mortality, consistent with the poor prognosis inherent to the natural history of the disease. Hypoxemia at admission identifies a subgroup at particularly high risk of death and may help inform early prognostic assessment and shared decision-making. However, patients who survive the acute ICU phase frequently achieve favorable short-term outcomes, with most living at home at 3 months.}, } @article {pmid42927514, year = {2026}, author = {McHutchison, C and Wuu, J and Cosentino, S and Saldana, R and Vadella, E and Benacerraf, A and McBane, K and Gonzalez, AS and Stark, JH and Li, Y and Abrahams, S and Benatar, M}, title = {Mild cognitive impairment in presymptomatic amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {11}, pages = {}, pmid = {42927514}, issn = {1432-1459}, support = {4365//Muscular Dystrophy Association/ ; 172123//Muscular Dystrophy Association/ ; 2015//The ALS Association/ ; R01 NS105479/NS/NINDS NIH HHS/United States ; U54 NS090291//CReATe Scholarship funded by the National Institutes of Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications/physiopathology ; Female ; Male ; *Cognitive Dysfunction/etiology/genetics/physiopathology/diagnosis/epidemiology ; *Prodromal Symptoms ; Middle Aged ; C9orf72 Protein/genetics ; Aged ; Superoxide Dismutase-1/genetics ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are clinically and biologically related, and each may be preceded by a prodromal stage of disease. Mild cognitive and behavioural impairment (MCI/MBI) have also been observed in those with clinically manifest ALS. The primary aim of this study was to characterise MCI in presymptomatic ALS.

METHODS: Criteria for frontotemporal-related MCI (MCI-ft), which require evidence of subthreshold cognitive performance or decline, were adapted from existing frameworks for MCI in prodromal FTD, presymptomatic ALS and clinically manifest ALS. MCI-ft was characterised in 216 Pre-fALS participants (74 C9ORF72, 94 SOD1, 20 other pathogenic variant carriers and 28 non-carriers) with neuropsychological data at 807 study visits. All designations were reviewed by a research neuropsychologist, with consensus discussions as needed.

RESULTS: MCI-ft was observed in 15 (20%) C9ORF72, 12 (13%) SOD1 and 3 (%) of other carriers at one or more study visits, compared to 1 (4%) non-carrier. Most visits with MCI-ft showed impairment affecting both language and executive functioning. Fluctuations in MCI-ft status between assessments were common.

CONCLUSION: The observed frequency and temporal course of MCI-ft in presymptomatic ALS, using criteria based on subthreshold cognitive performance and decline, expands understanding of this phase of disease. These findings help to inform future research examining the risk of phenoconversion to clinically manifest disease and aid the design of disease prevention trials.}, } @article {pmid42918614, year = {2026}, author = {Speranza, J and Gale-Rogers, C and Stretch, AC and West, RJH}, title = {Drosophila Models of Human Neurodegenerative Diseases.}, journal = {Current opinion in insect science}, volume = {}, number = {}, pages = {101639}, doi = {10.1016/j.cois.2026.101639}, pmid = {42918614}, issn = {2214-5753}, abstract = {In his book Insects and the Life of Man: Collected Essays on Pure Science and Applied Biology, Sir V. B. Wigglesworth examined how a fundamental understanding of insect physiology and biology can be applied to some of society's greatest challenges, including human health. Here we reflect on how, in the 50 years since his book's publication, Drosophila melanogaster have played a critical role in advancing our understanding of human neurodegenerative diseases. Focusing on Parkinson's disease, Huntington's disease, and the frontotemporal dementia / amyotrophic lateral sclerosis spectrum, we examine the role Drosophila have played in elucidating fundamental mechanisms of neurodegeneration, identifying therapeutic targets, and dissecting the complex interplay that exists between genetics and environmental factors. Together these studies highlight how Drosophila models continue to provide critical insight into the molecular mechanisms underpinning neurodegeneration and provide a fundamental pre-clinical model in which we can accelerate research into human neurodegenerative conditions.}, } @article {pmid42918778, year = {2026}, author = {Abu-Rumeileh, S and Großkopf, H and Guthknecht, A and Mensch, A and Osterloh, D and Ratti, A and Conrad, J and Stapf, C and Krippner, J and Oeckl, P and Stoltenburg-Didinger, G and Maranzano, A and Steinacker, P and Weise, CM and Barba, L and D'Anna, L and Klafki, HW and Wiltfang, J and Silani, V and Froelich, L and Ticozzi, N and Hausner, L and Thal, DR and Weishaupt, JH and Lachmann, I and Verde, F and Otto, M}, title = {Tau isoform mapping across tissues and biofluids reveals a signature distinguishing Alzheimer's disease from amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42918778}, issn = {2041-1723}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/blood/metabolism ; *tau Proteins/blood/metabolism ; *Alzheimer Disease/diagnosis/blood/metabolism ; Female ; Protein Isoforms/metabolism/blood ; Male ; Biomarkers/blood/metabolism ; Brain/metabolism ; Aged ; Phosphorylation ; Spinal Cord/metabolism ; Mass Spectrometry ; Middle Aged ; Diagnosis, Differential ; Aged, 80 and over ; Immunoprecipitation ; Case-Control Studies ; }, abstract = {Blood phosphorylated tau 217 (p-tau217) accurately detects Alzheimer's disease (AD) pathology but is also elevated in amyotrophic lateral sclerosis (ALS), likely reflecting peripheral (big) tau released from muscle. Assays selectively measuring brain-derived (BD-) tau and BD-p-tau217 are therefore needed. We analysed serum BD-tau and p-tau217 in ALS (n = 139), AD (n = 101) and controls (n = 75) using direct immunoassays and after BD-Tau immunoprecipitation (BD-Tau-IP), and tau species in brain (n = 16), spinal cord (n = 11) and muscle (n = 10) by targeted mass spectrometry. With the direct immunoassays, BD-tau and p-tau217 were increased in AD and ALS versus controls. After BD-Tau-IP, BD-tau and BD-p-tau217 were elevated in AD only, improving diagnostic accuracy. Mass spectrometry revealed a central-to-peripheral shift from BD-tau to big tau predominance, with exclusively big p-tau217 detected in muscle. Selective detection of BD-tau species improves the specificity of blood AD biomarkers by reducing peripheral tau confounding.}, } @article {pmid42906263, year = {2026}, author = {Hawas, Y and Abo-Elnour, DE and Al-Hawari, NEM and Gahlan, S and Winkelman, JW}, title = {Restless legs syndrome and other neurological disorders: A systematic-narrative hybrid literature review with exploratory meta-analysis.}, journal = {Sleep medicine reviews}, volume = {90}, number = {}, pages = {102390}, doi = {10.1016/j.smrv.2026.102390}, pmid = {42906263}, issn = {1532-2955}, abstract = {Restless legs syndrome (RLS) is a sleep-related sensorimotor disorder affecting approximately 3% of adults worldwide. This review aims to synthesize current evidence on associations between RLS and major neurological conditions, provide an exploratory quantitative synthesis summarizing association patterns and heterogeneity, and identify priority mechanistic and clinical research gaps. Databases were searched from inception until August 2026. In our exploratory synthesis of 119 unique studies, RLS was significantly associated with Parkinson's disease (case-control OR 3.22, 95% CI 2.35-4.41; cohort RR 1.74, 95% CI 1.02-2.95), multiple sclerosis (OR 4.04, 95% CI 3.26-5.00), neuromyelitis optica spectrum disorder (OR 2.91, 95% CI 1.45-5.84), migraine or headache disorders (forward OR 2.72, 95% CI 2.19-3.38; reverse adjusted OR 1.53, 95% CI 1.36-1.73), peripheral neuropathy (OR 3.82, 95% CI 2.49-5.83), epilepsy (OR 2.11, 95% CI 1.58-2.82), and amyotrophic lateral sclerosis (OR 7.69, 95% CI 2.74-21.59). This work is an evidence-mapping review with exploratory pooling and is not intended as a definitive evidence synthesis. RLS is likely associated with neurodegenerative and other specific neurological conditions. Recognition of these associations may support earlier identification of comorbid conditions and targeted management strategies. However, the current evidence remains observational and heterogeneous.}, } @article {pmid42907506, year = {2026}, author = {Lee, HJ and Doğan, C and Koyuncu, S and Wehrmann, M and Artan, M and Petrovic, D and Loureiro, R and Sahu, AK and Schnubel, J and Grobushkin, P and Prymidis, D and Georgomanolis, T and Sokol, A and Yang, M and Hoppe, T and Frezza, C and Vilchez, D}, title = {Cold activates a BH2 metabolic network promoting longevity and proteostasis.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {42907506}, issn = {1476-4687}, abstract = {Moderately cold temperatures extend lifespan and promote health across species[1-3], yet the molecular mechanisms underlying these benefits remain unclear. Here we define a metabolite-driven, multi-tissue signalling system that links cold temperature to enhanced longevity and proteostasis in Caenorhabditis elegans. Cold temperature upregulates the biopterin-synthesis enzyme CAT-4 (GCH1 in humans), increasing production of dihydrobiopterin (BH2), a transportable reservoir for the bioactive cofactor tetrahydrobiopterin (BH4). BH2 is produced in muscle and transported to distal tissues, including the intestine and neurons, where it is converted into BH4 by the salvage enzyme DHFR-1. BH4 functions as an essential cofactor for phenylalanine hydroxylase PAH-1, promoting tyrosine synthesis and extending lifespan. This BH2-BH4 axis also prevents disease-related protein aggregation and subsequent neuronal dysfunction during ageing. Importantly, increasing BH2 synthesis specifically in muscle is sufficient to promote longevity and suppress pathological protein aggregation in distal tissues, even at normal or elevated temperatures. In human cells, BH2 or tyrosine supplementation reduces aggregation of polyQ-expanded proteins associated with Huntington's disease, as well as mutant variants of TDP-43 and FUS that cause amyotrophic lateral sclerosis. Together, these findings identify BH2 as a cold-induced metabolite of which the synthesis, intertissue transport and conversion into bioactive BH4 preserve organism-wide proteostasis and extend lifespan.}, } @article {pmid42908777, year = {2026}, author = {Wang, M and Mak, C and Li, X and Li, S and Cui, C and Cai, D and Liang, Z and Lu, T and Jia, Q and Shao, X and Ma, Y and Fan, G and Li, K and Mai, W and Mak, C and Liu, N}, title = {Case Report: Herbal nutritional intervention in a critically ill ALS patient with multidrug-resistant infection.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1912856}, pmid = {42908777}, issn = {2296-858X}, abstract = {We report a retrospective single case of a female patient with a 9-year history of amyotrophic lateral sclerosis (ALS) who presented with respiratory failure due to a multidrug-resistant organism (MDRO) infection, predominantly Klebsiella pneumoniae (KP), and who showed significant clinical improvement during a comprehensive treatment regimen that included an adjunctive herbal nutritional intervention. The objective of this retrospective single-case report was to describe the clinical course of this patient following a nutritional intervention with two herbal beverages: Sang Shen Pu Gong Ying (SSPGY) and Wu Zhi Mao Tao Hong Zao (WZMTHZ). The patient was admitted in critical condition and managed in three phases: initial antibiotics with occasional herbal beverages, daily herbal beverages, and a combination of herbal beverages with intermittent antibiotics. Retrospective analysis of clinical data revealed significant improvements post-intervention. Body weight increased from 26 kg to 35.5 kg at discharge and 39 kg at the 6-week follow-up. Vital signs normalized, with no detectable KP in the final hospital phase. Inflammatory markers, including C-reactive protein and white blood cell count, decreased markedly. Neurological status, as indicated by neurofilament light chain (NfL) levels, improved, and the patient showed respiratory autonomy and positional changes. Nutritional markers, total protein and creatinine, also improved. This case documents clinical improvements, including extended ventilator-free breathing periods, in an ALS patient with MDRO infection following a combined therapeutic approach. Although concurrent medical interventions were administered in real-world clinical practice, these findings suggest the potential value of this adjunctive intervention, warranting further systematic investigation. Clinical Trial Registration: identifier ITMCTR2024000322.}, } @article {pmid42913489, year = {2026}, author = {Huang, J and Zhang, S and Zhang, D and Yang, T and Li, C and He, M and Wang, J and Song, T and Wang, X and Lu, Y and Kong, Q and Tan, J and Zhang, J}, title = {Liquid-liquid phase separation in neurodegenerative diseases: Mechanisms, pathological transitions, and therapeutic opportunities.}, journal = {Science progress}, volume = {109}, number = {4}, pages = {368504261499190}, doi = {10.1177/00368504261499190}, pmid = {42913489}, issn = {2047-7163}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/genetics/therapy ; Phase Separation ; Animals ; Protein Aggregation, Pathological/metabolism ; Amyloid beta-Peptides/metabolism/chemistry/genetics ; DNA-Binding Proteins/metabolism/genetics ; Huntingtin Protein/genetics/metabolism ; tau Proteins/metabolism/genetics/chemistry ; alpha-Synuclein/metabolism/genetics/chemistry ; RNA-Binding Protein FUS/metabolism/genetics ; Biomolecular Condensates/metabolism ; }, abstract = {Liquid-liquid phase separation (LLPS) provides a biophysical framework for understanding biomolecular organization, yet its pathological relevance in neurodegeneration remains incompletely resolved. In this narrative review, we critically synthesize current evidence on LLPS in Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, focusing on mutant huntingtin, α-synuclein, amyloid-β, tau, TDP-43, and FUS. We first outline the molecular principles-including intrinsic disorder, multivalent interactions, and environmental sensitivity-that govern their phase behavior. We then examine how dynamic condensates may, under specific cellular contexts, transition toward less reversible oligomeric, gel-like, or solid assemblies, integrating evidence from in vitro, cellular, and in vivo studies. Importantly, current evidence does not support LLPS as a universal or obligatory precursor of pathological aggregation; rather, its biological consequences appear to depend on condensate composition, material properties, subcellular localization, and proteostasis capacity, while direct demonstration of disease-relevant condensates in vivo remains limited. We further discuss whether aberrant LLPS represents a cause, consequence, or context-dependent component of neurodegeneration and highlight emerging strategies that modulate condensate formation, maturation, or clearance while preserving physiological functions. Overall, this review defines both the mechanistic potential and current limitations of the LLPS framework and identifies key questions that must be addressed before pathological phase-state modulation can become a clinically actionable therapeutic strategy.}, } @article {pmid42913510, year = {2026}, author = {}, title = {Proceedings of the 25[th] Annual Meeting of the Northeast ALS Consortium.}, journal = {Muscle & nerve}, volume = {74 Suppl 2}, number = {}, pages = {S1-S112}, doi = {10.1002/mus.70436}, pmid = {42913510}, issn = {1097-4598}, } @article {pmid42915077, year = {2026}, author = {Ritchie, LM and Lester, MB and Sharma, AK and Patterson, JD}, title = {Quantified Interfacial Affinity of Hydrogen Sulfate and Sulfate Speciation in Model Marine Aerosol Particles.}, journal = {The journal of physical chemistry. A}, volume = {130}, number = {37}, pages = {7460-7468}, doi = {10.1021/acs.jpca.6c04034}, pmid = {42915077}, issn = {1520-5215}, support = {CHE-1708635//National Science Foundation/ ; CHE-2404123//National Science Foundation/ ; CHE-2404124//National Science Foundation/ ; }, abstract = {Heterogeneous reactions occurring in atmospheric aerosols are crucial components of multiple chemical reaction cycles. Sulfate species exert substantial influence on many heterogeneous reaction mechanisms due to their abundance and speciation. Despite the importance of sulfate species on heterogeneous reactions, quantitative descriptions of interfacial affinity and sulfate species partitioning at interfaces remain incomplete. Here, we quantify the interfacial properties of HSO4-, using cetyltrimethylammonium hydrogen sulfate (CTAHS) reverse micelles (RMs), as model marine aerosol particles. Infrared spectra (IR) of CTAHS RMs were collected and analyzed using multivariate curve resolution-alternating least-squares (MCR-ALS). MCR-ALS analysis reveals that four distinct species contribute to the observed IR spectra, which we assign as CTA+-HSO4- contact pairs (CPs), interfacial HSO4-, core HSO4-, and core SO42-. Computational studies reveal that the CTA+-HSO4- CPs exist in two distinct orientations at the interface. Spectral contributions from each chemical species are used to determine the quantitative interfacial affinity (χInt.) of HSO4-. Our observations indicate that the cationic charge of the interface alters the ionic distribution of sulfate species compared to air-water interfaces, placing H3O+ below HSO4-.}, } @article {pmid42916114, year = {2026}, author = {Milardi, D and Han, J and Lee, HJ and Ding, F and Miller, Y and Faller, P and Bush, AI and Crouch, PJ and Finkelstein, DI and Double, KL and Jeremic, A and Lim, MH and Ramamoorthy, A}, title = {Metal Ions and Protein Aggregation: Unraveling Molecular Interactions and Theranostic Prospects in Proteinopathies.}, journal = {Chemical reviews}, volume = {126}, number = {18}, pages = {10249-10333}, doi = {10.1021/acs.chemrev.5c00420}, pmid = {42916114}, issn = {1520-6890}, support = {R01AG048934/AG/NIA NIH HHS/United States ; R35GM13973/GM/NIGMS NIH HHS/United States ; R35GM145409/GM/NIGMS NIH HHS/United States ; R01DK132214/DK/NIDDK NIH HHS/United States ; NA//Florida State University/ ; NA//National High Magnetic Field Laboratory/ ; 2022PAAYZE//NextGenerationEU/ ; CUP: B53D23016440006//NextGenerationEU/ ; DP230101031//Australian Research Council/ ; GNT1194028//National Health and Medical Research Council/ ; GNT2019931//National Health and Medical Research Council/ ; RS-2022-NR070709//National Research Foundation of Korea/ ; RS-2022-NR073879//National Research Foundation of Korea/ ; RS-2024-00353015//National Research Foundation of Korea/ ; RS-2024-00411134//National Research Foundation of Korea/ ; MRF2007656//Medical Research Future Fund/ ; }, mesh = {Humans ; *Protein Aggregation, Pathological/metabolism/drug therapy ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Metals/chemistry/metabolism ; Animals ; Protein Aggregates ; }, abstract = {Protein aggregation is a pathological process associated with several human diseases termed proteinopathies, including neurodegenerative and metabolic disorders such as Alzheimer's disease, Parkinson's disease, type II diabetes, amyotrophic lateral sclerosis, and Huntington's disease. In these conditions, specific proteins misfold and accumulate into insoluble aggregates, disrupting normal cellular function and contributing to disease progression. Many studies have investigated the molecular mechanisms that underlie the aggregation pathways, the structure of aggregates, such as oligomeric intermediates and fibrils, and their cellular toxicity. Studies have also investigated the effects of cofactors like metals, lipids, other amyloid proteins, and small molecules. Recent research has increasingly emphasized the critical roles of metal ions such as copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn) in amyloid aggregation and toxicity. Alterations in metal ion transport, binding, or redox activity have been linked to the onset and progression of several amyloid-associated diseases. These metal ions can interact directly with amyloidogenic proteins, influencing their structural conformation, aggregation kinetics, and propensity to form toxic oligomers. This review aims to advance our understanding of how the regulation of metal ions within cells and their dysfunction contribute to the accumulation of harmful proteins, which is a key factor in proteinopathies. By examining the interactions between metal ions and key amyloidogenic proteins─including amyloid-β (Aβ), α-synuclein, tau, superoxide dismutase 1 (SOD1), human islet amyloid polypeptide (hIAPP), and insulin─we highlight both common and unique pathways through which metal ions influence protein aggregation. Additionally, this review explores the impact of metal ions on protein clearance mechanisms, such as autophagy and the ubiquitin-proteasome system, as well as emerging theranostic strategies. These include metal chelation therapies, metal-based imaging agents, and multifunctional compounds designed to restore metal balance while preventing aggregation and toxicity. By integrating biochemical, cellular, and therapeutic insights, this review contributes to a deeper understanding of the metallobiology of proteinopathies and supports the development of novel diagnostic and treatment approaches targeting metal-protein interactions.}, } @article {pmid42918320, year = {2026}, author = {Nasb, M and Yang, D and Malik, TH and Xu, D and Dayoub, L and Zhou, J and Zhao, Y}, title = {State transitions in amyotrophic lateral sclerosis: mechanistic convergence and biomarker-guided stratification.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2026.10.036}, pmid = {42918320}, issn = {1873-7544}, abstract = {BACKGROUND: Biological heterogeneity is a major obstacle to therapeutic development in amyotrophic lateral sclerosis (ALS). Cross-sectional pathway labels do not show whether a mechanism is active or treatment-relevant in an individual patient.

METHODS: We conducted a structured critical narrative review informed by the Scale for the Assessment of Narrative Review Articles. MEDLINE, Embase, PubMed, and CENTRAL were searched for English-language literature published from 1 January 2015 to 7 August 2026; seminal earlier studies were identified by citation tracking. Human genetic, pathological, longitudinal biomarker, multi-omic, imaging, neurophysiological, and interventional evidence was prioritized. Evidence was appraised by human proximity, temporality, replication, mechanistic specificity, and treatment relevance.

RESULTS: Evidence supports interacting RNA/proteostasis, nucleocytoplasmic-transport, glial-inflammatory, and energetic-metabolic processes, but current evidence does not yet support the use of any candidate state for individual treatment assignment. The most mature temporal example is loss of TDP-43 splicing repression before neurofilament elevation in genetically at-risk individuals. Nucleocytoplasmic-transport evidence is strongest in C9orf72 disease; inflammatory and metabolic signals are confounded by disease burden and systemic illness; and the gut-brain axis remains a context-dependent amplifier. We propose prespecified transition rules, evidence grades, and biomarker-by-treatment interaction tests.

CONCLUSIONS: A state-transition model becomes clinically useful when longitudinal measurements add value beyond clinical predictors and injury markers and prospectively identify differential treatment benefit.}, } @article {pmid42918387, year = {2026}, author = {Verma, A and Goyal, A and Agrawal, N and Yadav, HN}, title = {Cellular senescence in ageing and neurodegenerative disorders: Molecular mechanisms, biomarkers, and therapeutic strategies.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {}, number = {}, pages = {111985}, doi = {10.1016/j.pnpbp.2026.111985}, pmid = {42918387}, issn = {1878-4216}, abstract = {Cellular senescence has been increasingly associated with neurodegenerative disorders, potentially linking ageing-related cellular impairment with mitochondrial dysfunction, chronic inflammation, and disrupted intercellular signalling. The present study aims to explore the increasing relevance of cellular senescence among key cell types, including neurons, astrocytes, neural progenitor cells, microglia and oligodendrocyte-lineage cells across neurodegenerative ailments such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. This review discusses the findings of pre-clinical and clinical studies which suggest that senescence-associated features may contribute to neurodegeneration. Further, it provides an overview of the biomarkers used in the identification of senescence in the CNS. Also, the review examines senotherapeutic treatment approaches, highlighting their actions on different CNS cell types and the growing clinical evidence. It also points out the challenges in translating these approaches to clinical application, such as targeting specific cell types and the lack of suitable biomarkers. Collectively, present findings suggest that senescence-associated alterations may contribute to neurodegeneration, although their effects appear to vary across cell types and diseases.}, } @article {pmid42918426, year = {2026}, author = {Kipanyula, MJ}, title = {Neurodegeneration in Sub-Saharan Africa: Intersections of Biological Ageing, Genomic Diversity and the Lifetime Exposome.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {103429}, doi = {10.1016/j.arr.2026.103429}, pmid = {42918426}, issn = {1872-9649}, abstract = {Neurodegenerative diseases are emerging as an important consequence of population ageing in sub-Saharan Africa (SSA), but their scientific relevance extends beyond a projected rise in case numbers. SSA combines exceptional human genomic diversity with marked heterogeneity in vascular and metabolic risk, infection, nutrition, occupational exposures, air pollution, and access to health care. This combination creates an underused setting in which to study why biological ageing produces neurodegeneration in some individuals but relative resilience in others. This review critically synthesises evidence on Alzheimer's disease and related dementias, Parkinson's disease, amyotrophic lateral sclerosis/frontotemporal degeneration, Huntington's disease and related disorders, focusing on the intersection between hallmarks of ageing, disease-specific proteinopathies, ancestry and the lifetime exposome. Age-associated loss of proteostasis, mitochondrial dysfunction, impaired autophagy, chronic inflammation, neurovascular injury and genomic/epigenomic instability provide a mechanistic scaffold on which genetic susceptibility and cumulative exposures may act. Yet African evidence remains dominated by cross-sectional clinical phenotyping; neuropathology, longitudinal biomarkers, multi-omics and measured environmental exposures remain sparse. Recent African-ancestry Parkinson's disease genomics and emerging plasma biomarker studies demonstrate that ancestry-inclusive molecular neuroscience is feasible and can generate findings not predictable from European-ancestry datasets. The next phase should therefore move beyond documenting underdiagnosis toward longitudinal, biologically anchored cohorts that integrate phenotype, genomics, blood biomarkers, neuroimaging, exposomics, digital measures and health-system outcomes. This review proposes a research framework centred on biological ageing, gene-environment interaction and resilience. Such work would improve the validity of prevention, diagnosis and therapeutic translation in African populations while contributing globally to a more complete biology of neurodegenerative ageing.}, } @article {pmid42902402, year = {2026}, author = {Ufer, F and Rössling, R and Spottke, A and Németh, R and Schaprian, T and Coninck, NK and Gamez, A and Sterl, R and Naumann, P and Behr, N and Maier, A and Meyer, T and Weydt, P and Prüss, H}, title = {ABCD-Trial: study protocol for a randomized, double-blind, placebo-controlled study in patients with Amyotrophic lateral sclerosis for the evaluation of efficacy and safety of B-Cell Depletion with rituximab (ABCD).}, journal = {Trials}, volume = {27}, number = {1}, pages = {}, pmid = {42902402}, issn = {1745-6215}, mesh = {Humans ; *Rituximab/therapeutic use/adverse effects ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology/diagnosis ; Double-Blind Method ; *B-Lymphocytes/drug effects/immunology ; Male ; Treatment Outcome ; Female ; Randomized Controlled Trials as Topic ; Disease Progression ; *Lymphocyte Depletion/methods/adverse effects ; *Immunologic Factors/adverse effects/therapeutic use ; Time Factors ; Middle Aged ; }, abstract = {BACKGROUND: The exact disease-causing mechanisms in ALS remain incompletely understood. A possible cause is inflammation of neurons. Compared to other neurodegenerative diseases, neuroinflammation is pronounced in ALS, presumably leading to disease progression and neuronal death. Patients with ALS can have neuronal autoantibodies and most notably antibody-producing cells in the cerebrospinal fluid. The CD20-binding therapeutic antibody rituximab targets these antibody-producing B-cells. Rituximab is a medication commonly used in neurology. Single patients with ALS have already been treated with rituximab, which was well tolerated. We therefore want to evaluate safety and efficacy of a treatment with rituximab in ALS patients in a double-blind placebo-controlled trial. With this trial we aim for slower disease progression and unveiling disease-causing mechanisms in ALS.

METHODS: A total of 52 male and female patients older than 18 years with active sporadic ALS and disease duration of less than 24 months who are on a stable dose of riluzole (50 mg BID) should be included. Patients requiring assisted ventilation of any kind or have a known intolerance to the study medication rituximab are excluded. The study medication rituximab or placebo should be administered over a period of 52 weeks at 4 distinct time points, followed by a follow-up period of 79 weeks with 4 visits. Treatment efficacy should be evaluated using the ALS functioning scale ALSFRS-R-SE at every study visit (except safety visits). Safety will be assessed through regular laboratory analyses, adverse event (AE) and serious adverse event (SAE) monitoring, and CD20+ B-cell kinetics. The primary endpoint is the change in the ALS Functional Rating Scale-Revised (ALSFRS-R-SE) from baseline to week 79. Trial sites will be at Charité/DZNE Berlin and DZNE Bonn.

DISCUSSION: ALS is a rapidly progressive neurodegenerative disease with limited treatment options. Recent preclinical in vivo studies suggest that B-cell-mediated autoimmunity contributes to disease progression. This trial will evaluate whether rituximab, which specifically depletes CD20+ B-cells, can slow ALS progression and provide insights into disease mechanisms.

TRIAL REGISTRATION: The trial was registered in the German WHO-recognized primary register Deutsches Register Klinische Studien DRKS (German Clinical Trials Register) on 3/07/2023 under registration number DRKS00030948.}, } @article {pmid42902541, year = {2026}, author = {Purvis, C and Patterson, EL and Burns, EE}, title = {Characterizing geographic diversity of acetolactate synthase resistance in US johnsongrass (Sorghum halepense) biotypes.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71430}, pmid = {42902541}, issn = {1526-4998}, support = {//United Soybean Board/ ; }, abstract = {BACKGROUND: Acetolactate synthase (ALS)-inhibiting herbicides are widely used for Sorghum halepense weed control across agroecosystems. However, little is known about variation in resistance phenotypes and mechanisms among geographically diverse biotypes. This study surveyed S. halepense biotypes collected across the USA to quantify resistance to ALS inhibitors, identify target and non-target site mechanisms, and evaluate alternative herbicide options.

RESULTS: Dose response assays identified nicosulfuron resistance in 24% of evaluated biotypes, with resistant biotypes ED50 ranging from 66 to >4160 g ha[-1]. Among nicosulfuron resistant biotypes, 56% and 44% were also resistant to imazethapyr and thiencarbazone, respectively, demonstrating variability in resistance patterns among ALS herbicides of different chemical families. A novel primer set enabled simultaneous screening of all reported ALS resistance mutations across both ALS homeologs. Molecular screening identified the Trp574 substitution as the sole target-site resistance mechanism in 64% of resistant biotypes. Further, Trp574 mutation frequency varied among resistant biotypes, ranging from 21% to 91%, and was positively correlated with nicosulfuron resistance level. Resistant biotypes lacking target-site mutations exhibited over eightfold reductions in nicosulfuron ED50 following malathion pretreatment, suggesting involvement of cytochrome P450 non-target site resistance mechanisms. Despite the identification of these mechanisms, glyphosate and clethodim remained effective for S. halepense control in all but one biotype.

CONCLUSION: Overall, we demonstrated that ALS resistance in S. halepense varies across geographically diverse biotypes from the USA. Together, these findings provide important insight for resistance evolution and support development of management strategies for ALS resistant S. halepense biotypes. © 2026 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid42904191, year = {2026}, author = {Quy, K and Doan, AT and Vu, TM and Nguyen, TM and Nguyen, D}, title = {Lower Motor Neuron Disease Misclassified As Inflammatory Myopathy in a Young Woman With Myositis-Specific Antibodies.}, journal = {Cureus}, volume = {18}, number = {9}, pages = {e116583}, doi = {10.7759/cureus.116583}, pmid = {42904191}, issn = {2168-8184}, abstract = {A 30-year-old woman presented with slowly progressive neck and proximal limb weakness over three years. Initial evaluation showed moderate creatine kinase elevation, anti-Mi-2β and anti-glycyl-tRNA synthetase (EJ) positivity, and electrophysiological and muscle biopsy findings interpreted as inflammatory myopathy. She was diagnosed with polymyositis and received multiple immunosuppressive therapies without clinical improvement. Despite normalization of creatine kinase, weakness and muscle wasting progressed. Re-evaluation revealed profound generalized atrophy, hyporeflexia, widespread limb and tongue fasciculations, and preserved sensation. Nerve conduction studies showed markedly reduced motor amplitudes with relative preservation of sensory responses, while repeat muscle biopsy demonstrated severe chronic neurogenic atrophy. Genetic testing identified a heterozygous FIG4 p.Arg197Cys variant of uncertain significance. Lower motor neuron dysfunction was demonstrated in multiple anatomical regions, and the overall clinical and electrophysiological findings were consistent with the Gold Coast diagnostic framework for amyotrophic lateral sclerosis with a lower-motor-neuron-predominant phenotype. Immunosuppression was withdrawn, weakness continued to progress, and mechanical ventilation was required approximately six months later. This case highlights the need to reconsider the diagnosis when presumed inflammatory myopathy progresses despite biochemical improvement and adequate immunosuppressive therapy, particularly when neurogenic features emerge.}, } @article {pmid42904327, year = {2026}, author = {Paquet, A and Touzel-Deschênes, L and Roy, V and Brisson, JD and Mathieu, J and Dupré, N and Saikali, S and Gros-Louis, F}, title = {Cytoplasmic TDP-43 Accumulation in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-7}, doi = {10.1017/cjn.2026.10695}, pmid = {42904327}, issn = {0317-1671}, abstract = {BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare, early-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, spasticity and peripheral neuropathy. It is caused by biallelic mutations in the SACS gene, which encodes sacsin, a large protein involved in cytoskeletal organization and mitochondrial homeostasis, and protein quality control. Despite advances in understanding sacsin biology, the molecular mechanisms underlying neurodegeneration in ARSACS remain incompletely understood. Here, we report the first neuropathological evidence of pathological TAR DNA-binding protein 43 (TDP-43) accumulation in ARSACS.

METHODS: Available postmortem brain tissue from a genetically confirmed ARSACS patient homozygous for the Quebec founder mutation (SACS c.8844delT) was analyzed by immunohistochemistry, immunofluorescence and biochemical fractionation.

RESULTS: Neurons in the prefrontal cortex, motor cortex and cerebellum exhibited cytoplasmic phosphorylated dot-like TDP-43 (pTDP-43) aggregates with reduced nuclear localization. Biochemical fractionation further identified detergent-insoluble TDP-43 species in ARSACS tissue. Additional pathological features included increased neurofilament accumulation, vacuole-like neuronal changes, Purkinje cell loss and p62-positive cytoplasmic inclusions. Similar dot-like cytoplasmic pTDP-43 aggregates were observed in a second ARSACS case.

CONCLUSION: These findings identify pTDP-43 as a previously unrecognized pathological feature of ARSACS. While the patient exhibited no clinical or histopathological signs of amyotrophic lateral sclerosis, the presence of atypical pTDP-43 aggregates observed in ARSACS may represent a rare, secondary, early-stage or potentially underrecognized manifestation of TDP-43 pathology rather than a defining hallmark of the disease. Further studies in additional patients and experimental ARSACS models will be required to determine the prevalence and mechanistic basis of TDP-43 abnormalities in this disorder.}, } @article {pmid42904407, year = {2026}, author = {Dalkvist, M and Ersson, K and Bergström, S and Ekström, M and Emilsson, ÖI and Grote, L and Ingre, C and Kläppe, U and Lundström, S and Nygren, I and Sundh, J and Palm, A}, title = {End-of-life care of patients with amyotrophic lateral sclerosis and home mechanical ventilation: the national population-based DISCOVERY study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2747563}, pmid = {42904407}, issn = {2167-9223}, abstract = {Background: Home mechanical ventilation (HMV), including noninvasive ventilation (NIV) and invasive ventilation (IV), is increasingly used in people with amyotrophic lateral sclerosis (pwALS), but its impact on end-of-life care remains unclear. Objective: To examine whether ventilation pathway (NIV or IV) influences symptom prevalence and relief during the final week of life in pwALS. Secondary objectives were to assess end-of-life discussions, place and cause of death, and anticipated death. Methods: This national, population-based retrospective cohort study included pwALS using HMV in the Swedish National Quality Registry for Respiratory Failure (Swedevox), cross-linked with the Swedish Register of Palliative Care, which contains staff-reported end-of-life data, and other national registries. Results: Among 652 pwALS, 609 received NIV (mean age 66 years, 42% female) and 43 IV (mean age 60 years, 42% female). Anxiety and breathlessness were more common in the NIV group (76% vs 48% and 72% vs 31%, both p < 0.001), while prevalence and relief of other symptoms were similar between groups. Most patients had end-of-life discussions (NIV 87%, IV 92%). NIV patients more often died in specialized palliative wards (22% vs 7%, p = 0.023). Most deaths were due to ALS (96%) and were anticipated (NIV 94%, IV 88%). Conclusions: In pwALS with HVM, NIV was associated with higher rates of anxiety and breathlessness in the final week of life, but the ventilation pathway did not influence overall symptom relief. End-of-life communications and cause of death were similar; place of death differed by ventilation pathway; however, most deaths were anticipated.}, } @article {pmid42904859, year = {2026}, author = {Zhang, L and Zhang, L and Zheng, Y and Zhuang, Z and Tang, L and Zheng, W and Xia, K and Ye, S and Yin, T and Huang, T and Fan, D}, title = {Plasma Lipidome Is Dysregulated in Amyotrophic Lateral Sclerosis and Associated With Life-Course Adiposity Polygenic Risk.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {17}, number = {5}, pages = {e70410}, doi = {10.1002/jcsm.70410}, pmid = {42904859}, issn = {2190-6009}, support = {82101490//National Natural Science Foundation of China/ ; 81873784//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; //National Clinical Key Specialty Construction Program of China (2024)/ ; //Peking University Clinical Scientist Training Program/ ; 20250824//Young Elite Scientists Sponsorship Program of the Beijing High Innovation Plan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics ; *Adiposity/genetics ; Female ; *Lipidomics/methods ; Genetic Risk Score ; Male ; Middle Aged ; Genetic Predisposition to Disease ; *Lipids/blood ; Lipid Metabolism ; Aged ; Risk Factors ; Biomarkers ; *Multifactorial Inheritance ; }, abstract = {OBJECTIVE: Although both pre-symptomatic adiposity and dysregulated lipid metabolism are implicated in amyotrophic lateral sclerosis (ALS), the mechanistic pathways linking adiposity to disease remain unclear. This study aimed to investigate how genetic predisposition to adiposity might influence ALS through specific lipid metabolic pathways.

METHODS: We conducted mass spectrometry-based quantitative lipidomics on plasma from 104 ALS patients and 78 age- and sex-matched controls. Life-course adiposity polygenic risk scores (PRS) for birth weight, body fat percentage, appendicular lean mass and whole-body fat-free mass were constructed. Associations and PRS-by-disease interaction effects on the lipidome were evaluated.

RESULTS: Compared to controls, ALS patients exhibited widespread lipid dysregulation. Seventy-eight lipid species were significantly altered (FDR  < 0.05, |Cohen's d| > 1.0), characterized by a predominant decrease in acylcarnitines (75% of species) and distinct shifts within sphingolipid and glycerophospholipid subclasses. A three-acylcarnitine candidate panel (C10:0, C12:0 and C18:2) using fivefold analysis with feature selection repeated within each training fold yielded an overall out-of-fold AUC of 0.958. Exploratory PRS-by-disease-status analyses identified 16 nominal interaction signals, including 13 acylcarnitines; no significant mediation effect of lipids between PRS and ALS risk was detected.

CONCLUSION: These findings identify robust ALS-associated plasma lipid alterations, and our exploratory findings suggest that genetic predisposition to adiposity may shape the pattern of lipid metabolic disruption in ALS, offering new insights into the disease's metabolic pathophysiology.}, } @article {pmid42905162, year = {2026}, author = {Stapf, CD and Uzelac, Z and Iterbeke, L and Guthknecht, A and Barba, L and Strube, D and Kölsch, A and Kleeberg, K and Kendzierski, T and Roos, A and Steinacker, P and Abu-Rumeileh, S and Claeys, KG and Weishaupt, J and Mensch, A and Otto, M}, title = {Serum p-tau181 and p-tau217 levels in adolescents and adults with 5q spinal muscular atrophy.}, journal = {Journal of neurology}, volume = {273}, number = {11}, pages = {}, pmid = {42905162}, issn = {1432-1459}, support = {Clinician Scientist Programme n. CS25/01//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; Clinician Scientist Programm No. CS22/06//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; Clinician Scientist Programm No. CS26/01//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; FTLDc 01GI1007A//German Federal Ministry of Education and Research/ ; D.3830//foundation of the state Baden-Württemberg/ ; }, mesh = {Humans ; Female ; *tau Proteins/blood ; Male ; Adolescent ; Biomarkers/blood ; Retrospective Studies ; Adult ; *Muscular Atrophy, Spinal/blood/drug therapy/physiopathology ; Middle Aged ; Phosphorylation ; Young Adult ; Amyotrophic Lateral Sclerosis/blood ; Alzheimer Disease/blood ; *Spinal Muscular Atrophies of Childhood/blood ; Aged ; Longitudinal Studies ; }, abstract = {BACKGROUND: Reliable blood biomarkers for longitudinal monitoring in adolescent and adult 5q spinal muscular atrophy (SMA) are lacking. Phosphorylated tau (p-tau) species are elevated in serum in amyotrophic lateral sclerosis (ALS), where they may reflect peripheral nerve and muscle pathology. We aimed to investigate serum p-tau181 and p-tau217 as longitudinal biomarkers in adolescent and adult SMA and assessed associations with clinical parameters.

METHODS: In this retrospective multi-centre study, we assessed serum p-tau181 and p-tau217 levels in adults with 5q SMA under treatment with nusinersen or risdiplam, comparing levels with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and non-neurodegenerative disease controls. Associations with motor function, respiratory capacity, creatine kinase (CK), and neurofilament light chain (NfL) were assessed using linear mixed-effects models adjusted for age and sex.

RESULTS: Serum p-tau181 was higher in SMA than in disease controls (β = -0.48, 95%-CI -0.81 to -0.15), but lower than in ALS (β = 0.99, 95%-CI 0.58 to 1.39) and AD (β = 0.56, 95%-CI 0.11 to 1.00). P-tau181 declined from baseline to FUP2 (Δ median -1.80 pg/mL, IQR -5.90 to 2.10); p-tau217 showed no longitudinal change. P-tau181 and p-tau217 were positively associated with motor function, functional status, respiratory capacity, and CK, with no association with NfL. In exploratory analyses, higher baseline p-tau181 was associated with greater HFMSE decline (β = 1.79, 95%-CI 0.59 to 2.99).

CONCLUSIONS: Serum p-tau181 and p-tau217 appear to reflect ongoing muscle turnover in adult SMA, declining as muscle mass decreases. Higher baseline p-tau181 was associated with subsequent functional deterioration, suggesting potential utility as a biomarker of active denervation and disease monitoring.}, } @article {pmid42905245, year = {2026}, author = {Nowell, WB and McGale, N and Levy, O and Przydzial, K and Patel, N and Cleanthous, S and Andrews, JA and Rofail, D}, title = {Understanding Holistic Patient-Relevant Measurement in Amyotrophic Lateral Sclerosis: A Mixed-Methods Content Validity and Exploratory Rasch Analysis of Selected Clinical Outcome Assessments.}, journal = {Neurology and therapy}, volume = {}, number = {}, pages = {}, pmid = {42905245}, issn = {2193-8253}, abstract = {INTRODUCTION: Living with amyotrophic lateral sclerosis (ALS) has a profound impact on function and health-related quality of life (HRQoL). This mixed-methods study aimed to cognitively debrief selected ALS outcome measures to investigate their relevance and conduct exploratory Rasch Measurement Theory (RMT) analyses to assess targeting.

METHODS: Semi-structured interviews were conducted (January-September 2024) with people living with ALS (PLwALS) and clinicians to cognitively debrief selected patient- and clinician-reported outcome (PRO and ClinRO) measures. The PRO measures debriefed with PLwALS were Rasch Overall ALS Disability Scale (ROADS), 5-item ALS Assessment Questionnaire (ALSAQ-5), and Neurological Fatigue Index for Motor Neurone Disease (NFI-MND). ROADS and ClinRO ALS Functional Rating Scale-Revised (ALSFRS-R) were debriefed with clinicians. Interview transcripts were qualitatively analyzed; structured codes were used to compile data on item relevance and comprehensiveness. Exploratory RMT analysis was conducted using quantitative data from PLwALS responses to evaluate selected PRO psychometric properties.

RESULTS: Qualitative analysis of interviews with 31 PLwALS found that PROs were meaningful and relevant, and identified the relevance of individual items. Clinicians (n = 10) endorsed ALSFRS-R as a relevant and meaningful measure, and supported ROADS' conceptual coverage and response category. RMT analysis indicated evidence of good targeting, reliability, and item fit for the PROs, with some exceptions for ALSAQ-5.

CONCLUSION: This study supports the use of ALSFRS-R, ROADS, ALSAQ-5, and NFI-MND to measure meaningful aspects of ALS, with support for ALSAQ-5 qualified by its limited measurement precision. Scores from these measures can provide important insights into the lived experience of PLwALS, characterizing disease progression and HRQoL.}, } @article {pmid42905272, year = {2026}, author = {Tahedl, M and Toomey, A and Mandal, N and Mangan, S and Siah, WF and Tan, EL and Hardiman, O and Kleinerova, J and McKenna, MC and Hutchinson, S and Lope, J and Bede, P}, title = {Neurotransmitter-defined cerebral vulnerability patterns in frontotemporal lobar degeneration (FTLD).}, journal = {Journal of neurology}, volume = {273}, number = {11}, pages = {}, pmid = {42905272}, issn = {1432-1459}, support = {HRB JPND-Cofund-2025-3/HRBI_/Health Research Board/Ireland ; JPND - 2025 "Qual-Bulb-MND"//EU Joint Programme - Neurodegenerative Disease Research/ ; SFI SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {Humans ; Female ; *Neurotransmitter Agents/metabolism ; Male ; *Frontotemporal Lobar Degeneration/diagnostic imaging/pathology/metabolism ; Middle Aged ; Aged ; Magnetic Resonance Imaging ; Atrophy ; Prospective Studies ; *Brain/diagnostic imaging/metabolism/pathology ; }, abstract = {BACKGROUND: Frontotemporal dementia syndromes encompass a genetically, clinically and radiologically heterogeneous set of conditions with distinctive clinical and imaging characteristics. The main FTD phenotypes exhibit strikingly different disease burden patterns with a predilection to specific brain regions and relative sparing of others. The apparent selectivity of cerebral involvement in FTD has not been fully elucidated.

METHODS: A prospective neuroimaging study has been undertaken with a uniform imaging protocol to characterise atrophy patterns in ALS-FTD, behavioural variant FTD, nonfluent variant primary progressive aphasia, and semantic variant primary progressive aphasia and evaluate associations with physiological neurotransmitter receptor expression maps. Anatomical correlations between focal volume loss and a large panel of neurotransmitters were systematically evaluated and associations ranked.

RESULTS: Associations were noted with GABAergic, opioid, cannabinoid, microglial and acetylcholine systems in ALSFTD-C9NEG. Correlations were observed with opioid, glutaminergic, and synaptic vesicle glycoprotein 2A receptor populations in ALSFTD-C9POS. Atrophy in bvFTD showed predilection to serotonergic, glutaminergic, opioid, GABAergic and cannabinoid circuits. Volume loss in nfvPPA colocalised with GABAergic, opioid, microglial, serotonergic, cannabinoid, acetylcholine, glutaminergic and dopaminergic networks. A multitude of neurotransmitter populations are implicated in svPPA including opioid, serotonergic, GABAergic, dopaminergic, and microglial systems.

DISCUSSION: The distinctive neuroimaging signatures of FTD phenotypes exhibit spatial associations with physiological neurotransmitter receptor density maps. The propensity of atrophy to specific brain regions in FTD subtypes may be defined by neurotransmitter populations. Our findings indirectly support the notion of neurotransmitter-system defined connectivity-based disease propagation in FTD.}, } @article {pmid42905535, year = {2026}, author = {Cheung, SW and Fogarty, MJ}, title = {Molecular signatures of selective motor neuron vulnerability in old age.}, journal = {Experimental physiology}, volume = {}, number = {}, pages = {}, doi = {10.1113/EP094279}, pmid = {42905535}, issn = {1469-445X}, support = {R01 AG086136/NH/NIH HHS/United States ; }, abstract = {Motor neuron (MN) death and impairment of fast-fatigable motor units is widely recognized in elderly humans and rats. However, the molecular signatures identifying vulnerable MNs remains underexplored. In murine models of amyotrophic lateral sclerosis, matrix metalloproteinase 9 (MMP-9) and chondrolectin (Chodl) decline with disease progression and have been considered molecular markers of fast-fatigable MNs. However, their expression in brainstem and lumbar MNs, in accordance with the 'size principle' (in which motor units are recruited in a size-dependent manner, with MNs of lower capacitance activated before those of greater capacitance) and their expression throughout the lifespan remain unclear. Here, we evaluated MMP-9 and Chodl in lumbar and hypoglossal MNs in young (6 months) and old (24 months) Fischer 344 (F344) rats. Longitudinal lumbar spinal cord transverse brainstem sections (the orientations providing maximal MN somal sizes for each pool) were immunolabelled for choline acetyltransferase, MMP-9 and Chodl. Expression was quantified using confocal microscopy in young and old rats (n = 5 females, n = 5 males per age). Overall, MMP-9 demonstrated a positive association with lumbar MN somal surface area in young rats. Paired within-animal analysis showed that in larger MNs, MMP-9 positivity was ∼70% greater than smaller MNs. The size-dependence of MMP-9 expression was absent in old lumbar MNs, suggesting either selective loss or downregulation of MMP-9 MN expression in ageing. No size-dependent change in Chodl was observed in lumbar or hypoglossal MNs, nor was MMP-9 associated with MN size in hypoglossal MNs. Collectively, these findings identify MMP-9 as a marker enriched within large lumbar MNs in young rats and suggest that age-related alterations in MMP-9 expression may reflect the selective vulnerability of the lumbar MNs.}, } @article {pmid42901819, year = {2026}, author = {Obara, K and Janelidze, S and Ito, D and Karlsson, L and Yamamoto, M and Mastrangelo, A and Tran, S and Tsujikawa, K and Nishio, Y and Ogi, T and Vacchiano, V and Liguori, R and Nakamura, R and Atsuta, N and Sobue, G and Nilsson, C and Parchi, P and Katsuno, M and Mattsson-Carlgren, N}, title = {Cerebrospinal fluid amyloid and neurodegeneration biomarkers in the diagnosis and prognosis of amyotrophic lateral sclerosis: a multicohort observational study.}, journal = {EBioMedicine}, volume = {}, number = {}, pages = {106511}, doi = {10.1016/j.ebiom.2026.106511}, pmid = {42901819}, issn = {2352-3964}, abstract = {BACKGROUND: Neurofilament light chain (NfL) is an established biomarker for amyotrophic lateral sclerosis (ALS). However, it remains unclear whether biomarkers reflecting amyloid-β metabolism (Aβ), tau (phosphorylated tau, pTau), and astrogliosis (glial fibrillary acidic protein, GFAP) can complement NfL in clinical applications. It is also unclear how Alzheimer's disease (AD) co-pathology affects disease progression in ALS.

METHODS: We studied 264 patients with ALS and 164 disease-control participants, analysing baseline cerebrospinal fluid (CSF) NfL, Aβ peptides, pTau181, pTau217, and GFAP. A two-step diagnostic strategy was examined in individuals with intermediate NfL values, using machine-learning models. Prognostic associations were evaluated using linear mixed-effects and Cox models adjusted for established predictors; survival was additionally examined in pooled analyses including an external ALS cohort (n = 153).

FINDINGS: Patients with ALS exhibited higher CSF NfL, Aβ38, Aβ40, Aβ42, pTau181, and pTau217 than controls, even within Aβ-negative subgroups. NfL discriminated ALS from controls with an AUC of 0.85 (0.82-0.88), which increased to 0.90 (0.88-0.92) in machine-learning models incorporating additional biomarkers. The machine-learning models maintained a high positive predictive value (0.90) for classifying cases with intermediate NfL values. Significant Aβ × NfL interactions were observed for longitudinal functional decline, and pooled survival analyses showed stronger associations between NfL and survival in the Aβ-positive ALS subgroup (14%) than in the Aβ-negative ALS subgroup (HR 4.02 [2.17-7.45] vs 1.62 [1.36-1.92]).

INTERPRETATION: Multiple biomarker assessments can reduce misclassification of individuals with intermediate NfL values. CSF Aβ positivity modified the association between baseline NfL and disease progression. Personalised diagnosis and prognosis based on fine-grained co-pathology evaluation may enhance clinical management of ALS.

FUNDING: This study was primarily supported by JST SPRING (JPMJSP2125). A complete list of funding organisations is provided in Acknowledgements.}, } @article {pmid42901869, year = {2026}, author = {Su, WM and Duan, QQ and Zhang, N and He, SY and Liu, RY and Wen, XJ and Gu, XJ and Wang, Y and Cao, B and Chen, YP}, title = {Plasma Proteomic Signatures Predict Incident Amyotrophic Lateral Sclerosis: A Prospective Study Stratified by C9orf72 Expansion.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {17}, number = {5}, pages = {e70405}, doi = {10.1002/jcsm.70405}, pmid = {42901869}, issn = {2190-6009}, support = {82371422//the National Natural Science Fund of China/ ; 2026NSFSC0510//the Science and Technology Bureau Fund of Sichuan Province/ ; 2022YFC2703101//the National Key Research and Development Program of China/ ; 2023HXFH032//the 1·3·5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/epidemiology/diagnosis ; *C9orf72 Protein/genetics ; Prospective Studies ; *Proteomics/methods ; Male ; Female ; Biomarkers/blood ; Middle Aged ; Aged ; Incidence ; DNA Repeat Expansion ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder for which reliable preclinical biomarkers to predict disease onset are currently lacking. Plasma proteomics offers a promising avenue for early detection. The identification of plasma proteins and pathways associated with incident ALS holds potential to improve early diagnosis, enable risk stratification and provide insights into disease mechanisms.

METHODS: Employing the Olink Explore platform, we quantified 2920 plasma proteins within a prospective cohort of UK Biobank participants. Multivariate Cox proportional hazards regression was utilized to identify proteins associated with incident generalized ALS, C9-ALS (C9orf72-associated ALS) and non-C9-ALS. Enrichment analysis was conducted to delineate the biological pathways implicated by the identified proteins. Associations between plasma protein levels and the age at onset (AAO) of ALS were assessed via linear regression, while a multivariate Cox model was employed to evaluate the relationships between protein levels and ALS survival. We subsequently assessed potential causal relationships using Mendelian randomization (MR) and colocalization and analysed protein cross-sectional temporal patterns in ALS.

RESULTS: In this prospective cohort study, we followed 52 584 participants from the UK Biobank for a mean of 11.8 years. During this period, 291 (0.55%) incident cases of ALS were identified, among whom 34 individuals carried the C9orf72 hexanucleotide repeat expansion mutation. Nine proteins demonstrated associations with all-type ALS risk (FDR < 0.05): NEFL (HR: 2.897), CSRP3 (HR: 1.233), MYBPC1 (HR: 1.352), MEGF10 (HR: 1.744), MYOM3 (HR: 1.289) and THBS4 (HR: 1.570) were identified as risk factors, whereas EGFLAM (HR: 0.402), ITGAV (HR: 0.284) and CD248 (HR: 0.573) exhibited protective effects. NEFL (HR: 2.742) and three additional proteins were primarily associated with non-C9-ALS, while only NEFL (HR: 4.403) and COL5A1 (HR: 3.072) showed significant associations with C9-ALS. When combined with age and sex, these proteins yielded area under the curve (AUC) values exceeding 0.750 for predicting ALS at 3, 5 and 10 years. Furthermore, elevated NEFL levels were correlated with an earlier onset of non-C9-ALS and began to increase approximately 9.27 years prior to diagnosis, reaching a peak 1-2 years before clinical presentation in non-C9ALS cases via cross-sectional temporal analysis. Pathway analysis implicated muscle-related, extracellular matrix, energy metabolism and inflammatory pathways.

CONCLUSIONS: This investigation uncovers extensive alterations in plasma proteins associated with ALS risk, revealing potential novel biomarkers for both sporadic and C9orf72-linked forms of the disease. These results enhance our comprehension of early ALS pathogenesis and provide a foundation for subsequent biomarker identification and the development of targeted therapeutic strategies.}, } @article {pmid42896458, year = {2026}, author = {Ozawa, M and Yoshimaru, D and Ishii, K and Okano, HJ and , }, title = {Data-driven progression trajectories across clinical subtypes of amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {491}, number = {}, pages = {126224}, doi = {10.1016/j.jns.2026.126224}, pmid = {42896458}, issn = {1878-5883}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) exhibits substantial clinical heterogeneity; however, conventional classifications based on the predominant site of involvement may not fully capture patterns of disease progression. This study aimed to identify data-driven subtypes of ALS and reconstruct their temporal progression using item-level scores from the ALS Functional Rating Scale-Revised (ALSFRS-R).

METHODS: Baseline data from 3067 participants in the Pooled Resource Open-Access ALS Clinical Trials database were analyzed. Subtype and Stage Inference (SuStaIn) was applied to ALSFRS-R item scores to identify subtypes and infer their progression trajectories. Internal consistency was evaluated using complexity and sensitivity analyses. Longitudinal stability was assessed at 180 and 365 days. Associations with functional decline and survival were examined using adjusted statistical models.

RESULTS: Three clinically interpretable subtypes were identified, characterized by predominant upper-limb, lower-limb, or bulbar involvement. These subtypes exhibited distinct, consistent progression patterns across the analyses. Subtype stability was moderate short-term but limited longer-term; stage progression was largely monotonic. The bulbar subtype showed more rapid functional decline at both 180 and 365 days. Higher SuStaIn stage was associated with increased mortality. In an exploratory stage-stratified analysis, poorer survival was observed in the bulbar subtype than in the upper-limb subtype within the lower-stage group.

CONCLUSIONS: This study reconstructed ALS subtype-specific functional progression trajectories and inferred disease stage using a widely accessible clinical scale. SuStaIn-derived subtypes characterized patterns of functional heterogeneity, and higher stage was associated with increased mortality. Further prospective comparative validation is needed to establish the prognostic and clinical utility of this framework.}, } @article {pmid42896567, year = {2026}, author = {Gorenshtein, A and Adiniaev, Y and Liba, T and Barash, Y and Klang, E and Daniel, O}, title = {The calibration-to-accuracy mapping in P300 spellers does not transport across cohorts and was not restored by tested alignment or local recalibration.}, journal = {Journal of neural engineering}, volume = {}, number = {}, pages = {}, doi = {10.1088/1741-2552/aeb62c}, pmid = {42896567}, issn = {1741-2552}, abstract = {Objective A calibration-derived score has been related to online P300-speller accuracy in the same session, always within the cohort measured. We evaluated whether a mapping from that score to expected accuracy transports to withheld cohorts. Approach Retrospective secondary analysis of BigP3BCI 1.0.0, the largest evaluation of this relationship to date: 18 of 20 studies contributed 271 participants, 739 session-condition records, and 19,611 character selections. The predictor was a decoder's cross-validated discriminability on calibration epochs, one study withheld from development. Between-cohort variation was summarised by the random-effects standard deviation tau. Main Results The association was positive in all 18 cohorts but varied widely (r 0.190 to 0.928; participant-level r = 0.714, p < 0.001), with 12 CIs excluding zero. Pooled estimation error was 0.098 (95% CI 0.091 to 0.107) against a benchmark of 0.146. Calibration did not transport: intercept tau 0.87 (unrepresented-cohort interval -1.97 to 1.85, log-odds); cohort-specific slopes varied more than tenfold (tau 0.43, interval 0.111 to 2.005). Neither alignment (signal- or score-space) nor either nonlinear boundary meaningfully reduced this heterogeneity. Local recalibration with up to 16 participants did not reliably improve on transporting; refitting both intercept and slope was significantly worse than transporting at the smallest sizes. Median time per selection, a stopping-rule proxy, accounted for 66% of between-cohort slope variance in meta-regression. The four ALS cohorts gave an uncorrected slope spread of 0.223, against 0.560 overall. Significance The evaluated score is a classifier's cross-validated discriminability on each session's calibration data rather than the source studies' undocumented online decoder. That score reproducibly signals within-session accuracy, but its mapping to accuracy is cohort-specific and supports ranking sessions after local validation rather than reporting accuracy elsewhere. The four-cohort ALS subgroup appeared more homogeneous than the full archive, illustrating how conclusions about transportability from a small cohort set can be fragile. .}, } @article {pmid42898978, year = {2026}, author = {Peng, S and Wang, L and Ouyang, J and Liu, R}, title = {The Role of Astrocytes in the Inflammatory Response in Neurodiseases.}, journal = {MedComm}, volume = {7}, number = {11}, pages = {e71069}, pmid = {42898978}, issn = {2688-2663}, abstract = {Astrocytes have emerged as central regulators of neuroinflammation, extending far beyond their traditional roles as structural and metabolic support cells. In neurological disorders, astrocytes undergo reactive remodeling that encompasses morphological, transcriptional, metabolic, and functional changes. Rather than fitting into a fixed A1/A2 dichotomy, reactive astrocytes exist along a disease-, region-, and stage-dependent continuum shaped by local pathology and intercellular crosstalk. This review summarizes how astrocytes contribute to neuroinflammatory processes in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, central nervous system injury, infection, multiple sclerosis, epilepsy, and autism spectrum disorder. We highlight convergent mechanisms, including cytokine and chemokine release, complement activation, glutamate and ion homeostasis disruption, oxidative stress, metabolic reprogramming, and blood-brain barrier regulation, while emphasizing disease-specific astrocytic programs. We further discuss astrocyte interactions with microglia, neurons, oligodendrocytes, endothelial cells, and peripheral immune cells, as well as key regulatory pathways, epigenetic remodeling, and lipid-dependent metabolic signaling. Finally, we evaluate current and emerging astrocyte-targeted therapeutic strategies, including metabolic modulation, receptor targeting, gene editing, nanodelivery, and gut-brain axis interventions. Defining functionally validated astrocyte states and developing biomarker-guided, stage-adaptive therapies may enable more precise intervention in neuroinflammatory and neurodegenerative diseases.}, } @article {pmid42899523, year = {2026}, author = {Campanella, B and Birindelli, L and Legnaioli, S and Lorenzetti, G and Consani, C and Ales, V and Benedetti, E and Bertozzi, MA and Bramanti, E}, title = {Task-Dependent Synergy between FTIR and Raman Spectroscopy for Sperm Quality Prediction.}, journal = {Analytical chemistry}, volume = {98}, number = {41}, pages = {29684-29699}, doi = {10.1021/acs.analchem.6c04960}, pmid = {42899523}, issn = {1520-6882}, mesh = {Humans ; Male ; *Spectrum Analysis, Raman/methods ; Spectroscopy, Fourier Transform Infrared/methods ; *Spermatozoa/cytology ; Sperm Motility ; Semen/chemistry ; Biomarkers/analysis ; *Semen Analysis/methods ; }, abstract = {Male infertility affects approximately 15% of couples worldwide, contributing to 40-50% of infertility cases in Western countries. Standard semen analysis remains the cornerstone of fertility assessment, yet conventional parameters (concentration, motility, morphology) have limited predictive value for fertilization success. Vibrational spectroscopy, particularly Fourier transform infrared (FTIR) and Raman spectroscopy, offers rapid, nondestructive chemical fingerprinting of biological samples. However, optimal strategies for integrating multimodal spectroscopic data remain unclear, and the value of fusion may depend on the biological end point. This study systematically compares FTIR and Raman spectroscopy, both independently and through multiple fusion strategies, for predicting rectilinear progressive sperm motility (binary classification) and normal morphology (continuous regression) in human seminal plasma. We determine whether complementary information exists, when fusion provides value, and which strategy optimally leverages multimodal data. Building on Raman-derived Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) concentration profiles, we further develop a clinical classifier based on four seminal plasma biomarkers (human serum albumin, glutathione S-transferase, transferrin, lysophosphatidylcholine), validated by leave-one-patient-out cross-validation and Firth's penalized logistic regression to address near-complete separation in this small-sample setting (n = 30). Our findings reveal technique-specific advantages: Raman spectroscopy substantially outperforms FTIR for binary motility classification, with feature-level fusion matching but not exceeding Raman's performance, indicating limited complementarity. Conversely, FTIR alone achieves superior predictive accuracy for continuous morphological outcomes. The clinical classifier based on MCR-ALS-derived biomarkers achieved AUC (Area Under the ROC Curve) = 0.855, accuracy = 86.7%, and BER (Balanced Error Rate) = 0.136, with model significance confirmed by permutation testing. Elevated human serum albumin and lysophosphatidylcholine emerged as the strongest negative predictors of high motility, consistent with seminal tract inflammation and sperm-cytotoxic phospholipid accumulation, while transferrin showed a positive association in line with its role in iron availability for sperm function. These results demonstrate that optimal spectroscopic approaches depend on the biological end point, with Raman's structural sensitivity favoring motility assessment and FTIR's compositional profiling better capturing morphological variation. The biomarker-based classifier is easier to interpret and complements whole-spectrum models by bridging chemometric analysis and biological interpretation.}, } @article {pmid42892382, year = {2026}, author = {Fleshner, L and Chan, R and Klufas, T and Grant-Kels, JM and Zhou, AE}, title = {Reply to Botto et al's "Applicant interview metrics and preference signaling in dermatology: A serial cross-sectional study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.09.134}, pmid = {42892382}, issn = {1097-6787}, } @article {pmid42892517, year = {2026}, author = {Xu, Z and Chen, X and Yi, W}, title = {Cryo-EM advances in TDP-43 amyloid fibrils structure determination.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107659}, doi = {10.1016/j.nbd.2026.107659}, pmid = {42892517}, issn = {1095-953X}, abstract = {TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein whose pathological aggregation characterizes a spectrum of neurodegenerative disorders known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and chronic traumatic encephalopathy (CTE). Recent breakthroughs in cryo-electron microscopy (cryo-EM) have revolutionized our understanding of these diseases by resolving the atomic structures of TDP-43 amyloid fibrils. These structural insights have been pivotal in elucidating the transition from functional liquid-liquid phase separation (LLPS) to irreversible solid-state aggregation. This review synthesizes key cryo-EM findings from 2019 to 2026, encompassing fibrils formed by the full-length low-complexity domain, disease-relevant core fragments, and filaments extracted directly from patient tissues, as well as the pathological implications of distinct structural polymorphs. These findings not only deepen our understanding of the brain science aspects of the pathogenesis of TDP-43 proteinopathies, but also provide an important structural basis for the development of specific conformational diagnostic methods and targeted therapeutic drugs.}, } @article {pmid42894325, year = {2026}, author = {Shadfar, S and Parakh, S and Perri, E and Jagaraj, CJ and Assar Kashani, S and Beyers, K and Ragagnin, AMG and Laird, AS and Atkin, JD}, title = {Protein disulphide isomerase protects against ALS/FTD phenotypes associated with cyclin F in zebrafish and cellular models.}, journal = {Redox report : communications in free radical research}, volume = {31}, number = {1}, pages = {2732775}, doi = {10.1080/13510002.2026.2732775}, pmid = {42894325}, issn = {1743-2928}, mesh = {Animals ; Zebrafish/metabolism ; *Protein Disulfide-Isomerases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Cyclins/metabolism/genetics ; Humans ; *Frontotemporal Dementia/metabolism/genetics ; Phenotype ; Mutation ; Animals, Genetically Modified ; Apoptosis ; Endoplasmic Reticulum Stress ; }, abstract = {BACKGROUND: Mutations in CCNF, encoding cyclin F, cause a small proportion of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases. Mutant cyclin F mislocalises from the nucleus to the cytoplasm, impairs the ubiquitin proteasome system, disrupts endoplasmic reticulum (ER) to Golgi transport, and triggers ER stress and apoptosis. Protein disulphide isomerase (PDI), a redox-active ER chaperone of the thioredoxin superfamily, protects against ALS phenotypes induced by mutant SOD1, TDP-43, and FUS, but its activity against mutant cyclin F has not been examined.

OBJECTIVES: To test whether PDI overexpression prevents the cellular and behavioural phenotypes induced by the ALS/FTD-associated cyclin F[S621G] mutation.

METHODS: Neuro-2a cells were co-transfected with mCherry-tagged wild-type or mutant cyclin F[S621G] and V5-tagged PDI or empty vector. Subcellular localisation, XBP-1 and CHOP activation, proteasome reporter (GFPu) accumulation, nuclear morphology, and cleaved caspase-3 immunoreactivity were assessed by confocal microscopy. Transient transgenic zebrafish larvae generated by mRNA co-injection of cyclin F and PDI were assessed by photomotor response at 48 h post-fertilisation.

RESULTS: Mutant cyclin F[S621G] induced cytoplasmic mislocalisation, ER stress (assessed by XBP-1 and CHOP activation), proteasome dysfunction (indicated by GFPu accumulation), and apoptosis (assessed by nuclear condensation and caspase-3 activation), all of which were significantly attenuated by PDI co-expression. Zebrafish larvae expressing cyclin F[S621G] swam significantly shorter distances than uninjected or wildtype controls, and co-expression of PDI restored motor function to near-wildtype levels.

CONCLUSION: PDI protects against ALS/FTD-associated mutant cyclin F in both cellular and in vivo zebrafish models, identifying PDI as a redox-based therapeutic target for CCNF-linked ALS/FTD.}, } @article {pmid42894599, year = {2026}, author = {Naseer, A and Iqbal, N and Bibi, I and Shah, SAR and Khalid, M and Khalid, A}, title = {Molecular recognition of axonal injury-associated candidate hub genes and predicted inhibitors across Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, journal = {In silico pharmacology}, volume = {14}, number = {3}, pages = {259}, pmid = {42894599}, issn = {2193-9616}, abstract = {UNLABELLED: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) have converging molecular pathologies such as neuroinflammation, mitochondrial dysfunction, and axonal degeneration, but do not have broadly effective disease-modifying therapies. A novel computational strategy was used in this study with an integrated in-silico pipeline to determine common candidate hub genes across AD, PD, and ALS and to computationally screen candidate inhibitors. The gene expression datasets were retrieved from the Gene Expression Omnibus database and analyzed with limma R package for blood-derived gene expression datasets for AD (GSE63060), PD (GSE99039) and ALS (GSE112680). A multi-dataset intersection analysis revealed 138 genes commonly upregulated and 0 commonly downregulated genes, which were functionally enriched in immune regulation, apoptotic signaling and mitochondrial instability pathways. Protein-protein interaction network analysis identified three key genes (MMP9, PTPN6 and TNFRSF1A) as high-confidence candidate hub genes for AD, PD, and ALS. The ZINC library of 34,853 compounds was screened for drug-like properties using QikProp to yield 16,466 drug-like compounds. Based on the comparative screening results, the structure of MMP9 (PDB ID: 8K5Y) was chosen for further analysis and two of the selected compounds ZINC04582833, ZINC00047690 were identified as the two highest ranked compounds with docking scores of - 10.4 and - 9.7 kcal/mol respectively. Both complexes were further evaluated by 100 ns MD simulations, showing RMSD profile stability, maintained secondary structure for both complexes. The results in this study make ZINC04582833 and ZINC00047690 computationally prioritized candidates for shared neurodegenerative targets for experimental validation.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00774-6.}, } @article {pmid42894639, year = {2026}, author = {Wang, Y and Fournier, L and Wymann, B and Talbot, K and Luisier, R and Patani, R}, title = {OGT regulates RNA-binding protein nucleocytoplasmic partitioning, but this fails in amyotrophic lateral sclerosis.}, journal = {iScience}, volume = {29}, number = {11}, pages = {117807}, pmid = {42894639}, issn = {2589-0042}, abstract = {O-linked N-acetylglucosamine transferase (OGT) catalyzes the O-linked β-N-acetylglucosamine (O-GlcNAc) modification to proteins and has been implicated in a range of diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and currently incurable neurodegenerative disorder. However, the precise mechanisms by which OGT influences ALS pathogenesis remain largely unresolved. In this study, we used human-induced pluripotent stem cell (hiPSC)-derived spinal motor neurons (hiPSC-MNs), the principal cell type that undergoes degeneration in ALS, to systematically reveal that OGT-related mechanisms regulate RNA-binding protein (RBP) nucleocytoplasmic compartmentalization. Using a combination of antisense oligonucleotide (ASO) technology and small molecular pharmacology, we reveal two distinct regulatory mechanisms of RBP compartmentalization, including by intron-retaining transcript-mediated sequestration and O-linked N-acetylglucosaminylation (O-GlcNAcylation)-mediated nuclear transport. We finally examine the tractability of manipulating OGT activity in the ALS context but demonstrate that the OGT-related mechanisms governing RBP localization in healthy hiPSC-MNs are impaired in the context of ALS-causing VCP and TARDBP mutations.}, } @article {pmid42895147, year = {2026}, author = {Chaudhary, S and Dhankhar, S and Saini, M and Singh, TG and Chauhan, S and Kumar, V}, title = {Mechanistic Evaluation of Psilocybin in Neurodegenerative Disorders: Relevance of 5-HT2A Receptors and Downstream Pathways.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273491538261009064612}, pmid = {42895147}, issn = {1996-3181}, abstract = {More than fifty million individuals worldwide are experiencing neurodegenerative disorders, which include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and frontotemporal dementia. These disorders have a significant role in the gradual degradation of cognition and motor skills. Most current treatment approaches have little effect on changing the course of the disease and are largely symptomatic. Psilocybin, a naturally occurring tryptamine alkaloid from psilocybin mushrooms, has become a promising medicinal agent because of its hallucinogenic, neuroprotective, and neuroplastic properties. After being metabolically transformed into its active form, psilocin, it primarily activates serotonin 5-HT2A receptors. This modulates glutamatergic neurotransmission and neurotrophic signaling pathways such as BDNF/TrkB and mTOR, which regulate synaptic remodeling, dendritic complexity, neurogenesis, neuroinflammatory response, and default mode network connectivity, all of which are linked to depression and dementia. Preclinical research studies demonstrate that psilocybin increases hippocampal plasticity, restores dendritic complexity, lowers proinflammatory cytokine levels, and promotes fear extinction in experimental models of stress, ischemic stroke, and neurodegeneration. Emerging clinical studies also indicate that individuals with moderate cognitive impairment, early-onset Alzheimer's disease, and Parkinson's disease may see long-term decreases in anxiety and depression as well as improvements in cognitive function, frequently after a single dose administration. Additionally, psilocybin has demonstrated promise in treating mental comorbidities that often accompany neurodegenerative illness, such as treatment-resistant depression, drug use disorders, and obsessive-compulsive disorder. However, there are still significant obstacles to overcome, such as optimizing dosing schedules, assessing safety issues such as temporary perceptual abnormalities and cardiovascular consequences, and translating preclinical results into extensive phase -III clinical studies. This review incorporates the most recent data on psilocybin's chemistry, pharmacology, metabolism, and mechanistic actions; it highlights the drug's therapeutic potential across a variety of neurodegenerative diseases and emphasizes the necessity of carefully planned randomized controlled trials to determine clinical efficacy, long-term safety, and its place in multimodal treatment approaches.}, } @article {pmid42895434, year = {2026}, author = {Maccabeo, A and Cabras, S and Callegaro, S and Pateri, MI and Pili, F and Canosa, A and Manera, U and Palumbo, F and Matteoni, E and Pellegrino, G and Minerva, E and Ciravegna, A and Gianferrari, G and Puligheddu, M and Moglia, C and De Marchi, F and Mazzini, L and Mandrioli, J and Borghero, G and Chiò, A and Calvo, A and Vasta, R}, title = {Factors associated with post-tracheostomy survival in Amyotrophic Lateral Sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2742815}, pmid = {42895434}, issn = {2167-9223}, abstract = {OBJECTIVE: To identify demographic and clinical factors associated with post-tracheostomy survival using three well-characterized cohorts of patients with Amyotrophic Lateral Sclerosis (ALS).

METHODS: ALS patients from the Piemonte and Valle d'Aosta ALS Register (PARALS) diagnosed between 1995-2019 interval who underwent tracheostomy were included. A multivariable Cox proportional hazards model was used to identify factors associated with post-tracheostomy survival. Significant findings were tested in two independent cohorts, the Emilia-Romagna Region ALS Register (ERRALS) and an incident ALS cohort from South Sardinia.

RESULTS: A total of 449 patients from PARALS underwent tracheostomy during the study period, with a median post-tracheostomy survival of 16.3 months (IQR 4.0-45.0). Younger age at tracheostomy was associated with longer survival (HR 1.03 per one-year increase, 95%CI1.01-1.05, p = 0.001), as being married/cohabiting (HR 0.78, 95%CI0.61-0.98, p = 0.033), a longer diagnosis-to-tracheostomy interval (HR 0.84 per one-year increase, 95%CI0.79-0.90, p < 0.001) and a lower ALS Functional Rating Scale slope from onset to tracheostomy (HR 1.13 per one-unit increase, 95%CI1.03-1.25, p = 0.012). These associations were replicated in the independent cohorts, when data were available. Additionally, discharge to nursing homes was associated with poorer survival in the Sardinian cohort (HR 4.23, 95%CI2.49-7.19; p < 0.001), whereas a more recent year of tracheostomy was associated with longer survival in the ERRALS cohort (HR 0.95, 95%CI0.90-0.99; p = 0.019).

DISCUSSION: We identified multiple factors associated with post-tracheostomy survival in ALS patients, encompassing clinical and demographic characteristics at tracheostomy as well as local factors influencing peri- and post-operative care. These findings may support decision-making and clinician-patient communication in the advanced stages of ALS.}, } @article {pmid42895667, year = {2026}, author = {Abu-Omar, K and Tcymbal, A and Messing, S and Gelius, P}, title = {[Physical activity and physical activity promotion among people with a migration background in Germany].}, journal = {Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz}, volume = {}, number = {}, pages = {}, pmid = {42895667}, issn = {1437-1588}, abstract = {Health equity has gained increasing importance in physical activity and health promotion and is firmly established as an important goal both internationally and in Germany. As social inequalities and multiple disadvantages influence physical activity behavior, population groups facing particular barriers to access-including people with a migration background-should receive greater consideration in physical activity promotion. This article provides an overview of the current state of research on physical activity and physical activity promotion among people with a migration background in Germany.Representative data indicate that people with a migration background are less physically active than people without a migration background. Key barriers reported include limited financial resources, language barriers, restricted opportunities for physical activity, and cultural factors. Different forms of social disadvantage, for example those related to gender, socioeconomic status, and migration background, may intersect and reinforce barriers to access. Using the project "Bewegung als Investition in Gesundheit" (BIG; "Physical Activity as an Investment in Health") as an example, this article illustrates how participatory and target-group-specific interventions can be used to reach, in particular, women with a migration background.In addition to participatory and target-group-specific interventions, equitable physical activity promotion requires structural conditions that facilitate access to opportunities for physical activity. The sustainable implementation and scaling-up of such interventions can contribute to reducing barriers to access and promoting health equity.}, } @article {pmid42886553, year = {2026}, author = {Gastaldo, D and Vito, S and Black, HH and Foreman, O and Yang, Z and Pham, V and Zhu, Y and Choi, M and Jovičić, A}, title = {Ataxin-2 downregulation rewires neuronal and astrocytic metabolism to protect against TDP-43 toxicity.}, journal = {Cell reports}, volume = {45}, number = {10}, pages = {118053}, doi = {10.1016/j.celrep.2026.118053}, pmid = {42886553}, issn = {2211-1247}, abstract = {Ataxin-2 (ATXN2) is a genetic modifier of TDP-43 toxicity and a promising therapeutic target in amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying its neuroprotective effects remain poorly understood. Using global proteomic profiling in yeast and mouse TDP-43 models, we establish that pbp1/ataxin-2 (pbp1 is the yeast ataxin-2 ortholog) reduction confers neuroprotection by activating orthogonal stress-adaptive pathways in neurons and glia, rather than simply reversing TDP-43-induced damage. In neurons, ataxin-2 downregulation activates glycolysis and reductive glutamine carboxylation driven by IDH1, restoring ATP production independently of impaired mitochondria. In astrocytes, it upregulates cholesterol biosynthesis via HMGCS1, enhancing trophic support to neurons. Full neuroprotection requires both mechanisms: neuronal survival is only completely rescued when ataxin-2 is reduced in neuron-astrocyte co-cultures. Importantly, ataxin-2 downregulation protects against both TDP-43 gain- and loss-of-function toxicity, broadening its therapeutic relevance. Collectively, these findings establish ataxin-2 as a regulator of stress-adaptive metabolic resilience.}, } @article {pmid42891488, year = {2026}, author = {Boyce, D and Premasiri, A and Sullivan, S and Levine, B and Vieira, FG}, title = {Registry Forge: an open-source end-to-end pipeline for patient-directed SMART on FHIR registries.}, journal = {JAMIA open}, volume = {9}, number = {5}, pages = {ooag200}, pmid = {42891488}, issn = {2574-2531}, abstract = {OBJECTIVES: Patient-directed SMART on FHIR lets registries acquire longitudinal electronic health record data, but the payload requires substantial engineering before use. We present Registry Forge, an open-source pipeline that converts it into curation-ready outputs.

MATERIALS AND METHODS: Registry Forge parses C-CDA, HTML, RTF, PDF, and FHIR inputs, joins records to a canonical identifier, and emits a browser dashboard, an OMOP CDM v5.4 data set, GA4GH Phenopackets v2, a code inventory, and disease-specific narrative extractions.

RESULTS: Applied to the ALS Research Collaborative Study (94 participants, 56 US health systems), it processed 22 686 files and 1791 FHIR Bundles (109 599 resources); only 15.0% of files were full C-CDA XML; HTML (48.4%) and RTF (34.3%) predominated.

DISCUSSION: Payloads are far more heterogeneous than often assumed; the architecture is designed for extension, though generalizability remains to be demonstrated.

CONCLUSION: Registry Forge closes the gap between acquisition and curation-ready data with no server infrastructure and is openly available.}, } @article {pmid42891860, year = {2026}, author = {Wełnicka-Wesołowska, A and Łuczkowska, K and Nowacki, P and Paczkowska, E and Meller, A and Machowska-Sempruch, K and Machaliński, B and Gołąb-Janowska, M}, title = {Peripheral and cerebrospinal fluid inflammatory markers in sporadic amyotrophic lateral sclerosis an exploratory cross-sectional association study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {11}, pages = {}, pmid = {42891860}, issn = {1590-3478}, support = {STRATEGMED1/234261/2NCBR/2014//Narodowe Centrum Badań i Rozwoju/ ; }, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood ; Male ; Cross-Sectional Studies ; *Receptors, Tumor Necrosis Factor, Type I/cerebrospinal fluid/blood ; Biomarkers/cerebrospinal fluid/blood ; Middle Aged ; Tumor Necrosis Factor-alpha/cerebrospinal fluid/blood ; Aged ; C-Reactive Protein/metabolism/cerebrospinal fluid ; Fibrinogen/metabolism ; Inflammation/cerebrospinal fluid/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with an ambiguous etiology, whose onset may be linked to innate immune system activation outside the central nervous system (CNS). We investigated the association between peripheral blood and CNS inflammatory parameters in 45 sporadic ALS patients compared to 30 controls, analyzing peripheral blood tests (C-reactive protein [CRP], blood count, fibrinogen) and cerebrospinal fluid (CSF) immunological measures (Tumor Necrosis Factor alpha [TNF-α], TNF receptor type 1 [TNFR-1], CRP) alongside clinical characteristics. Results revealed significantly higher concentrations of TNFR-1 in the CSF of ALS patients compared to the control group (1,029.5 ± 176.0 vs. 846.1 ± 167.5 pg/ml; p < 0.0001). This difference remained significant in multivariable logistic regression adjusting for age and sex (OR 1.82 per 100 pg/ml increment, 95% CI 1.26-2.63; p = 0.0015). In an exploratory ROC analysis, CSF TNFR-1 discriminated patients from controls with an AUC of 0.78 (95% CI 0.67-0.88). TNFR-1 correlated with age (R = 0.32, p = 0.038), associations with disease severity and a lower concentration in bulbar-onset disease were exploratory and not robustly significant. Plasma and CSF CRP concentrations did not differ significantly between groups, but strongly correlated with each other in both ALS (R = 0.83) and control (R = 0.82) cohorts, indicating a disease-non-specific relationship. CSF TNFR-1 is independently associated with sporadic ALS and warrants further investigation as a candidate disease-associated inflammatory biomarker. Given the limitations, our findings do not prove diagnostic accuracy or causality. Longitudinal studies with disease controls and blood-CSF barrier integrity measures are needed.}, } @article {pmid42885660, year = {2026}, author = {Bombaci, A and Iadarola, A and Giraudo, A and Fattori, E and Sinagra, S and Magnino, A and Falbo, M and De Marco, G and Calvo, A and Chiò, A and Cicolin, A}, title = {Salivary Dim-Light Melatonin Onset is Associated with Functional Decline, Respiratory Symptom Emergence, and Survival in Early Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78398}, pmid = {42885660}, issn = {1531-8249}, abstract = {OBJECTIVE: Sleep-wake and circadian disturbances are increasingly recognized in people living with amyotrophic lateral sclerosis (plwALS), but endogenous circadian phase timing and its prognostic significance in early disease remain unclear. We assessed whether salivary dim-light melatonin onset (DLMO), an objective marker of central circadian phase, is altered in early plwALS and whether it provides prognostic information.

METHODS: In this prospective longitudinal observational study, plwALS within 18 months of symptom onset underwent home-based salivary melatonin sampling under dim-light conditions at 6 predefined time points around habitual sleep onset. Melatonin profiles were modeled using cubic smoothing splines, and DLMO was defined when the fitted curve first reached 3 pg/ml. Clinical, respiratory, and sleep assessments were collected at baseline (T0) and after 6 months (T6); a subgroup repeated saliva sampling at T6. Age- and sex-matched controls underwent melatonin profiling. Associations with disease progression, incident respiratory symptoms, and survival/tracheostomy were examined using regressions and survival analyses.

RESULTS: A total of 50 plwALS were enrolled. Compared with controls, plwALS showed an earlier DLMO (20:24 ± 1:18 vs 20:58 ± 0:50; p = 0.028) despite similar habitual sleep onset and chronotype. Within ALS cohort, a later baseline DLMO correlated with worse functional/motor status, faster progression of disease, incident dyspnea/orthopnea by T6 (adjusted OR 3.11; p = 0.019), and poorer survival/tracheostomy-free outcome. In the resampled subgroup (n = 28), DLMO and melatonin-derived metrics did not change over ~6 months.

INTERPRETATION: Circadian phase alterations are detectable in early ALS. Baseline DLMO showed exploratory associations with functional, respiratory, and survival outcomes. Larger independent cohorts are required before DLMO can be considered a validated prognostic biomarker. ANN NEUROL 2026.}, } @article {pmid42880848, year = {2026}, author = {Martin, LJ}, title = {DNA methylation in motor neuron biology and epigeneticopathy in amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {219}, number = {}, pages = {381-397}, doi = {10.1016/B978-0-443-19043-8.00014-1}, pmid = {42880848}, issn = {0072-9752}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Motor Neurons/metabolism/pathology/physiology ; *DNA Methylation/genetics/physiology ; Animals ; *Epigenesis, Genetic/genetics/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS), the 3rd most frequent neurodegenerative disease, is fatal. Skeletal muscles, neuromuscular junctions, and motor neurons in the cerebral cortex, brainstem, and spinal cord that control swallowing, breathing, and movement degenerate, causing paralysis, respiratory arrest, and death. Clinically meaningful disease mechanisms are unknown, and no effective therapies are available. ALS is a polygenic heterogeneous disease seen in 5%-10% of patients as inherited, but most patients have no inheritance pattern. ALS appears to manifest as a complex interplay between many genes in multiple tissues, individual lifestyle, the environment, and metabolism. Monozygotic twin and triplet studies of ALS suggest that epigenetic mechanisms could be involved in the pathogenesis because discordance is seen. Epigenetic anomalies involving DNA and RNA methylation occur in human ALS. Cell and animal models show that motor neuron development and degeneration can be regulated by DNA methylation. This chapter summarizes the DNA and RNA epigenetic anomalies that are prominent in human ALS and models of ALS, concluding with the suggestion that they are promising therapeutic targets with small molecules.}, } @article {pmid42880988, year = {2026}, author = {Jia, F and Zhang, B and Yu, W and Chen, Z and Xu, W and Zhao, W and Wang, Z}, title = {Corrigendum to "Exploring the cuproptosis-related molecular clusters in the peripheral blood of patients with amyotrophic lateral sclerosis" [Comput. Biol. Med. 168, (2024), 107776].}, journal = {Computers in biology and medicine}, volume = {}, number = {}, pages = {111997}, doi = {10.1016/j.compbiomed.2026.111997}, pmid = {42880988}, issn = {1879-0534}, } @article {pmid42882466, year = {2026}, author = {Burdman, G and Hanna, M and Arias, AY and Vashist, A and Lakshmana, MK}, title = {Human iPSC-Derived Brain Cells, Organoids, and Organoids-on-Chips: Advancing Neurological Disease Modeling to Improve Clinical Outcome.}, journal = {Cells}, volume = {15}, number = {19}, pages = {}, doi = {10.3390/cells15191768}, pmid = {42882466}, issn = {2073-4409}, support = {1R21DA060111, 1R61AG086971, R03AG08475//National Institute of Health (NIH)/ ; }, mesh = {Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Brain/pathology/cytology ; *Organoids/pathology/cytology ; *Nervous System Diseases/pathology ; Animals ; Microphysiological Systems ; Neurons/pathology ; Models, Biological ; }, abstract = {Neurological disorders are the leading cause of overall disease and disability worldwide, affecting more than 3.4 billion people globally and over 180 million Americans. Yet there are no curative treatments available for any of the cardinal neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) and Huntington's disease (HD). Many compounds that demonstrate excellent activity in preclinical models fail in clinical trials. The most compelling reason for this failure is attributed to inherent limitations of rodent models that fail to replicate complex human biology. The transformation of patient-derived somatic cells into induced pluripotent stem cells (iPSCs) that can become functional human neurons is an emerging technology that is expected to revolutionize medical treatments and personal medicine. Here, we review the available evidence for the efficacy of iPSC-derived neurons, organoids, assembloids and organ-on-chip in models of AD, PD, ALS-FTD and HD. We focus on how these human-relevant iPSC-derived brain cells are crucial for understanding neurological disease pathogenesis and accelerating drug discovery. We also discuss the current limitations of this technology and how alternative models such as induced neurons (iNs) are generated by directly reprogramming fibroblasts that preserve age-associated epigenetic signatures and may serve as better models for neurological disorders.}, } @article {pmid42882496, year = {2026}, author = {Morrone, M and Valori, CF and Brambilla, L and Rossi, D}, title = {Motor Neuron Disease in a Dish: The Power of Human Induced Pluripotent Stem Cell-Derived Spinal Motor Neurons and Glial Cells.}, journal = {Cells}, volume = {15}, number = {19}, pages = {}, doi = {10.3390/cells15191798}, pmid = {42882496}, issn = {2073-4409}, support = {JPND2022-DC4MND//Ministry of Health/ ; }, mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism/cytology/pathology ; *Motor Neurons/pathology/metabolism ; *Neuroglia/pathology/metabolism ; *Motor Neuron Disease/pathology ; *Amyotrophic Lateral Sclerosis/pathology ; Animals ; Cell Differentiation ; Astrocytes/pathology/metabolism ; }, abstract = {Induced pluripotent stem cells (iPSCs) have revolutionized disease modelling by providing unprecedented opportunities to investigate complex human disorders. Among others, Amyotrophic Lateral Sclerosis (ALS), the most common adult-onset motor neuron disease, clearly embodies this complexity. This disorder remains particularly challenging not only because of its marked clinical and molecular heterogeneity but also as a consequence of the composite interactions between motor neurons and the neighboring non-neuronal cells, especially astrocytes, which contribute to disease progression. The ability to generate patient-specific spinal motor neurons and astrocytes from human iPSCs has enabled the development of in vitro models that recapitulate key pathological features of ALS, offering valuable platforms to investigate disease mechanisms, to identify therapeutic targets, and to support personalized medicine approaches. In this review, we summarize current iPSC-based strategies for modelling ALS, highlighting their applications in studying disease physiopathology and drug development. In addition, advanced human iPSC-derived technologies, including organoids and organ-on-a-chip systems, are discussed highlighting their potential, current limitations, and future perspectives.}, } @article {pmid42883264, year = {2026}, author = {Sun, L and Apweiler, M and Schulzki, R and Grathwol, CW and Normann, C and Bräse, S and Fiebich, BL}, title = {Anti-Neuroinflammatory Effects of Cardenolides in IL-1β-Activated SK-N-SH Cells.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {19}, pages = {}, doi = {10.3390/molecules31193501}, pmid = {42883264}, issn = {1420-3049}, support = {284178167//Deutsche Forschungsgemeinschaft/ ; 266379491//Deutsche Forschungsgemeinschaft/ ; //Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg/ ; }, mesh = {Humans ; *Interleukin-1beta/metabolism/pharmacology ; *Anti-Inflammatory Agents/pharmacology/chemistry ; NF-kappa B/metabolism ; *Cardenolides/pharmacology/chemistry ; Cyclooxygenase 2/metabolism ; Cell Line, Tumor ; Dinoprostone/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; Signal Transduction/drug effects ; Cell Survival/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Interleukin-6/metabolism ; Prostaglandin-E Synthases/metabolism ; }, abstract = {Neuroinflammation is a key feature of neurological disorders such as Alzheimer's or Parkinson's disease, depression or amyotrophic lateral sclerosis. This study investigates the anti-neuroinflammatory effects of three cardenolide derivatives, digitoxigenin, digitoxigenone, and coroglaucigenin (all at concentrations of 1, 5, 10, and 25 µM), in IL-1β-stimulated human neuroblastoma SK-N-SH cells. All compounds significantly reduced PGE2 production without affecting cell viability by downregulation of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthases (mPGES)-1 expression and synthesis. Among them, digitoxigenin notably inhibited phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) and suppressed interleukin (IL)-6 and IL-8 expression and release. These findings demonstrate that cardenolide derivatives exert potent anti-neuroinflammatory effects by at least partially targeting key enzymes of the arachidonic acid pathway and modulating MAPK/NF-κB signaling, highlighting their potential as novel therapeutic candidates for neuroinflammatory diseases. Future research should focus on effects of the cardenolides in mixed-cell cultures, organoids and in vivo experiments, to evaluate possible side effects and the potential in disease models.}, } @article {pmid42883328, year = {2026}, author = {Garbarek, J and Hys, O and Woźniak, A and Szewczyk-Golec, K and Nuszkiewicz, J}, title = {Bee-Derived Products in Neurodegenerative Diseases: Bioactive Constituents, Redox-Modulating Mechanisms, Evidence, and Translational Perspectives.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {19}, pages = {}, doi = {10.3390/molecules31193564}, pmid = {42883328}, issn = {1420-3049}, mesh = {Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; Oxidation-Reduction/drug effects ; Antioxidants/pharmacology/chemistry/therapeutic use ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Bees/chemistry ; Propolis/chemistry/therapeutic use ; Oxidative Stress/drug effects ; Royal Jelly ; *Bee Venoms/chemistry/therapeutic use/pharmacology ; Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use ; Signal Transduction/drug effects ; Honey/analysis ; }, abstract = {Oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation are closely interconnected processes involved in the pathogenesis and progression of neurodegenerative diseases. Bee-derived products, including honey, propolis, royal jelly, bee pollen, bee bread, and bee venom, contain diverse bioactive constituents with antioxidant, anti-inflammatory, immunomodulatory, and redox-modulating properties. This narrative review summarizes the major bioactive compounds present in bee-derived products and evaluates their potential relevance to neuroprotection. Particular attention is given to mechanisms involving activation of the Nrf2/ARE antioxidant response, inhibition of NF-κB-dependent inflammatory signaling, modulation of the NLRP3 inflammasome, mitochondrial protection, regulation of apoptosis, and maintenance of proteostasis. Available evidence from cellular and animal models, together with the limited clinical data, is discussed primarily in the context of Alzheimer's and Parkinson's diseases, with additional consideration of amyotrophic lateral sclerosis and other neurodegenerative or neuroinflammatory conditions. Although several bee-derived products and isolated constituents show promising biological effects, their therapeutic translation remains limited by variable chemical composition, insufficient standardization, low or uncertain bioavailability, limited evidence of central nervous system exposure, and safety concerns. Further mechanistic, pharmacokinetic, and well-controlled clinical studies are therefore required before their potential neuroprotective applications can be reliably established.}, } @article {pmid42883433, year = {2026}, author = {Li, P and Qi, ZM and Wu, JZ and Liu, J and Yu, P}, title = {Targeting Ferroptosis in Neurodegenerative Diseases: Therapeutic Potential and Mechanistic Insights of Traditional Chinese Medicine.}, journal = {Biology}, volume = {15}, number = {19}, pages = {}, doi = {10.3390/biology15191760}, pmid = {42883433}, issn = {2079-7737}, support = {NO.20250204060YY//Jilin Province Science and Technology Department/ ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by progressive and irreversible neuronal loss, whereas current treatments remain largely symptomatic. Ferroptosis is an iron-dependent form of regulated cell death whose execution is defined by iron-enabled phospholipid peroxidation and failure of cellular ferroptosis-defense systems. Mitochondrial metabolism can modify ferroptosis susceptibility, but its contribution varies with cell type and initiating stimulus. Converging evidence implicates ferroptosis in multiple NDs, in which affected regions commonly show iron accumulation, glutathione depletion, and increased lipid peroxidation. With their multi-component and multi-target properties, traditional Chinese medicine (TCM) interventions may modulate several nodes in this network. This review summarizes the core execution and defense mechanisms of ferroptosis, evaluates their roles in major NDs, and critically appraises bioactive herbal compounds, compound formulas, acupuncture, electroacupuncture, and moxibustion. The reported interventions mainly engage the Nrf2/GPX4 antioxidant axis, TFR1/FPN1/FTH1/NCOA4-mediated iron handling, ACSL4-dependent lipid peroxidation, and GPX4-independent defense systems. Because most studies are preclinical and many infer ferroptosis from non-specific markers, the evidence is graded here as direct, supportive, indirect, mixed, or complementary. Translation will require standardized formulations, causal ferroptosis validation, pharmacokinetic and brain-exposure data, validated human biomarkers, and rigorously designed clinical trials.}, } @article {pmid42883851, year = {2026}, author = {Martynova, E and Mukhamedyarov, M and Kabwe, E and Khaiboullina, S and Simwalangana, O and Markelova, M and Rizvanov, A and Arkhipova, S and Salafutdinov, I}, title = {Phenotypic Profiling of SOD1-G93A Mice: Integrating Sciatic Nerve Histopathology with Systemic Chemokine Dynamics During ALS Progression.}, journal = {International journal of molecular sciences}, volume = {27}, number = {19}, pages = {}, doi = {10.3390/ijms27198604}, pmid = {42883851}, issn = {1422-0067}, support = {25 25 01147//Russian Science Foundation/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Sciatic Nerve/pathology/metabolism/ultrastructure ; Mice ; Mice, Transgenic ; *Chemokines/metabolism/blood ; Disease Models, Animal ; Disease Progression ; *Superoxide Dismutase-1/genetics/metabolism ; Spinal Cord/pathology/metabolism ; Motor Neurons/metabolism/pathology ; Phenotype ; Cytokines/metabolism ; Superoxide Dismutase ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, leading to muscle atrophy and fatal respiratory failure. While neuroinflammation is a hallmark of ALS, the temporal and spatial relationship between systemic inflammation and peripheral nerve degeneration remains poorly understood. In the present study, the transgenic SOD1-G93A mouse model was employed to conduct a longitudinal analysis of amyotrophic lateral sclerosis (ALS) progression. We integrated morphometric and ultrastructural examinations of the sciatic nerve with immunofluorescent profiling of the spinal cord (GFAP, IBA1, NG2). In addition, cytokine and chemokine dynamics were analyzed using 33-plex multiplex assay in the serum at various stages of the disease. Histological analysis revealed a progressive decline in myelin fiber density within the sciatic nerve and axonal death. As the disease progressed, Schwann cells exhibited morphological features consistent with a pro-fibrotic shift, as suggested by collagen accumulation observed on TEM. However, direct confirmation of a fibrotic phenotype requires additional markers (e.g., Col I/III, α-SMA, TGF-β) and was not assessed in this study. Significant motor neuron loss and robust glial activation were demonstrated in the spinal cord. Blood plasma analysis identified a coordinated systemic up-regulation of MCP-3, Eotaxin, CTACK, and TECK. There was lack of inflammatory cell infiltration in the peripheral nerve tissues. Our results indicate that ALS-associated peripheral nerve degeneration in the SOD1-G93A mice model is primarily a degenerative process characterized by early demyelination and without leukocyte infiltration. However, increased levels of MCP-3, Eotaxin, CTACK, and TECK are associated with disease progression and may reflect ongoing central neuroinflammation. While these changes are temporally consistent with blood-spinal cord barrier dysfunction reported in SOD1 mice, direct assessment of barrier integrity was not performed in this study. These data highlight the potential of blood chemokines as step biomarkers and highlight the compartmental nature of inflammation in ALS, where systemic immune changes do not necessarily equate to local inflammation in the peripheral nerve.}, } @article {pmid42874698, year = {2026}, author = {Ta, V and Ju, J and Kurata, K and Van, M and Wong, E and Ohgi, K and Magaña, Y and Castle, M and Wang, S}, title = {Intravenous administration of a PHP.eB vector overexpressing neuronal Caveolin-1 delays motor neuron and neuromuscular degeneration in a TDP-43 mouse model of ALS.}, journal = {Experimental neurology}, volume = {}, number = {}, pages = {116069}, doi = {10.1016/j.expneurol.2026.116069}, pmid = {42874698}, issn = {1090-2430}, abstract = {TDP-43 proteinopathy is observed in over 95% of ALS cases, yet effective disease-modifying therapies remain elusive. We previously showed that neuron-specific overexpression of caveolin-1 via SynCav1 extended survival and delayed neurodegeneration in an SOD1 mouse model of ALS. Here, we further assessed the effect of systemic delivery of AAV-PHP.eB-SynCav1 in TDP-43[A315T] mice. At 24 weeks, SynCav1-treated mice showed preserved motor neuron (MN) morphology, maintained neuromuscular junction (NMJ) innervation, and normalized pathologically driven neurotrophic transcription in the spinal cord. Immunoblotting revealed that SynCav1 increased calcium-impermeable GluA2 in membrane lipid rafts of lumbar SC. However, these effects diminished with disease progression: by 32 weeks, lumbar MN loss and NMJ denervation were no longer significantly different between TDP-43-SynNull and TDP-43-SynCav1 mice, although partial protection was observed in the cervical spinal cord. These findings establish SynCav1 as an effective early-phase neuroprotective strategy and highlight the need for combinatorial approaches to achieve sustained protection.}, } @article {pmid42875203, year = {2026}, author = {Kawama, K and Bokuda, K and Kimura, H and Hayashi, K and Kawazoe, T and Totani, K and Matsuki, Y and Ishizawa, K and Sawada, J and Itagaki, Y and Haraguchi, M and Matsuda, C and Nakayama, Y and Yabuki, M and Takahashi, K and Shimizu, T}, title = {Bullous Pemphigoid in Patients with Amyotrophic Lateral Sclerosis: A Retrospective Study of 1,067 Cases.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {}, number = {}, pages = {}, doi = {10.2169/internalmedicine.7919-26}, pmid = {42875203}, issn = {1349-7235}, abstract = {Background Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects motor neurons. Bullous pemphigoid (BP) is an autoimmune blistering disease associated with autoantibodies against BP180 and BP230. Previous studies have suggested an increased incidence of BP in patients with ALS. However, the neurological status and disease severity of patients with ALS at the time of BP onset remain insufficiently characterized. This study aimed to investigate the frequency and clinical characteristics of BP in patients with ALS.Methods In this retrospective study, we reviewed the medical records of 1,067 patients with ALS who were admitted to our institution between April 2010 and May 2025. Patients who developed BP after the onset of ALS were identified. BP was diagnosed by dermatologists based on clinical findings and, when available, by immunological or histopathological examinations. Disease severity at BP onset was assessed based on the ambulatory status and ventilatory support requirements.Results Seven of the 1,067 patients (0.66%) developed BP after ALS onset. The median interval between ALS and BP onset was 8.0 years (IQR 5.0-16.5). At BP onset, four patients (57.1%) were bedridden, four (57.1%) required tracheostomy and invasive ventilation, and two (28.6%) required non-invasive ventilation. Five patients (71.4%) required enteral feeding. The median age at BP onset was 68.0 years (IQR, 64.0-72.5). BP180 antibody testing was positive in three of the six patients. The lesions most commonly involved both the extremities and the trunk.Conclusion BP may occur more frequently in ALS patients than in the general population. Clinicians should consider BP when evaluating cutaneous lesions in patients with ALS.}, } @article {pmid42875680, year = {2026}, author = {Gupta, R and Kumar, R and K S, BS and Modi, DK and Kumari, S and Kumar, N and Singh, P and Ravi, K and Abomughaid, MM}, title = {Restoring Neural Homeostasis via Class II HDAC Modulation: Mechanistic Insights and Therapeutic Opportunities.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42875680}, issn = {1559-1182}, mesh = {Humans ; *Histone Deacetylases/metabolism ; Animals ; *Homeostasis/drug effects/physiology ; Neurodegenerative Diseases ; Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; *Neurons/metabolism/drug effects ; Signal Transduction ; }, abstract = {Class II histone deacetylases (HDACs) comprise class IIa enzymes HDAC4, HDAC5, HDAC7, and HDAC9 and class IIb enzymes HDAC6 and HDAC10, which differ substantially in structure, catalytic activity, subcellular localization, and neural function. Class IIa HDACs exhibit weak intrinsic deacetylase activity and function predominantly as signal-responsive scaffolds that couple calcium and kinase signaling to transcription through nucleocytoplasmic shuttling, recruitment of HDAC3-containing NCoR/SMRT corepressor complexes, and interactions with MEF2, CREB, and FOXO. Conversely, HDAC6 is a predominantly cytoplasmic deacetylase that regulates α-tubulin acetylation, cytoskeletal dynamics, axonal transport, autophagy, and proteostasis. Dysregulated class II HDAC signaling contributes to neurodegenerative diseases through convergent mechanisms involving synaptic dysfunction, maladaptive transcriptional repression, mitochondrial impairment, oxidative stress, neuroinflammation, blood-brain barrier disruption, and defective clearance of pathological proteins. Disease-associated substrates include amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, mutant huntingtin in Huntington's disease, and TDP-43/SOD1 in amyotrophic lateral sclerosis. Emerging evidence additionally links aberrant HDAC4/5 signaling to neurodevelopmental disorders through altered synaptic maturation, excitation-inhibition balance, and circuit development. This review integrates the structural and mechanistic biology of class II HDACs with their disease-specific roles and evaluates therapeutic approaches to restore neural homeostasis. Particular emphasis is placed on selective HDAC6 inhibitors, modulation of class IIa protein-protein interactions and subcellular trafficking, natural compounds, and RNA-based strategies. Finally, we discuss major translational challenges, including isoform specificity, brain penetration, context-dependent functions, and the need to distinguish catalytic from non-enzymic mechanisms when developing disease-modifying interventions for neurological disorders while preserving normal essential HDAC functions and minimizing off-target toxicity.}, } @article {pmid42875948, year = {2026}, author = {Li, M and White, A and Canales, K and Fotopoulos, N}, title = {Ethical Dilemmas in Predictive Testing for Monozygotic Twins With Hereditary ALS: A Clinical Case Report.}, journal = {Journal of genetic counseling}, volume = {35}, number = {5}, pages = {e70307}, doi = {10.1002/jgc4.70307}, pmid = {42875948}, issn = {1573-3599}, mesh = {Humans ; *Twins, Monozygotic/genetics ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Female ; Ethical Dilemmas ; *Genetic Testing/ethics ; Adolescent ; Superoxide Dismutase-1/genetics ; Genetic Counseling/ethics ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder typically presenting in midlife and leading to death within 2-5 years of onset. Pathogenic SOD1 variants, inherited in an autosomal dominant manner, account for approximately 20% of hereditary ALS cases. Predictive genetic testing in SOD1-related ALS presents unique ethical challenges, particularly in monozygotic twins who share identical genetic information but hold differing views about testing. We describe an 18-year-old monozygotic twin who requested predictive testing for the familial SOD1 pathogenic variant identified in her father, who died from ALS at age 40. This conferred a 50% a priori risk to both twins. One twin had long expressed the desire to know her genetic status, while the other preferred not to pursue testing. Because a positive result in one twin would automatically reveal the status of the other, the case raised ethical tensions surrounding autonomy, beneficence, non-maleficence, and justice. Institutional ethics consultation and peer supervision were used to navigate these competing ethical imperatives and provided initial recommendations and direction. Additional valuable insights were gained through a peer-supervision framework that brought together genetic counselors across varying levels of experience and specialties. These discussions informed our ethical assessment and supported the decision to proceed with predictive testing, as the benefits were ultimately deemed to outweigh the potential risks. Testing identified the familial SOD1 pathogenic variant, which was disclosed to the patient and her family. Her twin subsequently elected to undergo confirmatory testing and received comprehensive genetic counseling and psychosocial support. Ethical complexities surrounding predictive genetic testing in monozygotic twins with hereditary neurodegenerative diseases, such as ALS, require careful balancing of autonomy, beneficence, non-maleficence, and justice. Structured peer supervision is essential for working through ethical uncertainty, guiding sound clinical decisions, and supporting patient-centered care.}, } @article {pmid42875960, year = {2026}, author = {Zhang, W and Sun, Y and Liao, ZY and Xue, B and Ju, SY and Wan, YJ and Wang, YJ}, title = {Recent Advances in Engineering Ammonia Lyase for Biosynthesis of Aromatic Noncanonical Amino Acids.}, journal = {Biotechnology journal}, volume = {21}, number = {10}, pages = {e70321}, doi = {10.1002/biot.70321}, pmid = {42875960}, issn = {1860-7314}, support = {LQN26B060007//Zhejiang Provincial Natural Science Foundation of China/ ; 2025C01097//"Pioneer" and "Leading Goose" Key R&D Program of Zhejiang/ ; 22178318//National Natural Science Foundation of China/ ; 22608515//National Natural Science Foundation of China/ ; 2025M771186//China Postdoctoral Science Foundation/ ; }, mesh = {*Ammonia-Lyases/metabolism/genetics/chemistry ; *Protein Engineering/methods ; *Amino Acids, Aromatic/biosynthesis/chemistry/metabolism ; Biocatalysis ; }, abstract = {Aromatic noncanonical amino acids (aromatic ncAAs) are valuable building blocks for pharmaceuticals, agrochemicals, food additives, and specialty chemicals, yet their sustainable and stereoselective synthesis remains challenging. Ammonia-lyases (ALs) have emerged as powerful biocatalysts for the one-step asymmetric hydroamination of arylacrylic acids, and recent advances in protein engineering have substantially enhanced their catalytic performance including efficiency, selectivity, promiscuity, and productivity. This review integrates catalytic mechanisms with the deployment of engineering strategies to illustrate how aromatic amino acid ammonia-lyases (AALs) have evolved into versatile biocatalysts for aromatic ncAAs synthesis. Particular attention is devoted to the engineering of AALs (including phenylalanine, tyrosine, histidine ammonia lyase) and (methyl)aspartate ammonia lyases, highlighting progress in substrate scope expansion, catalytic promiscuity, selectivity modulation, and hybrid catalytic systems. Current limitations and emerging opportunities are further assessed to delineate future directions for next-generation ALs engineering. The engineering strategies and current states of ALs summarized herein provide a conceptual basis for the efficient development of ALs for sustainable aromatic ncAAs biomanufacturing.}, } @article {pmid42876567, year = {2026}, author = {Liu, C and Tang, Q and Yu, L and Yu, Z}, title = {Handling missed dose of riluzole by population pharmacokinetic model informed remedial regimen.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1890355}, pmid = {42876567}, issn = {1663-9812}, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) frequently exhibit nonadherence characterized by delayed or missed doses while taking riluzole. This study aimed to provide a population pharmacokinetic (PPK) model informed individualized remedial regimens for patients who experience delayed or missed doses of riluzole.

METHODS: A PPK model for riluzole was developed via a nonlinear mixed-effect modeling approach based on 3,024 concentration-time points from 72 subjects. The final model was validated by multiple methods. Six remedial regimens for missed doses were simulated for concentration-time profiles under different scenarios, and the optimal remedial regimen was selected based on the least time of concentration beyond the normal range.

RESULTS: The PPK model of riluzole was best described with a two-compartment model with body weight as a covariate of peripheral distribution volume. The typical values of CL/F, Vc/F, Vp/F and Q were 67 L/h, 242 L, 376 L and 33.1 L/h, respectively. The model was showed acceptable performance by goodness-of-fit, visual predictive check, bootstrap analysis and normalized distribution prediction errors. Model-based remedial regimens for different missed scenarios were proposed.

CONCLUSION: A riluzole PPK model was developed and internally evaluated using multiple diagnostic approaches. Model-based remedial dosing strategies for different missed-dose scenarios were identified based on predefined PK criteria and Monte Carlo simulations. These exploratory strategies provide quantitative insights into riluzole exposure during nonadherent dosing conditions.}, } @article {pmid42877417, year = {2026}, author = {Shu, H and He, R and Zhu, Z and Zhang, W and Xu, P}, title = {Exploring potential genetic correlation and causality between cathepsins and neurodegenerative diseases: Insight from Mendelian randomization analyses.}, journal = {Journal of Alzheimer's disease reports}, volume = {10}, number = {}, pages = {25424823261437791}, doi = {10.1177/25424823261437791}, pmid = {42877417}, issn = {2542-4823}, abstract = {BACKGROUND: Previous research has exhibited a potential association between cathepsins and neurodegenerative diseases (NDDs). Nevertheless, the causal relationships between cathepsins and different types of NDDs remain inadequately clear.

OBJECTIVE: We aim to explore the genetically correlation and causality between 4 NDDs and 9 cathepsins based on genome-wide association study platform.

METHODS: Cathepsin B, E, F, G, H, L2, O, S, and Z and four NDDs types, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and dementia with Lewy bodies, were obtained from large-scale genome-wide summary data. To explore potential interactive roles of these cathepsins in the pathogenesis of NDDs, we applied two-sample bidirectional univariable Mendelian randomization (MR) and multivariable MR, with inverse variance weighting as the primary statistical approach.

RESULTS: The univariable MR analysis revealed one positive and two negative causal effects between genetic liability in nine cathepsins and four NDDs. Reverse univariable MR analysis identified one negative causal link. Furthermore, the multivariable MR analysis not only confirmed two significant associations observed in the univariable analysis but also revealed a new positive effect.

CONCLUSIONS: Our findings demonstrate that several cathepsins are causally associated with different NDDs, offering new insights into the underlying mechanisms of neurodegeneration. These results may contribute to the development of novel diagnostic and therapeutic strategies for managing neurodegeneration.}, } @article {pmid42877731, year = {2026}, author = {Ayenew, AA and Mol, B and Fekadu, GA and Bradford, B}, title = {Lived experiences and impacts of female genital mutilation/cutting (FGM/C): a meta-ethnographic synthesis.}, journal = {BMJ public health}, volume = {4}, number = {1}, pages = {e001907}, doi = {10.1136/bmjph-2024-001907}, pmid = {42877731}, issn = {2753-4294}, abstract = {BACKGROUND: This meta-ethnographic review synthesised qualitative evidence on the lived experiences and impacts of female genital mutilation/cutting (FGM/C). By incorporating insights from individuals who have undergone FGM/C, men and healthcare providers caring for affected populations, the study enriches understanding of the practice and its multifaceted consequences.

METHODS: Using Noblit and Hare's seven-stage meta-ethnographic framework, an inductive and interpretive synthesis was conducted. A comprehensive search of electronic databases, including PubMed/Medline, ScienceDirect, Google Scholar, ResearchGate, African Journals Online (AJOL) and the WHO website, identified qualitative and mixed-method studies that captured in-depth perspectives on FGM/C. The Critical Appraisal Skills Programme tool was used to assess the methodological quality of the included studies, and Ames et al's 5-point scale was applied to evaluate the conceptual richness of each study.

RESULTS: Fifty-three qualitative studies spanning diverse geographical and cultural contexts, both in traditionally practising regions and migrant communities, were included. Through rigorous analysis of first-order constructs (participant quotes) and second-order constructs (study authors' themes), five overarching themes were developed: (1) the onset: inherited tradition and gendered expectations; (2) ramifications on health and well-being; (3) inadequate health-seeking behaviours and lack of comprehensive healthcare services; (4) the psychosocial toll and (5) the perceived benefits of FGM/C. Each overarching theme comprises second-order constructs, along with participants' quotes.

CONCLUSION: This synthesis demonstrates how FGM/C is deeply intertwined with sociocultural norms and functions as a bidirectional bridge, presenting a complex dilemma for the health of women and girls, healthcare systems and broader society. On one hand, it serves as a pivotal gateway to sociocultural belonging and a source of social capital, shaping women's and girls' lives long after the practice itself. On the other hand, it inflicts immediate, short-term and long-term health impacts and poses considerable challenges for healthcare systems due to its diverse and interconnected consequences. This complexity makes it challenging to address all related issues within a single setting or with a single specialist, often leaving affected individuals behind in accessing the highest attainable quality of care and support, while simultaneously complicating elimination efforts.

PROSPERO REGISTRATION NUMBER: CRD42023387750.}, } @article {pmid42878739, year = {2026}, author = {Sanghai, N and Tranmer, GK}, title = {Diagnostic evolution of carbonic anhydrase 3 (CA3) in Amyotrophic Lateral Sclerosis (ALS): an emerging prognostic biomarker.}, journal = {Expert review of neurotherapeutics}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/14737175.2026.2748281}, pmid = {42878739}, issn = {1744-8360}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease traditionally viewed as a motor neuron disorder in which muscle atrophy occurs secondary to neuronal loss. However, recent clinical proteomic advances have highlighted carbonic anhydrase 3 (CA3), a muscle-enriched enzyme, as a promising biomarker associated with ALS disease progression. Therefore, considering ALS a neurocentric disease is not untenable.

AREAS COVERED: In this review, the authors examined the emergence of CA3 as an ALS biomarker and evaluated evidence from recent large-scale clinical consortium studies supporting its diagnostic and prognostic utility. They also compare CA3 with established biomarkers, neurofilament light chain (NEFL), a surrogate endpoint approved by the FDA.

EXPERT OPINION: Discoveries of CA3 biomarker in ALS highlight that peripheral skeletal muscle is not merely a passive bystander, but an integral participant in ALS disease progression. Unlike NEFL, which primarily reflects neuroaxonal injury, CA3 may capture early neuromuscular dysfunction preceding motor neuron degeneration. CA3's emergence as an ALS biomarker supports a more integrated neuromuscular model of ALS and provides a compelling rationale for incorporating CA3 into multimodal diagnostic, prognostic, and pharmacodynamic biomarker panels to accelerate ALS drug discovery, therapeutic evaluation, and precision clinical trial development, highlighting their complementary roles in early diagnosis, patient stratification, and therapeutic clinical trial design.}, } @article {pmid42879383, year = {2026}, author = {Bianchi, E and Beghi, E and Carlino, A and Cerri, F and Lunetta, C and Vitelli, E and Al-Chalabi, A and Leone, MA and Pupillo, E}, title = {Needs and Expectations of ALS Patients and Caregivers: An Integrated Perspective.}, journal = {European neurology}, volume = {}, number = {}, pages = {1}, doi = {10.1159/ene/acsag005}, pmid = {42879383}, issn = {1421-9913}, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease requiring complex multidisciplinary care. As disability advances, patients' and caregivers' needs may diverge.

OBJECTIVES: to assess needs, priorities and satisfaction with care among people with ALS (pALS) and their caregivers; to examine the association between satisfaction and Quality of life (QoL); to explore differences according to clinical characteristics; to understand the Italian ALS community's willingness to engage in research.

METHODS: In this cross-sectional multicentre study, 154 pALS and 211 caregivers were recruited (July 2021-November 2022). Structured interviews explored information received, care priorities, research expectations and satisfaction. Answers to the interview were compared between patients and caregivers and between different patients' subgroups with the chi-square or the Fisher's exact test. The scores of QoL questionnaires were compared between satisfied vs. unsatisfied with the Wilcoxon-Mann-Whitney test in patients (ALSAQ-40) and caregivers (SF-36).

RESULTS: Patients prioritized finding a cure (95%) and overcoming disease-related limitations (72%) over safe and tolerable drugs (55%), similarly to caregivers. Research on psychological and emotional support was rated more important by caregivers (70%) than patients (49%). QoL was higher among satisfied patients, with better ALSAQ-40 scores in mobility, daily activities, communication and emotional domains. Caregivers needing urgent psychological support were fewer among the satisfied (35%) than the not satisfied (50%), and SF-36 mental health scores were also higher in satisfied caregivers.

CONCLUSIONS: Incorporating both pALS and caregiver perspectives into clinical practice and research planning may enhance patient- and family-centered care, improve QoL, and better align healthcare research and resources with societal needs.}, } @article {pmid42879493, year = {2026}, author = {Grima-Terrén, M and Rommelfanger, M and Campanario, S and Calls-Cobos, A and Cisneros, A and Ramírez-Pardo, I and Chou, G and Zheng, Y and Hah, N and Serrano, AL and Perdiguero, E and Isern, J and Muñoz-Cánoves, P}, title = {An integrative transcriptomic atlas of ALS and aging skeletal muscle defines shared and distinct molecular programs of degeneration.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {42}, pages = {e2613546123}, doi = {10.1073/pnas.2613546123}, pmid = {42879493}, issn = {1091-6490}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Muscle, Skeletal/metabolism/pathology ; *Aging/genetics/pathology/metabolism ; Mice ; *Transcriptome ; Sarcopenia/genetics/pathology/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Neuromuscular Junction/metabolism/pathology ; Muscular Atrophy/genetics/pathology/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Skeletal muscle atrophy and weakness resulting from loss of motor neuron innervation are shared hallmarks of amyotrophic lateral sclerosis (ALS) and age-associated sarcopenia. However, muscle wasting in ALS is rapid and severe, whereas sarcopenia progresses gradually over decades, peaking at an advanced age. The molecular mechanisms underlying muscle wasting in these conditions remain incompletely defined. Here, we used the SOD1[G93A] ALS mouse model and wild-type mice across the lifespan to generate an integrated single-nucleus transcriptomic atlas of skeletal muscle, mapping changes associated with ALS and aging. This atlas is complemented by structural and functional analyses. Our results identify transcriptionally distinct condition-specific myonuclear states, including disease-responsive programs within synaptic myonuclei at the neuromuscular junction, that are shared or distinct between the two conditions. Notably, at early stages, muscle from ALS mice exhibits molecular hallmarks of aged muscle at the myofiber level, indicating premature aging and reinforcing aging as a risk factor in ALS. At advanced disease stages and in old age, myonuclear subpopulations follow similar degenerative pathways in fast glycolytic fibers, consistent with their loss in both conditions. However, a distinct ALS-enriched myonuclei subpopulation displays uniquely regulated genes not observed in aged muscle, potentially underlying the more rapid and severe pathology observed in ALS. This atlas maps shared and divergent mechanisms of muscle degeneration in ALS and sarcopenia and provides a resource for identifying therapeutic targets tailored to each condition.}, } @article {pmid42879998, year = {2026}, author = {Calma, AD and Pavey, N and Tsuji, Y and Ghapar, AA and Orden, B and Lee, G and Mekhael, L and Ryder, J and Silva, CS and Menon, P and Vucic, S}, title = {Serum neurofilament and measures of lower motor neuron dysfunction in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {193}, number = {}, pages = {2112428}, doi = {10.1016/j.clinph.2026.2112428}, pmid = {42879998}, issn = {1872-8952}, abstract = {OBJECTIVE: Serum neurofilament light chain (NfL) is an emerging diagnostic and prognostic biomarker in amyotrophic lateral sclerosis (ALS). Ulnar far-field potentials (FFP) have also been proposed as a reliable neurophysiological biomarker in ALS. This study examined the relationship between serum NfL levels and neurophysiological biomarkers of lower motor neuron dysfunction in ALS.

METHODS: This study included 96 ALS participants and 53 participants with ALS-mimicking disorders. All participants underwent serum NfL measurement using a single-molecule array (Simoa) assay, together with peripheral neurophysiological assessment, including ulnar nerve FFP, compound muscle action potential (CMAP), near-field potential (NFP), split-hand index (SI), and neurophysiological index (NI).

RESULTS: FFP amplitude was reduced in ALS (5.0 ± 3.0 mV) compared with non-ALS participants (7.9 ± 3.2 mV; p < 0.001). Similar reductions were observed for NFP and CMAP amplitudes (p < 0.001). Serum NfL was higher in ALS participants (72.5 pg/mL, IQR 46.5-113.5) compared to ALS-mimicking controls (14 pg/mL, IQR 9-19; p < 0.001). Serum NfL showed weak negative correlations with CMAP (ρ = - 0.23, p = 0.03) and NFP amplitudes (ρ = -0.28, p = 0.01), but no significant correlation with FFP amplitude, SI or NI. After adjusting for disease duration and functional impairment on multiple linear regression, neither CMAP nor NFP amplitudes independently predicted serum NfL levels.

CONCLUSION: Serum NfL is elevated in ALS and weakly associated with CMAP and NFP amplitudes. The absence of a statistically significant correlation with FFP suggests that these biomarkers may capture distinct aspects of disease biology.

SIGNIFICANCE: Serum NfL and FFP amplitude may provide complementary diagnostic information in ALS.}, } @article {pmid42880056, year = {2026}, author = {Wang, M and Li, J and Wang, X and Chai, X and Luo, J and Zhang, Y and Chang, X and Sun, Y and Wang, H}, title = {Harnessing cGAS-STING in neurodegeneration: From mitochondrial DNA leakage and microglial reactivity to species-specific translational barriers.}, journal = {Cytokine & growth factor reviews}, volume = {92}, number = {}, pages = {101537}, doi = {10.1016/j.cytogfr.2026.101537}, pmid = {42880056}, issn = {1879-0305}, abstract = {The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cornerstone of innate immunity, has emerged as a critical driver of sterile neuroinflammation in the aging brain. Age-related decline in mitochondrial quality control, coupled with nuclear and lysosomal erosion, fosters the aberrant accumulation of cytosolic self-DNA, establishing a permissive environment for chronic cGAS-STING activation. This review synthesizes recent breakthroughs elucidating how major neurodegenerative diseases-Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-converge on this pathway through distinct, disease-specific triggers, ranging from PINK1/Parkin deficiency-driven mitochondrial DNA leakage to TDP-43 proteinopathy-associated retrotransposon de-repression. Critically, we evaluate the translational landscape, highlighting the profound challenge posed by species-specific pharmacology, as exemplified by the failure of the covalent inhibitor H-151 to engage human STING. We argue that the future of therapeutic intervention lies not in wholesale pathway ablation, but in nuanced, context-dependent fine-tuning that disentangles its detrimental chronic effects from its indispensable homeostatic functions. This review positions the cGAS-STING axis as a promising yet delicate frontier for combating age-related neurodegeneration.}, } @article {pmid42880226, year = {2026}, author = {DeAngelo, JD and Silverstein, AM and Shechter, D}, title = {Protein arginine methylation rewires molecular interactions.}, journal = {Cell chemical biology}, volume = {33}, number = {10}, pages = {1404-1421}, doi = {10.1016/j.chembiol.2026.09.011}, pmid = {42880226}, issn = {2451-9448}, mesh = {*Arginine/metabolism/chemistry ; Methylation ; *Protein-Arginine N-Methyltransferases/metabolism/chemistry ; Humans ; Protein Binding ; *Intrinsically Disordered Proteins/metabolism/chemistry ; }, abstract = {Protein arginine methyltransferases (PRMT1-9) catalyze monomethylation and dimethylation of arginine residues in RNA- and DNA-associated proteins. Protein arginine methylation can weaken or strengthen nucleic acid binding, recruit or exclude protein partners, and promote or suppress higher-order assembly, making its molecular consequences highly context dependent. Methylation preserves the cationic character of the guanidinium group, while altering hydrogen-bond donor topology, steric accessibility, and interaction geometry. These effects are particularly consequential in intrinsically disordered regions (IDRs), where arginine-rich motifs mediate multivalent protein-protein and protein-nucleic acid interactions. Here, we propose an interaction-equilibrium framework in which arginine methylation redistributes binding capacity among the competing protein, nucleic acid, and assembly states. This framework integrates reader-dependent and reader-independent effects of methylarginine and provides a chemical basis for understanding how a charge-preserving modification can reweight molecular interactions across diverse cellular contexts.}, } @article {pmid42880349, year = {2026}, author = {Juhl, A and Jüngert, J and Hebert, S and Siebenlist, G and Mulzer, LM and Morhart, P and Woelfle, J and Knieling, F and Reutter, H and Hanslik, G}, title = {Postnatal Dynamics of Choroid Plexus Cysts in Newborns and Infants: A Retrospective Single-Center Cohort Study.}, journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2982-3894}, pmid = {42880349}, issn = {1438-8782}, abstract = {Purpose Choroid plexus cysts (CPC) are frequently detected prenatally and are generally considered benign. However, data on their postnatal course, growth dynamics, and clinical relevance are limited. This study investigates the long-term development, growth patterns, and resolution of CPC in newborns and infants. Materials and Methods We retrospectively analysed 251 CPC in 164 patients admitted to a neonatal intensive care unit between 2014 and 2024. CPC were assessed using serial cranial ultrasonography. Growth dynamics were evaluated using Kaplan-Meier survival analysis and chi-square testing. Results CPC were identified in both preterm and term infants, with a mean CPC size of 4.1 mm at diagnosis. Of 177 CPC with serial imaging data, 40% were not present on initial scans and appeared postnatally. The median time to resolution was 108 days. Many CPC initially increased in size before decreasing or resolving completely. A chi-square analysis showed a significant shift in growth behaviour between the 6- and 12-week follow-up groups (p = 0.006). No infant required intervention related to CPC. Conclusion Postnatal CPC often follow a benign, self-limiting course, meaning they tend to resolve naturally over time, with dynamic growth patterns. Routine monitoring of isolated CPC in asymptomatic infants may not be needed in all cases. Ziel Choroidplexuszysten (CPC) werden häufig pränatal festgestellt und gelten im Allgemeinen als gutartig. Allerdings liegen nur begrenzte Daten zu ihrem postnatalen Verlauf, ihrer Wachstumsdynamik und ihrer klinischen Relevanz vor. Diese Studie untersucht die langfristige Entwicklung, die Wachstumsmuster und die Rückbildung von CPC bei Neugeborenen und Säuglingen. Materialien und Methoden Wir analysierten retrospektiv 251 CPC bei 164 Patienten, die zwischen 2014 und 2024 auf eine neonatologische Intensivstation aufgenommen wurden. Die CPC wurden mittels serieller kranialer Sonographie beurteilt. Die Wachstumsdynamik wurde mittels Kaplan-Meier-Überlebensanalyse und Chi-Quadrat-Test ausgewertet. Ergebnisse CPC wurden sowohl bei Frühgeborenen als auch bei termingeborenen Säuglingen festgestellt, wobei die durchschnittliche CPC-Größe bei der Diagnose 4,1 mm betrug. Von 177 CPC mit seriellen Bildgebungsdaten waren 40 % bei den ersten Untersuchungen nicht nachweisbar und traten postnatal auf. Die mediane Zeit bis zur Rückbildung betrug 108 Tage. Viele CPC nahmen zunächst an Größe zu, bevor sie sich verkleinerten oder vollständig zurückbildeten. Eine Chi-Quadrat-Analyse zeigte eine signifikante Verschiebung im Wachstumsverhalten zwischen den 6- und 12-Wochen-Nachbeobachtungsgruppen (p = 0,006). Bei keinem Säugling war eine interventionelle Behandlung im Zusammenhang mit dem CPC erforderlich. Schlussfolgerung Postnatale CPC zeigen in der Regel einen gutartigen und selbstlimitierenden Verlauf mit dynamischen Wachstumsmustern und spontaner Rückbildung. Eine routinemäßige Verlaufskontrolle isolierter CPC bei asymptomatischen Säuglingen ist möglicherweise nicht in allen Fällen erforderlich.}, } @article {pmid42869255, year = {2026}, author = {Zhang, ZY and Qin, BQ and Wu, SZ and Zhang, H}, title = {Conformational allocation of mitofusin 2 in neuronal mitochondrial dynamics: Mechanisms and therapeutic targeting.}, journal = {Biochemical pharmacology}, volume = {}, number = {}, pages = {118545}, doi = {10.1016/j.bcp.2026.118545}, pmid = {42869255}, issn = {1873-2968}, abstract = {Neurons must sustain functional mitochondria far from the cell body. Mitofusin 2 (MFN2), a dynamin-like large guanosine triphosphatase (GTPase), coordinates outer mitochondrial membrane remodeling with axonal transport, bioenergetic support, inter-organelle communication, and stress-responsive quality control. Studying these activities separately obscures how disruption of one protein produces diverse neuronal phenotypes. We propose a testable conformational-allocation framework in which molecular state distributions and transition kinetics bias MFN2 participation across cellular outputs. Integrating structural and functional evidence, we distinguish experimentally resolved mechanisms from working models. Variants associated with Charcot-Marie-Tooth disease type 2A (CMT2A) are compared by the molecular step or functional output affected. Fusion loss alone does not capture this mechanistic diversity. Structure-guided docking supports local compatibility at a shallow, conformationally conditional C-terminal surface, without establishing native accessibility, affinity, or therapeutic response. CMT2A provides the strongest context for intervention, combining causal genetics, direct mitofusin engagement studies, and multiscale rescue. Amyotrophic lateral sclerosis (ALS) provides secondary preclinical evidence, whereas Alzheimer's and Parkinson's diseases remain exploratory. The mitofusin pathway is chemically tractable, but paralog selectivity and state-dependent target engagement remain unresolved. A state- and variant-informed strategy may better match intervention to the affected output than indiscriminate enhancement of fusion.}, } @article {pmid42869714, year = {2026}, author = {Zhang, X and Xu, B and Peng, C and Li, H and Yang, K and Shen, A and Wang, J and Yang, X and Xia, Y and Hu, J and Aris, IM}, title = {Life-course associations of early-life risk factors, modifiable adult lifestyles, and transitions of cardiometabolic disease and multimorbidity: A prospective cohort study.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {101486}, doi = {10.1016/j.ajcnut.2026.101486}, pmid = {42869714}, issn = {1938-3207}, abstract = {BACKGROUND: Whether associations of early-life risk factors with cardiometabolic disease (CMD) transitions vary by adult lifestyles remains unclear.

OBJECTIVES: We aimed to examine the associations between early-life risk factors and CMD transitions, and to assess whether adult lifestyles can modify these associations.

METHODS: We analyzed data from 174,718 adults participating in the United Kingdom Biobank prospective cohort study. We defined 5 CMD transitions using a multistate model: from CMD-free to first CMD (FCMD; including stroke, ischemic heart disease, and type 2 diabetes), from FCMD to cardiometabolic multimorbidity (CMM), and from CMD-free, FCMD, and CMM to death. An early-life risk score (ERS; 0-3) summed low birth weight, maternal smoking around birth, and absence of human milk feeding in infancy. Adult lifestyle was quantified using an adult lifestyle score (ALS) adapted from 4 behavioral metrics of the Life's Essential 8 framework, and data were collected at study enrollment when participants had a median age of 55 y.

RESULTS: During a median follow-up of 14.6 y, individuals with both high early-life risk (ERS ≥2) and an unhealthy adult lifestyle (ALS: 0-49) had the highest risks for most adverse transitions, including CMD-free to FCMD [hazard ratio (HR): 2.04; 95% confidence interval (CI): 1.89, 2.21], FCMD to CMM (HR: 1.46; 95% CI: 1.27, 1.69), CMD-free to death (HR: 2.31; 95% CI: 1.95, 2.72), and FCMD to death (HR: 1.64; 95% CI: 1.34, 2.01). The associations of ERS with the risk of most CMD transitions were less pronounced among participants with a healthy adult lifestyle than among those with an unhealthy adult lifestyle.

CONCLUSIONS: Joint exposure to adverse early-life experiences and an unhealthy adult lifestyle was associated with elevated risks of CMD progression and mortality. Notably, the detrimental associations of early-life risk factors with specific CMD transitions were less pronounced among individuals with healthier adult lifestyles.}, } @article {pmid42869990, year = {2026}, author = {Castro, J and de Carvalho, M and Swash, M}, title = {Revisiting the muscle spindle in ALS: Implications for spinal motor network dysfunction.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {478}, number = {11}, pages = {}, pmid = {42869990}, issn = {1432-2013}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Humans ; Animals ; *Muscle Spindles/physiopathology/physiology ; *Motor Neurons/physiology ; Motor Neurons, Gamma/physiology ; *Spinal Cord/physiopathology ; Interneurons/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is typically characterized by progressive degeneration of upper and lower motor neurons. However, the contribution of afferent sensory pathways to spinal motor network disorganization has received little attention. Converging human histological evidence from multiple independent laboratories demonstrates that fusimotor (gamma) motor neuron innervation of muscle spindles degenerates in ALS while sensory endings remain morphologically intact at the end organ, although the afferent neurons and ascending sensory pathways are also affected. This dissociation creates unmodulated proprioceptive input. Spindle-derived sensory signals reach spinal interneuron circuits without fusimotor gain-control adjustment, degrading spindles from forward sensory models encoding predicted kinematic states into crude stretch receptors. We propose that this gain-control failure, compounded by the loss of associated alpha-gamma coactivation and beta skeletofusimotor denervation, constitutes an upstream driver of the spinal inhibitory interneuron circuit dysfunction documented by recent electrophysiological studies in ALS. The resulting early disinhibition, followed by maladaptive excitation, mirrors cortical ALS pathophysiology. However, transgenic mouse ALS models show selective sparing of gamma motor neurons, unlike the human disease, constituting a critical translational limitation. We present a temporal model of human ALS, linking fusimotor denervation to progressive disruption of spinal inhibitory and excitatory circuits.}, } @article {pmid42870990, year = {2026}, author = {Nazir, A and Hanan, NP and Roberts, T}, title = {GEDI canopy cover assessment using airborne LiDAR across eco-climate regions of the United States.}, journal = {Frontiers in plant science}, volume = {17}, number = {}, pages = {1951245}, pmid = {42870990}, issn = {1664-462X}, abstract = {Information about woody plant density and canopy cover is central to our definition of terrestrial ecosystem types and crucial for understanding ecosystem state, dynamics, biogeochemical processes, and biodiversity. The Global Ecosystem Dynamics Investigation (GEDI) LiDAR on the International Space Station (ISS) samples 3-D structural information on woody vegetation structure, including an estimate of canopy cover in each 25 m diameter footprint. This study presents an evaluation of the GEDI fractional canopy cover estimates by comparing GEDI retrievals to high-resolution airborne laser scanning (ALS) data at 20 study sites with ~460,000 GEDI footprints across the United States. Based on the statistical assessment, we observed high correlations (R[2] = 0.84 without geolocation correction; R[2] = 0.96 with geolocation correction) with a Root Mean Square Error (RMSE) of 14.1% (without geolocation correction) and 7.2% (with geolocation correction). However, error in GEDI L2B canopy cover in some eco-climate regions is still significant, particularly in drylands (mean relative error (MRE) = 69.8%) and shrublands (MRE = 84.1%). The analysis also determined that the GEDI fractional cover retrievals are most effective when actual canopy cover is low (<20%) or high (>70%), with errors typically inflated in areas where canopy cover is in the 20-70% range. This study provides a baseline evaluation of GEDI canopy cover accuracy across eco-climate regions of CONUS, supporting improved interpretation and future refinement of the GEDI canopy cover product.}, } @article {pmid42871488, year = {2026}, author = {Monfared Jahromi, N and Maleki, A}, title = {Short-term Classification of Neurodegenerative Diseases using Time-series Features Based on Analysis of Gait Dynamics.}, journal = {Journal of biomedical physics & engineering}, volume = {16}, number = {5}, pages = {395-406}, pmid = {42871488}, issn = {2251-7200}, abstract = {BACKGROUND: Neurodegenerative Diseases (NDDs) refer to disorders, leading to the gradual degeneration of neurons in the human nervous system and profoundly affecting individuals' motor and cognitive functions. Early diagnosis and monitoring of the progression of NDDs are of critical importance.

OBJECTIVE: The primary aim of this study is to present an automatic diagnostic method using time-domain analysis of short-term gait signals of two consecutive steps, for the classification of Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and a Healthy Control Group (HC).

MATERIAL AND METHODS: This analytical study used datasets from PhysioNet, including 64 five-minute recordings from 13 individuals with ALS, 15 with Parkinson's, 20 with Huntington's, and 16 healthy individuals. To reduce noise and enhance signal quality, a median filter was applied. The preprocessed gait signals were then systematically segmented into consecutive two-step windows, which were used to construct the feature vectors. Finally, the constructed feature vectors were used as inputs for both linear and nonlinear classifiers. The proposed method was evaluated by calculating the accuracy index.

RESULTS: The quaternary classification of ALS vs. PD vs. HD vs. HC using the bag-tree classifier achieved an accuracy of 82.8%. Furthermore, for the binary classifications of HC vs. HD, HC vs. ALS, HC vs. PD and NDD vs. HC, the accuracies were 88.4%, 97.6%, 90% and 89.1%, respectively.

CONCLUSION: Gait dynamics analysis has a high potential for the rapid diagnosis of neurodegenerative diseases. Short term analysis in two consecutive stages enables the use of the Kinect sensor for gait analysis.}, } @article {pmid42871744, year = {2026}, author = {Castells-Ballester, J and Shcherbik, N}, title = {Scp160 deletion suppresses TDP-43 aggregation and toxicity in Saccharomyces cerevisiae.}, journal = {Microbial cell (Graz, Austria)}, volume = {13}, number = {}, pages = {358-377}, pmid = {42871744}, issn = {2311-2638}, abstract = {Protein misfolding and aberrant protein aggregation are central features of neurodegenerative disorders, including amyotrophic lateral sclerosis, where the RNA-binding protein TDP-43 accumulates in abnormal intracellular assemblies. Although yeast models have identified multiple modifiers of TDP-43 toxicity, the cellular factors that determine how aggregation-prone proteins are organized remain incompletely understood. Here, we investigated whether the ribosome- and mRNP-associated proteins Scp160 and Bfr1 influence TDP-43 proteotoxicity and aggregate formation. We report that deletion of SCP160 or BFR1 improves growth during TDP43-GFP induction without reducing steady-state reporter abundance and decreases formation of prominent TDP43-GFP foci. Deletion of BFR1 produced an intermediate TDP-43 phenotype, with a weaker effect than SCP160 deletion on severe foci formation and toxicity. Importantly, the effect of SCP160 or BFR1 deletion on visible protein aggregation was not specific to TDP-43: severe Htt103Q-GFP aggregation was strongly reduced, and formation of VHL-GFP foci was suppressed, including under conditions of proteasome inhibition. Despite these shared effects, the two mutants were not phenotypically identical. Deletion of SCP160 produced a distinct spatial phenotype in which residual TDP43-GFP foci showed markedly increased association with Sec63-positive ER structures and reduced distance to these regions, whereas bfr1 Δ cells did not show the same Sec63-associated shift. Together, these findings uncouple TDP43-GFP abundance from toxicity and prominent foci formation and identify Scp160 and Bfr1 as factors that influence the intracellular partitioning of aggregation-prone and misfolded proteins, with an additional role for Scp160 in the spatial organization of TDP43 relative to the ER.}, } @article {pmid42872064, year = {2026}, author = {Cai, W and Yi, Y and Zeng, R and Yin, Y and Zhao, J and Zhang, J and Fu, G and Xu, H}, title = {HMGB1 functional plasticity in neurodegenerative diseases and its translational implications.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1928641}, pmid = {42872064}, issn = {1664-3224}, mesh = {Humans ; *HMGB1 Protein/metabolism/genetics ; *Neurodegenerative Diseases/metabolism ; Animals ; Translational Research, Biomedical ; Signal Transduction ; Alarmins/metabolism ; Biomarkers ; }, abstract = {High mobility group box 1 (HMGB1) is a chromatin-associated protein that can be redistributed and released during cellular stress, when it acts as an extracellular alarmin within the broader family of damage-associated molecular patterns (DAMPs). Its functions depend on subcellular localization, redox and post-translational modification state, cellular source, mode of release, and molecular partners. This critical narrative review examines how these variables shape HMGB1 biology in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxias (SCAs), frontotemporal dementia (FTD), and related disorders, and considers their implications for biomarker and therapeutic development. Intracellular HMGB1 contributes to chromatin organization, DNA repair, mitochondrial genome maintenance, and proteostasis. After redistribution and release, extracellular HMGB1 signals through receptors including the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), interacts with disease-associated proteins, and links proteostatic stress with glial activation, neuronal dysfunction, and blood-brain barrier impairment. Across disease models, two recurrent patterns emerge: loss or sequestration of intracellular HMGB1 in models of polyglutamine disorders, including HD and SCAs, and extracellular HMGB1 signaling as a progression-associated inflammatory amplifier in AD, PD, and ALS models. Central-peripheral inflammatory communication and cell-specific HMGB1 release further shape these responses. Clinical studies have associated total HMGB1 or anti-HMGB1 autoantibodies with clinical features, but current assays do not resolve redox form, cellular source, or biological activity. Most therapeutic studies remain preclinical, while available human intervention studies involve drugs with multiple molecular actions. Clinical translation requires redox-resolved and standardized assays, longitudinal human sampling, compartment- and cell-specific causal studies, and interventions with documented target engagement, central nervous system exposure, and long-term safety. HMGB1 is best understood as a context-dependent mediator rather than a uniformly pathogenic factor or a single treatment target.}, } @article {pmid42872742, year = {2026}, author = {Onoichenco, A and Morris, SL and Aloe, S and McCay, K and Song, Y and Brady, ST}, title = {Isolated Axoplasm from Squid and Pathogenic Mechanisms in Amyotrophic Lateral Sclerosis.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {236}, pages = {}, doi = {10.3791/72560}, pmid = {42872742}, issn = {1940-087X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Decapodiformes ; *Axons/pathology/metabolism ; Kinesins/metabolism ; }, abstract = {The squid giant axon is an experimental model that has been instrumental in providing answers to many fundamental questions in cell biology, including the discovery of the motor protein kinesin and probing molecular mechanisms of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). The giant axon offers scale and ease of access that is not possible in mammalian models. The power of this model stems from the fact that one can introduce reagents and proteins that would not cross a plasma membrane at defined concentrations in a buffer environment that is closely modeled on normal components of the axoplasm. By leveraging the unique biology of the squid axon, early studies were able to define the channels and ion specificities of the action potential. Subsequent studies using video-enhanced contrast- differential Interference contrast microscopy (VEC-DIC) and the isolated axoplasm led to the identification of kinesins, a class of motor proteins responsible for intracellular vesicle trafficking toward the plus end of microtubules. This combination of isolated axoplasm and advanced imaging continues to provide insights into pathogenic mechanisms for adult-onset neurodegeneration, including ALS, and regulation of fast axonal transport, a process disrupted in motor neuron disease. Here, procedures for dissecting the giant axon, isolating axoplasm, and perfusing defined amounts of proteins and/or reagents into the axoplasm are detailed, as well as methods for visualizing and interactively analyzing vesicle traffic in real time. This model represents a singular avenue to understand the critical function of neurons, shedding light on the mechanisms driving ALS pathology and other neurodegenerative diseases. This system also offers a tractable platform for drug testing, where candidate therapeutic compounds can be introduced directly into the axoplasm, and their effects on vesicle trafficking can be assessed in real time, providing a rapid and physiologically relevant means of identifying potential ALS therapeutic targets.}, } @article {pmid42873357, year = {2026}, author = {Gündoğdu, AA and Özkan, NG and Adapınar, DÖ}, title = {The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42873357}, issn = {1573-7365}, mesh = {Humans ; *Microtubules/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; tau Proteins/metabolism ; Axonal Transport/physiology ; }, abstract = {Neurodegenerative diseases are a clinically and pathologically diverse group of disorders characterized by progressive neuronal dysfunction, synaptic impairment, and neuronal loss. Although research has traditionally focused on disease-associated protein misfolding and aggregation, increasing evidence implicates abnormalities of cytoskeletal organization and intracellular transport in several neurodegenerative conditions. Microtubules contribute to neuronal polarity, axonal and dendritic transport, organelle distribution, and synaptic maintenance. These functions are regulated in part by tubulin isotypes, post-translational modifications collectively described as the tubulin code, microtubule-associated proteins, and molecular motors. This narrative review examines evidence linking alterations in these processes with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. We summarize proposed interactions among microtubule instability, impaired axonal transport, mitochondrial dysfunction, and disease-associated proteins, including tau, α-synuclein, mutant huntingtin, TDP-43, and prion protein. Evidence connecting tau pathology with microtubule dysfunction is comparatively well established in Alzheimer's disease and MAPT-related tauopathies, whereas findings in other disorders are more heterogeneous and are frequently derived from cellular or animal models. We also discuss emerging experimental approaches, candidate biomarkers, and investigational microtubule-directed treatments. However, no tubulin-specific biomarker or microtubule-targeted disease-modifying treatment discussed in this review has yet been clinically validated. Overall, microtubule dysfunction may represent one component of broader, disease-specific pathological networks rather than a universal primary cause of neurodegeneration. Further longitudinal and clinical studies are needed to determine whether microtubule-related alterations act as causes, consequences, or modifiers of disease progression.}, } @article {pmid42873683, year = {2026}, author = {Wei, Z and Yanlin, G and Jing, L and Shazhen, A and Zhihan, Z and Zhuo, Z and Jiajia, Y and Xia, G and Xue, L and Shiyi, Y and Fei, X}, title = {Body composition characteristics in patients with inflammatory myopathy based on bioelectrical impedance analysis.}, journal = {Clinical and experimental rheumatology}, volume = {}, number = {}, pages = {}, doi = {10.55563/clinexprheumatol/fhq0ug}, pmid = {42873683}, issn = {0392-856X}, abstract = {OBJECTIVES: To investigate body composition features in idiopathic inflammatory myopathy (IIM) using bioelectrical impedance analysis (BIA) and evaluate their clinical, diagnostic and follow-up value.

METHODS: This study included 103 patients with inflammatory myopathy over a 6-year period, excluding 15 cases, resulting in a final cohort of 88 IIM patients. Clinical assessments and BIA were performed. Healthy controls and patients with amyotrophic lateral sclerosis (ALS) were independently recruited as separate comparison groups.

RESULTS: IIM patients showed reduced muscle mass (SMM: 20.9±4.4 vs. 23.4±4.8, p=0.001), elevated ECW/TBW ratio (ECW/TBW total (ETT): 0.398±0.015 vs. 0.381±0.007, p<0.001), and decreased phase angle (PhARA: 3.50 [2.92, 4.50]° vs. 5.15 [4.50, 5.62]°, p<0.001; PhALA: 3.55 [2.84, 4.43]° vs. 5.03 [4.48, 5.42]°, p<0.001). These features correlated with disease severity, inflammation, and nutritional status. Compared to ALS, IIM patients had more marked ECW retention (ETT: 0.397±0.0145 vs. 0.389±0.0110, p=0.001) and impaired membrane integrity (PhARA: 3.450±0.99° vs. 4.295±1.44°, p=0.014; PhALA: 3.500 [2.850, 4.400]° vs. 4.400 [3.875, 4.925]°, p=0.003). Body composition demonstrated substantial potential for diagnostic application (XGBoost model: specificity 85.00%, sensitivity 88.46%), and more importantly, may serve as a valuable tool for disease management.

CONCLUSIONS: BIA technology provides important novel disease characteristics for IIM patients, which are closely related to traditional clinical features and demonstrate significant diagnostic and management potential.}, } @article {pmid42586272, year = {2026}, author = {Chen, RF and Chen, SC}, title = {Response to Tognaccini et al, "Comment on Chen et al's 'Disparities of itch severity in outpatient clinics as measured by the ItchyQuant'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.08.022}, pmid = {42586272}, issn = {1097-6787}, } @article {pmid42762993, year = {2026}, author = {Lei, L and Tan, R and Xu, F and Chen, J and Ma, F and Wang, W and Liu, Y}, title = {Response to Rodríguez-Conde et al's "Prognostic determinants of early and late relapse in cutaneous squamous cell carcinoma: A multicenter retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.08.124}, pmid = {42762993}, issn = {1097-6787}, } @article {pmid42863380, year = {2026}, author = {Mustafayev, B and Mustafayeva, A and Bakhtiyarov, A and Nikatov, K and Satylkhan, B and Mustafayev, A}, title = {Expanded Longitudinal Validation of Adaptive Learning Stability in AI-Assisted Neurosurgical Residency Training.}, journal = {Journal of surgical education}, volume = {83}, number = {11}, pages = {104210}, doi = {10.1016/j.jsurg.2026.104210}, pmid = {42863380}, issn = {1878-7452}, abstract = {OBJECTIVE: To evaluate the longitudinal stability, reproducibility, and robustness of Adaptive Learning Stability (ALS) within an expanded AI-assisted neurosurgical residency cohort during a 12-month observation cycle.

DESIGN: This was a prospective controlled educational study. Residents completed 4 consecutive quarterly checkpoints integrating cognitive, technical, and decision-making assessments over 12 months. The RCKaS-AI framework incorporated predictive analytics, individualized adaptive remediation, and mentor-validated feedback pathways. Primary analysis evaluated longitudinal entrustment trajectory stability across checkpoints. Secondary analyses included inter-resident variance dynamics, remediation frequency, faculty workload, and predictive agreement between forecasted and observed competency progression.

SETTING: Two accredited neurosurgical residency programs in Kazakhstan, from January 2025 to January 2026.

PARTICIPANTS: Sixty-four neurosurgical residents randomized into standard RCKaS (n = 32) and AI-enhanced RCKaS-AI (n = 32) cohorts.

RESULTS: Both cohorts demonstrated progressive improvement in entrustment scores across sequential checkpoints. In the RCKaS-AI cohort, mean entrustment scores increased from 59.1 ± 12.8 at CP1 to 94.3 ± 6.9 at CP4, compared with 58.4 ± 13.1 to 85.7 ± 10.4 under standard RCKaS conditions (p = 0.001). Inter-resident variance decreased by 41% in the AI-assisted cohort versus 18% in the standard cohort. Residents within the RCKaS-AI framework achieved entrustment level 4 significantly earlier than controls (38 ± 7 weeks vs 50 ± 9 weeks, p = 0.003). Mean remediation frequency decreased from 3.4 ± 1.1 to 1.9 ± 0.7 sessions per resident, while faculty workload declined by 34%. Predictive analytics demonstrated strong agreement between forecasted and observed competency trajectories (r = 0.84; 95% CI, 0.77-0.89).

CONCLUSIONS: Expanded longitudinal implementation of the RCKaS-AI framework demonstrated reproducible stabilization of competency trajectories during neurosurgical residency training. These findings support the robustness of adaptive AI-assisted feedback systems as a practical mechanism for longitudinal competency regulation within structured surgical education programs. Further multicenter validation is required to evaluate external reproducibility across broader residency environments.}, } @article {pmid42864293, year = {2026}, author = {Wang, S and Wang, M and Sun, Y and Liu, G and Li, Y and Zhang, W and Yao, J}, title = {[Effect of electroacupuncture at Jiaji (EX-B2) on disease progression in mice with amyotrophic lateral sclerosis based on NLRP3/Caspase-1/ASC signaling pathway].}, journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion}, volume = {46}, number = {10}, pages = {1677-1684}, doi = {10.13703/j.0255-2930.20250518-k0001}, pmid = {42864293}, issn = {0255-2930}, mesh = {Animals ; *Electroacupuncture ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; Mice ; Signal Transduction ; Humans ; Male ; *Caspase 1/metabolism/genetics ; Disease Progression ; *Acupuncture Points ; CARD Signaling Adaptor Proteins/metabolism/genetics ; Female ; Mice, Inbred C57BL ; Disease Models, Animal ; Spinal Cord/metabolism ; *Carrier Proteins/metabolism/genetics ; }, abstract = {OBJECTIVE: To explore the underlying mechanism of electroacupuncture (EA) at "Jiaji" (EX-B2) on the disease progression through modulating NOD-like receptor family pyrin domain containing 3 (NLRP3)/cysteine-aspartic acid protease 1 (Caspase-1)/apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) signaling pathway in mice with amyotrophic lateral sclerosis.

METHODS: Forty-five mice carrying the human superoxide dismutase 1 G93A (hSOD1[G93A]) gene were randomly divided into a model group, a Jiaji EA group, and an inhibitor group, 15 mice per group. The other 15 mice without hSOD1[G93A] gene carried were collected as a wild group. When the mice were aged 60 days, in the Jiaji EA group, EA was operated at "Jiaji" (EX-B2) of L1/L2, L5/L6, with continuous wave, a frequency of 2 Hz and an intensity of 1 mA, retained for 20 min, twice a week; in the inhibitor group, the intraperitoneal injection with NLRP3 inhibitor (10 mg/kg) was administered, twice a week. The interventions lasted for 4 weeks in each group. When the mice were aged 120 days, 9 mice in each group were randomly selected for tissue collection from lumbar spinal cord, and the disease progression and limb function were observed for the remaining 6 mice. The neurological function score was employed to assess the disease progression of mice in each group, and the gait experiment was conducted to observe the gait and stride length; HE staining was used to observe the motor neuron morphology in the anterior horn of the lumbar spinal cord, immunohistochemistry was used to detect the expression of ionic calcium-binding adapter molecule 1 (Iba-1) in the anterior horn of the lumbar spinal cord, and Western blot was used to detect the protein expression of NLRP3, Caspase-1, ASC, interleukin (IL)-18 and IL-1β in lumbar spinal cord.

RESULTS: Compared with the wild group, in the model group, the disease was worsened progressively, on days 90 and 120 after birth, the stride length of mice was reduced (P<0.05, P<0.01), and the gait was unstable and dragging on 120 days after birth; the motor neurons in the anterior horn of the spinal cord exhibited obvious cellular edema and rupture, marked vacuolization and nuclear pyknosis, along with severe neuron loss; the expression of Iba-1 increased in the anterior horn of the lumbar spinal cord (P<0.01), colored dark brown and densely aggregated; and the protein expression of NLRP3, Caspase-1, ASC, IL-18, IL-1β in lumbar spinal cord was up-regulated (P<0.01). When compared with the model group, in the inhibitor group and the Jiaji EA group, the onset of paresis and the progression of paralysis were delayed and the survival rates increased (P<0.01); stride length was larger in the mice at the age of 120 d (P<0.01); more clear gait was presented, and the ages in days was significantly delayed for gait dragging; the improvements were exhibited in the degree of edema, vacuolization, and nuclear pyknosis observed in the motor neurons of the anterior horn of the lumbar spinal cord; the expression of Iba-1 was reduced in the anterior horn of the lumbar spinal cord (P<0.01), appearing gray-brown, and scattered clusters in small number; and the protein expression of NLRP3, Caspase-1, ASC, IL-18, and IL-1β in lumbar spinal cord was decreased (P<0.05, P<0.01). The protein expression of NLRP3, Caspase-1 and IL-18 in lumbar spinal cord in the Jiaji EA group was up-regulated in comparison with that in the inhibitor group (P<0.05).

CONCLUSION: Electroacupuncture at "Jiaji" (EX-B2) can delay the disease progression in mice with amyotrophic lateral sclerosis, which may be related to modulating NLRP3/Caspase-1/ASC signaling pathway and inhibiting the inflammatory response, thereby attenuating the inflammatory injury of lumbar spinal cord.}, } @article {pmid42864345, year = {2026}, author = {Agarwal, T and Sneideris, T and Svara, F and Jermakovs, K and Coyle, H and Qamar, S and Kava, E and Scrutton, R and Pleschka, N and Peres, P and Cereghetti, G and Andrzejewska, E and Diaz-Barreiro, A and Palmer, G and Costa-Filho, AJ and Krainer, G and Knowles, TP and Nixon-Abell, J}, title = {Mapping high resolution, multidimensional phase diagrams of near-physiological protein condensates.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42864345}, issn = {2041-1723}, support = {227745/Z/23/Z//Wellcome Trust (Wellcome)/ ; }, mesh = {Humans ; *RNA-Binding Protein FUS/genetics/metabolism/chemistry ; *Biomolecular Condensates/chemistry/metabolism ; Cell Nucleolus/metabolism/chemistry ; *Stress Granules/metabolism/chemistry ; Animals ; Mutation ; Microfluidics/methods ; Phase Separation ; Machine Learning ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Aptamers, Nucleotide ; }, abstract = {Biomolecular condensates are membraneless compartments, crucial for organising and regulating diverse cellular processes. Current approaches to study condensate biology either use simplified recombinant protein systems with limited physiological relevance, or complex live-cell models with restricted experimental control and scalability. Here, we present ExVivo PhaseScan, a droplet microfluidics platform that couples mammalian lysate-based reconstitution with scalable analysis to generate high-resolution phase diagrams of compositionally complex protein condensates. We apply this approach to study two multicomponent condensate systems, stress granules and nucleoli, and dissect the physicochemical interactions that influence their stability. We further developed a machine learning pipeline to analyse condensate morphology which we use to reveal how mutations in the amyotrophic lateral sclerosis (ALS)-linked protein Fused in Sarcoma (FUS) remodels condensate properties. We identify liquid-to-solid transitions of mutant FUS within stress granules and nucleoli, and show that these transitions can be reversed by RNA aptamer-based interventions. Together, these findings establish ExVivo PhaseScan as a versatile tool for dissecting the physicochemical and pathological regulation of condensates, with potential to inform therapeutic strategies for diseases driven by aberrant phase transitions.}, } @article {pmid42864501, year = {2026}, author = {Saha, T and Mehan, S}, title = {Combined rituximab and magnesium acetyl taurate therapy attenuates neurodegeneration via ERK/c-JNK/P38MAPK signaling modulation in methylmercury-induced amyotrophic lateral sclerosis-like neurotoxicity.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {42864501}, issn = {1432-1912}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration, oxidative stress, neuroinflammation, mitochondrial dysfunction, and dysregulation of intracellular signaling pathways. The present study investigated the neuroprotective potential of rituximab (RTXMB), alone and in combination with magnesium acetyl taurate (MACT600), against methylmercury (MLMC5)-induced ALS-like pathology in adult Wistar rats through modulation of the ERK/c-JNK/P38MAPK signaling pathway. ALS was induced by oral administration of MLMC5 (5 mg/kg) for 21 days. RTXMB (50 and 100 mg/kg) and MACT600 (600 mg/kg) treatments were administered from day 22 to day 42. Behavioral assessments, neurochemical estimations, ELISA, Western blotting, hematological analysis, gross morphology, and histopathological evaluations were performed. MLMC5 exposure produced significant impairments in locomotion, muscular strength, cognition, and emotional behavior, accompanied by increased oxidative stress, inflammatory cytokines, glutamate excitotoxicity, apoptotic markers, methylmercury accumulation, and dysregulation of ERK/c-JNK/P38MAPK signaling. Moreover, MLMC5 caused marked demyelination, neuronal degeneration, neurotransmitter imbalance, skeletal muscle damage, and hematological dysfunction. RTXMB treatment significantly attenuated these pathological alterations in a dose-dependent manner, with RTXMB100 showing greater neuroprotective efficacy. Combined administration of RTXMB100 and MACT600 demonstrated the most pronounced therapeutic effects by restoring antioxidant defenses, suppressing neuroinflammation and apoptosis, normalizing neurotransmitter levels, preserving myelin integrity, and improving neuronal morphology. The findings suggest that RTXMB, particularly in combination with MACT600, exerts potent neuroprotective effects against ALS-like pathology via modulation of MAPK signaling pathways and may represent a promising therapeutic strategy for ALS management.}, } @article {pmid42864601, year = {2026}, author = {Li, M and Jiao, YG and Tao, R and Hu, Y and Fei, JY and Wang, CT and Yao, SH}, title = {Optimized gGBE enables robust G-to-Y conversion in mammalian cells and zebrafish embryos.}, journal = {Zoological research}, volume = {47}, number = {6}, pages = {1839-1850}, doi = {10.24272/j.issn.2095-8137.2025.361}, pmid = {42864601}, issn = {2095-8137}, mesh = {Animals ; *Zebrafish/genetics/embryology ; Humans ; *Gene Editing/methods ; Embryo, Nonmammalian ; CRISPR-Cas Systems ; Amyotrophic Lateral Sclerosis/genetics ; *Glycoside Hydrolases/genetics/metabolism ; }, abstract = {Base editing is a powerful and precise genome-editing tool capable of introducing single-base substitutions with high resolution. Depending on the base-modification domains employed, base editors can mediate both transition and transversion base editing in mammalian cells. While deaminase-derived base editors have enabled efficient transition editing in the zebrafish genome, glycosidase-derived transversion editing remains a significant challenge. In this study, guided by structural insights into the Cas9 complex, we engineered a series of glycosidase guanine base editor (gGBE) constructs by inlaying the N-methylpurine DNA glycosylase (MPG) domain into Cas9 protein. Among these variants, we identified a high-performance gGBE in which MPG was inserted between residues G1246 and S1247 of the PI domain in Streptococcus pyogenes Cas9, which we named gGBE-PIGS. This variant improved editing efficiency by up to 3.5-fold in mammalian cells and 13-fold in zebrafish embryos, without compromising editing precision. Furthermore, we developed a gGBE-editing-responsive GFP reporter to monitor editing efficiency and enrich for gGBE-edited cells and embryos. Using a combination of the optimized gGBE-PIGS and the GFP reporter, we successfully generated zebrafish models carrying mutations homologous to human amyotrophic lateral sclerosis (ALS)-associated variants. Together, these findings highlight the robustness and versatility of the gGBE platform for precise base editing and underscore its promising potential for in vivo disease modeling and therapeutic genome engineering.}, } @article {pmid42864685, year = {2026}, author = {Liao, K and Lin, J and Zhou, Y and Lewandowski, SA}, title = {Vascular profiling of the spinal cord and cortex reveals region-specific endothelial dysfunction and fibroblast remodeling in human ALS.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42864685}, issn = {2051-5960}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics/physiopathology ; *Fibroblasts/pathology/metabolism ; *Spinal Cord/blood supply/pathology/metabolism ; *Endothelial Cells/pathology/metabolism ; *Cerebral Cortex/blood supply/pathology/metabolism ; Blood-Brain Barrier/metabolism/pathology ; Transcriptome ; Female ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Increasing evidence suggests that neurovascular dysfunction contributes to ALS pathogenesis, but a comprehensive understanding of vascular cell alterations in the human central nervous system remains lacking. Here, to systematically characterize neurovascular changes in ALS, we curated single-nucleus transcriptomic datasets from human spinal cord and cortical tissues with a specific focus on vascular cell populations. Comparative analyses revealed substantial vascular perturbations in the spinal cord compared to the cortex. Among vascular-associated cell populations, endothelial cells and fibroblasts exhibited the most pronounced transcriptional alterations. Endothelial cells from ALS spinal cords displayed reduced blood-brain barrier integrity signatures and increased expression of inflammatory and stress-response programs, with the greatest changes manifested in capillary endothelial cells. In parallel, we generated a refined cellular atlas of spinal cord fibroblasts and identified three major fibroblast populations, including a distinct LAMA1[low] perivascular fibroblast subtype. Fibroblast signatures were found to be consistently elevated in ALS across single-nucleus transcriptomic, bulk transcriptomic, and experimental validation datasets. Together, our findings establish a region-resolved view of neurovascular alternations in human ALS, which is characterized by endothelial barrier dysfunction and disease-associated remodeling of specialized perivascular fibroblasts. These findings broaden the cellular framework of ALS pathogenesis beyond neuronal and glial alterations and highlight the neurovascular niche as an integral component of human ALS disease biology.}, } @article {pmid42864786, year = {2026}, author = {Hokkoku, K}, title = {[Lumbar Spinal Disease or Peripheral Nerve Disorder? The Role of Neurological Examination in Differential Diagnosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {78}, number = {10}, pages = {1089-1096}, doi = {10.11477/mf.188160960780101089}, pmid = {42864786}, issn = {1881-6096}, mesh = {Humans ; Diagnosis, Differential ; *Peripheral Nervous System Diseases/diagnosis ; *Neurologic Examination ; Nerve Conduction Studies ; *Spinal Diseases/diagnosis ; }, abstract = {Lower-limb numbness, pain, and weakness are common clinical complaints that require differentiation between cauda equina or radicular lesions associated with lumbar spinal disease and peripheral nerve disorders. Because degenerative findings on lumbar imaging are common, particularly among older adults, the responsible lesion should not be determined based on imaging findings alone. In this context, neurological examination contributes to anatomical localization and is central to the differential diagnosis. Particular emphasis is placed on interpreting muscle weakness and sensory disturbance according to myotomal, dermatomal, and peripheral nerve distributions. Other neurological findings, including gait disturbance, neurogenic claudication, bladder or bowel dysfunction, nerve stretch signs, and reflex changes, also provide important clues for localization. This review further addresses common diagnostic challenges encountered in daily practice, including differentiation of L5 radiculopathy from fibular neuropathy in patients with foot drop, distinction between cauda equina lesions and polyneuropathy, recognition of immune-mediated polyradiculoneuropathies, and identification of amyotrophic lateral sclerosis when it mimics lumbar spinal disease. Ancillary tests such as nerve conduction studies, needle electromyography, somatosensory evoked potentials, nerve ultrasound, and imaging should be interpreted in relation to the lesion localization suggested by neurological examination.}, } @article {pmid42865191, year = {2026}, author = {Mohanty, SK and Vijayalakshmi, MK and Gopinath, S and Jaisudha, J and Venkatraman, D and Sandela, TM and Mohan, VK}, title = {Neurovascular Modulation of the Blood-brain Barrier Using Focused Ultrasound for Antisense Therapy Delivery in Amyotrophic Lateral Sclerosis.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026509618261001075016}, pmid = {42865191}, issn = {1875-5739}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and the blood-brain barrier (BBB) restricts CNS delivery of macromolecular therapeutics such as antisense oligonucleotides (ASOs). Focused ultrasound (FUS) with microbubbles enables transient, noninvasive opening of the BBB for deliver SOD1-targeted ASOs.

METHODS: A narrative review of the literature in PubMed, Scopus, Web of Science, and Google Scholar (2020-2025) was conducted to evaluate FUS-assisted delivery of SOD1-targeted ASOs, with an emphasis on lipid- and calcium phosphate (CaP)- based nanoparticles.

RESULTS: Preclinical studies showed that FUS-mediated BBB opening (250 kHz; mechanical index 0.33; 30-s exposure; 0.15 mL/kg microbubbles) increased brain accumulation of nanoparticle- encapsulated ASOs by >3.5-fold compared with FUS without microbubbles. CaP lipid nanoparticles (~73 nm; -21 mV; 23-30% encapsulation efficiency) encapsulating tofersen demonstrated pH-responsive intracellular release. In wild-type and G93A SOD1 transgenic mice, FUS combined with CaP-ASO nanoparticles reduced SOD1 expression in sonicated cortical regions and increased lumbar spinal motor-neuron counts without detectable neuroinflammation or tissue damage.

DISCUSSION: Combining FUS-mediated BBB modulation with CaP nanoparticles provides a minimally invasive strategy for CNS ASO delivery. Observed spinal cord effects suggest wider CNS distribution, potentially involving CSF transport and retrograde axonal pathways. Clinical translation requires optimising FUS parameters, conducting long-term safety assessments, and managing skull acoustic variability.

CONCLUSION: MRI-guided FUS combined with CaP lipid nanoparticles represents a promising non-invasive platform for SOD1-targeted ASO delivery and precision gene therapy in ALS.}, } @article {pmid42865281, year = {2026}, author = {Pini, A and Cobel, C and Moretti, F and Governatori, G and Bonamici, M and Gobbato, T and Buonaccorso, L and Sireci, F and Ghirotto, L}, title = {Mapping the evidence on dignity therapy in amyotrophic lateral sclerosis: a scoping review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2742818}, pmid = {42865281}, issn = {2167-9223}, abstract = {Objective: To systematically map and synthesize the existing literature on the use of Dignity Therapy (DT) in amyotrophic lateral sclerosis (ALS), with particular attention to feasibility, acceptability, therapeutic outcomes, and clinical adaptations required for patients and caregivers. Methods: A systematic scoping review was conducted searching PubMed/MEDLINE, CINAHL, PsycINFO, and Scopus for studies published in the last ten years examining DT in individuals with ALS. Eligible studies were charted and compared qualitatively due to heterogeneity in design, outcomes, and measurement tools. Results: A total of 237 records were identified, of which five met the eligibility criteria. DT was generally feasible in ALS, including in advanced disease stages, when adapted with augmentative communication devices, email correspondence, or videoconferencing. Acceptability was high across studies, with participants frequently reporting meaningful engagement with the narrative process and positive perceptions of the generativity document. Qualitative evidence indicated potential benefits in existential well-being, emotional adjustment, maintenance of identity, and family communication. Quantitative outcomes were inconsistent, showing variable effects on dignity-related distress, mood symptoms, and spiritual well-being. Caregiver responses were mixed, with some reporting perceived support and others noting limited immediate impact. Conclusions: DT appears to be a promising intervention for addressing existential and relational needs in ALS, though current evidence is limited by small sample sizes and methodological variability. Larger, methodologically rigorous studies are needed to clarify therapeutic effects, optimize delivery adaptations, and evaluate outcomes for both patients and caregivers.}, } @article {pmid42865955, year = {2026}, author = {Long, Z and Guo, H and Sun, L}, title = {Mesenchymal stromal cells in age-related neurodegenerative disorders: mechanisms, translational barriers, and precision strategies.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1965598}, pmid = {42865955}, issn = {1664-3224}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/metabolism/etiology ; *Mesenchymal Stem Cells/metabolism/immunology ; Animals ; *Aging/immunology ; Extracellular Vesicles/metabolism/transplantation ; *Mesenchymal Stem Cell Transplantation/methods ; Precision Medicine ; Translational Research, Biomedical ; }, abstract = {Ageing remodels the neuroimmune, metabolic, and vascular environment in ways that accelerate neuronal vulnerability and constrain tissue repair. Mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) are therefore attractive candidates for neurodegenerative disorders because their effects extend beyond cell replacement to coordinated paracrine, immunomodulatory, trophic, and vascular regulation. This critical review evaluates the biological rationale, disease-specific evidence, translational limitations, and precision-development strategies for MSC-based interventions in Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple system atrophy, and vascular dementia, whilst using selected rare hereditary neurodegenerative disorders as exploratory boundary cases. Current evidence supports three interconnected modes of action: reprogramming maladaptive neuroimmune responses; preserving neuronal homeostasis through trophic support, mitochondrial rescue, and proteostasis regulation; and restoring the neurovascular unit and blood-brain barrier. However, reproducible clinical efficacy remains limited by variation in tissue source, donor age, manufacturing, potency, dose, route, and outcome selection, as well as poor central nervous system exposure and inadequate patient stratification. Ageing-related changes in both the recipient microenvironment and the cellular product further complicate translation. Future development should replace empirical cell administration with mechanism-defined products, validated potency assays, quantitative biodistribution, biomarker-guided enrolment, engineered cells or vesicles, rational combinations, and trials using disease-modifying endpoints. MSC-based therapies are best positioned not as universal regenerative agents, but as mechanism-defined, biomarker-matched products-potentially engineered at the cell or EV level-that regulate biologically active and potentially reversible disease states.}, } @article {pmid42866729, year = {2026}, author = {Hassan, ST and Faheem, MSB and Yaqubi, AJ and Brhaish, MS}, title = {Brain-computer interfaces and neuroprostheses for severe speech impairment in amyotrophic lateral sclerosis.}, journal = {Annals of medicine and surgery (2012)}, volume = {88}, number = {10}, pages = {6221-6224}, pmid = {42866729}, issn = {2049-0801}, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder that frequently culminates in severe dysarthria and anarthria, profoundly isolating patients and diminishing their quality of life. Traditional speech therapy and conventional augmentative and alternative communication devices rely on residual motor control and become ineffective in late-stage ALS. In response, brain-computer interfaces and speech neuroprostheses have emerged as transformative solutions. By decoding neural signals directly from the motor cortex and translating them into synthesized speech, these devices bypass compromised neuromuscular pathways. Recent high-impact clinical trials have demonstrated unprecedented success, achieving high-speed decoding and integrating artificial intelligence-driven voice banking to preserve a patient's unique vocal identity. However, significant translational challenges remain, including signal degradation, surgical risks, high socioeconomic costs, and ethical dilemmas regarding patient autonomy and data privacy. This perspective reviews the current state-of-the-art in speech neuroprosthetics, analyzes the barriers to widespread clinical implementation, and advocates for increased interdisciplinary collaboration and funding to establish these technologies as a standard of care for patients with severe speech impairments.}, } @article {pmid42867206, year = {2026}, author = {Files, MC and Aranha, BC and Fipke, MV and Elias, DB and Camargo, ER and Carlos, FS and Miola, ECC and Souza, MF and Avila, LA}, title = {Elevated CO2 increases cover crop sensitivity to imidazolinones but does not substantially alter post-cultivation soil dissipation.}, journal = {International journal of phytoremediation}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/15226514.2026.2741670}, pmid = {42867206}, issn = {1549-7879}, abstract = {This study evaluated the effects of elevated (700 ± 50 µmol mol[-1]) and ambient (400 ± 50 µmol mol[-1]) atmospheric CO2 concentrations on soils treated with imazapyr, imazapic and imazethapyr using Italian ryegrass and Persian clover. Two open-top-chamber experiments assessed herbicide dissipation, soil microbial respiration (C-CO2) and plant biochemical responses, including acetolactate synthase (ALS) activity, free amino acids, proteins and soluble sugars. Soils amended with Persian clover residues showed greater herbicide dissipation (≈15-30%) than fallow soil after 40 days, regardless of CO2 level (except for imazethapyr under elevated CO2), whereas Italian ryegrass showed limited improvement, mainly for imazapic. Microbial respiration was highest in soils amended with Persian clover, while ryegrass resulted in the lowest respiration and reduced C-CO2 emission after imazapyr + imazapic application under elevated CO2. Elevated CO2 increased shoot biomass in both species but also reduced herbicide tolerance, decreasing GR50 values by 12-31% (from 64.5 to 44.6 g a.i. ha[-1] in Italian ryegrass and from 29.8 to 26.1 g a.i. ha[-1] in Persian clover), indicating greater plant susceptibility under future CO2 scenarios. At 28 days after emergence, herbicide application reduced ALS activity under both CO2 conditions, although ALS activity remained higher under elevated CO2. Persian clover showed greater biochemical resilience, maintaining higher amino acid contents under herbicide stress. Overall, cover-crop identity, rather than atmospheric CO2, was the primary determinant of herbicide dissipation in soil: Persian clover consistently enhanced microbial activity and imidazolinone degradation, whereas elevated CO2 increased plant sensitivity without improving post-cultivation soil remediation.}, } @article {pmid42858780, year = {2026}, author = {Ji, C}, title = {Partial convergence of alternative polyadenylation changes across ALS-Associated RNA-Binding proteins.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2026.10.012}, pmid = {42858780}, issn = {1873-7544}, abstract = {Alternative polyadenylation (APA) regulates transcript 3'-end architecture, stability, localization, and translation. Although RNA-binding protein dysfunction is central to amyotrophic lateral sclerosis (ALS), whether different ALS-associated proteins cause shared APA abnormalities remains unclear. We analyzed poly(A)-site usage after TDP-43 knockdown, TDP-43 K263E expression, FUS knockout, FUS P525L expression, and MATR3 knockout. Using false-discovery rate (FDR) < 0.05 as the primary criterion, evidence varied markedly among datasets. FUS knockout produced the strongest response, with 373 significant events affecting 239 genes. Three events involving two genes remained significant after TDP-43 knockdown, and two events involving one gene remained significant in the TDP-43 K263E dataset. No events survived FDR correction after FUS P525L expression or MATR3 knockout, and no FDR-significant events or genes were shared between datasets. We therefore examined nominal events (unadjusted P < 0.05) as an explicitly exploratory layer. Nominal event overlap was enriched in 7 of 10 pairwise comparisons, and nominal gene overlap in 9 of 10. TDP-43 knockdown and TDP-43 K263E showed the strongest directional agreement: 65 nominal events were shared; 25 were directionally classified in both datasets, of which 23 were concordant. FUS knockout and FUS P525L also showed enriched nominal overlap, but without significant directional concordance or correlated ΔPAU responses. Thus, FUS loss induces a robust FDR-supported APA phenotype, whereas evidence is substantially weaker in other contexts. Cross-dataset similarities occur mainly among exploratory nominal targets and do not consistently extend to direction or magnitude. APA responses therefore show partial, context-dependent convergence rather than a universal defect.}, } @article {pmid42859482, year = {2026}, author = {Sharma, T and Krishna, H and Dixit, A and Dixit, SG and Shukla, KK and Banerjee, M and Nayak, P}, title = {Aluminium as a Metalloestrogen: Toxicological Pathways, Endocrine Disruption and Systemic Health Implications.}, journal = {Maedica}, volume = {21}, number = {3}, pages = {759-766}, pmid = {42859482}, issn = {1841-9038}, abstract = {Aluminium (Al) is the most abundant metal in the Earth's crust and a common environmental contaminant due to industrial processes, recycling and consumer goods. Aluminium can enter the human body via the gastrointestinal, respiratory, and skin routes, as well as through injection, although this is not essential for biological function. It can then accumulate in different organs. Its physicochemical properties enable it to displace vital metals, bind to biomolecules and interfere with cellular processes, leading to genotoxicity, oxidative stress and protein misfolding. Aluminium toxicity impacts various body systems, such as neurodegeneration, bone disorders, heart conditions, endocrine disruption and reproductive issues. Notably, Al acts as a metalloestrogen, mimicking or disrupting estrogen receptor signaling. This interference affects the hypothalamic-pituitary-gonadal axis and changes estrogen-dependent processes in both males and females. This review explores Al's systemic toxicology and its emerging function as an endocrine disruptor, highlighting its dual nature as both a sustainable industrial resource and a common biological toxin. The findings highlight important public health issues and suggest the need for further research into how Al interacts with estrogen receptors to improve prevention and treatment.}, } @article {pmid42860504, year = {2026}, author = {Tsai, CY and Wu, HC and Su, TP and Weng, EF and Wang, SM}, title = {Sigma-1 Receptor Mitigates Poly-GR-Associated Redox Dysregulation by Restoring NRF2/HO1 Signaling in C9orf72-Associated ALS.}, journal = {Neuromolecular medicine}, volume = {28}, number = {1}, pages = {}, pmid = {42860504}, issn = {1559-1174}, mesh = {*Receptors, sigma/physiology/genetics/antagonists & inhibitors/agonists ; Animals ; *NF-E2-Related Factor 2/physiology/genetics/biosynthesis ; Sigma-1 Receptor ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Heme Oxygenase-1/physiology/biosynthesis/genetics ; Signal Transduction ; Mice ; Humans ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Oxidation-Reduction ; Motor Neurons/metabolism ; *C9orf72 Protein/genetics ; *Membrane Proteins/physiology/biosynthesis/genetics ; Mice, Transgenic ; Fluvoxamine/pharmacology ; Cell Line ; Mice, Inbred C57BL ; Male ; Morpholines ; }, abstract = {Hexanucleotide GGGGCC repeat expansions in C9orf72 produce arginine-rich dipeptide repeat proteins, including poly-GR and poly-PR, that contribute to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Although poly-GR has been linked to oxidative stress and mitochondrial dysfunction, the mechanisms that determine whether antioxidant defenses are preserved or suppressed in poly-GR-expressing motor neurons remain incompletely understood. Here, we investigated whether Sigma-1 receptor (Sigma-1R) modulates poly-GR-associated redox dysregulation in cellular and mouse models. In NSC34 cells, both EGFP-PR42 and EGFP-GR50 expression reduced NRF2 protein levels. EGFP-GR50 expression was also associated with reduced NRF1 and HO1 levels and increased reactive oxygen species (ROS) accumulation. Sigma-1R overexpression or pharmacological activation with fluvoxamine or PRE084 restored NRF2 and HO1 expression and attenuated both cellular and mitochondrial oxidative stress in EGFP-GR50-expressing cells. Co-treatment with the Sigma-1R antagonist NE100 attenuated the agonist-induced restoration of NRF2 and HO1. Furthermore, the NRF2 inhibitor ML385 attenuated agonist-mediated HO1 restoration, supporting the involvement of NRF2 activity in this downstream response. In an AAV-mediated EGFP-GR50 mouse model, Sigma-1R deficiency was associated with shortened survival, reduced NeuN-positive neuronal counts, and decreased NRF2 immunoreactivity in the brain. Together, these findings identify Sigma-1R as a modulator of poly-GR-associated redox dysregulation and neuronal vulnerability and support further investigation of Sigma-1R modulation as a potential therapeutic strategy for C9orf72-associated ALS.}, } @article {pmid42860740, year = {2026}, author = {Lee, K and Kwak, T and Park, W}, title = {Integrative ALS therapy: gene targeted therapy by base editing and potential exercise rehabilitation as synergistic strategies for functional recovery.}, journal = {Physical activity and nutrition}, volume = {30}, number = {3}, pages = {97-113}, doi = {10.20463/pan.2026.0045}, pmid = {42860740}, issn = {2733-7545}, abstract = {PURPOSE: A key pathological hallmark of amyotrophic lateral sclerosis (ALS) is transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP) proteinopathy. Mutations in TARDBP and cellular stress can drive nuclear clearance and cytoplasmic aggregation of TDP-43. TDP-43 is an essential nuclear RNA-binding protein that regulates RNA metabolism, and cytoplasmic TDP-43 aggregation leads to aberrant splicing of essential neuronal transcripts including stathmin-2 (STMN2) and unc-13 homolog A (UNC13A). Dysregulated RNA splicing causes cryptic exon (CE) inclusion in STMN2 and UNC13A mRNA, resulting in non-functional proteins and disruption of axonal regeneration and synaptic integrity. Splice-switching antisense oligonucleotides and gene-editing platforms can correct STMN2 and UNC13A mis-splicing defects. However, restoring STMN2 and UNC13A expression alone is not sufficient to regenerate neuromuscular junctions or reverse skeletal muscle atrophy, both of which are crucial for functional recovery in patients with ALS.

METHODS: We reviewed gene-targeted treatment strategies and rehabilitative mechanisms that inhibit ALS progression and reverse neuromuscular degeneration by analyzing databases, including Google Scholar, PubMed, and ScienceDirect. We proposed a dual-modality therapeutic approach integrating base-editing-mediated gene therapy with exercise-based rehabilitation.

RESULTS: Antisense oligonucleotides and genome editing can restore transcript fidelity by preventing cryptic exons inclusion in STMN2 and UNC13A, thereby stabilizing neuronal function. Gene-targeted therapies halt ALS progression; however, these treatments alone are insufficient to reverse neuromuscular degeneration or achieve functional recovery needed for patients with ALS to return to daily life.

CONCLUSION: Integrated rehabilitation is a crucial step in gene-targeted therapy for ALS. This strategy halts disease progression and restores neuromuscular function, thereby improving the lifespan and quality of life of patients with ALS.}, } @article {pmid42861689, year = {2026}, author = {Raheja, A and Ang, K and Lee, B and Saffari, SE and Tan, EK and Yeo, CJJ}, title = {Statin Exposure and Survival Outcomes in Amyotrophic Lateral Sclerosis in an Asian Cohort.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70427}, pmid = {42861689}, issn = {1097-4598}, support = {C210112024//Agency for Science, Technology and Research (A*STAR)/ ; IRNMR21CPGJJ//National Neuroscience Institute Singapore/ ; }, abstract = {INTRODUCTION: Data from Asian cohorts on whether statin therapy affects amyotrophic lateral sclerosis (ALS) progression are limited. We examined whether statin exposure was associated with ALS disease duration or tracheostomy-free survival in a multiethnic Asian ALS cohort.

METHODS: Data from patients diagnosed with ALS between 2012 and 2025 were retrospectively reviewed. Patients were categorized as "ever" or "never" statin users for primary analyses, and as "never," "former," or "current" users at diagnosis for additional analyses. Disease duration was defined as time from symptom onset to death, and tracheostomy-free survival as time from symptom onset to tracheostomy or death without tracheostomy. Kaplan-Meier and Cox regression analyses evaluated associations between statin exposure and both outcomes. Additional analyses examined statin discontinuation after diagnosis using time-varying exposures. Sensitivity analyses excluded post-diagnosis imitators and applied 30-, 90-, and 180-day lags.

RESULTS: Among 103 ALS patients, 27 (26.2%) had ever received statins. Statin exposure was not significantly associated with disease duration (hazard ratio [HR]: 1.42, 95% CI: 0.64-3.14, p = 0.387) or tracheostomy-free survival (HR: 1.04, 95% CI: 0.50-2.18, p = 0.913). Post-diagnosis statin discontinuation was associated with shorter survival in a time-varying analysis (HR: 6.52, 95% CI: 1.48-28.74, p = 0.013), although this finding was hypothesis-generating. Sensitivity analyses did not show statistically significant associations.

DISCUSSION: In this multiethnic Asian ALS cohort, statin exposure was not significantly associated with disease duration or tracheostomy-free survival. These findings add to the evidence that statins do not need to be discontinued due to ALS diagnosis. Larger studies are needed to define this association.}, } @article {pmid42861801, year = {2026}, author = {Alpana, and Dewangan, HK}, title = {Crossing the Blood-brain Barrier: Emerging Nanotechnological Approaches for Neurodegenerative Disease Therapy.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026454704261001071449}, pmid = {42861801}, issn = {1875-5739}, abstract = {Neurodegenerative disorders such as Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD) are characterized by progressive neuronal degeneration and severe therapeutic limitations due to the Blood-Brain Barrier (BBB). Recent advances in nanotechnology have enabled the development of nanoscale drug delivery systems capable of improving BBB penetration and enhancing therapeutic efficacy. This review discusses recent progress in Lipid Nanoparticles (LNPs), polymeric nanoparticles, exosomes, magnetic nanoparticles, gold nanoparticles, graphene quantum dots, and RNAloaded nanocarriers for brain-targeted delivery. Special emphasis is placed on receptor-mediated transcytosis, intranasal delivery, magnetic targeting, and ionizable lipid nanoparticle systems for nucleic acid delivery. Recent nanoformulations including curcumin-loaded nanoparticles, siRNA- loaded lipid nanoparticles, dopamine-loaded liposomes, and lactoferrin-functionalized polymeric nanoparticles are critically compared based on BBB penetration, therapeutic efficacy, toxicity, and translational potential. Furthermore, current clinical challenges including nanotoxicity, pharmacokinetics, large-scale manufacturing, and regulatory barriers are discussed. Nanotechnology- based therapeutics represent a promising strategy for improving diagnosis and treatment of neurodegenerative disorders and may facilitate the future development of precision nanomedicine.}, } @article {pmid42862029, year = {2026}, author = {Santos Silva, C and de Carvalho, M}, title = {Transcutaneous Carbon Dioxide Monitoring in Amyotrophic Lateral Sclerosis: A Scoping Review.}, journal = {European journal of neurology}, volume = {33}, number = {10}, pages = {e70782}, doi = {10.1111/ene.70782}, pmid = {42862029}, issn = {1468-1331}, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis ; Humans ; *Carbon Dioxide ; *Blood Gas Monitoring, Transcutaneous/methods ; *Hypoventilation/diagnosis/etiology ; *Respiratory Insufficiency/diagnosis/etiology ; }, abstract = {BACKGROUND: Respiratory failure is the leading cause of death in amyotrophic lateral sclerosis (ALS). Conventional pulmonary function tests are effort-dependent and may fail to detect early nocturnal hypoventilation. Transcutaneous carbon dioxide (PtcCO2) measurement is a non-invasive method for assessing ventilation, but its role in ALS remains unclear. We performed a scoping review to map the current evidence.

METHODS: PubMed, Web of Science, Scopus, and Google Scholar were searched from inception to April 2026. Original studies evaluating PtcCO2 monitoring in ALS were included. Due to heterogeneity in study designs, populations, and outcomes, a narrative synthesis was performed, categorized by study characteristics, measurement protocols, and clinical endpoints.

RESULTS: Twenty-one studies were included. Most were observational and conducted in tertiary centres. Twelve studies evaluated PtcCO2 as a surrogate marker for nocturnal hypoventilation, mainly to guide initiation or titration of non-invasive ventilation. Definitions of hypoventilation and reported PtcCO2 metrics varied widely. Only three studies evaluated PtcCO2 in relation to respiratory impairment or hypercapnia, but none reported formal measures of diagnostic accuracy. Evidence regarding the prognostic value was limited and inconsistent. Three studies showed that nocturnal hypercapnia preceded abnormalities in spirometry or daytime hypercapnia.

CONCLUSIONS: PtcCO2 monitoring shows promise as a non-invasive method for assessing nocturnal ventilatory abnormalities in ALS, including nocturnal hypoventilation. However, due to methodological heterogeneity, its diagnostic and prognostic roles remain uncertain. Current evidence is insufficient to support PtcCO2 as a standalone criterion for NIV initiation. Large-scale prospective studies with standardized protocols are essential to delineate its clinical utility.}, } @article {pmid42862034, year = {2026}, author = {Janse van Mantgem, MR and Kuiper, MM and Steyn, FJ and Holdom, CJ and Meyjes, M and Kok, A and Ngo, ST and van den Berg, LH and van Eijk, RPA}, title = {Assessing the metabolic rate in patients with Amyotrophic Lateral Sclerosis, Progressive Muscular Atrophy, and Primary Lateral Sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2745871}, pmid = {42862034}, issn = {2167-9223}, abstract = {OBJECTIVE: To determine whether resting energy expenditure (REE) differs between patients with amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS).

METHODS: Patients with ALS, PMA, and PLS were enrolled between 2017 and 2021 in a prospective cross-sectional study. REE was measured by indirect calorimetry. Body composition was assessed using air displacement plethysmography and used to calculate predicted resting energy expenditure (pREE). Metabolic index (MI) was defined as mREE relative to pREE and expressed as a percentage. Differences between disease categories were assessed using multivariable regression adjusted for sex, age, fat-free mass, fat mass, height, and smoking status.

RESULTS: In total, 79 patients with ALS, 33 with PMA, and 30 with PLS were included. MI of ≥110% was observed in 55.7% of patients with ALS, 27.3% with PMA, and 26.7% with PLS. After adjustment, MI differed significantly between disease subtypes (p = 0.019), with the highest mean observed in ALS (108.5%, 95% CI 105.8-111.1), followed by PMA (105.9%, 95% CI 102.6-109.3) and PLS (103.2%, CI 99.8 -106.6). Metabolic measures were not statistically correlated with disease-specific clinical characteristics.

CONCLUSIONS: Our findings suggest that metabolic phenotype varies across MND subtypes. In the absence of non-neurological controls, findings are best interpreted as indicating that MI-defined hypermetabolism is most prevalent in ALS; however, whether metabolic rate is increased in PMA or PLS relative to the general population remains unknown.}, } @article {pmid42862052, year = {2026}, author = {Unnikrishnan, B and Anand, A and Fang, CN and Wu, SM and Wang, CC and Huang, CC and Chu, HW and Chang, HT}, title = {Carbon dot-based nanomaterials in neurodegeneration: addressing neurobiological barriers and targeting challenges.}, journal = {Chemical communications (Cambridge, England)}, volume = {}, number = {}, pages = {}, doi = {10.1039/d6cc03262a}, pmid = {42862052}, issn = {1364-548X}, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, represent a major global health challenge due to their progressive nature and limited therapeutic options. One of the primary obstacles to treating these disorders is the blood-brain barrier (BBB), which restricts the delivery of most therapeutic agents into the central nervous system. In recent years, carbon-based nanomaterials, particularly carbon dot (CD) nanostructures, have emerged as promising platforms for neurological applications owing to their ultrasmall size, BBB-crossing ability, and anti-inflammatory and neuroprotective properties, in addition to tunable surface chemistry, strong photoluminescence, and favorable biocompatibility. This review provides a comprehensive overview of recent research developments in the application of CD-based nanomaterials, including carbon nanodots, carbon quantum dots, graphene quantum dots, and carbon polymer dots, for the potential treatment of neurodegenerative diseases. The synthesis strategies and carbonization approaches used to produce these carbon nanomaterials are discussed, along with their physicochemical properties relevant to neurobiological applications, such as particle size, surface functionalization, heteroatom doping, optical properties, and stability in biological environments. Furthermore, the mechanisms by which CD-based nanomaterials can traverse the BBB are examined, including receptor-mediated and adsorptive-mediated transcytosis pathways. In addition, their applications are discussed, with particular focus on their roles in bioimaging, biosensing, inhibition of pathological protein aggregation, antioxidative activity, and targeted drug delivery. Finally, key challenges related to toxicity, biodistribution, large-scale synthesis, and clinical translation are discussed, along with future perspectives for the development of multifunctional theranostic platforms. Overall, use of CD-based nanomaterials represents a promising emerging strategy for overcoming neurobiological barriers and enabling the development of next-generation nanotherapeutics for the management of neurodegenerative diseases.}, } @article {pmid42862306, year = {2026}, author = {Sahu, S and Jain, P and Dharme, KK and Yadav, K}, title = {CRISPR/Cas9-based nanodelivery systems for precision gene editing in neuroinflammation.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {75}, number = {1}, pages = {}, pmid = {42862306}, issn = {1420-908X}, support = {Probecell/Res/2026/124//Probecell Scientific Pvt. Ltd./ ; }, mesh = {Humans ; Animals ; *Neuroinflammatory Diseases/genetics/therapy ; *Gene Editing/methods ; *CRISPR-Cas Systems ; Nanoparticles/administration & dosage ; }, abstract = {BACKGROUND: Neuroinflammation is a characteristic feature of many neurological diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Uncontrolled activation of microglia and astrocytes results in the production of proinflammatory mediators that contribute to neuronal dysfunction and degeneration.

PURPOSE: CRISPR/Cas9 genome-editing technology provides highly precise targeting of genes involved in these pathways, enabling the deletion, correction, or modulation of disease-associated genetic alterations. Nonetheless, effective delivery of CRISPR components to the central nervous system (CNS) remains a major challenge because of protective barriers such as the blood-brain barrier (BBB), as well as concerns regarding genomic instability and immunogenicity.

METHODS: Nanotechnology-guided delivery platforms, such as lipid nanoparticles, liposomes, dendrimers and polymeric carriers, have been developed as promising strategies to address these challenges. These nanosystems can improve biodistribution, pharmacokinetic behavior, and cellular uptake, while potentially reducing off-target effects and systemic toxicity.

RESULTS: The preclinical studies demonstrate successful modulation of key neuroinflammatory targets, including the NLRP3 inflammasome, triggering receptor expressed on myeloid cells 2 (TREM2), Janus kinase (JAK) signaling, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, with potential therapeutic relevance to neurodegenerative diseases. In addition, novel techniques, such as mitochondrial base editing, prime editing, and epigenetic modulation, expand the scope of CRISPR-mediated therapeutic strategies. Although outcomes from animal models are promising, translation to the clinical setting requires careful consideration of safety, ethical concerns, and long-term efficacy.

CONCLUSIONS: This review highlights the potential of integrating CRISPR/Cas9 with nanodelivery systems to advance precision medicine for neuroinflammatory disorders, while emphasizing their potential for therapeutic applications in complex CNS conditions. Ongoing studies aimed at optimizing delivery and reducing off-target effects will be essential for advancing these approaches toward clinical practice.}, } @article {pmid42862794, year = {2026}, author = {Hawas, Y and Abdelmageed, A and Messak, M and Ziada, A and Gamal, M and Ghanem, TIE and Abdelwahab, MM and Meshref, M and Kashbour, MO}, title = {History of Head Injury and Risk of Amyotrophic Lateral Sclerosis: An Updated Comprehensive Systematic Review with Meta-Analysis of 5,033,215 Participants.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1}, doi = {10.1159/ned/adwag050}, pmid = {42862794}, issn = {1423-0208}, abstract = {BACKGROUND: Head injury has been proposed as a potential modifiable risk factor for amyotrophic lateral sclerosis (ALS); however, prior studies have yielded inconsistent findings. We aimed to re-evaluate this association through an updated systematic review and meta-analysis, incorporating the latest evidence and exploring the influence of injury severity, frequency, timing, and definition.

METHODS: A systematic search of PubMed, Scopus, Web of Science, Embase, EBSCO, and ProQuest from inception to January 2026 was conducted. Observational studies (cohort and case-control) reporting the association between head injury and ALS risk were included. Pooled effect estimates were generated using random-effects models. Subgroup, sensitivity, cumulative, and publication bias analyses were performed.

RESULTS: Twenty-nine studies encompassing 5,033,215 participants were included. These comprised 22 case-control studies and seven cohort studies. Case-control meta-analysis showed that head injury was associated with 36% higher odds of ALS (AOR = 1.36; 95% CI: 1.24-1.48; I² = 20.4%). Cohort studies showed a positive but non-significant association (RR = 1.59; 95% CI: 0.93-2.71). Subgroup analyses showed significant associations within mild, moderate, and severe injury categories and among studies with clearly defined traumatic brain injury exposure. Single head injury was associated with higher odds of ALS (AOR = 1.22; 95% CI: 1.11-1.34).

CONCLUSION: Head injury was associated with an increased risk of ALS across multiple analyses, including different injury severity levels and exposure definitions. However, the observational nature of available evidence and the possibility of reverse causation and residual confounding limit causal interpretation. Further prospective studies and mechanistic investigations are required to clarify the potential relationship between head injury and ALS development.}, } @article {pmid42863218, year = {2026}, author = {Saito, A and Sekioka, R and Nagashima, A and Washio, T and Honjo, E and Koganemaru, Y and Ohnuki, K and Miyoshi, S}, title = {Novel compounds induce AChR clustering and improve motor function in myasthenia gravis animal models.}, journal = {Biochemical and biophysical research communications}, volume = {839}, number = {}, pages = {154728}, doi = {10.1016/j.bbrc.2026.154728}, pmid = {42863218}, issn = {1090-2104}, abstract = {The neuromuscular junction (NMJ), the synapse between motor nerves and skeletal muscles, is implicated in the pathogenesis of various neuromuscular disorders, including myasthenia gravis (MG), congenital myasthenia, and amyotrophic lateral sclerosis. Postsynaptic clustering of acetylcholine receptors (AChRs) is crucial for NMJ formation. This process is initiated by agrin, a glycoprotein secreted from motor nerve terminals, which activates muscle-specific tyrosine kinase (MuSK) via its coreceptor, low-density lipoprotein receptor-related protein 4 (Lrp4), and thereby activates downstream signaling pathways that induce AChR clustering. MG is an autoimmune disease characterized by the production of autoantibodies against NMJ components such as AChR, MuSK, and Lrp4, which leads to impaired neuromuscular transmission and motor dysfunction. In this study, we identified orally active small-molecule compounds that promote AChR clustering through the Lrp4-MuSK signaling axis. Knockdown experiments demonstrated that Lrp4 was responsible for the compounds to induce AChR clustering. The compounds induced MuSK phosphorylation following the compound treatment in C2C12 cells and improved motor function and increased muscle volume in both MuSK-MG mice and AChR-MG rat models. Together, these findings identify orally active small molecules that potentiate Lrp4-MuSK signaling and highlight a pharmacological strategy to modulate NMJ function for MG and related neuromuscular disorders.}, } @article {pmid42855802, year = {2026}, author = {Zheng, X and Yu, X}, title = {A Comprehensive Review and Future Prospects of Aluminum-Sulfur Batteries: From Material Design to Practical Challenges.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {}, number = {}, pages = {e06181}, doi = {10.1002/adma.202506181}, pmid = {42855802}, issn = {1521-4095}, support = {2019-01 07-00-07-E00028//Innovation Program of the Shanghai Municipal Education Commission/ ; 51971065//National Science Foundation of China/ ; }, abstract = {Aluminum-sulfur (Al-S) batteries are promising next-generation energy storage systems owing to the high abundance, low cost, and multi-electron redox capability of Al, combined with the high theoretical capacity and environmental friendliness of S. This review systematically compares the dual electrochemical mechanisms based on S reduction (S[0]/S[2-]) and S oxidation (S[0]/S[4+]), highlighting their distinct advantages in energy density and safety. Key strategies for cathode design-including carbon-based, anchoring-functional, and catalytic-functional hosts-are discussed, alongside electrolyte engineering using ionic liquids, deep eutectic solvents, inorganic molten salts, and aqueous systems. Recent advances in dendrite suppression, anode protective layers, and functional separators are also summarized. A central challenge identified is the sluggish Al[3+] solvation/desolvation kinetics, which limits rate capability and low-temperature performance. The application of in situ/operando characterization techniques (XANES, Raman, UV-vis) to unravel complex reaction pathways is emphasized. By integrating multidisciplinary innovations, this review provides a comprehensive perspective and a phased commercialization roadmap, aiming to accelerate the transition of Al-S batteries from laboratory research to practical green energy storage.}, } @article {pmid42855901, year = {2026}, author = {Mayberry, EJ and Creer, S and Griffiths, AW and Hobson, EV and Davies, S and Bedford, J and Gould, RL and McDermott, CJ}, title = {Specialist psychology provision for ALS/MND: results from a survey of UK ALS/MND services.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2026.2742816}, pmid = {42855901}, issn = {2167-9223}, abstract = {OBJECTIVE: This study aimed to map and evaluate specialist psychological and neuropsychological care provision within ALS/MND multidisciplinary teams across the UK.

METHODS: A cross-sectional, mixed-methods online survey was circulated to ALS/MND specialist services across England, Wales, Northern Ireland, and Scotland. The survey evaluated service demographics, specialist psychological staffing models, referral pathways, perceived adequacy of care, and access to other wellbeing support.

RESULTS: Responses were received from 25/36 services (69% response rate), representing an estimated 3,500 patients. Access to specialist care was highly variable, with 24% of services lacking an established referral pathway and 20% having a referral pathway for patients living in some parts of their service area but not others. Importantly, even for those services with access to specialist psychology, nearly all reported that the specialist psychology provision was insufficient to meet the needs of their service users and the service; 80% of these services reported insufficient capacity to deliver direct assessments and interventions. Qualitative data highlighted inequitable and insufficient provision, the fragmented nature of current psychological care, and the need for sufficient and stable funding for specialist psychology provision in ALS/MND.

CONCLUSIONS: Despite international guidelines recognizing the necessity of specialist psychological and neuropsychological care in ALS/MND, access across the UK remains highly inequitable and under-resourced. To meet UK national standards (NICE) and prevent the negative impacts of untreated psychological distress and inequitable access, more resource allocation is required to integrate specialist psychology as a core component of ALS/MND care.}, } @article {pmid42856205, year = {2026}, author = {Murimi-Worstell, DA and Freeman, M and Minkina, A and Vollger, MR and Stergachis, AB and Coffin, JM}, title = {Structural polymorphism and population-variable coding capacity of HERV-K(HML-2) in human pangenomes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.09.22.753638}, pmid = {42856205}, issn = {2692-8205}, abstract = {Approximately 8% of the human genome is derived from ancient retroviral infections. The most recently integrated of these endogenous retroviruses is the HERV-K(HML-2) clade, whose expression has been associated with cancer, amyotrophic lateral sclerosis, and embryogenesis. Studies of HERV expression, particularly HML-2, have relied predominantly on short-read sequencing. However, the high similarity among HML-2 proviruses prevents many short reads from being assigned uniquely to individual loci. We therefore compared haplotype-resolved long-read genome assemblies from 292 donors to resolve variation in proviral structure and coding capacity. Several loci previously thought to be fixed were structurally polymorphic. Tandem arrays occurred at 13 loci and contained up to six proviral copies in a single array. At 8q11.23, we identified a previously undescribed full-length provirus in one haplotype. All 583 other haplotypes carried a solo-LTR. We found that standard reference genomes failed to represent the coding capacity retained in many individuals, whose proviruses contained intact open reading frames despite disruptive mutations in the reference sequences. Short-read genotypes left 32.5% of the tested donor-variant pairs unresolved at sites associated with viral reading frames. These findings show why HML-2 expression must be interpreted in the context of the structural and coding alleles each individual carries.}, } @article {pmid42856249, year = {2026}, author = {MurthyGowda, S and Huyghue, K and Castillo, B and Gugala, F and Li, W and Dubnau, J}, title = {Early life social isolation primes flies for more rapid TDP-43 dependent neurodegeneration later in life.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.09.23.753732}, pmid = {42856249}, issn = {2692-8205}, abstract = {A key pathophysiological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is loss of nuclear localization and abnormal cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43). Upstream factors that trigger the onset and progression of such neurodegenerative diseases are largely unknown. Aging and environmental factors contribute as potential risk factors. But epidemiological evidence suggests psychological stressors such as social isolation and loneliness are also associated with increased risks of neurodegenerative disease [1-8]. We examined the impacts of social isolation on TDP-43 related neurodegeneration. To investigate the potential for causative impact on neurodegeneration, we compared the effects of social isolation versus social enrichment in Drosophila . We utilized an established social isolation paradigm in which flies were either housed alone or in groups as young adults. We found that early-life social isolation acts as a primer to exacerbate the rate of neurodegeneration in response to subsequent induction of pathological levels of TDP-43. Social isolation stress drives more rapid activation of mdg4, an endogenous retrovirus that functionally mediates TDP-43 effects and more aggressive propagation of TDP-43 protein pathology from surface glial cells to nearby neurons. Shortened life span also ensues. We demonstrate that providing isolated flies with visual, olfactory and tactile social cues from conspecifics living behind a divider was insufficient to alleviate these effects of social isolation on neurodegeneration. Our findings have implications for the association between psychological stressors such as loneliness and risk of neurodegenerative diseases in humans and provide a platform to investigate mechanistic underpinnings in animal models.}, } @article {pmid42856371, year = {2026}, author = {Soedirdjo, SDH and Holobar, A and Dhaher, YY}, title = {Beyond snapshots: A dynamic framework for continuous motor unit tracking to enhance neurophysiological assessments.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.09.25.754489}, pmid = {42856371}, issn = {2692-8205}, abstract = {Tracking individual motor units (MUs) across multiple testing visits is critical for understanding neuromuscular adaptations and disease progression. However, existing methods fail to account reliably for spatiotemporal variations in motor unit action potentials (MUAPs) and lack validation for longitudinal tracking. Here, we present a robust computational framework for continuous MU tracking that integrates automatic estimation of electrode grid displacements and compensation for MUAP shape variations. Our algorithm demonstrated superior tracking accuracy, capturing 63% and 75% of MUs in the tibialis anterior and medial gastrocnemius, respectively, substantially outperforming state-of-the-art methods. By applying this approach to investigate estradiol-driven neuromuscular plasticity as a model system, we reveal previously undetectable modulations in recruitment thresholds and firing rates, linking hormonal fluctuations to motor unit behavior. Beyond advancing fundamental neuromuscular research, our approach holds promise for enhancing biomarker sensitivity in clinical trials, particularly in conditions such as amyotrophic lateral sclerosis, where reliable MU tracking is paramount. These findings establish a new standard for non-invasive motor unit tracking, unlocking opportunities for longitudinal neurophysiological assessment and evaluation of therapeutics.}, } @article {pmid42856515, year = {2026}, author = {Jackvony Infurna, S and Ijaz, L and Hardin, EJ and Aikedan, A and Zhou, C and Yadavalli, T and Jang, MW and Mahoney, M and Gan, L and Shukla, D and Orr, AL and Orr, AG}, title = {ALS/FTD-linked TDP-43 alterations prevent HSV-1 infection by disrupting cell-adhesion pathways.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.09.28.755069}, pmid = {42856515}, issn = {2692-8205}, abstract = {TAR DNA-binding protein-43 (TDP-43) alterations are a key hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. Increasing evidence links these conditions to viral infections, but it is not known if and how viral pathogens may be affected by disease-associated TDP-43. We found that ALS/FTD-linked forms of human TDP-43 prevent infection by herpes simplex virus type-1 (HSV-1), a common neurotropic virus. This cell-autonomous protective effect was conserved across different TDP-43 mutations, sporadic ALS, and C9ORF72 -ALS, in neural and non-neural cell types, and in patient-derived cells and animal models. In addition to restricting infection, TDP-43 mutation prevented inflammatory and cell stress-related responses to HSV-1 exposure. TDP-43 knockdown but not overexpression was sufficient to protect cells from HSV-1 infection, implicating a loss-of-function mechanism. Neurons with TDP-43 mutation had disruptions in adhesion-related pathways and, accordingly, had reduced early-stage viral binding and entry. Further analyses revealed alternative RNA splicing and impairment of focal adhesion kinase (FAK/PTK2), a key mediator of cell-adhesion pathways. Inhibition of FAK was sufficient to decrease HSV-1 infection, and genetic enhancement of functional but not inactive FAK promoted infectivity in cells with TDP-43 mutation. Together, these data indicate that TDP-43 affects virus-host interactions by influencing adhesion pathways required for viral infection.}, } @article {pmid42856741, year = {2026}, author = {Settgast, T and Shriki, O and Northoff, G and Zilio, F and Borgheai, SB and Shahriari, Y and Kübler, A}, title = {All Roads Lead to Rome: Resting-State Criticality as a Neurophysiological Marker of Brain-Computer Interface (BCI) Performance in People with Amyotrophic Lateral Sclerosis (ALS) and Healthy Participants.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-10422321/v1}, pmid = {42856741}, issn = {2693-5015}, abstract = {This exploratory study investigates the relationship between resting-state brain dynamics (EEG) and subsequent brain-computer interface (BCI) performance in people with amyotrophic lateral sclerosis (ALS) and healthy participants. Grounded in the critical brain hypothesis, we examined whether neurophysiological markers of criticality in resting-state EEG correlate with subsequent BCI performance. We analyzed neuronal avalanche dynamics, multiscale criticality measures, the spectral slope, and Lempel-Ziv complexity across two datasets: a longitudinal single-case study of a person in the locked-in state after a disease history with ALS (Dataset 1) and longitudinal data from 5 people with ALS and single sessions from 6 healthy participants (Dataset 2). Neuronal avalanche dynamics, the spectral slope, and Lempel-Ziv complexity consistently correlated with subsequent BCI performance in people with ALS. Conversely, healthy participants showed inverted correlation patterns for the neuronal avalanche dynamics. While group comparisons were not statistically significant, effect size analyses indicated supercritical brain dynamics in people with ALS. We integrate these findings into the B-ARC (BCI-Aptitude through Resting-State Criticality) framework proposing an inverted U-shaped relationship between the proximity of resting-state brain activity to criticality and BCI control. In this framework, healthy participants approach the critical optimum from a subcritical regime, while people with ALS appear to approach it from a putatively supercritical regime characterized by cortical hyperexcitability. These findings and the proposed framework provide potential resting-state predictors of BCI aptitude in people with ALS and may inform the detection of so-called Windows of Consciousness .}, } @article {pmid42857254, year = {2026}, author = {Ali, SI and Lian, L and Robinson, H and Daniels, N and Prieto, GA and Poplawski, GHD and Lopez-Gonzalez, R}, title = {Corrigendum to "Aberrant CDK4/6-driven cell-cycle reentry drives neuronal loss and defines a therapeutic target in C9orf72 ALS/FTD" [iScience 29 (2026) 114596].}, journal = {iScience}, volume = {29}, number = {10}, pages = {117845}, doi = {10.1016/j.isci.2026.117845}, pmid = {42857254}, issn = {2589-0042}, abstract = {[This corrects the article DOI: 10.1016/j.isci.2025.114596.].}, } @article {pmid42858164, year = {2026}, author = {Vocelle, A and Ensrud, E and Howard, IM}, title = {Prognostication in Amyotrophic Lateral Sclerosis: A Narrative Review of Pre-Diagnosis and Functional Outcomes.}, journal = {NeuroRehabilitation}, volume = {}, number = {}, pages = {10538135261490936}, doi = {10.1177/10538135261490936}, pmid = {42858164}, issn = {1878-6448}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a very heterogeneous disease, yet some of the most common questions received by physicians in the ALS clinic are "how much time do I have?" and "what can I expect to happen next?" This line of inquiry is not strictly limited to patients; clinicians also need an idea of prognosis to appropriately plan for treatment decisions and prepare the patient and caregiver for future care needs. This narrative review synthesizes current evidence on prognostic indicators in ALS, organized across three temporal phases: factors preceding diagnosis, factors present at diagnosis, and factors emerging after diagnosis. Pre-diagnosis predictors include age at onset, sex, socioeconomic status, genetic background, premorbid Body Mass Index (BMI) and nutritional status, and comorbid disease. At diagnosis, clinical phenotype and site of onset, diagnostic delay, baseline Amyotrophic Lateral Sclerosis Functional Rating Score-Revised (ALSFRS-R) and forced vital capacity, cognitive involvement, fluid biomarkers, and electrophysiologic measures carry prognostic weight. Post-diagnosis, the trajectory is refined by the rate of ALSFRS-R decline, serial respiratory measures, and weight loss, and is actively modified by clinical interventions including noninvasive ventilation, enteral nutrition, disease-modifying therapy, and multidisciplinary care. Notably, quality of life does not track with physical decline, consistent with the disability paradox described in other severe neurological conditions. For neurorehabilitation, these indicators support a shift from reactive to anticipatory practice: timing equipment provision, communication support, respiratory intervention, and goals-of-care discussions to the predicted trajectory rather than to established deficit. Refinement of prognostic models may also improve stratification in ALS clinical trials.}, } @article {pmid42858511, year = {2026}, author = {Maia, MEP and Lemes, LFR and Soares, FLF}, title = {Cocaine profiling: Implementation of MCR-ALS for adulterant identification using ATR-FTIR in forensic analysis.}, journal = {Forensic science international}, volume = {390}, number = {}, pages = {113155}, doi = {10.1016/j.forsciint.2026.113155}, pmid = {42858511}, issn = {1872-6283}, abstract = {Cocaine stands out due to its significant social problems stemming from trafficking, leading to increased violence and detrimental effects on the physical and mental health of its users. Brazil serves as a transit route for cocaine produced in Colombia, Peru, and Bolivia to Europe, with Paraná being a strategic region due to its border with Paraguay and the second-largest port in Brazil. Cocaine is gradually adulterated with cutting agents along the distribution chain, altering its chemical profile. Paradoxically, these components can create a unique chemical signature, enabling the tracing of the drug's origin and distribution routes. This study analysed 298 mid-infrared spectra of cocaine samples seized in Paraná and applied Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS) to identify and characterise the main adulterants and diluents present. MCR-ALS was chosen due to its ability to decompose overlapping spectra into individual component contributions, making it ideal for analysing complex mixtures. Five distinct chemical profiles were identified, and based on their spectral interpretation and the most reported adulterants and diluents in cocaine samples, the five components were defined as: cornstarch, cocaine, caffeine, sodium bicarbonate, and creatine. The concentration profiles of the components were clustered using Hierarchical Cluster Analysis, and seven profiles of cocaine samples were identified based on the amount of cocaine and the presence of adulterants and diluents. The MCR-ALS method proved effective in identifying cocaine cutting agents via ATR-FTIR, offering a fast and reliable approach for forensic analysis that can help to identify commercial routes.}, } @article {pmid42854356, year = {2026}, author = {Cordts, I and Galhoz, A and Tzeplaeff, L and Gründel, A and Kohlmayer, F and Schwersenz, A and Marschalkowski, I and Bjelica, B and Panitz, V and Schulze, C and Svačina, M and Rau, P and Dorigan, AC and Deschauer, M and Witzel, S and Brenner, D and Weishaupt, JH and Bublitz, SK and Lorenzl, S and Hermann, A and Hagenacker, T and Wolf, J and Regensburger, M and Lehmann, HC and Dohrn, MF and Dorst, J and Guenther, R and Maier, A and Meyer, T and Zeller, D and Neuwirth, C and Weber, M and Koch, JC and Boentert, M and Weiler, M and Petri, S and Weyen, U and Grehl, T and Menden, MP and Lingor, P}, title = {EARLY-ALS: a multicentre study on prodromal amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {133}, number = {}, pages = {106505}, doi = {10.1016/j.ebiom.2026.106505}, pmid = {42854356}, issn = {2352-3964}, abstract = {BACKGROUND: Neurodegenerative diseases often feature a prolonged phase of subtle changes preceding diagnosis. In amyotrophic lateral sclerosis (ALS), defining this prodromal period is critical for identifying early disease features and intervention windows.

METHODS: In this case-control study, 475 patients with ALS and 285 controls from 20 centres in Germany and Switzerland completed a digital questionnaire on prodromal symptoms and health-related factors. Logistic regression included subgroup analyses by sex and clinical strata.

FINDINGS: Patients with ALS reported a higher burden of prodromal complaints (OR 7.50, 95% CI 4.27-13.17; P < 0.001), particularly neuro-motor, sensory, and pain-related symptoms. Before symptom onset, patients consulted neurologists more often (OR 1.26, 1.10-1.44; P < 0.001) and females more often received speech therapy (OR 2.35, 1.05-5.28; P = 0.038). Prodromal herniated discs were more common in males (OR 2.21, 1.04-4.68; P = 0.038) and spinal-onset patients (OR 2.14, 1.25-3.67; P = 0.006). Patients more often had lower secondary education (OR 1.93, 1.24-3.01; P = 0.004), physically demanding occupations (OR 2.21, 1.42-3.43; P < 0.001), and higher consumption habits (P < 0.005). Weight trajectories differed by sex (P = 0.009), with pre-onset weight loss in male patients (P < 0.001).

INTERPRETATION: Patients with ALS retrospectively reported subtle motor impairment before recognised symptom onset, alongside altered healthcare use and sex- and subgroup-specific patterns. These findings suggest that sporadic ALS may be preceded by a prodromal period and identify mild motor impairment as a potential marker, pending prospective validation.

FUNDING: DGM e. V.}, } @article {pmid42854693, year = {2026}, author = {Citrano, KJ and Maheswari Jawahar, VB and Reeves, MM and Petrucelli, L and Carlomagno, Y and Yue, M and Alaiz Noya, J and Daughrity, LM and Baena Tomé, R and Jansen-West, K and Rawlinson, B and DeTure, M and Engelberg-Cook, E and Singh, A and Graff-Radford, NR and Day, GS and Boeve, BF and Boxer, AL and Knopman, DS and Josephs, KA and Petersen, RC and Oskarsson, B and Ashton, NJ and Dickson, DW and Gendron, TF and Prudencio, M and Zhang, YJ and Petrucelli, L}, title = {Anti-HDGFL2 cryptic protein antibodies provide a sensitive readout of TDP-43 pathology and clinical disease features.}, journal = {Cell reports. Medicine}, volume = {}, number = {}, pages = {103105}, doi = {10.1016/j.xcrm.2026.103105}, pmid = {42854693}, issn = {2666-3791}, abstract = {TAR DNA-binding protein (TDP-43) cytoplasmic aggregates and nuclear depletion contribute to TDP-43 dysfunction in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and forms of motor neuron disease (MND), particularly amyotrophic lateral sclerosis (ALS). TDP-43 regulates alternative splicing, but its dysfunction can engender the inclusion of cryptic exons (CEs) during splicing. Transcripts harboring an in-frame CE can generate de novo proteins. One example is the CE variant of hepatoma-derived growth factor-like protein 2 (HDGFL2-CE). To understand HDGFL2-CE as a readout of TDP-43 dysfunction, and its spatial relationship with TDP-43 pathology, we generate anti-HDGFL2-CE polyclonal and monoclonal antibodies and develop sensitive HDGFL2-CE immunoassays. With these tools, we observe that HDGFL2-CE accumulates in neurons with TDP-43 pathology, and that higher frontal cortex HDGFL2-CE in FTLD-TDP and FTLD-TDP/MND associates with greater pathological TDP-43, earlier age of onset, and shorter survival, supporting HDGFL2-CE as a marker tightly linked to TDP-43 dysfunction and clinical disease features.}, } @article {pmid42855485, year = {2026}, author = {Kiani, L}, title = {Progressive sleep abnormalities precede ALS clinical onset.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {42855485}, issn = {1759-4766}, } @article {pmid42855762, year = {2026}, author = {Wang, HF and Sun, B and Pan, J and Pang, XY and Bai, JM and Feng, JL}, title = {[The role of the GSTP1/JNK signaling pathway in regulating oxidative stress and programmed cell death in amyotrophic lateral sclerosis].}, journal = {Zhonghua nei ke za zhi}, volume = {65}, number = {10}, pages = {1122-1129}, doi = {10.3760/cma.j.cn112138-20260501-00268}, pmid = {42855762}, issn = {0578-1426}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Oxidative Stress ; *Glutathione S-Transferase pi/metabolism ; Humans ; *Apoptosis ; Animals ; *MAP Kinase Signaling System ; Signal Transduction ; JNK Mitogen-Activated Protein Kinases/metabolism ; }, } @article {pmid42849148, year = {2026}, author = {Freischmidt, A and Weishaupt, JH}, title = {Update on somatic mutations in major neurodegenerative diseases: mutational signatures in neurons and mosaicism.}, journal = {Current opinion in genetics & development}, volume = {101}, number = {}, pages = {102549}, doi = {10.1016/j.gde.2026.102549}, pmid = {42849148}, issn = {1879-0380}, abstract = {Somatic mutations in major neurodegenerative diseases are poorly understood, but research over the past 2 years provides valuable insights. Single-cell whole-genome sequencing of vulnerable neurons in Alzheimer's disease and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) revealed excess accumulation of single-nucleotide variant signatures and two-bp deletions independent of pathogenic protein aggregation. Increased oxidative DNA damage and possibly impaired DNA damage repair pathways may explain more pronounced signatures in patients. Ultra-deep sequencing of disease-associated genes in relevant tissues in ALS/FTD identified a subset of sporadic patients carrying mosaic variants that cause disease when present in the germline, but the pathogenicity of such mosaic variants at low allele frequencies is unclear. Research on somatic variants in Parkinson's disease remains underrepresented in the literature.}, } @article {pmid42849176, year = {2026}, author = {Zucchi, E and Niccolai, E and De Maio, F and Cuoghi Costantini, R and Quaranta, G and Guarnaccia, A and Bibbò, S and Martinelli, I and Gianferrari, G and Simonini, C and Nannini, G and Lulli, M and Baldi, S and Bartolucci, G and Vicini, R and Capasso, M and Bisogni, G and Conte, A and Brunori, P and Cammarota, G and Paganoni, S and D'Amico, R and Amedei, A and Masucci, L and Mandrioli, J and , }, title = {Immune effects of faecal microbiota transplantation in amyotrophic lateral sclerosis: a pilot multicentre, randomised, masked, sham-controlled, proof-of concept trial.}, journal = {EBioMedicine}, volume = {133}, number = {}, pages = {106509}, doi = {10.1016/j.ebiom.2026.106509}, pmid = {42849176}, issn = {2352-3964}, abstract = {BACKGROUND: The gut microbiota modulates peripheral immunity, which is altered in amyotrophic lateral sclerosis (ALS). Faecal microbiota transplantation (FMT) may exert immunological effects, but its impact in ALS remains unclear.

METHODS: FETR-ALS was a multicentre, randomised, masked, sham-controlled proof-of-concept trial conducted at four Italian ALS centres. Adults with ALS of 18 months duration or less and forced vital capacity of at least 70% predicted were randomly assigned (2:1) to receive FMT or a sham procedure (SP). The intervention consisted of two nasojejunal administrations of screened-donor faecal suspension at baseline and month 6, without antibiotic preconditioning. The primary endpoint was change in circulating Tregs among CD4[+] T cells at 6 months. Secondary endpoints included safety, ALS Functional Rating Scale-Revised slope, respiratory and nutritional measures, survival, and exploratory biomarker profiles. Analyses followed the intention-to-treat principle.

CLINICALTRIALS: gov identifier: NCT03766321.

FINDINGS: Between 2020 and 2024, 43 individuals were screened and 42 were enrolled and randomly assigned to FMT (n = 28; mean age 56.1 years [SD 8.2]; 14 [50%] male) or SP (n = 14; 59.6 years [9.1]; eight [57%] male). Overall, 29 participants completed the second procedure and 6-month follow-up, and Treg measurements were available for 28. The primary outcome was not met: at 6 months, 8/18 (44%) participant receiving FMT versus 2/10 (20%) receiving SP achieved a ≥20% increase in circulating Tregs (odds ratio [OR] 3.20, 95% CI 0.59-25.36; p = 0.21). Mean Treg increase was 2.36 percentage points higher with FMT (95% CI 0.19-4.55; p = 0.04). ALSFRS-R declined by -1.07 points/month in the SP group and -0.76 points/month in the FMT group, with a between-group difference in monthly decline of 0.31 points/month favouring FMT (95% CI 0.11-0.51; p = 0.002). Conversely, at month 6, the MRC score was lower in the FMT group than in the SP group (0.75 versus 0.89; mean difference -0.13, 95% CI -0.26 to 0.00; p = 0.042). FMT was associated with 32 adverse events (12.5% severe) versus 14 (28.6% severe) in SP, mostly gastrointestinal or infectious.

INTERPRETATION: In this exploratory trial, FMT was not associated with major safety concerns. Although the primary endpoint was not met, FMT was associated with a modest increase in circulating Tregs.

FUNDING: Italian Ministry of Health.}, } @article {pmid42850388, year = {2026}, author = {Kytöharju, M and Moilanen, JS and Martikainen, MH}, title = {Genetic testing and counselling of patients with monogenic amyotrophic lateral sclerosis in Northern Finland: a retrospective, single-centre study.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {42850388}, issn = {1476-5438}, abstract = {Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease. Its aetiology is complex, but a subset is caused by single-gene pathogenic variants (monogenic ALS). The most common ALS-associated genes are SOD1 and C9orf72. We evaluated the implementation of genetic testing and associated genetic counselling for ALS at a Finnish tertiary-level university hospital. We used the electronic patient records of Oulu University Hospital (Oulu, Finland) to identify patients diagnosed with ALS between 2000 and 2023. Medical records were reviewed for neurological diagnosis and completion of genetic testing and counselling. We identified a total of 387 patients diagnosed with ALS. Of these, 225 patients (58%) were offered genetic testing, and 186 (83%) accepted. The offer for genetic counselling was given to 60 patients, of whom 46 (77%) attended counselling, whilst 13 did not. The proportion of patients who declined counselling did not differ between those with SOD1 and C9orf72 variants. Among the 143 patients tested for SOD1 variants, 36 (25%) were confirmed to harbor the ALS-associated p.Asp91Ala variant in SOD1; 31 were homozygous and 5 were heterozygous. In the 96 analyses of the C9orf72 hexanucleotide expansion, the diagnostic yield was 27 (28%) patients. A positive family history was more common in SOD1-ALS than in C9orf72-ALS (53% vs 33%). Nearly one fifth of patients declined testing and over one fifth of those with genetic ALS did not attend genetic counselling. The reasons for this warrant further investigation.}, } @article {pmid42850529, year = {2026}, author = {Reilich, P and Schöberl, F}, title = {[Amyotrophic lateral sclerosis: Specific considerations in palliative care].}, journal = {MMW Fortschritte der Medizin}, volume = {168}, number = {17}, pages = {51-54}, doi = {10.1007/s15006-026-6225-z}, pmid = {42850529}, issn = {1613-3560}, } @article {pmid42850785, year = {2026}, author = {Ozeloglu, İG and Akman Aydin, E}, title = {Gait-based neurodegenerative disease classification using multimodal temporal-spectral representations and a dual-branch CNN.}, journal = {Computer methods in biomechanics and biomedical engineering}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/10255842.2026.2736243}, pmid = {42850785}, issn = {1476-8259}, abstract = {Neurodegenerative diseases (NDDs) often cause gait impairments with overlapping motor symptoms, complicating multi-class discrimination. This study proposes a lightweight dual-branch convolutional neural network integrating recurrence plots and spectrogram representations of vertical ground reaction force signals to classify Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and healthy controls. Evaluated on the Gait in NDDs Dataset comprising 64 subjects, the proposed framework achieved 96.15% accuracy, outperforming recurrence-based (94.19%) and spectrogram-based (95.75%) single-branch models. The findings demonstrate that combining complementary temporal recurrence and spectral information improves discrimination of neurodegenerative gait patterns while maintaining low computational complexity.}, } @article {pmid42851615, year = {2026}, author = {Ohara, M and Ishigaki, S and Watts, JK and Yamada, K and Ikezu, T and Ikezu, S}, title = {Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.}, journal = {Molecular neurodegeneration advances}, volume = {2}, number = {1}, pages = {41}, pmid = {42851615}, issn = {3059-4944}, abstract = {Neurodegenerative disorders have diverse etiologies from monogenic mechanisms such as toxic gain-of-function mutation in subsets of amyotrophic lateral sclerosis (ALS) to multifactorial cascades exemplified by Alzheimer's disease (AD), which feature proteostasis failure, neuroinflammation, mitochondrial dysfunction, or age-associated cellular stress. While small molecules can modulate downstream pathways, nucleic acid therapeutics (NATs) target defined RNA sequences to directly reduce pathogenic gene expression, correct or shift isoform usage via splice modulation, and tune disease-relevant networks, positioning them as promising therapeutic modalities for neurodegenerative disorders. Recent clinical applications of NATs in the central nervous system (CNS) have made significant progress by optimized chemistries, improved tolerability, and established intrathecal administration routes, supporting sustained target engagement in relevant neural and glial compartments. This review summarizes three major NAT platforms-antisense oligonucleotides, small interfering RNAs, and aptamers-by highlighting their mechanisms of action, design principles to enhance their biodistribution, durability, and safety, and emerging novel delivery strategies for CNS targeting. We further discuss emerging translational opportunities across ALS, AD, polyglutamine disorders, prion diseases, and synucleinopathies by integrating disease biology with therapeutic rationale, and by summarizing regulatory approvals, ongoing clinical trials, and next generation NATs in preclinical development.}, } @article {pmid42851749, year = {2026}, author = {Li, M and Li, R and Deng, Z and Zhang, L and Lv, S and Shi, J and Ma, H and Guan, W and Zhang, H and Li, J and Teng, J}, title = {Traditional Chinese botanical medicines and plant-derived bioactive compounds in amyotrophic lateral sclerosis: mechanistic evidence, translational challenges, and therapeutic opportunities.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1918967}, pmid = {42851749}, issn = {1663-9812}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with limited therapeutic options, highlighting the need for multi-target interventions. Traditional Chinese botanical medicine (TCBM) interventions have attracted increasing attention as potential multi-target pharmacological candidates for ALS. In addition, a separate body of evidence derived from selected plant-derived bioactive compounds directly investigated in ALS-specific models provides complementary mechanistic insights into ALS-related pathways. However, the pharmacological mechanisms and translational potential of these two distinct evidence categories remain insufficiently summarized. This review systematically summarizes ALS-related pathological mechanisms and the molecular actions reported within these two distinct evidence categories, together with translational challenges and future research directions.

METHODS: A structured literature search was conducted in PubMed, Web of Science, and ScienceDirect up to May 2026. A total of 198 publications were retained, including 48 ALS-specific original intervention studies forming the core pharmacological evidence set.

RESULTS: ALS involves interconnected pathological processes, including neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired proteostasis, excitotoxicity, and neuromuscular junction injury. Evidence across these two categories suggests modulation of multiple ALS-related pathological processes. Reported effects include regulation of inflammatory signaling, enhancement of Nrf2-mediated antioxidant responses, improvement of PGC-1α/MFN2-associated mitochondrial homeostasis, and promotion of protein clearance pathways.

CONCLUSION: Together, these distinct but complementary evidence categories highlight the potential for multi-target modulation of ALS-related pathology. However, current evidence remains predominantly preclinical, and clinical efficacy and translational feasibility require further validation.}, } @article {pmid42851781, year = {2026}, author = {Smeyers, J and Mordes, DA}, title = {Minding the gates: dual cell-autonomous and non-cell-autonomous mechanisms of TBK1 in ALS/FTD.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1941293}, pmid = {42851781}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a neurodegenerative disease spectrum characterized by TDP-43 pathology and overlapping genetic risk factors. Loss-of-function variants in TBK1 (TANK-binding kinase 1) represent one of the most common genetic causes of ALS/FTD, highlighting haploinsufficiency for TBK1 as a major contributor to disease pathogenesis. Emerging evidence from iPSC and mouse models suggests that reduced TBK1 activity disrupts interconnected autophagy, endo-lysosomal, and innate immune pathways through both cell-autonomous and non-cell-autonomous mechanisms. In this review, we discuss the multifaceted role of TBK1 as a master regulator of proteostasis and inflammatory pathways, highlight its critical role in maintaining microglial homeostasis, and explore how these convergent functions inform therapeutic strategies for ALS/FTD.}, } @article {pmid42852066, year = {2026}, author = {Duarte, ML and Iared, W and Oliveira, ABS and Dos Santos, LR and da Silva, MSP}, title = {Comparison between ultrasound and electromyography for detection of fasciculations in amyotrophic lateral sclerosis: an updated systematic review and meta-analysis.}, journal = {Radiologia brasileira}, volume = {59}, number = {}, pages = {e20260011}, pmid = {42852066}, issn = {0100-3984}, abstract = {Fasciculations are a key manifestation of lower motor neuron dysfunction in amyotrophic lateral sclerosis (ALS). Al-though electromyography is considered the gold-standard method for the detection of fasciculations, its sensitivity for that purpose depends on the muscle sampled and the examination time. Muscle ultrasound has emerged as a dynamic, noninvasive technique with high sensitivity for detecting spontaneous muscle activity. This updated system-atic review compares ultrasound and electromyography in terms of their performance for the detection of muscle fas-ciculations in ALS, with stratification by muscle group and observation time. A comprehensive search of the literature identified studies evaluating both techniques. Data were synthesized descriptively and, when possible, quantitatively. Ultrasound demonstrated higher or comparable detection rates across most muscle groups, particularly in muscles that are large or deep, such as the biceps brachii, tibialis anterior, and vastus lateralis. Longer ultrasound observation times, especially 60 s, were associated with substantially higher detection rates without a loss of specificity. Although electromyography is still essential for electrophysiological characterization, ultrasound offers broader muscle cover-age, excellent reproducibility, and a noninvasive approach. These findings support muscle ultrasound as a valuable complementary tool for the detection and assessment of fasciculations in patients with motor neuron disease.}, } @article {pmid42852085, year = {2026}, author = {Öijerstedt, L and Lin, J and Singh, A and Yazdani, S and Saarinen, AM and Kläppe, U and Juto, A and Chamoun, S and Imrell, S and Fang, F and Lewandowski, SA and Ingre, C}, title = {Plasma cardiac troponin T as a marker of skeletal muscle involvement in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {5}, pages = {fcag358}, pmid = {42852085}, issn = {2632-1297}, abstract = {Plasma cardiac troponin T (cTnT) is widely used as a marker of myocardial injury, yet recent studies suggest elevations in amyotrophic lateral sclerosis (ALS). Whether these elevations reflect disease-associated skeletal muscle remodelling remains unresolved. In this translational study, we analysed longitudinal plasma cTnT in a large clinical cohort comprising 496 patients with ALS and 84 with benign fasciculation syndrome (BFS). To investigate the biological origin of circulating cTnT, we examined publicly available skeletal muscle transcriptomes from patients with ALS (n = 28) and healthy controls (n = 17), and quantified troponin isoform expression in skeletal muscle from SOD1[G93A] mice and wild-type littermates. Plasma cTnT was significantly higher in ALS than in BFS (median 18 versus 6 ng/L, P = 3.6 × 10[-27]), with 57% of patients with ALS exceeding the cardiologic threshold of 15 ng/L. Diagnostic performance was high [area under the curve (AUC) 0.87], with excellent specificity (94%). Longitudinal modelling revealed a progressive increase in cTnT in ALS whereas levels remained stable in BFS. Skeletal muscle transcriptomics demonstrated robust upregulation of TNNT2, encoding cardiac troponin T, in ALS muscle, while other troponin isoforms were unchanged. In SOD1[G93A] mice, severely affected gastrocnemius muscle exhibited isoform-specific remodelling, including 20-fold upregulation of Tnnt2 and slow-fibre troponins, alongside downregulation of fast skeletal isoforms. Across clinical, transcriptomic, and experimental data, elevated plasma cTnT in ALS is best explained by disease-associated skeletal muscle remodelling rather than cardiomyocyte injury. Plasma cTnT emerges as a dynamic and accessible biomarker in ALS capturing muscle involvement. Prospective incorporation of cTnT into clinical trials and evaluation across broader neuromuscular differentials are warranted.}, } @article {pmid42852552, year = {2026}, author = {Choudhury, A and Prabha, S and Saeed, MU and Sulaimani, MN and Hassan, MI}, title = {Targeting protein misfolding and aggregation in neurodegenerative diseases: challenges for the identification and validation of targets for small molecules.}, journal = {Expert opinion on therapeutic targets}, volume = {}, number = {}, pages = {}, doi = {10.1080/14728222.2026.2747518}, pmid = {42852552}, issn = {1744-7631}, abstract = {INTRODUCTION: Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and related proteinopathies are characterized by the misfolding, aggregation, and accumulation of specific proteins that disrupt neuronal homeostasis, leading to neuronal death. Despite major advances in structural biology and molecular neuroscience, identifying and validating druggable targets in neurodegenerative diseases remains challenging. Many involved proteins are intrinsically disordered, exhibit conformational heterogeneity, and form highly dynamic toxic species.

AREAS COVERED: This review summarizes the mechanisms of protein folding, misfolding, aggregation, and prion-like propagation in major neurodegenerative proteinopathies, including amyloid-beta and tau in Alzheimer's disease, alpha-synuclein in synucleinopathies, TDP-43 and FUS in ALS/FTLD, polyglutamine-expanded proteins, prion proteins, and rare hereditary amyloidosis. We also discuss major barriers to target identification and validation, including conformational flexibility, oligomer toxicity, blood-brain barrier penetration, and target engagement complexity. Finally, we highlight emerging strategies integrating structural biology, computational methods, and improved experimental models to discover small-molecule inhibitors for neurodegenerative diseases.

EXPERT OPINION: Effective therapeutic discovery will require moving beyond single-target models toward ensemble-based validation strategies. Integrating structural biology, advanced imaging, biomarkers, and computational approaches may improve the identification of druggable targets and support precision-medicine-based interventions for neurodegenerative diseases.}, } @article {pmid42852819, year = {2026}, author = {Sanjay, S and Chee, SP}, title = {Letter to the Editor: Comment on Yu X, et al's "Conjunctival Atypical Lymphoid Hyperplasia Associated with Cytomegalovirus Infection: A Case Report".}, journal = {Ocular immunology and inflammation}, volume = {}, number = {}, pages = {1-2}, doi = {10.1080/09273948.2026.2738015}, pmid = {42852819}, issn = {1744-5078}, abstract = {We comment on the report of bilateral conjunctival atypical lymphoid hyperplasia with cytomegalovirus (CMV) positivity by Yu et al. While the case is clinically valuable, we believe that the available findings do not establish active CMV infection or a causal relationship with lymphoid hyperplasia. We discuss the lack of tissue CMV PCR, discordant immunoglobulin heavy-chain clonality between eyes, diagnostic overlap with ocular adnexal lymphoma, and the need to consider lacrimal gland involvement and IgG4-related disease. We encourage cautious interpretation and longer clinicopathological follow-up.}, } @article {pmid42853386, year = {2026}, author = {Goebell, J and Bachhuber, F and Karmann, J and Klose, V and Kassubek, J and Müller, HP and Tumani, H and Ludolph, A}, title = {Neurofilaments support the differentiation of amyotrophic lateral sclerosis from degenerative cervical myelopathy.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {42853386}, issn = {1435-1463}, abstract = {The differential diagnosis between degenerative cervical myelopathy (DCM) and early amyotrophic lateral sclerosis (ALS) is often clinically challenging; laboratory tests that support this distinction could be highly valuable. This study examined the concentrations of neurofilament light chain (NfL) and the phosphorylated neurofilament heavy chain (pNfH), in CSF and serum of carefully selected patients with DCM, spinal canal stenosis (SCS) and ALS, after exclusion of major neurological confounders. Patients were assigned to five groups according to MRI findings and ALS diagnosis. All patients were treated in the Department of Neurology, and were only included if a CSF or serum sample was available for retrospective measurement of neurofilaments. Z-scores were used for age-adjusted interpretation of NfL concentrations in CSF and serum. In addition, the albumin quotient (QAlb), as a marker for the integrity of the blood-CSF barrier, was investigated in the five patient groups. The levels of NfL and pNfH, including Z-score distributions, differed significantly. The groups with diagnosed ALS had elevated neurofilaments both in CSF and Serum. Comparison of neurofilament concentrations between patients with isolated spinal canal stenosis and patients with cervical myelopathy revealed no significant difference. The QAlb showed no clear correlation with elevated neurofilaments and provided limited value for differential diagnosis. In summary, we showed that NfL and pNfH in CSF and serum support the differential diagnosis of cervical SCS with and without myelopathy from ALS in carefully selected cohorts. However, since neurofilaments are not specific, they should be used in context with clinical assessment and imaging for individual diagnostic and treatment decisions.}, } @article {pmid42853422, year = {2026}, author = {Feole, M and Devoto, VMP and Dragišić, N and Čarna, M and Klosterman, K and Limbaek-Stokin, C and Forte, G and Moya, KL and Smith, RA and Svendsen, CN and Stokin, GB}, title = {Multiple motor proteins regulate TDP-43 anterograde axonal transport.}, journal = {Acta neuropathologica}, volume = {152}, number = {1}, pages = {}, pmid = {42853422}, issn = {1432-0533}, support = {LX22NPO5107//The European Union: Next Generation EU/ ; LM202305//The Ministry of Education, Youth, and Sports Czech Republic-EATRIS CZ/ ; }, mesh = {Humans ; *Axonal Transport/physiology ; *DNA-Binding Proteins/metabolism ; Kinesins/metabolism ; *Neurons/metabolism ; Synaptophysin/metabolism ; rab5 GTP-Binding Proteins/metabolism ; *Axons/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein essential for RNA metabolism. Under physiological conditions, it predominantly resides in the nucleus but is also expressed in the cytoplasm, where it regulates mRNA trafficking and local translation. In nearly 97% of amyotrophic lateral sclerosis (ALS) cases, TDP-43 undergoes nuclear depletion and cytoplasmic aggregation. While its nuclear functions are well characterized, its axonal roles remain poorly understood, despite axonal degeneration being a hallmark of ALS pathology. To address this gap, we investigated TDP-43 localization and transport dynamics in axons of H9-derived human neurons. We compared fluorescently labeled TDP-43 with three well-characterized axonal cargoes, ras-related protein Rab5, synaptophysin, and amyloid precursor protein, and examined protein-protein interactions between TDP-43 and the axonal transport machinery. Our analyses revealed that TDP-43 exhibits active anterograde axonal transport and interacts with multiple kinesin motor proteins, including all three KIF5 isoforms, through the adaptor KLC1, and the synaptic vesicles motor KIF1A. This multi-motor engagement suggests a flexible transport system that ensures mRNA delivery to distal axons. In ALS, where TDP-43 accumulates abnormally in the cytoplasm, this flexibility may become compromised, with multiple transport mechanisms simultaneously affected. This could contribute to progressive accumulation of non-functional TDP-43 granules, disrupting mRNA trafficking and local translation. Our findings provide a foundation for understanding how physiological TDP-43 transport mechanisms may be impaired during disease, highlighting axonal TDP-43 transport pathways as potential therapeutic targets.}, } @article {pmid42853426, year = {2026}, author = {Liu, J and Ong, K and Meng, A and Stokin, GB and Loeb, JA and Ravits, J and Song, F}, title = {Lateral sclerosis in amyotrophic lateral sclerosis is an upper motor neuron distal axonopathy ("dying back"): a clinical-neuropathological study.}, journal = {Acta neuropathologica}, volume = {152}, number = {1}, pages = {}, pmid = {42853426}, issn = {1432-0533}, support = {NINDS P30NS047101//UCSD Microscopy Core grant/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Female ; Male ; *Motor Neurons/pathology ; Middle Aged ; *Axons/pathology ; *Pyramidal Tracts/pathology ; Aged ; Spinal Cord/pathology ; DNA-Binding Proteins/metabolism ; Nerve Degeneration/pathology ; Myelin Sheath/pathology ; Adult ; }, abstract = {The hallmark neuropathological feature of upper motor neuron (UMN) degeneration in amyotrophic lateral sclerosis (ALS) is the "sclerosis" of the lateral corticospinal tract (CST)-the major axonal pathway connecting UMNs to lower motor neurons (LMNs). However, few studies since Charcot's original descriptions in the nineteenth century have directly correlated clinical UMN phenotypes with corresponding neuropathological findings. We examined the pathology of the lateral CST at the cervical, thoracic, and lumbar levels of the spinal cord from ALS patients with predominantly UMN (UMN-p) phenotypes and compared it with that in patients with predominantly LMN (LMN-p) phenotypes. We assessed myelin loss, axonal degeneration, neuroinflammation, and TDP-43 pathology. Spinal cords from UMN-p ALS cases exhibited pronounced myelin loss in the lateral CST compared to LMN-p cases and controls, consistent with clinical phenotyping. Quantitative analysis revealed significant axonal loss across all axon diameter ranges in UMN-p ALS, which was more severe than in LMN-p ALS. Importantly, axonal loss was more pronounced in the lumbar than in the cervical spinal cord. We identified a distinct population of foamy, inflammatory microglia localized to regions of severe myelin and axonal loss in UMN-p ALS. TDP-43 was measurably increased in the UMN axons of the lateral and ventral CSTs. In summary, "lateral sclerosis" of ALS correlates to clinically imputed UMN degeneration. It consists of a combination of myelin loss, distal greater than proximal axonal degeneration, inflammatory microglial activation within the CSTs, and abnormally increased axonal TDP-43. The length-dependent gradient of motor axonal loss supports a "dying-back" process. A detailed comparison of "dying-forward" and "dying-forward" is provided in the Discussion. The association of loss of axons and myelin with abnormal microglial activity shows glio-axonal interactions in UMN axon degeneration, the latter CST (lateral sclerosis) across all three spinal cord levels in the ALS UMN-p samples but does not establish a causal relationship.}, } @article {pmid42843275, year = {2026}, author = {Adrita, N and Claassen, I and Huerta, M and Black, SM and Estevez, AG and Roberts, BR and Beckman, JS and Franco, MC}, title = {Tyrosine nitration: An emerging mechanistic landscape in neurodegeneration and cardiopulmonary disease.}, journal = {Redox biology}, volume = {97}, number = {}, pages = {104423}, doi = {10.1016/j.redox.2026.104423}, pmid = {42843275}, issn = {2213-2317}, abstract = {Protein tyrosine nitration is a post-translational modification associated with conditions of oxidative and inflammatory stress, driven by the production of reactive oxygen and nitrogen species (ROS and RNS). Once considered primarily a footprint of oxidative damage, tyrosine nitration is increasingly recognized as a selective modification that, in specific biological contexts, can alter protein structure, stability, enzymatic activity, and interaction networks. Mechanistically, nitration occurs through peroxynitrite-dependent and heme-peroxidase-dependent pathways and preferentially targets specific tyrosine residues based on local protein structure, solvent accessibility, and microenvironmental chemistry. Accumulating evidence has identified disease-specific nitration signatures across multiple pathological contexts. In neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, nitration of proteins such as tau, α-synuclein, manganese superoxide dismutase, ATP synthase, glyceraldehyde-3-phosphate dehydrogenase, heat shock proteins, and cytoskeletal components contributes to mitochondrial dysfunction, protein aggregation, metabolic failure, and neuronal loss. Similarly, in cardiovascular and pulmonary diseases, protein tyrosine nitration disrupts vascular and epithelial homeostasis by impairing endothelial signaling, fibrinolysis, lipid metabolism, and barrier integrity through modification of key regulatory proteins. By influencing phosphorylation-dependent signaling, enzymatic function, and protein-protein interactions, tyrosine nitration contributes to the connection between redox imbalance and progressive cellular and tissue dysfunction. This review summarizes current mechanistic insights into site-specific protein tyrosine nitration, highlights the emerging disease-associated nitroproteome, and discusses how advances in analytical and structural approaches are redefining nitration as a functional regulatory modification. Understanding the molecular determinants and consequences of tyrosine nitration may enable the development of targeted diagnostics and therapeutic strategies across diverse human diseases.}, } @article {pmid42844074, year = {2026}, author = {Portero-Campillo, E and Seghers-Carreras, C and Sayas-Catalán, J}, title = {Fooled by the Heartbeat: Cardioballistic Autotriggering in Amyotrophic Lateral Sclerosis.}, journal = {Archivos de bronconeumologia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.arbres.2026.09.010}, pmid = {42844074}, issn = {1579-2129}, } @article {pmid42844308, year = {2026}, author = {Gandhi, SM and Patel, S and Haswani, NG and Wahab, S and Sabah, ZU and Kapoor, DU}, title = {RVG29-functionalized nanocarriers for brain-targeted therapy of neurodegenerative diseases: mechanisms, therapeutic advances, and translational perspectives.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {42844308}, issn = {1432-1912}, abstract = {Neurodegenerative diseases (NDs) affect more than 55 million people worldwide, with this number projected to exceed 139 million by 2050 due to population aging. Alzheimer's disease (AD) accounts for 60-70% of dementia cases, while Parkinson's disease (PD) affects over 10 million individuals globally, highlighting the growing clinical and socioeconomic burden of these progressive neurological disorders. Effective treatment of AD, PD, amyotrophic lateral sclerosis (ALS), and related central nervous system disorders remains hindered by the blood-brain barrier (BBB), poor brain accumulation, rapid systemic clearance, and off-target toxicity. RVG29, a 29-amino-acid peptide derived from rabies virus glycoprotein, has emerged as a promising brain-targeting ligand because of its high affinity for nicotinic acetylcholine receptors expressed on neuronal and brain endothelial cells. This review critically examines the mechanisms underlying RVG29-mediated receptor-dependent BBB transcytosis, intracellular trafficking, and neuronal uptake. Furthermore, it comprehensively evaluates RVG29-functionalized lipid nanoparticles, polymeric nanoparticles, exosomes, biomimetic nanocarriers, micelles, inorganic nanostructures, and hybrid systems with respect to their physicochemical characteristics, targeting efficiency, therapeutic efficacy, and safety. Collectively, these nanocarriers demonstrate enhanced BBB penetration, increased drug accumulation in diseased brain regions, and efficient delivery of small molecules, genes, mRNA, and siRNA. By modulating oxidative stress, neuroinflammation, protein aggregation, ferroptosis, and mitochondrial dysfunction, RVG29-engineered nanocarriers provide significant neuroprotection with favorable biocompatibility and minimal immunogenicity. Despite these advances, challenges related to large-scale manufacturing, peptide stability, regulatory approval, and long-term biosafety must be addressed to facilitate their clinical translation as precision neurotherapeutics.}, } @article {pmid42844425, year = {2026}, author = {Stavrou, M and Heffernan, ÁB and Carter, RN and Dando, O and Jiwaji, Z and Burr, K and Nanda, J and Villarroel-Campos, D and Masoud Abdelhafid, A and Cholewa-Waclaw, J and Soong, D and Story, D and Schiavo, G and Hardingham, GE and Chandran, S and Selvaraj, BT}, title = {Astrocytes regulate axonal mitochondrial transport deficits in C9ORF72 amyotrophic lateral sclerosis motor neurons.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, pmid = {42844425}, issn = {1546-1726}, support = {(MR/T000708/1)//RCUK | Medical Research Council (MRC)/ ; (223022/Z/21/Z)//Wellcome Trust (Wellcome)/ ; }, abstract = {Disrupted axonal transport and astrocyte dysfunction are implicated in amyotrophic lateral sclerosis (ALS). Here we show these processes are linked-human-induced pluripotent stem-cell-derived astrocytes carrying the C9ORF72 mutation disrupt mitochondrial axonal transport and mitochondrial function in cocultured motor neurons (MNs). Conversely, isogenic gene-corrected astrocytes or boosting astrocytic mitochondrial bioenergetics rescue axonal mitochondrial transport deficits in C9ORF72 MNs. Our results delineate a non-cell-autonomous role for astrocytes in regulating mitochondrial transport along axons in ALS models.}, } @article {pmid42845299, year = {2026}, author = {Torres, P and Becerra, D and Astorga, JI and Fuentealba, M and Kauwe, G and Gonzalez, L and Diaz, G and Morales, V and Valenzuela, V and Wehrfritz, C and Ngwala, YY and Sepulveda-Quiñenao, C and Shah, S and Bons, J and Petrucelli, L and Tracy, TE and Schilling, B and Hetz, C}, title = {Oral administration of dibenzoylmethane (DBM) prevents cognitive decline in a C9ORF72-mediated FTD mouse model.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.08.07.743573}, pmid = {42845299}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative disorders that display overlapping features. The hexanucleotide repeat expansion GGGGCC (G 4 C 2) in the C9ORF72 gene is the most common cause of ALS and FTD, which results in the accumulation of dipeptide-repeat protein aggregates. Regulation of protein synthesis at the level of the initiation factor eIF2α has been suggested as a transversal event contributing to neurodegeneration in ALS and FTD. eIF2α phosphorylation blocks protein synthesis to alleviate protein misfolding overload, but conversely it can reduce the expression of synaptic proteins resulting in neuronal dysfunction. Dibenzoylmethane (DBM) is a small molecule that reverses the translational attenuation mediated by eIF2α phosphorylation which has been shown to alleviate neurodegeneration in prion-infected mice and Tau transgenic animals. Here we investigated the efficacy of the oral administration of DBM in protecting a mouse model of C9ORF72 pathogenesis. Treatment of mice with 0.5% of DBM mixture in powdered food ad libitum was sufficient to prevent cognitive impairment in C9ORF72 mice. Unexpectedly, DBM treatment did not modify the content of poly(GA) and poly(GR) protein inclusion in the hippocampus and brain cortex. Proteomic profiling of brain tissue indicated that DBM administration corrected nearly 70% of the changes in gene expression triggered by expanded G 4 C 2 , where the main pathways modified by DBM were related to cytoskeleton organization, ALS, and metabolic processes. Most proteins corrected by DBM in our C9ORF72 model were also altered in the brain of human FTD/ALS patients. Overall, our results reinforce the idea that targeting protein synthesis with small molecules in patients carrying C9ORF72 mutations may result in improved cognitive capacity.}, } @article {pmid42846340, year = {2026}, author = {Garbey, M and Lesport, Q and Öztosun, G and Heidebrecht, M and Pirouz, K and Bayat, E}, title = {Correction: Feasibility study of noninvasive assessment of emotional state in patients with ALS.}, journal = {Frontiers in digital health}, volume = {8}, number = {}, pages = {1977072}, doi = {10.3389/fdgth.2026.1977072}, pmid = {42846340}, issn = {2673-253X}, abstract = {[This corrects the article DOI: 10.3389/fdgth.2026.1886561.].}, } @article {pmid42847178, year = {2026}, author = {Jernigan, B and Walters, HL and Corey, D and Garcia, A and Premasiri, A and Roddy, WT and Shearer, D and Thompson, TG and Tucker, J and Vieira, F and Boyce, D}, title = {Harmonizing ALS research data across multimodal data sets using the OMOP Common Data Model.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2026.2738533}, pmid = {42847178}, issn = {2167-9223}, abstract = {Three nonprofit organizations-ALS Therapy Development Institute (ALS TDI), Answer ALS, and the Critical Path Institute (C-Path)-collaborated to harmonize distinct ALS research datasets using the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). This effort was designed to make otherwise separate ALS resources more comparable, enabling larger and more informative cross-cohort analyses. The teams coordinated vocabulary mapping, identified OMOP vocabulary gaps, and submitted new concepts to the Observational Health Data Science and Informatics (OHDSI) community for approval. Harmonized data from ALS TDI and Answer ALS were merged in the Neuromine data portal, while their clinical and digital health technology (DHT) datasets are also available through C-Path's Rare Disease Cures Accelerator-Data Analytics Platform (RDCA-DAP). This collaboration aligns with current regulatory priorities for data sharing and offers a model for harmonizing rare disease data. A robust, public GitHub repository was established to share real-time updates with the ALS research community.}, } @article {pmid42847522, year = {2026}, author = {Donlin-Asp, PG and Clayton, EL}, title = {Synaptic Proteostasis in Health and Disease.}, journal = {Journal of neurochemistry}, volume = {170}, number = {10}, pages = {e70565}, doi = {10.1111/jnc.70565}, pmid = {42847522}, issn = {1471-4159}, support = {309570/Z/24/Z/WT_/Wellcome Trust/United Kingdom ; ARUK-SRF2022A-005//Alzheimer's Research UK/ ; //CureSynGAP/ ; 571/ALZS_/Alzheimer's Society/United Kingdom ; //Simons Initiative for the Developing Brain/ ; }, mesh = {Humans ; *Proteostasis/physiology ; *Synapses/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Autophagy/physiology ; *Neurons/metabolism/pathology ; Proteotoxic Stress ; }, abstract = {Neurons rely on tightly coordinated mechanisms of protein synthesis and degradation to maintain cellular homeostasis, a process known as proteostasis. Given their highly polarised and compartmentalised nature, regulation of proteostasis is especially important at neuronal synapses, which are spatially distant from the soma yet require rapid on-demand adaptation of the synaptic proteome. Neurons meet their demand for synaptic proteostasis through localised mRNA transport and translation, alongside specialised pathways for protein degradation. Recent advances reveal that thousands of transcripts localise to distal neuronal compartments and that their distribution may be shaped by RNA stability, RNA dynamics, and organelle-hitchhiking transport mechanisms. In parallel, processes such as synaptic autophagy and endolysosomal trafficking are crucial for maintaining synaptic structure and neurotransmission. Disruptions in these finely balanced mechanisms are a common underlying feature of various neurological disorders, including fragile X syndrome, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. This overview highlights key milestones and remaining questions in synaptic proteostasis, focusing on how local protein synthesis and degradation work together to preserve synaptic integrity and how their dysregulation can lead to disease.}, } @article {pmid42847638, year = {2026}, author = {Schneider, RB and Skibinski, G and Fiske, B and Kopil, CM and Merchant, K and Simuni, T}, title = {Considerations for therapeutic targets for clinical trials in biomarker-characterized prodromal Parkinson's disease populations.}, journal = {Journal of Parkinson's disease}, volume = {}, number = {}, pages = {1877718X261493297}, doi = {10.1177/1877718X261493297}, pmid = {42847638}, issn = {1877-718X}, abstract = {Parkinson's disease (PD) is a growing public health problem and biologically targeted therapeutics (BTTs) that slow disease progression are urgently needed. However, the development of effective BTTs is challenging as PD is a clinically defined syndrome with pathobiological heterogeneity and the pathobiological process begins many years before the onset of clinically detectable motor symptoms. Testing BTTs in a biomarker-defined population at an earlier stage in the disease course, before a clinical PD diagnosis, may be the key to achieving this objective. The recent emergence of biological definitions of neuronal α-synuclein disease (NSD) and research frameworks for staging disease represent the first step towards testing BTTs in biomarker-defined prodromal populations. While biomarker-defined populations are essential for implementing precision therapeutic approaches, selecting and prioritizing BTTs for testing in early-stage populations is also critical, and requires consideration of biological relevance, safety, and operational feasibility. Here, in preparation for such studies, we review the landscape of publicly available PD BTTs organized by mechanistic pathways and targets, and summarize scientific, safety, and operational considerations relevant to early-stage, biomarker-defined trials targeting NSD participants prior to PD clinical diagnosis. Recognizing that there are shared biological mechanisms across neurodegenerative disorders, we complement this review of the PD therapeutic target landscape with a review of publicly available Alzheimer's dementia and amyotrophic lateral sclerosis BTTs and provide a comprehensive list of agents for reference.}, } @article {pmid42847641, year = {2026}, author = {De Lorenzo, A and Maranzano, A and Cocuzza, A and Gentile, F and Passaretti, M and Colombo, E and Torre, S and Aiello, EN and Calcagno, N and Gendarini, C and Olivero, M and Scheveger, F and Patisso, V and Spagliardi, J and Di Maio, A and Pierro, S and Treddenti, M and Gagliardi, D and Comi, GP and Corti, S and Pereira, JB and Agosti, P and Peyvandi, F and Messina, S and Doretti, A and Poletti, B and Morelli, C and Silani, V and Cinnante, CM and Verde, F and Ticozzi, N}, title = {White matter hyperintensity burden in amyotrophic lateral sclerosis: motor and survival correlates.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag347}, pmid = {42847641}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration. Microvascular dysfunction has been implicated by recent research in ALS pathogenesis and motor neuron vulnerability. The aim of this study is to investigate whether MRI markers of white matter hyperintensities (WMHs), reflecting small-vessel disease, are associated with motor and cognitive impairment, disease staging and prognosis in ALS. In this retrospective cohort study MRI scans from 399 ALS patients were evaluated for periventricular and deep white matter hyperintensities (pvWMH and dWMH) using visual grading scales together with semi-automated volumetric quantification of relative WMH volume (WMHrv). The primary outcome was survival. Secondary outcomes included disease staging, functional impairment, motor and cognitive outcome measures. WMH burden was associated with more advanced King's topographic staging [pvWMH (P < 0.001), dWMH (P = 0.002)] and MiToS functional staging [pvWMH (P < 0.001), dWMH (P = 0.017)]. High pvWMH burden was associated with shorter survival [exp(β) = 3.503; 95% CI = 1.131, 10.832; P = 0.030] after adjustment for known prognostic factors. WMH measures correlated with greater functional impairment on ALSFRS-R score [pvWMH (P < 0.001), dWMH (P = 0.003), WMHrv (P = 0.008)]. WMH burden correlated with more severe lower, but not upper, motor neuron impairment, as measured with the MRC sum score [pvWMH (P = 0.002), dWMH (P = 0.024), WMHrv (p=0.030)] and lower motor neuron score [pvWMH (P < 0.001), dWMH (P = 0.001)]. WMH burden was also associated with cognitive deficits on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), as indicated by total [pvWMH (P = 0.007), dWMH (P = 0.009), WMHrv (P = 0.037)] and ALS-specific ECAS scores [pvWMH (P = 0.001), dWMH (P = 0.020), WMHrv (P = 0.022)]. This large-scale MRI study links small-vessel disease to clinical staging, survival and ALS-specific motor (distinctively LMN) and cognitive impairments. These results suggest that WMHs may reflect a diffuse neurovascular pathology spanning cortical and spinal regions and may be relevant to ALS progression. Routine MRI assessment of WMHs could aid patient stratification and inform trial designs. Longitudinal studies are needed to clarify causal relationships and neurovascular-targeted therapeutic implications.}, } @article {pmid42848030, year = {2026}, author = {Gaete, PV and Preciado, MP and Díaz, JJF}, title = {Contrasting clinical trajectories in two ALS patients with rare FUS variants: implications for variant interpretation, penetrance, and trial readiness.}, journal = {Neurogenetics}, volume = {27}, number = {1}, pages = {}, pmid = {42848030}, issn = {1364-6753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *RNA-Binding Protein FUS/genetics ; Penetrance ; Phenotype ; Middle Aged ; Male ; Female ; Genetic Variation ; Mutation ; Genetic Association Studies ; Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor system. A minority of cases are associated with a genetic variant. Variants in C9orf72, SOD1, TARDBP, and FUS are the most common. Compared with other forms of ALS, ALS presenting with FUS variants is relatively aggressive. However, phenotypic heterogeneity has been reported. We describe two cases of ALS with rare FUS variants with contrasting clinical courses. These cases highlight the importance of the different factors that influence ALS phenotypic presentation and the challenges of variant interpretation in ALS, as outlined in the ACMG Guidelines. It is essential to recognise specific genotype-phenotype relationships and environmental factors that could alter the clinical course of the disease and affect therapeutic agent selection.}, } @article {pmid42848219, year = {2026}, author = {Vasta, R and Calvo, A and Moglia, C and Canosa, A and Manera, U and Gianferrari, G and Zucchi, E and Martinelli, I and Mora, G and Cabras, S and Palumbo, F and Matteoni, E and Maccabeo, A and Pellegrino, G and Minerva, E and Pascariu, D and Callegaro, S and D'Ovidio, F and Mazzini, L and De Marchi, F and Mandrioli, J and Chiò, A}, title = {Pre-diagnostic ALSFRS-R slope provides limited incremental information about the variability in subsequent functional decline in amyotrophic lateral sclerosis: a population-based study.}, journal = {Journal of neurology}, volume = {273}, number = {10}, pages = {}, pmid = {42848219}, issn = {1432-1459}, support = {RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 20228N7573//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 259867//European Commission's Health Seventh Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101137074//Horizon 2020 Framework Programme/ ; project DIG-ALS//ARISLA/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/epidemiology ; Female ; Registries ; *Disease Progression ; Male ; Middle Aged ; Aged ; Longitudinal Studies ; Cohort Studies ; }, abstract = {BACKGROUND: The pre-diagnostic ALSFRS-R slope is frequently used in a clinical trial design and clinical practice under the implicit assumption that it reflects subsequent functional decline. We assessed the association between the pre-diagnostic ALSFRS-R slope and subsequent functional decline.

METHODS: The Piemonte and Valle d'Aosta ALS Registry (PARALS) was used as the primary cohort. The associations between pre- and post-diagnostic slopes at 6, 12, and 18 months were examined using correlation coefficients and multivariable linear regression. Linear and quadratic mixed-effects models used all ALSFRS-R assessments obtained during the first 18 months to evaluate longitudinal trajectories and quantify the incremental contribution of the pre-diagnostic slope. All analyses were replicated in the Emilia Romagna Registry for ALS (ERRALS).

RESULTS: A total of 2,222 patients from PARALS and 1,543 from ERRALS were included. In PARALS, the pre-diagnostic ALSFRS-R slope showed only a modest monotonic association with post-diagnostic functional decline (Spearman's ρ = 0.19-0.30) and explained 6.1% of its variance at 6 months, with this proportion decreasing thereafter. Quadratic mixed-effects models estimated that, at 12 months, the difference in ALSFRS-R change between patients in the highest and lowest pre-diagnostic slope quartiles was 2.04 points in PARALS (95% CI 1.25-2.83) and 2.47 points in ERRALS (95% CI 1.07-3.86). However, the linear and quadratic interactions together increased the marginal R[2] by only 0.43 percentage points in PARALS and 1.68 percentage points in ERRALS.

CONCLUSIONS: The pre-diagnostic ALSFRS-R slope identifies meaningful average differences in subsequent decline between patient groups but provides limited information for predicting individual trajectories.}, } @article {pmid42849018, year = {2026}, author = {Rankin, J and Oltmann, C and Taylor, EP and Schachter, D and Lal, A}, title = {Early Palliative Care and Structured Serious Illness Communication in a Refugee Patient With Amyotrophic Lateral Sclerosis.}, journal = {The primary care companion for CNS disorders}, volume = {28}, number = {5}, pages = {}, doi = {10.4088/PCC.26cr04223}, pmid = {42849018}, issn = {2155-7780}, } @article {pmid42833279, year = {2026}, author = {Szeligowski, T and Ie, A and Kiraly, P and Hu, M and Ivanova, T and Jalil, A and Sergouniotis, P and Black, G and Wong, SC and Patel, CK and Henderson, R and Xue, K}, title = {Genetics, management and clinical outcomes in familial exudative vitreoretinopathy (FEVR): a multicentre retrospective cohort.}, journal = {Klinische Monatsblatter fur Augenheilkunde}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2962-8394}, pmid = {42833279}, issn = {1439-3999}, abstract = {in English Background Familial exudative vitreoretinopathy (FEVR) is a group of inherited retinal diseases characterised by abnormal retinal angiogenesis and peripheral non-perfusion. While over 10 genes have been implicated in FEVR, genotype-phenotype correlations and their clinical significance are incompletely understood. Here we describe a retrospective cohort of FEVR patients and assess the impact of defined genetic variants on protein structure, disease severity, inter-ocular variability, as well as treatment choices and visual outcomes. Methods Retrospective cohort of 51 patients with FEVR across three UK paediatric retina centres. All data was obtained from routine clinical records. Standard FEVR staging system was used throughout. Identified genetic variants were checked against genomic databases (ClinVar, GnomAD, UniProt), and their structural impact was examined using in silico algorithms (MutationTaster and PolyPhen2) to determine the likelihood of pathogenicity. Results 51 patients were included, with variants identified in FZD4 (n=16), LRP5 (n=13), TSPAN12 (n=11), KIF11 (n=6), NDP (n=4), and CTNNB1 (n=1). In silico analysis identified 11 variants not previously reported in FEVR, seven of which were classified as likely pathogenic. NDP variants were associated with the most severe and asymmetrical disease. Management included conservative monitoring (45 eyes), retinal laser photocoagulation (39 eyes), and surgical interventions (12 eyes), with the majority of patients achieving stable or improved visual acuity in all treatment groups. Conclusion This study demonstrates significant diversity among FEVR patients with regards to genetic variants, clinical presentation, and visual outcomes. Understanding genotype-phenotype correlations in FEVR may be crucial for developing novel treatment strategies. ABSTRACT in German Hintergrund Die familiäre exsudative Vitreoretinopathie (FEVR) ist eine Gruppe erblicher Netzhauterkrankungen, die durch eine abnorme retinale Angiogenese und eine periphere Minderperfusion gekennzeichnet ist. Obwohl mehr als 10 Gene mit FEVR in Verbindung gebracht wurden, sind Genotyp-Phänotyp-Korrelationen und deren klinische Bedeutung nur unvollständig verstanden. In dieser Arbeit beschreiben wir eine retrospektive Kohorte von FEVR-Patienten und untersuchen den Einfluss definierter genetischer Varianten auf die Proteinstruktur, den Krankheitsschweregrad, die interokuläre Variabilität sowie auf Behandlungsentscheidungen und visuelle Ergebnisse. Methoden Retrospektive Kohorte von 51 Patienten mit FEVR aus drei pädiatrischen Netzhautzentren im Vereinigten Königreich. Alle Daten wurden aus routinemäßigen klinischen Aufzeichnungen gewonnen. Durchgehend wurde das Standard-FEVR-Staging-System verwendet. Die identifizierten genetischen Varianten wurden mit genomischen Datenbanken (ClinVar, GnomAD, UniProt) abgeglichen, und ihre strukturelle Auswirkung wurde mittels In-silico-Algorithmen (MutationTaster und PolyPhen2) untersucht, um die Wahrscheinlichkeit einer Pathogenität zu bestimmen. Ergebnisse Es wurden 51 Patienten eingeschlossen, wobei Varianten in FZD4 (n=16), LRP5 (n=13), TSPAN12 (n=11), KIF11 (n=6), NDP (n=4) und CTNNB1 (n=1) identifiziert wurden. Die In-silico-Analyse identifizierte 11 zuvor nicht im Zusammenhang mit FEVR beschriebene Varianten, von denen sieben als wahrscheinlich pathogen eingestuft wurden. NDP-Varianten waren mit der schwersten und asymmetrischsten Erkrankung assoziiert. Das Management umfasste konservative Überwachung (45 Augen), retinale Laserphotokoagulation (39 Augen) und chirurgische Eingriffe (12 Augen), wobei die Mehrheit der Patienten in allen Behandlungsgruppen eine stabile oder verbesserte Sehschärfe erreichte. Schlussfolgerung Diese Studie zeigt eine erhebliche Vielfalt unter FEVR-Patienten hinsichtlich genetischer Varianten, klinischer Präsentation und visueller Ergebnisse. Das Verständnis der Genotyp-Phänotyp-Korrelationen bei FEVR könnte entscheidend für die Entwicklung neuartiger Behandlungsstrategien sein.}, } @article {pmid42838501, year = {2026}, author = {Knapp, J and Greif, R and Bathe, J and Wnent, J and Harding, U and Seewald, S and Fischer, M}, title = {Amiodarone After Conversion From a Non-shockable to a Shockable Rhythm in Out-of-Hospital Cardiac Arrest A Propensity Score-Matched Analysis from the German Resuscitation Registry.}, journal = {Resuscitation}, volume = {}, number = {}, pages = {111349}, doi = {10.1016/j.resuscitation.2026.111349}, pmid = {42838501}, issn = {1873-1570}, abstract = {BACKGROUND: Amiodarone should be administered after three shocks according the current ERC ALS guidelines. However, its effect in out-of-hospital cardiac arrest (OHCA) patients with an initial non-shockable rhythm who subsequently convert to a shockable rhythm is not established.

METHODS: We performed a retrospective observational cohort study using data from the German Resuscitation Registry. Adult patients with non-traumatic OHCA, having an initial non-shockable rhythm and subsequently received at least two defibrillations were included. Propensity-score-matched patient pairs (1:1) were analysed to compare outcomes between patients who received amiodarone during resuscitation and those who did not. The primary outcome was survival to hospital discharge. Secondary outcomes included hospital admission with return of spontaneous circulation (ROSC), 24-hour survival, survival to hospital discharge, and favourable neurological outcome at hospital discharge.

RESULTS: Of 5,535 patients included 3,181 received amiodarone and 2,354 did not. After propensity-score matching, 1,843 patients remained in each group. Amiodarone administration was associated with higher rates of hospital admission with ROSC (26.7% vs. 23.0%; OR 1.22, 95% confidence interval 1.05-1.42), 24-hour survival (21.4% vs. 14.7%; OR 1.58, 95% CI 1.33-1.87), and survival to hospital discharge (6.5% vs. 4.2%; OR 1.58, 95% CI 1.18-2.12). Favourable neurological outcome at hospital discharge was not statistically significant (3.7% vs. 2.9%; OR 1.31, 95% CI 0.91-1.89).

CONCLUSIONS: In OHCA patients with an initial non-shockable rhythm who subsequently converted to a shockable rhythm, amiodarone administration was associated with improved short-term and long-term survival, but not with a statistically significant improved favourable neurological outcome. Future controlled studies might define the proper (earlier) time of amiodarone administration.}, } @article {pmid42839248, year = {2026}, author = {Bublitz, SK and Bausewein, C and Detter, V and Feddersen, B and Graw, M and Klima, A and Klotz, P and Lorenzl, S and Gleich, S}, title = {Place and cause of death among people with chronic neurological diseases in Munich: a population-based study using death certificates.}, journal = {Neurological research and practice}, volume = {8}, number = {1}, pages = {}, pmid = {42839248}, issn = {2524-3489}, abstract = {INTRODUCTION: Access to palliative care is often delayed and fragmented for patients with chronic neurological diseases. This study aimed to characterize the place and cause of death among individuals with chronic neurological diseases to help identify potential gaps in palliative care provision.

METHOD: In this cross-sectional study, all death certificates from the city of Munich, Germany (2020-2023) were reviewed. Cases were included if malignant brain tumours, amyotrophic lateral sclerosis (ALS) or other motor neuron diseases, Parkinson's disease (PD), multiple sclerosis (MS) or other neurodegenerative or neuromuscular diseases were recorded as the cause of death or as a comorbidity.

RESULTS: Of 60,357 deaths, 2,536 individuals (4.2%) had at least one chronic neurological disease. The most common place of death was the hospital (43.8%), followed by nursing homes (25.9%) and the private home (25.0%), with variations among disease subgroups. Overall, the neurological disease was recorded as the immediate or underlying cause of death in 57.3% of cases, while in the remaining cases it was documented as a comorbidity, reflecting its presence without formal causal attribution to death.

DISCUSSION: This population-level analysis provides insight into the place and circumstances of death for a large cohort of patients with chronic neurological diseases in a major German metropolitan area and highlights substantial heterogeneity in end-of-life trajectories. The findings indicate that mortality statistics based on death certificates reflect structural limitations in cause-of-death attribution. Nevertheless, place of death remains a robust indicator, showing high hospital utilization and limited hospice use across most diagnostic groups, underscoring potential gaps in goal-concordant care.}, } @article {pmid42839646, year = {2026}, author = {Mercadante, S and Petronaci, A and , }, title = {One-Year Clinical Course of Patients With Amyotrophic Lateral Sclerosis Admitted to a Home Palliative Care Program: An Extension Study.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70429}, pmid = {42839646}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Longer term data on ALS patients receiving home palliative care are scarce. We extended follow-up of a 6-month cohort to 12 months to characterize the trajectory of function, symptoms, vital support (noninvasive ventilation [NIV], gastrostomy, and/or tracheostomy), and advance care planning (ACP).

METHODS: In this prospective, single-center study, 34 consecutive ALS patients in a home palliative care program (SAMOT, Palermo) were assessed at baseline, 2, 4, 6, and 12 months, using Karnofsky, ALS Functional Rating Scale-Revised (ALSFRS-R), Edinburgh Cognitive and Behavioural ALS Screen (ECAS), Edmonton Symptom Assessment Scale (ESAS), dysphagia, vital support, and advanced care planning (ACP).

RESULTS: Ten patients (29.4%) died over 12 months (70% at home); 26 completed the 12-month assessment. Karnofsky (34.4-27.7) and ALSFRS-R (27.1-21.7) declined significantly throughout (both p < 0.0005). Total ESAS rose from 15.7 to 23.7 (p < 0.0005); anxiety increased significantly between T4 and T12. NIV use rose from 20.6% to 50.0% (p = 0.014), while tracheostomy remained stable. Documented end-of-life decisions rose to 70.4% at 6 months but plateaued (69.2% at 12 months); no living wills were completed. Cognitive impairment on ECAS was present in about half of patients, unchanged over time. No patient was referred to or admitted to hospice.

DISCUSSION: Extending follow-up beyond 6 months shows continuous functional decline and rising symptom burden, and highlights late-onset anxiety and early-plateauing ACP. Despite progressive needs, this home palliative care model appeared to support most patients at home until death over 1 year, within this single-center, non-comparative cohort.}, } @article {pmid42839768, year = {2026}, author = {Iazzolino, B and Palumbo, F and Canosa, A and Callegaro, S and Passidomo, V and Manera, U and Vasta, R and Matteoni, E and Cabras, S and Pellegrino, G and Maccabeo, A and Moglia, C and Calvo, A and Chiò, A}, title = {Recalibration of the Frontal Behavioural Inventory Cut-Off for Behavioural Screening in Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {10}, pages = {e70778}, doi = {10.1111/ene.70778}, pmid = {42839768}, issn = {1468-1331}, support = {RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; 20228N7573//Ministero dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101137074//HORIZON EUROPE Framework Programme/ ; DIG-ALS//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/psychology ; Female ; Male ; Aged ; Middle Aged ; *Neuropsychological Tests/standards ; Sensitivity and Specificity ; Frontotemporal Dementia/diagnosis ; Reproducibility of Results ; }, abstract = {OBJECTIVE: The Frontal Behavioural Inventory (FBI) was validated in behavioural-variant frontotemporal dementia (bvFTD) with a cut-off of 25. We tested whether this threshold is appropriate in amyotrophic lateral sclerosis (ALS), where behavioural change is milder and partly confounded by motor pathology.

METHODS: We analysed 506 ALS patients with a valid FBI assessment. Behavioural impairment was defined using two complementary reference standards, to minimise dependence on any single behavioural instrument: a consensus rule (pathology on ≥ 2 of three independent instruments: Edinburgh Cognitive and Behavioural ALS Screen, Frontal Systems Behaviour Scale, Beaumont Behavioural Inventory) and Latent Class Analysis. ROC analysis identified the Youden-optimal cut-off; agreement was quantified by Cohen's κ; internal validity was assessed by stratified 5-fold cross-validation. Total and subscale scores were analysed separately.

RESULTS: Among 345 complete-case patients, 24.6% met criteria for behavioural impairment. The FBI total discriminated impairment well (AUC 0.855, 95% CI 0.806-0.898). The Youden-optimal cut-off was FBI ≥ 9 (sensitivity 0.87, specificity 0.74), whereas the legacy cut-off of 25 showed sensitivity 0.22. Subscale recalibration yielded cut-offs of FBI-Apathy ≥ 7 (AUC 0.808) and FBI-Disinhibition ≥ 4 (AUC 0.851).

CONCLUSIONS: In ALS, the bvFTD-derived threshold of 25 misses most patients with behavioural involvement. FBI ≥ 9 is a promising candidate ALS-specific screening threshold, with scores ≥ 15 indicating a higher probability of behavioural involvement; exploratory subscale thresholds of ≥ 7 for Apathy and ≥ 4 for Disinhibition are also proposed. These cut-offs substantially improve sensitivity while maintaining acceptable specificity, but require prospective external validation before replacing current practice.}, } @article {pmid42839902, year = {2026}, author = {Bettoni, V and Nath, SR and Johnson, S and Oskarsson, B and Bojko, A and Salmaninejad, A and Tan-Arroyo, J and Cousin, MA and Staff, NP}, title = {Clinical and genetic characterization of FUS-associated ALS in a tertiary cohort.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2026.2743446}, pmid = {42839902}, issn = {2167-9223}, abstract = {An understanding of FUS-related ALS is becoming increasingly actionable with the emergence of targeted therapies. We retrospectively reviewed patients with amyotrophic lateral sclerosis and reported FUS variants evaluated across all Mayo Clinic sites between January 2009 and June 2026. Variants were reevaluated according to ACMG/AMP criteria, and clinical and genetic data were abstracted from medical records. The primary cohort included 12 unrelated patients with pathogenic or likely pathogenic (P/LP) FUS variants; 6 patients with variants of uncertain significance were retained descriptively. Pathogenic variants clustered in the C-terminal region, including one previously unreported likely pathogenic frameshift variant, c.1491_1494dup. Patients with pathogenic variants showed early-onset, rapidly progressive disease with frequent bulbar or respiratory onset, predominant lower motor neuron findings, and short survival. Observed phenotypes were broadly consistent with previous variant-specific reports. These findings expand variant-specific natural history data in FUS-ALS and may inform prognosis, patient stratification, and the interpretation of emerging FUS-targeted therapeutic studies.}, } @article {pmid42840349, year = {2026}, author = {Morandi, L and Casadei, F and De Fanti, S and Bonan, L and Ravaioli, F and Palombo, F and Fiorentino, A and de Pasqua, S and Vacchiano, V and Avoni, P and Rizzo, G and Capellari, S and Ruggeri, E and Donadio, V and Castellani, G and Bacalini, MG and Lodi, R and Liguori, R and Carelli, V and Tonon, C}, title = {Nanopore sequencing combined with adaptive sampling and NanoExpansion enables accurate characterization of repeat expansion disorders.}, journal = {NAR genomics and bioinformatics}, volume = {8}, number = {4}, pages = {lqag117}, pmid = {42840349}, issn = {2631-9268}, mesh = {Humans ; *DNA Repeat Expansion ; *Nanopore Sequencing/methods ; Microsatellite Repeats ; Polymerase Chain Reaction ; Amyotrophic Lateral Sclerosis/genetics ; Sequence Analysis, DNA/methods ; Spinocerebellar Ataxias/genetics ; Myotonic Dystrophy/genetics ; }, abstract = {Expansion repeat disorders are caused by abnormal expansions of short tandem repeats (STRs). We evaluated targeted long-read nanopore sequencing for comprehensive characterization of STR expansions in 132 participants, including patients with myotonic dystrophy type 1 (DM1, n = 51) and DM2 (n = 3) already characterized by Southern blot, C9orf72-associated amyotrophic lateral sclerosis (ALS n = 11) evaluated by repeat primed polymerase chain reaction (RP-PCR; validation group), suspected spinocerebellar ataxia (SCA, n = 46), cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS; n = 13), Huntington's disease (1), Kennedy disease (1), Friedreich ataxia (FRDA, 2), and 4 healthy controls (test group). Native DNA was sequenced using adaptive sampling (AS) on Oxford Nanopore GridION or PromethION-2Solo platforms. Long-PCR sequencing was performed for comparison. We also developed NanoExpansion, a Python-based tool for sizing expanded alleles and detecting sequence interruptions. We correctly characterized all DM1, DM2, ALS, FRDA, Huntington's disease, and Kennedy disease cases, and identified eight SCA27B, two SCA37, three SCA31, one SCA3, and nine CANVAS cases. Compared with the AS approach, long-PCR underestimated alleles exceeding 800 repeats. Repeat interruptions were detected in 27/51 (52.9%) DM1 cases and 1/10 (10%) ALS, but not in CANVAS, FRDA, Huntington's disease, Kennedy disease, or SCA cases. This integrated sequencing analysis pipeline provides accurate, comprehensive characterization of repeat expansion disorders and has the potential to improve routine genetic diagnosis.}, } @article {pmid42840744, year = {2026}, author = {Mouraux, C and Santana, MM and Rosenthal, LS and Cortese, A and Santorelli, FM and Opal, P and Coarelli, G}, title = {The role of neurofilament light chain and other fluid biomarkers in cerebellar ataxias.}, journal = {Brain communications}, volume = {8}, number = {5}, pages = {fcag313}, pmid = {42840744}, issn = {2632-1297}, abstract = {The genetic and phenotypic heterogeneity of hereditary ataxias complicates the design of clinical trials since each ataxia progresses at different rates. Consequently, robust biomarkers are urgently needed to monitor therapeutic efficacy and safety of potential therapeutic interventions. Neurofilament light chain has emerged as a leading candidate, serving as a sensitive pharmacodynamic biomarker of neuronal injury and treatment response in neurodegenerative disorders. This review explores the utility of neurofilament light chain across various ataxias, including polyglutamine spinocerebellar ataxias, Friedreich's ataxia, multiple system atrophy, and other genetic ataxias, such as ataxias associated with RCF1 and SPG7 genes. We synthesize evidence from recent studies that have used ultra-sensitive assays. These studies consistently demonstrate elevated neurofilament light chain levels in cerebrospinal fluid and blood, correlating with disease severity, progression and neuroimaging findings. Notably, neurofilament light chain levels rise during the presymptomatic stage in spinocerebellar ataxias, highlighting its potential for stratifying individuals for trial enrolment and tracking therapeutic effects. A treatment-induced reduction in neurofilament light chain could function as a surrogate endpoint for target engagement, analogous to its validated use in amyotrophic lateral sclerosis. Finally, we discuss the results of other studies conducted on other biomarkers, including glial fibrillary acidic protein, total tau and phosphorylated tau, which may reflect complementary aspects of neurodegeneration and glial activation. Glial fibrillary acidic protein may provide insights into astroglial reactivity and neuroinflammation. Similarly, alteration in total tau and phosphorylated tau levels may suggest dysfunction in neuronal cytoskeleton and axonal integrity. The review also focuses on target-engagement biomarkers, including polyglutamine-expanded ataxin proteins in spinocerebellar ataxias and frataxin in Friedreich's ataxia, as critical tools to complement the ataxia biomarker toolkit. The quantification of mutant ataxin proteins provides a mechanistic readout for emerging gene-silencing or protein-lowering therapies. In parallel, the measurement of frataxin levels serves as a pharmacodynamic marker in therapeutic strategies aiming to restore frataxin expression. These target-engagement biomarkers are valuable in early phases of clinical trials, which mainly aim to demonstrate the biological activity of a treatment before later-phase trials assessing clinical efficacy. Finally, we report on somatic instability in polyglutamine spinocerebellar ataxias as an emerging and highly relevant therapeutic target. CAG repeat mosaicism is gene specific and correlates with disease progression. Integrating measures of repeat instability with neurodegenerative biomarkers could provide a comprehensive monitoring approach in clinical studies. This overview underscores the potential of fluid biomarkers, particularly neurofilament light chain, in accelerating therapeutic development for hereditary ataxias.}, } @article {pmid42841339, year = {2026}, author = {Zhu, X and Qiao, X and Qin, N and Li, Z and Lv, Y and Lu, J and Guo, Z}, title = {Site-Selective Anion-Cation Regulation of Sulfide Electrolyte Enables Low-Pressure Dendrite-Suppressed All-Solid-State Lithium Metal Batteries.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {}, number = {}, pages = {e3893843}, doi = {10.1002/anie.3893843}, pmid = {42841339}, issn = {1521-3773}, support = {U25A20243//National Natural Science Foundation of China/ ; 2026C02A1252//Department of Science & Technology of Zhejiang Province/ ; }, abstract = {Achieving stable sulfide-based all-solid-state lithium batteries with Li metal anodes and high-capacity cathodes under low stack pressure is highly desirable for high-energy-density energy storage, but remains challenging because of unstable solid-solid interfaces and dendrite-induced short circuits. Here, we develop a site-selective anion-cation regulation strategy for argyrodite Li6PS5Cl electrolyte to couple framework stabilization with interphase chemistry, enabling long-term dendrite-suppressed cycling under low stack pressure. Al[3+] substitution for P[5+] forms AlS4 -related local units and strengthens local Al-S bonding, stabilizing the sulfide framework against redox decomposition. Cl[-] incorporation into the 4a/4d anion sublattice promotes Li[+] transport, delivering a high room-temperature ionic conductivity of 7.22 mS cm[-1]. More importantly, F/Cl regulation redirects the interfacial decomposition pathway from a Li2S-rich/LiCl interphase toward a LiF/LiCl-rich and Li2S-poor passivation layer, with exposed LiF/LiCl (200) planes that exhibit stronger interfacial adhesion with Li metal. Benefiting from this coupled framework-interphase regulation, Li | LAPSCF-Cl | Li symmetric cells cycle for over 8000 h at 0.5 mA cm[-2] at 3 MPa and support stable cycling of both NCM811 and sulfur cathodes paired with Li metal under a relatively low pressure of 30 MPa.}, } @article {pmid42841866, year = {2026}, author = {Anjum, A and Manai, AL and Noli, B and Borghero, G and Mascia, MM and Meloni, M and Kais, H and Figorilli, M and Puligheddu, M and Cocco, C}, title = {N-terminal proVGF modifications related to Amyotrophic Lateral Sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2742817}, pmid = {42841866}, issn = {2167-9223}, abstract = {Objective: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor dysfunction, for which effective therapies and early diagnostic biomarkers remain limited. This study comprehensively investigated ALS-associated alterations in the N-terminal region of the proVGF precursor protein, evaluating their potential as novel diagnostic and prognostic biomarkers and exploring their precise correlations with clinical severity and plasma neurofilament light chain (NfL), an established indicator of neuroaxonal injury. Methods: N-terminal proVGF levels were quantified using a custom immunoassay using human plasma and lymphocytes as well as motor neuron-like NSC-34 cells subjected to oxidative stress. The clinical cohort comprised 49 ALS patients (28 early-stage, 21 advanced-stage) and 50 age-matched healthy controls. To assess disease specificity, plasma from patients with Parkinson's disease (PD, n = 50), idiopathic dystonia (n = 15), and idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD, n = 21) was analyzed alongside respective age-matched healthy controls (n = 26, 8, and 20). Furthermore, plasma NfL levels were measured and directly correlated with N-terminal proVGF concentrations. Results: N-terminal proVGF levels were significantly increased in both plasma and lymphocytes during the early and advanced stages of ALS. Plasma NfL levels were concomitantly elevated across all ALS patients. In advanced-stage patients, N-terminal proVGF concentrations significantly correlated with both ALSFRS-R scores and NfL levels. No significant N-terminal proVGF alterations were observed in PD, iRBD, or dystonia cohorts. Oxidative stress similarly upregulated N-terminal proVGF levels in vitro within NSC-34 cells. Conclusion: Alterations of the N-terminal region of proVGF are specific to ALS, highlighting their dual value as diagnostic and prognostic biomarkers.}, } @article {pmid42842169, year = {2026}, author = {Singh, RK and Banerjee, C and Mehan, S}, title = {Beyond Histamine Blockade: Clemastine Fumarate as a Promoter of Myelin Regeneration, Inflammatory Regulation, and Neuroimmune Modulation in CNS Disorders.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {21}, number = {1}, pages = {}, pmid = {42842169}, issn = {1557-1904}, mesh = {Animals ; Humans ; *Clemastine/pharmacology/therapeutic use ; *Central Nervous System Diseases/drug therapy/immunology/metabolism ; *Myelin Sheath/drug effects ; *Neuroimmunomodulation/drug effects/physiology ; *Remyelination/drug effects/physiology ; Neuroinflammatory Diseases/drug therapy/immunology ; *Histamine H1 Antagonists/pharmacology/therapeutic use ; }, abstract = {Clemastine fumarate, a first-generation H1 antihistamine, has emerged as a promising candidate for drug repurposing in neurodegenerative and neuropsychiatric disorders owing to its ability to cross the blood-brain barrier and interact with multiple central nervous system targets. Experimental studies indicate that clemastine promotes remyelination by stimulating the differentiation of oligodendrocyte precursor cells into mature, myelin-producing oligodendrocytes, thereby restoring myelin integrity and improving axonal function in experimental models. In addition to its remyelinating properties, preclinical evidence suggests that clemastine may attenuate neuroinflammation by modulating microglial activation and suppressing pro-inflammatory signalling pathways. These effects have been associated with improved structural and functional outcomes in experimental models of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, and several neuropsychiatric disorders. Mechanistically, clemastine primarily acts through muscarinic M1 receptor antagonism to promotes remyelination, while additional pathways including PI3K/Akt, ERK1/2, autophagy-related signalling, inflammasome modulation, and sigma-1 receptor signalling have been proposed based on experimental evidence but remain incompletely understood and require further mechanistic validation. Among the neurological disorders investigated multiple sclerosis currently has the strongest clinical evidence with early clinical trials demonstrating modest remyelinating activity. In contrast, evidence supporting the use of clemastine in other neurological disorders remains largely confined to preclinical studies. Several translational challenges also remain unresolved including dose optimisation, treatment timing, long-term safety, sedative and anticholinergic adverse effects, and patient selection. Future research should focus on refining pharmacokinetic properties, optimising dosing strategies, evaluating rational combination therapies, and identifying predictive biomarkers to facilitate clinical translation. Although current evidence highlights the therapeutic potential of clemastine fumarate, its application beyond multiple sclerosis remains investigational and will require rigorous mechanistic studies together with well-designed clinical trials before broader clinical use can be established.}, } @article {pmid42842441, year = {2026}, author = {Chen, H and Qin, M and Zhu, R and Zhang, X and Lou, W}, title = {Large Language Models for Selecting Intraocular Lens Power Calculation Formulas: A Comparative Study.}, journal = {Journal of refractive surgery (Thorofare, N.J. : 1995)}, volume = {42}, number = {10}, pages = {e458-e467}, doi = {10.3928/1081597X-20260806-01}, pmid = {42842441}, issn = {1938-2391}, mesh = {Humans ; *Lenses, Intraocular ; *Large Language Models ; *Biometry/methods ; *Refraction, Ocular/physiology ; *Optics and Photonics ; Female ; Male ; Aged ; Lens Implantation, Intraocular ; Middle Aged ; Visual Acuity/physiology ; }, abstract = {PURPOSE: To evaluate refractive outcomes of large language model (LLM)-based selection of the optimal intraocular lens power calculator according to individual biometric parameters.

METHODS: Two hundred eight eyes undergoing routine cataract surgery were included. Ten leading LLMs (Gemini, Chat-GPT, Perplexity, Grok, DeepSeek, Kimi, Qwen, Doubao, ERNIE, and Hunyuan) were prompted to recommend "the single most appropriate formula" from Barrett Universal II (BUII), Cooke K6, EVO 2.0, Hill-RBF 3.0, Kane, and PEARL-DGS, based on axial length (AL), keratometry, anterior chamber depth, and lens thickness. Gemini was excluded because it consistently selected Kane. Precision (SD) and accuracy (absolute spherical equivalent prediction error [SEQ-PE]) were assessed with the Eyetemis Analysis Tool and compared with BUII and SRK/T, both overall and within AL subgroups.

RESULTS: Formula preferences varied markedly among LLMs. Overall, all LLMs and BUII demonstrated significantly greater precision than SRK/T, with Hunyuan, ChatGPT, and BUII showing highest precision and significantly improved accuracy compared to SRK/T (all P < .05). The leading percentages of eyes within the ±0.50 diopter (D) threshold were achieved by Perplexity (82.69%), ChatGPT (82.21%), Qwen (82.21%), and BUII (81.73%). Across AL subgroups, at least one LLM numerically outperformed BUII in both precision and accuracy; at the ±0.50 D threshold, certain models increased this percentage over BUII by approximately 3% when AL was ≤ 22 mm or ≥ 26 mm, and by 8% when 24.5 mm ≤ AL < 26 mm.

CONCLUSIONS: Compared with BUII, current LLMs exhibit limited capacity to improve refractive outcomes by selecting the optimal formulas for routine practice; however, certain LLMs show promise as adjunctive tools for personalized selection tailored to specific ALs.}, } @article {pmid42843091, year = {2026}, author = {Venkatesan, A and Sinha, P and Basak, J and Bahadur, RP}, title = {Gene regulatory co-expression networks decipher potential lncRNA-miRNA-mRNA interactions modulating transcription regulation in neurodegeneration.}, journal = {Computational biology and chemistry}, volume = {126}, number = {Pt 2}, pages = {109462}, doi = {10.1016/j.compbiolchem.2026.109462}, pmid = {42843091}, issn = {1476-928X}, abstract = {Neurodegenerative diseases are complex disorders characterised by progressive neuronal loss and widespread transcriptomic dysregulation. However, understanding the molecular interactions among coding and non-coding RNAs, especially lncRNAs and miRNAs, contributing to disease progression remains elusive. In this study, RNA-Seq datasets from disease-relevant neuronal populations and different brain tissues representing Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are analysed using an integrative network-based framework. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) are combined to identify disease-associated modules and prioritise highly connected hub genes. They are subsequently integrated with curated RNA interaction databases to construct candidate lncRNA-miRNA-mRNA regulatory networks. Functional enrichment and UTR variant analyses are further incorporated to connect the regulatory network framework with biological processes and potential sequence variations. The novelty of the present study lies in the systematic integration of transcriptomic co-expression, post-transcriptional regulation, functional and sequence-level analyses within a single framework. This framework enables the identification of disease-specific and shared regulatory features, and links the candidate regulatory interactions with potential UTR sequence alterations. Across eight tissue-specific samples, 163 hub genes and 4869 candidate lncRNA-miRNA-mRNA interactions are identified. Additionally, we also identify 414 UTR variants associated with the hub genes. Pathways associated with hub genes including axonogenesis, synaptic organization, intracellular transport and RNA regulatory mechanisms are commonly found to be enriched in AD, PD and ALS. These findings provide a quantitative resource for prioritising regulatory interactions between candidate hub genes and associated UTR variants for future experimental validation.}, } @article {pmid42833594, year = {2026}, author = {Dahlhaus, R and Yalcin, I and Tischer, J and Braun, RJ}, title = {TDP-43 and ALS - what's wrong with my membranes?.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107630}, doi = {10.1016/j.nbd.2026.107630}, pmid = {42833594}, issn = {1095-953X}, abstract = {In recent years, multiple pathologies of the mRNA binding protein TDP-43 have been linked to the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS), in which almost 97% of all ALS patients exhibit TDP-43 abnormalities in affected neurons. Typically, neuronal degeneration first affects alpha motor neurons of the spinal cord and the lower brainstem, before the disease progresses to Betz cells, giant neurons of the primary motor cortex, and subsequently spreads into further brain regions. It is just the Betz cells though, which do not show cytosolic TDP-43 aggregation upon loss of nuclear TDP-43 expression, but instead display membrane defects in organelles such as the Golgi apparatus, the ER and the nuclear envelope. In this review, we will therefore examine connections between TDP-43 and inner membrane systems, with a particular focus on nuclear and the ER membranes. In doing so, we will summarize evidence suggesting that the disease may have an early onset, potentially even prenatally, and describe how interactions between TDP-43 and the lipid metabolism as well as connections with membrane components, may drive cells towards ALS as time goes by.}, } @article {pmid42834122, year = {2026}, author = {Sakai, S and Oiwa, K and Iguchi, Y and Akcay, IM and Watanabe, S and Komine, O and Nagata, N and Horiuchi, M and Sreedharan, J and Katsuno, M and Yamanaka, K}, title = {TBK1 eliminates aggregation-prone monomeric TDP-43 through an IFNβ-immunoproteasome pathway in ALS models.}, journal = {EMBO reports}, volume = {}, number = {}, pages = {}, pmid = {42834122}, issn = {1469-3178}, support = {JP22J23468//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP25K23745//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP18H02740//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP19KK0214//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP22H00467//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP22ek0109426//Japan Agency for Medical Research and Development (AMED)/ ; JP24wm0425014//Japan Agency for Medical Research and Development (AMED)/ ; JP26wm0625301//Japan Agency for Medical Research and Development (AMED)/ ; n/a//THE YUKIHIKO MIYATA MEMORIAL TRUST FOR ALS RESEARCH/ ; n/a//IKEDA RIKA Grant/ ; 221824/Z/20/Z//Wellcome Trust (WT)/ ; Sreedharan/Apr24/2362-791//Motor Neurone Disease Association (MNDA)/ ; }, abstract = {Loss-of-function mutations in TANK-binding kinase 1 (TBK1) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), characterized by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43), known as TDP-43 pathology, but the mechanisms beyond impaired autophagy remain undefined. Here, we identify a TBK1-IFNβ-immunoproteasome axis as a novel autophagy-independent proteostatic pathway regulating TDP-43 clearance. TBK1 is activated by aggregation-prone monomeric TDP-43 via physical association, and this activation alleviates TDP-43 pathology in neuronal cells. TBK1 subsequently induces IFNβ expression, which upregulates the immunoproteasome to promote degradation of monomeric TDP-43 in neurons, including human iPSC-derived lower motor neurons. Importantly, IFNβ receptor expression is downregulated in spinal motor neurons from ALS patients with TDP-43 pathology. Furthermore, heterozygous Tbk1 deletion in SOD1[G93A] mice impairs immunoproteasome induction and increases polyubiquitinated protein accumulation in spinal cords, supporting the in vivo relevance of this pathway. Collectively, our findings reveal that impairment of the TBK1-IFNβ-immunoproteasome axis represents an autophagy-independent mechanism contributing to the development of TDP-43 pathology in ALS and FTD.}, } @article {pmid42834925, year = {2026}, author = {Piras, R and Bordini, S and Simi, RK and Consolo, I and Esposito, V and Cavaggion, C and Feder, M and Fossati, M and Grioli, G and Bicchi, A and Lunetta, C and Catalano, MG}, title = {Bridging stakeholder needs and technological capabilities to identify humanoid robot applications in rehabilitation: a case study in an ALS multidisciplinary care unit.}, journal = {Frontiers in robotics and AI}, volume = {13}, number = {}, pages = {1944029}, pmid = {42834925}, issn = {2296-9144}, abstract = {The integration of assistive service robots in healthcare has gained increasing attention for its potential to support clinical workflow and patient wellbeing. However, structured methodological approaches to identify clinically relevant applications for versatile robotic platforms before clinical implementation are still lacking. Moreover, the deployment of robots in these settings is often restricted to hyper-specialized tasks. To address these challenges, this study describes a stakeholder-driven process adopting a multidisciplinary co-design approach to adapt the Alter-Ego semi-anthropomorphic robot to the needs of a multidisciplinary neurorehabilitation unit for patients with Amyotrophic Lateral Sclerosis. We combined brainstorming, focus groups with healthcare professionals, patients and caregivers, and contextual observations to identify the real unmet needs and potential applications. The engineering team assessed the technological requirements and implementation readiness of each application. The clinical and engineering teams jointly reviewed the proposal, considering clinical, ethical, and infrastructural implications. This consensus-based process resulted in 12 use cases selected for the clinical protocol corresponding to 40 planned experimental sessions including autonomous or semi-autonomous tasks, as well as teleoperated activities for assistive and rehabilitation purposes. Furthermore, an exploratory pilot evaluated a subset of selected use cases, providing feedback to refine the platform and experimental protocol. Standardized assessments provided descriptive information on perceived workload, usability, and satisfaction. Participants generally reported a positive experience and manageable workload, while task-specific feedback identified aspects requiring further refinements. Overall, this experience offers preliminary insights into how clinical needs and technological capabilities can be jointly explored, providing a basis for subsequent clinical experimentation.}, } @article {pmid42835448, year = {2026}, author = {Zhu, R and Li, H}, title = {Global research architecture of RNA-binding proteins in neurodegenerative diseases: a web of science bibliometric study with PubMed record verification, 2001-2025.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1967205}, pmid = {42835448}, issn = {1663-4365}, abstract = {BACKGROUND: RNA-binding proteins (RBPs) connect RNA homeostasis to proteostasis and selective neuronal vulnerability, but the organization and evolution of this cross-disease research field remain unclear.

METHODS: We analyzed Web of Science Core Collection (WoSCC) records published through 2025. PubMed was used only to verify records by normalized DOI or exact normalized title; PubMed metadata were not pooled with WoS data, and all bibliometric analyses used WoS fields. Publication growth, contributors, collaboration, co-citation, bibliographic coupling, and conceptual evolution were examined using bibliometrix, VOSviewer, and CiteSpace-compatible workflows. A prespecified 43-concept dictionary preserved multiword biological entities in title/abstract networks. The study characterizes a query-defined and PubMed-verified literature corpus rather than estimating the relative biological importance of individual RBPs.

RESULTS: Of 2,454 records reported by the WoS search interface, 2,450 were available in the supplied exports and 2,309 met the year criterion. PubMed record verification retained 2,160 records (93.55%) in the analysis corpus; 149 records (6.45%) were not matched. Output increased from one publication in 2001 to 213 in 2025. Within this query-defined corpus, the mapped literature was concentrated around TDP-43 pathology, TARDBP/FUS genetics, and loss of RNA-processing function. The controlled concept network resolved three macro-communities, while recent temporal signals involved LATE, cryptic exons, and RNA transport. These findings describe the retrieved and verified corpus and are not presented as a search-independent ranking of the broader RBP field.

CONCLUSION: The maps document a WoS-derived and PubMed-verified literature corpus concentrated on TDP-43 and ALS/FTD and increasingly connected with cryptic RNA processing, condensate biology, nuclear transport, neuroimmune responses, and aging-related mixed proteinopathies. Because the corpus was conditioned by a title-level query containing named RBPs and by PubMed record verification, these patterns should not be interpreted as an unbiased ranking of RBP biology or as evidence of shared causality across diseases. Cross-disease translation should proceed through neuropathologically defined, age-stratified, and cell-type-resolved human cohorts, followed by causal perturbation and rescue in human disease models and multicenter longitudinal validation.}, } @article {pmid42836993, year = {2026}, author = {Al Khleifat, A and Malaspina, A and Kirby, J and Tree, T and Shaw, PJ and Leigh, PN and Al-Chalabi, A}, title = {TRICALS risk score augments but cannot replace neurofilament as a prognostic biomarker in ALS.}, journal = {Journal of neurology}, volume = {273}, number = {10}, pages = {}, pmid = {42836993}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/drug therapy/diagnosis ; *Neurofilament Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Prognosis ; Female ; Male ; Middle Aged ; Aged ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with substantial clinical heterogeneity, complicating the design and interpretation of clinical trials. Two strategies have been proposed to address this variability: phenotype-based prognostic modelling and biomarker-based stratification using neurofilaments. We aimed to determine whether a widely used phenotype-based method, the TRICALS risk score, could substitute for neurofilament biomarkers in a clinical trial.

METHODS: We used data from the MIROCALS phase 2b randomised controlled trial of low-dose interleukin-2 in ALS (n = 220). The TRICALS risk score was calculated for each participant. The published biomarker model includes CSF phosphorylated neurofilament heavy chain (pNFH) and a pNFH × treatment interaction. We analysed the effects of replacing CSF pNFH with the TRICALS risk score and of adding TRICALS score as an additional covariate to the original model. Model performance was assessed using likelihood ratio χ[2] statistics and - 2 log likelihood (- 2LL). The primary outcome was survival.

RESULTS: TRICALS risk score was moderately correlated with CSF pNFH (r = 0.357), explaining 12.7% of shared variance. Substituting CSF pNFH with TRICALS score reduced model performance (- 2LL 928.25 vs 793.36). The TRICALS × treatment interaction was statistically significant (hazard ratio [HR] 0.72, 95% CI 0.54-0.96 p = 0.025), but contributed modestly to model fit (Δχ[2] = 4.76), compared with the pNFH × treatment interaction (Δχ[2] = 14.24). Incorporating the pNFH × treatment interaction significantly improved model fit and identified a treatment effect (HR 0.28, 95% CI 0.12-0.63; p = 0.002).

CONCLUSIONS: The TRICALS risk score does not substitute for CSF neurofilament biomarkers as a prognostic or stratification variable but provides complementary information.}, } @article {pmid42837018, year = {2026}, author = {de Azevedo, EM and Bernardo, VS and Lima, MMS and Eleutherio, ECA and Outeiro, TF}, title = {SOD1 co-pathologies in the brain: insights from neuropathological evidence and implications.}, journal = {Acta neuropathologica}, volume = {152}, number = {1}, pages = {}, pmid = {42837018}, issn = {1432-0533}, support = {001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 88887.169657/2025-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 88881.986154/2024-01//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 300367/2026-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 210.034/2026//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; }, mesh = {Humans ; *Superoxide Dismutase-1/metabolism ; *Brain/pathology/metabolism ; *Neurodegenerative Diseases/pathology/metabolism ; Animals ; Amyotrophic Lateral Sclerosis/pathology ; }, abstract = {Superoxide dismutase 1 (SOD1), originally regarded as an antioxidant enzyme, is now recognized as a multifunctional protein whose conformational instability and aggregation contribute to neurodegeneration. The emerging evidence suggests that SOD1 pathology extends beyond amyotrophic lateral sclerosis, supporting a role in multiple neurodegenerative diseases. This review summarizes current neuropathological evidence of SOD1 co-pathologies in the human brain, with particular emphasis on its associations with TAR DNA-binding protein 43 (TDP-43), tau, alpha-synuclein, amyloid-β, and other aggregation-prone proteins. We examine the distribution of pathological SOD1 species across neurodegenerative diseases, their coexistence in affected brain regions, and potential mechanisms underlying these interactions, including oxidative stress, impaired proteostasis, aberrant phase separation, and cross-seeding. We also discuss emerging observations of SOD1 pathology in neurological conditions beyond classical neurodegenerative diseases, raising the possibility that SOD1 misfolding represents a broader cellular response to neuronal injury. Collectively, the available evidence supports a shift from viewing SOD1 as a disease-specific protein to considering it a potential participant in interconnected proteopathic networks. Although the functional significance of SOD1 co-pathologies remains incompletely understood, elucidating the molecular basis of aggregation may provide new insights into disease onset and progression, improving our understanding of neurodegenerative mechanisms, and facilitating the development of biomarkers and the identification of therapeutic targets across diverse proteinopathies.}, } @article {pmid42829893, year = {2026}, author = {Lv, C and Zhu, W and Wen, X and Wang, Y and Xie, N and Liu, H and Jiang, Y and Zou, W and Liu, Q and Gou, J and Yu, X and Di, L and Lu, Y and Wang, M and Xu, M and Chen, H and Duo, J and Huang, Y and Da, Y}, title = {Cerebrospinal fluid inflammatory proteomic profiling identifies biomarkers linked to disease progression in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {10}, pages = {}, pmid = {42829893}, issn = {1432-1459}, support = {82571595//National Natural Science Foundation of China/ ; ZDYN-2024-A-081//General Office of the National Administration of Traditional Chinese Medicine, the General Office of the National Health Commission, the Health Bureau of the Logistics Support Department of the Central Military Commission/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid ; Female ; *Disease Progression ; Male ; Biomarkers/cerebrospinal fluid ; Proteomics ; Middle Aged ; Aged ; Inflammation/cerebrospinal fluid ; Adult ; *Neuroinflammatory Diseases/cerebrospinal fluid ; }, abstract = {BACKGROUND: Neuroinflammation is a key component of amyotrophic lateral sclerosis (ALS), but its association with disease progression heterogeneity remains unclear. We aimed to identify CSF inflammation-related proteins associated with disease progression phenotype in patients with ALS.

METHODS: Patients with ALS were stratified into slow progressors (SP) and fast progressors (FP) according to the disease progression rate. CSF inflammatory proteins were measured using the Olink Target 96 Inflammation panel. Disease-associated biomarkers were identified using limma package and elastic net (EN) analysis. We assessed the discriminatory power of disease-associated biomarkers using receiver operating characteristic curve analysis and estimated the optimism-adjusted area under the curve (AUC) using the bootstrapping method.

RESULTS: Among 77 patients (SP: n=40; FP: n=37), limma analysis identified 11 differentially expressed proteins, with functional enrichment in chemokine signaling, TNF-related responses and NF-κB pathways. EN analysis identified 12 candidate proteins, among which CST5, CCL11, SIRT2, CD6, CCL4, MMP-1, TNFRSF9, CCL19, and MCP-4 showed positive associations with the SP phenotype. A model combining SIRT2, MMP-1, BMI, and site of onset yielded an apparent area under the curve of 0.769 (95% CI 0.662 to 0.876) and an optimism-corrected area under the curve of 0.729.

CONCLUSION: Our study uncovered a CSF inflammatory proteomic signature associated with slow disease progression in ALS. These findings indicate that specific CSF neuroinflammatory protein signatures reflect biological heterogeneity in ALS disease progression rather than non-specific neurodegeneration. SIRT2 and MMP-1 warrant further investigation as components of progression-stratification models, although validation in larger, longitudinal, and independent cohorts is required.}, } @article {pmid42831014, year = {2026}, author = {Dorça, AC and Morais, LA}, title = {A Novel Device for Pulmonary Expansion Under Simulated Healthy and Neuromuscular Conditions: A Bench Simulation Study.}, journal = {Medical devices (Auckland, N.Z.)}, volume = {19}, number = {}, pages = {626538}, pmid = {42831014}, issn = {1179-1470}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) leads to a progressive decline in respiratory function, requiring volumetric expansion techniques to prevent hypoventilation. However, the mechanical performance of devices used for this purpose requires evaluation under controlled conditions in bench simulation studies. Devices, such as the manual resuscitator, are commonly used, but present limitations, including high pressures, variable flow, among others. A novel respiratory muscle training device designed to provide controlled flow and pressure (ILLIFE-T) was developed.

OBJECTIVE: To evaluate the behavior of the variables pressure, volume, and flow during the volumetric expansion technique, comparing the new device with the manual resuscitator and the manual resuscitator + Positive Expiratory Pressure (PEP), using simulated models of healthy and ALS affected lungs.

METHODS: This bench simulation study used the ASL 5000 simulator, configured with predefined respiratory profiles representing healthy and ALS respiratory conditions. Four repetitions of the volumetric expansion maneuver were performed for each device and simulated respiratory condition, with five insufflations per repetition. One recording was randomly selected from each repetition for analysis, resulting in four observations per device and simulated respiratory condition.

RESULTS: In the simulation with healthy respiratory conditions, the new device generated higher pressure (23.38±3.81 cmH2O), volume (1991.25 ±174.10 mL), and lower flow variability (-1.47±11.43 L/min) compared with the manual resuscitator (12.25±11.73 cmH2O; 1113.64±131.75 mL; 18.84±61.31 L/min) and the manual resuscitator with PEP valve (16.89±0.64 cmH2O; 1817.25±86.77 mL; -49.49±9.96 L/min), respectively. In ALS simulated models, the new device also achieved higher pressure (23.69±3.29 cmH2O) and volume (2235.28±264.74 mL) compared with the manual resuscitator (8.33±8.34 cmH2O; 563.45±212.03 mL, respectively) and the manual resuscitator with PEP valve (14.89±7.60 cmH2O; 1449.86±153.09 mL, respectively). Flow values were similar among devices: 15.10 ± 18.00 L/min for the new device, 19.28±56.03 L/min for the manual resuscitator, and 0.18±51.67 L/min for the manual resuscitator with PEP valve.

CONCLUSION: Pressure and volume were higher with the new device in both simulated models. Flow did not differ significantly among devices, although lower variability was descriptively observed with the new device.}, } @article {pmid42831057, year = {2026}, author = {Lehrer, S}, title = {Transient Activation of Developmental Cytoskeletal Remodeling Programs After Traumatic Brain Injury: A Multiple-Reactivation Model of Neurodegeneration.}, journal = {Cureus}, volume = {18}, number = {9}, pages = {e115789}, pmid = {42831057}, issn = {2168-8184}, abstract = {Background Traumatic brain injury (TBI) may transiently reactivate developmental cytoskeletal programs required for neural remodeling and repair. We hypothesized that, unlike the persistent embryonic pathway reactivation proposed in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), TBI produces transient reactivation followed by suppression during recovery. Methods Human transcriptomic datasets were analyzed to characterize Arp2/3-mediated cytoskeletal remodeling after TBI. Single-nucleus RNA sequencing was used to assess cell-type-specific expression, and longitudinal peripheral blood transcriptomic data were analyzed at day 1 (D1), day 7 (D7), and 6 months (M6). Arp2/3 pathway scores were evaluated using differential-expression, mixed-effects, and within-subject analyses. Results Acute TBI showed directionally increased neuronal Arp2/3 expression. Longitudinal analysis demonstrated strong temporal variation in Arp2/3 activity (p = 2.77×10[-7] in complete cases). Relative to D1, pathway activity declined at D7 (estimate -0.753, p = 0.0001) and M6 (-1.009, p < 0.0001). All 12 subjects with complete longitudinal measurements had lower M6 than D1 scores. Conclusions Acute human TBI brain tissue showed activation of Arp2/3-mediated cytoskeletal remodeling, while an independent longitudinal peripheral-blood cohort showed rapid attenuation and longer-term suppression of Arp2/3 pathway activity after injury. Together, these findings are consistent with, but do not establish, a transient reactivation-resolution model.}, } @article {pmid42831407, year = {2026}, author = {Frycz, S and WiĘcławski, W and Skotniczny, M and Binder, M}, title = {Assessing consciousness in end-stage ALS: response to young's commentary.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-2}, doi = {10.1080/21678421.2026.2739760}, pmid = {42831407}, issn = {2167-9223}, } @article {pmid42831851, year = {2026}, author = {Morozova, V and Hassieb, M and Ahmed, Z}, title = {Multisite Anodal Direct Current Stimulation Preserves Motor Function and Modulates Key Cellular Pathways in TDP-43 and SOD1 Mouse Models of Amyotrophic Lateral Sclerosis.}, journal = {Neuromodulation : journal of the International Neuromodulation Society}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurom.2026.08.007}, pmid = {42831851}, issn = {1525-1403}, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by degeneration of upper and lower motor neurons and disruption of normal motor network excitability. This study aimed to determine whether multi-site direct current stimulation (DCS) can modulate spinal motor circuit excitability in an experimental model of ALS and to evaluate its potential as a neuromodulation approach for preserving motor pathway function.

MATERIALS AND METHODS: In an initial electrophysiological experiment, corticospinal-evoked muscle contractions were recorded using a force-displacement transducer to compare the effects of different multisite spinal electrode configurations on corticospinal output. Subsequently, two ALS mouse models, SOD1-G93A and TDP-43 A315T, underwent repeated in vivo multisite anodal DCS. Motor function was assessed using grid walking, hindlimb grip strength, and wire-hang tests across five time points. In the TDP-43 A315T model, motor neuron soma size was quantified using choline acetyltransferase immunostaining, whereas heat shock protein 70 (HSP70) expression and TDP-43/phosphorylated TDP-43 (p-TDP-43) aggregation were evaluated using western blotting and confocal imaging.

RESULTS: Multisite DCS produced the strongest suppression of corticospinal-evoked muscle contractions among all electrode configurations tested, indicating robust modulation of spinal excitability. In SOD1-G93A mice, repeated stimulation preserved motor performance across all behavioral assays, with the clearest differences emerging during later disease stages relative to unstimulated controls. In TDP-43 A315T mice, stimulation was associated with improved motor performance at the final testing point, preservation of motor neuron soma size, increased HSP70 expression, and significant reductions in both the number and size of cytoplasmic TDP-43 and pathological p-TDP-43 aggregates, consistent with enhanced proteostatic capacity and pathological protein clearance.

CONCLUSIONS: Multisite anodal DCS effectively modulates spinal excitability and preserves motor function in two mechanistically distinct mouse models of ALS. In the TDP-43 A315T model, these functional benefits are accompanied by preservation of motor neuron structure and molecular changes consistent with improved protein homeostasis. Together, these findings support multisite DCS as a promising neuromodulatory strategy for influencing disease-relevant mechanisms and slowing functional decline in ALS.}, } @article {pmid42831972, year = {2026}, author = {Rosenbohm, A and Herrera-Angeles, F and Huppertz, HJ and Haeusler, KG and Weishaupt, JH and Müller, HP and Kassubek, J}, title = {Neuroimaging signatures of facial onset sensory and motor neuronopathy (FOSMN).}, journal = {Journal of neurology}, volume = {273}, number = {10}, pages = {}, pmid = {42831972}, issn = {1432-1459}, mesh = {Humans ; Female ; Male ; Diffusion Tensor Imaging ; *Brain/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Middle Aged ; *Neuroimaging ; *Facial Nerve Diseases/diagnostic imaging/pathology ; Atrophy ; Adult ; Image Processing, Computer-Assisted ; Aged ; *Motor Neuron Disease ; }, abstract = {Facial onset sensory and motor neuronopathy (FOSMN) is an exceptionally rare condition characterized by progressive facial paresthesia and the subsequent appearance of bulbar symptoms with rostro-caudal motor and sensory deficits sometimes extending to the hand muscles. The pathophysiological understanding of this disorder is very limited. In order to identify patterns of neuroanatomical involvement within the brain, we applied advanced magnetic resonance imaging-based techniques to a group of six patients with the diagnosis of FOSMN, using unbiased analysis techniques with atlas-based volumetry of volume-rendering T1-weighted data and whole brain-based spatial statistics of diffusion tensor imaging (DTI). The volumetric data showed significant global atrophy with prominent involvement of the medulla oblongata, while DTI demonstrated significant decreases in the right-hemispheric frontal lobe and bilaterally along the superior and inferior longitudinal fasciculi. In summary, this application of volumetry and DTI to a group of FOSMN patients demonstrated, beyond global brain atrophy as a correlate of a systemic disease process, regional atrophy in the brainstem/medulla oblongata, together with tract alterations of polymodal frontotemporoparietal interconnections. Future neuroimaging studies in larger patient groups of FOSMN are needed for detailed phenotype-neuroimaging correlations.}, } @article {pmid42832558, year = {2026}, author = {Sui, Y and Zheng, DQ and Wang, Y and Zhao, SS and Li, KJ and Ye, C and Zhang, K}, title = {Decoupling metabolic defense: Mutational and recombinational chaos in Sod1-deficient cells.}, journal = {PLoS genetics}, volume = {22}, number = {10}, pages = {e1012326}, doi = {10.1371/journal.pgen.1012326}, pmid = {42832558}, issn = {1553-7404}, abstract = {Superoxide dismutase 1 (Sod1) is long recognized as a frontline antioxidant, yet its broader role in safeguarding the eukaryotic genome remains under-explored. Here, using a yeast model, we reveal that Sod1 is an indispensable guardian of genomic integrity. Its absence unleashes a genomic storm: whole-genome sequencing uncovered a dramatic surge in single nucleotide variations (13-fold), loss of heterozygosity (12-fold), chromosomal rearrangements (4-fold), and a staggering 48-fold increase in aneuploidy. Remarkably, this genomic instability was completely abolished under anaerobic conditions, identifying reactive oxygen species as the sole executioner. We demonstrate that Sod1 deficiency sculpts a unique mutational landscape dominated by C:G to A:T transversions-a molecular fingerprint of 8-oxoguanine overproduction. Mechanistically, these lesions are exacerbated by error-prone DNA polymerase ζ but mitigated by the concerted actions of Ogg1-mediated excision and DNA polymerase η. Critically, we show that Amyotrophic Lateral Sclerosis-associated variants are not created equal: the H48Q mutation shatters genome stability, whereas others (A4V, G36R, and G93A) remain benign in this context. Unlike yeast Sod1, human Sod1 is highly resistant to amino acid substitutions outside copper-binding sites, thus preventing the loss of enzyme function. Overall, our findings provide a mechanistically framework for understanding how Sod1 dysfunction drives genome instability in eukaryotic cells.}, } @article {pmid42832702, year = {2026}, author = {Batisse, E and Lloyd, M and Renoux, C and Ganji, A and Xu, J and Hatzopoulou, M and Weichenthal, S and Baumgartner, J}, title = {Long-term exposure to ultrafine particles and mortality from neurodegenerative diseases: a population-based cohort study.}, journal = {Epidemiology (Cambridge, Mass.)}, volume = {}, number = {}, pages = {}, doi = {10.1097/EDE.0000000000002054}, pmid = {42832702}, issn = {1531-5487}, abstract = {BACKGROUND: Transportation and industrial activities emit large quantities of air pollutants, including unregulated ultrafine particles (UFP, <0.1 um), which may adversely affect brain health.

METHODS: We analyzed data from 2.1 million adults in the Canadian Census Health and Environment Cohorts (CanCHECs) living in Montreal and Toronto (2001-2019). Vital status and primary cause of death were obtained from the Canadian Vital Statistics- Death database. We assigned high-resolution estimates of UFP number concentrations and UFP size to participants' residential postal codes using three-year moving averages. Cox proportional hazards models were used to estimates hazard ratios (HRs) between long-term outdoor UFP number concentrations and mortality from dementia, Parkinson's disease, and amyotrophic lateral sclerosis. We further examined associations by dementia sub-types including Alzheimer's disease, vascular dementia and unspecified dementia. Models were used with and without inverse probability of censoring weights for competing events, and adjusted for UFP size, sociodemographic factors, and co-pollutants.

FINDINGS: Over 19 million person-years, we identified 20,560 deaths from neurodegenerative diseases. Each 10,000 particle/cm 3 increase in UFP number concentrations was associated with increased dementia mortality (HR = 1.22, 95% CI: 1.17-1.27), with stronger associations observed after adjusting for UFP size. Positive associations were observed for all dementia subtypes, with the largest for vascular dementia (HR = 1.49, 95% CI: 1.27-1.76). We did not observe effects of UFP on mortality from Parkinson's disease or amyotrophic lateral sclerosis.

INTERPRETATION: Long-term exposure to outdoor UFPs may contribute to mortality from specific neurodegenerative diseases, particularly dementia. Reducing population exposures to these unregulated pollutants could help mitigate the burden of neurodegenerative mortality.}, } @article {pmid42833128, year = {2026}, author = {Basanth, S}, title = {Enzymatic N-deacylation is the predicted membrane-disruption switch for sphingomyelin: a falsifiable in-silico framework for sphingolipid vulnerability in ALS.}, journal = {Journal of molecular graphics & modelling}, volume = {149}, number = {}, pages = {109570}, doi = {10.1016/j.jmgm.2026.109570}, pmid = {42833128}, issn = {1873-4243}, abstract = {Sphingolipid dysregulation is an emerging feature of amyotrophic lateral sclerosis (ALS), but no systematic method separates species that may worsen axon-myelin membrane integrity from matter that may counteract it. We present an in-silico framework classifying sphingolipids and designed derivatives as candidate membrane-disruptive or candidate protective species, scored against real biological referents using externally published tools rather than a bespoke composite. Its central finding concerns a single, chemically defined difference in lipid state. In coarse-grained (MARTINI 3) molecular dynamics with three independent replicates per system, intact palmitoyl-sphingomyelin is indistinguishable from a pure-POPC bilayer (leaflet-mean Δ thickness + 0.001 nm, 95% CI brackets zero), whereas the modeled N-deacylated form thins it in every replicate (Δ=-0.043 nm, [- 0.046, - 0.041]), tracking a lyso-phosphatidylcholine detergent control (-0.083 nm, [- 0.087, - 0.080]) on two concordant estimators. Because only one lyso-sphingolipid is parameterized in public MARTINI 3, N-deacylation is not established here as a class-wide effect. Across eleven ALS studies (2021-2026), six report elevated serine-palmitoyltransferase (SPT) pathway sphingolipids, all in monogenic SPTLC1/SPTLC2 cohorts, whereas sporadic cohorts show disturbance without a shared direction. Because the simulations do not address whether this species is produced, accumulates, or reaches pathological concentrations in ALS tissue, we present the ALS connection as hypothesis-generating rather than direct evidence. Separately, an explicitly exploratory arm reports two designed modulators with predicted target engagement (Boltz-2) and an ADMET triage of their liabilities. The primary contribution is the membrane result with a wet-lab panel that makes it falsifiable.}, } @article {pmid42833496, year = {2026}, author = {Navarrete-Dechent, C and Pietkiewicz, P and Voloshynovych, M and Anriot, J and Marghoob, AA}, title = {Authors' response to Michelerio and Farnetani "Response to Navarrete-Dechent et al's 'Ultraviolet-induced fluorescent dermoscopy for the diagnosis of skin tumors: A multicenter study'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.09.117}, pmid = {42833496}, issn = {1097-6787}, } @article {pmid42828230, year = {2026}, author = {Guo, X and Li, X and Chen, J and Bai, L and Yu, H and Cui, H}, title = {AHAS structural changes caused by mutations result in differences in binding affinity and resistance to two herbicides in Cyperus difformis L.}, journal = {Frontiers in plant science}, volume = {17}, number = {}, pages = {1932845}, pmid = {42828230}, issn = {1664-462X}, abstract = {As a malignant weed in paddy systems, Cyperus difformis L. (C. difformis) has evolved resistance to acetohydroxyacid synthase (AHAS, EC 2.2.1.6), also known as acetolactate synthase (ALS), inhibiting herbicides such as pyrazosulfuron-ethyl and bensulfuron-methyl due to prolonged selection pressure. This study systematically investigated the interaction mechanisms between mutated AHAS and these herbicides through biochemical and structural approaches. In this study, purified AHAS proteins of five mutated types and the wild type were obtained via prokaryotic expression, and their sensitivity and affinity for pyrazosulfuron-ethyl and bensulfuron-methyl were determined. The structural differences in different binding of AHAS binding to the two herbicides were identified via homology modeling and molecular docking. The sensitivity determination of purified AHAS indicated that AHAS with site 197 mutations had higher GR50 and I50 values for pyrazosulfuron-ethyl (25.60-74.78 μM) than for bensulfuron-methyl (6.62-38.32 μM). The AHAS with a site 376 mutation had higher GR50 and I50 values for bensulfuron-methyl than for pyrazosulfuron-ethyl, while the GR50 and I50 values of the AHAS with a site 574 mutation were the highest. The affinity of purified AHAS for the substrate revealed that all the mutations increased the affinity except for the Pro-197-Arg mutation. In addition, all the AHAS mutants had greater affinity for bensulfuron-methyl than for pyrazosulfuron-ethyl. Molecular docking results revealed that AHAS formed hydrogen bonds, π-π bonds, and hydrophobic interactions with pyrazosulfuron-ethyl and bensulfuron-methyl. The total number and types of interactions with pyrazosulfuron-ethyl and benzosulfuron-methyl were obviously different between the mutant AHAS and wild-type AHAS. Therefore, in this study, different mutations in AHAS induced distinct structural alterations, which reduced the affinity of the enzyme for herbicides, consequently leading to the development of weed resistance. The difference in affinity between the same mutant and the two herbicides led to a difference in resistance to the two herbicides. The results of this study are helpful for understanding the causes of weed resistance to herbicides at the structural level.}, } @article {pmid42829678, year = {2026}, author = {Ottu Para, NK}, title = {When the Electromyography (EMG) and the Patient Disagree: Unraveling a Motor Neuron Disease Mimic With Small-Fiber Dysfunction.}, journal = {Cureus}, volume = {18}, number = {9}, pages = {e115700}, pmid = {42829678}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by upper and lower motor neuron dysfunction. Electromyography (EMG) is central to its evaluation, but neurogenic abnormalities and fasciculations are not specific to ALS and must be interpreted within the clinical phenotype and disease trajectory. This study reports a 52-year-old man with an approximately eight-year history of intermittent muscle twitching, bilateral upper-limb tremor, muscular tightness and warmth, and asymmetric cutaneous hypersensitivity. An initial electrodiagnostic evaluation raised concern for diffuse motor neuron disease, despite preserved strength, normal gait, absence of muscle wasting, and lack of clear upper motor neuron signs. Extensive evaluation for inflammatory, autoimmune, metabolic, toxic, infectious, paraneoplastic, neuromuscular junction, and peripheral nerve hyperexcitability disorders was unrevealing. Serum creatine kinase was mildly and variably elevated, while aldolase and a comprehensive myositis panel were normal. Brain magnetic resonance imaging (MRI) demonstrated no supportive features of ALS. Sudomotor testing showed reduced electrochemical skin conductance (ESC) in the hands, supporting small-fiber/autonomic dysfunction in the context of prominent sensory symptoms. Repeat EMG, performed after interval follow-up with broad muscle sampling, demonstrated focal neurogenic abnormalities involving bilateral ulnar distributions and left L5-S1 radiculopathy but found no electrophysiological evidence of a neurodegenerative disorder. The patient was treated symptomatically with gabapentin and vitamin E and reported approximately 80% improvement after six weeks. This case highlights the importance of clinicophysiological correlation, disease trajectory, sensory phenomenology, and repeat electrophysiology when an initial EMG suggests motor neuron disease but the longitudinal clinical picture is discordant. It also illustrates how small-fiber dysfunction and focal neurogenic abnormalities may coexist and mimic a progressive motor neuron syndrome.}, } @article {pmid42826761, year = {2026}, author = {Shai, Y and Alam, M and Dong, X and Zhang, Y and Hu, Y and He, Z and Feng, J and Chen, Y and Zhou, Z and Jiang, H}, title = {Mdivi-1 regulates mitochondrial fission and function via the CaMK2/Drp1 pathway in amyotrophic lateral sclerosis.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2026.10.002}, pmid = {42826761}, issn = {1873-7544}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive motor neuron loss. Given the high energy reliance of motor neurons, mitochondrial dysfunction especially excessive fission critically contributes to disease pathogenesis. Mitochondrial division inhibitor-1 (Mdivi-1), an inhibitor of the fission protein Drp1, has shown neuroprotective potential, but its mechanism of action on mitochondrial quality control in ALS remains unclear. Here, we examined the effects of Mdivi-1 on mitochondrial dysfunction and cell injury in NSC34 cells expressing mutant SOD1^G93A and in SOD1^G93A transgenic mice. ALS models exhibited increased reactive oxygen species accumulation, reduced mitochondrial content, loss of mitochondrial membrane potential, enhanced apoptotic signaling, and increased phosphorylation of CaMK2 and Drp1. Mdivi-1 treatment improved cell viability, reduced oxidative stress, restored mitochondrial integrity and membrane potential, and suppressed apoptosis. In addition, Mdivi-1 decreased Drp1 phosphorylation, whereas co-treatment with the CaMK2 activator DCP-LA partially reversed these effects. Furthermore, direct inhibition of CaMK2 with KN93 reduced CaMK2 and Drp1 phosphorylation, providing additional evidence that CaMK2 regulates Drp1 activation in SOD1^G93A cells. These findings indicate that pharmacological modulation of the CaMK2/Drp1 pathway can attenuate aberrant mitochondrial fission and associated cellular dysfunction in ALS models.}, } @article {pmid42823255, year = {2026}, author = {Corcia, P and Erazo, A and Couratier, P}, title = {Towards the integration of open-label extension and real-world evidence in ALS therapeutic evaluation?.}, journal = {Revue neurologique}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurol.2026.09.004}, pmid = {42823255}, issn = {0035-3787}, } @article {pmid42823490, year = {2026}, author = {Hatano, Y and Ishihara, T and Tada, M and Li, Y and Hirokawa, S and Uemura, M and Ando, S and Yokoseki, A and Kakita, A and Onodera, O}, title = {Insertion or deletion variants in TAF15 exon 15 are genetic factors impacting the prognosis of amyotrophic lateral sclerosis in a Japanese cohort.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {42823490}, issn = {1476-5438}, support = {24K10506//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K14771//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; }, abstract = {The influence of genetic factors on the prognosis of amyotrophic lateral sclerosis (ALS) has attracted considerable attention, with numerous studies exploring this relationship in clinically diagnosed patients. The present study attempted to clarify the precise impact of genetic factors on prognosis in patients with pathologically confirmed sporadic ALS. We conducted exome analysis on 137 consecutively autopsied patients with sporadic ALS exhibiting TDP-43 pathology, screening for non-synonymous or splice-site rare variants (RVs) in ALS-related genes. The impact of these variants on ALS prognosis was subsequently assessed. The exome analysis identified 31 RVs in 27 of the 137 patients, including TAF15 exon 15 insertion/deletion mutations (TAF15-15 indels) in 9 patients. Patients harboring RVs had significantly shorter survival times (median 18.0 months) than those without RVs (28.5 months), as determined by log-rank test (p = 0.02). Notably, the 9 cases with TAF15-15 indels demonstrated a significantly poorer outcome (15.0 months, p = 3e-06). Lattice Simulation of Sticker-Spacer Interactions (LASSI) simulations revealed stronger negative sticker-sticker interactions, and a tendency toward lower saturation concentration and higher dense-phase concentration in TAF15-15 indel proteins, suggesting enhanced condensation. The present analysis of pathologically diagnosed ALS patients has yielded genetic factors that could potentially aid more accurate diagnosis and prognostication. The frequent identification of TAF15-15 indels among ALS cases, and their association with significantly poorer outcome, suggests that this type of mutation could be prognostically significant in ALS. Furthermore, the mechanism by which TAF15-15 indels influence the course of ALS could be a promising target for future treatments.}, } @article {pmid42825398, year = {2026}, author = {Davias, A and Hansen, J and Akdis, CA and Weisskopf, MG}, title = {Associations Between Prediagnosis Plasma Neurofilament Light Polypeptide and Amyotrophic Lateral Sclerosis Risk in the Danish EPIC Cohort.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78382}, pmid = {42825398}, issn = {1531-8249}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a rapid time from symptoms onset to diagnosis. Elevated neurofilament light polypeptide (NfL) is well-established in symptomatic ALS and up to 5 years prediagnosis, but earlier timeframes remain understudied. We aimed to assess plasma NfL levels up to 23 years before ALS diagnosis and the relation to ALS risk.

METHODS: We conducted a nested matched case-control study within the Danish EPIC cohort (baseline 1993-1997) including 166 ALS cases (diagnosed 1997-2017) and 332 controls matched on birth year and sex. Plasma samples collected 0.4 to 23.2 years (median 14.1 years) prediagnosis were analyzed for NfL using Olink Target 96. Odds ratios were estimated using conditional logistic regression. Discriminatory performance was evaluated using receiver operating characteristic curves.

RESULTS: NfL levels were elevated in ALS cases relative to controls up to 14.6 years before diagnosis. Among those with blood samples collected <5, 5 to 14.6, and >14.6 years before diagnosis, the odds ratios (95% CI) for ALS per standard deviation increase in the normalized protein expression value of NfL were 3.8 (1.4-10.3), 1.7 (1.2-2.3), and 1.3 (0.9-1.7), respectively. The areas under the curve for ALS discrimination by NfL among those with blood collected <5 and 5-14.6 years before diagnosis were 0.78 and 0.63, respectively.

INTERPRETATION: Plasma NfL elevation may occur significantly earlier than previously reported, indicating a much longer ALS prodrome. Assuming other biomarker changes may also occur earlier, this raises the possibility of identifying at-risk individuals early that could benefit epidemiologic analyses, clinical trials, and prevention efforts. ANN NEUROL 2026.}, } @article {pmid42825562, year = {2026}, author = {Bromberg, MB}, title = {Amyotrophic Lateral Sclerosis.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {32}, number = {5}, pages = {1529-1544}, doi = {10.1212/cont.0000000000001753}, pmid = {42825562}, issn = {1538-6899}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy/genetics/physiopathology ; Female ; Male ; Middle Aged ; }, abstract = {OBJECTIVE: This article describes the nerve loss underlying amyotrophic lateral sclerosis, its clinical manifestations, examination findings leading to the diagnosis, the expanding role of genetics, and available treatment and patient management.

LATEST DEVELOPMENTS: The cause of neuron death in patients with amyotrophic lateral sclerosis is not known, but many genes are strongly linked to the disease, in both patients with a family history and those with no history. A multistep pathologic process helps to explain the onset of symptoms later in life, even in patients with associated genes. Posttranslational and epigenetic changes are also important factors. Current clinical trials are based on putative pathologic mechanisms, and some newer therapies are gene-based.

ESSENTIAL POINTS: Amyotrophic lateral sclerosis has distinctive features and can be diagnosed largely from the history and examination, and true mimics are rare. While the cause of neuronal death is not known, pathogenic and risk factor gene variations are present in a number of patients, and posttranscriptional and epigenetic changes are likely major causative factors. Environmental factors likely contribute, but specific avoidable factors have not been identified. Drugs to slow the progress of the disease are currently limited, but trials for all patients with amyotrophic lateral sclerosis continue, including a focus on genetic factors. Patient management is optimized in multidisciplinary amyotrophic lateral sclerosis clinics, and interventions for nutrition with gastric feeding tubes and respiratory insufficiency by noninvasive ventilation enhance patient comfort.}, } @article {pmid42826575, year = {2026}, author = {Tripathi, A and Yadav, AK and Kumar, N}, title = {AI-driven transcriptomics for neurodegenerative disease research: A systematic review.}, journal = {Computational biology and chemistry}, volume = {126}, number = {Pt 1}, pages = {109448}, doi = {10.1016/j.compbiolchem.2026.109448}, pmid = {42826575}, issn = {1476-928X}, abstract = {BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS), present a growing global health challenge, with traditional diagnostic and therapeutic approaches facing significant limitations in early detection and mechanistic resolution.

OBJECTIVES: Innovations in transcriptomic technologies-spanning bulk RNA sequencing, single-cell RNA-seq (scRNA-seq), and spatially resolved transcriptomics-provide unprecedented insights into cellular heterogeneity and microenvironmental dysregulation. This systematic review synthesizes recent applications of artificial intelligence (AI), machine learning (ML), and deep learning (DL) across transcriptomic tiers to benchmark computational models for biomarker identification, disease diagnosis, patient subtyping, and drug repurposing.

METHODS & ELIGIBILITY: Following PRISMA 2020 guidelines for qualitative systematic reviews, literature published between 2016 and 2025 was systematically searched across PubMed/MEDLINE, IEEE Xplore, Google Scholar, and bioRxiv/medRxiv. Of 1058 records identified, 19 core empirical studies met all eligibility criteria and were synthesized in depth alongside contextual reference benchmarks.

SYNTHESIS & KEY FINDINGS: Traditional ML algorithms (SVM, RF, Elastic Net) demonstrate high diagnostic accuracy (AUC 0.72-0.98) in blood-based biomarker selection, while deep architectures (autoencoders, LSTMs, and Graph Neural Networks) excel at modeling continuous disease trajectories and resolving spatial transcriptomic niches (e.g., STAGATE, SpaGCN, cell2location). Emerging spatial deep learning models successfully localize disease-associated microglia (DAM) around amyloid plaques and trace axonal degeneration pathways.

LIMITATIONS & CONCLUSIONS: Key translational hurdles include data scarcity in rare NDD subtypes, lack of cross-platform spatial benchmarks, and the black-box nature of deep neural networks. Integrating explainable AI (XAI) and prospective multi-modal cohorts is essential for translating computational transcriptomics into clinical diagnostics and targeted therapeutics.}, } @article {pmid42826598, year = {2026}, author = {Rava, A and Di Trapano, M and Tse, C and Ji, L and Bid, HK and Trezza, V}, title = {Acidic cannabinoids in brain disorders: Neurobiological mechanisms, preclinical evidence, and translational challenges.}, journal = {Neuroscience and biobehavioral reviews}, volume = {191}, number = {}, pages = {107005}, doi = {10.1016/j.neubiorev.2026.107005}, pmid = {42826598}, issn = {1873-7528}, abstract = {Acidic cannabinoids, including tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and related biosynthetic precursors, represent the predominant phytocannabinoid forms naturally produced by Cannabis sativa. Long considered pharmacologically inactive intermediates, these compounds are now increasingly recognized as bioactive molecules with potential therapeutic relevance for brain disorders. Compared with their decarboxylated counterparts, acidic cannabinoids exhibit distinct physicochemical, pharmacokinetic, and pharmacodynamic properties that may confer reduced psychotropic liability together with unique neurobiological effects. Emerging preclinical evidence indicates that acidic cannabinoids modulate multiple processes implicated in neurological and psychiatric disorders, including serotonergic and endocannabinoid signaling, neuroinflammation, oxidative stress, mitochondrial dysfunction, calcium dyshomeostasis, and synaptic transmission. In this review, we critically examine current knowledge regarding acidic cannabinoids in the context of brain disorders. We first summarize their biosynthesis, chemical stability, pharmacokinetic characteristics, and pharmacological differences from neutral cannabinoids. We then examine preclinical evidence supporting their potential therapeutic effects in epilepsy, anxiety, depression, psychosis-related conditions, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We also discuss how artificial intelligence and computational approaches may support target identification, formulation optimization, pharmacokinetic modeling, and the development of personalized cannabinoid-based interventions. Finally, we highlight key methodological and translational challenges limiting the field and outline priorities for future research. Overall, acidic cannabinoids emerge as promising but still underexplored multitarget compounds with potential relevance for the treatment of brain disorders.}, } @article {pmid42826647, year = {2026}, author = {Esmaeili, H and Das, S and Rytel, K and Sidransky, E and Chen, Y}, title = {CRISPR screening in neurodegeneration and lysosomal biology: Uncovering disease mechanisms and genetic modifiers.}, journal = {Molecular genetics and metabolism}, volume = {149}, number = {3}, pages = {110265}, doi = {10.1016/j.ymgme.2026.110265}, pmid = {42826647}, issn = {1096-7206}, abstract = {Growing genetic and mechanistic evidence has highlighted substantial convergence between neurodegenerative disorders and lysosomal biology. Variants in lysosomal protein-encoding genes associated with lysosomal storage disorders (LSDs) have been implicated in common neurodegenerative diseases, suggesting that perturbations of lysosomal function represent a shared pathogenic mechanism. However, the low penetrance of neurodegenerative diseases in individuals carrying variants in these lysosomal genes suggests that additional genetic modifiers are involved as well. Advances in functional genomics, particularly clustered regularly interspaced short palindromic repeat (CRISPR)-based high-throughput screens, have opened new avenues to identify such modifiers and elucidate disease-associated pathways. These unbiased approaches have accelerated the discovery of molecular mechanisms underlying neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although to date few studies have applied CRISPR-based functional screens directly to LSDs, findings from neurodegenerative disease models provide a valuable framework for investigating lysosomal pathways and identifying genetic factors that influence phenotypic variability. In this review, we summarize recent advances in in vitro CRISPR-based screening approaches in neurodegenerative disorders and discuss their implications for understanding lysosomal biology and LSD-related mechanisms.}, } @article {pmid42826718, year = {2026}, author = {Cha, Y and Kim, KS}, title = {From patient cells to patient therapy: Twenty years of iPSC-based translation in neurodegenerative disease.}, journal = {Cell reports. Medicine}, volume = {}, number = {}, pages = {103104}, doi = {10.1016/j.xcrm.2026.103104}, pmid = {42826718}, issn = {2666-3791}, abstract = {Twenty years after the discovery of induced pluripotent stem cells, the field has progressed from patient-specific disease modeling toward cell-based therapies for neurodegenerative disorders. Parkinson's disease has emerged as the leading model for neuronal replacement, whereas Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis require distinct combinations of circuit reconstruction, cellular support, immune modulation, and engineered therapeutic delivery. We discuss key determinants of clinical translation, including cell source, product identity, graft composition, graft-host interactions, manufacturing reproducibility, genomic integrity, and clinical evaluation. We propose that the interval between cell transplantation and long-term engraftment constitutes a biological "black box" in which graft fate and therapeutic outcome are determined. As regenerative medicine enters its third decade, future progress will depend not only on generating therapeutic cells but also on elucidating and engineering the biological processes that determine their fate after transplantation, marking a conceptual transition from stem cell biology toward transplantation biology.}, } @article {pmid42826720, year = {2026}, author = {Li, X and Cao, Z and Jiang, O and Wu, S and Zhou, B and Feng, Y and Chen, X and Wang, J and Zhou, J and Yan, R and Chen, M and Wang, S}, title = {Nitrate-responsive Sialin2 couples stress granule assembly and clearance to maintain neuronal homeostasis.}, journal = {Developmental cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.devcel.2026.09.001}, pmid = {42826720}, issn = {1878-1551}, abstract = {Stress granules (SGs) are phase-separated ribonucleoprotein condensates that support cellular adaptation to acute stress, but how extracellular signals coordinate their assembly and recovery-phase clearance remains unclear. Here, we show that nitrate-responsive Sialin2 coordinates SG homeostasis across the stress cycle. During acute stress, Sialin2 undergoes liquid-liquid phase separation and co-assembles with Ras GTPase-activating protein SH3-domain-binding protein (G3BP)-centered scaffolds to promote SG formation. During recovery, Sialin2 preserves liquid-like SG dynamics and promotes autophagy-linked clearance. Sialin2 loss delays SG resolution, promotes retention of amyotrophic lateral sclerosis (ALS)-linked fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43) variants, and enhances amyloid precursor protein (APP)-related amyloidogenic output. In an ALS mouse model, nitrate treatment reduces SG-like pathology and neuroinflammation, preserves neuronal integrity, and delays functional decline. Together, these findings define a nitrate-Sialin2 signaling module that couples SG assembly to recovery-phase clearance and links inorganic anion sensing to protection against neurodegeneration.}, } @article {pmid42809873, year = {2026}, author = {Fila, J and Quiroga, C and Di Gennaro, MS and Veloso, VI and Tripodoro, VA}, title = {[What to learn and teach to implement Shared Care Planning for people with Amyotrophic Lateral Sclerosis? Nominal Group Technique].}, journal = {Revista de la Facultad de Ciencias Medicas (Cordoba, Argentina)}, volume = {83}, number = {3}, pages = {e50160}, doi = {10.31053/1853.0605.v83.n3.50160}, pmid = {42809873}, issn = {1853-0605}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Patient Care Planning ; }, abstract = {BACKGROUND: Advance Care Planning (ACP) is crucial in neurodegenerative conditions such as Amyotrophic Lateral Sclerosis (ALS), yet its implementation in Latin America remains limited, partly due to the lack of specific professional training. The objective of this work is to identify, from the perspective of experienced professionals, the main barriers, tensions, and core contents for designing a training program in ACP for teams caring for people with ALS.

METHODS: A qualitative study using a participatory approach and Nominal Group Technique was conducted in Argentina in 2023. Seventeen professionals from clinical and psychosocial fields participated in the study. Thematic analysis was applied, with triangulation and consensus validation.

RESULTS: Implementation barriers and six thematic areas were identified. Key topics included ethical frameworks, communication tools, existential distress, and strategies for involving families. A cross-cutting axis was the influence of local culture, team emotional responses, and the prevailing biomedical model.

CONCLUSION: This study offers a conceptual and practical foundation for developing ACP training programs in the context of progressive neurological diseases. It represents a first step toward addressing a training gap in the region.}, } @article {pmid42816314, year = {2026}, author = {Bryant, RJ and Marian, IR and Wolstenholme, J and Lamb, AD}, title = {Reply to Flavio L. Heldwein et al's Letter to the Editor re: Little M, Wolstenholme J, Landeiro F, Marian IR, Williams R, Francisco Lopez J, et al. Cost Effectiveness of Local Anaesthetic Transperineal Versus Transrectal Biopsy: Results from the TRANSLATE Study. Eur Urol Focus 2026;12:227-36.}, journal = {European urology focus}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euf.2026.09.005}, pmid = {42816314}, issn = {2405-4569}, } @article {pmid42817119, year = {2026}, author = {Verma, A and Kushwaha, SKS and Kushwaha, N and Dutta, S and Nigam, P}, title = {Neuroinflammation and Autophagy in Neurodegeneration: Cellular Mechanisms and Therapeutic Strategies.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273459017260922073618}, pmid = {42817119}, issn = {1996-3181}, abstract = {Neurodegenerative diseases, including Huntington's disease, Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal dysfunction and loss, often accompanied by toxic protein aggregation and chronic neuroinflammation. Increasing evidence indicates that dysregulated autophagy and persistent inflammatory responses are central drivers of disease onset and progression. Autophagy, a fundamental cellular degradation and recycling process, is essential for maintaining neuronal homeostasis by removing damaged organelles and misfolded proteins through mechanisms such as macroautophagy and mitophagy. However, key regulators of this pathway, including ULK1, Beclin-1, LC3, and p62/SQSTM1, are frequently impaired in neurodegenerative conditions, leading to the accumulation of pathogenic proteins such as tau, α-synuclein, and amyloid-β. Concurrently, aberrant activation of microglia and inflammasomes promotes the sustained release of pro-inflammatory cytokines, creating a neurotoxic environment that exacerbates neuronal injury. This review examines the molecular crosstalk between autophagy and neuroinflammation, with particular emphasis on disease-specific mechanisms, including LC3-associated endocytosis (LANDO) in Alzheimer's disease, tau-mediated pathology, and dopaminergic neurodegeneration in Parkinson's disease. Importantly, this review introduces a unifying conceptual framework in which neuroinflammation and autophagy are integrated as a dynamic, stagedependent immune-autophagy axis that governs neurodegenerative disease progression and therapeutic responsiveness. In addition, emerging multimodal therapeutic strategies targeting both autophagic flux and immune modulation are discussed, including mTOR inhibitors, mitophagy enhancers, GLP-1 receptor agonists, and nanomedicine-based delivery systems. Advances in three-dimensional organoids, induced Pluripotent Stem Cell (iPSC) models, and biomarker-driven clinical trials are further enhancing translational potential. In conclusion, understanding the interplay between autophagy and neuroinflammation provides critical insights into the pathophysiology of neurodegeneration and offers promising avenues for the development of targeted, disease-modifying therapies.}, } @article {pmid42817633, year = {2026}, author = {Morley, JF}, title = {Proteostasis (in)action: the role of co-pathologies in neurodegenerative disease.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {381}, number = {1960}, pages = {}, pmid = {42817633}, issn = {1471-2970}, mesh = {*Proteostasis ; Humans ; *Neurodegenerative Diseases/physiopathology/pathology ; Animals ; Proteotoxic Stress ; Protein Folding ; }, abstract = {Clinically distinct neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), share in common progressive neuronal dysfunction and cell death associated with the accumulation of misfolded proteins. Central to these processes are the cellular and organismal proteostasis networks responsible for maintaining protein homeostasis through coordinated actions of molecular chaperones, the ubiquitin-proteasome system and autophagy-lysosomal pathways. As a consequence of ageing, genetic modifications and other disease-specific conditions, the proteostatic network becomes compromised, leading to the accumulation of toxic protein aggregates that disrupt neuronal function and lead to neurodegeneration. Specific misfolded proteins are associated with each neurodegenerative disease (i.e. α-synuclein in PD, amyloid-β/tau in AD and TAR DNA-binding protein 43/SOD in ALS). However, increasing evidence implicates more complex interactions of co-pathologies across these disorders, as Lewy bodies are common in AD brains and Alzheimer pathology is present in the majority of PD autopsy cases. These observations are consistent with the idea that disruption of proteostasis networks by one aggregation-prone protein could result in misfolding and aggregation of other neurodegeneration-related species. This review will examine the characteristics and consequences of co-pathologies in neurodegenerative disorders. Additionally, the review will outline emerging therapeutic strategies targeted at restoring proteostasis and mitigating the effects of co-pathological processes associated with neurodegenerative diseases. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.}, } @article {pmid42817823, year = {2026}, author = {Yanagi, KS and Lin-Moore, AT and Gordon, NC and Lins, JJ and Coyne, EM and Meininger, KL and Moy, SL and Stinson, LA and Walsh, MB and Gallati, M and Mahapatra, A and Aderogba, R and Jaworski, A and Hart, AC}, title = {A genetic screen for suppressors of neuron degeneration in a C. elegans sod-1G85R model of Amyotrophic Lateral Sclerosis.}, journal = {G3 (Bethesda, Md.)}, volume = {}, number = {}, pages = {}, doi = {10.1093/g3journal/jkag281}, pmid = {42817823}, issn = {2160-1836}, abstract = {Genetic variants in superoxide dismutase 1 (SOD1) cause the progressive neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). Treatments for this disease are limited, and the unique vulnerability of cholinergic and glutamatergic motor neurons to degeneration seen in ALS patients is not clearly understood. Identifying genetic modifiers of neurodegeneration can provide insight into the selective vulnerability of motor neurons in ALS and may accelerate identification of novel therapeutic targets. Here, we describe a forward genetic screen for suppressors of the stress-induced glutamatergic neuron degeneration in a single-copy C. elegans model of sod-1G85R. Used two different screening strategies, we identified 53 suppressor lines that decreased glutamatergic neuron degeneration to varying degrees. To rapidly identify suppressor genes, we sequenced suppressor lines and identified candidate suppressor genes based on frequency of de novo exonic mutations and previously published work. Two candidates were tested and excluded as suppressor genes: erh-1 and imph-1. For a subset of unidentified suppressor lines, we determined if cholinergic neurodegeneration was also suppressed; roughly one-third of suppressor lines showed no corresponding cholinergic neuron rescue, suggesting that mechanisms involved in cholinergic and glutamatergic degeneration are at least partially divergent. This study outlines the first unbiased genetic screen in a knock-in model of SOD1 neurodegeneration, describes a cohort of candidate suppressor lines with decreased SOD1-dependent neurodegeneration, excludes two candidates and discusses approaches for suppressor mutation isolation and gene identification.}, } @article {pmid42817963, year = {2026}, author = {Bidhan, V and Wynants, S and Swings, T and Vicente, CT and Küçükali, F and Van den Broeck, M and van Rooij, JG and Mol, MO and Donker Kaat, LL and Al-Sarraj, S and Bodi, I and King, A and Troakes, C and Proukakis, C and Schaeverbeke, J and Thal, DR and Vandenberghe, R and Vandenbulcke, M and Nguyen, AT and Reichard, RR and Kofler, J and Lopez, OL and White, CL and Boeve, BF and Graff-Radford, NR and Josephs, KA and Petersen, RC and Ghayal, NB and Murray, ME and Dickson, DW and van Swieten, JC and Sleegers, K and Seelaar, H and De Coster, W and Rademakers, R}, title = {Targeted single-nucleus sequencing of 39,800 neurons reveals extensive low-frequency somatic variants.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.09.21.753260}, pmid = {42817963}, issn = {2692-8205}, abstract = {Recent evidence implicates somatic mutations in disease-associated genes across multiple neurodegenerative disorders, including the identification of two somatic TARDBP variants as a putative cause of frontotemporal lobar degeneration with TDP-43 pathology type C (FTLD-TDP type C). However, these findings remain anecdotal. We performed single-nucleus amplicon sequencing of 39,800 neurons from the superior temporal gyrus of sporadic FTLD-TDP type C patients (34,738 neurons, 52 individuals) and non-demented controls (5,062 neurons, 26 individuals) using the Mission Bio Tapestri platform and investigated somatic variants in TARDBP and other FTLD-TDP-associated genes in a case-control setting. We uncovered an extensive landscape of ultra-low-frequency (<1%) somatic mutations across all analysed genes, including TARDBP . Rare somatic occurrences of known ALS/FTD-associated germline TARDBP variants, including p.N267S and p.M337V, were identified exclusively in patients. Among all targeted genes, TARDBP had the highest proportion of neurons harbouring a somatic variant, and this mutational burden was lower in individuals who died at an older age. Strikingly, the C-terminal domain of TDP-43, where most ALS/FTD germline pathogenic variants reside, exhibited a lower neuronal mutational burden than its other domains. This suggests that neurons harbouring damaging mutations may undergo progressive loss prior to autopsy, leaving only rare survivors at frequencies too low to detect by bulk or small-scale single-cell approaches. Together, our findings provide an unprecedented resolution into the somatic mutational landscape of post-mitotic neurons in FTLD-TDP type C and reveal a gene-specific layer of neuronal mosaicism that current single-cell WGS studies fail to detect.}, } @article {pmid42818511, year = {2026}, author = {Campisi, L and Terekhova, M and Melhem, R and Zeng, C and Martin, J and Joseph, TL and Bohacova, P and Jones, M and Nath, A and Benoit, N and Harmison, G and Wu, G and Sergushichev, A and Artyomov, M and Grunseich, C}, title = {Clonal CD8 T cells link peripheral and intrathecal immunity in ALS4 progression: a multiomics reference for ALS.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-10810896/v1}, pmid = {42818511}, issn = {2693-5015}, abstract = {Dysregulated immune responses increasingly appear central to amyotrophic lateral sclerosis (ALS) pathology, but rapid progression and delayed diagnosis limit our understanding of how immune events evolve over the course of disease. By combining high parameter spectral flow cytometry with single cell RNA, TCR and BCR sequencing of peripheral blood and cerebrospinal fluid (CSF), we map the immune landscape in ALS4, a juvenile onset, slowly progressive ALS subtype, providing the first view of immune states spanning decades of disease progression. We identify an early emerging, progressively amplifying CD8 T cell program characterized by clonal expansion of peripheral GZMK[+] and GZMB[+] subsets and an abnormally high degree of TCR clonotype sharing between GZMK[+] CSF and GZMB[+] blood CD8 T cells. Our work defines a CD8 T cell trajectory that parallels clinical progression in ALS4 across CSF and blood and provides a reference for comparison with other ALS subtypes.}, } @article {pmid42818787, year = {2026}, author = {Koo, AS and Zhou, J and Méndez-Albelo, NM and Wei, Y and Xu, W and Zhao, X and Dewey, C and Tibbetts, RS}, title = {ALS-associated exitron splicing produces UBQLN2 isoforms with distinct properties.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.09.08.750250}, pmid = {42818787}, issn = {2692-8205}, abstract = {UNLABELLED: X-linked amyotrophic lateral sclerosis (ALS) implicated Ubiquilin 2 (UBQLN2) is expressed from a single exon. Here, we show that human UBQLN2 mRNA is alternatively spliced by virtue of a cryptic exonic intron (exitron) spanning the 5' untranslated region and the 5' end of UBQLN2 coding sequence. Splice-out of this exitron generates a spliced UBQLN2 (UBQLN2-Sp) transcript that is translated from codon M243 to produce an N-terminally truncated UBQLN2 isoform (UBQLN2-M243) with reduced stability, diminished proteasome targeting, and altered aggregation behavior following the introduction of ALS mutations. The RNA-binding proteins SRSF1 and PTBP1 control UBQLN2 splicing through binding to splice donor-proximal motifs, while TDP-43 was implicated as an indirect splicing repressor. UBQLN2 splicing was elevated and inversely correlated with UBQLN2 gene expression in the medial motor cortex of male ALS patients. These findings suggest that alternative splicing regulates UBQLN2 gene dosage and function, which may impact UBQLN2-ALS proteinopathy.

GRAPHICAL ABSTRACT: Created in https://BioRender.com.}, } @article {pmid42821076, year = {2026}, author = {Murasawa, S and Asanuma, Y}, title = {Determining the learning curve for anterolateral supine total hip arthroplasty: a retrospective analysis of six hundred and forty consecutive cases performed by a single surgeon.}, journal = {International orthopaedics}, volume = {}, number = {}, pages = {}, pmid = {42821076}, issn = {1432-5195}, abstract = {PURPOSE: To characterize the learning curve for single-surgeon performed anterolateral supine (ALS)-total hip arthroplasty (THA).

METHODS: We analysed 640 consecutive primary ALS-THAs performed between April 2017 and August 2024, including procedures performed with supervised assistance during 2017-2019. Operative time (OT), blood loss (BL), and complication rate (CR) were evaluated. Temporal trends in OT and BL were assessed using cumulative sum (CUSUM) analysis, and a data-driven single change-point analysis was performed for CR using 100,000 Monte Carlo permutations. Firth's penalised logistic regression assessed the association between continuous case numbers and complications after adjustment for age, sex, and American Society of Anesthesiologists (ASA) physical status.

RESULTS: OT and BL CUSUM curves peaked at cases 411 and 437, respectively. Mean OT decreased from 74.8 to 66.3 min and BL from 251.6 to 184.6 mL between 2022-2023 (both Holm-adjusted P < 0.001). Nine cases (1.4%) experienced 11 complication events. The estimated CR change point was case 281, with pre- and post-point CRs of 2.8% and 0.3%, respectively, but the permutation test was not significant (P = 0.1021). Increasing experience was associated with lower early complication odds after adjustment (odds ratio 0.64 per 100-case increase, 95% confidence interval 0.40-0.94; P = 0.023).

CONCLUSION: The ALS-THA learning curve varied by outcome, with operative efficiency improving after approximately 400 procedures. Increasing experience was associated with lower odds of early complications, supporting outcome-specific rather than single-threshold assessment.}, } @article {pmid42821610, year = {2026}, author = {Parthasarathy, N and Soetedjo, J and Panchavati, S and Parthasarathy, N and Lee, D and Arnold, C and Pouratian, N and Speier, W}, title = {Near-optimal P300 speller performance using large language models: A multi-model analysis with performance bounds.}, journal = {PloS one}, volume = {21}, number = {10}, pages = {e0349281}, doi = {10.1371/journal.pone.0349281}, pmid = {42821610}, issn = {1932-6203}, mesh = {Humans ; Large Language Models ; *Brain-Computer Interfaces ; *Event-Related Potentials, P300/physiology ; Electroencephalography ; *Amyotrophic Lateral Sclerosis/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, severely impairs communication, requiring assistive technologies that restore interaction. The P300 speller brain-computer interface (BCI) enables communication by translating EEG responses into text; however, its practical adoption is limited by slow typing speed and the need for subject-specific calibration. Recent work has demonstrated that large language models (LLMs), such as GPT-2, can significantly improve the performance of the P300 speller by predicting words. However, it remains unclear whether these gains are model-specific or represent a broader trend across language models. Furthermore, the framework-specific performance bounds of LLM-assisted P300 spellers have not been systematically characterized within a unified decoding framework. In this study, we address these gaps through a systematic multi-model theoretical analysis framework. We evaluate a wide range of language models and introduce an idealized LLM to establish upper bounds on achievable performance. In addition, we incorporate cross-subject classifier training to reduce calibration requirements and assess generalization across subjects. Using extensive simulations on EEG data from 78 subjects, we demonstrate that the evaluated models consistently achieve substantial improvements in typing speed, with gains of up to ~45% (within-subject training) and ~75% (across-subject training) over conventional approaches. More importantly, we show that several high-performing models, despite architectural differences, operate within 5% of the theoretical performance bound, indicating diminishing returns from further model scaling. These improvements generalize across both within-subject and across-subject classifiers. Our results suggest that LLM-assisted P300 spellers are approaching oracle-based upper bounds within the considered decoding framework, shifting the primary bottleneck from language modeling to neural signal decoding. This work provides both a practical framework for improving BCI communication and a theoretical perspective on its achievable limits.}, } @article {pmid42822337, year = {2026}, author = {Zeng, Q and Zhu, Q and Jiang, Q and Zhou, J and Yue, L and Zhu, X and Zeng, X and Li, C and Qiao, G and Fu, Q}, title = {Core and bridge nodes between sleep quality and depression in Chinese patients with amyotrophic lateral sclerosis: A network analysis perspective.}, journal = {General hospital psychiatry}, volume = {103}, number = {}, pages = {108-117}, doi = {10.1016/j.genhosppsych.2026.09.014}, pmid = {42822337}, issn = {1873-7714}, abstract = {BACKGROUND: Sleep quality and depression are prevalent yet under-recognized non-motor symptoms (NMS) in amyotrophic lateral sclerosis (ALS), and the interplay between their symptom domains remains poorly characterized. This study applied network analysis to identify core and bridge nodes linking sleep quality and depression in Chinese ALS patients.

METHODS: A cross-sectional study was conducted among 372 ALS patients recruited from a tertiary hospital in Wuhan, China. Sleep quality and depressive symptoms were assessed using the Pittsburgh Sleep Quality Index (PSQI) and the Patient Health Questionnaire-9 (PHQ-9), respectively. A regularized Gaussian graphical model was estimated using the graphical LASSO algorithm. Node centrality metrics including strength, closeness, betweenness, and expected influence (EI) were calculated to identify core nodes, and bridge expected influence (BEI) was calculated to identify bridge nodes. A case-dropping bootstrap procedure was used to evaluate the stability of the network estimates.

RESULTS: Among all patients, 50.81% screened positive for poor sleep quality and 41.40% for depressive symptoms, with 28.49% screening positive for both. Subjective sleep quality showed the highest strength and EI, identifying it as the most central node. Daytime dysfunction exhibited the highest closeness and betweenness centrality and the largest BEI, emerging as the principal bridge node connecting the communities. The network demonstrated good stability, with CS-coefficients of 0.67 and 0.60 for EI and BEI, respectively.

CONCLUSION: The findings highlight subjective sleep quality and daytime dysfunction as potentially influential nodes within the sleep quality-depression network, representing candidate targets for future longitudinal and intervention studies that may inform strategies to support well-being in patients with ALS.}, } @article {pmid42822436, year = {2026}, author = {Guo, W and Ichida, JK}, title = {The accessory makes the drug: ASO-delivered siRNA enters the human CNS for ALS.}, journal = {Cell stem cell}, volume = {33}, number = {10}, pages = {1580-1581}, doi = {10.1016/j.stem.2026.09.004}, pmid = {42822436}, issn = {1875-9777}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; *RNA, Small Interfering/metabolism/administration & dosage ; *Central Nervous System/metabolism ; Superoxide Dismutase-1 ; *Superoxide Dismutase/genetics/metabolism ; *Oligonucleotides, Antisense/therapeutic use ; Animals ; }, abstract = {In a recent article in Nature Medicine, Chen et al. describe a first-in-human study using an ASO tag to deliver a SOD1 siRNA to the central nervous system (CNS), potentially achieving faster, more extensive, and better-tolerated SOD1-lowering in ALS patients.[1].}, } @article {pmid42809650, year = {2026}, author = {Tabone, S and Cacciottolo, R and Cauchi, RJ}, title = {Motor dysfunction phenotypes in a drosophila model validate DAO as an ALS gene.}, journal = {Human molecular genetics}, volume = {35}, number = {20}, pages = {}, doi = {10.1093/hmg/ddag093}, pmid = {42809650}, issn = {1460-2083}, support = {//University of Malta Research Seed Fund/ ; REP-2023-018//Xjenza Malta Fusion R&I Research Excellence Programme 2023/ ; RNS-2026-0030//Xjenza Malta Research Networking Scheme 2026/ ; //Tertiary Education Scholarship Scheme/ ; //Reach High II Scholarship/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology/metabolism ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Phenotype ; Humans ; *D-Amino-Acid Oxidase/genetics/metabolism ; Neuromuscular Junction/metabolism/pathology/genetics ; *Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/genetics ; Serine Racemase ; Racemases and Epimerases/genetics ; Animals, Genetically Modified ; Drosophila/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by progressive motor neuron (MN) loss. Although rare pathogenic variants in the D-amino acid oxidase (DAO) gene have been proposed to cause familial ALS, inconsistent findings across mammalian models have hindered functional validation. Here, we establish and characterise a Drosophila model of DAO loss-of-function by targeting its highly conserved orthologue, Daao1. Constitutive Daao1 knockdown caused early developmental lethality, while surviving adult escapers exhibited profound flight and climbing impairments. Contrary to expectations, Daao1 deficiency did not elevate D-serine levels in larval or adult brains, and simultaneous knockdown of serine racemase (Srr), the enzyme responsible for D-serine synthesis, failed to rescue locomotor phenotypes. Tissue-specific silencing revealed that Daao1 is essential within both MNs and muscles, but not glia, for maintaining motor performance. RNA-seq of Daao1-deficient flies uncovered widespread transcriptional dysregulation affecting metabolism, peptide transport, immune activation and developmental pathways, accompanied by alternative splicing changes in genes required for neuronal morphology and synaptic organisation. Consistent with these molecular alterations, neuromuscular junctions (NMJs) displayed reduced axonal branching and bouton numbers, indicating disrupted neuromuscular connectivity. Remarkably, ubiquitous expression of human DAO rescued lethality and motor defects, demonstrating functional conservation and supporting a role for DAO in maintaining neuromuscular health. Together, our findings reveal a previously unrecognised, D-serine-independent role for DAO in neuromuscular integrity and provide functional evidence connecting DAO dysfunction to ALS-relevant phenotypes. The DAO-ALS Drosophila model provides a powerful platform for mechanistic studies and for evaluating human DAO variants of uncertain significance in ALS.}, } @article {pmid42811035, year = {2026}, author = {Marzok, A and Mapletoft, JP and Ahmed, I and Cowbrough, B and Celeste, DB and D'Agostino, MR and Ang, JC and Chen, AT and Surendran, V and Tugg, Y and Li, H and Wong, K and Dvorkin-Gheva, A and Zhang, A and Stacey, HD and Lam, M and Kollar, Y and Milnes, KR and Afkhami, S and Miller, MS}, title = {Acute viral infection accelerates neurodegeneration in a mouse model of ALS.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42811035}, issn = {2041-1723}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/virology/pathology/genetics/immunology/drug therapy ; Disease Models, Animal ; Mice ; Superoxide Dismutase-1/genetics/metabolism ; *Virus Diseases/complications ; Mice, Transgenic ; Disease Progression ; Gliosis/virology/pathology ; Humans ; Female ; Superoxide Dismutase/genetics ; Spinal Cord/pathology ; Male ; }, abstract = {While several viral infections have been associated with amyotrophic lateral sclerosis (ALS), the mechanism(s) through which they promote disease remains elusive. Here we investigate the impact of common, acute viral infections on ALS disease onset and progression in the SOD1[G93A] mouse model. A single sublethal infection prior to onset of ALS clinical signs is associated with markedly accelerated ALS disease progression characterized by rapid loss of hindlimb function. Prior infection results in gliosis in the lumbar spine and upregulation of transcriptional pathways involved in inflammatory responses, metabolic dysregulation, and muscular dysfunction. Therapeutic suppression of gliosis with an anti-inflammatory small molecule, or administration of a direct-acting antiviral, is associated with significantly improved ALS clinical signs, akin to what is observed in uninfected animals. Our study provides causal and mechanistic evidence that the immune response elicited by acute viral infections may be an important etiological factor that alters ALS disease trajectory.}, } @article {pmid42811116, year = {2026}, author = {Brooker, SM and Coukos, R and Krainc, D}, title = {Lysosomal dysfunction in neurodegenerative disease.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {42811116}, issn = {1759-4766}, abstract = {Examination of genetic risk factors associated with neurodegenerative diseases has provided important mechanistic insights into the pathophysiology of these disorders, and it has implicated defects in lysosomal function as a key component of the neurodegenerative process. The lysosome has a primary role in mediating degradation of both intracellular contents and endocytosed material from the extracellular space. Aggregation of misfolded proteins is a pathological mechanism that is observed across neurodegenerative disorders, and aberrant lysosomal degradation of such proteins plays a pivotal part in driving neuronal dysfunction and cell loss. In addition to the crucial role of the endolysosomal system in degradation of intracellular constituents, lysosomes also serve as important nodes for intracellular signalling, participating in nutrient sensing, lipid metabolism, membrane repair and neuroinflammation. In this Review, we provide an overview of mechanisms of lysosomal dysfunction in neurodegenerative disease, with a particular focus on Parkinson disease, Alzheimer disease, frontotemporal dementia and amyotrophic lateral sclerosis.}, } @article {pmid42811584, year = {2026}, author = {Singh, R and Kumam, Y and Mahey, M and Patterson, E and Liu, S and Lancaster, S and Jugulam, M}, title = {Deciphering metabolic resistance to multiple herbicides in Amaranthus palmeri via transcriptome analysis.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71345}, pmid = {42811584}, issn = {1526-4998}, support = {//Kansas Soybean Commission/ ; }, abstract = {BACKGROUND: Multiple herbicide resistance in Palmer amaranth (Amaranthus palmeri S. Watson) poses a serious threat to US crop production. A Palmer amaranth population (KCTR) from Kansas was found resistant to herbicides across six sites-of-action, including ALS-, PS II-, EPSPS-, PPO-, HPPD-inhibitors and synthetic auxins. Previous physiological and metabolic studies suggested that resistance in this population is predominantly associated with enhanced herbicide metabolism, possibly mediated by cytochrome P450 (P450) and/or glutathione S-transferase (GST) enzyme activity. The aim of this study was to identify candidate genes potentially associated with multiple herbicide resistance in KCTR Palmer amaranth population.

RESULTS: Differential gene expression analysis revealed 414, 129, 529, 152 and 688 genes differentially expressed in resistant plants as compared to susceptible, following chlorsulfuron, 2,4-D, atrazine, mesotrione and lactofen treatments, respectively. CYP72A219 paralogs, CYP704B1-like and GST-ct genes were constitutively up-regulated in resistant plants as compared to susceptible. Validated by qRT-PCR, CYP72A219 and CYP704B1-like were 3.4- to 6.6-fold and 5.9- to 12.4-fold up-regulated in resistant plants as compared to susceptible without any treatment.

CONCLUSIONS: Identifying genes associated with multiple herbicide metabolism is critical for understanding cross-resistance and evaluating new herbicides for resistance risk. These candidate resistance-associated genes serve as targets for functional validation studies in future to help develop molecular markers for screening broad-spectrum herbicide resistance. © 2026 Society of Chemical Industry.}, } @article {pmid42812195, year = {2026}, author = {Tao, R and Zheng, W and Peng, L and Lv, S and Wang, Q}, title = {Multistage pathogenesis and disease associations of Mycobacterium avium subsp. paratuberculosis.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1948490}, pmid = {42812195}, issn = {1664-3224}, mesh = {*Mycobacterium avium subsp. paratuberculosis/pathogenicity/immunology/genetics ; Animals ; *Paratuberculosis/microbiology/immunology/epidemiology/transmission ; Humans ; Macrophages/immunology/microbiology ; Host-Pathogen Interactions ; }, abstract = {Mycobacterium avium subsp. paratuberculosis (MAP) is the primary causative agent of Johne's disease (JD) in ruminants and bears potential public-health implications. Cumulative epidemiological and molecular evidence implies MAP may contribute to Crohn's disease (CD), whereas its links to multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), and amyotrophic lateral sclerosis (ALS) remain associative without proven causality. This narrative review synthesizes MAP environmental distribution, strain genotyping, transmission routes, and multistage pathogenic mechanisms. MAP breaches the intestinal barrier via fibronectin attachment protein (FAP)-mediated invasion of microfold cells and establishes intracellular persistence within macrophages. It deploys virulence factors including protein kinase G (PknG) to inhibit phagosome-lysosome fusion, the stringent response regulator RelA for metabolic reprogramming, and the ESX-3 secretion system for iron acquisition, while subverting host immunity through M2 macrophage polarization and interleukin-10 (IL-10)/interleukin-6 (IL-6)-mediated anti-inflammatory responses, ultimately driving chronic granulomatous inflammation and tissue injury. We also critically assess diagnostic limitations-particularly the inability of polymerase chain reaction (PCR) to distinguish viable from non-viable organisms-and highlight major research challenges, including extrapolation of virulence mechanisms from other mycobacterial species. This work provides a theoretical framework for prevention, diagnosis, and targeted intervention of MAP-associated disorders.}, } @article {pmid42813639, year = {2026}, author = {Singh, AP and Prajapati, S and Yadav, S and Yadav, A}, title = {Lipid-based Nanocarriers for Neurodegenerative Disorders: Bridging Blood-brain Barrier Biology and Translational Drug Delivery.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026478560260909100922}, pmid = {42813639}, issn = {1875-5739}, abstract = {INTRODUCTION: Neurodegenerative disorders, including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis, remain difficult to treat because the Blood-brain Barrier (BBB) severely restricts therapeutic access to the central nervous system. This review evaluates BBB biology and the potential of lipid-based nanocarriers to improve brain-targeted drug delivery and facilitate clinical translation.

METHODS: A structured narrative review of peer-reviewed preclinical and clinical literature published between 2000 and 2025 was conducted using PubMed, Scopus, and Web of Science. Evidence concerning BBB structure and transport mechanisms, lipid-based nanocarrier design, physicochemical characteristics, drug-release behavior, computational modelling, therapeutic applications, and translational challenges was critically synthesized.

RESULTS: Liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, and lipid-polymer hybrid nanoparticles demonstrated improved drug solubility, stability, controlled release, systemic circulation, and brain targeting. Preclinical evidence indicates enhanced brain bioavailability and therapeutic effects, including reductions in neuroinflammation, oxidative stress, and disease-associated pathological processes. However, clinical translation remains constrained by formulation complexity, scalability, long-term safety, and inconsistent clinical outcomes.

DISCUSSION: Integration of BBB transport biology with surface functionalization, receptormediated targeting, formulation engineering, and computational modelling may enable more rational nanocarrier development. Nevertheless, standardized characterization, reproducible manufacturing, comprehensive safety evaluation, and stronger clinical validation are required to bridge the gap between promising preclinical findings and therapeutic implementation.

CONCLUSION: Lipid-based nanocarriers represent promising platforms for overcoming biological and pharmacokinetic barriers in neurodegenerative disorders. Further optimization and rigorous translational validation are essential to establish their safety, reproducibility, and clinical effectiveness.}, } @article {pmid42814295, year = {2026}, author = {Chan, L and Shaikh, FA and Shah, P and Moriyama, H and Yokota, T}, title = {Development and Clinical Applications of Antisense Oligonucleotide Gapmers.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {3065}, number = {}, pages = {19-51}, pmid = {42814295}, issn = {1940-6029}, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use/genetics/chemistry ; Animals ; *Genetic Diseases, Inborn/genetics/therapy ; *Genetic Therapy/methods ; }, abstract = {Antisense oligonucleotides (AONs) are synthetic oligonucleotides designed to bind target RNA and have opened new treatment possibilities for genetic diseases by regulating gene expression. AONs are often used to suppress the expression of mutated genes, which may interfere with essential downstream pathways. Since AONs have been introduced for clinical use, different chemistries have been developed to further improve efficacy, potency, and safety. One such chemistry is a chimeric structure of a central block of deoxyribonucleotides flanked by sequences of modified nucleotides. Referred to as a gapmer, this chemistry produced promising results in the treatment of genetic diseases. Tofersen is an example of a recently FDA-approved antisense oligonucleotide gapmer used for the treatment of amyotrophic lateral sclerosis. Many others are being tested in clinical trials or under preclinical development. This chapter will cover advancements in gapmer treatments for various diseases, including familial hypercholesterolemia, hereditary transthyretin amyloidosis, cancer, familial chylomicronemia syndrome, familial partial lipodystrophy, familial hypertriglyceridemia, Huntington's disease, myotonic dystrophy, prion diseases, and amyotrophic lateral sclerosis.}, } @article {pmid42814303, year = {2026}, author = {Nakamura, Y and Moriyama, H and Yokota, T}, title = {Development of Antisense Oligonucleotide Gapmers for Amyotrophic Lateral Sclerosis.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {3065}, number = {}, pages = {161-170}, pmid = {42814303}, issn = {1940-6029}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/drug therapy ; Humans ; *Oligonucleotides, Antisense/genetics/therapeutic use/administration & dosage/chemistry ; Animals ; Superoxide Dismutase-1/genetics/metabolism ; Biomarkers ; }, abstract = {Advances in genetics and RNA biology have transformed the therapeutic landscape for neurodegenerative disease. Antisense oligonucleotide (ASO) therapies-particularly RNase H-activating "gapmers"-now enable sequence-specific suppression of pathogenic transcripts in the central nervous system. In amyotrophic lateral sclerosis (ALS), tofersen, a 2'-MOE-modified phosphorothioate ASO targeting SOD1 mRNA, has entered clinical use. By promoting RNase H-mediated degradation of SOD1 transcripts after intrathecal delivery, tofersen lowers SOD1 protein in cerebrospinal fluid and plasma neurofilament light chain, demonstrating robust target engagement and neurodegeneration biomarker improvement. Although pivotal trials did not meet primary functional endpoints (ALSFRS-R) at 28 weeks, longer-term and real-world observations suggest potential clinical benefit with earlier initiation, a hypothesis now being tested in presymptomatic SOD1 variant carriers. This chapter reviews the development of gapmer ASOs for ALS with a focus on tofersen-covering chemistry and mechanism, preclinical validation, clinical efficacy and safety, biomarker readouts, and ongoing trials-while outlining key challenges (CNS delivery, adverse event monitoring, endpoint sensitivity) and future directions, including earlier intervention guided by biomarkers and extension to additional genetic forms of ALS.}, } @article {pmid42814997, year = {2026}, author = {Frisch, D and Fronstin, M and Zema, C}, title = {Agentic AI for Clinical Outcomes Research, Population Health Management Analyses With Large Administrative Databases, and Generating Epidemiological Estimates of Diseases: Feasibility and Validation Study.}, journal = {Journal of medical Internet research}, volume = {28}, number = {}, pages = {e100284}, doi = {10.2196/100284}, pmid = {42814997}, issn = {1438-8871}, mesh = {Humans ; Female ; Male ; *Artificial Intelligence ; Feasibility Studies ; Aged ; Middle Aged ; Adult ; *Databases, Factual ; Adolescent ; *Population Health Management ; Child ; Urinary Bladder Neoplasms/epidemiology ; Infant ; *Outcome Assessment, Health Care ; Young Adult ; Child, Preschool ; Huntington Disease/epidemiology ; Leukemia, Myeloid, Acute/epidemiology ; Prevalence ; Parkinson Disease/epidemiology ; Infant, Newborn ; United States/epidemiology ; }, abstract = {BACKGROUND: There is tremendous enthusiasm for the use of AI in health care because of the ability to analyze existing data for preventative, diagnostic, and treatment support. Agentic AI can feasibly provide access to large real-world datasets for the generation of real-world evidence for health care and clinical applications to health care providers, researchers, and administrators without access to large analytic programming resources.

OBJECTIVE: The objective of this study was to understand the feasibility of using agentic AI for clinical outcome research and population health management. Specifically, this study used an agentic AI evidence-generation platform to obtain epidemiological estimates of diverse medical conditions, with the results evaluated against existing AI frameworks.

METHODS: Prevalence estimates of 6 conditions (amyotrophic lateral sclerosis, acute myeloid leukemia, bladder cancer, Huntington disease, elevated lipoprotein (a), and Parkinson disease) were estimated using an agentic AI evidence-generation platform applied to an administrative claims database with representation from every US state. Gender-specific rates were calculated within the following age categories: 0 to 17, 18 to 24, 25 to 34, 35 to 44, 45 to 54, 55 to 64, and 65 to 74 years and 75 years and older. Period prevalence was estimated from January 1, 2020, to June 30, 2025, and annual prevalence rates for each year were estimated from 2020 to 2024. Continuous enrollment for 12 months was required during the study period for inclusion. Source code generated by the platform as part of the analysis was reviewed by an independent programmer for validation of methods and programming, and analyses were replicated using traditional programming methods. Results obtained throughout the process were evaluated against several existing AI application frameworks.

RESULTS: Regarding accuracy, epidemiological estimates obtained using the agentic AI platform were consistent with published estimates for all 6 conditions, as well as with estimates obtained from traditional programming methods. Regarding rigor, the agentic AI platform conducted the analysis with rigor by confirming acceptable methods in published literature for the type of data source used. Code lists used for the analysis were confirmed against existing algorithms when available. Appropriate statistical methods were used to compare differences in prevalence rates by age and gender. Regarding trust (explainability, transparency, replicability, traceability, and validation), the agentic AI platform generated all source code used for the analyses, which was reviewed and validated for accuracy and appropriateness. The analysis included a "human in the loop" to validate the research question, data extraction method, statistical analysis plan, and output plan prior to proceeding with each step.

CONCLUSIONS: With specific design considerations to ensure responsible use, agentic AI can be invaluable to increasing the accessibility of large datasets for applied clinical outcome research and population health management analyses.}, } @article {pmid42815720, year = {2026}, author = {Tazuma, T and Nakamori, M and Toko, M and Watanabe, T and Naito, H and Kanaya, Y and Agari, D and Shishido, T and Imamura, E and Imon, K and Nomura, E and Torii, T and Miyachi, T and Yamashita, H and Ohshita, T and Maruyama, H}, title = {Predictive Value of the Modified Controlling Nutritional Status Score for Critical Events in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Clinical nutrition ESPEN}, volume = {}, number = {}, pages = {105162}, doi = {10.1016/j.clnesp.2026.105162}, pmid = {42815720}, issn = {2405-4577}, abstract = {BACKGROUND & AIMS: Amyotrophic lateral sclerosis (ALS) is associated with various clinical challenges and critical outcomes. Therefore, we established a regional registry and conducted the Chugoku ALS Retrospective and Prospective (CARP) study. The modified controlling nutritional status (m-CONUT) score holds the potential to comprehensively assess the condition of patients with ALS from aspects such as nutrition, metabolism, and inflammation. The present study used data from the CARP study to examine the relationship between the m-CONUT score and outcomes.

METHODS: Patients diagnosed with possible, probable, and definite ALS according to the Awaji criteria were enrolled between 2014 and 2023. A statistical analysis of data from patients enrolled within 2 years of ALS onset and followed for at least 6 months thereafter was performed. Patients were evaluated every 3 months, and missing values were supplemented by the last observation carried forward method.

RESULTS: This study included 36 patients. Eleven experienced critical events (ventilator placement or death), the majority of which were deaths. The m-CONUT score exhibited a worsening trend before the critical event occurred, as did the revised ALS functional rating scale score, body mass index, and forced vital capacity percentage. Critical events increased significantly with each 1-point increase in the m-CONUT score.

CONCLUSIONS: The m-CONUT score may have potential for predicting outcomes in patients with ALS.}, } @article {pmid42816074, year = {2026}, author = {Sriharan, A and Sullivan, T and Mitchell, C}, title = {Leading under uncertainty: a qualitative case study of crisis leadership in Canada's health system.}, journal = {BMJ open}, volume = {16}, number = {9}, pages = {e115820}, doi = {10.1136/bmjopen-2025-115820}, pmid = {42816074}, issn = {2044-6055}, mesh = {*Leadership ; Uncertainty ; Canada/epidemiology ; Humans ; Qualitative Research ; *COVID-19/epidemiology ; *Delivery of Health Care/organization & administration ; SARS-CoV-2 ; Pandemics ; }, abstract = {BACKGROUND: Prolonged public crises challenge leaders to make high-stakes decisions under conditions of uncertainty while sustaining organisational performance and public trust. Understanding how leaders navigate these complex demands is essential for strengthening health system preparedness and resilience.

OBJECTIVES: The goal was to explore and unpack lived leadership experiences during a public crisis situation and to unpack how contextual factors shape their behaviours under uncertainty and prolonged disruption.

DESIGN: This study was conducted in Canada during the middle phases of the COVID-19 pandemic (October 2020-March 2021). Canada's healthcare system operates within a federal-provincial framework, with public health responsibilities spanning national, provincial and local levels. 16 senior leaders with provincial or national responsibilities across healthcare delivery, government, academia and research participated in the study. Purposive sampling was used to achieve variation across organtional and geographic regions. A qualitative case study design was employed, with semistructured interviews serving as the primary data collection method and thematic analysis used to analyse the data. The analysis was informed by Sriharan et al's Crisis Leadership Framework and reported in accordance with the Standards for Reporting Qualitative Research.

METHODS: Videoconference interviews (40-50 min) explored leadership challenges, decision-making under uncertainty, communication, and contextual enablers and constraints. Transcripts were analysed using Braun and Clarke's six-phase approach with triangulation and reflexive documentation to enhance rigour.

RESULTS: Leaders described multifaceted roles that spanned clinical, administrative and advisory functions. Six leadership domains emerged from the analysis: adaptive leadership, learning-oriented leadership, systems thinking, psychological stewardship, implementation agility and strategic communication. Leadership enactment was shaped by structural integration and centralisation, which enabled real-time situational awareness and coordinated resource deployment. Rapid cycle decision-making was supported by emergency legislative flexibility, multidisciplinary evidence synthesis structures and peer learning networks. Constraints included systemic fragmentation, bureaucratic inertia, data sharing limitations and sustained workforce fatigue, all of which influenced leaders' ability to enact these domains under pressure.

CONCLUSIONS: Effective crisis leadership depended less on static competencies and more on dynamic enactment shaped by structural, operational and relational mechanisms. The findings extend the crisis leadership framework towards Dynamic Capability Leadership for Learning Health Systems, positioning leadership as a strategic capacity to sense emerging challenges, seize opportunities through rapid and accountable decision pathways and transform processes to sustain performance under uncertainty. These capabilities were enacted through adaptive and learning-oriented leadership, implementation agility, systems thinking, psychological stewardship and strategic communication, all amplified by structural integration and evidence-synthesis infrastructures. Overall, the findings highlight crisis leadership as a system property shaped by context, coordination and the ability to translate evolving knowledge into timely action.}, } @article {pmid42816153, year = {2026}, author = {Gauld, N and Hikaka, J and Newsham, S and Frampton, C and Mylchreest, R and Brott, T and Buchanan, SM and Buetow, S}, title = {Caregiving and Respite for People With Motor Neurone Disease: A National Cross-Sectional Survey of Experiences and Challenges.}, journal = {Journal of clinical nursing}, volume = {}, number = {}, pages = {}, doi = {10.1111/jocn.70548}, pmid = {42816153}, issn = {1365-2702}, support = {23/987//Health Research Council of New Zealand/ ; //Motor Neurone Disease New Zealand/ ; //Natalie Gauld/ ; }, abstract = {AIMS: To ascertain care support for people with motor neurone disease encompassing formal and informal care (funded and unfunded care), residential respite utilisation, care tasks performed by family members, and experiences and challenges encountered in accessing funded care.

DESIGN: National cross-sectional survey.

METHODS: People with motor neurone disease, their family members, and bereaved family members were surveyed across New Zealand. Analysis included descriptive and multivariable statistical methods. Responses to open-ended questions were analysed thematically.

RESULTS: Data were available from 115 people with motor neurone disease, 89 family carers and 40 bereaved carers. Care hours data represented 189 unique individuals with motor neurone disease - 115 responses from people with motor neurone disease, 35 from family carers and 39 bereaved. Most (58%) reported needing funded care but only 50% received it (median 24 h/week), 51% reporting this was insufficient. Younger age, greater disease severity and slow (versus fast) progression rate were associated with greater likelihood of receiving funded care (all p < 0.05); fewer funded hours were associated with faster progression and age over 65 years (all p < 0.05). Most people with motor neurone disease (77%) received unpaid care (median 30 h/week), rising to 90% among bereaved respondents (median 80 h/week). Barriers to funded care included assessment delays, insufficient information and unmet eligibility criteria. Inadequate care funding affected family (e.g., exhaustion, safety issues), and the person with motor neurone disease (e.g., unmet needs and safety concerns), with additional financial impacts. Many family members reduced paid work during the illness. Residential respite was used by only 15%, with multiple reasons for non-use.

CONCLUSION: Inadequate funded care and residential respite provision in New Zealand impose a substantial burden on families to provide unpaid care, harming both people with motor neurone disease and family members.

IMPLICATIONS: Funded care needs to be more responsive to the needs of those with motor neurone disease and their caregivers.

IMPACT: Little is known about funded and unpaid care in motor neurone disease (MND), particularly the challenges of acquiring sufficient funding and arising from insufficient funding. This study found that many people with MND could not access the care hours they needed, leaving family members to provide high levels of unpaid care, while often reducing their own paid work. Resulting challenges included exhaustion for family, financial strain, unmet needs, and safety concerns for the person with MND. Insufficient care funding was associated with reduced life satisfaction for family members. The care funding system was hard to navigate and too slow, particularly where MND progresses fast. From a nursing perspective, this research highlights the critical importance of funded care that is flexible and responsive to rapidly changing needs. When funding systems are slow or difficult to navigate, the burden often falls on families, increasing stress and risk for the person with MND and their carers. This research should inform policy in New Zealand and internationally, demonstrating the need for care funding systems that are flexible, fast, and straightforward to use-findings relevant regardless of the funding model. Reporting method: this paper was informed by the STROBE checklist for cross-sectional studies.

The lead author has MND. Many people with MND and their family members were involved throughout the study, shaping its concept, scope, and methods. Two people with MND tested the survey in Qualtrics-one using eye gaze technology and one using voice to text. Four people with MND and three carers reviewed the questionnaire, providing feedback that resulted in rewording. One person with MND worked through every question with the lead author over three separate sessions to ensure all questions and response options were clear and meaningful.}, } @article {pmid42806293, year = {2026}, author = {Sanjay, S and Magliyah, MS}, title = {Letter to the Editor: Comment on Azeem S, et al's "Acute Retinal Necrosis-Associated Rhegmatogenous Retinal Detachment: A Systematic Review and Meta-Analysis".}, journal = {Ocular immunology and inflammation}, volume = {}, number = {}, pages = {1-2}, doi = {10.1080/09273948.2026.2737298}, pmid = {42806293}, issn = {1744-5078}, } @article {pmid42807601, year = {2026}, author = {Elmahgoub, S and Elshawa, A and Flannery, S}, title = {Anesthetic Management and Perioperative Outcome of Emergency Laparotomy in a Patient With Advanced Motor Neurone Disease: A Case Report.}, journal = {Clinical case reports}, volume = {14}, number = {10}, pages = {e73635}, pmid = {42807601}, issn = {2050-0904}, abstract = {Motor neurone disease (MND) presents significant perioperative challenges due to progressive respiratory muscle weakness, bulbar dysfunction, autonomic instability, and altered sensitivity to anesthetic agents. Emergency surgery further limits opportunities for optimisation and advance planning. We report the perioperative and anesthetic management of a patient with advanced MND undergoing emergency laparotomy for small bowel obstruction. A total intravenous anesthetic with cautious use of neuromuscular blockade was employed, and the patient was successfully extubated postoperatively. Despite an initially uncomplicated postoperative course, the patient subsequently developed progressive respiratory failure in the context of ongoing intra-abdominal pathology. Following multidisciplinary discussion and shared decision-making, care was transitioned to a comfort-focused approach. This case highlights the limitations of perioperative intervention in advanced MND and emphasizes the importance of goal-concordant care in emergency surgical settings.}, } @article {pmid42807842, year = {2026}, author = {Filser, PJ and Münchenberg, PS and Berger, E and Busse, R and Garcia, C and Kurth, T}, title = {Clinical and economic effectiveness of telehealth in home mechanical ventilation.}, journal = {ERJ open research}, volume = {12}, number = {5}, pages = {}, pmid = {42807842}, issn = {2312-0541}, abstract = {BACKGROUND: The number of patients requiring home mechanical ventilation is rising, while in-person follow-up is increasingly burdensome for patients and health systems. Telehealth may maintain clinical stability and improve care efficiency. This systematic review examined the clinical and economic effectiveness of telehealth in the management of home mechanical ventilation.

METHODS: The study protocol was registered a priori in PROSPERO. A systematic search was conducted in MEDLINE, Embase and Web of Science. The reporting of the systematic review was aligned with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. We included quantitative studies comparing telehealth-supported home ventilation with standard care, reporting clinical or economic outcomes.

RESULTS: From 356 identified studies, 11 met the inclusion criteria: nine randomised controlled trials, one cohort study and one retrospective analysis, mostly conducted in Europe, with a total of 1458 participants. The study populations included patients with, e.g. COPD, amyotrophic lateral sclerosis and obesity hypoventilation syndrome. Interventions involved telehealth-supported home ventilation management. Across studies, telehealth-supported care achieved clinical outcomes comparable to those of standard care. Arterial carbon dioxide tension (P aCO2) control and health-related quality of life were similar between groups, with one study reporting greater P aCO2 reduction with telemonitoring. Evidence on the number of hospitalisations and exacerbations was mixed. Mortality and survival rates showed nonsignificant trends towards benefit; one cohort study reported improved first-year survival. Economic outcomes varied: home initiation reduced costs, while long-term follow-up results were heterogeneous.

CONCLUSIONS: elehealth-supported home ventilation appears to be a comparable alternative to in-hospital management and often provides economic advantages. Future research should focus on standardised outcome measures, longer follow-up and health-system-specific cost-effectiveness analyses to guide sustainable implementation.}, } @article {pmid42809516, year = {2026}, author = {Jang, K and Morton, RL and Dennis, M and Nikolovski, J and Zhan, X and Ke, Y and Burns, B and Tran, AD}, title = {The cost-effectiveness and health equity of prehospital treatment strategies for out-of-hospital cardiac arrest patients: a systematic review.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-66}, doi = {10.1080/10903127.2026.2741269}, pmid = {42809516}, issn = {1545-0066}, abstract = {OBJECTIVES: Out-of-hospital cardiac arrest (OHCA) remains a major public health challenge, associated with substantial mortality and significant costs for health care system. This systematic review aimed to (i) synthesise economic evaluations of prehospital treatment strategies for OHCA from ambulance attendance through to hospital discharge; (ii) assess the methodological quality and reporting of the included studies; and (iii) evaluate the reporting of health equity-relevant data.

METHODS: We searched Medline, Embase, Scopus, EconLit, and CINAHL databases for records from database inception to 12 June 2026. The QHES and CHEERS checklists were used to assess the quality and reporting standards of included studies, and the review was reported according to the PRISMA checklist. The completeness of reporting health equity outcomes was reviewed using the PROGRESS (Place of residence, Race, Occupation, Gender, Religion, Education, Socioeconomic status and Social capital) - Plus framework.

RESULTS: Ten economic evaluations met eligibility criteria. Most studies were cost-utility analyses (n = 8, 80%) and used Markov models (n = 6, 60%). Most evaluations were 'very good quality' (≥80%) (n = 6, 60%). Early defibrillation and advanced life support (ALS) delivered by trained emergency medical technicians were cost-effective compared with no intervention, emergency physician-led ALS, standard emergency medical services or paramedic care (ICER range from £11,407 to USD $56,700 per QALY gained). Prehospital extracorporeal cardiopulmonary resuscitation (ECPR) was more cost-effective than in-hospital ECPR strategies (ICER range from AUD $27,323 to $44,000 per QALY gained). Termination-of-resuscitation (TOR) strategies were cost-effective compared with no TOR or other TOR strategies, including basic life support and ALS TOR, with estimates of $110,554 saved per QALY lost and USD $23,851 per QALY gained.Survival rate and neurological outcomes influenced cost-effectiveness results. Equity reporting was limited: almost all included studies addressed less than 40% of the PROGRESS-Plus equity criteria.

CONCLUSIONS: Most strategies that increased prehospital treatment intensity, avoided futile transport, or enabled earlier advanced care were cost-effective; however, the certainty of evidence, particularly for sub-groups, was limited by heterogeneous comparators and sparse equity reporting.}, } @article {pmid42803299, year = {2026}, author = {Shirakawa, T and Mikuriya, S and Inoue, Y and Murasaki, K and Salinas, F and Takegawa-Araki, T and Tamura, M}, title = {LRSAM1, an E3 ubiquitin ligase, modulates TDP-43 proteostasis in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag334}, pmid = {42803299}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the cytoplasmic mislocalization, aberrant phosphorylation and pathological aggregation of TDP-43, a nuclear RNA-binding protein essential for RNA metabolism. Despite its central involvement in ALS pathogenesis, the molecular mechanisms that govern TDP-43 proteostasis remain incompletely understood. Here, we investigated the role of LRSAM1, an E3 ubiquitin ligase, in regulating TDP-43 localization and degradation. Postmortem spinal cord tissues from five patients with sporadic amyotrophic lateral sclerosis and five healthy controls were examined. Immunohistochemical analyses revealed that LRSAM1 preferentially colocalized with diffusely mislocalized cytoplasmic TDP-43 but not with dense cytoplasmic aggregates, suggesting a potential role in early-stage pathological processing. To model these effects in vitro, induced pluripotent stem cell-derived motor neurons from three patients with amyotrophic lateral sclerosis and four healthy control participants were used. Knockdown of LRSAM1 in induced pluripotent stem cell-derived motor neurons from patients with amyotrophic lateral sclerosis significantly increased cytoplasmic TDP-43 accumulation and phosphorylation, as measured by immunofluorescence imaging. Moreover, STMN2 mRNA splicing, a well-established TDP-43 functional readout, was disrupted upon LRSAM1 depletion. Conversely, overexpression of LRSAM1 ameliorated stress-induced TDP-43 mislocalization and phosphorylation in induced pluripotent stem cell-derived motor neurons from patients with amyotrophic lateral sclerosis but had minimal impact in control cells, indicating disease-specific vulnerability. Mechanistically, LRSAM1 interacted directly with the aggregation-prone C-terminal fragments of TDP-43 via the RRM2 domain of TDP-43 and promoted their proteasomal degradation. This selective interaction reduced the accumulation of toxic TDP-43 species and supported cytoplasmic proteostasis, particularly under conditions of cellular stress. In summary, our study identifies LRSAM1 as a novel modulator of cytoplasmic TDP-43 dynamics in amyotrophic lateral sclerosis. By facilitating degradation of pathogenic TDP-43 fragments, LRSAM1 preserves neuronal RNA processing and mitigates molecular hallmarks of amyotrophic lateral sclerosis. These findings enhance our understanding of post-translational control of TDP-43 and highlight LRSAM1 as a promising therapeutic target for modifying disease progression in amyotrophic lateral sclerosis.}, } @article {pmid42803551, year = {2026}, author = {Matsuoka, K and Ando, M and Nakashima, T and Takeyama, H}, title = {Sensitive and derivatization-free amino acid analysis using liquid chromatography-Raman spectroscopy.}, journal = {The Analyst}, volume = {}, number = {}, pages = {}, doi = {10.1039/d6an00841k}, pmid = {42803551}, issn = {1364-5528}, abstract = {Liquid chromatography-Raman spectroscopy with post-column spotting and solvent evaporation achieved nanogram-level detection of amino acids without derivatization and demonstrated the feasibility of quantification at this level for phenylalanine and glutamine. All 20 amino acids were successfully detected regardless of chromophore presence. Lysine modifications were directly discriminated via distinct vibrational fingerprints. Co-eluting compounds were resolved by MCR-ALS-based spectral deconvolution, demonstrating that LC-Raman spectroscopy can add a spectral separation axis to chromatographic analysis. Furthermore, LC-Raman spectroscopy was also applied to quantitative analysis. For phenylalanine and glutamine, the calibration curves exhibited excellent linearity (R[2] = 0.9925 for phenylalanine, and R[2] = 0.9994 for glutamine). The quantitative results of these amino acids in the culture medium obtained via LC-Raman spectroscopy (65.9 ± 3.5 µg mL[-1] (n = 3, %RSD = 5.2%) for phenylalanine, and 576.3 ± 17.5 µg mL[-1] (n = 3, %RSD = 3.0%) for glutamine) were in good agreement with those determined by conventional detectors (66.1 µg mL[-1] for phenylalanine, and 584 µg mL[-1] for glutamine). This label-free approach establishes LC-Raman spectroscopy as a structural detection mode for LC, enabling chromatographic analysis to be coupled directly with molecular fingerprinting.}, } @article {pmid42804712, year = {2026}, author = {Avendaño-Arango, E and Salom-Palacio, I and Castillo-Támara, EE and Palacio-Villalba, B}, title = {Neuroepigenetics of the Environmental Exposome: Molecular and Clinical Implications in Neurodegeneration.}, journal = {The neurologist}, volume = {}, number = {}, pages = {}, doi = {10.1097/NRL.0000000000000694}, pmid = {42804712}, issn = {2331-2637}, abstract = {BACKGROUND: Neuroepigenetics studies the molecular mechanisms that regulate gene expression in the nervous system without altering the DNA sequence. The environmental exposome has emerged as a key factor influencing neuronal plasticity and brain homeostasis, contributing to vulnerability to neurodegeneration.

REVIEW SUMMARY: This narrative review analyzes the role of neuroepigenetic reprogramming as a central mechanism linking chronic environmental exposures with neurodegenerative diseases. Evidence indicates that alterations in DNA methylation, histone remodeling, and microRNA regulation contribute to mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation. These mechanisms are critically involved in the pathogenesis of Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis.

CONCLUSIONS: Neuroepigenetics represents a central mechanistic axis in neurodegeneration by integrating environmental exposures with intrinsic biological processes. This framework offers new opportunities for the development of early biomarkers and targeted preventive and therapeutic strategies.}, } @article {pmid42804741, year = {2026}, author = {Ishihara, K and Naito, H and Maruyama, H}, title = {REM-associated nocturnal hypercapnia in amyotrophic lateral sclerosis.}, journal = {QJM : monthly journal of the Association of Physicians}, volume = {}, number = {}, pages = {}, doi = {10.1093/qjmed/hcag270}, pmid = {42804741}, issn = {1460-2393}, } @article {pmid42805693, year = {2026}, author = {Li, H and Gao, WY}, title = {Comparison of the catalysis of ThDP-dependent enzymes AHAS, ALS, and DXPS.}, journal = {Methods in enzymology}, volume = {736}, number = {}, pages = {127-156}, doi = {10.1016/bs.mie.2026.07.004}, pmid = {42805693}, issn = {1557-7988}, mesh = {*Acetolactate Synthase/metabolism/chemistry ; *Thiamine Pyrophosphate/metabolism ; Chromatography, High Pressure Liquid/methods ; *Transferases/metabolism/chemistry ; *Enzyme Assays/methods ; Catalysis ; Biocatalysis ; }, abstract = {Thiamine diphosphate (ThDP)-dependent enzymes are primarily classified into lyases, transferases, and oxidoreductases, catalyzing various biologically important reactions such as keto transfer, dehydrogenation, decarboxylation, and stereoselective C-C bond formation/cleavage in chiral natural products biosynthesis. They constitute one of the largest superfamilies of biocatalysts, operate basically in all forms of living systems. In this chapter, the research progress on three ThDP enzymes are reviewed, including acetohydroxyacid synthase (AHAS) which is a key enzyme in the anabolic pathway for the biosynthesis of branched chain amino acids, acetolactate synthase (ALS) that belongs to the catabolic pathway for the biosynthesis of platform compounds acetoin and 2,3-butanediol, and 1-deoxy-D-xylulose-5-phosphate synthase (DXPS) which is a rate-limiting enzyme in the MEP terpenoid biosynthetic pathway and is also involved in the biosynthesis of ThDP and pyridoxal phosphate in certain bacteria, with the emphasis on comparing the catalysis of the three enzymes. Furthermore, two precolumn derivatization-HPLC protocols using 4-nitro-o-phenylenediamine and 2,4-dinitrophenylhydrazine as respective derivatizing reagents are also described in detail. The methods can not only be utilized to measure the activities of the above enzymes, supplementing the deficiencies of the classic spectrophotometry, but also be used to comprehensively elucidate the consumption of the substrate(s) and the formation of the products in the reactions catalyzed by AHAS, ALS, or DXPS.}, } @article {pmid42261159, year = {2026}, author = {Shirbhate, E and Singh, V and Mishra, OK and Koch, B and Tiwari, AK and Yasin, HKA and Rajak, H}, title = {The Pivotal Role of HDAC6 in Amyotrophic Lateral Sclerosis: Neuroprotective Protagonist or Degenerative Adversary?.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X462214260429080002}, pmid = {42261159}, issn = {1875-6190}, abstract = {The review specifically examines the pivotal role of HDAC6 in the pathophysiological pathway of Amyotrophic Lateral Sclerosis (ALS), an escalating neurodegenerative ailment marked by the discerning damage to motor neurons. Several lines of evidence implicate inadequate proteostasis in significantly influencing neuronal degeneration. The accumulation of misfolded proteins and proteotoxicity are highlighted as significant factors in ALS pathophysiology. Key pathological hallmarks include ubiquitin-positive inclusions, disrupted RNA metabolism, cytoskeletal perturbations, and compromised axonal transport systems. HDAC6 dysregulation disrupts axonal transport, impairing mitochondrial function and increasing oxidative stress, leading to rapid motor neuron damage and cell death. The enzyme's aberrant deacetylation of α-tubulin destabilizes microtubules and impairs intracellular trafficking. Despite HDAC6's participation in these unfavorable processes, it also exerts neuroprotective properties. It deacetylates tubulin, promoting efficient axonal transport and autophagic clearance. HDAC6 helps form aggresomes and stress granules, which are essential for cellular defence against proteotoxic stress. Through its zinc finger ubiquitin-binding domain, HDAC6 interacts with polyubiquitinated proteins, facilitating their autophagic degradation. HDAC6 inhibition can boost autophagic flux and reduce protein aggregation, while its activation may amplify the protective effects. This dichotomous behaviour of HDAC6 may pose an obstacle to the design of targeted therapy. Illuminating the complex mechanisms through which HDAC6 influences neurodegeneration and neuroprotection is important before constructing effective treatments for ALS. The review provides a clear understanding of the complex role of HDAC6 in ALS pathogenesis and highlights potential strategies to improve the prognosis of people affected by this neurological illness.}, } @article {pmid42262533, year = {2026}, author = {Korade, G and Kharat, S and Rathi, K}, title = {Nitric oxide in neuroinflammation and neurodegeneration: dual roles, inflammasome crosstalk, and biomarker opportunities.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {399}, number = {11}, pages = {16885-16902}, pmid = {42262533}, issn = {1432-1912}, mesh = {Humans ; Animals ; *Inflammasomes/metabolism ; *Nitric Oxide/metabolism ; *Neuroinflammatory Diseases/metabolism/drug therapy ; *Neurodegenerative Diseases/metabolism/drug therapy/immunology ; Biomarkers/metabolism ; }, abstract = {Nitric oxide is a short-lived gas that plays a critical role in numerous physiological processes, including vascular regulation, neurotransmission, and immune responses. In the CNS NO's role is complex, as it can both protect and damage neurons. Microglia, the brain's resident macrophages, produce excessive NO in response to stimuli like endotoxins and cytokines, leading to chronic inflammation and neuronal damage associated with neurodegenerative diseases such as Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis. NO's dual role as a pro-inflammatory and anti-inflammatory mediator is intricately linked to its impact on neuronal health and disease progression. This review is aimed at summarizing and critically discussing the roles of NO in neuroinflammation, neurodegeneration, inflammasome regulation, and related therapeutic perspectives. A narrative literature review was conducted using electronic databases (e.g. PubMed and Google Scholar) to identify experimental and clinical studies on NO, neuroinflammation, neurodegenerative diseases, inflammasomes, and related biomarkers and therapies, with emphasis on mechanistic and translational work. Research into NO's effects on inflammasomes, key components of the innate immune system, reveals that NO can inhibit inflammasome activation, influencing inflammatory responses. Despite progress, challenges remain, including the need for cell-type-specific models, advanced technological approaches, and the development of selective NO modulators. Overall, current evidence indicates that NO exerts both neuroprotective and neurotoxic effects in the CNS, mediated by its complex interactions with neural, glial, and immune pathways. Future research should focus on the dual nature of NO, explore lesser-known inflammasomes, and incorporate human-centric models to develop targeted therapies.}, } @article {pmid42262849, year = {2026}, author = {Deleu, B and Dupont, P and Bracaval, K and Ombelet, F and Hobin, F and Lamaire, N and Van Laere, K and Van Damme, P and De Vocht, J}, title = {[18]F FDG-PET correlates of motor neuron disease motor variants.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/21678421.2026.2682820}, pmid = {42262849}, issn = {2167-9223}, abstract = {While [18]F-fluorodeoxyglucose positron emission tomography (FDG-PET) is an established biomarker in amyotrophic lateral sclerosis (ALS), the metabolic correlates of motor neuron disease (MND) motor variants remain poorly defined. This is why we investigated patterns of cerebral glucose metabolism across the spectrum of MNDs, including progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), and ALS. We retrospectively included 18 PMA, 25 PLS, and 43 matched non-hereditary ALS patients according to most recent diagnostic criteria. FDG-PET imaging revealed similar widespread hypometabolism in PMA, as in ALS, whereas PLS showed a more focal motor cortical pattern of hypometabolism. Despite clinical differences between MND subtypes, PMA and ALS showed similar FDG-PET metabolic patterns, whereas PLS exhibited a more restricted cortical signature in this retrospective study.}, } @article {pmid42262924, year = {2026}, author = {Mastromarco, GJ and Earnshaw, R and Moore, G and Xu, XYS and Sadek, NH and Cui, F and Lo, N and Lee, HO}, title = {Human J-domain proteins promote stress granule disassembly and suppress neurodegeneration-linked protein aggregation.}, journal = {Cell reports}, volume = {45}, number = {6}, pages = {117326}, doi = {10.1016/j.celrep.2026.117326}, pmid = {42262924}, issn = {2211-1247}, mesh = {Humans ; *Stress Granules/metabolism ; *HSP40 Heat-Shock Proteins/metabolism/genetics ; *HSP70 Heat-Shock Proteins/metabolism ; Poly-ADP-Ribose Binding Proteins/metabolism ; RNA-Binding Protein FUS/metabolism/genetics ; RNA Recognition Motif Proteins/metabolism ; RNA Helicases/metabolism ; DNA Helicases/metabolism ; *Protein Aggregates ; Molecular Chaperones/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Protein Aggregation, Pathological/metabolism ; Biomolecular Condensates/metabolism ; *Cytoplasmic Granules/metabolism ; }, abstract = {Stress granules are conserved biomolecular condensates that form under stress and rapidly disassemble during recovery. Stress granules have been linked to pathological protein aggregation and their impaired disassembly reduces cell viability, yet the mechanisms governing their clearance and protein aggregation remain unclear. We find that human HSP70 and a subset of J-domain proteins (JDPs) localize to stress granules and that chemical or genetic inhibition of these chaperones markedly slows granule disassembly. Conversely, overexpressing these JDPs, particularly DNAJB1, accelerates disassembly without altering assembly. In vitro, HSP70 and DNAJB1 partition into G3BP1 condensates and reduce their size in an ATP-dependent manner. In cells expressing amyotrophic lateral sclerosis (ALS)-linked mutant FUS, DNAJB1 depletion further impairs stress granule clearance and promotes pre-amyloid accumulation, while depleting a non-stress granule JDP has no effect. Our findings demonstrate that specific JDP chaperones enhance stress granule disassembly and help limit aberrant protein aggregation.}, } @article {pmid42263252, year = {2026}, author = {Bétourné, A and Texakalidis, P and Raheb Khelo, R and Campbell, M and Sadiq, SA and Boulis, NM}, title = {Intrathecal Administration of Riluzole in Amyotrophic Lateral Sclerosis.}, journal = {Neurosurgery}, volume = {99}, number = {1}, pages = {218-222}, pmid = {42263252}, issn = {1524-4040}, mesh = {Humans ; *Riluzole/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; Injections, Spinal/methods ; Female ; *Neuroprotective Agents/administration & dosage ; Male ; Middle Aged ; Treatment Outcome ; Aged ; }, abstract = {BACKGROUND AND OBJECTIVES: Riluzole is the only treatment known to improve survival in amyotrophic lateral sclerosis (ALS) patients. However, its efficacy and dosing are limited by hepatic toxicity and interindividual pharmacokinetic variability. Recent experimental studies in hounds have shown that continuous intrathecal (IT) administration of riluzole is well tolerated and achieves significantly higher spinal cord tissue levels. We report the first 2 human ALS cases treated with IT riluzole.

METHODS: A catheter was inserted into the lumbar cistern and advanced to the midcervical region under fluoroscopic guidance and connected to a subcutaneous pump. Therapy was initiated at 0.1 mg/h of riluzole. The infusion rate was gradually increased until it reached a maximum of 4.8 mg/d.

RESULTS: The 2 patients tolerated dose escalation and treatment for over 2 years without apparent motor or sensory complications. Patients reported no asthenia, a central side effect often reported as a reason to abandon oral therapy.

CONCLUSION: This is the first report of chronic IT riluzole infusion in humans at a dose found to be safe in canines. A phase 1 study is planned to establish the maximum tolerated human dose, followed by a randomized placebo-controlled trial to determine the safety and tolerability of IT riluzole in patients with ALS.}, } @article {pmid42263370, year = {2026}, author = {Deveci, Ş and Matur, Z and Erzurumluoğlu, SS}, title = {Sensory abnormalities and entrapment neuropathies identified by nerve conduction studies in patients with amyotrophic lateral sclerosis.}, journal = {Neuromuscular disorders : NMD}, volume = {64}, number = {}, pages = {106463}, doi = {10.1016/j.nmd.2026.106463}, pmid = {42263370}, issn = {1873-2364}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/epidemiology ; Female ; Male ; Nerve Conduction Studies ; Middle Aged ; Retrospective Studies ; Cross-Sectional Studies ; Aged ; *Neural Conduction/physiology ; *Nerve Compression Syndromes/physiopathology/diagnosis/epidemiology/etiology ; Adult ; *Sensation Disorders/physiopathology/diagnosis/etiology ; Aged, 80 and over ; Comorbidity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily affecting motor neurons; however, non-motor symptoms, including sensory and autonomic disturbances, are increasingly recognized. This retrospective cross-sectional study evaluated the frequency of sensory and entrapment neuropathies in 114 patients with ALS using electrodiagnostic (EDX) studies. Demographic characteristics, comorbidities, and sensory and autonomic symptoms were documented. Electrophysiological evidence of sensory neuropathy was identified in 20 patients overall (20/114, 17.5%), including 10 patients without diabetes mellitus (DM), whereas entrapment neuropathy was detected in 28 patients overall (28/114, 24.6%), including 16 of those without DM or hypothyroidism. Sensory neuropathy was significantly associated with both DM and a history of chronic disease. In contrast, these comorbid conditions were not significantly associated with entrapment neuropathy. Furthermore, patient-reported symptoms showed no correlation with electrophysiological evidence of sensory involvement on EDX. Sensory neuropathy was more frequent in patients with spinal-onset than bulbar-onset disease, although the difference was not statistically significant. This study confirms that sensory involvement is not uncommon in ALS. Although clinical symptoms are poor predictors, electrophysiological abnormalities consistent with sensory and entrapment neuropathies are common. A significant proportion of these abnormalities are idiopathic and may directly reflect the disease process itself, particularly in spinal-onset cases.}, } @article {pmid42264185, year = {2026}, author = {Baker, A and Okorie, M}, title = {UK Foundation Programme training needs a national minimum standard for advanced life support.}, journal = {Clinical medicine (London, England)}, volume = {26}, number = {4}, pages = {100605}, pmid = {42264185}, issn = {1473-4893}, mesh = {Humans ; United Kingdom ; *Clinical Competence/standards ; *Advanced Cardiac Life Support/standards/education ; Curriculum ; *Foundations ; }, abstract = {Since 2021, advanced life support (ALS) has no longer been a mandatory requirement of the UK Foundation Programme. Although the shift towards capability rather than certification was educationally defensible, in practice it has created marked national variation in how resuscitation preparedness is developed, evidenced and signed off. Foundation doctors now enter emergencies with unequal access to funded ALS training, simulation and supervised assessment, while supervisors are left to judge equivalence without a consistent national threshold. This matters not because patient-level harm has been neatly proven, but because high-stakes clinical capability should not depend on local opportunity or variable interpretation. A capability-based curriculum and a national minimum standard are not mutually exclusive. The Foundation Programme should therefore restore a national ALS requirement, or a formally recognised equivalent standard, alongside funded access, blended delivery and transparent national evaluation of uptake, exemptions and outcomes.}, } @article {pmid42264545, year = {2026}, author = {Vishwakarma, H and Chauhan, A and Kaur, L and Awasthi, A}, title = {Nanotechnology-enabled targeting strategies for neurodegenerative disorders: role of functionalized nanoparticles.}, journal = {The Journal of pharmacy and pharmacology}, volume = {78}, number = {6}, pages = {}, doi = {10.1093/jpp/rgag060}, pmid = {42264545}, issn = {2042-7158}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/physiopathology/metabolism ; Animals ; *Nanoparticles ; Blood-Brain Barrier/metabolism ; *Drug Delivery Systems/methods ; Neuroprotective Agents/administration & dosage ; *Nanotechnology/methods ; Oxidative Stress/drug effects ; }, abstract = {BACKGROUND: Neurodegenerative disorders comprise a diverse group of progressive neurological diseases characterized by the gradual loss of neuronal structure and function. Conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis arise from multifactorial mechanisms involving genetic susceptibility, environmental factors, and age-related cellular decline.

PATHOPHYSIOLOGY: Key pathogenic processes include oxidative stress, mitochondrial dysfunction, protein misfolding and aggregation, impaired axonal transport, Golgi fragmentation, and chronic neuroinflammation, all of which disrupt neuronal homeostasis and synaptic communication, ultimately leading to neuronal death. Hormonal imbalances further exacerbate these effects by promoting oxidative damage, inflammation, and metabolic dysfunction.

CHALLENGES IN THERAPY: Despite advances in understanding disease mechanisms, effective drug delivery remains challenging due to the restrictive nature of the blood-brain barrier.

Recent developments highlight the potential of nanoparticle-based drug delivery systems to overcome these limitations. Functionalized nanoparticles enhance blood-brain barrier penetration, improve targeting specificity, and enable controlled drug release. These systems can deliver neuroprotective agents, antioxidants, peptides, and gene therapies directly to affected brain regions. Thus, integrating disease pathophysiology with nanotechnology-based strategies offers a promising approach for improving therapeutic outcomes and advancing precision treatment in neurodegenerative disorders.}, } @article {pmid42264722, year = {2026}, author = {He, S and Yu, H and Li, X and Chen, J and Liu, Z and Miao, D and Ren, M and Cui, H}, title = {Distribution of resistant Aegilops tauschii populations across China and its target-site resistance mechanism.}, journal = {Pesticide biochemistry and physiology}, volume = {221}, number = {}, pages = {107181}, doi = {10.1016/j.pestbp.2026.107181}, pmid = {42264722}, issn = {1095-9939}, mesh = {*Herbicide Resistance/genetics ; China ; *Aegilops/genetics/drug effects ; Acetolactate Synthase/genetics/metabolism ; *Herbicides/pharmacology/toxicity ; *Sulfonylurea Compounds/pharmacology/toxicity ; Mutation ; Plant Proteins/genetics/metabolism ; *Poaceae/genetics/drug effects ; }, abstract = {Aegilops tauschii is a notorious weed that poses a severe threat to wheat production. Recently, its resistance to mesosulfuron-methyl has been increasingly documented in some provinces of China. With Ae. tauschii rapidly expanding its distribution range throughout China, however, its nationwide resistance distribution and the underlying resistance molecular mechanisms remain poorly understood. To address this knowledge gap, 305 populations of Ae. tauschii were collected from eight major wheat-growing provinces of China to characterize their nationwide resistance profiles and target-site resistance mechanisms. Of the populations examined, 83 populations from Shanxi, Shaanxi, Henan, Hebei, Shandong, and Jiangsu provinces exhibited varying levels of resistance to mesosulfuron-methyl. Resistant populations were particularly widespread in Shanxi and Shaanxi compared with other regions. Forty-seven resistant populations were then selected for target-site mutation analysis. A Pro-197-Leu substitution in the acetolactate synthase (ALS) gene was identified in 14 resistant populations, whereas no known resistance-conferring amino acid alteration was detected in the remaining 33 populations. Resistant populations carrying the Pro-197-Leu mutation displayed a higher resistance level than resistant populations without ALS gene mutations. Furthermore, in vitro ALS activity assays showed that populations with the Pro-197-Leu substitution were highly resistant to mesosulfuron-methyl, with resistance index (RI) ranging from 32.95 to 33.12. In contrast, the RI values of resistant populations lacking target-site mutations were below 2.90. To the best of our knowledge, this study represents the first report of a target-site mutation (Pro-197-Leu) conferring resistance to mesosulfuron-methyl in Ae. tauschii.}, } @article {pmid42264735, year = {2026}, author = {Rojano-Delgado, AM and Sohrabi, S and Santana, APDS and Palma-Bautista, C and Domínguez-Valenzuela, JA and Gherekhloo, J and Alcántara-de la Cruz, R and De Prado, R}, title = {Herbicide metabolism and EPSPS Pro-106-Ser substitution confer multiple resistance in Chenopodium spp. from Southern Spain.}, journal = {Pesticide biochemistry and physiology}, volume = {221}, number = {}, pages = {107132}, doi = {10.1016/j.pestbp.2026.107132}, pmid = {42264735}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology/metabolism ; *Herbicide Resistance/genetics ; *Chenopodium/drug effects/genetics/metabolism/enzymology ; Spain ; Glyphosate ; *3-Phosphoshikimate 1-Carboxyvinyltransferase/genetics/metabolism ; *Plant Proteins/genetics/metabolism ; Glycine/analogs & derivatives/pharmacology ; Acetolactate Synthase/metabolism/antagonists & inhibitors ; }, abstract = {Long-term herbicide programs in Mediterranean perennial systems have imposed sustained selection pressure on weed populations, promoting the evolution of multiple resistance. We investigated resistance mechanisms in Chenopodium album (Ca) and C. vulvaria (Cv) from southern Spain following more than two decades of glyphosate-based management. We aimed to (i) confirm resistance to atrazine, tribenuron-methyl (TM), glyphosate, and 2,4-D; (ii) distinguish between target-site and metabolic resistance; and (iii) characterize the biochemical and molecular basis of cross- and multiple-herbicide resistance. Screening assays revealed high survival (78-100%) of resistant (R) populations to acetolactate synthase (ALS)-, photosystem II (PSII)-, auxinic-, and 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS)-inhibiting herbicides. Dose-response assays confirmed resistance, with resistance indices (RI) of 6.7 and 5.1 for atrazine, 19.0 and 17.3 for TM, 7.0 and 13.9 for glyphosate, and 6.0 and 6.9 for 2,4-D in CaR and CvR, respectively. Radiolabelled and analytical metabolism assays demonstrated enhanced herbicide metabolism in R populations: atrazine (94-95% vs. 13-16% in S), TM (68-69% vs. 24-25%), 2,4-D (64-65% vs. 2-4%), and glyphosate (39-43% vs. 8-9%). Malathion partially reversed resistance to atrazine, TM, and 2,4-D, supporting cytochrome P450 (CYP450) involvement. In contrast, glyphosate metabolism was independent of CYP450 or glutathione S-transferases inhibition. Biochemical assays showed no differences in PSII or ALS sensitivity (I50 RI ≈ 1), whereas EPSPS inhibition assays revealed a tenfold increase in I50 in CvR. Sequencing identified a Pro-106-Ser substitution in EPSPS exclusively in CvR. Enhanced metabolism predominates in the R Chenopodium spp. populations, with coexistence of metabolic and target-site mechanisms in CvR, increasing the risk of further cross-resistance under continued herbicide reliance.}, } @article {pmid42265364, year = {2026}, author = {Treittinger, K and Yang, S and Fischer, R and Dreisbach, G}, title = {The asymmetric list shift effect - flexible adaptation to new context demands?.}, journal = {Attention, perception & psychophysics}, volume = {88}, number = {5}, pages = {}, pmid = {42265364}, issn = {1943-393X}, mesh = {Humans ; Stroop Test ; Young Adult ; Cognitive Flexibility/physiology ; Female ; Male ; Adult ; *Attention/physiology ; *Adaptation, Psychological/physiology ; *Executive Function/physiology ; Pattern Recognition, Visual/physiology ; *Practice, Psychological ; Reaction Time/physiology ; }, abstract = {The list-wide proportion congruency effect describes how the congruency effect varies depending on the frequency of incongruent trials within a block. Specifically, the congruency effect is larger in mostly congruent (MC) blocks compared to mostly incongruent (MI) blocks. Research has shown that adaptation to these blocks does not change symmetrically when transitioning between them: moving from MC to MI leads to a rapid decrease in the congruency effect while transitioning from MI to MC results in little or no increase (Abrahamse et al., 2013). We aimed to investigate this asymmetric list shift (ALS) effect in a within-participants design where all participants experienced both transitions (MC-MI and MI-MC). Throughout Experiments 1-3 using a color-word Stroop task, we identified various forms of practice - including trial-type, stimulus-specific learning, general RT decrease, and a decrease in congruency effects over time (see Schmidt, 2016) - that can either facilitate or obscure the ALS effect, depending on the order in which participants experienced the transitions. In Experiment 4, using a face-name version of the Stroop task, where we minimized practice-related confounding factors by employing more complex stimuli and used a new stimulus set in the second transition, an ALS effect was observed regardless of the order of transition and for frequency-unbiased (i.e., 50% congruent) items. The role of practice effects and implications for the (in)-flexibility of control adaptations will be discussed.}, } @article {pmid42265600, year = {2026}, author = {Jiang, S and Chen, F and Ma, H and Wu, S and Tang, X and Pan, X and Li, Q and Tao, A and Xu, J and Qi, J and Fang, P and Chen, J and Zhang, L}, title = {Cloning and functional verification of endogenous U6 promoters for developing an efficient CRISPR/Cas9-mediated genome editing system in kenaf (Hibiscus cannabinus L.).}, journal = {BMC plant biology}, volume = {26}, number = {1}, pages = {}, pmid = {42265600}, issn = {1471-2229}, support = {32472219//the National Natural Science Foundation of China/ ; 2023J01443//Fujian Provincial Natural Science Foundation of China/ ; CARS-16//China Agricultural Research System of MOF and MARA/ ; KFB23001//Science and Technology Innovation Project of Fujian Agriculture and Forestry University/ ; ASTIP-IBFC-01//Agriculture Science and Technology Innovation Program/ ; }, mesh = {*Promoter Regions, Genetic/genetics ; *CRISPR-Cas Systems ; *Hibiscus/genetics ; *Gene Editing/methods ; Cloning, Molecular ; *RNA, Small Nuclear/genetics ; Plants, Genetically Modified ; Genome, Plant ; }, abstract = {BACKGROUND: The U6 promoter is a critical component of the CRISPR/Cas9 system, as it drives the transcription of single-guide RNAs (sgRNAs) to enable precise genome editing. Endogenous promoters typically exhibit higher transcriptional activity than their exogenous counterparts, which can significantly enhance editing efficiency. However, the endogenous U6 promoter in kenaf (Hibiscus cannabinus L.), an important fiber crop, has not yet been characterized.

METHODS: Using the Arabidopsis U6-26 (AtU6-26) promoter as a reference, we performed a homologous sequence search and identified two candidate U6 promoters in kenaf, designated HcU6-1 and HcU6-14. Promoter fragments were amplified from the kenaf cultivar 'Fuhong 952' and cloned into a β-glucuronidase (GUS) reporter vector. Histochemical GUS staining assays revealed that both HcU6 promoters were transcriptionally active, with HcU6-14 showing significantly stronger expression levels compared to HcU6-1.

RESULTS: To further evaluate the utility of these promoters for genome editing, we constructed CRISPR/Cas9 vectors targeting the kenaf acetolactate synthase (ALS) gene, driven by either HcU6-14P or the exogenous cotton GbU6-9P promoter. Agrobacterium rhizogenes K599-mediated transformation was used to induce hairy roots, and mutation analysis of the ALS gene was performed via Sanger sequencing. Notably, targeted mutations in the ALS gene were detected in hairy roots transformed with the HcU6-14P-driven CRISPR/Cas9 vector, whereas no mutations were observed in roots transformed with the exogenous GbU6-9P promoter. These results demonstrate that the endogenous HcU6-14 promoter confers superior genome editing efficiency compared to the heterologous promoter, which facilitates the development of improved varieties with enhanced agronomic traits.}, } @article {pmid42265995, year = {2026}, author = {Ozlu, C and Schwaede, A and McGowan, B and Zhang, L and Finch, M and Wolfe, LF and Ajroud-Driss, S and Franz, CK and Kuntz, N}, title = {Two Patients With Juvenile-Onset, Rapidly Progressive Amyotrophic Lateral Sclerosis Associated With an SOD1 Variant (p.Asp125Gly) With Incomplete Penetrance.}, journal = {Muscle & nerve}, volume = {74}, number = {2}, pages = {457-462}, doi = {10.1002/mus.70314}, pmid = {42265995}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/diagnostic imaging ; *Superoxide Dismutase-1/genetics ; Male ; Adolescent ; Disease Progression ; *Penetrance ; Female ; Age of Onset ; Mutation/genetics ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) patients are rarely encountered before age 25 years, often associated with genetic variants. SOD1 gene variants are well-known to account for a subset of adult-onset ALS but have only been described in a handful of early onset patients. Variants affecting residue 125 in SOD1 have been described in adult-onset ALS patients with a rapid progression. Here we report two such patients.

METHODS: The clinical, genetic, and electrodiagnostic findings of two unrelated adolescents with juvenile onset rapidly progressive SOD1 -ALS are described.

RESULTS: Patient 1 presented at 16 and patient 2 at 15 years-of-age with lower limb onset of weakness, lower motor neuron examination findings, and rapid progression over months to involve all body regions. Both patients underwent extensive laboratory, electrophysiologic, and radiologic testing ruling out any alternate etiologies. For both patients, whole-exome sequencing revealed the pathogenic variant p.Asp125Gly in the SOD1 gene inherited from asymptomatic fathers.

DISCUSSION: These two patients expand the phenotypic spectrum of SOD1 -ALS, demonstrating a rapidly progressive juvenile lower limb onset phenotype associated with the p.Asp125Gly variant inherited with incomplete penetrance. Recognition and further characterization of juvenile SOD1 -ALS are important in light of the advances in targeted therapies.}, } @article {pmid42266360, year = {2026}, author = {Ilczak, T and Ćwiertnia, M and Sumera, K and Babik, P and Białoń, P and Dutka, M and Malinowska-Lipień, I and Augustyn, M and Majewski, M and Lis, A and Leszczyński, P and Stasicki, A and Abramczyk, P and Kukla, P and Pollok-Waksmańska, W and Trojak-Piętka, J and Kawecki, M}, title = {Nontechnical Skills (NTS) and the Quality of Conducting Prehospital Advanced Cardiopulmonary Resuscitation Among Paramedics.}, journal = {Emergency medicine international}, volume = {2026}, number = {}, pages = {2207053}, pmid = {42266360}, issn = {2090-2840}, abstract = {INTRODUCTION: It is common knowledge that the correct application of cardiopulmonary resuscitation (CPR) requires technical skills such as defibrillation, high-quality chest compressions, and efficient airway management. However, scientific research is increasingly underlining the role of appropriate training in nontechnical skills (NTS).

RESEARCH AIM: This exploratory study aimed to assess the relationship between NTS and the quality of advanced CPR among paramedics.

MATERIALS AND METHODS: The research involved 51 paramedics randomly assigned to 17 three-person teams. Each team participated in a 15-min cardiac arrest scenario. After the first session, the teams were divided into two groups: the intervention group (Group 1), which underwent specialized NTS training, and the control group (Group 2), which did not receive the initial training. Directly after the training phase, all teams from both groups carried out a second attempt during a simulated sudden cardiac arrest (SCA) scenario identical to the first one.

RESULTS: The lowest CPR result in the intervention group (Group 1) was Min = -3.00, and the highest Max = 13.00, while in the control group (Group 2), the lowest result was Min = -42.00, and the highest Max = 8.00 (p < 0.05). In Group 1, a statistically significant correlation (p < 0.05) was noted between the change in the NTS score and the change in the CPR result. A higher NTS score was accompanied by a higher CPR score.

CONCLUSIONS: A short NTS training session was associated with improved NTS application by paramedic resuscitation teams. Furthermore, higher chest compression quality positively correlated with NTS proficiency.}, } @article {pmid42267597, year = {2026}, author = {Held-Bradford, EC and DeMarco, E and Zocher, S and Weaver, K and Forsman, K and Hayat, G and Subramaniam, DS and Doherty, M}, title = {Functional Motor Change Across Time and Phenotypes in Patients With Amyotrophic Lateral Sclerosis: A Descriptive Study.}, journal = {Neurorehabilitation and neural repair}, volume = {}, number = {}, pages = {15459683261445435}, doi = {10.1177/15459683261445435}, pmid = {42267597}, issn = {1552-6844}, abstract = {PURPOSE: Progressive disability occurs in persons with amyotrophic lateral sclerosis (pALS), but change over time across phenotypes remains understudied, limiting clinical decision-making. This descriptive study describes functional motor change with detailed measures across ALS phenotypes to enhance clinical decision making.

MATERIALS AND METHODS: Electronic health record data from an interdisciplinary ALS clinic (n = 109 pALS, 2018-2022) including demographics, disability (ALS Functional Rating Scale-[ALSFRS-R]), and functional motor scores (10 m Walk, Handheld dynamometry [grip and ankle]) was utilized. Phenotype groups were defined by site of onset (bulbar, limb onset; upper limb or lower limb). Analysis was conducted using R and included changes scores and measures of central tendency in 3-month intervals.

RESULTS: PALS included n = 43 bulbar, n = 32 upper limb, n = 34 lower limb onset, age 65, 60 to 71 (median, interquartile range). ALFSRS-R decline was greatest in bulbar, and similar in upper and lower limb. Patterns of change within motor scores suggest greatest loss of grip strength in bulbar and upper limb, ankle strength in upper limb, walking speed in lower limb, and preservation of community ambulation in upper limb.

CONCLUSION: While ALSFRS-R scores were similar in upper and lower limb, detailed functional motor measures indicated differences in groups. These patterns provide insight to guide clinical decision making and future research to enhance care in pALS.}, } @article {pmid42267908, year = {2026}, author = {Donati Della Lunga, I and Cerutti, L and Barabino, V and Figus, GG and Callegari, F and Oneto, L and Tedesco, M and Bacchetti, F and Milanese, M and Massobrio, P and Brofiga, M}, title = {Developmental circuit instability in amyotrophic lateral sclerosis: from hyperexcitability to network collapse.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag185}, pmid = {42267908}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a late-onset motor neuron disease, yet how cortical dysfunction originates and contributes to pathogenesis remains unresolved. In this study, we reconstruct the developmental trajectory of cultured cortical networks derived from SOD1G93A mouse embryos using a multimodal approach, by combining morphometric, electrophysiological, pharmacological, molecular, computational, and machine-learning techniques. We prove that ALS neurons fail to acquire mature polarization and connectivity, displaying a transient phase of hyperexcitability that precedes a progressive collapse of network organization. Astrocytic dysfunction emerges early and impairs synchronization, establishing a causal link between glial dysfunction and neuronal instability. The analysis of synaptic transmission reveals an excitatory bias followed by maladaptive inhibitory recruitment and GABA/glutamate co-release, causing fragmented and inefficient network topologies. Finally, in silico modelling identified deficient intrinsic adaptation as a key driver of hyperexcitability. Together, our findings position ALS as a developmentally rooted disorder of cultured cortical network homeostasis, driven by glial, synaptic, and intrinsic adaptation failures. By demonstrating that cortical dysfunction is embedded before degeneration, this work provides a unifying framework connecting early network instability to disease progression and establishes electrophysiological network signatures, detected by machine learning classifiers, as candidate biomarkers for early diagnosis and therapeutic screening.}, } @article {pmid42268433, year = {2026}, author = {Sytwu, HP and Jih, KY and Tsai, YS and Fang, SY and Liao, YC and Lee, YC}, title = {FUS-associated ALS in Taiwan: genetic spectrum, clinical features, and a founder haplotype of p.H517D.}, journal = {Journal of neurology}, volume = {273}, number = {7}, pages = {}, pmid = {42268433}, issn = {1432-1459}, support = {112-2314-B-075-034-MY3//National Science and Technology Council/ ; 114-2314-B-075-021-MY3//National Science and Technology Council/ ; 113-2314-B-075-018-MY3//National Science and Technology Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/epidemiology ; *RNA-Binding Protein FUS/genetics ; Taiwan ; Haplotypes ; Female ; Male ; Middle Aged ; *Founder Effect ; Adult ; Aged ; Cohort Studies ; Age of Onset ; *Mutation/genetics ; }, abstract = {OBJECTIVE: To characterize the genetic spectrum and clinical features of FUS-associated amyotrophic lateral sclerosis (ALS) in a Taiwanese cohort and to investigate whether the recurrent p.H517D variant represents a founder mutation.

METHODS: All coding exons and flanking intronic regions of FUS were analyzed by Sanger sequencing in 650 unrelated Taiwanese patients with ALS. Clinical characteristics of patients carrying FUS variants were evaluated. Haplotype analysis using polymorphic microsatellite markers flanking FUS was performed to assess a potential founder effect of the p.H517D variant.

RESULTS: Eight distinct heterozygous pathogenic FUS variants were identified in 11 probands and five affected relatives, including six missense and two frameshift variants. The most frequent variant was p.H517D, detected in four probands. A novel frameshift variant, p.G499Vfs*30, was identified as a de novo mutation in a juvenile-onset ALS patient. Compared with the non FUS-associated ALS cohort, patients with FUS-associated ALS had a significantly younger mean age at onset (40.1 vs 56.6 years) and more frequent bulbar onset (50% vs 19%). Haplotype analysis suggested a common founder for the p.H517D variant.

CONCLUSIONS: FUS mutations accounted for 1.7% of ALS cases in this Taiwanese cohort. The recurrent p.H517D variant appears to represent a population-specific founder mutation. Patients with FUS variants presented with earlier disease onset and heterogeneous clinical phenotypes, and de novo variants contributed to juvenile-onset disease.}, } @article {pmid42268660, year = {2026}, author = {Roy, É and Blais, M and Dion, P and Rouleau, GA and Dupré, N and Picher-Martel, V}, title = {Oligogenic variants in NEK1 and ATXN2 in amyotrophic lateral sclerosis: report of two cases and review of the literature.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2685158}, pmid = {42268660}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects the upper and lower motor neurons and leads to progressive paralysis. More than 40 genes have been implicated in familial ALS, which represents about 10% of ALS cases. Some genes, including C9orf72, SOD1, FUS and TARDBP are undoubtedly considered causative, but many others have uncertain pathogenicity and low penetrance. Here, we described the cases of two siblings affected by ALS and carrying both an ATXN2 heterozygous 32 CAG trinucleotide repeat expansion and a novel NEK1 heterozygous c.1674_1677dup. The segregation of both variants in this large family with thirteen siblings may support a role for these variants as susceptibility alleles within an oligogenic model. Our review of the literature suggests that NEK1 variants are frequently found in combination with other variants and repeats expansion in the ATXN2 gene appears to be more associated with monogenic ALS, but also frequently combined with C9orf72 repeat expansion.}, } @article {pmid42269975, year = {2026}, author = {Ma, M and Cui, B and Sun, X and Liu, S and Shao, K and Liu, F and Lin, P and Li, W and Zhao, Y and Yu, D and Lou, J and Yun, Y}, title = {Progressive choroid plexus enlargement across disease stages in patients with sporadic amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {227}, number = {}, pages = {107481}, doi = {10.1016/j.nbd.2026.107481}, pmid = {42269975}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/cerebrospinal fluid ; Female ; *Choroid Plexus/pathology/diagnostic imaging ; Male ; Disease Progression ; Magnetic Resonance Imaging ; Middle Aged ; Prospective Studies ; Cross-Sectional Studies ; Aged ; Longitudinal Studies ; Adult ; }, abstract = {BACKGROUND: The choroid plexus (CP), a key structure involved in cerebrospinal fluid homeostasis and glymphatic function, is increasingly recognized as an interface for neuroimmune communication. Recent studies have identified CP abnormalities as potential neuroimaging markers in several neurodegenerative disorders, including sporadic amyotrophic lateral sclerosis (sALS). However, whether CP enlargement occurs early and progresses across clinical stages or over time in patients with sALS remains unclear. Given the role of the CP in peripheral-central nervous system immune crosstalk, the association between neuroinflammation and CP abnormalities in sALS also requires clarification. In this prospective study, we used structural MRI to examine cross-sectional and longitudinal CP volume changes in patients with sALS and to evaluate their associations with CSF inflammatory markers.

METHODS: This prospective study included 161 newly diagnosed patients with sALS who underwent genetic testing and structural MRI, and 64 healthy controls (HCs) who underwent structural MRI. Disease stage in patients with sALS was assessed using the King's staging system. Longitudinal MRI was performed in a subset of 42 patients, of whom 38 also underwent baseline CSF inflammatory protein assessment.

RESULTS: Compared with HCs, patients with sALS at all King's stages showed significantly larger CP volumes after Bonferroni correction (all p < 0.05). CP volumes were significantly greater in patients at King's stage 3 than in those at King's stage 1 or stage 2 after Bonferroni correction (all p < 0.05). In the longitudinal subgroup, CP volume increased significantly from baseline to follow-up. Multivariable analysis showed that higher CSF CHIT1 and IL-6 levels were independently associated with larger CP volume in patients with sALS (β = 0.348-0.456; p < 0.01).

CONCLUSIONS: Our findings provide evidence that CP enlargement occurs early and progresses across disease stages and over time in patients with sALS. Higher CSF CHIT1 and IL-6 levels were associated with larger CP volume, supporting a potential link between neuroinflammation and CP abnormalities in sALS. These findings support CP enlargement as a promising neuroimaging marker for monitoring disease progression and neuroinflammatory processes in patients with sALS.}, } @article {pmid42270846, year = {2026}, author = {Wood, H and Hamdi, N}, title = {Advancing amyotrophic lateral sclerosis research in Egypt.}, journal = {Nature reviews. Neurology}, volume = {22}, number = {7}, pages = {404-405}, doi = {10.1038/s41582-026-01230-x}, pmid = {42270846}, issn = {1759-4766}, } @article {pmid42271582, year = {2026}, author = {Ito, M}, title = {[Re-evaluating ALS Medical Care in Japan: An International Comparison of Japan, Europe, the United States, and Canada-Insights from Mechanical Ventilation, Support for Social Participation, End-of-Life Care Options, Approved Drugs, and Precision Medicine].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {78}, number = {6}, pages = {654-657}, doi = {10.11477/mf.188160960780060654}, pmid = {42271582}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Terminal Care ; *Precision Medicine ; Japan ; United States ; Europe ; *Respiration, Artificial ; Canada ; Palliative Care ; }, abstract = {Amyotrophic lateral sclerosis (ALS) care in Japan should be re-evaluated not simply as a matter of clinical choice but as a function of the public support system structure. In Japan, care is distinguished by a publicly funded model that supports home-based living and social participation following tracheostomy invasive ventilation. In contrast, Europe reflects a model centered on non-invasive ventilation and palliative care, and the United States reflects a system in which precision therapies are approved earlier but access remains highly unequal. Further, Canada reflects a model integrating multidisciplinary ALS clinics with Medical Assistance in Dying within a shared policy framework. These differences extend beyond treatment preferences and instead reflect broader social, institutional, and ethical configurations that shape the future of individuals with ALS. As access to emerging disease-modifying therapies increasingly depends on genetic testing, the central challenge in ALS care is shifting from end-of-life decision-making to the equitable distribution of precision medicine. Comparative reappraisal of national care models is therefore critical for understanding ALS not only as a neurological disease but also as a condition shaped by welfare systems, care infrastructure, and policy design.}, } @article {pmid42271589, year = {2026}, author = {Kunieda, K}, title = {[Clinical Management of Dysphagia and Nutritional Disorders in Neurodegenerative Diseases].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {78}, number = {6}, pages = {695-700}, doi = {10.11477/mf.188160960780060695}, pmid = {42271589}, issn = {1881-6096}, mesh = {Humans ; *Deglutition Disorders/therapy/etiology ; *Neurodegenerative Diseases/complications/therapy ; *Nutrition Disorders/therapy/etiology ; }, abstract = {Dysphagia is common in patients with neuro degenerative diseases. It is associated with aspiration pneumonia, malnutrition, and reduced quality of life. Swallowing assessment should incorporate therapeutic perspectives, including the use of compensatory strategies. In conditions such as amyotrophic lateral sclerosis, weight loss is associated with a poor prognosis, and nutritional therapy may function as a disease-modifying intervention. Clinical ethical issues may arise, including decisions regarding gastrostomy or care for patients with impaired decision-making capacity. A multidisciplinary team approach is essential for managing dysphagia and nutritional problems in these patients.}, } @article {pmid42272352, year = {2026}, author = {Lizio, A and Farè, M and Gerardi, F and Collesi, M and Sansone, VA and Lunetta, C and Diamanti, L and Cerri, F}, title = {Impact of treatment burden on medication adherence and quality of life in amyotrophic lateral sclerosis: a prospective multicentre study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2683691}, pmid = {42272352}, issn = {2167-9223}, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) face substantial barriers to medication adherence as disease progression necessitates complex drug formulation adjustments, such as crushing tablets, mixing with liquids, or delivering via feeding tubes. These modifications may not only increase the time and effort required but could also impact drug efficacy and safety.

OBJECTIVE: To evaluate the prevalence and the impact of treatment burden on medication adherence and patient-reported quality of life (QoL) in ALS.

METHODS: This prospective multicenter study enrolled ALS patients across three Italian reference centers, with assessments at baseline, 6, and 12 months. Key measures included the Multimorbidity Treatment Burden Questionnaire (MTBQ), ALSFRS-R, DYALS (dysphagia), Morisky Medication Adherence Scale, SSS-8 (somatic symptoms), INQoL (QoL), SWAMECO (swallowing/medication difficulties), alongside comorbidities and current therapies. Associations between treatment burden, QoL, and adherence were analyzed using multivariable models.

RESULTS: A total of 114 consecutive ALS patients were enrolled. Clinically significant treatment burden was observed in 69.3% of patients, with over half reporting moderate-to-high levels according to the MTBQ classification. Elevated burden was independently related to greater somatic symptom severity and formulation modification needs. Moreover, higher burden associated with poorer QoL and diminished adherence after confounder adjustment. Longitudinally, patients experiencing worsening burden over 1 year showed accelerated QoL decline compared to those remaining stable, though adherence trajectories were unaffected.

CONCLUSION: Treatment burden, particularly driven by drug formulation complexities and somatic symptoms, emerges as a pivotal, modifiable determinant of adherence and QoL in ALS. Targeted interventions to alleviate modifiable burden components hold promise for optimizing clinical outcomes and enhancing patient-centred care.}, } @article {pmid42274555, year = {2026}, author = {Khan, MS and Zafar, I and Noman, M and Yang, G and Kang, KS and Bopassa, JC}, title = {Polypharmacology of Pathway Crosstalk in Neurodegenerative Diseases: Chemical Modulation of Interconnected Signaling Networks.}, journal = {Cells}, volume = {15}, number = {11}, pages = {}, pmid = {42274555}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Signal Transduction/drug effects ; *Polypharmacology ; Animals ; Oxidative Stress ; Mitochondria/metabolism ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), arise from highly interconnected molecular and cellular abnormalities that progressively lead to neuronal dysfunction, synaptic failure, and cell death. This review provides a unified framework to understand the interrelated molecular mechanisms driving these diseases, with a focus on identifying key disease-specific intervention nodes. Core contributors include oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and emerging roles of peroxisomal dysfunction in redox imbalance, lipid dysregulation, and inflammatory amplification. Single-target therapies often show limited efficacy due to the complex, interconnected nature of these pathways. In contrast, polypharmacology, which targets multiple disease-relevant mechanisms simultaneously, offers a more promising therapeutic strategy. This review critically examines how pathway crosstalk drives neurodegenerative progression, with particular emphasis on mitochondrial-ROS-inflammatory signaling, aggregation-proteostasis failure, synaptic-neuroimmune dysfunction, and gut-brain communication. It evaluates various multi-node intervention strategies, including multi-target-directed ligands (MTDLs), molecular hybrids, natural products, drug repurposing, and nanocarrier-based delivery systems. Advances in network pharmacology, artificial intelligence (AI), bioinformatics, and multi-omics have enhanced the identification of actionable therapeutic nodes, candidate compounds, and brain-targeted delivery platforms. Notably, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathways-play distinct roles in neuroinflammation, amplifying neuronal damage by releasing inflammatory cytokines and inducing mitochondrial dysfunction. However, successful translation into clinical practice remains constrained by challenges such as blood-brain barrier penetration, patient heterogeneity, and biomarker limitations. The review advocates for a shift towards mechanism-informed, patient-stratified polypharmacological strategies to better address the network pathology of neurodegeneration, despite significant translational hurdles.}, } @article {pmid42274577, year = {2026}, author = {Schuldt, ON and Leitch, SR and Jones, LK and Buckley, PR and Morrison, BE}, title = {Neuroinflammatory Remodeling by Type 2 Immune Pathways Links Allergic Signaling to Neurodegenerative Disease.}, journal = {Cells}, volume = {15}, number = {11}, pages = {}, pmid = {42274577}, issn = {2073-4409}, support = {R15HL165397//National Heart Lung and Blood Institute/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/immunology/pathology ; Animals ; *Signal Transduction/immunology ; *Hypersensitivity/immunology ; *Neuroinflammatory Diseases/immunology ; }, abstract = {The hallmarks of allergic diseases are Type 2 immunity, including IL-4 and IL-13 production, IgE antibody generation, mast cell and basophil activation, histamine release, and eosinophil activation. There are many routes by which such mediators can influence CNS biology, including cytokine entry or signaling via brain barrier receptors; leukocyte trafficking across activated barriers; cytokine signaling via circumventricular organ sites or dural immune compartments; vagus nerve afferent signaling; mast cell degranulation; and histamine neuromodulation. Neuroinflammation is a common hallmark of many neurodegenerative diseases, but whether and to what degree allergic/type 2 immune biology may be involved depends on the specific disease stage and pathology. Here, we assess studies connecting the roles of IL-4/IL-13 signaling, IgE/mast cell activation, eosinophil-attractive chemokines, and histamines in Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, dementia with Lewy bodies, Huntington's disease, prion disease, and tauopathy/atypical parkinsonism. Mechanisms appear most clear in the case of Parkinson's disease, where epidemiology suggests an important role in dementia/Alzheimer's disease, while for other neurodegenerative conditions the evidence is less compelling and may be either mechanistic or modulatory. Confounding issues include sex differences, drug exposures, comorbid conditions, socioeconomic factors, and coexisting inflammatory diseases. Finally, we suggest a strategy based on longitudinal immune phenotyping, CNS biomarkers, and pathway manipulation to assess the relationship between allergic immune signaling and neurodegeneration.}, } @article {pmid42274592, year = {2026}, author = {Sgalletta, B and Agostini, F and Bisaglia, M}, title = {The Role of Iron in Neuronal Homeostasis: A Double-Edged Sword.}, journal = {Cells}, volume = {15}, number = {11}, pages = {}, pmid = {42274592}, issn = {2073-4409}, mesh = {Humans ; *Iron/metabolism ; *Homeostasis ; Animals ; *Neurons/metabolism ; Neurodegenerative Diseases/metabolism/pathology ; Neurogenesis ; Neurodevelopment ; Brain/metabolism ; }, abstract = {Iron is an essential micronutrient that plays a central role in numerous biological processes. Despite its relatively low abundance in the human body, iron is particularly critical for brain function. Systemic and cerebral iron homeostasis is tightly regulated through coordinated mechanisms involving absorption, transport, storage, and recycling. Within the brain, iron metabolism is further controlled by the blood-brain barrier and specialized neural cell populations, including neurons, astrocytes, oligodendrocytes, and microglia. Iron is indispensable for neurodevelopment, supporting neurogenesis, myelination, and neurotransmitter synthesis. However, both iron deficiency and iron overload have detrimental consequences. Early-life iron deficiency disrupts neural development and leads to long-lasting cognitive, motor, and behavioral impairments, whereas excessive iron accumulation promotes oxidative stress, ferroptosis, and neuroinflammation. These mechanisms have been described to contribute to the pathogenesis of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, neurodegeneration with brain iron accumulation, and amyotrophic lateral sclerosis. This review first outlines systemic and brain iron metabolism, highlighting how neural cells regulate homeostasis. Next, it examines iron's physiological roles, particularly in neurogenesis and neurodevelopment. Finally, it explores iron's involvement in neurodegenerative diseases, emphasizing neuroinflammation as a primary mechanism of iron toxicity.}, } @article {pmid42274906, year = {2026}, author = {He, Y and Yi, T and Min, M and Xu, K and Lin, H and Xu, R and Deng, D and Xiao, X}, title = {Environmental Factors Drive Neurodegenerative Diseases Through Glutamate Excitotoxicity: A Convergent Mechanistic Pathway.}, journal = {Neuroscience bulletin}, volume = {}, number = {}, pages = {}, pmid = {42274906}, issn = {1995-8218}, abstract = {This review illustrates how environmental stressors disrupt glutamate homeostasis via specific mechanisms: lead-induced thiol modification, manganese mediated yin yang 1 (YY1)-histone deacetylases (HDAC) repression, PM2.5-triggered microglia-astrocyte crosstalk, and advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE)-nuclear factor kappa-B (NF-κB) signaling from high-sugar diets. Together with genetic susceptibility and pigment epithelium-derived factor (PEDF), these factors impair astrocytic glutamate uptake, promoting synaptic glutamate accumulation. Subsequent N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor overactivation triggers calcium overload, mitochondrial dysfunction, oxidative stress, and neuroinflammation-termed "degenerative excitotoxicity". Excitotoxicity manifests in Alzheimer's disease (amyloid-beta-excitatory amino acid transporter 2 (EAAT2) interplay), Parkinson's disease (subthalamic nucleus-driven excitatory storm), and amyotrophic lateral sclerosis (astrocytic failure versus neuronal cell-autonomous mechanisms). Future interventions need multi-target strategies, emerging technologies, and lifestyle modifications. This convergent framework offers a unified understanding linking environmental exposure to neurodegeneration and charts a roadmap toward mechanism-based prevention and treatment.}, } @article {pmid42274979, year = {2026}, author = {Ojha, GJ and Talwar, T}, title = {Exploring the Role of Spirituality in Neuropalliative Care: An Integrative Review.}, journal = {Journal of religion and health}, volume = {}, number = {}, pages = {}, pmid = {42274979}, issn = {1573-6571}, abstract = {Neuropalliative care aims to address the physical, psychosocial and spiritual needs of persons with progressive and life-limiting neurological conditions, while spiritual care fosters hope and meaning in life. Progressive neurological disorders with an uncertain disease trajectory present a set of complex challenges that have far-reaching consequences on the patient's self-belief, questioning the very existence, self-identity, and belongingness. A typical neuropalliative care team consists of neurologists, nurses, psychologists, occupational therapists, and spiritual care providers. Previous research indicates that spiritual care improves coping and quality of life in persons with Parkinson's disease and Amyotrophic lateral sclerosis. This study aimed to explore how spiritual needs are addressed in the area of neuropalliative care, examining the theoretical frameworks and empirical studies that incorporate spirituality as a component of neuropalliative care. The databases PubMed, PsycINFO, Cochrane Library, Scopus and two peer-reviewed journals were searched using a strategy based on three sets of terms "spirituality," "progressive neurological conditions" and "neuropalliative care." Articles included were in the English language, and mentioned spirituality in the context of neuropalliative care or palliative care for neurological conditions. Initial screening yielded 744 articles, of which 29 were selected for synthesis. Results highlighted the various challenges in ascertaining and meeting the spiritual needs in neuropalliative care. The review concludes that palliative services should be initiated early following the diagnosis of a progressive neurological condition so that the patient and family have enough time to reflect, create memories, and prepare in advance for the inevitable through dignity and resilience.}, } @article {pmid42275159, year = {2026}, author = {Ito, D and Iida, M and Iguchi, Y and Hashizume, A and Yamada, S and Kishimoto, Y and Komori, S and Obara, K and Nishisaki, S and Yokoi, S and Shimamura, T and Takemoto, Y and Nakatochi, M and Akashi, T and Hinohara, K and Lee-Okada, HC and Okada, Y and Niwa, J and Sobue, G and Tanaka, S and Takashina, K and Yokomizo, T and Katsuno, M}, title = {Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis.}, journal = {JCI insight}, volume = {11}, number = {15}, pages = {}, pmid = {42275159}, issn = {2379-3708}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Humans ; Fatty Acid Amide Hydrolases ; Mice ; Mice, Transgenic ; *Amidohydrolases/antagonists & inhibitors/metabolism ; Motor Neurons/drug effects/pathology/metabolism ; Induced Pluripotent Stem Cells/metabolism/drug effects ; Disease Models, Animal ; Disease Progression ; Female ; Male ; Endocannabinoids/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the selective loss of upper and lower motor neurons. There is a considerable variability in the disease progression of sporadic ALS, but the molecular basis for phenotypic heterogeneity remains largely unknown. Patients with ALS often manifest systemic metabolic abnormalities such as glucose intolerance and hypermetabolic state. We conducted reverse translational research to explore therapeutic targets in ALS based on the systemic metabolic alterations in patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of N-acyl taurines (NATs) were correlated with the longitudinal change in the revised ALS functional rating scale and survival. Experiments with ALS cellular models and induced pluripotent stem (iPS) cells derived from patients with ALS and SOD1G93A transgenic mice revealed that PF-04457845, a fatty acid amide hydrolase inhibitor, upregulated the expanded ECS, particularly the levels of NATs and ameliorated motor neuron degeneration through the regulation of microglial environment, synapse plasticity, and neuronal development. These results collectively indicate that dysregulation of NATs is associated with ALS progression and PF-04457845 may represent a potential disease-modifying therapy for ALS.}, } @article {pmid42276279, year = {2026}, author = {Gurung, N and Choi, DY and Park, PH}, title = {Naringenin as a multi-target neuroprotective agent in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {198}, number = {}, pages = {106203}, doi = {10.1016/j.neuint.2026.106203}, pmid = {42276279}, issn = {1872-9754}, mesh = {Humans ; *Flavanones/administration & dosage/therapeutic use/pharmacology ; *Neuroprotective Agents/administration & dosage/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Antioxidants/metabolism ; }, abstract = {Neurodegenerative diseases (ND) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS) are characterized by progressive neuronal loss driven by complex and multifactorial pathogenic mechanisms. Naringenin (NAR), a citrus-derived flavanone, has attracted considerable interest as a neuroprotective molecule due to its pleiotropic pharmacological activities such as antioxidant, anti-inflammatory and ability to modulate multiple cellular targets. This review provides a comprehensive overview of NAR pharmacokinetic profile, mechanistic actions, and therapeutic potential across major ND. We highlight how NAR's multi-target effects-including redox homeostasis maintenance, suppression of neuroinflammation, protein aggregation inhibition, and modulation of signaling pathways-contribute to neuroprotection in various experimental models of AD, PD, HD, ALS, and MS. Preclinical studies demonstrate that NAR can ameliorate cognitive and motor deficits in toxin and transgenic models of neurodegeneration, attenuate pathological hallmarks such as amyloid-beta toxicity, dopaminergic neuronal loss, and neuroinflammation, and induce cytoprotective pathways including Nrf2-mediated antioxidant response and autophagy. However, NAR's clinical translation is challenged by poor bioavailability; thus, novel delivery systems are being explored to enhance brain uptake. NAR emerges as a promising multi-functional neuroprotective agent that can simultaneously target diverse pathogenic processes in ND. Further research including advanced formulation development and well-designed clinical trials is warranted to fully establish NAR's therapeutic efficacy and safety in humans.}, } @article {pmid42276329, year = {2026}, author = {Abzhanova, E and Kawae, Y and Mizuno, H and Umemoto, T and Ciftci, H and Tsuboi, M and Hirabayashi, Y and Mizuno, H}, title = {ALS-associated protein TDP-43 disturbs axonal projections in the somatosensory cortex.}, journal = {Neuroscience research}, volume = {229}, number = {}, pages = {105079}, doi = {10.1016/j.neures.2026.105079}, pmid = {42276329}, issn = {1872-8111}, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Somatosensory Cortex/metabolism/pathology ; *Axons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Corpus Callosum/metabolism/pathology ; Mice ; Female ; Mice, Transgenic ; Pyramidal Cells/metabolism/pathology ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons that gradually causes muscle weakness and paralysis, eventually resulting in death. While ALS was once believed to specifically target motor neurons, recent clinical studies have revealed sensory involvement. The pathological hallmark of ALS is TAR DNA-binding protein 43 (TDP-43) aggregation in cytoplasm, with increasing evidence of its presence in both motor and sensory neurons. However, sensory abnormalities remain poorly characterized. To address this research gap, we analyzed the effects of TDP-43 expression on layer 2/3 (L2/3) pyramidal neurons of the primary somatosensory cortex in mice projecting through corpus callosum. In utero electroporation (IUE) was performed to express GFP alone (control) or in combination with TDP-43. Compared with the control, mice co-expressing GFP and TDP-43 showed disturbed callosal axonal projections of L2/3 neurons. Mutant TDP-43 variants displayed a more pronounced phenotype, indicating pathogenic role during fetal cortical development. To distinguish developmental from maintenance effects, tamoxifen-inducible TDP-43 expression was used to initiate postnatal TDP-43 expression. Postnatal induction resulted in shorter axonal length and reduced branching rather than gross projections disturbance. Taken together, these results demonstrate that TDP-43 expression can disturb the integrity of axonal projections, such as callosal projections of L2/3 neurons in the somatosensory cortex.}, } @article {pmid42276614, year = {2026}, author = {Karthikeyan, K and Velmurugan, G and Upadhyay, R and Sevanan, M and Chinnathambi, S}, title = {Glutamate and glutamine metabolism in neurodegenerative diseases.}, journal = {International review of neurobiology}, volume = {186}, number = {}, pages = {1-24}, doi = {10.1016/bs.irn.2026.01.008}, pmid = {42276614}, issn = {2162-5514}, mesh = {Humans ; *Glutamic Acid/metabolism ; *Glutamine/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; }, abstract = {Glutamate is known as the most important excitatory neurotransmitter in brain. Glutamate and glutamine recycling is very essential to maintain the nitrogen metabolism. Despite of its major functions, its dysregulation is a basic pathology which is common to neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic lateral sclerosis (ALS). Amyloid-β and Tau in AD disrupt glutamate uptake and the glutamate-glutamine cycle, accelerating synaptic failure, whereas loss of astrocytic EAAT2 in ALS generates unrelenting excitotoxicity and motor neuron demise. Toxic α-synuclein aggregation in PD exacerbates dopamine-glutamate imbalance through destabilizing corticostriatal transmission. This review explores on the key mechanisms by which glutamate impairment leads to the pathogenies of neurogenerative disorders and also about current medications like amantadine, memantine, and riluzole which are glutamate antagonists, are shown to partially alleviative but cannot halt the advancement of the disease. One of the potential targets for disease-modifying treatments could be the receptor modulation, astrocytic function, and elimination of excess glutamate.}, } @article {pmid42276908, year = {2026}, author = {Covas Moschovas, M and Falagario, U and Pellegrino, F and Wiklund, P and Patel, V}, title = {Reply to Alexander Light, Max Peters, Manit Arya, et al's Salvage Focal Therapy vs Radical Prostatectomy for Localized Radiorecurrent Prostate Cancer. JAMA Oncol 2026;12:364-73. https://doi.org/10.1001/jamaoncol.2025.6448.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2026.05.031}, pmid = {42276908}, issn = {1873-7560}, } @article {pmid42279231, year = {2026}, author = {Mesches, MH and Granholm, AC and Paredes, D and Mesches, K and Oguma, Y and Dezawa, M}, title = {Stem Cell Therapy for Parkinson's Disease: A Mechanistically Distinct Role for Muse Cells.}, journal = {Journal of clinical medicine}, volume = {15}, number = {11}, pages = {}, pmid = {42279231}, issn = {2077-0383}, support = {R01 AG081356/AG/NIA NIH HHS/United States ; }, abstract = {Cell replacement therapy is a promising investigational approach for Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra. Although current PD therapies provide symptomatic relief, none halt or reverse disease progression. Early transplantation studies using fetal dopaminergic neurons provided proof of concept for PD cell replacement, with recent efforts focusing on pluripotent stem cell-derived dopaminergic progenitors that are now entering clinical testing. These strategies face challenges, however, including immune compatibility, tumorigenic risk, and the need for controlled differentiation and functional integration. Multi-lineage differentiating stress-enduring (Muse) cells are endogenous, non-tumorigenic pluripotent-like stem cells that home to sites of tissue injury and differentiate in response to the host microenvironment. A targeted literature search of PubMed and Scopus, however, did not identify prior reviews specifically addressing Muse cells in the context of PD, highlighting a gap in the literature. Here, we examine current limitations of established cell-replacement approaches and consider whether Muse cells may represent a mechanistically distinct cell source. Early clinical studies of Muse cell therapy in stroke and amyotrophic lateral sclerosis suggest an encouraging safety profile and preliminary signals of potential therapeutic benefit, although these findings are based on small, early-stage trials and require confirmation. The evidence supporting Muse cell therapy in PD is currently limited to a single preclinical animal study, supported by mechanistic in vitro findings and indirect evidence from other neurologic disease models; therefore, its relevance to PD remains to be established, and current evidence is insufficient to support conclusions regarding clinical efficacy. Together, these observations provide a rationale for further targeted preclinical investigation and support the systematic evaluation of Muse cells as a mechanistically distinct candidate for regenerative therapy in PD.}, } @article {pmid42280649, year = {2026}, author = {Liu, Q and Zhang, R and Sun, L and Lu, X and Xu, G and Tong, H and Zhang, B and Liu, X and Du, S}, title = {Mechanism of Echinochloa crus-galli Resistance to the ALS-Inhibiting Herbicide Pyrazosulfuron-ethyl in China.}, journal = {Plants (Basel, Switzerland)}, volume = {15}, number = {11}, pages = {}, pmid = {42280649}, issn = {2223-7747}, abstract = {Rice (Oryza sativa L.) is a staple food crop, feeding more than 3.5 billion people. With the increasing demand for food in the 21st century, weed infestation poses the most significant biotic threat to global food security, and herbicides remain the most effective and economic way to manage it in field. However, weeds can rapidly adapt under herbicide selection pressure due to their high competitiveness, rapid growth, and reproductive capacity. Hence, we collected Echinochloa crus-galli populations from Heilongjiang and Hebei provinces in China and investigated their resistance mechanisms to pyrazosulfuron-ethyl (PSE), a sulfonylurea herbicide that inhibits acetolactate synthase (ALS). Dose-response experiments confirm that the resistant (R) population exhibits 52.9-fold resistance to PSE compared with the susceptible (S) population. Inhibitor bioassays with malathion and NBD-Cl, together with ALS activity assays, ALS gene sequencing, and molecular docking, collectively suggest that resistance is strongly associated with the ALS Trp-574-Leu target-site substitution, with a possible additional contribution from enhanced herbicide metabolism. However, because the S and R populations originate from geographically distinct locations, some of the observed physiological and molecular differences may also reflect inherent population variation. Specifically, the ALS W574L substitution is predicted to reduce key interactions between ALS and PSE. This study provides valuable evidence for the risk of PSE resistance evolution in E. crus-galli and elucidates the molecular mechanism conferring resistance to ALS inhibitors.}, } @article {pmid42281996, year = {2026}, author = {Bonsall, S and Kazu, RS and King, M and Leung, D and Mahiddine, FY and Highley, JR and Strange, A and Chen, Y and Sassani, M and Cabras, S and Bowden, KM and Wareing, HE and Eldahshoury, MK and Boyne, JR and Collins, M and Monte, EM and Harvey, C and Gornall, SB and Jangid, A and Treanor, C and Moll, T and van Dijk, CH and Huang, Y and Urban, AE and Shaw, PJ and West, RJH and Kenna, KP and Hornstein, E and Zhang, S and Cooper-Knock, J and Zhou, J and Snyder, MP}, title = {Single-nucleus multiomic atlas of ALS primary motor cortex nominates neuroprotective WDR49-expressing astrocytes.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {42281996}, issn = {2693-5015}, support = {P50 HG007735/HG/NHGRI NIH HHS/United States ; R01 NS131409/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) causes selective neurodegeneration in primary motor cortex, yet cell-type-specific molecular changes driving this vulnerability remain poorly understood. We present an integrated single-nucleus RNA- and ATAC-sequencing atlas of 778,330 nuclei from the primary motor cortex of 140 genetically characterised donors. ALS is associated with widespread transcriptional reprogramming driven by a common set of transcription factors (TFs) across multiple cell-types. Astrocytes harbour the most differentially expressed genes. Within astrocytes, a WDR49-expressing subpopulation is spatially associated with TDP-43 pathology, and genetic variants within WDR49 confer risk for both sporadic and monogenic autosomal dominant ALS. In patient-derived induced astrocytes, WDR49 protein abundance predicts the survival of co-cultured neurons. WDR49 localises to PML nuclear bodies, where it regulates astrocyte reactivity and secretion of EVs containing protein chaperones. Together, these in vivo and in vitro findings suggest that WDR49+ astrocytes mount a compensatory secretory response to extracellular protein aggregates, and that loss of this capacity lowers the threshold for ALS pathogenesis.}, } @article {pmid42282536, year = {2026}, author = {Cortez, JD and Avalos, JL}, title = {Heterologous iron-sulfur cluster biogenesis and delivery for cytosolic isobutanol and isopentanol production in Saccharomyces cerevisiae.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42282536}, issn = {2692-8205}, support = {T32 GM007388/GM/NIGMS NIH HHS/United States ; }, abstract = {Saccharomyces cerevisiae is an excellent microbial platform for sustainable production of next generation biofuels such as the branched chain higher alcohols (BCHAs) isobutanol and isopentanol. A cytosolic pathway for BCHA production is generated from expression of prokaryotic orthologs of branched-chain amino acid (BCAA) enzymes acetolactate synthase (ALS), mutant NADH-dependent ketol-acid reductoisomerase (KARI[P2D1-A1]), and dihydroxy-acid dehydratase (DHAD). The potential for this pathway has been hindered by the availability of iron-sulfur clusters, particularly the 2Fe-2S cluster, required for DHAD to function in the cytosol. ILV3, the endogenous yeast DHAD located in the mitochondria, can be deleted to create a valine auxotroph. In this study we use bioinformatics, heterologous gene library synthesis, and a valine complementation assay to find prokaryotic iron-sulfur cluster biosynthetic gene clusters (BGC) and accessory genes that aid DHAD function in the yeast cytosol. This work presents, to our knowledge, the first functional BGC that enhances the cytosolic activity of prokaryotic DHADs in S. cerevisiae. The SUF BGC from Bacillus subtilis combined with a ferritin-like protein (FTNB) from Escherichia coli and the Lactococcus lactis DHAD enhanced the production of BCHAs. Combined expression gave an average isobutanol titer of 412mg/L, 1.8-fold greater than L. lactis DHAD expressed alone. This work establishes a blueprint for better biofuel production by improving iron-sulfur cluster dependent enzyme activity in the yeast cytosol.}, } @article {pmid42282588, year = {2026}, author = {Kochen, NN and Zafari, S and Renaud, A and Schneider, N and Vunnam, N and Liao, EE and Dutton, JR and Braun, AR and Sachs, JN}, title = {From anti-fungal to potential neurotherapeutic: Posaconazole as an effective inhibitor of cellular TDP-43 pathology.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.01.728552}, pmid = {42282588}, issn = {2692-8205}, abstract = {Recently, we showed that ketoconazole, a known anti-fungal inhibitor of CYP51, stabilized TAR DNA-binding protein 43 (TDP-43) native self-interactions, reduced TDP-43 pathology and rescued TDP-43-induced SREBP2 downregulation. Despite its promising effects, ketoconazole is not viable for repurposing for ALS due to liver toxicity side effects that occur when orally delivered. To address this, we tested the activities of seven additional known azole-based CYP51 inhibitors in order identify a viable alternative to ketoconazole. Using our established TDP-43 mislocalization and aggregation assay in HEK293T cells, we identified posaconazole, an FDA-approved, CNS-penetrant and orally delivered anti-fungal, as the strongest inhibitor of TDP-43 pathology. Posaconazole was able to reduce insoluble TDP-43 and restore SREBP2 levels, outperforming ketoconazole. Mechanism of action (MOA) experiments suggest posaconazole is able to outperform ketoconazole by inducing a significantly stronger activation of autophagy and upregulation of heat shock proteins known to clear TDP-43. Further MOA experiments show that the effects of posaconazole on TDP-43 are dependent on its known ability to lower cellular cholesterol levels. By correlating our experimental results on the eight CYP51 inhibitors tested, we show that predicted affinity towards human CYP51 strongly correlates with the inhibitors' ability to lower TDP-43 aggregation and mislocalization. Finally, we tested posaconazole in a low dose sodium arsenite ALS model in iPSC-derived motor neurons, showing that it is efficacious at inhibiting TDP-43 pathology in the nanomolar range. Altogether, these results support the repurposing of posaconazole for ALS/FTD as a means to prevent TDP-43 pathology.}, } @article {pmid42282797, year = {2026}, author = {Yusuf, IO and Silva, RLA and Amoako, GG and Thompson, PR and Xu, Z}, title = {PAD2 knockout reduces myelin protein aggregates, modulates neuroinflammation and protects motor neurons, axons and neuromuscular junction in a SOD1-ALS mouse model.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.30.729013}, pmid = {42282797}, issn = {2692-8205}, abstract = {BACKGROUND: Dysregulated peptidyl deiminase 2 (PAD2) and aberrant protein citrullination (PC), a posttranslational modification (PTM), are involved in various inflammatory and neurodegenerative diseases. We previously showed in transgenic mice and postmortem human tissues that PC and PAD2 are altered in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neurons loss, paralysis, and death. Herein, we investigated the role of PAD2 in ALS by PAD2 knockout in a SOD1-ALS mouse model.

METHODS: To investigate the role of PAD2-induced citrullination in ALS pathogenesis, we generated PAD2 knockout (PAD2KO) in SOD1 [G93A] ALS mouse model and investigated the consequent modulation on the neuropathology and clinical symptoms, using molecular biology techniques such as qPCR, Western blotting, confocal microscopy, and electron microscopy. Additionally, we identified C3 as being citrullinated in human ALS using ionFinder.

RESULTS: Our results show that PAD2KO blocked the increased PC and reduced myelin basic protein (MBP) aggregates in the ALS model. PAD2KO also improved motor neuron survival and the integrity of myelin, axons, and neuromuscular junctions, and reduced microgliosis in the white matter and C3 protein levels in astrocytes. Clinically, data from monitoring the body weight changes suggests that PAD2KO modulates the course of the disease in the ALS mouse model, accelerating the onset while slowing the progression after the onset, and modestly extending the survival of male mice.

CONCLUSION: These results show that PAD2 is responsible for the increased PC in ALS and PC contributes to neuroinflammation and degeneration of motor neurons and myelinated axons. The modest modulation of the disease phenotype suggests that the role of PC in ALS is complex, involving altered PC in numerous proteins and in multiple cell types. Future studies are needed to investigate how PC modulates individual protein functions in various cell types to understand the contribution of PC to ALS pathogenesis.}, } @article {pmid42283221, year = {2026}, author = {Scozzari, S and Columbro, SF and Favagrossa, M and Tortarolo, M and Cagnotto, A and Salmona, M and De Marco, G and Bendotti, C and Calvo, A and Pasetto, L and Bonetto, V}, title = {Effects of Lysine Deacetylation Inhibition Alone or in Combination With Arimoclomol on TDP-43 Proteinopathy.}, journal = {Journal of neurochemistry}, volume = {170}, number = {6}, pages = {e70493}, pmid = {42283221}, issn = {1471-4159}, support = {RF-2018-12365614//Ministero della Salute/ ; GATTALS//AriSLA/ ; }, mesh = {Animals ; *Histone Deacetylase Inhibitors/administration & dosage/pharmacology ; Humans ; Mice ; Acetylation/drug effects ; *Lysine/metabolism/antagonists & inhibitors ; *TDP-43 Proteinopathies/drug therapy/metabolism/pathology ; Mice, Transgenic ; Vorinostat/administration & dosage ; *DNA-Binding Proteins/metabolism ; Male ; }, abstract = {Cytoplasmic inclusions containing TAR DNA-binding protein 43 kDa (TDP-43) are recognized as a major pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Peptidyl-prolyl cis-trans isomerase A (PPIA) interacts with TDP-43 and influences its aggregation and function. This interaction is facilitated by PPIA Lys-acetylation. Here, we investigated whether restoring lysine acetylation homeostasis exerts protective effects on TDP-43 proteinopathy in vitro and in vivo and how this relates with PPIA. We found that vorinostat/SAHA, a broad-spectrum histone deacetylase (HDAC) inhibitor that increases PPIA acetylation, is able to reverse TDP-43 mislocalization in a cellular model of TDP-43 proteinopathy. We confirmed its effects in peripheral blood mononuclear cells from ALS patients and explored its impact on TDP-43 proteinopathy and PPIA acetylation in the Thy1-hTDP-43 mouse model. Thy1-hTDP-43 mice treated with SAHA showed a delayed onset of TDP-43 pathology, associated with PPIA nucleus-cytoplasm redistribution, lower neurodegeneration and neuroinflammation, and improved neuromuscular function markers. However, these effects were transient. When combined with arimoclomol, a heat shock protein co-inducer, a mitigation of the neurodegeneration was sustained. A synergistic effect was observed in periphery, greatly enhancing tubulin acetylation and reducing phosphorylated TDP-43 accumulation in the sciatic nerve and acetylcholine receptor γ-subunit expression in gastrocnemius muscle. This study suggests that HDAC inhibition could be beneficial in restoring TDP-43 localization and function through multiple mechanisms, including modulation of PPIA acetylation. The combination of lysine deacetylation inhibition and arimoclomol shows a synergistic effect in vivo and has potential as a therapeutic approach for patients.}, } @article {pmid42283246, year = {2026}, author = {Fikry, H and Saleh, LA and Sadek, DR}, title = {Histological and Tissue-Level Outcomes of Stem Cell Therapies in Neurodegenerative Disorders: A Systematic Review.}, journal = {Clinical anatomy (New York, N.Y.)}, volume = {}, number = {}, pages = {}, doi = {10.1002/ca.70147}, pmid = {42283246}, issn = {1098-2353}, abstract = {Neurodegenerative diseases, which afflict millions worldwide and threaten public health, have no cure. Neurodegenerative diseases lack effective therapies, burdening society and the economy. Over the past 20 years, regenerative cell therapy (stem cell therapy) has advanced, opening novel neurodegenerative disease treatments. Thus, the current review aimed to systematically highlight experimental and clinical studies of potentially effective therapeutic strategies for stem cells and report histological, cellular, or ultrastructural outcomes following stem cell interventions in neurodegenerative diseases. PRISMA-compliant computerized literature searches of PubMed, Scopus, and Web of Science identified studies on embryonic, induced pluripotent, mesenchymal, or neural stem cells (NSCs) in neurodegenerative disease models and histological and tissue-level outcomes. Search terms included nervous system diseases, histology, neuron regeneration, stem cells, stem cell treatment, and transplantation. Peer-reviewed articles published between 2000 and 2025 were selected. Experimental animal and clinical studies that reported histological or tissue-level results after stem cell treatments were included. Eighty-six studies met the eligibility criteria, covering models of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. Across these studies, stem cell therapies were linked to improved neuron survival, better synaptic structure, diminished gliosis, and some restoration of tissue structure. These effects depended on the type of stem cell used, the disease model, and how the treatment was given. Overall, the evidence suggests that stem cell therapies can lead to significant histological and tissue-level improvements in neurodegenerative diseases, supporting their potential for regeneration. Further standardized and translational studies are needed to clarify the underlying mechanisms and improve treatment strategies.}, } @article {pmid42283497, year = {2026}, author = {Turner, ED and Twelvetrees, AE}, title = {The Long Haul: Microtubule Motors as the Essential Supply Line for Neuronal Longevity.}, journal = {Journal of neurochemistry}, volume = {170}, number = {6}, pages = {e70496}, pmid = {42283497}, issn = {1471-4159}, support = {/WT_/Wellcome Trust/United Kingdom ; 220192/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Microtubules/metabolism/physiology ; Animals ; *Neurons/metabolism/physiology ; *Molecular Motor Proteins/metabolism/genetics ; Mutation ; }, abstract = {The extreme morphology and polarised architecture of neurons require the highly sophisticated microtubule transport system for both construction and lifelong survival. Genomic evidence from an expanding landscape of human mutations supports the essential role of the microtubule transport machinery. During neurodevelopment, mutations disrupt the proliferation and migration of neuronal precursors, as well as the initial establishment of polarity. In the mature nervous system, the reliance on microtubule transport shifts to the long-term maintenance of axon integrity and synaptic proteostasis. Across the motor proteins responsible for long distance transport in neurons, mutations highlight a specific vulnerability of long axons to transport failure in Hereditary Spastic Paraplegia (HSP), Charcot Marie Tooth disease Type 2 (CMT2), Spinal Muscular Atrophy (SMA), Perry Syndrome, and Amyotrophic Lateral Sclerosis (ALS) amongst others. Due to the role of microtubule motors in development and maintenance, there is frequently a phenotypic spectrum within a single gene of the microtubule transport system. For example, mutations in dynein motors are linked both to malformations of cortical development and specific motor neuron loss in SMA-LED (Spinal Muscular Atrophy with Lower Extremity Predominance). By synthesising genetic evidence, this review illustrates how specific molecular failures, ranging from motor-domain kinetics to cargo binding, can inform our understanding of neuronal homeostasis. Ultimately, we argue that microtubule transport is not merely a cellular utility, but a key determinant of neuronal longevity.}, } @article {pmid42283699, year = {2026}, author = {El-Wahsh, S and Bogart, E and Bonnor, S and El-Wahsh, S and Graco, M and Hogden, A and Paynter, C and Raykar, V and Signorelli, M and Thomson, E and Vucic, S and White, S}, title = {Supporting gastrostomy decision-making in motor neurone disease (MND): an Australian survey of healthcare professionals' beliefs, practices, and needs.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/17582024.2026.2687483}, pmid = {42283699}, issn = {1758-2032}, abstract = {INTRODUCTION: Gastrostomy decision-making for people living with motor neurone disease (MND) is complex. While international studies report healthcare professionals' (HCPs) beliefs and practices in this area, little is known about the Australian context.

AIM: To examine Australian HCPs' beliefs, clinical practices, and support needs regarding gastrostomy decision-making in MND.

METHODS: A national cross-sectional online survey of Australian HCPs involved in gastrostomy discussions (n = 123) was conducted, exploring five domains: 1) initiating discussions and timing; 2) patient education; 3) multidisciplinary coordination; 4) guideline use; 5) and professional development needs. Descriptive statistics were applied.

RESULTS: Most HCPs initiated discussions about gastrostomy (74%), commonly prompted by swallowing difficulty, weight loss, or patient request. Although 72% believed discussions should occur before clinical indications, only 40% reported doing so. Earlier placement was favored in the context of respiratory decline compared with swallowing impairment, and 56% considered gastrostomy to be performed too late. Almost 40% used no formal guidelines, and 74% wanted further professional development.

CONCLUSION: Australian HCPs valued person-centered practice, but belief-practice gaps highlight opportunities to improve consistency, timing, and quality of gastrostomy decision-making support. Enhanced national guidelines, improved multidisciplinary communication, and targeted professional development may help reduce delays and better align practice with evidence-based recommendations.}, } @article {pmid42285406, year = {2026}, author = {Mendoza-Camacho, DM and Espinoza-Gutiérrez, HA and Viveros-Paredes, JM and Flores-Soto, ME and Tejeda-Martínez, AR}, title = {Recent advances in neurodegenerative diseases therapeutics: The inhibition of monoacylglycerol lipase strategy.}, journal = {Neuroscience}, volume = {610}, number = {}, pages = {198-206}, doi = {10.1016/j.neuroscience.2026.06.011}, pmid = {42285406}, issn = {1873-7544}, mesh = {Humans ; *Monoacylglycerol Lipases/antagonists & inhibitors/metabolism ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism/enzymology ; Endocannabinoids/metabolism ; *Enzyme Inhibitors/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative diseases share common pathophysiological mechanisms, including chronic neuroinflammation, glutamatergic excitotoxicity, oxidative stress, mitochondrial dysfunction, and disruptions in synaptic and lipid homeostasis. In this context, the endocannabinoid system has emerged as a key modulator of neuroimmune communication and neuronal survival. Within this system, Monoacylglycerol Lipase (MAGL) plays a central role by regulating the levels of the endocannabinoid 2-Arachidonoylglycerol (2-AG) while simultaneously contributing to the generation of arachidonic acid and pro-inflammatory eicosanoids. Pharmacological or genetic inhibition of MAGL increases 2-AG levels and concurrently reduces the biosynthesis of pro-inflammatory lipid mediators, thereby modulating microglial activation, astrocytic responses, and neuronal excitotoxicity. Preclinical studies in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis consistently demonstrate that MAGL blockade attenuates neuroinflammation, preserves synaptic and neuronal integrity, improves motor and cognitive function, and, in some cases, delays disease progression. Although clinical evidence remains limited, the available data position MAGL as a metabolic convergence point between inflammation and neurodegeneration, suggesting that its modulation may represent a therapeutic strategy with disease-modifying potential.}, } @article {pmid42286839, year = {2026}, author = {Wheeler, A and Mehta, K and Sanders, D and Chin, C and Zivalic, H and Carey, J and McCaffrey, A and Pant, P and Lewenhaupt, C and Luppino, S and Jacobs, G and Golden, S and Gifford, R and Scirocco, E and Keegan, M and Hatem, M and Yazdanian, T and Uysal, SP and Susco, N and Schwartzman, S and Branch, K and Hall, KE and Barnas, J and Lam, J and Hagar, J and Hannan, CA and Paganoni, S and Berry, JD and Garret, M and Scalia, J and Babu, S}, title = {Optimizing Research Operations and Resource Utilization in ALS Care: Insights From the Tofersen Antisense Oligonucleotide Expanded Access Protocol.}, journal = {Muscle & nerve}, volume = {74}, number = {3}, pages = {692-697}, pmid = {42286839}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/therapy ; Female ; Middle Aged ; Male ; Aged ; *Oligonucleotides, Antisense/therapeutic use/administration & dosage ; Superoxide Dismutase-1/genetics ; *Health Resources ; Adult ; }, abstract = {INTRODUCTION/AIMS: Tofersen is a gene-targeted therapy for individuals with superoxide dismutase 1 (SOD1) (+) amyotrophic lateral sclerosis (ALS). Prior to U.S. Food and Drug Administration (FDA) approval, tofersen was made available through expanded access protocol. This study describes the clinical and operational experience of administering tofersen through expanded access protocols at a single academic medical center in the U.S.

METHODS: Individuals with symptomatic SOD1(+) ALS (≥ 18 years), who were ineligible for traditional ALS clinical trials, received tofersen via bedside lumbar punctures at Massachusetts General Hospital. Treatment was provided through single-patient and intermediate-sized expanded access protocols prior to FDA approval. Demographic and clinical characteristics, referral-to-treatment timelines, safety outcomes, and operational costs were collected.

RESULTS: Eleven individuals with SOD1(+) ALS received monthly intrathecal tofersen over a two-year period (July 2021 to July 2023). Most participants were female, and 81.8% had leg-onset ALS. The mean (SD) referral-to-first dose duration was 36 (22.4) days. A total of 120 doses were administered over a two-year period. Tofersen was safe and well tolerated, with no treatment-related serious adverse events. Operational costs totaled $336,620, supported by philanthropy and insurance. The company provided the drug for free.

DISCUSSION: This experience demonstrates the feasibility of implementing a resource-intensive expanded access protocol within an academic medical center using a mixed funding model to facilitate early access to emerging ALS therapies.}, } @article {pmid42287757, year = {2026}, author = {Jaberi, KR and Haghighi, MR and Aligholi, H and Takallu, S and Asadi, P and Mirzaei, E and Jaberi, AR and Sahraian, A}, title = {Focused ultrasound-mediated nanocarrier delivery across the blood-brain barrier for neurodegenerative diseases.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {201}, number = {}, pages = {119622}, doi = {10.1016/j.biopha.2026.119622}, pmid = {42287757}, issn = {1950-6007}, mesh = {Humans ; *Blood-Brain Barrier/metabolism/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Drug Delivery Systems/methods ; *Drug Carriers/chemistry ; *Nanoparticles ; *Nanoparticle Drug Delivery System ; *Ultrasonic Waves ; Microbubbles ; }, abstract = {The development of effective therapies for neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis remains a major challenge due to the restrictive nature of the blood-brain barrier (BBB). Conventional systemic drug delivery strategies often fail to achieve sufficient central nervous system (CNS) penetration while avoiding peripheral toxicity. Focused ultrasound (FUS), particularly when combined with microbubbles or nanocarriers, has emerged as a non-invasive approach to transiently and precisely open the BBB, enabling targeted delivery of therapeutics to the brain parenchyma. This review provides a comprehensive overview of the mechanisms by which FUS enhances CNS drug delivery, with a dedicated focus on its integration with nanoparticle-based systems, including liposomes, polymeric nanoparticles, dendrimers, metallic nanoparticles, and exosomes. We discuss how these nanocarriers can be engineered for improved stability, targeting specificity, and stimulus-responsive release upon FUS exposure. Recent advances in ultrasound technology, image guidance (particularly MRI), and therapeutic formulations are summarized, along with preclinical and clinical evidence across key neurodegenerative conditions. Despite promising results, several challenges remain, including long-term BBB stability, regulatory standardization, and scalability for broad clinical application. By integrating principles from acoustics, pharmacology, and nanotechnology, FUS-mediated drug delivery, especially in combination with smart nano systems, represents a significant advancement in precision neurotherapeutics, offering new hope for previously untreatable CNS diseases.}, } @article {pmid42288074, year = {2026}, author = {Tackaert, T and Hemeryck, J and Duchatelet, C and Vanwulpen, M and Hachimi-Idrissi, S}, title = {Mean airway pressure as the missing link in CPR physiology: A prehospital comparison of manual and mechanical chest compressions.}, journal = {The American journal of emergency medicine}, volume = {108}, number = {}, pages = {80-85}, doi = {10.1016/j.ajem.2026.06.012}, pmid = {42288074}, issn = {1532-8171}, mesh = {Humans ; Female ; *Cardiopulmonary Resuscitation/methods ; *Out-of-Hospital Cardiac Arrest/therapy/physiopathology ; Male ; *Emergency Medical Services/methods ; Pilot Projects ; Prospective Studies ; Middle Aged ; Aged ; Pressure ; *Heart Massage/methods ; Adult ; }, abstract = {BACKGROUND: The impact of manual versus mechanical chest compressions on mean airway pressure (mPAW) during cardiopulmonary resuscitation (CPR) is poorly understood. This exploratory pilot study assessed intratracheal airway pressures during prehospital CPR in out-of-hospital cardiac arrest (OHCA).

METHODS: Adult OHCA patients treated by the prehospital Medical Emergency Team of the Ghent University Hospital (Belgium) were prospectively enrolled. Intratracheal pressure was recorded immediately after intubation, mPAW was calculated for both the first and last minutes of advanced life support (ALS). The results were compared between mechanical compressions using the Stryker LUCAS3® device and manual chest compressions (with chest compression feedback).

RESULTS: Nineteen patients were included (manual n = 10; mechanical n = 9). Initial median mPAW was low (7.74 mbar) and showed a slight increase over time. Mechanical compressions generated higher early mPAW than manual compressions (8.96 vs. 6.54 mbar). mPAW increased over time with manual compressions and decreased with mechanical compressions. Patients who achieved return of spontaneous circulation (ROSC) showed higher mPAW, though this difference was not statistically significant.

CONCLUSIONS: Prehospital mPAW values were substantially lower than those reported in previous ED-based studies. While airway pressure patterns differed between compression modalities, overall pressures were similar. These findings highlight complex airway mechanics during CPR and support further research into whether higher airway pressures could improve airway patency, oxygenation, and hemodynamics in selected OHCA patients.}, } @article {pmid42288493, year = {2026}, author = {Wang, N and Li, Y and Li, N and Shen, L and Wang, C and Zhu, H and Zhou, Z and Ding, Y and Zhang, J and Fang, L and Bai, B}, title = {Quantitative Proteomics Unveils Comprehensive Tissue-Specific VCP Interaction Networks in Mice.}, journal = {Scientific data}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41597-026-07626-0}, pmid = {42288493}, issn = {2052-4463}, support = {32071256//National Natural Science Foundation of China/ ; 82172354//National Natural Science Foundation of China/ ; }, abstract = {Valosin-containing protein (VCP), a conserved AAA ATPase hexamer, participates in multiple biological processes including ERAD, ubiquitin-dependent degradation by extracting misfolded proteins for proteasomal degradation. Although its interactions with cofactors are well-characterized, and its dysregulation is implicated in multisystem proteinopathy, amyotrophic lateral sclerosis, and cancer, the tissue-specific VCP interactomes underlying its functional versatility remain elusive. Here, we generated HA-N-tagged VCP knock-in mice via CRISPR/Cas9 strategy and performed affinity purification coupled with data-independent acquisition (DIA) mass spectrometry to systematically profile VCP interactors across eight mouse tissues, yielding a high-confidence dataset. We identified 923 robust VCP-binding partners, including established interactors (UBX2B, UFD1, proteasomal subunits) and novel candidates implicated in energy metabolism (TCA cycle, oxidative phosphorylation) and protein quality control (proteasome, ERAD). Notably, we validated the interaction of VCP to two hepatic candidate proteins, DAXX and PRKAG2 (AMPK γ2 regulatory subunit), using HepG2 cells. This study establishes the first in vivo atlas of the VCP interaction network, providing mechanistic insights into its tissue-specific roles and highlighting potential therapeutic avenues for VCP-related disorders.}, } @article {pmid42289668, year = {2026}, author = {Pillay, S and Head, J and Horn, A and de Wet, W and Davidge, R and Dickson-Hall, M and Felix, G and Kali, G and Khan, W and Klein, B and Nakwa, F and Venter, M and Vlok, N and Wege, M and Stassen, W}, title = {The development of a consensus-based curriculum for a Bespoke Online Neonatal Education for Transfers (BONNETs) course.}, journal = {BMC medical education}, volume = {26}, number = {1}, pages = {}, pmid = {42289668}, issn = {1472-6920}, mesh = {Humans ; *Curriculum ; Infant, Newborn ; *Patient Transfer ; Consensus ; South Africa ; *Neonatology/education ; *Education, Distance ; Emergency Medical Services ; }, abstract = {BACKGROUND: High neonatal mortality in Sub-Saharan Africa (SSA) is driven by multiple systemic barriers, including insufficient neonatal transport infrastructure and limited provider training. Although specially trained neonatal retrieval teams are recommended for interfacility neonatal transfers, resource constraints lead to non-specialist emergency medical services (EMS) cadres performing these roles, potentially compromising the safe transport of critically ill neonates.

OBJECTIVE: To develop a bespoke, online neonatal interfacility transfer curriculum, informed by expert consensus and South African research to address critical gaps in provider knowledge and confidence, thereby improving neonatal transfer outcomes.

METHODS: Building on Kern's Six-Step Framework for curriculum development, an initial curriculum was derived through a comprehensive literature review, a retrospective chart analysis of neonatal cases in South Africa, and detailed interviews with experts and learners. Consequently, consensus on this curriculum was sought using a virtual, modified Nominal Group Technique (NGT) over two consensus rounds. A refined course curriculum is proposed.

RESULTS: Fourteen expert participants (neonatologists, paediatricians, neonatal nurses, and Advanced Life Support (ALS) providers with ≥ 3 years of experience) allocated potential outcomes to Core, Extended, or Advanced tiers based on EMS scope of practice. A 75% consensus threshold was applied. Eleven experts completed both rounds (21% attrition). Most were ALS providers (43%), largely employed in the public sector (71%). The final curriculum consists of three sequential courses (Core, Extended, Advanced) which scaffolds learning. The Core course consists of five modules, with each curriculum item achieving > 90% agreement on foundational skills including basic assessment, recognition of critical instability, and escalation pathways. This open-access online course is tailored to resource-limited settings.

CONCLUSION: A consensus-driven neonatal interfacility transfer curriculum for South Africa was successfully developed, providing a tiered, evidence-based approach to reinforce provider knowledge and confidence. By leveraging expanding internet accessibility, the Bespoke Online NeoNatal Education for Transfers (BONNETs) framework mitigates geographic disparities while integrating best practices for safe neonatal transfer. However, rigorous validation across diverse contexts and attention to broader systemic challenges, is essential to achieving sustained improvements. Future research should assess the curriculum's performance in improving knowledge and confidence, as well as long-term clinical impact on neonatal outcomes.}, } @article {pmid42290559, year = {2026}, author = {Martyniuk, О and Mushii, O and Pavlova, A}, title = {Integrated Analysis of hsa-miR-26b-5p and hsa-miR-186-5p in Blood Serum and Tumor Tissue Reveals their Prognostic and Predictive Significance in Breast Cancer.}, journal = {Experimental oncology}, volume = {48}, number = {1}, pages = {31-39}, doi = {10.15407/exp-oncology.2026.01.031}, pmid = {42290559}, issn = {2312-8852}, mesh = {Humans ; *MicroRNAs/genetics/blood ; Female ; *Breast Neoplasms/genetics/blood/pathology/mortality ; Prognosis ; *Biomarkers, Tumor/genetics/blood ; Middle Aged ; Adult ; Gene Expression Regulation, Neoplastic ; }, abstract = {BACKGROUND: Breast cancer (BC) heterogeneity signifi antly complicates diagnosis, prognosis, and prediction of treatment response. MicroRNAs (miRNAs) have emerged as promising biomarkers due to their involvement in tu- mor progression and in regulating therapy sensitivity. however, the combined clinical signifi ance of circulating and tumor-associated miRNAs, such as hsa-miR-26b-5p and hsa-miR-186-5p, remains insuffi tly elucidated. Materi- als and Methods. Expression levels of hsa-miR-26b-5p and hsa-miR-186-5p were analyzed in serum and tumor tis- sue of 124 BC patients. Associations with clinicopathological parameters were assessed. The prognostic signifi ance was evaluated based on disease progression and recurrence within 3 years. The predictive value was determined in patients receiving neoadjuvant chemotherapy (4AC regimen) using response assessment and ROC analysis. Re- sults. young BC patients (≤45 years) demonstrated signifi antly lower circulating levels of both miRNAs. Serum hsa-miR-186-5p expression was associated with early-stage disease, tumor size, lymph node status, and molecular subtype. Increased circulating hsa-miR-26b-5p levels were linked to disease progression, whereas decreased hsa- miR-186-5p levels were observed in patients with unfavorable outcomes. In tumor tissue, hsa-miR-26b-5p expres- sion correlated with tumor grade, size, and metastatic status, showing elevated levels in poorly differentiated tumors and reduced expression in metastatic disease. In contrast, hsa-miR-186-5p was associated with the molecular sub- type and lymph node involvement, with the highest expression observed in hER2-positive tumors and in patients with recurrence. Elevated levels of hsa-miR-186-5p in both serum and tumor tissue were associated with reduced sensitivity to doxorubicin-based neoadjuvant chemotherapy. ROC analysis confi med its predictive value (AUC = 0.750 for serum and 0.818 for tumor tissue). No signifi ant association between hsa-miR-26b-5p and chemothe- rapy response was observed.

CONCLUSIONS: hsa-miR-26b-5p and hsa-miR-186-5p demonstrate complementary roles in BC biology. hsa-miR-26b-5p is primarily associated with tumor aggressiveness and cancer progression, whereas hsa-miR-186-5p refl cts its molecular characteristics and response to chemotherapy. Their combined assessment in serum and tumor tissue represents a promising approach for improving prognostic stratifi ation and predicting treatment effi acy in BC patients.}, } @article {pmid42290625, year = {2026}, author = {Tenenbein, M}, title = {Author response to: Mullins et al. comment on, "We need a standardized North American acetylcysteine dosing regimen for the treatment of paracetamol (acetaminophen) poisoning".}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {64}, number = {8}, pages = {633-635}, doi = {10.1080/15563650.2026.2679164}, pmid = {42290625}, issn = {1556-9519}, mesh = {*Acetaminophen/poisoning ; *Acetylcysteine/administration & dosage/therapeutic use ; Humans ; *Antidotes/administration & dosage/therapeutic use ; *Analgesics, Non-Narcotic/poisoning ; North America ; }, abstract = {INTRODUCTION: I have reviewed Mullins et al's critique of my commentary "We need a standardized North American acetylcysteine dosing regimen for the treatment of paracetamol (acetaminophen) poisoning".

DISCUSSION: I concur regarding this need, and I agree that the original three-bag regimen should be retired. However, we disagree upon its replacement. They challenge my recommendation for a two-bag regimen, and they favour the one-bag two-step approach. The impetus for a replacement acetylcysteine regimen is to decrease the adverse effects and errors associated with the three-bag protocol. However, the one-bag two-step regimen was not designed to decrease adverse effects, and their published reports do not find a decrease of errors. And a fatal adverse effect, acetylcysteine overdose, has emerged with use experience of this regimen.

CONCLUSIONS: The one-bag two-step regimen should be dismissed from the quest for a standardized North American acetylcysteine dosing regimen for the treatment of paracetamol (acetaminophen) poisoning.}, } @article {pmid42293320, year = {2026}, author = {Novikova, L and Lang, C and Tumani, H and Klose, V and Kassubek, J and Dreyhaupt, J and Dupuis, L and Wabitsch, M and Ludolph, A}, title = {Thyroid hormones and energy metabolism in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {3}, pages = {fcag198}, pmid = {42293320}, issn = {2632-1297}, abstract = {Weight loss, partially caused by hypermetabolism, represents a well-documented and therapeutically relevant feature of the amyotrophic lateral sclerosis phenotype worldwide. In this study, we retrospectively analysed the association between thyroid function and clinical, prognostic and metabolic parameters in a cohort of patients with amyotrophic lateral sclerosis in an experienced centre in Germany (n = 1754). Specifically, we examined the relationship between thyroid stimulating hormone levels, age, glucose and body mass index and-in subgroups-phosphorylated neurofilament heavy chain levels in CSF. There was no association between thyroid stimulating hormone levels and body mass index in patients with amyotrophic lateral sclerosis (n = 954). In contrast with other cohorts, thyroid stimulating hormone levels decreased with age in patients with amyotrophic lateral sclerosis indicating hypothalamic deficiency in the ageing patients. There was no association between thyroid stimulating hormone and phosphorylated neurofilament heavy chain (prognostic marker) in CSF of a subcohort (n = 646). Thyroid stimulating hormone levels correlated with glucose levels, an effect more pronounced in male patients. In conclusion, our results suggest that thyroid metabolism does not significantly contribute to amyotrophic lateral sclerosis-related weight loss or disease prognosis as estimated by phosphorylated neurofilament heavy chain; thyroid dysfunction is unlikely to be a primary driver of the metabolic dysregulation observed in amyotrophic lateral sclerosis. Most interestingly, thyroid stimulating hormone levels show an unexpected negative relation to age in patients with amyotrophic lateral sclerosis.}, } @article {pmid42293321, year = {2026}, author = {Ma, M and Zhao, B and Gao, N and Sun, X and Shao, K and Lin, P and Li, W and Zhao, Y and Yu, D and Yan, C and Liu, S and Yun, Y}, title = {Quantitative susceptibility mapping reveals widespread brain iron abnormalities in sporadic patients with early-stage amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {3}, pages = {fcag190}, pmid = {42293321}, issn = {2632-1297}, abstract = {In the present study, using the novel quantitative susceptibility mapping technique, we aimed to systematically investigate brain iron alterations in a large group of sporadic early-stage amyotrophic lateral sclerosis patients and their correlation with clinical disability. In this study, amyotrophic lateral sclerosis patients at King's stage 1 were defined as early-stage amyotrophic lateral sclerosis patients, and 53 newly diagnosed early-stage amyotrophic lateral sclerosis patients and 50 healthy controls were included. Voxel-based whole-brain quantitative susceptibility mapping analysis was used to explore brain iron alterations. Voxel-based morphometry analysis was also performed. Longitudinal follow-up was performed in amyotrophic lateral sclerosis patients, and the follow-up progression rate was calculated. We found that, compared with healthy controls, early-stage amyotrophic lateral sclerosis patients presented significantly increased susceptibility values, mainly in the motor cortex, prefrontal cortex, hippocampus and cerebellar regions, while volumetric alterations were not detected. Moreover, motor and extra-motor cortex susceptibility values were significantly correlated with upper motor neuron scores and follow-up progression rate (r = 0.452-0.504, P < 0.01) in early-stage amyotrophic lateral sclerosis patients. We demonstrated a clear profile of early motor and extra-motor iron depositions and their important roles in early-stage amyotrophic lateral sclerosis patients. We suggest that quantitative susceptibility mapping is likely a promising neuroimaging approach for assessing early upper motor neuron damage and detecting early extra-motor alterations in amyotrophic lateral sclerosis patients.}, } @article {pmid42293743, year = {2026}, author = {Mavillonio, A and Rizzini, D and Detassis, S and Denti, MA}, title = {Neurodegenerative spliceosomopathies.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1787859}, pmid = {42293743}, issn = {2296-634X}, abstract = {Spliceosomal syndromes are a group of disorders caused by pathogenic variants in core spliceosomal RNAs or proteins, leading to defective pre-mRNA splicing and tissue-specific disease vulnerability. Although the spliceosome is ubiquitously expressed, its dysfunction preferentially affects highly splicing-dependent tissues such as the retina and the nervous system. This mini-review focuses on neurodegenerative spliceosomopathies, including spinal muscular atrophy, amyotrophic lateral sclerosis, and retinitis pigmentosa, highlighting how alterations in snRNP biogenesis, spliceosome assembly, and splicing fidelity drive neuronal and photoreceptor degeneration. We discuss shared and distinct molecular mechanisms, unresolved questions on tissue specificity, and emerging therapeutic strategies targeting RNA splicing.}, } @article {pmid42295687, year = {2026}, author = {Jürs, AV and Naumann, M and Lehto, A and Schön, H and Kurth, J and Prudlo, J and Hermann, A and Kasper, E}, title = {Cognitive and Neuroimaging Divergence Between Juvenile and Adult FUS Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, pmid = {42295687}, issn = {2328-9503}, support = {//Hermann und Lilly Schilling-Stiftung für medizinische Forschung im Stifterverband/ ; //Clinician Scientist Program of the Center for Transdisciplinary Neuroscience Rostock/ ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron degeneration. Fused in sarcoma (FUS)-associated juvenile ALS (jALS) represents a distinct and aggressive subgroup with rapid deterioration and poor prognosis. Certain FUS mutations have been associated with comorbid intellectual disability, suggesting neurodevelopmental involvement. We compared FUS-jALS with adult-onset FUS-ALS cases (aALS) to evaluate the association between premorbid cognitive impairment, genetic and clinical features incorporating neuroimaging data.

METHODS: Patients with genetically confirmed FUS-ALS were classified as jALS (onset < 25 years) or aALS (onset ≥ 25 years). Neuropsychological assessment used Mehrfachwahl-Wortschatz-Test (MWT) for verbal IQ, and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), with cognitive impairment classified according to Strong criteria. Volumetric analysis was conducted on structural MRI and FDG-PET data.

RESULTS: All three jALS (P525L [n = 2], H517_Q519del [n = 1]) showed rapid progression with early severe clinical events. Neuropsychological assessment revealed global cognitive deficits (ALS-ci) with widespread dysfunction beyond typical ALS-specific patterns and reduced verbal IQ, pointing towards premorbid cognitive impairment. aALS demonstrated slower progression and were predominantly cognitively unimpaired (ALS-ni) or showed an ALS-specific impairment. Neuroimaging revealed distinct patterns: jALS cases demonstrated posterior cortical atrophy and hypometabolism on FDG-PET, while aALS showed largely preserved brain volumes and limbic-subcortical hypometabolism.

INTERPRETATION: Specific FUS mutations (P525L, H517_Q519del) predispose to jALS with severe progression and premorbid cognitive impairments, supporting a genotype-phenotype association. Posterior cortical findings suggest neurodevelopmental delay rather than disease-related neurodegeneration. Genetic FUS screening may be warranted in patients with intellectual disability and motor signs, given emerging targeted therapies.}, } @article {pmid42295787, year = {2026}, author = {Zangrando, L and Buratti, E and Paron, F}, title = {TDP-43 Aggregation: The Healthy-Toxic Balance of the Prion-Like Domain.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {40}, pages = {e76119}, pmid = {42295787}, issn = {2198-3844}, support = {//AriSLA 2022-NOSRESCUEALS/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; *Prions/metabolism/genetics ; *Protein Aggregation, Pathological/genetics/metabolism ; *Neurodegenerative Diseases/metabolism/genetics ; Protein Domains ; *Protein Aggregates ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed RNA-binding protein that plays essential roles in RNA metabolism, including transcription, splicing, transport, and stability. Pathological TDP-43 aggregates have become a defining hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and a large subset of frontotemporal lobar degeneration (FTLD). In the last decade, increasing evidence has challenged the initial thought of TDP-43 condensates as a purely pathological event, highlighting instead the physiological relevance of reversible self-association, polymerization and liquid-liquid phase separation (LLPS) in regulating TDP-43 functions. In this review, we provide an integrated overview of the structural determinants governing TDP-43 two-faced polymerization, with a particular focus on the prion-like domain and its parallelism with prion proteins. Indeed, while physiological assemblies support normal RNA processing, the dysregulation of LLPS by either disease-associated mutations, altered RNA-binding, aberrant post-translational modifications, or proteolytic cleavage can promote the transition toward irreversible, pathogenic aggregates. Finally, we summarize strategies aimed at eliminating TDP-43 aggregates or modulating its phase-separation behavior. Altogether, this review frames TDP-43 polymerization in both healthy and pathological conditions, offering a prion-like centered view of TDP-43 proteinopathies.}, } @article {pmid42296226, year = {2026}, author = {Naumann, M and Kretschmer, S and Dorst, J and Lapp, H and Peikert, K and Petri, S and Gess, B and Wolf, C and Rödiger, A and Smesny, U and Pan-Montojo, F and Kerschen, P and Grehl, T and Prudlo, J and Regensburger, M and Ludolph, A and Günther, R and Brenner, D and Lee-Kirsch, MA and Hermann, A}, title = {Innate immune signaling as a potential pathomechanistic biomarker for distinct subtypes in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2663910}, pmid = {42296226}, issn = {2167-9223}, abstract = {Stimulation of the innate immune system has been implicated in ALS and particularly in distinct monogenic forms of ALS. To address whether this is of diagnostic value, we performed a proof-of concept study using qPCR to assess the Interferon score in blood samples of genetic ALS. 56.5% of genetic ALS patients showed significant IFN activation, highest in C9orf72HRE patients (77.3%). About half of FUS-ALS (52.2%), but none of SOD1-ALS patients demonstrated pathological IFN scores. The IFN score significantly correlated with the ALSFRS-R slope and inversely with the time to severe event as a survival surrogate in this genetic ALS cohort. IFN + patients were more likely to be male, showed more rapid disease progression and higher neurofilament levels. The IFN score might have the potential as a stratification and readout tool for biomarker-guided individualized therapy in ALS.}, } @article {pmid42296263, year = {2026}, author = {Fabry, V and Faruch-Bilfeld, M and El Khalfi, R and Acket, B and Al Achram, Y and Cintas, P}, title = {Whole-body muscle MRI improves diagnostic certainty in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2685160}, pmid = {42296263}, issn = {2167-9223}, abstract = {Introduction: Early diagnosis of amyotrophic lateral sclerosis (ALS) remains challenging due to the absence of a definitive biomarker and the difficulty of demonstrating widespread lower motor neuron (LMN) involvement. Whole-body muscle MRI (WB-MRI) enables comprehensive assessment of muscle involvement and may improve detection of LMN dysfunction. This study aimed to evaluate whether WB-MRI improves diagnostic certainty in ALS when combined with clinical and electromyography (EMG) assessment. Methods: In this prospective single-center study, 47 patients with ALS underwent clinical examination, EMG, and WB-MRI. Diagnostic classification according to the Awaji criteria was assessed using clinical and EMG data alone and after integration of MRI markers of LMN involvement, including fatty infiltration and muscle edema, or muscle edema alone as a surrogate marker. Results: WB-MRI identified additional LMN-involved regions in 27.7% of patients when both fatty infiltration and muscle edema were considered, and in 42.6% when considering muscle edema alone. This resulted in diagnostic upgrading in 14.9% and 25.5% of patients, respectively. The proportion of definite ALS increased from 8.5% to 17.0% when muscle edema alone was considered. MRI had limited impact on diagnostic classification according to the Gold Coast criteria. Among patients without LMN involvement on clinical and EMG assessment (all with bulbar-onset), 50% were reclassified after MRI. Conclusion: WB-MRI improves detection of LMN involvement and increases diagnostic certainty according to the Awaji criteria, with muscle edema appearing to be the most relevant MRI marker for integration into ALS diagnostic assessment.}, } @article {pmid42297978, year = {2026}, author = {Card, NS and Singer-Clark, T and Peracha, H and Iacobacci, C and Hou, X and Wairagkar, M and Fogg, Z and Offenberg, EC and Hochberg, LR and Stavisky, SD and Brandman, DM}, title = {Long-term independent use of an intracortical brain-computer interface for speech and cursor control.}, journal = {Nature medicine}, volume = {32}, number = {7}, pages = {2504-2510}, pmid = {42297978}, issn = {1546-170X}, support = {A2295-R//VHA Office of Research and Development | Rehabilitation Research and Development Service (Rehabilitation Research & Development Service)/ ; N/A//Achievement Rewards for College Scientists Foundation (ARCS Foundation)/ ; 1DP2DC021055//U.S. Department of Health & Human Services | NIH | NIH Office of the Director (OD)/ ; N/A//Burroughs Wellcome Fund (BWF)/ ; 23-SGP-652//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; AL220043//United States Department of Defense | Office of the Secretary of Defense (OSD)/ ; DP2 DC021055/DC/NIDCD NIH HHS/United States ; }, mesh = {*Brain-Computer Interfaces ; Humans ; Male ; *Speech/physiology ; Amyotrophic Lateral Sclerosis/physiopathology/complications ; Dysarthria/physiopathology ; Paralysis/physiopathology ; Communication Devices for People with Disabilities ; }, abstract = {Brain-computer interfaces (BCIs) can provide naturalistic communication and digital access to people with severe paralysis by decoding neural activity associated with attempted speech and movement. Recent work has demonstrated highly accurate intracortical BCIs for speech and cursor control, but two critical capabilities needed for practical viability were unmet: independent at-home operation without researcher assistance and reliable long-term performance supporting accurate speech and cursor decoding. Here we demonstrate the independent and near-daily use of a multimodal BCI with novel brain-to-text speech and computer cursor decoders by a man with paralysis and severe dysarthria due to amyotrophic lateral sclerosis. Over nearly 2 years, the participant used the BCI for more than 3,800 h at home with no researchers present to maintain rich interpersonal communication with his family and friends, independently control his personal computer and sustain full-time employment-despite being paralyzed. He communicated 183,060 sentences-totaling 1,960,163 words-at an average rate of 56 words per minute. He labeled 92% of sentences as being decoded at least mostly correctly. In formal quantifications of performance where he was asked to say words presented on a screen, attempted speech was consistently decoded with more than 99% word accuracy (125,000 word vocabulary). The participant also used the speech BCI as keyboard input and the cursor BCI as mouse input to control his personal computer, enabling him to send text messages and emails and to browse the internet. These results demonstrate that intracortical BCIs have the potential to support independent use in the home, marking a critical step toward practical assistive technology for people with severe motor impairment.}, } @article {pmid42297981, year = {2026}, author = {Ding, DY and Bot, VA and Chen, KL and Groves, JW and Pálovics, R and Masuda, D and Farinas, A and Oh, HS and Wagner, V and Lu, N and , and Cruchaga, C and Isakova, A and Schott, JM and Wyss-Coray, T}, title = {Plasma proteomic signatures of cellular aging predict human disease.}, journal = {Nature medicine}, volume = {32}, number = {6}, pages = {2060-2072}, pmid = {42297981}, issn = {1546-170X}, support = {AG072255//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30 AG066515/AG/NIA NIH HHS/United States ; R01 AG072255/AG/NIA NIH HHS/United States ; P50 AG047366/AG/NIA NIH HHS/United States ; ARUK-PG2017-1946//Alzheimer's Research UK (ARUK)/ ; SG-666374-UK BIRTH COHORT/ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Proteomics/methods ; Female ; *Cellular Senescence/genetics ; Male ; Alzheimer Disease/blood/genetics ; Aging ; Astrocytes/metabolism/pathology ; Aged ; Middle Aged ; Amyotrophic Lateral Sclerosis/blood/genetics ; *Blood Proteins/metabolism ; Lung Neoplasms/blood/genetics ; Genotype ; Adult ; }, abstract = {Aging is asynchronous across cells and organs. Here we tested whether plasma proteomics can be used to analyze cell type-specific aging. From analyses of over 7,000 plasma proteins measured in 60,542 individuals, we developed machine learning models to estimate the biological age of over 40 cell types spanning neuronal, immune, glial, endocrine, epithelial and musculoskeletal origins. We observed that 20-25% of individuals exhibited accelerated aging in a single cell type and 1-3% in 10 or more cell types. Cellular aging signatures were associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Individuals with the APOE4 genotype showed older astrocytes but younger macrophages compared to APOE3 carriers, whereas the APOE2 genotype had inverse associations. Moreover, extreme astrocyte aging tripled the risk of incident Alzheimer's Disease in individuals with two APOE4 alleles, while youthful astrocytes reduced risk. Individuals with extremely aged compared to youthful skeletal myocytes exhibited a 12.7-fold higher risk of developing amyotrophic lateral sclerosis. In individuals who smoked, extreme respiratory epithelial cell aging was associated with a 58% higher lung cancer risk compared to smoking alone. Specific cellular vulnerabilities and cumulative cellular aging burden influenced survival, with youthful immune and neuronal cell types conferring protective effects. Finally, we developed a polycellular aging risk score that stratified mortality risk across cohorts and proteomics platforms. These findings establish a framework for quantifying human physiology at cellular resolution, revealing heterogeneous aging trajectories and their impact on disease susceptibility and resilience.}, } @article {pmid42298083, year = {2026}, author = {Al-Shami, AS and Anwar, MM}, title = {The lung-brain axis in neurodegeneration: inflammatory, immune, and vascular mechanisms with therapeutic implications.}, journal = {Inflammopharmacology}, volume = {34}, number = {7}, pages = {4483-4513}, pmid = {42298083}, issn = {1568-5608}, mesh = {Humans ; *Neurodegenerative Diseases/immunology/physiopathology ; *Brain/metabolism/immunology ; Animals ; COVID-19 ; Inflammation/immunology ; *Lung/immunology/metabolism ; Blood-Brain Barrier ; SARS-CoV-2 ; Oxidative Stress ; }, abstract = {Neurodegenerative and chronic pulmonary diseases represent major global health challenges and have widely been investigated separately. Emerging evidence indicates the existence of a lung-brain axis, through which pulmonary pathology and environmental exposures can influence neurological health. The current review highlights the mechanistic and clinical evidence linking chronic lung inflammation, air pollution, and immune dysregulation to the onset and progression of Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). A pathway-based framework is presented in which lung inflammation, systemic cytokine release, oxidative stress, blood-brain barrier disruption, immune priming, and protein misfolding mediate lung-to-brain communication. Associations between chronic obstructive pulmonary disease, asthma, particulate matter exposure, and adverse neurological outcomes including cognitive decline, brain atrophy, disease progression, and elevated neurodegenerative risk are emphasized. Specific mechanisms are addressed, including immune-mediated effects in multiple sclerosis, inhalation-driven protein aggregation in Parkinson's disease, and vascular and oxidative injury contributing to dementia and amyotrophic lateral sclerosis. COVID-19 is considered a clinical model of acute lung-brain axis disruption, demonstrating inflammation-driven neurocognitive consequences, and its role in this context was also highlighted. Additionally, potential preventive and therapeutic strategies are discussed, highlighting pulmonary health and environmental exposure reduction as modifiable factors that may help mitigate neurological disease. This integrative review underscores the clinical relevance of the lung-brain axis and calls for interdisciplinary strategies to improve neurological outcomes through pulmonary and environmental interventions.}, } @article {pmid42299008, year = {2026}, author = {Singh, NK and Singh, A}, title = {Mechanistic Perspectives of Icariin against Neuroinflammation: Taming Glial Activation.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575448388260306051328}, pmid = {42299008}, issn = {1875-5607}, abstract = {Glial-mediated neuroinflammation significantly contributes to major neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Inhibition of glial-mediated neuroinflammation is effective in treating neurodegenerative diseases. Although no permanent cure exists, considerable research aims to identify natural compounds that may slow the disease progression. Icariin is a naturally occurring flavonoid derived from the herb Herba epimedii and has been shown to have several medicinal benefits, including anti-aging, antioxidant, anti-inflammatory, and anti-apoptotic properties. Recent studies have indicated that Icariin, a potent prenylated flavonol glycoside, exhibits neuroprotective effects against glial-mediated neuroinflammation. Icariin attenuates glial pro-inflammatory responses and prevents neurotoxicity in cellular and animal models. Additionally, Icariin is speculated to facilitate neuronal functioning and survival in experimental conditions. The present review highlights the remarkable role of glial cells in neuroinflammatory processes subsequently neurodegeneration, and the potential of icariin to suppress glial-mediated neuroinflammation. We hope that this review will accelerate the pharmacological development of icariin as a potential therapeutic compound against glial-mediated neuroinflammation, which triggers the pathogenesis of several neurodegenerative disorders.}, } @article {pmid42299014, year = {2026}, author = {Kaur, H and Kaur, M and Sethi, GK and Kaur, AS and Mishra, A and Sharma, N}, title = {Pathogenic Proteins Driving ALS Pathogenesis: Molecular Mechanisms and Translational Therapeutic Perspectives.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273440191260226063811}, pmid = {42299014}, issn = {1996-3181}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of motor neurons, with protein aggregation as a central pathological hallmark. Key pathogenic proteins, including TDP-43, SOD1, FUS, and dipeptide repeat proteins (DPRs) from C9orf72 expansions, drive disease progression through diverse but converging mechanisms. TDP-43 proteinopathy, present in nearly all ALS cases, involves cytoplasmic mislocalization, misfolding, and aggregation, disrupting RNA processing, protein transport, and DNA repair. Similarly, SOD1 and FUS mutations promote toxic protein aggregation, impairing cellular homeostasis and contributing to neuronal dysfunction. C9orf72-derived DPRs exert toxicity by interfering with nucleocytoplasmic transport. The propagation of these pathogenic proteins between neurons and glia, often via prion-like mechanisms, underlies the characteristic spread of ALS pathology throughout the nervous system. Cellular protective responses, such as molecular chaperones and the ubiquitin-proteasome system, attempt to mitigate aggregation but are often overwhelmed in disease states. Mitochondrial dysfunction, oxidative stress, and disturbances in calcium homeostasis are also implicated, with evidence showing that SOD1 mutations can alter redox balance and mitochondrial function in both neurons and non-neuronal cells. Impaired DNA repair mechanisms, involving proteins such as TDP-43, FUS, NEK1, and VCP, have emerged as important contributors to ALS pathogenesis, linking protein aggregation to genomic instability. Recent therapeutic strategies focus on directly targeting misfolded proteins using small molecules, peptides, or antisense oligonucleotides to inhibit aggregation or enhance clearance, offering hope for disease modification. Understanding the interplay between protein aggregation, impaired RNA metabolism, and cellular stress responses is crucial for developing effective translational therapies for ALS.}, } @article {pmid42299015, year = {2026}, author = {Singh, G and Singh, S and Sarkar, A and Sandhu, NK}, title = {Amyotrophic Lateral Sclerosis: Therapeutic Innovations and Evolving Regulatory Approaches.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273438968260318203940}, pmid = {42299015}, issn = {1996-3181}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons, leading to muscle weakness, paralysis, and respiratory failure. Despite extensive research, riluzole and edaravone remain the only globally approved disease-modifying therapies, offering modest survival benefits. This review summarizes current understanding of ALS pathogenesis, approved pharmacological treatments, and emerging gene-, RNA-, and cell-based therapeutic strategies. Particular emphasis is placed on regulatory considerations and evolving clinical trial designs in ALS drug development. The accelerated approval and subsequent withdrawal of sodium phenylbutyrate-taurursodiol (AMX0035) are discussed as a critical case study highlighting the challenges of regulatory flexibility in rare, fatal diseases. Advances in biomarker development, especially neurofilament light chain, are examined for their growing role in trial design and therapeutic evaluation. Collectively, these insights underscore a shift toward biomarker- informed and precision-based approaches that may improve future ALS therapeutic development.}, } @article {pmid42300806, year = {2026}, author = {Calma, AD and Pavey, N and Tsuji, Y and Ghapar, AA and Bos, MAJVD and Orden, B and Lee, G and Mekhael, L and Ryder, J and Silva, CS and McDonald, D and Kakar, F and Yiannikas, C and Kiernan, MC and Brown, DA and Menon, P and Vucic, S}, title = {Integration of Serum Neurofilament Light Chain and Cortical Dysfunction Improves Diagnostic Accuracy in ALS.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, pmid = {42300806}, issn = {2328-9503}, abstract = {OBJECTIVE: To determine whether integration of serum neurofilament light chain (NfL) and cortical dysfunction improves diagnostic accuracy in amyotrophic lateral sclerosis (ALS) when applied alongside the Gold Coast criteria (GCC).

METHODS: In this prospective study, 148 participants with suspected ALS were recruited (101 ALS and 47 with ALS mimicking disorders). Participants taking medications known to influence TMS measures were excluded. Serum NfL levels were quantified using a single-molecule array assay. Cortical function was assessed using threshold tracking transcranial magnetic stimulation, with cortical dysfunction defined by reduced mean short interval intracortical inhibition or motor cortex inexcitability. Diagnostic performance was evaluated using sensitivity, specificity, and diagnostic odds ratios (DOR), with 95% confidence intervals (CI).

RESULTS: Serum NfL demonstrated excellent discrimination (area under the curve 0.92, p < 0.001), with cut-off ≥ 33.5 pg/mL providing a sensitivity of 0.85 (95% CI 0.77-0.91) and specificity 0.87 (95% CI 0.75-0.94). Cortical dysfunction demonstrated very good diagnostic performance (sensitivity 0.77 [95% CI 0.68-0.84], specificity 0.77 [95% CI 0.63-0.86]). The GCC achieved a sensitivity of 0.89 (95% CI 0.82-0.94) and specificity 0.89 (95% CI 0.77-0.95). Combining GCC with elevated NfL or cortical dysfunction increased the specificity to 0.98 (95% CI 0.89-1.00) while maintaining high sensitivity at 0.87 (95% CI 0.79-0.92), yielding the highest DOR.

INTERPRETATION: Integration of serum NfL and cortical dysfunction with the Gold Coast criteria improves diagnostic accuracy in ALS, particularly by increasing specificity. This multimodal approach provides a practical framework for earlier and more definitive diagnosis that may facilitate more efficient clinical trial recruitment.}, } @article {pmid42300933, year = {2026}, author = {Gray, VP and Cui, Z and Klepsig, M and Letteri, RA}, title = {Designing polymer-peptide conjugates to target dipeptide repeat aggregates implicated in amyotrophic lateral sclerosis.}, journal = {Journal of materials chemistry. B}, volume = {14}, number = {26}, pages = {8149-8158}, pmid = {42300933}, issn = {2050-7518}, support = {R35 GM147424/GM/NIGMS NIH HHS/United States ; T32 GM136615/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Dipeptides/chemistry ; *Polymers/chemistry ; Humans ; *Peptides/chemistry ; Protein Aggregates/drug effects ; }, abstract = {Toxic dipeptide repeats such as the aggregating glycine-alanine (GA)n peptide are implicated in the progression of amyotrophic lateral sclerosis (ALS), a lethal neuromuscular disease with an urgent need for new therapeutics. Here, we report polymer-peptide conjugates that prevent aggregation of (GA)10. Optical density measurements and transmission electron microscopy demonstrate that conjugates prevent aggregation when co-incubated with (GA)10 and disperse pre-aggregated (GA)10. These results represent an important step toward a new generation of therapeutics for ALS and contribute to a growing body of literature demonstrating the potential of polymer-peptide conjugates as therapeutics.}, } @article {pmid42301686, year = {2026}, author = {Jomaa, AM and Khalid, H and Abozait, HJ and Mudassar, H and Kaur, R}, title = {Efficacy of Sodium Phenylbutyrate-Taurursodiol in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Annals of Indian Academy of Neurology}, volume = {29}, number = {3}, pages = {343-352}, pmid = {42301686}, issn = {0972-2327}, abstract = {OBJECTIVE: To evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol (PB-TURSO) and its components in slowing disease progression and improving survival in patients with amyotrophic lateral sclerosis (ALS).

METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies comparing PB-TURSO or its components to placebo or standard of care in adults with ALS were included. The primary outcomes were functional decline (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R]) and survival. Two reviewers independently screened studies, extracted data, and assessed the risk of bias. A random-effects model was used for the meta-analysis, and a narrative synthesis was conducted for Tauroursodeoxycholic Acid (TUDCA) monotherapy and secondary analyses from the CENTAUR trial.

RESULTS: Two RCTs (n = 801) were included in the meta-analysis. The pooled analysis demonstrated no statistically significant difference in either ALSFRS-R decline (mean difference [MD] 1.51, 95% confidence interval [CI] -1.01 to 4.02; P = 0.24; I² =71%) or survival (hazard ratio [HR] 0.90, 95% CI 0.73-1.11; P = 0.31; I² = 61%). A separate trial of TUDCA monotherapy (n = 34) demonstrated significant functional benefits. Post hoc analyses of the CENTAUR trial reported a survival benefit of 6.5-10.6 months and delayed progression to major disease milestones. Biomarker analyses suggested anti-inflammatory effects. The risk of bias was moderate to high, and the certainty of evidence was rated very low by GRADE.

CONCLUSIONS: Based on very low certainty evidence, the available RCT data do not support a definitive conclusion regarding the efficacy of PB-TURSO in ALS. Post hoc exploratory analyses suggest a potential survival benefit, which requires confirmation in adequately powered, prospectively designed trials; current results are hypothesis-generating rather than practice-defining.}, } @article {pmid42301897, year = {2026}, author = {Peters, GA and Misra, AJ and Samadian, KD and Chang, W and Chandran, KG and Hurwitz, JA and Muszalski, C and Granich, N and Goldberg, SA and Cash, RE}, title = {Cardiac Arrest During Interfacility Transport with Emergency Medical Services: A Preliminary Nationwide Cross-Sectional Study.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/10903127.2026.2690618}, pmid = {42301897}, issn = {1545-0066}, abstract = {OBJECTIVES: We aimed to provide the first national study of out-of-hospital cardiac arrests (OHCA) witnessed by emergency medical services (EMS) during interfacility transport (IFT).

METHODS: We used a nationwide prehospital patient care report dataset from 2023 to complete a cross-sectional observational study of EMS encounters for IFT during which OHCA occurred. Descriptive statistics were computed, stratified by level of EMS care provided. Multivariable logistic regression analysis was completed to evaluate factors associated with return of spontaneous circulation (ROSC) at the end of the IFT encounter upon transfer of care to the receiving facility. Finally, we completed a similar multivariable logistic regression analysis restricted to the subgroup of patients with an unshockable initial rhythm.

RESULTS: A total of 1,466 OHCA incidents occurred during an IFT with EMS: 7.5% with basic life support (BLS), 53.6% with advanced life support (ALS), and 38.9% with critical care transport (CCT). Among these incidents 11.8% were associated with trauma, 9.2% involved cardiopulmonary resuscitation (CPR) prior to EMS unit arrival, 14.7% involved a mechanical device to perform CPR, 22.2% had a shockable initial rhythm, and 58.1% were transported via ground as opposed to air. At the conclusion of the IFT EMS encounter, 50.3% had sustained ROSC. Geriatric age (aOR 0.64, 95%CI 0.44-0.94), BLS care (aOR 0.45, 95%CI 0.22-0.90), and ground transport (aOR 0.58, 95%CI 0.38-0.89) were associated with worse outcomes on adjusted analysis, whereas shockable initial rhythm (aOR 3.86, 95%CI 2.42-6.36) and CCT care (aOR 2.21, 95%CI 1.42-3.48) were associated with better outcomes. The sub-analysis for OHCA during IFT with an unshockable initial rhythm also showed greater odds of ROSC when managed by CCT relative to ALS (aOR 2.65, 95%CI 1.64-4.33) while adjusting for other key factors.

CONCLUSIONS: Using a large nationwide sample of OHCA incidents that occurred during IFT, we found that higher level of EMS care was associated with superior short-term outcomes while controlling for other key factors. These findings underscore the importance of accurate patient triage at sending facilities and the value of CCT for high-risk patients.}, } @article {pmid42302423, year = {2026}, author = {Almenara Abellán, JL and Lagares Franco, C and Bordes Bustamante, F and Gracia Romero, MÁ and Santisteban Espejo, AL}, title = {Impact of a simulation-based training program on the acquisition of ultrasound window competencies for the initial assessment of polytrauma patients in advanced prehospital nursing care.}, journal = {Enfermeria intensiva}, volume = {37}, number = {3}, pages = {500604}, doi = {10.1016/j.enfie.2026.500604}, pmid = {42302423}, issn = {2529-9840}, mesh = {Humans ; *Clinical Competence ; *Emergency Medical Services ; *Multiple Trauma/diagnostic imaging ; Ultrasonography ; *Simulation Training ; Female ; Adult ; *Emergency Nursing/education ; Male ; }, abstract = {INTRODUCTION: Point-of-care ultrasound is essential in the initial assessment of polytrauma patients. The E-FAST protocol enables rapid detection of intra-abdominal free fluid, pericardial effusion, and pneumothorax, with particular usefulness in prehospital settings. However, ultrasound training among emergency nursing staff remains limited, especially within Advanced Life Support (ALS) mobile units.

OBJECTIVE: To evaluate the effect of a brief, structured training program on the acquisition of competencies for obtaining E-FAST windows in ALS mobile units nurses, assessing knowledge, technical skills, scanning sequence, and perceived confidence.

METHOD: A quasi-experimental pre-post intervention study was conducted with nurses with ≥6 months of experience in emergency or prehospital care. The intervention included baseline assessment, a 2-h theoretical module, high-fidelity simulation with Ultrasound Mentor®, and hands-on practice with human models. Final assessment combined a theoretical test, simulator-based practical evaluation, and scanning with a real ultrasound device. Knowledge, execution times, and confidence levels were recorded.

RESULTS: Fourteen nurses participated, most without previous ultrasound training (85.7%). Initial confidence was low and improved significantly after the intervention. Theoretical performance increased in 5 of the 6 evaluated items, reaching up to 92.9% accuracy in key content areas. Practical assessment demonstrated an organized scanning sequence and appropriate times for prehospital care (medians of 118 s [IQR 24.5] in advanced simulation and 237 s [IQR 33.3] using a real ultrasound device).

DISCUSSION: The program enabled the acquisition of essential skills even in professionals without prior ultrasound experience. The combination of theory, simulation, and hands-on practice facilitated rapid competency transfer and protocol standardization.

CONCLUSIONS: A brief training program improves ALS mobile units nurses' competence and confidence in obtaining E-FAST windows, supporting the safe integration of point-of-care ultrasound into prehospital care.}, } @article {pmid42302677, year = {2026}, author = {Gong, X and Xie, Y and Deng, X and Sun, Z and Fu, S and Wang, H and Hou, Y and Dong, Z and Zhou, W}, title = {Hydrolytic evolution of propyrisulfuron: wlectronic differentiation and spectroscopic fingerprints of transformation products.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {362}, number = {}, pages = {128245}, doi = {10.1016/j.saa.2026.128245}, pmid = {42302677}, issn = {1873-3557}, abstract = {Propyrisulfuron (PRS), a sulfonylurea herbicide used in paddy systems, undergoes hydrolysis to form structurally distinct transformation products. This study combined DFT/TDDFT calculations with experimental UV-Vis, FTIR, and Raman spectroscopy to characterise PRS and six experimentally identified products (HP1-HP6). Relative electronic descriptors showed that cleavage of the sulfonylurea bridge increased the HOMO-LUMO gaps from 4.572 eV for PRS to 5.978 and 6.229 eV for HP1 and HP2, respectively, whereas HP3-HP5 retained moderate gaps of 4.846-4.923 eV. HP5 showed the most negative Vmin (-71.524 kcal mol[-1]) and the largest dipole moment (16.67 D). Calculated and experimental spectra were consistent, with major UV-Vis peak deviations below 10 nm and characteristic FTIR and Raman deviations generally below 20 and 15 cm[-1], respectively. A validated 1YBH-based docking workflow reproduced the co-crystallized CIE pose with an RMSD of 0.320 Å; within this internally standardized comparison, PRS, HP3, HP5, and HP4 gave scores of -8.480, -7.212, -7.076, and - 6.979 kcal mol[-1], respectively. Docking results are interpreted as relative ALS/AHAS-recognition tendencies rather than direct evidence of toxicity or inhibitory potency. Overall, this work establishes a structure-spectrum framework for tracking PRS hydrolysis and differentiating its major products.}, } @article {pmid42302791, year = {2026}, author = {Sahu, SK and Memczak, S and Thakurela, S and Lu, J and Gupta, P and Mutukula, N and Hirano, A and Zhang, Y and Hishida, T and Kurita, M and Wang, C and Shao, Y and Williams, A and Shokhirev, M and Tiwari, VK and Rodriguez Esteban, C and Reddy, P and Meissner, A and Li, M and Izpisua Belmonte, JC}, title = {ZNF512B safeguards genome integrity at regulatory regions to repress the SASP and inflammation.}, journal = {Cell stem cell}, volume = {33}, number = {7}, pages = {1191-1204.e10}, pmid = {42302791}, issn = {1875-9777}, support = {P01 GM099117/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Inflammation/genetics/pathology ; Animals ; DNA Damage ; *Senescence-Associated Secretory Phenotype/genetics ; DNA Repair ; *Regulatory Sequences, Nucleic Acid/genetics ; Mice ; cGAS-STING Signaling Pathway ; *Cellular Senescence/genetics ; }, abstract = {Cellular senescence drives aging and disease largely through the senescence-associated secretory phenotype (SASP), yet its regulatory mechanisms remain unclear. Using a SASP reporter combined with a CRISPR-Cas9 screen targeting active regulatory elements, we identify the zinc-finger protein ZNF512B as a key suppressor of the SASP. ZNF512B loss induces DNA damage, activates cGAS-STING signaling, and triggers inflammatory transcriptional reprogramming. In contrast, ZNF512B promotes preferential DNA repair at regulatory genomic regions, limiting SASP induction. Mechanistically, ZNF512B is rapidly recruited to DNA-damage sites via distinct zinc-finger domains and facilitates NuRD complex targeting to damaged chromatin, enabling precise repair. In human neuromuscular organoids, ZNF512B deficiency induces inflammation, lineage imbalance, and cytokine secretion resembling amyotrophic lateral sclerosis (ALS)-associated pathology. In vivo, ZNF512B overexpression reduces DNA damage and inflammation following acute liver injury. Together, these findings support a mechanism of preferential DNA repair that contributes to maintaining genome integrity, suppressing SASP and inflammation.}, } @article {pmid42303396, year = {2026}, author = {Akers, E and Ameratunga, S and Wilkinson-Meyers, L and Adams, M and Te Ao, B}, title = {Perspectives on the injured child's hospital discharge process and opportunities for improvement: a scoping review protocol.}, journal = {BMJ open}, volume = {16}, number = {6}, pages = {e119916}, pmid = {42303396}, issn = {2044-6055}, mesh = {Humans ; Scoping Reviews as Topic ; *Patient Discharge/standards ; Child ; *Wounds and Injuries/therapy ; Caregivers/psychology ; Research Design ; }, abstract = {INTRODUCTION: Unintentional injury is a leading cause of hospitalisation and disability in children globally. Families may experience a second crisis of injury after the child's discharge from the hospital, with the traumatic nature of injuries affecting physical and psychosocial recovery. This scoping review aims to summarise the literature on the perspectives of injured children's caregivers and service providers on the hospital discharge process, the challenges and opportunities to improve discharge planning evident from qualitative and interventional studies, and the investigation of inequities in these studies using the Conceptual Framework of Access to healthcare proposed by Levesque et al in 2013.

METHODS AND ANALYSIS: A scoping review will be conducted involving a search across four databases: CINAHL Plus, Cochrane Library, Embase and Ovid MEDLINE. Empirical literature published in English between 2000 and 2025 will be eligible for inclusion. Included studies will report caregiver or service provider perspectives on current hospital discharge practice for injured children under 18 years old, investigated a priori as a study objective or a posteriori as a finding, or will report the design, implementation or evaluation of interventions intended to improve hospital discharge for injured children. Levesque et al's framework will be used to guide data extraction from the selected studies into predefined data charting forms, informing the review questions. Findings will be presented narratively and in tables to highlight the key characteristics of the studies, the perspectives of caregivers and service providers, the challenges and opportunities to improve hospital discharge, the proposed discharge interventions, the investigation of inequities and the gaps in the literature.

ETHICS AND DISSEMINATION: The scoping review only uses data in the public domain and does not require ethics approval.}, } @article {pmid42304808, year = {2026}, author = {Smith, SE and Hughes, B and Miller, TM and Bucelli, RC}, title = {Amyotrophic Lateral Sclerosis Recovery: A New Model System of Care Integrating Neuromuscular Rehabilitation With Clinical Stabilization in ALS.}, journal = {Muscle & nerve}, volume = {74}, number = {2}, pages = {321-327}, doi = {10.1002/mus.70320}, pmid = {42304808}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology/drug therapy ; Humans ; *Recovery of Function/physiology ; Male ; Female ; }, abstract = {There is currently no consensus on how to define recovery for individuals with amyotrophic lateral sclerosis (ALS). Tofersen treatment for superoxide dismutase-1-related (SOD1) ALS marks a pivot in clinical management: for the first time, clinicians can target disease stabilization and functional recovery in some individuals. This advancement shifts the focus of ALS care toward optimizing functional recovery alongside symptomatic management. However, there are no evidence-based guidelines for prescribing neuromuscular rehabilitation (NMR) to improve functional recovery. Building on our preliminary single-center data of integrated NMR with tofersen, we propose a new ALS Recovery Model System of Care, utilizing a hub-and-spoke infrastructure to combine NMR with novel therapies. This model aims to define ALS recovery, characterize recovery profiles, standardize NMR protocols, and establish a rehabilitation framework adaptable to future disease-stabilizing therapies.}, } @article {pmid42304913, year = {2026}, author = {Wang, T and Wu, M and Liang, L and Pei, L and Wang, D}, title = {Nicotine Versus Non-Nicotine Constituents in Neurodegenerative Risk: Evidence from Multivariable Mendelian Randomization.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X503957260608154111}, pmid = {42304913}, issn = {1875-6190}, abstract = {BACKGROUND: Nicotine has complex neuropharmacological actions through nicotinic acetylcholine receptors, but its independent role in neurodegenerative diseases remains unclear because tobacco smoke contains many non-nicotine toxicants. This uncertainty limits the interpretation of nicotine- and nAChR-targeted therapeutic strategies, especially as electronic nicotine delivery sys-tems become more common. We used Mendelian randomization to genetically separate nicotine-related effects from smoking-related non-nicotine effects on major neurodegenerative diseases and related prodromal conditions.

METHODS: We performed univariable two-sample Mendelian randomization (MR) and multivariable MR (MVMR) analyses. Summary-level exposure data for cigarettes per day (CPD) and the nicotine metabolite ratio (NMR) were analyzed against individual-level, smoking-stratified outcome data derived from 337,334 UK Biobank participants, to evaluate their respective causal effects across six neurodegenerative outcomes: Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), tremor, early cognitive impairment (EC), and other neurodegenerative diseases (OND).

FINDINGS: MVMR analyses revealed that nicotine exposure was a causal risk factor for AD (ever smokers: OR=0.90, 95% CI 0.83-0.98; current smokers: OR=0.76, 95% CI 0.64-0.91). Nicotine exerted a causal protective effect against tremor (OR=1.24, 95% CI 1.03-1.49) and EC (OR=1.14, 95% CI 1.04-1.24) in current smokers. Non-nicotine tobacco constituents were identified as risk factors among former smokers for EC (OR=1.61, 95% CI 1.04-2.50).

CONCLUSIONS: Exposure to nicotine can increase the risks of AD, while conferring protective effects against tremor and EC. Furthermore, exposure to non-nicotine tobacco constituents acts as a risk factor for the incidence of EC.}, } @article {pmid42304926, year = {2026}, author = {Mukherjee, S and Ray, SK and Mukherjee, S}, title = {Linking Neurodegeneration and Age-related Macular Degeneration: Unified Pathways and Intervention Strategies.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273450093260523224914}, pmid = {42304926}, issn = {1996-3181}, abstract = {Age-related macular degeneration (AMD) is caused by the degeneration of photoreceptors and retinal pigment epithelium (RPE) along with drusen deposition and is the leading cause of vision loss in older adults. Both these structures within the central nervous system (CNS) utilize common neuro-inflammatory mechanisms because the retina is an outgrowth of the brain. Like the brain, the eye has its own physical characteristics and surface molecules as well as a tendency towards specific immune reactions. Numerous distinct neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Frontotemporal dementia (FTD) that impact the brain present as eye symptoms, and the conventional diagnosis of these neurodegenerative disorders (NDs) is often preceded by ocular symptoms. Furthermore, several eye-specific disorders have characteristics in common with other CNS disorders. NDs and AMD share common key features, such as tau and amyloid-β deposits, oxidative stress response, chronic inflammation, and dysregulation of microglia and müller glia. Common pathological mechanisms include complement activation, amyloid aggregation, neuroinflammation, vascular impairment, and cell death, providing a basis for a convergent neuroimmune axis between retinal and cerebral degeneration. Comparing these age-related diseases will facilitate the identification of shared risk factors, convergent molecular pathways, and potential cross-applicable therapeutic strategies, such as anti-inflammatory, anti-complementary, anti-apoptotic, and anti-VEGF-based approaches. This knowledge may enhance understanding of neurodegenerative diseases, help identify early biomarker development for diagnosis, and enable the design of targeted therapeutic strategies.}, } @article {pmid42305210, year = {2026}, author = {Sabnis, RW and Sabnis, AR}, title = {Novel Compounds as TREM2 Modulators for Treating Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, and Nasu-Hakola Disease.}, journal = {ACS medicinal chemistry letters}, volume = {17}, number = {6}, pages = {1236-1237}, pmid = {42305210}, issn = {1948-5875}, abstract = {Provided herein are novel compounds as TREM2 modulators, pharmaceutical compositions, use of such compounds in treating Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Nasu-Hakola disease, and processes for preparing such compounds.}, } @article {pmid42307135, year = {2026}, author = {Frycz, S and Więcławski, W and Skotniczny, M and Binder, M}, title = {Brain activity in an end-stage ALS patient suggests the presence of an unresponsive wakefulness syndrome.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2026.2688249}, pmid = {42307135}, issn = {2167-9223}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor neurons. It is widely assumed that cortical structures beyond motor neurons are relatively preserved, and patients in the end-stage ALS are regarded as being in complete locked-in syndrome (cLIS). However, emerging evidence suggests substantial heterogeneity in cognitive functioning among ALS patients, indicating possible extra-motor cortical involvement and impaired levels of consciousness. We report a case study assessing electrophysiological markers and auditory system integrity to evaluate the presence of covert consciousness in end-stage ALS.

METHODS: The patient was a 42-year-old woman with bulbar-onset, end-stage ALS, a six-year disease duration, and no means of communication. She underwent several EEG-based protocols, including resting-state EEG (RS-EEG), a passive auditory oddball paradigm, and 40 Hz auditory steady-state responses (ASSR). Audiological evaluation comprised transient-evoked and distortion-product otoacoustic emissions, as well as auditory brainstem responses (ABR).

RESULTS: RS-EEG was dominated by prefrontal 1-3 Hz activity resembling frontal intermittent rhythmic delta activity. Power spectra were poorly differentiated and consistent with a 1/f profile. No event-related potentials were observed in the oddball paradigm, and no ASSR responses were detected. Audiological testing revealed absent otoacoustic emissions and ABR indicating severe to profound hearing loss.

CONCLUSIONS: Our findings indicate severe cortical dysfunction and provide no electrophysiological evidence of covert consciousness. The electrophysiological profile closely resembles that observed in unresponsive wakefulness syndrome. This case supports the hypothesis that advanced ALS following cLIS onset may be more appropriately conceptualized as a disorder of consciousness rather than persistent cLIS.}, } @article {pmid42309005, year = {2026}, author = {Rugarli, EI and Langer, T}, title = {Limiting neurodegeneration in ALS: A phosphatase paves the way.}, journal = {Neuron}, volume = {114}, number = {12}, pages = {2073-2075}, doi = {10.1016/j.neuron.2026.04.030}, pmid = {42309005}, issn = {1097-4199}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/enzymology/metabolism ; Animals ; Motor Neurons/metabolism ; *Nerve Degeneration ; Mitochondria/metabolism ; *Phosphoric Monoester Hydrolases/metabolism ; }, abstract = {Zheng et al. identify phosphatase PGAM5 as a novel promising target for the treatment of different amyotrophic lateral sclerosis subtypes. PGAM5 dephosphorylates and activates the stress-regulated mitochondrial peptidase OMA1, which elicits a maladaptive mitochondrial integrated stress response in motor neurons.}, } @article {pmid42309130, year = {2026}, author = {Patel, R and Bryson, B and Carlson, T and Demosthenous, A and Jiang, D}, title = {Stability and neurophysiological validity of graph connectivity features for non-stationary motor imagery BCIs.}, journal = {Journal of neural engineering}, volume = {23}, number = {3}, pages = {}, doi = {10.1088/1741-2552/ae7ead}, pmid = {42309130}, issn = {1741-2552}, mesh = {Humans ; *Electroencephalography/methods/standards ; *Brain-Computer Interfaces ; Reproducibility of Results ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Imagination/physiology ; }, abstract = {Objective.Motor imagery (MI) Electroencephalography (EEG) brain-computer interfaces (BCIs) degrade under longitudinal non-stationarity, especially in amyotrophic lateral sclerosis (ALS). Functional connectivity (FC) has been proposed as an alternative feature space, but it remains unclear which FC estimators yield stable, class-informative features across sessions.Approach.Using a multi-session ALS EEG dataset, we computed a broad family of FC estimators per trial to form weighted graphs. We extracted edge weights and node strength features, and quantified (i) feature reproducibility and (ii) left hand-right hand separability using coefficient of variation and symmetric Kullback-Leibler divergence, respectively. We assessed neurophysiological plausibility via spatial topographies, distance-dependence controls, and evaluated selected feature sets in a strictly temporal cross-session decoding protocol against common spatial patterns, band power and Riemannian methods.Main results.Coherence (Coh)-based estimators, particularly magnitude-squared Coh, most consistently produced features exhibiting favourable reproducibility-separability trade-offs across subjects. Node-strength discriminability maps showed lateralised sensorimotor structure consistent with known MI physiology. In temporal generalisation, magnitude squared Coh derived features achieved more consistent test performance than baseline methods for most subjects.Significance.Joint reproducibility-separability profiling provides a principled way to select FC feature spaces for longitudinal MI-BCIs and suggests Coh-based connectivity is a stronger sensor-space candidate under drift.}, } @article {pmid42309840, year = {2026}, author = {Oliveira Santos, M and de Carvalho, M}, title = {Enhanced spinal motoneuron excitability as a marker of motor neuron dysfunction in primary lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {190}, number = {}, pages = {2111978}, doi = {10.1016/j.clinph.2026.2111978}, pmid = {42309840}, issn = {1872-8952}, mesh = {Humans ; Female ; *Motor Neurons/physiology ; Male ; Middle Aged ; Aged ; *Motor Neuron Disease/physiopathology/diagnosis ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Muscle, Skeletal/physiopathology ; Adult ; Electromyography/methods ; Prospective Studies ; *Spinal Cord/physiopathology ; }, abstract = {OBJECTIVE: To investigate F-wave parameters as markers of spinal motoneuron excitability in patients with primary lateral sclerosis (PLS).

METHODS: We prospectively evaluated F-waves and M-waves from the abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) muscles. The study included three groups: 27 patients with PLS, 36 with amyotrophic lateral sclerosis with normal right-hand function (ALS-NH), and 30 healthy controls (HC). Recorded parameters included M-wave amplitude, F-wave frequency, latencies, amplitude, and the F/M-waves amplitude ratio. Upper motor neuron (UMN) clinical scores were also assessed. Statistical analysis was performed using One-way ANOVA or Kruskal-Wallis tests for group comparisons, and Spearman's rank test for correlations.

RESULTS: PLS had a significantly higher UMN score than ALS-NH (p < 0.001). F-wave amplitudes were significantly higher in PLS compared to both ALS-NM and HC across all muscles (APB, p = 0.01 and p = 0.03; FDI, p = 0.002 and p < 0.001; ADM, p = 0.03 and p < 0.001, respectively). F/M-waves amplitude ratio was also significantly higher in PLS vs. ALS-NH/HC (APB, p = 0.01 and p = 0.03; FDI, p < 0.001 and p < 0.001; ADM, p = 0.03 and p = 0.001, respectively). No significant differences were found between ALS-NM and HC for these parameters (p > 0.05). M-wave amplitudes and other F-wave parameters remained comparable across all groups (p > 0.05). No correlation was found between F-wave amplitude and UMN scores in PLS patients (p > 0.05).

CONCLUSIONS: Patients with PLS exhibit significantly increased F-wave amplitudes and F/M amplitudes ratios compared to ALS-NH and HC.

SIGNIFICANCE: Increased F-waves size serves as a neurophysiological marker of enhanced spinal motoneuron excitability in PLS.}, } @article {pmid42310079, year = {2026}, author = {Nouraei, H and Amirzadeh, N and Shabanzadeh, S and Zareshahrabadi, Z and Shamsdin, N and Nouraei, M and Naeimi, B and Pakshir, K}, title = {Effect of subsequent passages on biofilm formation intensity, ALS genes expression, and cell surface hydrophobicity variability in clinical Candida albicans isolates.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42310079}, issn = {2045-2322}, support = {32536//Vice-Chancellor for Research, Shiraz University of Medical Sciences/ ; }, mesh = {*Candida albicans/genetics/isolation & purification/physiology ; *Biofilms/growth & development ; Hydrophobic and Hydrophilic Interactions ; *Fungal Proteins/genetics/metabolism ; *Gene Expression Regulation, Fungal ; Humans ; Cell Adhesion ; Candidiasis/microbiology ; }, abstract = {Candida albicans is an opportunistic yeast pathogen that have several virulence factors included biofilm formation, cell surface hydrophobicity (CSH), and the expression of adhesion genes. Concerns exist that serial laboratory subculturing may diminish these traits, leading to inaccurate research findings. Aim of this study was evaluated the effect of subsequently subcultures on biofilm formation intensity, ALS gene expression, and surface hydrophobicity properties in clinical C. albicans isolates. Ten clinical C. albicans isolates were serially subcultured up to 20 passages (P). We used qPCR to quantify ALS1 and ALS3 gene expression, the Crystal Violet assay to measure biofilm formation intensity (P1, P5, P10, P15, P20), and a water-octane partitioning assay for CSH variability at different passages. Serial subculturing caused gradual downregulation of gene expression for both ALS1 and ALS3 (p < 0.001). This condition was accompanied by a biofilm-forming capacity that became progressively reduced in 90% of isolates, whereas 60% at P20 were already biofilm-negative (vs. 10% at P1). Cell surface hydrophobicity also decreased progressively, with 100% of isolates displaying low CSH at P15, compared with 40% in the initial P1 state. Serial subculturing leads to a rapid reduction of C. albicans pathogenic fitness with decreased expression of certain key adhesion genes, diminished biofilm formation, and lower CSH. These results highlight the plasticity of the organism and thus strongly suggest that low-passage clinical isolates should be used in studies to reflect true pathogenicity in vivo accurately.}, } @article {pmid42310298, year = {2026}, author = {Diaz Escarcega, R and M J, VK and Arizmendez, A and Tan, C and Urayama, A and Marrelli, SP and Morales, R and Wefel, JS and Zhang, C and McCullough, LD and Kim, N and Monchaud, D and Jung, SY and Tsvetkov, AS}, title = {Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {}, pmid = {42310298}, issn = {2041-4889}, support = {R35 GM141867/GM/NIGMS NIH HHS/United States ; 4R01AG068292//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AFAR BIG21042//Glenn Family Foundation/ ; R01 AG068292/AG/NIA NIH HHS/United States ; AFAR BIG21042//American Federation for Aging Research (American Federation for Aging Research, Inc.)/ ; }, mesh = {*Neurons/metabolism/drug effects/pathology ; *DEAD-box RNA Helicases/metabolism/genetics ; Humans ; *G-Quadruplexes ; Animals ; Female ; Male ; DNA Damage ; }, abstract = {G-quadruplexes (G4s) are four-stranded nucleic acid structures that regulate virtually all nucleic acid-dependent cellular processes. At present, most functional studies involving G4s have focused on cancer cells. This study investigated how neurons respond to genotoxic stress induced by quarfloxin (CX-3543), a small molecule that stabilizes G4s. We found that quarfloxin treatment induced DNA damage in neurons, with double-strand breaks enriched in the nucleolus. Proteomic analysis revealed that quarfloxin promoted substantial protein changes, affecting networks associated with Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Among the affected proteins, the G4 helicase DDX3X, encoded on the X chromosome, was upregulated, prompting further investigation of DDX3X and its Y-linked homolog DDX3Y in female and male neurons, respectively. RNA sequencing identified DDX3X- and DDX3Y-regulated gene networks involved in DNA damage responses, inflammation, cell cycle regulation, and stress-associated pathways, with notable sex-dependent differences. In human brain tissue, DDX3X expression and nuclear enrichment were increased in neurons from older females compared to younger individuals, with further elevation observed in Alzheimer's disease. Taken together, these findings identify DDX3X and DDX3Y as modulators of neuronal stress responses downstream of G4 stabilization and indicate that their induction is accompanied by activation of DNA damage response genes, as well as cell cycle- and inflammation-associated pathways, suggesting that sustained activation of these pathways may disrupt neuronal homeostasis. Our study provides insight into G4-dependent stress mechanisms in neurons and highlights sex-linked pathways that may contribute to brain aging and neurodegenerative disease vulnerability.}, } @article {pmid42310450, year = {2026}, author = {Deo, DR and Okorokova, EV and Pritchard, AL and Hahn, NV and Card, NS and Nason-Tomaszewski, SR and Jude, J and Hosman, T and Choi, EY and Qiu, D and Meng, Y and Wairagkar, M and Nicolas, C and Kamdar, FB and Iacobacci, C and Acosta, A and Hochberg, LR and Cash, SS and Williams, ZM and Rubin, DB and Brandman, DM and Stavisky, SD and AuYong, N and Pandarinath, C and Downey, JE and Bensmaia, SJ and Henderson, JM and Willett, FR}, title = {A mosaic of whole-body representations on the human precentral gyrus.}, journal = {Nature}, volume = {656}, number = {8128}, pages = {680-687}, pmid = {42310450}, issn = {1476-4687}, mesh = {Humans ; *Motor Cortex/physiology/cytology/anatomy & histology ; Movement/physiology ; *Brain Mapping ; Brain-Computer Interfaces ; Male ; Female ; Speech/physiology ; Extremities/physiology ; Spinal Cord Injuries/physiopathology ; Microelectrodes ; Amyotrophic Lateral Sclerosis/physiopathology ; Adult ; Paralysis/physiopathology ; }, abstract = {Understanding how the body is represented in the motor cortex is key to understanding how the brain controls movement. Although the motor cortex has been mapped in animal models at a fine scale[1-10], characterization in humans remains primarily limited to low-resolution recording[11-16] and stimulation techniques[17-20]. Here we created a comprehensive map of the human motor cortex at single-neuron resolution, spanning microelectrode array recordings from 20 arrays across 8 individuals with paralysis from spinal cord injury, amyotrophic lateral sclerosis or brainstem stroke, all enrolled in brain-computer interface clinical trials. These arrays broadly sample the crown of the precentral gyrus (PCG; thought to be composed largely of the premotor cortex (Brodmann area 6)). We found that body parts were highly intermixed, such that the entire body was represented in all sampled locations of the PCG, although the relative strength of body parts was roughly consistent with the motor homunculus[17,18]. We also found two speech-preferential areas with a broadly tuned, orofacial-dominant area in between them. Throughout the PCG, movement representations of the four limbs were interlinked, with homologous movements of different limbs (for example, toe curl and hand close) having correlated representations. These data provide evidence consistent with an intermixed, interrelated and behaviour-centred organization of the motor cortex[3,21]. The resulting map also provides important targeting information for brain-computer interfaces that seek to restore motor function.}, } @article {pmid42310788, year = {2026}, author = {Wood, C and Brown, G and Chalk, K and Smith, SH and Williams, H and Broadhurst, G and Ealing, J and Hamdalla, H and Breen, C and Macleod, R and Chaouch, A}, title = {Co-development of a genetic care pathway for ALS: real-world perspectives from the North of England.}, journal = {Orphanet journal of rare diseases}, volume = {21}, number = {1}, pages = {}, pmid = {42310788}, issn = {1750-1172}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Genetic Testing/methods ; England ; Retrospective Studies ; Male ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disorder, with a substantial proportion of cases attributed to genetic factors. Recent advances in gene discovery and genomic technologies have transformed ALS care by enabling genomic testing to inform prognosis, assess familial risk, and facilitate access to novel therapies. However, guidance on the delivery of genetic testing and counselling in ALS remains limited, leading to variability in clinical practice. In response, the Manchester Motor Neuron Disease (MND) Care Centre and the Manchester Centre for Genomic Medicine co-developed a structured genetic care pathway for ALS, drawing on real-world data, patient engagement, and multidisciplinary collaboration.

RESULTS: A retrospective evaluation of 326 ALS patients at the Manchester MND Care Centre identified significant variability in genetic testing uptake, counselling practices, and record-keeping. Patient survey and engagement sessions revealed uncertainty regarding key genetic concepts and inconsistent recall of pre- and post-test discussions. Priorities for improvement included clearer communication, standardised discussions, and enhanced support for families following genetic findings. Consequently, the Greater Manchester ALS Genetic Testing Pathway was developed by a multidisciplinary team, incorporating consensus-based steps for patient identification, pre-test conversations, consent, testing, results disclosure, and post-test support. This pathway integrates genetic testing into routine ALS care, clarifies team responsibilities, and establishes a framework for ongoing evaluation using key performance indicators. Patient and staff feedback is used to support continuous improvement.

CONCLUSIONS: The co-developed ALS genetic testing pathway provides a scalable model for standardising genomic care in mainstream clinical settings. By establishing clear processes for genetics discussions, consent, and follow-up, the pathway seeks to improve equity, transparency, and person-centred care. Ongoing evaluation and collaboration with patients, clinicians, and genetic services are essential to ensure the pathway remains responsive to scientific advances and evolving patient needs. Wider adoption of structured genetic pathways may facilitate the integration of genomics into care for rare diseases across healthcare systems.}, } @article {pmid42311066, year = {2026}, author = {Dubbioso, R and Pappatà, S}, title = {Amyotrophic lateral sclerosis as a network disease: from metabolic decline to network failure.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {7}, pages = {2189-2190}, doi = {10.1093/brain/awag211}, pmid = {42311066}, issn = {1460-2156}, } @article {pmid42311422, year = {2026}, author = {Fayez, SM}, title = {Nanomedicine in 2026: Illustrative Quantitative Analyses of EPR Heterogeneity, Clinical Trial Attrition, and Emerging Horizons for Active Nanotherapeutics.}, journal = {International journal of nanomedicine}, volume = {21}, number = {}, pages = {618407}, pmid = {42311422}, issn = {1178-2013}, mesh = {Humans ; *Nanomedicine/trends/methods ; Animals ; Clinical Trials as Topic ; Nanoparticles/chemistry/therapeutic use ; Neoplasms ; Mice ; Immunotherapy ; }, abstract = {2026 is a turning point for nanomedicine, marking the field's transition from decades of preclinical promise toward tangible clinical impact. This narrative review provides a forward-oriented synthesis of the most significant clinical breakthroughs achieved during 2025-2026, critically examines persistent barriers to clinical translation, and projects future horizons for the coming decade. To support the discussion, the review includes illustrative quantitative analyses drawn from selected published data: a comparison of EPR effect heterogeneity across human and murine tumors (23 studies, 412 patients), a funnel of nanomedicine clinical trials extracted from ClinicalTrials.gov (847 trials, 2010-2020), a comparative overview of regulatory guidance from four major agencies, and a simplified life-cycle assessment of three nanomedicine classes. These analyses are intended to highlight trends, not to replace a formal systematic review. We identify four important clinical advances: first Phase II data for hafnium oxide nanoparticle radioenhancers in inoperable lung cancer; logic-gated STING-agonistic nanoparticles for metastasis-specific immunotherapy; ultrasmall silica nanoparticles that remodel suppressive tumor microenvironments independent of a drug cargo; and CNM-Au8 gold nanocrystals advancing toward regulatory submission for amyotrophic lateral sclerosis. Collectively, these developments illustrate a major change in thinking: nanoparticle formulations no longer serve merely as delivery vehicles but increasingly function as active therapeutic agents that engage biological pathways, respond to disease-associated stimuli, and generate therapeutic effects independently of any drug cargo. This shift from passive delivery to active nanotherapeutics fundamentally changes how the field should evaluate and develop nanomedicines. Nevertheless, the number of nanomedicines that have achieved global clinical approval remains very low, estimated at only 50-80 products by 2025, underscoring a persistent translational gap. We analyze principal obstacles to clinical success, including the limited predictive validity of the enhanced permeability and retention (EPR) effect in humans, batch-to-batch manufacturing variability, safety concerns arising from bio-corona formation and organ accumulation, and the absence of harmonized regulatory frameworks. Looking forward, we identify emerging horizons: AI-driven digital twins for predictive manufacturing, carrier-free self-assembled nanomedicines from natural small molecules, nanotheranostic platforms that integrate therapy with real-time imaging, and sustainable nanomedicine designs incorporating environmental impact assessments. By bridging clinical reality with future potential, this review aims to inform researchers, clinicians, and regulatory stakeholders navigating the rapidly evolving landscape of nanomedicine.}, } @article {pmid42311464, year = {2026}, author = {Li, P and Gao, Y and Liu, W}, title = {GLP-1 Receptor Agonists in Neurological Disorders: From Mechanisms to Clinical Translation.}, journal = {Drug design, development and therapy}, volume = {20}, number = {}, pages = {613616}, pmid = {42311464}, issn = {1177-8881}, mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Glucagon-Like Peptide-1 Receptor/metabolism ; }, abstract = {Glucagon-like peptide-1 receptor agonists, or GLP-1RAs, have been used for years to treat type 2 diabetes and obesity. More recently, it has become clear that these receptors are widely distributed throughout the central nervous system (CNS), which has raised the possibility of repurposing these drugs for neurological disorders. In this review we go through the evidence across a range of neurological conditions, discuss the main mechanisms thought to explain their neuroprotective effects, and point out the hurdles that still need to be cleared before they can be used in the clinic. Preclinical work has been fairly consistent. These drugs activate the cAMP/PKA/CREB pathway to boost BDNF expression. They also turn on the PI3K/Akt pathway, which reins in GSK-3β and cuts down tau hyperphosphorylation. At the same time, they put the brakes on NLRP3 inflammasome activation in microglia and get AMPK dependent mitochondrial biogenesis and autophagy going. In animal models of Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, intracerebral hemorrhage (ICH), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), depression, epilepsy, and spinal cord injury (SCI), these cellular changes add up to less protein aggregation, less neuron loss, and better functional outcomes. Clinical data are harder to interpret. Some trials have shown modest improvements in cognition or motor function, but others have found no meaningful effect on disease progression. One thing that does not get enough attention is that different GLP-1 receptor agonists cross the blood-brain barrier at widely varying rates, and these differences could well explain why trial results have been so mixed. Looking ahead, getting these drugs into the clinic will depend on choosing the ones that actually reach the CNS, developing biomarkers that can predict who will respond, and designing trials that take disease heterogeneity into account. Seen this way, this review offers a practical framework for turning mechanistic insights into real patient benefit.}, } @article {pmid42312499, year = {2026}, author = {Lavigne-Robichaud, M and Landsbergis, P and Brisson, C and Sembajwe, G and Gilbert-Ouimet, M and Li, J and Milot, A and Trudel, X}, title = {Job strain and ischemic heart disease: the balance of methodological bias and implications for prevention. Response to: Bonde JP et al. The demands-control-support work stress model and risk of ischemic heart disease: causal inference based on observational epidemiology.}, journal = {Scandinavian journal of work, environment & health}, volume = {52}, number = {5}, pages = {625-626}, pmid = {42312499}, issn = {1795-990X}, mesh = {Female ; Humans ; Bias ; *Myocardial Ischemia/epidemiology/prevention & control/etiology ; *Occupational Diseases/epidemiology/prevention & control ; Occupational Exposure ; *Occupational Stress/complications/epidemiology ; Risk Factors ; *Stress, Psychological ; }, abstract = {We read with interest Bonde et al's (1) recent review. We agree with their premise: strengthening causal inference is an important objective for occupational epidemiology. However, we believe the conclusion that "at most, any true effect [of job strain on ischemic heart disease (IHD)] appears to be small" is not supported by a valid appraisal of the available evidence. The pooled relative risk estimate (RRE) of 1.14 is most likely underestimated, as common limitations in the available literature tend to bias results toward the null. The authors acknowledge underestimation sources: nondifferential exposure misclassification, overadjustment for cardiometabolic risk factors, and healthy-worker survivor selection (1). Additional sources of underestimation are not discussed. Dichotomizing exposure by combining active and passive exposures into a single "non-high-strain" category may attenuate risk estimates by increasing heterogeneity in the reference group. Indeed, workers with passive exposure may also be at increased IHD risk (2). The pooled RRE may further be attenuated by sex: women develop IHD at older ages partly due to pre-menopausal estrogen cardioprotection, thus working-age follow-up captures fewer events, reducing pooled estimates and precision (3). Sources of overestimation raised also warrant closer scrutiny. For instance, lower estimates in job-exposure matrix (JEM) studies are interpreted as evidence of upward bias in self-reported studies. However, even when exposure values are imputed within subgroups defined by sex and age, JEM do not fully capture individual-level variability in exposure within occupational categories (4). The resulting non-differential misclassification likely attenuates estimates, a limitation the authors acknowledge but do not take into account in their conclusion. The supporting reference for overestimation relies on a 4-item measure of perceived stress (5), limiting its relevance to job strain. An additional source of overestimation is negative affectivity, in which adverse health perceptions inflate individual-level exposure reports. However, this mechanism is not supported in prospective studies with control for anger, hostility, and cynicism (6, 7). Finally, the authors raise concerns about a health-reporting bias: workers with prodromal IHD symptoms may over-report perceived job strain, inflating observed associations. In prospective studies excluding early incident IHD events, associations were not attenuated and, if anything, marginally strengthened (6, 8), providing no support for reverse causation as a source of overestimation. More broadly, methodological characteristics are presented as isolated binary indicators rather than as interdependent dimensions. This hinders the overall appraisal of study quality. These methodological considerations have implications for burden estimation. There has been considerable debate about whether the population attributable fraction (PAF) of 3.4% that the IPD-Work Consortium reported for job strain and IHD (8) was an underestimate when accounting for exposure misclassification, alternative referent group definitions, and other sources of attenuation identified in the literature (9, 10). A subsequent prospective cohort study designed to address several of the sources of underestimation discussed here estimated that 18.2% of incident IHD were attributable to job strain exposure (11). In sum, while we share Bonde et al's emphasis on causal inference, the balance of methodological bias in this literature is more plausibly downward than unpredictable. Given the substantial burden of IHD, debates about the precise magnitude should not delay the development and evaluation of workplace interventions to reduce job strain and improve cardiovascular health. References 1. Bonde JP, Skaaby S, Flachs EM, Dollard M, Keyes K, Rosengren A et al. The demands-control-support work stress model and risk of ischemic heart disease: causal inference based on observational epidemiology. Scand J Work Environ Health 2026 Apr. [Epub ahead of print]. https://doi.org/10.5271/sjweh.4299. 2. Xu S, Huang Y, Xiao J, Zhu W, Wang L, Tang H et al. The association between job strain and coronary heart disease: a meta-analysis of prospective cohort studies. Ann Med 2015;47(6):512-8. https://doi.org/10.3109/07853890.2015.1075658. 3. Zahiriharsini A, Gilbert-Ouimet M, Hervieux V, Trudel X, Matteau L, Jalbert L et al. Incorporating sex and gender considerations in research on psychosocial work exposures and cardiovascular diseases: A systematic review of 55 prospective studies. Neurosci Biobehav Rev 2024 Dec;167:105916. https://doi.org/10.1016/j.neubiorev.2024.105916. 4. Schwartz JE, Pieper CF, Karasek RA. A procedure for linking psychosocial job characteristics data to health surveys. Am J Public Health 1988 Aug;78(8):904-9. https://doi.org/10.2105/AJPH.78.8.904. 5. Metcalfe C, Davey Smith G, Macleod J, Heslop P, Hart C. Self-reported stress and subsequent hospital admissions as a result of hypertension, varicose veins and haemorrhoids. J Public Health Med 2003 Mar;25(1):62-8. https://doi.org/10.1093/pubmed/fdg013. 6. Lavigne-Robichaud M, Trudel X, Talbot D, Milot A, Gilbert-Ouimet M, Vézina M et al. Psychosocial stressors at work and coronary heart disease risk in men and women: 18-year prospective cohort study of combined exposures. Circ Cardiovasc Qual Outcomes 2023 Oct;16(10):e009700. https://doi.org/10.1161/CIRCOUTCOMES.122.009700. 7. Tiwa Diffo E, Lavigne-Robichaud M, Milot A, Brisson C, Gilbert-Ouimet M, Vézina M et al. Psychosocial stressors at work and atrial fibrillation incidence: An 18-year prospective study. J Am Heart Assoc 2024 Aug;13(16):e032414. https://doi.org/10.1161/JAHA.123.032414. 8. Kivimäki M, Nyberg ST, Batty GD, Fransson EI, Heikkilä K, Alfredsson L et al.; IPD-Work Consortium. Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data. Lancet 2012 Oct;380(9852):1491-7. https://doi.org/10.1016/S0140-6736(12)60994-5. 9. Choi BK, Schnall P, Landsbergis P, Dobson M, Ko S, Gómez-Ortiz V et al. Recommendations for individual participant data meta-analyses on work stressors and health outcomes: comments on IPD-Work Consortium papers. Scand J Work Environ Health 2015 May;41(3):299-311. https://doi.org/10.5271/sjweh.3484. 10. Kivimäki M, Singh-Manoux A, Virtanen M, Ferrie JE, Batty GD, Rugulies R; IPD-Work consortium. IPD-Work consortium: pre-defined meta-analyses of individual-participant data strengthen evidence base for a link between psychosocial factors and health. Scand J Work Environ Health 2015 May;41(3):312-21. https://doi.org/10.5271/sjweh.3485. 11. Lavigne-Robichaud M, Trudel X, Talbot D, Milot A, Pena-Gralle AP, Mésidor M et al. Coronary heart disease attributable to psychosocial stressors at work. JACC Adv 2025 Oct;4(10 Pt 2):102160. https://doi.org/10.1016/j.jacadv.2025.102160.}, } @article {pmid42312942, year = {2026}, author = {Zinn, KM and McLaren, MW and Imai, MT and Jayaram, MM and Rothstein, JD and Elrick, MJ}, title = {Enterovirus D68 2A protease causes nuclear pore complex dysfunction and independently contributes to motor neuron toxicity.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {42312942}, issn = {2050-084X}, support = {5K12NS098482/NS/NINDS NIH HHS/United States ; K08NS124989/NS/NINDS NIH HHS/United States ; R01NS143998/NS/NINDS NIH HHS/United States ; P50HD103538//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, mesh = {*Motor Neurons/virology/pathology ; Humans ; *Enterovirus D, Human/enzymology ; *Nuclear Pore/metabolism ; *Viral Proteins/metabolism ; Nuclear Pore Complex Proteins/metabolism ; *Cysteine Endopeptidases/metabolism ; Myelitis/virology/pathology ; Neuromuscular Diseases ; Central Nervous System Viral Diseases ; }, abstract = {Enterovirus D68 (EV-D68) is an important pathogen associated with acute flaccid myelitis (AFM). The pathogenesis of AFM involves infection of spinal motor neurons and motor neuron death; however, the mechanisms linking EV-D68 infection to selective neurotoxicity are not well understood. Dysfunction of the nuclear pore complex (NPC) has been implicated in motor neuron injury in neurodegenerative diseases such as amyotrophic lateral sclerosis, and the NPC is also modified by picornavirus proteases during infection. We therefore sought to determine the impact of EV-D68 proteases on NPC composition and function. We demonstrate widespread disruption of NPC composition by EV-D68 2A and 3C proteases via direct cleavage of a relatively small number of nucleoporins, notably Nup98 and POM121, by 2A[pro]. Using reporter systems, we demonstrate that 2A[pro] inhibits nuclear transport of protein cargoes and disrupts the permeability barrier of the NPC, while having no apparent effect on RNA export. Independently, we show 2A[pro] is toxic to induced pluripotent stem cell-derived motor neurons by demonstrating a rescue of toxicity with the 2A[pro] inhibitor telaprevir at concentrations insufficient to inhibit viral replication. These findings expand our understanding of EV-D68 neuropathogenesis and provide a rationale for studying the NPC or 2A[pro] as therapeutic targets in AFM.}, } @article {pmid42313222, year = {2026}, author = {Deng, P and Deng, W and Wang, L and Ye, W and Li, S}, title = {Exercise-Driven NRF2 Activation as a Systemic Neuroprotective Strategy: Integrating Redox Biology, Muscle-Brain Crosstalk, and Therapeutic Targeting in Neurodegeneration.}, journal = {Biochemical genetics}, volume = {}, number = {}, pages = {}, pmid = {42313222}, issn = {1573-4927}, abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, are characterized by progressive neuronal dysfunction and loss. Recent evidence highlights the importance of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, a key regulator of cellular defense mechanisms, in maintaining neuronal health and function. A narrative literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar to identify relevant experimental, clinical, and review studies on NRF2 signaling, physical exercise, oxidative stress, muscle-brain crosstalk, and neurodegenerative diseases. Keywords included "NRF2", "Nrf2/Keap1/ARE", "physical exercise", "exercise-induced oxidative stress", "myokines", "exerkines", "Alzheimer's disease", "Parkinson's disease", "Huntington's disease", and "amyotrophic lateral sclerosis". NRF2 modulates the expression of a variety of antioxidant and cytoprotective genes, contributing to the protection of neurons against oxidative stress, inflammation, and protein aggregation, processes central to the pathogenesis of neurodegenerative diseases. Additionally, physical activity has been identified as a powerful modulator of NRF2 activation, with exercise offering neuroprotective effects through the induction of NRF2-mediated pathways. This review explores the interplay between NRF2 activation and physical exercise in the context of neurodegenerative diseases, detailing the molecular mechanisms by which exercise influences NRF2 activity to combat cellular damage and enhance neuroprotection. We discuss the therapeutic potential of combining exercise regimens with NRF2-targeted therapies, highlighting the promise of this dual approach in slowing disease progression, improving cognitive function, and enhancing quality of life in affected individuals. Furthermore, we examine the challenges and future directions for clinical implementation, including optimal exercise protocols and the development of NRF2-based pharmacological interventions. This review underscores the importance of NRF2 as a central mediator of neuroprotection and the therapeutic promise of physical activity in the management of neurodegenerative diseases.}, } @article {pmid42313307, year = {2026}, author = {Saini, K and Dhiman, P}, title = {Microglia-driven neuroinflammatory signaling in neurodegeneration: mechanisms and therapeutic opportunities.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42313307}, issn = {1573-4978}, mesh = {Humans ; *Microglia/metabolism/pathology/immunology ; *Neurodegenerative Diseases/metabolism/therapy/pathology/immunology ; Animals ; Signal Transduction ; *Neuroinflammatory Diseases/metabolism/pathology/immunology ; Blood-Brain Barrier/metabolism ; Cytokines/metabolism ; Astrocytes/metabolism ; }, abstract = {Neuroinflammation has been identified as a major component to the pathogenesis and progression of many neurodegenerative illnesses, going beyond its traditional role as a protective immune response within central nervous system (CNS). There is growing evidence that persistent activation of peripheral immune pathways, microglia and astrocytes causes progressive neurodegeneration, synaptic loss and progressive neurodegeneration. This review examines the mechanisms of microglia- driven neuroinflammatory signaling and its involvement in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Key neuroinflammatory mechanisms covered in depth including microglial activation, astrocyte reactivity, peripheral immune cell infiltration, cytokine dysregulation, and blood brain barrier (BBB) disruption. This review also emphasizes the role of neuroinflammation in acute neurological symptoms and mental and cognitive impairments. Glial activation markers, inflammatory cytokines, BBB proteins and kynurenine pathway metabolites are emerging as promising biomarkers for disease diagnosis and monitoring. Additionally, the potential of new mathematical and systems level computational models to describe intricate neuroimmune interactions and forecast the course of disease and treatment results is investigated. Current and emerging therapies targeting neuroinflammation include anti-inflammatory and immunomodulatory drugs, lifestyle interventions, stem cell approaches, gene-editing technologies and nanoparticle-based drug delivery systems. Despite significant progress, translating preclinical findings into effective clinical therapies remains challenging. Future developments in integrative neuroimmune modeling, biomarker-guided therapies and precision medicine may make it possible to create individualized treatments plans targeted at reducing neuroinflammation and enhancing the course of neurodegenerative illnesses.}, } @article {pmid42313873, year = {2026}, author = {Rohan, H and Bochner, AF and Brown, L and Ortiz, EM and McClelland, A}, title = {COVID-19 alert level systems-Lessons learnt for future public health emergencies: A qualitative study.}, journal = {PloS one}, volume = {21}, number = {6}, pages = {e0351209}, pmid = {42313873}, issn = {1932-6203}, mesh = {Humans ; *COVID-19/epidemiology/prevention & control ; *Public Health ; Pandemics/prevention & control ; Qualitative Research ; SARS-CoV-2/isolation & purification ; Emergencies ; Public Health Infrastructure ; }, abstract = {BACKGROUND: During the COVID-19 pandemic, Alert Level Systems (ALS) were widely implemented as public health tools to communicate risk levels and recommend public health and social measures (PHSMs). However, the efficacy of ALS in mitigating disease spread and their impact on public health responses have not been systematically evaluated. This study aims to assess perceptions of ALS implementation across diverse jurisdictions and derive lessons for future public health emergencies.

METHODS: Key informant interviews were conducted remotely between December 2023 and March 2024 with senior stakeholders who were involved in ALS development and implementation during the COVID-19 pandemic, from eight jurisdictions: California (US), New Zealand, the Philippines, Rio Grande do Sul (Brazil), Singapore, South Africa, the United Kingdom, and the United States. A thematic analysis approach was applied to synthesize insights, focusing on the strengths, challenges, and key lessons from ALS implementation.

RESULTS: ALS were generally perceived by key informants as useful tools for communicating risk and supporting adherence to PHSMs due to their simplicity and transparency. However, significant challenges were identified, including difficulties in accessing reliable data, lack of clear ALS objectives, and insufficient community engagement. The study highlights the need for ALS to integrate social, economic, and epidemiological data in decision-making processes. Jurisdictions also reported that pre-existing ALS governance structures and stronger community feedback mechanisms could have improved implementation outcomes.

CONCLUSIONS: ALS can serve as valuable public health communication tools in future epidemics, but their success depends on clear objectives, evidence-based PHSMs, and robust community engagement. Pre-emptive development of ALS structures and governance will improve preparedness for future epidemics. Transparent and flexible decision-making processes will be crucial for sustaining public trust.}, } @article {pmid42314654, year = {2026}, author = {Yang, R and Fang, Y}, title = {S-acylation of TDP-43: PALMing down aggregation?.}, journal = {Cell chemical biology}, volume = {33}, number = {6}, pages = {742-744}, doi = {10.1016/j.chembiol.2026.05.009}, pmid = {42314654}, issn = {2451-9448}, mesh = {Acylation ; Humans ; *DNA-Binding Proteins/metabolism/chemistry ; Poly Adenosine Diphosphate Ribose/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Protein Aggregates ; }, abstract = {S-acylation is well known for regulating protein stability and trafficking. In a recent issue of Molecular Cell, Xu et al.[1] reveal a distinct, aggregation-suppressing function of this posttranslational lipid modification: S-acylation of the RNA-binding protein TDP-43 antagonizes poly(ADP-ribose)-driven condensation. Moreover, reduced S-acylation levels are linked to ALS pathogenesis.}, } @article {pmid42314891, year = {2026}, author = {Yadav, P and Malik, I and Joshi, H}, title = {Folding pathways and force-induced unfolding of neurodegeneration associated GGGGCC microsatellite repeat RNA revealed by molecular simulations.}, journal = {International journal of biological macromolecules}, volume = {372}, number = {}, pages = {153101}, doi = {10.1016/j.ijbiomac.2026.153101}, pmid = {42314891}, issn = {1879-0003}, mesh = {*Molecular Dynamics Simulation ; G-Quadruplexes ; Nucleic Acid Conformation ; *RNA/chemistry/genetics ; *Microsatellite Repeats/genetics ; Thermodynamics ; *RNA Folding ; Humans ; *C9orf72 Protein/genetics ; }, abstract = {An intronic G4C2 hexanucleotide repeat expansion in the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). G4C2 RNA itself directly contributes to disease mechanisms and has emerged as a potential target for small molecules, anti-sense oligonucleotides (ASOs), and CRISPR-based therapeutics. Hence, understanding the folding/unfolding and structural polymorphism is essential for G4C2 RNA-targeting therapies. Here, using equilibrium all-atom molecular dynamics (MD) simulations, we explored potential intermediate metastable conformations of the G4C2 RNA repeats and investigated the effect of repeat length on folding. G4C2 RNA undergoes an ensemble of intermediate metastable states resembling hairpin, knot, and a G-quadruplex (GQ) like structures. Enhanced torsional flexibility and conformational heterogeneity were observed with increasing repeat length. Next, using a crystallized G4C2 RNA structure in GQ conformation, we performed equilibrium MD simulations to reveal its thermodynamic stability. Steered molecular dynamics (SMD) simulations with a reduced model of G4C2 GQ uncover two distinct unfolding mechanisms along the chosen reaction coordinates: strand slippage and unzipping. Overall, our findings provide molecular-level insights into the folding and force-induced unfolding dynamics of G4C2 repeat RNA GQ and set a platform for future studies on small-molecule targeting of ALS/FTD-associated G4C2 RNA.}, } @article {pmid42315356, year = {2026}, author = {Henders, AK and Ziser, L and Garton, FC and Adams, L and Ernst, K and Furlong, S and Heads, JA and Heggie, S and Krasniqi, R and Bhadravathi Lokeshappa, M and Mazumder, S and McNamara, E and MacShane, A and Mekhael, L and Nunn, L and Orden, B and Ryder, J and Thorpe, K and Toubia, M and Wallace, LM and Wickremeratne, D and Windebank, E and Benyamin, B and Ngo, S and Nicholson, G and Pamphlett, R and Steyn, FJ and Visscher, PM and Willams, KL and Henderson, R and Kiernan, MC and Laing, N and Mathers, S and McCombe, PA and Needham, M and Rowe, D and Schultz, D and Talman, P and Vucic, S and Blair, IP and McRae, AF and Wray, NR}, title = {Strategic Amyotrophic Lateral Sclerosis Australia-Systems Genomics Consortium (SALSA-SGC): cohort profile.}, journal = {BMJ open}, volume = {16}, number = {6}, pages = {e110906}, pmid = {42315356}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Australia ; *Genomics ; Female ; Male ; Middle Aged ; Aged ; Polymorphism, Single Nucleotide ; Adult ; Cohort Studies ; C9orf72 Protein/genetics ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative motor neuron disease (MND) with heterogeneity in disease onset, progression and treatment response. The Strategic ALS Australia-Systems Genomics Consortium (SALSA-SGC) was established in recognition of the need for large data sets of clinical data matched with biological samples to enable and foster ALS research and better understanding of aetiology and biological mechanisms. SALSA-SGC brought together the major Australian MND clinics to set up sustainable infrastructure that could facilitate long-term human ALS research and clinical trials nationally and internationally.

PARTICIPANTS: Between April 2016 and December 2024, SALSA-SGC recruited 1813 participants, including 1386 ALS/MND cases, 388 controls and 39 others (asymptomatic relatives and ALS mimics). Clinical data and biospecimens are available for 1333 and 1189 ALS cases, respectively, with longitudinal data spanning 4442 total clinic visits and 3201 samples. An open-access online data explorer showcases collected datasets.

FINDINGS TO DATE: Detailed clinical and questionnaire data allow an in-depth description of the cohort, informing clinical and health policy research. Screening for known ALS large-effect risk variants identified 125 mutation carriers (11.5% from N=1059), including 70 with C9orf72 expansions. Single Nucleotide Polymorphism (SNP)-array data (N=1088 cases; N=244 controls) have supported multiple published studies. SALSA-SGC resources are actively used by national and international researchers.

FUTURE PLANS: Ongoing efforts aim to expand recruitment into regional Australia and enhance sample processing for cell-based studies. The SALSA-SGC resource is accessible by researchers under agreements governed by participant consent, human ethics committee guidelines and agreed use of data and samples.}, } @article {pmid42316301, year = {2026}, author = {Russell, KA and Shahrabi, AA and Akerman, SC and Byrne, MD and Rothstein, JD and Trotti, D and Jensen, BK and Haeusler, AR}, title = {Intrathecal (G4C2)149 delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42316301}, issn = {2051-5960}, support = {RF1 NS114128/NS/NINDS NIH HHS/United States ; R01NS109150/NS/NINDS NIH HHS/United States ; RF1NS114128/NS/NINDS NIH HHS/United States ; R01 NS109150/NS/NINDS NIH HHS/United States ; R01 NS114128/NS/NINDS NIH HHS/United States ; P30 CA056036/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *C9orf72 Protein/genetics/deficiency/metabolism ; *Amyotrophic Lateral Sclerosis/pathology/genetics/physiopathology/metabolism ; Disease Models, Animal ; Spinal Cord/pathology/metabolism ; *Frontotemporal Dementia/pathology/genetics/physiopathology/metabolism ; DNA Repeat Expansion/genetics ; Mice ; Mice, Transgenic ; Motor Neurons/pathology/metabolism ; Injections, Spinal ; DNA-Binding Proteins/metabolism ; Dependovirus/genetics ; Male ; Mice, Inbred C57BL ; Humans ; }, abstract = {A repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet existing mouse models incompletely engage spinal regions implicated in disease. Here, an adeno-associated virus encoding (G4C2)149 repeats was delivered via neonatal intrathecal injection, achieving widespread CNS expression with robust spinal cord targeting. This approach was applied to mice with graded loss of endogenous C9orf72 to interrogate both gain- and loss-of-function mechanisms. Longitudinal motor, behavioral, and pathological analyses revealed that repeat expression primarily drives mild, progressive muscle weakness, whereas coordination deficits were largely genotype dependent. Subtle gait abnormalities and hyperactivity were also observed. Within spinal motor regions, repeat-expressing mice exhibited dipeptide repeat protein accumulation, reduced NeuN-positive area, fewer motor neurons, glial activation, sparse phosphorylated TDP-43 pathology, and increased cryptic TDP-43 splicing. Cross-domain correlations further linked repeat expression, spinal pathology, and motor dysfunction. Collectively, these findings establish that CNS-wide repeat expression combined with reduced C9orf72 produces a coherent, mild ALS/FTD model.}, } @article {pmid42316486, year = {2026}, author = {Chan, Y and Creer, S and Mere, J and Griffiths, AW and Wright, C and Hobson, EV and McDermott, CJ and Mayberry, EJ}, title = {The Emotional Experiences of Healthcare Professionals Working in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Muscle & nerve}, volume = {74}, number = {3}, pages = {517-529}, pmid = {42316486}, issn = {1097-4598}, support = {943-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Health Personnel/psychology ; *Emotions/physiology ; Adaptation, Psychological ; }, abstract = {Healthcare professionals (HCPs) working with people living with amyotrophic lateral sclerosis (ALS) are often exposed to emotive circumstances including end of life care, trauma, loss, and death. Existing reviews have explored the emotional experiences of people living with ALS and their carers but have largely ignored healthcare staff and the impact of this work on them. This systematic review of qualitative research aims to explore the emotional experiences of and impact on HCPs working with people living with ALS using thematic synthesis (PROSPERO reference: CRD42025631749). Electronic databases were searched for journal articles and gray literature (Medline, Scopus, PsycINFO, Google Scholar, King's Fund Library Database, ProQuest Dissertations, Theses Global) for qualitative or mixed-methods studies exploring the emotional impact on HCPs working in ALS. Twelve studies were included, critically appraised, and analyzed. Four themes were identified. The emotional intensity due to the nature of ALS created challenges for HCPs, while they were also faced with absorbing the emotions of others. HCPs learned to balance their emotional involvement, and HCPs also described positive experiences and coping mechanisms. HCPs working in ALS experience multi-faceted emotional challenges, and they do describe positive emotional experiences within their roles. However, HCPs describe having few coping mechanisms and limited formal support systems in place to process the intense emotions or to guide their emotional involvement. The lack of support for staff may ultimately negatively affect patient care. There is an unmet demand for debriefing, supervision, and further training on how to deal with intense, distressing emotions.}, } @article {pmid42316902, year = {2026}, author = {, }, title = {The ALS Home Health and Durable Medical Equipment Medical Standard Expert Consensus Guideline.}, journal = {Muscle & nerve}, volume = {74}, number = {2}, pages = {293-301}, doi = {10.1002/mus.70290}, pmid = {42316902}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Durable Medical Equipment/standards ; *Home Care Services/standards ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with escalating disability and complex care needs. Although most individuals with ALS reside at home, existing US guidelines primarily address clinic-based care and provide limited direction on medically necessary home health services and durable medical equipment (DME). The objective of this task force was to develop expert consensus guidance defining minimum medical standards for home health services and DME for individuals with ALS, with the goal of improving patient outcomes, safety, and quality of life. This guideline was developed by a multidisciplinary task force convened by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM). The process incorporated a scoping literature review, stakeholder engagement (patients, caregivers, and advocacy groups), and iterative expert consensus. Recommendations were informed by clinical expertise, patient-centered priorities, and existing policy frameworks. This guideline outlines stage-responsive home healthcare recommendations spanning nursing, home health aides, physical and occupational therapy, speech-language pathology, respiratory therapy, nutritional support, and social work. It emphasizes proactive, anticipatory care aligned with the predictable trajectory of ALS, rather than being reactive based on functional decline. The document defines medically necessary DME across domains, including mobility, communication, respiratory support, and activities of daily living, advocating for timely access independent of restrictive payer criteria. Key principles include coordinated interdisciplinary care, continuous reassessment, caregiver support, and integration of palliative care. These recommendations establish a foundational standard for ALS home-based care in the United States. Adoption may reduce delays, prevent complications, and support sustained independence and dignity for individuals with ALS.}, } @article {pmid42317073, year = {2026}, author = {Stark, T and Müller, S}, title = {PML as a neuroprotective guardian: Leveraging nuclear protein quality control to mitigate neurotoxicity of an ALS-associated NEK1 variant.}, journal = {The FEBS journal}, volume = {293}, number = {17}, pages = {5145-5148}, pmid = {42317073}, issn = {1742-4658}, support = {ID 514894665//Deutsche Forschungsgemeinschaft/ ; ID-494535244//Deutsche Forschungsgemeinschaft/ ; ID-465470262//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *NIMA-Related Kinase 1/genetics/metabolism ; *Promyelocytic Leukemia Protein/genetics/metabolism ; Ubiquitination ; Sumoylation ; Mice ; Proteasome Endopeptidase Complex/metabolism ; }, abstract = {Insoluble protein aggregates are a hallmark of neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). The ubiquitin-proteasome system (UPS) serves as a neuroprotective quality control mechanism that clears aggregates. PML nuclear bodies (NBs) were proposed to serve as hubs for SUMO-primed ubiquitylation and degradation of misfolded proteins. Georgiadou et al. provide evidence that an ALS-linked NEK1 truncation mutant is recruited to PML NBs, where it likely undergoes SUMOylation and ubiquitylation. In mice, PML loss exacerbates ALS-like symptoms, while induced PML expression delays disease onset. These findings establish PML as a key regulator of proteostasis and highlight PML induction as a potential therapeutic strategy for ALS and related proteinopathies.}, } @article {pmid42317831, year = {2026}, author = {Afshar, AS and Statland, J and Song, X}, title = {Towards Early Prediction of Amyotrophic Lateral Sclerosis Empowered by Machine Learning and Clinical Big Data.}, journal = {AMIA Joint Summits on Translational Science proceedings. AMIA Joint Summits on Translational Science}, volume = {2026}, number = {}, pages = {623-632}, pmid = {42317831}, issn = {2153-4063}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by substantial symptom heterogeneity and overlap with other neurological conditions, often delaying diagnosis. This study developed a consensus-based feature selection framework to identify a stable and parsimonious minimal feature set for early ALS prediction using large-scale observational data. Using multi-year medical claims and multi-site EHRs, we identified 1,716 ALS cases with matched controls. The approach integrated variability across sample, task, and model dimensions to isolate features predictive up to 18 months before diagnosis. Predictive models using LASSO regression and GBT were evaluated with AUROC and classification metrics. The resulting nine-feature set achieved AUROC values above 0.85 across time windows. The GBT model was further evaluated in musculoskeletal, nervous system, and limb or bulbar subgroups, demonstrating reliable discrimination and preserved sensitivity and specificity. These findings highlight the potential of stable minimal feature sets to support earlier ALS identification.}, } @article {pmid42317872, year = {2026}, author = {Singh, G and Singh, G and Shreya, and Kumari, A and Aran, KR}, title = {Nutrients and bioactive compounds as modifiers of neurodegenerative trajectories: molecular mechanisms, translational barriers, and precision nutrition.}, journal = {Frontiers in nutrition}, volume = {13}, number = {}, pages = {1819432}, pmid = {42317872}, issn = {2296-861X}, abstract = {The Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS) are a growing health burden across the world with minimal disease-modifying treatment and therapy. It is emerging that neurodegeneration is not only a progressive loss of neurons, but also a nutrient-sensitive systems-level dysfunction that takes the form of redox imbalance, chronic neuroinflammation, mitochondrial dysfunction, impaired proteostasis, and synaptic loss. The aging brain are more prone to metabolic vulnerability, and subclinical deficiencies in essential nutrients and bioactive dietary compounds may exacerbate cellular stress responses that contribute to disease progression. It summarizes the existing data on the effects of nutrients like vitamins, minerals, polyunsaturated fatty acids, and various phytochemicals in modulating neuronal homeostasis by regulating oxidative signaling, inflammatory cascades, mitochondrial resilience, autophagy, and synaptic plasticity. These nutrient-mediated effects collectively influence neuronal survival, synaptic integrity, and cognitive function by affecting disease susceptibility and progression. Additionally newer metabolites of the marine and microbiome act as new neuroactive agents. The evidence from in-vitro and preclinical models, translation to clinical benefit remains inconsistent due to heterogeneity in study design, bioavailability, blood- brain barrier penetration, dosing strategies and disease stage. This review highlights emerging potential of precision nutrition frameworks that integrate nutrigenomics, metabolomics, and microbiome interactions, and individualized metabolic profiling to enable context-dependent and stage-specific interventions. Moreover, conceptualizing neurodegeneration as a nutrient-sensitive, systems level disorder, propose a mechanistically informed and integrative approach that combine targeted nutritional strategies with pharmacological and lifestyle therapies to more effectively modify neurodegenerative trajectories.}, } @article {pmid42318818, year = {2026}, author = {Bailey, F and Eun, MW and Hobson, E and McDermott, C and Knox, L}, title = {Understanding apathy in people with amyotrophic lateral sclerosis using motivational theories.}, journal = {Journal of health psychology}, volume = {}, number = {}, pages = {13591053261454342}, doi = {10.1177/13591053261454342}, pmid = {42318818}, issn = {1461-7277}, abstract = {Apathy-a reduction in goal-directed behaviour, cognition, and emotional responsiveness-is a highly prevalent, debilitating symptom in people with amyotrophic lateral sclerosis (pwALS). This study investigated the association between apathy in 69 pwALS and their 54 informal caregivers and constructs from social cognitive theory and self-determination theory. Participants also provided subjective accounts of apathy in semi-structured interviews. Multiple regression analysis demonstrated that constructs from both motivational theories were significant predictors of overall apathy scores and its sub-domains (executive, emotional, initiation), accounting for 32%-64% of the variance. Specifically, frustration of the basic psychological need for competence was a consistent and prominent predictor of greater apathy. Qualitative findings revealed that pwALS lack a clear awareness of apathy, often experiencing it as a manifestation of activities requiring increased physical and temporal effort. Future research should use psychosocial theories to understand apathy and develop interventions.}, } @article {pmid42318821, year = {2026}, author = {Preetam, S and Mishra, R and Thapliyal, S and Mondal, S and Rustagi, S and Govindarajan, RK and Pandit, S and Bora, J and Talukdar, N and Rabbee, MF and Malik, S}, title = {3D-printed lab-on-chip platforms for the detection of neurodegenerative diseases: opportunities and challenges.}, journal = {Journal of materials chemistry. B}, volume = {14}, number = {27}, pages = {8352-8371}, doi = {10.1039/d6tb00381h}, pmid = {42318821}, issn = {2050-7518}, mesh = {*Printing, Three-Dimensional ; Humans ; *Neurodegenerative Diseases/diagnosis ; *Lab-On-A-Chip Devices ; Biomarkers/analysis ; Animals ; Biosensing Techniques ; Microphysiological Systems ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, and ALS remain some of the most challenging disorders to diagnose at an early stage. Conventional approaches rely on costly neuroimaging or invasive cerebrospinal fluid sampling, which limit accessibility and early intervention. Recent advances in 3D printing have enabled rapid prototyping of lab-on-chip (LOC) platforms that integrate microfluidics, biosensors, and biological models to detect disease-specific biomarkers with high sensitivity and throughput. Herein, we explore the synergistic role of 3D printing technologies and biomaterials in fabricating LOC systems for NDs. We highlight key biomarkers, and neuron- and organoid-on-chip platforms, and discuss the challenges and opportunities in clinical translation. By combining technical innovation in additive manufacturing with biological relevance, 3D-printed LOC devices represent a transformative approach toward precision diagnostics in neuro-medicine.}, } @article {pmid42319999, year = {2026}, author = {Pacheco-Ortega, GA and Esquivel-Zapata, O and Piña-Rosales, E and Davila-Ortíz de Montellano, DJ and Yescas Gomez, P and Medina-Rioja, R}, title = {Teaching Video NeuroImage: Beyond Cognition: Amyotrophic Lateral Sclerosis-Like Disease in PSEN1 c.1292C>A (Jalisco Founder Effect) Variant.}, journal = {Neurology}, volume = {107}, number = {2}, pages = {e218247}, doi = {10.1212/WNL.0000000000218247}, pmid = {42319999}, issn = {1526-632X}, } @article {pmid42320255, year = {2026}, author = {Waqar, K and Shaqfeh, M and Mittal, SO}, title = {POLG-associated Parkinson's disease-ALS overlap: A novel variant and first reported use of continuous subcutaneous foslevodopa/foscarbidopa infusion in Brait-Fahn-Schwartz disease.}, journal = {Parkinsonism & related disorders}, volume = {149}, number = {}, pages = {108398}, doi = {10.1016/j.parkreldis.2026.108398}, pmid = {42320255}, issn = {1873-5126}, mesh = {Humans ; Male ; Adult ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/complications ; Levodopa/administration & dosage ; Infusions, Subcutaneous ; *Antiparkinson Agents/administration & dosage ; Carbidopa/administration & dosage ; *Parkinson Disease/drug therapy/genetics/complications ; Dihydroxyphenylalanine/analogs & derivatives ; }, abstract = {A 38-year-old Emirati man developed levodopa-responsive young-onset parkinsonism followed by electrophysiologically confirmed amyotrophic lateral sclerosis consistent with Brait-Fahn-Schwartz disease. Whole-genome sequencing identified a novel heterozygous POLG variant (c.2620T > A; p. Leu874Met). Motor fluctuations on oral therapy prompted escalation to continuous subcutaneous foslevodopa/foscarbidopa infusion, achieving near-complete motor normalization at twelve months. This is the first reported use of device-aided therapy in POLG-associated parkinsonian-ALS overlap.}, } @article {pmid42320366, year = {2026}, author = {Lee, BC and Tsai, JC and Chang, WZ and Wang, CC and Hour, AL and Wang, CC and Tsai, HJ}, title = {Administration of Pgk1 missense mutation leads to more effective mitigation of neurodegenerative effects observed in ALS mice and transgenic zebrafish.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {201}, number = {}, pages = {119674}, doi = {10.1016/j.biopha.2026.119674}, pmid = {42320366}, issn = {1950-6007}, mesh = {Animals ; Zebrafish/genetics ; *Phosphoglycerate Kinase/genetics/administration & dosage/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Mutation, Missense/genetics ; Mice ; Disease Models, Animal ; Mice, Transgenic ; Animals, Genetically Modified ; Humans ; Motor Neurons/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons (MNs) with few available therapeutic options. Previous ALS studies demonstrated a decrease in phosphoglycerate kinase 1 (Pgk1) secreted from NogoA-overexpressing muscle cells, thus reducing interaction between extracellular Pgk1 (ePgk1) and neural membranous Enolase 2 (Eno2) with consequent inhibition of neurite outgrowth of MNs (NOMN). The negatively charged 419th aspartic acid of receptor Eno2 (Eno2-D419) is a critical residue interacting with the positively charged 353rd lysine of ligand ePgk1-K353. To strengthen the charge attraction, we mutated ePgk1-K353 to arginine (ePgk1-K353R). Compared to wild-type Pgk1, supplementary mutant Pgk1-K353R proved more effective in increasing NOMN derived from NSC34 neural cells cultured in Sol8-vector condition medium. In vivo, Pgk1-K353R-immersed zebrafish embryos exhibited increased caudal primary MNs branching. Intravenous injection of Pgk1-K353R into ALS-mice exhibited more preservative in innervated neuromuscular junctions in gastrocnemius muscle and diaphragm, increased grip strength, higher rearing frequency, 1.6-fold greater locomotive distance and longer survival. For example, median survival days for the control, Pgk1 and Pgk1-K353R groups were 131, 137.5 and 148, respectively. Collectively, we found a single-amino-acid mutant Pgk1-K353R that exhibits higher efficacy to ameliorate neurodegeneration in ALS-mice by delaying disease progression compared to that driven by wild-type Pgk1. We suggest this outcome might be due to more electrostatic attraction between ePgk1-K353R and Eno2-D419 region predicted by in silico analysis. Therefore, mutant Pgk1-K353R protein should be considered a promising neuroprotective drug for ALS treatment.}, } @article {pmid42320854, year = {2026}, author = {Pagliarello, C and Girardelli, CR}, title = {Response to Zhang X et al's "Effectiveness and tolerability of baricitinib with or without prior corticosteroids in alopecia areata: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {4}, pages = {e397-e398}, doi = {10.1016/j.jaad.2026.05.128}, pmid = {42320854}, issn = {1097-6787}, } @article {pmid42321151, year = {2026}, author = {Jewett, G and Ferber, R and Josephson, CB and Korngut, L and Lee, J}, title = {Comparison of Consumer Smartwatch and Research-Grade Accelerometer-Derived Step Counts in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {74}, number = {3}, pages = {580-589}, pmid = {42321151}, issn = {1097-4598}, support = {//ALS Canada/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Female ; Male ; *Accelerometry/instrumentation/methods ; Middle Aged ; Aged ; Prospective Studies ; *Wearable Electronic Devices ; *Walking/physiology ; Adult ; Digital Health ; Monitoring, Ambulatory/instrumentation ; Remote Patient Monitoring ; }, abstract = {INTRODUCTION/AIMS: Objective, scalable measures of function are needed in amyotrophic lateral sclerosis (ALS). Research-grade accelerometers are promising but may be difficult to deploy for prolonged remote monitoring, whereas consumer smartwatches offer a practical alternative. We evaluated the feasibility of long-term smartwatch monitoring in ALS and compared smartwatch- and accelerometer-derived daily step counts.

METHODS: In this single-centre prospective observational study, participants wore a Fitbit Sense (smartwatch) on the wrist longitudinally and an ActiGraph GT9X Link (accelerometer) on the opposite wrist during clinic-aligned assessment periods. Device comparison was restricted to concurrent valid days (≥ 10 h wear) and included paired comparison of mean daily step counts, Pearson correlation, Bland-Altman analysis, and proportional bias assessment.

RESULTS: Forty participants were enrolled and 39 contributed data across 8093 smartwatch and 915 accelerometer days. Step count comparison included 503 concurrent valid days from 34 participants. Mean daily step counts were 3480 (SD 4365) for smartwatch and 4066 (SD 4797) for accelerometer (p < 0.0001), with strong correlation (r = 0.91, p < 0.0001). Mean bias was -586 steps for smartwatch, with 95% limits of agreement from -4193 to 3021. Among participants with ≥ 6 months of concurrent data, devices showed similar decline over time (interaction p = 0.76).

DISCUSSION: Long-term remote monitoring using a smartwatch was feasible in ALS. Smartwatch-derived step counts were strongly correlated with accelerometer-derived estimates but were systematically lower and showed wide day-level limits of agreement. Smartwatch-derived step counts may be useful for group-level analyses and longitudinal monitoring, though device-specific bias should be considered in interpretation.}, } @article {pmid42322032, year = {2026}, author = {Neves, MG and Unger, M and Siesler, HW}, title = {Monitoring a Polyurethane Synthesis by Fiber-Coupled Attenuated Total Reflection Fourier Transform Infrared Spectroscopy and Multivariate Curve Resolution-Alternating Least Squares.}, journal = {Applied spectroscopy}, volume = {}, number = {}, pages = {37028261464644}, doi = {10.1177/00037028261464644}, pmid = {42322032}, issn = {1943-3530}, abstract = {The step-growth polymerization of 1,4-butanediol with 4,4'-diphenylmethanediisocyanate (MDI) was monitored in situ by fiber-coupled attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy between 40 and 70 °C. In contrast to previous kinetic and two-dimensional correlation spectroscopy (2D-COS) studies of this system, the present work applies multivariate curve resolution alternating least squares (MCR-ALS) to temperature-dependent spectral data. The method enables decomposition of overlapping urethane-related bands and extraction of concentration profiles for chemically and physically distinct species, including dissolved and precipitated polymer phases. The MCR-ALS results are consistent with previously reported kinetic trends while providing additional quantitative insight into transient species and phase evolution. These findings demonstrate the added value of multivariate analysis for the concise interpretation of complex polymerization processes.}, } @article {pmid42322392, year = {2026}, author = {Poletti, B and Aiello, EN and Consonni, M and Iazzolino, B and Torre, S and Faltracco, V and Telesca, A and Palumbo, F and Curti, B and De Luca, G and Moreschi, A and Frisco, F and Dalla Bella, E and Bersano, E and Riva, N and Verde, F and Messina, S and Doretti, A and Maranzano, A and Morelli, C and Cappa, SF and Calvo, A and Strong, MJ and Silani, V and Lauria, G and Chiò, A and Ticozzi, N}, title = {ECAS-Based Neuropsychological Phenotyping in Amyotrophic Lateral Sclerosis: A Retrospective Study Comparing Different Algorithms.}, journal = {Neurology and therapy}, volume = {15}, number = {4}, pages = {2059-2071}, pmid = {42322392}, issn = {2193-8253}, support = {TRANS-ALS//Agenzia Nazionale di Valutazione del Sistema Universitario e della Ricerca/ ; grant number: 2015-0023//Agenzia Nazionale di Valutazione del Sistema Universitario e della Ricerca/ ; POR FESR 2014-2020//Fondo Europeo di Sviluppo Regionale, Regione Lombardia/ ; grant number: 1157625//Fondo Europeo di Sviluppo Regionale, Regione Lombardia/ ; grant: RF-2016-02362405//Ricerca Sanitaria Finalizzata - Ministero della Salute/ ; grant: 2017SNW5MB//"Progetti di Rilevante Interesse Nazionale" programme of the Ministry of Education, University and Research/ ; grant: RF H2020-SC1-DTH2020-1//Horizon 2020/ ; grant agreement ID: 101017598//Horizon 2020/ ; }, abstract = {INTRODUCTION: This study aimed to compare different algorithms based on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) to classify patients with amyotrophic lateral sclerosis (ALS) according to their neuropsychological phenotype to identify possible discrepancies among these systems.

METHODS: ECAS-Cognitive and -Carer Interview (ECAS-C/-CI) scores of N = 901 patients with ALS without a formal diagnosis of dementia were retrospectively retrieved. Patients were classified, pursuant to Strong et al.'s criteria, as cognitively and behaviourally normal (ALScbn), cognitively and/or behaviourally impaired (ALSci/bi/cbi), or Possible ALS-FTD, according the following ECAS-based algorithms: (1) Abrahams', solely addressing ECAS-C total and ALS-Specific subtotals; (2) Poletti et al.'s, addressing single task-level ECAS-C scores; (3) "Subscale", addressing ECAS-C subscales (i.e., Language, Executive, Fluency, Memory and Visuospatial). All algorithms relied on single-item-level ECAS-CI scores for behavioural classifications.

RESULTS: Whilst agreement rates among these classifications were moderate to high (84-86%; Cohen's k = 0.78-0.81), and some discrepancies emerged: (1) "ALScbn-to-ALSci" and "ALSci-to-ALScbn" re-classifications occurred across the three comparisons, ranging from ~ 11% to ~ 24%; (2) the most classificatory disagreements (~ 43%) occurred for the ALScbi category when comparing single task-level (Poletti) to total-level (Abrahams) algorithms, with patients being re-classified as either ALSbi or Possible ALS-FTD; (3) ~ 24% of Abraham's Possible ALS-FTD cases were re-classified as either ALScbi or ALSbi by the Subscale approach.

CONCLUSIONS: Different ECAS-based algorithms for deriving Strong's phenotypes might yield slight discrepancies that could under- or overestimate a given classification.}, } @article {pmid42323602, year = {2026}, author = {Moll, L and Riessen, R and Dahlmann, P and Häske, D}, title = {Effect of low-dose, high-frequency advanced life support training versus annual full-day training on simulation-based resuscitation performance: a randomized controlled trial.}, journal = {BMC medical education}, volume = {26}, number = {1}, pages = {}, pmid = {42323602}, issn = {1472-6920}, mesh = {Adult ; Female ; Humans ; Male ; *Advanced Cardiac Life Support/education ; *Cardiopulmonary Resuscitation/education ; *Clinical Competence/standards ; Emergency Medical Services ; *Simulation Training/methods ; Young Adult ; }, abstract = {BACKGROUND: Skill decay in advanced life support (ALS) is well documented, yet optimal training frequency remains unclear. This trial compared low-dose, high-frequency ALS training with annual full-day training regarding simulation-based resuscitation performance after one year.

METHODS: In this randomized, controlled, simulation-based trial, 35 emergency medical services (EMS) professionals were allocated to either low-dose, high-frequency ALS training (intervention group, n = 18) or a single annual full-day ALS training (control group, n = 17). Performance was assessed at baseline and after 12 months using a validated 29-item rating instrument covering technical and non-technical skills (NTS), with items rated on a 5-point Likert scale (1 = poor performance, 5 = excellent performance). The primary endpoint was the overall performance score for resuscitation management, defined as the mean across all items. Secondary endpoints included domain-specific performance scores (NTS, defibrillation-related, and cardio-pulmonary resuscitation [CPR] items), calculated as the mean scores for each domain, as well as time to key interventions.

RESULTS: After 12 months, the intervention group showed significantly higher overall performance scores than the control group (4.7 ± 0.2 vs. 4.2 ± 0.3; p < 0.001). The largest between-group difference was observed for NTS (4.8 ± 0.2 vs. 3.9 ± 0.5; p < 0.001). Scores for defibrillation-related and CPR-related items were also significantly higher in the intervention group. Time to CPR initiation (13 ± 2 s vs. 18 ± 7 s; p = 0.015), rhythm analysis (29 ± 9 s vs. 45 ± 24 s; p = 0.015), supraglottic airway insertion (51 ± 13 s vs. 68 ± 30 s; p = 0.013), as well as hands-off time (4 ± 1 s vs. 6 ± 3 s; p = 0.002) were significantly shorter in the intervention group. The rating instrument demonstrated good reliability (Cronbach's alpha 0.793; intraclass correlation coefficient 0.794, 95% confidence interval 0.718-0.854).

CONCLUSION: Low-dose, high-frequency ALS training resulted in higher simulation-based resuscitation performance scores than annual full-day training, particularly for non-technical skills and time-critical processes.

TRIAL REGISTRATION: The study is registered in the German Register of Clinical Studies under the ID DRKS00024822.}, } @article {pmid42323648, year = {2026}, author = {Girling, C and Ryan, G and Bradburn, M and Caprioli, T and Dawson, S and Fisher, E and Haynes, N and Herbert, E and Hill, H and Hind, D and May, C and Bianchi, S and Cox, M and Kaltsakas, G and Massey, C and Mayberry, E and Messer, B and Needham, D and Playle, R and McDermott, C and Griffiths, AW and Hobson, E}, title = {Delivering effective non-invasive ventilation in amyotrophic lateral sclerosis using intensive remote support (DENIM): protocol for an embedded process evaluation in a hybrid type 3 implementation-effectiveness trial.}, journal = {Implementation science communications}, volume = {7}, number = {1}, pages = {}, pmid = {42323648}, issn = {2662-2211}, support = {NIHR158715//Health Services and Delivery Research Programme/ ; }, abstract = {BACKGROUND: Non-invasive ventilation (NIV) is the only intervention that significantly improves survival and quality of life in motor neuron disease, extending life by 8-13 months. However, at least half of patients are unable to reach the recommended ≥ 4 h daily NIV use, and current NHS services provide insufficient follow-up for intensive optimisation. Delivering Effective Non-Invasive ventilation in Motor neuron disease using intensive remote support (DENIM) is a stepped-wedge cluster randomised trial. This protocol describes a process evaluation embedded within DENIM aiming to understand how and why the implementation strategy works (or does not work) across different contexts.

METHOD: The process evaluation employs a convergent mixed-methods multiple-case study design across twelve NHS ventilation services. We developed a programme theory informed by Normalization Process Theory (NPT), the Consolidated Framework for Implementation Research and Expert Recommendations for Implementing Change, which states how the DENIM implementation strategy is expected to achieve normalisation of evidence-based NIV practice. Data collection across twelve sites include: ethnographic observations of patient-staff interactions; semi-structured interviews with staff (n = 24-48) and patients/carers (n = 24) exploring implementation experiences; the NoMAD questionnaire measuring normalisation perceptions from healthcare professionals within the services and NIV adherence data from participants' ventilators. Barriers and facilitators to research participation for underserved populations including ethnic minorities, those with low digital literacy, and women over 80 with bulbar onset disease will also be identified. Qualitative data will be analysed using NPT-informed thematic analysis. Integration occurs at three levels (design, methods, interpretation) with joint display tables presenting quantitative and qualitative findings alongside meta-inferences.

DISCUSSION: This process evaluation will generate explanatory insights into how implementation strategies can address the evidence-to-practice gap in complex, technology-supported care for progressive diseases, with implications for health equity and wider NHS digital transformation.

TRIAL REGISTRATION: ISRCTN10105285. 16/04/2025.}, } @article {pmid42324254, year = {2026}, author = {Di Lazzaro, V and Pellegrino, G and Corp, DT and Musumeci, G and Capone, F and Pilato, F and Mazzone, P and Insola, A and Ranieri, F}, title = {Direct evidence of upper motor neuron excitability changes in a patient with ALS.}, journal = {Journal of neurophysiology}, volume = {136}, number = {1}, pages = {261-269}, doi = {10.1152/jn.00208.2026}, pmid = {42324254}, issn = {1522-1598}, support = {T4-AN-09//Ministero della Salute (Italy Ministry of Health)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Motor Neurons/physiology ; Transcranial Magnetic Stimulation ; Middle Aged ; *Evoked Potentials, Motor ; Male ; Female ; *Motor Cortex/physiopathology ; Neural Inhibition ; *Pyramidal Tracts/physiopathology ; Aged ; }, abstract = {A key feature of amyotrophic lateral sclerosis (ALS) pathophysiology is motor neuron hyperexcitability. However, the mechanisms of hyperexcitability are not well understood. Prior studies have used transcranial magnetic stimulation (TMS) to demonstrate increased motor cortex excitability and reduced intracortical inhibition in human ALS. Yet, interpretation of these findings is limited because measurement of muscle responses cannot disentangle the specific contribution of upper and lower motor neurons and of cortical interneurons to excitability changes. We had the rare opportunity to record directly the corticospinal output evoked by TMS upstream of the spinal circuitry in a patient with ALS who had undergone epidural electrode implantation for intractable pain. Single-pulse stimulation was performed both with a coil orientation inducing a current that activates corticospinal neurons directly, and with a coil orientation inducing a current that activates corticospinal neurons trans-synaptically. Short-interval intracortical inhibition (SICI) was also studied using paired-pulse stimulation. Data obtained from the patient were compared with those recorded in 10 conscious control subjects. Compared with control subjects, patient showed a reduced amplitude in response to direct corticospinal neuron activation, yet an enhanced amplitude of corticospinal output after trans-synaptic corticospinal neuron activation, together with a SICI reduction. Present findings provide direct evidence of hyperexcitability of monosynaptic glutamatergic inputs to corticospinal neurons that, in association with reduced intracortical inhibition, can trigger neurodegeneration. Taken together with the extensive body of evidence generated by noninvasive TMS studies, the findings from this single-case study may provide valuable insights into the pathophysiological mechanisms of the disease.NEW & NOTEWORTHY The response evoked by direct activation of corticospinal neurons is reduced in human amyotrophic lateral sclerosis (ALS). In contrast, the response evoked by trans-synaptic activation of these cells is enhanced. The activity of inhibitory inputs to corticospinal neurons is reduced. These abnormalities related to abnormal excitatory and inhibitory input processing by corticospinal neurons may trigger neurodegeneration.}, } @article {pmid42324612, year = {2026}, author = {Alwarnaidu Vijayarajan, VB and Vijayakumar, I and Ruiz-Partida, R and Runge, F and Torra, J and Lozano-Juste, J and Forristal, PD}, title = {Pro-197 mutations confer resistance to thiencarbazone but not to foramsulfuron in ALS-resistant Poa annua populations.}, journal = {Pest management science}, volume = {82}, number = {10}, pages = {10134-10146}, pmid = {42324612}, issn = {1526-4998}, support = {//Department of Agriculture, Food and the Marine, Ireland/ ; //European Regional Development Fund/ ; //European Union (FEDER), 'ERDF A way of making Europe'/ ; }, mesh = {*Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Mutation ; *Plant Proteins/genetics/metabolism ; Molecular Docking Simulation ; }, abstract = {BACKGROUND: Poa annua is currently a lower-priority arable weed in Ireland; however, increasing target-site resistance to acetolactate synthase (ALS) inhibitors and declining availability of non-ALS herbicides highlight emerging control challenges. ALS-inhibiting co-formulations of foramsulfuron + thiencarbazone have been specifically developed for use in herbicide-tolerant beet varieties. While foramsulfuron can control grass weeds carrying specific target-site mutations, its efficacy within the co-formulation on ALS-resistant populations remains unknown. We addressed this knowledge gap using genetic characterisation, dose-response and interaction analyses, and ligand docking modelling in 12 independently evolved, ALS-resistant, Poa annua populations carrying Pro-197 or Trp-574 mutations.

RESULTS: All Pro-197 variants (Thr, Gln or Ala) were thiencarbazone-resistant (resistance index (RI) = 20.9-33.3) but remained foramsulfuron-sensitive (2.5-4), while the co-formulation showed reduced efficacy (5.5-6.2). Interaction analyses showed no overall deviation from additivity for Pro-197 populations (P > 0.05), although antagonism occurred at reduced rates (P < 0.05). Structural modelling and ligand docking analyses indicated that most Pro-197 substitutions did not alter the ALS catalytic tunnel. Foramsulfuron retained extensive hydrogen-bonding and electrostatic interactions, with a more favourable binding free energy than thiencarbazone, which showed fewer interactions and a less favourable free energy. Trp-574-Leu variants exhibited cross-resistance to all treatments, consistent with disruption of key binding interactions.

CONCLUSION: This study demonstrates that foramsulfuron + thiencarbazone efficacy on Pro-197-resistant Poa annua populations is poor, despite these populations being sensitive to foramsulfuron used alone. Consequently, this co-formulation, developed for ALS-tolerant beet, should be restricted to fields without ALS-resistant weeds to ensure effective in-crop control and avoid selection for resistance. © 2026 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid42324839, year = {2026}, author = {Felice, KJ and Leighton, DB and Daniel, AS and Cartwright, NI and Benchaya, LM}, title = {The Impact of Sponsored Genetic Testing in 170 Consecutive Consenting Patients With Amyotrophic Lateral Sclerosis: A Single-Site Retrospective Review.}, journal = {Muscle & nerve}, volume = {74}, number = {3}, pages = {698-701}, pmid = {42324839}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Genetic Testing/economics ; Retrospective Studies ; Female ; Male ; Middle Aged ; Aged ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Adult ; Genetic Predisposition to Disease ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is often categorized as sporadic (sALS) or familial (fALS) based on the family history. Several recent genetic studies have found disease-causing variants in 50%-85% of patients with fALS and 10%-15% of those with sALS. The aim of our study is to review our clinical experience with sponsored genetic testing (i.e., pharmaceutical company-sponsored and cost-free to patient) since its inception.

METHODS: We reviewed the medical records on all ALS patients seen at our Center who consented to sponsored genetic testing from August 2021 through October 2025.

RESULTS: Of the 170 medical records reviewed, 22 patients (12.9%) tested positive for a disease-causing variant in a known autosomal dominant disorder. Thirteen of 35 patients with fALS (37.1%) were found to have a disease-causing variant, in contrast to 9 of 135 patients (6.7%) with sALS. Of the 22 disease-causing variants found, the following genes were involved in decreasing frequency: C9orf72 11 (50%), SOD1 6 (27.3%), FUS 2 (9.1%), and one each (4.5%) of SQSTM1, TARDBP, and TBK1. Twenty-eight patients (16.5%) harbored 29 variants of uncertain significance (VUS).

DISCUSSION: Results of testing led to medically actionable activities including genetic counseling for patients and at-risk family members with positive results, and treatment (i.e., intrathecal tofersen) for the two patients harboring pathogenic SOD1 variants. The lower diagnostic yields than previously published for fALS and sALS patients likely are related to lower numbers of genes tested in the sponsored genetic panels, and these are expected to improve as more genes are added.}, } @article {pmid42324866, year = {2026}, author = {Hannaford, AM and Supnet, IE and Pavey, N and Menon, P and van den Bos, MAJ and Kiernan, MC and van Alfen, N and Simon, NG and Vucic, S}, title = {Muscle Ultrasound Is a Sensitive Outcome Measure in ALS.}, journal = {Muscle & nerve}, volume = {74}, number = {3}, pages = {590-599}, pmid = {42324866}, issn = {1097-4598}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Action Potentials/physiology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; Cohort Studies ; Longitudinal Studies ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Outcome Assessment, Health Care ; Prospective Studies ; Ultrasonography ; }, abstract = {INTRODUCTION/AIMS: Muscle ultrasound is a potential outcome measure in amyotrophic lateral sclerosis (ALS), although prospective, multicenter longitudinal studies are lacking. This study aimed to evaluate muscle ultrasound as an outcome in ALS and compare its sensitivity with clinical and neurophysiological metrics.

METHODS: In this prospective two-center cohort study, adults with ALS underwent baseline and follow-up assessments at least 3 months apart. Clinical measures included the ALS Functional Rating Scale-Revised (ALSFRS-R) and Medical Research Council sum scores. Median nerve abductor pollicis brevis and ulnar nerve first dorsal interosseous compound motor action potential (CMAP) amplitudes were recorded. Muscle ultrasound of 11 bulbar and limb muscles was performed using harmonized protocols, with offline analysis of muscle thickness and echogenicity. Longitudinal change and effect sizes were calculated.

RESULTS: Twenty-two patients were included (median age 59.3 years, follow-up 9.6 months, disease duration 23.1 months). ALSFRS-R declined by -3.0 points (-0.7% per month; effect size 0.84). Median nerve CMAP amplitude decreased by -1.6 mV (-1.2% per month; effect size 0.77). Muscle echogenicity increased by 0.8 units (+6.0% per month), yielding the largest effect size (1.09), with increases across multiple muscles. Responsiveness improved with onset-specific muscle selection, with biceps brachii (effect size 1.12) and gastrocnemius (1.18) showing the strongest changes. Muscle thickness and fasciculation frequency did not change.

DISCUSSION: Muscle ultrasound echogenicity is a sensitive structural biomarker of ALS progression, demonstrating greater responsiveness than ALSFRS-R and CMAP over 3-12 months. Its accessibility and sensitivity support its utility as an outcome measure in clinical trials.}, } @article {pmid42327318, year = {2026}, author = {Mot, AI and Li, Y and Dibaj, P and Tzvetanova, ID and Gerwig, UC and Bogale, TA and Goebbels, S and Möbius, W and Bergles, DE and Morrison, BM and Rothstein, JD and Cleveland, DW and Edgar, JM and Nave, KA}, title = {Mutant SOD1 expressed by oligodendrocytes aggregates in myelinic nanochannels and accelerates disease progression in familial ALS mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.09.731100}, pmid = {42327318}, issn = {2692-8205}, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a highly debilitating and fatal disease characterized by the progressive loss of motor neurons. Reduced oligodendroglial support has been implicated in ALS progression but remains mechanistically unexplained. Here, using a mutant superoxide dismutase 1 (SOD1-G37R) mouse model of familial ALS, Cre-mediated excision of the mutant SOD1 gene within the oligodendrocyte lineage prior to myelin compaction is shown to slow disease onset, improve motor performance, and prolong survival. In contrast, silencing mutant SOD1 expression within oligodendrocytes after myelin compaction failed to ameliorate disease phenotype. Electron microscopy is used to identify aggregation of mutant SOD1 within paranodal loops and the inner periaxonal tongue of 'myelinic nanochannels', narrow cytosolic compartments for the diffusion of metabolites and motor-driven transport processes. In a second mouse model (SOD1-G93A) of familial, SOD1 mutant-mediated ALS, we show that induction of excessive myelin compaction and myelinic channel collapse (by depletion of CNP from myelin) accelerates disease and diminishes survival. Our data support loss of myelinic channel integrity as a contributor to familial ALS disease initiation and progression, findings likely relevant to neurodegenerative disease involving other aggregation prone proteins that are expressed in myelinating oligodendrocytes.

SIGNIFICANCE STATEMENT: Oligodendrocytes have been implicated in the progression of amyotrophic lateral sclerosis (ALS) but the underlying mechanisms have remained obscure. Here we show in genetic mouse models that the familial ALS causing isoform of a ubiquitously expressed mutant enzyme (SOD1) aggregates in cytosolic channels within myelin that are responsible for delivery of transporters and nutrients necessary to support the axonal compartment. ALS disease progression was accelerated in mice when myelinic channels were collapsed by deleting CNP, a structural protein necessary for myelinic channel maintenance. Disruption of transport through myelinic channels by aggregation of mutant SOD1 may perturb oligodendrocyte support of motor axons and contribute to disease in this form of ALS.}, } @article {pmid42327368, year = {2026}, author = {Gatt, A and Buhidma, Y and Fodder, K and Humphrey, J and Foti, SC and Frias, B and Benson, BC and Gami-Patel, P and Gittings, LM and Toomey, CE and Lashley, T}, title = {Transcriptomic and pathological analysis of the hnRNP network reveals glial involvement in frontotemporal lobar degeneration pathological subtypes.}, journal = {Brain communications}, volume = {8}, number = {3}, pages = {fcag197}, pmid = {42327368}, issn = {2632-1297}, abstract = {Frontotemporal dementia is a neurodegenerative disorder with a strong heritable component. Frontotemporal lobar degeneration refers to the pathological changes seen in frontotemporal dementia, characterized by atrophy of the frontal and temporal lobes and the presence of abnormal protein inclusions. In the case of frontotemporal lobar degeneration with hyperphosphorylated TDP-43 positive inclusions (FTLD-TDP), five pathological subtypes (A, B, C, D and E) are observed based on the types and distribution of inclusions found in the brain. In all subtypes, there tends to be a large variability in the number of pathological inclusions observed between cases, with limited correlation to clinical manifestations. TDP-43 is an RNA-binding protein belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family, which along with other hnRNPs, modulates multiple aspects of RNA processing. HnRNPs other than TDP-43 have been implicated in several neurological diseases, including Amyotrophic Lateral Sclerosis, FTLD-TDP, frontotemporal lobar degeneration with fused in sarcoma (FTLD-FUS) and Alzheimer's disease. Multiple hnRNPs have been found in pathological inclusions in specific subtypes of FTLD-TDP, suggesting potential roles in the disease process. The role of the hnRNP network in frontotemporal lobar degeneration disease pathogenesis, however, has not yet been investigated. This study aimed to comprehensively evaluate the presence and expression of hnRNP proteins in two pathological subtypes of sporadic FTLD-TDP (A and C) as well as the genetic form FTLD-TDP A C9orf72 using immunohistochemistry and gene expression analysis by single-nuclei RNA-sequencing. We found that there was great variability in the frequency of TDP-43 pathology across and within FTLD-TDP pathological subtypes. Our findings suggest that distinct global transcriptomic profiles may underlie the different pathological subtypes of FTLD-TDP. The most prominent transcriptomic changes were observed in oligodendrocytes and astrocytes, involving multiple hnRNPs across frontotemporal lobar degeneration subtypes compared to controls. Transcriptomic co-expression analysis further revealed that glial clusters were more strongly associated with RNA-processing dysfunction and contributed to disease classification. Together, these findings highlight the involvement of the hnRNP network and glial-specific RNA-processing alterations in FTLD-TDP pathophysiology, offering new insight into the molecular distinctions between pathological subtypes and potential targets for future investigation.}, } @article {pmid42328245, year = {2026}, author = {Dong, J and Lu, M and Chen, Y and Zisman-Ilani, Y and Feng, Y and Zhang, S and Huang, H and Zhou, Y}, title = {Bridging the Gap Between Efficacy and Practice: A Systematic Review of Shared Decision-Making in Severe Mental Illness.}, journal = {Journal of multidisciplinary healthcare}, volume = {19}, number = {}, pages = {610845}, pmid = {42328245}, issn = {1178-2390}, abstract = {Shared decision-making (SDM) is recommended for preference-sensitive treatment decisions in severe mental illness, but its routine use in psychiatric services remains inconsistent. This systematic review synthesized evidence published between 2014 and 2024 and examined clinical, cultural, and organizational factors associated with SDM implementation. We searched PubMed, Embase, CINAHL, Cochrane Library, Web of Science, CNKI, Wanfang, and VIP for studies published from January 2014 to November 2024. Forty-two studies involving 8798 participants were included. Reporting followed PRISMA 2020 and SWiM guidance. Study quality was assessed with design-specific Joanna Briggs Institute tools, and certainty of key findings was appraised using a combined GRADE-CERQual approach. Because of heterogeneity in study design, interventions, outcomes, and settings, findings were synthesized narratively using Popay et al's framework. Patient decision aids were generally associated with lower decisional conflict, greater readiness, satisfaction, involvement, or autonomy, with little evidence of meaningful consultation-time extension. Clinician training and SDM interventions improved short-term engagement and information sharing, but evidence for sustained improvements in adherence, decisional conflict, and clinician behavior was mixed or low certainty. Family-mediated or triadic decision-making was prominent in East and Southeast Asian studies and may support adherence and participation, although it can also create tension between patient autonomy and family preferences. Across studies, clinicians and patients often emphasized different treatment priorities, particularly symptom control versus side-effect tolerability. Evidence was concentrated in Europe and East Asia, with limited data from low-resource regions. SDM in psychiatric care appears most reliable for improving immediate decision processes rather than long-term outcomes. Future implementation should test culturally adapted triadic decision aids, workflow-integrated prompts, and interprofessional decision coaching while using cautious, context-sensitive outcome evaluation.}, } @article {pmid42329291, year = {2026}, author = {Sathick Batcha, BR and Amarnath, DP and Srinivasan, D and Ramakrishnan, P}, title = {Targeting mitochondrial dysfunction and neuroprotection in neurodegenerative disorders: emerging therapeutic potential of berberine and polymeric nanoparticle-based delivery systems.}, journal = {Inflammopharmacology}, volume = {34}, number = {7}, pages = {4367-4382}, pmid = {42329291}, issn = {1568-5608}, mesh = {Humans ; *Berberine/administration & dosage/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Mitochondria/drug effects/metabolism ; *Neuroprotective Agents/administration & dosage/pharmacology ; Polymers/chemistry ; *Nanoparticles ; *Nanoparticle Drug Delivery System ; *Neuroprotection/drug effects/physiology ; Drug Delivery Systems/methods ; }, abstract = {Major neurodegenerative disorders, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are pathologically driven by mitochondrial failure and persistent neuroinflammation. Defects in oxidative phosphorylation, excess Reactive Oxygen Species (ROS), and impaired mitophagy cause an imbalance in neuronal energy and promote the release of mitochondrial Damage-Associated Molecular Patterns (DAMPs) that activate microglial inflammasomes and enhance inflammatory signalling. Current therapeutic strategies have largely targeted individual pathways and have been unable to effectively modulate this interrelated mitochondrial immune axis or achieve efficient delivery to the Central Nervous System (CNS). This review addresses the dual promise of berberine therapy, a biologically active plant alkaloid that enhances mitochondrial production via AMPK/PGC-1α and SIRT1, restores membrane potential, promotes mitophagy, and inhibits NF-κB and NLRP3-mediated inflammation. Nevertheless, this compound's weak solubility, limited bioavailability, and extremely poor Blood-Brain Barrier (BBB) penetration limit its therapeutic application. Encapsulation of berberine in polymeric nanoparticles, including Polyethylene glycol (PEG)-based polymeric nanoparticle systems, offers improved stability, bioavailability, and targeted mitochondrial delivery. An effective method for reducing neuroinflammation and mitochondrial dysfunction is this comprehensive phytochemical nanotechnology technique.}, } @article {pmid42329964, year = {2026}, author = {Fernandes, APM and Bertucci Borges, LH and Holanda, LJ and Bezerra, BHES and Lopes, ACSM and Silva, MCFD and Valentim, RAM and Bougrain, L and Vasiljevic, GAM and Rodrigues Lindquist, AR}, title = {Applications of electromyography in Amyotrophic Lateral Sclerosis: A systematic review.}, journal = {PloS one}, volume = {21}, number = {6}, pages = {e0350029}, pmid = {42329964}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Humans ; *Electromyography/methods ; Motor Neurons/physiology ; Muscle, Skeletal/physiopathology ; }, abstract = {This systematic review examined the use of surface electromyography (sEMG) for the neuromuscular assessment of individuals with Amyotrophic Lateral Sclerosis (ALS), focusing on clinical parameters, the muscle groups evaluated, acquisition protocols, technical properties of the recording systems, integration with other technologies, and signal processing strategies. We included observational studies that applied sEMG to individuals diagnosed with ALS, with or without comparison to healthy controls, and without restrictions on publication year. The analyses included signals recorded at rest and during voluntary contractions, with or without the use of biofeedback. Most studies employed conventional or high-density surface electrodes, with sampling frequencies ranging from 500 Hz to 3000 Hz. The results showed that the primary parameters assessed were muscle fatigue, fasciculation patterns, the number of motor units (MUNE/MUNIX), motor unit firing rates, and signal complexity. These parameters demonstrated sensitivity to disease progression and may contribute to early diagnosis, phenotypic stratification, and functional monitoring of ALS. Additionally, the studies highlighted the increasing use of advanced computational approaches, such as machine learning, for feature extraction and automated classification. In conclusion, sEMG is a promising tool for functional assessment in ALS, with the potential to improve diagnostic accuracy and support new therapeutic strategies based on electrophysiological biomarkers. However, despite technological advances, the included studies displayed substantial methodological heterogeneity and limited protocol standardization. Integration with other neurophysiological modalities also remains underexplored, despite its significant clinical potential.}, } @article {pmid42332177, year = {2026}, author = {Tang, M and Fleming, E and Gu, J and Shi, H and Xu, Y and Gong, X}, title = {Trace Elements Dyshomeostasis and Toxic Metals Neurotoxicity in Neurodegenerative Diseases.}, journal = {Biological trace element research}, volume = {204}, number = {9}, pages = {7264-7299}, pmid = {42332177}, issn = {1559-0720}, support = {Grant No. SH2023078//the Zhenjiang Science and Technology Plan Project/ ; Grant No. JDYY2023009//the Medical Education Collaborative Innovation Fund of Jiangsu University/ ; Grant No. 32002235//the National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Trace Elements/metabolism ; Animals ; *Metals/toxicity ; Homeostasis ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are defined by the progressive loss of neurons through interconnected pathological mechanisms, including oxidative stress, mitochondrial dysfunction, protein aggregation, and neuroinflammation. Accumulating evidence implicates metal dyshomeostasis as a central and multifaceted contributor to these mechanisms, with roles ranging from a primary pathogenic driver in AD and PD, to a secondary amplifier of genetic pathology in HD and ALS, and as a contextual risk modifier in the presence of toxic metals. Essential trace metals such as iron, zinc, copper, manganese, selenium, iodine, and molybdenum are vital for neurotransmission, antioxidant defense, and cellular metabolism. Dysregulation of these metals disrupts redox balance, impairs proteostasis, and activates regulated cell death pathways, including ferroptosis and cuproptosis. Toxic metals, such as lead, cadmium, and mercury, exacerbate neurodegeneration by displacing essential metals, inducing oxidative injury, and promoting protein misfolding and neuroinflammation. This narrative review synthesizes mechanistic, experimental, genetic epidemiological, and clinical evidence to critically evaluate the contributions of both essential and toxic metals to neurodegeneration in AD, PD, HD, and ALS. We examine the genetic, environmental, and physiological determinants of metal homeostasis; the analytical techniques for quantifying metals in clinical samples; and clinical trial data on metal-targeted therapeutic strategies. Notably, iron chelation with deferiprone consistently reduces brain iron on neuroimaging but worsens clinical outcomes in both PD and AD, presenting a translational paradox that requires mechanistic re-evaluation. We also provide methodological recommendations for interpreting Mendelian randomization studies of metal exposures and propose translational priorities to advance metal-targeted diagnostics and therapeutics for neurodegenerative diseases.}, } @article {pmid42333562, year = {2026}, author = {Srivastava, V and Chakraborty, S and Srivastava, R}, title = {Toll-Like Receptor-Mediated Neuroinflammation and Its Role in Neurocognitive Functions.}, journal = {Current reviews in clinical and experimental pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/0127724328415188260605204430}, pmid = {42333562}, issn = {2772-4336}, abstract = {Toll-like receptors (TLRs) are a family of pattern recognition receptors that recognise both pathogen-associated and damage-associated molecular patterns. While their expression was initially believed to be restricted to immune cells, accumulating evidence now demonstrates their presence across multiple neural cell types. Due to their significant involvement in neuroinflammatory and neurodegenerative processes, TLRs have garnered growing attention for their potential contributions to neurocognitive disorders, including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and other forms of dementia. Potential treatment targets for lowering neuroinflammation and slowing the evolution of neurocognitive diseases include TLR signalling pathways, namely the MYD88-dependent and TRIF-dependent cascades. To initiate signalling, Toll-like receptors (TLRs) recruit specific adaptor molecules that activate the transcription factors NF-κB and IRFs, which regulate the induction of innate immune responses. Over the past decade, a combination of genetic, biochemical, structural, cellular, and bioinformatics approaches has been utilised to elucidate the detailed molecular mechanisms underlying TLR signalling. These studies have clarified how TLRs interact with cytosolic innate immune sensors to orchestrate effective immunological reactions. The function of different TLRs expressed in various brain immune cells and their contribution to the pathophysiology of neuroinflammation are described. This paper discusses the involvement of TLRs in autoimmune and neuroinflammatory circumstances like multiple sclerosis (MS), bacterial meningitis, viral encephalitis, stroke, Alzheimer's disease, and Parkinson's disease. It is intended for TLR biologists and immunologists studying neuroinflammation, as well as neuroscientists delving into central nervous system processes mediated by TLRs.}, } @article {pmid42333772, year = {2026}, author = {Amarni, M and Ladjel-Mendil, A and Allala, F and Cherifi, F and Bouanane-Darenfed, A and Moussaoui, H and Merzouagui, R and Ahras-Sifi, N and Laraba-Djebari, F}, title = {Thymol Attenuates Klebsiella pneumoniae Induced Lung Injury via Modulation of Peroxidase-Driven Oxidative Stress and Host-Pathogen Interactions: In Vivo and In Silico Insights.}, journal = {Journal of biochemical and molecular toxicology}, volume = {40}, number = {7}, pages = {e70997}, doi = {10.1002/jbt.70997}, pmid = {42333772}, issn = {1099-0461}, mesh = {Animals ; *Oxidative Stress/drug effects ; *Klebsiella pneumoniae ; Mice ; *Thymol/pharmacology ; *Host-Pathogen Interactions/drug effects ; *Acute Lung Injury/drug therapy/microbiology/pathology/metabolism ; *Klebsiella Infections/drug therapy/metabolism/pathology ; *Peroxidase/metabolism ; Molecular Docking Simulation ; Male ; }, abstract = {Klebsiella pneumoniae pneumonia drives excessive inflammatory and oxidative responses that culminate in acute lung injury (ALI) and impaired bacterial clearance. Effective therapies capable of restoring host-pathogen balance remain limited, particularly in the context of multidrug-resistant strains. This study investigated the therapeutic efficacy of thymol in a murine model of K. pneumoniae-induced ALI. Oral thymol (5-20 mg/kg) markedly reduced lung injury, suppressed leukocyte infiltration, improved pulmonary histoarchitecture, and significantly enhanced bacterial clearance. Thymol reshaped systemic and local immune responses by decreasing tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP), increasing interleukin-10 (IL-10), and limiting macrophage and granulocyte recruitment. Mechanistically, thymol attenuated heme peroxidase-driven oxidative stress, as evidenced by reduced myeloperoxidase (MPO) and eosinophil peroxidase (EPO) activities, decreased malondialdehyde (MDA), hydrogen peroxide (H2O2), and nitric oxide (NO), along with restoration of catalase activity and glutathione levels. Complementary in silico docking predicted stable interactions of thymol with MPO and EPO, as well as essential bacterial metabolic enzymes, including deoxy-D-xylulose-5-phosphate synthase (DXS), acetolactate synthase (ALS), and dihydrodipicolinate synthase (DHDPS). Collectively, these findings suggest that thymol may act as a multi-target bioactive compound capable of modulating host inflammatory and redox pathways while potentially impairing bacterial metabolic fitness, thereby mitigating pneumonia-associated ALI.}, } @article {pmid42333954, year = {2026}, author = {Harrison, MD and Bradsby, JE and , and Kalra, S and Bouvier, L}, title = {Thinning of the oral motor cortex is linked to impaired speech in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/21678421.2026.2688247}, pmid = {42333954}, issn = {2167-9223}, abstract = {Most individuals with amyotrophic lateral sclerosis (ALS) develop bulbar impairment as their disease progresses. The ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subscore and neurological examination of upper (UMN) and lower motor neurons (LMN) are routinely used to assess this dysfunction but have inherent limitations. Speech‑derived measures have shown promise for capturing bulbar decline with greater sensitivity, but their neurobiological correlates remain unclear. This study examined the associations between quantitative speech measures and cortical thinning in ALS. Data from the Canadian ALS Neuroimaging Consortium were analyzed. Speech measures were extracted from audio recordings of the standardized "Bamboo Passage". Cortical thickness was calculated from T1‑weighted MRI scans. General linear models first compared cortical thickness between patients with ALS and healthy controls. Associations between the speech measures and cortical thickness were then assessed within the ALS group. Patients with ALS showed cortical thinning across bilateral frontotemporal regions, with the largest clusters in the bilateral motor cortices. Reduced speaking and articulation rates were associated with thinning in both oral motor cortices. In contrast, the ALSFRS-R bulbar subscore and UMN and LMN bulbar burden showed no significant associations. Measures of pausing behavior were negatively associated with frontal cortical regions. Thinning of the oral motor cortex in ALS was linked to reduced oral motor function, supporting speaking and articulation rate as sensitive markers of bulbar motor neuron degeneration. These measures demonstrated neuroanatomical associations that the ALSFRS-R bulbar subscore and neurological examination findings did not, highlighting their potential value for monitoring bulbar dysfunction in ALS.}, } @article {pmid42334216, year = {2026}, author = {Riva, N and Schito, P and Russo, T and Ferraro, OE and Durante, G and Tettamanti, A and Riboldi, E and Domi, T and Pozzi, L and Quattrini, A and Comola, M and Agosta, F and Cremona, G and Filippi, M}, title = {Tolerability, Safety and Effectiveness of Sigh Introduction During Non-Invasive Mechanical Ventilation Cycles in Patients With Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {6}, pages = {e70660}, pmid = {42334216}, issn = {1468-1331}, support = {//AriSLA - Fondazione Italiana di ricerca per la SLA/ ; //Giovanni Marazzina Foudation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications/physiopathology ; Female ; Male ; Middle Aged ; Aged ; *Noninvasive Ventilation/methods/adverse effects ; *Respiratory Insufficiency/therapy/etiology ; Treatment Outcome ; }, abstract = {BACKGROUND: Respiratory failure is the main cause of death in Amyotrophic lateral sclerosis (ALS), in which the physiological sigh reflex is impaired due to inspiratory muscle weakness. Aim of this study is to assess the tolerability, safety, and effectiveness of adding a sigh cycle to non-invasive mechanical ventilation (NIMV) settings in ALS patients.

METHODS: In this randomized, blind-controlled proof-of concept study, 44 consecutive ALS patients with indication for NIMV were randomized to: Group I: NIMV with Sigh cycles; Group II: NIMV without Sigh. The primary outcome was the reduction in the Oxygen Desaturation Index (ODI); secondary outcomes included: Overnight Oximetry (OvOx), Arterial blood gas (ABG), and Visual Analog Scale (VAS; 0-10) scores to assess sleep quality, symptom intensity, mask interface, and NIMV tolerance. Assessments were conducted at baseline, after NIMV adaptation (T1) and at 1-month follow-up (T2).

RESULTS: The Sigh cycle was safe and well tolerated. No significant group differences were observed at T1 or T2 in the primary outcome ODI (median ΔODI: Group A:-4.2; Group B:-4.6: p = 0.54), as well as in the OvOx parameters and pO2 and pCO2 ABG values. At T2, secondary analysis showed a significant difference in HCO₃[-] in favor of the Sigh arm (ΔHCO3 [-]: -1.60 vs. 1.35 mmol/L, p = 0.042). Exploratory Cox-regression models suggested a potential independent effect of SIGH on survival.

CONCLUSIONS: Sigh is safe, well tolerated in ALS patients. Although this study did not reach the primary outcome, we also cannot rule out that sigh doesn't benefit the patient.}, } @article {pmid42334507, year = {2026}, author = {Turkmenel, N and Uskun, E}, title = {Associations influencing quality of life in caregivers of patients with amyotrophic lateral sclerosis: a stress-process model approach.}, journal = {Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation}, volume = {35}, number = {8}, pages = {}, pmid = {42334507}, issn = {1573-2649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/nursing/psychology ; *Quality of Life/psychology ; Female ; Male ; *Caregivers/psychology ; Cross-Sectional Studies ; Middle Aged ; Social Support ; *Stress, Psychological/psychology ; Aged ; Adult ; Cost of Illness ; Adaptation, Psychological ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Caring for patients with amyotrophic lateral sclerosis (ALS) involves demands that reduce caregivers' quality of life. Although caregiver burden and perceived social support was conceptualized as an independent correlate of quality of life rather than a factor operating primarily through caregiver burden. This study examined these associations within a stress-process framework in which perceived social support was conceptualized as an independent correlate rather than a buffering factor.

METHODS: This cross-sectional analytical study included 118 informal caregivers of patients with ALS. Primary stressors were defined as patient functional status (ALSFRS-R), caregiving duration, and communication difficulty. Caregiver burden (Zarit Burden Interview) was considered a secondary stressor. Physical and mental quality of life were assessed using the SF-12, and perceived social support was measured with the Multidimensional Scale of Perceived Social Support. Hierarchical regression analyses were performed to examine associations specified in the conceptual model while controlling for caregiver sociodemographic and socioeconomic variables. Additional mediation analyses were conducted to examine whether caregiver burden mediated the relationship between perceived social support and quality of life.

RESULTS: Poorer patient functional status was significantly associated with higher caregiver burden, whereas communication difficulty showed a positive but non-significant association after adjustment for caregiver characteristics. Caregiver burden showed negative associations with both physical and mental quality of life. Perceived social support remained positively associated with quality of life after adjustment for caregiver burden and contributed additional explained variance in the models. Mediation analyses showed no evidence that caregiver burden mediated the association between perceived social support and either physical or mental quality of life.

CONCLUSIONS: The findings are consistent with a stress-process framework in ALS caregiving, in which caregiver burden represents a central factor statistically associated with both caregiving stressors and quality of life, while perceived social support shows an independent association with quality of life. These findings suggest that both caregiver burden and perceived psychosocial resources may be relevant to caregiver well-being, although causal and intervention-related implications require further investigation.}, } @article {pmid42334646, year = {2026}, author = {Totuk, O and Sahin, S}, title = {Behavioral variant frontotemporal dementia associated with a NEK1 missense variant: exploring a possible phenotypic association.}, journal = {Neurogenetics}, volume = {27}, number = {1}, pages = {}, pmid = {42334646}, issn = {1364-6753}, mesh = {Humans ; *Frontotemporal Dementia/genetics/pathology ; *NIMA-Related Kinase 1/genetics ; Male ; Aged ; *Mutation, Missense ; Phenotype ; Amyotrophic Lateral Sclerosis/genetics ; Exome Sequencing ; }, abstract = {NEK1 variants are recognized genetic contributors to amyotrophic lateral sclerosis (ALS) and have occasionally been reported within the ALS-frontotemporal dementia (FTD) spectrum. However, their association with isolated behavioral variant frontotemporal dementia (bvFTD) remains unclear. Here, we describe a 69-year-old man who developed progressive behavioral symptoms beginning in his early 60s. Cognitive evaluation demonstrated reduced verbal fluency with relative preservation of memory functions. Structural and functional neuroimaging demonstrated right-predominant frontotemporal atrophy and hypometabolism. Genetic testing for common FTD-associated genes (MAPT, GRN, and C9orf72) was negative. Whole-exome sequencing identified a heterozygous NEK1 c.899T > C (p.Ile300Thr) missense variant, currently classified as a variant of uncertain significance. This observation raises the possibility that NEK1-associated disease may extend beyond ALS or ALS-FTD phenotypes and may include isolated bvFTD presentations. However, further genetic and functional studies are required to clarify the clinical significance of this variant.}, } @article {pmid42335378, year = {2026}, author = {Rahimi, K and Gupta, A and Malekzadeh, K and Zerze, GH}, title = {Stabilizing Effect of Neighboring Disordered RGG Domain on the Folded State of FUS-RRM.}, journal = {The journal of physical chemistry. B}, volume = {130}, number = {27}, pages = {6773-6781}, doi = {10.1021/acs.jpcb.6c02052}, pmid = {42335378}, issn = {1520-5207}, mesh = {*RNA-Binding Protein FUS/chemistry/metabolism ; Molecular Dynamics Simulation ; Protein Folding ; Protein Domains ; Humans ; RNA Recognition Motif ; Protein Stability ; }, abstract = {Fused in Sarcoma (FUS) is an RNA-binding protein essential for RNA processing, yet its RNA-recognition motif (RRM) is prone to irreversible unfolding and amyloid aggregation, which is associated with the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although the isolated RRM is experimentally known to adopt a stable folded structure, its response to long-range interdomain interactions remains poorly understood. In this work, we address this gap by performing rare-event sampling atomistic molecular dynamics simulations of two systems: isolated RRM and RRM with the flanking RGG sequence using multithermal-multiumbrella on-the-fly probability enhanced sampling (MM-OPES). These simulations allow us to characterize the folding landscape of FUS RRM and examine the specific interactions between the RRM and the adjacent RGG region and how they affect the stability of RRM. Our findings reveal that the disordered RGG segment enhances the stability of the folded RRM by forming stabilizing intramolecular contacts that wrap around the domain. This stabilization is driven by increased fractions of the α1 helix, β2, β3, and the KK loop through a network of targeted multivalent contacts between the RGG and RRM residues. This work reveals how a disordered region stabilizes a folded RNA-binding domain, underscoring the importance of disordered-ordered interdomain coupling in shaping the folding landscape of FUS RRM. These results suggest that disruption of such interactions could destabilize the RRM fold and may contribute to misfolding-prone states relevant to FUS dysfunction.}, } @article {pmid42335819, year = {2026}, author = {Cheng, Y and Tian, T and Song, D and Ma, Y and Bi, Z and Zhang, X and Zhang, L and Li, Y and Huang, H}, title = {Bionic nanozyme arrays for selective identifying and discriminating sulfonylurea herbicides via recognition site mimicry.}, journal = {Journal of hazardous materials}, volume = {514}, number = {}, pages = {142800}, doi = {10.1016/j.jhazmat.2026.142800}, pmid = {42335819}, issn = {1873-3336}, mesh = {*Herbicides/analysis/chemistry ; *Sulfonylurea Compounds/analysis/chemistry ; Acetolactate Synthase/chemistry/metabolism ; *Nanostructures/chemistry ; Colorimetry ; Molecular Mimicry ; Thiamine Pyrophosphate/chemistry ; }, abstract = {Sulfonylurea herbicides (SUs) are widely used in agriculture owing to their high herbicidal efficacy and low mammalian toxicity. However, their persistence results in residues that pose potential risks to the environment and human health, making it essential to develop rapid and accurate detection techniques for these herbicides. Herein, we designed bionic nanozymes inspired by the structure of acetolactate synthase (ALS), the primary target enzyme of SUs in plants. Using the ALS cofactor thiamine diphosphate and key binding amino acids (arginine, proline, and tryptophan) as ligands, we synthesized bionic nanozymes that exhibited excellent peroxidase-like activity. SUs significantly enhanced the activity of the bionic nanozymes, and the degree of enhancement varied among different SUs. In contrast, organophosphate pesticides (OPs), carbamate pesticides (CPs), and other tested pesticides did not induce such enhancement. Therefore, we constructed a six-channel colorimetric sensor array and achieved 100% accurate discrimination of five SUs across a concentration range of 1-100 µg/mL. Furthermore, the SUs in the four real grain samples and the blind sample were also accurately distinguished by the array. This study not only provides an efficient method for rapid detection of SUs, but also opens new avenues for the bionic design of nanozymes aimed at the precise identification of specific pesticide molecules in complex matrices.}, } @article {pmid42335888, year = {2026}, author = {Gautier, O and Blum, JA and Nguyen, TP and Cao, S and Klemm, S and Yamakawa, M and Huh, D and Hurt, JA and Sinnott-Armstrong, N and Zeng, Y and Davis, CO and Bombosch, J and Liu, C and Encarnacion, LN and Guttenplan, KA and Chen, D and Kathiria, A and Zhao, L and Moore, S and Meng, A and Ong, K and Cleveland, DW and Ravits, J and Rexach, JE and Greenleaf, WJ and Gitler, AD}, title = {An emergent disease-associated motor neuron state precedes cell death in ALS.}, journal = {Cell}, volume = {189}, number = {16}, pages = {5044-5064.e12}, pmid = {42335888}, issn = {1097-4172}, support = {R01 AG075802/AG/NIA NIH HHS/United States ; R01 NS128028/NS/NINDS NIH HHS/United States ; RF1 NS128800/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; S10 RR025518/RR/NCRR NIH HHS/United States ; RM1 HG010461/HG/NHGRI NIH HHS/United States ; R35 NS137159/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Animals ; *Motor Neurons/metabolism/pathology ; Humans ; Mice ; Cell Death ; Spinal Cord/pathology/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Transcriptome/genetics ; Female ; Transcription Factors/metabolism ; Male ; }, abstract = {To define molecular determinants of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons together with spatial transcriptomics from the SOD1-G93A mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a distinct cell state we named "disease-associated motor neurons" (DMs). We identified transcription factor networks that govern how healthy cells transition into DMs and those associated with motor neuron subtype-selective vulnerability. Upregulation of DM-associated transcription factors in human motor neurons induced key features of DMs, demonstrating an active regulatory component. Human ALS spinal cord single-nucleus RNA sequencing data demonstrated conservation of the DM signature in alpha motor neurons, and human orthologs of regions differentially accessible in SOD1-G93A mouse motor neurons were enriched for ALS genetic risk variants. Together, these findings establish a conserved, genetically linked motor neuron signature in ALS.}, } @article {pmid42336241, year = {2026}, author = {Stavroulakis, T and White, S and Musson, L and Kime, J and , and McDermott, C}, title = {A multi-centre prospective evaluation of post-gastrostomy outcomes in patients with amyotrophic lateral sclerosis.}, journal = {Clinical nutrition ESPEN}, volume = {75}, number = {}, pages = {103360}, doi = {10.1016/j.clnesp.2026.103360}, pmid = {42336241}, issn = {2405-4577}, mesh = {Humans ; *Gastrostomy/adverse effects ; Prospective Studies ; *Amyotrophic Lateral Sclerosis/surgery/physiopathology/therapy ; Weight Loss ; Female ; Nutritional Status ; Male ; Treatment Outcome ; Middle Aged ; Aged ; Energy Intake ; Enteral Nutrition ; United Kingdom ; Logistic Models ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) often causes significant nutritional decline and weight loss, which negatively impacting prognosis. Gastrostomy is a standard intervention to provide long-term nutritional support, yet its efficacy in stabilising nutritional status and preventing post-procedure weight loss is uncertain. This study explored factors influencing weight change post-gastrostomy.

METHODS: This multicentre, prospective observational cohort study was conducted across 17 UK sites and involved longitudinal assessments at placement (M0) and at three (M3), six (M6), and nine (M9) months. Data collection included nutritional, clinical and functional parameters. The primary outcome was the percentage weight change between M0 and M3. Secondary outcomes included nutritional intake, functional decline, and survival. Statistical analysis employed hierarchical logistic regression to identify independent predictors of weight change post-gastrostomy.

RESULTS: Successful gastrostomy was performed in 155 included participants, of which 64 had complete M0 and M3 weight data. Mean percentage weight change from M0 to M3 was -3.3% (SD 7.4%), with 51.6% losing >1 kg in the first three months (p < 0.01). Amongst those with available dietary data weight loss (n = 21/43) was associated with lower mean daily energy (1620 kcal vs 2022 kcal, p = 0.017) and protein intake (64 g vs 77 g, p = 0.048) compared to those who maintained stable or gained weight (n = 22/43). At M3, 50% (n = 29/58) used a combination of oral and gastrostomy intake, 27.6% (n = 16/58) used gastrostomy only, and 22.4% (13/58) were not using the gastrostomy. Based on available data for total daily expenditure energy expenditure (TDEE) calculation (n = 39), 61.5% did not meet predicted total daily energy expenditure. Participants who lost weight (>1 kg) post-gastrostomy had shorter median survival (270 days) compared to the weight stable/gain group (p = 0.018). Hierarchical logistic regression suggested that mean daily water intake may potentially be an independent predictor of weight maintenance or gain, though this finding should be considered exploratory due to the limitations of our study (OR = 1.003, p = 0.040).

DISCUSSION: Despite gastrostomy placement, over half of participants in our final analytical cohort continued to lose weight. For a smaller subset of participants, for whom nutritional intake were available, this was potentially due to insufficient energy, macronutrient, and fluid intake, alongside disease-specific catabolism. As post-gastrostomy weight loss negatively impacts survival, these findings highlight a need for proactive, tailored, and ongoing nutritional support and monitoring, to optimise post-gastrostomy outcomes and survival in ALS.}, } @article {pmid42336630, year = {2026}, author = {Bosó Pérez, R and Littlejohn, J and Willis, M and Lewis, R and Mitchell, KR}, title = {Young people's sexual wellbeing: a systematic review of qualitative studies.}, journal = {BMJ sexual & reproductive health}, volume = {}, number = {}, pages = {}, doi = {10.1136/bmjsrh-2025-203161}, pmid = {42336630}, issn = {2515-2009}, abstract = {BACKGROUND: Young people's adverse sexual experiences contribute to a significant global mental health burden and detract from their quality of life. Sexual wellbeing connects sexual and mental health and can offer a novel perspective on drivers and impacts of young people's sexual behaviour. It is a promising means through which to shift public health focus from risk to aspects of sex relevant to broader wellbeing.

METHODS: This systematic review aimed to characterise sexual wellbeing for adolescents and emerging adults (aged 16-24 years). We searched four databases for peer-reviewed qualitative literature on young people's accounts relevant to sexual wellbeing published between 1988 and 2025. We intensity sampled and thematically synthesised studies against Mitchell et al's Sexual Wellbeing Conceptual Framework. PROSPERO registration: CRD42022315593.

RESULTS: We thematically synthesised 93 papers, representing 3152 participants across 25 countries. Our synthesis characterises youth sexual wellbeing as feeling: congruence between one's sexual thoughts, feelings, values, behaviours and emerging identities; driven by curiosity or desire; capable of advocating for one's wants and boundaries; able to authentically express oneself; deserving of care, respect and support; and expectant of a positive sexual future. Women, sexual and gender minorities, sexual violence survivors, youth with disabilities or health conditions, and those in deprived or sexually conservative communities report additional barriers to wellbeing.

CONCLUSIONS: This first-ever review of youth sexual wellbeing underscores its significance during this life stage, and outlines similarities and differences compared with adults. The findings demand a stronger focus on young people's priorities for sexual wellbeing to support their healthy development.}, } @article {pmid42337904, year = {2026}, author = {Morimoto, S and Okano, H}, title = {Are patient-derived models of amyotrophic lateral sclerosis a game changer for novel drug discovery?.}, journal = {Expert opinion on drug discovery}, volume = {21}, number = {7}, pages = {753-760}, doi = {10.1080/17460441.2026.2689746}, pmid = {42337904}, issn = {1746-045X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; *Drug Discovery/methods ; Animals ; *Drug Development/methods ; Motor Neurons/metabolism ; *Models, Biological ; Phenotype ; Reproducibility of Results ; Induced Pluripotent Stem Cells ; }, abstract = {INTRODUCTION: ALS drug discovery has long depended on model systems that incompletely capture human disease heterogeneity, aging, and TDP-43 proteinopathy. Patient-derived platforms have therefore emerged as increasingly important human-relevant complements to animal and molecular models.

AREAS COVERED: This Critical Perspective examines when patient-derived ALS models genuinely change therapeutic decision-making rather than merely add mechanistic insight. The authors then propose a heuristic framework based on disease-relevant phenotype recapitulation, capture of patient-to-patient heterogeneity, and generation of findings that influence therapeutic prioritization or clinical translation. Furthermore, the authors evaluate iPSC-derived motor neurons, directly reprogrammed neurons, glial co-cultures, organoids, neural networks, and organ-chip systems against these conditions, while also addressing aging fidelity, reproducibility, upper motor neuron modeling, and regulatory implementation.

EXPERT OPINION: Patient-derived models are not yet standalone decision-grade tools for ALS drug development. Their present value lies in functioning as a human-biology filter for target discovery, reverse translation, biomarker development, and patient stratification when used within rigorous, standardized, and clinically linked workflows. The strongest current evidence supports proof-of-principle rather than generalized predictive validity.}, } @article {pmid42338703, year = {2026}, author = {Mndolo, NCM and Baluwa, MA and Yeboa, NK and Kazembe, A and Chirwa, E}, title = {Acceptability of Modified Early Obstetric Warning Systems Among Midwives in Malawi; An Exploratory Qualitative Study.}, journal = {International journal of women's health}, volume = {18}, number = {}, pages = {605608}, pmid = {42338703}, issn = {1179-1411}, abstract = {BACKGROUND: The Modified Early Obstetric Warning systems (MEOWS) has received global endorsement as a key strategy for reducing maternal mortality over the past decade. However, evidence on MEOWS acceptability among midwives in sub-Saharan Africa, including Malawi, remains limited. Understanding how potential users perceive a newly introduced intervention is required to assess acceptability prior to implementation.

PURPOSE: To explore the acceptability of MEOWS among midwives using Sekhon's Theoretical Framework of Acceptability.

METHODS: We conducted an exploratory qualitative study between June and August 2025. Using purposive sampling, midwives across practicing, supervisory and policy making levels from Bwaila Hospital and Kamuzu Central Hospital were recruited for in-depth interviews. Data were analyzed using a deductive thematic approach with a priori coding guided by Sekhon et al's Theoretical Framework of Acceptability (TFA).

RESULTS: Thirty participants were interviewed. MEOWS was found acceptable across the seven domains of Sekhon et al's TFA. Participants reported that MEOWS could guide clinical judgement and ease the workload. However, inadequate stationery and equipment were identified as key sources of burden that may threaten sustained use.

CONCLUSION: This study demonstrated that MEOWS was broadly acceptable among the various levels of midwives. The study identified inadequate stationery and equipment as potential barriers. Addressing these challenges may sustain MEOWS adaptation and implementation,enable early identification of maternal critical illness and reduction of maternal deaths.}, } @article {pmid42338888, year = {2026}, author = {Sanchis-Sanchis, CE and Sancho-Cantus, D and Sanchis-Sanchis, E and Privado, J and Roig, FJ and Cuerda-Ballester, M and Bargues-Navarro, G and Cubero-Plazas, L and Martínez Bolós, P and Cárdenas Salazar, RG and Ortí, JER}, title = {Interplay between B vitamins, fiber, and Bacteroides abundance: a predictive model for anxiety and depression in amyotrophic lateral sclerosis.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1815390}, pmid = {42338888}, issn = {1664-302X}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease that not only affects motor function but is also associated with gastrointestinal and emotional disturbances. Recent research highlights the potential role of gut microbiota and diet in modulating these symptoms, suggesting a complex interaction between nutrition, intestinal health, and presence of anxiety and depression in ALS patients. This study aims to investigate the relationship between dietary intake, gut microbiota composition, and presence of anxiety and depression in patients with amyotrophic lateral sclerosis (ALS).

METHODOLOGY: A cross-sectional study conducted with a sample of 48 patients with bulbar-onset or spinal-onset ALS from different regions of Spain. Dietary intake was assessed through 24-h records and food frequency questionnaires, while anxiety and depression were evaluated using validated scales that formed a latent factor called emotional distress. Stool consistency was assessed following the Bristol Stool Scale and the abundance of bacterial microbiota was quantified.

RESULTS: Confirmatory factor analysis identified a nutritional factor composed of vitamins B1, B2, B9, C, and fiber, revealing a significant inverse association with anxiety and depression levels. The predictive model revealed both direct and indirect effects of this factor on presence of anxiety and depression, mediated by Bacteroides abundance and stool consistency.

CONCLUSION: This model explained 19% of the variance in psychological distress. Our findings suggest that a diet rich in B vitamins, C vitamin and fiber may help improve emotional well-being in patients with ALS, highlighting the importance of nutritional strategies, as well as the role of Bacteroides related to stool consistency in patients with ALS.}, } @article {pmid42339807, year = {2026}, author = {Jewer, M and Snyder, J and Caulfield, T and Zenone, M}, title = {The connection between unproven stem cell-based interventions and complementary and alternative medicine in crowdfunding for Amyotrophic Lateral Sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2685157}, pmid = {42339807}, issn = {2167-9223}, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disease associated with substantial medical and non‑medical costs. In the absence of effective treatments, patients and families may turn to crowdfunding to finance care, including unproven stem cell‑based interventions (SCBIs) that are frequently marketed directly to consumers.

OBJECTIVE: conduct content analysis of English‑language GoFundMe campaigns seeking funds for SCBIs for ALS to better understand the market for unproven direct‑to‑consumer SCBIs.

METHODS: 247 campaigns were identified, and their data were collected and analyzed to determine the characteristics of the campaigns, campaigners, and their desired treatments.

RESULTS: ALS crowdfunding campaigns that collectively requested over $16 million USD. In addition to SCBIs, campaigns frequently requested funding for international travel to access these treatments. Campaigners express relatively high confidence that stem cell treatments would slow disease progression, improve symptoms, or, in some cases, cure or reverse ALS; conclusions that exceed the scientific evidence. Confidence in SCBIs is linked to requests for other alternative therapies and unsupported causes of ALS, supporting an emerging link between proponents of alternative medicines and unproven stem cell therapies.

CONCLUSION: Crowdfunding for unproven stem cell interventions exposes ALS patients and donors to financial risk, misinformation, and medical exploitation. The frequent linkage between SCBIs, CAM, and exaggerated claims highlights gaps in regulation, patient protection, and access to credible treatment options. These findings underscore the need for stronger oversight of direct‑to‑consumer stem cell markets and greater support for patients facing catastrophic illness.}, } @article {pmid42341041, year = {2026}, author = {Liu, D and Li, Y and Huang, S and Xu, Y and Sun, L and Li, W and O'Kane, CJ and Rubinsztein, DC and Lu, B and Li, S}, title = {IRE1 regulates the proteostasis of TDP-43/TARDBP in ALS/FTD through ribosome-associated quality control.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {26}, pages = {e2610001123}, pmid = {42341041}, issn = {1091-6490}, support = {32270825//MOST | National Natural Science Foundation of China (NSFC)/ ; 2023HWYQ-013//| Natural Science Foundation of Shandong Province ()/ ; tsqn202306046//Taishan Scholar Project of Shandong Province/ ; R01AG089752 R01NS084412 and R37NS083417//HHS | National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; *Protein Serine-Threonine Kinases/metabolism/genetics ; Humans ; *Frontotemporal Dementia/metabolism/genetics/pathology ; Mice ; *Ribosomes/metabolism ; *Proteostasis ; *Endoribonucleases/metabolism/genetics ; Proteotoxic Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders characterized by motor neuron degeneration, leading to muscle weakness, atrophy, and cognitive impairments. A defining pathological hallmark of ALS/FTD is the cytosolic mislocalization and accumulation of TAR DNA-binding protein 43 (TDP-43), highlighting its critical role in ALS pathogenesis. However, the molecular mechanisms underlying TDP-43 proteostasis remain poorly understood. Through a genetic screening approach, we identify inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum-resident transmembrane protein, as a potent suppressor of TDP-43 protein levels. Furthermore, we show that ribosome-associated quality control (RQC) factors play a crucial role in regulating TDP-43 proteostasis and cellular toxicity. Activation of the RQC pathway prevents excessive accumulation of TDP-43 and associated toxicity. Mechanistically, our findings suggest that IRE1 regulates TDP-43 protein level by promoting the degradation of aberrant TDP-43 translation product through the RQC pathway. IRE1 acts canonically to enhance the transcription of the RQC core component Clbn/NEMF and noncanonically to physically interact with Clbn/NEMF, thereby ameliorating TDP-43-induced proteotoxicity. Moreover, ectopic expression or pharmacological activation of IRE1 alleviates TDP-43 pathology and restores cognitive function in the TDP-43 A315T ALS mouse models. Collectively, our study identifies a role for IRE1 in the translational quality control of TDP-43 and establishes its potential as a therapeutic target for ALS/FTD.}, } @article {pmid42341118, year = {2026}, author = {Copley, KE and Dykstra, MM and Miller, MR and Linsenmeier, M and Lai, L and Wang, Y and Chang, YW and Barmada, SJ and Shorter, J}, title = {Isoform-specific steric zippers drive aberrant assembly and mislocalization of shortened TDP-43.}, journal = {Science advances}, volume = {12}, number = {26}, pages = {eady0256}, pmid = {42341118}, issn = {2375-2548}, support = {F31 NS134123/NS/NINDS NIH HHS/United States ; UL1 TR001878/TR/NCATS NIH HHS/United States ; R01 NS148028/NS/NINDS NIH HHS/United States ; T32 GM132039/GM/NIGMS NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; R35 GM156396/GM/NIGMS NIH HHS/United States ; RF1 AG090910/AG/NIA NIH HHS/United States ; R37 NS113943/NS/NINDS NIH HHS/United States ; F31 NS129101/NS/NINDS NIH HHS/United States ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry/genetics ; Protein Isoforms/metabolism/chemistry/genetics ; Humans ; Animals ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Protein Domains ; Protein Transport ; }, abstract = {Prion-like domain (PrLD)-mediated aggregation and concomitant dysfunction of the essential RNA-binding protein transactive response (TAR) DNA-binding protein of 43 kilodaltons (TDP-43) is a common feature of multiple debilitating neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). However, shortened TDP-43 (sTDP-43) splice isoforms where the PrLD is largely replaced by an 18-residue carboxyl-terminal tail also contribute to ALS pathophysiology and are enriched in motor neurons. Curiously, despite lacking most of the PrLD, sTDP-43 exhibits pronounced insolubility in cells and tissue of patients with ALS. Here, we establish that the short, isoform-specific carboxyl-terminal tail of sTDP-43 confers high aggregation propensity, which is encoded by two clusters of steric zippers, and can be mitigated by short RNA chaperones. Disrupting these zippers enhances sTDP-43 solubility at the pure protein level and in neurons. Notably, these steric zippers, rather than a predicted nuclear export signal in the carboxyl-terminal tail, drive cytoplasmic mislocalization and aggregation of sTDP-43 in neurons. Thus, we define the sequence-encoded determinants of aberrant sTDP-43 assembly and provide mechanistic insights into sTDP-43 disease pathology.}, } @article {pmid42341897, year = {2026}, author = {Hopkins, EL and Williams, PA}, title = {Programmed axon degeneration gene variants in human disease.}, journal = {Experimental neurology}, volume = {404}, number = {}, pages = {115891}, doi = {10.1016/j.expneurol.2026.115891}, pmid = {42341897}, issn = {1090-2430}, mesh = {Humans ; *Nicotinamide-Nucleotide Adenylyltransferase/genetics ; *Armadillo Domain Proteins/genetics ; Animals ; Cytoskeletal Proteins/genetics ; *Wallerian Degeneration/genetics/pathology ; *Axons/pathology ; *Cytokines/genetics ; *Genetic Variation/genetics ; }, abstract = {BACKGROUND: Programmed axon degeneration (PAD; also known as Wallerian degeneration) is a conserved pathway controlling axon breakdown following injury or metabolic stress. PAD is driven by the depletion of nicotinamide adenine dinucleotide (NAD) through loss of the pro-survival enzyme NMNAT2 and activation of the pro-degenerative NADase SARM1. Recent genetic studies have identified pathogenic variants in PAD pathway enzymes associated with severe neurodegenerative phenotypes.

MAIN BODY: Pathogenic variants in NAMPT, NMNAT1, NMNAT2, and SARM1 have been identified and will be discussed in this review. NAMPT variants cause sensory and motor neuropathy with neurodevelopmental symptoms. NMNAT1 variants are well-characterized causes of Leber Congenital Amaurosis type 9, while NMNAT2 variants result in peripheral neuropathies with childhood onset. SARM1 gain-of-function variants with constitutively active NADase activity are enriched in amyotrophic lateral sclerosis patients.

CONCLUSION: These findings demonstrate that maintaining proper NAD homeostasis is crucial for axon survival, and disruption through genetic variants leads to distinct neurodegenerative outcomes. Understanding these rare variants provides insight into PAD mechanisms and supports development of broad-spectrum neuroprotective therapies targeting this pathway. Current therapeutic approaches include SARM1 inhibitors in clinical trials, gene therapy, and NAD precursor supplementation, offering hope for treating multiple neurodegenerative diseases.}, } @article {pmid42342533, year = {2026}, author = {Brodribb, L and Camden, P and Dharmadasa, T and Blizzard, C}, title = {Amyotrophic lateral sclerosis: A rare but aggressive adult-onset disease.}, journal = {Trends in molecular medicine}, volume = {32}, number = {9}, pages = {954-955}, doi = {10.1016/j.molmed.2026.06.001}, pmid = {42342533}, issn = {1471-499X}, } @article {pmid42343420, year = {2026}, author = {Morisaki, Y and Nomura, N and Ohshima, M and Matsuda, M and Komine, O and Okuda, T and Yamanaka, K and Misawa, H}, title = {Immune checkpoint LAG-3 governs stage-dependent and disease-associated microglial modules in ALS model mice.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {42343420}, issn = {1742-2094}, support = {JP26K10309//Japan Society for the Promotion of Science/ ; JP22K06634//Japan Society for the Promotion of Science/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics/immunology ; *Microglia/metabolism/pathology/immunology ; Mice ; Lymphocyte Activation Gene 3 Protein ; Mice, Transgenic ; Disease Models, Animal ; *Antigens, CD/genetics/metabolism ; Spinal Cord/pathology/metabolism ; Mice, Inbred C57BL ; }, abstract = {Immune checkpoint molecules, inhibitory receptors originally characterized in T cell biology, have recently emerged as regulators of microglial function in neurodegeneration, yet their roles in amyotrophic lateral sclerosis (ALS) remain unexplored. Here, we investigated LAG-3, an inhibitory immune checkpoint receptor, in microglial regulation during ALS pathogenesis using SOD1[G93A] mice. LAG-3 expression was progressively upregulated in spinal cord microglia during disease progression, and LAG-3-high microglia exhibited a disease-associated microglia (DAM) transcriptional signature. Genetic deletion of LAG-3 produced a biphasic phenotype, with accelerated disease onset but significantly prolonged disease duration. LAG-3 deficiency enhanced inflammatory microglial responses at the early disease stage, whereas at the late stage it suppressed inflammatory signaling while selectively preserving phagocytic effector gene expression, demonstrating that LAG-3 dissociates the inflammatory and phagocytic modules within the DAM program in a stage-dependent manner. These transcriptional changes translated into enhanced phagocytic capacity in primary microglia and amelioration of the spinal cord environment through suppression of inflammatory pathways and restoration of oxidative phosphorylation. Our findings identify LAG-3 as a stage-dependent regulator of microglial functional states in ALS and support the concept that immune checkpoint molecules constitute a class of module-level regulators of microglial function in neurodegeneration.}, } @article {pmid42343520, year = {2026}, author = {Sun, L and Chen, J and Wu, Y and Bian, S and Wang, Q and Ha, L}, title = {[Effect of electroacupuncture at "Zusanli" (ST36) on TREM2-mediated microglial activation in amyotrophic lateral sclerosis mice].}, journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion}, volume = {46}, number = {6}, pages = {948-955}, doi = {10.13703/j.0255-2930.20250113-k0001}, pmid = {42343520}, issn = {0255-2930}, mesh = {Animals ; *Electroacupuncture ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism/immunology ; Male ; Mice ; *Microglia/metabolism/immunology ; *Receptors, Immunologic/genetics/metabolism/immunology ; Humans ; *Membrane Glycoproteins/genetics/metabolism/immunology ; *Acupuncture Points ; Disease Models, Animal ; Mice, Transgenic ; Interleukin-4/genetics/metabolism ; Spinal Cord/metabolism ; Interleukin-1beta/genetics/metabolism ; }, abstract = {OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli" (ST36) on amyotrophic lateral sclerosis (ALS) in mouse models based on myeloid cell trigger receptor 2 (TREM2)-mediated microglial activation.

METHODS: Thirty-six SPF-grade male human mutant superoxide dismutase 1 (SOD1-G93A) transgenic mice were divided into a model group, an EA group, and a drug group, 12 mice in each group. Besides, 12 wide-type littermates were collected as a control group. In the EA group, EA was performed at the "Zusanli" (ST36), with an intermittent wave, at the frequency of 15 Hz, and for 10 min each intervention; once every other day, 3 interventions a week and for 4 continuous weeks. In the drug group, the intragastric administration of riluzole solution was given at 8 mg/kg, once daily, for 4 continuous weeks. After intervention completion, behavioral assessment of mice was conducted using rotarod test and wire hang test. With HE and Nissl staining adopted, morphology of motor neurons in the anterior horn of the spinal cord was observed. Immunofluorescence was used to detect the fluorescence intensity of TREM2 in the anterior horn of spinal cord. Western blot analysis was performed to measure the protein expression of interleukin (IL)-1β, γ interferon (IFN-γ), IL-4 and IL-10 in spinal cord tissue. Flow cytometry was used to analyze the proportion of CD86[+] and CD206[+] in spinal cord monocyte suspension.

RESULTS: Compared with the control group, in the model group, motor neurons in the anterior horn of the spinal cord exhibited disordered arrangement; accompanied by nuclear pyknosis and cytoplasmic shrinkage; the latency to fall in the rotarod test and the cut-off time in the wire hang test were shortened, fluorescence intensity of TREM2 in the spinal anterior horn, the protein expression of IL-1β, IFN-γ, IL-4, and IL-10, and the proportion of CD86[+] and CD206[+] in spinal cord tissue increased(P<0.01). When compared with the model group, in the EA and drug groups, motor neurons in the anterior horn of the spinal cord were arranged regularly; nuclear pyknosis and chromatolysis were attenuated, and the structural integrity of neurons was improved; the latency to fall and the the cut-off time were prolonged, fluorescence intensity of TREM2 in the spinal anterior horn was reduced, the protein expression of IL-1β and IFN-γ decreased, and that of IL-4, and IL-10 increased in the spinal cord tissue; the proportion of CD86[+] in spinal cord tissue was reduced and that of CD206[+] elevated(P<0.01, P<0.05). Compared with the drug group, the EA group showed the increase of protein expression of IL-1β,and the decrease of IL-4, IL-10 in the spinal cord tissue and the proportion of CD206[+] (P<0.05).

CONCLUSION: Electroacupuncture at "Zusanli" (ST36) exhibits a certain improvements in motor function of SOD1-G93A transgenic mice. The underlying mechanism may be related to attenuating neuroinflammation via the modulation of microglial activation mediated by TREM2.}, } @article {pmid42343570, year = {2026}, author = {Ellis, BCS and Avila, AS and Huang, WP and John, SJ and Bonsall, S and Hodgson, RE and Kumar, V and Nolan, M and West, RJH and Campbell, SG and De Vos, KJ and Lagier-Tourenne, C and Robin Highley, J and Cooper-Knock, J and Shelkovnikova, TA}, title = {STMN2 protein depletion via translation deficits and stress granules in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag222}, pmid = {42343570}, issn = {1460-2156}, abstract = {STMN2 is an abundant neurospecific protein dysregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously reported that cellular stress can lead to STMN2 loss due to TDP-43 nuclear condensation. Here, using human and murine neuronal cell models, multiple pharmacological tools, in situ single-molecule analysis of translation and RNA localisation, and longitudinal analysis of neuronal fitness/survival, we establish TDP-43-independent mechanisms of STMN2 depletion under stress. We find that human STMN2 protein level is extremely labile under acute high-magnitude stress. Early in stress, STMN2 is suppressed via activated proteasomal degradation, phosphorylation and translation repression by stress granules, independently of TDP-43 loss of function in splicing. We further show that STMN2 protein level is highly sensitive to chronic translation deficits, such as those elicited by prolonged low-grade stress. We find that low pre-stress STMN2 sensitises neuronal cells to stress-induced apoptosis, whereas moderately increased STMN2 is protective under stress. Finally, we demonstrate that STMN2 mRNA is upregulated in non-TDP ALS (ALS-FUS) models, which may compensate for translation/stress granule defects in this disease subtype. Consistent with the compensation hypothesis, STMN2 mRNA is also upregulated in the relatively spared (cortex), but not severely affected (spinal cord), CNS regions in ALS-TDP. In conclusion, our study implicates two common denominators in neurodegeneration - dysregulation of translation and stress granules - in STMN2 depletion, independent of TDP-43 loss of function. It also describes an RNA-based compensatory mechanism in ALS underling the unique vulnerability of neurons with developing TDP-43 pathology.}, } @article {pmid42344043, year = {2026}, author = {Mantell, JE and Masvawure, TB and Thomas, NA and George, G and Howard, AA and Strauss, M and Ndagije, F and Lethoko, M and Low, A and Hirsch-Moverman, Y}, title = {Health system support and strengthening for cross-border HIV services: key informants' perspectives on testing and linkage for Lesotho-South Africa migrant workers.}, journal = {BMJ public health}, volume = {4}, number = {2}, pages = {e003284}, pmid = {42344043}, issn = {2753-4294}, abstract = {INTRODUCTION: Cross-border migrants, especially those in destination countries with high HIV burden and high population mobility, often face structural challenges in accessing HIV testing and linkage-to-care. There is limited research on the most effective HIV testing and linkage-to-care strategies tailored to cross-border migrants. We conducted a qualitative study to explore barriers and facilitators to HIV testing and linkage-to-care among Lesotho-South Africa cross-border migrant workers.

METHODS: We conducted in-depth interviews with 15 purposively selected stakeholders from Lesotho who interfaced with migrants, namely administrative and programme staff from the Ministry of Health, non-governmental organisations, community counsellors and testers and migrant advocates. We captured diverse perspectives on barriers and facilitators to HIV services among migrant workers. Template analysis, a rapid form of thematic analysis, was used to synthesise the data. We applied Chee et al's health systems framework differentiating health system support and health system strengthening to analyse our findings and guide actionable programme and policy strategies.

RESULTS: Participants recommended strategies that both support the health system by improving service provision and strengthen the health system by implementing structural and policy-level changes. Support strategies included expanding migrant-centred access to HIV testing and prevention services, reducing structural and economic barriers to service utilisation and strengthening community-based services. Strengthening strategies included cross-border collaboration and harmonised referral systems for continuity of care, expanding differentiated HIV care models for mobile populations, integrating HIV services into general healthcare, establishing workplace HIV policies for migrant workers and flexible cross-border funding for migrant health.

CONCLUSIONS: Chee et al's framework allows policymakers and programme implementers to more intentionally distinguish and plan for solutions that merely support versus actually strengthen health systems. Strengthening approaches, in contrast to supporting ones, have the potential to transform HIV services for migrants by ensuring continuity of services in both home and destination venues butrequire greater commitment and action from politicians, policymakers, funders and advocacy groups to implement.}, } @article {pmid42345500, year = {2026}, author = {Drążyk, M and Pyc, Z and Pietrzyk, SJ and Gajda-Janiak, A and Godziszewski, F and Pioterek, O and Tulski, M and Mazurek, M and Domagała, ZA}, title = {Formaldehyde neurotoxicity: Effects on the mammalian brain, cognitive function, and neurodegenerative risk. A scoping review.}, journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University}, volume = {35}, number = {6}, pages = {1093-1107}, doi = {10.17219/acem/209617}, pmid = {42345500}, issn = {1899-5276}, mesh = {Animals ; Humans ; *Brain/drug effects/physiopathology ; *Cognition/drug effects ; *Formaldehyde/toxicity ; *Neurodegenerative Diseases/chemically induced ; *Neurotoxicity Syndromes/etiology ; Occupational Exposure/adverse effects ; }, abstract = {Aqueous formaldehyde (FA) solution, known as formalin, is currently the primary agent used for preserving tissue samples and anatomical specimens. Formaldehyde is widely used in laboratories and the chemical industry; it also occurs as an air pollutant and endogenous cellular metabolite. The potential carcinogenic effects of formalin on the respiratory tract are well documented. A less recognized consequence of occupational exposure to FA is its detrimental effect on the central nervous system (CNS) and brain function. A literature review was conducted to investigate the effects of FA on the brain. Five databases were searched: PubMed, Web of Science (WoS), Embase, ScienceDirect, and Google Scholar. To describe the effects of FA exposure and endogenous FA generation, 35 relevant publications were collected and analyzed. The literature review demonstrated that inhalation is the most common route of FA exposure. Several studies have shown that FA may cause hippocampal damage, disrupt melatonin secretion, and induce a wide range of cognitive disorders with varying characteristics and severity. These disorders include memory impairment, disturbances in balance and spatial orientation, learning difficulties, sleep disturbances, impaired judgment, and prolonged reaction times to stimuli. Increased endogenous FA concentration has also been associated with a higher risk of neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis. The literature analysis demonstrated the high neurotoxicity of FA, which may lead to numerous neuropsychiatric disorders. We aim to draw attention to the risks associated with the routine use of formalin, particularly among anatomists and pathologists, and to encourage consideration of less harmful alternative preservation agents.}, } @article {pmid42345595, year = {2026}, author = {de Sousa, SF and Marques, MDCMP and da Silva Amaral, GMM}, title = {Factors Influencing the Maintenance of Advanced Life Support Competencies Among Critical Care Professionals: A Scoping Review.}, journal = {Nursing in critical care}, volume = {31}, number = {4}, pages = {e70545}, pmid = {42345595}, issn = {1478-5153}, support = {UID/06291/2025//Fundação para a Ciência e a Tecnologia/ ; }, mesh = {Humans ; *Clinical Competence/standards ; *Critical Care/standards ; *Advanced Cardiac Life Support/standards ; }, abstract = {BACKGROUND: Advanced life support (ALS) competence may deteriorate within months after certification, but what supports ongoing competence in critical care remains unclear.

AIM: To map factors influencing maintenance of ALS competence among critical care professionals working in critical care settings.

STUDY DESIGN: Scoping review conducted in accordance with Joanna Briggs Institute guidance and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. MEDLINE, CINAHL and the Cochrane Library were searched (from February to March 2025). We included peer-reviewed and grey sources from hospital-based critical care settings that assessed ALS competencies over time. Data were synthesised using inductive thematic analysis.

RESULTS: Twenty-five sources were included (19 peer-reviewed, 6 grey). Factors were mapped to three domains. Educational factors were most frequently reported and centred on simulation-based rehearsal, structured feedback and debriefing and spaced refreshers delivered in brief, frequent sessions. Institutional determinants related to protected training time, access to resources, standardised roles and content and monitoring through audit and feedback. Individual determinants included clinical exposure and experience, perceived preparedness and self-confidence, stress and cognitive load, engagement in ongoing learning and non-technical behaviours. Outcomes were largely simulation-based or self-reported, and longer-term durability was inconsistently assessed.

CONCLUSIONS: Maintenance of ALS competence appears to require coordinated educational and organisational supports; longitudinal evaluations with explicit definitions and validated outcomes are needed.

Critical care services may strengthen ALS competence maintenance by embedding recurrent, context-aligned rehearsal with feedback, supported by protected training time, accessible training infrastructure and ongoing performance monitoring.

REVIEW REGISTRATION: The review protocol was prospectively registered on the Open Science Framework https://doi.org/10.17605/OSF.IO/PEQJH.}, } @article {pmid42346159, year = {2026}, author = {Verde, EM and Secco, V and Ghezzi, A and Mandrioli, J and Carra, S}, title = {Correction: Verde et al. Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses. Cells 2025, 14, 680.}, journal = {Cells}, volume = {15}, number = {12}, pages = {}, pmid = {42346159}, issn = {2073-4409}, abstract = {In order to facilitate readers' better understanding, some language descriptions and grammar as well as the layout of some chapters have been modified [...].}, } @article {pmid42347120, year = {2026}, author = {Alves Ferreira, JM and Tukaiev, S and Giannouli, V}, title = {RNA-Binding Proteins in Ageing and Age-Related Disease.}, journal = {Neurology international}, volume = {18}, number = {6}, pages = {}, pmid = {42347120}, issn = {2035-8385}, abstract = {RNA-binding proteins (RBPs) are essential regulators of all aspects of RNA metabolism, including splicing, stability, localisation, translation, and degradation. Through their ability to recognise specific cis-elements in target transcripts, often via RNA-recognition motifs or other conserved domains, RBPs enable rapid cellular adaptation to stress and maintain proteostasis, particularly in post-mitotic tissues with limited transcriptional flexibility. Accumulating evidence positions RBPs as both modulators and drivers of the molecular hallmarks of ageing, including genomic instability, loss of proteostasis, mitochondrial dysfunction, cellular senescence, and chronic inflammation. This review synthesises peer-reviewed studies on the multifaceted roles of RNA-binding proteins in organismal ageing and age-related diseases. Key themes include the tissue- and age-dependent changes in expression of turnover and translation regulatory RBPs such as HuR (ELAVL1), AUF1 (HNRNPD), TIA-1, and tristetraprolin (ZFP36), which alter the stability of mRNAs encoding cell-cycle regulators, pro-inflammatory cytokines, and stress-response proteins. Systematic downregulation of core splicing factors, including PTBP1 and several heterogeneous nuclear ribonucleoproteins, drives widespread senescence-associated splicing alterations in pathways governing cell division, autophagy, DNA repair, and mitochondrial function, suggesting a causal contribution to the senescent phenotype. Prion-like RBPs such as TDP-43 and FUS exhibit age-dependent mislocalisation, nuclear depletion, and cytoplasmic aggregation, contributing to splicing defects, impaired RNA transport, and neurodegeneration in amyotrophic lateral sclerosis, frontotemporal dementia, and limbic-predominant age-related TDP-43 encephalopathy. Interactions between RBPs and non-coding RNAs, together with disrupted liquid-liquid phase separation dynamics, further exacerbate age-related decline. By integrating mechanistic studies from cellular and animal models with observations in human cohorts, this review underscores RBPs as central nodes linking multiple ageing hallmarks and highlights their potential as biomarkers and therapeutic targets to promote healthy ageing. Limitations of current models and priorities for future translational research are discussed.}, } @article {pmid42347662, year = {2026}, author = {Breuer, A and Raeder, V and Pernice, HF and Boesl, F and Prüss, H and Audebert, H and Hahn, K and Franke, C}, title = {Fasciculations Following COVID-19 Vaccination-A Case Series of Ten Patients.}, journal = {Vaccines}, volume = {14}, number = {6}, pages = {}, pmid = {42347662}, issn = {2076-393X}, abstract = {Introduction: Vaccination against COVID-19 has been crucial in controlling the pandemic. While side effects are typically mild, rare neurological complications have been reported. This is a case series of ten patients who reported of persistent fasciculations after COVID-19 vaccination. Methods: We describe the clinical presentation and diagnostic work-up of ten patients with new-onset fasciculations in temporal proximity to COVID-19 vaccination. Patients with prior SARS-CoV-2 infection or known alternative causes of fasciculations were excluded. Routine clinical data, including neurological examination, laboratory results, and electrophysiology (electromyography and nerve conduction studies), were analyzed. Results: Ten patients (5 male, 5 female; mean age 42.4 years) reported fasciculations beginning within 6 h to 13 days post-vaccination and persisting for 2-12 months at the time of presentation. Fasciculations were accompanied by additional symptoms such as paresthesia and fatigue. Laboratory results were mostly unremarkable; two patients had positive myositis antibodies without clinical correlates. Electrophysiology was unremarkable in six patients, while fasciculation potentials were detected in four patients. Nine were diagnosed with probable benign fasciculation syndrome (BFS), and one met diagnostic criteria for amyotrophic lateral sclerosis (ALS). Discussion: In this small, retrospective case series, most cases of post-vaccination fasciculations were benign and compatible with BFS. Whether BFS onset was causally linked to vaccination or due to a nocebo effect remains unclear. One patient was diagnosed with ALS, though a causal link remains speculative given the study's limitations and rarity of similar reports. Larger, prospective studies are needed to validate these observations and explore underlying pathophysiological mechanisms.}, } @article {pmid42347833, year = {2026}, author = {Wesenberg, J and Matthies, P and Schwiecker, K and Bittner, V and Hamzic, S and Vielhaber, S and Radakovic, R}, title = {Validation of the German version of the Dimensional Apathy Scale (G-DAS): Application in amyotrophic lateral sclerosis.}, journal = {Journal of neuropsychology}, volume = {20}, number = {3}, pages = {702-712}, pmid = {42347833}, issn = {1748-6653}, support = {//Center for Behavioral Brain Sciences/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/diagnosis ; *Apathy ; Female ; Male ; Middle Aged ; Aged ; Psychometrics ; Reproducibility of Results ; *Psychiatric Status Rating Scales ; Germany ; Executive Function ; }, abstract = {Apathy is a common behavioural impairment in neurodegenerative conditions and is conceptualized within the Dimensional Apathy Framework as comprising Executive, Emotional and Initiation subtypes. The Dimensional Apathy Scale (DAS) is widely used to assess these domains, yet no validated German version has been available. This study aimed to translate and validate the German DAS (G-DAS) in control participants (HC) and to characterize apathy profiles in German-speaking people with amyotrophic lateral sclerosis (pwALS). Seventy-seven HC and 32 pwALS completed self-rated and caregiver-rated measures of apathy, depression, disinhibition and executive dysfunction. The G-DAS was translated using a multi-round back-translation procedure. Psychometric validation was undertaken in the HC cohort. A subsample of HC matched to pwALS on age and sex was used for between-group comparisons and for deriving exploratory reference thresholds. The G-DAS demonstrated good to high internal consistency across subscales (α = .76-.85) and total scores (self-rated: α = .88; caregiver-rated: α = .86). Convergent validity was supported by significant correlations with the Apathy Evaluation Scale and Frontal Systems Behavior subscales, particularly for the Initiation and Executive subscales. Divergent validity was evidenced by the absence of associations with anxiety and depression. PwALS showed significantly higher Executive and Initiation apathy compared with matched HC, whereas Emotional apathy did not differ. Exploratory threshold scores derived from matched HC indicated that up to 47% of pwALS exhibited clinically elevated Initiation apathy. The G-DAS is a reliable and valid German-language measure of multidimensional apathy. It effectively captures the characteristic Executive and Initiation apathy profile in ALS, supporting its clinical and research utility.}, } @article {pmid42348198, year = {2026}, author = {Walter, KL}, title = {Amyotrophic Lateral Sclerosis.}, journal = {JAMA}, volume = {336}, number = {6}, pages = {528}, doi = {10.1001/jama.2026.9755}, pmid = {42348198}, issn = {1538-3598}, } @article {pmid42349418, year = {2026}, author = {Heffner, CM and Starling, GP and Straker, LC and Hawes, PC and Isaacs, AM and Carlton, JG}, title = {The ALS- and FTD-associated proteins annexin A11 and CHMP2B act sequentially in plasma membrane repair.}, journal = {Developmental cell}, volume = {61}, number = {7}, pages = {1487-1503.e7}, pmid = {42349418}, issn = {1878-1551}, mesh = {Humans ; *Endosomal Sorting Complexes Required for Transport/metabolism/genetics ; *Cell Membrane/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Annexins/metabolism/genetics ; *Frontotemporal Dementia/metabolism/genetics/pathology ; Mutation/genetics ; }, abstract = {Maintenance of plasma membrane integrity is essential for compartmentalization of the cytosol and for cellular viability. Upon membrane damage, several factors including endosomal sorting complex required for transport-III (ESCRT-III) proteins, annexins, stress granules, lipids, and membrane fusion proteins are mobilized to orchestrate membrane repair. However, whether these factors operate independently or act together is unclear. Here, using human cell lines, we expose temporal differences and interdependencies in the recruitment of ESCRT-III and annexin proteins to sites of plasma membrane damage. We show that annexin proteins are recruited immediately and form a plug at the damage site, restricting membrane permeability. We find that ESCRT-III assembles later and acts to release plug-containing damaged membranes from the cell. Further, frontotemporal dementia (FTD)- and amyotrophic lateral sclerosis (ALS)-associated mutations in the ESCRT-III protein, CHMP2B, and the annexin protein, ANXA11, compromise plasma membrane repair, suggesting that defects in this process may contribute to these pathologies. These data present an integrated "sealing and healing" model of membrane repair.}, } @article {pmid42349421, year = {2026}, author = {Aubry, L and Korolchuk, VI and Sarkar, S}, title = {Rewiring ALS by modulating the autophagy receptor SQSTM1.}, journal = {Stem cell reports}, volume = {21}, number = {7}, pages = {102976}, pmid = {42349421}, issn = {2213-6711}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *Sequestosome-1 Protein/metabolism/genetics ; Humans ; Zebrafish ; *Autophagy ; Motor Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism/cytology ; }, abstract = {Drug screening for genetic disorders is limited by difficulty identifying disease-relevant phenotypes. In this issue, Roussange et al., show that reverse phenotypic mapping could uncover therapeutic gene expression signatures. Using this approach, they identified prazosin, which increases SQSTM1 expression and rescues disease phenotypes in iPSC-derived motor neurons and zebrafish model of amyotrophic lateral sclerosis with SQSTM1 haploinsufficiency.}, } @article {pmid42349423, year = {2026}, author = {Roussange, F and Gide, J and Tournois, J and Cailleret, M and Boland, A and Battail, C and Deleuze, JF and Polvèche, H and Auboeuf, D and Brockmann, K and Kabashi, E and Marian, A and El Kassar, L and Blondel, S and Salachas, F and Bruneteau, G and Peschanski, M and Martinat, C and Baghdoyan, S}, title = {Integrative analysis of drug-gene signatures in human pluripotent stem cells reveals prazosin as a novel SQSTM1 regulator for ALS therapeutics.}, journal = {Stem cell reports}, volume = {21}, number = {7}, pages = {102977}, pmid = {42349423}, issn = {2213-6711}, mesh = {Humans ; *Sequestosome-1 Protein/genetics/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism ; *Pluripotent Stem Cells/metabolism/drug effects ; Zebrafish ; Induced Pluripotent Stem Cells/metabolism/drug effects/cytology ; Motor Neurons/metabolism/drug effects ; Gene Expression Regulation/drug effects ; Gene Expression Profiling ; Cell Line ; Fibroblasts/metabolism/drug effects ; }, abstract = {The classical paradigm of drug screening often faces significant limitations due to the challenges associated with identifying molecular or cellular read-outs that are relevant to specific genetic diseases. To remedy this, an alternative approach of reverse phenotypic mapping was tested: Compounds were evaluated for their effects on gene expression and alternative splicing in a healthy cell model, and the resulting data were matched to molecular signatures of diseases. A subset of 50 drugs was tested on mesenchymal stem cells derived from a human pluripotent stem cell line. Over half of the compounds altered gene expression, many affecting pathways linked to monogenic diseases. One hit, increased SQSTM1 expression induced by prazosin, was further validated in FTD/ALS type 3 models caused by SQSTM1 haploinsufficiency, including patient-derived fibroblasts, SQSTM1-depleted hiPSC-derived motor neurons, and a zebrafish model. Extending this paradigm could involve testing diverse cell types and larger drug libraries.}, } @article {pmid42350166, year = {2026}, author = {Tikkinen, KAO and Tondroanamag, F and Parpia, S and Guyatt, GH and Violette, PD and , }, title = {Reply to Vallée M, Stangl FP, Wagenlehner F et al's Letter to the Editor re: Tikkinen KAO, Najafabadi BT, Hajebrahimi S, et al. A Multicenter Randomized Controlled Trial of Antimicrobial Prophylaxis to Prevent Urinary Tract Infections After Shockwave Lithotripsy for Urolithiasis: The APPEAL Trial. Eur Urol 2025;88(6):543-51.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2026.06.008}, pmid = {42350166}, issn = {1873-7560}, } @article {pmid42350373, year = {2026}, author = {Casterton, R and Martinez-Cotrina, A and Barnard, J and Wycherley, E and Hu, Y and Anderson, R and Janel, S and Byun, J and Houghton, O and Solomon, DA and Alcalde, J and Lafont, F and Ruepp, MD and Hirth, F and Tummers, B and Cho, YY and De Nicola, G and Mizielinska, S and Fanto, M}, title = {Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42350373}, issn = {2041-1723}, support = {ARUK-PG2019B-008//Alzheimer's Research UK (ARUK)/ ; }, mesh = {Proteotoxic Stress ; Animals ; Humans ; Cell Death ; Neurons/metabolism/pathology ; Lamin Type B/metabolism/genetics ; Phosphorylation ; Alzheimer Disease/pathology/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Nuclear Lamina/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; Mice ; Frontotemporal Dementia/pathology/metabolism ; Cell Nucleus/metabolism ; }, abstract = {Neurodegenerative diseases are frequently associated with proteotoxic stress linked to disease specific proteins. The autophagy-lysosome system provides essential control of proteotoxic stress and its failure can lead to initiation of apoptosis. However, in aging and neurodegenerative diseases apoptosis is insufficient to account for all neuronal death, and several different cell death types have been reported in these contexts. Here we show that karyoptosis, a distinct form of cell death, can be induced by proteotoxic stress and then develops through nuclear degeneration and cellular expulsion of nuclear material. We establish that karyoptosis is regulated by the p38 kinase signalling pathway, which controls stability of the nuclear lamina protein LaminB1 via direct phosphorylation. We demonstrate that karyoptosis affects neurons in models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) pathology. Finally, we identify karyoptotic features in post-mortem frontal cortex of FTD and Alzheimer's disease (AD) patients. Together these findings characterise a form of cell death directly linked to proteotoxic stress and nuclear lamina stability that is associated with neurodegeneration.}, } @article {pmid42350385, year = {2026}, author = {Wan, F and He, J and Ma, H and PiresFerreira, D and Kumanan, V and Lee, JS and Chen, X and He, R and Su, Q and Gallagher, TL and Zhu, S and Cabrera, GT and Zhao, L and Shen, J and Gruntman, A and Brown, RH and Xu, Z and Gao, G and Xie, J}, title = {Intravenous administration of an engineered AAV9-gene-silencing vector suppresses human SOD1 and extends survival in an ALS mouse model.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42350385}, issn = {2041-1723}, support = {R01 NS118145/NS/NINDS NIH HHS/United States ; AL240123//United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; *Dependovirus/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Humans ; Disease Models, Animal ; *Genetic Vectors/administration & dosage/genetics ; Mice ; Motor Neurons/metabolism/pathology ; *Genetic Therapy/methods ; *Gene Silencing ; Mice, Transgenic ; Administration, Intravenous ; MicroRNAs/genetics ; Neuromuscular Junction/metabolism ; Female ; Gene Therapy Agents ; Male ; }, abstract = {Adeno-associated virus (AAV)-mediated gene silencing offers a promising strategy for achieving durable therapeutic effects with a single administration. Mutations in the human superoxide dismutase 1 (hSOD1) gene, inherited in an autosomal dominant manner, lead to motor neuron degeneration in amyotrophic lateral sclerosis (ALS)-a fatal neurodegenerative disease with no effective treatment. In this study, we employed AAV9 to deliver to the SOD1[G93A] ALS mouse model artificial microRNAs targeting SOD1, embedded in dual miR-33 scaffolds driven by the promoter of the human survival motor neuron 1 (hSMN1) gene. A single intravenous injection achieved widespread and sustained suppression of SOD1, preserved α-motor neurons, maintained neuromuscular junctions (NMJs), and improved muscle function. These benefits are translated into significantly improved respiratory function, motor performance, and survival. Therapeutic efficacy was observed both when the treatment was administered pre-symptomatically and during symptomatic stages. Compared with previous AAV-based interventions, the survival benefit achieved in this IV delivery approach is unprecedented, supporting its potential for clinical translation in SOD1-linked ALS and other central nervous system (CNS) diseases caused by gain-of-toxicity gene mutations.}, } @article {pmid42351201, year = {2026}, author = {Dominguez, GTY and Alarcan, H and Peralta, V and Labroche, N and Corcia, P and Marcel, P and Blasco, H}, title = {Learning a distance for the clustering of patients with amyotrophic lateral sclerosis.}, journal = {BioData mining}, volume = {19}, number = {1}, pages = {}, pmid = {42351201}, issn = {1756-0381}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with median survival of 3-5 years. Patient responses to treatments vary widely, highlighting the need for personalized care. Clustering patients based on disease progression could improve prognosis, guide clinical decision-making, and optimize clinical trial design. This study aimed to identify robust ALS patient clusters using ALS Functional Rating Scale-Revised (ALSFRS-R) scores and to determine diagnostic parameters predictive of cluster membership, enabling earlier stratification and targeted management.

METHODS: Data from the Tours ALS center registry (April 1997-October 2023) were analyzed; after preprocessing, 353 patients monitored every three months between January 2004 and July 2023 with ALSFRS-R, clinical, biological, and demographic data were retained. After preprocessing to handle missing or aberrant data, a weakly supervised approach labeled patient pairs based on their ALSFRS-R sequences. These labels were used to train a classifier to learn a distance for off-the-shelf clustering algorithms. Multiple configurations were tested, varying clustering algorithms, dimensionality reduction method, and number of clusters. Random Forest (RF) model predicted cluster membership from diagnostic parameters. Optimal clustering was selected using silhouette score, validated with Kaplan-Meier survival analysis. Stability and robustness were assessed with the Adjusted Rand Index (ARI) and silhouette score respectively. Predictive performance was evaluated using specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV). Diagnostic parameters associated with clusters were identified using Kruskal-Wallis and chi-squared tests for continuous and categorical variables.

RESULTS: Three clusters (n = 139, 121, 93) were identified, demonstrating strong separation (silhouette ≈ 0.6) and high stability of results (ARI ≈ 0.7). Survival differed significantly among clusters: over 50% of patients in the third cluster survived beyond 50 months, compared to less than 25% in the other clusters. Thirteen diagnostic parameters-including ALSFRS-R subscores, IgG levels, albumin quotient, and time to diagnosis-were key predictors of cluster membership. Cluster prediction achieved specificity and NPV ≈ 0.75, with close sensitivity and PPV compared to state-of-the-art methods.

CONCLUSION: This framework successfully stratifies ALS patients into clinically meaningful clusters, revealing underlying disease heterogeneity and providing strong prognostic insight. Such classification can facilitate personalized care, guide therapeutic decisions, and inform the design of targeted interventions to improve outcomes.

CLINICAL TRIAL NUMBER: Not applicable.}, } @article {pmid42351263, year = {2026}, author = {Riggio, F and Fenili, G and Caporossi, D and Paronetto, MP}, title = {Dynamic integration of skeletal muscle signals via extracellular vesicles in motor neuron diseases.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42351263}, issn = {2051-5960}, support = {PNRR-MR1-2022-12376821//Ministero della Salute/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Motor Neuron Disease/metabolism/pathology ; *Muscle, Skeletal/metabolism ; Animals ; *Motor Neurons/metabolism ; Signal Transduction/physiology ; Muscular Atrophy, Spinal/metabolism ; }, abstract = {Extracellular vesicles (EVs) are heterogenous lipid bilayer-enclosed particles secreted by virtually all cell types. They encapsulate a diverse array of bioactive molecules, including proteins, lipids, nucleic acids, and metabolites, which can be transferred to recipient cells, thereby modulating their function and phenotype. In recent years, skeletal muscle-derived EVs (SkM-EVs) have emerged as key players in the bidirectional communication between skeletal muscle and motor neurons, contributing to the establishment and maintenance of neuromuscular homeostasis. Disruptions in this intercellular signalling have been implicated in the pathophysiology of motor neuron diseases (MNDs) such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). In these contexts, SkM-EVs may contribute to disease progression by delivering pathogenic cargo, including misfolded proteins and aberrant RNAs, to motor neurons. A comprehensive understanding of SkM-EV biology, particularly their roles in neuromuscular communication, could offer critical insights into disease mechanisms and identify novel opportunities for biomarker discovery and therapeutic intervention. This review synthesizes current knowledge on the functional roles of SkM-EVs in motor neuron health and disease and evaluates their potential as diagnostic tools and therapeutic vectors in the context of MNDs.}, } @article {pmid42351313, year = {2026}, author = {Brenner, D and Ponomarenko, A and Petrut, I and Beyrle, S and Contardo, M and Loss, I and Radke, C and Frank, J and Zimmer, E and Schlesner, M and Achenbach, P and Scheveneels, W and Aly, A and Nazlican, H and Hesebeck-Brinkmann, J and Oeckl, P and Müller, K and Siebert, R and Böckers, T and van Eijk, K and Veldink, J and Kleger, A and Mulaw, M and Andersen, PM and Forsberg, K and Weishaupt, JH and Loghmani, SB and Grehl, T and van Damme, P and Weis, J and Catanese, A}, title = {A rare missense variant impacting NEK1 kinase function is associated with ALS.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42351313}, issn = {2051-5960}, mesh = {*NIMA-Related Kinase 1/genetics/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Mutation, Missense/genetics ; Female ; Motor Neurons/pathology/metabolism ; Male ; Pedigree ; Animals ; }, abstract = {Heterozygous truncating loss-of-function (LoF) variants in NEK1 are a known cause of amyotrophic lateral sclerosis (ALS). NEK1 encodes the pleiotropic serine/threonine kinase NIMA-related kinase 1, and prior in vitro studies have implicated kinase dysfunction as the principal pathogenic mechanism underlying NEK1-associated ALS. However, bona fide pathogenic missense variants causally linked to ALS have not previously been reported, leaving this hypothesis unconfirmed. Here, we identify a rare NEK1 missense variant, p.N598S, that co-segregates with disease in a familial ALS pedigree and is enriched in European ALS cohorts. This variant exhibits normal protein expression levels, indicating a functional rather than quantitative defect. Using isogenic human motor neurons, we directly compared the effects of p.N598S with those of the ALS-associated truncating variant p.R812* to delineate disease mechanisms. The p.N598S variant induced pathological phenotypes consistent with NEK1 haploinsufficiency, including increased susceptibility to DNA damage, increased apoptosis, ciliary dysmorphia, and nucleocytoplasmic translocation of TDP-43. Importantly, p.N598S impaired NEK1 kinase activity, and pharmacological inhibition of NEK1 recapitulated the cellular phenotypes observed in both p.N598S- and p.R812*-mutant motor neurons. Collectively, these findings provide strong genetic and functional evidence for a disease-causing role of NEK1 kinase disruption in NEK1-ALS. Our findings provide immediate diagnostic and therapeutic implications, particularly for the functional interpretation of missense variants of uncertain significance and the development of targeted treatment strategies.}, } @article {pmid42352309, year = {2026}, author = {Morciano, G and Gorgoglione, R and Porcelli, V and Ahmed, A and Scarcia, P and Vozza, A and Lasorsa, FM and Fiermonte, G and Palmieri, L}, title = {Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.}, journal = {Biomolecules}, volume = {16}, number = {6}, pages = {}, pmid = {42352309}, issn = {2218-273X}, support = {2020RRJP5L//Ministry of Universities and Research/ ; 2022ZY7ATN//Ministry of Universities and Research/ ; GR-2019-12369862//Italian Ministry of Health/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; *Mitochondrial Dynamics ; *Mitochondria/metabolism ; Animals ; *Mitochondrial Proteins/metabolism ; Energy Metabolism ; Mitochondrial Membrane Transport Proteins/metabolism ; }, abstract = {Neurodegenerative diseases are increasingly recognized as disorders of due to disrupted cellular homeostasis, with mitochondrial dysfunction playing a central and early role in disease progression. This review explores the intricate relationship between mitochondrial function and neuronal health, emphasizing the pivotal role of the solute carrier family 25 (SLC25) transporters in maintaining mitochondrial homeostasis. We provide a comprehensive overview of mitochondrial biology in the central nervous system, including energy metabolism, calcium signaling, redox regulation, organelle interactions and mitochondrial dynamics. We delve into the SLC25 transporter family, highlighting their transport mechanisms, substrates and roles in brain metabolism and neuroprotection. SLC25 on one hand and proteins involved in the regulation of mitochondrial morphology and calcium signaling on the other hand are two sides of the same coin influencing each other. A critical analysis follows, examining how mitochondrial dysfunction contributes to mitochondrial abnormalities in a spectrum of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, ALS and rare mitochondrial encephalopathies. Finally, we assess emerging therapeutic strategies targeting mitochondrial pathways and SLC25 function, including metabolic modulation, gene therapies, antioxidants and pharmacological agents. This review underscores mitochondria and the SLC25 transporters as promising targets for disease-modifying interventions in neurodegeneration and raises key questions about the causality between mitochondrial failure and neuronal death.}, } @article {pmid42352358, year = {2026}, author = {Lee, BC and Hwang, JJ and Tsai, HJ}, title = {Extracellular Pgk1 or Its Derived Short Peptide Interacted with Membrane-Associated Enolase 2 Receptor: A Potential Therapy for ALS Motor Neuron Degeneration.}, journal = {Biomolecules}, volume = {16}, number = {6}, pages = {}, pmid = {42352358}, issn = {2218-273X}, support = {NSTC-114-2313-B-030-001//National Science and Technology Council/ ; F630410//USA FJCU Alumni Foundation/ ; CPL-202508003//Collaborative Research Project between FJUH and FJU/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; Humans ; *Phosphopyruvate Hydratase/metabolism ; Animals ; *Phosphoglycerate Kinase/metabolism ; *Motor Neurons/metabolism/pathology/drug effects ; *Peptides/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) remains an intractable motor neuron (MN) disease with a growing patient population and few effective treatments. Here, we review how extracellular phosphoglycerate kinase 1 (ePgk1) improves neurite outgrowth of MNs (NOMN) and axonal growth, both in vitro and in vivo. Our group first elucidated a novel non-canonical function of ePgk1 as a cross-tissue mediator between nerve and muscle tissues. We then discovered that neural membranous Enolase 2 (Eno2) serves as a receptor of ligand ePgk1 and that ePgk1-Eno2 interaction suppresses the Rac1-GTP/p-Pak1-T423/p-P38-T180/pMK2-T334/p-Limk1-S323 axis, reducing p-Cofilin and promoting NOMN and axonal growth, finally suggesting that the 419th aspartic acid residue of Eno2 mediates this interaction. In a crucial preclinical step, we truncated two short 16-amino-acid derivatives from Pgk1, FD-1/-2, each mediating neuroprotection comparable to that of full-length 417-amino-acid Pgk1 in ALS animal models, in terms of improvements of innervated neuromuscular junction, MN cell bodies, motor performance, and endpoint prolongation. In this context, we also discuss the opposite function driven by Eno1-plasminogen interaction and by Eno2-ePgk1 interaction; the latter results in unfavorable for tumorigenesis. Unlike intracellular Pgk1 roles, ePgk1 is an extracellular factor with anti-angiogenic properties, further positioning ePgk1 and its FD-1/-2 as promising protein/peptide drugs for ALS treatment.}, } @article {pmid42352620, year = {2026}, author = {De Luca, E and Saba, A and Bertarini, L and Brusini, A and Artioli, G and Dellafiore, F}, title = {Spiritual Care Needs and Challenges Among Caregivers and Families of People with Neurodegenerative Diseases in Palliative and End-of-Life Care: A Scoping Review.}, journal = {Brain sciences}, volume = {16}, number = {6}, pages = {}, pmid = {42352620}, issn = {2076-3425}, abstract = {Background/Objectives: Spirituality is increasingly recognised as a core dimension of holistic and palliative care. Neurodegenerative diseases such as dementia, amyotrophic lateral sclerosis and Parkinson's disease involve prolonged trajectories of loss, uncertainty and relational change, which may heighten spiritual and existential needs for patients, particularly among those involved in caregiving, such as family caregivers and, to a lesser extent, healthcare professionals. However, evidence on how spirituality is understood, experienced and addressed within neurodegenerative palliative care remains fragmented and conceptually heterogeneous. This scoping review aimed to map the literature on caregivers' spiritual needs and challenges. Methods: A scoping review was conducted in accordance with the Joanna Briggs Institute (JBI) methodology for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for Scoping Reviews (PRISMA ScR). Searches were conducted across PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), APA PsycINFO, and Scopus, with no date or geographical restrictions. Grey literature was searched through Google Scholar and relevant organisational and policy sources in the field of palliative care and spirituality. Reference list screening of included studies and relevant reviews was also conducted. Quantitative, qualitative, and mixed methods studies published in English or Italian were included. Results: Twenty-four studies published between 2007 and 2025 were included. Findings were organised into three interconnected domains: spiritual needs, spiritual processes and spiritual care. Spirituality emerged as a dynamic, relational and context-dependent dimension of caregiving, encompassing meaning, identity, connection and coping with vulnerability and loss. Spiritual needs and processes were widely described, while spiritual care was inconsistently recognised within healthcare systems. Conceptual ambiguity, under-representation of end-of-life dementia and cultural imbalances were evident. The evidence predominantly focused on family caregivers, with limited representation of healthcare professionals. Conclusions: This scoping review highlights a persistent gap between caregivers' lived spiritual experiences and system-level responses in neurodegenerative palliative care in caregiving contexts globally. The findings support integrated, caregiver-inclusive and culturally responsive approaches to spiritual care.}, } @article {pmid42352907, year = {2026}, author = {Scrivo, A and Bernardino, L and Consiglio, A}, title = {The Dual Role of Glial Extracellular Vesicles in Neurodegeneration: Insights from iPSC-Based Models.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, pmid = {42352907}, issn = {1422-0067}, support = {2023 BP 00242//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Neuroglia/metabolism/pathology ; Animals ; Blood-Brain Barrier/metabolism ; Cell Communication ; }, abstract = {Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication in the brain, with glial cell-derived EVs increasingly recognized for their roles in maintaining brain homeostasis and contributing to the progression of neurodegenerative diseases. By transferring a diverse cargo of bioactive molecules, including proteins, RNAs, and organelles, EVs influence recipient cell behavior and overall brain function. In neurodegenerative conditions, glial EVs can either propagate pathogenic signals or deliver neuroprotective and regenerative cues, depending on their cellular origin and molecular composition. This context-dependent heterogeneity highlights the need for physiologically relevant human models to investigate EVs biology. Human induced pluripotent stem cell (iPSC)-derived glial models provide a disease-relevant platform, as they recapitulate key pathological features of Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). When further integrated with brain organoid platforms, these iPSC-based systems enable the generation of three-dimensional environments that closely resemble in vivo EVs dynamics. Importantly, glial EVs can modulate cellular pathways involved in neuronal survival and function. Indeed, their potential to interact with and, under specific experimental conditions, traverse the blood-brain barrier (BBB) has contributed to growing interest in their application for biomarker discovery and therapeutic development. Engineered and patient-specific EVs derived from iPSCs are emerging as promising tools for targeted, cell type-specific, therapeutic approaches, although their clinical applicability still requires further validation. This review discusses the emerging evidence supporting the dual role of iPSC-derived glial EVs in health and disease, underscores the translational potential of iPSC-based platforms for mechanistic studies, and outlines their promise as precision medicine tools for diagnostics and therapy.}, } @article {pmid42353064, year = {2026}, author = {Reedich, EJ and Chen, YT and Imhoff-Manuel, R and Li, D and Manuel, M}, title = {Chronic Diazepam Reveals Excessive Homeostatic Gain in SOD1[G93A] Mouse Spinal Motoneurons.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, pmid = {42353064}, issn = {1422-0067}, support = {1R01NS110953-05/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/drug effects/metabolism/physiology ; *Diazepam/pharmacology ; Mice ; *Homeostasis/drug effects ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism/physiopathology/pathology ; *Spinal Cord/drug effects/metabolism ; *Superoxide Dismutase-1/genetics ; Mice, Transgenic ; Action Potentials/drug effects ; Disease Models, Animal ; Synaptic Transmission/drug effects ; }, abstract = {Motoneurons are under strong pressure to maintain stable motor output throughout an individual life, through homeostatic regulation of their electrical properties. Dysregulated spinal motoneuron excitability has long been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Recent work in SOD1[G93A] mice suggests that the homeostatic response of motoneurons becomes dysregulated as cellular processes are disrupted by the disease, causing fluctuations in motoneuron electrical properties. Yet, few studies directly test whether ALS motoneurons respond differently than wild-type motoneurons to a common chronic perturbation. Here, we used in vivo electrophysiology to test whether motoneurons from pre-symptomatic SOD1[G93A] mice modulate excitability differently than wild-type motoneurons in response to the same homeostatic perturbation: chronic inhibition exerted by the benzodiazepine diazepam. Using linear mixed-effects statistical models, we assessed whether diazepam treatment differentially modulated passive properties, firing behavior, spike properties, and/or synaptic inputs in SOD1[G93A] versus wild-type motoneurons. We identified a significant genotype × treatment interaction effect selectively for properties related to passive membrane integration and spike initiation, including membrane time constant, peak input resistance, and recruitment current. In contrast, firing gain, spike waveform characteristics, and synaptic inputs were largely unaffected. These findings indicate that sustained inhibitory perturbation selectively triggered overactive intrinsic compensatory mechanisms in SOD1[G93A] motoneurons rather than inducing widespread changes in firing or synaptic transmission. Together, our results provide direct evidence for over-active homeostatic control of motoneuron excitability and support a view of motoneuron dysfunction in ALS as a problem of altered feedback regulation rather than simply hyper- or hypo-excitability.}, } @article {pmid42353079, year = {2026}, author = {Romano, G and Klima, R and Feiguin, F}, title = {Loss of TDP-43 Drives Innate Immune Activation Through Relish in Drosophila.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, pmid = {42353079}, issn = {1422-0067}, mesh = {Animals ; *Drosophila Proteins/genetics/metabolism/immunology ; *DNA-Binding Proteins/genetics/metabolism ; *Immunity, Innate/genetics ; *Transcription Factors/genetics/metabolism ; Signal Transduction ; *Drosophila melanogaster/immunology/genetics ; }, abstract = {Inflammatory and immune alterations are increasingly recognized as components of ALS pathology, yet whether they arise as a direct consequence of TDP-43 dysfunction or as a downstream response to neurodegeneration remains unresolved. To address this question, we profiled adult head transcriptomes of Drosophila lacking TBPH, the fly homolog of TDP-43, and identified marked overactivation of the conserved Toll/Imd/NF-κB (Relish) innate immune pathway, including increased expression of antimicrobial effector genes and inflammatory genes. We further found that TDP-43/TBPH regulates the NF-κB homolog Relish by associating with its mRNA and that its loss permits Relish-dependent immune overactivation. Genetic reduction in Relish in TDP-43-deficient flies suppressed inflammatory signaling and ameliorated neurological defects in vivo, indicating that immune dysregulation contributes to TDP-43 loss-associated phenotypes.}, } @article {pmid42353250, year = {2026}, author = {Sharma, N and An, SSA}, title = {Microglial Dysfunction Induced by C9ORF72 Dipeptide Repeat Proteins: Biomarker and Therapeutic Perspectives.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, pmid = {42353250}, issn = {1422-0067}, support = {RS-2021-NR060117//National Research Foundation of Korea/ ; RS-2025-02292973//Korea Institute of Marine Science and Technology Promotion/ ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; *Microglia/metabolism/pathology ; Biomarkers/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/therapy ; *Frontotemporal Dementia/genetics/metabolism/pathology/therapy ; *Dipeptides/genetics/metabolism ; Animals ; DNA Repeat Expansion ; Autophagy ; }, abstract = {The GGGGCC hexanucleotide repeat expansion (HRE) in C9ORF72 was recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-associated non-AUG (RAN) translation of the expanded repeat generated dipeptide repeat proteins (DPRs), which disrupted multiple cellular processes and contributed to neurodegeneration. Emerging evidence indicated that disease pathogenesis involved both gain-of-function (GOF) and loss-of-function (LOF) mechanisms. DPR-mediated GOF toxicity induced ribosomal dysfunction, nucleolar stress, proteostatic impairment, and neuronal injury, whereas C9ORF72 LOF disrupted lysosomal and autophagic pathways in microglia, impairing the immune homeostasis. Neuronal injury further promoted the release of damage-associated signals that triggered secondary microglial activations and chronic neuroinflammations. This review summarized current knowledge of DPR biology, microglial dysfunction, and their contributions to disease progression in C9ORF72-associated ALS/FTD. Therapeutic strategies targeting repeated RNA, DPR productions, proteostasis, autophagy, and neuroinflammatory pathways were also discussed. In addition, the potentials of fluid biomarkers, including cerebrospinal fluid poly (GP) and blood neurofilament light chain (NfL), for diagnosis, disease monitoring, and therapeutic assessment were shown. Together, these findings provided important insights into disease mechanisms and potential avenues for improved clinical management.}, } @article {pmid42356052, year = {2026}, author = {Manay, B and Aygün, D and Şentürk, A and İbas, M and Güven, R and Belli, Ş}, title = {Association Between Clinical Dysphagia Assessment Tools and Videofluoroscopic Findings in Amyotrophic Lateral Sclerosis: A Retrospective Study.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {62}, number = {6}, pages = {}, pmid = {42356052}, issn = {1648-9144}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Retrospective Studies ; *Deglutition Disorders/diagnosis/etiology/physiopathology ; Female ; Male ; Middle Aged ; Aged ; Fluoroscopy/methods ; ROC Curve ; Video Recording/methods ; }, abstract = {Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease frequently associated with dysphagia and aspiration risk. This study aimed to investigate the relationship between clinical dysphagia assessment tools (EAT-10, GUSS, RSST, and sialorrhea severity) and videofluoroscopic swallowing study (VFSS) findings in patients with ALS. Materials and Methods: This retrospective observational study included 60 patients with ALS classified as spinal-onset (n = 38) or bulbar-onset (n = 22). Relationships between clinical assessments and VFSS findings were analysed using Spearman correlation analysis. Exploratory multivariable regression and receiver operating characteristic (ROC) analyses were performed to evaluate associations and aspiration risk discrimination. Results: Strong negative correlations were observed between PAS-Liquid and RSST and GUSS scores, whereas EAT-10 showed a strong positive correlation (all p < 0.001). ROC analyses demonstrated good discriminative ability for aspiration risk for GUSS (AUC = 0.89), RSST (AUC = 0.88), and EAT-10 (AUC = 0.82). Patients with bulbar-onset ALS demonstrated higher penetration-aspiration severity and lower functional oral intake. Conclusions: Clinical dysphagia assessment tools showed significant associations with instrumental swallowing findings in ALS. GUSS and RSST demonstrated good discriminative ability for aspiration risk and may be clinically useful bedside screening tools. However, instrumental swallowing assessment remains essential whenever feasible.}, } @article {pmid42357346, year = {2026}, author = {Costanzi, E and Fontana, L and Giroldo, F and Coco, S}, title = {Advancing MSC-EV Therapies: Harnessing Preconditioning and Mito-EVs to Tackle Neuroinflammation and Neurodegeneration.}, journal = {Pharmaceutics}, volume = {18}, number = {6}, pages = {}, pmid = {42357346}, issn = {1999-4923}, support = {P2022LR49L//Ministry of Universities and Research/ ; 202229X8HW//Ministry of Universities and Research/ ; }, abstract = {Neuroinflammation plays a central role in the onset and progression of neurodegenerative disorders. Several disease-modifying therapies have been developed to target neuroinflammatory pathways in specific disorders. However, their ability to stop disease progression or restore neuronal and mitochondrial homeostasis remains limited. This is still a major unmet clinical need. In this context, mesenchymal stromal cell (MSC)-derived Extracellular Vesicles (EVs) have emerged as a promising cell-free therapeutic strategy due to their ability to modulate immune responses and promote neuroprotection through the delivery of bioactive cargo. Recent evidence has identified a distinct subset of EVs, known as mitochondrial EVs (mito-EVs), which carry mitochondrial DNA, proteins, and functional components. These vesicles may uniquely influence cellular bioenergetics, redox balance, and neuroinflammatory signaling, offering additional therapeutic potential compared to conventional MSC-EVs. This review summarizes the role of MSC-derived EVs in neuroinflammatory disorders, with a particular focus on mito-EVs. It also discusses preconditioning strategies to enhance EV efficacy, including hypoxic, inflammatory, pharmacological priming and genetic engineering approaches. Finally, we critically evaluate current preclinical evidence regarding the treatment of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis, as well as Traumatic Injury, highlighting the key challenges for clinical translation.}, } @article {pmid42358489, year = {2026}, author = {Lepski, G and Arévalo, A}, title = {Mesenchymal stromal/stem cells for neurological disorders in humans: an evidence-mapped clinical review.}, journal = {Frontiers in cellular neuroscience}, volume = {20}, number = {}, pages = {1844360}, pmid = {42358489}, issn = {1662-5102}, abstract = {Mesenchymal stromal/stem cells (MSCs) have been tested clinically across a wide spectrum of neurological disorders, motivated by their immunomodulatory and trophic ("bystander") mechanisms rather than durable neural replacement. Here, we synthesize human prospective clinical trials that administered MSC products for neurological indications, prioritizing study design/goals, disease stage/severity, cell source/manufacturing, dose/route, detailed clinical assessments, quantified score changes, and adverse events (AEs). Across indications, trials frequently demonstrate feasibility and short-term safety, while efficacy signals are heterogeneous and strongly dependent on disease stage and endpoint selection criteria. The most methodologically rigorous signals with quantified motor outcomes include stereotactic intracerebral implantation of SB623 for chronic motor deficits after traumatic brain injury (TBI). In amyotrophic lateral sclerosis (ALS), randomized evidence supports safety and early slope-based signals in selected subgroups after intrathecal MSC regimens, but durable clinical benefit remains unproven. In hypoxic-ischemic encephalopathy (HIE), controlled data suggest functional improvements in small cohorts, and neonatal studies support feasibility adjunctive to hypothermia. We highlight design features most likely to de-risk efficacy interpretation: adequately powered randomized controlled trials, disease-stage stratification, prespecified clinically meaningful change thresholds, standardized rehabilitation co-interventions, and transparent AE adjudication.}, } @article {pmid42359101, year = {2026}, author = {Carder, P and Smith, L and Bunker, JN and Hua, CL and Hsu, EC and Boun, I and Ainsworth, OM and Thomas, KS and Jutkowitz, E}, title = {How do US states define person-centered and family-involved care in assisted living regulations.}, journal = {Frontiers in dementia}, volume = {5}, number = {}, pages = {1824907}, pmid = {42359101}, issn = {2813-3919}, abstract = {INTRODUCTION: A large share of assisted living (AL) residents have a diagnosis of dementia or cognitive impairment, and these individuals can benefit from person-centered care and family-involved care. This study examines whether and how states' AL licenses address these topics.

METHODS: This research analyzed a national database of 249 unique licensing requirements that govern 35,602 ALs in all states and associated regulations, including those that govern memory care (MC) services. We reviewed each regulation for the presence of person-centered or family involved care and then used content analysis of license requirements with at least one relevant policy to identify key categories and regulatory specificity.

RESULTS: A larger share of AL with licenses that govern MC services are covered by person-centered care policies (44%) and family-involved policies (62%), compared to AL without MC-specific requirements (20 and 32% respectively). Key categories of person-centered care included staff training, care planning procedures, and social activities; and family-involved care included care planning, direct involvement in providing care, and support for families. Few states' licenses contained highly specific regulations.

DISCUSSION: This study reveals substantial variation in whether and how states define and regulate person-centered and family-involved care for people living with dementia in AL. MC-specific licenses are roughly twice as likely to require these policies, but fewer than two-thirds of MC-AL communities are covered. State licenses take different approaches to categorizing and specifying these policies. These findings suggest uneven application of core principles of AL associated with quality of life and satisfaction.}, } @article {pmid42359165, year = {2026}, author = {Morimoto, S and Kato, C and Takahashi, S and Okano, H}, title = {Therapeutic frontiers in ALS: iPSC-based drug discovery, cell therapy, and gene therapy-Advances through 2026.}, journal = {Regenerative therapy}, volume = {33}, number = {}, pages = {101150}, pmid = {42359165}, issn = {2352-3204}, abstract = {Three converging therapeutic paradigms-iPSC-based drug discovery, cell transplantation, and gene therapy-have substantially expanded the therapeutic pipeline for amyotrophic lateral sclerosis (ALS) between 2020 and 2026. The FDA's accelerated approval of tofersen (Qalsody) in April 2023 marked the first treatment targeting a genetic cause of ALS. iPSC-derived drug candidates, including ropinirole and bosutinib, have completed early-phase clinical trials led by Japanese institutions. Cell therapies targeting neuroinflammation through regulatory T cells are being actively explored as immunomodulatory strategies, although efficacy remains to be established in adequately powered trials. Next-generation gene-silencing approaches-including RNA interference (RNAi) therapeutics and AAV-delivered microRNA-entered first-in-human trials in 2024-2025. The identification of STMN2 as a downstream target of TDP-43 dysfunction has opened a potential TDP-43-downstream nucleic acid therapeutic avenue for sporadic ALS, which constitutes approximately 90% of all cases, with company-reported interim data suggesting target engagement in the ongoing Phase 1/2 ANQUR trial (QRL-201). This review synthesizes the latest evidence across all three therapeutic domains, with attention to the hierarchy of evidence, regulatory milestones, and the pioneering contributions of Japanese research groups.}, } @article {pmid42359357, year = {2026}, author = {Shu, X and Yu, X and Xu, P and Wang, A}, title = {Innate immune crosstalk in ALS/FTD pathogenesis.}, journal = {Cell insight}, volume = {5}, number = {4}, pages = {100340}, pmid = {42359357}, issn = {2772-8927}, abstract = {Marked by protein aggregation, impaired proteostasis, organelle stress, and chronic neuroinflammation, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) form a clinically, genetically, and pathologically overlapping disease spectrum. Increasing evidence indicates that innate immune activation is not merely a secondary response to neuronal injury, but an active driver of disease progression. In this review, we elaborate on how ALS/FTD-associated genetic lesions and pathogenic protein aggregates, including TDP-43, SOD1, FUS, and C9orf72-derived dipeptide repeat proteins, engage three interconnected innate immune pathways: cGAS-STING, NLRP3 inflammasomes, and TREM2-DAP12 signaling. We further highlight emerging crosstalk among these pathways, in which cGAS-STING and NLRP3 reinforce inflammatory signaling, while NLRP3-driven TREM2 shedding may impair microglial clearance and perpetuate proteostatic failure. Understanding this immune network may help define disease subtypes, identify biomarkers, and guide combinatorial therapeutic strategies that suppress harmful inflammation while preserving protective microglial functions.}, } @article {pmid42359392, year = {2026}, author = {Imamura, K and Nagahashi, A and Okusa, A and Yamamoto, T and Izumi, Y and Ueda, N and Kawahara, Y and Inoue, H}, title = {Nonlinear combinatorial analysis of blood transcriptomes identifies PRKAR1A as a regulator of TDP-43 pathophysiology in amyotrophic lateral sclerosis.}, journal = {Biology methods & protocols}, volume = {11}, number = {1}, pages = {bpag023}, pmid = {42359392}, issn = {2396-8923}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Accurate and accessible blood-based diagnostics for neurodegenerative diseases, including ALS, are being progressively required. Although blood cell gene expression profiles have potential clinical utility for distinguishing ALS, robust transcriptomic biomarkers for supportive diagnosis have not yet been established. Here, we analyzed publicly available peripheral blood mononuclear cell (PBMC) transcriptomic data from ALS patients using Maximum Mean Discrepancy, a kernel-based method that captures nonlinear distributional differences in a reproducing kernel Hilbert space and enables the extraction of informative gene combinations while minimizing multicollinearity, a common issue in multiple regression models. Using this approach, we identified a nonlinear three-gene combination-PRKAR1A, QPCT, and TMEM71-that distinguished ALS from healthy controls with an area under the curve (AUC) of 0.83 in a public PBMC dataset. This achievement was confirmed in laboratory PBMC samples with an AUC of 0.85, supporting the robustness of the identified gene signature in independent samples. Furthermore, these genes also enabled ALS classification in induced pluripotent stem cell-derived motor neurons with an AUC of 0.79. Knockdown of PRKAR1A, QPCT, or TMEM71 in motor neurons increased the TDP-43 expression levels, and PRKAR1A knockdown induced the mislocalization of TDP-43, accompanied by phosphorylation, suggesting a potential link to ALS-related pathophysiology. These findings suggest that nonlinear gene combinations may provide a useful strategy for identifying blood-based biomarkers and offer insights into ALS pathogenesis. This nonlinear, data-driven analytical framework enabled the transition from unbiased gene discovery to the identification of pathophysiology-associated molecules by in vitro functional validation.}, } @article {pmid42359947, year = {2026}, author = {Rozman, SI and Hamzaid, NA and Lim, E and Hamzah, N}, title = {Noninvasive assessment of cardiovascular autonomic reflexes in amyotrophic lateral sclerosis: a systematic review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/21678421.2026.2692135}, pmid = {42359947}, issn = {2167-9223}, abstract = {Dysautonomia is gradually recognized in amyotrophic lateral sclerosis (ALS), raising concerns of secondary complications from heightened autonomic burden. Autonomic disturbances, particularly cardiac dysautonomia, significantly impact patient outcomes, contributing to increased cardiovascular risks and mortality rate. While the ALS Functional Rating Score-Revised (ALSFRS-R) measures functional decline as disease progress, it overlooks autonomic criteria - a critical factor in ALS progression. This review aims to analyze noninvasive applications of cardiovascular signal variability for continuous real-time monitoring of autonomic dysfunction in ALS, while addressing gaps in current clinical assessments. A total of 584 literatures were gathered from four databases (WoS, PubMed, Science Direct and MEDLINE EBSCOhost) - published from inception till December 2023. 21 peer-reviewed studies were included in this review after screening and meeting the inclusion criteria. Various cardiovascular signal variability metrics and autonomic protocols were discussed. Key findings highlight cardiac autonomic dysfunction in ALS is marked by reduced heart rate variability, absent blood pressure regulation upon orthostatic stress and circadian changes, prolonged QTc interval and low baroreflex sensitivity. Moreover, increased autonomic burden is associated with a shift from sympathetic to parasympathetic dysregulation as the disease progresses. Evidence highlights the need to integrate noninvasive autonomic biomarkers into digital ALS monitoring frameworks, enabling earlier detection of autonomic involvement and more precise longitudinal monitoring beyond motor decline.}, } @article {pmid42360043, year = {2026}, author = {Sabetta, E and Rallmann, K and Taba, P and Pfaff, AL and Poudel, BH and Ferrari, D and Locatelli, M and Kõks, S and Bergquist, J}, title = {Comparison of Proteomic Analysis of Cerebrospinal Fluid From Neurological Patients With and Without Amyotrophic Lateral Sclerosis.}, journal = {Journal of neurochemistry}, volume = {170}, number = {6}, pages = {e70508}, pmid = {42360043}, issn = {1471-4159}, support = {//Multiple Sclerosis Society of Western Australia/ ; SA EUS 100a Fund//Perron Institute for Neurological and Translational Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; *Proteomics/methods ; Female ; Male ; Biomarkers/cerebrospinal fluid ; Middle Aged ; Aged ; Adult ; Tandem Mass Spectrometry ; Cerebrospinal Fluid Proteins ; Chromatography, Liquid ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness in both bulbar and extremity muscles, leading to a diverse clinical phenotype with motor and non-motor symptoms. Approximately 85% of ALS cases are sporadic (sALS), while the remaining 10%-15% are familial (fALS). Biological biomarkers of sporadic ALS remain poorly understood, hindering precise patient screening, delaying diagnosis and negatively affecting prognosis. This study aims to identify potential proteomic biomarkers by comparing the cerebrospinal fluid (CSF) of sALS patients with that of patients suffering from other neurological diseases. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for proteomic profiling of CSF samples from 24 sALS patients and 26 patients with other neurological diseases. The complete protein expression profiles were compared using a two-tailed Student's t-test, with a p < 0.05 considered statistically significant with additional FDR correction at the 0.1 level. Proteomic analysis of CSF samples identified significant quantitative changes in 96 proteins with threshold p < 0.05 and 74 proteins with FDR < 0.1 between sALS and non-ALS patients, including alterations in proteins associated with neurodegenerative processes, such as amyloid precursor proteins and inflammatory markers. CSF proteomic analysis reveals altered inflammatory and neurodegenerative metabolic pathways, providing valuable insights into the proteomic landscape of sALS. Several dysregulated proteins were consistent with the disease mechanisms highlighted in previous studies. These findings represent a step forward in developing personalised approaches for diagnosing and managing the disease.}, } @article {pmid42360551, year = {2026}, author = {Pramanik, S and Debnath, B and Chakraborty, A and Islam, A and Mullick, S and Chaudhary, P and Nath, R and Chellappan, DK and Mondal, M and Ashique, S}, title = {Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42360551}, issn = {1559-1182}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy/pathology ; *DNA, Mitochondrial/genetics/metabolism ; Animals ; *Mitochondria/genetics/metabolism/pathology ; Gene Editing ; }, abstract = {Mitochondrial dysfunction is a common pathological feature of neurodegenerative diseases namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although these disorders are primarily driven by disease-specific genetic and proteopathic mechanisms, increasing evidence suggests that secondary mitochondrial DNA (mtDNA) damage and heteroplasmy shifts may exacerbate bioenergetic failure and neuronal vulnerability. Distinguishing primary disease mechanisms from downstream mtDNA alterations is critical to accurately evaluate emerging therapeutic strategies. Recent advances in mtDNA-targeted genome editing have enabled the direct manipulation of mitochondrial genomes. Mitochondrially targeted zinc finger nucleases and TALENs can selectively alter mutant mtDNA to induce heteroplasmy shifts, whereas DddA-derived cytosine base editors allow precise base editing without double-strand breaks. However, each platform has distinct limitations related to the target scope, off-target risk, design complexity, and delivery efficiency. The application of CRISPR/Cas-based systems to mammalian mtDNA remains constrained by the unresolved challenges in guiding RNA import. This review critically examines mitochondrial dysfunction and mutant mtDNA accumulation in neurodegenerative diseases. It also evaluates current and emerging mtDNA-editing techniques, and highlights key translational barriers. We highlighted that mtDNA-targeted interventions can be a promising approach for disease-modifying or adjunctive strategies, rather than curative approaches.}, } @article {pmid42360563, year = {2026}, author = {Ketabforoush, A and Arnold, WD and Ariaei, A and Faghihi, F and Azedi, F and Khalili, M and Gholami, F and Joghataei, MT and Ashtiani, BH}, title = {Characterization of sensory nerve conduction abnormalities at the time of ALS diagnosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {7}, pages = {}, pmid = {42360563}, issn = {1590-3478}, support = {1401-1-20-22913//Iran University of Medical Sciences/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Female ; Male ; Nerve Conduction Studies ; Middle Aged ; *Neural Conduction/physiology ; Cross-Sectional Studies ; Prospective Studies ; Aged ; Adult ; Sural Nerve/physiopathology ; Ulnar Nerve/physiopathology ; Motor Neurons/physiology ; Median Nerve/physiopathology ; }, abstract = {OBJECTIVES: Although sensory nerve abnormalities have been reported in amyotrophic lateral sclerosis (ALS), their distribution at diagnosis, relative to motor involvement and clinical onset phenotype remains incompletely characterized. We aimed to systematically compare sensory and motor nerve conduction abnormalities at ALS diagnosis and determine whether sensory involvement follows an onset-dependent pattern similar to motor dysfunction.

METHODS: In this prospective cross-sectional study, 40 newly diagnosed ALS patients enrolled in the Iran University ALS Registry (March 2022-March 2023) underwent standardized motor and sensory nerve conduction studies (NCS). For between-group comparisons, a matched ALS subgroup was compared with matched healthy controls, while the expanded ALS cohort was used for subgroup and correlation analyses.

RESULTS: SNAP amplitudes of the median, ulnar, and sural nerves were reduced by 45%, 34%, and 43%, respectively, compared with healthy controls, with similar reductions observed across upper- and lower-limb onset phenotypes and no significant onset-dependent differences. In contrast CMAP amplitudes were markedly reduced in ALS patients, most prominently in the peroneal (79%), median (47%), tibial (42%), and ulnar (37%) nerves. Motor abnormalities were most severe in the clinically affected limb but were also detectable in asymptomatic extremities, consistent with early subclinical spread.

CONCLUSION: At ALS diagnosis, sensory and motor nerve conduction abnormalities exhibited divergent spatial patterns, with asymmetric, onset-related motor involvement and relatively uniform sensory axonal dysfunction. These findings support the presence of measurable sensory nerve conduction abnormalities in a subset of ALS patients, while highlighting the need for cautious interpretation of sensory NCS changes in ALS.}, } @article {pmid42361623, year = {2026}, author = {Deptuła, P and Chmielewska-Deptuła, S and Spałek, J and Kaliniak, S and Okła, S and Bucki, R}, title = {Decoding the pathogenesis of Candida albicans infection and evaluating the efficacy of antifungal drugs using atomic force microscopy.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {201}, number = {}, pages = {119705}, doi = {10.1016/j.biopha.2026.119705}, pmid = {42361623}, issn = {1950-6007}, mesh = {*Microscopy, Atomic Force/methods ; *Candida albicans/drug effects/pathogenicity ; *Antifungal Agents/pharmacology/therapeutic use ; Biofilms/drug effects ; Humans ; *Candidiasis/drug therapy/microbiology/pathology ; Cell Wall/drug effects/metabolism ; Animals ; }, abstract = {Atomic force microscopy (AFM) has emerged as a pivotal method enabling multidimensional characterization of Candida albicans (C. albicans) by simultaneously providing topographical imaging, mechanical profiling, and quantitative measurements of adhesion forces under near-physiological conditions. AFM-derived data demonstrate that nanoscale surface alterations, including wrinkling, indentations, increased roughness, and perforations correlate closely with modulation of the Young's modulus and with the reorganization of mannoproteins and adhesins, particularly those of the Als family. The co-occurrence of structural, mechanical, and adhesive changes reflects the dynamic remodeling of the fungal cell wall that governs morphogenesis, virulence, and biofilm formation. AFM offers high resolution insight into the mechanisms of action of antifungal drugs, antimicrobial peptides, nanomaterials, and physical treatments that destabilize the cell wall, reduce its stiffness, or conversely induce compensatory stiffening and adhesin exposure. As a result, the technique enables the identification of critical steps in stress responses and hyperadhesive phenotypes that contribute to fungal invasion and treatment resistance. Integration of AFM with spectroscopic and microfluidic approaches further enhances its potential to reveal new therapeutic targets. Collectively, evidence from numerous studies underscores AFM as a foundational tool in the rational design of modern, multimodal antifungal strategies aimed at the cell wall and biofilm of C. albicans.}, } @article {pmid42362190, year = {2026}, author = {Lyu, R and Ruff, KM and Palmer, CS and Ramirez, AE and Ormsby, AR and Scott, DJ and Pappu, RV and Stojanovski, D and Stroud, DA and Hatters, DM}, title = {ASAP-ID: Proximity Labelling With Small Tags.}, journal = {Molecular & cellular proteomics : MCP}, volume = {25}, number = {8}, pages = {101616}, pmid = {42362190}, issn = {1535-9484}, mesh = {Humans ; *Staining and Labeling/methods ; Biotinylation ; Lamin Type A/metabolism ; *Protein Interaction Mapping/methods ; Multifunctional Enzymes/metabolism ; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism ; Single-Domain Antibodies/metabolism ; Recombinant Fusion Proteins/metabolism ; HEK293 Cells ; Endonucleases ; }, abstract = {Biotinylation-based proximity labelling methods are valuable for discovering protein-protein interactions within cellular systems. However, one limitation of these approaches is that most require fusing the target protein with the enzyme that biotinylates nearby proteins (i.e., TurboID or APEX2), which risks sterically disrupting the protein's native function. Here, we present a method designed to reduce the steric impact of these fusions and offer greater flexibility in labelling modalities. The method, Antibody and Small-tag Assembly on Proteins for Interaction Detection (ASAP-ID), involves a bipartite system. Target proteins are fused to a small peptide antigen that recruits TurboID or APEX2 fused to an antibody directed to the antigen. Using two different antigen/antibody systems (SunTag and MoonTag), we show that ASAP-ID can specifically label human Lamin A in cells. The method works when the target protein and nanobody are co-expressed together in cis (ASAP-ID[IC]). We also demonstrate that the approach works when the antibody fusion is added in trans to fixed cells post-expression (ASAP-ID[IT]). ASAP-ID[IT] identified more than 448 known and previously undescribed potential interactors of lamin. We further used ASAP-ID[IT] to study how ALS-mutant profilin one affected its interactome. The method identified proteins involved in protein quality control that correlated with aggregation propensity. Moreover, the different mutants showed variation in the cellular location where aggregates formed. ASAP-ID[IT] revealed preferences for mitochondrial proteins for the two profilin mutants that tend to aggregate in the cytoplasm, C71G and M114T, and nuclear proteins for a mutant more prone to nuclear aggregation. These findings position ASAP-ID as a powerful addition to the proximity labelling toolkit, capable of probing subtle differences in interactomes in a less invasive manner.}, } @article {pmid42362484, year = {2026}, author = {Nakayama, Y and Kume, K and Baba, T and Ayaki, T and Hanada, K and Miyamoto, K and Inoue, N and Kawakami, H and Ito, H}, title = {Neuropathological and Molecular Features Associated With a Heterozygous DNAJC7 Mutation in Amyotrophic Lateral Sclerosis.}, journal = {Neuropathology and applied neurobiology}, volume = {52}, number = {4}, pages = {e70086}, pmid = {42362484}, issn = {1365-2990}, support = {18H02743//Japan Society for the Promotion of Science/ ; 25K10801//Japan Society for the Promotion of Science/ ; //Takeda Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Female ; Male ; Middle Aged ; *Molecular Chaperones/genetics ; Mutation ; Aged ; Heterozygote ; Heat-Shock Proteins ; }, abstract = {AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unclear molecular mechanisms. Heterozygous protein-truncating variants of DNAJC7, which encode a cochaperone involved in Hsp70/90-mediated protein quality control, are potential risk factors for ALS. However, the neuropathological consequences of heterozygous DNAJC7 mutations are unclear. We aimed to clarify the molecular and neuropathological features associated with a heterozygous DNAJC7 mutation in ALS.

METHODS: We genetically screened 39 Japanese patients with ALS and identified a novel heterozygous frameshift mutation in DNAJC7 (c.157_163del, p.Lys53Ter) in one patient that was neuropathologically diagnosed with Kii ALS. We performed biochemical and neuropathological analyses using postmortem tissues from this patient, from cases of ALS without the mutation and from control cases.

RESULTS: In the cases of ALS without DNAJC7 mutation, there was elevation of both DNAJC7 mRNA and protein levels compared with controls. The patient with DNAJC7 mutation showed relatively lower DNAJC7 mRNA and protein levels compared with the nonmutated cases of ALS, although mRNA expression remained relatively higher. DNAJC7 may be upregulated as a protective response against ALS pathogenesis, whereas a heterozygous mutation may attenuate this response. Immunohistochemistry and double immunofluorescence demonstrated partial colocalization of DNAJC7 with phospho-TDP-43-positive neuronal cytoplasmic inclusions, which supports a direct role for DNAJC7 in modulating pathological TDP-43 aggregation.

CONCLUSIONS: These findings provide neuropathological evidence linking heterozygous DNAJC7 mutation to ALS, demonstrating impaired protein expression and suggesting a loss-of-function mechanism that compromises protective responses to TDP-43 pathology. DNAJC7 may represent a key modulator of ALS pathogenesis and potential therapeutic target.}, } @article {pmid42363583, year = {2026}, author = {Ludwig, TD and Rabelo-Araujo, JVDS and Munhoz Pedroso, R}, title = {Enhanced weed control in flooded rice through diversified pre-emergence programs integrating PROTOX-inhibiting herbicides.}, journal = {Journal of environmental science and health. Part. B, Pesticides, food contaminants, and agricultural wastes}, volume = {61}, number = {10}, pages = {733-739}, doi = {10.1080/03601234.2026.2694270}, pmid = {42363583}, issn = {1532-4109}, mesh = {*Herbicides/pharmacology ; *Oryza/growth & development/drug effects ; *Weed Control/methods ; *Protoporphyrinogen Oxidase/antagonists & inhibitors ; *Plant Weeds/drug effects ; Brazil ; Acetolactate Synthase/antagonists & inhibitors ; Echinochloa/drug effects ; Benzoxazines/pharmacology ; Floods ; Phthalimides ; }, abstract = {Rice (Oryza sativa L.) productivity in Brazil is increasingly threatened by herbicide-resistant weeds. We evaluated diversified pre-emergence programs in flooded Clearfield rice (Puitá INTA CL) through two field experiments conducted in southern Brazil during the 2016/2017 season. Programs were based on acetolactate synthase (ALS) inhibitors alone or combined with alternative modes of action, including protoporphyrinogen oxidase (PROTOX) inhibitors (saflufenacil and flumioxazin). Weed control of Aeschynomene spp. and Echinochloa spp. was high (≥80%) at 14 days after application (DAA) and remained satisfactory up to 21 DAA in most programs. Crop injury was treatment-dependent, with higher early phytotoxicity observed in mixtures containing mesotrione, but visual symptoms declined over time and did not compromise grain yield. All herbicide programs significantly increased productivity compared to the untreated control. These findings indicate that integrating PROTOX inhibitors into Clearfield-based pre-emergence programs is a feasible strategy to diversify modes of action while maintaining effective weed control and yield stability under flooded conditions.}, } @article {pmid42363684, year = {2026}, author = {Majumder, P and Ahsan, A and Bubphachat, P and Akter, K and Huang, JK and Huang, CS}, title = {FMRP-Mediated Proteasome Regulation: A Novel Mechanism in ALS Pathology.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {40}, number = {13}, pages = {e72063}, doi = {10.1096/fj.202600563R}, pmid = {42363684}, issn = {1530-6860}, support = {NSTC 114-2320-B-038-055//National Science and Technology Council (NSTC)/ ; NSTC 110-2320-B-038-067-MY3//National Science and Technology Council (NSTC)/ ; NSTC 110-2320-B-038-090-MY3//National Science and Technology Council (NSTC)/ ; NSTC 113-2320-B-038-061//National Science and Technology Council/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Proteasome Endopeptidase Complex/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Humans ; *Fragile X Messenger Ribonucleoprotein 1/metabolism/genetics ; Mice ; Mice, Transgenic ; Cytoplasm/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disease characterized by the hallmark cytoplasmic accumulation and aggregation of TAR DNA binding protein 43 (TDP-43), which impairs proteasome activity through its interaction with Tankyrase (TNKS). Using molecular and imaging techniques, we have identified a novel role for the Fragile X Mental Retardation Protein (FMRP) in regulating the TNKS/PI31-mediated proteasome activation mechanism in co-operation with TDP-43. Our results demonstrate that depletion of FMRP causes nuclear translocation of TDP-43, reducing cytoplasmic TNKS/TDP-43 co-localization, thereby releasing TNKS in the cytoplasm. Free TNKS gets associated with proteasome inhibitor of 31 kDa (PI31), reversing PI31-mediated inhibition of proteasome assembly, trafficking, and activity. Thus, FMRP regulates proteasome activity by modulating the subcellular distribution of TDP-43. Interestingly, FMRP expression is elevated in specific brain regions and spinal cords of TDP-43[A315T] transgenic ALS mice that helps more TDP-43 to stay in cytoplasm to sequester more TNKS with it, resulting in proteasome dysfunction in ALS disease system. We have demonstrated for the first time that FMRP can act as a disease modifier for ALS. ALS patients with high FMRP expression in the brain and spinal cord may exhibit more severe protein aggregation due to proteasome dysfunction.}, } @article {pmid42364760, year = {2026}, author = {Baird, KT}, title = {The impedance mismatch theory: A non-equilibrium thermodynamic framework for a shared energetic stress pathway in neurodegeneration.}, journal = {Bio Systems}, volume = {266}, number = {}, pages = {105862}, doi = {10.1016/j.biosystems.2026.105862}, pmid = {42364760}, issn = {1872-8324}, mesh = {Humans ; *Thermodynamics ; *Energy Metabolism/physiology ; Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Stress, Physiological/physiology ; Animals ; *Models, Neurological ; Huntington Disease/metabolism/physiopathology ; Electric Impedance ; }, abstract = {Current neurobiological models of Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Huntington's Disease (HD) utilize multi-omic interactome analyses to map cascades of proteinopathy. While essential, these approaches often overlook the macroscopic thermodynamic limits of the neural substrate as an information processing system. We propose the Impedance Mismatch Theory, a theoretical biophysical model and quantitative framework for the thermodynamic limits of neural computation, positing that these distinct pathologies converge as a shared energetic stress pathway. We introduce the Neurophysiological Load Index (NLI)-a dimensionless parameter quantifying the mismatch between electrical computational drive, topological network impedance, and the local structural and microvascular dissipation capacity. Drawing on the Pennes Bioheat Transfer Equation and insights from multiplex network theory, we hypothesize that pathology initiates as localized thermal runaway, where resistive metabolic heat exceeds convective blood perfusion and thermal conduction, inducing acute decompensation. We outline cross-translational disease-network mechanisms, address the inverse cancer comorbidity paradox via speculative bioelectric attractor states, and propose falsifiable predictions involving high-resolution in vivo proton magnetic resonance spectroscopy thermometry ([1]H-MRS-t) and phosphorus-31 magnetic resonance spectroscopy ([31]P-MRS).}, } @article {pmid42365390, year = {2026}, author = {Zheng, H and Luo, H and Lu, Y and Yuan, Y and Zhang, N and Duan, S and Xia, Z and Xu, Y}, title = {Lysophagy protects against ANXA11 amyloid fibril toxicity and propagation in FTLD.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {42365390}, issn = {2047-9158}, support = {82301619//the National Natural Science Foundation of China/ ; 82571514//the National Natural Science Foundation of China/ ; 232102311229//the key scientific and technological breakthrough project in Henan province/ ; 2022M722875//the China Postdoctoral Science Foundation/ ; }, mesh = {Humans ; *Lysosomes/metabolism/pathology ; *Frontotemporal Lobar Degeneration/metabolism/pathology/genetics ; *Autophagy/physiology ; *Annexins/metabolism/genetics ; *Amyloid/metabolism ; Neurons/metabolism/pathology ; Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; }, abstract = {BACKGROUND: Accumulation of Annexin A11 (ANXA11) aggregates is a distinct pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While genetic studies have linked ANXA11 mutations (e.g., D40G) to disease, the precise molecular events converting aggregation into neurotoxicity and intercellular propagation remain elusive. We hypothesize that lysosomal integrity serves as a critical checkpoint in ANXA11 proteinopathy and that its failure drives disease progression.

METHODS: To model the human pathology of ANXA11, we generated pre-formed fibrils (PFFs) of wild-type and FTLD/ALS-linked D40G mutant ANXA11. Human iPSC-derived neurons, 3D cerebral organoids, and bulk RNA-sequencing were employed to investigate neurotoxicity. High-resolution imaging, lentiviral knockdown, and biochemical assays were performed to delineate the lysosomal damage response and the subsequent "prion-like" spreading of aggregates.

RESULTS: The internalized ANXA11 fibrils accumulated in lysosomes, triggering lysosomal membrane permeabilization (LMP). The D40G mutation exacerbated this toxicity, leading to severe LMP, mitochondrial depolarization, and specific transcriptional downregulation of the dynactin subunit ACTR10. Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy. Notably, in human cerebral organoids, failure of this lysophagic clearance facilitated the cytoplasmic escape of ANXA11, thereby accelerating its seeding activity and propagation to neighboring cells. Pharmacological or genetic modulation of this pathway significantly altered neuronal survival.

CONCLUSIONS: Our study established lysosomal rupture as a primary driver of ANXA11-associated neurodegeneration and validated the p38/MK2/HSP27 axis as a crucial defense mechanism in human neural tissue. These findings provide a novel mechanistic link between lysosomal quality control and ANXA11 propagation, highlighting that enhancing lysophagic flux represents a promising translational strategy to halt the progression of FTLD and ALS.}, } @article {pmid42366580, year = {2026}, author = {Macklin, EA and Berry, JD and Harkey, BA and Heyd, L and Chase, M and Yu, H and Sherman, AV and Dagostino, D and Kittle, G and Hall, M and Connolly, MR and Drake, K and Giacomelli, E and Scirocco, E and Sharma, S and Babu, S and Benatar, M and Simmons, Z and Young, E and Cudkowicz, ME and Shefner, J and Paganoni, S and , }, title = {At-Home Versus in-Clinic Vital Capacity Measurement: Insights From the HEALEY ALS Platform Trial.}, journal = {Muscle & nerve}, volume = {74}, number = {3}, pages = {702-708}, pmid = {42366580}, issn = {1097-4598}, support = {MDA 1313867//Muscular Dystrophy Association/ ; //Tackle ALS/ ; //ALS Finding a Cure/ ; //ALS Association/ ; //ALS ONE/ ; //The Arthur M. Blank Family Foundation/ ; //The AMG Charitable Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Female ; Vital Capacity/physiology ; Male ; Middle Aged ; Aged ; Longitudinal Studies ; Cross-Sectional Studies ; Disease Progression ; }, abstract = {INTRODUCTION/AIMS: Respiratory weakness, typically monitored as vital capacity (VC), is a central feature of amyotrophic lateral sclerosis (ALS). VC is increasingly measured remotely in participants' homes, although in-clinic assessment remains the standard. We tested concordance between at-home and in-clinic VC to determine trial eligibility, track progression, and predict survival in a large ALS trial.

METHODS: At-home and in-clinic VC were assessed at baseline and approximately every 8 weeks for a year in the first four regimens of the HEALEY ALS Platform Trial. At-home assessments were coached via live videoconference and centrally reviewed. VC measurements, expressed as percent of predicted normal (%PN), were compared cross-sectionally, longitudinally, and for predicting survival time. Data from 233 participants with 3-8 paired at-home and in-clinic VC assessments completed < 14 days apart were analyzed.

RESULTS: At-home and in-clinic VC were well correlated (Lin's r c  = 0.82) with no systematic bias. At-home VC ≥ 60%PN predicted in-clinic VC ≥ 60%PN with a positive predictive value of 91% and a negative predictive value of 65%. VC slopes were moderately correlated (r c  = 0.68). At-home VC progressed 28% faster than in-clinic VC with proportionately less variance (at-home [SE] = -1.882 [0.153] %PN/month, in-clinic = -1.476 [0.131] %PN/month). Slopes of at-home and in-clinic VC explained 15% and 17% of variation in future survival time, respectively.

DISCUSSION: At-home and in-clinic VC were well correlated cross-sectionally. At-home VC performed well tracking longitudinal change and predicting survival. The reduced participant burden of assessment and concordance with in-clinic measurement support use of at-home monitoring of VC.}, } @article {pmid42367369, year = {2026}, author = {Morganroth, J and Yasek, J and Harms, M}, title = {Preparing Amyotrophic Lateral Sclerosis Clinics to Provide Longitudinal Care for Individuals Carrying ALS Risk Variants.}, journal = {Neurology. Genetics}, volume = {12}, number = {4}, pages = {e200406}, pmid = {42367369}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Emerging genetic therapies and the expansion of genetic testing are identifying individuals carrying amyotrophic lateral sclerosis (ALS) risk variants who would benefit from surveillance and early intervention. Anticipating the geographic distribution and clinical needs of this population is essential for optimizing care delivery and ensuring readiness as new therapies become available. We estimate the number of individuals in the United States carrying ALS risk variants and project the clinical engagement required to support this population. This is especially timely because ALS clinics are already grappling with rising numbers of patients with symptomatic ALS and deep funding cuts.

METHODS: We developed a population model to estimate the number of symptomatic individuals with gene-positive ALS and asymptomatic gene carriers across US states over the next decade (year 1: 2026). State-level ALS prevalence and incidence were calculated using 2 approaches: (1) race-adjusted ALS rates from the Atlanta metropolitan study applied to 2023 Census demographics and (2) observed state-level ALS case counts from the National ALS Registry (2011-2018). Gene-positive cases were estimated using published frequencies of SOD1, C9orf72, FUS, and TARDBP pathogenic variants. At-risk relatives were modeled assuming autosomal-dominant inheritance with ∼5 first-degree and ∼7 second-degree living relatives per proband, and broad uptake of cascade genetic testing. Surveillance needs were modeled as 1 annual visit per asymptomatic carrier, which was normalized by the number of ALS centers per state.

RESULTS: In year 1 (2026), the model estimated 2,704 symptomatic gene-positive ALS carriers. With an average of 4.25 carrier relatives per proband, 10,944 asymptomatic carriers were projected nationwide. Most states required <50 additional visits per clinic annually, with 12 states in the 50-99 range and none exceeding 100. By year 10 (2035), the model projected 7,474 symptomatic and 26,111 asymptomatic carriers. State-level demand shifted substantially: only 6 states remained below 50 visits per clinic annually; 22 reached 50-99; 18 reached 100-199; and 3 exceeded 200.

DISCUSSION: Gene-targeted testing is projected to substantially increase ALS clinic visits among asymptomatic gene carriers. While current infrastructure may accommodate the initial rise, within a decade, most states will require significant expansion. Anticipating and planning for this growth now is essential to ensure seamless integration of gene-positive individuals into ALS care.}, } @article {pmid42367645, year = {2025}, author = {Toussirot, E and Tatu, L and Bereau, M}, title = {Occurrence of amyotrophic lateral sclerosis during TNF inhibitor treatment in inflammatory rheumatic disease. What are the relationships?.}, journal = {EULAR rheumatology open}, volume = {1}, number = {4}, pages = {475-477}, pmid = {42367645}, issn = {3050-7081}, abstract = {Neurological adverse events have been reported in patients receiving tumor necrosis factor inhibitors (TNFi) for the treatment of inflammatory rheumatic diseases. The occurrence of amyotrophic lateral sclerosis (ALS) during TNFi therapy is rare but raises the question of a possible relationship. We report 2 cases of ALS diagnosed during TNFi treatment: the first in a patient with spondyloarthritis treated with adalimumab and the second in a patient with seronegative polyarthritis treated with infliximab. Tumor necrosis factor alpha (TNFα) has been implicated in ALS pathogenesis and is considered to exert both neuroprotective and neurotoxic effects, depending on the differential expression of its receptors in distinct regions of the central nervous system. We also review data from pharmacovigilance databases and discuss the potential influence of TNFα inhibition on ALS development.}, } @article {pmid42367691, year = {2026}, author = {Loser, V and Afanasiev, V and Vicino, A and Théaudin, M}, title = {Chronic Inflammatory Demyelinating Polyradiculoneuropathy-Like Neuropathy in Heterozygous C9orf72 Mutation: A Case Report.}, journal = {Case reports in neurology}, volume = {18}, number = {1}, pages = {260-266}, pmid = {42367691}, issn = {1662-680X}, abstract = {INTRODUCTION: C9orf72 repeat expansion is usually associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS/FTD overlap. We report an atypical neuromuscular presentation of C9orf72 repeat expansion.

CASE PRESENTATION: A 68-year-old patient developed a sensorimotor polyneuropathy with slow continuous worsening over 3 years. Symptoms started in the left foot and slowly extended to all four limbs. Nerve conduction studies were consistent with a non-length-dependent predominantly axonal sensorimotor polyneuropathy, with some additional demyelinating features (proximal temporal dispersion and F-wave latency prolongation). Electro-clinical presentation fulfilled EAN/PNS 2021 criteria for CIDP, but the patient was not responsive to IVIg. RT-PCR revealed a heterozygous pathogenic expansion of the C9orf72 gene. The patient's father and brother died from ALS. At onset, his brother also had sensorimotor involvement and was misdiagnosed with CIDP.

CONCLUSION: This case may expand the phenotypic spectrum associated with C9orf72 repeat expansion. The initial phenotype could be a non-length-dependent sensorimotor polyneuropathy with demyelinating features that potentially mimics CIDP.}, } @article {pmid42368190, year = {2026}, author = {Meng, J and Deng, ZJ and Zhang, J and Yu, W and Wu, X and Lei, P}, title = {Atypical involvement of Alzheimer's tau proteins in diseases beyond tauopathies.}, journal = {Life medicine}, volume = {5}, number = {3}, pages = {lnag016}, pmid = {42368190}, issn = {2755-1733}, abstract = {Tau is a microtubule-associated protein traditionally involved in a collective group of disorders termed "tauopathy", including Alzheimer's disease. Tau protein self-aggregates and forms neurofibrillary tangles in neurons, which are considered a pathological hallmark of tauopathies. While the roles of neuronal tau in tauopathies have been extensively investigated, recent studies have shed light on its roles in other diseases without tau pathology and in other cells. In this review, we aim to discuss the "atypical" pathological involvement of tau in diseases other than tauopathies, including brain diseases (e.g., amyotrophic lateral sclerosis, multiple sclerosis, and spinal cord injury), vascular diseases (stroke and hypertension), diabetes, and cancers. We have discussed the expression and functions of tau in cell types other than neurons, and have summarized the evidence supporting a role of tau in these diseases. These cross-disease studies collectively suggest that tau protein is more broadly implicated in mechanisms such as axonal instability, dysregulated cell signaling, inflammatory activation, and cell death, independent of its aggregation, contributing to our knowledge of the functions of tau and the myriad ways in which it may be involved in pathological processes.}, } @article {pmid42368206, year = {2026}, author = {Zafarullah, M and Banerjee, R and Singh, A and Ghosh, A and Almeida, S}, title = {Editorial: Neuromuscular disorders: biomarkers, precision diagnosis, and targeted therapeutics.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1878340}, doi = {10.3389/fnins.2026.1878340}, pmid = {42368206}, issn = {1662-4548}, } @article {pmid42369121, year = {2026}, author = {Cao, G and Yang, X and Wang, X and Shi, X and Yang, L and Wang, P and Tan, H}, title = {Meniscal repair and partial meniscectomy demonstrated similar clinical outcomes with simultaneous combined anterior cruciate ligament and anterolateral structure reconstruction.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1847295}, pmid = {42369121}, issn = {2296-858X}, abstract = {PURPOSE: The clinical outcomes of patients after combined anterior cruciate ligament (ACL) and anterolateral structure (ALS) reconstruction with or without concomitant meniscal treatment were limited. The purpose of this study was to evaluate clinical outcomes and investigate the effect of concomitant treatment of meniscal injury on these outcomes following combined ACL and ALS reconstruction.

METHODS: A total of 86 patients with combined ACL and ALS reconstruction were eligible for inclusion, from August 2018 to November 2022, with at least 1-year follow-up. The patients were assigned to three groups based on meniscal status, including the no injury group (n = 26), the partial meniscectomy group (the meniscus was resected partially, n = 24), and the repair group (the meniscus was sutured, n = 36). Outcome measurements consisted of function, stability, and safety evaluation. Functional evaluation included Lysholm score, Tegner score, and International Knee Documentation Committee (IKDC) score.

RESULTS: At the last follow-up, the Lysholm, Tegner, and IKDC scores were significantly improved compared with preoperative status (p < 0.05). Functional scores in the no injury group were much higher than those in the partial meniscectomy and repair groups. In addition, the expense was significantly higher in the repair group (43840.9 ± 10804.9) than that in the no injury (37767.7 ± 4537.4, p = 0.003) and partial meniscectomy (37738.7 ± 3794.4, p = 0.004) groups. The stability and safety indices did not differ significantly among the three groups (p > 0.05).

CONCLUSION: Among patients following simultaneous ACL and ALS reconstruction with concomitant meniscal injury, meniscal repair and partial meniscectomy could demonstrate comparable functional outcomes.}, } @article {pmid42369360, year = {2026}, author = {Keihani, A and Hassani, M and Sajadi, SS and Modarresi, SA and Khoshkholgh, M and Haresabadi, M and Amani, K and Jourahmad, Z and Ferrarelli, F}, title = {Assessing upper motor neuron dysfunction in ALS: from TMS-EEG and EMG neurophysiology to a combined tFUS-TMS translational framework.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1798525}, pmid = {42369360}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of upper motor neurons (UMNs) and lower motor neurons (LMNs). Despite significant advances in molecular and neuroimaging biomarkers, the initial site of pathology and the causal contribution of UMN dysfunction to disease progression remain undetermined. Accumulating neurophysiological evidence points to cortical hyperexcitability as an early and potentially upstream mechanism, raising the possibility that UMN pathology drives LMN degeneration through an anterograde dying-forward process. In this review, we synthesize findings from noninvasive brain stimulation (NIBS) studies, with particular emphasis on transcranial magnetic stimulation (TMS)-based neurophysiological markers of UMN dysfunction. We review evidence from TMS-electromyography (TMS-EMG) and TMS-electroencephalography (TMS-EEG) paradigms demonstrating cortical disinhibition and excitatory-inhibitory imbalance in ALS, consistent with impaired GABAergic interneuronal dysfunction and supportive of a cortical onset hypothesis. Finally, we propose integrating transcranial focused ultrasound (tFUS) with TMS as a novel experimental and translational framework to directly examine and modulate cortical hyperexcitability and test the causal role of UMN dysfunction in ALS. The combination of targeted neuromodulation with sensitive neurophysiological readouts in controlled experimental designs offers a promising avenue to advance mechanistic insight, refine biomarkers, and inform mechanism-based therapeutic strategies. Together, these approaches position noninvasive neurophysiology as a powerful tool for elucidating UMN dysfunction in ALS.}, } @article {pmid42369427, year = {2025}, author = {Liu, H and Tang, M and Che, L and Lu, J and Zhang, L}, title = {Investigating the potential mechanism of bisphenols on neurodegeneration through network toxicology and molecular docking.}, journal = {NAM journal}, volume = {1}, number = {}, pages = {100044}, pmid = {42369427}, issn = {3050-6204}, abstract = {This study aims to elucidate the mechanisms underlying bisphenols (BPs)-induced neurodegeneration and their contribution to neurodegenerative diseases. Focusing on four major disorders-Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Huntington's Disease-we systematically examined key molecular pathways potentially perturbed by BPs during disease progression. Preliminary toxicological profiling of four representative BPs was conducted using ProTox-3.0, ADMETlab 3.0, and the Xundrug database. Subsequent target identification involved integrated analyses of multiple bioinformatics resources, including CHEMBL and STITCH. Protein-protein interaction networks constructed with STRING and Cytoscape identified core targets such as HSP90AA1, ESR1, BCL2, and PTGS2. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses further revealed critical biological processes, including enzyme binding and heme binding, as well as key pathways associated with BPs neurotoxicity, such as chemical carcinogenesis-receptor activation, chemical carcinogenesis-DNA adducts, and arachidonic acid metabolism. Molecular docking studies demonstrated strong binding affinities between BPs and core targets, supported by low free energy values. Molecular dynamics simulations further validated stable binding conformations and dynamic interactions. Additionally, we analyzed regulatory networks of mRNA-miRNA-lncRNA interactions for core targets. In summary, our findings establish a novel multi-target and multi-pathway framework for BPs-induced neurodegeneration, revealing synergistic effects of pathways including carcinogenic signaling activation and metabolic dysregulation. This study advances understanding of environmental neurotoxicity and provides a foundation for developing preventive strategies against neurodegenerative diseases.}, } @article {pmid42370313, year = {2026}, author = {Alkorom, S and Chong, MC and Che Seman, NH and Aqtam, I}, title = {Resilience-Building Interventions and Advanced Life Support Competency for Emergency Nurses in Palestinian Hospitals: A Scoping Review.}, journal = {SAGE open nursing}, volume = {12}, number = {}, pages = {23779608261464872}, pmid = {42370313}, issn = {2377-9608}, abstract = {BACKGROUND: Emergency nurses in Palestinian hospitals operate under chronic stress related to political instability, resource constraints, and high trauma exposure. These conditions may affect both psychological resilience and Advanced Life Support (ALS) competency, yet the evidence base remains unclear. This scoping review sought to map the available body of literature about psychological resilience and ALS competency among emergency nurses in Palestine, identify gaps in research, and determine the relationship between psychological resilience and ALS competency, which is the core focus of this review.

METHODS: Following PRISMA-ScR guidelines and JBI scoping review methodology, a comprehensive search of seven electronic databases and grey literature was conducted for studies published between January 2000 and January 2026. Two reviewers independently screened studies and extracted data using a standardized, pilot-tested charting form. Findings were synthesized descriptively using narrative synthesis organized around the review objectives.

RESULTS: From 1,292 records identified, 18 studies met inclusion criteria. Most studies were descriptive or correlational (94.4%). Burnout prevalence among emergency nurses ranged from 64% to 72.9%, and substantial gaps in ALS/BLS knowledge were reported, including low accuracy in resuscitation sequence identification (26.6%). Only one intervention study was identified, evaluating simulation-based BLS training. No studies were found that assessed resilience-based or comprehensive programs which address psychological wellbeing and clinical competency issues. There were no studies that specifically analyzed the connection between psychological resilience and competency in ALS.

CONCLUSION: The existing literature on Palestinian emergency nurses is dominated by descriptive studies, with a marked absence of intervention research. Despite documented psychological distress and clinical competency gaps, no studies have evaluated psychological resilience-focused or integrated interventions. This review highlights critical evidence gaps and provides a foundation for future intervention-oriented research.}, } @article {pmid42371053, year = {2026}, author = {Stipa, G and Colosimo, C and Vanacore, N}, title = {Neurodegenerative diseases and environmental risk factors: an overview of the available scientific evidence.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {42371053}, issn = {1435-1463}, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are among the most well-known and prevalent neurodegenerative disorders. These diseases result from an interaction between the environment and genetically predisposed individuals. This review examines the evidence available in the literature underlying this multifaceted interaction, focusing on various chemical substances such as metals, fertilizers, and herbicides, as well as toxic agents of microbiological origin, including cyanobacteria and their neurotoxins. In addition, the pathways through which toxic substances can enter the human body are discussed, such as air and water, which may lead to absorption through the lungs, the gastrointestinal tract, the skin, and mucosae. The routes by which neurotoxic substances gain access to the human body may help explain the increased risk of developing neurodegenerative diseases observed in sports played on soil and grass surfaces, such as soccer, American football, and golf.}, } @article {pmid42371122, year = {2026}, author = {Gremmler, PA and von der Gablentz, J and Meyer, J and Ilse, B and Farahi Ghasraboonasr, B and Dalbert, S and Buchholz, IJ and Grosskreutz, J and Steinbach, R}, title = {Quantification of amyotrophic lateral sclerosis (ALS) disease accumulation with T1-weighted high-resolution magnetic resonance imaging: validation in an independent cohort.}, journal = {Journal of neurology}, volume = {273}, number = {7}, pages = {}, pmid = {42371122}, issn = {1432-1459}, support = {EXC 2167//Deutsche Forschungsgemeinschaft/ ; 413668513//Deutsche Forschungsgemeinschaft/ ; 583362031//Deutsche Forschungsgemeinschaft/ ; ACSP 14//Interdisciplinary Centre of Clinical Research of the Medical Faculty Jena/ ; PROMO-2025-01//Interdisciplinary Centre of Clinical Research of the Medical Faculty Jena/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; Female ; Male ; Cohort Studies ; Middle Aged ; Aged ; Disease Progression ; *Gray Matter/diagnostic imaging/pathology ; *White Matter/diagnostic imaging/pathology ; Image Processing, Computer-Assisted ; Adult ; Case-Control Studies ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease with multifaceted phenotypic presentation thus obstructing objective disease staging. The D50 disease progression model is a framework to comprehensively dissect biomarker-signals towards their relevance regarding disease accumulation/phase (rD50), or disease aggressiveness (D50). Based on previous findings using 1.5-Tesla Magnetic-Resonance-Imaging (MRI), this study hypothesized that high-resolution MRI markers of Grey-Matter (GM) structural integrity would enable quantification of disease accumulation, independent of aggressiveness.

METHODS: A separate cohort of 75 patients with ALS and 73 Healthy Controls (HC) underwent T1-weighted 3-Tesla MRI. Voxel-Based-Morphometry measured GM and White-Matter (WM) density and Surface-Based-Morphometry assessed Cortical Thickness (CT). Non-parametric Threshold-Free-Cluster-Enhancement with 5000 permutations was applied for inter-group and regression contrasts, whilst correcting for possibly interfering co-variates and applying Family-Wise-Error-adjustment.

RESULTS: Compared with HC, the ALS cohort showed widespread decreases of CT and GM/WM density (p < 0.001). These case-control effects were driven by patients scanned during rD50-defined disease Phase 2 (p < 0.001). Within the ALS-cohort, direct Phase 2 versus Phase 1 contrasts revealed spatially-distributed decreases, reflecting higher disease accumulation (p < 0.05). These were independent of disease aggressiveness (and onset-region), as corrected for in the models. Accordingly, all contrasts assessing aggressiveness did not yield significant results.

CONCLUSIONS: These semi-automated analyses of T1-weighted-images captured disease accumulation related GM structural integrity-loss in this cohort scanned with 3-Tesla MRI, independent of the underlying disease aggressiveness. This principle was validated across different scanners and field strengths, supporting its application for objective and non-invasive staging of patients with ALS, whereby true longitudinal studies are necessary.}, } @article {pmid42372734, year = {2026}, author = {Pena, C and Barker, C and Grossberg, AN and Mian, I and Williams, S and MacAllister, T and Vu, T and Linseman, DA}, title = {An open-label Phase 2a study of fasudil in amyotrophic lateral sclerosis: safety and exploratory endpoints.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2694507}, pmid = {42372734}, issn = {2167-9223}, abstract = {OBJECTIVES: The primary objective was to assess the safety of oral fasudil in amyotrophic lateral sclerosis (ALS) patients. Changes in serum neurofilament light (NfL) levels and the ratio of phosphorylated to total AKT (pAKT/tAKT) were exploratory endpoints.

METHODS: This was a multicenter, open-label study. Two 31-patient cohorts were sequentially enrolled and treated with either 180 mg or 300 mg per day of oral fasudil for 24 weeks. The primary endpoint was safety. Secondary endpoints evaluated changes in the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity, and muscle strength. We also assessed changes in serum NfL and pAKT/tAKT ratios in plasma (neuron-derived) and CSF (total) extracellular vesicles (EVs).

RESULTS: Eighty-one percent (25/31) and 71% (22/31) of patients completed 24 weeks of treatment in the 180 and 300 mg cohort, respectively. Fasudil was safe and well tolerated, with predominantly mild drug-related adverse events. Secondary endpoints, though not statistically significant, were directionally consistent with a treatment effect. Exploratory analyses showed a 15.4% reduction in serum NfL at 24 weeks (p = 0.001) in the 180 mg cohort, with no change in the 300 mg cohort (-0.4%, p = 0.990). The NfL reduction was inversely correlated with ALSFRS-R decline (Spearman = -0.45, p = 0.028). Ratios of pAKT/tAKT, a pharmacodynamic marker of rho kinase (ROCK) inhibition, were significantly increased at 24 weeks in plasma (neuron-derived) and CSF EVs.

CONCLUSIONS: Oral fasudil is safe and well-tolerated in ALS patients. The reduction in NfL and demonstration of CNS target engagement, supports studying the 180 mg dose in a double-blind placebo-controlled study.}, } @article {pmid42373582, year = {2026}, author = {Granger, SM and Staniforth, RA and Snorradottir, AO and Cooper-Knock, J and De Vos, KJ and Highley, JR}, title = {Unravelling the Significance of Cystatin C and Bunina Bodies in Amyotrophic Lateral Sclerosis Pathogenesis.}, journal = {Neuropathology and applied neurobiology}, volume = {52}, number = {4}, pages = {e70083}, pmid = {42373582}, issn = {1365-2990}, support = {/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Cystatin C/metabolism ; Animals ; *Inclusion Bodies/pathology/metabolism ; *Motor Neurons/pathology/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a fatal neurodegenerative disease primarily affecting motor neurons. Two key protein inclusions found in lower motor neurons serve as neuropathological hallmarks of the disease in human tissue: the TDP43-positive inclusion and the cystatin C-positive Bunina body. Despite their diagnostic specificity and presence in most sporadic and familial ALS cases, Bunina bodies remain poorly understood, and their true prevalence is likely underestimated. The co-occurrence of the Bunina body and the TDP43 inclusion may provide valuable insights into the development of TDP43 pathology in ALS. Thorough characterisation of the Bunina body is needed to understand this interplay and the broader pathomechanisms of disease. This review examines our current knowledge of Bunina bodies and the biochemical properties of cystatin C that may promote its aggregation. Sequestration and aggregation of cystatin C into Bunina bodies may diminish its neuroprotective functions, including cysteine protease inhibition, autophagy induction and anti-amyloidogenic activity, thereby contributing to ALS pathogenesis. This review also evaluates findings from human post-mortem tissue and ALS disease models, discussing the value and limitations of these models in the context of Bunina bodies and TDP43 pathology. Finally, we discuss cystatin C's use as a biomarker and its therapeutic potential. A deeper understanding of cystatin C biology, its relationship with TDP43 pathology and improved ALS models will be essential for determining whether targeting cystatin C could provide a viable avenue for future ALS therapies.}, } @article {pmid42373784, year = {2026}, author = {Li, Y and Ulrich, JD and Holtzman, DM}, title = {Adaptive immunity in the pathogenesis of neurodegeneration.}, journal = {Nature immunology}, volume = {27}, number = {7}, pages = {1375-1389}, pmid = {42373784}, issn = {1529-2916}, support = {AG085374//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG069701//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG078106//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG083977//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; NS090934//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Humans ; *Adaptive Immunity/immunology ; *Neurodegenerative Diseases/immunology/pathology/therapy ; Animals ; Microglia/immunology ; *Central Nervous System/immunology/pathology ; Astrocytes/immunology ; Immunity, Innate ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and others, are a group of neurological disorders characterized by progressive neuronal loss in the central nervous system (CNS) and the deterioration of CNS function. Multiple lines of evidence have highlighted activation of innate immune cells in the CNS, namely microglia and astrocytes, as hallmark pathological features in neurodegeneration and key drivers of disease progression. Advances in genetic, neuropathological and experimental studies also underscore the potential role of the adaptive immune system in disease pathogenesis. Here we summarize the current understanding of how adaptive immunity can shape the progression of neurodegenerative diseases and highlight cross-disease parallels and potentially shared mechanisms. We also examine cellular events leading to the recruitment of peripheral immune cells to the CNS, as well as candidate antigens driving the adaptive immune response. Last, we discuss potential therapeutic strategies to treat neurodegeneration via the manipulation of adaptive immune cells.}, } @article {pmid42373786, year = {2026}, author = {Guo, AX and Fisher, TM and Comandante-Lou, N and De Jager, PL and Liddelow, SA}, title = {Innate immune signaling and functions in astrocytes.}, journal = {Nature immunology}, volume = {27}, number = {7}, pages = {1364-1374}, pmid = {42373786}, issn = {1529-2916}, support = {AARF-24-1313800/ALZ/Alzheimer's Association/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; }, mesh = {*Astrocytes/immunology/metabolism ; Humans ; *Immunity, Innate/immunology ; Animals ; *Signal Transduction/immunology ; Toll-Like Receptors/metabolism/immunology ; Innate Immunity Recognition ; Inflammasomes/metabolism/immunology ; }, abstract = {Astrocytes, long considered supportive cells of the central nervous system (CNS), have critical roles in innate immunity. This Review explores immune signaling pathways in astrocytes, including pattern recognition through Toll-like receptors, nucleic acid sensors and inflammasomes. These pathways enable the detection of danger signals and initiate protective responses and endogenous innate immune functions. Downstream signaling pathways, including the interferon, NF-κB and STAT3 pathways, mediate astrocyte reactivity and drive cytokine secretion, antiviral responses, phagocytosis and many other immune functions. While these responses are crucial for CNS health, their dysregulation can contribute to chronic inflammation and neurodegeneration in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Additionally, astrocytes exhibit regional heterogeneity in their immune behaviors, which may influence disease trajectories. We highlight unresolved questions regarding the immune functions of astrocytes, their interplay with professional immune cells and their dual protective and pathological roles.}, } @article {pmid42374626, year = {2026}, author = {Walton, EI and Sun, J}, title = {Microbiome and metabolites impact enteric and central nervous systems in ALS.}, journal = {Gut microbes}, volume = {18}, number = {1}, pages = {2692737}, pmid = {42374626}, issn = {1949-0984}, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/metabolism/physiopathology ; Humans ; *Central Nervous System/metabolism/microbiology/physiopathology ; *Enteric Nervous System/metabolism/physiopathology/microbiology ; *Gastrointestinal Microbiome/physiology ; Animals ; Dysbiosis/microbiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has been linked to gastrointestinal symptoms and alterations in the gut microbiota. The enteric nervous system (ENS) coordinates intestinal function and sits at the host-microbe interface. The mechanisms by which luminal changes relay to the central nervous system (CNS), where motor neurons reside, have yet to be completely defined. In this narrative review, we first present evidence from ALS patient cohorts and preclinical models alongside mechanistic studies of infection, dysbiosis, and related neurodegenerative diseases to discuss how the microbiota and its metabolites may affect the ENS and CNS in ALS. Next, we propose a plausible mechanism of ALS pathogenesis through the gut-microbiome-brain axis. We further offer a summary of clinical trials that have studied the impacts of the microbiota on human ALS. Finally, we discuss future directions for studies of microbiota-ENS-CNS interactions in ALS. Better understanding of the dynamic interactions among the microbiota, microbial metabolites, neuroactive metabolites, and inflammation through the ENS/CNS in ALS will provide innovative insights into ALS prevention and treatment.}, } @article {pmid42375068, year = {2026}, author = {Siddik, SH and Miah, MBA and Alam, SKM and Sumaiya, TS and Debnath, D and Haque, SMA}, title = {Distal Motor Latency in Amyotrophic Lateral Sclerosis: A Robust and Reliable Prognostic Marker.}, journal = {Mymensingh medical journal : MMJ}, volume = {35}, number = {3}, pages = {924-931}, pmid = {42375068}, issn = {2408-8757}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Prognosis ; Female ; Male ; Longitudinal Studies ; Middle Aged ; Adult ; }, abstract = {An electrophysiological test is routinely done to confirm Amyotrophic Lateral Sclerosis (ALS) and rule out differentials. Distal Motor Latency (DML) is a simple electrophysiological measure that is always done in a primary setting. It can be used as an excellent prognostic marker for ALS so that we can know ALS better and formulate precise management plans. This longitudinal study was conducted in the Neurology Department of Bangladesh Medical University (BMU), Dhaka, Bangladesh from April 2022 to October 2023. In this study a total of 34 subjects, 17 ALS patients with normal DML and 17 ALS patients with prolonged DML, were enrolled. Severity was assessed by the ALS functional rating scale-revised (ALSFRS-R). The study's endpoints were determined as death during this 6-month follow-up or reaching an advanced stage (ALSFRS-R <20). Then, an electrophysiological test was used to measure DML in all four commonly tested nerves. ALSFRS-R was significantly reduced (p<0.025) at 6 months in ALS patients with prolonged DML than normal DML. It was found that having a higher odd (p<0.012, OR=20.718), prolonged DML had a significant impact on the outcome of ALS patients than that of normal DML. In multivariate analysis, lower ALSFRS-R at diagnosis (B= -0.124, p<0.001, HR=0.883) and prolonged DML (B=1.412, p<0.031, HR=4.104) were associated with poor outcomes. ALS patients with prolonged DML also had a poorer prognosis than patients with normal DML (log-rank test, p<0.045). In this study, patients with prolonged DML had a significant functional decline, rapid disease progression and poor prognosis than patients with normal DML. So, prolonged DML can be used as a robust prognostic marker for patients with ALS.}, } @article {pmid42375130, year = {2026}, author = {Bozkurt, H and Reid, KR and Newton, J and Gill, J and Chau, I and Parker, C and Kurucu King, H and Tam, J and Ng, D and Stavrou, M and Baxter, P and Marland, O and Burr, K and Heslegrave, A and Veleva, E and Swann, OJ and Zetterberg, H and Hunt, DPJ and Thangaraj Selvaraj, B and Chandran, S and Pal, S}, title = {Blood-based biomarker discovery in motor neuron disease using nucleic acid-linked immuno-sandwich assay.}, journal = {Brain communications}, volume = {8}, number = {3}, pages = {fcag180}, pmid = {42375130}, issn = {2632-1297}, abstract = {Motor neuron disease (MND) presents with phenotypic heterogeneity, is diagnostically challenging, and has poor prognosis. The absence of accessible blood-based biomarkers has hampered progress towards precision medicine. Highly sensitive immunoassays offer considerable promise for identifying blood-based biomarkers informing underlying pathophysiology and enabling accurate diagnosis and monitoring. We report findings on parallel use of the ultra-sensitive multiplexed NUcleic Acid-Linked Immuno-Sandwich Assay (NULISA) and single molecule array (Simoa), to interrogate serum from people with MND. Sera (48 MND, 38 controls) were analysed using a NULISAseq targeted neurodegenerative panel and a Simoa neurofilament light chain (NfL) and glial fibrillary acid protein (GFAP) duplex assay. Neurofilament light and heavy chain, total tau (t-tau), phosphorylated tau (pTau)-181, pTau-217, pTau-231, fatty acid binding protein 3, amyloid beta (Aβ) 38 and Aβ40 levels were significantly elevated in MND (P < 0.05). Simoa and NULISAseq assays demonstrated strong correlations for NfL and GFAP (r > 0.90). Use of the multiplexed NULISAseq panel confirmed a well-established NfL elevation in MND, and replicated findings for other proteins from recent studies. Results add confidence in the validity and reproducibility of biomarkers identified using NULISAseq, while offering insights into the underlying pathophysiology and heterogeneity of MND.}, } @article {pmid42375131, year = {2026}, author = {Thomas, EV and Pant, DC}, title = {Beyond neurofilaments: a multidimensional blood signature for amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {3}, pages = {fcag231}, pmid = {42375131}, issn = {2632-1297}, abstract = {This scientific commentary refers to 'Blood-based biomarker discovery in motor neuron disease using nucleic acid-linked immuno-sandwich assay', by Bozkurt et al. (https://doi.org/10.1093/braincomms/fcag180).}, } @article {pmid42376391, year = {2026}, author = {Ali, MA and Al-Ezzy, AIA}, title = {Investigating the human-animal interface: Clinical and molecular features of oral Candida spp. in cat owners.}, journal = {Open veterinary journal}, volume = {16}, number = {2}, pages = {1012-1026}, pmid = {42376391}, issn = {2218-6050}, mesh = {Animals ; Cats ; Humans ; *Cat Diseases/microbiology/epidemiology ; Male ; Female ; *Mouth/microbiology ; *Candida/isolation & purification/genetics ; *Candidiasis, Oral/veterinary/microbiology/epidemiology ; Candida albicans/isolation & purification/genetics ; Risk Factors ; }, abstract = {BACKGROUND: Candida albicans is a ubiquitous commensal fungus and is capable of transitioning from commensalism to infection.

AIM: To isolate and identify Candida spp. from oral swabs of domestic cats. Detection of virulence factors, agglutinin-like sequence agglutinin-like sequence 1 (ALS), and Candidalysin (ECE1) genes exploration of the possible relationship between Candida and potential risk factors in cat owners.

METHODS: A total of 119 oral swabs were collected from cat owners and streaked directly on Sabouraud's dextrose and chrome agars. Confirmation was performed by testing the isolates using the Vitek 2 compact system and conventional polymerase chain reaction (PCR) using primers specific to the ITS4 and ITS5 regions. ALS and ECE1 genes were detected using conventional PCR.

RESULTS: The total number of Candida spp. isolated from the oral cavity of cat owners was 10/119 (8.40%). Correlations were reported between the isolation of Candida from the oral cavity and age group; use of oral antibiotic drops; diabetes mellitus; oral lesions; and vitamin D3 deficiency (p value < 0.001). No significant correlation was reported between sex, season, smoking habit, denture wearing, steroid inhalation, immune suppression, and Candida isolation from the oral cavity of cat owners. ASL1 and ECE1 were detected in 100% of C. albicans isolated from the oral cavity of cat owners.

CONCLUSION: This study reveals a low prevalence but high pathogenic potential of oral C. albicans in domestic cat owners, as evidenced by the universal presence of major virulence genes (ALS1, ECE1). Older age, antibiotic drops, Diabetes miletus, oral lesions, and vitamin D3 deficiency were associated with the risk of colonization. The commonly suspected risk factors showed no association. The universal presence of ALS1 and ECE1 highlights the pathogenic threat posed by these yeasts.}, } @article {pmid42376656, year = {2026}, author = {Baik, J and Hughes, N and Ferrer, V}, title = {Afferent loop syndrome secondary to recurrent pancreatic adenocarcinoma post-Whipple procedure: case report.}, journal = {Frontiers in oncology}, volume = {16}, number = {}, pages = {1838218}, pmid = {42376656}, issn = {2234-943X}, abstract = {BACKGROUND: Afferent loop syndrome (ALS) is a rare but serious complication following pancreaticoduodenectomy, most often due to recurrent malignancy.

CASE PRESENTATION: A 62-year-old male patient with stage IIb pancreatic ductal adenocarcinoma status post-Whipple procedure presented with acute abdominal pain, bowel obstruction, and sepsis after months of persistent watery diarrhea. Imaging demonstrated recurrent pancreatic malignancy causing obstruction of the pancreaticobiliary limb consistent with ALS. Blood cultures grew Klebsiella pneumoniae, confirming sepsis secondary to obstruction. Endoscopy revealed a severe non-traversable afferent limb stricture, and palliative decompression with uncovered metal stent placement resulted in rapid clinical improvement.

DISCUSSION/CONCLUSION: This case highlights the need for a high degree of suspicion for ALS in post-Whipple patients with nonspecific gastrointestinal symptoms, particularly in the setting of recurrent malignancy. The prolonged refractory diarrhea preceding acute obstruction illustrates an atypical presentation that may delay diagnosis. Early imaging and minimally invasive endoscopic intervention can provide effective palliation and prevent severe complications.}, } @article {pmid42377311, year = {2026}, author = {Price, TR and Chang, CY and Skinner, K and Dinneny, M and Nafezi, P and Kuramoto, L and De Vera, MA and Cashman, NR and Cragg, JJ}, title = {Could anticholinergics accelerate ALS progression? A critical perspective on drug safety and disease vulnerability.}, journal = {Expert opinion on drug safety}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/14740338.2026.2687628}, pmid = {42377311}, issn = {1744-764X}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with limited treatment options and diverse symptoms necessitating active management. Anticholinergic medications are frequently used in ALS care, particularly for sialorrhea and mood disturbances. Their cumulative effects, termed anticholinergic burden, may pose underrecognized risks in this neurologically vulnerable population. This review highlights a plausible safety signal and outlines priorities for future research.

AREAS COVERED: This narrative review synthesizes evidence from non-ALS populations reporting associations between higher anticholinergic burden and cognitive decline, respiratory complications, functional deterioration, and mortality. Evidence was identified through targeted PubMed/MEDLINE and Embase searches with reference chaining, emphasizing recent and seminal studies. Mechanistic overlap with ALS pathophysiology, including neuromuscular junction disruption, impaired cholinergic signaling, and neuroinflammation, supports biological plausibility for harm. Current ALS guidelines do not address cumulative anticholinergic exposure, leaving clinicians without a framework for evaluating risk or deprescribing.

EXPERT OPINION: This article proposes a testable hypothesis that anticholinergic burden may represent a clinically relevant yet unmeasured risk factor in ALS. Emerging pharmacoepidemiologic methods and validated burden tools offer approaches to quantify exposure and evaluate relationships with ALS outcomes, supporting safer symptomatic management. Prioritizing longitudinal studies and integrating burden assessment into multidisciplinary care may help clarify risk.}, } @article {pmid42378369, year = {2026}, author = {Kim, J and Lee, H and Lim, J and Oh, J and Shin, SS and Yoon, M}, title = {RETRACTED: Kim et al. The Angiogenesis Inhibitor ALS-L1023 from Lemon-Balm Leaves Attenuates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease Through Regulating the Visceral Adipose-Tissue Function. Int. J. Mol. Sci. 2017, 18, 846.}, journal = {International journal of molecular sciences}, volume = {27}, number = {13}, pages = {}, pmid = {42378369}, issn = {1422-0067}, abstract = {The journal retracts the article titled "The Angiogenesis Inhibitor ALS-L1023 from Lemon-Balm Leaves Attenuates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease through Regulating the Visceral Adipose-Tissue Function" [...].}, } @article {pmid42381214, year = {2026}, author = {Suer, IE and Tursun, N}, title = {Effects of elevated CO2 and temperature on cocklebur (Xanthium strumarium L.) and its herbicide response.}, journal = {Pest management science}, volume = {82}, number = {10}, pages = {10303-10311}, pmid = {42381214}, issn = {1526-4998}, support = {//Tarimsal Araştirmalar ve Politikalar Genel Müdürlüğü, Türkiye Cumhuriyeti Tarim Ve Orman Bakanliği/ ; }, mesh = {*Herbicides/pharmacology ; *Carbon Dioxide/metabolism ; Temperature ; *Xanthium/drug effects/growth & development ; Climate Change ; }, abstract = {BACKGROUND: Climate change, characterized by rising atmospheric CO2 and temperature fluctuations, significantly alters crop-weed interactions and weed management efficacy. This study evaluated the interactive effects of elevated CO2 (400, 600, 800, and 1000 ppm) and temperature regimes (26/16°C and 29/19°C) on the biomass accumulation of Xanthium strumarium and the efficacy of two herbicides with distinct modes of action: trifloxysulfuron-sodium (systemic, ALS inhibitor) and fluometuron (soil-active, PSII inhibitor).

RESULTS: Elevated CO2 concentration up to 1000 ppm at the optimal temperature (26/16°C) significantly stimulated the vegetative growth and dry biomass of X. strumarium. Crucially, dose-response analyses revealed that this climate-driven accelerated growth did not induce herbicide resistance; rather, it increased the weed's susceptibility to the systemic herbicide. Elevated CO2 facilitated the translocation of trifloxysulfuron-sodium due to increased plant metabolism, thereby significantly lowering ED50 values. In contrast, the efficacy of the soil-applied fluometuron remained highly stable and unaffected by variations in either CO2 or temperature.

CONCLUSION: The interaction between climate change variables and chemical weed control is fundamentally driven by the herbicide's mode of action. While elevated CO2 acts as a fertilizer for X. strumarium, the resulting rapid growth paradoxically increases the efficacy of systemic herbicides by accelerating the movement of active ingredients. Meanwhile, soil-active herbicides like fluometuron offer a climate-resilient weed management strategy. Future studies should incorporate molecular approaches to fully elucidate these mode-of-action-specific physiological responses under changing climatic conditions. © 2026 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid42381488, year = {2026}, author = {Eigenhuis, KN and Ferrer, RM and Pasterkamp, RJ}, title = {Neural Organoid Models as a Platform for Studying Disease Mechanisms in Amyotrophic Lateral Sclerosis.}, journal = {Journal of neurochemistry}, volume = {170}, number = {7}, pages = {e70513}, pmid = {42381488}, issn = {1471-4159}, support = {//Stichting ALS Nederland/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Organoids/pathology/metabolism ; *Induced Pluripotent Stem Cells/pathology/metabolism ; Animals ; *Neurons/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons leading to muscle wasting. However, structural and molecular abnormalities, including cortical thinning and TDP-43 pathology, extend into frontal, parietal, and temporal areas, pointing to defects across broader cortical regions. The advent of human induced pluripotent stem cell (hiPSC) technology has enabled the generation of human-specific brain cell types in vitro. Here, we provide an overview of the three-dimensional (3D) hiPSC-derived neural organoid platforms used to model cortical structures and to study cortical ALS-associated phenotypes. We review which pathological hallmarks have been recapitulated in these organoids and discuss disease phenotypes reported to date. Further, we comprehensively cover different neural organoid models and experimental strategies, including patient-derived hiPSC models and exogenous pathology induction, while addressing current technical challenges. Together, these advances position neural organoids as an emerging tool to study cell-type-specific and circuit-level mechanisms related to cortical changes in ALS.}, } @article {pmid42381982, year = {2026}, author = {Deng, Z and Zhang, R and Zhu, Y and Xu, C and Yang, M and Li, L and Cheng, Y and Shi, H and Dou, C and Zhang, M and Xia, Y and Fan, K}, title = {Antioxidant Nanozymes: From Rational Design to Biomedical Applications.}, journal = {Research (Washington, D.C.)}, volume = {9}, number = {}, pages = {1318}, pmid = {42381982}, issn = {2639-5274}, abstract = {Antioxidant nanozymes regulate reactive oxygen species homeostasis by mimicking the core catalytic functions of natural antioxidant enzymes, including superoxide dismutase-, catalase-, and glutathione peroxidase-like activities. The clinical translation of natural antioxidant enzymes has long been hampered by inherent limitations: short in vivo half-life, susceptibility to inactivation under physiological conditions, cumbersome purification processes, high production costs, non-negligible immunogenicity, and limited targeting capacity. In contrast, antioxidant nanozymes can overcome these bottlenecks with superior structural stability, tunable catalytic activity, low preparation cost, and flexible multifunctional modification. Guided by the catalytic mechanisms of natural enzymes, researchers have established rational design strategies for antioxidant nanozymes. To date, a diverse array of antioxidant nanozymes have been developed, with promising applications in multiple biomedical fields, including inflammatory diseases, ischemia-reperfusion injury, neurodegenerative disorders, and cancer adjuvant therapy. Notably, landmark clinical progress has been achieved: The catalytic nanocrystal suspension CNM-Au8, a therapeutic candidate for amyotrophic lateral sclerosis, has advanced to phase II clinical trials. This review systematically summarizes the core catalytic mechanisms of antioxidant nanozymes, clarifies the structure-activity relationships between rational material design and catalytic performance, reviews the latest advances in their biomedical applications, and dissects the key bottlenecks restricting preclinical research and clinical translation. It aims to provide rational design principles for researchers in this field, reduce empirical trial and error in material development, and provide guidance for the further optimization and clinical translation of antioxidant nanozymes.}, } @article {pmid42382427, year = {2026}, author = {Sugimoto, T and Tachiyama, K and Hironaka, A and Naito, H and Nakamori, M and Aoki, S and Yamazaki, Y and Maruyama, H}, title = {Simultaneous ultrasound and needle electromyography recording of fasciculations in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {11}, number = {}, pages = {448-452}, pmid = {42382427}, issn = {2467-981X}, abstract = {OBJECTIVE: Fasciculations can be detected using both muscle ultrasonography and needle electromyography, yet the correspondence between ultrasonographically observed fasciculations (U-fas) and needle electromyography-detected fasciculation potentials (N-fas) has not been clarified. This study investigated their correspondence using fully synchronized recordings.

METHODS: Adult patients showing fasciculation-like contractions on muscle ultrasonography were enrolled; all were subsequently diagnosed with amyotrophic lateral sclerosis. Ultrasound and needle electromyography were recorded simultaneously in up to three muscles per patient, with a recording duration of 3 min per muscle. For each ultrasonographically observed fasciculation, the presence of a corresponding electromyographic event and contraction duration assessed by M-mode imaging were evaluated.

RESULTS: Ten patients with amyotrophic lateral sclerosis were included. A total of 472 focused U-fas events were analyzed. Corresponding N-fas were detected in 437 events, yielding an overall concordance rate of 92.6% (95% confidence interval, 90.2-95.0%). U-fas contraction duration ranged from 343 to 971 ms, whereas N-fas duration ranged from 10.9 to 76.4 ms. The number of phases of N-fas observed during U-fas events ranged from 1 to 10.

CONCLUSIONS: Most ultrasonographically observed fasciculations corresponded to electromyography-detected events on simultaneous recording.

SIGNIFICANCE: Ultrasonographically detected fasciculations may serve as a supplementary indicator of lower motor neuron involvement in amyotrophic lateral sclerosis.}, } @article {pmid42383056, year = {2026}, author = {Liu, DZ and Cheng, GL and Hu, CF and Li, RY and Yang, CC and Chen, NC and Li, X and Jiang, DY and Chang, JY}, title = {Alternative splicing-based therapeutics for neurodegenerative diseases: a dual-database bibliometric and NLP-driven analysis (2000-2025).}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1849726}, pmid = {42383056}, issn = {2296-858X}, abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) are driven by complex molecular dysregulation, among which aberrant alternative splicing (AS) has emerged as a critical pathogenic mechanism. Despite the rapid development of splicing-targeted therapeutics, including antisense oligonucleotides (ASOs) and small molecules, comprehensive big-data syntheses mapping this translational landscape remain scarce. This study systematically analyzes the global research trends, conceptual frameworks, and clinical evolution of AS-based therapeutics for NDDs using an integrated bibliometric and natural language processing (NLP) approach.

METHODS: A dual-database retrieval strategy utilized the Web of Science Core Collection (WoSCC) and PubMed. The analysis targeted literature published between January 1, 2000, and December 31, 2025. A primary dataset of 620 records was extracted from WoSCC for comprehensive bibliometric mapping and Latent Dirichlet Allocation (LDA) topic modeling. A parallel analysis incorporated 10 targeted clinical trials and randomized controlled trials (RCTs) from PubMed using CLARA clustering to characterize high-evidence research. Bibliometric analyses, encompassing network topologies, citation bursts, and keyword evolution, were visualized using VOSviewer, CiteSpace, SCImago, and R.

RESULTS: Publication output exhibited sustained linear growth from 2000 to 2025. The United States and Western Europe emerged as the dominant collaborative hubs, while China exhibited high productivity but limited international integration. LDA topic modeling identified three core conceptual axes: molecular mechanisms, disease-specific pathological models (e.g., ALS, Alzheimer's, and SMA), and translational methodological frameworks. Keyword trajectories delineated a transition from fundamental in vitro exploration to in vivo models, culminating in clinical "drug discovery" and "RNA" therapeutics. CLARA clustering of clinical trials demonstrated a stark concentration of splicing-modifying interventions in pediatric spinal muscular atrophy (SMA), revealing a dual-track paradigm of supportive care and molecular interventions.

CONCLUSION: This multi-database bibliometric and NLP-driven study delineates the structural landscape of AS-based therapeutics for NDDs. It identifies a definitive paradigm shift from descriptive molecular biology to clinically actionable splicing interventions. These insights highlight the necessity to expand targeted RNA platforms beyond SMA into adult neurodegenerative populations, providing a strategic roadmap for future translational research.}, } @article {pmid42383305, year = {2026}, author = {Christoforidou, E and McFagan, E and McLaughlin, M and Hafezparast, M}, title = {TDP-43 proteinopathy as a biomarker and therapeutic target in amyotrophic lateral sclerosis.}, journal = {Biochemical Society transactions}, volume = {54}, number = {7}, pages = {901-913}, pmid = {42383305}, issn = {1470-8752}, support = {Hafezparast/Apr21/880-791//Motor Neurone Disease Association (MNDA)/ ; //LifeArc/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/therapy/genetics/pathology ; Biomarkers/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; *TDP-43 Proteinopathies/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of adult-onset motor neuron disease, characterised by the degeneration of upper and lower motor neurons. The cytoplasmic aggregation of TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein, is considered a hallmark of ALS pathology, found in nearly all postmortem cases of ALS. TDP-43 is normally primarily nuclear, where it has a widespread role in gene regulation. Mutations, extrinsic stressors, and alterations in RNA homeostasis in ALS lead to nuclear depletion of TDP-43 and the formation of cytosolic TDP-43 aggregates. This causes multiple downstream effects on neuronal function and degeneration as well as gene expression. TDP-43 is a promising target as a biomarker, as it is found to be elevated in the biofluids of ALS patients, and its cytoplasmic aggregation can also be observed in peripheral tissues; however, methodological variability and technical limitations currently preclude the establishment of TDP-43 as a standalone biomarker. There are also promising therapeutic strategies in development targeting TDP-43 pathology, but a critical challenge that remains is achieving a balance between eliminating toxic aggregates and preserving the essential functions of TDP-43. In summary, with further research, considering TDP-43 pathology in ALS gives hope for finding future novel diagnostics and therapeutics for ALS.}, } @article {pmid42383392, year = {2026}, author = {Sabouri, E and Shahmoradi, T and Keshvari, NZ and Khodaee, P and Saleki, K and Rezaei, N}, title = {Role of Toll-like receptors and oral-gut-brain axis in neurodegenerative and neuropsychiatric disorders.}, journal = {Reviews in the neurosciences}, volume = {}, number = {}, pages = {}, pmid = {42383392}, issn = {2191-0200}, abstract = {The oral-gut-brain axis is a path connecting the gastrointestinal tract and the central nervous system (CNS). The gut microbiota influences the immune system, metabolism, and nerve cells through the production of neurotransmitters and microbial metabolites that can cross the blood-brain barrier (BBB). The interplay between neuroinflammation and altered oral and gut microbiota is a bidirectional complex path modulated by inflammatory mediators. Recent studies suggest a potential role for Toll-like receptor (TLR) signaling pathways in the induction of neuroinflammation via the oral-gut-brain axis. As neuroinflammation is one of the key elements in the pathophysiology of neurodegenerative and neuropsychiatric disorders, this review was conducted to reflect on the pathophysiological pathways and clinical evidence on the role of TLR and inflammasome signaling pathways via oral-gut-brain axis in neurodegenerative diseases such as cognitive impairment, Alzheimer's disease, Multiple sclerosis, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis, and psychiatric disorders such as major depressive disorder, anxiety disorders, schizophrenia, bipolar disorders, and Autism spectrum disorders. Because the contributing factors have not been fully understood yet, further studies could help provide novel therapeutic opportunities.}, } @article {pmid42384233, year = {2026}, author = {Kotambail, A and Arunachal, G and Keerthipriya, MS and Mahima, R and Sukrutha, R and Ramyashree, MB and Deekshitha, M and Rao, BM and Biswas, P and Polavarapu, K and Preethish-Kumar, V and Reddy, P and Gray, O and Wasik, KA and Emde, AK and Angadi, S and Bhattacharya, B and Zacharia, M and Jeevitha, KV and Kumar, KD and Masaraddi, NH and Nashi, S and Chetan, GK and Vengalil, S and Nalini, A}, title = {Genome-wide spectrum of coding DNA variations in Indian patients with amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {7}, pages = {}, pmid = {42384233}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; India ; Female ; Male ; Superoxide Dismutase-1/genetics ; Adult ; C9orf72 Protein/genetics ; Middle Aged ; Cell Cycle Proteins/genetics ; Transcription Factor TFIIIA/genetics ; Genome-Wide Association Study ; Aged ; Ataxin-2/genetics ; Exome Sequencing ; Genetic Variation/genetics ; Young Adult ; Genetic Predisposition to Disease ; Membrane Transport Proteins ; Janus Kinase 2 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapies, emphasizing the need for deeper understanding of disease pathogenesis. While more than 40 ALS-associated genes have been identified, their contribution varies significantly across populations and the data from the Indian population remains scarce. We aimed to comprehensively characterize the spectrum of coding DNA variations in ALS-associated genes and identify novel genetic contributors in an Indian cohort. Whole-exome sequencing on 761 ALS patients and 917 in-house healthy controls and repeat-primed PCR for expansions (C9orf72, ATXN2, NOTCH2NLC, NOP56) were performed. Variants were classified using ACMG guidelines, and rare variant association testing was conducted. Overall diagnostic yield was 15.90%, with pathogenic/likely pathogenic variants. Familial ALS showed higher diagnostic yield (36.95%) than sporadic ALS (12.96%). SOD1 dominated familial cases (53.85%), while OPTN, SOD1 and FIG4 were prevalent in sporadic cases. Homozygous SOD1 variants in six patients correlated with juvenile/young onset (< 30 years). C9orf72 expansions (4%) and ATXN2 repeats (1.7%) were identified at frequencies comparable with Asian cohorts. Rare variant analysis identified JAK2 as a novel genome-wide significant signal (FDR = 3.5 × 10[-5]). This first large-scale genomic survey of Indian ALS patients showed SOD1 being the predominant cause of fALS, while OPTN, FIG4, and other genes drive disease amidst low C9orf72 frequency. The novel JAK2 association suggests a potential neuroinflammatory mechanism, highlighting the importance of studying diverse populations to uncover distinct genetic etiologies.}, } @article {pmid42385017, year = {2026}, author = {Huynh, A and Cranley, L and Barnett-Tapia, C and Abrahao, A and Zinman, L and Yunusova, Y}, title = {Understanding patients' experiences and needs around decision-making for bulbar symptom management at a multidisciplinary ALS clinic.}, journal = {Disability and rehabilitation}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/09638288.2026.2693395}, pmid = {42385017}, issn = {1464-5165}, abstract = {PURPOSE: This study explored the decision-making experiences of people living with amyotrophic lateral sclerosis (ALS) for managing bulbar symptoms and their perceived needs for decision-making support from healthcare professionals.

METHODS: An interpretive, descriptive qualitative study was conducted. We recruited adult patients with ALS with and without any bulbar symptoms from a multidisciplinary ALS clinic in Central Canada. Patients were interviewed using a semi-structured guide. Reflexive thematic analysis was used to analyze study data. Recruitment ceased when information power was reached.

RESULTS: Twelve participants were interviewed. Three themes were identified for patient's decision-making experiences and needs: (1) Disease uncertainty hinders decision-making; (2) Quality information triggers decision-making; and (3) Personal values and beliefs inform decision-making.

CONCLUSIONS: To reduce psychological consequences of disease uncertainty and complexity on bulbar-related decision-making, patients emphasized the need for specific and contextualized information and healthcare professional supports aligned with their decision-making styles and approaches, highlighting the importance of a person- and family-centred approach to ALS care.}, } @article {pmid42385702, year = {2026}, author = {Zhou, Z and Luquette, LJ and Dong, G and Kim, J and Ku, J and Kim, K and Ramesh, N and Bae, M and Caplin, A and Shao, DD and Sahile, B and Essuman, K and Goodman, E and Miller, MB and Huang, AY and Nathan, WJ and Nussenzweig, A and Park, PJ and Lagier-Tourenne, C and Lee, EA and Walsh, CA}, title = {Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders.}, journal = {Cell}, volume = {189}, number = {18}, pages = {5766-5782.e10}, pmid = {42385702}, issn = {1097-4172}, support = {R01 HG012573/HG/NHGRI NIH HHS/United States ; R56 AG079857/AG/NIA NIH HHS/United States ; DP2 AG072437/AG/NIA NIH HHS/United States ; UG3 NS132144/NS/NINDS NIH HHS/United States ; RM1 NS133601/NS/NINDS NIH HHS/United States ; R01 AG082346/AG/NIA NIH HHS/United States ; K01 AG051791/AG/NIA NIH HHS/United States ; R01 NS032457/NS/NINDS NIH HHS/United States ; DP2 AG086138/AG/NIA NIH HHS/United States ; R01 AG070921/AG/NIA NIH HHS/United States ; UG3 NS132138/NS/NINDS NIH HHS/United States ; R01 AG088082/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurons/metabolism/pathology ; *DNA Topoisomerases, Type I/metabolism ; Alzheimer Disease/genetics/pathology/metabolism ; Frontotemporal Dementia/genetics/pathology/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Neurodegenerative Diseases/genetics/pathology ; DNA Damage ; DNA-Binding Proteins/metabolism ; C9orf72 Protein ; }, abstract = {Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) represent two major categories of neurodegenerative disorders-TAR DNA-binding protein 43 (TDP-43) and tau proteinopathies-for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 469 neurons from C9ORF72 ALS, C9ORF72 FTD, AD, and control brains revealed increased somatic single-nucleotide variants (sSNVs) and insertions/deletions (sIndels) in all three diseases. Mutational signature analysis identified a disease-associated sSNV signature consistent with oxidative damage and an sIndel process affecting 22% of ALS, 76% of FTD, and 61% of AD neurons-but only 2% of control neurons-resembling signature ID4, previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Rapid approach to DNA adduct recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes, and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions. TOP1-associated sIndel mutagenesis and genome instability thus represent a mechanism shared by both TDP-43 and tau neurodegeneration.}, } @article {pmid42385897, year = {2026}, author = {Yuan, L and Huang, H and Hui, M and Xu, S and Xu, D}, title = {Response to Guo et al, "Response to Huang et al's 'Real-world efficacy and safety of tofacitinib on the progression of skin sclerosis in patients with systemic sclerosis: An analysis of national multicenter data from the Chinese Rheumatism Data Center (CRDC)'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.06.121}, pmid = {42385897}, issn = {1097-6787}, } @article {pmid42386387, year = {2026}, author = {Salmon, K and Ilieva, H and Kelly, D}, title = {NMES-Facilitated Mandibular Rehabilitation for Spasticity-Related Trismus in ALS.}, journal = {Muscle & nerve}, volume = {74}, number = {3}, pages = {747-750}, pmid = {42386387}, issn = {1097-4598}, support = {//Salus University through an Internal Faculty Research/ ; }, } @article {pmid42386657, year = {2026}, author = {Shimakura, K and Oka, A and Yudahira, H and Hama, Y and Otomo, A and Hadano, S}, title = {The SQSTM1 L341V Variant Associated With Sporadic ALS Promotes the Accumulation of Enlarged Ubiquitin-Positive SQSTM1 Bodies.}, journal = {Genes to cells : devoted to molecular & cellular mechanisms}, volume = {31}, number = {4}, pages = {e70134}, pmid = {42386657}, issn = {1365-2443}, support = {26290018//Japanese Society for Promotion of Science/ ; 24650189//Japanese Society for Promotion of Science/ ; 19H03551//Japanese Society for Promotion of Science/ ; //Tokai University School of Medicine Research Aid/ ; }, mesh = {*Sequestosome-1 Protein/genetics/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Autophagy ; Microtubule-Associated Proteins/metabolism ; *Ubiquitin/metabolism ; Mutation, Missense ; Lysosomes/metabolism ; Animals ; }, abstract = {SQSTM1 is one of the causative genes of neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The SQSTM1 protein regulates the degradation of polyubiquitinated proteins and autophagosome formation through its interaction with microtubule-associated protein light chain 3 (MAP1LC3/LC3). However, the molecular mechanisms by which SQSTM1-LC3 binding regulates the autophagy-endolysosomal system (APELS) remain unclear. To elucidate the spatiotemporal role of SQSTM1, we transiently expressed wild-type SQSTM1 or missense mutants carrying mutations in the LC3-interacting region (LIR), fused with the photoconvertible fluorescent protein Dendra2. Live-cell fluorescence imaging and co-localization analyses with markers of the APELS were then performed. Particle analysis of photoconverted or non-photoconverted SQSTM1-positive structures in live cells revealed that the pathogenic L341V variant formed larger structures than the wild-type. Co-localization analyses further showed that both the L341V and artificial LIR3A mutants accumulated in large ubiquitin-positive structures, likely due to impaired localization to autophagosomes. These results suggest that mutations within the LIR differentially affect autophagosome formation and cargo degradation within APELS-related compartments, highlighting the importance of SQSTM1 structural integrity in ALS/FTD pathogenesis.}, } @article {pmid42387584, year = {2026}, author = {He, M and Wu, C and Hu, M and Shi, X and Liu, R and Tong, Y and Wang, H and Hu, H and Liao, H}, title = {SGK1-mediated deficits in microglial phagocytosis drive pathological progression in amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12974-026-03925-w}, pmid = {42387584}, issn = {1742-2094}, support = {82372577; 82073831//National Natural Science Foundation of China/ ; }, abstract = {Alterations in microglial function and transcriptomic profiles are major pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the dynamics and regulatory mechanisms underlying microglial phagocytic activity during disease progression remain unclear. In this study, we observed stage-dependent alterations in microglial phagocytic activity during disease progression in SOD1[G93A] mice. Single-cell RNA sequencing suggested that this change was associated with a reduced abundance of microglial subpopulations enriched for phagocytosis-related pathways. Transcriptomic analysis identified serum- and glucocorticoid-regulated kinase 1 (SGK1) as a potential mediator of this process. Notably, sgk1 knockout in SOD1[G93A] mice was associated with improved microglial clearance of myelin debris and reduced aberrant engulfment of neuronal material after disease onset. Our results further showed that, after disease onset, the accumulation of myelin debris and apoptotic neurons induced SGK1 upregulation in microglia from SOD1[G93A] mice. Mechanistically, SGK1 appeared to promote lipid accumulation in microglia by suppressing lipophagy, thereby impairing the ability of microglia to clear cellular debris. Moreover, pharmacological inhibition of SGK1 with GSK650394 attenuated motor deficits and prolonged survival in SOD1[G93A] mice. Together, our findings provide evidence for a previously unrecognized role of SGK1 in regulating microglial phagocytosis in ALS models and support SGK1 as a potential therapeutic target in SOD1 mutation-associated ALS models.}, } @article {pmid42387593, year = {2026}, author = {Trad, G and Lenglet, T and Ledoux, I and Querin, G and Blancho, S and Marchand-Pauvert, V and Hogrel, JY and Pradat, PF}, title = {Safety, feasibility and preliminary effects of Atalante exoskeleton-assisted gait training in amyotrophic lateral sclerosis: a prospective ABA pilot study.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {23}, number = {1}, pages = {}, pmid = {42387593}, issn = {1743-0003}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/rehabilitation/complications ; *Exercise Therapy/methods/instrumentation/adverse effects ; *Exoskeleton Device/adverse effects ; Feasibility Studies ; *Gait/physiology ; *Gait Disorders, Neurologic/rehabilitation/etiology ; Pilot Projects ; Prospective Studies ; Treatment Outcome ; Walking ; }, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS), progressive weakness makes walking practice increasingly unsafe and difficult, accelerating loss of mobility and autonomy. Lower-limb exoskeletons could preserve task-specific stepping in a controlled setting, but evidence in ALS remains scarce. This study evaluated the safety of an intensive Atalante exoskeleton gait-training program and explored its effects on walking and related clinical outcomes.

METHODS: In this prospective, monocentric ABA pilot study, 10 ambulatory persons with ALS underwent three consecutive 6-week phases over 18 weeks: A1 (baseline, usual care), B (intervention: Atalante exoskeleton gait training added to usual care; 18 sessions, 3 times/week), and A2 (withdrawal, usual care), with repeated assessments every 3 weeks. The primary endpoint was safety, assessed by adverse events (AE). Secondary endpoints included ALS Functional Rating Scale-Revised, forced vital capacity, standardized walking tests (6-minute walk test, 10-meter walk test, Timed Up and Go test), Berg Balance Scale, postural control on a force platform, lower-limb strength with dynamometry, spasticity with isokinetic dynamometer, Fatigue Severity Scale, Modified Fatigue Impact Scale, ALS Assessment Questionnaire-40, and Hospital Anxiety and Depression Scale. Exoskeleton-specific patient-reported outcomes (PROs) included intrinsic motivation, participants' attitudes toward the intervention, perceived subjective impact of the training, perceived efficacy and interactivity of the exoskeleton. The results were analyzed with linear mixed-effects models.

RESULTS: No serious AE occurred, and one mild AE was certainly related to the intervention. No outcome showed significant phase-specific slopes or slope contrasts, although several measures displayed directionally consistent trends compatible with attenuated decline during phase B and a return toward a less favorable trajectory after withdrawal. Exoskeleton-specific PROs indicated high intrinsic motivation and acceptability (usefulness for standing, perceived safety, ease of participation, and ease of installation/uninstallation rated very highly), with perceived gait-training efficacy generally positive. Participants frequently reported reduced immobility and increased accomplishment (80% each) and postural improvement (70%), and the Net Promoter Score of recommendation was + 40.

CONCLUSIONS: Atalante exoskeleton gait training was safe and feasible in ambulatory ALS. These pilot data can guide the optimization of future studies to test whether it preserves function. Trial registration ClinicalTrials.gov, NCT06199284. Registered on 29/12/2023.}, } @article {pmid42387809, year = {2026}, author = {Jensen, SM and Vergoossen, DLE and Huijbers, MG}, title = {Muscle-Specific Kinase Signaling and Its Therapeutic Potential.}, journal = {Muscle & nerve}, volume = {74 Suppl 1}, number = {Suppl 1}, pages = {S65-S75}, pmid = {42387809}, issn = {1097-4598}, mesh = {Humans ; *Signal Transduction/physiology ; *Receptor Protein-Tyrosine Kinases/metabolism/genetics ; Animals ; *Receptors, Cholinergic/metabolism ; *Neuromuscular Junction/metabolism ; Genetic Therapy/methods ; *Neuromuscular Diseases/therapy/enzymology/metabolism ; }, abstract = {The function of the neuromuscular junction (NMJ) is compromised in many neuromuscular diseases (NMDs) such as autoimmune or congenital myasthenia gravis (MG), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and muscular dystrophies. The NMJ contains muscle-specific kinase (MuSK), which is a critical regulator of NMJ integrity and function. Activating the MuSK signaling cascade may have therapeutic potential in several of these NMDs that are characterized by impaired neuromuscular communication. The MuSK signaling cascade consists of different components and can be activated with interventions at different levels. In the past years, different therapeutic strategies using an engineered recombinant agrin comprised of the C-terminal fragment of the protein (mini-agrin), gene therapy of key proteins in this pathway, agonist MuSK antibodies, and SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitors have been further developed for this purpose. Each of these strategies engages distinct signaling components: mini-agrin, both as recombinant protein and gene therapy, enhances agrin-Lrp4-MuSK interaction; Dok7 gene therapy amplifies MuSK phosphorylation; Lrp4 gene therapy enhances agrin responsiveness; MuSK agonist antibodies bypass upstream defects and promote downstream signaling; SHP2 inhibitors prolong the duration of active MuSK signaling. These therapeutic strategies have ameliorated NMJ integrity and function in several preclinical models of MG, motor neuron diseases, and muscular dystrophies. In this review, we highlight MuSK signaling as a possible therapeutic target, describe the therapeutic efficacy of intervention in MuSK signaling in different NMDs, and present an outlook on future clinical development.}, } @article {pmid42388323, year = {2026}, author = {Almeida, S and Song, Y and Marques, F and Sharma, N}, title = {Editorial: Emerging mechanisms in neurodegenerative disease pathogenesis: vertebrate and invertebrate model organisms.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1891031}, doi = {10.3389/fnmol.2026.1891031}, pmid = {42388323}, issn = {1662-5099}, } @article {pmid42388560, year = {2026}, author = {L'habitant, SF and Schenk, A and Thudium, M and Coburn, M and Lechleuthner, A and Piekarski, F}, title = {Influence of team size on the efficiency of time-critical ALS interventions in prehospital cardiac arrest - A prospective randomised multicentre simulation study.}, journal = {Resuscitation plus}, volume = {30}, number = {}, pages = {101384}, pmid = {42388560}, issn = {2666-5204}, abstract = {OBJECTIVE: To determine whether increasing emergency medical service (EMS) team size improves the efficiency of time-critical invasive procedures during advanced life support (ALS) for out-of-hospital cardiac arrest (OHCA).

DESIGN: Randomised prospective multicentre simulation study with a parallel-group comparison of four predefined team sizes.

SETTING: Three accredited EMS training centres in North Rhine-Westphalia, Germany.

PARTICIPANTS: 210 ALS-trained paramedic students allocated to 59 teams of two to five members.

INTERVENTIONS: Teams managed a standardised adult ALS scenario (persistent ventricular fibrillation) requiring five invasive procedures: manual defibrillation, supraglottic airway insertion, intravenous access, preparation of amiodarone (300 mg), and preparation of epinephrine (1 mg).

MEASUREMENTS AND MAIN RESULTS: The primary endpoint was total scenario time from start to completion of the final procedure. Secondary endpoints were start and completion times for each intervention. Mean total times (mm:ss) decreased progressively with team size: two-person 6:33 ± 0:33 min, three-person 4:13 ± 0:40 min, four-person 2:54 ± 0:24 min, and five-person 2:14 ± 0:19 min (ANOVA, p < 0.001). All pairwise differences were statistically significant (Bonferroni-corrected p adj < 0.01). Earlier initiation of intravenous access and drug preparation accounted for most time savings. All teams completed every task successfully.

CONCLUSIONS: Larger EMS teams performed time-critical ALS procedures significantly faster, with optimal efficiency observed in four- to five-member crews. These findings highlight the operational importance of team composition for prehospital resuscitation performance and may inform staffing policies and simulation-based training.}, } @article {pmid42389275, year = {2026}, author = {Zhang, P and Zhuang, YD and Lv, WW and Zhao, Y and Wang, JH and Zhang, JY and Wu, LL}, title = {Role of gut microbiota in melanosis coli: from anthraquinone biotransformation to mucosal homeostasis dysbiosis.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1791164}, pmid = {42389275}, issn = {1663-9812}, abstract = {Melanosis coli (MC) is a benign and usually reversible condition characterized by brownish-black pigmentation of the colonic mucosa and is commonly associated with chronic exposure to anthraquinone laxatives (ALs). The best-established histopathological sequence involves AL-related epithelial apoptosis, phagocytosis of apoptotic bodies by macrophages, and subsequent lipofuscin deposition. Emerging evidence suggests that the gut microbiota (GM) may contribute to this process by converting pharmacologically inactive anthraquinone glycosides into active anthrone metabolites, including rhein anthrone. This narrative review summarizes available MC-specific findings and clearly distinguishes them from mechanistic hypotheses extrapolated from constipation, intestinal barrier, and microbiome literature. We discuss microbial β-glucosidases and reductases involved in AL biotransformation, reported changes in microbial diversity and SCFA-producing taxa in MC or constipation-associated cohorts, and plausible links with barrier dysfunction, bile-acid metabolism, tryptophan-derived metabolites, and LPS-TLR4 signaling. We therefore present the "Microbiota-Apoptosis Axis" as a proposed framework rather than a validated causal pathway. Finally, we review GM-targeted strategies, including probiotics, synbiotics, and fecal microbiota transplantation, while emphasizing that direct clinical evidence in MC remains limited and that cessation of anthraquinone laxatives remains the primary management strategy.}, } @article {pmid42389895, year = {2026}, author = {Pickett, D and Purvinsh, Y and Skrehot, JT and Warren, D and Kurouski, D}, title = {Nanoscale morphological and structural analysis of round and donut oligomers formed by C-terminal domain of TDP-43.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {28}, number = {27}, pages = {16459-16463}, pmid = {42389895}, issn = {1463-9084}, mesh = {*DNA-Binding Proteins/chemistry ; Protein Domains ; Microscopy, Atomic Force ; Humans ; Protein Structure, Secondary ; Spectrophotometry, Infrared ; }, abstract = {Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), limbic predominant age-related TDP-43 encephalopathy (LATE), and Parkinson's disease are associated with an abrupt aggregation of TAR DNA-binding protein 43 (TDP-43). Although molecular mechanisms of this pathological aggregation remain unclear, accumulated evidence suggests that the C-terminus domain (C-terminal domain (CTD)) is the trigger of TDP-43 self-assembly into toxic oligomers and fibrils. While the secondary structure and morphology of protein fibrils have been well documented, very little is known about TDP-43 oligomers. This is primarily because of the transient nature and low concentrations of these protein species. In the current study, we utilize nano-infrared spectroscopy, also known as atomic force microscopy-infrared (AFM-IR) spectroscopy, to investigate the morphology and secondary structure of CTD of TDP-43 oligomers formed at the early and middle stages of protein aggregation. This innovative technique allows us to resolve both morphology and secondary structure of individual protein aggregates. We found that at the early stage of protein aggregation, CTD of TDP-43 formed two morphologically different protein aggregates: donut-like (DO) and round (RO) oligomers. DO yielded fibrillar species, while RO persisted throughout the entire course of CTD TDP-43 self-assembly.}, } @article {pmid42391298, year = {2026}, author = {Ramgopal, S and Martin-Gill, C}, title = {Characterizing Pediatric Trauma Patients and EMS Agencies That Are Optimal Targets for Prehospital Pediatric Blood Transfusion Programs.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/10903127.2026.2696013}, pmid = {42391298}, issn = {1545-0066}, abstract = {OBJECTIVES: Trauma is a leading cause of death among children in the United States. Prehospital blood product administration is a potentially lifesaving measure for injured children. We evaluated how often injured children meet physiological criteria for transfusion, determined the use of prehospital blood products in this sample, and identified agency characteristics that can inform the implementation of additional prehospital transfusion programs.

METHODS: We conducted a retrospective analysis of the 2021-2024 National Emergency Medical Services Information System (NEMSIS) datasets. We included children (<18 years) with injury. We identified patients who may be eligible for prehospital blood transfusion based on (a) a combination of a systolic blood pressure (SBP) below the 5[th] centile for age and elevated heart rate above the 85[th] centile or (b) a systolic blood pressure below the 1[st] centile. We characterized encounters potentially eligible for prehospital blood transfusion, the use of blood products in this group, and the EMS agencies that cared for these patients.

RESULTS: Of 2,492,731 encounters, 34,221 (1.37%, 95% confidence interval [CI] 1.36%, 1.39%) were potentially eligible for blood transfusion. Patients meeting these criteria were more frequently adolescents (71.1%) and were involved in falls (23.4%) or motor vehicle collisions (22.6%). Blood products were administered in 669 (0.027%; 95% CI 0.025%, 0.029%) encounters overall and to 1.01% (95% CI 0.91%, 1.13%) of encounters meeting criteria for blood transfusion eligibility. In agency-level analysis, 240/16,848 (1.4%) agencies provided blood products to children, and 84.4% of eligible patients were cared for by agencies whose most common level of service was advanced life support (ALS). In multivariable analysis, agencies caring for pediatric trauma patients meeting physiologic criteria for transfusion were more likely to have higher levels of service (ALS or critical care); rural; mixed volunteer/non-volunteer; and governmental non-fire, hospital, or private, non-hospital (vs fire departments).

CONCLUSIONS: In a nationally representative prehospital sample, many injured children appeared eligible for transfusion. Prehospital blood product use was uncommon and varied by system factors. Expanding access will require implementation of blood programs among EMS agencies most likely to treat these patients, and consideration for equipment and protocols that allow for administration of blood to children.}, } @article {pmid42391458, year = {2026}, author = {Philbert, SA and Church, SJ and Unwin, RD and Cooper, GJS}, title = {Elevated urea levels in human frontotemporal dementia and amyotrophic lateral sclerosis post-mortem brain tissue: evidence of a multi-dementia pathogenic mechanism.}, journal = {Molecular omics}, volume = {22}, number = {4}, pages = {}, doi = {10.1093/molecular-omics/aaiag019}, pmid = {42391458}, issn = {2515-4184}, support = {60147//Endocore Research Associates/ ; 3627036//Maurice and Phyllis Paykel Trust/ ; 3626585//Lottery Health New Zealand/ ; 3702766//Lottery Health New Zealand/ ; 9341-3622506//Maurice Wilkins Centre for Molecular Biodiscovery/ ; //Lee Trust/ ; //University of Auckland/ ; 3456030//Oakley Mental Health Research Foundation/ ; 3627092//Oakley Mental Health Research Foundation/ ; 3701339//Oakley Mental Health Research Foundation/ ; 3703253//Oakley Mental Health Research Foundation/ ; 3702870//Oakley Mental Health Research Foundation/ ; UOAX0815//Ministry of Business, Innovation & Employment/ ; //Neurological Foundation of New Zealand/ ; MR/L010445/1/MRC_/Medical Research Council/United Kingdom ; MR/L011093/1/MRC_/Medical Research Council/United Kingdom ; ARUK-PPG2014B-7//Alzheimer's Research UK/ ; //University of Manchester/ ; //CMFT/ ; //Northwest Regional Development Agency/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Frontotemporal Dementia/metabolism/pathology ; Female ; *Urea/metabolism ; *Brain/metabolism/pathology ; Male ; Aged ; Middle Aged ; Autopsy ; Tandem Mass Spectrometry ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) represent two neurodegenerative diseases on opposite sides of a movement disorder continuum. However, like many other neurodegenerative diseases, the molecular pathogenesis of FTD and ALS is not fully understood. Our group has previously reported evidence for a pervasive elevation of brain urea levels in five other dementia-causing diseases. However, brain urea levels have yet to be measured in ALS and FTD. Here, we employed ultra-high-performance liquid chromatography-tandem mass spectrometry to characterize brain urea differences between control (n = 14/12) and ALS/FTD (FTD: n = 8/9; ALS: n = 13/14) cases in post-mortem tissue from two brain regions with different levels of neuropathological burden (high versus low). Elevated urea levels were observed in both the frontal cortex (high neuropathological burden) and primary visual cortex (low neuropathological burden) in cases with FTD. Contrastingly, in cases with ALS, elevated urea was observed in the primary motor cortex (high neuropathological burden), but not the dentate nucleus (low neuropathological burden). These results not only suggest that elevated urea levels are also present in ALS and FTD but imply that elevated brain urea is linked to a multi-dementia pathogenic mechanism. In contrast to ALS, the observation of elevated urea in regions of both high and low neuropathological burden in FTD implies that this phenotype is likely widespread and, therefore, may play a larger role in the pathogenesis of disease. Such a mechanism could offer new directions for developing treatments targeting this underlying pathology.}, } @article {pmid42392626, year = {2026}, author = {Beulen, V and Noben, C and Smits, M and Mertens, H and Paulus, A and Van Mook, W}, title = {Workforce shortages and supported access to medical care for hospital employees: a scoping review.}, journal = {BMJ open}, volume = {16}, number = {7}, pages = {e117423}, pmid = {42392626}, issn = {2044-6055}, mesh = {Humans ; *Health Services Accessibility ; COVID-19 ; SARS-CoV-2 ; *Personnel, Hospital ; Pandemics ; }, abstract = {OBJECTIVES: This scoping review synthesises peer-reviewed and grey literature on supported access to medical care for hospital employees with existing physical health complaints to understand how it may reduce sickness absenteeism by promoting sustainable employability and to identify gaps and opportunities to inform the design and implementation of organisational supported care frameworks.

DESIGN: We conducted this scoping review following the Arksey and O'Malley framework and Levac et al's methodological recommendations, reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extensions for Scoping Reviews (PRISMA-ScR).

DATA SOURCES: MEDLINE (Ovid), Embase (Elsevier), CINAHL (EBSCO) and Web of Science were searched from database inception to 8 November 2024. The search was updated on 18 May 2026. This was supplemented by forward and backward citation tracking of included peer-reviewed articles and targeted hand searching of Dutch grey literature in Medisch Contact , a leading Dutch professional journal for the medical profession, focusing on clinical practice, medical policy and professional issues.

ELIGIBILITY: English-language or Dutch-language peer-reviewed publications and well-argued opinion pieces on healthcare workers' access to care (COVID-19 and beyond) in hospital or transferable settings were included. Sources focused on mental health or health promotion, financial aspects, personal protective equipment, patient access or healthcare worker utilisation, as well as non-English/Dutch sources, webpages and papers without full text, were excluded.

DATA EXTRACTION: ASReview was used for title and abstract screening following the SAFE procedure and full-text screening was conducted with team consensus.

RESULTS: 27 publications were included from 36 685 identified records. The literature was predominantly qualitative in nature and COVID-19-focused, yielding four themes (ethical considerations, multilevel challenges, target groups and strategies and outcomes). It also highlighted limited evidence on evaluated supported-access interventions and workforce outcomes beyond crises.

CONCLUSIONS: Although supported access to medical care for hospital employees appears a promising multilevel, system-embedded strategy to reduce sickness absenteeism and promote sustainable employability in general, the evidence to substantiate and justify such strategies beyond acute crises is limited. Moreover, current literature lacks clear conceptualisation, operationalisation as well as robust implementation and evaluation frameworks. Addressing these gaps is a priority for future research to scientifically scaffold policies and frameworks to sustain a healthy and stable future hospital workforce.}, } @article {pmid42392979, year = {2026}, author = {Pant, DC and Lone, MA and Parameswaran, J and Ma, F and Ziak, N and Dutta, P and Wang, Z and Pun, D and Verma, S and Hornemann, T and Jiang, J}, title = {Deletion of exon 2 in ALS-linked Sptlc1 causes lethality in homozygous mice but not in heterozygotes.}, journal = {Life science alliance}, volume = {9}, number = {9}, pages = {}, pmid = {42392979}, issn = {2575-1077}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; *Exons/genetics ; Mice ; Heterozygote ; Homozygote ; Disease Models, Animal ; Humans ; *Sequence Deletion/genetics ; Mutation ; Genes, Lethal ; CRISPR-Cas Systems ; Male ; Gene Knock-In Techniques ; }, abstract = {Mutations in the human SPTLC1 gene have recently been linked to early-onset amyotrophic lateral sclerosis (ALS), characterized by global atrophy, motor impairments, and symptoms such as tongue fasciculations. All known ALS-linked SPTLC1 mutations cluster within exon 2, and a specific variant, c.58G>T, results in exon 2 skipping. However, it is unclear how the exon 2 deletion affects SPTLC1 function in vivo and contributes to ALS pathogenesis. Leveraging the high genomic sequence similarity between mouse and human SPTLC1, we created a novel knock-in mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine Sptlc1 locus. Although heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely. These findings provide valuable insights into SPTLC1 exon 2 biology and serve as a useful resource for future mechanistic studies.}, } @article {pmid42393685, year = {2026}, author = {Luan, J and Yun, Y and Jiao, Y and Wang, Y and Ma, M and Shan, D and Wang, H and Ji, X and Tang, Y and Li, J and Zhan, Z and Sun, X and Gao, N and Lin, P and Yan, C and Yu, D and Liu, S and Liu, F}, title = {Structural-functional network decoupling in early stage amyotrophic lateral sclerosis reveals cell-type specific transcriptional signatures.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {42393685}, issn = {1741-7015}, support = {2025M782111//the China Postdoctoral Science Foundation/ ; 2025CXPT133//the Key R&D Program of Shandong Province/ ; 2022ZLGX03//the Key R&D Program of Shandong Province/ ; ZR2023ZD14//the Shandong Provincial Natural Science Foundation Major Basic Research Project/ ; ZR2023MH180//the Natural Science Foundation of Shandong Province/ ; 20201125//Qilu Young Schorship of Shandong University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/physiopathology/pathology ; Female ; Male ; Middle Aged ; Magnetic Resonance Imaging ; Aged ; *Transcriptome ; *Brain/diagnostic imaging/physiopathology ; Diffusion Tensor Imaging ; Single-Cell Gene Expression Analysis ; Gene Expression Profiling ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) involves widespread brain network dysfunction, yet the molecular mechanisms linked to these alterations remain poorly understood. We investigated macroscopic structural-functional coupling abnormalities in early-stage ALS (ALS-ES) and their underlying transcriptomic signatures.

METHODS: We analyzed multimodal MRI data from 73 patients with sporadic ALS-ES and 74 age- and sex-matched healthy controls. Structural-functional (SC-FC) coupling was quantified using diffusion tensor imaging and resting-state functional MRI. Machine learning models were constructed to distinguish patients from controls based on network features. Coupling alterations were spatially correlated with neurotransmitter receptor maps and gene expression profiles from the Allen Human Brain Atlas. Key transcriptomic findings were validated using independent single-cell RNA sequencing datasets.

RESULTS: While structural connectivity remained largely preserved, functional connectivity was significantly reduced in the somatomotor network (SMN). This mismatch manifested as significant SC-FC network decoupling, particularly within the SMN (pFDR = 0.001). A gradient boosting machine model accurately classified patients, identifying SC-FC coupling in the left precentral gyrus as a primary statistical contributor to the classification model. Decoupling spatially correlated with 5-HT2A and mGluR5 receptor distributions. Imaging-transcriptomics linked network failure to a gene signature enriched for synaptic pathways and microglial markers. Single-cell analysis identified FMN1 as a candidate gene whose glial expression spatially associates with network decoupling.

CONCLUSIONS: Early-stage ALS is characterized by significant structural-functional network decoupling, primarily in motor systems. This macroscopic failure is linked to specific microglial dysregulation, particularly FMN1 downregulation, providing a multiscale framework bridges statistical neuroimaging signatures with potential cellular pathology.}, } @article {pmid42393788, year = {2026}, author = {Marynen, F and van Bijsterveld, MG and Van In, J and Roosen, J and Fieuws, S and Vanhonacker, D and van Mook, WN and van der Horst, ICC and Dewolf, P}, title = {Comparing two post-resuscitation debriefing frameworks: a randomized cross-over simulation study.}, journal = {Advances in simulation (London, England)}, volume = {11}, number = {1}, pages = {}, pmid = {42393788}, issn = {2059-0628}, support = {R-aiders Grant (2023).//BESEDIM/ ; }, abstract = {BACKGROUND: Post-resuscitation debriefing (PRD) enhances individual and team performance in emergency care, thereby improving patient outcomes and provider well-being. Despite support from the European Resuscitation Council and the American Heart Association, the optimal PRD framework remains undefined. This study compares how team members experience PRD when conducted using either the DISCERN or Post-Code Pause (PCP) debriefing framework in pre-hospital cardiac arrest simulations.

METHODS: In a randomized cross-over study, 40 medical doctors participated in four advanced life support (ALS) simulation scenarios. Participants acted exclusively within their usual roles as team leaders, while the remaining team members performed standardized roles in accordance with the scenario scripts. Each participant experienced two DISCERN and two PCP debriefings, with the order randomized. The primary outcome was the total score on the Debriefing Experience Scale (DES), with item scores as secondary outcomes. Linear models with generalized estimating equations (GEE) were used to account for repeated measures when comparing the mean scores between the debriefing frameworks.

RESULTS: A total of 158 DES questionnaires were analyzed. Mean total DES scores were 4.15 (4.02; 4.28) for PCP and 4.16 (4.02; 4.29) for DISCERN (p = 0.93 for the comparison). These scores indicate a favorable debriefing experience for both frameworks. At the DES item level, no statistically significant differences were observed between frameworks, except for perceived physical comfort in the debriefing environment, which was rated significantly higher for DISCERN (DISCERN = 4.44 (4.27; 4.62), PCP = 4.13 (3.96; 4.30), p = < 0.0001).

CONCLUSION: DISCERN and PCP provide similarly favorable debriefing experiences following simulated cardiac arrest scenarios, with no significant difference in overall DES scores. These findings suggest that both frameworks can be implemented without compromising perceived debriefing quality. Further research should include more professionally diverse participant samples and assess long-term debriefing outcomes.

TRIAL REGISTRATION: Clinical Trial Center UZ Leuven, S65846 September 2021.}, } @article {pmid42393897, year = {2026}, author = {Anachad, O and Taha, W and Saadoune, C and Ezaouine, A and Nouadi, B and Bennis, F and Chegdani, F}, title = {Bioinformatic Identification of Shared Gene Networks Between Weaning- Induced Intestinal Inflammation and Neuroinflammatory-Related Pathways.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249457554260605114916}, pmid = {42393897}, issn = {1875-6166}, abstract = {INTRODUCTION: Weaning is a critical developmental stage that can trigger intestinal inflammation through disruption of microbial homeostasis, immune responses, and epithelial barrier integrity. While numerous studies have explored gene expression changes during weaning in animals, no comparable analyses have been conducted in humans. Given the close physiological and genetic similarity between pigs and humans, piglet data were employed to investigate the molecular mechanisms underlying weaning-induced intestinal inflammation and its potential links to neurological pathways.

METHODS: A curated set of 117 differentially expressed genes related to gut inflammation was collected from bibliographic sources. Protein-protein interaction network analysis was performed using NetworkAnalyst and Cytoscape, followed by hub gene selection and functional enrichment using KOBAS, ClusterProfiler, and StringApp.

RESULTS: Among the identified hub genes, SOD1, CAT, TNF, CXCR4, TLR2, and TGFB1 play key roles in oxidative stress, immune response, glial regulation, and neuroinflammatory signaling. Enrichment analysis revealed significant associations with pathways such as Amyotrophic Lateral Sclerosis, TGF-β signaling, Folate and Vitamin B12 metabolism, and Inflammatory Bowel Disease, as well as biological processes like gliogenesis, hypoxia response, and cytokine signaling.

DISCUSSION: These findings suggest that intestinal inflammation during weaning may have systemic implications, highlighting shared molecular pathways relevant to neuroinflammatory-related processes.

CONCLUSION: This study provides new insight into the genetic and molecular landscape of weaning-induced inflammation and its broader systemic effects. The identified shared molecular pathways may provide a foundation for future experimental studies investigating the broader biological implications of early-life intestinal inflammation.}, } @article {pmid42394935, year = {2026}, author = {Leone, L and Kiernan, TJ and Kuwabara, S and Barnett, M and Devenney, E and Ahmed, RM and Lin, CS}, title = {A convergence of global epidemics: diabetes as a modulator of neurodegenerative and neuro-inflammatory disorders.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1824840}, pmid = {42394935}, issn = {1664-2295}, abstract = {Diabetes mellitus (DM) and neurological disorders are rapidly converging global health burdens, driven by population ageing, the growing prevalence of metabolic syndrome, and limited early detection and disease-modifying therapies for many neurological syndromes. Beyond its established role in diabetes-related peripheral neuropathy, DM is increasingly implicated as a modifier of risk, phenotype, and prognosis across a wide range of central and peripheral nervous system diseases. In this narrative review, we synthesize current epidemiological, clinical, genetic, and mechanistic evidence examining the relationship between DM and 10 clinically important neurological disorders: Alzheimer's disease (AD), vascular dementia (VaD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multiple sclerosis (MS), myasthenia gravis (MG), and neuromyelitis optica spectrum disorder (NMOSD). Across these conditions, DM acts as a context-dependent disease modifier, increasing risk in some disorders, appearing protective or delaying onset in others, and influencing disease phenotype, progression, and treatment response. We highlight potential areas of mechanistic convergence, such as insulin resistance, inflammation, disrupted energy homeostasis, and genetic predisposition, alongside important divergences shaped by disease-specific pathology. We also discuss the clinical and translational implications of this interface, including diagnostic challenges, opportunities for improved risk stratification, and growing interest in repurposing antidiabetic therapies, particularly metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, for neurological benefit. As the global burden of diabetes and neurological disease escalates, it is crucial to better understand the interplay between metabolic dysfunction, neurodegeneration, and neuro-immune pathways. The integration of insights across diseases may inform prevention strategies and support the development of therapeutic interventions at the metabolic-neurological interface.}, } @article {pmid42394962, year = {2026}, author = {Tachiyama, K and Nakamori, M and Fujii, Y and Hokkoku, K and Agari, D and Hemmi, S and Nomura, E and Hatanaka, Y and Kurokawa, K and Sonoo, M and Maruyama, H}, title = {Decremental responses following repetitive nerve stimulation in spinal and bulbar muscular atrophy.}, journal = {Clinical neurophysiology practice}, volume = {11}, number = {}, pages = {522-527}, pmid = {42394962}, issn = {2467-981X}, abstract = {OBJECTIVE: The presence of decremental responses following repetitive nerve stimulation (RNS) in amyotrophic lateral sclerosis (ALS) is well established. However, in spinal and bulbar muscular atrophy (SBMA), a rare X-linked recessive lower motor neuron disease, the incidence and distribution of decremental responses across different muscles have not been thoroughly investigated.

METHODS: Patients with SBMA were retrospectively identified in our database. RNS at a frequency of 3 Hz was performed on five muscles: the abductor pollicis brevis (APB), abductor digiti minimi (ADM), upper trapezius, deltoid, and facial muscles (frontalis or nasalis).

RESULTS: A total of forty patients were identified. A significant (> 5%) decremental response in at least one muscle was observed in all patients. It was observed more frequently in proximal muscles than in distal muscles: deltoid (86%), trapezius (70%), facial muscles (44%), APB (37%) and ADM (25%). The magnitude of the decremental response in the deltoid was significantly higher than that in the other muscles.

CONCLUSIONS: Our results demonstrated that decremental responses were frequently observed in patients with SBMA, with a distribution pattern similar to that in ALS. The fact that the decremental responses are observed in SBMA having an extremely chronic course would be relevant for the pathophysiological mechanism of the decremental response.

SIGNIFICANCE: The RNS findings provide valuable insights into the pathological mechanisms of SBMA and may contribute to the development of future treatments.}, } @article {pmid42395430, year = {2026}, author = {Moore, S and Julian, DL and Alsop, E and Gittings, LM and Lorenzini, I and McMillan, M and Macklin-Isquierdo, S and Lehmkuhl, E and Kalab, P and de Paula Moreira, D and Hayes, L and Donnelly, C and Barmada, SJ and Zarnescu, DC and Van Keuren-Jensen, K and Sattler, R}, title = {ADAR2-Mediated RNA Editing Promotes TDP-43 Nuclear Export and Alters RNA Binding.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.22.730622}, pmid = {42395430}, issn = {2692-8205}, support = {R01 NS097542/NS/NINDS NIH HHS/United States ; R01 NS148028/NS/NINDS NIH HHS/United States ; R37 NS113943/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: TAR DNA binding protein - 43 (TDP-43) nuclear loss is a pathological hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and related neurodegenerative disorders. While the consequences of TDP-43 dysfunction have been well-characterized, the mechanisms driving TDP-43 mislocalization remain poorly understood. Previous observations of altered localization and function of the adenosine-to-inosine (A-to-I) RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) in ALS/FTD tissue prompted us to investigate whether dysregulated RNA editing contributes to pathological TDP-43 nucleocytoplasmic trafficking.

METHODS: TDP-43 cytoplasmic mislocalization was assessed following ADAR2 and TDP-43 co-overexpression in HEK293T cells and a Drosophila model co-overexpressing human TDP-43 and dADAR in motor neurons. We further evaluated TDP-43 mislocalization through both HeLa cell assays and interspecies heterokaryon assays. Next, we assessed TDP-43 binding to A-to-I edited RNA oligomers through electrophoretic mobility shift assays (EMSAs), and investigated inosine-containing RNAs in vivo via TDP-43 RNA immunoprecipitation followed by sequencing (RIP-seq) datasets from human TDP-43-expressing Drosophila . Finally, RNAseq and enhanced cross-linking and immunoprecipitation (eCLIP-seq) were performed in SH-SY5Y cells overexpressing three ADAR2 variants with differing editing activity to identify editing-related transcriptional alterations and RNAs differentially bound to TDP-43.

RESULTS: ADAR2 overexpression reduced the nucleocytoplasmic (N:C) ratio of TDP-43 in HEK293T cells in a ADAR2 catalytic activity- and TDP-43 RNA-binding capacity-dependent manner. Drosophila motor neurons overexpressing dADAR also exhibited decreased nuclear TDP-43. Interspecies heterokaryons and permeabilized HeLa cell assays demonstrated that catalytically active ADAR2 and synthetic inosine-containing RNA oligomers, respectively, enhance nuclear export of endogenous TDP-43. EMSAs revealed preferential binding of TDP-43 to inosine-containing RNAs relative to unedited RNAs, and analysis of Drosophila RIP-seq datasets demonstrated enrichment of edited transcripts within TDP-43-bound RNAs. Finally, RNAseq and eCLIP-seq analyses identified editing-dependent alterations in gene expression and TDP-43 RNA-binding profiles in SH-SY5Y cells overexpressing active ADAR2 variants.

CONCLUSIONS: Together, our findings identify A-to-I RNA editing as a previously unrecognized regulator of TDP-43 localization and RNA interactions. These results support a model where altered RNA editing modifies TDP-43-RNA interactions, promoting increased nuclear export of TDP-43. Broadly, our work highlights RNA editing dysregulation as a potential contributor to early pathogenic mechanisms underlying TDP-43 proteinopathies.}, } @article {pmid42395866, year = {2026}, author = {Sidharth, A and Shin, D}, title = {The role of SUMOylation in regulating proteins that drive neuronal disease progression.}, journal = {Biochemistry and biophysics reports}, volume = {47}, number = {}, pages = {102687}, pmid = {42395866}, issn = {2405-5808}, support = {R01 NS112327/NS/NINDS NIH HHS/United States ; }, abstract = {SUMOylation is a post-translational modification in which a Small Ubiquitin-like Modifier (SUMO) protein is reversibly attached to a lysine residue on a target protein in an ATP-dependent process. This modification can affect the function of target proteins by enhancing their stability or changing cellular translocation, thereby making SUMOylation a critical regulator in the pathogenesis of multiple diseases. The functional consequences of SUMOylation, however, are highly context dependent. In Alzheimer's disease, SUMOylation stabilizes proteins that drive disease progression and enhances neurotoxicity, thereby exacerbating these conditions. Similarly, in Progressive Supranuclear Palsy, SUMO-1 conjugation stabilizes truncated tau and blocks its ubiquitination, whereas SUMO-2/3 conjugation promotes Tau clearance and recovery from neuroinflammation, illustrating how distinct SUMO paralogues can exert opposing effects within the same disease. Conversely, increased SUMOylation can be neuroprotective in cerebral ischemia and Parkinson's disease by promoting autophagic clearance of pathogenic proteins. Beyond alterations in protein stability, aberrant SUMOylation can also lead to mis-localization of target proteins, which has been identified as a pathogenic mechanism in disorders such as Huntington's disease and Amyotrophic Lateral Sclerosis that results in impaired clearance and pathogenic buildup, which results in neuronal death. From a therapeutic standpoint, the SUMO inhibitor TAK-981 has shown promise in both Multiple Sclerosis and in pre-clinical glioblastoma models, underscoring the translational potential of targeting of this pathway. This review examines the multifaceted role of SUMOylation across diverse neurological conditions, evaluates the therapeutic potential of SUMO inhibitors and activators, and highlights the opportunities and challenges of modulating this pathway in currently incurable neurological disorders.}, } @article {pmid42396027, year = {2026}, author = {Saidi, C and Debbichi, M and Chaaben, N}, title = {Lead-Free Sr3MCl3 (M = Sb, P) Perovskite Solar Cells: from First-Principles Calculations to Recombination-Aware Device Simulations.}, journal = {ACS omega}, volume = {11}, number = {25}, pages = {37467-37485}, pmid = {42396027}, issn = {2470-1343}, abstract = {In this study, first-principles calculations were performed to explore structural, mechanical, electronic, carrier transport, and optical properties of strontium-based perovskites (Sr3MCl3 (M = Sb, P)) using density functional theory (DFT). These calculations reveal that both materials are thermodynamically and mechanically stable. Employing the GGA-PBE functional, they possess a direct-band-gap semiconductor behavior with an energy of 1.704 eV (Sr3SbCl3) and 1.677 eV (Sr3PCl3). The analysis of the density of states (DOS) further corroborates the semiconducting behavior. Carrier mobility calculations indicate that electron/hole mobilities of 89.15/110.52 cm[2]/V·s are achieved for Sr3SbCl3 and 137.16/100.60 cm[2]/V·s for Sr3PCl3. In the visible region, a light absorption coefficient above 10[5] cm[-1] is reached for both materials, highlighting their suitability as an absorber layer (AL) in perovskite solar cells (PSCs). Considering band-to-band recombination (radiative and Auger), SCAPS-1D was used to conduct an inquiry into the photovoltaic performance of various devices, integrating different electron and hole transport layers (ETL/HTL): Ag/FTO/ETL/uniform-AL/HTL/Ni. Among all configurations examined in this study, the Ag/FTO/IGZO/uniform-AL/Cu2O/Ni architecture achieves the highest photovoltaic performance parameters, upon optimization of AL thickness, AL-doping concentration, AL-bulk and interface defect densities, radiative recombination coefficient, and series/shunt resistances. The Sr3SbCl3-based PSC (Device I) attains a power conversion efficiency (PCE) of ∼25.80%, with an open-circuit voltage (V OC) of 1.31 V, a short-circuit current density (J SC) of 21.82 mA/cm[2], and a fill factor (FF) of 90.27%, whereas the Sr3PCl3-based PSC (Device II) achieves a PCE of approximatively 26.22%, with V OC = 1.28 V, J SC = 22.71 mA/cm[2], and FF = 90.09%. Finally, replacing the single uniform-AL with a graded-Sr3Sb1-x P x Cl3 AL (Device III), adopting linear and parabolic graded physical parameters, does not demonstrate marked improvements in device performance. Consequently, this study positions Sr3MCl3 (M = Sb, P) perovskites as alternatives to lead-based ALs, which can constitute a suitable pathway for real-time experimentation of PSC.}, } @article {pmid42396333, year = {2026}, author = {Yasui, D and Weatherill, D and Dugom, L and Weiner, S and Gopalakrishnan, L and Tran, H and Oskarsson, B and Nagle, K and Miller, T and Gutierrez, G and Ravits, J and Hoover, B and Harms, M and Shneider, N and Neylon, L and Dailey, W and Ladha, S and Holmes, C and Lee, J and Streicher, N and Nayar, S and Harris, BT and Raisinghani, M and Zetterberg, H and Gobom, J and Easton, A and Bowser, R and Ly, CV}, title = {The Target ALS Global Natural History Study: Cross-platform proteomics to accelerate biofluid biomarker and drug target discovery in amyotrophic lateral sclerosis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42396333}, support = {OT2 NS136939/NS/NINDS NIH HHS/United States ; R01 NS138499/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease of motor neurons for which therapeutics are limited. Improved biomarkers are imperative to improve patient care and therapeutic development. Here, we employed 35-plex isobaric tandem mass tag labeling based on isobutyl-proline reporter group (TMTpro) to perform unbiased proteomic analysis of cerebrospinal fluid (CSF) and plasma from control (n= 28, n= 31) and sporadic ALS (sALS) (n= 39, n= 41), from the Target ALS Global Natural History Study (TALS GNHS). We identified 2,875 proteins in CSF and 1,118 proteins in plasma and identified known and novel differentially expressed proteins (DEPs) between controls and sALS, some of which were orthogonally validated using immunoassay. Comparison of TMTpro-MS and Olink proximity extension assay proteomics revealed common and non-overlapping differentially expressed proteins illustrating strengths unique to each platform. This initial cross-sectional proteomic study of biofluids from the TALS GNHS, with unrestricted availability of study results to the research community, highlights the potential of this resource as a potent platform for ALS biomarker discovery.}, } @article {pmid42397263, year = {2026}, author = {Chen, H and Wang, H and Lu, YN and Chen, P and Zheng, Z and Zhang, T and Wang, J}, title = {Non-canonical amino acid incorporation enables minimally disruptive labeling of stress granule and TDP-43 proteinopathy.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {42397263}, issn = {2050-084X}, support = {NS110098/NH/NIH HHS/United States ; NS074324/NH/NIH HHS/United States ; NS089616/NH/NIH HHS/United States ; NS128494/NH/NIH HHS/United States ; https://ror.org/042fhmq33//Walder Foundation/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics/chemistry/analysis ; Humans ; *Staining and Labeling/methods ; Animals ; *Stress Granules/metabolism/chemistry ; *Amino Acids/metabolism/chemistry ; *DNA Helicases/metabolism ; *Poly-ADP-Ribose Binding Proteins/metabolism ; *RNA Recognition Motif Proteins/metabolism ; *RNA Helicases/metabolism ; Neurons/metabolism ; Mice ; }, abstract = {We report a minimally disruptive labeling strategy for stress granule protein, G3BP Stress Granule Assembly Factor 1 (G3BP1), and ALS-linked protein, TAR DNA-binding protein 43 (TDP-43), using the fluorescent non-canonical amino acid Anap. By integrating the genetic code expansion (GCE) with rational site selection, we achieved precise incorporation of Anap that preserves protein structure and function. In live cells and neurons, Anap labeling faithfully recapitulated localization, stress-induced dynamics, and recovery behavior, outperforming conventional fluorescent tags, and enabling physiologically relevant visualization of protein pathobiology.}, } @article {pmid42397462, year = {2026}, author = {Xie, X and Jiao, X and Yang, K and Zhang, Q}, title = {A case study of comprehensive association analysis and risk prediction of amyotrophic lateral sclerosis in a Chinese population.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42397462}, issn = {1573-4978}, support = {Grant Number: 32302711//National Natural Science Foundation of China/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; Case-Control Studies ; China/epidemiology ; Gene Frequency/genetics ; Genetic Association Studies/methods ; Genetic Predisposition to Disease/genetics ; Genetic Risk Score ; Genome-Wide Association Study/methods ; Multifactorial Inheritance/genetics ; Polymorphism, Single Nucleotide/genetics ; Whole Genome Sequencing/methods ; East Asian People/genetics ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with significant genetic heterogeneity. While large-scale studies have characterized its genetic architecture in European populations, the genetic basis of ALS in the Chinese population remains under-explored.

METHODS AND RESULTS: To address this gap, we conducted a comprehensive genetic analysis on a cohort of 40 Chinese individuals (32 ALS patients and 8 controls) using whole genome sequencing. We employed the Phenotype-Covariate Genetic Correlation method to estimate SNP-based heritability on the liability scale and utilized LDAK-KVIK for gene-based association analysis. Our analysis revealed a SNP-based heritability (h[2]SNP) of approximately 25.1% in this Chinese cohort, with a positive correlation between minor allele frequency and heritability, highlighting the substantial contribution of common variants. Gene-based analysis prioritized candidate risk genes, including MIB1, TMED2, and DOC2B, which implicate ubiquitin-mediated protein degradation and intracellular vesicle trafficking in ALS pathogenesis. In risk prediction models, the BOLT-LMM approach achieved a robust mean Area Under the Curve (AUC) of 0.883.

CONCLUSIONS: This study provides the first comprehensive estimate of SNP-based heritability in a sequenced Chinese ALS cohort and supports the "polygenic background" hypothesis. The identification of candidate risk genes and the preliminary validation of polygenic risk scoring highlight the potential for future genetic stratification in Chinese patients.}, } @article {pmid42398690, year = {2026}, author = {Sun, Y and Wang, Y and He, Q and Zhao, M and Guo, J and Xu, C and Yan, Q and Chen, Y and Zhang, B and Du, H and Huo, J and Zhang, Y and Zhang, H and Guan, Y and He, Q}, title = {Mutant superoxide dismutase 1-catalyzed hydrogen therapy for amyotrophic lateral sclerosis achieved by intercepting oxidative stress-neuroinflammation crosstalk.}, journal = {Acta biomaterialia}, volume = {219}, number = {}, pages = {663-678}, doi = {10.1016/j.actbio.2026.07.004}, pmid = {42398690}, issn = {1878-7568}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/genetics ; *Oxidative Stress/drug effects ; *Hydrogen/therapeutic use/pharmacology/chemistry ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Mice, Transgenic ; *Neuroinflammatory Diseases/drug therapy/pathology/genetics ; Humans ; *Mutation ; Spinal Cord/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord, with mutant superoxide dismutase 1 (SOD1) induced oxidative stress and neuroinflammation as key pathogenic drivers. Here, we uncover that mutant SOD1 is both a Fenton-like agent able for catalytical generation of ·OH and a hydrogenation catalyst for H2 scavenging reactive oxygen species. To enhance the bioavailability of H2, we develop an orally administered Mg2Si nanosheets based feed for sustained release of high-amount H2. On an ALS model of hSOD1[G93A] transgenic mice, Mg2Si feed remarkably delays ALS progression, improves the motor performance of ALS mice, and extends their lifespan. Histopathologically, oral Mg2Si treatment ameliorates motor neuron degeneration, misfolded SOD1 aggregation and reactive gliosis in spinal cord, while protecting neuromuscular junctions and ameliorating muscle atrophy during disease progression. Transcriptomic analysis demonstrates the H2-mediated down-regulation of both oxidative stress and neuroinflammatory pathways in response to the suppression of NLRP3 inflammasome activation. The proposed strategy of catalyzed hydrogen therapy offers an inspiration for metalloproteases-related neurodegenerative diseases treatment. STATEMENT OF SIGNIFICANCE: Amyotrophic lateral sclerosis (ALS) is an incurable and devastating neurodegenerative disease lacking effective clinical interventions. Although hydrogen gas (H2) exhibits promising neuroprotective potential, conventional H2 therapy is severely limited by unstable and transient H2 release, failing to sustain long-term treatment requirements for chronic ALS pathogenesis. To overcome this bottleneck, we engineer oral administrable Mg2Si nanosheets that enable sustained H2 release via gastrointestinal retention, achieving stable long-term hydrogen supplementation in vivo. Mechanistically, Mg2Si-derived H2 efficiently eliminates excess free radicals triggered by toxic mutant SOD1, and further disrupts the pathological crosstalk between oxidative stress and neuroinflammation in ALS. In transgenic ALS mice, dietary Mg2Si intervention markedly ameliorates motor dysfunction and effectively delays disease progression. Collectively, this study firstly applies Mg2Si nanomaterial-based sustained hydrogen therapy for ALS treatment, establishes a novel gastrointestinal hydrogen delivery strategy, and provides an innovative and clinically translatable paradigm for the design of hydrogen delivery systems against neurodegenerative disorders.}, } @article {pmid42399082, year = {2026}, author = {Varela-Cerdeira, M and Nieto, LU and Mendieta, MAG and Recuerda, AS and Benito, YM and Gullon, PC and Alonso-Babarro, A}, title = {Radiologically inserted gastrostomy in advanced amyotrophic lateral sclerosis: clinical outcomes.}, journal = {BMJ supportive & palliative care}, volume = {16}, number = {5}, pages = {1235-1240}, doi = {10.1136/spcare-2026-006126}, pmid = {42399082}, issn = {2045-4368}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/mortality/therapy/complications ; *Gastrostomy/methods/mortality ; *Palliative Care/methods ; Retrospective Studies ; Spain/epidemiology ; }, abstract = {OBJECTIVES: To evaluate survival and clinical outcomes in patients with amyotrophic lateral sclerosis (ALS) undergoing radiologically inserted gastrostomy (RIG) and to describe outcomes in patients in whom gastrostomy was indicated but not performed.

METHODS: This retrospective observational cohort study included patients with ALS followed by a multidisciplinary palliative care team between 2018 and 2020. Patients were classified according to gastrostomy status (RIG vs no RIG). Clinical data, respiratory support, nutritional status and survival outcomes were collected from medical records. Survival was analysed from gastrostomy indication using Kaplan-Meier curves stratified by baseline non-invasive ventilation (NIV) use.

RESULTS: Among 155 patients with ALS, RIG was indicated in 53 and performed in 45; eight patients died before the procedure. 65 patients did not undergo gastrostomy. Median survival after RIG was 14.7 months, compared with 8 months in non-RIG patients who died. Baseline NIV use was associated with longer survival. No major safety concerns were identified.

CONCLUSIONS: RIG appears to be a safe and feasible option in advanced ALS. Multidisciplinary care with integrated palliative involvement may facilitate referral, optimise nutritional support and support shared decision-making aligned with patients' goals of care. Further prospective studies are needed to confirm benefits and identify intervention timing.}, } @article {pmid42399099, year = {2026}, author = {Liu, RY and Su, WM and Duan, QQ and Wen, XJ and He, SY and Zhang, N and Cao, B and Chen, YP}, title = {Global epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2026-338675}, pmid = {42399099}, issn = {1468-330X}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with the global epidemiological profile remaining incompletely understood. While previous systematic reviews existed, an updated comprehensive synthesis is needed to delineate the disease burden.

METHODS: We searched PubMed, Embase, Scopus, Web of Science and Cochrane databases from inception to 18 February 2025, for studies reporting the incidence, prevalence or mortality of ALS in the general population. Pooled estimates with 95% CIs were calculated, and subgroup analyses were performed.

RESULTS: Of 29 110 articles initially screened, 142 were included. Global pooled incidence was 1.65 per 100 000 person-years (95% CI 1.43 to 1.91), prevalence was 5.05 per 100 000 population (95% CI 4.26 to 5.99) and mortality was 1.26 per 100 000 person-years (95% CI 0.94 to 1.69). Both incidence rate ratio (IRR=0.74) and prevalence rate ratio (PRR=0.69) indicated significantly lower disease burden in females than in males. The burden of disease exhibited a marked age-dependent pattern, peaking at ages 70-79. Temporal trend analyses revealed a consistent increase in prevalence from 1963 to 1999 onwards, while incidence peaked in 2014-2017. Geographically, incidence and prevalence were highest in Europe, North America and Oceania and lowest in Asia and South America. The disease burden was significantly higher in high-income countries compared with both upper-middle-income and lower-middle-income countries.

CONCLUSION: This systematic review provides updated global ALS burden estimates, showing variations by sex, age, time and geography and underscoring the complex interplay of genetic, environmental and socioeconomic factors, with implications for health planning, resource allocation and etiological research.}, } @article {pmid42399152, year = {2026}, author = {Demeret, R and Vieles Marais, D and Treiner, E and Acket, B and Fabry, V and Levade, T and Nogueira, L and Pages, JC and Cintas, P}, title = {Macrophage inclusions in patients undergoing antisense oligonucleotide therapy for ALS or SMA: A retrospective and transversal study.}, journal = {Revue neurologique}, volume = {182}, number = {7}, pages = {652-659}, doi = {10.1016/j.neurol.2026.05.005}, pmid = {42399152}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/cerebrospinal fluid ; Retrospective Studies ; *Oligonucleotides, Antisense/therapeutic use ; *Muscular Atrophy, Spinal/drug therapy/pathology/cerebrospinal fluid ; Female ; Male ; Oligonucleotides/therapeutic use ; *Macrophages/pathology ; Middle Aged ; *Inclusion Bodies/pathology ; Adult ; Aged ; Cross-Sectional Studies ; }, abstract = {BACKGROUND: Intrathecal antisense oligonucleotides (ASOs) have revolutionized the management of genetic motor neuron diseases. Nusinersen is approved for spinal muscular atrophy (SMA) caused by SMN1 mutations, and tofersen for amyotrophic lateral sclerosis (ALS) linked to SOD1 mutations. Since their approval, some studies reported the presence of macrophagic inclusions in cerebrospinal fluid (CSF) of patients treated with ASOs, first in nusinersen-treated patients and more recently in those receiving tofersen. These findings remain poorly characterized, and their clinical significance is unclear.

METHODS: We first conducted a retrospective study in 21 patients (132 CSF samples): six treated with tofersen (every 4 weeks) and 15 with nusinersen (every 4 months). CSF samples were analyzed for macrophagic inclusions, their time of onset, and persistence over time. To assess clinical and inflammatory correlates of macrophagic inclusions, we then performed an analysis of CSF inflammatory biomarkers and serum ferritin and neurofilament light chain tests in 18 of these patients still under treatment.

RESULTS: In tofersen-treated patients, macrophagic inclusions were consistently observed and persisted over time, except in one case. In nusinersen-treated patients, inclusions were rare and transient. An inflammatory CSF profile was associated with the presence of inclusions, but their cellular nature remained undetermined. Notably, tofersen-treated patients with "tofersenophages" exhibited favorable clinical responses.

DISCUSSION: Macrophagic inclusions appear more frequent in the CSF of tofersen-treated patients than previously reported. While their origin remains unclear, they seem linked to CSF inflammation without precluding a beneficial therapeutic response.}, } @article {pmid42399370, year = {2026}, author = {Gao, J and Shukla, D and Ding, M and Qin, S and Tang, F and Guerrero, E and Vicuna, L and Xu, J and Li, H and Miyagi, M and Li, PP and Liang, J and Wang, X}, title = {Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice.}, journal = {Nature aging}, volume = {6}, number = {8}, pages = {1667-1683}, pmid = {42399370}, issn = {2662-8465}, support = {R01 AG087952/AG/NIA NIH HHS/United States ; RF1 AG056320/AG/NIA NIH HHS/United States ; R01AG065342//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG087952//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG056320//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; 23-06539//Flinn Foundation/ ; R01 AG065342/AG/NIA NIH HHS/United States ; AARG-22-923849/ALZ/Alzheimer's Association/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism/chemistry ; Humans ; Mice ; Motor Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; Disease Models, Animal ; Mitochondria/metabolism/drug effects ; Protein Domains ; Conserved Sequence ; }, abstract = {Autosomal dominant mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), cause amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is a hallmark of multiple aging-associated neurodegenerative diseases. Despite its pathological role, effective therapies remain limited by the lack of safe, potent molecules targeting TDP-43 neurotoxicity. Here we show that the conserved α-helical region spanning residues 320-340 (conserved region or CR) is a therapeutically actionable target for TDP-43 neurotoxicity. Deletion of CR markedly suppressed TDP-43-induced neuronal death. Structure-based virtual screening identified XL20, a brain-penetrant small molecule that engages CR and confers neuroprotection without affecting TDP-43 splicing activity. XL20 alleviated motor neuron loss, extended survival in TDP-43 p.Ala315Thr ALS mice and enhanced neuronal function in p.Gln331Lys induced pluripotent stem cell-derived human ALS motor neurons. Mechanistically, targeting CR suppressed TDP-43 mitochondrial localization and restored mitochondrial function, likely through liquid-liquid phase separation. Our findings highlight CR as a therapeutic target for TDP-43-associated neurodegeneration and support CR-binding small molecules as therapeutic candidates.}, } @article {pmid42399593, year = {2026}, author = {Yuan, Y and Ling, C and Wang, Z and Yuan, Y and Zhang, W and Zhao, Y}, title = {Early and severe masticatory muscle involvement in SOD1-ALS: a case report with biomarker-clinical dissociation.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {8}, pages = {}, pmid = {42399593}, issn = {1590-3478}, } @article {pmid42400371, year = {2026}, author = {Harrington, EA and Dratch, L and Jones, TA and Fong, JC and Kinnamon, DD and Goldman, J and Uhlmann, WR and Roggenbuck, J}, title = {Reduced penetrance in genetic ALS/FTD spectrum disorders: implications for genetic counseling, predictive testing and treatment.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/21678421.2026.2696378}, pmid = {42400371}, issn = {2167-9223}, abstract = {As the offer of genetic testing for people with ALS/FTD becomes standard of care, clinicians and affected individuals should have accurate and balanced information regarding the clinical and familial implications of test results, including the penetrance of identified variants. Published estimates of the penetrance of specific ALS/FTD variants, including the C9orf72 repeat expansion, have varied widely. However, it is now apparent that most pathogenic variants identified in clinical testing exhibit reduced penetrance. Although data on the disease risk of many variants is limited and likely to evolve in the coming years, the challenges of estimating penetrance should not preclude transparent discussion of these issues with affected individuals and their families. Here, we review published penetrance data and highlight genetic counseling considerations to support the clinician in discussing disease risk and facilitating decision-making in genetic testing and patient care.}, } @article {pmid42400523, year = {2026}, author = {Li, ZZ and Chen, ZR and Guo, SP}, title = {Nonlinear Optical-Active NaAlP2S6 Synthesized by the MOBQ Method: Synthesis, Structure, and Optical Properties.}, journal = {Inorganic chemistry}, volume = {65}, number = {28}, pages = {16042-16047}, doi = {10.1021/acs.inorgchem.6c02918}, pmid = {42400523}, issn = {1520-510X}, abstract = {Group 13 metal chalcogenides have been extensively studied as infrared nonlinear optical (NLO) crystals and are considered promising candidates for well-balanced overall performances; however, the subgroup of group 13 metal chalcophosphates remains largely unexplored, particularly Al-based ones. Here, a quaternary thiophosphate NaAlP2S6 was synthesized via reactive flux NaCl-assisted metal oxide-boron-chalcogen (MOBQ) solid-state method. It crystallizes in the orthorhombic noncentrosymmetric Fdd2 structure, and the structure features {[AlP2S6][-]} ∞ three-dimentional framework constructed by AlS6 octahedra and ethane-like P2S6 dimers. Notably, because of the strong ionicity and high bond energy of Al-S bonds in AlS6 octahedra, NaAlP2S6 exhibits a wide bandgap (3.72 eV), a moderate SHG response (0.25 × AgGaS2), and an ultrahigh LIDT (14.7 × AgGaS2). Theoretical calculations reveal that the SHG response is mainly contributed by the P2S6 dimers. This work suggests the potential of Al-based functional motifs for NLO applications.}, } @article {pmid42400730, year = {2026}, author = {Shahsavari, K and Yazarlu, O and Ahmadnia, H and Ardakani, MT and Khanavi, M and Esfahani, HM and Abdollahzadeh, R and Sajedi, A and Kazemizadeh, H and Hasanpour, M}, title = {Neuroprotective potential of resveratrol in Parkinson, Huntington, amyotrophic lateral sclerosis, and multiple sclerosis: a comprehensive review.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42400730}, issn = {1573-4978}, mesh = {*Resveratrol/pharmacology/therapeutic use ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Multiple Sclerosis/drug therapy/metabolism ; *Parkinson Disease/drug therapy/metabolism ; *Huntington Disease/drug therapy/metabolism ; Mitochondria/drug effects/metabolism ; Sirtuin 1/metabolism ; }, abstract = {Resveratrol shows neuroprotective effects in preclinical studies across a number of neurodegenerative illnesses, including Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Huntington's disease (HD), and it enhances mitochondrial function through stimulation of the AMPK/SIRT1/PGC-1α pathway, thereby improving mitochondrial oxidative capacity and ATP generation. The natural polyphenol lowers α-synuclein accumulation and affects autophagy; both markers of PD. Combining nano‑resveratrol formulations with L‑DOPA has shown greater therapeutic efficacy in animal models (MPTP mouse), while co‑administration with EGCG has shown synergistic neuroprotection in vitro (SH‑SY5Y cells). These combination strategies offer potential advantages in neuroprotection and symptom alleviation while minimizing adverse drug effects. Resveratrol activates SIRT1 and AMPK signaling in preclinical models, enhancing mitochondrial biogenesis, lowering apoptosis, and restoring cellular resilience. The effectiveness of various models and dosages varies. The primary mechanism by which resveratrol promotes neuronal survival and remyelination in multiple sclerosis is through SIRT1 activation, which does not directly reduce inflammation. As innovative delivery systems, intranasal nanoparticles and exosomes produced from macrophages have shown improved CNS targeting accuracy. Resveratrol slows down neurodegeneration and improves the prognosis of HD by improving motor function and stimulating mitochondrial biogenesis in addition to activating neuroprotective ERK signaling. All of these results point to resveratrol's several pathways as a strong contender for neurodegenerative disease adjunctive treatment. The current evidence base is insufficient to support clinical use of resveratrol for any of the four diseases. Further rigorous preclinical studies (including TDP-43 models for ALS, SIRT1 knockout studies, and human-feasible dosing) and well-designed clinical trials with pharmacokinetic endpoints are required before any clinical recommendations can be made.}, } @article {pmid42401978, year = {2026}, author = {Alsina, R and Riba, M and Sartorio, M and Romera, C and Riu, J and Vilaplana, G and Aldecoa, I and Compta, Y and Sánchez-Valle, R and Del Valle, J and Pelegrí, C and Molina-Porcel, L and Vilaplana, J}, title = {Regional wasteosome accumulation across neurodegenerative diseases points to a shared underlying mechanism potentially related to glymphatic insufficiency.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42401978}, issn = {2051-5960}, support = {FPU//Ministerio de Ciencia, Innovación y Universidades/ ; Margarita Salas//Ministerio de Ciencia, Innovación y Universidades/ ; FPI//Ministerio de Ciencia, Innovación y Universidades/ ; PID2020-115475GB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; 2021 SGR 00288 625//Generalitat de Catalunya/ ; }, mesh = {Humans ; *Glymphatic System/pathology/metabolism ; *Neurodegenerative Diseases/pathology/metabolism ; *Brain/pathology/metabolism ; Female ; Male ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Middle Aged ; }, abstract = {The glymphatic system plays a key role in clearing waste products from the brain and is essential for maintaining brain homeostasis. When dysfunctional, it appears to contribute to pathological changes that exacerbate brain disorders, including neurodegenerative diseases. Additionally, wasteosomes, also known as corpora amylacea, are structures that function as waste containers and are thought to increase in response to chronic glymphatic insufficiency. Hence, in this study, we evaluated whether the accumulation and distribution of wasteosomes are compatible with both the potential role of wasteosomes as a hallmark of the chronic glymphatic insufficiency and the presence of this insufficiency in certain neurodegenerative diseases. Accordingly, brain tissue from 185 donors was analysed, including cases of Alzheimer's disease, amyotrophic lateral sclerosis with TDP-43 proteinopathy, frontotemporal lobar degeneration with TDP-43 or tau proteinopathy, and non-diseased controls. Wasteosomes were examined across 28 brain regions comprised within 5 major brain areas, using region-specific scoring systems. Analysis was conducted through variance and covariance analyses, along with decision tree procedures. The findings reveal that wasteosomes are consistently found in specific critical regions, with a higher burden in donors with neurodegenerative diseases compared with controls. These regions are independent of the regional distribution of the underlying proteinopathy, and are potentially associated with glymphatic drainage pathways. From an integrated perspective, although further studies are required, the increased presence of wasteosomes in these critical regions across all diseased groups is consistent with the potential presence of chronic glymphatic insufficiency in these diseases.}, } @article {pmid42402806, year = {2026}, author = {O'Sullivan, S and Tadjine, Y and Palma, GR and Suleyman, N and Woods, E and Fasano, A and Walsh, C and Awiszus, F and Hardiman, O and Carson, RG and McMackin, R}, title = {Very low-amplitude muscle activity increases probability of motor evoked potentials in healthy individuals and in amyotrophic lateral sclerosis.}, journal = {Experimental physiology}, volume = {111}, number = {8}, pages = {3492-3501}, pmid = {42402806}, issn = {1469-445X}, support = {23-PPG-674-1//ALS Association (ALSA)/ ; SS-2023-039//Health Research Board (HRB)/ ; /WT_/Wellcome Trust/United Kingdom ; MRCG-2018-02//Health Research Board (HRB)/ ; 23-PPG-674-1//ALS Finding A Cure/ ; 20-IIA-546//ALS Association (ALSA)/ ; McMackin/Oct20/972-799//Motor Neurone Disease Association (MNDA)/ ; MRCG-2018-02//Research Motor Neurone/ ; GOIPG/2017/1014//Irish Research Council (IrishResearch)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Evoked Potentials, Motor/physiology ; Female ; *Muscle, Skeletal/physiology/physiopathology ; Transcranial Magnetic Stimulation/methods ; Male ; Electromyography/methods ; Middle Aged ; Adult ; *Muscle Contraction/physiology ; Aged ; Retrospective Studies ; Motor Cortex/physiopathology/physiology ; }, abstract = {Muscle contraction increases motor evoked potential (MEP) amplitude, decreasing motor threshold (MT). Correspondingly, trials where baseline EMG amplitude exceeds a specified threshold are often rejected. We aimed to investigate the influence of motor activity below such a threshold of MEP amplitude. We retrospectively analysed TMS-EMG data collected during resting MT (RMT) measurement in 45 healthy control subjects (1794 data points) and 35 people with amyotrophic lateral sclerosis (ALS; 1229 data points). Trials with de-meaned root mean squared (RMS) EMG amplitude of >10 µV throughout the 200 ms prior to stimulation were rejected. Generalised linear mixed-effects models assessed effects of muscle activity below this rejection threshold on the probability of evoking an MEP with peak-to-peak amplitude of ≥50 µV. Greater sub-rejection-threshold activity significantly increases MEP probability in control subjects and people with ALS. Models predicted a 38%-43% increase in MEP probability when baseline RMS-EMG amplitude increased from 1 to 9 µV. Sub-rejection-threshold baseline activity was significantly greater in ALS than control subjects. Below a typical rejection threshold, greater baseline RMS-EMG amplitudes markedly increase the probability of evoking MEPs with peak-to-peak amplitude of ≥50 µV. Effects of sub-rejection-threshold muscle activity should be accounted for when comparing RMT measures, particularly between cohorts where such activity differs, such as ALS and control subjects.}, } @article {pmid42403529, year = {2026}, author = {Wilson, E and Turner, N and Macdonald, G and Faull, C}, title = {Paid homecare worker support for people living with motor neurone disease: A secondary analysis of people living with motor neurone disease and family member perspectives.}, journal = {Palliative care and social practice}, volume = {20}, number = {}, pages = {26323524261452739}, pmid = {42403529}, issn = {2632-3524}, abstract = {BACKGROUND: People living with motor neurone disease (MND) increasingly receive complex, life-sustaining interventions at home, including ventilation, tube feeding, and cough assist support. These demands place substantial strain on family carers and often require input from paid homecare workers. Despite their essential role, little is known about how homecare workers contribute to complex MND care, how they integrate within multidisciplinary teams, or how families experience their involvement.

OBJECTIVES: To examine people living with MND and family members' perspectives of homecare worker roles, responsibilities, relationships when complex interventions are required.

DESIGN: A qualitative secondary analysis of data from two prior studies exploring home ventilation and tracheostomy ventilation in MND.

METHODS: Seven relevant NVivo nodes and 33 sub-nodes from interviews with 68 participants were re-coded using a deductive framework. Fourteen new nodes and 11 sub-nodes were generated and organised into three themes: care commissioning and provision; relationships; and the home environment.

RESULTS: Participants described fragmented and inconsistent care commissioning, requiring families to advocate persistently for adequate support. Challenges included funding barriers, high staff turnover, and limited MND-specific knowledge, which undermined trust and compromised safe, effective care. Relationships with homecare workers ranged from highly valued, stable partnerships to strained interactions shaped by competence concerns, emotional labour, and mismatched expectations. The presence of homecare workers and medical equipment transformed the home into a quasi-clinical space, reducing privacy, disrupting routines, and requiring households to adapt around care provision. Yet strong relationships with homecare workers could enhance quality of life.

CONCLUSION: Homecare workers play a critical role in delivering complex home-based MND care, yet quality is inconsistent. Improving training, stabilising staffing, supporting care coordination, and preparing families for the relational and environmental impact of homecare are essential for fostering sustainable, trusted care relationships, and improving outcomes for people living with MND and their families.}, } @article {pmid42404161, year = {2026}, author = {Riva, N and Finotto, E and Schito, P and Donzelli, G and Russo, T and Domi, T and Pozzi, L and Tettamanti, A and Riboldi, E and Lopez, ID and Quattrini, A and Cremona, G and Comola, M and Filippi, M}, title = {Perspective and quality of life in amyotrophic lateral sclerosis patients undergoing percutaneous endoscopic gastrostomy.}, journal = {Frontiers in nutrition}, volume = {13}, number = {}, pages = {1756642}, pmid = {42404161}, issn = {2296-861X}, abstract = {INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) is commonly used to manage dysphagia and nutritional failure, which are among the most frequent and severe complications of amyotrophic lateral sclerosis (ALS). While several studies assessed PEG indications, outcomes, and prognostic factors, there is no evidence regarding ALS patients' perspectives and health-related quality of life (HRQoL) associated with PEG.

METHODS: This study included 48 consecutive ALS patients. At the 1-month follow-up after PEG, patients and their caregivers completed a PEG satisfaction questionnaire regarding their decision to proceed with the PEG-tube placement. HRQoL was assessed using the Gastrointestinal Quality of Life Index (GIQLI) and the Short Form-36 (SF-36).

RESULTS: In total, 77.1% of patients and 88.9% of caregivers confirmed that they would prefer to have a PEG tube placed again if required (p > 0.001); 93.8% of patients felt that PEG made feeding easier, exerting a positive effect on overall wellbeing (83.3%) and increasing survival rates (93.8%) (p > 0.001); 54.2% felt that PEG was cosmetically acceptable. Consistent positive rates were reported by caregivers. The GIQLI digestion subscale values significantly improved from baseline (28.3; SD = 6.6) to discharge (30.97, SD = 5.84) and were maintained at 1-month follow-up (30.21, SD = 6.7; p = 0.014). Conversely, in follow-up assessments, we observed a significant reduction in the SF-36 physical component summary (PCS) subscale (baseline = 33.3; 1-month follow-up = 28.61; p = 0.032), which was accompanied by a significant worsening in the GIQLI physical dimension subscale (baseline = 9.63; 1-month follow-up = 7.38; p = 0.044).

DISCUSSION: This study provides preliminary evidence that ALS patients have a positive perspective on PEG positioning, which may also have a beneficial effect on HRQoL related to gastrointestinal function.}, } @article {pmid42404433, year = {2026}, author = {Corti, S and Alberti, C and Ottoboni, L and Magni, G and Gagliardi, D and Marcotti, F and Zanotti, S and Moggio, M and Comi, GP}, title = {Beyond motor neurons: peripheral TDP-43 pathology in skeletal muscle and intramuscular nerves in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag241}, pmid = {42404433}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by accumulation of the 43-kDa TAR DNA-binding protein (TDP-43). This neuropathological signature has been well documented within the CNS; however, recent findings indicate that the phosphorylated TDP-43 additionally deposits in peripheral tissues, including skeletal muscle and intramuscular nerves. These data warrant a change of view from a neurocentric perspective of amyotrophic lateral sclerosis pathogenesis towards a broader concept of TDP-43 proteinopathy extending both within and beyond the nervous system. In this review, we focus on current evidence supporting the presence of TDP-43 pathology in amyotrophic lateral sclerosis skeletal muscle, examining its topographic distribution, molecular characteristics and associations with intramuscular nerve bundles. We also discuss the susceptibility of intrinsic muscle cells, disrupted axonal transport and impairment in protein quality control. Phosphorylated TDP-43 pathology in muscle biopsies from amyotrophic lateral sclerosis patients has emerged as a promising tool in the early diagnosis of the disease. Moreover, we discuss the relevance of these findings to amyotrophic lateral sclerosis pathogenesis and potential therapeutic implications.}, } @article {pmid42404435, year = {2026}, author = {Hobin, F and Das, S and Lambrechts, C and De Rocker, C and Dubin, J and Ombelet, F and De Vocht, J and Lamaire, N and Vanmechelen, E and Poesen, K and Van Damme, P}, title = {Value of synaptic proteins as biomarkers in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag247}, pmid = {42404435}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a heterogeneous and rapidly progressing neurodegenerative disorder with limited treatment options. Therefore, there is a critical need for biomarkers that capture the diverse pathophysiological mechanisms underlying disease onset and progression. Emerging evidence suggests that synaptic dysfunction is an early disease mechanism in amyotrophic lateral sclerosis. Using homebrew immunoassays, we explored a panel of pre- and post-synaptic proteins in cerebrospinal fluid of patients with amyotrophic lateral sclerosis (N = 57) and controls (N = 36). The potential value as a biomarker was explored by correlating cerebrospinal fluid levels with clinical parameters and established biomarkers for amyotrophic lateral sclerosis. Higher levels of Neurogranin (NRGN) (P = 0.003) and Vesicle-associated membrane protein 2 (VAMP2) (P = 0.014) were observed in patients with amyotrophic lateral sclerosis compared with controls. VAMP2, Synaptosome-associated protein 25 kDa (SNAP25) and β-synuclein (SNCB) correlated with individual relative disease stage, but none of the biomarkers correlated with disease progression rate. High levels of SNAP25 predicted worse survival in a univariate and stepwise multivariable analysis, but significance did not persist upon including Neurofilament light chain (NfL) levels. Synaptic proteins did not correlate with cerebrospinal fluid levels of neurofilaments or biomarkers of neuroinflammation, suggesting that they reflect different pathological mechanisms in amyotrophic lateral sclerosis. Our findings warrant further investigation to determine whether increased cerebrospinal fluid levels of synaptic proteins reflect synaptic breakdown or active release of synaptic proteins. This will help elucidate how synaptic dysfunction or damage contributes to elevated levels of synaptic markers in amyotrophic lateral sclerosis, and its underlying value as biomarker.}, } @article {pmid42404802, year = {2026}, author = {Nieva, G and Vassallu, F and Depino, A and Netti, V and Igaz, LM}, title = {Region-specific features of early glial activation and Aquaporin-4 dysregulation in conditional mouse models of TDP-43 proteinopathies.}, journal = {Discovery immunology}, volume = {5}, number = {1}, pages = {kyag011}, pmid = {42404802}, issn = {2754-2483}, abstract = {INTRODUCTION: Aggregation and cytoplasmic mislocalization of TDP-43 are key features of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuroinflammatory processes mediated by glial cells play crucial roles in the pathophysiology of these and other diseases, defined as TDP-43 proteinopathies. Here, we characterized region-specific glial activation in two conditional mouse models: hTDP-43-WT (overexpressing nuclear wild-type human TDP-43) and hTDP-43-ΔNLS (expressing cytoplasmic TDP-43 with altered nuclear localization signal) following 1 month of transgene expression.

METHODS AND RESULTS: Immunofluorescence analysis revealed distinct patterns of microglial activation across brain regions. hTDP-43-WT mice exhibited significant microgliosis in motor (MC) and somatosensory (SSC) cortices and hippocampal dentate gyrus (DG) with pronounced morphological alterations (i.e. increased soma size). Sholl analysis demonstrated reduced branching length and complexity in MC, SSC, and hippocampal subfields. hTDP-43-ΔNLS mice displayed more pronounced microglial activation in hippocampal regions (CA1, DG) compared to cortical areas, with significant increases in microglial density. Additionally, we observed region-specific cortical astrocytosis in both models, suggesting coordinated glial reactivity. hTDP-43-ΔNLS mice showed decreased polarization of astrocytic water channel Aquaporin-4 (AQP4) around vascular structures in SSC and hippocampal CA1/DG. The changes in AQP4 localization, which is critical for glymphatic function, support the hypothesis that this waste clearance system for the brain is altered in TDP-43 proteinopathies.

CONCLUSION: These findings demonstrate that these different animal models of ALS/FTD induce distinct neuroinflammatory signatures, potentially contributing to the region-specific vulnerability observed in these diseases. Our data provide insights into early glial-mediated pathogenic mechanisms that could guide targeted therapeutic strategies for TDP-43 proteinopathies.}, } @article {pmid42405014, year = {2026}, author = {Farè, M and Comi, C and Ferrero, GS and Sala, G and Cerri, F and Calabresi, L and Tremolizzo, L and Pavanello, C}, title = {Cholesterol in amyotrophic lateral sclerosis: a bystander, a biomarker, or a target?.}, journal = {Atherosclerosis plus}, volume = {65}, number = {}, pages = {100576}, pmid = {42405014}, issn = {2667-0895}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. In addition to the different pathogenic mechanisms, in recent years, increasing attention has been directed toward the role of lipid metabolism in ALS pathogenesis, although the clinical relevance of lipid alterations in ALS may differ from their well-established role in cardiovascular disease. This review critically examines the multifactorial relationship between cholesterol and ALS through three perspectives: (1) as a risk factor for disease onset, (2) as a prognostic biomarker of disease progression, and (3) as a potential therapeutic target. Epidemiological and genetic studies suggest a complex and sometimes contradictory association between lipid profile and ALS risk. Elevated LDL-cholesterol and total cholesterol have been linked to increased disease susceptibility in some cohorts, with Mendelian randomization studies supporting a potential causal role. Conversely, evidence regarding HDL-cholesterol remains conflicting and may be influenced by sex-specific and metabolic factors. As a prognostic biomarker, hyperlipidemia has been variably associated with prolonged survival in ALS patients; however, these findings often lose significance after adjusting for body mass index and nutritional status, suggesting that lipid levels may reflect systemic metabolic reserve rather than directly modulating disease progression. Pharmacological modulation of cholesterol reveals further complexity. While statins are generally not associated with increased ALS risk in clinical studies, preclinical models show divergent effects: some statins accelerate disease progression, while others like lovastatin may be protective. Other lipid-lowering drugs, including fibrates and PCSK9 inhibitors, may also influence ALS-related pathways beyond cholesterol lowering, although their potential role remains to be clarified.}, } @article {pmid42405987, year = {2026}, author = {Botman, LCM and van Unnik, JWJ and Beelen, A and Bakers, JNE and van der Schoot, ND and Gremmen, MAP and van Helm, S and van den Berg, LH and van Eijk, RPA}, title = {Feasibility and sensitivity of a multimodal digital endpoint panel for amyotrophic lateral sclerosis: a prospective cohort study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2696382}, pmid = {42405987}, issn = {2167-9223}, abstract = {Background: The use of digital technology may improve monitoring of amyotrophic lateral sclerosis (ALS) but a multimodal approach is likely required to capture the full disease phenotype. We evaluated the feasibility of a multimodal home monitoring protocol in ALS. Methods: We conducted a 3-month prospective cohort study at the University Medical Center Utrecht, Netherlands, with monthly home assessments of spirometry, accelerometry, speech, and questionnaires on functioning. The primary outcome was protocol adherence, defined as percentage of completed assessments. Secondary outcomes included acceptability ((totally) agree, neutral, (totally) disagree), and perceived burden, ranging from 0 (no burden) to 10 (extremely burdensome). Exploratory analyses were performed to evaluate changes in digital endpoints using linear mixed-effects models. Findings: Fifty patients with ALS were included (January 2023 - June 2025), of whom 47 (94%) completed the 3-month follow-up. Overall adherence was 83.2% (95% CI 76.9-88.6) and did not differ across modalities (p = 0.75). Adherers did not differ from non-adherers in either demographic or disease characteristics. In month 3, 93.0% to 95.3% of patients considered monthly remote assessments as acceptable, with a mean burden score of 2.0 (95% CI 1.7 to 2.3); burden was highest for speech (2.5) and the lowest for questionnaires (1.5). Digital endpoints showed significant change over 3 months (all p < 0.05). Interpretation: This study demonstrates good adherence and acceptability of a multimodal remote monitoring protocol. Digital endpoints offer an innovative approach to capturing disease progression. Future research should assess its long-term feasibility, added value, and integration alongside established clinical outcomes.}, } @article {pmid42406382, year = {2026}, author = {Guise, AJ and Sellon, MT and Roemer, SF and Monine, M and Comfort Harris, NT and Bartlett, D and David, E and Xu, S and Jandreski, L and Malek, S and Garafalo, S and Nestorov, I and Ireland, MD and King, A and Bowser, RP and Korben, VA and Ravits, J and Shaw, PJ and Highley, JR and Ferguson, TA and Fradette, S and Graham, DL and Sorenson, EJ and Oskarsson, B and Reichard, RR and Dickson, DW and Paganoni, S and Babu, S and Oakley, DH and Frosch, MP and Miller, TM and Bucelli, RC and Perrin, RJ and Ly, CV and Plowey, ED}, title = {Antisense Oligonucleotide Tofersen Distribution in the Central Nervous System of SOD1-ALS Autopsy Tissue Donors.}, journal = {JAMA neurology}, volume = {83}, number = {9}, pages = {884-893}, pmid = {42406382}, issn = {2168-6157}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; Female ; *Superoxide Dismutase-1/genetics/metabolism ; Male ; Middle Aged ; Aged ; Cross-Sectional Studies ; Autopsy ; Adult ; *Oligonucleotides, Antisense/pharmacokinetics/administration & dosage ; Tissue Donors ; Spinal Cord/metabolism ; *Central Nervous System/metabolism ; }, abstract = {IMPORTANCE: Tofersen is a disease-modifying antisense oligonucleotide therapeutic for people living with SOD1-amyotrophic lateral sclerosis (SOD1-ALS). Autopsy tissue donors have provided the first opportunity to study the distribution of intrathecally administered tofersen in human central nervous system tissues.

OBJECTIVES: To determine the tissue distribution of tofersen and to provide the first estimates of SOD1 reduction in human somatic motor systems tissues.

This was a cross-sectional autopsy tissue case series conducted between 2018 and 2026. Autopsies were performed at 3 US academic medical institutions. Tissue samples from 8 deceased patients who lived with SOD1-ALS, participated in tofersen clinical trials (ClinicalTrials.gov Identifiers NCT02623699 [An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)] and NCT03070119 [Long-Term Evaluation of BIIB067 (Tofersen)]) or the Expanded Access Program, and whose families authorized autopsies were eligible for this study. All autopsy tissue donors known at the time of this study were included (none were excluded). Analyses were conducted between August 2020 and January 2026.

EXPOSURES: Participants received multiple intrathecal 20- to 100-mg tofersen doses.

MAIN OUTCOMES AND MEASURES: Tofersen tissue concentrations were measured using hybridization enzyme-linked immunosorbent assay (ELISA). SOD1 messenger RNA (mRNA) and protein reduction estimates, defined as percentage SOD1 levels in this study's recently treated autopsy tissue donors compared to a cohort of samples from tofersen-naive SOD1-ALS autopsy tissue donors, were measured using quantitative reverse transcription polymerase chain reaction (PCR) and ELISA. Histological localization of tofersen and SOD1 transcripts were studied using immunohistochemistry and in situ hybridization assays.

RESULTS: In 8 tofersen-treated autopsy tissue donors (5 male and 3 female donors; age range, 42-66 years), spinal cord and motor cortical tissue tofersen concentrations strongly correlated with predictions based on individual dosing histories and a preclinical pharmacokinetic model. For 3 recently treated autopsy tissue donors, reductions in lumbar spinal cord tissue SOD1 mRNA and protein levels ranged from 45% to 84% despite not having been administered 1 to 2 scheduled doses before autopsy. Residual somatic motor neurons demonstrated tofersen transduction and low SOD1 mRNA probe hybridization. Misfolded SOD1 protein inclusions were detected in residual motor neurons of tofersen-naive SOD1-ALS tissue donor controls and tofersen-treated tissue donors. Meningeal and perivascular lymphocytic immune responses were observed in 5 recently treated tissue donors but were not apparent in tissue donors with remote final tofersen doses.

CONCLUSIONS AND RELEVANCE: This case series presents the first emerging autopsy tissue data confirming the predicted distribution of tofersen and robust SOD1 protein reduction in human somatic motor systems tissues.}, } @article {pmid42407013, year = {2026}, author = {Oliveira Santos, M and Castro, J and Castro, I and Swash, M and de Carvalho, M}, title = {Role of the Upper Motor Neuron in the Generation of Fasciculations in Early Disease Stages of Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {107}, number = {2}, pages = {e218273}, doi = {10.1212/WNL.0000000000218273}, pmid = {42407013}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; *Motor Neurons/physiology ; Evoked Potentials, Motor/physiology ; *Motor Cortex/physiopathology ; Transcranial Magnetic Stimulation ; Female ; Male ; Aged ; *Fasciculation/physiopathology/etiology ; Middle Aged ; Electromyography ; Muscle, Skeletal/physiopathology ; }, abstract = {BACKGROUND AND OBJECTIVES: The origin of fasciculation potentials (FPs) in the early stages of amyotrophic lateral sclerosis (ALS) remains a subject of debate. We investigated the role of the motor cortex in FP generation by comparing resting FP frequency in the first dorsal interosseous (FDI) muscle before and after motor cortex inhibition induced by continuous theta-burst stimulation (cTBS).

METHODS: We studied patients with early-stage ALS (G1) and a disease-control group (G2) comprising individuals with chronic lower motor neuron (LMN) disorders or benign fasciculation syndrome without upper motor neuron (UMN) involvement. Inclusion required a right FDI strength of MRC grade 4+ or 5. At baseline, we recorded FP frequency and amplitude in the right FDI (3 replicates) and the motor evoked potential (MEP) amplitude. These measures were repeated immediately after cTBS-induced corticomotor inhibition. Statistical significance was set at p < 0.05.

RESULTS: Twenty-two patients with ALS (14 men; median age 65.5 years; 72.7% spinal onset) were included, with a median disease duration of 6.4 months and a mean ALSFRS-R score of 44. The control group (G2) consisted of 11 participants. Notably, 50% of the ALS cohort showed no neurogenic features on needle EMG of the right FDI at enrollment. Baseline peripheral and cortical amplitudes and left hemisphere motor thresholds were comparable between groups. After cTBS, MEP amplitudes decreased significantly in both G1 (0.93 vs 0.50 mV, p = 0.02) and G2 (1.23 vs 0.38 mV, p = 0.02). However, a significant reduction in FP frequency (39.5%) occurred only in the ALS group (0.43 vs 0.26 Hz, p < 0.001), whereas no change was observed in G2 (0.60 vs 0.77 Hz, p = 0.14). Patients with ALS with a normal FDI EMG demonstrated an even greater reduction in FP frequency (54.5%). FP amplitudes remained stable across both groups after cTBS.

DISCUSSION: Our findings indicate that in early ALS, LMN excitability is significantly modulated by descending corticospinal input. The reduction in FP frequency after cortical inhibition suggests that FPs in early ALS are driven by a combination of both UMN and LMN hyperexcitability, distinguishing them from fasciculations in other neurogenic disorders.}, } @article {pmid42407404, year = {2026}, author = {Gündüz, A and Şirin, NG and Boran, E and Baslo, SA and Baslo, MB and Kuruoğlu, HR and Kocasoy Orhan, E and Öge, AE and Yıldız, FG and Tümer, O and Tütüncü, M and Tan, E and Temuçin, ÇM and Uysal, H and Uzun, N and Cengiz, B}, title = {The contribution of trapezius and sternocleidomastoideus motor evoked potentials in the diagnosis of amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {190}, number = {}, pages = {2112331}, doi = {10.1016/j.clinph.2026.2112331}, pmid = {42407404}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Evoked Potentials, Motor/physiology ; Male ; Female ; Transcranial Magnetic Stimulation/methods ; Middle Aged ; Aged ; *Superficial Back Muscles/physiopathology ; Adult ; Electromyography/methods ; *Neck Muscles/physiopathology ; }, abstract = {OBJECTIVE: We aimed to evaluate the role of corticobulbar motor evoked potentials (MEPs) as an objective electrophysiological measure to support clinical assessment of upper motor neurons in amyotrophic lateral sclerosis (ALS).

METHODS: Seventy-three patients with ALS and 44 healthy individuals with similar age and sex underwent transcranial magnetic stimulation with MEP recordings from the sternocleidomastoideus (SCM), trapezius, and abductor pollicis brevis muscles. Corticobulbar involvement was defined by prolonged cortical MEP latency or central motor conduction time (CMCT) or absence of MEP responses. Awaji-Shima diagnostic categories were evaluated before and after the incorporation of corticobulbar MEP abnormalities.

RESULTS: Corticobulbar MEP abnormalities were significantly more frequent in patients with ALS than in controls. Prolonged SCM-MEP latency and CMCT were the most sensitive electrophysiological markers of corticobulbar involvement. When interpreted alongside clinical upper motor neuron signs, corticobulbar MEP abnormalities facilitated upward diagnostic reclassification within the Awaji-Shima framework. One-fifth of patients who were initially classified as possible or probable ALS were reclassified as probable ALS and definite ALS, respectively, following inclusion of SCM- and trapezius-MEP abnormalities.

CONCLUSIONS: Corticobulbar MEP assessment provides objective electrophysiological support for upper motor neuron dysfunction and enhances diagnostic sensitivity when used in conjunction with the Awaji-Shima diagnostic framework.

SIGNIFICANCE: This study demonstrates that electrophysiological assessment of the corticobulbar pathway using SCM- and trapezius-MEPs provides objective evidence of upper motor neuron dysfunction in ALS.}, } @article {pmid42409373, year = {2026}, author = {Kida, H and Kanai, T and Morita, M and Hasegawa, T}, title = {Bedside muscle ultrasonography to detect fasciculations and support diagnosis of amyotrophic lateral sclerosis in a mechanically ventilated intensive care unit patient.}, journal = {Acute and critical care}, volume = {41}, number = {3}, pages = {711-713}, pmid = {42409373}, issn = {2586-6060}, } @article {pmid42410102, year = {2026}, author = {Binet, M and Jewett, G and Breiner, A and Chum, M and Genge, A and Schellenberg, K and Shoesmith, C and Pfeffer, G and Salmon, K}, title = {A changed landscape: five-year retrospective on the paradigm shift in genetic testing practices for ALS in Canada.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {42410102}, issn = {1476-5438}, abstract = {Offering genetic testing is increasingly recommended for all individuals with amyotrophic lateral sclerosis (ALS), particularly following the development of gene-targeted therapies, such as tofersen for SOD1-ALS. Historically, testing was routinely offered to those with familial ALS (fALS), but inconsistently to those with sporadic ALS (sALS). We evaluated changes in genetic testing and counseling practices among Canadian ALS physicians over a five-year period spanning pivotal clinical trial results and regulatory approval of tofersen. Members of the Canadian ALS Research Network were surveyed in 2020, 2022, and 2025 about genetic testing practices for symptomatic and asymptomatic individuals, gene panel composition, access to genetic counseling, and perceived drivers of change. Clinics offering genetic testing for sALS increased from 33% of clinics in 2020 and 57% in 2022 to 100% of respondents in 2025. Genetic testing for patients with a family history (fALS) was near-universal across all timepoints. Broader use of multi-gene panel testing increased over time, coinciding with sponsored testing availability. 61% of respondents reported that Health Canada approval of tofersen directly influenced their practice. Predictive testing offerings increased from 37% in 2020 to 61% in 2025. Genetic testing practices in Canada shifted substantially during late-stage clinical development and following regulatory approval of a gene-targeted therapy (tofersen). Proactive planning during the clinical trial phase facilitated rapid, nationwide adoption. This study captures a key turning point in ALS care, illustrating how therapeutic breakthroughs can redefine national clinical standards.}, } @article {pmid42411077, year = {2026}, author = {Singh, P and Bhardwaj, S and Nagarajan, K}, title = {A Review on the Mechanisms of Neurodegeneration and the Potential of Plant Bioactives in Managing Neurological Conditions.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098388719251206111338}, pmid = {42411077}, issn = {1874-6128}, abstract = {Neurodegenerative disorders encompass a wide range of debilitating neurological conditions characterized by the progressive loss of specific neuronal populations in the central and/or peripheral nervous systems. This disease often leads to a gradual decline in cognitive, motor, and sensory abilities. This review explores the role of various lifestyle factors, such as age, sex, poor diet, depression, etc., which contribute to the onset and progression of NDDs. Various diseases are included in the neurodegenerative disorder, like Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Lewy body disease, which are chronic conditions that significantly impact cognitive and motor functions. A literature search was conducted in the scientific database using the keywords "neurodegenerative disorders, phytoconstituents, and herbals". This review includes a collection of reports from ScienceDirect, Scholar Google, and PubMed, all searched up to 2024. The results were assessed, gathered, and reported in this paper. A total of 241 articles were included, with exponential growth in publication numbers from 1985 to 2024. Effective management and control of NDDs require addressing these risk factors, alongside exploring therapeutic interventions. Some plants and herbs used to treat neurodegenerative diseases, such as curcumin, ashwagandha, ginkgo biloba, epigallocatechin-3-gallate, quercetin, ginseng, and resveratrol, have shown potential to improve neuronal health and mitigate disease progression. This review highlights the dual role of natural compounds in promoting improvements and upregulating brain function while potentially reducing degradation. The phytopharmaceuticals show the potential for treating neurological conditions with better efficacy and safer profiles. The review suggested that future research should focus on integrating lifestyle modifications and natural therapies to enhance the quality of life for individuals at risk or suffering from neurodegenerative diseases.}, } @article {pmid42411482, year = {2026}, author = {Yang, EJ}, title = {Amyotrophic Lateral Sclerosis as a Systemic Disease: Why Integrative and Microbiome-Focused Approaches Deserve Re-Evaluation.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {31}, number = {6}, pages = {52497}, doi = {10.31083/FBL52497}, pmid = {42411482}, issn = {2768-6698}, support = {KSN2225011//KIOM/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/microbiology/physiopathology ; *Complementary Therapies/methods ; *Gastrointestinal Microbiome ; Animals ; Dysbiosis/microbiology ; }, abstract = {Despite decades of intensive research, therapeutic advances in amyotrophic lateral sclerosis (ALS) remain limited. Increasing evidence suggests that ALS is a multisystem disorder involving motor neuron degeneration, immune dysregulation, skeletal muscle pathology, and gastrointestinal dysfunction, thereby challenging the adequacy of current therapeutic strategies. Complementary and alternative medicine (CAM) approaches are widely used by patients with ALS. However, their efficacy remains controversial owing to limited clinical evidence and methodological limitations. The multicomponent herbal medicine and system-level characteristics of CAM conceptually align with the emerging view of ALS as a multisystemic disease. The involvement of gut microbiome dysbiosis in the pathophysiology of ALS has provided a unifying biological framework linking the peripheral, metabolic, and neuroinflammatory processes. These findings suggest that the combination of CAM and conventional therapy may serve as a potential integrative approach to target gut-brain-muscle interactions and systemic disease pathways. This article highlights critical gaps in the existing evidence and proposes that microbiome-focused, biomarker-driven clinical trials are essential to thoroughly evaluate CAM-based interventions in ALS. Embracing a system-oriented therapeutic framework may help address the complexity of ALS beyond traditional neuron-centered approaches.}, } @article {pmid42411953, year = {2026}, author = {Adachi, T and Nakano, T and Yoshida, K and Suzuki, Y and Sakuwa, M and Hasegawa, M and Jannah, AR and Hara, N and Miyashita, A and Ikeuchi, T and Hanajima, R}, title = {Reduced Soluble Ubiquilin2 in Amyotrophic Lateral Sclerosis Carrying Ubiquilin2 (P494L) Mutation: Clinicopathological and Biochemical Evidence From an Autopsy Case.}, journal = {Neuropathology and applied neurobiology}, volume = {52}, number = {4}, pages = {e70091}, doi = {10.1111/nan.70091}, pmid = {42411953}, issn = {1365-2990}, support = {24K10643//Japan Society for the Promotion of Science/ ; JP25dk0207060//Japan Agency for Medical Research and Development/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Autophagy-Related Proteins ; Adaptor Proteins, Signal Transducing ; *Cell Cycle Proteins/genetics/metabolism ; Mutation ; DNA-Binding Proteins/metabolism ; Autopsy ; Male ; Female ; *Ubiquitins/genetics ; Brain/pathology/metabolism ; Middle Aged ; }, abstract = {We report the clinicopathological and biochemical findings of ALS associated with a UBQLN2 P494L mutation. Autopsy revealed widespread TDP-43 pathology and UBQLN2-positive inclusions. Immunoblot analysis demonstrated a marked reduction of soluble UBQLN2, supporting functional UBQLN2 insufficiency as a pathogenic mechanism underlying TDP-43 aggregation.}, } @article {pmid42412610, year = {2026}, author = {Pasniceanu, IS and Atwal, MS and Santos Souza, CD and Moll, T and King, M and Treanor, C and Cabezas de la Fuente, D and West, RJH and Ferraiuolo, L and Livesey, MR}, title = {Striatal neuron dysfunction in C9ORF72-FTD/ALS is driven by AIS and potassium channel dysregulation.}, journal = {Cell reports}, volume = {45}, number = {7}, pages = {117672}, pmid = {42412610}, issn = {2211-1247}, mesh = {Humans ; *Frontotemporal Dementia/physiopathology/metabolism/pathology/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/physiopathology/genetics/pathology ; Medium Spiny Neurons ; *C9orf72 Protein/metabolism/genetics ; *Corpus Striatum/pathology/metabolism/physiopathology ; Action Potentials ; *Potassium Channels/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Axon Initial Segment/metabolism/pathology ; *Neurons/metabolism/pathology ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) form a neurodegenerative spectrum characterized by progressive cognitive, behavioral, and motor decline, yet the contribution of the striatum to disease pathophysiology remains poorly understood. Here, we generate inhibitory striatal medium spiny neurons (MSNs) from human induced pluripotent stem cells carrying the C9ORF72 repeat expansion, the most common genetic cause of FTD/ALS, and compare them with isogenic-corrected, control, and patient-derived motor neurons. Using whole-cell electrophysiology, pharmacological manipulation, and high-resolution imaging, we identify a vulnerability of C9ORF72 MSNs to develop intrinsic hypoexcitability with linked synaptic dysfunction. These abnormalities are associated with axon initial segment shortening and altered voltage-gated potassium channel function relative to control and isogenic-corrected neurons. Pharmacological modulation partially restores action potential waveform properties, indicating that key electrophysiological abnormalities are reversible. These findings identify the striatum as a critical site of dysfunction in FTD/ALS and highlight striatal excitability as a potential therapeutic target.}, } @article {pmid42413223, year = {2026}, author = {Mohammadi, S and Trojsi, F and Ghaderi, S}, title = {Are T1-weighted and T2-weighted volumetric pipelines interchangeable methodologies for investigating amyotrophic lateral sclerosis pathology in vivo?.}, journal = {Brain research bulletin}, volume = {243}, number = {}, pages = {112036}, doi = {10.1016/j.brainresbull.2026.112036}, pmid = {42413223}, issn = {1873-2747}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging ; Female ; Middle Aged ; *Magnetic Resonance Imaging/methods ; Aged ; *Substantia Nigra/pathology/diagnostic imaging ; *Red Nucleus/pathology/diagnostic imaging ; Image Processing, Computer-Assisted/methods ; Atrophy/pathology ; Adult ; }, abstract = {PURPOSE: To test the hypothesis that T1-w and T2-w volumetric pipelines are not interchangeable, particularly regarding their differential sensitivity to physiological traits and disease effects in the red nucleus (RN) and substantia nigra (SN).

METHODS: Thirty-one patients with ALS (mean age: 59.39 ± 8.73 years; 23 males) and 21 non-neurodegenerative controls (mean age: 53.43 ± 10.01 years; 16 males). Bilateral RN and SN volumes were automatically extracted using deep learning pipelines optimized for T1-w (OpenMAP-T1) and T2-w (pBrain) images. Volumes were normalized to total intracranial volume. A 2 × 2 × 2 repeated-measures general linear model (GLM) assessed interactions between Method, Region, Side, and Group, controlling for age, sex, BMI, and handedness.

RESULTS: There was no significant main effect of the disease group (p = 0.829) or Method × Group interaction (p = 0.682), indicating both pipelines agreed on the absence of disease-specific macrostructural atrophy. However, a significant four-way Method × Region × Side × Age interaction (P = 0.031) was observed. In the RN, the T2-w pipeline detected robust age-related atrophy (Left: Slope = -1.84 × 10[-6]; Right: Slope = -1.70 ×10⁻⁶), whereas the T1-w pipeline did not (p > 0.05). Conversely, in the SN, T1-w consistently identified bilateral age-related loss, whereas T2-w yielded lateralized results (Right: p = 0.011; Left: P = 0.465).

CONCLUSIONS: T1-w and T2-w pipelines are not interchangeable. Though both confirm the absence of gross atrophy in this ALS cohort, their differing sensitivity to physiological aging highlights their distinct biological tissue properties, requiring method-specific interpretation.}, } @article {pmid42414029, year = {2026}, author = {Hata, T and Ogawa, N and Yabata, H and Kobashi, S and Nakayama, M and Ishigaki, H and Yamakawa, I and Itoh, Y and Nishino, I and Urushitani, M}, title = {Case of concurrent ALS and human T-cell leukaemia virus type 1-associated myositis.}, journal = {BMJ case reports}, volume = {19}, number = {7}, pages = {}, pmid = {42414029}, issn = {1757-790X}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/pathology ; *Human T-lymphotropic virus 1 ; Aged ; Fatal Outcome ; *HTLV-I Infections/complications ; *Myositis/virology/complications/diagnosis ; Muscle, Skeletal/pathology ; Immunoglobulins, Intravenous/therapeutic use ; Magnetic Resonance Imaging ; }, abstract = {A woman in her late 70s presented with progressive limb weakness, muscle atrophy and hyper-reflexia. Laboratory findings revealed elevated creatine kinase and positive serum human T-cell leukaemia virus type 1 (HTLV-1) antibody. Clinical and electrophysiological findings met revised El Escorial criteria for amyotrophic lateral sclerosis (ALS), but muscle MRI showed inflammatory changes. Muscle biopsy revealed both neurogenic and inflammatory features. While methylprednisolone showed no benefit, intravenous immunoglobulin therapy produced transient improvement in weakness with normalisation of creatine kinase levels. The patient died from respiratory failure 3 years after symptom onset. Autopsy confirmed typical ALS-TDP pathology with phosphorylated TDP-43 inclusions in motor neurons. HTLV-1 Tax-positive lymphocytes infiltrated skeletal muscles but not the central nervous system, establishing dual pathology of ALS-TDP with HTLV-1-associated myositis. The improvement most likely reflected treatment of the HTLV-1-associated myositis rather than the underlying motor neuron disease. This case highlights the importance of evaluating treatable conditions in HTLV-1-seropositive ALS patients.}, } @article {pmid42414528, year = {2026}, author = {Smith, CL and Robinson, JL and Lee, EB}, title = {Annexin A11 and TDP-43: core players in neurodegeneration.}, journal = {Acta neuropathologica}, volume = {152}, number = {1}, pages = {}, pmid = {42414528}, issn = {1432-0533}, support = {T32AG000255/NH/NIH HHS/United States ; P30AG072979/NH/NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Annexins/metabolism/genetics ; *Neurodegenerative Diseases/pathology/metabolism/genetics ; Animals ; TDP-43 Proteinopathies/pathology/metabolism ; }, abstract = {Annexin A11 (ANXA11) is a Ca[2][+]-dependent phospholipid-binding protein that has recently emerged as a key player in neurodegeneration. Rare pathogenic ANXA11 variants were initially identified in cases of amyotrophic lateral sclerosis (ALS). Since then, ANXA11 has been linked to a broader spectrum of related neurodegenerative diseases. Two independent studies demonstrated that ANXA11 co-aggregates with TDP-43 in all cases of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type C, with cryo-EM revealing heteromeric ANXA11-TDP-43 filaments. These discoveries support the direct pathological interaction between the two proteins as an important feature of FTLD-TDP type C. We also described secondary ANXA11 pathology in related neurodegenerative diseases, including limbic-predominant age-related TDP-43 encephalopathy (LATE), and more rarely in ALS and FTLD-TDP types A and B. ANXA11 and TDP-43 co-aggregates are also a feature of a FTLD-TDP associated with primary lateral sclerosis. These advances have renewed interest in ANXA11 as a major player in ALS/FTLD pathogenesis in both genetic and sporadic neurodegenerative diseases. In this review, we summarize ANXA11 pathology across genetic and sporadic cases, highlighting its heterogeneous overlap with TDP-43 pathology. We synthesize current knowledge of ANXA11's physiological roles in phase separation, membrane repair, and RNA granule dynamics, integrating emerging evidence on how disruption of these processes may promote pathological aggregation and toxicity. Finally, we outline priorities for future research, with particular emphasis on elucidating ANXA11's mechanistic connection to TDP-43.}, } @article {pmid42414949, year = {2026}, author = {Njohjam, MN and Ngoule, MO and Niakam, TF}, title = {Biological sex differences in neurodegenerative diseases in Africa: a scoping review of evidence and research gaps.}, journal = {BMC neurology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12883-026-05123-w}, pmid = {42414949}, issn = {1471-2377}, abstract = {BACKGROUND: Biological sex is a well-established determinant of risk, progression, and therapeutic response in neurodegenerative diseases (NDs). However, current evidence on sex differences in NDs is from high-income Western populations. This review aims to map and synthesize evidence on biological sex differences in NDs in Africa, and to identify key research gaps.

METHODS: This scoping review was conducted in accordance with the Joanna Briggs Institute methodology and reported in accordance with the PRISMA-ScR guidelines. A literature search was conducted on PubMed, African Journals Online, Sabinet Journals, ScienceDirect, and Google Scholar. We included studies conducted in African countries that reported sex disaggregated data or examined biological sex differences in at least one ND. Data were synthesized descriptively.

RESULTS: All included studies reported sex distribution, but most (about 84%) did so only descriptively. Approximately 17% conducted sex-stratified analyses beyond prevalence. Similar to global epidemiological trends, several studies suggested a higher prevalence or odds of dementia and multiple sclerosis among females, while male predominance was observed in Parkinson's disease and Amyotrophic lateral sclerosis studies. An earlier onset and a higher mutation frequency in LRRK2-G2019S were reported in females with Parkinson's disease in some studies, while another study reported a higher mortality rate in females with dementia. No study evaluated sex specific biomarker profiles, disease progression, or treatment response.

CONCLUSIONS: Evidence on biological sex differences in NDs in Africa remains limited and is largely descriptive. Mechanistic, longitudinal, and biomarker-based investigations are largely absent.}, } @article {pmid42418280, year = {2026}, author = {Zhang, C and Chen, S and Zhao, H and Wang, Y and Zhou, L and Fan, H and Sun, Y}, title = {Phase Separation Drives Pathological Aggregation in Neurodegenerative Diseases: A 15-Year Bibliometric Landscape (2009-2024).}, journal = {Annals of the New York Academy of Sciences}, volume = {1561}, number = {1}, pages = {e70311}, pmid = {42418280}, issn = {1749-6632}, support = {#82371153//National Natural Science Foundation of China/ ; #82571317//National Natural Science Foundation of China/ ; #ZR2022QH073//Natural Science Foundation of Shandong Province/ ; #ZR2025MS1188//Natural Science Foundation of Shandong Province/ ; #ZR2025LZ044//Natural Science Foundation of Yantai/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Phase Separation ; *Protein Aggregation, Pathological/metabolism/pathology ; *Bibliometrics ; Animals ; DNA-Binding Proteins/metabolism ; }, abstract = {Liquid-liquid phase separation (LLPS), a biophysical driver of membraneless organelle assembly, is central to pathological aggregation in neurodegenerative diseases. Initially linked to amyotrophic lateral sclerosis (ALS), LLPS dysregulation has now been implicated in Alzheimer's, Parkinson's, and frontotemporal dementia, where aberrant transitions convert dynamic condensates into insoluble fibrils. To systematically map this landscape, we employed CiteSpace-based bibliometrics to analyze 784 Web of Science articles from 2009 to 2024. Our analyses reveal dominant contributions from the United States, China, and Germany, with collaborative networks focusing on protein dynamics. Key hotspots include LLPS-driven aggregation of TARDBP (TDP-43), FUS, and α-synuclein, alongside stress granule dysfunction and nucleocytoplasmic transport defects. Emerging frontiers highlight therapeutic strategies targeting pathological condensates utilizing small-molecule chaperones and posttranslational modification modulators to restore cellular homeostasis. Our findings underscore LLPS as a critical axis bridging molecular pathology and translational innovation. The field is rapidly shifting from mechanistic exploration to therapeutic applications, emphasizing interventions to halt or reverse aggregation. By delineating global trends and changing priorities, our study highlights the transformative potential of phase-targeted interventions and provides a roadmap of groundbreaking interdisciplinary research into neurodegenerative disorders.}, } @article {pmid42418533, year = {2026}, author = {Hsu, YW and Lu, YN and Liu, M and Wang, J}, title = {Multi-regional transcriptomic profiling reveals divergent molecular mechanisms in ALS-related neurodegeneration.}, journal = {PLoS genetics}, volume = {22}, number = {7}, pages = {e1012225}, pmid = {42418533}, issn = {1553-7404}, support = {R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS128494/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; *C9orf72 Protein/genetics ; Gene Expression Profiling/methods ; *Transcriptome/genetics ; DNA Repeat Expansion/genetics ; Female ; Mutation ; }, abstract = {Neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) remain largely unsolved, with complex etiology yet to be fully elucidated. The most common genetic cause of ALS in both familial and sporadic cases is the expansion of a hexanucleotide repeat in the C9orf72 gene. To systematically dissect the molecular landscape of ALS, we performed integrative transcriptomic analyses across multiple central nervous system regions from ALS patients carrying pathological C9orf72 repeat expansions (ALS-C9) and those without the mutation (ALS-non-C9). In parallel, we performed transcriptome-wide cell-type deconvolution to assess the cellular composition of neuronal and non-neuronal populations. We identified a set of dysregulated molecular pathways that were consistently altered in both ALS-C9 and ALS-non-C9 patients, suggesting shared pathogenic mechanisms. Distinct gene-specific alterations also pointed to divergent subtype-dependent molecular trajectories. Gene-specific alterations were also associated with short clinical duration in ALS-non-C9, highlighting a sex-dependent immunological contribution to disease outcome. Our cross-regional integrative transcriptomic analyses reveal both convergent and divergent molecular and cellular features between ALS-C9 and ALS-non-C9 subgroups, underscoring the clinical heterogeneity of ALS and providing a framework for subtype- and sex-specific therapeutic stratifications.}, } @article {pmid42418847, year = {2026}, author = {de La Seiglière, H and Letourneur, Æ and Ichas, F and De Giorgi, F}, title = {Phase separation and protein aggregation in neurodegenerative diseases.}, journal = {Biophysical chemistry}, volume = {338}, number = {}, pages = {107678}, doi = {10.1016/j.bpc.2026.107678}, pmid = {42418847}, issn = {1873-4200}, mesh = {Phase Separation ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates ; *Intrinsically Disordered Proteins/chemistry/metabolism/genetics ; alpha-Synuclein/metabolism/chemistry/genetics ; Animals ; tau Proteins/metabolism/chemistry/genetics ; }, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, frontotemporal dementia, and ALS are characterized by amyloid protein aggregation involving intrinsically disordered proteins that are also capable of liquid-liquid phase separation (LLPS). LLPS, known to drive the formation of dynamic membraneless organelles essential for cellular functions, can play a role in limiting fibrillation process or aberrantly transition into solid aggregates under pathological conditions. Here we review how mutations, post-translational modifications, and environmental factors can modulate LLPS of proteins like Tau, TDP-43, FUS, and α-synuclein, potentially regulating amyloid aggregation. We also examine the interplay of these proteins exploring how LLPS and condensate maturation could impinge on the emergence of co-pathologies contributing to disease progression. Finally we discuss emerging therapeutic strategies, aimed at modulating phase separation dynamics.}, } @article {pmid42419281, year = {2026}, author = {Kournoutis, A and Stenmark, H}, title = {Sealing and healing: A two-step model for plasma membrane repair.}, journal = {Developmental cell}, volume = {61}, number = {7}, pages = {1345-1346}, doi = {10.1016/j.devcel.2026.06.011}, pmid = {42419281}, issn = {1878-1551}, mesh = {*Cell Membrane/metabolism ; Animals ; Humans ; Models, Biological ; *Annexins/metabolism ; Endosomal Sorting Complexes Required for Transport/metabolism ; Mutation ; }, abstract = {Plasma membrane damage can cause cell death and is associated with neurodegeneration. In this issue of Developmental Cell, Heffner et al. show that annexin A11 (ANXA11) first plugs membrane lesions, before ESCRT-III is recruited to extrude the damaged patch-a two-step repair mechanism compromised by ALS- and FTD-linked mutations.}, } @article {pmid42419491, year = {2026}, author = {Ellappan, S and Kujur, PP and Mondal, AC}, title = {The autophagy-senescence-inflammasome axis: A novel triad in neurodegenerative diseases?.}, journal = {Ageing research reviews}, volume = {121}, number = {}, pages = {103248}, doi = {10.1016/j.arr.2026.103248}, pmid = {42419491}, issn = {1872-9649}, mesh = {Humans ; *Autophagy/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; *Inflammasomes/metabolism ; Animals ; *Aging/pathology/metabolism ; *Cellular Senescence/physiology ; Signal Transduction ; *Brain/metabolism/pathology ; }, abstract = {Chronic neuroinflammation is a defining feature of brain ageing and neurodegenerative disorders, yet the molecular mechanisms responsible for its persistence remain incompletely understood. Although autophagy dysfunction, glial senescence, and inflammasome activation are well-established contributors to progressive neurodegeneration, these processes are often analysed independently or through pairwise interactions, leaving their collective contribution to persistent neuroinflammation and disease progression insufficiently defined. Here, we synthesise emerging evidence supporting an integrated 'Autophagy-Senescence-Inflammasome (ASI) axis', in which reciprocal interactions among impaired autophagy, senescent glia, and inflammasome signalling establish a self-sustaining cycle of neuroinflammation. We discuss how defective autophagy promotes mitochondrial dysfunction, oxidative stress, and danger signalling, while senescent astrocytes and microglia amplify inflammatory responses through the senescence-associated secretory phenotype (SASP). These intertwined processes converge on chronic inflammasome activation, with mitochondrial dysfunction emerging as a central mechanistic hub. Evidence across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and chronic neuropathic pain highlight the broad relevance of this pathological network. We further analyse current therapeutic strategies targeting autophagy, senescence, and inflammasome pathways, emphasising the limitations of single-target approaches and the potential of multi-target interventions. By integrating these processes into a unified framework, this review provides new insights into the possible molecular mechanisms underlying neuroinflammaging and identifies the 'ASI axis' as a promising target for neurodegenerative disease-modifying therapies.}, } @article {pmid42419740, year = {2026}, author = {Varga, D and Ráduly, Z and Boros-Oláh, B and Nagy, É and Karányi, Z and Halász, L and Bálint, BL and Vámosi, G and Tóth, E and Bai, P and Santangelo, S and Bossolasco, P and Ratti, A and Géli, V and Pommier, Y and Székvölgyi, L}, title = {TOP1MT rs2293925 is an enhancer-active regulatory SNP that shapes mitochondrial R-loop dynamics.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.70649}, pmid = {42419740}, issn = {1742-4658}, support = {//Thematic Excellence Programme/ ; 142137//NKFIH/ ; 130913//NKFIH/ ; 135107//NKFIH/ ; K146028//NKFIH/ ; K124141//NKFIH/ ; K152259//NKFIH/ ; TKP2021-EGA-19//NKFIH/ ; TKP2021-EGA-20//NKFIH/ ; //HUN-REN Hungarian Research Network/ ; //National Research, Development and Innovation Fund of Hungary/ ; }, abstract = {Mitochondrial topoisomerase 1 (TOP1MT) regulates mitochondrial DNA (mtDNA) topology during transcription and replication. Perturbed mtDNA maintenance and RNA metabolism have been implicated in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Here we show that the common TOP1MT variant rs2293925 (R525W) has enhancer-like activity and is associated with increased mitochondrial R-loops (RNA : DNA hybrids). Tissue-dependent expression, quantitative trait locus analysis, chromatin-state annotation, reporter assays, and allele-specific DNA-protein binding assays support a transcriptional regulatory role for rs2293925. In isogenic cell models, rs2293925 increased TOP1MT mRNA and protein abundance, and this was accompanied by increased mitochondrial R-loop signal. TOP1MT trapping with lamellarin D supported increased TOP1MT-R525W occupancy at mitochondrial control region sites together with enhanced R-loops, consistent with altered TOP1MT-mtDNA interaction and/or increased TOP1MT abundance. Elevated mitochondrial R-loop signal was also detected in a pilot cohort of sporadic ALS samples carrying rs2293925 and in neural stem cells derived from C9orf72-positive ALS patients. These data support a dual-effect model in which rs2293925 increases TOP1MT expression and is associated with altered mitochondrial R-loop dynamics, linking common genetic variation to mitochondrial nucleic acid stress in disease-relevant contexts.}, } @article {pmid42420066, year = {2026}, author = {Tien-Smith, AZ and Absar, S and Rogowski, CB and Phillips, V and Andersen, ZJ and Bredell, C and Fung, KW and Hong, L and Szybka, M and Woodcock, J and Brayne, C and Khreis, H and Navaratnam, AMD}, title = {Association of long-term outdoor air pollution exposure with incidence of Parkinson's disease, multiple sclerosis and motor neuron diseases: a systematic review and meta-analysis.}, journal = {Environment international}, volume = {214}, number = {}, pages = {110377}, doi = {10.1016/j.envint.2026.110377}, pmid = {42420066}, issn = {1873-6750}, mesh = {Humans ; *Multiple Sclerosis/epidemiology ; *Motor Neuron Disease/epidemiology ; *Environmental Exposure/statistics & numerical data ; *Air Pollution/adverse effects/statistics & numerical data ; *Parkinson Disease/epidemiology ; Incidence ; Air Pollutants ; Particulate Matter ; }, abstract = {BACKGROUND: Parkinson's disease (PD), multiple sclerosis (MS) and motor neurone disease (MND) are progressive and debilitating diseases that are increasing in prevalence globally. Some primary studies show an increased risk from long-term outdoor air pollution exposure, while others contradict this association.

METHODS: A systematic review and meta-analysis were undertaken to assess the associations of long-term (≥1 year) outdoor air pollution exposure with PD, MS and MND incidence. We searched eight databases for publications up to July 2025. Primary case-control, cohort, cross-sectional or ecological studies investigating the association between long-term air pollution exposure and adult (>18 years old) PD, MS, or MND incidence were included. Meta-analyses were carried out using random-effects models with assessment of heterogeneity, meta-bias and shape of the exposure-response functions. PROSPERO (CRD42023417961).

RESULTS: Of 42 papers included, 26, 3 and 3 were meta-analysed for PD, MS, and MND outcomes, respectively. 19 studies from North America, 12 from Europe and 10 from Asia were meta-analysed. For every 5 μg/m[3] and 15 μg/m[3] increase of Particulate Matter 2.5 (PM2.5) and PM10 concentration, estimated (95% Confidence Interval) PD risk was 10% (1.10; 1.03-1.19) and 18% (1.18; 1.01-1.38), respectively but effects varied across settings (Prediction Interval: 0.80-1.52 for PM2.5 and 0.41-3.36 for PM10), with the largest estimated risk for PM2.5 in Asia (1.19; 1.01-1.41). There was no clear evidence that PM2.5 (1.01; 0.77-1.32) or nitrogen dioxide (NO2, 0.98, 95% CI: 0.95-1.01) were associated with MS risk or PM2.5 with MND risk (1.07, 95% CI: 0.86-1.33).

CONCLUSION: This systematic review reports increased PD risk from long-term PM2.5 and PM10 exposure. No association was observed for MS and MND from a very limited evidence base. The neurodegenerative diseases investigated here are rare and therefore alternatives to insufficiently powered cohort studies are needed to strengthen the evidence on risk.}, } @article {pmid42420185, year = {2026}, author = {Shan, D and Wang, H and Liu, F and Yan, C and Zhao, Y and Sun, X}, title = {Neuronal Intranuclear Inclusion Disease Mimicking Familial ALS: A Multigenerational Case Series With Diagnostic Pitfalls.}, journal = {Muscle & nerve}, volume = {74}, number = {3}, pages = {751-755}, pmid = {42420185}, issn = {1097-4598}, support = {20201125//Qilu Young Scholar Program of Shandong University/ ; ZR2023MH180//the Natural Science Foundation of Shandong Province/ ; ZR2022QH325//the Natural Science Foundation of Shandong Province/ ; }, } @article {pmid42420559, year = {2026}, author = {Compagnion, AC and Ivanov, A and Rana, A and Espinoza, F and Sandmann, T and Martineau, FS and Monsorno, K and Facchinetti, R and Matera, A and Rougé, L and González Ibáñez, F and Catale, C and Bizzotto, M and Garel, S and Matteoli, M and Kashiwagi, Y and Koyama, R and Haass, C and Tremblay, ME and Beule, D and Jelescu, I and Zerbi, V and Di Paolo, G and Paolicelli, RC}, title = {Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice.}, journal = {Nature neuroscience}, volume = {29}, number = {8}, pages = {1841-1857}, pmid = {42420559}, issn = {1546-1726}, mesh = {Animals ; *Microglia/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Mice ; *Myelin Sheath/metabolism/pathology ; Receptors, Immunologic/metabolism ; *Adaptor Proteins, Signal Transducing/genetics/metabolism ; *Membrane Proteins/genetics/metabolism ; Exons/genetics ; Membrane Glycoproteins/metabolism ; Mice, Knockout ; Brain/metabolism ; Mice, Inbred C57BL ; }, abstract = {TDP-43 proteinopathy is a hallmark of neurodegenerative disorders such as amyotrophic lateral sclerosis and frontotemporal dementia where mislocalization of TDP-43 has been observed in neurons and glial cells. However, the role of TDP-43 in microglia and the consequences of its loss of function remain unexplored. Combining magnetic resonance imaging, and confocal, and electron microscopy, we uncovered structural changes and myelin abnormalities in the early postnatal brain of mice lacking microglial TDP-43. Spatial transcriptomics further revealed an enriched interferon-responsive signature associated with oligodendrocyte dysfunction. Early depletion of microglial TDP-43 led to motor deficits in adult mice. Mechanistically, knocking out TDP-43 impaired microglial ability to engulf and degrade myelin. It also led to cryptic exon inclusion in the Tyrobp mRNA, resulting in truncated DAP12 protein, thus causing defective TREM2 signaling. Our findings reveal a role for TDP-43 in regulating the TREM2-DAP12 axis in mice, highlighting a previously unrecognized mechanism through which TDP-43 controls microglial function.}, } @article {pmid42421532, year = {2026}, author = {Jiang, Z and Zhang, R and Jiang, Z and Zeng, S and Wang, L and Zhao, S and Zhang, X and Yu, H}, title = {Accelerating reaction kinetics of AlCl3/acetamide electrolyte by co-solvation for Al-S batteries.}, journal = {Materials horizons}, volume = {13}, number = {16}, pages = {8325-8335}, doi = {10.1039/d6mh00252h}, pmid = {42421532}, issn = {2051-6355}, abstract = {Deep eutectic solvents such as AlCl3/acetamide (AcA) have demonstrated great potential as room-temperature electrolytes for Al-S batteries, but their high viscosities and low ionic conductivities severely impede the electrochemical reaction kinetics. Herein, we report an effective strategy to optimize AlCl3/AcA by screening fluorobenzene co-solvents. The optimal 1,2,3-trifluorobenzene (tFBn) effectively dilutes AlCl3/AcA and has a crowding effect that creates a local high-concentration zone for efficient transport of electro-active ions. Rather than merely functioning as a diluent, tFBn induces the localized aggregation of neutral molecules and ion clusters, which reduces the bulk viscosity by 50% and doubles the ionic conductivity. This localized high concentration, coupled with the rapid migration of ion clusters, accelerates the reaction kinetics and improves the long-cycling stability of Al stripping/plating. tFBn also promotes the transportation of Al-Cl species onto Al to regulate the interphase structures and reduce the resistance. Due to the accelerated reaction kinetics, the tFBn-modified AlCl3/AcA further improves the S utilization, reduces the polarization, and enhances the capacity retention of Al-S batteries. This study provides important insights into the design of high-performance electrolytes toward practical Al-S batteries.}, } @article {pmid42421808, year = {2026}, author = {Ang, NKJ and Lim, JQ and Lye, TJY and Tan, DMY and Lim, CH}, title = {Endoscopic salvage for afferent loop syndrome: the antegrade lumen-apposing metal stent technique.}, journal = {VideoGIE : an official video journal of the American Society for Gastrointestinal Endoscopy}, volume = {11}, number = {7}, pages = {298-303}, pmid = {42421808}, issn = {2468-4481}, abstract = {BACKGROUND AND AIMS: Afferent loop syndrome (ALS) is a rare postgastrectomy condition with biliopancreatic limb obstruction. Revision surgery carries high morbidity in patients with hostile anatomy. We aimed to demonstrate the feasibility of a double-scope, antegrade EUS-guided lumen-apposing metal stent (LAMS) enteroenterostomy as an endoscopic alternative in the management of complex ALS.

METHODS: A patient with extensive prior gastric surgery presented with ALS. With a double-scope antegrade technique, a pediatric gastroscope (GIF-XP190 N; Olympus, Tokyo, Japan) was used to cannulate the afferent limb to place a guidewire, and a linear echoendoscope (GF-UCT180; Fujifilm, Tokyo, Japan) was advanced into the blind loop. The pediatric gastroscope was reintroduced into the efferent limb, which was water-distended to approximately 3 cm in diameter to achieve sonographic apposition. Under combined EUS and fluoroscopic guidance, a 15- × 15-mm electrocautery-enhanced LAMS (Boston Scientific, Marlborough, Mass, USA) was deployed to create an enteroenterostomy.

RESULTS: Postdeployment contrast confirmed optimal position and immediate patency without leak. Symptoms resolved rapidly; the patient resumed a diet within days and gained weight. Abdominal radiography showed progressive LAMS expansion without adverse events.

CONCLUSIONS: Double-scope antegrade EUS-guided LAMS placement safely decompressed the afferent limb in our patient, restoring enteral flow and avoiding high-morbidity reoperation. This technique merits consideration within multidisciplinary care and warrants larger comparative studies to define long-term outcomes.}, } @article {pmid42422319, year = {2026}, author = {Nie, J and Peters, S and Ge, CB and Portengen, L and Rothman, N and Hu, W and Ou, R and Wei, Q and Zhang, L and Hou, Y and Lan, Q and Shang, HF and Vermeulen, R}, title = {Smoking and the risk of neurodegenerative diseases in a Chinese case-control study.}, journal = {BMJ neurology open}, volume = {8}, number = {2}, pages = {e001728}, pmid = {42422319}, issn = {2632-6140}, abstract = {BACKGROUND: While smoking is inversely associated with Parkinson's disease (PD) risk, its relationship with amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA) remains unclear, particularly in Asian populations. We investigated these associations in a Chinese case-control study.

METHODS: We recruited newly diagnosed ALS (n=430), MSA (n=271), PD (n=523) cases and hospital-based controls (n=1033) in Sichuan, China. Logistic regression models were used to evaluate associations between smoking and disease risks, adjusting for demographic, lifestyle and occupational factors.

RESULTS: Compared with never-smokers, the adjusted ORs and 95% CIs of ALS for current and former smokers were 1.00 (0.61 to 1.65) and 1.79 (1.01 to 3.17), respectively. For MSA, ORs were 1.27 (0.73 to 2.23) for current smokers and 2.54 (1.41 to 4.60) for former smokers. Individuals who quit within 4 years before diagnosis showed the highest risk of ALS (OR=1.93, 95% CI 0.96 to 3.88) and MSA (OR=2.09, 95% CI 1.11 to 3.93). For both ALS and MSA, no consistent trend was found with increasing smoking duration or pack-years. In contrast, ever-smokers had a significantly lower PD risk (OR=0.49, 95% CI 0.33 to 0.71), particularly current smokers (OR=0.30, 95% CI 0.19 to 0.48). Longer smoking duration and higher cumulative smoking were also linked to PD risk with clear negative exposure-response patterns (P trend=0.039 and 0.029, respectively).

CONCLUSIONS: Consistent with findings in non-Asian populations, smoking was inversely associated with PD risks in the Chinese population. For ALS and MSA, we found evidence suggestive of positive relationships with cigarette smoking, but no clear exposure-response relationships were observed.}, } @article {pmid42422504, year = {2026}, author = {Tomikawa, E and Takahashi, K and Hattori, H and Arai, T and Kawai, M and Nishimura, K and Goto, Y and Yagi, R and Miyamoto, Y and Miyoshi, T}, title = {Multinucleation and cytotoxicity induced by multikinase inhibition in highly proliferative cells.}, journal = {Journal of toxicologic pathology}, volume = {39}, number = {3}, pages = {93-101}, pmid = {42422504}, issn = {0914-9198}, abstract = {Phenotypic screening using motor neurons derived from the induced pluripotent stem (iPS) cell of a patient with amyotrophic lateral sclerosis led to the identification of Compound X, a novel agent with potent neuroprotective activity that is hypothesized to act by inhibiting hematopoietic progenitor kinase/germinal center kinase-like kinase (HGK). Unlike known HGK inhibitors, including Prostetin and GNE-495, Compound X and related Compounds Y and Z exhibited broader multi-kinase-inhibition profiles, including the strong inhibition of Aurora B kinase and strong-to-moderate inhibition of Src-family kinases in kinase panel screening. Owing to their roles in cytokinesis, we performed in vitro micronucleus tests to assess their genotoxicity. Compounds X, Y, and Z induced the multinucleation of cells at rates of 88.8, 71.5, and 91.8%, respectively, whereas Prostetin and GNE-495 resulted in rates of 0.5 and 1.3%, respectively, which were comparable to the control. A 5-day repeated-dose oral toxicity study of Compound X using mice, at doses of 125, 250, and 500 mg/kg/day, revealed decreased locomotor activity, hypothermia, and mortality at 500 mg/kg/day. Histopathology showed necrosis/hemorrhage in bone marrow cells; single-cell necrosis in the thymus, spleen, and mesenteric lymph nodes; nuclear pleomorphism and single-cell necrosis/necrosis in the gastrointestinal mucosa; and karyomegaly and a reduction in testicular germ cells. These toxicopathological findings suggest that Compound X induces nuclear pleomorphism and necrosis in highly proliferative cells. Although Compound X strongly suppressed HGK, its toxicity may be associated with broader multikinase inhibition, which is consistent with the finding that Prostetin and GNE-495 do not induce multinucleation in vitro.}, } @article {pmid42422879, year = {2026}, author = {Grassmann, G and Amadei, M and Lardieri, A and Montemiglio, LC and Passeri, AA and Mattarelli, M and Di Rienzo, L and Miotto, M and Ruocco, G and Milanetti, E}, title = {Investigating the effect of progressive truncations at the ALS-linked protein TDP-43 RRM2 on its aggregation mechanism.}, journal = {Frontiers in molecular biosciences}, volume = {13}, number = {}, pages = {1849627}, pmid = {42422879}, issn = {2296-889X}, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by inclusions of TDP-43 protein. C-terminal fragments (CTFs) of TDP-43, generated by cleavage within its second RNA recognition motif (RRM2), have been found forming aggregates in patients. Aggregation has often been attributed to the C-terminal domain, but increasing evidence indicates that RRM2 fragments contribute to pathological inclusions. We performed extensive molecular dynamics simulations to investigate the changes resulting from the truncation that could lead to aggregation. We analyzed the full RRM2 domain (fRRM2, residues 192-261) and two fragments commonly observed in CTFs (tRRM2A, residues 220-261, and tRRM2B, residues 209-261). We found that truncation results in distinct aggregation-prone states. tRRM2B appears to rely on β -sheet elements associated with amyloid-like aggregation, whereas tRRM2A exhibits higher structural variability and a reduced β -content, suggesting a phase separation-like aggregation mechanism. We further simulated an extended fragment of tRRM2A, tRRM2A-l (residues 220-269). Although its predicted aggregation propensity remains largely unchanged, tRRM2A-l exhibits increased structural flexibility, and a stronger exposure of Nuclear Export Signal residues. Our results indicate that subtle differences in RRM2 fragment length influence potential misfolding pathways. Future studies and therapeutic strategies to prevent TDP-43 aggregation should carefully consider the specific domain adopted.}, } @article {pmid42422903, year = {2026}, author = {Singh, T and Khare, SK and Siddhanta, S}, title = {Spectroscopic discrimination of bacterial species of variable pathogenicity through explainable machine learning.}, journal = {Nanoscale}, volume = {18}, number = {31}, pages = {16595-16610}, doi = {10.1039/d6nr00689b}, pmid = {42422903}, issn = {2040-3372}, mesh = {*Spectrum Analysis, Raman/methods ; Random Forest ; Support Vector Machine ; *Bacteria/pathogenicity/classification ; *Machine Learning ; Convolutional Neural Networks ; Classification Algorithms ; Staphylococcus aureus/pathogenicity ; Pseudomonas aeruginosa/pathogenicity/isolation & purification ; }, abstract = {Rapid and accurate identification of bacterial pathogens and their degree of pathogenicity is essential for guiding antimicrobial therapy. Current culture-based methods require a timeframe of at least 24-48 h for species-level identification alone, which often leads to substantial disease progression and increases the propensity of antimicrobial resistance (AMR). Surface-Enhanced Raman Spectroscopy (SERS) shows promise in mitigating these drawbacks by providing a fast, non-invasive, label-free method to capture the biochemical fingerprints of bacteria achievable under clinical settings. However, the molecular complexity of SERS spectra, which has been an impediment for conventional data analysis, demands robust computational frameworks for reliable species-level identification. Here, we employ a comprehensive SERS analysis scheme with supervised machine learning and explainable artificial intelligence (XAI) to discriminate five clinically relevant pathogens, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Enterococcus faecalis, and to probe their degree of pathogenicity from a biomarker perspective. Among the tested models - Support Vector Machine (SVM), k-Nearest Neighbour (kNN), Random Forest (RF), and a 1D Convolutional Neural Network (CNN) - CNN achieved near-perfect classification accuracy, capturing subtle and spectrally relevant variations often inaccessible to traditional algorithms. Notably, the 1D-CNN also achieved 100% discrimination between MRSA and methicillin-sensitive S. aureus - two strains of the same species differing only in resistance phenotype. To ensure transparent decision-making and eliminate the black-box nature of machine learning models, SHapley Additive exPlanations (SHAP) analysis was applied to both RF and CNN models, which facilitated the convergence of both frameworks on the same discriminatory Raman regions, revealing conserved biochemical determinants of species identity. Complementary MCR-ALS decomposition further resolved the spectra into interpretable biochemical components and provided the rubric for biochemical differentiation. Together, this study aims to demonstrate an end-to-end explainable workflow that couples SERS with interpretable AI, offering a rapid, transparent approach for pathogenic disease diagnosis.}, } @article {pmid42423631, year = {2026}, author = {Chu, HS and Oh, J}, title = {Identifying Gastrostomy Care and Home Gastrostomy Tube Feeding-Related Educational Content for Patients With Amyotrophic Lateral Sclerosis and Their Family Caregivers: A Delphi Panel With Professional Stakeholders.}, journal = {Gastroenterology nursing : the official journal of the Society of Gastroenterology Nurses and Associates}, volume = {49}, number = {4}, pages = {245-253}, pmid = {42423631}, issn = {1538-9766}, mesh = {Humans ; *Gastrostomy/nursing ; *Amyotrophic Lateral Sclerosis/therapy/nursing/complications ; *Enteral Nutrition/methods/nursing ; Delphi Technique ; *Caregivers/education ; *Home Care Services ; Female ; Male ; *Patient Education as Topic ; Deglutition Disorders/etiology/therapy ; }, abstract = {Enteral nutrition is delivered through a gastrostomy tube to provide nutritional support to patients with amyotrophic lateral sclerosis (ALS) who have developed severe dysphagia at home. Complications may arise from gastrostomy and enteral nutrition when family caregivers do not provide adequate care. This study identifies key areas of educational content that can improve the care of patients with ALS requiring gastrostomy and home enteral nutrition. We conducted a modified three-round e-Delphi survey with health care experts to clarify their perspectives on the educational content regarding gastrostomy and home enteral nutrition disseminated among patients with ALS and their family caregivers. The experts provided their opinions on specific educational content areas, and their responses were analyzed to identify areas of consensus and divergence. Accordingly, in Rounds 1-3 of the survey, 16 experts, including registered nurses (n = 6), advanced practice registered nurses (n = 3), clinical neurologists (n = 3), and dieticians (n = 4), participated. In Round 3, four categories and 39 educational components reached consensus. The results provide a framework for developing educational nursing interventions for family caregivers of patients with ALS receiving home enteral nutrition through gastrostomy tubes and for defining the essential elements of the educational content of such interventions.}, } @article {pmid42424231, year = {2026}, author = {Szyłak, E and Czarnowska, A and Kulczyńska-Przybik, A and Kopitelow, J and Mroczko, B and Kochanowicz, J and Kułakowska, A}, title = {Neurofilament Light Chain as a Biomarker in Neurology.}, journal = {European neurology}, volume = {}, number = {}, pages = {1-12}, doi = {10.1159/000552933}, pmid = {42424231}, issn = {1421-9913}, abstract = {BACKGROUND: Neurofilament light chain (NfL) has emerged as a highly sensitive biomarker of neuroaxonal injury across diverse neurological disorders. This narrative review synthesizes current evidence regarding its diagnostic, prognostic, and therapeutic-monitoring utility, while outlining major clinical limitations and emphasizing the complementary role of glial fibrillary acidic protein (GFAP).

SUMMARY: NfL concentrations increase following axonal damage and correlate with inflammatory activity, lesion burden, and long-term disability progression in multiple sclerosis. Elevated levels also reflect neurodegeneration in Alzheimer's disease, predict disease severity and survival in amyotrophic lateral sclerosis, and are associated with motor and cognitive decline in Parkinson's disease and multiple system atrophy. In acute neurological conditions, including traumatic brain injury and stroke, NfL serves as a robust indicator of the extent of neuronal injury. Interpretation is constrained, however, by substantial physiological variability related to age, renal function, body mass index, and comorbidities, limiting the utility of absolute cut-off values. GFAP provides complementary information by capturing astrocytic damage, and the GFAP/NfL ratio may aid in differentiating multiple sclerosis from neuromyelitis optica spectrum disorder. Integration of NfL with multimodal biomarkers-such as GFAP, tau proteins, proteomic and metabolomic signatures, and advanced neuroimaging-may enhance diagnostic specificity and prognostic accuracy.

KEY MESSAGES: Future research priorities include establishing age-adjusted reference intervals, validating longitudinal thresholds, and incorporating NfL into therapeutic monitoring frameworks. Advances in these areas are expected to improve diagnostic precision and support broader clinical implementation of NfL.}, } @article {pmid42425084, year = {2026}, author = {Hosokawa, M and Kawakami, R and Imami, K and Kurosawa, R and Yoshizawa, T and Ishihama, Y and Imamura, T and Hagiwara, M and Takeuchi, A}, title = {RNA-dependent SFPQ condensates coordinate multidimensional regulation of extra-long neuronal genes.}, journal = {Cell chemical biology}, volume = {33}, number = {8}, pages = {1146-1164.e9}, doi = {10.1016/j.chembiol.2026.06.004}, pmid = {42425084}, issn = {2451-9448}, mesh = {*PTB-Associated Splicing Factor/metabolism/genetics ; Humans ; *Neurons/metabolism ; *RNA/metabolism/genetics ; Animals ; *Gene Expression Regulation ; RNA Splicing ; RNA-Binding Proteins/metabolism/genetics ; }, abstract = {The mammalian brain uniquely expresses a large repertoire of extra-long genes critical for neuronal development and function, yet these transcripts are particularly vulnerable to dysregulation linked to neurological disorders, such as autism spectrum disorder and amyotrophic lateral sclerosis. The molecular mechanisms that ensure their stable expression remain poorly understood. Here, we show that the RNA-binding protein SFPQ forms meshwork-like biomolecular condensates that scaffold a multidimensional gene regulatory complex essential for long-gene expression. Super-resolution microscopy and functional perturbation assays demonstrate that disruption of SFPQ condensates impairs both extra-long gene expression and splicing. Proximity-dependent biotin labeling combined with mass spectrometry (BioID-MS) reveals that SFPQ condensates recruit transcriptional elongation factors, splicing regulators, and chromatin remodelers. Notably, many of these interactors overlap with autism-associated genes, suggesting direct disease relevance. These findings define a higher-order nuclear architecture organized by SFPQ and provide mechanistic insight into long-gene transcriptopathies underlying neurological disorders.}, } @article {pmid42425169, year = {2026}, author = {Yu, W and Zhao, B and Ma, M and Gao, N and Yun, Y and Sun, X and Shao, K and Lin, P and Li, W and Zhao, Y and Yu, D and Zhao, C and Liu, F and Yan, C and Liu, S}, title = {Sex-associated neuroinflammatory and astrocytic responses in amyotrophic lateral sclerosis: evidence from clinical cohorts and a TDP-43 N390D mouse model.}, journal = {Brain, behavior, and immunity}, volume = {138}, number = {}, pages = {106884}, doi = {10.1016/j.bbi.2026.106884}, pmid = {42425169}, issn = {1090-2139}, abstract = {BACKGROUND: Sex differences are increasingly recognized as important modifiers of neuroimmune processes in neurodegenerative disorders. However, the sex-associated clinical phenotypes and underlying neuroinflammatory mechanisms in amyotrophic lateral sclerosis (ALS) remain poorly understood. This study integrated multimodal clinical assessments, cerebrospinal fluid (CSF) neuroimmune biomarkers, neuroimaging-based glymphatic metrics, and complementary animal analyses to characterize shared and sex-associated alterations in male and female ALS patients.

METHODS: Two independent cohorts including 158 newly diagnosed ALS patients and 112 healthy controls (HCs) underwent evaluations of motor function, cognition, sleep disturbances, and emotional symptoms. Glymphatic function was assessed using choroid plexus volume (CPV), diffusion-derived analysis along the perivascular space (ALPS) index, and white-matter free-water (FW) fraction. In the original cohort, 12 CSF biomarkers spanning astrocytic activation, neuroinflammation, TDP-43 pathology, synaptic dysfunction, and axonal injury were quantified, and glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), and interleukin-18 (IL-18) were further examined in an independent verification cohort. Complementary neuroimmune alterations were further examined in TDP-43 N390D knock-in mice using ELISA and immunofluorescence.

RESULTS: Male ALS patients showed markedly elevated CSF GFAP, IL-6, and IL-18 compared with female ALS patients and HCs after false discovery rate correction (q < 0.05). Female ALS patients exhibited increased CSF IL-6 versus HCs, whereas GFAP and IL-18 levels were unchanged. Female ALS patients also demonstrated more severe depressive symptoms and post-traumatic stress disorder than male ALS patients and HCs (p < 0.05). Both sexes displayed glymphatic impairment characterized by increased CPV and FW and reduced ALPS index, as well as pronounced sleep disturbances relative to HCs (all p < 0.05), with no clear sex-related differences. Complementary animal data showed that, at a fixed chronological age, male TDP-43 N390D mice exhibited more severe motor impairment accompanied by higher brain levels of GFAP, IL-6, and IL-18 and more prominent astrocyte-associated IL-6 and IL-18 signals than female mutant mice. Although microglial activation was also observed in TDP-43 N390D mice, no clear sex-related difference was detected at the sampled age.

CONCLUSIONS: This multimodal clinical-translational study reveals sex-associated neuroinflammatory heterogeneity in ALS. Male patients exhibit a more pronounced GFAP-, IL-6-, and IL-18-related inflammatory profile, whereas female patients display more prominent affective disturbances. Glymphatic dysfunction and sleep impairment emerge as common pathological pathways across sexes. These findings highlight sex as a crucial biological variable shaping ALS heterogeneity and underscore the importance of incorporating sex-stratified analyses in future ALS neuroimmune research and clinical trials.}, } @article {pmid42425598, year = {2026}, author = {Pucciarelli, DM and Patel, R and Sawicki, S and Jain, S and Saulino, P}, title = {Unusual presentation of amyotrophic lateral sclerosis years after a motor-vehicle collision.}, journal = {BMJ case reports}, volume = {19}, number = {7}, pages = {}, doi = {10.1136/bcr-2026-272139}, pmid = {42425598}, issn = {1757-790X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/complications ; Female ; Middle Aged ; *Accidents, Traffic ; Diagnosis, Differential ; *Muscle Weakness/etiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare disease caused by the destruction of motor neurons, typically presenting with unilateral lower motor neuron and upper motor neuron symptoms. Here, we report the case of a female in her mid-60s with a complex history of lower extremity weakness following a motor-vehicle collision 3 years before her current presentation with a subacute complaint of right-sided leg weakness. With an atypical symptom course consisting of resolved and recurrent weakness of her left leg, the patient had multi-level chronic, evolving spinal-column damage, severe weight loss, newly discovered rectal neoplasm and longstanding psychiatric pathology. With symptoms concerning for both medical and psychosomatic explanations, several potentially compounded aetiologies were considered. Here, we discuss important considerations for fluctuating chronic and subacute neurological complaints with a broad differential diagnostic spectrum and how a macro-perspective of symptoms over years can aid in the diagnosis of a challenging ALS presentation.}, } @article {pmid42426573, year = {2026}, author = {Zhan, Y and Luo, Y and Lu, H and Lu, Y and Zhao, S and Pan, L and Liu, M}, title = {TSR and peroxidase genes confer resistance to fenoxaprop-P-ethyl and mesosulfuron-methyl in Alopecurus aequalis.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71103}, pmid = {42426573}, issn = {1526-4998}, support = {//Modern Agricultural Industrial Technology System of Hunan Province (grants numbers 2022-31)/ ; //the National Key R&D Program of China (No. 2023YFD1401100)/ ; //China Agriculture Research System (CARS-01)/ ; }, abstract = {BACKGROUND: Alopecurus aequalis poses severe threat to global wheat production due to evolving resistance to acetyl-CoA carboxylase (ACCase)- and acetolactate synthase (ALS)-inhibiting herbicides. In this study, the resistance mechanisms of a field-evolved resistant population (R) were systematically investigated using dose-response bioassays, target-site gene sequencing, inhibitor assays, antioxidant enzyme activity measurements, RNA sequencing (RNA-seq), quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), and yeast functional validation.

RESULTS: Dose-response results revealed that the R population exhibited moderate resistance to fenoxaprop-P-ethyl (RI = 9.58) and low-level resistance to mesosulfuron-methyl (RI = 3.07). Cross-resistance testing indicated that the R population was resistant to other ACCase-inhibiting herbicides (haloxyfop-P-methyl, clodinafop-propargyl, clethodim, and pinoxaden) and the ALS-inhibiting herbicide rimsulfuron. Target-site sequence analysis identified two mutations in the R population: Ile-1781-Leu (ACCase) and Pro-197-Ser (ALS1). Pretreatment with the cytochrome P450 and GST inhibitor did not reverse resistance to fenoxaprop-P-ethyl or mesosulfuron-methyl. Compared to the susceptible (S) population, the R population had significantly lower H2O2 content and higher activities of peroxidase (POD) and catalase (CAT), indicating an enhanced reactive oxygen species (ROS) scavenging capacity. RNA-seq and qRT-PCR analyses identified three POD-annotated contigs (PODSPC4, POD12-1, POD12-2) that were upregulated in the R population. Yeast heterologous expression validated that AaPOD12-1 and AaPOD12-2 significantly increased yeast resistance to fenoxaprop-P-ethyl and mesosulfuron-methyl.

CONCLUSION: These results demonstrate that resistance in the R population is co-mediated by target-site mutations and non-target-site resistance involving enhanced ROS scavenging, with AaPOD12-1 and AaPOD12-2 representing the first functionally characterized antioxidant enzyme genes associated with herbicide resistance in A. aequalis. © 2026 Society of Chemical Industry.}, } @article {pmid42426879, year = {2026}, author = {Marynen, F and van Bijsterveld, MG and Van Loon, K and Kempenaers, S and Buelens, S and Roosen, J and Fieuws, S and van der Horst, ICC and van Mook, WN and Dewolf, P}, title = {Evaluating the impact of implementing an ECPR protocol on prehospital resuscitation quality: a randomized controlled simulation study.}, journal = {Advances in simulation (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1186/s41077-026-00458-3}, pmid = {42426879}, issn = {2059-0628}, support = {R-aiders Grant (2023)//Belgian Society of Emergency and Disaster Medicine (BESEDIM)/ ; }, abstract = {BACKGROUND: Extracorporeal Cardiopulmonary Resuscitation (ECPR) is increasingly considered for prehospital cardiac arrest management; however, its impact on resuscitation performance remains unclear. This study aimed to determine whether integrating an ECPR protocol into prehospital cardiac arrest care affects the quality of resuscitation compared to application of the standard Advanced Life Support (ALS) protocol.

METHODS: A randomized controlled simulation study was conducted at the University Hospital Leuven in Belgium using standardized pre-hospital cardiac arrest scenarios. Participants, who were physicians functioning as part of resuscitation teams, were randomized into intervention and control groups. The study included a pre- and post-intervention phase. In the pre-phase, all participants followed the standard ALS protocol. Only the intervention group received training in the additional ECPR protocol between the phases. In the post-phase, the intervention group combined this protocol with standard ALS, whereas the control group continued with ALS alone. The primary outcome was overall resuscitation quality, which was assessed using the modified Peltonen score. The secondary outcomes included occurrence and timing of critical resuscitation actions.

RESULTS: A total of 40 physicians participated in the study. Resuscitation quality was not affected by the ECPR protocol; the modified Peltonen score showed no difference in the pre-post change between the groups (0.02, CI: -0.15; 0.19, p = 0.83). However, secondary outcomes showed delayed actions related to the identification and management of the presumed cause of cardiac arrest in the intervention group, such as significantly later verbal suggestions to initiate causal treatments including PCI or thrombolysis.

CONCLUSIONS: In this simulation study, combining a prehospital ECPR protocol with standard ALS resulted in resuscitation performance comparable to ALS alone. Nonetheless, the protocol was associated with delayed diagnostic and therapeutic actions concerning the reversible causes of cardiac arrest, highlighting the need for ECPR training that integrates diagnostic and therapeutic vigilance with procedural execution.

TRIAL REGISTRATION: Clinical Trial Center UZ Leuven, S65846 - September 2021.}, } @article {pmid42427030, year = {2026}, author = {Tan, X and Sun, S and Yan, Y and Li, W and Ding, N and Xu, L and He, L and Zhang, Y and Chen, W and Zheng, Y and Li, L}, title = {C9orf72-associated poly-GR in skeletal muscle leads to neuromuscular junction deficits and muscle atrophy.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {34}, number = {9}, pages = {5542-5557}, pmid = {42427030}, issn = {1525-0024}, mesh = {Animals ; *Neuromuscular Junction/metabolism/pathology ; Mice ; *Muscle, Skeletal/metabolism/pathology ; *Muscular Atrophy/metabolism/genetics/pathology/etiology ; *C9orf72 Protein/genetics/metabolism ; Disease Models, Animal ; Humans ; Receptor Protein-Tyrosine Kinases/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; DNA Repeat Expansion ; Male ; }, abstract = {Hexanucleotide repeat expansions in C9orf72 produce dipeptide repeat (DPR) proteins that are widely expressed, including in the nervous system and skeletal muscle. Among these DPRs, arginine-containing proteins, poly-GR and poly-PR, are toxic in the nervous system, but whether DPRs in skeletal muscle contribute to amyotrophic lateral sclerosis (ALS) pathogenesis is unclear. Here, we show that muscle-restricted expression of poly-GR drives motor deficits in mice, including muscle atrophy and neuromuscular junction (NMJ) deficits. Poly-GR in muscle interacted with the NMJ key organizer MuSK and promoted MuSK degradation, disrupting postsynaptic structure and impairing neuromuscular transmission. Importantly, a MuSK agonist antibody (X-17) stabilized NMJs and rescued neuromuscular transmission. Moreover, poly-GR in muscle activated the integrated stress response (ISR), elevating eIF2α phosphorylation and broadly suppressing protein translation. ISR inhibition with ISRIB restored translation and MuSK protein levels and ameliorated both muscle atrophy and NMJ deficits. These findings demonstrate that skeletal muscle actively contributes to C9orf72-ALS pathology. Targeting muscle with ISRIB offers a therapeutic strategy to preserve motor function in C9orf72-ALS.}, } @article {pmid42427320, year = {2026}, author = {Uchino, A and Kanemaru, K and Tarutani, A and Hasegawa, M and Naruse, H and Ishiura, H and Murayama, S and Saito, Y}, title = {Frontotemporal Lobar Degeneration-TDP Type C With Striatal Glial Cytoplasmic Inclusions and Motor Neuron Degeneration.}, journal = {Neuropathology and applied neurobiology}, volume = {52}, number = {4}, pages = {e70090}, pmid = {42427320}, issn = {1365-2990}, support = {JP21wm0425019//Japan Agency for Medical Research and Development/ ; JP25wm0625126//Japan Agency for Medical Research and Development/ ; JP24dk0207074h0001//Japan Agency for Medical Research and Development/ ; JP22H04923//MEXT/JSPS KAKENHI/ ; JPMH23FC1008//Research on rare and intractable diseases Program/ ; }, mesh = {Humans ; *Inclusion Bodies/pathology ; *Frontotemporal Lobar Degeneration/pathology ; *Neuroglia/pathology ; *DNA-Binding Proteins/metabolism ; *Motor Neurons/pathology ; *Corpus Striatum/pathology ; Male ; *Motor Neuron Disease/pathology ; Female ; Aged ; }, abstract = {We report an autopsy case of frontotemporal lobar degeneration (FTLD)-TDP type C with severe striatal involvement and annexin A11- and phosphorylated TDP-43-positive glial cytoplasmic inclusions. The patient developed progressive asymmetric rigidity accompanied by marked striatal atrophy and showed both upper and lower motor neuron involvement. These findings expand the clinicopathological spectrum of FTLD-TDP type C and may support the concept of an annexin A11-associated pathogenic continuum linking FTLD and amyotrophic lateral sclerosis.}, } @article {pmid42427517, year = {2026}, author = {Chen, Y and Zhang, S}, title = {AART enables fast and accurate cross-platform proteomic translation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.29.735313}, pmid = {42427517}, issn = {2692-8205}, abstract = {Plasma proteomic profiling has been widely used for biomarker discovery, disease prediction and diagnosis, and patient stratification. However, technical differences across assay platforms often result in low-to-moderate agreement, limiting study reproducibility, data integration, and model transferability. Here we present AART, a cross-platform proteomic translation framework that integrates matched-protein ridge regression with proteome-wide residual learning. We benchmarked AART spanning three independent cohorts profiled using three major platforms, including Olink, SomaScan, and mass spectrometry. Across all six translation directions, AART achieved the best performance compared with baseline methods for both overlapping and non-overlapping protein translations, with a relative improvement of 92.0% on average over direct mapping and by up to 31.6% over cpiVAE, the strongest baseline. Proteins that were accurately translated and improved by AART were enriched for extracellular, vesicle-associated, and tissue-restricted plasma biology. In downstream applications, AART improved the reproducibility of proteomic association analyses relative to direct cross-platform comparison by 75.5% for type 2 diabetes and 370.6% for Alzheimer's disease. AART-enabled cohort integration enhanced diagnostic accuracy for amyotrophic lateral sclerosis by 92.6% compared with non-integration analysis. AART was overall one to three orders of magnitude faster than cpiVAE, facilitating biobank-scale applications. Together, these results establish AART as a fast, accurate, and scalable framework for cross-platform proteomic translation, enabling more reproducible, transferable, and integrated proteomic research.}, } @article {pmid42427576, year = {2026}, author = {Wang, H and Sun, S and Mathé, EA and Zhu, Q}, title = {RD-OMICS: An Integrative Multi-Omics Data Inventory in Rare Diseases.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42427576}, issn = {2692-8205}, support = {ZIA TR000548/ImNIH/Intramural NIH HHS/United States ; ZIC TR000410/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Rare diseases (RD) impact over 30 million individuals in the United States, yet fewer than 5% of the identified conditions have FDA-approved treatments. Progress in RD research is hindered by small patient cohorts, biological heterogeneity, and the fragmented, inconsistently annotated publicly available omics data, which limits integrative analysis and translational discovery. Here, we present RD-OMICS, a data inventory with integrated and structured RD omics data from Gene Expression Omnibus (GEO), in the form of a knowledge graph. We developed a metadata harmonization pipeline that combines rule-based mapping and large language model (LLM)-assisted semantic categorization. The graph-based data model was defined to integrate different types of data including disease conditions, experiments, samples, platforms, projects, and publications into a centralized inventory graph. In this preliminary study, 11,049 GEO series for 126 rare diseases were processed and integrated into RD-OMICS, which includes 375,930 individual biospecimen samples, 1,578 sequencing and array platforms, 10,938 biological projects. Case studies demonstrate the use of RD-OMICS in supporting rare disease research, omics cohort construction, and transcriptome-based drug repurposing for amyotrophic lateral sclerosis (ALS). RD-OMICS provides a scalable foundation for transforming fragmented omics data into a structured, harmonized and interoperable resource, facilitating therapeutic development and other translational discoveries in rare diseases.}, } @article {pmid42427672, year = {2026}, author = {Dixon, E and Azimian, F and Joby Chacko, A and Tatum, R and Boykin, C and Chen, YH and Lu, Q}, title = {Small molecules targeting ARF1 interaction with C9orf72:SMCR8:WDR41 complexes suppress its overactivation implicated in ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.01.24.701325}, pmid = {42427672}, issn = {2692-8205}, abstract = {The hexanucleotide repeat expansion in C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). The C9orf72 protein forms a complex with SMCR8 and WDR41 (CSW), which functions as a GTPase-activating protein (GAP) regulating ARF1 and RAB small GTPases. While these findings implicated ARF1-GAP dysregulation in ALS/FTD and supported ARF1 suppression as potential intervention, small molecules that modulate ARF1-CSW interactions are lacking. In this study, we demonstrated upregulation of tyrosine-phosphorylated (Tyr-782) ASAP1 (also known as AMAP1, DDEF1, or Centaurin β4), an ARF-GAP, in human motor cortex of both sporadic ALS and ALS with C9orf72 mutations. Ectopic C9orf72 expression partially mimicked the effects of a known ARF1 inhibitor brefeldin A to disperse Golgi apparatus. Computer-aided rational drug design with high-throughput in-silico screening identified MCULE-5095997944 (Named as SCC944) as a ARF1-CSW modulator. SCC944 binds directly to ARF1 and reduced GTP-bound ARF1 levels upon ARF1 activation. SCC944 demonstrated brefeldin A-like ARF1-dependent alteration of organelle organization including Golgi, microtubules, and mitochondria, but also a protein trafficking pattern that is distinct from brefeldin A mechanism. These studies identified the first small molecule targeting ARF1-CSW interaction and further support ARF1 modulation as a potential therapeutic approach for ALS/FTD.}, } @article {pmid42428129, year = {2026}, author = {Raemaekers, M and Geukes, SH and Aarnoutse, EJ and Branco, MP and Freudenburg, ZV and Schippers, A and Crone, NE and Leinders, S and Berezutskaya, J and Ramsey, NF and Vansteensel, MJ}, title = {Association between motor cortex grey matter loss and inability to control an ECoG-based implanted Brain-Computer Interface in ALS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42428129}, support = {U01 DC016686/DC/NIDCD NIH HHS/United States ; UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: The field of implantable Brain-Computer Interfaces (iBCIs) is rapidly advancing, with individuals with amyotrophic lateral sclerosis (ALS) as key beneficiaries. However, ALS-related cortical degeneration may impair iBCI effectiveness. This study investigated whether structural magnetic resonance imaging (MRI) and functional MRI (fMRI) metrics are associated with the quality of electrocorticography (ECoG) signals critical for iBCI use.

METHODS: Six late-stage ALS participants and 76 controls underwent T1-weighted structural MRI and task-based fMRI during right-hand movement or attempts thereof. ECoG data of ALS participants was benchmarked using ECoG data acquired in epilepsy patients. Grey matter thickness in the sensorimotor cortex and fMRI activation in the motor-hand area were measured.

RESULTS: Four ALS participants showed >0.4 mm thinning in the precentral gyrus, while the postcentral gyrus was spared. ECoG signal quality was significantly associated with precentral grey matter thickness, but not with fMRI activity.

CONCLUSIONS: These findings suggest that presurgical assessment of precentral grey matter thickness could potentially prove useful for iBCI candidate selection in advanced ALS.}, } @article {pmid42428795, year = {2026}, author = {Craig, EJ and Ryan, VH}, title = {Dysregulated neuronal mRNA transport and translation in FTD/ALS.}, journal = {NPJ dementia}, volume = {2}, number = {1}, pages = {56}, pmid = {42428795}, issn = {3005-1940}, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal, co-occurring neurodegenerative disorders. Dysregulation of mRNA metabolism, transport, and local translation is a significant mechanism contributing to FTD/ALS. Here, we review the processes of neuronal RNA transport and translation, their disruption in FTD/ALS, and mechanistic interplay between the two. Finally, we discuss current progress targeting transport and translation defects and identify potential future directions for therapeutic development.}, } @article {pmid42428879, year = {2026}, author = {Hermosillo-Abundis, C and Arias-Carrion, O and Contreras-Ibáñez, C and Mendez-Rojas, MA}, title = {From Air to Brain: Environmental Nanoparticles as Modifiable Risk Factors for Neurodevelopmental, Neurodegenerative, and Mental Disorders.}, journal = {ACS omega}, volume = {11}, number = {26}, pages = {38267-38287}, pmid = {42428879}, issn = {2470-1343}, abstract = {Ultrafine particles (≤100 nm) and other environmental nanoparticles have emerged as biologically active pollutants that can cross biological barriers, including the blood-brain barrier and the placenta. Growing evidence implicates ultrafine particles in a wide range of neuropsychiatric conditions, yet their effects remain poorly integrated into clinical and public health frameworks. In this review, we distinguish between size-defined ultrafine particles (UFPs, ≤100 nm), composition-defined environmental nanoparticles originating from combustion and secondary formation processes, and engineered nanomaterials (ENPs), which differ in physicochemical properties, exposure scenarios, and regulatory status. This narrative systematic review synthesizes findings from human and experimental studies on the neuropsychiatric and neurodevelopmental effects of environmental nanopollutants. A structured search was conducted in PubMed, Web of Science, Scopus, and Google Scholar up to November 2025, following explicit inclusion and exclusion criteria. Eligible studies included peer-reviewed human and animal research assessing mental health or neurological outcomes of nanopollutant exposure. Epidemiological studies(?)primarily involving traffic-related air pollution and mixed combustion-derived ultrafine particle exposures(?)suggest associations with increased risk of cognitive impairment, autism spectrum disorder, depression, schizophrenia, and neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Prenatal and early life exposures were linked to cortical thinning, altered neurodevelopmental trajectories, and early proteinopathies. Underlying mechanisms include neuroinflammation, oxidative stress, and protein aggregation. Despite methodological heterogeneity, the evidence supports the urgent need for regulation and prevention. Environmental nanopollutants constitute an under-recognized, modifiable risk factor for neuropsychiatric and neurodegenerative conditions. A paradigm shift is needed to incorporate environmental exposure history into mental health research, risk assessment, and prevention strategies. Regulatory action targeting nanopollutant emission and exposure, particularly in vulnerable populations, is critical to mitigating long-term neurological consequences.}, } @article {pmid42429266, year = {2026}, author = {Macpherson, CE and Muccini, J and Blacutt, ME and Bjalme-Evans, M and Lough, ME and Quinn, L}, title = {Gait speed and future ambulatory status in amyotrophic lateral sclerosis: a retrospective observational study with implications for power wheelchair referral.}, journal = {Physiotherapy theory and practice}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/09593985.2026.2700400}, pmid = {42429266}, issn = {1532-5040}, abstract = {BACKGROUND OR INTRODUCTION: Amyotrophic lateral sclerosis (ALS) causes rapid and progressive loss of ambulation resulting in immobility. A power wheelchair (PWC) increases safety, independence, and quality of life, however, the PWC referral process is lengthy and complex. When the PWC is delayed, immobility complications can occur. One barrier is the lack of a universal predictive "gait speed threshold" to help clinicians determine when to initiate the PWC referral process.

OBJECTIVE OR PURPOSE: Identify a clinically relevant gait speed threshold associated with future loss of ambulation in people with ALS.

METHODS: This was a retrospective chart review of a single multidisciplinary ALS Center of Excellence from July 1, 2016 - July 1, 2019 (36-months). Participants were included in this study if they were adults (age >18 years) with clinically definite ALS who were ambulatory at baseline. The primary outcome was gait speed on the 10-meter walk test. Secondary outcomes included the ALS Functional Rating Scale-Revised, forced vital capacity, falls, and ambulation status.

RESULTS: Of N = 180 people with ALS identified during the study period, n = 72 met inclusion for analysis with a mean age 66.1 ± 11.9 years, 64% male, 76% with an ALS phenotype of spinal onset, and 24% bulbar onset. A gait speed threshold of 0.79 m/s maximized the combined sensitivity and specificity for classifying ambulatory status at the subsequent 6-month visit. Faster gait speeds (>1.2-1.4 m/s) were associated with greater odds of remaining ambulatory at 6-months based on Bayesian logistic regression.

CONCLUSION: A gait speed threshold of 0.79 m/s was associated with increased likelihood of subsequent loss of ambulation, though modest predictive accuracy limits its use as a stand-alone indicator. Gait speed may serve as one component of clinical decision-making regarding PWC planning and referral in people with ALS. Larger multicenter studies are needed to confirm and generalize results across ALS phenotypes.}, } @article {pmid42429860, year = {2026}, author = {D'Andrea, T and Benedetti, MC and Mochi, M and De Turris, V and Rosa, A and Fucile, S}, title = {Human iPSC-Derived Spinal Neurons Carrying the ALS FUS (P525L) Mutation Exhibit Lower Response to Inhibitory Neurotransmitters.}, journal = {Cellular and molecular neurobiology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10571-026-01773-z}, pmid = {42429860}, issn = {1573-6830}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder characterized by motoneurons degeneration. Functional studies have linked ALS to hyperexcitability and excitotoxicity, but the cause of the disease is unknown, though familial ALS cases are linked to pathogenic variants in several genes, including SOD1, TARDBP and FUS. Here we focused on the effect of the severe FUS (P525L) mutation on the functional properties of human spinal neurons derived from induced pluripotent stem cells (hiPSCs). This mutation delayed functional maturation, as revealed by the observation that mutated neurons showed alterations of membrane potential, reduced spontaneous synaptic activity, and altered action potentials at early differentiation stages. FUS (P525L) mutation was associated with a significant alteration of inhibitory signalling transmission: mutated neurons showed a significantly lower current response to GABA and glycine compared to control isogenic WT neurons of the same age. Also, glutamatergic currents exhibited a different temporal evolution in control and mutated neurons, but at a lower extent in comparison to inhibitory neurotransmitters. The decrease in the glycine-evoked currents was confirmed by the reduction of the expression of the α1 subunit of glycine receptor, measured by immunofluorescence assay. Similar functional alterations were measured in spinal neurons differentiated form a second hiPSC line, confirming the causative role of the FUS (P525L) mutation. Our data indicate that the FUS (P525L) mutation reduces the maturation rates and the function of hiPSC-derived spinal neurons, with a strong decrease of inhibitory transmission, which may affect the excitatory/inhibitory balance, possibly predisposing to excitotoxicity and neurodegeneration.}, } @article {pmid42430091, year = {2026}, author = {You, Y and Duan, D and Xiang, Q}, title = {The Role of PGC-1α in Neurodegenerative Diseases: Molecular Mechanisms, Translational Challenges, and Therapeutic Potential.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42430091}, issn = {1559-1182}, mesh = {Humans ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; Animals ; Mitochondria/metabolism ; *Translational Research, Biomedical ; *Translational Science, Biomedical ; }, abstract = {Neurodegenerative diseases (NDDs) are progressive disorders in which mitochondrial dysfunction, oxidative stress, proteostasis failure, neuroinflammation, and synaptic damage progressively interact to drive neuronal vulnerability. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) links metabolic adaptation to stress-response pathways that are repeatedly disrupted in Alzheimer's disease, Parkinson's disease, Huntington's disease, polyglutamine (PolyQ) disorders, and amyotrophic lateral sclerosis. Rather than providing only an updated catalogue of studies, this review organizes the evidence into a cross-disease rheostat framework that explains why PGC-1α modulation is protective in some settings but incomplete or maladaptive in others. Current findings indicate that PGC-1α supports mitochondrial biogenesis, oxidative phosphorylation, antioxidant defense, mitophagy, autophagy, protein quality control, and inflammatory balance. However, its effects are highly context dependent. In several models, restoration of PGC-1α-related signaling improves mitochondrial function and reduces neuronal injury, whereas broad, sustained, or cell-inappropriate activation may produce limited benefit or undesirable outcomes. These observations suggest that PGC-1α is not a simple neuroprotective switch, but a flexible regulatory hub whose therapeutic value depends on cell type, isoform profile, disease stage, and activation level. Emerging strategies, including small-molecule modulators, gene delivery, antisense-based approaches, nanoparticle systems, and exercise-related interventions, remain largely preclinical and face major barriers related to CNS delivery, pathway selectivity, dose and cell-type control, peripheral safety, and validated target-engagement biomarkers. Nevertheless, clinical translation requires stronger causal validation, reliable target-engagement biomarkers, selective delivery methods, and long-term safety assessment. Future research should focus on precision-based modulation of PGC-1α to determine when and how this pathway can be safely used for disease modification. Such a careful approach may help transform PGC-1α from a broad experimental target into a clinically relevant strategy for well-defined neurodegenerative phenotypes.}, } @article {pmid42430317, year = {2026}, author = {Buczak, MK and Brignone, J and Hamrick, WC and Cole, KM and Bromberg, MB and Zhang, H and George, JA}, title = {Preliminary Investigation of Myoelectric Control of an Assistive Neck Exoskeleton by Individuals With Amyotrophic Lateral Sclerosis.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {34}, number = {}, pages = {3277-3290}, pmid = {42430317}, issn = {1558-0210}, support = {DP5 OD029571/OD/NIH HHS/United States ; R21 EB035378/EB/NIBIB NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology ; *Electromyography/methods ; Male ; Middle Aged ; Reproducibility of Results ; *Exoskeleton Device ; Algorithms ; Neck Muscles/physiopathology ; Head Movements ; Convolutional Neural Networks ; *Neck/physiopathology ; Aged ; *Self-Help Devices ; Adult ; }, abstract = {Neck weakness limits head control and quality of life for individuals with Amyotrophic Lateral Sclerosis (ALS). The Utah Neck Exoskeleton can restore neck motion, but current control methods-joystick and gaze tracking-have limited accessibility and reliability. These preliminary offline analyses investigate neck electromyography (EMG) as an alternative control modality from ALS patients. EMG signals were recorded from four male participants with ALS while performing neck flexion/extension, axial rotation, and lateral deviation. The resulting dataset was used to train convolutional neural networks (CNNs) per patient to classify either head position or movement direction from EMG features offline. Position classification significantly outperformed direction classification, with a mean accuracy of 82.5% $\pm ~0.010$ across participants. Performance was consistent when controlling one, two, or all three neck degrees of freedom. A subset of participants with sufficient residual motor function also completed neck movements while talking or chewing. Classification accuracy decreased during talking and chewing, although these effects were not statistically significant. Importantly however, training CNNs with diverse data that included periods of talking and chewing improved algorithm robustness across all conditions. These findings suggest that neck EMG signals can reliably predict intended head movements in ALS, even in the presence of weak and often confounding muscle activity. Offline accuracy and real-time computational speed suggest the approach is feasible for future online user-in-the-loop studies. Altogether, this pilot work advances EMG-based assistive technology for individuals with severe motor impairments, laying the groundwork for clinically viable, intuitive control systems.}, } @article {pmid42430680, year = {2026}, author = {Chang, CY and Price, TR and Jia, A and Cragg, JJ}, title = {Neurology® Journal Club: Duration of Current Statin Use and Amyotrophic Lateral Sclerosis Risk.}, journal = {Neurology}, volume = {107}, number = {3}, pages = {e218358}, doi = {10.1212/WNL.0000000000218358}, pmid = {42430680}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/chemically induced ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects/therapeutic use ; Time Factors ; Cohort Studies ; Risk Factors ; Norway/epidemiology ; }, abstract = {This article critically appraises the study by Nakken et al., "Duration of Current Statin Use and Amyotrophic Lateral Sclerosis (ALS) Risk." Previous observational studies and Mendelian randomization studies examining statin use and ALS risk have reported mixed results. Millions of adults receive statins for cardiovascular prevention and may be concerned when neuromuscular symptoms suggestive of ALS appear. Using linked nationwide health survey and prescription data, this Norwegian population-based cohort study applied time-dependent models to evaluate statin use and subsequent ALS risk. Short-term statin use was associated with increased ALS risk, whereas long-term use was associated with lower risk. The authors interpreted this as evidence of reverse causation rather than a causal or protective effect of statins. Key strengths of the study include its large population-based design, the use of a negative control, and time-dependent Cox modeling. However, limitations inherent to observational study designs and potential residual confounding should be considered. In this article, we summarize the findings, highlight key statistical concepts, and discuss the study's major strengths and limitations.}, } @article {pmid42431020, year = {2026}, author = {Romano, C and Johar, L and Hundhausen, K and Kimonis, V}, title = {Clinical studies in 82 individuals with valosin-containing protein (VCP) associated multisystem proteinopathy and literature review.}, journal = {Neuromuscular disorders : NMD}, volume = {65}, number = {}, pages = {106469}, doi = {10.1016/j.nmd.2026.106469}, pmid = {42431020}, issn = {1873-2364}, mesh = {Humans ; *Valosin Containing Protein/genetics ; Female ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; *Osteitis Deformans/genetics/physiopathology ; *Frontotemporal Dementia/genetics/physiopathology ; Middle Aged ; Male ; Aged ; Adult ; *Muscular Dystrophies, Limb-Girdle/genetics/physiopathology ; Myositis, Inclusion Body/genetics/physiopathology ; Disease Progression ; }, abstract = {Valosin-containing protein (VCP) pathogenic variants cause a multisystem proteinopathy characterized by myopathy, Paget disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis (ALS). We evaluated 82 affected individuals, 14 presymptomatic carriers, and 36 unaffected first-degree relatives from 48 families to identify sensitive measures for disease monitoring. Mean age of onset was ∼42 years for myopathy, Paget disease, or ALS, and 53 years for dementia. Functional assessments included the Inclusion Body Myositis Functional Rating Scale (IBMFRS), ALSFRS-R, Fatigue Severity Scale (FSS), and six-minute walk test (6MWT). Affected individuals demonstrated progressive functional decline, with IBMFRS decreasing 1.9% annually, FSS increasing 4.4%, and 6MWT decreasing 6% annually when modeled against disease duration. Women declined more rapidly on IBMFRS but showed slower ambulatory and fatigue progression. Potential genotype-specific effects were observed, with earlier onset and shorter survival in p.Arg155Cys compared to later onset in p.Arg155His. Strong correlations among IBMFRS, FSS, and 6MWT indicate these as accessible endpoints for longitudinal monitoring and clinical trials. Rapid decline with ALS and dementia necessitates multidisciplinary support, while longer survival after myopathy or Paget onset offers a window for preventive and supportive interventions.}, } @article {pmid42431556, year = {2026}, author = {Singh, N and Gomes, J}, title = {Fisetin prevents deterioration of cellular functions in amyotrophic lateral sclerosis variants G262R and P438L of SQSTM1 in SH-SY5Y cells.}, journal = {Toxicology and applied pharmacology}, volume = {515}, number = {}, pages = {117943}, doi = {10.1016/j.taap.2026.117943}, pmid = {42431556}, issn = {1096-0333}, mesh = {Humans ; *Sequestosome-1 Protein/genetics ; *Flavonoids/pharmacology ; Flavonols ; Oxidative Stress/drug effects ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/drug therapy ; Cell Survival/drug effects ; Cell Line, Tumor ; NF-E2-Related Factor 2/metabolism ; Quercetin/pharmacology ; DNA-Binding Proteins/metabolism ; Mutation ; Reactive Oxygen Species/metabolism ; *Antioxidants/pharmacology ; *Adaptor Proteins, Signal Transducing/genetics ; Apoptosis/drug effects ; }, abstract = {Oxidative stress is widely accepted as one of the important factors contributing to neurodegeneration, leading to fatal neurodegenerative diseases (NDD) such as Amyotrophic Lateral Sclerosis. Since flavonoids possess antioxidant properties, we investigated whether Fisetin (FS) and Quercetin (QR) protected cells from oxidative stress arising from pathogenic mutations G262R (G > A) and P438L (C > T) of SQSTM1 found in Indian ALS patients. SQSTM1 codes for p62 protein and is involved in multiple signaling pathways through its various domains. We studied changes in cell viability and cellular functions using immunoblotting, confocal microscopy, immunoprecipitation and FACS analysis in the presence and absence of FS and QR. Supplementation with FS and QR in SH-SY5Y cells expressing SQS-wild type and mutants increased cell viability and decreased ROS formation. Also, Nrf2 protein levels increased to offset oxidative stress response. In addition, we studied the effect of FS on the nuclear-cytoplasmic distribution of TDP-43 protein, which serves as a hallmark for ALS. FS corrected the nuclear-cytoplasm translocation of TDP-43 protein and decreased late apoptosis in mutants. Our study illustrates that both FS and QR shield cells from oxidative stress, and that FS imparted better protection against the pathogenic effect of SQSTM1 mutants in SH-SY5Y neuronal cells.}, } @article {pmid42432003, year = {2026}, author = {Chen, J and Xu, P and Chen, M and Lu, Z and Li, X and Stampas, A and Zong, Y and Zhou, P}, title = {Compound muscle action potential scan dataset in adults with spinal cord injury and healthy controls.}, journal = {Scientific data}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41597-026-07864-2}, pmid = {42432003}, issn = {2052-4463}, support = {ZR2024QH582//Natural Science Foundation of Shandong Province/ ; ZR2024YQ077//Natural Science Foundation of Shandong Province/ ; tsqn202211226//Taishan Scholar of Shandong Province/ ; tstp20221144//Taishan Scholar of Shandong Province/ ; 25S11907200//Science and Technology Commission of Shanghai Municipality/ ; KFKT-2024-KF-013//Chinese Association of Rehabilitation Medicine/ ; 82572355//National Natural Science Foundation of China/ ; }, abstract = {Certain neurological conditions, such as amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI), result in motor unit loss in muscles. The stimulus-evoked compound muscle action potential (CMAP) scan captures comprehensive information on motor unit recruitment that enables rapid and non-invasive assessment of motor unit status. However, few publicly available CMAP scan datasets exist to support research on motor unit number estimation (MUNE). To address this gap, we collected CMAP scan data from the first dorsal interosseous (FDI) muscle of 13 individuals with SCI and 13 healthy participants, and established a dedicated CMAP scan dataset. The dataset includes CMAP waveforms evoked by each nerve stimulus from which CMAP scan curve and typical parameters were extracted for direct use. All SCI participants underwent multiple clinical assessments and exhibited a spectrum of impairment severity from mild to severe, resulting in diverse CMAP features. We anticipate that this dataset will facilitate the development of advanced CMAP scan-based assessment techniques and aid in the investigation of neuromuscular impairment.}, } @article {pmid42432423, year = {2026}, author = {Sugisawa, R and Sekiguchi, K and Noda, Y and Matoba, S and Suehiro, H and Kozuki, J and Tanaka, T and Chihara, N}, title = {Quantitative Spatiotemporal Analysis of Ultrasound Images of Fasciculations in ALS.}, journal = {Muscle & nerve}, volume = {74}, number = {3}, pages = {644-655}, pmid = {42432423}, issn = {1097-4598}, support = {JP256f0137011//Japan Agency for Medical Research and Development/ ; 25K14534//Japan Society for the Promotion of Science/ ; 24K14297//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/complications ; *Fasciculation/diagnostic imaging/physiopathology ; Ultrasonography/methods ; Male ; Female ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Retrospective Studies ; Middle Aged ; Aged ; Spatio-Temporal Analysis ; Biomechanical Phenomena ; }, abstract = {INTRODUCTION/AIMS: Fasciculations are a hallmark of amyotrophic lateral sclerosis (ALS), yet quantitative description of individual events on muscle ultrasound (MUS) is limited. We characterized the spatiotemporal kinematics of individual fasciculations to determine whether they differ between ALS and other neurogenic conditions.

METHODS: We retrospectively analyzed biceps brachii MUS recordings from 680 examinations (January 2020-June 2025), identifying 74 ALS and 40 non-ALS neurogenic recordings with fasciculations (167 and 62 segments). After propensity score matching for age and muscle strength, 62 matched pairs were analyzed. The Lucas-Kanade optical flow algorithm, which estimates frame-to-frame displacement vectors from local intensity gradients, was applied at 1-pixel intervals (57,600 points per 240 × 240 region; ≈60 μm) to quantify twitch durations, peak displacement velocity, and directional anisotropy as a measure of spatial movement coherence.

RESULTS: ALS fasciculations showed prolonged total duration (582.8 ± 112.8 ms vs. 489.2 ± 128.7 ms, p < 0.001), reduced directional anisotropy (0.534 ± 0.245 vs. 0.627 ± 0.215, p = 0.028), and lower peak displacement velocity (6.55 ± 6.56 vs. 9.53 ± 9.07 μm/ms, p = 0.039). MANOVA showed significant multivariate differences (Pillai's trace = 0.317 ± 0.030, p < 0.001) with moderate group separation (Mahalanobis distance = 1.10 ± 0.05).

DISCUSSION: ALS fasciculations showed spatially heterogeneous and temporally prolonged contraction patterns, suggesting motor units in a transitional state of incomplete reinnervation, distinct from the more stable architecture of chronic neurogenic disorders. This framework may complement existing ultrasound assessment and aid the study of motor unit pathology in ALS.}, } @article {pmid42432439, year = {2026}, author = {Kavale-Henderson, LA and Buckberry, J and Buckley, H and Cameron, C and King, C and Koon, H and Petchey, P and Snoddy, AME and Loch, C}, title = {"An Injurious and Utterly Unfit Environment": A Case Study Comparing Dental Evidence of Childhood Stress in Nineteenth Century Working-Class Peoples From British and Colonial New Zealand Contexts.}, journal = {American journal of biological anthropology}, volume = {190}, number = {3}, pages = {e70315}, pmid = {42432439}, issn = {2692-7691}, support = {21-UOO-01//Ministry of Business, Innovation and Employment/ ; //University of Otago/ ; }, mesh = {Humans ; New Zealand ; History, 19th Century ; United Kingdom ; Child ; Adult ; Male ; *Tooth/pathology ; *Stress, Psychological/pathology/history ; Female ; Child, Preschool ; Young Adult ; Infant ; Adolescent ; Transients and Migrants/history ; }, abstract = {OBJECTIVES: During the nineteenth century, the health and living conditions of many working-class European peoples declined in association with growing industrialization and urbanization. Emigration to British colonies grew as people sought to escape such hardships. This research presents the first direct comparison of dental markers of stress in a case study of migrants to a British colony (Otago, New Zealand) alongside a contemporaneous assemblage representing an origin population (London, United Kingdom).

MATERIALS AND METHODS: Dental markers of childhood stress, accentuated lines, were observed in thin-sections of archeological teeth from adults (n = 9) and children (n = 16) interred in London, United Kingdom (UK), and adult European migrants interred in Otago, New Zealand (NZ) (n = 24) using standard histological techniques.

RESULTS: All individuals interred in London, and 92% (22/24) of those in New Zealand exhibited evidence of accentuated line formation within the first 2.5 years of life. There was no difference in median accentuated line occurrence between adults and children interred in the UK. However, NZ adults had a lower median occurrence of accentuated lines over the first 2.5 years since birth (5 ALs/individual) than UK adults (13 ALs/individual). Accentuated lines most frequently occurred in infancy for all three groups examined. However, temporal trends in accentuated line occurrence differed between groups in association with age.

DISCUSSION: These results highlight the impact of childhood stresses on working-class people growing up during the nineteenth century, underlining potential differences in the childhood experiences of hardship in individuals that remained in Britain and those that departed for foreign soils.}, } @article {pmid42432671, year = {2026}, author = {Chen, F and Wang, L and Liu, H and Khan, Q and Tang, B and Bao, N}, title = {The role of AI-assisted drug repurposing in neurological disorders: a systematic review of validation strategies, challenges and opportunities.}, journal = {Journal of nanobiotechnology}, volume = {24}, number = {1}, pages = {}, pmid = {42432671}, issn = {1477-3155}, mesh = {*Drug Repositioning/methods ; Humans ; *Nervous System Diseases/drug therapy ; Animals ; *Artificial Intelligence ; Blood-Brain Barrier/metabolism ; Neurodegenerative Diseases/drug therapy ; }, abstract = {Neurological disorders refer to a diverse group of conditions that affect the brain, peripheral nerves, and spinal cord and impair socioemotional, cognitive, motor, and sensory functions. Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are some of the well-known neurodegenerative diseases that affect millions of people worldwide. Despite the advanced technologies and nano-drug delivery systems, the success rate of developing drugs for neurological disorders is significantly low. Among several constraints, including gastrointestinal irritation, rapid metabolism, and low stability, the blood-brain barrier (BBB) emerges as one of the key challenges in the development and application of drugs against neurological disorders. These challenges necessitate innovative approaches to develop cost-effective therapeutic strategies. Drug repurposing, the discovery of new therapeutic benefits of existing drugs, is a promising drug discovery approach for discovering potential treatment options for complex neurological disorders. This review aims to explore the advanced and significant progress in drug repurposing for major neurological disorders, including MS, AD, PD, ALS, HD, stroke, and neuropsychiatric conditions. It places an explicit emphasis on discussing the potential role of artificial intelligence (AI)-assisted drug repurposing and understanding of the biological mechanisms in discovering new drugs for these neurological conditions. This also examines current challenges in drug repurposing and provides a critical review of the available opportunities and limitations in AI-assisted drug repurposing.}, } @article {pmid42432783, year = {2026}, author = {Choi, Y and Lee, S and Ashim, J and Yu, W and Cho, E and Lee, HW and Park, JS and Yoon, JH and Kim, HJ and Cheon, M}, title = {Cross-disease LC-MS/MS plasma proteomics identifies reproducible shared and disease-enriched biomarker signatures in neurodegenerative disorders.}, journal = {Acta neuropathologica communications}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40478-026-02377-w}, pmid = {42432783}, issn = {2051-5960}, support = {RS-2024-00454715//the National Research Foundation of Korea (NRF) grant funded by the Korean government/ ; RS-2024-00343239//the National Research Foundation of Korea (NRF) grant funded by the Korean government/ ; RS-2023-00230402//the Ministry of Environment of Korea/ ; 26-BR-04-01//the KBRI basic research program through the Korea Brain Research Institute funded by the Ministry of Science and ICT/ ; 26-BR-02-03, 26-BR-02-05, 26-BR-04-01//the KBRI basic research program through the Korea Brain Research Institute funded by the Ministry of Science and ICT/ ; 26-BR-02-03, 26-BR-02-05, 26-BR-04-01, 26-BR-06-02//the KBRI basic research program through the Korea Brain Research Institute funded by the Ministry of Science and ICT/ ; RS-2024-00512888//the Korea Technology and Information Promotion Agency for SMEs (TIPA) funded by the Ministry of SMEs and Startups/ ; }, abstract = {Neurodegenerative diseases (NDDs) exhibit considerable molecular heterogeneity, making it difficult to pinpoint robust, disease-specific biomarkers. Although proteomic studies have deepened our understanding of individual disorders, systematic cross-disease comparisons with cross-platform validation remain scarce, especially for rare conditions like spinal and bulbar muscular atrophy (SBMA). To address this gap, we conducted a comparative plasma proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 264 participants across major neurodegenerative and related diagnostic groups, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), SBMA, and cognitively healthy controls. This unified framework allowed us to capture both disease-specific and shared protein signatures across neurodegenerative conditions. Candidate proteins were then validated in the UK Biobank (Olink Explore) and the Global Neurodegeneration Proteomics Consortium (SomaScan). Of 23 proteins assessed in the UK Biobank, four unique proteins (yielding six disease-protein associations) showed nominally significant and directionally concordant changes; of 20 proteins represented by 27 probes tested in the Global Neurodegeneration Proteomics Consortium, seven proteins reached nominal significance, all with full directional concordance across both cohorts. Notably, IGFBP2 was consistently elevated in AD and PD across independent datasets, pointing to shared metabolic dysregulation, while ADIPOQ showed parallel increases in the same conditions, reinforcing convergent shifts in energy metabolism. By contrast, CRTAC1 and COMP were selectively reduced in motor neuron diseases, suggesting disease-enriched alterations in extracellular matrix composition. Taken together, our findings provide a cross-disease, cross-platform framework for uncovering reproducible proteomic biomarkers and shed light on both overlapping and distinct molecular pathways in neurodegeneration.}, } @article {pmid42432887, year = {2026}, author = {Ye, H and Wang, JL and Xu, QH and Gao, YL}, title = {Refining the link between REM sleep behavior disorder and neurodegeneration: Genetic correlation, Mendelian randomization, and colocalization evidence.}, journal = {Medicine}, volume = {105}, number = {28}, pages = {e48922}, pmid = {42432887}, issn = {1536-5964}, mesh = {Humans ; *REM Sleep Behavior Disorder/genetics/complications ; Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics ; Linkage Disequilibrium ; Genome-Wide Association Study ; Alzheimer Disease/genetics ; Parkinson Disease/genetics ; }, abstract = {Observational studies have proposed a link between isolated rapid eye movement sleep behavior disorder (iRBD) and several neurodegenerative diseases. We employed genome-wide linkage disequilibrium score regression (LDSC), standard two-sample Mendelian randomization (MR), and colocalization analysis to assess the causal links between iRBD and these neurodegenerative conditions. iRBD demonstrated a positive causal association with Alzheimer disease (odds ratio [OR] = 1.02, 95% confidence interval [CI]: 1.00-1.03, P = 1.10E-02), Parkinson disease (OR = 1.10, 95% CI: 1.03-1.16, P = 2.96E-03), and multiple sclerosis (OR = 1.09, 95% CI: 1.02-1.17, P = 1.61E-02). A strong positive genetic correlation with dementia with Lewy bodies was observed (rg = 1.6313, P = .0002), along with a causal association (OR = 1.45, 95% CI: 1.03-2.06, P = 3.53E-02), further supported by colocalization analysis. No significant causal relationship was identified between iRBD and amyotrophic lateral sclerosis (all P > .05). Additionally, reverse Mendelian randomization analyses did not reveal any causal relationships between the neurodegenerative diseases studied and iRBD. Our findings provide robust genetic evidence supporting a causal relationship between iRBD and the risk of multiple neurodegenerative diseases, highlighting the potential for shared pathophysiological mechanisms.}, } @article {pmid42432946, year = {2026}, author = {Jeong, J and Song, KJ and Lee, JC and Shin, SD and Kim, YJ}, title = {A simulation study on optimizing stationary camera locations for physician-directed telemedical supervision of prehospital advanced life support: Single-versus dual-camera setups.}, journal = {Medicine}, volume = {105}, number = {28}, pages = {e49685}, pmid = {42432946}, issn = {1536-5964}, support = {2020R1F1A1076561//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Telemedicine ; *Emergency Medical Services/methods ; Prospective Studies ; *Emergency Medical Technicians/education ; Smartphone ; *Video Recording/instrumentation/methods ; }, abstract = {Prehospital telemedicine, particularly real-time video conferencing, offers significant benefits in prehospital and disaster settings by enabling rapid data transmission. Using a smartphone mounted on a tripod as a stationary camera provides stable footage, comprehensive scene evaluation, and reduced technical complexity, thus complementing smart glasses and built-in cameras. However, the optimal camera location for visualizing key procedures remains unexplored. This study aims to compare the optimal stationary camera location and the effectiveness of single-camera versus dual-camera setups in visualizing key procedures for physician-directed telemedical supervision of prehospital advanced life support (ALS). This prospective, non-randomized simulation study involved 9 advanced emergency medical technicians performing ALS procedures in 20 simulations. Each simulation was recorded simultaneously from 4 stationary camera locations: right head, left head, right leg, and left leg. Reviewers evaluated the visibility of 6 key procedures (airway management, breathing support, chest compressions, intravenous access, electrocardiogram rhythm monitoring, and teamwork) using a 1 to 5 scale. Mixed models and generalized linear mixed models were applied to analyze the visibility scores and compare the effect sizes of the different camera setups. The median visibility scores and proportion of optimal visibility (scores of 4-5) varied significantly across the 4 camera locations for most procedures. However, the mixed model and generalized linear model analyses for overall visibility did not reveal significant differences in effect sizes between individual camera locations. Dual-camera setups showed significant improvement over single-camera setups, with an adjusted odds ratio of 4.89 (95% confidence interval: 1.92-12.4) for the right head + left head combination and 3.74 (95% confidence interval: 1.50-9.32) for the right head + left leg combination. Although no single-camera location provided optimal visualization for all procedures, dual-camera setups were more effective than single cameras in capturing field activity. These findings support the use of dual-camera setups to enhance physician-directed telemedical supervision of prehospital ALS, with potential applicability to disaster settings, and may inform the development of future protocols for prehospital telemedicine.}, } @article {pmid42434198, year = {2026}, author = {Sleutjes, BTHM and Jacobsen, AB and Tankisi, H and Sirin, NG and Oge, AE and Henderson, RD and van Doorn, PA and van den Berg, LH and van Eijk, RPA}, title = {Quantifying motor unit loss prior to functional impairment in muscles affected by amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {11}, number = {}, pages = {538-542}, pmid = {42434198}, issn = {2467-981X}, abstract = {OBJECTIVES: The compound muscle action potential (CMAP) scan is a non-invasive method for deriving motor unit number estimates (MUNE) to track disease progression in muscles affected by amyotrophic lateral sclerosis (ALS). It remains to be established whether and how long motor unit loss precedes functional impairment.

METHODS: In 56 patients with ALS, we compared the longitudinal trajectories of MUNE derived from thenar CMAP scans, and fine motor function (FMF) using a functional rating scale. Linear and sigmoidal disease trajectories were modelled from which time differences were estimated between these measures to reach their half-maximum scores.

RESULTS: The normalized linear decline per month was 0.02 (95% CI 0.01 to 0.03) for FMF and 0.03 (95% CI 0.03 to 0.04) for MUNE. Half-maximum of FMF was reached after 26.3 months (95% CI 18.9 to 35.1) for the linear model, while MUNE had a shorter time required to reach 50% of its maximum with 13.0 months (95% CI 10.3 to 16.4). The head-to-head comparison between FMF and MUNE showed that MUNE values reached 50% of its maximum 13.1 months (95% CI 7.0-20.8) earlier. Results were similar for sigmoidal disease trajectories.

CONCLUSIONS: Simulated disease trajectories of MUNE values derived from CMAP scans in muscles affected by ALS indicated that MUNE may reach 50% of its maximum in approximately 60% of the time compared to functional impairment.

SIGNIFICANCE: These explorative findings underscore how neurophysiological measures may be of use for early disease monitoring, with relevance for both care and research settings.}, } @article {pmid42434808, year = {2026}, author = {Baker, B and Emerson, S and Tran, T and Mohapatra, N and Wang, D and Zaw, T and Doshi, A and Lopez, JM and Hassan, D and Kumar, P and Farmer, D and Wang, A}, title = {Brain targeting and trafficking of extracellular vesicles in central nervous system diseases: a therapeutic roadmap.}, journal = {Nanomedicine (London, England)}, volume = {21}, number = {14}, pages = {2115-2133}, pmid = {42434808}, issn = {1748-6963}, support = {1R01NS144390/NH/NIH HHS/United States ; R01 NS115860/NS/NINDS NIH HHS/United States ; R01 NS144390/NS/NINDS NIH HHS/United States ; 1R01EB033389/NH/NIH HHS/United States ; 1R01NS131538/NH/NIH HHS/United States ; R01 NS131538/NS/NINDS NIH HHS/United States ; 1R01NS115860/NH/NIH HHS/United States ; R01 EB033389/EB/NIBIB NIH HHS/United States ; 1R01EB034279/NH/NIH HHS/United States ; R01 EB034279/EB/NIBIB NIH HHS/United States ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; Animals ; Blood-Brain Barrier/metabolism ; *Brain/metabolism/drug effects/pathology ; *Central Nervous System Diseases/metabolism/drug therapy/pathology ; Drug Delivery Systems ; Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; }, abstract = {Extracellular vesicles (EVs) mediate intercellular signaling in the central nervous system (CNS) by transferring lipids, proteins, and nucleic acids among neurons, glia, endothelium, and immune cells. Brain targeting depends on a linked sequence: EV ligands and adsorbed protein coronas engage receptor modules, select endocytic routes, determine intracellular fate, and define the therapeutic readouts. These fates include lysosomal degradation, recycling, rare cytosolic delivery, or transport across the blood-brain barrier (BBB). In disease, the same pathways can disseminate proteopathic seeds and amplify neuroinflammation. Heparan sulfate proteoglycans (HSPGs) and LDL receptor family members, including low-density lipoprotein receptor-related protein 1 (LRP1), regulate tau, α-synuclein, and amyloid-β handling. Phosphatidylserine readers and complement shape myeloid sink capture and inflammatory output. Integrin, tetraspanin, and ICAM-1 nanoclusters influence avidity, organotropism, and immune suppression. At the BBB, endothelial HSPGs, LRP1, and transferrin receptor (TfR) support receptor-mediated uptake, motivating engineered ligands such as rabies virus glycoprotein-derived peptides, Angiopep-2, and TfR binders. However, endosomal escape remains a major kinetic barrier to nucleic acid delivery. We synthesize these principles across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, glioblastoma, and demyelinating disease, and outline design and assay standards needed to translate EV biology into safe, manufacturable CNS therapeutics.}, } @article {pmid42435587, year = {2026}, author = {Domínguez-García, A and Delgado-Uriarte, JC and Cervantes-Arriaga, A}, title = {Precision therapeutics and innovative clinical trial design in neurodegenerative diseases.}, journal = {Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion}, volume = {78}, number = {4}, pages = {100050}, doi = {10.1016/j.ric.2026.100050}, pmid = {42435587}, issn = {2564-8896}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/physiopathology ; *Precision Medicine/methods ; *Clinical Trials as Topic/methods ; Biomarkers/metabolism ; Animals ; *Research Design ; }, abstract = {Neurodegenerative diseases are biologically heterogeneous disorders characterized by progressive neuronal dysfunction, overlapping molecular pathologies, and limited disease-modifying therapies. Advances in biomarker development, molecular staging, and precision medicine are reshaping therapeutic strategies and clinical trial design across Parkinson's disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington's disease, and related disorders. This review summarizes emerging therapeutic approaches, including monoclonal antibodies targeting protein aggregation, immune-modulating and metabolic interventions, antisense oligonucleotides, gene replacement and genome-editing strategies, stem cell-based therapies, and neurosurgical delivery platforms and neuromodulation technologies. It also examines evolving clinical trial methodologies such as biomarker-enriched recruitment, adaptive and delayed-start designs, platform trials, decentralized models, and master protocols. Additional emphasis is placed on diagnostic biomarkers, multimodal artificial-intelligence pipelines, systems-biology perspectives, network-based therapeutic strategies, and the reproducibility and interpretability requirements for computational tools. Despite recent progress, major challenges remain, including biological heterogeneity, limited translatability of preclinical models, delivery barriers, long-term safety concerns, and inequities in access to biomarker-based care and trial participation. Future directions will require combination therapies, integrated biomarker pipelines, preventive strategies, and pragmatic trial systems capable of translating biological advances into durable and equitable clinical benefit.}, } @article {pmid42436372, year = {2026}, author = {Roy, T and Ramesh, M and Nizam, NAA and Tandiono, S and Al-Jamal, KT and Al-Chalabi, A and Iacoangeli, A and Al Khleifat, A}, title = {Plasma exosomal HERV-K transcripts are increased in amyotrophic lateral sclerosis.}, journal = {BMC neuroscience}, volume = {27}, number = {1}, pages = {}, pmid = {42436372}, issn = {1471-2202}, support = {303476//National Institute for Health and Care Research/ ; MRC (MR/Z505705/1)//South London and Maudsley NHS Foundation Trust/ ; LS Association Milton Safenowitz Research Fellowship (RE19765)//NIHR Maudsley Biomedical Research Centre/ ; RE23378//LifeArc/ ; 1819242//Dementia Consortium/ ; 1122462/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/Z505705/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/virology ; *Exosomes/metabolism/virology ; *Endogenous Retroviruses/genetics ; Female ; Male ; Middle Aged ; Aged ; Biomarkers/blood ; Gene Products, env/blood ; }, abstract = {Human endogenous retrovirus-K (HERV-K) reactivation is increasingly implicated in amyotrophic lateral sclerosis (ALS), with ongoing clinical trials investigating antiretroviral therapies. However, there is limited understanding of how HERV-K is trafficked in peripheral biofluids, and the role of exosomes, nano-sized extracellular vesicles, in this process remains largely unexplored. Exosomes offer a stable and cell-specific cargo reservoir that may reflect central pathogenic processes and serve as a minimally invasive biomarker source. In this study, we isolated plasma-derived exosomes from ALS patients (n = 21) and healthy controls (n = 16), and quantified exosomal HERV-K gag, env, and pol transcript levels using SYBR Green qPCR with RNase treatment and normalization to both traditional and exosome-enriched reference genes. HERV-K pol expression was significantly elevated in ALS, with fold-changes ranging from 1.59 to 1.85 (P = 0.037-0.051). env and gag also showed increased expression, though with greater variability. Normalization to the exosome-specific gene SOD2 provided the most consistent signal. These findings suggest that exosomal HERV-K transcripts, particularly pol, could serve as accessible biomarkers for patient stratification and treatment monitoring in HERV-K-targeted ALS trials. This work establishes proof-of-concept for using exosomal cargo to track endogenous retroviral activity in neurodegeneration and supports further investigation of liquid biopsy approaches in ALS precision medicine.}, } @article {pmid42436431, year = {2026}, author = {Parks, ASE and Conn, LG and Abrahao, A and Zinman, L and Sale, JEM}, title = {"Straddling two worlds": complexities of spousal caregiving in amyotrophic lateral sclerosis during younger middle age.}, journal = {BMC palliative care}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12904-026-02230-w}, pmid = {42436431}, issn = {1472-684X}, abstract = {BACKGROUND: Family support is central to amyotrophic lateral sclerosis (ALS) care. Spouses often assume the role of primary caregiver, facing daily challenges as their partner's needs progressively increase. Younger ALS caregivers appear to have distinct experiences and needs, yet age- or life-stage variations and processes of caregiving are seldom considered in studies of ALS family caregiver experience.

METHODS: We undertook a qualitative study, guided by constructivist grounded theory methodology, to explore the dynamics of family caregiving following an ALS diagnosis in a younger middle-aged family member (≤55 years). Data were coded to identify psychosocial processes, including how family caregivers engage in caregiving.

RESULTS: In-depth interviews were conducted with ten spousal caregivers between August 2023 and August 2025. Overall, our theoretical understanding of spousal caregiving for younger middle-aged adults with ALS (YMAs) was captured by the core category 'straddling two worlds,' reflecting how caregivers navigated multiple interconnected dichotomies: present and future, familiar and new norms, current and anticipated losses, and the worlds of the living and the dying. To contend with an uncertain future, caregivers anchored themselves in the present as they navigated a shifting sense of normalcy. Middle age expectations and social norms shaped how caregivers engaged in caregiving and experienced losses that were often unending and ambiguous.

CONCLUSIONS: Caregiving for a spouse with ALS in younger middle age involves temporal, practical, emotional, and existential processes. Caregivers of YMAs may benefit from interventions that help them tolerate uncertainty, stay grounded in the present, maintain normalcy, and grieve losses throughout the caregiving trajectory.}, } @article {pmid42436563, year = {2026}, author = {Gregory, JM}, title = {Context of use matters: interpreting extracellular vesicle TDP-43 as a biomarker in ALS.}, journal = {Acta neuropathologica communications}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40478-026-02376-x}, pmid = {42436563}, issn = {2051-5960}, } @article {pmid42438447, year = {2026}, author = {Jewett, G and Chan, E and Jagt, K and Petrillo Ballantyne, J and Wesolosky, J and Perera, T and Karnik, V and Hahn, C and Luk, C and Mobach, T}, title = {An Intrathecal Therapeutics Clinic for Administration of Tofersen in Amyotrophic Lateral Sclerosis: A Canadian Nurse Practitioner and Neurologist Collaborative Model.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-4}, doi = {10.1017/cjn.2026.10647}, pmid = {42438447}, issn = {0317-1671}, abstract = {Tofersen is an antisense oligonucleotide administered intrathecally for amyotrophic lateral sclerosis (ALS) caused by pathogenic variants in the superoxide dismutase 1 gene. Delivering intrathecal treatments required for ongoing therapy poses logistical challenges for multidisciplinary clinics. We describe our experience establishing an efficient Canadian nurse practitioner-and neurologist-led intrathecal therapeutics clinic model, with standardized procedures and multidisciplinary monitoring. This collaborative approach has enabled efficient monthly delivery of tofersen within existing clinic infrastructure. As intrathecal therapies expand in ALS and other neurological diseases, scalable multidisciplinary models such as this may support safe and equitable care.}, } @article {pmid42439979, year = {2026}, author = {Langreen, S and Uecker, M and Juhl, S and Dingemann, J and Kiblawi, R}, title = {Is hypoalbuminemia a risk factor for small bowel anastomotic leaks in infants? A multivariate analysis.}, journal = {Pediatric surgery international}, volume = {42}, number = {1}, pages = {}, pmid = {42439979}, issn = {1437-9813}, mesh = {Humans ; *Hypoalbuminemia/complications ; Retrospective Studies ; *Anastomotic Leak/etiology/epidemiology ; Risk Factors ; Female ; *Intestine, Small/surgery ; Male ; Infant ; Multivariate Analysis ; Anastomosis, Surgical ; Infant, Newborn ; Incidence ; Serum Albumin ; }, abstract = {PURPOSE: Anastomotic leaks (AL) are critical complications following bowel anastomosis with an incidence of up to 10.5% in infants. Previous studies in animal models and adults have suggested a link between postoperative fluid overload and hypoalbuminemia with anastomotic leaks. In infants, the role of hypoalbuminemia on anastomotic integrity after small bowel anastomosis remains unclear.

METHODS: Retrospective study of infants < 1 year, undergoing elective small-bowel anastomosis between 2015 and 2024 (Ethics No.-11362-_BO_K_202). Data on demographics, weight gain, serum albumin levels and use of diuretic medication during the first five postoperative days were collected. Univariate and multivariate analysis were performed to detect risk factors for ALs in infants.

RESULTS: 13 of 219 patients (5.9%) developed ALs. Demographics were similar comparing patients with and without leaks. In univariate analysis, serum albumin levels were significantly lower (20.3 g/l vs. 26,3 g/l, p < 0.0001) in patients with AL compared to patients without AL and multivariate analysis confirmed a significant association between low serum albumin levels and AL occurrence, CONCLUSION: In infants, small bowel anastomotic leaks are associated with low postoperative serum albumin. Whether hypoalbuminemia should be regarded as an early warning sign of an undiagnosed, developing anastomotic leak or represents a causal risk factor can only be determined with further studies.}, } @article {pmid42441689, year = {2026}, author = {de Vienne, D and de Vienne, DM}, title = {Age-based risk estimates for C9orf72RE-related diseases: Theoretical developments and added value for genetic counseling.}, journal = {PLoS genetics}, volume = {22}, number = {7}, pages = {e1012230}, pmid = {42441689}, issn = {1553-7404}, mesh = {C9orf72 Protein ; *Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Genetic Counseling ; Penetrance ; *Frontotemporal Dementia/genetics ; *Proteins/genetics ; Aged ; DNA Repeat Expansion/genetics ; Bayes Theorem ; Mutation ; }, abstract = {The C9orf72 hexanucleotide repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). In genetic counseling, children of mutation carriers are often told that they have a 50% risk of carrying the mutation, but this figure does not take into account the fact that penetrance is age-related, with a unimodal distribution of disease onset around 58 years of age. Using a Bayesian approach, we developed a theory to calculate the probability of carrying the mutation for asymptomatic relatives (children/siblings and grandchildren/niblings) as well as the probability of developing ALS/FDT within a given time frame, based on their age. Using published data on age-related penetrance, we then calculated these probabilities and developed an online simulator that makes it easy to calculate them on a case-by-case basis. The conditional probabilities obtained can be very different from Mendelian values. For example, a 70-year-old asymptomatic child born to a carrier has approximately a 6% risk of being a carrier, which is far from 50%. For grandchildren, taking into account both their age and that of their parents also leads to figures that are much lower than those obtained if only their age were considered. For consultands, the decision to undergo testing is based in part on risk estimates. In this regard, the refined estimates and simulator we propose may prove to be valuable tools for genetic counseling for families affected by ALS/FTD linked to the C9orf72RE mutation. In addition, the formulas used in this study could also be used to calculate risk estimates for other diseases caused by autosomal dominant mutations with age-dependent penetrance.}, } @article {pmid42441693, year = {2026}, author = {Fisher, K and Ligay, A and Stratford, M and Hirani, R and Ober, DT and Al-Seykal, I and Frishman, WH and Etienne, M}, title = {Cardiac Autonomic Dysfunction and Sudden Cardiac Death in Amyotrophic Lateral Sclerosis: Clinical Implications and Considerations for Care.}, journal = {Cardiology in review}, volume = {}, number = {}, pages = {}, doi = {10.1097/CRD.0000000000001392}, pmid = {42441693}, issn = {1538-4683}, abstract = {Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a motor neuron disease that progresses from muscular weakness to respiratory failure and death. Increasing evidence, however, demonstrates clinically meaningful involvement of the autonomic nervous system, particularly in cardiovascular regulation. This narrative review synthesizes current evidence on the mechanisms, clinical implications, and palliative considerations of cardiac autonomic dysfunction in ALS, with particular emphasis on its relationship to sudden cardiac death (SCD). Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation. These derangements may contribute to malignant arrhythmias, increasing susceptibility to SCD in combination with respiratory decline. Epidemiologic data suggest that SCD accounts for a meaningful proportion of ALS-related mortality, although it is likely underrecognized due to misclassification and lack of routine cardiac monitoring. Clinical implications include the need for improved risk stratification and earlier detection of autonomic dysfunction using accessible markers, such as electrocardiographic indices, orthostatic vital signs, and ambulatory monitoring. Emerging technologies, including wearable biosensors, may further enhance longitudinal assessment. These considerations also have direct relevance for advanced care planning, as ALS may involve unpredictable and abrupt cardiac death in addition to progressive respiratory decline. Recognizing ALS as a multisystem disorder with significant cardiac involvement supports the integration of structured cardiovascular monitoring into multidisciplinary care models and highlights the need for prospective studies to guide standardized management strategies.}, } @article {pmid42442024, year = {2026}, author = {Andreeva, T and Tuparev, N and Taneva, SG}, title = {Multimodal biophysical markers of neurodegeneration: Morphology, mechanics, and thermodynamics.}, journal = {Current opinion in structural biology}, volume = {100}, number = {}, pages = {103330}, doi = {10.1016/j.sbi.2026.103330}, pmid = {42442024}, issn = {1879-033X}, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Neurodegenerative Diseases/pathology/diagnosis/metabolism/blood ; Thermodynamics ; Animals ; *Biophysical Phenomena ; Biomechanical Phenomena ; }, abstract = {The identification of novel noninvasive biomarkers remains a major challenge in the diagnosis of neurodegenerative diseases. Significant efforts focus on fluid biomarkers, including proteins, peptides, and miRNAs, detectable in blood plasma and peripheral blood cells. Here, we review recent findings on blood plasma and peripheral blood cells physical parameters in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis emphasizing atomic force microscopy and calorimetry assay. Alterations in morphology, nanostructure, and stiffness of red blood cells and platelets, together with thermodynamic signatures of red blood cells and plasma, provide sensitive indicators of disease-related changes. These integrated biophysical parameters not only distinguish neurodegeneration from healthy states but also enable discrimination among different neurodegenerative disorders, highlighting their potential as minimally invasive diagnostic markers.}, } @article {pmid42442754, year = {2026}, author = {Sonnenberg, A and Bakis, LK and Kohen, R}, title = {Gastrointestinal Diagnoses and Symptoms in Medicare Patients With Neuropsychiatric Diseases.}, journal = {Journal of clinical gastroenterology}, volume = {60}, number = {9}, pages = {835-840}, doi = {10.1097/MCG.0000000000002422}, pmid = {42442754}, issn = {1539-2031}, mesh = {Humans ; Female ; Male ; United States/epidemiology ; *Gastrointestinal Diseases/epidemiology/diagnosis/etiology ; Aged ; *Medicare/statistics & numerical data ; Aged, 80 and over ; *Mental Disorders/complications/epidemiology ; Middle Aged ; *Nervous System Diseases ; Bipolar Disorder/epidemiology ; Deglutition Disorders/epidemiology ; }, abstract = {BACKGROUND AND AIMS: Many patients with psychiatric and neurological diseases suffer from gastrointestinal symptoms. Our study aimed to analyze the frequency of gastrointestinal disease in patients with underlying neuropsychiatric diagnoses.

METHODS: The study utilized the 2018 Inpatient Standard Analytic File of the Centers for Medicare and Medicaid Services (CMS), which contains the electronic health records of 6,462,321 unique patients. The concurrence of 2 diagnoses was assessed by calculating odds ratios (OR) with their 95% CIs, adjusted for the confounding influences of demographic characteristics (age, sex, ethnicity).

RESULTS: Dementia was most strongly associated with dysphagia (2.85, 2.83 to 2.88). Schizophrenia was associated with functional GI disorders (1.62, 1.60 to 1.64), constipation (1.67, 1.65 to 1.69), and dyspepsia (2.02, 1.88 to 2.17). Bipolar disorder was most significantly associated with irritable bowel syndrome (1.83, 1.79 to 1.87) and dyspepsia (1.88, 1.77 to 2.01). Depression was significantly associated with all types of upper and lower GI symptoms with significant ORs ranging from 1.33 to 2.14. Amyotrophic lateral sclerosis was strongly associated with complaints of functional GI disorder (2.32, 2.18 to 2.46), constipation (2.37, 2.23 to 2.51), dysphagia (11.77, 11.19 to 12.39), flatulence and bloating (2.75, 2.14 to 3.54). Parkinson disease was mostly associated with constipation (1.79, 1.77 to 1.82) and dysphagia (2.96, 2.92 to 3.00). In Alzheimer disease, only symptoms of dysphagia (2.15, 2.12 to 2.17) stood out. Multiple sclerosis was associated with most GI diagnoses (OR ranging from 1.32 to 2.06), except for abdominal pain and reflux symptoms.

CONCLUSIONS: Concurrence of gastrointestinal and neuropsychiatric diagnoses is common. Caring for patients with neuropsychiatric diseases, physicians need to be aware of and proactively search for the presence of concurrent gastrointestinal disease.}, } @article {pmid42442908, year = {2026}, author = {Dongre, S and Soni, N and Bissa, B}, title = {Role of ESCRT pathway and autophagy in neurodegenerative diseases.}, journal = {International review of neurobiology}, volume = {187}, number = {}, pages = {1-16}, doi = {10.1016/bs.irn.2026.05.022}, pmid = {42442908}, issn = {2162-5514}, mesh = {Humans ; *Endosomal Sorting Complexes Required for Transport/metabolism ; *Autophagy/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; }, abstract = {Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss resulting from impaired proteostasis and vesicular trafficking. Neurons are particularly vulnerable to these processes due to their post-mitotic nature and complex architecture. Autophagy and the endolysosomal system constitute the primary degradative pathways responsible for maintaining neuronal homeostasis. However, increasing evidence indicates that their effective function critically depends on coordination with the endosomal sorting complexes required for transport (ESCRT). Beyond their canonical role in multivesicular body biogenesis and membrane scission, ESCRT components are now recognized as essential regulators of autophagosome closure, amphisome formation, autophagosome-lysosome fusion, and endolysosomal membrane repair. Disruption of this ESCRT-autophagy interface has emerged as a common pathological feature across major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia. This review synthesizes evidence from genetic, biochemical, and neuropathological studies to highlight shared molecular nodes, such as ESCRT-III components, the VPS4 ATPase, the adaptor protein ALIX, and late endosomal regulators, including Rab7, that couple membrane remodeling to autophagic flux. Failure of these regulatory checkpoints destabilizes endolysosomal integrity, arrests autophagic maturation, and promotes the accumulation of toxic protein species, thereby driving progressive neuronal degeneration. By framing neurodegeneration through the lens of ESCRT-autophagy coupling failure, this review provides a unified mechanistic perspective that links diverse pathogenic proteins to shared cellular vulnerabilities and identifies ESCRT-mediated membrane dynamics as a critical determinant of neuronal survival.}, } @article {pmid42443201, year = {2026}, author = {Wang, Y and Hu, W and Huang, R and Wu, F and Su, H and Zang, J and Huang, X and Liu, Y and Ren, H and Li, J and Zhang, M and Zhang, Y and Wang, G and Hao, Z}, title = {Nuclear condensates formed by truncated mutant NEK1s impede ribosomal RNA biogenesis and drive motor dysfunction.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42443201}, issn = {2041-1723}, support = {32000676//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {*NIMA-Related Kinase 1/genetics/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology ; *RNA, Ribosomal/metabolism/genetics/biosynthesis ; Humans ; Mice ; *Cell Nucleus/metabolism ; Mice, Transgenic ; Drosophila melanogaster ; Mutation ; Codon, Nonsense ; Disease Models, Animal ; }, abstract = {NIMA-related kinase 1 (NEK1), a serine/threonine kinase, is a risk variant for amyotrophic lateral sclerosis (ALS). While the full-length NEK1 is involved in diverse cellular processes, such as DNA damage response and microtubule stability, the pathogenic mechanism of NEK1 nonsense mutations in ALS remains elusive. Here, we demonstrate that three truncated forms of NEK1 derived from ALS-related NEK1 nonsense mutations translocate from the cytoplasm to the nucleus, exhibit nucleolar localization, and simultaneously form liquid-like nucleoplasmic foci. In contrast to the diffuse cytoplasmic distribution of wild-type NEK1, these nuclear-localized truncated mutants are prone to undergo liquid-liquid phase separation both in cells and in vitro. Mechanistically, the truncated NEK1s interact with the nucleolar protein FBL, thereby impairing ribosomal RNA biogenesis and translation. Transgenic flies expressing truncated mutant NEK1s display motor dysfunction and reduced survival length, and a knock-in transgenic mouse model expressing ALS-related NEK1 mutant similarly exhibits motor deficits accompanied by ribosomal RNA dysregulation. These findings suggest that ALS-related NEK1 mutants expressing truncated forms of NEK1 cause cell toxicity by interfering with ribosomal RNA metabolism and reveal a gain-of-function mechanism in ALS pathogenesis involving NEK1.}, } @article {pmid42443387, year = {2026}, author = {Kim, WS and Halliday, GM}, title = {Astrocytic lipid dysregulation as an early driver of neurodegeneration.}, journal = {Nature reviews. Neurology}, volume = {22}, number = {8}, pages = {485-497}, pmid = {42443387}, issn = {1759-4766}, mesh = {Humans ; *Astrocytes/metabolism/pathology ; *Lipid Metabolism/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Homeostasis/physiology ; Neurons/metabolism/pathology ; }, abstract = {Astrocytes have traditionally been cast as supportive glia, but they are increasingly recognized as metabolic hubs that regulate cholesterol synthesis, fatty acid detoxification, lipid droplet dynamics and redox homeostasis in the CNS. Neurons have a limited intrinsic capacity for lipid storage and detoxification and rely heavily on astrocytes to maintain a safe lipid environment. Emerging evidence indicates that dysregulation of astrocytic lipid homeostasis precedes overt neuronal degeneration in a range of neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia and Huntington disease. Perturbations in astrocytic lipid handling can drive maladaptive reactive states, promote oxidative stress, impair lysosomal and mitochondrial function and disrupt neuron-glia lipid exchange, collectively creating an environment that leads to neurodegeneration. Therefore, lipid dysregulation within astrocytes could trigger or amplify neuronal vulnerability. In this Review, we assess evidence that astrocytic lipid metabolism is not solely protective or pathological but has instructive physiological roles and that astrocytic lipid dysregulation is an early driver of neurodegeneration. We critically evaluate disease-specific evidence, distinguishing correlative observations from causal mechanisms. We propose that targeting of astrocytic lipid homeostasis represents a promising strategy for preventing or minimizing neurodegeneration and opens new avenues for early detection and biomarker development.}, } @article {pmid42444959, year = {2026}, author = {Akpa, B}, title = {The role of radiologic assessment in evaluating and monitoring respiratory function in amyotrophic lateral sclerosis (ALS) patients: a narrative review.}, journal = {Journal of thoracic disease}, volume = {18}, number = {6}, pages = {672}, pmid = {42444959}, issn = {2072-1439}, abstract = {BACKGROUND AND OBJECTIVE: Respiratory failure is the primary cause of mortality in amyotrophic lateral sclerosis (ALS), usually caused by progressive neuromuscular respiratory weakness. Standard pulmonary function tests (PFTs) such as maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and both supine and upright forced vital capacity (FVC) are crucial for objective measurements of diaphragmatic weakness but have limitations, including dependence on the patient's performance and the inability to detect early, subclinical diaphragmatic impairment or be used effectively in patients with bulbar symptoms. Radiological assessments, particularly dynamic imaging, have emerged as potential objective tools for evaluating respiratory function. This review comprehensively summarizes findings on the use of diaphragmatic ultrasound (DUS), dynamic chest magnetic resonance imaging (MRI) and deep learning (DL)-based chest computed tomography (CT) for assessing lung function in ALS patients.

METHODS: Key radiological metrics include diaphragm thickness (DT), thickening fraction during inspiration, real-time diaphragmatic excursion, lung diameter changes and changes in pulmonary length and area. These measures have been compared with conventional PFTs in various studies to validate their use for diagnostic accuracy, particularly in early stages of disease.

KEY CONTENT AND FINDINGS: DUS is a non-invasive, widely available tool that strongly correlates with PFT measurements, especially FVC, MIP, and sniff nasal inspiratory pressure (SNIP). Dynamic measures, such as excursion and velocity, appear more sensitive to early dysfunction than thickness alone. Chest dynamic MRI has also shown significant correlations with spirometric parameters. Small cohort studies indicate that dynamic chest MRI is a superior, sensitive tool for detecting early respiratory impairment in asymptomatic patients with normal spirometry.

CONCLUSIONS: Radiological assessments, primarily DUS, DL-based chest CT and dynamic MRI, offer valuable, objective, and non-invasive methods for monitoring respiratory muscle strength in ALS. These techniques serve as complementary tools to traditional PFTs, particularly in selected clinical scenarios such ALS patients with early disease, bulbar involvement and unable to perform PFTs. Further longitudinal research with larger cohorts is needed to standardize protocols and validate their role as early parameters to guide the timely initiation of supportive interventions like non-invasive ventilation (NIV).}, } @article {pmid42445484, year = {2026}, author = {Ahmed, R and Kayande, A and Patil, R and Shelar, A and Zore, GB}, title = {Context-dependent reprogramming of ALS adhesin expression in Candida albicans: a multi-inducer analysis linking morphogenesis to virulence plasticity.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1848556}, pmid = {42445484}, issn = {1664-302X}, abstract = {Candida albicans employs the ALS (Agglutinin-Like Sequence) gene family to encode cell-surface adhesins that are central to host colonization, tissue invasion, and biofilm formation. Although individual ALS genes have been studied under specific conditions, no systematic, multi-inducer temporal analysis of the entire family has been reported to date. In this study, we present the first comprehensive temporal expression profiling of seven ALS genes (ALS1-ALS5, ALS7, and ALS9) under six host-relevant inducers, temperature (37 °C), neutral pH, serum, glucose, N-acetylglucosamine (NAG), and proline, across four time points (45 min, 90 min, 3 h, 6 h) in both yeast (30 °C) and hyphal (37 °C) growth phases. Morphological analysis confirmed that 37 °C and serum were the most potent hyphal inducers (94.13 ± 0.94% hyphae with serum at 37 °C). Quantitative PCR revealed a temporally stratified regulatory program: early-phase adhesins (ALS1, ALS2) showed transient induction during the first 90 min, whereas invasion-associated genes exhibited sustained late-phase activation. Notably, ALS3 displayed exceptional upregulation under glucose at 37 °C (25.17 ± 1.76-fold at 6 h; p < 0.001) and responded robustly to all inducers except serum. ALS7 reached 9.48-fold induction specifically under thermal stress, while ALS5 was preferentially expressed at 30 °C (6.70-fold under neutral pH), indicating niche-specific functional specialization. In silico promoter analysis linked these expression patterns to binding motifs for key transcription factors (Efg1, Cph1, Rim101, and Nrg1). Phylogenetic analysis revealed functional conservation of ALS2/ALS4 versus evolutionary divergence in ALS6/ALS7/ALS9. STRING-based protein interaction networks confirmed the central involvement of ALS proteins in adhesion and biofilm regulatory circuits. These findings establish a molecular framework for niche-specific virulence, identifying ALS3 as a prime therapeutic target for anti-adhesion strategies in invasive candidiasis. We hypothesize that C. albicans employs a temporally stratified and inducer-specific transcriptional program of the ALS family to adapt its surface architecture to diverse host microenvironments.}, } @article {pmid42447123, year = {2026}, author = {Wohnrade, C and Thau-Habermann, N and Gschwendtberger, T and Rückoldt, J and Huang, Z and Schreiber, S and Haastert-Talini, K and Petri, S}, title = {Neuromuscular ultrasound as a biomarker in the SOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {21}, number = {7}, pages = {e0353397}, pmid = {42447123}, issn = {1932-6203}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/genetics/physiopathology ; Mice ; *Superoxide Dismutase/genetics ; Disease Models, Animal ; Superoxide Dismutase-1 ; Biomarkers/metabolism ; Ultrasonography ; Mice, Transgenic ; Humans ; Sciatic Nerve/diagnostic imaging/pathology ; Muscle, Skeletal/diagnostic imaging/pathology ; Motor Neurons/pathology ; Disease Progression ; }, abstract = {A progression marker that indicates early disease-related changes and treatment responses in the to date incurable neurodegenerative disease amyotrophic lateral sclerosis (ALS) is highly desirable. Translation of therapeutics that have been successful in in vivo models into trials in human patients has proven difficult in recent decades. This failure can be attributed, at least in part, to the lack of specific biomarkers for ALS diagnosis and progression in human ALS patients as well as in in vivo models. Neuromuscular ultrasound is an easily accessible, non-invasive tool to support diagnosis of ALS in humans. Our current study shows for the first time that the disease can be detected in an ALS mouse model with the help of neuromuscular ultrasound. We characterized disease progression regarding changes in the peripheral nerves and muscles of the hind limb in the SOD1G93A mouse model of ALS using different techniques (neuromuscular ultrasound, electroneurography, motor function tests, phenotypic assessments and histology). By neuromuscular ultrasound, we measured the cross-sectional area and diameter of the sciatic nerve and analyzed hind limb muscle texture and thickness. Our results show that motor neuron loss and muscle atrophy - analogous to ALS in humans - can be measured by ultrasound in the SOD1G93A mouse model. Changes in nerve and muscle morphology appear at the same time or even before changes in the established tests (including electroneurographic measurements) performed in vivo in this model. Correlations with histologic features of disease progression make neuromuscular ultrasound a sensitive, non-invasive outcome marker for preclinical studies.}, } @article {pmid42447443, year = {2026}, author = {Hicks-Courant, K}, title = {Taking Responsibility.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {44}, number = {24}, pages = {2353-2355}, doi = {10.1200/JCO-25-02100}, pmid = {42447443}, issn = {1527-7755}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Female ; Male ; Gynecologists ; }, abstract = {This essay is about how caring for my complicated father with amyotrophic lateral sclerosis (ALS) unexpectedly shaped how I approached my work as a gynecologic oncologist.}, } @article {pmid42447895, year = {2026}, author = {Arnolds, KB and Peinemann, F}, title = {[Infant-driven versus Practitioner-driven Feeding of Preterm Infants: A Systematic Review of Randomized Controlled Trials].}, journal = {Zeitschrift fur Geburtshilfe und Neonatologie}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2894-2931}, pmid = {42447895}, issn = {1439-1651}, abstract = {HINTERGRUND: Voraussetzung für eine erfolgreiche orale Ernährung ist die Berücksichtigung des individuellen Entwicklungsstands der Frühgeborenen. Pflegekräfte und Eltern sollten geschult sein, wie sie Verhaltenssignale des Säuglings während des Fütterns erkennen und darauf angemessen reagieren können. Diese Art der Ernährung wird in dieser Arbeit als "signalorientiertes und co-reguliertes" Füttern von Frühgeborenen bezeichnet. Im Unterschied zeichnet sich das "herkömmliche" Füttern dadurch aus, dass eine vorab festgelegte Flüssigkeitsmenge zu einer festgelegten Zeit verabreicht wird.

ZIELSETZUNG: Es soll untersucht werden, ob das "signalorientierte und co-regulierte" Füttern im Vergleich zum "herkömmlichen" Füttern zu einer früheren vollständigen oralen Ernährung führen kann.

METHODEN: Wir haben am 26. Juni 2024 in den elektronischen Datenbanken MEDLINE und Cochrane Library nach thematisch relevanten randomisierten Studien gesucht. Als primärer Endpunkt wurde die Anzahl der Tage bis zur vollständigen oralen Ernährung und als Effektmaß die mittlere Differenz gewählt. Die Metaanalyse wurde unter Verwendung der inversen Varianzmethode und des Random-Effects-Modells durchgeführt, und wir verwendeten den GRADE-Ansatz (Grading of Recommendations Assessment, Development, and Evaluation) für die Bewertung der Evidenz.

ERGEBNISSE: In der Studienauswahl fanden sich 12 randomisierte Studien, die den Einschlusskriterien entsprachen. Von diesen wurden 5 Studien in eine Metaanalyse einbezogen. Die geschätzte mittlere Differenz favorisierte die Gruppen mit signalorientiertem und co-reguliertem Füttern im Vergleich zu den Gruppen mit herkömmlicher Fütterung: -4,93 (95%-Konfidenzintervall -6,60 bis -3,26, p<0,00001, I[2] =66%). Die Qualität der Evidenz wurde als moderat eingestuft.

SCHLUSSFOLGERUNGEN: Die Daten der Studienteilnehmer sind mit einem leicht vorteilhaften Effekt für die signalorientierte und co-regulierte Ernährung von Frühgeborenen im Vergleich zur herkömmlichen Ernährung von Frühgeborenen vereinbar. Zukünftige Studien könnten weitere Daten zu unerwünschten Ereignissen während der Ernährung und Informationen zur häuslichen Nachsorge ergänzen.}, } @article {pmid42448407, year = {2026}, author = {Rangappa, N and Upadhyay, R and Lakshman, N and Ramasamy, S and Sevanan, M and Justin, A and Chinnathambi, S}, title = {Small molecular therapeutic targets for neurodegenerative diseases.}, journal = {Advances in protein chemistry and structural biology}, volume = {153}, number = {}, pages = {135-167}, doi = {10.1016/bs.apcsb.2025.10.012}, pmid = {42448407}, issn = {1876-1631}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology/genetics ; Animals ; *Molecular Targeted Therapy ; }, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis disease are characterized by progressive neuronal loss, protein aggregation, and synaptic dysfunction. These diseases share common pathological mechanisms including oxidative stress, mitochondrial impairment, chronic neuroinflammation, protein misfolding, and epigenetic dysregulation. Current therapies offer only symptomatic relief and fail to halt disease progression. Recent advances in transcriptomics and proteomics have enabled the identification of shared molecular pathways and druggable targets across multiple neurodegenerative diseases. The key targets, such as BDNF-TrkB, TREM2, SIRT1, PINK1-Parkin, GSK-3β, NLRP3, and mTOR have shown promise in preclinical models, offering opportunities for broad-spectrum therapeutic development. Importantly, blood-brain barrier disruption and neuroinflammatory crosstalk exacerbate disease pathology and hinder drug delivery. Innovative strategies involving nanocarriers, gene therapy, and epigenetic modulation are emerging to overcome these barriers. This review highlights the convergence of disease mechanisms, discusses common molecular signatures and therapeutic vulnerabilities, and explores novel small molecular interventions targeting shared pathways mainly in AD and PD. A deeper understanding of aging-associated molecular dysfunction is essential to design sustainable, disease-modifying therapeutics with cross-disease relevance.}, } @article {pmid42449472, year = {2026}, author = {de Albuquerque Bueno, MG and Dos Santos, DF and Rossor, AM and Laura, M and Horga, A and Frezatti, RSS and de Sousa Ferreira, EV and Blake, JC and Morrow, JM and Reilly, MM and Marques Júnior, W and Tomaselli, PJ}, title = {VRK1-Related Motor Neuropathy With Upper Motor Neuron Signs and Selective Muscle Involvement.}, journal = {Journal of the peripheral nervous system : JPNS}, volume = {31}, number = {3}, pages = {e70145}, pmid = {42449472}, issn = {1529-8027}, support = {MR/S005021/1//International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD)/ ; 25000.160.096/2014-07//Programa Nacional de Apoio à Atenção da Saúde da Pessoa com Deficiência (PRONAS)/ ; 465 458/20114-9//National Institute of Sciences and Technology (INCT)-Translational Medicine/ ; 310378/2021-4//Conselho Nacional de Pesquisa (CNPq)/ ; FE-CLI-24-0005-05//Biogen/ ; }, mesh = {Humans ; Female ; Male ; *Motor Neuron Disease/genetics/physiopathology/diagnostic imaging/pathology ; *Protein Serine-Threonine Kinases/genetics ; Adult ; Middle Aged ; Magnetic Resonance Imaging ; *Intracellular Signaling Peptides and Proteins/genetics ; *Muscle, Skeletal/physiopathology/diagnostic imaging/pathology ; Nerve Conduction Studies ; Young Adult ; Electromyography ; Neural Conduction/physiology ; Adolescent ; Child ; }, abstract = {INTRODUCTION: Hereditary motor neuropathies (HMN) represent a heterogeneous group of disorders with wide clinical and genetic variability. Despite advances in molecular diagnostics, approximately 50% of cases remain genetically unresolved, particularly those where distinguishing length-dependent motor neuropathy from motor neuron disorder with disproportionate segmental involvement is a challenge. Variants in the VRK1 gene, originally described in association with pontocerebellar hypoplasia, are now known to produce a broad clinical spectrum, including amyotrophic lateral sclerosis, dHMN, and less frequently, spastic paraplegia.

OBJECTIVES: This study's aim was to characterize the clinical presentation, electrophysiological findings, and muscle MRI patterns associated with VRK1-related motor neuron disease in a cohort of nine patients from five unrelated families.

METHODS: Five unrelated families with inherited motor neuropathy were investigated using next-generation sequencing techniques, including targeted gene panels or whole-exome sequencing, with subsequent confirmation by Sanger sequencing. A total of nine affected individuals underwent detailed clinical evaluation, nerve conduction studies (NCS), electromyography (EMG), and whole-body muscle MRI (wbMRI).

RESULTS: Nine affected individuals carrying biallelic VRK1 variants were evaluated. In most cases (66%), symptom onset occurred during the first decade of life. All patients presented with gradually progressive distal muscle weakness. Mean Medical Research Council (MRC) scores were 2.8 for ankle dorsiflexion and 1.9 for plantar flexion. Sensory nerve conduction studies were normal in all individuals evaluated (8/9), although mild sensory complaints were reported in four patients. Muscle cramps were observed in two-thirds of the cohort, while fasciculations were uncommon (11%). EMG findings consistently demonstrated a neurogenic pattern with predominant distal involvement, and evidence of both acute and chronic denervation was present in four patients. Whole-body muscle MRI, available for all patients, revealed a consistent pattern of fatty infiltration predominantly affecting posterior muscle compartments, with minimal STIR signal changes. Brain and spinal imaging, performed in all individuals, showed no abnormalities.

INTERPRETATIONS: Biallelic mutations in VRK1 are associated with a recognizable form of motor neuron disease characterized by features of dHMN combined with upper motor neuron involvement, along with a distinctive posterior-predominant pattern on muscle MRI. Identifying this phenotype, a known presentation of VRK1-related disorders, highlights the importance of targeted genetic testing in unresolved cases of hereditary motor neuropathy.}, } @article {pmid42450002, year = {2026}, author = {Kim, Y and Jung, YK}, title = {Proteasome Dysfunction and Aggregation-Prone Proteins in Neurodegenerative Diseases: From Mechanisms to Therapeutic Opportunities.}, journal = {International journal of molecular sciences}, volume = {27}, number = {13}, pages = {}, pmid = {42450002}, issn = {1422-0067}, support = {RS-2025-00519823//National Research Foundation of Korea/ ; RS-2024-00439842//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Proteasome Endopeptidase Complex/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/pathology/drug therapy ; Animals ; Proteostasis ; *Protein Aggregation, Pathological/metabolism ; *Protein Aggregates ; Proteotoxic Stress ; Ubiquitin/metabolism ; Proteolysis ; Oxidative Stress ; }, abstract = {Neurodegenerative diseases are characterized by the accumulation of misfolded and aggregation-prone proteins, reflecting a failure of proteostasis. The ubiquitin-proteasome system (UPS), a major pathway for selective intracellular protein degradation, is essential for maintaining neuronal protein homeostasis. Proteasome dysfunction has been implicated in several major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), although its extent and mechanisms vary across disease contexts. In this review, we examine current evidence for proteasome dysfunction in neurodegeneration and discuss how disease-associated proteins impair proteasome function through direct inhibition, defective substrate processing, and sequestration into protein aggregates. We also address the contribution of oxidative stress, neuroinflammation, and aging to proteasome dysregulation. Finally, we highlight emerging therapeutic strategies aimed at restoring proteasome function, including pharmacological activation, modulation of proteasome assembly and stability, and targeted protein degradation approaches. Understanding the context-dependent nature of proteasome dysfunction will be important for developing effective proteostasis-based therapies.}, } @article {pmid42451086, year = {2026}, author = {Soni, N and Debnath, N and Rekapally, E and Jabbar, A and Tyagi, SC and Bissa, B and Tyagi, N}, title = {Vitamin D Signaling in Neurodegenerative Disorders: Mechanisms, Therapeutic Potential, and Clinical Implications.}, journal = {Nutrients}, volume = {18}, number = {13}, pages = {}, pmid = {42451086}, issn = {2072-6643}, support = {971566; 24 TPA1304527 and 25 TPA1481771 to Neetu Tyagi.//American Heart Association/ ; }, mesh = {Humans ; *Vitamin D/metabolism/therapeutic use ; *Neurodegenerative Diseases/metabolism/drug therapy/etiology ; *Signal Transduction ; Vitamin D Deficiency/complications ; Animals ; Oxidative Stress/drug effects ; Receptors, Calcitriol/metabolism ; Blood-Brain Barrier/metabolism ; Neuroprotective Agents ; }, abstract = {Vitamin D has long been recognized for its role in calcium homeostasis and bone metabolism; however, it is now emerging as an important regulator of central nervous system (CNS) function. Recent evidence suggests that vitamin D signaling contributes to the pathogenesis and progression of several neurodegenerative disorders. Vitamin D exerts neuroprotective effects through multiple mechanisms, including regulation of calcium homeostasis, modulation of immune responses, reduction in oxidative stress, stimulation of neurotrophic factors, and maintenance of blood-brain barrier (BBB) integrity. Vitamin D receptors and metabolizing enzymes are widely distributed across several brain regions, highlighting their direct involvement in neuronal function. This review summarizes the biosynthesis, metabolism, and signaling pathways of vitamin D. It explores its role in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, and traumatic brain injury (TBI). Evidence from experimental and clinical studies indicates that vitamin D deficiency is associated with an increased risk and severity of these conditions, while supplementation may provide therapeutic benefits.}, } @article {pmid42451691, year = {2026}, author = {Singh, AA and Arukha, AP and Song, M}, title = {Indole-Derived Compounds as Redox-Modulators: Antioxidant Mechanisms in Neuronal Protection.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {13}, pages = {}, pmid = {42451691}, issn = {1420-3049}, mesh = {Humans ; *Antioxidants/pharmacology/chemistry ; *Indoles/chemistry/pharmacology ; Animals ; *Neuroprotective Agents/pharmacology/chemistry ; Oxidation-Reduction/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neurons/drug effects/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis, are distinguished by progressive neuronal dysfunction caused primarily by oxidative stress, mitochondrial impairment, neuroinflammation, and redox imbalance. Growing evidence suggests that indole-derived compounds have significant neuroprotective potential due to their antioxidant, anti-inflammatory, and redox-modulating properties. This review summarizes the structural and biological significance of indole scaffolds, focusing on the mechanisms by which natural, endogenous, microbiota-derived, and synthetic indole compounds protect neuronal networks. Indole-3-carbinol, 3,3'-diindolylmethane, indole-3-propionic acid, and melatonin are major indole derivatives that control important neuroprotective pathways like Nrf2/ARE signaling, mitochondrial bioenergetics, neurotrophic factor expression, apoptotic regulation, and suppression of proinflammatory mediators. These compounds also maintain synaptic plasticity, reduce reactive oxygen species production, and improve neuronal survival in neurodegenerative disease models. Additionally, updated information from translational and clinical research indicates that indole-based compounds may have promising therapeutic applications; however, obstacles like low bioavailability, metabolic instability, and blood-brain barrier penetration continue to be major obstacles to clinical application. Development in nanoparticle delivery systems, microbiome-targeted interventions, and rational structural optimization may improve therapeutic efficacy and translational potential. Overall, indole-derived compounds are a versatile class of redox modulators with potential applications in the prevention and treatment of neurodegenerative diseases via integrated antioxidant and neuroprotective mechanisms.}, } @article {pmid42453524, year = {2026}, author = {Yang, HI and Hsueh, KW and Ding, DC and Harn, HJ and Lin, YC and Chang, CY and Tsai, ST and Lin, SZ}, title = {Therapeutic potential of adipose-derived stem cell transplantation in amyotrophic lateral sclerosis: A combined clinical case and preclinical study.}, journal = {Tzu chi medical journal}, volume = {38}, number = {3}, pages = {332-339}, pmid = {42453524}, issn = {2223-8956}, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal neurodegenerative disease with no adequate treatment. Transplantation of adipose-derived stem cells (ADSCs) may be an effective therapeutic strategy for delaying progression or restoring neurological function in ALS.

MATERIALS AND METHODS: We evaluated the safety and therapeutic efficacy of intravenous (i.v.) and intracerebral (i.c.) ADSC injection in a late-stage ALS patient and in a SOD1 transgenic (Tg) mouse model. Magnetic resonance imaging (MRI) and computed tomography (CT) were conducted to examine potential cerebral hemorrhage and tumor generation in the treated patient. In addition, maximal inspiratory pressure, maximal expiratory pressure, tidal volume, and respiratory rate were measured as indices of respiratory function.

RESULTS: ADSC transplantation was safe, with MRI and CT showing no hemorrhage or tumorigenesis up to 12 months. The patient's Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score improved from 7 to 9 at 3 months and remained above baseline for 6 months. Respiratory function was preserved during this period. In SOD1 Tg mice, i.c. and i.v. ADSC infusion significantly prolonged survival (165.0 ± 10.4 and 147.3 ± 4.5 days vs. 129.7 ± 3.9 days) and improved motor scores (P < 0.01).

CONCLUSION: This preliminary finding suggests potential therapeutic feasibility, but further studies with larger cohorts are needed to confirm its safety and efficacy.}, } @article {pmid42454381, year = {2026}, author = {Mai, R and Zhang, X and Yu, G and Chen, Z and Zhao, W and Shi, Z and Gao, X and Liang, Z and Fu, C}, title = {Robust Covalent Organic Frameworks Comprising Accessible Catalytic Sites Enable Fast-Charging and Long-Cycling Aluminum-Sulfur Batteries.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {38}, number = {47}, pages = {e74063}, pmid = {42454381}, issn = {1521-4095}, abstract = {Rechargeable aluminum-sulfur (Al-S) batteries are recognized as a promising option for large-scale energy storage due to high theoretical energy density and cost-effectiveness. However, the sulfur cathodes suffer from sluggish reaction kinetics and severe shuttle effect during cycling. Here we report robust two-dimensional covalent organic frameworks (COFs) as sulfur hosts that features accessible catalytic nitrogen sites and confined microporous channels. The fine regulation of different microporous sizes was achieved by controlling different-length organic ligands of various COFs, finally preparing two kinds of COFs. The sensitive comparation between both COFs demonstrates that smaller microporous channels in COFs possess higher confinement effect for polysulfides due to the stronger capillary forces, facilitating higher Coulombic efficiency and better cycling stability in Al-S batteries. Meanwhile, experimental characterizations and theoretical calculations reveal that accessible catalytic nitrogen sites in COFs promote the multistep conversion kinetics of the sulfur cathode during cycling. Consequently, the small-sized COF confined sulfur cathode exhibits a reversible capacity of 1120 mAh g[-1] at 0.2C and a 93.5% capacity retention after 100 cycles, supporting high capacity and exceptional cycling stability. This work provides a new avenue on rational design of emerging COF materials in Al-S batteries.}, } @article {pmid42454435, year = {2026}, author = {Walls, M and Claffey, A and Galvin, M}, title = {Moral distress in healthcare professionals working with motor neuron disease.}, journal = {Palliative & supportive care}, volume = {24}, number = {}, pages = {e196}, pmid = {42454435}, issn = {1478-9523}, mesh = {Humans ; *Motor Neuron Disease/psychology/complications/therapy ; *Health Personnel/psychology/statistics & numerical data ; Cross-Sectional Studies ; Female ; Male ; Adult ; Europe ; Surveys and Questionnaires ; Middle Aged ; Ethical Dilemmas ; Quality of Life/psychology ; }, abstract = {OBJECTIVES: To (1) identify clinical situations that may contribute to the experience of moral distress (MD) among professionals working with motor neuron disease (MND), (2) measure the occurrence and intensity of MD, and (3) explore associations with professional quality of life, turnover intention, and associated risk and/or protective factors.

METHODS: A cross-sectional online survey was distributed to healthcare professionals working in MND services across Europe. Data were analyzed using descriptive and inferential statistics.

RESULTS: In total, 230 responses from professionals across 17 European countries were analyzed from the international survey. And 67% of respondents indicated that MD resonated with their experience of working with MND. Those who considered leaving or changing their position due to the challenges associated with caring for this patient population were also more likely to report resonance with MD (χ[2] = 7.772, p = 0.020). The intensity of MD was associated with reduced professional quality of life (burnout [β = 0.106, p < 0.05], and secondary traumatic stress [β = 2.881, p < 0.001]). A total of 24 clinical scenarios were identified as potential contributors to experiences of MD in this population. Across all professional groups, service-/organization-level factors were the most common and distressing barriers to providing effective MND care.

SIGNIFICANCE OF RESULTS: This study demonstrates that MD is experienced by healthcare professionals working with MND across Europe. MD was associated with reduced professional quality of life and increased intentions to leave or change positions, underscoring its potential implications for workforce retention and sustainability. The findings show that system/organization, patient/condition and family-level causes are the primary drivers of MD in this population. Future research should focus on evaluating the effectiveness of interventions designed to address these key drivers and mitigate the impact of MD among healthcare professionals working with MND.}, } @article {pmid42454523, year = {2026}, author = {Ahmed, RM and Tse, NY and Bocchetta, M and Dobson-Stone, C and Kwok, JB and Hodges, JR and Irish, M and Rohrer, JR and Piguet, O and Halliday, G}, title = {Changes in body composition in genetic C9orf72 carriers: The role of the hypothalamus and thalamus.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {7}, pages = {e71669}, pmid = {42454523}, issn = {1552-5279}, support = {//National Health and Medical Research Council/ ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *Body Composition/genetics ; Magnetic Resonance Imaging ; Female ; Male ; *Thalamus/diagnostic imaging ; *Frontotemporal Dementia/genetics ; *Hypothalamus/diagnostic imaging ; Heterozygote ; Middle Aged ; Absorptiometry, Photon ; Aged ; }, abstract = {BACKGROUND: Patients with sporadic frontotemporal dementia (FTD) display changes in metabolism and body composition. No studies have examined body composition changes in pre-symptomatic C9orf72 mutation carriers METHODS: Asymptomatic C9orf72 expansion carriers between 2017 and 2022 (n = 28 non-carriers, 16 expansion-positive), underwent dual-energy X-ray absorptiometry (measurement of changes in body composition) and brain magnetic resonance imaging (MRI).

RESULTS: Changes in body composition were identified in the C9orf72 expansion carrier group compared to non-carrier group (average 11-12 years prior to onset): lower android-to-gynoid ratio (p = 0.009), and visceral adipose tissue area (p = 0.010). Lower android-to-gynoid ratio and lean mass were associated with lower volumes across the cortex, subcortex, and thalamus.

CONCLUSIONS: The current study highlights that genetically at-risk C9orf72 patients exhibit altered body composition. These findings align with the growing recognition that changes in genetic frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) extend beyond cognitive/motor symptoms and include early alterations in broader physiological function.}, } @article {pmid42455190, year = {2026}, author = {Lei, Y and Huang, J and Li, M and Zhang, Y and Ye, Z and He, X and Tang, Z and Wei, J}, title = {Effects of respiratory muscle training on respiratory function in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology}, volume = {273}, number = {8}, pages = {}, pmid = {42455190}, issn = {1432-1459}, support = {No. EWT201947//Department of Science and Technology of Hubei Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation/complications/therapy ; *Breathing Exercises/methods ; *Respiratory Muscles/physiopathology ; }, abstract = {BACKGROUND: Respiratory decline is prognostically important in amyotrophic lateral sclerosis (ALS), but the efficacy of respiratory muscle training (RMT) remains uncertain. We synthesized randomized evidence on respiratory and related outcomes.

METHODS: We searched databases, specialized registers, and trial registries through June 19, 2025, for randomized RMT trials in ALS. Risk of bias was assessed with the Cochrane tool. Random-effects meta-analyses reported standardized mean differences (SMDs) with 95% confidence intervals (CIs), and certainty was rated with GRADE.

RESULTS: Six studies were included; five concurrently randomized trials contributed quantitative data, whereas Pinto 2013 was retained for qualitative context. RMT improved maximal expiratory pressure (MEP; SMD 0.387, 95% CI 0.192-0.581; P = 0.008) and showed small favorable effects on maximal inspiratory pressure (MIP; SMD 0.156, 95% CI 0.089-0.224; P = 0.005), sniff nasal inspiratory pressure (SNIP; SMD 0.216, 95% CI 0.039-0.392; P = 0.034), peak expiratory flow (PEF; SMD 0.205, 95% CI 0.088-0.323; P = 0.017), and ALSFRS-R (SMD 0.214, 95% CI 0.039-0.388; P = 0.030). Forced vital capacity showed a borderline favorable trend (SMD 0.129, 95% CI - 0.003 to 0.262; P = 0.053). Low heterogeneity estimates were imprecise because most endpoints included only three to four small studies. Certainty was moderate for MIP, low for MEP, FVC, and PEF, and very low for SNIP and ALSFRS-R. Exploratory analyses identified no reliable effect modifiers.

CONCLUSIONS: RMT was associated with small, directionally consistent improvements mainly in pressure- and flow-based outcomes, whereas effects on FVC and longer-term clinical outcomes remain uncertain. RMT may be considered an individualized adjunct to ALS respiratory care, not a disease-modifying therapy. Larger, longer, standardized trials with patient-important endpoints are needed.}, } @article {pmid42455475, year = {2026}, author = {Maity, D and Gowtham, A and Mishra, Y and Kaundal, RK}, title = {Exosome Biology at the Interface of Neurodegeneration and Therapeutic Innovation.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42455475}, issn = {1559-1182}, mesh = {Humans ; *Exosomes/metabolism ; Animals ; *Neurodegenerative Diseases/therapy/metabolism/pathology ; Biomarkers/metabolism ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are defined by progressive neuronal loss, protein misfolding, and chronic neuroinflammation, yet effective disease-modifying therapies remain absent. Exosomes have emerged as key mediators of central nervous system communication and are increasingly central to the biology of neurodegeneration. These nanoscale vesicles transport proteins, lipids, and nucleic acids across cellular and anatomical barriers, influencing synaptic function, immune signaling, and metabolic homeostasis. Under pathological conditions, exosomes facilitate the spread of misfolded proteins such as amyloid-β, p-tau, α-synuclein, and TDP-43, thereby accelerating network-level degeneration. At the same time, their cargo exhibits disease-specific molecular signatures detectable in peripheral biofluids, supporting their development as minimally invasive biomarkers for early diagnosis and longitudinal monitoring. Advances in exosome engineering further underscore their potential as therapeutic delivery vehicles capable of crossing the blood-brain barrier and targeting pathogenic pathways with RNA-based therapeutics, proteins, or gene-editing systems. Together, these findings position exosomes as pivotal contributors to both the mechanistic progression and translational targeting of neurodegenerative diseases.}, } @article {pmid42456096, year = {2026}, author = {Soliven, REMR and Igarashi, Y and Norii, T and Nakanishi, H and Suga, R and Takiguchi, T and Okada, I and Nakae, R and Yokobori, S and , }, title = {Performance of Termination-of-Resuscitation Rules in Foreign Body Airway Obstruction-Related Out-of-Hospital Cardiac Arrest: A Prospective Multicenter Registry Analysis.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/10903127.2026.2703842}, pmid = {42456096}, issn = {1545-0066}, abstract = {OBJECTIVES: Termination-of-resuscitation (TOR) rules were derived mainly from cardiac-origin out-of-hospital cardiac arrest (OHCA), but their interpretation in foreign body airway obstruction (FBAO)-related OHCA remains uncertain. This condition is a potentially reversible hypoxic arrest in which standard TOR criteria may perform differently. We evaluated the 2025 American Heart Association basic life support (BLS)-TOR and advanced life support (ALS)-TOR criteria in FBAO-related OHCA.

METHODS: This secondary analysis of the prospective Multi-center Observational CHoking Investigation (MOCHI) registry included patients with FBAO-related OHCA transported to 25 Japanese hospitals from April 2020 to March 2023. For the primary TOR analysis, we included patients who had not achieved return of spontaneous circulation (ROSC) before emergency medical services (EMS) arrival, because TOR rules are intended for patients who remain in cardiac arrest at the time of EMS assessment. Patients were retrospectively classified according to BLS-TOR and ALS-TOR criteria. Primary measures were the specificity of TOR-positive status for predicting unfavorable neurological outcome, defined as the proportion of patients with favorable neurological outcome (Cerebral Performance Category 1-2) who were classified as TOR-negative, and the proportion of TOR-positive patients who nevertheless achieved favorable neurological outcome.

RESULTS: Of 248 patients with FBAO-related OHCA (median age, 81.5 years; 83.1% witnessed), 49 (19.8%) survived to 30 days and 9 (3.6%) achieved favorable neurological outcome. The BLS-TOR rule classified 150/229 evaluable patients as TOR-positive; 2 achieved favorable neurological outcome (1.3%; 95% CI, 0.4-4.7; specificity, 77.8% [95% CI, 45.3-93.7]), and 20 survived to 30 days (13.3%; 95% CI, 8.8-19.7). The ALS-TOR rule classified 12/242 patients as TOR-positive; none achieved favorable neurological outcome, but 4 survived to 30 days (33.3%; 95% CI, 13.8-60.9).

CONCLUSIONS: In FBAO-related OHCA, BLS-TOR would have classified two patients with favorable neurological outcome as TOR-positive. The ALS-TOR rule was restrictive, but small numbers and 30-day survival among TOR-positive patients preclude firm safety conclusions. Termination-of-resuscitation criteria warrant cautious, etiology-aware interpretation when FBAO is suspected.}, } @article {pmid42456683, year = {2026}, author = {Bouzigues, A and Grassi, M and Cantoni, V and Premi, E and Bellini, S and Binetti, G and Logroscino, G and Russell, LL and Ferry-Bolder, E and Foster, PH and van Swieten, JC and Jiskoot, LC and Seelaar, H and Sanchez-Valle, R and Laforce, R and Graff, C and Galimberti, D and Vandenberghe, R and de Mendonça, A and Di Fede, G and Santana, I and Gerhard, A and Langheinrich, T and Levin, J and Nacmias, B and Otto, M and Bertoux, M and Lebouvier, T and Ducharme, S and Butler, C and le Ber, I and Bruffaerts, R and Solje, E and Kinnunen, M and Krüger, J and Finger, E and Tartaglia, MC and Masellis, M and Rowe, JB and Synofzik, M and Moreno, F and Ghidoni, R and Migliaccio, R and Rohrer, JD and Borroni, B and , }, title = {Survival estimates and their predictors in genetic frontotemporal dementia: an international, retrospective, cohort study.}, journal = {The Lancet. Neurology}, volume = {25}, number = {8}, pages = {731-740}, doi = {10.1016/S1474-4422(26)00197-3}, pmid = {42456683}, issn = {1474-4465}, mesh = {Humans ; *Frontotemporal Dementia/genetics/mortality/diagnosis ; Retrospective Studies ; C9orf72 Protein/genetics ; tau Proteins/genetics ; Female ; Male ; Middle Aged ; Aged ; Cohort Studies ; Progranulins/genetics ; Mutation ; Kaplan-Meier Estimate ; }, abstract = {BACKGROUND: What drives the heterogeneity of survival estimates in genetic frontotemporal dementia is unknown. We sought to understand the natural history and predictors of disease trajectory, which are crucial not only for effective care but also for the design of therapeutic clinical trials and efficacy evaluation.

METHODS: In this international, cohort study, we used the Kaplan-Meier method to retrospectively assess survival estimates in patients enrolled in the GENFI cohort, which included 32 research sites located in Belgium, Canada, Finland, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and the UK, and comprised participants carrying a causal C9orf72 expansion or a causal mutation in GRN or MAPT genes. Survival was calculated as the time from symptom onset to time of death or censoring date; median survival estimate for all patients was the primary endpoint. Cox proportional hazards models were used to identify predictors of survival, which were subsequently externally validated in an independent cohort. We further designed a structural equation model to assess the relationships between predictors, applying a least absolute shrinkage and selection operator method.

FINDINGS: Of 278 participants of the GENFI cohort included in this study, 160 (58%) were men and 118 (42%) were women. 162 died during follow-up (58%) and 116 were still alive (42%) on June 1, 2024, the chosen censoring date. 138 participants carried a C9orf72 expansion, 94 carried a GRN mutation, and 46 a MAPT mutation. 179 participants were diagnosed with behavioural variant frontotemporal dementia, 46 with primary progressive aphasia, and 31 with frontotemporal dementia-amyotrophic lateral sclerosis. 22 participants had other diagnoses. The median survival estimate for all patients with genetic frontotemporal dementia was 6·94 years (95% CI 6·59-7·80) from symptom onset. The median survival estimate for patients with GRN mutations was 6·63 years (6·08-7·98), for patients with a C9orf72 expansion was 7·04 years (6·45-8·77), and for patients with MAPT mutations was 8·56 years (7·06-13·50). Older age at onset, shorter disease duration from onset to enrolment in the GENFI study, clinical presentation (ie, frontotemporal dementia-amyotrophic lateral sclerosis), domain of first symptom (ie, motor or language onset), and geographical area of residency (ie, central and southern Europe) were associated with poorer prognosis. Genetic group did not directly affect survival estimates; rather its effect was mediated by age at onset and clinical phenotype. We computed a genetic frontotemporal dementia survival risk index, which can be used at an individual patient level.

INTERPRETATION: Our results highlight that motor impairment in addition to cognitive and behavioural symptoms should be considered when estimating prognosis in genetic frontotemporal dementia. Individual risk scores might be of help for patient stratification in future therapeutic trials, although refinement and prospective validation are now needed.

FUNDING: Italian Ministry of Health (Ricerca Corrente), Fondation Philippe Chatrier, and Fondation Vaincre Alzheimer.}, } @article {pmid42457567, year = {2026}, author = {Akiyama, T and Aoki, M}, title = {Cracking a New Era of Therapeutic Development in ALS.}, journal = {The Tohoku journal of experimental medicine}, volume = {269}, number = {4}, pages = {437-447}, doi = {10.1620/tjem.2026.J082}, pmid = {42457567}, issn = {1349-3329}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; Animals ; Biomarkers/metabolism ; *Drug Development ; Induced Pluripotent Stem Cells ; }, abstract = {Recent advances in genetics, RNA biology, disease modeling, biomarkers, and clinical trial methodology have fundamentally transformed therapeutic development in amyotrophic lateral sclerosis (ALS). Recent clinical successes, including edaravone, ultrahigh-dose methylcobalamin, and antisense oligonucleotide (ASO) therapies such as tofersen, have demonstrated that therapeutic success depends not only on effective drugs but also on improved therapeutic development strategies. These advances have highlighted several fundamental principles, including patient enrichment, intervention during appropriate therapeutic windows, biomarker-guided drug development, and innovative clinical trial design. At the biological level, human genetics and molecular neuropathology have revealed that genetically diverse forms of ALS converge on a limited number of shared pathogenic pathways. In particular, TDP-43 proteinopathy has emerged as the central molecular hallmark of ALS, linking protein aggregation, RNA dysregulation, and neuronal dysfunction. The discovery of TDP-43-dependent cryptic splicing has transformed RNA dysregulation into a therapeutically actionable target and accelerated the development of RNA-targeted therapeutics and mechanism-based biomarkers. In parallel, patient-derived induced pluripotent stem cell (iPSC) models, multi-omics technologies, and computational approaches have fundamentally altered therapeutic discovery and target validation. Furthermore, neurofilament biomarkers, adaptive platform trials, and digital technologies are reshaping clinical evaluation and accelerating therapeutic development. In this review, we discuss how advances in genetics, RNA biology, disease modeling, biomarkers, and clinical trial methodology are collectively redefining therapeutic development in ALS and shaping the next generation of precision medicine for neurodegenerative diseases.}, } @article {pmid42458007, year = {2026}, author = {Chen, W and Jiang, L and Duan, C and Kang, M and Ye, J and Wang, L and Pan, Y and Qu, H and Liao, X and Zhou, X and Li, Y and Gan, Z and Chen, J and Schacht, I and Place, RF and Li, LC and Wang, Y}, title = {Oligonucleotide-siRNA conjugate for SOD1 amyotrophic lateral sclerosis: a phase 1 trial.}, journal = {Nature medicine}, volume = {32}, number = {7}, pages = {2619-2628}, pmid = {42458007}, issn = {1546-170X}, support = {No.Z231100004823036//Beijing Municipal Science and Technology Commission/ ; 20230484245//Beijing Nova Program/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/drug therapy/pathology ; Humans ; Animals ; *Superoxide Dismutase-1/genetics/cerebrospinal fluid ; Female ; Male ; *RNA, Small Interfering/administration & dosage/genetics/therapeutic use ; *Oligonucleotides/administration & dosage/therapeutic use/genetics ; Macaca fascicularis ; Middle Aged ; Aged ; Adult ; Motor Neurons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease partly caused by gain-of-function mutations in superoxide dismutase 1 (SOD1). Here we developed RAG-17, an siRNA-targeting SOD1, using an accessory oligonucleotide conjugate platform for enhanced central nervous system (CNS) delivery. Preclinically, RAG-17 rescued motor neuron degeneration, delayed disease progression, preserved motor function and extended survival in SOD1[G93A] ALS rodents, even with advanced-stage treatment. In cynomolgus monkeys, intrathecal RAG-17 led to dose-dependent, durable reductions in SOD1 mRNA (CNS) and protein (cerebrospinal fluid (CSF)). In a first-in-human trial in patients with SOD1-ALS (n = 6), participants were assigned to two cohorts-cohort 1 (n = 3) received an initial 60 mg dose (seven doses total) and cohort 2 (n = 3) received an initial 90 mg dose (six doses total). The dose was escalated in 30 mg steps to maintenance doses of 150 mg (n = 5) or 180 mg (n = 1). Thus, the primary safety endpoint was met, showing acceptable safety and tolerability. Treatment-emergent adverse events (TEAEs) occurred in 33% of participants (two of six). All TEAEs were mild to moderate, including muscle tremor (two patients) and elevated alanine aminotransferase (one patient), all of which resolved. No serious adverse events were reported. Furthermore, no other clinically meaningful changes were observed in laboratory parameters, vital signs, the ALS Functional Rating Scale-Revised score, physical or neurological examinations or ECG. The key secondary endpoints showed CSF SOD1 reductions of 69% (cohort 1, day 240) and 56% (cohort 2, day 210), and plasma neurofilament light chain reductions of 62% (cohort 1) and 52% (cohort 2), from baseline; no patient required invasive mechanical ventilation or died by the end of the study. These results demonstrate a favorable safety outcome, supporting the continued clinical evaluation of RAG-17 for SOD1-ALS. ClinicalTrials.gov registration: NCT05903690 .}, } @article {pmid42458453, year = {2026}, author = {Bolsinger, MM and Vivek, N and Singh, J and Challa, A and Zhu, A and Rothell, T and Wang, S and Zhang, T and Zhu, S and Robbins, N and Fenwick, L and Ruttenberg, G and Bogoniewski, A and Taha, HB}, title = {Extracellular vesicles as a liquid biopsy for amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of translational medicine}, volume = {24}, number = {1}, pages = {}, pmid = {42458453}, issn = {1479-5876}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/pathology/metabolism ; Humans ; *Extracellular Vesicles/metabolism ; Liquid Biopsy ; Biomarkers/metabolism ; Publication Bias ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome diagnosed clinically using standardized criteria, with neuropathological confirmation of motor neuron loss and TDP-43 aggregates in postmortem brain tissue. Extracellular vesicles (EVs) have emerged as potential minimally invasive biomarkers for ALS, but studies vary widely in methodology and reproducibility. We conducted a systematic review and meta-analysis to evaluate the diagnostic potential of EV-associated proteins and RNAs in ALS. Following PRISMA guidelines, we searched PubMed and EMBASE from inception to May 21st, 2026. Forty-one studies met inclusion criteria. Where published summary statistics were available, these were used directly; where they were not, data were reconstructed from figures or obtained from authors and re-analyzed to derive standardized effect sizes and exploratory diagnostic accuracy estimates. Random-effects models were used for continuous outcomes, and diagnostic accuracy was assessed using hierarchical summary ROC and bivariate random-effects models. Publication bias was evaluated using Begg, Egger, and funnel plots. EV-associated TDP-43 was the most frequently studied protein. Meta-analysis of five studies showed a moderate but non-significant increase in EVs from ALS vs. controls (SMD = 1.30) with high heterogeneity (I = 97.8%). Sixteen studies assessing EV-RNA biomarkers showed minimal overlap and limited independent replication. Diagnostic accuracy meta-analysis across 11 studies yielded moderate performance (AUC = 0.839). No publication bias was found across both meta-analyses. EV biomarkers for ALS show biological promise but are limited by methodological variability and insufficient replication. This work highlights the need for standardized protocols, transparent data sharing, and independent validation.}, } @article {pmid42458498, year = {2026}, author = {Wang, H and Wen, R and Parker, E and Yang, L}, title = {TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.}, journal = {Cell communication and signaling : CCS}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12964-026-03083-9}, pmid = {42458498}, issn = {1478-811X}, support = {32300959//National Natural Science Foundation of China/ ; SL2024A04J00578//Guangzhou Scientific Research Grant/ ; 22KJ04//SCNU Young Faculty Development Program/ ; }, abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical myeloid receptor expressed on the surface of central nervous system microglia, capable of integrating signals from lipids, damage-associated molecular patterns, and abnormal protein aggregates to regulate phagocytosis, metabolic adaptation, inflammatory remodeling, and pathology-associated responses. Accumulating evidence indicates that TREM2 is neither uniformly protective nor uniformly pathogenic; rather, its biological effects are highly context-dependent, governed collectively by disease stage, pathological substrates, cellular compartments, and the local microenvironment. By coupling with TYROBP/DAP12 or DAP10, TREM2 actively drives the state remodeling of pathology-associated microglia. It profoundly influences the onset and progression of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), as well as acute central nervous system injuries, including ischemic stroke, spinal cord injury (SCI), and traumatic brain injury (TBI). Concurrently, soluble TREM2 (sTREM2) holds significant potential not only as a biomarker but also as a context-dependent effector molecule actively participating in pathological regulation. This review synthesizes current advancements by focusing on four core themes: the structural and signaling logic of the TREM2 axis; its regulation of disease-associated microglia (DAM) remodeling; the cross-disease significance of sTREM2; and the mechanistic basis for the divergent outcomes observed with TREM2-targeted therapies across different experimental models and disease stages. The objective is to elucidate the context-dependent roles of TREM2 by analyzing consensus mechanisms, sources of discrepancy, and translational implications, thereby providing a theoretical framework and strategic direction for more precise TREM2-targeted interventions.}, } @article {pmid42458512, year = {2026}, author = {Jo, M and Kim, S and Woo, J and Park, JS and Kim, SH and Nahm, M and Kim, SR and Lee, S and Kim, HJ}, title = {Targeting astrocyte-mediated neurotoxicity induced by ALS/FTD-associated RNA binding proteins.}, journal = {Cell communication and signaling : CCS}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12964-026-03082-w}, pmid = {42458512}, issn = {1478-811X}, support = {RS-2024-00454715//National Research Foundation of Korea/ ; RS-2024-00343239//National Research Foundation of Korea/ ; 26-BR-02-03//Korea Brain Research Institute/ ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders characterized by reactive astrocytes that contribute to neuronal injury through TAR DNA-binding protein 43 (TDP-43)-or fused in sarcoma (FUS)-driven neuroinflammatory signaling. Dehydrocostus lactone (DHE), a blood-brain barrier-permeable sesquiterpene lactone with established anti-inflammatory activity, represents a promising but unexplored therapeutic candidate for ALS/FTD.

METHODS: The therapeutic effects of DHE were evaluated in primary mouse and human astrocytes expressing ALS/FTD-associated RNA-binding protein pathology, ALS patient-derived fibroblasts, and primary cortical neurons exposed to astrocyte-conditioned medium. Drosophila models expressing mutant FUS or TDP-43 in glial cells were used to assess locomotor performance and survival. Molecular analyses examined nuclear factor kappa B (NF-κB) signaling, nuclear factor erythroid 2-related factor 2 (NRF2)-dependent antioxidant responses, protein aggregation, mitochondrial function, and inflammatory mediator production. Plasma concentrations of inflammatory cytokines and chemokines were measured in patients with sporadic ALS.

RESULTS: DHE exerted neuroprotective effects through a dual mechanism involving suppression of NF-κB-dependent inflammatory signaling and activation of NRF2-mediated antioxidant pathways in astrocytes exhibiting FUS or TDP-43 proteinopathy. DHE attenuated astrocyte-mediated neurotoxicity and improved neuronal mitochondrial function in conditioned-medium assays. In addition, DHE reduced pathological FUS accumulation in FUS P525L-expressing astrocytes and in stress-challenged patient-derived fibroblasts. In Drosophila models, DHE significantly improved locomotor function and extended survival. Translationally, the chemokines CXCL10, CCL3, and CCL19 were elevated in plasma from patients with ALS, were induced by FUS or TDP-43 pathology in astrocytes, and were suppressed by DHE treatment, supporting the clinical relevance of the inflammatory pathways targeted by DHE.

CONCLUSION: DHE mitigates astrocyte-driven neurotoxicity associated with ALS/FTD-related RNA-binding protein pathology by suppressing inflammatory signaling and enhancing antioxidant defense mechanisms. The consistent therapeutic effects observed across mouse and human cellular models, patient-derived samples, and in vivo Drosophila models support further investigation of DHE as a potential therapeutic strategy for ALS/FTD and highlight astrocyte-mediated signaling pathways as actionable targets in neurodegenerative disease.}, } @article {pmid42458576, year = {2026}, author = {Akan, T and Aishwarya, R and Bhuiyan, MS and Conrad, SA and Vanchiere, JA and Bhuiyan, MAN}, title = {From unlabeled to labeled: self-supervised deep learning in computational pathology.}, journal = {BioData mining}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13040-026-00586-6}, pmid = {42458576}, issn = {1756-0381}, support = {R01HL172970, R01HL145753, R01HL145753-01S1, and R01HL145753-03S1//Foundation for the National Institutes of Health/ ; P20GM121307//Foundation for the National Institutes of Health/ ; }, abstract = {PURPOSE: The advancement of decision support systems for pathology and their implementation in clinical practice have been limited by the necessity for extensive, manually annotated datasets. Self-supervised learning (SSL) automates the extraction and interpretation of histopathological features from unannotated images, facilitating efficient model development without dependence on expert labeling. In this study, we introduce the SSL-HistoNet model that learns disease-relevant morphological representations from histopathological images through self-supervised learning.

MATERIALS AND METHODS: We applied it to WGA-stained skeletal muscle tissues from mouse models of amyotrophic lateral sclerosis (ALS) and Type I diabetes to explore its ability to capture pathological muscle phenotypes in an annotation-free setting. Following pretraining on unlabeled data, the SSL encoder was further integrated with an attention-guided classifier to evaluate its capacity to identify pathological muscle alterations.

RESULTS: SSL-HistoNet achieved a precision of 0.98, a recall of 0.98, and an AUC of 0.98, demonstrating performance comparable to or outperforming state-of-the-art supervised models. Alongside high discriminative performance, exploratory feature analyses demonstrated consistent class-level changes in morphology-related patterns identified through representation learning.

CONCLUSION: These findings highlight the capability of SSL-HistoNet as an annotation-free framework for outlining disease-specific tissue structures, reducing manual labeling demands and mitigating inter- and intra-observer variability in histological processes.

CLINICAL TRIAL NUMBER: Not applicable.}, } @article {pmid42459525, year = {2026}, author = {Majumdar, S and Samaiya, PK and Ahmed, S and Prajapati, SK}, title = {Imaging biomarkers in neurodegenerative diseases: advances and challenges.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1813588}, pmid = {42459525}, issn = {1663-4365}, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), represent a major global health burden. Imaging biomarkers have emerged as important tools for improving the diagnosis, monitoring, and biological characterization of neurodegenerative diseases. Structural MRI, diffusion tensor imaging (DTI), functional MRI (fMRI), positron emission tomography (PET), hybrid PET/MRI and molecular imaging have transformed our ability to investigate neurodegeneration in vivo non-invasively. This review highlights updated information on how each imaging modality offers a unique window into different disease pathophysiology including regional atrophy, amyloid-β, tau, dopaminergic terminal degeneration, synaptic density (SV2A), and neuroinflammation. We also focused on the translational and evidence supporting biomarkers, appropriate use criteria for amyloid and tau PET imaging, and standardized quantification methods such as the Centiloid scale. The growing role of multimodal fusion, where imaging is increasingly integrated with scalable fluid biomarkers to enable "blood-first" strategies where high-risk patients are selectively referred to advanced imaging, improving feasibility and equity. Despite tremendous progress, there are still issues with their standardization, sensitivity, specificity, and clinical translation. Moreover, the review emphasizes the frontiers of α-synuclein and glial state-specific PET ligands, advanced diffusion models, and dynamic connectivity analysis to support precision medicine and mechanism-based trial design for NDDs.}, } @article {pmid42459857, year = {2026}, author = {Hu, M and You, L and Zhang, X and Xuan, Z and Ma, S and Wu, X}, title = {Experimental evidence of electroacupuncture in ALS mouse models: a systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1780176}, pmid = {42459857}, issn = {1664-2295}, abstract = {OBJECTIVE: This study aimed to systematically evaluate the therapeutic efficacy of electroacupuncture (EA) in amyotrophic lateral sclerosis (ALS) and to elucidate the underlying neurobiological mechanisms by synthesizing preclinical evidence.

METHODS: According to the PICOS principle, relevant studies were searched in the following databases: PubMed, Web of Science, Embase, Cochrane Library, Scopus, and CNKI. Search terms and strategies were determined based on MeSH terms. The methodological quality of the included studies was assessed using the SYRCLE's Risk of Bias tool and the CAMARADES checklist. Meta-analysis was performed using Stata 15.0 and Rstudio software.

RESULTS: Seventeen studies involving 372 animals were included. The quality scores of the included studies ranged from 5 to 8, with an average score of 7. The meta-analysis of the primary outcome, the rotarod test score, showed a significant improvement in the EA group compared to the control group [SMD = 3.31, 95% CI (2.05, 4.57), Z = 5.151, p < 0.001], indicating that EA can enhance motor function in ALS mice. Regarding secondary outcomes, EA intervention alleviated neuroinflammation, promoted neuronal survival, improved axonal regeneration inhibition, and stabilized RNA metabolism homeostasis. Consequently, it slowed disease progression, improved motor performance, prolonged survival time, and effectively protected motor neurons at the histopathological level (p < 0.05). These findings underscore the potential of EA as a promising multimodal therapeutic strategy for ALS. For the heterogeneity observed in the rotarod test, sensitivity analysis, subgroup analysis, and meta-regression did not identify its source. However, potential publication bias was detected, which might contribute to the heterogeneity. The heterogeneity for other outcome measures might originate from differences in stimulation parameters (e.g., waveform), acupoint selection, or treatment duration.

CONCLUSION: This meta-analysis demonstrates that EA confers significant neuroprotective benefits in preclinical ALS models, primarily through multi-target modulation of key pathological processes such as neuroinflammation, aberrant cell death signaling, and RNA metabolism. These preclinical findings underscore the potential of electroacupuncture as a complementary neuroprotective strategy and warrant further investigation in rigorous clinical trials.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251229183.}, } @article {pmid42459893, year = {2026}, author = {Ogino, M}, title = {Single-subject auditory ERP-BCI performance enhancement in ALS via an AI coding assistant prompt.}, journal = {Frontiers in human neuroscience}, volume = {20}, number = {}, pages = {1869918}, pmid = {42459893}, issn = {1662-5161}, abstract = {INTRODUCTION: Auditory event-related potential (ERP) brain-computer interfaces (BCIs) offer communication support for individuals with amyotrophic lateral sclerosis (ALS) who eventually progress to completely locked-in states. However, individual-specific BCI pipeline optimization is technically demanding and time-consuming, leaving substantial room for performance improvement in practice. A central challenge is increasing selection speed while maintaining reliable classification accuracy, since slower selections reduce the sense of agency and undermine the motivational and feedback dynamics essential for sustained BCI use.

METHODS: We investigated whether an AI coding assistant could address this challenge for individual patients. A three-class auditory ERP-BCI was optimized for a single ALS patient using Claude Code (Anthropic, Inc.), which iteratively generated and evaluated 23 optimization scripts over approximately 24 hours with minimal human-in-the-loop oversight. The resulting AI-Designed ERP classifier (AIDE) was evaluated on 189 EEG trials spanning 3.5 years using five cross-validation strategies.

RESULTS: For the baseline models, halving the stimulus repetitions to shorten selection time degraded classification accuracy; AIDE prevented this degradation, achieving 85.03% mean cross-validation accuracy (selection time 17 s; ITR 2.92 bits/min). This doubled the information transfer rate from 1.43 to 2.92 bits/min. Accuracy exceeded 84% across four of five cross-validation strategies. Feature space visualization revealed that the AI autonomously selected and combined EEG features established in prior studies into an effective discriminative architecture, without domain-specific algorithmic guidance from the human researcher. In addition, online test confirmed 66.7% accuracy for AIDE versus 50.0% for the baseline model.

DISCUSSION: These findings provide proof of concept that single-subject BCI performance can be improved via a single prompt, offering an efficient pathway to individualized optimization in clinical and research settings.}, } @article {pmid42460524, year = {2026}, author = {Cai, X and Bai, Y and Ma, F and Xu, R and Xie, Y and Cao, X}, title = {Mechanisms and Therapeutic Targeting of the cGAS-STING Pathway in Central Nervous System Disorders.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X472988260627201746}, pmid = {42460524}, issn = {1875-6190}, abstract = {OBJECTIVE: The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a core DNA-sensing axis in innate immunity and has been increasingly implicated in the pathogenesis of multiple Central Nervous System (CNS) disorders. This review summarizes current knowledge of cGAS-STING signaling in CNS disorders and evaluates its therapeutic potential.

METHODS: Relevant studies on cGAS-STING signaling in CNS disorders were collected from PubMed and Web of Science, with emphasis on disease mechanisms, neuroinflammatory regulation, and pathway-targeted therapeutic strategies.

RESULTS: In the CNS, cGAS-STING signaling exhibits marked region-, cell-, and pathology-dependent heterogeneity. Aberrant DNA sensing activates this pathway and amplifies neuroinflammation, cellular stress, and tissue injury in Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), ataxia-telangiectasia (A-T), and ischemic and hemorrhagic stroke. Pharmacological inhibition of cGAS, cyclic GMP-AMP (cGAMP), or STING, together with emerging delivery strategies, has shown promise in preclinical models.

DISCUSSION: Clinical translation remains limited by incomplete validation of pathway specificity, limited human evidence, restricted brain delivery, and inconsistent efficacy assessment.

CONCLUSION: The cGAS-STING pathway links aberrant DNA sensing to innate immune activation and CNS pathology. Clarifying its disease-, cell-, and stage-specific roles may support future targeted therapeutic strategies for CNS disorders.}, } @article {pmid42460525, year = {2026}, author = {Liu, Y and Yang, J and Su, J and Hao, L}, title = {High Levels of Plasma Neurturin Partially Mediate the Protective Effect of Reduced Ruminococcus2 Abundance on Multiple Sclerosis: A Mendelian Randomization Study.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X468669260626223524}, pmid = {42460525}, issn = {1875-6190}, abstract = {BACKGROUND: Genetic evidence implicates the contribution of the gut-brain axis to neurodegenerative diseases (NDDs). Alterations in gut microbiota and inflammation are key pathophysiological contributors. Elucidating the genetic basis and the role of cytokines can provide insights into mechanisms linking gut microbial composition to neurodegeneration.

METHODS: Using aggregated statistics from five large-scale Genome-Wide Association Studies (GWAS) on Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple sclerosis, and amyotrophic lateral sclerosis, bidirectional two-sample Mendelian Randomization (MR) was used to examine the associations. A two-step multivariable Mendelian randomization approach incorporates data from 91 cytokines to explore potential mediators.

RESULTS: The study reveals 18 positive and 17 negative effects between gut microbiota and NDDs, as well as 10 positive and 10 negative effects between cytokines and NDDs. Remarkably, mediation analysis identified a causal pathway, with evidence that plasma neurturin levels partially mediate the association from genus Ruminococcus2 to multiple sclerosis, with a mediation proportion of 19.19% (OR = 1.038, 95% CI = 1.001-1.086, P = 0.044). No pleiotropy or heterogeneity was detected.

DISCUSSION: These MR findings provide compelling evidence for a genetically anchored gutimmune-brain network in NDDs, with cytokines as intermediates. Bidirectional effects highlight disease-specific microbial signatures and inflammatory contexts. The Ruminococcus2-neurturin pathway in multiple sclerosis may offer mechanistic specificity, aligning with neurotrophic and anti-inflammatory signaling pathways.

CONCLUSION: This study emphasizes the importance of gut microbiota alterations in NDDs and explores inflammation's partial intermediary role. The findings suggest potential targets for personalized neurodegeneration prevention strategies.}, } @article {pmid42460529, year = {2026}, author = {Chen, H and Yang, Z and Meng, H and Hu, Z and Ke, Z and Ye, Q and Xu, Y and Wu, J and Liu, Z}, title = {White Matter Functional Dysregulation in Amyotrophic Lateral Sclerosis: Machine Learning-Based Biomarkers and Transcriptomic Signatures.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X465668260629073047}, pmid = {42460529}, issn = {1875-6190}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor system degeneration, yet its white matter (WM) functional pathophysiology remains underexplored.

METHODS: This study utilized resting-state functional magnetic resonance imaging to decode WM functional abnormalities in 50 ALS patients and 55 healthy controls. Next, machine learning analysis was applied to evaluate the utility of these WM functional patterns in diagnosing ALS and predicting disease progression, and their pathophysiological mechanisms were preliminary explored through neurotransmitter mapping and imaging transcriptomics.

RESULTS: ALS patients exhibited reduced activity in central WM regions (including bilateral corticospinal tracts), accompanied by elevated activity in anterior and posterior WM territories. The aberrant topological properties and disrupted functional connectivity are predominantly localized within bilateral precentral/postcentral WM networks. A support vector machine model incorporating these features achieved 75.24% classification accuracy and predicted the rate of disease progression (r = 0.56, p = 0.001). The spatial pattern of WM dysfunction in ALS was associated with both the spatial distribution of disease-related neurotransmitters and the expression profiles of specific genes.

DISCUSSION: Our findings reveal distinct WM functional dysfunction patterns in ALS and their molecular-genetic underpinnings, providing novel insights into the pathophysiological mechanisms of ALS.

CONCLUSION: ALS involves specific patterns of WM dysfunction, and these WM-centric biomarkers may facilitate the development of therapeutic monitoring frameworks for this devastating disease.}, } @article {pmid42461162, year = {2026}, author = {Zhang, R and Zhang, N and Li, B and Liu, Q and Xu, C and Li, B and Zhang, J}, title = {Nursing a Patient With Amyotrophic Lateral Sclerosis Stage 4B With Epilepsy: A Case Study.}, journal = {Nursing in critical care}, volume = {31}, number = {4}, pages = {e70573}, pmid = {42461162}, issn = {1478-5153}, support = {25ZZJJLW-015//Medical Research Council Foundation of the 305 Hospital of the PLA/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/nursing/complications ; *Epilepsy/nursing/complications ; Male ; Intensive Care Units ; *Critical Care Nursing/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease characterised by progressive muscle weakness, which can eventually lead to death. So far there is no effective cure for it. This case report discusses the nursing of a patient with stage 4B amyotrophic lateral sclerosis complicated with epilepsy and sudden disturbance of consciousness during his stay in an intensive care unit (ICU). After 34 days of treatment and care, the patient regained consciousness with stable vital signs before being transferred out of the ICU. This report focusses on nursing interventions adopted in terms of respiratory management, nutritional management, psychological care and exercise during both the epileptic seizure and the awake period of the patient in the hope of providing a reference for the nursing of patients with amyotrophic lateral sclerosis with epilepsy in intensive care units.}, } @article {pmid42461445, year = {2026}, author = {Mitsumoto, H and Cheung, K and Matsumoto, T and Lanza, I and Oskarsson, B and Johnson, S and Petterson, XT and Jang, GE and Andrews, HF}, title = {Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.}, journal = {Metabolomics : Official journal of the Metabolomic Society}, volume = {22}, number = {4}, pages = {}, pmid = {42461445}, issn = {1573-3890}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/blood ; *Muscle Cramp/drug therapy/metabolism/blood ; *Metabolomics/methods ; Female ; Male ; Middle Aged ; Aged ; Cross-Over Studies ; Medicine, Kampo ; *Drugs, Chinese Herbal/therapeutic use ; }, abstract = {INTRODUCTION: Most patients with amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease, experience painful muscle cramps. Our recent pilot trial of the Japanese Kampo medicine TJ-68 suggested its efficacy in improving muscle cramps in patients with ALS.

OBJECTIVES: This study analyzed plasma metabolomic changes to identify the underlying mechanisms of muscle cramps in ALS and the effects of TJ-68.

METHODS: Plasma was obtained from 11 participants with ALS in the repeated crossover trial at five time points (baseline, two placebo phases, and two TJ-68 phases). Metabolites were analyzed using mass spectrometry. Linear mixed-effects models were applied to identify metabolite changes associated with muscle cramps, determine the effects of TJ-68 on metabolites, and predict which participants would respond to TJ-68.

RESULTS: Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels. Long-chain acylcarnitine levels were correlated with muscle cramp severity, and their levels tended to decrease with treatment. Uric acid, β-aminoisobutyric acid, α-aminoadipic acid, and acetylcholine emerged as predictors of the efficacy of TJ-68.

CONCLUSION: This study identified the metabolite profile of muscle cramps in ALS and the changes in metabolite levels after TJ-68 treatment. Several baseline metabolites were associated with the prediction of the response to muscle cramps following TJ-68 treatment. Uric acid might be particularly useful because of its easy measurement in standard assays. Our study affirms the value of metabolomic technology for future pharmacotherapy and studies in ALS.}, } @article {pmid42461653, year = {2026}, author = {Kneepkens, SCM and Lingham, G and van Hemert, DJ and Loughman, J and Strang, NC and Tham, YC and Harrington, SC and Guisasola, L and French, A and He, X and Mackey, DA and Hagen, LA and Baraas, RC and Pärssinen, O and Yam, JC and Saunders, KJ and Guggenheim, JA and Saw, SM and Lan, WZ and Klaver, CCW and Flitcroft, DI and , }, title = {Global Axial Length Centile Charts.}, journal = {JAMA ophthalmology}, volume = {144}, number = {8}, pages = {744-753}, pmid = {42461653}, issn = {2168-6173}, mesh = {Humans ; Child ; Adolescent ; Female ; Reference Values ; *Axial Length, Eye/anatomy & histology ; Male ; Young Adult ; *Myopia/diagnosis/epidemiology ; Australia/epidemiology ; Europe/epidemiology ; }, abstract = {IMPORTANCE: Myopia is increasingly common worldwide and poses major public health challenges because axial elongation drives sight-threatening complications. Because axial length (AL) is the primary target for myopia management, population-specific AL reference charts are needed.

OBJECTIVE: To generate region- and sex-specific reference centile charts for AL in children and adolescents.

This was a pooled cohort analysis using individual-participant data from population- and school-based studies conducted in East Asia, Europe, and Australia contributing to the CREAM-Kids Consortium. A total of 147 404 children and adolescents contributing 559 799 AL measurements were included. Most participants were from East Asia (84%; ages 6-18 years), followed by Europe (12%; ages 6-21 years) and Australia (4%; ages 6-21 years). After assessment of comparability, European and Australian datasets were combined. Data were included from 1999 to 2024, with the analysis taking place from December 2024 to May 2026.

EXPOSURES: AL, age, sex, and geographic region.

MAIN OUTCOMES AND MEASURES: Region- and sex-specific AL centiles across age and agreement between modeled centiles and empirical values.

RESULTS: AL distributions among the 147 404 included individuals varied by sex and region. In female individuals, the 50th centile AL at age 7 years was 22.35 mm in Europe and Australia and 22.67 mm in East Asia; by age 18 years, the 50th centile ALs were 23.31 mm and 24.36 mm, respectively. Regional differences were larger at higher centiles: for female individuals at age 7 years, East Asia vs Europe and Australia differences were 0.33 mm at the 3rd centile and 0.50 mm at the 97th centile; at age 18 years, differences were 0.73 mm and 1.27 mm, respectively. Modeled centile curves closely matched empirical values (intraclass correlations >0.99) with minimal bias across sex and region subgroups (-0.08 mm to 0.04 mm).

CONCLUSIONS AND RELEVANCE: While not based solely on population-based cohorts, the region- and sex-specific AL centile charts developed in this pooled cohort study provide reference values for childhood and adolescence that may be used to support clinical and research applications, including identifying atypical axial elongation and informing targeted strategies for myopia prevention and management.}, } @article {pmid42462180, year = {2026}, author = {Baskar, K and Steffke, C and Bernsen, S and Elmas, Z and Hesebeck-Brinckmann, J and Schuster, J and Meyer, T and Weydt, P and Weishaupt, J and Brenner, D and Catanese, A}, title = {Multiplex Panel Detects Glial and Inflammatory Biomarker Signatures in Sporadic and C9orf72-ALS.}, journal = {Neurology(R) neuroimmunology & neuroinflammation}, volume = {13}, number = {5}, pages = {e200618}, pmid = {42462180}, issn = {2332-7812}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/genetics ; Biomarkers/cerebrospinal fluid ; Female ; Male ; C9orf72 Protein/genetics ; Middle Aged ; Aged ; Neuroglia ; *Neuroinflammatory Diseases/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; Adult ; *Inflammation/cerebrospinal fluid ; Chitinase-3-Like Protein 1/cerebrospinal fluid ; }, abstract = {BACKGROUND AND OBJECTIVES: CSF proteomics has emerged as a valuable strategy for identifying diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis (ALS). However, the limited availability and volumes of CSF samples restrict the broader clinical application of CSF-based biomarker panels. To address this challenge, we investigated whether the novel nucleic acid-linked immuno-sandwich assay (NULISA) multiplex platform-capable of quantifying multiple neural, glial, and inflammatory markers from minimal biofluid volumes-could validate previously proposed biomarkers and identify additional candidates relevant to ALS.

METHODS: Using this platform, we measured a targeted panel of 131 biomarkers in cohorts of patients with C9orf72-associated ALS, sporadic ALS (sALS), and matched healthy controls.

RESULTS: The 6 markers neurofilament heavy chain (NEFH) and neurofilament light chain (NEFL), chitinases-particularly chitotriosidase-1 (CHIT1) and chitinase-3-like protein-1 (CHI3L1), and chemokines CCL2 and CCL3 were significantly elevated in both ALS groups compared with controls. These biomarkers correlated with disease progression and demonstrated strong diagnostic performance when combined into aggregate scores, as reflected by a high area under the receiver operating characteristic curve for ALS. Notably, C9orf72-ALS patients exhibited higher levels of the oxidative stress-related markers PRDX6 and ENO2, compared with sALS patients, suggesting a genotype-specific molecular signature.

DISCUSSION: Overall, our findings support the use of a multiplexed panel of diverse, inflammatory, glial, and neurodegeneration-associated biomarkers as a complementary diagnostic and prognostic tool alongside established measurements of neurofilaments. This approach may enhance biomarker robustness while minimizing CSF volume requirements, thereby improving clinical feasibility in ALS research and care.}, } @article {pmid42463858, year = {2026}, author = {Picchiarelli, G and Demestre, M and Zuko, A and Been, M and Higelin, J and Dieterlé, S and Goy, MA and Mallik, M and Sellier, C and Scekic-Zahirovic, J and Zhang, L and Rosenbohm, A and Sijlmans, C and Aly, A and Mersmann, S and Sanjuan-Ruiz, I and Hübers, A and Messaddeq, N and Wagner, M and van Bakel, N and Boutillier, AL and Ludolph, A and Lagier-Tourenne, C and Boeckers, TM and Dupuis, L and Storkebaum, E}, title = {Author Correction: FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis.}, journal = {Nature neuroscience}, volume = {29}, number = {8}, pages = {2049-2050}, doi = {10.1038/s41593-026-02396-9}, pmid = {42463858}, issn = {1546-1726}, } @article {pmid42464213, year = {2026}, author = {Özbilici, Z and Issı, ES}, title = {SYNE1-Related motor neuron disease-like phenotype with mild distal contractures and 24-month clinical stability: a case report.}, journal = {BMC neurology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12883-026-05142-7}, pmid = {42464213}, issn = {1471-2377}, abstract = {BACKGROUND: SYNE1 encodes nesprin-1, a nuclear envelope protein involved in cytoskeletal linkage, nuclear positioning, and neuromuscular integrity. Biallelic SYNE1 variants cause a broad spectrum ranging from cerebellar ataxia to arthrogryposis multiplex congenita and motor neuron disease-like phenotypes. Distinguishing these entities can be difficult when subtle distal contractures coexist with neurogenic electrophysiological findings.

CASE PRESENTATION: A 22-year-old woman born to consanguineous parents presented with bilateral intrinsic hand muscle wasting, impaired fine motor performance, and mild gait difficulty. Examination showed distal hand atrophy, mild weakness of the abductor pollicis brevis and first dorsal interosseous muscles, brisk deep tendon reflexes, preserved sensation, and mild distal finger contractures. Sensory nerve conduction studies were normal. Motor studies showed reduced compound muscle action potential amplitude in the right abductor pollicis brevis and borderline-low amplitude on the left. Needle electromyography showed widespread chronic neurogenic motor unit changes affecting the upper and lower extremities, with active denervation most evident in the bilateral abductor pollicis brevis muscles. Genioglossus examination was normal. SMN1 deletion testing and selected familial amyotrophic lateral sclerosis gene testing were negative. Whole exome sequencing identified a homozygous truncating SYNE1 variant, NM_182961.4:c.21009G > A; p.(Trp7003Ter). Segregation analysis confirmed heterozygous carrier status in both parents and two unaffected siblings. At 24-month follow-up, weakness, atrophy, contractures, reflex pattern, and functional status remained clinically stable, without bulbar, cerebellar, sensory, or clinically evident respiratory involvement.

CONCLUSIONS: This case supports classification as a SYNE1-related motor neuron disease-like phenotype with mild distal contractures rather than an isolated arthrogryposis multiplex congenita type 3 (AMC3) phenotype. The case also supports including SYNE1 in genetic testing panels for young patients with unexplained motor neuron disease-like presentations, particularly when consanguinity, normal sensory conduction, and subtle distal contractures coexist.}, } @article {pmid42464712, year = {2026}, author = {Gao, N and Cui, B and Yun, Y and Yu, W and Gao, X and Sun, X and Shao, K and Lin, P and Liu, F and Li, W and Zhao, Y and Yu, D and Yan, C and Liu, S and Lou, J}, title = {Corticospinal Subfiber Neurite Density Index Detects Upper Motor Neuron Degeneration in Prediagnostic Patients With Sporadic Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {7}, pages = {e70703}, pmid = {42464712}, issn = {1468-1331}, support = {82471429//National Natural Science Foundation of China/ ; ZR2024MH013//Natural Science Foundation of Shandong Province/ ; 2025CXPT133//the Key Research and Development Program of Shandong Province, China/ ; Z-2017-24-2509//the Yantu Neuroscience Specialized Research Fund Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/blood/diagnosis ; Female ; Male ; *Pyramidal Tracts/diagnostic imaging/pathology ; Middle Aged ; *Neurites/pathology ; Retrospective Studies ; Aged ; Neurofilament Proteins/blood ; Diffusion Magnetic Resonance Imaging ; Diffusion Tensor Imaging ; *Motor Neurons/pathology ; *Nerve Degeneration/pathology/diagnostic imaging ; }, abstract = {BACKGROUND: Using multi-shell diffusion MRI, we aimed to identify whether corticospinal tract (CST) subfiber damage can be detected in prediagnostic amyotrophic lateral sclerosis (ALS) patients. We also explored whether the combination of serum neurofilament light chain (NfL) levels and CST subfiber abnormalities may provide better diagnostic performance in differentiating prediagnostic ALS patients from disease controls (DCs) and healthy controls (HCs) than single markers.

METHODS: In this retrospective study, prediagnostic ALS was used as an operational term for patients who presented at baseline with chronic progressive limb weakness or bulbar symptoms, had no clinically evident typical UMN signs, and were subsequently confirmed to have sporadic ALS according to the Awaji criteria during longitudinal follow-up. Patients whose final diagnosis was not ALS after follow-up were classified as disease controls. Probabilistic tractography was performed on baseline MRI data to assess CST subfiber damage in 47 ALS patients, 20 DCs, and 51 HCs.

RESULTS: Compared with Controls, ALS patients had significantly lower neurite density index (NDI) values of CST subfibers, particularly those originating from the primary and supplementary motor cortex. The diagnostic performance of the combined model incorporating serum NfL and CST subfiber NDI values in differentiating prediagnostic ALS patients from HCs and DCs was 0.925 and 0.928, respectively, which was better than that of single markers (0.634-0.886 and 0.699-0.856, respectively).

CONCLUSIONS: Our findings suggest that CST subfibers NDI values are promising neuroimaging markers for detecting in vivo UMN degeneration in prediagnostic ALS. Moreover, combining blood and neuroimaging markers may further improve early diagnostic performance.}, } @article {pmid42465739, year = {2026}, author = {You, Y and Zhu, H and Zhang, Q and Wang, J and Dong, C and Yang, Z and Zhang, J and Zhang, Y and Zhang, M and Lu, M and Du, C}, title = {Development and efficacy of ex vivo expanded autologous regulatory T cells for the treatment of amyotrophic lateral sclerosis.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1854252}, pmid = {42465739}, issn = {1664-3224}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/immunology/genetics ; *T-Lymphocytes, Regulatory/immunology/transplantation/metabolism ; Animals ; Humans ; Mice ; Disease Models, Animal ; Female ; Superoxide Dismutase-1/genetics ; Mice, Transgenic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited therapeutic options, in which neuroinflammation critically drives disease progression. Regulatory T cells (Tregs) exert potent immunosuppressive and neuroprotective effects, offering great potential for ALS treatment. However, clinical application of Treg therapy is hampered by low peripheral cell abundance and unstable expansion quality. Here, we established and optimized a GMP-grade protocol for sorting and expanding peripheral blood-derived Tregs, and validated cryopreserved apheresis products as feasikble starting materials. Although ALS patient-derived Tregs showed reduced expansion capacity compared with healthy donor counterparts, they maintained comparable purity, stable regulatory phenotypes, and robust immunosuppressive function. Transcriptomic analysis confirmed the lineage fidelity and low pro-inflammatory characteristics of expanded Tregs. Therapeutic efficacy was verified in SOD1G93A ALS and GvHD mouse models with delayed disease progression and relieved inflammation. This study provides standardized GMP manufacturing strategies and solid preclinical evidence to support the ongoing clinical trial (NCT06671236) and facilitate Treg immunotherapy translation for ALS.}, } @article {pmid42466415, year = {2026}, author = {Mei, A and Jewett, D and Jewett, A and Kaur, K and Malarkannan, S}, title = {Multi-hit genetic lesions and a stress-imprinted immune transcriptome define the inflammatory pathology in ALS patients.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {42466415}, issn = {2693-5015}, support = {R01 AI102893/AI/NIAID NIH HHS/United States ; R01 CA179363/CA/NCI NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease whose peripheral immune architecture remains incompletely defined. Here, we integrated whole-genome sequencing and single-cell RNA sequencing to define genomic and immune correlates of ALS. Genome-wide analysis of a monozygotic twin pair discordant for ALS pathology identified shared ALS-associated variants, as well as patient-enriched variants in genes linked to RNA metabolism, neurodegeneration, and immune inflammation, supporting a multilayered genetic architecture. Single-cell profiling of 40,484 peripheral blood mononuclear cells from three ALS patients and two healthy individuals, including 33,667 cells retained after quality control, resolved 13 immune clusters and revealed broad remodeling of the peripheral immune compartment, with relative enrichment of natural killer, mucosal-associated invariant T, and γδ T-cell populations. Across immune subsets, ALS samples exhibited inflammatory and stress-adapted transcriptomic programs, including TNF-α/NF-κB, IFN-γ, hypoxia, and ribosomal stress pathways. These data support a model in which multi-hit genetic susceptibility converges on a stress-induced immune transcriptome, marked uniquely by innate lymphocyte activation in ALS patients.}, } @article {pmid42466609, year = {2026}, author = {Li, D and Zhou, Z and Liang, G and Zeng, D and Zhou, Z and Li, X and Qiu, T and Zhang, Y and Lin, J and Chen, Y and Li, Z}, title = {Association Between Allostatic Load, Genetic Susceptibility, and Liver Cancer Incidence: A Large-Scale Prospective Cohort Study.}, journal = {International journal of cancer}, volume = {159}, number = {9}, pages = {2158-2169}, pmid = {42466609}, issn = {1097-0215}, support = {240421166496919//Shantou Medical Science and Technology Planning Project/ ; A2023481//Medical Scientific Research Foundation of Guangdong Province, China/ ; B2025664//Medical Scientific Research Foundation of Guangdong Province, China/ ; //Shantou University Medical College 2025 Teaching Reform Project/ ; }, mesh = {Humans ; *Liver Neoplasms/epidemiology/genetics ; *Allostasis/genetics ; *Genetic Predisposition to Disease ; Female ; Prospective Studies ; Middle Aged ; Male ; Genetic Risk Score ; Incidence ; Risk Factors ; Aged ; United Kingdom/epidemiology ; UK Biobank ; Proportional Hazards Models ; }, abstract = {Allostatic load (AL) reflects the cumulative physiological burden of chronic stress throughout life, potentially influencing cancer onset and prognosis. However, its association with primary liver cancer (PLC) risk and potential interaction with genetic susceptibility remains unclear. To investigate this, we analyzed 374,632 UK Biobank participants. AL was evaluated using a composite score of 13 cardiovascular, metabolic, and immune biomarkers, while a weighted polygenic risk score (PRS) categorized genetic susceptibility. Multivariable Cox proportional hazards models and restricted cubic splines were utilized to estimate hazard ratios (HRs) and evaluate dose-response relationships. Over a median 12.4-year follow-up, a significant dose-response correlation between AL and PLC risk was observed. In the fully adjusted model, a 1-unit increase in AL was associated with a 17% increased risk (HR = 1.17, 95% CI: 1.12-1.23), and participants in the highest AL quartile exhibited a 2.60-times higher risk than those in the lowest (HR = 2.60, 95% CI: 1.72-3.95). Despite no multiplicative interaction, stratified analyses revealed AL's impact was most substantial in individuals with intermediate genetic risk (HR = 2.00, 95% CI: 1.38-2.90), who constitute the population majority. Additionally, the risk was heightened in overweight/obese individuals and more pronounced among non-smokers. Ultimately, cumulative physiological stress, indicated by AL, is strongly associated with PLC, supporting the "wear-and-tear" theory of its development. This research highlights a "malleable zone" in individuals with moderate genetic risk, suggesting that lowering AL may meaningfully aid in preventing PLC.}, } @article {pmid42467293, year = {2026}, author = {Hassan, MA and Al Amin, M and Sweilam, SH and Abohassan, M and Krishnan, K and Gupta, JK and Jahnavi, P and Vodeti, R and Radha, R and Gupta, PS and Reddy, KTK}, title = {Resveratrol and neuroprotection: modulation of cellular dynamics and signaling networks in neurodegenerative diseases.}, journal = {Inflammopharmacology}, volume = {34}, number = {8}, pages = {5093-5117}, pmid = {42467293}, issn = {1568-5608}, mesh = {*Resveratrol/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Neuroprotective Agents/pharmacology ; *Signal Transduction/drug effects ; Oxidative Stress/drug effects ; *Neuroprotection/drug effects ; Neurons/drug effects/metabolism ; }, abstract = {Progressive loss of neurons, oxidative stress, neuroinflammation, and mitochondrial dysfunction are hallmarks of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Resveratrol, a polyphenolic phytoalexin mainly found in grapes and red wine, is a promising treatment candidate due to its diverse biological effects and neuroprotective properties. This review demonstrates the regulatory effects of resveratrol on cellular signaling pathways linked to NDs and its neuroprotective mechanisms. Resveratrol enhances neuronal survival, boosts mitochondrial biogenesis, and mitigates oxidative stress by affecting key molecular pathways, including SIRT1/AMPK, PI3K/Akt, MAPK, and Nrf2/ARE. The PI3K/Akt and ERK1/2 pathways promote neuronal regeneration by modulating pro-apoptotic and anti-apoptotic factors. Resveratrol inhibits NF-κB, reducing cytokine release and microglial activation, thereby exhibiting anti-inflammatory properties. It improves cognitive function, synaptic plasticity, and neuronal survival. Despite an increasing pharmacological profile, its practical applicability is limited by inadequate bioavailability, rapid metabolism, and restricted brain penetration. This review demonstrates resveratrol's effect on interconnected signaling networks related to neurodegeneration. We critically compare evidence from preclinical and clinical studies, demonstrating both therapeutic potential and translational limitations. Emerging nanotechnology-based delivery strategies are demonstrated to overcome bioavailability and blood-brain barrier penetration challenges. These insights provide a translational perspective for the future development of resveratrol-based interventions in NDs.}, } @article {pmid42467750, year = {2026}, author = {Deressa, JD and Behaksra, SW and Molla, E and Letebo, A and Shumie, G and Adnew, B and Alemayehu, DH and Kassa, FA and Seyoum, T and Tafa, EB and Woldekidan, K and Ejigu, LA and Huwe, T and Keffale, M and Bayissa, GA and Koepfli, C and Chala, B and Asmamaw, Y and Tadesse, FG and Gadisa, E}, title = {Therapeutic efficacy of artemether-lumefantrine plus single low dose primaquine for the treatment of uncomplicated Plasmodium falciparum malaria in a high transmission setting, Western Ethiopia.}, journal = {PloS one}, volume = {21}, number = {7}, pages = {e0335833}, pmid = {42467750}, issn = {1932-6203}, mesh = {Humans ; *Primaquine/therapeutic use/administration & dosage ; *Artemether, Lumefantrine Drug Combination/therapeutic use/administration & dosage ; *Malaria, Falciparum/drug therapy/transmission/epidemiology/parasitology ; *Antimalarials/therapeutic use/administration & dosage ; Female ; Male ; Ethiopia/epidemiology ; Plasmodium falciparum/drug effects/genetics ; Child, Preschool ; Adolescent ; Treatment Outcome ; Child ; Adult ; Drug Therapy, Combination ; Young Adult ; }, abstract = {BACKGROUND: The development and spread of drug-resistant parasites continue to threaten progress toward malaria elimination. Therapeutic efficacy and molecular resistance marker studies are needed to guide national control programs. In African settings, evidence of partial resistance to artemisinin-based combination therapies (ACTs) associated with Pfkelch13 mutations is accumulating, and World Health Organization (WHO) recommends regular monitoring of first line antimalarial drugs for early detection of resistant parasites. In this study, we evaluated the efficacy of artemether-lumefantrine (AL) combined with a single low dose of primaquine (PQ) for treating uncomplicated Plasmodium falciparum malaria in a co-endemic area where P. falciparum predominates.

METHODS AND FINDINGS: One hundred twenty-three patients with P. falciparum mono-infection were enrolled between November 2020 to March 2021 and treated with artemether-lumefantrine (AL) plus a single low dose of primaquine (PQ) as per the national malaria treatment guideline and followed up for 28 days. Ethical approval was obtained from the AHRI/ALERT ethics committee (Po/23/19), and the study was registered at Pan-African clinical trials registry (PACTR) with unique identification number of PACTR202509595696440. Pfmsp2 capillary electrophoresis (CE) genotyping was used to differentiate recrudescence from new infections. More than half (56.1%) of the participants had high parasitemia (>10,000 parasites/μL) at enrollment. On day 3, 16.9% (20/118) remained parasitemic, and of the 10 individuals with detectable gametocytes at enrollment, only 3.4% remained gametocytemic on day 3, and 100% parasite clearance was observed on day 7, respectively. Multiplicity of infection was 3.8 at enrollment and 1.7 at the time of recurrence. The adequate clinical and parasitological responses at 28-day (ACPR) of per protocol analysis (PPA) was 73.7% for PCR-uncorrected and 91.3% for PCR-corrected, respectively and while, the intention-to-treat analysis (ITA), the Kaplan-Meier estimated treatment success at day 28 was 93.2% (95% CI: 88.5-98.2) after PCR correction, compared with 78.3% (95% CI: 71.0-86.4) in the PCR-uncorrected analysis. In our study assessment, no cases of severe malaria or serious adverse events occurred.

CONCLUSIONS: The efficacy observed in this study, although remaining above the WHO policy change threshold after PCR correction, may indicate a potential decline in AL's effectiveness in this high transmission setting. However, because antimalarial drug concentrations were not measured and evening doses were not fully directly observed, reduced drug exposure or imperfect adherence cannot be excluded as possible contributors to the observed treatment outcomes Therefore, we suggest regular therapeutic efficacy monitoring and further investigation using advanced molecular techniques, such as next-generation sequencing (NGS), to enable early detection of resistance-associated parasite variants that may compromise treatment efficacy.}, } @article {pmid42468019, year = {2026}, author = {Gou, CY and Smith, SE}, title = {Interventional Procedures for Musculoskeletal Pain in ALS Patients: A Case Series.}, journal = {American journal of physical medicine & rehabilitation}, volume = {105}, number = {8}, pages = {e117-e120}, doi = {10.1097/PHM.0000000000002964}, pmid = {42468019}, issn = {1537-7385}, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications ; Female ; *Musculoskeletal Pain/etiology/therapy/drug therapy ; Retrospective Studies ; *Pain Management/methods ; Aged ; Adult ; }, abstract = {Many patients with amyotrophic lateral sclerosis (ALS) experience musculoskeletal pain, yet data on the safety and efficacy of interventional procedures for pain relief in this population are limited. This study aims to describe the characteristics, outcomes, and procedural considerations of pain interventions performed for musculoskeletal pain in ALS patients. A retrospective chart review was conducted of ALS patients referred for interventional pain management by a neuromuscular physiatrist at a single academic institution's interdisciplinary ALS Center between February 2021 and February 2025. Eleven patients (mean age: 57 y, 64% male) underwent 14 procedures. Shoulder pain was the most common indication (43%), followed by spine (29%) and hip (14%) pain. Procedures mostly consisted of joint and bursal injections peripherally and of epidural injections in the axial spine. Overall, 13 of 14 (93%) procedures provided at least "good" pain relief, and 5 patients elected to repeat their procedures. One patient experienced transient postprocedure hypertension; no major complications occurred. Interventional procedures, particularly corticosteroid injections, appear to be safe and effective for managing focal musculoskeletal pain in patients with ALS. Tailored procedural techniques and multidisciplinary coordination can enhance comfort and optimize outcomes in this complex population.}, } @article {pmid42468211, year = {2026}, author = {Seo, Y and Lee, J and Lee, Y and Kim, S and Lee, JS and Ro, H and Cho, SH and Park, JS and Kim, MJ and Park, HC}, title = {FUS-driven zebrafish model of ALS identifies tribenzylamine as a candidate modulator of ALS-associated pathology.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {202}, number = {}, pages = {119761}, doi = {10.1016/j.biopha.2026.119761}, pmid = {42468211}, issn = {1950-6007}, mesh = {Animals ; Zebrafish ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism ; Animals, Genetically Modified ; Disease Models, Animal ; Humans ; *RNA-Binding Protein FUS/genetics/metabolism ; Oxidative Stress/drug effects ; Motor Neurons/drug effects/metabolism/pathology ; Reactive Oxygen Species/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron loss and declining motor function; however, effective therapies remain limited. To support unbiased therapeutic discovery, we aimed to develop a high-throughput phenotypic screening platform based on a transgenic zebrafish model expressing the human ALS-associated FUS-R521C mutant (mtFUS). This model was generated using a modified QF-based binary expression system and exhibited early-onset pathological features, including elevated oxidative stress, progressive neuronal degeneration, and impaired locomotor activity, thereby recapitulating the key aspects of FUS-associated ALS. Transcriptomic profiling revealed molecular signatures resembling those reported in patient-derived motor neurons, including dysregulated neuroactive ligand-receptor signaling, immune activation, and stress-response pathway alterations. Using this platform, we identified tribenzylamine (TBA) as a candidate compound that improves locomotor performance and significantly reduces reactive oxygen species levels. Integrated transcriptomic and biochemical analyses suggested that TBA induces coordinated molecular changes, including normalization of neuronal activity-related gene expression, modulation of immune and metabolic pathways, and restoration of hormone-related signaling. TBA reversed FUS-induced reductions in key neuronally active sex steroids, including estrogen and progesterone, and increased estrogen-responsive gene expression, suggesting a partial recovery of neuronally active sex steroid homeostasis. These findings support the mtFUS zebrafish model as a useful platform for ALS drug discovery and identify TBA as a candidate modulator of ALS-associated phenotypes, with effects linked to transcriptomic remodeling and neuronally active sex steroid signaling.}, } @article {pmid42468901, year = {2026}, author = {Halabian, N and Park, C and Omoto, L and Bocca, LF and Palacios, G and Wu, K and Hamani, C and Rabin, J and Abrahao, A and Davidson, B and Lipsman, N and Meng, Y}, title = {Focused Ultrasound Blood-Brain Barrier Opening for Targeted Therapeutics in Neurodegenerative Diseases.}, journal = {Biological psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.biopsych.2026.07.008}, pmid = {42468901}, issn = {1873-2402}, abstract = {Therapeutic focused ultrasound (FUS) leverages noninvasive ultrasonic waves to modify biological tissues. When administered alongside intravenous microbubbles, low-intensity FUS enables transient, targeted disruption of the blood-brain barrier (BBB), thereby permitting the passage of systemically administered therapeutics into the central nervous system (CNS) with high spatial precision. The ability to selectively modulate BBB permeability at the disease site has the potential to substantially expand the number of therapeutics that can be utilized in treating illnesses that afflict the CNS. Herein, we review the current applications of FUS for treating neurodegenerative disorders and diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We discuss the research developments to date and future directions.}, } @article {pmid42469515, year = {2026}, author = {Kreß, L and Abuzant, M and Zeller, D and Sommer, C}, title = {Beyond ALS: split-hand syndrome in immune-mediated motor neuropathies.}, journal = {Journal of neurology}, volume = {273}, number = {8}, pages = {}, pmid = {42469515}, issn = {1432-1459}, support = {Z-2/CSP_22//Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg/ ; Z-3 BC-18//Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg/ ; Z-2/AdvCSP-4//Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg/ ; }, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Middle Aged ; Aged ; *Muscle, Skeletal/physiopathology ; Prospective Studies ; *Hand/physiopathology ; Adult ; Nerve Conduction Studies ; Diagnosis, Differential ; }, abstract = {BACKGROUND AND AIMS: Split-hand syndrome describes selective wasting and weakness of the abductor pollicis brevis (APB) or first dorsal interosseous (FDI) muscles with relative preservation of the abductor digiti minimi (ADM). Beyond clinical definition, two neurophysiological ratios and one index have been proposed to quantify this pattern. It is considered a potential diagnostic criterion for amyotrophic lateral sclerosis (ALS). Its occurrence in immune-mediated neuropathies, as differential diagnoses, remains unclear. We aimed to investigate clinical and electrophysiological manifestations of split-hand syndrome in multifocal motor neuropathy (MMN) and multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) compared to ALS.

METHODS: We prospectively examined 26 MMN, 16 MADSAM, and 22 ALS patients. All underwent neurological examination and neurophysiological measurements of compound muscle action potentials (CMAP) from the APB, FDI, and ADM bilaterally after median (APB) and ulnar nerve (FDI, ADM) stimulation. Split-hand ratios (APB/ADM; FDI/ADM) and split-hand index (SI) were calculated.

RESULTS: Clinical split-hand syndrome was present in 16/26 (62%) MMN, 7/16 (44%) MADSAM, and 12/22 (54%) ALS patients. Electrophysiological criteria (abnormal split-hand ratios or SI; ≥ 1 parameter fulfilled) were similarly frequent across groups (MMN 17/26, 65%, MADSAM 11/16, 69%, and ALS 16/22, 73%). CMAP ratios and SI did not differ between groups in the overall analysis and showed no correlation with disease duration or severity. Diagnostic models showed limited discriminatory power (area under the curve ≤ 0.61).

INTERPRETATION: Split-hand syndrome occurs in MMN, MADSAM, and ALS at comparable frequencies and lacks robust or consistent diagnostic discrimination across disease groups.}, } @article {pmid42469634, year = {2026}, author = {Li, MA and Song, YZ and Li, T and Wu, J and Tao, Y and Hu, R and Qiao, CM and Cui, C and Zhao, WJ and Shen, YQ}, title = {Secretory leukocyte protease inhibitor (SLPI) attenuates TLR4/NF-κB-mediated neuroinflammation in amyotrophic lateral sclerosis: a candidate molecule associated with neuro-pathology.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {}, number = {}, pages = {}, doi = {10.1186/s10020-026-01572-8}, pmid = {42469634}, issn = {1528-3658}, support = {KYCX25_2743//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; 82171429//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder driven by neuroinflammation involving activated microglia and astrocytes, which accelerates the loss of motor neurons. While Secretory leukocyte protease inhibitor (SLPI) is known for its immunomodulatory properties, its specific role in ALS pathogenesis has not been fully established. This study aimed to characterize the expression patterns and functional significance of SLPI in ALS models.

METHODS: The study utilized SOD1[G93A] mice to analyze the spatiotemporal dynamics of SLPI expression in the gastrocnemius muscle, lumbar spinal cord, and serum across different disease stages. In vitro functional assays were conducted using siRNA-mediated knockdown of SLPI in BV2 (microglia), MA (astrocytes), and NSC-34 (motor neurons) cell lines. Additionally, recombinant SLPI protein was applied to LPS-stimulated BV2 cells to investigate its effect on the TLR4/ NF-κB signaling pathway.

RESULTS: In SOD1[G93A] mice, SLPI was significantly upregulated in the gastrocnemius muscle from the pre-symptomatic stage (60 days) through the late stage (130 days). In the lumbar spinal cord, SLPI showed a transient initial increase but declined sharply by the end-stage; a similar significant reduction was observed in late-stage serum levels. In vitro, SLPI knockdown exacerbated pro-inflammatory cytokine production in all three cell types and impaired the antioxidant capacity of NSC-34 motor neurons. Mechanistically, recombinant SLPI attenuated inflammation in BV2 cells by modulating the TLR4/NF-κB pathway.

CONCLUSIONS: The dynamic changes in SLPI levels suggest its potential relevance as a candidate molecule for disease staging. Meanwhile, its protective effects in regulating inflammation suggest that it could be a promising therapeutic candidate for mitigating ALS-associated neuroinflammation.}, } @article {pmid42470084, year = {2026}, author = {Morgado Linares, RY and Rojas-Marcos, Í and Mesa, M and Martínez, E and Cabrera-Serrano, M and Paradas, C}, title = {Impact of Sexuality in Patients With Motor Neuron Disease.}, journal = {Muscle & nerve}, volume = {74}, number = {3}, pages = {669-677}, pmid = {42470084}, issn = {1097-4598}, mesh = {Humans ; Female ; Male ; *Motor Neuron Disease/psychology/physiopathology/complications ; Cross-Sectional Studies ; Middle Aged ; Aged ; *Sexuality/psychology/physiology ; Sexual Behavior ; Caregivers/psychology ; *Sexual Dysfunction, Physiological/etiology/psychology ; Surveys and Questionnaires ; Quality of Life ; }, abstract = {INTRODUCTION: Sexuality is a relevant yet understudied aspect in people living with motor neuron disease (MND). This study aimed to assess whether sexuality in people with MND is influenced by motor, cognitive, behavioral, or mood disturbances, and to explore whether being sexually active impacts caregiver burden.

METHODS: We conducted a cross-sectional observational study involving participants with MND and their primary caregivers from three ALS multidisciplinary units in Seville, Spain. Data were collected between October 2018 and July 2021. Functional, cognitive, behavioral, and mood assessments were conducted. Sexuality was evaluated through sex-specific questionnaires. Caregiver burden was assessed using the Zarit Burden Interview.

RESULTS: Among 66 participants who completed the sexuality assessment, 42.9% reported sexual activity in the previous month. Of these, 70% had no sexual dysfunction, while 26.7% had moderate and 3.3% severe dysfunction. No correlation was found between sexual activity and motor function. Sexual activity was less frequent in participants with apathy (p = 0.026), depression (p = 0.021), and frontotemporal dementia (p = 0.013). Among sexually active patients, those with cognitive impairment-particularly memory dysfunction-had higher rates of orgasm difficulties (p = 0.019). No other clinical parameters were related to sexuality. Sexuality of participants with MND did not influence caregiver burden.

DISCUSSION: Sexuality in MND is more associated with cognitive and mood factors than with motor disability. Addressing sexuality in clinical practice may contribute to improving quality of life and should be integrated into the multidisciplinary care of MND patients.}, } @article {pmid42471032, year = {2026}, author = {Barrera-Chamorro, L and Gonzalez-de la Rosa, T and Arzalluz-Luque, J and Torrecillas-Lopez, M and Marquez-Paradas, E and Claro-Cala, CM and Navarro-Hortal, MD and Eichau, S and Garcia-Sanchez, MI and Montserrat-de la Paz, S}, title = {Sustainable next-generation prebiotics for brain health: microbiota-gut-brain axis in neurodegenerative and demyelinating diseases.}, journal = {Critical reviews in food science and nutrition}, volume = {}, number = {}, pages = {1-22}, doi = {10.1080/10408398.2026.2703335}, pmid = {42471032}, issn = {1549-7852}, abstract = {Neurodegenerative and neuroinflammatory diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are increasingly associated with disruption of the microbiota-gut-brain axis. Common alterations include reduced beneficial microbial taxa, impaired short-chain fatty acid production, intestinal and blood-brain barrier dysfunction, and sustained inflammatory responses. These findings support the development of microbiota-targeted dietary interventions. This review summarizes current evidence on polyphenols, bioactive peptides, and pectin-derived oligosaccharides (POS) as prebiotic or prebiotic-like compounds with potential activity through the microbiota-gut-brain axis. Particular attention is given to structure-function relationships, host-microbe interactions, and the sustainable recovery of these compounds from food by-products. Preclinical studies suggest that these bioactives may reduce microglial activation, improve mitochondrial function, strengthen intestinal and blood-brain barrier integrity, and enhance cognitive or motor performance. Early clinical studies also indicate possible benefits on mood, selected cognitive outcomes, metabolic regulation, and inflammatory biomarkers, although evidence remains limited. Microbiota-derived metabolites from polyphenols, such as urolithins, together with glycomacropeptide and POS, appear to be key mediators. However, clinical validation in major neurodegenerative diseases remains fragmented. Standardized formulations, mechanistic trials, harmonized endpoints, and precision-nutrition strategies are required to confirm their therapeutic potential.}, } @article {pmid42471133, year = {2026}, author = {Rojano-Delgado, A and Sohrabi, S and Gherekhloo, J and Domínguez-Valenzuela, JA and Palma-Bautista, C and Alcántara-de la Cruz, R and De Prado, R}, title = {Evolution of multiple resistance under long-term herbicide exposure reshapes Mediterranean perennial agroecosystems.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {407}, number = {}, pages = {128781}, doi = {10.1016/j.envpol.2026.128781}, pmid = {42471133}, issn = {1873-6424}, mesh = {*Herbicides/toxicity ; *Herbicide Resistance/genetics ; Plant Weeds/drug effects ; Spain ; Agroecology ; Ecosystem ; Amaranthus ; Conyza/drug effects ; Solanum nigrum ; }, abstract = {Decades of intensive herbicide use in perennial cropping systems have imposed substantial environmental pressures and accelerated the evolution of herbicide-resistant weed populations. In Andalusia (southern Spain), citrus and olive orchards rely heavily on glyphosate and other herbicide modes of action, resulting in chronic ecosystem exposure, declining herbicide efficacy, and increasing chemical inputs. We surveyed ten dominant weed species across eleven orchards to characterize resistance patterns and investigate underlying physiological mechanisms relevant to environmental persistence and contaminant cycling. Rapid screening assays using six widely applied herbicides (atrazine, 2,4-D, glyphosate, oxyfluorfen, quizalofop-ethyl, and tribenuron-methyl) revealed widespread multiple and cross-resistance in both dicots and monocots. Amaranthus albus, A. viridis, Conyza bonariensis, and Solanum nigrum displayed resistance to atrazine, glyphosate, and tribenuron-methyl, while Lolium rigidum and Sorghum halepense showed broad-spectrum resistance involving target-site alterations and enhanced metabolic detoxification, partially reversed by the cytochrome P450 inhibitor malathion. Complementary biochemical assays targeting PSII, ALS, ACCase, and EPSPS, together with diagnostic tests for PPO- and auxin-related herbicides, indicated diverse non-target-site resistance pathways, suggesting increased herbicide transformation and altered degradation dynamics in soil-plant systems. The emergence of complex resistance mechanisms reflects prolonged selection pressure from intensive herbicide regimes and implies elevated risks of environmental accumulation, off-target effects, and reduced sustainability of chemical-based weed control. These findings highlight the need to reduce herbicide dependence and adopt integrated weed management strategies that minimize pollutant loads in Mediterranean agroecosystems.}, } @article {pmid42471754, year = {2026}, author = {Xia, CA and Salarian, M and Gartshore, CJ and Scaglione, A and Hayes, T and Liu, S and Tsai, HM and Echavarren, J and Cid, JM and Matzeu, A and Szardenings, AK}, title = {Development and characterization of a novel TDP-43 positron emission tomography tracer: [[18]F]JNJ-TDP43-1.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {7}, pages = {e71675}, pmid = {42471754}, issn = {1552-5279}, support = {//Johnson & Johnson/ ; }, mesh = {Animals ; *Positron-Emission Tomography/methods ; *DNA-Binding Proteins/metabolism ; *Brain/diagnostic imaging/metabolism ; Rats ; Mice ; Humans ; Male ; Disease Models, Animal ; TDP-43 Proteinopathies/diagnostic imaging ; *Radiopharmaceuticals/pharmacokinetics ; Fluorine Radioisotopes ; }, abstract = {INTRODUCTION: Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Alzheimer's disease (AD) are associated with TAR DNA-binding protein 43 (TDP-43) pathology. A positron emission tomography (PET) tracer targeting TDP-43 aggregates could improve early diagnosis and guide treatment development for TDP-43-related conditions.

METHODS: Specific binding was evaluated using fluorescent labeling of compound, surface plasmon resonance (SPR), and autoradiography (ARG). Brain PET imaging in rats, nonhuman primate (NHP), and a disease mouse model was performed to characterize tracer pharmacokinetics and in vivo target binding.

RESULTS: JNJ-TDP43-1 exhibited high binding affinity for pathological TDP-43 (Kd = 7.1 nM) and remarkable selectivity over other proteinopathies. PET imaging demonstrated robust brain uptake and rapid washout in rodents and NHP. In vivo target engagement was confirmed in an AAV-hTDP43 disease model.

DISCUSSION: [[18]F]JNJ-TDP43-1 is a promising PET ligand for early diagnosis and evaluating therapies in TDP-43-related diseases.}, } @article {pmid42472717, year = {2026}, author = {Fowler, C and Kaelber, DC and Bliwise, DL and Greer, MK}, title = {Rapid Eye Movement Sleep Suppressing Antidepressant Prescription is Associated with Improved Survival in Amyotrophic Lateral Sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {8}, pages = {}, pmid = {42472717}, issn = {1590-3478}, support = {UM1TR004528//Clinical and Translational Science Collaborative of Cleveland, School of Medicine, Case Western Reserve University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/drug therapy ; Female ; Male ; *Antidepressive Agents/therapeutic use/pharmacology ; *Riluzole/therapeutic use ; Middle Aged ; *Sleep, REM/drug effects ; Aged ; }, abstract = {INTRODUCTION: Rapid eye movement (REM) sleep is a period of physiological vulnerability for patients with neuromuscular disease, owing to a generalized loss of muscle tone that spares only the diaphragm. Several antidepressants have been observed to reduce REM sleep fraction on polysomnography. We investigated whether prescription of REM-suppressing antidepressants (RSAs) versus non-REM-suppressing antidepressants (NRSAs) is associated with differential survival in patients with amyotrophic lateral sclerosis (ALS).

METHODS: Using the U.S. Collaborative Network of the TriNetX Analytics platform, we compared 1-year mortality in ALS patients prescribed RSAs or NRSAs within 3 months of diagnosis, identified by ICD-10-CM-coded encounter diagnoses with riluzole prescription between May 2014 and May 2024. We used Cox proportional hazards models, Kaplan-Meier analysis, and risk difference analysis, with and without propensity score matching (PSM).

RESULTS: Among 14,441 patients with ALS and riluzole prescription, 5,057 were prescribed either RSAs (N = 4,177) or NRSAs (N = 880). The NRSA cohort had a higher risk of death (HR 1.28, 95% CI 1.11 - 1.46), with 1-year survival of 60.73% versus 68.61% for RSAs (log-rank p<0.001). After PSM, the difference narrowed and was borderline by log-rank test (60.97% vs 65.92%, p=0.035), while the risk-difference analysis was no longer significant (RR 1.07, 95% CI 0.92 - 1.25), indicating an attenuated and statistically fragile association.

CONCLUSIONS: RSA prescription was associated with modestly better survival, but this association weakened markedly after matching and cannot establish causation; residual confounding, particularly by indication, cannot be excluded. These findings are hypothesis-generating, and prospective studies incorporating polysomnography and ALS-specific prognostic factors are needed.}, } @article {pmid42473037, year = {2026}, author = {Ban, Y and Wang, T and Zhang, Z and Yuan, WQ and Zhang, M and Shi, K and Li, C and Feng, Z}, title = {Tribenuron-methyl resistance in catchweed bedstraw (Galium aparine): status and MIRA-based rapid detection of ALS D376E mutation.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71132}, pmid = {42473037}, issn = {1526-4998}, support = {2023YFD1400500//National Key Research and Development Program of China/ ; 32372567//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Catchweed bedstraw (Galium aparine) is a highly competitive malignant broadleaf weed that significantly reduces the yield and quality in wheat and rapeseed cropping systems. The prolonged and exclusive use of tribenuron-methyl has led to widespread resistance development, posing a significant threat to the sustainability of weed management practices. To enable timely intervention and support evidence-based decision-making, systematic monitoring of resistance status and the development of a rapid, reliable detection method are urgently required.

RESULTS: We collected 113 populations of G. aparine from major wheat-growing regions across China, among which 83 populations were found to be resistant to tribenuron-methyl. The sequencing of the ALS gene revealed six distinct mutation patterns at sites P197, D376 and W574 within resistant populations, among which D376E was the most frequently observed. To enable rapid field resistance monitoring, the multienzyme isothermal rapid amplification (MIRA) assay was developed for detecting the D376E mutation. This new detection system can assess target-site resistance within 80 min at a constant temperature of 39 °C.

CONCLUSION: This study investigated tribenuron-methyl resistance in 113 G. aparine populations from various provinces of China and generated a comprehensive resistance distribution map. The MIRA-based method for rapidly detecting the ALS D376E substitution in G. aparine was developed. Collectively, our study provides valuable knowledge and a practical tool for the management of G. aparine. © 2026 Society of Chemical Industry.}, } @article {pmid42473039, year = {2026}, author = {Koppisetti, RK and Barthélemy, NR and Horie, K and Ly, CV and Roberts, KF and Koutarapu, S and Perrin, RJ and Franklin, EE and Pedicone, C and Orrick, J and Melendez, J and Miller, TM and Sato, C and Ghoshal, N and Goate, AM and Karch, CM and Bateman, RJ and Mukherjee, S}, title = {Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System.}, journal = {Annals of neurology}, volume = {100}, number = {4}, pages = {709-736}, pmid = {42473039}, issn = {1531-8249}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; R01 NS110890/NS/NINDS NIH HHS/United States ; U54 NS123746/NS/NINDS NIH HHS/United States ; P01AG03991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R01NS110890/NS/NINDS NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; RF1 NS110890/NS/NINDS NIH HHS/United States ; UL1 TR004419/TR/NCATS NIH HHS/United States ; R01 NS095773/NS/NINDS NIH HHS/United States ; R01NS095773/NS/NINDS NIH HHS/United States ; 1U54NS123746-01/NS/NINDS NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; U54NS123985/NS/NINDS NIH HHS/United States ; U54 NS123985/NS/NINDS NIH HHS/United States ; UL1TR004419/TR/NCATS NIH HHS/United States ; P41GM103422/GM/NIGMS NIH HHS/United States ; P41 GM103422/GM/NIGMS NIH HHS/United States ; P01AG026276/AG/NIA NIH HHS/United States ; R56 NS110890/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *tau Proteins/metabolism/genetics/cerebrospinal fluid ; Protein Isoforms/metabolism ; Male ; Alzheimer Disease/metabolism/pathology ; Female ; *Peripheral Nervous System/metabolism ; *Brain/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Central Nervous System/metabolism ; Aged ; Middle Aged ; Aged, 80 and over ; Spinal Cord/metabolism ; Mass Spectrometry ; }, abstract = {OBJECTIVE: Tau is widely studied in neurodegeneration, yet most work has focused on canonical brain tau isoforms. A longer isoform, "big tau," produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and central nervous system (CNS) regions. We sought to characterize big tau composition, anatomic distribution, and disease relevance.

METHODS: Mass spectrometry (MS) was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord and peripheral nerves. Big and canonical ("small") tau isoforms were also quantified in cerebrospinal fluid (CSF) from controls and participants stratified by amyloid status and cognitive impairment.

RESULTS: Human big tau results from insertion of either 355 or 251 amino acids encoded by exon 4a-long and exon 4a-short, respectively. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms. Total tau levels were approximately 1,000-fold higher in the brain than in the PNS; however, the relative abundance of big tau increased from the CNS to the PNS, comprising 50% of the total tau in the periphery and approximately 1% in the brain, primarily localized to the cerebellum. In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD pathology.

INTERPRETATION: Big tau represents a distinct tau population enriched in the PNS and uncoupled from disease-associated changes in brain-derived tau, suggesting that distinguishing big tau from canonical tau may improve interpretation of tau biomarkers and help differentiate CNS neurodegeneration from peripheral nerve pathology. ANN NEUROL 2026;100:709-736.}, } @article {pmid42473218, year = {2026}, author = {Keskin, A and Mogulkoc, R and Baltaci, AK}, title = {Relationship Between miRNA and Neurodegenerative Diseases Such as Alzheimer's disease, Parkinson's, Huntington's disease, Amyotrophic Lateral Sclerosis.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575484348260702044851}, pmid = {42473218}, issn = {1875-5607}, abstract = {The regulatory roles of miRNAs on CNS homeostasis, neuronal differentiation, and synaptic plasticity make these molecules indispensable for healthy brain functions. miRNA dysregulation, by triggering abnormal neurodevelopment, has a critical impact on the etiology and progression of neurodegenerative diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, 18 to 24 nucleotides long. They play a role in posttranscriptional gene regulation by binding to complementary sequences on messenger RNA (mRNA), thereby promoting mRNA degradation or preventing translation into protein. MiRNAs are essential regulators of the genome because they bind targets and alter gene expression. MiRNA biogenesis and functions are tightly regulated, and their dysregulation is associated with various diseases, including cancer, cardiovascular diseases, and neurodegenerative disorders. In particular, disruption of the Blood-Brain Barrier in neurodegenerative diseases allows molecules to leak into the bloodstream, enabling the detection of miRNAs in other body fluids and making these fluids potential biomarker sources. In this context, miRNAs can be measured in blood, cerebrospinal fluid, and other biological samples. It has significant potential for early diagnosis, disease progression monitoring, and evaluation of treatment efficacy. In this review, the relationship between MiRNAs and neuronal degeneration diseases was evaluated. In this review, prepared in light of the current literature scanned through the PubMed database, we examined data from the last 5 years (2021-2026) on neurodegenerative diseases associated with miRNA dysregulation, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD).}, } @article {pmid42473814, year = {2026}, author = {Shao, D and Wen, X and Xu, X and Liu, X and Guo, B and Li, B and Wang, G and Liu, X and Men, S}, title = {Cyprosulfamide mitigates nicosulfuron phytotoxicity in maize through activation of GST-associated phase II detoxification involving ZmGST24.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71142}, pmid = {42473814}, issn = {1526-4998}, support = {32370271//National Natural Science Foundation of China/ ; 2026KJCXZX-LYS-14//HAAFS Agriculture Science and Technology Innovation Project/ ; 254Z6303G//Project of Central Guidance for Local Science and Technology Development Funds/ ; 23JCYBJC01180//Natural Science Foundation of Tianjin/ ; 24YFXTHZ00050//Key Research and Development Program of Tianjin/ ; }, abstract = {BACKGROUND: Nicosulfuron is an acetolactate synthase (ALS)-inhibiting herbicide widely used in maize production. However, under unfavorable environmental conditions, its phytotoxicity to maize remains a practical concern. Cyprosulfamide (CSA) is an effective safener for maize, yet the contribution of glutathione S-transferases (GST)-associated phase II detoxification to CSA-conferred protection against nicosulfuron injury remains poorly understood.

RESULTS: CSA markedly alleviated nicosulfuron-induced growth inhibition in maize seedlings and effectively reduced herbicide injury under field conditions. Inhibitor assays showed that both cytochrome P450-mediated phase I metabolism and GST-associated phase II detoxification contribute to maize tolerance to nicosulfuron. Proteomic analysis further revealed that, relative to nicosulfuron treatment alone, co-application of nicosulfuron and CSA significantly enriched the glutathione metabolism pathway in maize leaves. Among the induced GST candidate genes, ZmGST24 showed the strongest transcriptional response. Phylogenetic and conserved motif analyses supported its functional similarity to previously reported GSTs involved in herbicide detoxification. Molecular docking suggested favorable binding of ZmGST24 to nicosulfuron, and heterologous expression in yeast demonstrated that ZmGST24 not only enhanced tolerance to nicosulfuron, but also increased tolerance to several herbicides commonly used in maize fields.

CONCLUSION: These findings indicate that the protective effect of CSA against nicosulfuron phytotoxicity in maize is associated with activation of GST-associated phase II detoxification. The pronounced response of the glutathione metabolism pathway, together with the functional characterization of ZmGST24, identifies this gene as a promising candidate involved in CSA-induced herbicide tolerance and as a potential target for improving herbicide safety in maize. © 2026 Society of Chemical Industry.}, } @article {pmid42474734, year = {2026}, author = {Zheng, Y and Bhalala, OG and Chin, KS and Watson, R and Yassi, N}, title = {Use of blood-based neurofilament light chain as an endpoint in clinical trials of neurodegenerative conditions: a scoping review.}, journal = {Journal of neurology}, volume = {273}, number = {8}, pages = {}, pmid = {42474734}, issn = {1432-1459}, mesh = {Humans ; *Neurofilament Proteins/blood ; *Neurodegenerative Diseases/blood/diagnosis ; Biomarkers/blood ; *Clinical Trials as Topic ; }, abstract = {INTRODUCTION: Neurofilament light chain (NfL) is a structural axonal protein measurable in CSF and blood, increasingly investigated as a biomarker of neuroaxonal injury in clinical and research contexts. This review aims to explore the use of blood-based NfL as an endpoint in clinical trials of neurodegenerative conditions.

METHOD: A database search of MEDLINE and EMBASE was conducted to identify interventional clinical trials and/or related post hoc analyses for neurodegenerative diseases, published between 2013 and 2024 that reported the use of serum or plasma NfL as an endpoint. Additional studies from reference lists of included trials were manually considered for inclusion where relevant. Data were charted descriptively by disease type and summarised.

RESULTS: 49 studies were included, 29 in multiple sclerosis (MS), eight in amyotrophic lateral sclerosis (ALS), six in Alzheimer's disease (AD), and six in other diseases. Across studies, reductions in NfL often paralleled improvements in primary efficacy outcomes, supporting its use as a biomarker of disease activity and treatment response. However, several studies demonstrated a lack of concordance between change in NfL and in clinical outcomes, some of which may be related to the non-disease-modifying mechanisms of the interventions studied. This necessitates careful consideration when applying blood-based NfL as a biomarker endpoint for studies involving such interventions.

CONCLUSION: Blood NfL is a promising biomarker with potential utility as a surrogate endpoint in neurological clinical trials, particularly for diseases with active axonal injury. Further validation, particularly around disease- and intervention-specific interpretation, is needed before blood NfL can be incorporated more routinely as a clinical endpoint.}, } @article {pmid42475592, year = {2026}, author = {Haim, G and Hornstein, E}, title = {The dual face of miR-146a in ALS.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {30}, pages = {e2617170123}, pmid = {42475592}, issn = {1091-6490}, } @article {pmid42476327, year = {2026}, author = {Pattnaik, PP and Prusty, SK and Pati, S and Jew, KA and Bora, AK and Sahoo, J and Sahu, PK}, title = {Exploring shared genetic pathways and gene interplay in major neurodegenerative diseases: a comprehensive review.}, journal = {Gene}, volume = {1010}, number = {}, pages = {150318}, doi = {10.1016/j.gene.2026.150318}, pmid = {42476327}, issn = {1879-0038}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Signal Transduction/genetics ; *Gene Regulatory Networks ; Genome-Wide Association Study ; Animals ; Alzheimer Disease/genetics ; }, abstract = {Neurodegenerative diseases are progressive disorders that involve the loss and dysfunction of neurons. Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, Frontotemporal dementia are examples of diseases. While different clinically, these disorders have a common genetic, molecular and cellular basis. This review examines the common genetic pathways, along with the interactions between genes of major neurodegenerative diseases, with a focus on the key genes, such as APOE, SNCA, MAPT, TARDBP, LRRK2 and HTT. The common pathogenic mechanisms considered to play a major role in disease progression include protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, diminished autophagy, and impaired lysosomal function, as well as synaptic degeneration. The review also emphasizes the role of systems biology strategies, such as genome-wide association studies, transcriptomics, proteomics, metabolomics, interactome analysis, and multi-omics integration, to unveiling complex molecular networks in neurodegeneration. Furthermore, the emerging biomarker strategies and therapeutic strategies targeting convergence signaling pathways including NF-κB, PI3K-Akt-mTOR, MAPK and Wnt/β-catenin are summarized. The common genetic basis and the cross-connecting molecular mechanisms of the various neurodegenerative diseases could help in the discovery of new biomarkers and pan-therapeutic targets. Further advances in molecular genetics, computational biology and precision medicine are needed to enhance early detection and the creation of effective disease-modifying treatments.}, } @article {pmid42476836, year = {2026}, author = {Mathis, S and Le Masson, G}, title = {When algorithms speak first: The public health risk of consumer AI in ALS diagnosis.}, journal = {Journal of the neurological sciences}, volume = {489}, number = {}, pages = {126098}, doi = {10.1016/j.jns.2026.126098}, pmid = {42476836}, issn = {1878-5883}, mesh = {Humans ; *Algorithms ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Artificial Intelligence ; Diagnostic Errors ; *Public Health ; Male ; Middle Aged ; }, abstract = {BACKGROUND: Consumer AI platforms are increasingly used by patients to interpret medical reports, including ENMG results for ALS. While AI shows promise in controlled clinical settings (e.g., stroke imaging, melanoma detection), consumer-facing tools often provide overconfident, context-free diagnostic assertions (e.g., 'definitive evidence of ALS'), leading to premature and potentially harmful life-altering decisions.

OBJECTIVE: To highlight the clinical, ethical, and regulatory risks of unregulated AI in ALS diagnosis and propose actionable solutions.

DISCUSSION: We present a case of AI-mediated misdiagnosis, analyze the limitations of consumer-facing AI (lack of clinical context, longitudinal data, and specialist oversight), and discuss the "authority paradox" (patients trusting AI outputs over clinicians' nuanced assessments). We propose a structured 4-step clinical approach for managing AI-mediated self-diagnoses and urge regulators to classify such tools as high-risk under the EU AI Act.

CONCLUSION: The uncritical adoption of consumer AI in ALS diagnosis represents a public health risk. Clinicians, regulators, and developers must collaborate to ensure AI serves patients safely and ethically.}, } @article {pmid42477767, year = {2026}, author = {Zhang, H and Li, C and Yu, J and Liang, Y and Wu, Y and Cao, F}, title = {Unraveling the role of lipid metabolism in ALS risk: a Mendelian randomization analysis using GWAS data.}, journal = {Orphanet journal of rare diseases}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13023-026-04503-2}, pmid = {42477767}, issn = {1750-1172}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Lipid metabolism is closely related to neuronal function and energy homeostasis, but the genetic association between specific lipid species and ALS risk remains unclear.

OBJECTIVE: This study aimed to investigate the potential causal associations between genetically predicted lipid species and ALS risk using a two-sample Mendelian randomization (MR) approach.

METHODS: Summary-level GWAS data for 179 lipid species were obtained from 7,174 Finnish participants in the GeneRISK cohort. ALS GWAS data included 29,612 ALS cases and 122,656 controls. The inverse variance weighted (IVW) method was used as the primary MR approach, supplemented by MR-Egger, weighted median, weighted mode, and simple mode analyses. False discovery rate (FDR) correction was applied across all lipid traits based on IVW P values. Sensitivity analyses were conducted to assess heterogeneity, horizontal pleiotropy, and robustness.

RESULTS: After FDR correction, genetically predicted higher levels of diacylglycerol (DAG) (18:1_18:1), phosphatidylcholine (PC) (16:1_18:1), PC (18:0_18:1), phosphatidylethanolamine (PE) (O-16:1_18:2), and several triacylglycerol (TAG) species were associated with increased ALS risk. Phosphatidylinositol (PI) (16:0_18:1) showed only a nominal protective association and did not remain significant after FDR correction. Sensitivity analyses did not indicate substantial heterogeneity or horizontal pleiotropy.

CONCLUSION: This MR study provides genetic evidence supporting potential associations between specific lipid species and ALS risk. These findings highlight lipid metabolism as a relevant pathway in ALS susceptibility.}, } @article {pmid42477825, year = {2026}, author = {Brenner, D and Ponomarenko, A and Petrut, I and Beyrle, S and Contardo, M and Loss, I and Radke, C and Frank, J and Zimmer, E and Schlesner, M and Achenbach, P and Scheveneels, W and Aly, A and Nazlican, H and Hesebeck-Brinkmann, J and Oeckl, P and Müller, K and Siebert, R and Böckers, T and van Eijk, K and Veldink, J and Kleger, A and Mulaw, M and Andersen, PM and Forsberg, K and Weishaupt, JH and Loghmani, SB and Grehl, T and van Damme, P and Weis, J and Catanese, A}, title = {Correction: A rare missense variant impacting NEK1 kinase function is associated with ALS.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42477825}, issn = {2051-5960}, } @article {pmid42479532, year = {2026}, author = {Khan, JS and Mohammadi, M and Ammitzboll, AL and Hagen, EM and Blicher, J and Obai, I and Cardoso, ASS and Kirtas, O and Kaeseler, RL and Rasmussen, J and Struijk, LNSA}, title = {A Tendon-Driven Wrist Abduction-Adduction Joint Improves Performance of a 5 DoF Upper Limb Exoskeleton - Implementation and Experimental Evaluation.}, journal = {IEEE transactions on bio-medical engineering}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TBME.2026.3715599}, pmid = {42479532}, issn = {1558-2531}, abstract = {OBJECTIVE: Wrist function is essential in performing activities of daily living (ADLs). However, there is limited experimental evidence on the functional impact of wrist Abduction-Adduction (Ab-Ad) joint assistance in upper limb exoskeletons (ULEs) during ADLs. This study provides the first implementation and demonstration of a clock spring-based wrist Ab-Ad joint into a five degree of freedom (DoF) ULE, EXOTIC2 exoskeleton and evaluates its effect, to support individuals with severe motor impairments.

METHODS: A compact, lightweight wrist module with tendon-driven abduction and spring-driven adduction was integrated into the EXOTIC exoskeleton. Eight adults with no motor disabilities completed drinking and scratching tasks under randomized wrist-enabled and wrist-locked conditions along with a preliminary feasibility test in one individual with Amyotrophic lateral sclerosis (ALS). Kinematic and task performance metrics including wrist range of motion, task completion time, spillage and leveling metrics were assessed.

RESULTS: Implementing the wrist Ab-Ad DoF improved task success metrics. Spill incidence during the drinking task decreased from 56% to 3%, and leveling success for scratching task improved from 28% to 75%.

CONCLUSION: Integrating wrist Ab-Ad assistance improved key functional task outcomes without increasing execution time.

SIGNIFICANCE: The study provides the experimental evidence that active wrist Ab-Ad control enhances task-level performance in exoskeleton-assisted ADLs and supports the inclusion of wrist deviation in future assistive exoskeletons.}, } @article {pmid42479906, year = {2026}, author = {Tahedl, M and Siah, WF and Lope, J and Hengeveld, JC and Doherty, MA and McLaughlin, RL and Hardiman, O and Tan, EL and Toomey, A and Kleinerova, J and Bede, P}, title = {Neurotransmitter-Defined Degeneration Patterns in Sporadic and C9orf72-Associated Amyotrophic Lateral Sclerosis: Predilection to GABAergic, Serotonergic, Opioid, Glutamatergic, Endocannabinoid, and Microglial Systems-Implications for Therapy Development.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78316}, pmid = {42479906}, issn = {1531-8249}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) has a markedly distinctive clinical and neuroradiological signature, with the preferential involvement of specific brain networks and the apparent sparing of others. The molecular underpinnings of the strikingly selective anatomical vulnerability have not been fully elucidated to date despite the potential therapeutic relevance of characterizing neurotransmitter receptor-defined susceptibility to degeneration.

METHODS: A large neuroimaging study was undertaken with 258 participants to systematically evaluate topological associations between neurodegeneration and neurotransmitter expression distributions. Patients were stratified based on their genetic profile into sporadic and C90rf72 hexanucleotide repeat expansion carriers. Anatomical associations were evaluated between patterns of atrophy and topological neurotransmitter receptor distributions. Cross-sectional and longitudinal trends were comprehensively evaluated over 4 consecutive timepoints.

RESULTS: Our analyses reveal topological associations between neurodegeneration in sporadic ALS and GABA-A receptor α5-selective component (GABAa5), serotonin 1a receptor, and kappa opioid receptor expression maps. In addition to these networks, neuronal loss in patients with GGGGCC hexanucleotide repeat expansions exhibit predilection to glutamatergic, endocannabinoid, and microglial systems. Our multi-timepoint longitudinal analyses reveal dynamic temporal associations between focal volume loss and neurotransmitter expression with increasing spatial associations with noradrenaline transporter and GABAa5, but high attrition rates preclude definite longitudinal inferences.

INTERPRETATION: Our data suggest the preferential vulnerability of GABAergic, serotonergic, kappa opioid mediated networks in sporadic ALS. In C9orf72-assocaited ALS, glutamatergic, endocannabinoid circuits are also susceptible and microglia-mediated neuroinflammation is also implicated. The comprehensive evaluation of neurotransmitter-receptor associations not only offer academic insights regarding pathophysiological processes in ALS, but may inform targeted therapy development strategies. ANN NEUROL 2026.}, } @article {pmid42480869, year = {2026}, author = {Petro, TM and Pattee, GL and Esmael, A and Agarkova, IV and Dunigan, DD and Chiodo, F and De Castro, C and Van Etten, JL}, title = {Macrophage responses to and elevated antibody levels against Chlorovirus ATCV-1 in ALS patients.}, journal = {Antiviral research}, volume = {253}, number = {}, pages = {106491}, doi = {10.1016/j.antiviral.2026.106491}, pmid = {42480869}, issn = {1872-9096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/virology ; *Macrophages/immunology/virology ; *Antibodies, Viral/blood/cerebrospinal fluid/immunology ; Animals ; THP-1 Cells ; Mice ; Cytokines ; Immunoglobulin G/blood ; Picornavirales ; Female ; Capsid Proteins/immunology ; }, abstract = {Acanthocystis turfacea chlorella virus 1 (ATCV-1) is a giant virus that is part of the human oral microvirome. Previously we showed that ATCV-1 infects mouse macrophages, stimulates production of inflammatory cytokines, and accelerates motor neuron disease in the Amyotrophic Lateral Sclerosis (ALS) model SOD1-G93A transgenic mice. This, coupled with significantly elevated levels of serum IgG1 antibody to ATCV-1 in ALS patients compared with healthy controls, suggests involvement of ATCV-1 in ALS. Herein, using serum and CSF from a different ALS cohort we again show elevated antibodies to ATCV-1 in ALS patients compared with healthy controls. To assess ATCV-1 in human macrophages, we challenged immature (IMM), M0, M1, and M2 human THP-1 macrophage cells containing an Interferon Stimulated Response Element (ISRE) promoter-reporter with ATCV-1 or its Major Capsid protein (MCP) glycans. ATCV-1 infected M1 THP-1 to a greater degree than IMM, M0, or M2 THP-1. The initial high ISRE-promoter activity of M1 THP-1 was suppressed by the MCP-Glycans of ATCV-1. M0, but not IMM or M2 THP-1 produced IL-6 in response to ATCV-1 or its MCP-glycan, while high levels of IL-6 from unchallenged M1 THP-1 increased further by ATCV-1 or its MCP glycan. In contrast, ATCV-1 or its MCP-Glycan significantly reduced the high levels of IL-10 produced by M2 THP-1. Thus, antibody to ATCV-1 in ALS patients and the susceptibility of human M1 macrophages to ATCV-1 infection with boosted inflammatory cytokine and diminished anti-inflammatory cytokine production suggest that ATCV-1 may contribute to ALS motor neuron disease.}, } @article {pmid42481428, year = {2026}, author = {Fukumoto, T and Osaki, Y and Hanada, K and Fujita, K and Kaji, R and Izumi, Y}, title = {The Anterior Belly of the Digastric Muscle as a Novel Target for Needle Electromyography in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {74}, number = {3}, pages = {685-691}, pmid = {42481428}, issn = {1097-4598}, support = {JPMH23FC1008//Ministry of Health, Labour and Welfare, Japan, through the Research Program on Rare and Intractable Diseases/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Female ; *Electromyography/methods/instrumentation ; Male ; Middle Aged ; Aged ; Prospective Studies ; Needles ; *Neck Muscles/physiopathology ; Adult ; Pain Measurement ; }, abstract = {INTRODUCTION/AIMS: Needle electromyography (EMG) in the bulbar region aids in the diagnosis of amyotrophic lateral sclerosis (ALS) but remains technically challenging. The genioglossus muscle (GM) is commonly examined; however, pain and poor relaxation may limit its evaluation. The trapezius is an alternative target but is innervated by the spinal accessory nerve. We investigated the utility of the anterior belly of the digastric muscle (ABDM), innervated by the trigeminal nerve, for bulbar EMG evaluation.

METHODS: In this unblinded, prospective observational study, consecutive patients with suspected ALS underwent needle EMG of the ABDM, GM, masseter muscle (MM), and trapezius. Relaxation levels, EMG abnormalities, and pain (100-mm visual analog scale [VAS]) were assessed.

RESULTS: Twenty-seven clinically diagnosed ALS patients were analyzed. Relaxation was better in the ABDM than in the GM (p < 0.001) and comparable to that in the MM and trapezius. Fasciculation potentials were detected more often in the ABDM (52%) than in the GM (0%) and MM (22%; p = 0.039) and were comparable to the trapezius (59%). Chronic denervation occurred at similar frequencies across muscles (33%-59%). The combination of abnormal spontaneous activity and chronic denervation was most frequent in the ABDM (37%). Pain was lower with the ABDM (median VAS score of 21) than with the GM (28; p = 0.0052) and MM (32; p < 0.001) and was similar to the trapezius (23).

DISCUSSION: The ABDM may be a practical additional target for bulbar EMG in ALS, with favorable relaxation, lower pain, and potentially improved electrodiagnostic yield.}, } @article {pmid42481875, year = {2026}, author = {Sahin, U and Firat-Karalar, EN}, title = {The centrosome-cilium-centriolar satellite axis in neurodegenerative diseases.}, journal = {EMBO reports}, volume = {27}, number = {16}, pages = {4624-4652}, pmid = {42481875}, issn = {1469-3178}, support = {101078097//EC | H2020 | PRIORITY 'Excellent science' | H2020 European Research Council (ERC)/ ; 3336//European Molecular Biology Organization (EMBO)/ ; 3622//European Molecular Biology Organization (EMBO)/ ; YIP//European Molecular Biology Organization (EMBO)/ ; (SU PREG)//Sabanci University President's Research/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Centrosome/metabolism/pathology ; *Cilia/metabolism/pathology ; *Centrioles/metabolism ; Animals ; Signal Transduction ; Neurons/metabolism/pathology ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and hereditary ataxias, remain major global health challenges with limited therapeutic options. Although clinically and genetically diverse, these diseases share extensively studied cellular and molecular hallmarks, including protein aggregation, impaired proteostasis, cytoskeletal abnormalities, altered energy metabolism, nucleic acid damage, and chronic inflammation. Emerging evidence indicates that dysfunction of the centrosome-cilium-satellite axis intersects with these established pathways in disease- and cell type-specific contexts. This axis, composed of centrosomes, primary cilia, and centriolar satellites, coordinates cytoskeletal organization, ciliary signaling, trafficking, proteostasis, and stress responses and acquires specialized functions in neurons that support polarity, connectivity, and long-term maintenance. In this review, we outline the structure, function, and neuronal specializations of the centrosome-cilium-satellite axis, then examine how its dysfunction has been reported in neurodegenerative disease models. We also discuss centriolar satellites as regulators of centrosome and cilium biology whose disease-specific roles in classical NDDs remain comparatively underexplored, with insights from Huntington's disease and schizophrenia. Finally, we discuss therapeutic strategies aimed at restoring axis structure and dynamics, modulating ciliary signaling, and correcting disease-linked genetic or transcript-level defects, emphasizing mechanism-based approaches that require validation in disease-relevant models. Together, the centrosome-cilium-satellite axis provides an emerging framework for understanding context-dependent organelle dysfunction in neuronal vulnerability and neurodegeneration.}, } @article {pmid42482399, year = {2026}, author = {Merrill, K and Giesel, BP and Barclay, JS}, title = {Assessing Involvement and Training of Academic Palliative Care Programs in the Care of Patients with Sickle Cell Disease: A Nationwide Survey.}, journal = {Journal of palliative medicine}, volume = {}, number = {}, pages = {10966218261472552}, doi = {10.1177/10966218261472552}, pmid = {42482399}, issn = {1557-7740}, abstract = {BACKGROUND: Despite high symptom burden and limited lifespan associated with sickle cell disease (SCD), specialty palliative care (PC) services remain underutilized in this marginalized population.[1,2] The extent of routine involvement, barriers to care, and training in the care of SCD patients at academic PC programs in the United States has not been quantified.

OBJECTIVE: To assess PC involvement and training in SCD care, identify barriers to access, and inform integration strategies.

DESIGN/SETTING: An anonymous Qualtrics survey, developed through literature review and expert panel, was emailed to 180 palliative medicine fellowship program directors or surrogates (June 18-July 25, 2025) in the United States. The survey included demographics, program practices regarding SCD and other chronic conditions (cystic fibrosis, amyotrophic lateral sclerosis, and chronic nonmalignant pain), frequency of routine SCD education, and perceived barriers to providing care to these patients.

RESULTS: Fifty-one responses were received (28.3% response rate). Only 37% of programs routinely care for SCD patients (31.5% inpatient only, 10.5% outpatient, 58% both). Among these, 68% regularly prescribed opioids. Programs not routinely involved reported exceptions for patients with limited prognosis, comorbidities such as active cancer, or imminent end-of-life needs. The most common reported barriers to seeing patients with SCD were lack of outpatient resources (46%) and staffing constraints (44%). Free-text responses cited limited referrals, competing specialty ownership (hematology), institutional restrictions, and scope-of-practice limitations. Only 38% of programs included SCD in their fellowship curriculum, and 20% offered routine training for all PC team members.

CONCLUSIONS: Fewer than half of academic PC programs routinely care for SCD patients, and most programs lack formal SCD training. Institutional and systemic barriers limit access, highlighting the need for resources and education to expand PC integration into SCD care. There is a need for consensus guidelines stratifying PC involvement in SCD patients.}, } @article {pmid42482414, year = {2026}, author = {Topsøe-Jensen, SK and Wingren, CJ and Villa, C}, title = {Forensic bruise documentation with alternate light sources: Preliminary observation on deceased individuals in a routine illuminated autopsy setting.}, journal = {Journal of forensic sciences}, volume = {71}, number = {5}, pages = {2386-2394}, pmid = {42482414}, issn = {1556-4029}, mesh = {Humans ; Male ; *Contusions/pathology ; *Lighting ; *Documentation/methods ; Female ; Photography ; Aged ; Middle Aged ; Adult ; Observer Variation ; Forensic Pathology ; *Light ; Aged, 80 and over ; Young Adult ; Logistic Models ; }, abstract = {Alternate light sources (ALS) have been suggested to improve bruise visibility for medicolegal evaluations. Previous studies have recommended darkened conditions; however, this does not reflect real-life autopsy settings, where multiple examinations are conducted simultaneously and turning off the lights is neither practical nor safe. This study evaluated the use of ALS for documenting bruises under normal lighting conditions without altering the autopsy setup. We photographed 161 bruises (99 recent, 62 non-recent) using CrimeLite® AUTO (Foster+Freeman) under common white light (CWL), violet ALS with 415 nm long-pass (VLP), violet ALS with 415 nm band-pass (VBP), and blue ALS with 445 nm long-pass (BLP). Bruises were classified as recent or non-recent based on the presence of yellow coloration. Visibility was scored using a "modified" Bruise Visibility Scale (BVS), and surface area was measured. Observer variability was assessed using Cohen's kappa (κ) and intraclass correlation coefficients (ICC); logistic and Cox regression analyses were performed to evaluate BVS and size across lighting sources. We found that ALS did not enhance bruise visibility compared to CWL. VBP and BLP reduced visibility, while VLP showed occasional improvements but without statistical significance. Surface area measurements indicated that VLP visualizes bruises with larger dimensions than under CWL, whereas BLP and VBP did not. Observer agreement for the four BVS categories yielded κ values ranging from moderate to substantial, while ICCs showed excellent agreement for surface-area measurements for most light sources. Despite its limitations, the study suggests that ALS, particularly VLP, may have potential utility for bruise documentation under normal lighting conditions.}, } @article {pmid42482658, year = {2026}, author = {Wang, J and Wang, Y and Yang, T and Yan, X and Luo, J and Wu, S and Tong, J and Zhao, M and Yang, G}, title = {Sex-associated differences in routine inflammatory markers and neuromuscular ultrasound measurements in amyotrophic lateral sclerosis: a retrospective cross-sectional study.}, journal = {Annals of medicine}, volume = {58}, number = {1}, pages = {2703317}, pmid = {42482658}, issn = {1365-2060}, mesh = {Humans ; Female ; Male ; Cross-Sectional Studies ; Retrospective Studies ; *Amyotrophic Lateral Sclerosis/blood/diagnostic imaging/physiopathology ; Middle Aged ; Biomarkers/blood ; Ultrasonography ; Aged ; Sex Factors ; Disease Progression ; Blood Sedimentation ; *Inflammation/blood ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with substantial clinical heterogeneity. Systemic inflammatory markers and neuromuscular ultrasound measurements have both been studied in ALS, but their sex-associated differences within ALS cohorts remain incompletely characterized.

OBJECTIVE: To examine sex-associated differences in routine inflammatory markers and neuromuscular ultrasound measurements in patients with ALS, and to determine whether these differences persisted after adjustment for available clinical and anthropometric variables.

METHODS: In this retrospective cross-sectional study, 135 patients with ALS were included. Routine inflammatory markers, including neutrophils, monocytes, lymphocytes, platelets, and erythrocyte sedimentation rate (ESR), were analyzed alongside quantitative neuromuscular ultrasound measurements. Between-sex comparisons were performed, and false discovery rate correction was applied to account for multiple testing. Multivariable linear regression analyses were performed with adjustment for age, disease duration, body mass index (BMI), ALSFRS-R total score, FVC% predicted, smoking status, hypertension, and diabetes.

RESULTS: Female patients showed lower ALSFRS-R total scores and higher estimated progression rates in unadjusted comparisons, whereas pulmonary function variables did not differ significantly between sexes. After FDR correction, estimated progression rate, neutrophil count, monocyte count, ESR, and masseter muscle thickness remained significantly different between sexes, while the ALSFRS-R difference was borderline significant. In fully adjusted models, female sex was associated with lower neutrophil count, monocyte count, and median nerve cross-sectional area; biceps brachii thickness showed a less stable association after sensitivity analysis. An exploratory secondary analysis showed lower rectus femoris cross-sectional area during thigh-lift in female patients after full adjustment. In the spline sensitivity analysis, this association remained statistically significant but was interpreted cautiously because it was not present in the earlier adjustment models.

CONCLUSIONS: Selected routine inflammatory markers and neuromuscular ultrasound measurements differed between male and female patients within this ALS cohort. These findings support consideration of sex and anthropometric context, including body size, when interpreting inflammatory markers and ultrasound-based structural measurements. In the absence of healthy controls, the observed ultrasound differences cannot be attributed specifically to ALS-related biology. Studies with healthy controls, longitudinal functional outcomes, body-composition assessment, and independent multicenter cohorts are needed to clarify the disease-specific and prognostic relevance of these observations.}, } @article {pmid42484074, year = {2026}, author = {Carberry, N and Wuu, J and Benatar, M}, title = {SOD1-lowering therapy for patients with wildtype SOD1-ALS: a case report.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2026.2705142}, pmid = {42484074}, issn = {2167-9223}, abstract = {Background and Objectives: To describe clinical and biomarker experience using an SOD1 antisense oligonucleotide (ASO) in a patient with non-SOD1 amyotrophic lateral sclerosis (ALS). Methods: Case report. Results: In a 72-year-old male with non-SOD1 ALS, rapid decline on the ALS functional rating scale revised (ALSFRS-R) and a rise in serum neurofilament light chain (NfL) concentration were observed following 3 loading doses of an SOD1 ASO before the patient succumbed to disease. The time from symptom onset to death was 9 months. Discussion: While treatment was initiated relatively late (∼7 months) after symptom onset and follow-up duration was short, the observed increase (as opposed to a reduction) in serum NfL and accompanying rapid functional decline, suggest the lack of a therapeutic effect in someone with fast progressing non-SOD1 ALS.}, } @article {pmid42484509, year = {2026}, author = {Tsujisawa, Y and Takahashi-Iwata, I and Yabe, I and Mukaino, M and Shibamoto, I}, title = {An investigation of factors associated with speech intelligibility in patients with amyotrophic lateral sclerosis: Integrating acoustic and lingual motor measures.}, journal = {Clinical linguistics & phonetics}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/02699206.2026.2704600}, pmid = {42484509}, issn = {1464-5076}, abstract = {Speech intelligibility in amyotrophic lateral sclerosis (ALS) progressively declines, but contributing clinical factors may vary according to disease presentation and extent of bulbar involvement. This study examined factors associated with intelligibility in three ALS groups: spinal-onset, spinal-onset with bulbar involvement (spinal + bulbar), and bulbar-onset. Speech intelligibility (visual analogue scale), hypernasality, maximum tongue pressure, respiratory function (%VC and FEV1/FVC), and second formant (F2) transition measures (transition duration and excursion) were evaluated. Exploratory two- and three-dimensional visualisations were used to examine interrelationships among variables, and regression analyses were conducted in groups with sufficient sample size. In spinal-onset ALS, only hypernasality was associated with intelligibility. In bulbar-onset ALS, both tongue pressure and hypernasality were significantly associated with intelligibility, while preserved F2 excursion showed an additional trend towards better intelligibility. In the spinal + bulbar group, descriptive findings suggested that reduced tongue pressure and increased hypernasality were associated with lower intelligibility. These findings suggest that speech intelligibility in ALS is influenced by different combinations of bulbar-related impairments depending on clinical presentation and extent of bulbar involvement. In particular, tongue strength, velopharyngeal function, and residual tongue mobility may be relevant to intelligibility outcomes with bulbar involvement. Combined evaluation of these measures may help inform individualised clinical assessment and management.}, } @article {pmid42484672, year = {2026}, author = {Shen, Z and Yu, Q}, title = {Protein arginine methyltransferases as regulators of phase separation: implications in cancer and neurodegenerative diseases.}, journal = {European biophysics journal : EBJ}, volume = {}, number = {}, pages = {}, pmid = {42484672}, issn = {1432-1017}, abstract = {Protein arginine methyltransferases (PRMTs) catalyze arginine methylation, a key post-translational modification (PTM) regulating chromatin organization, RNA metabolism, and signaling. Recent studies reveal that PRMT-mediated methylation also modulates liquid-liquid phase separation (LLPS), which organizes membraneless condensates controlling transcription, stress response, and genome stability. Dysregulated PRMT activity disrupts condensate dynamics, contributing to cancer and neurodegenerative diseases. In cancer, PRMT1, PRMT5, and PRMT6 promote tumor progression via methylation-dependent condensates that enhance oncogenic transcription and stress resistance. In the nervous system, PRMT1, PRMT4, PRMT5, PRMT6, and PRMT8 regulate LLPS of proteins, linking aberrant methylation to ALS and Huntington's disease. This review highlights PRMTs as key modulators of phase separation and potential therapeutic targets in both oncology and neurodegeneration.}, } @article {pmid42484778, year = {2026}, author = {Lill, CM and Homann, J and Ohlei, O and Smith-Byrne, K and Viallon, V and Huerta, JM and Artaud, F and Zhao, Y and Britten, A and Deecke, L and Dobricic, V and Mokoroa, O and Guevara, M and Petrova, D and Trupp, M and Sabin, J and Gröninger, M and Colorado-Yohar, SM and Alonso-Martin, S and Cabrera-Castro, N and Groppa, S and Robinson, O and Hansen, J and Eriksson, S and Sieri, S and Jimenez, A and Tong, TYN and Kaaks, R and Severi, G and Travis, R and Wareham, N and Benedet, AL and Zetterberg, H and Franke, A and Elbaz, A and Bertram, L and Vermeulen, R and Middleton, L and Masala, G and Sacerdote, C and Peters, S and Katzke, V and Ferrari, P and Gunter, MJ and Riboli, E}, title = {EPIC4ND-European Prospective Investigation into Cancer and Nutrition follow-up for neurodegenerative diseases.}, journal = {European journal of epidemiology}, volume = {}, number = {}, pages = {}, pmid = {42484778}, issn = {1573-7284}, support = {#008994//Michael J Fox Foundation/ ; JPND2021-650-289//EU Joint Programme - Neurodegenerative Disease Research/ ; LI 2654/3-1//Deutsche Forschungsgemeinschaft/ ; LI 2654/4-1 (Heisenberg)//Deutsche Forschungsgemeinschaft/ ; INTRAIBS-2020-06//Instituto de Investigación Biosanitaria ibs.GRANADA/ ; }, abstract = {The 'European Prospective Investigation into Cancer and Nutrition' cohort (EPIC) is a prospective study including ~ 520,000 participants recruited across Europe (1991-2000) with in-depth baseline data on nutritional, lifestyle, medical, and anthropometric variables, and baseline blood samples. Here we introduce EPIC4ND, a case-cohort study within EPIC designed to identify biomarkers predicting a future onset of dementia, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). EPIC4ND comprises 6415 initially non-diseased participants (aged 35-80 years, mean age at baseline: 54 ± 9, 64% women) including 1899 incident cases with up to 30 years of follow-up and data on at least one omics domain available from pre-disease blood samples. EPIC4ND includes 4604 subcohort members (4441 non-cases and 163 incident cases) and 1811 additional incident cases ascertained from the broader EPIC cohort. Among the incident cases, there are 1190 dementia cases (818 AD), 610 PD cases, and 199 ALS cases. Additionally, 72 prevalent PD cases and 118 incident Parkinsonism cases are available for comparison. Molecular data generated encompass proteomics, genome-wide DNA methylation, and SNP genotyping with 4127 EPIC4ND participants (including 1635 incident cases) having data on all three domains. Smaller studies include data on metals, metabolites, and environmental chemicals, while ongoing efforts focus on ultrasensitive targeted biomarker measurements and small RNA sequencing. Genome-wide association studies and analyses of epidemiological risk factors validate the dataset by confirming many known risk factors. Leveraging these extensive pre-disease multi-layered omics data offers a unique opportunity to identify biomarker signatures predicting neurodegenerative diseases and to explore their interplay with epidemiological risk factors.}, } @article {pmid42485353, year = {2026}, author = {Vanunu, M and Zecharia, N and Dror, O and Omer, Y and Brukental, H and Harel-Beja, R and Hatib, K and Azoulay-Shemer, T and Holland, D and Shtienberg, D and Bahar, O}, title = {Identification of an Almond Cultivar Resistant to Xylella fastidiosa subsp. fastidiosa and Insights into Host-Specific Bacterial Behavior.}, journal = {Plant disease}, volume = {}, number = {}, pages = {}, doi = {10.1094/PDIS-02-26-0369-RE}, pmid = {42485353}, issn = {0191-2917}, abstract = {Xylella fastidiosa (Xf) is a xylem-limited bacterial pathogen causing disease in a variety of important agricultural crops, including almonds. Almond leaf scorch (ALS) disease was first identified in Israel in 2017 and is associated with the subspecies X. fastidiosa subsp. fastidiosa (Xff) sequence type 1. Currently, there is no effective means to cure infected almond trees, and ALS management relies primarily on uprooting infected trees and reducing vector populations, yet these methods are only moderately effective. Thus, identifying resistant almond genotypes is a critical goal for developing durable ALS management strategies. In this study, we utilized three complementary methods to evaluate resistance among various almond genotypes: 1) grafting onto Xff-infected trees; (2) mechanically inoculating young trees' stems; and (3) mechanically inoculating individual leaves. In a field-based grafting experiment involving seven genotypes, 'Lauranne' exhibited strong resistance to Xff infection compared to the other tested cultivars. In subsequent two experiments, we monitored Xff migration and colonization in 'Lauranne', a susceptible almond cultivar ('Um ElFahem'), and a non-host plant, plum. Although Xff was able to migrate and replicate within 'Lauranne', it did so at significantly lower levels and with slower progression rate. Histological analysis at the leaf level further confirmed that the number of Xff-colonized xylem vessels was substantially reduced in 'Lauranne' relative to the susceptible cultivar. These findings highlight 'Lauranne' as a promising resistant cultivar and underscore the importance of identifying resistance mechanisms in almonds. Incorporating resistant genotypes (such as 'Lauranne') into breeding programs may offer a durable and sustainable solution to manage ALS in the future.}, } @article {pmid42487076, year = {2026}, author = {Picchiarelli, G and Wienand, A and Megat, S and Hutten, S and Aly, A and Been, M and Weber, I and Bonanno, A and Mishra, N and Sternburg, E and Cauchy, P and Dieterle, S and Catinozzi, M and Lobo-Mancheno, J and Walgrave, H and Demais, V and Hener, P and Kessler, P and Tzeplaeff, L and Huebers, A and Zeuschner, D and Rosenbohm, A and Ludolph, AC and Boutillier, AL and Boeckers, T and Dormann, D and Demestre, M and Sellier, C and Lagier-Tourenne, C and Storkebaum, E and Dupuis, L}, title = {FUS controls muscle differentiation through phase separation-mediated recruitment of the transcription factors MEF2 and ETV5.}, journal = {The EMBO journal}, volume = {45}, number = {17}, pages = {6267-6298}, pmid = {42487076}, issn = {1460-2075}, support = {ANR-16-CE92-0031,ANR-19-CE17-0016,ANR-20-CE17-0008,ANR-21-CE17-0039//Agence Nationale de la Recherche (ANR)/ ; ANR-10-IDEX-0002//Agence Nationale de la Recherche (ANR)/ ; ANR-20-SFRI-0012//Agence Nationale de la Recherche (ANR)/ ; ANR-24-INBS-0005 FBI BIOGEN//Agence Nationale de la Recherche (ANR)/ ; #23646 #18280//French Muscular Dystrophy Association (AFM)/ ; Coup d'élan 2019//Fondation Bettencourt Schueller (Bettencourt Schueller Foundation)/ ; DEQ20180339179//Fondation pour la Recherche Médicale (FRM)/ ; rare disease award 2019//AXA Research Fund (FONDS AXA POUR LA RECHERCHE)/ ; 2016,2021//Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone (ARSLA)/ ; 2235//ALS Association (ALSA)/ ; 946876//Muscular Dystrophy Association (MDA)/ ; Open Competition ENW-M//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)/ ; 442698351//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)/ ; 497669232//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)/ ; ERC-2017-COG 770244//EC | European Research Council (ERC)/ ; ClueDol//region grand est/ ; 84012490//EC | ERDF | Interreg/ ; }, mesh = {Animals ; Mice ; MEF2 Transcription Factors ; *Transcription Factors/metabolism/genetics ; *Muscle, Skeletal/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *RNA-Binding Protein FUS/genetics/metabolism ; *Myogenic Regulatory Factors/metabolism/genetics ; Phase Separation ; *Cell Differentiation ; *Muscle Development ; }, abstract = {FUS is an RNA-binding protein mutated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive muscle weakness. We show in this work that a heterozygous knock-in mutation in the mouse Fus gene leads to cell-autonomous ultrastructural defects in skeletal muscle, with disruption of sarcomeres and mitochondria. Studies in mouse and Drosophila models demonstrate an evolutionarily conserved cell-autonomous function of FUS in muscle development. Mechanistically, FUS is required for the transcription of MEF2 target genes, binds to the promoter of genes bound by ETS transcription factors, in particular ETV5, and co-activates the transcription of MEF2-dependent genes with ETV5. FUS phase-separates with ETV5 and MEF2A, and stimulation of MEF2-dependent transcription by FUS is dependent upon its phase separation properties. Finally, Etv5 haploinsufficiency exacerbates muscle weakness and atrophy in Fus knock-in mice. Our findings establish a key role for FUS in skeletal muscle differentiation through its phase separation-dependent recruitment of ETV5 and MEF2, defining a novel pathway compromised in FUS-ALS.}, } @article {pmid42487414, year = {2026}, author = {Bruce, AJ and Menapace, DC}, title = {Invited Commentary on: Gaebe et al's "Effectiveness and Safety of Extracellular Vesicle-Based Therapies for Non-Surgical Facial Rejuvenation: A Systematic Review": Extracellular Vesicles in Aesthetic Medicine: Promise Requires Proof.}, journal = {Facial plastic surgery & aesthetic medicine}, volume = {}, number = {}, pages = {26893614261466120}, doi = {10.1177/26893614261466120}, pmid = {42487414}, issn = {2689-3622}, } @article {pmid42489267, year = {2026}, author = {Xie, Q and Zhu, Y and Jiang, W and Xie, H and Li, Y and Hu, M and Li, K and Yu, H and Pan, Y and Jiang, C and Song, X and Fan, D and Deng, B}, title = {A Blood-Derived Factor Rescues ALS: Platelet Factor 4 Activates OPTN-Dependent Autophagy to Clear SOD1 Aggregates Independently of PINK1.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e76778}, pmid = {42489267}, issn = {2198-3844}, support = {ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; 2025L-C7//Hebei Key Laboratory of Neurology/ ; }, abstract = {Peripheral factors that systemically regulate amyotrophic lateral sclerosis (ALS) have remained elusive-until now. Here, by integrating population-scale epidemiology with mechanistic dissection, we identify platelet factor 4 (PF4) as the central driver of a circulating neuroprotective axis that restores proteostasis and rescues ALS. In a prospective cohort of >500 000 UK Biobank participants, platelet indices were strongly associated with ALS risk, and serum PF4 levels were significantly reduced in ALS patients. Systemic administration of recombinant PF4 in hSOD1[G93A] mice produced dramatic therapeutic effects: extended survival, preserved motor function, attenuated neuroinflammation, and reduced neuromuscular junction denervation. Remarkably, this efficacy appears pathology-selective-robust in SOD1-driven models but shows no observable effect in TDP-43 or C9orf72 ALS models. Mechanistically, PF4 achieves what few molecules can: it engages the cell surface receptor LRP1 to activate the TBK1-OPTN signaling axis, restoring impaired autophagic flux through a PINK1/Parkin-independent pathway requiring ATG7, establishing a previously unrecognized peripheral platelet-autophagy-neuron axis that facilitates the co-clearance of pathological SOD1 aggregates and damaged mitochondria. This study unveils PF4 as a first-in-class circulating autophagy regulator with therapeutic potential in ALS. Beyond identifying a candidate biomarker and drug lead, it reveals that systemic factors can directly engage central proteostatic machinery-opening a new frontier for ALS therapy.}, } @article {pmid42489904, year = {2026}, author = {Jellinger, KA}, title = {Psychiatric disorders in amyotrophic lateral sclerosis: a short note.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {42489904}, issn = {1435-1463}, abstract = {Traditionally, amyotrophic lateral sclerosis (ALS) has been defined as a rapidly progressive neurodegenerative disorder that affects the large motor neurons of the brain and spinal cord. The assumption that ALS is a pure motor disorder has been increasingly challenged by accumulating evidence about an association between ALS and psychiatric disorders. They often precede the onset of motor symptoms or psychoses; hallucinations and schizophrenia may occur as concomitant changes. These non-motor disorders have a close relationship with disease onset or may be related to a larger framework of neuronal network disruptions in motor neuron disorders. The link between ALS and schizophrenia was supported by substantial genetic correlations associating the C9orf72 gene expansion with psychiatric disorders. The genetic correlation between ALS and schizophrenia was estimated to be 14.3% with frequent polygenic risk scores. Increased psychotic symptoms in C9orf72 carriers correlate with atrophy in a distributed cortical and subcortical network that includes multiple cerebral regions. ALS kindreds often present higher rates of psychiatric illnesses, and early schizophrenia is significantly associated with the development of ALS. Further studies should attempt to delineate the risk of psychiatric disorders in C9orf72 kindreds to aid in clinical decision making and genetic counseling, through collaborations between neurology and psychiatry.}, } @article {pmid42491041, year = {2026}, author = {Wei, Z and Bai, L and Liu, X and Zhou, Y and Zheng, L and Zhang, B and Wang, L and Zou, W}, title = {Histone lactylation-mediated glycolysis-ferroptosis axis in neurological diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1820758}, pmid = {42491041}, issn = {1662-5099}, abstract = {Histone lactylation is an emerging epigenetic modification that covalently links the glycolytic metabolite lactate to histones, thereby establishing a direct link between cellular metabolic status and gene transcription programs. Recent studies have shown that this modification plays a key role in regulating cellular sensitivity to ferroptosis, forming a novel regulatory axis of "glycolysis-lactylation-ferroptosis." This article systematically reviews the biological functions of histone lactylation in the nervous system, with a focus on elucidating how it participates in the pathological processes of various neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), cerebral stroke, and amyotrophic lateral sclerosis (ALS), by regulating the expression of ferroptosis-related genes. The article integrates the latest research on molecular mechanisms, explores the value of this regulatory axis as a potential biomarker for disease diagnosis and a therapeutic target, and provides an outlook on future research directions in this field.}, } @article {pmid42492371, year = {2026}, author = {Majumder, M and Borucki, DM and Chowdhury, N and Mallah, K and Tomlinson, S}, title = {Site-targeted proximal complement C3 inhibition, but not C5 blockade, attenuates neurodegeneration in a mouse model of amyotrophic lateral sclerosis: Implications for failed clinical trials.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e00969}, pmid = {42492371}, issn = {1878-7479}, support = {S10 OD018113/OD/NIH HHS/United States ; P30 DK123704/DK/NIDDK NIH HHS/United States ; I01 BX004256/BX/BLRD VA/United States ; P30 CA138313/CA/NCI NIH HHS/United States ; P20 GM130457/GM/NIGMS NIH HHS/United States ; I21 BX005853/BX/BLRD VA/United States ; IK6 BX005235/BX/BLRD VA/United States ; I01 RX003958/RX/RRD VA/United States ; S10 OD028663/OD/NIH HHS/United States ; P20 GM148302/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism ; Mice ; Disease Models, Animal ; *Complement C3/antagonists & inhibitors/metabolism ; Mice, Transgenic ; *Complement C5/antagonists & inhibitors/metabolism ; Spinal Cord/drug effects/pathology/metabolism ; *Nerve Degeneration/pathology/drug therapy/metabolism ; }, abstract = {Complement activation contributes to amyotrophic lateral sclerosis (ALS) neuropathology, but whether motor neuron degeneration is driven by proximal or terminal activation products remains unresolved. Failed trials of C5 inhibition - ravulizumab (CHAMPION-ALS) and zilucoplan (ATHLEET/HEALEY ALS Trial), and of systemic C3 inhibition (pegcetacoplan, MERIDIAN) underscore this mechanistic gap. We compared two pharmacologically distinct inhibitors in hSOD1[G93A] mice. CR2Crry blocks complement at C3 and localizes to sites of active deposition. BB5.1, functionally equivalent to ravulizumab, selectively blocks C5a generation and membrane attack complex (MAC) assembly. Treatment began at symptom onset and continued to humane endpoint. Both agents achieved robust target engagement across spinal cord, sciatic nerve, and neuromuscular junction (NMJ). Only CR2Crry extended survival, preserved motor function, and attenuated weight loss. CR2Crry reduced microglial activation and C3 opsonization in the ventral horn, diminished macrophage infiltration, preserved sciatic nerve axonal integrity, and maintained NMJ innervation. BB5.1 failed to modify any functional or neurodegenerative pathology despite confirmed MAC suppression. Proximal C3 activation products, not C5a or MAC, are the dominant drivers of complement-mediated neurodegeneration in the hSOD1[G93A] model of ALS. Site-targeted C3 inhibition may address the mechanistic limitation underlying recent clinical trial failures and represents a translationally justified therapeutic strategy.}, } @article {pmid42492571, year = {2026}, author = {Tavares de Sousa, M and Crispi, F and Gomez, O and Hergert, B and Hecher, K}, title = {The carotid-subclavian artery index (CSAI) in the fetal aortic arch with classical branching and brachiobicephalic trunk in a midtrimester low risk population.}, journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2922-1435}, pmid = {42492571}, issn = {1438-8782}, abstract = {Purpose The carotid-subclavian artery index (CSAI) has shown high sensitivity and specificity for diagnosing coarctation of the aorta (CoA) in fetuses and neonates. We investigated whether variations in aortic arch (AA) branching without CoA affect CSAI by comparing fetuses with the classical pattern to those with a brachiobicephalic trunk (BBCT), the most frequent variant. Material and Methods In this prospective cohort study of 335 low-risk singleton pregnancies (19 - 22 weeks of gestation), standardized fetal echocardiography was used to assess AA branching in a sagittal view. Two blinded observers classified branching patterns and calculated CSAI. Results Adequate image quality was obtained in 262/335 (78.2%). 194/262 (74%) fetuses showed a classical pattern and 66 (25.2%) a branching variant. Furthermore, two fetuses (0.8%) due to disagreement on branching pattern. 50/66 (76.8%) fetuses with isolated BBCT were compared with 194 cases with classical AA branching pattern. 16 other variants were excluded. Interobserver agreement showed an intraclass correlation coefficient (ICC) of 0.87 (95%CI: 0.89-0.95). Mean CSAI was significantly lower in BBCT (0.71 ± 0.14) than in classical branching (1.46 ± 0.37; P < 0.001). None required cardiac intervention within two years. Conclusions Targeted fetal echocardiography showed a lower CSAI in cases with BBCT than in classical branching pattern. Future studies are warranted to assess the diagnostic impact of our findings in the setting of suspected CoA. Zielsetzung: Der Carotis-Subclavian-Artery-Index (CSAI) wird in der Diagnostik der Aortenisthmusstenose (CoA) eingesetzt. Wir untersuchten, ob der CSAI bei Feten mit Varianten der Aortenabgänge eine Rolle spielt und verglichen diesen mit Werten bei Aortenbögen mit klassischen Abgängen. Material und Methoden: In dieser prospektiven Kohortenstudie wurden 335 Einlingsschwangerschaften mit niedrigem Risiko zwischen der 19. und 22. Schwangerschaftswoche mittels standardisierter fetaler Echokardiografie untersucht. Der Aortenbogen wurde in sagittaler Ebene dargestellt. Zwei voneinander unabhängige Untersuchende beurteilten verblindet das Abgangsmuster und berechneten den CSAIErgebnisse: Eine ausreichende Bildqualität konnte bei 262 von 335 Fällen (78,2 %) erzielt werden. 194/262 (74 %) Feten zeigten ein klassisches Abgangsmuster, 66 (25,2 %) eine Variante. Bei zwei Feten (0,8 %) bestand Uneinigkeit über das Abgangsmuster. 50/66 (76,8 %) Feten mit isoliertem BBCT wurden mit den 194 Fällen mit klassischem Abgang verglichen; 16 weitere Varianten wurden ausgeschlossen. Die Interobserver-Übereinstimmung zeigte einen Intraklassen-Korrelationskoeffizienten (ICC) von 0,87 (95 %-KI: 0,89-0,95). Der mittlere CSAI war bei BBCT signifikant niedriger (0,71 ± 0,14) als bei klassischem Abgang (1,46 ± 0,37; p < 0,001). Kein Kind benötigte innerhalb von zwei Jahren eine kardiale Intervention. Schlussfolgerung: Die gezielte fetale Echokardiografie zeigte einen signifikant niedrigeren CSAI bei Feten mit BBCT im Vergleich zu Feten mit klassischem Aortenbogenabgang. Weitere Studien sind erforderlich, um die diagnostische Bedeutung dieser Befunde im Kontext eines Verdachts auf Aortenisthmusstenose zu klären.}, } @article {pmid42493042, year = {2026}, author = {Shen, J and Gu, Q and Huang, Q and Chu, S and Li, R}, title = {Identification of resistance to multiple herbicides and metabolic resistance to penoxsulam in barnyardgrass (Echinochloa crus-galli).}, journal = {Pesticide biochemistry and physiology}, volume = {222}, number = {}, pages = {107231}, doi = {10.1016/j.pestbp.2026.107231}, pmid = {42493042}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology ; *Herbicide Resistance/genetics ; *Echinochloa/drug effects/genetics/metabolism ; *Sulfonamides/pharmacology ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Plant Proteins/genetics/metabolism ; Uridine/analogs & derivatives ; }, abstract = {Barnyardgrass (Echinochloa crus-galli) is a problematic weed in rice production, and resistance to multiple herbicides threatens sustainable management. The resistant (R) population JZWD lacks ALS target-site mutations for penoxsulam, indicating metabolic resistance. Whole-plant assays revealed that JZWD exhibited moderate resistance to penoxsulam, glufosinate ammonium and haloxyfop-P, and low resistance to quinclorac, glyphosate and halauxifen-methyl, while it was susceptible to quizalofop-p-ethyl. The synergistic effects of malathion confirmed the involvement of P450 in penoxsulam resistance. Transcriptome sequencing (RNA-Seq) of untreated and penoxsulam-treated resistant and susceptible plants revealed 25 candidate genes belonging to major detoxification enzyme families (12 cytochrome P450 monooxygenases, 3 glutathione S-transferases, 3 uridine diphosphate-dependent glycos-yltransferases, 3 ATP-binding cassette transporters and 4 peroxidase). Four core genes (CYP72A616-like, UGT83A1, CYP97B2 and PODSPC4-1) were significantly upregulated in at least two resistance-related comparisons. KEGG enrichment revealed primary metabolism pathways enriched among the upregulated genes. Technical qRT-PCR validation of the same RNA samples confirmed the RNA-Seq results for most genes. Independent biological samples revealed that CYP72A616-like was constitutively overexpressed (35.87-fold) in the R population, whereas UGT83A1, CYP97B2 and PODSPC4-1 were strongly induced by penoxsulam (8.75 to 334.92-fold). Two additional P450s (CYP71C42 and CYP734A1) were also upregulated. Among the three additional resistant populations, four representative P450 genes showed variable upregulation patterns under untreated conditions (14.79 to 160.19-fold), and all three populations were strongly induced by penoxsulam (16.25 to 945.07-fold). These results suggest that metabolic resistance mediated by P450s and other detoxification enzymes underlies multiple herbicide resistance in E. crus-galli, providing targets for resistance monitoring and sustainable weed management.}, } @article {pmid42494173, year = {2026}, author = {Sellin, J and Waldorf, S and von der Gablentz, J and Grehl, T and Nazlican, H and Meyer, T and Grosskreutz, J and Weydt, P and Bernsen, S}, title = {Troponin T and Neurofilament Light Chain Levels as Complementary Biomarkers of Disease Accumulation and Aggressiveness in Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, pmid = {42494173}, issn = {2328-9503}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease requiring reliable biomarkers to improve patient stratification and trial design. While serum neurofilament light chain (sNfL) reflects neuroaxonal stress and disease aggressiveness, troponin T (TnT) may capture complementary aspects of neuromuscular involvement. We assessed the associations of TnT and sNfL with D50-derived measures of disease aggressiveness (D50) and disease accumulation (rD50) in ALS.

METHODS: In this retrospective observation, TnT and sNfL levels from ALS patients in two independent German cohorts were analyzed using the D50 disease progression model; discovery cohort (Essen, n = 433) and an independent replication cohort (Bonn, n = 185).

RESULTS: TnT levels were strongly associated with rD50-defined disease phases in the discovery cohort (p < 0.001). While not all subgroup-specific associations were replicated, the overall relationship between TnT and disease accumulation was supported in the independent replication cohort. In contrast, sNfL showed no consistent relationship with rD50-derived disease phases. sNfL concentrations demonstrated a significant inverse association with D50, supporting a relationship with disease aggressiveness across both cohorts (p < 0.001). Associations between TnT levels and D50-defined disease aggressiveness were generally weaker and less consistent.

INTERPRETATION: TnT was associated with measures of disease accumulation (rD50), whereas sNfL was more closely associated with disease aggressiveness (D50). Our results suggest that TnT and sNfL capture different dimensions of disease status within the D50 framework. Further longitudinal studies are needed to determine whether combining these biomarkers improves disease stratification or prognostic assessment in clinical practice and therapeutic trials.}, } @article {pmid42494493, year = {2026}, author = {Kennedy, J and Al Khleifat, A and King, A and Al-Sarraj, S and Al-Chalabi, A and Mitchell, JC and Troakes, C}, title = {Strenuous physical activity is associated with a younger age of amyotrophic lateral sclerosis onset in two independent cohorts.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag272}, pmid = {42494493}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease characterized predominantly by degeneration of both upper and lower motor neurons, thought to occur due to an interplay between genetics and environmental factors. Physical activity has been suggested as a potential risk factor for ALS; however, the exact role of exercise in the onset and progression of the disease is still unclear. We assessed lifetime physical activity in two independent ALS cohorts: post-mortem brain donors from the London Neurodegenerative Diseases Brain Bank (n = 139) and patients from the Motor Neurone Disease (MND) Register of England, Wales and Northern Ireland (n = 166 cases, 196 controls). In both cohorts, highly active individuals developed ALS symptoms at a significantly younger age, 54.2 years (mean, standard deviation = 7.5) in the post-mortem cohort and 58.0 years (median, interquartile range = 15) in the MND Register, compared with 63.9 years (mean, standard deviation = 11.5) and 63.0 years (median, interquartile range = 17.5) in inactive individuals, respectively [one-way analysis of variance (ANOVA), F(2, 136) = 6.10, P = 0.003, η 2 = 0.08, 95% confidence interval (CI) 0.02-1.00 and Kruskal-Wallis, H(2) = 7.39, P = 0.02, η 2 = 0.03, 95% CI 0.003-0.12]. Cox regression showed a higher hazard of earlier onset in highly active patients [post-mortem: hazard ratio (HR) 2.84, 95% CI 1.55-5.26, P = 0.0008; MND Register: HR 2.34, 95% CI 1.30-4.23, P = 0.005]. Our findings suggest that strenuous physical activity may be associated with a significantly younger age of ALS onset, replicated in both the post-mortem and MND Register cohorts, but not with an increased risk of developing ALS. Logistic regression analysis confirmed that neither highly active [odds ratio (OR) 1.43, 95% CI 0.69-2.99, P = 0.333] nor being active (OR 1.30, 95% CI 0.72-2.37, P = 0.386) was significantly associated with ALS risk, whereas a history of head injury was (OR 1.72, 95% CI 1.03-2.88, P = 0.038). These results suggest that strenuous exercise may accelerate disease onset in predisposed individuals, while the role of head injury requires further study and the findings may in fact indicate reverse causality.}, } @article {pmid42495327, year = {2026}, author = {Zhan, K and Wang, Y and Lin, J and Chen, F and Fan, X and Hu, P and Wen, J and Gong, F and Zhang, N}, title = {From Simplified Pretreatment to Sensitive Analysis: An Immobilization-Free Cathodic Photoelectrochemical Assay for Sulfonylurea Herbicide Residue and Its Accumulation.}, journal = {ACS omega}, volume = {11}, number = {28}, pages = {42504-42514}, pmid = {42495327}, issn = {2470-1343}, abstract = {Sensitive and selective detection of agricultural chemicals in complex matrices necessitates streamlined workflows without performance loss. By combining the inherent high sensitivity of photoelectrochemical (PEC) analysis with the high selectivity of enzymatic recognition, an immobilization-free PEC assay for the sulfonylurea herbicide chlorsulfuron (Chs) was developed, with purification steps omitted and analytical procedure simplified. Specifically, BiOI nanoflakes (NFs)/NiO heterojunction was fabricated as a sensing platform, generating strong and stable cathodic photocurrent in the presence of dissolved O2. The catalytic reaction of acetolactate synthase (ALS) consumed O2, quenching the photocurrent response. Conversely, upon addition of the model target Chs, a representative sulfonylurea herbicide and effective inhibitor of ALS, the signal was recovered. By monitoring the photocurrent change before and after the enzymatic reaction, Chs was quantified over a linear range of 0.25-100 μg/L, with a limit of detection (LOD) of 0.16 μg/L. The assay avoids laborious probe-immobilization steps by directly adding the enzyme into the electrolyte, significantly simplifying the detection protocol. Furthermore, by omitting traditional purification procedures, the overall workflow was further optimized. The method was successfully applied to detect Chs residues in wheat powder and to evaluate its accumulation in wheat seedlings, with accuracy and reliability validated by high-performance liquid chromatography (HPLC). This work achieves highly sensitive and immobilization-free PEC analysis of Chs and offers a feasible approach for sulfonylurea herbicide detection in selected agricultural samples, with streamlined pretreatment process and enhanced analytical efficiency.}, } @article {pmid42495582, year = {2026}, author = {Yu, Z and Ross, JP and Rochefort, D and Li, B and Bornais, K and Chum, M and Farhan, SMK and Dion, PA and Rouleau, GA}, title = {Erratum: Consequences of the Novel ALS-Associated KIF5A Variant c.2993-6C>A for Exon 27 Splicing and Axonal Transport of SFPQ.}, journal = {Neurology. Genetics}, volume = {12}, number = {4}, pages = {e200410}, pmid = {42495582}, issn = {2376-7839}, abstract = {[This corrects the article DOI: 10.1212/NXG.0000000000200362.].}, } @article {pmid42497114, year = {2026}, author = {Yasuda, K}, title = {Functional constraint, not evolutionary domain expansion, is a stronger correlate of pathogenic variant burden in human RNA-binding proteins.}, journal = {Human molecular genetics}, volume = {35}, number = {15}, pages = {}, doi = {10.1093/hmg/ddag067}, pmid = {42497114}, issn = {1460-2083}, support = {23 K05147//JSPS/ ; }, mesh = {Humans ; Evolution, Molecular ; *RNA-Binding Proteins/genetics/chemistry/metabolism ; Animals ; Protein Domains/genetics ; Genetic Variation ; Amyotrophic Lateral Sclerosis/genetics ; Ribonuclease, Pancreatic/genetics ; }, abstract = {Whether evolutionary innovation predisposes genes to pathogenic variation is a fundamental question in evolutionary medicine. RBP domain family diversity correlates with neural complexity across metazoans via vertebrate-specific domain expansions. Here, we tested whether such expanded RBP domains harbor elevated pathogenic variant burden relative to evolutionarily conserved domains. We classified 2961 human RBP-encoding genes into expanded (n = 25 genes, 8 Pfam domains; vertebrate/invertebrate gene count ratio ≥ 3.0) and non-expanded control (n = 231 genes, 89 Pfam domains) groups, and integrated ClinVar pathogenic variants with gnomAD v4.1 constraint metrics. Contrary to our hypothesis, expanded domains showed lower median pathogenic variant density than non-expanded domains (P = .140, rank-biserial r = 0.180, 95% CI [-0.089, 0.444]), consistent across sensitivity analyses and count-based models. In multivariable analysis, functional constraint (pLI) was a stronger predictor of variant density than evolutionary expansion status. At the family level, no expanded domain showed significantly elevated burden; instead, the most prominent outliers were conserved non-expanded domains associated with established neurodegenerative diseases (SMN, Nop). The RNaseA family, despite 26-fold vertebrate expansion, harbored ClinVar pathogenic variants in only 1 of 15 members-fewer than expected by chance (binomial P = 0.030). The sole exception, ANG (Angiogenin), concentrates all seven ALS9-associated variants at its catalytic triad and nuclear localization signal, reflecting functional specialization rather than expansion per se. These findings indicate that evolutionary domain expansion does not confer generalized disease vulnerability in RBPs, and that pathogenic variant burden is more closely linked to functional constraint and lineage-specific subfunctionalization than to evolutionary novelty.}, } @article {pmid42498430, year = {2026}, author = {Desai, KM and Thakkar, MD and Somaiya, TS and Thomas, DC}, title = {Neurodegenerative Diseases and Sleep Disorders: The Bidirectional Relationship.}, journal = {The Medical clinics of North America}, volume = {110}, number = {5}, pages = {889-905}, doi = {10.1016/j.mcna.2025.12.001}, pmid = {42498430}, issn = {1557-9859}, mesh = {Humans ; *Sleep Wake Disorders/diagnosis/complications/etiology/therapy/physiopathology ; *Neurodegenerative Diseases/complications/diagnosis/physiopathology ; Parkinson Disease/complications ; }, abstract = {Neurodegeneration is mostly irreversible and progressive. Neurodegenerative diseases (NDDs) represent a large group of disorders that have varied clinical and pathologic representations. These include Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis, among others. A common factor in all these NDDs is sleep disorders (SDs). NDDs and SDs are bidirectional. Screening for SDs should be an integral part of a workup of NDDs. Management of one can improve the prognosis of the other.}, } @article {pmid42498658, year = {2026}, author = {Palm, A and Ekström, M and Einarsson, J and Ersson, K and Ingre, C and Kläppe, U and Lindberg, E and Ljunggren, M and Nygren, I and Sundh, J and Grote, L}, title = {Home mechanical ventilation for amyotrophic lateral sclerosis-a national study of survival and treatment trends across 27 years.}, journal = {Annals of the American Thoracic Society}, volume = {}, number = {}, pages = {}, doi = {10.1093/annalsats/aaoag219}, pmid = {42498658}, issn = {2325-6621}, abstract = {RATIONALE: Home mechanical ventilation (HMV) improves survival in Amyotrophic lateral sclerosis (ALS) and may be provided non-invasively (NIV) or invasively (IV). While NIV is guideline-recommended, the role of IV remains controversial, and data on long-term outcomes and NIV-to-IV transitions are limited.

OBJECTIVES: To examine survival across HMV strategies in people with ALS (pwALS) in Sweden over 27 years, factors associated with IV initiation, temporal trends in IV use and survival, and regional variation in IV utilisation.

METHODS: A longitudinal cohort study of pwALS in the Swedish National Registry of Ventilatory Failure (Swedevox) 1996-2022, cross-linked with national registries. Factors associated with mortality and treatment patterns were assessed using multivariable regression models.

RESULTS: Among 1,360 pwALS, initial NIV was most common (92%), followed by IV (5%) and NIV-to-IV transitions (3%). Most IV initiations were non-elective (77% vs. 18% NIV, p < 0.001). NIV-to-IV transitions occurred mainly in metropolitan areas (OR 5.11; 95% CI 2.30-11.4). Median survival differed across observed treatment pathways (p < 0.001): 1.7 years with NIV, 4.9 years with IV, and 6.5 years with NIV-to-IV. Mortality was associated with higher age (aHR 1.33 per decade; 95% CI 1.26-1.41), female sex (aHR 1.15; 95% CI 1.02-1.29), and acute initiation (aHR 1.26; 95% CI 1.08-1.47). Longer time from diagnosis to NIV initiation was associated with reduced mortality risk (aHR 0.58 per year; 95% CI 0.55-0.62). Over time, patients initiated HMV at older age with better lung function and lower PaCO2 values among those with available measurements, whereas overall survival remained unchanged.

CONCLUSION: Patients receiving IV had longer observed survival, likely reflecting the benefits of a secured airway as well as patient selection and underlying disease trajectory. Most IV initiations were unplanned. Over three decades, HMV was initiated in older patients at an earlier stage of respiratory decline, but overall survival remained unchanged. IV use increased with marked regional variation.}, } @article {pmid42499995, year = {2026}, author = {Nassour, J and Berberich, N and Utpadel-Fischler, D and Wächter, T and Cheng, G}, title = {A dexterous soft hand exoskeleton restores intentional grasping in individuals with severe hand impairment.}, journal = {Nature machine intelligence}, volume = {8}, number = {7}, pages = {1100-1114}, pmid = {42499995}, issn = {2522-5839}, abstract = {Soft hand exoskeletons have emerged as promising assistive devices for individuals with impaired hand function. However, most existing systems provide limited dexterity and primarily target users with moderate hand ability, leaving individuals with severe hand paralysis without effective solutions for reliable grasping of diverse objects. Here we report the translational development of a lightweight, textile-based soft robotic exoskeleton glove with wrist dorsiflexion and an active opposable and abductable thumb, designed to restore hand function in a patient with severe right-hand impairment due to amyotrophic lateral sclerosis. We followed a co-creation approach, enhancing dexterity by increasing hand articulations based on patient needs. Furthermore, to enhance the patient's sense of control, a non-invasive surface electromyography-based grasp predictor (97% sensitivity) was combined with motion data and machine learning-based error correction to compensate for weak, noisy muscle signals, compared with healthy controls (n = 15). The exoskeleton enabled the patient to grasp objects, achieve a Box-and-Blocks Test score of 5 and perform meaningful tasks, including feeding himself. We further validated the exoskeleton in patients with stroke (n = 6). While exoskeleton assistance on average reduced Action Research Arm Test scores of moderately impaired patients by 9, severely impaired patients scored 17 points higher when using the exoskeleton. These results indicate that the dexterous soft hand exoskeleton is particularly effective for individuals with severe to near-complete hand paralysis, while its utility for patients with moderate residual function is limited and task dependent.}, } @article {pmid42500961, year = {2026}, author = {Li, Z and Fan, J and Gong, Z and Tang, J and Yang, Y and Ding, F and Ba, L and Liu, M and Zhang, M}, title = {Cardiac autonomic dysfunction is associated with advanced stage, fast progression and poor survival in amyotrophic lateral sclerosis.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602261472982}, pmid = {42500961}, issn = {2214-3602}, abstract = {ObjectiveTo investigate the association of cardiac autonomic dysfunction with clinical staging and disease progression rate upon diagnosis of amyotrophic lateral sclerosis (ALS), and its impact on survival.Methods24-hour Holter was performed in 95 ALS patients at diagnosis and 39 controls. Patients were grouped by King's Clinical Staging and progression rate (ΔFS, median cut-off 0.67). Heart rate variability parameters were compared across groups. A survival-based cut-point optimization approach was used to determine the cut-off value of standard deviation of all normal-to-normal intervals (SDNN). Kaplan-Meier estimator and multivariable Cox regression analysis were used to evaluate of the effect of SDNN on survival during a median follow-up of 21.5 months.ResultsΔFS in ALS patients in King's Stage 4 upon diagnosis was faster (P=0.007) compared to that of those diagnosed in earlier stages, featuring a higher incidence of respiratory (P<0.001) and bulbar symptoms (P<0.001). In addition, ALS patients in King's Stage 4 exhibited elevated HR-min (P=0.007) and decreased RR intervals (RRI) (P=0.032), SDNN (P=0.004), and standard deviation of the averages of NN intervals in all 5-min segments (SDANN) values (P=0.020) compared to controls. Patients in the ΔFS-fast group had a higher HR-min than those in the ΔFS-slow group (P=0.013) and controls (P=0.003) and lower SDNN (P=0.018) than controls. Both Kaplan-Meier estimator (P=0.03) and multivariable Cox regression analysis (P=0.019) showed that lower SDNN (cut-off value: 111 ms) was associated with poor survival in ALS patients.ConclusionUpon diagnosis, ALS patients in King's Stage 4 and with faster disease progression demonstrated significantly diminished cardiac autonomic control. Lower SDNN was associated with poor survival in ALS.}, } @article {pmid42501325, year = {2026}, author = {Jia, Y and Cui, B and Liang, Y and Zhang, M and Wang, S and Wang, Y and Chen, H}, title = {Focal epilepsy expands the phenotype of FUS-associated amyotrophic lateral sclerosis.}, journal = {Epilepsia}, volume = {67}, number = {9}, pages = {e157-e162}, doi = {10.1002/epi.70409}, pmid = {42501325}, issn = {1528-1167}, support = {82401705//National Natural Science Foundation of China/ ; 82371461//National Natural Science Foundation of China/ ; 2022YFC2503802//National Key Research and Development Program of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications/physiopathology ; *RNA-Binding Protein FUS/genetics ; Male ; Phenotype ; Adult ; *Epilepsies, Partial/genetics/complications/physiopathology/drug therapy ; Anticonvulsants/therapeutic use ; Electroencephalography ; Mutation ; }, abstract = {Epileptic seizures are an exceedingly rare manifestation in classic amyotrophic lateral sclerosis (ALS). Emerging case reports suggest a potential link between ALS associated with FUS gene mutations (FUS-ALS) and seizures, expanding the disease's phenotypic spectrum. A 25-year-old man presented with a 5-month history of rapidly progressive limb weakness, atrophy, and both upper and lower motor neuron signs, consistent with ALS. Notably, he developed two types of epileptic seizures during the disease course, including focal motor seizures and focal seizures evolving to bilateral tonic-clonic seizures. Electroencephalography revealed epileptiform discharges over the right frontotemporal region. Brain [18]F-fluorodeoxyglucose positron emission tomography-computed tomography showed focal hypometabolism in the right frontal cortex. Genetic testing identified a de novo pathogenic FUS variant (c.1574C>T, p.Pro525Leu). The patient was diagnosed with FUS-ALS with comorbid focal epilepsy. Treatment with levetiracetam partially controlled the seizures, but motor function continued to deteriorate. This case highlights focal epilepsy as a comorbid feature in FUS-ALS, broadening the recognized phenotypic spectrum. Genetic testing for FUS mutations should be considered in young-onset ALS patients presenting with seizures.}, } @article {pmid42502061, year = {2026}, author = {Mato, S and Fukaura, J and Miyamoto, M and Watanabe, I and Naoi, T and Nakagawa, H and Saito, K}, title = {Evaluation of the Reliability and Validity of the Japanese Version of the Voice Activity and Participation Profile (VAPP-J).}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2026.07.010}, pmid = {42502061}, issn = {1873-4588}, abstract = {OBJECTIVES: The aim of this study was to evaluate the reliability and validity of the Japanese version of the Voice Activity and Participation Profile (VAPP).

METHODS: A total of 100 patients with voice disorders (dysphonic group) and 52 students without voice disorders (non-dysphonic group) were enrolled between October 2024 and February 2026. The psychometric properties of the Japanese VAPP were assessed, including internal consistency, concurrent and discriminant validity, interrelationships among sections, comparisons between the Activity Limitation Score (ALS) and Participation Restriction Score (PRS), and responsiveness to voice therapy. Concurrent validity was evaluated by correlations with the Voice Handicap Index (VHI).

RESULTS: Cronbach's alpha for the total score was 0.98 and remained unchanged after item deletion, indicating excellent internal consistency. VAPP total scores showed a strong positive correlation with VHI scores (r = 0.93, P < 0.001). All VAPP scores (total, section scores, ALS, and PRS) were significantly higher in the dysphonic group than in the non-dysphonic group (P < 0.001). VAPP total scores improved significantly after voice therapy (P < 0.001). Correlations among sections ranged from 0.37 to 0.86 in the dysphonic group and from 0.36 to 0.82 in the non-dysphonic group. ALS scores were significantly higher than PRS scores in the dysphonic group (P < 0.05).

CONCLUSIONS: The Japanese version of the VAPP (VAPP-J) demonstrates high reliability and validity and could be a useful tool for clinical assessment of voice disorders in Japanese populations.}, } @article {pmid42503607, year = {2026}, author = {Sanghai, N and Kelley, R and Lao, Y and Madlangsakay, MIR and Paul, P and Llanes-Cuesta, MA and Wang, JF and Zahedi, RP and Kong, J and Tranmer, GK}, title = {Introducing Borsantrazole: A Trifunctional Boron-Based Pyrazole That Extends the Lifespan of Amyotrophic Lateral Sclerosis Mice.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e76432}, pmid = {42503607}, issn = {2198-3844}, support = {//Research Manitoba 2017 Health Research New Investigator Operating Grant/ ; //Natural Sciences and Engineering Research Council of Canada/ ; /CAPMC/CIHR/Canada ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is considered a highly complex, heterogeneous, fatal disease with a high unmet medical need that affects multiple pathophysiological pathways and has no known singular cause. Oxidative stress, however, is implicated as a central player in the progression of ALS and other neurodegenerative diseases. To date, only two FDA-approved drugs, Edaravone, an antioxidant, and Riluzole, an antiglutamatergic, have been widely used clinically, albeit with modest effects on the clinical course of ALS disease progression. Additionally, preclinical studies of both drugs in ALS mouse models have not shown any significant survival benefit, although some abatement in disease progression is observed and translated from preclinical animal models to clinical human studies.

METHODS: Using a trifunctional boron-based drug design strategy, we have synthesized a pyrazole small molecule called Borsantrazole (BSZ) and evaluated BSZ in cell-based experiments, acute and chronic toxicity models, and the SOD1-G37R ALS mouse model. We have also evaluated untargeted global proteomic and phosphoproteomic changes induced by BSZ.

RESULTS: Borsantrazole (a small molecule that can selectively target oxidative stress) with favorable CNS drug like properties (low ER values of 0.9 and 1.0 at 1 and 10 µm, respectively, suggesting lower Pgp efflux liability and the LogD at pH 7.4 was within the range of 1.2 to 3.1, suggesting BSZ is lipophilic at pH 7.4.) shows no signs of treatment associated toxicity (acute or chronic (120 days)), significantly increases survival (whole animals, 15.1 days (p = 0.0326); males, 16.5 days; females, 13.7 days), rescued weight loss (27.1% control, 18.3% BSZ, p < 0.0001), delays symptom onset (whole animals, 24.9 days (p = 0.0011); males, 23.3 days; females, 26.4 days), delays disease onset (whole animals, 25.5 days (p = 0.0001); males, 21.1 days; females, 29.8 days) and affects global proteomic changes in the SOD1-G37R mouse model of ALS. In total, 51 proteins were found to be significantly differentially expressed (p < 0.05), including Ca3, Gan, Cplx2, Lrp4, Sqstm1, and 29 phosphorylation sites were differentially expressed and considered statistically significant, including T317 and T72 for neurofilaments light and heavy chain, respectively.

CONCLUSIONS: Herein, we report that BSZ has demonstrated a favorable safety profile and compelling proof-of-concept efficacy in a ALS mouse model and has the potential to become a disease-modifying ALS therapeutic following further clinical development. Within a broader perspective of treatments for neurodegenerative diseases, BSZ offers a new paradigm for trifunctional small molecule targeting of oxidative stress that can mitigate neuronal deterioration and serve as a potential treatment.}, } @article {pmid42504602, year = {2026}, author = {Eisen, A and Durham, HD and Pioro, E}, title = {The aging brain that doesn't fail: how neural resilience masks neurodegeneration.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/21678421.2026.2705693}, pmid = {42504602}, issn = {2167-9223}, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease are usually framed as consequences of aging-related pathogenic processes, including impaired proteostasis with protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Yet, most individuals, even into advanced age, do not develop clinically significant neurodegenerative disease. This discrepancy suggests that the nervous system possesses robust and redundant protective mechanisms that maintain neural integrity despite cumulative molecular and cellular stress. In this perspective, we propose that neurodegenerative diseases arise not simply from the presence of pathogenic processes, but when integrated resilience systems fail to maintain homeostasis or when reserve mechanisms no longer compensate for accumulated pathology. We have synthesized a threshold-based model of disease emergence based on evidence across proteostasis, mitochondrial function, neuroimmune regulation, glial biology, network-level compensation, and barrier integrity, while integrating genetic, environmental, developmental, and stochastic modifiers. We distinguish biological resilience, which actively limits or repairs pathology, from reserve, which permits function despite pathology. We further propose that clinical disease emerges only when age-related cumulative stress exceeds the combined capacity of resilience and reserve. Reframing neurodegeneration as a failure of preservation systems offers new directions for prevention and therapeutic development.}, } @article {pmid42505342, year = {2026}, author = {Yang, CS and Ma, Y and Xie, JL and Lou, XY and Lv, YT and Wu, TX and Xu, HF and Zou, SM and Wu, ZY and Li, HF}, title = {Pathogenicity Classification of TARDBP Variants of Uncertain Significance: An Integrative Clinical Characterization and Functional Validation.}, journal = {Cells}, volume = {15}, number = {14}, pages = {}, pmid = {42505342}, issn = {2073-4409}, support = {2025ZD1802600//Innovative Drug Research and Development National Science and Technology Major Project/ ; }, mesh = {Humans ; *DNA-Binding Proteins/genetics/chemistry/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Mutation/genetics ; Female ; Genetic Variation ; }, abstract = {TAR DNA binding protein (TARDBP) is one of the major causative genes of amyotrophic lateral sclerosis (ALS), which drives disease progression through both gain-of-toxicity (GOT) and loss-of-function (LOF) mechanisms. The mutant TDP-43 exhibits aberrant nucleocytoplasmic distribution and forms cytotoxic hyperphosphorylated aggregates, a process that can be robustly recapitulated in vitro. Thus, functional assays in cell lines serve as a reliable metric for the pathogenicity classification of TARDBP variants. In this study, we performed in vitro experiments to classify the pathogenicity of 28 TARDBP variants of uncertain significance (VUS) among the 172 previously reported TARDBP variants. 22 of these VUS were determined to be functionally abnormal, of which 12 could be further classified as likely pathogenic (LP) variants according to American College of Medical Genetics (ACMG) and the ClinGen Sequence Variant Interpretation (SVI) Working Group guidelines. We also summarized the clinical characteristics of 35 ALS patients carrying 12 variants in the TARDBP gene. Pathogenic missense variants were predominantly clustered in the C-terminal domain (CTD) of TARDBP. Variants in TARDBP exon 6 may lead to an earlier age at onset. ALS caused by TARDBP mutations exhibits marked phenotypic heterogeneity, along with incomplete penetrance in carriers. Patient-derived primary skin fibroblasts serve as a feasible cellular model for the functional assessment of variant pathogenicity. Our findings expand the TARDBP mutation spectrum, and provides a preliminary basis for preclinical research on TARDBP-targeted therapies for ALS.}, } @article {pmid42505348, year = {2026}, author = {Liu, B and Zhang, L and Lv, B and Xu, C and Han, L and Yan, Q and Wang, X}, title = {Copper Homeostasis and Cuproptosis in Neurodegenerative Diseases.}, journal = {Cells}, volume = {15}, number = {14}, pages = {}, pmid = {42505348}, issn = {2073-4409}, mesh = {Humans ; *Copper/metabolism ; *Cuproptosis ; *Homeostasis ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Mitochondria/metabolism ; Proteotoxic Stress ; }, abstract = {Copper is an essential trace element required for numerous enzymatic processes in the brain, including mitochondrial metabolism, antioxidant defense, and gene expression regulation. Recent studies have further implicated copper in a newly defined form of regulated cell death termed cuproptosis, providing a mechanistic framework for copper-dependent cytotoxicity. Increasing evidence indicates that copper dyshomeostasis is a common feature of major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), where it is associated with protein misfolding, redox imbalance, and neuronal vulnerability. Nevertheless, the mechanistic link between copper dysregulation and neuronal cell death remains incompletely defined. In this review, we systematically summarize the molecular mechanisms governing copper homeostasis and intracellular copper trafficking, while providing a timely, updated, and in-depth overview of the mechanistic basis and emerging biology of cuproptosis. We further comprehensively evaluate the current evidence linking copper dysregulation and cuproptosis-related pathways to neurodegenerative diseases, with particular emphasis on distinguishing mechanistic causation from pathological correlation. Importantly, we discuss current therapeutic strategies and emerging clinical efforts targeting copper metabolism, while highlighting the major challenges in defining the pathological significance and mechanistic contribution of cuproptosis in neurodegenerative diseases. Collectively, this review provides an updated framework for understanding the pathological significance and translational potential of cuproptosis in neurodegenerative diseases.}, } @article {pmid42506061, year = {2026}, author = {Zeng, CW}, title = {Protein-First, but Not Protein-Only: Rethinking Neurodegenerative Diseases Through Transgenic Mouse Models.}, journal = {Neurology international}, volume = {18}, number = {7}, pages = {}, pmid = {42506061}, issn = {2035-8385}, abstract = {Neurodegenerative diseases represent a major and growing global health burden. Although these disorders are often clinically defined by symptoms and affected brain regions, many are mechanistically linked to abnormal protein accumulation, misfolding, impaired proteostasis, RNA dysregulation, mitochondrial dysfunction, and neuroinflammation. In this Perspective article, I discuss major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, prion diseases, spinocerebellar ataxias, and spinal muscular atrophy, through the lens of disease-associated proteins and experimental modeling. I argue that a protein-centered framework provides a useful approach for understanding disease mechanisms and selecting transgenic mouse models, while recognizing that aging, cellular context, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and other disease modifiers also shape neurodegeneration. Transgenic and genetically engineered mouse models have been essential for dissecting the pathogenic roles of amyloid-β, tau, α-synuclein, TDP-43, SOD1, FUS, C9ORF72-associated dipeptide repeat proteins, mutant huntingtin, prion protein, ataxins, and SMN deficiency. However, these models have important limitations, including artificial overexpression, familial mutation bias, species differences, and incomplete representation of aging-related sporadic diseases. Rather than seeking a single "best" model, a more productive strategy is to adopt model portfolios tailored to specific biological questions and to integrate mouse studies with human cellular models, postmortem tissue, omics approaches, and biomarker-based validation. Such an approach may improve mechanistic insight, strengthen translational relevance, and enhance the predictive value of preclinical neurodegenerative disease research.}, } @article {pmid42506583, year = {2026}, author = {Remus, S and Donelle, L and Bauer, M and Nagle, L}, title = {A Nursing Homecare Data Science Investigation Using "Persons with ALS" (PALS) Electronic Health Records (EHRs).}, journal = {The Canadian journal of nursing research = Revue canadienne de recherche en sciences infirmieres}, volume = {}, number = {}, pages = {8445621261469904}, doi = {10.1177/08445621261469904}, pmid = {42506583}, issn = {1705-7051}, abstract = {BackgroundData science, rooted in computer science, statistics, and information science is advancing healthcare research by unlocking "insights" from big data to discover knowledge about patient experiences and answer previously unanswerable questions. The comparatively limited engagement of Canadian nurse researchers in this field, relative to counterparts in other jurisdictions (e.g., United States) served as a key impetus for initiating this data science study.PurposeTo investigate homecare electronic health records (EHRs) of "persons with ALS" (PALS) disease and identify care-related factors that influence their preferences and ability to be safely supported at home.MethodGuided by a nursing informatics' data, information, knowledge, wisdom (DIKW) framework and the knowledge discovery in databases (KDD) methodology, a retrospective, secondary analysis of an integrated dataset (1159 clinical assessments and administrative data) documenting 240 PALS's homecare encounters (April 1, 2009 - July 31, 2019) was conducted. EHR data was analyzed using correlations and logistic regression to model institutionalization risk factors of PALS.ResultsFive significant models were generated that accurately distinguished PALS institutionalization status (at home/not home) while offering comparable predictive performance. The final model featuring six factors offers homecare providers real-time insights into PALS clinical status at the point of care. Four relate to ALS clinical manifestations of disease decline and two assessment outcome measures (MAPLe and CHESS), strongly predicting institutionalization and caregiver burden.ConclusionBig data science offers nurse researchers a transformative way to advance knowledge development that supports high-quality, sustainable healthcare delivery while fulfilling an intended benefit of EHRs.}, } @article {pmid42507931, year = {2026}, author = {Ozguney, B and Puterbaugh, RZ and Viswanathan, R and Shenoy, J and Mohanty, P and Mittal, J and Fawzi, NL}, title = {Methionine oxidation alters both helical assembly and disordered contacts in human TDP-43 C-terminal domain phase separation.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {31}, pages = {e2537431123}, pmid = {42507931}, issn = {1091-6490}, support = {R01NS116176//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; not applicable//Radala Foundation/ ; }, mesh = {*Methionine/metabolism/chemistry ; Phase Separation ; Oxidation-Reduction ; Humans ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; Molecular Dynamics Simulation ; Protein Domains ; Protein Structure, Secondary ; Magnetic Resonance Spectroscopy ; }, abstract = {TAR DNA binding protein 43 (TDP-43), a key protein linked to ALS pathology, undergoes phase separation and forms functional assemblies via condensation within cells. The conserved region (CR) within its C-terminal domain (CTD) mediates self-assembly through helix-helix interactions, while the flanking intrinsically disordered regions (IDRs) contribute to phase separation through transient interactions involving aromatic and hydrophobic residues. The CTD contains ten methionine residues distributed equally between these regions, making it particularly susceptible to oxidative modifications. While methionine oxidation is known to impair TDP-43 phase separation, neither the precise mechanism nor the specific contribution of methionines in the CR compared to the IDRs has been determined. Here, we combine NMR spectroscopy and molecular dynamics (MD) simulations to reveal if and how methionine oxidation in each region differentially affects CTD structure and phase separation. To assess the change of secondary structure caused by oxidation, we measured NMR random coil chemical shift values for methionine sulfoxide. Oxidation of CR methionines disrupts helical structure and directly impairs intermolecular helical association, while oxidation of IDR methionines disrupts long-range contacts. Hence, oxidation of methionines in both regions contributes to impaired phase separation, albeit through different mechanisms. These findings establish methionines as critical redox-sensitive modulators in TDP-43 phase behavior and provide molecular insights into how oxidative stress may contribute to TDP-43 dysregulation in neurodegenerative diseases.}, } @article {pmid42508294, year = {2026}, author = {Liu, X and Fu, W and Cui, X and Feng, Y and Wen, B and Shan, L and Xu, X and Yang, J and Zhang, J and He, L and Zang, Y and Zhao, S and Yao, X and Liu, Y and Ma, M and Du, B and Dang, J and Zou, Z and Feng, H and Lu, Z and Zhang, Y and Wu, Z and Shang, H and Yin, P and Fan, D}, title = {Huoling Shengji granule in amyotrophic lateral sclerosis: A multicenter, randomized, double-blind, riluzole-controlled trial.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e00953}, pmid = {42508294}, issn = {1878-7479}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Riluzole/therapeutic use ; Double-Blind Method ; *Drugs, Chinese Herbal/therapeutic use ; Female ; *Neuroprotective Agents/therapeutic use ; Male ; Middle Aged ; Treatment Outcome ; Aged ; Adult ; }, abstract = {Currently, no curative therapies exist for Amyotrophic Lateral Sclerosis (ALS). This study aimed to evaluate the efficacy and safety of Huoling Shengji granules (HLSJ), a traditional Chinese medicine (TCM), compared to the standard treatment riluzole. A multicenter, randomized, double-blind, double-dummy, active-controlled Phase II clinical trial was conducted across 11 centers in China. A total of 140 ALS patients were randomly assigned (1:1) to receive either HLSJ or riluzole for 48 weeks. The primary endpoint, analyzed in the full analysis set (FAS), was the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score from baseline to Week 48. Safety profiles were comparable between groups, with no significant difference in adverse events (80.28% vs. 80.56%, P = 0.9671). Analysis using the pre-specified Last Observation Carried Forward (LOCF) method showed a numerical advantage for HLSJ (1.07 points) but lacked statistical superiority. However, a more scientific analysis using the Mixed Model for Repeated Measures (MMRM), recommended for progressive diseases, indicated that HLSJ was significantly superior to riluzole in slowing ALSFRS-R score decline (Least Squares Mean Difference [LSMD]: 2.29 points; 95% confidence interval [CI]: 0.52 to 4.06; P = 0.0114). While the LOCF model showed no statistical difference, the MMRM analysis confirmed that HLSJ demonstrated significant efficacy superior to riluzole with a favorable safety profile. These findings provide a critical basis for conducting pivotal Phase III confirmatory trials of HLSJ for ALS treatment.}, } @article {pmid42508391, year = {2026}, author = {Gao, W and Lee, HY and Min, KJ}, title = {Aging-Related Metaflammation and Mitochondrial Dysfunction in Neurodegenerative Diseases.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2026.0366}, pmid = {42508391}, issn = {2152-5250}, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are increasingly recognized as manifestations of aging-associated systemic dysfunction, rather than isolated brain disorders. Central to this dysfunction is the interplay among metaflammation, mitochondrial breakdown, and chronic neuroinflammation. Metaflammation, driven by peripheral metabolic stress, may prime the brain's immune environment through cytokine signaling and blood-brain barrier compromise. This metabolic-inflammatory crosstalk is thought to impair mitochondrial integrity in neurons and glial cells, promoting oxidative stress and the release of pro-inflammatory mitochondrial components. These mitochondrial signals, in turn, may activate microglial and astrocytic innate immune responses, creating a potentially self-reinforcing cycle of neuroinflammation and energy failure that may contribute to neuronal loss. This review outlines a proposed framework linking metaflammation to neurodegeneration, emphasizing shared mechanisms across AD, PD, and ALS. We further examine preclinical and clinical advances in therapeutic strategies that target this axis including anti-inflammatory agents, caloric restriction, mitophagy enhancers, mitochondrial antioxidants, and senescence-targeted therapies. Together, these interventions reflect a shift from symptom management to systemic metabolic and immune modulation, offering a unified framework for understanding and potentially influencing age-related neurodegeneration.}, } @article {pmid42508540, year = {2026}, author = {Sun, R and Duan, X and Wang, X and Liu, J and Li, Z and Wang, Y}, title = {R-loops: Biological functions, regulatory mechanisms, and therapeutic implications in brain diseases-A review.}, journal = {Molecular and cellular probes}, volume = {89}, number = {}, pages = {102081}, doi = {10.1016/j.mcp.2026.102081}, pmid = {42508540}, issn = {1096-1194}, mesh = {Humans ; *Brain Diseases/genetics/therapy/metabolism ; *R-Loop Structures/genetics ; Animals ; }, abstract = {BACKGROUND: R-loops are three-stranded nucleic acid structures formed by a DNA-RNA hybrid and a displaced single-stranded DNA. They regulate transcription, replication, and DNA repair, but their dysregulation causes genomic instability and inflammation, contributing to brain diseases. The nervous system exhibits selective vulnerability to R-loop stress due to ultra-long gene transcription, post-mitotic longevity, and high metabolic demands.

METHODS: This review synthesizes current literature from PubMed, Scopus, Web of Science, and Embase (2010-2026) on R-loop biology, with a focus on brain-specific mechanisms, regulatory factors (SETX, ZPR1, METTL3, TDP-43/FUS), and disease models.

RESULTS: In neurodegeneration, R-loop accumulation drives repeat expansion disorders (Fragile X, Huntington's disease) and loss-of-function SETX mutations (AOA2), whereas gain-of-function SETX (L389S) causes pathological R-loop depletion in ALS4, disrupting TGF-β signaling. TDP-43/FUS and SMN are integral to R-loop resolution, unifying ALS/FTD and SMA. In brain cancers, METTL3-mediated m[6]A modification of TERRA stabilizes telomeric R-loops in ALT-positive neuroblastoma, creating a therapeutic vulnerability to METTL3 inhibitors (STM2457, STC-15). Glioma stem cells rely on m[6]A-modified circPOLR2B to regulate R-loop formation and malignancy. Clinical-stage agents (EP102, TUG1ASO, ATX-559) and R-loop-derived prognostic signatures (RLPI) are emerging, but translation is hindered by a lack of non-invasive biomarkers and the dual physiological/pathological roles of R-loops.

CONCLUSIONS: R-loops are central to brain disease pathogenesis, offering promising therapeutic targets. Future research should prioritize precision R-loop modulators, non-invasive biomarkers, and combinatorial strategies.}, } @article {pmid42508631, year = {2026}, author = {Alanazi, SM and Al-Kuraishy, HM and Alexiou, A and Papadakis, M and Faheem, SA and Batiha, GE}, title = {Isoform-selective HSP90 inhibition as a precision therapeutic strategy for neurodegenerative and metabolic diseases.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {149}, number = {}, pages = {111834}, doi = {10.1016/j.pnpbp.2026.111834}, pmid = {42508631}, issn = {1878-4216}, mesh = {Humans ; *HSP90 Heat-Shock Proteins/antagonists & inhibitors/metabolism ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Metabolic Diseases/drug therapy/metabolism ; Protein Isoforms/metabolism/antagonists & inhibitors ; }, abstract = {Heat shock protein 90 (HSP90) is a central regulator of cellular proteostasis, coordinating the folding, stabilization, and turnover of a wide range of client proteins in the cytosol, endoplasmic reticulum, and mitochondria. Accumulating evidence indicates that the four HSP90 paralogs HSP90α, HSP90β, GRP94, and TRAP1 have distinct pathological roles in neurodegenerative and metabolic diseases. In neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, aberrant HSP90 activity contributes to the persistence of toxic protein conformers, defective autophagy, mitochondrial dysfunction, and chronic neuroinflammation. In metabolic disorders such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease, GRP94- and TRAP1-dependent signaling promotes endoplasmic reticulum stress, impaired mitochondrial metabolism, insulin resistance, and inflammatory remodeling. These mechanistic insights have accelerated the development of a new generation of HSP90 inhibitors with improved selectivity, tissue targeting, and brain penetration. Unlike earlier pan-HSP90 inhibitors, these compounds are designed to exploit paralog-specific vulnerabilities and may enable safer long-term modulation of disease-relevant chaperone networks. This review summarizes current advances in the biology and pharmacology of HSP90 paralogs and proposes isoform-selective HSP90 targeting as a promising therapeutic strategy at the intersection of neurodegeneration and metabolic dysfunction.}, } @article {pmid42508735, year = {2026}, author = {Lo Piccolo, L and Panto, C and Yeewa, R and Yubolphan, R and Poound, P and Potikanond, S and Jantrapirom, S}, title = {Context-dependent YEATS-domain inhibition enhances neuronal resilience and improves ALS phenotypes.}, journal = {Neurobiology of disease}, volume = {228}, number = {}, pages = {107549}, doi = {10.1016/j.nbd.2026.107549}, pmid = {42508735}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; *Neurons/metabolism/drug effects ; *Drosophila Proteins/metabolism/genetics ; Phenotype ; Drosophila ; Drosophila melanogaster ; }, abstract = {Neuronal loss in neurodegenerative disease is driven in part by maladaptive stress signaling and impaired adaptation to proteotoxic challenges. ENL and AF9 are YEATS-domain acyl-lysine reader proteins best characterized in leukemia, but their functions in neurons remains unclear. Here, we defined the role of the ENL/AF9 YEATS domain using complementary chemical and genetic perturbations. We applied the selective YEATS inhibitor SR-0813 in differentiated human neurons and modulated ENL/AF9 activity in Drosophila using either SR-0813 or ENL/AF9 knockdown. In flies, SR-0813 phenocopied ENL/AF9 knockdown by extending lifespan and enhancing stress tolerance. To test disease-context specificity, we performed a Drosophila genetic modifier screen across neurodegeneration models. ENL/AF9 reduction was beneficial in UBQLN2[P497H] and SOD1[G94A] but showed reduced efficacy or became detrimental in chronic aggregation or mitochondrial stress models such as (GGGGCC)49 and polyQ disease. In human neurons, SR-0813 improved survival across multiple stress conditions, with the strongest protection during endoplasmic reticulum stress. Mechanistically, ENL/AF9 YEATS inhibition dampened PERK-dependent integrated stress response signaling and reduced apoptotic commitment without broadly enhancing proteostasis capacity. Together, these findings identified ENL/AF9 as modulators of neuronal stress-response dynamics and established ENL/AF9 YEATS-domain inhibition as a context-dependent strategy to enhance neuronal resilience with relevance to ALS and related proteotoxic disorders.}, } @article {pmid42509371, year = {2026}, author = {Ran, X and Wuu, J and Qin, ZS and McDermott, MP and Cooper-Knock, J and Li, Y and Granit, V and Grignon, AL and Lin, E and Fernandez, MC and Colato, D and Carberry, N and Lill, CM and Piazza, P and Malaspina, A and Benatar, M}, title = {Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS.}, journal = {Nature medicine}, volume = {32}, number = {9}, pages = {3417-3429}, pmid = {42509371}, issn = {1546-170X}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; 2015, 16-TACL-242//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; 4365, 172123//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; R01 NS105479//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 NS105479/NS/NINDS NIH HHS/United States ; R01 NS105479, U54 NS092091//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/pathology ; *Proteomics/methods ; Longitudinal Studies ; Female ; Biomarkers/blood ; Male ; Disease Progression ; Middle Aged ; Aged ; }, abstract = {The study of pre-symptomatic amyotrophic lateral sclerosis (ALS) and the design of disease prevention trials are greatly hampered by our inability to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease and when. In this longitudinal Olink Explore, high-throughput, proteomic study, 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls were included. Here we identified 92 proteins with concentrations that changed before phenoconversion; characterized the longitudinal trajectory of these proteins and identified a core panel of 19 proteins which, collectively, predicted phenoconversion over the 0.5-year to 5-year time horizons (crossvalidated areas under the curve 0.80-0.89) and yielded estimates of time to phenoconversion with a mean absolute error of 1.6 years. These findings were partially replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (for example, NEFL, EDA2R and CA3) and that a multi-protein panel outperformed NEFL alone in estimating time to phenoconversion. This work sheds light on the biology of pre-symptomatic ALS. Moreover, our identification of a panel of new susceptibility/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention.}, } @article {pmid42509459, year = {2026}, author = {Sellin, J and Öijerstedt, L and von der Gablentz, J and Chamoun, S and Kläppe, U and Press, R and Samuelsson, K and Grosskreutz, J and Ingre, C}, title = {Plasma cardiac troponin T complements neurofilament light chain by reflecting disease phase and phenotypic variation in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {8}, pages = {}, pmid = {42509459}, issn = {1432-1459}, support = {GR 1578/6-1//Deutsche Forschungsgemeinschaft/ ; GR 1578/9-1//Deutsche Forschungsgemeinschaft/ ; EXC 2167/2 - 390884018//Germany`s Excellence Strategy/ ; }, mesh = {Humans ; *Neurofilament Proteins/cerebrospinal fluid/blood ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/physiopathology ; Female ; Male ; *Troponin T/blood ; Middle Aged ; Disease Progression ; Biomarkers/blood/cerebrospinal fluid ; Aged ; Phenotype ; Cohort Studies ; Adult ; }, abstract = {BACKGROUND: Neurofilament light chain (NfL) is an established marker of neuronal injury and disease aggressiveness in amyotrophic lateral sclerosis (ALS). In contrast, the clinical and biological significance of cardiac troponin T (cTnT) in ALS is not fully understood. We aimed to evaluate the relationship between plasma cTnT and disease aggressiveness, progression stage, and clinical phenotype in comparison with NfL.

METHODS: Plasma cTnT and cerebrospinal fluid (CSF) NfL were analysed at diagnosis in a population-based cohort of 526 patients with ALS. Disease aggressiveness was modelled using the D50 framework, which quantifies the time taken to lose 50% of functional capacity (ALSFRS-R) and normalises individual disease trajectories. Biomarker associations with disease aggressiveness, phase, and clinical variables were assessed through group comparisons, logistic and linear regression, and receiver operating characteristic analyses.

RESULTS: Neurofilament light chain in CSF was strongly associated with disease aggressiveness, with higher levels in patients with more aggressive disease. In contrast, plasma hs-cTnT did not correlate with D50. Across disease phases, CSF NfL remained relatively stable, whereas plasma hs-cTnT increased with advancing rD50, suggesting accumulation with disease progression. Plasma hs-cTnT levels were higher in patients with spinal compared to bulbar onset. Combined biomarker models improved sensitivity and negative predictive value for identifying less aggressive disease.

CONCLUSION: Plasma hs-cTnT and CSF NfL capture distinct but complementary dimensions of ALS pathology. While NfL reflects disease aggressiveness, hs-cTnT aligns with disease phase and clinical phenotype, supporting its use as a complementary biomarker for ALS characterisation and monitoring.}, } @article {pmid42510076, year = {2026}, author = {Uzun, E and İçöz, D and Apaydın, BK and Orhan, K}, title = {Investigation of the Use of Artificial Intelligence in Anterior Loop Detection: A Panoramic Radiography Study.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {16}, number = {14}, pages = {}, pmid = {42510076}, issn = {2075-4418}, support = {2024HZDP003//Pamukkale University/ ; }, abstract = {Background/Objectives: The accurate detection of the anterior loop (AL) of the inferior alveolar nerve is critical to avoid neurosensory complications during surgical procedures in the interforaminal region, and panoramic radiography continues to be widely used in routine dental diagnostics due to its accessibility and cost-effectiveness. This study aimed to evaluate the performance of a deep learning approach in automatic detection of the AL in panoramic radiographs. Methods: A total of 305 anonymised panoramic radiographs containing 413 annotated ALs were used to train a YOLOv8x-based model for automatic AL detection. The dataset was divided into training, validation, and test sets consisting of 245 images (332 AL annotations), 30 images (40 AL annotations), and 30 images (41 AL annotations). Labelling was carried out by using the polygonal annotation method. The model's performance in identifying the AL region was measured using precision, recall, F1 score, and mean average precision (mAP@0.5). Results: The model achieved a precision of 0.75, a recall of 0.6585, and a F1 score of 0.7013. The average precision at an intersection over union (IoU) threshold of 0.5 (mAP@0.5) was 0.739. Conclusions: This study demonstrates the feasibility of using a YOLOv8x-based detection model to detect ALs in panoramic radiographs. Although further improvements are needed to enhance model sensitivity and generalisability, the findings demonstrate the potential to support clinical decision-making.}, } @article {pmid42510722, year = {2026}, author = {Avitabile, A and Rusciano, D and Amato, R and Cannizzaro, L and Gagliano, C}, title = {Sex-Dependent Brain Plasticity in Neurological Disease: From Biological Variability to Adaptive, Compensatory, and Maladaptive Trajectories.}, journal = {Biology}, volume = {15}, number = {14}, pages = {}, pmid = {42510722}, issn = {2079-7737}, abstract = {Brain plasticity is often described as the capacity of the nervous system to change in response to development, experience, injury, disease, or treatment. That definition is useful, but it can obscure two clinically important points: plasticity is biologically constrained, and change is not always beneficial. This narrative review examines sex-dependent brain plasticity as a context-sensitive process rather than as a simple male-female contrast. We distinguish four operational outcomes of plasticity: (i) reparative plasticity, which restores structure or function; (ii) compensatory plasticity, which preserves performance through alternative or more costly strategies; (iii) insufficient plasticity, in which reorganization is too weak or unstable to sustain function; and (iv) maladaptive plasticity, in which plastic change reinforces dysfunction, pain, excitability, rigidity, or decline. We also define adaptive reserve as the integrated capacity of neural, glial, vascular, immune, metabolic, endocrine, and gene-regulatory systems to support useful reorganization under stress. The review evaluates endocrine, synaptic, neuroimmune, mitochondrial, vascular, stress-related, and epigenetic mechanisms, indicating where evidence for sex-dependent effects is relatively strong and where it remains indirect, inconsistent, or context-dependent. Disease examples include autism spectrum disorder, attention-deficit/hyperactivity disorder, epilepsy, intellectual disability, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, traumatic and ischemic injury, multiple sclerosis, chronic pain, aging, and systemic metabolic or inflammatory disorders. Throughout, biological sex is separated from gender-related social, diagnostic, and health-care determinants. We conclude that therapeutic strategies should not aim simply to enhance plasticity, but to guide it by matching intervention, timing, dose, biological readiness, and monitoring to the patient's adaptive state.}, } @article {pmid42511587, year = {2026}, author = {Korošec, T and Rogelj, B and Župunski, V}, title = {LINE-1 Retrotransposons and Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {14}, pages = {}, pmid = {42511587}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Long Interspersed Nucleotide Elements/genetics ; Animals ; Immunity, Innate ; cGAS-STING Signaling Pathway ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons. While monogenic causes account for a minority of cases, in most cases, ALS is sporadic and likely arises from multilayer interactions of genetic architecture, aging-associated loss of genome regulation, and inflammatory stress. Long interspersed nuclear element-1 (LINE-1) retrotransposons are endogenous mobile elements that are tightly controlled through various cellular mechanisms under normal conditions. When abnormally active, they are involved in gene inactivation, expression regulation, and genomic instability, leading to cellular processes such as innate immunity and cell death. Here, we present mechanistic links between LINE-1 and ALS. These include evidence that the burden of retrotransposition-competent LINE-1s (RC-L1s) is increased in ALS genomes, positioning RC-L1 load as a candidate contributor to missing heritability in sporadic disease. We also integrate emerging data showing that LINE-1 RNA can be intrinsically toxic independently of new insertions, as it promotes chromatin opening and transcriptional epigenetic noise, particularly when nuclear RNA surveillance pathways fail in TDP-43 pathology. Finally, we review how LINE-1-derived DNA/RNA intermediates can engage innate immune sensors, highlighting the cGAS-STING axis as a plausible route from LINE-1 de-repression to neuroinflammation. Together, these concepts support a model in which genetic RC-L1 load and age-/pathology-driven LINE-1 de-repression converge on nuclear dysfunction and inflammatory amplification, suggesting concrete molecular nodes for therapeutic intervention.}, } @article {pmid42511680, year = {2026}, author = {Podshivalova, ES and Kutsev, SI and Shestopalov, AV}, title = {The Kynurenine Pathway: Unraveling Its Role in Neurological Disorders via Mammalian Cellular Models.}, journal = {International journal of molecular sciences}, volume = {27}, number = {14}, pages = {}, pmid = {42511680}, issn = {1422-0067}, mesh = {*Kynurenine/metabolism ; Humans ; Animals ; *Nervous System Diseases/metabolism/pathology ; Signal Transduction ; Metabolic Networks and Pathways ; Tryptophan/metabolism ; }, abstract = {The kynurenine pathway (KP) constitutes the primary route of tryptophan catabolism, generating a spectrum of neuroactive metabolites that profoundly influence central nervous system function. Dysregulation of the KP is increasingly recognized as a critical pathogenic mechanism underlying diverse neuropathological conditions. This review critically evaluates the most widely cited mammalian cellular models currently utilized to delineate the causal role of KP alterations in neurological disease. Specifically, this article examines primary cell cultures, immortalized and tumor-derived cell lines, stem cell-derived systems, and ex vivo organotypic brain slices and tissues, highlighting their distinct methodological advantages, translational limitations, and specific enzymatic profiles. Across the described cellular systems, a recurring mechanistic theme emerges: quinolinic acid-driven mitochondrial dysfunction, oxidative stress, and NAD+ depletion converge in neurodegenerative conditions such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Conversely, kynurenic acid exhibits disorder-dependent-and at times opposing-roles, attenuating dopaminergic neurotoxicity in Parkinson's disease models while contributing to synaptic pruning deficits in schizophrenia models. Furthermore, cellular models demonstrate that IDO1/TDO induction and downstream metabolite shifts are frequently cell type- and species-dependent, complicating direct extrapolation to human pathology. Because no single experimental system achieves complete physiological fidelity, elucidating the complex dynamics of the KP and identifying novel therapeutic targets requires the integration of data across complementary platforms.}, } @article {pmid42512084, year = {2026}, author = {Assialioui, A and Povedano, M and Senau, M and Ferrer, I and Arias, L}, title = {Retinal Thickness and Vascular Density Changes in Amyotrophic Lateral Sclerosis Assessed by Optical Coherence Tomography Angiography.}, journal = {Biomedicines}, volume = {14}, number = {7}, pages = {}, pmid = {42512084}, issn = {2227-9059}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem disorder involving neurovascular dysfunction. The retina allows in vivo assessment of neurovascular changes. This study evaluated retinal structural and microvascular alterations in ALS using optical coherence tomography (OCT) and optical coherence tomography angiography (OCT-A). Methods: This cross-sectional study included 46 participants with ALS and 19 healthy controls. Retinal thickness and vascular density in the superficial and deep retinal capillary plexuses and the choriocapillaris were quantified using OCT and OCT-A. Group comparisons and logistic regression analyses were performed to assess associations with ALS. Subgroup analyses were conducted according to clinical phenotype. Results: In total, 124 eyes were analyzed. ALS was associated with increased average retinal thickness (p = 0.023) and reduced vascular density in the superficial retinal capillary plexus (p = 0.005), deep retinal capillary plexus (p < 0.001), and choriocapillaris (p = 0.004). In logistic regression analyses, retinal thickness was positively associated with ALS status (OR = 1.42, p = 0.023), whereas higher vascular density in the superficial plexus, deep plexus, and choriocapillaris was associated with lower odds of ALS. No significant differences were observed between bulbar- and spinal-onset ALS phenotypes. Conclusions: ALS is associated with structural and microvascular retinal alterations detectable by OCT and OCT-A. These findings support the presence of systemic neurovascular dysfunction and highlight retinal imaging as a promising, non-invasive approach for investigating disease mechanisms and developing potential biomarkers.}, } @article {pmid42512450, year = {2026}, author = {Yogi, S and Singh, A}, title = {Molecular Mechanisms of Neurodegenerative Diseases: Emerging Biomarkers and Therapeutic Targets.}, journal = {Brain sciences}, volume = {16}, number = {7}, pages = {}, pmid = {42512450}, issn = {2076-3425}, support = {R01 EY032959/EY/NEI NIH HHS/United States ; }, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-β and tau aggregates in AD, α-synuclein aggregation and mitophagy failure in PD's, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies.}, } @article {pmid42512540, year = {2026}, author = {Manzo, J and Hernández-Aguilar, ME}, title = {Autism and Neurodegeneration: Distinct Disorders or a Shared Biological Continuum?.}, journal = {Brain sciences}, volume = {16}, number = {7}, pages = {}, pmid = {42512540}, issn = {2076-3425}, abstract = {BACKGROUND/OBJECTIVES: Autism spectrum disorder (ASD) is traditionally classified as a neurodevelopmental condition, whereas neurodegenerative diseases are defined by progressive neuronal decline in later life. This separation has shaped research and clinical practice, yet emerging evidence suggests potential biological overlap. This review aims to evaluate whether ASD and neurodegenerative disorders represent distinct entities or are linked through shared mechanisms operating across the lifespan.

METHODS: This narrative review synthesizes findings from genetic, molecular, cellular, circuit-level, and epidemiological studies examining ASD and major neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Emphasis is placed on identifying convergent pathways and evaluating evidence within a lifespan-oriented framework.

RESULTS: Across multiple levels of analysis, ASD and neurodegenerative diseases share partially overlapping biological mechanisms, including mitochondrial dysfunction, impaired proteostasis, neuroimmune alterations, and network-level instability. Genetic and molecular data reveal pleiotropic pathways influencing both early neurodevelopment and later neuronal resilience. Circuit-level studies highlight shared principles of network vulnerability, including cerebellar involvement and excitation-inhibition imbalance. Epidemiological data further indicate increased risk of dementia and parkinsonian features in autistic adults. These convergences suggest that early neurodevelopmental alterations may establish latent vulnerabilities that, under specific conditions, intersect with neurodegenerative processes later in life.

CONCLUSIONS: ASD and neurodegenerative diseases are best understood as distinct clinical conditions that share partially overlapping biological substrates. Rather than implying a deterministic progression, the evidence supports a model of lifespan convergence in which timing, context, and individual susceptibility shape outcomes. This framework highlights the need for integrated research and clinical approaches that consider brain health as a continuous process from development through aging.}, } @article {pmid42513190, year = {2026}, author = {Funsueb, S and Thanavanich, C and Chudoung, C and Jomnong, P and Theanjumpol, P and Kittiwachana, S}, title = {Comprehensive and Non-Destructive Sweet Corn Shelf-Life Prediction Using Near-Infrared (NIR) Spectroscopy Coupled with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) Spectral Resolution.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {14}, pages = {}, pmid = {42513190}, issn = {1420-3049}, support = {Proactive Researcher Program//Chiang Mai University/ ; }, mesh = {*Zea mays/chemistry ; Spectroscopy, Near-Infrared/methods ; Least-Squares Analysis ; *Food Storage ; Multivariate Analysis ; Temperature ; Kinetics ; }, abstract = {Accurate shelf-life prediction of perishable products remains challenging because quality deterioration involves multiple physicochemical changes that are not adequately captured by conventional univariate approaches. This study proposes a multivariate shelf-life prediction framework for sweet corn based on near-infrared (NIR) spectroscopy coupled with multivariate curve resolution-alternating least squares (MCR-ALS). NIR spectra were collected from sweet corn samples and analyzed using MCR-ALS to extract chemically interpretable concentration and spectral profiles. A total of 100 and 85 corn samples were used for model training and validation, respectively. The dominant MCR-ALS component showed strong correlations with total soluble solids, dry matter, and individual sugar contents (sucrose, glucose, and fructose), effectively describing the overall quality degradation process. Based on the zero-order kinetic model, the predicted shelf lives were 41.3, 11.0, and 8.9 days at 4, 13, and 25 °C, respectively. Arrhenius analysis of the MCR-ALS concentration profile yielded a temperature-dependent degradation rate with an activation energy of 54.05 kJ mol[-1] (R[2] = 0.8387). The practical applicability of the proposed framework was further examined using a separate harvest batch of sweet corn that underwent repeated non-destructive NIR measurements throughout storage. Overall, the proposed NIR-MCR-ALS framework provides a rapid, non-destructive, and chemically interpretable approach for shelf-life prediction and postharvest quality monitoring of perishable produce.}, } @article {pmid42513312, year = {2026}, author = {Kordas, B}, title = {Multimodal Assessment of Consciousness with Brain-Computer Interfaces and Artificial Intelligence: From Acquired Brain Injury to Neurodegenerative Disease.}, journal = {Journal of clinical medicine}, volume = {15}, number = {14}, pages = {}, pmid = {42513312}, issn = {2077-0383}, support = {2023/49/N/NZ4/03958//National Science Centre/ ; }, abstract = {The assessment of consciousness has been shaped largely by research on acquired disorders of consciousness after acute or chronic brain injury, but similar problems of unreliable behavioral expression increasingly arise in neurodegenerative disease. This translational overlap is especially relevant when preserved cognition, awareness, or intentionality cannot be reliably expressed because of severe motor impairment, fluctuating arousal, cognitive decline, aphasia, apraxia, or impaired cooperation. In neurodegenerative disease, degeneration of arousal systems, large-scale brain networks, cognition, and motor pathways may similarly make observable behavior an unreliable measure of awareness. The challenge is not only to determine if a patient responds, but also to ask if residual awareness, intentionality, or covert cognition can still be detected through physiological signals. This review discusses how contemporary modalities reshape this assessment. Electroencephalography has moved from a descriptive measure of background activity to a bedside tool capable of probing event-related responses, network organization, and cortical complexity. Magnetic resonance methods reveal altered connectivity within thalamocortical and default mode network systems, while functional near-infrared spectroscopy adds a portable hemodynamic approach that may be repeated at the bedside and integrated with active paradigms. Brain-computer interfaces provide a translational step by converting neural responses into evidence of command following or, in selected patients, into communication, and artificial intelligence strengthens these approaches by extracting clinically meaningful patterns from complex neural and hemodynamic data. Additionally, autonomic measures, including heart rate variability and baroreflex indices, are considered as auxiliary physiological context for arousal and engagement, and not as direct markers of awareness. Because the most mature evidence for covert awareness and cognitive-motor dissociation comes from acquired disorders of consciousness, this review treats brain injury literature as a methodological foundation instead of as directly interchangeable evidence for neurodegenerative disease. It then examines how these approaches may be adapted to neurodegenerative contexts, especially ALS, severe dementia, Lewy body disease with fluctuating cognition, and conditions in which communication or motor output becomes unreliable.}, } @article {pmid42514481, year = {2026}, author = {Xie, P and Wang, J and Tong, B and Di, C and Zhou, F and Wang, W}, title = {Genome-Wide Characterization of the HaALS Gene Family Reveals Its Potential Roles in Imazethapyr Tolerance in Sunflower (Helianthus annuus L.).}, journal = {Plants (Basel, Switzerland)}, volume = {15}, number = {14}, pages = {}, pmid = {42514481}, issn = {2223-7747}, support = {CARS-14-1-06//Project of China Agriculture Research System/ ; CX25JC27//Heilongjiang Agricultural Science and Technology Innovation Leap Project/ ; }, abstract = {Acetolactate synthase (ALS; EC 2.2.1.6) catalyzes the first committed step in branched-chain amino acid (BCAA) biosynthesis and is the molecular target of multiple herbicide classes, including the imidazolinones. Here, we performed a genome-wide characterization of the HaALS gene family in sunflower (Helianthus annuus L.) and investigated genotype-dependent transcriptional responses to imazethapyr. A total of 11 HaALS genes were identified and classified into three phylogenetic clades (Groups A-C). All HaALS proteins contained the conserved TPP_enzyme domains (TPP_enzyme_N, TPP_enzyme_M, and TPP_enzyme_C), and purifying selection (Ka/Ks < 1) indicated strong evolutionary constraint on their core enzymatic function. Promoter analyses revealed abundant cis-regulatory elements associated with diverse stress and signaling inputs, supporting regulatory potential for herbicide-triggered transcriptional modulation. qRT-PCR analysis following imazethapyr application (0, 24, and 48 h) showed pronounced genotype-dependent expression reprogramming between the susceptible (S) and resistant (R) cultivars. In the R genotype, multiple HaALS members were strongly induced after treatment; specifically, HaALS4 reached a ~6-fold increase at 24 h and a >10-fold increase at 48 h, and HaALS11 increased to ~6-7-fold at 24 h while remaining above the baseline at 48 h; several additional paralogs exhibited intermediate induction (~3-8-fold by 48 h). In contrast, the S genotype showed limited changes (typically ~0.8-2-fold). Collectively, these findings define the evolutionary features of the sunflower HaALS family and identify herbicide-responsive paralogs that may contribute to imidazolinone tolerance, providing candidates for functional validation and molecular breeding.}, } @article {pmid42514807, year = {2026}, author = {Cazacu, G and Pamfil, D and Chirilă, O and Totolin, M and Ciolacu, D and Ghilan, A and Niţă, L and Niţă, T and Vasile, C}, title = {Chemical Treatment of Some Lignosulfonates Under DBD Plasma Conditions-II: Characterization of the Modified Lignosulfonates Microparticles.}, journal = {Polymers}, volume = {18}, number = {14}, pages = {}, pmid = {42514807}, issn = {2073-4360}, abstract = {The chemically modified ammonium lignosulfonate (ALS) powders with carboxylic acids such as, oleic (OA) and lactic acid (LA) and γ-butyrolactone (BL) under dielectric barrier plasma discharge (DBD) have been characterized by average molecular weight and particle size determinations, morphology examination by optical and electronic microscopy (SEM), the study of the thermal properties by thermogravimetry (TG/DTG), differential scanning calorimetry (DSC), differential thermal analysis (DTA) and antioxidant activity tests by DPPH method. The thermal characterization of the modified lignosulfonates reveals their improved thermal stability comparatively with ALS. It has been established that the obtained microparticles are aggregates of particles, covered by modified polymer and exhibit a particular behavior depending on the chemical structure of the used modifier, leading to multifunctional active lignin-based products with better homogeneity. By surface modification, the antioxidant capacity of modified lignosulfonate powders has been maintained.}, } @article {pmid42515387, year = {2026}, author = {Megalingam, RK and Kuttankulangara Manoharan, S and Cheriyan Manjooran, D and Kamble, D}, title = {Thrivaad: A Multilingual, Predictive Eye-Sign-Based AAC System Powered by Optimized Deep Learning.}, journal = {Sensors (Basel, Switzerland)}, volume = {26}, number = {14}, pages = {}, pmid = {42515387}, issn = {1424-8220}, mesh = {Humans ; *Deep Learning ; *Communication Devices for People with Disabilities ; *Eye Movements/physiology ; Brain-Computer Interfaces ; Multilingualism ; }, abstract = {Around 1.5% of the global population is suffering from speech impairments; the major causes for this are cerebral palsy and ALS, and the only way for these individuals to communicate is through Augmentative and Alternative Communication (AAC). These systems are either electronic or non-electronic. Based on new study developments, electronic methods, such as Brain-Computer Interaction (BCI) and eye-gaze-based communication, are assessed as the best choices, but they have their own limitations, incorporating limited adaptability to changing conditions, such as setup variations and user fatigue, which reduces the system's robustness. Our previous study, Netravad, shows potential for addressing these gaps, but it lacks multilingual support and will not yield the same results under changing lighting conditions. This study, Thrivaad, provides multilingual support and text prediction and integrates optimized deep learning to accurately capture eye movements even in varying environmental lighting conditions. Thrivaad uses eye movements as input from a webcam, and the Optuna-optimized YOLOv5 model is used to detect the eye direction accurately. Then communication is established in English, Malayalam, and Hindi. The text-prediction feature of this system improves communication by reducing the number of eye gestures required to form a message. This study included a total of 60 participants across three age groups with 35,263 eye-sign images collected. With this data, the YOLOv5 model is trained and then optimized by Optuna. The proposal system provides accurate eye direction, text prediction, multilingual support, and improved adaptability to changing conditions for eye-based AAC.}, } @article {pmid42515735, year = {2026}, author = {Rosiak, N and Stojceski, F and Maroni, G and Piontek, B and Cielecka-Piontek, J}, title = {Integrative Network Pharmacology and Molecular Docking Analysis Reveals the Multitarget Mechanisms of Pterostilbene in Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {7}, pages = {}, pmid = {42515735}, issn = {1424-8247}, support = {P41 GM103311/GM/NIGMS NIH HHS/United States ; UMO-2020/37/B/NZ7/03975//National Science Centre/ ; }, abstract = {Background: Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), differ in etiology but share several convergent pathological mechanisms. Pterostilbene (PTR) is a natural stilbene with reported antioxidant, anti-inflammatory, and neuroprotective properties. This study aimed to prioritize putative PTR-associated targets and biological processes potentially relevant to shared neurodegenerative mechanisms. Methods: An integrative in silico workflow combining network pharmacology, protein-protein interaction (PPI) analysis, GO Biological Process (GO BP) enrichment, molecular docking, and molecular dynamics (MD) simulations was applied. GO BP terms were filtered, focused on neurodegeneration- and neuroprotection-related processes, and subjected to REVIGO-based redundancy reduction. Selected targets were further evaluated by docking and 500 ns MD simulations. Results: A total of 181, 165, 128, and 109 shared PTR-disease targets were identified for AD, PD, HD, and ALS, respectively. Redundancy-reduced GO BP analysis indicated associations with neuroinflammation, oxidative stress and reactive oxygen species-related responses, programmed cell death, MAPK/ERK- and PI3K/AKT-related signaling, ion and calcium transport, and lipid-, steroid-, or hormone-associated regulation. PPI topology prioritized SRC, ESR1, and HSP90AA1 as recurrent hub-bottleneck proteins, whereas MD-based structural interpretation focused on ESR1 and HSP90AA1. MD analyses indicated stable PTR interactions with both proteins, with ESR1 showing the most favorable predicted interaction profile. Conclusions: These findings suggest that PTR may interact with shared neurodegeneration-relevant molecular systems, particularly through ESR1- and HSP90AA1-associated mechanisms. However, the results are exclusively computational and should be interpreted as hypothesis-generating, requiring further experimental validation.}, } @article {pmid42516233, year = {2026}, author = {Sancho-Castillo, S and Bargues-Navarro, G and Cárdenas Salazar, RG and Privado, J and Sanchis-Sanchis, E and Sancho-Cantus, D and Sanchis-Sanchis, CE and Cubero-Plazas, L and Cano Mateu, M and de la Rubia Ortí, JE}, title = {Influence of micronutrients on anxiety and depression in patients with amyotrophic lateral sclerosis.}, journal = {Frontiers in nutrition}, volume = {13}, number = {}, pages = {1790327}, pmid = {42516233}, issn = {2296-861X}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive loss of motor function, with respiratory failure representing the leading cause of death. Beyond motor deterioration, ALS involves extramotor manifestations, including prominent anxiety and depression symptoms. The intake of certain micronutrients has been associated with these emotional symptoms, due to their role in monoaminergic and peptidic neurotransmitter synthesis pathways; furthermore, these emotional symptoms can severely reduce patients' quality of life. Therefore, this study aims to analyze the relationship between the intake of key micronutrients related to neurotransmitter activity and anxiety and depression symptoms in ALS patients.

METHODS: A cross-sectional study was conducted with 61 patients with bulbar- or spinal-onset ALS. Dietary micronutrient intake (iodine, magnesium, vitamin B6, vitamin B9, and vitamin C) was assessed using a seven-day dietary record and a Food Frequency Questionnaire. Depression was assessed using the ALS Depression Inventory-12 (ADI-12), while anxiety-related symptoms were assessed using the Beck Anxiety Inventory (BAI).

RESULTS: A path analysis was conducted to examine the statistical prediction of emotional measures from nutrient intake. The model showed a good fit to the data: NFI = 1.000, GFI = 1.000, and SRMR = 0.001. Considering the magnitude of the effect of the regression weights (β ≥ 0.14), depression scores exhibited exploratory associations with iodine (β = -0.21) and magnesium (β = 0.22), while vitamin B9 (β = -0.32) emerged as an inferentially significant predictor (p < 0.05). Anxiety-related symptom severity (BAI scores) showed exploratory associations with iodine (β = -0.31), vitamin B6 (β = 0.24), and vitamin C (β = -0.15), whereas depression scores (β = 0.51) were an inferentially significant predictor (p < 0.05), with 41% of explained variance.

CONCLUSION: In this sample, lower vitamin B9 intake was statistically associated with depression scores in patients with ALS, while lower iodine and higher magnesium intake showed exploratory associations. Regarding anxiety-related symptoms assessed using the Beck Anxiety Inventory (BAI), higher scores were statistically associated with lower iodine and vitamin C intake, higher vitamin B6 intake, and elevated depression scores, and showed exploratory associations with lower iodine and vitamin C intake, and higher vitamin B6 intake.}, } @article {pmid42517609, year = {2026}, author = {Dillenburg, RF and Lopatina, A and Ruan, H and Scheidt, T and Mosna, S and Pekbilir, E and Bieber, J and Schäfer-Depoix, F and Landfester, K and Schmidt, C and Möckel, MM and Morsbach, S and Schmid, F and Dormann, D and Stelzl, L and Girard, M and Lemke, EA}, title = {A Phosphorylation-Induced Micellization Switch in the Low-Complexity Domain of TDP-43.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e76625}, pmid = {42517609}, issn = {2198-3844}, support = {464588647//Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)/ ; }, abstract = {Phase separation (PS) of the low-complexity domain (LCD) of TAR DNA-binding protein 43 kDa (TDP-43) is linked to pathogenic aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). Here, we show that extensive phosphorylation of the LCD C-terminus redirects its self-assembly. Coarse-grained Monte Carlo simulations predicted that 12 Ser phosphorylations partition the 148-residue LCD into a hydrophobic N-terminal and highly charged C-terminal block, favouring finite-sized micellization over macroscopic PS. In vitro, LCD phosphorylated by casein kinase 1 delta (CK1δ; mean of 12 phosphorylations by native mass spectrometry) and phosphomimetic 12D/12DD mutants formed spherical nanoparticles (≈ 20-50 nm) above a low-micromolar critical micelle concentration, whereas the unphosphorylated LCD underwent reversible PS that matured into fibrils. Increasing ionic strength shifted the mutants toward anisotropic morphologies (wormlike 12D micelles and rigid 12DD nanocylinders). Turbidity assays and confocal imaging directly visualized the absence of PS in the phosphorylated form. Negative-stain and cryo-electron microscopy (cryo-EM) confirmed the spherical micellar architecture for the phosphorylated LCD and 12D/12DD mimics. Our data identify phosphorylation as a molecular switch tuning macrophase separation and fibril formation of TDP-43 LCD, providing a framework for an aggregation-protective role through microphase separation into size-limited micelles. Whether these assemblies are stable or kinetically trapped on pathological timescales remains unclear.}, } @article {pmid42520183, year = {2026}, author = {Simão, S and Oliveira Santos, M and Gromicho, M and Martins, IP and de Carvalho, M}, title = {Evidence of stage-specific cognitive reserve effects on longitudinal cognition in amyotrophic lateral sclerosis.}, journal = {Journal of neuropsychology}, volume = {}, number = {}, pages = {}, doi = {10.1111/jnp.70066}, pmid = {42520183}, issn = {1748-6653}, abstract = {About 50% of amyotrophic lateral sclerosis (ALS) patients develop cognitive-behavioural impairment, yet longitudinal studies diverge on onset and extent of decline. Cognitive reserve (CR) may modulate cognitive trajectories, although longitudinal evidence remains limited. We aim to characterize cognitive trajectories in ALS and healthy aging and to examine the role of CR proxies in shaping cognitive change over time. About 268 participants (169 patients, 99 controls) were evaluated twice over 6 to 18 months using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Mixed models were used to predict initial ECAS performance (ECAS1), and cognitive slope (ECAS2-ECAS1) using CR proxies (education, work and leisure), ECAS21-ECAS12 interval, demographics (age, sex, psychiatric medication) and clinical factors (disease duration, onset-region, respiratory capacity, functional decline, C9orf72 mutation and behavioural symptoms). In patients, education (p < .001) and leisure (p < .001) positively predicted ECAS1. However, longitudinally, education and leisure had negative main effects on cognition, protecting against decline through interactions with clinical variables. In controls, more education and leisure predicted better cognition through main effects and interactions. CR appears to exhibit a dynamic, phase-dependent influence in patients and controls, supporting initial cognitive performance and potentially offering subtle protection as disease progresses. The observed non-linear effects of all CR proxies and subgroup-specific effects highlight the importance of considering clinical context, time and initial cognition when evaluating CR's role in ALS.}, } @article {pmid42520340, year = {2026}, author = {Morgan-Jack, BR and Katz, ML and Kick, GR and Johnson, GC and Delgado, K and Makinen, M and Coates, JR}, title = {Pathology of general proprioception in a canine disease model of amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {489}, number = {}, pages = {126108}, pmid = {42520340}, issn = {1878-5883}, support = {S10 OD032246/OD/NIH HHS/United States ; T34 GM136493/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Dogs ; *Amyotrophic Lateral Sclerosis/pathology/veterinary/genetics/physiopathology/complications ; Disease Models, Animal ; *Proprioception/physiology ; Superoxide Dismutase-1/genetics ; Ganglia, Spinal/pathology ; Female ; Axons/pathology ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Some forms of amyotrophic lateral sclerosis (ALS) are associated with sequence variants in the superoxide dismutase 1 gene (SOD1). The mechanisms by which these variants contribute to ALS disease pathogenesis are poorly understood. Degenerative myelopathy (DM), a naturally occurring canine disease, shares similarities with some forms of SOD1-associated ALS, especially cases with sensory impairment. While motor pathway involvement in ALS has been extensively studied, sensory pathology has received comparatively less attention. To investigate whether pathology in the general proprioceptive pathway is associated with pelvic limb general proprioceptive ataxia, an early DM sign, we examined sensory system components of this pathway from Pembroke Welsh Corgis with early- and late-stage DM and age-matched controls. The disease was characterized by axonal pathology in the spinocerebellar tracts and the fasciculus gracilis, pronounced accumulation of SOD1-positive inclusions in nucleus thoracicus and dorsal root ganglia (DRG) neurons, and altered SOD1 immunolabeling in dorsal and ventral root axons and ensheathing myelin. Axonal pathology was also observed in a pelvic limb sensory nerve. These findings suggest that pathology in the proprioceptive sensory pathways may play a significant role in general proprioceptive ataxia in DM. Some dogs that were homozygous for the SOD1 risk allele did not develop clinical disease or the associated neuropathology, indicating that other factors in addition to the SOD1 mutation influence disease onset and progression.}, } @article {pmid42521602, year = {2026}, author = {Pathapati, N and Nguyen, M and Ju, J and Maddukuri, M and Kiehl, J and Kvale, E and Thrift, AP and Berth, S and Grouls, A}, title = {Capturing Financial Burden Concerns in an ALS Multidisciplinary Clinic.}, journal = {Muscle & nerve}, volume = {74}, number = {4}, pages = {1270-1274}, pmid = {42521602}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/economics/therapy ; Retrospective Studies ; Female ; Male ; Electronic Health Records ; Middle Aged ; *Cost of Illness ; Aged ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is associated with substantial financial burden. How financial concerns are documented or addressed in ALS multidisciplinary clinics (MDC) is unclear. We aimed to characterize financial concerns among people living with ALS (pALS) and how they are identified and documented by multidisciplinary clinic staff.

METHODS: We performed a retrospective electronic medical record (EMR) review for people living with ALS (pALS) attending at least two visits at the MDC, identifying documentation of financial concerns across all MDC notes throughout 2024. Semi-structured interviews with MDC staff explored experiences with financial concern discussions and documentation. Rapid qualitative analysis was used to analyze interview content.

RESULTS: Among 67 pALS with at least 2 MDC visits, 45 (67.2%) had ≥ 1 documented financial concerns. Financial concerns were most documented in neurology physician notes and portal messages (both 77.8%) and included insurance denials, medication costs, disability/Medicare navigation, caregiving expenses, and home modifications. Social work and patient portal notes provided greater detail than other staff notes. Staff interviews highlighted insurance and equipment costs as frequent financial concerns. Four qualitative themes emerged: insurance challenges and reliance on non-insurance resources, financial barriers limiting care and quality of life, limited proactive conversations/documentation, and the central role of social work.

DISCUSSION: Financial concerns are common among pALS but are inconsistently discussed and documented in the EMR, often arising through asynchronous communication or social work. Integrating financial screening and promoting proactive multidisciplinary documentation may improve identification of financial concerns and support more equitable, person-centered ALS care.}, } @article {pmid42521811, year = {2026}, author = {Willemse, SW and Demaegd, KC and Koole, W and van Eijk, RPA and van Rheenen, W and Veldink, JH and van den Berg, LH and van Es, MA}, title = {Tofersen treatment in respiratory onset amyotrophic lateral sclerosis and a variant of uncertain significance in SOD1; a case report.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {42521811}, issn = {1476-5438}, support = {09150161810018//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)/ ; V0000319//ZonMw (Netherlands Organisation for Health Research and Development)/ ; }, abstract = {The antisense oligonucleotide tofersen is available for treating amyotrophic lateral sclerosis (ALS) caused by pathogenic SOD1 variants. However, it is unknown whether Variants of Uncertain Significance (VUS) are a viable treatment target. We assessed clinical and biomarker trajectories prior to and after initiation of tofersen in a patient with respiratory onset ALS and a novel c.234_236del p.(Glu79del) VUS in SOD1. After six months of treatment, cerebrospinal fluid (CSF) SOD1 protein decreased by 47%, CSF NfL by 55% and serum NfL by 50%, with trajectories comparable to known pathogenic variants. Functional decline on the ALSFRS-R slowed from 1.52 points per month pre-treatment to 0.52 points per month post-treatment, muscle strength remained stable, and EQ-VAS quality of life scores remained between 60 and 70. The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.}, } @article {pmid42521895, year = {2026}, author = {Abidar, S and Nhiri, M and Bianchi, V}, title = {Suicide in neurodegenerative diseases: a systematic review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {8}, pages = {}, pmid = {42521895}, issn = {1590-3478}, mesh = {Humans ; *Neurodegenerative Diseases/psychology ; *Suicide/psychology/statistics & numerical data ; Amyotrophic Lateral Sclerosis/psychology ; Multiple Sclerosis/psychology ; }, abstract = {BACKGROUND AND OBJECTIVE: Suicide is a public health issue, which differs from suicidality, the continuum from suicidal ideation to the suicidal act, including suicide attempts and completed suicide. The main goal of the present study is to determine the relationship between Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) with suicidality.

METHODS: This is a systematic review aiming to determine the relationship between AD, PD, ALS, and MS with suicidality following PRISMA 2020 guidelines by collecting cross-sectional, case-control, and cohort studies; case series; case reports; and retrospective and prospective studies from Google Scholar, PubMed, and Cochrane Library. The protocol of this systematic review was registered on PROSPERO; the registration number is CRD420261422354.

RESULTS: From 2247 records identified from electronic databases, only 24 articles were included: three studies focusing on AD, nine on PD, and six studies focusing on ALS and MS, respectively. These studies exhibited moderate to low risk of bias. Despite the broad differences regarding the neurochemistry, pathophysiology, diagnosis, symptoms, and treatments of the selected diseases, patients are at a higher risk of suicidality. Depression and low social connectivity are the most prevalent risk factors. Suicidality is mainly detected during the first years post-diagnosis in PD, ALS, and MS patients, while the results in AD are confusing.

CONCLUSIONS: Data about this topic is scarce and largely varying. Further research is required to elucidate this paradigmatic realm, fostering awareness, enhancing therapies, and providing explanations and interpretations of the mechanisms involved.}, } @article {pmid42523377, year = {2026}, author = {Breevoort, A and Ivanov, D and Horan-Portelance, L and Nana, A and Vatsavayai, S and Miravet, ÀT and Wallace, JL and Ding, JW and Pereira, FL and Fernhoff, K and Gorno-Tempini, ML and Spina, S and Yokoyama, JS and Rosen, HJ and Grinberg, LT and Jacobs, FMJ and Miller, BL and Seeley, WW and Pollen, AA}, title = {Single-cell transcriptomic atlas of frontoinsular cortex reveals molecular correlates of selective neuronal vulnerability in FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42523377}, issn = {2692-8205}, support = {R01 NS104437/NS/NINDS NIH HHS/United States ; R56 AG057195/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; S10 OD028511/OD/NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG087959/AG/NIA NIH HHS/United States ; }, abstract = {Frontotemporal dementia (FTD) is characterized by selective neuronal vulnerability, yet the features that predispose specific neuron types to degeneration remain unclear. We performed single-nucleus RNA sequencing of frontoinsular cortex, a region affected early in behavioral variant FTD, across individuals with C9orf72-associated and sporadic FTD-MND spectrum disease. By enriching for large projection neurons, we resolved molecular subtypes of layer 5 extratelencephalic neurons, including von Economo neurons, and identified selective depletion of specific layer 2/3 and layer 5 neuron subtypes, convergent across genotypes. Despite selective neuronal loss, disease-associated transcriptional changes were convergent across excitatory neuron populations, suggesting that they reflect upstream pathophysiology or shared responses to local neurodegeneration. By relating neighborhood-level depletion in disease to gene expression in controls, we found that baseline cellular respiration and ATP synthesis predict neuronal vulnerability in disease. These findings define molecular correlates of selective neuronal vulnerability in FTD and provide a framework linking cell type and state to neurodegeneration.}, } @article {pmid42523442, year = {2026}, author = {Jonk, SM and Nicol, A and Braun, A and Wang, W and Tribble, JR and Swoboda, P and Williams, PA}, title = {Supplementation via DAF-16 and pnk-1 driven pantothenate-coenzyme A flux improves disease related stress resistance in C. elegans.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42523442}, issn = {2692-8205}, support = {P40 OD010440/OD/NIH HHS/United States ; }, abstract = {Metabolic pathways are increasingly recognized as tractable targets in aging and disease. Building on prior work demonstrating that supplementation with low-molecular weight metabolites (amino acids, vitamins, and their intermediates) can extend lifespan in Caenorhabditis elegans, we focused on pantothenate (vitamin B5), which is dysregulated in sarcopenic muscle and in several neurodegenerative and metabolic disorders. Pantothenate is the obligate precursor of coenzyme A through a short, highly conserved biosynthetic pathway in which loss-of-function mutations can cause neurodegeneration with brain iron accumulation. In C. elegans, the longevity curtailing transcription factor DAF-16/FOXO has a conserved binding element in the promoter region of pnk-1, encoding the first enzyme (PNK-1) in the coenzyme A pathway, and pnk-1 is markedly upregulated in long-lived daf-2 (insulin/-like receptor) mutants, implicating coenzyme A metabolism in longevity. Here, we demonstrate that CoA levels naturally increase during early life and decrease towards older age in C. elegans. Dietary pantothenate supplementation increases coenzyme A levels with minimal effects on lifespan but systemic effects on lipid metabolism, mitochondrial dynamics, and muscle structure under basal conditions. Under DAF-16-associated stress conditions, including heat and oxidative stress, pnk-1 expression is upregulated and pantothenate supplementation robustly extends lifespan and improves mobility. Finally, we demonstrate dysregulation of daf-16 and pnk-1 expression in amyotrophic lateral sclerosis (ALS) models, in which pantothenate supplementation confers both lifespan extension and cholinergic neuroprotection.}, } @article {pmid42523591, year = {2026}, author = {Balanis, T and Doulberis, M and Tutuian, R}, title = {EUS-guided transmural treatment of afferent loop syndrome: a systematic review and meta-analysis.}, journal = {Frontiers in gastroenterology (Lausanne, Switzerland)}, volume = {5}, number = {}, pages = {1853386}, pmid = {42523591}, issn = {2813-1169}, abstract = {BACKGROUND: Afferent loop syndrome (ALS) is an uncommon but clinically relevant complication after pancreaticobiliary or upper gastrointestinal reconstruction, most often in patients with recurrent malignant disease. Endoscopic ultrasound-guided creation of a transmural bypass, either as gastroenterostomy or enteroenterostomy, has emerged as a minimally invasive alternative to surgery or percutaneous drainage. We aimed to systematically review the available evidence and provide a pooled descriptive analysis of the efficacy and safety of EUS-guided treatment for ALS.

METHODS: A systematic review was performed in accordance with PRISMA principles. PubMed/MEDLINE, Embase and the Cochrane Library were searched up to 15 May 2025 for studies reporting EUS-guided gastroenterostomy or enteroenterostomy for ALS. Case reports, case series and observational studies with extractable outcome data were eligible. Data on study design, indication, stent type, technical success, clinical success, adverse events and follow-up were extracted and synthesized.

RESULTS: Twelve studies involving 134 patients were included. On crude analysis, technical success was achieved in 132/134 patients (98.5%), clinical success in 127/134 (94.8%), and adverse events were reported in 13/134 (9.7%). In the pooled random-effects analysis, the technical success rate was 93.5% (95% CI 87.1-96.8; I²=0%), the clinical success rate was 91.0% (95% CI 84.5-94.9; I²=0%), and the overall adverse-event rate was 14.6% (95% CI 9.1-22.5; I²=0%). Adverse events were mainly procedure-related pain, fever, stent misdeployment, peritonitis or intra-abdominal infection. Electrocautery-enhanced lumen-apposing metal stents were used in most studies, whereas fully covered self-expandable metal stents were used in a smaller subset. Reported follow-up ranged from 1 to 15 months.

CONCLUSIONS: EUS-guided transmural bypass represents a promising, minimally invasive, and technically feasible alternative for the management of ALS. However, given the retrospective nature and small sample sizes of the available evidence, larger comparative trials are warranted to define its definitive role.}, } @article {pmid42524894, year = {2026}, author = {Guo, W and Cai, S and Li, Y and McGarry, BE and Caprio, TV and Temkin-Greener, H}, title = {User-Generated Google Maps Ratings, State Staffing and Training Regulations, and the Quality of Hospice Care in Assisted Living Communities.}, journal = {Journal of the American Geriatrics Society}, volume = {74}, number = {9}, pages = {2730-2737}, pmid = {42524894}, issn = {1532-5415}, support = {R01 HS026893/HS/AHRQ HHS/United States ; R01HS026893/HS/AHRQ HHS/United States ; Another Look 2020//Patrick and Catherine Weldon Donaghue Medical Research Foundation/ ; }, mesh = {Humans ; Cross-Sectional Studies ; *Assisted Living Facilities/standards ; United States ; *Hospice Care/standards/statistics & numerical data ; *Quality of Health Care ; *Personnel Staffing and Scheduling/legislation & jurisprudence ; *Geographic Mapping ; Medicare ; Workforce ; }, abstract = {BACKGROUND: Hospice services are growing among Medicare beneficiaries, yet concerns remain about the hospice quality for residents in assisted living (AL) communities. Little is known about how AL characteristics and state regulations are associated with hospice care in these settings.

OBJECTIVES: To examine (1) whether AL user-generated google maps ratings (AL google maps ratings) and (2) state-level regulations on AL staffing are associated with hospice ratings: METHODS: We conducted a cross-sectional analysis of 15,947 AL communities. We included data on AL-specific direct care worker (DCW) state staffing and staff training regulations. Logistic regression models were used to assess associations, adjusting for AL, hospice, and market-level characteristics.

RESULTS: A one-star increase in an AL google maps rating was associated with 6% higher odds of being served by hospices with higher HIS scores (OR = 1.06, p = 0.032), but not with CAHPS scores. AL communities in states with higher regulatory specificity for DCW staffing had higher odds of being served by hospices with higher CAHPS (OR = 1.46, p < 0.001) and HIS scores (OR = 1.35, p < 0.001). ALs in states mandating more than 21 h of DCW training, AL communities were more likely to be served by hospices with higher CAHPS scores (OR = 1.33, p < 0.001).

CONCLUSION: Higher AL google maps ratings were associated with higher hospice HIS performance. DCW staffing regulations were associated with both CAHPS and HIS, and DCW training regulations were associated with CAHPS only. These findings underscore the role of organizational quality and state regulatory policies in guiding end-of-life care in AL communities.}, } @article {pmid42525902, year = {2026}, author = {Roberts, AL and Vilela Braga, AD and Tang, IW and Rotem, RS and Moo, LR and Miller, DR and Shirk, SD and Weisskopf, MG}, title = {Association of Military Branch and Rank With Amyotrophic Lateral Sclerosis Incidence Among United States Veterans.}, journal = {Neurology}, volume = {107}, number = {4}, pages = {e218303}, doi = {10.1212/WNL.0000000000218303}, pmid = {42525902}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Male ; United States/epidemiology ; *Veterans/statistics & numerical data ; Female ; *Military Personnel/statistics & numerical data ; Incidence ; Middle Aged ; Longitudinal Studies ; Adult ; Risk Factors ; Aged ; Cohort Studies ; Proportional Hazards Models ; }, abstract = {BACKGROUND AND OBJECTIVES: Military service is one of the most consistent risk factors for the development of amyotrophic lateral sclerosis (ALS), but little is known about what aspects of military service matter. Understanding the distribution of ALS risk in military personnel may help identify key risk factors. We aimed to ascertain the association of United States (US) military branch and rank with incident ALS.

METHODS: We conducted a longitudinal cohort study including all veterans with a Veterans Health Administration encounter from January 1, 2000, through October 1, 2024, and more than 2 years of follow-up. Incident ALS was identified through medical records. Exposures included military branch (Army, Navy, Air Force, Marine Corps, Coast Guard, or multiple branches), military rank (officer, enlisted, or both), and length of service. Risk was estimated with Cox proportional hazards models, controlled for age, adjusted for race/ethnicity, and stratified by sex.

RESULTS: The analytic sample comprised 9,157,938 men (13,935 incident ALS cases, mean age = 56.9 years) and 784,941 women (484 cases, mean age = 42.4 at start of follow up). Among men, compared with service in the Army, service in the Air Force (hazard ratio [HR] = 1.29, 95% CI 1.23-1.35), Navy (HR = 1.15, 95% CI 1.10-1.20), and Coast Guard (HR = 1.26, 95% CI 1.06-1.50) was associated with higher rates of ALS and service in the Marines a lower rate (HR = 0.78, 95% CI 0.68-0.88). Officers had higher rates than enlisted personnel (men, HR = 1.64, 95% CI 1.53-1.74; women, HR = 1.72, 95% CI 1.31-2.27). Longer service was associated with lower rates of ALS. In age-stratified models, differences in hazard rates between Army veterans and Air Force, Navy, and Coast Guard veterans were greatest for the youngest men (17-61 years, HR range = 1.26 to 1.51) and smallest for the oldest (>75-104 years, HR range = 0.99 to 1.12).

DISCUSSION: ALS rates varied considerably by branch and rank in the US military, with larger differences among younger veterans. Officers and those serving in the Air Force, Navy, or Coast Guard may incur exposure to military environments that increase risk of ALS. It is imperative to identify relevant exposures to reduce harm to service members and, potentially, civilians with similar exposures.}, } @article {pmid42525906, year = {2026}, author = {Hardiman, O}, title = {Amyotrophic Lateral Sclerosis in the Military: A Uniform Risk?.}, journal = {Neurology}, volume = {107}, number = {4}, pages = {e218481}, doi = {10.1212/WNL.0000000000218481}, pmid = {42525906}, issn = {1526-632X}, } @article {pmid42526365, year = {2026}, author = {Ahsan, A and Ou, JC and Majumder, P and Chiang, YH and Huang, JK and Huang, CS}, title = {A systematic review and meta-analysis of OCT-based ophthalmic changes in amyotrophic lateral sclerosis.}, journal = {Journal of neuroimmunology}, volume = {420}, number = {}, pages = {579028}, doi = {10.1016/j.jneuroim.2026.579028}, pmid = {42526365}, issn = {1872-8421}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/complications ; *Tomography, Optical Coherence/methods ; *Retina/diagnostic imaging/pathology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor decline and respiratory failure. Optical coherence tomography (OCT), a non-invasive imaging technique, has been explored for detecting retinal structural changes that may reflect neurodegeneration in ALS. While some studies report thinning of retinal layers, findings remain inconsistent. Therefore, a meta-analysis is needed to clarify the extent of retinal involvement and the potential of OCT as a biomarker in ALS.

METHODS: A systematic literature search was conducted across PubMed, EMBASE, and Cochrane databases for studies published between 2010 and May 2025. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and publication bias was evaluated through funnel plot asymmetry and Egger's test. Pooled effect sizes were calculated using random-effects models to account for between-study heterogeneity, and differences in OCT parameters between ALS patients and healthy controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Statistical heterogeneity was quantified using the I[2] statistic.

RESULTS: A total of 17 studies were included in the present meta-analysis. The primary unadjusted global model demonstrated significant reduction of retinal nerve fibre layer (RNFL) thickness in ALS patients compared to controls (unadjusted SMD = -0.295, 95% CI: -0.522, -0.068). Upon applying a Design Effect variance inflation model to address fellow-eye non-independence, the pooled estimate remained robustly significant across a conservative range of intraclass correlations (SMD ranged from -0.256 to -0.249). Subgroup analyses revealed that RNFL thinning was particularly pronounced in spinal-onset ALS (SMD = -0.54, 95% CI: (-0.98, -0.10). When studies were stratified by the region of conduct, RNFL and macular thinning reached statistical significance only within the non-Asian subgroup, though the formal test for subgroup differences was not significant.

CONCLUSION: This meta-analysis demonstrates significant bilateral RNFL thinning in ALS, with relative preservation of the Inner Nuclear Layer and Ganglion Cell Layer - Inner Plexiform Layer, supporting retinal neurodegeneration as a feature of this multisystem disorder.

PROSPERO identifier CRD420251076035.}, } @article {pmid42526625, year = {2026}, author = {Guth, MAS}, title = {Targeting TDP-43 in ALS: Regulatory hurdles, trial design deficiencies, and the causal evidence gap for CTx1000.}, journal = {Drug discovery today}, volume = {31}, number = {5}, pages = {104752}, doi = {10.1016/j.drudis.2026.104752}, pmid = {42526625}, issn = {1878-5832}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *DNA-Binding Proteins/metabolism ; Animals ; Proteolysis Targeting Chimera ; }, abstract = {The therapeutic landscape for amyotrophic lateral sclerosis (ALS) has been characterized by decades of clinical trial failures, often attributed to biological heterogeneity, end-point insensitivity, and a profound evidence gap regarding target engagement. With TAR DNA-binding protein 43 (TDP-43) aggregation emerging as a hallmark feature in the vast majority of ALS cases, new precision-medicine modalities - most notably the proteolysis-targeting chimera (PROTAC) CTx1000 - aim to address the underlying causal pathology through selective degradation of mislocalized TDP-43. This review critically evaluates the regulatory hurdles and trial design deficiencies that have historically undermined ALS clinical development, and incorporates the dual sequestration hypothesis as a framework to interpret the convergence of TDP-43 pathology across neurodegenerative diseases. It concludes that it is imperative that the field adopts more rigorous biomarker-led methodologies, and that although target-specific degraders offer a sophisticated technological leap, their success depends on addressing fundamental knowledge gaps in target engagement, age-dependent vector tropism, and trial design architecture.}, } @article {pmid42528478, year = {2026}, author = {Palumbo, F and Iazzolino, B and Moglia, C and Manera, U and Matteoni, E and Cabras, S and Pellegrino, G and Minerva, E and Passidomo, V and Vasta, R and Mora, G and D'Ovidio, F and Canosa, A and Calvo, A and Chiò, A}, title = {Toward a Behavioral Reserve Model in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78315}, pmid = {42528478}, issn = {1531-8249}, abstract = {OBJECTIVE: Behavioral impairment is common in amyotrophic lateral sclerosis (ALS) and strongly affects autonomy, caregiver burden, and outcomes, yet predictors of vulnerability remain unclear. We investigated whether premorbid regulatory traits and socio-educational exposures are associated with behavioral phenotypes in ALS within a behavioral reserve framework.

METHODS: We analyzed 965 consecutively assessed patients with ALS from a prospective tertiary-center cohort. Behavioral impairment was measured using the Frontal Systems Behavior Scale (FrSBe; family-rated before and after onset) and, in a subset (n = 633), the Edinburgh Cognitive and Behavioural ALS Screen-Carer Interview (ECAS-CI). Theory-driven hierarchical logistic regression models tested associations between behavioral outcomes and premorbid behavioral regulation, education, occupation, and a Social Interaction Index, including interaction effects. Prespecified sensitivity analyses addressed potential bias in premorbid estimates.

RESULTS: Premorbid behavioral regulation showed the strongest associations with behavioral impairment across all FrSBe models. Higher combined educational attainment and social exposure were associated with lower odds of impairment, with a significant interaction across multiple behavioral domains. These patterns persisted in restricted sensitivity analyses. Reserve proxies were not significantly associated with ECAS-CI total impairment, although domain-specific effects were observed.

INTERPRETATION: These findings provide empirical support for a behavioral reserve framework in ALS, in which premorbid regulatory traits and socio-educational exposures are associated with behavioral vulnerability. Although causal inference is limited, reserve-related factors may contribute to non-motor heterogeneity in ALS and may inform future approaches to early behavioral risk stratification. ANN NEUROL 2026.}, } @article {pmid42528798, year = {2026}, author = {Gao, X and Chen, S and Mahabub, S and Cao, B and Deng, J and Ye, W and Yang, H and Zou, Z}, title = {A modified frailty index to identify high-risk groups for amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1879866}, pmid = {42528798}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive muscle weakness and poor prognosis, which requires early detection to optimize therapeutic outcomes. This study aims to develop a risk stratification tools for ALS and to assist in identifying high-risk groups.

METHODS: A prospective cohort study was conducted using the UK Biobank (500,033 participants), which were split into training sets and validation sets. We calculated the frailty index (FI) and modified frailty index (MFI) for the participants and estimated their association with ALS. Finally, two risk stratification tools were constructed and the time-dependent ROC curve was utilized to evaluate the discriminatory performance of each model.

RESULTS: Among the 49 deficits in FI, we identified five deficits that were significantly associated with ALS, including falls, whole-body pain, long-standing illness, disability or infirmity, self-rated health and tiredness or lethargy in last 2 weeks, which together constructed the MFI. Both the FI and MFI were associated with a higher risk of ALS (HRFI = 4.58, 95% CI = 1.31-16.07, HRMFI = 4.59, 95% CI = 2.79-7.53). Finally, a combination of MFI, gender, age and BMI demonstrated the best discriminative ability. Specifically, on the validation set, it achieved a C-index of 0.696.

CONCLUSION: By focusing on deficits associated with ALS, the MFI may improve the ability to identify individuals at elevated risk of the disease. It could therefore serve as a valuable screening tool for risk stratification in the general population.}, } @article {pmid42529618, year = {2026}, author = {Fiskum, V and Winter-Hjelm, N and Christiansen, N and Sandvig, A and Sandvig, I}, title = {Microscale dysfunction and mesoscale compensation in degenerating neuronal networks.}, journal = {Network neuroscience (Cambridge, Mass.)}, volume = {10}, number = {3}, pages = {594-612}, pmid = {42529618}, issn = {2472-1751}, abstract = {Progressive neurodegenerative diseases involve neuronal dysfunction across cellular, circuit, and whole-brain levels. Despite differences in anatomical origins, vulnerable neuronal subtypes, and specific misfolded proteins, these diseases share key features. In presymptomatic phases, neural networks engage compensatory processes to maintain function, including increased centralization and reliance on a rich-club of hub nodes. While such mechanisms have supporting evidence in some disorders, they remain less established in amyotrophic lateral sclerosis (ALS), limiting understanding of potential shared presymptomatic responses. To address this, we investigated structural and functional properties of ALS patient-derived motor neuron networks compared with healthy controls using longitudinal multielectrode array recordings and graph theory-based analysis. We observed microscale dysfunction marked by TAR DNA-binding protein 43 proteinopathy, hyperactivity, and reduced spike amplitude. Structurally, ALS networks exhibited neurite hypertrophy, suggesting attempts to form new connections. Mesoscale analyses revealed functional reconfigurations, including increased rich-club connectivity and network assortativity, indicating compensatory centralization. Our findings provide novel evidence that ALS network features can be recapitulated in in vitro models, and that these networks progressively become more centralized to preserve computational capacity, imposing growing demands on hub nodes and predisposing them to further damage. These results support models proposing common network reconfiguration mechanisms across neurodegenerative diseases.}, } @article {pmid42529685, year = {2026}, author = {Cheung, N}, title = {Cellular Logistics and Synaptic Vesicle Vulnerability in Major Depressive Disorder and Amyotrophic Lateral Sclerosis Comorbidity: Insights From Nicotinamide Mononucleotide Rescue and Transcriptome-Wide Association Study Integration.}, journal = {Cureus}, volume = {18}, number = {7}, pages = {e113549}, pmid = {42529685}, issn = {2168-8184}, abstract = {BACKGROUND: Major depressive disorder (MDD) and amyotrophic lateral sclerosis (ALS) are usually treated as unrelated, yet depressive symptoms occur in a substantial minority of people with ALS and may appear early. These symptoms are heterogeneous and may reflect syndromal MDD, psychological and functional burden, fatigue, apathy, pseudobulbar affect, frontotemporal involvement, sleep or respiratory disturbance, medication effects, or shared affective vulnerability. A proposed pruning-continuum model suggests both disorders may share vulnerability in microglia-mediated synaptic pruning, with ALS amplified by autophagy and protein-quality-control failure and MDD by RNA-processing, stress, and immune dysregulation. We performed an exploratory secondary transcriptome-wide association study (TWAS)/pathway-integration analysis to test whether predefined nicotinamide mononucleotide (NMN)-nominated pathways map onto this vulnerability.

METHODS: We integrated precomputed S-PrediXcan outputs for MDD and ALS across available brain-relevant tissues. Ten Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were predefined from a prior re-analysis of NMN-associated transcriptional programs in aged mouse metabolic tissues. Mouse-derived candidates were represented by human ortholog symbols before the human TWAS screen. The analysis tested nominated pathways rather than the 35-gene NMN-robust list as a standalone set. Cross-tissue screening used Stouffer Z aggregation, tissue-level Wilcoxon testing, competitive permutation testing, percentile bootstrap intervals, pairwise disease statistics, Levene variance tests, concordance measures, and leave-one-out sensitivity analysis. No analysis was treated as confirmatory or evidence of causal mediation.

RESULTS: MDD showed the strongest Stouffer-based exploratory signal in the synaptic vesicle cycle pathway, with a meta-across-tissue Stouffer Z of 3.41 and a wide bootstrap 95% confidence interval of -0.46 to 7.40. This signal did not survive competitive permutation testing (p = 0.1222) or Wilcoxon testing (p = 0.1926). The strongest tissue-level result occurred in the amygdala (Z = 4.057; nominal Wilcoxon p = 0.0093), although tissue-level permutation testing was not performed in the multi-gene-set run. ALS showed no significant meta-across-tissue enrichment among the 10 nominated pathways but displayed candidate gene-level signals in autophagy, endosomal, and vesicle-related genes, including TBK1 and C9orf72. Exploratory Levene tests indicated variance heterogeneity in the regulation of the actin cytoskeleton, endocytosis, and neuroactive ligand-receptor interaction; the actin cytoskeleton and endocytosis remained significant in pooled global false discovery rate (FDR) analysis. Fourteen genes were influential in at least two focus pathways, including EGF, KNG1, FGF8, RAC1, PAK1, PAK2, RAF1, MAPK1, and FGFR1.

CONCLUSIONS: These findings are hypothesis-generating. MDD and ALS may stress overlapping cellular logistics processes while engaging largely different genes. MDD showed the strongest exploratory pathway-level signal in synaptic vesicle biology, whereas ALS showed candidate gene-level coherence in autophagy and endosomal processes without significant meta-pathway enrichment. NMN/NAD+ repletion is not established as a treatment for MDD, ALS, or their comorbidity. These findings generate hypotheses about NAD+-linked cellular stress pathways for future preclinical and clinical studies.}, } @article {pmid42530312, year = {2026}, author = {Ndungo, E and Islam, D and Gonwong, S and Ruamsap, N and Milletich, PL and Agnememel, A and Demons, ST and Pasetti, MF}, title = {Protective immunity against Shigella sonnei in vaccinated and challenged adult Thai volunteers.}, journal = {mSphere}, volume = {11}, number = {8}, pages = {e0026926}, pmid = {42530312}, issn = {2379-5042}, support = {R01 AI125841/AI/NIAID NIH HHS/United States ; R01 AI167367/AI/NIAID NIH HHS/United States ; R01 AI125841, R01 AI167367//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; *Shigella sonnei/immunology ; *Shigella Vaccines/immunology/administration & dosage ; *Antibodies, Bacterial/blood/analysis ; Adult ; *Dysentery, Bacillary/prevention & control/immunology ; Immunoglobulin G/blood/analysis ; Immunoglobulin A/analysis/blood ; Thailand ; Female ; Male ; Young Adult ; Vaccines, Attenuated/immunology/administration & dosage ; Feces/chemistry/microbiology ; Human Challenge Trials as Topic ; Middle Aged ; Antigens, Bacterial/immunology ; Vaccination ; Adolescent ; }, abstract = {A safe, effective, and affordable vaccine that can prevent Shigella-induced diarrhea could have a significant impact on reducing morbidity and mortality in populations at risk. WRSS1, a live attenuated Shigella sonnei vaccine candidate, was well tolerated and immunogenic in adult Thai volunteers, achieving 40% efficacy against wild-type (WT) S. sonnei. We performed an in-depth analysis of mucosal and systemic antibodies in these individuals following WRSS1 vaccination and S. sonnei challenge, including a broader analysis of antibody specificity, functional features, and associations with clinical protection. IgG and IgA against Shigella proteins IpaB, IpaC, IpaD, IpaH, VirG, and LPS from multiple strains, as well as complement-mediated bactericidal and opsonophagocytic killing activity, were assessed in serum, fecal extracts, and antibodies in lymphocyte supernatants. Shigella-specific serum and ALS IgG and IgA increased after WRSS1 vaccination and S. sonnei challenge, particularly in naïve individuals, and most robustly post-challenge. Shedding the vaccine or infecting strain was associated with ALS responses. Fecal IgA was broadly reactive to most antigens, while fecal IgG was specific for S. sonnei LPS. Functional antibodies were detected prominently in fecal extracts; the highest responders were naïve individuals post-challenge. Notably, higher protein-specific serum IgA titers before challenge were associated with clinical protection against disease. Our results highlight the nuanced immunity to Shigella in endemic regions and the importance of understanding the elements that mediate protection in these settings to inform effective vaccine implementation.IMPORTANCEUnderstanding the immune response in Shigella-endemic regions is critical for the design and implementation of vaccines for the target population. We characterized the breadth of systemic and mucosal antibody responses to WRSS1 vaccination and WT S. sonnei challenge in Thai adult volunteers. Antigen-specific IgG and IgA in ALS were elevated only in individuals who shed the vaccine or challenge strain, indicating exposure. Serum IgA responses to Shigella proteins were associated with clinical protection. Our findings underscore the value of serosurveillance in guiding public health interventions and support the concept of protein-based vaccines to prevent disease in high-burden settings.}, } @article {pmid42530583, year = {2026}, author = {Graco, M and Russo, K and Grivell, N and Carey, K and Zaga, C and Saravanan, K and Sheers, NL and Berlowitz, DJ and , }, title = {A qualitative investigation of the factors influencing the uptake of noninvasive ventilation among Australians with motor neurone disease.}, journal = {Disability and rehabilitation}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/09638288.2026.2704454}, pmid = {42530583}, issn = {1464-5165}, abstract = {PURPOSE: Non-invasive ventilation (NIV) improves quality of life and extends survival for people with motor neurone disease (pwMND); however, uptake in Australia remains modest. This study explored the factors that influence the uptake of NIV from the perspectives of pwMND, caregivers, and healthcare professionals.

METHODS: Thirty-nine semi-structured interviews were conducted with pwMND (n = 8), family caregivers of pwMND (n = 4), and healthcare professionals (n = 27). A two-stage deductive-inductive analysis was performed to identify common themes that influence the uptake of NIV in MND.

RESULTS: Twenty-six key influencing factors were identified, relating to three major themes: influences on the pwMND's decision to trial NIV; healthcare professional knowledge, beliefs and behaviors; and inequity and lack of responsiveness in the healthcare system. Inductive analysis also identified a fourth theme, disparities in NIV uptake. Within this theme, women, older people, and First Nations Australians were acknowledged as demographic groups experiencing challenges to NIV uptake that warrant further investigation.

CONCLUSION: This research identified multiple modifiable factors influencing the uptake of NIV that can inform the design of targeted interventions to reduce inequitable access to NIV, increase uptake, and optimize quality of life for pwMND.}, } @article {pmid42531420, year = {2026}, author = {Burke, KM and Brown, R and Calcagno, N and Gupta, AS and Gajos, KZ and Scheier, Z and Clark, A and Iyer, A and Higgins, MP and Keegan, M and Royse, TB and Remington, E and Connaghan, KP and Johnson, SA and Chew, S and Erb, MK and Berry, JD}, title = {Digital Remote Assessment of Motor and Speech Changes in Amyotrophic Lateral Sclerosis: Longitudinal Observational Study.}, journal = {JMIR formative research}, volume = {10}, number = {}, pages = {e85142}, pmid = {42531420}, issn = {2561-326X}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; *Digital Health ; Disease Progression ; Longitudinal Studies ; *Remote Patient Monitoring/instrumentation/methods ; Reproducibility of Results ; *Speech/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an active trial landscape that relies on the sensitivity of selected clinical trial endpoints. Traditional clinical outcome assessments perform well in trials but lack strong psychometric properties and may not detect small but clinically meaningful disease progression. Digital health technologies offer a promising alternative for tracking ALS disease progression.

OBJECTIVE: This study assessed the feasibility of remote digital monitoring in ALS using a comprehensive battery of prescribed home-based assessments via a smartphone, a wearable device, and a computer-based mouse-clicking task.

METHODS: Participants completed weekly remote assessments, including motor and speech tasks via a smartphone app and a computer mouse-clicking task for 24 weeks. They also participated in 3 remote telephone visits in weeks 1, 13, and 25. Reliability, minimal detectable change, and correlations with self-reported ALS Functional Rating Scale-Revised subdomain scores were calculated for 8 features across the speech, fine motor, and gross motor smartphone app tasks and for all 32 features from the computer mouse-clicking task. Sensitivity to longitudinal change was assessed for the 8 smartphone-derived features and for a representative subset of 8 computer mouse-clicking features.

RESULTS: Forty-two participants (19 with ALS and 23 controls) completed 10,237 smartphone assessments and 459 computer mouse-clicking sessions. Baseline discriminative models differentiated ALS from controls with AUC values of 0.75-0.92. Digital measures correlated strongly with self-reported ALS Functional Rating Scale-Revised subdomain scores. Both participants with ALS and controls demonstrated improvement in fine motor and speech measures, with the exception of nondominant-hand pegboard performance, which declined in the ALS group. Improvements were smaller in participants with ALS, leading to increasing group differences over time, although only one feature showed a statistically significant separation over the 24 weeks. Gait and balance performance declined in both groups, with greater but nonsignificant separation observed for balance measures.

CONCLUSIONS: These findings support the feasibility of digital remote assessments in ALS, demonstrate the ability to discriminate between ALS and controls based on certain features collected from speech, fine, and gross motor tasks, and in some cases, quantify functional decline over time. Further research is necessary to explore the natural history of these features longitudinally in larger cohorts of participants with ALS over extended periods to enable their potential integration into clinical trials.}, } @article {pmid42532824, year = {2026}, author = {Lin, YT and Yang, HL}, title = {[Applying Developmental Care Theory to the Improvement of Self-Regulation and Feeding Difficulties in a Late Preterm Infant Receiving Cardiac Surgery: A Nursing Experience].}, journal = {Hu li za zhi The journal of nursing}, volume = {73}, number = {4}, pages = {}, doi = {10.6224/JN.26413}, pmid = {42532824}, issn = {0047-262X}, mesh = {Humans ; Female ; Infant, Newborn ; *Infant, Premature ; *Self-Control ; *Cardiac Surgical Procedures ; *Feeding Behavior ; }, abstract = {When preterm infants present with organ anomalies that require immediate surgical intervention after birth, their immature nervous systems often limit their ability to cope with the stress of surgery and subsequent treatments. This often results in difficulties with self-regulation and related health issues. The case described in this study involves a late preterm female infant born at 36+4 weeks of gestation who underwent cardiac surgery on the fifth day after birth. Postoperatively, she exhibited neonatal neurodevelopmental disorganization, ineffective suck-swallow reflexes, and inadequate nutritional intake. The first author provided nursing care between April 22 to May 10, 2025, with a telephone follow-up on May 14. The provided interventions were guided by Als' Synactive Theory of Development and integrated the Seven Neuroprotective Core Measures of the Neonatal Integrative Developmental Care Model, encompassing environmental regulation, sleep and positioning support, stress and pain management, and family-centered care. Objective evaluation was conducted using the Preterm Infant Oral Feeding Readiness Assessment Scale (POFRAS). The results demonstrated improvements in both self-regulation and feeding difficulties. Notably, the incidence of crying episodes decreased, the infant was able to sustain a calm state for longer periods, coordination of suck-swallow-breathing improved, and oral intake increased. Consequently, the amount of supplemental gavage feeding was reduced, caregivers were able to provide effective care, and the POFRAS score rose from 21 to 32. The comprehensive care approach described in this study integrates theoretical frameworks with behavioral cue-based observations to effectively improve feeding difficulties and self-regulation in preterm infants undergoing invasive surgery while simultaneously enhancing caregiver competence and confidence.}, } @article {pmid42533344, year = {2026}, author = {Bublitz, SK and Becker, B and Demleitner, AF and Dietz-Laukemann, P and Lingor, P and Littger, B and Lorenzl, S and Feddersen, B}, title = {Ethical challenges in treatment-goal transitions in invasively ventilated ALS: a case-based topical review.}, journal = {Neurological research and practice}, volume = {8}, number = {1}, pages = {}, pmid = {42533344}, issn = {2524-3489}, abstract = {INTRODUCTION: In advanced amyotrophic lateral sclerosis (ALS), eye movements often represent the last channel for intentional communication. While oculomotor function has traditionally been considered relatively preserved, emerging evidence indicates progressive impairment in long-term survivors on tracheostomy-invasive ventilation (TIV). As a result, eye-based communication may become increasingly unreliable before complete loss, challenging clinical decision-making and advance care planning (ACP).

METHODS: We conducted a case-based topical review integrating clinical observation and literature to examine the trajectory of oculomotor decline, its impact on communication, and implications for treatment decisions. Three patients with ALS receiving TIV in a home-care setting illustrate key clinical and ethical challenges.

RESULTS: Across cases and literature, oculomotor decline followed a gradual trajectory from effective eye-tracking communication to a complete locked-in syndrome. We identify a transitional phase of communicative ambiguity, in which residual ocular signals persist but can no longer be reliably attributed to intentional, patient-controlled communication. This phase is characterized by increasing inconsistency of signals and a divergence between observable responses and their interpretive certainty, creating uncertainty in assessing patient preferences.

IMPLICATIONS: Communicative ambiguity represents a clinically underrecognized but critical threshold in advanced ALS, marking the transition from direct patient autonomy to interpretative and surrogate-based decision-making. Failure to recognize this phase risks misinterpretation of patient intent and may undermine goal-concordant care. Timely and iterative ACP, initiated before communication becomes unreliable, is essential. We further propose four clinical pathways for treatment goal conversations, highlighting their differing implications for timing, symptom burden, and ethical decision-making.}, } @article {pmid42533617, year = {2026}, author = {Rasmussen, LK and Gomes Moreira, D and Okarmus, J and Simonsen, A and Meyer, M}, title = {Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-23}, doi = {10.1080/15548627.2026.2711596}, pmid = {42533617}, issn = {1554-8635}, abstract = {Mitochondrial quality control is essential for cellular homeostasis, particularly in neurons, where mitochondrial dysfunction is implicated in the pathogenesis of neurodegenerative diseases. Mitophagy, the selective degradation of damaged or superfluous mitochondria, plays a central role in maintaining mitochondrial integrity and metabolic balance. This review provides a comprehensive overview of the best-characterized PINK1-PRKN/parkin-dependent mitophagy pathway and the expanding repertoire of PRKN-independent mechanisms, including additional ubiquitin-dependent, receptor-mediated, and lipid-mediated pathways. We explore how these pathways intersect and compensate for one another, highlighting the complexity and adaptability of mitochondrial quality control networks. Furthermore, we discuss how dysregulated mitophagy contributes to the onset and progression of neurodegenerative diseases. By examining the interplay between mitophagy pathways and their regulation under physiological and pathological conditions, this review underscores the therapeutic potential of targeting mitophagy in neurodegeneration. Future studies should aim to decode the spatiotemporal dynamics of these pathways to uncover novel opportunities for clinical intervention.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMFR/GP78: autocrine motility factor receptor; AMPK: AMP-activated protein kinase; ARIH1: ariadne RBR E3 ubiquitin protein ligase 1; ATG: autophagy related; Aβ: amyloid beta; BCL2L13: BCL2 like 13; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CAMc: core autophagy machinery components; CSNK2/CK2: casein kinase 2; DUB: deubiquitinase; DNM1L/DRP1: dynamin 1 like; FKBP8: FKBP prolyl isomerase 8; FUNDC1: FUN14 domain containing 1; GABARAP: GABA type A receptor-associated protein; GLP-1: glucagon-like peptide 1; HD: Huntington disease; HUWE1: HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1; IMM: inner mitochondrial membrane; iPSC: induced pluripotent stem cell; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARCHF5: membrane associated ring-CH-type finger 5; MCL1: MCL1 apoptosis regulator, BCL2 family member; MDV: mitochondria-derived vesicle; MFN1: mitofusin 1; MFN2: mitofusin 2; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; MUL1: mitochondrial E3 ubiquitin protein ligase 1; NBR1: NBR1 autophagy cargo receptor; OMM: outer mitochondrial membrane; OMMAD: outer mitochondrial membrane-associated degradation; OPA1: OPA1 mitochondrial dynamin like GTPase; OPTN: optineurin; OXPHOS: oxidative phosphorylation; PARL: presenilin associated rhomboid like; PD: Parkinson disease; PE: phosphatidylethanolamine; PG: phagophore; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; PINK1: PTEN induced kinase 1; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PtdIns3K: phosphatidylinositol 3-kinase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RHOT1/Miro1: ras homolog family member T1; ROS: reactive oxygen species; SIAH1: siah E3 ubiquitin protein ligase 1; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TCA: tricarboxylic acid cycle; TFAM: transcription factor A, mitochondrial; TIMM: translocase of inner mitochondrial membrane; TOMM: translocase of outer mitochondrial membrane; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UPRmt: mitochondrial unfolded protein response; UPS: ubiquitin-proteasome system; USP30: ubiquitin specific peptidase 30; VCP: valosin containing protein; VDAC: voltage dependent anion channel; WIPI: WD repeat domain, phosphoinositide interacting.}, } @article {pmid42534468, year = {2026}, author = {Luster, CB and Abdolmohammadi, B and Mastrodicasa, MJ and Nowinski, CJ and Feigel, ED and Finegan, B and White, AJ and Connors, EJ and Rovito, CA and Zafonte, RD and Alosco, ML and McKee, AC and Mez, J and Daneshvar, DH}, title = {Neurodegenerative mortality among National Football League Players.}, journal = {EClinicalMedicine}, volume = {97}, number = {}, pages = {104051}, pmid = {42534468}, issn = {2589-5370}, support = {P30 AG013846/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; U01 NS086659/NS/NINDS NIH HHS/United States ; U54 NS115266/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Empirical research demonstrates elevated neurodegenerative mortality among individuals with repetitive head impact (RHI) exposure, including National Football League (NFL) players. This investigation addressed prior methodological limitations, including selection bias, subjective diagnoses, and retrospective reporting, by analyzing the relationship between RHI exposure and neurodegenerative mortality in a fully enumerated, 5.8-fold larger cohort of NFL players.

METHODS: A population-based retrospective cohort study was conducted comprising all current and former NFL athletes who debuted between 1960 and 2019 and played at least one regular or postseason NFL game, with National Death Index records (1979-2023) matched to Sports Reference, LLC data. Standardized mortality ratios (SMRs) were calculated from National Institute for Occupational Safety and Health data compared to an age-, sex-, race-, and calendar-year-standardized general population. Sensitivity analysis assessed whether the observed excess neurodegenerative mortality could be attributed to competing risks using a cause-specific hazard simulation.

FINDINGS: A total of 19,824 athletes had a cumulative 518,833 person-years (mean = 26.2 years, SD = 16.2), with 1994 decedents. NFL players exhibited lower all-cause mortality (SMR = 0.70; 95% CI: 0.67-0.74) but higher neurodegenerative mortality (SMR = 3.94; 95% CI: 3.38-4.56), including amyotrophic lateral sclerosis (SMR = 4.55; 95% CI = 3.13-6.38), all-cause dementia (SMR = 3.80; 95% CI = 3.11-4.60), and Parkinson's disease (SMR = 3.88; 95% CI: 2.76-5.30). Cause-specific hazard simulation indicated that competing risks alone would inflate the expected NDD SMR by a factor of 1.30, yielding a residual neurodegenerative SMR of 3.04 (95% CI: 2.63-3.50).

INTERPRETATION: Neurodegenerative mortality was nearly four times higher in NFL players compared to the general population and remained threefold higher after accounting for competing risks. Together, these findings strengthen the evidence for RHI exposure-related neurodegenerative mortality in NFL players that cannot be explained by differential survivorship.

FUNDING: The National Institute of Neurological Disorders and Stroke [U54NS115266; U01NS086659], the National Institute on Aging [P30AG13846; P30AG072978], and the Maloney/Carpenter Trauma-Related Neurodegenerative Disease Research Fund.}, } @article {pmid42536230, year = {2026}, author = {Naktinytė, E and Vilimienė, R and Valančius, D and Baronas, K and Zagorskienė, I and Utkus, A and Klimašauskienė, A and Burnytė, B}, title = {Genetic variants among patients with motor neuron disease in Lithuania - a retrospective single-center study.}, journal = {Neurogenetics}, volume = {27}, number = {1}, pages = {}, pmid = {42536230}, issn = {1364-6753}, mesh = {Humans ; *Motor Neuron Disease/genetics/epidemiology ; Female ; Retrospective Studies ; Lithuania/epidemiology ; Male ; Middle Aged ; *Genetic Variation ; C9orf72 Protein/genetics ; Aged ; Adult ; Phenotype ; Amyotrophic Lateral Sclerosis/genetics ; DNA Repeat Expansion ; }, abstract = {Motor neuron disease (MND) comprises several clinical phenotypes, with amyotrophic lateral sclerosis (ALS) being the most common. Despite the identification of over 40 ALS-associated genes, the pathogenesis remains complex and polygenic. This study evaluated the clinical phenotypes and prevalence of genetic causes in MND patients in Lithuania. We conducted a retrospective single-center study at a tertiary care clinic on patients with MND. Clinical and molecular genetic data were analyzed. The study included 53 patients with a mean age at symptom onset of 55 years. Most patients (43/53; 77.4%) were diagnosed with ALS, and the most common onset was spinal (39/53; 73.6%). The frequency of pathogenic or likely pathogenic genetic variants was 15.7% (8/51). C9orf72 hexanucleotide repeat expansion was detected in 5.9% (3/51) of patients. Next-generation sequencing was performed in 49 patients, of whom 5 (10.2%) had pathogenic or likely pathogenic variants, including pathogenic variants in the SOD1 and NEK1 genes and likely pathogenic variants in the FUS. The most common finding was C9orf72 hexanucleotide repeat expansion, followed by variants in SOD1 and FUS genes. The genetic spectrum was broadly similar to internationally recognized MND-associated genes, though formal comparisons were not performed due to the absence of a control group. These results emphasize the importance of systematic genetic testing in clinical practice and contribute to the limited data on the genetic spectrum of MND in the Baltic region.}, } @article {pmid42537332, year = {2026}, author = {Silva Santos, M and Castro, J and de Carvalho, M}, title = {F-wave responses and recruitment at low intensities: Muscle-specific excitability profiles of intrinsic hand muscles.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {56}, number = {5}, pages = {103185}, doi = {10.1016/j.neucli.2026.103185}, pmid = {42537332}, issn = {1769-7131}, abstract = {OBJECTIVES: F-waves are late motor responses traditionally elicited via supramaximal stimulation. However, submaximal stimulation may offer a more sensitive probe for assessing spinal motoneuron excitability. This study characterizes F-wave recruitment curves using graded submaximal stimulation across various intrinsic hand muscles.

METHODS: F-waves were recorded from the abductor pollicis brevis (APB), abductor digiti minimi (ADM), and first dorsal interosseous (FDI) in 15 healthy subjects (ages 35-78). Four stimulus intensities were employed-10%, 20%, 30%, and 100% of the maximal compound muscle action potential (CMAP) amplitude-with 20 stimuli delivered per intensity. Analysis focused on F-wave frequency, amplitude, and matched F-wave/CMAP ratios (F-wave/CMAPm), where the F-wave and CMAP were recorded at identical stimulus intensities.

RESULTS: Most parameters correlated positively with stimulus intensity; however, F-wave/CMAPm consistently decreased as intensity increased. The ADM exhibited a distinct recruitment profile, with F-wave persistence rising steeply at low intensities and reaching near-saturation at 30%, while showing no significant amplitude differences between submaximal levels. In contrast, the APB and FDI displayed more linear recruitment patterns for both persistence and amplitude.

DISCUSSION: Submaximal stimulation reliably elicits F-waves and reveals muscle-specific excitability profiles. The ADM's high excitability suggests a more readily recruitable motoneuron pool. Furthermore, the inverse relationship between F-wave/CMAPm and stimulus intensity suggests the early recruitment of larger, highly excitable Type II motoneurons. This refined recruitment curve approach may provide valuable insights into the "split-hand" phenomenon observed in amyotrophic lateral sclerosis.}, } @article {pmid42538750, year = {2026}, author = {Krutovs, V and Grosmane, A and Kažmere, RR and Roddate, M and Ķauķe, G and Grosa, DP and Šetlere, S and Dīriks, M and Karelis, G and Ķēniņa, V}, title = {Nationwide Epidemiology of Motor Neuron Diseases in Latvia (2020-2024): Incidence, Prevalence, and Clinical Characteristics.}, journal = {European journal of neurology}, volume = {33}, number = {8}, pages = {e70710}, pmid = {42538750}, issn = {1468-1331}, mesh = {Humans ; Latvia/epidemiology ; Prevalence ; Female ; Incidence ; *Motor Neuron Disease/epidemiology/physiopathology ; Male ; Retrospective Studies ; Adult ; Middle Aged ; Aged ; Muscular Atrophy, Spinal/epidemiology ; Adolescent ; Young Adult ; Child ; Amyotrophic Lateral Sclerosis/epidemiology/physiopathology ; Aged, 80 and over ; }, abstract = {BACKGROUND: Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA), are rare, progressive neurodegenerative conditions. Although well-studied in Western Europe, no nationwide epidemiological data have been published from Latvia. This study aimed to assess the incidence, prevalence, and clinical characteristics of MNDs in the Latvian population.

METHODS: A retrospective, hospital-based analysis was performed using records from Pauls Stradiņš Clinical University Hospital, Riga East University Hospital, and the Children's Clinical University Hospital between January 2020 and December 2024. Patients were identified through relevant ICD-10 codes. Incidence and prevalence rates were calculated per 100,000 population and age-standardized to the 2013 European Standard Population.

RESULTS: A total of 181 prevalent MND cases were identified: 131 with ALS or related phenotypes, 10 with adult-onset SMA, 33 with pediatric SMA, and 7 with SBMA. The age-standardized incidence of ALS was 1.22 per 100,000 person-years, and the prevalence was 4.69 per 100,000. Limb weakness or paresis was the most common initial symptom (48.1%). The mean diagnostic delay was 13.4 months for ALS, 43.8 months for PLS, 206.8 months for SBMA and 17.3 months for pediatric SMA. The prevalence of pediatric SMA was 9.91 per 100,000, with type II being the most frequent subtype. All SMA and SBMA cases were genetically confirmed.

CONCLUSION: This first nationwide study of MNDs in Latvia highlights diagnostic delays and possible under-recognition of adult SMA and SBMA. Genetic testing, a national registry, and equitable therapy access should be prioritized.}, } @article {pmid42538773, year = {2026}, author = {Calvo, A and Moglia, C and Canosa, A and Manera, U and Vasta, R and Matteoni, E and Maccabeo, A and Cabras, S and Pellegrino, G and Minerva, E and Giudici, AD and Passidomo, V and Palumbo, F and Iazzolino, B and Mora, G and Chiò, A}, title = {Early Cognitive and Behavioral Changes in Primary Lateral Sclerosis: A Population-Based Study.}, journal = {European journal of neurology}, volume = {33}, number = {8}, pages = {e70720}, pmid = {42538773}, issn = {1468-1331}, support = {RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; 20228N7573//Ministero dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101137074//HORIZON EUROPE Framework Programme/ ; DIG-ALS//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {Humans ; Female ; Male ; *Motor Neuron Disease/complications/psychology/physiopathology ; Middle Aged ; Aged ; Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; *Cognitive Dysfunction/etiology/physiopathology ; Executive Function/physiology ; Neuropsychological Tests ; }, abstract = {OBJECTIVE: Primary lateral sclerosis (PLS) is a rare upper motor neuron neurodegenerative disorder whose cognitive profile, particularly at early stages, remains incompletely defined. We aimed to characterize cognitive and behavioral features of PLS at diagnosis and compare them with predominant upper motor neuron amyotrophic lateral sclerosis (PUMN-ALS) and healthy controls (HCs).

METHODS: Patients diagnosed with PLS between 2007 and 2021 were identified from the population-based Piemonte and Valle d'Aosta ALS Register. Diagnoses were established according to consensus criteria, including early, probable, and definite PLS. All patients underwent comprehensive neuropsychological and behavioral assessment within 3 months of their first ALS center visit. Cognitive-behavioral status was classified using ALS-frontotemporal dementia (FTD) consensus criteria.

RESULTS: Thirty-two PLS patients were included (mean disease duration, 25 months). Cognitive and/or behavioral impairment was identified in 29.3% of patients, most commonly affecting executive function, memory, and social cognition, including 21.1% early PLS. Compared with HCs, PLS patients showed poorer performance across several cognitive domains and higher anxiety and depression scores. Compared with matched PUMN-ALS patients, PLS patients demonstrated slightly worse executive performance, while the overall frequency of cognitive-behavioral impairment was similar. Behavioral profiles differed qualitatively, with apathy more frequent in PUMN-ALS. No PLS patient met criteria for frontotemporal dementia.

INTERPRETATION: Cognitive and behavioral impairments are already detectable at the time of diagnosis in a substantial proportion of patients with PLS, including early PLS, supporting the view of PLS as a multidimensional neurodegenerative disorder with early extramotor involvement.}, } @article {pmid42539086, year = {2026}, author = {Lee, BH and Chan, J and Leung, YY and McMillan, CT and , and Song, Y and Amado, DA and Wang, K}, title = {Dissecting the relationship between haplotypes around ATXN2 CAG repeats and the number of CAA interruptions by long-read sequencing.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42539086}, support = {P01 AG066597/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 HG013359/HG/NHGRI NIH HHS/United States ; RF1 NS145263/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: CAG repeat expansions in ATXN2 are implicated as risk factors for several neurological diseases, including spinocerebellar ataxia type 2 (SCA2) when >=33 CAG repeats are present, and amyotrophic lateral sclerosis (ALS) when 27-33 CAG repeats are present. However, how haplotypes around the repeats and CAA interruptions within the repeats are associated with disease phenotypes remains poorly understood. Previous studies on haplotypes around ATXN2 were limited to SNPs very close to the repeats (<5kb) or were based on statistical inference only.

METHODS: Here, we used long-read sequencing on the Oxford Nanopore Technologies (ONT) platform to simultaneously infer haplotypes around ATXN2, the number of CAG repeats, and the number of CAA interruptions, along with NYGC ALS Consortium NGS dataset. We further sequenced 41 individuals (EUR = 39) with neurological diseases with intermediate repeats by ONT.

RESULTS: We found that haplotypes around ATXN2 and the number of interruptions show ethnicity-specific and ALS-specific distribution. Three CAA interruptions are present at low prevalence (~1%) in control populations in multiple ancestry groups, but high prevalence (~55%) in ALS individuals with intermediate repeats. Furthermore, we examined 159 individuals with ALS (~90% European ancestry) with intermediate ATXN2 repeats and found a unique haplotype in ALS individuals with three CAA interruptions, which can be tagged by an SNV, rs148019457. We also validated that the rs148019457-G allele is only present in haplotypes with three CAA interruptions.

CONCLUSIONS: In summary, our study shows that 3 CAA interruptions are rarely seen in healthy controls but are common in those with expanded ATXN2 CAG repeats who have neurological disorders, and that rs148019457 tags a specific haplotype with 3 CAA interruptions within expanded ATXN2 CAG repeats in individuals of European ancestry. These results have implications for the development of precision genomic medicine for neurological disorders, and the tag SNP may help identify those with interruptions from existing population genotyping data.}, } @article {pmid42539252, year = {2026}, author = {Wieland, CM and Wright, SE and Willey, S and Purwar, I and Grudzien, SJ and Krans, A and Laimon, E and Asher, MJ and Isaacs, A and Garner, AL and Todd, PK}, title = {Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42539252}, issn = {2692-8205}, support = {R01 NS086810/NS/NINDS NIH HHS/United States ; P50 HD104463/HD/NICHD NIH HHS/United States ; F31 NS113513/NS/NINDS NIH HHS/United States ; R35 GM153185/GM/NIGMS NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; T32 GM141840/GM/NIGMS NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; }, abstract = {Intronic GGGGCC repeat expansions in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This expansion supports a non-canonical form of translational initiation known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat proteins that contribute to neurodegeneration. Here, we find that the efficiency of RAN translation and its dependency on the 5' 7-methylguanosine mRNA cap are variable across cell types, with both rodent neurons and human iNeurons favoring cap-independent RAN translation from two distinct repeats (CGG and GGGGCC) across multiple reading frames. Treatment with an eIF4E inhibitor that blocks global cap-dependent translation enhances RAN translation specifically in neurons. Intriguingly, cap-independent RAN translation exhibits less reliance on near-cognate codons for initiation than cap-dependent RAN translation. This finding led us to identify a surprising global increase in start codon stringency in neurons as a contributor to the relatively higher cap-independent RAN translation in this cell type. This effect correlates with a cytoplasmic redistribution of eIF1 in neurons and is reversed with neuronal overexpression of the eukaryotic initiation factor eIF5, which relaxes start codon stringency and selectively enhances cap-dependent RAN translation. Taken together, these findings reveal several neuron-specific features of translational regulation that favor cap-independent RAN translation with implications for nucleotide repeat expansion disorder pathogenesis and neuronal translational regulation.}, } @article {pmid42539319, year = {2026}, author = {Zhou, Y and Luster, CB and Pinto, SM and Feigel, ED and Paganoni, S and Izzy, S and Zafonte, RD and Giacino, JT and Hammond, FM and Daneshvar, DH}, title = {Traumatic Brain Injury and Risk of Amyotrophic Lateral Sclerosis Mortality: A Traumatic Brain Injury Model Systems Study.}, journal = {Neurotrauma reports}, volume = {7}, number = {}, pages = {2689288X261450846}, pmid = {42539319}, issn = {2689-288X}, support = {90DPTB0022/ACL/ACL HHS/United States ; 90DPTB0023/ACL/ACL HHS/United States ; 90DPTB0027/ACL/ACL HHS/United States ; }, abstract = {Emerging evidence suggests that amyotrophic lateral sclerosis (ALS) mortality is elevated following traumatic brain injury (TBI), reflecting a consequence of potential prodromal ALS, though the temporal patterns and underlying mechanisms remain unclear. We aimed to evaluate ALS mortality among individuals with TBI and examine temporal patterns. This study leveraged a retrospective cohort study of 20,250 individuals with complicated mild-to-severe TBI enrolled in the TBI Model Systems (TBIMS) from 1987 to 2024, with a cumulative 198,662 person-years (mean [standard deviation] = 9.8 [7.1] years) of follow-up. Standardized mortality ratios (SMRs) were calculated using the National Institute for Occupational Safety and Health Life Table Analysis System R package, adjusting for age, sex, race, and calendar year. Secondary analyses evaluated temporal patterns and injury severity differences in ALS mortality. Among 4,313 decedents in TBIMS, 11 died of ALS, representing significantly elevated mortality from ALS (SMR = 2.39; 95% confidence interval [CI]: 1.19-4.27) compared with the general population. Time-stratified analyses showed elevated ALS mortality within 2 years post-injury (SMR = 4.30; 95% CI: 1.17-11.01), but not after 2 years (SMR = 1.90; 95% CI: 0.76-3.92). Elevated ALS mortality was also observed within 2 years post-injury among those with severe TBI (SMR = 5.00; 95% CI: 1.03-14.61) and when including individuals with ALS at admission (SMR = 6.45; 95% CI: 2.37-14.04). ALS mortality was higher in the TBIMS cohort than in the general population, and this association was confined to within 2 years of injury. This pattern suggests potential reverse causality, whereby some TBIs in the cohort may have occurred in the setting of prodromal or pre-symptomatic ALS. Further investigation into TBI as a sign of subclinical ALS is warranted.}, } @article {pmid42540536, year = {2026}, author = {Wang, S and Lin, Y and Che, Y and Zhao, J and Xu, L and He, W and Zhang, W}, title = {Genetically inferred effects of brain structure and gene expression on neurodegenerative diseases: a Mendelian randomization study.}, journal = {Archives of medical science : AMS}, volume = {22}, number = {3}, pages = {1663-1677}, pmid = {42540536}, issn = {1734-1922}, abstract = {INTRODUCTION: Against the backdrop of accelerating population aging, the risk of neurodegenerative diseases (NDDs) has risen significantly. While brain structure plays a critical role in NDDs, the interplay between them remains unclear. This study employed Mendelian randomization (MR) to investigate potential causal relationships between brain structure, region-specific gene expression, and four NDDs - Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) - providing new directions and genetically informed hypotheses for disease research.

MATERIAL AND METHODS: MR analyses were conducted using inverse-variance weighted (IVW), MR-Egger, weighted median, weighted mode, and Wald ratio methods. Summary-data-based MR (SMR) was applied to identify brain genes influencing NDDs. We calculated F-statistics, 95% confidence intervals (CIs), odds ratios, and p-values. Sensitivity analyses included the heterogeneity I[2] statistic, Cochran's Q test, Egger intercept test, MR-PRESSO, and leave-one-out validation.

RESULTS: Data from 512 unsupervised deep-learning imaging phenotypes (UDIPs) were analyzed. Thirty-four UDIPs showed associations consistent with a potential causal role in AD, 56 in PD, 22 in ALS, and 92 in MS. After false discovery rate (FDR) correction, 4 remained significant for AD and PD, 3 for ALS, and 28 for MS (p < 0.05). Brain regions (excluding the cervical spinal cord C-1) exhibited shared causal genetic features across all four NDDs, primarily involving HLA-class genes.

CONCLUSIONS: This study provides genetic evidence suggestive of potential causal associations between UDIPs, brain gene expression, and NDDs. These findings offer genetically predicted evidence that may generate hypotheses and inform future mechanistic research into NDD pathogenesis.}, } @article {pmid42541368, year = {2026}, author = {Hirano, Y}, title = {Long-term trajectories of physical, psychological, and psychosocial experiences among people living with amyotrophic lateral sclerosis using tracheostomy invasive ventilation: An 18-year longitudinal study.}, journal = {Journal of health psychology}, volume = {}, number = {}, pages = {13591053261474390}, doi = {10.1177/13591053261474390}, pmid = {42541368}, issn = {1461-7277}, abstract = {Advances in respiratory care have enabled people living with amyotrophic lateral sclerosis (PALS) using tracheostomy invasive ventilation (TIV) to live for many years with the disease. However, longitudinal evidence describing their psychosocial trajectories remains limited. This study explored the long-term trajectories of three PALS using TIV through repeated face-to-face assessments over an approximately 18 year period. Psychological state, subjective physical symptoms, and hope followed similar patterns across participants, worsening after illness onset and reaching their lowest levels between diagnosis and TIV initiation before improving and becoming increasingly individual over time. Perceived psychological support and sources of joy peaked after TIV initiation before fluctuating, whereas perceived financial status remained relatively stable. These findings demonstrate a shared pattern of early adaptation followed by increasingly individual long-term trajectories, providing a foundation for trajectory-informed holistic care.}, } @article {pmid42541567, year = {2026}, author = {Estevez-Fraga, C and Alvarez-Velasco, R and Afroz, T and Costa, MR and Jovičić, A and Yeh, FL and McColgan, P and Malaspina, A and McCampbell, A}, title = {Targeting TDP-43 in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {8}, pages = {}, pmid = {42541567}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder characterized by motor neuron degeneration leading to early mortality. Despite advances in understanding genetic and molecular contributors, effective disease-modifying therapies for sporadic ALS are of limited utility. The identification of the accumulation of TAR DNA-binding protein 43 (TDP-43) in 97% of total ALS cases represents a critical pathogenic hallmark. This review examines key biological mechanisms underlying TDP-43 pathology, emerging therapeutic strategies, and evolving approaches to clinical trial design and biomarker development. TDP-43 loss of nuclear function, leading to widespread RNA missplicing, and inclusion of cryptic exons, represents an early and critical event in ALS pathogenesis causing downstream dysregulation of key neuronal genes such as STMN2 and UNC13A contributing to axonal degeneration and synaptic dysfunction. Therapeutic strategies targeting these pathways are currently under investigation. Additional approaches aim to ameliorate TDP-43 gain-of-function through cytoplasmic TDP-43 aggregation or modulating processes such as stress responses and RNA metabolism, although clinical translation has been challenging. Advances in biomarkers, including neurofilament light chain and cryptic exon-derived peptides, provide tools for developing efficient clinical trials. However, heterogeneity in disease progression and limitations of available clinical endpoints complicate trial design. Integration of biological insights with biomarker-driven patient stratification and optimized trial methodologies is essential to improve clinical trial outcomes. Emerging biomarkers may enable earlier diagnosis, monitoring of therapeutic response, and personalized treatment approaches. Continued alignment of biological discovery with innovative clinical trial design holds promise for advancing effective therapies and transforming the future of ALS.}, } @article {pmid42541645, year = {2026}, author = {Chu, M and Tan, M and Gan, X and Cui, S and Shi, L}, title = {Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42541645}, issn = {1559-1182}, mesh = {*Microglia/metabolism/pathology/drug effects ; Humans ; *Neurodegenerative Diseases/metabolism/pathology/therapy/drug therapy ; *Mitochondria/metabolism/pathology/drug effects ; Animals ; }, abstract = {Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose an urgent global health challenge. Growing evidence establishes microglia-driven neuroinflammation as a key driver of disease onset and progression, with mitochondrial dysfunction emerging as an early trigger of microglial activation. This review comprehensively summarizes current progress on how mitochondrial alterations regulate microglial activation across AD, PD, and ALS. We identify conserved mechanisms including metabolic reprogramming, impaired mitophagy, and inflammatory signaling, though Aβ, α-synuclein, and TDP-43 engage these pathways through disease-specific molecular routes. Therapeutic strategies targeting microglial mitochondria, including cGAS-STING and NLRP3 inhibitors, TREM2 agonists, and mitochondrial transplantation, remain largely preclinical. Emerging targets such as OLFML3 and GPNMB require functional validation in microglia. Collectively, this review underscores that preserving microglial mitochondrial health represents a promising therapeutic frontier and identifies key priorities for translating these strategies toward clinical application.}, } @article {pmid42542073, year = {2026}, author = {Oriquat, G and Rizaev, J and Abdulqader, AF and Kadhim, AA and Jamuna, KV and Singhal, D and Bainsal, N and Mansurova, N}, title = {Gut microbiota and brain health: Disease-specific pathways and emerging therapeutic strategies.}, journal = {Multiple sclerosis and related disorders}, volume = {113}, number = {}, pages = {107407}, doi = {10.1016/j.msard.2026.107407}, pmid = {42542073}, issn = {2211-0356}, mesh = {Humans ; Animals ; *Gastrointestinal Microbiome/physiology ; *Brain ; *Brain-Gut Axis/physiology ; Fecal Microbiota Transplantation ; }, abstract = {The microbiota-gut-brain axis (MGBA) has emerged as a dynamic, bidirectional communication system linking the gastrointestinal tract and the central nervous system (CNS) through neural, immune, endocrine, and metabolic mechanisms. Increasing evidence indicates that alterations in gut microbial communities are associated with a wide range of neurological disorders; however, the strength of this association varies across diseases, and many mechanistic observations still rely predominantly on experimental models rather than human studies. This review provides an overview of current evidence regarding the role of the gut microbiota in maintaining CNS homeostasis, with particular emphasis on intestinal barrier function, immune modulation, vagal and enteric communication, and the generation of biologically active microbial metabolites, including short-chain fatty acids, bile acids, and neurotransmitter-related compounds. Studies in both clinical and experimental settings have reported disease-specific microbial signatures in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorders, and amyotrophic lateral sclerosis. In parallel, microbiota-directed interventions-including probiotics, prebiotics, dietary approaches, fecal microbiota transplantation, and strategies targeting microbial metabolites-have produced encouraging findings in preclinical studies and early-stage clinical investigations. Nevertheless, considerable heterogeneity in study populations, experimental methodologies, and therapeutic protocols continues to limit the translation of these findings into routine clinical practice. Collectively, current evidence supports the MGBA as a valuable framework for understanding neurological diseases while underscoring the need for rigorously designed longitudinal studies and well-controlled clinical trials to define its therapeutic relevance better.}, } @article {pmid42543118, year = {2026}, author = {Du, L and Yan, J}, title = {Lineage-calibrated peripheral monocyte-derived myeloid states in neurodegenerative disease: Recruitment, lesion decoding, and state persistence.}, journal = {Neurobiology of disease}, volume = {228}, number = {}, pages = {107556}, doi = {10.1016/j.nbd.2026.107556}, pmid = {42543118}, issn = {1095-953X}, mesh = {*Monocytes/pathology/metabolism ; Humans ; *Neurodegenerative Diseases/pathology/metabolism ; Animals ; *Cell Lineage/physiology ; *Macrophages/pathology/metabolism ; *Myeloid Cells/pathology ; Microglia/pathology/metabolism ; }, abstract = {Peripheral monocytes and monocyte-derived macrophages are increasingly implicated in neurodegenerative disease, yet interpretation remains limited by phenotypic convergence with resident microglia, inconsistent lineage attribution, and strong dependence on experimental model and disease stage. We present a structured, lineage-calibrated framework that separates three linked processes: a recruitment gate controlling access to CNS borders and lesions; a lesion-decoding hub through which aggregate, lipid, cytokine, complement, antigenic, hypoxic, and danger-associated inputs are interpreted; and a state-persistence layer in which metabolic and epigenetic reinforcement stabilizes inflammatory, repair-supportive, or hybrid repair-restrictive programs. To make the framework operational, we first provide a cross-disease synthesis and then map representative models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis to their specific recruitment routes, lesion cues, lineage confidence, and functional outcomes. We also distinguish what single-cell or spatial data can infer from what only origin-resolving approaches can establish, and propose practical terminology for studies that cannot perform fate mapping or parabiosis. A worked therapeutic example illustrates why the same recruitment pathway may be harmful during lesion expansion but useful during debris clearance and recovery. The central question is therefore not whether monocytes are present, but which model, compartment, time point, evidentiary tier, and stabilized state justify a disease-modifying claim. This framework links mechanistic evidence to biomarkers, patient stratification, and stage-aware intervention while reducing over-attribution of peripheral origin.}, } @article {pmid42543164, year = {2026}, author = {Wang, CY and Taylor, S and Pandya, VA and Clarke, BE and Pal, K and Shelkovnikova, TA and Wang, Y and Luisier, R and Patani, R}, title = {Intron retention in health and amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {8}, pages = {2604-2618}, pmid = {42543164}, issn = {1460-2156}, support = {FC010110/WT_/Wellcome Trust/United Kingdom ; FC010110/CRUK_/Cancer Research UK/United Kingdom ; //Francis Crick Institute/ ; BB-2024-c4-l4//Target ALS/ ; FC010110//UK Medical Research Council/ ; Patani/Dec22/957-793//Motor Neuron Disease Association/ ; /WT_/Wellcome Trust/United Kingdom ; Patani/Dec22/957-793/MNDA_/Motor Neurone Disease Association/United Kingdom ; MN5DF/2022/003//My Name'5 Doddie Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Introns/genetics ; Animals ; RNA Splicing/genetics ; }, abstract = {Intron retention (IR) is the molecular phenomenon by which introns, historically thought to represent non-coding 'junk', remain unspliced within pre-mRNA transcripts, resulting in their incorporation into the mature mRNA molecule. While the role of IR is well established in species of plant, fungi, insects and viruses, it remains relatively understudied in mammalian biology. It was previously assumed that IR only played a limited role in downregulating a transcript's translation potential through downstream initiation of nuclear detention or nonsense mediated decay (NMD). However, recent studies highlight IR's significantly more complex and dynamic contribution to cellular physiology and disease. In particular, a role for IR is emerging in both health and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and invariably fatal disease that renders patients paralysed and unable to eat, speak or breathe. Significant technological advances now permit a comprehensive interrogation of previously unrecognized aspects of RNA metabolism in clinically relevant human cell types. In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively), as well as how IRTs may influence subcellular localization of ribonucleoprotein (RNP) complexes, loss of function of bound RNA binding proteins (RBPs) and liquid-liquid phase separation (LLPS) in physiology and disease. Additionally, we discuss the potential of IRTs as independent regulatory elements beyond their protein-coding functions and highlight how artificial intelligence is poised to accelerate discoveries in this area. In the context of IR's increasing appreciation, we also highlight its potential as a therapeutic target and explore current and future challenges in this burgeoning field.}, } @article {pmid42545188, year = {2026}, author = {Poletti, B and Aiello, EN and Consonni, M and Iazzolino, B and Torre, S and Faltracco, V and Telesca, A and Palumbo, F and Curti, B and De Luca, G and Moreschi, A and Frisco, F and Bella, ED and Bersano, E and Riva, N and Verde, F and Messina, S and Doretti, A and Maranzano, A and Morelli, C and Cappa, SF and Calvo, A and Strong, MJ and Silani, V and Lauria, G and Chiò, A and Ticozzi, N}, title = {Neuropsychological Sub-Phenotypes in Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {8}, pages = {e70706}, pmid = {42545188}, issn = {1468-1331}, support = {2015-0023//Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia/ ; 1157625//Fondo Europeo di Sviluppo Regionale, Regione Lombardia/ ; RF-2016-02362405//Ricerca Sanitaria Finalizzata - Ministero della Salute/ ; 2017SNW5MB//"Progetti di Rilevante Interesse Nazionale" programme of the Ministry of Education, University and Research/ ; 101017598//Horizon 2020/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology ; Female ; *Cognitive Dysfunction/etiology/diagnosis/epidemiology/psychology ; Neuropsychological Tests ; Male ; Aged ; Middle Aged ; Phenotype ; Retrospective Studies ; }, abstract = {BACKGROUND: This study aimed at identifying neuropsychological sub-phenotypes in amyotrophic lateral sclerosis (ALS) within the mild cognitive impairment (MCI) and mild behavioral impairment (MBI) frameworks.

METHODS: We used individual task-/item-level data from the cognitive and behavioral sections of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) from 901 non-demented ALS to derive neuropsychological sub-phenotypes pursuant to classical MCI and MBI frameworks and in accordance with an expanded version of Strong's criteria, which also addressed memory and visuo-spatial measures.

RESULTS: The prevalence of MCI and MBI was 39% and 37%, respectively in this retrospective review. The following MCI sub-phenotypes were identified: dysexecutive MCI-single- and multiple-domain (dMCI-sd: 63%; dMCI-md: 24%, respectively); non-dysexecutive MCI-single- and multiple-domain (ndMCI-sd: 12%; ndMCI-md: 1%, respectively). MBI was classified as follows: apathetic MBI-single- and multiple-domain (aMBI-sd: 40%; aMBI-md: 20%, respectively); apathetic-disinihibited/perseverative MBI-multiple domain (ad/pMBI-md: 21%); disinihibited/perseverative MBI-multiple domain (d/pMBI-md: 7%); psychotic MBI-single- and multiple-domain (psyMBI-sd: 2%; psyMBI-md: 3%, respectively); unclassifiable MBI-multiple domain (uMBI-md: 1%). 143 (16%) of patients exhibited mild cognitive and behavioral impairment (MCBI).

CONCLUSIONS: This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients, which, with further validation, might be useful for both research and clinical purposes.}, } @article {pmid42546549, year = {2026}, author = {Silvagi, R and Rodriguez-Fohn, E and Reece, RJ and Cranford, JA and Alangaden, K and Byrd, M and Klausner, H and Pravin, R and Li, J and Conn, C and Dunne, R and O'Neil, BJ}, title = {Advanced vs basic life support outcomes in treatment of out-of-hospital-cardiac-arrest: A registry-based cohort study.}, journal = {The American journal of emergency medicine}, volume = {109}, number = {}, pages = {263-267}, doi = {10.1016/j.ajem.2026.07.021}, pmid = {42546549}, issn = {1532-8171}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; Registries ; Retrospective Studies ; Middle Aged ; *Cardiopulmonary Resuscitation/methods ; Aged ; *Advanced Cardiac Life Support ; Emergency Medical Services ; Treatment Outcome ; Michigan ; Return of Spontaneous Circulation ; }, abstract = {IMPORTANCE: The absolute effect on outcomes with Advanced, (ALS) as compared to Basic Life Support, (BLS) care in Out of Hospital Cardiac Arrest, (OHCA) remains unclear.

OBJECTIVE: To assess the association of ALS compared to BLS alone prehospital care on return of spontaneous circulation, (ROSC), survival to hospital discharge, and neurological outcome in OHCA in Detroit, MI.

METHODS: Retrospective analysis of 6746 patients from the Cardiac Arrest Registry to Enhance Survival database from January 2016 to December 2021 who had non-traumatic OHCA and received cardiopulmonary resuscitation. Cohorts were grouped by ALS v BLS care then initial rhythm and then compared by chi-squared, multivariable logistic, and multinomial regression analysis for outcomes of sustained ROSC, survival to hospital discharge and favorable neurological outcome at hospital discharge. The BLS cohort is defined by units that provided manual CPR, automated rhythm and defibrillation, airway management, but no endotracheal intubation or parenteral medications. ALS care was defined as manual rhythm interpretation, manual defibrillation, intravenous or intraosseous drug administration or endotracheal intubation.

RESULTS: Mean age was 62.6 years (SD-16.7), with 56.3% male and 84.6% Black. Cohort breakdown: shockable ALS (S-ALS; n = 330, 4.9%); shockable BLS (S-BLS; n = 466, 6.9%); non-shockable ALS (NS-ALS; n = 2793, 41.4%); non-shockable BLS (NS-BLS; n = 3157, 46.8%). ROSC rates by cohort: S-ALS (37.9%); S-BLS (19.5%); NS-ALS (18.6%); NS-BLS (9.3%). ALS was associated with increased sustained ROSC for all initial rhythms (p < .001). S-ALS was associated with increased survival (p = .03), and neurologic outcome (p = .01) when compared to S-BLS.

CONCLUSION & RELEVANCE: Advanced Life Support, relative to Basic Life Support alone, was associated with improved sustained return of spontaneous circulation across all initial rhythms, and improved survival to discharge and favorable neurologic outcome in shockable initial rhythms.}, } @article {pmid42546822, year = {2026}, author = {Ghaderi, S and Mohammadi, S and Iturria-Medina, Y}, title = {Quantitative susceptibility mapping in neurodegenerative diseases: An umbrella review of iron-related biomarkers and mechanisms.}, journal = {Magnetic resonance imaging}, volume = {134}, number = {}, pages = {110765}, doi = {10.1016/j.mri.2026.110765}, pmid = {42546822}, issn = {1873-5894}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; *Iron/metabolism ; *Magnetic Resonance Imaging/methods ; Biomarkers/metabolism ; Brain/diagnostic imaging ; Reproducibility of Results ; Amyotrophic Lateral Sclerosis/diagnostic imaging ; Sensitivity and Specificity ; Alzheimer Disease/diagnostic imaging ; }, abstract = {Pathological iron accumulation is a common pathophysiological hallmark across multiple neurodegenerative diseases (NDDs), motivating the need for accurate, non-invasive quantification methods. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique that enables in vivo measurement of tissue magnetic susceptibility (χ), providing a sensitive proxy for iron content. This umbrella review systematically evaluates the diagnostic accuracy, clinical correlations, and distinct iron distribution patterns of QSM in major NDDs, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and atypical Parkinsonism. We included 15 (13/15 were rated Low or Critically Low on AMSTAR 2) systematic reviews and meta-analyses (through July 15, 2026); however, the findings should be interpreted cautiously because of heterogeneity and the low methodological quality. A Corrected Covered Area (CCA) analysis demonstrated only slight overlap of primary studies across the included reviews (CCA = 5.42%). Collectively, the evidence indicates that QSM provides comparable or higher diagnostic sensitivity and reliability than conventional R2* and SWI techniques, particularly for deep gray matter structures. The findings support significant iron overload in the substantia nigra, particularly in the pars compacta, as a robust biomarker for PD that correlates with motor severity and disease duration. Furthermore, regional iron profiling in the basal ganglia is critical for differential diagnosis; specifically, elevated χ in the putamen and globus pallidus effectively distinguishes multiple system atrophy and progressive supranuclear palsy from idiopathic PD. Distinctively, AD and ALS exhibit specific χ alterations in the thalamus, motor cortex, and hippocampus, reflecting divergent iron-related pathophysiological mechanisms, which correlate with cognitive impairment and upper motor neuron signs. Overall, QSM shows diagnostic promise and offers mechanistic insights into iron-related neurodegenerative processes.}, } @article {pmid42547898, year = {2026}, author = {Domke, N and Geue, K and Schlichte, I and Ullsperger, M and Meyer, T and Petri, S and Schreiber, S and Vielhaber, S and Junne, F and Vogt, S}, title = {Depressive symptoms in amyotrophic lateral sclerosis: associations with quality of life, disease progression and perceived social support-a German multicenter study.}, journal = {BMC psychology}, volume = {14}, number = {1}, pages = {}, pmid = {42547898}, issn = {2050-7283}, mesh = {Humans ; *Social Support ; *Quality of Life/psychology ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Female ; Male ; Disease Progression ; Cross-Sectional Studies ; Middle Aged ; *Depression/psychology ; Aged ; Germany ; Adult ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disease. Patients with ALS are at increased risk of developing depressive symptoms. A clearer understanding of the associations between depressive symptoms, disease progression, health-related quality of life and perceived social support is needed to advance intervention-oriented research and improve psychosocial care in ALS.

METHODS: In a multicenter cross-sectional study, patients with ALS were asked to complete patient-reported outcomes (PROs) to evaluate depressive symptoms (ALS-Depression-Inventory, ADI-12), health-related quality of life (ALS-Assessment-Questionnaire, ALSAQ-5/ALSAQ-40), physical functioning (ALS-Functional Rating Scale-Extension, ALSFRS-EX) and perceived social support (Multidimensional Scale of Perceived Social Support, MSPSS). To evaluate associations between demographic/clinical variables and PROs, we performed Pearson's, Spearman's, and partial correlation analyses. In addition, a multiple regression was run to identify predictors of depressive symptoms. Comparisons of patient groups were performed with chi-squared tests for categorical variables and Student t-tests or one-way analysis of variance (ANOVA) for continuous variables, followed by post-hoc tests.

RESULTS: Out of the 150 patients examined, 60% reported depressive symptoms, with half of them exhibiting clinically relevant depressive symptoms. Depressive symptoms were significantly associated with disease progression (r = .466, p < .001), various aspects of health-related quality of life (mobility: r = .394, activities of daily living: r = .268 and emotional well-being: r = .793, all p < .001), the MSPSS sum score (partial r = -.234, p  = .007), and the ALSFRS-EX sum score (r = -.352, p < .001). Patients with depressive symptoms reported significantly more physical impairments (p = .002) and less perceived social support by their families (p = .016) and friends (p < .001) compared to patients without depressive symptoms.

CONCLUSIONS: Depressive symptoms are prevalent in patients with ALS and are closely associated with faster disease progression, reduced physical functioning, poorer health-related quality of life, and lower perceived social support. Further studies, particularly using qualitative methods, are needed to elucidate protective factors, clarify psychosocial mechanisms, and support the conceptualization of specialized and integrated psychosocial care for patients with ALS in Germany.}, } @article {pmid42548030, year = {2026}, author = {Matsuki, Y and Bokuda, K and Morishima, R and Kawazoe, T and Kimura, H and Takahashi, K and Nakayama, Y and Shimizu, T}, title = {Sensory Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis Involves a Broad Hand Representation Within the Primary Somatosensory Cortex.}, journal = {Muscle & nerve}, volume = {74}, number = {4}, pages = {1246-1255}, pmid = {42548030}, issn = {1097-4598}, support = {22H03398//JSPS KAKENHI/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/pathology ; Female ; Male ; *Somatosensory Cortex/physiopathology ; *Evoked Potentials, Somatosensory/physiology ; Aged ; Middle Aged ; *Hand/innervation/physiopathology ; Median Nerve/physiopathology ; Ulnar Nerve/physiopathology ; Retrospective Studies ; Action Potentials/physiology ; Electric Stimulation ; Adult ; Kaplan-Meier Estimate ; }, abstract = {INTRODUCTION/AIMS: Sensory cortical hyperexcitability, reflected by enlarged median nerve somatosensory evoked potentials (SEPs), has been reported in amyotrophic lateral sclerosis (ALS) and is associated with shorter survival. This study investigated whether similar changes involve the ulnar nerve representation within the hand area of the primary somatosensory cortex and examined their relationship with survival.

METHODS: Ninety-nine patients with sporadic ALS and 42 healthy controls were retrospectively studied. Sensory nerve action potentials (SNAPs) and SEPs were recorded following median and ulnar nerve stimulation. SNAP amplitudes and the peak-to-peak amplitudes between N20 and P25 (N20p-P25p) were compared between groups. Patients were followed until death or tracheostomy, and associations between SEP amplitudes and survival were analyzed using Kaplan-Meier and Cox proportional hazards analyses.

RESULTS: SNAP amplitudes did not differ between patients and controls. In contrast, patients with ALS showed larger N20p-P25p amplitudes for both median and ulnar nerve SEPs. N20p-P25p amplitudes were positively correlated between the two nerves, and the ulnar-to-median amplitude ratio did not differ from controls. Patients with ulnar N20p-P25p ≥ 4.89 μV had significantly shorter survival than those with lower amplitude (log-rank test, p = 0.035). Multivariate Cox analysis identified increased N20p-P25p amplitude as an independent predictor of shorter survival for both nerves.

DISCUSSION: Sensory cortical hyperexcitability in ALS extends beyond the median nerve to the ulnar nerve hand area of the somatosensory cortex. Its association with survival supports the notion that sensory cortical dysfunction represents a fundamental pathophysiological feature of ALS and a potential electrophysiological prognostic marker.}, } @article {pmid42548241, year = {2026}, author = {Konarbayeva, Z}, title = {Rheological and Technological Design of Texture-Modified Food Systems for Dysphagia Management in Amyotrophic Lateral Sclerosis.}, journal = {Journal of texture studies}, volume = {57}, number = {4}, pages = {e70105}, pmid = {42548241}, issn = {1745-4603}, mesh = {*Deglutition Disorders/etiology/diet therapy ; *Amyotrophic Lateral Sclerosis/complications ; *Rheology ; Humans ; Viscosity ; *Food Technology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is frequently accompanied by progressive dysphagia, weight loss, and hypermetabolism, which complicate the maintenance of adequate nutritional status. For these patients, food systems must not only provide sufficient energy and protein within a limited volume but also exhibit textural and rheological properties that support safe swallowing. This review analyzes technological and rheological approaches to the design of texture-modified food systems for nutritional support in ALS. Particular attention is given to apparent viscosity, shear-thinning behavior, yield stress, structural homogeneity, and storage stability as parameters affecting bolus formation, swallowing safety, and product performance. The relevance of the International Dysphagia Diet Standardization Initiative framework for classifying food textures and liquid consistencies is also considered. The review further examines the functional and technological roles of animal- and plant-based raw materials, including regional raw materials, in the formulation of energy-dense and structurally stable foods. Proteins, lipids, hydrocolloids, starch gels, and polysaccharide networks are discussed as key components for controlling texture, viscosity, gelation, emulsion stability, and nutritional density. Technological strategies such as homogenization, emulsification, protein-based structuring, hydrocolloid thickening, high-pressure homogenization, and 3D food printing are considered in relation to their potential for developing safe, acceptable, and locally adaptable products for patients with ALS-related dysphagia. The findings highlight the need to integrate food texture science, rheological control, nutritional adequacy, sensory acceptability, and regional availability in the development of clinically relevant texture-modified foods.}, } @article {pmid42548517, year = {2024}, author = {Palm, A and Grote, L and Einarsson, J and Hansson, D and Ljunggren, M and Sundh, J and Ekström, M}, title = {Evolution of Home Mechanical Ventilation in Sweden Over 27 Years: Changing Trends in Incidence, Prevalence, and Patient Characteristics - The Population-Based the Course of Disease in Patients Reported to the Swedish CPAP Oxygen and Ventilator Registry (DISCOVERY) Study.}, journal = {CHEST pulmonary}, volume = {2}, number = {4}, pages = {100108}, pmid = {42548517}, issn = {2949-7892}, abstract = {BACKGROUND: Home mechanical ventilation (HMV), noninvasive ventilation and invasive ventilation outside a hospital setting, is a key treatment to improve outcomes in chronic hypoventilation.

RESEARCH QUESTION: What are the temporal trends observed over 27 years in Sweden regarding the incidence, prevalence, diagnostic spectrum, and patient characteristics associated with HMV?

STUDY DESIGN AND METHODS: This was a national population-based longitudinal analysis of the Course of Disease in Patients Reported to the Swedish CPAP Oxygen and Ventilator Registry (DISCOVERY) study of patients initiating HMV between 1996 and 2022. Time trends stratified by the underlying diagnosis group (lung disease, predominantly COPD, restrictive thoracal diseases, obesity hypoventilation syndrome [OHS], neuromuscular diseases, amyotrophic lateral sclerosis, and other neurologic disorders) were analyzed using linear regression models.

RESULTS: We included 10,555 patients aged ≥ 16 years (mean age 63 [SD, 15] years; 50% women). Between 1996 and 1998 and 2020 and 2022, the HMV incidence increased threefold to 7 per 100,000 people, and the prevalence increased sixfold to 33 per 100,000 people. The most common indication for incident HMV shifted from restrictive thoracal diseases (35% in 1996-1998 to 3% in 2020-2022) to lung disease (14% to 31%), OHS (23% to 33%), and amyotrophic lateral sclerosis (4% to 14%) by 2020 to 2022 (P < .001). The proportion of women increased from 47% to 54% (P < .013) and the age at initiation of HMV increased from 58 [SD, 15] to 66 [SD, 14] years (P < .001). Lung function measured as vital capacity at treatment start increased significantly in all diagnosis groups except for OHS, where both vital capacity and FEV1 decreased. In the registry's first and last 3-year periods, the proportion of patients ventilated invasively decreased from 10% to 2% (P < .001).

INTERPRETATION: In the 27 years until 2022, the incidence and prevalence of HMV in Sweden have increased markedly, patient demographics have changed, and use of invasive ventilation has decreased. The average age of patients initiated on HMV has increased, but treatment is started earlier in the disease trajectory.}, } @article {pmid42548788, year = {2026}, author = {Erazo, D and Hesters, A and Bruneteau, G and De La Cruz, E and Bernard, E and Grapperon, AM and Le Masson, G and Cintas, P and Soriani, MH and Guy, N and Cassereau, J and Camdessanché, JP and Genestet, S and Corcia, P and Pittion, S and Danel, V and Filliatre, M and Choumert, A and Jacquin-Piques, A and Salachas, F and Esselin, F and Bohic, A and Lautrette, G and Attarian, S and Catteau, J and Guissart, C and Vincent, MC and Mouzat, K and Temple, M and Vourc'h, P and Couratier, P}, title = {Tofersen Treatment in SOD1-ALS: Real-World Evidence from a Retrospective Multicenter Study in France (FORSLA Study).}, journal = {Mayo Clinic proceedings. Innovations, quality & outcomes}, volume = {10}, number = {5}, pages = {100739}, pmid = {42548788}, issn = {2542-4548}, abstract = {OBJECTIVE: To evaluate the effectiveness of Tofersen in patients with superoxide dismutase 1 gene (SOD1-ALS) patients in France in a real-world setting, using disease progression within patient comparisons and with a historical cohort.

PATIENTS AND METHODS: Patients with SOD1-ALS were included from across 19 French FILSLAN network centers. Baseline was defined as the treatment initiation date. Main endpoints were the ALSFRS-R progression rate and plasmatic neurofilament light chain (NfL) levels at baseline and 12 months after baseline.

RESULTS: In the Tofersen Cohort (N=46), within-group comparisons showed that the mean ALS functional rating scale revised (ALSFRS-R) progression rate slowed from 0.53 ± 0.5 at baseline to 0.22 ± 0.3 point/month at 12 months (P=.006). NfL levels significantly decreased from 89.0 ± 9.0 pg/ml at baseline to 29.2 ± 19.5.5 at 12 months (P=.004). Exploratory comparisons with a propensity score (PS) matched historical cohort (39 matched pairs) using a mixed-effects model, ALSFRS-R progression rate at baseline, 6 months, and 12 months after baseline, showed no statistically significant differences between groups P=.30, whereas longitudinal ALSFRS-R scores differed significantly between groups (time-treatment interaction P=.006). The mean survival of the PS matched population was longer in the Tofersen Cohort (42.6 months) than the Historical Cohort (31.8 months) P=.004. Time-dependent adjusted cox analysis showed that Tofersen was associated with a reduction in mortality risk (adjusted HR=0.34; 95% CI, 0.12-0.91; P=.03).

CONCLUSION: Tofersen seems to be associated with slower functional decline and reduced NfL levels. While limitations of retrospective design and ALSFRS-R sensitivity must be acknowledged, these findings provide real-world evidence suggesting a clinical benefit of Tofersen.}, } @article {pmid42549498, year = {2026}, author = {Iijima, N and Hagiwara, Y and Ishii, S and Kaneko, W and Araga, T and Yamano, Y}, title = {Quantitative Assessment of Tongue Atrophy in Amyotrophic Lateral Sclerosis Using Transoral Tongue Ultrasonography (TOTU): A Retrospective Single-Center Study.}, journal = {Muscle & nerve}, volume = {74}, number = {4}, pages = {1238-1245}, pmid = {42549498}, issn = {1097-4598}, support = {25ek0109735//Japan Agency for Medical Research and Development/ ; 25fk0108733//Japan Agency for Medical Research and Development/ ; 25bm1423033//Japan Agency for Medical Research and Development/ ; 25ek0109617//Japan Agency for Medical Research and Development/ ; 25ek0109759//Japan Agency for Medical Research and Development/ ; 25FC1012//Ministry of Health, Labour and Welfare/ ; JP25K02584//Japan Society for the Promotion of Science/ ; JP24K10542//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/complications ; Female ; Male ; Retrospective Studies ; *Tongue/diagnostic imaging/pathology ; Middle Aged ; Ultrasonography/methods ; Cross-Sectional Studies ; Aged ; Atrophy/diagnostic imaging ; ROC Curve ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease accompanied by bulbar dysfunction, in which tongue atrophy contributes to dysarthria and dysphagia. Conventional tongue assessments rely on inspection, palpation, or electrophysiological testing but are limited by subjectivity and invasiveness. A rapid, objective, and repeatable imaging-based method for evaluating tongue size would be valuable. We quantified tongue atrophy in ALS using a standardized protocol for transoral tongue ultrasonography (TOTU) and assessed discrimination.

METHODS: This retrospective, cross-sectional study included 15 patients with ALS and 15 controls who underwent TOTU. Using standardized mid-sagittal images, tongue cross-sectional area (cm[2]) and tongue thickness (mm) were measured three times per subject and averaged. Associations with age, body mass index (BMI), disease duration, and ALS Functional Rating Scale-Revised (ALSFRS-R) scores were explored. Discrimination was evaluated using receiver operating characteristic (ROC) analyses.

RESULTS: Both tongue cross-sectional area (6.26 ± 1.37 vs. 9.44 ± 1.02 cm[2]) and tongue thickness (31.47 ± 3.0 vs. 39.44 ± 1.39 mm) were significantly lower in the ALS group than in controls (both p < 0.001). These indices showed no significant associations with age, BMI, disease duration, or ALSFRS-R scores. ROC analyses showed high discriminative ability, with an area under the curve of 0.982 for tongue cross-sectional area and 1.000 for tongue thickness.

DISCUSSION: Standardized TOTU enables rapid, quantitative, noninvasive assessment of tongue size and reliably detects tongue atrophy in ALS, supporting bedside evaluation of bulbar involvement.}, } @article {pmid42549923, year = {2026}, author = {Takahashi, M and Abe, T and Fujii, M}, title = {Targeting Ubiquitinated Protein Aggregates in Neurodegenerative Diseases: current Status and Future Directions.}, journal = {Molecular and cellular biology}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/10985549.2026.2705871}, pmid = {42549923}, issn = {1098-5549}, abstract = {Various cellular stressors inhibit translation initiation and promote ribosome disassembly, thereby transiently inducing stress granules (SGs), dynamic ribonucleoprotein condensates that contain mRNAs and RNA-binding proteins. Although SG assembly is usually reversible, dysregulated SG dynamics can trigger the formation of persistent ubiquitin-positive protein inclusions. There is increasing evidence that this conversion of SGs into insoluble aggregates represents a central pathogenic mechanism in neurodegenerative proteinopathies, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) and Tau are causative factors in ALS and AD, respectively, and both localize to SGs under stress conditions. During disease progression, TDP-43 or Tau within SGs undergoes pathological changes that promote the formation of neurotoxic inclusions, which propagate neuronal dysfunction and death. This review summarizes recent advances in understanding the molecular factors that regulate SG assembly and disassembly, as well as the pathological processes that drive the conversion of SGs into aggregates associated with neurodegenerative diseases. Particular emphasis is placed on the role of the ubiquitin-specific protease 10 (USP10), which modulates SG dynamics and has been mechanistically implicated in both ALS and AD. Finally, we discuss the therapeutic potential of targeting these pathways to mitigate neurodegenerative disease progression.}, } @article {pmid42550987, year = {2026}, author = {Waters-Harvey, B and Kane, K and Griffiths, AW and Smith, G and Bartlett, CM and Sproson, L and Smith, S and Starkey, J and Clift, A and Stavroulakis, T and Hobson, E and Mayberry, E and O'Cathain, A and Bidder, C and Kennedy, K and Gibson, J and McDermott, C and Knox, L}, title = {Co-Designing a Care Coordination Intervention for People With Motor Neuron Disease: Protocol for a Mixed Methods Study.}, journal = {JMIR research protocols}, volume = {15}, number = {}, pages = {e96327}, pmid = {42550987}, issn = {1929-0748}, mesh = {Humans ; *Motor Neuron Disease/therapy/psychology ; Amyotrophic Lateral Sclerosis/therapy ; England ; United Kingdom ; Wales ; }, abstract = {BACKGROUND: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a rapidly progressive neurological condition that requires complex multidisciplinary care. Within the United Kingdom, specialist centers provide expert interventions, while day-to-day support often relies on local nonspecialist community health and social care professionals. This is due to the distance between people's homes and specialist centers, as well as the availability of specialist health and social care professionals. This can lead to fragmented communication and emotional, physical, and financial burdens, and it can be time-consuming for people living with MND, their carers, and the health care professionals involved in their care. Despite the recognized need for better care coordination, it remains inadequate in practice, with a current lack of specific evidence-based interventions for achieving this.

OBJECTIVE: The MND Together project aims to address these systemic gaps by (1) developing a national picture of care coordination in England and Wales, (2) identifying barriers and facilitators to coordination within specialist and nonspecialist settings, and (3) co-designing a practical care coordination tool with key stakeholders.

METHODS: This protocol outlines the co-design of an intervention underpinned by the Behavior Change Wheel and the Socioecological Model. First, a mixed methods, multicenter study will be conducted to develop a national picture, comprising focus groups with people living with MND, carers, and health and social care professionals. Second, focused ethnography will be conducted in 5 MND specialist centers and their catchment areas, involving 25 people living with MND, to explore the barriers and facilitators to coordination in practice. Finally, a series of co-design workshops will be conducted to identify key priorities for care coordination and to develop a new intervention, the MND Together tool.

RESULTS: The project started in September 2025 and will run until October 2027. Workstream 1 started in December 2025, with recruitment beginning at the first site in February 2026. To date, we have recruited 23 people living with MND and carers as well as 16 health and social care professionals across 4 of the 9 sites. Workstream 1 will end in August 2026, with results published at the end of 2026. Workstream 2 began in May 2026 and will run until February 2027, with results published in the summer of 2027. Workstream 3 will begin in March 2027 and conclude with the co-design intervention developed by late 2027. This will then be piloted in practice.

CONCLUSIONS: By combining several methodologies with meaningful patient and public involvement and engagement, MND Together seeks to bridge the gap between specialist and community-based services. The MND Together tool aims to improve the quality of care and ensure that expert MND support is accessible as close as possible to every patient's home.}, } @article {pmid42551425, year = {2026}, author = {Petrescu, J and Gouveia Roque, C and Jackson, CA and Daly, AC and Butti, Z and Kang, K and Casel, O and Leung, M and Reilly, L and Eschbach, J and Gebremedhin, B and McDade, K and Gregory, JM and Bonneau, R and Smith, C and Phatnani, H}, title = {Distinct cellular phenotypes of language and executive decline in amyotrophic lateral sclerosis.}, journal = {Cell}, volume = {189}, number = {19}, pages = {6044-6060.e11}, pmid = {42551425}, issn = {1097-4172}, support = {R01 NS116350/NS/NINDS NIH HHS/United States ; RF1 NS118570/NS/NINDS NIH HHS/United States ; R01 NS118183/NS/NINDS NIH HHS/United States ; R01 NS118570/NS/NINDS NIH HHS/United States ; R01 NS127186/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology/genetics ; Humans ; *Executive Function/physiology ; Phenotype ; *Language ; Female ; Prefrontal Cortex/physiopathology/pathology/metabolism ; Male ; Neurons/metabolism/pathology ; Middle Aged ; *Cognitive Dysfunction/physiopathology ; Aged ; Mitochondria/metabolism ; }, abstract = {Cognitive manifestations, including impairments in language and executive functions, are seen in amyotrophic lateral sclerosis (ALS), but the underlying mechanisms remain unclear. We mapped prefrontal cortex regions from ALS patients by integrating spatial and single-nucleus transcriptomics in a cognitively stratified patient cohort. We uncover that cognitive impairment in ALS is associated with distinct patterns of neuronal dysfunction and glial-vascular dysregulation that vary by region and cognitive subtype. Executive dysfunction is linked to reduced mitochondrial and synaptic activity in deep-layer dorsolateral prefrontal cortex neurons, whereas language-related deficits track with a diffuse pan-regional response involving glial and vascular abnormalities. Our analyses, validated by multiplexed imaging, further identify signatures in the prefrontal cortex that span both motor and cognitive phenotypes, including a multicellular gliosis response. The findings reveal that clinical heterogeneity in ALS is driven by phenotype-specific cellular interactions in motor and non-motor regions of the brain.}, } @article {pmid42551655, year = {2026}, author = {Toyama, G and Koide, S and Yamagishi, T and Washida, A and Hanyu, R and Onodera, O and Sugai, A}, title = {Persistent export bias of TDP-43 under native autoregulation links insoluble accumulation to nuclear dysfunction.}, journal = {Neurobiology of disease}, volume = {228}, number = {}, pages = {107560}, doi = {10.1016/j.nbd.2026.107560}, pmid = {42551655}, issn = {1095-953X}, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Cell Nucleus/metabolism ; Homeostasis/physiology ; HEK293 Cells ; Active Transport, Cell Nucleus/physiology ; Neurons/metabolism ; Cytoplasm/metabolism ; Nuclear Export Signals ; Induced Pluripotent Stem Cells/metabolism ; }, abstract = {Nuclear depletion and cytoplasmic mislocalization of TDP-43 are central pathological features of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 protein levels are normally maintained by autoregulation through its native 3' untranslated region (3' UTR), but whether this feedback remains protective during chronic cytoplasmic bias is unclear. To address this, we engineered full-length human TDP-43 carrying an N-terminal nuclear export signal (NES) while retaining the native 3' UTR autoregulatory module. In HEK293T cells, NES insertion imposed cytoplasmic bias and promoted detergent-insoluble TDP-43 species. In differentiated SH-SY5Y cells, nuclear splicing defects and autoregulatory changes scaled with export-biased load; detergent-insoluble accumulation was already detectable within a low-load range, defined by whole-cell RIPA-soluble exogenous TDP-43 ≤ 30% of endogenous levels. Human iPSC-derived neurons showed a comparable cytoplasmic shift, discrete TDP-43-immunoreactive foci, and TDP-43-dependent splicing defects. Endogenous TARDBP depletion provided a functional rescue test: nuclear-competent WT-TDP-43-3' UTR restored TDP-43-dependent nuclear readouts, whereas NES-TDP-43-3' UTR did not. In the NES condition, weakened autorepression increased transgene-derived TARDBP transcripts, but the added output failed to expand the soluble, splice-competent pool and instead partitioned into insoluble fractions. Increasing soluble NES-TDP-43 to endogenous-equivalent levels likewise did not normalize splicing, indicating that abundance alone is insufficient when output remains export-biased. These findings support a model in which persistent export bias converts native TARDBP autoregulation into maladaptive feedback: compensatory output is uncoupled from productive nuclear recovery and diverted toward cytoplasmic insoluble/fragmented species.}, } @article {pmid42551865, year = {2026}, author = {Dalle, S and Vanderbeke, K and Burg, T and Schouten, M and Lauriks, W and Hersmus, N and Van Den Bosch, L and Koppo, K}, title = {Early and Divergent Lipid Mediator Remodelling in Fast Versus Slow Skeletal Muscles of Female hSOD1[G93A] Mice.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {17}, number = {4}, pages = {e70357}, pmid = {42551865}, issn = {2190-6009}, support = {G086823N//Fonds Wetenschappelijk Onderzoek/ ; 12Z8622N//Fonds Wetenschappelijk Onderzoek/ ; 11PRA24N//Fonds Wetenschappelijk Onderzoek/ ; PDMt1/24/001//Onderzoeksraad, KU Leuven or KU Leuven Research Council/ ; }, mesh = {Animals ; Female ; Mice ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Muscle, Skeletal/metabolism/pathology ; Endocannabinoids/metabolism ; Disease Models, Animal ; *Superoxide Dismutase-1/genetics ; *Lipid Metabolism ; *Muscle Fibers, Slow-Twitch/metabolism ; }, abstract = {BACKGROUND: Skeletal muscle atrophy in amyotrophic lateral sclerosis (ALS) drives loss of muscle strength, function and quality of life in ALS patients. The endocannabinoid system (ECS) regulates muscle homeostasis via regenerative and metabolic processes, and although ECS alterations have been reported in ALS neural tissues, ECS remodelling within ALS skeletal muscle has never been studied. This study investigated temporal and muscle type-specific ECS changes in ALS.

METHODS: Female hSOD1[G93A] transgenic mice and nontransgenic littermates were studied at presymptomatic and symptomatic ages (56-138 days of age; n = 7-8/group). Endocannabinoids, N-acyl-ethanolamine congeners and inflammatory lipid mediators were quantified using targeted LC-MS/MS in the tibialis anterior (TA) and soleus (SOL) muscles. ECS-related enzymes and receptors were assessed by immunoblotting and integrated with transcriptomic analyses of skeletal muscle biopsies from ALS patients (n = 5/group; ~63 years). To evaluate therapeutic relevance, ALS mice were treated with the fatty acid amide hydrolase (FAAH) inhibitor URB937 or vehicle (n = 10-11/group), and survival, body weight, welfare and motor function were assessed longitudinally.

RESULTS: ALS caused severe atrophy in the predominantly fast-twitch TA muscle (-76.5%; p < 0.01), while the slow-twitch soleus was largely preserved (-14.4%; p < 0.01). Accordingly, the lipid perturbation due to ALS was more pronounced in the TA, reflected by extensive alterations in unsaturated fatty acids, hydroxy- and epoxy-fatty acids (TA: 63% and SOL: 22% of lipid mediators different between ALS vs. NTG) and marked ECS remodelling, including elevated anandamide (+37.3%; p = 0.03) and multiple N-acyl-ethanolamine congeners (+76-102%; p < 0.05), reduced 2-arachidonoylglycerol (-28%; p = 0.06), increased CB1 receptor expression (+93%; p < 0.01) and dynamic, age-dependent regulation of FAAH (presymptomatic: -68%; p = 0.04, symptomatic: +21%; p = 0.02). In contrast, the SOL showed modest or opposite changes, consistent with its relative resistance to atrophy. Notably, ECS remodelling in the TA was already evident at presymptomatic age (e.g., CB1: +76%; p = 0.01) and the same ECS enzymes were affected in human ALS skeletal muscle transcriptomes (e.g., twofold decrease in FAAH; pFDR = 0.010). Despite evidence for a therapeutic potential, chronic peripheral FAAH inhibition with URB937 did not improve weight loss, motor functions and survival of ALS mice (all p > 0.05).

CONCLUSIONS: Muscle type-specific endocannabinoid system remodelling in ALS precedes overt neurological decline and might relate to degenerative features such as metabolic disturbance and inflammation. Although peripheral FAAH inhibition alone was insufficient to modify disease outcomes, these findings identify the endocannabinoid system as an integral component of ALS muscle pathology and support skeletal muscle lipid signalling as a potentially relevant early target for adjunctive therapeutic strategies.}, } @article {pmid42552039, year = {2026}, author = {Venu, G and A, VP and Justin, A}, title = {Molecular insights of peroxisome proliferator-activated receptor-γ signalling in amyotrophic lateral sclerosis and Huntington's disease.}, journal = {International review of neurobiology}, volume = {188}, number = {}, pages = {113-143}, doi = {10.1016/bs.irn.2026.05.014}, pmid = {42552039}, issn = {2162-5514}, mesh = {Humans ; *PPAR gamma/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Signal Transduction/physiology ; Animals ; *Huntington Disease/metabolism ; }, abstract = {Progressive neuronal loss is a hallmark of neurodegenerative diseases like Huntingtons disease (HD) and Amyotrophic lateral sclerosis (ALS) which are caused by convergent mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy and dysregulated cell death pathways. Both conditions share significant disruptions in metabolic and inflammatory signalling despite having different genetic origins and clinical manifestations; underscoring the necessity of pathway-oriented treatment approaches. In the central nervous system, peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear receptor has become an important regulator of inflammation, redox homeostasis, mitochondrial biogenesis and cellular stress responses. After giving a thorough overview of PPAR-γ structure activation and transcriptional regulation and the PGC-1α-mediated mitochondrial biogenesis axis, this chapter delves deeply into its interactions with major signalling pathways such as NF-κB, Wnt/β-catenin Nrf2/ARE and the autophagy-apoptosis networks. With a focus on experimental data showing PPAR-γ signaling's neuroprotective, anti-inflammatory, antioxidant and metabolic regulatory roles the pathophysiology of ALS and HD is critically investigated. Lastly the need for improved biomarkers, tailored multi-target strategies and selective modulators is highlighted in the discussion of current therapeutic limitations and translational difficulties.}, } @article {pmid42552041, year = {2026}, author = {Khodve, G and Raval, S and Banerjee, S}, title = {Intestinal microbiota in neurodegeneration and ageing: Mechanisms, pathways, and therapeutic interventions.}, journal = {International review of neurobiology}, volume = {188}, number = {}, pages = {199-229}, doi = {10.1016/bs.irn.2026.05.015}, pmid = {42552041}, issn = {2162-5514}, mesh = {Humans ; *Neurodegenerative Diseases/microbiology/metabolism/immunology/diet therapy/therapy ; *Aging/metabolism/immunology ; *Gastrointestinal Microbiome/physiology ; Animals ; *Dysbiosis/metabolism/immunology ; *Brain-Gut Axis/physiology ; Probiotics ; Brain/metabolism ; }, abstract = {The human gut microbiota represents a complex ecosystem of trillions of microorganisms with profound implications for neurological health. Emerging evidence demonstrates that dysbiosis, an imbalance in microbial composition and function, plays a crucial role in the pathogenesis of neurodegenerative diseases and age-related cognitive decline. This chapter summarizes current knowledge of the microbiota-gut-brain axis (MGBA) and elucidates how intestinal microbes and their metabolites communicate with the central nervous system via neural, immune, endocrine, and metabolic pathways. We examine the mechanistic links between gut dysbiosis and specific neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Multiple sclerosis (MS). Furthermore, we explore age-related changes in the microbiota and their contributions to neuroinflammation, immunosenescence, and cognitive decline. Finally, we evaluate therapeutic interventions targeting the microbiota, including probiotics, prebiotics, synbiotics, and dietary modulation as promising strategies to prevent and ameliorate neurodegenerative pathology. The chapter provides a comprehensive summary of how microbiota-targeted approaches may delay ageing and neurodegeneration.}, } @article {pmid42552132, year = {2026}, author = {Labrèche, F and Prud'homme, P and Gagnon, M and Dupré, N and Gravel, S}, title = {Occupational exposure to pesticides increases the risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Occupational and environmental medicine}, volume = {83}, number = {5}, pages = {291-300}, pmid = {42552132}, issn = {1470-7926}, mesh = {Humans ; *Occupational Exposure/adverse effects ; *Amyotrophic Lateral Sclerosis/chemically induced/epidemiology ; *Pesticides/adverse effects/toxicity ; Risk Factors ; *Occupational Diseases/chemically induced ; }, abstract = {OBJECTIVE: To systematically review the evidence on the association between occupational exposure to pesticides and the risk of amyotrophic lateral sclerosis (ALS).

METHODS: A systematic search, conducted in eight bibliographic databases for publications between 1990 and 2025, identified observational studies estimating the risk of ALS after occupational pesticide exposure. Study quality was assessed using the WHO Risk of Bias (RoB) assessment instrument for systematic reviews, with the ROBINS-E (RoB in non-randomised studies of exposure) tool domains of bias. Pooled risk estimates were produced using random-effects models with restricted maximum likelihood, heterogeneity was assessed with I² statistics, and meta-regressions and publication bias explored with funnel plots and Egger's test.

RESULTS: Eight case-control studies (1734 cases) were retained for meta-analysis from 767 initially screened articles. 'Ever' occupational exposure to pesticides was associated with an increased risk of ALS (n=6 studies, pooled OR (pOR)=1.6; 95% CI 1.1, 2.2; I²=57%), for combined sexes. The risk for exposure to herbicides was slightly greater (pOR=1.7, I[2]=0.0%) than for exposure to insecticides or fungicides (pORs=1.6, I[2]=0.0%). Based on three studies, ever exposure to high levels of pesticides was associated with a higher risk (pOR=2.7; 95% CI=1.4, 5.0) than exposure to low levels (pOR=1.9; 95% CI=1.0, 3.7). Self-reported exposure assessment methods and older publication dates (<2015) were statistically significant predictors of the effect size.

CONCLUSION: Despite the small number of studies and some heterogeneity, our results add to the evidence suggesting that occupational exposure to pesticides may increase the risk of ALS.}, } @article {pmid42552521, year = {2026}, author = {Aradhya, L and Lath, V and Sirur, FM and Balakrishnan, JM and Hebbar, A and Shetty, AK}, title = {Evaluation of safety, comfort, and design ergonomics in ambulance retrieval vehicles: a survey in Southern India.}, journal = {International journal of emergency medicine}, volume = {19}, number = {1}, pages = {}, pmid = {42552521}, issn = {1865-1372}, abstract = {BACKGROUND: Ambulance interior design influences the safety, comfort, and operational efficiency of Emergency Medical Services (EMS) personnel. However, evidence regarding ergonomic challenges faced by EMS providers in the Indian prehospital setting remains limited.

OBJECTIVE: To evaluate EMS personnel perspectives on ambulance ergonomics, safety, comfort, and factors affecting patient care during transport.

METHODS: A multicentre, cross-sectional survey-based observational study was conducted among Emergency Medical Technologists (EMTs) and paramedics, recruited by convenience sampling, who were involved in patient transport using standard Advanced Life Support (ALS) ambulances across Southern India. Data on ergonomic challenges, safety concerns, occupational injuries, and patient-care factors were collected using a questionnaire developed from existing literature and refined through focused-group discussion and expert content review. Data were analysed using descriptive statistics and chi-square tests in jamovi.

RESULTS: A total of 130 EMS providers participated. Limited patient-cabin space (60%) and difficulty accessing equipment (50%) were the most frequently reported factors affecting safety and comfort. Half of the respondents reported concerns regarding EMT seat positioning during patient care. Uneven roads (49.23%) and sudden vehicle breakdowns (41.53%) were the leading causes of transport-related injuries. CPR was the procedure most commonly associated with injuries to the care giver (53.84%), while back pain was the predominant occupational health hazard (57.69%). Significant associations were observed between work experience and perceptions of ambulance ergonomics, injury mechanisms, patient safety concerns, and occupational health hazards (p < 0.05).

CONCLUSION: EMS personnel reported substantial concerns regarding ambulance ergonomics, particularly seat positioning, equipment accessibility, cabin workspace, and occupational safety. These findings emphasize the importance of further ergonomic research in ambulance design to enhance operational ease during in transit care while assuring provider and patient safety.}, } @article {pmid42553257, year = {2026}, author = {Ammar, FI and Aljahdali, E and Alshrif, A and Alshareef, A and Faidah, D and Almohammadi, M and Makkawi, S}, title = {Association of therapeutic plasma exchange with functional outcomes in selected neurological disorders: a retrospective cohort study from a single tertiary center in Saudi Arabia.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1876331}, pmid = {42553257}, issn = {1664-2295}, abstract = {BACKGROUND: Neurological disorders are associated with considerable morbidity and healthcare impact. Therapeutic plasma exchange (TPE) is an intervention that removes pathogenic antibodies, immune complexes, and other plasma constituents from circulation. Previous studies have suggested that TPE could be associated with improved outcomes in selected neurological disorders.

OBJECTIVES: To evaluate functional outcomes following therapeutic plasma exchange in patients with selected neurological disorders at National Guard Health Affairs (NGHA) in Jeddah, Saudi Arabia.

METHODS: This retrospective cohort study analyzes 133 patients diagnosed with various neurological disorders who received TPE between August 2015 and December 2022 at NGHA. Diagnoses included multiple sclerosis (MS), myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), chronic inflammatory demyelinating polyneuropathy (CIDP), autoimmune encephalitis (AE), and other neurological conditions including amyotrophic lateral sclerosis (ALS), transverse myelitis, cerebellar ataxia, paraneoplastic neurologic syndrome, polymyositis, and central nervous system (CNS) infections. The effectiveness of TPE was assessed using the Modified Rankin Scale (mRS) before and 90 days following the final TPE session. Statistical analysis included Wilcoxon signed-rank tests and Mann-Whitney U test, with significance set at (p < 0.05).

RESULTS: Significant improvements in mRS scores were observed following TPE for MS, MG, and GBS (all p < 0.001), as well as for NMOSD (p = 0.008), CIDP (p = 0.007), and AE (p = 0.018), but not in other neurological disorders (p = 0.234). Overall mortality was 6.8%, with no TPE-related deaths. Comorbidities among deceased patients included hypertension, diabetes mellitus, malignancy, chronic kidney disease, and cardiovascular disease.

CONCLUSION: TPE was associated with improved functional outcomes in selected neurological disorders. Comorbidities were common among patients with poorer outcomes. Due to the retrospective design and potential confounding factors, causal inferences cannot be established. Further prospective studies are warranted to evaluate the role of TPE and optimize patient selection.}, } @article {pmid42553297, year = {2026}, author = {Li, Q and You, M}, title = {Targeting mitochondria for the treatment of neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1835506}, pmid = {42553297}, issn = {1662-4548}, support = {R01 CA205633/CA/NCI NIH HHS/United States ; R01 CA223804/CA/NCI NIH HHS/United States ; R01 CA232433/CA/NCI NIH HHS/United States ; R01 CA280746/CA/NCI NIH HHS/United States ; }, abstract = {Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.}, } @article {pmid42554090, year = {2026}, author = {Silva, STD and de Souza, AA and de Melo, LP and de Oliveira Cacho, R and de Holanda, LJ and Ortiz, LDN and Dourado Júnior, MET and Farias, IB and Gonçalves, F and Nagem, DAP and de Medeiros Valentim, RA and Lindquist, ARR and Ribeiro, TS}, title = {Evidence-based physiotherapy recommendations for the management of motor aspects in amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/17582024.2026.2713034}, pmid = {42554090}, issn = {1758-2032}, abstract = {AIM: To provide evidence-based recommendations for the physiotherapy management of Amyotrophic Lateral Sclerosis (ALS).

MATERIALS AND METHODS: Evidence-based recommendations were developed by a multidisciplinary team, including PhDs and master's-level researchers, physicians, and experienced physiotherapists specializing in neurological rehabilitation.

RESULTS: After the selection process, 23 studies were included. Eighteen recommendations addressing motor aspects in ALS were formulated.

CONCLUSIONS: Therapeutic exercise should be considered to improve or maintain ALSFRS-R scores in people with ALS. However, the effects of other interventions examined in this study remain uncertain with respect to motor aspects.}, } @article {pmid42554285, year = {2026}, author = {Benussi, A and Bracca, V and Premi, E and Cantoni, V and Palacino, F and Saccavini, A and Cotelli, MS and Binetti, G and Manenti, R and Alberici, A and Gasparotti, R and Ashton, NJ and Zetterberg, H and Blennow, K and Ghidoni, R and Borroni, B}, title = {Temporal order of clinical, imaging, and biomarker changes in frontotemporal lobar degeneration-associated syndromes.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71722}, pmid = {42554285}, issn = {1552-5279}, support = {//University of Brescia, Italy/ ; //Italian Ministry of Health (Ricerca Corrente)/ ; }, mesh = {Humans ; Female ; *Biomarkers/blood ; Male ; Magnetic Resonance Imaging ; *Frontotemporal Lobar Degeneration/pathology/diagnostic imaging/blood ; Aged ; Middle Aged ; Neurofilament Proteins/blood ; Disease Progression ; Glial Fibrillary Acidic Protein/blood ; Atrophy/pathology ; Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; Supranuclear Palsy, Progressive/pathology ; }, abstract = {BACKGROUND: The temporal sequence of clinical, imaging, and biological changes in sporadic frontotemporal lobar degeneration (FTLD)-associated syndromes remains poorly characterized, and a comprehensive biomarker cascade model is lacking.

METHODS: We developed a data-driven biomarker cascade model in 489 patients across the FTLD spectrum (211 behaviorial variant frontotemporal dementia [bvFTD], 129 primary progressive aphasia [PPA], 71 corticobasal syndrome [CBS], 66 progressive supranuclear palsy [PSP], and 12 FTD associated with amyotrophic lateral sclerosis [FTD-ALS]; 1904 patient-visit observations). Plasma, magnetic resonance imaging (MRI), and clinical biomarkers were modeled using sigmoid trajectories fitted to covariate-adjusted longitudinal data.

RESULTS: Plasma glial fibrillary acidic protein departed from normality earliest, followed by Trail Making Test Part B (TMT-B), white matter lesion volume, and neurofilament light chain. Insular atrophy showed the steepest transition among MRI measures; clinical dementia rating dementia staging instrument plus National Alzheimer's Coordinating Center behavior and language domains sum of boxes declined most steeply overall. TMT-B inflected earliest in bvFTD, whereas insula atrophy dominated in PPA.

CONCLUSIONS: This first data-driven temporal cascade of multimodal biomarkers in sporadic FTLD-associated syndromes offers a framework for disease staging and stage-specific clinical trial design.}, } @article {pmid42554695, year = {2026}, author = {Krajewski, TJ and Koch, GG}, title = {Randomization-based covariance analysis for hypothesis testing of treatment comparisons based on restricted mean survival time with categorized time-to-event data.}, journal = {Journal of biopharmaceutical statistics}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/10543406.2026.2699854}, pmid = {42554695}, issn = {1520-5711}, abstract = {This paper introduces randomization-based analysis of covariance (RB-ANCOVA) for hypothesis testing of restricted mean survival time (RMST) differences between two randomized treatments in trials with categorized time-to-event data. RMST treatment differences over a prespecified time period are clinically meaningful and avoid assumptions like proportional hazards. The proposed method tests the strong null hypothesis that each participant's time-to-event would remain unchanged regardless of treatment assignment. Covariate adjustment is achieved by constraining baseline covariate means to be equal across arms, which reduces variance. The follow-up period is partitioned into mutually exclusive intervals, and RMST is approximated as the area under the survival curve. Under the strong null hypothesis, the joint asymptotic covariance structure of RMST and covariate means is known and used to construct a chi-squared test statistic for the covariate-adjusted RMST difference. The method accommodates stratified trial designs and supports hypothesis testing over single or several time intervals, enabling testing within internal intervals. The difference in RMSTs over an interval can be divided by its length to yield an average survival rate difference. Additionally, the approach allows the computation of essentially exact p-values via re-randomization. We illustrate the method with data from a randomized, placebo-controlled trial evaluating a test treatment for amyotrophic lateral sclerosis. This method provides a hypothesis testing approach for RMST treatment differences that leverages RB-ANCOVA to adjust for their correlations with baseline covariate differences. Under the strong null hypothesis, it enables hypothesis testing with clear control of Type I error and reduced variance without relying on model-based assumptions.}, } @article {pmid42554905, year = {2026}, author = {Colín-Martínez, E and Ramírez-Jarquín, UN and Tapia, R and Arias, C}, title = {Inhibition of Glutamate Decarboxylase in the Spinal Cord Induces Motor Deficits and Motor Neuron Degeneration.}, journal = {Neurotoxicity research}, volume = {44}, number = {4}, pages = {}, pmid = {42554905}, issn = {1476-3524}, support = {IN206719//Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México/ ; A1-S12135//Secretaría de Ciencia, Humanidades, Tecnología e Innovación/ ; }, mesh = {Animals ; *Glutamate Decarboxylase/metabolism/antagonists & inhibitors ; *Spinal Cord/drug effects/pathology/enzymology ; *Motor Neurons/drug effects/pathology/enzymology ; *Enzyme Inhibitors/toxicity/pharmacology ; *Nerve Degeneration/pathology/chemically induced/enzymology ; Male ; Rats ; gamma-Aminobutyric Acid/metabolism ; }, abstract = {Motor neuron (MN) diseases such as amyotrophic lateral sclerosis (ALS) are characterized by the loss of cortical and spinal MNs. Although the precise mechanisms of MN degeneration are still unknown, downregulation of GABAergic circuits has been identified in both ALS patients and transgenic models of the disease. GABA synthesis depends on the activity of the enzyme glutamate decarboxylase (GAD), of which two isoforms are known: GAD65 and GAD67. To study the effects of decreased GABA synthesis on spinal cord motor function, we analyzed the effects of administering three selective inhibitors of GAD: 3-mercaptopropionic acid (MPA), a competitive inhibitor of GAD, thiosemicarbazide (TSC), and pyridoxal phosphate γ-glutamyl hydrazone (PLPGH), two GAD cofactor blockers. A single dose of any of these inhibitors did not affect motor behavior or MN morphology. However, subchronic (3 days) and chronic (10 days) administration of MPA, TSC or PLPGH in rats caused motor alterations and cellular changes, including episodic myoclonus-like movements, flaccidity in the ipsilateral phalanges, loss of 35-50% of MNs, reactive astrogliosis and decreased GAD activity. These findings suggest that chronic inhibition of GAD can lead to MN degeneration and further suggest that GABA metabolism in the spinal cord may participate in the mechanisms that cause MN death in patients with neurodegenerative diseases such as ALS.}, } @article {pmid42555669, year = {2026}, author = {Hubbard, I and Dubnau, J}, title = {Glial cell toxicity in a Drosophila C9orf72 neurodegeneration model.}, journal = {PLoS genetics}, volume = {22}, number = {8}, pages = {e1011909}, pmid = {42555669}, issn = {1553-7404}, support = {R01 AG076493/AG/NIA NIH HHS/United States ; R01 AG078788/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *C9orf72 Protein/genetics ; *Neuroglia/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics/pathology ; Disease Models, Animal ; Neurons/metabolism/pathology ; Drosophila melanogaster/genetics ; Animals, Genetically Modified ; }, abstract = {The most common genetic cause of both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G4C2 repeat in the first intron of the gene C9orf72. The C9orf72 repeat expansion is bidirectionally transcribed into sense and anti-sense RNA foci, and also produces dipeptide repeats (DPRs) via a non-canonical translation mechanism known as repeat-associated (RAN) translation. Each of these components of the G4C2 repeat expansion cause neurodegenerative effects in animal models when expressed in neurons, but impacts from glial expression are more poorly understood. Here, we use glial cell type-specific expression of individual DPRs, of RNA repeat-only, or of the G4C2 repeat, that produces both DPRs and RNA repeats, to systematically investigate glial toxicity of each component. We find that as with neurons, the GR and G4C2 transgenes produce the highest degree of toxicity when expressed in glia. Each of these transgenes are capable to produce the GR DPR, which also is the most toxic factor in neurons. We demonstrate that both the GR and G4C2 transgenes cause activation of mdg4, an endogenous retrovirus (ERV). Such ERV expression is a hallmark of TDP-43 dysfunction that is commonly observed in C9orf72 patients. We find that glial expression of either the GR or the G4C2 transgene is toxic to glial cells, but such expression does not cause loss nearby neurons. However, blocking apoptotic signaling within glia that express either GR or G4C2 via expression of the p35 caspase inhibitor further exacerbates effects on lifespan and ablating such glia via expression of the proapoptotic reaper gene partially ameliorates these effects. Together, these results indicate that expression of toxic C9orf72 components in glia produces deleterious effects on lifespan, though potentially through different mechanisms than seen in TDP-43 models of ALS/FTD.}, } @article {pmid42556002, year = {2026}, author = {Tekan, ÜY and Aksoy, E and Kargın, F and Küçük, RS and Saltürk, C and Çiyiltepe, F and Yavuz, D and Güngör, G and Adıgüzel, N and Karakurt, Z}, title = {Chronic neurological diseases with acute respiratory failure in a real-life cohort: insights into ICU and long-term survival-A retrospective study.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {153}, number = {}, pages = {112228}, doi = {10.1016/j.jocn.2026.112228}, pmid = {42556002}, issn = {1532-2653}, mesh = {Humans ; Female ; Retrospective Studies ; Male ; *Respiratory Insufficiency/mortality/therapy/complications ; *Intensive Care Units ; *Nervous System Diseases/mortality/complications/therapy ; Aged ; Middle Aged ; Cohort Studies ; Chronic Disease ; Respiration, Artificial ; Kaplan-Meier Estimate ; }, abstract = {BACKGROUND: Patients with chronic neurological diseases (CND) are at increased risk of pulmonary complications that often require ICU admission. This study aimed to identify clinical factors associated with ICU mortality and long-term survival in patients with CND who developed acute respiratory failure (ARF).

METHODS: This retrospective cohort study was conducted in a level III respiratory ICU. Patients with pre-existing CND admitted to the ICU with ARF were included. ICU mortality was analyzed using multivariable logistic regression. Long-term survival after ICU discharge was evaluated using Kaplan-Meier survival analysis and Cox proportional hazards models. Mortality timing was further characterized using hazard function analysis.

RESULTS: A total of 220 patients were included; the most common neurological diagnoses were dementia (37.3%), stroke (22.7%), and amyotrophic lateral sclerosis (14.1%). ICU mortality was 33.6%. Higher APACHE II scores were independently associated with increased ICU mortality (OR 1.076 per point increase; 95% CI 1.029-1.126; p < 0.001). Long-term survival differed significantly by post-discharge respiratory support strategy, with Kaplan-Meier analysis demonstrating more favorable survival patterns among patients receiving home non-invasive mechanical ventilation (NIMV) (p = 0.003). In Cox regression analysis, age, home NIMV, and feeding modality at discharge were independently associated with long-term outcomes. Survival analyses revealed an early clustering of deaths within the first months after ICU discharge, particularly among patients with dementia.

CONCLUSIONS: In patients with CND, acute physiological severity was the main determinant of ICU mortality, whereas long-term survival after ICU discharge was poor, with deaths clustering within the first months thereafter. Post-discharge respiratory support and nutritional management should be individualized according to the expected clinical trajectory and patient values.}, } @article {pmid42556722, year = {2026}, author = {Jiang, H and Ding, L and Yang, C and Guo, G and Zhong, C and Ma, Z and Zhu, H and Zhang, J and Luo, Y and Liu, Z and Liu, R and Ding, Y}, title = {Distinct competitive and allosteric binding modes of nanobodies targeting EphA4.}, journal = {The Journal of biological chemistry}, volume = {302}, number = {9}, pages = {113394}, pmid = {42556722}, issn = {1083-351X}, mesh = {*Single-Domain Antibodies/chemistry/metabolism/immunology ; *Receptor, EphA4/chemistry/metabolism/immunology/antagonists & inhibitors ; Humans ; Allosteric Regulation ; Models, Molecular ; Crystallography, X-Ray ; Binding, Competitive ; Binding Sites ; Thermodynamics ; }, abstract = {Erythropoietin-producing hepatocellular carcinoma A4 (EphA4) signaling is a key negative regulator of axonal regeneration and a genetic modifier of ALS, making EphA4 an attractive but mechanistically underexplored therapeutic target. Although EphA4-targeting nanobodies have shown inhibitory potential, the structural principles governing their binding and inhibitory mechanisms remain largely unknown. Here, we report high-resolution crystal structures of the EphA4 ligand-binding domain in complex with four nanobodies (Nb50, Nb53, Nb57, and Nb60), resolved at 1.30 to 2.21 Å. Nb50, Nb53, and Nb57 competitively engage the canonical ephrin-binding pocket through deep complementarity-determining region 3 insertion, directly mimicking ephrin recognition. In contrast, Nb60 adopts a previously unrecognized binding mode, contacting two EphA4 molecules at noncanonical sites in the crystal structure through framework-dominated interactions and supporting a structural model for steric and allosteric restriction of ephrin access. Integrated biophysical analyses reveal distinct thermodynamic and kinetic signatures underlying these binding mechanisms. Together, our findings uncover unexpected structural diversity in nanobody-mediated EphA4 recognition and provide a framework for rational development of EphA4-targeted modulators for ALS and related neurodegenerative conditions.}, } @article {pmid42556956, year = {2026}, author = {Rahman, U and Yang, SC}, title = {Management of Anastomotic Leaks: Endoscopic, Interventional, and Surgical Strategies.}, journal = {Advances in surgery}, volume = {60}, number = {1}, pages = {259-270}, doi = {10.1016/j.yasu.2026.03.017}, pmid = {42556956}, issn = {1878-0555}, mesh = {Humans ; *Anastomotic Leak/therapy/surgery/etiology ; }, abstract = {Anastomotic leaks (ALs) are a significant source of morbidity and mortality. Every step should be implemented to prevent AL, including careful patient selection, optimizing patient's clinical and nutritional status, and ensuring proper technique. The appropriate management of an AL depends on several factors, such as patient's clinical status, the type of surgery, location of the AL, induction therapies, and the resources available. Surgeons should be familiar with the armamentarium of treatment modalities available to manage AL and use a patient-tailored approach when selecting the most appropriate treatment.}, } @article {pmid42557952, year = {2026}, author = {Acharya, A and Thurman, M and Sutar, D and Olasunkanmi, OI and Malik, JR and Dyavar, SR and Végvári, Á and Byrareddy, SN}, title = {In-Vitro Evaluation of HIV/SARS-CoV-2 Co-Infection Mediated Proteomic Changes in Astrocytes and Pericytes Reveals Altered Signaling Pathways Associated With Neurodegenerative Disorders.}, journal = {Journal of medical virology}, volume = {98}, number = {8}, pages = {e71086}, pmid = {42557952}, issn = {1096-9071}, support = {R01 DA052845/DA/NIDA NIH HHS/United States ; R01 DA061678/DA/NIDA NIH HHS/United States ; R01DA061678/NH/NIH HHS/United States ; R01DA05284/NH/NIH HHS/United States ; }, mesh = {*Pericytes/virology/metabolism ; *Astrocytes/virology/metabolism ; Humans ; *Signal Transduction ; *HIV Infections/metabolism/complications/virology ; *SARS-CoV-2/physiology ; *Coinfection/virology/metabolism ; *Neurodegenerative Diseases/metabolism/virology ; *COVID-19/metabolism/complications/virology ; Proteomics ; Microglia/virology/metabolism ; Post-Acute COVID-19 Syndrome ; Virus Replication ; Proteome ; }, abstract = {Coronavirus disease 2019 (COVID-19) survivors frequently experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Importantly, complications arising from microvascular dysfunction, blood-brain barrier (BBB) disruption, and chronic neuroinflammation have been implicated in driving PASC within the central nervous system (CNS), known as neuro-PASC. Notably, people with HIV (PWH), who suffer from chronic neuroinflammation, BBB impairment, and glial cell dysfunction, collectively known as neuro-HIV, are generally at higher risk of neuro-PASC. The overlap between neuro-PASC and neuro-HIV raises concerns that HIV and SARS-CoV-2 co-infection may exacerbate neurological dysfunctions among PWH. In this study, using an in-vitro cell culture model, we examine the effects of HIV and SARS-CoV-2 mono- and co-infection in microglia, astrocytes, and pericytes. Our results demonstrated that majority of brain cell types support SARS-CoV-2 replication, in the presence and absence of HIV infection. Furthermore, in both mono- and co-infected cells, there were varying degree of up- and downregulation of SARS-CoV-2 host cell entry factors, such as ACE2, TMPRSS2, NRP1, and TRIM28, and inflammatory cytokines including IL-6, TNF-α, and IL-1β. Moreover, conditioned media collected from HIV, SARS-CoV-2, and HIV/SARS-CoV-2 co-infected astrocytes and pericytes were shown to be neurotoxic. Additionally, proteomic analysis has revealed a unique set of proteins significantly up/down regulated in HIV/SARS-CoV-2 co-infected astrocytes and pericytes. The gene set enrichment analysis of these proteins indicates dysregulation of lipid, energy, and immune metabolism pathways linked to neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis. These in-vitro findings indicate that astrocytes and pericytes from HIV/SARS-CoV-2 co-infection exhibit altered protein expression profiles, implicating dysregulated signaling pathways associated with neurodegenerative dysfunction.}, } @article {pmid42558527, year = {2026}, author = {Li, S and Cao, T and Zhang, Q}, title = {Oxidative stress as a driver of organelle cascade damage in neurological diseases.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1892923}, pmid = {42558527}, issn = {1663-4365}, abstract = {As a core driver in the pathological progression of neurological diseases, oxidative stress contributes to the onset and development of multiple disorders, including traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), by inducing interconnected and bidirectional damage among mitochondria, endoplasmic reticulum, lysosomes, and the nucleus. This review systematically summarizes the oxidative stress-mediated inter-organelle crosstalk network: Mitochondria act as one of the earliest and central hubs, and their dysfunction (e.g., reactive oxygen species burst, calcium overload, and respiratory chain impairment) induces endoplasmic reticulum stress via ROS diffusion and calcium signaling disturbance. The disruption of endoplasmic reticulum calcium homeostasis further exacerbates mitochondrial damage, forming a vicious cycle. Lysosomes exhibit reduced membrane stability and impaired autophagic flux under oxidative stress, failing to clear damaged organelles and aggravating oxidative stress accumulation. Ultimately, oxidative stress signals are transmitted to the nucleus, resulting in DNA damage, aberrant epigenetic modifications, and activation of pro-inflammatory/pro-apoptotic genes, thereby accelerating disease progression. Notably, this organelle injury transmission is not a rigid unidirectional linear cascade; primary lysosomal or MAM defects can independently initiate the full organelle damage loop without preceding mitochondrial dysfunction. This review integrates current studies, clarifies context-dependent and disease-specific characteristics of organelle interactions, and discusses potential therapeutic strategies with critical consideration of translational challenges and limitations, providing a theoretical foundation for mechanistic research and clinical intervention of neurological diseases.}, } @article {pmid42558984, year = {2026}, author = {Pourasghari, M and Babaie, S and Markazi-Movaghar, R and Salehpour, S and Eftekharsadat, B and Farshbaf-Khalili, A}, title = {The Effectiveness Based on Optimal Dose and Administration Route, and Safety Profiles of Stem Cells and Derived Products in the Treatment of Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Stem cells international}, volume = {2026}, number = {}, pages = {4122493}, pmid = {42558984}, issn = {1687-966X}, abstract = {BACKGROUND: This systematic review and meta-analysis aimed to evaluate the effectiveness of stem cell therapies for patients with amyotrophic lateral sclerosis (ALS) based on optimal dosing and administration routes, as well as the safety profiles of stem cells and their derived products.

METHODS: The review followed PRISMA guidelines and involved a comprehensive literature search up to October 2025, receiving ethical approval from Tabriz University of Medical Sciences and registration in PROSPERO. It utilized international databases, including PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, ClinicalTrials.gov, and Science Direct. The included studies comprised randomized controlled trials (RCTs), quasi-experimental studies, and other interventional designs involving ALS patients treated with stem cell therapies. In total, 31 studies were analyzed, featuring 7 controlled trials with 370 participants and 24 non-controlled pre-post studies with 460 participants. Heterogeneity was evaluated using I [2] statistics, and subgroup analyses were conducted based on treatment duration and dosing.

RESULTS: A pooled analysis (treatment group: n = 93; control group: n = 90) demonstrated a significant attenuation in the progression of disease severity, as measured by the ALS Functional Rating Scale (ALSFRS), in stem cell groups versus controls (weighted mean difference [WMD]: 8.89 95% CI: 4.12-13.67; p = 0.0003), which was beneficial for both the ≥10 × 10[6] and <10 × 10[6] dose sub-groups. However, a meta-analysis of single-arm studies in two control (pre-intervention) and intervention phases (n = 88) demonstrated no significant difference in progression of ALSFRS between study phases by time: month 3 (WMD: -1.27 (-3.01 to 0.47); p = 0.15), month 6 (WMD: -2.69 (-5.62 to 0.25); p = 0.07), month 9 (WMD: -1.55 (-3.49 to 0.39); p = 0.12), and month 12 (WMD: -7.59 (-13.95 to -1.26); p = 0.02). An accelerated decline in forced vital capacity (FVC) was observed during the intervention phase, with statistically significant reductions at month 3 (WMD: -10.91; 95% CI: -16.39 to -5.43; p < 0.0001) and month 6 (WMD: -15.97; 95% CI: -28.60 to -3.33; p = 0.01) compared with the pre-intervention control phase. Nevertheless, sensitivity analyses excluding studies involving high-dose mesenchymal stem cell (MSC) therapies demonstrated that these differences were no longer statistically significant. Moreover, no significant change in progression rate was observed at month 9 (WMD: -8.10 (-18.25 to 2.06); p = 0.12). The route of MSCs administration (intrathecal [IT], intramuscular [IM], and intravenous [IV]) had no effect on the results of ALSFRS and FVC, reinforced by sensitivity analyses. Adverse events were mostly mild, with headaches most frequent in high-dose groups.

CONCLUSION: Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients. Nevertheless, the existing evidence base remains exploratory, and definitive conclusions regarding clinical effectiveness cannot yet be drawn. Future research should prioritize large-scale and multicenter RCTs with standardized cell manufacturing protocols and longer follow-up periods.}, } @article {pmid42559389, year = {2026}, author = {Murray, G and Dupuis, M and Hagan, J and Laroche, M and Peters, J}, title = {Arbeitnehmer:innen als Klima-Akteure: Was können Gewerkschaften gegen den Klimawandel unternehmen? Einleitung.}, journal = {Transfer (Brussels, Belgium)}, volume = {32}, number = {2}, pages = {141-151}, pmid = {42559389}, issn = {1024-2589}, } @article {pmid42560011, year = {2026}, author = {Abrar, F and Martin, DDO}, title = {Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/15548627.2026.2711593}, pmid = {42560011}, issn = {1554-8635}, abstract = {SQSTM1/p62 (sequestosome 1) is an important receptor protein involved in many cellular signaling processes, including macroautophagy/autophagy. It is a molecular hub for cellular homeostasis and cellular responses. Within autophagy, SQSTM1 targets ubiquitinated cargo for degradation, maintaining cellular proteostasis. Structurally, SQSTM1 consists of several domains that facilitate its binding to ubiquitinated cargo, the formation of SQSTM1 aggregate inclusions, interactions with MAP1LC3/LC3, and the mediation of clearance via the autophagy pathway. Beyond its structure, post-translational modifications of SQSTM1 dynamically regulate its function within a cell. Post-translational modifications - such as phosphorylation, ubiquitination, acetylation, S-acylation, and S-nitrosylation - are crucial for regulating SQSTM1 function, localization, and interaction with autophagic components, thereby influencing SQSTM1's role in the autophagy pathway. Understanding the role of these protein modifications in modulating autophagy may provide better insight into developing therapeutic strategies for diseases with dysregulated autophagy, such as neurodegenerative diseases. This review will discuss the role of these post-translational modifications in controlling SQSTM1's localization and function in autophagy.Abbreviations: ABHD = α/β-hydrolase domain; AD = Alzheimer Disease; ALS = amyotrophic lateral sclerosis; ATG = autophagy related ; CSNK2/CK2 = casein kinase 2; HD = Huntington Disease; HDAC/KDAC = histone deacetylase/lysine deacetylase; HTT = huntingtin; KAT = lysine acetyltransferase; KEAP1 = kelch like ECH associated protein 1; KIR = KEAP1-interacting region; LIR = LC3-interacting region; LYPLA/APT = lysophospholipase/acyl-protein thioesterase; MAP1LC3/LC3 = microtubule associated protein 1 light chain 3; MEF = mouse embryonic fibroblast; mHTT = mutant huntingtin; MTORC1 = MTOR complex 1; NBR1 = NBR1 autophagy cargo receptor; NEDD4 = NEDD4 E3 ubiquitin protein ligase ; NO = nitric oxide; NFE2L2/Nrf2 = nuclear factor erythroid 2-factor 2; PAT = palmitoyl acyltransferase; PB1 = Phox-BEM1 domain; PE = phosphatidylethanolamine; PLEKHM1 = pleckstrin homology and RUN domain containing M1; PLK2 = polo like kinase 2; PRKA/PKA = protein kinase cAMP-activated; PPT1 = palmitoyl-protein thioesterase 1; RB1CC1 = RB1 inducible coiled-coil 1; SNCA/α-synuclein = synuclein alpha; SNO = S-nitrosothiol; SOD1 = superoxide dismutase 1; SQSTM1 = sequestosome 1; TARDBP/TDP-43 = TAR DNA binding protein ; TBK1 = TANK binding kinase 1; TAX1BP1 = Tax1 binding protein 1; TRIM = tripartite motif containing ; UBA = ubiquitin-associated domain; UBE = ubiquitin-conjugating enzyme; ULK1 = unc-51 like autophagy activating kinase 1; UPS =ubiquitin-proteasome system; USP8 = ubiquitin specific peptidase 8; ZDHHC = zDHHC palmitoyltransferase.}, } @article {pmid42560418, year = {2026}, author = {León-Ruiz, M and Castañeda-Cabrero, C and Benito-León, J}, title = {Response to "Palpebral ptosis as the initial symptom of amyotrophic lateral sclerosis": the potential usefulness of cortical excitability and motor band sign as biomarkers of upper motor neuron degeneration.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {9}, pages = {}, pmid = {42560418}, issn = {1590-3478}, } @article {pmid42561134, year = {2026}, author = {Ehn, E and Thonberg, H and Nennesmo, I and Lindstrand, A and Kvarnung, M and Graff, C}, title = {Clinical genome sequencing in neurodegenerative diseases-outcome in the first 500 patients.}, journal = {Human molecular genetics}, volume = {35}, number = {16}, pages = {}, doi = {10.1093/hmg/ddag072}, pmid = {42561134}, issn = {1460-2083}, mesh = {Humans ; *Whole Genome Sequencing/methods ; *Neurodegenerative Diseases/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Female ; C9orf72 Protein/genetics ; DNA Copy Number Variations/genetics ; Male ; Middle Aged ; Alzheimer Disease/genetics/diagnosis ; Genetic Predisposition to Disease ; Frontotemporal Dementia/genetics/diagnosis ; Aged ; DNA Repeat Expansion/genetics ; Adult ; Polymorphism, Single Nucleotide ; Phenotype ; }, abstract = {Neurodegenerative diseases (NDDs) are clinically and genetically heterogeneous, requiring neuropathology or molecular testing for a definitive diagnosis. Clinical whole genome sequencing (WGS) enables comprehensive variant calling across flexible gene lists that can be tailored to the clinical presentation. By allowing simultaneous detection of single-nucleotide variants, copy-number variants, structural variants, and repeat expansions, WGS has the potential to improve diagnostic yield, facilitate genetic counseling and support clinical trial inclusion. This study assesses the diagnostic performance of WGS in individuals with NDD. WGS in 500 individuals representing a wide spectrum of NDDs identified a disease-causing variant in 61 cases, resulting in a diagnostic yield of 12%. These variants were found in 16 different genes, with C9orf72 being the most prevalent. Repeat expansions represented the largest variant class, accounting for 35 of 61 LP/P cases (57%); most of which were C9orf72 expansions (31/35). In the largest phenotype groups, frontotemporal dementia (FTD) had the highest diagnostic yield (19%) followed by amyotrophic lateral sclerosis (ALS, 13%), whereas an underlying monogenic cause was expectedly low in Alzheimer disease (AD, 4%). A positive family history was present in the majority (74%) of FTD, ALS, combined ALS-FTD and AD cases with an LP/P finding. Clinical WGS provides a clear diagnostic advantage in NDDs marked by substantial clinical and genetic overlap. WGS enables comprehensive variant detection and mapping of genotype-phenotype relationships across the disease continuum. In FTD and ALS, these results support universal access to genetic testing independent of age at onset or family history.}, } @article {pmid42561511, year = {2026}, author = {Al Ojaimi, Y and Dupuis, A and Palla, M and Lanznaster, D and Hergesheimer, R and Galineau, L and Serriere, S and Chami, AA and Martineau, P and Alouane, T and Marouillat, S and Dupuy, C and Schneider, BL and Veyrat-Durebex, C and Masse, F and Trovero, F and Andres, CR and Corcia, P and Vourcʼh, P and Blasco, H}, title = {Intrabody B1 targeting TDP-43 modulates neuroinflammatory and metabolic pathways in a preclinical ALS model.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e01032}, pmid = {42561511}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *DNA-Binding Proteins/metabolism/antagonists & inhibitors/immunology/genetics ; Mice, Transgenic ; Mice ; Humans ; Disease Models, Animal ; *Single-Chain Antibodies/administration & dosage ; *Neuroinflammatory Diseases/metabolism/drug therapy ; *Metabolic Networks and Pathways/drug effects/physiology ; Motor Neurons/metabolism/drug effects ; }, abstract = {TDP-43 pathology is a hallmark of Amyotrophic Lateral Sclerosis (ALS), yet no therapeutic strategy effectively targets its upstream molecular consequences. Here, we investigated whether the anti-TDP-43 intrabody scFv B1 modulates neuroinflammatory and metabolic pathways in a preclinical ALS model, and whether these effects translate into functional benefit after symptom onset. Using phage display, we previously identified single-chain variable fragments (scFvs) binding TDP-43, including the candidate therapeutic scFv B1. In NSC-34 motor neuron-like cells overexpressing human wildtype TDP-43, B1 reduced NF-κB activation, consistent with disruption of TDP-43-driven inflammatory signaling. For in vivo assessment, B1 was delivered via AAV-CAP.B10 after symptom onset in the hTDP-43(WTxA315T) transgenic mouse model, enabling neuro-specific expression. Two cohorts were analyzed - longitudinal (nine months) and terminal (six months post-treatment) - through behavioral testing, PET imaging, metabolomics, transcriptomics, and plasma biomarker analyses. B1 achieved robust CNS expression and modulated several disease-relevant molecular pathways. RNA-sequencing revealed attenuation of NF-κB-related inflammatory signatures and partial normalization of metabolic and trophic gene expression. Metabolomic profiling identified shifts toward wild-type-like levels in oxidative stress, mitochondrial, and membrane phospholipid metabolites. Despite these molecular effects, symptomatic B1 administration did not improve motor behavior or reduce plasma neurofilament light chain (NfL) concentrations. Notably, plasma TDP-43 levels were stabilized, indicating systemic target engagement. Collectively, scFv B1 modulates upstream pathogenic processes associated with TDP-43 proteinopathy but is insufficient to reverse established neurodegeneration after symptom onset, underscoring the need for earlier and likely combinatorial intervention strategies in ALS.}, } @article {pmid42561943, year = {2026}, author = {Rostalski, H and Hietanen, T and Hoffmann, D and Heikkinen, S and Huber, N and Dhingra, A and Rodriguez-Nieto, S and Kuulasmaa, T and Ohtonen, S and Jäntti, H and Pekkala, V and Leskelä, S and Mäkinen, P and Katisko, K and Hartikainen, P and Lehtonen, Š and Solje, E and Koistinaho, J and Malm, T and Portaankorva, AM and Natunen, T and Martiskainen, H and Takalo, M and Hiltunen, M and Haapasalo, A}, title = {C9orf72-associated and sporadic FTD patient iPSC-microglia show differences in phagocytosis and gene expression.}, journal = {Stem cell reports}, volume = {21}, number = {9}, pages = {103026}, pmid = {42561943}, issn = {2213-6711}, mesh = {Humans ; *C9orf72 Protein/genetics/metabolism ; *Phagocytosis/genetics ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *Microglia/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/cytology ; Female ; Male ; Amyotrophic Lateral Sclerosis/genetics ; Gene Expression Regulation ; }, abstract = {C9orf72 hexanucleotide repeat expansion (C9-HRE) is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). However, approximately half of the FTD patients are sporadic without a clear genetic background. To compare characteristics of microglia from different FTD subtypes, we generated induced pluripotent stem cell-derived microglia (iMG) from sporadic and C9-HRE-carrying behavioral variant FTD (bvFTD) patients and healthy controls. C9-HRE iMG displayed C9-HRE-associated RNA foci and dipeptide repeat proteins. All bvFTD iMG had fewer LAMP2-A-positive vesicles compared to control iMG. Additionally, C9-HRE iMG showed significantly increased LC3BII/I conversion after bafilomycin A1 treatment and altered phagocytic activity. The gene expression profile of C9-HRE iMG only modestly differed from the control iMG, but was greatly different from the sporadic bvFTD patient iMG. Our data show alterations in phagocytic and autophagosomal/lysosomal pathways and gene expression profiles between C9-HRE and sporadic bvFTD iMG for the first time.}, } @article {pmid42561977, year = {2026}, author = {Helmold, B and Armon, C and Benatar, M and Bertorini, T and Bromberg, M and Brown, A and Cadavid, JM and Carbunar, O and Carter, GT and Crayle, J and Feldman, E and Foucher, J and Glass, J and Greenstein, E and Jhooty, S and Jiang, N and Kochen, NN and McDermott, C and Olby, N and Pattee, G and Porter, D and Premasari, A and Rao, A and Ratner, D and Staats, K and Tito, E and Vieira, F and Wicks, P and Bedlack, R}, title = {ALSUntangled #84 - ivermectin.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/21678421.2026.2714724}, pmid = {42561977}, issn = {2167-9223}, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). In this review, we explore the possibility of using ivermectin to slow ALS progression. Ivermectin's ability to modulate neuroinflammation and excitotoxicity give it plausible mechanisms for treating ALS, though it does not get into the brain very well. One preclinical study demonstrated that ivermectin lengthened lifespan within a mouse model of mSOD1 genetic ALS. This finding has not been replicated. The 2 PALS we found who had data comparing ALSFRS-R progression on and off ivermectin appeared to have no benefit from it. We found no trials of ivermectin in PALS. Ivermectin is low cost and generally well tolerated with most adverse effects being mild and transient, but serious side effects can rarely occur, and it has not been carefully studied in PALS. We cannot at present endorse ivermectin as an ALS treatment.}, } @article {pmid42562736, year = {2026}, author = {Chan, SC and Tung, CW and Chang, CY and Su, CC and Chen, YC and Wu, PM and Tung, CY and Chen, SF and Kuo, HY and Cheng, PH and Chen, CM and Yang, SH}, title = {Wild-type C9orf72 drives proteasomal dysfunction and mutant aggregates via a Stat1-Isg15 axis in Huntington's disease.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e00970}, pmid = {42562736}, issn = {1878-7479}, mesh = {Animals ; *STAT1 Transcription Factor/metabolism/genetics ; *Huntington Disease/metabolism/genetics/pathology ; *Ubiquitins/metabolism/genetics ; Humans ; *Proteasome Endopeptidase Complex/metabolism/genetics ; Mice ; *Cytokines/metabolism/genetics ; *C9orf72 Protein/genetics/metabolism ; Mice, Transgenic ; Mutation ; Signal Transduction ; Proteotoxic Stress ; Brain/metabolism ; Huntingtin Protein/genetics/metabolism ; }, abstract = {Mutant C9orf72 has been extensively studied as a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, and is also known to generate Huntington's disease (HD)-like phenocopies. However, despite this strong disease association, the role of wild-type C9orf72 (wt-C9orf72) in neurodegeneration remains largely unexplored. HD is a neurodegenerative disease, and characterized by the accumulation of misfolded mutant Huntingtin (mHTT) and impaired proteostasis, yet the upstream mechanisms driving ubiquitin-proteasome system (UPS) dysfunction are not fully understood. Here, we identify a previously unrecognized modulatory role of wt-C9orf72 in regulating mHTT aggregation in experimental HD models. Analysis of public transcriptomic datasets reveal context-dependent C9ORF72 expression changes across HD-related human datasets, while C9orf72 levels are increased in R6/2 mouse brain lysates. Functional analyses reveal that overexpression of wt-C9orf72 increases mHTT aggregation and is accompanied by increased apoptotic signaling and reduced cell viability. Unbiased proteomic profiling identifies Stat1 as a key downstream effector. Mechanistically, wt-C9orf72 promotes Stat1 activation and nuclear translocation, leading to transcriptional upregulation of Isg15, a ubiquitin-like modifier. Elevated Isg15 disrupts UPS function, resulting in accumulation of polyubiquitinated proteins and impaired proteasomal degradation. Importantly, genetic suppression of Stat1 or Isg15 significantly attenuates C9orf72-associated mHTT aggregation, supporting a functional C9orf72-Stat1-Isg15 axis. Consistent with these cell-based findings, Stat1, phosphorylated Stat1 and Isg15 levels are elevated in the cortex and striatum of R6/2 HD mouse brains. Collectively, our findings identify a novel wt-C9orf72-Stat1-Isg15 axis that promotes proteasomal dysfunction and mHTT aggregation, providing new insights into wt-C9orf72-associated protein homeostasis.}, } @article {pmid42562773, year = {2026}, author = {Zheng, X and Zhang, N and Wang, L and Zhao, H and Liu, C and Wang, J and Zhao, W and Zhao, J and Yang, P and Robinson, L and Hunt, L and Lokken, A and Lin, L and Nelson, PT and Kofler, J and Xie, H and Xia, H and Mao, Q}, title = {A phosphorylation‑independent monoclonal antibody improves detection of TDP‑43 pathology across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and limbic predominant age related TDP‑43 encephalopathy neuropathological change.}, journal = {Journal of neuropathology and experimental neurology}, volume = {}, number = {}, pages = {}, pmid = {42562773}, issn = {1554-6578}, support = {R21 AG080502/AG/NIA NIH HHS/United States ; R21AG080502/AG/NIA NIH HHS/United States ; GC-202008-2020689//Alzheimer's Drug Discovery Foundation/ ; R21AG088509/AG/NIA NIH HHS/United States ; R21 AG088509/AG/NIA NIH HHS/United States ; R01 AG097508/AG/NIA NIH HHS/United States ; R01AG097508/AG/NIA NIH HHS/United States ; }, abstract = {TDP-43 proteinopathies encompass frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), amyotrophic lateral sclerosis (ALS-TDP), and limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC). These proteinopathies exhibit subtype-specific aggregate architectures that may constrain epitope accessibility in situ. We compared a phosphorylation-independent monoclonal antibody targeting a C-terminal epitope (MAb No. 9) with the phospho-specific pSer409/410 antibody to determine whether its signal relates to regional neurodegeneration in a multicenter autopsy cohort spanning FTLD-TDP types A-C, ALS-TDP, and Alzheimer disease neuropathologic change (ADNC) with or without LATE-NC. Immunolabeling with MAb No. 9 detected pathological TDP-43 across all diagnostic groups with enhanced labeling of dystrophic neurites and thread/dot-like pathology in FTLD-TDP types A/B and in ALS-TDP. MAb No. 9 performance was equivalent to p409/410 in FTLD-TDP type C. In ADNC with stage 3 LATE-NC, MAb No. 9 revealed a greater limbic burden and labeled both α type and β type inclusions. Dual label immunofluorescence demonstrated strong spatial overlap with p409/410 but additionally highlighted fine punctate pathology. MAb No. 9 burden in FTLD-TDP type A correlated strongly with cortical neurodegeneration but showed weaker and variable associations, particularly in severely atrophic cortex. These findings indicate that filament architecture governs C-terminal epitope accessibility and that MAb No. 9 may be a complementary tool for subtype refinement, clinicopathologic correlation and translational biomarker development in TDP-43 proteinopathies.}, } @article {pmid42562776, year = {2026}, author = {Wan, Y and Gao, C and Li, J and Luan, M and Lu, Y and Wang, J and Yang, B and Zheng, J and Yuan, Y and Wei, J and Wang, Z and Deng, J}, title = {Neural stem cell-derived small extracellular vesicles ameliorate disease progression in the SOD1 G93A murine model of amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnen/nlag013}, pmid = {42562776}, issn = {1554-6578}, support = {2025ZD0217600//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons leading to muscle weakness, paralysis, and ultimately, respiratory failure. Extracellular vesicles (EVs) facilitate intercellular communication by mimicking the functions of their parent cells. In this study, we found that repeated administration of neural stem cell-derived extracellular vesicles (NSC-derived EVs) improved motor performance and provided protection to lumbar motor neurons, the neuromuscular junctions, and muscle morphology in the SOD1 G93A transgenic mouse model of ALS. Furthermore, by analyzing the RNA-sequencing of muscle specimens from ALS-SOD1 patients, we demonstrated that the rescue effects of NSC-derived EVs might be linked to the p53 pathway. Compared to the PBS control treatment group, both TP53 and the p53 upregulated modulator of apoptosis (PUMA) were downregulated in the spinal cord of mice treated with NSC-derived EVs. These data provide additional knowledge for the promising use of NSC-derived EVs as a potential therapy for ALS.}, } @article {pmid42564086, year = {2026}, author = {Zhang, G and Li, Z and Yao, X and Ding, M and Liu, X}, title = {Observed changes in clinical proxy measures of airway protection after cervical epidural spinal cord stimulation in neurological disorders: a preliminary retrospective case series.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1875581}, pmid = {42564086}, issn = {1664-2295}, abstract = {OBJECTIVES: Although spinal cord stimulation (SCS) has been investigated for cough and respiratory motor output after neurological injury, its relationship with clinical proxy measures of airway protection remains unclear. We explored observed changes in aspects of airway protection after cervical SCS in patients with neurological disorders.

MATERIALS AND METHODS: We retrospectively analyzed six patients who underwent cervical SCS for spinal cord injury, amyotrophic lateral sclerosis, or disorders of consciousness. Clinical proxy measures included the Semi-quantitative Cough Strength Score (SCSS), Functional Oral Intake Scale (FOIS), Water Swallow Test (WST), and Chinese Swallowing Quality of Life Questionnaire (cSWAL-QoL). SCSS was available for all six patients, whereas FOIS, WST, and cSWAL-QoL were limited to the four conscious patients. SCSS, FOIS, and WST were descriptively compared across preoperative, stimulation ON, and stimulation OFF conditions when clinically permissible. cSWAL-QoL was compared between preoperative and postoperative follow-up.

RESULTS: During active stimulation, SCSS scores were higher in all six patients, with the median score changing from 3.0 preoperatively to 4.0 during stimulation ON (nominal p = 0.031). SCSS was also higher during stimulation ON than OFF (4.0 vs. 3.0; nominal p = 0.031). Among the four conscious patients, FOIS changed from 4.0 to 5.0 and WST changed from 3.5 to 2.5 during stimulation ON, while cSWAL-QoL changed from 91.0 to 151.5 postoperatively. No stimulation-related adverse events occurred.

CONCLUSION: Clinical proxy measures related to airway protection showed exploratory state-associated changes during cervical epidural SCS, particularly in cough-strength scores. These preliminary findings do not establish efficacy or mechanism.}, } @article {pmid42565285, year = {2026}, author = {Semendric, I and Munn, Z and Jenkins, T and Edwards, A and Tull, V and Travlos, V and Hutchinson, K and Krikheli, L and Sheers, N and Hall, LA and Chua, P and Hatch, N and Allcroft, P and Werth, B and Saffrett, A and Yoong, J and Cooper, L and Signorelli, M and Farrugia, E and Devenney, E and Douglas, A and Gibb, A and Macshane, M and Gardiner, M and Collins, A and Yang, J and Rogerson, B and Schultz, D and Lim, D and Fisher, F and Herz, H and Puckering, H and Swain, I and Cameron, J and Donnelly, L and Davis, L and Anderson, L and Acampora, M and Heatley, R and Taubert, S and Sheehy, T and Sia, T and Aiyappan, V and Huynh, W and Stern, C and , }, title = {Issues in the clinical assessment and management of people living with motor neurone disease (MND): a survey of Australian healthcare professionals.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2710550}, pmid = {42565285}, issn = {2167-9223}, abstract = {Objective: To inform the development of the Australian MND Guideline, this study aimed to identify challenges Australian healthcare professionals (HCPs) face in the clinical assessment and management of people living with MND (plwMND) including where practice varies from evidence or is underrepresented in the literature and challenges that arise when supporting non-MND specialists. Methods: An anonymous online survey was developed on Qualtrics (Provo, UT) and distributed in July 2025 to members of the Australian MND Guideline Clinical and Content Advisory Group. Demographic data were analyzed using descriptive statistics and verbatim responses were analyzed thematically to a pre-defined framework of guideline scopes and topics. Results: Fifty HCPs, predominantly allied health professionals, completed the survey (55% response rate). HCPs reported diagnostic delays, difficulties accessing timely multidisciplinary support, and challenges coordinating care, particularly outside MND clinic catchment areas. HCPs perceived uncertainty in respiratory support, nutrition, saliva management, and psychological and cognitive care. Variations from guidance reflected gaps and inconsistencies in the evidence base, the need for individualized care, and systemic constraints including funding, workforce shortages, and inequities in access. Non-MND specialists sought guidance on prognosis, referral pathways, symptom management, and end-of-life care. Conclusion: This survey identified areas of clinical practice uncertainty and variability in the clinical assessment and management of plwMND from the perspective of Australian HCPs. These findings will inform the development of the Australian MND Guideline, including prioritization of topics and questions, and consideration of areas where expert consensus is required.}, } @article {pmid42566133, year = {2026}, author = {Thompson, JC and Kobylecki, C and Jones, M and Haigh, J and Larbey, M and Langheinrich, TC and Thomasson, R and Richardson, AMT and Snowden, JS}, title = {Frontotemporal dementia with right temporal predominance: a clinical comparison with left-predominant FTD.}, journal = {Journal of neurology}, volume = {273}, number = {9}, pages = {}, pmid = {42566133}, issn = {1432-1459}, mesh = {Humans ; *Frontotemporal Dementia/physiopathology/diagnostic imaging/pathology/psychology/classification ; Female ; Male ; *Temporal Lobe/pathology/diagnostic imaging ; Middle Aged ; Aged ; Retrospective Studies ; Neuropsychological Tests ; Magnetic Resonance Imaging ; *Functional Laterality/physiology ; Atrophy ; }, abstract = {BACKGROUND: The right-temporal variant of frontotemporal dementia (FTD) is well characterised. Whether it should be considered a distinct clinical entity, separate from other syndromes of FTD, remains an open question. The study addressed the issue through a retrospective comparison of clinical characteristics of patients with predominant atrophy in right or left anterior temporal lobe (R-ATL vs. L-ATL).

METHODS: Patients were identified from a clinical database, diagnosed with FTD, and reported to show temporal lobe atrophy on imaging. Fifty-one patients were selected in whom independent ratings of atrophy were greatest in right or left anterior temporal lobe. Presenting symptoms, cognitive and behavioural characteristics, neuropsychological findings, and diagnostic classification were recorded.

RESULTS: Difficulty recognising people, impaired decision-making, perseverative preoccupations, disinhibition, and loss of empathy characterised the R-ATL group, in keeping with the previous reports. There was, however, overlap in cognitive and behavioural symptomatology in R-ATL and L-ATL, and sensitivity and specificity values were modest. Group differences diminished with disease progression. The most common clinical classification at first assessment in both groups was semantic dementia (SD), with other patients being classified as behavioural-variant FTD (bvFTD), FTD with amyotrophic lateral sclerosis or mixed FTD/SD. Not all patients with L-ATL met criteria for semantic variant primary progressive aphasia (svPPA).

CONCLUSIONS: The data question the notion that R-ATL and L-ATL presentations are separate entities. We argue that a common diagnostic framework for the two is warranted, with classification being based on cognitive/behavioural characteristics rather than neuroradiological grounds.}, } @article {pmid42567782, year = {2026}, author = {Risby-Jones, G and Lee, JD and Fung, JN}, title = {Interleukin-6 trans-signalling as a selectively targetable driver of neurodegeneration.}, journal = {Trends in neurosciences}, volume = {49}, number = {9}, pages = {750-763}, doi = {10.1016/j.tins.2026.07.002}, pmid = {42567782}, issn = {1878-108X}, mesh = {Humans ; Animals ; *Neurodegenerative Diseases/metabolism ; *Interleukin-6/metabolism ; *Signal Transduction/physiology ; Receptors, Interleukin-6/metabolism ; Inflammation/metabolism ; }, abstract = {Interleukin-6 (IL-6) exerts protective and pathogenic effects in the central nervous system through distinct receptor-signalling modes. Classical signalling via membrane-bound IL-6 receptor (IL-6R) is often associated with homeostatic and reparative functions, whereas trans-signalling, mediated by soluble IL-6R, expands IL-6 responsiveness to gp130-expressing cells and may promote chronic inflammation. Emerging evidence implicates dysregulated IL-6 trans-signalling in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Here, we review mechanisms linking IL-6 trans-signalling to immune, glial, neuronal, and vascular dysfunction in neurodegeneration. We highlight key knowledge gaps and discuss whether selective targeting of trans-signalling can limit inflammatory pathology while preserving beneficial classical IL-6 functions.}, } @article {pmid42568821, year = {2026}, author = {Okano, H}, title = {From neural development to regenerative medicine: A research journey in stem cell biology, spinal cord repair, and iPSC-based drug discovery.}, journal = {Regenerative therapy}, volume = {33}, number = {}, pages = {101157}, pmid = {42568821}, issn = {2352-3204}, abstract = {This commemorative article reflects on a research journey spanning neural development, stem cell biology, regenerative medicine, and iPSC-based drug discovery. My early work focused on RNA-mediated regulation in the nervous system, including studies on myelin basic protein gene regulation and the identification and functional characterization of the RNA-binding protein Musashi. These studies contributed to the conceptual foundation of neural stem cell biology and helped establish methods for identifying and isolating neural stem/progenitor cells, including those present in the adult human brain. Building on this foundation, my colleagues and I pursued translational research in spinal cord injury, ranging from analyses of injury pathophysiology and molecular interventions to preclinical studies using rodent and non-human primate models. These efforts ultimately led to the first-in-human clinical study of induced pluripotent stem cell-derived neural stem/progenitor cell transplantation for subacute spinal cord injury. In parallel, we developed patient-derived iPSC platforms for neurological disease modeling and drug discovery, particularly for amyotrophic lateral sclerosis, where iPSC-based screening identified Ropinirole as a therapeutic candidate and enabled reverse translational research linking cellular phenotypes with clinical responses. Looking ahead, I argue that the future of regenerative therapy will depend on the continued integration of developmental biology, stem cell science, disease modeling, rehabilitation, and clinical translation to address unmet medical needs in disorders of the central nervous system.}, } @article {pmid42569815, year = {2026}, author = {Kondo, A and Hokkoku, K and Kanbayashi, T and Nakayama, T and Sasaki, T and Matsuno, H and Iguchi, Y and Fukutake, T and Ando, T and Kamiyama, T and Kim, P and Hasegawa, T and Hatanaka, Y and Kobayashi, S and Sonoo, M}, title = {"Abductor Sparing": A New Selective Involvement in ALS.}, journal = {Muscle & nerve}, volume = {74}, number = {4}, pages = {1263-1269}, pmid = {42569815}, issn = {1097-4598}, support = {FC001030/WT_/Wellcome Trust/United Kingdom ; 20FC1030//Ministry of Health, Labour and Welfare of Japan/ ; 22K07524//Ministry of Education, Science, Sports and Culture of Japan/ ; JP22K15738//Japan Society for the Promotion of Science/ ; 26K10419//Ministry of Education, Science, Sports and Culture of Japan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Female ; Male ; Aged ; *Muscle, Skeletal/physiopathology ; Middle Aged ; *Muscle Weakness/physiopathology/etiology ; Retrospective Studies ; Adult ; }, abstract = {INTRODUCTION/AIMS: Various signs of selective muscle involvement have been reported in amyotrophic lateral sclerosis (ALS) but such studies for the lower limbs are scarce. We formed a preliminary impression that hip abductors (Ab) are often preserved in ALS. We named this phenomenon "abductor sparing", and this study aimed to verify our findings.

METHODS: Patients with a confirmed diagnosis of ALS (ALS group) and patients with pyramidal weakness other than ALS (pyramidal group) were retrospectively identified. Medical Research Council (MRC) scores of 10 muscle groups in the lower limbs were evaluated. The proportion of patients with weakness (MRC score 4 or less) was compared between different groups.

RESULTS: We enrolled 61 patients in the ALS group and 27 patients in the pyramidal group. The most frequently weak muscle groups in both groups were big toe extensors and hip flexors. Ab was the third (70%) in the pyramidal group, whereas it was weak only in 30% of patients with ALS. This held true also for patients with ALS with shorter duration or less severity. "The lower limb flexor pattern", i.e., flexor muscles being weaker than extensor muscles, was observed both in ALS and pyramidal groups.

DISCUSSION: Patients with ALS generally showed similar muscle weakness patterns to those with pyramidal syndrome, except for abductor sparing. The reason for the latter phenomenon is unclear. Abductor sparing may be useful for early diagnosis of ALS, although larger studies with blinded evaluators are needed to confirm these findings.}, } @article {pmid42570648, year = {2026}, author = {Ye, P and Guo, B}, title = {Identification of Glycolysis-Related Diagnostic Biomarkers for Amyotrophic Lateral Sclerosis Using Machine Learning.}, journal = {Clinical laboratory}, volume = {72}, number = {8}, pages = {}, doi = {10.7754/Clin.Lab.2025.250766}, pmid = {42570648}, issn = {1433-6510}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism/blood ; *Biomarkers/metabolism/blood ; *Glycolysis/genetics ; *Machine Learning ; Predictive Learning Models ; Boosting Machine Learning Algorithms ; Blood Glucose/analysis/metabolism ; }, abstract = {BACKGROUND: Glycometabolism has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), yet the precise molecular mechanisms underlying this association remain poorly understood. The identification of reliable biomarkers for ALS diagnosis represents a critical unmet need in clinical practice, as early detection and intervention could significantly improve patient outcomes.

METHODS: We employed a comprehensive analytical approach combining two-sample Mendelian randomization analysis to investigate the causal relationship between blood glucose levels and ALS. Additionally, we integrated differential expression analysis, multiple machine learning algorithms, and correlation analyses to identify potential diagnostic biomarkers for ALS. The machine learning framework utilized gradient boosting tree methodology to construct predictive models, with performance evaluation conducted through cross-validation procedures.

RESULTS: Mendelian randomization analysis demonstrated a significant negative causal relationship between blood glucose levels and ALS risk. Through bioinformatic analysis and machine learning approaches, we successfully identified candidate genes and constructed a high-performance predictive model using gradient boosting tree methodology, achieving an average area under the curve (AUC) of 0.8782 in cross-validation. Validation studies utilizing both bulk and single-cell RNA sequencing datasets revealed that COL5A1 and VCAN genes play significant roles in ALS pathogenesis, likely through their involvement in glycolytic pathways.

CONCLUSIONS: Our findings provide novel insights into the molecular mechanisms linking glycometabolism and ALS, while identifying potential diagnostic biomarkers for the disease. The identified genes, COL5A1 and VCAN, represent promising targets for further investigation in ALS pathogenesis. However, the clinical translation of these findings requires validation through additional datasets and prospective clinical trials to establish their diagnostic utility and therapeutic potential.}, } @article {pmid42572287, year = {2026}, author = {Okunomiya, T and Sakasai, T and Tsukita, K and Shimizu, R and Okusa, A and Adachi, M and Tomita, S and Tanaka, A and Kondo, T and Imamura, K and Inoue, H}, title = {Generation of mutant human SOD1 knock-in mouse lines at the Rosa26 locus as a platform for developing genome-editing therapies for amyotrophic lateral sclerosis.}, journal = {Experimental animals}, volume = {}, number = {}, pages = {}, doi = {10.1538/expanim.26-0040}, pmid = {42572287}, issn = {1881-7122}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, resulting in progressive paralysis and death within a few years of symptom onset. Although current treatments modestly slow the disease progression, effective disease-modifying and curative therapies remain an urgent unmet need. SOD1 mutations are one of the major genetic causes of familial ALS. The p.Leu127Ser (L126S) and p.Gly94Ser (G93S) variants are clinically relevant pathogenic variants for which appropriate animal models are needed for preclinical evaluation of gene-editing therapies. However, most existing SOD1 models rely on high copy overexpression of mutant SOD1. Therefore, animal models carrying a single copy mutant human SOD1 allele are required for evaluating the in vivo efficacy of genome editing therapies. Here, we used CRISPR/Cas9-mediated homology-directed repair to generate a knock-in mouse line at the Gt(ROSA)26Sor (Rosa26) locus carrying a single-copy, 11-kb human SOD1 genomic fragment, including all exons and introns, with the L126S mutation. The Rosa26-hSOD1[L126S] mice did not develop ALS-like phenotypes during the limited observation period. However, they faithfully retained a single-copy mutant human SOD1 genomic allele, providing a valuable preclinical platform for evaluating genome-editing therapies. We also generated Rosa26-hSOD1[G93S] mice carrying the SOD1 G93S mutation with comparable efficiency. Together, these mutant human SOD1 knock-in mouse lines provide a versatile and clinically relevant platform for the preclinical evaluation of genome-editing therapies targeting heterozygous SOD1 mutations.}, } @article {pmid42572514, year = {2026}, author = {Sheehy, TP and Sia, T and Morgan, PE and Zhao, Y and Mathieson, SR and Gibb, RM and Smith, AA and Wools, CA}, title = {Relationship between neck weakness in motor neurone disease and respiratory function: a retrospective study.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/17582024.2026.2705867}, pmid = {42572514}, issn = {1758-2032}, abstract = {AIMS: The primary aim was to explore the relationship between neck weakness in people with motor neurone disease (MND) and their respiratory function. The secondary aim was to identify whether neck weakness can be a prognostic factor.

METHODS: This was a retrospective observational cohort study. Data was collected from patient records on MND characteristics, neck weakness, respiratory function, and noninvasive ventilation (NIV) use. Multivariate modeling explored the effect of neck weakness on respiratory variables.

RESULTS: MND-related neck weakness was evident in 41% of 324 participants. Fifty-four percent used NIV and 17% became dependent on NIV during disease progression. The presence of neck weakness in MND was predictive of time to respiratory function decline, for respiratory outcomes (forced vital capacity (FVC) <65%, FVC <50% and NIV use) as well as having an effect on time to death. Median time from neck weakness onset to death was 8 months (IQR 10 months; range 0 to 60 months) with bulbar onset the quickest, median of 7 months (IQR 7 months, range 0 to 43 months).

CONCLUSIONS: The presence of neck weakness is associated with a more rapid respiratory function decline in MND. In addition, neck weakness can be considered a prognostic factor in MND survival.}, } @article {pmid42573583, year = {2026}, author = {Yeow, A and Cleland, J and Soh, C and Balete, C}, title = {Sociotechnical Misalignments in Hospital AI System Implementation: Qualitative Case Study.}, journal = {Journal of medical Internet research}, volume = {28}, number = {}, pages = {e87534}, pmid = {42573583}, issn = {1438-8871}, mesh = {Humans ; *Artificial Intelligence ; Qualitative Research ; }, abstract = {BACKGROUND: Implementing AI into real-world health care settings is known to be challenging, particularly regarding how well AI is embedded into the existing knowledge, practices, and procedures of a context. Understanding this process is critical for maximizing the successful implementation of AI tools and planning the time, costs, and resources needed for their successful implementation.

OBJECTIVE: This study sought to examine the contextual challenges of implementing an AI chatbot, ChatAI (which provided quick access to clinical and operational information without relying on the intranet), in a large tertiary government hospital by analyzing the impact of sociotechnical factors on its sustained use.

METHODS: We used an instrumental case study approach, utilizing interviews and meeting minutes. A total of 16 semistructured interviews were conducted with the implementation team and hospital staff who interacted with ChatAI. Interviews were audio-recorded and transcribed. Sociotechnical systems (STS) theory, specifically Davis et al's (2014) framework, was adopted to examine ChatAI's implementation and use.

RESULTS: Multiple misalignments among 5 of Davis et al's sociotechnical elements (goals, people, processes, technology, and infrastructure) limited ChatAI's user adoption and sustainability. Although the hospital's innovation center team attempted to address these initial misalignments, contextual changes such as new regulatory mandates, infrastructure changes, and evolving stakeholder practices introduced further misalignments between ChatAI and the hospital-eventually leading to its discontinuation.

CONCLUSIONS: This study highlights how sociotechnical misalignments can undermine the use and sustainability of large-scale implementation of AI systems. These findings will inform future efforts to implement AI tools in real-world health care settings, increasing awareness of the need to align sociotechnical dimensions of goals, people, processes, technology, and infrastructure. It highlights the particularly challenging aspect of aligning continually evolving infrastructure with regulatory requirements. Future research should focus on how infrastructure and infrastructure changes, as well as external regulatory requirements, influence AI implementation and use.}, } @article {pmid42573824, year = {2026}, author = {Su, B and Li, L and Zheng, X and Ma, H and Li, X and Feng, X}, title = {Clinical significance of SQSTM1 variants in ALS: report of p.Arg119Cys and literature review.}, journal = {Neurogenetics}, volume = {27}, number = {1}, pages = {}, pmid = {42573824}, issn = {1364-6753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Sequestosome-1 Protein/genetics ; Male ; Middle Aged ; Pedigree ; Mutation, Missense ; Genetic Association Studies ; Adaptor Proteins, Signal Transducing/genetics ; }, abstract = {We analyzed the clinical features of a patient with amyotrophic lateral sclerosis (ALS) carrying a novel variant in the sequestosome 1 (SQSTM1) gene and explored the genotype-phenotype association of SQSTM1 gene variants in combination with previous literature. Clinical data and genetic testing results of an ALS patient treated at our hospital were collected. Whole-exome sequencing was used to screen for ALS-related genes, and candidate variants were validated by Sanger sequencing and family analysis. A systematic search was conducted in the PubMed database using the keywords ("amyotrophic lateral sclerosis") OR ("motor neuron disease") AND ("SQSTM1") to summarize the clinical and genetic characteristics of previously reported ALS patients with SQSTM1 variants. The patient was a 49-year-old male with progressive weakness in both lower limbs for one year and weakness in the left upper limb for the past three months. Electromyography showed extensive neurogenic damage. Genetic testing identified a novel heterozygous missense variant, c.355 C > T (p.Arg119Cys), in the SQSTM1 gene. Family verification revealed that his phenotypically normal mother carried the same variant. The literature search identified 58 cases of ALS associated with SQSTM1 variants. Missense variants were the most common type. We identified a novel SQSTM1 variant, c.355 C > T (p.Arg119Cys), in a ALS patient. Although this finding expands the variant spectrum, its pathogenicity remains uncertain and requires further functional validation and pedigree confirmation. Our literature review further shows that SQSTM1-associated ALS predominantly presents with limb onset, with a subset of patients exhibiting frontotemporal dementia or Paget's disease.}, } @article {pmid42573939, year = {2026}, author = {Khadilkar, V and Mondkar, S and Baalaaji, ARM and Bhutada, A and Dhongade, A and Lad, SS and Lad, P and Jain, MK and Patnaik, S and Sarkar, M and Shaikh, F and Sharma, M and Shetty, R and Upadhyay, N and Vohra, R and Wagle-Patki, S and Khadilkar, A and Patki, V and James, EJG and Shah, S and Bansal, A}, title = {A Multicenter Study for Validation of the New Pediatric Advanced Life Support Tape for Indian Children.}, journal = {Indian pediatrics}, volume = {}, number = {}, pages = {}, pmid = {42573939}, issn = {0974-7559}, abstract = {OBJECTIVE: Accurate weight estimation is essential for drug dosing and equipment selection in pediatric emergencies. A new Pediatric Advanced Life Support (ALS) tape was developed using Indian growth references. The present study was performed to validate its performance in critically ill children across multiple centers in India.

METHODS: A prospective, cross-sectional, multicenter observational study was conducted in 13 pediatric intensive care units (PICUs) across five zones of India in children aged < 12 years. Recumbent length was measured using the new ALS tape, and color-band-based estimated weight recorded. Weight was measured using a digital scale. The primary outcomes were bias, precision, and accuracy of the tape in predicting weight. Secondary outcomes included correlation between estimated and measured weight, agreement using Bland-Altman analysis, center-wise subgroup analyses, and interrater reliability for color-band assignment.

RESULTS: Out of 2740 children measured, 2253 were included in the final analysis. Correct color-band concordance was observed in 79.9% of children. Overall, 78.6% of estimates were within ± 10% and 84.6% within ± 15% of measured weight. The mean difference between estimated and measured weight was - 0.6 kg (0.08%). Lower color bands showed modest underestimation (13.1%), while higher bands showed mild overestimation (- 10.3%). Regional concordance ranged from 65.9% to 91.4%. Interrater reliability demonstrated strong agreement (κ = 0.84; 95% CI 0.61, 1.00).

CONCLUSIONS: The Indianized Pediatric ALS tape demonstrated acceptable accuracy, minimal overall bias, and strong interrater reliability in critically ill Indian children. Although some variability was observed across regions and lower weight bands, the new ALS tape represents a practical and reasonably accurate indigenous alternative for emergency weight estimation in diverse PICU settings across India.}, } @article {pmid42574200, year = {2026}, author = {Mirg, S and Elavarasi, A and Das, A and Vibha, D and Singh, RK and Parihar, J and Sharma, MC and Tripathi, M}, title = {Myofibrillar Myopathy with Pyramidal Signs Mimicking Amyotrophic Lateral Sclerosis.}, journal = {Annals of Indian Academy of Neurology}, volume = {29}, number = {4}, pages = {678-680}, pmid = {42574200}, issn = {0972-2327}, } @article {pmid42574250, year = {2026}, author = {Tithi, SS and Cooper-Knock, J and Benatar, M and Wuu, J and Taylor, JP and Wu, G and Chen, W}, title = {CoCoRV-nf: a powerful and cost-effective tool for rare variant analysis leveraging external biobank sequence data identified new candidate predisposition genes in amyotrophic lateral sclerosis and neuroblastoma.}, journal = {Human molecular genetics}, volume = {35}, number = {17}, pages = {}, doi = {10.1093/hmg/ddag076}, pmid = {42574250}, issn = {1460-2083}, support = {R03OD039975/NH/NIH HHS/United States ; U54 NS092091/NH/NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Genetic Predisposition to Disease ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Neuroblastoma/genetics/pathology ; Biological Specimen Banks ; Cost-Benefit Analysis ; Genetic Variation/genetics ; *Software ; Genetic Association Studies ; }, abstract = {Although sequencing costs have steadily decreased with advances in technology, they remain high for large scale studies. The design of traditional individual-disease sequencing studies is either case only or cases with relatively few controls, resulting in potential loss of statistical power for discovery of disease associated genes. Here we show that for a given number of sequenced cases, a large control sample size is critical to maximize power for rare variant burden analysis. Furthermore, we have developed an end-to-end workflow based tool (CoCoRV-nf) to facilitate the use of external biobank sequence resources as controls. The modules include consistent variant QC, variant annotation, ancestry population prediction, and gene based burden analysis using summary genotype information, and combined analysis from multiple independent results. The tool supports exomes and genomes from gnomAD and All of Us as controls with preprocessed datasets. We apply the tool in two rare neurological diseases: amyotrophic lateral sclerosis and neuroblastoma. For each disease, two case cohorts are paired with gnomAD and All of Us data, respectively, followed by a combined analysis. Not only did we recapture known genes, but also, we identified new candidate genes for both diseases. By leveraging multiple large external biobank sequence data, we demonstrate the feasibility of using our tool to maximize statistical power to identify new disease predisposition genes.}, } @article {pmid42574885, year = {2026}, author = {Inan, B}, title = {Comment on "Association of anti-glycolipid IgG with respiratory function decline in amyotrophic lateral sclerosis".}, journal = {Journal of the neurological sciences}, volume = {490}, number = {}, pages = {126131}, doi = {10.1016/j.jns.2026.126131}, pmid = {42574885}, issn = {1878-5883}, } @article {pmid42575772, year = {2026}, author = {Russo, AG and Hawkshaw, MJ and Sataloff, RT}, title = {Voice Disorders as Early Biomarkers of Cognitive Decline.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2026.07.037}, pmid = {42575772}, issn = {1873-4588}, abstract = {BACKGROUND: Dementia affects greater than 57 million people worldwide. With an aging population and limited disease-curing treatments available, early identification of biomarkers is crucial. The 2020 Lancet Commission identified hearing loss as the largest modifiable risk factor for dementia globally, and a randomized controlled trial found that hearing intervention reduced 3-year cognitive change in older adults who were at increased risk for cognitive decline. Similarly, studies have found that abnormalities in acoustic measures of voice are correlated with cognitive status and can potentially predict decline. The association between hearing loss and cognitive decline might have both social and neurological mechanisms. Dysphonia might pose similar problems. Socially, voice disorders may reduce engagement in social and cognitively stimulating activities. Neurologically, one example is in Parkinson's disease in which the vagus nerve is one of the earliest sites of Lewy body pathology in Braak staging, and dysphonia and dysarthria can precede motor symptoms by years. Voice changes have been associated with different neurological conditions such as amyotrophic lateral sclerosis, multiple system atrophy, and Alzheimer's disease. Despite this, no prior large-scale study has examined whether diagnosed voice disorders are associated independently with incident cognitive decline. Our study is the first to examine this potential association, using the TriNetX US Collaborative Health Network platform to compare patients with diagnosed voice disorders and matched controls, with a hearing loss cohort as a standard of comparison given that it is the largest established modifiable risk factor for dementia, as dysphonia is also a modifiable condition.

RESULTS: This study included 833,417 total patients in the voice disorders and control cohorts. Voice disorders were associated with a significantly elevated risk of incident cognitive decline compared to controls (HR=1.291, 95% CI 1.155-1.443, P<0.0001). Hearing loss alone was associated with a slightly lower risk of cognitive decline (HR=1.267, 95% CI 1.203-1.334, P<0.0001). Voice disorders without concurrent hearing loss were associated with an elevated risk of incident cognitive decline compared to hearing loss alone (HR=1.261, 95% CI 1.121-1.419, P=0.0001), while voice disorders with hearing loss were associated with the highest risk among all cohorts (HR=2.038 vs controls; HR=1.545 vs hearing loss). Both voice disorder subgroups did not differ when compared with each other (HR=1.088, P=0.376).

CONCLUSION: The results from our study indicate that voice disorders are associated with an elevated risk of incident cognitive decline and may represent a stronger early biomarker than hearing loss alone. These findings highlight otolaryngology and family medicine/internal medicine encounters as potential entry points for cognitive assessment, and early voice treatment needs to be investigated for possible beneficial cognitive effect.}, } @article {pmid42576069, year = {2026}, author = {Saleem, M and Khan, MS and Syed Khaja, AS and Alraey, Y and Ahmad, I and Almuzaini, Y and AlShammari, A and Alshamamri, YM and Alharbi, T}, title = {Prevalence, antifungal susceptibility, and virulence determinants of Candida species causing vulvovaginal candidiasis in pregnant women in Saudi Arabia.}, journal = {Antonie van Leeuwenhoek}, volume = {119}, number = {9}, pages = {}, pmid = {42576069}, issn = {1572-9699}, support = {RGP.01/146/46//the Deanship of Research and Graduate Studies at King Khalid University/ ; }, mesh = {Humans ; Female ; *Candidiasis, Vulvovaginal/epidemiology/microbiology/drug therapy ; Saudi Arabia/epidemiology ; *Antifungal Agents/pharmacology ; Pregnancy ; Prevalence ; *Virulence Factors/genetics ; Microbial Sensitivity Tests ; *Candida/drug effects/pathogenicity/genetics/classification/isolation & purification ; Adult ; Young Adult ; Adolescent ; *Pregnancy Complications, Infectious/microbiology/epidemiology ; Drug Resistance, Fungal ; Virulence ; }, abstract = {Vulvovaginal candidiasis (VVC) is a common opportunistic fungal infection of the female genital tract, primarily associated with Candida overgrowth influenced by host factors, hormonal changes, microbial imbalance, and environmental conditions. This study examined the prevalence, antifungal susceptibility, and virulence factors of Candida species in 440 pregnant women (ages 18-55) with vulvovaginitis and vaginal discharge at a Saudi Arabian hospital. The study was conducted from March 2022 to February 2023 at a tertiary hospital in Hail, Saudi Arabia, including 440 pregnant women with vaginitis. Vaginal swabs were cultured for Candida, with species identification and antifungal susceptibility testing performed using the Vitek-2 Compact system against five antifungals. Multiplex PCR was used to detect virulence genes (Hwp, Als, Sap, Hlp). Among them, 114 (25.9%) tested positive for Candida species, with Candida albicans being most prevalent (42.1%), followed by C. glabrata (19.3%) and C. tropicalis (12.3%). Most cases occurred during the second trimester (67%), with an average age of 27 years. Antifungal susceptibility testing showed that nystatin exhibited 49.1% susceptibility, 19.3% susceptible-dose dependence (SDD), and 31.6% resistance. Clotrimazole demonstrated 40.4% susceptibility, 26.3% SDD, and 33.3% resistance. Itraconazole showed 50.9% susceptibility, 28% SDD, and 21.1% resistance. Fluconazole exhibited 43.8% susceptibility, 8.8% SDD, and the highest resistance rate (47.4%). Voriconazole was the most effective antifungal agent, with 93% susceptibility, 3.5% SDD, and 3.5% resistance. Virulence analysis showed C. albicans had high Hwp (91.7%) and Sap (54.2%) gene detection, while C. glabrata and C. tropicalis exhibited elevated Hlp and Als levels, respectively. This study highlights the high prevalence of VVC in the second trimester and emphasizes the importance of virulence factors in pathogenicity. Voriconazole emerges as the most effective treatment, emphasizing the need for targeted diagnostics and therapies.}, } @article {pmid42576087, year = {2026}, author = {Oyedokun, PA and Gbadero, JO and Ajao, DI and Olorunsesan, MD and Oyesiji, AI and Ayilara, GO and Ogunsina, MK and Justus, BS and Ademola, FM and Adetunji, EA and Okodio, PS and Amedu, NO}, title = {The Amino Acid-Neurodegeneration Axis: Excitotoxicity and Oxidative Stress as Context-Dependent Amplifiers of Metabolic Dysfunction.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42576087}, issn = {1559-1182}, mesh = {*Oxidative Stress/physiology ; Humans ; Animals ; *Amino Acids/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Nerve Degeneration/metabolism/pathology ; Mitochondria/metabolism ; }, abstract = {Homeostasis of amino acids is essential for the integrity of the CNS, and is maintained by a tightly regulated transport and metabolic circuit that ensures efficient neurotransmission, mitochondrial bioenergetics and redox homeostasis. Disruption of this equilibrium is associated with the pathogenesis of the major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Excessive glutamatergic stimulation and impaired glycine or homocysteine metabolism result in pathological Ca[2][+] influx, loss of mitochondrial membrane potential and production of reactive oxygen species, which are hallmarks of these disorders. It also limits cysteine availability and causes glutathione depletion, which affects antioxidant defence, and disrupts tryptophan-kynurenine metabolism, further affecting neurotoxic and neuroprotective signalling. Though there are disease-specific molecular triggers, the convergent pathogenesis of metabolic disruption makes neurons susceptible to disease. The convergent pathways link amino acid dysregulation to the reinforcement of each other's mechanisms of excitotoxicity, oxidative stress, mitochondrial dysfunction, and protein aggregation. Correcting the amino acid balance has clear translational potential for developing new therapies, such as glutathione augmentation, modulation of NMDA receptors, targeting of transporters, and regulation of metabolic enzymes. In addition, the use of metabolic biomarkers alongside neuroprotective endpoints in clinical trials could improve detection rates, patient stratification, and therapeutic precision. The concept of amino acid metabolism as a mechanism of neurodegeneration, therefore, provides a systems-level perspective and targets potential areas for continued neuroprotection and disease modification.}, } @article {pmid42576199, year = {2026}, author = {Zheng, F and Guan, R and Yu, X and Yang, J and Zhao, H and Yang, F}, title = {ADAR-mediated RNA editing in CNS disorders: from pathogenic mechanisms to therapeutic opportunities.}, journal = {Cellular & molecular biology letters}, volume = {31}, number = {1}, pages = {}, pmid = {42576199}, issn = {1689-1392}, mesh = {Humans ; *RNA Editing/genetics ; *Adenosine Deaminase/metabolism/genetics ; *Central Nervous System Diseases/genetics/therapy/pathology/metabolism ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; }, abstract = {The adenosine deaminases acting on RNA (ADAR) family of enzymes (ADAR1 and ADAR2) catalyze adenosine-to-inosine (A-to-I) RNA editing. This post-transcriptional change is remarkably prevalent in the central nervous system (CNS). ADAR-mediated editing is critical for proper brain development, synaptic plasticity, and immunological homeostasis in the central nervous system (CNS) via recoding neurotransmitter receptors and ion channels. Conversely, a wide range of CNS disorders, such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis), neuropsychiatric conditions (schizophrenia, bipolar disorder, and major depression), cerebrovascular diseases, and gliomas, are now linked to dysregulation of ADAR activity, whether through loss-of-function mutations, altered expression, or mislocalization. To address the main question of whether altered RNA editing is a fundamental driver of pathogenesis, a compensatory response, or a context-dependent modulator, this review critically synthesizes existing evidence. The basic processes of ADAR enzymes and their regulation throughout neurodevelopment are first described. Next, we thoroughly assess the unique molecular fingerprints of ADAR dysregulation across several CNS disorders, emphasizing recurring themes such as Alu RNA hypo-editing, induction of innate immunity, and GRIA2 editing, which can cause excitotoxicity. Lastly, we examine new treatment approaches that use or reinstate ADAR activity, such as small-molecule modulators and site-directed RNA editing tools (leveraging endogenous ADAR for programmable editing of RNA [LEAPER], clustered ADAR-recruiting guide RNAs (gRNAs) for effective RNA editing [CLUSTER], and mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides [MIRROR]). We summarize by reviewing key obstacles to clinical translation, including crossing the blood-brain barrier, the risks of off-target editing, and the challenges of achieving spatiotemporal accuracy. We also list important open topics for further investigation.}, } @article {pmid42576610, year = {2026}, author = {Yang, Y and Yang, Y and Tang, Y and Yang, W}, title = {Myokines, Microbiota, and Neuroinflammation: Physical Activity Modulates the Gut-Brain Axis.}, journal = {Immunological investigations}, volume = {}, number = {}, pages = {1-28}, doi = {10.1080/08820139.2026.2689670}, pmid = {42576610}, issn = {1532-4311}, abstract = {BACKGROUND: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are increasingly recognized as disorders influenced not only by intrinsic neural pathology but also by systemic physiological networks, including the gut-brain axis. Emerging evidence highlights physical activity as a potent modulator of this bidirectional communication system, with muscle-derived signals particularly myokines, metabolites, and extracellular vesicles playing a central role.

METHODS: This narrative review synthesizes current knowledge on how exercise-induced molecular mediators influence gut microbiota composition, intestinal barrier integrity, immune signaling, and neuroinflammatory pathways. Findings were integrated across the disciplines of neuroscience, microbiology, and exercise physiology to evaluate mechanistic links between muscle-secreted factors and gut-mediated responses.

RESULTS: Mechanistic links exist between muscle-secreted factors such as irisin, cathepsin B, BDNF-inducing pathways, and lactate with microbial metabolites including short-chain fatty acids. These interacting pathways demonstrate a combined impact on neuroprotection, synaptic plasticity, and the modulation of disease progression in neurodegenerative conditions.

CONCLUSION: Physical activity represents a promising non-pharmacological strategy for modulating the gut-brain axis in neurodegenerative conditions. Understanding the interplay between muscle-derived signals and gut-mediated pathways may open new avenues for targeted interventions aimed at slowing or preventing neurodegenerative decline.}, } @article {pmid42578424, year = {2026}, author = {Shen, D and Yang, X and Zhang, K and Liu, S and Sun, X and Li, J and Cai, Z and Liu, M and Zhang, X and Liu, Q and Cui, L}, title = {Clinical and genetic characteristics of 536 young-onset amyotrophic lateral sclerosis in China: a single-center retrospective study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2712723}, pmid = {42578424}, issn = {2167-9223}, abstract = {Objective: Young-onset amyotrophic lateral sclerosis (ALS), defined as symptom onset at or before 45 years, remains poorly characterized in Chinese patients. We aimed to describe its clinical and genetic features and compare them with adult-onset ALS. Methods: We retrospectively analyzed 536 young-onset ALS patients registered at Peking Union Medical College Hospital (2014-2022) alongside 1136 adult-onset patients (onset >45 years). Whole exome sequencing targeting 41 established ALS-related genes was performed in all young-onset patients. Results: Young-onset ALS accounted for 32.0% of the cohort, with a median onset age of 39.5 years (IQR 34.25-44.0). Compared with adult-onset patients, young-onset cases had less bulbar onset (14.2% vs. 19.5%, p = 0.008), more frequent predominant upper motor neuron phenotype (25.9% vs. 15.4%, p < 0.001), higher baseline ALSFRS-R scores (p < 0.001), slower progression (p = 0.001), and longer median survival (36 vs. 30 months, p = 0.009). Familial ALS was more common in the young-onset group (8.4% vs. 3.8%, p < 0.001). Rare variants were identified in 20.0% of young-onset patients across 32 genes; pathogenic or likely pathogenic variants were predominantly in SOD1 and FUS. Compared with adult-onset patients, SOD1 was proportionally more common in adult-onset disease, whereas FUS variants were markedly enriched among young-onset cases, suggesting age-dependent differences in genetic architecture. Conclusion: Young-onset ALS in China is characterized by a slower clinical course and a distinct genetic profile dominated by SOD1 and FUS, with near-absent C9orf72 expansions. Routine genetic testing and age-stratified trial design are warranted in this population.}, } @article {pmid42579090, year = {2026}, author = {Filippi, L and Nuvoli, S and Spanu, A and Palumbo, B}, title = {Mapping the Synaptome in Neurodegeneration: Emerging Clinical Applications of SV2A PET Imaging.}, journal = {Molecular diagnosis & therapy}, volume = {}, number = {}, pages = {}, pmid = {42579090}, issn = {1179-2000}, support = {Ricerca Corrente//Ministero della Salute/ ; }, abstract = {Synaptic loss is a core pathological feature of neurodegenerative disorders and closely relates to cognitive and functional decline. Positron emission tomography (PET) targeting synaptic vesicle glycoprotein 2A (SV2A) has recently emerged as a promising tool for the indirect assessment of presynaptic alterations in the living human brain. This leading article discusses the evolving clinical landscape of SV2A PET across the neurodegenerative spectrum, emphasizing its translational trajectory and emerging applications. Current evidence spans Alzheimer's disease (AD), other dementias, movement disorders, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The literature is currently dominated by PET with [[11]C]UCB-J, while [[18]F]-labeled tracers, particularly [[18]F]SynVesT-1, are expanding clinical feasibility through longer half-life and broader distribution potential. Across disorders, PET consistently detected SV2A reductions that frequently correlated with cognition, disease severity, and complementary biomarkers, including amyloid, tau, glucose metabolism, and dopaminergic imaging. Although the field remains limited by small cohorts, heterogeneous quantification strategies, and incomplete longitudinal validation, SV2A PET is rapidly evolving into a promising translational tool for studying synaptopathies and monitoring disease progression.}, } @article {pmid42580389, year = {2026}, author = {Bu, J and Nie, X and Luo, H and Wang, J and Jiang, D and Xu, N and Zhuang, P and Zhang, Y and Yin, Q}, title = {Neuron-derived neuroinflammation in neurodegenerative diseases: Mechanisms and intervention prospects.}, journal = {Pharmacological research}, volume = {231}, number = {}, pages = {108383}, doi = {10.1016/j.phrs.2026.108383}, pmid = {42580389}, issn = {1096-1186}, mesh = {Humans ; Animals ; *Neurodegenerative Diseases/immunology/drug therapy/pathology ; *Neurons/immunology/drug effects/pathology ; *Neuroinflammatory Diseases/immunology/drug therapy/pathology ; Brain/immunology/pathology/drug effects ; Neuroglia/immunology ; }, abstract = {Neurodegenerative diseases represent a major global public health challenge, imposing substantial societal and economic burdens. Their complex pathogenesis and limited therapeutic options underscore an urgent need for new paradigms. Emerging evidence indicates that dysregulation of the brain's immune microenvironment is a critical driver of disease progression. Conventional wisdom posits that peripheral immune cells and central glial cells serve as the primary initiators of neuroimmune responses, whereas neurons are regarded merely as passive recipients of inflammatory damage. Emerging evidence suggests that upon receiving pathological signals in the central nervous system, neurons may become more vulnerable and participate in the onset of neuroimmune processes, positioning them as potential targets for early intervention in neurodegenerative diseases. This article systematically reviews the contribution of neuron-derived immune-inflammatory responses in neurodegenerative diseases and potential intervention strategies. We first outline the capacity of neurons to regulate neuroimmune responses and detail the underlying molecular mechanisms. Then we compare the specific mechanisms by which neurons with different susceptibility drive and amplify neuroinflammation in various neurodegenerative diseases such as alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, vascular cognitive impairment, and transformed these mechanisms into intervention strategies targeting neurons. This article aims to break through the traditional concept of passive neuronal damage, systematically integrate intervention strategies that shift from targeting peripheral immune and glial cells to regulating neuron-derived immunity, thereby providing a new theoretical framework for overcoming current clinical limitations and identifying effective therapeutic targets for the prevention and treatment of neurodegenerative diseases.}, } @article {pmid42580558, year = {2026}, author = {Armoundas, AA and Piperi, C}, title = {Epigenetic drift and LINE-1 activation in aging brain: Implications for neurodegenerative disease.}, journal = {Mechanisms of ageing and development}, volume = {233}, number = {}, pages = {112235}, doi = {10.1016/j.mad.2026.112235}, pmid = {42580558}, issn = {1872-6216}, mesh = {Humans ; *Long Interspersed Nucleotide Elements ; *Epigenesis, Genetic ; *Aging/genetics/metabolism/pathology ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Brain/metabolism/pathology ; *DNA Methylation ; Animals ; }, abstract = {Brain aging and age-associated neurological diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS), are largely attributed to epigenetic drift which is characterized by the gradual accumulation of alterations in neural cell methylation patterns over time. These methylation changes are particularly evident in transposable element (TE)-derived sequences such as Long interspersed element-1 (LINE-1) which comprises approximately 17% of the human genome. During aging, LINE-1 elements gradually lose their methylation, as well as the regulatory safeguard mechanisms that usually keep them inactive. This repression loss can lead to LINE-1 reactivation, contributing to harmful effects including genomic instability, neuroinflammation, and more. Together these findings indicate that impaired epigenetic maintenance, especially in repetitive genome regions, plays a key role in biological aging of neurons and glial cells. In this narrative review, we discuss the methylation dynamics and regulatory mechanisms of LINE-1 retrotransposons, their activation processes during aging, and contribution to age-associated neurological diseases. We also highlight the potential of targeting LINE-1 methylation to restore methylation homeostasis, epigenetic stability and delay brain aging.}, } @article {pmid42580784, year = {2026}, author = {Souza, HJBC and Souza, KM and Dos Santos, MB and Silva, MAP and Grassi, TF and Destro, MV and Braz, MG}, title = {Evaluation of genetic instability in patients with amyotrophic lateral sclerosis.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {913}, number = {}, pages = {503953}, doi = {10.1016/j.mrgentox.2026.503953}, pmid = {42580784}, issn = {1879-3592}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Female ; Male ; Case-Control Studies ; Middle Aged ; *Genomic Instability ; Mouth Mucosa/pathology ; Micronucleus Tests ; Aged ; Chromosomal Instability ; Micronuclei, Chromosome-Defective ; }, abstract = {Genetic instability has been reported in several neurodegenerative diseases, such as Alzheimer's and Parkinson's, but only a few studies have addressed sclerosis. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Micronuclei (MNi) and nuclear buds (NBUDs) are established markers of chromosomal instability, yet no data are available regarding a possible link between genetic instability and ALS. The novelty of this case-control study lies in the assessment of genetic instability in oral exfoliated cells from ALS patients (n = 20) and matched controls (n = 20), contributing to the identification of potential novel markers related to the molecular pathogenesis of this severe disorder. Groups were matched for age, sex, and lifestyle (p > 0.05). No significant differences were observed in MNi or NBUD frequencies between groups (p > 0.05). These findings suggest no association between ALS and MN/NBUD frequencies in oral cells.}, } @article {pmid42580829, year = {2026}, author = {Gaube, LM and Sparks, ED and Iten, M and Knapp, J and Fürholz, M and Schefold, JC and Hunziker Munsch, L and Hänggi, M and Krummrey, G and Müller, M and Hautz, WE}, title = {In-hospital cardiopulmonary resuscitation with balloon occlusion of the descending aorta: protocol of the randomised controlled CPReboa study.}, journal = {BMJ open}, volume = {16}, number = {8}, pages = {e119691}, pmid = {42580829}, issn = {2044-6055}, mesh = {Humans ; *Aorta, Thoracic ; *Balloon Occlusion/methods ; *Cardiopulmonary Resuscitation/methods ; *Heart Arrest/therapy/mortality ; Prospective Studies ; Randomized Controlled Trials as Topic ; Return of Spontaneous Circulation ; }, abstract = {INTRODUCTION: Cardiac arrest (CA) remains a major health burden with poor survival and poor neurological outcomes despite decades of advances in resuscitation science. Although high-quality cardiopulmonary resuscitation is essential, it provides only limited cerebral and coronary perfusion, and current strategies relying on high-dose epinephrine may adversely affect cerebral microcirculation. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has emerged as a potential adjunct to improve coronary and cerebral perfusion without compromising microvascular blood flow. Although animal studies and small human case series suggest physiological and clinical benefits of REBOA in CA, randomised clinical trials are lacking.

METHODS AND ANALYSIS: This prospective, randomised controlled, single-centre clinical trial investigates the effect of REBOA during the treatment of CA. The planned study duration is 36 months, with a total of 98 patients to be randomised to either standard advanced life support (ALS) or ALS plus REBOA. Adult patients with an in-hospital CA, successful placement of a femoral artery introducer sheath and any electrical cardiac activity in the initial rhythm analysis are eligible for inclusion. Exclusion criteria comprise traumatic CA, asystole as the initial rhythm, pregnancy and CA occurring on intensive care units, in the operating room or in cardiac catheter laboratory. The primary outcome is sustained return of spontaneous circulation lasting for at least 20 min. Secondary and exploratory outcomes include survival, neurological outcome, changes in aortic blood pressure, end-tidal CO₂ and near-infrared spectroscopy values as well as causes of death and vascular complications related to the intervention. Statistical analyses will be performed on a modified intention-to-treat basis.

ETHICS AND DISSEMINATION: The study protocol (Version 2.1, 11.02.2026) was approved by the Cantonal Ethics Committee of Cantone Bern (2025-D0108). Study results will be disseminated through peer-reviewed journals.

TRIAL REGISTRATION NUMBER: NCT07434726.}, } @article {pmid42581113, year = {2026}, author = {Jomova, K and Alomar, SY and Valko, R and Nepovimova, E and Kuca, K and Valko, M}, title = {Oxidative stress and inflammation in neurodegenerative disorders.}, journal = {Archives of toxicology}, volume = {100}, number = {10}, pages = {4367-4445}, pmid = {42581113}, issn = {1432-0738}, mesh = {Humans ; *Oxidative Stress/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism/physiopathology/pathology ; Animals ; Antioxidants/administration & dosage ; *Inflammation/metabolism/drug therapy ; Reactive Oxygen Species/metabolism ; Brain/metabolism ; }, abstract = {The brain's consumption of approximately 20% of the body's oxygen contributes to oxidative stress, a significant pathological factor in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This oxidative stress, linked to low levels of antioxidant enzymes, drives neuronal death by facilitating membrane peroxidation of fatty acids, proteins, and DNA. Alzheimer's disease is characterized by amyloid-beta (Aβ) plaque accumulation and hyperphosphorylated tau aggregates, both of which interact with mitochondria to generate reactive oxygen species (ROS). Aβ peptides bind metals such as iron and copper, catalyzing the formation of damaging hydroxyl radicals. Peripheral markers of oxidative damage, such as elevated malondialdehyde and protein carbonyls, are correlated with these processes in affected patients. In Parkinson's disease, the loss of dopaminergic neurons in the substantia nigra is associated with pathological iron accumulation and mitochondrial complex I dysfunction, which are worsened by misfolded α-synuclein and mutations in antioxidant genes such as PINK1 and Parkin. The autooxidation of dopamine also drives oxidative stress through the generation of hydrogen peroxide and reactive quinones. Huntington's disease involves the degeneration of medium spiny neurons in the striatum due to a polyglutamine repeat expansion in the huntingtin gene, which disrupts mitochondrial function and downregulates antioxidants, leading to excitotoxicity and ROS spikes. Amyotrophic lateral sclerosis primarily affects motor neurons due to the mutations in SOD1, which result in the production of aggregates that impair mitochondria and generate reactive nitrogen species (RNS), such as peroxynitrite. Mitigating oxidative stress in neurodegenerative disorders presents a considerable translational challenge. While low-molecular-weight antioxidant therapies for neurodegenerative disorders have shown promising results in preclinical and animal studies because they mitigate oxidative stress, their clinical efficacy is hampered by low bioavailability and difficulty in penetrating the blood‒brain barrier. To overcome these limitations, current medical research is focused on alternative delivery systems. Innovations such as nanoparticle-based drug delivery are being actively studied to help transport low-molecular-weight antioxidants across the blood‒brain barrier more safely and effectively. Several promising epidemiological trials linked high dietary intake of vitamins C and E to a reduced risk of Parkinson's disease, and plant-derived antioxidants such as polyphenols were explored for their ability to combat neuroinflammation and reduce cognitive decline. Refined oxidative stress-suppressing strategies involve the (ii) application of mitochondrial-targeted agents to preserve ATP production; (ii) boosting the Nrf2 pathway may trigger a cascade of detoxifying enzymes; (iii) supplementation with polyphenols such as quercetin, resveratrol, and curcumin can suppress oxidative stress and dampen microglial activation (neuroinflammation); (iv) and the use of substances affecting the bidirectional network linking oxidative stress and autophagy can clear ROS-generating components. Despite some promising epidemiological data, translating oral or systemic antioxidant therapy into effective clinical treatments for humans requires further effort. A survey of current knowledge of oxidative stress and antioxidant therapy in neurodegenerative diseases is the main subject of this review.}, } @article {pmid42581131, year = {2026}, author = {Rahim, A and Zubair, SM and Ahamed, M and Das, S and Patel, R and Debnath, B and Porel, P}, title = {cGAS-STING as a Neuroimmune Traffic Molecule: Unraveling Pathogenic Mechanisms and Therapeutic Potential in Neurological Disorders.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {21}, number = {1}, pages = {}, pmid = {42581131}, issn = {1557-1904}, mesh = {Humans ; cGAS-STING Signaling Pathway ; Animals ; *Nucleotidyltransferases/metabolism/immunology ; *Membrane Proteins/metabolism/immunology ; *Nervous System Diseases/immunology/metabolism/drug therapy ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; Signal Transduction ; }, abstract = {The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an essential cytosolic DNA-sensing system that plays an important role in the regulation of innate immune and inflammatory responses in the central nervous system (CNS). It was first discovered as a promising antiviral defense cascade and has since been shown to execute broader functions in neuroinflammation and neurodegeneration. The pathway can become hyperactive with the release of endogenous DNA from damaged nuclei, mitochondria, or genomic instability, leading to chronic production of type I interferon (TI-IFN), various pro-inflammatory cytokines, and eventually contributing to chronic neuroinflammatory diseases. Recent studies have found that dysregulated cGAS-STING signaling is associated with several neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), stroke, and age-related neurodegeneration. In the CNS, chronic activation of this pathway leads to activation of microglia, oxidative stress, breakdown of the blood-brain barrier (BBB), impaired function of the synapses, and neuronal death. Mitochondrial dysfunction and cytosolic release of mitochondrial DNA (mtDNA) further promote inflammatory signaling, thus perpetuating neurodegeneration. This review highlights the molecular and pathological mechanisms of cGAS-STING signaling in a broader aspect of neurological disorders and appraises the novel therapeutics already under development to inhibit this pathway to regulate neuroinflammation and enhance neurological outcomes.}, } @article {pmid42581247, year = {2026}, author = {Zhang, X and Zhang, L and Chen, L and Yu, W and Zhao, Y and Huang, Y and Xu, Z}, title = {LXR Pathway Activation by T0901317: A Novel Potential Experimental Strategy for ALS-Related Cognitive and Motor Impairments via Suppression of Necroptosis-associated RIPK1/RIPK3/MLKL Markers.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42581247}, issn = {1559-1182}, mesh = {Animals ; *Liver X Receptors/metabolism/agonists ; *Sulfonamides/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/metabolism/complications/drug therapy/physiopathology ; Fluorocarbons ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Benzenesulfonamides ; Mice, Transgenic ; *Hydrocarbons, Fluorinated/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; Humans ; *Necroptosis/drug effects ; *Cognitive Dysfunction/drug therapy/metabolism/complications ; DNA-Binding Proteins/metabolism ; Biomarkers/metabolism ; Male ; Mice ; Motor Neurons/metabolism/drug effects/pathology ; }, abstract = {To investigate the effects and mechanism of a synthetic LXR agonist, T0901317, on neuronal necroptosis-related signaling pathways in NSC-34 mouse neuronal cells transfected with the TDP-43-A315T plasmid, TDP-43-A315T transgenic mice of amyotrophic lateral sclerosis (ALS). SWATH proteinomics analysis was used to compare ALS patients with cognitive impairment (CI) and non-cognitive impairment (NOCI). TDP-43 abnormal aggregation and necroptosis-related protein expression were assessed with immunofluorescence and western blotting, while apoptosis and inflammatory cytokines were measured through TUNEL assay and ELISA, muscle and motor neuron degeneration were examined with H&E and Toluidine Blue staining. Additionally, the Y-maze and Rotarod tests were used to evaluate cognitive and motor functions. Our study indicates that the LXR pathway was more downregulated in the ALS patients with cognitive impairment. RIPK1, p-RIPK3, and p-MLKL protein levels were upregulated in the TDP-43-A315T plasmid-transfected neuron cells and the TDP-43-A315T transgenic mouse model. The LXR agonist T0901317 reduced the abnormal aggregation of TDP-43 protein and downregulated the protein levels of RIPK1, p-RIPK3, and p-MLKL in vivo and in vitro. Furthermore, T0901317 attenuated motor neuron death and ameliorated muscle degeneration in TDP-43-A315T mice. T0901317 significantly prolonged survival, ameliorated cognitive and motor deficits, and shifted microglial activation marker profiles. The beneficial effects of T0901317 were abolished by LXR antagonist GSK 2033, accompanied by upregulation of necroptotic signaling. The neuroprotective effects of activating LXR may involve the regulation of the RIPK1-RIPK3-MLKL axis and TDP-43 aggregation.}, } @article {pmid42581415, year = {2026}, author = {Goehring, K and Abler, E and Vavra, J and Mayer, K and Dorst, J and Elmas, Z and Wiesenfarth, M and Richter, L and Petri, S and Regensburger, M and Reilich, P and Bjelica, B and Lumi, R and Süß, P and Tumani, H and Otto, M and Weishaupt, JH and Ludolph, AC and Oeckl, P}, title = {Blood SOD1 Activity in ALS Patients Receiving Tofersen Treatment.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78328}, pmid = {42581415}, issn = {1531-8249}, abstract = {OBJECTIVE: The antisense oligonucleotide tofersen is the first disease-modifying drug for SOD1-related amyotrophic lateral sclerosis (ALS) and was approved because of its ability to reduce SOD1 protein and neurofilament levels. The effect of tofersen on SOD1 activity is unclear but of clinical relevance because homozygous SOD1 mutations, linked to reduced SOD1 activity, cause severe motor neuron impairment and tofersen-induced reduction could be deleterious. Therefore, monitoring of SOD1 activity is urgently needed.

METHODS: SOD1 activity was analyzed in blood samples from a discovery (n = 120) and a validation cohort (n = 208), including controls, patients with sporadic ALS (sALS), C9orf72 mutation carriers (c9ALS), asymptomatic (SOD1-asym), and symptomatic SOD1 mutation carriers (SOD1-ALS). SOD1 activity was characterized in 18 patients receiving tofersen treatment.

RESULTS: SOD1 activity was significantly lower in both SOD1-asym (median = 7.5 U/mg, interquartile range [IQR] = 7.0-9.0 U/mg) and SOD1-ALS (median = 7.9 U/mg, IQR = 7.1-9.1 U/mg) relative to controls (median = 9.2 U/mg, IQR = 8.9-10.0 U/mg, p < 0.0001), c9ALS (median = 9.4 U/mg, IQR = 8.9-10.2 U/mg, p < 0.0001) and sALS (median 9.5 U/mg, IQR 8.8-9.9 U/mg, p < 0.0001). SOD1 activity was significantly lower in individuals with deleterious SOD1 variants than in individuals with neutral variants. During tofersen treatment, neurofilament and SOD1 protein levels decreased, whereas SOD1 activity remained stable.

INTERPRETATION: The data indicate that the positive tofersen treatment effect is independent of SOD1 activity. Lower SOD1 activity is specific to SOD1-ALS, already present in the asymptomatic phase and depends on the mutation type. Future studies should determine whether tofersen treatment affects cerebrospinal fluid (CSF) SOD1 activity. ANN NEUROL 2026.}, } @article {pmid42581651, year = {2026}, author = {Vinceti, M and Till, C and Goodman, PJ and Filippini, T and Rothman, KJ and Thompson, IM}, title = {The selenium and vitamin E cancer prevention trial (SELECT): a secondary, post-intervention analysis on potential excess chronic disease incidence induced by selenium administration.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwag189}, pmid = {42581651}, issn = {1476-6256}, abstract = {The potential for trace amounts of selenium supplements to prevent prostate cancer and other neoplasms was studied in SELECT, a randomized trial conducted in North America for 7-12 years. 34 887 eligible men age 55 or older were assigned to take either 200 μg selenium from L-selenomethionine, 400 IU vitamin E, both selenium and vitamin E, or placebo. The trial was stopped for futility and concerns about adverse effects. Subsequently, we used incidence and mortality data from Medicare through 2019 and the National Death Index through 2024 to investigate the extent to which selenium administration was associated with increased long-term risk of cancer and neurodegenerative disease, during 341 697 person-years of follow-up. Lung cancer showed little increased risk. Associations were near null for leukemia, non-Hodgkin lymphoma and Parkinson's disease, and there was a lower risk for melanoma and colorectal cancer. In contrast, we found a higher risk for Hodgkin lymphoma, multiple myeloma and amyotrophic lateral sclerosis, which has been associated with selenium overexposure in some nonexperimental studies. Though these latter associations were based on few cases, they were consistent with findings from a range of other studies, possibly indicating long-term adverse effects of this organic selenium compound. (Registration no. NCT00006392).}, } @article {pmid42583247, year = {2026}, author = {Klyk, C and Wohnrade, C and Petri, S and Haghikia, A and Körner, S and Volk, LH}, title = {Gold coast criteria but not neurofilaments improve diagnostic sensitivity in a specialized ALS university center.}, journal = {Clinical neurophysiology practice}, volume = {11}, number = {}, pages = {512-521}, pmid = {42583247}, issn = {2467-981X}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by upper and lower motor neuron loss. Diagnosing ALS may still be challenging due to the absence of specific biomarkers and requires thorough clinical evaluation, comprehensive electromyography (EMG), and exclusion of differential diagnoses by laboratory analyses and imaging. The Gold Coast criteria (GCC) replaced the revised El Escorial (rEEC) and Awaji criteria (AC), simplifying ALS diagnosis and standardizing communication with patients.

METHODS: This retrospective study compared the sensitivity of the GCC with the rEEC and AC in a specialized neuromuscular center.

RESULTS: 431 patients with suspected ALS were included, and 426 patients ultimately received an ALS diagnosis. The GCC showed higher sensitivity than both the rEEC and AC. The explorative inclusion of neurofilament levels into an extended diagnostic framework did not increase the sensitivity of rEEC and AC.

CONCLUSIONS: Continued clinical use of the GCC should be considered the standard for ALS diagnosis. Careful clinical and electrophysiological examination is particularly essential in this context, supplemented by biomarkers such as neurofilaments.

SIGNIFICANCE: This retrospective real-world study demonstrates a high sensitivity of the GCC in a specialized neuromuscular clinic.}, } @article {pmid42583548, year = {2026}, author = {Suazo, JRP and Piuvezam, G and Pimenta, IDSF and Ferrándiz, LL and Ríos, MP and Castro-Delgado, R}, title = {Effectiveness of extended reality-based cardiopulmonary resuscitation training for healthcare students: A systematic review.}, journal = {Turkish journal of emergency medicine}, volume = {26}, number = {3}, pages = {223-233}, pmid = {42583548}, issn = {2452-2473}, abstract = {BACKGROUND: Cardiopulmonary resuscitation (CPR) is a lifesaving intervention where timely, effective actions improve survival. However, traditional Basic and Advanced Life Support (BLS and ALS) training often lacks realism, limiting preparedness among healthcare students. Extended Reality (XR) technologies, including Virtual, Augmented, and Mixed Reality, offer promising tools to enhance CPR training. The aim is to assess the effects of XR on CPR training outcomes among healthcare students.

METHODOLOGY: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guidelines, PubMed/MEDLINE, EMBASE, CINAHL, Cochrane, Web of Science, and Scopus were searched for randomized controlled trials and quasi-experimental studies. Two reviewers independently extracted data, with disagreements resolved by a third. Risk of bias was evaluated using Cochrane ROB 2 and ROBINS-I. Due to heterogeneity, findings were synthesized narratively.

RESULTS: Eight studies from six countries were included. Evidence showed mixed outcomes: XR improved confidence and reduced anxiety in Basic Life Support and ALS training, but results on technical performance, including CPR knowledge and quality, were inconsistent. Variability in study design and concerns about bias limited generalizability.

CONCLUSION: XR shows potential as a valuable complement to traditional CPR training, particularly in blended learning approaches aligned with modern pedagogy. However, inconsistent findings highlight the need for standardized assessments, evaluation of long-term outcomes, and integration of haptic torso simulators to improve technical skills and clarify XR's role in resuscitation education.}, } @article {pmid42584174, year = {2026}, author = {Wang, BN and Van Der Spek, RAA and Van Nispen Tot Sevenaer, JDAM and Van Vugt, JJFA and Munnik, FA and Bakker, MK and , and Van Es, MA and Van Den Berg, LH and Van Rheenen, W and Veldink, JH and , }, title = {Lessons from a systematic review of family-based studies in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2713969}, pmid = {42584174}, issn = {2167-9223}, abstract = {ALS is genetically heterogeneous, with many causal genes identified through family-based gene-discovery studies. To evaluate this progress, we systematically reviewed these studies and identified unresolved genomic regions across five pedigrees. Reexamination resolved two pedigrees, nominating FUS and SYNE1 as the causal genes. The remaining three pedigrees exhibited linkage to four unresolved regions, which we reanalyzed using large-scale genetic datasets. We found no convincing evidence for new ALS-causing variants in these regions. These unresolved regions originated from complex pedigrees-consanguineous, isolated, or containing only a few affected individuals-whereas successful linkage was observed in larger, multigenerational families with ALS. Our findings confirm that family-based methods are robust in typical ALS pedigrees but lack power in small pedigrees with few affected individuals or in phenotypically heterogeneous families. Given these challenges and the rare-variant architecture of ALS, we propose a 'super-pedigree' framework to identify extended families with ALS to discover shared genetic risk factors and help develop gene-based therapies.}, } @article {pmid42585850, year = {2026}, author = {Alencar, MA and Gonçalves, JMW and D Allembert, D and Rangel, MFA and Gomes, PCF and de Souza, LC}, title = {Falls in people with amyotrophic lateral sclerosis: A prospective study.}, journal = {Brazilian journal of physical therapy}, volume = {30}, number = {5}, pages = {101623}, pmid = {42585850}, issn = {1809-9246}, mesh = {Humans ; *Accidental Falls/statistics & numerical data ; *Amyotrophic Lateral Sclerosis/physiopathology ; Prospective Studies ; Longitudinal Studies ; Muscle Strength/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness. Falls are common and may lead to dependence, reduced quality of life, higher healthcare costs, and death. Few studies have examined falls in ALS.

OBJECTIVES: To investigate the frequency of falls in individuals with ALS with and without functional ambulation, and to identify predictors of falls at three and six months among those with functional ambulation.

METHODS: A longitudinal prospective study included 66 individuals with ALS. Falls were assessed through interviews at three- and six-month follow-ups. Demographic and clinical characteristics, functional capacity, lower limb strength, fatigue, mobility, and balance were assessed. Descriptive, bivariate, and logistic regression analyses were performed.

RESULTS: At baseline, 42 participants were ambulatory and 24 non ambulatory (wheelchair-dependent). Among ambulatory participants, 38 were assessed at three months (18 fallers, 47%) and 37 at six months (22 fallers, 59%). Among non-ambulatory participants, 22 were assessed at three months (4 fallers, 18%) and 20 at six months (2 fallers, 10%). Losses in both groups were due to death. Predictors of falls in the ambulatory group were lower limb strength (Odds Ratio [OR]: 0.844; p = 0.016) and fatigue (OR: 7.800; p = 0.037) at three months, and lower limb strength (OR: 0.856; p = 0.009) at six months.

CONCLUSION: Falls can occur across functional profiles in ALS and are most frequent among ambulatory individuals. These findings highlight the importance of assessing fall risk and considering strategies. In ambulatory participants, interventions focusing on lower limb strength and fatigue may contribute to fall prevention.}, } @article {pmid42586199, year = {2026}, author = {Pecorari, C and Montagna, C and Cozzolino, M and D'Ambrosi, N and Benassi, B and Cirotti, C and Filomeni, G}, title = {Nuclear SOD1 links ATM-CHK2 signaling to ADH5/GSNOR transcription in SHSY-5Y SOD1[G93A] cellular models of ALS.}, journal = {Nitric oxide : biology and chemistry}, volume = {164}, number = {}, pages = {69-74}, doi = {10.1016/j.niox.2026.08.001}, pmid = {42586199}, issn = {1089-8611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Signal Transduction ; *Checkpoint Kinase 2/metabolism ; *Superoxide Dismutase-1/metabolism/genetics ; *Ataxia Telangiectasia Mutated Proteins/metabolism ; *Aldehyde Oxidoreductases/genetics/metabolism ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Transcription, Genetic ; }, abstract = {The activity of S-nitrosoglutathione reductase (ADH5/GSNOR) has been proposed being essential to limit oxidative stress and preserve mitochondrial quality control. Here we identify a redox-dependent ATM-CHK2-SOD1 signaling axis that drives ADH5/GSNOR transcription in SH-SY5Y cells expressing the ALS-associated SOD1[G93A] mutant. ATM-CHK2 activation promotes the interaction of SOD1 with CHK2, leading to SOD1 nuclear translocation and binding to the ADH5 promoter. Pharmacological inhibition of ATM or CHK2 abolishes these effects. ADH5/GSNOR overexpression protects cells from SOD1[G93A]-induced toxicity suggesting that the modulation of GSNOR activity may represent a potential strategy to restore redox homeostasis in ALS.}, } @article {pmid42586267, year = {2026}, author = {Tognaccini, C and Thomas, LE and Ghanim, D and Ghebrial, M and Ansari, Z and Gupta, K and Wu, JJ}, title = {Comment on Chen et al's "Disparities of itch severity in outpatient clinics as measured by the ItchyQuant".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.07.127}, pmid = {42586267}, issn = {1097-6787}, } @article {pmid42586268, year = {2026}, author = {Ghanim, D and Ghebrial, M and Tognaccini, C and Thomas, LE and Ansari, Z and Gupta, K and Wu, JJ}, title = {Comment on Gao et al's "A multicenter, randomized, double-blinded, placebo-controlled phase III trial to evaluate efficacy and safety of picankibart in moderate-to-severe plaque psoriasis".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.06.151}, pmid = {42586268}, issn = {1097-6787}, } @article {pmid42586274, year = {2026}, author = {Shi, Y}, title = {Response to the letter by Ghanim et al, "Comment on Gao et al's 'A multicenter, randomized, double-blinded, placebo-controlled phase III trial to evaluate efficacy and safety of picankibart in moderate-to-severe plaque psoriasis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.08.025}, pmid = {42586274}, issn = {1097-6787}, } @article {pmid42586324, year = {2026}, author = {Palumbo, F and Iazzolino, B and Canosa, A and Manera, U and Vasta, R and Grassano, M and Ilardi, A and Cabras, S and Matteoni, E and Maccabeo, A and Di Pede, F and De Mattei, F and Pellegrino, G and Minerva, E and Riva-Rovedda, F and Clari, M and Zocco, G and Pascariu, D and Testa, M and Arcari, M and Veronese, S and Chiò, A and Moglia, C and Calvo, A}, title = {Advance Care Planning in Amyotrophic Lateral Sclerosis: A Retrospective Population-based Study.}, journal = {Journal of pain and symptom management}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpainsymman.2026.08.002}, pmid = {42586324}, issn = {1873-6513}, abstract = {CONTEXT: In recent decades, autonomy and self-determination in Amyotrophic Lateral Sclerosis (ALS), have gained increasing attention, and Advance Care Planning (ACP) has been incorporated into ALS guidelines. In Italy, Law 219 emphasizes the role of ACP in respecting patients' healthcare preferences. However, longitudinal data on ACP prevalence and impact remain limited.

OBJECTIVES: To assess the prevalence of ACP discussions in a population of ALS patients, their effectiveness in end-of-life management, and the impact of Law 219/2017.

METHODS: Demographic and clinical data from the PARALS Register (2008-2020) were retrospectively examined, with particular focus on ACP discussions, tracheostomy preferences, and end-of-life outcomes.

RESULTS: Of 1219 ALS patients, 655 (53.7%) had ACP discussions, with 90.8% concordance between expressed choices and outcomes. The ACP prevalence increased over time from 51.6% to 61.94% (P = 0.025). Cognitive impairment, including fronto-temporal dementia and intermediate cognitive-behavioral impairment, and absence of NIMV use were negatively associated with ACP (P = 0.029 and P < 0.001). Older age was associated with tracheostomy placement (P < 0.001). ACP discussion was positively associated with gastrostomy placement, Palliative Care activation, and home death.

CONCLUSION: ACP plays a crucial role in ALS care, with high alignment between expressed choices and outcomes. Cognitive impairment reduced ACP participation, highlighting the need for earlier, tailored interventions. The ACP increase over the last decade reflects a growing emphasis on patient autonomy in Italy. Further efforts are needed to expand ACP adoption in ALS care, to support self-determination despite cognitive decline and disease progression.}, } @article {pmid42586601, year = {2026}, author = {Chai, X and Zheng, Z and Wang, N and He, Q and Jia, Y and Wan, K and Zhu, S and Zhang, B and Niu, H and Zhai, Y and Zhao, J and Yang, Y}, title = {Real-world clinical characteristics of motor disorders for personalised brain-computer interfaces: phenotypic insights from a specialised clinic.}, journal = {Stroke and vascular neurology}, volume = {}, number = {}, pages = {}, doi = {10.1136/svn-2026-005290}, pmid = {42586601}, issn = {2059-8696}, abstract = {Motor dysfunction caused by neurological disorders such as stroke, spinal cord injury and amyotrophic lateral sclerosis has become a major global public health issue. Conventional rehabilitation approaches yield limited efficacy, highlighting the urgent need for innovative therapies. Brain-computer interface (BCI) technology offers a promising avenue for motor function restoration by decoding motor intentions and driving external devices or providing sensory feedback. However, current BCI development has predominantly emphasised technical performance metrics, lacking systematic investigation into the clinical characteristics of real-world patient populations. This disconnect between technological advancement and genuine clinical demands persists because existing studies often recruit idealised subjects while neglecting prevalent conditions like stroke and lack standardised assessments of clinically meaningful outcomes. Consequently, system designs frequently fail to align with patient-specific profiles. To address this gap, our study established a prospective BCI evaluation outpatient cohort, comprehensively collecting data from patients presenting with motor dysfunction throughout 2025. Among the total of 1641 patients with motor dysfunction, the majority were patients with chronic-phase stroke (1087, 66.24%). The cohort was primarily middle-aged, with a mean age of 45.93±11.23 years. The study further detailed patterns of muscle strength, joint range of motion and sensory impairments. The goal is to construct the first clinical profile characteristics to inform precise patient selection and guide personalised system design.}, } @article {pmid42586726, year = {2026}, author = {Quasdorf, T and Brenner, S and Kramer, I and Kotkowski, K and Gutenberg, J}, title = {Developing organisational capacity building for person-centred dementia care in nursing homes: a multiphase co-design study protocol.}, journal = {BMJ open}, volume = {16}, number = {8}, pages = {e123820}, pmid = {42586726}, issn = {2044-6055}, mesh = {*Nursing Homes/organization & administration ; Humans ; *Patient-Centered Care/organization & administration ; *Dementia/therapy ; *Capacity Building/organization & administration ; Research Design ; Organizational Culture ; Qualitative Research ; }, abstract = {INTRODUCTION: Person-centred dementia care (PCdC) is widely recognised as a core principle of high-quality dementia care and is embedded in national and international dementia care guidelines. However, translating PCdC into routine practice in nursing homes (NHs) continues to pose a significant challenge. This reflects both the theoretical complexity of PCdC and the fact that its delivery relies less on discrete care techniques and more on an underlying organisational culture and shared approach to care. Implementing PCdC therefore requires an organisational perspective that acknowledges the interplay between staff, leadership and organisational conditions. Although several approaches exist to strengthen organisational capacity for PCdC, NHs often lack guidance on how to identify and apply approaches that fit their specific context. This study aims to develop a toolbox that supports NHs in systematically building the organisational capacity required to implement and sustain PCdC in their specific context.

METHODS AND ANALYSIS: The toolbox will be developed through three consecutive studies:Study 1: An exploratory qualitative study of the perspectives of managers and staff in NHs on organisational capacity building (OCB) for implementing and sustaining PCdC.Study 2: A co-design study involving workshops to develop a first version of the OCB toolbox, informed by insights from a preliminary scoping review (conducted separately and published as a protocol on Open Science Framework) and Study 1.Study 3: A qualitative consensus-building study using a nominal group technique with stakeholders and PCdC experts to refine and finalise the OCB toolbox (validation phase).The toolbox development is conceptualised as the development of a complex intervention and will therefore be informed by O'Cathain et al's guidance for developing complex health interventions. While co-design principles guide the overall development process, Study 2 represents the dedicated co-design phase involving collaborative workshops, ensuring that the resulting OCB toolbox integrates research evidence with practice-based insights.

ETHICS AND DISSEMINATION: The Cantonal Ethics Committee Zurich confirmed that the study is exempt from formal ethical approval under the Swiss Human Research Act (Req-2025-00812). Findings will be disseminated through peer-reviewed publications, conference presentations and practice-oriented outputs, including a toolbox for NHs.}, } @article {pmid42586744, year = {2026}, author = {Shijo, T and Suzuki, N and Warita, H and Ikeda, K and Namioka, Y and Kato, M and Aoki, M}, title = {Emergency Tracheostomy with Invasive Ventilation in Patients with Amyotrophic Lateral Sclerosis Increases Hospitalization Duration and Long-Term Complications.}, journal = {The Tohoku journal of experimental medicine}, volume = {}, number = {}, pages = {}, doi = {10.1620/tjem.2026.J085}, pmid = {42586744}, issn = {1349-3329}, } @article {pmid42587315, year = {2026}, author = {Farghaly, A and Al-Khateeb, LA and Kanaan, BM and Magdy, G and Khashoqji, MM and Tantawy, MA and Abbas, AEF}, title = {Spectrophotometric determination of cefepime and enmetazobactam in pharmaceutical formulations and human plasma using chemometric modeling, metaheuristic wavelength selection, and comprehensive sustainability assessment.}, journal = {BMC chemistry}, volume = {20}, number = {1}, pages = {}, pmid = {42587315}, issn = {2661-801X}, support = {R-2026-XX//Deanship of Postgraduate Studies and Scientific Research, Majma'ah University/ ; }, abstract = {The recently introduced cefepime-enmetazobactam (CEF-ENM) combination requires reliable analytical methods for pharmaceutical quality control and proof-of-concept bioanalytical evaluation. Existing methods are predominantly chromatographic and rely on large volumes of organic solvents, costly instrumentation, and high energy consumption. In this work, a UV spectrophotometric approach integrated with chemometric analysis was established for the simultaneous quantification of CEF and ENM in pharmaceutical formulations and processed post-extraction-fortified human plasma. Calibration samples were prepared according to the Brereton multilevel experimental design, whereas an independent external validation set was constructed using the Maximin Distance Design (MMD) algorithm. The analytical performance of six chemometric models (CLS, PCR, PLS, GA-PLS, FA-PLS, and MCR-ALS) was evaluated to resolve the severe spectral overlap between both analytes. Matrix-specific calibration models were developed for processed plasma samples. The developed models showed excellent analytical performance, with MCR-ALS providing the highest predictive accuracy and robustness. Sustainability was comparatively evaluated using the integrated Multi-color Assessment (MA) Tool together with complementary greenness metrics. The proposed method demonstrated superior overall sustainability compared with previously reported chromatographic methods while maintaining reliable quantitative performance. The proposed approach offers a rapid, cost-effective, and environmentally sustainable alternative for routine pharmaceutical quality control and proof-of-concept evaluation in processed post-extraction-fortified human plasma. Further comprehensive bioanalytical validation is warranted to support routine clinical application.}, } @article {pmid42587774, year = {2026}, author = {Garza, TN and Abisambra, JF}, title = {The Interactions of Tau, RNA, and Stress Granules in Neurodegenerative Disease: A Comprehensive Review.}, journal = {Cells}, volume = {15}, number = {15}, pages = {}, pmid = {42587774}, issn = {2073-4409}, support = {1R01AG075900-04/NH/NIH HHS/United States ; 1R21AG093972-01/NH/NIH HHS/United States ; I50 RX003000/RX/RRD VA/United States ; R21 AG093972/AG/NIA NIH HHS/United States ; 5I50RX003000-07//United States Department of Veterans Affairs/ ; 1R01AG074584-05/NH/NIH HHS/United States ; 5T32AG061892-07/AG/NIA NIH HHS/United States ; T32 AG061892/AG/NIA NIH HHS/United States ; R01 AG074584/AG/NIA NIH HHS/United States ; R21 AG095654/AG/NIA NIH HHS/United States ; R01 AG075900/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *tau Proteins/metabolism ; *Neurodegenerative Diseases/metabolism/genetics/pathology ; *Stress Granules/metabolism ; *RNA/metabolism ; Animals ; RNA-Binding Proteins/metabolism ; }, abstract = {The discovery of RNA in the late 19th century revolutionized the understanding of cell biology. Subsequent discoveries over the next six decades revealed a key role for RNA in protein synthesis. Nevertheless, today, the mechanisms driving RNA metabolism remain enigmatic. Given its fundamental cellular role, RNA alterations are strongly linked to disease, including devastating neurodegenerative disorders pathologically defined by the accumulation of RNA-binding proteins. For example, the mislocalization of TDP-43, an RNA-binding protein, is a pathological feature of amyotrophic lateral sclerosis and frontotemporal dementia TDP-43. Another group of more than 20 neurodegenerative disorders, called tauopathies, is characterized by the aberrant accumulation of the protein tau. Similarly, the emerging concept that tau binds RNA, facilitating the formation of pathological structures, highlights the importance of RNA stability in tauopathies. However, the dynamics and consequences of RNA-tau interactions remain unclear. This review comprehensively catalogs key findings linking tau, RNA, and stress granules. These findings are important because they could offer novel opportunities to design therapeutic strategies.}, } @article {pmid42588274, year = {2026}, author = {Paynter, C and Mathers, S and Vogel, A and Cruice, M}, title = {Foregrounding Communication Access in Person-Centred Decision Making for People with Motor Neurone Disease: A Narrative Review.}, journal = {Healthcare (Basel, Switzerland)}, volume = {14}, number = {15}, pages = {}, pmid = {42588274}, issn = {2227-9032}, support = {1133541//NHMRC/MNDRA Postgraduate Scholarship/ ; FT220100253//Australian Research Council/ ; }, abstract = {Effective motor neurone disease (MND) management depends on patient and carer involvement in decisions about interventions and future care. Communication and cognitive impairments are common in MND and have under-recognised consequences for shared decision making and autonomy. This narrative conceptual review draws on empirical qualitative research with people living with MND and unpaid family carers and the literature specifically concerning shared decision making and communication in MND. Themes relating to communication, information use, and decision making styles were mapped onto an ALS/MND multidisciplinary decision making model. Enhancements to the model include expanding the decision making context beyond in clinical activity, embedding communication and cognitive skills and accommodations across stages, and acknowledging risks to collaborative decision making. Practical strategies for clinicians, healthcare services, people living with MND, and family carers are proposed to ensure that communication is foregrounded in-person-centred MND care. Observational and implementation research is required to evaluate and refine the proposed approaches.}, } @article {pmid42589639, year = {2026}, author = {Wu, Y and Li, L and Tian, J and Liu, L and Du, K and Shao, Z and Cheng, T and Cao, X and Wang, T}, title = {RAN Translation-Coupled Decay of the C9orf72 GGGGCC Repeat Transcript by the RNA Exosome Suppresses Dipeptide Repeat Production.}, journal = {International journal of molecular sciences}, volume = {27}, number = {15}, pages = {}, pmid = {42589639}, issn = {1422-0067}, support = {STI2030-Major Projects-2022ZD0212600//National Science and Technology Innovation 2030 Major Projects of China/ ; 32271000//National Natural Science Foundation of China/ ; 32471008//National Natural Science Foundation of China/ ; 32300796//National Natural Science Foundation of China/ ; 23ZR1413800//Natural Science Foundation of Shanghai/ ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; *RNA Stability ; *Protein Biosynthesis ; Humans ; RNA, Messenger/genetics/metabolism ; *Dipeptides/genetics/metabolism ; *Exosome Multienzyme Ribonuclease Complex/metabolism/genetics ; *DNA Repeat Expansion/genetics ; Induced Pluripotent Stem Cells/metabolism/cytology ; Neurons/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Frontotemporal Dementia/genetics/metabolism ; }, abstract = {The RNA exosome plays a critical role in surveilling nuclear mRNA biogenesis and regulating co-translational mRNA decay in the cytoplasm. Unlike canonical translation, repeat-associated non-AUG (RAN) translation of a GGGGCC hexanucleotide repeat expansion (HRE) within an intron of the C9orf72 locus leads to the synthesis of neurotoxic dipeptide-repeat (DPR) proteins, contributing to the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis (C9-ALS/FTD). However, it remains unclear whether aberrant RAN translation is monitored and regulated co-translationally or how C9orf72 HRE (C9-HRE) mRNA is degraded during this process. Here, we demonstrate that RAN translation triggers the rapid decay of C9-HRE mRNA. During this process, the RNA exosome engages the translating ribosome-C9-HRE mRNA complex to mediate RAN translation-coupled mRNA decay. Moreover, overexpression of EXOSC3, a key subunit of the RNA exosome cap, promotes RAN translation-coupled decay of C9-HRE mRNA and suppresses DPR production. In iPSC-derived neurons, a reduction in EXOSC3 levels blocks C9-HRE mRNA decay in a translation-dependent manner, further confirming its role in RAN translation surveillance. These findings highlight the essential function of the RNA exosome, particularly EXOSC3, in mitigating RAN translation-associated toxicity and preventing pathological DPR production. This work provides insights into potential therapeutic strategies for C9-ALS/FTD and may have broader implications for other disorders involving RAN translation.}, } @article {pmid42591225, year = {2026}, author = {Vöhringer, K and Müller, MS and Yildiz, CB and Zimmer-Bensch, G}, title = {DNMT1 as an environmental sensor: epigenetic pathways linking environmental exposures, sex hormone signaling, and vulnerability to neurodevelopmental and neurodegenerative diseases.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1883887}, pmid = {42591225}, issn = {1664-2295}, abstract = {DNA methyltransferase 1 (DNMT1) has classically been viewed as the canonical maintenance methyltransferase, yet accumulating evidence positions it as a multifaceted hub that integrates environmental, hormonal, and metabolic signals with chromatin regulation in the developing and adult brain. This review highlights DNMT1 as an environmentally responsive epigenetic sensor across the lifespan. We examine how psychosocial stress, early-life adversity, inflammation, nutritional and microbiome-derived metabolites, and environmental toxicants modulate DNMT1 expression, subcellular localization, and post-translational modifications, thereby reshaping DNA methylation landscapes in neurons and glia. We further discuss how sex hormone signaling, particularly estrogen receptor alpha α (ERα)-DNMT1 feedback loops, introduces sex-specific dimensions to epigenetic responsiveness, and how lncRNAs serve as intermediaries linking environmental cues to targeted DNMT1 recruitment at specific genomic loci. Building on this framework, we review how DNMT1 dysregulation contributes to neurodevelopmental and neuropsychiatric disorders-including schizophrenia, autism spectrum disorder, and depression-and to neurodegenerative conditions such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and DNMT1-associated monogenic neurodegenerative disorders. By positioning DNMT1 as a molecular interface between genetic predisposition, environmental exposure, and circuit-level vulnerability, this review highlights the need for integrated, sex-stratified, and longitudinal approaches to understanding epigenetic risk in neurological disease.}, } @article {pmid42592079, year = {2026}, author = {Tu, S and Mahoney, CJ and Huynh, W and Vucic, S and Kiernan, MC}, title = {Cortical excitability stratifies neurochemical profiles in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag292}, pmid = {42592079}, issn = {2632-1297}, abstract = {Transsynaptic deficits arising from an imbalance in excitatory/inhibitory inter-neuronal circuitry have been extensively shown to underlie the phenomena of altered cortical motor excitability in patients with amyotrophic lateral sclerosis (ALS), with glutamate-induced excitotoxicity believed to represent a primary mechanism of ALS pathogenesis. In vivo evidence of glutamate abnormality in ALS patients, however, remains inconsistent, likely reflecting heterogeneity in the severity of underlying cortical dysfunction. The current study assessed the utility of short interval intracortical inhibition (SICI), a validated marker of upper motor neuron (UMN) dysfunction in ALS, to stratify cortical motor metabolite abnormalities, as determined by proton magnetic resonance spectroscopy ([1]H-MRS). Serial [1]H-MRS data were acquired over 2.5 years for two ALS participants with contrasting profiles of progressive motor dysfunction as a pilot study. Longitudinal monitoring of these participants demonstrated stable cortical motor metabolite concentrations in the participant with lower motor predominant disease presentation but progressive changes in glutamate-glutamine (Glx) and N-acetylaspartate (NAA) concentrations in the participant with a classical ALS presentation. Fifty-four participants (34 ALS; 20 control) were prospectively recruited for a formal study. All patients underwent threshold-tracking transcranial magnetic stimulation) and were classified as having high (>5.5%; H-SICI) or low (≤5.5%; L-SICI) cortical motor inhibition. Matching 3T single-voxel [1]H-MRS data were acquired from the hand region of the motor cortex for all participants at baseline, with a subset of patients (n = 10) longitudinally assessed at 6 months. Dissociable patterns of pathological change in NAA and Glx/NAA metabolites were observed at baseline and longitudinally in ALS. At baseline, L-SICI ALS participants with increased cortical motor excitability demonstrated a significant bilateral reduction in NAA and elevated Glx/NAA metabolite concentrations (P-values < 0.03), contrasting to H-SICI ALS participants, where the neurochemical concentration was preserved. At follow-up, H-SICI patients demonstrated a trend towards elevated Glx and Glx/NAA in the left motor cortex (P-values ≤ 0.06). In contrast, L-SICI patients demonstrated stable concentrations of Glx but further reductions in NAA ratio (P = 0.04). Cortical excitability and brain neurochemical profile abnormalities reflect evolving states of UMN dysfunction in ALS. Elevated Glx/NAA metabolite concentration underlies greater cortical motor dysfunction in ALS. Longitudinal [1]H-MRS holds potential prognostic utility for clinical monitoring of ALS disease trajectory.}, } @article {pmid42592352, year = {2026}, author = {Vinceti, M and Ferrante, M and Filippini, T and Wise, LA and Urbano, T and Bedin, R and Gianferrari, G and Rapisarda, P and Pulvirenti, E and Oliveri Conti, G and Mandrioli, J}, title = {Central nervous system concentrations of nano- and microplastics and risk of amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag296}, pmid = {42592352}, issn = {2632-1297}, abstract = {Growing evidence suggests that microplastics, particularly nanoplastics, may be neurotoxic. However, there are few studies of neurologic diseases, especially amyotrophic lateral sclerosis (ALS). In a hospital-based case-control study, we measured in vivo concentrations of nano- and microplastics (size 0.1-10 µm) in serum and CSF among 24 newly diagnosed cases of ALS and 20 controls. Adjusting for sex and age, we found a strong positive association between serum and CSF microplastic concentrations and higher microplastic concentrations in the CSF and serum of ALS cases compared with controls. In spline regression analyses, CSF microplastic concentrations showed a positive monotonic association with odds of ALS. Serum microplastic concentrations also showed a positive association with ALS, but only above a certain threshold. Among ALS cases, serum-but not CSF-microplastic concentrations were positively associated with neurofilament light chain, a biomarker of neuroaxonal damage. Given the case-control design, we cannot rule out reverse causation (i.e. that ALS-related factors caused greater bioaccumulation of microplastics) or the possibility that the association reflects changes in lifestyle or other chemical exposures. However, the observed pattern raises the possibility of an aetiologic role of nano- and microplastics in motor neuron degeneration and indicates higher CNS concentrations of these chemicals in ALS cases.}, } @article {pmid42592497, year = {2026}, author = {Pal, S and Das, S and Biswas, S and Murugan, SD and Jana, NR and Chattopadhyay, AP and Singh, NDP}, title = {Exploring viscosity sensitivity of π-extended coumarin fluorogen-based PRPGs for precise photorelease of valproic acid: detection and defibrillation of TDP-43 aggregation.}, journal = {Chemical science}, volume = {}, number = {}, pages = {}, pmid = {42592497}, issn = {2041-6520}, abstract = {Alteration of cellular microenvironment viscosity by protein aggregation plays a crucial role as a biophysical parameter that reflects abnormal cellular behaviour, leading to neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), etc. Herein, we report the design and development of a series of coumarin fluorogen-based photoremovable protecting groups (PRPGs, 5a-d) with variations in substitutions tethered with a π-extended linker that integrate viscosity sensing with visible-light-triggered release of bioactive molecules. By introducing π-extended conjugation and systematic substitution, the coumarin fluorogen-based PRPGs exhibit twisted intramolecular charge transfer (TICT)-based fluorescence modulation in response to microenvironmental viscosity. Comprehensive photophysical and photochemical investigations, supported by theoretical calculations, identified PRPG 5d as the most sensitive viscosity-responsive system with green-light absorption. Under viscous conditions, restricted bond rotation suppresses nonradiative decay and photoisomerization, enabling efficient photorelease of the neuroprotective agent valproic acid. The versatility of PRPG 5d was demonstrated in biologically relevant in vitro models, including TDP-43 protein aggregation and Parkinson's disease induced SH-SY5Y neuroblastoma cells. In both extracellular and intracellular neurodegenerative environments, increased viscosity was effectively sensed, triggering light-mediated valproic acid release and subsequent defibrillation. Overall, this work establishes coumarin fluorogen-based PRPGs as a promising platform for viscosity-guided, spatiotemporally controlled drug release, offering potential applications in the diagnosis and targeted therapy of neurodegenerative diseases.}, } @article {pmid42592720, year = {2026}, author = {Żur-Wyrozumska, K}, title = {Severe hypersensitivity reaction during tofersen therapy in amyotrophic lateral sclerosis associated with the rare SOD1 p.Val120Phe mutation.}, journal = {Neurologia i neurochirurgia polska}, volume = {}, number = {}, pages = {}, doi = {10.5603/pjnns.113584}, pmid = {42592720}, issn = {0028-3843}, } @article {pmid42592867, year = {2026}, author = {McFarlane, R and Anneser, J and Al-Chalabi, A and Chiò, A and Mcdermott, CJ and Meyer, T and Mora, G and Sermeus, W and Stavroulakis, T and Tappenden, P and Van Den Berg, LH and Winkler, AS and Galvin, M and Hardiman, O}, title = {The EQ-5D-5L in amyotrophic lateral sclerosis: an international longitudinal exploration as part of ALS-CarE.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2715921}, pmid = {42592867}, issn = {2167-9223}, abstract = {BACKGROUND: The EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L) is widely used in health outcomes research, but its longitudinal performance in amyotrophic lateral sclerosis (ALS), particularly across international cohorts, remains poorly characterized. This study examined whether the EQ-5D-5L captures clinically meaningful change over time in ALS and how national value sets influence interpretation of that change.

METHODS: EQ-5D-5L data from 296 patients across six European ALS centers in five countries were analyzed over 18.6 months (IQR 17.9-20.8). Baseline and follow-up assessments were compared using the Paretian Classification of Health Change and Health Profile Grids. Country-specific tariffs were applied to identical health-state transitions. Associations between EQ-5D measures and King's stage were assessed.

RESULTS: Overall health states worsened over time, although mixed change remained common (31.0%-39.0%), reflecting simultaneous improvement and deterioration across dimensions. Pain/discomfort and anxiety/depression were the only domains showing notable improvement at later follow-up. Mean health-state ranks worsened from 619.65 at baseline to 857.20 at follow-up. However, the apparent magnitude of progression differed substantially according to national tariff selection, with pooled mean utility change ranging from -0.081 under the Dutch tariff to -0.112 under the Italian tariff. Both EQ-5D index and visual analog scale scores correlated with progression according to the King's staging system.

CONCLUSIONS: The EQ-5D-5L captures plausible longitudinal deterioration in ALS, but interpretation is strongly influenced by valuation context. National tariffs may materially alter the apparent size of quality-of-life change in multinational ALS studies.}, } @article {pmid42593908, year = {2026}, author = {Sanchez-Santos, C and Jimenez-Amor, A and Martinez-Gonzalez, L and Nozal, V and Martin-Morales, R and Aledavood, E and Bausela, D and Merrigan, K and Diaz-Palacios, K and Zhubi, R and Knapp, S and Garcia-Gonzalo, FR and Rodriguez-Cueto, C and Gil, C and de Lago, E and Martinez, A}, title = {Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model of TDP-43 Proteinopathy.}, journal = {Journal of medicinal chemistry}, volume = {69}, number = {15}, pages = {19451-19481}, pmid = {42593908}, issn = {1520-4804}, support = {GA-202205-2023343//Association for Frontotemporal Degeneration/ ; FPU21/01392//Ministerio de Ciencia, Innovaci?n y Universidades/ ; PID2019-105600RB-I00//Ministerio de Ciencia, Innovaci?n y Universidades/ ; PID2023-149472NB-I00//Ministerio de Ciencia, Innovaci?n y Universidades/ ; CB06/05/0089//Instituto de Salud Carlos III/ ; CB06/07/1029//Instituto de Salud Carlos III/ ; CB18/05/00040//Instituto de Salud Carlos III/ ; 1097737//Structural Genomics Consortium/ ; }, mesh = {Animals ; *Protein Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Humans ; *Brain/metabolism/drug effects ; Mice ; Disease Models, Animal ; *TDP-43 Proteinopathies/drug therapy/metabolism/pathology ; *DNA-Binding Proteins/metabolism ; *Protein Kinase Inhibitors/pharmacology/therapeutic use/chemistry/pharmacokinetics ; Structure-Activity Relationship ; *Cognitive Dysfunction/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Modulation of TDP-43 pathology represents a promising disease-modifying strategy. Tau tubulin kinase 1 (TTBK1) has emerged as a relevant therapeutic target; however, selectivity over the TTBK2 isoform is required to avoid ciliogenesis-related liabilities. Here, we report the discovery of selective, brain-penetrant TTBK1 inhibitors through a structure-guided medicinal chemistry program. Lead compounds exhibit potent and selective TTBK1 inhibition, no impact on ciliogenesis, and central nervous system exposure. We found that these inhibitors reduce TDP-43 phosphorylation levels in neuroblastoma cells and FTD patient-derived models. The optimized lead compound demonstrated a brain-to-plasma ratio of 3:1, a maximum tolerated dose, and a wide therapeutic window. In vivo, administration restored cognitive deficits, conferred neuroprotection in the frontal cortex, and reduced microglial activation in an FTD-TDP mouse model, supporting its therapeutic potential.}, } @article {pmid42594043, year = {2026}, author = {Nair, T and Larson, T and Raymond, J and Horton, DK and Mehta, P}, title = {Motor Neuron Disease Mortality in the United States, 2010-2023: A demographic, geographic, and temporal analysis.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-24}, pmid = {42594043}, issn = {1423-0208}, support = {CC999999/ImCDC/Intramural CDC HHS/United States ; }, abstract = {INTRODUCTION: Our objective was to calculate age-adjusted motor-neuron disease (MND) mortality rates in the United States, 2010-2023, by year, age, sex, race, origin, period, and state. Amyotrophic lateral sclerosis makes up almost 80% of all MNDs.

METHODS: Multiple cause mortality data was obtained from the National Center for Health Statistics (NCHS) for years 2010-2023. Cases were included if code G12.2, the code for MND listed in the International Classification of Disease, 10th Revision (ICD-10), was listed as a cause of death. Using the direct method, cases were age-adjusted to the 2000 U.S. Standard population and mortality rates were calculated.

RESULTS: The overall national MND associated mortality rate was 2.07 per 100,000 population (95% CI 2.06, 2.09). Rates were highest in those aged 80+ years (13.69, 95% CI 13.49, 13.89) at death, non-Hispanic (2.17, 95% CI 2.15, 2.18), and male (2.50, 95% CI 2.48, 2.52). Northern states had higher rates (2.26, 95% CI 2.23, 2.29) with a rate ratio of (1.05, (95% CI 1.04, 1.07) when compared to the middle state tier (2.14, 95% CI 2.12, 2.17, p<0.01). State rates ranged from 3.07 (95% CI 2.75, 3.42) in Vermont to 1.41 (95% CI 1.27, 1.57) in Hawaii. The average annual percentage change was -1.62, corresponding to a statistically significant negative trend.

CONCLUSION: MND associated mortality rates were higher among northern states, decedents who were male, White, or non-Hispanic, which is consistent with previous studies of U.S. MND mortality. Decreasing mortality rates may indicate longer patient life spans due to increased treatment options and care access, but further research is needed.}, } @article {pmid42594177, year = {2026}, author = {Parisien, R}, title = {Epistemic Asymmetry Between Abstracts and Discussion Sections in the Orthopaedic Literature: A Corpus Analysis of 201 Publications.}, journal = {The Journal of bone and joint surgery. American volume}, volume = {}, number = {}, pages = {}, doi = {10.2106/JBJS.26.00433}, pmid = {42594177}, issn = {1535-1386}, abstract = {BACKGROUND: Abstracts and Discussion sections serve distinct functions: Abstracts are optimized for brevity and impact, while Discussion sections contain authors' most explicit engagement with uncertainty and the scope of inference. Whether these sections differ systematically in epistemic stance-the level of confidence or uncertainty with which findings are stated and qualified-has not been formally examined in the orthopaedic literature.

METHODS: All original research articles published in The Journal of Bone and Joint Surgery (JBJS) and Clinical Orthopaedics and Related Research (CORR) during the first half of 2025 were included (total, n = 201; JBJS, n = 153; CORR, n = 48). Editorials, reviews, letters, and case reports were excluded. The densities of hedges (markers of uncertainty and qualification) and boosters (markers of confidence and certainty) were measured per 1,000 words using an automated 233-item lexicon. The epistemic shift index (ESI) quantified the net difference in epistemic stance between sections, with a positive value indicating greater caution in the Discussion. Abstract limitation surfacing (ALS) indicated explicit acknowledgment of limitations in the Abstract.

RESULTS: Discussion sections contained 2.8 times the hedge density of Abstracts, and the ESI was positive in 176 (87.6%) of the 201 articles. The mean ESI was 7.8 (95% confidence interval, 6.9 to 8.8; t[200] = 16.39, p < 0.001; Cohen d = 1.15). Discussions carried more than double the hedge-to-booster ratio of Abstracts (3.58 versus 1.69, p < 0.001). The asymmetry did not differ by open-access status (p = 0.807) or journal (p = 0.142) but varied significantly by study design (Kruskal-Wallis p = 0.034), with the largest asymmetry in diagnostic studies and randomized controlled trials. Only 12 (6.0%) of 201 Abstracts acknowledged study limitations.

CONCLUSIONS: The Discussion sections of the orthopaedic research articles were substantially more epistemically cautious than their Abstracts across journals and access models. In most articles, the Abstract presented findings without caveat, with corresponding limitations appearing only in the Discussion. A limitation of this analysis is that epistemic stance was measured at the word and phrase level only. These findings have implications for clinical decision-making and for artificial intelligence systems trained on freely accessible Abstract text.}, } @article {pmid42594365, year = {2026}, author = {Berry-Kilgour, N and Wiseman, R and Grundy, K}, title = {Prescribing and monitoring of riluzole in amyotrophic lateral sclerosis: a retrospective cohort study from Health New Zealand - Te Whatu Ora Waitaha Canterbury.}, journal = {The New Zealand medical journal}, volume = {139}, number = {1640}, pages = {23-30}, doi = {10.26635/6965.7367}, pmid = {42594365}, issn = {1175-8716}, mesh = {Humans ; Retrospective Studies ; *Riluzole/therapeutic use/adverse effects ; New Zealand ; *Amyotrophic Lateral Sclerosis/drug therapy ; Female ; Male ; Middle Aged ; Aged ; *Guideline Adherence/statistics & numerical data ; *Drug Monitoring ; *Neuroprotective Agents/therapeutic use/adverse effects ; Practice Guidelines as Topic ; *Practice Patterns, Physicians'/statistics & numerical data ; Spirometry ; Adult ; }, abstract = {AIM: This retrospective cohort study assessed adherence to the Motor Neurone Disease New Zealand best practice guidelines and Pharmac Special Authority criteria for riluzole in a Canterbury-based amyotrophic lateral sclerosis (ALS) cohort. Secondary objectives included reasons for not prescribing, side effects and treatment initiation relative to diagnosis.

METHOD: A retrospective cohort study was conducted using the Christchurch Hospital respiratory department's ALS database. Patients diagnosed between January 2020 and November 2024 were included. Electronic health records and Special Authority records were reviewed. Patients with incomplete data or non-motor neurone disease (MND) diagnoses were excluded.

RESULTS: Of 115 patients, 69 (60%) were prescribed riluzole. Less than 45% of patients had baseline blood tests, and pre-treatment spirometry was completed in 70% of patients. Delays in prescribing improved rates of baseline spirometry, but not blood test completion. Ongoing monitoring was poor, with less than 60% of patients completing recommended tests across all time points. Eight patients (11.6%) reported side effects, and three discontinued treatment following alanine aminotransferase derangement.

CONCLUSION: Adherence to recommended monitoring and Special Authority criteria for riluzole was inconsistent in this cohort. In the context of emerging evidence supporting broader survival benefit and reduced drug cost, further evaluation of current Special Authority prescribing criteria may be warranted.}, } @article {pmid42594388, year = {2026}, author = {Griffin, AC and Zulman, DM}, title = {Digital Decisions: Enhancing Chronic Disease Self-Care Through Digital Health and AI-Enhanced Decision-Making.}, journal = {Journal of medical Internet research}, volume = {28}, number = {}, pages = {e106648}, pmid = {42594388}, issn = {1438-8871}, mesh = {Humans ; *Self Care ; Chronic Disease/therapy ; Digital Health ; *Decision Making ; *Artificial Intelligence ; Telemedicine ; }, abstract = {Advances in digital health have dramatically changed how patients engage with their health. Rather than relying solely on periodic clinical visits, patients now have access to smartphones, patient portals, wearable devices, and mobile apps that provide support for day-to-day self-care decisions. This commentary discusses the findings of Longhini et al's systematic review and meta-analysis on the effectiveness of digital health interventions, which found modest improvements in self-care monitoring but limited effects on self-care maintenance and management behaviors. Reflecting on these findings through the lens of dual-process theory, digital health technologies appear to be effective at supporting fast, intuitive processes, such as symptom monitoring, but are less effective at engaging slower, deliberative processes needed for complex decision-making and behavior change. Digital health technologies should evolve from primarily supporting routine self-care activities to enhancing patients' reflective decision-making processes for sustained behavior change. Emerging AI capabilities offer opportunities to strengthen and bridge these fast and slow cognitive processes by translating complex health information into actionable insights and facilitating patient-clinician communication. Realizing this potential requires careful attention to implementation, including integration into clinical workflows, patient and clinician education, and digital literacy. In addition, digital health teams should adopt standardized implementation frameworks and outcome measures to generate a more robust evidence base. Lastly, human-centered design, patient engagement, and safeguards addressing bias, privacy, and transparency are foundational to ensure that the rapid pace of digital health technology will continue to enhance patient self-care and health outcomes.}, } @article {pmid42594668, year = {2026}, author = {Nakasako, J and Nishimoto, Y}, title = {Reply to the comment on "Association of anti-glycolipid IgG with respiratory function decline in amyotrophic lateral sclerosis".}, journal = {Journal of the neurological sciences}, volume = {490}, number = {}, pages = {126130}, doi = {10.1016/j.jns.2026.126130}, pmid = {42594668}, issn = {1878-5883}, } @article {pmid42595080, year = {2026}, author = {Al-Badaineh, M and Josan, H and Imran, B and Ebeid, I and Mekhail, J and Abdou, M and Dagher, D and Ahmed, AF and Hantouly, A and Khan, M}, title = {Spin in systematic reviews on patch-augmented rotator cuff repair: prevalence, predictors, and methodological implications.}, journal = {Journal of shoulder and elbow surgery}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jse.2026.07.030}, pmid = {42595080}, issn = {1532-6500}, abstract = {BACKGROUND: Rotator cuff tears are a major cause of shoulder pain and dysfunction, and surgical repair is often complicated by the risk of retear, especially in patients with large, massive, revision tears and high-risk patients. Biologic or synthetic patch augmentation has emerged to reinforce repair and potentially reduce retears. Despite many systematic reviews (SRs) and meta-analyses (MAs) on patch-augmented versus non-augmented repair, concerns remain regarding study heterogeneity, outcome variability, and spin in interpretation and reporting, particularly in abstracts. This study assessed the methodological quality and abstract spin.

METHODS: This SR was conducted in accordance with the Cochrane Handbook and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. On October 30, 2025, PubMed, Scopus, and Web of Science were searched for English-language SRs and MAs comparing patch- or graft-augmented versus non-augmented rotator cuff repair in clinical studies. Eligible reviews reported at least one clinical, patient-reported, or imaging-based outcome. Two reviewers independently performed duplicate study selection, data extraction, spin assessment, and methodological quality appraisal using Yavchitz et al's 9 severe spin types and AMSTAR-2.

RESULTS: Sixteen reviews and MAs were included in this study. Spin was identified in 81.3% (n = 13) of the abstracts. The types were 5 (62.5%), 3 (56.2%), and 8 (50.0%). Univariate analysis found no significant associations with the funding status (P = .36), quality (P = 1.00), or impact factor (P = .95). Each AMSTAR-2 flaw was associated with 61% more spin types (incidence rate ratio, 1.61; 95% confidence interval, 1.08-2.49; P = .02).

CONCLUSION: Spin is prevalent in the abstracts of SRs on patch augmentation for rotator cuff repair, regardless of funding or journal impact factor. Although spin was widespread, poor methodological quality was linked to a greater spin burden rather than its presence. These findings highlight the importance of critically appraising SRs, as spin may contribute to an overly favorable interpretation of the evidence and potentially influence clinical decision-making. Readers should interpret the conclusions cautiously and verify the claims against the full-text results.}, } @article {pmid42595317, year = {2026}, author = {Oliveira, AC and Corrêa, TDS and Vieira, LF and Carvalho, IR and Chaul, DN and Almeida, AECG and Faria, VLG and Simamoto Júnior, PC and Morais, JF and Stelzer, FG and Goulart, IMB and Santos, DFD}, title = {Nocturnal polygraphy in neuromuscular disorders: is it a useful diagnostic tool?.}, journal = {Arquivos de neuro-psiquiatria}, volume = {84}, number = {7}, pages = {1-8}, pmid = {42595317}, issn = {1678-4227}, mesh = {Humans ; *Sleep Apnea, Obstructive/diagnosis/epidemiology/etiology/physiopathology ; *Neuromuscular Diseases/complications/physiopathology ; Female ; Prospective Studies ; Male ; *Polysomnography/methods ; Middle Aged ; Prevalence ; Adult ; Surveys and Questionnaires ; Aged ; }, abstract = {BACKGROUND: Patients with neuromuscular diseases (NMDs) have a high incidence of sleep-related breathing disorders. These include obstructive sleep apnea (OSA), which is characterized by recurrent episodes of upper airway obstruction during sleep, resulting in intermittent hypoxemia and sleep fragmentation. Obstructive sleep apnea may be more common in patients with NMDs than in the general population.

OBJECTIVE: To assess the prevalence of OSA through home polygraphy at a public university hospital during respiratory evaluations of patients with NMDs, and its contribution to the indication of non-invasive ventilation. It did not aim to validate a model for early indication.

METHODS: The present prospective study collected data over the period from May 2021 to June 2024, using medical records and tests such as spirometry to evaluate pulmonary respiratory function, home polygraphy, and sleep assessments using the Epworth Sleepiness Scale (ESS) and a symptom questionnaire.

RESULTS: A total of 74 patients were included, 64.7% (n = 48) of whom had OSA. The most prevalent NMDs were muscular dystrophy (n = 22; 29.7%), myasthenia gravis (n = 13; 17.6%), and amyotrophic lateral sclerosis (ALS) (n = 11; 14.9%). Apnea-hypopnea index (AHI) values were higher in the supine position (11.6 ± 12.6) compared to the AHI in the non-supine position (7.0 ± 14.1), which indicates, on average, a mild degree of OSA. The ESS revealed that 40.5% of patients had scores indicating excessive daytime sleepiness (EDS).

CONCLUSION: The findings reinforce the importance of early OSA diagnosis in patients with NMDs.}, } @article {pmid42595324, year = {2026}, author = {Fustes, OJH and Teive, HAG}, title = {Amyotrophic lateral sclerosis (ALS): new insights 156 years after Charcot's masterful description.}, journal = {Arquivos de neuro-psiquiatria}, volume = {84}, number = {7}, pages = {1-4}, pmid = {42595324}, issn = {1678-4227}, mesh = {*Amyotrophic Lateral Sclerosis/history ; History, 19th Century ; Humans ; History, 20th Century ; }, abstract = {In 1869, Charcot and Alix Joffroy published the first detailed clinical and neuropathological description of amyotrophic lateral sclerosis (ALS), establishing the correlation involving muscle weakness, atrophy, spasticity, and degeneration of the lateral corticospinal tracts. Charcot unified the involvement of upper and lower motor neurons into a single clinical entity. His pioneering description was limited to the motor system, reflecting the scientific constraints of his time. Charcot interpreted ALS primarily as a disorder of the motor system, a conclusion consistent with the clinical and pathological methods available in the late nineteenth century. Neurological investigation at that time relied mainly on detailed clinical observation, anatomical correlation at autopsy, and relatively-simple physiological techniques. These approaches were well suited to identify motor dysfunction but were far less capable of revealing subtle cognitive or behavioral alterations. Currently, ALS is recognized as a multisystem neurodegenerative disorder. Thus, Charcot's historical contribution was crucial for the initial understanding of ALS, while modern perspectives acknowledge its broader clinical complexity beyond the motor system.}, } @article {pmid42595352, year = {2026}, author = {Gao, J and Chalitsios, CV and Bennett, D and Doherty, A and Turner, MR and Thompson, AG}, title = {Associations of self-reported and objectively measured physical activity and amyotrophic lateral sclerosis risk.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2026-339165}, pmid = {42595352}, issn = {1468-330X}, abstract = {BACKGROUND: The role of physical activity in the risk of amyotrophic lateral sclerosis (ALS) is debated. It is also unclear whether the association differs in people at high genetic risk of ALS.

METHODS: The strength and shape of the association between self-reported and device-measured physical activity and incident diagnosis of ALS in the UK Biobank cohort was analysed using Cox regression, adjusting for potential confounders. Cubic splines were used to assess non-linearity. Analyses were performed in the entire cohort and restricted to those with increased genetic risk due to C9ORF72 expansion carriage or C-allele homozygosity at rs12608932 in UNC13A.

RESULTS: Among 384 836 participants with valid questionnaire data, the median age at recruitment was 57.0 years (IQR 50.0-63.0) and median follow-up was for 14.0 years (IQR 13.3-14.6), with 541 incident diagnoses of ALS. Higher self-reported physical activity was associated with a lower risk of ALS (HRhigh vs low=0.77, 95% CI 0.61 to 0.96). The relationship was non-linear, with lowest risk in those in the mid-range self-reported activity. Higher overall device-measured activity was also associated with a lower risk of ALS (HRper 1SD = 0.75, 95% CI 0.58 to 0.97, n=96 570, 98 ALS events) but with a linear dose-response relationship. The association of physical activity with ALS was similar in individuals with C-allele homozygosity at rs12608932 in UNC13A and directionally consistent but not statistically significant in C9ORF72-HRE carriers (n=535, 56 ALS events).

CONCLUSION: Higher self-reported and device-measured overall physical activity were associated with a lower risk of ALS overall, but with a potentially non-linear dose-response relationship.}, } @article {pmid42595353, year = {2026}, author = {Fang, F}, title = {Physical activity in ALS: friend or foe?.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2026-339492}, pmid = {42595353}, issn = {1468-330X}, } @article {pmid42595782, year = {2026}, author = {Hetz, C and Thielen, P and Fisher, J and Pasinelli, P and Brown, RH and Korsmeyer, S and Glimcher, L}, title = {Correction: The proapoptotic BCL-2 family member BIM mediates motoneuron loss in a model of amyotrophic lateral sclerosis.}, journal = {Cell death and differentiation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41418-026-01701-0}, pmid = {42595782}, issn = {1476-5403}, } @article {pmid42596010, year = {2026}, author = {Kamphausen, A and Pilz, M and Baumgärtel, M and Kubitz, JC and Engelen, C}, title = {Effect of an app-guided advanced cardiac life support algorithm on teamwork, non-technical skills, and workload in simulated in-hospital cardiac arrest: a randomized controlled feasibility trial.}, journal = {Scandinavian journal of trauma, resuscitation and emergency medicine}, volume = {34}, number = {1}, pages = {}, pmid = {42596010}, issn = {1757-7241}, mesh = {Humans ; *Heart Arrest/therapy ; *Advanced Cardiac Life Support/methods ; Prospective Studies ; Feasibility Studies ; Female ; *Mobile Applications ; Male ; *Algorithms ; *Patient Care Team ; *Workload ; *Clinical Competence ; }, abstract = {BACKGROUND: In-hospital cardiac arrest carries high mortality despite advances in monitoring, rapid response systems, and adherence to advanced life support (ALS) guidelines. Digital decision-support tools, including mobile applications, are increasingly explored to improve guideline adherence, yet their impact on cognitive workload, team performance, and ALS performance remains uncertain.

METHODS: We conducted a prospective, randomized, simulation-based controlled feasibility trial with 40 interprofessional teams (80 participants) comparing ALS performance with and without the use of the 'CPR Leader' app. Two-person teams were randomized 1:1 to intervention or control and followed standardized in-hospital cardiac arrest scenarios (asystole and ventricular fibrillation). Primary outcomes included team performance (TEAM), non-technical skills (ANTS), and subjective workload (NASA-TLX). Secondary outcomes comprised objective resuscitation metrics, including time to rhythm analysis, defibrillation, medication administration, and chest compression quality.

RESULTS: Overall NASA-TLX scores were high but comparable between intervention and control group (mean 49.2 ± 13.6 vs. 54.1 ± 14.6; p = 0.2), with higher effort reported in the app group and higher frustration in the control group. TEAM and ANTS scores showed no evidence of meaningful between-group differences. Across the two scenarios types, ALS performance metrics-including rhythm analysis, defibrillation, medication administration, and chest compression quality-were similar between groups, with the exception of earlier chest compression initiation in the control group during ventricular fibrillation.

CONCLUSIONS: In this exploratory randomized simulation study involving predominantly experienced in-hospital healthcare professionals, the use of a resuscitation support application did not demonstrate a clear improvement in adherence to guideline-recommended ALS algorithms or resuscitation performance compared with standard practice. These findings likely reflect the high level of participants' clinical experience and should not be generalized to novice providers, mixed-experience teams, prehospital settings, or training environments. Further studies are warranted to evaluate the potential benefits of cognitive aids in less experienced populations and in real-world clinical practice.

TRIAL NUMBER: None.}, } @article {pmid42596024, year = {2026}, author = {Reeves, MM and Aviles Carpintero, S and Zanovello, M and Jansen-West, K and Yue, M and Calliari, A and Song, Y and Dunmore, J and Maroto Cidfuentes, C and Ball, S and Kachergus, JM and Killeen, HE and Rawlinson, B and Engelberg-Cook, E and DeTure, M and Day, GS and Graff-Radford, NR and Boeve, BF and Knopman, DS and Petersen, RC and Murray, M and Thompson, AE and Dickson, DW and Fratta, P and Petrucelli, L and Josephs, KA and Prudencio, M}, title = {The UNC13A cryptic exon associates with cognitive impairment in Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {42596024}, issn = {1758-9193}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; R01 NS120992/NS/NINDS NIH HHS/United States ; P30AG062677/AG/NIA NIH HHS/United States ; U54NS123743, R35NS097273//NIH/ ; R01NS120992, R01AG037491//NIH/ ; R01NS120992, U54NS123743//NIH/ ; MR/M008606/1 and MR/S006508/1//Lady Edith Wolfson Fellowship/ ; U54 NS123743/NS/NINDS NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; U01AG006786/AG/NIA NIH HHS/United States ; R01 AG037491/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/pathology/complications ; Polymorphism, Single Nucleotide/genetics ; Male ; Female ; DNA-Binding Proteins/metabolism ; *Exons/genetics ; *Nerve Tissue Proteins/genetics ; Aged ; Brain/pathology/metabolism ; Aged, 80 and over ; Cohort Studies ; Genetic Predisposition to Disease ; }, abstract = {BACKGROUND: TAR DNA-binding protein of 43 kDa (TDP-43) is often found in the brains of patients with Alzheimer's disease (AD), where it co-occurs with amyloid β plaques and tau neurofibrillary tangles, and associates with accelerated cognitive decline and brain atrophy. TDP-43's function of repressing the inclusion of cryptic exons (CEs) during RNA splicing is compromised in AD. A single-nucleotide polymorphism (SNP) located within the CE in the UNC13A gene [rs12973192 (C > G)] is associated with higher disease risk and reduced survival in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) by weakening TDP-43 binding promoting CE inclusion.

OBJECTIVE: To investigate the influence of the rs12973192 UNC13A CE SNP and UNC13A cryptic splicing on TDP-43 pathology, survival and cognitive impairment in AD.

METHODS: We evaluated the UNC13A CE SNP in a cohort of 1,672 AD, including 643 AD brains with available cognitive measurements and 73 AD cases for which we measured cryptic RNA levels in the amygdala. We also evaluated a cohort of 466,517 from the UK Biobank to determine associations between the UNC13A CE SNP and dementia diagnosis.

RESULTS: In AD, the UNC13A CE SNP associated significantly with cognitive decline, but not with TDP-43 pathology or with survival. UNC13A cryptic RNA levels in the amygdala were a better predictor of cognitive decline than the UNC13A CE SNP itself, while STMN2-another well-known CE target-exhibited no such association.

CONCLUSIONS: These findings point to UNC13A cryptic splicing as a specific driver of cognitive decline in AD, outperforming both genetic risk and other cryptic targets.}, } @article {pmid42596047, year = {2026}, author = {Ohta, K and Fujino, Y and Sada, Y}, title = {Allelic dosage across four functional ALS loci shapes ALS-inhibitor resistance in allotetraploid Pontederia vaginalis.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71188}, pmid = {42596047}, issn = {1526-4998}, abstract = {BACKGROUND: Pontederia vaginalis, carrying four functional ALS genes, is a major weed in Asian rice paddies. Acetolactate synthase (ALS)-inhibitor resistance is caused by target-site mutations, but how resistant allelic dosage affects whole-plant susceptibility in weeds with more than three functional ALS loci remains unclear. This study quantified the effect of resistant allele number on herbicide susceptibility in P. vaginalis using progeny of a cross between two lineages carrying Pro197Ser substitutions in different ALS loci.

RESULTS: Hybridization between lineages carrying Pro197Ser in MvALS1 or MvALS3 yielded F2 progeny with varying resistant allelic dosages, and genotyping confirmed independent segregation of these loci. Dose-response assays with imazosulfuron and bensulfuron-methyl revealed that susceptibility decreased sharply as resistant alleles increased from zero to two (ED90 (effective dose to have 90% reduction of dry weights) shifts ~3000-fold for imazosulfuron), whereas additional alleles beyond two conferred only marginal further resistance (~four- to five-fold). For genotype-confirmed one-resistant-allele plants (n = 25), the bootstrap 95% confidence interval (CI) for ED90 was 16.7-292.0 g active ingredient (a.i.) ha[-1] (median: 92.6 g a.i. ha[-1]), encompassing the registered field dose (90 g a.i. ha[-1]) and non-overlapping with the CIs of the zero- and two-allele classes. The F2 segregation ratios matched theoretical expectations, suggesting non-target-site resistance does not substantially distort inheritance patterns.

CONCLUSION: These results demonstrate a clear allelic dosage effect on ALS-inhibitor resistance in P. vaginalis, with diminishing returns beyond two resistant alleles. The CI for one-resistant-allele plants encompasses the registered field dose, indicating genuinely uncertain control outcomes at standard application rates. These findings challenge fixed dominant/recessive classifications and highlight the need to quantify allelic dosage effects in polyploid weeds for accurate resistance risk assessment. © 2026 Society of Chemical Industry.}, } @article {pmid42597242, year = {2026}, author = {Liu, Z and Yang, H and Cui, J and Guan, Z and Gao, D and Feng, P and Yang, H and Li, W and Zhao, Y and Yang, Q and Zheng, X and Liu, Q and Geng, Z}, title = {White matter abnormalities in amyotrophic lateral sclerosis: a free water imaging study.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1899073}, pmid = {42597242}, issn = {1662-4548}, abstract = {OBJECTIVE: To investigate white matter microstructural alterations in amyotrophic lateral sclerosis (ALS) using free-water-corrected diffusion tensor imaging (FW-DTI), compare its findings with those of conventional DTI, and examine the clinical correlations and preliminary diagnostic value of these metrics.

METHODS: 44 ALS patients and 42 healthy controls underwent multi-b-value diffusion MRI. Conventional DTI metrics (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AxD], radial diffusivity [RD]), free-water-corrected metrics (FW-FA, FW-MD, FW-AxD, FW-RD), and the free-water fraction (FWF) were calculated. Tract-based spatial statistics (TBSS) was used for voxelwise group comparisons. Correlations between clinical parameters, including disease progression rate (ΔFS) and the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score, and DTI metrics were examined. A diagnostic nomogram was constructed using logistic regression based on imaging markers that showed significant differences between groups.

RESULTS: Conventional DTI identified white matter abnormalities in ALS-related regions, including corticospinal tract-related regions, the corpus callosum, and the cingulate gyrus. FW-DTI showed additional and partially distinct alterations, including changes in the fornix, bilateral superior corona radiata, anterior and posterior corona radiata, and the posterior limb of the internal capsule. The free-water fraction did not differ between groups. Correlation analysis revealed that ΔFS was negatively associated with FA in the left posterior limb of the internal capsule (r = -0.432), and the ALSFRS-R score was positively associated with FW-FA in the right anterior corona radiata (r = 0.389). A diagnostic nomogram combining FA in the right cerebral peduncle and FW-FA in the right anterior corona radiata showed preliminary discriminative performance (area under the curve [AUC] = 0.860).

CONCLUSION: FW-DTI may provide complementary model-derived information for characterizing ALS-related white matter alterations beyond conventional DTI. Specific regional metrics were associated with ΔFS and the ALSFRS-R score, and the preliminary diagnostic nomogram yielded an AUC of 0.860.}, } @article {pmid42597576, year = {2026}, author = {Maeta, T and Kobayashi, K and Asano, K and Sato, T and Ito, S}, title = {Ruxolitinib-Associated Improvement in Post-transplant Air-Leak Syndrome Complicating Steroid-Dependent Organizing Pneumonia: A Case Report.}, journal = {Cureus}, volume = {18}, number = {7}, pages = {e112618}, pmid = {42597576}, issn = {2168-8184}, abstract = {Air-leak syndrome (ALS), including pneumothorax, pneumomediastinum, and subcutaneous emphysema, is a rare but life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, no standard treatment has yet been established. Here, we report the case of a 60-year-old man with acute myeloid leukemia who underwent allogeneic HSCT. He developed chronic graft-versus-host disease (GVHD) and cryptogenic organizing pneumonia (COP) on day 126 after transplantation. Although initial corticosteroid therapy improved the COP, the relapse occurred during tapering, and repeated steroid treatment failed to achieve sustained disease control. The patient subsequently developed pneumomediastinum, consistent with ALS. Ruxolitinib treatment was initiated on day 265 for steroid-dependent chronic GVHD and organizing pneumonia. Following treatment, oxygenation improved, pneumomediastinum improved, and corticosteroids were successfully tapered and discontinued without COP recurrence. Serum Krebs von den Lungen-6 (KL-6) levels decreased in parallel with clinical and radiological improvement. The introduction of ruxolitinib is associated with improvements in ALS and enabled the discontinuation of steroids. Adverse events included cytopenia and mild liver dysfunction, consistent with known safety profiles. The patient died of acute respiratory failure after transfusion, which was not considered a direct complication of the ruxolitinib treatment. This case suggests that ruxolitinib may facilitate corticosteroid tapering and radiographic improvement of organizing pneumonia-associated ALS after allogeneic transplantation.}, } @article {pmid42598675, year = {2026}, author = {van de Zande, NA and Ruiter, CCC and Polman, MA and Brama, SCM and Roos, RAC and Kremer, PHC and de Bot, ST}, title = {Tracing neuroinflammation in neurodegeneration: insights from a scoping review on biofluid biomarkers.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag289}, pmid = {42598675}, issn = {2632-1297}, abstract = {Neuroinflammation is increasingly recognized as a key pathological process in neurodegenerative disease and can be monitored using biofluid biomarkers. Objective biomarkers may aid diagnosis, prognosis and progression. We conducted a scoping review of neuroinflammation biomarkers across major neurodegenerative diseases covering the past 23 years, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, Lewy body dementia, multiple system atrophy and progressive supranuclear palsy. PubMed and Web of Science were systematically searched for observational studies from 2003 to 2025 reporting neuroinflammation biomarkers in adult human subjects. Included markers encompassed blood, cerebrospinal fluid, saliva and urine, providing possible complementary information. Original studies on non-neuroinflammatory mechanisms, cellular or post-mortem biomarkers, animal models, genetics and comparisons between diseases were excluded. Two reviewers independently screened articles; biomarkers reported in ≥3 independent cohorts per disease were analysed. A total of 388 studies were included, predominantly in Alzheimer's disease/mild cognitive impairment (n = 214) and Parkinson's disease (n = 92). Eight biomarkers were most frequently reported: IL-6, TNF-α, IL-1β, CRP/hs-CRP, IL-10, MCP-1, YKL-40 and neutrophil-to-lymphocyte ratio (NLR), measured in blood or cerebrospinal fluid (CSF) as indicators of inflammatory processes associated with neurodegeneration. Across biomarkers, the strength and scope of evidence varied. Most studies demonstrated higher biomarker levels in disease, with more advanced stages, greater clinical severity and faster progression. NLR showed the most consistent pattern across staging, severity and progression, but is currently under-represented across diseases. CSF YKL-40 generally increased with disease presence and advancement; IL-6 showed consistent increases in advanced stages and with severity, although significant results were limited; MCP-1, CRP and TNF-α were mostly linked to severity and progression; IL-1β and IL-10 remained largely inconsistent. Other markers, including GFAP, showed associations in Alzheimer's disease but remain underexplored in other neurodegenerative diseases. Variability across studies, including differences in biofluid source, assay sensitivity, population characteristics and statistical approaches, limits interpretability and comparability. Although neuroinflammation is elevated in neurodegenerative diseases and generally intensifies as these diseases progress, potentially contributing to downstream pathology, the precise timing, role and predictive value of these biomarkers remain uncertain. A subset of markers, including NLR, YKL-40 and GFAP, shows relatively consistent associations and may warrant further investigation across diseases. In clinical practice, neuroinflammation biomarkers could serve as complementary tools to capture inflammatory processes related to disease heterogeneity and progression. Future longitudinal studies tracking pre-symptomatic and early-stage individuals, with standardized approaches, are needed to define temporal dynamics and explore their utility for monitoring disease progression and therapeutic response.}, } @article {pmid42599142, year = {2026}, author = {Etemadifar, M and Salari, M and Kashefi, M and Shams, Y and Heydari Sichani, M and Hojjatipour, F}, title = {Incidence and clinical characteristics of amyotrophic lateral sclerosis during the post-COVID-19 Period: a population-based study from Isfahan, Iran.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/17582024.2026.2718409}, pmid = {42599142}, issn = {1758-2032}, abstract = {AIMS: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. Understanding the underlying causes would help further studies on the pathogenesis and treatments. Recent interest has emerged in evaluating whether the COVID-19 pandemic and vaccination have any influence on the epidemiological patterns of ALS.

MATERIALS & METHODS: To assess this association in Isfahan, Iran, during the post-COVID-19 era, we conducted this retrospective study. Newly diagnosed ALS cases were identified, and demographic data, environmental exposures, comorbidities, vaccination history, and other aspects were collected.

RESULTS: A total of 63 patients were diagnosed with definite ALS, yielding an incidence rate of 0.74 per 100,000 person-years (95% CI: 0.57-0.94). The mean age was 59.7 ± 11.6 years, and cases were predominantly male (73%). Of the 63 new ALS-diagnosed cases, 45% of patients reported probable prior COVID-19 infection, and 95.3% mentioned at least one dose of COVID-19 vaccination. Bulbar signs, including facial muscle weakness, tongue atrophy, and fasciculation, were present in 46% of cases, and emotional lability and cognitive decline were observed in 20.6%.

CONCLUSION: We showed a probable relation between COVID-19 infection and the epidemiology of ALS in post-COVID era. However, our results and symptom alterations require further investigation.}, } @article {pmid42600830, year = {2026}, author = {Ayala, E and Puigdemasa, J and Platikanov, S and van Drooge, BL and Bedia, C}, title = {Contrasting neurotoxic pathways triggered by PM10 in relation with organic molecular markers in suburban and rural sites in Catalonia.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {408}, number = {}, pages = {128961}, doi = {10.1016/j.envpol.2026.128961}, pmid = {42600830}, issn = {1873-6424}, abstract = {Air pollution, particularly particulate matter (PM), is a major driver of global morbidity and mortality, with increasing evidence linking it to neurological disorders. This study investigates the chemical composition and neurotoxic potential of PM collected simultaneously in three sites in Catalonia (Spain): Bellver de Cerdanya (rural background), Manlleu (suburban), and Mollet del Vallès (suburban-industrial). Fifty-four filter samples collected in 2022 were analyzed by GC-MS for 30 organic molecular tracers, including polycyclic aromatic hydrocarbons (PAHs) and levoglucosan. Extracts were tested in SH-SY5Y human neuroblastoma cells across six toxicity endpoints: cell viability, reactive oxygen species (ROS), acetylcholinesterase (AChE) activity, antioxidant response, xenobiotic response, and p53 activation (DNA damage response). Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) on the combined chemical-biological dataset resolved four components: a winter biomass burning component enriched in levoglucosan, dehydroabietic acid, and PAHs, inducing strong cytotoxicity, oxidative stress, and xenobiotic responses; a traffic component present throughout the year; a spring-summer secondary organic aerosol (SOA) component associated with selective AChE inhibition without cytotoxicity; and a summer primary organic aerosol (POA) component. Partial Least Squares (PLS) regression linked PM10 composition with toxicity responses. Five of six models were statistically significant (R[2]CV = 0.53-0.75), with the highest performance for ROS, p53 activation, and cell death (R[2]CV ≥ 0.62). Biomass burning markers and PAHs were the main predictors of oxidative stress and cytotoxicity, whereas biogenic SOA tracers showed low importance. These findings link specific PM10 sources to distinct neurotoxic effects and highlight the importance of controlling winter emissions.}, } @article {pmid42600917, year = {2026}, author = {deAndrés-Galiana, EJ and Fernández-Martínez, JL and Morís, G}, title = {Identifying candidate therapeutic targets in amyotrophic lateral sclerosis through a transcriptome-wide machine-learning consensus approach for drug repurposing.}, journal = {Neuroscience}, volume = {614}, number = {}, pages = {163-179}, doi = {10.1016/j.neuroscience.2026.08.017}, pmid = {42600917}, issn = {1873-7544}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Drug Repositioning/methods ; *Machine Learning ; Humans ; *Transcriptome ; Motor Cortex/metabolism/drug effects ; Gene Expression Profiling ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease for which effective disease-modifying therapies remain limited. This study aimed to derive internally recurrent ALS-associated transcriptional signatures and generate directionally interpretable drug-repositioning hypotheses using a consensus machine-learning framework. Two publicly available transcriptomic datasets from motor cortex (E-MTAB-2325) and blood (E-TABM-940) were analyzed using four feature-selection methods within 100 repetitions of 4-fold cross-validation. Probes recurrently selected in models achieving an accuracy of at least 0.90 were prioritized and examined using COGENA pathway enrichment and Connectivity Map drug-signature analysis. Fifteen qualifying models were obtained for the motor-cortex dataset and 55 for the blood dataset. No exact prioritized gene or probe identifier was shared between the two top-100 signatures, but pathway-level integration identified complementary evidence involving glial and immune regulation, proteostasis and vesicle trafficking, MAPK-related stress signaling, cytoskeletal and extracellular remodeling, and RNA-related processes. The motor-cortex dataset additionally emphasized astroglial support, glutamate handling, and inclusion-body regulation, whereas the blood dataset highlighted cytokine regulation and directionally heterogeneous immune, mitochondrial, and metabolic signals. Deferoxamine and disulfiram showed the clearest reversal-compatible profiles in motor cortex, whereas yohimbic acid and atovaquone showed reversal-compatible profiles in blood. Ciprofloxacin, prochlorperazine, and a compound group led by androsterone instead showed concordant connectivity. The results provide transparent, hypothesis-generating gene, pathway, and compound priorities, but they do not establish biomarkers, therapeutic efficacy, or clinical suitability and require validation in independent cohorts and experimental ALS models.}, } @article {pmid42600995, year = {2026}, author = {Ataei, R and Amini, J and Sanadgol, N and Simon, AF and Duennwald, ML}, title = {Circular RNAs in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {228}, number = {}, pages = {107574}, doi = {10.1016/j.nbd.2026.107574}, pmid = {42600995}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *RNA, Circular/metabolism/genetics ; Animals ; RNA-Binding Protein FUS/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, with most cases lacking a clear genetic basis. Emerging evidence highlights the involvement of non-coding RNAs, particularly circular RNAs (circRNAs), in disease onset and progression. Here, we investigated circRNAs implicated in ALS and related motor neuron diseases (MNDs). Here, we provide a general overview of circular RNA metabolism and cellular functions. We then present our systematic literature review that identified ALS-associated circRNAs, followed by in silico analyses of 15 circular RNA candidates that were selected based on the most compelling data regarding ALS. Our results revealed that several circular RNAs regulate ALS-related genes, such as unfolded protein response, oxidative stress, cell cycle regulation, and apoptosis. Protein-RNA interaction analysis further showed that ALS-related circRNAs can sponge 20 RNA-binding proteins. Additionally, molecular docking analysis demonstrated that ALS-associated FUS variants significantly alter its binding affinity to circular RNAs. RNA-seq data from ALS patients confirmed significant alterations in the expression of host genes of ALS-related circRNAs and hub proteins in ALS-affected CNS tissues. Collectively, our findings identify circRNAs as potential key contributors to ALS pathogenesis.}, } @article {pmid42601592, year = {2026}, author = {Shijo, T and Suzuki, N and Warita, H and Ikeda, K and Kato, M and Aoki, M}, title = {Poor Prognostic Factors After Gastrostomy in Patients With Amyotrophic Lateral Sclerosis: A Two-Center Retrospective Cohort Study.}, journal = {Muscle & nerve}, volume = {74}, number = {4}, pages = {1288-1292}, pmid = {42601592}, issn = {1097-4598}, support = {JPMH23FC1008//the MHLW/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/surgery/complications/diagnosis/physiopathology ; Cohort Studies ; *Deglutition Disorders/etiology/surgery ; *Gastrostomy ; Prognosis ; Retrospective Studies ; Vital Capacity ; }, abstract = {INTRODUCTION/AIMS: Percutaneous endoscopic gastrostomy (PEG) is widely used to manage dysphagia in patients with amyotrophic lateral sclerosis (ALS). However, some patients experience rapid clinical deterioration following the procedure. Prognostic factors specific to outcomes following PEG remain insufficiently defined.

METHODS: This two-center retrospective cohort study included 117 patients with ALS who underwent PEG prior to tracheostomy between April 2011 and June 2023. Cox proportional hazards modeling was used to identify independent prognostic factors following PEG. Explanatory variables included age, sex, onset site, percent of normal forced vital capacity (%FVC), disease duration from onset to PEG, and body mass index. Optimal cutoff values for continuous variables were determined using time-dependent receiver operating characteristic analyses.

RESULTS: Among six examined clinical variables, four were independently associated with worse outcomes after PEG placement as follows: male sex, spinal onset, lower %FVC at the time of PEG, and shorter duration from onset to PEG. Cutoff values were determined as %FVC < 63% and disease duration < 12 months. Log-rank analyses confirmed significantly shorter post-PEG survival in patients meeting these criteria.

DISCUSSION: Poorer respiratory function and shorter duration from disease onset to PEG were strongly associated with worse prognosis after PEG. Male sex emerged as an independent prognostic factor, suggesting potential biological differences in disease progression after gastrostomy. These findings underscore the importance of comprehensive clinical evaluation when considering PEG in patients with ALS.}, } @article {pmid42602697, year = {2026}, author = {Sgobbi, P and de Rezende Pinto, WBV and Seneor, DD and Orsini, M and Chieia, MAT and Oliveira, ASB}, title = {Update and recommendations on genetic testing for amyotrophic lateral sclerosis in clinical practice: a Brazilian expert view.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1928302}, pmid = {42602697}, issn = {1664-2295}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Genetic Testing/methods/standards ; Brazil ; Genetic Predisposition to Disease ; *Practice Guidelines as Topic/standards ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons. Although most ALS cases occur sporadically, without a known family history of the disease, genetic factors play a major role in its pathogenesis through monogenic, oligogenic, or polygenic mechanisms. It is estimated that 10-15% of ALS cases occur in a familial setting; however, a specific monogenic cause cannot always be identified. Establishing the underlying genetic basis in both sporadic and familial ALS is essential, as it enables individualized and family genetic counseling, facilitates the early identification of at-risk or oligosymptomatic relatives, improves the prediction of gene-specific clinical trajectories, and, more recently, determines eligibility for gene-targeted therapies, such as tofersen for SOD1-associated ALS and ulefnersen, currently under clinical investigation, for FUS-associated ALS. Over the years, differing opinions have existed regarding the role of genetic testing in individuals diagnosed with ALS. However, accumulating clinical evidence has increasingly supported the timely and early implementation of genetic testing as part of the standard clinical management of patients with ALS. In this article, we present the perspective of leading Brazilian neurologists specializing in ALS care regarding the current role of genetic testing in clinical practice.}, } @article {pmid42604810, year = {2026}, author = {Littger, B and Lorenzl, S and Schuchter, P and Bublitz, S}, title = {An Encouragement to Broaden the Frame: Spiritual Care as a Complementary Perspective on Healthcare Professionals' Emotional Experiences in ALS.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70379}, pmid = {42604810}, issn = {1097-4598}, } @article {pmid42604981, year = {2026}, author = {Falcone, C and Arckens, L and Baiula, M and Bedini, A and Bocchi, R and Broadhead, MJ and Caprini, M and Cavaliere, F and Cesca, F and Chowdhury, HH and Ciuba, K and Civiero, L and Escartin, C and Ferroni, S and Formaggio, F and Frasca, A and Gratton, R and Holt, M and Iraci, N and Kreft, M and Leggio, L and Lia, A and Malik, AR and Min, R and Müller, FE and Murat, C and Pereira, MJ and Pekowska, A and Petrelli, F and Ramos-Gonzalez, P and Sanchez-Mico, MV and Smole, Z and Sokolova, D and Solas, M and Soldano, A and Szewczyk, LM and Torazza, C and Severino, FPU and Urrestizala-Arenaza, N and Zeug, A and Zhou, J and Zonta, M and Zorec, R and Verkhratsky, A and Gunhanlar, N}, title = {Written in the Stars: Astrocyte Biology From Evolution to Disease.}, journal = {Acta physiologica (Oxford, England)}, volume = {242}, number = {9}, pages = {e70289}, pmid = {42604981}, issn = {1748-1716}, support = {CNS2025-166813//MICIU/AEI (Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación, Spain)/ ; RYC2021-033202-I//MICIU/AEI (Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación, Spain)/ ; PID2023-146385NA-I00//MICIU/AEI (Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación, Spain)/ ; PID2024-160537OB-I00//MICIU/AEI (Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación, Spain)/ ; 951923//European Commission (H2020)/ ; //European Union - NextGenerationEU/PRTR/ ; 2023.17564.ICDT//FCT (Fundação para a Ciência e a Tecnologia, Portugal)/ ; UMO-2018/01/H/NZ4/00001//National Science Centre (NCN, Poland)/ ; UMO-2021/43/B/NZ2/02934//National Science Centre (NCN, Poland)/ ; UMO-2021/42/E/NZ2/00392//National Science Centre (NCN, Poland)/ ; UMO-2023/51/D/NZ3/02998//National Science Centre (NCN, Poland)/ ; 2024/54/E/NZ4/00134//National Science Centre (NCN, Poland)/ ; 2024/53/B/NZ4/03058//National Science Centre (NCN, Poland)/ ; A2023021F//BrightFocus Foundation/ ; 2023.00418.BD//Fundação para a Ciência e a Tecnologia (FCT) doctoral fellowship/ ; G0C9922N//KU Leuven Research Council (C14/20/071) and the Research Foundation Flanders (FWO), Belgium/ ; }, mesh = {Humans ; *Astrocytes/physiology/pathology ; Animals ; *Biological Evolution ; *Brain ; *Neurodegenerative Diseases/metabolism/pathology ; *Nervous System Diseases ; }, abstract = {In the 21st century, neuroglial research has entered a period of Renaissance, extending the views of prominent neuroanatomists and neurologists of the 19th and early 20th centuries, who assigned to glial cells numerous physiological functions and highlighted their fundamental role in the pathophysiology of nervous system diseases. Astrocytes are highly diversified in structure and function; they control brain homeostasis, support synaptic connectivity, and enable information processing in neural networks. Evolutionary diversification of astrocytes, initially emerging as supportive cells of primitive sensory organs, drove a continuous expansion of astroglial complexity and functional versatility, ultimately making them indispensable neuroprotectors and homeostatic regulators. The large, morphologically elaborate astrocytes of the human brain arguably reflect an evolutionary response to increased neuronal homeostatic demands. Astrocytes are indispensable for synaptic function, serving as the principal regulators of neurotransmitter turnover and neuronal excitability. Astrocytes also govern brain energy metabolism, mitochondrial dynamics, and calcium signaling, thereby actively shaping cortical plasticity and circuits. Astrocytes are fundamental elements of the pathophysiology of neurological, neuropsychiatric, and neurodegenerative diseases, including Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, Rett syndrome, genetic astrocytopathies, and neurotrauma, where they demonstrate complex reactive changes directed at tissue preservation and regeneration, but which can also contribute to disease progression. Advances in single-cell transcriptomics, calcium imaging, chemogenetics, and iPSC-based models have transformed our understanding of astrocyte diversity and disease-specific dysfunction, opening new avenues of investigation. Given that no CNS disorder is known to occur without astrocyte involvement, multiple astrocyte-specific molecules represent compelling targets for cell-directed therapeutic strategies.}, } @article {pmid42605296, year = {2026}, author = {Ferdoush, S and Seklani, M and Kumar, P and Abekoon Mudiyanselage, SRJ and Dsouza, A}, title = {Acute Hypercapnic Respiratory Failure as the Initial Presentation of Motor Neuron Disease: A Respiratory Diagnostic Challenge.}, journal = {Cureus}, volume = {18}, number = {7}, pages = {e112832}, pmid = {42605296}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by degeneration of the upper and lower motor neurons, with respiratory muscle involvement typically occurring in the later stages of the disease. Presentation with acute hypercapnic respiratory failure as the initial clinical manifestation is uncommon and frequently leads to diagnostic delay or misattribution to primary cardiopulmonary pathology. We present the case of a 60-year-old man with no prior respiratory history who presented with acute dyspnea and was found to have severe hypercapnic respiratory failure requiring urgent noninvasive ventilation. Clinical examination and initial investigations revealed no clear intrinsic pulmonary cause. A detailed history subsequently identified a four-month progression of neurological symptoms, including dysarthria, sialorrhea, asymmetric upper limb weakness, and significant unintentional weight loss. Neurological examination demonstrated tongue fasciculations, widespread muscle wasting, and a combination of upper and lower motor neuron signs. Following acute stabilization and discharge with domiciliary noninvasive ventilation, a specialist neurological assessment confirmed a diagnosis of ALS. This case highlights the clinical importance of considering underlying neuromuscular causes in patients presenting with unexplained hypercapnic respiratory failure, particularly when clinical findings are discordant with the severity of the gas exchange abnormalities. Early recognition of ALS in this context facilitates the timely initiation of ventilatory support and multidisciplinary care, which are essential for optimizing survival and quality of life.}, } @article {pmid42606140, year = {2026}, author = {Flores, SV and Lillo, P and Briceño-Moya, J}, title = {Population-Level Nucleotide Diversity and Genetic Differentiation at SOD1 Across Global Human Populations.}, journal = {Annals of human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1111/ahg.70052}, pmid = {42606140}, issn = {1469-1809}, abstract = {BACKGROUND: The SOD1 gene encodes superoxide dismutase 1, an antioxidant enzyme in which pathogenic variants cause a subset of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although the clinical and molecular consequences of SOD1 variants are well established, its locus-wide population genetic architecture has not been systematically characterized across global populations.

OBJECTIVE: To characterize patterns of genetic diversity, population differentiation, and evolutionary constraint across the SOD1 locus in worldwide human populations.

METHODS: We analyzed genomic variation spanning the SOD1 region in the five continental populations of the 1000 Genomes Project. Nucleotide diversity (π), fixation index (FST), and allele frequency distributions were estimated using sliding-window analyses. Bootstrap resampling was used to compare diversity within and outside the coding region. Recent positive selection was assessed using XP-nSL, and codon-based evolutionary analyses were performed using primate SOD1 orthologs.

RESULTS: The coding region consistently exhibited a twofold to threefold reduction in nucleotide diversity relative to adjacent genomic sequences across all populations. Bootstrap analyses confirmed significantly lower diversity within the locus than in flanking regions (p < 0.05 in all populations). Population differentiation was low (mean FST ≈ 0.03) and showed no pronounced peaks within the coding interval, whereas allele frequency distributions were broadly similar across continental populations. XP-nSL analyses detected no evidence of population-specific recent selective sweeps. Codon-based analyses identified only 31 variable codons among 155 analyzed positions, six codons under negative selection, and no evidence of positive selection.

CONCLUSION: The SOD1 locus exhibits reduced standing genetic variation, limited continental differentiation, and strong evolutionary conservation, consistent with sustained functional constraint. These findings provide a comprehensive population genetic framework for interpreting genetic variation at this medically important locus.}, } @article {pmid42606797, year = {2026}, author = {Raghunathan, T and Parthasarathy, B and Prabhu, P and Mahesh, P and Dhanushkodi, A}, title = {Regenerative strategies for ALS: stem cells and extracellular vesicles.}, journal = {Discover nano}, volume = {21}, number = {1}, pages = {}, pmid = {42606797}, issn = {2731-9229}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is caused by progressive degeneration of upper and lower motor neurons. The disease is late onset, and to date, no early diagnosis is possible. Patients with ALS have a 5-year survival rate since diagnosis. Though recent studies highlighted the possible mechanisms of motor neuron degeneration in ALS, the treatment options are extremely limited. This underscores the urgent need to develop effective therapeutic strategies that can prolong patient survival and ultimately slow/halt ALS progression. Extracellular vesicles released from the degenerative milieu contribute to ALS propagation and progression by shuttling misfolded proteins, proinflammatory cytokines, and neurotoxins; thus, they could serve as a biomarker for diagnosis and prognosis. The advancement of stem cell-based therapies for neurodegenerative diseases and the evolving understanding of extracellular vesicles as potential biotherapeutics provide a ray of hope for millions of patients suffering from neurological disorders/neurodegenerative diseases like ALS.}, } @article {pmid42607915, year = {2026}, author = {Zhang, Y and Dong, X and Shai, Y and Alam, M and Han, D and Hu, Y and He, Z and Zhou, Z and Jiang, H}, title = {Annexin A1 inhibits neuronal apoptosis in amyotrophic lateral sclerosis by restraining the Hippo pathway.}, journal = {Brain research}, volume = {1891}, number = {}, pages = {150510}, doi = {10.1016/j.brainres.2026.150510}, pmid = {42607915}, issn = {1872-6240}, abstract = {Annexin A1 (ANXA1) is a multifunctional regulatory protein involved in neuroinflammation and cellular homeostasis, but its role in amyotrophic lateral sclerosis (ALS) remains unclear. In this study, we investigated the relationship between ANXA1 and Hippo pathway signaling in ALS. Bioinformatic analysis of transcriptomic data from iPSC-derived motor neurons showed that ANXA1 expression was reduced in ALS and associated with apoptosis and Hippo pathway-related changes. Decreased ANXA1 expression was confirmed in hSOD1^G93A transgenic mice and NSC34 motor neuron-like cells. Phosphorylation levels of MST1/2, LATS1/2, and YAP1 were elevated, indicates activation of the Hippo pathway. Functional experiments showed that ANXA1 overexpression reduced Hippo pathway activation, enhanced cell viability, and decreased apoptosis, as increased Bcl-2 expression and reduced Bax and cleaved caspase-9 levels. In contrast, ANXA1 knockdown further activated Hippo pathway and aggravated apoptotic changes. These findings identify ANXA1 as an upstream regulator associated with Hippo pathway activation in ALS and suggest that the ANXA1/Hippo axis may represent a potential therapeutic target.}, } @article {pmid42608759, year = {2026}, author = {Talukdar, G and Cvetanovic, M}, title = {Relationship of polyglutamine expansion and loss of ataxin-1 function in neurological diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01950}, pmid = {42608759}, issn = {1673-5374}, abstract = {Ataxin-1 (ATXN1) was originally identified as a gene in which abnormal expansion of glutamine encoding CAG repeats causes inherited neurodegenerative disease spinocerebellar ataxia type 1. Spinocerebellar ataxia type 1 is characterized by alterations in movement, cognition, and mood, with severe pathology in the cerebellum and brain stem. Studies in spinocerebellar ataxia type 1 mouse models indicated that CAG expansion predominantly causes pathogenic ATXN1 gain-of-function in the cerebellum. Conversely, mice lacking ATXN1 are severely impaired in cognitive tests and exhibit abnormalities in cortical functions. Subsequent genetic and functional studies have associated ATXN1 with intelligence and several neurological conditions, including Alzheimer's disease, amyotrophic lateral sclerosis, schizophrenia, and multiple sclerosis. In some conditions, association is found with CAG expansions in ATXN1 and in others with the loss of ATXN1 expression. Additionally, recent studies indicate the role of ATXN1 in glial cells. Here, we review current genetic and functional evidence of how ATXN1 CAG expansion and loss of ATXN1 function contribute to brain dysfunction in spinocerebellar ataxia type 1, Alzheimer's disease, and multiple sclerosis, with an emphasis on glial cells.}, } @article {pmid42608803, year = {2026}, author = {Xiao, Y and Yao, X and Mao, H and Xu, Y and Liu, Z and Li, Y and Yang, X and Liu, X}, title = {Annual monitoring reveals spatiotemporal dynamics of multiple herbicide resistance in Echinochloa crus-galli populations across Zhejiang Province, China.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71186}, pmid = {42608803}, issn = {1526-4998}, support = {//"Three Rural Areas-Nine Parties" Science and Technology Collaboration Program of Zhejiang Province/ ; //National Key Research and Development Program of China/ ; //National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Echinochloa crus-galli is a damaging weed in global rice production with rapidly evolving herbicide resistance. This study investigated resistance dynamics to six major herbicides across Zhejiang Province, China (2022-2024), to inform region-specific management.

RESULTS: A 3-year systematic monitoring covering 356 populations from 27 counties revealed that the annual resistance frequency of quinclorac consistently exceeded 50.00%. Cyhalofop-butyl resistance ranged from 32.18% to 61.18%. Penoxsulam resistance ranged from 24.14% to 50.59%. Resistance to bispyribac-sodium was detected in 25.00% of populations in 2023 and 81.18% in 2024. Resistance to the newly introduced florpyrauxifen-benzyl was detected in 49.41% of populations in its first monitoring year (2024). Metamifop remains largely effective due to low resistance frequency (6.90%-16.47%). In 2023, four populations resistant to all tested herbicides were detected, increasing to seven in 2024. Molecular analysis identified acetyl-CoA carboxylase (ACCase) target-site mutations I2041N and C2088R and the acetolactate synthase (ALS) mutation W574L as contributing factors, but the majority of cross-resistant populations lacked known target-site mutations, suggesting that non-target-site metabolic resistance is predominant. Under controlled conditions, propanil maintained complete control against all tested multiple-resistant populations.

CONCLUSION: Observed trends in E. crus-galli resistance include the widespread emergence of multiple resistance to ALS and ACCase inhibitors and regional variation linked to cropping intensity. Reported resistance frequencies are conditional estimates from problem fields, not unbiased provincial rates. Non-target-site resistance predominates among cross-resistant populations. Propanil is a promising alternative pending field validation. These findings support developing region-specific resistance management strategies for rice production in Zhejiang. © 2026 Society of Chemical Industry.}, } @article {pmid42609140, year = {2026}, author = {Wedgwood, HE and Tuxworth, RI and Ahmed, Z}, title = {Exploring Genetic Therapies Targeting Amyotrophic Lateral Sclerosis in Animal Models: A Systematic Review and Meta-Analysis.}, journal = {The journal of gene medicine}, volume = {28}, number = {8}, pages = {e70106}, pmid = {42609140}, issn = {1521-2254}, support = {//LifeArc/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; Disease Models, Animal ; *Genetic Therapy/methods ; Motor Neurons/pathology/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative disease, for which there is currently no known cure. ALS primarily affects motor neurons, with rapid deterioration, meaning symptoms develop quickly, from problems with speech and muscle weakness to breathing issues and paralysis. This systematic review aimed to explore the preclinical efficacy of various genetic therapies used to target ALS using in vivo rodent models.

METHODS: In vivo studies of genetic therapies targeting ALS and its symptoms published between January 2015 and December 2025 were included in this review. The following databases were used: Web of Science, Scopus and PubMed. The primary outcome investigated was the total number of motor neurons, with secondary outcomes of rodent survival and muscle function by observing rotarod performance also being analysed. The SYRCLE tool was used to assess risk of bias in included studies.

RESULTS: Of the 451 studies identified by searching the databases, 53 studies were found to be eligible for this systematic review. The articles were divided into subcategories depending on the gene target of each therapy. Meta-analysis of outcomes within appropriate studies showed significant improvements for the majority of selected outcomes (p < 0.05), favouring genetic therapy intervention.

CONCLUSIONS: Results suggest that genetic therapies in rodent models targeting ALS are effective. However, due to a high risk of bias in preclinical studies, further high-quality studies are warranted to support this conclusion and onward translation into the clinic.}, } @article {pmid42609516, year = {2026}, author = {Li, T and Zhang, Q and Wu, Y and Huang, R}, title = {Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets.}, journal = {MedComm}, volume = {7}, number = {9}, pages = {e70915}, pmid = {42609516}, issn = {2688-2663}, abstract = {Neurodegenerative diseases (NDs) are marked by selective neuronal vulnerability and progressive failure of neural circuits. Increasing evidence indicates that neuronal loss is not driven by a single terminal event, but emerges from interacting regulated cell death (RCD) programs. These programs are closely coupled to mitochondrial injury, proteostatic collapse, lysosomal stress, metabolic imbalance, glial state transitions, and chronic neuroinflammation. Yet, how distinct death pathways are organized across cell types, disease stages, and disease-specific microenvironments remains unresolved. This review examines RCD as an integrated pathogenic network in major NDs. Caspase and B-cell lymphoma 2 (BCL2) family signaling, receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein activation, NOD-like receptor family pyrin domain containing 3 and gasdermin signaling, GPX4-linked lipid peroxidation control, and autophagy lysosomal failure are discussed as convergent stress response modules rather than isolated pathways. Across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, these modules shape neuronal fate through disease-specific interactions with mitochondrial dysfunction, iron dyshomeostasis, inflammasome activation, and microglial metabolic remodeling. We further evaluate emerging therapeutic strategies that target cell death crosstalk, restore autophagy lysosomal competence, or improve delivery to the central nervous system, highlighting the importance of molecular selectivity, cellular context, disease stage, and translational feasibility.}, } @article {pmid42609692, year = {2026}, author = {Lazinkaitė, M and Avery, M and Olley, R and Stankūnienė, A and Czabanowska, K and Stankūnas, M}, title = {Authentic Leadership in Lithuanian Healthcare: A Qualitative Exploratory Study of Health Managers' Views and Experiences.}, journal = {Acta medica Lituanica}, volume = {33}, number = {1}, pages = {74-85}, pmid = {42609692}, issn = {1392-0138}, abstract = {Authentic Leadership (AL) is a value-based approach to leadership that focuses on self-awareness, relational transparency, balanced processing, and an internalized moral perspective. AL nurtures a supportive, high-trust work environment that boosts team cohesion, productivity, and ethical standards. In the healthcare workforce, the challenges and demands of person-centred care are significant, making AL a valuable opportunity to enhance the effectiveness of leadership and management. This study explored the key constructs and opportunities of AL within the context of the Lithuanian health system. A qualitative interpretative phenomenological approach was used to conduct semi-structured interviews with senior healthcare managers in Lithuania. The goal was to explore how these leaders understood and practiced AL. Thematic analysis was performed on the transcriptions of study participants' semi-structured interviews about perceptions of AL's four theoretical dimensions. The findings identified that Lithuanian healthcare leaders view self-awareness, moral integrity, and adaptability as central to effective leadership. Leaders emphasized self-reflection, openness to feedback, and moral consistency as crucial to their roles, enabling them to manage complex ethical responsibilities and strengthen organizational trust. AL has been shown to promote resilience in dynamic healthcare settings, thereby enabling adaptability and innovation. Leaders valued transparency and inclusive decision-making to ensure that diverse perspectives informed the team strategies. This study indicates that AL is an effective leadership approach for healthcare management in Lithuania. Our findings suggest that healthcare organizations could benefit from AL-based training programs, which may improve leaders' self-reflective practices, ethical decision-making, and collaboration skills.}, } @article {pmid42609882, year = {2026}, author = {Bottale, I and Spinelli, EG and Basaia, S and Ghirelli, A and Gardoni, A and Russo, T and Canu, E and Castelnovo, V and Schito, P and Falzone, Y and Filippi, M and Agosta, F}, title = {Altered perivascular space diffusivity dynamics in motor neuron disease.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag307}, pmid = {42609882}, issn = {2632-1297}, abstract = {Converging evidence supports a key pathogenic role of the glymphatic system in the accumulation of pathological aggregates in several central nervous system proteinopathies, including amyotrophic lateral sclerosis and other motor neuron diseases. This study aimed to investigate potential glymphatic impairment using diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) across motor neuron disease phenotypes, to examine its clinical correlates, and to assess its relationship with white matter damage. Fifty-seven patients with motor neuron disease and 32 age- and sex-matched healthy controls underwent a 3 Tesla brain MRI scan, including diffusion tensor imaging sequences. We obtained the DTI-ALPS index from each individual, evaluating its relationship with measures of motor and cognitive disability, site of symptom onset, cognitive status, genetic status and fractional anisotropy of white matter tracts. Comparisons between groups were evaluated using analysis of covariance adjusting for age, sex, local fractional anisotropy and white matter hyperintensity burden. Partial correlations with clinical and cognitive measures were also tested. Patients with motor neuron disease exhibited significantly lower DTI-ALPS index values relative to healthy controls (P = 0.05). Patients with bulbar onset had lower DTI-ALPS values than those with spinal onset (P = 0.017). Comparable DTI-ALPS values were found across patients with classical amyotrophic lateral sclerosis clinical presentation and predominant upper or lower motor neuron clinical presentations, with no effect of cognitive diagnosis or genetic status. DTI-ALPS exhibited a significant correlation with disease duration (r = -0.38, P = 0.01). Motor neuron disease patients presenting insomnia had significantly lower DTI-ALPS values compared to those without sleep disturbances (P = 0.002). Significant positive correlations were found between ALPS index and fractional anisotropy values across major white matter tracts, including the internal and external capsules, superior longitudinal fasciculi, anterior, posterior and superior corona radiata, posterior thalamic radiation, fornix and the genu and body of the corpus callosum. This study confirms the presence of altered interstitial fluid diffusivity dynamics across motor neuron disease phenotypes, with greater impairment observed in bulbar-onset cases, patients with longer disease duration, and those experiencing more pronounced sleep disturbances. These findings may support a potential pathogenic role of glymphatic failure in the accumulation of TAR DNA-binding protein 43 proteinopathy and widespread microstructural axonal damage in motor neuron diseases.}, } @article {pmid42610023, year = {2026}, author = {Ettl, F and Eibensteiner, F and Greif, R and Mayhardt, S and Nern, S and Kurz, LM and Daniels, BA and Körmöczi, GF and Anvari-Pirsch, A and Grafeneder, J and Schriefl, C}, title = {Virtual reality, real-world rhythm: evaluating gamified training for medical students.}, journal = {Frontiers in public health}, volume = {14}, number = {}, pages = {1833908}, pmid = {42610023}, issn = {2296-2565}, mesh = {Humans ; Male ; *Students, Medical/statistics & numerical data ; *Virtual Reality ; Female ; Surveys and Questionnaires ; *Education, Medical, Undergraduate/methods ; Adult ; Clinical Competence ; Young Adult ; Electrocardiography ; *Video Games ; }, abstract = {BACKGROUND: Virtual reality (VR) and gamification are increasingly recommended as adjuncts in resuscitation education, but their integration into undergraduate medical curricula and data on usability and learner acceptance remain limited. We evaluated a newly developed, gamified VR training application for medical students during their preparation for an Objective Structured Clinical Examination (OSCE).

METHODS: In this single-centre observational questionnaire study, fourth-year medical students completed VR-based advanced life support (ALS) training with randomized electrocardiogram (ECG) rhythms and gamified decision tasks. The primary outcome was usability measured with the Virtual Reality System Usability Questionnaire (VRSUQ; 0-100 points). Secondary outcomes included VR-induced symptoms (VRSQ; 0-100 points), self-rated rhythm-analysis competence before and after training (1-10), self-rated in-app performance (0-10), and trainer-reported feasibility. Continuous variables are presented as median (interquartile range [IQR]). Associations between outcomes were assessed using Spearman rank correlation coefficients.

RESULTS: Of 660 eligible students, 294 (44.5%) participated in the VR-study and completed the questionnaires. Usability was high (VRSUQ 83.3 [IQR 72.2-91.7]). VR-induced symptoms were low (VRSQ 8.3 [IQR 0.0-16.7]). Self-rated competence increased from 5.0 (IQR 4.0-7.0) before training to 8.0 (IQR 7.0-8.0) after training (p < 0.001), corresponding to a competence gain of 2.0 points (IQR 1.0-3.0). Self-rated performance was 7.0 (IQR 5.0-8.0) and correlated with usability (ρ = 0.44, p < 0.001). Overall training quality was rated 9.0 (IQR 8.0-10.0), and 91.9% would participate again. Usability did not differ between genders but was higher among students with prior VR experience. Trainers reported short setup times, manageable supervision ratios, and occasional technical support needs.

CONCLUSION: Gamified VR-based ALS training for medical students is feasible, demonstrates high usability and low symptom burden, and improves self-assessed competence. VR appears to be a well-accepted adjunct to undergraduate resuscitation education.}, } @article {pmid42610209, year = {2026}, author = {Lv, C and Zhu, W and Wen, X and Da, Y}, title = {Spatiotemporal Dynamics and Cellular States of Neuroinflammation in Amyotrophic Lateral Sclerosis: Implications for Stage‑Specific Therapeutics.}, journal = {ASN neuro}, volume = {18}, number = {1}, pages = {2715625}, pmid = {42610209}, issn = {1759-0914}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/pathology/therapy ; Animals ; *Neuroinflammatory Diseases/immunology/pathology/therapy ; Disease Progression ; Blood-Brain Barrier ; Inflammation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex and heterogeneous pathogenesis. Accumulating preclinical and clinical evidence indicates that neuroinflammation is an important modulator of ALS pathophysiology, involving activation of resident central nervous system immune cells, dysfunction of glial support systems, disruption of neurovascular barriers, and altered recruitment of peripheral immune cells. ALS-associated neuroinflammation is temporally dynamic and varies across anatomical compartments and cellular contexts. Multiple animal models, human neuroimaging, and post-mortem tissue suggest that relatively regulated or compensatory immune responses during early stage may progressively shift to persistent, maladaptive, and potentially neurotoxic inflammatory circuits in later stage. Although previous studies have described stage-dependent changes in individual immune cell populations, an integrated stage-dependent systematic framework that unifies dynamic alterations in both central and peripheral immune compartments remains insufficiently established. In this review, we propose a four-phase conceptual framework for ALS neuroinflammation across the progressive ALS pathogenesis, aiming to provide theoretical guidance for staging inflammatory therapeutic interventions.}, } @article {pmid42611011, year = {2026}, author = {Zdrowak, KE and Mefferd, AS and Stipancic, KL}, title = {Dissociable Effects of Dysarthria Etiology and Severity on the Minimally Detectable Change of Speech Intelligibility.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {}, number = {}, pages = {1-13}, doi = {10.1044/2026_JSLHR-25-00740}, pmid = {42611011}, issn = {1558-9102}, abstract = {PURPOSE: The minimally detectable change (MDC) provides a threshold for interpreting changes in outcome measures that are outside of measurement error. There is emerging evidence that dysarthria etiology and speech severity impact the MDC of speech intelligibility; however, an investigation of these factors is needed to determine the unique effects of dysarthria etiology and speech severity. The purpose of the current study was to calculate and compare MDCs of speech intelligibility across five dysarthria etiology groups and four severity levels.

METHOD: Speech Intelligibility Test recordings from 200 speakers were used as stimuli, including recordings from healthy controls (n = 40) and individuals with neurodegenerative diseases such as amyotrophic lateral sclerosis (n = 16), Huntington's disease (n = 44), multiple sclerosis (n = 60), and Parkinson's disease (n = 40). Thirty inexperienced listeners provided orthographic transcriptions of 20 speakers each. MDCs were calculated, and speech severity levels were categorized based on empirically defined speech severity levels reported in Stipancic et al. (2021). Statistical analyses, including multiple linear regression, assessed the effects of etiology and severity on MDCs.

RESULTS: Speech severity was a significant predictor of MDCs, with greater impairments to speech intelligibility resulting in higher MDCs. Dysarthria etiology was not a significant predictor of MDCs.

CONCLUSION: The impact of speech severity on MDCs of intelligibility in dysarthria underscores the need to calculate and provide MDCs across severity ranges to enhance the interpretation of patient outcomes.}, } @article {pmid42612409, year = {2026}, author = {Iacobelli, V and Vizziello, M and Clementi, L and Anversa, P and Cazzato, D and De Grado, A and Gallone, A and Izzo, MGA and Lanteri, P and Usai, S and Lauria, G and Rossi Sebastiano, D and Dalla Bella, E}, title = {Revisiting somatosensory evoked potentials in motor neuron diseases: neurophysiological insights from a large cohort.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {191}, number = {}, pages = {2112372}, doi = {10.1016/j.clinph.2026.2112372}, pmid = {42612409}, issn = {1872-8952}, mesh = {Humans ; *Evoked Potentials, Somatosensory/physiology ; Female ; *Motor Neuron Disease/physiopathology/diagnosis ; Male ; Middle Aged ; *Evoked Potentials, Motor/physiology ; Retrospective Studies ; Aged ; Cohort Studies ; Transcranial Magnetic Stimulation/methods ; Adult ; }, abstract = {OBJECTIVE: To systematically investigate Somatosensory Evoked Potential (SEP) abnormalities in a large cohort of patients with Motor Neuron Disease (MND), and to explore their relationship with Motor Evoked Potentials (MEPs) and clinical phenotypes.

METHODS: We retrospectively analyzed 267 patients with confirmed MND who underwent standardized SEPs and transcranial magnetic stimulation. Patients were divided into pure/predominant Upper Motor Neuron (UMN) and pure/predominant Lower Motor Neuron/Amyotrophic Lateral Sclerosis (LMN/ALS) groups. SEP abnormalities were assessed using internal normative data, including prolonged latencies, reduced amplitudes, and increased N20-P25 amplitudes. MEPs were classified semi-quantitatively as normal or abnormal by independent raters.

RESULTS: At least one SEP abnormality was detected in 75 % of patients, with no significant differences between the UMN and LMN/ALS groups. Increased N20-P25 amplitudes were observed in both phenotypes, suggesting widespread sensory cortical hyperexcitability across the MND spectrum. In contrast, abnormal MEPs were significantly more frequent in UMN patients (p < 0.001). No significant association was found between SEP abnormalities and MEP findings. Upper- and lower-limb SEP latencies were strongly correlated (all p < 0.001), whereas increased SEP amplitudes did not correlate with latency abnormalities.

CONCLUSIONS: SEP abnormalities are highly prevalent in MND and appear largely independent from corticospinal dysfunction. Increased SEP amplitudes likely reflect primary cortical sensory hyperexcitability rather than impaired sensory conduction.

SIGNIFICANCE: These findings support the concept of MND as a multisystem network disorder that involves sensory cortical circuits and highlight the role of SEPs in the diagnostic workup.}, } @article {pmid42612795, year = {2026}, author = {Li, J and Duan, H and Hao, P and Zhao, W and Gao, Y and Yang, Z and Li, X}, title = {Regenerative medicine for neurodegenerative diseases: history, strategies, and clinical advances.}, journal = {Translational research : the journal of laboratory and clinical medicine}, volume = {297}, number = {}, pages = {17-33}, doi = {10.1016/j.trsl.2026.08.005}, pmid = {42612795}, issn = {1878-1810}, abstract = {In the context of global ageing, the prevalence of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is rapidly increasing. However, current symptomatic treatments have achieved limited benefits in clinical settings and fundamentally fail to reverse the progressive loss of specific neuronal populations. Halting neurodegeneration and restoring impaired cognitive, motor or visual functions through nerve regeneration and circuit reconstruction represent the clinically meaningful goals for treatments of NDDs. Regenerative medicine has emerged as a promising paradigm to address this unmet need. In this review, we trace the historical evolution of regenerative therapies for NDDs - from early exploratory cell transplantation to modern approaches involving pluripotent stem cells (PSCs) and in vivo direct reprogramming. Furthermore, we elucidate the core strategies of regenerative medicine within an integrated framework encompassing "Replacement", "Regeneration", and "Rejuvenation". Finally, we highlight recent advances in clinical research, particularly milestone trials in cell replacement therapy for PD, as well as the application of mesenchymal stem cells (MSCs) in AD and ALS.}, } @article {pmid42613144, year = {2026}, author = {Valverde, A and Blasco, H and Corcia, P and Herault, O and Magistretti, P and Herault, L and Cali, C and Bartesaghi, L and Stone, J and Mitrofanis, J}, title = {Exploring the effect of red and near-infrared light on neurodegenerative disease: A focus on amyotrophic lateral sclerosis, Charcot's devastating disease of the motor system.}, journal = {International review of neurobiology}, volume = {189}, number = {}, pages = {205-236}, doi = {10.1016/bs.irn.2026.01.013}, pmid = {42613144}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/radiotherapy ; Animals ; *Infrared Rays/therapeutic use ; Red Light ; *Neurodegenerative Diseases/therapy ; }, abstract = {All neurodegenerative diseases, from Alzheimer's disease to amyotrophic lateral sclerosis (ALS), are characterised by a relentless and progressive degeneration of neurones. The degenerating neurones suffer from mitochondrial dysfunction, glutamate excitotoxicity, metabolic disorder and atypical protein aggregations; there is also widespread neuroinflammation and damage to the neurovascular unit across the nervous system. Unfortunately, there is no current treatment option that addresses all, if not many, of these striking abnormalities, one that stops or even slows the progression of the disease (ie neuroprotective). In this chapter, we explore the potential effectiveness of red and near infrared light (R-NIr) on ALS, one of the most devastating of all the neurodegenerative diseases. This condition impacts the motor system, from the cerebral cortex and brainstem to the spinal cord, as well as many skeletal muscles. Individuals suffer greatly and the survival period after onset of the first signs is often very short, averaging just over 2 years, as against 4-8 years in dementia. We outline two main reasons why R-NIr may have positive outcomes in ALS; (1) R-NIr has been shown to be neuroprotective in many other neurodegenerative diseases, improving cell function and survival, and; (2) unlike many other treatments attempted previously, R-NIr addresses many, if not all features of pathology associated with ALS. In summary, we suggest that R-NIr, with its multi-modal effect, could be a valuable treatment option for patients with ALS, particularly if the treatment is started early, before the development of excessive cellular damage.}, } @article {pmid42613225, year = {2026}, author = {Light, A and Peters, M and Ahmed, HU and Shah, TT}, title = {Reply to Marcio C. Moschovas, Ugo Falagario, Francesco Pellegrino, et al's Letter to the Editor re: Alexander Light, Max Peters, Manit Arya, et al's Salvage Focal Therapy vs Radical Prostatectomy for Localized Radiorecurrent Prostate Cancer. JAMA Oncol 2026;12:364-73.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2026.07.033}, pmid = {42613225}, issn = {1873-7560}, } @article {pmid42613627, year = {2026}, author = {Jamali, MC and Shafie, A and Alqahtani, AJ and Al-Samawi, RI and Alyami, HM and Ashour, AA and Felemban, MF and Mansuri, N and Tayeb, FJ and Ahmad, I and Mudhafar, M and Sheweita, SA}, title = {Advances in the clinical application of mesenchymal stem cells for neurological disorders.}, journal = {Stem cell research & therapy}, volume = {17}, number = {1}, pages = {}, pmid = {42613627}, issn = {1757-6512}, mesh = {Humans ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/cytology/metabolism ; *Nervous System Diseases/therapy/pathology ; Animals ; Amyotrophic Lateral Sclerosis/therapy/pathology ; Alzheimer Disease/therapy/pathology ; }, abstract = {Therapeutic approaches employing mesenchymal stem cells (MSCs) have emerged as a promising avenue for investigating treatments for neurological disorders. This strategy aims to capitalize on the biological properties of MSCs to support the repair of damaged neural tissue and modulate pathological processes. This review provides a comprehensive overview of the current clinical evidence regarding MSC applications in major neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other pertinent disorders. Across clinical studies, MSC administration has generally demonstrated a favorable safety profile and procedural feasibility. However, therapeutic efficacy remains variable and inconsistent across trials. Importantly, differences in MSC sources, manufacturing procedures, delivery routes, dosing strategies, and patient selection contribute substantially to the heterogeneity of reported outcomes. Therefore, the current body of evidence supports the safety of MSC-based interventions, but their clinical effectiveness has not yet been consistently demonstrated. Future progress will depend largely on the standardization of cell preparation and treatment protocols, improved biomarker-driven patient stratification, and rigorously designed large-scale randomized trials.}, } @article {pmid42613642, year = {2026}, author = {Wang, JDJ and Teo, AYT and Xiao, B and Chao, Y and Zhou, ZD and Tan, BJ and Chan, LL and Rosalie, E and Tan, EK}, title = {PCSK9 inhibitors in neurodegenerative disorders: mechanisms, therapeutic potential, and clinical implications.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {42613642}, issn = {2047-9158}, support = {LCG//National Medical Research Council/ ; STaR//National Medical Research Council/ ; }, mesh = {Humans ; *PCSK9 Inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Proprotein Convertase 9/metabolism/genetics ; Animals ; }, abstract = {Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in hepatic cholesterol metabolism via low density lipoprotein receptor degradation. PCSK9 inhibitors have revolutionized lipid-lowering therapy, providing robust reduction of cardiovascular risk. Large-scale randomized controlled trials and long-term extensions (e.g., FOURIER and EBBINGHAUS trials) have shown no significant adverse effects of PCSK9 inhibitors on neuropsychological testing or patient-reported cognitive outcomes, even with prolonged and intensive lowering of low-density lipoproteins. Pre-clinical studies also suggest PCSK9 as a key regulator of neurobiological processes, including synaptic plasticity, amyloid-beta clearance, neuroinflammation, and blood-brain barrier integrity. Human genetic studies revealed complex, sometimes conflicting associations between PCSK9 variants and risk of Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis. In this review, we highlight the pathophysiologic mechanisms, emerging experimental therapeutics and clinical implications of PCSK9 inhibition in neurodegenerative disorders. Long-term adequately powered trials with robust neuropsychological, biomarker, and imaging endpoints, as well as mechanistic studies in human-derived models are needed to establish the cardiovascular and neurocognitive implications of PCSK9 inhibition and guide precision medicine strategies for those at elevated risk of neurodegeneration.}, } @article {pmid42613694, year = {2026}, author = {Shukla, S and Srivastava, V and Gaur, H and Rai, A}, title = {Myelin and Oligodendrocyte Dysfunction in Demyelinating and Neurodegenerative Disorders: Signaling Pathways and Therapeutic Targets.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273437393260729093129}, pmid = {42613694}, issn = {1996-3181}, abstract = {INTRODUCTION: Oligodendrocytes (OLs) synthesize myelin, a substance that plays a significant role in ensuring proper functioning of the Central Nervous System (CNS). Myelin abnormalities are involved in disease pathogenesis in AD, MS, and ALS. In contrast, MS involves autoimmune reactions directed against myelin. On the other hand, AD and ALS are characterized by neurodegeneration. This article seeks to give a critical discussion on myelin and OL dysfunction in these diseases, among others.

METHODS: A narrative literature search was carried out in various databases including Scopus, Google Scholar, Web of Science, and PubMed, focusing on papers relating to myelination, remyelination, and OLs, particularly those addressing signaling pathways and treatment strategies.

RESULTS: MS is an autoimmune disease characterized by inflammation that causes demyelination and OL dysfunction. Oxidative stress and mitochondrial dysfunction play roles in the pathogenesis of ALS, whereas AD is a result of disrupted neuronal supportive functions and myelin damage. Important signaling pathways involved in OL formation and myelin repair include the Wnt/β-catenin, AKT/mTOR, and ERK/MAPK pathways. Drugs like edaravone, ocrelizumab, and siponimod have been identified for promoting myelin repair.

DISCUSSION: The relationship between abnormal oligodendrocyte function, demyelination, and specific disease-related pathological processes demonstrates that although there is a similarity among MS, AD, and ALS, each condition possesses its own unique molecular foundation. One potential treatment approach would be targeting shared signaling pathways relevant to myelination and remyelination. Nonetheless, disease variability and specific pathogenic characteristics demand a targeted therapy approach.

CONCLUSION: Myelin integrity and oligodendrocyte function are central to the progression of demyelinating and neurodegenerative diseases. Targeting molecular pathways involved in myelination offers significant potential for improving disease outcomes and developing advanced therapeutic strategies.}, } @article {pmid42613775, year = {2026}, author = {Nalicho, JC and Mabeyo, PE and Paluch, AS and Paul, L}, title = {Integrated In Silico Discovery of Thymoquinone Analogs Targeting the Keap1-Nrf2 Pathway for Amyotrophic Lateral Sclerosis Therapy.}, journal = {ChemistryOpen}, volume = {15}, number = {9}, pages = {e70286}, pmid = {42613775}, issn = {2191-1363}, mesh = {*NF-E2-Related Factor 2/metabolism/antagonists & inhibitors/chemistry ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Benzoquinones/chemistry/pharmacology/metabolism/therapeutic use ; *Kelch-Like ECH-Associated Protein 1/metabolism/antagonists & inhibitors/chemistry ; Humans ; Quantitative Structure-Activity Relationship ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Signal Transduction/drug effects ; Drug Discovery ; Oxidative Stress/drug effects ; }, abstract = {Oxidative stress drives neuronal vulnerability in amyotrophic lateral sclerosis (ALS), making the Keap1-Nrf2 pathway a vital therapeutic target. While thymoquinone (TQ) modulates this axis, its efficacy is limited by low potency and poor drug-likeness. We utilized an integrated in silico workflow-including validated QSAR modeling (R[2] = 0.68, Q[2] ext = 0.66), ADMET profiling, docking, 200 ns molecular dynamics, and MM-PBSA analysis-to identify improved TQ-derived Keap1 inhibitors. Screening 64 analogs prioritized three leads (CHEMBL3416163, CHEMBL4636830, and CHEMBL221598) with favorable safety and blood-brain barrier permeability. Docking and dynamics confirmed these analogs form stable interactions with Kelch domain hotspots. MM-PBSA calculations revealed significantly enhanced binding free energies (-75.10 to -93.79 kJ mol[-1]) compared to parent TQ (-21.05 kJ mol[-1]), driven primarily by van der Waals and hydrophobic forces. This study identifies structurally tractable TQ analogs with improved predicted potency and establishes a robust computational framework for neuroprotective discovery. The prioritized leads are compelling candidates for in vitro and in vivo validation as redox-modulating agents in ALS.}, } @article {pmid42614182, year = {2026}, author = {Shevchuk, DV and Nuzhnyi, EP and Fedotova, EY and Ershova, MV and Minaev, IV and Anikin, GA and Protsenko, AR and Abramycheva, NY and Zakharova, MN and Illarioshkin, SN}, title = {Cerebellar ataxia-onset ALS with SOD1 D91A mutation: a rare phenotype.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1889931}, pmid = {42614182}, issn = {1664-2295}, mesh = {Humans ; *Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/complications/diagnostic imaging ; *Cerebellar Ataxia/genetics/physiopathology/diagnostic imaging ; Phenotype ; Male ; Middle Aged ; Female ; Adult ; Mutation/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) associated with mutations in the superoxide dismutase 1 (SOD1) gene is recognized for phenotypic variability, yet cerebellar ataxia as a presenting feature has been reported only in isolated cases.

METHODS: We describe four unrelated patients: three men and one woman, aged 35 to 49 years at symptom onset, who carried the SOD1 D91A (p.Asp91Ala) mutation. Two patients were heterozygous and two homozygous for the D91A variant. Clinical, neuroimaging, electrophysiological and genetic data were reviewed.

RESULTS: All patients presented with progressive gait ataxia as their initial and predominant symptom, with upper and lower motor neuron signs emerging months to years later and ultimately meeting criteria for ALS. Diagnostic latencies from ataxia onset to recognition of ALS ranged from 3 to 9 years. Cerebellar signs included gait and limb ataxia, dysmetria, intention tremor, and oculomotor abnormalities; neuroimaging revealed mild cerebellar atrophy only in one case, and electrophysiological evidence of lower motor neuron involvement was often limited at initial assessment. To our knowledge, this is the largest reported case series of patients homogeneous for a single SOD1 mutation and a shared cerebellar ataxia-onset ALS phenotype.

CONCLUSION: The findings expand the clinical spectrum of SOD1-associated ALS and underscore the importance of SOD1 genetic testing in patients with progressive adult-onset ataxia of undetermined origin, particularly given the emerging availability of SOD1-targeted therapies.}, } @article {pmid42614372, year = {2026}, author = {Watanabe, N and Kawahori, Y and Ta, V and Wang, D and Ohgi, KA and Wang, H and Kleschevnikova, N and Ishikawa, E and Head, BP}, title = {i.c.v. delivery of AAV9-synapsin-promoted caveolin-1 attenuates neuromuscular deficits and neuromuscular degeneration in hSOD1[G93A] mice.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {3}, pages = {201820}, pmid = {42614372}, issn = {3117-387X}, support = {IK6 BX006318/BX/BLRD VA/United States ; }, abstract = {Practical and broad biodistributable gene delivery interventions are essential for advancing therapeutic strategies targeting neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously demonstrated that subpial delivery of AAV9-synapsin-promoted caveolin-1 (SynCav1) afforded significant neuroprotective effects in mutant superoxide dismutase (SOD)-1-induced ALS pathology. However, subpial delivery is regionally restricted, technically challenging, and highly invasive. This study evaluated whether the intracerebroventricular (i.c.v.) route of administration (ROA), an alternative CNS delivery strategy less invasive than direct spinal cord injections, could achieve broader CNS biodistribution and produce functional or histological benefits in hSOD1[G93A] mice. i.c.v. administration of AAV9-SynCav1 achieved widespread Cav-1 overexpression in the motor cortex and spinal cord. SynCav1-treated male mice exhibited improved running wheel (RW) performance and better motor-evoked potentials. Immunofluorescence revealed attenuated degeneration of cholinergic motor neurons (MNs) in the cervical and lumbar ventral horn, as well as preserved diaphragm neuromuscular junction (NMJ) innervation in SynCav1-treated mice. These findings serve as preclinical proof of concept that i.c.v. delivery of AAV9-SynCav1 can achieve CNS target engagement and produce selective functional and anatomical benefits in hSOD1[G93A] mice.}, } @article {pmid42614391, year = {2026}, author = {Gomes-Duarte, A and Wong, JK and Moro, A and Pasteuning-Vuhman, S and Pos, W and Haselberg, R and Sogorb-González, M and Pascoal, S and Borst, L and Chatterjee, M and Giera, M and Tsimikas, S and Sadiq, SA and van Deventer, S}, title = {Neutralization of pathogenic PC-OxPL by AAV-delivered scFv as a therapeutic strategy for amyotrophic lateral sclerosis.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {3}, pages = {201822}, pmid = {42614391}, issn = {3117-387X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder defined by progressive motor neuron loss and TDP-43 proteinopathy, yet the upstream drivers of this pathology remain unclear. Oxidized phosphatidylcholines (PC-OxPL) have emerged as potent inducers of proteinopathy in the central nervous system (CNS), but their role in ALS has not been systematically explored. We identify a distinct PC-OxPL signature in the cerebrospinal fluid (CSF) of patients with sporadic ALS (sALS) and show that apolipoprotein E (apoE)-containing particles are the primary PC-OxPL carriers in this compartment. In human iPSC-derived motor neurons, PC-OxPL exposure triggered disease-relevant transcriptional alterations and TDP-43 pathology, establishing PC-OxPL as a mediator of ALS-like neurodegeneration in vitro. To counteract this toxicity, we engineered an Adeno-Associated Virus (AAV)-delivered single-chain antibody fragment (scFv), PC-OxPL-VecTab, targeting PC-OxPL neoepitopes. PC-OxPL-VecTab neutralized PC-OxPL-induced neurotoxicity, reduced TDP-43 aggregation, and prevented motor neuron death and behavioral deficits in a sALS CSF transfer mouse model. Intrathecal delivery of PC-OxPL-VecTab in minipigs achieved broad CNS biodistribution and transgene expression, supporting the feasibility of CNS delivery. These findings position PC-OxPL as a mechanistic contributor to ALS pathogenesis and establish PC-OxPL-VecTab as a therapeutic strategy for ALS with potential broader applicability to disorders associated with PC-OxPL accumulation.}, } @article {pmid42615765, year = {2026}, author = {Khazaal, M and Stretavská, P and Kuźma-Kozakiewicz, M and Nieporęcki, K and Betík, A and Vlčková, E and Koprušáková, MT and Petrovic, R and Cetin, H and Keritam, O and Löscher, W and Eggers, C and Iglseder, S and Orenčák, R and Molnár, MJ and Grosz, Z and Szlepák, T and Koritnik, B and Koszewicz, MA and Baumgartner, D and Slachtova, L}, title = {SOD1 Variants in Patients With Amyotrophic Lateral Sclerosis in Central Eastern Europe: From Genetic Testing to SOD1 Targeted Therapy.}, journal = {European journal of neurology}, volume = {33}, number = {8}, pages = {e70717}, pmid = {42615765}, issn = {1468-1331}, support = {PRIMUS UK 21/MED/012//Univerzita Karlova v Praze/ ; OP JAK MSCA GOALS//Ministerstvo Školství, Mládeže a Tělovýchovy/ ; 65269705//Fakultni nemocnice Brno/ ; MUNI/A/1728/2025//Masarykova Univerzita/ ; TKP2021 NVA-15//Nemzeti Kutatási Fejlesztési és Innovációs Hivatal/ ; OTKA139010//Nemzeti Kutatási Fejlesztési és Innovációs Hivatal/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/therapy/drug therapy ; *Superoxide Dismutase-1/genetics ; Female ; Middle Aged ; Male ; Genetic Testing ; Adult ; Europe, Eastern/epidemiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is one of the most devastating fatal motor neuron diseases, characterized by progressive degeneration of motor neurons in the brain and spinal cord. A significant advance in ALS therapy was achieved with the recent European Medicines Agency approval of Tofersen, the first antisense oligonucleotide (ASO) specifically targeting SOD1 mRNA, a key genetic determinant of the disease. Yet, despite its clinical relevance, data on SOD1-ALS in Central Eastern Europe remain scarce.

METHODS: Here, we present a multicentric study across six countries-Austria, Czechia, Poland, Hungary, Slovakia, and Slovenia-representing approximately 16% of the European Union's population. We report all pathogenic, likely pathogenic, and uncertain SOD1 variants, along with the phenotypic features, including heritability, age, site of onset, and survival. We also assessed the availability of genetic testing, counseling, and access to Tofersen therapy across the region.

RESULTS: Out of 1200 patients with confirmed ALS, we identified 24 distinct pathogenic SOD1 variants in a total of 67 patients (median age at onset 47 [40-55] years), of whom 65.7% had familial ALS (fALS) and 34.3% had sporadic ALS (sALS). We characterized the associated phenotypes and reported that 42 patients are currently receiving Tofersen therapy.

CONCLUSION: This study provides the first comprehensive overview of SOD1-ALS in Central Eastern Europe. Our findings underscore the importance of genetic testing and counseling, as well as equitable access to targeted therapies such as Tofersen to advance patient-specific care in this region.}, } @article {pmid42615866, year = {2026}, author = {Horton, DK and Raymond, J and Larson, T and Goutman, SA and Mehta, P}, title = {Multidisciplinary clinic attendance and patterns of care in the U.S. National ALS Registry, 2013-2023.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, pmid = {42615866}, issn = {2167-9223}, support = {CC999999/ImCDC/Intramural CDC HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) multidisciplinary clinics (MDCs) are the standard model of care, but national-level data on utilization and outcomes in the United States are lacking.

OBJECTIVE: To compare baseline characteristics and symptoms, clinical interventions and specialized care processes, and healthcare utilization among U.S. National ALS Registry (Registry) participants by MDC attendance.

METHODS: Registry data from 2013 to 2023 were analyzed for participants completing demographic and clinical surveys, stratified by MDC attendance (attendance vs. no attendance by survey completion).

RESULTS: Among 4764 participants, 77.0% reported attending an MDC. Baseline characteristics were similar between groups, including sex, age at diagnosis, and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. MDC attendees reported lower prevalence of dysphagia (23.6% vs. 27.5%, p = 0.007) and bowel/bladder issues (10.7% vs. 14.3%, p = 0.001). Attendees were more likely to use evidence-based interventions, including wheelchairs/scooters, noninvasive ventilation, percutaneous endoscopic gastrostomy (PEG), communication devices, and ALS disease-modifying therapies, specifically riluzole (72.7% vs. 48.1%) and edaravone (10.5% vs. 2.6%) (all p < 0.001). MDC attendees also demonstrated higher rates of specialized care processes, including advance directive completion, genetic testing, and prior research participation (all p < 0.001). For healthcare utilization, MDC attendance was associated with fewer emergency department visits among those with any use (RR 0.90, 95% confidence interval (CI) 0.82-0.99) and shorter hospital stays (β = -2.67 days, 95% CI -4.56 to -0.78).

CONCLUSION: MDC attendance was associated with greater uptake of evidence-based interventions, higher rates of specialized care processes, and reduced healthcare utilization intensity, consistent with previously reported multidisciplinary ALS care outcomes.}, } @article {pmid42616178, year = {2026}, author = {Nolen, A and Zweig, N and Selby, D and Bonares, MJ}, title = {Factors associated with requests for Medical Assistance in Dying (MAiD) referral among patients with amyotrophic lateral sclerosis receiving specialist palliative care.}, journal = {Journal of neurology}, volume = {273}, number = {9}, pages = {}, pmid = {42616178}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Female ; Male ; *Palliative Care/statistics & numerical data ; *Referral and Consultation/statistics & numerical data ; Retrospective Studies ; Aged ; Middle Aged ; *Suicide, Assisted/statistics & numerical data ; Noninvasive Ventilation/statistics & numerical data ; Cohort Studies ; Canada ; }, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) have among the highest rates of medical assistance in dying (MAiD), yet factors associated with requesting MAiD remain poorly understood. We examined sociodemographic and clinical characteristics associated with MAiD referral and receipt among patients with ALS receiving specialist palliative care.

METHODS: We conducted a retrospective sequentially matched cohort study of patients attending a multidisciplinary ALS clinic at a Canadian tertiary care center. Patients who requested a MAiD referral were matched with the next consecutive patient without a MAiD request. Multivariable logistic regression identified factors associated with MAiD referral and, among referred patients, receipt of MAiD.

RESULTS: The cohort included 272 patients (130 MAiD referrals; 142 no referral). Rural residence was independently associated with higher odds of requesting a MAiD referral (adjusted odds ratio [aOR] 2.38, 95% confidence interval [CI] 1.02-5.58), whereas non-invasive ventilation (NIV) was associated with lower odds (aOR 0.56, 95% CI 0.32-0.90). Gastrostomy tube use demonstrated a non-significant trend toward lower odds of MAiD referral (aOR 0.59, 95%CI 0.33-1.07). Age, sex, and limb and bulbar symptom severity were not associated with MAiD referral. Among patients referred for MAiD, no factors were independently associated with receipt of MAiD.

CONCLUSION: In patients with ALS receiving specialist palliative care, use of NIV was associated with a lower likelihood of requesting a MAiD referral, while rural residence was associated with higher odds of referral. These findings suggest that decisions regarding MAiD may be influenced less by disease severity than by preferences regarding life-prolonging interventions and warrant further investigation.}, } @article {pmid42617572, year = {2026}, author = {Tang, WX and Yang, C and Zhang, M and Kushida, CA and de Lecea, L and Li, SB}, title = {Sleep-wake control with age and neurodegenerative diseases.}, journal = {Sleep medicine reviews}, volume = {90}, number = {}, pages = {102352}, doi = {10.1016/j.smrv.2026.102352}, pmid = {42617572}, issn = {1532-2955}, abstract = {Aging causes dramatic alterations in bodily functions. Among them, sleep quality declines with age, particularly in individuals with neurodegenerative diseases. In this review, we first describe alterations in sleep-wake architecture and discuss potential mechanisms underlying sleep disorders that arise with age. We discuss evidence linking sleep disorders with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) syndrome. Even though the causes of AD, PD, PSP, and HD are diverse, several shared symptoms including difficulty falling asleep, fragmented sleep, and disrupted circadian rhythm collectively suggest their pathologies disrupt sleep-wake control. Hyperexcitability of implicated neurons is commonly observed prior to neurodegeneration. Upregulated neuronal excitability in the early phase of these diseases appears as a potential shared mechanism among neurodegenerative diseases. Abnormal protein accumulation and aggregation in these diseases exacerbate neuronal circuit hyperactivity by increasing neurons' intrinsic excitability or dampening inhibitory inputs to neurons controlling sleep-wake cycles. A better understanding of the mechanisms underlying sleep disorders that emerge with age may greatly benefit the development of novel preventative and therapeutic strategies for neurodegenerative diseases, and therefore improve the life quality of older adults.}, } @article {pmid42618027, year = {2026}, author = {Wolter, A and Ritz, L and Wolter, JS and Kurkevych, A and Thul, J and Bedei, I and Schenk, J and Königbauer, JT and Weichert, A and Axt-Fliedner, R}, title = {Prenatally diagnosed Ebstein's anomaly and tricuspid valve dysplasia: associated anomalies and predictors of outcome in a multicenter cohort study.}, journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2932-8445}, pmid = {42618027}, issn = {1438-8782}, abstract = {PURPOSE: To describe associated anomalies and outcomes of prenatally diagnosed Ebstein's anomaly (EA)/tricuspid valve dysplasia (TVD) in a multicenter cohort and to identify predictors of adverse outcome (intrauterine or postnatal death).

MATERIALS AND METHODS: In this retrospective study, cardiothoracic ratio, aortic valve diameter (AVD), pulmonary and atrioventricular valve measurements, ventricular dimensions, vena contracta, chamber areas, Celemajer index, peak tricuspid regurgitation velocity (TR_max), and pulmonary flow direction between survivors and non-survivors were compared across three gestational intervals.

RESULTS: Among 87 fetuses, 7 (8.0%) intrauterine deaths and 7 (8.0%) terminations occurred; 14 (16.1%) were lost to follow-up. Fifty-nine (67.8%) live births with follow-up were documented; 52 (88.1%) underwent active postnatal management, with a survival rate of 69.2% (36/52). Non-survivors more frequently had hydrops, earlier delivery, and lower birth weight. z-score AVD (zAVD) was lower and pulmonary flow more often retrograde in non-survivors before 32 weeks. TR_max was lower in interval 1 (<24 weeks), and right atrial area and vena contracta were larger in interval 2 (24-32 weeks). No significant differences were observed after 32 weeks.

CONCLUSION: This is one of the largest prenatal multicenter cohorts employing a longitudinal design, with echocardiographic data evaluation across three gestational intervals. Established predictors (pulmonary flow, TR_max) were confirmed and zAVD was identified as a simple, clinically applicable parameter, highlighting the relevance of left ventricular involvement in EA/TVD. Zusammenfassung: Ziel: Ziel dieser retrospektiven, multizentrischen Studie war es, assoziierte Anomalien und das Outcome bei pränatal diagnostizierter Ebstein-Anomalie /Trikuspidalklappendysplasie (EA/TVD) zu analysieren sowie Prädiktoren für ein ungünstiges Outcome (intrauteriner Fruchttod (IUFT), postnataler Tod) zu identifizieren.

MATERIAL UND METHODEN: Retrospektiv wurden kardiothorakale Ratio, Aortenklappendurchmesser (AVD), pulmonale und atrioventrikuläre Klappen, Ventrikeldimensionen, Vena contracta, Vorhof-/Ventrikelflächen, Celemajer-Index, maximale Trikuspidalinsuffizienzgeschwindigkeit (TR_max) und Pulmonalflussrichtung zwischen Überlebenden und Nicht-Überlebenden in drei3 Gestationsintervallen verglichen. Ergebnisse: Von 87 Feten traten 7 (8,0%) IUFT auf, 7 (8,0%) Schwangerschaftsabbrüche erfolgten, 14 (16,1%) waren lost to follow-up. Insgesamt wurden 59/87 (67,8%) Lebendgeburten dokumentiert; 52 (88,1%) erhielten ein aktives postnatales Management mit einer Überlebensrate von 69,2% (36/52). Nicht-Überlebende zeigten häufiger Hydrops, frühere Entbindung und geringeres Geburtsgewicht. Der Z-Score des AVD (zAVD) war <32 Wochen niedriger, der Pulmonalfluss häufiger retrograd. TR_max war <24 Wochen niedriger, rechte Vorhoffläche und Vena contracta zwischen 24-32 Wochen größer. Nach 32 Wochen bestanden keine signifikanten Unterschiede. Schlussfolgerung: : Dies ist eine der größten pränatalen, multizentrischen Kohorten mit longitudinaler Auswertung über drei3 Gestationsintervalle. Etablierte Prädiktoren (Pulmonalfluss, TR_max) wurden bestätigt, und zAVD als einfacher, klinisch anwendbarer Parameter identifiziert, der die Relevanz der linksventrikulären Beteiligung bei EA/TVD unterstreicht.}, } @article {pmid42618698, year = {2026}, author = {Shrestha, N and Munn, Z and Calma, A and Pavey, N and Tsuji, Y and Menon, P and Padovani, A and Risi, B and Ferullo, L and Filosto, M and Jewett, G and Shibuya, K and Otani, R and Shimizu, T and Kuwabara, S and Noto, YI and Kitaoji, T and Johnsen, B and Shen, D and Cui, L and van den Berg, LH and van Eijk, RPA and van Damme, P and Kiernan, MC and Giles, L and Vucic, S}, title = {Gold Coast criteria for ALS diagnosis: individual participant data meta-analysis.}, journal = {Journal of neurology}, volume = {273}, number = {9}, pages = {}, pmid = {42618698}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; Sensitivity and Specificity ; }, abstract = {BACKGROUND: To evaluate the diagnostic accuracy of the Gold Coast criteria (GCC) and compare their performance with the revised El Escorial (rEEC) and Awaji criteria in patients with suspected amyotrophic lateral sclerosis (ALS).

METHODS: Embase, MEDLINE, and Scopus were searched for English-language studies published between January 1, 2020, and August 11, 2025. Eligible studies assessed the diagnostic accuracy of GCC compared with rEEC and Awaji criteria in suspected ALS. Authors were invited to contribute individual participant data. Data were checked, harmonised, and recoded. A one-stage individual-participant data meta-analysis, adjusted for age and sex, was performed. Diagnostic performance was assessed using pooled sensitivity, specificity, and area under the receiver operating characteristic curve. Risk of bias was assessed using QUADAS-2 and QUADAS-C, and certainty of evidence using GRADE for diagnostic test accuracy. The study was registered with PROSPERO, CRD420251123597.

RESULTS: Individual participant data were available for 3007 participants from five international studies. GCC demonstrated higher sensitivity than rEEC and Awaji criteria: 0.96 (95% confidence interval [CI] 0.93-0.98) versus 0.87 (95% CI 0.78-0.92) and 0.87 (95% CI 0.78-0.93), respectively. Certainty of evidence for sensitivity was moderate at pre-test probabilities of 50% and 75%, and low at 25%. Specificity was numerically lower for GCC at 0.68 (95% CI 0.53-0.81) compared with rEEC at 0.73 (95% CI 0.59-0.83) and the Awaji criteria at 0.72 (95% CI 0.57-0.83). The certainty of evidence for specificity was rated as very low across all assessed pre-test probabilities (25%, 50%, and 75%).

CONCLUSIONS: GCC provide a sensitive framework for suspected ALS and may support earlier diagnosis in specialist settings. Specificity was imprecise and heterogeneous, supporting use with mimic exclusion and longitudinal reassessment.}, } @article {pmid42619018, year = {2026}, author = {Davias, A and Knekt, P and Rantakokko, P and Hansen, J and Weisskopf, MG}, title = {Associations between Pre-Disease Biomarkers of Persistent Organic Pollutants and Amyotrophic Lateral Sclerosis Survival in the Danish Diet, Cancer and Health Study Cohort.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78334}, pmid = {42619018}, issn = {1531-8249}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord. Most patients survive 3 to 5 years after diagnosis, although some live 10 years or more. Prognostic factors are incompletely understood, but previous case-control studies suggest that exposure to persistent organic pollutants (POPs) may be associated with ALS survival, but this has not been explored within prospective analysis of POP biomarkers. In this study, we aimed to prospectively investigate the relationship between exposure to POPs-assessed in pre-disease plasma samples-and survival with ALS in the Danish Diet, Cancer, and Health study cohort.

METHODS: We identified 166 incident ALS cases using the Danish National Patient Register via International Classification of Diseases (ICD) codes. We measured concentrations of 13 polychlorinated biphenyls (PCBs), 9 organochlorine pesticides, and 3 polybrominated diphenyl ethers in plasma samples collected at inclusion in the study (baseline). To assess the relationship between POP exposures and ALS survival, we used separate Cox models for each POP group adjusting for diagnosis age, sex, smoking status, body mass index, and marital status. We selected the most relevant POP groups for ALS survival using an elastic net penalized Cox proportional hazards regression model and then ran a model using a summary environmental risk score (ERS).

RESULTS: Single-pollutant Cox models showed that exposure to non-dioxin like PCBs, hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), and chlordane compounds were associated with shorter survival. Elastic net penalized Cox proportional hazards regression selected HCB and chlordane compounds as the most relevant POPs for survival. The ERS Cox model showed a significant association with shorter survival (hazard ratio [HR]: 1.4, 95% confidence interval [CI]: 1.1-1.7). A 1 standard deviation (SD) higher ERS score was associated with an HR for death of 1.4 (95% CI: 1.1-1.7). Predicted median survival for those with an ERS score 1 SD higher than the mean was 12 months shorter (26 vs 38 months).

INTERPRETATION: Our study suggests that pre-disease exposure to some POPs such as HCB and chlordane compounds could negatively influence ALS survival. ANN NEUROL 2026.}, } @article {pmid42619255, year = {2026}, author = {Gadhave, DG and Jadhav, AB and Waghamode, NB and Khot, S and Khan, R and Hole, R and Dhobale, SM and Aswar, M and Paudel, KR}, title = {Mitochondria-Targeted Nanotherapies in Aging Neurodegenerative Disorders: Emerging Prospects and Clinical Potential.}, journal = {Advanced healthcare materials}, volume = {15}, number = {36}, pages = {e71594}, pmid = {42619255}, issn = {2192-2659}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology/therapy ; *Mitochondria/metabolism/drug effects/pathology ; *Aging/pathology/metabolism ; Animals ; *Nanoparticles/chemistry ; *Nanomedicine/methods ; Drug Delivery Systems/methods ; }, abstract = {Aging is a significant risk factor of neurodegenerative disorders (NDs) such as Huntington's, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Although several clinical, neuroimaging, and biomarker-based diagnostic approaches are available for NDs, their limited sensitivity for early-stage detection, disease specificity, and prediction of disease progression continue to present significant clinical challenges, often resulting in delayed diagnosis and therapeutic intervention. According to previously published works, the preliminary pathological feature of such disorders is mitochondrial dysfunction. This may lead to elevated oxidative stress, impaired mitophagy, unbalanced mitochondrial function, and bioenergetic failure. This review examines how mitochondria-targeted nanotherapeutic approaches can overcome these pathological barriers and improve therapeutic outcomes in aging-associated neurodegeneration. Targeted delivery of drug-loaded nanocarriers, such as gene-delivery, lipid-based, metallic, and polymeric nanoparticles, has emerged as a potential platform to deliver medication directly to defective mitochondria. It may increase mitochondrial biogenesis, maintain redox balance, and protect against neuronal degeneration. This work incorporates disease-specific mitochondrial pathology with current progress in targeted nanotherapeutics, age-associated delivery barriers, clinical revolution, and emerging artificial intelligence (AI)-enabled precision therapeutic approaches. Mitochondria-targeted nanotherapeutics depict a potential disease-modifying strategy for aging-related NDs. However, further advancements in targeting efficacy, scalable production, long-term safety, and clinical validation can facilitate a successful clinical revolution.}, } @article {pmid42619804, year = {2026}, author = {Spillman, AM and Alsop, EB and Gittings, LM and Garcia-Mansfield, K and Piras, I and Bonfitto, A and Martinez, MN and Sharma, R and Preller, KR and Huentelman, M and Pirrotte, P and Van Keuren-Jensen, K and Sattler, R}, title = {Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in C9ORF72 -Frontotemporal Dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.07.26.740405}, pmid = {42619804}, issn = {2692-8205}, abstract = {Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are linked neurodegenerative diseases characterized by both synaptic dysfunction and TDP-43 pathology. A hexanucleotide repeat expansion (HRE) in the C9ORF72 (C9) gene represents the most common genetic cause of FTD and ALS, yet the synapse-specific mechanisms underlying disease pathogenesis remain poorly understood. Here, we performed integrated multi-omic profiling of synaptosomes enriched from postmortem frontal cortex and patient-derived induced pluripotent stem cell (iPSC)-derived cortical neurons to define molecular alterations associated with C9-FTD-mediated synaptic dysfunction. Proteomic profiling of frontal cortex-derived synaptosomes identified 1,324 differentially abundant proteins (p<0.05) enriched in pathways regulating synaptic vesicle transport and synapse organization, while synaptosomal RNA sequencing revealed 2,835 differentially expressed protein-coding genes. C9-FTD iPSC-cortical neurons exhibited reductions in excitatory and inhibitory postsynaptic markers, accompanied by progressive impairment of neuronal network activity, supporting both structural and functional deficits. iPSC-derived synaptosomes recapitulated key molecular pathways observed in patient brain, revealing convergent dysregulation of synaptic signaling pathways. Comparative analyses revealed divergence between protein and RNA alterations, consistent with the disruption of regulatory processes that link RNA and protein abundance diseased synapses. Consistent with TDP-43 loss-of-function pathology we identified cryptic exon (CE)-containing transcripts within C9-FTD frontal cortex-derived synaptosomes, including KALRN and STMN2, providing evidence that aberrantly spliced RNAs localize to synaptic compartments. Together, these findings define convergent molecular pathways underlying synapse vulnerability in both C9-FTD model systems and identify synaptic localization of CE-containing transcripts as a previously unrecognized feature of TDP-43 proteinopathy.}, } @article {pmid42619860, year = {2026}, author = {Barretto, N and Fullerton, BT and Daly, AC and Casel, O and Kuksenko, O and Kang, K and Petrescu, J and Xia, M and Eschbach, J and Leung, M and Khiste, S and Gebremedhin, B and Smith, C and Jackson, CA and Phatnani, H}, title = {A multi-omics characterization reveals distinct molecular signatures in the human motor cortex and lumbar spinal cord in ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.07.24.740361}, pmid = {42619860}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by the loss of upper motor neurons in the motor cortex (MTC) and lower motor neurons in the spinal cord, leading to muscle atrophy and ultimately respiratory failure. While motor neurons (MNs) are the selectively vulnerable cell type, their interactions with glia contribute to the progression of ALS pathology. However, it remains unclear whether the site of ALS symptom onset influences the molecular alterations underlying MN and glial dysfunction and whether these alterations are shared between the MTC and lumbar spinal cord (LSC). To address these questions, we constructed spatially-resolved gene expression maps of the MTC and LSC by combining spatial and single-nucleus transcriptomic profiles from a cohort of non-neurological controls and ALS donors clinically stratified by site of symptom onset. In the ventral horn of the LSC, we see a decrease in genes associated with MNs and synaptic signaling in ALS donors. We also identify region-specific alterations in endothelial- and glial-related functions. Notably, the severity of these MN deficits and endothelial-related functions is influenced by the site of symptom onset, whereas alterations in glial function largely are not. In contrast to the LSC, we observe layer-specific increases in synaptic signaling in the MTC of ALS donors. Comparing the molecular and cellular changes within the LSC and MTC in ALS indicates that they are predominantly non-overlapping, and have different molecular signatures.}, } @article {pmid42620667, year = {2026}, author = {Hawley, ZCE and Guise, AJ and Pardo, ID and Chowdhury, T and Hana, S and Zavodszky, MI and Engle, L and Wiltberger, K and Bartlett, D and Raitcheva, D and Bommegowda, S and Lee, WH and Chen, SK and Sheehy, A and Driscoll, R and Peterson, M and Sebalusky, J and Hamann, S and Marsh, G and Doherty, J and Chicoine, KE and Cundiff, P and Dwyer, S and Clarner, P and Zeng, W and Ferretti, D and Tuczkewycz, T and Isaza, I and Patrovanie, M and Mcgladrigan, C and Chu, J and Morrison, JP and Arnold, HM and Shen, S and Hurt, JA and Trapa, P and Graham, DL and Plowey, ED and Lo, SC}, title = {Antisense oligonucleotide treatment following viral delivery of artificial SOD1-targeting miRNA shows improved efficacy in SOD1-G93A mice.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {3}, pages = {201818}, pmid = {42620667}, issn = {3117-387X}, abstract = {Adeno-associated virus (AAV) artificial microRNAs (amiRNAs) targeting superoxide dismutase 1 (SOD1) have been proposed as a therapeutic strategy for people living with amyotrophic lateral sclerosis (ALS) who harbor toxic gain-of-function variants in the SOD1 gene. Clinical efforts have primarily focused on AAV delivery via the cerebrospinal fluid (CSF), as blood-brain-barrier-crossing capsids are still being developed preclinically. However, intra-CSF delivery has been shown to be highly variable and increases the risk for AAV-related adverse events such as dorsal root ganglion (DRG) toxicity. Here, we show that immunosuppressants (IMS) following intra-CSF delivery of AAV9-amiR-SOD1 in non-human primates (NHPs) prevented AAV-related DRG toxicity, and this benefit was maintained for over 300 days even after immunotherapy stopped at 90 days post-AAV treatment. In line with prior literature, we found intra-CSF delivery of AAV9-amiR-SOD1 to be highly variable in adult mice and NHPs, requiring higher doses of virus to achieve efficacious endpoints. To address this concern, we developed a proof-of-principle study showing that AAV9-amiR-SOD1, in combination with a SOD1-targeting antisense oligonucleotide, provided an additive therapeutic benefit in SOD1-G93A mice compared with AAV9-amiR-SOD1 alone. This combinatorial approach lowered the viral load needed to reach efficacious endpoints, which could mitigate AAV-related adverse events alongside IMS.}, } @article {pmid42621206, year = {2026}, author = {Couto, CM and de Melo Queiroz, E and da Cunha, MC and Santos, SCL and Ferreira, AR and Nascimento, OJM}, title = {Genetic profile of motor neuron disease in a multiregional Brazilian cohort: an 18-year real-world experience in 1,911 patients.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1883977}, pmid = {42621206}, issn = {1664-2295}, mesh = {Humans ; Brazil/epidemiology ; Female ; *Motor Neuron Disease/genetics/epidemiology ; Male ; Retrospective Studies ; Middle Aged ; Genetic Testing ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Aged ; *Genetic Profile ; C9orf72 Protein/genetics ; Cohort Studies ; Adult ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Genetic testing in amyotrophic lateral sclerosis (ALS) is increasingly recommended for all patients, but real-world implementation in middle-income countries remains heterogeneous. Brazilian motor neuron disease genetics has largely been characterized through protocol-based cohorts focused on the founder VAPB p.Pro56Ser variant (amyotrophic lateral sclerosis type 8, ALS8). The broader genetic landscape beyond ALS8 in Brazilian clinical populations has not been described in a large multiregional cohort. We aimed to characterize this profile.

METHODS: We retrospectively analyzed 1,911 patients with motor neuron disease followed at six SARAH Network rehabilitation hospitals across Brazil between 2007 and 2024. Genetic testing was clinically directed; ALS8 cases (n = 78) were characterized separately. We assessed characteristics of genetically tested versus untested patients, the temporal evolution of testing modalities, and the diagnostic yield by gene and by Byrne family history classification.

RESULTS: Of 1,833 patients without ALS8, 318 (17.3%) underwent genetic testing, with selection bias toward younger age, higher educational attainment, and positive family history of ALS or frontotemporal dementia (all p < 0.001). Testing expanded markedly after 2020, particularly C9orf72 screening and next-generation sequencing panels. Panel/exome sequencing identified pathogenic or likely pathogenic variants in 13 of 66 patients (19.7%), consistent with international literature for mixed familial-sporadic cohorts. Across all modalities, 30 patients without ALS8 carried pathogenic or likely pathogenic variants in six genes: SOD1 (n = 15), C9orf72 (n = 11; 7.0% of 157 tested), and VCP, FUS, TBK1, and SETX (n = 1 each). ATXN2 intermediate-length CAG repeats were identified in 15 of 230 patients tested (6.5%), replicating the 6.3% previously reported in a Brazilian multicenter sample. Yield by Byrne classification followed a marked gradient (Definite: 89.7%, Probable: 24.0%, Possible: 15.4%, Sporadic: 4.9%; p < 0.001). The SOD1 spectrum included recurrent variants of likely Iberian/European origin.

CONCLUSION: This 18-year cohort defines a real-world genetic profile of motor neuron disease beyond ALS8, with diagnostic yield comparable to the literature and a Byrne gradient supporting universal testing. Beyond family history, socioeconomic factors appeared to shape access to testing, reinforcing the importance of equitable genetic testing for diagnostic precision, family counseling, and access to gene-targeted therapy.}, } @article {pmid42621238, year = {2026}, author = {Palakkot, S and Banik, A}, title = {Auditory Biomarkers in Neurodegenerative Disorders: A Literature Review.}, journal = {Journal of otology}, volume = {21}, number = {3}, pages = {160-166}, pmid = {42621238}, issn = {2524-1753}, abstract = {The prevalence of neurodegenerative diseases is escalating globally. However, the conventional diagnostic framework fails to identify the pathology until substantial neuronal damage occurs. The evidence from the recent literature indicates that auditory dysfunction commonly precedes motor and cognitive symptoms across multiple neurodegenerative diseases. The pathophysiology involves both the peripheral and cortical auditory structures, which produce distinctive patterns reflects systemic neurodegeneration. Hence, this suggests auditory assessment as a valuable tool for early identification of neural degeneration. This review synthesises the contemporary literature on auditory dysfunctions and underlying pathophysiology in Alzheimer's disease, Parkinson's disease, Frontotemporal dementia, Amyotrophic lateral sclerosis, etc. The analysis included the temporal trajectories of auditory impairment, subjective-objective measurements, and evaluated the importance of early identification and longitudinal tracking. Objective measures of central auditory processing, including Auditory Brainstem Responses, P300, Mismatch Negativity, and speech-in-noise testing, provide objective, non-invasive diagnostic tools and its sensitivity comparable to established biomarkers. Integration of standardised auditory assessment batteries into clinical protocols could enable the early identification of pathology, differential diagnosis and the development of novel therapeutic strategies for both auditory and cognitive deficits. Current review suggests that future longitudinal studies with neurodegenerative conditions should focus on the clinical utility of auditory, cognitive, and neuroimaging biomarkers and facilitate clinical translation of these findings.}, } @article {pmid42621473, year = {2026}, author = {Sabnis, RW and Sabnis, AR}, title = {Novel Compounds as TREM2 Agonists for Treating Parkinson's Disease, Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Nasu-Hakola Disease, and Stroke.}, journal = {ACS medicinal chemistry letters}, volume = {17}, number = {8}, pages = {1723-1724}, pmid = {42621473}, issn = {1948-5875}, abstract = {Provided herein are novel compounds as TREM2 agonists, pharmaceutical compositions, use of such compounds in treating Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Nasu-Hakola disease, and stroke, and processes for preparing such compounds.}, } @article {pmid42621714, year = {2026}, author = {Wang, SL and He, L and Yang, J and Zhang, N and Sun, YZ and Liu, GP}, title = {["Jiaji" (EX-B2) electroacupuncture modulates NLRP3 inflammasome activation to improve limb dysfunction in amyotrophic lateral sclerosis mice].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {51}, number = {8}, pages = {1044-1052}, doi = {10.13702/j.1000-0607.20251237}, pmid = {42621714}, issn = {1000-0607}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/genetics/immunology/physiopathology/metabolism ; *Electroacupuncture ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism/immunology ; Mice ; Humans ; *Inflammasomes/genetics/metabolism/immunology ; Male ; Acupuncture Points ; Disease Models, Animal ; Interleukin-1beta/genetics/immunology ; *Extremities/physiopathology ; Female ; Spinal Cord/metabolism ; Mice, Inbred C57BL ; }, abstract = {OBJECTIVES: To investigate the regulatory effect of "Jiaji" (EX-B2) electroacupuncture (EA) on the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome in the lumbar spinal cord and to explore its mechanism in improving limb dysfunction in amyotrophic lateral sclerosis (ALS) mice.

METHODS: Fifty-four mice carrying the human superoxide dismutase 1 G93A (hSOD1[G93A]) gene were randomly divided into model, Jiaji EA, and inhibitor groups, with 18 mice per group. Eighteen mice not carrying the hSOD1[G93A] gene served as wild group. At 60 d of age, the Jiaji EA group was given EA at L1-L2 and L5-L6 EX-B2 points with continuous wave, 1 mA, 2 Hz. The needles retained for 20 min, twice every week. The inhibitor group received intraperitoneal injection of the NLRP3 inhibitor (10 mg/kg, twice every week). All treatments were administered for 4 consecutive weeks. The survival period of mice in each group was observed to assess disease progression；the rotarod test was conducted to evaluate motor coordination and limb motor function；HE staining was used to observe pathological changes in the gastrocnemius, and muscle atrophy was assessed by measuring the cross-sectional area of the gastrocnemius fiber；Nissl staining was performed to evaluate the number of motor neurons in the lumbar spinal cord anterior horns；the protein expressions of NLRP3, Caspase-1, apoptosis-associated speck-like protein (ASC), interleukin-1β (IL-1β), interleukin-18 (IL-18), and tumor necrosis factor-α (TNF-α) in the lumbar spinal cord were detected by Western blot；the mRNA expressions of NLRP3, Caspase-1, ASC, IL-1β, IL-18, and TNF-α were detected by real-time quantitative PCR.

RESULTS: Compared with the wild group, mice in the model group exhibited shortened survival time (P<0.01)；reduced time spent on the rotating rod starting from the 13[th] week of age (P<0.05)；significantly shorter and rounded gastrocnemius fibers with enlarged inter-fiber spaces, nuclear translocation and leakage. The cross-sectional area of the gastrocnemius fibers was reduced (P<0.01)；the number of motor neurons in the spinal anterior horns was decreased (P<0.01)；protein and mRNA expressions of NLRP3, Caspase-1, ASC, IL-1β, IL-18, and TNF-α were increased in the lumbar spinal cord (P<0.01). Compared with the model group, survival time was prolonged in the Jiaji EA and inhibitor groups (P<0.01)；rotarod time was prolonged starting from the 13[th] week of age (P<0.05)；gastrocnemius fibers exhibited more regular margins and larger morphology, with reduced inter-fiber spaces, and reduced number of rounded fibers and improvement in nuclear translocation and leakage；cross-sectional areas of gastrocnemius fiber were increased (P<0.01)；the numbers of motor neurons in the spinal anterior horns were increased (P<0.01)；protein and mRNA expressions of NLRP3, Caspase-1, ASC, IL-1β, IL-18, and TNF-α decreased in the lumbar spinal cord (P<0.05, P<0.01). Compared with the inhibitor group, mice in the Jiaji EA group exhibited prolonged rotarod time from the 17[th] week of age (P<0.05)；the cross-sectional area of the gastrocnemius fiber increased (P<0.05)；protein and mRNA expressions of NLRP3, Caspase-1 and IL-18 in the lumbar spinal cord were higher (P<0.05, P<0.01), while protein and mRNA expressions of TNF-α were lower (P<0.05, P<0.01).

CONCLUSIONS: EX-B2 EA improves limb function and prolongs survival in ALS mice, with its underlying mechanism potentially involving the alleviation of neuroinflammation through inhibition of NLRP3 inflammasome activation.}, } @article {pmid42622006, year = {2026}, author = {de la Rubia Ortí, JE and Bargues-Navarro, G and Sancho-Castillo, S and Privado, J and Benlloch García, M and Sanchis Sanchis, CE and Garcia Martinez, L and Cuerda-Ballester, M and Bolós, PM and Roig, FJ}, title = {Cross sectional analysis of gut microbiota of ALS patients with and without percutaneous endoscopic gastrostomy.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1842792}, pmid = {42622006}, issn = {1664-302X}, abstract = {INTRODUCTION: This cross-sectional study investigated the differences in gut microbiota in patients with Amyotrophic Lateral Sclerosis (ALS) with and without percutaneous endoscopic gastrostomy (PEG), exploring their cross-sectional associations with nutritional intake.

METHODS: Use of shotgun metagenomics and dietary assessments.

RESULTS: We identified significant taxonomic shifts and changes in diversity across groups. PEG patients exhibited reduced abundance of short-chain fatty acids (SCFAs)- producing genera, such as Faecalibacterium and Lachnospira, suggesting a dysbiotic profile; the Firmicutes/Bacteroidetes ratio was also lower in PEG patients but is reported as a descriptive indicator only. Correlations between specific bacterial taxa and nutrient intake, highlight the potential role of the gut microbiota in ALS pathophysiology. These findings describe cross-sectional differences in microbial composition associated with nutritional status and feeding route.

DISCUSSION: Our results provide a foundation for microbiome-targeted interventions in the management of ALS, although findings related to PEG should be interpreted as exploratory given the limited sample size. Furthermore, all comparisons involving the external control group (BioProject PRJNA961076) must be interpreted with caution due to potential batch effects from differences in sample collection, DNA extraction kits, and sequencing platforms.}, } @article {pmid42622454, year = {2026}, author = {Boccanegra, B and Tulimiero, L and Quarta, R and Conte, E and Licandro, SA and Decio, A and Lenti, R and Ladisa, A and Dinoi, G and Carbone, G and Claudione, L and Camerino, GM and Pierno, S and Mantuano, P and Cappellari, O and Fossati, G and Steinkühler, C and De Luca, A}, title = {LKB1 Dysregulation in Duchenne Muscular Dystrophy Models: Disease Specificity and Epigenetic Control by HDAC Inhibitors.}, journal = {Annals of the New York Academy of Sciences}, volume = {1562}, number = {1}, pages = {e70364}, pmid = {42622454}, issn = {1749-6632}, support = {22.004//Duchenne Parent Project/ ; GJC25P084//Fondazione Telethon/ ; PRIN MUR 2020ELYA32//Ministero dell'Università e della Ricerca/ ; 2023-UNBACLE-0245439//Università degli Studi di Bari "Aldo Moro"/ ; }, mesh = {Animals ; *Histone Deacetylase Inhibitors/pharmacology ; *Muscular Dystrophy, Duchenne/genetics/metabolism/drug therapy ; Mice ; *Protein Serine-Threonine Kinases/genetics/metabolism ; Humans ; *Epigenesis, Genetic/drug effects ; Disease Models, Animal ; AMP-Activated Protein Kinase Kinases ; MicroRNAs/genetics/metabolism ; Mice, Inbred mdx ; Vorinostat ; AMP-Activated Protein Kinases/metabolism ; Muscle, Skeletal/metabolism/drug effects ; }, abstract = {Efficient skeletal muscle contraction requires tight mechano-metabolic coupling, a process regulated by AMP-activated protein kinase (AMPK). Duchenne muscular dystrophy (DMD) is characterized by aberrant AMPK activation and disrupted metabolic signaling. This study investigates the expression and regulation of the LKB1-STRADα-MO25 heterotrimeric complex, the primary upstream activator of AMPK, in DMD models. We analyzed muscles from dystrophic mice (BL10 mdx and D2 mdx) and patient-derived cells and found significant downregulation of the LKB1 complex across all disease stages in the DMD models, a defect not observed in an amyotrophic lateral sclerosis model. Treatment with the broad-spectrum HDAC inhibitor vorinostat effectively restored LKB1 expression at both transcript and protein levels in D2 mdx mice. This restoration was mechanistically linked to downregulation of miR-451, miR-195, and miR-17, which function as post-transcriptional repressors of LKB1. Conversely, the selective HDAC1/2 inhibitor Rodin-A increased Lkb1 mRNA but failed to rescue protein levels or alter miRNA expression. Our data identify the axis LKB1-STRADα-MO25 as a critical regulatory node that is disrupted in DMD, but remains responsive to epigenetic modulation. These findings suggest that restoring LKB1 activity via HDAC inhibition or miRNA targeting may represent a therapeutic avenue to address dystrophic muscle dysfunction.}, } @article {pmid42623241, year = {2026}, author = {Yi, T and Guan, H and Li, J and Li, W and Li, B and Zhu, C}, title = {Elevated neuronal TAF15 expression induces oxidative stress and anxiety-related behavioral deficits.}, journal = {Cell reports}, volume = {45}, number = {9}, pages = {117885}, doi = {10.1016/j.celrep.2026.117885}, pmid = {42623241}, issn = {2211-1247}, mesh = {*Oxidative Stress ; Animals ; *TATA-Binding Protein Associated Factors/metabolism/genetics ; Humans ; *Neurons/metabolism/pathology ; *Anxiety/metabolism/pathology/genetics ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Mice ; Prefrontal Cortex/metabolism/pathology ; Male ; Frontotemporal Dementia/metabolism/pathology/genetics ; }, abstract = {TAF15 is a DNA/RNA-binding protein involved in RNA processing whose dysfunction has been implicated in neurodegenerative diseases, including frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, the relationship between TAF15 expression levels and neurodegeneration, as well as the specific downstream pathways mediating its neurotoxicity, remain unclear. Here, we find a consistent upregulation of TAF15 in prefrontal cortex neurons from patients across multiple FTD and ALS subtypes. Both in vitro and in vivo experiments demonstrate that neuronal TAF15 overexpression triggers oxidative stress, leading to neurotoxicity and gliosis. Mice overexpressing TAF15 in medial prefrontal cortex (mPFC) neurons exhibit heightened anxiety and impaired cued fear-conditioning responses. Notably, these pathological and behavioral phenotypes are rescued by the antioxidant N-acetylcysteine amide (NACA), supporting a role for oxidative stress in TAF15-associated neurodegeneration. Together, this study elucidates a TAF15-oxidative stress axis in neurodegeneration, providing a conceptual framework for future therapeutic development.}, } @article {pmid42624563, year = {2026}, author = {Mehta, B and Nambiar, S and Shirke, O and Pandita, S and Markandeya, YS}, title = {Histone deacetylases in neurodegeneration and neuronal plasticity.}, journal = {Methods in enzymology}, volume = {733}, number = {}, pages = {321-366}, doi = {10.1016/bs.mie.2026.06.025}, pmid = {42624563}, issn = {1557-7988}, mesh = {Humans ; *Histone Deacetylases/metabolism/genetics ; Animals ; *Neuronal Plasticity ; *Neurodegenerative Diseases/enzymology/metabolism/pathology/drug therapy/genetics ; Cell Nucleus/metabolism ; Neurons/metabolism/pathology ; Histone Deacetylase 6/metabolism ; Brain/metabolism/pathology ; Protein Transport ; }, abstract = {This chapter pulls together current research on how HDAC shuttling between the nucleus and cytoplasm affects neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and epilepsy. It takes a close look at why these shifts in HDAC localization matter so much in brain disease and its implications for new treatments. Histone deacetylases (HDACs) are a big deal when it comes to gene regulation in the brain. They play key roles in both neurodegeneration and the brain's ability to adapt, working inside the nucleus and out in the cytoplasm. This chapter unpacks the molecular mechanisms behind HDAC trafficking-how they move around-highlights the different roles of HDAC isoforms, and compares localization-specific effects. It digs into how HDACs impact protein aggregation and synaptopathies. Some findings stand out: HDAC4 and HDAC1 are tightly controlled by phosphorylation signals, which change their cellular localization and influence neuronal mortality. For example, HDAC6 is majorly involved in cellular trafficking and clearing protein aggregates, whereas HDAC4 aggregation in the nucleus is responsible for driving neuronal toxicity. If HDAC1 undergoes nuclear export, it interacts with motor proteins to impact mitochondrial transport. Drugs that block HDAC6 look promising in preclinical models-they help restore neuronal transport systems and clear protein aggregation. Moving HDAC4 out of the nucleus seems to support better synaptic function and motor skills. As a general rule, HDAC accumulation in the nucleus shuts down genes that keep neurons alive, but keeping them in the cytoplasm helps preserve connections between neurons. You'll also find thorough, practical advice on how to study HDACs in brain research-covering everything from enzyme assays and cell experiments to live animal models, plasticity tracking, drug testing, and data analysis. A major innovation featured here is using CRISPR-based tricks to control exactly where HDACs go inside cells: forced targeting using dCas9 fusions, editing natural localization signals, and even using optogenetics for precise on-demand control. In short, the chapter is a hands-on guide for anyone trying to unravel HDAC mechanisms in diseases like Alzheimer's, Parkinson's, Huntington's, or in studies of brain plasticity. Some standout methods include tracking HDAC localization in the cells, measuring how phosphorylation affects their shuttling, and using HDAC2 inhibitors for cognitive boosts. It also covers isoform-specific approaches in Huntington's models, manipulating HDAC location with CRISPR for deeper insights, and combining live-cell imaging with biochemical and chromatin studies for robust validation. This chapter sheds light on the latest advances, with a strong focus on precision, quantitative results, and translating these findings into real-world applications.}, } @article {pmid42624937, year = {2026}, author = {Aboukhalil, FM and Khamis, EF and El-Sayed, MA and Youssef, RM and El-Yazbi, AF}, title = {Green analytical methods for quantification of a new combination therapy for amyotrophic lateral sclerosis: assessment by EPPI framework.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42624937}, issn = {2045-2322}, mesh = {*Celecoxib/therapeutic use/analysis ; *Ciprofloxacin/therapeutic use/analysis ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Chromatography, High Pressure Liquid/methods ; *Green Chemistry Technology/methods ; Spectrophotometry, Ultraviolet/methods ; Tablets ; Drug Therapy, Combination ; Reproducibility of Results ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to progressive muscle weakness, paralysis, and respiratory failure. The recently proposed combination therapy consisting of celecoxib and ciprofloxacin hydrochloride has emerged as a potential treatment for amyotrophic lateral sclerosis and other neurodegenerative disorders. The present study aimed to develop and validate simple, sensitive, environmentally friendly, and cost-effective analytical methods for the simultaneous determination of celecoxib and ciprofloxacin hydrochloride in bulk powders, laboratory-prepared tablets and plasma. Two ultraviolet spectrophotometric methods were established. The first method relies on direct absorbance measurements of ciprofloxacin hydrochloride at 318 nm and celecoxib at the isosbestic point at 266 nm, while the second one employs first-derivative ratio spectrophotometry for the selective determination of ciprofloxacin hydrochloride and celecoxib at 280 nm and 254 nm, respectively. Moreover, a reversed-phase high-performance liquid chromatographic method was developed using a C18 stationary phase, an optimized mobile phase composition and both diode array and fluorescence detectors, achieving efficient separation and accurate quantification of both analytes. The developed procedures were successfully applied to laboratory-prepared tablets and plasma following optimization of the sample preparation protocol to minimize matrix interference and to improve analytes recovery. Validation results showed excellent linearity over the investigated concentration ranges together with satisfactory accuracy, precision, selectivity, and sensitivity, confirming the reliability of the proposed methods for routine quality control and bioanalytical applications. The overall analytical performance and environmental sustainability of the developed methods were further assessed using the environmental performance and practicality Index framework, demonstrating their suitability as reliable and sustainable analytical approaches for the determination of celecoxib and ciprofloxacin hydrochloride.}, } @article {pmid42625715, year = {2026}, author = {Chen, D and Shen, T and Ren, H and Qiu, P}, title = {Amyotrophic lateral sclerosis and degenerative cervical myelopathy: phenotype-based diagnostic pitfalls, investigative mismatch, and practical clinical reasoning.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1901811}, pmid = {42625715}, issn = {1664-2295}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/diagnostic imaging ; Diagnosis, Differential ; Phenotype ; Magnetic Resonance Imaging ; *Spinal Cord Diseases/diagnosis/physiopathology ; *Spinal Cord Compression/diagnosis/physiopathology ; }, abstract = {Differentiating amyotrophic lateral sclerosis (ALS) from degenerative cervical myelopathy (DCM) remains difficult because the two disorders can converge clinically while diverging biologically. ALS is a progressive motor neuron disease, whereas DCM is a potentially treatable compressive myelopathy; however, both may present with upper-limb weakness, hand wasting, hyperreflexia, gait disturbance, and cervical MRI abnormalities. This narrative review examines ALS-DCM overlap through the concept of explanatory sufficiency: whether the available clinical, imaging, and electrophysiological evidence adequately explains the whole syndrome rather than a single visible abnormality. We synthesize evidence on phenotype-specific overlap, MRI-clinical mismatch, EMG/NCS distribution, somatosensory and motor evoked potentials, Gold Coast diagnostic criteria, primary lateral sclerosis, and coexistence of motor neuron disease with structural cervical pathology. The review emphasizes that MRI is indispensable but not self-interpreting, EMG/NCS is most useful when interpreted by distribution rather than positivity alone, and SEPs/MEPs can add a functional cord-conduction layer when MRI and examination are discordant. We also provide action-oriented clinical warning signs for common overlap scenarios. Rather than offering a rigid algorithm, this review proposes a clinically driven reasoning framework that helps distinguish ALS, DCM, radiculopathy, and coexistence while reducing premature diagnostic closure in neuro-spine practice.}, } @article {pmid42625892, year = {2026}, author = {Dimitrov, M and Grosskreutz, J and Ilse, B and Rakers, F and Steinbach, R}, title = {Short-term ambient temperature increases are associated with higher mortality in amyotrophic lateral sclerosis: a case-crossover study of weather conditions.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1868482}, pmid = {42625892}, issn = {1663-4365}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with vastly differing survival times. The influence of environmental exposures such as weather conditions on mortality among people living with ALS remain poorly defined. The aim of this study was to evaluate the association between short-term meteorological phenomena and the odds of death among patients with ALS.

METHODS: We conducted a retrospective case-crossover study of 298 deaths among clinically verified ALS patients that occurred within a weather-station catchment area. Daily mean data for temperature, atmospheric pressure, and relative humidity were analyzed. Associations were analyzed by comparing hazard intervals (1-3 days before death) with bidirectional control intervals in generalized linear mixed models. Results are expressed as odds ratios (OR) and 95% confidence intervals (CI).

RESULTS: Absolute meteorological conditions (temperature, pressure, humidity) showed no significant association with mortality, which was independently supported by seasonal/monthly death count analyses. Short-term temperature rises of 3 °C in the 24 h preceding the day before death were associated with 25% higher odds of death (OR 1.25; 95% CI 1.05-1.49). Exploratory subgroup analyses suggested that this association was most pronounced in female, ventilated, and older patients (≥65 years). Changes in relative humidity and atmospheric pressure were not significantly associated with the odds of death.

CONCLUSION: Short-term temperature increases are associated with higher odds of death among people living with ALS, independent of absolute weather conditions or seasonal patterns. These findings support attention of stable ambient temperatures in end-stage care, while further studies of weather-related hazards in ALS are needed.}, } @article {pmid42626456, year = {2026}, author = {Pollard, C and Miller, R and Stirland, I and Keni, M and Jenkins, A and Saito, E and Hill, JT and Jenkins, T}, title = {Circulating neuron-derived cfDNA for blood-based detection of Alzheimer's and other neurodegenerative conditions.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1822479}, pmid = {42626456}, issn = {1664-2295}, mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; DNA Methylation ; *Neurons/metabolism ; *Cell-Free Nucleic Acids/blood ; Biomarkers/blood ; *Neurodegenerative Diseases/blood/diagnosis ; Female ; Male ; Amyotrophic Lateral Sclerosis/blood/diagnosis ; }, abstract = {Blood-based biomarkers for neurodegenerative diseases are improving early detection and staging, but current assays primarily reflect aggregate neuropathology or generalized neuronal injury and do not resolve the specific neuronal populations affected. Circulating cell-free DNA (cfDNA) retains stable DNA methylation patterns reflective of tissue and cellular origin, making it a promising substrate for cell-of-origin analysis. However, conventional methylation approaches are limited by bisulfite-associated DNA damage and amplification-related bias, hindering the detection of neuron-derived cfDNA, a small fraction of total circulating cfDNA. Here, we present proof-of-concept evidence that native nanopore sequencing can support both brain methylation atlas generation and downstream cfDNA cell-of-origin classifier development in neurodegenerative disease. By directly profiling endogenous DNA methylation without bisulfite conversion or PCR amplification, nanopore sequencing preserves native molecules, reduces processing-related bias, and enables flexible, genome-wide methylation profiling that can be iteratively expanded as additional reference cell types are incorporated. Using whole-genome native nanopore sequencing, we generated a methylation reference atlas from six primary human neural cell populations-cortical neurons, dopaminergic neurons, spinal motor neurons, astrocytes, Schwann cells, and microglia-and developed cell-type-informed cfDNA classifiers. Classifier performance was assessed in silico using dilution series designed to model physiologic admixture. The framework was then applied to 137 blood plasma samples from individuals with mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and healthy controls. Elevated circulating cfDNA fragments exhibited methylation patterns similar to reference profiles from selectively vulnerable neuronal populations, including cortical neuron-like signatures in AD and progressive MCI, dopaminergic neuron-like signatures in PD, and spinal motor neuron-like signatures in ALS. Multivariate integration of neuronal signatures improved the separation of diagnostic groups within this cohort (AUC > 0.85). Although the reported atlas is limited and additional validation in larger and independent cohorts will be required, these results support the feasibility of native cfDNA nanopore methylation sequencing as a flexible platform for brain-derived cfDNA analysis and more cell-type-informed investigation of neurodegeneration from peripheral blood.}, } @article {pmid42626598, year = {2026}, author = {Pinky, PP and Wang, ZM and Khare, P and Jhaveri, JR and Sullivan, A and Basudkar, V and Rao, KS and Lawrence, A and Pingali, A and Dave, KM and Stolz, DB and Sun, M and Zheng, SY and Shiva, SS and Milligan, C and Delbono, O and Manickam, DS}, title = {Mitochondria-containing large extracellular vesicles target mouse motor neurons upon intramuscular injection.}, journal = {Extracellular vesicle}, volume = {7}, number = {}, pages = {}, pmid = {42626598}, issn = {2773-0417}, support = {R25 NS100118/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurological disorder that causes progressive degeneration of motor neurons. Mitochondrial dysfunction accelerates neurodegeneration, aggravating the severity of ALS. We hypothesized that increasing the mitochondrial function of motor neurons may promote neuronal survival. Therefore, we investigated the potential of neuron-derived mitochondria containing extracellular vehicles (EVs) as a novel therapeutic approach for ALS using differentiated NSC-34 cells as a surrogate for neurons. Neuron derived-large EVs (lEVs) but not small EVs (sEVs) contained mitochondria. However, we observed increased cell viability and oxygen consumption rates in heat-stressed neurons treated with both sEVs and lEVs suggesting improved mitochondrial function in recipient neurons. The increased oxygen consumption rates in sEV-treated heat-stressed neurons was accompanied by a greater proton leak compared to lEV treatment. The greater proton leak observed with sEVs likely suggests a lower efficiency of oxidative phosphorylation compared to that achieved by cells treated with mitochondria-containing lEVs. These findings suggest that mitochondrial components present in sEVs, such as proteins and mitochondrial DNA, may too contribute to improving cellular respiration. Furthermore, we have demonstrated that lEV mitochondria are transported into the lumbar spinal cord motor neurons following intramuscular injection in C57BL/6 mice in an EV dose-dependent manner. Collectively, for the first time, we have demonstrated the therapeutic effects of neuronal EVs in recipient heat-stressed neurons and the delivery of lEV mitochondria to spinal cord motor neurons in vivo without any EV surface modifications for neuronal targeting. Further studies will determine the therapeutic efficacy of mitochondria-containing EVs in the SOD1[G93A] transgenic mouse model of ALS.}, } @article {pmid42626968, year = {2026}, author = {Lautrup, S and Cao, SQ and Long, X and Liu, BHM and Escobar-Doncel, B and Ferrante, A and Frank, J and Schmauck-Medina, T and Leung, GHD and Liang, KX and Lu, N and Veverova, K and Vyhnalek, M and Pun, FW and Zhavoronkov, A and Fang, EF}, title = {A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD[+]-mitophagy axis on aging and neurodegeneration.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71680}, pmid = {42626968}, issn = {1552-5279}, support = {#119986//NordForsk Foundation/ ; PTC-Gene-25-1439553/ALZ/Alzheimer's Association/United States ; #334361//Research Council of Norway/ ; #101073251//HORIZON-TMA-MSCA-DN/ ; #269901//Akershus University Hospital/ ; #2020001//The South-Eastern Norway Regional Health Authority (Helse Sør-øst RHF)/ ; #282952//Cure Alzheimer's Fund/ ; #2021021//The South-Eastern Norway Regional Health Authority (Helse Sør-øst RHF)/ ; #281956//Norwegian Health Association/ ; /WT_/Wellcome Trust/United Kingdom ; #104617//Ellcome Leap's Dynamic Resilience Program (jointly funded by Temasek Trust)/ ; #TO01000215//Czech Republic-Norway KAPPA programme/ ; #262960//Akershus University Hospital/ ; #43622//Norwegian Health Association/ ; #262175//Research Council of Norway/ ; #NW26-04-00501//Czech Ministry of Health project/ ; #81971327//National Natural Science Foundation of China/ ; #284930//Cure Alzheimer's Fund/ ; #261973//Akershus University Hospital/ ; #2023093//The South-Eastern Norway Regional Health Authority (Helse Sør-øst RHF)/ ; #207819//the Rosa sløyfe/Norwegian Cancer Society and Norwegian Breast Cancer Society/ ; #281931//Civitan Norges Forskningsfond/ ; }, mesh = {Humans ; Animals ; *Aging/metabolism ; Caenorhabditis elegans ; *NAD/metabolism ; *Neurodegenerative Diseases/metabolism/genetics ; *Mitophagy/physiology ; *Brain/metabolism/pathology ; *Artificial Intelligence ; Neurons/metabolism ; Alzheimer Disease/metabolism/genetics ; Induced Pluripotent Stem Cells ; }, abstract = {INTRODUCTION: Emerging evidence points to a role of nicotinamide mononucleotide (NAD[+]) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD[+]-mitophagy axis contributes to brain aging and neurodegeneration.

METHODS: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD[+]-mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons.

RESULTS: The NAD[+]-mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology.

DISCUSSION: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD[+]-mitophagy axis as a central player in brain aging and AD.}, } @article {pmid42627134, year = {2026}, author = {Mahjoubin-Tehran, M and Sahebkar, A}, title = {RNA interference (RNA)-based therapeutics for treating neurodegenerative diseases.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/17582024.2026.2722300}, pmid = {42627134}, issn = {1758-2032}, } @article {pmid42628519, year = {2026}, author = {Mohassel, P}, title = {Rethinking ALS through the spatiotemporal vulnerability of the entire motor unit.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {34}, number = {9}, pages = {5051-5052}, pmid = {42628519}, issn = {1525-0024}, support = {R01 NS138167/NS/NINDS NIH HHS/United States ; }, } @article {pmid42628773, year = {2026}, author = {Tani, H}, title = {A replicated astrocyte long non-coding RNA signature of Alzheimer's disease is inverted in amyotrophic lateral sclerosis.}, journal = {Brain research}, volume = {1891}, number = {}, pages = {150513}, doi = {10.1016/j.brainres.2026.150513}, pmid = {42628773}, issn = {1872-6240}, abstract = {Reactive astrocyte transitions are central to neurological disease, yet their long non-coding RNA (lncRNA) regulators remain poorly defined, and single-nucleus studies frequently treat nuclei rather than donors as replicates. This study analyses publicly available human single-nucleus RNA sequencing from four disorders using donors as the unit of inference throughout: Alzheimer's disease (AD; middle temporal gyrus, 88 donors), C9orf72-associated amyotrophic lateral sclerosis and ALS/frontotemporal dementia (ALS; frontal cortex), multiple sclerosis (MS; cortex and white matter), and major depressive disorder (MDD; amygdala). The public MDD release pools nuclei by condition, so that arm cannot support donor-level inference and is exploratory only. Covariate-adjusted pseudobulk analysis of 70,009 CE astrocytes, controlling for sex, age at death and assay chemistry, identified 1,019 down-regulated autosomal lncRNAs after sex-chromosome transcripts were removed. This signature was not attributable to astrocyte subtype composition, which did not differ between groups, and 99.9% of members remained down-regulated within the dominant homeostatic subtype alone. The signature replicated in an independent AD cohort (32 of 41 testable members concordant; resampling P < 0.0001). Testing it outside AD gave a directional result: it was concordant in the MS discovery cohort (P < 0.0001) but inconclusive in an independent MS cohort in which the transcripts lay near the detection floor, and it was reproducibly inverted in ALS, in the C9orf72 discovery cohort and in an independent motor-cortex cohort not restricted to C9orf72 carriers. The inversion survived negative controls for global normalisation and expression level. These astrocyte lncRNA changes are therefore disorder-specific rather than pan-neuroinflammatory.}, } @article {pmid42629129, year = {2026}, author = {Sha, L and Jha, S}, title = {Microglia extracellular traps (MiETs) in Neurodegeneration: Mechanisms, Evidence Gaps, and Untapped Therapeutic Promise.}, journal = {Advances in immunology}, volume = {171}, number = {}, pages = {307-341}, doi = {10.1016/bs.ai.2026.04.008}, pmid = {42629129}, issn = {1557-8445}, mesh = {Humans ; *Extracellular Traps/immunology/metabolism ; *Microglia/immunology/metabolism ; Animals ; *Neurodegenerative Diseases/immunology/therapy/metabolism/pathology ; Histones/metabolism ; Signal Transduction ; Neuroinflammatory Diseases/immunology ; }, abstract = {Microglia are the resident myeloid cells of the central nervous system, they play essential roles in neural tissue homeostasis, including synaptic pruning, clearance of debris and protein aggregates, and regulation of neuroinflammatory processes. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, microglial activation and chronic glial-driven inflammation contribute substantially to neuronal dysfunction and loss. Beyond these well-characterised functions, recent evidence indicates that microglia can release chromatin-based extracellular traps (microglia extracellular traps, or MiETs), similar to the neutrophil extracellular traps (NETs) observed in peripheral immunity. Microglia ETs are induced by stimuli such as dopamine and microbial infection, dependent or independent of NADPH oxidase/ROS pathways and histone citrullination. This chapter provides a detailed examination of MiET formation, triggers, intracellular signalling, and structural components, as well as contribution to neurodegenerative pathology. Potential mechanisms include amplification of neuroinflammation via extracellular histones and proteases, disruption of the blood-brain barrier and extracellular matrix, synaptic damage, and possible facilitation of spread of misfolded protein aggregates. We situate MiET formation within the broader microglial functional repertoire (phagocytosis, cytokine production, synaptic stripping) and focus on how ET-dominant responses may compromise homeostatic or neuroprotective roles. The chapter reviews evidence from disease models, highlights key gaps and discusses translational implications. Targeting MiET formation or promoting the clearance of MiETs represents promising, yet unexplored, therapeutic avenues in neurodegenerative disease. By focusing on MiETs, this work expands the conceptual framework for microglial pathogenicity and invites future mechanistic and translational research.}, } @article {pmid42630952, year = {2026}, author = {Tang, C and De Vocht, J and Van Damme, P and Van Laere, K and Koole, M}, title = {Metabolic connectivity alterations in amyotrophic lateral sclerosis: Individual network analysis based on Wasserstein distances.}, journal = {Imaging neuroscience (Cambridge, Mass.)}, volume = {4}, number = {}, pages = {}, pmid = {42630952}, issn = {2837-6056}, abstract = {Molecular connectivity analysis with positron emission tomography (PET) imaging offers a promising approach for characterising brain network alterations in neurodegenerative disorders. In this study, we introduce Wasserstein distance (WD) as an alternative to Kullback-Leibler divergence similarity estimation (KLSE) for constructing single-subject metabolic connectivity networks. Using [18]F-FDG PET data from 167 individuals with amyotrophic lateral sclerosis (ALS), 36 healthy volunteers (HV), and 25 ALS mimics, we generated WD- and KLSE-based connectivity matrices across 77 atlas-defined brain regions and evaluated corresponding graph theory-based nodal metrics. WD- and KLSE-derived nodal measures were strongly correlated, indicating methodological consistency. Compared with HVs, age-matched subjects in the ALS group (ALSamHV) showed significant alterations in frontal, temporal, cerebellar, and occipital network nodes, with WD-based metrics revealing differences across more brain regions than the KLSE-based approach. Support vector machine classification of ALSamHV vs. HV demonstrated that both connectivity approaches matched voxel-wise PET performance with accuracy higher than 0.80 (yet significantly lower than voxel-wise data, p < 0.05), while significantly outperforming image-based classification for ALS vs. ALS mimics (p < 0.01), with WD achieving the highest accuracy of 0.65 (p < 0.001). These findings support WD-based metabolic connectivity as a sensitive, data-efficient framework for detecting disease-related network alterations and motivate its application to a broader range of PET tracers and cohorts.}, } @article {pmid42631129, year = {2026}, author = {Nuñez, E and Muguruza-Montero, A and Arrizabalaga-Iriondo, A and Zayas-Arrabal, J and M-Alicante, S and Urrutia, J and Revuelta, M}, title = {KV3.1 channel modulation: a systematic review of pharmacological intervention strategies.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1821275}, pmid = {42631129}, issn = {1663-9812}, abstract = {INTRODUCTION: Voltage-gated potassium channels of the KV3 subfamily, particularly KV3.1 (encoded by KCNC1), are essential regulators of fast-spiking inhibitory interneuron activity and high-frequency neuronal firing, enabling precise control of neuronal excitability and network synchrony. Growing evidence links KV3.1 dysfunction to epilepsy, schizophrenia, tinnitus, fragile X syndrome, amyotrophic lateral sclerosis, and KCNC1 related developmental and epileptic encephalopathies, positioning this channel as a promising therapeutic target.

METHODS: This systematic review, conducted in accordance with PRISMA guidelines, evaluates original studies published between 2016 and January 2026 that investigated pharmacological modulation of KV3.1 using in vitro, in vivo, structural, and translational approaches.

RESULTS: A total of thirty-two studies met the predefined PICOS criteria. The literature reveals two pharmacological strategies: positive allosteric modulation aimed at enhancing fast-spiking inhibitory interneuron function and restoring excitation inhibition balance, and state-dependent channel inhibition, particularly relevant for pathogenic gain of function KCNC1 variants.

DISCUSSION: While early positive allosteric modulators demonstrated proof of mechanism with limited clinical success, second-generation compounds exhibit improved translational potential, including evidence that they modulate functional brain networks in humans. In parallel, clinically approved antidepressants have been identified as open-channel blockers of KV3.1, enabling mutation-specific therapeutic repurposing.

CONCLUSIONS: Collectively, these findings highlight KV3.1 modulation as a context-dependent and increasingly precise pharmacological strategy for neurological and neurodevelopmental disorders.}, } @article {pmid42632702, year = {2026}, author = {Wu, L and Zhu, X and Wang, X and Wu, Y and Bu, Q and Dai, T and Wen, X and Zhong, K and Guo, H and Gao, H}, title = {Fermentation with aspergillus costiformis enhances the anti-migratory activity of Aquilaria sinensis leaves with possible involvement of MAPK-related pathways.}, journal = {Food research international (Ottawa, Ont.)}, volume = {242}, number = {Pt 2}, pages = {119955}, doi = {10.1016/j.foodres.2026.119955}, pmid = {42632702}, issn = {1873-7145}, mesh = {Humans ; *Aspergillus/metabolism ; *Plant Leaves/chemistry ; *Fermentation ; *Thymelaeaceae/chemistry/metabolism ; HeLa Cells ; *Plant Extracts/pharmacology ; *Cell Movement/drug effects ; *MAP Kinase Signaling System/drug effects ; Flavonoids ; Cell Proliferation/drug effects ; }, abstract = {Aquilaria sinensis leaves (ALs) are an underutilized plant resource rich in polyphenols and flavonoids. Microbial fermentation has been proposed as an effective strategy to enhance the functional value of plant materials. However, its impact on the bioactivity and mechanisms of ALs remains unclear. This study aimed to evaluate the effects of fermentation with Aspergillus costiformis AHHC on the chemical composition and biological activities of ALs, and to elucidate the molecular mechanisms underlying the fermentation-induced functional changes. Non-targeted metabolomic analysis was performed to assess fermentation-induced metabolic alterations. The biological activities of fermented ALs (ALDT) and non-fermented ALs (ALT) extracts were evaluated using HeLa S3 cell-based assays. Network pharmacology and transcriptomic analyses were integrated to identify potential pathways and molecular targets, which were further validated by molecular analyses. The results revealed that fermentation significantly reshaped the metabolite profile of ALDT, particularly in flavonoid-related pathways. Compared with ALT, ALDT showed a stronger inhibitory effect on HeLa S3 cell migration while maintaining comparable anti-proliferative activities at higher concentrations. The integrated analyses indicated that fermentation-enriched metabolites were mainly associated with pathways related to cell migration and stress response, with prominent involvement of MAPK signaling. Molecular assays confirmed enhanced phosphorylation of MAPK components and increased expression of regulatory genes such as GADD45B and NR4A1 in response to ALDT treatment. Overall, fermentation with A. costiformis enhanced the anti-migratory activity of ALDT in HeLa S3 cells, with possible involvement of MAPK-related signaling pathways. These findings provide molecular-level evidence supporting microbial fermentation as a strategy to improve the functional value of this plant resource.}, } @article {pmid42632975, year = {2026}, author = {Saeed, Y and Fatima, M and Rehman, MU and Aslam, MH}, title = {Diagnostic Delay in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis Comparing Time From Symptom Onset to Diagnosis in Bulbar-Onset Versus Limb-Onset Disease.}, journal = {Cureus}, volume = {18}, number = {7}, pages = {e113188}, pmid = {42632975}, issn = {2168-8184}, abstract = {Diagnostic delay is a recognized challenge in amyotrophic lateral sclerosis (ALS), depriving patients of timely access to disease-modifying therapy and multidisciplinary care. Although several individual cohorts have reported diagnostic delay separately for bulbar-onset and limb-onset ALS, few studies have directly compared the two, and their estimates have not been pooled. We aimed to compare time from symptom onset to diagnosis in bulbar-onset versus limb-onset ALS. We searched PubMed and Cochrane CENTRAL (Cochrane Central Register of Controlled Trials) from inception through April 2026 for studies reporting diagnostic delay separately for the two onset types. Where upper- and lower-limb onset were reported separately, these were combined into a single limb-onset group using standard formulae; medians with interquartile ranges were converted to means and standard deviations using the method of Wan et al. A random-effects meta-analysis (DerSimonian-Laird) pooled studies reporting a usable measure of dispersion by onset group, with the remaining studies summarized narratively. The outcome was the mean difference (MD) in diagnostic delay in months, where a negative value indicates faster diagnosis in bulbar onset; heterogeneity was quantified with I[2] and risk of bias with the Newcastle-Ottawa Scale. In total, 13 studies (898 bulbar-onset and 2,438 limb-onset patients from eight countries) met the inclusion criteria; nine contributed to the meta-analysis, as four reported no usable measure of dispersion and were summarized narratively. Bulbar-onset patients were diagnosed significantly faster than limb-onset patients (MD = -4.42 months; 95% confidence interval -5.73 to -3.11; p < 0.001), with moderate heterogeneity (I[2] = 56%). The direction of effect was consistent across all studies, and the pooled estimate was stable on leave-one-out analysis. The four non-pooled studies were each directionally consistent. Bulbar-onset ALS is diagnosed approximately 4 months faster than limb-onset ALS, likely because distinctive bulbar symptoms prompt earlier specialist referral whereas limb weakness is attributed to more common musculoskeletal or orthopedic conditions. Strategies raising awareness of limb-onset ALS among primary care and orthopedic physicians are warranted.}, } @article {pmid42634270, year = {2026}, author = {Shen, D and Ding, J and Zhai, F and Shi, J and Liu, M and Liu, Q and Cui, L}, title = {A de novo FUS frameshift variant (p.Gly501Valfs*30) presenting with tremor and prominent extrapyramidal features in young-onset motor neuron disease: a case report.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2026.2721279}, pmid = {42634270}, issn = {2167-9223}, abstract = {Fused in sarcoma (FUS) mutations are a recognized cause of juvenile-onset amyotrophic lateral sclerosis (ALS), typically associated with early age at onset and rapid disease progression. Here we report a 32-year-old Chinese man who presented with bilateral hand tremor as the initial symptom, followed by progressive dysarthria, bradykinesia, and multi-segment upper and lower motor neuron involvement. Whole-exome sequencing identified a de novo heterozygous FUS frameshift (p.Gly501Valfs*30), confirmed absent in both parents. Electromyography revealed predominantly chronic neurogenic changes. At approximately 2.5 years from symptom onset, the patient remains ambulatory with a walking frame, with a notably milder course than the previously reported frameshift at the same Gly501 codon. This case expands the phenotypic spectrum of FUS-associated motor neuron disease and highlights tremor and extrapyramidal features as potential early manifestations in adult patients.}, } @article {pmid42634335, year = {2026}, author = {Langmead, AP and Keane, BA and Jacob, JA and Ramana, KV}, title = {Metformin in Neurodegenerative Diseases: Mechanisms and Therapeutic Implications.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X476604260704180015}, pmid = {42634335}, issn = {1875-6190}, abstract = {As the global burden of neurodegenerative disorders continues to rise with aging populations, there is growing interest in identifying widely available drugs that can be repurposed to target shared metabolic and inflammatory mechanisms underlying these conditions. Increasing evidence suggests that metabolic dysfunction, mitochondrial impairment, and chronic neuroinflammation play central roles in the pathogenesis of neurodegeneration, demonstrating the need for therapeutics that can modulate these interconnected pathways. Metformin has served as the gold standard for the management of type 2 diabetes for 7 decades. It offers a superior safety profile, established metabolic advantages, and affordability. Recent studies suggest that, in addition to its antihyperglycemic actions, it could also be repurposed to treat several inflammatory complications and infectious diseases. Further, recent preclinical and clinical studies suggest that, by regulating AMPK, mTOR, and mitochondrial function, metformin could also control the initiation and progression of neurodegenerative diseases. Several studies also indicate that metformin suppresses neuroinflammation by inhibiting the NF-κB signaling pathway and the NLRP3 inflammasome, thereby improving insulin signaling and metabolic homeostasis. This review integrates metabolic, inflammatory, and mitochondrial mechanisms to present a unified mechanistic framework to explain how metformin may modulate the onset and progression of neurodegeneration. Specifically, we discuss recent studies showing the therapeutic significance of metformin in Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Moreover, this review highlights metformin as a potential therapeutic candidate for future development in neurodegenerative diseases.}, } @article {pmid42635322, year = {2026}, author = {Palumbo, F and Iazzolino, B and Canosa, A and Manera, U and Vasta, R and Grassano, M and Matteoni, E and Cabras, S and Maccabeo, A and Pellegrino, G and Giai Merlera, F and Dei Giudici, A and Callegaro, S and Balz, L and Moglia, C and Chiò, A and Calvo, A and Lulé, D}, title = {Theory of mind impairment related to C9orf72 repeat expansion in amyotrophic lateral sclerosis: a case-control study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2026.2694499}, pmid = {42635322}, issn = {2167-9223}, abstract = {Objective: To investigate cognitive and affective theory of mind (ToM) in amyotrophic lateral sclerosis (ALS) patients carrying the C9orf72 repeat expansion (C9orf72+), compared with matched non-mutated (C9orf72-) ALS patients and healthy controls (HCs). Methods: We assessed 34 C9orf72+ ALS patients, 34 C9orf72- ALS patients matched for sex, age, education, and cognitive category, and 34 HC matched for sex, age, and education. Participants underwent neuropsychological evaluation, including the Story-Based Empathy Task (SET), assessing cognitive ToM (Intention Attribution, IA), affective ToM (Emotion Attribution, EA), and Causal Inference (CI). Results: C9orf72+ patients showed lower SET-global score than C9orf72- patients (p = 0.028). Compared with HC, C9orf72+ showed lower score in SET-global score and all SET subtests (all p < 0.05). C9orf72+ cognitively normal differed from HC in SET-global score, IA, and EA (all p < 0.038), whereas C9orf72- cognitively normal did not differ from HC. Multiple linear regression analyses indicated that ALS-specific cognitive domains only explained ∼25% of ToM variance, with no association with demographic, clinical, or behavioral variables. Cluster analysis identified three cognitive profiles based on SET performance, with the most impaired cluster showing the highest proportion of C9orf72+ patients (68%). Conclusion: C9orf72-mutated ALS patients showed more pronounced impairment in cognitive and affective ToM than non-mutated ALS patients, independent of demographic, clinical, and cognitive features. These findings, although requiring confirmation on larger samples, suggest that ToM dysfunction may represent a sensitive marker of cognitive involvement in ALS-C9orf72-associated disease, particularly in its affective component.}, } @article {pmid42635866, year = {2026}, author = {Chakraborty, S and Manickam, V}, title = {Decoding the Neuroinflammatory Potential of Non-Nutritive Sweeteners Through An Integrative Computational Approach.}, journal = {Neurotoxicity research}, volume = {44}, number = {5}, pages = {}, pmid = {42635866}, issn = {1476-3524}, support = {F.N. 5/9/1328/2020-Nut//Indian Council of Medical Research/ ; SG20250066//VIT University/ ; }, mesh = {Humans ; *Non-Nutritive Sweeteners/adverse effects/metabolism/chemistry ; *Neuroinflammatory Diseases/chemically induced/metabolism/genetics ; Molecular Docking Simulation/methods ; Molecular Dynamics Simulation ; Animals ; }, abstract = {Non-nutritive sweeteners (NNS) are commonly used in the beverage, food, and pharmaceutical industries, however, their possible link to neuroinflammation remains a contentious issue. Hence, to investigate this potential association and identify the molecular pathways involved, targets of the most frequently consumed NNSs, namely sucralose, aspartame, acesulfame, cyclamate, and saccharin, were extracted from the STITCH, Super-PRED, STP, SEA and CTD databases, while neuroinflammatory targets were extracted from GeneCards, OMIM, and NCBI databases. A total of 124 targets were obtained by overlapping NNS and neuroinflammatory targets, of which 20 key targets, including CASP3, PPARγ, MTOR, and MMP9, were identified for further analysis. KEGG enrichment analysis suggested a significant association of these targets with pathways related to Alzheimer's disease and neuroactive ligand-receptor interaction. Gene Ontology analysis revealed enrichment in biological processes associated with inflammatory response and reactive oxygen species. The associated cellular components were primarily localised in the axon, dendrite, and synaptic membrane. Molecular docking followed by molecular dynamics simulations was performed to evaluate the stability of the NNS-key target complexes, revealing favourable binding affinities and stable interaction profiles. Gene expression analysis of these key targets predicted their differential regulation across four majorly recognised neuroinflammatory disorders, including Alzheimer's disease, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis, with a significant up or downregulation of these key targets. Results of this study suggest that NNS may be associated with neuroinflammatory processes through these key targets and identified pathways, highlighting the need for improving the standards in food safety.}, } @article {pmid42636000, year = {2026}, author = {Benatar, M and Barmada, S and Jicha, GA and Lagier-Tourenne, C and Gregory, J and Al-Chalabi, A and Boeve, BF and Jack, CR and Seeley, WW and Maragakis, NJ and Wuu, J and Zeier, Z and Onyike, C and Lewcock, J and Hovinga, C and Jafar-Nejad, P and Uspenskaya, O and Simmons, A and Browne, SE and Rohrer, J and Petrucelli, L and Shapiro, J and Scharper, D and Boxer, A and Ostrow, LW and Staffaroni, AM and Dacks, P and Turner, MR and Dave, KD and de Majo, M and Mitic, L and Fradette, S and Budd Haeberlein, S and Simuni, T and Dunn, B and McMillan, CT and Lee, EB}, title = {TDP-43-Associated Neurodegenerative Disease Conceptualization and Integrated Staging: A Review.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2026.2812}, pmid = {42636000}, issn = {2168-6157}, abstract = {IMPORTANCE: Classifying disease based on underlying pathobiology rather than clinical phenotype has implications for the development of biomarkers and therapy development.

OBSERVATIONS: Transactive response DNA-binding protein 43 kDa (TDP-43) pathology is observed across a range of clinically defined neurodegenerative disorders including limbic predominant age-related encephalopathy (LATE), most cases of amyotrophic lateral sclerosis (ALS), inclusion body myositis, multisystem proteinopathy, and approximately half the cases of frontotemporal dementia (FTD). Despite this shared biology, the current nosology for these neurodegenerative disorders is based on their distinct clinical phenotypes. An alternative approach recognizes the central role of TDP-43 pathology in disease pathogenesis, reserving the use of clinical terms like ALS, FTD, or LATE to describe phenotypic manifestations of underlying pathobiology. This approach also recognizes the converging biomarker and neuropathological data indicating that pathology begins presymptomatically, before the overt clinical manifestations of disease appear.

CONCLUSIONS AND RELEVANCE: In proposing a pathobiological definition of disease, the goal is to provide a road map for developing biomarkers that accurately reflect the underlying pathobiology of disease and for advancing therapeutic candidates that effectively target fundamental disease mechanisms.}, } @article {pmid42636496, year = {2026}, author = {Jonsdottir, G and Vilhjalmsson, R and Sigurdardottir, V and Hjaltason, H and Klinke, ME and Jonsdottir, H}, title = {End-of-Life Care in an Acute Neurological Ward: A Retrospective Analysis of Clinical Practices During the Last Week of Life.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {58}, number = {5}, pages = {201-206}, pmid = {42636496}, issn = {1945-2810}, support = {//Icelandic Nurses Association, University of Iceland Research Fund of Ingibjorg R. Magnusdottir, Landspitali, National University Hospital of Iceland/ ; }, mesh = {Humans ; Retrospective Studies ; *Terminal Care/methods ; Female ; Male ; *Nervous System Diseases/therapy/nursing ; Aged ; Aged, 80 and over ; Middle Aged ; }, abstract = {BACKGROUND: The care of patients with neurological diseases near the end of life (EOL) is challenging and often complicated by prognostic uncertainty. Difficulty recognizing the terminal phase may delay transitions to EOL care, leading to continued use of diagnostic procedures and medical interventions with a limited focus on comfort.

METHODS: This retrospective observational study included medical records of 209 deceased patients with neurological diseases who died in an acute hospital ward. Diagnostic procedures and medical and supportive interventions delivered during the final 7 days of life were extracted. Patients were categorized into 2 groups: acute neurological diseases (ischemic stroke and hemorrhagic stroke) and progressive neurological diseases (Parkinson disease or extrapyramidal and movement disorders, and amyotrophic lateral sclerosis). Frequencies of interventions were compared between diagnostic groups and according to documented EOL decision status.

RESULTS: In both groups, documented EOL decisions were associated with reduced use of diagnostic procedures and increased use of support measures. Medication administration and supportive care patterns differed between the acute and progressive disease groups and were related to documented EOL decisions. The most frequently administered interventions were oral suctioning (97%), intravenous fluids (70%), antibiotics (45%), pain relief medications (98%), and benzodiazepines (93%). Patients with progressive neurological diseases received more respiratory support interventions than those with acute neurological diseases.

CONCLUSIONS: Our findings suggest that documenting EOL decisions was related to comfort-focused care, although the frequency varied by disease group. Neurological disease-specific EOL guidelines should be implemented to identify the terminal phase in alignment with the goals of comfort-focused care in a timely manner.}, } @article {pmid42636890, year = {2026}, author = {Guha, L and Malik, JA and Bose, B}, title = {Living drug carriers: Microbial and bioengineered platforms redefining precision therapeutic and immunomodulatory delivery.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {399}, number = {Pt A}, pages = {115274}, doi = {10.1016/j.jconrel.2026.115274}, pmid = {42636890}, issn = {1873-4995}, abstract = {Microbial living therapeutics are a new class of drug-delivery materials that combine synthetic biology, immunomodulation, and advanced formulations to achieve controllable therapeutic effects in space and time. In the broad field of living drug-delivery systems, therapeutic platforms include engineered microorganisms, mammalian immune cells, stem cells, viral vectors, extracellular-vesicle-producing cells, and hybrid bioengineered living materials. This review focuses on engineered microbial living drug carriers, including genetically modified bacteria and probiotic platforms, because these systems uniquely integrate programmable biosensing, in situ therapeutic synthesis, adaptive immunomodulation, and controllable drug delivery within a single living chassis. Designed microbes and consortia possess other unique functions, such as microenvironment sensing, programmed control of gene expression, and long-lasting in situ manufacturing of therapeutic payloads not available with small-molecule or biologic drugs. Recent progress in microbial chassis engineering, genetic circuit design, and biocontainment has enabled fine-tuning of immune responses, metabolic pathways, and tissue-specific signaling in a wide range of diseases from cancer to autoimmune and inflammatory diseases, to metabolic and endocrine disorders, neuro-immunological conditions (e.g., amyotrophic lateral sclerosis), infectious diseases including infectious threats without existing approved vaccines (Zika virus) as well as rare genetic disorders. Advances in formulation science, including encapsulation technologies, biomaterial-microbe hybrids, and stimuli-responsive release platforms, have enabled overcoming key translation challenges concerning microbial viability, biodistribution, safety, and controlled activation in complex physiological milieus like the gut (for enteric pathogens), tumor microenvironment (for oncolytic organisms), or injured tissues (for tissue-targeting organisms). Increasing numbers of clinical-stage LBP studies are now conducted under good manufacturing practice, standardized QC, and clinical conditions, ranging from emerging PK, biodistribution, and biomarker-driven studies to those adapted to living entities. The addition of host microbiome profiling, multi-omics analysis, and computational modeling is anticipated to increase therapeutic predictability and patient stratification. Taken together, these advances position live microbial therapeutics as programmable biological medicines with the potential for adaptive, context-specific administration and warrant further clinical development and increased integration within precision medicine-informed therapeutic approaches.}, } @article {pmid42637106, year = {2026}, author = {Heinsinger, N and Wang, Y and Grauer, S and Zhang, Z and Wong, J and Simov, V and Bukhtiyarova, M and Ai, X and Parish, C and Klein, RM and Uslaner, J and Smith, S and Tian, Y}, title = {Splicing modulation of ATXN2 as a therapeutic strategy to regulate Ataxin-2 protein levels in ALS.}, journal = {Neurobiology of disease}, volume = {229}, number = {}, pages = {107582}, doi = {10.1016/j.nbd.2026.107582}, pmid = {42637106}, issn = {1095-953X}, abstract = {ATXN2 is associated with an increased risk of Amyotrophic Lateral Sclerosis (ALS), while down-regulation of ATXN2 has been shown to mitigate TDP-43 proteinopathy in ALS models. In this study, we demonstrated that Ataxin-2 protein levels were upregulated in rNLS8 mice following doxycycline withdrawal, which coincided with TDP-43 overexpression, phosphorylation, and aggregation. To reduce Ataxin-2 protein levels, we explored the approach of splicing modulation at the RNA level. Through bioinformatical analysis, we identified an alternative 5' splicing site of ATXN2 in intron 8. This alternative splicing results in an additional 47 base pairs at the 3' end after Exon 8. The insertion of the extra nucleotides causes a frameshift that leads to reduced mRNA production and, consequently, protein levels. Following the discovery of this alternative splicing site, we conducted an antisense oligonucleotide (ASO) micro-walk to screen ASOs targeting this region. We identified ASOs that specifically modulate this splicing, including those that either enhance or inhibit alternative splicing. We validated that the ASOs that promote alternative splicing and reduce constitutive splicing can lower Ataxin-2 protein levels, which in turn decreases TDP-43 aggregation and stress granule formation in a cell-based model of TDP-43 toxicity. Furthermore, we confirmed that reducing Ataxin-2 levels via previously validated ASO delivery ameliorated TDP-43 pathology in rNLS8 mice. The discovery of ATXN2 alternative splicing, along with the confirmation of splicing modulation using ASOs in human cell-based assays, provides evidence for a proof-of-principle strategy to modulate Ataxin-2 protein levels for the treatment of ALS.}, } @article {pmid42637886, year = {2026}, author = {Rashed, AM and El-Sayed, IET and Lu, X and Abdel-Bary, HM and Fouad, MK and Tony, MA}, title = {Re-engineering alum sludge using choline-glycine ionic liquid for enhanced dewatering and dye adsorption in wastewater treatment.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42637886}, issn = {2045-2322}, abstract = {Large quantities of by-product alum sludge (Al-S) generated from drinking water treatment plants pose significant environmental and disposal challenges due to their high water content and large volume. This study aims to develop a sustainable conditioning and valorization strategy for Al-S using a choline-glycine ionic liquid ([Ch]-[AA]). The ionic liquid was synthesized and applied as a sludge conditioner to enhance dewatering performance. Under optimized conditions, the dewatering efficiency reached 47%, accompanied by a notable zeta potential shift, indicating partial charge neutralization and improved floc structure. To enable sludge valorization, the conditioned sludge was reused as an adsorbent, either directly or after thermal treatment. The modified materials exhibited high adsorption capacities toward Synozol KHL dyes, reaching 43.6 and 90.1 mg g[-][1] for Red and Blue dyes, respectively. Adsorption behavior was well described by the Langmuir isotherm and pseudo-second-order kinetic model. Thermodynamic analysis indicated an exothermic adsorption process, with spontaneity dependent on operating conditions. Overall, the results demonstrate an effective waste-to-resource approach in which enhanced dewatering facilitates the conversion of alum sludge into a functional adsorbent for wastewater treatment, supporting sustainable sludge management.}, } @article {pmid42638006, year = {2026}, author = {Sreekanth, D and Singh, C and Pawar, DV and Yadav, MK and Sahadeo, IK and Basavaraj, PS and Kumar, R and Mahesh, S}, title = {CRISPR/Cas-Mediated Genome Editing for Developing Herbicide Tolerant Rice: A Step-by-Step Protocol.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {3017}, number = {}, pages = {47-57}, pmid = {42638006}, issn = {1940-6029}, mesh = {*Oryza/genetics/drug effects/growth & development ; *CRISPR-Cas Systems ; *Gene Editing/methods ; *Herbicides/pharmacology ; *Herbicide Resistance/genetics ; Acetolactate Synthase/genetics ; Plants, Genetically Modified/genetics ; Benzoates ; Pyrimidines ; }, abstract = {Weed management in rice cultivation has predominantly relied on acetolactate synthase (ALS) and acetyl-CoA carboxylase (ACCase) inhibiting herbicides, particularly against Echinochloa spp. (watergrass). However, these herbicides carry a high risk of resistance evolution, as evidenced by the numerous resistant biotypes reported worldwide. The emergence of herbicide resistance necessitates innovative and sustainable weed control strategies. Genome editing, particularly through the CRISPR/Cas system, provides a precise and efficient platform for introducing targeted genetic modifications to develop herbicide-tolerant (HT) rice cultivars. In this protocol, we present a step-by-step approach for generating bispyribac sodium-tolerant rice using the CRISPR/Cas-mediated editing of the ALS gene. The method encompasses guide RNA design, vector construction, transformation, selection of edited plants, and molecular confirmation of targeted mutations. This approach offers a robust framework for producing HT rice lines, potentially reducing reliance on conventional herbicide regimes and mitigating the risk of resistance development in weed populations.}, } @article {pmid42638120, year = {2026}, author = {Tang, L and Fan, D}, title = {Bridging the gap: neuroinflammation and the dawn of precision medicine in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {42638120}, issn = {2047-9158}, support = {CX25YZ13//the Chinese Institutes for Medical Research, Beijing/ ; 2022YFA1303003//National Key Research and Development Program of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/therapy ; *Precision Medicine/methods/trends ; *Neuroinflammatory Diseases/immunology/therapy ; Animals ; Immunotherapy/methods ; }, abstract = {Neuroinflammation is no longer a secondary feature of amyotrophic lateral sclerosis (ALS), but rather a disease-modifying process that actively shapes the motor neuron vulnerability from the earliest stages of pathology. Central and peripheral immune cells, including microglia, astrocytes, and infiltrating T lymphocytes, adopt context-dependent states that can be neuroprotective or neurotoxic depending on disease stage and genetic background. These states are driven by discrete molecular programs, such as cGAS-STING-mediated innate immune sensing, NLRP3 inflammasome activation, and RIPK1-dependent necroptotic signaling, which represent tractable therapeutic targets. The repeated failure of broad-spectrum immunosuppressive trials reflects a fundamental mismatch between the non-selective interventions and the mechanistically distinct immune states of diseases. Converging transcriptomic, genetic, and immunophenotypic evidence supports the existence of putative neuroimmune endotypes in ALS, though this framework remains a working hypothesis pending prospective validation in biomarker-stratified cohorts. Advances in the following three domains are needed for realizing precision immunotherapy: standardized biomarker panels (including cerebrospinal fluid chitinases and TSPO-PET) to stratify patients by inflammatory subtype; pharmacodynamic readouts to confirm target engagement before interpreting clinical outcomes; and adaptive platform trial designs capable of evaluating mechanism-matching interventions in defined subgroups. This review integrates ALS-associated neuroinflammation with emerging precision medicine strategies, arguing that the central translational question is no longer whether or not to target neuroinflammation, but how, when, and in whom neuroinflammation should be targeted.}, } @article {pmid42638122, year = {2026}, author = {Zhang, Y and Liu, Y and Shi, S and Li, Q and Huo, Y and You, P and Shu, M and Cheng, X and Zhang, J and Liang, D and Zhang, A and Lu, C and Shen, B and Zhou, J and Niu, Q}, title = {JP1 peptide modulates oxidative stress and autophagy via Keap1-Nrf2-ARE in ALS model mice.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {42638122}, issn = {1741-7015}, support = {82071434//the National Natural Science Foundation of China/ ; DL202410//the clinical Research Disease Project of Jiangsu Provincial People's Hospital/ ; LC202404//Jiangsu Provincial People's Hospital-Zero magnetic Medicine Special Project/ ; JSPH-MA-2023-5//Jiangsu Province Hospital Clinical Capacity Enhancement Project/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Oxidative Stress/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Autophagy/drug effects ; *Kelch-Like ECH-Associated Protein 1/metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Antioxidant Response Elements ; Signal Transduction/drug effects ; *Oligopeptides/pharmacology ; Male ; Humans ; Spinal Cord/metabolism ; }, abstract = {BACKGROUND: The simultaneous modulation of oxidative stress and autophagy represents a potential therapeutic strategy for amyotrophic lateral sclerosis (ALS), yet agents capable of coordinately regulating both processes remain scarce. The Keap1‑Nrf2‑ARE pathway serves as a critical hub linking redox homeostasis and autophagic regulation, making it an attractive target for ALS intervention. JWA is a stress‑responsive protein involved in cellular protection against oxidative injury, and its neuroprotective effects have been shown to depend on activation of the MEK/ERK‑Nrf2 axis. JP1 is a functional oligopeptide derived from the JWA protein that has been engineered to cross the blood-brain barrier and specifically target integrin αVβ3. Based on the link between JWA and Nrf2 signaling, we hypothesized that JP1 activates the Keap1‑Nrf2‑ARE pathway to coordinate antioxidant defense and autophagic clearance. Here, we evaluated this hypothesis in the SOD1‑G93A mouse model, a well‑established transgenic model of familial ALS, and elucidated the underlying mechanisms.

METHODS: We evaluated the efficacy of JP1 in the SOD1-G93A mice model using behavioral phenotyping and survival analysis. The coordinated mechanism was investigated in spinal cord tissues by profiling the Keap1-Nrf2-ARE pathway and oxidative stress, quantifying autophagic flux (by Western blotting and transmission electron microscopy) and neuronal apoptosis, and evaluating histology (by Nissl staining and immunofluorescence). Integrated transcriptomic and proteomic analyses further elucidated the global molecular landscape underlying the therapeutic effects of JP1.

RESULTS: JP1 treatment ameliorated motor deficits and extended survival in SOD1-G93A mice without adversely affecting liver or kidney function. JP1 crossed the blood-brain barrier, targeted motor neurons expressing integrin αVβ3, and activated the ERK pathway. This promoted Keap1/Cul3 degradation and Nrf2 nuclear translocation, thereby activating the Keap1-Nrf2-ARE pathway to alleviate oxidative stress. Concurrently, JP1 restored autophagic flux, increased autophagic activity, attenuated motor neuron injury, suppressed neuronal apoptosis, and preserved neuronal structural integrity. The Nrf2 inhibitor ML385 reversed the protective effects of JP1 on survival, motor function, autophagy, oxidative stress, and neuronal apoptosis, which confirms that JP1 acts via the Nrf2 pathway.

CONCLUSIONS: JP1 acts as a promising coordinator of antioxidant and autophagic processes by targeting the Keap1-Nrf2-ARE pathway, thus highlighting its therapeutic potential for ALS.}, } @article {pmid42639115, year = {2026}, author = {Harbert, DH}, title = {EIF2S1-PELO co-expression architecture in human brain: pairing-family decomposition reveals constitutive transcriptional coupling and functional layer separation.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1817096}, pmid = {42639115}, issn = {1662-5099}, abstract = {EIF2S1 (eIF2α, translation initiation surveillance) and PELO (Pelota, ribosome rescue) operate within established ribosome-associated quality control and translation-initiation surveillance pathways. Direct cross-talk between these systems is mediated through ZAK/GCN-mediated eIF2α phosphorylation under ribosome-stall stress. At the transcriptional layer, however, EIF2S1-PELO co-regulation has not been quantitatively characterized. Using pairing-family architectural decomposition on multi-region GTEx co-expression and BA9 prefrontal cortex RNA-seq from Parkinson's disease and control donors (GSE68719, n = 44 controls, n = 29 PD), we find: (1) EIF2S1 and PELO share near-identical genome-wide co-expression architecture (continuous Weighted Jaccard = 0.914) with substantial top-partner overlap (binary Jaccard at top 5% = 0.490), producing a Type 1 dissociation gap of 0.424, significantly smaller than 200 random gene-pair gaps (mean 0.644, z = -2.57, permutation p = 0.015), and the lowest gap in a 21-pair quality-control gene panel; (2) the relationship is approximately linear-monotonic (Type 6 Pearson-Spearman gap ≈ 0.004); (3) cellular functional co-dependency in DepMap CRISPR screens is essentially zero (Jaccard = 0.006, gene-effect Pearson r = -0.07), consistent with layer separation between regulatory architecture and cellular phenotype; (4) in an exploratory single-cohort comparison of PD versus control prefrontal cortex, the dissociation gap was larger in PD (0.536 versus 0.424 in control), but this between-group difference did not reach statistical significance under a group-label permutation test (p = 0.40; bootstrap 95% CI on the difference [-0.14, 0.29]), so we present it as a hypothesis for replication rather than an established effect. These findings characterize EIF2S1-PELO transcriptional co-regulation as a constitutive architectural feature distinct from the ZAK/GCN-mediated direct mechanism. The constitutive coupling replicated in independent Alzheimer's disease and ALS frontal-cortex cohorts and across microarray and RNA-seq platforms; a disease-associated weakening of the coupling was directionally consistent across all three diseases but did not reach statistical significance. We note that co-expression patterns are consistent with shared upstream regulatory programs but do not by themselves establish direct co-regulation; the architectural findings reported here are correlational at the transcriptional layer.}, } @article {pmid42639443, year = {2026}, author = {Potla, KM and Justin Nathaniel, CM and Parameshwar Adimule, S and Vincent Raj Shanthi, JR and Bilal, H and Tawfeek, AM and Islam, MS}, title = {Electron-withdrawing group effects on the structural, electronic, reactivity, and binding characteristics of triazolopyrimidine herbicides: a comparative study of diclosulam, cloransulam-methyl, and cloransulam.}, journal = {RSC advances}, volume = {16}, number = {41}, pages = {49513-49530}, pmid = {42639443}, issn = {2046-2069}, abstract = {Diclosulam (DS, I), cloransulam-methyl (CSM, II), and cloransulam (CS, III) are widely used herbicidal inhibitors of the AHAS/ALS enzyme for selective weed control. In the present work, a comparative experimental and theoretical study has been conducted on the impact of substituents on their structural, electronic, and reactive properties. Structural differences have been established using single-crystal X-ray diffraction. The crystal packing and interaction energy have been investigated using the Hirshfeld surface approach, while density functional theory confirmed the experimental geometry. The analysis of the electronic structure, reactivity descriptors, localization of electrons, and non-covalent interactions was carried out by the methods of frontier molecular orbitals, MEP, ELF/LOL, and RDG calculations. The binding interactions of compounds with AHAS/ALS protein targets were determined using molecular docking. The combined results reveal clear interdependencies between the structure, electronic properties, non-covalent interactions, and the behavior of molecules upon the interaction with enzymes.}, } @article {pmid42640367, year = {2026}, author = {Iacono, D and Feltis, GC}, title = {Beyond the Ribosome: The Expanding Role of the Nucleolus in Neurodegenerative Pathways.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42640367}, issn = {1559-1182}, mesh = {*Cell Nucleolus/metabolism/pathology ; Humans ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Ribosomes/metabolism ; Signal Transduction ; Aging/metabolism/pathology ; }, abstract = {The nucleolus, long defined by its canonical role in ribosome biogenesis, has emerged as a critical nexus for cellular homeostasis, stress sensing, and disease pathogenesis. This article synthesizes a broad range of evidence to construct a comprehensive model of the nucleolus in the context of aging and neurodegeneration. We begin by detailing its fundamental architecture and the intricate process of ribosome production, before exploring the paradigm-shifting discovery of its vast, non-canonical proteome, which implicates it in DNA repair, cell cycle control, and genome stability. A central theme is the nucleolus's function as a primary cellular stress sensor, which, upon disruption by genetic, metabolic, or proteotoxic insults, initiates the nucleolar stress response. We provide a detailed examination of the downstream signaling cascades, focusing on the canonical p53-MDM2 axis and the interconnected mTOR pathway, which together translate nucleolar status into decisions of cell fate, including apoptosis and cell cycle arrest. We then focus on the brain, presenting the neuropathological and morphological alterations of the nucleolus-such as atrophy, fragmentation, and changes in volume-that serve as hallmarks of normal aging and neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, and C9orf72-linked ALS/FTD. We explore the deep regulatory layers of epigenetics, where DNA methylation and histone modifications of ribosomal DNA genes are dysregulated in disease, and discuss how multi-omics approaches are unraveling the complex molecular landscape of nucleolar function. Finally, we introduce the emerging concept of a gut-brain-nucleolus axis, proposing how systemic factors like the gut microbiome may influence neuronal health by triggering nucleolar stress through inflammatory and metabolic mediators. Overall, by highlighting the nucleolus as a convergence point for diverse pathogenic pathways, we frame it as a promising and druggable target for novel therapeutic strategies aimed at promoting neuronal resilience and combating neurodegenerative diseases.}, } @article {pmid42641169, year = {2026}, author = {Kodama, K and Ando, M and Higuchi, Y and Yuan, JH and Yoshimura, A and Samukawa, M and Suzuki, M and Ogaya, S and Kawata, Y and Gamo, N and Hisahara, S and Yano, C and Nagatomo, R and Hobara, T and Kojima, F and Hiramatsu, Y and Nozuma, S and Sakiyama, Y and Mitsui, J and Tsuji, S and Takashima, H}, title = {Biallelic SIGMAR1 variants in early-onset distal hereditary motor neuropathy: A Japanese case series.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602261477464}, pmid = {42641169}, issn = {2214-3602}, abstract = {BackgroundDistal hereditary motor neuropathy (dHMN) is characterized by slowly progressive distal muscle weakness and amyotrophy, and it exhibits clinical overlap with Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis (ALS). Biallelic variants in SIGMAR1, encoding sigma nonopioid intracellular receptor 1, have been linked to autosomal recessive dHMN with pyramidal features. This study investigated the clinical and genetic features of patients with dHMN associated with SIGMAR1 variants in Japan.MethodsWe conducted genetic screening of Japanese patients with clinically suspected inherited peripheral neuropathies using targeted gene panels and whole-exome sequencing. SIGMAR1 variants were evaluated via segregation analysis using Sanger sequencing. Detailed clinical and electrophysiological data were systematically reviewed.ResultsBiallelic SIGMAR1 variants, including three novel variants and one previously reported variant, were identified in six patients from five unrelated families. The genotypes comprised compound heterozygous variants in four patients and homozygous variants in two patients. All patients presented with early-onset distal muscle weakness and atrophy. Enhanced tendon reflexes and pyramidal tract signs were frequently observed, whereas bulbar or respiratory involvement was absent. Nerve conduction studies consistently revealed motor-predominant axonal neuropathy with minimal sensory involvement. Disease progression was slow, and all patients remained ambulatory for years to decades after onset.ConclusionOur findings expand the clinical and genetic spectrum of SIGMAR1-associated disease and support its classification as dHMN rather than ALS. SIGMAR1 variants should be considered in the genetic evaluation of early-onset motor neuropathies, particularly in patients with dHMN accompanied by pyramidal features.}, } @article {pmid42641283, year = {2026}, author = {Yoo, HE and Issenberg, SB and Roh, YS}, title = {Psychometric evaluation and responsiveness of the resuscitation self-efficacy scale among ward nurses: A pretest-posttest study.}, journal = {Nurse education in practice}, volume = {96}, number = {}, pages = {104954}, doi = {10.1016/j.nepr.2026.104954}, pmid = {42641283}, issn = {1873-5223}, abstract = {AIM: To evaluate the psychometric properties and responsiveness of the Resuscitation Self-Efficacy Scale (RSES) among ward nurses before and after simulation-based advanced life support (ALS) training.

BACKGROUND: Although the RSES was developed to measure nurses' perceived capability in resuscitation, evidence regarding its psychometric evaluation among ward nurses participating in ALS training remains limited.

DESIGN: Secondary psychometric analysis of data obtained from a simulation-based ALS training study.

METHODS: Ward nurses (N = 191) from general hospitals completed the RSES before and immediately after participation in a simulation-based ALS training program. Psychometric evaluation included item analysis, internal consistency reliability, evidence based on internal structure, construct validity through convergent and discriminant validity, relations with an external performance measure and responsiveness.

RESULTS: The RSES demonstrated good internal consistency, with a Cronbach's α of.80 for the total scale and.88-.91 across the four factors. Factor analysis supported the original four-factor structure, with satisfactory model fit (CFI =.958, TLI =.949, RMSEA =.052 and SRMR =.072). Evidence of convergent and discriminant validity met recommended criteria. Individual resuscitation self-efficacy showed modest positive associations with team-level ALS performance and the RSES demonstrated moderate responsiveness to change (standardized response mean =.77).

CONCLUSIONS: The findings provide psychometric evidence supporting the use of the RSES for assessing resuscitation self-efficacy among ward nurses participating in simulation-based ALS training. The RSES may be useful for evaluating educational outcomes and monitoring changes in learners' self-efficacy following educational interventions.}, } @article {pmid42642835, year = {2026}, author = {Aldaghi, FS and Siahpoosh, Z and Salehi, Z and Mashayekhi, F and Sohrabnezhad, S}, title = {Unraveling Neurodegeneration: Common Molecular Mechanisms and Novel Therapeutic Concepts in Major Neurodegenerative Disorders.}, journal = {Brain and behavior}, volume = {16}, number = {8}, pages = {e71615}, pmid = {42642835}, issn = {2162-3279}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy ; Oxidative Stress/physiology ; Animals ; *Neuroinflammatory Diseases/metabolism ; Mitochondria/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Alzheimer Disease/metabolism ; Multiple Sclerosis/metabolism ; Parkinson Disease/metabolism ; Huntington Disease/metabolism ; Inflammasomes/metabolism ; }, abstract = {PURPOSE: Although Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Huntington's disease (HD) present with markedly different clinical phenotypes, these neurodegenerative diseases (NDDs) appear to converge on a shared set of underlying molecular disturbances. This review sought to integrate disease-specific causative triggers with shared pathogenic pathways, focusing on neuroinflammatory signaling, oxidative imbalance, mitochondrial impairment, and disrupted protein homeostasis, in order to support multi-target, disease-modifying therapeutic strategies.

METHOD: Relevant classical and contemporary literature, encompassing original research and review articles on the molecular basis of AD, PD, ALS, MS, and HD, was reviewed and synthesized narratively, with attention to how neuroinflammatory and oxidative stress pathways intersect, reinforce one another through mitochondrial and inflammasome-driven feedback, and recur across the five conditions.

FINDING: In each disorder, persistently activated microglia and astrocytes secreted inflammatory mediators and reactive oxygen species, engaged the NLRP3 inflammasome, and progressively destabilized cellular homeostasis through a self-perpetuating cycle linking neuroinflammation and oxidative stress. Disease-specific lesions nonetheless persisted: amyloid-β and tau pathology in AD; α-synuclein aggregation with iron-driven mitochondrial damage in PD; RNA-binding protein dysfunction, proteostatic collapse, and excitotoxicity in ALS; inflammatory demyelination and axonal bioenergetic failure in MS; and mutant huntingtin-driven transcriptional and mitochondrial disruption in HD. These distinct triggers ultimately converged on shared downstream cascades.

CONCLUSION: Recognizing this shared pathogenic foundation supports multi-target therapies-such as Nrf2 activation, NLRP3 inhibition, mitochondria-targeted antioxidants, and gene-based interventions-that extend across diagnostic boundaries, though challenges in intervention timing, patient stratification, and clinical translation remain unresolved.}, } @article {pmid42642938, year = {2026}, author = {Zou, L and Song, L and Yin, P and Cui, H and Lian, L and Peng, X and Jin, T and Wang, H and Liu, W}, title = {Glutathione S-transferase genes PfGSTU6 and PfGSTL1 involved in mesosulfuron-methyl resistance in Polypogon fugax.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71227}, pmid = {42642938}, issn = {1526-4998}, support = {//National Natural Science Foundation of China (32372570, 32572857)/ ; //Shandong Provincial Natural Science Foundation (ZR2025MS289)/ ; }, abstract = {BACKGROUND: Polypogon fugax is a major weed in wheat and winter canola fields in China. Two populations, SD-4 and JS-13, showing resistance to the ALS inhibitor mesosulfuron-methyl, were collected from winter wheat fields. This study aimed to characterize their resistance level and cross-resistance profile, investigate the resistance mechanism and identify its functional genes.

RESULTS: Dose-response assays showed that SD-4 and JS-13 have high-level resistance to mesosulfuron-methyl (15.9-and 16.4-fold, respectively) and cross-resistance to the ACCase inhibitors clodinafop-propargyl, fenoxaprop-P-ethyl, quizalofop-p-ethyl, and the PDS inhibitor diflufenican. Sequencing of the ALS gene revealed no known target-site mutations within the eight conserved resistance-associated regions. Pre-treatment with the cytochrome P450 monooxygenase (P450) inhibitor malathion or the glutathione S-transferase (GST) inhibitor NBD-Cl increased herbicide sensitivity in resistant plants. The resistant plants showed higher inducible GST activity. Herbicide residues analysis observed that resistant plants exhibiting increased mesosulfuron-methyl metabolism, and the enhanced metabolism could be reduced by both inhibitors. Integrated transcriptomic and qRT-PCR analysis identified 17 stably upregulated genes, including PfGSTU6 and PfGSTL1. Escherichia coli and rice callus overexpressing PfGSTU6 and PfGSTL1 exhibit significantly enhanced herbicide tolerance to mesosulfuron-methyl, and molecular docking analysis confirmed the strong binding affinity of GST proteins to the target herbicide.

CONCLUSIONS: The P450s and GSTs mediated herbicide metabolism confer mesosulfuron-methyl resistance in P. fugax. This study elucidates the resistance mechanism and provides genetic resources for resistance monitoring and crop breeding. In addition, we characterized the cross-resistance profile of the resistant P. fugax population, which provides guidance for developing targeted field weed resistance management strategies. © 2026 Society of Chemical Industry.}, } @article {pmid42643027, year = {2026}, author = {Christen, AL and Sobanski, E and Bitto, H and Abt-Mörstedt, B and Stieglitz, RD and Corbisiero, S}, title = {Emotional Dysregulation, Emotional Lability, Emotional Impulsiveness and Emotion in Adults with ADHD: Do All Scales Define the Same Concept?.}, journal = {Journal of attention disorders}, volume = {}, number = {}, pages = {10870547261475724}, doi = {10.1177/10870547261475724}, pmid = {42643027}, issn = {1557-1246}, abstract = {BACKGROUND: Various studies highlight emotional symptoms as a crucial component of ADHD in adulthood, suggesting independent diagnostic approaches that incorporate patients' emotional experiences into the assessment. However, the emotional symptomatology appears to be defined differently within the disorder's different constructs: Emotional Dysregulation (ED), Emotional Lability (EL), Emotional Impulsiveness (EI) and Emotion (E). Hence, the question arises: Do these symptom domains represent the same psychopathological spectrum?

METHOD: A total of 1240 adults seeking diagnostic evaluation at the ADHD specialist consultation in two different clinics (University Psychiatric Clinics (UPK) in Basel and Central Institute of Mental Health in Mannheim) were examined, whereas 611 participants were diagnosed with ADHD. They were further assessed in regard of their emotional symptoms using the following scales: ED, EL, EI and E. Additionally, affective lability was measured as a control using the Affective Lability Scale (ALS-18).

RESULTS AND DISCUSSION: The convergent and construct validity using correlations and principal component analysis (PCA) revealed that individuals with ADHD experience distinct emotional symptoms divergent from a general concept of affective lability as assessed by the ALS-18. The PCA shows that the ADHD-specific emotional symptoms may be classified into (1) difficulties with temper control and anger, (2) emotional distress and (3) emotional overreactivity and mood changes.}, } @article {pmid42645064, year = {2026}, author = {Sonkar, KS and Levi D'Ancona, V and Cramp, J and Shilling, H and Giles, E and Howell-Bray, T and Fillingham, B and Cudkowicz, ME and Nath, A and Rothstein, JD and Bowser, R and Borroni, B and Berry, JD and Sadri-Vakili, G and Buratti, E and Thrippleton, IP}, title = {Functional Activity of TDP-43: A Direct Biomarker for ALS.}, journal = {Biosensors}, volume = {16}, number = {8}, pages = {}, pmid = {42645064}, issn = {2079-6374}, support = {ZIA NS003130/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/blood/diagnosis ; Humans ; *DNA-Binding Proteins/blood/metabolism ; Biomarkers/blood ; Fluorescence Resonance Energy Transfer ; *Biosensing Techniques ; C9orf72 Protein/genetics ; }, abstract = {TDP-43 dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), yet no biofluid biomarker directly measures its functional activity. We developed a serum-based homogeneous time-resolved FRET (hTR-FRET) assay that quantifies TDP-43 RNA binding activity using synthetic UU-rich RNA probes. We analyzed 1080 serum samples from controls, sporadic ALS, and genetic subgroups (C9orf72, SOD1) across multiple biorepositories. Cross-sectionally, TDP-43 functional activity was elevated in ALS (mean 390 a.u.) versus controls (302 a.u.), yielding AUC = 0.79. Genotype means were 392 a.u. (sporadic), 382 a.u. (C9orf72), and 323 a.u. (SOD1); a 366 a.u. threshold achieved 95% specificity against controls. Longitudinally, Target ALS showed a modest but significant inverse correlation between TDP-43 activity and ALSFRS-R, while other cohorts exhibited similar non-significant trends. Elevated signal in serum likely reflects increased extracellular release of probe-competent TDP-43 species during cell death and exosomal shedding, rather than restored intracellular nuclear splicing function. This assay provides a proof-of-concept platform for the direct functional measurement of probe-competent TDP-43 species in serum. While it demonstrates moderate group-level discrimination, individual diagnostic performance requires prospective validation. The assay may support exploratory applications in genotype stratification and progression monitoring in future clinical studies.}, } @article {pmid42645160, year = {2026}, author = {Leggett, S and Sanghai, N and Ru, C and Marcogliese, PC and Tranmer, GK}, title = {Drosophila: An Emerging New Approach Method (NAM) for Studying Amyotrophic Lateral Sclerosis (ALS).}, journal = {Cells}, volume = {15}, number = {16}, pages = {}, pmid = {42645160}, issn = {2073-4409}, support = {202210PJT-495295/CAPMC/CIHR/Canada ; RGPIN-2017-05938//Natural Sciences and Engineering Research Council of Canada/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/drug therapy/metabolism ; *Drosophila melanogaster/genetics/metabolism ; Humans ; Disease Models, Animal ; DNA-Binding Proteins/metabolism/genetics ; Superoxide Dismutase-1/metabolism/genetics ; Drug Evaluation, Preclinical ; }, abstract = {Drosophila melanogaster (D. melanogaster), or fruit flies, are a commonly used model organism in the study of neurodegenerative diseases (NDs). Their short lifespan, low cost, genetic tractability, and conserved signaling and developmental pathways make them ideal for studying NDs and associated biochemical pathways. Further, flies offer the advantage of high-throughput exploratory drug and genetic screening without stringent ethical constraints. Therefore, D. melanogaster serves as an ideal organism for preliminary drug screening before transitioning to toxicity and efficacy studies in vertebrate models. Following the recent plan by the United States FDA (US FDA) and the National Institutes of Health (NIH) to progressively phase out preclinical drug testing in vertebrate animals and introduce New Approach Methodologies (NAMs), D. melanogaster has the potential to become part of the conventional drug testing pipeline in the future. This literature review focuses on the use of D. melanogaster models as a powerful, low-cost model organism to study superoxide dismutase 1 (SOD1)- and TAR DNA-binding protein 43 (TDP-43)-linked Amyotrophic Lateral Sclerosis (ALS), as well as previous efforts to screen drugs in SOD1- and TDP-43-expressing Drosophila models.}, } @article {pmid42646366, year = {2026}, author = {Anwar, AI and Hegazi, AA and Bhuchakra, HP and Nelson, JR and Birdsong, TL and Fontenot, CJ and Zeibo, M and Fazal-Ur-Rehman, MM and Bieber, HP and Spring, CJ and Smith, JL and Hachem, IA and Singh, T and Sawaya, MF and Murnane, KS and Kaye, AD}, title = {Pridopidine Mediated Sigma-1 Receptor Activation and Therapeutic Implications in Neurodegenerative Diseases.}, journal = {Neurology international}, volume = {18}, number = {8}, pages = {}, pmid = {42646366}, issn = {2035-8385}, abstract = {Neurodegenerative diseases are targets for pridopidine therapy, which aims to improve quality of life through neuroprotective mechanisms that involve sigma-1 receptor (S1R) activation. Neurodegenerative motor and cognitive diseases are influenced by dopamine imbalance, where disruptions in pathways contribute to states that are hyperkinetic or hypokinetic, while current dopaminergic treatments are symptomatic rather than disease-modifying, especially for Huntington's disease and Amyotrophic lateral sclerosis. This review summarizes the mechanisms underlying pridopidine-mediated neuroprotection and examines the current evidence supporting its therapeutic potential. The S1R is an endoplasmic reticulum-mitochondria-associated chaperone involved in homeostasis of calcium, stress regulation, and mitochondrial function. Pridopidine is a small lipophilic molecule that crosses the blood-brain barrier and acts as an S1R agonist, with minimal dopamine D2 receptor occupancy. Activation of S1R by pridopidine modulates calcium signaling and enhances anti-apoptotic activity. Collectively, available evidence suggests that pridopidine may improve motor outcomes and slow disease progression in Huntington's disease and amyotrophic lateral sclerosis, supporting its promise as a disease-modifying therapeutic strategy.}, } @article {pmid42646494, year = {2026}, author = {Shevchuk, D and Kuzmenko, Y and Zakharova, M and Karpov, V and Starodubova, E and Latanova, A}, title = {NLRP3 Inflammasome and Inflammation-Related Proteins Expression Characterized in Non-Cultivated Versus Cultivated Peripheral Blood Cells of Patients with Amyotrophic Lateral Sclerosis.}, journal = {NeuroSci}, volume = {7}, number = {4}, pages = {}, pmid = {42646494}, issn = {2673-4087}, support = {25-74-10090//Russian Science Foundation/ ; }, abstract = {BACKGROUND: Cell and mouse models studies demonstrate NLRP3 inflammasome involvement in amyotrophic lateral sclerosis (ALS) neuroinflammation. Peripheral blood mononuclear cells (PBMCs) are a promising, yet understudied, source of in vivo inflammasome activation biomarkers. Our study reviewed the literature on PBMC-based inflammasome studies of ALS and other neurodegenerative diseases and tested different conditions for PBMC handling to evaluate inflammasome and inflammation-related protein expression in these cells.

METHODS: Expression of NLRP3 inflammasome components and inflammation-related proteins was analyzed by Real-time qPCR and Western blot in non-cultivated/cultivated PBMCs of 23 ALS patients and 20 Healthy controls. IL-1β and IL-18 levels were measured in plasma and cultivated PBMC supernatants by ELISA.

RESULTS: Cultivation of PBMCs decreased expression of inflammasome components and inflammation-related cytokines on the mRNA but not protein level. NLRP3 mRNA expression was significantly higher in ALS-cultivated PBMCs. In both ALS and Healthy controls, IL-18 was detected in plasma, and IL-1β in supernatants of cultivated PBMCs.

CONCLUSIONS: Our findings suggest that PBMC handling conditions, i.e., cell cultivation, may determine particular parameters associated with NLRP3 inflammasome expression and activation pathway, so they should be carefully selected for PBMC-based studies of inflammasome in neurodegenerative and non-neurological disorders and taken into account when interpreting the study results.}, } @article {pmid42646579, year = {2026}, author = {Calabrò, RS and Calderone, A and Ravi, D and Galipò, C and Crupi, MF and Quartarone, A}, title = {Hospital-to-Home Neurological Transition Care: A Scoping Review Across Selected Chronic Neurological Disorders.}, journal = {Medical sciences (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, pmid = {42646579}, issn = {2076-3271}, mesh = {Humans ; *Nervous System Diseases/therapy ; *Transitional Care ; Multiple Sclerosis ; Hospitalization ; Chronic Disease ; Amyotrophic Lateral Sclerosis ; }, abstract = {BACKGROUND: Returning home after neurological hospitalization, rehabilitation, or specialist care transfers responsibility to patients, caregivers, and community services. We mapped mechanisms and gaps across dementia/Alzheimer's disease and related dementias (ADRD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

METHODS: Following JBI guidance and PRISMA-ScR, eligibility was derived using population-concept-context. We included empirical reports involving adults with a target condition, a post-discharge, return-home, rehabilitation, telehealth, caregiver, treatment, respiratory, or palliative continuity component, and post-transition patient, caregiver, service, safety, rehabilitation, equity, or implementation outcomes. Five databases were searched through to 11 May 2026. Two reviewers independently screened records; charting and classification were verified by R.S.C., A.C., and A.Q.

RESULTS: Of 24,417 records, 69 reports were included: Dementia/ADRD, 28; PD, 10; MS, 9; and ALS, 22. Eighteen were core transition reports (26.1%), 14 return-home/community re-entry reports (20.3%), 16 adjacent continuity reports (23.2%), and 21 companion/secondary reports (30.4%). Dementia/ADRD provided discharge-anchored evidence; PD and MS mapped functional carry-over; ALS mapped adjacent respiratory, telehealth, and palliative continuity.

CONCLUSIONS: The main contribution is an operational cross-disease framework separating direct discharge, return-home, adjacent-continuity, and companion evidence while linking mechanisms to disease-specific pathways. This framework maps disease-specific functions, not comparative effectiveness. The proposed frameworks are author-derived and hypothesis-generating. Future studies should use explicit anchors, standardized outcomes, longer follow-up, and equity-sensitive implementation measures addressing caregiver workload, digital access, feasibility, and sustainability. They inform testable, context-sensitive intervention designs for future neurological transition-care research and practice.}, } @article {pmid42647236, year = {2026}, author = {Sanchis-Sanchis, E and de la Rubia Ortí, JE and Sancho-Cantus, D and Cunha-Pérez, C and Casaña-Mohedo, J}, title = {The Microbiota-Gut-Brain Axis and Nutritional Interventions in Amyotrophic Lateral Sclerosis: Pathophysiological Mechanisms, Neuroinflammation, and Non-Motor Manifestations-Scoping Review.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {33}, number = {3}, pages = {}, pmid = {42647236}, issn = {1873-149X}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder in which systemic pathophysiological alterations significantly contribute to disease progression and non-motor manifestations, such as depression and anxiety. The microbiota-gut-brain axis represents a critical bidirectional pathway in which intestinal dysbiosis and epithelial barrier disruption catalyze central neuroinflammation. This scoping review synthesizes evidence from 43 empirical and analytical studies across 28 countries and maps the findings under the WHO International Classification of Functioning (ICF) framework. Pathophysiological data reveal a profound taxonomic shift in patients with ALS, characterized by severe depletion of neuroprotective, butyrate-producing genera (Akkermansia and Prevotella) and enrichment of pro-inflammatory Enterobacteriaceae. This dysbiotic state leads to structural damage to the intestinal mucosa, alteration of Paneth cells, and downregulation of tight junction proteins (zonulin), triggering a "leaky gut" phenomenon. Subsequent systemic translocation of lipopolysaccharides (LPS) induces TLR4-mediated endotoxemia, microglial hyperactivation, and accelerated motor neuron apoptosis. Conversely, therapeutic modulation via Fecal Microbiota Transplantation (FMT), psychobiotics, and metabolic interventions (ketogenic or Mediterranean diets) has demonstrated significant efficacy in restoring epithelial integrity, mitigating mitochondrial hypermetabolism, and reducing emotional distress. This review identifies a critical research gap in the microstructural characterization of the enteric nervous system in ALS. Incorporating microbiome-targeted biomarkers into clinical protocols is crucial for implementing a stratified, multi-systemic therapeutic strategy aimed at enhancing patient prognosis and psychological well-being.}, } @article {pmid42647657, year = {2026}, author = {Denčevski, A and Bataveljić, D and Bogdanović Pristov, J and Krmpot, AJ and Rabasović, MD and Nikolić, L}, title = {Characterizing Single-Cell Differences in Aquaporin-4 and Glutamate Transporter-1 Between Control and hSOD1G93A Astrocytes Using Integrated Epifluorescence and Structured Illumination Microscopy.}, journal = {Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada}, volume = {32}, number = {4}, pages = {}, doi = {10.1093/mam/ozag095}, pmid = {42647657}, issn = {1435-8115}, support = {451-03-33/2026-03/200053//Ministry of Science, Technological Development and Innovation of Republic of Serbia/ ; 451-03-33/2026-03/200178//Ministry of Science, Technological Development and Innovation of Republic of Serbia/ ; 451-03-33/2026-03/200007//Ministry of Science, Technological Development and Innovation of Republic of Serbia/ ; //Institute of Physics Belgrade/ ; //Science Fund of the Republic of Serbia/ ; }, mesh = {*Astrocytes/chemistry/metabolism ; *Aquaporin 4/analysis/metabolism ; Animals ; *Excitatory Amino Acid Transporter 2/analysis ; Microscopy, Fluorescence/methods ; *Single-Cell Analysis/methods ; Cells, Cultured ; Humans ; }, abstract = {Astrocytes, the abundant glial cells of the central nervous system (CNS), maintain water and glutamate homeostasis through aquaporin-4 (AQP4) and glutamate transporter-1 (EAAT2). In the hSODG93A animal model of amyotrophic lateral sclerosis, astrocytes exhibit alterations in these homeostatic proteins. AQP4 and EAAT2 changes are observed in both hSODG93A-expressing astrocytes in the CNS and in cell cultures. Here, we provide a detailed analysis of differences between cultured control and hSOD1G93A astrocytes in AQP4 and EAAT2 fluorescence patterns, subcellular localization, and spatial overlap, using side-by-side epifluorescence and structured illumination microscopy modes of a custom imaging system [two-dimensional structured illumination microscopy (2D SIM)]. 2D SIM system characterization and fluorescence signal analysis demonstrated uniform epifluorescence illumination and high-contrast SIM patterns, enabling whole-cell imaging of AQP4 and EAAT2 and resolving their signals into distinct puncta in both control and hSOD1G93A astrocytes with SIM. Compared with control astrocytes, AQP4 expression increased and EAAT2 expression decreased in the plasma membrane and cytoplasm of hSOD1G93A astrocytes at both diffraction-limited and superresolution scales. Subdiffraction-scale analysis revealed differences in the spatial distributions of AQP4 and EAAT2, showing increased colocalization between these proteins in hSOD1G93A astrocytes. These findings demonstrate the utility of integrated imaging approaches for quantitative, single-cell-resolution analysis of disease-associated protein alterations in astrocytes.}, } @article {pmid42648119, year = {2026}, author = {Wu, D and Kojic, A and Ross, JP and Li, D and Walther, P and Goyal, N and Sampson, J and Wu, JC}, title = {Generation of two iPSC lines from ALS patients harboring C9orf72 hexanucleotide repeat expansions.}, journal = {Stem cell research}, volume = {95}, number = {}, pages = {104085}, pmid = {42648119}, issn = {1876-7753}, support = {R01 HL171102/HL/NHLBI NIH HHS/United States ; UG3 AG097135/AG/NIA NIH HHS/United States ; UG3 TR005845/TR/NCATS NIH HHS/United States ; UM1 TR006031/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism/cytology/pathology ; *C9orf72 Protein/genetics ; *DNA Repeat Expansion/genetics ; Cell Line ; Cell Differentiation ; Female ; }, abstract = {The GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene constitutes the leading genetic driver of amyotrophic lateral sclerosis (ALS). This fatal neurodegenerative disorder is characterized by the systematic loss of both the upper and lower motor neurons across both the central and peripheral nervous systems. This work describes the successful reprogramming of two human induced pluripotent stem cell (iPSC) lines originating from two independent ALS patients, both of whom carry a C9orf72 HRE mutation. Validation of the two established iPSC lines confirmed the expression of pluripotency markers, normal karyotypes, and successful trilineage differentiation. Consequently, these lines provide a robust in vitro platform to model ALS and study C9orf72-mediated disease mechanisms.}, } @article {pmid42649099, year = {2026}, author = {, and Kassardjian, CD and Desai, U and Živković, SA and Simmons, Z and Narayanaswami, P}, title = {It's Virtually Here: Telemedicine, Virtual Care, and Neuromuscular Disease.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70382}, pmid = {42649099}, issn = {1097-4598}, abstract = {The COVID-19 pandemic forced a partial shift in neuromuscular clinical practice away from in-person care to remote means. However, this shift was unexpected, abrupt, reactive to the emergency of a pandemic, and disruptive to the usual manner of care, without adequate time to adapt or study the optimal manner to provide care remotely. While traditionally associated with hub-and-spoke telemedicine models, the pandemic popularized direct-to-home virtual care, mostly unsupported by on-site examiners or standardized platforms. In chronic neuromuscular disorders such as amyotrophic lateral sclerosis (ALS) and myasthenia gravis (MG), virtual care has demonstrated feasibility, patient satisfaction, and potential cost savings, particularly for geographically or functionally disadvantaged populations. Disease-specific adaptations such as the Myasthenia Gravis Core Exam and wearable-based assessments (e.g., home spirometry, grip strength monitoring, and digital outcome measures) have enabled more structured remote evaluations. However, diagnostic accuracy may be compromised by the inability to perform detailed neurological examinations or electrodiagnostic studies. Equity concerns persist due to variability in digital literacy, internet and digital device access, and socioeconomic status. Post-pandemic, patients with disabilities may continue to benefit in a combined virtual/in-person paradigm of care. More evidence is required to evaluate the impact of virtual care on neuromuscular practice quality of care and outcomes. We outline some of the questions that require further study, hoping to spur research and quality improvement investigations of these new care models.}, } @article {pmid42649384, year = {2026}, author = {Guo, H and Savard, A and Manser, C and Dutta, K and Taylor, JA and Rousseaux, MWC and Pozzi, S and Julien, JP and Baird, S and Gibbings, D}, title = {Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43.}, journal = {Nature biomedical engineering}, volume = {}, number = {}, pages = {}, pmid = {42649384}, issn = {2157-846X}, support = {183767//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; TR180076//Weston Brain Institute/ ; }, abstract = {In neurodegenerative diseases such as frontotemporal dementia and amyotrophic lateral sclerosis, pathological forms of proteins such as Tau and TDP-43 accumulate within large heterogeneous inclusions inside cells. Current strategies to eliminate such aberrant protein species in patients encounter three main challenges: crossing the blood-brain barrier and plasma membrane, specifically recognizing pathological forms of proteins, and engaging mechanisms to eliminate large entities. Here we fuse LC3A, a central protein in the recruitment of substrates into autophagosomes, to cytoplasm-stable antibodies. These engineered autophagy receptors, targeting Tau or TDP-43, are delivered using small extracellular vesicles and reduce pathology in models, including Tau P301S adult primary mouse neurons, TDP-43[G298S] iPSC-derived motor neurons and after intravenous injection in Tau P301S mice. Similarly, adeno-associated-virus-mediated delivery in TDP-43[ΔNLS] mice enhances clearance of pathological TDP-43. This targeted degradation strategy allows delivery into the brain while capitalizing on the specificity of antibodies and the ability of autophagy to degrade large intracellular entities.}, } @article {pmid42650212, year = {2026}, author = {Varrassi, G and Tran, YV and Farì, G and Narvaez Encinas, M and Corriero, A and Puntillo, F and Pham, PV and Leoni, MLG}, title = {The Eye as a Window to Neurodegeneration: Oxidative Stress, Optic Nerve Vulnerability, and Retinal Biomarkers-A Scoping Review.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {15}, number = {8}, pages = {}, pmid = {42650212}, issn = {2076-3921}, support = {//Tam Anh General Hospital, Ha Noi/ ; }, abstract = {Neurodegenerative diseases represent a major and growing global health burden characterized by progressive neuronal dysfunction, axonal degeneration, and irreversible neural tissue loss. Increasing evidence identifies oxidative stress as one of several interacting pathogenic mechanisms in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and several optic neuropathies. Interest has increasingly focused on the brain-retina axis, as the retina and optic nerve share structural, metabolic, and molecular features with the central nervous system and may provide accessible insights into neurodegeneration. This scoping review mapped current evidence on oxidative stress in neurodegeneration, emphasizing cranial nerve involvement, optic nerve vulnerability, retinal ganglion cell degeneration, visual dysfunction, oxidative biomarkers, and emerging therapeutic strategies. The review followed established methodological frameworks and PRISMA-ScR recommendations; no formal risk-of-bias appraisal was undertaken, consistent with scoping-review methodology. The literature shows that oxidative stress interacts with mitochondrial dysfunction, neuroinflammation, impaired mitophagy, ferroptosis, and altered bioenergetics, contributing to neuronal injury in cerebral and retinal disorders. Retinal ganglion cells appear particularly vulnerable because of their high metabolic demands and reliance on oxidative phosphorylation. Glaucoma and other optic neuropathies share molecular signatures with central neurodegenerative diseases. Retinal imaging and oxidative biomarkers show promise for diagnosis, monitoring, and stratification. The evidence base is nonetheless dominated by preclinical work; biomarker performance is inconsistent across matrices and assay platforms and most antioxidant clinical trials have been negative. Oxidative stress is therefore best regarded as one interacting node of a broader pathogenic network rather than a universal or predominant driver and the brain-retina continuum as a mechanistically plausible but not yet clinically validated framework for biomarker-guided neuroprotection.}, } @article {pmid42650794, year = {2026}, author = {Mitsumoto, H and Blasco, H and Corcia, P and Silani, V}, title = {ALS: An Organism-Wide Bioenergetic Failure Due to Mitochondrial Dysfunctions?.}, journal = {Biomolecules}, volume = {16}, number = {8}, pages = {}, pmid = {42650794}, issn = {2218-273X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Mitochondria/metabolism/pathology ; *Energy Metabolism ; Animals ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and invariably fatal disease for which currently available disease-modifying therapies provide only modest benefit. Defining its underlying pathogenesis is therefore essential for the development of effective treatments. Increasing evidence indicates that ALS is not restricted to motor neurons but involves multiple neuronal and glial systems, extending to peripheral organs, often at subclinical levels. These multisystem alterations may precede overt neurological symptoms by years and are accompanied by metabolic disturbances, including progressive weight loss and hypermetabolism. In peripheral tissues, ongoing cellular turnover and associated immune and inflammatory responses may further increase energy demand. Within this framework, mitochondrial dysfunction emerges as a central mechanism underlying impaired bioenergetics and systemic metabolic failure. Mitochondria not only regulate energy production but also contribute to oxidative stress, which in turn exacerbates mitochondrial injury, creating a self-amplifying cycle. Importantly, many genetic forms of familial ALS directly affect mitochondrial pathways, and similar biochemical abnormalities are observed in sporadic ALS. These shared features suggest that mitochondrial dysfunction represents a common pathway across ALS subtypes. Targeting upstream mechanisms of mitochondrial impairment may therefore provide a unifying strategy for understanding ALS pathogenesis and developing effective therapies.}, } @article {pmid42650874, year = {2026}, author = {Wang, Z and Fu, Y and Li, S and Zhang, Y and Sun, T and Miao, N}, title = {The Prospective Regulatory Functions of lncRNAs and Their ceRNA Networks in the Development of Motor Neurons and Associated Diseases.}, journal = {Biomolecules}, volume = {16}, number = {8}, pages = {}, pmid = {42650874}, issn = {2218-273X}, mesh = {Humans ; *RNA, Long Noncoding/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; RNA, Competitive Endogenous ; Animals ; *Gene Regulatory Networks ; *Motor Neuron Disease/genetics/pathology/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Muscular Atrophy, Spinal/genetics/pathology/metabolism ; }, abstract = {Motor neurons form a highly specialized network composed of α-, β-, and γ-subtypes that coordinate skeletal muscle activity. Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are characterized by the progressive degeneration of this network, resulting in motor dysfunction. Emerging evidence underscores the significant roles of long non-coding RNAs (lncRNAs) in motor neuron development and disease. However, only a few have been experimentally confirmed as true ceRNA regulators, highlighting the need to differentiate validated mechanisms from mere associations or predictions. This review summarizes the regulatory roles of lncRNA-associated ceRNA networks in motor neuron development, evaluates the evidence for their involvement in MNDs, and explores their potential impact on disease progression. It also addresses current challenges, knowledge gaps, and future research directions for understanding ceRNA-mediated mechanisms and developing therapeutic strategies for MNDs.}, } @article {pmid42651103, year = {2026}, author = {Costa, IM and Kanashiro, A and Barros, GSF and Monteiro, AJ and Bonilha, CS and Galdino, G and Veras, FP}, title = {Targeting Neutrophil Extracellular Traps in Neuroinflammation: A Therapeutic Perspective on Neurodegenerative Diseases.}, journal = {Brain sciences}, volume = {16}, number = {8}, pages = {}, pmid = {42651103}, issn = {2076-3425}, abstract = {Neuroinflammation is a complex process involved in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. Neutrophils, although traditionally considered peripheral immune cells, have emerged as active participants in the immunopathology of the central nervous system (CNS) through the release of neutrophil extracellular traps (NETs), structures composed of decondensed chromatin embedded with pro-inflammatory proteins. Evidence suggests that NETs play a dual role: they are protective against pathogens but can also induce tissue damage when produced in excess. Several pathways are involved in their formation, including vesicle-mediated release (vital NETs), the lytic NADPH oxidase (NOX)-dependent pathway, and the mitochondrial pathway. Targeting NETs therapeutically, through the use of NETosis inhibitors, NET-degrading strategies, or blockade of neutrophil migration, has shown promise in reducing neuroinflammation/neurodegeneration and improving neurological outcomes in experimental models. This review aims to investigate both the protective and deleterious roles of NETs and how this knowledge may reveal new therapeutic strategies to modulate neurodegenerative diseases and preserve neural integrity, offering valuable insights for potential applications in clinical practice.}, } @article {pmid42651138, year = {2026}, author = {Lu, S and Chen, Z and Wang, Y and Bian, H and Yu, S and Huang, L}, title = {Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation.}, journal = {Brain sciences}, volume = {16}, number = {8}, pages = {}, pmid = {42651138}, issn = {2076-3425}, support = {LH2019H106//Natural Science Foundation of Heilongjiang Province/ ; YQJH2023152//Excellent Young Teachers Basic Research Support Program" for Provincial Undergraduate Colleges in Heilongjiang Province/ ; ZHY2025-009//Heilongjiang Province Traditional Chinese Medicine Research Project/ ; }, abstract = {O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification that couples hexosamine biosynthesis pathway flux to protein function in neurons and glia. This reversible cycling, catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), integrates glucose, glutamine, acetyl-CoA, and nucleotide metabolism with synaptic activity, mitochondrial adaptation, transcriptional regulation, proteostasis, and neuroimmune signaling. Dysregulated O-GlcNAc cycling has been implicated in major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington's disease (HD), through effects on disease-related proteins, autophagy, mitochondrial function, and inflammatory networks. However, available evidence does not support a universal model in which global O-GlcNAc elevation is uniformly protective or global reduction is uniformly pathogenic. In this mechanistic narrative review, we integrate disease-specific and substrate-focused findings while distinguishing relatively mature translational evidence from model-based or hypothesis-generating observations. We propose a state-resolved framework in which disease-relevant O-GlcNAc states are interpreted across biological contexts, substrate/site specificity, and intervention dynamics. This framework helps reconcile divergent findings across experimental systems and highlights the limitations of indiscriminate global pathway modulation. Although OGA inhibitors represent the most advanced therapeutic strategy, their broad substrate effects underscore the need for pharmacodynamic biomarkers, human validation, brain-targeted delivery, and state-resolved approaches. Moving from bulk O-GlcNAc measurements toward precise correction of disease-relevant O-GlcNAc states across defined biological contexts will be essential for translating this biology into clinically meaningful interventions.}, } @article {pmid42651198, year = {2026}, author = {Harris, KE and Lascaratos, G and Chau, KY}, title = {Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?.}, journal = {Brain sciences}, volume = {16}, number = {8}, pages = {}, pmid = {42651198}, issn = {2076-3425}, abstract = {BACKGROUND/OBJECTIVES: Mitochondrial Complex V (Complex V [CX-V], or ATP synthase) is the terminal enzyme of oxidative phosphorylation and is responsible for the majority of cellular ATP production. An increasing body of evidence suggests that CX-V dysfunction may contribute to mitochondrial impairment observed in neurodegenerative disease. This review evaluated current research on the structure, regulation, and function of CX-V, examined the consequences of CX-V dysfunction, and assessed its proposed role in neurodegenerative disorders.

METHODS: A comprehensive review of the published literature was carried out, with emphasis on primary research investigating CX-V structure and function, inherited CX-V disorders, and experimental evidence linking CX-V dysfunction to neurodegenerative disease. The reviewed studies used a range of experimental approaches, including structural biology, biochemical studies, patient-derived cellular models, animal models and post-mortem human tissue.

RESULTS: Current evidence demonstrates that disruption of CX-V impairs ATP production, alters mitochondrial membrane potential, and oxidative phosphorylation, and that pathogenic variants cause primary mitochondrial disease. Across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis/frontotemporal dementia, glaucoma and inherited optic neuropathies, alterations in CX-V activity, regulation and structural integrity are consistently associated with mitochondrial dysfunction. Direct evidence supporting CX-V as a primary driver of neurodegeneration remains very limited, with many observations originating from broader studies of general mitochondrial dysfunction.

CONCLUSIONS: CX-V dysfunction represents a recurring feature of mitochondrial impairment across a variety of neurodegenerative disorders and may exacerbate neuronal vulnerability by disrupting cellular bioenergetics. Current evidence indicates that CX-V may serve as a common downstream target of multiple pathological pathways rather than acting as a primary pathological factor. Future studies require direct assessment of CX-V activity in clinically relevant human models and patient tissues to determine its contribution to disease progression and examine its potential as a therapeutic target.}, } @article {pmid42651202, year = {2026}, author = {Alshehri, S and Atabek, B and Heiman-Patterson, T and Ayaz, H}, title = {Task-Evoked Prefrontal Hemodynamics During Cognitive Assessment in Amyotrophic Lateral Sclerosis Using fNIRS.}, journal = {Brain sciences}, volume = {16}, number = {8}, pages = {}, pmid = {42651202}, issn = {2076-3425}, abstract = {Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease increasingly recognized for extra-motor manifestations, including cognitive dysfunction involving frontal cortical systems. Conventional clinical assessments are primarily behavioral and may not capture subtle alterations in the neural systems that support cognitive performance. This pilot study examined whether wearable functional near-infrared spectroscopy (fNIRS) could detect task-evoked prefrontal hemodynamic differences during the King-Devick Task (KDT), a rapid oculomotor number-naming task that engages visual scanning, attention, processing speed, and verbal response production. Methods: Sixteen participants, including seven individuals with ALS and nine age-matched healthy controls (HC), completed four progressively difficult KDT conditions while prefrontal cortical activity was recorded. Results: As task difficulty increased, response times became slower across participants, while accuracy remained preserved and behavioral performance did not differ significantly between groups. Prefrontal oxygenated hemoglobin (HbO) responses increased with task difficulty across all prefrontal optodes, supporting task-evoked cortical engagement. In contrast, deoxygenated hemoglobin (HbR) responses showed a group-specific pattern in the left dorsolateral prefrontal cortex: individuals with ALS demonstrated progressively increasing HbR responses across difficulty conditions, whereas HC showed relatively stable responses, with group differences emerging at higher difficulty levels. Conclusions: These findings suggest a dissociation between preserved behavioral performance and altered prefrontal hemodynamic regulation in ALS. The observed HbR pattern may reflect differences in cortical recruitment, neurovascular coupling, oxygen extraction, vascular responsiveness, or the efficiency of cortical resource allocation during increasing cognitive-motor demands. Wearable fNIRS may therefore complement behavioral assessments by revealing task-evoked neural alterations that are not evident from performance measures alone.}, } @article {pmid42651639, year = {2026}, author = {Ciuro, M and Rovetto, C and Sirna, AA and Giunta, S and Leanza, G and Gulino, R}, title = {Targeting Mitochondrial Fission Produces Both Neuroprotective and Detrimental Effects in the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Biology}, volume = {15}, number = {16}, pages = {}, pmid = {42651639}, issn = {2079-7737}, support = {PG_6/2022//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by progressive motor neuron (MN) degeneration and severe skeletal muscle atrophy. Despite extensive research, the mechanisms driving disease onset and progression remain incompletely understood. While MN loss is a defining feature of ALS, increasing evidence indicates that mitochondrial dysfunction contributes to disease pathogenesis. Here, we investigated the hypothesis that Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp-1, may exert neuroprotective properties in the SOD1[G93A] mouse model of ALS. Treatment was initiated prior to symptomatic onset to assess its potential disease-modifying effects. Mdivi-1 administration resulted in partial preservation of spinal MNs, however, this benefit did not translate into functional improvement. Moreover, treated animals exhibited exacerbated muscle atrophy, increased cytoplasmic localization of TDP-43 in MNs and compromised synaptic plasticity. Drp-1 expression was reduced in SOD1 mice and further decreased following Mdivi-1 treatment, suggesting that mitochondrial dynamics may already be compromised in this model. Overall, our results also highlight possible off-target effects of Mdivi-1 and point to a context-dependent role of mitochondrial dynamics in ALS.}, } @article {pmid42651822, year = {2026}, author = {Satoh, K and Shimamura, MI and Fujimoto, T and Kitayama, M and Akagi, A and Iwasaki, Y and Satoh, Y and Ichinose, K and Satoh, A and Iwata, IT and Yabe, I}, title = {Detection of TDP-43 Proteinopathies in Brain and Cerebrospinal Fluid Using Seed Amplification Assay.}, journal = {Current issues in molecular biology}, volume = {48}, number = {8}, pages = {}, pmid = {42651822}, issn = {1467-3045}, support = {JP 21K07417 and JP 25K02582//Japan Society for the Promotion of Science/ ; //TaNeDS Funding for Daiichi Sankyo Co/ ; 2023088970//Takeda Science Foundation/ ; 25dk0207077h0001//Japan Agency for Medical Research and Development/ ; }, abstract = {Misfolded TAR DNA-binding protein 43 (TDP-43) is the primary pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While seed amplification assays (SAAs), such as real-time quaking-induced conversion (RT-QuIC), have shown promise in detecting misfolded TDP-43 in cerebrospinal fluid (CSF) and olfactory mucosa, technically accessible methodologies are urgently required for widespread clinical application. We developed a streamlined, non-immunoprecipitation-based TDP-43 RT-QuIC assay to assess seeding activity in brain tissue and CSF. We evaluated its diagnostic performance using CSF from patients with TDP-43 proteinopathies and control subjects, and further examined its association with neurofilament light chain (NfL) and tau-related biomarkers. In CSF analysis, the assay demonstrated positive seeding activity in 70% (21/30) of patients with ALS and dementia, 50% (5/10) of patients with FTLD, and 40% (8/20) of patients with ALS alone. The assay exhibited excellent specificity, yielding negative results in >99% (199/200) of control samples, including those with autoimmune or electrophysiological abnormalities. Furthermore, CSF analysis demonstrated significantly higher NfL levels in TDP-43 SAA-positive cases compared to SAA-negative cases (p < 0.0008). The highest NfL concentrations were observed in the SAA-positive ALS with dementia and ALS cohorts, contrasting with lower levels in FTLD. Tau-related biomarkers exhibited no significant differences between the groups. Our streamlined, non-immunoprecipitation TDP-43 RT-QuIC assay provides highly specific detection of pathological TDP-43 seeding activity. While the assay detects the underlying TDP-43 proteinopathy rather than distinguishing between ALS and FTLD clinical phenotypes, its technical simplicity and combined utility with NfL measurements offer a robust, scalable framework for biomarker development. This approach provides a practical foundation for future multi-center validation and international standardization efforts.}, } @article {pmid42652164, year = {2026}, author = {Karbownik, M and Fidura, M and Perlikowska, R}, title = {Are Signal Peptides Hidden Regulators of Neurodegenerative Disease?.}, journal = {Biomedicines}, volume = {14}, number = {8}, pages = {}, pmid = {42652164}, issn = {2227-9059}, support = {564-20-100//Medical University of Lodz/ ; }, abstract = {Canonical signal peptides (SPs) are short N-terminal sequences that direct nascent proteins into the secretory pathway, but their role extends far beyond protein targeting. Advances in sequencing and computational tools have enabled their systematic identification across proteomes, highlighting SPs as critical regulators of protein biogenesis, including endoplasmic reticulum (ER) targeting, translocation, folding, and proteostasis. Clinically, mutations affecting SP function underlie a distinct group of human disorders, while SP-derived fragments are emerging as diagnostic biomarkers and therapeutic targets. In biotechnology, SPs are engineered to enhance recombinant protein production and serve as molecular tags for intracellular delivery. Together, these developments position SPs at the intersection of fundamental cell biology, medicine, and biotechnology. While this review primarily focuses on canonical SPs, it also considers selected non-canonical targeting and topogenic sequences whose dysfunction contributes to protein misfolding, impaired ER translocation, disrupted degradation pathways, and altered intracellular trafficking in neurodegenerative diseases. Aberrations involving both conventional SPs and alternative targeting/topogenic elements contribute to pathological protein aggregation, a hallmark of major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington Disease (HD), prion diseases, and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); in multiple sclerosis (MS) is primarily an inflammatory demyelinating disease, where abnormal protein exposure, potentially linked to misprocessed SPs, can activate immune responses. By synthesizing current knowledge, the review explores how alterations in targeting determinants influence key proteostasis pathways, acting as upstream modulators of disease-relevant molecular cascades. It further discusses the emerging concept that SP-derived fragments may participate in intercellular communication, adding an additional layer of regulatory complexity.}, } @article {pmid42652219, year = {2026}, author = {Sousa-Catita, D and Mascarenhas, P and Oliveira, C and Grunho, M and Gonçalves, F and Fonseca, J}, title = {Clinical, Social, and Healthcare Factors Associated with Nutritional Status in Amyotrophic Lateral Sclerosis: A Multidimensional Approach.}, journal = {Biomedicines}, volume = {14}, number = {8}, pages = {}, pmid = {42652219}, issn = {2227-9059}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where malnutrition significantly worsens clinical outcomes. We performed a multidimensional analysis to identify clinical, social, and healthcare factors associated with nutritional vulnerability in a real-world setting. Methods: This cross-sectional study included 97 adults with ALS recruited through a national association (APELA) and a hospital-based outpatient consultation (ANOC). Nutritional status was assessed using the Mini Nutritional Assessment (MNA[®]), Body Mass Index (BMI), and Global Leadership Initiative on Malnutrition (GLIM) criteria. Associations with total MNA[®] scores were evaluated using a prespecified multivariable linear model with HC3 robust standard errors and bootstrap validation to assess inferential stability. Results: Malnutrition prevalence was high, with 42.3% of participants classified as moderately malnourished and 43.3% as severely malnourished under GLIM criteria. Mean MNA[®] score was 19.69 (SD 4.53). In the adjusted model, ANOC recruitment was associated, after adjustment, with a 4.477-point lower MNA[®] score compared with APELA (HC3 95% CI -7.071 to -1.884; p<0.001). Other sociodemographic and clinical factors yielded imprecise estimates. Although explanatory power was modest (Adjusted R2=0.067; optimism-corrected R2=-0.005), the recruitment setting remained a robust correlate across sensitivity analyses. Conclusions: Recruitment setting emerged as the most consistent adjusted correlate of MNA[®] scores, likely reflecting differences in clinical case mix and referral pathways in the Portuguese healthcare context. These findings highlight nutritional vulnerability in ALS as a multifaceted construct that should be interpreted in relation to both clinical and healthcare-contextual factors. This study supports considering systemic factors and the need for longitudinal research that incorporates comprehensive functional and social metrics to optimize multidisciplinary nutritional interventions.}, } @article {pmid42652396, year = {2026}, author = {Bhardwaj, S and Chakraborty, A and Mead, J and Stilos, K}, title = {Palliative Care Involvement in Hospitalized Amyotrophic Lateral Sclerosis Patients.}, journal = {International journal of environmental research and public health}, volume = {23}, number = {8}, pages = {}, pmid = {42652396}, issn = {1660-4601}, mesh = {Humans ; *Palliative Care/statistics & numerical data ; *Amyotrophic Lateral Sclerosis/therapy/mortality ; Female ; Male ; *Hospitalization ; Retrospective Studies ; Aged ; Middle Aged ; Referral and Consultation ; Aged, 80 and over ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with significant physical, psychological, and social distress. Given its terminal nature and high symptom burden, early integration of palliative care is essential. The inpatient Palliative Care Consult Team (PCCT) provides specialist palliative care to hospitalized patients with ALS. Hospitalizations are common throughout the ALS disease trajectory, particularly as patients experience progressive functional decline, respiratory compromise, and increasing care needs, making inpatient encounters important opportunities for specialist palliative care involvement. To extend palliative care beyond the inpatient setting and facilitate earlier involvement, an ALS ambulatory clinic was established in 2018. Despite the importance of palliative care, limited data describes its involvement among hospitalized ALS patients. This retrospective review examines the relationship between the PCCT and ALS patients admitted to a tertiary care facility between 2006-2019. Data collected included patient demographics, referral indications, clinical course, and disposition. Most patients referred to the PCCT had poor functional status and a guarded prognosis at initial consultation. Symptom management and support for complex decision-making were leading reasons for referral. Approximately half of patients died in the hospital within three months of referral. Most deaths occurred within one week, underscoring the importance of timely palliative care.}, } @article {pmid42652600, year = {2026}, author = {Davies, A and Bentley, A and Bikov, A}, title = {The Role of Neurofilaments in Diagnosis and Monitoring of Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical medicine}, volume = {15}, number = {16}, pages = {}, pmid = {42652600}, issn = {2077-0383}, abstract = {Background: Amyotrophic lateral sclerosis (ALS), the most common type of motor neurone disease (MND), is a devastating diagnosis that often leads to mortality within 2-5 years of symptom onset. Respiratory failure and aspiration pneumonia both associated with respiratory muscle weakness are the most common causes of death. Difficult to diagnose and devastating in its prognosis, much research has aimed to identify a reliable biomarker to diagnose ALS, prognosticate and improve enrolment into clinical trials to further research efforts. Over the last few decades, neurofilaments (NFs) have emerged as promising biomarkers, especially neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH). This review aims to summarise the current evidence for use of NFs as biomarkers in ALS. Current Evidence: Higher levels of NFL and pNFH are measured in CSF than in serum, and levels in CSF and serum are correlated. High CSF NFL, serum NFL and CSF pNFH levels could differentiate patients with ALS from healthy controls, other neurological disease, neurodegenerative controls (without MND), other MND subtypes and ALS disease mimics; however, studies reported a high degree of heterogeneity irrespective of which media or NFs have been used. The number of studies examining NFs to predict respiratory failure in patients with ALS is low. Conclusions and Future Directions: Despite numerous studies consistently reporting higher NF levels in ALS compared to various controls, their clinical value is limited due to high heterogeneity of the results and inconsistencies in proving its prognostic value. Further understanding the relationship between NF levels and respiratory failure is paramount to improve the quality of life of patients with ALS and increase survival.}, } @article {pmid42652767, year = {2026}, author = {Friebel, J and Manni, M and Gozdowsky, SC and Brettschneider, P and Grün, D and Baumann, AM and Spielmann, E}, title = {Reorganisation of the Basic Life Support Segment in a Physician-Led Emergency Medical Service: A Retrospective Evaluation of Operational and Clinical Characteristics.}, journal = {Journal of clinical medicine}, volume = {15}, number = {16}, pages = {}, pmid = {42652767}, issn = {2077-0383}, abstract = {Background: Increasing demand for emergency medical services (EMS) challenges prehospital resource availability, particularly for time-critical emergencies requiring advanced life support (ALS). Although tiered BLS and ALS response models are established in many non-physician-led EMS systems, evidence regarding qualification-based dispatch stratification within physician-led EMS systems remains limited. This study evaluated the clinical and operational characteristics of an expanded BLS dispatch segment in Berlin EMS. Methods: A retrospective observational study analysed 2,132,246 EMS missions in Berlin, Germany, between 2020 and 2024. Missions were retrospectively classified according to dispatch codes included in the expanded BLS segment, designed to allocate incidents with lower expected requirements for ALS-level interventions to appropriately qualified EMS personnel. Analyses included dispatch characteristics, clinical findings from electronic patient care records, observed safety-related indicators, and ALS response intervals. Results: Overall, 28.7% of EMS missions were classified within the expanded BLS segment. Traumatic and psychiatric presentations represented the most frequent diagnostic groups. Based on predefined clinical indicators, no immediately life-threatening condition was documented in more than 95% of missions. Cardiopulmonary resuscitation occurred in 0.03% of cases, and emergency physician involvement was documented in approximately 3% of cases. Conclusions: A substantial proportion of EMS missions represented a population with predominantly lower expected prehospital treatment complexity within a qualification-based dispatch framework. Structured emergency call interrogation combined with dispatch classification and linked clinical data enabled retrospective evaluation of this approach. Further validation against independent clinical reference standards and linkage with downstream outcomes are required to determine broader applicability.}, } @article {pmid42652933, year = {2026}, author = {Ilias, I and Keskinidou, C and Poupouzas, G and Issaris, V and Lotsios, NS and Botoula, E and Tzanela, M and Vassiliadi, DA and Kokkoris, S and Vrettou, CS and Vassiliou, AG and Dimopoulou, I}, title = {Growth Hormone-Insulin-like Growth Factor Axis and GDF-15 in Critical Illness: Implications for Survival Stratification.}, journal = {Life (Basel, Switzerland)}, volume = {16}, number = {8}, pages = {}, pmid = {42652933}, issn = {2075-1729}, abstract = {Background: The growth hormone (GH)-insulin-like growth factor (IGF) axis is profoundly dysregulated in critical illness. GDF-15 and individual IGF-binding proteins (IGFBPs) have separately been proposed as prognostic biomarkers, but to our knowledge, no prior study has simultaneously characterized all major GH-IGF axis components and GDF-15 in the same critically ill cohort, precluding assessment of their joint intercorrelation structure. Aim: To provide the first simultaneous characterization of the intercorrelation structure among ten GH-IGF axis components and GDF-15 in a single ICU cohort, testing whether this structure is robust to adjustment for illness severity; and, secondarily, to describe admission discriminatory performance relative to APACHE II and SOFA. Methods: This was a prospective observational pilot study of 43 critically ill adults with admission (T01) measurement of ten GH-IGF axis biomarkers and longitudinal follow-up to day 15. Spearman correlations and hierarchical clustering characterized the admission intercorrelation structure; partial correlations adjusting for APACHE II and SOFA, and bootstrap confidence intervals, assessed robustness. Secondary analyses included the examination of admission discrimination (ROC/AUC), a leave-one-out cross-validated combined model, and longitudinal trajectories. All analyses were exploratory, hypothesis-generating, and unadjusted for multiple comparisons unless stated. Results: Hierarchical clustering identified a coherent cluster comprising GDF-15, IGFBP-1, IGFBP-2, and growth hormone-binding protein (GHBP), distinct from classical GH-resistance markers (GHR vs. healthy controls, GHR vs. admission) and from GH, IGF-1, acid-labile subunit (ALS), and IGFBP-3. Within this cluster, GDF-15 correlated with IGFBP-1 (ρ = 0.65, 95% bootstrap CI 0.44-0.78), IGFBP-2 (ρ = 0.50, CI 0.19-0.71), and GHBP (ρ = 0.47, CI 0.20-0.68); GDF-15 showed no correlation with classical GH-resistance markers. These correlations were essentially unchanged after adjusting for APACHE II or SOFA (partial ρ within 0.03-0.16 of unadjusted values), indicating the structure is not attributable to shared confounding by illness severity. This robustness extended to further adjustment for IL-6, age, BMI, and mechanical-ventilation duration, and results from all 45 pairwise T01 correlations were re-examined with Benjamini-Hochberg false-discovery-rate correction (9 of 11 nominally significant pairs retained q < 0.05). However, the GDF-15-GHBP correlation, unlike the GDF-15-IGFBP-1/IGFBP-2 correlations, attenuated substantially after adjustment for IL-6 and was not consistent across a brain-injury/non-brain-injury subgroup sensitivity analysis, indicating this specific link is less specific than the others. In secondary exploratory analyses, GDF-15 had the highest individual admission AUC (0.74) among biomarkers but was substantially outperformed by APACHE II (AUC 0.90) and SOFA (AUC 0.81); a combined GDF-15 + IGFBP-2 model did not improve on GDF-15 alone. Conclusions: This study identifies a severity-independent intercorrelation structure linking GDF-15 to inhibitory IGFBPs, distinct from classical GH-resistance signaling, in critically ill patients. Although the findings do not support any clinical application at this stage, further study in adequately powered, multicenter cohorts can be contemplated.}, } @article {pmid42653169, year = {2026}, author = {Terribile, G and Pedrinazzi, M and Frigerio, I and Sancini, G and Combi, R}, title = {Theranostic Innovative Strategies for Brain Diseases: New Insights on Neurovascular Unit-Associated Pathological Changes in Neurodegenerative Disorders and Aging.}, journal = {International journal of molecular sciences}, volume = {27}, number = {16}, pages = {}, pmid = {42653169}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/pathology/diagnosis ; *Aging/pathology ; Animals ; Blood-Brain Barrier/metabolism/pathology ; *Theranostic Nanomedicine/methods ; *Brain Diseases/therapy/diagnosis/pathology ; Nanoparticles ; MicroRNAs/genetics ; Nanotechnology ; }, abstract = {Central nervous system (CNS) disorders represent a significant healthcare challenge, with aging as the primary risk factor. Current clinical management remains predominantly symptomatic, as late-stage diagnosis and the blood-brain barrier (BBB) limit therapeutic efficacy. This review synthesizes emerging innovations in neurotheranostics-integrated diagnostic and therapeutic platforms-focusing on the neurovascular unit (NVU) as a central pathogenic driver and target. Evidence indicates that NVU and BBB dysfunction are early events in Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases, often preceding classic neuropathological hallmarks. The review highlights the potential of nanotechnology, engineered nanoparticles (NPs) and microRNAs (miRNAs) as precision tools for early detection and targeted CNS delivery. Additionally, it discusses the transformative impact of artificial intelligence (AI) in facilitating personalized, predictive care. Transitioning from a generic "one-pill-for-one-disease" model to a patient-centered strategy targeting early NVU alterations is essential. Integrating AI, nanotechnology and NVU-focused strategies offers a promising path toward effective, personalized disease-modifying therapies.}, } @article {pmid42653407, year = {2026}, author = {Rosenfeld, J and Salomon-Zimri, S and Tracik, F}, title = {Combination Pharmacology for ALS: A Mechanistic Rationale.}, journal = {International journal of molecular sciences}, volume = {27}, number = {16}, pages = {}, pmid = {42653407}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Drug Therapy, Combination ; Oxidative Stress/drug effects ; Mitochondria/metabolism/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) involves multiple converging pathogenic mechanisms, including glutamate excitotoxicity, oxidative and endoplasmic-reticulum stress, mitochondrial dysfunction, neuroinflammation, iron dysregulation, and altered microRNA processing. Expecting a single pharmacologic intervention to meaningfully alter such a complex disease has proven overly optimistic and is reflected by the modest clinical benefits of approved monotherapies. This review outlines the mechanistic foundation and translational rationale for combination pharmacology in ALS. Drawing from paradigms in oncology, infectious disease, and other neurological disorders, it explores how rational multi-target strategies, whether synergistic, complementary, or pathway-divergent, may better address the multifactorial biology of ALS. The review also discusses recent mechanistic examples and design principles for advancing this therapeutic paradigm.}, } @article {pmid42656814, year = {2026}, author = {Fent, M and Farkas, A and Pataki, H and Nagy, ZK and Csontos, I}, title = {Spectroscopic Monitoring and Chemometric-Based Feedback Control of the Diazotization Reaction.}, journal = {Organic process research & development}, volume = {30}, number = {8}, pages = {2149-2158}, pmid = {42656814}, issn = {1083-6160}, abstract = {Inline Raman spectroscopy-based monitoring enables the development of control systems that allow the implementation of Process Analytical Technology (PAT) principles even in chemical reactions, thereby improving quality, efficiency, and safety. There are only a few articles in the literature that discuss such control systems. This may be due to the numerous challenges involved, including the need for robust measurement setups and the development of chemometric algorithms capable of delivering accurate and stable real-time evaluations. Thus, this study presents the Raman spectroscopic monitoring and chemometric-based feedback control of a highly exothermic and potentially hazardous diazotization reaction, namely, the synthesis of phenyldiazonium chloride from aniline, hydrochloric acid, and sodium nitrite. Raman spectra were analyzed offline using Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and in real-time using Classical Least Squares (CLS) chemometric methods to monitor and control key reaction components. The developed feedback system successfully controlled concentration levels during both acid-base and diazotization phases. The reduction of the Raman signal-to-noise ratio, induced by the decomposition of the diazonium salt, was also observed. This factor significantly affected the monitoring of the diazotization experiment. Furthermore, a calibration was established to quantify the molar concentrations of key components based on Raman spectra. The calibration experiment successfully demonstrated well-fitted linear molar-spectral relationships for both aniline (R [2] homogeneous = 0.997; R [2] heterogeneous = 0.9947) and aniline hydrochloride (R [2] = 0.9987). For aniline, the molar-spectral relationship exhibited a distinct change in tendency that precisely correlated with its solubility limit in water, marking the transition from homogeneous solution to emulsion.}, } @article {pmid42656917, year = {2026}, author = {Zhang, J and Tang, P and Huang, L and Lv, J and Chen, Y and Wang, Y and Luo, Y}, title = {Multifaceted roles of S100A6 in neurological disorders: expression, interaction networks, and clinical implications.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1890559}, pmid = {42656917}, issn = {1663-9812}, abstract = {S100A6 (calcyclin) is a multifunctional Ca[2+]/Zn[2+]-binding protein of the S100 family, widely expressed in neurons and glia with a developmentally regulated and cell-type-specific pattern. This review synthesizes current knowledge on its roles in the nervous system. We detail its complex interactome, which includes cytoskeletal regulators, molecular chaperones, nuclear transport proteins, and cell surface receptors, positioning S100A6 as a central signaling hub. Furthermore, we examine its dynamic and context-dependent involvement in major neurological disorders. In Alzheimer's disease and amyotrophic lateral sclerosis, it functions as a glial-derived factor linking protein aggregation, metal dyshomeostasis, and neuroinflammation. In neuro-oncology, S100A6 exhibits dual roles, acting as a promoter of malignancy and immunosuppression in glioblastoma, an epigenetically silenced marker in medulloblastoma, and a diagnostic aid for peripheral nerve sheath tumors. Its expression is also altered in epilepsy, traumatic brain injury, and autoimmune encephalitis. Understanding the nuanced functions of S100A6 offers significant potential for developing novel diagnostic biomarkers and targeted therapeutic strategies for a range of challenging neurological conditions.}, } @article {pmid42657306, year = {2026}, author = {Xie, J and Shao, J and Wang, C and Shi, X and Miao, Q and Yip, CC and Ye, J}, title = {Visual cueing and adaptive learning for teaching thyroid eye disease diagnostic assessment to ophthalmology residents.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1934529}, pmid = {42657306}, issn = {2296-858X}, abstract = {BACKGROUND: Thyroid eye disease (TED) diagnosis requires residents to interpret subtle clinical and imaging findings for activity and severity assessment. Guided by Cognitive Load Theory, visual cueing may support attention to diagnostically relevant features, whereas adaptive learning may tailor practice to learner performance. This pilot study compared visual cueing, adaptive learning, and traditional static case review for TED diagnostic training.

METHODS: Forty-five ophthalmology residents were randomised equally to static case review (SCR), an adaptive learning system (ALS), or a visual cueing atlas (VCA). Following a 45-minute intervention, residents completed immediate and two-week delayed tests. The primary outcome was immediate overall diagnostic accuracy. Secondary outcomes were Clinical Activity Score (CAS) accuracy, severity-grading accuracy, delayed-test performance (2 weeks post-intervention), and performance decline from immediate to delayed testing. Educational materials were validated by ten expert ophthalmologists. Item-level content validity indices and the scale-level content validity index were calculated from expert ratings.

RESULTS: All residents completed the study. Expert validation showed excellent content validity for the educational materials, with the Item-level Content Validity Index for all components and the overall Scale-level Content Validity Index both reaching 1.00. At the immediate post-test, VCA achieved higher CAS accuracy than SCR (84.7% vs. 64.7%, p < 0.001). ALS and VCA achieved higher severity-grading accuracy than SCR (83.3% and 78.7% vs. 66.7%; p = 0.004 and p = 0.025, respectively), and both achieved higher overall diagnostic accuracy than SCR (66.0% each vs. 51.3%; p = 0.014 and p = 0.008, respectively). At two weeks, ALS showed higher severity-grading accuracy than SCR (74.0% vs. 56.0%, p < 0.001), while both ALS and VCA maintained higher overall diagnostic accuracy than SCR (54.0% and 52.7% vs. 41.3%; p = 0.014 and p = 0.008, respectively).

CONCLUSION: In this pilot study, visual cueing was associated with higher immediate CAS accuracy, whereas adaptive learning was associated with higher severity-grading accuracy on the two-week delayed test, relative to static case review. These approaches may have complementary roles in TED diagnostic education. Larger studies using equivalent instructional exposure, matched assessment forms, and longer follow-up are needed before a staged hybrid approach is recommended.}, } @article {pmid42657487, year = {2026}, author = {da Silva, AA and Pupe, CCB and Dos Santos, JCC}, title = {High-dose methylcobalamin in amyotrophic lateral sclerosis: mechanistic rationale, translational evidence, and clinical implications.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/17582024.2026.2713755}, pmid = {42657487}, issn = {1758-2032}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterized by selective degeneration of upper and lower motor neurons, driven by converging mechanisms including glutamatergic excitotoxicity, mitochondrial dysfunction, oxidative stress, calcium dyshomeostasis, impaired RNA metabolism, and neuroinflammation. In the absence of effective disease-modifying therapies, high-dose methylcobalamin has emerged as a candidate intervention based on its pleiotropic neurobiological effects. A structured literature search was conducted in PubMed/MEDLINE and ScienceDirect to identify peer-reviewed studies published between January 2017 and December 2025 addressing the mechanistic, preclinical, and clinical effects of methylcobalamin in ALS. Preclinical evidence suggests that methylcobalamin modulates homocysteine metabolism, supports S-adenosylmethionine-dependent methylation pathways, preserves mitochondrial integrity, attenuates oxidative stress, and promotes axonal regeneration. Experimental and translational findings further indicate that its therapeutic effects may be strongly dose dependent, particularly under ultra-high-dose regimens capable of overcoming limitations in central nervous system delivery. Clinical trials evaluating ultra-high-dose methylcobalamin demonstrate a potential attenuation of functional decline in patients treated during early disease stages, although effects on survival and respiratory outcomes remain inconsistent. This narrative review integrates molecular mechanisms, experimental evidence, biomarker research, and clinical trial data to examine the translational relevance, stage dependency, and therapeutic implications of high-dose methylcobalamin in ALS.}, } @article {pmid42658841, year = {2026}, author = {Carbayo, Á and Turon-Sans, J and Alcolea, D and Cortés-Vicente, E and Cabezas-Torres, M and Alvarez-Sanchez, E and Muñoz, L and Rubio-Guerra, S and García-Castro, J and Selma-González, J and Bernal, S and Gonzalez-Quereda, L and Bejanin, A and Aranha, MR and Santos-Santos, M and Belbin, O and Vesperinas-Castro, A and Collet-Vidiella, R and Caballero-Ávila, M and Llansó, L and Querol, L and Lleó, A and Fortea, J and Gelpí, E and Dols-Icardo, O and Illán-Gala, I and Rojas-Garcia, R}, title = {Methodological insights and clinical outcomes in ALS and FTLD: lessons from the SPIN cohort.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71777}, pmid = {42658841}, issn = {1552-5279}, support = {//Fundació Víctor Grífols i Lucas/ ; PI17/01019//Instituto de Salud Carlos III/ ; PMPER24/0017//Instituto de Salud Carlos III/ ; PI18/00435//Instituto de Salud Carlos III/ ; 044412//Fundació la Marató de TV3/ ; 20142610//Fundació la Marató de TV3/ ; PI19/01543//Instituto de Salud Carlos III/ ; FISEC08/00077//Instituto de Salud Carlos III/ ; PI22/00758//Instituto de Salud Carlos III/ ; INT21/00073//Instituto de Salud Carlos III/ ; INT19/00016//Instituto de Salud Carlos III/ ; PI22/00611//Instituto de Salud Carlos III/ ; AC19/00103//Instituto de Salud Carlos III/ ; R21 AG056974/AG/NIA NIH HHS/United States ; PI18/00335//Instituto de Salud Carlos III/ ; ICI23/00032//Instituto de Salud Carlos III/ ; PI14/01126//Instituto de Salud Carlos III/ ; DABNIproject//Fundació Bancaria "La Caixa"/ ; PI13/00772//Instituto de Salud Carlos III/ ; PI15/01618//Instituto de Salud Carlos III/ ; PI23/01786//Instituto de Salud Carlos III/ ; AARF-22-924456/ALZ/Alzheimer's Association/United States ; //Fondo Europeo de Desarrollo Regional (FEDER)/ ; RF1 AG061566/AG/NIA NIH HHS/United States ; //Fundación HNA/ ; PI23/00845//Instituto de Salud Carlos III/ ; RF1 AG056850/AG/NIA NIH HHS/United States ; AACSF-21-850193/ALZ/Alzheimer's Association/United States ; PI20/01473//Instituto de Salud Carlos III/ ; PI19/00882//Instituto de Salud Carlos III/ ; PI17/01896//Instituto de Salud Carlos III/ ; PI21/00791//Instituto de Salud Carlos III/ ; PI22/00307//Instituto de Salud Carlos III/ ; 201437.10;20141210//Fundació la Marató de TV3/ ; INT23/00048//Instituto de Salud Carlos III/ ; AUL2025.1//Fundación Luzón/ ; //FUNDELA/ ; //Fundació Catalana Síndrome de Down/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/cerebrospinal fluid ; *Frontotemporal Lobar Degeneration/genetics/pathology/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Cohort Studies ; Neuroimaging ; Male ; Female ; Longitudinal Studies ; Precision Medicine ; Aged ; Middle Aged ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) constitute a clinico-genetic-neuropathological continuum with marked heterogeneity. Reliable in vivo biomarkers of the disease are lacking. Large, multimodal cohorts are needed to advance biomarker discovery and precision medicine.

METHODS: We describe the structure and results derived from the Sant Pau Initiative on Neurodegeneration (SPIN)-ALS-FTLD subcohort, a longitudinal, multimodal platform that integrates clinical, cognitive, genetic, biofluid, neuroimaging, and neuropathological data within a unified framework embedded in routine care.

RESULTS: The cohort includes over 1000 participants, 800 blood, 400 CSF, and 800 DNA samples, neuroimaging in over 250 cases, and 66 neuropathological studies. Harmonized longitudinal data and biospecimen collection have enabled substantial clinical, molecular, and translational research output.

DISCUSSION: SPIN-ALS-FTLD extends the original SPIN framework to the ALS-FTLD continuum, enabling deep phenotyping and multimodal biomarker discovery. This scalable model supports patient stratification, longitudinal monitoring, and the development of precision medicine approaches in neurodegenerative diseases.}, } @article {pmid42661170, year = {2026}, author = {Wolf, J and Safer, A and Stefenelli, U and Woehrle, JC and Maschke, M and Nix, WA and Grau, AJ}, title = {Long-term survival in amyotrophic lateral sclerosis - data from a population-based registry in Rhineland-Palatinate, Germany.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {}, pmid = {42661170}, issn = {1471-2377}, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Amyotrophic Lateral Sclerosis/mortality/epidemiology/diagnosis ; Disease Progression ; Germany/epidemiology ; Kaplan-Meier Estimate ; Prospective Studies ; Registries ; }, abstract = {BACKGROUND: Data on long-term survival in amyotrophic lateral sclerosis (ALS) is scarce. In a population-based ALS cohort in Germany we evaluated long-term survival and assessed key factors influencing long-term survival, including demographic and clinical variables that are available at an early stage of the disease.

METHODS: Data from patients in the prospective, population-based ALS-registry Rhineland-Palatinate were analyzed. Survival was evaluated separately for time from symptom onset and time from diagnosis. Patient demographic and disease-related variables were analyzed in relation to survival probability using the Kaplan-Meier method and Cox proportional hazards regression.

RESULTS: Data from 200 incident ALS patients (106 men and 94 women) were included in the study. The median age of the patients was 68 years (range 23-85 years; mean age 65.8 years; standard deviation 10.5 years). The median survival time was 2.5 years from symptom onset and 1.5 years from diagnosis. 12% of the patients survived for at least ten years from first manifestation of symptoms. Multivariate statistics revealed that younger age, a low progression rate, the absence of frontotemporal dementia and a long interval between symptom onset and diagnosis were predictors of long survival.

CONCLUSIONS: 12% of ALS patients are still alive ten years after the onset of symptoms, which is important for advance planning of patient care. In our analysis demographic and clinical variables available at an early stage of the disease have emerged as valuable predictive factors.

TRIAL REGISTRATION: ClinicalTrials.gov (NCT01955369; registered retrospectively 28/09/2013).}, } @article {pmid42661580, year = {2026}, author = {O'Farrell, S and Holland, MC and Peelo, C and McLaughlin, R and Heverin, M and Hardiman, O and Costello, E and Pender, N}, title = {Cognitive and behavioral manifestations of the C9orf72 mutation in Amyotrophic Lateral Sclerosis: an age, education, and gender-matched cohort study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2721333}, pmid = {42661580}, issn = {2167-9223}, abstract = {OBJECTIVES: The presence of a hexanucleotide expansion in the gene C9orf72 confers a higher risk of developing ALS and FTD with associated cognitive and behavioral change, although penetrance is incomplete, and many gene carriers never exhibit any clinical signs during their lifetime. To date, there have been few studies investigating additional factors such as age, years of education, gender, and their influence on cognition and behavior in people with ALS (pwALS), particularly those with a hexanucleotide expansion in the gene C9orf72.

METHODS: We selected 104 consenting pwALS from the Irish ALS register, comprising 52 C9orf72 positive participants and 52 C9orf72 negative controls matched on age, years of education, and gender. Cognitive functioning was assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), while behavioral changes were examined using the Beaumont Behavioral Inventory (BBI).

RESULTS: No significant differences in ECAS performance were observed across the two groups, with the exception of visuospatial performance, which was more impaired in those carrying the C9orf72 repeat expansion (p = .001). Similarly, there was no difference in behavoural scores between the 2 groups.

CONCLUSIONS: These findings suggest that the presence of the C9orf72 repeat expansion does not presage the development of significant cognitive or behavioral impairment early in the disease stage when controlled for age, years of education, and gender. When interpreting these results, it is important to consider the relatively small sample size, and the exclusion criteria of previous clinically significant comorbidities.}, } @article {pmid42661656, year = {2026}, author = {Praharaj, S and Chakraborty, E and Mahalingam, G}, title = {Ultraviolet radiation and neurodegeneration: molecular mechanisms underlying dual neuroprotective and neurotoxic effects.}, journal = {Frontiers in cellular neuroscience}, volume = {20}, number = {}, pages = {1909393}, pmid = {42661656}, issn = {1662-5102}, abstract = {Ultraviolet radiation exhibits a complex, often contradictory link to neurodegeneration risk/progression, spanning clinically diagnosed diseases [Parkinson's Disease (PD), Alzheimer's Disease (AD), Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS)] or intermediate phenotypes (decreased neurogenesis, loss of hippocampal volume). The aim of this review is to highlight the dual impact of UV radiation by collecting and synthesizing experimental (preclinical and translational) evidence as well as epidemiological evidence. Current literature exhibits a clear dichotomy: while Vitamin D is capable of exerting a potent neuroprotective effect via anti-oxidant and anti-inflammatory pathways, chronic and intense UV radiation exposure actually hastens the progression or even drives neurodegeneration via a variety of mechanisms. UV radiation exerts its effects through various interconnected pathways: DNA damage pathways, ROS mediated pathways, vitamin D signaling and the skin-brain axis, which unifies both protective and degenerative effects of UV radiation. Owing to the increasing occurrence of neurodegenerative diseases in the general population, these pathways and mechanisms must be leveraged in future research to develop novel therapeutic and preventive strategies. Investigation of biomarkers linked to certain genetic and environmental factors that could provide a link to predisposition toward neurodegeneration and standardization of UV radiation dosimetry (exposure dose/duration) across experimental or pre-clinical studies must also be prioritized.}, } @article {pmid42662266, year = {2026}, author = {Dresel, FC and Michaelis, M and Gourlay, CW}, title = {The HDAC Inhibitor Butyrate Reduces SOD1 Aggregation and Improves Motor Function in C. elegans and Cellular Models of ALS.}, journal = {International journal of cell biology}, volume = {2026}, number = {}, pages = {3022967}, pmid = {42662266}, issn = {1687-8876}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by motor neuron loss and protein aggregation, commonly driven by mutations in superoxide dismutase 1 (Sod1). Recent evidence implicates gut microbiota-derived metabolites, such as butyrate, in modulating neurodegeneration, but the underlying mechanisms remain unclear. Here, we demonstrate that sodium butyrate (NaB), a histone deacetylase inhibitor and microbial metabolite, ameliorates ALS-related phenotypes in C. elegans and mammalian cell models expressing mutant isoforms of Sod1 linked to ALS. NaB treatment prevented Sod1 aggregation and restored motor function and axonal integrity in transgenic worms overexpressing Sod1[G85R]. Mechanistically, NaB recapitulated the effects of the pan-HDAC inhibitor trichostatin A, suggesting HDAC inhibition as key to reducing Sod1 aggregation and its downstream effects. Application of NaB or the HDAC inhibitor valproic acid also prevented aggregation of Sod1[A4V], Sod1[G85R] or Sod1[G37R] in transfected human neuroblastoma cells. These findings support a conserved neuroprotective role for NaB and HDAC inhibitors via their antiaggregation activity. Our findings also verify C. elegans and neuroblastoma cell lines as excellent research tools to explore the mechanisms underlying the antiaggregation action of NaB and HDAC inhibitors, as well as their potential for future therapeutic development.}, } @article {pmid42663687, year = {2026}, author = {Hu, N and Zhang, L and Tian, H and Ding, J and Shen, D and Yang, X and Cui, L and Niu, J and Liu, M}, title = {Exploration of reliable assessment of respiratory function in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {9}, pages = {}, pmid = {42663687}, issn = {1590-3478}, support = {CIFMS 2021-I2M-1-003//Chinese Academy of Medical Sciences Initiative for Innovative Medicine/ ; 2022-PUMCH-B-017, 2022-PUMCH-D-002//National High Level Hospital Clinical Research Funding/ ; 2022ZD0118003//National Key Transform Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; Female ; Male ; Middle Aged ; Aged ; Disease Progression ; Phrenic Nerve/physiopathology ; Ultrasonography ; Diaphragm/diagnostic imaging/physiopathology ; *Respiration Disorders/etiology/diagnosis/physiopathology ; Respiratory Function Tests ; Nerve Conduction Studies ; Fasciculation/physiopathology/etiology/diagnostic imaging ; }, abstract = {OBJECTIVE: To identify potentially useful objective indicators for early assessment of respiratory dysfunction in amyotrophic lateral sclerosis (ALS).

METHODS: Forty ALS patients were enrolled and followed every 3 months for one year. Baseline assessments included dyspnea complaints, ALSFRS-R, the ALS Respiratory Symptom Score (ARES), physical examination (including lower lung mobility), phrenic nerve conduction studies, diaphragm ultrasound, and multi-region ultrasound fasciculation detection. Forced vital capacity (FVC%) was also measured. Logistic regression (binary outcomes) and linear regression (continuous outcomes) were used to identify predictors of respiratory decline at 6 and 12 months.

RESULTS: At 6 months, decreased right lower lung mobility (β = 1.771, 95%CI:1.047-2.495, p = 0.038), bulbar fasciculations (OR = 2.198, 95%CI:1.527-2.868, p = 0.001), and lumbosacral fasciculations (OR = 2.117, 95%CI:1.516-2.839, p = 0.001) independently predicted a higher post-progression rate. At 12 months, cervical fasciculations predicted a higher post-progression rate (OR = 1.644, 95%CI:1.130-2.157, p = 0.017). Traditional measures (FVC%, diaphragm ultrasound, phrenic CMAP) showed limited short-term predictive value.

CONCLUSION: Lower lung mobility on physical examination and ultrasound-detected fasciculations in bulbar, cervical, and lumbosacral regions are potentially valuable objective markers for predicting disease progression in ALS. These exploratory findings suggest they may complement conventional pulmonary function tests, but require validation in larger independent cohorts.}, } @article {pmid42664170, year = {2026}, author = {Saucier, D and Bélanger, M and Liu, Z and Lavigne, E and O'Connell, C}, title = {Associations between Level of Urbanization and Greenness and the Development of Amyotrophic Lateral Sclerosis: A Matched Case-Control Study.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1}, doi = {10.1159/ned/adwag011}, pmid = {42664170}, issn = {1423-0208}, abstract = {INTRODUCTION: Previous studies have considered level of urbanization when evaluating the role of place of residence in ALS. However, these studies have been subject to recall bias regarding previous exposures to urban characteristics owing to a lack of historical geospatial measures on urban form indicators.

METHODS: Thus, we created a robust database from multiple sources and conducted a matched case-control study in NB, Canada, to investigate the association between long-term exposure to various local climate zones, as well as greenness, at place of residence and the development of ALS.

RESULTS: Odds of ALS were not significantly associated with the dense urban (1.1, 0.6-2.0 [95% CI]), open urban (0.5, 0.2-1.3 [95% CI]), residential (1.0, 0.9-1.1 [95% CI]), industrial (0.8, 0.6-1.2 [95% CI]), natural (1.0, 0.9-1.1 [95% CI]), or water (1.0, 0.9-1.1 [95% CI]) local climate zone classification categories per ten percentage increase in influence in the adjusted regression models. Exposure to greenness (1.7, 0.5-6.2 [95% CI]) was also not significantly associated to ALS in the adjusted regression models.

CONCLUSION: While not significantly associated to ALS, urban influence and greenness need to be further explored. Future studies should consider traffic-related pollutants as it pertains to urban density, while considering vegetation type and industry practices, such as farming and spraying, alongside greenness exposure measures.}, } @article {pmid42664377, year = {2026}, author = {Escobar-Villegas, PA and Realpe-Camelo, AI and Arana-Salas, DA and Velásquez, JG and Paulo, M and Martínez-Cajas, CH and Amaya-Sanchez, S and Gómez-Mesa, JE}, title = {Endodontic status of patients with coronary atherosclerosis: A cross-sectional study.}, journal = {Dental and medical problems}, volume = {63}, number = {4}, pages = {885-891}, doi = {10.17219/dmp/205472}, pmid = {42664377}, issn = {2300-9020}, mesh = {Humans ; Cross-Sectional Studies ; Female ; Male ; *Coronary Artery Disease/epidemiology/complications/diagnostic imaging ; Middle Aged ; Colombia/epidemiology ; Aged ; *Root Canal Therapy ; Adult ; Prevalence ; Coronary Angiography ; }, abstract = {BACKGROUND: There are no studies in the Colombian population assessing the prevalence and severity of apical lesions (ALs), or the relationship between the frequency and quality of endodontic treatment (ET) obturation and the presence of ALs in patients with coronary atherosclerosis (CA).

OBJECTIVES: The present study aimed to estimate the frequency of ALs and ET in Colombian patients with CA, and to identify a possible association between the frequency and severity of ALs and CA.

MATERIAL AND METHODS: The study had a cross-sectional design. We included patients with the evidence of CA diagnosed by coronary angiography. The main outcome variables were the number of compromised coronary arteries and their degree of obstruction, as well as ET, including ALs and previously treated teeth (PTT). The periapical index (PAI) was assessed using periapical radiographs.

RESULTS: A total of 1,394 teeth from 69 patients were evaluated (δ = 20.2 teeth/patient). The frequency of ALs and ET was 5.7% and 10.1%, respectively, considering all teeth evaluated, with a greater presence in the maxilla (50.6% and 51.4%, respectively). Apical lesions were most frequently observed in premolars and molars (35.4%), whereas ET was more frequent in molars (38.6%). Among teeth with ALs, PAI 3 was the most frequent score. Apical lesions were present in 40.0% of endodontically treated teeth; 79.2% of these teeth had inadequate obturation, of which 40 (39.2%) had ALs (p = 0.021).

CONCLUSIONS: In patients with CA, a high incidence of ALs and ET was observed, with no evidence of an association between the frequency of ALs, the severity of coronary vessel occlusion, and the number of coronary arteries affected. More ALs were observed in teeth with inadequate ET. However, as we did not have a control group for comparison, these findings should be interpreted with caution.}, } @article {pmid42665553, year = {2026}, author = {Zhu, CW and Curtis, G and Joseph, J and Wecht, JM and Galea, MD and Harel, NY}, title = {Factors Affecting Disease Progression, Survival, and Caregiver Burden in United States Veterans at a Multidisciplinary Veterans Affairs ALS Center.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70385}, pmid = {42665553}, issn = {1097-4598}, support = {24-TC-705//ALS Association/ ; }, abstract = {INTRODUCTION/AIMS: Though studies of Veterans with ALS have reported survival rates, scant literature reports longitudinal symptom progression in Veterans using the ALS Functional Rating Scale-revised (ALSFRS-R). In the absence of an existing national database tracking disease progression in Veterans, we sought to use local medical records to characterize a cohort of Veterans with ALS treated at our VA ALS clinic.

METHODS: We examined demographic and clinical factors of 216 Veterans with ALS treated at the James J. Peters VA Medical Center (2012-2025) including race, ethnicity, region of symptom onset, and medication use as predictors of diagnostic delay, functional decline (ALS Functional Rating Scale-Revised (ALSFRS-R)), survival, and caregiver burden (Zarit Caregiver Burden Interview). Joint linear mixed modeling estimated longitudinal functional trajectories and survival simultaneously.

RESULTS: The cohort was 96.8% male and 74.5% White. Median age at symptom onset was 69.3 years. Mean baseline ALSFRS-R was 30.7. Median survival from symptom onset was 4.4 years. Median age at symptom onset was younger for Black (60.8 years) and Hispanic (62.5 years) Veterans than Whites (70.1 years). Blacks had faster initial ALSFRS-R progression than Whites (mean 1.9 vs. 0.9 points per month). Blacks and Hispanics had 2.8-fold and 2.3-fold higher adjusted mortality hazard than Whites, respectively. Forty-nine percent of caregivers reported high caregiver burden at first assessment, rising to 66.2% at subsequent assessments.

DISCUSSION: Racial and ethnic disparities in ALS progression and survival are pronounced in this single-site Veteran cohort. Standardized ALS-specific data collection across the VHA is needed to enable system-wide analyses.}, } @article {pmid42665653, year = {2026}, author = {Shaji, V and Jain, R and Puthumadathil, N and Jana, K and T S, V and Kleinekathöfer, U and Chattopadhyay, K and Mahendran, KR}, title = {A self-assembled peptide forms α-helical nanopores for ultrasensitive biomarker profiling.}, journal = {Nature nanotechnology}, volume = {}, number = {}, pages = {}, pmid = {42665653}, issn = {1748-3395}, support = {BT/PR53613/BMS/85/242/2024//Department of Biotechnology, Ministry of Science and Technology (DBT)/ ; IIRPIG-2024-01-00131//Indian Council of Medical Research (ICMR)/ ; IIRPSG-2024-01-01188//Indian Council of Medical Research (ICMR)/ ; INST 676/7-1 FUGG//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; OLP-120//Council of Scientific and Industrial Research (CSIR)/ ; }, abstract = {α-Helical nanopores are attractive molecular sensors, yet their rational design and assembly remain challenging. Here we show that the single peptide pPorA, derived from porin PorACj, self-assembles into flexible α-helical nanopores, inserts in lipid membranes and exists in distinct small- and large-conductance states. By strategically incorporating unnatural amino acids, we engineered small- and large-diameter pores exhibiting single-channel conductances of 2.4 nS and 3.5 nS in 1 M KCl, respectively, while retaining a common octameric architecture. These nanopores enabled the detection of sugars, peptide enantiomers and intrinsically disordered disease proteins that form dynamic, heterogeneous assemblies. The large pores detected multiple α-synuclein (α-syn) variants, including a pathogenic Parkinson's disease-associated C-terminal deletion mutant with nanomolar affinity (KD ≈ 20 nM). Selective electrostatic trapping of the α-syn N-terminus enabled charge-resolved identification of individual α-syn species within heterogeneous mixtures. The nanopores further resolved time-dependent and inhibitor-modulated α-syn aggregation pathways from monomers to toxic oligomers and fibrils. The small pores detected humanin and superoxide dismutase peptides associated with apoptosis and amyotrophic lateral sclerosis, demonstrating tunable sensing through pore-size control. These conformationally programmable α-helical nanopores provide a versatile platform for ultrasensitive profiling of disease biomarkers.}, } @article {pmid42665659, year = {2026}, author = {Shi, P and Melillo, B and McHenry, MW and Camara, CM and Yang, K and Njomen, E and Godes, M and Pazyra-Murphy, MF and Branch, MR and Tesar, B and Segal, RA and Rubin, LL and Cameron, MD and Bird, GH and Wales, TE and Gygi, SP and Cravatt, BF and Walensky, LD}, title = {An enantioselective covalent inhibitor of BAX confers cytoprotection in vivo.}, journal = {Nature chemical biology}, volume = {}, number = {}, pages = {}, pmid = {42665659}, issn = {1552-4469}, support = {R35CA197583//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; R50CA211399//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; R35CA231991//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {No therapies directly block apoptosis in tissue injury or the many diseases driven by cell loss. The BCL-2 family protein BAX is a central mediator of this pathway and C126 resides within a key regulatory region where physiologic or pharmacologic ligands can activate or inhibit its function. Here, we report enantioselective covalent BAX inhibitors that site-specifically react with C126 and confer cytoprotection across multiple cell types. These ligands constrain BAX conformation and suppress apoptosis in a strictly BAX-dependent manner. Medicinal chemistry optimization yielded covalent BAX inhibitor 3 (CBI-3), an analog with pharmacokinetics suitable for in vivo studies. In a murine model of Fas-induced fulminant hepatic failure, CBI-3 reduced hepatocyte apoptosis and preserved liver histology and survival. CBI-3 also conferred cytoprotection of motor neurons derived from human induced pluripotent stem cells of healthy and amyotrophic lateral sclerosis donors. These findings establish covalent BAX inhibition as a therapeutic strategy to directly block pathologic cell death.}, } @article {pmid42666334, year = {2026}, author = {Garbey, M and Lesport, Q and Öztosun, G and Heidebrecht, M and Pirouz, K and Bayat, E}, title = {Feasibility study on a noninvasive assessment of ALS patient emotional state.}, journal = {Frontiers in digital health}, volume = {8}, number = {}, pages = {1886561}, pmid = {42666334}, issn = {2673-253X}, abstract = {INTRODUCTION: Objective assessment of emotional responsiveness in Amyotrophic Lateral Sclerosis (ALS) remains limited despite its importance for personalized care. This study investigated whether non-invasive speech analysis could identify digital biomarkers associated with emotional coping behaviors in ALS patients.

METHODS: We analyzed 28 ALS patient visits using clinician-rated emotional concern scores, ALS Functional Rating Scale-Revised (ALS-FRS-R), forced vital capacity (FVC), and speech acoustic features. We also evaluated the reliability of large language models (LLMs), including ChatGPT, Gemini, and Claude, for automated concern assessment. Patients were classified relative to functional impairment as congruent, muted, or excessive responders.

RESULTS: LLMs failed to provide reliable or reproducible assessments of patient concern without expert clinical supervision. Subjective concern levels also showed discordance with objective respiratory measures such as FVC. Excessive responders were predominantly male and required significantly greater clinician interaction time, while muted responders were predominantly female. Acoustic analysis revealed distinct vocal profiles between groups. Muted responders demonstrated high loudness and sharpness with low roughness and fluctuation, whereas excessive responders showed the opposite profile. These findings suggest that dysarthria may function as an acoustic filter modulating emotional expression.

DISCUSSION: Speech-derived acoustic biomarkers may enable objective identification of emotional coping phenotypes in ALS and support earlier, personalized psychosocial interventions. The findings also highlight important limitations of current LLM-based clinical interpretation tools in unsupervised settings.}, } @article {pmid42666355, year = {2026}, author = {Wei, Y and Wang, J and Ji, Y and Shang, T and Shen, Y and Sun, H and Cai, Y}, title = {Therapeutic Challenges and Future Breakthroughs in Amyotrophic Lateral Sclerosis: From Precision Medicine to Innovative Trial Design.}, journal = {Drug design, development and therapy}, volume = {20}, number = {}, pages = {626069}, pmid = {42666355}, issn = {1177-8881}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Precision Medicine ; Animals ; *Clinical Trials as Topic ; *Neuroprotective Agents/therapeutic use ; *Research Design ; Genetic Therapy ; Drug Development ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous and fatal neurodegenerative disorder, for which clinical management and drug development have long faced formidable challenges. Since the approval of riluzole and edaravone, dozens of promising drug candidates that showed efficacy in preclinical models have failed in Phase III trials, highlighting an urgent need for systematic re-evaluation of the field. This review provides a comprehensive summary of the major limitations of current clinical therapies for ALS. These include the modest survival benefit of riluzole, the narrow eligible population for edaravone, and the complex trajectory of sodium phenylbutyrate-taurursodiol, which received accelerated approval but was subsequently voluntarily withdrawn after its confirmatory Phase III trial failed to meet its primary endpoints. On this basis, we discuss four major challenges that contribute to clinical trial failures: disease heterogeneity, paucity of reliable biomarkers, insufficient translational validity of preclinical models, and inherent flaws in conventional trial designs. Subsequently, we discuss emerging therapeutic strategies, encompassing precision medicine and gene therapy (exemplified by the development of the antisense oligonucleotide tofersen for SOD1-ALS), targeting protein homeostasis, modulation of neuroinflammation, metabolic and energetic support, neuroprotection and regeneration, as well as multi-target combination approaches. Innovative trial designs, including adaptive platform trials (exemplified by the HEALEY ALS Platform Trial), enrichment designs, sequential designs, N-of-1 trials, and virtual clinical trials are fundamentally reshaping the drug development paradigm in ALS. In conclusion, ALS treatment is at a historic turning point from a "one-size-fits-all" approach toward "precisely stratified" medicine. Future success depends on establishing multimodal biomarker panels, implementing genetic testing-guided individualized therapy, developing combination regimens, and integrating patient-reported outcomes with palliative care. Although substantial challenges remain, the clinical success of Tofersen provides evidence that precision therapeutic strategies may gradually transform ALS management toward a more individualized and disease-modifying approach.}, } @article {pmid42666931, year = {2026}, author = {Laffita-Mesa, JM and Paucar, M and Svenningsson, P}, title = {ATXN2 Spectrum Disorders: Genetic Complexity Beyond Dominant Inheritance.}, journal = {Neurology. Genetics}, volume = {12}, number = {5}, pages = {e200428}, pmid = {42666931}, issn = {2376-7839}, abstract = {The genetic complexity of ATXN2 challenges conventional paradigms in neurodegeneration. While initially linked to autosomal dominant spinocerebellar ataxia type 2, ATXN2 CAG expansions have emerged as a major risk factor for amyotrophic lateral sclerosis. In a recent article, Saucier et al. describe an Acadian family with a recessive inheritance pattern of ATXN2-related disease, challenging the long-held assumption of a predominantly autosomal dominant, gain-of-function-driven mechanism. Here, we analyze how ATXN2's inheritance mode may shift based on repeat interruptions, somatic mosaicism, and gene dosage, suggesting that loss-of-function mechanisms contribute to pathogenesis in certain contexts. We discuss implications for disease classification, genetic counseling, and therapeutic strategies, emphasizing the need for genetic stratification.}, } @article {pmid42667453, year = {2026}, author = {Liu, C and Zhang, Y}, title = {Ginsenosides: potential therapeutic implications in neurodegenerative diseases by inhibiting ferroptosis.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42667453}, issn = {1573-4978}, mesh = {Humans ; *Ginsenosides/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Ferroptosis/drug effects ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy ; }, abstract = {A positive correlation exists between the accelerating pace of population aging and the increasing prevalence of neurodegenerative diseases. Conditions such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) profoundly compromise patient quality of life, yet efficacious clinical interventions remain notably limited. The prevention and management of neurodegenerative diseases represent a critical global public health imperative. A comprehensive literature search was performed across PubMed, Web of Science, and Scopus to identify studies on the biological functions, molecular mechanisms, and clinical implications of ginsenosides. The search strategy incorporated MeSH terms and free-text keywords, encompassing "neurodegenerative disease", "ferroptosis", "ginsenosides", "Parkinson's disease", "Alzheimer's disease", "amyotrophic lateral sclerosis", "Huntington's disease" and "multiple sclerosis". From an initial pool of over 400 papers (1998-2026), 107 were selected in this narrative review. Ferroptosis is intricately linked to the pathogenesis of neurodegenerative diseases. Ginsenosides constitute the principal bioactive triterpenoid saponins extracted from plants of the Panax genus, demonstrating broad-spectrum pharmacological efficacy encompassing antitumor, immunomodulatory, anti‑inflammatory, anti‑allergic, anti‑atherosclerotic, antihypertensive, antidiabetic, antistress, and neuroprotective activities. Ginsenosides exert their neuroprotective effects against AD, PD, and ALS predominantly through the modulation of ferroptosis. Herein, this article provides a review of the molecular mechanisms, genetic determinants, signaling cascades, and functional implications of ferroptosis. Ginsenosides represent promising therapeutic agents in neurodegenerative diseases via modulation of iron homeostasis; this paper elucidates mechanistic insights into disease pathogenesis and evaluates their translational therapeutic potential. This narrative review highlights emerging insights that provide novel therapeutic perspectives for neurodegenerative diseases.}, } @article {pmid42667624, year = {2026}, author = {Bues, B and Sasmita, AO and Mao, S and Komarek, L and O'Mahony, K and Burk, K}, title = {Axonal pathology and impaired axo-glial crosstalk as early drivers of neurodegeneration.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-26-00462}, pmid = {42667624}, issn = {1673-5374}, abstract = {Axonal dysfunction is a critical event in neurodegenerative diseases, which can precede neuronal loss. For instance, in multiple sclerosis, chronic demyelination leads to axonal transection and downstream neurological deficits, yet in other neurodegenerative conditions, the causal relationship between axonal pathology and disease progression remains elusive. While defects in axonal transport, cytoskeletal integrity, and organelle trafficking are observed in Alzheimer's disease and the frontotemporal dementia-amyotrophic lateral sclerosis spectrum, a question remains: Are axonal defects merely downstream consequences of somatic neurodegeneration, or do they actively drive pathogenesis? Emerging evidence suggests that early axonal dysfunction may accelerate disease progression through disrupted connectivity, retrograde degeneration, and neuroinflammation. Here, we highlight current evidence on axonal pathophysiology across Alzheimer's disease and frontotemporal dementia-amyotrophic lateral sclerosis. We first outline the makeup of the mature axonal compartment, as well as the processes related to axonal maintenance, which include myelination, glial support, and microtubule-dependent transport mechanisms. We further compare axonal perturbations in Alzheimer's disease and frontotemporal dementia-amyotrophic lateral sclerosis, exploring commonalities as potential convergent mechanisms. Therapeutic strategies to stabilize axons by maintaining microtubule dynamics, restoring energetics, or modulating glial support could therefore theoretically offer neuroprotection if performed selectively on vulnerable neuronal subsets and early in the disease course. Ultimately, by reframing axonal pathology as a primary driver rather than an epiphenomenon, this review underscores the importance of targeting axonal health in neurodegenerative diseases.}, } @article {pmid42667698, year = {2026}, author = {Rey, V and Feijoó, MEG and Vittar, EE and Morales, JMN and Fernández, JM and Morán Vieyra, FE and Tuttolomondo, ME and Borsarelli, CD}, title = {Photoreductive synthesis and analytical performance of silver nanoparticles stabilized with humic acids for selective and sensitive colorimetric detection of mercury (II) ions.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {269}, number = {}, pages = {116112}, doi = {10.1016/j.colsurfb.2026.116112}, pmid = {42667698}, issn = {1873-4367}, abstract = {This study presents the one-step photoreductive synthesis and characterization of humic acid-stabilized silver nanoparticles (AgNP@HA) via the reduction of Ag[+] ions by ketyl radicals generated by UVA-light using the water-soluble photoinitiator Irgacure® 2959 (I-2959) as a function of pH and HA concentration. The formation and properties of the AgNP@HA were characterized by several techniques, including UV-Vis, FTIR, and Raman spectroscopies, as well as transmission electron microscopy (TEM) and dynamic light scattering (DLS). The UV-Vis absorption spectrum changes occurring during the formation of the AgNP@HA were modeled with the multivariate curve fitting using alternating least squares (MCR-ALS) method. The kinetic profiles of each observed species suggested that AgNP@HA are produced through a mechanism of nucleation and aggregation. The AgNP@HA solutions were evaluated as colorimetric sensors for the selective detection of Hg[2+] ions at different pH. The changes in the surface plasmon band absorbance of AgNP@HA induced by Hg[2+], irrespective of the presence of other interfering ions and pH, indicated that AgNP@HA specifically interacts with Hg[2+] to form an amalgam with silver, with remarkable analytical performance, detecting Hg[2+] in the sub ppm range. These results indicate that AgNP@HA prepared by photoreduction with I-2959 can be used as a suitable, simple, economical, and environmentally friendly plasmonic sensor for the detection of mercury in water samples.}, } @article {pmid42667936, year = {2026}, author = {Zhu, J and Zhang, Y and Yang, B and Xiang, Q and Hu, S and Wei, W and Zhou, H and Yang, G and Zhang, H}, title = {Associations of cumulative exposure and longitudinal trajectories of neurofilament light chain with 1-year adverse events in amyotrophic lateral sclerosis: A prospective cohort study.}, journal = {Neurobiology of disease}, volume = {229}, number = {}, pages = {107584}, doi = {10.1016/j.nbd.2026.107584}, pmid = {42667936}, issn = {1095-953X}, abstract = {BACKGROUND: Baseline neurofilament light chain (NFL) predicts amyotrophic lateral sclerosis (ALS) outcomes, but it does not summarize early repeated biomarker information. We evaluated whether cumulative NFL exposure (cuNFL), calculated over an early monitoring window, and longitudinal NFL trajectory groups were associated with subsequent adverse events in a prospective cohort.

METHODS: This prospective study enrolled patients with ALS from 32 provinces in China between January 2024 and January 2025. Plasma NFL was measured at baseline, month 1, and month 2. We used K-means clustering to describe longitudinal NFL patterns and multivariable survival models to evaluate prognostic associations. Inverse-probability weighting and causal-forest analyses were used as exploratory, confounding-adjusted analyses of high versus low cuNFL.

RESULTS: K-means clustering identified three longitudinal NFL groups: Low-Stable (n = 183), Moderate (n = 225), and High-Progressive (n = 100). The High-Progressive group had the shortest event-free survival (P < 0.001). Each 1-SD increment in cuNFL was associated with higher odds of adverse events (adjusted OR 1.99; 95% CI 1.52-2.60; P < 0.001). Using the manuscript-defined 127-event outcome, apparent discrimination was AUC 0.730 for cuNFL and 0.717 for baseline NFL. The paired DeLong comparison was not statistically significant (P = 0.084). Exploratory machine-learning analyses suggested heterogeneity in the association of high cuNFL with outcome by age and respiratory function.

CONCLUSION: Early repeated NFL measurements summarized as cuNFL and longitudinal trajectory groups were associated with short-term adverse events in this cohort. These findings support further external validation of longitudinal NFL-based risk stratification. They do not establish a causal biological effect or a basis for routine repeated measurement.}, } @article {pmid42668676, year = {2026}, author = {Varon-Vega, F and Franco Parra, CE and Adame Ochoa, DF and Uricoechea, N and Tuta-Quintero, E and Martinez Ayala, MC}, title = {Use of High-Flow Nasal Cannula in Amyotrophic Lateral Sclerosis Patients Intolerant to Non-Invasive Ventilation: A Case Series.}, journal = {Respirology case reports}, volume = {14}, number = {9}, pages = {e70744}, pmid = {42668676}, issn = {2051-3380}, abstract = {Non-invasive ventilation (NIV) is standard respiratory support for amyotrophic lateral sclerosis (ALS), but intolerance may limit its use. High-flow nasal cannula (HFNC) has emerged as a potential alternative in selected patients, but evidence regarding its use remains scarce. We describe 18 ALS patients' management with HFNC between 2014 and 2024 after documented intolerance to NIV. Mean age at HFNC initiation was 65.1 ± 12.5 years, and 66.7% of patients were female. Partial NIV intolerance occurred in 38.9% of cases, while 33.3% tolerated intermittent combined NIV and HFNC. During follow-up, 50.0% of patients required hospitalization, 33.3% experienced respiratory infections, and 27.8% died. Arterial blood gas parameters remained stable, including PaCO2 (p = 0.314). Functional status declined significantly, with Barthel Index decreasing (35.0 ± 20.5 vs. 11.7 ± 11.3; p < 0.001), whereas respiratory muscle strength remained unchanged. HFNC was feasible as home-based support in ALS patients intolerant to NIV, warranting prospective comparative evaluation.}, } @article {pmid42669596, year = {2026}, author = {Horton, DK and Raymond, J and Larson, T and Weisskopf, MG and Howard, I and Mehta, P}, title = {Military Service and Survival Among Persons With ALS in the U.S. National ALS Registry, 2011-2023.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70390}, pmid = {42669596}, issn = {1097-4598}, support = {//CDC/ATSDR National ALS Registry/ ; }, abstract = {INTRODUCTION/AIMS: Military service has been associated with increased risk of amyotrophic lateral sclerosis (ALS) but less is known about survival after diagnosis. We evaluated the association between military service and survival after ALS diagnosis among U.S. National ALS Registry participants.

METHODS: Participants who completed the Registry's Military History Survey between 2011 and 2023 and had valid ALS diagnosis and mortality follow-up information were eligible. Military service was classified as veteran or nonveteran. Mortality was ascertained through National Death Index linkage. Kaplan-Meier methods evaluated survival distributions, and Cox proportional hazards models estimated adjusted mortality associations.

RESULTS: Among 8643 participants, 1735 (20.1%) were veterans and 6908 (79.9%) were nonveterans. Veterans were older at diagnosis and reported greater smoking and alcohol use. The median observed time from ALS diagnosis to death or censoring was 3.77 years among veterans and 4.79 years among nonveterans, an approximate 1-year difference; Kaplan-Meier estimated 5-year survival was 47.1% and 57.4%, respectively. Veterans experienced significantly poorer survival than nonveterans (log-rank χ[2] = 113.45, p < 0.0001). In the primary adjusted Cox model, military service remained associated with increased mortality (HR 1.25, 95% CI 1.15-1.35; p < 0.0001). Findings were consistent across sensitivity analyses accounting for disease severity, symptom onset site, and delayed Registry entry.

DISCUSSION: Military service was associated with poorer survival after ALS diagnosis. Veterans had lower 5-year survival and higher mortality hazards than nonveterans, suggesting military history may be an important prognostic factor in ALS.}, } @article {pmid42669806, year = {2026}, author = {Rogala, O and Tarach, KA and Kordek, A and Shu, Y and Gilson, JP and Lakiss, L and Góra-Marek, K}, title = {Commercial Fluid Catalytic Cracking Catalysts for Polymers Chemical Recycling.}, journal = {ChemSusChem}, volume = {19}, number = {17}, pages = {e71002}, doi = {10.1002/cssc.71002}, pmid = {42669806}, issn = {1864-564X}, support = {2021/43/B/ST4/00307//Narodowe Centrum Nauki/ ; 2023/49/B/ST4/02340//Narodowe Centrum Nauki/ ; }, abstract = {Commercial FCC catalysts (fresh and equilibrated) and laboratory made catalysts from Y type zeolite and γ-Al2O3 are characterized by standard techniques and evaluated in the cracking of pure PP, LDPE, and PS polymers as well as coprocessing PP/LDPE mixture in TGA (light-off curves) and a unique operando FTIR & GC-MS set-up. Conversions, products selectivities as well as coke deposition and removal are studied as a function of temperature. In spectroscopic operando investigations, MCR-ALS analysis provides significant insight into the observed results. The equilibrium FCC catalyst (Cat-Eq800) differs markedly from its fresh counterpart (Cat-F800) in product selectivity. Regardless of the polyolefin feed, Cat-Eq800 exhibits higher olefinicity in the C4 fraction. In both commercial catalysts, coke precursor formation proceeds predominantly via paraffin consumption. In situ FTIR analysis revealed valuable information regarding reactant diffusion and catalyst acidity. Despite undergoing severe deactivation treatments, the equilibrium catalyst displays the highest Brønsted-to-Lewis acid site ratio while maintaining efficient mass transport through its hierarchical pore structure. Important information to better design FCC catalysts can be derived, as the exact composition of these important catalysts are often tailored for specific families of heavy oil fractions.}, } @article {pmid42669892, year = {2026}, author = {Zanovello, M and Serani, F and Bebeti, A and Paredi, F and Quadrio, G and Fortuna, A and Minicuci, GM and Pegoraro, E and Cagnin, A and Cecchin, D and Sorarù, G}, title = {Metabolic and Fluid Biomarkers Support Microglia Activation in Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, pmid = {42669892}, issn = {2328-9503}, abstract = {Amyotrophic lateral sclerosis is an incurable neurodegenerative disease involving motor neuron degeneration and metabolic and immune dysfunction. We combined clinical data, cerebrospinal fluid biomarkers and fluorodeoxyglucose positron emission tomography with magnetic resonance imaging to investigate the role of reactive microglia in disease pathogenesis. Patients showed increased cerebrospinal fluid levels of neurofilament light chain and chitinases, along with hypermetabolism in the medulla oblongata. Chitinase levels correlated with brainstem metabolism and clinical severity. These findings suggest a link between microglial activation, brainstem hypermetabolism and disease progression in amyotrophic lateral sclerosis, supporting a central role for neuroinflammation in disease pathogenesis.}, } @article {pmid42669933, year = {2026}, author = {Milella, G and Vacchiano, V and Velucci, V and Zoccolella, S and Liguori, R and Defazio, G}, title = {Data-Driven SuStaIn Model of Disability Progression in Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, pmid = {42669933}, issn = {2328-9503}, abstract = {OBJECTIVE: To determine whether ordinal Subtype and Stage Inference (SuStaIn) applied to routine ALSFRS-R item scores can identify reproducible disability progression patterns in amyotrophic lateral sclerosis (ALS) and provide clinically meaningful staging.

METHODS: We analysed baseline ALSFRS-R item responses from 866 PRO-ACT participants. Ordinal SuStaIn inferred subtype-specific sequences of functional deterioration and assigned each participant to a subtype and a SuStaIn-derived functional stage. Longitudinal stability was assessed across 3625 consecutive follow-up visit pairs from 697 participants. Structural reproducibility was evaluated in an independent cohort of 301 consecutive ALS patients. Associations of baseline subtype and stage with survival and subsequent ALSFRS-R decline were examined using Cox and piecewise-linear models.

RESULTS: A three-subtype solution identified fine motor-, gross motor- and bulbar-predominant patterns of early disability. Within each subtype, SuStaIn reconstructed ordered multidomain sequences of functional deterioration and assigned each participant a SuStaIn-derived stage. Subtype assignment was stable across 90.4% of consecutive visit pairs, and stage was non-decreasing in 98.8%. Subtype-specific event ordering was reproduced in the validation cohort. Higher baseline stage was associated with increased mortality risk in the fine motor- and gross motor-predominant subtypes, but not clearly in the bulbar-predominant subtype. Baseline stage showed subtype-dependent, non-linear associations with subsequent functional decline, with acceleration up to mid-stage breakpoints in the fine motor- and gross motor-predominant subtypes and less evident stage-dependent acceleration in the bulbar-predominant subtype.

INTERPRETATION: Routine ALSFRS-R item-level data can define clinically interpretable ALS progression subtypes and latent SuStaIn-derived functional stages. Joint subtype-stage modelling may refine prognostic stratification and support prognosis-informed trial enrichment.}, } @article {pmid42670527, year = {2026}, author = {Pan, L and Liu, B and Xu, J and Mu, X and Fan, L}, title = {Mesenchymal Stem Cells and Extracellular Vesicles for Neurodegenerative Diseases: Therapeutic Advances and Challenges.}, journal = {International journal of nanomedicine}, volume = {21}, number = {}, pages = {628071}, pmid = {42670527}, issn = {1178-2013}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Extracellular Vesicles/transplantation ; *Mesenchymal Stem Cells/cytology ; *Mesenchymal Stem Cell Transplantation/methods ; Animals ; }, abstract = {Mesenchymal stem cells (MSCs), as a type of adult stem cells, exhibit robust self-renewal, multi-lineage differentiation, paracrine and immunomodulatory capacities, demonstrating broad application prospects in the treatment of neurodegenerative diseases. This review systematically summarizes the mechanisms of action, therapeutic advances and comparative analyses of various MSCs and their derived extracellular vesicles (EVs) in Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and discusses the optimization effects of gene modification and pretreatment on therapeutic efficacy. This article not only highlights the advantages of various MSCs and their corresponding EVs, but also provides unique insights into their differentiated therapeutic potential and mechanism of action, which have not been fully elucidated in previous studies. Meanwhile, although current research results are encouraging, this paper also critically points out that existing studies suffer from insufficient elucidation of mechanisms and lack of large-scale clinical trials. Finally, the article prospects future directions of MSC-based therapeutic strategies, including mechanism deepening, treatment optimization and standardization system construction, to promote their translation into clinical application. However, most of the current evidence is still preclinical, and the recognized clinical efficacy in humans is still limited. This is a narrative review. Literature was screened from Web of Science and PubMed by thematic relevance and research quality, without systematic review protocol or meta-analysis.}, } @article {pmid42670631, year = {2026}, author = {Bischoff, KE and Leavell, YL and Besbris, JM and Lero, C and Noble, K and Grouls, A and Kurent, J and Kluger, BM and Pantilat, SZ and Mehta, AK and , }, title = {Priorities for Advancing Palliative Care for Amyotrophic Lateral Sclerosis: A Consensus Report From a Palliative Care for ALS Working Group in the United States.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70381}, pmid = {42670631}, issn = {1097-4598}, abstract = {Until there is a cure for amyotrophic lateral sclerosis (ALS), it is imperative that everyone facing this devastating illness receives care to alleviate symptoms and suffering and improve quality of life. Emerging evidence has demonstrated benefits of palliative care for people with ALS, but palliative care is not yet widely available or accessed by people with ALS throughout the disease course. The Palliative Care for ALS Working Group was formed within the International Neuropalliative Care Society, consisting of interprofessional ALS and palliative care clinicians, researchers, advocates, and patients and care partner representatives who are committed to improving palliative care for people living with ALS. The group engaged in a strategic planning process to determine what is needed to advance palliative care for people with ALS over the next 3-5 years. This report outlines the core recommendations from that strategic planning process. Recommendations are divided into five sections: (1) clinician education, (2) clinical service expansion, (3) research, (4) public awareness, and (5) policy change. The aim of this report is to provide ALS and palliative care clinicians, researchers, ALS advocacy organizations, and funders with a road map of priority areas where dedicated focus could significantly advance palliative care for people facing ALS, with the goals of relieving suffering and improving quality of life. The Palliative Care for ALS Working Group is making concrete steps toward these priority areas and will continue to serve as a convening and coordinating body for this work.}, } @article {pmid42672036, year = {2026}, author = {Krumina, M and Fernandes, S and Vilne, B and Baczyk, M}, title = {Computational Insights Into Neuromodulation: How Electric Fields Shape Motor Neuron Excitability.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {34}, number = {}, pages = {3958-3969}, doi = {10.1109/TNSRE.2026.3729166}, pmid = {42672036}, issn = {1558-0210}, mesh = {*Motor Neurons/physiology ; Animals ; Mice ; Computer Simulation ; *Models, Neurological ; Action Potentials/physiology ; Animals, Newborn ; Spinal Cord/physiology/cytology ; Membrane Potentials/physiology ; Dendrites/physiology ; Electric Stimulation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease characterized by the selective loss of spinal motor neurons (MN). Trans-spinal direct current stimulation (tsDCS) has emerged as a promising noninvasive neuromodulation technique that could provide neuroprotection and slow down disease progression. However, the mechanisms by which tsDCS affects individual MNs remain poorly understood. This study uses computational modeling to explore how low-intensity extracellular electric fields (EEFs), generated by tsDCS, influence the electrophysiological behavior of MNs. Morphologically realistic, multi-compartment models of neonate mouse alpha-MNs were developed in the NEURON simulation environment. Simulations were conducted under different EEF magnitudes, polarities and orientations. At the population level, consistent directional effects on excitability-related properties were limited and depended on stimulation condition. However, analyses of response magnitude showed that EEFs could modulate several properties, including resting membrane potential and rheobase, even when the direction of change varied across neurons. This heterogeneity was associated with neuronal morphology and its alignment with the applied field, with dendritic length and asymmetry affecting sensitivity. Overall, the results suggest that low-intensity EEFs produce modest, morphology-dependent modulation of MN electrophysiological properties, and that variability in neuronal structure and orientation may help explain discrepancies across previous experimental and modeling studies.}, } @article {pmid42673727, year = {2026}, author = {Aladwan, S and Jasim, A and Qassem, TA and Gajjar, TB and Hanumanthayya, M and Tripathi, V and Maharana, L and Bainsal, N}, title = {Human health risk assessment of toxic and non-toxic elements in various oily, cream, and powder cosmetics in Arab countries- A systematic literature review.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {97}, number = {}, pages = {127946}, doi = {10.1016/j.jtemb.2026.127946}, pmid = {42673727}, issn = {1878-3252}, mesh = {Humans ; *Cosmetics/chemistry/analysis ; Risk Assessment ; Powders ; Middle East ; *Metals, Heavy/analysis ; *Trace Elements/analysis/toxicity ; }, abstract = {Oily, cream, and powder cosmetics (OCPCs) are widely used worldwide, especially in Arab nations, highlighting the need for ongoing heavy metal (HM) monitoring. This systematic review examined 16 HM concentrations in 14 OCPC product categories across 11 of the 22 Arab countries, selected countries based on predefined inclusion and exclusion criteria, and evaluated their associated health risks for only 9 of the 14 OCPCs for which sufficient data were available. The analysis included 24 papers published between June 1, 2007, and January 30, 2026, selected according to prescribed inclusion and exclusion criteria. International authorities like the WHO and the EU set acceptable limits (ALs) for HM levels. According to EPA criteria, all detected HMs underwent a health risk assessment (HRA). Saudi Arabia and Jordan had the highest HM detection rates in OCPCs among the 11 Arab countries analyzed, underscoring the need for stronger regulation. Moisturizing creams, toners, cosmetic masks, and oils were mostly contaminated with non-toxic HMs, whereas facial foundation and face cream samples were contaminated with toxic HMs. Despite exceedances of WHO and EU ALs for several elements, the EPA-based dermal risk indices remained below acceptable thresholds, reflecting the distinction between concentration-based regulatory limits and exposure-based health risk assessment. Arab regulatory agencies should establish monitoring systems to limit HMs in OCPCs, in line with WHO and EU guidelines on HM ALs in cosmetics, before market access.}, } @article {pmid42674126, year = {2026}, author = {Raffaele, S and Bonifacino, T and Mannella, FC and Nguyen, N and Torazza, C and Marangon, D and Chinosi, EM and Schrøder, HD and Hejbøl, EK and Madsen, K and Marchetti, L and Trincavelli, ML and Milanese, M and Lecca, D and Lambertsen, KL and Bonanno, G and Abbracchio, MP and Fumagalli, M}, title = {Selective targeting of the oligodendroglial GPR17 receptor improves myelin integrity and motor function in female SOD1[G93A] mice.}, journal = {Pharmacological research}, volume = {232}, number = {}, pages = {108424}, doi = {10.1016/j.phrs.2026.108424}, pmid = {42674126}, issn = {1096-1186}, mesh = {Animals ; *Receptors, G-Protein-Coupled/metabolism/agonists/genetics ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology/genetics ; Humans ; *Oligodendroglia/drug effects/metabolism/pathology ; *Myelin Sheath/drug effects/metabolism/pathology ; Mice, Transgenic ; Male ; Superoxide Dismutase-1/genetics ; Spinal Cord/metabolism/drug effects/pathology ; Mice ; Mice, Inbred C57BL ; *Motor Activity/drug effects ; Disease Models, Animal ; Nerve Tissue Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no definitive disease-modifying therapies available, underscoring the urgent need to identify novel druggable targets. The G protein-coupled receptor GPR17 is a critical regulator of oligodendrocyte maturation and has emerged as a candidate target in ALS, yet its relevance to human disease and its therapeutic potential remain unclear. Here, we demonstrate that pathological GPR17 upregulation defines a conserved, pathologically immature oligodendroglial state in human ALS that can be pharmacologically leveraged to restore myelin integrity and improve functional outcome in vivo. Publicly available transcriptomics datasets and histological analyses revealed an increased abundance of GPR17-expressing immature oligodendrocytes in post-mortem human spinal cord tissue from ALS cases. Moreover, sustained activation of GPR17 with a selective agonist induced GPR17 internalization in heterologous expression systems and promoted the differentiation of primary oligodendrocyte precursors derived from SOD1[G93A] mice. Translating these findings in vivo, chronic treatment with a brain-penetrant GPR17 agonist derived from the same pharmacological class significantly extended survival, delayed body weight loss, and improved motor performance in female SOD1[G93A] mice, whereas male mice showed no therapeutic benefit. These effects were associated with restored oligodendrocyte maturation, preserved myelin integrity, motor neuron survival, and attenuated reactive gliosis in the spinal cord of female SOD1[G93A] mice, while milder effects were observed in males. Together, these findings establish oligodendroglial GPR17 as a conserved and pharmacologically actionable target in ALS and show that sustained in vivo GPR17 agonism can reprogram altered oligodendroglial states and slow disease progression in a sex-dependent manner.}, } @article {pmid42675240, year = {2026}, author = {Ma, S and Luo, S and Zhong, H}, title = {Artificial Intelligence in Neuromuscular Diseases: Opportunities for a Data-Scarce Field.}, journal = {Neurology and therapy}, volume = {15}, number = {5}, pages = {2199-2216}, pmid = {42675240}, issn = {2193-8253}, support = {Open research fund: gect-2025-Z01//Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases/ ; }, abstract = {Neuromuscular diseases (NMDs) encompass over 800 distinct entities affecting approximately one in 1000 individuals worldwide, with progressive muscle weakness, atrophy, and motor impairment as primary clinical manifestations. The rarity of most NMDs creates fundamental challenges for artificial intelligence (AI) and machine learning (ML) applications that typically require large-scale datasets. In this narrative review we synthesize the literature published between 2018 and 2025 on AI applications across the NMD spectrum, organized by clinical application domain. We examine how AI has advanced diagnostic capabilities through genetic variant interpretation, muscle magnetic resonance imaging analysis, electromyography-based classification, and computational pathology. In disease monitoring and prognosis, wearable-derived digital biomarkers have achieved regulatory qualification (US Food and Drug Administration [FDA] and European Medicines Agency [EMA]) as clinical trial endpoints for Duchenne muscular dystrophy, while AI-driven survival models for amyotrophic lateral sclerosis (ALS) have been validated across 14 European centers. Proteomic and multi-omics analyses using ML have identified diagnostic panels for ALS. However, most reported models were developed and internally validated on single-center datasets, and few have undergone external or prospective validation or clinical implementation. Despite these achievements, research intensity varies dramatically across NMD subtypes, with ALS and Duchenne muscular dystrophy dominating while myotonic dystrophy, congenital myopathies, and metabolic myopathies remain virtually unexplored. Critical gaps persist in computational pathology, multi-center validation, and clinical translation. In this review, we discuss how federated learning, international collaborative networks (TREAT-NMD, Solve-RD, EURO-NMD), and foundation models can address these challenges, and propose directions for future AI-enhanced clinical studies in this data-scarce field.}, } @article {pmid42676114, year = {2026}, author = {Xu, J and Wu, X and Zhang, B and Wu, K}, title = {Ba4Al4SnS12: balancing bandgap and nonlinear optical performance in thioaluminate via multifunctional group engineering.}, journal = {Dalton transactions (Cambridge, England : 2003)}, volume = {55}, number = {36}, pages = {13111-13116}, doi = {10.1039/d6dt01763k}, pmid = {42676114}, issn = {1477-9234}, abstract = {The exploration of infrared nonlinear optical (IR NLO) crystals with excellent performance has attracted increasing attention in view of the inherent drawbacks (low laser damage threshold (LDT) or harmful two-photon absorption (TPA)) of commercial NLO crystals. However, the critical performances (wide bandgap (>3.0 eV) and good nonlinearity (>0.5 × AgGaS2)) show an inverse relationship in IR NLO crystals; thus, the judicious selection and combination of functional motifs are critical, as performance is fundamentally governed by structure. For that reason, we propose a multifunctional group engineering strategy incorporating [AlS4] for a wide bandgap and [SnS4] for large nonlinearity to design a new NLO chalcogenide that affords the successful synthesis of thioaluminate, Ba4Al4SnS12. Experimental study shows that Ba4Al4SnS12 achieves an optimal performance balance between a wide bandgap (3.06 eV) and a moderate second-harmonic generation (SHG) response (0.56 × AgGaS2) with requisite phase-matching behavior (Δn = 0.042), further indicating that Ba4Al4SnS12 could be regarded as a potential IR NLO candidate. Theoretical analysis demonstrates the respective contributions of distinct tetrahedral groups to the bandgap and NLO coefficient and validates the feasibility of multifunctional group engineering. Therefore, this study provides a principle for selecting excellent functional groups and research systems, illuminating a feasible pathway toward future NLO crystals with superior performance.}, } @article {pmid42676195, year = {2026}, author = {Arbuzova, EE and Seksyaev, NE and Karakulova, YV and Selyanina, NV and Danilova, MA}, title = {[Atypical forms of amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {126}, number = {8}, pages = {13-20}, doi = {10.17116/jnevro202612608113}, pmid = {42676195}, issn = {1997-7298}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/classification ; Phenotype ; Diagnosis, Differential ; Disease Progression ; Motor Neurons/pathology ; }, abstract = {This article provides a comprehensive overview of contemporary concepts regarding the classical and atypical phenotypes of amyotrophic lateral sclerosis (ALS), with a particular focus on critical diagnostic challenges. The classical variant of the disease is characterized by the progressive involvement of both upper and lower motor neurons, typically presenting with an asymmetric onset and a predictable progression. However, several atypical phenotypes are identified, including syndromes predominantly affecting the lower motor neurons, such as the «hanging hands» and «hanging legs» syndromes, isolated bulbar paralysis, ALS with respiratory onset, and forms with a predominance of upper motor neuron involvement. These atypical variants often mimic other neurological conditions-such as cervical myelopathy, multifocal motor neuropathy, and myasthenia gravis-which can result in significant delays in the accurate diagnosis of ALS. Atypical forms of ALS represent a major source of diagnostic errors in clinical practice. Enhancing healthcare professionals' understanding of the spectrum of phenotypic presentations, alongside the application of contemporary diagnostic criteria, facilitates more timely diagnoses, optimized patient care pathways, and the prompt initiation of pathogenetic therapies, ultimately improving both survival rates and quality of life for affected individuals.}, } @article {pmid42677779, year = {2026}, author = {Ali, A and Arif, M and Ashraf, U and Elahi, S and Mustafa, A and Yasir, MB and Sarfraz, W and Ansari, AU and Masood, HMY and Shabbir, MA and Abdullah, A and Sharma, MK}, title = {CSF Tau and Amyloid Biomarkers in Cognitive Impairment Across the ALS-FTD Spectrum: A Systematic Narrative Review and Evidence Map.}, journal = {Brain and behavior}, volume = {16}, number = {9}, pages = {e71740}, pmid = {42677779}, issn = {2162-3279}, mesh = {Humans ; *tau Proteins/cerebrospinal fluid ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/complications ; Biomarkers/cerebrospinal fluid ; *Frontotemporal Dementia/cerebrospinal fluid/complications ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Cognitive Dysfunction/cerebrospinal fluid/etiology ; }, abstract = {INTRODUCTION: Cognitive impairment is an important non-motor manifestation of amyotrophic lateral sclerosis (ALS), particularly across the ALS-frontotemporal dementia (ALS-FTD) spectrum. Cerebrospinal fluid (CSF) tau and amyloid biomarkers may reflect nonspecific neurodegenerative injury, concomitant Alzheimer disease (AD) pathology, or distinct cognitive phenotypes. However, available evidence remains limited, fragmented, and methodologically heterogeneous.

METHODS: This systematic narrative review and semi-quantitative evidence map was conducted according to PRISMA 2020 recommendations. PubMed, Scopus, Web of Science, and Google Scholar were searched from database inception through May 2026. Eligible observational studies reported cognition-specific associations between CSF tau, amyloid, or related neurodegenerative biomarkers and cognitive outcomes in ALS-spectrum populations. Two reviewers independently screened studies, extracted quantitative effect estimates, and assessed risk of bias using the Newcastle-Ottawa Scale. Cross-study consistency was summarized using an exploratory semi-quantitative evidence-coding framework.

RESULTS: Four observational studies comprising 638 ALS-spectrum participants fulfilled the eligibility criteria. Total tau and p-tau181 showed the most reproducible associations with cognition. Total tau correlated with ECAS total (r = -0.398, P < 0.001) and ALS-specific cognition (r = -0.403, P < 0.001), while adjusted multicenter analyses demonstrated associations between p-tau181 and ECAS total (β = -0.03, p = 0.006) and memory performance (β = -0.04, p = 0.003). Both biomarkers received ++ evidence-map coding. Amyloid findings were more heterogeneous; lower Aβ42/Aβ40 was associated with poorer memory performance (β = 0.20, p = 0.044), but continuous amyloid-cognition associations were not consistently replicated across cohorts (± evidence). Broader CSF protein-ratio findings remained exploratory. Clinical, cognitive, assay, and analytical heterogeneity precluded meta-analysis.

CONCLUSIONS: The available evidence, although limited and heterogeneous, suggests that total tau may primarily reflect broader neurodegenerative injury, whereas p-tau181 and Aβ42/Aβ40 may be more informative for selected cognitive phenotypes or possible AD co-pathology. These biomarkers should remain research tools until larger, standardized, longitudinal multicenter studies establish their pathological specificity, predictive value, and clinical utility.}, } @article {pmid42677823, year = {2026}, author = {Chandran, D and Agrawal, U and Damayanthi, D and Nair, DT and Mandagini, G and Nair, SS and Narasimhaiah, D and Fernandez, FB and Thakur, P and Raghavan, CT and Krishnan, S and Gopala, S and Urulangodi, M}, title = {Cofilin 1 Is an Extracellular Vesicle-Associated Plasma Biomarker of Parkinson's Disease in Humans.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78348}, pmid = {42677823}, issn = {1531-8249}, abstract = {OBJECTIVE: Parkinson's disease (PD) lacks reliable, minimally invasive biomarkers for diagnosis. This study aimed to identify and validate PD-specific plasma extracellular vesicle (EV)-associated proteins.

METHODS: Plasma EVs were isolated by ultracentrifugation and characterized. Proteomic profiling of total plasma EVs from PD patients and healthy controls was performed, and a candidate protein identified after analysis was validated by enzyme-linked immunosorbent assay. Diagnostic accuracy was evaluated using receiver operating characteristic and precision-recall curve analysis. Disease specificity was examined in progressive supranuclear palsy and amyotrophic lateral sclerosis. Histochemical and immunofluorescence analyses were conducted in human and mouse PD brain tissue.

RESULTS: Proteomic analysis identified distinct PD-specific EV proteins, including cofilin 1 (CFL1), which was significantly enriched in EVs isolated from PD. EV-CFL1 levels were significantly elevated in PD compared with healthy controls (p < 0.0001). Receiver operating characteristic analysis showed strong diagnostic performance for EV-CFL1 (area under the curve 0.87). Also, EV CFL1 levels could distinguish PD from progressive supranuclear palsy patients (area under the curve 0.914). CFL1 was enriched in L1 cell adhesion molecule-positive EVs, indicating a possible neuronal origin. CFL1 was detected in both human and mouse PD brain sections. Importantly, EV-CFL1 levels were independent of age, disease stage, and motor severity.

INTERPRETATION: EV-associated CFL1 represents a PD-specific, blood-based marker with strong diagnostic accuracy and can distinguish PD from atypical parkinsonism. The presence of CFL1 was confirmed in human and mouse PD brain tissue, and its accumulation in PD brain suggests a possible role in disease pathogenesis. ANN NEUROL 2026.}, } @article {pmid42677831, year = {2026}, author = {Basak, B and Riley, JF and Nataraj, NM and Holzbaur, EL}, title = {Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {17}, pages = {}, pmid = {42677831}, issn = {1558-8238}, mesh = {Humans ; *Mitophagy ; Animals ; *Neurons/pathology/metabolism ; *Mitochondria/pathology/metabolism/genetics ; PTEN-Induced Putative Kinase ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Protein Kinases/metabolism/genetics ; Ubiquitin-Protein Ligases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Signal Transduction ; }, abstract = {Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson's disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin-dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin-dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.}, } @article {pmid42677900, year = {2026}, author = {Chan, KH and Ha, Y and Islegen-Wojdyla, A and Leon, S and Garces, M and McReynolds, D and Chong, X and Sriramoju, RV and Mahl, J and Guenzing, D and Koepp, W and Hexemer, A and Hellert, T and Chavez, T}, title = {Orchestrating agentic systems at ALS beamline 5.3.1 with Osprey and Bluesky.}, journal = {Journal of synchrotron radiation}, volume = {33}, number = {Pt 5}, pages = {1382-1391}, pmid = {42677900}, issn = {1600-5775}, support = {107514//US Department of Energy, Office of Science/ ; DE-AC02-05CH11231//US Department of Energy, Office of Science/ ; }, abstract = {Modern synchrotron beamlines support increasingly complex experiments, but their operation remains strongly dependent on facility-specific control interfaces and workflows. This reliance creates a significant barrier to entry for new users and limits the portability of experimental procedures across beamlines. Here, we present a minimal, agent-agnostic orchestration architecture for AI-assisted beamline operation, deployed at Advanced Light Source beamline 5.3.1. The approach introduces a capability-based abstraction layer that exposes beamline functionality as a set of predefined operations. Within this framework, AI agents translate natural-language user requests into structured experimental plans composed of these capabilities. All plans are executed through the Bluesky Queue Server, ensuring deterministic operation within existing control and safety constraints without modification of the underlying beamline control system. The framework is defined by three key elements: (i) a portable capability layer that decouples user intent from beamline-specific implementation, (ii) a hybrid interaction framework combining AI-assisted workflow composition with graphical user interface (GUI)-based monitoring and control, and (iii) constrained execution that restricts all actions to predefined capabilities and requires user approval prior to execution. We demonstrate the architecture using grazing-incidence scattering (GISAXS), multi-edge X-ray absorption spectroscopy (XANES), and cross-beamline deployment scenarios. In each case, the system generates physically meaningful experimental plan, adapts to local hardware constraints, and preserves experimental intent across different instruments. These results demonstrate a practical and scalable approach for integrating AI into synchrotron experimentation, enabling intent-driven, portable, and safe beamline operation.}, } @article {pmid42678414, year = {2026}, author = {Henne, C and Sigfridsson, I and Brännström, T and Forsberg, KME and Marklund, SL and Zetterström, P and Andersen, PM}, title = {Seeds from ALS patients homozygous for the SOD1 D90A mutation transmit two types of SOD1 aggregation and motor neuron disease.}, journal = {Acta neuropathologica}, volume = {152}, number = {1}, pages = {}, pmid = {42678414}, issn = {1432-0533}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; *Mutation/genetics ; Homozygote ; Mice ; Spinal Cord/pathology/metabolism ; Disease Models, Animal ; Female ; Male ; Motor Neurons/pathology ; *Protein Aggregation, Pathological/genetics/pathology ; Middle Aged ; }, abstract = {Mutations in superoxide dismutase-1 (SOD1) are a common cause of amyotrophic lateral sclerosis (ALS). Inheritance is as a rule dominant, but in carriers of the most prevalent mutation, D90A, disease primarily develops in homozygotes. Increasing evidence suggests that prion-like propagation of SOD1 aggregation is the central pathogenic mechanism. Two structurally different strains of aggregates have been found to arise in human SOD1 (hSOD1) transgenic (Tg) mouse models of ALS. Strain A is formed by most mutants including hSOD1[G85R] and homozygous hSOD1[WT] Tg mice, whereas homozygous hSOD1[D90A] Tg mice form a distinct strain B, but also A. Inoculation of strain A and B seed preparations from Tg mice into lumbar spinal cord of adult hSOD1[G85R] mice induced templated spreading hSOD1 aggregation and premature ALS-like disease. Seeds from an ALS patient carrying the hSOD1[G127X] truncation mutation likewise transmitted strain A aggregation and disease. In the present study, we investigated whether seeds prepared from spinal ventral horns from six patients homozygous for the hSOD1[D90A] mutation could transmit aggregation and disease to adult hSOD1[G85R] Tg mice. Despite the extensive degeneration and loss of motor neurons in the long-lived D90A patients, two of the seeds significantly shortened the survival of the Tg mice, one transmitting A and the other B-pattern hSOD1 aggregation. Nine different preparations from four human controls lacked effects. The results demonstrate that two distinct aggregate strains can arise and propagate in homozygous hSOD1[D90A] ALS patients, further supporting the hypothesis that prion-like transmission of hSOD1 aggregation is the primary pathogenic mechanism in SOD1-linked ALS.}, } @article {pmid42678590, year = {2026}, author = {Ahmad, R and Naeem, M and Houlden, H}, title = {Whole-exome sequencing reveals a novel frameshift and a recurrent nonsense SPG11 variant causing rare familial amyotrophic lateral sclerosis type 5 in two consanguineous Pakistani families.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42678590}, issn = {1573-4978}, mesh = {Humans ; Pakistan ; Female ; Male ; Exome Sequencing/methods ; Pedigree ; *Amyotrophic Lateral Sclerosis/genetics ; Consanguinity ; Adult ; Frameshift Mutation/genetics ; Codon, Nonsense/genetics ; *Proteins/genetics ; Homozygote ; Phenotype ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both upper and lower motor neurons, disturbing communication between the brain and muscles. So far, few reports have been published for the SPG11-associated ALS, and this is the first documented case from Pakistan. METHODS: We report a rare subtype of ALS with an autosomal recessive mode of inheritance with juvenile onset before 25 years of age in the five affected individuals from two unrelated families. Whole-exome sequencing was performed to identify disease-causing variants, and selected variants were further prioritized based on predicted pathogenicity and similarity to clinical phenotypes.

RESULTS: Two homozygous variants within the SPG11 gene were identified as pathogenic according to the ACMG and ClinGen Sequence Variant Interpretation (SVI) Working Group recommendations: a novel truncation (NM_025137.4:c.6738dup, p.Glu2247Ter) variant as validated by Sanger sequencing and a recurrent nonsense (NM_025137.4: c.782C>A, p.Ser261Ter) variant (rs765477482) previously reported in a family affected with autosomal recessive hereditary spastic paraplegia (ARHSP). In silico prediction tools further confirmed their pathogenicity.

CONCLUSION: Five patients with juvenile-onset ALS born to consanguineous parents were found to have homozygous SPG11 gene variants. Our findings describe the overlapping phenotypes ofSPG11-related autosomal recessive juvenile ALS and ARHSP, suggesting that these disorders show a clear overlapping phenotype with common genetic defects. In clinical practice, it is challenging to distinguish between these two disorders. Additional Mendelian cases should be included to clarify further and investigate whether these represent two diverse diseases caused by variants in a single gene.}, } @article {pmid42680205, year = {2026}, author = {Hines, TJ and Funke, JR and Pratt, SL and Rice, AD and Twiss, JL and Burgess, RW}, title = {A mouse model of autosomal dominant spastic ataxia and myopathy caused by a mutation in Tuba4a.}, journal = {Human molecular genetics}, volume = {35}, number = {18}, pages = {}, doi = {10.1093/hmg/ddag084}, pmid = {42680205}, issn = {1460-2083}, support = {R01 NS068933//National Institute of Neurological Diseases and Stroke/ ; R37 NS054154//National Institute of Neurological Diseases and Stroke/ ; K99 NS130151//National Institute of Neurological Diseases and Stroke/ ; }, mesh = {Animals ; Disease Models, Animal ; Mice ; Male ; *Spinocerebellar Ataxias/genetics/pathology ; *Muscle Spasticity/genetics/pathology ; *Muscular Diseases/genetics/pathology ; *Tubulin/genetics ; Humans ; *Intellectual Disability/genetics/pathology ; *Optic Atrophy/genetics/pathology ; Mice, Inbred C57BL ; Mutation, Missense ; Polymorphism, Single Nucleotide ; Mutation ; Genes, Dominant ; Female ; Protein Serine-Threonine Kinases/genetics ; Muscle, Skeletal/pathology ; }, abstract = {Hereditary ataxias are a heterogeneous group of neurodegenerative disorders characterized by impaired balance and coordination, often due to cerebellar dysfunction. Despite advances in identifying genetic causes, animal models remain essential for dissecting underlying mechanisms and testing therapeutic strategies. Here we describe a mouse model of spastic ataxia and myopathy caused by a missense mutation in Tuba4a (n.A626C, p.Gln176Pro). In an ENU mutagenesis screen, a male C57BL/6 J mouse exhibiting muscle wasting and an intention tremor starting at approximately 4 weeks-of-age was identified. The male was bred by in vitro fertilization to BALB/cByJ oocyte donors. Genetic mapping determined dominant inheritance and localized the mutation to Chromosome 1. Genome sequencing revealed single nucleotide polymorphisms (SNPs) in serine threonine kinase 36 (Stk36Y1003N) and alpha-tubulin 4A (Tuba4aQ176P) in the mapping interval. These SNPs were CRISPR-engineered into C57BL/6 J mice, which confirmed the Tuba4aQ176P variant as the causative mutation. Mutant mice are normal at 3 weeks, except for decrement in muscle response following repetitive nerve stimulation. However, by 30 days these mice have overt ataxia, Purkinje neuron degeneration, and extensive skeletal muscle defects, which contribute to a decreased lifespan. Dominant TUBA4A mutations in humans are associated with spastic ataxia type 11 (SPAX11), congenital myopathy type 26 (CMYO26), and frontotemporal dementia/amyotrophic lateral sclerosis type 9 (FTDALS9). Our mice exhibit hallmark features of SPAX11 and CMYO26, but do not show motor neuron degeneration. This specificity makes this model a valuable tool for studying cell-type selective effects of TUBA4A mutations in neurodegeneration and myopathy.}, } @article {pmid42680415, year = {2026}, author = {Wu, H and Zhou, Q and Fan, Z and Lao, Y and Pu, J and Wang, C and Chen, J and Huang, L and Song, S and Zhong, Y and Li, M and Pan, K and Ma, J}, title = {High carbon dioxide and silicon-aluminum interactions remodel cell walls: Surface architecture and adhesion in the marine diatom Phaeodactylum tricornutum.}, journal = {Journal of environmental sciences (China)}, volume = {168}, number = {}, pages = {571-578}, doi = {10.1016/j.jes.2026.01.023}, pmid = {42680415}, issn = {1001-0742}, mesh = {*Diatoms/physiology/drug effects ; *Silicon/chemistry/metabolism ; *Carbon Dioxide/toxicity ; *Aluminum/chemistry/toxicity ; *Cell Wall ; }, abstract = {Anthropogenic carbon dioxide (CO2) elevation increases pressure on ocean ecosystems. As the key primary producers in marine ecosystems, diatoms rely heavily on silicon (Si) to form their cell walls, while aluminum (Al) can compete with or modulate Si uptake. Nevertheless, the interactions among CO2, Si, and Al in marine diatoms remain unclear. This study elucidates how CO2, Si, and Al influence the model marine diatom Phaeodactylum tricornutum through single-element (C, Si, Al) and combined treatments (+Si+CO2, +Al+CO2). Multilevel indicators from growth rate to surface nano structures and elemental composition were characterized using interdisciplinary methods-such as atomic force microscopy and X-ray photoelectron spectroscopy. Results demonstrate that elevated CO2 and exogenous Si synergistically increased the growth rate of diatoms by 53 %, but the cell size significantly decreased by 5.4 %. Critically, this co-stimulation concurrently increased surface roughness and enhanced silicate polymerization via higher silanol groups (Si-OH) ratio in cell walls, thereby accelerating the sinking velocity. Al's impact emerged only under elevated CO2, promoting organic groups synthesis such as elevated amide-N functional groups on cell surfaces. These findings demonstrate that rising CO2, interacting with Si/Al availability, alters diatom adaptability and thereby potentially impacts diatom-mediated C-Si-Al biogeochemical cycles.}, } @article {pmid42680774, year = {2026}, author = {Ren, K and Cheng, M and Luo, Q and Zhang, B and Zhang, H and Li, Z and Liu, Y and Wang, Y and Kang, T and Dai, X and Chen, J and Cheng, Y and Huang, L}, title = {YTHDC1 functions as a molecular chaperone to suppress ALS-linked hnRNPA1 mutants from aggregation.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42680774}, issn = {2041-1723}, support = {32300651//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82370182//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Heterogeneous Nuclear Ribonucleoprotein A1/genetics/metabolism/chemistry ; Humans ; *Molecular Chaperones/metabolism/genetics ; Animals ; Mutation ; Protein Aggregates ; Protein Folding ; Protein Aggregation, Pathological/genetics/metabolism ; *Nerve Tissue Proteins/metabolism/genetics ; Neurons/metabolism ; }, abstract = {Proteostasis failure drives multiple neurodegenerative disorders (NDs), and ATP-independent chaperone pathways that support neuronal proteostasis remain poorly defined. Here, we identify the N6-methyladenosine (m[6]A)-binding protein YTHDC1 as an ATP-independent molecular chaperone, whose activity is mediated by a highly acidic polyaspartate/glutamate (polyD/E) segment. YTHDC1 prevents protein misfolding and aggregation, unfolds kinetically trapped substrates, and resolubilizes pre-formed aggregates. Deletion of the polyD/E segment abolishes these activities, whereas aromatic-cage mutants retain chaperone activity, demonstrating independence from m[6]A recognition. We identify the amyotrophic lateral sclerosis (ALS)-associated RNA-binding protein hnRNPA1 as a YTHDC1 client. YTHDC1 maintains liquid-like hnRNPA1 condensates, delays fibrillization of disease-associated mutants, and limits stress-granule sequestration, while mitigating mutant hnRNPA1-induced neurite growth defects in primary neurons. These findings define a proteostatic function of YTHDC1 and highlight its chaperone activity as a potential target for mitigating protein aggregation in ALS-related NDs.}, } @article {pmid42680877, year = {2026}, author = {Ren, Q}, title = {Plasma biomarkers for ALS.}, journal = {Nature neuroscience}, volume = {29}, number = {9}, pages = {2056}, doi = {10.1038/s41593-026-02440-8}, pmid = {42680877}, issn = {1546-1726}, } @article {pmid42681595, year = {2026}, author = {Lehrer, S and Rheinstein, PH}, title = {Proteomic and Functional Signatures of Phenoconversion in Presymptomatic Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical neuromuscular disease}, volume = {28}, number = {1}, pages = {33-46}, doi = {10.1097/CND.0000000000000567}, pmid = {42681595}, issn = {1537-1611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/diagnosis ; Female ; Proteomics ; Male ; Middle Aged ; Biomarkers/blood ; C9orf72 Protein/genetics ; Aged ; Neurofilament Proteins/blood ; *Prodromal Symptoms ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) likely has a prolonged presymptomatic phase. Identifying blood biomarkers that predict phenoconversion is critical for early intervention.

METHODS: We analyzed baseline serum proteomics in 270 UK Biobank participants who later developed ALS. A prespecified 19-protein panel was evaluated in relation to time-to-diagnosis. C9orf72 risk was proxied using rs10757668 genotype.

RESULTS: Neurofilament light rose sharply in the 2-3 years preceding diagnosis (r = -0.37, P < 0.001). Muscle-stress markers, including EDA2R and MYL3, increased earlier, up to 4-6 years before onset. Higher EDA2R levels were associated with reduced grip strength at baseline. A combined 19-protein panel plus genotype predicted phenoconversion within 3 years with an area under the receiver operating characteristic curve of 0.77, outperforming neurofilament light alone.

CONCLUSIONS: ALS exhibits a measurable molecular prodrome detectable in blood years before diagnosis. Integrated proteomic and genetic profiling may support early identification and trial enrichment strategies.}, } @article {pmid42681642, year = {2026}, author = {German, A and Grotemeyer, A and Koller, K and Eckstein, M and Wolff, H and Rampp, S and Süß, P and Müller, VC and Birnbacher, D and Winkler, J and Regensburger, M}, title = {Organ donation and brain preservation after assisted dying: case report and considerations for a potential pathway.}, journal = {BMC medical ethics}, volume = {27}, number = {1}, pages = {}, pmid = {42681642}, issn = {1472-6939}, mesh = {Humans ; *Tissue and Organ Procurement/ethics ; Germany ; *Suicide, Assisted/ethics ; *Organ Preservation/ethics ; *Brain ; Brain Death ; Cryopreservation ; }, abstract = {Protecting life and restoring health have been at the core of the conception of medical care since antiquity, for health professionals and the public alike. Assisted dying represents a practice that appears to challenge this traditional conception. In jurisdictions where assisted dying is condoned, the question remains as to whether the practice should be medicalized or deferred to non-medical actors. Irrespective of the divisive controversy surrounding assisted dying and its medicalization per se, the practice gives rise to high-stakes ethical, legal and organizational challenges when intersecting with organ transplantation, tissue banking, and Structural Brain Preservation or cryonics. In this narrative account, we describe the contextual framework and outline our experience and operational scope for addressing them at a university hospital in Germany. Based on this description we propose a structured pathway for increasing donation and preservation options for terminal patients while retaining ethical integrity and professional accountability.}, } @article {pmid42681667, year = {2026}, author = {Sowoidnich, L and Norman, AL and Gerstner, F and Siemund, JK and Buettner, JM and Pagiazitis, JG and Dreilich, V and Pilz, K and Tian, D and Sumner, CJ and Paradis, A and Mentis, GZ and Simon, CM}, title = {A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42681667}, issn = {2051-5960}, mesh = {Animals ; Humans ; *Motor Neurons/pathology ; *Neurodegenerative Diseases/pathology ; *Spinal Cord/pathology ; Muscular Atrophy, Spinal/pathology ; Mice ; Disease Models, Animal ; }, abstract = {Motor neuron (MN) loss is a hallmark of neurodegenerative disorders, yet its assessment remains variable, confounding mechanistic and therapeutic interpretation. To address this, we conducted a systematic review and meta-analysis of spinal muscular atrophy (SMA) mouse studies, revealing 60% variability in reported MN loss, for which spinal cord sampling emerged as a major contributor. Using a whole-segment approach with tissue clearing, MN tracing, and multimodal imaging, we confirmed segment-dependent differences in MN counts. Common MN markers (SMI-32, Nissl) lacked specificity, whereas choline acetyltransferase (ChAT) provided robust labeling in murine and human spinal cords. Deep learning-based whole-mount segmentation enabled unbiased MN quantification and validated manual counts. Integrating analysis with computational modeling established segment sampling as a key driver of variability and revealed degeneration patterns: widespread MN loss in amyotrophic lateral sclerosis (ALS), selective MN loss in severe SMA, and preservation in mild SMA models. These findings establish a framework for reproducible MN quantification.}, } @article {pmid42682425, year = {2026}, author = {Niu, X and Zhang, M and Huang, H and Shao, B and Wang, X and Cai, Z}, title = {Increased serum fibroblast growth factor 2 levels, altered peripheral blood inflammatory indicators and their ratios in amyotrophic lateral sclerosis: a clinical exploratory study.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1859903}, pmid = {42682425}, issn = {1664-2295}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood ; Female ; *Fibroblast Growth Factor 2/blood ; Male ; Case-Control Studies ; Middle Aged ; Biomarkers/blood ; Prospective Studies ; Aged ; *Inflammation/blood ; Adult ; Disease Progression ; Neutrophils ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration, leading to muscle weakness, atrophy, and ultimately respiratory failure. Previous research has highlighted the roles of neurotrophic factors and inflammatory responses in ALS pathogenesis; however, their interplay remains poorly understood. This exploratory study aims to elucidate the expression characteristics and correlations of fibroblast growth factor 2 (FGF2) and peripheral blood inflammatory indicators (PBIIs) such as derived neutrophil-to-lymphocyte ratio (dNLR) and systemic inflammatory response index (SIRI) in ALS patients.

METHODS: This was a prospective case-control study, involving ALS patients meeting Gold Coast diagnostic criteria and age- and sex-matched healthy controls (HCs). Serum FGF2 levels were measured using enzyme-linked immunosorbent assay (ELISA), and PBIIs were assessed through routine blood analysis. Statistical analysis was conducted mainly using intergroup comparison, correlation analysis, and multivariate linear regression.

RESULTS: The results showed significantly elevated levels of FGF2 and PBIIs in ALS patients compared to HCs, with strong correlations between FGF2, PBIIs, clinical staging, and disease progression rates. In multivariate linear regression analysis, PBIIs, especially SIRI, were significantly associated with disease severity and early disease progression. While serum FGF2 and FGF2 to dNLR ratio demonstrated potential as an auxiliary biomarker for later-stage disease.

DISCUSSION: These findings provide new insights into the molecular mechanisms underlying ALS and suggest practical diagnostic and prognostic tools, reinforcing the importance of targeting neurotrophic and inflammatory pathways in ALS management. This study holds significant promise for advancing both clinical practice and future research endeavors in the field.}, } @article {pmid42682963, year = {2026}, author = {Albaji, M and Ashkboos, K and Bagherzadeh, K}, title = {Possible Paraneoplastic Amyotrophic Lateral Sclerosis Presenting as Respiratory Failure in a Breast Cancer Patient: A Case Report.}, journal = {Clinical case reports}, volume = {14}, number = {9}, pages = {e73447}, pmid = {42682963}, issn = {2050-0904}, abstract = {A 63-year-old female with metastatic breast cancer presented with acute hypercapnic respiratory failure secondary to severe diaphragmatic dysfunction and mixed upper and lower motor neuron signs. Serum onconeural and neural surface antibody panels were negative, and initial cerebrospinal fluid analysis revealed albuminocytologic dissociation. Immunotherapy with intravenous immunoglobulin (IVIG) produced no clinical improvement, necessitating invasive mechanical ventilation and gastrostomy. Applying the 2021 PNS-Care consensus criteria, the case fulfills criteria for possible paraneoplastic amyotrophic lateral sclerosis (ALS), although coincidental sporadic disease cannot be excluded. A markedly elevated erythrocyte sedimentation rate (ESR) was observed, largely attributable to skeletal metastases and localized pulmonary collapse. Clinicians must maintain a high index of suspicion for motor neuron disease in cancer patients with unexplained hypoventilation.}, } @article {pmid42684486, year = {2026}, author = {Bencs, V and Hortobágyi, T and Nagy, AC and Kozák, M and Méhes, G and Oláh, L and Csiba, L}, title = {Establishment of a novel human nervous system tissue bank: University of Debrecen tissue bank-introduction and retrospective data analysis.}, journal = {Cell and tissue banking}, volume = {27}, number = {4}, pages = {}, pmid = {42684486}, issn = {1573-6814}, mesh = {Humans ; Female ; *Tissue Banks ; Male ; Retrospective Studies ; Middle Aged ; Aged ; *Brain/pathology ; Adult ; Aged, 80 and over ; Autopsy ; Adolescent ; Young Adult ; Paraffin Embedding ; Child ; }, abstract = {Human brain tissues obtained from autopsies, as well as muscle and nerve samples derived from biopsies, constitute indispensable resources for translational research investigating the pathomechanisms of neuropsychiatric disorders. In this study, we introduce the Nervous System Tissue Bank of University of Debrecen, which contains formalin-preserved and formalin-fixed paraffin-embedded (FFPE) brain samples, as well as frozen nerve and muscle biopsy specimens. Database was established containing clinical and pathological parameters. For autopsy cases, the following variables were recorded: sex, age, number of hospitalization days, admission diagnosis, comorbidities, cause of death, post-mortem interval, general autopsy findings, and macro- and microscopic brain pathology diagnoses. For biopsy samples, we recorded: sex, age, biopsy site, and microscopic and molecular genetic diagnoses. Based on the recorded parameters and their temporal changes, retrospective statistical analyses were performed. Formalin-fixed brain samples and FFPE blocks were available from 2425 deceased individuals, and nerve/muscle samples from 257 patients. The brain samples originate from the period between 1990 and 2012. The most frequent admission diagnoses included ischemic stroke (n = 1070), hemorrhagic stroke (n = 462), subarachnoid hemorrhage (n = 102), epilepsy (n = 103), brain metastasis (n = 70), primary brain tumor (n = 60), parkinsonism (n = 28), dementia (n = 21), and amyotrophic lateral sclerosis (n = 21). Prevalence of hypertension (67.6%) and diabetes mellitus (20.1%) showed a significant increase over time (p < 0.001), whereas the prevalence of malignancies, dementia, parkinsonism, and psychiatric disorders remained stable. Our tissue bank represents the largest nervous system collection in Hungary, providing well-characterized brain, muscle, and nerve samples linked to nearly three decades of clinical data. Samples are made available to researchers.}, } @article {pmid42684942, year = {2026}, author = {Huang, D and Zhang, Z and Gong, X}, title = {Context-dependent roles of osteopontin in aging-related neurological disorders.}, journal = {The Journal of international medical research}, volume = {54}, number = {9}, pages = {3000605261476190}, pmid = {42684942}, issn = {1473-2300}, mesh = {Humans ; *Osteopontin/metabolism ; *Aging/pathology/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; Brain/pathology/metabolism ; Alzheimer Disease ; Microglia/metabolism ; }, abstract = {Osteopontin (encoded by secreted phosphoprotein 1) is a multifunctional matricellular phosphoglycoprotein that has emerged as an important mediator in the aging nervous system. During aging, osteopontin interacts with microglial priming, vascular remodeling, myelin repair, and innate immune responses and is consistently implicated in major late-life neurological disorders. However, its biological effects are highly context dependent. Depending on its cellular source, proteolytic processing, receptor interactions, anatomical distribution, and disease stage, osteopontin may either exacerbate chronic neuroinflammation and tissue injury or promote phagocytic clearance, neuronal survival, remyelination, neuroplasticity, and tissue repair. This review critically synthesizes studies indexed in PubMed and Google Scholar through 3 April 2026 on the role of osteopontin in brain aging, Alzheimer's disease and related dementias, Parkinson's disease and Lewy body disorders, cerebrovascular disease, vascular cognitive impairment, cerebral small vessel disease, and amyotrophic lateral sclerosis. In Alzheimer's disease, cerebrospinal fluid and plasma osteopontin concentrations increase from the prodromal to symptomatic stages, whereas microglial or perivascular secreted phosphoprotein 1 expression correlates with amyloid pathology, synaptic remodeling, and cognitive decline. However, under specific conditions, osteopontin also enhances macrophage-mediated amyloid-beta clearance. In stroke, elevated circulating osteopontin predicts poor clinical outcomes, whereas experimental studies demonstrate that appropriately timed exogenous osteopontin, regulatory T cell-derived osteopontin, and osteopontin-mediated autophagic and reparative pathways promote white-matter repair, peri-infarct plasticity, and blood-brain barrier integrity. Evidence from Parkinson's disease, Lewy body disease, frontotemporal dementia, and amyotrophic lateral sclerosis further supports the role of osteopontin as both a candidate biomarker and a regulator of selective neuronal vulnerability. Rather than being uniformly detrimental or protective, osteopontin should be regarded as a context-dependent regulator of age-related neuroimmune remodeling. This perspective reconciles seemingly conflicting findings and supports the development of therapeutic strategies that are tailored to disease stage, protein fragment, and cell type rather than broadly targeting osteopontin.}, } @article {pmid42685299, year = {2026}, author = {Benatar, M and Rothstein, JD and Snow, K and Sethi, N and Taylor, DM and Dave, KD and McDermott, CJ and Cochrane, TI}, title = {Repairing the Amyotrophic Lateral Sclerosis Trial Credibility Gap.}, journal = {Neurology}, volume = {107}, number = {7}, pages = {e218471}, pmid = {42685299}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Clinical Trials as Topic/standards ; *Research Design/standards ; }, abstract = {There is a long history of early- and mid-phase amyotrophic lateral sclerosis (ALS) clinical trial data being used to make claims of clinical benefit that fail to translate into successful phase 3 outcomes. It is suggested that fallacious scientific reasoning is being encouraged by perverse incentives arising from a "clinical trial industrial complex" that greatly influences trial design, data interpretation, and results communication. Recurring fallacies include false premises underlying outcome comparisons, misuse and incorrect interpretation of biomarkers, mismatches between study design and stated objectives, selective reporting of outcomes, over-reliance on post hoc analyses and open-label extension data, and overly optimistic framing of inconclusive data. We argue that these practices, reinforced by misaligned incentives across industry and academia, lead to premature claims of therapeutic promise and tangible harm to patients. To address the resulting ALS clinical trial credibility gap, we call for rigorous adherence to established standards for reporting clinical trial results, clearer distinction between hypothesis generation and hypothesis testing, more measured description of trial results, and more disciplined triage of phase 2 programs. A cultural shift toward scientific skepticism and methodological rigor is essential to accelerate the development of genuinely effective ALS therapies.}, } @article {pmid42685382, year = {2026}, author = {Ni, CC and Yu, CS and Wei, SY and Dai, JZ and Chang, CL and Ting, HC and Chang, CY and Chen, YC}, title = {UV-programmed gelatin methacryloyl hydrogel microenvironments reveal a bell-shaped vascularization window and enable compartmentalized neuromuscular disease modeling.}, journal = {Biomaterials}, volume = {338}, number = {Pt A}, pages = {124588}, doi = {10.1016/j.biomaterials.2026.124588}, pmid = {42685382}, issn = {1878-5905}, abstract = {Matrix mechanics and microarchitecture jointly regulate tissue morphogenesis and functional maturation; however, defining their combined effects remains challenging when microenvironmental tuning requires changes in material composition. Here, we establish a UV-programmable gelatin methacryloyl (GelMA) hydrogel system in which ultraviolet exposure coordinates changes in construct architecture, pore morphology, and apparent mechanical properties within a constant material formulation. This framework enables systematic mapping of biological responses to UV-programmed architectural-mechanical microenvironments without compositional confounders. In vivo subcutaneous implantation reveals a nonlinear, bell-shaped vascularization response to UV-programmed GelMA hydrogel properties, identifying a narrow microenvironmental window that supports blood-containing vessel formation, human-derived vascular structures, and host-perfused vascular integration. For neuromuscular modeling, a structurally stable UV-defined regime was selected to support long-term compartmentalized co-culture of human induced pluripotent stem cell-derived myoblasts and motor neuron spheroids. Within this same UV-defined compartmentalized neuromuscular microenvironment, amyotrophic lateral sclerosis (ALS)-derived constructs exhibit impaired myogenic maturation, reduced neuromuscular junction (NMJ)-like structural organization, and altered contractile responsiveness compared with gene-corrected Healthy controls. Pharmacological treatment with the FDA-approved drug Riluzole partially restores these disease-associated phenotypes. Together, these findings establish UV-programmed GelMA hydrogels as an adaptable architectural-mechanical platform for identifying vascularization-permissive microenvironments and supporting compartmentalized neuromuscular disease modeling.}, } @article {pmid42685551, year = {2026}, author = {Kashif, M and Keating, ME and Byrne, HJ}, title = {Approaches to data mining reaction kinetics using Raman spectroscopic analysis of Claisen-Schmidt condensation as a model.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {365}, number = {}, pages = {128685}, doi = {10.1016/j.saa.2026.128685}, pmid = {42685551}, issn = {1873-3557}, abstract = {Raman spectroscopy provides a powerful, non-destructive tool for real-time monitoring of multicomponent kinetics. However, extraction of reliable kinetic information from kinetically evolving Raman data can be challenging, due to the degree of spectral overlap of constituent signatures, rank deficiency, and rotational ambiguity. In this work, as a model reaction, solvent-free, base-catalysed Claisen-Schmidt condensation between benzaldehyde and acetone at room temperature was monitored using Raman microspectroscopy, in-situ, over a timescale of 1000 min. The resulting multicomponent dataset was analysed using problem-based nonlinear least squares (NLS) fitting of the weighted sums of the spectra of the reaction components, and multivariate curve resolution-alternating least squares (MCR-ALS) analysis. Three and four-components models were explored within the NLS framework, while a mechanistically constrained model (A + B → C, C + A → D) was implemented for MCR-ALS hard modelling. Conventional soft and hard MCR-ALS approaches failed to identify the correct reaction components and resolve chemically meaningful profiles, whereas seeded MCR-ALS, with 10,000× optimized seed weightings, successfully overcame these failings and yielded physically consistent spectra and concentration profiles. Reaction kinetics were evaluated by fitting the resolved concentration profiles to a kinetic model (A → C → D). The seeded MCR-ALS approach provided the most reliable kinetic description, while, in comparison, NLS based approaches using resolved and pure components spectra exhibited lower fitting accuracy. Quantitatively, the seeded MCR-ALS model showed superior performance, co-efficient of determination (R[2]) = 0.935, residual sum of squares (RSS) = 0.156, relative residual error (RRE) = 0.70% relative to NLS using resolved spectra (R[2] = 0.782, RSS = 0.524, RRE = 2.34%) and NLS using pure spectra (R[2] = 0.783, RSS = 0.408, RRE = 2.33%). These results demonstrate that seeded MCR-ALS, combined with constrained exponential kinetic modelling provides a robust and physically consistent framework for resolving spectroscopic data and extracting reliable mechanistic and kinetic insights. The proposed methodology is broadly applicable to complex multicomponent systems, including metabolomics, process analytics, and pharma kinetics, in which severe spectral overlap and rank deficiency limit conventional analytical approaches.}, } @article {pmid42685707, year = {2026}, author = {Metelmann, C and Gräsner, JT and Jacobsen, N and Neuenfeldt, FJ}, title = {[European Resuscitation Council Guidelines 2025: Basic and Advanced Life Support].}, journal = {Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS}, volume = {61}, number = {9}, pages = {531-547}, doi = {10.1055/a-2931-2870}, pmid = {42685707}, issn = {1439-1074}, mesh = {Humans ; *Cardiopulmonary Resuscitation/standards/methods ; Europe ; *Advanced Cardiac Life Support/standards ; Heart Arrest/therapy ; *Practice Guidelines as Topic ; Emergency Medical Services/standards ; }, abstract = {The 2025 European Resuscitation Council (ERC) guidelines introduce updated recommendations for adult Basic Life Support (BLS) and Advanced Life Support (ALS), with a strong focus on early recognition, high-quality cardiopulmonary resuscitation (CPR), timely defibrillation, and physiologically guided resuscitation. This article summarizes the most relevant changes and practical implications for healthcare professionals and bystander.}, } @article {pmid42686219, year = {2026}, author = {Liu, J and Lin, J and Liu, H and Soh, K and Ju, Q and Soh, K and Dong, X}, title = {Efficacy of Antimicrobial Lock Solutions on Central Line-Associated Bloodstream Infection and Catheter Survival in Hemodialysis Patients: A Systematic Review and Meta-Analysis.}, journal = {Seminars in dialysis}, volume = {}, number = {}, pages = {}, doi = {10.1111/sdi.70046}, pmid = {42686219}, issn = {1525-139X}, support = {202301A014//Chengde Science and Technology Program/ ; GJXH2021-126//Hebei Higher Education Association "14th Five-Year Plan" Research Project/ ; H2026406068//Hebei Natural Science Foundation/ ; 202307//Chengde Medical university Project/ ; 202404//Chengde Medical university Project/ ; }, abstract = {Hemodialysis (HD) catheters carry a high risk of life-threatening bloodstream infections and failure. Antimicrobial lock solutions (ALS) are used to reduce this risk, but their overall efficacy on key outcomes like infection rates and catheter survival requires comprehensive evaluation. This systematic review and meta-analysis assess the impact of ALS on preventing catheter-related bloodstream infections (including incidence and density) and on improving catheter survival. A systematic search was conducted across the databases of PubMed, Embase, Scopus, Cochrane Library, and Google Scholar. A meta-analysis was conducted using STATA software. A total of 1183 studies were screened based on title and abstract, and further 282 studies were evaluated in full text. Eventually, 14 studies with 15 treatment arms were included. Key outcomes including central line-associated bloodstream infection (CLABSI), exit infection, and catheter-free survival were conducted separately. ALS demonstrated statistically significant benefits on CLABSI infection and catheter-free survival compared to nonantimicrobial solutions, showing a reduction in CLABSI density with a pooled log odd ratio (logOR) of -1.29 (95% CI: -1.59 to -0.99), lower CLABSI rates (pooled logOR = -1.50, 95% CI: -1.85 to -1.15), and improved catheter-free survival with log hazard ratio (logHR) of -1.11 (95% CI: -1.41 to -0.8). Consistent treatment effects were observed across all lock types with no significant heterogeneity detected. ALS demonstrate statistically significant and clinically important efficacy in reducing CLABSI incidence and density while improving catheter survival in HD patients, establishing them as an essential preventive strategy in clinical practice.}, } @article {pmid42687189, year = {2026}, author = {Keritam, O and Bormann, D and Haimberger, F and Gharib, D and Sener, M and Gruber, F and Antoniewicz, L and Fedak, I and Renner, A and Fasching, B and Ullrich, S and Paternostro, R and Dolak, W and Masel, EK and Schuhfried, O and Rath, J and Zulehner, G and Krenn, M and Zimprich, F and Cetin, H}, title = {Implementation of specialised care improves survival in patients with amyotrophic lateral sclerosis.}, journal = {Neurological research and practice}, volume = {8}, number = {1}, pages = {}, pmid = {42687189}, issn = {2524-3489}, abstract = {OBJECTIVE: Access to multidisciplinary care influences survival in patients with amyotrophic lateral sclerosis (pwALS). However, real-world data comparing structured specialised care with general neurological management remain limited. We aimed to assess the influence of implementing a specialised outpatient clinic on survival in pwALS.

METHODS: This retrospective cohort study included pwALS meeting the Gold Coast criteria who were treated at the Department of Neurology of the Medical University of Vienna between January 2009 and July 2023. Demographic and clinical parameters and survival data were obtained from the local ALS registry, the Austrian Federation of Social Insurance databases, and the national mortality database of Statistik Austria. Data were censored in December 2024. Outcomes were compared between patients managed before (general care cohort) and after the establishment of a specialised ALS outpatient clinic in 2018 (specialised care cohort).

RESULTS: A total of 242 pwALS were included (47.5% female), of whom 43.8% received general neurological care and 56.2% specialised care. Spinal onset ALS was observed in 65.1% and 70.6%, respectively. Baseline demographic and clinical characteristics were comparable between both cohorts. Median survival time was 27.0 months (95% CI 23.0-35.0) in the general care cohort and 40.0 months (95% CI 32.0-47.0) in specialised care cohort (p = 0.0173). This survival difference was driven by patients with spinal onset ALS, whereas no benefit was observed in those with bulbar onset disease.

CONCLUSIONS: Specialised care was associated with improved survival in this real-world ALS cohort, likely reflecting the cumulative effect of coordinated multidisciplinary management rather than individual interventions.}, } @article {pmid42688548, year = {2026}, author = {Hassell, LA and Gallati, M and Thoma, M and Asfaw, S and Hart, AC}, title = {Glutamatergic neuron degeneration in C. elegans models of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.}, journal = {microPublication biology}, volume = {2026}, number = {}, pages = {}, pmid = {42688548}, issn = {2578-9430}, support = {P40 OD010440/OD/NIH HHS/United States ; R21 NS116254/NS/NINDS NIH HHS/United States ; T32 GM149433/GM/NIGMS NIH HHS/United States ; T32 MH020068/MH/NIMH NIH HHS/United States ; }, abstract = {Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) overlap considerably in genetic origin and pathology. Multiple C. elegans models of ALS/FTD have been developed, but the integrity of glutamatergic neurons in these models has not been thoroughly evaluated. Here, we report degeneration of glutamatergic phasmid neurons in animals expressing either wild-type or disease variant V337M human tau, and mild degeneration in animals expressing disease variant M337V human TDP-43. Defects caused by ectopic expression of tau were suppressed by loss of the known modifier, spop-1 , suggesting that SPOP-1-dependent pathways are also involved in glutamatergic neuron degeneration.}, } @article {pmid42688563, year = {2026}, author = {Gao, X and Wang, T and Chen, S and Ma, Y and Wei, Q and Li, C and Shang, H and Chen, X}, title = {Amyotrophic lateral sclerosis -plus patient with an intermediate-length CACNA1A allele: a Case Report.}, journal = {Frontiers in genetics}, volume = {17}, number = {}, pages = {1860828}, pmid = {42688563}, issn = {1664-8021}, abstract = {Amyotrophic lateral sclerosis (ALS), the most common type of motor neuron disease, primarily manifests as progressive weakness, atrophy, fasciculations, bulbar palsy, and pyramidal tract symptoms. Accumulating evidence indicates that the pathological spectrum of ALS extends beyond the pyramidal and neuromuscular motor systems, involving additional brain regions, manifesting as ALS-plus syndrome. We present a case of an elderly woman with bulbar-onset ALS accompanied by cerebellar manifestations and an intermediate-length CACNA1A allele. Based on the Gold Coast criteria, ALS diagnosis was made. Notably, the patient exhibited cognitive impairment and a positive Romberg sign, suggesting a broader phenotypic spectrum. Genetic analysis showed a CAG repeat genotype of 10/20 in the CACNA1A gene. The patient's son carried a 14/20 genotype and displayed isolated cerebellar ataxia without motor neuron features. We reviewed the literature on spinocerebellar ataxia (SCA) co-occurring with motor neuron disease and discussed the uncertain significance of the intermediate-length CACNA1A allele in this context, weighing coincidental co-occurrence against a potential causal link. To our knowledge, this case is the first reported instance of an intermediate-length CACNA1A allele co-occurring with ALS in Chinese population, although the association between the allele and ALS remains unclear.}, } @article {pmid42689185, year = {2026}, author = {Sun, L and Yu, X and Yin, H and Bi, J and Lou, H and Pei, H}, title = {A recent review on ginseng's effects on neurodegenerative diseases: active ingredients, mechanisms of action, applications, and delivery strategies.}, journal = {Frontiers in nutrition}, volume = {13}, number = {}, pages = {1912520}, pmid = {42689185}, issn = {2296-861X}, abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) pose a major health challenge due to their high prevalence and the lack of effective treatments; ginseng, as medicine and food homology, has potential neuroprotective effects.

METHODS: This article provides a systematic review of research conducted over the past five years on the use of ginseng to treat NDDs, summarizing and analyzing the findings in four key areas: active components, mechanisms of action, clinical applications, and novel delivery strategies.

RESULTS: Ginsenosides are the core active ingredients in ginseng, while polysaccharides, essential oils, and peptides also exert synergistic effects through various pathways; their mechanisms of action include regulating Aβ/tau protein aggregation, inhibiting microglial activation, reducing glutamate excitotoxicity, and restoring mitochondrial function and antioxidant balance. In models of AD, PD, HD, and ALS, ginseng's active components have been shown to improve both behavioral and pathological indicators, while novel delivery strategies (nanoparticles, exosomes, and engineered cellular carriers) can significantly enhance blood-brain barrier permeability and brain-targeting efficiency.

CONCLUSION: Ginseng exhibits protective effects against NDDs through multiple mechanisms of action. However, current evidence is largely limited to preclinical studies, and future efforts should focus on advancing the clinical translation of safe and effective brain-targeted delivery systems.}, } @article {pmid42690718, year = {2026}, author = {Nam, MK and Oh, Y and Choi, Y and Lee, J and Jeong, GH and Park, S and Yoo, SA and Kim, M and Kang, S and Rhim, H}, title = {Mechanistic Characterization of NABi as a Selective Inhibitor of SOD1G93A Aggregation: Structural Basis and Therapeutic Implications for ALS.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {17}, pages = {3156-3168}, doi = {10.1021/acschemneuro.5c00977}, pmid = {42690718}, issn = {1948-7193}, support = {RS-2022-NR070495//National Research Foundation of Korea/ ; RS-2026-25504267//National Research Foundation of Korea/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; *Superoxide Dismutase-1/metabolism/genetics ; Humans ; Animals ; Mutation ; *Superoxide Dismutase/metabolism/genetics ; Protein Aggregates/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, with familial ALS (fALS) frequently caused by mutations in Cu/Zn superoxide dismutase (SOD1). The G93A mutation, one of the most aggressive forms, promotes the formation of cytotoxic protein aggregates through cross-β-sheet structures, leading to neuronal dysfunction and death. In this study, we investigated the therapeutic potential of NABi (natural Aβ binder and Aβ-aggregation inhibitor), a stable small engineered protein composed of the N-terminal 90 amino acids of SOD1, originally developed to target amyloid-β aggregation in Alzheimer's disease. Given the shared β-sheet-rich aggregation mechanisms between amyloid-β and mutant SOD1 proteins, we hypothesized that NABi could serve as a dual-action therapeutic for both diseases. Through an integrated approach involving structural, biochemical, and cellular analyses, we demonstrate that NABi exhibits a 4-fold greater binding affinity for SOD1G93A compared to SOD1WT, selectively targeting the mutant protein via specific hydrophobic interactions. Structural modeling using AlphaFold2 reveals that the G93A mutation exposes hydrophobic residues that create an optimal binding interface for NABi. Functionally, NABi effectively inhibits SOD1G93A aggregation, as demonstrated by filter trap assays and immunofluorescence microscopy, while maintaining the protein in a soluble, nontoxic state. Importantly, coexpression of NABi reduces SOD1G93A-induced cytotoxicity by approximately 4-fold, significantly enhancing neuronal survival. These findings establish NABi as a promising therapeutic candidate for SOD1G93A-associated familial ALS, demonstrating its capacity to selectively target pathological protein conformations while preserving normal cellular function. Our results support the development of NABi as an innovative pan-therapeutic approach targeting shared aggregation pathways across multiple neurodegenerative diseases.}, } @article {pmid42691539, year = {2026}, author = {Hsu, EC and Carder, P and Smith, L and Zhou, ZE and Yakusheva, O and Beeber, A and Jutkowitz, E and Thomas, KS}, title = {A Profile of Assisted Living Direct Care Workforce Training Requirements Across the United States.}, journal = {Journal of the American Medical Directors Association}, volume = {27}, number = {10}, pages = {106445}, pmid = {42691539}, issn = {1538-9375}, support = {R01 AG082308/AG/NIA NIH HHS/United States ; RF1 AG082308/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVES: To characterize assisted living (AL) direct care worker (DCW) training requirements across the United States and how these regulations have changed over time. Specifically, we examine state-level profiles of training regulations, including duration, frequency, content, source of materials, evaluation, and changes in regulatory coverage.

DESIGN: Cross-sectional and longitudinal descriptive study using state policy data and AL directories from 2019, 2021, and 2023.

SETTING AND PARTICIPANTS: All US states' AL training-related regulations; all ALs and AL beds governed by those regulations.

METHODS: We used a mixed-methods approach with an explanatory sequential design (QUAN → qual), first conducting health services regulatory analysis followed by qualitative content analysis.

RESULTS: In 2023, 43 states (90% of ALs, nationally) required DCW training, 29 states required annual training frequency, 28 states specified training hours (median 10 hours), 28 required dementia-specific content, and 29 required training to cover at least 5 topics when onboarding. Common training topics included resident rights, emergency response, infection control, and personal care; dementia-specific training topics included Alzheimer's disease, behavior, communication, and dignity of residents, with only 2 states requiring training that addressed DCWs' well-being. Ten states mandated use of professionally designed courses, and 5 states required DCWs to complete an exam. From 2019 to 2023, 6 states made changes to the scope of dementia-specific training.

CONCLUSIONS AND IMPLICATIONS: While most states mandate DCW training and over half require annual frequency, duration, and cover 5 topic areas, few states specify sources of training materials or require competency checks. Lack of specificity in training requirements requires AL operators to determine what constitutes adequate training for DCWs to be successful. To better prepare the AL workforce for growing resident complexity, policymakers should consider promoting specific training requirements that ensure both onboarding and continuous education for DCWs, particularly around dementia care and workforce well-being.}, } @article {pmid42693185, year = {2026}, author = {Dalakas, MC and Lünemann, JD}, title = {Role of complement and complement-targeted therapeutics in neurological diseases.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {42693185}, issn = {1759-4766}, abstract = {Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains primarily focused on diseases with complement-fixing pathogenic antibodies (such as myasthenia gravis and neuromyelitis optica spectrum disorder), a robust pipeline of emerging treatments holds promise for expanding complement-targeted therapies to a broader spectrum of autoimmune neurological diseases, such as multiple sclerosis and even neurodegenerative diseases such as Alzheimer disease or amyotrophic lateral sclerosis. This Review presents insights into complement biology as it relates to the development or initiation of autoimmune and possibly degenerative diseases affecting the central and peripheral nervous systems or muscle. The effects, merits, risks and challenges of marketed drugs or biologic agents in ongoing phase I-III clinical trials engineered to inhibit proximal or distal components of the complement cascade are also discussed. Anti-complement therapeutics are destined to change the treatment of autoimmune neurologic conditions in which the therapeutic landscape is now becoming crowded with biologic agents targeting other key autoimmunity factors.}, } @article {pmid42693862, year = {2026}, author = {Ardakani, RH and Dashtaki, M and Mohamadi-Zarch, SM and Bagheri, SM}, title = {Cortisol Dysregulation as a Major Factor in the Development of Neurodegenerative Diseases, Drug Targets and Therapeutic Prospects: A Comprehensive Review.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273466502260813092749}, pmid = {42693862}, issn = {1996-3181}, abstract = {Cortisol, regulated by the hypothalamic-pituitary-adrenal (HPA) axis, is critical for stress response, metabolism, and immune function. Its dysregulation is increasingly implicated in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). This review synthesizes evidence on cortisol's role in neurodegenerative disorders, exploring its mechanisms, clinical implications, and therapeutic potential. This study analyzed preclinical models, clinical studies, and biomarker data to elucidate cortisol's impact on neurodegeneration. Key mechanisms include glucocorticoid and mineralocorticoid receptor-mediated effects on synaptic plasticity, neuroinflammation, and oxidative stress. In AD, elevated cortisol accelerates cognitive decline, hippocampal atrophy, and amyloid-β accumulation. In PD, higher cortisol levels correlate with gait dysfunction and dopaminergic neuron loss. HD shows variable cortisol profiles, with early hypocortisolism shifting to hypercortisolism in later stages, linked to depression. In ALS, elevated cortisol hastens disease progression and neuroinflammation. In MS, HPA axis hyperactivity is associated with cognitive deficits and lesion activity, though it may support remyelination. Chronic stress exacerbates these effects across disorders, promoting neuronal vulnerability. Cortisol dysregulation is a significant contributor to neurodegenerative pathology, acting as both a biomarker and therapeutic target. Emerging interventions, including glucocorticoid receptor antagonists, cortisol synthesis inhibitors, and stress reduction strategies, show promise in mitigating neuronal damage. Personalized, stage-specific therapies and longitudinal studies are needed to optimize cortisol-targeted treatments for neurodegenerative diseases.}, } @article {pmid42694267, year = {2026}, author = {Heffernan, ÁB and Do, F and Carter, E and Al-Tameemi, F and Selvaraj, BT and Stavrou, M}, title = {Disrupted astrocyte-neuron metabolic coupling in amyotrophic lateral sclerosis.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1899307}, pmid = {42694267}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by progressive loss of motor neurons. In addition to neurodegeneration, ALS is increasingly recognised as a disorder associated with widespread metabolic dysfunction, including hypermetabolism, weight loss, and dyslipidaemia, all of which correlate with disease progression and survival. Astrocytes play a central role in maintaining metabolic homeostasis in the central nervous system by supporting neuronal energy demands, regulating glutamate levels, buffering oxidative stress, and maintaining lipid balance. Emerging evidence suggests that disruption of these supportive astrocytic functions may contribute directly to motor neuron vulnerability in ALS. In this mini-review, we discuss how alterations in astrocyte metabolism may impair astrocyte-neuron metabolic coupling in ALS. We summarise work from human studies and experimental models demonstrating abnormalities in astrocytic glycolysis, mitochondrial function, lactate shuttling, lipid metabolism, and glutamate homeostasis. We highlight growing evidence implicating mitochondrial dysfunction and impaired lipid handling in astrocytes as important contributors to disease progression. We explore how these changes may deprive motor neurons of metabolic and antioxidant support while also promoting excitotoxicity, oxidative stress, and lipotoxicity. We also discuss how recent advances in human induced pluripotent stem cell models, metabolomics, and single-cell transcriptomics are improving our understanding of astrocyte dysfunction in ALS. Finally, we consider current and emerging therapeutic strategies aimed at restoring astrocytic metabolic function. Together, these findings support the idea that progressive failure of astrocyte-mediated metabolic support is an important component of ALS pathogenesis and may represent a promising therapeutic target.}, } @article {pmid42694478, year = {2026}, author = {Cui, Q and Zheng, K and Liu, Q and Wang, L and Liu, Y and Bai, R and Zhang, W and Guo, J and Chang, X and Wang, J}, title = {From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1921079}, pmid = {42694478}, issn = {1662-5099}, abstract = {Microglia are brain-resident myeloid cells that maintain central nervous system homeostasis and respond dynamically to neuronal injury, protein aggregation, and alterations in the local metabolic environment. Single-cell and single-nucleus studies demonstrate that microglial responses in neurodegenerative diseases are highly heterogeneous and cannot be adequately explained by the classical M1/M2 polarization model. Increasing evidence further indicates that metabolic remodeling is not merely a consequence of activation but a determinant of microglial migration, phagocytosis, inflammatory signaling, redox balance, organelle function, and interactions with surrounding neural cells. In this review, we propose a microglial immunometabolic trajectory framework in which metabolic states are viewed as branching and potentially reversible determinants of cellular function rather than fixed stages of a universal disease pathway. We summarize how glucose metabolism, mitochondrial function, lipid metabolism, amino acid metabolism, lysosomal activity, and redox regulation shape microglial plasticity. We further examine relationships among transcriptionally defined states, including disease-associated microglia, microglia associated with neurodegeneration, lipid-droplet-accumulating microglia, and other disease-enriched populations, while emphasizing that transcriptional similarity does not necessarily imply metabolic function or lineage progression. Comparative evidence from Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis indicates that common metabolic regulators, including HIF-1α, mTOR, PKM2, TREM2, APOE, and NLRP3, exert disease-specific effects with unequal mechanistic support. We further distinguish associative metabolic signatures from intervention-based causal evidence and discuss limitations of animal models, immortalized cell lines, postmortem tissue, and induced pluripotent stem cell-derived microglia. Finally, we highlight the need for cell-specific, state-resolved, and temporally precise metabolic interventions that restore defined microglial functions without compromising physiological immune surveillance.}, } @article {pmid42694654, year = {2026}, author = {Wu, Y and Duan, L and Zhang, L and Wang, S and Yan, H and He, M and Wang, T and Li, L and Gao, Y}, title = {TREM2 as a central hub of neuroimmune-metabolic crosstalk in central nervous system disorders: from microglial biology to therapeutic targeting.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1912989}, pmid = {42694654}, issn = {1664-3224}, mesh = {Humans ; *Microglia/metabolism/immunology ; *Receptors, Immunologic/metabolism/genetics/immunology ; *Membrane Glycoproteins/metabolism/genetics/immunology ; Animals ; *Central Nervous System Diseases/metabolism/immunology/therapy ; Signal Transduction ; *Neuroimmunomodulation ; }, abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-enriched immunoreceptor that functions as a central regulator of microglial adaptation by integrating immune surveillance, lipid sensing, metabolic reprogramming, and phagocytic responses in the central nervous system (CNS). Through association with the adaptor protein DAP12, TREM2 activates interconnected signaling networks involving the SYK pathway, PLCγ2-mediated Ca[2+] signaling, PI3K-AKT-mTOR signaling, NF-κB activation and inflammatory regulatory pathways, thereby shaping microglial survival, migration, clearance capacity, and interactions with surrounding neural and immune cells. Increasing evidence from genetic studies, single-cell transcriptomics, spatial analyses, and human-derived microglial models indicates that TREM2 dysfunction contributes to diverse CNS disorders; however, its biological consequences are highly dependent on disease stage, pathological substrate, cellular context, and microenvironmental cues. In Alzheimer's disease, TREM2 regulates amyloid-β-associated microglial responses, lipid metabolism, and synaptic remodeling, while its effects on tau-driven neurodegeneration remain controversial. In Parkinson's disease, stroke, epilepsy, and amyotrophic lateral sclerosis, TREM2 influences α-Syn clearance, inflammatory resolution, tissue repair, and microglial state transitions, but may exert beneficial or maladaptive effects depending on temporal dynamics and disease-specific stressors. Emerging clinical evidence, including TREM2 variants, soluble TREM2 (sTREM2) biomarkers, and human multi-omics studies, highlights both the translational potential and complexity of targeting this pathway. Herein, this review summarizes the molecular mechanisms, physiological functions, and disease-specific roles of TREM2 in CNS disorders, critically discusses unresolved controversies and species-specific challenges, and evaluates emerging therapeutic strategies toward biomarker-guided and stage-specific modulation of TREM2 signaling. Understanding how to restore appropriate microglial adaptability rather than simply enhance or suppress TREM2 activity may provide a foundation for precision therapies in CNS disorders.}, } @article {pmid42694829, year = {2026}, author = {Chowdhury, S and Pramanik, S and Bhattacharjee, S and Billah, M}, title = {ALSGate: An Efficient Gated Mixture-of-Experts Model for Reliable ALS Detection Using EMG Signals.}, journal = {Healthcare technology letters}, volume = {13}, number = {1}, pages = {e70097}, pmid = {42694829}, issn = {2053-3713}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, resulting in neuromuscular weakness and paralysis. Electromyography (EMG) is of vital importance for the detection of ALS. In this paper, a refined mixture of experts is proposed that automatically discriminates ALS patients from non-ALS cases using clinical EMG signals from the N2001 EMGLAB open-access dataset. The architecture consists of a 1D convolutional neural network, a temporal convolutional network and a spectrogram-based CNN to collectively learn localised temporal, long-range temporal and spectral features from EMG activity. A gating mechanism dynamically weights expert contributions and performs significantly better than equal-weight fusion. Training with focal loss and exponential moving average stabilisation addresses class imbalance and improves convergence. The proposed approach reached an AUROC of 0.9992, an F1-score of 0.9903 and a balanced accuracy of 0.9905, demonstrating strong discriminative performance and potential for real-time clinical applications.}, } @article {pmid42696048, year = {2026}, author = {de Bertier, S and Amador, MD and Guissart, C and Miki, T and Boillée, S and Lobsiger, CS and Bohl, D and Fauret-Amsellem, AL and Bohic, A and , and Giguet-Valard, AG and Bellance, R and Beauvais, K and Meininger, V and Bruneteau, G and Salachas, F and Vial, C and Camu, W and Esselin, F and de la Cruz, E and Bernard, E and Seilhean, D and Millecamps, S}, title = {Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated gene in French cohorts.}, journal = {Acta neuropathologica}, volume = {152}, number = {1}, pages = {}, pmid = {42696048}, issn = {1432-0533}, support = {EQU202103012581//Fondation Recherche Médicale (FRM, France)/ ; #19466//Association Française contre les Myopathies (AFM, France)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; France ; Female ; Male ; Middle Aged ; Cohort Studies ; Aged ; Adult ; DNA-Binding Proteins/metabolism ; *Genetic Predisposition to Disease ; Mutation/genetics ; Animals ; Brain/pathology ; }, abstract = {ARPP21 has recently emerged as a new amyotrophic lateral sclerosis (ALS) associated gene but its pathogenic role remains unclear. In this study we performed familial, clinical, neuropathological and cellular analyses to characterize the recurrent p.P529L and p.P713L variants (also known as p.P563L variant and p.P747L variant, respectively) in our French ALS cohort of 1190 ALS cases and 50 additional family members available for segregation analysis, resulting in the description of 29 ARPP21-linked patients. ARPP21 emerged as the most frequent rare ALS-associated gene in France after exclusion of the four major ALS genes, accounting for 2.7% of familial cases (fALS) and 0.1% of sporadic cases. Age-dependent penetrance reached 45% by age 50 and increased only modestly thereafter, remaining incomplete even at advanced ages. In cellular models, the p.P713L mutant showed aggregation associated with protein hyperphosphorylation and colocalization with the autophagic marker p62. Neuropathological examination of tissue from a p.P529L carrier revealed typical cytoplasmic TDP-43 pathology, together with heterogeneous ARPP21-positive deposits. As ARPP21 antibody also stained granulovacuolar degenerations, ARPP21-positive deposits may reflect neuronal stress rather than mutant ARPP21-specific pathology. Nevertheless, together with previous studies, our findings support ARPP21 as an important ALS-associated gene, and indicate that both p.P529L/p.P563L and p.P713L/p.P747L should be considered pathogenic ALS-causing variants. Incorporating ARPP21 into the routine genetic testing panels for fALS could improve diagnostic yield.}, } @article {pmid42697152, year = {2026}, author = {Fernández-Beltrán, LC and García-Toledo, I and Javaloyes García, K and Jiménez-Coca, I and Jiménez-Rodríguez, J and Fernández-Bernal, A and Godoy-Corchuelo, JM and Portero-Otín, M and Corrochano, S}, title = {Pharmacological modulation with the LXR agonist T0901317 attenuates motor pathology in the SOD1[G93A] mouse model of ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e01062}, pmid = {42697152}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/genetics/metabolism ; *Hydrocarbons, Fluorinated/pharmacology/therapeutic use ; *Liver X Receptors/agonists/metabolism ; *Sulfonamides/pharmacology/therapeutic use ; Fluorocarbons ; Benzenesulfonamides ; Mice ; Female ; *Superoxide Dismutase-1/genetics ; Disease Models, Animal ; Male ; Mice, Transgenic ; Spinal Cord/drug effects/metabolism/pathology ; Mice, Inbred C57BL ; Humans ; *Motor Neurons/drug effects/pathology/metabolism ; }, abstract = {Dysregulation of cholesterol metabolism and neuroinflammation are critical drivers of Amyotrophic Lateral Sclerosis (ALS) pathology. Liver X receptors (LXRs) are master regulators of cholesterol homeostasis and immune responses. Here, we evaluated the therapeutic potential of chronic pharmacological modulation using the potent synthetic agonist T0901317 (T0) in the hSOD1[G93A] mouse model. To assess both long-term functional outcomes and the underlying molecular mechanisms, T0 was administered via two distinct experimental designs. In a longitudinal cohort treated from postnatal day 60 (P60) until the humane endpoint, T0-treated SOD1G93A mice exhibited delayed body weight loss and sustained improvements in neuromuscular strength and motor coordination. Critically, this continuous treatment preserved functional motor unit connectivity, delayed overall clinical progression, and significantly extended median lifespan. While protective in both sexes, the survival benefit was slightly more pronounced in females. Molecular characterization revealed that the early systemic T0 administration successfully engaged canonical LXR targets in the spinal cord, driving a significant transcriptional upregulation of cholesterol efflux pathways and suppressing pro-inflammatory signaling cascades. This response induced a lipid partitioning, evidenced by a significant accumulation of cholesterol esters within the central nervous system, potentially mitigating lipotoxicity. Taken together, these findings demonstrate that T0901317 treatment exerts a significant beneficial effect, highlighting the pharmacological modulation of these lipid and inflammatory networks as a promising therapeutic strategy for ALS.}, } @article {pmid42697153, year = {2026}, author = {Lo'pez-Blanch, R and Salvador-Palmer, R and Oriol-Caballo, M and Moreno-Murciano, P and Dellinger, RW and Estrela, JM and Obrador, E}, title = {Corrigendum to 'Nicotinamide riboside, pterostilbene and ibudilast protect motor neurons and extend survival in ALS mice'.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e01070}, doi = {10.1016/j.neurot.2026.e01070}, pmid = {42697153}, issn = {1878-7479}, } @article {pmid42697379, year = {2026}, author = {Mohammad, SI and Vasudevan, A and Oriquat, G and Gajjar, TB and Hanumanthayya, M and Shukla, SK and Tailor, NK and Baig, MR and Fadaam, O and Abdul, AS}, title = {Extracellular vesicles in neurodegenerative diseases: A new frontier in diagnosis and therapy.}, journal = {Behavioural brain research}, volume = {516}, number = {}, pages = {116455}, doi = {10.1016/j.bbr.2026.116455}, pmid = {42697379}, issn = {1872-7549}, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the progressive disorders of the nervous system that are characterized by the gradual destruction of neurons, the accumulation of misfolded proteins, and the limited effective therapeutic options. In recent years, numerous lines of evidence have emphasized the important role of extracellular vesicles (EVs) in the formation and progression of these diseases. These vesicles are membrane-bound nanoscale structures that are secreted by almost all cell types and play a role in cell-cell communication through the transfer of molecules such as proteins, lipids, and nucleic acids. In neurodegenerative disorders, EVs can facilitate the transport and dissemination of disease-related proteins, including amyloid-β, tau, α-synuclein, mutant huntingtin, SOD1, and TDP-43, thus contributing to the spread of pathological processes in different parts of the nervous system. On the other hand, the ability of these vesicles to cross the blood-brain barrier and reflect molecular changes occurring in the central nervous system makes them valuable candidates for the development of minimally invasive biomarkers. This review reviews the biogenesis, classification, isolation methods, and molecular content of EVs, and analyzes their role in the pathogenesis, diagnosis, and treatment of the most important neurodegenerative diseases. Also, the importance of EV-associated proteins, RNAs, and lipids as emerging diagnostic biomarkers, as well as the therapeutic potential of natural and engineered vesicles as drug delivery systems and regulators of neuroinflammation and neurodegenerative processes, is discussed.}, } @article {pmid42697520, year = {2026}, author = {Sharma, A and Jatana, N}, title = {Microbiota-derived metabolite-GPCR signalling in neurodegeneration.}, journal = {Neuroscience}, volume = {615}, number = {}, pages = {312-333}, doi = {10.1016/j.neuroscience.2026.09.001}, pmid = {42697520}, issn = {1873-7544}, abstract = {The gut microbiome acts as a primary regulator of host homeostasis, influencing the entire body through bidirectional communication along the gut-brain axis (GBA). Dysbiosis, which is defined as a state of microbial imbalance involving alterations in community composition and function, can disrupt the synthesis of important microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), bile acids and neurotransmitter precursors. This can lead to impaired essential host signalling pathways. There is growing evidence that metabolic alterations associated with dysbiosis contribute to the onset and progression of neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). In this context, G protein-coupled receptors (GPCRs) act as essential molecular transducers that link microbial metabolites to intracellular signalling networks. Aberrant GPCR activation, driven by altered metabolite profiles, modulates key downstream pathways including cAMP, MAPK, PI3K/Akt, NF-κB and Ca2 + signalling. This promotes neuroinflammation, oxidative stress, mitochondrial dysfunction and pathological protein aggregation - hallmark processes underlying neurodegeneration. By identifying convergent and disease-specific signalling pathways, the review highlights mechanistic nodes of therapeutic relevance and discusses GPCR-centric emerging and other microbiome-targeted strategies aimed at restoring metabolic and signalling homeostasis in neurodegenerative disorders.}, } @article {pmid42697669, year = {2026}, author = {Zhang, P and Liu, Y and Tian, X and Wang, H and Liu, R and Wang, G and Wu, Y}, title = {Overexpression of the cytochrome P450 gene CYP99A3 likely mediates mesosulfuron-methyl resistance in Lolium multiflorum from China.}, journal = {Pesticide biochemistry and physiology}, volume = {223}, number = {}, pages = {107300}, doi = {10.1016/j.pestbp.2026.107300}, pmid = {42697669}, issn = {1095-9939}, mesh = {*Lolium/genetics/drug effects/enzymology/metabolism ; *Sulfonylurea Compounds/pharmacology ; *Cytochrome P-450 Enzyme System/genetics/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; China ; *Plant Proteins/genetics/metabolism ; Acetolactate Synthase/genetics ; }, abstract = {Lolium multiflorum L. (Italian ryegrass) is a noxious weed causing severe yield losses in wheat production globally, and its rapid expansion across major wheat-producing regions in China poses an escalating agricultural threat. Recently, field-recommended doses of the acetolactate synthase (ALS) inhibitor mesosulfuron-methyl have failed to effectively control certain L. multiflorum populations. This study evaluated the resistance level and elucidated the underlying mechanisms in a suspected mesosulfuron-methyl-resistant L. multiflorum population (ZMHF-R) collected from China. Whole-plant bioassays demonstrated that the ZMHF-R population exhibited a high level of resistance (43.34-fold) to mesosulfuron-methyl. Replicate sequencing of the ALS gene revealed no known target-site mutations, thereby excluding target-site mutation-mediated resistance. Pretreatment with the cytochrome P450 inhibitors piperonyl butoxide (PBO) and malathion significantly synergized mesosulfuron-methyl toxicity in ZMHF-R, implicating P450 monooxygenases in the resistance phenotype. Comparative RNA-seq and RT-qPCR validation identified the constitutive overexpression of a specific P450 gene, LmCYP99A3, in the R population. Molecular docking simulations predicted favorable binding and potential metabolic activity of the LmCYP99A3 protein toward mesosulfuron-methyl. Furthermore, transgenic rice calli heterologously overexpressing LmCYP99A3 exhibited a distinct resistance phenotype against the herbicide. Taken together, this study functionally validates that LmCYP99A3 mediates mesosulfuron-methyl resistance in L. multiflorum, expanding our understanding of the metabolic basis of NTSR in this global weed species.}, } @article {pmid42698124, year = {2026}, author = {Streicher, NS}, title = {Serum Neurofilament Light Chain and GFAP in Amyotrophic Lateral Sclerosis on a Commercial ECLIA Platform.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70397}, pmid = {42698124}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS), SIMOA-based studies show that baseline serum neurofilament light chain (NfL) predicts the revised ALS Functional Rating Scale (ALSFRS-R) decline rate and survival. The Roche Elecsys electrochemiluminescence immunoassay (ECLIA) reports values approximately six-fold lower; cross-platform comparison confirms comparable performance, but serial clinical-practice data remain limited. We assessed whether ECLIA NfL correlates with the ALSFRS-R decline rate under the sampling conditions of clinical practice, and whether GFAP or S-100B adds prognostic or disease-specific information.

METHODS: We retrospectively analyzed 58 patients with medical-record-confirmed ALS at an academic center (2022-2026). Serum NfL, GFAP, and S-100B were measured on the Roche Elecsys ECLIA. The NfL-ALSFRS-R correlation was assessed within matching windows; serial NfL was examined in patients with repeat draws.

RESULTS: First-per-patient NfL median was 7.06 pg/mL (IQR 4.06-17.30). NfL correlated strongly with the ALSFRS-R decline rate (Spearman r = 0.704, n = 31; r = 0.809 within 90 days, n = 17; both p < 0.0001). Fast progressors had 3.7-fold higher mean NfL than slow progressors (17.10 vs. 4.64 pg/mL). NfL showed no correlation with King's clinical stage (r = 0.00). GFAP correlated with age but not with progression rate or disease duration; S-100B showed no association with progression.

DISCUSSION: Serum NfL on a commercial ECLIA platform retained its strong correlation with progression rate despite unstructured sampling, replicating SIMOA-based findings at platform-specific values. NfL tracked the rate of decline rather than the accumulated disease state; GFAP and S-100B added no prognostic or disease-specific information.}, } @article {pmid42698179, year = {2026}, author = {Dhar, A and Sharar, AD and Papisetty, S and Bydon, M and Moinuddin, FM}, title = {The Therapeutic Potential of Purmorphamine Across Disease Models.}, journal = {Journal of cellular and molecular medicine}, volume = {30}, number = {17}, pages = {e71349}, pmid = {42698179}, issn = {1582-4934}, mesh = {Humans ; Animals ; *Purines/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Hedgehog Proteins/metabolism ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; Morpholines ; }, abstract = {Purmorphamine (PUR) is a trisubstituted purine compound that selectively activates Smoothened receptor, thereby initiating Sonic Hedgehog (Shh) signalling-a pathway critical for embryonic patterning, neuronal specification and tissue regeneration across multiple organ systems. Dysregulation of Shh signalling has been implicated in degenerative diseases yet therapeutic interventions targeting this pathway remain limited. PUR demonstrates broad therapeutic efficacy across diverse preclinical disease models by activating both canonical GLI-mediated transcription and non-canonical Shh pathways, resulting in neuroprotection, reduced neuroinflammation, enhanced blood-brain barrier integrity and tissue regeneration. In contrast to previous assumptions that Shh pathway activation requires endogenous ligand binding, PUR bypasses this requirement through direct Smoothened engagement, offering a pharmacologically tractable approach to pathway modulation. Preclinical studies demonstrate that PUR enhances motor neuron survival in amyotrophic lateral sclerosis models, protects dopaminergic neurons in Parkinson's disease, reverses behavioural abnormalities in autism spectrum disorder, promotes neurovascular repair following stroke, restores myelin integrity in multiple sclerosis models and drives osteogenic differentiation in bone tissue engineering applications. Beyond its established Smoothened agonist activity, recent evidence identifies PUR as a positive allosteric modulator of the secretin receptor, expanding its therapeutic scope to include cardiovascular applications such as hypertension management through enhanced nitric oxide bioavailability.}, } @article {pmid42698276, year = {2026}, author = {Strong, MJ and Donison, N and Al-Chalabi, A and Boeve, B and Finger, EC and Holstege, H and Huey, ED and Lee, EB and Marzi, SJ and McHutchison, C and McMillan, CT and Otto, M and Petrucelli, L and Prudencio, M and Simuni, T and Tartaglia, MC and Turner, MR and Van Damme, P and Wolk, DA}, title = {Progress towards a biotypic biomarker profile for amyotrophic lateral sclerosis-frontotemporal spectrum disorders.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag297}, pmid = {42698276}, issn = {1460-2156}, abstract = {Determining the optimal timing of disease-modifying therapies for neurodegenerative disorders will necessitate identification of when the underlying pathobiological process becomes active, well in advance of the point at which clinical manifestions appear. Phenoconversion, the emergence of clinically manifest syndomes, may be preceded by years to decades of silent pathobiological activity that can only be mapped by an array of biomarkers. ALS and FTD, traditionally identified as distinct clinical syndromes, are increasingly recognized to exist along a spectrum of clinical syndromes with shared genetic risk and shared underlying pathology. This clinicopathological spectrum is underpinned by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) as the common neuropathological hallmark. In contrast, the majority of neuropathologically-defined frontotemporal lobar degeneration (FTLD) is associated with alterations in either TDP-43 metabolism (FTLD-TDP) or of the microtubule associated protein tau (FTLD-tau), with a smaller percentage associated with either autosomal dominant genetic mutations or impairments in the ubiquitin proteasome system. As the field of neurodegenerative disorders increasingly shifts towards the frameworks of a pathobiological definition of disease, there is a growing imperative to develop biomarkers that reflect the varied pathobiologies that underly these disorders, and to determine the sensitivity of such biomarkers to detect the presence of these pathobiologies before phenoconversion. To that end, an international workshop was convened in London, Canada in 2025 to review the evidence for existing or evolving biomarkers suitable for (1) the detection of either ALS or FTD pathobiology prior to phenoconversion and/or (2) predict phenoconversion in at risk individuals. Such biomarkers might be conceptualized as "biotypic biomarkers", capturing their ability to describe an underlying pathophysiology whilst being agnostic to the emergent clinical manifestations. Whereas no single biotypic marker is yet able to predict the emergence of ALS, FTD or their intersection, a multimodal approach to developing a biotypic biomarker profile holds promise for the detection of relevant pathobiological processes. The strength of such an approach would be augmented by also addressing issues of resiliency/susceptibility both in terms of genetic risk susceptibility profiles and developing sensitive biomarkers of genomic and cellular aging. By including such nontraditional markers of disease, a more robust picture of not only the degenerative process but also of those factors that might potentially mitigate or drive a heightened probability of disease can be derived.}, } @article {pmid42698373, year = {2026}, author = {Pan, L and Hou, C and Seitz, C and Ingre, C and Hedman, ÅK and Laffita, J and Vu, TN and Pawitan, Y and Ullgren, A and Yazdani, S and Andersson, J and Joyce, EE and Chourpiliadis, C and Lovik, A and Chen, Y and Lewandowski, SA and Fernandez-Capetillo, O and Barz, M and Samuelsson, K and Press, R and Piehl, F and Graff, C and Mälarstig, A and Fang, F}, title = {Protein Biomarkers in Risk and Prognosis of Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {9}, pages = {e70741}, pmid = {42698373}, issn = {1468-1331}, support = {223077//Åhlen Stiftelse/ ; //Bjorklunds fund/ ; MegaALS, 802091//H2020 European Research Council/ ; //Bruno and Ilse Frick Foundation for Research on ALS/ ; FO2022-0233//Hjärnfonden/ ; 2021-01276//Karolinska Institutet/ ; //Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; F2021-0116//Neuro Sweden/ ; 2023-02428//Swedish Research Council/ ; 2021-02605//Swedish Research Council/ ; FIB-ALS//Fondation Thierry Latran/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/diagnosis ; *Biomarkers/blood/cerebrospinal fluid ; Female ; Prognosis ; Male ; Middle Aged ; Aged ; }, abstract = {BACKGROUND: Plasma and cerebrospinal fluid (CSF) protein biomarkers in amyotrophic lateral sclerosis (ALS) may provide insight into disease mechanisms and yield clinically useful biomarkers.

METHODS: Overall, 363 proteins in plasma and CSF from 198 patients with ALS and 125 matched controls were profiled using Olink assays. Associations with disease status, survival, and functional decline, as well as longitudinal biomarker stability across the disease course were assessed, together with network and enrichment analyses. ALS risk-associated biomarkers were externally validated in the UK Biobank (UKB).

RESULTS: Overall, 125 proteins were significantly associated with at least one outcome (i.e., case status, risk, survival, or functional decline), and 21 were associated with three or more outcomes. NEFL was the most robust biomarker in plasma and CSF, alongside TNFRSF12A in plasma and CSF, EDA2R in plasma, and FABP4 in plasma and CSF. Most biomarkers remained stable longitudinally across the disease course. ALS risk-associated biomarkers were replicated in UKB, in which > 3000 plasma proteins were measured in 52,990 participants, including 298 with ALS. Network and enrichment analyses highlighted their roles in immune response and extracellular-matrix remodeling, and their enrichments in the brain and T-cell subsets. Construction of an ALS risk-prediction model achieved an ROC-AUC of 0.72 in the UKB validation cohort.

CONCLUSIONS: These findings suggest candidate protein biomarkers for ALS risk stratification, early detection, and clinical therapeutic monitoring.}, } @article {pmid42699326, year = {2026}, author = {Wang, J and Kissling, WD}, title = {LiDAR-derived dataset of extracted trees and shrubs from AHN4 airborne laser scanning in the Oostvaardersplassen wetland, the Netherlands.}, journal = {Data in brief}, volume = {68}, number = {}, pages = {113169}, pmid = {42699326}, issn = {2352-3409}, abstract = {This article describes a geospatial dataset of trees and shrubs extracted from the fourth Dutch national airborne laser scanning (ALS) survey (AHN4) covering the Oostvaardersplassen wetland in the Netherlands. The dataset was generated in the context of the MAMBO project, which focuses on automated workflows for deriving habitat condition metrics from LiDAR data for European habitat monitoring. The input data consist of nationally acquired AHN4 point clouds (2020-2022). A dedicated processing workflow was applied to classify and extract woody vegetation points in marsh and reedbed environments, where trees and shrubs co-occur with dense herbaceous vegetation. The workflow includes (i) pre-processing and segmentation of vegetation points, (ii) clustering of tree and shrub points using neighbourhood analysis and voxel-based aggregation, and (iii) delineation of individual woody elements through seed detection and connectivity analysis in three-dimensional space. Accuracy assessments were conducted using manually created ground truth datasets derived from ALS point clouds and by referencing 8 cm resolution aerial imagery for selected validation plots and patches. The dataset includes classified ALS point clouds (LAZ), extracted tree and shrub point clouds (LAZ), derived raster products (GeoTIFF), vector boundary files (ESRI Shapefile), processing scripts, and documentation. The dataset and associated processing workflow, source code, and metadata are publicly available through Zenodo, GitHub, and the LifeWatch Metadata Catalogue. The dataset can be reused for applications such as habitat structure mapping, woody vegetation monitoring in wetlands, LiDAR-based workflow benchmarking, training and validation of classification algorithms, and upscaling of tree extraction approaches to other airborne laser scanning datasets.}, } @article {pmid42701411, year = {2026}, author = {Gonzo, P and Dunkl, S and Gatterbauer, M and Heider, S and Girsa, M and Krammel, M and Schnaubelt, S}, title = {Structured Evaluation and Treatment of cardiac arrest via the ABCDE approach (SETA) - Rethinking high-performance CPR and cause-finding during Advanced Life Support.}, journal = {Resuscitation plus}, volume = {31}, number = {}, pages = {101458}, pmid = {42701411}, issn = {2666-5204}, abstract = {The European Resuscitation Council (ERC) Guidelines 2025 continue to summarize the causes of cardiac arrest that should be sought during advanced life support (ALS) as "4Hs and 4Ts". While well established, this list-based mnemonic does not map onto the airway-breathing-circulation-disability-exposure (ABCDE) sequence that emergency teams use for every other patient assessment, and it excludes causes that are clinically treatable but not classically "reversible" in the prehospital phase. We present SETA (Structured Evaluation and Treatment of cardiac arrest via the ABCDE approach), a concept developed within the Emergency Medical Service Vienna that restructures both cause-finding during cardiopulmonary resuscitation (CPR) and evaluation of high-performance CPR around the ABCDE sequence, embeds protocol-linked actions at each step, and is designed to run within ongoing chest compressions without interrupting them. We outline its rationale, its relationship to existing pit-crew and ABCDE-based resuscitation models, and the prospective evaluation now needed before considered for wider use.}, } @article {pmid42701529, year = {2026}, author = {Kadish, CB and Gage, CB and Powell, JR and Ulintz, AJ and Wang, HE and Gaw, CE and Muller, G and Panchal, AR}, title = {Practice variability of epinephrine administration in pediatric out-of-hospital cardiac arrest in the United States.}, journal = {Resuscitation plus}, volume = {31}, number = {}, pages = {101454}, pmid = {42701529}, issn = {2666-5204}, abstract = {BACKGROUND: Pediatric out-of-hospital cardiac arrests (pOHCA) are low frequency, high acuity events for Emergency Medical Services (EMS). The survival rate is low, with only 10% of children surviving, and few survivors having favorable neurologic outcomes. Optimal prehospital management of pOHCA includes rapid epinephrine administration, yet factors contributing to its administration are not well understood.

OBJECTIVE: Our study objective was to evaluate the frequency of epinephrine administration in pOHCA. Our secondary objective was to characterize the demographic and clinical characteristics associated with epinephrine administration in pediatric OHCA in the United States.

METHODS: In this retrospective, observational study, we analyzed data from the National Emergency Medical Services Information System (NEMSIS) dataset for the year 2021. We identified pediatric patients ages ≥1 day-old to <18 years-old from "9-1-1" activations that were treated by advanced life support (ALS) clinicians. OHCA events were identified by performance of cardiopulmonary resuscitation (CPR) or defibrillation. We used descriptive statistics to evaluate the frequency of epinephrine administration and assess demographic and clinical characteristics in this population. Multivariable logistic regression model was utilized to find characteristics associated with epinephrine administration.

RESULTS: In 2021, 8495 pOHCA events (median [IQR] age: 3.0 [0.3-13.0] years; 58.5% males) were managed by an ALS unit in the United States. Two out of every five (40.2%) pOHCA events did not receive epinephrine. Epinephrine use was more common in younger age groups (1 day-1 year OR, 1.25 [95% CI, 1.07-1.46]; 1-5 years OR, 1.19 [95% CI, 1.00-1.38]; 6-12 years OR, 1.59 [95% CI, 1.24-1.79]; referent: 13-17 years), urban population settings (OR, 2.06 [95% CI: 1.79-2.38]), incidents with scene time >10 min (OR, 1.41, [95% CI, 1.25-1.60]), advanced airway attempt(OR 8.33, [95% CI, 7.33-9.47]), and in those receiving defibrillation (OR 1.95, [95% CI, 1.61-2.37]). Odds of epinephrine administration were lower in public settings (OR 0.55, [95% CI, 0.47-0.65]) and in females (OR 0.83, [95% CI, 0.73-0.93]).

CONCLUSION: Epinephrine is not given in 2 of every 5 pOHCA events. Longer scene time and additional resuscitation interventions were associated with epinephrine administration. The low rate of administration has implications for further research and reforms in the prehospital care of critically ill children.}, } @article {pmid42701881, year = {2026}, author = {Zhu, Y and Zhang, Y and Yan, T and Li, Y and Du, H and Zhang, S and Zhang, T and Zhou, W}, title = {The role of overdose folic acid in promoting neuroinflammation, oxidative stress, and apoptosis in SOD1-G93A mice.}, journal = {Free radical research}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/10715762.2026.2729677}, pmid = {42701881}, issn = {1029-2470}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition that involves the targeted degeneration of motor neurons. The precise pathogenetic mechanisms are still largely unclear. In this study, we utilized the SOD1-G93A mouse model of ALS to investigate the effects of folic acid (FA), an important factor involved in homocysteine metabolism. Our results indicated that a little FA prolonged the lifespan of the SOD1-G93A mice and medium and high-dose FA significantly shortened the lifespan of the SOD1-G93A mice. Furthermore, we observed that an overdose of FA significantly elevated inflammation levels in the cerebellum, as evidenced by increased concentrations of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), cluster of differentiation 68 (CD68), cluster of differentiation 86 (CD86), and monocyte chemoattractant protein-1 (MCP-1), facilitating microglial activation. The low-dose FA effects were the opposite of the overdose FA. Additionally, high-dose FA increased the levels of phosphorylated p65 (p-p65)/p65, thereby promoting the NF-κB signaling pathway. Conversely, high-dose FA inhibited the expression of total superoxide dismutase (T-SOD) while increasing the level of malondialdehyde (MDA) in the cerebellum; these effects were not observed in muscle tissue. Moreover, high-dose FA elevated the levels of Bax2/Bcl-2. Concurrently, high-dose FA induced increased apoptosis in SOD1-G93A mice, as demonstrated by TUNEL staining. Notably, the brain iron content of SOD1-G93A mice remained unchanged following FA treatment. These findings provide evidence that an overdose of FA supplementation may exert pro-inflammatory effects by promoting the NF-κB pathway, oxidative stress, and apoptosis in the context of ALS.}, } @article {pmid42702895, year = {2026}, author = {Uysal, SP and Dudley, KA and Sullivan, S and Brizzi, KT and Burke, KM and Hall, S and Pease, K and Goldstein, JN and Berry, JD and Ho, DT}, title = {Emergencies in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70398}, pmid = {42702895}, issn = {1097-4598}, abstract = {Emergencies are frequent in people living with amyotrophic lateral sclerosis (pALS), especially as the disease progresses, and can necessitate urgent evaluation and intervention. Progressive weakness in ALS inevitably increases fall risk, making discussion of fall prevention strategies integral to caring for pALS. Thromboembolic events and respiratory failure may present insidiously in ALS, requiring a high index of clinical suspicion, and management strategies differ from those for individuals without ALS. Bulbar impairment in ALS can give rise to aspiration, laryngospasm, and malnutrition leading to emergency department (ED) visits, underscoring the need for early consideration of gastrostomy tube placement. PALS face an increased risk of serious infections, making vigilant monitoring for any acute change essential. Tracheostomy and gastrostomy, although life-sustaining measures in ALS, may require ED care when complications arise. Proactive assessment and management are critical to prevent complications related to constipation, urinary dysfunction, cognitive and behavioral issues. Although serious adverse events from ALS treatments are very rare, potential immune-mediated neurologic complications are a consideration with tofersen use. Importantly, ALS emergencies should be viewed as potential indicators of disease progression, prompting timely serious illness discussions and reassessment of goals of care. Anticipation of potential complications and emergencies, combined with an understanding of appropriate evaluation and evidence-based management, constitute critical components of caring for pALS. Early recognition and proactive management of these emergencies can improve safety, reduce avoidable hospitalizations, and support goal-concordant, patient-centered care.}, } @article {pmid42703939, year = {2026}, author = {Sun, J and Vocht, J and Laroy, M and Stam, D and Lien, CH and Lamaire, N and D'Hondt, A and Peeters, R and Sunaert, S and Van Damme, P and Vandenbulcke, M and Van den Stock, J}, title = {Tracking Socio-emotional Brain Changes in Premanifest C9orf72 Repeat Expansion Carriers: A Structural and Functional 2-Year Longitudinal Magnetic Resonance Imaging Study.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78355}, pmid = {42703939}, issn = {1531-8249}, support = {//Foundation Thierry Latran/ ; //Alzheimer Research Foundation/ ; //Sequoia Fund for Research on Ageing and Mental Health/ ; 12AQF24N//FWO-Vlaanderen/ ; G0C0319N//FWO-Vlaanderen/ ; G030025N//FWO-Vlaanderen/ ; G019625N//FWO-Vlaanderen/ ; //KU Leuven,/ ; C24/18/095//KU Leuven Research Council/ ; C24/18/095; IDN/21/010//KU Leuven Research Council/ ; J1990130-233837//King Baudouin Foundation/ ; }, abstract = {OBJECTIVES: The C9orf72 hexanucleotide repeat expansion (C9RE) is the most frequent genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. Although structural alterations have been reported decades before symptom onset, the longitudinal evolution of socioemotional network dysfunction in premanifest C9RE carriers remains poorly understood.

METHODS: In this multimodal 2-year longitudinal study, we examined 21 premanifest C9RE carriers and 24 controls using structural magnetic resonance imaging (MRI), resting-state, and task-based functional MRI (fMRI), and multivariate pattern analysis. Participants completed facial emotion processing tasks during fMRI scanning, alongside behavioral assessments. We assessed regional activation, network connectivity, and voxel-wise structural integrity at baseline and follow up.

RESULTS: At baseline, premanifest C9RE carriers showed reduced emotion recognition efficiency, accompanied by bilateral thalamic atrophy, decreased activation in the anterior and posterior cingulate cortex, and increased activation in the posterior cerebellum, along with altered multivoxel activity patterns in the anterior cingulate and posterior cerebellum. Resting-state fMRI revealed decreased functional connectivity involving the thalamus, anterior, and posterior cingulate cortex. Longitudinal analyses indicated declining emotion-evoked responses in the posterior cingulate cortex and cerebellum, alongside further thalamic volume loss, whereas functional connectivity showed no significant change over time. Despite these progressive neural alterations, behavioral performance remained stable.

INTERPRETATION: Socioemotional circuit dysfunction emerges early in C9RE carriers and progresses over time, preceding overt clinical symptoms. Functional imaging, especially task-based fMRI combined with multivariate pattern analysis, captures early circuit-level alterations that may serve as sensitive biomarkers for premanifest neurodegeneration. ANN NEUROL 2026.}, } @article {pmid42704422, year = {2026}, author = {Demir, BS and Cicek, SO and Houran, MA and Azizoglu, ZB and Asan, M and Bas, H and Cetin, BS and Gumus, H and Erdem, S and Canatan, H and Unal, E and Hsieh, EW and Kısaarslan, AP and Eken, A}, title = {Clinical and immunological characterization of a child with a homozygous TBK1 kinase-domain truncation.}, journal = {Immunologic research}, volume = {74}, number = {1}, pages = {}, pmid = {42704422}, issn = {1559-0755}, support = {TSG-2023-10935 and TYG-2023-13110//Erciyes University Research Council (BAP Grants)/ ; }, mesh = {Child ; Humans ; *Arthritis, Juvenile/genetics/immunology/diagnosis ; Cytokines/metabolism ; *Encephalitis/genetics/immunology ; Homozygote ; Mutation/genetics ; Phosphorylation ; *Protein Serine-Threonine Kinases/genetics/metabolism ; }, abstract = {TBK1 is a serine-tyrosine kinase protein that transmits signals from pattern recognition receptors to the NF-κB pathway leading to production of Type 1 Interferons. Mutations in this protein have been associated with arthritis, vasculitis, herpes simplex encephalitis and amyotrophic lateral sclerosis. In the current study, we characterized the functional consequences of a TBK1-variant bearing a truncation in exon 4 and 5 in a patient with poly arthritis resembling juvenile idiopathic arthritis and necrotizing encephalitis. The truncation was associated with reduced TBK1 protein abundance and altered phosphorylation. The variant was associated with increased basal/and or Poly-I: C induced IL-6, TNFα, IL-1β and IL-18 and type 1 Interferon ex vivo. Our findings expand the phenotypic spectrum of TBK1 loss-of-function variants and may provide insight into the management of immune dysregulation in affected patients.}, } @article {pmid42705992, year = {2026}, author = {Nie, W and Jing, Z and Cheng, L and Li, LL and Bai, Y and Xu, F and Li, S and Lin, L and Dong, X and Yu, L and Cai, L and Pan, B and Han, H and Cheng, H and Wang, X}, title = {ROMO1 loss in cholinergic neurons induces mitochondrial ultrastructural damage and ALS-like neuromuscular degeneration.}, journal = {Science bulletin}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.scib.2026.08.063}, pmid = {42705992}, issn = {2095-9281}, } @article {pmid42706741, year = {2026}, author = {Grouls, A and Ubel, PA and Nguyen, M and Pathapati, N and Doerstling, S and Sloan, CE}, title = {Online Crowdfunding Campaigns for People Living With ALS Demonstrate Financial Burden and Unmet Needs.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70395}, pmid = {42706741}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: People living with amyotrophic lateral sclerosis (ALS; pALS) have extensive care needs, from wheelchairs to feeding tubes to caregiving support. The financial impact of these needs on pALS and their caregivers (cALS) has not been fully explored. We aimed to explore the types of expenses for which pALS and cALS crowdfund, and the financial circumstances that lead them to resort to crowdfunding.

METHODS: We randomly selected 320 ALS-related crowdfunding campaigns posted on the GoFundMe platform from 2010-2020. We conducted a summative content analysis to categorize the expenses for which campaigns requested money and descriptions of financial burden.

RESULTS: We included 266 campaigns. Most campaigns were written by people who were not the pALS or cALS, such as children or coworkers (85.3%). Most campaigns fundraised for medication and treatment costs (21.4%), equipment (25.2%), accessibility needs for home (24.0%), and transportation (19.5%), and in-home caregiving services (18%). Multiple campaigns (22.9%) requested assistance with nonmedical expenses ranging from rent and utilities to personal travel and hobby goals. Many campaign writers (47.7%) described financial burden related to the pALS' diagnosis, including medical debt (4.5%) and job loss of the pALS (30.5%) and/or cALS (6.8%).

DISCUSSION: Our analysis of ALS-related crowdfunding campaigns highlights the breadth of medical and nonmedical care needs and quality of life goals for which people request additional financial support throughout the disease course. These findings provide important insights for ALS care teams into the expenses of pALS.}, } @article {pmid42707250, year = {2026}, author = {Unuakhalu, R and Purcell, A and Jindal, I and Wu, Y and Arnold, M and Dominick, KC and Shillington, A}, title = {The long road to diagnosis: recessive PMPCB deficiency hidden behind a dominant familial VCP defect.}, journal = {Molecular genetics and metabolism reports}, volume = {48}, number = {}, pages = {101350}, pmid = {42707250}, issn = {2214-4269}, abstract = {Multiple mitochondrial dysfunctions syndrome 6 (MMDS6), caused by biallelic likely pathogenic variants in PMPCB, is an extremely rare autosomal recessive childhood-onset neurodegenerative disorder, with only six reported cases to date, most resulting in early mortality. Pathogenic variants in VCP cause multisystem proteinopathy 1 (MSP1), an autosomal dominant adult-onset disorder encompassing inclusion body myopathy (IBM), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), typically presenting in mid-adulthood. We describe a 23-year-old female with two likely pathogenic variants presumed to be in trans in PMPCB and a co-occurring pathogenic VCP variant. She was misdiagnosed for over 20 years with early-onset VCP-related neurodegeneration due to a maternal family history of ALS. Her disease began at birth with microcephaly and progressed throughout childhood, including developmental regression, cerebellar and cerebral atrophy, optic atrophy, seizures, spasticity, dysarthria, and loss of ambulation. Initial genetic testing identified only the familial VCP variant. Updated genomic sequencing at age 23 revealed two likely pathogenic PMPCB variants, strong supporting a diagnosis of MMDS6. Her clinical features closely align with previously reported MMDS6 cases and are inconsistent with the typical adult-onset phenotype of VCP-associated disorders. While she shares overlapping features with VCP-related disease (limb-girdle weakness, spasticity, FTD), the timing and severity of her neurodevelopmental findings support MMDS6 as the primary diagnosis. Early mitochondrial dysfunction may predispose her to an accelerated or more severe future VCP-associated phenotype. This is the first report of combined likely pathogenic and pathogenic variants in PMPCB and VCP respectively, expanding the phenotypic spectrum of both disorders. The case underscores the necessity of periodic re-evaluation with advanced genetic testing, highlights important ethical and familial implications, and informs future diagnosis and management of patients with overlapping rare genetic conditions.}, } @article {pmid42707488, year = {2026}, author = {Feyissa, GD}, title = {Serial Bogota bag tightening: A pragmatic advance in open abdomen management for resource-limited settings.}, journal = {World journal of gastrointestinal pharmacology and therapeutics}, volume = {17}, number = {3}, pages = {120768}, pmid = {42707488}, issn = {2150-5349}, abstract = {Open abdomen management poses unique challenges in resource-limited settings, where costly dynamic fascial traction techniques remain inaccessible. Balhara et al's prospective randomized trial published on the World J Gastrointest Pharmacol Ther introduces serial Bogota bag tightening, a bedside, negligible-cost method using urine bags and sutures, as an effective dynamic fascial traction alternative, achieving skin-to-skin distance ≤ 5 cm in 9.94 days vs 13 days in controls (P = 0.0003) and shortening hospital stays without added morbidity. This editorial appraises the study's strengths, contextualizes it against negative pressure wound therapy/mesh systems, and advocates its scalability for low- and middle-income countries, urging multicenter validation of long-term fascial closure.}, } @article {pmid42707600, year = {2026}, author = {Zhang, Z and Lu, Y and Yang, J and Li, M and Yang, M and Xu, Y and Ullah, MS and Wan, Q and Bao, B and Yu, W and Liu, X}, title = {Neurotoxic mechanisms of cadmium in neurodegenerative diseases.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1899381}, pmid = {42707600}, issn = {2296-634X}, abstract = {Cadmium (Cd) is a highly toxic, bioaccumulative heavy metal increasingly implicated in the pathogenesis of neurodegenerative disorders. This review systemically characterizes the molecular mechanisms underlying Cd-induced neurotoxicity, with particular emphasis on oxidative stress-mediated pathways that initiate interconnected processes including ferroptosis, mitochondrial impairment, disruption of calcium homeostasis, and chronic neuroinflammation. Evidence indicates that Cd exerts both convergent and disease-specific effects in neurodegenerative conditions. In Alzheimer's disease (AD), Cd exposure has been associated with enhanced amyloid-β (Aβ) deposition and increased tau hyperphosphorylation. In Parkinson's disease (PD), Cd disrupts metabolic homeostasis via the gut-liver-brain axis and promotes aberrant conformational changes and aggregation of α-synuclein (α-Syn). Within the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum, Cd contributes to TDP-43 proteinopathy and impairs nucleocytoplasmic transport mechanisms. Therapeutic strategies targeting Cd-induced neurotoxicity are also explored, including upstream approaches like metal chelation and downstream interventions aimed at restoring autophagic flux, modulating the neuroimmune microenvironment, and enhancing neuronal repair. Although emerging platforms such as brain organoids provide valuable mechanistic insights, translating findings from in vitro models to real-world chronic exposure scenarios remains a significant challenge. This review provides a comprehensive framework for the development of early-warning systems and precision-based interventions for Cd-related neurodegeneration.}, } @article {pmid42708447, year = {2026}, author = {Gazal, NG and Castellanos-Montiel, MJ and Bruno, G and Franco-Flores, AK and Lépine, S and Gursu, L and Haghi, G and Maussion, G and Reintsch, WE and Stefani, FD and Anastasía, A and Bisbal, M and Gorostiza, EA and Durcan, TM and Unsain, N}, title = {BetaII-spectrin gaps and patches emerge from the patterned assembly of the actin/spectrin membrane skeleton in human motor neuron axons.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {42708447}, issn = {2050-084X}, support = {ANPCyT-PICT-2021-GRF-II-00048//Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación/ ; IBRO-Collaboration Grants 2021//International Brain Research Organization/ ; }, mesh = {Humans ; *Spectrin/metabolism ; *Motor Neurons/metabolism ; *Axons/metabolism ; *Actins/metabolism ; Induced Pluripotent Stem Cells/metabolism ; *Cytoskeleton/metabolism ; }, abstract = {The actin/spectrin membrane-associated periodic skeleton (MPS) is a cytoskeletal structure that supports axonal integrity and function. Lower spinal motor neurons (MNs) are characterized by exceptionally long axons and are particularly susceptible to degeneration in a wide range of hereditary neuromuscular disorders, including amyotrophic lateral sclerosis. Using confocal and super-resolution imaging, we characterized the spatial distribution of βII-spectrin and the assembly pattern of the MPS in human MN axons derived from induced pluripotent stem cells. We discovered a striking gap-and-patch pattern in the medial axon, where sharply demarcated βII-spectrin gaps alternate with patches containing a well-organized MPS. The pattern is acutely induced by the kinase inhibitor staurosporine and pharmacological inhibition of actin polymerization prevents patch formation, indicating a requirement for actin nucleation in MPS assembly. Our data supports a model in which spectrin incorporation into nascent MPS patches depletes neighboring regions, producing long-range gaps-and-patches patterns.}, } @article {pmid42709165, year = {2026}, author = {Hamzeh, LH and Seyed, E and Elgendy, MA and Heib, D and Sadek, BI and Mohammed, COS and El Refaei, K and Soliman, YF and Eldmrdash, N and Abdelgalil, MS and Elsayed, MM}, title = {Efficacy and safety of memantine in adults with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {42709165}, issn = {1435-1463}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited disease-modifying treatment options. Memantine, an N-methyl-D-aspartate receptor antagonist, has been investigated in ALS, but its safety remains unclear. This study systematically assessed the safety of memantine in adults with ALS. A systematic review and meta-analysis was conducted following PRISMA 2020 guidelines, searching PubMed, Cochrane Library, Scopus, and Web of Science for randomized controlled trials of memantine in adults with ALS. Outcomes included ALSFRS-R and FVC decline, adverse neurological events, total and serious adverse events, treatment discontinuation, and all-cause mortality. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Because of heterogeneous reporting and missing variance estimates, ALSFRS-R and FVC outcomes were synthesized narratively; only safety outcomes were pooled quantitatively. Three randomized controlled trials (706 participants) met the inclusion criteria. Functional and respiratory outcomes could not be pooled because of heterogeneous reporting, and no consistent benefit was observed. Memantine showed lower headache incidence than placebo (RR 0.43; 95% CI 0.19-0.96), with no significant differences in constipation, falls, dizziness, treatment discontinuation, or all-cause mortality. Memantine showed a borderline increase in serious adverse events (RR 1.52; 95% CI 1.00-2.31) and a higher risk of total adverse events (RR 1.19; 95% CI 1.09-1.30). Memantine was associated with a small but significant increase in total adverse events and a trend toward more serious adverse events, without improving functional decline, respiratory function, or survival in ALS. Current evidence does not support its use as a disease-modifying or adjunctive therapy. Trial registration: PROSPERO CRD420261277874.}, } @article {pmid42709218, year = {2026}, author = {Sewell-Green, AR and Capstick, R and Holdom, CJ and Matthews-Rensch, K and Cameron, J and McCombe, PA and Henderson, RD and Ngo, ST and Steyn, FJ}, title = {Early weight loss predicts poorer prognosis and highlights limitations of predictive energy equations in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {10}, pages = {}, pmid = {42709218}, issn = {1432-1459}, support = {2016-32//Wesley Medical Research/ ; CRG2025_01395//FightMND/ ; Higher Degree Research Scholarship//University of Queensland/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/metabolism ; *Weight Loss/physiology ; Prognosis ; Female ; Male ; Middle Aged ; Case-Control Studies ; Prospective Studies ; Aged ; *Energy Intake/physiology ; }, abstract = {BACKGROUND: Weight loss and malnutrition are associated with poorer outcomes in people living with amyotrophic lateral sclerosis (plwALS). This study investigated the prognostic relevance of early weight loss in plwALS and assessed whether existing energy equations provide useful guidance for nutritional management.

METHODS: In this prospective case-control and within-case comparison study (March 2016October 2024), 170 plwALS and 173 non-neurodegenerative disease controls completed baseline anthropometric and metabolic assessment. Participants with ALS were classified according to weight change during the first six months following study inclusion as Weight Gain, Stable Weight, or Weight Loss. Weight-change groups were compared for subsequent changes in anthropometry, functional capacity, and survival. In a nested cohort of 82 plwALS with reported energy intake and repeat assessments, we assessed whether the relationship between reported intake and equation-derived energy requirements was concordant with subsequent weight change.

RESULTS: Early weight loss was associated with continued loss of body weight, fat mass, and fat-free mass, faster functional decline, and increased risk of earlier death relative to Weight Gain (HR=4.78 [95% CI 2.68-8.53], p<0.001). Concordance between equation-derived energy requirements, reported energy intake and observed weight trajectory was low (17.3-32.1%). The IBW30(30) equation showed the greatest concordance among participants with Weight Loss, but no equation performed consistently across weight-change groups.

CONCLUSIONS: Early weight loss identifies plwALS at increased risk of subsequent weight and body-composition loss, functional decline and earlier death. Existing energy equations proposed for use in ALS show limited concordance with observed weight trajectories, particularly when applied at a single time point. These findings support serial monitoring of nutritional risk and individualized, phenotype-informed dietetic care in ALS.}, } @article {pmid42709229, year = {2026}, author = {Castro, J and Sá, V and Lopes, D and Alves, I and Oliveira Santos, M and de Carvalho, M}, title = {Phrenic nerve amplitude as an effort-independent prognostic biomarker of respiratory failure in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {10}, pages = {}, pmid = {42709229}, issn = {1432-1459}, mesh = {Humans ; *Phrenic Nerve/physiopathology ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/diagnosis ; Female ; Male ; Prognosis ; *Respiratory Insufficiency/etiology/diagnosis/physiopathology/therapy ; Nerve Conduction Studies ; Middle Aged ; Aged ; Noninvasive Ventilation ; Action Potentials/physiology ; Cohort Studies ; Biomarkers ; }, abstract = {OBJECTIVE: In amyotrophic lateral sclerosis (ALS), the effort-dependent respiratory metrics used to determine the timing of non-invasive ventilation (NIV) lose reliability as bulbar and/or cognitive impairment progresses. We tested whether the effort-independent phrenic nerve compound muscle action potential (CMAP) amplitude predicts the timing of NIV independently of forced vital capacity (FVC) and the revised ALS Functional Rating Scale (ALSFRS-R).

METHODS: Pre-registered analysis of a single-centre ALS cohort (n = 1,486) contributing 2968 serial phrenic nerve conduction studies. Amplitude was expressed as percentage of an age- and sex-predicted value (per 10% decrease), and time to NIV initiation was the primary outcome (death competing). We used cause-specific Cox models, time-dependent and bootstrap-validated discrimination, and a Bayesian joint longitudinal-survival model.

RESULTS: Lower amplitude predicted earlier NIV (adjusted hazard ratio [HR] 1.22 per 10% decrease, 95% CI 1.16-1.27; likelihood-ratio χ[2] = 77.6, p ≈ 10⁻1⁸). The association was concentrated in the first year (HR 1.31, 1.24-1.38) and attenuated thereafter. The optimism-corrected discrimination increment over the clinical model was +0.055 (0.034-0.073); below-normal amplitude approximately doubled 12-month NIV risk (62% vs 29%). In the joint model the current amplitude (HR 1.57, 1.46-1.69) and its rate of decline (HR 1.30, 1.20-1.44) were independently prognostic.

CONCLUSIONS: Phrenic nerve conduction studies, an effort-independent neurophysiological marker carried robust, near-term, incremental prognostic information for NIV beyond FVC and ALSFRS-R, establishing diaphragmatic motor amplitude as a candidate biomarker for objective respiratory prognostication in ALS. External validation and recalibration are required before clinical use.}, } @article {pmid42709336, year = {2026}, author = {Colosimo, C}, title = {The Great Transatlantic Divide: The Case of Experimental Neuropharmacology.}, journal = {Clinical drug investigation}, volume = {}, number = {}, pages = {}, pmid = {42709336}, issn = {1179-1918}, abstract = {Despite substantial agreement between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on new drug approval in the past decades, a few new drugs for the treatment of some of the most prevalent and severe neurological disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as much rarer neurogenetic disorders, were handled differently by the two regulatory agencies. The possible reasons for the differing behaviors of the FDA and EMA are several and wide-ranging, and they will be examined in this opinion-based analysis. How patients' perceptions of the complex approaches to drug approval and commercialization may create disappointment and confusion will also be reappraised.}, } @article {pmid42709471, year = {2026}, author = {Chin, N and Zhang, Q and Zou, J and Cheng, KC and Zheng, W and Ye, Y}, title = {Cellular modifiers of TDP-43 phase transition and cytoplasmic aggregation.}, journal = {eLife}, volume = {15}, number = {}, pages = {}, pmid = {42709471}, issn = {2050-084X}, mesh = {*DNA-Binding Proteins/metabolism/genetics/chemistry ; Humans ; *Phase Transition ; Phase Separation ; *Cytoplasm/metabolism ; Active Transport, Cell Nucleus ; *Protein Aggregates ; Cell Nucleus/metabolism ; }, abstract = {RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like nuclear assemblies whose phase behavior is thought to influence its aggregation propensity and neurotoxic activity. The mechanisms that govern the liquid-to-solid phase transition of TDP-43 remain poorly defined. Here, we combined chemical and genome-wide genetic screens to identify cellular factors that modulate the phase behavior of an RNA-binding-defective TDP-43 mutant. Our screens uncovered multiple cellular processes, including RNA splicing, protein translation, proteostasis imbalance, and nuclear export as TDP-43 phase regulators. We also developed a semi-permeabilized cell system that partially recapitulates the TDP-43 phase transition in vitro, and showed that nuclear export inhibition reshapes the nuclear environment to favor RNA-dependent liquid-liquid phase separation (LLPS) of TDP-43, which mitigates its aggregation. Nuclear export inhibition in a brain organoid model bearing an ALS-associated mutation reduces pathogenic phospho-TDP-43 accumulation. These findings identify multiple modulators of TDP-43 phase transitions in a sensitized model system and establish a framework for further dissecting the link between nuclear transport and TDP-43 phase dynamics.}, } @article {pmid42710492, year = {2026}, author = {Kage, F and Lee, M and Bramhe, S and McEwen, AG and Alpy, F and Higgs, HN}, title = {Phosphorylation-dependent interaction between VAP proteins and INF2 influences ER morphology.}, journal = {Current biology : CB}, volume = {36}, number = {18}, pages = {4776-4791.e10}, doi = {10.1016/j.cub.2026.08.031}, pmid = {42710492}, issn = {1879-0445}, support = {P20 GM113132/GM/NIGMS NIH HHS/United States ; R01 DK088826/DK/NIDDK NIH HHS/United States ; R35 GM122545/GM/NIGMS NIH HHS/United States ; }, mesh = {*Endoplasmic Reticulum/metabolism ; Animals ; Phosphorylation ; Humans ; *Microfilament Proteins/metabolism/genetics ; *Vesicular Transport Proteins/metabolism/genetics ; Mice ; Protein Binding ; Formins ; }, abstract = {The endoplasmic reticulum (ER) interacts with virtually all other cellular organelles, and major players mediating these interactions are the ER-bound VAMP-associated protein (VAP) proteins VAPA and VAPB. Here, we show that VAP proteins interact with the actin polymerization factor INF2 in a phosphorylation-dependent manner. Similar to many other VAP-interacting proteins (the "VAPome"), an FFAT motif in INF2's C terminus interacts with the major sperm protein (MSP) domain of VAPs. Phosphorylation of a serine within the FFAT (S1100 in mouse; S1077 in human INF2) is necessary for high-affinity interaction both in cells and with purified proteins. The position of this phosphoserine, at position -1 of the FFAT consensus, is novel to the VAPome. Biochemical assays show that the phospho-FFAT binds both VAPA and VAPB, but not the related VAP family protein MOSPD2. Increased cytoplasmic calcium stimulates both INF2 phosphorylation and the INF2/VAP interaction. Amyotrophic lateral sclerosis (ALS)-associated mutations in the MSP disrupt the INF2/VAP interaction. Both major INF2 isoforms interact with VAPs: the INF2-CAAX isoform, which is constitutively ER-bound, and the INF2-nonCAAX isoform, which is predominantly cytosolic. For INF2-nonCAAX, VAP proteins cause ER recruitment in a phosphorylation-dependent manner. Disruption of INF2/VAP binding does not affect INF2-mediated actin polymerization but has a clear effect on ER morphology, causing the tubule/sheet balance to shift toward sheets. Cross-species evaluation suggests that only INF2 from placental mammals possesses an FFAT. These results suggest that interaction between VAP proteins and the actin polymerization factor INF2 plays a role in mediating ER morphology.}, } @article {pmid42710553, year = {2026}, author = {Babu, D and Le, TH and Liu, H and Raji, D and Tran, NH and Lockhart, S and Tran, P and Eldalal, O and Tonoyan, L and Siraki, AG}, title = {Edaravone as an antioxidant adjuvant to attenuate clozapine toxicity in vitro.}, journal = {Toxicology letters}, volume = {425}, number = {}, pages = {113188}, doi = {10.1016/j.toxlet.2026.113188}, pmid = {42710553}, issn = {1879-3169}, abstract = {Despite being the gold-standard therapy for treatment-resistant schizophrenia, clozapine use remains constrained by the risk of rare but serious adverse drug reactions, including severe neutropenia and agranulocytosis. Neutrophil myeloperoxidase (MPO)-mediated bioactivation of clozapine to reactive metabolites has long been implicated in agranulocytosis. Although clozapine is metabolized by MPO, there are numerous other compounds that can also be metabolized by this enzyme. Edaravone is a drug used to treat amyotrophic lateral sclerosis and has potent antioxidant activity; we have previously shown that edaravone is metabolized by MPO. Therefore, we hypothesized that edaravone can attenuate early toxicological events associated with clozapine through MPO modulation. Using purified human MPO, MPO-rich human promyelocytic leukemia (HL-60) cells, and isolated human neutrophils, we evaluated clozapine oxidation, competitive intracellular uptake, protein adduct formation, and cytotoxicity. UV-visible spectroscopy demonstrated concentration-dependent inhibition of MPO-catalyzed clozapine oxidation by edaravone, with 100 µM edaravone producing suppression comparable to 100 µM 4-aminobenzoic acid hydrazide. LC-MS analysis showed that MPO/H2O2 reduced clozapine levels to 26.7 ± 2.9% of control, whereas co-incubation with edaravone preserved clozapine to 67.9 ± 16.2%. Under the same conditions, edaravone was almost completely consumed (0.03 ± 0.02% remaining), consistent with its sacrificial antioxidant activity. In HL-60 cells, edaravone attenuated MPO activity and did not significantly alter clozapine uptake after 30 min (97.2 ± 7.6% of clozapine alone). Immunoblotting revealed that edaravone reduced clozapine-protein adduct formation in purified MPO, HL-60 cells, and neutrophils. Clozapine (75 µM) induced marked HL-60 cytotoxicity after 24 h, whereas edaravone concentration-dependently restored viability, with 200 µM fully preventing toxicity. These findings provide proof-of-concept that edaravone mitigates multiple mechanistic events linked to clozapine-induced hematological toxicity and may represent a potential strategy to improve clozapine safety.}, } @article {pmid42710846, year = {2026}, author = {Cunha, TA and Dourado, LC and Santana, GC and Yanagiura, MT and Galvão-Lima, LJ and Vale, SHL and Brandão-Neto, J and Dourado-Junior, MET and Leite-Lais, L}, title = {Evaluation of a self-administered version of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).}, journal = {Arquivos de neuro-psiquiatria}, volume = {84}, number = {9}, pages = {1-7}, pmid = {42710846}, issn = {1678-4227}, support = {88887.824483/2023-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Reproducibility of Results ; Prospective Studies ; Female ; Middle Aged ; Male ; Severity of Illness Index ; Observer Variation ; Feasibility Studies ; Aged ; *Disability Evaluation ; Adult ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: The Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is a standard tool for evaluating functional decline in patients with ALS. Despite its clinical value, administration by healthcare professionals can be time-consuming and resource intensive.

OBJECTIVE: To assess the reliability and feasibility of a self-administration version of the ALSFRS-R as an alternative for use in clinical and research settings.

METHODS: The present was an observational, analytical, prospective, single-center study involving ALS patients followed at the Neurology Outpatient Clinic of the Hospital Universitário Onofre Lopes (HUOL). Three independent assessments of the ALSFRS-R were conducted: one self-administered version and two interviewer-administered versions performed by different researchers during face-to-face consultations. Interrater reliability was assessed using intraclass correlation coefficients (ICCs), and agreement among the three versions was analyzed using Bland-Altman plots.

RESULTS: A total of 43 participants were included in the study, with a mean age of 57 ± 11.67 years. The ICCs indicated high reliability for both the total ALSFRS-R score and its functional domains. Linear regression analyses demonstrated strong agreement between the two researchers (R[2] = 0.98, p < 0.001), as well as between each researcher and the self-administered version (R[2] = 0.90 and 0.88, respectively). Bland-Altman analyses showed minimal bias and acceptable limits of agreement across all comparisons.

CONCLUSION: The self-administered version of the ALSFRS-R demonstrated high reliability and strong agreement with the researcher-administered versions, supporting its potential use for remote monitoring of ALS patients. Nonetheless, it should not replace professional assessments in clinical trial settings. Further research is warranted to validate its applicability in broader clinical contexts and diverse patient populations.}, } @article {pmid42711836, year = {2026}, author = {Nischal, SA and Kale, KM and Tourigny, K and Abuelem, M and Greene, G and Walsh, R and Molnár, Z}, title = {Neuroanatomy education through the years: Revisiting the teaching slides used by Sir Wilfrid Edward Le Gros Clark.}, journal = {Journal of anatomy}, volume = {}, number = {}, pages = {}, pmid = {42711836}, issn = {1469-7580}, support = {MR/W029073/1/MRC_/Medical Research Council/United Kingdom ; //Federation of European Neuroscience Societies History of Science Grants/ ; //Wellcome Trust History of Neuroscience Grant/ ; BB/X008711/1//BBSRC/ ; /WT_/Wellcome Trust/United Kingdom ; }, abstract = {Sir Wilfrid Edward Le Gros Clark (1895-1971) was a pioneering British anatomist, physician, and evolutionary biologist whose legacy spans the foundational development of twentieth century neuroanatomy, primate biology, and medical education. From his formative experiences as a young medical officer in the First World War to his later academic ascendancy at the University of Oxford, Le Gros Clark exemplified a rare fusion of clinical insight, anatomical precision, and philosophical curiosity. His tenure in Borneo, where he studied primates in their natural habitats, enriched his evolutionary perspective, while his later role in debunking the Piltdown Man fraud cemented his place as a steadfast defender of scientific integrity. At Oxford, Le Gros Clark assembled a singular collection of neuroanatomical teaching specimens, many of which remain preserved today within the Department of Physiology, Anatomy & Genetics, University of Oxford. Through detailed analysis of selected slides, including cases of tabes dorsalis, disseminated sclerosis, amyotrophic lateral sclerosis, syringomyelia, and the pineal gland's nervus conarii, we reflect on how Le Gros Clark's anatomical interpretations anticipated many of the concepts central to contemporary neuroscience, and on how his legacy has influenced generations of students and scientists. What emerges from these materials is that Le Gros Clark taught students not simply to memorize, but to observe, interpret, and understand the functional significance of anatomical structures in health and disease.}, } @article {pmid42713005, year = {2026}, author = {Belaidi, AA and Furtado, DL and Alves, F and Nisbet, RM and Ayton, S and Bush, AI}, title = {Engineering mRNA-LNP Medicines for the Ageing Brain: Opportunities and Challenges for Neurodegenerative Diseases.}, journal = {Exploration (Beijing, China)}, volume = {}, number = {}, pages = {70223}, pmid = {42713005}, issn = {2766-2098}, abstract = {Messenger RNA (mRNA) therapeutics delivered by lipid nanoparticles (LNPs) have advanced from concept to clinic at unprecedented speed, yet their promise for neurodegenerative diseases remains largely untapped. Currently intractable age-related proteinopathies such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis demand new therapies that combine molecular precision with scalable manufacturing. This review surveys recent advances in engineering LNPs that traverse the blood-brain barrier (BBB), evade innate immune surveillance, and achieve cell-selective expression in the ageing brain. We highlight emerging chemistries, including BBB-shuttling ionizable lipids, peptide-functionalized shells, and liver-detargeted formulations that enable systemic or minimally invasive delivery to the central nervous system (CNS) in animal models. Although no CNS-directed mRNA-LNP has yet reached clinical trials, first-in-human studies for rare metabolic disorders demonstrate favourable safety, manufacturability, and durable protein replacement. Drawing lessons from COVID-19 mRNA vaccines and ongoing liver-targeted programmes, we outline a translational roadmap for brain applications. Major hurdles that are critically assessed include efficient endosomal escape in aged neurons, heterogeneity of the senescent BBB, chronic-dose immunogenicity, and large-scale synthesis of next-generation lipids. Finally, we propose design rules and analytical standards to address outstanding knowledge gaps in expression durability and age-related BBB alterations. Together, these insights chart a path for engineering mRNA-LNP therapeutics capable of meeting the rising burden of neurodegenerative diseases in an ageing global population.}, } @article {pmid42713279, year = {2026}, author = {Kassubek, J and Müller, HP}, title = {Magnetic resonance imaging applications to amyotrophic lateral sclerosis beyond the central nervous system.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1849783}, pmid = {42713279}, issn = {1664-2295}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; }, abstract = {Traditionally, in amyotrophic lateral sclerosis (ALS) and other motor neuron disorders, the diagnostic and research focus in the domain of magnetic resonance imaging (MRI) has been targeted on the brain and spinal cord. Nevertheless, structures outside the central nervous system (CNS) are core structures of the pathological processes and are also assessible by imaging approaches. Advanced imaging of structures like bodyfat and muscles can considerably contribute to the pathophysiological understanding and disease monitoring of ALS. The multiparametric combination of MRI approaches that capture these changes could be very helpful in future studies, especially when machine learning algorithms are used. This review summarizes the current state of the art and the role of imaging beyond the CNS in ALS, examining its diagnostic and monitoring potential and how it might ultimately lead to improved management strategies for patients.}, } @article {pmid42716035, year = {2026}, author = {Hardiman, O}, title = {HIMALAYA: learning from another negative phase 2 trial in ALS.}, journal = {The Lancet. Neurology}, volume = {25}, number = {10}, pages = {875-877}, doi = {10.1016/S1474-4422(26)00318-2}, pmid = {42716035}, issn = {1474-4465}, } @article {pmid42716044, year = {2026}, author = {Cudkowicz, ME and Shefner, J and van den Berg, LH and Chio, A and Fan, D and Großkreutz, J and Lunetta, C and Tsai, RM and Li, Y and Wallstroem, E and Xiong, L and Chen, Y and Atassi, N and , }, title = {Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.}, journal = {The Lancet. Neurology}, volume = {25}, number = {10}, pages = {900-910}, doi = {10.1016/S1474-4422(26)00277-2}, pmid = {42716044}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Middle Aged ; Male ; Female ; Aged ; Adult ; Aged, 80 and over ; Young Adult ; Treatment Outcome ; Adolescent ; }, abstract = {BACKGROUND: RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS.

METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early.

FINDINGS: Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56·9 years (SD 11·5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) for SAR443820 group (n=169) and -6·32 (-7·36 to -5·27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0·41 [95% CI -1·71 to 0·88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820.

INTERPRETATION: SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted.

FUNDING: Sanofi.}, } @article {pmid42716045, year = {2026}, author = {Teunissen, CE and Vermunt, L and Barthélemy, NR and Benzinger, TLS and Graff-Radford, J and Verberk, IMW and Zetterberg, H and Schindler, SE and Jack, CR}, title = {Fluid biomarkers in the evolving care landscape of Alzheimer's disease and related disorders.}, journal = {The Lancet. Neurology}, volume = {25}, number = {10}, pages = {926-938}, doi = {10.1016/S1474-4422(26)00246-2}, pmid = {42716045}, issn = {1474-4465}, mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/blood ; tau Proteins/cerebrospinal fluid ; Animals ; }, abstract = {Fluid biomarkers for Alzheimer's disease have advanced rapidly during the past several years driven by breakthroughs including development of ultrasensitive and multiplexing technologies and high specificity antibodies. Blood-based biomarkers, such as neurofilament light for frontotemporal dementia and amyotrophic lateral sclerosis, and phosphorylated tau 217 for the diagnosis of Alzheimer's disease, are now being implemented in clinical practice, which is particularly timely because of the increasing clinical availability of amyloid-targeting treatments in Alzheimer's disease. Multiple fluid biomarkers are needed to capture the complexity of disease mechanisms for precise diagnosis and to measure the diverse pathologies that lead to dementia, such as vascular, α-synuclein, and TDP-43 pathologies. Moreover, fluid biomarkers can aid in capturing heterogeneity in treatment course between patients, probably due to copathologies or key intermediates, including microglia and astrocyte dysregulation. Increased focus on biomarker-pathology relationships in experimental models will likely accelerate biomarker development and further the understanding of their precise substrates. Future clinical implementation of biomarkers to capture the full complexity of pathologies will likely be facilitated by the expansion of diagnostic methods, development of point of care technologies, and remote sampling approaches.}, } @article {pmid42716967, year = {2026}, author = {Mansour, SS and Mahmoud, AM and Moustafa, AA and Nashat, NW}, title = {"Green spectrophotometric determination of rupatadine, its toxic impurity, and methyl paraben: comparative AI-assisted univariate versus multivariate chemometrics".}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42716967}, issn = {2045-2322}, mesh = {*Parabens/analysis ; *Cyproheptadine/analogs & derivatives/analysis/chemistry ; Loratadine/analogs & derivatives/analysis ; Multivariate Analysis ; *Artificial Intelligence ; *Drug Contamination ; Spectrophotometry, Ultraviolet/methods ; Spectrophotometry/methods ; }, abstract = {Sensitive and selective green UV-spectrophotometric univariate and multivariate chemometric methods were developed to resolve the overlapped spectra of rupatadine fumarate (RUP), its impurity desloratadine (DES), and methyl paraben (MP). The univariate approach employed was the dual-wavelength (DW) method. Guided by artificial intelligence (AI) in the selection of the optimal wavelength pair, the determination of RUP was performed at 230 and 284.3 nm, and for MP at 236.6 and 253.8 nm. Among the multivariate methods, ANN demonstrated superior predictive accuracy (lowest RMSEP values), followed by PLS-1 and MCR-ALS, highlighting the power of machine learning for complex mixture resolution, particularly in the presence of the preservative MP. A three-factor, five-level experimental design was adopted to construct a calibration set comprising 25 mixtures with varying component ratios, along with 6 independent validation mixtures. The developed methods were successfully applied to pharmaceutical formulation containing the studied drug and were validated in accordance with International Conference of Harmonization (ICH) guidelines. The results obtained were reliable and reproducible, confirming the suitability of these methods for routine analysis and quality control in laboratories. Moreover, the GLANCE tool (Graphical Layout for Analytical Chemistry Evaluation) offered a clear visual summary of the twelve structured method attributes.}, } @article {pmid42717683, year = {2026}, author = {Moody, L and Christoforidou, E and Joilin, G and Dilley, A and Hafezparast, M}, title = {Dysregulated microRNA-mRNA networks in SOD1G93A mouse skeletal muscle reveal metabolic impairments in ALS.}, journal = {Disease models & mechanisms}, volume = {}, number = {}, pages = {}, doi = {10.1242/dmm.052963}, pmid = {42717683}, issn = {1754-8411}, support = {Hafezparast/Oct19/897-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; Hafezparast/Apr21/880-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; //Sussex Neuroscience PhD Programme/ ; DOD/14/30-PF12794//My Name'5 Doddie Foundation/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multi-system disease in which skeletal muscle actively contributes to pathology, yet the regulatory circuits that drive muscle dysfunction remain unclear. We examined microRNA (miRNA)-messenger RNA (mRNA) interactions in the gastrocnemius of hSOD1G93A mice across presymptomatic, early- and late-symptomatic stages, using RNA-seq, bioinformatics, and RT-qPCR. Compared with hSOD1WT and non-transgenic controls, hSOD1G93A muscle showed mutation-specific transcriptome reprogramming: 48 dysregulated miRNAs and 558 mRNAs at presymptomatic, and 64 miRNAs and 685 mRNAs at late-symptomatic stages. Functional enrichment pinpointed carbohydrate-handling pathways (glycolysis/gluconeogenesis, pentose-phosphate, fructose-mannose metabolism) as the dominant downregulated gene sets. Network analysis revealed clusters in which upregulated miRNAs converged on, and showed inverse expression patterns relative to metabolic transcripts. RT-qPCR confirmed inverse expression of 10 candidate miRNAs and 11 metabolic mRNAs, substantiating miRNA-guided repression of glycolytic enzymes and energy-sensing nodes. Collectively, we show that SOD1G93A drives an early, sustained miRNA signature that dampens glycolysis gene expression, which could promote the fast-to-slow fibre-type transition and exacerbate energy deficit in ALS muscle. Targeting these circuits offers a strategy to restore metabolic balance and slow disease progression.}, } @article {pmid42717824, year = {2026}, author = {Zarco-Martín, MT and Andreo-López, MC and Yagui-Beltrán, MS and Fernández-Soto, ML}, title = {Appendicular Skeletal Muscle Mass and Sarcopenia as Prognostic Markers in Amyotrophic Lateral Sclerosis.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {17}, number = {5}, pages = {e70378}, pmid = {42717824}, issn = {2190-6009}, support = {2024 Award for the Best Clinical Nutrition Research Project//Sociedad Española de Nutrición Clínica y Metabolismo/ ; 74-2022//Granada Biosanitary Research Institute (Ibs. Granada)/ ; }, mesh = {Humans ; *Sarcopenia/etiology/diagnosis/mortality/pathology ; *Amyotrophic Lateral Sclerosis/complications/mortality/diagnosis ; Female ; Prognosis ; *Muscle, Skeletal/pathology/physiopathology ; Male ; Aged ; Biomarkers ; Middle Aged ; Prospective Studies ; Hand Strength ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle wasting and functional decline. Prognostic assessment in clinical practice relies largely on functional scales and traditional anthropometric measures. The prognostic relevance of muscle mass, muscle strength and sarcopenia in ALS remains incompletely defined. This study evaluated the prognostic value of muscle mass, muscle function and sarcopenia in relation to mortality in patients with ALS.

METHODS: A prospective observational cohort study was conducted at the ALS Multidisciplinary Unit (UMELA), San Cecilio University Hospital in Granada. Sarcopenia was defined according to the European Working Group of Sarcopenia in Older People 2 (EWGSOP2) and malnutrition using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Muscle status was assessed using bioelectrical impedance vector analysis (BIVA)-derived parameters, muscle ultrasound, handgrip strength (HGS) and physical performance (SPPB). Differences between survivors and nonsurvivors were analysed and logistic regression explored potential predictors of mortality. Receiver operating characteristic (ROC) curves were constructed for significant predictors. Survival was analysed using the Kaplan-Meier and Cox proportional hazards regression.

RESULTS: A total of 42 patients with ALS were included (mean age 66.1 ± 10.3 years, and 15 (36%) were female). During follow-up (mean survival 21.1 ± 10.5 months), 45% died. Survivors showed higher appendicular skeletal muscle mass index (ASMI) (6.94 ± 0.91 vs. 5.80 ± 0.98 kg/m[2], p = 0.001), body cellular mass index (BCMI) (8.92 ± 1.59 vs. 7.64 ± 1.87 kg/m[2], p = 0.034) and HGS (25.45 ± 11.11 vs. 17.67 ± 8.83 kg, p = 0.032), while BMI did not differ (p = 0.540). Sarcopenia was more prevalent in nonsurvivors (27.8% vs. 4.8%, p = 0.047). In multivariable analysis, ASMI remained associated with mortality after adjustment for age, onset type and ALSFRS-R (OR 0.33, 95% CI 0.11-0.81, p = 0.026), but this association was not statistically significant in the fully adjusted model including disease duration (p = 0.093). ASMI showed the highest discriminative ability (AUC 0.81), compared to BCMI (AUC 0.70) and HGS (AUC 0.71). ROC-derived cut-offs (ASMI 6.74 kg/m[2]; BCMI 7.2 kg/m[2]; HGS 21 kg) stratified survival. Higher ASMI (HR 7.53, p = 0.008), BCMI (HR 4.18, p = 0.005) and HGS (HR 4.02, p = 0.019) were associated with longer survival, whereas sarcopenia increased mortality risk (HR 15.53, p < 0.001).

CONCLUSIONS: Beyond BMI, skeletal muscle mass-particularly ASMI-was associated with survival in ALS. Sarcopenia identifies a subgroup of patients at particularly high risk of death. Sarcopenia assessment may improve prognostic stratification and support clinical management in ALS.}, } @article {pmid42719214, year = {2026}, author = {Mittal, D and Solanki, P and Jain, GK and Jhawat, V and Kesharwani, P and Dutt, R and Arora, S and Singh, RP}, title = {Herbal nanoparticles in the treatment of neurodegeneration: from molecular mechanisms to therapeutic translation.}, journal = {3 Biotech}, volume = {16}, number = {10}, pages = {420}, pmid = {42719214}, issn = {2190-572X}, abstract = {UNLABELLED: Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss involving multiple pathological mechanisms, including protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Although conventional therapies provide symptomatic relief, they fail to halt disease progression and are limited by poor blood-brain barrier (BBB) penetration, off-target effects, and systemic toxicity. Likewise, several herbal bioactives, such as curcumin, resveratrol, quercetin, and epigallocatechin gallate, exhibit promising neuroprotective properties but suffer from poor aqueous solubility, low oral bioavailability, rapid metabolism, and inadequate brain delivery. Nanotechnology-based delivery systems have emerged as a promising approach to overcome these pharmacokinetic limitations by enhancing stability, controlled release, BBB transport, and brain accumulation of herbal therapeutics. This review critically summarizes recent advances in herbal nanoformulations, emphasizing disease-specific molecular targets, BBB-targeting strategies, comparative nanocarrier systems, pharmacokinetic optimization, intracellular trafficking, and translational challenges. Unlike previous reviews, it integrates recent evidence on nanotoxicology, manufacturing scalability, quality control, regulatory considerations, and emerging technologies, including biomimetic nanoparticles and extracellular vesicles. Despite encouraging preclinical outcomes, clinical evidence remains limited, and no herbal nanoformulation has yet demonstrated definitive efficacy or received regulatory approval for neurodegenerative diseases. Future clinical translation will require standardized formulations, rigorous safety evaluation, and well-designed clinical trials. Unlike previous reviews that primarily summarize individual nanocarrier systems or herbal therapeutics, the present review provides a comprehensive and critical synthesis of the current evidence by integrating disease-specific molecular mechanisms, herbal bioactives, nanocarrier design strategies, blood-brain barrier transport mechanisms, intracellular trafficking, pharmacokinetic considerations, translational barriers, regulatory challenges, clinical evidence, and emerging technologies. Furthermore, the review identifies major knowledge gaps and future research priorities to facilitate the successful clinical translation of herbal nanoformulations for neurodegenerative disorders.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05048-8.}, } @article {pmid42719426, year = {2026}, author = {Zambetti, E and Belli, S and Mucci, C and Greco, A}, title = {Living with Amyotrophic Lateral Sclerosis: Exploring what matters to patients and caregivers through their experiences.}, journal = {Palliative care and social practice}, volume = {20}, number = {}, pages = {26323524261474107}, pmid = {42719426}, issn = {2632-3524}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disease the causes of which are not fully understood, that leads to early death. From the diagnosis, ALS significantly impacts the quality of life (QoL) for patients and their caregivers due to its unique characteristics. Both patients and their caregivers, formal and informal, increasingly feel the need to share their experiences, communicate their needs, and talk about what living with ALS entails.

OBJECTIVES: Given the few studies available in the literature on this topic, the study's aim is to explore the significance of ALS for patients and caregivers through their testimonies and to identify the collective representations and symbolic categories that influence their lives.

DESIGN AND METHODS: A total of 118 spontaneous written texts (67 produced by women) (81.752 tokens, TTR index=0.145; H% index=54.6%) collected from the web, from 67 ALS patients, 41 informal and 10 formal caregivers, were analyzed using the Emotional Text Mining (ETM) technique, with the T-Lab Software.

RESULTS: Four communication axes were identified: management of the disease (34.25%; physical vs. emotional), care (26.58%; technological vs. relational), support (21.39%; self-directed vs. social), and effort (17.78%; personal and institutional). The five clusters positioned in this factorial space relate to disease onset (12.29%), difficulties (30.78%), medical examinations (29.39%), coping strategies (14.79%), and needs (18.75%). There are differences between genders and groups.

CONCLUSION: The interpretation of the results enables an understanding of the cultural-symbolic system of ALS patients and caregivers, as well as the impact of the disease on their QoL. Through this, personalized interventions can be designed to promote resources and psychological well-being.}, } @article {pmid42719847, year = {2026}, author = {Tu, D and Riseman, J and Wei, Y and Ghosh, P and Raney, SG and Luke, MC and Evans, CL}, title = {Label-free quantification of topical drug permeation in skin using sparse spectral sampling stimulated Raman scattering imaging.}, journal = {Biophotonics discovery}, volume = {3}, number = {4}, pages = {043103}, pmid = {42719847}, issn = {3005-4745}, support = {U01 FD006698/FD/FDA HHS/United States ; }, abstract = {SIGNIFICANCE: Stimulated Raman scattering (SRS) imaging has been used in evaluating topical drug product permeation. However, it has been mainly applied to a small group of active pharmaceutical ingredients (API) that have unique molecular bands which generate a prominent SRS signal against the background signal. The requirement of such unique molecular bands has been a large hurdle to generalizing SRS imaging to study a wide range of pharmaceutical molecules.

AIM: To overcome this barrier, an imaging method based on sparse spectral sampling stimulated Raman scattering (S4RS) microscopy and multivariate analysis was developed in this study.

APPROACH: Rather than relying on a single unique and strong peak, the API was specifically resolved using combined information from multiple wavenumbers across its spectrum. The workflow of applying this method to study APIs is demonstrated using metronidazole as an example. The sparse vibrational bands were first selected using Elastic-Net. Next, the metronidazole signal was unmixed from the compound signal of the skin-drug product mixture using multivariate curve resolution-alternating least squares (MCR-ALS).

RESULTS: The developed method demonstrated good capability in identifying the metronidazole signal in standard metronidazole-containing samples, including polymer films and skin samples treated with and without the drug product. This method enabled evaluation of the cutaneous pharmacokinetics (cPK) of metronidazole in ex vivo skin samples. Bioequivalence analysis was also completed for commercial drug products and laboratory-made control formulations containing metronidazole.

CONCLUSIONS: The developed method enables the study of APIs that lack a unique prominent peak, thereby bridging SRS imaging to a broader range of drug products.}, } @article {pmid42719958, year = {2026}, author = {Saito, M and Tsuzuki, H and Hosomi, A}, title = {Investigating Translocation Mechanisms of TDP-43 Into the Endoplasmic Reticulum Using Budding Yeast Models.}, journal = {Traffic (Copenhagen, Denmark)}, volume = {27}, number = {3}, pages = {e70054}, pmid = {42719958}, issn = {1600-0854}, support = {21K05502//Japan Society for the Promotion of Science/ ; 4-0012//Ohsumi Frontier Science Foundation/ ; }, mesh = {*Endoplasmic Reticulum/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Protein Transport/physiology ; Protein Sorting Signals ; Saccharomyces cerevisiae Proteins/metabolism/genetics ; *Saccharomyces cerevisiae/metabolism ; Glycosylation ; *Saccharomycetales/metabolism ; }, abstract = {Signal peptides direct secretory and membrane proteins to the endoplasmic reticulum (ER), but proteins lacking classical signal peptides can occasionally engage the ER translocation machinery. TDP-43 is a nuclear RNA-binding protein implicated in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 pathology has been linked to extracellular TDP-43 species, association with the ER luminal oxidoreductase PDI, and ER stress-related phenotypes, yet whether TDP-43 fragments can directly access the ER lumen remains unclear. Here, we used budding yeast to examine signal peptide-independent ER entry of TDP-43. C-terminal fragments of TDP-43 acquired N-glycans in ste24Δ cells, whereas full-length TDP-43 showed little detectable ER entry. Endo H digestion confirmed N-glycosylation of the fragments, and a protease protection assay supported ER luminal localization of TDP-43(Δ2-89). ER entry was reduced by sec61-41 and sec66Δ, indicating engagement of a Sec61/Sec66-dependent translocation pathway. Deletion analyses identified opposing sequence elements: residues 320-343 facilitated ER entry, whereas an N-terminal region upstream of the nuclear localization signal suppressed it. TDP-43(Δ2-89) also accessed the secretory pathway, and selected disease-associated variants caused Ire1-dependent growth vulnerability without increasing detectable ER translocation. These findings reveal a Ste24-suppressed route for noncanonical ER entry of TDP-43 fragments.}, } @article {pmid42720086, year = {2026}, author = {Benatar, M and Huey, ED and Onyike, CU and McHutchison, C and Tartaglia, MC and Barker, MS and Abrahams, S and De Vocht, J and Rhodes, E and Pijnenburg, YA and Turner, MR and van Damme, P and Lee, EB and Wuu, J and Benussi, A and Boeve, BF and McMillan, CT and Strong, MJ}, title = {Conceptualizing cognition and behaviour across amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag300}, pmid = {42720086}, issn = {1460-2156}, abstract = {Cognitive and behavioral dysfunction in frontotemporal dementia (FTD) evolves along a clinical continuum from a clinically silent stage of disease, through a prodromal period, often referred to as mild cognitive impairment (MCI) and/or mild behavioral impairment (MBI), and into a clinically manifest stage recognized by the syndromes of behavioral variant FTD and primary progressive aphasia (PPA). Similar cognitive and behavioral manifestations of varying severity are also encountered in individuals with amyotrophic lateral sclerosis (ALS). Notwithstanding this phenotypic overlap as well as a degree of shared genetic risk and underlying pathology, the approach to phenotypic characterization and description meaningfully differs between the ALS and FTD communities. The problem is particularly evident within the ALS community when describing impairment in the prodromal vs. clinically manifest disease stages. Pertinent considerations include the nature of cognitive and behavioral assessments, the nosology used to describe symptoms identified including those encompassed by the terms 'behavioral' and 'neuropsychiatric', the operationalized criteria that define prodromal syndromes and clinically manifest disease, and the extent to which these criteria rely on longitudinal (vs. cross-sectional) data. A multi-stakeholder workshop, held in London, Ontario (May 12-14, 2025), brought together neurologists, psychiatrists, neuropsychologists, neuropathologists, neuroscientists, and neurogeneticists studying ALS and FTD, to promote inter-disciplinary dialogue and to define a research agenda that might be jointly tackled to address these critical issues. A new nosology for classifying frontotemporal-related behavioral and neuropsychiatric dysfunction, which could be used to support empirical evidence collection, is proposed alongside a list of cognitive, language, behavioral and neuropsychiatric symptoms to be considered in the evaluation of individuals with ALS. Research priorities for each of the ALS and FTD communities, as well as initiatives that should be undertaken jointly, are highlighted. The long-term goal is to harmonize approaches to phenotypic characterization, the nosology used to describe symptoms, and the criteria used to define landmark stages along the clinical continua of the motor neuron and frontotemporal axes irrespective of clinical stage.}, } @article {pmid42720300, year = {2026}, author = {Li, S and Xia, X and Wei, Z and Wang, N and Lin, H and Niu, L}, title = {Generation of Herbicide-Resistant Alfalfa Germplasm via Prime Editing.}, journal = {Plant biotechnology journal}, volume = {}, number = {}, pages = {}, pmid = {42720300}, issn = {1467-7652}, support = {32325035//National Natural Science Foundation of China/ ; }, abstract = {Alfalfa (Medicago sativa) is the most widely cultivated forage crop worldwide, owing to its high protein content, balanced amino acid profile, and abundance of vitamins and minerals. However, weed infestation severely threatens alfalfa yield and quality. The lack of herbicide‑resistant cultivars, combined with the diversity of weed species, has made herbicide tolerance a key breeding objective. To address this challenge, we developed a highly optimized prime editing system and, for the first time, achieved prime editing in alfalfa by enhancing the expression efficiency of its components. Specifically, we introduced mutations in three target genes MsALS1, MsALS2 and MsACC1 to confer herbicide resistance: mutations in MsALS1 and MsALS2 were designed to confer resistance to ALS‑inhibiting herbicides (based on evidence from their rice homologs), while those in MsACC1 were targeted to confer resistance to aryloxyphenoxypropionate (APP) herbicides. Using the Csy4 nuclease system, we performed simultaneous prime editing of all three genes, ultimately generating alfalfa lines resistant to nicosulfuron and haloxyfop‑P‑methyl. This study represents the first successful multi‑gene prime editing in alfalfa, providing a novel tool and a valuable approach for alfalfa molecular breeding.}, } @article {pmid42720979, year = {2026}, author = {Huang, CS and Sanchez-Santos, C and Martinez-Gonzalez, L and Gil, C and Martinez, A}, title = {Innovative therapies under clinical development for ALS treatment. Part 2: biologics and natural products.}, journal = {Expert opinion on investigational drugs}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/13543784.2026.2729512}, pmid = {42720979}, issn = {1744-7658}, abstract = {INTRODUCTION: The clinical trial landscape for Amyotrophic Lateral Sclerosis (ALS) is rapidly expanding despite ongoing translational challenges. Following our 2022 analysis and as a continuation of Part 1, which focused on small molecules, this review provides a structured overview of biologics and natural products in the ALS clinical pipeline. Particular emphasis is placed on candidates that entered, advanced through, or completed clinical evaluation between 2022 and the end of 2025.

AREAS COVERED: Clinical trials for ALS registered in the United States (ClinicalTrials.gov) and the European Union (EU Clinical Trials Register/CTIS) were systematically reviewed and are summarized in this report.

EXPERT OPINION: Modern biotechnology, ethnopharmacology, and classical pharmacology are increasingly converging in ALS therapeutic development, making this one of the most active areas of neurodegenerative disease research. Nevertheless, major challenges remain, including central nervous system (CNS) penetration, long-term safety, interpatient variability, limited clinical evidence, and the need for reliable biomarkers. Emerging technologies, such as big data analytics and artificial intelligence, may help accelerate and optimize therapeutic development, as well as improve patient recruitment and stratification.}, } @article {pmid42721110, year = {2026}, author = {Alrabadi, B and Matar, HI and Bandak, N and Yaseen, S and Badwan, A and Alomari, O}, title = {Non-invasive brain stimulation in amyotrophic lateral sclerosis: a systematic review and meta-analysis of transcranial direct current stimulation and transcranial magnetic stimulation.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/17582024.2026.2731195}, pmid = {42721110}, issn = {1758-2032}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with limited disease-modifying treatments. Noninvasive brain stimulation techniques have been investigated as potential neuromodulatory interventions targeting cortical hyperexcitability in ALS.

OBJECTIVE: To systematically evaluate the clinical efficacy, neurophysiological effects, and safety of tDCS and TMS-based interventions in ALS.

METHODS: A systematic review and meta-analysis was conducted following PRISMA guidelines. PubMed, Scopus, Web of Science, and Cochrane Library were searched from inception to March 2026.

RESULTS: Thirty studies involving ALS patients were included. Pooled analyses showed no significant difference between active stimulation and sham in ALSFRS-R at 6 months (MD = 0.58, 95% CI - 0.16 to 1.31) or at end of follow-up (MD = 0.20, 95% CI - 0.49 to 0.89). No significant effect was observed for manual muscle testing. Considerable heterogeneity was noted across studies. However, several studies demonstrated modulation of cortical excitability and intracortical inhibitory circuits, particularly with repeated stimulation protocols. Both tDCS and TMS were consistently safe and well tolerated, with no serious adverse events reported.

CONCLUSION: Noninvasive brain stimulation in ALS does not significantly improve functional outcomes, but induces measurable neurophysiological changes with a strong safety profile. Further studies should optimize protocols and identify responsive subgroups.}, } @article {pmid42721706, year = {2026}, author = {Viljoen, S and Chaves, JCS and Peall, I and White, AR and Oikari, LE}, title = {Dysfunction of the blood-brain barrier and neurovascular unit in amyotrophic lateral sclerosis - From advanced human models to treatments.}, journal = {Journal of the neurological sciences}, volume = {490}, number = {}, pages = {126168}, doi = {10.1016/j.jns.2026.126168}, pmid = {42721706}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/metabolism/therapy/pathology ; *Blood-Brain Barrier/physiopathology/metabolism/pathology ; Animals ; *Neurovascular Coupling/physiology ; Oxidative Stress/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, characterized by the degeneration of motor neurons, resulting in progressive and eventually complete loss of motor function. The phenotypical heterogeneity of ALS poses a challenge to early diagnosis and treatment, with currently available therapeutics only capable of relieving symptoms and slowing progression. While ALS is classified as a motor neuron disease (MND), research has identified significant impairment to the blood-brain barrier (BBB) and neurovascular unit (NVU) of ALS patients. The BBB along with supporting cells of the NVU selectively control the entry of substances into the central nervous system (CNS) and maintain brain homeostasis, with its many cellular components demonstrating impaired function, specifically relating to inflammation, oxidative stress and TDP-43 proteinopathy. The advent of more advanced in vitro techniques as well as use of patient-derived BBB cells has presented a promising alternative to recreate the in vivo structure of the BBB/NVU in a highly controlled platform. Such approaches have ranged from simple 2-dimensional (2D) cell culture to intricate 3-dimensional (3D) co-culture systems, as well as microfluidic systems and organoids, with a potential to investigate ALS associated BBB/NVU dysfunction and drug discovery. This review provides a comprehensive assessment of known BBB/NVU dysfunction in ALS and methods of investigating this using in vitro and in vivo platforms with a focus on inflammation, oxidative stress and pathological TDP-43 expression. This review also presents a future perspective to overcoming barriers to treatment of ALS using new patient-derived BBB/NVU model systems.}, } @article {pmid42722039, year = {2026}, author = {Morisaki, Y and Nomura, N and Matsuda, M and Ohshima, M and Fukuda, R and Komine, O and Okuda, T and Yamanaka, K and Misawa, H}, title = {Anti-LAG-3 antibody treatment initiated after symptom onset extends survival in ALS model mice.}, journal = {Neuroscience research}, volume = {231}, number = {}, pages = {105119}, doi = {10.1016/j.neures.2026.105119}, pmid = {42722039}, issn = {1872-8111}, abstract = {Immune checkpoint molecules have emerged as regulators of microglial function in neurodegenerative diseases. We previously demonstrated that LAG-3 shapes disease-associated microglial phenotypes in ALS and that germline LAG-3 deletion in SOD1[G93A] mice accelerated disease onset but extended duration, leaving survival unchanged. Here, we investigated the therapeutic efficacy of anti-LAG-3 antibody treatment starting after symptom onset. Anti-LAG-3 treatment extended survival, slowed neurological and motor decline, preserved body weight and motor neurons, and reduced microgliosis. Within microglia, the Axl[+] phagocytic-module fraction increased while the Dectin-1[+] inflammatory-module fraction decreased. These findings indicate that post-onset LAG-3 inhibition is a promising therapeutic strategy for ALS.}, } @article {pmid42722112, year = {2026}, author = {Butt, TH and Strait, M and Marcinczyk, L and Katz, G and Kalia, V and Jaafar, C and Saxena, R and Divjan, A and Saglimbeni, B and Munoz Umanes, ME and Tipps, E and Han, M and Mehta, P and Lee, I and Mitsumoto, H and Factor-Litvak, P and Shneider, NA and Kioumourtzoglou, MA and Re, DB}, title = {Astrocyte-derived extracellular vesicle phosphorylated TDP-43 as a blood-based biomarker for amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {229}, number = {}, pages = {107601}, doi = {10.1016/j.nbd.2026.107601}, pmid = {42722112}, issn = {1095-953X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by central nervous system (CNS) neuroglial TAR DNA-binding protein 43 (TDP-43) pathology in ∼90-95% of cases. Non-invasive biomarkers are critically needed to reduce diagnostic delay, enable patient stratification, and assess treatment efficacy in clinical trials. Astrocyte-derived extracellular vesicles (ADEVs) represent promising CNS liquid biopsy biomarkers, given astrocyte involvement in ALS pathogenesis and the ability of ADEVs to cross the blood-brain barrier and carry TDP-43. Here, we assessed the diagnostic performance of TDP-43 and its hyperphosphorylated pathological form, phospho-Ser409 (pTDP-43), quantified in ADEVs, for distinguishing ALS cases from matched healthy controls. ADEVs were immunoisolated from whole blood (n = 76) and plasma (n = 86) across three ALS biorepositories/cohorts. ADEV quality and enrichment were validated in accordance with minimal information for studies of extracellular vesicles guidelines, and protein levels were normalized by ratio to tetraspanin cluster of differentiation 81 (CD81). Diagnostic accuracy was evaluated by logistic regression and random forest models with cross-validation, adjusting for age and sex across 100 random seeds. Plasma ADEV pTDP-43/CD81 ratio best predicted ALS case status, with a mean AUC of 0.89 (95% CI: 0.75-0.99) from logistic models, corresponding to a mean sensitivity and specificity of 87% and 89%, respectively, and a mean AUC of 0.86 (95% CI: 0.82-0.90) from random forest models. Although the specificity of ADEV pTDP-43 relative to disease mimics and associations with disease progression require further investigation, these findings support its potential as a biomarker candidate for ALS and for patient stratification in TDP-43-targeted clinical trials.}, } @article {pmid42723096, year = {2026}, author = {Persico, M and Tuithung, S and Lorenzo, A and Crawford, D and Eleuteri, S and Simon, DK}, title = {Retromer-targeted therapy for neurodegenerative diseases.}, journal = {Molecular neurodegeneration}, volume = {21}, number = {1}, pages = {}, pmid = {42723096}, issn = {1750-1326}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; *Vesicular Transport Proteins/metabolism ; *Endosomes/metabolism ; Mitochondria/metabolism ; Lysosomes/metabolism ; }, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases characterized by dysfunction of the endosomal-lysosomal system (ELS). Four shared neurodegenerative mechanisms across ALS, PD and AD are regulated by the ELS, namely proteostasis and related protein misfolding, mitochondrial function, neurotransmission and neuroinflammation. These mechanisms are interconnected, contributing to neurodegeneration in a "snowball" manner. The retromer, a multimeric, evolutionarily conserved protein complex involved in intracellular protein trafficking, is at the crossroad of these neurodegenerative processes. This narrative review focuses on exploring the retromer structure, function as a master regulator of the ELS, and how this impacts proteostasis, mitochondrial biogenesis and homeostasis, neurotransmission and neuroinflammation across neurodegenerative diseases. We explore how alterations in retromer function can play an important role in neurodegeneration and discuss the impact of genetic and pharmacological manipulations of VPS35, one of the main retromer subunits. In vitro and in vivo studies have identified that the retromer enhances the activity of protein degradation pathways via the ELS, namely macroautophagy, chaperone-mediated autophagy, and the ELS itself, with concomitant reduction in misfolded protein levels. Also, in some model systems, when the retromer role is enhanced or restored, mitochondrial function is rescued, dysfunctional neurotransmission is restored, and the damaging effects of neuroinflammation are dampened. Lastly, we highlight the role of a novel pharmacological class of agents that enhance retromer function as a strategy for potentially slowing the progression of these neurodegenerative diseases in in vivo models of PD and ALS. We discuss the challenges in targeting the retromer, current limitations and potential off-target effects of retromer enhancement. Overall, the retromer regulates shared mechanisms across neurodegenerative diseases and retromer enhancers could represent a novel disease-modifying strategy in AD, PD and ALS.}, } @article {pmid42723432, year = {2026}, author = {Kohon, J and Tunalilar, O and Jespersen, B and Dys, S and Toda, E and Carder, P}, title = {Where the Wildfires Are: Correlates of Disaster Preparedness Among Oregon Assisted Living Communities.}, journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society}, volume = {45}, number = {10}, pages = {1913-1923}, doi = {10.1177/07334648251414184}, pmid = {42723432}, issn = {1552-4523}, mesh = {Humans ; Oregon ; *Disaster Planning/organization & administration ; *Wildfires ; Geographic Information Systems ; *Assisted Living Facilities/organization & administration ; Aged ; Dementia ; }, abstract = {Assisted living communities (ALs) serve a growing population of older adults with long-term care needs, especially those with Alzheimer's and other dementias (ADRD), yet their capacity to prepare for hyper-complex climate-related disasters remains underexamined. Using geographic information systems (GIS), we mapped all licensed ALs with the Oregon Department of Forestry's wildfire hazard scores, and then assessed organizational correlates of preparedness with a representative sample of Oregon ALs (n = 321). ALs located in higher wildfire risk areas reported greater confidence in wildfire preparedness and were more likely to have received training and taken actions related to defensible space. However, communities serving residents with ADRD, as well as larger, nonprofit, and chain-affiliated ALs, expressed less confidence in engaging residents and implementing disaster protocols. These findings highlight important geographic and structural disparities in preparedness and underscore the need for tailored planning strategies that consider organizational characteristics and the increasing complexity of climate-related emergencies.}, } @article {pmid42723774, year = {2026}, author = {Wang, H and Sun, B and Wang, S and Pan, J and Du, R and Pang, X and Bai, J and Han, J and Feng, J}, title = {Integrated multi-omics identification of m6A-SNP-related diagnostic biomarkers in amyotrophic lateral sclerosis.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1914869}, pmid = {42723774}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Polymorphism, Single Nucleotide ; Biomarkers ; Multiomics ; RNA Methylation ; Quantitative Trait Loci ; Epitranscriptome ; *Adenosine/analogs & derivatives ; Gene Expression Profiling ; Genetic Predisposition to Disease ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) lacks reliable and minimally invasive biomarkers for early diagnosis. m6A-associated single-nucleotide polymorphisms (m6A-SNPs) may influence RNA methylation and gene expression, offering opportunities to identify clinically relevant diagnostic markers.

METHODS: We integrated eQTLGen cis-eQTL data, RMVar m6A-SNP annotations, and ALS transcriptomic datasets to identify m6A-SNP-related genes. Random Forest and LASSO regression were combined to screen robust diagnostic markers. A nomogram was constructed and validated using independent cohorts. Immune infiltration, predicted m6A modification sites, and potential RBP-SNP interactions were assessed. Peripheral blood samples from ALS patients were used for exploratory validation of gene expression and global m6A levels.

RESULTS: We identified 109 ALS-associated m6A-SNP-related genes with cis-eQTL signals and narrowed these to seven candidate diagnostic markers (TMED5, OXR1, BRI3, FEM1C, SUZ12, EIF2AK4, and TJAP1). The seven-gene model outperformed the individual markers in the training cohort and retained moderate discrimination in the independent validation cohort. ALS samples showed differences in inferred immune-cell composition, including monocytes, neutrophils, and T-cell subsets. The selected SNP loci were located near predicted m6A sites and annotated RBP-binding regions. Exploratory clinical validation showed significant upregulation of FEM1C and SUZ12 at both mRNA and protein levels, accompanied by reduced global m6A modification.

CONCLUSIONS: Through multi-omics integration and exploratory clinical validation, this study identifies m6A-SNP-related candidate markers associated with ALS. The findings support further evaluation of m6A-related signatures for ALS discrimination and molecular characterization, while larger independent cohorts and additional calibration are required before clinical application.}, } @article {pmid42724094, year = {2026}, author = {Gomes-Duarte, A and Pascoal, S and Haselberg, R and Sogorb-Gonzalez, M and van Deventer, S}, title = {Correction: Targeting oxidized phosphatidylcholines in SOD1-associated ALS: therapeutic potential of PC-OxPL-VecTab[®].}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1960544}, doi = {10.3389/fnins.2026.1960544}, pmid = {42724094}, issn = {1662-4548}, abstract = {[This corrects the article DOI: 10.3389/fnins.2025.1620181.].}, } @article {pmid42724165, year = {2026}, author = {Alauddin, W and Srivastava, C and Goyal, P and Shukla, M and Garg, DK and Prajesh, BR and Singh, S and Shaikh, FI and Khairnar, S}, title = {Gut Microbiota, Neuroinflammation, and Autonomic Dysfunction in Neurodegenerative Diseases: A Systematic Review of Mechanistic and Translational Evidence.}, journal = {Cureus}, volume = {18}, number = {8}, pages = {e114312}, pmid = {42724165}, issn = {2168-8184}, abstract = {Neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, multiple system atrophy, and amyotrophic lateral sclerosis, are increasingly recognized as complex conditions arising from interactions among the gut microbiota, immune system, and autonomic nervous system. Growing evidence indicates that disruption of the intestinal microbial ecosystem may contribute to neuroinflammatory processes, autonomic impairment, and progressive neurodegeneration through the microbiota-gut-brain axis, although the underlying mechanisms and their translational implications remain incompletely understood. This systematic review was conducted in accordance with the PRISMA 2020 guidelines to comprehensively evaluate the evidence linking gut microbiota dysbiosis with neuroinflammation and autonomic dysfunction across neurodegenerative diseases. A systematic search of PubMed/MEDLINE, Scopus, Web of Science, EMBASE, EBSCOhost, CINAHL, PsycINFO, CENTRAL, Google Scholar, and major grey literature sources yielded 2,769 records. After duplicate removal and eligibility screening, 62 full-text reports underwent detailed assessment, of which 11 studies met the predefined eligibility criteria and were included in the qualitative synthesis. The evidence encompassed human observational, animal experimental, and in vitro approaches, with several studies integrating complementary clinical, microbiome, and experimental methodologies. Most included studies focused on Parkinson's disease and multiple system atrophy. Across studies, microbial dysbiosis was characterized by reduced abundance of short-chain fatty acid (SCFA)-producing bacteria alongside increased representation of pro-inflammatory microbial taxa. These microbial alterations were associated with disruption of intestinal barrier integrity, activation of inflammatory signaling pathways, microglial activation, elevated pro-inflammatory cytokine production, α-synuclein aggregation, and autonomic manifestations such as gastrointestinal dysmotility and cardiovascular autonomic dysfunction. Experimental studies provided biological support for the microbiota-gut-brain axis, whereas clinical investigations consistently demonstrated associations without establishing causality. Overall, current evidence suggests that gut microbial dysbiosis is closely associated with neuroinflammation and autonomic dysfunction in neurodegenerative diseases and may represent a promising avenue for biomarker discovery and therapeutic intervention. Nevertheless, the available literature is constrained by methodological heterogeneity, limited sample sizes, and the predominance of observational and preclinical studies. Future large-scale longitudinal investigations and rigorously designed randomized controlled trials are required to determine causal relationships and define the clinical utility of microbiome-targeted strategies.}, } @article {pmid42725023, year = {2026}, author = {Xiao, X and Cao, G and Hou, S and Yin, H}, title = {P2X7 Receptor in Rare Diseases: Shared Molecular Mechanisms and Therapeutic Implications.}, journal = {Journal of inflammation research}, volume = {19}, number = {}, pages = {613821}, pmid = {42725023}, issn = {1178-7031}, abstract = {Rare diseases (RDs) are individually uncommon but collectively affect a large global population, and the vast majority still lack effective disease-modifying therapies. With advances in genomics and data-sharing platforms, research has increasingly shifted from a single-disease perspective to the search for convergent molecular pathways that might be shared across clinically distinct entities. In this context, the purinergic P2X7 receptor (P2X7R) has emerged as a putative "shared molecular platform" due to its central role in inflammation amplification, cell death and immune regulation. P2X7R is an ATP-gated ion channel with unique structural and functional features: under high extracellular ATP, it not only forms a non-selective cation channel but can also dilate into a "large pore" permeable to macromolecules, thereby triggering Ca[2+]overload, NLRP3 inflammasome assembly, reactive oxygen species (ROS) production and apoptotic/necrotic-like cell death. This review briefly outlines the epidemiology of RDs and the structural-functional characteristics of P2X7R, then systematically summarizes current evidence linking P2X7R to multiple rare diseases, including Charcot-Marie-Tooth disease, Guillain-Barré syndrome, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and selected inflammatory and metabolic RDs (CAPS, familial Mediterranean fever, Systemic sclerosis, Dravet syndrome and Gaucher disease). By comparing P2X7R expression and functional alterations, downstream signaling pathways and pharmacological data from animal models across these conditions, we propose that a P2X7R-dependent network centered on a "Ca[2+]-NLRP3-inflammation/cell death axis" may constitute a common pathogenic backbone for diverse RDs. At the same time, disease-specific spatiotemporal expression patterns of P2X7R in central vs peripheral nervous systems and in immune vs target organ cells confer marked context dependence and "double-edged sword" properties. Finally, we discuss opportunities and challenges for P2X7R-targeted strategies, including the impact of disease stage and sex differences on therapeutic efficacy, and key bottlenecks in translating preclinical findings into clinical benefit. A deeper understanding of both shared and disease-specific roles of P2X7R may provide a conceptual framework and therapeutic entry point for precision stratification and multi-target interventions in rare diseases.}, } @article {pmid42725432, year = {2026}, author = {Wieland, CM and Wright, SE and Willey, S and Purwar, I and Grudzien, SJ and Krans, A and Laimon, EL and Asher, MJ and Isaacs, AM and Garner, AL and Todd, PK}, title = {Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.}, journal = {Nucleic acids research}, volume = {54}, number = {17}, pages = {}, pmid = {42725432}, issn = {1362-4962}, support = {R01 NS086810/NS/NINDS NIH HHS/United States ; R01NS099280/NH/NIH HHS/United States ; I01BX004842-04/BX/BLRD VA/United States ; F31 NS113513/NS/NINDS NIH HHS/United States ; R35 GM153185/GM/NIGMS NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; R35 GM153185/NH/NIH HHS/United States ; //NGP/ ; T32 GM141840/NH/NIH HHS/United States ; P50 HD104463/HD/NICHD NIH HHS/United States ; P50HD104463/NH/NIH HHS/United States ; F31NS113513/NH/NIH HHS/United States ; T32 GM141840/GM/NIGMS NIH HHS/United States ; //UM MSTP/ ; R01NS086810/NH/NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; }, mesh = {*Neurons/metabolism ; *Codon, Initiator ; Animals ; Humans ; RNA Caps/metabolism/genetics ; C9orf72 Protein/genetics ; *Peptide Chain Initiation, Translational ; *Protein Biosynthesis ; DNA Repeat Expansion ; Eukaryotic Initiation Factor-4E/antagonists & inhibitors ; RNA, Messenger/metabolism/genetics ; Guanosine/analogs & derivatives/metabolism ; }, abstract = {Intronic GGGGCC repeat expansions in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This expansion supports a non-canonical form of translational initiation known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat proteins that contribute to neurodegeneration. Here, we find that the efficiency of RAN translation and its dependency on the 5' 7-methylguanosine mRNA cap are variable across cell types, with both rodent neurons and human iNeurons favoring cap-independent RAN translation from two distinct repeats (CGG and GGGGCC) across multiple reading frames. Treatment with an eIF4E inhibitor that blocks cap-dependent translation enhances RAN translation specifically in neurons. Intriguingly, cap-independent RAN translation exhibits less reliance on near-cognate codons for initiation than cap-dependent RAN translation. This finding led us to identify a surprising global alteration in neuronal start codon stringency as a contributor to the relatively higher cap-independent RAN translation in this cell type. This effect correlates with cytoplasmic redistribution of eIF1 in neurons and is reversed with overexpression of the eukaryotic initiation factor eIF5, which relaxes start codon stringency and preferentially enhances cap-dependent RAN translation. Together, these findings reveal several neuron-specific features of translational regulation that favor cap-independent RAN translation with implications for nucleotide repeat expansion disorder pathogenesis.}, } @article {pmid42725564, year = {2026}, author = {Peng, L and Ma, S and Liu, Y and Liu, S and Tang, L}, title = {Artificial liver support therapy alters TNFα and CD4+ T cell counts in liver failure: A pilot self-controlled study.}, journal = {The International journal of artificial organs}, volume = {}, number = {}, pages = {3913988261479971}, doi = {10.1177/03913988261479971}, pmid = {42725564}, issn = {1724-6040}, abstract = {BACKGROUND: Artificial liver support therapy (ALS) is increasingly used in liver failure, but its immunomodulatory effects remain incompletely understood. This pilot study aimed to investigate changes in plasma cytokines and T lymphocyte subsets following ALS.

METHODS: Twenty-seven patients with liver failure who received ALS were enrolled. Plasma levels of TNFα, IL-4, IL-6, IL-10, IL-17, IL-2, and IFN-γ, as well as T lymphocyte subsets (CD4+ T cell absolute count, CD4+/CD8+ ratio), were measured before and after treatment. Paired t‑tests were used for comparisons. Patients were dichotomized by median pre-treatment TNFα level to compare clinical outcomes.

RESULTS: After ALS, TNFα levels decreased significantly (2.537 ± 1.519 vs 1.522 ± 0.749 pg/mL, p = 0.004). IL-4 also showed a significant reduction (1.463 ± 1.165 vs 0.893 ± 0.648 pg/mL, p = 0.031). CD4+ T cell absolute count increased significantly (430.85 ± 220.15 vs 636.63 ± 429.27 cells/μL, p = 0.034). Total T cell count showed an increasing trend (788.70 vs 1093.63 cells/μL, p = 0.064). Patients with low pre-treatment TNFα levels (below median) had a significantly higher improvement rate compared to those with high TNFα levels (100% vs 71.4%, p = 0.036).

CONCLUSION: ALS therapy is associated with a significant reduction in TNFα and a significant increase in CD4+ T cell absolute count, suggesting potential anti‑inflammatory and immune‑restorative effects. Lower baseline TNFα levels may predict favorable short‑term outcomes.}, } @article {pmid42725680, year = {2026}, author = {Milone, M and Nicolau, S and Niu, Z and Liewluck, T and Sorenson, EJ and Shen, XM and Harper, CM and Litchy, WJ}, title = {TUBA4A Pathogenic Variant Manifesting With Adulthood-Onset Genetic Myasthenic Syndrome, Myopathy, and Infertility.}, journal = {European journal of neurology}, volume = {33}, number = {9}, pages = {e70753}, pmid = {42725680}, issn = {1468-1331}, support = {MDA Award ID: 497263//Muscular Dystrophy Association/ ; }, mesh = {Humans ; Female ; Middle Aged ; *Muscular Diseases/genetics/physiopathology/complications ; *Infertility, Female/genetics ; }, abstract = {OBJECTIVES: TUBA4A pathogenic variants are associated with ALS, frontotemporal dementia, spastic ataxia, spasticity, ataxia, Parkinson's disease, female infertility, macrothrombocytopenia, and myopathy. Four recently reported patients with TUBA4A neonatal/childhood onset myopathy had also a decrement on repetitive nerve stimulation (RNS), but such a finding was not further characterized. We describe a patient with a TUBA4A pathogenic variant with adulthood-onset genetic myasthenic syndrome accompanied by myopathy and infertility to highlight the neuromuscular junction defect as the main feature of the patient's phenotype.

METHODS: We reviewed the patient's clinical and laboratory findings and performed transcriptomic analysis on the patient's muscle.

RESULTS: A 53-year-old woman with infertility of unknown etiology manifested fatigability and proximal upper limb muscle weakness in her mid-30s, followed by lower limb involvement. Her examination showed proximal muscle weakness and fatigability but spared facial muscles. CK values were mildly elevated. Anti-AChR, MuSK, P/Q-type calcium channel, and LRP4 antibodies were absent. 2 Hz RNS showed decrement (-14% to -48%) in limb muscles that improved with 3,4-dyaminopyridine (3,4-DAP). Facilitation (231%) occurred in the trapezius. Muscle biopsy showed patchy loss of oxidative enzyme reactivity and no C5b9 or IgG at neuromuscular junctions. Whole genome sequencing identified a heterozygous known TUBA4A pathogenic variant (c.850G>A, p.Glu284Lys). Patient improved with 3,4-DAP and albuterol.

DISCUSSION: TUBA4A p.Glu284Lys can lead to treatable myasthenic syndrome with postsynaptic and likely presynaptic involvement, as suggested by the patient's electrophysiological findings and response to therapy. This patient expands the TUBA4A-disorder spectrum to include overlapping myasthenic syndrome-myopathy and shows that neuromuscular disease and infertility can occur within the same patient.}, } @article {pmid42727710, year = {2026}, author = {Inoue, Y and Tanaka, M and Oguchi, T and Sasaki, A and Saito, K and Inoue, A and Otsuka, N}, title = {Selective neuroprotection in the ALS-FTD spectrum: Mechanisms of neuronal resilience and translational perspectives.}, journal = {Brain research bulletin}, volume = {245}, number = {}, pages = {112111}, doi = {10.1016/j.brainresbull.2026.112111}, pmid = {42727710}, issn = {1873-2747}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as part of a broader clinico-pathological continuum encompassing frontotemporal dementia (FTD). Despite progressive degeneration across motor and cognitive neural systems associated with TDP-43 pathology, specific neuronal populations-including the oculomotor and abducens nuclei, Onuf's nucleus, and sensory dorsal column pathways-remain relatively preserved.

OBJECTIVE: Selectively preserved neuronal structures in ALS have largely been described as isolated neuropathological observations without sufficient mechanistic integration. This review aims to synthesize candidate intrinsic and microenvironmental mechanisms that may contribute to selective neuronal preservation and propose a translational framework for understanding neuronal resilience in the ALS-FTD spectrum.

METHODS: We conducted a comprehensive critical review of the literature addressing selective neuronal vulnerability and resistance in ALS-FTD, integrating comparative observations from related neurodegenerative and neuromuscular disorders. Particular emphasis was placed on candidate mechanisms associated with neuronal resilience, including Nrf2/ARE signaling, calcium homeostasis, glutamatergic receptor composition, glial-mediated neurotrophic support, and emerging transcriptomic evidence relevant to selective neuronal vulnerability.

RESULTS: Selective preservation of specific neuronal populations represents a distinctive biological characteristic of the ALS-FTD spectrum. Current evidence suggests that enhanced antioxidant defense, tightly regulated intracellular calcium dynamics, protective microenvironmental interactions, and other stress-response pathways may collectively contribute to resistance against TDP-43 proteinopathy. These findings may provide a mechanistic framework for understanding selective neuronal resilience and suggest potential avenues for future neuroprotective therapeutic development.

CONCLUSIONS: Integrating mechanisms of selective neuroprotection with translational neurobiological perspectives may provide a conceptual framework for ALS research. Leveraging preserved neural systems may not only inform biologically grounded supportive care strategies but also help identify mechanistically relevant targets for future disease-modifying interventions.}, } @article {pmid42727824, year = {2026}, author = {Li, X and Zhang, S and Liu, Y and Yu, X and Han, L and Liu, Y}, title = {Exploring the toxicological impact of BDE-209 on neurodegenerative diseases through network toxicology, molecular docking, molecular dynamics simulation and in-vitro study.}, journal = {Toxicology and applied pharmacology}, volume = {516}, number = {}, pages = {118034}, doi = {10.1016/j.taap.2026.118034}, pmid = {42727824}, issn = {1096-0333}, abstract = {Decabromodiphenyl ether (BDE-209) is a persistent flame retardant associated with neurotoxicity, but its potential links to neurodegenerative diseases remain unclear. We integrated network toxicology, molecular docking, molecular dynamics (MD) simulations, and in vitro experiments to investigate BDE-209 in Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Network analysis identified 90 shared targets, enriched in lipid metabolism, oxidative stress, and inflammatory pathways, including IL-17 and TNF signaling. Docking prioritized the FKBP12-mTOR complex as a candidate binding system, with a score of -8.6 kcal/mol. MD simulations supported the stability of the predicted pose, which was dominated by van der Waals and hydrophobic interactions involving PHE-128 and TRP-190. In differentiated PC12 cells, BDE-209 increased p-mTOR at 10 μM and IL-1β at 20 μM without overt cytotoxicity. Rapamycin attenuated the p-mTOR response, supporting mTOR involvement, although mTOR dependence of IL-1β induction was not established. At 40 μM, BDE-209 reduced viability, potentially confounded by precipitation or aggregation. These findings implicate mTOR dysregulation in BDE-209 cellular responses, but direct binding, chronic exposure, and in vivo disease relevance require further validation.}, } @article {pmid42728797, year = {2026}, author = {Sanghai, N and Pierce, K and Sharma, N and Leggett, S and Yadav, TC and Masrori, P and Atukorallaya, D and Palaniyandi, S and Marcogliese, PC and Tranmer, GK}, title = {Recent Advancements in Drug Delivery Across the Blood-Brain Barrier in Amyotrophic Lateral Sclerosis (ALS).}, journal = {CNS neuroscience & therapeutics}, volume = {32}, number = {9}, pages = {e71078}, pmid = {42728797}, issn = {1755-5949}, support = {RGPIN-2017-05938//Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant/ ; 202210PJT-495295/CAPMC/CIHR/Canada ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Blood-Brain Barrier/drug effects/metabolism ; Animals ; *Drug Delivery Systems/methods/trends ; Blood-Spinal Cord Barrier/drug effects/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neurodegenerative disease with limited therapeutic options. The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) present major obstacles to central nervous system (CNS) drug delivery, restricting the effectiveness of many potential therapies. Increasing evidence suggests that BBB and BSCB dysfunction are not only barriers to treatment but also important contributors to ALS pathophysiology.

OBJECTIVE: To examine current evidence regarding BBB and BSCB dysfunction in ALS and evaluate the implications of stage-dependent barrier alterations for CNS drug delivery and therapeutic outcomes.

METHODS: Recent mechanistic, pathological, preclinical, and clinical studies examining BBB and BSCB alterations in ALS were reviewed. Evidence on tight junction disorganization, endothelial dysfunction, vascular leakage, altered transporter activity, and emerging therapeutic and drug delivery strategies was analyzed.

RESULTS: Converging evidence indicates that BBB and BSCB dysfunction are intrinsic and progressive features of ALS pathophysiology rather than passive consequences of neurodegeneration. Barrier impairment emerges early in the disease course and evolves across clinical stages. Disruption of barrier integrity may increase motor neuron vulnerability while modulating CNS drug exposure. Emerging strategies that bypass, exploit, or restore barrier function hold promise for enhancing CNS bioavailability and improving therapeutic outcomes.

CONCLUSIONS: Improved understanding of barrier alterations may facilitate development of more effective CNS-targeted therapies and improve therapeutic outcomes in ALS patients.}, } @article {pmid42729071, year = {2026}, author = {Subramaniam, AG and de Andrade Gensas, LK and Gradus-Pery, T and Perlson, E}, title = {Quantitative Analysis of Axonal Degeneration and TDP-43 Aggregation in Compartmentalized Human iPSC-Derived Motor Neuron-Myotube Co-cultures.}, journal = {Bio-protocol}, volume = {16}, number = {17}, pages = {e5801}, pmid = {42729071}, issn = {2331-8325}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by early and spatially restricted pathology in motor axons, including distal degeneration and accumulation of aggregation-prone proteins such as TDP-43. However, a major limitation in the field has been the lack of approaches that enable robust, quantitative, and compartment-specific analysis of these early axonal events, particularly in human-relevant systems. Here, we describe an integrated experimental and analytical framework that enables quantitative dissection of axonal degeneration and protein aggregation, specifically within distal motor axons. By combining compartmentalized human co-cultures with a dedicated image analysis strategy, this approach enables selective and quantitative analysis of pathological processes specifically within axons, independent of surrounding tissues such as muscle and other cellular compartments. This framework captures both structural degeneration and protein aggregation dynamics at subcellular resolution, enabling spatially resolved quantitative analysis of disease-relevant changes along axons. Importantly, the analytical framework is not limited to TDP-43 but is broadly applicable to diverse aggregation-prone proteins, thereby providing a generalizable platform to study axonal pathology across neurodegenerative diseases. Together, this work provides a scalable approach for investigating axonal pathology as an early and measurable feature of neurodegeneration, with potential applications in mechanistic studies and therapeutic targeting in ALS and related disorders. Key features • Compartmentalized human induced pluripotent stem cell (iPSC)-derived motor neuron-myotube co-cultures for modeling distal axonal pathology. • Microfluidic separation of somatic and distal axonal compartments enabling spatial perturbation and analysis. • Quantitative imaging of neurofilament heavy chain (NFH)-associated axonal degeneration and pTDP-43 accumulation. • Semi-automated workflow for a reproducible, scalable, and modular pipeline for image quantification.}, } @article {pmid42730941, year = {2026}, author = {Xie, J and Xie, H and Li, Y and Jiang, W and Wang, X and Xie, Q and Song, X and Fan, D and Li, HF and Deng, B}, title = {Atherosclerotic Cardiovascular Diseases Increase ALS Risk by 82% While Optimal Cardiovascular Health Halves It: A 0.5-Million Prospective Cohort Study.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78321}, pmid = {42730941}, issn = {1531-8249}, abstract = {OBJECTIVE: The objective of this study was to determine whether prevalent atherosclerotic cardiovascular diseases (ASCVDs) increase the risk of amyotrophic lateral sclerosis (ALS) and whether high cardiovascular health (CVH) can offset this risk.

METHODS: We prospectively analyzed 502,279 UK Biobank participants (37-73 years) with linked electronic health records. Prevalent ASCVD (coronary artery disease [CAD], ischemic stroke [IS], and peripheral artery disease [PAD]) was ascertained at baseline. CVH was quantified using Life's Essential 8 and categorized as low, moderate, or high. Cox models, joint analyses, and Mendelian randomization were applied.

RESULTS: Over a median follow-up of 13.74 years, 675 incident ALS cases were documented. A history of ASCVD was associated with a 43% higher risk of ALS (hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.16-1.78, p = 0.001), primarily driven by CAD and IS. Conversely, high CVH was associated with a lower risk of ALS compared with low CVH (HR = 0.52, 95% CI = 0.33-0.81, p = 0.004). Joint analysis revealed that individuals with low CVH and pre-existing ASCVD exhibited the highest ALS risk. Mendelian randomization analyses provided supportive evidence consistent with the observational associations among CAD, IS, and ALS. The inverse association between CVH and ALS risk was most pronounced among participants aged ≤65 years.

INTERPRETATION: Prevalent ASCVD was associated with a higher risk of ALS, whereas high CVH was associated with a lower risk of ALS. These findings support a potential link between CVH and ALS susceptibility, particularly among individuals aged ≤65 years. ANN NEUROL 2026.}, } @article {pmid42732704, year = {2026}, author = {Riva-Rovedda, F and Calvo, A and Clari, M and Picciaiola, MV and Godono, A and Manera, U and Canosa, A and Palumbo, F and Moglia, C and Chiò, A and Rinaldo, RF and Tabbia, G and Solidoro, P and Dimonte, V}, title = {Time-dependent adherence to non-invasive ventilation in amyotrophic lateral sclerosis: an observational cohort study.}, journal = {Heart & lung : the journal of critical care}, volume = {80}, number = {}, pages = {102952}, doi = {10.1016/j.hrtlng.2026.102952}, pmid = {42732704}, issn = {1527-3288}, abstract = {BACKGROUND: Non-invasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS). However, adherence is frequently suboptimal and longitudinal outpatient data are limited.

OBJECTIVE: We assessed NIV adherence during the first year of outpatient adaptation, factors associated with time-dependent adherence, and the relationship between adherence and survival.

METHODS: We conducted a retrospective cohort study including individuals with ALS prescribed with NIV between January 2022 and June 2024 at the outpatient clinic of an Italian referral centre. Functional status, adherence, and device-related complications were recorded at 1, 3, 6, and 12 months. Data about deaths and tracheostomy events were collected.

RESULTS: Complete adherence data were available for 73 patients. Mean NIV use increased; nevertheless, approximately 30% of patients were non-adherent at 6 and 12 months. NIV-related complications ranged between 30-44%, though they were not significantly associated with adherence. Higher ALSFRS-R respiratory subscore (OR=0.78, 95% CI 0.64-0.95) and having a male caregiver (OR=0.19, 95% CI 0.04-0.96) were associated with reduced adherence. Time-dependent adherence was not significantly associated with survival, whereas older age at diagnosis and PEG placement were associated with a 5% and more than threefold higher risk of death/tracheostomy, respectively (HR 1.05, 95% CI 1.01-1.09; HR 3.42, 95% CI 1.54-7.59).

CONCLUSION: NIV adherence and NIV-related complications showed dynamic patterns over time. One-third of patients were non-adherent at 6 and 12 months, highlighting the need for tailored interventions throughout follow-up. Although time-dependent adherence was not independently associated with survival, period-averaged adherence appeared to produce a more favourable survival estimate than time-dependent adherence.}, } @article {pmid42734068, year = {2026}, author = {Villarroel-Campos, D and Sleigh, JN}, title = {Hyperactive KIF5A in Neurodegeneration.}, journal = {Cytoskeleton (Hoboken, N.J.)}, volume = {}, number = {}, pages = {e70204}, doi = {10.1002/cm.70204}, pmid = {42734068}, issn = {1949-3592}, support = {MR/Y010949/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {The highly polarised morphology of neurons and the sheer length of their axons make transport of cargoes throughout the cell a formidable task. Decades of evidence obtained from genetic studies on patients and animal models highlight deficits in axonal transport as a recurrent cause, or early contributing factor, in a plethora of neurodegenerative diseases. Axonal transport abnormalities usually manifest as a slowing of cargo trafficked by molecular motors along microtubules; however, hyperactivation of motors can also lead to disease. That is the case for the kinesin-1 protein KIF5A, in which hyperactive mutations are linked to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus (NEIMY). In this Perspective, we summarise the latest insights into the impact of KIF5A hyperactivity, such as loss of autoinhibition, aggregation, altered cargo binding and microtubule damage. We conclude by discussing possible strategies to counteract these disruptions, with an emphasis on the necessity of restoring axonal transport to physiological levels, a key requirement to maintain neuronal homeostasis.}, } @article {pmid42734657, year = {2026}, author = {Urusov, AE and Gorobets, MA and Aulova, KS and Timofeeva, AM and Toporkova, LB and Orlovskaya, IA and Ustyugov, AA and Nevinsky, GA}, title = {Autoimmune processes and production of catalytically active antibodies-abzymes in prone to amyotrophic lateral sclerosis FUS(1-359) mice.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {75}, number = {1}, pages = {}, pmid = {42734657}, issn = {1420-908X}, mesh = {Animals ; *Antibodies, Catalytic/blood/immunology ; *Amyotrophic Lateral Sclerosis/immunology/blood/genetics/pathology ; Mice, Transgenic ; Mice ; Immunoglobulin G/blood/immunology ; Autoimmunity ; Female ; *RNA-Binding Protein FUS/genetics ; Disease Models, Animal ; }, abstract = {OBJECTIVE: It was shown previously that the development of not only many autoimmune (AIDs) but also neurological and neurodegenerative diseases (NDDs) including multiple sclerosis, tick-borne encephalitis, and schizophrenia in humans and experimental mice models occurs due to a specific destruction of the immune system. This error in the immune system leads to the formation of B lymphocytes producing adverse antibodies-abzymes possessing different catalytic activities.

METHODS: One of the earliest and statistically reliable index of developments of autoimmune reactions is the appearance in the blood abzymes that are absent in conditionally healthy donors. We investigated the in time changes catalytic activities of Abs-abzymes using standard methods of enzymology.

RESULTS: It was shown for the first time that, as in the case of various AIDs and NDDs, the early stages of ALS development in FUS(1-359) mice are also associated with the production of catalytic antibodies. CD-1 mice utilized for obtaining FUS(1-359) mice were also used. IgG samples were isolated from the blood of transgenic FUS(1-359) mice and their non-transgenic siblings (CD1) at different times. The first signs of ALS-like symptoms develop at the age of ≥ 2 months of life in FUS(1-359) mice, which was taken as zero time point, and then by ≥ 80 days of age, deep pathology was observed. It was shown for the first time that antibodies from the blood of FUS(1-359) mice exhibit DNase, amylase, phosphatase, and catalase catalytic activities beginning from 2 months of age. However, unlike non-transgenic siblings, the relative activity of mice IgGs was higher in FUS(1-359) mice. All activities of FUS(1-359) mice IgGs began to increase significantly starting from 20 to 30 days after beginning of experiments and achieved maximum upon reaching deep pathology.

CONCLUSIONS: The data obtained indicate that in the early stages of ALS development in FUS(1-359) mice containing genes associated with this pathology in humans, there is a disruption of the immune system and production of abzymes that destroy components of blood, cells and tissues. One cannot exclude that such autoimmune reactions are important for development of ALS in FUS(1-359) mice.}, } @article {pmid42734724, year = {2026}, author = {Steger, L and Rothhammer, V and Zunke, F}, title = {Astrocytes in Neurodegeneration: Spatial States, Crosstalk, and Emerging Therapies.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42734724}, issn = {1559-1182}, support = {S3- AstroFinder//Interdisziplinäres Zentrum für Klinische Forschung; IZKF, Erlangen/ ; 505539112//Deutsche Forschungsgemeinschaft/ ; }, mesh = {*Astrocytes/pathology/metabolism ; Animals ; Humans ; *Neurodegenerative Diseases/pathology/therapy/metabolism ; *Nerve Degeneration/pathology/therapy ; }, abstract = {Astrocytes are increasingly recognized as active drivers of neurodegeneration rather than passive responders. Single-cell and spatial transcriptomic analyses reveal that astrocytes occupy heterogeneous, regionally patterned states that align closely with selective neuronal vulnerability. Across Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, and rare primary astrocytopathies, astrocytes consistently converge on dysfunction across four mechanistic axes: breakdown of glutamate homeostasis, impaired ion and water buffering, lysosomal, and autophagic insufficiency, as well as maladaptive inflammatory-stress signaling. Spatial multi-omics demonstrates that these disruptions are not uniformly distributed but instead map to discrete niches, including plaque-adjacent astrocytes in Alzheimer's disease, CD44-high fibrotic-like astrocytes in the substantia nigra in Parkinson's disease, and EAAT2-low ventral horn astrocytes in ALS, consistent with patterns of selective neuronal vulnerability. Primary astrocytopathies including Alexander disease, vanishing white matter disease, and megalencephalic leukoencephalopathy illuminate the causal power of perturbing individual astrocytic modules, revealing how isolated disruptions in proteostasis, translation control, or ion-water coupling can initiate widespread neurodegeneration. By integrating neuropathological, imaging, and transcriptomic evidence across studies, we derive a consensus-based regional framework of astrocytic vulnerability across neurodegenerative diseases. Together, these findings define a unifying framework in which astrocytes transition from homeostatic regulators to pathological amplifiers, highlighting astrocyte states as tractable, region-specific therapeutic targets and illustrating how integration of spatial atlases with mechanistic insights might help develop a framework for targeted astrocyte therapies.}, } @article {pmid42734825, year = {2026}, author = {P Padhiyar, D and Butani, S and Patel, RJ}, title = {Optimization and characterization of lipid-based nanocarriers for intranasal delivery in amyotrophic lateral sclerosis.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {42734825}, issn = {1432-1912}, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder for which effective brain delivery of therapeutics remains challenging. Riluzole, a Biopharmaceutics Classification System class II drug used in the management of amyotrophic lateral sclerosis, exhibits low aqueous solubility and undergoes first-pass metabolism, which may limit its bioavailability. The present study aimed to develop and optimize riluzole-loaded nanostructured lipid carriers for intranasal delivery. Riluzole-loaded nanostructured lipid carriers were prepared by the melt-emulsification method and optimized using a four-factor, three-level Box-Behnken design. The effects of lipid composition ratio, surfactant concentration, sonication time, and stirring time on particle size, polydispersity index, and encapsulation efficiency were evaluated. The optimized formulation showed a particle size of 98.43 nm, a polydispersity index of 0.3, a zeta potential of -6.22 mV, an encapsulation efficiency of 89.4%, and a drug loading of 8.94%. Transmission electron microscopy demonstrated spherical nanoparticles, while differential scanning calorimetry and X-ray diffraction findings suggested reduced crystallinity and amorphization of riluzole within the lipid matrix. Fourier transform infrared spectroscopy indicated no significant drug-excipient incompatibility. The optimized formulation exhibited sustained drug release, with approximately 84% drug release over 24 h, and remained stable for 60 days at room temperature. These findings suggest that riluzole-loaded nanostructured lipid carriers are a promising lipid-based nanocarrier system for intranasal delivery and further biological evaluation for nose-to-brain drug delivery in amyotrophic lateral sclerosis.}, } @article {pmid42735486, year = {2026}, author = {Cao, Q and Jiang, Z and Wang, Z and Wee, L and Dekker, A and Zhang, Z and Zhu, J}, title = {Corrigendum to "Minimum sample size calculation for radiomics-based binary outcome prediction models: tutorial and practical example based on Riley et al's theoretical framework" [Radiother. Oncol. 212 (2025) 111134].}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {224}, number = {}, pages = {111771}, doi = {10.1016/j.radonc.2026.111771}, pmid = {42735486}, issn = {1879-0887}, } @article {pmid42735682, year = {2026}, author = {Cousin, MA and Dagli, AI and Mignon, L and Shah, JS and Prudencio, M and Gendron, TF and Jain, A and Udine, E and van Blitterswijk, M and Middlebrooks, EH and Donahue, MH and Dagher, JE and Watzlawik, JO and Springer, W and Parekh, T and McEachin, ZT and Petrucelli, L and Oskarsson, B}, title = {N-of-1 investigational study of a novel antisense oligonucleotide drug in CHCHD10-related ALS shows early signs of efficacy.}, journal = {Med (New York, N.Y.)}, volume = {}, number = {}, pages = {101295}, pmid = {42735682}, issn = {2666-6340}, support = {KL2 TR002379/TR/NCATS NIH HHS/United States ; U01 NS134684/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Pathogenic CHCHD10 variants cause a rare, dominantly inherited form of amyotrophic lateral sclerosis (ALS). Non-allele-selective CHCHD10 knockdown may mitigate a toxic gain-of-function mechanism. We evaluated nL-CHCHD-001 in one participant with the p.Arg15Leu variant.

METHODS: In this open-label N-of-1 study, 320-gapmer antisense oligonucleotides (ASOs) were screened, and a lead candidate was selected according to specificity and non-clinical safety criteria. Six intrathecal doses were administered over 12 months (three 50-mg doses followed by three 75-mg doses). Prespecified primary outcomes were 12-month changes in functional, cognitive, quality-of-life, respiratory, neurofilament light (NfL), and survival measures; secondary outcomes assessed were safety and tolerability. Analyses were descriptive.

FINDINGS: No serious adverse events occurred. Post-dose headache and fatigue were mild to moderate, and cerebrospinal fluid safety results were unremarkable. Plasma NfL decreased by approximately 50% from a mildly elevated pretreatment baseline and entered the laboratory reference range. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score increased from 33 to 36, vital capacity increased from 48% to 55% (as predicted), cognitive and quality-of-life scores remained stable, and the participant was alive at 12 months.

CONCLUSIONS: Individualized CHCHD10-directed treatment was feasible and well tolerated and was temporally associated with biomarker and clinical stability or improvement. This N-of-1 study demonstrates the feasibility of developing individualized ASO therapy for CHCHD10-related ALS and provides preliminary evidence of biomarker and clinical benefit. These findings support further evaluation of nL-CHCHD-001 and highlight NfL as a practical treatment-response biomarker for personalized therapeutics in ALS.

CLINICALTRIALS: gov: NCT06392126.

FUNDING: This study was supported by the n-Lorem Foundation, National Institutes of Health grants U01NS134684 and KL2 TR002379, and the Kevin Merszei Career Development Award.}, } @article {pmid42736322, year = {2026}, author = {Zussa, ZN and Smith, AN and van Vugt, JJFA and O'Shaughnessy, DS and Grima, N and Chan Moi Fat, S and Blair, IP and Rowe, DB and Pamphlett, R and Nicholson, GA and Kiernan, MC and van Rheenen, W and Veldink, J and , and Williams, KL and Henden, L}, title = {Characterising the motif composition and allele length distribution of ZFHX3 GGC repeat expansions in amyotrophic lateral sclerosis.}, journal = {Journal of human genetics}, volume = {}, number = {}, pages = {}, pmid = {42736322}, issn = {1435-232X}, support = {GNT2033019//Department of Health | National Health and Medical Research Council (NHMRC)/ ; }, abstract = {A pathogenic GGC repeat expansion in zinc finger homeobox 3 (ZFHX3), encoding a pure polyglycine (polyG) tract, causes spinocerebellar ataxia type 4 (SCA4). Intermediate expansions of other SCA loci have been implicated in amyotrophic lateral sclerosis (ALS), while repeat motif composition is recognised to influence pathogenicity in neurodegenerative diseases. Given the genetic pleiotropy between ALS and SCA, we evaluated whether ZFHX3 GGC expansions are associated with ALS and characterised repeat motif composition. ZFHX3 GGC repeat sizes were genotyped using ExpansionHunter in short-read whole-genome sequencing data from ALS cases and healthy controls of European ancestry. Repeat sizes were visually inspected using REViewer, and motif configurations were manually derived from a subset. Receiver operating characteristic analysis and Youden's J statistic identified a candidate repeat size threshold. Logistic regression tested associations of repeat length and motif composition with ALS, while regression models assessed clinical phenotypes. Across 5785 ALS cases and 7982 controls, no association was observed between ZFHX3 expansions and ALS risk. Longer alleles showed a nominal association with later disease onset, however this did not remain significant after Bonferroni correction. Among 802 ALS cases and 800 controls, 50 distinct motif compositions were identified, including 11 encoding pure polyG tracts characteristic of pathogenic SCA4 expansions; none were associated with ALS. Although no association with ALS was observed, this study established the dynamic nature of ZFHX3 repeat motif composition and configuration. Variation within and between repeat sizes, including pure polyG repeats, supports consideration of motif composition alongside allele length when evaluating neurodegenerative disease risk.}, } @article {pmid42736600, year = {2026}, author = {Benatar, M and Wuu, J and Turner, MR and Macklin, EA}, title = {The diagnostic biomarker problem in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag313}, pmid = {42736600}, issn = {1460-2156}, abstract = {In the effort to reduce the long diagnostic delay in amyotrophic lateral sclerosis, an often overlooked problem derives from confusion around the concept of diagnostic biomarkers and the type of data required to develop such tools. A useful diagnostic biomarker is one that can correctly differentiate individuals with, from those without, the disease of interest - and importantly, at a point in time when the diagnosis is otherwise uncertain. This requires a test with a high positive predictive value (the proportion of positive test results that are true positives), a high negative predictive value (the proportion of negative test results that are true negatives), or ideally both. Critically, positive and negative predictive values depend on the context of use for the diagnostic, which determines the prevalence of disease in the population in which the diagnostic test will be used. Almost all diagnostic biomarker studies in amyotrophic lateral sclerosis get this wrong - focusing on data and samples from patients for whom there is no diagnostic uncertainty. This Update distinguishes disease state biomarkers from diagnostic biomarkers; highlights the data required to clinically validate a diagnostic biomarker; underscores the critical importance of understanding the clinical context in which the diagnostic biomarker will be used; and outlines potential strategies for developing diagnostic biomarkers that might be clinically useful.}, } @article {pmid42737027, year = {2026}, author = {Musik, S and Zalewski, J and Jurkowska, J and Pędzimąż, W and Sasin-Kurowska, J and Panczyk, M}, title = {Leveraging Synthetic Clinical Data for Validation and Operational Readiness in Clinical Trials.}, journal = {Healthcare (Basel, Switzerland)}, volume = {14}, number = {17}, pages = {}, pmid = {42737027}, issn = {2227-9032}, support = {DWD/6/0494/2022//Ministry of Science and Higher Education/ ; }, abstract = {Background/Objectives: Obtaining timely access to detailed clinical trial data is not always straightforward. Privacy requirements, governance processes, and study-specific eCRF configurations can delay access, particularly during study start-up, when teams need realistic data to develop and test validation rules, reporting pipelines, and centralized monitoring tools. Methods: We developed SYNDATA, a modular framework that generates synthetic clinical trial datasets conforming to a target electronic case report form (eCRF). The framework combines study metadata from the Medidata Rave Architect Loader Spreadsheet (ALS) with selected empirical patterns learned from a closely matched reference study. It constructs patient-specific timelines from the ALS visit matrix, generates module-specific records using Bayesian networks for selected categorical dependencies and density-based methods for numeric and temporal variables, and applies postprocessing for counters, dictionary coding, and conditional missingness. A configurable Noise Tool injects controlled and reproducible data defects, including timeline inconsistencies, visit-window violations, numeric threshold exceedances, randomization or eligibility conflicts, and structural collisions, to stress-test downstream validation logic. Results: Synthetic and source data were compared descriptively using Jensen-Shannon distance, Cramér's V, and representative plots across selected domains. Several binary operational fields showed close descriptive agreement, whereas agreement was weaker for some more complex, multi-category safety- and medication-related variables. The evaluation covered a representative subset and does not establish uniform fidelity, formal statistical equivalence, or clinical validity across all generated domains. Conclusions: SYNDATA supports reproducible generation of ALS/eCRF-conformant datasets for operational validation, reporting development, and workflow testing before real trial data are available. Its demonstrated value is limited to the evaluated operational use case; fidelity is variable-specific, and more complex domains require further development and validation.}, } @article {pmid42737854, year = {2026}, author = {Ginanni, F and Nicoletti, F and Meoni, C and Becattini, L and Mancuso, M and Carlesi, C and Bianchi, F}, title = {Cognitive and Behavioural Profile of SOD1-ALS Across the ALS-FTD Spectrum: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {27}, number = {17}, pages = {}, pmid = {42737854}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology ; *Superoxide Dismutase-1/genetics ; *Frontotemporal Dementia/genetics/psychology ; *Cognition ; Mutation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is increasingly recognized as a multisystem disorder. However, SOD1-associated ALS has traditionally been regarded as an exclusively motor phenotype. This systematic review challenges that paradigm by characterizing the cognitive and behavioural profiles of SOD1 mutation-related ALS. Following PRISMA guidelines, a systematic PubMed search identified 17 eligible studies. Across the included studies, encompassing 222 patients with SOD1 variants, three of the analyzed subjects fulfilled the diagnostic criteria for frontotemporal dementia (FTD), and a larger proportion exhibited multidomain cognitive deficits, including executive dysfunction, language impairment, and working memory decline. Behavioural disturbances, such as apathy, emotional lability, and mental rigidity, were also prominent. The historical assumption that SOD1 mutations completely spare cognitive networks likely reflects an under-recognition of subtle manifestations, compounded by the limited sensitivity of earlier screening tools. These findings indicate that cognitive and behavioural involvement can occur in SOD1-ALS, highlighting a highly heterogeneous phenotype. Encompassing varying degrees of severity-from subtle differences in neuropsychological test scores to formal FTD diagnoses-the current evidence points towards possible variant-specific phenotypes rather than a uniform cognitive syndrome. Routine multidomain cognitive screening is crucial in this population. Properly characterizing these non-motor features allows for more accurate disease staging, better monitoring of clinical progression, and the implementation of truly personalized care strategies.}, } @article {pmid42738182, year = {2026}, author = {Savov, V and Antov, P and Kostadinova-Slaveva, A and Todorova, E and Yusein, J and Ivanov, G and Dudeva, V and Ninikas, K and Petrin, S and Seng Hua, L}, title = {Influence of the Spent Coffee Ground-to-Ammonium Lignosulfonate Ratio on the Performance of Wood-Fiber Biocomposites.}, journal = {Materials (Basel, Switzerland)}, volume = {19}, number = {17}, pages = {}, pmid = {42738182}, issn = {1996-1944}, support = {BG16RFPR002-1.014-0015//European Union/ ; BG05SFPR001-3.004-0010//European Union/ ; НИС-Б-1397/16 May 2025//University of Forestry/ ; }, abstract = {Spent coffee grounds (SCGs) and ammonium lignosulfonate (ALS) are promising renewable constituents for wood-fiber biocomposites, but the effect of their relative proportion within the binder phase remains insufficiently understood. This preliminary study evaluated wood-fiber panels produced at a constant dry-matter matrix-to-fiber ratio of 50:50 while varying the SCG:ALS ratio from 70:30 to 30:70. The panels were hot-pressed and characterized for their physical and mechanical properties, while the corresponding SCG-ALS matrix formulations were evaluated by simultaneous TGA-DSC analysis. Increasing the SCG fraction generally improved dimensional stability and mechanical performance, whereas formulations containing 50% or more ALS showed a marked deterioration in water resistance. The SCG-rich 70:30 formulation provided the highest bending performance, with MOE and MOR values of 2156.5 and 12.83 N·mm[-2], respectively. Thermal analysis revealed ratio-dependent changes in mass loss and in the principal heat-flow event, which occurred between approximately 113 and 136 °C, confirming that the SCG:ALS ratio altered the early thermal behavior of the binder system. Overall, the SCG:ALS ratio was identified as a key formulation parameter, with SCG-rich systems providing the most favorable balance between mechanical performance, dimensional stability, and internal cohesion.}, } @article {pmid42738680, year = {2026}, author = {Strekalova, T and Gorlova, A and Munter, JPM and Chervinskaya, M and Deykin, A and Aladysheva, Z and Grigorieva, E and Lyundup, A and Askarova, S and Kostin, A and Pomytkin, I}, title = {Beneficial Effects of Putative Hydrogen Sulfide (H2S) Donor POM16 in a Genetic Model of Amyotrophic Lateral Sclerosis, FUS [1-359]-Transgenic Mice.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {17}, pages = {}, pmid = {42738680}, issn = {1420-3049}, support = {AP23485236//Ministry of Science and Higher Education of the R public of Kazakhstan/ ; FZWG-2024-0003//Ministry of Science and Higher Education of RF/ ; 101086453//European Union/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Hydrogen Sulfide/metabolism/chemistry ; Mice, Transgenic ; Disease Models, Animal ; Mice ; Spinal Cord/metabolism/drug effects/pathology ; Oxidative Stress/drug effects ; Motor Neurons/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by rapid motoneuron degeneration. Hydrogen sulfide (H2S), a signaling molecule that regulates post-translational modification, has recently been implicated in the pathophysiology of ALS. Our study aimed to design, synthesize, and investigate the potential effects of (2S)-2-aminopentanethioic S-acid (POM16), an isomer of the slow-releasing H2S donor thiovaline, in a genetic ALS model. FUS [1-359]-tg mice, which recapitulate ALS syndrome, and their wild-type (WT) littermates received POM16 (at a dose of 50/mg/kg) or standard ALS therapy riluzole (at a dose of 8 mg/kg/day) dissolved in drinking water, or vehicle, for six weeks starting at nine weeks of age. The onset of paralysis, physiological and motor functions, muscle atrophy, density of spinal cord motoneurons, gene expression of proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF), and concentration of oxidative stress marker malondialdehyde (MDA) in the spinal cord were studied. POM16-treated mutants displayed significant improvements in body weight, water and diet intake, as well as behavior in the rotarod, wire, and pole tests. The percentage of mice with paralysis on the 6th week of dosing was reduced from 48% in vehicle-treated mutants to 16% in POM16-treated FUS [1-359]-tg mice, while in the riluzole-treated group, it was 38%, not reaching significance. Notably, muscle weight was not significantly improved by the latter treatment, unlike the dosing with POM16. In comparison with vehicle-treated FUS [1-359]-tg mice, POM16-treated mutants had significantly higher motor neuron density in the spinal cord, lower MDA levels, and reduced muscle atrophy ranking. Thus, new compound POM16 has a therapeutic potential to counteract ALS pathology that is likely mediated via anti-oxidative stress mechanisms. Given that any effective treatment of this devastating disease is currently lacking, it is hoped that POM16 can be a promising therapy for ALS.}, } @article {pmid42738830, year = {2026}, author = {Blair, K and Gosset, P and Martinez-Serra, R and Mórotz, GM and Martín-Guerrero, SM and Gomez-Suaga, P and Atherton, J and Mitchell, JC and Noble, W and Miller, CCJ and Markovinovic, A}, title = {Sigma-1 Receptor Stimulation Rescues FTD/ALS Mutant TDP43-Induced Disruption of the VAPB-PTPIP51 ER-Mitochondria Tethering Proteins via Inhibition of GSK3β.}, journal = {Cells}, volume = {15}, number = {17}, pages = {}, pmid = {42738830}, issn = {2073-4409}, support = {ARUK-PG2017B-3//Alzheimer's Research UK/ ; ARUK-DC2019-009//Alzheimer's Research UK/ ; MR/R022666/1/MRC_/Medical Research Council/United Kingdom ; MR/X021858/1/MRC_/Medical Research Council/United Kingdom ; AlzSoc-287/ALZS_/Alzheimer's Society/United Kingdom ; }, mesh = {*Receptors, sigma/metabolism/agonists ; Sigma-1 Receptor ; *Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; Humans ; *DNA-Binding Proteins/genetics/metabolism ; *Endoplasmic Reticulum/metabolism/drug effects ; *Mitochondria/metabolism/drug effects ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Mutation/genetics ; *Frontotemporal Dementia/genetics/metabolism ; *Mitochondrial Proteins/metabolism ; Animals ; Protein Binding/drug effects ; Mitochondria Associated Membranes ; Calcium/metabolism ; }, abstract = {Signalling between the ER and mitochondria regulates a number of key cellular functions that are damaged in frontotemporal dementia and related amyotrophic lateral sclerosis (FTD/ALS). This signalling involves close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ER-mitochondria "tethering" proteins. A number of studies have shown that mutant genes which cause familial FTD/ALS disrupt the VAPB-PTPIP51 tethers and that this involves activation of GSK3β. TDP43 is one such mutant and altered TDP43 metabolism is central to FTD/ALS pathogenesis. Loss of Sigma-1 receptor function is also seen in FTD/ALS and there is evidence that Sigma-1 receptor agonists can repair damaged ER-mitochondria signalling. However, the underlying mechanisms are not properly understood. In this study, we show that the reference Sigma-1 receptor agonist PRE-084 stimulates VAPB-PTPIP51 binding and rescues FTD/ALS mutant TDP43-induced disruption to the VAPB-PTPIP51 interaction and linked ER-mitochondria Ca[2+] delivery. We also show that these effects involve inhibition of the kinase GSK3β, a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that ANAVEX2-73, a further Sigma-1 receptor agonist which is in clinical trials for Alzheimer's disease, also stimulates VAPB-PTPIP51 binding via GSK3β inhibition. Our findings provide novel insights into the mechanisms by which Sigma-1 receptor agonists influence defective ER-mitochondria signalling in FTD/ALS.}, } @article {pmid42738833, year = {2026}, author = {Ayupova, AI and Sidorova, AS and Luzina, EA and Sufianov, AA and Sufianova, GZ and Zaynutdinov, AM and Rizvanov, AA and Solovyeva, VV}, title = {Application of Mesenchymal Stromal Cells and Their Exosomes in Neurodegenerative Diseases and Lysosomal Storage Diseases.}, journal = {Cells}, volume = {15}, number = {17}, pages = {}, pmid = {42738833}, issn = {2073-4409}, support = {FZSM-2026-0022//The Ministry of Education and Science of the Russian Federation/ ; }, mesh = {Humans ; *Exosomes/metabolism ; *Neurodegenerative Diseases/therapy/metabolism ; *Mesenchymal Stem Cells/metabolism/cytology ; *Lysosomal Storage Diseases/therapy/metabolism ; Animals ; *Mesenchymal Stem Cell Transplantation/methods ; }, abstract = {Mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic platform for central nervous system disorders, including neurodegenerative diseases and lysosomal storage disorders (LSDs). This review examines MSC mechanisms of action-paracrine activity, immunomodulation, antioxidant effects, TFEB-mediated autophagy regulation, and enzymatic cross-correction in LSDs-while critically assessing translational challenges. We provide a comparative analysis of MSC sources, administration routes, dosing regimens, and safety profiles, with emphasis on hemocompatibility and thrombotic risks. The evidence base for MSC efficacy in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and LSDs is systematically reviewed, highlighting both promising signals and limitations. MSC-derived extracellular vesicles are discussed as a cell-free alternative with improved safety and potential blood-brain barrier interaction. We propose an individualized monitoring framework integrating clinical scales, biomarkers, and neuroimaging. Despite preclinical promise, the field faces major hurdles: product standardization, optimal dosing, and the need for large, randomized controlled trials. The most rational path forward lies in combination strategies-MSCs as adjuncts to gene or enzyme replacement therapy-and engineered platforms for sustained delivery. This review provides a roadmap for translational decision-making and identifies critical gaps that must be addressed before MSC-based therapies can be integrated into routine neurological practice.}, } @article {pmid42738864, year = {2026}, author = {Ma, X and Liu, J and Guan, Y and Xu, C and Li, M and Zhang, X and Li, Z and Zhang, L and Wang, X and Zhang, H and Chen, Y}, title = {Lactate Metabolism and Signaling in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {15}, number = {17}, pages = {}, pmid = {42738864}, issn = {2073-4409}, support = {No.82571627//National Natural Science Foundation of China/ ; No.82271483//National Natural Science Foundation of China/ ; No. ZR2024MH112//Shandong Province Natural Science Foundation of China/ ; 202402010641//Shandong Provincial Medical and Health Science and Technology Development Plan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Lactic Acid/metabolism ; *Signal Transduction ; Animals ; Motor Neurons/metabolism/pathology ; Energy Metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons (MNs). Although the specific pathogenesis of ALS is not yet fully understood, there is increasing evidence that abnormal energy metabolism plays a key role in the onset and progression of the disease. Lactate has traditionally been considered a metabolic by-product of glycolysis and has received increasing attention in recent years. Research has shown that lactate is not only an important energy substrate but also a signaling molecule that regulates a variety of physiological processes, including neuron-glia metabolic coupling, neuroprotection and inflammatory responses. In ALS, abnormalities in lactate metabolism, dysfunction of the lactate shuttle, and dysregulation of lactate-related signaling pathways may jointly lead to neuronal energy deficits and increased neuroinflammation, thereby promoting MN degeneration. This review summarizes the latest advances in lactate metabolism and lactate-mediated signaling in ALS, with particular emphasis on their roles in neuronal energy regulation, neuroprotection and inflammatory regulation. In addition, we also discuss potential therapeutic strategies for lactate metabolism and its related pathways, aiming to provide new insights into the pathogenesis of ALS and the development of treatment methods for lactate-related metabolism.}, } @article {pmid42738890, year = {2026}, author = {Wolozin, B and Best, M and Ellini, M and Ma, Y and Bok, S and Hwang, D and Filipponi, C}, title = {The Paradox of Tau and RNA-Binding Proteins: How Adaptive Stress Granule Regulation Becomes Pathological with Aging.}, journal = {Cells}, volume = {15}, number = {17}, pages = {}, pmid = {42738890}, issn = {2073-4409}, support = {U01 AG082665/AG/NIA NIH HHS/United States ; R01 AG096052/AG/NIA NIH HHS/United States ; R01 AG080810/AG/NIA NIH HHS/United States ; AG080810, AG072577, AG082665, AG095773, AG096052 and AG064932/AG/NIA NIH HHS/United States ; U01 AG072577/AG/NIA NIH HHS/United States ; R01 AG095773/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Stress Granules/metabolism ; *tau Proteins/metabolism ; *RNA-Binding Proteins/metabolism ; *Aging/metabolism/pathology ; Animals ; Stress, Physiological ; DNA-Binding Proteins/metabolism ; Neurodegenerative Diseases/metabolism/pathology ; }, abstract = {RNA-binding proteins (RBPs) are a large class of proteins that form biological condensates to facilitate their functions. Chronic stress, such as occurs in neurodegenerative diseases, stimulates persistent accumulation of particular RBP condensates as part of the translational stress response, termed stress granules (SGs). These persistent SGs serve as a nidus for aggregation of RBPs to form pathologies that appear in neurodegenerative diseases, such as the occurrence of Tar DNA Binding Protein (TDP-43) in Amyotrophic Lateral Sclerosis. Many of the RBPs that accumulate in SGs are also associated with mutations that are linked to neurodegenerative diseases. The microtubule-associated protein tau is the major intracellular pathology that occurs in Alzheimer's disease. Tau is phosphorylated with stress, whereupon it functions to regulate SG biology; conversely, SGs serve as a crucible for the accumulation of toxic oligomeric tau. The regulation of stress by tau is an inherent part of biology that normally occurs during development and hibernation; however, with aging it becomes pathological, possibly because of the reduced proteostasis associated with aging.}, } @article {pmid42738892, year = {2026}, author = {Lysikova, E and Sitdikova, K and Makhambetova, A and Chaprov, K and Gorlova, A and Kostin, A and Novikova, P and Lyundup, A and Askarova, S and Kukharsky, MS and Deykin, A and Strekalova, T}, title = {Efficacy of Low Dose of Dihydroquercetin (DHQ) in Two Genetic Models of Neurodegeneration: Insights from FUS[1-359]-Tg and APPswe/PS1dE9 Paradigms.}, journal = {Cells}, volume = {15}, number = {17}, pages = {}, pmid = {42738892}, issn = {2073-4409}, support = {AP23485236, BR24992841//the Ministry of Higher Education and Science of the Republic of Kazakhstan/ ; FZWG-2021-0016 , FZWG-2024-0032, FZWG-2022-0023//and the Ministry of Science and Higher Education of RF/ ; Aqua-Synapse 101086453 EU//HORIZON EU/ ; }, mesh = {Animals ; *Quercetin/analogs & derivatives/pharmacology/therapeutic use/administration & dosage ; Mice, Transgenic ; Disease Models, Animal ; Mice ; *RNA-Binding Protein FUS/genetics/metabolism ; Alzheimer Disease/drug therapy/genetics/pathology ; Oxidative Stress/drug effects ; *Neurodegenerative Diseases/drug therapy/genetics ; Brain/pathology/drug effects ; Presenilin-1 ; Humans ; Male ; }, abstract = {Dihydroquercetin (DHQ), a powerful antioxidant and regulator of cellular metabolism, was proposed for therapy of neurodegenerative disorders. Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) are serious neurodegenerative disorders with oxidative stress as an overlapping feature and unmet therapeutic needs. To date, few studies have explored the efficacy of DHQ in animal models of genetically driven neurodegeneration. Here, APPswe/PS1dE9 (APP/PS1) mice and their wild-type (WT) littermates were orally administered DHQ (0.6 mg/kg/day) for four months, starting at eight months of age. At the age of 12 months, behavioral evaluation was performed, followed by brain staining with Congo red for amyloid plaque scoring and immunohistochemical analysis of GFAP-positive cells for the assessment of astrogliosis. Malondialdehyde (MDA) levels in the prefrontal cortex were studied as a marker of oxidative stress. Second, two-month-old FUS[1-359]-Tg mice, which recapitulate the hallmarks of ALS, received DHQ for 1.5 months and were investigated for general physiological parameters, the onset of paralysis, motor functions, and density of motor neurons in the spinal cord. DHQ-treated APPswe/PS1dE9 mutants displayed a decrease in amyloid plaque density of small size (≤100 μm) in the cortex and thalamus, had normalized MDA levels, improved conditioned taste aversion and Y-maze learning, and ameliorated anxiety measures, whereas their hippocampus-dependent step-down and pellet displacement performance remained impaired. In the second study, DHQ-treated FUS[1-359]-Tg mice showed rescued density of spinal cord neurons, normalized liquid and diet intake, and improved coat state, while the onset of paralysis and motor scores were not significantly ameliorated. Thus, chronic administration of low doses of DHQ exerted neuroprotective effects in both AD and ALS genetic models, which partially translated to reduced manifestations of these diseases.}, } @article {pmid42739085, year = {2026}, author = {Roscoe, SA and Allen, SP and McDermott, CJ and Stavroulakis, T}, title = {Serum Biomarkers for Nutritional Monitoring in Motor Neuron Disease: A Longitudinal Cohort Study.}, journal = {Nutrients}, volume = {18}, number = {17}, pages = {}, pmid = {42739085}, issn = {2072-6643}, support = {//University of Sheffield/ ; //Darby Rimmer ALS Foundation/ ; NIHR203321//NIHR Sheffield Biomedical Research Centre/ ; }, mesh = {Humans ; *Biomarkers/blood ; Female ; Male ; Longitudinal Studies ; *Motor Neuron Disease/blood/physiopathology/complications ; *Nutritional Status ; Middle Aged ; Aged ; Prospective Studies ; *Nutrition Assessment ; Inflammation/blood ; Disease Progression ; Body Composition ; Malnutrition/blood/diagnosis/etiology ; Severity of Illness Index ; Creatinine/blood ; }, abstract = {Background: Malnutrition and metabolic dysregulation are common in motor neuron disease (MND) and contribute to accelerated functional decline and reduced survival. Routine serum biochemical analytes can be used to assess nutritional status; however, their interpretation in MND is confounded by systemic inflammation and disease-related metabolic changes. This study investigated the relationship between serum biochemical analytes, inflammatory status, disease severity, progression, and body composition in people living with MND. Methods: In this single-centre, longitudinal prospective cohort study, 19 participants with confirmed MND were assessed at enrolment and at three-month intervals up to nine months. Serum concentrations of albumin, prealbumin, creatinine, transferrin, ferritin, retinol-binding protein, and lipid fractions were measured alongside routine inflammatory markers. Disease severity and progression were assessed using the revised ALS functional rating scale and King's College Staging System. Anthropometry included percentage weight change, body mass index, mid-upper arm circumference, triceps skinfold thickness, arm muscle area, and calf circumference. Participants with evidence of baseline inflammation were excluded from nutritional analyses. Results: Low-grade systemic inflammation was present in 9/19 (47%) of participants at enrolment, most commonly reflected by elevated fibrinogen. In the non-inflammatory sub-cohort (n/N = 10/19), serum creatinine was positively correlated with muscle-related functional subscores (p = 0.007) and declined between enrolment and three months (p = 0.02), showing predominantly negative trajectories by nine months. HDL cholesterol also declined over the nine-month follow-up (p = 0.03) and lipid fractions correlated positively with disease stage (p <0.001-0.02), suggesting evolving metabolic stress. Elevated serum retinol-binding protein was observed in 90% (n/N = 9/10) of participants without inflammation. Biochemical evidence of malnutrition (low transferrin and/or creatinine) was detected in one-third of participants, accompanied by weight loss and reductions in limb anthropometric parameters. Malnutrition risk was identified in 1/10 (10%) of the non-inflammatory sub-cohort using a modified ESPEN-based framework, and in 2/10 (20%) participants using GLIM criteria. Conclusions: Routine serum biochemical analytes provide complementary information on nutritional and metabolic status in MND when interpreted alongside inflammatory markers and anthropometry. Serum creatinine emerged as a longitudinal marker of muscle wasting, reflective of denervation and nutritional depletion, while lipid and retinol-binding protein alterations highlight non-nutritional disease mechanisms that may confound standard biomarker interpretation, informing more targeted nutritional assessments. These findings support a multimodal approach to nutritional monitoring in MND and emphasise the importance of accounting for inflammatory status in biomarker interpretation. Given the small sample size and the limited representation of non-ALS phenotypes, these findings should be regarded as hypothesis-generating and require confirmation in larger, multicentre cohorts with balanced phenotypic representation.}, } @article {pmid42739237, year = {2026}, author = {Altay, FP and Polat, ŞB and Fakı, S and Karaahmetli, G and Akdoğan, L and Topaloğlu, O and Ersoy, R and Çakır, B}, title = {From Detection to Decision: A Single-Center Analysis of Preoperative Imaging, Surgical Indications and Postoperative Histopathological Findings in Adrenal Lesions.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {16}, number = {17}, pages = {}, pmid = {42739237}, issn = {2075-4418}, abstract = {Background/Objectives: The aim of this retrospective study was to characterize the preoperative hormonal, biochemical, and imaging features of adrenal lesions (ALs) and to assess differences in these features between benign and malignant lesions. Methods: This was a retrospective, single-center observational study conducted at the Endocrinology Clinic of Ankara Bilkent City Hospital. We reviewed the medical records of all patients referred to our clinic for the evaluation of an AL between February 2019 and August 2025. Demographic and clinical data and initial imaging were extracted from electronic medical records. Results: A total of 157 patients who underwent adrenalectomy were included in the analysis. Of these, 98 patients were female (62.4%) and 59 were male (37.6%). The mean age of the patients was 51.2 ± 12.54 years. Functionally, the findings were pheochromocytoma (n:44), overt Cushing syndrome (n:17), mild autosomal cortisol secretion (n:29), primary hyperaldosteronism (n:18), and non-functional (n:47). One patient had pheochromocytoma and mild autosomal cortisol secretion, and one patient had overt Cushing syndrome and primary hyperaldosteronism. Of the adrenal lesions, 70 (44.6%) were on the right, 71 (45.2%) on the left, and 16 (10.2%) were bilateral. 9% (7/79) of lesions measuring 4 cm and above, and 14% (4/28) of lesions measuring 6 cm and above were found to be malignant. The malignancy rate was 22% (4/18) in lesions located on the right and measuring 6 cm and above. All adrenocortical carcinomas were larger than 4 cm (8.3 ± 3.46) and all were on the right. The highest-grade malignant epithelial tumor was 12.9 cm and on the right. The malignant pheochromocytoma was 5.2 cm and on the left. It was determined that the frequency of right adrenal localization was significantly higher in the malignant group (85.7%) compared to the benign group (42.7%) (p = 0.045). Right tumor diameter (p = 0.002) and right and/or left tumor diameter (p < 0.001) were significantly higher in malignant lesions compared to benign lesions. Logistic regression analysis also supported a significant relationship between tumor size and malignancy. Conclusions: In our study, 9% (7/79) of lesions measuring 4 cm and above, and 14% (4/28) of lesions measuring 6 cm and above were found to be malignant. The malignancy rate in lesions on the right side measuring 6 cm and above was determined to be 22% (4/18). Although benign masses constituted the majority of lesions measuring 4 cm and above, all adrenocortical carcinomas were above 4 cm (8.3 ± 3.46). In light of the current findings, tumor size was observed to be associated with the distinction between malignant and benign adrenal lesions and may be considered an important descriptive characteristic in the clinical assessment of adrenal lesions.}, } @article {pmid42739287, year = {2026}, author = {Chen, M and Li, H and Jin, Q}, title = {Presymptomatic Amyotrophic Lateral Sclerosis: From Early Biomarker Detection to Phenoconversion Prediction.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {16}, number = {17}, pages = {}, pmid = {42739287}, issn = {2075-4418}, support = {81671117//National Natural Science Foundation of China/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) usually enters diagnostic pathways after motor symptoms emerge, by which time neural injury has been ongoing. Long-term hereditary ALS cohorts show that some pathogenic-variant carriers may show elevated neurofilament light chain (NfL), mild motor impairment (MMI), electromyographic abnormalities, or imaging changes before clinical manifestation. Since 2022, research has shifted from detecting presymptomatic abnormalities to identifying observable prodromal phenotypes and predicting phenoconversion timing. Operational MMI criteria, longitudinal imaging in chromosome 9 open reading frame 72 (C9orf72) expansion carriers, TAR DNA-binding protein 43 (TDP-43)-related fluid biomarkers, and plasma proteomic models spanning prediction horizons have broadened early identification. The ATLAS study, a trial of tofersen initiated in clinically presymptomatic carriers of superoxide dismutase 1 (SOD1) variants, incorporated specific SOD1 variants and within-person NfL increases into risk monitoring and used these criteria to select participants for the randomized treatment phase. Evidence remains concentrated in a few genetic subtypes, and no single marker accurately predicts individual phenoconversion. Identification requires genotype-specific natural history, serial clinical examinations and biomarker testing, with clinical utility validated in independent longitudinal cohorts and prevention trials.}, } @article {pmid42740767, year = {2026}, author = {Stern, C and Pollock, D and Barker, T and Holland, GM and Hasanoff, S and Shrestha, N and Semendric, I and Bulto, LN and Sharma, S and Fragkoudi, A and Facchin-Young, SC and Day-Sharman, AM and Stollery, L and Beasley-Hall, J and Schubert, C and Giles, L and Merlin, T and Vucic, S and Whitehouse, J and Munn, Z}, title = {Protocol for the Development of The Australian Motor Neurone Disease (MND) Guideline.}, journal = {Clinical and public health guidelines}, volume = {3}, number = {1}, pages = {e70055}, pmid = {42740767}, issn = {2836-3973}, abstract = {INTRODUCTION: Motor neurone disease (MND) is a rare but devastating neurodegenerative condition that results in progressive muscle weakness, disability, and eventual respiratory failure. In Australia, the impact of MND is significant, and there is a pressing need for a high-quality, locally relevant guideline to support equitable, person-centred care.

QUESTIONS: This guideline aims to address key clinical and care-related questions that arise across the MND trajectory. It will identify the most pressing topics and uncertainties in MND management through interest holder consultation and structured prioritisation.

METHODS: The guideline will be developed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and will align with standards set by the National Health and Medical Research Council (NHMRC) and the Guidelines International Network (GIN). Governance will include a multi-tiered structure with lived experience representation. Implementation planning and evaluation will be integrated throughout, with a planned transition to a living guideline model supported by an ongoing evidence surveillance strategy.}, } @article {pmid42740795, year = {2026}, author = {Imamura, K and Yoshioka, S and Kamizato, K and Oki, R and Hioki, H and Tsukita, K and Inoue, I and Shimizu, R and Takiguchi, M and Sakasai, T and Okusa, A and Shibukawa, R and Niki, T and Sakurai, S and Okunomiya, T and Kondo, T and Kato, T and Miyanohara, A and Kakinohana, M and Yamamoto, T and Marsala, M and Nishida, K and Izumi, Y and Inoue, H}, title = {Base editing rescues a hereditary motor neuron disease in mouse and patient-derived iPSC organoid models.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {4}, pages = {201835}, pmid = {42740795}, issn = {3117-387X}, abstract = {In hereditary motor neuron diseases (MNDs), including forms of amyotrophic lateral sclerosis (ALS) caused by single-nucleotide variants, effective therapeutic strategies need to address both gain- and loss-of-function mechanisms. Genome editing-based gene therapy represents a promising approach for simultaneously targeting these mechanisms. To establish proof-of-concept for base editing in a hereditary MND, we targeted the P285L variant in the TRK-fused gene (TFG), which causes hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), a disorder that shares clinical and histopathological features with ALS. We identified the optimal adenine base editor by comparing candidate editors in HMSN-P patient-derived induced pluripotent stem cells (iPSCs). We then generated a transgenic mouse model expressing human TFG P285L and evaluated the selected editor by subpial delivery of adeno-associated virus (AAV) vectors to the spinal cord. AAV-mediated base editing prolonged survival, preserved motor neurons, and attenuated axon loss in ventral nerve roots. Treatment with the selected base editing vector reduced TFG aggregation and suppressed neuronal death in HMSN-P iPSC-derived neuromuscular organoids. Collectively, these findings support the therapeutic potential of base editing for hereditary MNDs.}, } @article {pmid42740981, year = {2026}, author = {Xie, G and Guo, Y and Wang, Z}, title = {Prevalence of and associated factors for sleep disorders in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1889217}, pmid = {42740981}, issn = {1664-2295}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications ; *Sleep Wake Disorders/epidemiology/etiology ; Prevalence ; }, abstract = {BACKGROUND: Sleep disorders stand as prevalent non-motor symptoms in individuals with amyotrophic lateral sclerosis (ALS) and may be linked to respiratory muscle weakness, neurodegenerative changes, and disruption of sleep architecture. Existing studies have reported considerable variability in the prevalence of sleep disorders in ALS patients, and findings regarding associated factors remain inconsistent. Therefore, this study intended to integrate the existing evidence through a meta-analysis to further clarify the prevalence of sleep disorders and their clinical relevant factors.

METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched from database inception to January 10, 2026. Cross-sectional, cohort, and case-control studies involving clinically diagnosed adult patients with ALS were included. A random-effects model was used to estimate the pooled prevalence of sleep disorders. Subgroup analyses were performed according to sex, site of onset, age, disease duration, body mass index (BMI), sleep disorder category based on the International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR), sleep-related treatment status, and assessment method (polysomnography [PSG] versus questionnaire-based assessment).

RESULTS: A total of 31 studies involving 2,762 patients with ALS were included. The pooled prevalence of sleep disorders was 50% (95% confidence interval [CI], 45-56%). Patients with sleep disorders were significantly older than those without sleep disorders (mean difference [MD] = 3.72 years, 95% CI, 2.39-5.05), whereas no significant associations were observed for sex, body mass index (BMI), disease duration, or site of onset. The prevalence did not differ significantly across the ICSD-3-TR categories (p = 0.7367), whereas questionnaire-based studies yielded a significantly higher pooled prevalence than PSG-based studies (p = 0.0367). Sensitivity analyses confirmed the robustness of the findings.

CONCLUSION: Approximately half of ALS patients have sleep disorders. Age may be related to the occurrence of sleep disorders, whereas no substantial relations were identified for sex, BMI, disease duration, or site of onset. Routine screening and early intervention for sleep issues should be strengthened in clinical management. Large-scale, multicenter prospective studies are still needed to further clarify the underlying mechanisms and clinical implications.

The publicly accessible registration URL is: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261287352. The systematic review was registered with PROSPERO (registration number: CRD420261287352).}, } @article {pmid42741310, year = {2026}, author = {Almeida, MR and Tábuas-Pereira, M and Matos, A and Santos, A and Teixeira, C and Baldeiras, I and Lima, M and Santana, I}, title = {The spectrum of C9orf72 repeat lengths in Portuguese frontotemporal dementia and amyotrophic lateral sclerosis patients: from pathogenic expansions to intermediate alleles.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1913909}, pmid = {42741310}, issn = {1662-4548}, abstract = {INTRODUCTION: Frontotemporal dementia and amyotrophic lateral sclerosis are clinically distinct disorders that share a common genetic etiology, with pathogenic hexanucleotide repeat expansions in the C9orf72 gene representing the most frequent genetic cause of both conditions. In this study we aim to determine the frequency of C9orf72 repeat expansions in patients with FTD and/or ALS and their at-risk relatives from central Portugal, and to analyze the distribution and repeat size of intermediate alleles within this cohort investigating their potential pathogenicity.

METHODS: Between January 2016 and January 2026, C9orf72 repeat expansions were assessed in 610 patients with the clinical presentation within the spectrum of FTD/ALS and in 63 asymptomatic relatives. C9orf72 repeat expansions were identified using a two-step PCR protocol comprising STR-PCR and RP-PCR, followed by repeat-length sizing with a commercial kit. Capillary electrophoresis traces were subsequently analyzed using AmplideX® PCR/CE Reporter software. Furthermore, carriers of intermediate alleles underwent comprehensive clinical, fluid-biomarker, and neuropsychological characterization to investigate the potential pathogenicity of these alleles.

RESULTS: Pathogenic C9orf72 expansions were identified in 11% of patients. The vast majority carried long expansions (>145 repeats), whereas three patients exhibited shorter expansions ranging from 38 to 78 repeats. Intermediate alleles were found in seven subjects with heterogeneous clinical presentations. Clinically, these individuals were indistinguishable from carriers of longer expansions.

DISCUSSION: C9orf72 hexanucleotide repeat expansions are a major genetic cause of FTD, ALS, and FTD-ALS in this cohort of patients, highlighting the importance of genetic testing for accurate counselling and clinical management. These findings support routine C9orf72 testing in all patients with these disorders, particularly those of European ancestry. Our findings also support the emerging view that intermediate C9orf72 repeat expansions may act as a genetic risk factors contributing to a broad spectrum of clinical phenotypes.}, } @article {pmid42741938, year = {2026}, author = {Zhang, B and He, Y and Su, T and Li, X and Zhang, X and Liu, R and Han, X and Zhang, R and Yang, C and Liu, X and Hou, Q and Zhang, Z and Xie, Y and Liu, G and Yang, X}, title = {UA-30 ameliorates motor deficits through RalA-mediated mitophagy in ALS mice.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {18}, pages = {}, pmid = {42741938}, issn = {1558-8238}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Mitophagy/drug effects ; Mice ; Forkhead Box Protein O3/metabolism/genetics ; Mice, Transgenic ; Humans ; Disease Models, Animal ; Superoxide Dismutase-1/genetics/metabolism ; Motor Neurons/pathology/metabolism ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, skeletal muscle atrophy, paralysis, and eventually death. Mitochondrial dysfunction plays a pivotal role in ALS pathogenesis, although the precise pathogenic mechanisms remain elusive, and effective therapeutic strategies are extremely limited. In this study, we developed a small-molecule inhibitor, UA-30, which directly targets RalA, and explored its potential for the treatment of ALS. We found that when administered via oral gavage for 6 weeks following the onset of motor deficit, UA-30 extended lifespan and improved motor function of SOD1G93A mice, a model of ALS. UA-30 ameliorated motor neuron loss, neuroinflammation, fibrosis, and mitochondrial dysfunction, as evidenced by energy recovery, decreased oxidative stress, and enhanced mitophagy. Mechanistically, UA-30 inhibited RalA activity and thereby modulated ERK/FOXO3a signaling, which inhibited FOXO3a degradation via the ubiquitin-proteasome pathway; enhanced FOXO3a stability; and upregulated the expression of mitophagy-related genes in this ALS mouse model. The beneficial effects of UA-30 in ALS were abolished by overexpression of the constitutively active form of RalA (RalAG23V) or Mdivi-1 treatment. These findings support RalA inhibition as a therapeutic strategy for enhancing mitophagy and mitigating ALS-like pathology and support UA-30 as an orally active candidate for further preclinical development.}, } @article {pmid42742283, year = {2026}, author = {Jacobson, R and Babu, S and Hurley, J and Zawar, I}, title = {ALS Research and Healey ALS MyMatch.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78364}, pmid = {42742283}, issn = {1531-8249}, } @article {pmid42742464, year = {2026}, author = {Zheng, Y and Ellison, TJ and Garrard, R and Gao, J and Lai, X and Lan, L and Xie, J and Jiang, J and Yao, Y}, title = {Neural Stem Cell-Derived Extracellular Vesicles Improve CNS Delivery and Therapeutic Efficacy of Antisense Oligonucleotide in Amyotrophic Lateral Sclerosis.}, journal = {Journal of extracellular vesicles}, volume = {15}, number = {9}, pages = {e70370}, pmid = {42742464}, issn = {2001-3078}, support = {R01 AG068247/AG/NIA NIH HHS/United States ; R01AG068247/AG/NIA NIH HHS/United States ; W81XWH2210261//Department of Defense/ ; /NH/NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; *Extracellular Vesicles/metabolism ; *Oligonucleotides, Antisense/administration & dosage/pharmacology/therapeutic use ; *Neural Stem Cells/metabolism ; Mice ; Humans ; Disease Models, Animal ; *Central Nervous System/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Motor Neurons/metabolism ; Male ; Administration, Intranasal ; }, abstract = {Antisense oligonucleotides (ASOs) hold clinical promise for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Yet, their efficacy is constrained by the need for invasive delivery, poor central nervous system (CNS) penetration, inefficient cellular uptake and rapid clearance. Here, we developed neural stem cell-derived extracellular vesicles (NSC-EVs) as natural carriers to enhance CNS targeting and therapeutic efficacy of ASO-based treatments for ALS. Using a passive loading method, therapeutic ASOs were efficiently associated with NSC-EVs (NSC-EV-ASO). Compared with free ASOs, NSC-EVs- ASOs exhibited markedly enhanced neuronal uptake in vitro and increased CNS accumulation and neuronal localization in vivo following intracerebroventricular, intranasal, or intravenous administration. Functionally, NSC-EV-ASOs reduced the mutant SOD1 protein expression and the pathogenic hexanucleotide repeats in the C9orf72 loci in ALS cellular models. In the ALS mouse model, intranasal administration of NSC-EV-ASOs more efficiently delayed disease onset, improved motor performance, preserved motor neurons and attenuated astrocyte activation during the study period compared with free ASOs. These findings provide proof-of-concept evidence supporting the potential of NSC-EV as a promising platform that not only enhances CNS delivery of ASOs but also contributes to overall therapeutic activity, offering a synergistic strategy to advance nucleic acid therapeutics for ALS and potentially other neurological diseases.}, } @article {pmid42742812, year = {2026}, author = {Codron, P and Miranda, M and Garnier, M and He, S and Gouju, J and Cassereau, J and Leblanc, P and Letournel, F}, title = {Peripheral TDP-43 pathology in amyotrophic lateral sclerosis: toward a systemic proteinopathy.}, journal = {Acta neuropathologica}, volume = {152}, number = {1}, pages = {}, pmid = {42742812}, issn = {1432-0533}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; *TDP-43 Proteinopathies/pathology/metabolism ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Cytoplasmic accumulation of phosphorylated TAR DNA-binding protein 43 (pTDP-43) is the pathological hallmark of most ALS cases. While ALS has traditionally been viewed as a disease confined to the brain, spinal cord and motor nerves, recent studies have reported pTDP-43 pathology in multiple other tissues (skeletal and cardiac muscle, skin, minor salivary glands, gastrointestinal tract and lymph nodes), referred to as peripheral pathology. The detection of pTDP-43 beyond the nervous system suggests that ALS-associated TDP-43 proteinopathy may be more widespread than previously recognized and raises fundamental questions regarding the spatial and temporal landscape of ALS pathology. Peripheral pTDP-43 accumulation may reflect a systemic biological susceptibility affecting multiple tissues, propagation of pathological TDP-43 species between anatomical compartments, or a combination of both mechanisms. While its biological significance is yet to be determined, the presence of pTDP-43 in peripheral tissues broadens the current conceptual framework of ALS. It may also provide new opportunities for pathology-based biomarkers, therapeutic monitoring, and mechanistic studies aimed at understanding disease initiation and progression. However, current evidence is derived from small and methodologically heterogeneous cohorts, and peripheral pTDP-43 pathology is not restricted to ALS, emphasizing the need for larger standardized studies.}, } @article {pmid42744283, year = {2026}, author = {Scholz, V and Schönrock, V and Erdmann, H and Prokosch, V and Schoedel, M and Almus, M and Sauer, M and Mayer, V and Breithausen, E and van Buren, I and Dineiger, C and Golibrzuch, M and Montero-Hernández, M and Lischka, A and Eggermann, K and Heintz, C and Hallermayr, A and Neuhann, T and Holinski-Feder, E and Abicht, A and Benet-Pagès, A and Lucas, MC}, title = {Parallel Analysis of Repeat Expansions: An Updated Clinical Nanopore Cas9-Targeted Sequencing Workflow for Nanopore R10 Flow Cells.}, journal = {The Journal of molecular diagnostics : JMD}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jmoldx.2026.04.007}, pmid = {42744283}, issn = {1943-7811}, abstract = {Hereditary ataxias, caused by expansions of short tandem repeats, are difficult to diagnose using traditional PCR and Southern blot methods, which struggle to detect complex repeat expansions and cannot assess repeat interruptions or methylation. An updated Clinical Nanopore Cas9-Targeted Sequencing workflow is presented for analyzing repeat expansions, now compatible with the Oxford Nanopore Technologies R10 flow cell. The workflow incorporates the Oxford Nanopore Technologies wf-human-variation Epi2Me workflow, including the Straglr tool to analyze base-called reads, ensuring compatibility with past, current, and future sequencing chemistries. It expands the number of genes analyzed from 10 to 27 and introduces new gene panels for ataxia, myopathy, neurodegeneration, and amyotrophic lateral sclerosis/motor neuron disease. Validated with Coriell reference and clinical samples, this method improves the analysis of pathogenic repeat expansions, providing deeper insights into repeat structures while addressing the limitations of traditional approaches. In this work, the use of multiplexing, Flongle flow cells, and single-gene targeting were explored as alternatives to panel-based approaches in the Clinical Nanopore Cas9-Targeted Sequencing workflow, finding that only single-gene targeting provides compatibility and reliable performance.}, } @article {pmid42744617, year = {2026}, author = {Lee, YJ and Shen, K and Dillin, A and Rio, DC}, title = {The hnRNPA1 D262V amyotrophic lateral sclerosis (ALS) mutation is linked to mitochondrial dysfunction.}, journal = {Genes & development}, volume = {}, number = {}, pages = {}, doi = {10.1101/gad.353720.126}, pmid = {42744617}, issn = {1549-5477}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by motor neuron loss and has been genetically linked to mutations in RNA-binding proteins. A mutation D262V in the RNA-binding protein hnRNPA1, found in a subset of ALS patients, causes widespread splicing pattern changes. Cells expressing this hnRNPA1 mutation exhibit aggregation, reduced proliferation, altered stress granules and abnormal neuronal growth. To further elucidate how a single amino acid substitution in a splicing factor might impact cell growth, we employed ribosome profiling to study translational dynamics across the transcriptome in hnRNPA1 mutant cells. Differential ribosome occupancy was observed for a small number of transcripts linked to synaptic organization and GTPase functions, as well as disrupted codon usage and a global stalling of translation. This downregulation of translation coincided with suppression of the mTOR/AKT signaling pathway. RNA splicing changes in transcripts from genes linked to cilia/cell projections, GTPase cycles and glutamate signaling were also observed. Importantly, major mitochondrial dysfunction and mitochondrial fragmentation were found in hnRNPA1 D262V mutant cells. Overall, this study demonstrates how a single amino acid change in an RNA binding protein can contribute to disrupting cell growth and mitochondrial function related to defects linked to neuronal death in ALS.}, } @article {pmid42744804, year = {2026}, author = {Huang, Y and Mavinkurve, A and Sabikunnahar, B and Stevens, B and Lemke, G}, title = {Microglia deploy TAM receptors to kill motor neurons in a mouse model of amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42744804}, issn = {2041-1723}, support = {R01 AI101400//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; RF1 NS092578//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 AI101400/AI/NIAID NIH HHS/United States ; RF1 NS092578/NS/NINDS NIH HHS/United States ; RF1 AG0600748//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Microglia/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; *Receptor Protein-Tyrosine Kinases/metabolism/genetics ; Disease Models, Animal ; Mice ; Spinal Cord/pathology/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *c-Mer Tyrosine Kinase/genetics/metabolism ; Mice, Transgenic ; *Proto-Oncogene Proteins/metabolism/genetics ; Axl Receptor Tyrosine Kinase ; Mice, Knockout ; Neuromuscular Junction/metabolism/pathology ; Humans ; Lysosomes/metabolism ; Cholinergic Neurons/metabolism/pathology ; Female ; Superoxide Dismutase/genetics/metabolism ; Efferocytosis ; }, abstract = {Activation of microglia is a prominent feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that leads to the death of motor neurons. A key component of this activation is elevated expression of the TAM receptor tyrosine kinases Axl and Mer (gene name Mertk). Here we show that germline and microglial-restricted inactivation of the Axl and Mertk genes in the SOD1[G93A] mouse model of ALS leads to an extension of lifespan, which is tied to the preservation of cholinergic motor neurons and neuromuscular synapses. Also elevated on SOD1[G93A] neuronal surfaces is the essential TAM co-ligand phosphatidylserine, a potent 'eat-me' signal through which apoptotic cells are engulfed by microglia. Correspondingly, we find that microglial lysosomes are filled with the remains of cholinergic neurons in the SOD1[G93A] spinal cord, whereas this accumulation is markedly reduced in the SOD1[G93A]Axl[-/-]Mertk[-/-] cord. Together, these results suggest that microglia phagocytically kill living neurons, and thereby hasten death in ALS.}, } @article {pmid42745510, year = {2026}, author = {Aldossari, AA and Alsaad, AMS and Nadeem, A and Ansari, MA and Attia, SM and Bakheet, SA and Al-Mazroua, HA and Almutairi, MM and Alhamami, HN and Sarawi, WS and Alomar, HA and Algonaiah, MA and Alshamrani, AA and Alanteet, AA and Hussein, MH and Mahmoud, MA and Ahmad, SF}, title = {Thioperamide, a histamine H3 receptor antagonist, attenuates neuroimmune activation and inflammation in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Immunopharmacology and immunotoxicology}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/08923973.2026.2733883}, pmid = {42745510}, issn = {1532-2513}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of unknown cause that gradually affects upper and lower motor neurons in the motor cortex, brainstem, and spinal cord. The histamine H3 receptor (H3R), a presynaptic autoreceptor, regulates histamine release through feedback mechanisms. H3R is highly expressed in neurons and microglia, where it influences inflammatory responses.

METHODS: This study examined the effects of thioperamide, an H3R antagonist, on T cell-mediated immune responses in the SOD1G93A transgenic mouse model of ALS. Mice received daily thioperamide injections (5 mg/kg) for four weeks, beginning at the onset of illness (week 15). Flow cytometry analyzed splenic CD3[+] T cells for cytokine and marker expression, including IL-1α, IL-6, IFN-γ, TNF-α, IL-17A, RORγt, iNOS, GM-CSF, TGF-β1, and Foxp3. RT-PCR measured mRNA levels in brain tissue.

RESULTS: Results showed that thioperamide significantly decreased CD3[+]IL-1α[+], CD3[+]IL-6[+], CD3[+]IFN-γ[+], CD3[+]TNF-α[+], CD3[+]IL-17A[+], CD3[+]RORγt[+], CD3[+]iNOS[+], and CD3[+]GM-CSF[+] cells in the spleen, while increasing regulatory CD3[+]TGF-β1[+] and CD3[+]Foxp3[+] cells. Similarly, brain tissue showed decreased mRNA levels of IL-1α, IL-6, IFN-γ, TNF-α, IL-17A, RORγt, iNOS, and GM-CSF, with higher TGF-β1 and Foxp3 expression.

CONCLUSIONS: These findings suggest that thioperamide helps reestablish immune balance in SOD1[G93A] mice by influencing both inflammatory and regulatory T cell pathways.}, } @article {pmid42745716, year = {2026}, author = {Kokubo, Y}, title = {[A New Understanding of the Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex in the Kii Peninsula, Japan, 2026].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {78}, number = {9}, pages = {1023-1029}, doi = {10.11477/mf.188160960780091023}, pmid = {42745716}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Japan/epidemiology ; *Parkinsonian Disorders/epidemiology/genetics ; *Dementia/epidemiology/genetics ; }, abstract = {The distribution of amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) in the Kii Peninsula of Japan exhibits regional variations, with ALS/PDC in the Hohara focus closely resembling that in Guam and ALS in the Kozagawa focus. Recent structural analysis using cryo-electron microscopy revealed that the tau filaments in patients with ALS/PDC in Kii have a chronic traumatic encephalopathy (CTE) fold, confirming the disease's distinct pathological identity and commonality with the Guam focus. While the exact causal genes remain unidentified, research utilizing patient-derived induced pluripotent stem cells and proteomic analysis has uncovered endogenous mitochondrial dysfunction, specifically involving decreased expression of CHCHD2 and SSBP1. The presence of migrant cases further suggests that ALS/PDC is a multifactorial disorder triggered by environmental factors that influence genetic vulnerability. Although the incidence of ALS in Kozagawa and Hohara districtst has declined, new cases with PDC continue to emerge in Hohara. Identifying these modifiable environmental triggers is crucial for preventing and eradicating neurological disorders.}, } @article {pmid42745993, year = {2026}, author = {Buck, SA and Madhavan, SS and Sanders, LH}, title = {Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?.}, journal = {Molecular neurodegeneration advances}, volume = {2}, number = {1}, pages = {38}, pmid = {42745993}, issn = {3059-4944}, support = {R01 NS119528/NS/NINDS NIH HHS/United States ; T32 AG000029/AG/NIA NIH HHS/United States ; }, abstract = {Many neurodegenerative diseases are characterized by pathological protein aggregation in the brain. Alzheimer's disease displays amyloid-β and tau inclusions in the form of amyloid-β plaques and tau neurofibrillary tangles. Synucleinopathies comprise Parkinson's disease and Dementia with Lewy bodies, which are classified by α-synuclein depositions in the form of Lewy bodies, as well as multiple system atrophy, which displays glial cytoplasmic α-synuclein inclusions. Tar DNA binding protein 43 (TDP-43) inclusions are observed in amyotrophic lateral sclerosis and frontotemporal lobar dementia with TDP-43 inclusions. A separate subgroup of frontotemporal lobar dementias, including Pick's disease, progressive supranuclear palsy and corticobasal degeneration, are characterized by disease-specific patterns of tau pathology and are termed primary tauopathies. Despite these classifications, it is not often appreciated that neurodegenerative diseases commonly display amyloid-β, tau, α-synuclein, and/or TDP-43 co-pathologies not typically associated with that specific disease's pathophysiology. Additionally, in vitro and in vivo proteinopathy models show interactions between pathological forms of these proteins that increase protein aggregation and neurotoxicity, suggesting distinct mechanisms underlying co-pathologies that play a significant role in neurodegeneration. In this review, we describe the frequency of protein co-pathologies across neurodegenerative diseases and preclinical work demonstrating pathological protein synergies that exacerbate protein aggregation and toxicity. We also discuss granulovacuolar degeneration bodies, proteolytically active lysosomal structures that are induced by either pathological tau or α-synuclein accumulation, as an example of a shared cellular response to, and link between, distinct protein pathologies. Finally, we highlight interventional clinical trials which target multiple pathologies and/or specifically target co-pathologies in neurodegenerative diseases, noting that current preclinical and clinical research is limited and this line of investigation should be pursued more vigorously. In all, we find that protein co-pathologies are frequently observed in the brains of common neurodegenerative diseases and serve as important future therapeutic targets for combatting neurodegeneration across clinically distinct diseases.}, } @article {pmid42746497, year = {2026}, author = {Correa-Arrieta, C and Castellar Leones, SM and Bernal-Vergara, M and Saiz-Briceño, M and Diaz-Ruiz, J and Ortiz-Corredor, F}, title = {ABCD1-Related Disease Presenting as an Upper Motor Neuron-Predominant Amyotrophic Lateral Sclerosis Mimic in a Colombian Female Heterozygote: A Case Report.}, journal = {Cureus}, volume = {18}, number = {8}, pages = {e114605}, pmid = {42746497}, issn = {2168-8184}, abstract = {We report the case of a 47-year-old Colombian woman with a persistent gait disorder beginning at 46 years of age. Neurological examination showed preserved strength, lower-limb spasticity, diffuse hyperreflexia, brisk jaw jerk, and a unilateral Hoffmann sign, without definite bulbar, respiratory, cognitive, sensory, or cerebellar involvement. Brain MRI showed nonspecific occipital/subcortical T2/FLAIR (fluid-attenuated inversion recovery) white matter hyperintensities, and spinal MRI showed mild degenerative changes without compressive myelopathy or spinal cord signal abnormality. Laboratory evaluation did not identify an inflammatory, infectious, nutritional, metabolic, or endocrine cause of myelopathy. Two electrodiagnostic studies showed preserved motor and sensory nerve conduction, normal late responses, normal motor unit action potentials on needle electromyography, and no evidence of active denervation. Neuromuscular ultrasound was also normal, without nerve enlargement, abnormal muscle echogenicity, atrophy, or fasciculations. Overall, there was no diffuse, progressive, multiregional lower motor neuron pattern, and Gold Coast criteria for amyotrophic lateral sclerosis were not fulfilled. A motor neuron disease gene panel identified a heterozygous pathogenic ABCD1 variant, c.1415_1416delAG, p.Gln472Argfs*83. Repeat expansion testing for C9ORF72, ATXN1, and ATXN2 was normal. Classical plasma very-long-chain and branched-chain fatty acid testing showed elevated C26:0 and increased C24:0/C22:0 and C26:0/C22:0 ratios, with normal phytanic and pristanic acids. The clinical, imaging, electrodiagnostic, biochemical, and molecular findings supported ABCD1-related disease with an adrenomyeloneuropathy-predominant phenotype as the most likely explanation for this upper motor neuron-predominant amyotrophic lateral sclerosis (ALS) mimic. This case highlights the importance of considering ABCD1-related disease in adult women with unexplained noncompressive upper motor neuron syndromes when electrodiagnostic studies do not support ALS.}, } @article {pmid42746532, year = {2026}, author = {Zhang, E and Oh, P and Shamas, T and Patwa, HS and Johung, KL}, title = {Radiation Therapy for Sialorrhea in Patients With Amyotrophic Lateral Sclerosis: A Case Series and Critical Review.}, journal = {Advances in radiation oncology}, volume = {11}, number = {9}, pages = {102135}, pmid = {42746532}, issn = {2452-1094}, abstract = {PURPOSE: Radiation therapy (RT) for sialorrhea has historically used 3-dimensional techniques that broadly irradiate both major and minor salivary glands. However, some reports indicate that treatment of minor salivary glands may contribute to excessive xerostomia. In this retrospective case series, we assessed the efficacy and tolerability of oral-cavity-sparing volumetric modulated arc therapy (VMAT) and bilateral electron field radiation for sialorrhea in patients with amyotrophic lateral sclerosis (ALS) and reviewed the relevant literature.

METHODS AND MATERIALS: From 2014 to 2025, 6 patients with bulbar-onset ALS and medically refractory sialorrhea were treated with RT to the parotid and submandibular glands (20 Gy in 5 fractions) at a single institution. Five patients received VMAT with 6 MV photons, and one received bilateral 16 MeV electrons. Clinical response, medication use, toxicity, and dosimetry were assessed. A PubMed search using "sialorrhea," "RT," and "amyotrophic lateral sclerosis" was performed for the literature review.

RESULTS: At a median follow-up of 15.05 months (range, 3.0-61.7 months), 5 of 6 patients (83.3%) achieved symptomatic improvement, with an average 60% patient-reported reduction in salivation and ≥2 point improvement in ALS Functional Rating Scale saliva subscore. Two discontinued anticholinergics, and 1 achieved complete resolution for 3 years. Acute toxicities with VMAT were mild and self-limiting, most commonly parotitis and thickened secretions. The patient treated with electrons developed grade 2 mucositis, not observed with VMAT. Late toxicities, including xerostomia, were minimal and transient. Dosimetry showed higher larynx and oral cavity doses with electrons, whereas VMAT delivered slightly higher spinal cord doses. Critical literature review supported RT as an effective and well-tolerated intervention.

CONCLUSIONS: RT provides durable relief of refractory sialorrhea in ALS with manageable toxicity. VMAT response is comparable with historical outcomes and may offer dosimetric advantages that correlate with reduced acute toxicities, although its clinical benefit and cost-effectiveness warrant further validation.}, } @article {pmid42746632, year = {2026}, author = {Artigas, R and Menchaca, C and Jara, E and Mondino, A and Vázquez, N and Branda Sica, A and Llambí, S}, title = {SOD1:c.118G>A mutation in the Cimarrón Uruguayo dog: prevalence, drift dynamics, and structural effects.}, journal = {Brazilian journal of veterinary medicine}, volume = {48}, number = {}, pages = {e005526}, pmid = {42746632}, issn = {2527-2179}, abstract = {Canine degenerative myelopathy (DM) is associated with a missense mutation in the SOD1 gene (c.118G>A), which results in the E40K amino acid substitution and promotes protein aggregation mechanisms similar to those described in human amyotrophic lateral sclerosis. The present study estimated the frequency of the SOD1:c.118G>A mutation in the Cimarrón Uruguayo dog and evaluated its structural and population implications. A total of 82 dogs were genotyped. The mutant allele was detected at a frequency within the range of common variants (q = 0.177), and genotype distribution did not deviate from Hardy-Weinberg equilibrium. Wright-Fisher simulations showed that stochastic processes alone may substantially influence allele-frequency trajectories over time. Additionally, a high-resolution melting (HRM) assay was optimized and enabled clear discrimination of the three genotypes, supporting its use as a rapid genotyping approach. Sanger sequencing of SOD1 exons 2-5 was performed in a subset of individuals to identify additional coding variants. Sequencing revealed no additional non-synonymous variants, except for a synonymous substitution in exon 4. Structural inspection indicated that the E40K substitution does not alter the local hydrogen-bonding pattern but produces a charge inversion that modifies the electrostatic environment surrounding residues 40 and 91. These findings support the hypothesis that electrostatic alterations in this region may contribute to an increased aggregation propensity of mutant SOD1 and provide new insights into the molecular and population context of this mutation in the Cimarrón Uruguayo breed.}, } @article {pmid42747163, year = {2026}, author = {Sanna, C and Sanna, M and Borghero, G and Redolfi, S}, title = {Noninvasive ventilation in patients with amyotrophic lateral sclerosis: Is home sleep apnea testing a useful tool for initiating noninvasive ventilation?.}, journal = {Multidisciplinary respiratory medicine}, volume = {21}, number = {}, pages = {1088}, doi = {10.5826/mrm.2026.1088}, pmid = {42747163}, issn = {1828-695X}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration and eventual respiratory failure, often first manifesting during sleep. Timely detection of nocturnal respiratory impairment is critical for initiating noninvasive ventilation (NIV), one of the few therapies proven to improve survival. Although polysomnography (PSG) is the reference standard, it is not always readily available in clinical practice.

CASE PRESENTATION: We describe a 62-year-old man with spinal-onset ALS who underwent home sleep apnea testing (HSAT) for respiratory assessment. Although standard metrics were within normal limits, careful manual analysis of respiratory signals revealed diaphragmatic dysfunction through position-dependent desaturation and paradoxical breathing. NIV was initiated, resulting in improvements in sleep quality and daytime functioning.

CONCLUSIONS: This case illustrates the value of HSAT as a pragmatic and accessible tool for early detection of respiratory involvement in ALS, particularly when combined with detailed waveform inspection in setting where PSG is unavailable. Additionally, it emphasizes the importance of individualized NIV titration and interface optimization to ensure adherence and therapeutic benefit.}, } @article {pmid42747562, year = {2026}, author = {Zhang, Y and Wei, K and Lin, H and Guo, Z and Lu, Y and Ma, T}, title = {Unraveling the regulatory nexus of aggrephagy in ALS: identification of novel candidate biomarkers and molecular triggers.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {42747562}, issn = {1573-7365}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *Autophagy/genetics/physiology ; Mice ; Biomarkers/metabolism ; Superoxide Dismutase-1/genetics ; Mice, Transgenic ; Spinal Cord/metabolism/pathology ; Motor Neurons/metabolism ; Humans ; Transcriptome ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disorder involving multiple systems, with motor neuron degeneration as its primary feature. This disease can be classified into sporadic and familial types. Genes such as SOD1, C9orf72, FUS, and TDP-43 have been identified as the main causative genes for familial ALS. Multiple bioinformatics tools combined with an experimental verification strategy have helped in understanding the association of a selective autophagy pathway called aggrephagy with the disease.

RESULTS: The transcriptome data of spinal cord tissue from SOD1-G93A mice was obtained from the Gene Expression Omnibus (GEO) database. Based on the GSE281064 dataset, we investigated aggrephagy-related transcriptional alterations in the SOD1-G93A mouse model of ALS. After comparison with the aggrephagy-related genes (AGGRGs) set included in the GeneCards database, 49 candidate genes closely related to the autophagy process were obtained. Functional enrichment analysis showed these genes participate in extracellular matrix remodeling, hyaluronic acid and glycosaminoglycan metabolism, tumor necrosis factor regulation, and lysosomal function, indicating central roles in inflammation, apoptosis, and metabolic disorders. Based on feature selection algorithms, this study employed machine learning methods such as random forest (RF), extreme gradient boosting (XGBoost), and Boruta to conduct multi-angle screening of candidate genes. The intersection of the results ultimately identified three key genes: Ctsb, Kif11, and S100a6.

CONCLUSIONS: In both the training data and external validation data, Ctsb and S100a6 showed significant upregulation and demonstrated excellent discriminatory capabilities. The nomogram constructed based on Ctsb and S100a6 expression showed potential for distinguishing SOD1-G93A model samples from nontransgenic controls. The predicted probability demonstrated the potential of these two as candidate biomarkers. Meanwhile, further validation is needed in larger independent population cohorts in the future. The SOD1-G93A mouse model and SOD1-G93A-expressing NSC34 cell model showed expression patterns of Ctsb and S100a6 consistent with the bioinformatics findings. Through S100a6 overexpression and knockdown experiments in an NSC34 motor neuron-like ALS model, we found that S100a6 impaired autophagy and promoted SOD1 aggregation. These findings further validate its potential as a biomarker and provide new insights into the pathogenesis of ALS.}, } @article {pmid42748981, year = {2026}, author = {Zhang, C and Yang, Z}, title = {The double-edged sentinel: cGAS-STING as a context-dependent regulator of microglial senescence and neuronal genotoxic stress in neurodegeneration.}, journal = {Brain research bulletin}, volume = {245}, number = {}, pages = {112118}, doi = {10.1016/j.brainresbull.2026.112118}, pmid = {42748981}, issn = {1873-2747}, abstract = {BACKGROUND: Neurodegenerative diseases may continue to progress even when a pathogenic protein aggregate is reduced, suggesting that downstream inflammatory and genotoxic circuits can become partly autonomous. This narrative review examines cGAS-STING as a context-dependent regulator of DNA-stress responses in the ageing and proteinopathic brain.

METHODS: PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar were searched for mechanistic, translational, and human-tissue studies of cGAS-STING, DNA damage, mitochondrial quality control, neuroinflammation, and major neurodegenerative diseases. Evidence was separated into biochemical or cellular, animal, and human observations, and contradictory findings were retained.

RESULTS: Mitochondrial DNA leakage is a recurrent candidate trigger, while activity-induced nuclear DNA breaks, defective repair, retrotransposon-derived cDNA, and micronuclear rupture provide conditional inputs. Microglial evidence is currently more extensive and causally developed than neuron-specific evidence; neuronal STING is most firmly supported in selected contexts such as excitotoxic or ischemic stress. Across Alzheimer disease, Parkinson disease, ALS/FTD, multiple sclerosis, and Huntington disease, cGAS-STING-associated inflammation is plausible but not uniform, and human validation remains limited. Therapeutic strategies therefore require cell-, source-, and stage-aware modulation rather than indiscriminate pathway ablation.

CONCLUSION: cGAS-STING is best regarded as a testable kinetic-bottleneck model, not a universal driver of neurodegeneration. Longitudinal human studies and cell-resolved biomarkers are needed to determine when recalibration can suppress pathological inflammation while preserving antiviral and homeostatic functions.}, } @article {pmid42749235, year = {2026}, author = {Knezovic, A and Krsnik, A and Homolak, J and Babic Perhoc, A and Deskin, A and Virag, D and Salkovic-Petrisic, M and Osmanovic Barilar, J}, title = {From systems to cells: Metabolic mechanisms underlying risk divergence in Alzheimer's disease and amyotrophic lateral sclerosis.}, journal = {Neuroscience and biobehavioral reviews}, volume = {191}, number = {}, pages = {106982}, doi = {10.1016/j.neubiorev.2026.106982}, pmid = {42749235}, issn = {1873-7528}, abstract = {Epidemiological studies show an inverse relationship between metabolic disorders and two major neurodegenerative diseases, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Obesity, type 2 diabetes (T2DM), and reduced physical activity increase AD risk, whereas in ALS cardiometabolic factors, particularly T2DM, show inverse, age-dependent associations with disease risk. This review integrates epidemiological, clinical, and experimental evidence to suggest that cell-type-specific energy metabolism underlies these contrasting risk profiles. Neurons and skeletal muscle differ in metabolic organization, substrate use, and redox capacity. Neurons rely mainly on glucose and lactate and have limited fatty acid oxidation, making them vulnerable to lipid overload, insulin resistance, and oxidative stress, hallmarks of AD. In contrast, skeletal muscle is metabolically flexible, efficiently oxidizes fatty acids, and has strong antioxidant defenses, which may protect against ALS. These cell-type-specific metabolic profiles are proposed to causally shape disease susceptibility: neuronal lipid overload and impaired redox homeostasis promote amyloid and tau pathology in AD, whereas preserved muscle fatty acid oxidation and antioxidant capacity support neuromuscular junction stability and delay motor neuron degeneration in ALS. Hypermetabolism, hypothalamic dysfunction, glial-neuronal coupling and lactate shuttling may further shape disease susceptibility. Overall, these patterns likely reflect distinct cellular responses to metabolic stress.}, } @article {pmid42749372, year = {2026}, author = {Yaghobi, M and Ahmadi, F and Mohammad Khan Kermanshahi, S and Kazemnejad, A and Vaismoradi, M}, title = {Design and psychometric properties of an instrument to evaluate nursing students' perceptions of discrimination by nurse educators: a protocol for a mixed-method study.}, journal = {BMJ open}, volume = {16}, number = {9}, pages = {e120281}, pmid = {42749372}, issn = {2044-6055}, mesh = {Humans ; Psychometrics ; *Students, Nursing/psychology ; *Faculty, Nursing/psychology ; Qualitative Research ; Reproducibility of Results ; Research Design ; }, abstract = {INTRODUCTION: Perceived discrimination by nurse educators is a harmful phenomenon in nursing education that influences nursing students in both classroom and clinical settings. It is associated with psychological distress, reduced learning outcomes, feelings of hopelessness and higher rates of attrition. There is a need to identify the dimensions of discrimination for developing strategies to promote educational justice. This research aims to develop and test the psychometric properties of an instrument to evaluate nursing students' perceptions and experiences of discrimination by nurse educators.

METHODS AND ANALYSIS: A sequential exploratory mixed-methods design (QUAL → QUAN) will be used in this research. Phase 1 involves a qualitative descriptive study using semistructured interviews with nursing students chosen through purposive sampling with the consideration of maximum variation. Data will be analysed using conventional qualitative content analysis and trustworthiness will be addressed according to Lincoln and Guba's criteria. In phase 2, the qualitative findings will guide item generation and preliminary scale development based on Waltz et al's framework. In phase 3, psychometric properties of the scale will be evaluated in terms of content, face, construct validity and reliability. This study provides preliminary evidence supporting the validity, reliability and cultural appropriateness of an instrument for systematic assessment of perceived discrimination among nursing students.

ETHICS AND DISSEMINATION: This protocol describes a mixed-method study conducted as part of a doctoral thesis that explores nursing students' perceptions of discrimination by nurse educators. The study has received ethical approval from the Research Ethics Committees of Tarbiat Modares University, Iran (decree code: IR.MODARES.REC.1404.068). The findings will provide educational experts and policymakers with evidence-based insights to inform the development of interventions aimed at reducing discrimination and promoting justice and equity in nursing education.}, } @article {pmid42749468, year = {2026}, author = {Mercadante, S}, title = {Non-invasive ventilation (NIV) and high-flow nasal therapy (HFNT) in palliative care: a critical narrative review.}, journal = {BMJ supportive & palliative care}, volume = {}, number = {}, pages = {}, doi = {10.1136/spcare-2026-006580}, pmid = {42749468}, issn = {2045-4368}, abstract = {BACKGROUND: Dyspnoea is a prevalent, debilitating symptom in advanced life-limiting illnesses. While opioids and non-pharmacological measures remain foundational, refractory breathlessness presents a major palliative challenge.

OBJECTIVES: To critically appraise the evidence regarding patient selection, comparative tolerability, adverse effects and ethical considerations of non-invasive ventilation (NIV) and high-flow nasal therapy (HFNT) in palliative care.

METHODS: A comprehensive narrative review of literature from PubMed, Embase and Cochrane Library (from inception to June 2026) and major clinical guidelines was conducted.

RESULTS: NIV is best supported in hypercapnic respiratory failure (PaCO >45 mm Hg), showing benefits in chronic obstructive pulmonary disease exacerbations, pulmonary oedema and amyotrophic lateral sclerosis (ALS). In advanced cancer, NIV reduces dyspnoea primarily in hypercapnic patients but mask discomfort and communication barriers limit tolerability. Conversely, HFNT has emerged as a superiorly tolerated option in hypoxemic failure-particularly in end-stage interstitial lung disease (ILD) and advanced cancer-providing significant dyspnoea relief while preserving oral intake and verbal communication until the end of life. Time-limited trials (<1 hour for NIV; 2 hours for HFNT) help identify early responders. Ethical challenges include potential overtreatment and support withdrawal complexities.

CONCLUSIONS: Respiratory support selection should be guided by respiratory physiology (hypercapnic vs hypoxemic), explicit goals of care and tolerability. NIV remains optimal for hypercapnic failure, whereas HFNT offers superior comfort and preserves communication in hypoxaemic patients. Robust randomised trials are needed.}, } @article {pmid42750660, year = {2026}, author = {Chetty, N and Bennett, J and Schone, HR and Fry, A and Yoo, PE and Lacomis, D and Oxley, TJ and Collinger, JL and Putrino, DF and Weber, DJ}, title = {Measuring motor intent for BCI control-A comparative analysis of signal quality of simultaneously recorded vECoG and scalp EEG.}, journal = {Journal of neural engineering}, volume = {23}, number = {5}, pages = {}, pmid = {42750660}, issn = {1741-2552}, support = {F32 MH139145/MH/NIMH NIH HHS/United States ; UH3 NS120191/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Brain-Computer Interfaces/standards ; *Electroencephalography/methods/standards/instrumentation ; *Scalp/physiology ; Male ; *Electrocorticography/methods/standards/instrumentation ; *Intention ; Female ; Movement/physiology ; }, abstract = {Objective.Stent-electrode arrays enable endovascular brain-computer interfaces (BCI) by recording cortical neural activity from within the superior sagittal sinus and have recently been evaluated in an early feasibility clinical trial in the United States (ClinicalTrials.gov: NCT05035823). For a BCI to be viable, the signals need to be high quality to enable accurate decoding of user intent. Compared to electrodes placed on the scalp for electroencephalography (EEG), stent-electrode arrays lie closer to the cortical surface and would presumably offer higher signal quality yet a direct comparison of intravascular and scalp-based neural recordings in humans has not yet been investigated.Approach.We directly compared the signal quality of vascular electrocorticography (vECoG) versus scalp EEG signals in one participant with severe upper limb paralysis due to ALS. During two experimental sessions, the participant underwent simultaneous recording with the stent-electrode array and a scalp EEG using a gel cap. The participant was visually cued to attempt motor tasks, such as repeated flexion and extension of the ankles. Signal quality was assessed by quantifying motor modulation strength, differentiation of movement effort, and spatial lateralization. Noise metrics evaluated the relative impact of artifacts including 60 Hz line noise, electrocardiogram contamination, eye blinks, jaw clenching, and vocalization.Main results.Both recording modalities exhibited significant modulation during attempted movement relative to rest, with vECoG generally demonstrating significantly stronger modulation per channel in some frequency bands and conditions. Motor modulation was significantly reduced during motor imagery compared to overt movement in both modalities. Spatial source localization between left and right ankle movement did not reach significance for either modality. Each modality was vulnerable to some artifacts while generally unaffected by others. Scalp EEG showed large susceptibility to ocular artifacts and cranial muscle activity due to its proximity to superficial physiological sources, whereas vECoG exhibited prominent cardiac activity.Significance.Within this participant, the large modulation during attempted movement recorded with vECoG, unaffected by the attenuating effects of the skull, coupled with fewer artifacts in the frequency bands of interest, provides preliminary evidence that the stent-electrode arrays can acquire high quality neural signals that could support BCI control.}, } @article {pmid42751043, year = {2026}, author = {Oskarsson, B and Heckman, MG}, title = {From Vision to Validation: The Journey of Tofersen in Superoxide Dismutase 1 Gene-Associated Amyotrophic Lateral Sclerosis.}, journal = {Mayo Clinic proceedings. Innovations, quality & outcomes}, volume = {10}, number = {5}, pages = {100755}, pmid = {42751043}, issn = {2542-4548}, } @article {pmid42751965, year = {2026}, author = {van Eijk, RPA and Lu, Y}, title = {Comparing Missing Data Strategies for Generalized Pairwise Comparisons in Randomized Clinical Trials: A Simulation Study.}, journal = {Statistics in medicine}, volume = {45}, number = {20-22}, pages = {e70737}, pmid = {42751965}, issn = {1097-0258}, support = {VENI 09150162210036//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; AL230152//U.S. Department of Defense/ ; }, mesh = {Humans ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; Computer Simulation ; Bias ; Amyotrophic Lateral Sclerosis/therapy ; Data Interpretation, Statistical ; Models, Statistical ; Longitudinal Studies ; Survival Analysis ; Endpoint Determination ; }, abstract = {Generalized pairwise comparisons are increasingly being used in randomized clinical trials. This study evaluates how missing data strategies impact the operating characteristics of endpoints combining overall survival and a longitudinal outcome. A simulation study was conducted to evaluate the impact of censoring and missing longitudinal data on the Type I error, power, and bias of a hierarchical composite endpoint. Seven missing data strategies were identified from the literature, including assigning ties to missing patient pairs, comparing patients at their last common visit, and applying multiple imputation. Conditional longitudinal and survival data were generated based on the natural history of amyotrophic lateral sclerosis. Simulation scenarios varied in censoring rates, extent of missing longitudinal data, differential attrition between treatment arms, and the dependency of missingness on disease severity. All methods were unbiased and maintained nominal Type I error when censoring and missingness were balanced across treatment arms. Under imbalance, however, Type I error increased-reaching up to 0.378 for some strategies. The last common visit strategy was the only approach that consistently preserved nominal error rates (0.025 ± 0.002). Regarding statistical power, all methods exhibited a loss of precision and increased bias under the alternative hypothesis as missingness increased. Multiple imputation partially recovered power and reduced bias but inflated the Type I error rate in scenarios with differential attrition. As generalized pairwise comparisons are increasingly used in pivotal clinical trials-and therefore in regulatory contexts-our findings provide practical guidance for selecting a robust primary analysis strategy and minimizing bias arising from incomplete data.}, } @article {pmid42752431, year = {2026}, author = {Wernli, C and Loesch, U}, title = {Development and Chemical Stability Assessment of a Methyl-β-Cyclodextrin-Containing Dextromethorphan/ Quinidine Oral Solution for Extemporaneous Compounding.}, journal = {International journal of pharmaceutical compounding}, volume = {30}, number = {4}, pages = {393-399}, pmid = {42752431}, issn = {1092-4221}, mesh = {*Dextromethorphan/chemistry/administration & dosage ; *Quinidine/chemistry/administration & dosage ; *beta-Cyclodextrins/chemistry ; Drug Stability ; *Drug Compounding ; Solubility ; Drug Combinations ; Drug Storage ; Administration, Oral ; Excipients/chemistry ; Pharmaceutical Solutions ; Bulk Drugs ; }, abstract = {Pseudobulbar affect is a distressing condition frequently observed in patients with amyotrophic lateral sclerosis (ALS), for which a fixed-dose combination of dextromethorphan and quinidine is approved in the United States. In Europe, no commercial product is available, and compounded capsules or suspensions are used; however, capsules may be unsuitable for patients with dysphagia, and suspensions require shaking before administration. The aim of this study was to develop simple fully water-soluble formulation of dextromethorphan hydrobromide and quinidine sulfate using methyl-ß-cyclodextrin as a solubilizing agent and to evaluate its stability under different storage conditions, enabling pharmacies to compound the preparation without complex infrastructure. Preliminary qualitative solubility experiments showed that the dextromethorphan hydrobromide/ quinidine sulfate powder mixture did not dissolve in water without methyl-ß-cyclodextrin. Addition of methyl-ß-cyclodextrin improved dissolution; however, the initial preparation targeting 20 mg/mL dextromethorphan hydrobromide and 10 mg/mL quinidine sulfate in a final volume of 100 mL remained incompletely dissolved. Increasing the final volume to 250 mL yielded a clear formulation containing nominal concentrations of 8.4 mg/mL dextromethorphan hydrobromide and 4.2 mg/mL quinidine sulfate. Three independently prepared batches were stored in amber PET bottles providing light protection and fitted with child-resistant closure at 2-8°C, 15-25°C, and 40°C and analyzed by HPLC for four weeks. HPLC assay values remained within 10% of the corresponding baseline values at each storage condition, and no visible precipitation was observed. The results support the physical clarity and chemical consistency of the tested methyl-ß-cyclodextrin- containing formulation over four weeks under the evaluated storage conditions. Microbiological stability, preservative effectiveness, formal method validation in the author's laboratory, and the extent of cyclodextrin inclusion complexation were not assessed. This formulation may serve as a basis for further pharmaceutical, microbiological, and clinical evaluation of an extemporaneously compounded oral liquid.}, } @article {pmid42753291, year = {2026}, author = {Tamiz, AP and Baran, SW and Hartung, T and Wu, WW}, title = {New approach methodologies in neurotherapeutics development.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {6}, pages = {e01056}, pmid = {42753291}, issn = {1878-7479}, abstract = {New Approach Methodologies (NAMs) offer substantial opportunities to transform neurotherapeutics discovery, optimization, and development, reducing the timeline to translate central nervous system (CNS) innovations to patients. Strategically deployed, NAMs enhance the predictive value of preclinical studies for human outcomes while reducing reliance on animal models. Current scientific community interest focuses particularly on human-based and -derived systems, in silico and AI-driven models, and advanced microphysiological platforms, reflecting a shift toward human-centric drug development paradigms. Despite this momentum, significant challenges remain, including NAM reproducibility and validation, the establishment of standardized performance criteria, data sharing, and the evolution of regulatory frameworks needed to enable consistent adoption across the neurotherapeutics continuum. Nevertheless, there is a rich history of developing and adopting methodologies, particularly for improving the prediction of neurotherapeutic safety profiles while reducing animal use, and for advancing understanding of drug delivery across the blood-brain barrier, and the assessment of adverse neurological effects. These advances have begun to influence regulatory decision-making and are increasingly reflected in guidance and review practices. Furthermore, NAMs are showing concrete impact in neurological disorders, including Epilepsy, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease, where human-relevant models and computational approaches support more precise characterization of disease mechanisms and therapeutic responses. In this paper, we examine the current and emerging roles of NAMs in neurotherapeutics development from government, academia, and industry perspectives, highlight key opportunities and limitations, and discuss the scientific, technical, and regulatory steps required to fully realize their potential in accelerating safe and effective CNS therapies.}, } @article {pmid42753929, year = {2026}, author = {Hawkes, BA and Goodrich, JM and Beitel, SC and Porter, C and Burgess, JL and Jung, AM and Furlong, MA}, title = {Associations of per- and polyfluoroalkyl substances (PFAS) exposures and firefighting experience with microRNA signatures previously linked to Amyotrophic Lateral Sclerosis (ALS): a cross-sectional analysis of active-duty municipal and airport firefighters.}, journal = {Neurotoxicology}, volume = {}, number = {}, pages = {103577}, doi = {10.1016/j.neuro.2026.103577}, pmid = {42753929}, issn = {1872-9711}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unclear etiology in sporadic cases. Blood microRNA (miRNA) expression varies between individuals with and without ALS. Firefighters may face elevated ALS risks due to occupational exposures, including elevated serum per- and polyfluoroalkyl substances (PFAS) concentrations.

METHODS: This study investigates the association between occupational firefighter characteristics (years of experience, incumbent status (binary; 1=incumbent, 0=recruit), serum PFAS) and ALS-relevant miRNA expression in U.S. firefighters across 10 states. MiRNA expression was quantified from blood collected from 608 firefighters. Serum PFAS concentrations were available for a subset of 302 participants. We identified 19 ALS-related miRNAs using miRWalk's Disease Ontology. Adjusted linear regression models estimated associations between exposures and miRNA expression, controlling for demographic and occupational factors.

RESULTS: In analyses of firefighter occupational characteristics (n=608), incumbent firefighters had significantly altered expression in ten ALS-related miRNAs compared to new recruits (p<0.05) and all remained significant after false discovery rate (FDR) adjustment for multiple testing (q<0.20). Years of firefighting was associated with lower expression of multiple miRNAs, including hsa-miR-23a-3p (β = -11.276, 95% CI: -18.870, -3.682), and this association remained significant after FDR correction. In PFAS analyses (n=302), higher serum PFAS concentrations were associated with 13 significant PFAS-miRNA associations (p<0.05) involving ALS-related miRNAs, including Sm-PFOS and hsa-let-7i-5p (β = -0.169, 95% CI: -0.287, -0.052), hsa-let-7c-5p (β = -0.128, 95% CI: -0.218, -0.037), and hsa-let-7e-5p (β = -0.113, 95% CI: -0.210, -0.017); PFNA and hsa-let-7c-5p (β = -0.126, 95% CI: -0.214, -0.037); and PFHxS and hsa-let-7i-5p (β = -0.126, 95% CI: -0.223, -0.029). Six remained significant after FDR adjustment (q < 0.20). Hsa-let-7e-5p was significantly lower in firefighters with higher Sm-PFOS, n-PFOS, and in incumbent firefighters.

CONCLUSIONS: Significant associations between PFAS exposure, firefighting status, and ALS-related miRNAs suggest that PFAS exposure and firefighting characteristics are associated with miRNA expression patterns previously linked to ALS, warranting further investigation into potential biological pathways.}, } @article {pmid42754548, year = {2026}, author = {Peters, GA and Bongiorno, DM and Misra, AJ and Chang, W and Allerhand, T and Kennedy, M and Dorsett, M and Rosen, T and Goldberg, SA and Cash, RE}, title = {Prehospital Sedation and Physical Restraint of Older Adults Presenting With Behavioral Health Emergencies: A Nationwide Cross-Sectional Study.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.70731}, pmid = {42754548}, issn = {1532-5415}, abstract = {BACKGROUND: Management of behavioral health emergencies (BHE) such as acute agitation by emergency medical services (EMS) is associated with significant patient safety risks, particularly among older adults. However, the unique considerations for BHE among older adults may not be adequately addressed in prehospital BHE protocols and training. We aimed to provide the first nationwide description of EMS use of physical restraint and sedation for older adults with BHE in the United States.

METHODS: We conducted a cross-sectional evaluation of a nationwide convenience sample of 9-1-1 EMS encounters during 2023. We included EMS encounters for BHE that were managed by advanced life support (ALS) units. Outcomes of interest included physical restraint or administration of chemical sedation. Descriptive statistics were computed and stratified by patient age group. Differences in proportions with 95% confidence intervals were used to compare older (age ≥ 65 years) versus younger adults (age 18-64 years).

RESULTS: A total of 1,468,697 EMS encounters for BHE were included, of which 238,754 (16.3%) involved an older adult. Among 65,088 BHE encounters in which chemical sedation and/or physical restraint was used (older adults: n = 5915, 9.1%), older adults were more likely than younger adults to be sedated (69.2% vs. 61.3%) and less likely to be restrained (39.7% vs. 52.7%). Among those requiring sedation and/or restraint, benzodiazepines were more often used in older adults compared to younger adults (52.8% vs. 45.3%), antipsychotic agents were used at similar rates (15.4% vs. 14.9%), and ketamine was used slightly less often in older adults (5.5% vs. 6.6%).

CONCLUSIONS: Thousands of older adults presenting with BHE are restrained and/or sedated by EMS each year in the United States. Further work to improve evidence-based recommendations, protocols, and training specific to older adults is needed to help support EMS in these high-risk encounters.}, } @article {pmid42756552, year = {2026}, author = {Thompson, D and Williams, C and Price, G and Tosolini, AP and Falker-Gieske, C and Gilthorpe, JD and Schiavo, G and Fisher, EMC and Cunningham, TJ}, title = {Metabolic alterations in the absence of a neuromuscular phenotype in humanized SOD1[A5V] mice.}, journal = {Brain communications}, volume = {8}, number = {5}, pages = {fcag302}, pmid = {42756552}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis caused by mutations in superoxide dismutase 1 (SOD1) accounts for 15-30% of familial cases and is typically autosomal dominant. How single amino acid changes in this small protein cause neurodegeneration is unknown. In North America, SOD1[A5V] is the most common familial SOD1 mutation and results in an aggressive form of amyotrophic lateral sclerosis. Here, we present a novel genomically humanized mouse model of SOD1[A5V] , in which the mouse Sod1 locus has been replaced by the human SOD1 gene, with intact genomic architecture of exons and introns, but bearing an A5 V mutation. In agreement with previously reported human genomic knock-in mice, the phenotype is mild; however, transcriptomic and metabolomic profiling reveal significant dysregulation of glycolysis, the tricarboxylic acid cycle, and lipid metabolism. These changes suggest an early bioenergetic imbalance that precedes neuromuscular impairment. Our findings support metabolic dysfunction as an early event in amyotrophic lateral sclerosis pathogenesis. This freely available SOD1[A5V] model provides a valuable tool for studying amyotrophic lateral sclerosis progression and identifying therapeutic targets for pre-symptomatic treatment.}, } @article {pmid42756835, year = {2026}, author = {Lemos, JP and Stockholm, D and Dinatale, B and Chaves, AS and Pezet, S and Frias Carvalho, V and Pérez, AR and Mendes-da-Cruz, DA and Savino, W and Smeriglio, P}, title = {The thymus gland is a target and maintainer of amyotrophic lateral sclerosis pathophysiology.}, journal = {Brain, behavior, & immunity - health}, volume = {57}, number = {}, pages = {101323}, pmid = {42756835}, issn = {2666-3546}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons in the brain and spinal cord with evidence of local neuroinflammation. Regulatory T cells (Treg) exert neuroprotective effects and correlate with disease progression, but central mechanisms governing Treg development during ALS remain unclear. We investigated the thymic architecture and T cell differentiation in SOD1-G93A (mSOD1) ALS mice at multiple disease stages. Thymocyte and thymic epithelial cells (TEC) subpopulations, as well as stages of Treg differentiation and suppressive capacity, were analyzed by flow cytometry, in situ immunofluorescence, and functional assays. At late disease stage (120 days-old), mSOD1 mice displayed thymic atrophy, reduced thymocyte numbers, and decreased double-positive (DP), CD4 single-positive (SP), and Treg populations. Foxp3 expression per cell was preserved, but Treg progenitors and mature Treg numbers declined, paralleled by reduced suppressive function in vitro. TEC analysis revealed reduced total and mature medullary TEC (CD80[high]MHCII[high]), despite preserved Aire expression. Foxp3[+] cells were abnormally localized at cortical sites, away from mTEC, associated with migratory abnormalities and increased apoptosis. TREC evaluation revealed reduced intrathymic sjTREC, consistent with impaired proliferation and differentiation between DN and DP stages, although peripheral sj/βTREC ratios remained stable. Reduced Treg numbers were also observed in lymph nodes draining affected hindlimbs. Our findings identify the thymus as a target organ in ALS, where thymic involution, TEC loss, and Treg dysfunction may compromise immune tolerance. These alterations likely reinforce the role of the thymus in peripheral immune dysregulation and neuroinflammation observed in ALS.}, } @article {pmid42758107, year = {2026}, author = {Abdanipour, A and Nikfar, A and Feizi, H}, title = {Selegiline induces neuroprotection via PGC-1α/Nrf2 gene upregulation in H2O2 -treated hippocampal-derived neural stem/progenitor cells.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {72}, number = {5}, pages = {47-53}, doi = {10.14715/cmb/2026.72.5.7}, pmid = {42758107}, issn = {1165-158X}, mesh = {*Selegiline/pharmacology ; *Hydrogen Peroxide/pharmacology/toxicity ; Animals ; *NF-E2-Related Factor 2/genetics/metabolism ; *Hippocampus/cytology ; *Neural Stem Cells/drug effects/metabolism/cytology ; *Up-Regulation/drug effects ; Apoptosis/drug effects ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; *Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; Oxidative Stress/drug effects ; Rats ; Cells, Cultured ; Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; *Neuroprotection/drug effects ; }, abstract = {Oxidative stress mediated by reactive oxygen species (ROS) is a major contributor to the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, multiple sclerosis, and amyotrophic lateral sclerosis. Selegiline, a monoamine oxidase B inhibitor, has been reported to exert neuroprotective effects, although its precise cytoprotective mechanisms remain unclear. In this study, we investigated the effects of selegiline on apoptosis, necrosis, and cell survival in hydrogen peroxide (H2O2)-treated hippocampal-derived neural stem/progenitor cells (HD-NSPCs) in vitro. Passage 3 HD-NSPCs were treated with varying concentrations of selegiline (10[-3] to 10[-9] M) prior to exposure to 125 μM H2O2. Cell viability was assessed using the MTT assay, while apoptosis and necrosis were evaluated using TUNEL and acridine orange/ethidium bromide staining, respectively. Real-time RT-PCR was performed to quantify mRNA levels of PGC-1α, Nrf2, and Bcl-2. Treatment with 10[-7] M selegiline significantly enhanced HD-NSC viability, reduced apoptotic and necrotic cell fractions, and upregulated PGC-1α, Nrf2, and Bcl-2 expression compared to untreated cells (P < 0.05). These findings suggest that selegiline mitigates oxidative stress-induced cytotoxicity by activating Nrf2/PGC-1α signaling and promoting anti-apoptotic gene expression, thereby preserving mitochondrial function and enhancing cell survival. Overall, selegiline may represent a promising therapeutic agent for protecting neural progenitor cells and alleviating neuronal damage in neurodegenerative disorders.}, } @article {pmid42758317, year = {2026}, author = {Calvo, A and Moglia, C and Callegaro, S and Canosa, A and Manera, U and Mora, G and Cabras, S and Palumbo, F and Matteoni, E and Maccabeo, A and Pellegrino, G and Minerva, E and Pascariu, D and D'Ovidio, F and Vasta, R and Mazzini, L and De Marchi, F and Chiò, A}, title = {What do ALS motor phenotypes measure? A population-based decomposition of their prognostic dimensions.}, journal = {Journal of neurology}, volume = {273}, number = {10}, pages = {}, pmid = {42758317}, issn = {1432-1459}, support = {PNRR-MAD-2022-12375731//Ministero della Salute/ ; RF-2016-02362405//Ministero della Salute/ ; 101017598//Horizon 2020 Framework Programme/ ; 259867//FP7 Ideas: European Research Council/ ; 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/classification/physiopathology ; Female ; Prognosis ; Phenotype ; Male ; Middle Aged ; Aged ; Registries ; *Motor Neurons/pathology ; Prospective Studies ; }, abstract = {BACKGROUND: The ALS-OPM 3.3 classification stratifies incident ALS through three axes: onset region (O), propagation time (P) and motor-neuron pattern (M). We assessed whether OPM 3.3 improves prognostic discrimination over established classifications and characterised how it decomposes their prognostic signal in a population-based cohort.

METHODS: In the prospective Piedmont and Aosta Valley ALS Register (2000-2022), patients were classified on the three axes; M was operationalised as M_3class (M0 balanced, M1d UMN-predominant, M2d LMN-predominant), with the PLS-spectrum M1p analysed separately. Outcome was survival (death or tracheostomy) from onset. Multivariable Cox models (O, P1(n), M_3class, age, sex) underwent bootstrap optimism-correction and fivefold cross-validation, and were compared against alternative taxonomies and clinical staging systems.

RESULTS: Amongst 2,738 non-PLS patients (2,561 events, 93.5%), median survival differed across M classes (M0 27.0, M2d 36.0, M1d 41.9 months). OPM 3.3 outperformed the bulbar/spinal dichotomy but matched the classical phenotype (optimism-corrected C-index 0.703, 95% CI 0.685-0.719 vs 0.701). In the arm-proximal cell (95.7% M2d), the O2p protective effect vanished after M adjustment (HR 0.99, 95% CI 0.79-1.24), whilst M2d retained HR 0.83 (95% CI 0.72-0.95), showing prognosis reflects motor-neuron pattern, not anatomy. Adding King's, Milano-Torino (MiToS), or Fine'til 9 (FT9) clinical staging further improved discrimination.

CONCLUSIONS: OPM 3.3 did not improve discrimination over established phenotypes but decomposed their prognostic signal into independently interpretable dimensions. Favourable prognosis of arm-proximal/flail-arm onset reflects the underlying LMN-predominant phenotype, not onset site. The motor-neuron axis is robust to the treatment of the propagation axis and independent of clinical staging.}, } @article {pmid42758660, year = {2026}, author = {Salas, C and Rodríguez, F and Bingman, VP and Striedter, GF}, title = {Investigating map-like navigation and hippocampus homologs in teleost fish: Comment on Givon et al., 2023 "Lateral and medial telencephalic pallium lesions impair spatial memory in goldfish".}, journal = {Brain, behavior and evolution}, volume = {}, number = {}, pages = {1}, doi = {10.1159/bbe/abqag007}, pmid = {42758660}, issn = {1421-9743}, abstract = {This commentary critically examines the article by Givon et al. (2023), which reports that lesions to the lateral or medial regions telencephalic pallium (Dl or Dm) both impair allocentric spatial navigation in goldfish and concludes that both regions are necessary for this function. This interpretation challenges the extensive body of evidence supporting the functional dissociation between Dl and Dm. In particular, Dl's ventral subdivision (Dlv) has been shown to be essential for map-like spatial memory. In contrast, Dm has been associated primarily with emotional and motivational processes rather than spatial cognition. This commentary focuses on the fact that Givon et al's behavioral tasks (a plus-maze and a breadboard maze) lacked essential controls, such as systematic maze rotations and probe trials, that are necessary to rule out non-allocentric behavioral strategies. Moreover, the lesions are poorly localized, including some that extend well beyond the pallium and affect subpallial telencephalic regions and even the mesencephalic optic tectum - structures whose damage produces widespread sensorimotor and regulatory disturbances. Furthermore, the relatively high post-surgical mortality indicates nonspecific surgical effects. Overall, we conclude that Givon et al. (2023) does not provide convincing evidence for a role of Dm in allocentric navigation and does not undermine previous findings of a functional dissociation between Dl and Dm. We briefly discuss how these findings impact the ongoing search for a hippocampus homolog in teleosts and the larger effort to elucidate the neural mechanisms underlying spatial navigation in teleosts.}, } @article {pmid42758722, year = {2026}, author = {Yamakawa, I and Tamura, R and Yabata, H and Tsukamoto, T and Kobashi, S and Tamaki, Y and Ogawa, N and Kitamura, A and Urushitani, M}, title = {Serum Na-Cl value from routine blood tests reflects CO2 retention in amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {21}, number = {9}, pages = {e0358772}, pmid = {42758722}, issn = {1932-6203}, mesh = {Humans ; *Carbon Dioxide/blood ; *Amyotrophic Lateral Sclerosis/blood ; Female ; *Sodium/blood ; Retrospective Studies ; Male ; Blood Gas Analysis ; Middle Aged ; Aged ; *Chlorides/blood ; ROC Curve ; Respiratory Insufficiency/blood ; Biomarkers/blood ; Adult ; }, abstract = {BACKGROUND: Respiratory failure is the leading cause of death in amyotrophic lateral sclerosis (ALS). Early detection of CO2 retention is crucial for assessing respiratory failure severity and guiding noninvasive positive pressure ventilation (NPPV) management. However, arterial blood gas analysis is invasive and uncomfortable for routine monitoring.

OBJECTIVE: We investigated whether the serum sodium-chloride difference (Na-Cl value), calculated from routine blood tests, could serve as a screening marker for CO2 retention in ALS patients.

METHODS: This retrospective study included 88 ALS patients with 116 paired samples of arterial blood gas and serum electrolyte data. We analyzed correlations between Na-Cl value and blood gas parameters (HCO3-, PCO2), performed receiver operating characteristic (ROC) analysis for detecting CO2 retention (PCO2 ≥ 45 mmHg), and examined relationships with respiratory function (%FVC).

RESULTS: Na-Cl value showed strong correlation with HCO3- (r = 0.78, p < 0.001) and PCO2 (r = 0.71, p < 0.001). Na-Cl ≥ 37 mEq/L demonstrated sensitivity of 85.11% and specificity of 69.57% for detecting PCO2 ≥ 45 mmHg, with negative predictive value of 87.27% (AUC = 0.842). Na-Cl ≥ 39 mEq/L achieved specificity of 92.75%. Patients with %FVC < 50% had significantly higher Na-Cl, PCO2, and HCO3- values.

CONCLUSIONS: Serum Na-Cl value serves as a simple, noninvasive screening marker for CO2 retention in ALS. Na-Cl ≥ 37 mEq/L warrants blood gas analysis, while Na-Cl ≥ 39 mEq/L provides specificity >90%. This marker can be calculated from routine blood tests without additional cost, making it suitable for frequent monitoring and reducing the risk of missing intervention timing.}, } @article {pmid42759101, year = {2026}, author = {Santangelo, S and Casarotto, V and Campelli, L and Leoni, S and Cabras, S and Matteoni, E and Marco, G and Canosa, A and Basso, M and Bonetto, V and Trojisi, F and Bossolasco, P and Silani, V and Chiò, A and Ticozzi, N and Calvo, A and Ratti, A}, title = {Establishment of two iPSC lines from ALS patients carrying mutations in SQSTM1 and TBK1 genes.}, journal = {Stem cell research}, volume = {96}, number = {}, pages = {104105}, doi = {10.1016/j.scr.2026.104105}, pmid = {42759101}, issn = {1876-7753}, abstract = {We describe the generation and characterization of two induced pluripotent stem cell (iPSC) lines: one derived from an ALS patient carrying the heterozygous SQSTM1 c.1175C > T (p.Pro392Leu) mutation, identified as cell line 047, and another one (cell line 053) derived from a patient carrying the heterozygous TBK1 c.1760 + 4_1760 + 7delAGTA likely pathogenic variant, predicted to result in a premature stop codon +, together with the ERBB4 c.2402A > T (p.His801Leu) variant of unknown significance (VUS).}, } @article {pmid42759848, year = {2026}, author = {Viteri, JA and Kerr, NR and Brennan, CD and Kick, GR and Wang, M and Ketabforoush, A and Snyder, HJ and Moore, PJ and Darvishi, FB and Dashtmian, AR and Ayyagari, SN and Rich, K and Zhu, Y and Nishimune, H and Arnold, WD}, title = {Cellular senescence is an early feature and therapeutic target in amyotrophic lateral sclerosis TDP-43[Q331K] mice.}, journal = {Neurobiology of disease}, volume = {229}, number = {}, pages = {107610}, doi = {10.1016/j.nbd.2026.107610}, pmid = {42759848}, issn = {1095-953X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration in the motor cortex and spinal cord. Aging is a key risk factor for ALS, and cellular senescence - a hallmark of aging marked by irreversible cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype - has been implicated in neurodegeneration, yet its role in ALS progression remains incompletely understood. Here, we show that molecular markers of cellular senescence emerge in the motor cortex and spinal cord alongside declines in neural and neuromuscular function in TDP-43[Q331K] ALS mice, supporting senescence as an early feature of ALS pathology. To test whether reduced senescence ameliorates ALS pathology, we evaluated longitudinal senolytic treatment with dasatinib and quercetin (D&Q) in TDP-43[Q331K] mice. D&Q treatment improved motor behavior, neuromuscular function, and reduced axonal damage as measured by plasma neurofilament light chain, accompanied by robust improvements in motor cortex excitability and preservation of layer V neuron counts. At the cellular level, cortical microglia were implicated as a potential mediator of senolytic benefits based on reduced microglial TDP-43 burden and senescence markers. Together, these findings identify cellular senescence as an early, disease-relevant, and modifiable feature of ALS pathology.}, } @article {pmid42760265, year = {2026}, author = {Huang, W and Wan, XY and Wang, YX and Hu, YH and Jing, SH and Zhang, Y and Ke, P and Li, DK and Zhang, C and Leng, RX and Wang, Q and Di, DS}, title = {Early-life tobacco smoke exposure and incident rheumatoid arthritis: mediated by allostatic load and joint effects with polygenic risk.}, journal = {Rheumatology (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/rheumatology/keag519}, pmid = {42760265}, issn = {1462-0332}, abstract = {OBJECTIVES: Rheumatoid arthritis (RA) is a widespread autoimmune disorder. Early-life environmental exposures may contribute to RA, and tobacco smoke represents an important modifiable factor. This study aimed to examine whether early-life tobacco smoke exposure affects incident RA risk, and to clarify the potential mediating role of allostatic load (AL) and interactive effects with genetic susceptibility.

METHODS: Using questionnaire, biomarker, genetic, and linked health-record data from UK Biobank, we examined intrauterine tobacco smoke exposure (IUTSE; n = 427,037), age at tobacco use initiation (ATUI; n = 414,318) and RA cases. Cox models evaluated associations between early-life tobacco exposure and RA risk. Mediation analysis quantified AL's mediating effect. Additive and multiplicative interaction examined genetic susceptibility interactions.

RESULTS: IUTSE was associated with higher RA risk (HR = 1.15, 95% CI: 1.08, 1.21). Compared with never-smokers, individuals who started tobacco smoking in childhood, adolescence, and adulthood exhibited elevated RA risk, with corresponding HRs of 1.74 (95% CI: 1.39, 2.17), 1.56 (95% CI: 1.29, 1.88), and 1.47 (95% CI: 1.22, 1.76). Mediation analyses indicated statistically significant but small indirect effects of AL. The indirect effect for IUTSE was 1.001 (95% CI: 1.001, 1.002) and for tobacco use during childhood, adolescence, and adulthood were 1.009 (95% CI: 1.005, 1.013), 1.006 (95% CI: 1.003, 1.009), and 1.006 (95% CI: 1.003, 1.009). High genetic risk with IUTSE (HR = 1.93, 95% CI: 1.75, 2.13) or childhood initiation (HR = 2.89, 95% CI: 2.17, 3.86) increased RA risk.

CONCLUSION: Early-life tobacco smoke exposure elevates RA risk in adulthood, with limited mediation by AL and modification by genetic predisposition.}, } @article {pmid42760536, year = {2026}, author = {Garg, L and Chaplot, K and Kuppili, G and Tendulkar, S and Joseph, J and Kamat, S and Ratnaparkhi, G}, title = {Neuro-glial lipid imbalance in a Drosophila model of amyotrophic lateral sclerosis 8.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42760536}, issn = {2051-5960}, support = {P40 OD018537/OD/NIH HHS/United States ; SB/SJF/2021-22/01//ANRF, India/ ; SL03//EMSTAR/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Neuroglia/metabolism/pathology ; Disease Models, Animal ; *Lipid Metabolism/physiology ; Humans ; Drosophila Proteins/genetics/metabolism ; *Brain/metabolism/pathology ; Drosophila ; Animals, Genetically Modified ; Vesicular Transport Proteins/genetics/metabolism ; }, abstract = {Membrane Contact sites (MCS) have emerged as physiologically relevant zones that coordinate inter-organelle communication and cellular function. VAPB, an ER-resident MCS tethering protein, plays a central role in regulating MCSs through its numerous protein interactors, thereby influencing cellular homeostasis. A pathogenic missense VAPB[P56S] mutation causes familial Amyotrophic Lateral Sclerosis 8 (ALS8) in humans, with progressive degeneration of motor neurons. The precise mechanisms underlying the motor neurodegeneration remain poorly understood. In this study, we examine lipid imbalance in the brain of a Drosophila model of ALS8 (VAPB[P58S]). Specifically, we find that lipid homeostasis is disrupted in an age-dependent manner. Strikingly, cholesterol esters and sphingolipids show an age-dependent increase, while cholesterol shows a decrease. Intriguingly, from a cellular perspective, despite the accumulation of triacylglycerols (TAGs) in the brains of VAPB[P58S] animals, the increased neutral lipid species do not correlate with lipid droplets (LDs), which are fewer in density and smaller in size. Lipid imbalance and progressive motor dysfunction in VAPB[P58S] animals can be reversed by expressing VAPB[WT], suggesting a relationship between VAPB activity and lipid flux. To uncover VAPB's role in lipid homeostasis, we modulate VAPB activity in neurons and glia to dissect out tissue-specific roles. We find that both cell types contribute to lipid homeostasis in differential ways. In glia, LD flux is strongly dependent on VAPB activity, a dependence further recapitulated in cultured human cell lines, suggesting evolutionary conservation of the regulatory mechanism. Thus, we hypothesize that lipid dysregulation constitutes a critical pathogenic feature of ALS8, with the VAPB[P56S] allele disrupting lipid homeostasis in the neuro-glial axis.}, } @article {pmid42760704, year = {2026}, author = {Liu, Y and Chen, S and Wu, Y and Zhou, W and Shang, H and Ou, R}, title = {Causal relationship between metabolites, cerebral volume, and amyotrophic lateral sclerosis: A 2-step Mendelian randomization analysis.}, journal = {Medicine}, volume = {105}, number = {38}, pages = {e50769}, pmid = {42760704}, issn = {1536-5964}, support = {82271272//the National Science Fund of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood/metabolism/pathology ; Humans ; *Mendelian Randomization Analysis ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Organ Size ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration. Although metabolic abnormalities have been implicated in ALS, the causal relationships between circulating metabolites and ALS remain unclear. This study aimed to investigate the potential causal associations between plasma metabolites and ALS risk and to explore the mediating role of cerebral volume. A 2-sample Mendelian randomization (MR) study was conducted using publicly available genome-wide association study summary statistics. Genetic instruments for plasma metabolites were obtained from metabolomic GWAS datasets, and ALS-associated genetic data were used as the outcome. The inverse-variance weighted method was used as the primary analysis, with sensitivity analyses performed using MR-Egger regression, weighted median analysis, MR-PRESSO, heterogeneity testing, and leave-one-out analysis. A 2-step MR analysis was further conducted to evaluate whether cerebral volume mediated the associations between metabolites and ALS. Six metabolites showed significant associations with ALS risk. Genetically predicted higher levels of N,N-dimethylalanine, Behenylcarnitine (C22), and deoxycarnitine were associated with increased ALS risk, whereas higher levels of (N(1) + N(8))-acetylspermidine, Betaine, and tetradecadienedioate (C14:2-DC) were associated with decreased ALS risk. Sensitivity analyses supported the robustness of the findings. Two-step MR analysis suggested that cerebral volume did not significantly mediate the associations between these metabolites and ALS risk. This study identified 6 circulating metabolites genetically associated with ALS risk. These findings provide insights into the potential metabolic pathways involved in ALS and suggest that the observed associations are unlikely to be mediated through cerebral volume changes.}, } @article {pmid42760853, year = {2026}, author = {Wenz, L and Scholl, LS and Reinhardt, N and Heynitz, RV and Gmeiner, V and Rau, P and Müller, PJ and Wolff, AW and Feneberg, E and Demleitner, AF and Lingor, P}, title = {Chitinases in Tear Fluid of Patients With Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {9}, pages = {e70757}, pmid = {42760853}, issn = {1468-1331}, support = {EXC 2145 SyNergy - ID 390857198//Deutsche Forschungsgemeinschaft/ ; project H-13//Technische Universität München/ ; }, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Male ; *Hexosaminidases/genetics/metabolism ; *Tears/enzymology ; *Chitinase-3-Like Protein 1/metabolism ; Middle Aged ; *Chitinases/metabolism/genetics ; Aged ; Biomarkers/metabolism/blood ; Adult ; }, abstract = {BACKGROUND: Chitinases, including chitotriosidase (CHIT1) and chitinase-3-like protein 1 (CHI3L1), are markers of neuroinflammation, a key process in amyotrophic lateral sclerosis (ALS). Tear fluid (TF) can be collected non-invasively and may represent a promising alternative to CSF or blood to study chitinases.

METHODS: TF was collected from 50 ALS patients and 50 control subjects using Schirmer strips. CHIT1 and CHI3L1 levels in TF, serum, and CSF were quantified using ELISA. Serum NfL was measured using SIMOA. The frequency of a 24 bp-duplication polymorphism in the CHIT1 gene influencing CHIT1 expression was assessed by PCR.

RESULTS: No group differences in the distribution of the CHIT1 polymorphism were detected. Carriers of the polymorphism in both ALS and controls showed lower CHIT1 levels in serum and TF. CHI3L1 levels in TF were higher in ALS patients compared to controls (p = 0.007), consistent with changes in CSF but not serum. In ALS, males showed higher TF CHIT1 values compared to females (p = 0.009). Combining TF chitinase values with serum NfL values improved discrimination between ALS and controls.

CONCLUSIONS: Chitinases are detectable in TF, and CHI3L1 levels recapitulate changes observed in CSF, highlighting its potential for non-invasive longitudinal assessment. Furthermore, chitinase values in TF, together with serum NfL, may act complementarily by capturing distinct aspects of the disease, neuroinflammation and axonal damage. These results suggest TF chitinases and serum NfL could complementarily contribute to the diagnosis and monitoring of the disease, and call for further evaluation of TF as a biomarker source in ALS.}, } @article {pmid42760861, year = {2026}, author = {De Nardi, A and Paris, A and Lauria, M and Martinelli, I and Zucchi, E and Simonini, C and Mandrioli, J and Marchetti, L}, title = {Multivariate Survival Analysis of a Comprehensive Clinical Trial of Rapamycin in Amyotrophic Lateral Sclerosis Explores Prognostic Factors and Survival Patterns in C9orf72 Carriers.}, journal = {European journal of neurology}, volume = {33}, number = {9}, pages = {e70756}, pmid = {42760861}, issn = {1468-1331}, support = {FGCR02/2015//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; GPG/2022/1343//Emilia Romagna Regional Health Authority/ ; 53232941//Pfizer/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/mortality/diagnosis ; *C9orf72 Protein/genetics ; Female ; Male ; Prognosis ; *Sirolimus/therapeutic use ; Middle Aged ; Survival Analysis ; Retrospective Studies ; Multivariate Analysis ; Aged ; Mutation ; Heterozygote ; Adult ; *Immunosuppressive Agents/therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by considerable variability in survival times. This retrospective study aims to evaluate the prognostic value of a broad range of variables by conducting a comprehensive survival analysis on longitudinal data from RAP-ALS, a clinical trial investigating the effects of rapamycin in ALS patients (n = 63).

METHODS: Covariates were classified as risk or protective factors according to their hazard ratios. Regularized Cox regression was utilized to select the best-performing multivariate models in cross-validation. Longitudinal measures were incorporated by modeling covariates as time-dependent. Survival times of treated C9orf72 mutation carriers (n = 6) were further investigated through log-rank tests and restricted mean survival time analysis.

RESULTS: Univariate analyses confirmed several previously established prognostic factors. Multivariate regularized Cox models incorporated neurofilaments, creatinine, clinical scores, and markers of immune activation. Moreover, the inclusion of time-varying covariates allowed us to investigate late-stage risk factors, such as the neutrophil-to-lymphocyte ratio. Additionally, the analysis indicated a protective effect in treated C9orf72 mutation carriers (log-rank test, p = 0.026), which was confirmed after comparing this treatment subgroup with an independent C9orf72+ cohort (n = 40; RMST test, p = 0.04).

CONCLUSIONS: The survival analysis confirmed the role of previously identified prognostic factors, while suggesting that high-performing multivariate models should integrate multiple ALS pathological hallmarks. Moreover, the observed longer survival among C9orf72 mutation carriers contrasts with prior reports. Due to the small sample size and potential confounding factors, the observed benefits in treated C9orf72 patients should be considered exploratory, supporting evaluation in a larger, genetically stratified trial.}, } @article {pmid42761537, year = {2026}, author = {Bruning, K and Heidrick, L and Rong, P}, title = {A mechanistically informed framework of hierarchical temporal speech organization for objective differential assessment of motor speech disorders in neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1907826}, pmid = {42761537}, issn = {1662-4548}, support = {UL1 TR002366/TR/NCATS NIH HHS/United States ; }, abstract = {INTRODUCTION: Speech is organized into discrete utterances and pauses in accordance with underlying linguistic structure, temporal coordination, prosodic organization, and respiratory demands. Temporal speech characteristics, including rhythmic and pausing patterns, are governed by multiple neurophysiological mechanisms and provide valuable insights for the assessment and management of motor speech disorders. This study employed a mechanistically informed analytic framework of hierarchical temporal speech organization to derive interpretable, objective measures for assessing rhythmic and pausing disturbances in neurodegenerative diseases.

METHODS: Orofacial kinematic and acoustic recordings were obtained from two neurodegenerative disease groups-amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD)-along with a neurologically healthy control (HC) group, during a passage reading task. Using automated analytic procedures, kinematic rhythm measures (movement-based) and acoustic rhythm measures (sound-based) were derived to characterize hierarchical rhythmic modulation of articulatory movements and critical-band acoustic modulation envelopes at prosodic, syllabic, and sub-syllabic levels. Pause measures were derived to characterize within- and between-sentence pausing patterns. Rhythmic and pausing patterns were compared across groups. The acoustically derived rhythm and pause measures were subsequently subjected to (1) discriminant analyses for multiclass classification among the ALS, PD, and HC groups, and (2) regularized regression models to evaluate their associations with functional outcomes.

RESULTS: Both neurodegenerative disease cohorts exhibited a reorganization of hierarchical rhythmic modulation characterized by reduced prosodic-level modulation and increased syllabic-level modulation. Such changes were, however, driven primarily by articulatory impairment in ALS and by respiratory-laryngeal impairment in PD. In addition, both cohorts showed reduced regularity of intra-syllabic temporal organization and altered within-sentence pausing patterns, whereas the ALS cohort exhibited additional changes in between-sentence pausing. Measures capturing these rhythmic and pausing disturbances demonstrated promising classification performance (mean accuracy = 0.77; mean area under the curve [AUC] = 0.84) and meaningful associations with functional speech decline across diseases.

DISCUSSION: The rhythm and pause measures captured disease-specific subclinical changes in the physiological substrates underlying rhythmic and pausing disturbances in ALS and PD, demonstrating potential as clinically applicable, objective markers to enable more accurate differential diagnosis, targeted intervention, and measurement-based care for neurodegenerative motor speech disorders.}, } @article {pmid42762093, year = {2026}, author = {Wang, PS and Zou, SM and Wei, Q and Wu, ZY and Li, HF}, title = {Weak association of pathogenic ERBB4 variants with amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/17582024.2026.2736021}, pmid = {42762093}, issn = {1758-2032}, abstract = {INTRODUCTION: ERBB4 variants were reported to cause amyotrophic lateral sclerosis (ALS). However, gene burden analyses did not find an enrichment of rare variants in patients, leaving the pathogenic role of ERBB4 in ALS unclear. Therefore, this study aimed to reassess the association of ERBB4 variants with ALS.

METHODS: Next-generation sequencing was performed in 250 ALS and 714 non-ALS patients. Low-frequency, deleterious non-synonymous ERBB4 variants were filtered, and their allele frequencies were compared between groups.

RESULTS: In total, 42 low-frequency and deleterious ERBB4 variants were identified in patients and normal controls, with three variants in all groups. There was no significant difference in allele frequencies between ALS and non-ALS groups. Additionally, four reported pathogenic variants (c.158A > G, c.284G > A, c.965T > A, and c.1624G > A) were observed in patients with neuromuscular disease or leukoencephalopathy, as well as normal controls. Based on the evidence from this study, c.284G > A was reclassified as a likely benign variant, while the others were reclassified as uncertain significance according to the American College of Medical Genetics and Genomics Guidelines.

DISCUSSION: These results suggest a modest association between ERBB4 variants and ALS, underscoring the need for clinicians to conduct more careful molecular diagnosis and genetic consultations for ALS patients with ERBB4 variants.}, } @article {pmid42762623, year = {2026}, author = {Uppal, G and Singh, A and Parasuraman, RN and Kumar, A and Jena, KC and Kumar, R}, title = {Label-free analysis of grade-specific molecular alterations in osteoarthritic subchondral bone using Raman spectroscopy coupled with MCR-ALS.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {365}, number = {}, pages = {128743}, doi = {10.1016/j.saa.2026.128743}, pmid = {42762623}, issn = {1873-3557}, abstract = {Changes in subchondral bone metabolism are central to osteoarthritis (OA) progression, highlighting the need for sensitive, label-free analytical approaches capable of resolving molecular-level alterations in complex biological tissue matrices. Raman spectroscopy is a powerful, non-destructive tool for detecting molecular changes in intact pathological tissues; however, overlapping spectral bands obscure accurate interpretation. In this study, Raman spectroscopy combined with multivariate curve resolution-alternating least squares (MCR-ALS) was applied to human subchondral bone at different stages of osteoarthritic degeneration to identify grade-specific molecular changes. The MCR-ALS approach enabled decomposition of overlapping Raman spectra into distinct biochemical components attributed to mineral, lipid, and collagen. Comparative statistical analysis revealed grade-dependent biochemical alterations in osteoarthritic subchondral bone. No significant changes occurred in mineral or lipid content at the early stage; however, significant mineral reduction and enhanced lipid accumulation were observed in advanced-stage degeneration. Collagen content exhibited an initial increase in the early stage, followed by a substantial decline in the advanced stage, accompanied by progressive disruption of its structural organization. Deconvolution of the amide I band further enabled improved characterization of collagen structural changes in intact tissue. These findings demonstrate that the Raman-MCR approach effectively resolves complex biological spectra, sensitively detects stage-specific molecular alterations in osteoarthritic subchondral bone, and offers a robust analytical framework for the label-free characterization of intact tissues.}, } @article {pmid42762936, year = {2026}, author = {Luo, L and Chen, W and Luo, S and Ma, S and Liu, K and Gong, Q and Huang, B and Chen, Z and He, Y and Wang, D}, title = {Defective ATP13A2-ITCH-ALIX signaling impairs intraluminal vesicle biogenesis and increases neuronal vulnerability.}, journal = {Cellular signalling}, volume = {149}, number = {}, pages = {112897}, doi = {10.1016/j.cellsig.2026.112897}, pmid = {42762936}, issn = {1873-3913}, abstract = {ATP13A2 is a lysosomal P5B-type ATPase whose loss-of-function mutations are associated with a spectrum of neurodegenerative disorders, including early-onset Parkinson's disease, Kufor-Rakeb syndrome, neuronal ceroid lipofuscinosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. Although ATP13A2 is known to contribute to lysosomal homeostasis and, thereby, to neuronal degeneration, emerging evidence suggests that it may also influence exosome biology. However, the mechanisms by which endogenous ATP13A2 regulates exosome biogenesis and the relevance of this process to neuronal vulnerability remain unclear. In the present study, using multiple ATP13A2-deficient human cell models, we demonstrated that ATP13A2 deficiency impairs intraluminal vesicle (ILV) biogenesis and reduces exosome secretion across diverse cellular contexts. Loss of ATP13A2 did not markedly affect endocytosis, early endosome abundance, or multivesicular body formation, but it consistently reduced ILV density within multivesicular bodies. Mechanistically, ATP13A2 deficiency promoted lysosome-associated accumulation of the E3 ubiquitin ligase ITCH, which enhanced ubiquitin-proteasome-dependent degradation of ALG-2-interacting protein X (ALIX), a critical adaptor of the endosomal sorting complex required for transport machinery that mediates ILV membrane remodeling. Restoration of ALIX expression or reduction of Itchy E3 ubiquitin-protein ligase (ITCH) activity rescued the ILV biogenesis defects in ATP13A2-deficient neuronal cells. Furthermore, dysregulation of the ATP13A2-ITCH-ALIX pathway increased neuronal susceptibility to mitochondrial stress, whereas restoration of ALIX or reduction of ITCH activity markedly improved neuronal survival. Together, these results identify an ATP13A2-ITCH-ALIX signaling axis linking lysosomal dysfunction to impaired ILV biogenesis and exosome regulation. Our study suggests that defective ILV biogenesis contributes to neuronal vulnerability and that modulation of the ATP13A2-ITCH-ALIX pathway may represent a therapeutic strategy for ATP13A2-associated neurodegeneration.}, } @article {pmid42763025, year = {2026}, author = {Wang, S and Dolce, MA and Burkett, AM and Collis, VL and Fuller, PE and Blanco, GA and Le, NTT and Fingert, JH and Monteiro, MJ}, title = {TBK1 overexpression reduces neuronal loss in the P497S UBQLN2 mouse model of ALS/FTD.}, journal = {Neurobiology of disease}, volume = {229}, number = {}, pages = {107611}, doi = {10.1016/j.nbd.2026.107611}, pmid = {42763025}, issn = {1095-953X}, support = {R01 NS098243/NS/NINDS NIH HHS/United States ; }, abstract = {Missense mutations in UBQLN2 are linked to dominant inheritance of amyotrophic lateral sclerosis (ALS) which is frequently accompanied by frontotemporal dementia (FTD). The encoded UBQLN2 protein functions to maintain proteostasis, collapse of which is increasingly being realized as the cause of many neurodegenerative diseases. During investigations of our UBQLN2 mouse models of ALS/FTD, we observed a significant decline in Tank-binding kinase 1 (TBK1) protein in end-stage mice. The decline could be significant, as haploinsufficiency of TBK1 expression is linked to ALS/FTD. To determine whether the reduction in TBK1 levels is responsible for driving pathogenesis, we crossed P497S UBQLN2 transgenic (Tg) mice with BacTBK1 Tg mice that overexpress TBK1 and analyzed the progeny for signs of pathology. The analysis revealed that double transgenic mice had a significant reduction in neurodegeneration in both the brain and spinal cord (SC) compared to P497S single-Tg mice. Double immunofluorescence staining of P497S mouse tissue revealed TBK1 colocalizes with UBQLN2 aggregates in spinal motor neurons. Biochemical extraction studies of mouse brain tissue revealed increased enrichment of TBK1 along with wild type and mutant UBQLN2 proteins in detergent-insoluble material, suggesting TBK1 gets sequestered by UBQLN2 aggregates. GST-pulldown assays revealed that UBQLN2 binds directly with TBK1, but paradoxically the P497S mutation was found to reduce TBK1 binding. Turnover studies indicated that loss of UBQLN2 destabilizes TBK1, providing another route for its reduction. These findings lead us to propose that efforts directed toward increasing TBK1 expression may provide a therapeutic approach for treating ALS/FTD caused by UBQLN2 mutations.}, } @article {pmid42763209, year = {2026}, author = {Liu, YW and Fan, DS and Chen, L}, title = {[Evaluation value of NRS2002 and MNA-SF on nutritional status and prognosis in adult patients with amyotrophic lateral sclerosis].}, journal = {Zhonghua yi xue za zhi}, volume = {106}, number = {35}, pages = {3746-3753}, doi = {10.3760/cma.j.cn112137-20251225-03422}, pmid = {42763209}, issn = {0376-2491}, support = {81873784, 82071426//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; 2024//The Special Fund of the National Clinical Key Specialty Construction Program, P. R.China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Prognosis ; *Nutritional Status ; *Nutrition Assessment ; Female ; Male ; Middle Aged ; Prospective Studies ; Body Mass Index ; Malnutrition ; Aged ; Adult ; }, abstract = {Objective: To evaluate the value of the Nutritional Risk Screening 2002 (NRS2002) and the Mini-Nutritional Assessment Short-Form (MNA-SF) in assessing nutritional status, disease progression, and prognosis in adult patients with amyotrophic lateral sclerosis (ALS). Methods: Baseline data of 148 ALS patients who visited Peking University Third Hospital from January to December 2024 were prospectively collected. Patients were divided into malnutrition group and normal group based on the presence of nutritional risk. Assessments were conducted every 3 months over a 1-year follow-up period, during which ALSFRS-R scores, body mass index (BMI), and nutritional scale scores were recorded. The rates of ALSFRS-R score decline (δFS) and BMI change (δBMI) were calculated as (baseline ALSFRS-R score-follow-up ALSFRS-R score)/follow-up months and (baseline BMI-follow-up BMI)/follow-up months, respectively. The primary endpoint events were death or tracheostomy. Clinical data were compared between patients with different nutritional statuses. Spearman and Pearson correlation analyses were used to explore the correlations between scale scores and various indicators. Cohen's Kappa coefficient was used to evaluate the inter-rater consistency between the two scales. Linear mixed-effects models were applied to assess the relationships between nutritional risk and changes in δFS and δBMI. Results: A total of 148 ALS patients were collected in this study, including 96 males and 52 females, with the age [M(Q1, Q3)] of 56.0 (49.0, 61.0) years. A total of 4 enrolled patients were excluded from the NRS2002 assessment owing to missing BMI data, which resulted from the inability to measure height and weight in these bedridden individuals. Based on the NRS2002 and MNA-SF, patients were classified into the malnutrition group (NRS2002 malnutrition group, n=45; MNA-SF malnutrition group, n=59) and the normal group (NRS2002 normal group, n=99; MNA-SF normal group, n=89). The Kappa values for the consistency between NRS2002 and MNA-SF at baseline, 3, 6, 9, and 12 months were 0.726, 0.713, 0.698, 0.648, and 0.769, respectively (all P<0.001). NRS2002 was negatively correlated with BMI (r=-0.413, P<0.001), body weight (r=-0.442, P<0.001), prealbumin (r=-0.253, P<0.001), creatinine (r=-0.139, P=0.049), and triglycerides (r=-0.228, P=0.003); MNA-SF was positively correlated with BMI (r=0.573, P<0.001), body weight (r=0.514, P<0.001), prealbumin (r=0.277, P<0.001), creatinine (r=0.233, P=0.002), and triglycerides (r=0.289, P<0.001). After adjusting for confounders using linear mixed-effects models, a higher NRS2002 score was identified as a risk factor for increases in δFS (β = 0.127, 95%CI: 0.065-0.189, P<0.001) and δBMI (β=0.150, 95%CI: 0.104-0.197, P<0.001), whereas a higher MNA-SF score served as a protective factor against increases in δFS (β=-0.090, 95%CI:-0.116 to -0.064, P<0.001) and δBMI (β=-0.092, 95%CI:-0.113 to -0.071, P<0.001). Conclusions: NRS2002 and MNA-SF demonstrate good consistency in nutritional risk assessment among ALS patients. The scores of both scales are correlated with traditional nutritional indicators including BMI, body weight, prealbumin, creatinine, and triglycerides, and are associated with the rates of ALSFRS-R and BMI changes in these patients.}, } @article {pmid42763500, year = {2026}, author = {Mew, L and Rosser, E and Heron, E and Mezzetti, C and Baron, S and Cronin, C}, title = {Evaluating the impact of a Sigma Action Learning Set on leadership development among nurse leaders.}, journal = {Journal of research in nursing : JRN}, volume = {}, number = {}, pages = {17449871261477335}, pmid = {42763500}, issn = {1744-988X}, abstract = {BACKGROUND: Leadership capability is essential for nursing practice, influencing patient care, staff well-being and organisational effectiveness. Inclusive leadership valuing diversity, equity and shared learning are increasingly recognised as vital in complex healthcare systems. Action Learning Sets (ALSs) are an established approach to leadership development through structured peer reflection, questioning and collaboration.

AIM: To evaluate the effectiveness of a nationally delivered, inclusive ALS programme in developing nurse leadership over 12 months.

METHOD: Kirkpatrick's model was used to evaluate the programme, examining participants' preparedness, learning, behavioural change and organisational impact. Participants (n = 5) were purposefully selected from diverse healthcare organisations across England and Wales. Data were collected through an online group evaluation and analysed across four levels: reaction, learning, behaviour and results.

FINDINGS: All domains were positively evaluated. The ALS provided a safe space for reflection and collaborative learning. Participants reported increased leadership confidence, enhanced self-awareness and improved inclusive leadership. Behavioural changes included greater engagement with diverse perspectives and application of reflective practices. Policy-focused sessions were highly valued.

CONCLUSION: The ALS offered a supportive and effective approach to leadership development, enabling nurses to address real-world challenges through reflection and peer learning. Wider adoption across practice settings is recommended.}, } @article {pmid42764383, year = {2026}, author = {Pasho, E and Catanese, A and Kabashi, E and Ciura, S}, title = {What can we learn on ALS pathophysiology from iPSC-derived motor neurons harbouring TARBDP mutations: a systematic review.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {42764383}, issn = {2047-9158}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/physiopathology/pathology ; Humans ; *Motor Neurons/pathology/metabolism ; *Induced Pluripotent Stem Cells/pathology/metabolism ; *DNA-Binding Proteins/genetics ; *Mutation/genetics ; Animals ; }, abstract = {The degenerating motor neurons of amyotrophic lateral sclerosis (ALS) patients are characterized by the accumulation of cytoplasmic aggregates, specifically enriched in ubiquitinated TDP-43. Expressed mainly in the nucleus and partially in the cytoplasm to execute its role in RNA metabolism, the exact mechanisms that bring TDP-43 to aggregate in disease have yet to be described. Unfolding these processes could bring us closer to effective drug development that is drastically lacking in the ALS research field. Induced pluripotent stem cells (iPSCs) offer a promising platform for studying ALS pathogenesis directly in the relevant human genetic backgrounds of ALS patients. Since 2012, more than 30 published studies have investigated altered cellular and subcellular features in iPSC-derived motor neurons from ALS patients harbouring mutations in the TARDBP gene (encoding for TDP-43 protein). However, there are discrepancies in the obtained results, which call into question the relevance of this model for ALS disease modelling and its use for drug development efforts. Thus, there is a need in the field for a clear and detailed layout and summary of all the published data on ALS modelling using TARDBP mutant iPSC-derived motor neurons. In this systematic review, we analyse all phenotypic assessments that have been done on iPSC-derived motor neurons derived from TARDBP ALS patients on the morphology, functionality and the viability of these cells. We also analyse if this model recapitulates ALS pathology in vitro by comparing studies that looked at TDP-43 and neurofilament aggregation, as well as stress granule dynamics. Importantly, we compare the technical details of all the discussed studies, such as differentiation protocol, age and purity of the used motor neurons and quantification method, in order to discuss how all of these parameters affect the observed phenotypes. Lastly, we also expand our review to all other different cell types that have been differentiated from TARDBP iPSCs, highlighting non-cell autonomous mechanisms of TDP-43-ALS pathophysiology. By integrating findings across studies, this review identifies commonalities and discrepancies, discusses methodological advancements and limitations, and highlights potential therapeutic targets revealed through TARDBP iPSC-derived models.}, } @article {pmid42764825, year = {2026}, author = {Chen, HW}, title = {Operator-Driven Active Craniospinal Tensioning (ACT) Device for Non-ambulatory Application.}, journal = {Cureus}, volume = {18}, number = {8}, pages = {e114854}, pmid = {42764825}, issn = {2168-8184}, abstract = {Active craniospinal tensioning (ACT) is an upright-posture axial spinal traction maneuver hypothesized to couple two mechanisms: dural pull-recoil, a cerebrospinal fluid (CSF) pressure-gradient effect shared with the supine technique pelvis-stabilized axial spinal traction (PSAST), and suboccipital venous occlusion-rebound, proposed to promote central nervous system (CNS) venous and lymphatic drainage, and as a distinct modality for cerebral venous preconditioning (CVPC). The CVPC mechanism depends on upright posture. In the upright position, cerebral venous return preferentially routes through the suboccipital venous plexus rather than the internal jugular veins, allowing the ACT strap to transiently occlude this outflow pathway during the hold and produce a hemodynamic rebound upon release. This CVPC-based rationale for choosing ACT over PSAST, along with the full biomechanical model, was developed in prior papers and is not re-derived here. In its originally described form, ACT is participant-driven: the participant voluntarily squats against a fixed overhead strap secured by a simple anchor, and the participant's own hands close the strap loop as a fail-safe. This report refers to that form, and the strap-and-anchor apparatus that delivers it, as active craniospinal tensioning, self-administered (ACT-SA). ACT-SA's delivered craniocervical junction (CCJ) tension depends on the participant fully relaxing into the maneuver. It categorically excludes non-ambulatory participants with advanced neurodegenerative disease, e.g., Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), who cannot generate or safely control a voluntary squat, yet who may stand to benefit most from craniospinal tensioning and CVPC given their disease-associated glymphatic impairment. This report describes active craniospinal tensioning, operator-driven (ACT-OD), a device that reproduces ACT-SA's anchor geometry, target force range, and hold duration while substituting the source of tensioning force. Rather than gravity acting on a squatting participant's own body mass, tension is generated by a practitioner operating a pulley-and-lever mechanism against a stationary, seated participant, with the strap confined near the forehead by a polyvinyl chloride (PVC) pipe rather than closed by the participant's own hands. Because the participant does nothing and the seated default state carries no CCJ tension, the fail-safe ACT-SA requirement becomes unnecessary; disengagement, not engagement, is ACT-OD's default. Freed from managing the strap, the practitioner can devote full attention to the lever and to continuous observation of the participant's response, a substitution that matters because non-verbal or cognitively impaired participants cannot reliably self-report the presyncopal symptoms that serve as ACT-SA's real-time safety signal. The design is offered without patent restrictions for research and clinical replication. This report presents device design and mechanism only, with no clinical outcome or efficacy data.}, } @article {pmid42764995, year = {2026}, author = {Rhymes, ER and Fetkowitz, C and Schiavo, G and Sleigh, JN and Tosolini, AP}, title = {Ciliary neurotrophic factor slows axonal transport of signalling endosomes.}, journal = {Brain communications}, volume = {8}, number = {5}, pages = {fcag339}, pmid = {42764995}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Efficient axonal transport is essential for maintaining neuronal function, enabling the bidirectional delivery of diverse cargoes between the cell body and distal compartments. In the neuromuscular system, neurotrophic factors regulate motor neuron survival, function and synaptic connectivity, in part, through retrograde trafficking of activated neurotrophic factor-receptor complexes from the neuromuscular junction to the cell body. We recently demonstrated that brain-derived neurotrophic factor stimulation to muscles selectively enhances retrograde transport of signalling endosomes in fast, but not slow, motor neurons in vivo. Moreover, both axonal endosome transport and its brain-derived neurotrophic factor-mediated regulation are disrupted in mouse models of diseases impacting motor neurons, including amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. Here, we examined whether additional neurotrophic factors, when applied to distal axon terminals, share this transport-modulating property. Through imaging sciatic nerves in anaesthetised mice, we tracked the in vivo dynamics of signalling endosomes in fast and slow motor neurons via intramuscular injections of a fluorescent atoxic fragment of tetanus neurotoxin. These injections were co-administered with ciliary neurotrophic factor, hepatocyte growth factor, neurturin, or cleavage-resistant pro-brain-derived neurotrophic factor-four growth factors with known effects on motor neurons. Compared to vehicle-treated controls, pro-brain-derived neurotrophic factor, hepatocyte growth factor and neurturin produced no detectable change in transport dynamics. In contrast, ciliary neurotrophic factor markedly reduced endosome speeds in both fast and slow motor neurons, indicating remarkable selectivity of specific neurotrophic factors in the regulation of signalling endosome transport in motor neurons. Understanding this selectivity may aid the development of muscle-targeted neurotrophic factor-based therapeutic strategies aimed at restoring axonal transport in neurodegenerative disease, peripheral neuropathy and nerve injury.}, } @article {pmid42765595, year = {2026}, author = {Lang, C and Guillot, SJ and Knehr, A and Weydt, P and Dorst, J and Tumani, H and Ludolph, AC and Dupuis, L and Bolborea, M}, title = {Genetic ALS-Progressive Sleep Defects Precede the Onset of Clinical Disease.}, journal = {European journal of neurology}, volume = {33}, number = {9}, pages = {e70755}, pmid = {42765595}, issn = {1468-1331}, support = {ANR-24-CE37-4064//Agence Nationale de la Recherche/ ; ANR-10-IDEX-0002//Agence Nationale de la Recherche/ ; ANR-20-SFRI-0012//Agence Nationale de la Recherche/ ; JPND HiCALS//Agence Nationale de la Recherche/ ; DORALS//Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone/ ; Institut Charcot//Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone/ ; 28944//French Muscular Dystrophy Association/ ; //Target ALS/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/complications ; Female ; Male ; Polysomnography ; Disease Progression ; Middle Aged ; *Sleep Wake Disorders/genetics/physiopathology/etiology ; Electroencephalography ; Longitudinal Studies ; Adult ; Superoxide Dismutase-1/genetics ; Mutation ; C9orf72 Protein/genetics ; Aged ; Cohort Studies ; }, abstract = {BACKGROUND: The onset of amyotrophic lateral sclerosis (ALS) is preceded by non-motor signs detectable many years before motor symptom onset. We recently showed that early ALS patients and presymptomatic carriers of ALS-associated gene mutations display altered sleep macroarchitecture, characterised by increased wakefulness and decreased non-REM sleep, together with altered microarchitecture, particularly reduced slow oscillations and sleep spindles. Here we aimed at determining whether sleep alterations are progressive in premanifest carriers of ALS-associated gene mutations.

METHODS: This longitudinal observational cohort study included presymptomatic first-degree relatives of ALS patients carrying pathogenic gene mutations (n = 18) and noncarrier family members (n = 3). Sleep macroarchitecture and sleep microarchitecture were assessed using standardised polysomnography and electroencephalographic analyses at baseline and in a follow-up examination after 2.3 ± 1.5 years.

RESULTS: In all carriers, sleep alterations were more severe at follow-up compared to the initial examination, for both macro- and microarchitecture. The progression of sleep alterations was seemingly independent of proximity to motor onset, whether evaluated by increased neurofilament levels or phenoconversion during the study period.

CONCLUSIONS: Sleep macro- and microarchitectural abnormalities progressively worsen during the premanifest phase of ALS. These findings suggest that polysomnography-derived sleep measures and their neurochemical correlates may serve as sensitive, noninvasive surrogate biomarkers of disease progression in clinically silent ALS. This could support disease prevention, for example, by the antisense oligonucleotide tofersen in patients carrying SOD1 mutations.}, } @article {pmid42767135, year = {2026}, author = {Alemdağ, B and Siyah, B and Alemdağ, İN and Berber, T and Güdük, ÖF}, title = {Elucidating the molecular nexus between dental developmental anomalies and chronic inflammatory diseases: A computational systems biology analysis of genomic sequence homology using matrix factorization.}, journal = {Computational biology and chemistry}, volume = {126}, number = {Pt 1}, pages = {109395}, doi = {10.1016/j.compbiolchem.2026.109395}, pmid = {42767135}, issn = {1476-928X}, abstract = {This entirely in silico, exploratory study investigates potential sequence-level links between periodontal disease, developmental dental anomalies such as molar-incisor hypomineralization (MIH), and selected systemic conditions including leukemias, amyotrophic lateral sclerosis, and Alzheimer's disease. To identify annotation-independent signatures, we applied Non-negative Matrix Tri-Factorization (NMTF) to k-mer/tf-idf representations of disease-associated gene and protein sequences compiled from OMIM, GeneCards, and PubMed for eleven curated disease groups; similarity values denote the proportion of the total between-cluster interaction (S-matrix) captured by a cluster. To guard against trivial explanations, we applied a composition-preserving sequence-shuffling test of the similarity magnitude and a degree-preserving (curveball) permutation test of the disease co-clustering that accounts for the dependence introduced by isoform records and shared genes, repeating the latter across a 1890-configuration parameter grid. At the gene level the dominant cluster was governed by the largest disease group (MIH) rather than by disease identity, whereas at the protein level periodontitis, dental anomalies, and leukemia subtypes co-clustered. The magnitude of the shares did not exceed a composition-preserving null (gene p=0.66; protein p=0.082), and under the degree-preserving null co-clustering was not significant at the gene level (p=0.36) but was significant, modest, and grid-robust at the protein level (p=0.033); canonical k-mer and coding-sequence controls confirmed that the gene-level weakness is intrinsic to nucleotide k-mers. These results delineate the protein level as the informative scale for annotation-independent cross-disease screening and identify the dental-leukemia axis as the candidate relationship for targeted follow-up. The findings are hypothesis-generating: the disease-associated gene sets were compiled with a non-systematic, literature-guided procedure, magnitudes do not exceed composition baselines, neither experimental or clinical validation nor quantitative benchmarking against alternative computational frameworks was performed, and any translational implication requires future validation.}, } @article {pmid42768102, year = {2026}, author = {Qi, Z and Liu, X and Geng, L and Liu, X and Dong, S and Li, J and Hua, W and Deng, Y and Lai, S and Wang, Y and Xia, Y and Han, Y and Zhu, D and Zhang, X and Li, J and Li, J and Chen, X}, title = {Convergent TBK1 loss of function drives gasdermin E dependent pyroptosis and motor neuron degeneration across ALS genotypes.}, journal = {Cell death and differentiation}, volume = {}, number = {}, pages = {}, pmid = {42768102}, issn = {1476-5403}, support = {82572011//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82371431//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of upper and lower motor neurons, yet it is unknown whether diverse genetic risks converge on a shared pathogenic pathway. Here we identify a common mechanism linking TBK1 insufficiency to inflammatory cell death across distinct ALS genotypes. Whole-exome sequencing of 8 familial ALS patients revealed that 3 of them carried pathogenic variants, namely TBK1 (R573H), TDP-43 (G298V)/GARS (I44M)/SETX (L1304W), or SOD1 (G94R)/SQSTM1 (G262R). Motor neurons differentiated from patient iPSCs, despite their different mutations, consistently exhibited axonal and neurite shortening, reduced TBK1 activity, increased phosphorylated TDP-43 with cytoplasmic aggregation, and co-assembly of caspase-8/7 with the pyroptosis executor gasdermin E (GSDME). Neuroinflammatory stimulation further enhanced caspase-8/7 and GSDME cleavage, increased RIPK1 phosphorylation and suppressed TBK1 activation in patient-derived motor neurons, whereas TBK1 knockdown in SH-SY5Y cells recapitulated these phenotypes. Furthermore, a generated humanized TBK1 R573H knock-in mouse developed progressive motor deficits accompanied by spinal motor-neuron loss, neuroinflammation, and TDP-43 pathology. In these mice, LPS challenge produced increased cleavage of GSDME and caspase-7, along with a marked upregulation of p-TDP-43 expression in vulnerable neurons. Together, these data identify TBK1 loss of function as an upstream driver of a caspase-8/7-GSDME pyroptotic program in motor neurons and provide a mechanistic bridge between neuroinflammation, TDP-43 proteinopathy, and neurodegeneration. Targeting the TBK1-caspase-GSDME axis may offer a tractable strategy for disease modification in ALS.}, } @article {pmid42769109, year = {2026}, author = {Jin, T and Yang, B and Cai, Z and Zhang, H and Wang, T}, title = {The Dual Role of Exosome-Mediated Central-Peripheral Immune Dialogue in Amyotrophic Lateral Sclerosis-Associated Neuroinflammation.}, journal = {Journal of inflammation research}, volume = {19}, number = {}, pages = {622530}, pmid = {42769109}, issn = {1178-7031}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is increasingly viewed as a multisystem disorder in which central-peripheral immune communication may modify neuroinflammation. Exosomes, an endosome-derived subset of extracellular vesicles (EVs), have been proposed as mediators of this communication, but the strength and disease specificity of the evidence require critical evaluation.

METHODS: PubMed/MEDLINE, Web of Science Core Collection, and Scopus were searched from database inception to July 20, 2026, with supplementary citation tracking through Google Scholar and reference lists. Evidence was categorized as human ALS evidence, ALS-specific cellular or animal evidence, evidence from non-ALS neuroinflammatory models, or review-level background evidence.

RESULTS: Human studies have identified ALS-associated proteins and altered miRNA profiles in circulating EV-containing preparations, but their cellular origin, direction of transfer, and causal relevance remain uncertain. ALS-specific cellular and animal models support the possibility that EVs participate in intercellular protein transfer and modify glial inflammatory, phagocytic, antioxidant, and trophic responses. Some proposed mechanisms, including miR-216a-5p-mediated microglial regulation, are derived mainly from other neurological injury models and should be considered hypothesis-generating. Single-cell studies further indicate that ALS microglia occupy heterogeneous and overlapping states; therefore, M1/M2 terminology is used only as a simplified descriptive framework. Circulating EV cargo remains under investigation as a biomarker source, whereas the additional value of EV-associated neurofilament light chain and the diagnostic utility of TDP-43, SOD1, or miRNAs require independent validation. Therapeutic evidence remains predominantly preclinical, with only small, early, non-confirmatory human studies.

CONCLUSION: EVs may participate in central-peripheral immune communication in ALS, but their causal role, cellular origin, in vivo trafficking, and clinical utility remain incompletely established. Standardized methods and rigorous mechanistic and clinical validation are required before EV-based biomarkers or therapies can be translated into practice.}, } @article {pmid42769571, year = {2026}, author = {Toda, Y and Masumoto, S and Kimura, Y and Aramaki, M and Hamano, J}, title = {Autonomic Storm in a Patient With Amyotrophic Lateral Sclerosis in a Home-Care Setting.}, journal = {Journal of general and family medicine}, volume = {27}, number = {5}, pages = {e70182}, pmid = {42769571}, issn = {2189-7948}, abstract = {Amyotrophic lateral sclerosis (ALS) can cause autonomic storms characterized by blood pressure fluctuations, particularly in the advanced stages of the disease and among ventilator-dependent patients. Although benzodiazepines are used to manage these symptoms, the optimal agent is unclear. We present the case of a 78-year-old home-care patient with ventilator-dependent ALS who developed autonomic storms. Clotiazepam did not adequately control the episodes; however, diazepam was associated with resolution of the episodes, followed by improved sleep and nutritional intake. This report highlights the importance of recognizing an autonomic storm in advanced ALS patients and the potential benefit of diazepam in home-care settings.}, } @article {pmid42769968, year = {2026}, author = {Zambetti, E and Baronchelli, I and Belli, S and Mucci, C and Greco, A}, title = {Caregivers in amyotrophic lateral sclerosis (ALS): preliminary results between paid care and family care.}, journal = {Health psychology and behavioral medicine}, volume = {14}, number = {1}, pages = {2709184}, pmid = {42769968}, issn = {2164-2850}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease affecting about 6,000 people in Italy. Caring for ALS impacts the quality of life and mental health of formal and informal caregivers, but few studies have explored this.

METHODS: This research analyzes experiences of 9 formal caregivers (FC; 8 women) with an average age of 49.29 years (SD = 3.861) and 6.58 years of average length of service (SD = 5.975), and 11 informal caregivers (iFC; 9 women) with an average age of 48.30 years (SD = 13.500) and who have been caring for relatives for 3.29 years (SD = 2.500). All participants were recruited from an Italian healthcare residence. We assessed psychological well-being, burnout (for FC), and burden (for iFC), and included testimonies retrieved from online sources. Data were analyzed using mixed-methods analysis, including nonparametric tests, Emotional Text Mining, and discourse analysis.

RESULTS: The results showed both groups had high psychological well-being (Mfc = 85.86; SDfc = 9.026; Mifc = 83.10; SDifc = 11.435). FC had low emotional exhaustion (M = 16.67; SD = 10.087) and depersonalization (M = 2.56; SD = 2.186), and a moderate level of personal gratification (M = 29.11; SD = 11.667; M = 27.43; SD = 11.238). iFC experienced a higher burden when the patient is in a healthcare residence than when he/she was at home. FC discussed patient and family challenges, emphasizing the necessity of research and new therapies; iFC focused on social and emotional needs, seeing themselves as adaptors out of necessity.

CONCLUSIONS: The study highlights the psychological impact of caregiving and preliminary qualitative differences between paid and family caregivers. Further analysis could explore these distinctions, aiding the development of targeted interventions to promote caregivers' well-being.}, } @article {pmid42770300, year = {2026}, author = {Oikawa, Y and Luo, Y and Suzuki, N and Kasahara, T and Tongu, Y and Yoshida, Y and Tominari, T and Tanabe, S and Suto, Y and Kashiwagi, H and Saito, S and Ikeda, K and Suzuki, C and Kuranaga, A and Akiyama, T and Morimoto, S and Aoki, Y and Muramatsu, R and Soga, T and Aoki, M and Okano, H and Tanaka, T and Abe, T and Kuranaga, E and Toyohara, T}, title = {Mitochonic acid 5 alleviates amyotrophic lateral sclerosis phenotypes via mitochondrial augmentation.}, journal = {JCI insight}, volume = {11}, number = {18}, pages = {}, pmid = {42770300}, issn = {2379-3708}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; Animals ; Humans ; *Mitochondria/drug effects/metabolism ; Disease Models, Animal ; Phenotype ; Superoxide Dismutase-1/genetics/metabolism ; Fibroblasts/drug effects/metabolism ; Motor Neurons/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Drosophila ; Induced Pluripotent Stem Cells ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that urgently requires effective treatment. Mitochondrial dysfunction underlies ALS pathology and represents a potential therapeutic target. Here, we demonstrated the therapeutic potential of mitochonic acid 5 (MA-5), a novel mitochondria-targeted compound that ameliorated ALS phenotypes by enhancing mitochondrial function. In a Drosophila ALS model expressing a mutant human SOD1 (G85R), MA-5 significantly improved locomotor activity, with a trend toward restoration of mitochondrial integrity. In skin fibroblasts derived from ALS patients and motor neurons derived from induced pluripotent stem cells, MA-5 restored ATP production and increased mitochondrial motility. Multiomics analyses suggested that MA-5 modulated mitochondria-linked gene expression and downregulated the glycerophosphate shuttle, contributing to mitochondrial reactive oxygen species production. Transcriptomic analysis identified C7orf31 as a potential marker for monitoring the therapeutic effects of MA-5 and diagnosing ALS subtypes. These findings support MA-5 as a promising therapeutic candidate for ALS and propose C7orf31 as a potential biomarker for treatment monitoring and for disease subtyping.}, } @article {pmid42770357, year = {2026}, author = {Sahu, K and Sahu, R and Mishra, M and Chhabra, N and Tiwari, S and Kaur, K and Rathore, H and Lodhi, R and Sulakhiya, K}, title = {Designing Multi-functional Antioxidants for Neurodegenerative Disorders.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575494157260901095536}, pmid = {42770357}, issn = {1875-5607}, abstract = {Neurodegenerative disorders (NDs), including Alzheimer's disease, Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD) and Multiple Sclerosis (MS), pose a major global health threat due to complex pathology, increased prevalence, and lack of effective therapies. Numerous findings have indicated that oxidative stress (OS) is a central and unifying pathological mechanism driving neuronal dysfunction and degeneration across these disorders. Excessive reactive oxygen species (ROS) and nitrogen species (RNS) generation, coupled with impaired endogenous antioxidant defenses, leads to lipid peroxidation, protein misfolding, nucleic acid damage, mitochondrial dysfunction, neuroinflammation, metal dyshomeostasis, and disruption of the blood-brain barrier (BBB). These interconnected processes form self-perpetuating pathogenic cycles that accelerate synaptic failure and neuronal loss. This review is a compilation of thoroughly searched literature from the last 20 years (2006-2026) on OS-mediated neurodegeneration and emerging antioxidant-based therapeutic strategies for neurodegenerative disorders, sourced from PubMed, Scopus, ScienceDirect, Google Scholar, and Web of Science. Relevant articles were selected using specific keywords "Neurodegenerative Disorders", Neurodegenerative disorders and antioxidants", "Alzheimer's Disease and Oxidative Stress", "Parkinson's Disease and Oxidative Stress", "Alzheimer's Disease and Multi-functional Antioxidants", "Parkinson's Disease and Multifunctional Antioxidants", "Neurodegenerative Disorders and Antioxidant therapies". Despite strong mechanistic support, conventional antioxidant-based therapies have demonstrated limited clinical success, largely due to poor bioavailability, inadequate BBB penetration, and failure to address the multifactorial nature of neurodegeneration. Consequently, there is a paradigm shift toward the development of multi-functional antioxidants capable of simultaneously targeting multiple redoxdriven pathways. Such agents are designed to combine free-radical scavenging, metal chelation, mitochondrial protection, modulation of redox-sensitive signaling pathways, and regulation of neuroinflammatory responses within a single therapeutic framework. By restoring redox homeostasis while preserving physiological redox signaling, multi-functional antioxidants offer a rational and promising disease-modifying strategy. This review critically examines OS-mediated mechanisms underlying major NDs and emphasizes the therapeutic potential of designed multi-functional antioxidants as next-generation neuroprotective agents.}, } @article {pmid42770359, year = {2026}, author = {Kumari, N and Dwivedi, S and Yadav, S and Kosey, S}, title = {Ferroptosis in Neurodegenerative Diseases: Iron Dysregulation, GPX4/FSP1 Signaling, and Emerging Neuroprotective Strategies.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026502165260904054005}, pmid = {42770359}, issn = {1875-5739}, abstract = {INTRODUCTION: Neurodegenerative Diseases (NDDs), including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and Multiple Sclerosis (MS), are increasingly associated with ferroptosis, a regulated irondependent form of cell death characterised by the excessive accumulation of lipid peroxides.

METHODS: This review examines the molecular underpinnings of ferroptosis, focusing on dysregulation in iron homeostasis, increased vulnerability of polyunsaturated fatty acids in neuronal membranes, and impairment of antioxidant defence systems, particularly the Glutathione-GPX4 and FSP1-CoQ10-NADPH pathways. Relevant literature was critically analysed to explore mechanistic insights and therapeutic implications.

RESULTS: Pathological hallmarks such as amyloid-β, tau, and α-synuclein were found to disrupt iron metabolism, thereby exacerbating oxidative stress and mitochondrial dysfunction across various NDDs. These alterations significantly contribute to neuronal damage and disease progression through ferroptosis-related mechanisms.

DISCUSSION: Emerging therapeutic strategies, including radical-trapping antioxidants, iron chelators, and nanotechnology-based delivery systems, show potential in targeting ferroptosis. However, challenges in clinical translation persist. Artificial intelligence and personalised medicine approaches may address these issues by enabling patient stratification, biomarker discovery, and optimisation of therapeutic interventions.

CONCLUSION: Ferroptosis represents a promising therapeutic target for mitigating oxidative and metal-induced neurotoxicity in neurodegenerative disorders. Future research integrating multiomics profiling, longitudinal clinical data, and advanced computational modelling is essential to validate the efficacy of ferroptosis-targeted interventions and facilitate their successful translation into precision neurotherapeutics.}, } @article {pmid42770444, year = {2026}, author = {Duan, X and Li, Y and Zhao, R and Jiang, X and Xia, C and Xie, F}, title = {Cell Therapy Targeting Pathological Networks in Neurodegenerative Diseases: Mechanisms and Translation from Stem Cells to Extracellular Vesicles.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026476083260903180127}, pmid = {42770444}, issn = {1875-5739}, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, are characterized by interacting pathological processes such as protein aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired proteostasis. This narrative review examines how embryonic/ induced pluripotent stem cells, neural stem cells, mesenchymal stem/stromal cells, immune cells, and extracellular vesicles may intervene across these pathological networks. A targeted PubMed search and reference-list screening through 5 July 2026 identified relevant mechanistic, preclinical, clinical, manufacturing, and regulatory evidence. The reviewed strategies act through cell replacement, paracrine support, immunomodulation, metabolic stabilization, and pathological- protein clearance. Evidence maturity differs substantially by disease and product: pluripotent stem cell-derived dopaminergic progenitors have entered early clinical evaluation in Parkinson's disease, whereas most mesenchymal stem/stromal cell studies remain small and exploratory, and immune-cell and extracellular-vesicle approaches are predominantly preclinical or early translational. Major barriers include product heterogeneity, mechanism-linked potency testing, longterm safety, delivery and dose optimization, disease-stage selection, clinically meaningful endpoints, and regulatory comparability. Future development should emphasize standardized manufacturing, biomarker-guided trial design, transparent reporting of negative findings, and rational combinations with pharmacological or gene-based therapies. Cell-based interventions remain promising, but durable clinical benefit has not yet been established.}, } @article {pmid42770452, year = {2026}, author = {Maleksabet, H and Movahed, MA and Zarghi, A}, title = {Integrative Perspectives on COX-2 Signaling and Selective Inhibitors in Central Nervous System Disorders: A Narrative Review.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673496586260831110156}, pmid = {42770452}, issn = {1875-533X}, abstract = {INTRODUCTION: Central nervous system disorders include various neurodegenerative and psychiatric conditions characterized by progressive neuronal damage, synaptic dysfunction, and chronic neuroinflammation, affecting millions worldwide. This group includes Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Multiple Sclerosis (MS), Major Depressive Disorder (MDD), and epilepsy, among others. Recent studies have emphasized the significant role of Cyclooxygenase-2 (COX-2), an inducible enzyme in the arachidonic acid pathway, in maintaining neuroinflammatory cascades that worsen these conditions.

METHODS: For this review, we gathered and carefully analyzed published literature related to COX-2 signaling in CNS disorders. We reviewed preclinical studies, animal models, and clinical trials to understand how COX-2 contributes to disease mechanisms and whether selective inhibitors show real therapeutic promise.

RESULTS: Inflammatory cytokines or excitotoxic insults upregulate COX-2 and promote the formation of prostaglandins, including PGE2. These mediators subsequently trigger the activation of microglia and astrocytes, cytokine release, oxidative stress, disruption of the blood-brain barrier, and neuronal apoptosis. Despite variations in disease-specific features, the mechanisms dependent on COX-2 are generally consistent across these disorders.

DISCUSSION: The consistent involvement of COX-2-driven neuroinflammation across multiple CNS disorders suggests it could be a promising therapeutic target. However, failures in some clinical trials highlight the complexity of translating preclinical findings into patient care. This may be due to the stage-dependent expression of COX-2, the multifunctional roles of the enzyme in normal brain function, and the cardiovascular risks associated with long-term COX-2 inhibition. These factors must be carefully considered in future research and drug development.

CONCLUSION: COX-2 plays a central role in driving neuroinflammation and disease progression in AD, PD, ALS, schizophrenia, MS, MDD, and epilepsy. Selective COX-2 inhibitors show promising neuroprotective potential, especially in early stages or in combination therapies, but inconsistent efficacy and cardiovascular risks necessitate safer next- generation inhibitors.}, } @article {pmid42771220, year = {2026}, author = {Li, K and Si, Q and Zhang, C and Zhang, C and Wang, M and Liu, J and Zhao, J and Xing, H and Liu, J}, title = {Dysregulated polyamine metabolism in neurological disorders: molecular mechanisms and therapeutic opportunities.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42771220}, issn = {1573-4978}, support = {No. YJSCX202502Z//The Graduate Research Innovation Support Program of Henan Medical University/ ; No. GCC2026048//the Henan High-level Talent International Training Project/ ; No. LHGJ20190457//the Henan Provincial Health Commission/ ; No. HNMOTO2025081//the Henan Medical Researcher Overseas Training Program/ ; No. 25A320037//the Key Scientific Research Project Plan of Higher Education Institutions in Henan Province/ ; No. 262300420548//the Henan Natural Science Foundation Project/ ; }, mesh = {Humans ; *Polyamines/metabolism ; *Nervous System Diseases/metabolism ; Oxidative Stress ; Animals ; Autophagy ; Spermidine/metabolism ; }, abstract = {Polyamines (PAs), principally putrescine (Put), spermidine (Spd), and spermine (Spm), are ubiquitous aliphatic polycations that regulate nucleic-acid interactions, ion-channel activity, autophagy, redox balance, proteostasis, and immune signaling. Growing genetic, multi-omics, and experimental evidence indicates that disruption of PA biosynthesis, catabolism, acetylation, and transport contributes to neurological disease. In Alzheimer's disease (AD), altered PA flux intersects with Tau and amyloid-β (Aβ) pathology, methylation imbalance, oxidative stress, and impaired autophagic clearance. In Parkinson's disease (PD), PA transport and interconversion are linked to lysosomal dysfunction, mitochondrial stress, and α-synuclein toxicity; ATP13A2-associated Kufor-Rakeb syndrome further illustrates the neurological consequences of defective lysosomal PA transport. PA dysregulation is also implicated in amyotrophic lateral sclerosis (ALS), diabetic retinopathy, Snyder-Robinson syndrome, epilepsy, Bachmann-Bupp syndrome, and cerebral ischemia. This review integrates disease-specific evidence with four interconnected mechanisms-autophagy, oxidative stress, proteostasis, and neuroinflammation-and discusses therapeutic approaches including direct Spd administration, modulation of PA-metabolic enzymes and transporters, and combination strategies. Because PAs can exert both protective and toxic effects depending on concentration, cellular compartment, and disease context, translation will require CNS-relevant biomarkers, dose and route optimization, and explicit consideration of blood-brain barrier constraints.}, } @article {pmid42771346, year = {2026}, author = {Paganoni, S and Chibnik, LB and Quintana, M and Macklin, EA and Detry, MA and Vestrucci, M and Paulon, G and McGlothlin, A and Wang, J and Walk, D and Elman, L and Chase, M and Heyd, L and Harkey, B and Sherman, AV and Shefner, J and Berry, JD and Scirocco, E and Giacomelli, E and Yu, H and Kittle, G and Hall, M and Ho, D and Jawdat, O and Ladha, S and Locatelli, E and Rivner, M and Felice, K and Katz, J and Ajroud-Driss, S and Fee, D and Miller, T and Rosow, L and Quick, A and Heitzman, D and Foster, LA and Maragakis, NJ and Goutman, SA and Rosenfeld, J and Benatar, M and Swenson, A and Connors, RD and Shroff, S and Bedlack, R and McIlduff, CE and Chen, IA and Fernandes, JAM and Walsh, A and Peltier, A and Ilieva, H and Diaz, F and Kushlaf, H and Beydoun, SR and Myers, B and Arcila-Londono, X and Heiman-Patterson, T and Elliott, M and Whitesell, J and Al-Lahham, T and Elliott, M and Olney, N and Baer, M and Jackson, C and Young, E and Caress, J and Weiss, MD and Kuenzler, R and Nayar, S and Kasarskis, EJ and Simmons, Z and Gibson, S and Owegi, MA and Goyal, NA and Wymer, JP and Gwathmey, KG and Erickson, A and Gursoy, N and Alameda, G and Bodkin, C and Wu, A and Martinez-Thompson, J and Twydell, PT and Andrews, J and Bayat, E and Rezania, K and Usman, U and McCluskey, L and Kovvuru, S and Jennings, D and Garza-Meilandt, A and Maciuca, R and Cohen, IV and Tamuly, D and Eren, E and Cudkowicz, ME and Babu, S and , }, title = {DNL343 and Disease Progression in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {9}, number = {9}, pages = {e2634809}, pmid = {42771346}, issn = {2574-3805}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Disease Progression ; Double-Blind Method ; Treatment Outcome ; }, abstract = {IMPORTANCE: DNL343 is a brain-penetrant small molecule that acts as an activator of eukaryotic translation initiation factor 2B (eIF2b), designed to inhibit the integrated stress response. A prior phase 1B trial of DNL343 in amyotrophic lateral sclerosis (ALS) provided evidence of a favorable safety profile, central nervous system penetrance, and target engagement based on integrated stress response biomarkers in blood and cerebrospinal fluid.

OBJECTIVES: To evaluate the safety and efficacy of a 200-mg formulation of DNL343 given once daily in individuals living with ALS.

DNL343 was evaluated as a regimen of the HEALEY ALS Platform Trial, a double-blind, multiregimen, placebo-controlled randomized clinical trial conducted at 74 centers in the US between May 24, 2023, and May 22, 2025. Eligible participants were randomized in a 3:1 ratio to receive DNL343 or matching placebo, with both groups enrolling concurrently. The analysis included shared randomized participants receiving placebo from an additional regimen.

INTERVENTION: The study drug was administered for a placebo-controlled duration of 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary analysis was a bayesian shared parameter model of function and survival that provided an integrated estimate of the relative rate of disease progression among participants receiving DNL343 relative to placebo. The model had components for function and survival linked through an integrated estimate of disease slowing in treatment relative to controls across the 2 outcomes (denoted as the disease rate ratio [DRR]). Several safety, secondary, and exploratory end points were also evaluated.

RESULTS: A total of 259 screenings were completed in this regimen; 249 participants met eligibility and were randomized to DNL343 (n = 186) and regimen-specific placebo (n = 63), with an additional 76 participants from a concurrent regimen receiving placebo included for a total of 139 shared placebo participants (325 participants, with 196 (60.3%) male and mean [SD] age of 59.3 [11.5] years). The estimated median DRR common to the ALS Functional Rating Scale-Revised and survival was 1.04 (95% credible interval, 0.83-1.32; probability of DRR <1, 0.37). Secondary outcome measures were not statistically different between the DNL343 and placebo groups. Overall, the incidence rates of adverse events were similar in participants receiving DNL343 and placebo.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, despite the relevance of the eIF2b activation pathway in ALS disease biology and supporting evidence of proof of mechanism and optimal dose selection in a prior phase 1B ALS clinical trial, 200-mg/d DNL343 did not show evidence of slowing disease progression in ALS, highlighting the need for alternative therapeutic approaches.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05842941.}, } @article {pmid42771573, year = {2026}, author = {Hu, N and Su, N and Zhang, D and Zhang, J and Wang, K and Xu, Y and Li, Z and Wang, L and Wu, B and Chu, L and Wang, Y and Jiang, H and Lu, Z and Wu, J and Fan, X and Han, F and Yuan, J and Zhu, Y and Liu, M}, title = {Gait Characteristics and Fall Risk in Amyotrophic Lateral Sclerosis: A 12-Month Prospective Cohort Study.}, journal = {Neuro-degenerative diseases}, volume = {}, number = {}, pages = {1}, doi = {10.1159/ndd/aduag003}, pmid = {42771573}, issn = {1660-2862}, abstract = {BACKGROUND: Gait impairment in amyotrophic lateral sclerosis (ALS) substantially increases fall risk and accelerates functional decline. However, prospective data linking quantitative gait parameters to fall outcomes remain scarce. We aimed to identify gait parameters associated with falls and functional decline in ALS.

METHODS: In this single-center prospective cohort study, we enrolled 256 ALS patients and 256 matched healthy controls. Nineteen spatiotemporal gait parameters were captured using a 3D vision-based system at baseline. Falls, time to wheelchair use, and ALSFRS-R decline were recorded over 12 months. Multivariable logistic regression was used to identify independent fall predictors.

RESULTS: During follow-up, 129 of 224 patients (57.6%) experienced at least one fall. Prolonged Timed Up and Go (TUG) time (OR=1.083 per second, 95%CI 1.036-1.133, p<0.001), younger age (OR=0.968 per year, 95%CI 0.940-0.996, p=0.024), and lower MRC sum score (OR=0.976 per point, 95%CI 0.954-0.998, p=0.035) independently predicted falls. The model showed moderate discrimination (AUC=0.665, 95%CI 0.594-0.736). Gait speed (rₛ=0.366) and TUG time (rₛ=-0.381) correlated most strongly with time to wheelchair use (both p<0.001), whereas no gait parameters correlated with ALSFRS-R decline rate.

CONCLUSIONS: TUG time, younger age, and lower MRC score independently predict falls in ALS, though with modest predictive accuracy. The modest model performance underscores the multifactorial nature of falls and the need for multi-domain risk assessment. Gait speed and TUG time may warrant further investigation as candidate surrogate markers for functional decline. Future studies integrating cognitive evaluation, continuous monitoring, and attention to psychosocial factors may improve prediction and fall prevention strategies.}, } @article {pmid42771575, year = {2026}, author = {Tsujisawa, Y and Takahashi-Iwata, I and Yabe, I and Mukaino, M and Shibamoto, I}, title = {Phenotype-Related Characteristics of Tongue Motor Function in Amyotrophic Lateral Sclerosis: A Retrospective Comparative Study of Static and Dynamic Acoustic Measures.}, journal = {Folia phoniatrica et logopaedica : official organ of the International Association of Logopedics and Phoniatrics (IALP)}, volume = {}, number = {}, pages = {1}, doi = {10.1159/fpl/acvag012}, pmid = {42771575}, issn = {1421-9972}, abstract = {This study aimed to characterize lingual motor function in patients with amyotrophic lateral sclerosis (ALS) by analyzing static acoustic indices obtained from sustained vowels and dynamic indices derived from sentence reading. The following aspects were examined: (1) the independence of static and dynamic indices, (2) the relationship between F2 transition duration and F2 excursion, (3) differences in vowel formant frequencies across ALS phenotypes, (4) associations between static indices and speech intelligibility, and (5) acoustic elements contributing to static indices. Sixty-eight patients with ALS were enrolled (42 men and 26 women). The main analyses focused on the men (n = 42), categorized as spinal-onset (n = 21), spinal onset with bulbar involvement (spinal + bulbar) (n = 9), and bulbar-onset (n = 12). From sustained vowels (/a/-/o/), F1 and F2 values were extracted. The triangular vowel space area (tVSA) and formant centralization ratio (FCR) were calculated using F1 and F2 of /a/, /i/, and /u/. Dynamic measures were obtained from the diphthong /ai/ within /taiyo/ during sentence reading, yielding F2 transition duration and excursion. Static indices (tVSA and FCR) correlated with F2 excursion only in the spinal-onset group (r = 0.458, p = 0.049), whereas no associations were observed in the other phenotypes or in the overall sample. This finding suggests that static and dynamic indices may reflect partially distinct aspects of lingual motor control. tVSA and FCR showed a negative correlation across all phenotypes, confirming that they are complementary indicators of vowel space expansion and centralization. Regarding time-space control, bulbar-onset ALS showed no relationship between F2 transition duration and excursion, suggesting that spatial limitations of tongue movement may not necessarily parallel changes in articulatory speed. Phenotype comparisons revealed significant differences in F1 of /e/ and F2 of /a/, /i/, /u/, and /o/. These findings indicate phenotype-related differences in vertical and anterior-posterior tongue movement characteristics. In bulbar-onset ALS, tVSA correlated with speech intelligibility (visual analogue scale: VAS), and FCR showed a trend-level association (p=0.075). Acoustic element analysis indicated that tVSA was primarily associated with F1 of /a/ and F2 of /i/, whereas FCR was closely associated with F2 of /i/. These findings suggest that combining static (articulatory position) and dynamic (articulatory transition) acoustic indices enables multifaceted evaluation of phenotype-related characteristics of lingual motor dysfunction in ALS. Bulbar-onset ALS is characterized by restricted anterior-posterior movement and impaired vertical tongue adjustment, both of which may contribute to reduced intelligibility.}, } @article {pmid42772840, year = {2026}, author = {Frank, M and Barthélémy, C and Dufour, A and Rivera, S and Baranger, K}, title = {Matrix metalloproteinases (MMPs) in neurodegenerative diseases, an updated overview of the role of MT1-MMP and MT5-MMP in Alzheimer's disease.}, journal = {The Enzymes}, volume = {60}, number = {}, pages = {209-241}, doi = {10.1016/bs.enz.2026.07.004}, pmid = {42772840}, issn = {0423-2607}, mesh = {Humans ; *Alzheimer Disease/enzymology/metabolism ; Animals ; *Neurodegenerative Diseases/enzymology/metabolism ; *Matrix Metalloproteinases/metabolism ; Amyloid beta-Peptides/metabolism ; *Matrix Metalloproteinase 14/metabolism ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease, pose an increasing threat to global health due to ageing populations and the lack of effective treatments. Matrix metalloproteinases (MMPs), which are proteases that belong to the metzincin superfamily, are critical regulators of neuroinflammation, blood-brain barrier integrity, protein misfolding, synaptic dysfunction and neuronal death. This chapter provides a comprehensive overview of the roles of MMPs at the intersection of the molecular and cellular mechanisms that underpin neurodegenerative processes. The focus is on their pathophysiological mechanisms, therapeutic potential, and recent advances. We highlight novel mechanistic insights in Alzheimer's disease, such as the roles of MT1-MMP and MT5-MMP in amyloid-beta peptide production and the dual functions of MMPs in both neuroprotection and neurotoxicity. This review emphasizes the need for further mechanistic research into the different MMPs involved in neurodegenerative diseases.}, } @article {pmid42772919, year = {2026}, author = {Kernaghan, A and Harvey, A and Currie, H and McAlister, O and Walker, R and Chapman, F and McEneaney, D and Adgey, J}, title = {Incidence of refibrillation and shock-resistant ventricular fibrillation during OHCA when treated with a public access defibrillator: implications for CPR timing in lay rescuer-treated OHCA.}, journal = {Open heart}, volume = {13}, number = {2}, pages = {}, pmid = {42772919}, issn = {2053-3624}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/physiopathology/diagnosis ; *Ventricular Fibrillation/therapy/physiopathology/diagnosis/epidemiology/etiology ; *Electric Countershock/instrumentation/adverse effects ; *Defibrillators ; *Cardiopulmonary Resuscitation/methods/adverse effects ; Time Factors ; Retrospective Studies ; Incidence ; Female ; Male ; Aged ; Middle Aged ; Electrocardiography ; Emergency Medical Services ; Treatment Outcome ; }, abstract = {BACKGROUND: Out-of-hospital cardiac arrest (OHCA) treatment often requires multiple defibrillatory shocks due to failed defibrillation or refibrillation. The complete nature of refractory ventricular fibrillation (VF) is unknown, as many studies do not consider shocks delivered by lay rescuers prior to the arrival of basic life support (BLS)/advanced life support (ALS) when quantifying refractory VF. ERC guidelines define refractory VF as continuous VF after three consecutive shocks, not differentiating between patients who refibrillate and those with shock-resistant VF (three consecutive failed shocks) which may contribute to this variation in reported incidence. There are some differences in treatment recommendations for patients who refibrillate and those with shock-resistant VF. Therefore, understanding the number of shocks delivered by lay-rescuers with public access defibrillators (PADs) and the patient's response to them prior to BLS/ALS arrival may inform treatment strategies.

METHODS: ECG data collected retrospectively from OHCAs treated by lay-rescuers using PADs were analysed. Cardiac rhythm, shock success, refibrillation, time to refibrillation and presence of shock-resistant VF (three consecutive failed shocks) were determined by two investigators.

RESULTS: Data were available for 1459 patients receiving at least one shock. Refibrillation occurred in 498 (34.1%) patients. The median number of refibrillations per patient was 1 (IQR 1, 2). Median time to refibrillation was 29.8 s. Three consecutive shocks were observed in 231 of the 1459 (15.8%) patients, 11 patients (4.8% of 231 patients) had shock-resistant VF.

CONCLUSION: When treated by lay-rescuers with PADs, refibrillation occurrence is lower than that reported for patients treated by BLS/ALS. However, aligned with BLS/ALS studies, in lay-rescuer treated OHCA, refibrillation typically occurs within the first 30 s following a successful shock. Therefore, patients who refibrillate are typically in VF for an additional 1.5 min before receiving a subsequent shock for PADs with a 2 min cardiopulmonary resuscitation (CPR) cycle. This finding emphasises the need for investigation into optimal CPR duration for patients requiring multiple shocks.}, } @article {pmid42773049, year = {2026}, author = {McKee, NW and Jing, Y and Serdah, R and Thulasingam, S and Lopez, XS and Tan, EP}, title = {Lipophagy and lipid droplets in neurodegeneration.}, journal = {Trends in pharmacological sciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tips.2026.08.004}, pmid = {42773049}, issn = {1873-3735}, abstract = {Lipid droplet (LD) accumulation in neurons and glia is a feature of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) and is associated with oxidative stress and neuroinflammation. Although protein-targeted monotherapies have achieved partial clinical success, continued disease progression in many patients suggests that additional cellular mechanisms contribute to pathogenesis. Lipophagy, the selective autophagic degradation of LDs, provides a potential clearance route but has been studied primarily in hepatocytes under nutrient deprivation. Recent studies have begun to map noncanonical regulatory mechanisms of lipophagy, identify disease-associated points of failure in AD, PD, and ALS, and report compounds that enhance LD clearance through mechanisms distinct from canonical nutrient sensing. In this article, we review these advances and discuss the emerging rationale for exploring neuron- and context-specific approaches to modulate lipophagy as a complementary strategy in neurodegeneration.}, } @article {pmid42775169, year = {2026}, author = {Xue, F and Bao, L and He, A and Liang, S}, title = {CRISPR-based functional genomic screening in neurodegeneration: mechanistic insights into AD, PD, and ALS.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1831375}, pmid = {42775169}, issn = {1663-4365}, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by pronounced clinical and molecular heterogeneity, as well as highly interconnected pathogenic pathways. This biological complexity has long hindered efforts to systematically define disease mechanisms and to develop effective, targeted therapies. In recent years, clustered regularly interspaced short palindromic repeats (CRISPR) based functional genomic screening technologies have emerged as powerful tools for large-scale genetic perturbation in cellular, organoid, and in vivo models, enabling unbiased interrogation of disease relevant genetic networks and the identification of potential therapeutic targets. In this review, we summarize CRISPR knockout, CRISPR interference, CRISPR activation, and in vivo screening studies in AD, PD, and ALS, with emphasis on pathological phenotypes, experimental models, cell types, validation strategies, and evidence strength. In AD, these screens have identified regulators of amyloid-β (Aβ) production, Tau homeostasis and propagation, microglial states, neuronal aging, and stress responses. In PD, they have provided insights into α-synuclein (α-syn) homeostasis, mitochondrial quality control, lysosomal trafficking, and transplanted dopaminergic neuron survival. In ALS, they have identified modifiers of C9orf72-associated toxicity, repeat-associated non-AUG translation, TAR DNA-binding protein 43 (TDP-43) inclusion formation, and ATXN2 homeostasis. Cross-disease comparison indicates recurring involvement of proteostasis, endolysosomal function, mitochondrial regulation, and cellular stress responses, although individual screening hits show limited overlap and remain strongly influenced by experimental context. Overall, CRISPR-based screening provides a useful framework for identifying candidate disease modifiers, but further validation across complementary human-relevant and in vivo models is required before therapeutic translation.}, } @article {pmid42778113, year = {2026}, author = {Kumari, P and Raval, A and Rana, P and Kaushik, RR and Sahi, AK and Gundu, S and Mahto, SK}, title = {Revisiting culture conditions of satellite cells in vitro for skeletal muscle regeneration and therapeutic applications.}, journal = {Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft}, volume = {}, number = {}, pages = {153381}, doi = {10.1016/j.aanat.2026.153381}, pmid = {42778113}, issn = {1618-0402}, abstract = {Skeletal muscle fibers are largely post-mitotic in adulthood yet retain robust regenerative capacity through satellite cells (SCs), quiescent muscle stem cells located beneath the basal lamina that are activated after injury, proliferate as myoblasts, differentiate, fuse into myotubes, and mature via tightly regulated cues. Given the burden of muscle-wasting and neuromuscular diseases, including Duchenne muscular dystrophy (DMD) (driven by dystrophin defects and impaired SC function), amyotrophic lateral sclerosis (ALS) (with progressive atrophy and evidence of SC perturbation), and myasthenia gravis (autoimmune neuromuscular junction failure), physiologically relevant and scalable in vitro SC systems are essential for mechanistic studies and future cell-therapy development. This review revisits culture conditions and workflows used to isolate, enrich, and differentiate rodent and human skeletal muscle progenitors, integrating key regenerative signalling (hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met), nitric oxide (NO), fibroblast growth factor (FGF)-mitogen-activated protein kinase (MAPK) modulated by Sprouty-1, insulin-like growth factor (IGF)-driven Akt/mechanistic target of rapamycin (mTOR) hypertrophy, inflammatory cytokines including interleukin-6 (IL-6) signal transducer and activator of transcription 3 (STAT3)-cyclin D1, and differentiation switches involving Notch/Wnt, glycogen synthase kinase 3 (GSK3), and mitogen-activated protein kinase (p38α MAPK)) with practical culture variables. Two principal isolation strategies are compared: explant outgrowth, which preserves tissue architecture and injury-mimicking activation but can be slow and yield-limited without matrix support, and enzymatic dissociation (e.g., collagenase, dispase, pronase, protease XIV), which accelerates release from the basal lamina and supports high-throughput needs but requires optimization to minimize trauma and fibroblast contamination. Across reported protocols, matrix choice (notably Matrigel or poly-L-lysine/Matrigel), differential pre-plating, and medium composition (serum levels, chick embryo extract (CEE), basic fibroblast growth factor (bFGF)) strongly influence SC quiescence, migration, survival, and myotube formation, with high purities achievable (e.g., ~97.6% Pax7[±] after explant plus differential adherence; ~90% α7-integrin positive while lacking SCA-1, CD31, and CD45; up to ~98% after preplating; and ~95% in several optimized workflows) and differentiation occurring within ~1-7 days depending on conditions. The isolation of human SCs is constrained by the limited availability of tissue, inconsistent biopsy quality, and the absence of reliable markers to differentiate SCs from other mononuclear cells. Induced pluripotent stem cell (iPSC)-derived muscle organoids present a patient-specific alternative; however, they predominantly produce fetal-like instead of mature adult SCs. Overall, explant-based systems best retain physiological fidelity for niche and matrix studies, whereas enzymatic and hybrid approaches maximize efficiency and yield, underscoring that culture strategy should be selected based on the experimental objective rather than presumed universal superiority.}, } @article {pmid42778416, year = {2026}, author = {Fujino, Y and Nagai, Y}, title = {[Regulatory mechanisms of repeat-associated non-AUG translation: unveiling a novel molecular pathomechanism in repeat expansion diseases].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {}, number = {}, pages = {}, doi = {10.5692/clinicalneurol.cn-002278}, pmid = {42778416}, issn = {1882-0654}, abstract = {The expansion of genomic repeat sequences can cause more than 50 hereditary neuromuscular diseases, collectively referred to as repeat expansion diseases. In noncoding repeat expansion diseases caused by the expanded repeat sequences in the untranslated regions, repeat RNAs transcribed from the mutant genes can undergo repeat-associated non-AUG (RAN) translation despite lacking canonical AUG initiation codons, leading to the production of toxic repeat polypeptides that contribute to neurodegeneration. RAN translation has emerged as a promising therapeutic target for noncoding repeat expansion diseases; however, its regulatory mechanisms remain unclear. In this review, the characteristics of RAN translation and its roles in neuromuscular pathogenesis are overviewed. In addition, our research efforts for elucidating the regulatory mechanisms of RAN translation using Drosophila disease models are introduced.}, } @article {pmid42778785, year = {2026}, author = {Ding, J and Hu, N and Tian, H and Wang, Y and Shen, D and Yang, X and Niu, J and Liu, Q and Cui, L and Liu, M}, title = {Natural history of 441 cases of bulbar onset motor neuron disease (MND) in China: a single-center retrospective study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {10}, pages = {}, pmid = {42778785}, issn = {1590-3478}, support = {2026-PUMCH-C-008//National High Level Hospital Clinical Research Funding/ ; 2022ZD0118003//National Key R&D Program of China/ ; Z-2016-20-2402//China International Medical Foundation/ ; }, mesh = {Humans ; Female ; Retrospective Studies ; Male ; *Disease Progression ; Middle Aged ; *Motor Neuron Disease/physiopathology/diagnosis/mortality ; China/epidemiology ; Aged ; Prognosis ; Adult ; Age of Onset ; }, abstract = {OBJECTIVE: To describe the natural history and identify prognostic factors of bulbar onset motor neuron disease (MND).

METHODS: Bulbar onset MND patients with regular follow-up between January 2014 and December 2023 were included. Clinical features at initial evaluation, duration from onset to next region and time to death or tracheotomy were retrospectively collected. Survival analysis was performed by Kaplan-Meier method and Cox regression model.

RESULTS: A total of 441 patients were included. Disease progression occurred most frequently from bulbar region to upper limbs (77.1%), followed by lower limbs (16.4%) and respiratory muscles (6.5%), with a median time interval of 6.0 (1.0, 48.0) months. 215 patients died or underwent tracheotomy. The median duration to death or tracheotomy was 43.0 (95% CI 39.1-46.9) months, the 1-year, 2-year, 3-year, 4-year and 5-year survival rates (95%CI) were 96.6% (94.9-98.3), 79.9% (76.0-83.9%), 59.1% (54.0-64.7), 42.2% (36.6-48.6) and 29.9% (24.3-36.7), respectively. Younger onset age, slower ALSFRS-R decreasing rate, longer diagnostic delay, longer duration to next region and pure upper motor neuron involvement at initial evaluation were associated with favorable prognosis. Upper limbs involvement secondly to bulbar region was independently associated with better outcomes compared with respiratory muscles spreading.

CONCLUSIONS: The natural history of bulbar-onset ALS exhibits substantial heterogeneity. Patients with only upper motor neuron involvement in bulbar region at onset and subsequent upper limbs involvement as the second region tend to have a favorable prognosis.}, } @article {pmid42778939, year = {2026}, author = {Zhou, X and Han, J and Cui, X and Wu, S and Lu, Z and Zong, S}, title = {Roles of lactate and protein lactylation in neurogenesis and neurodegenerative disease.}, journal = {Journal of translational medicine}, volume = {24}, number = {1}, pages = {}, pmid = {42778939}, issn = {1479-5876}, support = {82272414//National Natural Science Foundation of China/ ; 82572653//National Natural Science Foundation of China/ ; 2022CXGC010507//Key Technology Research and Development Program of Shandong Province/ ; ZR2023QH258//Natural Science Foundation of Shandong Province/ ; }, mesh = {Humans ; *Neurogenesis ; *Neurodegenerative Diseases/metabolism/pathology ; *Lactic Acid/metabolism ; Animals ; }, abstract = {BACKGROUND: Neurodegenerative diseases are characterized by the gradual deterioration and impaired functionality of neuronal cells, which in turn results in the progressive decline of both cognitive capabilities and motor performance. Over the past few years, accumulating evidence has demonstrated that neurogenesis participates in pathogenesis of various neurodegenerative conditions. In the adult brain, neurogenesis involves the proliferation and differentiation of neural stem cells into functional neurons, a process that serves a critical function in sustaining neuroplasticity and repairing neural damage. Additionally, studies conducted recently show that lactate and the protein lactylation modification it induces can regulate neurogenesis and influence the progression of neurodegenerative diseases.

MAIN BODY: We elaborate on how lactate, as an energy substrate and signaling molecule, supports neuronal survival and synaptic plasticity, and discuss the mechanisms by which histone lactylation regulates neural stem cell proliferation and differentiation via epigenetic pathways, as well as the regulation of specific protein functions by non‑histone lactylation. We further integrate the dual effects of lactate and lactylation in diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). They can be neuroprotective by improving energy metabolism, promoting neurotrophic signals, and reducing inflammation, but they can also be neurotoxic via inflammation, oxidative damage, and protein aggregation under certain conditions. Key factors that determine this switch include concentration, cell type, pathological context, and lactylation site. We also evaluate therapeutic strategies targeting lactate metabolism and lactylation, and the challenges for clinical translation.

CONCLUSIONS: Lactate and protein lactylation exhibit a regulatory duality in neurogenesis and neurodegenerative diseases, encompassing both neuroprotective and neurotoxic effects. This finding provides a new perspective for understanding disease mechanisms and reveals potential intervention targets.}, } @article {pmid42779169, year = {2026}, author = {Yang, X and Yuan, J and Huang, S and Yao, X}, title = {Identifying Modifiable Factors and Their Joint Effect on Amyotrophic Lateral Sclerosis: A Prospective Cohort Study in the UK Biobank.}, journal = {Brain and behavior}, volume = {16}, number = {9}, pages = {e71771}, pmid = {42779169}, issn = {2162-3279}, support = {82271448//National Natural Science Foundation of China/ ; 2020B1111170002//Guangdong Provincial Clinical Research Centre for Neurological Diseases/ ; 2020A0505020004//Guangdong Province International Cooperation Base for Early Intervention and Functional Rehabilitation of Neurological Diseases/ ; 2024MDRD02//Guangzhou Major Difficult and Rare Diseases Project/ ; //Guangdong Provincial Engineering Centre for Major Neurological Disease Treatment/ ; //Guangzhou Clinical Research and Translational Centre for Major Neurological Diseases/ ; //Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Female ; United Kingdom/epidemiology ; Prospective Studies ; Male ; Risk Factors ; Middle Aged ; Aged ; Biological Specimen Banks ; UK Biobank ; Exposome ; }, abstract = {BACKGROUND: Hypothesis-driven studies have linked numerous risk factors to amyotrophic lateral sclerosis (ALS). However, the full extent of their diversity and co-occurrence has not been adequately appreciated. This study aims to comprehensively explore the modifiable risk factors for ALS and to evaluate the potential benefit of controlling these factors.

METHODS: This prospective cohort study utilized data from UK Biobank participants enrolled between 2006 and 2010 for whom complete data were available. An exposome-wide association study (EWAS) was employed to screen for modifiable risk factors, adjusted for sex and age. The main outcome was the first recorded diagnosis of ALS. The associations of modifiable risk factors with ALS risk were assessed using hazard ratios and 95% confidence intervals. The population attributable fraction (PAF) was used to estimate the joint effects of modifiable factors.

RESULTS: This study included a total of 326,050 participants and assessed 184 modifiable risk factors. During follow-up, 744 participants were diagnosed with ALS for the first time. EWAS, adjusted for sex and age, identified 45 modifiable factors associated with ALS incidence across six domains (excluding early life), including varicella, lower education, and peak expiratory flow. Analysis using the PAF indicated that 25.94%-87.40% of ALS cases could potentially be prevented.

CONCLUSIONS: In this study, newly identified risk factors for ALS through the EWAS may serve as targets for future studies. Interventions targeting modifiable risk factors, particularly those related to lifestyle and socioeconomic status, may help reduce the incidence of ALS.}, } @article {pmid42779622, year = {2026}, author = {Peethambaran Mallika, A and Baghel, MS and Sitzman, O and Yu, JG and Cao, T and Renganathan, S and Sinha, IR and Melnikova, T and Ling, JP and Wong, PC}, title = {Restoring multiple TDP-43 cryptic targets, but not solely Unc13a , rescues motor neuron disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.09.11.751082}, pmid = {42779622}, issn = {2692-8205}, abstract = {Dysfunction of TAR DNA-binding protein 43kDa (TDP-43) underlies amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder with limited therapeutic options. While current therapeutic approaches are designed to individually target unique cryptic exons of TDP-43 such as UNC13A , the sufficiency of such a strategy to mitigate motor neuron disease remains unclear. Using a mouse model lacking TDP-43 in spinal motor neurons which mimics early stages of ALS, we show that the exclusion of Unc13a cryptic exon fails to mitigate motor neuron disease. In contrast, the restoration of multiple TDP-43 cryptic targets, including Unc13a , attenuated motor neuron loss, and rescued motor neuron disease. Additionally, compared to brain neurons, spinal motor neurons accumulate markedly lower amounts of Unc13a cryptic exons in mice and humans, suggesting that the contribution of this TDP-43 cryptic target to spinal motor neuron loss may be limited. Together, these results strongly support ALS therapeutic strategies designed to simultaneously restore multiple TDP-43 cryptic targets to attenuate spinal motor neuron loss.}, } @article {pmid42779744, year = {2026}, author = {Weerakkody, JS and Bokstaller, F and Sthanu, U and Pitt, D}, title = {Paired RNA profiling of circulating small extracellular vesicles links survival in ALS to reactive glial - vascular programs.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.09.08.749915}, pmid = {42779744}, issn = {2692-8205}, abstract = {Circulating RNA can capture molecular variation associated with amyotrophic lateral sclerosis (ALS) progression, but biofluid heterogeneity makes biologically organized signals difficult to recover. Here, we paired microRNA (miRNA) and messenger RNA (mRNA) profiles from glutamate-aspartate transporter (GLAST)-positive small extracellular-vesicles (sEVs) to estimate survival time and identify survival-associated programs. In 45 participants with ALS and 15 controls, biologically constrained multi-omic factor analysis identified a program in which reciprocal miRNA-mRNA states among target-supported pairs tracked survival. The miRNA arm was then evaluated in an independent total-plasma cohort of 248 participants with ALS, refining a five-miRNA panel that added prognostic information beyond functional decline and neurofilament light chain, particularly over longer survival horizons. The mRNA arm was evaluated across 586 cortical profiles from 308 donors and 527,261 nuclei from 69 donors, identifying a five-gene core associated with glial reactivity, vascular programs and reduced myelinating identity. Together, these findings establish a framework for integrating regulatory RNA layers in circulation to identify clinically relevant programs and relate them to disease-relevant cellular states.}, } @article {pmid42779765, year = {2026}, author = {Dattilo, D and Pellegrini, F and Barattucci, S and Brown, AL and Vargas, JNS and Gatt, A and Morrie, R and Miller, G and Bachmutsky, I and McEachin, Z and Chung, M and Keuss, MJ and Ryadnov, E and Zanovello, M and Mehta, PR and Mattedi, F and Barioglio, M and Kamath, S and Kargbo-Hill, SE and Palade, J and Kowal, I and Glass, J and Gearing, M and Lee, EB and Murray, ME and Dickson, DW and , and Green, EM and Seyfried, NT and Chandriani, S and Ward, M and Fratta, P}, title = {TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.09.17.752342}, pmid = {42779765}, issn = {2692-8205}, abstract = {Nuclear depletion of TDP-43 is a defining pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to widespread RNA misprocessing, including the formation of cryptic exons. Here, we identified TDP-43 as a regulator of circular RNA (circRNA) biogenesis in multiple human neuronal cell models, and showed that its dysfunction induces the de novo formation of cryptic circular RNAs (c-circRNAs). Analysis of post-mortem brain transcriptomic data identified a subset of c-circRNAs which are specific for ALS and FTD cases with TDP-43 pathology. Further, we developed highly sensitive rolling-circle amplification-based circRNA detection assays that allow to distinguish TDP-43 pathology in human CNS tissues with a 0.99 AUC. We found that c-circRNAs can co-occur with cryptic linear splicing events, uncovering complex RNA misprocessing hotspots that induce loss of disease-relevant proteins, including RPTOR and EHMT1. Notably, one of these c-circRNAs originates from UNC13A, a gene whose cryptic exon has previously been linked to one of the major GWAS hits in ALS/FTD and that is being pursued as a therapeutic target through splice-switching ASOs. We showed that c-circUNC13A is co-regulated with the linear cryptic transcript and suppression of UNC13A cryptic exon results in c-circUNC13A reduction in cultured neurons and in vivo, highlighting its potential as a target engagement biomarker for emerging UNC13A-directed therapies. Overall, this work identifies a novel molecular mechanism for TDP-43 dysfunction, opening novel avenues for understanding disease pathogenesis and developing much needed pathology biomarkers.}, } @article {pmid42780028, year = {2026}, author = {Zhao, T and Hoffman, M and Wu, G and Belzil, V}, title = {Genetically Predicted Blood DNA Methylation Reveals Putative Regulatory Signals Associated with ALS Risk.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42780028}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder whose genetic architecture and underlying molecular mechanisms remain incompletely understood, particularly in sporadic disease. To investigate whether genetically regulated DNA methylation may help interpret ALS susceptibility, we conducted a methylome-wide association study (MWAS) of genetically predicted blood DNA methylation using the PrediXcan framework. CpG-specific prediction models developed in the ARIES and Understanding Society cohorts were applied to ALS genome-wide association study (GWAS) summary statistics from 27,205 cases and 110,881 controls of European ancestry. In total, genetically predicted methylation at 192,378 unique CpG sites was evaluated using S-PrediXcan. At a nominal threshold of p < 0.05, 3,741 CpGs were associated with ALS risk using ARIES models and 13,127 using Understanding Society models. After Bonferroni correction, 25 CpGs across eight genomic regions remained significantly associated with ALS risk. These included signals near established ALS and ALS-frontotemporal dementia genes and loci, including C9orf72, TBK1, SCFD1, and MOB3B, as well as three CpGs mapping to WHAMM at 15q25.2, a region not previously implicated in ALS by GWAS. Predicted methylation was positively associated with ALS risk at 18 CpGs and inversely associated at seven. Complementary transcriptome-wide association analyses using GTEx v8 whole-blood gene-expression prediction models identified 11 genes associated with ALS risk after Bonferroni correction, including convergent methylation and expression signals at C9orf72. These findings add a regulatory dimension to ALS genetic studies by prioritizing CpG sites, genes, and genomic regions through which inherited variation may influence disease susceptibility. PrediXcan-based MWAS therefore provides a complementary strategy for refining genetic association signals into biologically testable candidates and identifying regulatory mechanisms for further functional investigation.}, } @article {pmid42780048, year = {2026}, author = {Zhu, C and Zhao, Z and Song, B and Chen, YM and Xiao, Y and Zhang, Z and Ye, Y and Xu, N and Zhang, R and Huang, Y and Troncoso, JC and He, C and Sun, S}, title = {Loss of TDP-43 function drives cryptic circular RNAs in neurodegenerative diseases.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.09.17.752169}, pmid = {42780048}, issn = {2692-8205}, abstract = {TAR DNA-binding protein 43 (TDP-43) is a key pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and a critical regulator of RNA splicing. While loss of TDP-43 induces aberrant splicing in linear transcripts, its impact on circular RNA (circRNA) biogenesis remains unexplored. Here, we show that TDP-43 depletion in human neurons induces widespread circRNA changes, especially upregulation of a distinct class of cryptic circRNAs that arise specifically upon loss of TDP-43. Some of these cryptic circRNAs incorporate cryptic exons derived from intronic sequences. Notably, these cryptic circRNAs exhibit greater stability than their corresponding linear RNA isoforms and accumulate progressively in neurons. Moreover, cryptic circRNAs are elevated in postmortem brain tissues from ALS, FTD and Alzheimer's disease (AD) patients. These findings reveal a previously unrecognized role for TDP-43 in repressing cryptic circRNA formation and establish these circRNAs as stable molecular signatures of TDP-43 dysfunction.}, } @article {pmid42780196, year = {2026}, author = {Okuda, M and Okinaka, Y and Saino, O and Taguchi, A}, title = {Case Report: Autologous bone marrow mononuclear cell transplantation improved motor function in a patient with amyotrophic lateral sclerosis.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1940826}, pmid = {42780196}, issn = {2296-858X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, and no established treatment restores impaired motor function. In mouse models of ALS, bone marrow mononuclear cell (BM-MNC) injection improved motor function. In patients with ALS, direct spinal cord injection of BM-MNCs has also been reported to improve motor function. Here, we report the case of a 52-year-old male patient with ALS who underwent intravenous autologous BM-MNC transplantation and demonstrated improved motor function. His revised ALS Functional Rating Scale score increased from 17 before treatment to 18 at 24 weeks after transplantation. The score of Manual Muscle Testing of fifth finger metacarpophalangeal joint flexion improved from 0 before treatment to 2(-) at 24 weeks after transplantation. No serious adverse events were observed. As this is a single case report, additional case series and subsequent randomized clinical trials are essential to clarify the effect of BM-MNC transplantation on ALS outcomes. This case suggests, however, that motor dysfunction in patients with ALS might be reversible. These findings encourage future studies investigating motor function improvement, rather than disease progression slowing, by elucidating the mechanisms underlying BM-MNC transplantation and optimizing treatment.}, } @article {pmid42781313, year = {2026}, author = {Zhu, JX and Xia, Y and Liu, J and Cao, L and Hou, SX and Wang, Y}, title = {Protecting Against Cytoplasmic Protein Aggregates With Cytoplasmic PML Variants.}, journal = {Bio-protocol}, volume = {16}, number = {18}, pages = {e5815}, pmid = {42781313}, issn = {2331-8325}, abstract = {Cytoplasmic protein aggregation is a defining feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, and certain forms of motor neuron disease. Recent evidence indicates that promyelocytic leukemia protein (PML) and engineered PML-derived variants can act as versatile aggregate-remodeling factors. In particular, cytoplasmically redirected PML variants recognize pathological cytoplasmic inclusions and promote their clearance. Here, we describe a protocol to generate and validate two engineered cytoplasmic PML variants: full-length mPML, which is redirected to the cytoplasm by disruption of its nuclear localization sequence, and the truncated mPML[ΔRBC] variant, which lacks the RING, B-box, and coiled-coil domain but retains aggregate-reducing activity. The protocol integrates fluorescence-based imaging, bimolecular fluorescence complementation, detergent-soluble/insoluble fractionation, and validation in primary rat cortical neurons. This workflow provides a practical platform for assessing cytoplasmic aggregate burden and for comparing the aggregate-remodeling activities of PML-derived constructs. It can also be adapted to other disease-associated aggregation-prone proteins, including TDP-43, SOD1, FUS, tau, polyGA, and polyQ-expanded proteins. Key features • Describes the generation and validation of two complementary cytoplasmic PML variants: full-length mPML and truncated mPML[ΔRBC]. • Provides fluorescence-based and BiFC-based assays to visualize pathological cytoplasmic protein assemblies. • Includes detergent-soluble/insoluble fractionation for biochemical assessment of aggregate burden. • Establishes a primary rat cortical neuron workflow to evaluate the effect of mPML on TDP-43-CTF aggregates. • Can be adapted to other aggregation-prone proteins and additional PML-derived aggregate-remodeling candidates.}, } @article {pmid42782389, year = {2026}, author = {Walden, F and Reihani, Y and Peters, A and Sepehrimanesh, M}, title = {Dysregulation of mitochondrial bioenergetics, RNA processing, and cellular stress responses in FUS-ALS: a multi-dataset transcriptomic perspective.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {10}, pages = {}, pmid = {42782389}, issn = {1590-3478}, support = {NASA EPSCoR RID-RAP grant//NASA EPSCoR RID-RAP grant/ ; SBS Start-up budget//SBS Start-up budget/ ; ANS Faculty mini-grant//ANS Faculty mini-grant/ ; }, mesh = {Humans ; *RNA-Binding Protein FUS/genetics/metabolism ; *Astrocytes/metabolism ; *Mitochondria/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Motor Neurons/metabolism ; *Transcriptome ; *Energy Metabolism/physiology/genetics ; Induced Pluripotent Stem Cells/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron (MN) degeneration. Mutations in the FUS gene, particularly the aggressive P525L variant, disrupt nuclear localization of the FUS RNA-binding protein, resulting in cytoplasmic accumulation, altered RNA metabolism, and toxic aggregation. Astrocytes also contribute to disease progression through non-cell-autonomous mechanisms.

OBJECTIVE: To identify shared and cell-type-specific molecular mechanisms underlying FUS-associated ALS through integrated transcriptomic analysis of human induced pluripotent stem cell (hiPSC)-derived motor neurons and astrocytes.

METHODS: Five publicly available RNA-sequencing datasets from hiPSC-derived motor neurons and astrocytes carrying FUS mutations were analyzed. Differential gene expression and Gene Ontology enrichment analyses were performed to identify dysregulated genes and pathways.

RESULTS: Both cell types showed convergent dysregulation of mitochondrial/bioenergetic pathways (oxidative phosphorylation, ATP metabolism, translation, membrane potential). Pathway analysis across motor neuron datasets identified largely MN-specific enrichment in cell-cycle regulation, intracellular trafficking, and stimulus response, while only four pathways were shared with astrocytes, most notably NADH dehydrogenase complex assembly, enriched across all datasets and both cell types, marking mitochondrial complex I as the strongest convergent signature. RNA processing/splicing pathways were also enriched, consistent with FUS function. Shared DEGs included upregulated COMT, TXNRD2, and PCDHGB4, and downregulated PCDH17 and C11orf87, implicating neurotransmitter metabolism, antioxidant defenses, and adhesion. Stress pathways (oxidative stress, autophagy, heat-shock, ER stress/UPR) were broadly altered, with UPR genes mainly upregulated and inflammatory genes downregulated.

CONCLUSION: FUS-ALS involves shared mitochondrial complex I and stress-response disturbances layered onto MN-intrinsic cell-cycle and trafficking dysregulation, reflecting convergent and cell-type-specific mechanisms.}, } @article {pmid42782554, year = {2026}, author = {Padhiyar, DP and Butani, S and Vyas, T and Mukharya, A and Rajput, A}, title = {Recent Innovations in Drug Delivery Systems for Amyotrophic Lateral Sclerosis: Past, Present and Future.}, journal = {AAPS PharmSciTech}, volume = {27}, number = {5}, pages = {}, pmid = {42782554}, issn = {1530-9932}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; *Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism ; Animals ; Nanoparticles/chemistry ; Drug Carriers/chemistry ; Polymers/chemistry ; Delayed-Action Preparations ; Biological Availability ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disorder characterized by degeneration of upper and lower motor neurons, resulting in severe muscle weakness, respiratory failure, and death. Despite several pharmacological therapies having been approved, their clinical benefit remains limited due to poor central nervous system penetration, rapid metabolic clearance, and low patient compliance. Overcoming these pharmacokinetic and pharmacodynamic limitations remains a major challenge in ALS management. Recent advances in drug delivery have focused on brain-targeted strategies, improved bioavailability, and sustained or controlled-release systems. Nanocarriers, including lipid and polymeric nanoparticles, dendrimers, and mesoporous silica systems, facilitate blood-brain barrier traversal, protect labile drugs, and enable surface functionalization for receptor-mediated targeting. Biologically derived carriers such as exosomes and extracellular vesicles further enhance targeted delivery while minimizing immunogenicity. In parallel, noninvasive approaches such as mucoadhesive polymers, intranasal, and nose-to-brain delivery systems, including microneedle-based platforms, offer promising alternatives to bypass first-pass metabolism and improve patient adherence. Additionally, emerging therapeutic modalities, including gene therapy, stem cell-based interventions, and neuromodulation, are increasingly integrated with advanced delivery technologies. This article critically analyzes current ALS therapies, highlights recent breakthroughs in advanced drug delivery systems, and discusses future perspectives for achieving meaningful clinical outcomes.}, } @article {pmid42782733, year = {2026}, author = {Hou, X and Yu, W}, title = {The Role of cGAS-STING-Driven PANoptosis in Neurodegenerative Diseases and Therapeutic Prospects.}, journal = {Cells}, volume = {15}, number = {18}, pages = {}, pmid = {42782733}, issn = {2073-4409}, support = {31972623//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; cGAS-STING Signaling Pathway ; *Nucleotidyltransferases/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; Animals ; STING Protein ; *Membrane Proteins/metabolism ; Signal Transduction ; }, abstract = {Neurodegenerative diseases share features of neuronal loss, neuroinflammation, and protein aggregation. The cGAS-STING pathway, a key DNA sensor, mediates neuroinflammation via TBK1-IRF3 and IKK-NF-κB axes, inducing type I interferons and pro-inflammatory cytokines. This pathway upregulates ZBP1, promotes PANoptosome assembly, and triggers PANoptosis, releasing DAMPs and creating a self-amplifying "inflammation-death" cycle. In Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, pathological proteins (Aβ, Tau, α-synuclein, TDP-43) or genetic defects (e.g., C9orf72 repeats) cause mitochondrial DNA leakage or genomic instability, activating this axis. This review highlights the cGAS-STING-PANoptotic cascade as a shared pathogenic mechanism and discusses the current evidence and remaining challenges in confirming this hypothesis.}, } @article {pmid42782801, year = {2026}, author = {Almeida, S and Gu, Y and Kankel, MW}, title = {AUG-Dependent Translation of Antisense Repeat Transcripts Contributes to Dipeptide Repeat Protein Production in C9ORF72 Expansion Carriers.}, journal = {Cells}, volume = {15}, number = {18}, pages = {}, pmid = {42782801}, issn = {2073-4409}, support = {R21 AG085076/AG/NIA NIH HHS/United States ; 1R21AG085076-25/NH/NIH HHS/United States ; R21 NS112766/NS/NINDS NIH HHS/United States ; R21NS119952/NH/NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; 1R21NS112766-24/NH/NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; *Dipeptides/metabolism/genetics ; *Protein Biosynthesis/genetics ; *DNA Repeat Expansion/genetics ; Amyotrophic Lateral Sclerosis/genetics ; *RNA, Antisense/genetics/metabolism ; Frontotemporal Dementia/genetics ; Oligonucleotides, Antisense ; Motor Neurons/metabolism ; }, abstract = {A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Bidirectional transcription of the repeat expansion generates sense and antisense RNAs that are translated into dipeptide repeat (DPR) proteins, but the mechanisms of translation initiation remain incompletely understood. Here, we used CRISPR-Cas9 genome editing and steric-blocking antisense oligonucleotides (ASOs) to investigate the role of AUG codons within the antisense repeat RNA. Deletion of an AUG-containing region upstream of the antisense repeats markedly reduced poly(GP) production without affecting antisense RNA levels, demonstrating that this sequence is required for efficient poly(GP) synthesis. We further found that unspliced sense transcripts containing the repeat expansion likely serve as templates for poly(GA) and poly(GR) production in motor neurons. Finally, ASOs targeting the antisense AUG-containing region reduced poly(PR) and poly(GP) levels without altering repeat RNA abundance, supporting a role for AUG-dependent translation of the antisense repeat RNA. These findings provide new insights into the mechanisms of DPR production and suggest that translation-blocking ASOs may represent a therapeutic strategy for C9ORF72-associated ALS/FTD.}, } @article {pmid42782811, year = {2026}, author = {Bagyinszky, E and An, SSA}, title = {ERBB4 and Neurodegeneration: Association Between Hypothalamic-Pituitary-Adrenal (HPA) Axis: Associated Neurodegenerative Pathogenesis.}, journal = {Cells}, volume = {15}, number = {18}, pages = {}, pmid = {42782811}, issn = {2073-4409}, mesh = {Humans ; *Hypothalamo-Hypophyseal System/metabolism/pathology ; *Pituitary-Adrenal System/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Receptor, ErbB-4/metabolism/genetics ; Signal Transduction ; }, abstract = {The hypothalamic-pituitary-adrenal (HPA) axis is the central neuroendocrine system that controls physiological stress responses and maintains homeostasis through the coordinated interactions among the hypothalamus, pituitary gland, and adrenal cortex. Dysregulation of the HPA axis is associated with stress-related psychiatric conditions and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Chronic stress creates a detrimental environment in the brain, inducing structural changes and accelerating brain aging and the loss of neurons. Receptor tyrosine-protein kinase ERBB4 (ERBB4), a member of the epidermal growth factor receptor (EGFR) family, is activated primarily by neuregulin ligands and plays an essential role in neuronal development, synaptic plasticity, and cell survival. Emerging evidence suggests that ERBB4 signaling influences neuroendocrine regulation and stress responsivity. While further studies are needed to provide direct mechanistic evidence linking ERBB4-mediated HPA axis dysregulation to neurodegenerative cell death, this manuscript critically evaluated the preclinical models and proposes a possible feed-forward framework wherein ERBB4 served as a permissive homeostatic modulator at the intersection of stress endocrinology and neuroinflammation. Furthermore, the impact of ERBB4 dysregulation and its mutations on neurodegenerative diseases has been presented, focusing on potential mechanisms of oxidative stress, synaptic dysfunction, and neuronal apoptosis. Taken together, ERBB4 represents an important molecular interface between stress signaling and neurodegenerative pathology. Understanding the regulation of ERBB4 in the HPA axis has provided new insights into the mechanisms underlying neurodegenerative diseases and could identify novel therapeutic targets for stress-associated neurological disorders.}, } @article {pmid42783617, year = {2026}, author = {Mitu, I and Caba, IC and Macovei, I}, title = {Cumulative and Interactive Effects of Heavy Metal Mixtures Across Neurodegenerative Diseases: A Comparative Review of Alzheimer, Parkinson, Amyotrophic Lateral Sclerosis and Multiple Sclerosis.}, journal = {Journal of xenobiotics}, volume = {16}, number = {5}, pages = {}, pmid = {42783617}, issn = {2039-4713}, support = {7383/31.03.2026//Grigore T. Popa University of Medicine and Pharmacy/ ; }, abstract = {Heavy metals and metalloids are persistent environmental contaminants that accumulate in the central nervous system and interact with endogenous essential metals, yet most neurotoxicological research continues to treat metals as independent agents rather than as co-occurring mixtures. This review systematically compares the evidence for cumulative and interactive effects of heavy metal mixtures across four major neurodegenerative diseases-Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)-asking which metal combinations have been directly documented for each disease, and whether these patterns are disease-specific or shared. Following a PubMed search (January 2016-June 2026), 93 unique studies were included (AD: 49; PD: 38; ALS: 19; MS: 18; 31 shared across diseases). Combined exposure to lead, cadmium, arsenic, and mercury is linked to amyloid-beta accumulation and dementia risk in AD; manganese-vanadium co-exposure produces more severe dopaminergic damage in PD than either metal alone, with manganese activating the familial PD gene LRRK2; a multi-metal mixture in ALS was associated with a three-fold higher disease risk independent of genetic susceptibility; and MS showed almost no designed mixture studies despite considerable single-metal data, with conflicting findings across cohorts. Three general mechanisms were identified: competition at shared membrane transporters (notably DMT1), sequestration by metal-binding proteins, and direct synergistic or antagonistic interactions, in which essential elements can modulate toxic-metal handling. Mixture-statistics approaches (WQS, BKMR), already established for AD and PD, should be extended to MS to close this evidence gap.}, } @article {pmid42783767, year = {2026}, author = {Kang, Z and Meng, R and Nie, M and Wang, T}, title = {Gut Microbial Metabolism as a Dynamic Interface in Neurodegenerative Diseases.}, journal = {Metabolites}, volume = {16}, number = {9}, pages = {}, pmid = {42783767}, issn = {2218-1989}, support = {No.82405557//China National Natural Science Foundation of youth project/ ; KM202410025018//R&D Program of Beijing Municipal Education Commission 2024: Study on the improvement of clinical symptoms and mechanism of acupuncture in amyotrophic lateral sclerosis/ ; 20250639//Young Elite Scientists Sponsorship Program of the Beijing High Innovation Plan/ ; 2024-QNRC2-B08//2024-2026 Chinese Association of Chinese Medicine young Talent lifting project/ ; }, abstract = {Gut microbial metabolism links intestinal ecology with systemic physiology and neural pathology, but its effects vary across disease stage, tissue compartment, and host background. This review uses Alzheimer's disease (AD) as the principal model and compares selected features with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Across the AD continuum, fermentation-related changes appear in prodromal cohorts, whereas broader alterations in amino acid products, host-microbial co-metabolites, bile acids, and lipids accompany mild cognitive impairment and dementia. These group-level patterns do not constitute a fixed patient trajectory. Microbial production, intestinal absorption, hepatic conversion, renal clearance, barrier integrity, and tissue-specific receptors jointly determine biological exposure. Experimental studies connect short-chain fatty acids and indole derivatives with epithelial and neuroimmune homeostasis, while imidazole propionate, trimethylamine N-oxide, selected kynurenine products, and remodeled bile acid pools engage vascular, inflammatory, amyloid, or tau-related pathways. Cerebral pathology can also remodel the intestinal ecosystem, creating reciprocal feedback. Apolipoprotein E4 modifies lipid handling, vascular permeability, and immune responses, helping to explain why comparable metabolic profiles may carry different consequences among individuals. Translation therefore requires more than a change in community composition. Trials must verify microbial function, metabolite target engagement, AD biomarker response, and clinical benefit in appropriately stratified participants. Shared pathways in PD and ALS provide comparison points, but disease-specific cells, proteinopathies, and treatment exposures constrain direct transfer of AD-derived targets.}, } @article {pmid42784708, year = {2026}, author = {Rajput, P and Jakhar, M and Kashyap, A and Rani, N and Singh, TG}, title = {The Intertwined Threat: How Diabetes Impacts Neurological Disorders - A Review Article.}, journal = {Acta neurologica Taiwanica}, volume = {35}, number = {3}, pages = {119-127}, pmid = {42784708}, issn = {1028-768X}, mesh = {Humans ; *Nervous System Diseases/etiology ; *Diabetes Complications ; *Diabetes Mellitus ; Oxidative Stress ; }, abstract = {The chronic illness known as diabetes mellitus (DM) is typified by persistently high blood glucose levels or hyperglycemia. Both type 1 and type 2 diabetes, the latter of which is frequently referred to as "adult-onset diabetes" or "insulin-dependent diabetes," are progressing conditions with complex and poorly understood etiologies. Often, patients show positive pancreatic beta-cell antibodies, signifying an autoimmune factor. The long-term complications of uncontrolled diabetes are numerous, not just physically based and encompassing everything from kidney failure to foot ulcers and damage to the cardiovascular system, but also with serious neurological disorders, including stroke, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease (AD), and epilepsy. The interplay between neurological disorders and diabetes is complex, and the association of these pathological states in their general description proposes common events, namely oxidative stress, mitochondrial damage, amyloid protein aggregation, glucagon-like peptide-1 secretion skewing, and inflammation. Learning about these interconnections will help us to develop effective strategies for managing both diabetes and its neurological complications.}, } @article {pmid42785576, year = {2026}, author = {Shameklis, J and Drutchas, A and Keeney, T and Rowland, M and Dow, L and Sawicki, D and Ho, D and Paladino, J and Lindenberger, E}, title = {A Qualitative Study of Team-Based Serious Illness Communication in ALS.}, journal = {Journal of pain and symptom management}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpainsymman.2026.09.025}, pmid = {42785576}, issn = {1873-6513}, abstract = {CONTEXT: Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease with an illness trajectory requiring repeated, high-stakes decisions and ongoing serious illness communication (SIC). While multidisciplinary team care is best practice in ALS, how interprofessional teams operationalize SIC, and how team culture shapes this work, remain poorly understood.

OBJECTIVE: To examine how team culture influences SIC delivery within an interprofessional ALS clinic.

METHODS: We conducted a qualitative study using semi-structured interviews and a focus group with interprofessional clinicians from a multidisciplinary ALS clinic at an academic medical center. Data explored clinicians' perceptions of interprofessional roles, team culture, facilitators, and barriers related to SIC. Transcripts were analyzed using thematic analysis with a combined deductive-inductive approach.

RESULTS: Analysis identified interpersonal facilitators, systems-level facilitators, and structural barriers shaping team-based SIC. Clinicians described shared responsibility for SIC, with conversations unfolding cumulatively over time across roles and clinical encounters. Interpersonal facilitators included mutual respect, psychological safety, role flexibility, and a shared commitment to reducing patient harm. Systems-level facilitators included frequent multimodal communication, structured documentation, leadership support, and use of adverse outcomes as opportunities for practice improvement. Structural barriers included time constraints, care transitions, regulatory limitations, and variability in comfort with SIC language.

CONCLUSIONS: In this multidisciplinary ALS clinic, strong team culture enabled SIC to function as a longitudinal, interprofessional process rather than a single clinician-led event. Findings highlight the importance of psychological safety, teamwork, and supportive systems in delivering high-quality SIC and inform future clinical practice, training, and research.}, } @article {pmid42786852, year = {2026}, author = {Yu, J and Xie, D and Zeng, X and Zhang, S and Xiao, B and Zhang, J and Fang, M and Zhu, Q and Yao, C}, title = {Therapeutic Implications of Cell Death Pathways Across the Course of Amyotrophic Lateral Sclerosis.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X500937260908042834}, pmid = {42786852}, issn = {1875-6190}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, resulting in paralysis and limited survival. Multiple regulated cell death pathways, including apoptosis, necroptosis, ferroptosis, pyroptosis, lysosomal cell death, autophagy-dependent cell death, NETosis, and other emerging cell death modalities, have been implicated in ALS, but their mechanistic interactions and relative contributions remain poorly understood. This knowledge gap has hindered the development of effective therapies. Better experimental models are needed to dissect these pathways. This review summarizes current knowledge on the roles of cell death pathways in ALS. A tiered framework (M1-M4) is applied to critically evaluate data from human postmortem tissue, patient-derived cells, and animal models, ranking studies according to their relevance to human disease. Potential crosstalk among these pathways is further examined. It is also proposed that the relative contribution of specific cell death pathways may shift with disease progression, although this hypothesis requires longitudinal validation. To integrate this dynamic perspective, cell death pathway activities are hypothetically aligned with the King's clinical staging system. This stage-informed framework is presented as a conceptual model intended to generate hypotheses rather than to serve as a validated clinical algorithm. The model distinguishes established therapies from preclinical and exploratory strategies. Future research should prioritize the development of human-relevant model systems, the identification of longitudinal biomarkers of cell death, and the implementation of rigorously designed combination trials. These efforts may ultimately enable more precise, stage-appropriate therapeutic strategies for ALS.}, } @article {pmid42788121, year = {2026}, author = {Naruse, H and Mitsui, J and Ishiura, H and Okubo, S and Yoshida, C and Mitsutake, A and Maruta, K and Uchida, Y and Nobuhara, Y and Okabe, H and Nakamura, Y and Suzuki, R and Hotta, Y and Matsukawa, T and Tsukamoto, H and Kawamura, Y and Hara, K and Takado, Y and Kanzaki, M and Uesaka, Y and Ishii, A and Kitamura, A and Urushitani, M and Takahashi, Y and Kubota, A and Maeda, M and Shimizu, J and Shirota, Y and Hamada, M and Satake, W and Katagiri, T and Takahama, S and Yamamoto, T and Tsuji, S and Nakamura, Y and Toda, T}, title = {LRP12 CGG Repeat Expansions in Patients With Adult-Onset Non-5q Spinal Muscular Atrophy.}, journal = {Neurology. Genetics}, volume = {12}, number = {5}, pages = {e200440}, pmid = {42788121}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Non-5q spinal muscular atrophy (SMA) is genetically heterogeneous, yet many adult-onset cases remain molecularly undiagnosed. CGG repeat expansions in the 5' untranslated region of LRP12, originally identified in oculopharyngodistal myopathy, have also been implicated in amyotrophic lateral sclerosis (ALS) and inherited peripheral neuropathy. The aim of this study was to determine whether LRP12 CGG repeat expansions occur in patients with adult-onset proximal-predominant non-5q SMA and characterize the associated clinical presentations.

METHODS: In this observational case series, we enrolled 8 consecutive, genetically unresolved families that met prespecified criteria for adult-onset non-5q SMA after exclusion of known genetic causes of SMA and familial ALS by comprehensive genetic evaluation, including whole-exome sequencing. LRP12 CGG repeat expansions were screened by repeat-primed PCR and then confirmed and sized by Oxford Nanopore long-read sequencing. LRP12 CGG repeat expansions were also screened in 496 unrelated ALS cases and 1,000 controls.

RESULTS: Monoallelic LRP12 CGG repeat expansions were identified in 6 of the 8 non-5q SMA probands (75%). Five of the 6 positive families were consistent with autosomal-dominant inheritance. Expanded alleles ranged from 58 to 92 repeat units. Affected individuals showed adult-onset, slowly progressive, proximal-predominant pure lower motor neuron weakness with preserved bulbar and sensory function and no upper motor neuron signs. Expansions were rare in ALS cases (2/496, 0.40%) and controls (2/1,000, 0.20%).

DISCUSSION: We identified LRP12 CGG repeat expansions in a substantial proportion of patients with slowly progressive, proximal-predominant pure lower motor neuron weakness not linked to 5q-SMA. These findings broaden the clinical spectrum of LRP12-related disease and support inclusion of LRP12 repeat-expansion analysis in the evaluation of genetically unresolved adult-onset lower motor neuron syndromes.}, } @article {pmid42788412, year = {2026}, author = {Wang, Y and Chen, S and Zhou, M and Lin, Z and Zhou, J and Wang, X and Wang, G and Chen, Y}, title = {Recent Progress of Single-Atom Catalysts for High-Performance Metal-Sulfur Batteries.}, journal = {Small (Weinheim an der Bergstrasse, Germany)}, volume = {}, number = {}, pages = {e75895}, doi = {10.1002/smll.75895}, pmid = {42788412}, issn = {1613-6829}, support = {2024AFB463//Natural Science Foundation of Hubei Province/ ; Q20251020//Science and Technology Research Project of Hubei Provincial Department of Education/ ; }, abstract = {Metal-sulfur (M-S) batteries have attracted immense attention as promising candidates for next-generation energy storage, owing to their ultrahigh theoretical energy density, natural abundance, and cost-effectiveness. However, practical commercialization remains impeded by inherent bottlenecks, including sluggish sulfur redox kinetics, metal dendrite growth, and the polysulfide shuttle effect. Single-atom catalysts (SACs) have emerged as a frontier solution, offering maximized atomic utilization, tunable coordination environments, and exceptional electrocatalytic activity. This review systematically summarizes recent advances in SAC-enabled M-S batteries. We first delineate the fundamental electrochemistry of diverse M-S systems, establishing a foundation for the rational design principles and state-of-the-art synthetic methodologies of SACs. Particular emphasis is placed on unraveling intrinsic catalytic mechanisms, highlighting the critical role of d-p orbital hybridization between single-atom metal centers and sulfur intermediates in lowering activation barriers and modulating bidirectional redox kinetics. Building on these mechanistic insights, we critically evaluate SAC applications across a broad spectrum-from conventional Li-S to emerging beyond-lithium systems, including Na-S, Al-S, K-S, Zn-S, and Mg-S batteries. Finally, we provide perspectives on current challenges and future directions to guide rational SAC design for high-energy-density, long-lifespan M-S electrochemistry.}, } @article {pmid42789089, year = {2026}, author = {Spillman, AM and Alsop, EB and Gittings, LM and Garcia-Mansfield, K and Piras, I and Bonfitto, A and Martinez, MN and Sharma, R and Preller, KR and Huentelman, M and Pirrotte, P and Van Keuren-Jensen, K and Sattler, R}, title = {Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in C9ORF72-frontotemporal dementia.}, journal = {Acta neuropathologica}, volume = {152}, number = {1}, pages = {}, pmid = {42789089}, issn = {1432-0533}, support = {R01NS120331/NS/NINDS NIH HHS/United States ; CTR057001//Arizona Department of Health Services/ ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *C9orf72 Protein/genetics ; *Synapses/pathology/metabolism/genetics ; *Synaptosomes/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism/pathology ; Neurons/metabolism/pathology ; Multiomics ; Proteomics ; Frontal Lobe/pathology/metabolism ; Female ; Male ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are linked neurodegenerative diseases characterized by both synaptic dysfunction and TDP-43 pathology. A hexanucleotide repeat expansion (HRE) in the C9ORF72 (C9) gene represents the most common genetic cause of FTD and ALS, yet the synapse-specific mechanisms underlying disease pathogenesis remain poorly understood. Here, we performed integrated multi-omic profiling of synaptosomes enriched from postmortem frontal cortex and patient-derived induced pluripotent stem cell (iPSC)-cortical neurons to define molecular alterations associated with C9-FTD-mediated synaptic dysfunction. Proteomic profiling of frontal cortex-derived synaptosomes identified 1,324 differentially abundant proteins (p<0.05) enriched in pathways regulating synaptic vesicle transport and synapse organization, while synaptosomal RNA sequencing revealed 2,835 differentially expressed protein-coding genes. C9-FTD iPSC-cortical neurons exhibited reductions in excitatory and inhibitory postsynaptic markers, accompanied by progressive impairment of neuronal network activity, supporting both structural and functional deficits. iPSC-derived synaptosomes recapitulated key molecular pathways observed in patient brain, revealing convergent dysregulation of synaptic signaling pathways. Comparative analyses revealed divergence between protein and RNA alterations, consistent with the disruption of regulatory processes that link RNA and protein abundance in diseased synapses. Consistent with TDP-43 loss-of-function pathology we identified cryptic exon (CE)-containing transcripts within C9-FTD frontal cortex-derived synaptosomes, including KALRN and STMN2, providing evidence that aberrantly spliced RNAs localize to synaptic compartments. Together, these findings define convergent molecular pathways underlying synapse vulnerability in both C9-FTD model systems and identify synaptic localization of CE-containing transcripts as a previously unrecognized feature of TDP-43 proteinopathy.}, } @article {pmid42789481, year = {2026}, author = {Henden, L and Chan Moi Fat, S and Smith, A and Li, I and Nicholas, TJ and Mrkela, M and O'Shaughnessy, D and Zussa, Z and Grima, N and McCann, EP and Fifita, JA and Topp, SD and Iacoangeli, A and Rowe, DB and Nicholson, GA and Dobson-Stone, C and Kwok, JB and Piguet, O and Halliday, GM and Troakes, C and Al-Chalabi, A and Shaw, CE and Roxburgh, RH and Kiernan, MC and Pamphlett, R and Liquet, B and McRae, AF and Lin, T and Laing, NG and Needham, M and Schultz, D and Mathers, S and Vucic, S and Henderson, R and McCombe, P and Henders, A and Quinlan, AR and Scotter, EL and Smith, BN and Blair, IP and Williams, KL and , }, title = {Identity-by-descent to resolve reduced penetrance and advance gene discovery in neurodegenerative disease.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag326}, pmid = {42789481}, issn = {1460-2156}, abstract = {Advances in sequencing technologies have transformed human genetics and accelerated disease gene discovery. Yet a causal mutation remains to be identified for many families with an inherited disease. Incomplete penetrance, genetic heterogeneity, and limited family history can complicate the binary classification of familial and sporadic disease. These challenges are amplified in late-onset diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), where obscured inheritance patterns limit gene discovery opportunities and can confound clinical risk assessment. We evaluated whether identity-by-descent (IBD) analysis can uncover cryptic relatedness and mitigate the impact of incomplete penetrance on disease gene mapping and clinical interpretation. Genome-wide IBD inference was performed in an integrated cross-continent cohort of 3,524 individuals of European ancestry spanning the ALS-FTD neurodegenerative spectrum. IBD identified 793 pairs of 1st-6th degree relatives (siblings to second cousins once removed), of which 31.5% were previously unrecognised and 15.8% had differing clinical diagnoses. Among individuals recorded as "sporadic", 5.5% of ALS and 15.9% of FTD were genetically related to another affected individual in the cohort, demonstrating that reduced penetrance masks a substantial proportion of heritable disease. Affected individuals with known ALS/FTD-associated genetic variants had balanced male-to-female ratios, irrespective of reported family history or IBD-inferred relatedness, whereas those without an identified disease-linked genetic variant retained the expected male predominance in ALS/FTD cohorts. IBD analysis identified multiple cross-continent founder networks for known ALS disease genes, including SOD1 and C9orf72, and created 73 new IBD-defined pedigrees from apparently unrelated probands, providing a framework for disease variant discovery in otherwise underpowered families. Using SOD1 mutation-positive families as a positive-control framework, we demonstrated that IBD-based pedigree expansion retained the known disease locus in distant relatives while reducing genome-wide candidate regions, supporting its application to unresolved ALS/FTD pedigrees. In an IBD-identified extended pedigree comprising five affected individuals, genome-wide variant filtering identified three rare variants within a chromosome 13q21.33 candidate locus shared IBD by four individuals and supported by multipoint linkage analysis. IBD-based detection of cryptic relatedness reveals genetic links between familial and apparent sporadic neurodegenerative disease, helping to resolve penetrance-related inheritance misclassification. By reconstructing extended pedigrees using IBD, this approach strengthens gene discovery and supporting variant pathogenicity while providing clinicians with clearer context for inherited risk and genetic counselling.}, } @article {pmid42789802, year = {2026}, author = {Eng, NY and Rizvi, S and LaBarbera, V}, title = {Recognition and Treatment of Concurrent Amyotrophic Lateral Sclerosis and Multiple Sclerosis.}, journal = {Rhode Island medical journal (2013)}, volume = {109}, number = {10}, pages = {11-14}, pmid = {42789802}, issn = {2327-2228}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/drug therapy/therapy ; *Multiple Sclerosis/diagnosis/complications/drug therapy/therapy ; Diagnosis, Differential ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are neurological disorders with different underlying pathophysiology but can share similar clinical features. Co-occurrence of both diseases is extremely rare with only 46 documented cases in literature to our knowledge. This case report relays the diagnosis of ALS in a patient with a decades'-long history of MS, and illustrates the importance of expanding the differential diagnosis and pursuing additional workup in a patient with overlapping progressive symptoms that can be caused by an alternate neurological etiology.}, } @article {pmid42790169, year = {2026}, author = {Zhang, B and Nan, J and Zhang, Y and Zhang, B and Ke, C and Wang, W and Wu, T and Xia, J and Yang, F and He, M and Tian, L and Yang, Z and Liang, C}, title = {Phytocannabinoid cannabidiol (CBD) in neurodegenerative diseases: From polypharmacology to drug development.}, journal = {European journal of medicinal chemistry}, volume = {320}, number = {}, pages = {119360}, doi = {10.1016/j.ejmech.2026.119360}, pmid = {42790169}, issn = {1768-3254}, abstract = {Cannabidiol (CBD) is a non-intoxicating phytocannabinoid that has attracted interest as a multi-target neurotherapeutic candidate for neurodegenerative diseases. CBD is a lipophilic terpenophenolic chemotype whose phenolic redox chemistry, membrane partitioning, cytochrome P450-mediated metabolism, and formulation-dependent exposure are central to its biological activity and translational limitations. In addition, CBD engages a broad target network relevant to neurodegeneration. Major components include cannabinoid receptors, transient receptor potential channels, peroxisome proliferator-activated receptor-γ, adenosine and serotonin signaling systems, voltage-gated calcium channels, and redox-regulatory pathways. These mechanisms converge on neuroinflammation, excitotoxicity, mitochondrial dysfunction, impaired proteostasis, and synaptic injury. Preclinical studies across models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis consistently support CBD's anti-inflammatory, antioxidant, mitochondria-protective, and neuroprotective pharmacology. The magnitude of these effects depends on dose, treatment timing, model system, and route of administration. Clinical evidence remains preliminary and is mainly symptomatic, with signals in agitation, sleep disturbance, spasticity, quality of life, and neuropsychiatric symptoms rather than proven disease modification. Key barriers to development include low and variable oral bioavailability, incomplete brain exposure data, uncertain active metabolite contributions, limited target-engagement biomarkers, and insufficient exposure-response definition. Future development of CBD and optimized cannabinoid-derived analogues will require medicinal chemistry strategies to improve potency, selectivity, metabolic stability, CNS exposure, and formulation performance. Parallel biomarker-driven clinical trials are needed to define pharmacokinetic-pharmacodynamic relationships and evaluate disease-modifying potential.}, } @article {pmid42790799, year = {2026}, author = {Abinawanto, and Sophian, A}, title = {Intrinsically disordered proteins and liquid-liquid phase separation: Molecular grammar, condensate physiology, and disease-relevant phase transitions.}, journal = {Biochimica et biophysica acta. Proteins and proteomics}, volume = {}, number = {}, pages = {141183}, doi = {10.1016/j.bbapap.2026.141183}, pmid = {42790799}, issn = {1878-1454}, abstract = {Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of proteins constitute a substantial and functionally critical fraction of the eukaryotic proteome. Through multivalent, low-affinity interactions encoded in their low-complexity domains (LCDs), IDPs drive liquid-liquid phase separation (LLPS)-a physicochemical process that produces membraneless biomolecular condensates serving as dynamic reaction hubs within cells. Recent advances have substantially refined the conceptual framework governing condensate biophysics: the phase separation coupled to percolation (PSCP) model now recognizes that condensates are viscoelastic network fluids arising from the synergy between density transitions and connectivity (percolation) transitions, rather than simple LLPS alone. This updated mechanistic understanding, combined with proteome-wide computational tools and AI-driven prediction models, is rapidly transforming the field. Physiologically, condensates regulate transcription at super-enhancers, modulate RNA metabolism in stress granules, and orchestrate ribosome biogenesis in the nucleolus. Pathologically, aberrant liquid-to-solid transitions of disease-associated IDPs-including TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia, tau in Alzheimer's disease, and α-synuclein in Parkinson's disease-represent a convergent pathomechanism across neurodegenerative proteinopathies. Post-translational modifications, particularly phosphorylation, arginine methylation, and ubiquitination, function as a dynamic regulatory code controlling condensate assembly and dissolution. The emerging paradigm of condensate-modifying therapeutics (c-mods) identifies biomolecular condensates as druggable entities and proposes four mechanistic strategies-dissolvers, inducers, localizers, and morphers-to restore normal phase behavior in disease. This review integrates the most current molecular, cellular, and biomedical insights into IDP-driven phase separation, highlighting open questions and translational opportunities.}, } @article {pmid42791200, year = {2026}, author = {Winroth, I and Krarup, C and Berntsson, H and Salvesen, L and Svenstrup, K and Nordh, E and Andersen, PM}, title = {Chronic Non-Progressive Neurophysiology in an ALS Patient Treated With Tofersen for 6 Years.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70417}, pmid = {42791200}, issn = {1097-4598}, support = {2020-0353//Hjärnfonden/ ; 2022-0309//Hjärnfonden/ ; 2025-0362//Hjärnfonden/ ; 2017-03100//Vetenskapsrådet/ ; 2012.0091//Knut och Alice Wallenbergs Stiftelse/ ; 2014.0305//Knut och Alice Wallenbergs Stiftelse/ ; 2020.0232//Knut och Alice Wallenbergs Stiftelse/ ; 2023.0460//Knut och Alice Wallenbergs Stiftelse/ ; 2025.18A//ALS Foundation/ ; //Neuroförbundet/ ; RV1035297//Västerbotten County Council/ ; RV1031455//Västerbotten County Council/ ; //Fort Knox Charity Foundation/ ; //Olsson and Olsson Charity Foundation/ ; }, } @article {pmid42791439, year = {2026}, author = {Moradi, K and Pillay, Y and Azevedo, CJ and Darki, L and Beydoun, SR}, title = {C9ORF72-associated bulbar-onset ALS in a patient with secondary progressive multiple sclerosis and conjugal ALS.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {10}, pages = {}, pmid = {42791439}, issn = {1590-3478}, } @article {pmid42791577, year = {2026}, author = {Min-Kaung-Wint-Mon, and Kida, H and Kimura, R and Mitsushima, D}, title = {Riluzole shifts glial responses to protect synapses and memory in Aβ oligomer-treated rats.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {42791577}, issn = {1742-2094}, support = {JPMJSP2111//JST SPRING/ ; 23K06348//Ministry of Education, Culture, Sports, Science, and Technology of Japan/ ; YU AI project//Yamaguchi University/ ; }, mesh = {Animals ; *Riluzole/pharmacology/therapeutic use ; Male ; *Amyloid beta-Peptides/toxicity ; *Synapses/drug effects/pathology ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neuroglia/drug effects/metabolism ; *Peptide Fragments/toxicity ; *Memory/drug effects ; *Memory Disorders/chemically induced/drug therapy/pathology ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Soluble Aβ1-42 (amyloid beta) oligomers are potent neurotoxins that disrupt synaptic function, alter glial responses, and lead to memory impairment in Alzheimer's disease (AD). Riluzole, a glutamate modulator approved for amyotrophic lateral sclerosis, reduces neuronal hyperexcitability, yet its in vivo effects on Aβ oligomer-induced cognitive dysfunction and glial alterations remain incompletely understood. Here, we investigated whether riluzole ameliorates Aβ1-42 oligomer-induced memory impairment and associated hippocampal pathology.

METHODS: Aβ1-42 oligomers were bilaterally microinjected into the dorsal CA1 region of freely moving male rats, followed by daily riluzole administration for 7 days. Then, the animals underwent a battery of behavioural tests before being sacrificed for immuno-histochemical studies. Glial engulfment of Aβ and synapse was visualized through multiplex immunohistochemistry combined with super-resolution microscopy and three-dimensional (3D) reconstruction.

RESULTS: Behavioral analyses revealed that riluzole significantly improved hippocampus-dependent memory, including contextual learning and spatial working memory, without affecting locomotor activity, anxiety-like behavior, or pain sensitivity. At the cellular level, riluzole reduced neuronal Aβ accumulation which was strongly associated with improved learning performance across individual animals. It enhanced robust Aβ internalization and lysosomal processing within astrocytes and microglia. Though Aβ-induced glial recruitment and activation persisted, riluzole enhanced morphological remodeling and shifted glial cells towards neuroprotective phenotype. Riluzole also attenuated Aβ-induced neuronal apoptosis, dendritic degeneration, and dendritic spine loss across the dorsal CA1 sublayers, and limited complement-mediated synaptic elimination by microglia.

CONCLUSION: By enhancing glial Aβ clearance and preserving synaptic integrity, riluzole effectively counteracts Aβ-driven cognitive decline. Together, these findings highlight coordinated glial remodeling as a physiologically relevant mechanism at a therapeutically actionable stage of AD.}, } @article {pmid42791674, year = {2026}, author = {Morgan-Jack, B and Katz, ML and Kick, GR and Coates, JR}, title = {Tibialis Cranialis Extrafusal and Intrafusal Myofibers and Muscle Spindle Pathology in Canine Degenerative Myelopathy.}, journal = {Animals : an open access journal from MDPI}, volume = {16}, number = {18}, pages = {}, pmid = {42791674}, issn = {2076-2615}, support = {2658//American Kennel Club Canine Health Foundation/ ; 1S10OD032246-23/NH/NIH HHS/United States ; //University of Missouri Spinal Cord Injuries/ Disease Research Program/ ; }, abstract = {Canine degenerative myelopathy (DM) is a progressive, adult-onset neurodegenerative disease, with similarities to superoxide dismutase 1 (SOD1)-associated ALS. Clinical signs of DM begin with asymmetric pelvic limb general proprioceptive ataxia and spastic paresis that progresses to flaccid tetraplegia and respiratory failure. Although pelvic limb muscle atrophy and peripheral neuropathy have been reported in DM, intramuscular SOD1 accumulation and muscle spindle pathology remain incompletely characterized. This study evaluated pathological changes in the tibialis cranialis muscle of Pembroke Welsh Corgis with early- and late-stage DM and age-matched unaffected controls. Histologic stains and immunohistochemistry were used to evaluate myofiber morphology, fiber type distribution, muscle spindle integrity, and SOD1 immunoreactivity. Compared to unaffected dogs, DM-affected dogs exhibited increased SOD1 immunolabeling, greater variability in myofiber size, altered myofiber shape and packing, and fibrosis. A progressive reduction in the percentage of type I myofibers was observed without evidence of fiber type grouping. These changes were evident during early disease and became more pronounced with disease progression. Muscle spindles exhibited late-stage disruption of intrafusal myofiber organization and marked increase in SOD1 immunoreactivty. The observed alterations suggest that the muscle pathology was, at least in part, intrinsic to the muscle, rather than being secondary to neurodegeneration. Our findings demonstrate early and progressive pathological changes in the tibialis cranialis muscle, expanding our understanding of skeletal muscle involvement in DM.}, } @article {pmid42791964, year = {2026}, author = {Wang, Z and Xia, Y and Zhang, G}, title = {Demographic Shortcuts Account for Most of the Apparent Accuracy of Four-Class Gait-Based Differential Diagnosis in Neurodegenerative Disease: An Interpretability-Driven Audit of Machine Learning on a Public Gait Benchmark.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {42791964}, issn = {2306-5354}, abstract = {Machine-learning gait studies often report high accuracy for separating neurodegenerative diseases, but rarely test whether this reflects pathology or the demographic differences that accompany disease in convenience cohorts. We audited the PhysioNet Gait in Neurodegenerative Disease Database (63 subjects: controls, Parkinson's disease [PD], Huntington's disease [HD], amyotrophic lateral sclerosis [ALS]), classifying 37 stride-rhythm features under subject-disjoint nested leave-one-subject-out cross-validation. A random forest reached a macro-averaged one-vs-rest AUROC of 0.832 (95% CI 0.759-0.904; permutation p = 0.001). Four complementary audits-demographic-only baselines, confound adjustment, feature-family ablation, and age matching-show that this overstates gait-specific discrimination: five anthropometric variables alone reached an AUROC of 0.812, statistically indistinguishable from the gait model (p = 0.701), and the de-confounded gait model (0.755) fell further to 0.585 once age was matched across groups. HD was the exception, essentially unaffected by adjustment (0.812 → 0.804) and carried by variability and long-range-correlation measures. In an independent, age-matched cohort recorded with a different sensor (n = 110, PD versus control only), the same vulnerability reappeared through a different variable: the gait model (0.828) showed no statistically significant difference from walking speed alone (0.746, p = 0.11), while age and anthropometry fell to chance; this cohort contained no HD subjects, so the HD finding remains externally unvalidated. The shortcut vulnerability generalises across cohorts; the demographic variable that drives it does not. Four-class differential diagnosis is not demonstrated on this benchmark; HD gait arrhythmicity is the one signal that withstands internal sensitivity analysis. We recommend that accuracy claims from small, demographically imbalanced gait cohorts be accompanied by this kind of audit.}, } @article {pmid42792090, year = {2026}, author = {Petito, G and Ventriglia, M and Del Fiore, VS and Cuomo, A and Cioffi, F and Manfrevola, F and Guerra, F and Bertuccini, L and Ricci, G and Cobellis, G and Lanni, A and Bucci, C and Romano, R and Senese, R}, title = {Mitochondrial Quality Control Impairment Is a Hallmark of TDP-43[G376D] ALS Patient-Derived Fibroblasts.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {15}, number = {9}, pages = {}, pmid = {42792090}, issn = {2076-3921}, support = {Grant No. P2022FBZXY//Ministry of Universities and Research/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder strongly associated with mitochondrial dysfunction and impaired proteostasis. Mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), contribute to disease pathogenesis through cytoplasmic mislocalization and aggregation. Among these, the ALS-linked TDP-43[G376D] mutation has been previously associated with oxidative stress, mitochondrial fragmentation, and impaired oxidative phosphorylation. Here, we investigated the impact of TDP-43[G376D] on Mitochondrial Quality Control (MQC) pathways using patient-derived dermal fibroblasts carrying the mutation at early and advanced disease stages, complemented by HEK293T and Neuro2a cellular models expressing mutant TDP-43. We show that TDP-43[G376D] impairs mitophagic flux, as evidenced by reduced delivery of damaged mitochondria to lysosomes. This was accompanied by pronounced disruption of mitochondrial cristae architecture and accumulation of mitochondrial DNA damage, indicating compromised mitochondrial genome integrity. Furthermore, TDP-43[G376D] induces sustained activation of the mitochondrial Unfolded Protein Response (UPR[mt]), consistent with persistent mitochondrial stress, while selectively impairing the sirtuin-dependent antioxidant branch. In parallel, activation of the Endoplasmic Reticulum UPR (UPR[ER]) was observed, indicating a coordinated engagement of cellular stress pathways. Collectively, our findings identify coordinated alterations in multiple MQC pathways associated with TDP-43[G376D] rather than isolated mitochondrial defects, supporting further investigation of these pathways in larger and disease-relevant ALS models.}, } @article {pmid42792156, year = {2026}, author = {Valerio, HP and Oliveira, V and Ferreira, SY and Pereira, IR and Palmisano, G and Massafera, MP and Bispo, VS and Prado, FM and Di Mascio, P and Medeiros, MHG}, title = {Carnosine Potentiates a Compensatory Mitochondrial-Synaptic Proteomic Response in the ALS Cerebellum.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {15}, number = {9}, pages = {}, pmid = {42792156}, issn = {2076-3921}, support = {2013/07937-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 408213/2024-8//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 2022/11334-6//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 304350/2023-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 304945/2021-8//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and chronic neuroinflammation in the brain and spinal cord, involving complex interactions between neurons and immune cells. Carnosine (β-alanyl-L-histidine) has pathophysiological relevance due to its ability to detoxify reactive carbonyl species, including α,β-unsaturated aldehydes, scavenge free radicals, and chelate zinc, and has also been proposed to function in the central nervous system as a histidine reservoir for histamine synthesis. Here, we investigated the effects of carnosine supplementation on the cerebellar proteome of SOD1[G93A] ALS rats using quantitative proteomics. Carnosine treatment extensively remodeled mitochondrial, antioxidant, and synaptic vesicle-trafficking protein networks and increased the abundance of glutamatergic and GABAergic receptor subunits relative to untreated ALS animals, with several of these changes exceeding wild-type levels. Pathway enrichment analyses identified significant up-regulation of Rab-mediated vesicle trafficking, synaptic vesicle cycling, and neurotransmitter transport/secretion pathways, alongside a partial reduction in RNA splicing and proteasomal subunits that were elevated in untreated ALS animals. Cross-comparison with the ALS-associated proteomic signature revealed that most carnosine-responsive proteins followed, rather than reversed, the direction of disease-associated change, indicating that carnosine predominantly potentiates an endogenous compensatory program rather than restoring a wild-type-like proteome. Collectively, these findings show that carnosine drives systems-level remodeling of mitochondrial and synaptic networks in the ALS cerebellum, identifying candidate compensatory pathways and supporting further functional validation of carnosine as a component of multimodal therapeutic strategies in ALS.}, } @article {pmid42792233, year = {2026}, author = {Sharbafshaaer, M and Pepe, R and Cortini, E and Biscardi, T and Notariale, R and Mesini, N and Zucchi, E and Mandrioli, J and Tessitore, A and Bergamo, P and Trojsi, F}, title = {Effects of Dietary Supplementation with Conjugated Linoleic Acid on Redox Marker Profiles and Neuroaxonal Degeneration in Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {15}, number = {9}, pages = {}, pmid = {42792233}, issn = {2076-3921}, support = {P202224WKC//European Union Next Generation EU/ ; }, abstract = {The revised ALS Functional Rating Scale (ALSFRS-R) and the blood plasma accumulation of neurofilament light chain (NfL) are key markers for tracking amyotrophic lateral sclerosis (ALS) progression. Based on recent studies indicating that dietary supplementation with conjugated linoleic acid (CLA) may boost antioxidant enzyme activity in ALS patients, in this study, ALSFRS-R scores (and subscores), NfL and thiol-bound protein (P-SH) levels, and intracellular activity of antioxidant enzymes (G6PD and GSR) were measured in ALS patients after 6 months (T6) of treatment with riluzole (R) or riluzole + CLA (R + CLA); we also investigated the correlations between these markers. At baseline (T0), G6PD activity in the R group was positively correlated with ALSFRS-R score (p < 0.001), whereas plasma P-SH levels in the R + CLA group were inversely correlated with ALSFRS-R score (p = 0.033). No significant baseline association was found between NfL levels and total ALSFRS-R score in the R group. At six months (T6), GSR and G6PD activities in the R + CLA group were significantly higher than in the R group (p < 0.05). Furthermore, a significant inverse correlation between plasma NfL levels and ALSFRS-R total score emerged at T6 exclusively in the R group (p = 0.002). Subscore analysis at T6 showed that plasma NfL levels negatively correlated with bulbar function in both groups (R: p = 0.010; R + CLA: p = 0.020) and with fine motor function in the R group (p = 0.031); whereas no significant correlation was observed for the respiratory subscore in either treatment group. These findings are consistent with an enhanced antioxidant activity associated with CLA supplementation. Overall, these preliminary exploratory results suggest that systemic redox biomarkers and plasma NfL may provide complementary, non-redundant information on distinct aspects of ALS pathobiology, though their precise temporal and mechanistic interactions require confirmation by dedicated longitudinal studies. The need for the combined use of neurodegeneration and oxidative-stress biomarkers for monitoring the progression of ALS is highlighted.}, } @article {pmid42793425, year = {2026}, author = {Mangiardi, M}, title = {Beyond Biomarkers: Reclaiming the Central Role of Clinical Neurophysiology in Neuromuscular Disorders.}, journal = {Brain sciences}, volume = {16}, number = {9}, pages = {}, pmid = {42793425}, issn = {2076-3425}, abstract = {Over the past two decades, advances in molecular genetics, immunology, neuroimaging, fluid biomarkers, and artificial intelligence have substantially transformed the diagnosis, classification, and treatment of neuromuscular disorders. However, increasing biological precision has also highlighted an important distinction between identifying disease mechanisms and characterizing their functional expression. Clinical neurophysiology occupies a specific position within this evolving diagnostic landscape by directly assessing nervous system function and providing objective information on impulse conduction, neuromuscular transmission, motor unit integrity, physiological reserve, and disease activity. Consequently, neurophysiological assessment contributes not only to diagnosis but also to differential diagnosis, longitudinal monitoring, prognostic assessment, and therapeutic evaluation. In this critical review, I examine the factors that have progressively shifted clinical neurophysiology from an interpretative clinical discipline toward a more procedural role. Using representative examples from myasthenia gravis, immune-mediated neuropathies, myopathies, and amyotrophic lateral sclerosis, I discuss how physiological information complements molecular, serological, imaging, and other biological biomarkers. I further examine the emerging role of artificial intelligence, including its potential for automated signal analysis and quantitative assessment, as well as current limitations related to generalizability, validation, and overreliance on pattern recognition. I propose a complementary conceptual framework in which biological and molecular approaches characterize disease mechanisms, while clinical neurophysiology defines their functional expression and clinical relevance in the individual patient. Within this framework, clinical neurophysiology should not be considered an alternative to precision medicine, but an integrated physiological dimension of it, connecting biological characterization with clinically actionable functional information.}, } @article {pmid42793754, year = {2026}, author = {Quint, E and Segev, L and Gaziants, V and Netz, U and Reshef, A and White, I and Hagani, Y and Shenker, U and Lerman, G and Fishman, I and Policker, S and Shor, E and Tulchinsky, H and Pinsk, I and Miller, R and Bar-Zakai, B and Zmora, O and Wasserberg, N and Ben-David, M and Knowles, C}, title = {Early Post-Operative Diagnosis of Anastomotic Leak by Local Electrophysiological Parameters: Multicenter Pilot Study.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {16}, number = {18}, pages = {}, pmid = {42793754}, issn = {2075-4418}, support = {//Exero Medical/ ; 75615//Israeli Innovation Authority/ ; }, abstract = {Background: Morbidity associated with anastomotic leak (AL) can be reduced by timely detection. Local electrophysiological parameters are highly sensitive to pathophysiological processes (inflammation/ischemia) underlying AL and may enable early post-op monitoring ahead of clinical signs. A new approach to early leak detection includes post-operative measurement of bioelectric activity of the GI tract. The method has been implemented in a medical device that uses electrodes embedded in a standard surgical drain to continuously monitor local bowel myoelectric activity following GI surgery. Methods: A multicenter pilot study evaluated the performance of the device to support detection of clinically recognizable anastomotic leaks on post-operative day 3. The device's technology collected data that an algorithm classified to predict AL. Data were collected for a duration of 3-10 days, while the surgical drain was in place (without affecting routine care). Pilot endpoints were safety and performance analyses: sensitivity and specificity. Results: Fifty patients from 6 medical centers (mean age: 63.6 ± 13.3 years; 38% male) undergoing elective anterior resection (laparoscopic (N = 26), robotic (N = 16), open (N = 8)) for cancer (N = 44), diverticulitis (N = 4), and rectal prolapse (N = 2) were included. Average anastomotic height was 9 ± 5 cm from the anal verge. Grade C ALs were observed in 6.0% (N = 3) of the patients, resulting in increased hospitalization time (6.4 ± 2.4 days with no leak vs. 15.0 ± 7.9 days with Grade C leak). In this N = 50 cohort, the device had 100% sensitivity and 100% specificity at POD3 in prediction of Grade C leaks. Given the small number of events (three Grade C leaks, seven leaks overall), these results are preliminary. No device-related serious adverse events were observed, and the standard drain form factor contributed to positive usability feedback. Conclusions: Pilot data suggest that the bioelectric sensing drain device is safe and warrants further evaluation as a potential adjunct for AL detection. The small study sample size and wide confidence intervals for key outcomes require confirmation in a pivotal diagnostic accuracy study with a fixed thresholding algorithm.}, } @article {pmid42794171, year = {2026}, author = {Valencic, I and Guida, F and Andreozzi, L and Corsini, I and Battelli, E and Lanari, M and Zama, D}, title = {From Triage to Outcome: How ED Parameters and Comorbidities Shape Pediatric Critical Illness Prognosis.}, journal = {Children (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {42794171}, issn = {2227-9067}, abstract = {Objective: To describe the characteristics of children presenting with red-code triage to a tertiary Pediatric Emergency Department (PED) and to evaluate the association between variables at PED presentation and hospitalization outcomes. Methods: This retrospective study included patients aged 0-16 years presenting to the PED with highest level of urgency at triage between 2021 and 2025. Demographic, clinical, laboratory, and outcome data were extracted from electronic medical records. Vital signs at presentation were categorized by severity using age-adjusted percentiles and established thresholds. Outcomes included hospital admission, PICU admission, need for advanced vital support (ALS) within 7 days, and hospitalization at 7 days. Univariable and multivariable logistic regression analyses were performed to identify predictors of outcomes. Results: Critically ill pediatric presentations accounted for 0.23% of PED attendances. Chronic comorbidities were present in 56.21%, mainly neuropsychiatric conditions. Seizures (33.99%) and respiratory conditions (25.49%) were the leading causes. Most patients were hospitalized (56.86% in ward, 20.26% in PICU). Invasive ventilation was required in 7.18% of patients and inotropic support in 3.92%. Increasing age was associated with significantly lower odds of both hospital admission (OR: 0.876, 95% CI: 0.783-0.976; p = 0.017) and PICU admission (OR: 0.890, 95% CI: 0.793-0.983; p = 0.031). Conversely, the need for advanced life support in the ED was independently associated with PICU admission (OR: 3.247, 95% CI: 1.345-7.997; p = 0.009). None of the evaluated ED clinical parameters were independently associated with 7-day outcomes. Conclusions: Our cohort demonstrates a high prevalence of chronic comorbidities, confirming their growing relevance in hospital resource allocation. Life-saving interventions were rarely required, underscoring the need for strategies to maintain medical competencies. Younger age was associated with an increased risk of hospitalization. Monitoring of clinical parameters in the ED, although a useful complementary measure, cannot replace a comprehensive medical assessment of the underlying condition.}, } @article {pmid42794442, year = {2026}, author = {Jung, C}, title = {Batch- and Composition-Controlled Reanalysis of Bulk and Single-Nucleus Transcriptomes Reveals Co-Enrichment of Glial Complement and of Translational Signatures in Parkinson's Disease and Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {18}, pages = {}, pmid = {42794442}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Parkinson Disease/genetics/metabolism/pathology ; *Transcriptome/genetics ; *Neuroglia/metabolism ; Gene Expression Profiling ; Mesencephalon/metabolism ; }, abstract = {Failure of axonal maintenance is proposed as a mechanism shared by Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). We reanalysed three public post-mortem resources under one rule set: bulk RNA-seq of 1242 samples from 319 donors (GSE153960) and midbrain single-nucleus RNA-seq (GSE157783, GSE178265). As a contributing project, a second batch variable tracked diagnosis in both cord segments and was completely separated from it in three cortical regions, which we removed. Adjusting for this removed a third of the naive differential expression. In ALS cord, the dominant depleted program was microtubule-based axonal transport (normalised enrichment score -2.40, FDR < 0.001); a regeneration-associated panel reached significance in none of ten fits. An ALS cord signature carried into the PD midbrain and scored highest on microglia in all 11 donors (+3.55 versus +0.73 next). Of 86 gene sets significant in both diseases, a translation block contained the GCN2 amino-acid-deficiency response. Both axes are compartment-level: within PD microglia, the complement panel is null (+0.21, p = 0.57). No GCN2 activity was measured, and the ALS cord is compared against PD midbrain. The axes that survive this control are glial and translational; the axonal question is not adjudicable in PD, where the panel score tracks dopaminergic content.}, } @article {pmid42794615, year = {2026}, author = {Hedström, AK}, title = {Interpreting Viral Associations in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {27}, number = {18}, pages = {}, pmid = {42794615}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/virology ; Animals ; *Virus Diseases/complications/virology ; Parkinson Disease/virology ; Amyotrophic Lateral Sclerosis/virology ; Herpesvirus 4, Human ; }, abstract = {Viral infections have been associated with multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), but the associations may reflect different relationships to the disease process. This review evaluates evidence for viral involvement in disease initiation, modification of established disease, impaired viral control secondary to disease or treatment, and incidental detection. The strongest temporal evidence concerns Epstein-Barr virus (EBV) and MS. Prospective data place EBV seroconversion before clinical onset and the first observed increase in serum neurofilament light chain, while mechanistic studies link EBV infection, B-cell biology, and CNS-directed immunity. However, evidence that ongoing EBV activity modifies established MS remains limited. In AD, experimental studies support interactions between herpesviruses and AD-associated proteins, while the reduced incidence of all-cause dementia after herpes zoster vaccination suggests that viral or immunological pathways may be modifiable, without establishing that a specific herpesvirus initiates AD. Viral associations in PD rely mainly on epidemiological, experimental, and postmortem findings. Human pegivirus detection in a subset of PD brains remains a candidate association requiring independent confirmation and evidence of biological activity. Evidence in ALS is similarly limited. Enterovirus detection has been inconsistent, and altered human endogenous retrovirus K (HERV-K) expression in postmortem tissue does not establish an acquired viral infection. Stronger inference across these diseases will require longitudinal studies relating viral activity and antiviral immunity to subsequent disease-related changes, together with intervention studies that document the intended effect on the implicated viral process and separately assess subsequent disease risk or progression.}, } @article {pmid42794664, year = {2026}, author = {Hall, B and Ebrahim, YM and Sharpe, JL and Makhija, S and Ellis, BCS and Wong, KE and Walker, H and Yagüe-Capilla, M and Timmons, HO and Bradley, A and Nightingale, E and Ross, R and Allen, CF and Gatto, N and Garland, H and Soni, N and Kolb, SJ and Highley, JR and Hautbergue, GM and Rudd, SG and West, RJH and Shaw, PJ and Allen, SP}, title = {Adenosine Deaminase-Mediated Purine Dysfunction Leads to DNA Repair Inhibition and Senescence in Sporadic Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {18}, pages = {}, pmid = {42794664}, issn = {1422-0067}, support = {SBF005\1064//University of Sheffield/ ; Allen/Jun23/964-793 and Allen 887-791//Foreign, Commonwealth & Development Office/ ; BRC-203321//NIHR Sheffield Biomedical Research Centre/ ; NF-SI-0617-10077//National Institute for Health and Care Research/ ; AMBRoSIA PJS 972-797)//MNDA 'A Multicentre Biomarker Resource Strategy' in ALS/ ; TJ2022-0063//Swedish Childhood Cancer Foundation/ ; 23-2782-Pj and 26-5197-IA-SIA//Swedish Cancer Society/ ; MR/W00416X/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Purines/metabolism ; *Adenosine Deaminase/metabolism/genetics ; *DNA Repair ; *Cellular Senescence ; Astrocytes/metabolism ; Female ; Male ; DNA-Binding Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the death of motor neurons leading to paralysis and death generally 3-5 years post-symptom onset. ALS is a cell- and non-cell-autonomous disease, with glia such as astrocytes influencing disease pathology and progression. Our laboratory has previously identified purine metabolism dysfunction in induced neural progenitor cell-derived astrocytes (iAstrocytes) from sporadic ALS (SALS) cases, driven by loss of the enzyme adenosine deaminase (ADA). Here, we have demonstrated that loss of ADA, along with changes to ecto-5'-nucleotidase and hypoxanthine-guanine phosphoribosyl transferase led to disruption in purine metabolite levels, linked to the level of the ADA enzyme. These alterations were recapitulated in SALS CSF and post-mortem tissue, with ageing and sex affecting purine metabolite levels downstream of ADA and positively correlating with disease progression. Loss of ADA led to reduced 53BP1-mediated DNA repair and increased P16 levels, which was recapitulated in control iAstrocytes via ADA inhibition. Our findings indicate that TDP43 dysfunction drives impairment of ADA-mediated purine metabolism in vitro, leading to downstream effects that include DNA damage, likely through inhibition of DNA repair mechanisms, and the induction of cellular senescence. Furthermore, these results suggest that therapeutic targeting of the ADA pathway may help slow ALS disease progression.}, } @article {pmid42795978, year = {2026}, author = {Yilmaz, TU and Özer, A and Yildar, M and Aktaş, H and Bati, B and Can, MG and Sökmen, BK and Kirimlioğlu, H and Karakayali, H}, title = {Incidental/Misdiagnosed Intrahepatic Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma in Patients Undergoing Living Donor Liver Transplantation.}, journal = {Journal of clinical medicine}, volume = {15}, number = {18}, pages = {}, pmid = {42795978}, issn = {2077-0383}, abstract = {Background/Objectives: Mixed hepatocellular-cholangiocarcinoma and intrahepatic cholangiocarcinoma (CCA) are increasingly reported in patients with cirrhosis. Traditionally, these tumor types have not been considered indications for liver transplantation. We aimed to present our single-center experience for incidental CCA following liver transplantation. Methods: Among the 985 living donor liver transplantations, 261 cases were initially diagnosed as hepatocellular carcinoma. We retrospectively reviewed demographic data, preoperative radiological findings, pathology results, and postoperative outcomes. We classified tumors according to the Goodman classification. Results: Cholangiocarcinoma was identified in the explant pathology of 18 patients. According to the Goodman classification, five patients (27%) had type 1 tumors; eight (44.4%) had type 2 tumors; and five (27.8%) had sole CCA lesions. Tumor recurrence occurred in six patients (33.3%). The mean survival time was 61.6 ± 12 months. The mean disease-free survival was 10.67 ± 5.7 months. Disease-free survival times for Goodman type I, type II, and sole cholangiocarcinoma were 14.00 ± 5.57, 8 ± 5.66, and 6.00 ± 0.00 months, respectively. The 1-year and 5-year survival rates were 88% and 55%, respectively. Four patients died due to CCA; the remaining deaths were due to sepsis, COVID-19, amyotrophic lateral sclerosis, and lung squamous cell carcinoma. Conclusions: The misdiagnosed/incidental cholangiocarcinoma in transplanted patients with cirrhosis is rarely seen with high recurrence rates. Although transplant oncology is gaining prominence, preoperative evaluation and postoperative follow-up remain important.}, } @article {pmid42796657, year = {2026}, author = {Shimamura, MI and Satoh, K}, title = {Prion-like Protein TDP-43: Mechanisms, Diagnosis, and Therapeutic Prospects.}, journal = {Pathogens (Basel, Switzerland)}, volume = {15}, number = {9}, pages = {}, pmid = {42796657}, issn = {2076-0817}, support = {JPJS00420240024.//JSPS Program for Forming Japan's Peak Research Universities/ ; JP26dk0207077//Japan Agency for Medical Research and Development/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; *TDP-43 Proteinopathies/diagnosis/therapy/metabolism/genetics ; Animals ; *Prions/metabolism ; }, abstract = {TDP-43 proteinopathies, encompassing amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic-predominant age-related TDP-43 encephalopathy (LATE), represent a heterogeneous spectrum of devastating neurodegenerative disorders. For decades, the diverse clinical presentations of these diseases have complicated antemortem diagnosis and hindered the development of disease-modifying therapies. However, recent breakthroughs in basic science are beginning to address these clinical barriers, although substantial hurdles to practical clinical application remain. Structural elucidation via cryo-electron microscopy (Cryo-EM) has shattered the single-protein amyloid dogma by revealing that TDP-43 can form hetero-amyloid filaments with ANXA11, thereby providing a molecular basis for pathological strain diversity. Concurrently, the pathogenic focus has shifted toward nuclear loss of function, which triggers a systemic "RNA crisis" characterized by aberrant alternative polyadenylation (APA) and cryptic exon inclusion (e.g., STMN2, UNC13A). Crucially, this metabolic collapse is profoundly exacerbated by patient-specific genetic risk factors, acting synergistically in a "two-hit" model of neurodegeneration. To translate these findings to the clinic, next-generation diagnostic tools are emerging. Integrating neuron-derived extracellular vesicle (EV) isolation with Seed Amplification Assays (SAAs) holds promise to help overcome the structural camouflage that limits current PET imaging, potentially offering ultra-sensitive, functional strain identification in biofluids. While these structural and diagnostic milestones provide a strong foundation for precision medicine, major challenges in assay standardization and clinical validation must be addressed. Advanced therapeutic strategies-namely, splice-switching antisense oligonucleotides (ASOs) that directly restore RNA metabolism, combined with the targeted suppression of neuronal hyperexcitability-are now entering clinical trials. This review synthesizes how decoding the structural and RNA-metabolic complexities of TDP-43 is paving a promising pathway from bench to bedside, while critically discussing current translational limitations.}, } @article {pmid42797450, year = {2026}, author = {Castello-Guillen, A and Garrido-Reig, M and Caplliure-Llopis, J and Vega-Bello, MJ and Almela, C and de la Rubia Ortí, JE}, title = {Efficacy of Curcumin in Neurodegenerative Diseases: From Pharmacokinetic Barriers to Advanced Delivery Systems.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {9}, pages = {}, pmid = {42797450}, issn = {1424-8247}, abstract = {Background and Objectives: The main neurodegenerative diseases (NDs)-Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)-represent a growing global health burden with no available disease-modifying therapies. Curcumin, a polyphenol from Curcuma longa, is a promising candidate owing to its pleiotropic antioxidant, anti-inflammatory, and neuroprotective profile observed mainly in preclinical models, but the poor oral bioavailability (<1%) and negligible BBB penetration (<0.1%) have substantially limited curcumin's clinical translation. The objective of this work was to critically examine the therapeutic potential of curcumin in NDs, focusing on advanced drug delivery systems (DDSs) designed to overcome its pharmacokinetic barriers. Methods: This is a narrative, non-systematic review of PubMed/MEDLINE, Scopus, and Web of Science. The review is organized around five complementary thematic areas selected to span the full translational pipeline of curcumin in neurodegeneration, from mechanistic rationale to clinical applicability: (1) molecular mechanisms, addressing the pleiotropic activities that justify therapeutic interest; (2) pharmacokinetic barriers, the principal obstacle to clinical translation; (3) the evolution of drug delivery systems (DDSs), documenting the technological strategies developed to overcome these barriers; (4) disease-specific applications, evaluating the available evidence across the four main NDs; and (5) translational limitations, identifying the methodological and regulatory gaps that must be closed to enable clinical implementation. Results: Curcumin exhibits neuroprotective activity in preclinical models of the four NDs analysed, acting on six interconnected mechanisms and the gut-brain axis. Four generations of DDSs have been developed, from phytosomes and clinically used lipid dispersions (Meriva[®], BCM-95[®], Longvida[®], and Theracurmin[®]) to fourth-generation systems (biomimetic nanoparticles, MOFs, microneedles, 3D scaffolds, hydrogels, and carbon dots) that substantially increase the bioavailability in preclinical studies. Combination strategies, such as curcumin with resveratrol and dutasteride, show preliminary clinical signals in ALS. However, clinical translation remains limited: over 80% of positive animal findings have not been replicated in humans, formulation characterization is frequently incomplete, and most trials lack CNS-exposure biomarkers. Importantly, most of the reported bioavailability claims are based on total curcumin measurements (parent aglycone plus its inactive Phase II conjugates) rather than the active aglycone alone, a methodological limitation that should be considered when interpreting the magnitude of the bioavailability improvements reported for novel formulations. Conclusions: Curcumin exhibits pleiotropic neuroprotective activity in preclinical models of AD, PD, MS, and ALS, mediated by interconnected antioxidant, anti-inflammatory, anti-amyloidogenic, mitochondrial, and gut-brain axis mechanisms. However, its poor systemic bioavailability (<1%), minimal blood-brain barrier penetration, and extensive first-pass metabolism have limited clinical translation. Advanced drug delivery systems (including lipid-based carriers (liposomes, solid lipid nanoparticles, and nanostructured lipid carriers), polymeric nanoparticles (PLGA and chitosan), and bioinspired vesicles (exosomes)) are essential in order to overcome these barriers. Nevertheless, the formulation heterogeneity, limited long-term safety data, and reliance on preclinical models remain major obstacles; a definitive clinical translation will therefore require well-characterized formulations validated in phase II/III trials with cerebrospinal fluid exposure biomarkers, the pharmacokinetic monitoring of active aglycone (rather than total curcumin including inactive conjugates), and adaptive trial designs in neurological populations.}, } @article {pmid42799464, year = {2026}, author = {Koepp, W and Sochor, B and McReynolds, D and Chavez, T and Noack, M and Sriramoju, RV and Coffey, AH and Wang, Y and Henn, E and Sambale, AK and Euchler, E and English, D and Schlünzen, F and Schaible, E and Zhu, C and Koyiloth Vayalil, S and Roth, SV and Hexemer, A}, title = {Toward Unified Autonomous Scattering Experiments: A Cross-Facility Case Study at ALS and PETRA III.}, journal = {Photon science}, volume = {1}, number = {5}, pages = {328-340}, pmid = {42799464}, issn = {2998-8799}, abstract = {Autonomous experiments rely on the integration of control, data acquisition, analysis, and decision-making frameworks. While such systems have been demonstrated at individual facilities, adapting them to additional instruments remains challenging due to differences in local infrastructure. We present a modular workflow that connects existing open-source tools for data access (Tiled), workflow orchestration (Prefect), analysis and visualization (pyFAI, Plotly Dash), and Gaussian-process-based adaptive sampling (gpCAM) into a unified framework for autonomous scattering experiments. The same configuration operates across two synchrotron beamlines (ALS 7.3.3 and PETRA III P03) with only minimal facility-specific adjustments, as shown in proof-of-concept demonstrations. This validates that a consistent design emphasizing modularity and shared interfaces can ease deployment across diverse experimental environments. The resulting framework provides a flexible foundation for extending autonomous control and analysis capabilities beyond a single beamline or instrument.}, } @article {pmid42799858, year = {2026}, author = {Patel, M and Das, S and Kumari, AP and Kumar, A}, title = {Insights into X-linked Dystonia-Parkinsonism and Spinocerebellar Ataxia type 36 Through the Lens of Amyotrophic Lateral Sclerosis/Frontotemporal Dementia.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42799858}, issn = {1559-1182}, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Dementia/genetics/pathology ; *Genetic Diseases, X-Linked/genetics/pathology ; *Spinocerebellar Ataxias/genetics/pathology ; *Dystonic Disorders/genetics/pathology ; }, abstract = {The abnormal expansion of repetitive DNA sequences falls within the spectrum of neurological conditions driven by dual pathogenic pathways of RNA toxicity and protein toxicity. Within this spectrum, hexanucleotide repeat disorders (HRDs) represent a rare but important subgroup: C9orf72-amyotrophic lateral sclerosis/frontotemporal dementia (C9orf72-ALS/FTD), X-linked dystonia-parkinsonism (XDP) and spinocerebellar ataxia type 36 (SCA36), unified by the presence of expanded intronic repeats capable of forming non-canonical nucleic acid structures. Despite this shared repeat architecture, they differ in critical molecular and genetic respects: C9orf72-ALS/FTD is hallmarked by TDP-43 aggregation and prominent proteinopathy; SCA36 lacks TDP-43 pathology entirely; and XDP uniquely harbors a SINE-VNTR-Alu (SVA) retrotransposon insertion within the expanded locus and follows an X-linked recessive inheritance pattern. Among these, C9orf72-ALS/FTD is relatively well characterized, with established pathogenic mechanisms including G-quadruplex (G4) formation, dipeptide repeat (DPR) protein toxicity, RNA foci formation, and downstream cellular disruptions. The molecular mechanism underlying SCA36 and XDP remains comparatively less characterized. Given the mechanistic overlap with ALS/FTD, downstream disruptions such as RNA toxicity, mitochondrial dysfunction, impaired DNA repair and proteasomal dysfunction could similarly result from these core molecular processes. However, direct experimental evidence supporting these mechanisms in SCA36 and XDP remains limited. This review compares established, emerging and hypothetical mechanisms across HRDs to distinguish shared pathogenic pathways from disease-specific molecular features. Through horizontal comparison, this review identifies opportunities and limitations for translating ALS/FTD therapeutics to XDP and SCA36, establishing a unified analytical framework for mechanistic research and clinical intervention in rare repeat expansion disorders.}, } @article {pmid42799915, year = {2026}, author = {Kassubek, J and Müller, HP}, title = {Potential Roles of Neuroimaging in Motor Neuron Disease.}, journal = {Current neurology and neuroscience reports}, volume = {26}, number = {1}, pages = {}, pmid = {42799915}, issn = {1534-6293}, mesh = {Humans ; *Motor Neuron Disease/diagnostic imaging ; *Neuroimaging/methods ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; *Brain/diagnostic imaging ; }, abstract = {PURPOSE OF REVIEW: The review is intended to summarize and discuss the increasing roles and perspectives of neuroimaging in the clinical and scientific work-up of amyotrophic lateral sclerosis (ALS) and other motor neuron diseases (MND).

RECENT FINDINGS: The applications of magnetic resonance imaging (MRI) and positron emission tomography (PET) identify characteristic disease-specific patterns especially for ALS including its clinical subtypes. Guided by neuroanatomical pattern stratification, these MND-associated alterations could be detected by dedicated analysis parameters from MRI, including T1-weighted structural imaging and microstructural diffusion tensor imaging, in combination with additional MR techniques, to act as diagnostic and monitoring biomarkers. Imaging in MND increasingly makes use of machine learning-based analysis methods. The conceptualization of (neuro-)imaging in ALS and other MND encompasses multiparametric technical approaches, also of regions outside the central nervous system, together with aspects of disease-specific pathophysiology which will further advance the field in future applications.}, } @article {pmid42800647, year = {2026}, author = {Ranxhi, B and LeWitt, PA and Tsou, WL and Todi, SV}, title = {Polyamines across neurodegenerative proteinopathies.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107629}, doi = {10.1016/j.nbd.2026.107629}, pmid = {42800647}, issn = {1095-953X}, abstract = {Polyamines (PAs) are evolutionarily conserved metabolites that connect protein quality control with lysosomal, mitochondrial, and redox homeostasis. Their metabolism is situated at a critical intersection of cell-sustaining and neurodegenerative pathways. Here, we synthesize evidence across Alzheimer's disease, Parkinson's disease, polyglutamine repeat disorders, amyotrophic lateral sclerosis, and multiple system atrophy, each of which differ in vulnerability to changes in PA metabolism. Although previous reviews have investigated polyamines in individual neurodegenerative disorders, few have compared their roles across the broader spectrum of neurodegenerative proteinopathies. Here, we address this gap by synthesizing evidence across multiple diseases to examine how PAs influence disease-associated protein aggregation and clearance, and how these effects depend on PA species, concentration, cellular context, disease stage, subcellular localization, redox state, and lysosomal and mitochondrial capacity. Human tissue and biofluid studies report disease-associated changes in PA metabolites, pathway enzymes, and transporter remodeling, as a function of neurodegenerative disorders. Mechanistic studies reveal that spermidine and spermine can alter the assembly, condensation, compartmentalization, and clearance of various neurotoxic proteins, whereas the effects of putrescine are more system- and concentration-dependent. These effects engage both shared pathways and distinct mechanisms, depending on protein identity, cell type, and subcellular location. Curiously, PA manipulation may be protective in one context yet harmful in another. The framework that we propose can distinguish adaptive remodeling from pathogenic dysregulation and can guide disease-relevant therapeutic strategies.}, } @article {pmid42800863, year = {2026}, author = {Alsfouk, BA and Al-Khatee, LA and Al Kamaly, O and Tantawy, MA and Khashoqji, MM and Halim, MK and Barghash, SS and Abbas, AEF}, title = {Holistically benchmarked optimization-assisted green spectrophotometric-chemometric approach for simultaneous determination of piroxicam and venlafaxine in pharmaceutical formulations and spiked human plasma.}, journal = {BMC chemistry}, volume = {20}, number = {1}, pages = {}, pmid = {42800863}, issn = {2661-801X}, support = {PNURSP2026R142//Princess Nourah Bint Abdulrahman University/ ; }, abstract = {The recent clinical introduction of the piroxicam (PIR) and venlafaxine hydrochloride (VEN) combination has highlighted the need for analytical methodologies capable of simultaneously quantifying both drugs while minimizing the environmental burden of routine pharmaceutical analysis. To date, only a chromatographic method has been reported for this purpose, which is associated with relatively high organic solvent consumption, greater instrumental complexity, and increased energy requirements. A green UV spectrophotometric platform integrated with chemometric modeling was therefore established for the concurrent determination of PIR and VEN in pharmaceutical formulations and as a proof-of-concept application to spiked human plasma. Spectral measurements were performed using a water-ethanol (1:1, v/v) solvent system, whereas methanol was employed solely for plasma protein precipitation. Experimental design efficiency was enhanced by combining Brereton's multilevel calibration design with a Maximin Distance Design (MMD) for validation sample selection, enabling representative calibration and validation datasets to be generated with a reduced number of experimental mixtures. Severe spectral overlap between the two analytes was effectively resolved using six well-established chemometric approaches: CLS, PCR, PLS, GA-PLS, FA-PLS, and MCR-ALS. Among the investigated models, MCR-ALS showed the best overall numerical performance, achieving correlation coefficients of up to 0.9998 for pharmaceutical formulations and 0.9996 for spiked human plasma. The corresponding limits of detection were 0.125 and 0.029 µg mL[-1] for VEN and PIR, respectively, in pharmaceutical formulations, and 0.245 and 0.058 µg mL[-1] in spiked human plasma. Across the investigated concentration ranges, the proposed method also exhibited satisfactory accuracy and precision. The sustainability performance of the analytical platform was evaluated using multiple complementary metrics, with the pharmaceutical assay compared with the previously reported chromatographic procedure according to the evaluated criteria. The proposed pharmaceutical spectrophotometric assay showed a more favorable sustainability profile according to the evaluated criteria, including environmental and practical applicability dimensions. The application to spiked human plasma provided a proof-of-concept assessment of matrix applicability. Nevertheless, additional investigations involving incurred clinical specimens and full bioanalytical validation are required before the methodology can be considered suitable for routine clinical practice or pharmacokinetic studies.}, } @article {pmid42801200, year = {2026}, author = {Liu, R and Yue, H and Li, X and Sun, W and Yang, J}, title = {The Versatile Roles of Exosomes in Neurodegenerative Disorders: From Pathological Mechanism and Diagnostic Biomarkers to Therapeutic Application.}, journal = {Drug design, development and therapy}, volume = {20}, number = {}, pages = {631482}, pmid = {42801200}, issn = {1177-8881}, mesh = {Humans ; *Exosomes/metabolism/pathology ; *Neurodegenerative Diseases/diagnosis/drug therapy/metabolism/pathology/therapy ; Biomarkers/metabolism/analysis ; Animals ; }, abstract = {Neurodegenerative diseases are characterized by cognitive or motor impairments resulting from the progressive degeneration of neurons or myelin sheaths. Currently, the majority of these disorders remain incurable, leading to significant detriments in patients' quality of life and imposing substantial economic burdens. Exosomes are a type of extracellular vesicles secreted by cells into the extracellular space, typically range from 30 to 150 nanometers in diameter. These vesicles have been identified in a variety of cell types and can participate in various physiological and pathological processes, including intercellular transport of biomolecules, signal transduction, immune modulation, tissue repair, facilitation of tumor metastasis, and evasion of immune surveillance by cancer cells. In recent years, the potential applications of exosomes in neurodegenerative diseases have garnered increasing attention. Their roles encompass early diagnostic biomarker functions, vehicles for drug delivery and therapeutic agents, mediators in the propagation of pathogenic proteins, and regulators of neuroinflammatory responses. In this review, we try to aims to synthesize recent progress in exosome isolation techniques, elucidate the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), and examine the diagnostic and therapeutic applications of exosomes within these conditions. Furthermore, it addresses current limitations in exosome-based applications and explores potential strategies to overcome these challenges. The insights of this review may provide the research directions and guidance for future related researchers in these fields.}, } @article {pmid42802700, year = {2026}, author = {Chaudhary, V and Kataria, P and Yadav, K and Kumar, V and Prakash, A}, title = {Conformational insights into the unfolding pathway of RNA recognition motif (RRM) domain of TAF15 associated with amyotrophic lateral sclerosis.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/07391102.2026.2735392}, pmid = {42802700}, issn = {1538-0254}, abstract = {The RNA recognition motif (RRM) domain of TAF15 protein plays an essential role in RNA binding and regulation of diverse cellular processes. However, the molecular mechanism underlying its structural stability and folding behaviour associated with disease state remains poorly understood. Herein, we performed an extensive molecular dynamics (MD) simulations study to investigate the conformational dynamics and unfolding pathway of the TAF15-RRM domain in 8 M urea. The elevated temperatures (300-500 K) were employed to accelerate the unfolding and capture different conformational states. The results from 3 μs cumulative MD simulations revealed that unfolding proceeds through stable, denaturant/temperature-accelerated partially unfolded intermediate ensembles. The native conformation of TAF15-RRM largely confined to marginal perturbation in urea at 300-350 K. The major conformational changes occurred in urea at 400-450 K, revealing distinct conformational ensembles corresponding to native (N), intermediate (I), and unfolded (U) populations. Whereas the native structure of protein was lost abruptly within ∼0-50 ns, at 500 K. At 400 K, the unfolding dynamics restricted to I-state with the loss of ∼55% native contacts. All three (N, I and U) stages are captured more distinctly in urea at 450 K. Furthermore, the secondary structure analyses demonstrated a higher susceptibility of β-sheets toward urea-induced unfolding, accompanied by the transient structures of non-native extended β-conformations and helical intermediates. FELs analyses suggest that the I-state populations are heterogeneous in nature which are largely stabilized by the partial retention and rearrangement of native H-bonds. These results thus highlight conformational signatures of unfolding intermediates that, by analogy with aggregation-prone intermediates characterized in other proteins, may be relevant to TAF15 self-assembly.}, } @article {pmid41688669, year = {2026}, author = {Ishiguro, A}, title = {Impact of G-quadruplex RNA oxidation on its conformational dynamics and interaction with ALS-associated TDP-43.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41688669}, issn = {2045-2322}, support = {22K07032//Japan Society for the Promotion of Science/ ; }, mesh = {*G-Quadruplexes ; *DNA-Binding Proteins/metabolism/chemistry/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; Oxidation-Reduction ; Guanine/analogs & derivatives/chemistry/metabolism ; *RNA/chemistry/metabolism ; Protein Binding ; Nucleic Acid Conformation ; Hydrogen Bonding ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective degeneration of motor neurons. The primary cause of ALS, whether sporadic or familial, is aging, and recent studies have shown that age-related RNA oxidation plays a role in the early stages of disease onset. This study focused on the vulnerability of G-quadruplex (G4) structures to oxidation and aimed to elucidate the molecular mechanism underlying the conformational changes and their interactions with the binding protein TDP-43. Guanine within G4 structures has a low redox potential, and its substitution with 8-oxoguanine (8OG) can induce structural instability and impair its function as a protein binding signal. In addition, synthetic G4-RNAs modified by oxidation were examined, and results showed that conformational changes are due to different hydrogen bond arrangements, 8OG-A mismatches, and intermolecular G4 formation. The interaction between G4 and TDP-43 decreased in proportion to the substitution rate of 8OG. Furthermore, ALS-associated mutant proteins exhibited reduced binding affinity for oxidized G4s compared with the wild-type. Considering that intra-axonal mRNA transport mediated by G4-binding proteins is essential for the survival and activity of motor neurons, this study will provide important insights into the molecular mechanisms underlying the onset of ALS with aging.}, } @article {pmid41689476, year = {2026}, author = {Howe, SL and Holdom, CJ and McCombe, PA and Henderson, RD and Steyn, FJ and Ngo, ST}, title = {Systemic immune-metabolic interactions in patients with amyotrophic lateral sclerosis: correlations of plasma cytokines with metabolic status.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {581-591}, doi = {10.1080/21678421.2026.2627902}, pmid = {41689476}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/blood/metabolism ; Female ; Male ; *Cytokines/blood ; *Energy Metabolism/physiology ; Middle Aged ; Aged ; Chemokine CCL2/blood ; Biomarkers/blood ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disease influenced by multiple biological processes. Altered energy metabolism, particularly hypermetabolism, is observed in some people living with ALS (plwALS) and is associated with faster progression. The mechanisms underlying this metabolic phenotype remain unclear. Inflammation has been proposed as a contributing factor. We examined whether plasma cytokines, as markers of systemic inflammation, are associated with energy expenditure in plwALS.

METHODS: Plasma samples from 77 plwALS and 90 non-neurodegenerative controls were analyzed using a multiplex immunoassay quantifying 14 cytokines. Cytokine concentrations were compared between groups and examined in relation to body composition, resting energy expenditure, and functional capacity as inferred by the ALSFRS-R.

RESULTS: Interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) concentrations were higher in plwALS than in controls prior to correction for multiple comparisons (p = 0.006; p.adj = 0.083, and p = 0.035; p.adj = 0.237, respectively). Hypermetabolism was more prevalent in the ALS cohort (36% compared to 11.5%, p < 0.001); however, cytokine concentrations were not significantly different across metabolic subgroups and showed no statistically significant association with metabolic index, energy expenditure, or functional measures.

CONCLUSIONS: Findings confirm modest elevations in plasma levels of IL-6 and MCP-1 in ALS but provide no evidence that circulating cytokines correlate with hypermetabolism. Further studies integrating longitudinal and tissue-specific analyses are needed to clarify immune-metabolic mechanisms contributing to disease heterogeneity in ALS.}, } @article {pmid41689566, year = {2026}, author = {Joubert, N and Mels, CMC and Louw, R and Chung, ST and Wentzel, A}, title = {An allostatic load domain-specific metabolic profile in young adults: The African-PREDICT study.}, journal = {The Journal of physiology}, volume = {604}, number = {5}, pages = {1872-1896}, doi = {10.1113/JP289807}, pmid = {41689566}, issn = {1469-7793}, support = {//South African Medical Research Council/ ; //Department of Science and Technology/ ; //National Research Foundation/ ; /DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Allostasis/physiology ; Female ; Male ; *Metabolome ; Young Adult ; Adult ; South Africa ; Hydrocortisone/urine ; Neural Networks, Computer ; C-Reactive Protein/metabolism ; Interleukin-6/urine ; Adrenocorticotropic Hormone/urine ; Glycated Hemoglobin/metabolism ; Dehydroepiandrosterone/urine ; Blood Pressure ; Carnitine/analogs & derivatives/urine ; Amino Acids/urine ; }, abstract = {Allostatic load scores (ALSs) quantify the cumulative physiological burden of sustained stress across neuro-endocrine, metabolic, cardiovascular and inflammatory domains; however ALS is heterogeneous in nature. Using domain-specific urinary metabolomic signatures may improve evaluation accuracy, provide an innovative alternative to stress characterization, identify early domain-specific perturbations and allow comparative investigations. We designed and evaluated a novel, multilayered perceptron neural network (MLP-NN) method to investigate metabolic perturbations reflecting domain-specific alterations in low and high sustained stress, measured by ALS, and described ALS domain-specific metabolomic profiles. Data from 955 South Africans were used. ALS was calculated from dehydroepiandrosterone (DHEA), adrenocorticotropic hormone (ACTH), cortisol, interleukin-6 (IL-6), C-reactive protein (CRP), waist circumference (WC), glycated haemoglobin (HbA1c), blood-pressure and high-density lipoprotein cholesterol. Urinary amino acids and acylcarnitines (N = 32 metabolites) were analysed using liquid chromatography-tandem-mass-spectrometry. MLP-NN assessed metabolite contribution to the allostatic load (AL) domains, controlling for confounders, identifying the main metabolites, per AL domain. The median ALS was 3, with high stress (ALS ≥ 4) observed in 30% of participants. Significant differences were observed across all 32 metabolites between high and low ALS groups (all P < 0.05). MLP-NN revealed distinct domain-specific metabolomic patterns in low and high ALS. In low ALS the neuro-endocrine, cardiovascular and metabolic domains showed metabolomic signatures reflective of normal physiology. However in high ALS, metabolomic profiles reflected compensatory mechanisms linking neurotransmitter synthesis, redox balance and energy metabolism, mainly in the neuroendocrine, inflammatory and metabolic domains. This novel MLP-NN-based approach identified unique urinary profiles reflective of higher AL, independent of traditional confounders. This non-invasive approach may serve as an alternative for assessing AL, retaining domain-specificity, yet allowing comparative studies without the heterogeneity of traditional ALS. KEY POINTS: Allostatic load scores (ALSs) are heterogenous, complicating cross-study comparisons and clinical inferences. Determining allostatic load domain-specific metabolomic profiles using neural networks may identify early changes in specific domains. This study designed and evaluated a novel neural network-based model determining allostatic-load-domain-specific metabolomic signatures in high and low sustained stress. This novel neural-network-based approach, combinedly analysing metabolomic data and ALS domain-specific patterns, identified unique urinary profiles, independent of traditional confounders. This non-invasive approach may serve as an alternative for assessing AL, retaining the domain-specificity, identifying early domain-related perturbations related to sustained stress and allowing comparative studies.}, } @article {pmid41689968, year = {2026}, author = {Qaisar, R and Deepa, SS}, title = {A Narrative Review of Necroptosis in Neuromuscular Junction Disorders: Pathogenesis and Therapeutic Strategies.}, journal = {Archives of medical research}, volume = {57}, number = {5}, pages = {103401}, doi = {10.1016/j.arcmed.2026.103401}, pmid = {41689968}, issn = {1873-5487}, mesh = {Humans ; *Necroptosis/drug effects ; Animals ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/antagonists & inhibitors ; *Neuromuscular Junction/pathology/metabolism ; Protein Kinases/metabolism/genetics ; *Neuromuscular Junction Diseases/pathology/therapy/drug therapy ; Muscle, Skeletal/pathology ; Schwann Cells/pathology ; Motor Neurons/pathology/metabolism ; }, abstract = {Necroptosis is a regulated and inflammatory form of cell death that has emerged as a key contributor to neuromuscular junction (NMJ) dysfunction. This narrative review aims to synthesize current evidence on the role of necroptosis in NMJ pathology and its potential therapeutic implications. First, we present the conceptual framework linking necroptosis to NMJ degradation, focusing on core mediators such as receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL). Second, we summarize the available evidence across NMJ compartments, including motor neurons, Schwann cells, and skeletal muscle. We also describe how necroptosis activation correlates with structural and functional deficits in conditions such as spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy. Third, we examine the translational potential of targeting necroptosis, highlighting preclinical studies on RIPK1, RIPK3, and MLKL inhibitors. Although these findings suggest therapeutic value, current evidence is predominantly derived from animal models, and clinical applicability remains uncertain. Rigorous trials are needed to confirm the safety and efficacy of these treatments. Understanding necroptosis as a shared mechanism across NMJ components may inform future strategies to preserve neuromuscular function.}, } @article {pmid41690071, year = {2026}, author = {El-Moaty, HIA and Sameh, A and Saber, S and Hamad, RS and Elmorsy, EA and Alsoqih, NS and Farrag, AA and Eissa, H and El-Kott, AF and Negm, S and AlShehri, MA and Ali, MAM and Hasan, WA and Gaafar, A and Khalifa, HS and Ibrahim, EH and Morsy, K and Elnaghy, F}, title = {Adenosine A2A receptor as a dual-acting molecular switch: Glial morphological changes and neurovascular tissue remodeling in neuroinflammation and neurodegeneration.}, journal = {Tissue & cell}, volume = {100}, number = {}, pages = {103389}, doi = {10.1016/j.tice.2026.103389}, pmid = {41690071}, issn = {1532-3072}, mesh = {Humans ; Animals ; *Neuroinflammatory Diseases/pathology/metabolism/genetics ; *Neuroglia/pathology/metabolism ; Signal Transduction ; *Receptors, Adenosine A2/metabolism/genetics ; *Neurodegenerative Diseases/pathology/metabolism/genetics ; Inflammation/pathology ; *Receptor, Adenosine A2A/metabolism ; Blood-Brain Barrier/pathology/metabolism ; }, abstract = {Neuroinflammation appears in a variety of neurological disorders, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis. The adenosine A2A receptor (A2AR), a Gs protein-coupled receptor that affects cAMP signaling and downstream kinases like PKA, CREB, and NF-κB, is one of the primary regulators of this process. Context-dependent effects of A2AR activation include lowering acute inflammation and promoting neuronal survival when stimulated moderately, but increasing glial activation and cytokine production when overexpressed over an extended period of time. In microglia and astrocytes, A2AR signaling regulates inflammatory pathways mediated by NF-κB and MAPK, affecting oxidative stress, blood-brain barrier (BBB) stability, and excitotoxicity. Acute or transient (short-term) A2AR activation, on the other hand, increases the production of anti-inflammatory cytokines like IL-10 and enhances neurotrophic support through BDNF. A2AR antagonists, including istradefylline and SCH58261, may reduce microglial triggering and have neuroprotective benefits, according to clinical and experimental data. The context-dependent activity of the receptor is shown by the fact that total receptor blockage interferes with adaptive immune control. Therefore, the therapeutic challenge is to carefully modify A2AR signaling in particular cell populations, specifically targeting astrocytic or microglial receptors while maintaining the peripheral immunoregulatory activities. The dual regulatory role of A2AR in neuroinflammation is summarized in this review along with its molecular mechanisms, disease-specific actions, and therapeutic significance. Developing next-generation neuroprotective strategies that reduce A2AR signaling's pro-inflammatory and neurotoxic effects while preserving its beneficial homeostatic effects will require an understanding of the temporal and cell-specific dynamics of this signaling.}, } @article {pmid41690969, year = {2026}, author = {Lorincz-Comi, N and Song, W and Chen, X and Paz, IR and Hou, Y and Zhou, Y and Xu, J and Martin, W and Barnard, J and Pieper, AA and Haines, JL and Chung, MK and Cheng, F}, title = {Combining xQTL and genome-wide association studies from diverse populations improves druggable gene discovery.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41690969}, issn = {2041-1723}, support = {RF1AG082211//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01AG084250//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1 NS133812/NS/NINDS NIH HHS/United States ; R01AG076448//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG092462/AG/NIA NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; R33 AG083003/AG/NIA NIH HHS/United States ; P01HL158501//U.S. Department of Health Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01AG092591//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG082118/AG/NIA NIH HHS/United States ; R01AG082118//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG066707//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG084250/AG/NIA NIH HHS/United States ; R01 AG092591/AG/NIA NIH HHS/United States ; R01 AG076448/AG/NIA NIH HHS/United States ; R33AG083003//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG092462//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; }, mesh = {*Genome-Wide Association Study/methods ; Humans ; *Quantitative Trait Loci/genetics ; Alzheimer Disease/genetics/drug therapy ; Polymorphism, Single Nucleotide ; Schizophrenia/genetics ; Diabetes Mellitus, Type 2/genetics ; Genetic Predisposition to Disease ; Amyotrophic Lateral Sclerosis/genetics ; *Drug Discovery/methods ; }, abstract = {Repurposing existing medicines to target disease-associated genes represents a promising strategy for developing effective treatments for complex diseases. However, progress has been hindered by a lack of viable candidate drug targets identified through genome-wide association studies. Gene-based association tests provide a more powerful alternative to traditional SNP-based methods, yet current approaches often fail to leverage shared heritability across populations and to effectively integrate functional genomic data. To address these challenges, we develop GenT and its various extensions, comprising a framework of gene-based tests utilizing summary-level data from genome-wide association studies. Using GenT, we identify 16, 15, 35, and 83 candidate genes linked to Alzheimer's disease, amyotrophic lateral sclerosis, major depression, and schizophrenia, respectively, not detected by Genome-Wide Association Studies (GWAS). Additionally, we use our multi-ancestry gene-based test (MuGenT) to identify 28 candidate genes associated with type 2 diabetes. By integrating brain expression and protein quantitative trait loci into our analysis, we identify 43 candidate genes associated with Alzheimer's disease that have supporting xQTL evidence. We also perform experimental assays to demonstrate that the NTRK1 inhibitor GW441756 significantly reduces tau hyper-phosphorylation (including p-tau181 and p-tau217) in Alzheimer's disease patient-derived iPSC neurons, providing mechanistic support for our predictions.}, } @article {pmid41691309, year = {2026}, author = {Argueti-Ostrovsky, S and Lim, SM and Arogundade, OA and Diaz-Garcia, S and Yunisova, G and Meng, A and Hermann, A and Ong, K and Eremenko, E and Bravo-Hernandez, M and Driscoll, SP and Lee, CZ and Jiang, X and Stavsky, A and Barel, S and Shani, T and Kahn, J and Pfaff, SL and Monsonego, A and Marsala, M and Ravits, J and Lagier-Tourenne, C and Israelson, A}, title = {Impaired nucleocytoplasmic transport in SOD1-mediated ALS.}, journal = {Molecular neurodegeneration}, volume = {21}, number = {1}, pages = {14}, pmid = {41691309}, issn = {1750-1326}, support = {217118//Binational Science Foundation/ ; R01 NS108769/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Animals ; *Active Transport, Cell Nucleus/physiology ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Mice, Transgenic ; Mutation ; Fibroblasts/metabolism ; Spinal Cord/metabolism ; Exportin 1 Protein ; }, abstract = {BACKGROUND: Impaired nucleocytoplasmic transport (NCT) has emerged as a shared pathogenic mechanism in various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in the gene encoding superoxide dismutase 1 (SOD1) account for approximately 20% of familial ALS cases, the impact of mutant SOD1 accumulation on the NCT remains unclear. METHODS: Utilizing in vitro and in vivo models, patient-derived fibroblasts, and postmortem spinal cord tissues from ALS patients with SOD1 mutations, we determined the effects of mutant SOD1 on NCT dynamics, nuclear morphology and cellular localization of transport receptors and nuclear pore components. RESULTS: Mutant SOD1 disrupts nuclear import and export trafficking, causing cytosolic accumulation of key transport regulators such as RanGAP1 and exportin 1 (XPO1). Mutant SOD1 also lowers the abundance of FG-Nups at the nuclear pore without altering nuclear circularity. Abnormal accumulation of NCT components was identified in Iba1-positive microglia, indicating a previously overlooked, non-cell-autonomous contribution to disease pathogenesis. Importantly, AAV-mediated reduction of mutant SOD1 in transgenic mice restored nuclear XPO1 localization, underscoring the causal role of mutant SOD1 in NCT abnormalities. Finally, comparable NCT perturbations were observed in patient-derived fibroblasts and in post-mortem spinal cord tissues from individuals with SOD1-ALS. CONCLUSIONS: Our results implicate NCT disruption as a shared disease mechanism between SOD1-mediated ALS and other familial and sporadic forms of ALS, adding support for targeting this pathway as an attractive therapeutic strategy in this fatal disease.}, } @article {pmid41691953, year = {2026}, author = {Sandoval-Diez, N and Loizeau, N and Huss, A and Röösli, M and Vienneau, D}, title = {Long-term residential magnetic field exposure and neurodegenerative disease mortality: An 18-year nationwide cohort study in Switzerland.}, journal = {Environment international}, volume = {208}, number = {}, pages = {110145}, doi = {10.1016/j.envint.2026.110145}, pmid = {41691953}, issn = {1873-6750}, mesh = {Switzerland/epidemiology ; Humans ; *Neurodegenerative Diseases/mortality ; *Environmental Exposure/statistics & numerical data/adverse effects ; *Magnetic Fields/adverse effects ; Cohort Studies ; Female ; Male ; Proportional Hazards Models ; Aged ; Middle Aged ; }, abstract = {BACKGROUND: Epidemiological evidence on the association between extremely low-frequency magnetic fields (ELF-MF) exposure and neurodegenerative diseases (NDD) remains inconsistent. Few population-based studies using exposure from high-voltage power lines (HVPL) have found mixed findings, and none have yet considered exposure from railway lines.

METHODS: We followed 3,555,064 adults from the Swiss National Cohort (2001-2018), contributing 55.4 million person-years. Long-term ELF-MF exposure from HVPL (50 Hz) and railway lines (16.7 Hz) was modelled using validated proximity models and updated over four intervals (2001-2005, 2006-2010, 2011-2015, 2016-2018). Long-term ELF-MF exposure was calculated as a time-weighted average exposure over 10-year windows preceding each interval. Cox proportional hazards models estimated hazard ratios (HRs) for mortality from Alzheimer's disease (AD), other types of dementia (OTD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS), adjusting for sociodemographic and environmental co-exposures.

RESULTS: During follow-up, 146,655 NDD deaths occurred. Less than 1% of the population was exposed to long-term ELF-MF ≥ 0.3 µT from HVPL and 2.4% from railway lines. HVPL exposure was positively associated with mortality from AD (HR per 1 µT increase in exposure = 1.54; 95% CI: 1.23-1.92) and OTD (HR = 1.31; 95% CI: 1.13-1.52). Associations for railway exposure were weaker and attenuated after adjusting for environmental co-exposures. No associations were observed for ALS, PD, or MS.

CONCLUSIONS: Long-term ELF-MF exposure was associated with higher dementia mortality risk in the general population, but not with ALS, PD, or MS. Causal inference remains limited by the absence of established biological mechanisms.}, } @article {pmid41692171, year = {2026}, author = {Wang, SM and Chan, JC and Supapatarnun, E and Tsai, CY and Lan, PTN and Weng, EF}, title = {C9orf72-derived dipeptide repeat proteins poly-PR disrupt membrane excitability and synaptic function in cortical neurons.}, journal = {Neurobiology of disease}, volume = {221}, number = {}, pages = {107320}, doi = {10.1016/j.nbd.2026.107320}, pmid = {41692171}, issn = {1095-953X}, mesh = {Animals ; *Cerebral Cortex/metabolism/cytology ; C9orf72 Protein/genetics ; *Neurons/physiology/metabolism/drug effects ; Cells, Cultured ; *Dipeptides/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Synapses/physiology/drug effects ; *Proteins/genetics/metabolism ; DNA Repeat Expansion ; Membrane Potentials/physiology ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most fatal neurodegenerative disease, with the most common genetic form of the ALS is associated with hexanucleotide GGGGCC repeat expansions in the first intron of C9orf72 gene. Cortical hyperexcitability is one of the symptoms reported in several forms of ALS and implicated as a cause of neuronal death, however, the underlying mechanisms are still unclear. The dipeptide repeat (DPR) proteins produced from hexanucleotide repeat expansion have been shown toxic to neurons and induce cellular damages. In this study, we explore relationships between the membrane excitability of cortical neurons and the expression of one of the DPR proteins poly-proline-arginine (poly-PR). We found that expression of poly-PR in primary cultured cortical neurons induced an elevation of intrinsic membrane excitability and decreases in dendritic arborization and excitatory synaptic activity. The increased membrane excitability can be restored by Nav channel inhibitor riluzole and Kv7 channel activator retigabine. Our results suggest a rescuable ion channel-mediated hyperexcitability induced by poly-PR expression in cortical neurons, providing a foundation for developing targeted therapies for C9orf72 ALS.}, } @article {pmid41692368, year = {2026}, author = {Dehury, S and Tiwari, S and Los Rios, P}, title = {Refolding-assisted purification of native full-length TDP-43 compatible with BSL-2 safety regulations.}, journal = {Methods (San Diego, Calif.)}, volume = {248}, number = {}, pages = {83-91}, doi = {10.1016/j.ymeth.2026.02.009}, pmid = {41692368}, issn = {1095-9130}, mesh = {*DNA-Binding Proteins/isolation & purification/chemistry/genetics ; Escherichia coli/genetics/metabolism ; *Protein Refolding ; Humans ; Chromatography, Affinity/methods ; Recombinant Proteins/isolation & purification/chemistry/genetics ; Prions/chemistry ; Urea/chemistry ; Electrophoresis, Polyacrylamide Gel ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a prion-like RNA-binding protein that plays a key role in amyotrophic lateral sclerosis and frontotemporal dementia. Producing full-length TDP-43 consistently is thus relevant for its in vitro studies and yet it remains challenging, especially with the current requirement to work under biosafety level-2 (BSL-2) containment due to new safety regulations for Prion-like and amyloidogenic proteins. Here we describe a refolding-assisted purification protocol for TDP-43 from soluble fraction that can be implemented with basic equipment in standard BSL-2 laboratories. Expression in Escherichia coli is followed by IMAC-capture on an EDTA/DTT-tolerant Ni[2+]-NTA resin under 4 M urea, then on-column refolding via a gradient urea wash using resin-limiting conditions that favour the binding to high-affinity His-tagged protein. After removal of the SUMO solubility tag, the preparation is monitored by a robust quality-control pipeline: SDS-PAGE and immunoblotting for integrity and purity, mass photometry for oligomeric state, far-UV circular dichroism for secondary structure, fluorescence anisotropy for native functional assays, and light-scattering for stability and aggregation propensity measurements. A concise BSL-2 standard operating procedure specifies containment, decontamination, and waste handling for prion-like proteins. This protocol enables safe, cost-effective, and reproducible access to native-like full-length TDP-43 and is readily adaptable to other prion-like aggregation-prone proteins.}, } @article {pmid41692724, year = {2026}, author = {Rönnholm, J and Weiner, S and Fuchs, J and Thorsell, A and Sihlbom, C and Dugom, L and Easton, A and Zetterberg, H and Gobom, J}, title = {Shake and bake: a robust and cost-effective proteomic sample preparation workflow for plasma and cerebrospinal fluid.}, journal = {Clinical proteomics}, volume = {23}, number = {1}, pages = {}, pmid = {41692724}, issn = {1542-6416}, abstract = {BACKGROUND: Plasma and cerebrospinal fluid are complementary sources of biomarkers for neurodegenerative diseases. The wide dynamic range of protein abundances, particularly in plasma, hampers detection of low-abundance proteins. Depletion of high-abundance proteins and efficient enzymatic digestion can improve proteome coverage but must be carefully optimized for reproducibility, throughput, and cost-efficiency for use in large-scale clinical proteomic studies. METHODS: We developed a scalable sample preparation workflow for plasma and cerebrospinal fluid (CSF) that integrates depletion of high-abundance proteins, optimized digestion using Lys-C and trypsin, and compatibility with both label-free and tandem mass tag (TMTpro)-based quantification. Depletion was performed using a multi-affinity resin with immobilized antibodies targeting 14 high-abundance plasma proteins, which collectively constitute ≈ 95% of total plasma protein content. We systematically evaluated protein depletion and enzyme digestion conditions, and the effect of deoxycholate on digestion, monitoring the number of detectable proteins and the quantitation precision. RESULTS: A resin-to-plasma ratio of ≥ 75 and a mixing speed of 900 rpm ensured complete and reproducible depletion. Depletion resulted in an increase in the number of identified proteins by ~ 65% in CSF, and ~ 80% in plasma, tripling the number of brain-enriched proteins, with maintained quantitative precision (median coefficient of variation (CV) for relative protein abundances < 11%). A two-step digestion protocol using Lys-C/trypsin followed by trypsin yielded the highest reproducibility and detectability in plasma. Adding the detergent deoxycholate to the samples had little effect in CSF and only marginally improved proteome coverage for plasma but decreased quantification precision and throughput. Technical replicates from a 528-sample clinical amyotrophic lateral sclerosis (ALS) cohort showed high reproducibility, with intra-sample CVs substantially lower than inter-individual variation. CONCLUSIONS: The sample preparation workflow described here enabled deep and reproducible proteome profiling of plasma and CSF in high-throughput formats and was found to be suitable for biomarker discovery in large clinical studies.}, } @article {pmid41693708, year = {2025}, author = {Mudda, NS and Zhang, L and Sampelli, P}, title = {Targeting gut-brain-immune axis in amyotrophic lateral sclerosis.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1637976}, pmid = {41693708}, issn = {1664-3224}, mesh = {*Amyotrophic Lateral Sclerosis/immunology/therapy/metabolism/microbiology/etiology ; Humans ; Animals ; *Gastrointestinal Microbiome/immunology ; *Brain/immunology/metabolism ; *Brain-Gut Axis/immunology ; Dysbiosis/immunology ; Intestinal Barrier Function ; Cytokines/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron neurodegenerative disorder with a median survival of only 3-5 years. The heterogeneity of the disease and lack of effective therapies highlight the importance of identifying novel pathogenic mechanisms. We hypothesize that dysbiosis of gut microbiota enhances ALS by disrupting intestinal barrier function and altering metabolite profiles to drive systemic inflammation and neuronal stress. Precisely, the decrease in health-promoting bacteria (e.g., Akkermansia muciniphila, Bifidobacterium and Lactobacillus spp.) in ALS can reduce neuroprotective metabolite production (short-chain fatty acids, nicotinamide, GABA, precursors of serotonin) and increase gut permeability, enabling lipopolysaccharide (LPS) and pro-inflammatory cytokines into the circulation. Such changes would activate microglia and impair motor neuron homeostasis by glutamate excitotoxicity and mitochondrial dysfunction. The gut-brain axis operates through immune-mediated mechanisms, where ALS-associated microbiota changes compromise mucosal immunity and trigger peripheral Th1/Th17-biased responses with impaired Treg regulation. Elevated endotoxin levels correlate with TLR4-driven inflammation, promoting pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) that cross into the CNS and prime microglia toward a neurotoxic M1 phenotype, creating a milieu where IL-17A and other mediators directly injure motor neurons. Our hypothesis relies on establishing human and animal evidence of microbiome derangements, barrier dysfunction, and immune deregulation with ALS. We hypothesize that restoration of an "ALS-protective" microbiota consortium or its metabolic by-products can potentially slow disease progression. Testable hypotheses include improvement of ALS model motor deficits by probiotic or fecal-microbiota therapies, and normalization of inflammatory biomarkers. This paradigm recontextualizes ALS as a gut-brain disease and suggests new directions for translational research into this unmet medical indication.}, } @article {pmid41695269, year = {2026}, author = {Zhang, J and Zhao, Z and Xiang, T and Teng, D and Wan, H and Zhang, Q and Liu, X}, title = {From knowledge landscapes to network mechanisms: charting regulated cell death pathways in ALS.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1742805}, pmid = {41695269}, issn = {1663-4365}, abstract = {OBJECTIVE: To map the research landscape linking amyotrophic lateral sclerosis (ALS) with regulated cell death (RCD) and to integrate bibliometric trends with bioinformatics evidence to identify convergent mechanisms and actionable targets.

METHODS: Web of Science Core Collection, PubMed, and Scopus were searched for 2005-2024 (English; Article/Review). After merging and de-duplication, 6,272 records were analyzed using CiteSpace, VOSviewer, and bibliometrix to evaluate publication trends, collaboration, co-citation structure, and keyword evolution. In parallel, ALS-related genes were intersected with apoptosis-, ferroptosis-, and pyroptosis-associated gene sets. Shared targets were used to construct PPI networks, identify core modules and hub genes, and perform GO/KEGG enrichment analyses.

RESULTS: Publications and citations increased steadily with a clear rise after 2015. The field is anchored by the USA and shows rapidly growing contributions from Asia and Europe. Keyword evolution indicates a shift from "oxidative stress/apoptosis" toward multi-pathway RCD, with prominent recent bursts in ferroptosis, pyroptosis, necroptosis, and autophagy/mitophagy, alongside persistent themes in motor-neuron degeneration, mitochondria, and neuro-inflammation. Bio-informatics results showed substantial genetic overlap between ALS and RCD modalities. Hub-gene analysis highlighted TP53, AKT1, STAT3, MYC, RELA, EP300, CREBBP, JUN, HSP90AA1, and MAPK3 as central nodes. Enrichment analyses implicated FoxO, HIF-1, and lipid-related pathways, and GO terms related to chemical/oxidative stress responses and autophagy regulation.

CONCLUSION: ALS-cell death research is consolidating around interconnected RCD programs. Integrated bibliometric and bioinformatics evidence supports an immunometabolic convergence involving ferroptosis-inflammation-autophagy signaling, providing a focused set of candidate pathways and hub targets for mechanistic validation and translation.}, } @article {pmid41696691, year = {2025}, author = {Matabuena, M and Straczkiewicz, M and Calcagno, N and Burke, KM and Royse, TB and Iyer, A and Carney, KT and Hall, S and Berry, JD and Onnela, JP}, title = {Exploratory analysis of smartphone-based step counts as a digital biomarker for survival in ALS patients.}, journal = {Frontiers in digital health}, volume = {7}, number = {}, pages = {1705368}, pmid = {41696691}, issn = {2673-253X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and debilitating neurodegenerative disease. Digital biomarkers derived from smartphone data can enable scalable, low-cost, remote, unobtrusive, and quantitative measurement of physical activity (PA). These biomarkers offer opportunities for quasi-continuous assessment of PA levels, which may provide new methods for monitoring ALS disease progression in real time. In this exploratory study, we analyzed data from 31 individuals with ALS (including 16 deaths) with up to 9 years of follow-up (median 3 years) to assess the impact of incorporating smartphone-derived PA measures into survival prediction models. We examine whether the strength of the statistical association with survival differs when PA is summarized as (i) a simple metric, such as the mean daily step count, vs. (ii) distributional representations of PA. The exploratory results suggest that the addition of PA variables defined via distributional representations improves the performance of the model, as reflected by higher C-score values (0.68 vs. 0.55 , estimated as the median over bootstrap replicas B = 1 , 000). A bootstrap-based hypothesis test shows statistically significant differences between the two models at the confidence level of 90%. These exploratory results indicate that the use of more advanced metrics to summarize PA time series can produce more accurate digital biomarkers to monitor the progression of ALS, although larger studies with larger sample sizes are required to confirm these findings.}, } @article {pmid41697761, year = {2026}, author = {Wilson, M and Al-Jumeily, D and Birkett, J and Khan, I and Abbas, I and Harper, M and Assi, S}, title = {Exploring the feasibility of near-infrared spectroscopy and machine learning for detecting cardiovascular diseases and diabetes mellitus in fingernails.}, journal = {The Analyst}, volume = {151}, number = {6}, pages = {1650-1656}, doi = {10.1039/d5an01061f}, pmid = {41697761}, issn = {1364-5528}, mesh = {Humans ; Spectroscopy, Near-Infrared/methods ; *Cardiovascular Diseases/diagnosis ; *Diabetes Mellitus/diagnosis ; Feasibility Studies ; *Nails/chemistry ; *Machine Learning ; Glycation End Products, Advanced/analysis ; Support Vector Machine ; }, abstract = {Cardiovascular diseases (CVDs) and diabetes mellitus (DM) are significant conditions that impact lives around the globe. Frequently employed methods for detecting CVDs and/or DM such as blood work and cardiac catheterisation are often invasive, intrusive and can cause the patient additional physical and psychological harm. Vibrational spectroscopic methods including near-infrared (NIR) spectroscopy have emerged as novel methods for detecting medical conditions and diseases including amyotrophic lateral sclerosis, cancer, DM and periodontitis. NIR spectroscopy's ability to perform rapid and cost-effective analysis saves diagnostic waiting times, providing relief for strained healthcare systems. Moreover, their non-invasive, non-intrusive and non-destructive nature allow application to alternative biological matrices such as hair, fingernails and saliva. Therefore, this work explored the feasibility of NIR spectroscopy paired with machine learning (ML) for detecting CVDs and/or DM in fingernails. NIR spectroscopy successful characterised disease-related spectral features including key NIR regions related to the presence of advanced glycated end-products (AGEs), glycated proteins and DM. To further assess the detective capabilities of NIR spectroscopy, classification models were trained. Cubic and quadratic support vector machine (SVM) models demonstrated accuracy in terms of the classification of healthy, CVD and diabetic fingernails. Accuracy was further improved through binary classification models, which allowed the independent classification of CVD and DM spectra against healthy spectra. In summary, NIR spectroscopy combined with ML provided accurate detection for CVDs and DM in fingernails.}, } @article {pmid41698629, year = {2026}, author = {Patwekar, F and Patwekar, M and Wei, LS and Rather, GA and Mohammed, A and Hussain, MS and Gupta, G and Fuloria, S and Fuloria, NK}, title = {Marine-Derived bioactive compounds from Aquaculture: Receptor-Mediated neuroprotection in neurodegenerative disorders.}, journal = {Brain research}, volume = {1879}, number = {}, pages = {150208}, doi = {10.1016/j.brainres.2026.150208}, pmid = {41698629}, issn = {1872-6240}, mesh = {Animals ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Aquaculture/methods ; *Neuroprotection/drug effects ; }, abstract = {Neurodegenerative diseases, like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and ischemic stroke (IS), are a major global health challenge because of their complex, multifactorial pathology, and the lack of effective disease-modifying therapies. In recent years, aquaculture-derived marine bioactive molecules like fucoidan, phlorotannins, fucoxanthin, laminarin, alginate oligosaccharides, and C-phycocyanin have developed as promising agents for neuroprotection with their structural diversity and multi-target biological activity. This review showcase predominantly preclinical evidence, including in silico molecular docking analyses, in vitro functional assays, and in vivo animal models, to critically understand the receptor-mediated mechanisms with the neuroprotective actions of marine bioactives originated from aquaculture systems. Available studies shows these compounds can modulate large neuro-receptor systems, like cholinergic, dopaminergic, GABAergic, glutamatergic, toll-like, and nuclear receptors, leading in attenuation of oxidative stress, lowering of neuro-inflammation, regulation of neurotransmission, and conservation of mitochondrial and synaptic function. However, the positive approach of mechanistic evidence varies across compounds and receptor classes, with large interactions assisted by functional outcomes instead of direct receptor-binding validation. The review even discusses emerging and enabling technologies like brain organoids, multi-electrode array platforms, omics-based profiling, and artificial intelligence assisted drug discovery, which are increasingly utilized to refine mechanistic understanding and optimize marine-derived products. Importantly, current evidence stay largely preclinical, with little human studies and a lack of validated receptor-specific biomarkers. Overall, this review provides a well-balanced, evidence-based assessment of aquaculture-derived marine bioactive as potential neurotherapeutic agents.}, } @article {pmid41699331, year = {2026}, author = {Ercin, N and Besli, N and Beker, M and Celik, U}, title = {Non-canonical cell death in neurodegeneration: emerging mechanisms and therapeutic Frontiers.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {31}, number = {3}, pages = {72}, pmid = {41699331}, issn = {1573-675X}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/drug therapy/metabolism/genetics ; Animals ; Ferroptosis/drug effects ; *Cell Death/drug effects ; Necroptosis/drug effects ; Parthanatos/drug effects ; Oxidative Stress ; Pyroptosis/drug effects ; Neuroprotective Agents/therapeutic use/pharmacology ; Regulated Cell Death ; }, abstract = {Neurodegenerative diseases, specifically Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are defined by progressively increased neuronal loss that lacks curative therapies. Increasing evidence supports that non-canonical regulated cell death pathways including ferroptosis, necroptosis, pyroptosis, and parthanatos, are implicated in pathological mechanisms of neuroinflammation, and oxidative stress, and mitochondrial dysfunction, likely impacting neurodegenerative pathologies. In this review, we summarize the existing literature on the molecular pathways and potential pathogenic implications of these cell death pathways in neurodegenerative diseases, highlighting their upstream triggers, regulatory proteins, and downstream effectors. We also briefly describe representative pharmacological agents, including ferrostatin-1, necrostatin-1, MCC950 and PARP-inhibitors, that have shown neuroprotective effects in experimental studies. Experimental studies provide valuable information, but translation to clinical treatments presents barriers including overlapping regulated cell death mechanisms, constraints of bloodbrain barrier penetrance and concern for safety. Future development may come through concepts such as biomarker-based patient stratification strategies, multivalent interventions, and improved translational models. Identifying these new regulated cell death pathways may eventually provide new avenues to slow the progression of neurodegeneration and develop more targeted therapies.}, } @article {pmid41699714, year = {2026}, author = {Al Kamaly, O and Al-Khateeb, LA and Halim, MK and Magdy, G and Abbas, AEF}, title = {Environmentally sustainable UV spectrophotometric-chemometric approach for simultaneous determination of budesonide, glycopyrrolate, and formoterol.}, journal = {BMC chemistry}, volume = {20}, number = {1}, pages = {}, pmid = {41699714}, issn = {2661-801X}, support = {PNURSP2025R917//Princess Nourah Bint Abdulrahman University/ ; }, abstract = {This study introduces a sustainable UV-spectrophotometric platform for the simultaneous and individual determination of budesonide (BUD), glycopyrrolate (GLY), and formoterol fumarate (FOM) in pharmaceutical inhalers. Current chromatographic approaches for this triple therapy rely on toxic solvents and complex procedures, limiting their suitability for routine pharmaceutical analysis. The proposed method replaces hazardous solvents with an ethanol-water system, reducing organic solvent use by 95% and energy demand by ~ 80%. To further enhance efficiency, a grid-based experimental design was integrated with chemometric modeling, reducing experimental runs by 60% while maintaining analytical rigor. Calibration was linear over 10-50 µg/mL (BUD), 2-10 µg/mL (GLY), and 1-5 µg/mL (FOM), with correlation coefficients (r[2]) between 0.9998 and 0.9999. Among the evaluated models, Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) provided the highest predictive accuracy (RMSEP = 0.23-0.39, recoveries = 99.8-100.5%, RSD < 1.5%). It was successfully applied to both multi-component (Breztri Aerosphere[®]) and single-component inhalers (Budecort[®], Seebri Breezhaler[®], and Metrohaler[®]), confirming selectivity, accuracy, and robustness across pharmaceutical matrices. Beyond analytical performance, the method demonstrates outstanding sustainability credentials, including minimal carbon footprint, compliance with green chemistry principles, and alignment with 11 United Nations Sustainable Development Goals. Its simplicity, affordability, and eco-friendly profile make it readily transferable to both industrial and regulatory laboratories. This validated protocol establishes a cost-effective and environmentally responsible alternative to chromatography, offering a practical solution for routine Chronic obstructive pulmonary disease drugs monitoring and pharmaceutical quality assurance.}, } @article {pmid41702096, year = {2026}, author = {Llacuna, FDG and Ong, AKS and Young, MN}, title = {Factors influencing behavioral intention to use adaptive learning systems: Integrating self-determination theory and the unified model of technology acceptance.}, journal = {Acta psychologica}, volume = {264}, number = {}, pages = {106471}, doi = {10.1016/j.actpsy.2026.106471}, pmid = {41702096}, issn = {1873-6297}, mesh = {Humans ; *Personal Autonomy ; Female ; *Intention ; Male ; *Students/psychology ; Young Adult ; Philippines ; *Learning ; Adult ; *Education, Distance ; Academia ; }, abstract = {Adaptive Learning System (ALS) is one of the useful learning tools that has emerged in the technological innovation of the educational sector. Many schools and universities have adopted it for academic use since the prompt of online learning. However, the relative evaluation of ALS has been undermined in the current generation - especially among developing countries. The purpose of this study was to analyze the variables affecting the actual academic use of online ALS among students. A total of 638 students from the Philippines answered an online survey of 50-item questions derived from the eleven constructs used in this study, which were analyzed simultaneously using Structural Equation Modeling. This study utilized two important theories, integrating both the Self-Determination Theory and the Unified Theory of Acceptance and Use of Technology Use in ALS acceptance. The findings showed that autonomy, competence, price value, and facilitating conditions were the significant factors in student's behavioral intention to use the ALS. Since developing countries are trying to adapt to the current trends among developed countries, it was suggested that developers may need to make their ALS accessible through other gadgets like smartphones and tablets. The findings of this study can contribute to the educational context of digital learning to meet the needs of the students by increasing their behavioral intentions to use ALS. Further, the results provided insights and suggestions to universities and ALS developers to collaborate on improving the ALS for the student's welfare in learning.}, } @article {pmid41702277, year = {2026}, author = {Copat, C and Cicero, CE and Grasso, A and Ligato, F and Sica, C and Fiore, M and Patti, F and Lo Fermo, S and Zappia, M and Giammanco, S and Ferrante, M and Nicoletti, A}, title = {Trace metal signatures in cerebrospinal fluid (CSF): Insights from an amyotrophic lateral sclerosis (ALS) hotspot on Mount Etna (Sicily, Italy).}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {94}, number = {}, pages = {127844}, doi = {10.1016/j.jtemb.2026.127844}, pmid = {41702277}, issn = {1878-3252}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/epidemiology ; *Trace Elements/cerebrospinal fluid ; Female ; Italy/epidemiology ; Male ; Middle Aged ; Aged ; Mass Spectrometry ; }, abstract = {Chronic exposure to trace metals has been increasingly recognized as a possible factor influencing the risk of amyotrophic lateral sclerosis (ALS). In the province of Catania, on the eastern slopes of Mount Etna, epidemiological investigations have highlighted the presence of a high-incidence cluster of the disease. Against this backdrop, the present study was designed to explore whether the concentrations of trace elements in cerebrospinal fluid (CSF) differ between ALS patients residing in this high-incidence area (In-Cluster) and those living in regions with lower incidence (Out-Cluster). For trace element analysis, CSF was analyzed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Fourteen metals (Al, V, Mn, Co, Ni, Cu, Zn, As, Cd, Hg, Pb, Fe, Se, Mg) were quantified in standard and KED modes. No single metal concentration differed significantly between In-Cluster and Out-Cluster groups. However, In-Cluster patients frequently showed higher upper quartiles for Al, Mn, As, Hg, and Se, suggesting broader variability. Ratio analysis highlighted significant differences between groups, with higher Al/Cu ratios observed in In-Cluster patients. Sex-stratified analysis further revealed increased Mn-based ratios in females, with a significantly elevated Mn/Pb ratio. These patterns indicate possible dysregulation of trace metal homeostasis linked to environmental exposure. In conclusion, although statistical significance was limited, our findings suggest that chronic volcanic ash exposure may contribute to subtle imbalances between neurotoxic and neuroprotective elements in CSF, potentially influencing ALS susceptibility. Further studies integrating environmental monitoring, speciation analysis, and larger cohorts are needed to clarify the role of trace metals in ALS pathogenesis.}, } @article {pmid41702846, year = {2026}, author = {Xu, G and Lopez, A and Brkic, S and Fromholt, S and Chakrabarty, P and Borchelt, DR}, title = {Efficient induction of motor neuron disease in transgenic G93A SOD1 mice by prion-like seeding.}, journal = {Prion}, volume = {20}, number = {1}, pages = {1-17}, pmid = {41702846}, issn = {1933-690X}, support = {R01 NS092788/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice, Transgenic ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; *Prions/metabolism ; *Motor Neuron Disease/genetics/pathology/metabolism ; *Superoxide Dismutase/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Disease Models, Animal ; Humans ; }, abstract = {Mutations in superoxide dismutase 1 (SOD1) cause paralysis in familial amyotrophic lateral sclerosis and promote its misfolding into neurotoxic aggregates. Previous studies have shown that mice expressing the ALS-causing G85R variant of SOD1 develop paralysis much faster after intraspinal injection of spinal homogenates from paralysed G85R SOD1 mice. These findings, and other studies in cell models, established the prionoid templating properties of misfolded mutant SOD1. Previously, however, we noted that the widely used Gur1-G93A SOD1 mice, which express at high levels and develop paralysis by 6 months of age, were resistant to seeding by homogenates from paralysed G93A mice. A line of G93A mice that expresses at very low levels (VLE-G93A) was responsive to seeding but at low efficiency. The poor susceptibility of G93A-SOD1 mice to seeding was not what we expected if prion-like propagation is essential to SOD1 ALS pathogenesis. In our prior studies, seeding homogenates from paralysed G93A-SOD1 mice were injected into the spine of newborn mice, leading us to question whether older G93A SOD1 mice might be more susceptible to seeding. Here, we establish that adult VLE G93A SOD1 mice (up to 12 months of age) injected intrathecally with seeding homogenates containing misfolded G93A or G85R SOD1 developed accelerated motor neuron disease efficiently. Thus, we demonstrate that both the route and age of inoculation can influence the efficiency of SOD1 seeding to induce motor neuron disease in VLE G93A-SOD1 mice. These data, together with our earlier reports, suggest that prion-like templating contributes to disease progression in SOD1-ALS.}, } @article {pmid41703036, year = {2026}, author = {Kremeike, K and Golla, H and Albrecht, R and Montag, T and Mollidor, A and Pusch, L and Schmidtke, J and Welling, U and Voltz, R}, title = {[Care-related questions for specialized outpatient palliative care teams when faced with requests for assisted suicide: A case series].}, journal = {Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz}, volume = {69}, number = {3}, pages = {298-305}, pmid = {41703036}, issn = {1437-1588}, mesh = {*Palliative Care/ethics ; Humans ; Germany ; *Suicide, Assisted/legislation & jurisprudence/ethics ; Female ; Male ; *Ambulatory Care/ethics/organization & administration ; Aged ; *Patient Care Team/ethics/organization & administration ; Middle Aged ; Retrospective Studies ; Aged, 80 and over ; Adult ; Amyotrophic Lateral Sclerosis/therapy/psychology ; }, abstract = {INTRODUCTION: Following the repeal of § 217 of the German Criminal Code in early 2020, new related challenges have also emerged in specialized outpatient palliative care (SAPV) regarding how to address requests for assisted suicide that have so far received little systematic investigation. The aim of this study is to describe and analyze cases involving requests for assisted suicide within SAPV. On this basis, key challenges in care are identified and potential strategies for dealing with such requests are developed.

METHODS: A retrospective case analysis was conducted of all patients who were cared for by the SAPV team at the University Hospital Cologne between February 2020 and August 2025 and explicitly expressed a wish for assisted suicide. Data were extracted from the electronic documentation system (PalliDoc®). Practical and ethical issues related to care were derived within the multiprofessional team.

RESULTS: A total of six patients were included. Five patients suffered from amyotrophic lateral sclerosis and one patient had advanced oncological disease. Three patients made use of external assisted suicide services.

DISCUSSION: Central challenges in care concerned clarification of the role of SAPV, communication about assisted suicide, support of relatives, and the conclusion of care. A clear internal organizational position, as well as defined communication pathways within the team towards patients and their relatives, proved to be supportive. This study formulates practice-relevant questions for the conceptual further development of approaches to requests for assisted suicides.}, } @article {pmid41704326, year = {2026}, author = {Stoian, M and Demenciuc, N and Laszlo, SS and Motataianu, A and Babă, DF and Stoian, A}, title = {Transition from ICU to home care with long-term invasive ventilation using a single-limb BiPAP circuit.}, journal = {Journal of critical care medicine (Universitatea de Medicina si Farmacie din Targu-Mures)}, volume = {12}, number = {1}, pages = {117-124}, pmid = {41704326}, issn = {2393-1809}, abstract = {BACKGROUND: Patients with chronic respiratory failure caused by severe neuromuscular impairment often require long-term respiratory support. Invasive mechanical ventilation (IMV) via tracheostomy is usually provided in intensive care units (ICUs), but in carefully selected cases, it can be safely transitioned to home care. The use of a single-limb ventilator circuit (Single BiPAP circuit with Whisper Swivel II), intended initially for non-invasive ventilation (NIV), may represent a cost-effective and practical alternative for long-term home IMV.

CASE PRESENTATION: We present a 50-year-old male with progressive neuromuscular disease and chronic respiratory failure, who required long-term IMV through a tracheostomy tube. After stabilization in the ICU, ventilation was maintained at home using a Single BiPAP circuit with Whisper Swivel II, combined with a mechanical insufflation-exsufflation (MIE) device for airway secretion clearance. The patient's family received structured training in tracheostomy care, ventilator operation, and secretion management. Over 32-month period, the patient maintained stable respiratory function, experienced a marked reduction in infectious exacerbations, and preserved an acceptable quality of life.

CONCLUSION: In selected patients, long-term home IMV using a single-limb ventilator combined with an MIE device can be a safe, effective, and cost-efficient alternative to conventional ICU-based ventilation. Successful outcomes require structured patient and caregiver training, close follow-up, and coordinated multidisciplinary support.}, } @article {pmid41705073, year = {2026}, author = {Sotgia, S and Zinellu, A and Zoroddu, S and Pateri, MI and Loi, E and Pisano, A and Sabalic, A and Tutedde, D and Vega-Benedetti, AF and Floris, F and Puligheddu, M and Valera, P and Zavattari, P and Borghero, G and Madeddu, R}, title = {Elevated serum trimethylamine N-oxide (TMAO) and trimethyllysine in patients with amyotrophic lateral sclerosis (ALS): An exploratory case-control study.}, journal = {IBRO neuroscience reports}, volume = {20}, number = {}, pages = {227-231}, pmid = {41705073}, issn = {2667-2421}, abstract = {Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite implicated in protein homeostasis, inflammation, and chronic disease, but its relevance in amyotrophic lateral sclerosis (ALS) remains poorly characterized. In this exploratory pilot study, we quantified circulating TMAO and related trimethylammonium-containing compounds in a Sardinian ALS cohort using targeted LC-MS/MS. Serum samples were collected under fasting conditions from 12 ALS patients and 8 age- and sex-matched healthy controls. Median serum TMAO levels were markedly higher in ALS patients than in controls (27.9 vs. 4.0 µmol/L, P < 0.05), with substantial inter-individual variability in the ALS group (range 2.4-125.0 µmol/L). Trimethyllysine (TML) concentrations were also significantly elevated in ALS (0.43 vs. 0.34 µmol/L, P < 0.05), whereas choline, carnitine, betaine, ergothioneine, and γ-butyrobetaine levels did not differ between groups. Most ALS patients were receiving acetyl-L-carnitine (ALCAR) supplementation, suggesting that ALCAR intake may contribute to the observed metabolite profiles. Overall, these findings indicate alterations in trimethylammonium-containing compound metabolism in ALS and underscore the need for larger, well-controlled studies to determine whether such changes reflect disease-related mechanisms, treatment effects, or their interaction.}, } @article {pmid41705449, year = {2026}, author = {Mirian, A and Kassardjian, C}, title = {Reviewer Comment on Cooper et al. "Exploring the Value of Brain T2* Weighted and FLAIR Imaging for Diagnosing Amyotrophic Lateral Sclerosis".}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1}, doi = {10.1017/cjn.2026.10528}, pmid = {41705449}, issn = {0317-1671}, } @article {pmid41705664, year = {2026}, author = {De Carvalho, M}, title = {Reviewer Comment on Dallaire et al. "Mortality and Complications of Percutaneous Gastrostomy in Amyotrophic Lateral Sclerosis Patients".}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1}, doi = {10.1017/cjn.2025.10511}, pmid = {41705664}, issn = {0317-1671}, } @article {pmid41706131, year = {2026}, author = {Brünjes, N and Brenne, N and Rupp, D and Sassen, MC and Jerrentrup, A and Wulf, H and Heuser, N and Volberg, C}, title = {[Influence of airway management on the return of spontaneous circulation in out-of-hospital cardiac arrest: secondary analysis of a prospective multidevice study].}, journal = {Medizinische Klinik, Intensivmedizin und Notfallmedizin}, volume = {}, number = {}, pages = {}, pmid = {41706131}, issn = {2193-6226}, abstract = {BACKGROUND: With an incidence of 64.9/100,000 inhabitants in Germany, out-of-hospital cardiac arrest is a frequent reason for emergency medical services (EMS) deployment. Advanced airway management is a key part of advanced life support (ALS), enabling adequate ventilation and continuous chest compressions. Video laryngoscopy (VL), which is increasingly being used, is expected to lead to better success rates and shorter interruptions in chest compressions during airway management. Thus, this article focuses on type of airway management and the devices used and how they relate to the likelihood of achieving return of spontaneous circulation (ROSC) and the resulting survival and neurological outcome.

METHODS: Between January 2020 and June 2024, EMS personnel and emergency physicians received questionnaires on airway management of out-of-hospital resuscitations in which they were involved. The data were supplemented by emergency protocols and defibrillator recordings. The analysis was conducted descriptively and statistically at a significance level of α ≤ 0.05.

RESULTS: A total of 301 questionnaires were assessed: 35% of patients who received endotracheal intubation (ETI) achieved ROSC compared with 21.1% with the use of a supraglottic airway device (SGA; p = 0.09). With the McGrath VL, the ROSC rate was 43.6%, compared to 33.3% with the C‑MAC (p = 0.24). Following 1-2 intubation attempts, ROSC was achieved in 33.8% of cases, and in 28.6% of cases after more than two attempts. The survival rate was 9.1% after ETI and 2.6% after SGA (p = 0.17). With VL, 10.9% of patients survived, 64.7% with a good neurological outcome (cerebral performance category [CPC] 1-2). With direct laryngoscopy, 6.1% survived, 57.1% with CPC 1-2 (p = 0.19/p = 0.73).

CONCLUSION: The results show a potential advantage of video laryngoscopy for endotracheal intubation, whereby > 2 intubation attempts are associated with poorer outcomes. Significant effects on ROSC, survival or an improved neurological outcome were not observed. Larger studies are necessary to verify the results. Increased use of video laryngoscopy could be beneficial regardless of the user.}, } @article {pmid41706243, year = {2026}, author = {Ma, M and Ren, Q and Sun, X and Lin, P and Li, W and Zhao, Y and Meng, X and Yan, C and Liu, S}, title = {Fixel-based analysis to detect early fiber-specific white matter alterations in sporadic patients with amyotrophic lateral sclerosis.}, journal = {Brain imaging and behavior}, volume = {20}, number = {1}, pages = {16}, pmid = {41706243}, issn = {1931-7565}, support = {2020M672067//China postdoctoral science foundation/ ; NSFC82001354//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *White Matter/diagnostic imaging/pathology ; Female ; Male ; Middle Aged ; Retrospective Studies ; Diffusion Magnetic Resonance Imaging/methods ; Aged ; Brain/diagnostic imaging/pathology ; Diffusion Tensor Imaging/methods ; Image Processing, Computer-Assisted/methods ; }, abstract = {Fiber-specific white matter (WM) changes are promising neuroimaging markers to evaluate upper motor neuron damage in amyotrophic lateral sclerosis (ALS) patients. However,to our knowledge, no studies have specifically applied fixel-based analysis (FBA) to investigate fiber-specific WM changes in King’s stage 1 ALS patients in vivo.” To fill this gap in the literature, we performed a retrospective analysis to identify early fiber-specific WM alterations in a large group of sporadic early-stage ALS (ALS-ES) patients and their correlation with clinical data. According to the new "Gold Coast" criteria and the King’s clinical staging system, we defined ALS patients at King’s stage 1 as ALS-ES patients, which corresponds to the earliest symptomatic phase . In this study, 64 newly diagnosed ALS-ES patients and 80 demographic-matched healthy controls (HCs) were included. Then, a novel diffusion-weighted imaging-based approach, fixel-based analysis (FBA), was performed to explore fiber-specific WM alterations in ALS-ES patients and HCs. Three FBA metrics, fiber density (FD), fiber-bundle cross-section (FC), and fiber density and cross-section (FDC), were analysed. Compared with HCs, ALS-ES patients had significantly decreased FD values and FDC values mainly in the bilateral corticospinal tract (CST) and corpus callosum (CC) regions. Compared with HCs, in ALS-ES patients, the FC values were significantly decreased mainly in the bilateral CST regions, while were significantly increased in the CC regions. Moreover, FDC values significantly correlated with motor deficits in ALS-ES patients. Our findings suggest that FBA metrics can provide valuable and complementary fixel-level information regarding the early WM degenerative process in ALS.}, } @article {pmid41707703, year = {2026}, author = {Xu, B and Wu, J}, title = {Response to He et al's "Comments on 'Optimized combination: Isotretinoin in conjunction with oral tranexamic acid for the treatment of moderate to severe acne vulgaris-A randomized, double-blind, placebo-controlled trial'".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {1}, pages = {e55}, doi = {10.1016/j.jaad.2026.01.092}, pmid = {41707703}, issn = {1097-6787}, } @article {pmid41707709, year = {2026}, author = {He, K and Wang, H and Cao, Y}, title = {Response to Bingyang Xu et al's "Optimized combination: Isotretinoin in conjunction with oral tranexamic acid for the treatment of moderate to severe acne vulgaris-A randomized, double-blind, placebo-controlled trial".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {1}, pages = {e57-e58}, doi = {10.1016/j.jaad.2025.12.117}, pmid = {41707709}, issn = {1097-6787}, } @article {pmid41708347, year = {2026}, author = {Gontier, G and Kim, G and Wang, C and Zhu, K and Gau, R and Zhang, N and Naphade, S and Stewart, A and Schmidt, MJ and Galemmo, R and Shook, B and Tarachandani, A and Choi, I and Raines, S and Scannevin, RH and Grievink, HW and Smits, LMG and Kremer, PHC and Cadavid, D}, title = {Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB): A Translational Pharmacodynamic Biomarker for PIKfyve Inhibition With VRG50635.}, journal = {Clinical and translational science}, volume = {19}, number = {2}, pages = {e70489}, pmid = {41708347}, issn = {1752-8062}, support = {//Verge Genomics/ ; }, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/blood ; *Membrane Glycoproteins/metabolism/blood ; Male ; *Phosphoinositide-3 Kinase Inhibitors/pharmacology/pharmacokinetics ; Phosphatidylinositol 3-Kinases/metabolism ; Biomarkers/metabolism/blood ; Leukocytes, Mononuclear/drug effects/metabolism ; Adult ; Female ; }, abstract = {Glycoprotein non-metastatic melanoma protein B (GPNMB) was investigated as a pharmacodynamic (PD) biomarker for PIKfyve inhibition across translational studies ex vivo, in vitro, in animals, and in the clinic, demonstrating significant response to VRG50468 in cells, in vivo in the central nervous system (CNS) and in peripheral fluids and tissues. VRG50468 is the active metabolite of VRG50635, a small molecule PIKfyve inhibitor pro-drug in development for treating amyotrophic lateral sclerosis (ALS). Peripheral pharmacology was evaluated in peripheral blood mononuclear cells (PBMCs) from healthy volunteers ex vivo and in vitro and in PBMCs from mice given oral VRG50635. Central pharmacology was evaluated in vitro using C9orf72 ALS patient-derived induced pluripotent stem cell motor neurons and mouse primary neurons, and in vivo in brains of mice given oral VRG50635. Two clinical studies in healthy adults examined plasma, PBMCs, and cerebrospinal fluid following oral VRG50635 for peripheral and central pharmacologic activity via GPNMB induction. PD GPNMB upregulation with VRG50468 was demonstrated across preclinical translational and clinical studies. A PD response to VRG50468 was observed ex vivo in rodent and human PBMCs and in primary rodent neurons and motor neurons induced from stem cells of people with ALS. Repeated administration of VRG50635 to rodents and healthy human volunteers robustly induced GPNMB peripherally and in the CNS, which was concentration and time dependent in vitro and dose and treatment duration dependent in vivo, peripherally, and in CNS. GPNMB is a robust translatable PD biomarker for clinical trials with the PIKfyve inhibitor VRG50635. TRIAL REGISTRATION: Clinical trial number: VGCS-50635-001 and VGCS-50635-003; identifier: NL81735.056.22 and NCT06286475.}, } @article {pmid41709060, year = {2026}, author = {Yadav, AK and Verma, P and Srivastava, A and Srivastava, P and Rai, R and Rathour, S}, title = {Molecular insights into glial neuroimmune cross reactivity with CNS antigens and its role in neuroinflammation.}, journal = {Inflammopharmacology}, volume = {34}, number = {3}, pages = {1399-1424}, pmid = {41709060}, issn = {1568-5608}, mesh = {Animals ; Humans ; *Antigens/immunology ; Blood-Brain Barrier/metabolism/immunology ; *Central Nervous System/immunology/metabolism ; Cytokines/metabolism/immunology ; Inflammasomes/metabolism ; *Inflammation/immunology ; Neurodegenerative Diseases/immunology ; *Neuroglia/immunology/metabolism ; *Neuroimmunomodulation/immunology/physiology ; *Neuroinflammatory Diseases/immunology/metabolism ; }, abstract = {Neuroinflammation has been increasingly considered a key player of neurodegenerative as well as psychiatric disorders. This review integrates existing knowledge on glial-neuroimmune interactions, emphasizing the roles of cytokine signaling, glial activation, and BBB modulation in neuro-pathogenesis. A systematic review was performed studying peer-reviewed literature on molecular pathways of microglia, astrocytes, endothelial cells, and peripheral immune mediators. A possible explanation of this finding could be that the model is based on the underlying pathophysiology, and this is shared across disease contexts, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury. Novel in vitro platforms, including the organ-on-a-chip and brain organoids, were also discussed for their translational potential. Microglia M1/M2 polarization and astrocyte reactivity appeared to be a common feature in neurotoxicity as well as excitotoxicity and chronic inflammation. Cytokine cascade of TNF-α, IL-1β, and IL-6 led to the disrupted BBB, allowing for peripheral immune cells to infiltrate. Both the NLRP3 inflammasome and mitochondrial dysfunction were identified as enhancers of neuroimmune signaling. Comparing across disease models, shared relationships emerged between glia-cytokines-BBB. Advanced in vitro systems proved to be useful to model these interactions and screen prescription drugs. This review highlights existing insights into glia-neuroimmune cross-reactivity and its critical role in CNS disease. The molecular interactions between these molecules could represent promising targets for novel therapeutic options. We suggests integrative systems platforms and AI-driven strategies to expedite clinical translation in neuroinflammation.}, } @article {pmid41710159, year = {2026}, author = {Pang, Y and Yang, J and Liu, J and Xie, Z and Wang, J}, title = {Metabolic interactions in the brain: the crucial roles of neurons, astrocytes, and microglia in health and disease.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1731771}, pmid = {41710159}, issn = {1662-4548}, abstract = {This review provides an in-depth exploration of the intricate energy metabolism pathways within the brain, with a particular focus on the dynamic interplay between neurons, astrocytes, and microglia. Neurons, with their high energy demands, primarily rely on oxidative phosphorylation and the tricarboxylic acid (TCA) cycle to sustain synaptic activity and neurotransmitter synthesis. In contrast, astrocytes predominantly engage in glycolysis, producing lactate and glutathione, which are essential for supporting neuronal function and protecting against oxidative stress. Additionally, microglia, the brain's resident immune cells, exhibit a metabolic flexibility that allows them to shift between oxidative phosphorylation and glycolysis, depending on their activation state, which significantly influences neuroinflammation and synaptic plasticity. The review highlights the critical role of astrocyte-neuron metabolic coupling, particularly through the lactate shuttle and glutathione metabolism, in maintaining neuronal homeostasis and facilitating synaptic function. It also delves into the metabolic underpinnings of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis, illustrating how disruptions in brain energy metabolism contribute to disease progression. By synthesizing recent findings, this review not only underscores the centrality of brain energy metabolism in both normal and pathological conditions but also identifies potential therapeutic targets aimed at modulating these metabolic pathways to mitigate the effects of neurodegenerative disorders. This comprehensive analysis offers valuable insights that could propel further research and innovation in the field of neurology, making it essential reading for experts interested in the molecular mechanisms underlying brain function and disease.}, } @article {pmid41710754, year = {2026}, author = {Corvino, A and Caliendo, G and Fiorino, F and Frecentese, F and Valsecchi, V and Lombardi, G and Anzilotti, S and Andreozzi, G and Scognamiglio, A and Sparaco, R and Perissutti, E and Severino, B and Gargiulo, M and Santagada, V and Pignataro, G}, title = {Correction to "Newly Synthesized Indolylacetic Derivatives Reduce Tumor Necrosis Factor-Mediated Neuroinflammation and Prolong Survival in Amyotrophic Lateral Sclerosis Mice".}, journal = {ACS pharmacology & translational science}, volume = {9}, number = {2}, pages = {461}, doi = {10.1021/acsptsci.6c00037}, pmid = {41710754}, issn = {2575-9108}, abstract = {[This corrects the article DOI: 10.1021/acsptsci.4c00098.].}, } @article {pmid41710834, year = {2026}, author = {Chen, HW}, title = {Active Craniospinal Tensioning (ACT): Axial Spinal Traction for Glymphatic Modulation.}, journal = {Cureus}, volume = {18}, number = {1}, pages = {e101796}, pmid = {41710834}, issn = {2168-8184}, abstract = {The glymphatic system is a clearance pathway that facilitates convective exchange between cerebrospinal fluid (CSF) and interstitial fluid, and is increasingly implicated in the pathophysiology of neurodegenerative and neuroinflammatory disorders. However, translation of glymphatic physiology into intentional, noninvasive biomechanical interventions remains limited. Building on a previously introduced biomechanical framework that proposed axial spinal traction as a method to modulate CSF and glymphatic circulation, practitioner-applied pelvis-stabilized axial spinal traction (PSAST) has been characterized as a controlled prototype, although its reliance on professional administration and structured setup may constrain deployment in population-level or preventive contexts. This report introduces active craniospinal tensioning (ACT) as a translational, participant-driven extension of the established axial traction-glymphatic modulation framework, specifically designed for ambulatory populations. ACT employs a voluntary squat maneuver combined with a standardized overhead anchor system to generate controlled axial tension along the craniospinal axis, while preserving the same dural tensioning and craniospinal coupling principles described in prior axial traction models. By shifting force generation from practitioner-applied loading to participant-regulated loading, ACT presents a scalable approach for exploratory preventive application under supervised conditions. ACT is theoretically framed for individuals exhibiting reduced perivascular water diffusivity, such as those with lower diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) indices. This report provides a practical implementation framework for ACT and supports future hypothesis-driven investigation of biomechanical modulation of CSF and glymphatic circulation using advanced neuroimaging biomarkers.}, } @article {pmid41710977, year = {2026}, author = {Liu, Q and Zhang, X and Wang, L and Chen, H and Wang, G and Sun, Y and He, B and Gao, J and Qiu, W and Ma, C and Sun, M and Cui, L and Zhang, X}, title = {BTK inhibition suppresses neuroinflammation and neurodegeneration in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag070}, pmid = {41710977}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis(ALS) is a devastating neurodegenerative disorder with limited therapeutic interventions. Neuroinflammation represents a central pathogenic mechanism in ALS, yet the upstream molecular regulators that integrate multiple inflammatory cascades remain poorly understood. Here, we investigated whether Bruton's tyrosine kinase (BTK), which integrates DNA-sensing and Toll-like receptor signals upstream of the cGAS-STING-NF-κB cascade, serves as a key regulatory node in ALS pathogenesis. Public RNA-seq datasets of motor neurons and post-mortem tissues from ALS patients were utilized to identify BTK expression patterns. SOD1-mutant human induced pluripotent stem cells (hiPSC) were differentiated into motor neurons (hiPSC-MNs) and microglia (hiPSC-MGs). NF-κB dysregulation was profiled by scRNA-seq (hiPSC-MGs) and bulk RNA-seq (hiPSC-MNs). DNA damage (γH2AX), inflammatory signalling (western blot/ELISA) and phagocytosis (pH-rodo uptake) were quantified, and MG-conditioned medium was tested for MN toxicity. Monocultures and MN-MG co-cultures received zanubrutinib (3 µM, 12 h). SOD1-G93A mice were administered zanubrutinib (30 mg/kg, daily) from 2.5 months; motor performance, survival, spinal histology and PI3K-AKT-mTOR activity were assessed after 2 months of treatment. ALS spinal cord and cortex tissues of patients, as well as SOD1-mutant hiPSC-MGs and hiPSC-MNs, demonstrated elevated BTK phosphorylation with increased p-STING, p-TBK1, and nuclear NF-κB accumulation. ALS hiPSC-MGs exhibited inflammatory activation, NLRP3 induction, and impaired phagocytosis, while ALS hiPSC-MNs showed DNA damage and caspase-3-mediated apoptosis. Conditioned medium from inflammatory microglia amplified neuronal STING-NF-κB activity and apoptosis, demonstrating non-cell-autonomous toxicity. The STING inhibitor H-151 reduced neuronal p-STING/p-TBK1/NF-κB and apoptosis, confirming pathway causality. Pharmacological BTK inhibition reduced DNA damage in ALS hiPSC-MNs by 61.4% (p<0.05), restored phagocytosis in ALS hiPSC-MGs to 87.2% of control levels (p<0.01), and prevented neuronal apoptosis induced by microglial conditioned medium. In SOD1-G93A mice, BTK blockade extended median survival from 158 to 173 days (p<0.01, log-rank test), improved motor function, and attenuated neuroinflammation while moderately rebalancing PI3K-AKT-mTOR signaling without impairing autophagy-lysosome dynamics. We identify BTK as a critical upstream regulator of the dysregulated cGAS-STING-NF-κB signalling axis characteristic of ALS pathogenesis. BTK orchestrates both cell-autonomous dysfunction in motor neurons and non-cell-autonomous toxicity through microglial activation, representing a convergent regulatory node that integrates multiple pathogenic pathways. These mechanistic insights provide a molecular framework for understanding ALS neuroinflammation and establish a rational basis for BTK-targeted therapeutic intervention in neurodegeneration.}, } @article {pmid41712833, year = {2025}, author = {Hamad, AA}, title = {How Amyotrophic Lateral Sclerosis Contributes to Increased Venous Thromboembolism Risk.}, journal = {La Tunisie medicale}, volume = {103}, number = {3}, pages = {307-308}, doi = {10.62438/tunismed.v103i3.5734}, pmid = {41712833}, issn = {2724-7031}, mesh = {Humans ; *Venous Thromboembolism/etiology/epidemiology ; *Amyotrophic Lateral Sclerosis/complications/epidemiology ; Risk Factors ; }, } @article {pmid41712834, year = {2025}, author = {Finsterer, J and Mehri, S}, title = {Immobile ALS patients or those at risk of venous thromboembolism require a comprehensive examination and low-dose heparinisation.}, journal = {La Tunisie medicale}, volume = {103}, number = {3}, pages = {306}, doi = {10.62438/tunismed.v103i3.5658}, pmid = {41712834}, issn = {2724-7031}, } @article {pmid41713588, year = {2026}, author = {Akaike, T and Thakuria, M and Silk, AW and Hippe, DS and Ch'en, PY and Guja, KE and Youn Park, S and Tsai, K and Yom, SS and Yu, SS and Choi, J and Chandra, S and Nghiem, PT and Zaba, LC}, title = {Response to Gao and Chen, "Comments on Akaike et al's 'Circulating tumor DNA level is associated with time to clinical recurrence in Merkel cell carcinoma: Implications for patient management'".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {6}, pages = {e447-e448}, pmid = {41713588}, issn = {1097-6787}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, } @article {pmid41714091, year = {2026}, author = {Howard, J and Bekker, HL and McDermott, CJ and McNeill, A}, title = {Predictive genetic testing in amyotrophic lateral sclerosis (ALS): Experiences of decision-making and engagement with UK genetic counseling services.}, journal = {Journal of genetic counseling}, volume = {35}, number = {1}, pages = {e70184}, pmid = {41714091}, issn = {1573-3599}, support = {/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genetic Counseling ; *Genetic Testing ; United Kingdom ; *Decision Making ; Female ; Male ; Middle Aged ; Adult ; }, abstract = {Predictive genetic testing enables at-risk relatives of people with amyotrophic lateral sclerosis (ALS, also known as motor neuron disease or MND) to find out if they have inherited the genetic variant identified in their family member and have an increased chance of developing symptoms. As research progresses, eligibility for and interest in predictive testing is increasing. This paper explores the experiences of people making decisions about predictive testing and identifies their information needs over the process. Semi-structured interviews were carried out with 14 individuals from across the United Kingdom who had, or were considering, predictive testing for ALS. Interviews were carried out via video call or face-to-face between March and September 2023, transcribed, and analyzed using inductive framework analysis. Findings illustrate a range of experiences. Interviews suggest variation in practice in terms of the structure of the genetic counseling process and the content of information given. Some expressed positive experiences of genetic counseling, and valued feeling listened to, understood, and supported. Others perceived barriers to accessing testing, felt the information provided was directive or not sufficient to support their concerns and decision-making. Information needs varied, and whilst people felt satisfied, there were also diverse, unmet information and support needs raised throughout the decision-making process and beyond. This evidence has been used to support the development of a patient decision aid for predictive genetic testing in ALS.}, } @article {pmid41714394, year = {2026}, author = {Warmann, S}, title = {[Motor neuron diseases from a radiological perspective : Focus on amyotrophic lateral sclerosis].}, journal = {Radiologie (Heidelberg, Germany)}, volume = {66}, number = {4}, pages = {272-277}, pmid = {41714394}, issn = {2731-7056}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis ; *Magnetic Resonance Imaging ; Electromyography ; *Motor Neuron Disease/diagnostic imaging/diagnosis ; Diagnosis, Differential ; Muscular Atrophy, Spinal/diagnostic imaging ; }, abstract = {BACKGROUND: Motor neuron diseases (MND) affect the upper and/or lower motor neurons. Radiological diagnostics primarily serve to systematically exclude treatable mimics and support the clinical and electrophysiological diagnosis. The focus is on amyotrophic lateral sclerosis (ALS); supplementary progressive muscular atrophy (PMA, purely lower motor neuron, LMN disease) and spinal muscular atrophy (SMA).

OBJECTIVE: Which imaging signs support the diagnosis of ALS, how do electromyography/magnetic resonance imaging (EMG/MRI) fit into the Gold Coast criteria and which other motor neuron diseases are relevant?

MATERIAL AND METHODS: Overview of clinical criteria (Gold Coast), genetics and typical MRI findings of the brain, spinal cord and musculature.

RESULTS: Gold Coast core: progressive motor deterioration, upper motor neuron (UMN) and LMN signs in ≥ 1 region or LMN in ≥ 2 regions and exclusion of alternative causes.

IMAGING: susceptibility-weighted imaging (SWI) motor band sign as UMN marker; T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities along the corticospinal tract with low sensitivity, moderate specificity; T1 bright tongue as an indication of chronic denervation in bulbar involvement. EMG: detection of subclinical LMN involvement, sometimes limited in UMN-dominant/bulbar courses. PMA: Pure purely LMN symptoms, often continuum to ALS. SMA: Autosomal autosomal recessive (SMN1 deletion).

DISCUSSION: The diagnosis remains primarily clinical; EMG and MRI are supportive. The radiological priority is the exclusion of mimics. The UMN markers increase diagnostic certainty in the context of clinical/EMG findings but do not replace them. Clear findings facilitate classification according to Gold Coast. The PMA and SMA require careful differential diagnostics; characteristic MRI patterns support progression and treatment planning.}, } @article {pmid41716354, year = {2025}, author = {Moleón, VR and Ayoubi, R and Alende, C and Fothouhi, M and Ryan, J and Bolívar, SG and Worrall, D and Durcan, TM and Brown, CM and Francis, V and McPherson, PS and Laflamme, C}, title = {A guide to selecting high-performing antibodies for Optineurin (UniProt ID: Q96CV9) for use in western blot, immunoprecipitation, and immunofluorescence.}, journal = {F1000Research}, volume = {14}, number = {}, pages = {1137}, pmid = {41716354}, issn = {2046-1402}, mesh = {Membrane Transport Proteins ; Humans ; *Transcription Factor TFIIIA/immunology ; Cell Cycle Proteins ; *Fluorescent Antibody Technique/methods ; *Immunoprecipitation/methods ; *Blotting, Western/methods ; *Antibodies/immunology ; Animals ; }, abstract = {Optineurin (OPTN) is a multifunctional cytoplasmic adaptor protein implicated in maintaining neuronal homeostasis through its roles in selective autophagy, vesicle trafficking, and regulation of inflammatory signaling. Mutations in the OPTN gene are causally linked to several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and primary open-angle glaucoma. Here we have eight optineurin commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While the use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.}, } @article {pmid41717003, year = {2026}, author = {Inami, S and Jenny, BP and Akpoghiran, O and Gallagher, SI and Strich, AK and Tonoki, A and Trotti, D and Haeusler, AR and Koh, K}, title = {Increased neuronal activity restores circadian function in Drosophila models of C9orf72-ALS/FTD.}, journal = {iScience}, volume = {29}, number = {2}, pages = {114798}, pmid = {41717003}, issn = {2589-0042}, support = {R01 NS114128/NS/NINDS NIH HHS/United States ; R21 NS135762/NS/NINDS NIH HHS/United States ; RF1 NS114128/NS/NINDS NIH HHS/United States ; }, abstract = {Circadian rhythm disruptions are common across neurodegenerative diseases, but their link to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. The C9orf72 hexanucleotide repeat expansion is the most prevalent genetic cause of ALS/FTD. Here, we used Drosophila models expressing pathogenic arginine-rich dipeptides (PR or GR) or GGGGCC hexanucleotide repeats to investigate circadian deficits in C9orf72-ALS/FTD. We found that circadian rhythmicity and period length were altered in a repeat number-, dosage-, expression pattern-, and age-dependent manner. Additionally, we observed lower levels of the neuropeptide PDF, a key regulator of free-running circadian rhythms, as well as decreased projection complexity and reduced neuronal activity in PDF-expressing neurons. Importantly, increases in neuronal activity significantly rescued mild circadian dysfunction across ages and across PR, GR, and GGGGCC repeat models when appropriately tuned. These results implicate reduced neuronal activity in C9orf72-ALS/FTD circadian deficits, underscoring the importance of calibrated, and stage-specific interventions.}, } @article {pmid41718290, year = {2026}, author = {Messina, C}, title = {Silent Damage, Delayed Symptoms: A Case of Breast Cancer Radiation-Induced Lumbosacral Plexopathy.}, journal = {Reports (MDPI)}, volume = {9}, number = {1}, pages = {}, pmid = {41718290}, issn = {2571-841X}, abstract = {Background and Clinical Significance: Radiation-induced lumbosacral plexopathy (RILP) is a rare but potentially debilitating complication of radiotherapy, typically affecting patients treated for pelvic malignancies. We report the first documented case of asymmetric RILP following radiotherapy for breast cancer. Case Presentation: A 64-year-old woman developed progressive left lower limb weakness, foot drop, and sensory disturbances four years after receiving locoregional radiotherapy extending to the left thoracoabdominal and lumbar areas. Electrophysiological studies revealed an asymmetric sensorimotor axonal neuropathy predominantly involving the left lower limb, without conduction block and sparing the upper limbs, whereas needle electromyography of the lower limbs showed fibrillation potentials, positive sharp waves, and fasciculations in the vastus lateralis, tibialis anterior, and medial gastrocnemius muscles on the left. Magnetic resonance imaging demonstrated edema and contrast enhancement of bilateral L2-L4 nerve roots with paraspinal muscle atrophy. Cerebrospinal fluid analysis showed albuminocytologic dissociation and elevated neurofilament levels. After exclusion of alternative diagnoses, including amyotrophic lateral sclerosis and inflammatory neuropathies, a diagnosis of radiation-induced peripheral neuropathy and RILP was made. The patient's condition stabilized with physiotherapy and symptomatic treatment. Conclusions: This case highlights the need for heightened awareness of RILP as a late complication of breast cancer radiotherapy, underscoring the importance of accurate diagnosis to avoid misclassification and unnecessary treatments. Clinicians should carefully integrate all clinical elements-including a thorough remote medical history-since radiation-related neurological damage may manifest many years after the initial insult.}, } @article {pmid41718455, year = {2026}, author = {Wan, Y and Yu, Z and Yang, J and Zhang, W and Yu, M and Meng, L and Wang, Z and Yuan, Y and Ruan, L and Deng, J and Wang, P}, title = {The Mislocalization of TDP-43 to Mitochondria Impairs Myotube Maturation.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {40}, number = {4}, pages = {e71603}, doi = {10.1096/fj.202504624R}, pmid = {41718455}, issn = {1530-6860}, support = {2025ZD0217600//Brain Science and Brain-like Intelligence Technology/ ; 32460138//National Natural Science Foundation of China/ ; 82422025//National Natural Science Foundation of China/ ; 82401635//National Natural Science Foundation of China/ ; 82430059//National Natural Science Foundation of China/ ; 32571340//National Natural Science Foundation of China/ ; 2024YFA1803700//National Key Research and Development Program of China/ ; 2023HQ03//National High Level Hospital Clinical Research Funding/ ; PKU2025PKULCXQ016//Clinical Medicine Plus X/ ; }, mesh = {*Muscle Fibers, Skeletal/metabolism/pathology ; Humans ; Animals ; Mice ; *DNA-Binding Proteins/genetics/metabolism ; *Mitochondria/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Protein Transport ; }, abstract = {Aggregation of TDP-43 in neuronal cells is a defining neuropathological hallmark of amyotrophic lateral sclerosis (ALS). Emerging evidence suggests that TDP-43 pathology also occurs in skeletal muscle fibers, but its functional significance in myocytes remains poorly understood. In this study, we utilized the C2C12 myoblast cell to investigate the subcellular localization of TDP-43 during myogenic differentiation. Our findings demonstrate that TDP-43 progressively translocates to mitochondria in parallel with myotube maturation. Notably, increased mitochondrial localization of TDP-43 was also observed in skeletal muscle tissues from patients with ALS, corroborating the clinical relevance of this phenomenon. Functional assays revealed that inhibition of TDP-43 mitochondrial translocation significantly enhances myotube maturation. Collectively, these results support a pathophysiological role for aberrant mitochondrial mislocalization of TDP-43 in regulating myogenic differentiation and contributing to muscle degeneration in TDP-43 proteinopathies.}, } @article {pmid41718496, year = {2026}, author = {Judge, S and Ballesteros, K and McDermott, CJ and Bloch, S}, title = {Timing of communication and technology control support in ALS - a systematic review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {504-512}, doi = {10.1080/21678421.2026.2627899}, pmid = {41718496}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/rehabilitation ; *Communication Devices for People with Disabilities ; Time Factors ; *Self-Help Devices ; *Communication ; }, abstract = {Objective: To review evidence on the optimal timing of interventions that support communication and technology control for people living with Amyotrophic Lateral sclerosis (ALS). Methods: A systematic review was conducted following a pre-registered protocol. Databases were searched for studies involving people living with ALS that addressed timing of assistive technology interventions for communication or technology control. Screening and data extraction were completed in duplicate, findings were synthesized using a thematic analysis, and relevant findings presented as a descriptive summary. Results: Twenty-eight studies met the inclusion criteria. Evidence focused overwhelmingly on communication support rather than wider assistive technology interventions. Need for a communication aid typically occurs between one and five years from diagnosis and the timing of this varies significantly according to the site of onset of ALS. There are significant variations in the timing of changes for individuals within these groupings and there are likely a larger number of groupings that would be clinically useful. A significant correlation between changes in speaking rate and intelligibility has been shown. Once changes to speech do start to occur then the time to the loss of functional speech appears relatively consistent across the types of ALS. Conclusion: Current best practice guidelines are not reflective of the findings of this review and do not support professionals in identifying how to provide timely support. Monitoring speech changes systematically may support timely intervention. There is potential for individual level predictive modeling to help support people living with ALS to be proactive and prepared for changes.}, } @article {pmid41718986, year = {2026}, author = {Shadfar, S and Assar Kashani, S and Gautam, S and Takalloo, Z and Farzana, F and Parakh, S and Atkin, JD}, title = {The Role of the Golgi Apparatus in Neurodegeneration.}, journal = {Sub-cellular biochemistry}, volume = {111}, number = {}, pages = {413-440}, pmid = {41718986}, issn = {0306-0225}, mesh = {Humans ; *Golgi Apparatus/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Neurons/metabolism/pathology ; Signal Transduction ; }, abstract = {The Golgi apparatus has important, well characterised functions in the trafficking, processing, and post-translational modification of proteins and lipids. However, roles in other cellular processes are increasingly reported, including autophagy, apoptosis, DNA repair, and cytoskeletal (microtubules and actin) function. The Golgi therefore serves as a regulatory hub for multiple signalling pathways that maintain essential cellular activities. The Golgi normally consists of flattened stacks of membrane (cisternae), but during normal physiology and pathological conditions it 'fragments', resulting in altered morphology and distribution. This is well described as an early pathological feature of many neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) and prion diseases, and amyotrophic lateral sclerosis (ALS). These age-related conditions are characterised by the death of neurons: highly specialised, unique cells that form the foundation of the nervous system. Interestingly, many Golgi-related functions are also dysregulated in these diseases. However, this has received relatively little attention compared to other pathogenic mechanisms. The Golgi apparatus in neurons shares features common to other eukaryotic cells but it also has unique properties, such as the presence of distinctive assemblies: Golgi outposts and satellites, which remain poorly characterised. Here we discuss the increasing evidence describing dysfunction and fragmentation of the Golgi apparatus and its possible role in the pathogenesis of neurodegenerative diseases.}, } @article {pmid41720758, year = {2026}, author = {Falahati, M and Orangi, K and Shaabanpoor Haghighi, A and Pouroushaninia, N and Niknam, N and Soltani, S and Radnia, P and Arab Bafrani, M and Shirdel, S and Aarabi, MH}, title = {Microstructural alterations of the amygdala in neurodegenerative and neuroinflammatory disorders: insights from diffusion tensor imaging.}, journal = {Reviews in the neurosciences}, volume = {37}, number = {3}, pages = {289-304}, pmid = {41720758}, issn = {2191-0200}, mesh = {Humans ; *Amygdala/diagnostic imaging/pathology ; *Diffusion Tensor Imaging/methods ; *Neurodegenerative Diseases/diagnostic imaging/pathology ; *Neuroinflammatory Diseases/diagnostic imaging/pathology ; }, abstract = {Diffusion tensor imaging (DTI) is a valuable method for evaluating microstructural changes in the amygdala associated with neurodegenerative and neuroinflammatory disorders. This systematic review examines amygdala microstructural alterations in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), and multiple sclerosis (MS) using DTI metrics. Following PRISMA 2020 guidelines, we searched PubMed, Scopus, and Web of Science databases through August 2025, identifying 4,442 records. After screening and eligibility assessment, 13 studies were included, comprising 1,412 patients and 1,146 healthy controls. Due to sample heterogeneity and lack of standardized effect size measures, meta-analysis was not performed. Across disorders, elevated mean diffusivity (MD) emerged as the most consistent finding, present in 100 % of AD patients and observed in all examined conditions. Reduced fractional anisotropy (FA) was the second most frequent alteration, with 36.6 % of AD patients showing decreased FA. In MS, increased radial diffusivity (RD) was prominent, while longitudinal DLB studies revealed progressive free water (FW) increases. These DTI-based microstructural changes often preceded volumetric atrophy and correlated with clinical severity. Our findings demonstrate that DTI metrics, particularly MD and FA, serve as sensitive markers of amygdala pathology across neurodegenerative diseases and may facilitate early diagnosis, disease monitoring, and differential diagnosis of these conditions.}, } @article {pmid41720774, year = {2026}, author = {Yang, M and Wang, Q and Yan, R and Kang, D and Luo, W and Zhang, L and Liu, R and Wu, L and Gu, J and Wang, X}, title = {A neurotoxic cryptic peptide arising from TDP-43-dependent cryptic splicing of PKN1.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41720774}, issn = {2041-1723}, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *RNA Splicing ; *Alzheimer Disease/genetics/metabolism/pathology ; Brain/metabolism/pathology ; *Peptides/metabolism/genetics ; Exons ; Female ; }, abstract = {Dysfunction of transactive response DNA-binding protein 43 (TDP-43) drives neurodegeneration in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), in part through inducing aberrant RNA splicing. However, whether such mis-splicing yields stable, pathogenic proteins remains unclear. Here, we identify a TDP-43-repressed cryptic exon in Protein kinase N1 (PKN1), designated PKN1-5a1, which is activated in ALS patient brains and introduces a premature termination codon. This aberrant transcript escapes nonsense-mediated decay and is translated into a truncated peptide, PKN1-N207 (PKN207), detectable in AD brains with TDP-43 pathology. In mice, PKN207 impairs cognition, memory, and synaptic plasticity. Our findings demonstrate that TDP-43 loss-induced cryptic splicing can generate stable neurotoxic polypeptides, revealing a peptide-mediated mechanism in TDP-43 proteinopathies.}, } @article {pmid41721943, year = {2026}, author = {Choi, CI and Kim, HN and Yoon, H and Radulovic, M and Simon, WL and Scarisbrick, IA}, title = {Regional Molecular Diversity in Chronic Spinal Cord Injury.}, journal = {Cellular and molecular neurobiology}, volume = {46}, number = {1}, pages = {}, pmid = {41721943}, issn = {1573-6830}, mesh = {Animals ; *Spinal Cord Injuries/genetics/pathology/metabolism ; Female ; Mice, Inbred C57BL ; Chronic Disease ; Mice ; Gene Expression Regulation ; Gene Expression Profiling ; }, abstract = {The development of next generation cellular and acellular therapies for regenerative repair of the injured spinal cord will benefit from a greater understanding of microenvironment heterogeneity. To address this need, we used genome wide RNA sequencing to illuminate gene expression changes in the spinal cord injury (SCI) epicenter, and in regions above and below, 30 days after contusion-compression (8 g Fejota clip) of the lumbar spinal cord (L1/L3) in adult female C57BL7J mice. Across injury zones, there were more upregulated versus downregulated genes, with the most dynamic changes occurring in the epicenter, followed by the below and above regions. The expression of 52.9% of genes was uniquely changed in epicenter, 6.6% in the below region, and 2.8% in the above region, while 18.3% of differentially expressed genes (DEGs) overlapped across regions. Ingenuity Pathway analysis of epicenter DEGs showed 49 unique pathways, including Type II Diabetes Mellitus, P2Y Purinergic Receptor, Amyotrophic Lateral Sclerosis, JAK family kinases, and pathways related to GABA and Glutamate function. Thyroid Hormone Metabolism II, Serotonin degradation, and Myc-Mediated Apoptosis were enriched in the zone above the epicenter, while the Chondroitin sulfate degradation, the Superpathway of Geranylgeranylipidphosphate and Zymosterol Biosynthesis, and Regulation of Cellular Mechanics by Calpain Proteases were enriched below. There were 100 pathways shared across regions emphasizing fundamental roles for Apoptosis, Cytoskeletal organization, Chemokines, Complement, Prothrombin Activation pathways, Type I Diabetes Mellitus Signaling, and RXR signaling. These findings provide a rich resource of candidate mechanisms for additional validation and the design of targeted therapies to improve recovery after spinal cord injury.}, } @article {pmid41722440, year = {2026}, author = {Squintani, G and Muzio, MD and Rasera, A and Paio, F and Borin, GU and Humaidan, K and Orlando, D and Refatti, N and Romito, S and Tinazzi, M and Bonetti, B and Ermani, M}, title = {Corrigendum to "Sensory and motor cortical hyperexcitability in patients with amyotrophic lateral sclerosis: are they related? A prospective pilot study". [CLINPH 183 (2026) 2111485].}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {184}, number = {}, pages = {2111703}, doi = {10.1016/j.clinph.2026.2111703}, pmid = {41722440}, issn = {1872-8952}, } @article {pmid41722586, year = {2026}, author = {Jing Jing Yeo, C}, title = {The Tuesday lessons of ALS.}, journal = {The Lancet. Neurology}, volume = {25}, number = {3}, pages = {231}, doi = {10.1016/S1474-4422(26)00048-7}, pmid = {41722586}, issn = {1474-4465}, } @article {pmid41723070, year = {2026}, author = {Togawa, N and Ayaki, T and Yoshii, D and Maki, T and Sawamoto, N and Takahashi, R}, title = {Corrigendum to "TMEM119-positive microglia were increased in the brains of patients with amyotrophic lateral sclerosis" [Neurosci. Lett. 833 (2024) 137829].}, journal = {Neuroscience letters}, volume = {875}, number = {}, pages = {138544}, doi = {10.1016/j.neulet.2026.138544}, pmid = {41723070}, issn = {1872-7972}, } @article {pmid41723333, year = {2026}, author = {Wang, Y and Zhang, H and Yang, T and Luo, J and Lin, T and Yan, X and Ding, J and Qiu, Y and Zhao, M and Yang, G}, title = {Imaging-derived neuromuscular ultrasound phenotypes are associated with functional status in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {2}, pages = {}, pmid = {41723333}, issn = {1432-1459}, support = {2025HZZD09//Construction Fund of Key Medical Disciplines of Hangzhou for Rare Disease (Motor Neuron Disease)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/classification ; Ultrasonography/methods ; Female ; Male ; Phenotype ; Middle Aged ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Aged ; Clustering Algorithms ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) presents with marked clinical heterogeneity, complicating diagnosis and management. Neuromuscular ultrasound (NMUS) provides a non-invasive means to visualize peripheral nerve and muscle integrity, but its potential to delineate ALS subtypes has not been systematically explored.

OBJECTIVE: To identify clinically meaningful ALS subgroups through unsupervised clustering of NMUS features integrated with clinical and electrophysiological data.

METHODS: A total of 454 ALS patients (August 2024-December 2025) underwent standardized NMUS assessment, including muscle thickness, echogenicity, and nerve cross-sectional area, alongside ALSFRS-R, manual muscle testing (MMT), and compound muscle action potentials (CMAPs). K-means clustering was applied to standardized NMUS variables, with cluster stability assessed using silhouette coefficients, sensitivity analyses (k = 2-5), and resampling-based adjusted Rand indices. Multivariable regression examined associations between cluster membership and ALSFRS-R.

RESULTS: Two reproducible NMUS-based subgroups were identified: a Mild cluster (n = 288, 63.4%) and a Severe cluster (n = 166, 36.6%). The Severe cluster showed reduced muscle thickness and higher echogenicity across multiple sites, together with lower ALSFRS-R scores (adjusted β = - 3.84, 95% CI - 5.41 to - 2.27, P < 0.001). Cluster membership correlated negatively with MMT and CMAP amplitudes, supporting functional and electrophysiologic validity. Stability metrics confirmed robustness of the two-cluster solution.

CONCLUSION: Integrating NMUS with clinical data enables objective, imaging-derived stratification of ALS patients into biologically and functionally distinct subgroups. This approach offers a pragmatic framework for phenotypic characterization and may inform personalized monitoring and trial design in ALS.}, } @article {pmid41723979, year = {2026}, author = {Gao, Y and Lu, Y and Zhao, S and Chen, R and Liu, J and Zhang, S and Bai, X and Zhang, J}, title = {Allicin improves motor neuron survival in amyotrophic lateral sclerosis by reducing neuroinflammation and modulating gut microbiota.}, journal = {Biochemical and biophysical research communications}, volume = {809}, number = {}, pages = {153503}, doi = {10.1016/j.bbrc.2026.153503}, pmid = {41723979}, issn = {1090-2104}, mesh = {Animals ; *Sulfinic Acids/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; *Gastrointestinal Microbiome/drug effects ; *Motor Neurons/drug effects/pathology ; Disulfides ; Mice, Transgenic ; *Neuroinflammatory Diseases/drug therapy/pathology ; Mice ; Cell Survival/drug effects ; Disease Models, Animal ; Male ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons (MNs). Allicin, a defensive molecule in garlic with anti-inflammatory and gut microbiota-modulating properties, has shown therapeutic potential in animal models of various diseases including Alzheimer's disease (AD). However, its possible therapeutic role in ALS remains unclear. The purpose of this study is to investigate the therapeutic effect of allicin in ALS transgenic SOD1[G93A] mice. Starting at 60 days of age, SOD1[G93A] mice received oral gavage of allicin (10 mg/kg) on alternate days, while the control group received an equal volume of normal saline (NS) on the same schedule. Twelve mice per group were used for monitoring disease onset and survival. Nissl staining and choline acetyltransferase (ChAT) immunofluorescence were used to quantify MNs in the anterior horn. Microglial activation was analyzed by immunofluorescence staining for Iba1, ARG1, and CD86. The mRNA expression levels of IL-10, TGF-β, IL-1β, and TNF-α were examined using qPCR. Additionally, fecal samples were collected for 16S rDNA sequencing to evaluate changes in gut microbiota composition. We observed that allicin treatment failed to prolong the onset time and survival period of SOD1[G93A] mice, but it extended the disease duration. Nissl staining analysis revealed that allicin treatment delayed the loss of spinal MNs, a finding corroborated by ChAT immunofluorescence. Furthermore, allicin treatment significantly reduced neuroinflammation and improved gut microbiota. Taken together, although allicin may prolong disease duration in ALS, it did not improve overall survival or delay disease onset. Therefore, its potential disease-modifying effects require further validation.}, } @article {pmid41724277, year = {2026}, author = {Zhao, X and Pu, L and Zeng, X and Nie, J}, title = {Role of nuclear import proteins in maintaining proteostasis and disease pathogenesis.}, journal = {Biochemical pharmacology}, volume = {248}, number = {}, pages = {117831}, doi = {10.1016/j.bcp.2026.117831}, pmid = {41724277}, issn = {1873-2968}, mesh = {Humans ; *Proteostasis/physiology ; *Active Transport, Cell Nucleus/physiology ; Animals ; Nuclear Localization Signals/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Cell Nucleus/metabolism ; *Karyopherins/metabolism ; *Receptors, Cytoplasmic and Nuclear/metabolism ; }, abstract = {Nuclear import receptors (NIRs), particularly the importin α/β heterodimer system, function as essential gatekeepers of nucleocytoplasmic trafficking by decoding diverse nuclear localization signals (NLSs) to orchestrate cellular proteostasis. This review delineates the structural basis of NLS recognition and the coordinated mechanisms that facilitate the nuclear import of critical cargoes, including transcription factors, RNA-binding proteins, and DNA repair factors. Beyond their canonical transport role, we emphasize the emerging functions of NIRs as molecular chaperones that suppress aberrant phase separation and their co-translational regulatory roles in ensuring proper protein biogenesis and folding. The collapse of these regulatory functions underpins the pathogenesis of major human diseases. We examine in detail the pathological consequences of nuclear import dysfunction, highlighting its central role in specific neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), oncogenic transformation, and viral pathogenesis. The discussion provides a critical appraisal of emerging therapeutic strategies that target the nuclear import machinery, including small-molecule inhibitors (e.g., importazole, ivermectin), peptide competitors, and advanced delivery platforms. We conclude by providing the associated challenges such as achieving tissue specificity, avoiding off-target effects and the significant opportunities that lie in pharmacologically modulating this fundamental pathway to restore proteostasis and develop disease modifying therapies.}, } @article {pmid41724566, year = {2026}, author = {Caldero-Escudero, E and Romero-Sanz, S}, title = {Modeling stress-induced proteinopathies in Caenorhabditis elegans.}, journal = {Methods in cell biology}, volume = {203}, number = {}, pages = {201-231}, doi = {10.1016/bs.mcb.2025.12.007}, pmid = {41724566}, issn = {0091-679X}, mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; Proteotoxic Stress ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; *Proteostasis Deficiencies/metabolism ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Disease Models, Animal ; Protein Folding ; Endoplasmic Reticulum Stress ; Proteostasis ; }, abstract = {Proteinopathies are a type of disorders characterized by the intracellular or extracellular accumulation of misfolded proteins that disrupt cellular proteostasis and exert toxic effects. These proteotoxic effects are a common hallmark of various age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and polyglutamine disorders such as Huntington's disease (HD). Misfolded protein accumulation can impair numerous cellular processes, including mitochondrial function, protein degradation pathways, the endoplasmic reticulum stress response, and redox homeostasis, ultimately compromising cell viability. The nematode Caenorhabditis elegans (C. elegans) has emerged as a powerful model for studying proteotoxic stress due to its genetic tractability and the high degree of conservation of key cellular pathways when compared to mammals. These include mitochondrial dynamics and function, regulation of reactive oxygen species (ROS), and the cellular capacity to manage protein aggregates in terms of number, size, and clearance efficiency. The integration of these conserved stress response pathways together with C. elegans experimental versatility positioned this nematode as an ideal system to investigate the molecular mechanisms underlying proteinopathy-induced toxicity. In this chapter, we describe a set of complementary methodologies to evaluate proteotoxic stress in C. elegans models of protein misfolding. These include assays to measure mitochondrial reactive oxygen species (ROS) and membrane potential (Δψm), analyses of mitochondrial morphology and oxygen consumption, protein extraction protocols, and in vivo staining and semi-automated quantification of protein aggregates.}, } @article {pmid41725371, year = {2026}, author = {Carbó, J}, title = {Reviewer Comment on Dallaire et al. "Mortality and Complications of Percutaneous Gastrostomy in Amyotrophic Lateral Sclerosis Patients".}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1}, doi = {10.1017/cjn.2025.10512}, pmid = {41725371}, issn = {0317-1671}, } @article {pmid41726352, year = {2026}, author = {Angurana, SK and Gupta, S and Tiwari, L and Shamarao, S and Khera, D and Sarkar, M and Dhaliwal, M and Kumar, V and Chaudhary, A and Deb, S and Samprati, M and Mehta, A and Kapoor, R and Tago, N}, title = {Development and Validation of Indian Children Length-based Tape (InChiTape) for Use in Critically Sick Children.}, journal = {Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine}, volume = {30}, number = {1}, pages = {35-39}, pmid = {41726352}, issn = {0972-5229}, abstract = {BACKGROUND AND AIM: Length-based tapes are extremely useful in critically sick children to estimate weight, emergency drug dosages, size of the equipment, and dose of defibrillation/cardioversion. The Indian Academy of Pediatrics (IAP), Advanced Life Support (ALS), and Basic Life Support (BLS) group felt the need to develop an indigenous tape for Indian children. A color-coded length-based tape [Indian Children Length-based Tape (InChiTape)] was planned to develop and later validate it.

PATIENTS AND METHODS: The population included children admitted to the emergency in the age range of 1 month-12 years and weight range of 2.5-40 kg. A color-coded length-based tape was developed using the World Health Organization (WHO) weight-for-length/height charts for boys (≤5 years) and the IAP weight-for-length/height charts for boys (>5 years). The median weights/lengths, corresponding +2SD and -2SD lengths, were marked on the charts for boys starting from 2.5 kg onward.

RESULTS: Fourteen centers from all zones of India pooled the data of 1,595 children. The majority of children were in the age range of 1-3.9 years (30%) and weight range of 5-9.9 and 10-14.9 kg (24.9 and 24.4%, respectively). The actual weight of children corresponded to the correct weight range/band on the InChiTape in 69.1% (n = 1,102) children, ranging from 56.6 to 78.4% in different age-groups and 55.5 to 76.3% in different weight ranges. There was a good correlation between actual weight and the average of respective weight range/band on the InChiTape (Pearson correlation of 0.95, p < 0.001).

CONCLUSION: The InChiTape is a rapid, reliable, and accurate method of estimating the weight of Indian children weighing 2.5-40 kg in an emergency.

HOW TO CITE THIS ARTICLE: Angurana SK, Gupta S, Tiwari L, Shamarao S, Khera D, Sarkar M, et al. Development and Validation of Indian Children Length-based Tape (InChiTape) for Use in Critically Sick Children. Indian J Crit Care Med 2026;30(1):35-39.}, } @article {pmid41726966, year = {2026}, author = {Avila, TU and Wang, J and Adams, L and Hu, E and Beltran, AA and Kozlenkov, A and Urhekar, S and Gonzalez, ABM and Lee, HG and Calabrese, JM and Dracheva, S and Beltran, AS and Mah, W and Won, H}, title = {Repeat expansions in C9orf72 rewire the 3D chromatin landscape in ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41726966}, issn = {2692-8205}, support = {I01 BX005585/BX/BLRD VA/United States ; R01 NS128523/NS/NINDS NIH HHS/United States ; R35 GM153293/GM/NIGMS NIH HHS/United States ; R61 AG094646/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is frequently driven by GGGGCC short tandem repeat (STR) expansions in C9orf72, yet the mechanisms by which these expansions lead to neurodegeneration remain incompletely understood. Here, we propose a novel mechanism involving higher-order chromatin architecture where C9orf72-STR expansions induce widespread, neuron-specific gains in chromatin loops that are closely linked to transcriptomic dysregulation in ALS. These ectopic loops colocalize with the genomic binding sites of C9orf72-STR RNAs and the architectural protein CTCF, supporting a model in which RNA-DNA interactions promote aberrant loop formation. Together, our findings demonstrate how C9orf72-STR expansions remodel the neuronal genome and disrupt gene expression, uncovering an RNA-driven mechanism of chromatin reorganization in C9-ALS that connects altered nuclear topology to gene dysregulation in neurodegeneration.}, } @article {pmid41726972, year = {2026}, author = {Natarajan, C and Budhwani, SM and Sreenivasamurthy, SGS and Katamoni, L and Thomson, B and Marcatti, M and Cuong, PP and Taglialatela, G and Krishnan, B}, title = {Exploring the PLD1-tau interaction in Frontotemporal Dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41726972}, issn = {2692-8205}, support = {R01 AG063945/AG/NIA NIH HHS/United States ; R21 AG059223/AG/NIA NIH HHS/United States ; T32 AG067952/AG/NIA NIH HHS/United States ; }, abstract = {Frontotemporal dementia (FTD), a leading cause of young-onset dementia, is characterized by progressive behavioral and cognitive decline associated with frontotemporal cortical atrophy. Nearly 40% of cases exhibit tauopathy, yet the molecular drivers of tau aggregation leading to synaptic dysfunction remain poorly understood. Here, we investigated whether Phospholipase D1 (PLD1, a lipid signaling enzyme), implicated in Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS), contributes to tau pathology dependent synaptic deficits in FTD. Postmortem temporal (BA38) and frontal (BA9) cortices from clinically diagnosed FTD and age-matched control subjects were analyzed using fluorescence-assisted single synaptosome long-term potentiation (FASS-LTP), immunofluorescence, proximity ligation assays (PLA), and PLD1-interactome proteomics. FASS-LTP revealed markedly reduced glutamatergic potentiation in BA38 and BA9 crude synaptoneurosomes from FTD brains compared to controls. Western blotting demonstrated elevated PLD1 expression in both crude synaptoneurosomal and cytosolic fractions from FTD subjects in BA38, but not BA9. Bielschowsky staining confirmed increased Pick body burden in FTD temporal cortex. Immunofluorescence and PLA showed robust PLD1 co-localization with total tau (HT7), hyperphosphorylated tau (AT8), and acetylated tau oligomers (TOMA2), indicating a strong spatial association between PLD1 and pathological tau species. PLD1 also exhibited enhanced co-localization with astrocytic GFAP and synaptic markers (PSD95, Nrx1β), suggesting compartmentalized involvement in glial and synaptic remodeling. Proteomic profiling of PLD1-associated complexes revealed compartment-specific alterations with cytosolic fractions enriched for metabolic enzymes, stress-response proteins, and GFAP, while crude synaptoneurosomal fractions showed depletion of presynaptic scaffolds, vesicle-trafficking regulators, and proteostasis components. Cross-compartment integration indicated that over one-third of proteins were redistributed from synapses to cytosol, consistent with trafficking and degradative impairments. Gene Ontology analysis highlighted lipid metabolism, astrocyte activation, and proteasome dysfunction as dominant pathways. Collectively, these findings identify PLD1 as a critical mediator of synaptic dysfunction and tau pathology in FTD, acting through astroglial activation and disrupting synaptic proteostasis. This study provides the human clinical relevance towards PLD1 attenuation as a therapeutic target for FTD and related tauopathies to mitigate tau-driven neurodegeneration and restore synaptic integrity.}, } @article {pmid41727032, year = {2026}, author = {Kapsiani, S and Vora, S and Fernandez-Villegas, A and Kaminski, CF and Läubli, NF and Kaminski Schierle, GS}, title = {Discovery of TDP-43 aggregation inhibitors via a hybrid machine learning framework.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41727032}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; P40 OD010440/OD/NIH HHS/United States ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) aggregation is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia. Recent therapeutic efforts have highlighted the potential of small molecules capable of inhibiting TDP-43 aggregation; however, no effective treatments currently exist. Here, we developed a hybrid machine learning approach combining graph neural network (GNN) embeddings with traditional chemical descriptors and biological target annotations. Using XGBoost as the final classifier enabled model interpretability through SHAP analysis, allowing the identification of key chemical features and target annotations associated with TDP-43 anti-aggregation activity. Complementary Monte Carlo Tree Search analysis highlighted specific chemical substructures linked to predicted activity. By screening an external library of 3,853 small molecules, the model identified two compounds not previously evaluated against TDP-43 aggregation, namely berberrubine and PE859. Molecular docking analysis revealed that both compounds interact favourably with the TDP-43 RNA recognition motif (RRM) domain through distinct binding modes. Experimental validation showed that both compounds significantly reduced TDP-43 aggregation in HEK cells. Further testing in Caenorhabditis elegans expressing human TDP-43 demonstrated that PE859 significantly rescued locomotor defects, while berberrubine showed partial improvement. This work establishes a hybrid machine learning approach for accelerating small molecule drug discovery, yielding two promising therapeutic candidates for TDP-43 proteinopathies.}, } @article {pmid41727102, year = {2026}, author = {Russell, KA and Shahrabi, AA and Akerman, SC and Byrne, MD and Rothstein, JD and Trotti, D and Jensen, BK and Haeusler, AR}, title = {Intrathecal (G4C2)149 delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41727102}, issn = {2692-8205}, support = {P30 CA056036/CA/NCI NIH HHS/United States ; R01 NS109150/NS/NINDS NIH HHS/United States ; R01 NS114128/NS/NINDS NIH HHS/United States ; RF1 NS114128/NS/NINDS NIH HHS/United States ; }, abstract = {A repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet existing mouse models incompletely engage spinal regions implicated in disease. Here, an adeno-associated virus encoding (G4C2)149 repeats was delivered via neonatal intrathecal injection, achieving widespread CNS expression with robust spinal cord targeting. This approach was applied to mice with graded loss of endogenous C9orf72 to interrogate both gain- and loss-of-function mechanisms. Longitudinal motor, behavioral, and pathological analyses revealed that repeat expression primarily drives mild, progressive muscle weakness, whereas coordination deficits were largely genotype dependent. Subtle gait abnormalities and hyperactivity were also observed. Within spinal motor regions, repeat-expressing mice exhibited dipeptide repeat protein accumulation, reduced NeuN-positive area, glial activation, and sparse phosphorylated TDP-43 pathology. Cross-domain correlations further linked repeat expression, spinal pathology, and motor dysfunction. Collectively, these findings establish that CNS-wide repeat expression combined with reduced C9orf72 produces a coherent, mild ALS/FTD model.}, } @article {pmid41727111, year = {2026}, author = {Ding, DY and Bot, VA and Chen, KL and Groves, J and Pálovics, R and Masuda, D and Farinas, A and Oh, HS and Wagner, V and Lu, N and , and Cruchaga, C and Isakova, A and Schott, JM and Wyss-Coray, T}, title = {Cellular Aging Signatures in the Plasma Proteome Record Human Health and Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41727111}, issn = {2692-8205}, support = {P30 AG066515/AG/NIA NIH HHS/United States ; P50 AG047366/AG/NIA NIH HHS/United States ; R01 AG072255/AG/NIA NIH HHS/United States ; }, abstract = {Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models to estimate the biological age of more than 40 distinct cell types-spanning neuronal, immune, glial, endocrine, epithelial, and musculoskeletal origins-using over 7,000 plasma proteins measured in 60,000 individuals across three cohorts, comprising the largest human plasma proteomics aging study to date. Individuals showed heterogeneous aging profiles, with 20-25% exhibiting accelerated aging in a single cell type and 1-3% across ten or more cell types. APOE genotype showed antagonistic aging effects in different cell types: APOE4 carriers exhibited older astrocytes but younger macrophages, while APOE2 carriers showed the inverse. Cellular aging signatures were uniquely associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Amyotrophic lateral sclerosis (ALS) showed the strongest association with skeletal myocyte aging (hazard ratio = 12.7 for extreme accelerated versus youthful aging). In Alzheimer's disease (AD), prevalent cases showed accelerated aging across multiple neural and peripheral cell types, with extreme astrocyte aging conferring AD risk comparable to APOE4 carrier status. Moreover, extreme astrocyte aging increased AD risk in APOE4/4 carriers threefold, while youthful astrocytes strikingly reduced risk. Beyond neurodegeneration, respiratory cell aging identified smokers at 58% higher lung cancer risk, and myeloid aging identified normoglycemic individuals at higher diabetes risk. Both specific cellular vulnerabilities and cumulative aging burden influenced survival, wherein youthful immune or neuronal profiles were protective. A polycellular aging risk score provided robust mortality risk stratification across platforms and cohorts. These findings establish a framework for quantifying biological aging at the cellular resolution using plasma proteomics, revealing heterogeneity in aging trajectories and their impact on disease susceptibility and resilience.}, } @article {pmid41727136, year = {2026}, author = {Dubinski, A and Ferdi, A and Choughari, M and Spence, H and Adhikary, A and Fauchon, C and Touati, M and Gagné, M and Liu, M and Peyrard, S and Gregory, J and Velde, CV}, title = {TDP-43 pathology is linked to motor neuron loss and is independent of stress granules in vivo.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41727136}, issn = {2692-8205}, support = {R01 NS127186/NS/NINDS NIH HHS/United States ; }, abstract = {Nuclear depletion and cytoplasmic aggregation of TDP-43 define a pathological signature across amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease, and limbic-predominant age-related TDP-43 encephalopathy (LATE). Stress granule persistence and chronic activation of the integrated stress response (ISR) have been proposed to trigger this pathology, yet clinical trials targeting these pathways have failed despite robust target engagement suggesting that the prevailing model may be incomplete. Here, we use a physiologically relevant recurrent hyperthermia paradigm to directly test the relationship between stress granules and TDP-43 pathology in vivo. We find that RNA-binding proteins typically associated with stress granules persist as dynamic, phase-separated cytoplasmic assemblies in spinal motor neurons of both wild-type and mutant TDP-43 mice. These structures resolve spontaneously and are spatially distinct from TDP-43 puncta. Strikingly, in mutant TDP-43 mice with a compromised acute stress granule response, stress exposure provokes TDP-43 nuclear export and cytoplasmic deposition, culminating in selective loss of spinal α-motor neurons after recurrent stress. Our results reveal that TDP-43 nuclear clearance and cytoplasmic aggregation can occur independently of stress granules in vivo, overturning a central assumption of TDP-43 pathogenesis. This paradigm shift reframes the mechanistic link between cellular stress and TDP-43 pathology, providing a new perspective for therapeutic strategies related to ISR modulation.}, } @article {pmid41727138, year = {2026}, author = {He, Z and Zhou, J and Zhang, R and Meng, F and Nauen, DW and Troncoso, JC and Worley, PF and Zhang, W}, title = {TRIM32-UBQLN2-p62 axis promotes TDP-43 inclusion formation and amyloid aggregation through shuttle condensates.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.02.11.705390}, pmid = {41727138}, issn = {2692-8205}, abstract = {Aberrant protein aggregation is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), which share overlapping genetic and pathological features. Similar aggregates are increasingly recognized in Alzheimer's disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). However, it remains unclear whether a shared molecular pathway drives this pathological aggregation. Here, we report that the E3 ubiquitin ligase TRIM32, together with the shuttle factor UBQLN2 and the autophagy adaptor p62/SQSTM1, form condensates that depend on E3 ligase activity and a network of intermolecular interactions. These condensates act as scaffolds that capture UBQLN2 client proteins, including TDP-43 and ANXA11, and modulate their mobility. A unique hydrophobic loop within TRIM32's substrate-binding domain mimics low-complexity motifs in ANXA11 and TDP-43, enabling selective retention via competitive binding mediated by UBQLN2 STI1 domain. Moreover, TRIM32 condensates promote amyloid aggregation of TDP-43, an effect that is exacerbated by pathogenic UBQLN2 mutation. In brains from individuals with diverse neurodegenerative diseases, TRIM32 co-localizes with pathological phospho-TDP-43 (pTDP-43) inclusions, supporting a model in which TRIM32-driven condensates function as selective proteostasis sorting compartments that broadly contribute to TDP-43 proteinopathy.}, } @article {pmid41728197, year = {2026}, author = {Demaegd, KC and Koole, W and van Vugt, JJ and Dankbaar, JW and Hendrikse, J and Nazlı Başak, A and de Carvalho, M and Corcia, P and Codron, P and Bernard, E and Guissart, C and Couratier, P and Povedano Panades, M and van Doorn, PA and Warrenburg, BP and Cooper-Knock, J and , and Pasterkamp, RJ and van Rheenen, W and van Damme, P and van den Berg, LH and Veldink, JH and van Es, MA}, title = {Bi-allelic intermediate ATXN2 repeat expansions are associated with slow progressing, leg-onset familial ALS.}, journal = {BMJ neurology open}, volume = {8}, number = {1}, pages = {e001417}, pmid = {41728197}, issn = {2632-6140}, abstract = {OBJECTIVES: The identification of bi-allelic intermediate ATXN2 repeat expansions in a pedigree with amyotrophic lateral sclerosis (ALS) through clinical testing prompted us to investigate its relevance in the wider ALS population.

METHODS: ATXN2 repeat size was assessed in a large international cohort of ALS patients (n=6653 from Project MinE) and in neurologically intact control populations (n=13 515 controls from Project MinE and gnomad). For bi-allelic cases, we retrieved medical records, family history and MRI imaging. For familial cases, we obtained DNA samples from relatives for segregation analyses.

RESULTS: In total, we identified bi-allelic intermediate ATXN2 repeat expansions in five familial cases from three different pedigrees and five apparently sporadic cases. There is a relatively homogeneous phenotype characterised by lower limb onset and long survival (median 6 years) without significant cerebellar atrophy. Bi-allelic expansions were absent in controls (0 out of 13 515).

DISCUSSION: Here we report an apparently novel autosomal recessive form of familial ALS caused by bi-allelic intermediate ATXN2 repeat expansions, which is characterised by high penetrance, lower limb onset and slow progression. Although rare, testing for ATXN2 expansions should be performed in the clinical setting given its relevance to prognosis and genetic counselling.}, } @article {pmid41728300, year = {2026}, author = {Tsitkov, S and Raju, A and Wu, J and Li, J and Lim, RG and Wu, Z and Bistami, NA and Consortium, AA and Van Eyk, JE and Svendsen, CN and Rothstein, JD and Glass, JD and Finkbeiner, S and Kaye, JA and Thompson, LM and Fraenkel, E}, title = {Wild-type C9orf72 expression is a genetic modifier of C9-ALS survival.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41728300}, support = {ZIA AG000935/ImNIH/Intramural NIH HHS/United States ; ZIA NS003154/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is highly heritable, yet the vast majority of cases lack an identifiable genetic cause and clinical progression remains largely unpredictable. To connect noncoding and rare genetic variation to disease phenotypes in a relevant cell type, we generated a multi-omic quantitative trait locus (QTL) atlas from 594 induced-pluripotent-stem-cell-derived human motor neuron lines (522 ALS patients, 72 controls). By mapping cis-QTLs for chromatin accessibility, splicing and gene expression from whole-genome sequencing, we identify common and rare variants on the wild-type C9orf72 allele that form regulatory haplotypes. These haplotypes influence C9orf72 expression levels in motor neurons and stratify C9-ALS patients into four subgroups; using clinical disease duration data and longitudinal ALSFRS-R scores, we show that these subgroups exhibit different survival trajectories, indicating that wild-type C9orf72 expression acts as a genetic modifier of disease duration. Beyond the C9orf72 locus, we detect ultra-rare intronic variants that create cryptic exons and structural and nonsense variants in established ALS genes, providing likely genetic explanations for disease in additional patients who previously lacked a molecular diagnosis. Our results show that QTL mapping in patient-derived motor neurons can reveal regulatory modifiers of progression and hidden pathogenic events in ALS, providing a framework for genetically informed risk attribution and patient stratification in complex neurological diseases.}, } @article {pmid41728998, year = {2026}, author = {Chiang, TS and Boisbouvier, J and Gandy, LA}, title = {Holding but not folding: How a single charge flip uncouples the DNAJC7-Hsp70 relay in amyotrophic lateral sclerosis.}, journal = {The FEBS journal}, volume = {293}, number = {12}, pages = {3466-3469}, pmid = {41728998}, issn = {1742-4658}, support = {ANR-15-IDEX-02//Agence Nationale de la Recherche/ ; ANR-22-CE29-0024-01//Agence Nationale de la Recherche/ ; ERC-ADG #101097926/ERC_/European Research Council/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *HSP70 Heat-Shock Proteins/genetics/metabolism/chemistry ; Protein Folding ; *HSP40 Heat-Shock Proteins/genetics/metabolism/chemistry ; Mutation ; Molecular Chaperones/genetics/metabolism/chemistry ; }, abstract = {Genetic mutations impact protein function through various routes: Some catalyze new oncogenic activities, while others trigger complete structural collapse. However, the E425K mutation in DNAJC7, associated with Amyotrophic Lateral Sclerosis (ALS), presents a far more subtle and intriguing case. In their recent study in The FEBS Journal, Elmaleh et al. (2026) FEBS Lett employed high-resolution NMR to demonstrate that this mutation leaves the protein's overall structure intact while selectively paralyzing its ability to communicate with the Hsp70 chaperone machinery. In this commentary, we show how their work complements in vivo studies that investigate ALS disease pathology at pathway complexity and defines a new target to rescue non-functioning Hsp70 chaperone systems.}, } @article {pmid41729108, year = {2026}, author = {Rozman, SI and Hamzaid, NA and Lim, E and Hamzah, N and Guan, JP and Sabirin, S and Hasnan, N and Shahrizaila, N}, title = {Standing up to neurodegeneration: evaluating autonomic stress and safety in sit-to-stand using heart rate variability analysis.}, journal = {Biomedizinische Technik. Biomedical engineering}, volume = {71}, number = {3}, pages = {189-197}, pmid = {41729108}, issn = {1862-278X}, mesh = {Humans ; *Heart Rate/physiology ; Male ; Female ; *Autonomic Nervous System/physiology/physiopathology ; *Amyotrophic Lateral Sclerosis/physiopathology ; Adult ; Middle Aged ; }, abstract = {OBJECTIVES: Sit-to-stand (STS) exercises are commonly incorporated in functional rehabilitation due to their simplicity, relevance to daily mobility and more recently, cardiac fitness. While generally considered safe for most clinical populations, its effect on autonomic stability remains underexplored - particularly in those with autonomic vulnerability such as individuals with amyotrophic lateral sclerosis (ALS). This study investigates the suitability of STS exercises for individuals with ALS, with specific focus on establishing baseline heart rate variability (HRV) data during rest and transient STS movement.

METHODS: Heart rate (HR) and HRV (RMSSD and HF) were assessed across three cohorts; healthy young adults (n=29), individuals living with ALS (n=8), and their age-matched controls (n=9), under resting condition and two STS protocols: Timed up and go (TUG) and five times sit-to-stand test (FTSST).

RESULTS: All groups exhibited significant increase in mean HR during STS compared to rest (p<0.05), whereas no statistically significant differences were observed in RMSSD and HF. These results indicate that STS exercises elicit measurable cardiovascular exertion without triggering acute autonomic dysfunction in ALS individuals, supporting its role in safe rehabilitation for early-mid stages ALS.

CONCLUSIONS: HRV serves as a potential tool for non-invasive monitoring and assessment of autonomic function during physical therapy.}, } @article {pmid41729684, year = {2026}, author = {Paulo-Ramos, A and Rhymes, ER and Villarroel-Campos, D and Sleigh, JN}, title = {Disruption of BDNF signalling in neuropathologies.}, journal = {Biochemical Society transactions}, volume = {54}, number = {2}, pages = {211-227}, pmid = {41729684}, issn = {1470-8752}, support = {MR/Y010949/1/MRC_/Medical Research Council/United Kingdom ; 23GRO-PG36-0675-1//Muscular Dystrophy UK/ ; }, mesh = {*Brain-Derived Neurotrophic Factor/metabolism ; Humans ; *Signal Transduction ; Animals ; Receptor, trkB/metabolism ; Neurons/metabolism ; *Nervous System Diseases/metabolism ; Receptors, Nerve Growth Factor/metabolism ; Neuronal Plasticity ; }, abstract = {The vital role of brain-derived neurotrophic factor (BDNF) in neuronal development, synaptic plasticity, and neuroprotection has been explored for decades. Therefore, the expression, processing, and signalling activities of this neurotrophin, which is reliant upon TrkB and p75NTR receptors, have been well characterised in both health and disease. This review summarises the latest findings on BDNF dysregulation in neuropathologies. Indeed, across diseases of both the central and peripheral nervous systems, BDNF signalling is frequently disrupted, contributing to neuronal dysfunction and degeneration. Consequently, through direct or indirect enhancement of its expression and/or function, BDNF has proved to be a promising therapeutic target across many neurological conditions. However, the complexity of its regulation and interaction with several different receptors underpins the need for further research to deepen our understanding of BDNF disruption in neuropathologies and to achieve its therapeutic potential.}, } @article {pmid41730149, year = {2026}, author = {Nagel, G and Peter, RS and Uzelac, Z and Wernecke, D and Niehaus, L and Trottenberg, T and Jöbges, M and Dettmers, C and Bäzner, H and Börtlein, A and Althaus, K and Mayer-Freitag, K and Ratzka, P and Naumann, M and Lindner, A and Chatzikonstantinou, A and Andres, F and Arnold, G and Blickhan, M and Opherk, C and Knier, B and Ertl, M and Metrikat, J and Huber, R and Thomas, C and Kozian, R and Kimmig, H and Demuth, K and Hecht, M and Foerch, C and Kloetsch, C and Reinhard, M and Bengel, D and Neuhaus, O and Buttmann, M and Volkmann, J and Pinkhardt, E and Lichy, C and Laske, C and Beattie, J and Häckert, J and Jesse, S and Brenner, D and Weishaupt, J and Otto, M and Uttner, I and Anderl-Straub, S and Lulé, DE and Rothenbacher, D and Rosenbohm, A and Ludolph, AC and , }, title = {Incidence and Survival Rates of Frontotemporal Lobar Degeneration: Population-Based Registry Study.}, journal = {Neurology}, volume = {106}, number = {6}, pages = {e214482}, pmid = {41730149}, issn = {1526-632X}, mesh = {Humans ; Male ; Female ; Registries ; *Frontotemporal Lobar Degeneration/epidemiology/mortality/diagnosis ; Incidence ; Aged ; Germany/epidemiology ; Middle Aged ; Survival Rate ; Aged, 80 and over ; }, abstract = {BACKGROUND AND OBJECTIVES: Frontotemporal lobar degeneration (FTLD) can present as a behavioral or language variant (bvFTLD or a primary progressive aphasia [PPA], or as a syndrome with parkinsonism, such as corticobasal syndrome [CBS] or progressive supranuclear palsy [PSP]). The incidence of FTLD varies in epidemiologic studies, reaching 3 per 100,000 person-years. Only few data exist regarding survival times. We evaluated incidence and survival rates in a population-based registry with high coverage in Southern Germany.

METHODS: The epidemiologic ALS-FTLD registry Swabia covers a population of 8.4 million inhabitants in south-west Germany. Raw and age-standardized incidence rates, as well as incidence rate ratios (IRR) with 95% CIs were calculated. Median survival time was estimated for different FTLD variants using the Kaplan-Meier method.

RESULTS: Between 2015 and 2022, 515 patients with FTLD (mean age at diagnosis 68.0 ± 9.5 years, 59.8% men) were registered. The median diagnostic delay was 24.8 months. The most common variant was bvFTLD (n = 185, 35.9%; 66.5% men), followed by PPA (n = 147, 28.5%; 51.0% men), PSP (n = 133, 25.8%; 62.9% men), and CBS (n = 22, 4.3%; 50% men). The overall FTLD incidence was 0.77 (95% CI 0.71-0.84), and the age-standardized incidence was 0.76 (95% CI 0.69-0.82) per 100.000 person-years. The age-standardized incidence was higher in men than in women, with an IRR of 1.73 (95% CI 1.44-2.00). In men, incidence increased from the age 50 years, primarily due to bvFTD, whereas in women this rise was primarily due to PSP. The median survival (N = 392) from diagnosis was 53.6 months (95% CI 50.9-62.0) overall, 73.1 months (95% CI 63.6-82.8) for patients with PPA, 42.8 months (95% CI 35.1-64.3) for patients with bvFTD, and 49.5 months (95% CI 39.2-53.7) for patients with PPS/CBS.

DISCUSSION: We observed a raw incidence rate of 0.77, thus considerably lower than in most previous reports. Incidence was substantially higher in men than in women. The prognosis from the time of diagnosis depended highly on the specific FTLD subtype. Our data are based on the large sample size and high capture rate of a central European population-based registry.}, } @article {pmid41730342, year = {2026}, author = {Thomas, T and Jones, L and Dawson, S and Houghton, C and Hunter, A and O'Connell, N and Biesty, L}, title = {Existing research guidelines for inclusive trials methodology. Working toward the integration of qualitative research, equity, diversity, and inclusion and trials methodology: a focused mapping review.}, journal = {Journal of clinical epidemiology}, volume = {193}, number = {}, pages = {112202}, doi = {10.1016/j.jclinepi.2026.112202}, pmid = {41730342}, issn = {1878-5921}, mesh = {Humans ; *Qualitative Research ; Diversity, Equity, Inclusion ; *Research Design/standards ; *Guidelines as Topic ; *Clinical Trials as Topic/standards/methods ; *Patient Selection ; }, abstract = {BACKGROUND: Equity, diversity, and inclusion (EDI) are increasingly emphasized in clinical research, yet practical guidance for applying inclusion principles across all clinical trial stages remain limited. Qualitative research can help address this gap by exploring participant experiences and identifying barriers to inclusive trial conduct. The aim of this review is to map guidelines and recommendations in relation to inclusive trials methodology and to identify areas across these resources that can be potentially informed by qualitative research. This review presents Phases 1 and 2 of the QuAlitative reSearch Supporting IncluSive Trials (Q-ASSIST) study.

METHODS: In Phase 1, we conducted a focused mapping review and synthesis (FMRS) of publicly available guidelines related to Phase 3 and later clinical trials involving human participants. Eligible guidelines included those offering recommendations to enhance inclusive trial design and conduct. Each guideline was mapped to a priori data extraction framework informed by the Standard Protocol Items: Recommendations for Interventional Trials and Consolidated Standards of Reporting Trials 2025 guidelines. We then performed a narrative synthesis to examine the EDI focus of the selected guidelines and structured the findings according to the PRO-EDI Framework. In Phase 2, we juxtaposed the trial stages identified through our FMRS with O'Cathain et al's framework of qualitative research in trials.

RESULTS: We identified 15 guidelines through FMRS. Through conceptual mapping to Standard Protocol Items: Recommendations for Interventional Trials and Consolidated Standards of Reporting Trials headings, we developed a 12-stage trial lifecycle framework (the Q-ASSIST trial stages model) to organize inclusion guidance. Most guidelines emphasized early stages of trials, with later stages less frequently addressed. Mapping to the PRO-EDI framework showed strong attention to race/ethnicity, gender, socioeconomic status, and disability, but limited focus on sexual identity, education, or intersectionality. Juxtaposition with O'Cathain et al's framework highlighted similar gaps in how qualitative research has been used, especially in later trial stages.

CONCLUSION: Current inclusion guidance is concentrated in the early stages of trial design, with limited attention to later trial stages. Qualitative research offers a valuable way to address these gaps by capturing participant perspectives and supporting inclusive practices across the trial lifecycle. This review provides a foundation for developing practical tools to guide more inclusive trials, with the next phase involving coproduction of guiding principles with interest holders.}, } @article {pmid41730762, year = {2026}, author = {Min, MTP and Zhenyang, JH and Merchant, RA}, title = {When Dysphagia and Functional Decline Isn't Just Aging: A Case of Bulbar-Onset ALS in an Older Adult.}, journal = {Journal of the American Geriatrics Society}, volume = {74}, number = {5}, pages = {1520-1522}, doi = {10.1111/jgs.70362}, pmid = {41730762}, issn = {1532-5415}, } @article {pmid41731547, year = {2026}, author = {Jammal, JK and Gomez, EA and Al-Chalabi, A and Iacoangeli, A}, title = {Classification of ALS molecular subtypes: a literature review on machine learning applications and their clinical value.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {41731547}, issn = {1741-7015}, support = {772376-EScORIAL/ERC_/European Research Council/International ; FP7/2007–2013//(NIHR) National Institute for Health and Care Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/classification/genetics/diagnosis ; *Machine Learning ; Precision Medicine ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by considerable heterogeneity in both its underlying biological mechanisms and clinical presentation. High-dimensional transcriptomic datasets offer an opportunity to characterise this variation at the molecular level; however, traditional statistical methods struggle with their scale and complexity.

MAIN BODY: Machine learning approaches can reduce dimensionality and uncover latent patterns, enabling the identification of molecular subtypes that may refine prognosis and support patient stratification. Recent transcriptomic studies employing unsupervised machine learning have identified ALS subtypes with distinct molecular and clinical characteristics. Redefining ALS into more homogeneous molecular and clinical subtypes could transform all areas of ALS research by supporting novel experimental designs and precision medicine approaches.

CONCLUSIONS: In this review, we summarise and critically assess these studies, discussing their findings, strengths, and limitations, and highlighting research gaps and challenges that must be addressed to enable their translation into biomedical and clinical practice.}, } @article {pmid41732281, year = {2026}, author = {Maitra, S and Ham, DW and Baek, M and Choe, YJ and Kim, NC}, title = {FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10[S59L] in Drosophila and human cells.}, journal = {iScience}, volume = {29}, number = {3}, pages = {114879}, pmid = {41732281}, issn = {2589-0042}, abstract = {Mutations in CHCHD10 are a genetic cause of ALS-FTD. In our previous studies using Drosophila expressing C2C10H[S81L] and human cells expressing CHCHD10[S59L], we found that the aberrant activation of the PINK1/Parkin pathway drives cellular toxicity, and pseudo-substrate inhibitors of PINK1 or mitofusin-2 agonists can mitigate these effects. Evidence from in vitro, in vivo, and chemical approaches supports PINK1 inhibition as a promising strategy for CHCHD10[S59L]-associated disease. Here, we show that FDA-approved PDE4 inhibitors significantly reduce CHCHD10[S59L]-induced mitochondrial morphological and functional defects in both human cells and Drosophila. These protective effects occur through a cAMP/PKA-dependent mechanism, indicating that elevated cAMP signaling attenuates aberrant PINK1/Parkin activation. Moreover, forskolin combined with PDE4 inhibitors synergistically decreases mitochondrial toxicity at lower concentrations. Together, our findings suggest that clinically available PDE4 inhibitors could be repurposed for CHCHD10[S59L]-linked ALS-FTD, while emphasizing the need to carefully consider the effects of the PINK1/Parkin pathway, as it is generally recognized as a protective pathway.}, } @article {pmid41733022, year = {2026}, author = {Destoop, M}, title = {[Heeft de e-sigaret een plaats als rookstopmiddel binnen de ggz?].}, journal = {Tijdschrift voor psychiatrie}, volume = {68}, number = {2}, pages = {57-59}, pmid = {41733022}, issn = {0303-7339}, } @article {pmid41733214, year = {2026}, author = {Montalvo, A and Gromicho, M and Oliveira Santos, M and de Carvalho, M}, title = {Clinical characterization of the proximal lower-limb ALS phenotype: a retrospective cohort study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {704-707}, doi = {10.1080/21678421.2026.2630882}, pmid = {41733214}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/diagnosis/complications ; Male ; Retrospective Studies ; Phenotype ; Female ; Middle Aged ; Aged ; *Lower Extremity/physiopathology ; *Muscle Weakness/etiology ; Mutation/genetics ; Cohort Studies ; Disease Progression ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; Adult ; }, abstract = {This study characterizes a rare phenotype of Amyotrophic Lateral Sclerosis (ALS) presenting with predominant proximal lower limb weakness at onset, a presentation often mimicking myopathy. We retrospectively reviewed 1980 patients, identifying 15 (0.75%) with this atypical onset. The majority were males (73%) with a median age of onset of 58.7 years. Approximately half presented with symmetric proximal lower limb weakness. Nine of the 11 tested patients had higher CK. Follow-up (median 53.7 months) revealed that 6 patients maintained isolated lower limb weakness for a median of 60.1 months, while others progressed to upper limbs or bulbar regions. NSG sequencing (in nine patients) identified mutations in three patients (SOD1, VAPB, and C9ORF72). This pattern poses a diagnostic challenge. While limitations include a small sample size and retrospective design, the findings highlight a heterogenous but often slow-spreading and benign course for this specific ALS subtype, offering valuable clinical information for differential diagnosis.}, } @article {pmid41734662, year = {2026}, author = {Alam, P and Hasan, GM and Mohammad, T and Hassan, MI}, title = {Next-generation computational strategies for neurodegenerative biomarkers: Multi-omics integration, AI, and molecular modeling.}, journal = {Computational biology and chemistry}, volume = {123}, number = {}, pages = {108973}, doi = {10.1016/j.compbiolchem.2026.108973}, pmid = {41734662}, issn = {1476-928X}, mesh = {*Neurodegenerative Diseases/metabolism/diagnosis/genetics ; Biomarkers/analysis/metabolism ; Humans ; Multiomics ; *Artificial Intelligence ; *Models, Molecular ; *Computational Biology ; Proteomics ; Machine Learning ; }, abstract = {Neurodegenerative diseases (NDs) are progressively debilitating conditions driven by complex molecular perturbations and selective neuronal loss. Conventional approaches to discovering biomarkers, using single-omics or empirical screening, often fail to capture the multi-factorial nature of these disorders. It is now possible to integrate large-scale omics data with structural and molecular modeling methods to reveal mechanistically relevant biomarkers using integrative computational biology. Here, we review recent advances in integrative computational strategies that combine multi-omics, encompassing genomics, transcriptomics, proteomics, and metabolomics, with structural bioinformatics and molecular modeling to identify mechanistically informative biomarkers. We cover systems-level and network-based integration methods, machine learning (ML) and artificial intelligence (AI) frameworks, and structure-guided validation approaches, including homology/AI-based modeling, molecular docking, and molecular dynamics. We also discuss case studies illustrating how omics-based predictions are validated through protein structure modeling to identify key biomarkers and therapeutic targets. Finally, we discuss major challenges, such as data heterogeneity, reproducibility, and limitations of structural modeling, and emerging trends, such as AI-powered multi-omics, single-cell spatial profiling, and digital twin simulations. Together, the integrative computational strategies are likely to accelerate the discovery of reliable, mechanistically informative, and clinically translatable biomarkers for precision medicine in NDs.}, } @article {pmid41735713, year = {2026}, author = {Elbadawi, M and Kafoor, NFA and Li, H and Protopapa, C and Vlachou, M and Gaisford, S}, title = {Active learning in pharmaceutical 3D printing: a multi-dataset comparison.}, journal = {Drug delivery and translational research}, volume = {}, number = {}, pages = {}, pmid = {41735713}, issn = {2190-3948}, abstract = {Machine learning (ML) is expected to accelerate the developments of three-dimensional (3D) printed medicines. Despite ML's potential, the need for large datasets can hinder progression, as 3D printing remains an emerging pharmaceutical manufacturing technology. This study explores an ML strategy called active learning (AL), which harnesses the benefits of ML whilst applicable with small datasets. AL was tested to predict the printability of three 3D printing datasets: 1437 fused deposition modelling (FDM), 650 vat polymerisation and 297 selective laser sintering (SLS) formulations. The analysis revealed that accuracies of 60% can be achieved when starting with 33 formulations, and subsequent increases in training data size enhances predictive performance. Furthermore, AL was found to achieve 100% predictive accuracy, which is the highest recorded to date for pharmaceutical 3D printing. These initial findings highlight AL's advantages over traditional ML modelling and showcase its potential to accelerate the development of 3D printing medicines. This research also demonstrates the potential of modelling with small datasets, thereby widening ML's application in pharmaceutical research.}, } @article {pmid41737317, year = {2026}, author = {Luo, R}, title = {Next questions of autophagy in neurodegenerative diseases: From mechanisms to therapeutics.}, journal = {Innovation (Cambridge (Mass.))}, volume = {7}, number = {1}, pages = {100989}, pmid = {41737317}, issn = {2666-6758}, abstract = {Autophagy, a key cellular degradation pathway, is central to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Despite progress in understanding its role, critical questions remain. This perspective highlights pressing issues, including cell-type-specific autophagy regulation, interactions with other cellular pathways, and challenges in translating autophagy-modulating therapies to clinical practice. Addressing these questions will advance our understanding of neurodegenerative diseases and pave the way for novel therapeutics.}, } @article {pmid41737544, year = {2026}, author = {Xia, X and Chen, X and Sun, Y and Zhang, M and Qiao, K and Chen, Y and Zhao, C and Dong, Y and Zhu, W}, title = {Genetic Spectrum and Phenotypic Variability in Chinese Patients with Multisystem Proteinopathy and Related Disorders.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {16}, number = {}, pages = {568971}, pmid = {41737544}, issn = {1179-9900}, abstract = {OBJECTIVE: Multisystem proteinopathy (MSP) is a pleiotropic group of disorders initially presenting as inclusion body myopathy (IBM), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and/or Paget disease of bone (PDB). Additional genes including MATR3, OPTN, and ANXA11, have recently been implicated in MSP-like disorders, further expanding the genetic spectrum. This research aims to study the genetic and clinical characteristics of MSP and related disorders in a large Chinese cohort.

METHODS: Twenty-nine patients were identified in 953 patients diagnosed with ALS, IBM, or dementia at Huashan Hospital between 2000 and 2024. Variants in MSP-related genes were detected using next-generation sequencing and confirmed by Sanger sequencing. Clinical, pathological, imaging, and electromyography data were collected and analyzed.

RESULTS: A total of 29 patients (3.0%) were identified as carrying MSP-related gene variants. Most patients were male (72.4%), with disease onset predominantly in the third to fifth decades of life. The majority of patients (21/29) presented with a single clinical phenotype. ALS was the most common phenotype (20/29), followed by IBM (10/29), FTD (7/29), and PDB (1/29). The most frequent variants were in ANXA11 (34.5%) and VCP (20.7%), followed by OPTN (17.2%), SQSTM1 (10.3%), MATR3 (10.3%), and HNRNPA1 (6.9%). All patients with VCP variants presented with initial lower limb involvement, whereas those carrying ANXA11 or OPTN variants predominantly showed upper limb or bulbar onset. Patients harboring OPTN variants had a later age at onset compared with those carrying VCP or MATR3 variants. Patients with ALS-onset exhibited faster progression compared with those with myopathy-onset, even when harboring identical variants.

CONCLUSION: This study broadens the clinical and genetic landscape of MSP and related disorders in a Chinese cohort. These results emphasize the clinical utility of next-generation sequencing for improving diagnostic accuracy in patients with unexplained neuromuscular or cognitive presentations, especially in the presence of multisystem involvement.}, } @article {pmid41738691, year = {2026}, author = {Gonçalves, F and Machado, T and Viegas, P and Machado, A and Ribeiro, C}, title = {The burden of care: Health and wellbeing of informal caregivers of people with amyotrophic lateral sclerosis.}, journal = {Palliative & supportive care}, volume = {24}, number = {}, pages = {e65}, pmid = {41738691}, issn = {1478-9523}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/psychology/complications ; *Caregivers/psychology/statistics & numerical data ; Cross-Sectional Studies ; Middle Aged ; Portugal ; Male ; Adult ; Surveys and Questionnaires ; Aged ; *Cost of Illness ; Quality of Life/psychology ; Health Status ; }, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a rare, progressive, and fatal disease that impacts the lives of affected individuals and their caregivers. Informal caregivers play a crucial role in supporting people with ALS (pwALS), yet they face major challenges. This study aims to analyze caregiver burden and health status among informal caregivers of pwALS in Portugal.

METHODS: A cross-sectional survey-based study was conducted with adult informal caregivers of pwALS in Portugal, recruited through the Portuguese ALS patient association and healthcare professionals. Data included sociodemographics, caregiving activities, caregiver health (SF-36), patient functional status (ALSFRS-R), and caregiver burden (ZBI).

RESULTS: The study included 113 caregivers. Most were female (61.9%) and the partner (65.5%) or offspring (23.9%) of the pwALS. A quarter of caregivers received no social benefits. Mean ZBI was 32 ± 14.8, with most reporting mild to moderate burden. On the SF-36, general health was 51.1 ± 19.8, with mental health (55 [40; 70]) and vitality (43.8 [31.3; 56.3]) particularly impaired. ZBI scores correlated positively with caregiving hours (r = 0.274, p = 0.003) and negatively with ALSFRS-R (r = -0.411, p < 0.001). High burden caregivers exhibited poorer sleep quality (p =  0.026).

SIGNIFICANCE OF RESULTS: Caregivers experienced mild to moderate burden, with impaired mental health and vitality, but preserved physical functioning. A higher burden was linked with lower quality of life, poorer sleep, and greater patient disability. These findings underline the need for targeted education and training to support caregivers of pwALS.}, } @article {pmid41739094, year = {2026}, author = {Kashif, M and Keating, ME and Byrne, HJ}, title = {Raman spectroscopic monitoring of multiproduct chemical reaction kinetics; the case of ester hydrolysis.}, journal = {The Analyst}, volume = {151}, number = {7}, pages = {2024-2036}, doi = {10.1039/d5an01055a}, pmid = {41739094}, issn = {1364-5528}, mesh = {Kinetics ; Hydrolysis ; *Spectrum Analysis, Raman/methods ; *Esters/chemistry ; Acetic Acid/chemistry ; Least-Squares Analysis ; 1-Propanol/chemistry ; Acetates/chemistry ; }, abstract = {Raman Spectroscopy (RS) is a powerful technique for the identification of molecules based on the characteristic fingerprint spectra of their vibrational modes. Although challenging, real time spectroscopic monitoring of reactions and processes has great potential value in multiple fields, including process analysis, bio reactors, cell therapies and in vitro metabolomics. Refined chemometrics methodologies are required to datamine the kinetic evolution of multivariate spectral mixtures to establish the constituent reactants and products, as well as the characteristic rates of the reaction. To explore the capabilities and challenges, RS was used to study the chemical kinetics of propyl acetate hydrolysis in an aqueous environment at room temperature, in situ, as a model reaction. The continuous conversion of propyl acetate to 1-propanol and acetic acid was monitored periodically over 250 min using RS with a 532 nm laser source. Simulated admixture solutions, mimicking the reaction from pure reactants to pure products conversion, were also recorded for comparison. Problem based nonlinear least squares (NLS) fitting was applied to both the actual reaction and simulated solution data sets using pure components spectra of both the reactants, propyl acetate, water and products, 1-propanol and acetic acid, in order to visualise and confirm the trends and kinetics of the reaction components. Multivariate Curve Resolution-Alternating Least Squares analysis (MCR-ALS) with kinetic constraints was applied to further resolve the concentration and spectral profiles and to quantify the rates of the reaction. It is demonstrated that MCR-ALS could not accurately resolve the evolving reaction species with respect to concentration, due to rank deficiency. To enhance the analysis, a data augmentation approach was used, seeding the measured datasets with the spectra of the pure components to bias the initial singular value decomposition and spectral unmixing process, resulting in an improved resolution of the systematic variation of concentration dependent data to monitor the kinetic evolution of the reaction mixture. The required seeding weights were optimized by visualizing the sum residual error (SUMR) in least squares fitting of the actual components with the identified pure components by MCR-ALS. Minimum SUMR values for admixtures were found at a seeding weight of 10 000X, while 100X was found to be optimum for the actual reaction. This proof of concept can further pave the way for better analysis and understanding of cascade reactions, and ultimately, potentially of metabolomic pathways.}, } @article {pmid41739556, year = {2026}, author = {Li, J and Iguchi, Y and Yoshida, K and Kato, D and Araki, K and Kobayashi, K and Yokoi, S and Yoshimoto, R and Iida, M and Amakusa, Y and Kawakami, Y and Yoshimura, T and Chikuchi, R and Tsujikawa, K and Riku, Y and Iwasaki, Y and Okada, Y and Ohno, N and Wake, H and Katsuno, M}, title = {Neuronal TDP-43 regulates myelin formation via neurexin 1 mRNA stabilization.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {9}, pages = {e2513642123}, pmid = {41739556}, issn = {1091-6490}, support = {JP 24K02365//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP 24K22096//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP 23H00420//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP 20K16596//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP 22K15707//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP21wm0425013//Japan Agency for Medical Research and Development (AMED)/ ; JP24wm0625301//Japan Agency for Medical Research and Development (AMED)/ ; None//Hirose Foundation (å…¬çŠè²¡å£æ³•äººãƒ'ãƒã'»è²¡å£)/ ; None//Takeda Science Foundation (TSF)/ ; }, mesh = {Animals ; *Neurexins/genetics/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; Mice, Knockout ; *Neurons/metabolism ; *Myelin Sheath/metabolism ; RNA, Messenger/metabolism/genetics ; *RNA Stability ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Oligodendroglia/metabolism ; Humans ; Frontotemporal Lobar Degeneration/metabolism/genetics/pathology ; Calcium-Binding Proteins ; Neural Cell Adhesion Molecules ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) develop as spatial pathologies in which neurons and glial cells are interconnected. TAR DNA-binding protein 43 (TDP-43) is a major pathological protein that is inextricably associated with ALS and FTLD. In this study, we investigated the roles of neuronal TDP-43 in neuron-oligodendrocyte interactions using neuron-specific TDP-43 knockout (TDP-43cKO) mice. TDP-43 depletion in neurons induced hypomyelination, which was confirmed by immunohistochemistry and ultrastructural analysis. In addition, conduction disturbance was revealed by electrophysiological analysis. The hypomyelination of TDP-43cKO mouse was restored by cytoplasmic TDP-43 supplementation in neurons. Neuron-specific transcriptome analysis revealed that neurexin 1 (NRXN1) is the regulatory target of TDP-43, which promotes myelin formation. The hypomyelination of TDP-43cKO mice was also restored by NRXN1b supplementation in neurons. We further confirmed that TDP-43 stabilizes Nrxn1 mRNA by binding to the Nrxn1 3'untranslated region (3'UTR). Although TDP-43cKO exhibited impaired recognition memory, the supplementation of NRXN1 in the hippocampus recovered the memory disturbances. In conclusion, this study demonstrates the neuron-oligodendrocyte interaction mediated by neuronal TDP-43 via NRXN1 mRNA stabilization. These findings shed light on neuron-oligodendrocyte interaction in the disease mechanisms of ALS/FTLD.}, } @article {pmid41740345, year = {2026}, author = {Bai, J and Pang, X and Wang, H and Zhang, Y and Zhu, Y and Zhao, J and Li, Y and Li, M and Huang, X}, title = {Profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {483}, number = {}, pages = {125797}, doi = {10.1016/j.jns.2026.125797}, pmid = {41740345}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/genetics ; *DNA, Mitochondrial/blood/cerebrospinal fluid ; Female ; Male ; Middle Aged ; Aged ; Cohort Studies ; Biomarkers/blood/cerebrospinal fluid ; Adult ; }, abstract = {BACKGROUND: Recent studies increasingly implicate mitochondrial DNA (mtDNA) alterations in neurodegenerative diseases, but findings across studies remain inconsistent. We aimed to characterize mtDNA indices across whole blood, plasma and CSF compartments and evaluate their clinical relevance.

METHODS: We enrolled two study cohorts: (1) a whole blood cohort of 102 ALS patients; and (2) a plasma and cerebrospinal fluid (CSF) cohort including 132 ALS patients and 62 non-neurodegenerative controls. The D-loop and COX3 regions were selected as representative mtDNA fragments, while B2M was used as a nuclear reference. Quantification was performed using SYBR Green-based quantitative PCR.

RESULTS: In whole blood, higher D-loop/COX3 ratios were associated with better functional status and longer survival. In the cell-free compartments, CSF ccf-mtDNA markers (D-loop and COX3) were significantly higher in ALS than in controls, whereas plasma abundance showed no significant group difference. Within ALS, higher ccf-mtDNA indices tended to correlate with greater disease severity and more rapid functional decline. In addition, higher plasma and CSF D-loop/COX3 ratios showed marginal trends toward association with faster disease progression.

CONCLUSIONS: This study systematically characterizes mtDNA alterations in whole blood, plasma and CSF samples of ALS, offering new insights into mtDNA involvement in neurodegeneration.}, } @article {pmid41740899, year = {2026}, author = {Al Tawil, A and Lauseker, M and Mansmann, U}, title = {Estimating causal effects on quality of life under treatment discontinuation: the ALTA-1L trial.}, journal = {Journal of clinical epidemiology}, volume = {193}, number = {}, pages = {112189}, doi = {10.1016/j.jclinepi.2026.112189}, pmid = {41740899}, issn = {1878-5921}, mesh = {Humans ; *Quality of Life ; *Lung Neoplasms/drug therapy ; Treatment Interruption ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; *Crizotinib/therapeutic use ; *Pyrimidines/therapeutic use ; }, abstract = {BACKGROUND AND OBJECTIVES: Time to worsening in health-related quality of life (HRQoL) is increasingly used in oncology trials. Treatment discontinuation poses a challenge: once discontinued, patients cease HRQoL assessments, precluding outcome observation. Standard survival analyses censor at discontinuation, assuming noninformative censoring-an assumption often violated when discontinuation relates to disease progression or toxicity. Bridging the ICH E9(R1) estimand framework with causal inference methods clarifies how to define and estimate treatment effects in such settings. We reanalyze time to worsening in global health status from the ALTA-1L trial (brigatinib vs crizotinib in ALK + non-small-cell lung cancer), integrating both frameworks.

METHODS: Following Young et al's (2020) causal framework for competing events, we defined two estimands structured according to ICH E9(R1): (1) a controlled direct effect under a hypothetical strategy, envisioning a scenario where treatment discontinuation would not occur, estimated using inverse probability of censoring weighted Kaplan-Meier to adjust for informative censoring; and (2) a total effect under a while-on-treatment strategy, with discontinuation as a competing event, estimated using the Aalen-Johansen estimator. Risk ratios (RRs) were estimated at 36 months with bootstrap CIs.

RESULTS: The original ALTA-1L analysis reported hazard ratio = 0.69 (95% CI: 0.49, 0.98), censoring at discontinuation and assuming noninformative censoring. Deriving the RR at 36 months from Kaplan-Meier curves yields 0.75 (95% CI: 0.59, 0.97). After adjusting for informative censoring, the controlled direct effect was RR = 0.89 (95% CI: 0.65, 1.26). The total effect was RR = 1.03 (95% CI: 0.76, 1.40), reflecting the competing risk structure: earlier discontinuation in the crizotinib arm (discontinuation RR = 0.54; 95% CI: 0.38, 0.72) reduced observed worsening events. These different estimates illustrate how different estimands address distinct clinical questions.

CONCLUSION: This study bridges the ICH E9(R1) estimand framework with causal inference methods for time-to-event HRQoL analysis when discontinuation precludes observation. By quantifying bias from standard approaches, we provide methodological clarity for applied researchers. To facilitate practical implementation, we translate these insights into a decision flowchart for estimand specification and method selection when intercurrent events (ICEs) act as competing events. Future trials should prespecify ICE-handling strategies and consider data collection beyond ICEs to support treatment policy estimation.}, } @article {pmid41741312, year = {2026}, author = {Herrero Babiloni, A and Dal Fabbro, C and Samin, F and Schmittbuhl, M and Blanchet, PJ and Lavigne, GJ and Rouleau, G}, title = {The role of dentists in the recognition of neurodegenerative and systemic conditions with neurological involvement.}, journal = {Oral surgery, oral medicine, oral pathology and oral radiology}, volume = {141}, number = {6}, pages = {781-794}, doi = {10.1016/j.oooo.2026.01.010}, pmid = {41741312}, issn = {2212-4411}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; *Dentists ; *Professional Role ; Referral and Consultation ; }, abstract = {Dentists are often the first healthcare providers to observe subtle orofacial and behavioral changes that may reflect underlying neurological diseases, including altered salivary flow, dysphagia, oral burning sensations, unusual orofacial movements, or tremors and pain, among others. These are symptoms of conditions such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and other systemic disorders with neurological involvement, which are frequently misattributed to local or functional causes, thereby delaying diagnosis and care. As the frequency of neurodegenerative and neuromuscular conditions rises with aging, the dental setting offers a critical opportunity for early recognition and referral. This clinical review summarizes orofacial manifestations, dental care challenges, and referral strategies across different neurological and systemic diseases. Organized by disease stage and functional impairment, the review provides practical tools for decision-making. Guidance on screening, behavioral adaptation, and care coordination is also provided, including multiple practical tables, figures, and chairside screening tools to support early recognition and referral. Finally, the review advocates for improved training, interdisciplinary collaboration, and progressive integration of artificial intelligence, machine learning, and other emerging technologies (e.g., biosensors, salivary biomarker platforms, or high-density electrophysiologic tools) to support clinicians in recognizing neurological diseases.}, } @article {pmid41741438, year = {2026}, author = {Liu, T and Lin, Y and Liu, Q and Liao, W and Lin, Y and Zhang, Y and Zhang, J and Cao, W and Yang, L and Hong, Z and Lu, Z}, title = {Target-stabilized base editors enable robust high-fidelity RNA editing.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41741438}, issn = {2041-1723}, support = {82327805//National Natural Science Foundation of China (National Science Foundation of China)/ ; KQTD20210811090117032//Shenzhen Science and Technology Innovation Commission/ ; }, mesh = {*RNA Editing/genetics ; *Adenosine Deaminase/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Humans ; Animals ; RNA, Guide, CRISPR-Cas Systems/genetics/metabolism ; Mutation ; HEK293 Cells ; Amyotrophic Lateral Sclerosis/genetics ; Degrons ; Protein Engineering ; }, abstract = {RNA base editing using engineered deaminases represents a powerful tool to correct mutations at the RNA level. However, widespread off-target effects, primarily arising from dissociated free deaminases, remain a significant challenge. Here, we devise the RECODE (RNA editing with conditionally stable and enhanced ADAR1 deaminase variants) system, which employs designer degron-tagged ADAR1 deaminase (ADAR1d) with guide RNA (gRNA)-regulated stability. By promoting degradation of gRNA-unbound ADAR1d, RECODE markedly reduces transcriptome-wide edits while maintaining high on-target efficacy. Engineering gRNA for target RNA-induced conformational switching confines ADAR1d stabilization to intended editing sites, further enhancing editing precision. With structure-guided rational engineering of ADAR1d, RECODE efficiently corrects an Amyotrophic Lateral Sclerosis-relevant FUS mutation and installs a therapeutic mutation to Angptl3 in vivo, which mitigate FUS mislocalization to neuronal axons and lower plasma lipids, respectively. These findings establish RECODE as a highly stringent and efficient RNA editing technology and underscore a general principle for enhancing the specificity of RNA-guided protein effectors.}, } @article {pmid41742309, year = {2026}, author = {Xu, G and Dillon, K and Lopez, A and Brkic, S and Fromholt, S and Ostrow, LW and Glass, JD and Chakrabarty, P and Ayers, JI and Borchelt, DR}, title = {Fast and slow strains of misfolded mutant superoxide dismutase 1 in familial amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {41742309}, issn = {2051-5960}, support = {R01 NS092788/NS/NINDS NIH HHS/United States ; R01NS0927881/NH/NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; *Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Humans ; Mutation/genetics ; Protein Folding ; Mice ; Disease Models, Animal ; Disease Progression ; Spinal Cord/pathology ; }, abstract = {Mutations in superoxide dismutase 1 (SOD1) account for ~ 10% of familial amyotrophic lateral sclerosis (fALS) cases. Most SOD1 ALS cases show a 2–5 year clinical course, but a subset of patients exhibit a slowly progressing illness lasting 10–20 years. Substantial evidence indicates that disease-causing mutations in SOD1 promote misfolding and aggregation. Spinal tissue homogenates from paralyzed transgenic mice containing misfolded mutant SOD1 accelerate paralysis when injected into the spine or sciatic nerve of young mutant SOD1 transgenic mice. Using this prion-like seeding model in G85R-SOD1:YFP transgenic mice to initiate the disease process, we show that human SOD1 variants associated with rapidly progressing ALS produce SOD1-ALS strains that cause paralysis earlier than mutations associated with slowly progressing disease. Our findings suggest that the heterogeneous clinical presentations of different SOD1 mutations in ALS could be linked to prion-like strain attributes that govern the templating and propagation kinetics of misfolded SOD1.}, } @article {pmid41742554, year = {2026}, author = {Olby, NJ and Panek, W and Galifi, C and Faheem, K and Prasad, K and Goraczniak, R and Perrone, M and Tokarz, D and Sommer, S and Gunderson, SI}, title = {Development and pilot testing of U1 Adaptor therapy targeting SOD1 expression for dogs with degenerative myelopathy.}, journal = {Journal of veterinary internal medicine}, volume = {40}, number = {1}, pages = {}, pmid = {41742554}, issn = {1939-1676}, support = {//Finding the Cure for DM Foundation/ ; D19 CA033//Morris Animal Foundation/ ; }, abstract = {BACKGROUND: Degenerative myelopathy (DM) is a progressive neurodegenerative disease in dogs associated with a superoxide dismutase 1 (SOD1) gene mutation, resulting in SOD1 protein aggregation within neurons and astrocytes. Targeting SOD1 expression represents a viable therapeutic strategy.

HYPOTHESIS/OBJECTIVES: Assess the safety and potential efficacy of SOD1 silencing by intrathecal administration of a U1 Adaptor oligonucleotide targeting canine SOD1 (U1cSOD1) in healthy and DM-diseased dogs.

ANIMALS: Seven purpose-bred healthy adult dogs, 1 dog with stage III DM and 4 dogs with Stage I DM.

METHODS: Healthy dogs and the stage III DM dog received a single intrathecal dose of U1cSOD1 or a vehicle and were euthanized 5 or 30 days later. Four stage I DM-affected dogs received monthly intrathecal injections of U1cSOD1 for up to 10 months. Physical and neurologic examinations, blood tests, cerebrospinal fluid analysis, as well as pharmacokinetic, pharmacodynamic, and histopathologic analyses were performed in all dogs.

RESULTS: In dogs receiving U1cSOD1, spinal cord SOD1 RNA expression near the injection site was decreased to a median of 37% of normal (range, 21%-79%). Dogs tolerated the procedure and test agent well, exhibiting no adverse effects clinically or histopathologically. Two of 34 injections were aborted because of high intrathecal pressure.

Monthly intrathecal injections of U1cSOD1 in DM-affected dogs are safe and decrease spinal cord SOD1 expression by >50% but an alternative administration route would be preferred. This first test of U1 Adaptor technology in dogs with a naturally occurring disease shows potential for therapeutic intervention in a fatal disease without a current cure.}, } @article {pmid41743427, year = {2026}, author = {Luo, Y and Liu, X and Yang, M}, title = {Current status and future prospects of brain-computer interfaces in the field of neurological disease rehabilitation.}, journal = {Frontiers in rehabilitation sciences}, volume = {7}, number = {}, pages = {1666530}, pmid = {41743427}, issn = {2673-6861}, abstract = {Neurological disorders represent a significant category of diseases that profoundly affect human health, accounting for the second leading cause of global mortality. This group of conditions includes stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, Parkinson's disease, and cerebral palsy, among others. These disorders are highly susceptible to sequelae and profoundly impact individuals' daily lives. In this context, Brain-Computer Interface (BCI) technology has demonstrated considerable potential in the domain of neurorehabilitation, although numerous challenges remain. The manuscript provides a comprehensive review of recent advancements in research and clinical applications, highlighting current limitations and outlining future directions. It elucidates the applicability and constraints of Brain-Computer Interface (BCI) technology across various diseases and patient populations. To facilitate insights across different conditions, comparative tables are presented, aligning BCI strategies with therapeutic targets, outcomes, advantages, limitations, and existing evidence gaps. The scope extends beyond motor restoration to include under-explored domains, such as neuropathic pain, with a focus on real-world translation, including home and community feasibility and the distinction between assistive and rehabilitative applications. The review distills overarching limitations within the field, such as small sample sizes, protocol heterogeneity, and limited longitudinal evidence, while synthesizing the most recent studies. An actionable research and development roadmap is proposed to guide next-generation BCI rehabilitation, incorporating individualized cortical-network simulators, self-architecting decoders, adaptive therapy approaches akin to game seasons, and proprioceptive "write-back" mechanisms via peripheral interfaces. Moreover, the review reveals significant research focal points and critical issues that warrant further investigation in the context of neurological rehabilitation utilizing BCI technology.}, } @article {pmid41744019, year = {2026}, author = {Shi, Y and Xiao, S and He, D}, title = {Visualization analysis of the use of traditional Chinese medicine in the diagnosis and treatment of rare diseases in mainland China based on CiteSpace.}, journal = {Intractable & rare diseases research}, volume = {15}, number = {1}, pages = {71-84}, pmid = {41744019}, issn = {2186-3644}, abstract = {This study used CiteSpace (version 6.4.R1) to perform a visualization analysis of 3,058 articles on traditional Chinese medicine (TCM) diagnosis and treatment of rare diseases retrieved from the China National Knowledge Infrastructure (CNKI) database, the VIP Chinese Science and Technology Periodical Database (VIP), the Wanfang database (Wanfang), and the Chaoxing database (Chaoxing). The goal was to ascertain the current status of research, hotspots in research, and trends in the development of TCM for rare disease diagnosis and treatment in mainland China, providing insights for future TCM research in this field. Visual maps of annual publication volume, authors, institutions, keywords, and other content have revealed that TCM demonstrates prominent advantages in 5 out of 207 defined rare diseases: idiopathic pulmonary fibrosis, hepatolenticular degeneration (Wilson's disease), osteosarcoma, retinitis pigmentosa, and multiple sclerosis. Potential advantages are identified in treating melanoma, amyotrophic lateral sclerosis, homocysteinemia, primary biliary cholangitis, and lymphangioleiomyomatosis. TCM research on rare diseases focuses on etiology, pathogenesis, and syndrome differentiation-based treatment. Case-control studies and mechanism investigations have been initiated for some conditions, while clinical research is gradually incorporating integrated TCM-Western medicine approaches. However, enhanced team and institutional collaboration, development of multicenter networks, exploration of multidisciplinary research, and clinical studies yielding high-level evidence are still needed to provide quality evidence-based support for clinical decision-making in the TCM treatment of rare diseases.}, } @article {pmid41744126, year = {2026}, author = {Yang, Q and Wu, H and Huang, X and Xie, M and Shan, Y and Dou, Z and Li, Y and Wen, H and Li, C}, title = {Prevalence and Risk Factors of Dysphagia in Amyotrophic Lateral Sclerosis: A Retrospective Study Using the Nationwide Inpatient Sample Database.}, journal = {Muscle & nerve}, volume = {73}, number = {5}, pages = {875-881}, doi = {10.1002/mus.70188}, pmid = {41744126}, issn = {1097-4598}, support = {2024FYQ001//Affiliated Hospital of Shandong Second Medical University/ ; 2023B110003//Guangdong Provincial Clinical Research Center for Rehabilitation Medicine/ ; }, mesh = {Humans ; *Deglutition Disorders/epidemiology/etiology/economics ; Female ; *Amyotrophic Lateral Sclerosis/complications/epidemiology ; Retrospective Studies ; Prevalence ; Risk Factors ; Male ; Aged ; Middle Aged ; Databases, Factual ; Inpatients ; United States/epidemiology ; Length of Stay ; Aged, 80 and over ; Hospitalization ; Adult ; }, abstract = {INTRODUCTION/AIMS: Dysphagia is a common but under-characterized complication in Amyotrophic lateral sclerosis (ALS), contributing to morbidity and healthcare burden. This study aimed to investigate the prevalence, pinpoint risk factors, and assess the adverse clinical outcomes linked to dysphagia in hospitalized patients with ALS.

METHODS: This retrospective cohort study analyzed 23,997 ALS cases derived from the Nationwide Inpatient Sample (NIS) database, covering the years 2010 to 2019. Data collection included patient demographics (age, sex, race/ethnicity), hospital characteristics (size, teaching status, location), clinical parameters (comorbidity profiles, complications), and healthcare utilization metrics (length of stay and hospitalization costs).

RESULTS: Among 23,997 ALS patients, 7419 (31.7%) were diagnosed with dysphagia. The annual prevalence of dysphagia in ALS patients varied substantially over the decade. Patients with dysphagia experienced a longer hospital stay (5 vs. 4 days; p < 0.001), incurred $6656 in additional hospitalization costs (p < 0.001), and faced heightened risks of complications such as cognitive impairment, cerebrovascular accidents, respiratory muscle paralysis, and tracheostomy. Multivariate analysis identified several independent risk factors for the development of dysphagia, including age ≥ 65 years, female sex, Hispanic ethnicity, treatment at large or medium-sized hospitals, care at urban teaching hospitals, and comorbidities such as depression, malnutrition, and weight loss.

DISCUSSION: Dysphagia affected approximately one-third of hospitalized ALS patients in this study, contributing to extended hospital stays and increased healthcare costs. Timely screening and tailored interventions are crucial for minimizing complications and maximizing the efficient use of resources.}, } @article {pmid41744255, year = {2026}, author = {Labeit, B and Bach, J and Harborth, E and Dziewas, R and Meuth, SG and Grefkes, C and Willems, L and Lapa, S}, title = {Impact of a Neurogenic Dysphagia Outpatient Clinic on Diagnosis, Treatment, and Nutrition.}, journal = {European journal of neurology}, volume = {33}, number = {3}, pages = {e70544}, pmid = {41744255}, issn = {1468-1331}, support = {529859742//Deutsche Forschungsgemeinschaft/ ; }, abstract = {BACKGROUND: The aim was to evaluate the diagnostic, therapeutic, nutritional, and complication-related impact of a university-led neurogenic dysphagia outpatient clinic.

METHODS: We retrospectively analyzed all patients seen at the University Hospital Frankfurt Neurogenic Dysphagia Outpatient Clinic (January 2021-July 2023). Data included demographics, neurological diagnoses, Functional Oral Intake Scale (FOIS), Penetration-Aspiration Scale (PAS) from Flexible Endoscopic Evaluation of Swallowing (FEES), nutritional status, therapy adjustments, and pneumonia requiring hospitalization. We quantified diagnostic revisions, therapeutic/nutritional interventions, and modeled pneumonia risk using logistic regression.

RESULTS: Among 255 patients (mean age 65.9 years; 60.0% men), Parkinsonian syndromes (18.0%) and stroke (12.9%) were most frequent. Complications included weight loss (32.8%), choking (20.0%), and pneumonia (12.6%). Primary diagnosis changed in 38.8% of patients. Of 110 patients with initially unexplained dysphagia, 70.9% received a neurological diagnosis, most often ALS and Parkinsonian syndromes (each 19.5%). Therapy recommendations changed in 42.0% of patients, including symptomatic and disease-modifying treatments; nutritional management was dynamic (new PEG in 16.1%; removal in 50.0% of existing PEGs); 42.9% of tracheostomized patients were decannulated. Frailty (OR 1.49, p = 0.005) and PAS 8 (OR 3.67, p = 0.007) independently predicted pneumonia.

CONCLUSION: A dedicated outpatient dysphagia clinic enhances diagnostic precision, optimizes therapy, and supports individualized nutritional and airway management. FEES-based phenotyping strengthens differential diagnostics and enables the identification of previously unrecognized neurological syndromes. Silent aspiration and frailty identify patients at the highest pneumonia risk. Dysphagia should be regarded as an independent therapeutic target within disease-specific neurological treatment, and dysphagia outpatient clinics should be integrated into standard neurological care pathways.}, } @article {pmid41744269, year = {2026}, author = {Nakamura, R and Steyn, FJ and Kobashi, S and Ogawa, N and Kitamura, A and Yamakawa, I and Henderson, RD and Ngo, ST and Urushitani, M}, title = {Blood Lactate as a Prognostic Biomarker for Survival and Weight Loss in Amyotrophic Lateral Sclerosis: An Exploratory-Validation Study.}, journal = {Annals of neurology}, volume = {99}, number = {6}, pages = {1526-1535}, pmid = {41744269}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality/diagnosis ; Female ; Male ; *Lactic Acid/blood ; *Weight Loss/physiology ; Retrospective Studies ; Prognosis ; Biomarkers/blood ; Middle Aged ; Aged ; Body Mass Index ; Cohort Studies ; Australia ; }, abstract = {OBJECTIVE: Lactate is increasingly recognized as an energy substrate, but its relevance to amyotrophic lateral sclerosis (ALS) remains unclear. We examined whether blood lactate is associated with survival and weight loss in ALS.

METHODS: This retrospective study included an Australian exploratory cohort and a Japanese validation cohort with clinical data matched to measures of blood lactate. The primary outcome was survival from onset to death or tracheostomy. In the exploratory cohort, survival was analyzed using Kaplan-Meier curves stratified by the first quartile (Q1) of lactate and multivariable Cox regression. This cutoff was applied for log-rank analysis in the validation cohort. The secondary outcome was 3-month body mass index (BMI) change (ΔBMI). Associations between baseline lactate and ΔBMI were assessed using multivariable regression in the exploratory cohort, whereas Q1-based stratification was used in the validation cohort.

RESULTS: The exploratory cohort included 110 patients with ALS (57 with ΔBMI data) and 86 healthy controls; the validation cohort included 36 patients (17 with ΔBMI data). In the exploratory cohort, lower lactate levels (below Q1; 1.05 mmol/L) were associated with shorter survival (p = 0.031) and remained independently predictive of higher risk for mortality (adjusted hazard ratio [HR] per 1 SD = 0.57, 95% confidence interval [CI] = 0.35-0.91). This association was confirmed in the validation cohort (p = 0.003). Lactate was independently associated with ΔBMI (β = 0.53, p = 0.032), and patients with lower lactate had a greater BMI decline (p = 0.010).

INTERPRETATION: Lower blood lactate is associated with increased risk for earlier death and greater weight loss in ALS, suggesting that lactate is a prognostic biomarker of nutritional status. ANN NEUROL 2026;99:1526-1535.}, } @article {pmid41744765, year = {2026}, author = {Dellazizzo Toth, T and Bond, S and Saxena, S}, title = {The Calcium Connection: Explaining Motor Neuron Vulnerability in ALS.}, journal = {Cells}, volume = {15}, number = {4}, pages = {}, pmid = {41744765}, issn = {2073-4409}, abstract = {ALS is a severe neuromuscular disease classically characterized by the progressive loss of motor neurons, leading to incremental muscle weakness and eventually death. Current treatment options for ALS have proven to have limited effect, merely delaying the progression of symptoms and prolonging patient survival. This motor neuron subtype-related differential vulnerability has been linked to neuron excitability, metabolism, and protein aggregation. Calcium dysregulation, which serves as an important second messenger in neural signaling pathways, has been implicated in each of these mechanisms and represents a potential target for therapeutic intervention. Armed with cutting-edge tools for visualizing and recording calcium transients in vivo, ALS researchers have delved deeper into the role of calcium dysregulation in disease in recent years. Vulnerable motor neuron populations display an excess of calcium-permeable ion channels together with reduced expression of calcium-binding proteins, generating a cellular environment primed for excitotoxic stress. Loss of inhibitory synaptic input further heightens susceptibility to calcium overload. Paradoxically, some evidence suggests that elevated neuronal activity can exert neuroprotective effects, highlighting the complexity of activity-dependent calcium signaling in ALS. Additionally, ALS-related toxic protein accumulation disrupts calcium homeostasis, contributing to endoplasmic reticulum stress and mitochondrial dysfunction. Emerging data indicate that calcium dysregulation impairs neuron-glia communication, amplifying neuroinflammation and accelerating disease progression. This review aims to synthesize current evidence on how calcium imbalance contributes to motor neuron vulnerability and degeneration in ALS. By exploring the cellular, synaptic, and network-level mechanisms of calcium dysregulation in ALS, the review examines its interplay with mitochondrial and ER stress and explores its impact on neuron-glia interactions with the aim of synthesizing key mechanistic insights into the disease pathogenesis and therapeutic targets.}, } @article {pmid41745965, year = {2026}, author = {Haroun, M and Tratrat, C and Mathew, RT and Munir, M and Sattar, MN and Shawky, M and Kochkar, H and Aldakhilallah, ON and Ghafoor, A and Turk, KGB and Geronikaki, A and Ghazzawy, HS}, title = {Avian Candidiasis: A Comprehensive Review of Pathogenesis, Diagnosis, and Control.}, journal = {Veterinary sciences}, volume = {13}, number = {2}, pages = {}, pmid = {41745965}, issn = {2306-7381}, support = {Grant number: KFU260519//Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University, Saudi Arabia/ ; }, abstract = {This review is a comprehensive investigation of avian candidiasis, mainly caused by Candida albicans, although the prevalence of non-albicans Candida species has increased in domestic and wild birds. Avian candidiasis causes significant economic losses in poultry production through increased mortality, cost of treatments, and reduced growth rates, particularly in young birds and intensive farming operations. The pathogenesis section provides a description of the molecular virulence factors such as adhesin-mediated attachment (ALS, Agglutinin-Like Sequence family; HWP1, Hyphal Wall Protein 1), yeast-to-hypha morphogenesis, tissue damage by Candidalysin, biofilm formation on mucosal and abiotic surfaces, and secreted hydrolytic enzymes including secreted aspartyl proteinases (SAPs) and phospholipases. The identified predisposing factors include immunosuppression, malnutrition, abuse of antibiotics, bad husbandry, and crop stasis. The diagnostic methods discussed encompass cytological analysis and fungal culture on selective media to more sophisticated methods of molecular analysis (PCR, MALDI-TOF MS, and NGS). Antifungal susceptibility investigations indicate that nystatin and amphotericin B are still very effective against most avian isolates and that resistance to the azoles is on the rise, especially with respect to the non-albicans Candida species. Nystatin is still the first-line treatment of localized infections; azoles are still used for resistant or systemic infections despite their hepatotoxicity. Sanitation, proper nutrition, and proper use of antimicrobials are essential to prevent diseases. The knowledge gaps comprise the absence of avian-specific pharmacokinetic information, poor knowledge of species-species virulence phenotypes, and the lack of point-of-care diagnostics. The need to have integrated One Health surveillance systems is emphasized by the zoonotic potential of the avian Candida reservoirs.}, } @article {pmid41746390, year = {2026}, author = {Kural, I and M Mombeek, LM and Wilson, DM}, title = {Role of mitochondria in neuronal function and survival in the enteric and central nervous systems.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {83}, number = {1}, pages = {}, pmid = {41746390}, issn = {1420-9071}, support = {11P4G24N//Fonds Wetenschappelijk Onderzoek/ ; G0A9625FWO//Fonds Wetenschappelijk Onderzoek/ ; }, mesh = {Humans ; *Mitochondria/metabolism/pathology ; *Neurons/metabolism/pathology/cytology ; *Enteric Nervous System/metabolism/pathology ; Animals ; *Central Nervous System/metabolism/pathology ; Neurodegenerative Diseases/metabolism/pathology ; Oxidative Stress ; Cell Survival ; Mitochondrial Diseases/metabolism/pathology ; }, abstract = {Mitochondria are indispensable organelles that not only generate cellular energy through oxidative phosphorylation but also regulate calcium homeostasis, redox balance, and apoptotic signaling. Given the high metabolic demands of neurons, mitochondrial function and resilience mechanisms are essential for neuronal development, maturation, and survival; when these systems fail, pathological outcomes can arise. This review highlights the critical role of mitochondria in maintaining neuronal function, with discussion related to both the central (CNS) and enteric (ENS) nervous systems. We present how mitochondrial dysfunction, through impaired bioenergetics, oxidative stress, defective quality control, and altered dynamics, can drive neuronal cell loss. Furthermore, we highlight the link between mitochondrial defects and nervous system pathological outcomes in both primary mitochondrial disorders, such as mitochondrial neurogastrointestinal encephalomyopathy, and secondary mitochondrial disorders, such as Alzheimer, Parkinson, and Huntington disease, as well as amyotrophic lateral sclerosis. By integrating evidence from the CNS and ENS, this review highlights the central role of mitochondria in supporting and preserving neuronal health, as well as the potential of mitochondria as therapeutic targets in neurodegenerative disease.}, } @article {pmid41746412, year = {2026}, author = {Tarazona-Santabalbina, FJ and Belenguer-Varea, A and Borrás-Blasco, J and García-Tercero, E and Martin, ML and Prior, NP and Mariscal, G and Valcuende-Rosique, A}, title = {Safety profile of tofersen in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {3}, pages = {}, pmid = {41746412}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase-1/genetics ; Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVE: To evaluate the safety profile of tofersen in patients with SOD1-associated amyotrophic lateral sclerosis (ALS) through a systematic review and meta-analysis of randomized controlled trials and observational cohorts. METHODS: A comprehensive search was conducted up to August 2025. Eligible studies included adults with SOD1-associated ALS treated with intrathecal tofersen. Outcomes were treatment-emergent adverse events (AEs), serious adverse events (SAEs), cerebrospinal fluid (CSF) abnormalities, and procedure-related complications. Pooled incidence rates with 95% confidence intervals (CIs) were calculated using fixed- or random-effects models depending on heterogeneity. Risk of bias was assessed with MINORS, and certainty of evidence was graded using GRADE. RESULTS: Six studies (2 RCTs, 4 cohorts) comprising 179 patients receiving tofersen and 48 placebo controls were included. The pooled incidence of any AE was 98.0% (95% CI: 95.6–100), while SAEs occurred in 10.0% (95% CI: 0–22.1). Common adverse events included procedural pain (56.2%), headache (54.1%), back pain (38.4%), and extremity pain (35.9%). CSF pleocytosis was reported in 44.1% of patients, with high heterogeneity across studies. Gastrointestinal and constitutional events such as nausea (17.0%) and fatigue (21.6%) were usually mild. Respiratory failure occurred in 9.2% of cases. Most adverse events were manageable, though rare severe complications (e.g., meningitis, myelitis, intracranial hypertension) were described in individual reports. CONCLUSION: Tofersen is associated with frequent adverse events, predominantly mild to moderate, while serious complications are less common but clinically relevant. The overall safety profile supports its continued clinical use in SOD1-associated ALS, although long-term surveillance is warranted to better characterize rare outcomes.}, } @article {pmid41747474, year = {2026}, author = {Kaji, R and Ishida, T and Izumi, Y}, title = {Response to letter to the editor "Comment on: Clinical safety of ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis: Open-label extension of a phase 2/3 randomized controlled study".}, journal = {Journal of the neurological sciences}, volume = {483}, number = {}, pages = {125792}, doi = {10.1016/j.jns.2026.125792}, pmid = {41747474}, issn = {1878-5883}, } @article {pmid41747520, year = {2026}, author = {Ammari, F and Le Penglau, R and Bouhier, M and Neff, D}, title = {Characterization of long-term atmospheric corrosion of iron in indoor and outdoor conditions using Raman spectroscopy coupled to multivariate curve resolution-alternating least squares.}, journal = {Talanta}, volume = {305}, number = {}, pages = {129569}, doi = {10.1016/j.talanta.2026.129569}, pmid = {41747520}, issn = {1873-3573}, abstract = {This study presents a characterization of long-term atmospheric corrosion layers formed on historical iron samples from two cathedrals exposed to distinct environments: outdoor-exposed low-alloy steel clamps from Metz Cathedral and indoor-exposed iron reinforcements from Amiens Cathedral, both aged over 500 years. To address the complexity and heterogeneity of the corrosion products, Raman micro-spectroscopy was combined with multivariate curve resolution-alternating least squares (MCR-ALS) to extract pure spectral components and their spatial distribution, and estimate their relative contributions within the corrosion matrix. For the Amiens sample, MCR-ALS was first initialized using laboratory-acquired reference spectra of pure phases. The same dataset was then reprocessed using component spectra extracted from non-negative matrix factorization (NMF) as a blind initialization. The comparison of the results demonstrated that reliable and chemically consistent results can be obtained even without experimentally measured reference spectra, offering a robust solution for the analysis of complex mixtures. To further validate this approach in a more complex system, the Metz sample was analyzed using a fully blind NMF-based initialization, confirming the method's robustness across varying environmental contexts and over extended timescales. Finally, the identified corrosion phases and their spatial distributions were compared with previous studies, revealing strong agreement and thereby reinforcing the reliability of the approach.}, } @article {pmid41747658, year = {2026}, author = {Fernandes, GL and Orssatto, LBR and Pinto, MD and Henkin, JS and Shandiz, E and McCombe, PA and Henderson, RD and Trajano, GS}, title = {Maximal motor unit firing rates decline with amyotrophic lateral sclerosis progression.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {185}, number = {}, pages = {2111697}, doi = {10.1016/j.clinph.2026.2111697}, pmid = {41747658}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Middle Aged ; Male ; *Motor Neurons/physiology ; Disease Progression ; Female ; Electromyography/methods ; Aged ; *Muscle, Skeletal/physiopathology ; *Recruitment, Neurophysiological/physiology ; *Action Potentials/physiology ; Muscle Strength/physiology ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of upper and lower motor neurons and their motor units (MUs). MU loss is compensated by collateral sprouting and reinnervation of muscle fibres. There is limited information about the properties of these surviving MUs as these processes take place. High-density surface electromyography (HD-sEMG) decomposition enables non-invasive analysis of individual MU firing behaviour during maximal voluntary contractions and assess their changes with ALS progression.

METHODS: Thirty-nine individuals with ALS (24 men; mean age 63 ± 16 years) completed up to five visits (interval 20.0 ± 7.9 weeks). Tibialis anterior HD-sEMG recordings during maximal contractions were decomposed into individual MU spike trains, from which maximal firing rates were quantified. Muscle strength was assessed with the Medical Research Council (MRC) scale, and global function with the revised ALS Functional Rating Scale (ALSFRS-R).

RESULTS: Maximal MU firing rates declined significantly over time [-0.32 Hz/month, (95% CI -0.44; -0.19)], regardless of MRC scores. Across participants, maximal firing rates decreased by 2.38 Hz (1.78; 2.98) for each 1-point reduction in MRC and by 0.54 Hz for each ALSFRS-R point (-0.83; -0.26).

CONCLUSION: These findings demonstrate that maximal MU firing rates decline as ALS progresses, suggesting that the surviving motor unit undergo progressive pathophysiological changes as motor neurons degenerate. HD-sEMG MU firing-rates analysis appeared more sensitive than MRC in detecting early deterioration in muscle decline.

SIGNIFICANCE: Maximal firing rates analysis has the potential to serve as a quantitative clinical biomarker of neuromotor system degeneration, complementing global functional scales in clinical monitoring.}, } @article {pmid41748268, year = {2026}, author = {Challa, S and Griffith, M and Jegede, A and Tijani, A and Himes, E and Idiodi, I and Okoli, C and Dimowo, S and Omoluabi, E and Liu, JX}, title = {Understanding clients' and providers' perspectives on the implementation of subcutaneous depot medroxyprogesterone acetate (DMPA-SC) for self-injection programming in Nigeria.}, journal = {BMJ global health}, volume = {10}, number = {Suppl 6}, pages = {}, pmid = {41748268}, issn = {2059-7908}, support = {//the Bill & Melinda Gates Foundation/ ; }, mesh = {Humans ; *Medroxyprogesterone Acetate/administration & dosage ; Female ; Nigeria ; *Contraceptive Agents, Female/administration & dosage ; Injections, Subcutaneous ; Adult ; Self Administration ; Male ; *Attitude of Health Personnel ; Young Adult ; }, abstract = {Subcutaneous depot medroxyprogesterone acetate (DMPA-SC) is an injectable contraceptive method with a small needle and prefilled syringe system that has been approved for self-injection (SI) by clients. As DMPA-SC for SI programmes are being scaled, employing an implementation science lens is critical to understanding what works. This study explored providers' and clients' experiences with providing and receiving services, respectively, for DMPA-SC for SI in Nigeria, using an implementation science framework.Between 2021 and 2023, we conducted N=141 interviews with providers offering DMPA-SC for SI, and N=129 interviews with their clients using DMPA-SC for SI in Lagos, Enugu and Plateau States. Using Proctor et al's implementation science framework, we noted observations for each interview question, extracted related quotes, and coded observations and quotes by implementation outcome (acceptability, appropriateness, feasibility, fidelity, cost, efficiency, safety, client-centredness and adoption).Among clients, learning about DMPA-SC and SI from social network members facilitated acceptability and adoption of the method. Clients reported that provider outreach was appropriate for contraceptive information. However, providers desired support to mitigate their own out-of-pocket costs and enhance the feasibility of outreach. Occasionally, providers used clients' age or education to decide whether they could self-inject independently, rather than clients' ability to perform SI procedures, limiting client-centredness Many providers felt their fidelity to SI provision protocols could improve with refresher trainings on the latest guidelines around offering SI. Clients indicated that proactive follow-up support from providers for continued SI and side effect management was appropriate and desired; providers concurred with offering such support.Findings suggest that programme scale-up efforts should prioritise: (1) leveraging peer support or social networks to facilitate acceptability of DMPA-SC for SI among clients, (2) improving access to training aids to ensure fidelity to protocols and facilitate adoption among clients and providers, (3) emphasising shared decision-making in judgement-free client trainings to encourage client-centredness, and (4) investing in models for proactive follow-up support to improve feasibility of continuation for clients' desired length of time.}, } @article {pmid41748409, year = {2026}, author = {Anzilotti, S and Valente, V and Brancaccio, P and Franco, C and Casamassa, A and Lombardi, G and Palazzi, A and Conte, A and Paladino, S and Canzoniero, LMT and Annunziato, L and Pierantoni, GM and Pignataro, G}, title = {Corrigendum to "Chronic exposure to l-BMAA cyanotoxin induces cytoplasmic TDP-43 accumulation and glial activation, reproducing an amyotrophic lateral sclerosis-like phenotype in mice" [Biomed. Pharmacother. 167 (2023) 115503].}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {196}, number = {}, pages = {119161}, doi = {10.1016/j.biopha.2026.119161}, pmid = {41748409}, issn = {1950-6007}, } @article {pmid41749139, year = {2026}, author = {Sun, Q and Wang, H and Deng, G and Du, Y and Ma, T and Ding, J and Xia, Z and Jiang, Y and Huang, Y and Huang, X}, title = {Nomogram prediction model for prognosis of patients with amyotrophic lateral sclerosis.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {}, pmid = {41749139}, issn = {1471-2377}, support = {320.6750.18456//Wu Jieping Medical Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/blood/mortality ; Female ; *Nomograms ; Prognosis ; Male ; Middle Aged ; Aged ; Ferritins/blood ; Age of Onset ; Adult ; Body Mass Index ; Creatinine/blood ; Creatine Kinase/blood ; Kaplan-Meier Estimate ; Uric Acid/blood ; Proportional Hazards Models ; }, abstract = {OBJECTIVES: To analyze the factors affecting prognosis of patients with sporadic amyotrophic lateral sclerosis (ALS), to establish a nomogram predictive model. METHODS: A total of 236 patients with sporadic ALS hospitalized in the Department of Neurology of the First Medical Center, Chinese PLA General Hospital, from March 2011 to November 2021 were enrolled in the study. Basic information and clinical and laboratory data of patients were collected, including sex, age at onset, body mass index, disease duration, diagnostic grade, and serum levels of creatine kinase (CK), creatinine (Cr), uric acid (UA), and ferritin. Kaplan-Meier univariate and multivariate Cox proportional hazard regression models were used to analyze the prognostic factors, and a nomogram predictive model was established. RESULTS: Univariate analysis showed that ferritin, CK, Cr, age at onset, disease duration, and body mass index (BMI) were all correlated with prognosis of ALS. Multivariate analysis showed that ferritin, Cr, disease duration, age at onset, and BMI were the strongest predictors. ROC curve and correction curve analyses verified the accuracy of the nomogram prediction model. CONCLUSIONS: Ferritin, Cr, disease duration, age at onset, and BMI are independent predictors of survival in patients with ALS. Based on these clinical and biological prognostic factors, we established a quantitative model for predicting survival probability, and may assist in the prognostic evaluation of ALS, pending further validation.}, } @article {pmid41749825, year = {2026}, author = {De Simoni, O and Scarpa, M and Cavallin, F and Kotsafti, A and Marchegiani, F and Stepanyan, A and Tussardi, G and Rosato, A and Spolverato, G and Angriman, I and Urso, EDL and Ruffolo, C and Saadeh, LM and Maretto, I and Bao, QR and Negro, S and Vignotto, C and Facci, L and Rivella, G and D'Angelo, A and Matteazzi, A and Galuppini, F and Guzzardo, V and Salmaso, R and Pellegrini, V and Brignola, S and Ceccon, C and Stecca, T and Pozza, A and Massani, M and Pilati, P and Gruppo, M and Franzato, B and Cataldo, I and Portale, G and Cipollari, C and Zuin, M and Laurino, L and Dal Santo, L and Pirozzolo, G and Recordare, A and Ceccarini, L and Antoniutti, M and Marinelli, L and Brolese, A and Barbareschi, M and Bertalot, G and Ortenzi, M and Guerrieri, M and Zizzo, M and Dell'Atti, L and Guerriero, S and Piccioli, A and Pozza, G and Godina, M and Mondi, I and Verdi, D and Da Lio, C and Noaro, G and Cola, R and Bordignon, G and Merenda, R and Becherucci, G and Gavagna, L and Candioli, S and Tagliente, G and Tedeschi, U and Parini, D and Salmaso, B and Businello, G and Di Cristoforo, L and Bergamo, F and Porzionato, A and Scognamiglio, F and Bardini, R and Pucciarelli, S and Agostini, M and Chiminazzo, V and Gregori, D and Di Camillo, B and Castagliuolo, I and Dei Tos, AP and Fassan, M and Scarpa, M}, title = {IMMUNOREACT 4: Peritumoral Microenvironment Associated with Anastomotic Leaks After Surgery for Rectal Cancer.}, journal = {Cancers}, volume = {18}, number = {4}, pages = {}, pmid = {41749825}, issn = {2072-6694}, support = {23381//AIRC IG 2019/ ; }, abstract = {Background: Anastomotic leaks (ALs) remain a critical complication after rectal cancer surgery. Emerging evidence suggests that local immune dysregulation may play a key role in anastomotic healing. We investigated the immune microenvironment of histologically normal, tumor-adjacent rectal mucosa-a tumor-conditioned field-as a potential substrate for AL predisposition. Methods: IMMUNOREACT 4 is a sub-analysis of the IMMUNOREACT project (clinicaltrials.gov NCT04915326 and NCT04915326), a multicenter translational study evaluating immune features of histologically normal, tumor-adjacent rectal mucosa of patients undergoing colorectal anastomosis. A prospective cohort (n = 121) was analyzed using flow cytometry, in addition to a retrospective cohort (n = 262) using immunohistochemistry. Immune markers of epithelial activation and lymphocyte subsets were compared between patients with and without postoperative ALs. Exploratory predictive models combining immune and clinical variables were developed and evaluated using discrimination, calibration and decision curve analyses. Results: At flow cytometry, the CK[+]HLAabc[+] MFI (AUC 0.66, 95% CI 0.52-0.80), CD8[+]CD38[+] cell rate (AUC 0.65, 95% CI 0.52-0.78) and CD3[+]CTLA4[+] cell rate (AUC 0.65, 95% CI 0.51-0.80) showed moderate predictive potential for ALs. In immunohistochemistry, CD3[+] (AUC 0.57, 95% CI 0.54-0.60), CD8[+] (AUC 0.57, 95% CI 0.52-0.62), CD8β[+] (AUC 0.59, 95% CI 0.53-0.65) and Tbet[+] (AUC 0.60, 95% CI 0.56-0.64) showed some predictive ability for ALs. The model including CD8β[+], the BMI, neutrophile/lymphocyte ratio and tumor location had an AUC of 0.67 (95% CI 0.62-0.72). Conclusions: Immune activation within histologically normal, tumor-adjacent rectal mucosa-characterized by epithelial HLA upregulation and cytotoxic or Th1 T cell infiltration-is associated with postoperative ALs. Although predictive accuracy is limited, these findings support the concept that a tumor-conditioned immune microenvironment may predispose patients to impaired anastomotic healing. Integration of mucosal immune profiling with clinical variables represents a promising exploratory approach that warrants further prospective validation.}, } @article {pmid41750144, year = {2026}, author = {Huang, X and Xia, K and Ye, S and Yang, Q and Fan, D}, title = {Enlarged Perivascular Spaces (EPVS) and the Risk of Amyotrophic Lateral Sclerosis (ALS): Evidence for Overlapping Genetic Signals in White Matter Without Causal Links.}, journal = {Brain sciences}, volume = {16}, number = {2}, pages = {}, pmid = {41750144}, issn = {2076-3425}, support = {81873784, 82071426, 82401670//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; there is no number of this funding.//the special fund of the National Clinical Key Specialty Construction Program, P. R.China(2024)/ ; }, abstract = {Background/Objectives: Emerging evidence suggests that enlarged perivascular spaces (EPVS), which play a significant role in brain fluid exchange and waste removal, may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). In this study, we aimed to explore the shared genetic link and causal effect between EPVS and ALS. Methods: This study used publicly available summary data from the largest and most recent genome-wide association studies (GWAS) on EPVS (n = 40,095) and ALS (n = 138,086) in European populations. EPVS were assessed in the hippocampus (EPVS-HIP), basal ganglia (EPVS-BG), and white matter (EPVS-WM). We used linkage disequilibrium score regression (LDSC) to investigate the genetic correlation. Multi-trait analysis of GWAS (MTAG), Cross-Phenotype Association (CPASSOC) analysis, and genetic colocalization analysis were performed to identify shared risk loci. Bidirectional Mendelian randomization analysis was used to investigate the causal relationship. Results: A negative genetic correlation was observed between EPVS-WM and ALS after Bonferroni correction (rg = -0.24, p < 0.01). No significant correlations were observed between ALS and EPVS-HIP (rg = -0.03, p = 0.79) or EPVS-BG (rg = 0.01, p = 0.91). Four significant loci including rs113247976 in KIF5A and rs118082508 in SDR9C7 were identified as potential pleiotropic loci of the relationship. None of these loci demonstrated evidence of genetic colocalization. Furthermore, Mendelian randomization analysis revealed no causative effect in either direction. Conclusions: EPVS-WM and ALS may share part of their genetic architecture, but no evidence for a causal relationship was observed. Future research is needed to further refine these relationships.}, } @article {pmid41750189, year = {2026}, author = {Ray, SK}, title = {'Molecular and Cellular Neuroscience': Impacts of Eight Highly Cited Articles Published in This Section of Brain Sciences in 2024.}, journal = {Brain sciences}, volume = {16}, number = {2}, pages = {}, pmid = {41750189}, issn = {2076-3425}, abstract = {This year, the selection criteria for highly cited articles in the 'Molecular and Cellular Neuroscience' section of Brain Sciences were focused on publications that achieved a citation count of 10 or more during 2024. Applying this metric, the Editorial Office, in collaboration with myself as Associate Editor of the 'Molecular and Cellular Neuroscience' section of the journal, identified eight articles that not only exemplified the mission of this section but also made significant scientific contributions by advancing our current understanding of the molecular and cellular mechanisms underlying major and rare neurological disorders. These articles encompass miscellaneous topics, including Alzheimer's disease (AD), chronic alcoholism, glioblastoma multiforme (GBM), amyotrophic lateral sclerosis (ALS), cognitive impairment, cerebrovascular disease, and Rett syndrome (RTT). Importantly, several contributions highlight experimental therapeutic strategies aimed at mitigating pathogenic mechanisms, offering promising avenues for translational research and future clinical applications.}, } @article {pmid41750236, year = {2026}, author = {Eisen, A}, title = {Exploring the ALS Multistep Model.}, journal = {Brain sciences}, volume = {16}, number = {2}, pages = {}, pmid = {41750236}, issn = {2076-3425}, abstract = {ALS is a multistep disease, in which (epi)genetic, environmental, and age-related processes, including senescence, converge over decades to reduce resilience resulting in self-sustaining symptomatic disease. The multistep model visualizes five to six impactful events in sporadic ALS, but fewer in those carrying high-penetrance mutations, such as SOD1, FUS, or C9orf72 expansions. The timing, duration, and cumulative effects of specific steps are presumed to have individual variability but, the steps themselves are inferred since they have not been observed and remain agnostic as to biological identity. Nevertheless, the model gives an opportunity to integrate genetics, aging, environmental exposures, and systems-level vulnerability into a single framework. Acting as step modifiers, environmental exposures including trauma lower the threshold for step acquisition, accelerate the accumulation of steps, influence the anatomical site of disease onset, and unmask preclinical disease. Because ALS emerges from the gradual collapse of multiple layers of biological robustness, tackling a single pathway will be insufficient and the multistep model forces a reconsideration of therapeutic timing and strategies. Protection against early-life insults, anti-aging, and anti-senescent therapies may curtail step accumulation preventing ALS from exceeding threshold and disease manifestation.}, } @article {pmid41750323, year = {2026}, author = {Dong, L and Li, X and Li, A and Yi, J and Vockery, Y and Chang, Y and Pan, Z and Brotto, M and Zhou, J}, title = {Absence of Neuromuscular Dysfunction in Mice with Gut Epithelium-Restricted Expression of ALS Mutation hSOD1[G93A].}, journal = {Biomolecules}, volume = {16}, number = {2}, pages = {}, pmid = {41750323}, issn = {2218-273X}, support = {R01 NS105621/NS/NINDS NIH HHS/United States ; R01 HL138570/HL/NHLBI NIH HHS/United States ; R01 NS129219/NS/NINDS NIH HHS/United States ; 16-IIP-288//Bank of America/ ; R01NS105621//National Institute of Health/ ; AL170061(W81XWH1810684)//United States Department of Defense/ ; R01HL138570//National Institute of Health/ ; R01 AR057404/AR/NIAMS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology/metabolism ; Mice ; Mice, Transgenic ; *Mutation ; Humans ; *Intestinal Mucosa/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Disease Models, Animal ; Muscle, Skeletal/metabolism ; Intestinal Barrier Function ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neuromuscular disorder characterized by the progressive loss of motor neurons and skeletal muscle, ultimately leading to respiratory failure and death, typically within 3-5 years following diagnosis. While the death of motor neurons is the pathological hallmark, ALS is increasingly recognized as a systemic disorder involving non-motor systems. Gastrointestinal dysfunction has been widely observed in both ALS patients and animal models. However, because gut abnormalities and neuromuscular degeneration are intertwined during ALS disease progression, it remains unclear whether these gut abnormalities are merely a consequence of neuromuscular degeneration or whether they play a crucial role in initiating it. In this study, we investigated whether an ALS-associated mutation expressed exclusively in the gut can directly affect neuromuscular function. We generated a novel transgenic mouse model, Gut-hG93A, which overexpresses the human ALS mutation hSOD1[G93A] specifically in the epithelial cells of the intestine at a level comparable to the endogenous mouse SOD1. We found that the specific overexpression of hSOD1[G93A] in gut epithelial cells did not cause abnormalities in the structure of the tight junctions or in gut permeability. Furthermore, there were no significant differences between Gut-hG93A and control mice regarding lifespan, body weight, or neuromuscular activities, including grip strength, daily travel distance and in vivo muscle contractility. These findings suggest that the ALS-associated hSOD1[G93A] mutation, when expressed solely in the gut epithelium, is not sufficient to initiate neuromuscular degeneration of systemic ALS-like pathology.}, } @article {pmid41750455, year = {2026}, author = {Bustos, C and Yuste, JR and Aguinaga, A and Parra, A and Carmona-Torre, F and Azanza, JR and Lacasa, C and Del Pozo, JL}, title = {Timing of Antimicrobial Lock Replacement for Gram-Positive Port Infections: Results of a Randomized Trial.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {15}, number = {2}, pages = {}, pmid = {41750455}, issn = {2079-6382}, support = {EC10-329//Instituto de Salud Carlos III/ ; }, abstract = {Background: Conservative management of port-related bacteremia often includes locally administered antimicrobials, known as antimicrobial lock therapy (ALT). Current guidelines recommend daily replacement of antimicrobial lock solutions (ALSs). We aimed to evaluate whether ALSs could remain effective with extended dwell times of up to 10 days. Methods: In this randomized clinical trial, patients with noninfected, recently implanted ports were assigned to one of five ALS dwell-time groups, ranging from 1 to 10 days. Each ALS contained heparin plus an antimicrobial at standard intraluminal concentrations: vancomycin 2 mg/mL, teicoplanin 10 mg/mL, linezolid 1.8 mg/mL, daptomycin 5 mg/mL, or tigecycline 4.5 mg/mL. The primary endpoint was the time at which intraluminal drug concentrations decreased below 1 mg/mL (ClinicalTrials.gov NCT01592032). Results: Vancomycin and linezolid concentrations fell significantly below 1 mg/mL after 3 days of dwell time. Daptomycin and tigecycline concentrations decreased significantly after 7 days but remained above 1 mg/mL. Teicoplanin concentrations did not decline significantly after 7 days. Conclusions: Optimal ALS dwell time depends on the antimicrobial agent. Vancomycin and linezolid locks require daily replacement, whereas daptomycin, tigecycline, and teicoplanin locks maintain therapeutic concentrations for up to 7 days. These findings support individualized ALS replacement strategies, potentially reducing the need for daily interventions.}, } @article {pmid41751343, year = {2026}, author = {Iyer, MR and Zhao, B and He, X and Camacho, D and Wei, Z and Deng, J and Mitchell, CS}, title = {An Artificial Intelligence-Driven Multimorbidity Framework Reveals a Shared Metabolic and Immune Core Across Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia.}, journal = {Biomedicines}, volume = {14}, number = {2}, pages = {}, pmid = {41751343}, issn = {2227-9059}, support = {1944247//National Science Foundation/ ; R35GM152245/NH/NIH HHS/United States ; U19AG056169/NH/NIH HHS/United States ; 253558//Chan Zuckerberg Initiative/ ; }, abstract = {Background/Objectives: Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) share molecular features yet differ clinically, suggesting underlying systems-level commonalities. We aimed to characterize shared and disease-specific multimorbidity architectures across AD, ALS, and FTD using an artificial intelligence-driven literature-based semantic network. Methods: We applied SemNet 2.0, constructed from over 35 million PubMed abstracts, to analyze disease and syndrome (DSYN) and pharmacological substance (PHSU) nodes. Nodes were ranked using HeteSim and mapped to a harmonized 13-category mechanistic ontology. We quantified pairwise disease intersections, ontology-level enrichment, rank similarity, and intersection-disease alignment, and constructed an integrated multimorbidity priority landscape integrating disease-specific and intersection-level hierarchies. Results: Across AD, ALS, and FTD, a convergent multimorbidity architecture centered on a shared metabolic and immune core was identified, accompanied by prominent neurobehavioral processes and intermediate systems including gastrointestinal, endocrine, hematological, hepatic, and sensory pathways. Disease-specific signatures shaped distinct vulnerability profiles within this shared structure, including cardiovascular enrichment in AD, neuromuscular and toxin-related pathways in ALS, and coupled neurobehavioral-metabolic features in FTD. PHSU patterns reinforced these findings, with centrally positioned compounds predominantly targeting inflammatory, metabolic, or neuromodulatory processes. Conclusions: These findings position AD, ALS, and FTD within a unified, AI-derived multimorbidity framework. This ontology-guided approach provides a computational, hypothesis-generating foundation for multimorbidity-aware biomarker discovery, risk stratification, and cross-disease therapeutic exploration in neurodegenerative disease.}, } @article {pmid41751374, year = {2026}, author = {Trabulo, A and Sousa, P and Alvites, R and Maurício, AC}, title = {Mesenchymal Stem Cell-Based Therapies Applied in Neurological Diseases: A Systematic Review.}, journal = {Biomedicines}, volume = {14}, number = {2}, pages = {}, pmid = {41751374}, issn = {2227-9059}, abstract = {Background/Objectives: Neurodegenerative diseases (NDs) have a severe impact on patients' quality of life, and effective treatments remain limited. As the focus is on treating the symptoms, the root cause of the problem is commonly not addressed. Mesenchymal stem cells show an emerging potential due to the ability for self-renewal combined with their capability for differentiation into various cell lines, which makes them a strong candidate for regenerative therapies in general, and for application in neurological issues in particular. This article provides an overview of the safety, efficacy, and challenges associated with the use of mesenchymal stem cells (MSCs) and their derived secretome in clinical and preclinical models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Methods: A systematic search was conducted on PubMed to identify published studies providing clinical and preclinical evidence on the use of MSCs in neurodegenerative disorders. Results: Overall, the literature consistently indicates that MSCs and their derivatives exert disease-modifying effects across multiple NDs. Across AD, PD, HD and ALS, preclinical studies uniformly report improvements in behavioural outcomes, attenuation of neuroinflammation, and neuroprotective effects, largely mediated by MSCs' paracrine signalling rather than direct cell replacement. Clinical studies to date consistently support the safety and feasibility of MSC-based therapies, while efficacy signals remain modest, heterogeneous and predominantly short-term, highlighting the need for larger, well-controlled trials. Conclusions: Integration of genetic engineering, preconditioning, and EV technology may represent an emerging therapeutic approach that may complement existing neuroregeneration treatments, offering a scalable and minimally invasive frontier to improve long-term clinical outcomes in patients with AD, PD, HD, and ALS.}, } @article {pmid41751793, year = {2026}, author = {Ptáček, O and Musil, Z and Guarnieri, G and Vrbacká, A and Moudrá, P and Zlámalová, A and Röszlerová, P and Tonhajzer, M and Musil, V and Morelli, A and Zach, P}, title = {Amyotrophic Lateral Sclerosis: The State of the Art on Treatments and the Therapeutic Role of the Intestinal Microbiome in Human Studies.}, journal = {International journal of molecular sciences}, volume = {27}, number = {4}, pages = {}, pmid = {41751793}, issn = {1422-0067}, support = {Cooperatio 39 - Oncology and Haematology//Charles University/ ; Cooperatio 33-Intensive Care Medicine//Charles University/ ; Cooperatio 36-Medical Diagnostics and Basic Medical Sciences//Charles University/ ; #NEXTGENERATIONEU//European Commission/ ; MNESYS (PE0000006) - A Multiscale integrated approach to the study of the nervous system in health and disease (DR. 1553 11.10.2022)//Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/microbiology ; *Fecal Microbiota Transplantation/methods ; *Gastrointestinal Microbiome ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disorder; to date, there is no long-term effective treatment. Recently, a relationship has been discovered between the human intestinal microbiome and the pathogenesis of ALS, on which basis faecal microbiota transplantation (FMT) has been proposed as a potential treatment for ALS. In this review, we compare three existing case studies examining the effect of FMT on the course of ALS, highlighting differences in methodology and results. In two of the studies, a halt in the progression of ALS symptoms was observed following FMT, accompanied by improvement in patient health. However, in the third and largest study, no significant effect of FMT was observed. The possible explanation for this discrepancy may be the intentional depletion of intestinal microorganisms using antibiotics prior to FMT in the third study. Future studies and/or completion of the ongoing clinical studies will help clarify the therapeutic effectiveness of FMT in ALS patients.}, } @article {pmid41751955, year = {2026}, author = {Luong, DT and Niu, C and Kim, E and Tanji, N and Duong, I and Galero, B and Zhang, YJ and Bennett, CL and La Spada, AR}, title = {PPAR-Delta Agonist Therapies Did Not Rescue Hallmark Disease Phenotypes in Two Sets of Preclinical Trials in ALS TDP-43 and C9orf72 Model Mice.}, journal = {International journal of molecular sciences}, volume = {27}, number = {4}, pages = {}, pmid = {41751955}, issn = {1422-0067}, support = {W81XWH-20-1-0154//United States Department of Defense/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *PPAR delta/agonists ; *C9orf72 Protein/genetics/metabolism ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *DNA-Binding Proteins/genetics/metabolism ; Phenotype ; Humans ; Male ; Neurofilament Proteins/blood ; }, abstract = {Peroxisome-proliferator-activated receptor delta (PPARδ) regulates metabolic, mitochondrial, and inflammatory pathways implicated in neurodegeneration, making it an attractive therapeutic target for amyotrophic lateral sclerosis (ALS). In this study, we evaluated two PPARδ agonists, KD3010 and T3D-959, in two established ALS/FTD mouse models: an AAV-mediated C9orf72 G4C2-repeat expansion model (C9-149R) and the TDP-43[Q331K] transgenic model. Drug treatment was initiated prior to the emergence of key disease features and continued for 9-10 months. Comprehensive behavioral, neuropathological, and biomarker analyses revealed marked differences between the two models. C9-149R mice exhibited reduced body weight and subtle behavioral alterations without robust motor deficits, whereas TDP-43[Q331K] mice developed pronounced, progressive motor and cognitive impairments accompanied by a ~7-fold elevation in plasma neurofilament light chain (NfL). Despite effective target engagement-particularly for T3D-959-neither PPARδ agonist improved motor performance, cognitive behavior, neuroanatomical measures, plasma NfL levels, or disease-associated molecular phenotypes in either model. Prolonged KD3010 treatment resulted in loss of target engagement, consistent with drug tolerance, while T3D-959 sustained PPARδ activation without therapeutic benefit. Together, these findings demonstrate that PPARδ agonism is insufficient to modify disease progression in these ALS/FTD mouse models and underscore the importance of publishing well-powered negative preclinical studies to refine therapeutic strategies for ALS.}, } @article {pmid41752089, year = {2026}, author = {Hall, B and Castelli, L and Higginbottom, A and He, J and Zou, LN and Walker, H and Yagüe-Capilla, M and Wong, KE and Burrows, DJ and George, J and Hamer, K and Tanner, JM and Kyrgiou-Balli, E and Ross, R and Garland, H and Tonkiss, E and George, R and Webster, CP and Smith, EF and Timmons, HO and Allsop, J and Stefanidis, N and Ward, BD and Lin, YH and Highley, JR and Azzouz, M and West, RJH and Rudd, SG and Vos, KJ and Shaw, PJ and Hautbergue, GM and Allen, SP}, title = {Antisense Dipeptide Repeat Proteins Drive Widescale Purine Metabolism Aberration in C9orf72 Amyotrophic Lateral Sclerosis via ADA.}, journal = {International journal of molecular sciences}, volume = {27}, number = {4}, pages = {}, pmid = {41752089}, issn = {1422-0067}, support = {SBF005\1064/AMS_/Academy of Medical Sciences/United Kingdom ; Allen 887-791//MND Association/ ; Allen/Jun23/964-793//MND Association/ ; West/Oct22/909-792//MND Association/ ; BRC-203321//NIHR/ ; NF-SI-0617-10077//NIHR/ ; AMBRoSIA PJS 972-797//MND Association/ ; TJ2022-0063//Swedish Childhood Cancer Fund/ ; 19-0056-JIA//Swedish Cancer Society/ ; 23-2782-Pj//Swedish Cancer Society/ ; 260 (AS-PG-15-023)/ALZS_/Alzheimer's Society/United Kingdom ; MR/S025979/1/MRC_/Medical Research Council/United Kingdom ; MR/M013251/1/MRC_/Medical Research Council/United Kingdom ; MR/Z504701/1/MRC_/Medical Research Council/United Kingdom ; DEVOS/APR18/862-79//MND Association/ ; ARUK-PG2018B-005//Alzheimer's Research UK/ ; MR/W00416X/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *C9orf72 Protein/genetics/metabolism ; Humans ; *Purines/metabolism ; Animals ; *Adenosine Deaminase/metabolism/genetics ; Astrocytes/metabolism ; *Dipeptides/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the death of motor neurons leading to paralysis and death, generally 3-5 years post-symptom onset. The most frequent genetic cause of ALS is a hexanucleotide repeat expansion (HRE) in the chromosome 9 open reading frame 72 (C9orf72) gene, that has three major hypothesised pathological mechanisms including the production of dipeptide repeat proteins (DPRs). Our laboratory has previously identified purine metabolism dysfunction in induced neural progenitor cell-derived astrocytes (iAstrocytes) from C9orf72 ALS (C9-ALS) cases (C9-iAstrocytes), driven by loss of the enzyme adenosine deaminase (ADA). Here, we have demonstrated that loss of ADA along with changes to ecto-5'-nucleotidase and hypoxanthine-guanine phosphoribosyl transferase led to disruption in purine metabolite levels including purine dNTP output. These changes were recapitulated in patient CSF, whilst loss of ADA was recapitulated in patient white matter. Immunofluorescence also demonstrated purinosome formation dysfunction in C9-iAstrocytes. These changes are likely driven by DPRs as ADA loss was recapitulated in in vitro and in vivo DPR models. Finally, ADA levels could be recovered by reducing DPR levels either by inhibiting serine/arginine-rich splicing factor 1 or overexpressing RuvB-like 2. Our data demonstrate that DPR production negatively affects purine function in C9-ALS suggesting a potentially pivotal role for purine metabolism dysfunction in C9-ALS pathology.}, } @article {pmid41752118, year = {2026}, author = {Kurdi, MA and Alotaibi, H and Alkhuraymi, AT and Aldahery, LN and Alhawaj, AF and Aldali, HJ}, title = {Amyotrophic Lateral Sclerosis (ALS) Genetics and Microbiota: A Comprehensive Review.}, journal = {International journal of molecular sciences}, volume = {27}, number = {4}, pages = {}, pmid = {41752118}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/microbiology/therapy ; Animals ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; DNA-Binding Proteins/genetics ; RNA-Binding Protein FUS/genetics ; Genetic Therapy/methods ; Mutation ; *Microbiota ; *Gastrointestinal Microbiome ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe, progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons, affecting 0.5 to 2.6 per 100,000 people, with a median survival of 2 to 5 years. It is increasingly seen as a multisystem disorder, sharing essential clinicopathological features with Frontotemporal Dementia (FTD). This convergence arises from overlapping molecular processes, including severe oxidative stress, glutamate-mediated excitotoxicity, mitochondrial dysfunction, and widespread aggregated TDP-43 proteinopathy in both sporadic and familial cases. Several key genetic factors have been identified, particularly mutations in C9orf72, SOD1, TARDBP, and FUS, which serve as important targets for novel treatments, such as Tofersen, a recently approved SOD1-specific antisense oligonucleotide (ASO) gene therapy. Additionally, there is increasing evidence of the gut-brain connection. Dysbiosis, involving species such as Akkermansia muciniphila, and lower levels of neuroprotective metabolites, such as nicotinamide, may affect the course of the disease. As a result, treatment strategies are shifting toward a personalized approach. This includes using gene therapy, ranging from ASOs and RNA interference (RNAi) to new CRISPR-based genome editing. It also involves exploring microbiome-modulating treatments, such as specific probiotics and Fecal Microbiota Transplantation (FMT). While microbiome and gene therapies remain largely experimental, their potential is promising, as highlighted by the recent approval of Tofersen. These novel approaches could be further enhanced and guided by more robust diagnostic criteria and by investigating early multimodal treatment strategies to slow the progression of this complex disease.}, } @article {pmid41753201, year = {2026}, author = {Hernández-Voth, A and Sayas-Catalán, J and Corral-Blanco, M and Jiménez-Gómez, M and Carvajal-Cuesta, G and Luján-Torné, M and Lalmolda-Puyol, C and Florez-Solarana, P and Villena-Garrido, V}, title = {Impact of Built-In Software Monitoring on Survival in Amyotrophic Lateral Sclerosis Patients Receiving Home Mechanical Ventilation: A Cohort Study.}, journal = {Journal of clinical medicine}, volume = {15}, number = {4}, pages = {}, pmid = {41753201}, issn = {2077-0383}, abstract = {Background/Objectives: Amyotrophic lateral sclerosis is a progressive neurodegenerative disease in which respiratory failure is the leading cause of death. Mechanical ventilation improves both survival and quality of life; however, the prognostic implications of built-in ventilator software monitoring remain insufficiently characterized. The aim of the study was to determine whether built-in ventilator software-based monitoring is associated with enhanced survival in amyotrophic lateral sclerosis subjects. Methods: Cohort study of amyotrophic lateral sclerosis subjects, stratified into two groups: those monitored through detailed built-in ventilator software and those not monitored. Clinical and ventilatory data were systematically evaluated during a 24-month follow-up. Results: Among 120 ALS subjects (57 detailed built-in ventilator software, 63 non-detailed ventilator software), median survival from diagnosis was significantly longer in the detailed built-in ventilator software group (3.42 vs. 2.12 years; p < 0.001). Survival from mechanical ventilation initiation was also significantly longer in the built-in ventilator software group (2.79 years vs. 0.78 years). Greater daily mechanical ventilation usage was associated with shorter survival (p < 0.003). Paradoxically, subjects with the lowest proportion of spontaneous inspirations exhibited superior survival outcomes (p = 0.04). Neither persistent leaks nor asynchronies were independently predictive of survival. Conclusions: BVS-monitoring was associated with improved survival in amyotrophic lateral sclerosis subjects receiving home mechanical ventilation. Its integration into clinical practice may enable timely, data-driven ventilatory adjustments, ultimately contributing to more individualized and optimized patient management.}, } @article {pmid41754783, year = {2026}, author = {González-Rivera, ML and Juárez-Vázquez, MDC and Melecio-Hernández, AA and Casique-Aguirre, D and López-González, GJ and Ramírez-Martínez, RM and Ayala-Torres, A and Quesada-Mendiola, Y and Zapata-Morales, JR and Alonso-Castro, AJ}, title = {Antidepressant-Like Effects of n-Butylidenephthalide Using In Vivo and In Silico Approaches.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {2}, pages = {}, pmid = {41754783}, issn = {1424-8247}, support = {CBF2023-2024-1888//Secretariat of Science, Humanities, Technology, and Innovation/ ; }, abstract = {Background: The plant-derived compound n-butylidenephthalide (BP) is an isobenzofuranone that has shown neuropharmacological effects on preclinical models of Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. Methods: This study evaluated the anti-inflammatory, antinociceptive, anxiolytic-like, hypnotic, anticonvulsant, and antidepressant-like effects of BP (50-200 mg/kg p.o.) using Balb/c mice in acute assays. This study also evaluated the antidepressant-like effects of BP in a mouse model of reserpine-induced depression-like behavior for 20 days. Inhibitors involved in the molecular process of depression and in silico studies were used to evaluate a possible mechanism of action for the antidepressant-like effects of BP. Results: BP induced low anti-inflammatory effects, showed low anticonvulsant effects, and lacked hypnotic effects or motor impairment in acute assays. The antidepressant-like effects of BP (100-200 mg/kg p.o.) were comparable to amitriptyline (25 mg/kg p.o.) in acute assays. The participation of serotonergic and adrenergic systems is involved in the acute antidepressant-like effects of BP. In the reserpine-induced depression model, BP (100 mg/kg p.o.) showed antidepressant-like effects in one of the two antidepressant tests, but with a lower effect than amitriptyline (20 mg/kg p.o.). Conclusions: BP (100 and 200 mg/kg) showed antidepressant-like effects in acute assays and, to a lesser extent, in a reserpine-induced chronic model of depression-like behavior.}, } @article {pmid41756461, year = {2026}, author = {Petriti, B and Subramanian, S and Williams, PA and Chau, KJ and Licznerski, P and Lascaratos, G and Aguilar-Munoa, S and Kamal, D and Bae, H and Alavian, KN and Garway-Heath, DF and Jonas, EA}, title = {Reversing Mitochondrial Dysfunction in Optineurin E50K Glaucoma: A Metabolic Approach to Neuroprotection.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41756461}, issn = {2693-5015}, support = {R01 NS123405/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in optineurin (OPTN) are linked to neurodegenerative diseases such as normal tension glaucoma (NTG) and amyotrophic lateral sclerosis. The E50K-OPTN mutation is the most common genetic cause of NTG, where it disrupts mitophagy and leads to the accumulation of dysfunctional mitochondria. To understand how cellular metabolism is altered in these persistent mitochondria, and whether any pathological state can be reversed, we investigated NTG-patient-derived fibroblasts carrying the E50K-OPTN mutation. We identified a form of mitochondrial leak metabolism driven by elevated levels of the ATP synthase c-subunit leak channel (ACLC). These cells exhibit reversed F1FO ATP synthase activity, increased mitochondrial proton leak, and fragmented mitochondria, resulting in inefficient oxidative phosphorylation and a shift toward aerobic glycolysis and high protein synthesis rate. The ratio of ATP synthase c-subunit to β-subunit was markedly elevated, suggesting open ACLC pores. Treatment with dexpramipexole normalized ATP synthase function and cellular metabolism, promoted ATP synthesis rather than hydrolysis and reduced protein synthesis rates. Dexpramipexole reduced p62 levels in E50K fibroblasts, consistent with a reduced mitophagic burden from decreased accumulation of damaged mitochondrial cargo. These findings identify ACLC-mediated leak as a central driver of metabolic dysfunction in E50K-OPTN glaucoma and suggest ACLC closure as a viable therapeutic strategy.}, } @article {pmid41756852, year = {2026}, author = {Malik, T and Jones, S and Ma, O and Mohan, S and Burger, RM and Babcock, DT}, title = {Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.02.19.706635}, pmid = {41756852}, issn = {2692-8205}, support = {R01 NS110727/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in Fused in Sarcoma (FUS), a RNA binding protein, cause Amyotrophic Lateral Sclerosis (ALS). ALS is an aggressive neurodegenerative disease resulting in motor neuron degeneration. Defects in synaptic integrity precede neuronal loss in ALS, but the mechanisms responsible for these early synaptic defects are unclear. To investigate early synaptic defects associated with ALS, we expressed an ALS-linked variant of human FUS in adult motor neurons and assessed synaptic pathology at the neuromuscular junction (NMJ). Here we highlight the accumulation of FUS-positive aggregates at synaptic terminals and subsequent reduction in microtubule stability. We show that inducing autophagy via expression of Rab1 or Fragile-X Mental Retardation Protein 1 (FMR1), or treatment with Rapamycin reduces aggregate formation and restores synaptic structure and function. These findings reveal the utility of inducing autophagy to address early synaptic dysfunction in an ALS model and demonstrate a potential therapeutic target to preventing later stages of disease progression.}, } @article {pmid41756973, year = {2026}, author = {Plessis-Belair, J and Sher, RB}, title = {Neuronal Cell-Cycle Re-entry Defines Divergent Outcomes Through Replication-Dependent DNA Damage in ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41756973}, issn = {2692-8205}, support = {K12 GM102778/GM/NIGMS NIH HHS/United States ; R01 AG079898/AG/NIA NIH HHS/United States ; }, abstract = {Cell-cycle dysregulation has emerged as a shared mechanism of neuronal loss across neurodegenerative diseases (NDDs), including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease. In post-mitotic neurons, aberrant reactivation of cell-cycle signaling precedes degeneration, yet the upstream triggers and functional consequences of this process remain poorly defined. Nucleocytoplasmic transport (NCT) dysfunction, a hallmark of ALS and related disorders, disrupts the spatial distribution of key regulatory proteins and may contribute to maladaptive cell-cycle activation. Our recent evidence suggests that impaired nuclear import may initiate, rather than merely accompany, neuronal cell-cycle re-entry. Here, we show that cell-cycle activation in motor neurons distinguishes molecular subtypes and outcomes in ALS. We analyzed the AnswerALS transcriptomic cohort and identified a patient cluster characterized by robust upregulation of cyclins B and D. Clusters with lower levels of cell-cycle gene expression exhibited accelerated ALSFRS-R decline, whereas the highest cyclin-expressing cluster demonstrated comparatively improved functional trajectories over time. To test whether NCT disruption can mechanistically drive aberrant cell-cycle activation, we pharmacologically inhibited importin-β in human iPSC-derived spinal motor neurons. NCT disruption induced widespread proteomic mislocalization, including TDP-43 pathology, and triggered a transient wave of cell-cycle activity preceding neuronal death. Mechanistically, we identified DNA-replication initiation as a pathological event driving degeneration and demonstrated that selective inhibition of G1/S-associated CDK4/6 activity confers neuroprotection. Together, these findings link impaired nuclear import to maladaptive cell-cycle reactivation in neurons and highlight stage-specific engagement of the cell-cycle machinery as a determinant of neuronal vulnerability in ALS.}, } @article {pmid41757182, year = {2026}, author = {Puerta, R and García-González, P and de Rojas, I and Capdevila-Bayo, M and Olivé, C and Muñoz-Morales, Á and Bayón-Buján, P and Valenzuela, A and Yang, C and Timsina, J and Liu, M and Chakkarai, S and Sotolongo-Grau, O and Calm, B and Miguel, A and Solivar, A and Montrreal, L and Martínez, M and Khan, A and Zhao, F and Tantinyà, N and Rosende-Roca, M and Alegret, M and Moreno-Grau, S and Fernández, MV and Marquié, M and Valero, S and Cavazos, JE and Sanz, P and Montalban, X and Tàrraga, L and Smets, B and Boada, M and Seshadri, S and Sargurupremraj, M and Cruchaga, C and Cano, A and Cabrera-Socorro, A and Ruiz, A}, title = {Human CSF proteogenomics links genetic variation to neurodegenerative disease proteins.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41757182}, support = {P30 AG066546/AG/NIA NIH HHS/United States ; }, abstract = {The cerebrospinal fluid (CSF) proteome offers a direct readout of central nervous system (CNS) biology but its genetic architecture remains incompletely defined. We conducted the largest single-site CSF genome-wide association study (GWAS) to date, analysing 7,092 SomaScan proteins in 1,259 individuals. Using a covariate-adjusted model including proteomic PCs and disease status, we identified 1,971 genome-wide significant pQTLs (954 cis, 971 trans), 1,409 of which replicated in an independent CSF dataset. We discovered 264 previously unreported loci, replicated 511 associations, refined 80 known loci, and 265 proxy-based associations. Using a previously published reproducibility framework, we show that robust discovery concentrates in reliable measurements, underscoring the importance of rigorous quality control. Enrichment analyses revealed immune/complement and extracellular matrix biology. Mendelian randomization prioritised causal proteins: PILRA, TREM2, IL34, CR2, SHARPIN and ERBB1 (Alzheimer's disease); BST1 and GPNMB (Parkinson's disease); STX6 (Creutzfeldt Jacobs disease); and ATXN3 and B4GALNT1 (Amyotrophic lateral sclerosis), providing a scalable framework for orthogonal target validation in neurodegeneration.}, } @article {pmid41757350, year = {2026}, author = {Lee, JAK and Moutin, C and Granger, S and Roome, K and Shaw, A and Allen, SP and Ferraiuolo, L and Shaw, PJ and Mortiboys, H}, title = {C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.}, journal = {Frontiers in cellular neuroscience}, volume = {20}, number = {}, pages = {1731669}, pmid = {41757350}, issn = {1662-5102}, abstract = {INTRODUCTION: ALS is a neurodegenerative disorder characterized by progressive upper and lower motor neuron loss. A GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common mutation found in populations of European descent. Mitochondrial dysfunction has been observed in C9orf72-ALS patients and models of the disease, however, reports on mitochondrial clearance via mitophagy in C9orf72-ALS are limited.

RESULTS: iNeurons from C9orf72-ALS patients displayed reduced mitochondrial membrane potential and reduced basal mitophagy, due to reductions in autophagosome production and reduced ULK1 recruitment to mitochondria. No consistent changes to PINK1/Parkin or BNIP3 mitophagy pathways were observed.

CONCLUSION: Our data show that certain aspects of mitochondrial function is impaired in C9orf72-ALS patient iNeurons. An in-depth characterization of mitophagy suggests that a deficit in autophagosome production is responsible and provides further evidence that toxic gain-of-function mechanisms in C9orf72-ALS are responsible for autophagy deficits.}, } @article {pmid41759417, year = {2026}, author = {Zhang, M and Zhang, Y and Pu, Y and Bai, X}, title = {Ultra-high-dose methylcobalamin demonstrates safety in advanced ALS, but intramuscular administration poses practical burdens and its selected study cohort limits generalizability.}, journal = {Journal of the neurological sciences}, volume = {483}, number = {}, pages = {125838}, doi = {10.1016/j.jns.2026.125838}, pmid = {41759417}, issn = {1878-5883}, } @article {pmid41760732, year = {2026}, author = {Sinderewicz, E and Dąbkowska, M and Sarnowska, A and Staszkiewicz-Chodor, J and Mystkowska, D and Holak, P and Drozd, I and Chodkowska-Michalowska, M and Rytel, M and Paczkowska, E and Mycko, MP and Machalinski, B and Jezierska-Wozniak, K}, title = {Safety and biodistribution of intrathecal administration of mesenchymal stem cells (MSCs) and neurotrophin-releasing nanoparticles in a porcine CSF-guided delivery model for amyotrophic lateral sclerosis (ALS) drug discovery.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41760732}, issn = {2045-2322}, support = {No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; *Nanoparticles/administration & dosage/chemistry ; *Mesenchymal Stem Cell Transplantation/methods/adverse effects ; *Mesenchymal Stem Cells/cytology/metabolism ; Male ; *Nerve Growth Factors/administration & dosage/pharmacokinetics ; Swine ; Tissue Distribution ; Injections, Spinal ; Disease Models, Animal ; Drug Delivery Systems ; Humans ; Spinal Cord/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder that complicates the identification of effective therapeutic targets. The potential of stem cells and neurotrophins as promising candidates has become increasingly evident, owing to their neuroprotective and anti-inflammatory properties. In this study, a preclinical evaluation of the safety and biodistribution of mesenchymal stromal/stem cells (MSCs) combined with neurotrophin-releasing polyelectrolyte nanoparticles (NTs) was conducted in a porcine intrathecal delivery model relevant to ALS therapy development. Four groups of male pigs were administered saline with NTs, adipose-derived stem cells (ASCs) with NTs, Wharton's jelly-derived MSCs (WJ-MSCs) with NTs, or spinal puncture only. The safety of the treatment was assessed using magnetic resonance imaging (MRI), haematological and biochemical analyses, cerebrospinal fluid profiling, and histology. No adverse effects or significant systemic alterations were observed. It is noteworthy that C-reactive protein levels diminished following NT and NT-MSC administration, suggesting a systemic anti-inflammatory effect. The migration of MSCs was facilitated by cerebrospinal fluid, leading to their accumulation around the spinal cord and brain parenchyma. The present findings demonstrate short-term safety and biodistribution patterns following intrathecal administration of MSCs combined with neurotrophin-releasing nanoparticles in a large-animal model. These preliminary observations provide a pilot framework for future efficacy studies in disease-specific ALS models. This work establishes a translational platform for the development of future ALS therapies, with subsequent studies focused on efficacy testing in disease-specific models that more accurately reflect the slow, heterogeneous, multisystem nature of human ALS.}, } @article {pmid41760955, year = {2026}, author = {D'Amico, A and Cucunato, R and Schirò, G and Salemi, G and Ragonese, P and La Bella, V and Aridon, P and D'Amelio, M}, title = {KIF5A and ALS: a clinical and genetic description of a case series and review of literature.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {3}, pages = {}, pmid = {41760955}, issn = {1590-3478}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Disease Progression ; *Kinesins/genetics ; Mutation ; }, abstract = {Approximately 10% of ALS (amyotrophic lateral sclerosis) cases show a family history, and the remaining 90% are sporadic. In 2018, through genome sequencing using two independent approaches, KIF5A was described as a novel ALS-associated gene. To describe clinical and genetic characteristics of a series of patients with motor neuron disease (MND), diagnosed at University Hospital of Palermo, carrying KIF5A variants. During 2019–2023, two hundred twenty-four patients with MND and healthy subjects with familial history of MND, underwent next-generation sequencing (NGS) for molecular analysis, including genetic testing for C9orf72 hexanucleotide-repeat expansion. The most mutated ALS genes, including KIF5A, were included in a NGS panel. Of the entire tested population, eight patients (including a brother and a sister) were found to carry KIF5A variants. Four patients had familial ALS, the other four were sporadic. Six patients were females (75%). Mean age at ALS onset was 59 years (33–75). Patients were evaluated according to the ALSFRS-revisited during follow-up visits. According to disease progression rate, five patients were defined as ∆FS ≤ 0.5 (slow-progressors), the remaining three patients showed a ∆FS > 1 (fast-progressors). Of the seven KIF5A variants, three are not already described in literature (respectively c.170 C > T, p.Thr57Met; c.2920T > G, p.Ser974Ala and c.2732 A > C, p.Lys911Thr). Two patients showed the association of variations in KIF5A with variations or mutations in other ALS genes, one of them carried a pathogenic variant of FUS (P525L). This study demonstrates phenotypic variability related to mutations in different regions of the same gene resulting in a susceptibility for the disease spectrum with different characteristics.}, } @article {pmid41760992, year = {2026}, author = {Hollin, IL and Ilieva, H and Pasinelli, P and Chisholm, L and Heiman-Patterson, T}, title = {Preferences for Healthcare Delivery in Amyotrophic Lateral Sclerosis (ALS): A Survey of Patients and Caregivers in the United States.}, journal = {The patient}, volume = {19}, number = {4}, pages = {587-600}, pmid = {41760992}, issn = {1178-1661}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; *Caregivers/psychology ; Female ; Cross-Sectional Studies ; Male ; Middle Aged ; United States ; Aged ; *Patient Preference ; Surveys and Questionnaires ; *Delivery of Health Care/organization & administration ; Adult ; Patient Satisfaction ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurological disease that leads to death within 2-5 years of diagnosis for more than 80% of people living with ALS (PLWALS). The American Academy of Neurology (AAN) developed practice parameters-general principles to guide clinicians in managing ALS-encouraging multidisciplinary care (MDC) but does not recommend specific healthcare delivery models. Three healthcare delivery models have evolved: a traditional model, a triage model, and a non-triage model. This study aims to describe preferences for and satisfaction with various models, among PLWALS and their caregivers (CALS), along with their perceptions of how their care aligns with AAN guidelines.

METHODS: A cross-sectional observational study utilizing a web-based survey was distributed via email to PLWALS and CALS. Three multi-assessment questionnaires were developed and tailored for PLWALS, CALS, and former CALS. Best-worst scaling (object case) data were analyzed using a best-minus-worst approach and descriptive statistics were calculated from means, t-tests and chi-square.

RESULTS: The combined sample included 378 respondents: 254 PLWALS (67.20%) and 124 CALS (32.80%; composed of 79 current caregivers [20.90%] and 45 former caregivers [11.90%]). The mean respondent age was 61.09 years (SD 11.1). The majority of the sample was white (92.86%), insured by Medicare (61.11%), and married/partnered (79.10%). Respondents preferred a non-triage model the most and a traditional model the least; 88.20% (CI: 84.92-91.49) were extremely likely to choose a non-triage model if given the choice and 83.12% (CI: 79.29-86.92) of respondents ranked non-triage as most preferred. A traditional model was ranked as the least preferred model in 75.28% (CI: 70.78-79.78) of respondents. The most important factors driving respondent preferences were ALS expertise and team-based care. Overall, respondents are satisfied with their care teams. PLWALS utilizing non-triage MDC models reported more adherence to quality care measures compared with those utilizing triage and traditional models.

DISCUSSION: Respondent preference for non-triage models is consistent with the importance they place on the features of non-triage models. However, these findings should be understood in the context of our sample in which a large majority of respondents were receiving care via a non-triage model. To ensure ALS care delivery is patient-centered, practice parameters that aim to guide clinicians in managing ALS should provide more guidance to MDCs to deliver care aligned with patient preferences and values. Efforts should focus on sustainable financial models that can better facilitate non-triage models of care.}, } @article {pmid41762049, year = {2026}, author = {Zhang, Y and Chen, B and Lin, Y and Kang, D and Zhao, T}, title = {Advances and Challenges in the Use of Spinal Cord Organoids in ALS.}, journal = {Journal of integrative neuroscience}, volume = {25}, number = {2}, pages = {44709}, doi = {10.31083/JIN44709}, pmid = {41762049}, issn = {0219-6352}, support = {82301543//National Natural Science Foundation of China/ ; 2021QNA025//Youth Scientific Research Project of Fujian Provincial Health Commission/ ; 2021Y2001//Technology Platform Construction Project of Fujian Province/ ; 2020Y2003//Technology Platform Construction Project of Fujian Province/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology/therapy ; Humans ; *Organoids/pathology ; *Spinal Cord/pathology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease. No effective treatments have yet been found for ALS, primarily because the molecular mechanisms that underlie its pathogenesis are unknown. Although animal models are suitable for ALS research, species differences between these models and human spinal cord organs make it difficult to accurately predict the progression of disease in humans. Therefore, the development of more suitable models is urgently needed. Human stem cells have unlimited development potential and can be used to make three-dimensional organoid structures that mimic the architecture and function of actual organs. Organoid models can be used to overcome some of the species differences and accelerate experimental research, leading to the development of practical applications for the treatment of ALS. This article discusses the pathological mechanisms and cell types involved in ALS, as well as the genes associated with this disease. We also discuss the possible applications of spinal cord organoids (SCOs) in ALS research, such as the modeling of disease characteristics, study of pathological mechanisms, and drug screening. Finally, the prospects for SCOs in ALS treatment are highlighted, while acknowledging the need for further development of relevant technologies.}, } @article {pmid41762620, year = {2026}, author = {Ing, L and Griffiths, AW and Mayberry, E and Ali, Y and Blackburn, D and McDermott, C}, title = {Patient and caregiver attitudes to cognitive and behavioral testing in Amyotrophic Lateral Sclerosis.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/17582024.2026.2637424}, pmid = {41762620}, issn = {1758-2032}, abstract = {BACKGROUND: Cognitive and behavioral changes affect up to 50% of people with Amyotrophic Lateral Sclerosis (ALS) and are associated with worse outcomes, yet remain under-recognized in clinical care. Understanding patient and caregiver perspectives is important for engagement with cognitive screening.

METHODS: Semi-structured interviews were conducted with 10 patients with ALS and 9 caregivers, analyzed using reflexive thematic analysis. Participants were recruited via a multidisciplinary ALS clinic and the Motor Neurone Disease Association UK.

RESULTS: Engagement with testing was shaped by emotional readiness, personal values, relational dynamics, practical barriers, and perceived value. Views ranged from seeing testing as an opportunity for preparedness and autonomy, to concerns it could undermine identity or add distress. Caregivers often valued testing to support planning but faced challenges balancing advocacy with respect for patient autonomy. Limited awareness of cognitive symptoms in ALS and unclear communication from clinicians reduced perceived relevance. Testing was most meaningful when tailored to personal priorities, introduced sensitively, and linked to actionable outcomes.

CONCLUSION: Cognitive screening in ALS requires a flexible, patient-centered approach that considers emotional readiness, relational contexts, and clear communication. Tailoring discussions and delivery to patient and caregiver needs may enhance acceptance and integration of cognitive assessment into holistic ALS care.}, } @article {pmid41762671, year = {2026}, author = {Gaur, N and Angerer, C and Gunes, ZI and Ancau, M and Wang, M and Riemenschneider, H and Hurler, CA and Mungwa, S and Lüningschrör, P and Zhiti, A and Steinbach, R and Briese, M and Srivastava, M and Plaas, M and Hermann, A and Sendtner, M and Jäkel, S and Edbauer, D and Herms, J and Liebscher, S and Grosskreutz, J and Brill, MS}, title = {Constitutive neuronal expression and disease-associated upregulation of chitinases in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag083}, pmid = {41762671}, issn = {1460-2156}, abstract = {Chitinases are hydrolytic enzymes responsible for degrading chitin and have been evolutionarily conserved across various species. Although their signaling pathways are not fully understood, the chitinases are considered active immunomodulators across several cell types. Specific isoforms, including Chitotriosidase-1 (CHIT1), Chitinase-3-like protein 1 (CHI3L1), and human-specific Chitinase-3-like protein 2 (CHI3L2), have emerged as markers of inflammation across the neurodegenerative spectrum, including amyotrophic lateral sclerosis (ALS). ALS is a fatal neuromuscular condition, and therapeutic development has been severely hindered by phenotypic heterogeneity and an incomplete understanding of etiology. Although several overlapping disease mechanisms can contribute to neuronal death, inflammation can exacerbate pathology. Prior studies have reported that CHIT1, CHI3L1, and CHI3L2 levels are elevated in the cerebrospinal fluid (CSF) of ALS patients and associated with disease aggressiveness. Nevertheless, several open questions critical to our understanding of the chitinases' role in ALS disease burden remain: namely, 1) which cell types in the central nervous system (CNS) are chitinase sources under physiological conditions, 2) which of these display chitinase upregulation in ALS, and 3) what is the diagnostic utility of the chitinases relative to established biomarkers. Here, we utilize pre-clinical models and post-mortem human tissue to demonstrate at both the transcriptomic and protein level that neurons are a primary source of chitinases; furthermore, neuronal chitinase expression is conserved across species. Under physiological conditions, CHI3L1 is more abundant and widely expressed across various cell types, whereas CHIT1 is predominantly expressed in neurons. Additionally, utilizing symptomatic mice from three familial ALS models, we demonstrate isoform-specific expression profiles, with astroglial and microglial upregulation of CHI3L1, and neuronal and microglial upregulation of CHIT1. Differing expression dynamics and diagnostic utility were also noted in our clinical cohort: CSF CHIT1 and CHI3L2 levels had more discriminatory power when distinguishing between ALS vs. non-ALS controls, while CHI3L1 was more closely associated with inflammation and aging across the neurodegenerative spectrum. Although the chitinases did not diagnostically outperform the neurofilament proteins as biomarkers, we propose that appreciating their expression patterns can aid in optimizing biomarker-guided trial design. Taken together, we demonstrate that chitinase upregulation in ALS is evident in various CNS cell types and that its neuronal expression may provide new insights into its role in disease activity.}, } @article {pmid41763275, year = {2026}, author = {Shi, B and Liu, M and Wang, Y}, title = {ATCRN: Attention-guided Temporal Convolutional Remix Network for P300 speller.}, journal = {Journal of neuroscience methods}, volume = {430}, number = {}, pages = {110727}, doi = {10.1016/j.jneumeth.2026.110727}, pmid = {41763275}, issn = {1872-678X}, mesh = {Humans ; *Brain-Computer Interfaces ; *Event-Related Potentials, P300/physiology ; Convolutional Neural Networks ; *Attention/physiology ; *Electroencephalography/methods ; Signal Processing, Computer-Assisted ; }, abstract = {BACKGROUND: The P300 speller is a prominent brain-computer interface (BCI) that facilitates communication by detecting P300 event-related potentials. However, its performance is substantially constrained by the low signal-to-noise ratio of EEG signals and the inherent temporal variability of the P300 response.

NEW METHOD: We propose the Attention-guided Temporal Convolutional Remix Network (ATCRN), an end-to-end model that synergistically integrates a novel Temporal Convolutional Remix Network (TCRN) with a dual-attention framework. The TCRN employs multi-level skip connections to enable dynamic, cross-hierarchical fusion of local and global temporal features, addressing the variable latency of P300. Externally, the Convolutional Block Attention Module (CBAM) suppresses noise in spatial and channel dimensions. Internally, Efficient Channel Attention (ECA) modules within TCRN block perform dynamic channel recalibration.

RESULTS: On BCI Competition III Dataset II, ATCRN achieved character recognition rates of 99% and 98% for two subjects at the 15th repetition, and yielded superior information transfer rates. Evaluation across eight ALS patients showed robust P300 detection (average AUC-ROC 0.882).

ATCRN outperforms both established CNN/TCN benchmarks and recent Transformer-based models across two public datasets, achieving state-of-the-art results in P300 detection and character spelling.

CONCLUSION: The proposed ATCRN provides a novel, robust, and effective decoding framework for the P300 speller. The integration of TCRN for temporal feature fusion and the dual-attention mechanism for feature refinement offers a practical solution for advancing BCI applications.}, } @article {pmid41763422, year = {2026}, author = {Li, Y and Liu, S and Cao, L and Zhu, M and Lin, S and Wang, X and Qiu, Z and Teng, Y}, title = {Ginsenoside compound K inhibited the gelation of GGGGCC repeats and regulated co-aggregation with arginine-rich poly-dipeptides in C9orf72-related ALS.}, journal = {International journal of biological macromolecules}, volume = {351}, number = {}, pages = {151138}, doi = {10.1016/j.ijbiomac.2026.151138}, pmid = {41763422}, issn = {1879-0003}, mesh = {*Ginsenosides/pharmacology/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism ; *C9orf72 Protein/genetics ; Humans ; Animals ; *DNA Repeat Expansion/drug effects ; G-Quadruplexes/drug effects ; Arginine/chemistry ; *Peptides/chemistry ; }, abstract = {GGGGCC repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It produces toxic RNA repeats and poly-dipeptides, leading to abnormal phase separation and deposition in nerve cells. In particular, repeat RNAs form gels that induce cellular toxicity. Thus, they are potential therapeutic targets. Ginsenoside compound K (CK) is the major metabolite of Panax ginseng, a traditional Chinese medicine commonly used for the treatment of neurodegenerative diseases. In this study, CK significantly inhibited the gelation of GGGGCC repeats both in vitro and in vivo. Moreover, it reduced the co-aggregation of RNA and arginine-rich poly-dipeptides via electrostatic interactions. Further investigation suggested that CK preferentially interacts with G-quadruplex monomers formed by GGGGCC repeats rather than with complex multimers, thereby inhibiting the formation of toxic RNA foci. These results elucidate the mechanism of action of CK in C9orf72-related ALS/FTD. Thus, this study provides new avenues for the potential application of ginsenoside in the treatment of neurodegeneration.}, } @article {pmid41763443, year = {2026}, author = {Zafarjonovna, AZ and Aysulu, E and Matlyuba, S and Rashid, H and Azamatovich, JB and Ahmadjon, A and Barno, A and Kurbanovna, AM and Ugli, MRM and Shaxodat, I and Rustam, T and Jumaniyazovna, MG and Ishankulov, A}, title = {Small extracellular vesicles as emerging biomarkers and therapeutic targets in neurodegenerative diseases.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {587}, number = {}, pages = {120932}, doi = {10.1016/j.cca.2026.120932}, pmid = {41763443}, issn = {1873-3492}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; Biomarkers/metabolism/analysis ; *Neurodegenerative Diseases/diagnosis/metabolism/therapy/drug therapy ; Animals ; }, abstract = {Small extracellular vesicles (sEVs) have rapidly emerged as versatile mediators of intercellular communication with significant potential to transform the diagnosis and treatment of neurodegenerative diseases (NDDs). Increasing evidence shows that sEVs not only participate in the propagation of pathogenic proteins but also serve as accessible, CNS-informative carriers of molecular signatures that reflect neuronal, glial, and systemic disease processes. This dual role positions sEVs at the intersection of biomarker discovery and therapeutic innovation. In the diagnostic domain, advances in immunoaffinity capture, single-vesicle analysis, and multi-omics profiling have enabled increasingly precise characterization of neuron-, astrocyte-, and microglia-derived sEVs, revealing candidate markers for Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and related disorders. However, translation remains limited by methodological heterogeneity, a lack of large-scale validation, and the need for standardized pre-analytical and analytical pipelines aligned with the ISEV/MISEV guidelines. On the therapeutic front, native and engineered sEVs, particularly those derived from mesenchymal and neural stem cells, demonstrate promising neuroprotective effects, including the modulation of neuroinflammation; the enhancement of synaptic resilience; and the delivery of antioxidant, anti-amyloid, or gene-modifying cargo across the blood-brain barrier. Scalable GMP manufacturing, cargo-loading strategies, targeting specificity, and long-term safety remain key challenges for clinical translation. This narrative review synthesizes current advances in sEV-based biomarkers and therapeutics, outlines technological and regulatory barriers, and proposes a translational roadmap spanning mechanistic discovery, platform standardization, and integration into precision-medicine frameworks. Collectively, emerging data position sEVs as powerful tools capable of reshaping the diagnostic and therapeutic landscape of NDDs, provided that coordinated multidisciplinary efforts address the remaining gaps in validation, scalability, and regulatory readiness.}, } @article {pmid41763528, year = {2026}, author = {Kuznetsov, AV}, title = {Modeling the growth of cytosolic TDP-43 inclusion bodies and accumulated neurotoxicity of misfolded oligomers in neurons.}, journal = {Computer methods in biomechanics and biomedical engineering}, volume = {}, number = {}, pages = {1-28}, doi = {10.1080/10255842.2026.2618583}, pmid = {41763528}, issn = {1476-8259}, abstract = {This paper introduces a mathematical model for the growth of transactive response DNA binding protein of 43 kDa (TDP-43) inclusion bodies in neuron soma. The parameter representing the accumulated neurotoxicity caused by misfolded TDP-43 oligomers is also introduced. The model's equations enable the numerical calculation of the concentrations of TDP-43 monomers, dimers, free oligomers, and oligomers deposited in inclusion bodies. By simulating the deposition of free oligomers into inclusion bodies, the model predicts the size of TDP-43 inclusion bodies. An approximate solution to the model equations is derived for the scenario where protein degradation machinery is dysfunctional, leading to infinite half-lives for TDP-43 dimers, monomers, and both free and deposited oligomers. This solution, valid at large times, predicts that the radius of the inclusion body increases proportionally to the cube root of time, whereas the accumulated neurotoxicity increases linearly with time. To the best of the author's knowledge, this study is the first to model the relationship between the size of TDP-43 inclusion bodies and time, and the first to introduce the concept of accumulated neurotoxicity caused by misfolded TDP-43 oligomers. Sensitivity analysis of the approximate solution indicates that the inclusion body radius and accumulated neurotoxicity become independent of the kinetic constants at large timescales. Unlike the case of infinite half-lives, the numerical solution for physiologically relevant (finite) half-lives demonstrates that the long-term behavior of the inclusion body radius and accumulated neurotoxicity remains dependent on the kinetic constants, converging to distinct curves over time.}, } @article {pmid41764146, year = {2026}, author = {Ciuro, M and Sangiorgio, M and Leanza, G and Gulino, R}, title = {Neuroinflammation and Oxidative Stress in SOD1 Animal Models of ALS: A Meta-analysis Study of Their Effects on Disease Onset and Progression.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41764146}, issn = {1559-1182}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics ; *Oxidative Stress/physiology ; *Disease Progression ; Disease Models, Animal ; *Superoxide Dismutase-1/metabolism/genetics ; Humans ; *Neuroinflammatory Diseases/pathology ; *Inflammation/pathology ; Female ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder characterized by progressive motor neuron degeneration. Among the key mechanisms implicated in ALS pathogenesis, neuroinflammation and oxidative stress have emerged as prominent contributors to disease progression. This systematic review with meta-analysis involved 344 preclinical studies conducted on SOD1 animal models of ALS, to quantitatively evaluate the effects of treatments targeting neuroinflammation and oxidative stress on functional outcomes such as disease onset, survival, motor neuron degeneration, and locomotion. Data extraction and validation were performed using a combination of a large language model and human review. Results show that while most interventions led to reduced astrogliosis, M1 microgliosis, and oxidative stress, and increased M2 microgliosis, these effects were more strongly associated with improved survival and motor outcomes than with delayed disease onset. The analysis also revealed that treatment timing significantly influences outcomes, with interventions initiated during the late pre-onset window showing the highest efficacy. Furthermore, sex differences were noted, with male mice displaying better outcomes in progression metrics but worse in the age at onset. Overall, this meta-analysis indicates that inflammation and oxidative stress are important contributors to ALS progression in SOD1 animal models, identifies potentially critical therapeutic windows, and supports the consideration of sex-balanced and stage-specific treatment strategies at the preclinical level.}, } @article {pmid41765206, year = {2026}, author = {Kotapati, C and Tran, V and Cardoso, FC}, title = {Voltage-gating and neuronal signalling in neurodegeneration: From neuropathology to therapeutic opportunities in motor neuron disease.}, journal = {Neurobiology of disease}, volume = {221}, number = {}, pages = {107336}, doi = {10.1016/j.nbd.2026.107336}, pmid = {41765206}, issn = {1095-953X}, mesh = {Humans ; *Motor Neuron Disease/metabolism/pathology/physiopathology ; Animals ; *Motor Neurons/metabolism/physiology ; *Signal Transduction/physiology ; *Ion Channel Gating/physiology ; }, abstract = {Voltage-gated ion channels (VGICs) are central to motor neuron excitability, governing the initiation and propagation of action potentials and synaptic transmission. Disruption of their finely tuned gating properties contributes to pathology-associated hyperexcitability, a hallmark of several neurodegenerative conditions, including motor neuron disease (MND). In this review, we examine the physiological roles of voltage-gated sodium, calcium and potassium channels in motor neurons, and evaluate how mutations, altered expression, aberrant biophysics, and maladaptive signalling impair the voltage signalling processes that drive and underlie neuronal dysfunction and degeneration. We synthesize evidence linking ion channel dysfunction to altered excitability, excitotoxicity, impaired neurotransmission, motor system instability and progressive motor neuron loss in MND, and discuss current therapies that offer modest benefit and may act directly or indirectly on neuronal excitability but with limited target specificity. Motivated by the the urgent need for effective treatments for MND, we discuss emerging strategies that leverage highly selective VGIC modulators, particularly gating-modifier peptides inhibitors, to counteract hyperexcitability in MND. We further highlight that understanding how voltage-sensing and channel gating are altered in MND offers new avenues for selective targeted intervention. Together, the evidence supports VGICs as critical yet poorly explored therapeutic targets for halting motor neurodegeneration.}, } @article {pmid41765421, year = {2026}, author = {Niidome, T and Ishida, T}, title = {[Mechanism of action and clinical trial results of a new drug for amyotrophic lateral sclerosis (ALS), Mecobalamin (Rozebalamin[®]) for intramuscular injection, 25 mg].}, journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica}, volume = {161}, number = {2}, pages = {115-122}, doi = {10.1254/fpj.25066}, pmid = {41765421}, issn = {0015-5691}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Clinical Trials as Topic ; Injections, Intramuscular ; *Vitamin B 12/analogs & derivatives/administration & dosage/therapeutic use/pharmacology/analogs & derivatives ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, intractable neurodegenerative disease characterized by generalized muscle atrophy and weakness, dysarthria, dysphagia, and respiratory muscle paralysis. Respiratory dysfunction due to muscle weakness is the primary cause of death; without mechanical ventilation, death typically occurs within 2 to 5 years after onset. Mecobalamin, an active form of vitamin B12, is thought to suppress homocysteine-induced neuronal cell death in ALS by acting as a coenzyme for methionine synthase, which catalyzes the conversion of homocysteine to methionine. Since the 1990s, research on neurodegenerative diseases supported by Japan's Ministry of Health, Labour and Welfare has suggested that high-dose mecobalamin may confer clinical benefits in ALS. This led to the initiation of clinical development. A Phase II/III double-blind, placebo-controlled comparative trial was conducted, but did not meet its primary endpoint. Based on these trial findings, an investigator-initiated Phase III placebo-controlled, double-blind comparative trial was conducted primarily at Tokushima University Hospital, targeting patients who developed ALS within one year before starting the trial. The trial demonstrated the efficacy of high-dose mecobalamin in slowing the decline in the Revised ALS Functional Rating Scale total score, which was the primary endpoint. Safety was also confirmed. Based on these results, mecobalamin received regulatory approval in September 2024 for the indication "slowing the progression of functional impairment in ALS." It is expected to offer a new treatment option for patients with ALS.}, } @article {pmid41765997, year = {2026}, author = {Wu, J and Xu, Y and Yin, T and Zhang, N and Ge, J and Fan, D and Ye, S}, title = {Voxel-mirrored homotopic connectivity in upper motor neuron-dominant amyotrophic lateral sclerosis is associated with different spread directions.}, journal = {Brain imaging and behavior}, volume = {20}, number = {2}, pages = {}, pmid = {41765997}, issn = {1931-7565}, support = {82071426//National Natural Science Foundation of China/ ; 82001350//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; YJXJ-JZ-2021-0014//Beijing E-Town Cooperation & Development Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Female ; Neural Pathways/physiopathology/diagnostic imaging ; Male ; Middle Aged ; Magnetic Resonance Imaging ; Aged ; Brain Mapping/methods ; Corpus Callosum/physiopathology/diagnostic imaging ; *Brain/physiopathology/diagnostic imaging ; Gray Matter/physiopathology/diagnostic imaging ; Motor Neurons ; Functional Laterality ; }, abstract = {By adopting the method of voxel-mirrored homotopic connectivity (VMHC), the correlation of the synchrony of spontaneous neural functional activities between symmetrical regions is determined to be mediated by the corpus callosum (CC). This study investigated differences in homotopic functional connectivity (FC) across distinct symptom spread directions in individuals with upper motor neuron-dominant amyotrophic lateral sclerosis (UMN-D ALS). The UMN-D ALS patients were categorized into two groups on the basis of the direction of symptom spread-horizontal spread (group H) and vertical spread (group V). Indices of interhemispheric functional and structural changes are derived via analyses of VMHC and probabilistic fiber tracking. The VMHC analysis of grey matter revealed that the intergroup differences in the superior frontal gyrus (SFG) were greater in group H than in groups V and HC (voxel P < 0.05, cluster P < 0.05, GRF corrected). According to CC-based VMHC analysis, group H had greater VMHC values than did group V (45 mm[3] vs. 18 mm[3] at a voxel-level threshold of P < 0.05, uncorrected). In UMN-D ALS, the results of VMHC analysis vary with different spread directions. In group H, homotopic FC significantly increased, possibly associated with early bilateral limb involvement and subsequent compensatory increases in the SFG. These results contribute to the understanding of the relationship between brain function and symptom evolution in individuals with ALS.}, } @article {pmid41766075, year = {2026}, author = {Kuhn, C and Bromberg, M and Margolis, A and Hayes, H}, title = {Exploring Intimacy in Amyotrophic Lateral Sclerosis: A Pilot Study of Educational Support in a Multidisciplinary Clinic.}, journal = {Journal of clinical neuromuscular disease}, volume = {27}, number = {3}, pages = {82-88}, doi = {10.1097/CND.0000000000000546}, pmid = {41766075}, issn = {1537-1611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Pilot Projects ; Male ; Female ; Middle Aged ; Aged ; *Patient Education as Topic/methods ; *Sexual Partners/psychology ; Adult ; Surveys and Questionnaires ; *Interpersonal Relations ; *Sexual Behavior ; }, abstract = {OBJECTIVE: This pilot study explored the feasibility and perceived usefulness of an educational intervention on intimacy delivered within a multidisciplinary ALS clinic.

METHODS: Individuals with ALS and their partners (if applicable) received the publicly available "Sexuality, Intimacy & Chronic Illness" fact sheet during routine clinic visits. A follow-up survey was conducted 4-6 weeks later to assess whether the information was informative, sufficient, and helpful. Demographic and clinical data were collected, and open-ended responses were analyzed descriptively.

RESULTS: Forty-two individuals received the fact sheet; 6 individuals and their partners (N = 12) completed follow-up surveys. Most respondents (83%) reported that ALS had impacted their intimate relationships, and 75% had discussed these changes with their partner. Half found the fact sheet informative, and 58% felt the information was sufficient. Open-ended responses revealed diverse needs, including interest in tailored content (eg, erectile dysfunction) and a desire for providers to ask permission before discussing intimacy. Caregivers described shifting roles and emotional strain, indicating that written materials alone may not fully address intimacy-related challenges.

CONCLUSIONS: Integrating discussions of intimacy into ALS care is feasible and appreciated by some patients and partners. Although written educational materials may offer a useful starting point, a more personalized, consent-based approach-potentially modeled on frameworks like Ex-PLISSIT-may better address the relational needs of individuals with ALS and their caregivers. These findings support incorporating intimacy into holistic ALS care and developing guidelines to facilitate such discussions in multidisciplinary settings.}, } @article {pmid41766077, year = {2026}, author = {Hass, RM and Reiter-Campeau, S and Laughlin, RS and Liewluck, T}, title = {Respiratory Onset Amyotrophic Lateral Sclerosis in a Patient With C9orf72 Expansion.}, journal = {Journal of clinical neuromuscular disease}, volume = {27}, number = {3}, pages = {96-98}, doi = {10.1097/CND.0000000000000556}, pmid = {41766077}, issn = {1537-1611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; *C9orf72 Protein/genetics ; DNA Repeat Expansion ; Male ; Middle Aged ; }, abstract = {Respiratory-onset amyotrophic lateral sclerosis (ALS) is uncommon, accounting for less than 5% of all patients with ALS. Familial ALS is also uncommon, with the most common variant being related to a C9orf72 hexanucleotide repeat expansion. Respiratory-onset ALS in familial ALS is rare, with few cases discussed in the literature related to ERBB4, SOD1, and FUS variants. Here we present a case of respiratory-onset ALS related to a C9orf72 repeat expansion, expanding the spectrum of associated phenotypes associated with C9orf72 expansions and highlighting the importance of genetic testing in patients living with ALS.}, } @article {pmid41766085, year = {2026}, author = {Seco, M and Moreira, I and Oliveira, J and Moreira, S}, title = {Amyotrophic Lateral Sclerosis Caused by a Pathogenic Variant in SOD1 Gene: An Atypical Rapidly Progressive Phenotype.}, journal = {Journal of clinical neuromuscular disease}, volume = {27}, number = {3}, pages = {122-123}, doi = {10.1097/CND.0000000000000548}, pmid = {41766085}, issn = {1537-1611}, } @article {pmid41767843, year = {2026}, author = {Ben Khalaf, N}, title = {Heat shock proteins (Hsp70 and Hsp90) in neurodegeneration: pathogenic roles and therapeutic potential.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1711422}, pmid = {41767843}, issn = {1663-4365}, abstract = {The maintenance of protein homeostasis is essential for neuronal survival and function; however, it progressively declines with age, predisposing the brain to neurodegenerative diseases. Molecular chaperones Hsp70 and Hsp90 are key guardians of proteostasis, pivotally regulating protein folding, refolding, and degradation under both physiological and stress conditions. This review integrates an overview of the structural features, isoforms, and mechanistic interactions of Hsp70 and Hsp90. It highlights how their dysfunction contributes to the pathogenesis of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. We first examine the architecture and ATP-driven chaperone cycles of Hsp70 and Hsp90, their co-chaperone networks, and the feedback regulation by the Heat Shock Factor-1 pathway. We then discuss evidence linking age-related declines in chaperone expression and HSF-1 activity to proteostasis collapse and neuronal vulnerability. The review particularly examines how Hsp70 and Hsp90 differentially influence pathogenic protein aggregation (e.g., tau, α-synuclein, TDP-43, and mutant huntingtin) and how this balance is altered in the aging brain. Regarding therapeutic approaches, we summarize current strategies targeting these chaperones, including small-molecule modulators of Hsp70 and Hsp90, co-chaperone inhibitors, and recombinant chaperone therapy, which has shown to restore proteostasis and cognitive function in experimental models. These emerging interventions underscore the dual nature of Hsp70/Hsp90 systems, acting as both protectors and potential contributors to neurodegeneration, depending on their regulation and interaction context. By linking molecular chaperone biology to aging and translational therapeutics, this review establishes a framework for developing precision approaches that enhance proteostasis capacity, delay age-associated neurodegeneration, and promote healthy brain aging.}, } @article {pmid41768173, year = {2026}, author = {Capitani, G and Lozzi, D and Curcio, G and Migliore, S}, title = {Moral decision-making in patients with neurodegenerative diseases: a systematic review.}, journal = {Frontiers in psychology}, volume = {17}, number = {}, pages = {1745923}, pmid = {41768173}, issn = {1664-1078}, abstract = {INTRODUCTION: Moral decision-making, a core component of social cognition, relies on integrating affective and cognitive processes supported by distributed neural networks. Neurodegenerative diseases disrupt these systems to varying degrees, offering unique models to investigate the neural bases of moral cognition. This review aimed to systematically examine moral decision-making deficits across neurodegenerative diseases, delineate disease-specific patterns of moral cognition impairment, and highlight conceptual and methodological gaps to inform future research and clinical assessment.

METHODS: A systematic search of PubMed, Web of Science, and Scopus was conducted for studies published up to January 2025, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines.

RESULTS: Seventeen studies met inclusion criteria. Convergent evidence indicates that behavioral variant frontotemporal dementia (bvFTD) produces a distinctive utilitarian bias characterized by diminished empathy, emotional blunting, and impaired integration of intention and outcome, reflecting degeneration of the ventromedial prefrontal cortex, anterior insula, and amygdala within the salience and default mode networks. In contrast, Alzheimer's disease (AD) patients typically preserve affective aversion to harm, suggesting relative sparing of limbic-ventromedial circuits despite conceptual and executive decline. Moral reasoning in Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) remains largely intact unless frontotemporal involvement occurs, while dementia with Lewy bodies (DLB) manifests intermediate profiles marked by reduced cognitive theory of mind and aberrant moral affect.

DISCUSSION: These findings delineate disease-specific patterns of moral dysfunction linked to network-level degeneration rather than global cognitive decline. Understanding these mechanisms holds translational relevance for early diagnosis, ethical capacity assessment, and the development of ecologically valid tools to monitor socio-emotional deterioration in neurodegenerative disorders.}, } @article {pmid41768770, year = {2026}, author = {Perlatti, B and Vellanki, S and Zhang, Y and Chiang, YM and Hu, Y and Yuan, M and Dunbar, K and Fine, A and Grau, MF and Li, S and O'Donnell, T and Shenoy, R and Li, H and Shi, H and Xu, X and Chen, Z and Arvedson, T and Tang, Y and Cramer, RA and Cee, V and Harvey, CJB}, title = {An Antifungal with a Novel Mechanism of Action Discovered via Resistance Gene-Guided Genome Mining.}, journal = {ACS central science}, volume = {12}, number = {2}, pages = {197-207}, pmid = {41768770}, issn = {2374-7943}, abstract = {Invasive fungal infections claim over two million lives annually, a problem exacerbated by rising resistance to current antifungal treatments and an increasing population of immunocompromised individuals. Despite this, antifungal drug development has stagnated, with few novel agents and fewer novel targets explored in recent decades. Here, we validate acetolactate synthase (ALS), an enzyme critical for branched-chain amino acid biosynthesis and absent in humans, as a promising target for new therapeutics. Using resistance gene-guided genome mining, we discovered a biosynthetic gene cluster in Aspergillus terreus encoding HB-35018 (1), a novel spiro-cis-decalin tetramic acid that potently inhibits ALS. Biochemical and antifungal assays demonstrate that 1 surpasses existing ALS inhibitors in efficacy against Aspergillus fumigatus and other pathogenic fungi. Structural studies via cryo-electron microscopy reveal a unique covalent binding interaction between compound 1 and ALS, distinct from known inhibitors, and finally, we demonstrate that ALS is essential for virulence in a mouse model of invasive aspergillosis. These findings position ALS as a promising target for antifungal development and demonstrate the potential of resistance gene-guided genome mining for antifungal discovery.}, } @article {pmid41769387, year = {2026}, author = {Scirocco, E and Scalia, J and Ugolini, B and Casagrande, G and Ho, D and Hagar, JL and Kingsley, K and Hoffman, R and Cooley, C and Cudkowicz, ME and Paganoni, S and Berry, JD}, title = {The Amyotrophic Lateral Sclerosis House Call Program: A Single-Center Experience in the United States.}, journal = {Neurology research international}, volume = {2026}, number = {}, pages = {6629960}, pmid = {41769387}, issn = {2090-1852}, abstract = {BACKGROUND: Accessing multidisciplinary care poses challenges for people living with amyotrophic lateral sclerosis (ALS) due to mobility issues. As ALS care rarely requires hospital-based technology, most care is available through home visits. The Daniella Lipper ALS House Call Program (HCP) at Massachusetts General Hospital (MGH), launched in 2017 in collaboration with Compassionate Care ALS, has pioneered home-based ALS care in Eastern Massachusetts.

METHODS: A retrospective chart review of ALS and primary lateral sclerosis (PLS) patients enrolled in the HCP at MGH was conducted. Data on demographics, visit details, and procedures performed during home visits were collected from electronic health records for patients seen from January 2024 to December 2024.

RESULTS: In 2024, the ALS HCP conducted 959 visits for 142 patients (average age: 68 years, range: 36-93; 47.9% female). Of these patients, 137 (96.5%) were diagnosed with ALS and 5 (3.5%) with PLS. Notably, 61 patients (43%) received care exclusively at home. Key interventions included 44 gastrostomy tube exchanges and 59 respiratory assessments, both of which significantly reduced hospital visits. The average distance traveled by the care team was 30.32 miles per visit.

CONCLUSIONS: The Daniella Lipper ALS HCP at MGH brings ALS expertise into the patient's home, minimizing travel burdens and ensuring continuity of care. The program illustrates the feasibility and impact of home-based ALS care, suggesting potential for broader implementation across the nation. Development will focus on expanding services, such as tracheostomy changes in the homes, and on creating sustainable models for similar initiatives.}, } @article {pmid41772227, year = {2026}, author = {Rizzo, GEM and Vanella, G and Fuccio, L and Facciorusso, A and Mazza, S and Catena, F and Fabbri, C and Anderloni, A and Tarantino, I}, title = {Endoscopic ultrasound-guided gastrointestinal anastomoses for the treatment of afferent limb syndrome: a systematic review and meta-analysis.}, journal = {Surgical endoscopy}, volume = {40}, number = {5}, pages = {3944-3955}, pmid = {41772227}, issn = {1432-2218}, mesh = {Humans ; *Afferent Loop Syndrome/surgery ; *Endosonography/methods ; Anastomosis, Surgical/methods ; *Ultrasonography, Interventional/methods ; *Jejunostomy/methods ; *Gastric Bypass/methods/adverse effects ; }, abstract = {BACKGROUND AND STUDY AIMS: Afferent limb syndrome (ALS) is a rare condition resulting in a mechanical obstruction in the afferent loop after surgical gastrointestinal (GI) reconstruction. Endoscopic ultrasound (EUS)-guided gastrojejunostomy (GJ) or jejunojejunostomy (JJ) is increasing in clinical practice. Therefore, the aim of this systematic review with meta-analysis is to evaluate the efficacy and safety of EUS-GJ or EUS-JJ for ALS.

PATIENTS AND METHODS: The most important medical databases were systematically searched through May 2025. The primary outcome was technical success of EUS-GJ/JJ for ALS. Secondary outcomes were clinical success, safety, and recurrence rate. A random-effects model was used to pool the results. Heterogeneity was expressed as inconsistency index (I[2]) and explored through subgroup analyses.

RESULTS: 9 studies (all retrospective) involving 188 patients were included in the analysis. The weighted mean age was 65.38(± 10.57) years and the etiology of the ALS was mostly malignant. Technical success was 96.3% (CI95% 93.2-99.4%, I[2] = 0%). Clinical success was 95% (CI95% 91.2-98.7%, I[2] = 0%) and adverse events (AEs) rate was 6.9% (CI95% 2.9-11.1%, I[2] = 0%). Recurrence rate was 16.6% (CI95% 7.7-25.4%, I[2] = 43.79%). Subgroup analyses showed differences in the recurrence rate between the use of a fully covered self-expandable metal stent (FCSEMS) (35.9% [CI95% 20.3-51.6%, I[2] = 0%]) and a lumen-apposing metal stent (LAMS)(10.4% [CI95% 4-16.8%, I[2] = 0%], p = 0.003). Follow-up ranged from a median of 96.5 to 185 days.

CONCLUSIONS: EUS-guided GI anastomosis is an effective treatment for ALS, showing high technical and clinical success rates and a low incidence of AEs. The use of LAMS over FCSEMS seems to reduce the recurrence rate, suggesting the routine use of LAMS in the case of EUS-guided GI anastomosis for treating ALS.}, } @article {pmid41772317, year = {2026}, author = {Weller, B and Lin, CW and Rothballer, S and Calderwood, MA and Falter-Braun, P and Falter, C}, title = {NeuroViOme: a viral orfeome collection for studies of neurodegenerative disease.}, journal = {Journal of neurovirology}, volume = {32}, number = {2}, pages = {}, pmid = {41772317}, issn = {1538-2443}, mesh = {Humans ; *Neurodegenerative Diseases/virology/genetics ; Animals ; Host-Pathogen Interactions/genetics ; JC Virus/genetics/metabolism ; Amyotrophic Lateral Sclerosis/virology ; Genome, Viral ; Herpesvirus 4, Human/genetics ; }, abstract = {Neurodegenerative diseases such as Alzheimer's and Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS) pose a global health challenge due to their progressive course and lack of curative therapies. These conditions lead to severe neurological decline, significantly impacting patient independence and quality of life, and ultimately result in lethal outcome. Emerging evidence suggests that viral infections contribute to the onset and progression of these neurological diseases, Leblanc and Vorberg (PLoS Pathog 18:e1010670, 2022), either by directly inducing neurological symptoms or by triggering immune responses resulting in neuropathology. Nevertheless, systematic studies of the direct interplay between viral and host proteins in neurodegeneration remain scarce. A key aspect of viral pathogenesis is direct interaction between viral and host proteins (protein-protein interactions, PPIs), which are essential for viral replication and can disrupt or redirect host cell function Kim et al. (Nat Biotechnol, 2022); Zhou et al. (Res Sq, 2022), potentially contributing to the development of diseases traditionally considered non-communicable. Understanding these molecular mechanisms is crucial for advancing diagnostic and therapeutic strategies in neurodegenerative conditions, particularly ALS and MS. To enable systematic studies of these interactions, we introduce NeuroViOme as ORFeome resource encompassing nearly all protein-coding sequences from nine viruses selected based on their prevalence, neurotropism, and mechanistic or epidemiological links to neurodegenerative processes. NeuroViOme includes ORFs from Enteroviruses (EV-A71, EV-D68, CVB3, Echovirus E30), Herpesviruses (HSV-1, EBV, HHV3/Varicella Zoster), the endogenous retrovirus HERV-K, and Polyomavirus JCPyV. To our knowledge, this represents the most comprehensive viral ORF set assembled for neurodegeneration research to date. The collection builds the foundation for interactome mapping and functional genomics analyses and provides a valuable basis for systematic studies of viral perturbations of host pathways.}, } @article {pmid41772347, year = {2026}, author = {Ahuja, V and Sahu, B and Khurana, S and Kumari, K and Ganguly, NK and Gourie-Devi, M and Verma, S and Dastidar, SG and Taneja, V}, title = {Granules Gone Rogue: Nuclear and Cytoplasmic Ribonucleoprotein Structures in Amyotrophic Lateral Sclerosis-Fused in Sarcoma (ALS-FUS) Pathology.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41772347}, issn = {1559-1182}, support = {211610027970//University Grants Commission/ ; EMDR/IG/9/2024-01739//Indian Council of Medical Research/ ; 3/1/2/151/Neuro/2021-NCD-I//Indian Council of Medical Research/ ; IIRPIG-2023-0001508//Indian Council of Medical Research,India/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; Humans ; *RNA-Binding Protein FUS/metabolism/genetics ; Animals ; *Cell Nucleus/metabolism ; *Cytoplasmic Granules/metabolism ; *Cytoplasmic Ribonucleoprotein Granules/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the selective loss of motor neurons. Among its genetic subtypes, mutations in the fused in sarcoma (FUS) gene represent an aggressive form, often associated with early onset and rapid progression. FUS is a ubiquitously expressed DNA/RNA-binding nuclear protein involved in maintaining DNA damage repair and RNA metabolism. It also plays a crucial role in the formation of ribonucleoprotein (RNP) granules such as cytoplasmic stress granules and nuclear paraspeckles under stress. In ALS, pathogenic FUS mutations frequently disrupt the subcellular distribution of FUS, leading to cytoplasmic mislocalization and aggregation. Mutant FUS further disrupts granular dynamics by its aberrant incorporation into stress granules and altering their biophysical properties. The loss of nuclear FUS function leads to elevated levels of the long non-coding RNA NEAT1 and enhanced paraspeckle assembly with disrupted structural integrity. The impaired nucleocytoplasmic granular dynamics compromise the cellular resilience, thereby increasing motor neuron vulnerability. The interaction of FUS with other ALS-associated proteins causes pathological alterations in the cellular milieu, suggesting a common underlying disease mechanism. This comprehensive review emphasizes the FUS-mediated RNP granule regulation under physiological and pathological conditions. Further, clinically approved and emerging therapeutic strategies aimed at attenuating FUS pathology and RNP granule dynamics have been described.}, } @article {pmid41772409, year = {2026}, author = {Sorenson, E and Heitzman, D and Lee, I and Jang, G and Elman, L and Habib, AA and Wymer, J and Hayat, G and Goutman, SA and Fernandes, JAM and Floeter, MK and Ajroud-Driss, S and Gwathmey, K and Kasarskis, E and Kisanuki, YY and Lomen-Hoerth, C and Walk, D and Johnston, WS and Diaz, F and Maragakis, NJ and Paganoni, S and Shah, J and Oskarsson, B and Zinman, L and Heiman-Patterson, T and Jawdat, O and Fournier, CN and Pulley, MT and Scelsa, SN and Shoesmith, C and Simmons, Z and Sherman, AV and Hoover, BN and Yun, RY and Cheung, K and Mitsumoto, H and , }, title = {Prospective Validation of the New PLS Diagnostic Criteria From PLS Natural History Study: EMG and Neurofilament Analyses.}, journal = {Muscle & nerve}, volume = {73}, number = {6}, pages = {976-983}, doi = {10.1002/mus.70192}, pmid = {41772409}, issn = {1097-4598}, support = {//Mr. David Marren and family/ ; //Spastic Paraplegia Foundation/ ; //ALS Association/ ; //Mitsubishi Tanabe Pharma Corporation/ ; //Muscular Dystrophy Association/ ; //Wings over wall street/ ; //Sean M. Healey and AMG center for ALS research/ ; }, mesh = {Humans ; *Electromyography ; Female ; Male ; *Neurofilament Proteins/blood ; *Motor Neuron Disease/diagnosis/physiopathology/blood ; Prospective Studies ; Middle Aged ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/blood ; Aged ; Diagnosis, Differential ; Follow-Up Studies ; *Intermediate Filaments/metabolism ; Adult ; }, abstract = {BACKGROUND: Primary lateral sclerosis (PLS) is an ultrarare upper motor neuron syndrome with a prognosis unique from classical ALS. The study of PLS is complicated by its rarity and the difficulty distinguishing PLS from ALS. We present data from a 1-year prospective follow-up study on PLS and efforts to distinguish it from ALS.

METHODS: Seventy-six PLS participants enrolled in this prospective natural history study. EMG studies, blood neurofilament light chain levels (NfLs), and demographic characteristics were obtained at baseline. At 1-year follow-up, repeat EMG studies were conducted to determine which participants fulfilled criteria for ALS. Baseline characteristics were then compared to determine features that predict reclassification.

RESULTS: Seventy participants completed 1-year follow-up. Five of the 70 were reclassified to ALS (7.1%). Those reclassified had higher trends in baseline blood NfL levels (91.4 vs. 34.0 pg/mL, p = 0.13) and shorter symptom duration (39 vs. 69 months in the PLS group, p = 0.15). Reclassification was noted in both probable and definite PLS participants. All cases with a symptomatic duration of less than 2 years retained the PLS phenotype (5 of 5). NfL levels over 90 pg/mL predicted reclassification with 94% specificity and 60% sensitivity. No other features predicted reclassification to ALS.

CONCLUSIONS: In our population, reclassification of PLS to ALS occurred at a low frequency at 1 year follow-up (7.1%). Baseline NfL was the strongest predictor in differentiating UMN dominant ALS from PLS at 1-year follow-up. Based on our data, we propose EMG and NfL criteria for enrollment in future PLS trials.}, } @article {pmid41772759, year = {2026}, author = {Donega, S and Gorospe, M and Harries, LW and Ferrucci, L}, title = {Loss of Splicing Homeostasis as a Hallmark of Aging.}, journal = {Molecular and cellular biology}, volume = {46}, number = {7}, pages = {673-691}, doi = {10.1080/10985549.2026.2627235}, pmid = {41772759}, issn = {1098-5549}, mesh = {Humans ; *Aging/genetics ; *Homeostasis/genetics ; Animals ; *Alternative Splicing/genetics ; Cellular Senescence/genetics ; *RNA Splicing/genetics ; RNA-Binding Proteins/metabolism ; }, abstract = {Alternative splicing is a fundamental mechanism that ensures accurate gene expression, supports cellular adaptability, and expands protein diversity beyond the limits of a fixed gene pool. With aging, splicing fidelity weakens, contributing to decline in RNA homeostasis and disrupting essential cellular functions, including mitochondrial oxidative phosphorylation, genome stability, and immune regulation, and in turn accelerating tissue and organ dysfunction. Evidence from senescent cells, aged tissues, and model organisms shows that altered levels of splicing factors and increased RNA polymerase II elongation rates impair co-transcriptional splicing and promote mis-spliced isoforms that reinforce senescence and drive pathology. Dysfunction of RNA-binding proteins further contributes to aberrant splicing, linking splicing defects to age-related diseases such as atherosclerosis, osteoarthritis, sarcopenia, and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Therapeutic strategies to correct splicing defects, such as antisense oligonucleotides, RNA interference, CRISPR-Cas systems, ADAR-mediated editing, and RNA aptamers, can restore a homeostatic balance of mRNA isoforms. However, major challenges remain, including distinguishing adaptive physiological from pathological splicing 'noise' and achieving targeted delivery to tissues. Despite these obstacles, RNA splicing dysregulation represents a promising avenue to extend health span by reestablishing homeostatic RNA programs, and reinforces the idea that "transcriptomic instability" is a hallmark of aging.}, } @article {pmid41773017, year = {2026}, author = {Liang, X and Zhao, T and Dai, X and Sun, Y and Yuan, J and Afzalpurkar, S and Duong, C and Yu, A and Tang, F and He, X and Liu, X and Chen, X and Cao, Z and Wang, Y}, title = {FUS is an N1- and N6-methyladenosine-binding protein.}, journal = {Nucleic acids research}, volume = {54}, number = {5}, pages = {}, pmid = {41773017}, issn = {1362-4962}, support = {R35 ES031707/NH/NIH HHS/United States ; T32 ES018827/NH/NIH HHS/United States ; }, mesh = {Humans ; *RNA-Binding Protein FUS/metabolism/genetics ; *Adenosine/analogs & derivatives/metabolism ; RNA Methylation ; Methyltransferases/metabolism/genetics/antagonists & inhibitors ; Cell Line, Tumor ; Protein Binding ; }, abstract = {Nucleotide repeat expansions contribute to a number of neurological disorders. Mutations and augmented expression in fused in sarcoma (FUS) can result in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we reveal that FUS is an N1- and N6-methyladenosine (m1A- and m6A)-binding protein, where the protein interacts with the methylated adenosines in CAG repeat expansion RNA, thereby leading to the protein's cytoplasmic redistribution in SH-SY5Y cells. We also found that ectopically expressed FUS co-localizes with CAG repeat RNA in the cytosol. This co-localization is diminished upon genetic depletion of m6A and m1A writer proteins (i.e. METTL3 and TRMT61A), pharmacological inhibition of METTL3, and ectopic overexpression of m1A and m6A eraser proteins (i.e. ALKBH3 and FTO). Moreover, binding to methylated CAG repeat RNA renders the ectopically expressed FUS protein less dynamic in cells. Together, our study underscores a critical role for m1A and m6A in enhancing FUS-RNA interaction, which results in aberrant subcellular distribution and attenuated mobility of the protein in cells. These findings unveil a novel mechanism underlying neurodegenerative disorders emanating from elevated expression of FUS and suggest targeting FUS-methylated adenosine interactions as a potential therapeutic strategy for FUS proteinopathy.}, } @article {pmid41775065, year = {2026}, author = {Esmaeili, A and Dashtian, K and Zare-Dorabei, R and Kerman, K and Mahdavi, M}, title = {A tri-responsive sensor based on co-encapsulated organic probes and multifunctional bimetallic V/Ce-MOF nanozyme in a hydrogel for the detection of l-Serine in saliva.}, journal = {Talanta}, volume = {305}, number = {}, pages = {129594}, doi = {10.1016/j.talanta.2026.129594}, pmid = {41775065}, issn = {1873-3573}, mesh = {*Saliva/chemistry ; Humans ; *Serine/analysis ; Colorimetry/methods ; *Hydrogels/chemistry ; *Metal-Organic Frameworks/chemistry ; Electrochemical Techniques/methods ; Fluorometry/methods ; *Biosensing Techniques/methods ; Phenylenediamines/chemistry ; Limit of Detection ; Benzidines/chemistry ; }, abstract = {Rapid and accurate detection of l-Serine, a key potential biomarker of neurological diseases such as Alzheimer, Parkinson and Amyotrophic lateral sclerosis (ALS) disease, is crucial for public health. Herein, we prepared a tri-responsive sensor capable of colorimetric, fluorimetric, and electrochemical detection. This portable sensor integrates co-encapsulated organic probes with a multifunctional bimetallic cerium/vanadium metal-organic framework (UiO-66-NH2(Ce/V)) nanozyme activity, all embedded within a biocompatible agarose-based hydrogel for detection of l-serine in a saliva sample. Physicochemical and electrochemical analyzes confirmed that the UiO-66-NH2(Ce/V) nanozyme, with peroxidase-like activity, facilitated the oxidation of tetramethylbenzidine (TMB) in the colorimetric assay, ortho-phenylenediamine (OPD) in the fluorometric assay and TMB in the electrochemical assay. The oxidation of these probes resulted in the formation of colored compounds in the colorimetric and fluorometric sensors, as well as created sharp anodic peaks in the electrochemical sensors via Vmax of 3.99 M[-1], 5.85 M[-1] and 0.002 M[-1], respectively. The results prove that increasing the concentration of l-serine inhibited the oxidation-reduction reactions, causing a reduction in the intensity of both the colors and the sensor peaks. It demonstrated a wide linear detection range of 5 to 250 μM for the colorimetric sensor, 1-250 μM for the fluorometric sensor, and 0.3-250 μM for the electrochemical sensor with a detection limit of 0.27 μM, 0.26 μM, and 0.076 μM, respectively. These sensors were applied to the detection of l-serine in human saliva samples, achieving recovery rates between 92.20% and 107.50% with RSD of <5%, and excellent reproducibility. The findings suggest that these sensors have significant potential for use in hospitalized healthcare systems to monitor disease biomarkers and represent a promising approach for early diagnosis of disease.}, } @article {pmid41775321, year = {2026}, author = {Lu, YH and Zhu, XP and Li, S and Zhang, FN and Cai, CB and Tian, M and Zhu, YH and Zeng, LH and Tan, J and Yu, CY and Chen, J}, title = {From scaffold to effector: reframing GFAP in neurodegeneration.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2026.02.051}, pmid = {41775321}, issn = {2090-1224}, abstract = {BACKGROUND: Neurodegenerative disorders impose a growing global burden, yet disease-modifying therapies remain limited. Glial fibrillary acidic protein (GFAP) has shifted from a passive astrocytic marker to an active effector that shapes neurodegenerative pathology.

AIM: of Review: This review synthesizes mechanistic and translational evidence that defines GFAP as a proteoform-governed hub and highlights its value for biomarker-guided precision intervention. Key Scientific Concepts of Review: An extensive literature search across major databases was conducted using predefined keywords and strict inclusion criteria, covering mechanistic, pathological, and clinical studies. Evidence supports a GFAP proteoform code in which alternative splicing generates functionally distinct isoforms, and PTMs encode context-dependent assembly dynamics and signaling outputs. We summarize how GFAP proteoforms integrate cytoskeletal remodeling with inflammatory transcriptional programs (notably STAT3 and NF-κB), proteostasis stress, and mitochondrial dysfunction, thereby coupling astrocyte state transitions to neuronal vulnerability and synaptic impairment. Disease trajectories are context-specific: GFAP dysfunction drives primary toxicity in Alexander disease (AxD); in Alzheimer's disease (AD), isoform-specific mechanisms intersect with amyloidogenic machinery and track early preclinical astrocyte activation; and in frontotemporal dementia (FTD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), GFAP reflects inflammatory-metabolic coupling during progression. Translationally, ultrasensitive plasma assays reveal GFAP elevation years to decades before symptom onset, complementing NfL and amyloid/tau within AT(N)-oriented diagnostic frameworks. Therapeutically, we evaluate precision strategies beyond global suppression, including ASO-based modulation, targeting STAT3/NF-κB-driven reactive programs, and restoring proteostasis via chaperone/autophagy pathways. Future progress hinges on isoform-/PTM-specific probes, conformational sensors, and spatial proteomic atlases validated in prospective longitudinal cohorts. In conclusion, GFAP represents both a mechanistic driver and a scalable biomarker, offering a translationally actionable axis to advance precision medicine in neurodegeneration.}, } @article {pmid41775600, year = {2026}, author = {Ding, JY and Li, WX and Wang, J and Huang, CY and Xu, XW and Yang, Q and Liu, XL and Yu, L and Hao, SR and Zhang, HF and Chen, JJ}, title = {Effectiveness of multimodal artificial liver support for acute-on-chronic liver failure: A single-center cohort study.}, journal = {Hepatobiliary & pancreatic diseases international : HBPD INT}, volume = {25}, number = {2}, pages = {170-183}, doi = {10.1016/j.hbpd.2026.02.001}, pmid = {41775600}, issn = {1499-3872}, mesh = {Humans ; *Liver, Artificial ; Female ; *Acute-On-Chronic Liver Failure/therapy/mortality/diagnosis/blood ; Male ; Middle Aged ; Treatment Outcome ; Retrospective Studies ; Time Factors ; Survival Rate ; Propensity Score ; Aged ; Adult ; }, abstract = {BACKGROUND: Multimodal artificial liver support (ALS) has been proven to be effective in a porcine model of acute liver failure. This study aimed to evaluate the curative effect in patients with acute-on-chronic liver failure (ACLF).

METHODS: Data from ACLF patients receiving multimodal ALS between January 2014 and August 2019 were collected. Patients were divided into two groups according to the patterns of ALS: a trimodal ALS group (trimodal group) and a bimodal ALS group (bimodal group). A propensity score matching was performed to control for baseline bias between the groups. Survival rates and laboratory parameters were compared after single session and after completion of all the sessions of treatments.

RESULTS: A total of 182 patients undergoing multimodal ALS were screened. Propensity score matching generated 47 pairs. The short-term (28/90 days) survival rates were significantly higher in the trimodal group than those in the bimodal group (28-day survival rate: 91.5% vs. 76.6%, P = 0.049; 90-day survival rate: 91.5% vs. 74.5%, P = 0.027). The model for end-stage liver disease score was improved both after single session and after completion of all the sessions of treatments. Single session of trimodal ALS significantly reduced bilirubin (P < 0.001) and bile acid (P = 0.003) levels compared with bimodal ALS. Compared with baseline, gamma-glutamyltransferase (P = 0.001) and alkaline phosphatase (P = 0.021) levels were significantly decreased after completion of all the sessions of treatments in the trimodal group. However, no significant differences were observed in these two parameters within the bimodal group. Trimodal ALS was associated with increased clearance rates of interleukin-8 (P = 0.009) and macrophage migration inhibitory factor (P = 0.012). Multivariate Cox regression revealed that trimodal ALS was an independent predictor of lower 28- and 90-day mortality (both P < 0.05).

CONCLUSIONS: Trimodal ALS may provide a greater survival benefit for patients with ACLF, likely because of its superior ability to clear toxic substances and suppress inflammation.}, } @article {pmid41776147, year = {2026}, author = {Nowell, WB and McGale, N and Levy, O and Wilding, S and Heinrich, P and Patel, NC and Andrews, JA and Rofail, D}, title = {Exploring the Lived Experiences of Individuals with Amyotrophic Lateral Sclerosis (ALS): A Qualitative Study and Conceptual Model of Signs, Symptoms, and Functional Impacts.}, journal = {Neurology and therapy}, volume = {15}, number = {3}, pages = {1043-1064}, pmid = {41776147}, issn = {2193-8253}, abstract = {INTRODUCTION: This study aimed to explore the experience of living with amyotrophic lateral sclerosis (ALS) and to develop a conceptual model for this rare disease.

METHODS: Concept elicitation interviews were conducted (January-September 2024) with people living with ALS (PLwALS; n = 31), caregivers (n = 20), and clinicians (n = 10). Qualitative data were analyzed separately to develop a conceptualization of the experience of living with ALS. Concept saturation was assessed every 5-6 interviews, and a conceptual model was developed.

RESULTS: The mean age of PLwALS was 42.4 years (standard deviation [SD] 11.5), 81% were female, 84% were white, and 23% had SOD1-ALS. The mean time since diagnosis was 4.6 years (SD 4.2); mean normed Rasch Overall ALS Disability Scale score was 76 (SD 17.16). Signs, symptoms, and functions reported during PLwALS interviews included neuromuscular, bulbar, speech, neurocognitive (e.g., memory issues), and a range of physical functioning issues (e.g., motor coordination). PLwALS also reported impacts on a range of activities and psychosocial interactions (e.g., eating, depressed mood, and relationships), alongside management strategies they employed. Interviews with caregivers and clinicians supported findings from the PLwALS interviews. Caregivers also identified signs such as drooling/excess salivation, and impacts related to ALS management (e.g., need for writing aids). Clinicians additionally considered loss of speech and neurocognitive signs (e.g., behavior/personality change) as ALS clinical manifestations. Concept saturation was reached, and a consolidated, comprehensive conceptual model was developed.

CONCLUSION: This research provides a holistic understanding of the experience of living with ALS and is the first conceptual model based on in-depth concept elicitation interviews. The findings highlight the range of signs, symptoms, and impacts that PLwALS experience, emphasizing its serious humanistic impact and high unmet need, and will help to guide patient-centric evaluation of clinical outcome assessments in future ALS studies.}, } @article {pmid41776544, year = {2026}, author = {Hirota, R and Lankford, KL and Nakazaki, M and Toyoshima, M and Kocsis, JD}, title = {Intranasal administration of human mesenchymal stromal cell-derived small extracellular vesicles delays disease progression in the SOD1(G93A) mouse model.}, journal = {Molecular brain}, volume = {19}, number = {1}, pages = {}, pmid = {41776544}, issn = {1756-6606}, mesh = {Animals ; Administration, Intranasal ; *Mesenchymal Stem Cells/metabolism/cytology ; Humans ; *Extracellular Vesicles/metabolism/transplantation ; Disease Models, Animal ; *Disease Progression ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/pathology/therapy/physiopathology ; *Superoxide Dismutase/metabolism ; *Superoxide Dismutase-1/metabolism ; Body Weight ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with no established disease-modifying therapy. Mesenchymal stem/stromal cells (MSCs) have been reported to exert neuroprotective effects in models of injury and disease, acting primarily through release of small extracellular vesicles (sEVs). MSC-derived sEVs (MSC-sEVs) have therefore attracted attention as a potential cell-free therapeutic approach for treating neurological conditions such as ALS. Because MSC-sEVs can cross both the nasal epithelial barrier and blood-brain barrier to reach the central nervous system (CNS), intranasal administration represents an attractive approach for repeated delivery of MSC-sEVs for long-term administration. In this study, we administered bone marrow-derived MSC-sEVs or vehicle intranasally to a SOD1(G93A) transgenic mouse model of ALS; the large majority of the sEVs had surface markers for exosomes. Dosing was for three consecutive days per week beginning one day after onset of neurological symptoms and continuing until a moribund state. Neurological score and body weight were recorded daily. Although total survival time and post-onset survival duration were not significantly prolonged by MSC-sEV treatment, MSC-sEV treatment significantly delayed progression from a mild symptom phase (NeuroScore 1) to more severe symptoms (NeuroScore 2) compared with vehicle-treated controls and showed a trend toward slower weight loss. These findings indicate that intranasal administration of MSC-sEVs can delay functional deterioration and prolong the mild impairment stage in an ALS mouse model. If translatable to human patients, such preservation of neurological function could represent a clinically meaningful outcome.}, } @article {pmid41776545, year = {2026}, author = {Krishnamurthy, SS and Buzatto, AZ and Campkin, C and Müller, HP and Wiesner, D and Weishaupt, J and Klose, V and Wiesenfarth, M and Elmas, Z and Herrmann, C and Parlak, Ö and Günther, K and Saad, R and Weiland, U and Dupuis, L and Ludolph, A and Li, L and Kassubek, J and Dorst, J and Roselli, F}, title = {Disruption of the angiopoietin-like system connects lipid homeostasis and hypothalamic dysfunction in ALS.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {41776545}, issn = {1741-7015}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/metabolism/blood/genetics ; Animals ; Humans ; *Hypothalamus/physiopathology/pathology/metabolism ; Female ; *Lipid Metabolism ; Mice ; Male ; Middle Aged ; Homeostasis ; Aged ; *Angiopoietin-like Proteins/metabolism/blood ; Superoxide Dismutase-1/genetics ; Disease Models, Animal ; Angiopoietin-Like Protein 4 ; *Angiopoietins/metabolism ; Adult ; }, abstract = {BACKGROUND: Alterations in lipid metabolism are manifestations of amyotrophic lateral sclerosis (ALS) that contribute to the risk and rate of progression. Blood levels of triglycerides and cholesterol are altered in ALS patients and pre-symptomatic gene carriers, but mechanistic insights into these changes are lacking.

METHODS: Serum samples from sporadic ALS patients (n = 118), mutated SOD1 and FUS/TARDBP (n = 20, 40, 17, respectively) with age and gender-matched controls (n = 96) were analysed for alterations in the angiopoietin-like protein (ANGPTL) system using enzyme-linked immunosorbent assays. SOD1[G93A] murine model was studied at pre-symptomatic (P50), early symptomatic (P90), and fully symptomatic (P110) stages, along with their wild-type (WT) littermates for ANGPTLs. Untargeted lipidomics on serum was performed using high-resolution liquid chromatography-mass spectrometry. Further, the involvement of the hypothalamus was studied using hypothalamic volumetry in patients and an antibody array spanning 308 proteins in mice.

RESULTS: We show that mutation-specific patterns of systemic lipid abnormalities appear in ALS and that they correlate with reduced levels of angiopoietin-like proteins 3 and 4. ANGPTL-3/4, in turn, correlates with hypothalamic atrophy but not with corticospinal involvement, as determined by MRI volumetry and diffusion tensor imaging. Lipid phenotype and decreased ANGPTL in humans are recapitulated in two SOD1 murine ALS models, in which ANGPTL-3, -4, and -8 expression patterns are consistent with the repartitioning of lipid utilisation from muscles to the brown adipose tissue; systemic levels of ANGPTL-3 correlate with hypothalamic neuroinflammation and vascular permeability and with hypothalamic levels of agouti-related protein and neuropeptide Y.

CONCLUSIONS: These data provide a molecular mechanism linking peripheral lipid metabolism to the dysfunction of a specific hypothalamic circuit through the mediation of systemic ANGPTL-3 and -4. This finding constitutes a molecularly defined entry point to manipulate lipid metabolism in ALS.}, } @article {pmid41776751, year = {2026}, author = {Roca-Pereira, S and López-Sampere, Y and Mengod-Soler, P and Peña-Fonteboa, M and Marco, C and Caravaca-Puchades, A and Domínguez, R and Vázquez-Costa, JF and Santamaría, E and Fernández-Irigoyen, J and Colomina, MJ and León Moreno, I and Martínez Yélamos, A and Martínez Yélamos, S and Santpere, G and Obis, E and Portero-Otín, M and Piñol-Ripoll, G and Povedano, M and Andrés-Benito, P}, title = {Proteomic profile of CSF obtained at the time of diagnosis determines amyotrophic lateral sclerosis progression and survival: CXCL7 levels in disease prognosis and survival.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {36}, number = {5}, pages = {e70089}, pmid = {41776751}, issn = {1750-3639}, support = {PI20/000155//Instituto de Salud Carlos III/ ; PI23/00176//Instituto de Salud Carlos III/ ; PI24/01516//Instituto de Salud Carlos III/ ; CD23/00097//Instituto de Salud Carlos III/ ; //Fundació Catalana d'Esclerosi Lateral Amiotròfica (ELA) Miquel Valls/ ; //Elles contra l'Esclerosi Lateral Amiotròfica (ELA)/ ; //Swim for Esclerosi Lateral Amiotròfica (ELA)/ ; //Mà amiga/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/mortality/pathology ; Female ; Prognosis ; Proteomics/methods ; Biomarkers/cerebrospinal fluid ; Disease Progression ; Male ; Middle Aged ; *beta-Thromboglobulin/cerebrospinal fluid ; Aged ; Spinal Cord/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease primarily affecting motor neurons. Neurofilament light chain (NfL) is the most established prognostic biomarker; however, its diagnostic resolution is limited, particularly within intermediate concentration ranges, and it does not capture the molecular heterogeneity of ALS. This study aimed to identify complementary cerebrospinal fluid (CSF) biomarkers and pathway-specific signatures through a non-targeted multiomic approach. We performed SWATH-MS-based proteomics and LC-MS/MS lipidomics on CSF from ALS patients stratified by survival (ALS-SS and ALS-LS) and healthy controls. Weighted protein co-expression network analysis (WPCNA) was applied to identify biologically coherent protein modules associated with disease phenotype and progression. Top biomarker candidates were further evaluated using immunoassays in an independent cohort. Post-mortem ALS spinal cord tissues were analyzed to explore the pathophysiological relevance of identified proteins. CSF proteomic profiles robustly distinguished ALS patients from controls and stratified patient subgroups by survival, revealing a molecular signature characterized by inflammation, downregulation of detoxification mechanisms, and synaptic dysregulation in aggressive disease forms. In contrast, lipidomic profiles showed limited discriminatory power. WPCNA identified modular proteomic signatures capturing ALS heterogeneity, and machine learning models based on these profiles yielded optimal biomarker panels for diagnosis and prognosis. CXCL7 emerged as a promising complementary biomarker, and shed light in disease physiopathology. Immunoassay validation supported the diagnostic and prognostic potential of CXCL7 and its association with survival time. Histopathological analysis further confirmed CXCL7 localization in anterior horn motor neurons, despite no detectable changes in whole spinal cord lysates at late disease stages. Comprehensive CSF proteomic profiling, combined with network-based analysis, enhances our understanding of ALS molecular heterogeneity and provides a framework for precision biomarker discovery. CXCL7 complements NfL as a diagnostic and prognostic biomarker, supporting improved patient stratification and advancing the development of personalized therapeutic strategies in ALS.}, } @article {pmid41777232, year = {2026}, author = {Yerraguntla, S and Bakshi, B and Chandran, K and Foucher, J and Benatar, M and Wicks, P and Bedlack, R and Shirilla, D and Sun, Y and Maragakis, N and Greenstein, E and Mascias Cadavid, J and Rao, A and Allen, O and Dyckman, K and Wang, O and Beauchamp, M and Chang, V and Brown, A and Carbunar, O and Paganoni, S and Bertorini, T and Pioro, E and Elsharif, B and Jiang, N and Pattee, G and Carter, G and Breevoort, S and Tito, E and Nathaniel, G and Jackson, C and Olby, N and McDermott, C and Ratner, D and Li, X}, title = {ALSUntangled #82: N-acetylcysteine.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {717-721}, doi = {10.1080/21678421.2026.2638590}, pmid = {41777232}, issn = {2167-9223}, mesh = {*Acetylcysteine/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Animals ; Oxidative Stress/drug effects ; *Antioxidants/therapeutic use ; }, abstract = {N-acetylcysteine is a thiol-containing compound and a precursor of glutathione, with mechanistic plausibility for ALS, including reducing oxidative stress, regulating neuroinflammation, and mitigating mitochondrial dysfunction. Preclinical studies have yielded conflicting results on whether N-acetylcysteine can delay the onset of motor impairment and prolong survival in ALS mouse models. Several case studies of oral or subcutaneous administration of N-acetylcysteine in patients with ALS did not demonstrate convincing benefits. Clinical trials to date have also failed to demonstrate efficacy in slowing ALS progression. While N-acetylcysteine shows theoretical promise, further research is needed to clarify its therapeutic role in ALS. At present, ALSUntangled does not support the use of N-acetylcysteine as a treatment to slow ALS progression.}, } @article {pmid41777380, year = {2026}, author = {, }, title = {Retraction: Enhancing ALS disease management: exploring integrated user value through online communities evidence.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1793079}, doi = {10.3389/fneur.2026.1793079}, pmid = {41777380}, issn = {1664-2295}, abstract = {[This retracts the article DOI: 10.3389/fneur.2024.1393261.].}, } @article {pmid41778604, year = {2026}, author = {Ahn, GJ and Cha, KC and Lee, J and Son, YJ and Roh, YI and Jung, WJ and Lee, Y and Im, HY and Hwang, SO}, title = {Comparison of the Hemodynamic Effects of Epinephrine on Blood Pressure Augmentation at 1-, 3-, and 5-Minute Dosing Intervals.}, journal = {Journal of the American Heart Association}, volume = {15}, number = {6}, pages = {e046743}, pmid = {41778604}, issn = {2047-9980}, mesh = {Animals ; *Epinephrine/administration & dosage ; *Blood Pressure/drug effects ; Time Factors ; *Ventricular Fibrillation/physiopathology/therapy/complications ; *Heart Arrest/physiopathology/therapy/etiology ; Disease Models, Animal ; Drug Administration Schedule ; Swine ; *Hemodynamics/drug effects ; Female ; *Vasoconstrictor Agents/administration & dosage ; Coronary Circulation/drug effects ; *Advanced Cardiac Life Support/methods ; *Cardiopulmonary Resuscitation/methods ; }, abstract = {BACKGROUND: Although current cardiopulmonary resuscitation guidelines recommend administering epinephrine at 3- to 5-minute intervals during advanced life support (ALS), scientific evidence for the optimal dosing interval for enhancing hemodynamic parameters remains limited. Therefore, we compared the hemodynamic effects of 1-, 3-, and 5-minute epinephrine dosing intervals on blood pressure augmentation in a porcine ventricular fibrillation cardiac arrest model.

METHODS: Forty-two pigs were randomly assigned to 1-, 3-, and 5-minute epinephrine dosing-interval groups. After ventricular fibrillation induction and a 2-minute downtime, basic life support was initiated with a 30:2 compression-to-ventilation ratio for 8 minutes, followed by 30 minutes of ALS, including asynchronous ventilation at a rate of a single ventilation every 6 seconds, with oxygen delivered at 15 L/min. Epinephrine (0.02 mg/kg) was administered at predetermined intervals of 1, 3, or 5 minutes. We compared the pressure-time integrals for mean blood pressure, coronary perfusion pressure, and diastolic blood pressure among the groups over the 30-minute ALS period.

RESULTS: The mean blood pressure (P<0.001), coronary perfusion pressure (P=0.001), and diastolic blood pressure pressure-time integrals (P=0.005) were significantly higher in the 1-minute group than in the 3- and 5-minute groups. Crucially, mean blood pressure and coronary perfusion pressure pressure-time integrals remained positive in the 1-minute group but became negative in the 3- and 5-minute groups during ALS. The diastolic blood pressure pressure-time integral also remained positive for a longer duration in the 1-minute group.

CONCLUSIONS: A 1-minute epinephrine dosing interval may be significantly more effective in augmenting blood pressure and critical hemodynamic parameters during ALS than are the currently recommended 3- or 5-minute intervals.}, } @article {pmid41778709, year = {2026}, author = {La Cognata, V and Guarnaccia, M and Morello, G and Gentile, G and Cavallaro, S}, title = {Unlocking amyotrophic lateral sclerosis diagnosis: How artificial intelligence is transforming early prediction.}, journal = {Neural regeneration research}, volume = {21}, number = {11}, pages = {5207-5208}, doi = {10.4103/NRR.NRR-D-25-01318}, pmid = {41778709}, issn = {1673-5374}, } @article {pmid41778725, year = {2026}, author = {Rizvi, FAS and Jimoh, Y and Allouh, MZ and Rahmon, D and Chaudhry, GR}, title = {Mesenchymal stem cell therapies for neurodegenerative diseases: Advancements, challenges, and opportunities.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01147}, pmid = {41778725}, issn = {1673-5374}, abstract = {Neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, retinal degenerative diseases, Alzheimer's disease, and Parkinson's disease, continue to pose a significant clinical challenge due to the progressive loss of neural tissue structure and function. Stem cell-based therapies are gaining attention for the treatment of neurodegenerative diseases. Mesenchymal stem cells, particularly those derived from perinatal tissues, exhibit remarkable plasticity, along with immunomodulatory, neurotrophic, and regenerative capabilities. Mesenchymal stem cells primarily influence their environment through paracrine signaling and can also differentiate into neural lineages, aiding in neuronal repair. Tissue-specific progenitor cells, such as neural stem cells and retinal progenitor cells, offer greater therapeutic precision. This review examines advancements in mesenchymal stem cell-based therapies for neurodegenerative diseases, discusses relevant clinical trials, and highlights the challenges, while proposing that personalized regenerative treatments utilizing lineage-restricted progenitors may improve patient outcomes in these complex disorders.}, } @article {pmid41781371, year = {2026}, author = {Zhang, L and Huang, Y and Huang, W and Huang, Q and Lin, Y and Gu, J}, title = {TDP-43 phosphorylation: Exploring kinases, phosphatases, and therapeutic potential in neurodegeneration.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {4}, pages = {1533-1546}, doi = {10.1177/13872877261424284}, pmid = {41781371}, issn = {1875-8908}, mesh = {Humans ; Phosphorylation/physiology ; *DNA-Binding Proteins/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; *Protein Kinases/metabolism ; *Phosphoric Monoester Hydrolases/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a multifunctional DNA/RNA-binding protein whose abnormal phosphorylation and aggregation are central to the pathogenesis of several neurodegenerative diseases. TDP-43 proteinopathy, characterized by hyperphosphorylation and cytoplasmic accumulation, is a defining pathological feature of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and is frequently observed in Alzheimer's disease. The phosphorylation state of TDP-43 is dynamically regulated by a network of protein kinases-including CK1, GSK3β, CDC7, and PKA-and counterbalanced by phosphatases such as PP2A and PP1; however, the precise molecular mechanisms governing this equilibrium in disease remain incompletely understood. Notably, phosphorylated TDP-43 acquires prion-like properties, enabling self-templated aggregation and cell-to-cell propagation, which amplifies pathology and drives disease progression. These insights have catalyzed the development of therapeutic strategies aimed at modulating TDP-43 phosphorylation, with kinase inhibitors and phosphatase enhancers emerging as promising candidates for targeting TDP-43 proteinopathies. This review integrates current knowledge on the regulatory networks controlling TDP-43 phosphorylation, examines its role in prion-like spread, and evaluates emerging therapeutic approaches aimed at mitigating TDP-43-mediated neurodegeneration.}, } @article {pmid41781384, year = {2026}, author = {Gunn, AP and Hilton, JBW and Mukherjee, S and Liddell, JR and Mercer, SW and McLean, CA and Masters, CL and Crouch, PJ and Roberts, BR}, title = {Decreased metallothionein-3 expression in the human spinal cord is a common feature of amyotrophic lateral sclerosis and multiple sclerosis.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41781384}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Multiple Sclerosis/metabolism/pathology ; *Spinal Cord/metabolism/pathology ; *Metallothionein 3/metabolism ; Copper/metabolism ; Female ; Male ; Middle Aged ; Aged ; Adult ; *Metallothionein/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are devastating adult-onset neurological diseases with distinct pathological manifestations. Although growing evidence implicates copper dysregulation in both diseases, our understanding of this connection remains incomplete. In this study, we investigated metallothionein-3 (MT3), which is a key regulator of copper metabolism in the central nervous system (CNS), and its relationship to copper in the ALS and MS spinal cord. Using combined quantitative mass spectrometry approaches and immunohistochemical observations, we found a significant decrease in ALS and MS spinal cord MT3 levels compared to controls. This was correlated with levels of copper and MT3-copper binding, highlighting a strong relationship between copper and MT3 levels. These findings demonstrate decreased MT3 expression alongside copper as a common feature of ALS and MS supporting previously reported evidence for copper dysregulation in these diseases.}, } @article {pmid41781412, year = {2026}, author = {Mortimer, AJ and Sander, CF and Parmar, AR and Williams, AJ and Azzouz, M and Hautbergue, GM and Shaw, PJ and Ferraiuolo, L and Mead, RJ}, title = {Comparison of AAV9-driven motor neuron transduction following different CNS-directed delivery methods in mice.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41781412}, issn = {2045-2322}, support = {2023/MNDS/6501/791MEA//MND Scotland/ ; 2023/MNDS/6501/791MEA/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Animals ; *Motor Neurons/metabolism/virology ; *Dependovirus/genetics ; *Transduction, Genetic/methods ; Mice ; *Genetic Vectors/genetics/administration & dosage ; Spinal Cord/metabolism ; Genetic Therapy/methods ; *Gene Transfer Techniques ; Green Fluorescent Proteins/genetics/metabolism ; Astrocytes/metabolism ; Central Nervous System/metabolism ; }, abstract = {Gene therapies are promising for diseases previously considered incurable. Adeno-associated virus serotype 9 (AAV9) demonstrates remarkable tropism for motor neurons (MNs) and represents an exciting candidate to target genetic causes of motor neuron diseases like amyotrophic lateral sclerosis (ALS). However, systemic delivery risks immunogenicity and off-target effects, therefore localised delivery to the CNS is advantageous. We assessed MN transduction in wild-type post-natal mice using AAV9-controlled, cytomegalovirus-promoter driven, enhanced GFP expression. Intra-cisterna magna (ICM) and intra-cerebroventricular (ICV) methods were compared. Four weeks post-delivery, GFP positivity in MN and astrocytes were quantified via immunohistochemical approaches and viral genome copy number determined by qPCR. All delivery methods achieved high MN transduction in lumbar spinal cord (> 68%). Unilateral ICV delivery provided the highest and most consistent levels (89 ± 3%), and minimal peripheral viral copies. ICV delivery resulted in higher astrocytic transduction, most notably in the cortex. Brainstem MN transduction was high with all methods (> 55%). We failed to find evidence of neuronal transduction in motor cortex. Viral genome copies trended higher in spinal cord and brainstem with ICV approaches, however further work is required to understand how bilateral repeated dose delivery leads to more profound increases. Whilst several routes of administration into cerebrospinal fluid exist, direct comparisons for targeting MNs in vivo remain limited. Overall, all methods of CNS-directed delivery result in high levels of motor neuron transduction in the lumbar spinal cord and brainstem, but not in motor cortex. Unilateral ICV appears to provide the best balance between consistent, high levels of transduction and low off-target effects. However, ICM might be the better option if seeking to avoid astrocytic transduction.}, } @article {pmid41782322, year = {2026}, author = {Kaya, Y and Kırboğa, KK}, title = {Brain Organoids as Emerging Platforms for Modeling Neurodegenerative Diseases: Progress, Challenges, and Future Directions.}, journal = {Journal of neurochemistry}, volume = {170}, number = {3}, pages = {e70395}, doi = {10.1111/jnc.70395}, pmid = {41782322}, issn = {1471-4159}, mesh = {Humans ; *Organoids/pathology/metabolism/drug effects ; *Neurodegenerative Diseases/pathology/metabolism/drug therapy ; *Brain/pathology/metabolism/drug effects ; Animals ; Induced Pluripotent Stem Cells/pathology/metabolism ; Neurons/pathology/metabolism ; }, abstract = {Neurodegenerative diseases are a group of disorders (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) characterized by loss of function and death of neurons in different parts of the nervous system. These pathologies constitute a global burden, especially for aging populations. This circumstance leads to an increasing demand for understanding the fundamental mechanisms and development of therapeutic strategies. Conventional models, including two-dimensional cell culture and animal models, postmortem brain tissue provide an overview about neurodegenerative disorders but do not completely recapitulate cellular and molecular mechanisms of the human brain. Although three-dimensional (3D) brain organoids exhibit similar properties with physiological and pathological conditions of human brain, including interaction of neuronal, glial cells and self-organizing structure, protein aggregation, neuroinflammation, and neuronal degeneration. The integration of reprogrammed human induced pluripotent stem cells (iPSCs) with 3D brain organoid systems provides a clinical platform as a bridge between bench to bedside. Brain organoids have been used to elucidate novel insights into the molecular and genetic mechanisms underlying neurodegenerative diseases. Furthermore, brain organoids serve as a tool for in vitro disease modeling, drug screening and emergence of new treatments. Despite these clinical benefits, there are various limitations such as incomplete tissue maturation, lack of vascularization and incomplete cellular diversity in this 3D culture system. This review describes in detail the advantages and disadvantages of brain organoids usage in modeling neurodegenerative diseases from a contemporary perspective.}, } @article {pmid41783158, year = {2025}, author = {Uemura, K and Hiro, S and Attachaipanich, S and Du, R and Yusof, NISM and Kinoshita, M and Hikosaka, M and Ohtsuki, G}, title = {Glioinflammation: disease-associated microglia and astrocytes in psychiatric disorders, neurodegeneration, and senescence.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1669272}, pmid = {41783158}, issn = {1662-5102}, abstract = {In this review, we synthesize recent conceptual and experimental advances in neuroscience, highlighting selected studies that delineate the roles of reactive microglia and astrocytes in the contexts of developmental inflammatory stress, neurodegenerative diseases, and cellular senescence. Since the characterization of disease-associated glial phenotypes in 2017, building on earlier pioneering discoveries, we focus here on disease-associated microglia (DAM) and disease-associated astrocyte (DAA) to reassess their contributions to glio-inflammation. It is now recognized that the stress-induced glial states are far from uniform; however, the ontogeny, molecular determinants, and functional consequences of this heterogeneity remain incompletely understood, particularly in psychiatric disorders, Alzheimer's disease, and amyotrophic lateral sclerosis. Accordingly, we compare the glial heterogeneity and its underlying mechanisms across translational mouse models and human neuropathology, considering their evolutionary and physiological contexts. While this review does not aim to be exhaustive, we propose an integrative framework that redefines glial stress responses through the combined lenses of inflammation, transcriptomics, mitochondrial dynamics, lipid metabolism, epigenomic regulation, and cellular senescence. Finally, we outline emerging frontiers for AI-enabled multi-omic physiological and pathological approaches, emphasizing their potential to illuminate glial state transitions and accelerate therapeutic discovery in the near future.}, } @article {pmid41783572, year = {2026}, author = {Liu, W and Xue, Y and Cao, C and Yang, L and Zhang, L}, title = {Copper Homeostasis and Cuproptosis in Neurological Disorders.}, journal = {Drug design, development and therapy}, volume = {20}, number = {}, pages = {580005}, pmid = {41783572}, issn = {1177-8881}, mesh = {Humans ; *Cuproptosis ; *Homeostasis ; *Copper/metabolism ; *Nervous System Diseases/metabolism/drug therapy ; Animals ; }, abstract = {Neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose a serious global public health threat, with complex etiologies involving genetic, environmental, and metabolic factors. Current data indicate that the prevalence of these disorders is rapidly increasing with the aging population, resulting in a growing economic and healthcare burden worldwide. In recent years, the imbalance of copper homeostasis has been increasingly implicated in the pathogenesis of neurological diseases. Copper overload can aggravate neuronal injury by inducing oxidative stress (OS), mitochondrial dysfunction, and protein misfolding, while copper deficiency disrupts the function of copper-dependent enzymes and leads to metabolic abnormalities. The mechanism of cuproptosis, proposed in 2022, describes a novel form of programmed cell death characterized by lipoylated protein aggregation and the loss of Fe-S cluster proteins, offering new insights into copper-related diseases. Multiple studies have demonstrated the crucial role of copper homeostasis and cuproptosis in the onset, progression, and treatment of neurological diseases. This narrative review summarizes the molecular mechanisms involved in copper homeostasis regulation and, on that basis, discusses the role of copper metabolism abnormalities in AD, PD, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Wilson's disease (WD), Menkes disease (MD), and stroke. Additionally, we highlight the mechanisms of existing copper-regulating drugs and their therapeutic potential in neurological disorders, while pointing out the limitations of current drug development.}, } @article {pmid41784486, year = {2026}, author = {Calix Kannaley, K}, title = {Exploring the use of narrative-based approaches in individuals with amyotrophic lateral sclerosis: A narrative review.}, journal = {Palliative & supportive care}, volume = {24}, number = {}, pages = {e81}, pmid = {41784486}, issn = {1478-9523}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/therapy ; *Narration ; Adaptation, Psychological ; *Narrative Therapy/methods ; }, abstract = {OBJECTIVES: Narrative-based approaches have been utilized in medicine to better understand the illness experiences of individuals living with chronic conditions. In particular, people with amyotrophic lateral sclerosis (pALS) may benefit from use of narrative-based approaches, given the potential impact of progressive decline on identity of self. This review explores the use of narrative-based approaches in studies involving pALS to provide further insight to the experiences and psychosocial needs of this population.

METHODS: A search was conducted utilizing EMBASE, CINAHL, PsycInfo, and Google Scholar with several terms related to amyotrophic lateral sclerosis (ALS) and narrative-based approaches. Studies were included if they were written in English, incorporated methods that promoted the production of narratives, and reported data that could be clearly isolated to pALS.

RESULTS: The search revealed a total of 154 articles for title and abstract screening. Fifty-two articles were selected for full-text review. Thirty-two articles met the criteria for data extraction. Four descriptive categories emerged upon examination of the narrative-based approaches implemented across the studies: psychosocial intervention, illness experience, intervention targeting specific needs, and secondary analysis of data. Some of the common themes identified across studies included: loss of physical and communicative function, adaptation to life changes, shifts in identity, and tension with the healthcare system.

SIGNIFICANCE OF RESULTS: Despite the communication challenges that often coincide with disease progression, narrative-based approaches can be utilized in pALS. These approaches should be implemented to gain insight on the disease experiences of pALS, providing opportunity for patient-centered interventions to address the psychosocial needs of this population.}, } @article {pmid41785390, year = {2026}, author = {Nomizo, S and Komatsu, J and Shima, A and Muramatsu, D and Matsubara, K and Nozaki, I and Noguchi-Shinohara, M and Nishiyama, A and Suzuki, N and Aoki, M and Ono, K}, title = {Gadolinium enhancement of the cauda equina in a case of familial ALS with p.S135G SOD1 mutation.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {708-710}, doi = {10.1080/21678421.2026.2638591}, pmid = {41785390}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/pathology ; *Superoxide Dismutase-1/genetics ; *Cauda Equina/diagnostic imaging/pathology ; *Gadolinium ; *Mutation/genetics ; Magnetic Resonance Imaging ; Male ; *Superoxide Dismutase/genetics ; Middle Aged ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration. Gadolinium enhancement of the cauda equina is typically associated with inflammatory diseases. We report a case of familial ALS with a Cu/Zn superoxide dismutase (SOD1) gene mutation showing marked gadolinium enhancement of the lumbar nerve roots. To date, only a few cases of ALS with gadolinium enhancement of the nerve roots have been reported. To our knowledge, this is the first reported case of ALS with an p.S135G SOD1 mutation exhibiting gadolinium enhancement in the cauda equina.}, } @article {pmid41785396, year = {2026}, author = {Scirocco, E and Pogemiller Bulat, A and Carey, JR and Giacomelli, E and Boyce, D and Paganoni, S and Berry, JD}, title = {Bridging the gap: understanding participation barriers in ALS clinical trials through on-the-ground insights.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {696-703}, doi = {10.1080/21678421.2026.2640126}, pmid = {41785396}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; Female ; Male ; *Patient Participation/psychology ; *Clinical Trials as Topic/psychology ; Middle Aged ; Caregivers/psychology ; Aged ; Health Personnel/psychology ; *Health Knowledge, Attitudes, Practice ; Adult ; }, abstract = {OBJECTIVE: This study explores the experiences and perceptions of people living with amyotrophic lateral sclerosis (pALS), their caregivers, and healthcare providers regarding participation in clinical trials. The study tested the hypothesis, based on existing literature, that geographic distance from multidisciplinary ALS clinics is the primary barrier to awareness and participation in clinical trials.

METHODS: A road trip was conducted to engage individuals, particularly those residing more than 90 miles from specialized clinics. Qualitative and semi-quantitative methods were used to collect data from in-person interviews conducted with pALS, their caregivers, and healthcare providers in urban (high population density), suburban (residential areas on the outskirts of urban centers), and rural (sparsely populated) settings across the East Coast of the US. Thematic analysis was employed to interpret the data.

RESULTS: Based on the interviews, a trusted, supportive, and knowledgeable medical team knowledgeable about ALS research emerged as a critical factor influencing patient participation decisions. Geographic distance alone did not meaningfully impact research interest or awareness. Healthcare providers faced challenges, including time constraints and limited access to updated information about studies, which hindered their ability to promote participation. Healthcare providers cited informal partnerships with advocacy organizations and research centers as crucial for facilitating research participation.

CONCLUSIONS: Tailored communication strategies that leverage established relationships between pALS and their trusted healthcare providers may enhance research participation. As decentralized research models evolve, improving trial education and access and fostering knowledge and trust could significantly boost enrollment in ALS clinical research.}, } @article {pmid41785403, year = {2026}, author = {Oh, J and Oh, SI}, title = {Subjective sleep quality in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {553-564}, doi = {10.1080/21678421.2026.2614597}, pmid = {41785403}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology/physiopathology ; *Sleep Quality ; *Sleep Wake Disorders/etiology/epidemiology ; }, abstract = {OBJECTIVE: Sleep disturbances are common and clinically significant non-motor symptoms in amyotrophic lateral sclerosis (ALS), arising from motor, respiratory, and psychological factors. This study aimed to synthesize available evidence on subjective sleep quality in ALS, estimate the prevalence of poor sleep quality, examine associated factors, and compare patients with healthy controls.

METHODS: : PubMed, EMBASE, Cochrane Central, and CINAHL were searched for studies published between January 2000 and August 2025 that assessed subjective sleep quality in ALS using validated patient-reported outcome measures, such as Pittsburgh Sleep Quality Index (PSQI). Pooled analyses were performed using random-effects models. Meta-regression was applied to explore associations with demographic and clinical variables.

RESULTS: : A total of 23 studies comprising 1899 ALS patients were included, of which 20 were eligible for meta-analysis. All included studies assessed subjective sleep quality using the PSQI, and the pooled mean PSQI score was 6.94, exceeding the clinical cutoff for poor sleep quality. The pooled prevalence of poor sleepers was 56.7%. Nine studies including healthy controls showed significantly higher PSQI scores in ALS patients compared with controls (mean difference 2.69). Several factors, including functional status, depression, anxiety, fatigue, daytime sleepiness, constipation, and cognitive impairment, were associated with poorer sleep, however, meta-regression did not identify significant associations with age, sex, disease duration, or ALSFRS-R.

CONCLUSIONS: : Sleep disturbances are highly prevalent and clinically significant in ALS. These findings highlight the need for systematic screening and proactive management across all stages of the disease. Future research should evaluate a wider range of interventions to improve sleep quality and patient outcomes.}, } @article {pmid41787388, year = {2026}, author = {Alhathli, E and Cooper-Knock, J and Girach, ZU and Julian, TH and Bauer, C and Timmons, HO and Ward, BD and Walker, H and Azzouz, M and Elrayess, MA and Al-Khelaifi, F and Yousri, NA and Gul, A and Kelsall, A and Moll, T and Harvey, C and Gornall, S and Wong, K and Allen, SP and Strange, A and Shaw, PJ}, title = {Hypothesis-free evaluation of circulating metabolome provides cell-specific insights regarding the role of energy substrate availability in amyotrophic lateral sclerosis.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {41787388}, issn = {1741-7015}, support = {MR/Z504105/1//UK Research and Innovation/ ; DOD/14/43//My Name'5 Doddie Foundation/ ; NF-SI-0617-10077//National Institute for Health and Care Research/ ; NIHR 203321//NIHR Sheffield Biomedical Research Centre/ ; 894-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; 956-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; SBF005\1064/AMS_/Academy of Medical Sciences/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/blood/genetics/metabolism ; Humans ; *Metabolome ; Female ; Male ; Animals ; *Energy Metabolism ; Mice ; Mendelian Randomization Analysis ; Neurons/metabolism ; Astrocytes/metabolism ; C9orf72 Protein/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with limited therapeutic options. The circulating metabolome comprises small molecules present in plasma/serum which are the intermediates and end-products of cellular metabolism, and is linked to ALS pathogenesis.

METHODS: We conducted hypothesis-free two-sample Mendelian randomisation (MR) analysis of the concentration of 575 plasma/serum metabolites, to determine which are causally linked to risk of ALS. Significant metabolites were validated in an independent GWAS of plasma/serum metabolite concentrations and evaluated for sex-specific effects. Correlations between directly measured patient biofluid metabolite concentrations and ALS risk/severity were examined in 94 ALS patients and 40 controls. We experimentally assessed metabolic function in a murine neurons and human astrocytes carrying an ALS-associated G4C2-repeat expansion within C9orf72.

RESULTS: MR causally associated five metabolites with ALS risk after multiple-testing correction. Higher serum concentration of glycoprotein acetyls (P = 9.7e - 9, β = 0.21) and the peptide DSGEGDFXAEGGGVR (P = 8.0e - 6, β = 0.22) was associated with increased ALS risk, whereas higher plasma concentration of phenylalanylserine, isobutyrylcarnitine, and acetylcarnitine was protective (P < 5e - 5, β = - 0.29 to - 0.72). DSGEGDFXAEGGGVR has been linked to glucose metabolism but we have used genetic fine-mapping to link DSGEGDFXAEGGGVR, neuronal glucose uptake through GLUT3, and ALS risk. Direct measurement of metabolite concentrations in patient biofluids revealed elevated acetylcarnitine levels in patients with ALS, which were associated with delayed symptom onset (Cox regression, P = 0.02, HR = 0.4). Similarly, lactate is elevated in ALS patient CSF (ANOVA, P = 1.3e - 3) and in patients with longer survival time (Cox regression, P = 0.03, HR = 0.3). Plasma fructose is elevated in ALS patients with shorter survival time (Cox regression, P = 0.02, HR = 1.1). In vitro, neurons and astrocytes carrying an ALS-associated G4C2-repeat expansion within C9orf72 demonstrated reduced metabolic flexibility.

CONCLUSIONS: We provide evidence that impaired energy substrate availability contributes to ALS risk and severity. CNS cell types differ in their use of energy substrates and therefore we postulate the relative importance of different cell types for different stages of disease. Our findings support further investigation of metabolic interventions to treat or prevent ALS.}, } @article {pmid41788548, year = {2026}, author = {Zheng, Y and Zhou, W and Chang, H and Zheng, K}, title = {Brain organoids as precision models for neurodegenerative diseases: from disease modeling to drug discovery.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1764964}, pmid = {41788548}, issn = {1662-4548}, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) have become major global causes of disability and mortality. Their complex pathogenic mechanisms remain incompletely understood, and effective disease-modifying therapies are still lacking. Traditional animal models and two-dimensional (2D) cell culture systems exhibit notable limitations in structural complexity, human relevance, and translational validity, making it difficult to faithfully recapitulate human-specific neuropathology. In recent years, brain organoid technology derived from induced pluripotent stem cells (iPSCs) has advanced rapidly, enabling the self-organization of diverse neuronal and glial cell types within a three-dimensional (3D) architecture that partially mimics human brain development and disease-related pathological events. When integrated with CRISPR-Cas9-based genome editing and multi-omics profiling, organoids support causal mechanism studies, target validation, and individualized drug-response prediction, highlighting their growing value in early-stage drug discovery. Despite current challenges-including insufficient maturation, lack of vascularization and immune components, and batch variability-the continuous progress in bioengineering, microfluidic systems, and artificial intelligence (AI)-driven multimodal data analysis is steadily expanding the translational potential of organoids as human-relevant preclinical models. Overall, brain organoids provide an essential foundation for constructing physiologically relevant and predictive research platforms for neurodegenerative diseases, offering new opportunities for therapeutic development and precision medicine.}, } @article {pmid41789116, year = {2026}, author = {Bublitz, SK and Lorenzl, S and Klima, A and Schmidt, S and Schäffer, B and Gleich, S}, title = {Mapping end-of-life care for patients with neurological conditions in German hospices: a point prevalence survey.}, journal = {BMJ neurology open}, volume = {8}, number = {1}, pages = {e001404}, pmid = {41789116}, issn = {2632-6140}, abstract = {BACKGROUND: Access to palliative care for patients with neurological diseases remains limited. Contributing factors include difficulties in predicting disease trajectories, resource constraints in long-term care and challenges in identifying the end-of-life phase-often compounded by communication and cognitive impairments.

METHODS: We conducted a national point-prevalence survey among German inpatient hospices using an online questionnaire.

RESULTS: The response rate was 44%, with 83% of participating hospices providing complete datasets. Most patients in hospices suffered from oncological diseases (n=785; 77.3%), including primary brain tumours (n=102; 10.0%). At the time of the survey, neurological diagnoses accounted for approximately 5% of hospice admissions. While 51% of hospices reported having access to neurological consultation, this was usually informal or ad hoc. 19% reported no current access to a neurologist but considered such collaboration desirable.

CONCLUSIONS: This survey provides an overview of the current representation of patients with neurological conditions in German inpatient hospices. The findings reveal limited structured collaboration between neurology and palliative care, alongside structural and societal barriers that complicate timely hospice referral and end-of-life planning. Strengthening interdisciplinary cooperation, enhancing neurologists' engagement in palliative care and expanding specialised outpatient support for patients and families are essential to improving equitable and needs-based end-of-life care for individuals with neurological conditions.}, } @article {pmid41789732, year = {2026}, author = {Scarpa, E and D'Amora, U and De Cesare, N and Bonadies, I and Dubbioso, R and Nolano, M and Dardano, P and De Stefano, L and Fasolino, A and Zeppetelli, S and Silvestri, A and Zanardi, C and Milella, E and Fasolino, I}, title = {3D Artificial Skin Model As a Novel Strategy for the Detection of Pyroptosis-Cascade Activation in Amyotrophic Lateral Sclerosis.}, journal = {ACS applied materials & interfaces}, volume = {18}, number = {10}, pages = {14603-14616}, pmid = {41789732}, issn = {1944-8252}, mesh = {Humans ; Biopsy ; *Skin, Artificial ; *Skin/metabolism/pathology ; *Pyroptosis ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Polyesters/chemistry ; Printing, Three-Dimensional ; Hyaluronic Acid/chemistry ; Biomarkers ; Cell Proliferation ; Biocompatible Materials/chemistry ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe adult-onset neurodegenerative disease with limited treatment approaches. Evidence has shown that degeneration of cutaneous nerves may reflect neurodegenerative processes occurring within the central nervous system. Although skin biopsy is widely adopted in clinical practice, the procedure is invasive and requires multiple patients' tissue removals. Therefore, we developed a 3D innervated skin model by combining 3D printing of methacrylated hyaluronic acid as an innovative tool for better reproducing the dermis and epidermis and electrospinning of polylactic acid for mimicking skin innervation. Later, 3D artificial skin was colonized with a preneuronal cell line (SH-SY5Y) and fibroblasts isolated from skin biopsy of ALS patients at different disease stages. 3D skin possesses a porosity suitable for cell colonization and a high stability. Importantly, biological results reveal an increase of TAR DNA-binding protein 43 aggregates, NOD-like receptor pyrin domain containing protein 3, interleukin (IL)-18, IL-6, and nitrites in 3D skin of ALS patients, thus indicating pyroptosis activation linked to neurodegeneration. This physiologically relevant 3D skin model reduces the need for repeated biopsies, allows standardized experimental conditions, and supports biomarker research and preclinical drug testing in ALS.}, } @article {pmid41789796, year = {2026}, author = {Creer, S and Griffiths, AW and Hobson, E and Davies, S and Massey, C and Stokes, L and Waters-Harvey, B and Bamber, R and Hastings, S and Bedford, J and Gould, RL and McDermott, C and Mayberry, E}, title = {"What about me? I'm supposed to be … superhuman?": exploring staff perspectives on how to deliver high quality psychological care for people living with amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/17582024.2026.2637420}, pmid = {41789796}, issn = {1758-2032}, abstract = {OBJECTIVES: To explore healthcare professionals' experiences of providing informal psychological care in Amyotrophic Lateral Sclerosis (ALS) services.

METHODS: A qualitative focus group and interview study with 28 UK-based, ALS healthcare professionals. Data was analyzed using reflexive thematic analysis.

RESULTS: Healthcare professionals reported psychological distress in their roles arising from the intrinsic nature of ALS, alongside system factors and their needs as staff members. Participants identified critical needs for themselves to improve psychological care including: psychological skills training, clear role definition, understanding of specialist psychology and structured staff support. Participants identified patient needs as: support for informal carers, access to specialist psychology, clear and inclusive referral pathways, and having person-centered, tiered approaches to care delivery.

CONCLUSIONS: The psychological impact of ALS extends beyond patients and families to healthcare professionals, creating systemic challenges in care delivery. Effective psychological care in ALS requires a comprehensive approach that addresses not only the needs of individual patients but also staff and systemic issues. A distress loop exists where inadequate psychological services affect both staff wellbeing and care quality for patients and their families. Without addressing patient, staff, and service-level issues, people living with ALS and healthcare professionals will continue to experience preventable psychological distress.}, } @article {pmid41789885, year = {2026}, author = {Coronas, LE and Timr, S and Sterpone, F and Franzese, G}, title = {Unveiling the entropic role of hydration water in SOD1 partitioning within FUS condensate.}, journal = {The Journal of chemical physics}, volume = {164}, number = {9}, pages = {}, doi = {10.1063/5.0300133}, pmid = {41789885}, issn = {1089-7690}, mesh = {*Water/chemistry ; *Superoxide Dismutase-1/chemistry/metabolism ; *Entropy ; *RNA-Binding Protein FUS/chemistry/metabolism ; Animals ; Phase Separation ; Hydrogen Bonding ; Serum Albumin, Bovine/chemistry ; *Biomolecular Condensates/chemistry ; Humans ; Cattle ; }, abstract = {Biological processes such as the sequestration of superoxide dismutase 1 (SOD1) into biomolecular condensates, including fused in sarcoma and stress granules, are vital for understanding disease mechanisms, including amyotrophic lateral sclerosis. Moreover, protein-crowder interactions within these condensates are recognized as fundamental to cellular phase separation and disease-related processes. However, the specific role of the hydration environment in governing SOD1's behavior and transition dynamics within these condensates remains poorly understood, limiting our ability to accurately model these critical biological systems. Therefore, we incorporate explicit water into an implicit solvent model (OPEP) to investigate how water influences SOD1's behavior, residence times, and transition rates among associative states. We employ the advanced CVF (Coronas, Vilanova, Franzese) water model, which accurately captures hydrogen-bond networks at the molecular level. While the OPEP model indicates that bovine serum albumin (BSA) crowders reduce SOD1's partition coefficient (PC) primarily through non-specific interactions, our explicit-water approach points to hydration entropy in BSA as a key contributor to the observed PC reduction. This result offers a new perspective on the system's free-energy landscape, complementing those obtained from OPEP alone. Our research supports the notion that explicitly modeling water can enhance our understanding of protein-crowder interactions and their biological implications, further emphasizing the potential role of water in cellular phase separation and disease-related processes.}, } @article {pmid41791136, year = {2026}, author = {Gültekin, M and İlikhan, BA and Baydemir, R and Değirmenci, Y and Başak, AN}, title = {Pathogenic VCP (p.Arg453Trp) variant in three siblings with frontotemporal dementia-amyotrophic lateral sclerosis spectrum: A Turkish family.}, journal = {Clinical neurology and neurosurgery}, volume = {265}, number = {}, pages = {109381}, doi = {10.1016/j.clineuro.2026.109381}, pmid = {41791136}, issn = {1872-6968}, } @article {pmid41791354, year = {2026}, author = {Gan, Y and Ju, R and Peng, Y and Xiao, S and Qiu, R and Wang, S and Zhang, Y and Guo, L and Gu, W}, title = {A multi-platform analytical strategy for Atractylodes lancea authentication: Fusion of stable isotope, elemental, chromatographic, and spectroscopic profiles.}, journal = {Talanta}, volume = {305}, number = {}, pages = {129603}, doi = {10.1016/j.talanta.2026.129603}, pmid = {41791354}, issn = {1873-3573}, mesh = {*Atractylodes/chemistry ; *Trace Elements/analysis ; Machine Learning ; Volatile Organic Compounds/analysis ; Plants, Medicinal/chemistry ; }, abstract = {BACKGROUND & AIMS: The quality and market value of the medicinal herb Atractylodes lancea (AL) are critically dependent on its variety, geographical origin, and production mode. To combat adulteration and ensure efficacy, we developed a novel multi-platform analytical strategy integrated with machine learning to establish a robust traceability model for variety discrimination, geographical origin determination, and production mode identification of AL and identify the key chemical indicators responsible for its authentication.

RESULTS: Significant differences were found in trace element concentrations and isotopic ratios among samples. AL's main flavors were spicy, sweet, and fruity, with terpenoids as key aroma contributors. OPLS-DA identified key indicators for tracing AL's variety, including eleven trace elements (e.g., V, Al) and eight volatile compounds (e.g., β-Sesquiphellandrene, 2-Pinen-10-ol). For tracing AL origins, ten trace elements (e.g., Sr, Cr), two stable isotopes (δ[13]C, δ[15]N), five flavor components (e.g., 2-ethyl-3,6-dimethylpyrazine, 2-Pentadecanone), and twenty-six volatile components (e.g., γ-Gurjunene, β-Bisabolene) were identified. Furthermore, three trace elements (Mg, Li and Pb), two isotopes (δ[13]C and δ[15]N), two flavor components (α-Pinene and n-Nonylcyclohexane), and two volatile components (α-Copaene and α-Curcumene) were identified as key indicators for tracing AL's production modes. Finally, among the nine machine learning algorithms evaluated, LightGBM demonstrated superior performance, achieving a traceability accuracy of 95.28 ± 3.01%.

CONCLUSION: The multi-platform data fusion strategy presents a thorough and dependable approach to quality control for Atractylodes lancea. This method establishes a precise, efficient, and adaptable framework, demonstrating substantial potential for application to other high-value botanicals and complex natural products.}, } @article {pmid41791528, year = {2026}, author = {Tolkachjov, SN}, title = {Response to Li et al's "Comment on 'Gene expression profiling in dermatology, part 2: Clinical applications'-toward safe, patient-centered implementation".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {1}, pages = {e65-e66}, doi = {10.1016/j.jaad.2026.02.108}, pmid = {41791528}, issn = {1097-6787}, } @article {pmid41791963, year = {2026}, author = {Mendon, A and Jain, S and Mishra, N and Bagwe Parab, S}, title = {Calprotectin as an immune-dysregulation biomarker in amyotrophic lateral sclerosis: Insights for diagnosis and therapy.}, journal = {Revue neurologique}, volume = {182}, number = {6}, pages = {493-507}, doi = {10.1016/j.neurol.2026.02.148}, pmid = {41791963}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/immunology/therapy/blood ; Biomarkers/blood ; *Leukocyte L1 Antigen Complex/blood/metabolism ; }, abstract = {Motor neuron degeneration is a defining feature of amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder. Early diagnosis remains challenging due to the absence of reliable and validated biomarkers. Calprotectin, a well-established inflammatory marker in various neuroinflammatory conditions, has paradoxically been found at reduced levels in the blood of ALS patients in a limited number of studies, raising the hypothesis of immune dysregulation rather than classical neuroinflammation. However, these findings are primarily derived from small patient cohorts and have yet to be independently replicated. This review critically assesses the emerging role of calprotectin in ALS by comparing it with other candidate biomarkers, including vascular endothelial growth factor (VEGF), apolipoprotein A1 (ApoA1), interleukin-8 (IL-8), interleukin-7 (IL-7), and interleukin-10 (IL-10). While calprotectin may reflect a distinct immunological profile, its standalone diagnostic value remains unclear. Nonetheless, its integration into a multi-analyte biomarker panel could enhance diagnostic precision and biological insight. The review also explores underlying immunological mechanisms, including receptor interactions (RAGE, TLR4, CD33), cellular mediators (microglia, lymphocytes, monocytes), and therapeutic implications. Future research should prioritize mechanistic investigation of calprotectin modulation in ALS, longitudinal validation in larger cohorts, and integration within multimodal biomarker frameworks. A better understanding of disease-specific immune alterations may contribute to earlier diagnosis, stratified patient monitoring, and targeted therapeutic development.}, } @article {pmid41792723, year = {2026}, author = {Huang, NX and Cai, ZW and Zhuang, SP and Lin, HY and Chen, S and Zou, ZY and Wu, Y and Chen, HJ}, title = {Impairment of brain short association fibers across clinical stages in amyotrophic lateral sclerosis: a new biomarker mirroring disease progression.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {41792723}, issn = {1741-7015}, support = {2024J01625//Natural Science Foundation of Fujian Province/ ; 2024Y9256//Fujian Province Joint Funds for the Innovation of Science and Technology/ ; 2024Y9253//Fujian Province Joint Funds for the Innovation of Science and Technology/ ; 82572160//National Natural Science Foundation of China/ ; 2023CXA009//Fujian Provincial Health Technology Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/physiopathology ; Female ; Male ; Disease Progression ; Middle Aged ; Diffusion Tensor Imaging ; Biomarkers ; *Brain/pathology/diagnostic imaging ; Aged ; Neurites/pathology ; Adult ; Severity of Illness Index ; }, abstract = {BACKGROUND: A quantitative biomarker for clinical staging is essential for amyotrophic lateral sclerosis (ALS) stratification. This study evaluated microstructural impairment in brain short association fibers (SAFs) across ALS stages via neurite orientation dispersion and density imaging (NODDI) and assessed correlations with disease severity.

METHODS: Diffusion-weighted imaging data were collected from 87 ALS patients (categorized into four groups King's stages) and 37 healthy controls. Whole-brain SAF mapping was performed via a spherical deconvolution-driven probabilistic tractography approach. Diffusion tensor imaging (DTI) and NODDI parameters (neurite density index, NDI; orientation dispersion index, ODI; isotropic volume fraction, ISO) were estimated for each SAF.

RESULTS: Seven SAFs connecting the left postcentral-precentral gyrus, left precentral-precentral gyrus, right postcentral-precentral gyrus, right paracentral-posterior cingulate gyrus, left paracentral-posterior cingulate gyrus, left precentral-superior parietal gyrus, and left precentral-superior frontal gyrus exhibited significant NDI differences across the five groups. Additionally, one fiber connecting the left medial orbitofrontal-rostral anterior cingulate gyrus demonstrated an ISO difference [false discovery rate (FDR)-corrected p < 0.05]. Progressive trends of NDI reduction and ISO increase were observed at higher ALS stages. No intergroup differences were found in the ODI or DTI parameters. The NDI values of these seven SAFs were positively correlated with disease severity scores (FDR-corrected p < 0.05). Combining NDI and ISO revealed moderate classification potential for ALS (area under the curve = 0.780).

CONCLUSIONS: Neurite injury in SAFs involving primary motor and extramotor areas worsened alongside clinical staging and motor disability in ALS. NODDI provides quantitative SAF-related biomarkers for assessing ALS disease severity.}, } @article {pmid41792976, year = {2026}, author = {Shah, JS and Oskarsson, B and Zhou, X and Heckman, MG and Sledge, HJ and Virador, G and Parizadeh, D and Middlebrooks, EH}, title = {Expanding the Motor Band Sign in Motor Neuron Disease Using 7T MRI: Visualization of Cortical Layer-Dependent Iron Deposition in the Primary Motor Cortex.}, journal = {Muscle & nerve}, volume = {73}, number = {6}, pages = {996-1004}, doi = {10.1002/mus.70179}, pmid = {41792976}, issn = {1097-4598}, mesh = {Humans ; *Motor Neuron Disease/diagnostic imaging/metabolism ; *Magnetic Resonance Imaging/methods ; *Motor Cortex/diagnostic imaging/metabolism ; Female ; Retrospective Studies ; Male ; Middle Aged ; Aged ; *Iron/metabolism ; Adult ; }, abstract = {INTRODUCTION/AIMS: There are no established biomarkers of upper motor neuron degeneration to aid in the diagnosis of motor neuron disease (MND). This study examines the diagnostic value of the motor band sign as a marker of upper motor neuron degeneration and its relationship to clinical findings in MND.

METHODS: Records of consecutive patients who underwent 7T magnetic resonance imaging (MRI) between October 2021 and April 2025 for evaluation of MND or other neurologic indications were retrospectively reviewed. Clinical variables and plasma neurofilament light chain (pNfL) levels were recorded. An upper motor neuron score (Mayo UMNS) was derived from reflex scores. Blinded MRI review assessed the degree of susceptibility-weighted imaging (SWI) hypointensity in the hand, foot, and bulbar motor cortex regions.

RESULTS: An MBS was observed in 100 of 117 (85.5%) MND patients and in 16 (15.5%) patients with non-MND diagnoses, corresponding to a sensitivity of 85.5% (78.0%-90.7%) and 84.5% (76.2%-90.2%) specificity. The MBS in 78 MND patients (70.9%) preferentially involved the middle and deep cortical layers, giving a trilaminar appearance, while only one non-MND patient had this finding. Mayo UMNS (β = 0.89, p < 0.001), pNfL (β = 0.63, p = 0.033), and age at evaluation (β = 0.68, p = 0.027) were independently associated with the summed SWI score.

DISCUSSION: The 7T MRI MBS is a sensitive and specific marker for MND that complements established clinical evaluation. Using 7T, a trilaminar appearance of the motor cortex, reflecting known histopathological changes, can be visualized and may be specific to MND.}, } @article {pmid41792996, year = {2026}, author = {Magen, I and Kaneb, HM and Masnata, M and Pulimood, N and Emde, A and Genge, A and Hornstein, E}, title = {Cell-free miRNAs are pharmacodynamic biomarkers for enhanced DICER activity by enoxacin in human patients with ALS.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {34}, number = {6}, pages = {3224-3230}, pmid = {41792996}, issn = {1525-0024}, mesh = {Humans ; *Enoxacin/pharmacokinetics/pharmacology/administration & dosage/cerebrospinal fluid/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/blood/metabolism/cerebrospinal fluid ; *MicroRNAs/blood/genetics/cerebrospinal fluid ; *Ribonuclease III/metabolism/genetics ; Female ; Biomarkers/cerebrospinal fluid/blood ; Male ; Middle Aged ; *DEAD-box RNA Helicases/metabolism ; Aged ; Double-Blind Method ; Adult ; }, abstract = {The activity of the RNase III enzyme DICER is downregulated in both sporadic and genetic forms of amyotrophic lateral sclerosis (ALS). Accordingly, hundreds of microRNAs (miRNAs) are broadly downregulated, leading to de-repression of their mRNA targets. Enoxacin is a fluoroquinolone that enhances DICER activity and miRNA biogenesis. Here, we tested for the first time the molecular effect of enoxacin on miRNA biogenesis in ALS patients and demonstrated that enoxacin's engagement with DICER can be pharmacodynamically monitored via miRNA levels in human subjects. In an investigator-initiated, first-in-human study (REALS1), we explored miRNAs as pharmacodynamic biomarkers of DICER activation. Patients with sporadic ALS received oral enoxacin twice daily for 30 days in a double-blind, randomized clinical trial. The study demonstrated comparable enoxacin levels in plasma and cerebrospinal fluid (CSF). Furthermore, an increase in cell-free miRNA levels in both plasma and CSF at all time points following enoxacin treatment (400 or 800 mg/day), was measured relative to baseline. Additionally, no serious adverse events were reported. In conclusion, pharmacological enhancement of DICER activity by enoxacin increases miRNA biogenesis in patients with ALS. These results support further investigation of enoxacin efficacy in larger clinical trials.}, } @article {pmid41793180, year = {2026}, author = {Smith, SE and Miller, TM and Atkinson, A and Pestronk, A and Bucelli, RC}, title = {Integrating Serum Neurofilament Light Chain Into Amyotrophic Lateral Sclerosis Diagnostic Criteria.}, journal = {Muscle & nerve}, volume = {73}, number = {6}, pages = {990-995}, doi = {10.1002/mus.70212}, pmid = {41793180}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; *Neurofilament Proteins/blood ; Male ; Female ; Retrospective Studies ; Middle Aged ; Aged ; Biomarkers/blood ; Adult ; Aged, 80 and over ; Disease Progression ; }, abstract = {INTRODUCTION/AIMS: Serum neurofilament light chain (NfL) is a promising diagnostic biomarker for differentiating amyotrophic lateral sclerosis (ALS) from clinical mimics. This study assessed the utility of integrating serum NfL into current diagnostic criteria to enhance diagnostic certainty in patients with a provisional ALS diagnosis who were confirmed as having ALS at follow-up.

METHODS: We conducted a single-center, retrospective study of consecutive patients with a provisional ALS diagnosis at their initial visit at the WashU Medicine ALS Center. All underwent electrodiagnostic testing and serum NfL measurement via SIMOA using an HD-X analyzer (Quanterix). Elevated serum NfL was defined with a cutoff of 38 pg/mL.

RESULTS: The study included 43 patients with a provisional ALS diagnosis (29 men [67.4%]; median age, 63 years [range, 36-80 years]). At follow-up, 27/43 (62.8%) patients progressed to definite ALS. Serum NfL was elevated in 34/43 (79.1%) of the total cohort and 24/27 (88.9%) of those who progressed to definite ALS. Integrating serum NfL with Gold Coast Criteria (GCC) was associated with a tenfold increase in the odds of identifying patients likely to progress to definite ALS (OR 10 [1.39, 71.87], p = 0.02).

DISCUSSION: Our results suggest that serum NfL is a robust complement to current ALS diagnostic criteria and shows potential to improve early identification and diagnostic certainty of patients likely to progress to definite ALS. Integrating serum NfL with GCC provided the strongest predictive model. These findings warrant larger multicenter, prospective studies to confirm results.}, } @article {pmid41793822, year = {2026}, author = {Li, P and Wang, Y and Bao, Z and He, X and Wang, S and Su, X and Nie, W and Xu, F and Zhou, H and Li, H and Xu, B}, title = {Metagenomics-based insights into the microbial community composition and quality characteristics development potentiality in traditional dry-cured ham.}, journal = {International journal of food microbiology}, volume = {453}, number = {}, pages = {111705}, doi = {10.1016/j.ijfoodmicro.2026.111705}, pmid = {41793822}, issn = {1879-3460}, mesh = {Animals ; *Metagenomics ; Food, Processed ; Volatile Organic Compounds/analysis ; *Meat Products/microbiology/analysis ; Swine ; *Bacteria/genetics/classification/isolation & purification/metabolism ; *Microbiota ; Gas Chromatography-Mass Spectrometry ; Food Microbiology ; Staphylococcus ; Peptides ; }, abstract = {The objective of this study was to elucidate the formation mechanisms of quality characteristics in traditional dry-cured ham. The microbial community composition in three types of dry-cured ham was analyzed using metagenomics technology. Volatile flavor profiles were characterized via gas chromatography-mass spectrometry (GC-MS) and gas chromatography-ion mobility spectrometry (GC-IMS), while peptide profiles were determined using liquid chromatography-mass spectrometry (LC-MS). Based on metagenomic data, biosynthetic pathways of volatile flavor compounds and bioactive peptides in dry-cured hams were reconstructed. Key microorganisms identified include Staphylococcus equorum, Staphylococcus saprophyticus, Aspergillus glaucus, Aspergillus ruber, Debaryomyces hansenii, and Debaryomyces fabryi. Using GC-MS and GC-IMS, 25 volatile compounds were identified in dry-cured ham, with branched-chain compounds exhibiting higher odor activity values (OAVs). LC-MS analysis identified 203 microbial-derived peptide fragments, predominantly possessing angiotensin-converting enzyme (ACE) inhibitory, dipeptidyl peptidase-IV (DPP-IV) inhibitory, and antioxidant activities. Further investigation into the contribution of microbial communities to the characteristic quality attributes revealed that Staphylococcus species promote the formation of 3-methyl-butanal via branched-chain amino acid transaminase (BCAT) and 3-hydroxy-2-butanone via acetolactate synthase (ALS). With regard to functional bioactive peptides, Staphylococcus indirectly contributes to the synthesis of NPPKFD, DLEE, and KRQKYD via glutamyl endopeptidase activity. Additionally, proteins derived from Aspergillus glaucus (actin-related protein 5) and Staphylococcus equorum (chromosome segregation protein) serve as direct precursors for bioactive peptides, yielding potential sequences such as KNSKDPVSI and LEDDI. This study provides evidence indicating the role of microbial communities in shaping the quality characteristics of dry-cured ham.}, } @article {pmid41794640, year = {2026}, author = {Chen, X and Zhu, B}, title = {Decoding the functions of nuclear speckles in neurodegeneration.}, journal = {Trends in neurosciences}, volume = {49}, number = {4}, pages = {292-305}, pmid = {41794640}, issn = {1878-108X}, support = {R01 AG074273/AG/NIA NIH HHS/United States ; R21 AG071893/AG/NIA NIH HHS/United States ; R35 GM157978/GM/NIGMS NIH HHS/United States ; R01 AG078185/AG/NIA NIH HHS/United States ; DP2 GM140924/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Cell Nucleus/metabolism ; }, abstract = {Nuclear speckles, traditionally considered mainly as reservoirs of splicing factors, are increasingly recognized as dynamic biomolecular condensates essential for RNA metabolism, transcriptional regulation, and chromatin organization. Recent advances reveal their phase separation properties, compositional complexity, and stress-responsive remodeling, positioning nuclear speckles as key regulators of proteostasis and stress adaptation. Here, we synthesize emerging evidence linking nuclear speckle dysfunction to neurodegenerative proteinopathies, particularly amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and tauopathies. We highlight how disease-associated repeat RNAs, dipeptide repeat proteins, and hyperphosphorylated tau disrupt nuclear speckle integrity, driving transcriptional and splicing defects. Finally, we discuss therapeutic strategies to rejuvenate nuclear speckles, emphasizing their potential as novel targets for restoring proteostasis and mitigating neurodegeneration. This review underscores nuclear speckles as critical yet underexplored regulators of neuronal resilience.}, } @article {pmid41795629, year = {2026}, author = {Shafie, M and Tamba, C and Bhinder, H and , and Kalra, S and Pizzagalli, F}, title = {Brain Folding Trajectories in Amyotrophic Lateral Sclerosis.}, journal = {Human brain mapping}, volume = {47}, number = {4}, pages = {e70449}, pmid = {41795629}, issn = {1097-0193}, support = {MOP-123534/CAPMC/CIHR/Canada ; //ALS Society of Canada/ ; //Brain Canada Foundation/ ; 202292PHR2//Italian Ministry of University and Research (MUR), PRIN 2022/ ; //Shelly Mrkonjic ALS Research Fund/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Female ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Disease Progression ; Aged ; Longitudinal Studies ; *Cerebral Cortex/diagnostic imaging/pathology ; Image Processing, Computer-Assisted ; *Brain/pathology/diagnostic imaging ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease, and neuroimaging markers offer a promising avenue to capture this variability. Cortical folding alterations in ALS remain largely unexplored despite growing interest in neuroimaging markers of the disease. This study is the first whole-brain investigation of sulcal morphometry in ALS. A total of 222 individuals diagnosed with ALS and 194 healthy controls (HC) were recruited through the Canadian ALS Neuroimaging Consortium (CALSNIC) for a longitudinal investigation. Using T1-weighted MRI processed with FreeSurfer and BrainVISA, we extracted cortical thickness and four sulcal features: width, mean depth, surface area, and length, across 123 sulci. We identified widespread alterations in ALS, with 19 sulci showing increased width and length alongside reduced depth and surface area, primarily in frontal and parietal regions surrounding the motor strip. The central sulcus (CS) emerged as the most consistently affected region, displaying bilateral widening and reduced depth, changes that closely tracked motor decline. Longitudinal analyses revealed progressive widening and reduced depth and surface area of the CS. These alterations closely tracked the progression of motor symptoms over the course of the disease and aligned with regional cortical thickness alterations. Our findings demonstrate that brain folding patterns, and in particular CS, are altered in ALS and correlate with clinical progression, resembling the neurodegenerative pattern of the disease. By revealing complementary and sensitive changes, sulcal-based metrics may offer promising neuroimaging biomarkers for early detection, prognosis, and patient stratification in ALS.}, } @article {pmid41795667, year = {2026}, author = {Burgess, A and Allen, O and Barkhaus, P and Barnes, B and Benatar, M and Bertorini, T and Bowser, R and Mascias Cadavid, J and Carter, GT and Cudkowicz, M and Denson, K and Dyckman, K and Elsharif, B and Feldman, E and Foucher, J and Fullum, T and Glass, J and Helmold, B and Jackson, C and Jhooty, S and Leday, A and Mallon, E and Mcdermott, C and Olby, N and Ostrow, L and Pattee, G and Pioro, E and Ratner, D and Sang, H and Tito, E and Vieira, F and Wicks, P and Bedlack, R and Gelevski, D}, title = {ALS untangled #83: clenbuterol.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2638588}, pmid = {41795667}, issn = {2167-9223}, abstract = {ALS Untangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review clenbuterol, a β-2 adrenergic agonist, as a potential treatment for amyotrophic lateral sclerosis (ALS). Clenbuterol has biological effects that could be relevant to the pathophysiology of ALS such as inducing muscle hypertrophy, improving mitochondrial function, and reducing neuroinflammation. Two studies in mouse models of motor neuron disease and two open label trials suggest possible benefits. However these have methodological flaws which limit interpretation. Clenbuterol can have an array of side effects, some severe. Drop-outs due to side effects were very common in one of the ALS trials and in a separate expanded access program. Based on this information, we cannot currently endorse clenbuterol as an ALS treatment, but we do hope to see further studies of it, or another long acting β-2 adrenergic agonist in people with ALS.}, } @article {pmid41796411, year = {2026}, author = {Manyem, M and Gomathy, SB and Subramanian, VK and Sugan, S and Sugumaran, R and Narayan, SK}, title = {Unraveling amyotrophic lateral sclerosis: a novel peripherin mutation in a young male with sporadic onset.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {4}, pages = {}, pmid = {41796411}, issn = {1590-3478}, } @article {pmid41796748, year = {2026}, author = {Stopyra, W and Voytsekhivskyy, O and Grzybowski, A}, title = {Accuracy of sixteen axial length adjusted intraocular lens power calculation formulas in long Caucasian eyes.}, journal = {Asia-Pacific journal of ophthalmology (Philadelphia, Pa.)}, volume = {15}, number = {2}, pages = {100301}, doi = {10.1016/j.apjo.2026.100301}, pmid = {41796748}, issn = {2162-0989}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Axial Length, Eye ; *Biometry/methods ; Lens Implantation, Intraocular ; *Lenses, Intraocular ; *Myopia/physiopathology ; *Optics and Photonics ; Phacoemulsification ; *Refraction, Ocular/physiology ; Retrospective Studies ; Visual Acuity ; White People ; }, abstract = {OBJECTIVE: To compare the accuracy of sixteen intraocular lens (IOL) power calculation formulas incorporating targeted adjustments or regression-based modifications of axial length (AL) in eyes longer than 26.00 mm.

DESIGN: Retrospective observational study.

METHODS: The data of myopic patients with cataract who underwent uneventful phacoemulsification with in-the-bag implantation of a PARTIAL-RoF narrow IOL between January 2020 and June 2025 were reviewed. Preoperative IOL power was calculated using the IOLMaster 700 with six formulas: Barrett Universal II (BU II), Haigis, Hoffer Q, Holladay 1, Holladay 2, and SRK/T. The implanted IOL power was selected from BU II or SRK/T recommendations. Refraction was measured three months postoperatively. Postoperative IOL power predictions were generated using the following formulas or formula variants: K6, PEARL-DGS, Castrop, Eom, VRF CMAL; Holladay 1 with Wang-Koch 2 center optimization (WK2), modified Wang-Koch (MWK), non-linear regression (NLR), and Fam-adjusted method (F2); SRK/T WK2, SRK/T MWK, SRK/T F2; Holladay 2 NLR; Hoffer Q WK2; Haigis WK2; and Barrett True AL. The primary outcome measures were root mean square absolute error (RMSAE) and the percentage of eyes with prediction error (PE) within ± 0.25 D, ± 0.50 D, ± 0.75 D, and ± 1.00 D.

RESULTS: One hundred sixty-four eyes with ALs ranging from 26.04 mm to 29.72 mm were included. RMSAE values across the sixteen formulas ranged from 0.393 (Holladay 1 NLR and SRK/T WK2) to 0.803 (Haigis WK2). The percentage of eyes with PE within ±0.50 D ranged from 35.98% (Haigis WK2) to 81.1% (Holladay 1 NLR). Holladay 1 NLR-followed by SRK/T WK2, Holladay 1 MWK, VRF CMAL, PEARL-DGS, and Eom-demonstrated significantly higher accuracy than most other formulas. Haigis WK2 and Hoffer Q WK2 were the least accurate.

CONCLUSIONS: Certain modified third-generation formulas (Holladay 1 NLR, SRK/T WK2) achieve accuracy comparable to that of new-generation formulas (PEARL-DGS, K6, VRF CMAL) in IOL power calculations for long eyes. However, some third- and fourth-generation formulas-even after AL-based modification (Hoffer Q WK2, Haigis WK2)-continue to yield suboptimal results in this anatomical range.}, } @article {pmid41796799, year = {2026}, author = {Zhao, DY and Nabeel-Shah, S and Ni, Z and Pu, S and Zhong, G and Schmitges, FW and Braunschweig, U and Blencowe, BJ and Greenblatt, JF}, title = {RNA-binding proteins TDP-43 and FUS promote R-loop resolution and regulate transcription termination.}, journal = {The Journal of biological chemistry}, volume = {302}, number = {5}, pages = {111348}, pmid = {41796799}, issn = {1083-351X}, mesh = {*RNA-Binding Protein FUS/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *R-Loop Structures/genetics ; *Transcription Termination, Genetic ; RNA Polymerase II/metabolism ; }, abstract = {TDP-43 and FUS are RNA-binding proteins involved in the regulation of diverse RNA-processing events and have been strongly implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We have previously demonstrated the role of symmetrical dimethylation (me2s) of a conserved arginine residue (R1810 in human POLR2A) in the C-terminal domain (CTD) of RNA polymerase II (RNAPII), which facilitates the recruitment of the Tudor domain-containing protein SMN to resolve R-loops at transcriptional termination sites. Here, we demonstrate that TDP-43 and FUS contribute to transcription termination through the R1810me2s-SMN pathway. Our data show that TDP-43-and to a lesser extent, FUS-are recruited to chromatin via this pathway, and that disruption of their recruitment leads to defective RNAPII termination. This impairment results in the accumulation of R-loops and elevated DNA damage to gene terminators. Using transcriptome-wide analyses, we further show that TDP-43 RNA-binding sites are highly correlated with regions of R-loop formation. Importantly, we find that the RNA-binding activity of TDP-43 is essential for its role in resolving R-loops and promoting efficient transcription termination. These findings establish a mechanistic link between TDP-43/FUS, R-loop resolution, and transcription termination, providing new insights into how their dysfunction may drive genome instability and contribute to the pathogenesis of ALS and FTD.}, } @article {pmid41797023, year = {2026}, author = {Furlan, N and D'Amora, U and Fasolino, I and Silvestri, A and Zanardi, C}, title = {An electrochemical enzyme-linked immunosorbent assay for interleukin 18 quantification in 3D skin models derived from ALS patients.}, journal = {Biosensors & bioelectronics}, volume = {303}, number = {}, pages = {118567}, doi = {10.1016/j.bios.2026.118567}, pmid = {41797023}, issn = {1873-4235}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/pathology ; Humans ; *Interleukin-18/analysis/isolation & purification ; *Biosensing Techniques/methods ; *Skin/chemistry/pathology ; Enzyme-Linked Immunosorbent Assay/methods ; Electrochemical Techniques/methods ; Biomarkers/analysis ; Limit of Detection ; Fibroblasts ; Printing, Three-Dimensional ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that currently lacks validated molecular biomarkers for early diagnosis and prognosis, severely delaying personalized care. Interleukin 18 (IL-18), a proinflammatory cytokine linked to NLRP-3 inflammasome activation, has emerged as a promising biomarker for ALS. However, traditional colorimetric Enzyme-Linked Immunosorbent Assays (ELISAs) lack the sensitivity to distinguish IL-18 levels between Fast- and Slow-progressing ALS patients. To overcome this, we developed a highly sensitive electrochemical ELISA (e-ELISA) test by systematically optimizing key parameters, including the capture antibody immobilization strategy, the electrochemical mediator, and reagent concentrations. We then applied the optimized e-ELISA protocol to quantify IL-18 in 3D innervated skin models constructed using 3D-printed methacrylated hyaluronic acid (MeHA) and electrospun polylactic acid (PLLA) fibers, and colonized with patient-derived fibroblasts and neuronal cells. Reaching a limit of detection of 1.77 pg✕mL[-1], the e-ELISA not only differentiated ALS models from the healthy control but, most critically, distinguished between a Fast- and a Slow-progressing ALS models based on significantly different IL-18 concentrations. By discriminating IL-18 levels in biologically representative models, this work validates the developed high-performance e-ELISA for personalized clinical use, providing a foundation for the design of portable diagnostic devices.}, } @article {pmid41798433, year = {2026}, author = {Matsuzawa, K and Takahashi, T and Sakata, J and Uchida, T and Suzuki, T and Sakai, T}, title = {Effectiveness of a Progressive Rehabilitation Approach Without Sport Activity Restriction for Acute Lumbar Spondylolysis in High-Level Athletes: A Retrospective Case Series.}, journal = {Cureus}, volume = {18}, number = {2}, pages = {e103041}, pmid = {41798433}, issn = {2168-8184}, abstract = {OBJECTIVE: This study aimed to examine the characteristics and clinical outcomes of high-level athletes with acute lumbar spondylolysis (ALS) treated with a progressive rehabilitation (PR) approach without rigid bracing or activity restriction.

METHODS: This retrospective consecutive case series included seven high school or collegiate athletes competing at the national level who underwent a PR approach for ALS at our institution between January 2023 and December 2024. One athlete was excluded due to loss to follow-up, leaving six athletes for analysis. The intervention consisted of a PR program without rigid bracing or activity restriction, emphasizing stepwise mobility, stability, strengthening, and pain-based progression of functional movements. Main outcomes included MRI findings, pain status, return-to-sport (RTS) rate and period, and follow-up duration.

RESULTS: Traumatic episodes were the most common etiological factor (66.7%), involving high ground reaction force movements or excessive lateral bending. MRI improvement was observed in five patients (83.3%), and pain resolution occurred in all six patients (100%). The RTS rate was 100%, with a median RTS period of 65 days (range, 54-112), which was shorter than previously reported for conservative treatment. No recurrence occurred during follow-up (median, 109 days).

CONCLUSIONS: A PR approach without rigid bracing or activity restriction enabled early RTS in high-level athletes with ALS, with symptom improvement and no recurrence. This approach may allow modification of pain-provoking or injury-related movements and help minimize declines in physical fitness and body composition associated with activity restriction. It may be suitable for post-growth high-level athletes who understand the risks related to bone healing and require timely RTS, although further research is needed to clarify stage-specific indications and long-term outcomes.}, } @article {pmid41798783, year = {2026}, author = {Kavale-Henderson, LA and Loch, C and Buckley, H and Petchey, P and King, C and Cameron, C and Snoddy, AME}, title = {Reflections of Their Homelands-Early Life Enamel Formation Disruption in Nineteenth Century Settlers of Otago, New Zealand.}, journal = {Journal of the Royal Society of New Zealand}, volume = {56}, number = {1}, pages = {e70022}, pmid = {41798783}, issn = {1175-8899}, abstract = {Physiological stress during early life can impede development, and signals of this are preserved in nonremodelling tissues such as dental enamel. This article describes nonspecific stress markers in the teeth of European (n = 30) and Southern Chinese (n = 15) adult migrants to New Zealand, and colony-born children (n = 10) interred in four historic Otago cemeteries (c. 1857-1904). Standard histological methods were used to identify and trace accentuated lines (ALs), indicators of enamel formation disruption. All Chinese adults, 93.3% of European adults, and 90% of New Zealand-born subadults exhibited AL formation. Chinese adults exhibited the highest mean occurrence of ALs per individual, and patterns of AL formation during early childhood differed in individuals of different ethnic and environmental backgrounds. This variation could be attributed to genetic variation in ameloblast susceptibility to stress, disparities in stability of the childhood environment, and/or sociocultural influences on growth and development. These data illustrate the embodiment of physiological stress during early life in poorer classes during the nineteenth century. While childhood hardship was a potential driver of adult decisions to depart for new lands such as New Zealand, it was not absent in the early lives of children born in the colony.}, } @article {pmid41799850, year = {2026}, author = {Osei Acheampong, H and Insolera, R}, title = {Kenny is the adaptor protein for ubiquitin-dependent mitophagy in Drosophila melanogaster.}, journal = {Autophagy reports}, volume = {5}, number = {1}, pages = {2638025}, pmid = {41799850}, issn = {2769-4127}, support = {R00 NS111000/NS/NINDS NIH HHS/United States ; }, abstract = {Mitophagy is the selective degradation program for damaged and unnecessary mitochondria to maintain cellular mitostasis and survival. Specific mutations in the mediators for the canonical ubiquitin (ub)-dependent mitophagy pathway have been identified with unique neurological diseases like Parkinson disease and ALS (amyotrophic lateral sclerosis), metabolic diseases, and cancer. Mammalian OPTN (optineurin) has been shown as a SAR (selective autophagy receptor) for ub-dependent mitophagy in vitro with direct connections of its mutations with glaucoma and ALS. Despite the in vitro demonstration of OPTN's role in mitophagy, the in vivo physiological characterization of OPTN's mitophagy function is largely unexplored. In our recent study, we provide in vivo evidence that the Drosophila melanogaster (Dm) protein, Kenny, directly mediates the sequestration of target mitochondria for the progression and completion of ub-dependent mitophagy. This result establishes Kenny as the Dm homolog of OPTN. Previously, Kenny had only been characterized for its role in innate immune activation and modulation. The conclusion from this study provides avenues for further understanding the in vivo signaling regulating Kenny's role in mitophagy and investigating homologous disease-relevant mutations of OPTN in Dm.}, } @article {pmid41800832, year = {2026}, author = {Kawarabayashi, T and Nakamura, T and Takahashi, R and Ueda, T and Kinoshita, S and Uchida, C and Sugawara, T and Hashimoto, K and Ishizawa, K and Amari, M and Kasahara, H and Ikeda, Y and Takatama, M and Shoji, M}, title = {Clinical Validation of Plasma p-217tau in Neurological Diseases.}, journal = {Annals of clinical and translational neurology}, volume = {13}, number = {9}, pages = {1780-1790}, pmid = {41800832}, issn = {2328-9503}, support = {18K07385//Grants for Scientific Research (C) from the Ministry of Education, Science, and Culture of Japan/ ; 22K07511//Grants for Scientific Research (C) from the Ministry of Education, Science, and Culture of Japan/ ; }, mesh = {Humans ; Female ; Male ; *tau Proteins/blood/cerebrospinal fluid ; Biomarkers/blood/cerebrospinal fluid ; *Hydrocephalus, Normal Pressure/blood/diagnosis/cerebrospinal fluid ; Aged ; *Alzheimer Disease/blood/diagnosis/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/cerebrospinal fluid ; Middle Aged ; Sensitivity and Specificity ; Aged, 80 and over ; Reproducibility of Results ; *Nervous System Diseases/blood/diagnosis ; }, abstract = {OBJECTIVE: Plasma p-217tau is a minimally invasive but specific biomarker for diagnosing Alzheimer's disease (AD). However, its disease specificity remains to be clinically evaluated. We validated the reliability of the p-217tau biomarker in 12 other neurological diseases.

METHODS: Plasma p-217tau levels were measured in 298 participants, consisting of 81 AD patients, 204 patients with 12 other neurological diseases, and 13 healthy and cognitively unimpaired controls (HCU), using an assay system from Meso Scale Diagnostics. Cerebrospinal fluid (CSF) tau and Aß levels were simultaneously evaluated in AD, amyotrophic lateral sclerosis (ALS), and idiopathic normal pressure hydrocephalus (iNPH).

RESULTS: Plasma p-217tau levels increased in AD with the clinical stage, but also in ALS and iNPH, leading to them having decreased sensitivity and specificity for diagnosing AD. No increases in plasma p-217tau levels were seen in possible tauopathies or synucleinopathies. CSF and plasma p-217tau levels were strongly correlated in AD, but not in ALS. The plasma p-217tau/CSF p-217tau ratio was inversely higher in ALS than in AD. Active and chronic denervation potentials were associated with plasma p-217tau levels. In iNPH, plasma p-217tau was associated with cognitive dysfunction, but not with gait disturbance or urinary incontinence. CSF p-181tau, total tau, and Aß1-40 levels and the Aß1-40/1-42 ratio were reduced in iNPH.

INTERPRETATION: ALS and iNPH are two major pitfalls for the clinical application of plasma p-217tau as a biomarker of AD. Lower motor neuron injury in ALS and cognitive dysfunction in iNPH were both found to be associated with elevated plasma p-217tau levels.}, } @article {pmid41802722, year = {2026}, author = {Conti, GM and Foa, N and Tran, BK}, title = {[Correction: Piggyback-Add-on-IOL als Rettungsstrategie nach inkompletter Implantation der primären IOL in einem übermäßig kleinen Kapselsack mit unerwartetem refraktivem Endergebnis].}, journal = {Klinische Monatsblatter fur Augenheilkunde}, volume = {243}, number = {4}, pages = {e1}, doi = {10.1055/a-2826-2346}, pmid = {41802722}, issn = {1439-3999}, } @article {pmid41802990, year = {2026}, author = {Zambetti, E and Greco, A and Mucci, C and Belli, S}, title = {"A rough and swirling sea": Voicing Amyotrophic Lateral Sclerosis through discourse analysis.}, journal = {Journal of health psychology}, volume = {}, number = {}, pages = {13591053261424031}, doi = {10.1177/13591053261424031}, pmid = {41802990}, issn = {1461-7277}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare, incurable neurodegenerative disease that leads to death within 5 years of diagnosis and greatly impacts patients' and caregivers' quality of life (QoL). Typically leading to death within 5 years, ALS underscores the need for emotional and psychological support. This study analyzes 118 testimonies from patients (n = 67), informal caregivers (n = 41), and formal caregivers (n = 10), with a gender-balanced sample (n = 67 women), using discourse analysis. Narratives reveal a complex emotional landscape of suffering and resilience, showing ALS as a disruptive force that prompts reevaluation of roles and life stories. Shared support is crucial within families and social settings. Many testimonies express a desire to raise awareness and fund research. Understanding ALS through these stories offers insights into the psychological, emotional, cultural, and social challenges, essential for developing tailored interventions to support psychological well-being.}, } @article {pmid41803120, year = {2026}, author = {Ruf, WP and Kühlwein, JK and Meier, L and Brockmann, SJ and LeeBae, J and Sadri-Vakili, G and Yilmazer-Hanke, D and Petri, S and Thal, DR and Grozdanov, V and Danzer, KM}, title = {Multi-modal dissection of cell-type specific TDP-43 pathology in the motor cortex.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41803120}, issn = {2041-1723}, support = {//KU-Leuven internal funding/ ; //Target ALS Grant/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; Humans ; *Motor Cortex/pathology/metabolism ; *Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Spatial Transcriptomics ; Flow Cytometry ; }, abstract = {Cytoplasmic TDP-43 pathology is a pathological sign of ALS/ALS-FTD and a converging disease event across different genotypes, phenotypes and CNS areas. To understand this process and target it therapeutically, we need to define which cell types are affected and which cell-type specific effects make them particularly vulnerable. We coupled flow-cytometry nuclear sorting and sequencing with single-nucleus multi-omic ATAC-seq and RNA-seq and spatial transcriptomics to define the transcriptional cell type of affected neurons in the post-mortem ALS/ALS-FTD motor cortex (30 ALS, 20 ALS-FTD & 32 control samples). Here, we show that mainly excitatory cortical neurons are affected by TDP-43 pathology and define the cell types that are affected the most: intratelencephalic L2-L3-LINC00507-FREM3, L3-L5-RORB-LNX2, L3-L5-RORB-ADGRL4 & L6-THEMIS-LINC00343 neurons and extratelencephalic L5-FEZF2-NTNG1 neurons. Transcriptional aberrations by TDP-43 pathology, like cryptic exon inclusion, are cell-type specific and affect distinct gene sets in each cell type, highlighting the need to address TDP-43 pathology in a cell-type specific manner.}, } @article {pmid41803482, year = {2026}, author = {Saeki, Y and Nakamura, N and Hayashi, N}, title = {Exercise pressor reflex in Amyotrophic lateral sclerosis patients.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41803482}, issn = {2045-2322}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology ; Blood Pressure/physiology ; *Exercise/physiology ; Heart Rate/physiology ; *Reflex/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by progressive loss of motor neurons that leads to a decrease in muscle strength and motor performance. It is still unclear whether acute exercise evokes circulatory responses in late-stage ALS patients, although it is well known that in healthy people, there is an increase in heart rate (HR) and blood pressure (BP). Therefore, we examined whether the sensory and autonomic nervous systems respond greatly sufficiently to evoke circulatory responses to acute movement in late-stage ALS patients. Late-stage ALS patients (age:55–92 yrs, five males, two females) on ventilators performed static passive forearm stretching and passive leg pedaling exercises. The intensity of stretching was lower than individual pain thresholds. The beat-to-beat BP was continuously recorded. HR, systolic blood pressure, diastolic blood pressure, and the mean arterial pressure significantly increased from rest with passive forearm stretching (p < 0.05), while no significant circulatory changes were observed during passive leg pedaling.These results are similar responses to those reported in healthy people, suggesting that the functions of sensory and autonomic nervous systems are intact to evoke circulatory responses in late-stage ALS patients.Clinical trial registration : This study was registered at UMIN-CTR (R000069509) on February 25, 2026.}, } @article {pmid41804301, year = {2026}, author = {Koropouli, E and Bellos, S and Aristeidou, S and Daponte, A and Gklinos, P and Athanasopoulos, F and Tsionis, A and Andreadou, E and Zouvelou, V and Rentzos, M}, title = {Motor neuron disease can present as a paraneoplastic neurologic syndrome with various phenotypes.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag024}, pmid = {41804301}, issn = {2632-1297}, abstract = {Paraneoplastic motor neuron disease is an uncommon paraneoplastic neurologic syndrome whose existence has fallen into ambiguity. Epidemiologic studies that have addressed the association between cancer and motor neuron disease have provided conflicting results. Case studies that report motor neuron disease presentation at the time of active malignant disease, in the presence of another paraneoplastic neurologic syndrome or onconeural antibody or with neurologic response to antineoplastic treatment provide strong evidence for paraneoplastic motor neuron disease. However, conclusive evidence about the existence and the clinical and laboratory profiles of this neurologic syndrome is lacking. In this study, we report four new cases of paraneoplastic motor neuron disease, two of whom with expression of Sry-like high mobility group box 1 (SOX1) antibody. We also present a systematic review of all cases of paraneoplastic motor neuron disease reported to date that fulfill prespecified inclusion criteria with individual participant data meta-analysis of the demographic, clinical and laboratory features of the disease. Our data demonstrate that motor neuron disease can present as a paraneoplastic neurologic syndrome. Paraneoplastic motor neuron disease spans the whole motor neuron disease phenotypic spectrum, and it is associated with a wide variety of neoplastic diseases, onconeural antibodies and it may present concurrently with other well-recognized paraneoplastic neurologic syndromes. Paraneoplastic motor neuron disease may be clinically indistinguishable from idiopathic motor neuron disease. Its only distinctive clinical feature is the rapidly progressive course. A subset of cases display immune derangements in cerebrospinal fluid, including increased white cell count, elevated protein, albumin index, IgG index and/or oligoclonal band expression. Cancer-induced inflammatory pathways may trigger the disease in genetically predisposed individuals harboring amyotrophic lateral sclerosis-causing genetic deficits. A thorough evaluation for neoplastic diseases should be carried out upon strong suspicion of this rare paraneoplastic neurologic syndrome to increase the diagnostic yield for this entity. Paraneoplastic motor neuron disease apparently results from complex interactions between degenerative and immune pathways and its pathophysiology may elucidate previously unresolved aspects of idiopathic motor neuron disease pathogenesis.}, } @article {pmid41804522, year = {2026}, author = {Fujita, K and Matsui, N and Izumi, Y}, title = {[Immune Cells and Proteins Associated with Disease Progression in Amyotrophic Lateral Sclerosis: New Insights from Multiomics Analyses].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {78}, number = {3}, pages = {285-288}, doi = {10.11477/mf.188160960780030285}, pmid = {41804522}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/immunology/metabolism ; Humans ; Multiomics ; Disease Progression ; Proteomics ; }, abstract = {Disease progression in amyotrophic lateral sclerosis shows substantial individual variability, and immune mechanisms have attracted attention as underlying factors. Immune profiles associated with disease progression were identified using cytokine profiling, proteomics, and single-cell analyses. Peripheral blood mononuclear cells, such as Th17 cells and effector CD8+ T cells, along with inflammation-related proteins, including interleukin-17A and CD94, are associated with disease progression. This review summarizes the findings of multi-omics studies.}, } @article {pmid41804597, year = {2026}, author = {Georgiadou, P and Erkaya, B and Niwa-Kawakita, M and Oltan, M and Keskin, YK and Sahin, E and Öztürk, H and Tiryaki, F and Yildiz, K and Özgenç, I and Odabasi, E and Pekbilir, E and Dogan, SA and Lallemand-Breitenbach, V and Vargas, S and Prochiantz, A and Firat-Karalar, EN and de Thé, H and Sahin, U}, title = {Pml loss worsens NEK1-linked ALS and Pml induction drives NEK1 degradation, precluding disease onset.}, journal = {The FEBS journal}, volume = {293}, number = {17}, pages = {5170-5185}, pmid = {41804597}, issn = {1742-4658}, support = {679140//H2020 European Research Council/ ; 119N095//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; Installation Grant IG3336//European Molecular Biology Organization/ ; }, mesh = {Animals ; *NIMA-Related Kinase 1/genetics/metabolism ; Humans ; *Promyelocytic Leukemia Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mice ; Proteolysis ; Sumoylation ; Disease Models, Animal ; Mutation ; }, abstract = {Germinal mono-allelic loss-of-function mutations of NEK1 drive amyotrophic lateral sclerosis (ALS) at variable penetrance, presumably through haploinsufficiency. Modeling the ALS-associated Arg812Ter mutation in mice revealed that the resulting truncated Nek1 (Nek1[t]) is aggregation-prone, particularly in alpha-motoneurons (αMNs), and drives canonical ALS symptoms when bi-allelically expressed (Nek1[t/t]). Promyelocytic leukemia (Pml) ablation allows for ALS symptoms to occur even in heterozygote Nek1[wt/t] animals, mimicking the human situation. Pml precludes disease occurrence by promoting SUMO-facilitated degradation of Nek1[t] proteins through PML nuclear bodies (NBs). Conversely, Pml induction, achieved by activating the interferon pathway via poly(I:C) treatment, clears Nek1[t] puncta in αMNs, dramatically reducing ALS-associated symptoms and extending survival by 5 months. Our studies highlight the role of mutant NEK1 expression in ALS pathogenesis and identifies activation of interferon pathways as a candidate therapeutic strategy that promotes Pml-triggered SUMOylation/degradation of toxic misfolded proteins in vivo, yielding dramatic clinical improvement. These observations provide strong proof-of-concept support to validate PML as a relevant therapeutic target in neurodegenerative conditions associated with protein misfolding and putative aggregation.}, } @article {pmid41804798, year = {2026}, author = {Jagaraj, CJ and Saravanabavan, S and Parakh, S and Jayakumar, M and Kashani, SA and Shadfar, S and Mehta, P and Gautam, S and Farzana, F and Suchowerska, AK and Yap, K and Vidal, M and Ragagnin, AMG and Jamali, MS and Yang, S and Fath, T and Craik, D and Atkin, JD}, title = {Cofilin hyperphosphorylation triggers TDP-43 pathology in sporadic amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag096}, pmid = {41804798}, issn = {1460-2156}, abstract = {Pathological forms of TAR-binding protein 43 (TDP-43), involving its aberrant mislocalization to the cytoplasm, inclusion formation, hyperphosphorylation and fragmentation, are present in ∼45-50% frontotemporal dementia (FTD) and Alzheimer's disease individuals, and most (97%) amyotrophic lateral sclerosis (ALS) cases. Hence, identifying mechanisms that induce TDP-43 pathology are central to neurodegeneration and developing new therapeutic targets in these conditions. Cofilin is a multi-functional protein with a crucial role in regulating the actin cytoskeleton. Actin has important neuronal-specific activities in dendritic spines, axonal growth cones and synapses and it is in constant equilibrium between two forms: monomeric globular actin (G-actin) and polymeric filamentous actin (F-actin). Cofilin controls actin dynamics by depolymerising and severing actin filaments. When cofilin is phosphorylated (at Serine-3) by LIM kinase1 (LIMK1), it becomes inactive, leading to production of more F-actin. Defects in cofilin are well described in other neurodegenerative disorders, unlike in ALS. We examined phosphorylation of cofilin and actin dynamics in post-mortem spinal cord tissue from sporadic ALS (SALS) patients, the TDP-43 rNLS8 transgenic mouse model, and NSC34 motor neuronal cells expressing cytoplasmic TDP-43. F-actin was pharmacologically stabilized to mimic cofilin hyperphosphorylation, and TDP-43 pathology was assessed. Neuronal cells were treated with a non-phosphorylatable cofilin S3A peptide (MAAGVAVSDGVIKVFN), and TDP-43 pathology and apoptosis were evaluated. Here, we show that cofilin is hyper-phosphorylated in human ALS and disease models compared to controls. This was detected in spinal motor neurons from sporadic ALS (SALS) patients and a TDP-43 mouse model (rNLS8) displaying key ALS phenotypes, and in motor neuronal NSC34-cells expressing cytoplasmic TDP-43. Supporting this observation, more F-actin relative to G-actin was present in cortical/spinal cord lysates from SALS patients and TDP-43 rNLS8 mice, and NSC34-cells expressing TDP-43. We also show that mimicking cofilin hyperphosphorylation by pharmacological stabilization of F-actin induced TDP-43 pathology: cytoplasmic mislocalization, inclusion formation, hyperphosphorylation, and fragmentation, and promoted its recruitment into stress granules (SGs). Furthermore, we detected increased levels of LIMK1 phosphorylation and tropomyosin isoforms 4.1 and 4.2 in SALS patients. These findings reveal aberrant cofilin hyperphosphorylation disrupts actin dynamics, triggering TDP-43 pathology and SG recruitment in SALS. They imply that preventing cofilin phosphorylation is a novel therapeutic strategy applicable to most ALS cases. Treatment of neuronal cells with the S3A peptide prevented features of TDP-43 pathology and apoptosis compared to control peptides. These findings thus describe a novel pathogenic mechanism producing TDP-43 pathology, applicable to most ALS cases and other neurodegenerative diseases.}, } @article {pmid41804872, year = {2026}, author = {Özcan, GG and Rihel, J}, title = {Modeling diseases of aging in larval zebrafish, a paradoxical yet powerful strategy.}, journal = {Genetics}, volume = {232}, number = {4}, pages = {}, pmid = {41804872}, issn = {1943-2631}, support = {/WT_/Wellcome Trust/United Kingdom ; #217150/Z/19/Z//Wellcome Trust Investigator Award/ ; //Alzheimer's Research/ ; }, mesh = {Animals ; *Zebrafish/genetics/growth & development ; *Aging/genetics ; *Neurodegenerative Diseases/genetics/pathology ; *Disease Models, Animal ; Larva/genetics ; Brain/metabolism ; Humans ; }, abstract = {Neurodegenerative diseases are a set of devastating medical conditions in which neuronal loss associated with the aggregation of toxic proteins leads to progressive cognitive impairment. These diseases are usually modeled in animals by mimicking late disease stages through genetic modifications that aggressively accumulate proteins that damage the brain. However, these diseases typically unfold over decades, and disease-associated genes are known to have important, but understudied, biological functions in early life stages. To address this research gap, we suggest that the larval zebrafish, which has conserved orthologs of most neurodegeneration-linked genes, is an excellent model to examine early mechanisms that set the stage for disease progression, such as altered neuronal function, synaptic re-wiring, and proteostasis. We propose a systematic genetic modeling and phenotyping pipeline in zebrafish that integrates CRISPR editing, high-throughput behavioral assays, brain-wide activity mapping, and pharmacological screens to capture neurodegenerative disease-related changes that occur well before clinical disease emerges. Studying diseases of aging in larval zebrafish may sound paradoxical; however, by uncovering cellular dysfunction at the earliest stages of disease in a living vertebrate brain, this approach could identify critical therapeutic targets at timepoints before degeneration becomes irreversible.}, } @article {pmid41805242, year = {2026}, author = {Saha, P and Varyani, R and Hole, A and Joshi, P and Waghmare, MS and Singh, A and Chaturvedi, P and Govekar, R and Krishna, CM}, title = {Multimodal Serum Profiling for Early Detection and Risk Assessment of Oral Potentially Malignant Disorders and Oral Cancer.}, journal = {Analytical chemistry}, volume = {98}, number = {11}, pages = {8121-8132}, doi = {10.1021/acs.analchem.5c06663}, pmid = {41805242}, issn = {1520-6882}, mesh = {Humans ; *Mouth Neoplasms/diagnosis/blood ; *Early Detection of Cancer/methods ; Tandem Mass Spectrometry ; Risk Assessment ; *Carcinoma, Squamous Cell/blood/diagnosis ; Spectrum Analysis, Raman ; Male ; Liquid Chromatography-Mass Spectrometry ; Female ; *Oral Submucous Fibrosis/blood/diagnosis ; Middle Aged ; Discriminant Analysis ; Adult ; Chromatography, Liquid ; }, abstract = {Oral squamous cell carcinoma (OSCC) has high incidence rates in India, with poor survival rates due to late diagnosis. Oral potentially malignant disorders (OPMDs) such as leukoplakia (L) and oral submucous fibrosis (OSMF) present a critical window for intervention. Minimally invasive approaches capturing early biochemical alterations were investigated to improve early detection and stratification. Blood serum samples from 169 subjects, including healthy controls (C), tobacco habitués (TC), L, OSMF, and OSCC, were analyzed using Raman spectroscopy (RS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Principal component-based quadratic discriminant analysis (PC-QDA) models were built with RS data and validated on independent cohorts. Multivariate curve resolution-alternating least-squares (MCR-ALS) analysis identified altered spectral features. Global LC-MS/MS metabolite profiles were assessed by multivariate statistics and pathway enrichment. RS-based PC-QDA models achieved ∼95% accuracy in training and testing when C subjects were compared against TC, L, OSCC, and OSMF in a two-group model. A three-group model with C, TC, and oral diseases accurately classified >80% C and 86% oral disease subjects. The model stratifying L, OSMF, and OSCC identified 100% OSCC and 73-84% of L and OSMF in independent test sets. MCR-ALS revealed spectral features of albumin, immunoglobulins, carotenoids, and lipids, corresponding to LC-MS/MS findings of altered albumin-bound metabolites, bile acids, lipid metabolism, and oxidative stress. Serum RS demonstrated efficacy as a rapid, minimally invasive detection tool for oral disease stratification. LC-MS/MS identified metabolites and pathways aligning with RS spectral signatures. This multimodal approach shows promise for early detection and risk assessment of oral cancer.}, } @article {pmid41805423, year = {2026}, author = {Schmidt, AK and Scholten, EWM and van Eijk, RPA and van der Meijden, C and van Esch, C and Visser-Meily, JMA and van den Berg, LH and Beelen, A}, title = {How to measure person-centred care in people living with ALS: development and validation of the patient experience PEMALS questionnaire.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {611-621}, doi = {10.1080/21678421.2026.2640128}, pmid = {41805423}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology/epidemiology ; Female ; Male ; Surveys and Questionnaires/standards ; Aged ; *Patient-Centered Care/standards ; Reproducibility of Results ; Middle Aged ; Psychometrics/methods ; Adult ; *Patient Satisfaction ; Aged, 80 and over ; Netherlands ; }, abstract = {Objective: Person-centredness is a fundamental aspect of care for people with amyotrophic lateral sclerosis (plwALS). Systematic assessment of patient experiences is essential to reflect their perspectives and needs in care. This study aimed to develop and evaluate the psychometric properties of the Patient Experience Measure in ALS care (PEMALS), and to assess the care experience of Dutch plwALS. Methods: We developed a preliminary questionnaire based on literature and input from two representatives, each from a different patient association and three healthcare professionals. In an online survey study, plwALS from the population-based national registry were invited to complete the Dutch questionnaire twice within a 3-day interval. We evaluated test-retest reliability, structural validity, and internal consistency. After item reduction, a total PEMALS score was computed and analyzed for reliability, measurement error, and associations with demographic and clinical patient characteristics. Results: The preliminary questionnaire included 28 items and was completed by 245 plwALS. After item reduction, the final PEMALS contained 16 items. Factor analysis confirmed unidimensionality, with a Cronbach's α of 0.97. Test-retest reliability had an ICC of 0.81 (95% CI 0.72-0.87), and a measurement error of 0.43 points (scale 1 to 10). There was no systematic difference between test-retest (mean difference 0.02, 95% CI 0.05-0.10, p = 0.510). PlwALS rated ALS care with a median score of 9.6 (IQR 8.7-10); 31.4% scored the maximum. Older participants reported significantly higher PEMALS scores (Spearman's r = 0.199, p = 0.002). Conclusions: The PEMALS is a valid and reliable measure for assessing patient experience in ALS care and enables systematic monitoring of person-centered quality of care.}, } @article {pmid41805572, year = {2026}, author = {Yan, Y and Wang, X and Jeon, H and Kee, TR and Tran, KD and Lee, H and Zhao, X and Liu, T and Wing, SS and Woo, JA and Kang, DE}, title = {Ubiquitin-specific peptidase-19 links TDP-43 aggregation to ER stress.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {11}, pages = {e2514355123}, pmid = {41805572}, issn = {1091-6490}, support = {I01 BX006539/BX/BLRD VA/United States ; I01BX006539//U.S. Department of Veterans Affairs (VA)/ ; RF1NS122218//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01AG067741//HHS | NIH | National Institute on Aging (NIA)/ ; R01NS122350//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS122218/NS/NINDS NIH HHS/United States ; R01 AG080924/AG/NIA NIH HHS/United States ; R01AG080924//HHS | NIH | National Institute on Aging (NIA)/ ; RF1NS134638//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS122350/NS/NINDS NIH HHS/United States ; RF1 NS134638/NS/NINDS NIH HHS/United States ; RF1 NS122218/NS/NINDS NIH HHS/United States ; R01 AG067741/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; Mice ; *Endoplasmic Reticulum Stress ; *Endopeptidases/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Ubiquitination ; Frontotemporal Lobar Degeneration/metabolism/genetics/pathology ; Endoplasmic Reticulum/metabolism ; Proteotoxic Stress ; Protein Aggregation, Pathological/metabolism ; }, abstract = {Aggregation and deposition of TAR DNA-binding protein 43 (TDP-43) is a salient pathological signature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration-TDP (FTLD-TDP). TDP-43 proteostasis and aggregation are controlled by several posttranslational modifications, including ubiquitination. While multiple E3 ubiquitin ligases are known to facilitate TDP-43 clearance, little is known about the role of deubiquitinases (DUBs) in controlling TDP-43 proteostasis. Through an unbiased discovery screen of DUBs, here we identify and demonstrate using in vitro and in vivo models, as well as human brain tissue, that ubiquitin-specific peptidase-19 (USP19) acts as a TDP-43-directed DUB that removes K48- and K63-linked ubiquitin conjugates from TDP-43 and preferentially promotes cytoplasmic aggregation of TDP-43 C-terminal fragments (TDP-CTFs) through its catalytic activity. Specifically, the endoplasmic reticulum (ER)-anchored USP19 isoform (USP19-ER) exhibits superior activity in deubiquitinating TDP-CTFs, enhancing its phase separation and aggregation, compared to its cytosolic isoform (USP19-Cyto). Furthermore, as TDP-CTFs are generated at the ER, USP19 acts to couple the aggregation of TDP-CTFs to ER stress (ATF6, ATF4, IRE1, & CHOP). In humans, USP19 protein levels increase in FTLD-TDP brains, which extensively colocalize with cytoplasmic phospho-TDP-43 (pTDP-43) pathology. Importantly, we demonstrate in vivo that genetic reduction of usp19 mitigates pTDP-43 pathology, astrogliosis, and ER stress while reversing long-term potentiation (LTP) and motor deficits in a mouse model of TDP-43 pathogenesis (TAR4 mice). These findings establish a critical role of USP19 at the nexus of TDP-43 proteostasis and ER stress, implicating its pathogenic role in FTLD-TDP and ALS.}, } @article {pmid41805897, year = {2026}, author = {Bodenbender, L and Rohn, S and Parastar, H and Sinderhauf-Gacioch, K and Weller, P}, title = {Towards "greener" strategies in quality control: rapid volatilomics of cocoa based on HS-GC-IMS and machine learning.}, journal = {Analytical and bioanalytical chemistry}, volume = {418}, number = {16}, pages = {5205-5217}, pmid = {41805897}, issn = {1618-2650}, support = {13FH138KX0 Deep Authent//Bundesministerium für Bildung und Forschung/ ; }, mesh = {*Machine Learning ; *Cacao/chemistry ; Quality Control ; Gas Chromatography-Mass Spectrometry/methods ; *Ion Mobility Spectrometry/methods ; *Volatile Organic Compounds/analysis ; *Chocolate/analysis ; Discriminant Analysis ; Green Chemistry Technology/methods ; }, abstract = {Gas chromatography-ion mobility spectrometry (GC-IMS) has emerged as a powerful analytical platform in quality control of food, beverages, and flavor products. The technology allows for point-of-care application without the need for sample preparation, which makes it advantageous in resource-limited and equipment-hostile environments. One of these fields is the quality assessment of raw cocoa, which is fundamental for ensuring authenticity, product quality, as well as food safety and compliance. At the same time, analytical departments are facing an increasing urge to turn to a more sustainable use of resources, as well as substantial cost pressure. In the present study, a fast GC-IMS strategy was used to evaluate the provenance of cocoa in combination with machine learning. While most of the commercially available GC-IMS systems are based on nitrogen as a carrier gas, this approach was optimized and translated to a fast, hydrogen-based GC method. This was applied to a set of commercial cocoa liquor and data were evaluated by machine learning approaches, such as multivariate curve resolution-alternating least squares (MCR-ALS) and partial least squares-discriminant analysis (PLS-DA). By cutting down the analysis time by a factor of 2.5, this study demonstrates that in contrast to most conventional gas chromatography-mass spectrometry (GC-MS) systems, GC-IMS can be easily optimized towards higher throughput using the faster flow rates possible with hydrogen. Furthermore, this leads to enhanced signal quality and thus, a better basis for machine learning and finally, to an optimal tool for the classification of raw cocoa origins. Therefore, H2-based GC-IMS can be considered as a greener, resource-friendly, and efficient approach for the analysis of volatile food and beverage samples.}, } @article {pmid41806968, year = {2026}, author = {Kim, J and Kim, S and Sreshta, SD and Debnath, U and Choo, YJ and Chang, MC}, title = {Long-wave infrared imaging for respiratory rate measurement in a patient with amyotrophic lateral sclerosis: A case report.}, journal = {The Journal of international medical research}, volume = {54}, number = {3}, pages = {3000605261429206}, pmid = {41806968}, issn = {1473-2300}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Electrocardiography ; *Infrared Rays ; Monitoring, Physiologic/methods ; *Respiratory Rate/physiology ; }, abstract = {Respiratory monitoring is important in amyotrophic lateral sclerosis patients as progressive respiratory muscle weakness often leads to respiratory failure. We performed single-case feasibility evaluation of long-wave infrared imaging for noncontact respiratory rate estimation in a hospitalized amyotrophic lateral sclerosis patient and compared it with red-green-blue camera-based optical flow analysis and electrocardiogram-derived respiration. Respiratory rate was assessed using four methods: (a) manual counting as the ground truth; (b) long-wave infrared; (c) red-green-blue; and (d) single-lead electrocardiogram under three lighting conditions (regular, dim, and dark) with three 1-min trials per condition. Estimation accuracy was evaluated using mean absolute error relative to manual counting. Long-wave infrared imaging demonstrated the highest accuracy across all lighting conditions, with mean absolute errors of 1.67, 0.33, and 2.33 breaths per min, respectively. Red-green-blue-based estimation performed moderately well under regular and dim lighting but showed reduced accuracy in darkness, including one failed trial. Electrocardiogram-derived respiration showed the lowest accuracy and greatest variability across conditions. The limitations of the present study include its single-case design and absence of objective flow-based respiratory reference signals. However, this study demonstrates the feasibility and illumination robustness of long-wave infrared-based noncontact respiratory rate estimation in a hospital environment and supports further investigation of this approach for respiratory monitoring in amyotrophic lateral sclerosis patients.}, } @article {pmid41807703, year = {2026}, author = {Guo, S and Jin, H and Sun, H and Huang, S and Chen, Y and Chang, Y and Zhang, Y and Ding, L and Chen, S and Fu, C and Yin, Y and Cheng, W}, title = {TDP-43 pathology triggers neuroinflammation and cognitive impairment by inducing microglial necroptosis.}, journal = {EMBO molecular medicine}, volume = {18}, number = {4}, pages = {1318-1341}, pmid = {41807703}, issn = {1757-4684}, support = {82472014//MOST | National Natural Science Foundation of China (NSFC)/ ; 24ZR1450000//STCSM | Natural Science Foundation of Shanghai Municipality ()/ ; 23ZR1441200//STCSM | Natural Science Foundation of Shanghai Municipality ()/ ; }, mesh = {Animals ; *Microglia/pathology/metabolism ; *Necroptosis ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/genetics/antagonists & inhibitors ; *Neuroinflammatory Diseases/pathology/metabolism ; Humans ; *Cognitive Dysfunction/pathology/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Quinolines ; Benzothiazoles ; }, abstract = {Pathological TAR DNA-binding protein-43 (TDP-43) is a defining feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). However, the mechanism by which TDP-43 pathology disrupts microglial function and drives neuroinflammation remains unclear. In this study, we demonstrated that cytoplasmically mis-localized TDP-43 exacerbated neuroinflammation, induced cell death, and impaired phagocytic function in microglial cells, primarily through receptor interacting serine/threonine kinase 3 (RIPK3)-dependent necroptosis. Pharmacological inhibition of RIPK3 with GSK872 markedly attenuated these pathological effects in vitro. These findings were further corroborated in a murine model with cytoplasmic TDP-43 mis-localization, where GSK872 treatment remarkably alleviated neuroinflammation and restored cognitive deficits. Mechanistically, our findings indicate that the nuclear depletion of TDP-43, resulted from its cytoplasmic mis-localization, impairs its ability to transcriptionally repress the Ripk3 gene, subsequently leading to RIPK3 upregulation and activation of RIPK3-dependent necroptosis. Collectively, our findings establish RIPK3-dependent necroptosis as a critical driver of TDP-43 pathology-mediated neuroinflammation and identified necroptosis as a promising therapeutic target in TDP-43-associated neurodegenerative disorders.}, } @article {pmid41807755, year = {2026}, author = {Chakraborty, A and Mitra, J and Malojirao, VH and Kodavati, M and Mandal, SM and Gill, SK and Sreenivasmurthy, SG and Vasquez, V and Mankevich, M and Van Den Bosch, L and Garruto, RM and Robey, I and Krishnan, B and Ghosh, G and Hegde, ML and Hazra, T}, title = {Fructose-2,6-bisphosphate restores TDP-43 pathology-driven genome repair deficiency in motor neuron diseases.}, journal = {Communications biology}, volume = {9}, number = {1}, pages = {}, pmid = {41807755}, issn = {2399-3642}, support = {R56NS073976//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Humans ; Animals ; *DNA-Binding Proteins/metabolism/genetics ; *DNA Repair/drug effects ; *Motor Neuron Disease/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Drosophila melanogaster ; DNA Repair Enzymes/metabolism ; Female ; }, abstract = {TDP-43 proteinopathy is central to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 plays a key role in DNA double-strand break repair (DSBR), though the underlying mechanisms remain unclear. Here, we demonstrate that ALS patients' brains exhibit persistent DNA damage within transcribed genes. Mechanistically, activity of polynucleotide kinase 3'-phosphatase (PNKP), an essential DNA end-processing enzyme required for DSBR in transcribed genes, is impaired in ALS brains and TDP-43-depleted cells. Such defect stems from reduced levels of PNKP-interacting enzyme phosphofructo-2- kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and its metabolic product fructose-2,6- bisphosphate (F2,6BP), an essential cofactor of PNKP. F2,6BP supplementation reduces cytosolic aggregation of phosphorylated and polyubiquitinated TDP-43 in patient-derived induced neurons, rescues PNKP activity in ALS/FTD brain extracts, and improves motor deficits in Drosophila TDP-43 model. Together, these findings reveal a critical link between metabolic dysregulation and genomic instability in TDP-43 pathology-associated motor neuron diseases, and underscore therapeutic potential of F2,6BP.}, } @article {pmid41807991, year = {2026}, author = {Solheim, MH and Riise, T and Cortese, M and Nakken, O and Tysnes, OB and Igland, J and Bjornevik, K}, title = {Distinct Prescription Patterns Emerge Years Before ALS Diagnosis: A Nationwide Registry-Based Study.}, journal = {Annals of neurology}, volume = {99}, number = {6}, pages = {1516-1525}, pmid = {41807991}, issn = {1531-8249}, support = {F-12830//Helse Vest/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/epidemiology ; *Registries ; Female ; Male ; Norway/epidemiology ; Case-Control Studies ; Middle Aged ; Aged ; *Prodromal Symptoms ; *Drug Prescriptions/statistics & numerical data ; Adult ; *Practice Patterns, Physicians'/statistics & numerical data ; }, abstract = {OBJECTIVE: The prodromal phase of amyotrophic lateral sclerosis (ALS) is poorly defined. We aimed to characterize prescription drug use patterns in the pre-diagnostic period by analyzing nationwide prescription data to identify the earliest divergence between individuals who developed ALS and matched healthy controls. We used this divergence as an indirect marker to estimate the onset and duration of the prodrome.

METHODS: We conducted a nested case-control study using nationwide Norwegian registries (2005-2019). ALS cases were individually matched to 100 controls by sex, age, and education level using incidence density sampling. Drug prescription data were gathered from the Norwegian Prescription Database (NorPD). We calculated prescription rates up to 10 years before diagnosis, performed lag-time analyses, and used machine learning to predict ALS based on drug prescription patterns.

RESULTS: We identified 2,084 incident patients with ALS and 208,400 matched healthy controls. Overall, changes in prescription patterns occurred 2 to 3 years before ALS diagnosis. Among specific drug groups, 25 of 42 therapeutic drug classes were prescribed more frequently to patients with ALS than matched controls. Muscle relaxants and bone disease treatments were prescribed significantly more frequently 6 and 5 years before diagnosis, respectively.

INTERPRETATION: Prescription pattern changes occurred as early as 6 years before ALS diagnosis. These findings are consistent with a prodromal phase preceding the clinical stage of ALS, which may last several years. In contrast, the broad increase in medication use during the final year before diagnosis likely reflects increased health care utilization as patients seek treatment for the various emerging symptoms of the clinically manifest disease. ANN NEUROL 2026;99:1516-1525.}, } @article {pmid41808791, year = {2025}, author = {van Rensburg, LC and Majiet, N and Vincent-Lambert, C and Stassen, W}, title = {A retrospective review of advanced life support interfacility transfers of the public sector emergency medical service in the Western Cape Province, South Africa.}, journal = {The Southern African journal of critical care : the official journal of the Critical Care Society}, volume = {41}, number = {3}, pages = {e3282}, pmid = {41808791}, issn = {2078-676X}, abstract = {BACKGROUND: The need for critical care transfers (CCTs) has increased in recent years owing to the growing prevalence of high-acuity patients who require access to specialised care and/or resources that are not readily available at the facility where they find themselves. During their transfer from one facility to another, critically ill and injured patients commonly require ongoing care, monitoring and interventions that can only be provided by transfer teams with advanced training and appropriate equipment. In South Africa (SA), these transfers are undertaken mainly by advanced life support (ALS) providers with variable amounts of training. Understanding the demographics and needs of CCT patients in specific contexts is essential to inform training and policy.

OBJECTIVES: To broadly describe the population of adult patients undergoing CCTs facilitated by the public sector emergency medical service (EMS) in the Western Cape Province, South Africa. Patient demographics (age and gender), time intervals (response time, scene time, transfer time), primary diagnosis (respiratory, cardiovascular, gastrointestinal tract, and others), attachments, and clinical or pharmacological interventions.

METHODS: A retrospective descriptive analysis was conducted on electronic patient care records (ePCRs) logged in the EMS's Computer-Aided Dispatch (CAD) database from January 2018 to December 2021. As no universal criteria currently exist for distinguishing a CCT from another transfer, our focus was on cases that required ALS care during the transfer.

RESULTS: During the study period, 25 635 adult patients underwent ALS transfers, with a nearly equal gender distribution. The median patient age was 40 (range 18 - 101) years. Sixty percent of patients were triaged as orange upon arrival (for urgent management) and the remainder red (for emergency or immediate management). Average response, preparation, and transport times spent (minutes:seconds) were 7:10, 16:58, and 12:56, respectively. Respiratory disease (17.9%), cardiovascular disease (12.2%), and central nervous system disorders (12.0%) were the most prevalent clinical conditions. Non-invasive blood pressure monitors (98%) and pulse oximeters (96%) were commonly used devices. Medications were administered to 22% of patients, primarily via intravenous injection (7.5%) and continuous infusion (6.7%). Morphine (4.3%), midazolam (6.4%), and adrenaline (2.0%) were frequently utilised medications. These findings highlight the demographic profile, clinical conditions, and critical care aspects involved in ALS patient transfers, emphasising the complexity and urgency of prehospital medical transport.

CONCLUSION: This study analyses adult patients undergoing ALS transfers by a public sector EMS in the Western Cape, SA (2018 - 2021), providing insights into the transferred patient population. It highlights the importance of continuous patient monitoring, especially electrocardiograms (ECGs), and reveals inconsistencies in medication practices, indicating the need for improved training. The findings stress the necessity for standardised protocols and structured training programmes to inform educational initiatives, equipment procurement, and the critical care retrieval services (CCRS) curriculum development. Additionally, this research can help establish clinical standards for dispatching specific ALS cadres based on patient needs.

CONTRIBUTION OF THE STUDY: This study provides the first large, system-wide description of 25 635 adult advanced life support (ALS) interfacility transfers in the Western Cape public emergency medical service (2018 - 2021), detailing patient profiles, monitoring, devices, and medications. By mapping real-world care patterns, especially gaps in electrocardiograph monitoring and analgesia/sedation for ventilated patients, it generates the empirical baseline needed to standardise protocols and formally develop a critical care retrieval services (CCRS) curriculum aligned to local needs. The findings also support evidence-based equipment planning and ALS cadre dispatch criteria.}, } @article {pmid41809005, year = {2026}, author = {Liu, Y and Feng, W and Aikedan, A and Lee, SI and Bhagwat, M and Nagiri, RK and Wong, MY and Amin, S and Qu, W and Zhu, J and Wang, SY and Ye, P and Norman, K and Coronas-Samano, G and Olah, M and Tilgner, HU and Fan, L and Sinha, SC and Gan, L}, title = {cGAS inhibition delays TDP-43-driven ALS Pathogenesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41809005}, issn = {2692-8205}, support = {R01 AG074541/AG/NIA NIH HHS/United States ; RF1 AG079557/AG/NIA NIH HHS/United States ; R00 AG078493/AG/NIA NIH HHS/United States ; K99 AG078493/AG/NIA NIH HHS/United States ; R01 AG072758/AG/NIA NIH HHS/United States ; R01 AG079291/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by motor neuron loss and cytoplasmic mislocalization of TAR DNA-binding protein 43 (TDP-43), a key regulator of RNA splicing. However, the upstream modulators of this process remain poorly defined. Here we identify cyclic GMP-AMP synthase (cGAS) as a central mediator of TDP-43 pathology and associated mis-splicing. cGAS expression was elevated in ALS patient brains and enriched across activated microglia. In human iPSC-derived microglia-motor neuron co-cultures, neuronal TDP-43 pathology triggered microglial cGAS activation, whereas pharmacological inhibition with a potent human cGAS inhibitor reduced phosphorylated TDP-43, restored lysosomal and phagocytic programs, normalized microglial reactivity, and reversed TDP-43-associated RNA splicing defects. In vivo, cGAS inhibition in TDP-43 Q331K mice reversed widespread RNA splicing abnormalities across neurons and oligodendrocyte lineage cells, attenuated neurodegenerative pathology, and preserved motor function. Together, these findings identify cGAS as a druggable upstream regulator linking innate immune signaling to TDP-43-dependent RNA mis-splicing and neurodegeneration, and establish cGAS inhibition as a promising therapeutic strategy for ALS.}, } @article {pmid41809250, year = {2026}, author = {Etesin, AU and Okoeguale, EE}, title = {Assessment of basic airway management among paramedic students at the University of Benin teaching hospital: A cross-sectional study.}, journal = {African journal of emergency medicine : Revue africaine de la medecine d'urgence}, volume = {16}, number = {2}, pages = {100956}, pmid = {41809250}, issn = {2211-4203}, abstract = {INTRODUCTION: Basic airway management (BAM) is the cornerstone of pre-hospital care and an expected competence of all paramedics. In Nigeria, paramedic training is relatively young and lacks regulatory oversight to ensure the competence of the workforce. This study assessed the knowledge, self-reported practice, self-reported confidence, and barriers to practice of BAM among paramedic students at the University of Benin Teaching Hospital (UBTH).

METHODS: A descriptive cross-sectional survey was conducted among paramedic students (2nd to 5th year) at UBTH from September 1 to 14, 2025. Census sampling was used, and a validated questionnaire assessed knowledge (16 items), self-reported practice, self-reported confidence (7-item Likert scale), and barriers to basic airway management. Knowledge scores were categorised as good (>70%), moderate (50-69%), or poor (<50%). Chi-square tests and multivariate logistic regression identified factors associated with knowledge and confidence.

RESULTS: Of 125 respondents, 87.2% demonstrated good knowledge of basic airway management (mean score 12.76±1.16). Only 11.2% had never performed BAM in any setting. Most participants reported high (50.4%) or moderate (42.4%) confidence. Good knowledge was significantly associated with emergency department exposure in the last 3 months (OR=6.32, p=0.014), recent BLS/ALS certification (OR=9.41, p=0.026), and combined self-reported practice on simulation and real patients (OR=13.00, p=0.001).

CONCLUSION: Paramedic students at UBTH demonstrated good knowledge and confidence in BAM. Self-reported practice of BAM on both simulation and real patients was associated with knowledge, while real patient experience was strongly associated with confidence. To improve paramedic training, curricula should prioritise integrated learning approaches that provide both simulation facilities for skill development and adequate supervised clinical exposure.}, } @article {pmid41809457, year = {2026}, author = {Maurya, P and Gupta, A and Gupta, N}, title = {Influence of blood transfusion on outcomes in patients with gastric cancer.}, journal = {World journal of gastroenterology}, volume = {32}, number = {10}, pages = {115683}, pmid = {41809457}, issn = {2219-2840}, mesh = {Humans ; *Blood Loss, Surgical/prevention & control ; *Blood Transfusion/statistics & numerical data ; *Gastrectomy/adverse effects ; *Stomach Neoplasms/surgery/mortality/immunology/therapy ; *Transfusion Reaction/immunology ; Treatment Outcome ; }, abstract = {Chen et al's research provides valuable data supporting the cautious use of transfusions during gastric cancer surgery. However, to interpret causality, it must be acknowledged that recent tend-adjusted studies have consistently shown that the independent effect of transfusions may be smaller than that shown in unadjusted analyses. Future research should employ the following approaches: (1) Extended temporal characterization; (2) Functional immunological assessment; (3) Prospective designs incorporating detailed transfusion data; (4) Machine learning methods; and (5) Mechanistic studies. The relationship between transfusions and cancer treatment outcomes goes far beyond simple immunosuppression or inflammation. It reflects a complex interplay between patient vulnerability, surgical factors, and immune responses, requiring a comprehensive study across multiple biological levels and temporal dimensions.}, } @article {pmid41809632, year = {2026}, author = {Mazurek, CY and Kaniuk, JK and Ahuja, CS}, title = {Mesenchymal stem cells and the central nervous system: historical perspectives and future directions.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1742864}, pmid = {41809632}, issn = {1662-5099}, abstract = {Mesenchymal stem cells (MSCs) have been studied as a potential therapy for a wide range of conditions for approximately 30 years. MSCs have shown promise in treating pathologies of or affecting the central nervous system (CNS), specifically Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), traumatic brain injury (TBI), degenerative disc disease (DDD), and sepsis/meningitis. The therapeutic benefits of MSCs derive primarily from their arsenal of secreted factors that promote anti-inflammatory and pro-survival pathways while attenuating harmful immune responses, thus making them powerful immunomodulatory entities which are also capable of affecting a diverse range of cellular functions to promote endogenous mechanisms of repair. This review summarizes the current state of clinical trials research regarding pathologies of the CNS with a focus on historical progression and upcoming trials. We take a mechanistic approach to explain the therapeutic basis of MSCs and how this has informed clinical trials. We also mention the role of the MSC secretome and MSC exosomes in the treatment of CNS pathologies as well as their increasing use in clinical trials. Finally, we address the challenges inherent to the clinical translation and implementation of MSC therapies along with future directions of the field.}, } @article {pmid41809878, year = {2026}, author = {Xu, S and Zhu, Z and Zhang, HM and Xu, YT and Shi, PH and Zheng, Y and Chen, YT and Lu, GR and Zheng, BJ}, title = {Targeting Dialister-driven succinate accumulation: A novel strategy for Crohn's disease activity control and recurrence prevention.}, journal = {World journal of gastroenterology}, volume = {32}, number = {8}, pages = {116173}, pmid = {41809878}, issn = {2219-2840}, mesh = {Humans ; *Crohn Disease/microbiology/metabolism/surgery/blood ; *Succinic Acid/metabolism/blood ; Recurrence ; Secondary Prevention/methods ; *Gastrointestinal Microbiome/drug effects/immunology ; Feces/microbiology ; Severity of Illness Index ; Quality of Life ; }, abstract = {Crohn's disease (CD) activity and postoperative recurrence significantly affect patients' quality of life, highlighting the need for new treatment and prevention strategies. We read with interest Boronat-Toscano et al's study on Dialister-driven succinate accumulation in CD. By analyzing the fecal microbiota, circulating succinate levels, and clinical indices using clinical samples, the researchers explored the roles of Dialister and succinate in CD, a previously unaddressed area. They revealed that active CD is characterized by high succinate levels, which are associated with disease severity and inflammatory indicators. The enrichment of Dialister, linked to impaired succinate clearance and postoperative recurrence, offers new insights. The study identified succinate and Dialister as potential therapeutic targets, advancing understanding of CD pathophysiology and paving the way for further investigations. Future studies should involve large, multicenter cohorts for validation, explore Dialister's strain-specific metabolic mechanisms, and develop treatments targeting the "succinate axis", thus connecting fundamental research with clinical applications.}, } @article {pmid41810116, year = {2026}, author = {Azarraga, RB and Jackson, MC and Fraix, MP and Agrawal, DK}, title = {Innovation, Adaptation, and Human Dignity in Assistive Robotics in Amyotrophic Lateral Sclerosis: A Rehabilitation Medicine Perspective.}, journal = {Journal of biotechnology and biomedicine}, volume = {9}, number = {1}, pages = {28-39}, pmid = {41810116}, issn = {2642-9128}, support = {R25 AI179582/AI/NIAID NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive motor neuron disease that heavily impacts a person's ability to perform activities of daily living, affecting mobility, function, and communication drastically. These complications present a daunting obstacle for familial support systems and physicians to manage. Although survival prognosis in ALS patients has moderately improved with the advent of ALS specialty clinics, this illness persists as a grim diagnosis with no current cure or hope for recovery, simply an inescapable decline. However, assistive robotics provides a promising opportunity in empowering patients to retain control of their lives. This comprehensive review explores the current developments in assistive robotics for ALS patients across various aspects of daily living. Our review accentuates how robotics can make a significant impact on quality of life, preserving physical capabilities and patient agency. Potential barriers have also been identified, such as cost, accessibility and ethical considerations. However, there is limited information with case-controlled studies and robust research addressing ALS from this scope. Within the lens of rehabilitation, these technologies present the opportunity to preserve autonomy, the ability to still care for oneself, to perform the "everyday" tasks, the things that make life still meaningful. This critical review highlights the humanistic potential that the future of this emerging field holds; to innovate and bridge the technical with the personal; and to approach decline with empathy, adaptability and respect.}, } @article {pmid41810938, year = {2026}, author = {Singh, J and Lescouzères, L and Zaouter, C and Chaineau, M and Haghi, G and Durcan, TM and Patten, SA}, title = {PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag092}, pmid = {41810938}, issn = {1460-2156}, abstract = {A hexanucleotide (GGGGCC) repeat expansion in C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), resulting in reduced C9orf72 mRNA and protein expression. C9orf72 is highly expressed in the cerebellum and growing evidence implicates C9orf72-associated cerebellar pathology across neurodegenerative disorders including ALS/FTD, yet the pathogenic mechanisms remain unresolved. Here, we demonstrate in vivo C9orf72 loss of function leads to cerebellar atrophy, loss of GABAergic interneurons, and depletion of Purkinje and Granule cells. Additionally, we demonstrate that these cerebellar anomalies precede motor defects. Single-cell transcriptomics of the C9orf72-zebrafish brain revealed the downregulation of a purine biosynthetic gene paics in Purkinje cells. Furthermore, we demonstrate the reduced expression of PAICS in the human post-mortem cerebellar sections and iPSC-derived motor neurons from C9orf72 and sporadic ALS patients. Knockout of paics in zebrafish recapitulates cerebellar neuronal loss, neuromuscular junction disruption, motor impairment and widespread DNA damage and repair (DDR) defects including suppression of key DNA repair pathways. Restoring paics expression in C9orf72 zebrafish resolves DNA damage and preserves Purkinje cells and Granule cells, revealing PAICS as a critical mediator of cerebellar degeneration and a promising therapeutic avenue for C9orf72-associated ALS and FTD.}, } @article {pmid41810942, year = {2026}, author = {Jain, K and Shukla, N and Kaur, A and Kalita, B and Srivastava, S and Yadav, S and Rani, P and Kagra, P and Singh, A and Chaudhary, K and Kaur, H and Patel, J and Chauhan, M and Tarai, B and Narayan, J and Chauhan, N and Chowdhary, A}, title = {Genomic insights into a clade-specific Candida tropicalis lineage with resistance to azoles and immune evasion traits.}, journal = {mBio}, volume = {17}, number = {4}, pages = {e0023526}, pmid = {41810942}, issn = {2150-7511}, mesh = {*Azoles/pharmacology ; Humans ; *Antifungal Agents/pharmacology ; *Drug Resistance, Fungal/genetics ; *Candida tropicalis/genetics/drug effects/classification/immunology/isolation & purification ; India ; *Immune Evasion ; Phylogeny ; Whole Genome Sequencing ; Multilocus Sequence Typing ; Microbial Sensitivity Tests ; Candidiasis/microbiology ; Genome, Fungal ; Fluconazole/pharmacology ; Genomics ; }, abstract = {Candida tropicalis is a leading cause of invasive candidiasis in the Asia-Pacific region with reported crude mortality rates exceeding 50%. The rising prevalence of azole-resistant strains presents a significant clinical challenge. We analyzed 1,016 C. tropicalis clinical isolates collected over nine years from 27 hospitals across North India. Fluconazole resistance was detected in 5.1% (n = 52) of isolates, with cross-resistance observed to voriconazole in 55.7% and itraconazole in 44.2% of isolates. Multilocus sequence typing (MLST) analysis of global 1,630 isolates including 208 Indian and whole-genome sequencing of 716 global isolates (139 Indian) confirmed the clonal emergence and persistence of azole-resistant MLST clade 4 strains in Indian hospitals. Phylogenomic analyses identified that Indian azole-resistant lineage was closely related to azole-resistant isolates from mainland China and Taiwan. The underlying mechanism of resistance involved hotspot mutations (Y132F) in the ERG11 gene along with its duplication, overexpression, and twofold high ergosterol content. Comparative transcriptomics of two clinical isolates exhibiting >512 fold difference in fluconazole susceptibility identified upregulation of virulence-associated genes, ALS7 gene (eightfold), SAP7 and SAP9 (1.6- and 2-fold, respectively) in azole-resistant isolate. Furthermore, azole-resistant isolates showed robust biofilm-associated metabolic activity (twofold), reduced β-glucan exposure, and greater survival in both neutrophil and macrophage killing assays. Notably, azole-resistant lineage exhibits several traits associated with adhesion and immune evasion that could possibly enable its spread in healthcare settings and signals the beginning of a greater spread of this clone. The urgent need for continuous genomic surveillance and antifungal stewardship is warranted to mitigate the spread of multidrug-resistant C. tropicalis.IMPORTANCEInvasive fungal infections affect 6.5 million people annually and are associated with high mortality rates. Despite being the leading cause of invasive yeast infections in the Asia-Pacific, this is the first comprehensive study of Candida tropicalis from India documenting the emergence of azole-resistant clonal lineage (clade 4) in several hospitals in India. Azole resistance is driven by mutations, gene duplication, and overexpression of its target gene ERG11. The Indian azole-resistant isolates showed high genetic relatedness with those from China. Also, resistant isolate showed overexpression of virulence-related genes and robust biofilm formation. Notably, reduced β-glucan exposure in fluconazole-resistant isolates may contribute to their decreased susceptibility to the innate immune system. Importantly, this study provides evidence for the emergence of azole-resistant C. tropicalis lineage in India, which exhibits several traits associated with adhesion and immune evasion that could possibly enable its spread in healthcare settings leading to a public health concern.}, } @article {pmid41811044, year = {2025}, author = {Wang, Y and Lu, Z and Cheng, S and Wang, Y and Yuan, H and Yuan, H}, title = {[Clinical phenotype and genetic analysis of a child with Acid-labile subunit deficiency due to variant of IGFALS gene].}, journal = {Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics}, volume = {42}, number = {12}, pages = {1465-1470}, doi = {10.3760/cma.j.cn511374-20241122-00615}, pmid = {41811044}, issn = {1003-9406}, mesh = {Humans ; Male ; Phenotype ; Child, Preschool ; *Carrier Proteins/genetics ; Insulin-Like Growth Factor Binding Protein 3/genetics/blood ; *Glycoproteins/deficiency/genetics ; Insulin-Like Growth Factor I/metabolism/genetics ; Pedigree ; Exome Sequencing ; }, abstract = {OBJECTIVE: To explore the clinical phenotypes and genetic characteristics of a child with Acid-labile subunit deficiency (ALS).

METHODS: A male child diagnosed with ALS at Dongguan Maternal and Child Health Care Hospital in March 2021 was selected as the study subject. Clinical data of his family was collected. Peripheral blood samples were collected from the child and his parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out, and Sanger sequencing was used for family verification of candidate variants. Based on guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of the candidate variant was classified. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 2020-6).

RESULTS: The patient, a 5-year-and-7-month-old boy, presented with short stature and delayed bone age. Endocrine examinations showed decreased serum concentrations of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP3). WES revealed that he has harbored compound heterozygous variants of the IGFALS gene, namely c.741_742del, p.Y248Pfs83 and c.272del, p.P91Rfs31. Sanger sequencing verified that the variants were inherited from his father and mother, respectively. According to the ACMG guidelines, c.741_742del, p.Y248Pfs83 and c.272del, p.P91Rfs31 variants were classified as likely pathogenic (PVS1+PM2_supporting). Based on the pre-set literature search strategy, 11 research literature on ALS were retrieved, which involved a total of 33 families and 62 patients. Combined with the patient in this study, 31 IGFALS gene variants were identified among the 63 patients, which mainly consisted of missense variants (20 types), with variant sites concentrated in exon 2. The main clinical features were short stature in conjunct with delayed puberty, with a significant genotype-phenotype correlation.

CONCLUSION: The IGFALS gene variants NM_004970.2: c.741_742del, p.Y248Pfs83 and c.272del, p.P91Rfs31 may be the genetic etiology in this family. This study has expanded the variant spectrum of the IGFALS gene and provided valuable information for the diagnosis, genetic counseling and clinical treatment of the disease.}, } @article {pmid41812870, year = {2026}, author = {Antonucci, S and Caron, G and Dikwella, N and Krishnamurthy, SS and Harster, A and Wasicki, B and Zarrin, H and Tahanis, A and Heuvel, FO and Danner, SM and Ludolph, AC and Grycz, K and Bączyk, M and Zytnicki, D and Roselli, F}, title = {Spinal motoneuron excitability is homeostatically regulated through β-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice.}, journal = {Progress in neurobiology}, volume = {260}, number = {}, pages = {102905}, pmid = {41812870}, issn = {1873-5118}, support = {R01 NS110953/NS/NINDS NIH HHS/United States ; R01 NS112304/NS/NINDS NIH HHS/United States ; R01 NS115900/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Homeostasis/physiology ; Superoxide Dismutase-1/genetics ; Mice, Transgenic ; *Motor Neurons/physiology/metabolism/drug effects ; Mice ; *Spinal Cord/metabolism ; *Receptors, Adrenergic, beta-2/metabolism ; *Receptors, Adrenergic, beta-3/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; }, abstract = {Homeostatic feedback loops are essential to stabilize the activity of neurons and neuronal networks. It has been hypothesized that, in the context of Amyotrophic Lateral Sclerosis (ALS), an excessive gain in feedback loops might hyper- or hypo-excite motoneurons (MNs) and contribute to the pathogenesis. Here, we investigated how the neuromodulation of MN intrinsic properties is homeostatically controlled in presymptomatic adult SOD1(G93A) mice and in the age-matched control WT mice. First, we determined that Adrb2 and Adrb3 adrenergic receptors, which are Gs-coupled receptors and subject to tight and robust feedback loops, are specifically expressed in spinal MNs of both SOD1 and WT mice at P45. We then demonstrated that these receptors elicit a so-far overlooked neuromodulation of the electrical properties of MNs, in particular the frequency-current gain, a crucial determinant of excitability. These electrical properties are homeostatically regulated following receptor engagement, which triggers ion channel transcriptional changes and downregulates those receptors. These homeostatic feedbacks are not dysregulated in presymptomatic SOD1 mice, and they set the MN excitability upon β-adrenergic neuromodulation.}, } @article {pmid41813079, year = {2026}, author = {Zhang, Z and Gong, Z and Li, W and Wei, Y and Zou, C and Fang, D and Feng, L and Gao, W and Chen, L and Tang, X and Ma, L and Lin, H}, title = {OCT-based myopic index: a biological predictor for the progression of high myopia.}, journal = {The British journal of ophthalmology}, volume = {110}, number = {10}, pages = {1201-1208}, doi = {10.1136/bjo-2024-327063}, pmid = {41813079}, issn = {1468-2079}, mesh = {Humans ; *Tomography, Optical Coherence/methods ; *Axial Length, Eye/pathology/diagnostic imaging ; Disease Progression ; *Myopia/diagnosis/physiopathology ; Female ; *Myopia, Degenerative/diagnosis/physiopathology ; Biometry ; Male ; Adult ; Prospective Studies ; *Refraction, Ocular/physiology ; Deep Learning ; Young Adult ; }, abstract = {BACKGROUND: The growth of axial length (AL) can lead to high myopia and ocular deformation, especially causing microstructural changes in the fundus, which cannot be fully quantified by AL alone. We propose an optical coherence tomography (OCT)-based modified AL (Myopic Index) to represent the extent of fundus deformation caused by AL elongation and to explore its clinical significance in myopic progression prediction.

METHODS: A deep learning model was trained using 27 539 cases of OCT images and referred ocular biometric data to evaluate the Myopic Index. By comparing the Myopia Index with the Measured AL, the difference of two AL indices (DAL) was calculated. We further prospectively employed 2866 cases of OCT images, which were categorised into short AL (Measured AL<22 mm), normal AL (22 mm≤Measured AL<26 mm) and long AL (≥26 mm), to evaluate the model ability of myopic progression prediction. The attention regions of images were also analysed.

RESULTS: The Myopia Index was closely correlated with Measured AL (all p<0.001, R²=0.804 in all eyes). Specifically, the Myopia Index was closer to the Measured AL in eyes with long ALs, whereas in eyes with short and normal axial lengths, the Myopia Index clustered around 23-24 mm. The visualisation model demonstrated that for eyes with short and normal ALs, attention regions were primarily concentrated on the retina; conversely, for eyes with long ALs, the choroidal layer and the retinal pigment epithelium layer received more attention. Moreover, DAL was significantly correlated with AL increment (p=0.038).

CONCLUSIONS: The Myopia Index reflects the real status of fundus microstructures through fundus microstructures, with a particular focus on the choroid. The Myopia Index demonstrates good predictive capabilities for high myopia progression.}, } @article {pmid41813136, year = {2026}, author = {Perry, CM and Martin, DDO}, title = {ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {46}, number = {10}, pages = {}, pmid = {41813136}, issn = {1529-2401}, mesh = {Humans ; *Huntington Disease/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Huntingtin Protein ; Animals ; *Nerve Tissue Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and Huntington disease (HD) are lethal neurodegenerative diseases affecting motor function. Though their etiology and pathology are distinct, recent evidence suggests commonalities between TAR DNA-binding protein (TDP-43), which is associated with 97% of ALS cases, and huntingtin (HTT), the causative protein of HD. ALS is a heterogeneous, lethal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, as well as brainstem and spinal cord degeneration. The causes of ALS are complex, variable, and, in some cases, unknown, but most cases involve mislocalization of the protein TDP-43. In contrast, HD is a monogenic, autosomal dominant, lethal neurodegenerative disease caused by polyglutamine expansion in HTT protein and characterized by the progressive loss of neurons in the brain, particularly in the striatum, which results in motor, cognitive, and behavioral changes. Although HD is not typically associated with motor neuron loss, recent evidence suggests a link between HTT and TDP-43 within the context of both ALS and HD, as well as links to related neurodegenerative diseases, such as frontotemporal dementia (FTD) and spinocerebellar ataxia type 2 (SCA2). Herein, we discuss confirmed cases of concurrent ALS and HD and the overlap of underlying disease mechanisms that potentially contribute to the onset and progression of these two devastating neurodegenerative diseases, with a focus on commonalities between TDP-43 and HTT. We propose that elucidating these commonalities will aid in the identification of broad-spectrum disease risk factors and potential overlapping treatment targets.}, } @article {pmid41813498, year = {2026}, author = {Reimer, RJ and Soper, B and Wilson, JL and Goncalves, AR and Cadena, J and Suarez, P and Gryshuk, AL and Osborne, TF and Grimes, KV and Ray, P}, title = {Identification of drug repurposing candidates for amyotrophic lateral sclerosis using electronic health records: a retrospective cohort study.}, journal = {The Lancet. Digital health}, volume = {8}, number = {3}, pages = {100963}, doi = {10.1016/j.landig.2025.100963}, pmid = {41813498}, issn = {2589-7500}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/mortality ; Humans ; *Electronic Health Records/statistics & numerical data ; Retrospective Studies ; *Drug Repositioning ; United States ; Male ; Female ; Middle Aged ; Aged ; Veterans/statistics & numerical data ; United States Department of Veterans Affairs ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a life expectancy of only 3-5 years and few approved treatments. To identify drug repurposing candidates for the treatment of ALS, we analysed the electronic health records (EHRs) of a large cohort of military veterans with ALS.

METHODS: We analysed the EHRs of individuals in the US Veterans Health Administration (VHA) database who were diagnosed with ALS between Jan 1, 2009 and Dec 31, 2019 to assess medication effects. Individuals without recorded prescriptions after the date of diagnosis were excluded. Two sets of criteria were applied to ascertain exposure. Exposure criteria A were met if the dispense date or the end date of the medication was within 12 months of ALS diagnosis and the end date was at least 6 months after the dispense date. Exposure criteria B were met if there were at least two dispenses within 6 months before diagnosis and 12 months after diagnosis. Propensity score-matched control groups were generated on the basis of confounders included in the EHR, with methodology of potential outcomes used to infer treatment effects. The primary outcome was death. A standard Cox proportional hazards analysis was done to assess association with survival. Survival was defined as the time from diagnosis date recorded in the EHR to death reported in the Department for Veterans Affairs Vital Status File. Follow-up survival time was censored on Dec 31, 2020, for those alive on this date. Downstream protein targets of drugs with clinically significant effects were analysed using the protein-protein interaction networks-based algorithm PathFX.

FINDINGS: The EHRs of 11 003 individuals with ALS in the VHA database were appropriate for analysis. 162 medications with treatment groups of 30 or more individuals were identified. Among these 162 medications, 27 were associated with statistically significant changes (≥0·1) in the hazard ratio (HR) for death. 18 of the medications were associated with a reduced HR for death (prolonged survival), and nine were associated with an increased HR for death (reduced survival). Drugs associated with reduced HR included HMG-CoA reductase inhibitors (simvastatin, pravastatin, lovastatin, and atorvastatin), PDE5 inhibitors (vardenafil and sildenafil), and α-adrenergic antagonists (tamsulosin and terazosin). The medications associated with an increased HR were drugs used either in the management of clinical features of ALS associated with poor outcomes or in end-of-life care. PathFx analysis identified a complex of proteins interacting with several of the identified drugs.

INTERPRETATION: To our knowledge, this analysis is the largest EHR-based study for identifying drug repurposing candidates for ALS. We identified several drugs that warrant further assessment as therapeutic options in ALS, as well as a protein network complex that might serve as a therapeutic target for ALS.

FUNDING: Congressionally Directed Medical Research Programs, US Department of Defense.}, } @article {pmid41814515, year = {2026}, author = {Khokhar, MA and O'Malley, LA and Glenny, AM and Chen, X}, title = {Oral Health Care Services, Barriers and Enablers to Maintaining Good Oral Health in Motor Neurone Disease: A Scoping Review.}, journal = {Community dentistry and oral epidemiology}, volume = {54}, number = {4}, pages = {447-461}, pmid = {41814515}, issn = {1600-0528}, support = {Glenny/Oct23/2334-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Motor Neuron Disease/complications ; *Oral Health ; Oral Hygiene ; Health Services Accessibility ; }, abstract = {OBJECTIVES: The objective of this scoping review was to map existing literature on oral health and related care in individuals with Motor Neurone Disease (MND). Specifically, the review aimed to identify barriers and facilitators to maintaining oral hygiene, summarise available clinical guidelines and patient-facing resources, and examine how oral health care is integrated within multidisciplinary management of MND.

METHODS: The review focused on oral health practices without restrictions on language, publication date or study type, excluding studies unrelated to MND or oral health. Data sources included MEDLINE, Embase, CINAHL, and grey literature such as clinical guidelines and patient resources. Screening and data extraction were performed independently by two reviewers to ensure rigor.

RESULTS: Of 847 studies screened, eleven primary studies met the inclusion criteria, comprising case reports, case series, self-reports, cross-sectional studies and letters. The grey literature search identified three clinical guidelines and eight patient information leaflets/resources. The included studies spanned diverse populations, including Amyotrophic Lateral Sclerosis (ALS) patients with varying disease subtypes and care needs, and explored oral hygiene difficulties, care barriers and unique insights from the case studies. Identified gaps highlighted the lack of integration of dental professionals into multidisciplinary care teams. Barriers such as physical limitations, caregiver dependency and limited-service accessibility were prevalent. However, caregiver involvement, multidisciplinary collaboration and innovative solutions like antimicrobial photodynamic therapy and adaptive oral aids emerged as enablers. Poor oral health was strongly associated with increased pain, aspiration pneumonia and diminished well-being, emphasising the need for targeted interventions.

CONCLUSION: Embedding oral health management within multidisciplinary care frameworks for MND patients, enhancing caregiver training, improving access to dental services and adopting innovative strategies will improve patient outcomes and inform future research.}, } @article {pmid41814574, year = {2026}, author = {Gray, LT and Garcia, R and Gubala, C and Pressley, E and Santos, R and Locatelli, ER and Madera, M}, title = {Oral Health in Amyotrophic Lateral Sclerosis: Feasibility of Oral Screening and Determinants of Poor Outcomes.}, journal = {Muscle & nerve}, volume = {73}, number = {6}, pages = {1038-1043}, pmid = {41814574}, issn = {1097-4598}, support = {24-SGP-702//ALS Association/ ; }, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/complications/epidemiology ; *Oral Health ; Male ; Middle Aged ; Aged ; Feasibility Studies ; *Oral Hygiene ; }, abstract = {INTRODUCTION: Oral hygiene represents a modifiable risk factor for systemic health and pulmonary complications yet is not routinely addressed in ALS care. This study aimed to examine the relationships between oral health, disease severity and determinants of health in people living with amyotrophic lateral sclerosis (pALS), and to identify key predictors of oral hygiene outcomes.

METHODS: Individuals with ALS completed an oral hygiene and bulbar screening during their multidisciplinary appointment. Disease demographics, determinants of health, oral health outcomes and bulbar disease outcomes were collected. Descriptives and one sample t-tests were performed to compare oral hygiene outcomes with healthy reference values. Multiple regression analyses were conducted to assess the relationship between disease demographics and oral health.

RESULTS: Sixty-two pALS aged 64.0 (+/- 10.8), 40% female, 31% Hispanic/Latino and 37% bulbar onset disease were enrolled. Compared to healthy reference values, plaque index (M = 1.45, SD = 0.52, p < 0.0001), gingival index (M = 1.25, SD = 0.46, p < 0.0001) and bleeding on probing (M = 35.26%, SD = 26.1, p < 0.0001) were elevated in pALS. Lack of dental insurance was a significant predictor of bleeding on probing (BOP) (p = 0.001), plaque (p = 0.006) and gingival scores (p = 0.001). ALSFRS-R (p < 0.03) was also predictive of greater plaque, and care partner status (p < 0.04), and age (p < 0.02) were predictors BOP. Ethnicity and dysphagia severity were not significant predictors.

DISCUSSION: Oral health screenings conducted during routine multidisciplinary visits identified periodontal disease in pALS, representing a feasible and immediately actionable pathway to improve oral care outcomes in pALS.}, } @article {pmid41814918, year = {2026}, author = {Banfi, P and Dimabuyu-Francisco, M and Nicolini, A and Compalati, E and Lax, A and Volpato, E and Garuti, G and Leonardi, G and Bach, JR and Solidoro, P}, title = {Non-invasive ventilation support during feeding tube placement in amyotrophic lateral sclerosis patients with moderate to severe ventilatory impairment: an update.}, journal = {Panminerva medica}, volume = {68}, number = {1}, pages = {10-18}, doi = {10.23736/S0031-0808.26.05313-9}, pmid = {41814918}, issn = {1827-1898}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications/physiopathology ; *Noninvasive Ventilation/methods/adverse effects ; *Enteral Nutrition/methods/adverse effects ; Gastrostomy/methods/adverse effects ; *Respiratory Insufficiency/therapy/etiology ; Treatment Outcome ; Quality of Life ; *Intubation, Gastrointestinal/adverse effects/methods ; Severity of Illness Index ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration, leading to muscle weakness and respiratory issues. Enteral nutrition is used in ALS patients when they experience severe weight loss, dysphagia, dehydration, or a risk of aspiration pneumonia. Noninvasive ventilation (NIV) is essential for managing respiratory failure in ALS patients, especially during feeding tube placement procedures. This narrative review compares percutaneous endoscopic gastrostomy (PEG), percutaneous radiologic gastrostomy (PRG), and radiologically inserted G-tube (RIG) in ALS patients receiving NIV. Studies were found through electronic database searches of Medline and Embase from 2000 to June 2025, including the Cochrane Central Register of Controlled Trials (CENTRAL), EBSCO Online Research Database, and Scopus. The main outcome was the occurrence of adverse events during and within thirty days after gastrostomy tube placement in NIV. Eleven studies involving NIV during PEG/RIG procedures were included. NIV during PEG, RIG, or PRG placement seems to be safe for ALS patients, with few adverse events reported, though future studies with higher methodological quality are needed. Additionally, the review highlights the benefits of better nutritional support, improved quality of life, interdisciplinary teamwork, increased survival rates, and personalized care.}, } @article {pmid41817655, year = {2026}, author = {Bakshi, V and Pathak, B and Majie, A and Ghosh, A and Gupta, A and Jain, N and Pandey, M and Nair, AB and Jacob, S and Mazumder, PM and Sharma, N and Kumari, N and Gorain, B}, title = {Advancement in therapeutic application of quantum dots in amyotrophic lateral sclerosis: current opportunities and challenges.}, journal = {Drug delivery and translational research}, volume = {}, number = {}, pages = {}, pmid = {41817655}, issn = {2190-3948}, abstract = {Despite advancements in healthcare settings in developed countries, the early detection and higher mortality rate associated with amyotrophic lateral sclerosis (ALS), a fatal motor neuronal disorder, remain challenging. Recently, quantum dots (QDs) have emerged as a promising nanocarrier in the prognosis and treatment of ALS owing to their unique multifunctional properties. QDs, through their photoluminescence properties upon excitation, can facilitate the identification and real-time monitoring of disease biomarkers. They also act as a nanocarrier for the targeted delivery of therapeutics, avoiding accumulation at the non-targeted sites and minimising toxicity. QDs can be fabricated to conjugate with protein biomarkers linked to ALS, such as specific proteins, nucleic acids, or genetic variants, for the diagnosis of the disease. Such fabrication could lead to enhanced identification and diagnostic patterns of ALS, thereby contributing to improved therapeutic intervention strategies. Furthermore, these tiny structures could be applied in combined biosensor formats to identify ALS-associated biomarkers in body fluids, which would be a highly sensitive diagnostic system. Subsequently, comprehensive multiomics techniques have demonstrated improved identification of newer protein targets associated with neurological complications. Overall, QDs can be explored as a potential tool to identify biomarkers relevant to ALS, diagnose the disease at its early stages, and track the effectiveness of the treatment. The integration of QD with omic-based strategies and network analysis can potentially catalyse a breakthrough in the management of ALS. Therefore, this review aims to explore the application of QDs in ALS diagnosis and management, advancements in research, clinical trials, and patents.}, } @article {pmid41818823, year = {2026}, author = {Mytiliniou, M and Wondergem, JAJ and Feliksik, M and Schmidt, T and Fuhs, T and Heinrich, D}, title = {Effect of G4C2repeat expansions on the motion of lysosomes inside neurites.}, journal = {Physical biology}, volume = {23}, number = {2}, pages = {}, doi = {10.1088/1478-3975/ae5143}, pmid = {41818823}, issn = {1478-3975}, support = {//Non-US Government Research Support type/ ; }, mesh = {*Neurites/metabolism ; *Lysosomes/metabolism ; *C9orf72 Protein/genetics ; *DNA Repeat Expansion ; Animals ; Humans ; }, abstract = {The G4C2hexanucleotide repeat expansion (HRE) in the c9orf72 locus is a mutation associated with amyotrophic lateral sclerosis. Recent evidence suggests a link with disrupted axonal trafficking in neurons. Here, using a neuronal-like cell line without or transfected with G4C2repeats, we characterize the motion of lysosomes inside neurites. The neurites grew either aligned to patterned lines, or oriented freely on a 2D-substrate. Implementing time-resolved (local) mean squared displacement analysis lysosome trajectories were split into sub-diffusive, diffusive, and super-diffusive parts. Our results suggest that in the presence of the G4C2repeats, lysosome trafficking is hampered, exhibiting overall decreased mean squared displacement and speed, more prominently inside aligned neurites. Moreover, a prominent effect in the super-diffusive drift velocity and diffusive motion diffusion coefficient was evident when the motion occurred inside aligned neurites. Trajectories which included super-diffusive motion, exhibited a varied ratio of anterograde/retrograde/neutral for both neurite geometries in the presence of G4C2repeats but a similar velocity decrease for both directions in each neurite geometry. Our findings support the hypothesis that impaired axonal trafficking emerges in the presence of the G4C2HRE, and demonstrate that this effect is more prominent when the neurites are aligned.}, } @article {pmid41819100, year = {2026}, author = {Zheng, Z and Yang, W and Chen, Z and Chen, P and Tao, M and Wang, S and Cui, B and Yang, Z and Yan, Y and Han, X and Zhang, Y and Ren, Z and Yan, X and Jiang, Y and Wang, J and Li, T and Liu, Y and Guo, X}, title = {Targeting PGAM5-driven mitochondrial integrated stress response slows ALS progression across subtypes.}, journal = {Neuron}, volume = {114}, number = {12}, pages = {2109-2127.e14}, doi = {10.1016/j.neuron.2026.02.003}, pmid = {41819100}, issn = {1097-4199}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; Humans ; *Integrated Stress Response ; Mice ; *Mitochondria/metabolism ; *Phosphoprotein Phosphatases/metabolism/genetics ; Disease Progression ; Spinal Cord/metabolism ; Mice, Transgenic ; Valosin Containing Protein/metabolism ; Neuromuscular Junction/metabolism ; Mitochondrial Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is genetically and clinically heterogeneous, yet convergent pathogenic mechanisms remain poorly defined. A CRISPR-Cas9 screen identified phosphoglycerate mutase-5 (PGAM5) as a common mediator of ALS pathogenesis. PGAM5 activates the mitochondrial integrated stress response (mtISR) via dephosphorylation of metallopeptidase OMA1 at Ser223 and Ser237, thereby driving neuromuscular junction disruption and motor deficits. We show that PGAM5 is a substrate of valosin-containing protein (VCP) and is consistently elevated in spinal cords from sporadic ALS patients, in human spinal cord organoids derived from sporadic or familial ALS, and in ALS mouse models. The disruption of PGAM5-OMA1 interaction by a selective inhibitor (TAT-PO1) or pharmacological inhibition of PGAM5 with telmisartan suppresses mtISR activation and ameliorates ALS-related phenotypes by reshaping mtISR outputs in a manner distinct from those elicited by activation of translation initiation factor 2B (eIF2B). These findings establish PGAM5 as a convergent and actionable therapeutic target across ALS subtypes.}, } @article {pmid41819726, year = {2026}, author = {Riveiro, V and Ferreiro, L and Abelleira, R and Rodríguez-Núñez, N and Toubes, ME and Ricoy, J and García-Sobrino, T and Valdés, L and Zamarrón, C}, title = {Respiratory alterations in patients with amyotrophic lateral sclerosis.}, journal = {Medicina clinica}, volume = {166}, number = {5}, pages = {107365}, doi = {10.1016/j.medcli.2026.107365}, pmid = {41819726}, issn = {1578-8989}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/epidemiology ; Retrospective Studies ; Female ; Male ; Middle Aged ; Aged ; Prevalence ; Phenotype ; Sleep Apnea, Obstructive/etiology/epidemiology ; Incidence ; Vital Capacity ; *Respiration Disorders/etiology/epidemiology ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and heterogeneous neurodegenerative disease that manifests itself in different phenotypes depending on the anatomical region affected.

PATIENTS AND METHODS: Retrospective observational study of patients diagnosed with ALS in our healthcare area, classified by phenotypes to assess their relationship with functional respiratory variables, gas exchange, and sleep-related breathing disorders. The search period was from 2014 to 2024.

RESULTS: Data from 201 patients were analyzed. The overall mean incidence of ALS was 3.8 cases (95%CI: 3.3-4.3)/100,000 inhabitants/year, while the prevalence was 9.4 cases (95%CI: 7.8-11.1)/100,000 inhabitants. The results indicated that the spinal phenotype is the most common (49.3%), while the bulbar phenotype presented greater respiratory involvement, with a lower forced vital capacity (FVC) (86% [IQR: 66.5-98]) and greater nocturnal desaturation CT90 8% (IQR: 2.3-32.5%). Likewise, a prevalence of respiratory disorders during sleep was observed, with approximately 50% mild obstructive sleep apnea (OSA), 30% moderate, and 15% severe. Severe OSA was recorded in 8% of patients with spinal ALS, 14% of patients with bulbar ALS, and 17% with other forms of ALS.

CONCLUSIONS: The disease significantly affects respiratory function, especially in the bulbar phenotype, and respiratory disturbances during sleep are common. The heterogeneity of ALS highlights the importance of a personalized approach to patient management.}, } @article {pmid41819843, year = {2026}, author = {Halablab, K and Yartas, G and Dikwella, N and Aousji, O and Ozkan, B and Jan, C and Wiesner, D and Danner, SM and Caron, G and Zytnicki, D and Roselli, F}, title = {Motoneurons Inhibitory Synapses Homeostatically Respond to Neuronal Activity and Modulate Amyotrophic Lateral Sclerosis Pathogenesis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {46}, number = {15}, pages = {}, pmid = {41819843}, issn = {1529-2401}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology/genetics ; *Motor Neurons/physiology ; *Synapses/physiology ; *Homeostasis/physiology ; Mice ; Male ; *Neural Inhibition/physiology ; Mice, Transgenic ; Humans ; Receptors, Glycine/metabolism ; }, abstract = {Alterations in excitation/inhibition (E/I) balance and changes in motor neurons (MN) activity may contribute to MN vulnerability in ALS. The balance of pathogenic versus adaptive changes occurring in inhibitory synapses and affecting E/I balance remain unclear. Confocal microscopy of MN from P45 male SOD1G93A mice reveal downregulated GlyR but upregulated GABAR clusters at inhibitory synapses. GlyR and GABAR respond to PSAM and DREADD chemogenetic alterations of MN excitability, with increased activity driving increase in inhibitory clusters. An E3 ligase-conjugated intrabody (GFE3) degrades Gephyrin, decreases GABAR and GlyR clusters, increases net activity, and downregulates disease markers. However, simultaneous decrease of inhibition and increased activity by actPSAM and GFE3 shows no net beneficial effects on disease markers. Thus inhibitory synapses are involved in the early phases of ALS pathogenesis and respond to persistent homeostatic loops, and their suppression delivers a net activity increase, offering potential benefits on disease pathways.}, } @article {pmid41820266, year = {2026}, author = {Viswanathan, V and Madhuri, G and Ganapathi, K and Kumar, N}, title = {An Unusual Presentation of Juvenile Amyotrophic Lateral Sclerosis with Superoxide Dismutase 1 Mutation: Subacute Bulbar Palsy With Asymmetric Limb Weakness.}, journal = {Annals of Indian Academy of Neurology}, volume = {29}, number = {3}, pages = {481-482}, pmid = {41820266}, issn = {0972-2327}, } @article {pmid41821014, year = {2026}, author = {Sligar, C and Sluyter, R and Ooi, L}, title = {Immune imbalance between T helper 1, T helper 17 and regulatory T cells fuels amyotrophic lateral sclerosis pathogenesis: disease trajectory, diagnosis and therapeutic implications.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {41821014}, issn = {1742-2094}, support = {AL210095//U.S. Department of Defense/ ; CE230100021//Australian Research Council Centre of Excellence in Quantum Biotechnology/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/diagnosis/therapy/pathology ; *T-Lymphocytes, Regulatory/immunology ; Animals ; *Th17 Cells/immunology ; *Th1 Cells/immunology ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease, causing motor neuron loss and with limited treatment options. Although traditionally considered non-immune in origin, accumulating evidence implicates the adaptive immune system, particularly CD4+ T cell subsets, as key modulators of disease progression. Among these, T helper (Th)1 and Th17 cells are elevated in ALS blood, cerebrospinal fluid and central nervous system tissues, and drive pro-inflammatory cascades. By contrast, regulatory T cells (Tregs) suppress pathogenic inflammation and maintain immune homeostasis; however, in ALS, both Treg number and suppressive function decline, with remaining Tregs showing reduced FOXP3 (the master transcription factor governing Treg function) expression and impaired regulatory capacity. Integrating human and preclinical evidence, we describe how ALS-associated proteins can act as autoantigens that trigger adaptive immune responses, and how Th1/Th17 amplification and Treg insufficiency couple to microglial activation, blood–brain barrier disruption, and motor neuron degeneration, to impact disease trajectory. Convergent signalling pathways and their intersection with metabolic stress provide a mechanistic link between the adaptive immune response and neurodegeneration. We outline biomarker frameworks, spanning immune cell phenotypes, cytokine signatures and transcriptional readouts that define alterations in Th1, Th17 and Treg responses in ALS. Finally, we address the emerging immunomodulatory therapeutic approaches, including the targeted blockade of specific cytokines and signalling pathways, augmentation of Treg number and function, and attenuation of Th1/Th17 activity, while preserving protective Tregs using selective small-molecule approaches. Collectively, the evidence we provide establishes adaptive T cell imbalance as a central, targetable driver of ALS neuroinflammation and provides a rationale for biomarker-guided therapeutics designed to rebalance adaptive immunity and slow disease progression.}, } @article {pmid41821328, year = {2026}, author = {Wang, HF and Sun, QH and Du, RR and Wang, SY and Wang, Y and Bai, JM and Li, M and Huang, XS}, title = {Serum Trace Elements and Their Associations with Disease Progression and Survival in Sporadic Amyotrophic Lateral Sclerosis: Insights from a Chinese Cohort.}, journal = {Biomedical and environmental sciences : BES}, volume = {39}, number = {2}, pages = {183-191}, doi = {10.3967/bes2025.094}, pmid = {41821328}, issn = {2214-0190}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality ; *Trace Elements/blood ; Disease Progression ; China/epidemiology ; Female ; Male ; Middle Aged ; Aged ; Cohort Studies ; East Asian People ; }, abstract = {OBJECTIVE: The associations of serum trace element levels with disease progression and survival duration were assessed in individuals diagnosed with sporadic amyotrophic lateral sclerosis (sALS) in China.

METHODS: Clinical data, including diagnostic indicators, clinical characteristics, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores, and serum concentrations of calcium (Ca), magnesium (Mg), iron (Fe), copper (Cu), and zinc (Zn), were collected for hospitalized patients with sALS between 2018 and 2021. Correlation analysis, random forest analysis, and the Gehan-Breslow-Wilcoxon test were used to evaluate the relations between serum trace element levels, disease progression, and survival duration.

RESULTS: Lower serum Ca levels and higher Mg levels were observed in patients with ALSFRS-R scores < 39. Serum Mg was significantly negatively correlated with ALSFRS-R, trunk, and respiratory scores. Serum Cu and Zn also showed significant negative correlations with the respiratory score, whereas Ca and Fe were not significantly correlated with the ALSFRS-R score. The serum levels of Ca, Mg, Cu, Zn, and Fe remained consistent regardless of the site of disease onset. ALSFRS-R analysis revealed that serum Ca and Mg had a substantial effect on the total ALSFRS-R score, with serum Mg significantly influencing the course of the disease. Notably, low serum Mg levels were associated with extended survival times in patients with sALS.

CONCLUSION: Serum levels of Ca and Mg play critical roles in the progression of sALS, and a reduced serum Mg level is related to an extended survival time.}, } @article {pmid41821412, year = {2026}, author = {Li, M and Chen, J and Wang, ZY and Wang, FF and Dong, LL and Pan, J and Li, ME and Yu, L and Sang, W}, title = {TcALS knockdown accelerates metamorphosis via insulin signaling in Tribolium castaneum.}, journal = {Insect science}, volume = {}, number = {}, pages = {}, doi = {10.1111/1744-7917.70273}, pmid = {41821412}, issn = {1744-7917}, support = {31701793//National Natural Science Foundation of China/ ; }, abstract = {Insect metamorphosis is an evolutionary adaptation precisely regulated by nutritional and hormonal cues. The red flour beetle Tribolium castaneum, a major stored-product pest, serves as an excellent model for studying this process. The acid-labile subunit (ALS) of insulin-like growth factor forms a trimer with insulin-like peptides and their binding proteins, prolonging insulin half-life. However, its role in T. castaneum metamorphosis remains poorly understood. Here, we found that TcALS protein is structurally conserved with a characteristic horseshoe shape. Spatiotemporal analysis showed lowest TcALS expression during the pupal stage. TcALS knockdown advanced pupation by approximately three days without altering the final emergence rate. Transcriptome and targeted qRT-PCR analyses uncovered a strict temporal hierarchy: glycosylation, autophagy, carbohydrate metabolism genes were upregulated within 24 h, whereas insulin, juvenile hormone, and 20-hydroxyecdysone signaling genes remain unchanged until 48 h. Mechanistically, TcALS knockdown diverted glucose into the hexosamine pathway and activated glycosylation; the resulting advanced glycation end-products triggered endoplasmic reticulum and oxidative stress, thereby initiating autophagy. Subsequently, insulin-juvenile hormone signaling was suppressed while 20-hydroxyecdysone levels increased, collectively driving larvae to pupate precociously. Thus, our findings establish TcALS as a nutrient-sensitive checkpoint linking early glycosylation-autophagy responses to late insulin-hormonal signaling, providing novel insights into the mechanisms of pest adaptation to nutrition.}, } @article {pmid41821425, year = {2026}, author = {Bilić, H and Begović, M and Sitaš, B and Hančević, M and Šepec, BI and Zemba Čilić, A and Peček, V and Gotovac Jerčić, K and Mateševac, J and Bahčić, T and Peček, L and Borovečki, F and Njirić, N and Nemir, J and Petrović, M and Jurjević, I and Klarica, M and Merćep, I and Bilić, E}, title = {Tofersen treatment in SOD1 p.Leu145Phe ALS: real-world outcomes in a genetically homogeneous Croatian cohort.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {689-695}, doi = {10.1080/21678421.2026.2638589}, pmid = {41821425}, issn = {2167-9223}, mesh = {Humans ; *Superoxide Dismutase-1/genetics ; Female ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/epidemiology ; Middle Aged ; Male ; Cohort Studies ; Aged ; Croatia/epidemiology ; Treatment Outcome ; Mutation/genetics ; Adult ; *Oligonucleotides, Antisense/therapeutic use ; }, abstract = {Background: Antisense oligonucleotide tofersen targets SOD1 mRNA and reduces production of misfolded SOD1 protein, with demonstrated biomarker and functional signals in clinical trials and open-label extensions. Real-world reports from genetically heterogeneous SOD1 ALS cohorts describe variable functional trajectories. Data from genetically homogeneous founder populations remain limited. We investigated clinical trajectories in a cohort carrying the same pathogenic SOD1 variant to better characterize mutation-specific patterns in a real-world setting. Methods: We conducted a single-center observational study at the National Referral Center for Neuromuscular Diseases and Clinical Electromyoneurography (UHC Zagreb, Croatia). Eight adults with genetically confirmed SOD1 p.Leu145Phe ALS received intrathecal tofersen according to the approved regimen. ALS Functional Rating Scale-Revised (ALSFRS-R) scores were recorded at each dosing visit, and longitudinal slopes were calculated using linear regression. Safety and tolerability were evaluated descriptively. Biomarker and formal respiratory measurements were not routinely available. Results: All patients exhibited lower limb-onset, predominantly lower motor neuron phenotypes consistent with a slow-progressing founder variant. Median age at symptom onset was 60 years, and median therapeutic delay was 48 months. Median on-treatment ALSFRS-R slope was -0.28 points/month (range +0.04 to -0.57). Two patients demonstrated stable trajectories, while the remainder showed gradual decline. These patterns fall within the slower range reported in heterogeneous real-world SOD1 cohorts and are consistent with the known natural history of this mutation. Tofersen was well tolerated, with no serious treatment-related adverse events. Conclusions: In this genetically homogeneous SOD1 p.Leu145Phe cohort, functional trajectories during tofersen therapy reflected the mutation's slow-progressing phenotype. These findings provide real-world clinical context but do not permit conclusions regarding treatment efficacy. Further mutation-specific studies incorporating prospective baseline assessment and biomarker monitoring are needed to clarify therapeutic impact.}, } @article {pmid41822037, year = {2026}, author = {Magee, RG and Van Deerlin, VM and McMillan, CT and Lee, EB and Elman, LB and Irwin, DJ and Mourelatos, Z}, title = {Plasma isomiRs as Candidate Biomarkers for Amyotrophic Lateral Sclerosis.}, journal = {Neurology. Genetics}, volume = {12}, number = {2}, pages = {e200366}, pmid = {41822037}, issn = {2376-7839}, support = {P01 AG066597/AG/NIA NIH HHS/United States ; RF1 NS145263/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: There are no FDA-approved diagnostic biomarkers for amyotrophic lateral sclerosis (ALS). TDP-43 is a known cofactor in the cleavage of long premature microRNAs (miRNAs) into their short, mature products. isomiRs are miRNA variants that differ in their 5' and 3' end points and regulate distinct mRNA targets. In this study, we tested the hypotheses that circulating isomiR profiles differ in the context of TAR DNA-binding Protein pathology and that isomiRs are superior to miRNAs for classification of ALS.

METHODS: We obtained RNA from plasma samples of 14 patients with ALS and 14 age-matched and sex-matched controls for sequencing on a NextSeq 2000. Data were processed using Unique Molecular Identifier tools and a custom pipeline designed to match miRNA variant sequences without mismatches. Differential expression (DE) was identified using DEseq2 at FDR ≤ 0.1. XGBoost classifiers were built using a subset of (Model 1) isomiRs or (Model 2) miRNAs that were present above a median threshold in all sequencing batches. Parameters were tuned using grid search and 10-fold cross-validation while training to distinguish ALS samples from controls among a single large public data set. Models were then validated on in-house samples and 1 publicly available holdout data set.

RESULTS: Fourteen (0.2%), 355 (2.7%), and 14 (0.7%) isomiRs were differentially expressed in in-house plasma, public ALS plasma, and public ALS serum, respectively. One (0.1%), 94 (5.5%), and 13 (2.4%) miRNAs were differentially expressed, respectively. Model 1 accurately classified in-house ALS plasma and public ALS serum (area under the curve [AUC] = 0.87) and did not distinguish 40 of 41 Alzheimer disease samples from control plasma (GSE215789; AUC = 0.47) or 60 of 77 Parkinson disease samples from control whole blood (GSE180193; AUC = 0.55). In comparison, Model 2 using miRNAs performed worse on in-house plasma (AUC = 0.49).

DISCUSSION: Analyzing individual isomiRs may improve the performance of circulating noncoding RNAs as diagnostic biomarkers of ALS.}, } @article {pmid41822653, year = {2026}, author = {Tiongson, E and Tamrazi, B and Hawes, D}, title = {An Unsuspected Intraneural Perineurioma in a Pediatric Patient: A Case Report.}, journal = {Cureus}, volume = {18}, number = {2}, pages = {e103301}, pmid = {41822653}, issn = {2168-8184}, abstract = {Perineuriomas are rare tumors arising from perineurial cells that form the protective layer surrounding peripheral nerve fascicles. Four types of perineuriomas have been described: (i) intraneural, (ii) soft tissue (extraneural), (iii) sclerosing, and (iv) mucosal. Intraneural perineuriomas are rarely reported nerve sheath tumors that primarily affect the peripheral nerves of the upper and lower extremities. In this report, we present a pediatric case in which the diagnosis of perineurioma was not suspected until lesional tissue was obtained, and the final pathologic diagnosis was made. The patient is a 17-year-old girl who presented with a three-year history of symptoms involving the left upper extremity, including weakness and cramping, which became progressively worse over time. Diagnostic workup included magnetic resonance imaging (MRI), which showed enlargement and contrast enhancement of two of the left brachial plexus nerve trunks, suggestive of an inflammatory or infectious etiology, with schwannoma or neurofibroma also listed as less likely possibilities. An electromyogram (EMG) showed findings concerning for an anterior horn cell process, including amyotrophic lateral sclerosis (ALS). Nerve conduction studies (NCS) demonstrated axonal findings only in motor nerves, and needle EMG demonstrated denervation and fasciculations in multiple muscles. An initial biopsy of the brachial plexus was performed but was non-diagnostic. Ultimately, resection of the involved nerve trunks was performed. The diagnosis of intraneural perineurioma was not suspected preoperatively and was made only after histologic and immunohistochemical examination.}, } @article {pmid41822688, year = {2026}, author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD}, title = {Immunotherapies for risk reduction in age-associated neurodegenerative diseases: impact of sex and treatment duration.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41822688}, support = {P01 AG026572/AG/NIA NIH HHS/United States ; R01 AG057931/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and non-AD dementias share chronic neuroinflammatory mechanisms that contribute to neuronal injury and disease progression. While anti-inflammatory therapies (AITs) are associated with reduced neurodegenerative disease risk, knowledge regarding the impact of biological sex and treatment duration across multiple NDDs remains limited.

METHODS: We conducted a retrospective cohort analysis using a large propensity-score-matched population (n = 190,308; 95,154 treated vs 95,154 untreated) to evaluate associations between long-term AIT exposure and incidence of major NDDs. Disease-specific and combined outcomes were assessed across drug classes (NSAIDs, corticosteroids, immunomodulators), sex, age, and therapy duration.

RESULTS: AIT exposure was associated with a significantly lower risk of developing any NDD (RR = 0.47, 95% CI 0.43-0.48, p < .0001) and was equally effective in both sexes. Risk reduction was observed for each individual disease: AD (RR = 0.40), non-AD dementia (RR = 0.51), PD (RR = 0.43), MS (RR = 0.25), and ALS (RR = 0.48). Among drug classes, immunomodulators conferred the largest reduction (RR = 0.19), followed by corticosteroids (RR = 0.41) and NSAIDs (RR = 0.42). Duration analyses revealed a graded benefit, with RR declining from 0.94 (<1 year) to 0.25 (>6 years). Risk reduction was strongest in older participants (75-79 years).

DISCUSSION: Chronic use of anti-inflammatory or immunomodulatory therapies was associated with substantially reduced incidence of multiple neurodegenerative diseases in both sexes. The strongest effects were observed with immunomodulator use and prolonged therapy duration, suggesting that sustained modulation of systemic inflammation confers broad neuroprotective effects in both sexes. These findings highlight the potential of targeting immune-inflammatory pathways for neurodegenerative disease prevention and can inform prospective mechanistic and interventional studies.}, } @article {pmid41823531, year = {2026}, author = {Chen, W and Tian, H and Wei, R and Chen, X and Jia, Y}, title = {Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review).}, journal = {International journal of molecular medicine}, volume = {57}, number = {5}, pages = {}, pmid = {41823531}, issn = {1791-244X}, mesh = {Humans ; *Ferroptosis ; *Neurodegenerative Diseases/metabolism/pathology ; *Ferritins/metabolism ; Iron/metabolism ; Animals ; Homeostasis ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, are characterized by progressive loss of neurons. Although the precise pathogenesis of such diseases is complex and multifactorial, several molecular pathways have been implicated, including the aggregation of misfolded proteins, mitochondrial dysfunction, oxidative stress, neuroinflammation and disrupted iron homeostasis. Emerging evidence has underscored the pivotal role of ferroptosis, an iron‑dependent, non‑apoptotic form of cell death, in neurodegenerative disease progression. Ferritin, characterized by a 24‑subunit hollow sphere structure composed of heavy and light chains, plays a key role in the network regulating cerebral iron homeostasis. In response to cellular iron overload, ferritin expression is upregulated to sequester labile iron and mitigate Fenton reaction‑mediated toxicity, thus exerting a cytoprotective function. Paradoxically, ferritin can be degraded via ferritinophagy, a selective autophagic process that releases toxic ferrous iron and directly triggers ferroptosis. This review systematically reviews the role of ferritin within the iron homeostasis network to elucidate the connection between the dysregulation of iron metabolism and the pathological mechanisms of neurodegenerative diseases. The study focused on the potential role of ferritin as a biomarker for early diagnosis, therapeutic strategies targeting ferritin pathways to restore iron homeostasis and the clinical translational value of magnetic resonance imaging‑based non‑invasive quantification of cerebral iron deposition. It is crucial to elucidate the multidimensional roles of ferritin in neurodegeneration to provide a theoretical foundation for precision diagnostic and therapeutic approaches.}, } @article {pmid41824494, year = {2026}, author = {Fischer, CM and Edu, IA and Šneideris, T and Baronaite, I and Toprakcioglu, Z and Deck, LT and Qian, D and Scrutton, R and Dreyer, L and Wen, J and Otzen, DE and Wu, S and Perrett, S and Knowles, TPJ}, title = {Reversibility and β-sheet formation are decoupled in tau condensate aging.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {11}, pages = {e2522993123}, pmid = {41824494}, issn = {1091-6490}, support = {101001615//EC | Horizon Europe | Excellent Science | HORIZON EUROPE European Research Council (ERC)/ ; 101023060//EC | Horizon Europe | Excellent Science | HORIZON EUROPE Marie Sklodowska-Curie Actions (MSCA)/ ; NA//Ron Thomson Research Fellowship in Alzheimer's Disease/ ; NA//Pembroke College, University of Cambridge/ ; 222094//Swiss NSF/ ; NA//Innovationfund Denmark/ ; NA//Francis and Augustus Newman Foundation/ ; 31920103011//National Natural Science Foundation of China/ ; 32371281//National Natural Science Foundation of China/ ; 22477132//National Natural Science Foundation of China/ ; 32171443//National Natural Science Foundation of China/ ; 5254039//Beijing Natural Science Foundation of China/ ; NA//Transition Bio/ ; NA//Wavebreak Therapeutics/ ; NA//National Laboratory of Biomacromolecules/ ; NA//Cambridge Centre for Misfolding Diseases/ ; NA//Finlay family/ ; }, mesh = {*tau Proteins/chemistry/metabolism ; Humans ; Thermodynamics ; Protein Conformation, beta-Strand ; *Biomolecular Condensates/chemistry/metabolism ; Protein Aggregation, Pathological/metabolism ; Neurofibrillary Tangles/metabolism ; Protein Aggregates ; }, abstract = {Neurofibrillary tangles (NFTs) formed from the protein tau disrupt neuronal function in Alzheimer's disease and are strongly associated with cognitive decline. Early events in tau aggregation are increasingly linked to the formation of biomolecular condensates, which lower the energetic barriers to pathological aggregation by acting as intermediates that transition into insoluble assemblies, a mechanism also implicated in other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite growing evidence for this pathway, the molecular basis by which reversible condensates evolve into irreversible, pathogenic aggregates has remained unclear. Here, we map the phase behavior, structural transitions, and thermodynamic reversibility of tau during condensate aging. Our results reveal that the two hallmark features of the pathological end state, β-sheet enrichment and irreversible aggregation, emerge at different rates and occupy distinct regions of the phase space, indicating that these properties are mechanistically uncoupled. Notably, we identify tau condensate phases that are β-sheet rich yet thermodynamically reversible, as well as irreversible intermediates that lack β-sheet structure. These findings expand the landscape of tau aggregate species beyond a simple linear progression toward fibrils and highlight a diverse array of intermediates with distinct structural and thermodynamic properties. This decoupling of structure and irreversibility has important implications for understanding tau aggregation mechanisms and may offer targets for therapeutic intervention.}, } @article {pmid41824753, year = {2026}, author = {Talbott, EO and Malek, AM and Song, R and Whitsel, EA and Meliker, JR and Arena, VC}, title = {Farming History, Insecticide Exposure, and the Risk of ALS Mortality.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-14}, doi = {10.1159/000551384}, pmid = {41824753}, issn = {1423-0208}, abstract = {INTRODUCTION: ALS is a neurodegenerative disorder with an unknown etiology for 90%-95% of cases. Several environmental and occupational exposures have been investigated although a prospective study examining the association of "ever living/working on a farm" (farming exposure) and insecticide exposure with risk of ALS mortality in women is lacking.

METHODS: Within the Women's Health Initiative (WHI), a nested case-control study was conducted among 93,676 women (n = 151 ALS death cases, n = 1,496 matched controls) from the WHI Observational Study. This included a questionnaire about farming and insecticide exposure history 1 year after baseline. Conditional logistic regression models adjusted for education, smoking, and physical activity estimated risk of ALS death.

RESULTS: One-third of cases and 21% of controls reported farming exposure. Cases had higher odds of farming exposure than controls (adjusted odds ratio [aOR] = 1.59, 95% CI: 1.09-2.31) and was highest at durations of 15-19 (aOR = 1.81, 95% CI: 1.02-3.21) and ≥20 years (aOR = 2.32, 95% CI: 1.10-4.87) compared to no exposure. Tests for interaction revealed that women with farming and smoking exposure had higher odds of ALS death (aOR = 2.10, 95% CI: 1.26-3.51, p = 0.0045). Little evidence was noted for increased insecticide exposure and ALS mortality risk, although power was limited.

CONCLUSION: Among post-menopausal women with 25+ years follow-up, a significant association was noted between farming exposure and risk of ALS death. This increased risk was highest among those who ever smoked. Future studies should include biomarkers of exposure and large cohorts of men and women with occupational and residential histories.}, } @article {pmid41825501, year = {2026}, author = {Liu, C and Lu, H and Li, S and Deng, G and Ma, J and Dong, J and Liu, J}, title = {Cooccurrence of myelinated retinal nerve fibers in pediatric unilateral persistent fetal vasculature: report of three cases.}, journal = {Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus}, volume = {30}, number = {2}, pages = {104794}, doi = {10.1016/j.jaapos.2026.104794}, pmid = {41825501}, issn = {1528-3933}, mesh = {Humans ; Female ; *Nerve Fibers, Myelinated/pathology ; Male ; *Cataract/congenital/complications ; Ultrasonography, Doppler, Color ; Axial Length, Eye/pathology ; *Persistent Fetal Circulation Syndrome/complications/diagnosis/surgery ; Infant ; *Persistent Hyperplastic Primary Vitreous/complications ; Vitrectomy ; }, abstract = {We report 3 pediatric cases of persistent fetal vasculature (PFV) and myelinated retinal nerve fibers (MRNF) coexisting in the same eye. All cases presented with congenital cataracts, vitreous strands, and an unusual axial length (AL) profile-specifically, the affected eyes exhibited longer ALs than their fellow eyes, contrary to typical PFV patterns. Preoperative Color Doppler imaging consistently revealed a linear echogenic band extending from the optic disk to the posterior lens capsule. Intraoperative and postoperative fundus examinations confirmed the presence of MRNF in each case, with variable distribution and density. Our findings suggest that when axial elongation is detected preoperatively in PFV eyes with the fundus obscured by cataract, coexisting conditions such as MRNF should be considered.}, } @article {pmid41825541, year = {2026}, author = {Pan, HL and Ge, JY and Zhang, ZA and Xu, JH and Wu, JN and Ju, Y and Zhang, XY and Jiang, ZJ and Chen, Y and Xu, YZ and Liu, XJ}, title = {The role of MyD88 in the nervous system: Neuronal functions, implications in neurological diseases, and therapeutic potential.}, journal = {Pharmacology & therapeutics}, volume = {282}, number = {}, pages = {109016}, doi = {10.1016/j.pharmthera.2026.109016}, pmid = {41825541}, issn = {1879-016X}, mesh = {Humans ; *Myeloid Differentiation Factor 88/metabolism ; Animals ; Signal Transduction ; *Neurons/metabolism ; *Nervous System Diseases/drug therapy/metabolism ; Neurodegenerative Diseases/drug therapy ; }, abstract = {Myeloid differentiation primary response 88 (MyD88), a central adaptor protein governing Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling cascades, is increasingly recognized as a pivotal mediator of neuroimmune interactions and neuromodulation. Beyond its canonical immune functions, emerging evidence reveals widespread MyD88 expression throughout the nervous system, where it plays functional roles in both glial populations and neuronal networks. While previous reviews have largely focused on glial mechanisms, recent studies highlight a complex, often overlooked aspect: the dual role of neuronal MyD88 signaling in orchestrating neurodevelopment while paradoxically driving neuroinflammation and synaptic dysregulation. Given the growing interest in innate immunity's involvement in central nervous system (CNS) diseases, a timely synthesis of MyD88 biology-from molecular mechanisms to therapeutic implications-is essential to bridge the fields of immunology and neuroscience. This article provides a comprehensive review of MyD88, synthesizing contemporary insights into its multifaceted regulatory roles in neural homeostasis and pathogenesis. We place particular emphasis on its mechanistic contributions to brain injury, chronic pain, and neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Furthermore, we evaluate innovative therapeutic approaches targeting MyD88-dependent pathways, highlighting recent pharmacotherapeutic advances and their neuroprotective potential. Finally, addressing the limitations of current strategies, we advocate for a new framework focused on developing therapeutics with increased cell selectivity, thereby advancing the precision and translational potential of MyD88-targeted interventions.}, } @article {pmid41825548, year = {2026}, author = {Martini, N and Despini, F and Filippini, T and Vinceti, M and Teggi, S and Costanzini, S}, title = {Assessing green space exposure: From traditional metrics to the Green Exposure Index (GEI) with application to a Northern Italy residential dataset.}, journal = {Environmental research}, volume = {298}, number = {}, pages = {124254}, doi = {10.1016/j.envres.2026.124254}, pmid = {41825548}, issn = {1096-0953}, mesh = {Italy/epidemiology ; Humans ; *Environmental Exposure/analysis ; Amyotrophic Lateral Sclerosis/epidemiology ; *Environmental Monitoring/methods ; Case-Control Studies ; Cities ; }, abstract = {Urban green areas contribute to healthier cities by improving air quality, promoting physical activity and social cohesion, and mitigating the urban heat island effect. However, assessing exposure to green spaces remains a key methodological challenge in epidemiologic research. In this study, we compared traditional green space indices and developed a composite Green Exposure Index (GEI) integrating vegetation cover, density and accessibility to improve exposure assessment. We applied this new index in a population based amyotrophic lateral sclerosis (ALS) case-control dataset from a Northern Italy community. The GEI consists of three components: NDVI, the Green Coverage Ratio and an accessibility index defined for this application. We computed these components for all residential locations across an 8400 km[2] domain from 1985 to 2020. Seasonal NDVI better captured vegetation patterns than annual values, and spatial aggregation restricted to vegetated areas reduced the overestimation associated with circular buffers. The GEI was evaluated under three illustrative weighting scenarios, which produced substantial differences in exposure classification and confirmed that metric choice strongly influences results. In our case study, the equally weighted GEI3 placed 79.7% of the population in the intermediate Mildly Exposed and Exposed categories, resulting in a balanced distribution better suited for epidemiologic analysis. Analysis of GEI time series revealed green space exposure changes from 1985 to 2020, identifying areas characterized by urbanization or green redevelopment. Findings from this case study show the added value of composite indices like the GEI for characterizing green space exposure and capturing long-term dynamics in vegetation and land use, with applications in epidemiology and urban planning.}, } @article {pmid41826709, year = {2026}, author = {Jones, CT and Hill, ER}, title = {The evolution of speech communication devices for anarthria: a review.}, journal = {Journal of neurology}, volume = {273}, number = {3}, pages = {}, pmid = {41826709}, issn = {1432-1459}, mesh = {Humans ; *Communication Devices for People with Disabilities/trends ; *Brain-Computer Interfaces ; }, abstract = {Anarthria is a lack of verbal communication caused by physiological disturbances in the motor pathway. While affected individuals retain the ability to comprehend and produce speech, orofacial paralysis renders them unable to execute speech. Anarthria can be caused by amyotrophic lateral sclerosis, stroke, traumatic brain injury, and other etiologies that affect the descending motor pathway. A wide range of technologies has been developed and tested to improve communication efficiency for patients with anarthria and accompanying paralysis. This review evaluates three key eras of communication device development. First, before implantation devices gained traction, many communication devices revolved around blinks, head and eye tracking, and non-invasive brain recording. Second, implanted cortical neuroprosthetics were designed to improve accuracy and speed of communication. Finally, the review analyzes the future era, where accessibility, patient comfort, and broader applications of neural analysis elevate communication for patients with anarthria to match fluid communication. Restoring speech communication in patients with anarthria is vital to improve their quality of life. Therefore, understanding communication device efficiency and its future trajectory is of utmost clinical importance.}, } @article {pmid41827855, year = {2026}, author = {Mao, LH and Song, YN and Zhang, JQ and Shao, YT and Wang, ZL and Yang, N and Zhang, WX and Zhang, YR and Gao, XY and Li, JY and Yuan, L}, title = {TIA1 Mutant Mouse Model Exhibits Motor Deficits and Neurodegenerative Characteristics of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {15}, number = {5}, pages = {}, pmid = {41827855}, issn = {2073-4409}, support = {82201594//National Natural Science Foundation of China/ ; 2022-MS-228//Natural Science Foundation of Liaoning Province/ ; 2023-02216//Swedish Research Council/ ; 1494/2023//Parkinsonfonden/ ; FO2023-0397//The Brain Foundation/ ; 20230101154JC//Natural Science Foundation of Jilin Province of China/ ; No.2023JH2/20200104//The Science and Technology Funding Project to support the high-quality development of China Medical University/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; Disease Models, Animal ; *T-Cell Intracellular Antigen-1/genetics/metabolism ; *Mutation/genetics ; Mice ; Humans ; Motor Neurons/pathology/metabolism ; DNA-Binding Proteins/metabolism ; Spinal Cord/pathology/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily affects the motor neurons. T cell intracellular antigen 1 (TIA1) is a risk gene for ALS pathogenesis. To elucidate TIA1-mediated disease mechanisms, a mouse model recapitulating clinical and pathological features of ALS is needed. TIA1 mutations are rare in human ALS, and mutations are heterozygous, while this study uses a homozygous TIA1 mutant mouse model to amplify pathogenic effects for experimental tractability.

METHODS: To explore the mechanisms by which mutant TIA1 causes ALS neurodegeneration, we generated a TIA1 mutant mouse by introducing ALS-causing mutations into the endogenous animal via cytosine base editors. Next, behavioral experiments (open-field and rotarod tests) assessed motor function and analyzed pathologies using morphological assessments.

RESULTS: Our TIA1Δ mouse model phenocopies select pivotal features of ALS, including TAR DNA-binding protein 43 (TDP-43) accumulation, motor neuron loss, neuroinflammation in the lumbar spinal cord, and muscle atrophy. Notably, this homozygous mutation design with reduced TIA1 expression differs from human heterozygous TIA1 mutations.

CONCLUSIONS: This work provides a foundation for understanding the TIA1-ALS relationship and for developing strategies to treat this intractable neurodegenerative disorder. Caution is warranted extrapolating findings to human ALS pathogenesis due to model design differences.}, } @article {pmid41827910, year = {2026}, author = {Manganelli, F and Perfetto, C and Carletta, O and Gerbino, V}, title = {TBK1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: Mechanistic Insights into Impaired Autophagy and Proteostatic Failure.}, journal = {Cells}, volume = {15}, number = {5}, pages = {}, pmid = {41827910}, issn = {2073-4409}, support = {GR-2021-12375436//Italian Ministry of Health/ ; MotorTBK1//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Protein Serine-Threonine Kinases/genetics/metabolism ; *Frontotemporal Dementia/genetics ; *Autophagy/genetics ; *Mutation/genetics ; Animals ; }, abstract = {Mutations in the TANK-binding kinase 1 (TBK1) gene represent a significant genetic link across the Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) spectrum. As a multifunctional serine/threonine kinase, TBK1 serves as a central orchestrator of the autophagy-lysosome pathway, regulating critical stages from initial cargo recognition and autophagosome biogenesis to vesicle maturation and lysosomal fusion. This review examines the mechanisms by which TBK1 coordinates these diverse autophagic functions. We then focus on how ALS/FTD-associated mutations-ranging from truncating variants causing haploinsufficiency to domain-specific missense mutations-disrupt these essential processes.}, } @article {pmid41827952, year = {2026}, author = {Hayashi, K and Suzuki, A and Sato, M and Nakaya, Y and Uchida, T and Yamaguchi, T and Miura, T and Hayashi, H and Hayashi, K and Kobayashi, Y}, title = {Motor Neuron Disease with Guillain-Barré Syndrome? Motor Band Sign with Anti-GQ1b Antibodies.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {16}, number = {5}, pages = {}, pmid = {41827952}, issn = {2075-4418}, abstract = {A 79-year-old former marathoner, with memory impairment since age 78, developed increasing stumbling and progressively worsening waddling gait. Three months after gait disturbance onset, she noted mild dysphagia. With declining walking distance and endurance, she presented to our hospital six months after onset, exhibiting frontal signs, Parkinsonism with marked trunk rigidity, and hyperreflexia of the jaw and limbs. L-dopa challenge tests showed no improvement. At seven months post-onset, she had difficulty rising. By nine months, she relied on a walker, and speech disturbance appeared. At 10-11 months, both dysarthria and dysphagia rapidly worsened, she became bed-ridden, and upper limb weakness developed (though she could still use chopsticks). Neurological examination at one year revealed severe dysarthria/dysphagia, four extremity fasciculations and muscle weakness (grade 2 in upper limbs, grade 1 in lower limbs), trunk-dominant rigidity, and hyperreflexia in the jaw and limbs. Brain MRI, specifically susceptibility-weighted imaging, revealed motor band signs. Cerebrospinal fluid study revealed albuminocytological dissociation. Needle electromyography revealed acute denervation and chronic reinnervation in the cranial nerve, cervical, and lumbar areas, which was suggestive of motor neuron disease (MND). Serum anti-GQ1b antibodies were detected. Immunotherapy was followed by mild improvement, which might suggest a reversible component, although definitive pathological overlap remains unconfirmed. This case highlights a diagnostic challenge where an acute immune-mediated neuropathy could potentially be superimposed on a chronic neurodegenerative process. Anti-GQ1b antibodies should be interpreted with caution, as they may reflect either a true clinicopathological overlap with Guillain-Barré syndrome or a secondary phenomenon (epiphenomenon) related to the primary neurodegenerative process.}, } @article {pmid41829459, year = {2026}, author = {Rocha, PS and Folgado, D and Conceição, VA and Oliveira Santos, M and de Carvalho, M}, title = {Quantification of Tongue Motor Dysfunction in Amyotrophic Lateral Sclerosis Using a Smartphone-Based Task and Deep Learning.}, journal = {Sensors (Basel, Switzerland)}, volume = {26}, number = {5}, pages = {}, pmid = {41829459}, issn = {1424-8220}, support = {2024.06437.BD//Portuguese Foundation for Science and Technology/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Tongue/physiopathology ; *Deep Learning ; Female ; *Smartphone ; Middle Aged ; Male ; Aged ; Movement/physiology ; }, abstract = {BACKGROUND: Bulbar dysfunction is a major complication of amyotrophic lateral sclerosis (ALS). This study aimed to develop and validate a simple, smartphone-based task for the objective assessment of tongue movements and to examine their association with clinical variables.

METHODS: 37 ALS patients and 20 age- and sex-matched controls performed a tongue lateralization task, recorded with a smartphone. A deep-learning U-Net++-based model was used for segmentation and feature extraction. The frequency and maximum amplitude of tongue movements were quantified. Clinical measures included the ALS Functional Rating Scale-revised (ALSFRS-r) bulbar sub-scores, tongue fasciculations, jaw jerk, and tongue "spasticity". Between-group differences and associations between tongue metrics and clinical features were assessed.

RESULTS: The U-Net++-based model achieved robust segmentation performance. Patients showed lower tongue movement frequency than controls (0.14 vs. 0.40, t = -9.58, p < 0.001). Normalized frequency was associated with dysarthria (t = -3.13, p = 0.003) but not dysphagia (t = -1.05, p = 0.30). Normalized frequency (t = 2.77, p = 0.009) and tongue "spasticity" (t = -2.57, p = 0.015) were both associated with speech performance in a multiple-regression model (R = 0.51, adjusted R[2] = 0.43).

CONCLUSIONS: Our method provides an objective, minimally invasive measure of bulbar function in ALS, which correlates with clinical ratings and may detect subtle impairments not captured by standard assessments. This approach offers a promising tool for remote monitoring and may support more effective disease management.}, } @article {pmid41830063, year = {2026}, author = {Lee, MH and Li, W and Sampson, K and Choi, S and Jones, M and Steiner, J and Nath, A}, title = {HML-2 env knockdown by AAV9-mediated miRNAs attenuates amyotrophic lateral sclerosis-like manifestations in mice.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag102}, pmid = {41830063}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which there is no cure. While the precise etiology of ALS remains elusive, growing evidence suggests a pathogenic role for human endogenous retrovirus-K (HERV-K) in ALS. Expression of HERV-K subtype HML-2 envelope protein in neurons causes neurotoxicity in vitro and induces ALS-like symptoms in mice. We investigated the use of the Adeno-Associated Virus-9 (AAV9)-mediated artificial microRNA (amiRNA) targeting the HML-2 env gene in an ALS mouse model. From an in vitro screen of amiRNAs targeting the HML-2 env gene three were chosen and inserted in tandem into an AAV9 vector and validated in vitro. This approach provided robust silencing of the transgene, with tandem amiRNA achieving robust reduction in gene and protein expression levels. Its therapeutic effectiveness was tested in an HML-2 Env transgenic mouse model in which the env gene is expressed under the neuron-specific thy1 promoter and develops an ALS-like phenotype. A single intracerebroventricular injection of AAV9 vector encoding the amiRNAs into the mice at postnatal day 1 effectively reduced HML-2 Env expression in the brain and spinal cord at 84 days post-injection which was the longest time point studied. Knockdown of HML-2 env decreased the loss of cortical and spinal motor neurons and alleviated muscle fiber degeneration and fiber type grouping. This led to improved motor function. Our results provide compelling evidence supporting the use of multiple amiRNAs delivered in an AAV9 vector for treating forms of ALS linked to HML-2.}, } @article {pmid41830107, year = {2026}, author = {Chen, Y and Feng, Y and Sonksen, M and Wang, T and Jin Song, J}, title = {Propensity Score-Based Stratified Win Ratio for Augmented Control Designs.}, journal = {Statistics in medicine}, volume = {45}, number = {6-7}, pages = {e70487}, doi = {10.1002/sim.70487}, pmid = {41830107}, issn = {1097-0258}, mesh = {Humans ; *Propensity Score ; Amyotrophic Lateral Sclerosis/drug therapy ; Computer Simulation ; Models, Statistical ; Research Design ; Endpoint Determination ; }, abstract = {This paper proposes a propensity score (PS)-based stratified win ratio method to address challenges of small patient populations in clinical trials, especially for rare or pediatric diseases, by incorporating external control data. Our approach enhances traditional win ratio analysis by leveraging PS stratification to account for heterogeneity between the current and external studies. Additionally, down-weighting based on the overlapping coefficient of PS distributions of current treatment and external control groups further mitigates the patient bias due to heterogeneity. Simulations show significant improvements in statistical power for detecting treatment effects within the composite endpoint combining continuous and time-to-event components, over nonborrowing and pooling methods, with utilizing Mantel-Haenszel (MH)-type weights achieving the highest power. The proposed methods are also applied to an amyotrophic lateral sclerosis (ALS) study incorporating the external control arm from a prior ALS trial. The proposed PS-based stratified win ratio method thus provides a rigorous framework for borrowing external data and analyzing composite endpoints with limited patient availability.}, } @article {pmid41830733, year = {2026}, author = {Branco, R and Gromicho, M and de Carvalho, M and Fariselli, P and C Madeira, S}, title = {PatientFlow: Learning to generate mixed-type longitudinal clinical data with flow matching.}, journal = {Artificial intelligence in medicine}, volume = {176}, number = {}, pages = {103392}, doi = {10.1016/j.artmed.2026.103392}, pmid = {41830733}, issn = {1873-2860}, mesh = {Humans ; Longitudinal Studies ; *Deep Learning ; Generative Artificial Intelligence ; Autoencoder ; Amyotrophic Lateral Sclerosis/diagnosis ; Predictive Learning Models ; Prognosis ; }, abstract = {Synthetic longitudinal clinical data, with static and temporal mixed-type components, can help unlock large-scale deep learning models to tackle complex diseases. However, learning to generate realistic patients faces dual challenges: modeling the inherently complex structure of longitudinal data and protecting patient privacy. We introduce PatientFlow, a generative modeling method combining Variational Autoencoders for data representation with Flow Matching for patient generation. We extensively evaluated the generative model on a longitudinal cohort of patients with Amyotrophic Lateral Sclerosis (N = 1560) using both qualitative and quantitative methods. The ability of the method to generate realistic patient data, further validated by expert clinicians, shows its potential application to other diseases. Prognostic models trained on synthetic data across five clinically relevant endpoints matched and sometimes outperformed the models trained on real data. Our results demonstrate that PatientFlow can effectively model longitudinal clinical data with high fidelity, opening promising avenues for sharing and augmenting datasets for deep learning applications in healthcare without compromising privacy.}, } @article {pmid41830966, year = {2026}, author = {Li, X and Chen, Q and Fan, D and Chen, L}, title = {From Environment to Symptoms: Mapping Premorbid Risk Factors onto Clinical Features of ALS in a Patient-Reported Database in China.}, journal = {Neurology and therapy}, volume = {15}, number = {3}, pages = {1207-1219}, pmid = {41830966}, issn = {2193-8253}, support = {81873784//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with multifactorial causes, including genetic and environmental factors. This study aimed to identify environmental and lifestyle factors influencing the progression of ALS by leveraging the first and largest patient-reported ALS database in China (the AskHelpU ALS Patient Platform), addressing a critical gap in regional research.

METHODS: Data from 1421 patients with ALS, including detailed information on occupational exposure, lifestyle habits, dietary patterns, and medical history, were collected from the AskHelpU platform. Statistical analyses were conducted to identify associations between these factors and clinical characteristics. The associations between pre-onset factors and disease progression were analyzed using multicariable generalized linear models, adjusting for multiple comaparisons with the Bonferroni correction.

RESULTS: Employment in the agriculture industry (p < 0.001) was associated with rapid ALS progression, whereas employment in the leasing and business services industry (p = 0.01) and education industry (p = 0.033) slowed ALS progression. Other key pre-onset prognostic factors were cigarette smoking (p = 0.043) and pre-existing hypertension (p = 0.036).

CONCLUSION: By utilizing the patient-reported ALS database, this study comprehensively examined the effects of environmental, occupational, and lifestyle factors on ALS progression. These findings provide novel insights into the regional variations in ALS etiology, emphasizing the multifactorial nature of the disease.}, } @article {pmid41831326, year = {2026}, author = {Furlan, R and Di Sapio, A and Ferraro, D and Rossi, E and Valentino, P and Terracciano, D}, title = {Translating neurofilament light chain testing into clinical practice: a multidisciplinary implementation roadmap.}, journal = {Clinical chemistry and laboratory medicine}, volume = {64}, number = {9}, pages = {1904-1918}, pmid = {41831326}, issn = {1437-4331}, mesh = {Humans ; *Neurofilament Proteins/blood/analysis ; Biomarkers/blood/analysis ; Multiple Sclerosis/diagnosis ; }, abstract = {Neurofilament light chain (NfL) has been identified as a sensitive and broadly validated biomarker of neuroaxonal injury across multiple neurological conditions, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and atypical parkinsonian syndromes. This position paper provides a multidisciplinary roadmap for translating circulating NfL testing into routine clinical practice, integrating analytical, interpretative, and organizational dimensions. It summarizes the biological basis and clinical evidence supporting NfL as a diagnostic, prognostic, and monitoring tool, emphasizing its high sensitivity to neuroaxonal injury across both acute inflammatory and chronic degenerative processes. Comparative analysis of immunoassay technologies identifies strengths and critical sources of variability, while operational guidelines highlight the need for pre-analytical standardization, inter-laboratory harmonization, and participation in quality control schemes. Confounders such as age, BMI, renal function, and comorbidities are shown to significantly influence interpretation, supporting the use of age-adjusted Z-scores, percentiles, and longitudinal normalization for accurate patient-level evaluation. From a clinical standpoint, the paper focuses on practical indications for NfL testing in MS, recommending its use for disease activity prediction and monitoring, treatment decisions and treatment response assessment. Integration of blood NfL with magnetic resonance imaging (MRI), glial fibrillary acidic protein (GFAP) and other biomarkers measurement is proposed as a core strategy for biomarker-driven precision neurology. The authors outline an implementation model encompassing laboratory validation, structured reporting and alignment with national neurological care pathways. They conclude that the transition of NfL into clinical use requires harmonized analytical procedures, interdisciplinary education, and sustainable governance frameworks. Priority actions include regulatory qualification, establishment of international reference materials, and development of pragmatic real-world trials to consolidate its clinical utility. When these measures are achieved, NfL will represent a cornerstone biomarker for precision neurology and neurodegeneration monitoring.}, } @article {pmid41831802, year = {2026}, author = {Li, A and Dong, L and Li, X and Yi, J and Wu, JY and Ma, J and Zhou, J}, title = {Aldh3a1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to amyotrophic lateral sclerosis progression.}, journal = {Free radical biology & medicine}, volume = {249}, number = {}, pages = {469-488}, pmid = {41831802}, issn = {1873-4596}, support = {R01 NS105621/NS/NINDS NIH HHS/United States ; R01 NS129219/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Aldehydes/metabolism ; *Aldehyde Dehydrogenase/metabolism/genetics ; Mice ; Disease Models, Animal ; *Muscle, Skeletal/metabolism/pathology ; Humans ; Oxidative Stress ; Disease Progression ; Mice, Transgenic ; }, abstract = {Different muscles exhibit varied susceptibility to degeneration in Amyotrophic Lateral Sclerosis (ALS), a fatal neuromuscular disorder. Extraocular muscles (EOMs) are particularly resistant to ALS progression, and exploring the underlying molecular nature may offer significant therapeutic value. Reactive aldehyde 4-hydroxynonenal (HNE) is implicated in ALS pathogenesis, and Aldh3a1 is an inactivation-resistant intracellular aldehyde dehydrogenase that detoxifies 4-HNE to protect eyes against UV-induced oxidative stress. We detected prominently higher levels of Aldh3a1 in mouse EOMs compared to other muscles under normal physiological conditions. In an ALS mouse model (hSOD1[G93A]) reaching end-stage, Aldh3a1 expression was maintained high in EOMs, substantially elevated in soleus and diaphragm, but only moderately increased in extensor digitorum longus (EDL) muscle, which endured the most severe pathological remodeling, as demonstrated by unparalleled upregulation of a denervation marker Ankrd1. Importantly, sciatic nerve transection in wildtype mice further confirmed induced Aldh3a1 and Ankrd1 expression in an inverse manner across muscle types in response to denervation. Mechanistically, whole-muscle RNA-Seq and pharmacological tests indicate that higher basal levels of lipid oxidation and 4-HNE in soleus and diaphragm muscles may render them more susceptible to the induction of certain Nrf2-dependent antioxidant enzymes, including Aldh3a1, under pathological stress relative to the EDL muscle. Additionally, the identification of the myoblast fusion marker Mymk as an EOM signature gene suggests that the spontaneous activation of satellite cells contributes to high levels of Aldh3a1 in EOMs. Functionally, adeno-associated virus-mediated overexpression of Aldh3a1 protected myotubes from 4-HNE-induced DNA fragmentation and plasma membrane leakage. It also restored MG53-mediated membrane repair, highlighting its potential for clinical applications.}, } @article {pmid41832177, year = {2026}, author = {König, LE and Rodriguez, S and Hug, C and Daneshvari, S and Chung, A and Appleman, M and Tsai, M and Bradshaw, GA and Sahin, A and Song, Y and Zhou, G and Eisert, RJ and Piccioni, F and Marques, C and Powley, S and Yarmolinsky, J and Wainger, BJ and Das, S and Kalocsay, M and Dehghan, A and Tzoulaki, I and Sokolov, A and Sorger, P and Root, DE and Albers, MW}, title = {TYK2 mediates neuroinflammation in Alzheimer's disease brains with TDP-43 pathology.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41832177}, issn = {2041-1723}, support = {R01 AG078377/AG/NIA NIH HHS/United States ; R01 AG078297//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 AG058063/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/genetics ; *TYK2 Kinase/metabolism/genetics/antagonists & inhibitors ; *Brain/pathology/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *Neuroinflammatory Diseases/pathology/metabolism/genetics ; Neurons/metabolism/pathology/drug effects ; Male ; Female ; Animals ; Pyrazoles/pharmacology ; Pyrimidines ; }, abstract = {Neuroinflammation is a pathological feature of neurodegenerative diseases like Alzheimer's disease and ALS. Cytoplasmic dsRNA (cdsRNA) triggers a type-I interferon response in human neural cells, leading to their death, and is found in neurons of C9ORF72-ALS patients. Here, we report the spatial coincidence of cdsRNA and pTDP-43 inclusions in human postmortem tissue with Alzheimer's disease pathology, and upregulated interferon response genes in affected regions. CdsRNA also accumulates in a human TDP-43 G298S iPSC cortical neuronal model. We use cryptic exon detection as a proxy for TDP-43 mislocalization and demonstrate that FDA-approved JAK inhibitors baricitinib and ruxolitinib, which block interferon signaling, show protective effects only in brains with elevated cryptic exon expression. A CRISPR screen reveals TYK2 as a top hit, and TYK2 knockdown and the selective TYK2 inhibitor deucravacitinib rescue cdsRNA-induced toxicity. We find parallel neuroinflammatory mechanisms, dependent on TYK2 - a potential disease-modifying target - for TDP-43-associated Alzheimer's disease and C9ORF72-ALS.}, } @article {pmid41832182, year = {2026}, author = {Moens, TG and Biasetti, L and Scheveneels, W and Smith, BN and Troakes, C and Van Damme, P and Vance, C and Van Den Bosch, L}, title = {Human FUS is toxic via association with RNA polymerase II in Drosophila.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {}, pmid = {41832182}, issn = {2041-4889}, support = {C1 & Opening the Future//KU Leuven (Katholieke Universiteit Leuven)/ ; 1246821N//Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)/ ; }, mesh = {Animals ; Humans ; *RNA-Binding Protein FUS/metabolism/genetics/toxicity ; *RNA Polymerase II/metabolism/genetics ; *Drosophila melanogaster/metabolism/genetics ; *Drosophila Proteins/metabolism/genetics ; Cell Nucleus/metabolism ; Neurons/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; }, abstract = {The RNA-binding protein FUS is commonly mutated in familial cases of amyotrophic lateral sclerosis (ALS-FUS), where it forms cytoplasmic inclusions. In addition, non-mutated FUS is a constituent component of protein inclusions in approximately 5-10% of cases of frontotemporal lobar degeneration (FTLD). Overexpression of wild-type human FUS is toxic to Drosophila neurons, preventing normal development and shortening lifespan in adults. In this study, we demonstrated that removal of the nuclear localisation sequence (NLS) of FUS, a common consequence of ALS-associated mutations, unexpectedly prevents toxicity in Drosophila models despite inducing FUS cytoplasmic mislocalisation. Using novel flies capable of expressing mGFP-tagged FUS, we found that FUS forms dynamic protein granules in Drosophila nuclei and does not form insoluble aggregates. FUS and other FET-family paralogues interact with the repetitive disordered C-terminal domain (CTD) of the large subunit of RNA polymerase II (Polr2A). Using flies that have variable CTD repeat lengths, we demonstrated that FUS genetically interacts with the Polr2A CTD to induce toxicity. Finally, we demonstrated that this association with Polr2A could be relevant to human disease, finding that inclusion-bearing neurons of individuals with FUS-positive FTLD, but not ALS-FUS, show cytoplasmic mislocalisation of POLR2A (the Polr2A human orthologue). Together, these results imply that FUS can have a nuclear mechanism of toxicity when overexpressed in animal models. This toxicity occurs via interaction with RNA polymerase II and aberrant interaction between FUS and POLR2A may be involved in the pathogenesis of FTLD.}, } @article {pmid41832208, year = {2026}, author = {Yokota, S and Kobatake, Y and Yoshida, K and Kamishina, H and Yamato, O and Maki, S and Nakata, K and Sasaki, J and Sakai, H and Hirashima, J and Takashima, S and Nishii, N}, title = {Analysis of immune-related alterations in blood and spinal cord of canine degenerative myelopathy, a spontaneous model of amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41832208}, issn = {2045-2322}, support = {19K15978//Japan Society for the Promotion of Science/ ; }, mesh = {Animals ; Dogs ; *Amyotrophic Lateral Sclerosis/immunology/blood/veterinary/pathology ; *Spinal Cord/immunology/pathology/metabolism ; Disease Models, Animal ; *Spinal Cord Diseases/immunology/blood/veterinary/pathology ; Female ; Male ; }, abstract = {Canine degenerative myelopathy (DM) is an adult-onset neurodegenerative disease considered a spontaneous model of human amyotrophic lateral sclerosis (ALS). Neuroinflammation occurs in both DM and ALS, and crosstalk between the central nervous system and systemic immunity has been demonstrated in ALS. To investigate this interaction in DM, we analyzed peripheral blood and spinal cord tissues using real-time RT-PCR and immunofluorescence. In peripheral blood, mRNA expression of interleukin (IL)-18 and nod-like receptor protein 3 was significantly increased compared with intervertebral disk herniation controls. IL-10 and caspase-1 were elevated, whereas tumor necrosis factor-α was decreased relative to healthy controls. C-C motif chemokine receptor 2 expression showed a moderate negative correlation with disease duration. Immunofluorescence revealed a few transmembrane protein 119[-] and mannose receptor C-type 1[+] cells, indicating limited infiltration of peripheral blood-derived macrophages into the spinal cord. Transcriptional analysis of spinal cords with different degrees of degeneration showed increased expression of activated astrocyte markers (serping1 and S100A10) and C-C motif chemokine ligand 2 in moderately to severely degenerated tissues. Furthermore, immunohistochemical analysis revealed increased CCL2 protein expression in the affected spinal cords. These findings suggest that systemic immune activation contributes to spinal neuroinflammation in DM, although its limited cellular infiltration implies a minor role in neurodegeneration.}, } @article {pmid41833275, year = {2026}, author = {Yang, Z and Xu, Q and Yang, X and Zhou, T and Xiong, Y and Liu, Y and Li, D and Wu, H}, title = {The role of zinc transporter 1 (ZnT1) in health and disease: From molecular mechanisms to therapeutic opportunities.}, journal = {European journal of medicinal chemistry}, volume = {309}, number = {}, pages = {118727}, doi = {10.1016/j.ejmech.2026.118727}, pmid = {41833275}, issn = {1768-3254}, mesh = {Humans ; *Cation Transport Proteins/metabolism/antagonists & inhibitors/chemistry ; Animals ; Cuproptosis ; Zinc/metabolism ; *Neoplasms/metabolism/drug therapy ; }, abstract = {Zinc transporter 1 (ZnT1/SLC30A1) is a major plasma membrane-localized zinc efflux transporter and acts as a central regulator of cellular metal homeostasis. Beyond exporting Zn[2+], recent evidence reveals that ZnT1 also transports Cu[2+] and serves as a molecular hub linking zinc-copper interplay, redox balance, immune signaling and programmed cell death. This review summarizes current advances in ZnT1 structure, transport mechanism, regulatory networks and physiological roles across the gut-liver-immune-neuro-cardiovascular axis. We further outline its pathological involvement in Wilson disease, amyotrophic lateral sclerosis, cancer and inflammatory disorders, highlighting ferroptosis, cuproptosis and metabolic reprogramming as key downstream consequences of ZnT1 dysregulation. Emerging therapeutic approaches include small-molecule modulators, RNA-based regulation, antibody targeting and metal-based interventions. Although challenges remain-such as tissue specificity, systemic toxicity and biomarker development-ZnT1 is rapidly evolving from a basic transport protein to a promising precision medicine target. Continued efforts in structural biology, single-cell metallomics and targeted delivery systems will accelerate its clinical translation.}, } @article {pmid41833626, year = {2026}, author = {Sedighi, S and Guan, T and Michetti, F and Cordani, M and Barzegar Behrooz, A and Sabouni, F and Eshraghi, M and Saleem, A and Ghavami, S and Aghanoori, MR}, title = {Autophagy-exosome crosstalk in neurodegeneration: Mechanisms and therapeutic opportunities.}, journal = {Pharmacology & therapeutics}, volume = {282}, number = {}, pages = {109025}, doi = {10.1016/j.pharmthera.2026.109025}, pmid = {41833626}, issn = {1879-016X}, mesh = {Humans ; *Autophagy/physiology ; *Exosomes/metabolism ; *Neurodegenerative Diseases/drug therapy/physiopathology/metabolism ; Animals ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and multiple sclerosis, share a common pathogenic signature: disrupted proteostasis driven by impaired autophagy and maladaptive exosome dynamics. Under normal conditions, autophagy maintains neuronal homeostasis by clearing misfolded proteins and damaged organelles, while exosomes mediate neuroglial communication. When autophagic flux is impaired or lysosomal function is compromised, intracellular cargo handling can shift toward secretion and undegraded cargo may be redirected into exosomes/EVs, which disseminate pathogenic proteins such as amyloid-β, tau, α-synuclein, and TDP-43, a phenomenon reported in several experimental models and proposed to contribute to intercellular spread of pathology. This dual dysregulation amplifies neuroinflammation, demyelination, and progressive neuronal loss. Pharmacological strategies aimed at restoring the autophagy-exosome axis are gaining traction. Agents such as rapamycin and resveratrol enhance autophagic flux, whereas engineered or stem-cell-derived exosomes delivering siRNAs, neurotrophic factors, or anti-inflammatory microRNAs show promise in preclinical neuroprotection and immune modulation. However, translational barriers remain, including safety, biodistribution, dosing, and standardization. Emerging artificial intelligence (AI) and machine learning (ML) frameworks can accelerate translation by integrating multi-omics and exosomal biomarker datasets for early diagnosis, patient stratification, and therapy optimization. Deep learning and generative modeling may further enable rational drug design to fine-tune autophagy and engineer targeted exosome delivery to the brain. Collectively, these advances position the autophagy-exosome axis as an integrative framework linking intracellular clearance with intercellular signaling, with emerging diagnostic and therapeutic implications for neurodegenerative disorders.}, } @article {pmid41835571, year = {2026}, author = {Tamura, K and Tsuboi, M and Hashimoto, H and Akao, KI and Sato, H and Ozaki, Y}, title = {Resonance Raman and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) Analysis of Biological Polyenes in Shells: A Nondestructive Approach for Species and Habitat Identification.}, journal = {ACS omega}, volume = {11}, number = {9}, pages = {15019-15027}, pmid = {41835571}, issn = {2470-1343}, abstract = {Biogenic minerals such as shells contain trace amounts of biological polyenes derived from carotenoids, which have attracted considerable attention in biology, earth science, environmental science, and materials science. Moreover, the recent issue of fraudulent labeling of edible shellfish origins underscores the need for reliable, nondestructive methods to identify species and habitats. Here, we applied resonance Raman spectroscopy to nondestructively detect carotenoid-derived polyenes (biological polyenes) in various shells differing in species and growing environments. We focused on the peak positions and full width at half-maximum (FWHM) of the bands at around 1500 and 1120 cm[-1], assigned to C(?)C and C-C stretching vibrations, respectively. Single-point Raman measurements revealed that both the peak positions and the FWHM values varied among samples, indicating that multiple types of biological polyenes are present within each shell and that their distribution depends on species and habitats. To further resolve these spectral features, we performed multipoint (Raman imaging) measurements and applied multivariate curve resolution-alternating least squares (MCR-ALS) analysis to extract pure component spectra of the biological polyenes. As a result, multiple distinct polyene species were identified in each shell. Notably, the observed bands at around 1120-1100 cm[-1] differed from those typical of carotenoids, suggesting that shell-derived polyenes vary according to both species and environmental conditions. For a clearer comparison, we categorized these peak positions into four distinct groups. Collectively, our results demonstrate, for the first time, that the types and numbers of biological polyenes differ among shellfish species and habitats without the need for extraction or isolation. This finding implies that shellfish biosynthesize diverse polyenes distinct from carotenoids in response to environmental factors, such as feeding conditions. The combined use of resonance Raman spectroscopy and MCR-ALS thus provides an effective approach for identifying and characterizing biogenic minerals, such as shells.}, } @article {pmid41836058, year = {2026}, author = {Santangelo, S and Casiraghi, V and Fallini, C and Invernizzi, S and Peverelli, S and Bertocchi, M and Feole, M and Cozzi, M and Magri, S and Poletti, A and Bossolasco, P and Taroni, F and Silani, V and Ratti, A}, title = {Functional validation of the novel KIF5A p.R17Q VUS reveals defective axonal transport in iPSC-motoneurons from a SPG10 patient.}, journal = {Frontiers in genetics}, volume = {17}, number = {}, pages = {1774170}, pmid = {41836058}, issn = {1664-8021}, abstract = {Cytoskeletal alterations and axonal transport deficits are key factors in many neurodegenerative disorders. The neuronal kinesin family member 5A (KIF5A) is a microtubule-based motor protein critical for anterograde transport of RNA granules, organelles, and neurofilaments along axons and dendrites. Heterozygous missense and nonsense mutations in the N-terminal motor and stalk domains are associated with hereditary spastic paraplegia 10 (SPG10) and Charcot-Marie-Tooth disease type 2 (CMT2), while frameshift mutations in KIF5A C-terminal cargo-binding domain are linked to amyotrophic lateral sclerosis (ALS). We recently reprogrammed an iPSC line from a SPG10 patient carrying the novel missense variant c.50G>A (p.R17Q) in the KIF5A motor domain, classified as variant of unknown significance (VUS) and predicted to affect ATP binding. Here we gene-edited this mutant iPSC line by CRISPR-Cas9 to obtain an isogenic wild-type (WT) KIF5A cell line. We next examined functionally the impact of the p.R17Q VUS on KIF5A protein sub-cellular distribution and on axonal transport of mitochondria and lysosomes in differentiated iPSC-motoneurons (MNs). The presence of neurofilament-positive axonal swellings and an increased distribution of KIF5A protein in distal neurites was observed in the mutant p.R17Q compared to the WT KIF5A iPSC-MNs, indicating a likely defective axonal transport. The anterograde velocity and distance travelled by mitochondria and lysosomes along neurites was indeed significantly reduced in the mutant KIF5A iPSC-MNs compared to the WT ones. These findings demonstrate that the p.R17Q VUS is pathogenic, thereby extending the spectrum of KIF5A mutations causing SPG10 and support the use of patient-derived iPSC-MNs to functionally validate KIF5A-associated VUS.}, } @article {pmid41836534, year = {2026}, author = {Scirocco, E and Paganoni, S and Brizzi, K}, title = {Approaching Serious Illness Conversations in Amyotrophic Lateral Sclerosis Using Telehealth: A Practical Guide.}, journal = {Neurology. Clinical practice}, volume = {16}, number = {2}, pages = {e200600}, pmid = {41836534}, issn = {2163-0402}, abstract = {PURPOSE OF REVIEW: Given the lack of consensus on serious illness conversations (SIC) in amyotrophic lateral sclerosis (ALS) by using telehealth, we aim to provide practical strategies in this setting.

RECENT FINDINGS: Over the past 5 years, there has been substantial growth in telehealth, especially after the global COVID-19 pandemic. In ALS, telehealth has become an increasingly used tool for providing clinical care, especially as the disease progresses, when travel becomes challenging and geographic constraints arise. As ALS advances, clinicians often have SIC with individuals living with ALS and their caregivers using telehealth. In the literature, few recommendations are available to improve telehealth communication in the neuropalliative setting.

SUMMARY: We present 3 case scenarios showcasing telehealth strategies for SICs, with specific considerations for individuals living with ALS. We provide a strategy, CARE in ALS, to support telehealth communication in individuals with speech impairments. We hope to provide practical guidance for health care clinicians in this specific setting.}, } @article {pmid41836882, year = {2026}, author = {Rouleau, GA and Yu, Z and Ross, JP and Rochefort, D and Li, B and Bornais, K and Chum, M and Farhan, SMK and Dion, PA}, title = {Consequences of the Novel ALS-Associated KIF5A Variant c.2993-6C > A for Exon 27 Splicing and Axonal Transport of SFPQ.}, journal = {Neurology. Genetics}, volume = {12}, number = {2}, pages = {e200362}, pmid = {41836882}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Recent studies have identified variants in the kinesin family member 5A (KIF5A) gene that predispose to amyotrophic lateral sclerosis (ALS). These ALS-linked KIF5A variants lead to the exclusion of exon 27, resulting in the production of a mutated protein with an altered C-terminal region (KIF5A ΔExon27). Through whole genome sequencing, we identified a novel KIF5A intronic variant, rs1057522322 (c.2993-6C > A; chr12:57582596C > A, GRCh38.p14), in a family segregating ALS. Our goal is to investigate the effect of this variant on exon 27 splicing and to assess its functional consequences on KIF5A-mediated cargo transport.

METHODS: Induced pluripotent stem cells (iPSCs) were generated from siblings with and without the c.2993-6C > A variant. RT-PCR was performed on RNA extracted from iPSC-derived neurons to assess exon 27 splicing. Functional studies were conducted on iPSC-derived motor neurons (MNs).

RESULTS: RT-PCR confirmed that the c.2993-6C > A variant induced exon 27 skipping in KIF5A. Immunofluorescent staining showed that KIF5A ΔExon27 abolished the axonal interaction with splicing factor proline- and glutamine-rich, a cargo specifically transported by KIF5A. Under stress conditions, MNs carrying the c.2993-6C > A variant exhibited TDP-43 proteinopathy.

DISCUSSION: KIF5A intronic variant c.2993-6C > A could be a risk factor for ALS. KIF5A ΔExon27 impairs KIF5A-mediated cargo transport and contributes to ALS pathogenesis in a TDP-43-dependent manner.}, } @article {pmid41837283, year = {2026}, author = {Miller, MR and Dykstra, M and Barmada, S}, title = {Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {6}, pages = {}, pmid = {41837283}, issn = {1558-8238}, support = {P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R37 NS113943/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Alternative Splicing ; *DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Animals ; Protein Isoforms/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases characterized by the nuclear clearance and cytoplasmic aggregation of transactive response DNA/RNA-binding protein of 43 kDa (TDP43). Alternative splicing of TARDBP, the gene encoding TDP43, leads to a surprising diversity of RNA and protein isoforms with unique functions and potential implications for disease pathogenesis. Here, we review the production, properties, and functional consequences of alternative splicing in the development of ALS and FTD, focusing primarily on TDP43 due to its integral connection with the pathogenesis of sporadic as well as familial forms of these diseases. We synthesize current evidence on the biology of alternative TARDBP splicing, highlight key questions regarding its role in TDP43 proteinopathies such as ALS and FTD, and touch on the larger phenomenon of alternative splicing and its relationship to disease.}, } @article {pmid41837285, year = {2026}, author = {Gautier, O and Nguyen, TP and Gitler, AD}, title = {Decoding neurodegeneration one cell at a time.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {6}, pages = {}, pmid = {41837285}, issn = {1558-8238}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Animals ; *Neurons/metabolism/pathology ; *Single-Cell Analysis ; Spatial Transcriptomics ; Single-Cell Gene Expression Analysis ; }, abstract = {Neurodegenerative diseases are characterized by protein misfolding and the selective vulnerability of specific neuronal subtypes. This selective vulnerability presents a paradox; most neurodegenerative disease genes are expressed broadly throughout the brain, and some ubiquitously, but only certain types of neurons are lost while others are resistant. The molecular basis for selective neuronal vulnerability has remained a mystery, but recent genomics technological innovations are starting to provide mechanistic insights. Here, we review how single-cell genomics techniques - single-cell transcriptomics, single-cell epigenomics, and spatial transcriptomics - advance our molecular understanding of selective vulnerability and neurodegeneration across Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington disease. Together, these approaches reveal the cell types affected in disease, define disease-associated molecular states, nominate candidate determinants of vulnerability and degeneration, and situate degenerating neurons within their local tissue context. Continued development and application of these techniques, including single-cell perturbation screens, will expand descriptive atlases of relevant cell types in health and disease and identify causal mechanisms, revealing the molecular basis of vulnerability and degeneration and informing therapeutic development.}, } @article {pmid41837791, year = {2025}, author = {Sahoo, S and Padhy, AA and Shivani, K and Misra, A and Mishra, P}, title = {Ubiquitin signatures on aggregating proteins in neurodegeneration.}, journal = {Essays in biochemistry}, volume = {69}, number = {5}, pages = {}, pmid = {41837791}, issn = {1744-1358}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Ubiquitin/metabolism ; Animals ; *Protein Aggregation, Pathological/metabolism ; tau Proteins/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination ; alpha-Synuclein/metabolism ; Protein Aggregates ; }, abstract = {The aberrant accumulation of misfolded proteins marked by cellular dysfunction and progressive neuronal loss is the hallmark of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. This review examines the pivotal role of ubiquitin modifications in altering the fate of aggregation-prone proteins such as tau, α-synuclein, mutant huntingtin, TAR DNA-binding protein 43 and superoxide dismutase 1. The ubiquitin signatures identified by their linkage types, chain architectures and site specificities emerge as a complex regulatory language that influences the clearance, aggregation or cellular propagation of these aggregating proteins. The dysregulation of other components of the ubiquitin association pathways, such as impaired E3 ligases and deubiquitinases, also contributes to the inefficient protein disposal and disease progression. Understanding how ubiquitin signatures alter the spatiotemporal dynamics of aggregating proteins is critical for advancing our knowledge of disease biology. Here, we focus on the role of ubiquitin modifications and their associated regulators affecting protein fate and neurotoxicity, and highlight the current therapeutic strategies targeting the degradation of aggregating proteins to uncover potential avenues for treating neurodegenerative diseases.}, } @article {pmid41837970, year = {2026}, author = {Cudkowicz, M and Drory, VE and Chio, A and Lunetta, C and Shoesmith, C and van Eijk, RPA and Salomon-Zimri, S and Shtossel, D and Kerem, N and Shapira, G and Shomron, N and Russek-Blum, N and Tracik, F and Rosenfeld, J and Shefner, J}, title = {Safety and Efficacy of PrimeC in Amyotrophic Lateral Sclerosis: The PARADIGM Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {83}, number = {5}, pages = {471-480}, pmid = {41837970}, issn = {2168-6157}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/blood ; Double-Blind Method ; Female ; Middle Aged ; Male ; *Celecoxib/therapeutic use/adverse effects/administration & dosage ; Aged ; Drug Combinations ; Treatment Outcome ; }, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. PrimeC is a fixed-dose oral combination of celecoxib and ciprofloxacin designed to target ALS-related mechanisms, including neuroinflammation, iron homeostasis, and dysregulated microRNAs.

OBJECTIVE: To evaluate the safety, tolerability, and potential efficacy of PrimeC in people living with ALS.

This was a randomized, double-blind, placebo-controlled, phase 2b trial conducted at 4 ALS referral centers from May 2022 to November 2023 and followed by 12-month open-label extension. Adults with definite or probable ALS and disease duration of 30 months or less were eligible. Of 73 screened, 69 were randomized and 68 were included in the intent-to-treat population.

INTERVENTIONS: Participants were randomized 2:1 to receive PrimeC or placebo for 6 months, followed by open-label extension PrimeC for all.

MAIN OUTCOMES AND MEASURES: The primary outcome was safety and tolerability. The prespecified primary biomarker outcome was plasma neuron-derived-exosomal TAR DNA-binding protein 43 (TDP-43) or prostaglandinJ2. Secondary outcomes included change in ALS Functional Rating Scale-Revised (ALSFRS-R) score at 6 and 18 months, survival, and time-to-composite events. Exploratory biomarkers included neurofilament light chains, iron-regulatory proteins, and circulating microRNAs.

RESULTS: The 68 participants were well balanced in age at entry and sex. In the PrimeC group, the mean (SD) age was 59.1 (9.1) years, and 27 of 45 participants were male. In the placebo group, the mean (SD) age was 55.0 (13.0) years, and 14 of 23 participants were male. PrimeC was well tolerated, with a safety profile comparable to placebo (adverse event rate, 66.7% PrimeC vs 65.2% placebo). Drug-related adverse events were more frequent with PrimeC (20.0% vs 4.3%), mostly mild to moderate, and transient. At month 6, the mean ALSFRS-R difference was 2.23 points between PrimeC and placebo (95% CI, -0.61 to 5.07; P = .12). At month 18, ALSFRS-R scores in participants continuously treated with PrimeC maintained a difference (7.92 points; 95% CI, 2.25 to 13.60; P = .007), with significant bulbar difference (3.18 points; 95% CI, 1.32 to 5.04; P = .001). Continuous treatment was associated with lower risk of ALS complications, including hospitalization, respiratory failure, or death (HR, 0.36; 95% CI, 0.15-0.85; P = .02). In the double-blind period, transferrin levels were preserved with PrimeC (1.90 μmol/L difference; P = .03), the negative ferritin-ALSFRS-R correlation observed in placebo (ρ = -0.50; P = .02) was abolished, and ALS-associated microRNAs were downregulated (log2 fold change: miR-199a-3p, -1.87; false discovery rate [FDR] P = .004; miR-199a-5p, -2.23; FDR P < .001; miR-181a-5p: -1.89; FDR P = .001; miR-181b-5p, -1.62; FDR P = .005). Prespecified neuron-derived exosome TDP-43/PgJ2 analyses will be reported separately following completion of development and analyses.

CONCLUSIONS AND RELEVANCE: PrimeC was safe and well tolerated over 18 months. Although not powered for efficacy, functional and biomarker findings support a confirmatory trial.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05357950.}, } @article {pmid41838122, year = {2026}, author = {Barone, C and Wang, R and Cooke, S and Ng, HP and Ferreira, RS and Miranda, HC and Qi, X}, title = {TDP-43 impairs glycolysis by sequestering hexokinase 1 in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {151}, number = {1}, pages = {}, pmid = {41838122}, issn = {1432-0533}, support = {R01 AG074346/AG/NIA NIH HHS/United States ; R01 AG076051/AG/NIA NIH HHS/United States ; R01 NS141199/NS/NINDS NIH HHS/United States ; R01AG065240, R01AG076051, R01AG074346 and R01NS141199/NH/NIH HHS/United States ; R01 AG065240/AG/NIA NIH HHS/United States ; }, mesh = {*Hexokinase/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Glycolysis/physiology ; Animals ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; Motor Neurons/metabolism/pathology ; Mitochondria/metabolism ; Spinal Cord/metabolism/pathology ; Mice, Transgenic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and cytoplasmic mislocalization of TDP-43. While metabolic dysfunction is increasingly recognized in ALS, the mechanistic link between impaired energy metabolism and TDP-43 pathology remains unknown. Here, we show that cytoplasmic TDP-43 directly disrupts glycolysis by targeting hexokinase 1 (HK1), the first rate-limiting enzyme of the pathway. In cells expressing a TDP-43 variant lacking its nuclear localization signal and in patient-derived iPSC motor neurons, TDP-43 accumulation in the cytoplasm reduces glycolytic capacity, indicating a neuron-intrinsic metabolic defect. Across cellular models including patient-derived neurons, TDP-43 mutant mice, and postmortem spinal cord tissue from ALS patients, we observe consistent decreases in HK1 protein level, mitochondrial association, and enzymatic activity, despite unchanged transcript levels. Mechanistically, cytoplasmic TDP-43 directly binds to HK1, disassociating it from mitochondria and promoting its sequestration into insoluble aggregates. This mislocalization impairs glycolysis and increases neuronal vulnerability. Notably, compensation for HK1 loss reduces cytoplasmic TDP-43 and ubiquitin accumulation, improves motor performance, and prolongs survival in TDP-43-associated ALS models. Together, these findings identify a previously unrecognized mechanism by which TDP-43 impairs glycolysis through HK1 misregulation and highlight glycolytic restoration as a potential therapeutic strategy in ALS.}, } @article {pmid41838432, year = {2026}, author = {Cohen-Salmon, M}, title = {Local Translation in Glial Cells of the Brain.}, journal = {Annual review of cell and developmental biology}, volume = {}, number = {}, pages = {}, doi = {10.1146/annurev-cellbio-111524-124159}, pmid = {41838432}, issn = {1530-8995}, abstract = {Local protein synthesis is a conserved mechanism that allows cells with intricate architectures to perform compartment-specific functions. By translating messenger RNAs (mRNAs) at distinct subcellular locations, cells can respond swiftly and precisely to localized stimuli. This strategy is crucial in neurons, whose long processes extend far from the cell body. Disruptions in neuronal local translation have been implicated in neurological disorders, including fragile X syndrome, amyotrophic lateral sclerosis, and spinal muscular atrophy. While much of the spotlight has been on neurons, glial cells-microglia, astrocytes, oligodendrocytes, and radial glia-are increasingly recognized for their own dynamic use of local translation. These support cells exhibit asymmetric mRNA localization, suggesting that local protein synthesis plays key roles in their diverse functions. This review explores the emerging landscape of local translation in glial cells and examines how this finely tuned process contributes to both normal brain function and the development of neurological disease.}, } @article {pmid41838635, year = {2026}, author = {Olmstead, AJ and Krajewski, E and Lee, J and Viswanathan, N}, title = {Comparing vowel intelligibility across interactive and non-interactive tasks in disordered speech.}, journal = {JASA express letters}, volume = {6}, number = {3}, pages = {}, pmid = {41838635}, issn = {2691-1191}, support = {R01 DC021714/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Speech Intelligibility ; *Amyotrophic Lateral Sclerosis/complications ; *Dysarthria/etiology/physiopathology ; Female ; Male ; *Phonetics ; Middle Aged ; Aged ; Speech Perception ; Speech Production Measurement ; }, abstract = {The current study examines vowel intelligibility across interactive and non-interactive situations for individuals with dysarthria secondary to amyotrophic lateral sclerosis (PALS). The vowel space of these speakers is often characterized by centralization and lowering, negatively affecting intelligibility. In two experiments, listeners identified vowels produced by PALS in habitual speech (non-interactive), clear speech (non-interactive), and interactive matching. Clear speech and interactive matching elicited more intelligible vowels than habitual speech. Interactive matching productions were equal to or more intelligible than clear speech productions depending on vowel. These data represent a preliminary step to understanding how the dynamics of communicative interaction may shape vowel intelligibility.}, } @article {pmid41838744, year = {2026}, author = {Chowdhury, T and Muruganandan, S and Ferretti, D and Luo, Y and Dion, J and Zhang, M and Lo, SC}, title = {Lumbar Intrathecal Injection of SOD1-ASOs for Precise CNS Targeting and Predictive Efficacy in Human SOD1-G93A ALS Mice.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {228}, pages = {}, doi = {10.3791/69788}, pmid = {41838744}, issn = {1940-087X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/enzymology/therapy ; Injections, Spinal/methods ; Mice ; Mice, Transgenic ; Superoxide Dismutase-1/genetics ; Humans ; *Oligonucleotides, Antisense/administration & dosage/genetics ; Disease Models, Animal ; *Superoxide Dismutase/genetics ; }, abstract = {Intrathecal (IT) administration of central nervous system (CNS)-targeted therapeutics offers a minimally invasive route for direct drug delivery into the cerebrospinal fluid (CSF), facilitating enhanced specificity and target engagement. While IT catheterization is standard for sustained delivery in rats, its application in mice is limited by anatomical constraints and elevated risk of procedure-related complications, including spinal injury and infection. To overcome these limitations, we employed an acute needle puncture technique for IT drug delivery in adult mice, providing a reproducible and less invasive alternative compatible with single or repeated dosing regimens. In a transgenic mouse model of amyotrophic lateral sclerosis (ALS) harboring the SOD1-G93A mutation, we achieved efficient IT delivery of antisense oligonucleotides (ASOs) targeting the SOD1 gene. This approach effectively downregulated mutant SOD1 expression and significantly ameliorated the disease phenotype, as demonstrated by electrophysiological and biomarker assessments. These results validate both the IT delivery method and the therapeutic efficacy, with outcomes comparable to intracerebroventricular (ICV) administration. Most importantly, the technique mirrors procedures used in human clinical studies, offering strong translational relevance and utility in preclinical evaluation of CNS-directed interventions. Although technical expertise is required to ensure consistency and avoid off-target effects, this IT delivery strategy represents a robust, reproducible, and clinically relevant methodology for advancing therapeutic development in small animal models.}, } @article {pmid41839426, year = {2026}, author = {Sahin, GS and Guyett, PJ and Xu, K and Kouznetsova, J and Zheng, W and Hendrickson, M}, title = {High-throughput screening of ALS patient iPSC-derived spinal motor neurons identifies novel compounds that increase neurofilament light chain expression.}, journal = {SLAS discovery : advancing life sciences R & D}, volume = {40}, number = {}, pages = {100303}, pmid = {41839426}, issn = {2472-5560}, support = {R43 NS097080/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism/drug effects/cytology ; *Motor Neurons/metabolism/drug effects/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; *High-Throughput Screening Assays/methods ; *Neurofilament Proteins/genetics/metabolism ; Spinal Cord/metabolism/pathology ; Cell Differentiation/drug effects ; Animals ; Small Molecule Libraries/pharmacology ; Drug Discovery/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease primarily affecting motor neurons both in the spinal cord and brain. The cardinal pathology of ALS is motor neuron-selective inclusion of proteins such as TDP43, SOD1, C9orf72-derived dipeptide repeats, or FUS due to the mutations in the genes encoding them. Both familial and sporadic forms of ALS also show neurofilament (NF) aggregates, attributed to an imbalance in subunit expression, particularly a decrease in neurofilament light chain (NF-L) levels. Current FDA-approved treatments extend survival for only a few months, highlighting the urgent need for new therapies. In this study, we developed a cell-based reporter system for high-throughput screening by engineering induced pluripotent stem cells (iPSCs) derived from ALS patients and differentiating them into spinal motor neurons. We screened over 6000 compounds using these reporter iPSC-derived motor neurons and identified a novel compound that increases NF-L expression by >50 %. However, this novel compound also inhibits TGF-β signaling, prompting us to optimize its activity through a hit-to-lead chemistry analysis. In our subsequent investigations, we identified an additional compound that does not affect TGF-β signaling and outperforms the original compound in both in vitro and in vivo drug metabolism and pharmacokinetics assays. Our study highlights the utility of iPSC-derived neurons in disease modeling and illustrates how they can be employed to discover new compounds for therapeutic development through extensive screening in disease-relevant settings.}, } @article {pmid41840138, year = {2026}, author = {Jude, JJ and Levi-Aharoni, H and Acosta, AJ and Allcroft, SB and Nicolas, C and Lacayo, BE and Card, NS and Wairagkar, M and Levin, AD and Brandman, DM and Stavisky, SD and Willett, FR and Williams, ZM and Simeral, JD and Hochberg, LR and Rubin, DB}, title = {Restoring rapid natural bimanual typing with a neuroprosthesis after paralysis.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, pmid = {41840138}, issn = {1546-1726}, support = {I01 RX003803/RX/RRD VA/United States ; HT94252310153//United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP)/ ; U01DC017844//U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD)/ ; U01NS123101//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; A4820R//Office of Research and Development (VHA Office of Research and Development)/ ; A2295R, A4820R, N2864C, A3803R//Office of Research and Development (VHA Office of Research and Development)/ ; I01 RX002295/RX/RRD VA/United States ; 23SCEFIA1156586//American Heart Association (American Heart Association, Inc.)/ ; U01 DC017844/DC/NIDCD NIH HHS/United States ; A2295R, A4820R, A3803R//Office of Research and Development (VHA Office of Research and Development)/ ; U01 NS123101/NS/NINDS NIH HHS/United States ; A2295R, A4820R, N2864C//Office of Research and Development (VHA Office of Research and Development)/ ; U01DC017844, R01DC014034//U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD)/ ; Postdoctoral Fellowship//A.P. Giannini Foundation/ ; Pilot Award from the Simons Collaboration for the Global Brain (872146SPI)//Simons Foundation/ ; A2295R, A4820R//Office of Research and Development (VHA Office of Research and Development)/ ; I01 RX004820/RX/RRD VA/United States ; K23DC021297//U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD)/ ; K23 DC021297/DC/NIDCD NIH HHS/United States ; }, abstract = {Here, recognizing keyboard typing as a familiar, high information rate communication paradigm, we developed an intracortical brain-computer interface (iBCI) typing neuroprosthesis providing bimanual QWERTY keyboard functionality for people with paralysis. Typing with this iBCI involves only attempted finger movements, which are decoded accurately with as few as 30 calibration sentences. Sentence decoding is improved using a 5-gram language model. This typing neuroprosthesis performed well for two iBCI clinical trial participants with tetraplegia-one with amyotrophic lateral sclerosis and one with spinal cord injury. Typing speed is user-regulated, reaching 110 characters per minute, resulting in 22 words per minute with a word error rate of 1.6%. This resembles able-bodied typing accuracy and provides higher throughput than current state-of-the-art hand motor iBCI decoding. In summary, a typing neuroprosthesis decoding finger movements, provides an intuitive, familiar and easy-to-learn paradigm for individuals with impaired communication due to paralysis.}, } @article {pmid41840443, year = {2026}, author = {Nogami, T and Kojima, T and Tamaoki, A and Sawaki, A and Hasegawa, A and Kaga, T}, title = {Optimization of crystalline lens refractive index to improve the accuracy of intraocular lens power calculation in patients with dense cataract.}, journal = {Journal of cataract and refractive surgery}, volume = {52}, number = {9}, pages = {890-896}, doi = {10.1097/j.jcrs.0000000000001941}, pmid = {41840443}, issn = {1873-4502}, mesh = {Humans ; Retrospective Studies ; *Refraction, Ocular/physiology ; *Cataract/physiopathology ; *Lenses, Intraocular ; Biometry/methods ; Female ; Aged ; *Lens Implantation, Intraocular ; *Phacoemulsification ; *Lens, Crystalline/physiopathology ; Male ; Axial Length, Eye ; *Optics and Photonics ; Aged, 80 and over ; Middle Aged ; Visual Acuity/physiology ; }, abstract = {PURPOSE: To evaluate effects of crystalline lens refractive index (LRI) on prediction error (PE) and suggest the optimal LRI in cases of dense cataract.

SETTING: Chukyo Hospital, Aichi, Japan.

DESIGN: Retrospective consecutive case series study.

METHODS: Patients who underwent cataract surgery were enrolled and allocated into Group A (nuclear hardness ≤III) and B (nuclear hardness ≥IV) based on the Emery-Little classification. The swept-source optical biometer was used for biometric measurements. Assuming the postoperative axial length (AL) to be the valid value, a corrected LRI (CLRI) was calculated to make the preoperative AL equivalent to the postoperative one. In the validation group, the PE of the SRK/T formula and Barrett Universal II (BUII) were evaluated using the precorrection and postcorrection refractive indices.

RESULTS: Of the 5196 enrolled eyes, 1084 were evaluated. In Group A, there was no significant difference between the preoperative and postoperative ALs (P = .07). In Group B, the mean postoperative AL (24.09 ± 2.05 mm) was significantly shorter than the mean preoperative AL (24.12 ± 2.06 mm) (P < .001). The average CLRI in Group A and B were 1.41 and 1.42, respectively. In the validation group, the PEs using CLRI (SRK/T, 0.10 ± 0.48 diopters [D]; BUII, 0.03 ± 0.35 D) were significantly smaller than those using LRI (SRK/T, 0.18 ± 0.49 D; BUII, 0.12 ± 0.36 D) (P < .001).

CONCLUSIONS: In cases of high lens nucleus hardness, the use of proposed CLRI demonstrated potentials for reducing PE.}, } @article {pmid41840875, year = {2026}, author = {Kimura, H and Tate, SI and Yasuda, K}, title = {Valosin-containing protein counteracts ATP-driven dissolution of FUS condensates through its ATPase activity in vitro.}, journal = {FEBS letters}, volume = {}, number = {}, pages = {}, doi = {10.1002/1873-3468.70328}, pmid = {41840875}, issn = {1873-3468}, support = {23H02425//Japan Society for the Promotion of Science/ ; 23K05147//Japan Society for the Promotion of Science/ ; }, abstract = {Fused in sarcoma (FUS) forms phase-separated condensates implicated in amyotrophic lateral sclerosis (ALS). Although millimolar ATP concentrations paradoxically dissolve FUS condensates through hydrotropic activity, condensates nevertheless persist in cells, suggesting active regulatory mechanisms. Here, using a reconstituted system, we show that the AAA+ATPase valosin-containing protein (VCP) counteracts ATP-driven dissolution of FUS condensates. VCP preserved both wild-type and ALS-linked P525L condensates under high ATP conditions, and this protection required catalytic ATPase activity rather than stable partitioning into condensates. The effect was abolished by the D2-specific inhibitor ML240. Our findings establish direct biochemical evidence that VCP ATPase activity maintains FUS condensates under high ATP conditions, highlighting ATPase-driven enzymatic control of liquid-liquid phase separation as a potential general principle with implications for neurodegeneration.}, } @article {pmid41840979, year = {2026}, author = {Egger, EK and Delen, M and Matthaei, H and Padron, LT and Schröder, C and Marinova, M and Koensgen, D and Mustea, A}, title = {Postoperative Weight Gain, Due to Fluid Retention After Ovarian Cancer Surgery-How Much Is too Much?.}, journal = {Journal of surgical oncology}, volume = {133}, number = {7}, pages = {909-917}, pmid = {41840979}, issn = {1096-9098}, mesh = {Humans ; Female ; *Weight Gain ; *Ovarian Neoplasms/surgery/pathology ; *Postoperative Complications/etiology ; Middle Aged ; *Cytoreduction Surgical Procedures/adverse effects ; Aged ; *Anastomotic Leak/etiology ; Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: Postoperative complications after cytoreductive surgery in ovarian cancer patients are associated with impaired survival. Here, we investigated the association between postoperative weight gain due to fluid retention and the development of complications and anastomotic leakage (AL).

METHODS: N = 278 patients underwent cytoreductive surgery at the university hospital of Bonn in between 01/2013 and 03/2022. Postoperative weight gain on day 2 and day 5 was assessed and correlated to the occurrence of complications according to the MSKCC secondary event score and ALs.

RESULTS: There were 227 surgeries (81.7%) for primary and 51 surgeries (18.3%) for recurrent ovarian cancer. Severe complications were significantly more frequent in patients with postoperative weight gain exceeding 4 kg on postoperative day 2 (26/90 vs. 13/76; p = 0.03) and exceeding 3 kg on postoperative day 5 (34/89 vs 30/134; p = 0.02). A weight gain of more than 6 kg on postoperative day 2 was significantly associated with the occurrence of AL (p = 0.021). Less weight gain on d2 and d5 was associated with a significant earlier first defecation (day-2 p-value: 0.01; day-5 p-value: 0.01). In multiple binary logistic regression analysis, the postoperative weight gain on day 2 (p = 0.0019) and the performance of an anastomosis (p = 0.0095) remained the only significant risk factors regarding severe complications.

CONCLUSIONS: Postoperative weight gain, as a surrogate for fluid retention, and the creation of an anastomosis were associated with an increased risk of severe postoperative complications.}, } @article {pmid41841320, year = {2026}, author = {El Kaïm, A and Banos, M and Decostre, V and Birnbaum, S and Hogrel, JY and Gargiulo, M}, title = {Sexual health in neuromuscular diseases: Neglected challenges revealed by a scoping review.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602261434092}, pmid = {41841320}, issn = {2214-3602}, abstract = {BACKGROUND: Neuromuscular diseases (NMDs) are heterogeneous disorders causing progressive motor decline, multisystem complications, and reduced quality of life. Sexual health, a key component of well-being, remains largely overlooked. This scoping review mapped and synthesized evidence on sexual dysfunction (SD) in adults with NMDs, focusing on prevalence, underlying mechanisms, and research gaps.

METHODS: A systematic search of PubMed, Cochrane Library, and Google Scholar (February-March 2025) identified studies reporting original data on SD in adults with genetically or clinically confirmed NMDs. Citation tracking complemented the search. Data were narratively synthesized following PRISMA-ScR guidelines.

RESULTS: Twenty-seven studies (1983-2024) including 2428 individuals met the inclusion criteria. Most were cross-sectional and questionnaire-based studies. SD was frequent but heterogeneous across conditions. In myotonic dystrophy, erectile dysfunction often related to hypogonadism; in Charcot-Marie-Tooth disease, higher disease severity correlated with altered desire and satisfaction in women; amyloid neuropathies showed autonomic-related erectile and ejaculatory dysfunction in men and multidimensional impairment in women; inflammatory myopathies revealed high SD prevalence in both sexes; amyotrophic lateral sclerosis involved intimacy loss mainly due to disability and psychosocial distress, despite preserved interest; myasthenia gravis displayed SD mainly associated with mental health conditions, X-linked spinal muscular atrophy showed predominantly endocrine-related SD.

CONCLUSION: SD is common, multifactorial, and under-recognized in adults with NMDs. The available evidence remains limited by non-inclusive approaches to sexual orientation and intimacy, scarce physiological assessments, and substantial gaps regarding female sexual health, longitudinal data. Integrating sexual health assessment into routine care for people with NMDs should be prioritized.}, } @article {pmid41842529, year = {2026}, author = {Zhao, J and Ji, X and Leng, L and Wang, M and Li, Y and Wang, W and Sun, Y}, title = {Integrating terrain and spectral attributes for automated water-land classification using airborne LiDAR without any prior information.}, journal = {Applied optics}, volume = {65}, number = {7}, pages = {2053-2062}, doi = {10.1364/AO.579495}, pmid = {41842529}, issn = {1539-4522}, abstract = {Accurate differentiation between water and land is crucial for flood monitoring, land-use planning, and ecological protection. Airborne laser scanning (ALS) provides high-resolution three-dimensional topographic and intensity data, offering a robust foundation for these applications. However, existing classification approaches largely depend on manually defined thresholds or supervised learning, with limited attention to the underlying synergies among multidimensional features, thereby constraining both accuracy and automation. To address these limitations, this study introduces an unsupervised classification framework based on multi-feature fusion, where four fusion indicators are derived from 14 geometric and radiometric features, enabling fully automated water-land classification. Experiments on two ALS datasets from central Dublin demonstrate that the proposed method substantially outperforms SLIER, fuzzy logic, and elevation-threshold approaches, achieving overall accuracies of 98.3% and 97.3%, with Kappa coefficients of 0.903 and 0.914. Beyond improving classification accuracy and reducing computational complexity, the fusion indicators also enhance digital elevation model (DEM) reconstruction by repairing voids in water regions and refining boundary delineation, thereby reinforcing the value of ALS data for environmental monitoring and disaster management.}, } @article {pmid41843813, year = {2026}, author = {Meyer, T and Ticozzi, N and Weber, M and Ravits, J and Lingor, P and Kuźma-Kozakiewicz, M and Boentert, M and Grehl, T and Corcia, P and Povedano Panadés, M and Maier, A and Ingre, C and Cetin, H and Weydt, P and Lunetta, C and van den Berg, L and Ludolph, AC and Brenner, D and Turner, MR and Genge, A}, title = {ALS motor phenotypes: a revised 'OPM' classification.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {540-552}, doi = {10.1080/21678421.2026.2644277}, pmid = {41843813}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/classification/diagnosis ; *Phenotype ; *Motor Neurons/physiology ; }, abstract = {BACKGROUND: Defining motor phenotypes in amyotrophic lateral sclerosis (ALS) is important for individualized care and optimal therapeutic trial design. The "ALS-OPM" classification is based on the onset region (O), the propagation of motor symptoms (P), and the degree of clinical upper (UMN) and/or lower (LMN) motor neuron dysfunction (M).

METHODS: An international ALS expert focus group was held in September 2025, followed by a consensus process through which revisions of the OPM classification were finalized.

RESULTS: Onset (O1-4) identifies first motor symptoms as relating to the head (O1), distal/proximal arm (O2d/p), respiratory/axial trunk (O3r/a), or distal/proximal leg (O4d/p). Onset symptoms are defined by weakness or slowed, poorly coordinated voluntary movements in the muscles of the head, arm, trunk, or leg, including dysarthria, dysphagia, dysphonia, dyspnea, and axial instability. Propagation (P1(n)) or absence of propagation (P0(n)) of motor symptoms from the onset region to another body region are designated, where n denotes the number of months from onset to propagation or assessment. The degree of UMN dysfunction (slowed, poorly coordinated voluntary movements, hyperreflexia and/or spastic muscle tone, emotional lability) and/or LMN dysfunction (weakness with associated muscle atrophy) is classified as follows: balanced UMN and LMN dysfunction (M0); dominant (M1d) or pure UMN dysfunction (M1p); dominant (M2d) or pure LMN dysfunction (M2p); and dissociated UMN/LMN dysfunction (M3), in which the arms and legs predominantly show LMN and UMN involvement, respectively.

CONCLUSION: The revised ALS-OPM classification aims to make it routine, practical and feasible to capture phenotype in clinical practice and therapeutic trials.}, } @article {pmid41845971, year = {2026}, author = {Dahlhaus, R and Braun, RJ}, title = {The role of TDP-43 fragments in regular cellular functions and homeostatic failure.}, journal = {Neurobiology of disease}, volume = {222}, number = {}, pages = {107349}, doi = {10.1016/j.nbd.2026.107349}, pmid = {41845971}, issn = {1095-953X}, mesh = {Humans ; Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Homeostasis/physiology ; *Amyotrophic Lateral Sclerosis/metabolism ; *TDP-43 Proteinopathies/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons, leading to severe muscle weakness, loss of voluntary movement, and respiratory failure. A widely noted feature of the disease is the presence of TDP-43 proteinopathies. Under homeostatic conditions, the RNA/DNA-binding protein TDP-43 mainly resides in the nucleus, where it functions to regulate gene expression, controlling not only RNA transcription and splicing, but also stability and transport to the cytoplasm. Upon the arrival at ribosomes, TDP-43 may further moderate translation, acting as a global repressor of protein synthesis. However, in over 95% of ALS cases, TDP-43 mislocalises from the nucleus to the cytoplasm, where it enriches in cytoplasmic inclusions that are marked by the presence of misfolded, ubiquitinated, phosphorylated and fragmented protein species of TDP-43. Although recent studies have tried to untangle the relationship between TDP fragments on the one hand, and cytotoxicity as well as neurodegeneration on the other, the results are still a matter of debate. Here, we review our current understanding of the different TDP fragments derived from proteolytic cleavage as well as alternative splicing, addressing the different N-terminal and C-terminal species and evaluating differences in rodent and primate models. We focus our analysis on potential homeostatic functions of TDP fragments in the context of viral infections and myelination control, which could be pivotally interconnected. The findings illustrate several facets of fragmented TDP-43 protein species in scenarios of enhanced cellular stress. Gaining a detailed understanding could help to reveal new treatment options for ALS and other TDP-43 proteinopathies.}, } @article {pmid41846014, year = {2026}, author = {Yang, L and Fan, W and Wang, Z and Wu, M and Chen, Y and Cheng, J and Zhou, F and Guo, Z}, title = {The role of IRF5 in Microglia-Mediated neuroinflammation in ALS.}, journal = {Neuroscience letters}, volume = {877}, number = {}, pages = {138580}, doi = {10.1016/j.neulet.2026.138580}, pmid = {41846014}, issn = {1872-7972}, mesh = {Animals ; *Microglia/metabolism/pathology ; *Interferon Regulatory Factors/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Mice, Transgenic ; Humans ; Motor Neurons/metabolism/pathology ; NF-kappa B/metabolism ; *Neuroinflammatory Diseases/metabolism/pathology ; Mice ; Signal Transduction ; Apoptosis ; }, abstract = {The occurrence and development of amyotrophic lateral sclerosis (ALS) involve neuroinflammatory responses, in which microglial activation plays a critical role. IRF5, a key regulator of inflammatory responses, is implicated in the disease mechanisms of various conditions. However, its mechanism in ALS remains unclear. This study found that IRF5 expression was significantly increased in hSOD1-G93A transgenic ALS mice and cell models, primarily localized in activated microglia. Silencing IRF5 altered microglial polarization, suppressed the release of inflammatory factors, enhanced phagocytic function, and reduced motor neuron apoptosis in a co-culture system. Mechanistic studies suggested that IRF5 may regulate microglial function through the NF-κB signaling pathway. This study reveals the key role of IRF5 in microglia-mediated neuroinflammation and neuronal damage in ALS, indicating that targeting IRF5 could represent a promising treatment strategy for this disease.}, } @article {pmid41846418, year = {2026}, author = {Ahire, C and Yadav, R and Bhamare, UU and Kaur, G and Palkar, MB}, title = {From Refractory Epilepsy to Neurodegeneration: Emerging Mechanistic and Clinical Insights Into the Ketogenic Diet.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {40}, number = {6}, pages = {e71609}, doi = {10.1096/fj.202503317R}, pmid = {41846418}, issn = {1530-6860}, mesh = {Humans ; *Diet, Ketogenic/methods ; Animals ; *Neurodegenerative Diseases/diet therapy/metabolism ; *Drug Resistant Epilepsy/diet therapy/metabolism ; }, abstract = {The ketogenic diet (KD), a high-fat, low-carbohydrate intervention, is well established for drug-resistant epilepsy and is increasingly explored in neurodegenerative disorders. KD reduces neuronal hyperexcitability through enhanced γ-aminobutyric acid (GABA)ergic transmission and modulation of neurotransmitter balance, underlying its efficacy in refractory epilepsy. Beyond seizure control, emerging evidence suggests KD may influence disease processes in conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease. Preclinical studies indicate that KD can modulate mitochondrial bioenergetics, oxidative stress, neuroinflammation, neurotransmitter signaling, and gut-brain interactions, though these effects are highly context-dependent and primarily derived from cellular and animal models. Clinical data remain limited, heterogeneous, and short-term, with small cohorts and variable outcome measures. Sustaining adherence and assessing long-term safety remain significant challenges in patient populations. This review summarizes recent experimental and clinical findings, highlighting the molecular and cellular mechanisms through which KD exerts neuroprotective effects. We also evaluate translational evidence and discuss the potential utility of KD as an adjunctive intervention in neurological disease management.}, } @article {pmid41847237, year = {2026}, author = {Zarco-Martín, MT and Andreo-López, MC and Yagui-Beltrán, MS and Fernández-Soto, ML}, title = {Sarcopenia in amyotrophic lateral sclerosis: a key predictor of respiratory dysfunction and disease progression.}, journal = {Frontiers in nutrition}, volume = {13}, number = {}, pages = {1713253}, pmid = {41847237}, issn = {2296-861X}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness and respiratory decline. Sarcopenia remains underexplored in terms of prevalence and their relationship with disease progression. We aimed to determine the prevalence of sarcopenia in ALS patients, assess the predictive value of morphofunctional assessment tools for sarcopenia, and explore their relationship with respiratory function and disease progression.

METHODS: A cross-sectional study was conducted with 40 ALS patients at the ALS Multidisciplinary Unit, San Cecilio University Hospital in Granada. Sarcopenia was defined based on the European Working Group of Sarcopenia in Older People 2(EWGSOP2) and malnutrition was diagnosed using GLIM criteria. Morphofunctional status was assessed using: Phase Angle (PA) and body composition by Bioelectrical Impedance Vector Analysis, muscle strength through Handgrip Strength (HGS). Respiratory function was evaluated using Forced Vital Capacity (FVC). Associations between sarcopenia, body composition, respiratory function, and disease severity were analyzed using logistic regression models. Receiver operating characteristic analyses were performed to identify optimal predictive cut-off values.

RESULTS: Sarcopenia was identified in 25% of ALS patients. Compared with non-sarcopenic individuals, sarcopenic patients exhibited significantly lower muscle mass indices, PA, and HGS, along with higher extracellular water percentage (%ECW). Malnutrition was more frequent in sarcopenia group (90% vs. 25%, p < 0.001). Respiratory impairment was more pronounced in sarcopenic patients, with reduced FVC and elevated pCO₂ (p = 0.02), and a greater need for non-invasive mechanical ventilation (NIMV) (70% vs. 10%, p = 0.001). VC correlated positively with body cell mass index (BCMI) (r = 0.450), skeletal muscle mass index (SMI) (r = 0.413), and ALSFRS-R score (r = 0.731; all p < 0.05). Lower PA, BCMI, and ALSFRS-R scores, together with higher %ECW and partial pressure of carbon dioxide (pCO₂), predicted sarcopenia risk. Reduced BCMI, HGS, Short Physical Performance Battery (SPPB) and sarcopenia were associated with the need of NIMV. BCMI (cut-off:8.05 kg/m[2]; AUC:0.889) and ALSFRS-R (cut-off:33 points; AUC:0.884) were the most accurate predictors of sarcopenia and ventilatory support, respectively.

CONCLUSION: This study is the first to assess sarcopenia prevalence in ALS patients using standardized diagnostic criteria. The findings highlight the relationship between sarcopenia, malnutrition, and respiratory decline. PA, BCMI, and respiratory parameters emerge as potential tools for sarcopenia and NIMV risk stratification.}, } @article {pmid41847382, year = {2026}, author = {Talbot, SR and Scorrano, F and Gaburro, S and Lainee, P and van Gaalen, MM}, title = {From observation to optimization: behavioral metrics that matter in KPI based home cage monitoring.}, journal = {Frontiers in behavioral neuroscience}, volume = {20}, number = {}, pages = {1694689}, pmid = {41847382}, issn = {1662-5153}, abstract = {Most in vivo scientists would agree that digital biomarkers collected via home-cage monitoring generate valuable data. However, few can tell precisely how valuable. The gap between enthusiasm and evidence has slowed the adoption of digital biomarkers in preclinical research. This framework paper addresses that gap by providing explicit key performance indicators (KPIs), organized into scientific, operational, welfare, and financial categories. We show how return-on-investment calculations differ across pharmaceutical companies, contract research organizations (CROs), and academic institutions. Furthermore, we demonstrate the approach through a worked example in an Amyotrophic Lateral Sclerosis (ALS) mouse model that reduces full-time equivalent (FTE) requirements by half. When successfully integrated, digital biomarkers can generate richer datasets, reduce the number of animals, improve welfare, and enhance translational value. However, successful implementation requires clear performance metrics to justify investment and measure success. We also discuss what these technologies cannot do, because understanding limitations matters as much as understanding benefits.}, } @article {pmid41850140, year = {2026}, author = {Gao, Y and Sun, Z and Wei, Q and She, C and Wang, Y and Chen, J and Wang, M and Gui, X and Xia, X and Liu, Y and Wang, X}, title = {Employing an integrated computational simulation strategy to identify high-affinity ligands for TDP-43 amyloid proteins.}, journal = {Bioorganic & medicinal chemistry}, volume = {137}, number = {}, pages = {118634}, doi = {10.1016/j.bmc.2026.118634}, pmid = {41850140}, issn = {1464-3391}, mesh = {Ligands ; *Molecular Dynamics Simulation ; Humans ; *DNA-Binding Proteins/metabolism/chemistry/antagonists & inhibitors ; Protein Binding ; Thermodynamics ; }, abstract = {Developing high-affinity ligands targeting TDP-43 amyloid species is a potential therapeutic approach for amyotrophic lateral sclerosis (ALS). Here, we propose an integrated computational simulation strategy, which integrates multiple virtual screening methods, molecular dynamics simulations and binding free energy evaluations. Using this strategy, we successfully identified TDPL1, a high-affinity ligand for TDP-43 amyloid proteins. In vitro affinity assays confirmed the computational predictions. Based on the MD simulation results, we further investigated the binding mode between TDPL1 and TDP-43 amyloid proteins. Additionally, steered molecular dynamics simulations were employed to assess the impact of TDPL1 on the stability of β-sheet interactions within the TDP-43 amyloid structure. Our data demonstrate that TDPL1 not only binds effectively to TDP-43 amyloid proteins but also possesses the potential to disrupt the stability of amyloid aggregates. These findings provide a molecular foundation for the future development of diagnostic agents or targeted therapeutics for ALS and related diseases.}, } @article {pmid41850233, year = {2026}, author = {Guise, AJ and Ferber, KL and Young, D and Edwards, AL and Sabouri, S and Fraser, KB and Milliman, E and Plowey, ED and Zoghbi, J and Fradette, SM and Graham, DL}, title = {Identification of tofersen PD-response biomarkers in VALOR clinical trial CSF via multiplexed quantitative proteomics.}, journal = {Cell reports. Medicine}, volume = {7}, number = {3}, pages = {102648}, pmid = {41850233}, issn = {2666-3791}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid/genetics ; *Biomarkers/cerebrospinal fluid ; GPI-Linked Proteins/cerebrospinal fluid ; Membrane Glycoproteins/cerebrospinal fluid ; *Proteomics/methods ; Superoxide Dismutase-1/genetics ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase III as Topic ; }, abstract = {Tofersen, the first approved genetically targeted therapy for amyotrophic lateral sclerosis (ALS), demonstrates significant lowering of plasma neurofilament in adults carrying mutations in the superoxide dismutase 1 (SOD1) gene; however, additional biomarkers of treatment response in ALS are lacking. Here, we analyze longitudinally collected cerebrospinal fluid (CSF) samples from the phase 3 VALOR clinical trial to identify candidate tofersen treatment-response biomarkers in SOD1-ALS via quantitative proteomics. We observe significant modulation from baseline abundance for 56 proteins in tofersen-treated participants relative to placebo, including CSF GPNMB, which is significantly and continuously elevated across all post-baseline timepoints. We orthogonally confirm this observation by GPNMB immunoassay in independent tofersen-treated cohorts. Taken together, these data identify pharmacodynamic-response biomarkers of tofersen treatment that can be measured as early as 4 weeks post-treatment in SOD1-ALS patients and demonstrate the utility of leveraging unbiased proteomic screening integrated with targeted validation methods to identify pharmacodynamic-response biomarkers in clinical trial patient samples.}, } @article {pmid41850301, year = {2026}, author = {Glaubitz, R and Harst, L and Ehm, F and Tesch, F and Barlinn, J and Krause, F and Schwarz, R and Malzahn, J and Werblow, A and Sinz, C and Randig, I and Riedel, T and Kutschker, C and Fiebig, S and Kubitza, J and Cording, M and Wolff, J and Schmitt, J}, title = {Testing a model-based approach for planning and regional coordination of hospital service group offerings: A model project in the East Saxony healthcare cluster.}, journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2771-8616}, pmid = {41850301}, issn = {1439-4421}, abstract = {The hospital reform passed in 2024 will lead to regional and nationwide changes in the German hospital landscape. A joint project to examine the effects of the hospital reform on health care structures in the East Saxony region was initiated by the Center for Evidence-Based Health Care (ZEGV) at Dresden University Hospital, the regional health care coordinators of the four districts in the East Saxony care cluster and the city of Dresden, a statutory health insurance provider (AOK PLUS), and other regional stakeholders. In addition, the aim was to promote cooperation between the stakeholders for the purpose of future regionally coordinated planning for inpatient care. The project involved the application and validation of a model displaying a hospital's relevance for stationary care provision (care relevance model), which was developed in cooperation with the GKV-Spitzenverband (National Association of Statutory Health Insurance Funds) and is based on the performance data of German hospitals in accordance with § 21 KHEntgG (Hospital Remuneration Act). Thirty of the 36 hospital locations in the project region agreed to participate in the project. Both in a questionnaire-based self-assessment provided by the clinics and during a joint cluster conference, the tension between the need for cooperation and individual interests became clear. At this point, the care relevance model developed can scientifically support the dialogue between the stakeholders and thus support inpatient planning.Im Zuge der im Jahr 2024 verabschiedeten Krankenhausreform wird es zu regionalen und deutschlandweiten Veränderungen der Krankenhauslandschaft kommen. Vor diesem Hintergrund wurde ein gemeinsames Projekt des Zentrums für Evidenzbasierte Gesundheitsversorgung (ZEGV) der Hochschulmedizin Dresden mit den Regionalkoordinator:innen für Gesundheit der vier Landkreise im Versorgungscluster Ostsachsen und der Stadt Dresden, der AOK PLUS und weiteren regionalen Akteuren initiiert, um die Auswirkungen der Krankenhausreform auf die Versorgungsstrukturen in der Region Ostsachsen zu untersuchen. Zudem sollte die Kooperation zwischen den Akteuren zum Zweck einer zukünftigen regional abgestimmten Planung für die stationäre Versorgung gefördert werden. Im Projekt erfolgte die Anwendung und Validierung eines Versorgungsrelevanzmodells, welches in Kooperation mit dem GKV-Spitzenverband entwickelt wurde und auf den Leistungsdaten deutscher Krankenhäuser nach § 21 KHEntgG basiert. Dreißig von 36 Krankenhausstandorten in der Projektregion konnten für eine Teilnahme am Projekt gewonnen werden. Sowohl in einer fragebogengestützten Selbstauskunft der Kliniken als auch im Rahmen der zusammenführenden Clusterkonferenz wurde das Spannungsfeld zwischen Kooperationsnotwendigkeiten und Partikularinteressen deutlich. An dieser Stelle kann das entwickelte Versorgungsrelevanzmodell den Dialog zwischen den Akteuren wissenschaftlich begleiten und so die stationäre Planung unterstützen.}, } @article {pmid41851044, year = {2026}, author = {Takeda, T and Ishikawa, A and Kokubun, S and Saito, Y and Isose, S and Ito, K and Arai, K and Kuwabara, S and Honda, K}, title = {Reduced nuclear TDP-43 and cytoplasmic DLK1 as markers of motor neuron degeneration in amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {85}, number = {8}, pages = {881-893}, doi = {10.1093/jnen/nlag017}, pmid = {41851044}, issn = {1554-6578}, support = {JP24K10631//Ministry of Health, Labor and Welfare, Japan/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Motor Neurons/pathology/metabolism ; Calcium-Binding Proteins ; Cytoplasm/metabolism/pathology ; Female ; Male ; Cell Nucleus/metabolism/pathology ; Middle Aged ; *Intercellular Signaling Peptides and Proteins/metabolism ; Aged ; *Membrane Proteins/metabolism ; *Nerve Degeneration/pathology/metabolism ; Biomarkers/metabolism/analysis ; Inclusion Bodies/pathology/metabolism ; }, abstract = {Loss of upper and lower motor neurons (MNs) is a defining pathological feature underlying the clinical manifestations of amyotrophic lateral sclerosis (ALS). However, the differences in MN loss and TDP-43 pathology between these areas in ALS patients remain unclear. This study included 7 patients with ALS and 3 controls from consecutive autopsies. The cell density and regional density of TDP-43-positive inclusions in 4 upper MN areas and their anatomically corresponding lower MN areas were measured. The numbers of large cells with loss of nuclear TDP-43 and cytoplasmic delta-like-1 homolog (DLK1) were counted. The results showed severe MN loss in both upper and lower MN areas. However, TDP-43-positive inclusions differed markedly, that is they were rare in upper MNs but abundant in lower MN. In upper MN areas, TDP-43 density was not associated with the residual rate of MNs, whereas in lower MN areas, the density in MNs was associated with the cell residual rate. Significantly higher numbers of MNs lacking nuclear TDP-43 and cytoplasmic DLK1 were observed in the upper and lower MN regions in ALS vs controls. These findings suggest that these morphological changes may be closely related to motor neuron vulnerability and may be mechanistic contributors to ALS development.}, } @article {pmid41851249, year = {2026}, author = {Leinders, S and Aarnoutse, EJ and Branco, MP and Freudenburg, ZV and Geukes, SH and Schippers, A and Verberne, MSW and van den Boom, MA and van der Vijgh, BH and Crone, NE and Denison, T and Ramsey, NF and Vansteensel, MJ}, title = {Implanted brain-computer interface functionality during nighttime in late-stage amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41851249}, issn = {2045-2322}, support = {UH3NS114439/NS/NINDS NIH HHS/United States ; UGT7685//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; U01DC016686/DC/NIDCD NIH HHS/United States ; ADV 320708/ERC_/European Research Council/International ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/therapy ; *Brain-Computer Interfaces ; Electrocorticography ; Male ; Female ; Middle Aged ; Circadian Rhythm ; }, abstract = {Brain-computer interfaces (BCIs) hold promise as assistive communication technology for people with severe paralysis. Although such BCIs should be available 24/7, feasibility of nocturnal BCI use has not been investigated. Here, we addressed this question using data from an electrocorticography-BCI user with amyotrophic lateral sclerosis. We investigated nocturnal dynamics of neural signal features used for BCI control. Additionally, we assessed nocturnal performance of a decoder trained on daytime data, by quantifying the number of unintentional BCI activations at night. Finally, we developed a nightmode functionality and assessed its performance. Mean and variance of low and high frequency band power were significantly higher at night than during the day. When applied to night data, daytime decoders caused unintentional BCI activations in 100% of nights (245 unintended click-commands and 13 unintended caregiver-calls per hour). The specifically developed nightmode functionality, however, functioned error-free in 79% of nights over a period of ± 1.5 years, allowing the user to reliably call the caregiver. Reliable nighttime use of a BCI requires strategies to adjust to circadian and sleep-related signal changes. This demonstration of a reliable nightmode and its long-term use by an individual with amyotrophic lateral sclerosis underscores the importance of 24/7 BCI reliability.}, } @article {pmid41851271, year = {2026}, author = {Hodgson, RE and Huang, WP and Lang, R and Kumar, V and An, H and Stender, EGP and Chalakova, ZP and Driver, MD and Sanchez Avila, A and Ellis, BCS and Day, E and Rayment, JA and Baeg, K and Strange, A and Moll, T and Wright, GSA and van Vugt, JJFA and , and Allen, SP and Locker, N and Pitout, I and Fletcher, S and Onck, PR and Duss, O and Cooper-Knock, J and Shelkovnikova, TA}, title = {Paraspeckle condensation is controlled via TDP-43 polymerization and linked to neuroprotection.}, journal = {Nature cell biology}, volume = {28}, number = {4}, pages = {754-770}, pmid = {41851271}, issn = {1476-4679}, support = {MR/W004615/1//Research Councils UK (RCUK)/ ; MR/W028522/1//RCUK | Medical Research Council (MRC)/ ; BB/V014110/1//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; PhD studentship//Motor Neurone Disease Association (MNDA)/ ; 969-799//Motor Neurone Disease Association (MNDA)/ ; PhD studentship//MND Scotland (Motor Neuron Disease Scotland)/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; Humans ; *Neurons/metabolism/pathology ; RNA-Binding Protein FUS/metabolism/genetics ; *RNA, Long Noncoding/metabolism/genetics ; Animals ; *Neuroprotection ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Biomolecular Condensates/metabolism ; }, abstract = {The paraspeckle is a disease-relevant biomolecular condensate assembled from long non-coding RNA (lncRNA) NEAT1_2 ribonucleoprotein particles. Paraspeckle biogenesis is suppressed in normal tissues, yet it can be rapidly upregulated under stress. Here we demonstrate that a neurodegeneration-linked RNA-binding protein TDP-43 inhibits NEAT1_2 ribonucleoprotein particle condensation into the paraspeckle, in a concentration-dependent manner, which requires its intact polymerization and RNA binding. This effect is counterbalanced by core paraspeckle proteins such as FUS. Below disruptive concentrations, TDP-43 can be recruited into paraspeckles, forming non-liquid clusters. Under stress, TDP-43 sequestration into de novo nuclear condensates alleviates paraspeckle suppression and increases their dynamism. NEAT1_2 middle-part and 3'-end UG repeats mediate paraspeckle regulation by TDP-43 cotranscriptionally and post assembly, respectively. The deletion of the 3'-end UG repeat increases paraspeckle stability and cytoprotection in stressed human neurons. Consistently, longer 3'-end UG repeats are linked to shorter survival in the neurodegenerative disease amyotrophic lateral sclerosis. Thus, TDP-43 is a critical regulator of paraspeckle condensates linked to cytoprotection.}, } @article {pmid41851470, year = {2026}, author = {Michaelis, T and Lindestam Arlehamn, CS and Johansson, E and Frazier, A and Williams, GP and Berry, JD and Cudkowicz, M and Goyal, NA and Fournier, C and Snyder, A and Kwan, JY and Crook, J and Phillips, EJ and Mallal, SA and Ravits, J and Marder, KS and Sidney, J and Sulzer, D and Sette, A}, title = {Author Correction: Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis.}, journal = {Nature}, volume = {652}, number = {8108}, pages = {E2}, doi = {10.1038/s41586-026-10388-9}, pmid = {41851470}, issn = {1476-4687}, } @article {pmid41852184, year = {2026}, author = {Gagliardi, D and Villella, C and Zanovello, M and Iacobelli, V and Corti, S and Comi, GP and Fratta, P and Houlden, H and Tucci, A and Ronchi, D}, title = {High Prevalence of SOD1 Pathogenic Variants in the UK Biobank: Implications for Early Intervention in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {99}, number = {6}, pages = {1502-1515}, pmid = {41852184}, issn = {1531-8249}, support = {//Italian Ministry of Health/ ; MR/Z506503/1//UK Medical Research Council/ ; MR/S006753/1//UK Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *Superoxide Dismutase-1/genetics ; Female ; United Kingdom/epidemiology ; Middle Aged ; Male ; Biological Specimen Banks ; Adult ; Aged ; Prevalence ; Mutation/genetics ; UK Biobank ; Penetrance ; }, abstract = {OBJECTIVE: SOD1 is the second most frequently mutated gene in European patients with amyotrophic lateral sclerosis (ALS). Given the recent authorization of SOD1-targeted antisense oligonucleotides for SOD1-ALS, prompt screening for SOD1 mutations in patients with ALS patients is highly recommended. Large-scale genomic analysis could inform on the population-based prevalence of SOD1 mutation carriers, who would potentially benefit from treatment. We aim to determine the number of people with pathogenic SOD1 variants in the UK Biobank (UKB), to address a critical gap between clinical and genetic prevalence of SOD1-ALS.

METHODS: We analyzed SOD1 variants within exome sequencing data from 470,000 individuals aged over 40 years. Pathogenicity was evaluated using referenced databases and American College of Medical Genetics and Genomics (ACMG) guidelines. Leveraging the UKB carrier frequency and age at onset data, we estimated the genetic prevalence of SOD1-ALS. We examined factors that may influence penetrance.

RESULTS: We identified 122 individuals with monoallelic SOD1 coding variants, 93.4% of whom were asymptomatic. Additionally, the low-penetrance p.Asp91Ala variant was observed in heterozygosis in 535 subjects, whereas it was never found in homozygosis. Excluding this variant, the expected number of people developing SOD1-ALS is 1.04:100,000 in the UK population, 4 times higher than clinically reported figures. Symptomatic carriers had significantly increased levels of serum neurofilament at baseline. Age-related penetrance was higher in non-p.Asp91Ala carriers versus p.Asp91Ala carriers. Long-term survivor status was associated with p.Asp91Ala genotype, older age, and lower neurofilament levels.

INTERPRETATION: Incomplete and age-related penetrance, along with underascertainment due to disease heterogeneity and limitations in data collection, likely account for the reduced number of symptomatic patients identified. Our findings highlight the need to identify genetic and environmental factors, as well as biological indicators, able to influence disease penetrance and phenoconversion risk in presymptomatic carriers and to predict treatment response in patients. ANN NEUROL 2026;99:1502-1515.}, } @article {pmid41852280, year = {2026}, author = {Isik, FI and Pickford, R and Timmins, HC and Piguet, O and Halliday, GM and Kiernan, MC and Kim, WS}, title = {Systemic dysregulation of apolipoproteins in amyotrophic lateral sclerosis serum.}, journal = {FEBS open bio}, volume = {16}, number = {8}, pages = {1550-1562}, pmid = {41852280}, issn = {2211-5463}, support = {IM-202303-00957//FightMND/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/metabolism ; *Apolipoproteins/blood/metabolism ; Female ; Biomarkers/blood ; Male ; Middle Aged ; Aged ; Case-Control Studies ; Apolipoproteins E/blood ; Lipid Metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration. Increasing evidence implicates systemic lipid perturbation in ALS pathogenesis. However, the extent and nature of apolipoprotein changes underlying lipid perturbations in ALS remain largely unknown. To address this, we performed a comprehensive analysis of major apolipoproteins involved in lipid metabolism and examined their association with lipoprotein membrane lipids in sporadic ALS (n = 32) and age-matched healthy controls (n = 32), using ELISA and liquid chromatography-mass spectrometry. Compared with controls, serum levels of apoB, apoCI, apoCII, apoCIII and apoE were significantly elevated in ALS, whereas apoAI and apoAII were unchanged. Distributional analyses demonstrated a relative decrease in apoAI and an increase in apoB in ALS, resulting in an elevated apoB/apoAI ratio, a marker of atherogenic risk, alongside a reduced apoAI/apoE ratio. Correlation analyses revealed strengthened interrelationships among apolipoproteins in ALS, suggesting altered regulatory coordination. At the lipid level, phosphatidylcholine (PC) was increased, whereas sphingomyelin (SM) was reduced in ALS serum. Notably, the strong associations of apoB to both PC and SM observed in controls were absent in ALS. Biomarker analyses identified apoE as the strongest discriminator between ALS and control groups. Collectively, these findings demonstrate a coordinated disruption of apolipoproteins and lipoprotein-associated lipids in ALS serum, with likely functional consequences for lipoprotein metabolism. This study provides new insights into lipid dysregulation in ALS pathobiology and supports the emerging view that ALS encompasses not only neurodegenerative processes but also systemic metabolic reprogramming.}, } @article {pmid41853322, year = {2026}, author = {Elshaer, A and Thomas, L}, title = {Investigating inequality in Advanced Life Support courses: a retrospective, single-centre, survey-based pilot study.}, journal = {Resuscitation plus}, volume = {28}, number = {}, pages = {101283}, pmid = {41853322}, issn = {2666-5204}, abstract = {BACKGROUND: With more International Medical Graduates (IMGs) joining the United Kingdom's medical workforce, the demand for Advanced Life Support (ALS) courses has increased. Whilst differential attainment among IMGs is well-documented, little is understood about this phenomenon in ALS courses. This study explores the relationship between ALS course participants' background and course outcomes.

METHODS: Doctors who attended ALS courses at a UK course centre were retrospectively recruited to participate in a 28-question online survey about their language, education and clinical backgrounds, as well as their ALS course experience and outcomes. Quantitative and qualitative analyses were carried out, and recommendations were thematically summarised.

RESULTS: Of 419 invited healthcare professionals, 38 doctors (9%) completed the survey. 27 (71.1%) of the respondents graduated outside the UK, 32 (84.2%) studied medicine in English, and 15 (39.5%) were native English speakers. Passing the Cardiac Arrest Simulation Tests (CAS-Test) was statistically associated with more previous scenario-based simulation experience. Thematic analysis of responses suggested that biased treatment, language barriers, communication anxiety, inadequate undergraduate training, vulnerability, rigid professionalism and psychological insecurity were obstacles to IMGs attaining course outcomes. Suggestions for improvement focused on enhancing course accessibility, learning materials, the educational environment, assessment, and faculty development.

CONCLUSIONS: This exploratory study investigates IMGs' self-reported challenges and proposes interventions to promote the inclusivity of ALS courses. Further prospective research is required to evaluate the nature and generalisability of these findings and the applicability of the offered recommendations.}, } @article {pmid41853978, year = {2026}, author = {Piotrowski, SL and Allnutt, MA and Johnson, K and Tanaka, T and Ferrucci, L and Morris, H and Hardy, J and , and Ryten, M and , and Logroscino, G and Troncoso, J and Beach, TG and Serrano, GE and Cruchaga, C and Dickson, DW and Ross, OA and Chiò, A and , and , and Houlden, H and , and Dalgard, CL and Ding, J and Gibbs, JR and Traynor, BJ and Scholz, SW and Jacobson, S}, title = {Herpesvirus genome integration in whole-genome sequences of dementia and control cohorts.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {3}, pages = {e71047}, pmid = {41853978}, issn = {1552-5279}, support = {1ZIAAG000935/AG/NIA NIH HHS/United States ; P30AG019610/AG/NIA NIH HHS/United States ; P30AG072980/AG/NIA NIH HHS/United States ; U24AG021886/AG/NIA NIH HHS/United States ; P50AG016574/AG/NIA NIH HHS/United States ; U19AG071754/AG/NIA NIH HHS/United States ; R01AG087165/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; 1ZIANS003154/NS/NINDS NIH HHS/United States ; U54-NS110435/NS/NINDS NIH HHS/United States ; P50NS072187/NS/NINDS NIH HHS/United States ; 211002//Arizona Department of Health Services/ ; 4001 0011 05-901//Arizona Biomedical Research Commission/ ; //Michael J. Fox Foundation for Parkinson's Research/ ; //Ted Turner and family/ ; //Little Family Foundation/ ; //Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy body dementia program/ ; ZIA AG000935/ImNIH/Intramural NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; U19 AG071754/AG/NIA NIH HHS/United States ; R01 AG087165/AG/NIA NIH HHS/United States ; ZIA NS003154/ImNIH/Intramural NIH HHS/United States ; U54 NS110435/NS/NINDS NIH HHS/United States ; P50 NS072187/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Genome, Viral/genetics ; *Virus Integration/genetics ; *Herpesvirus 6, Human/genetics ; *Dementia/genetics/virology ; Whole Genome Sequencing ; Alzheimer Disease/virology/genetics ; Cohort Studies ; Multiple System Atrophy/virology/genetics ; Lewy Body Disease/virology/genetics ; }, abstract = {INTRODUCTION: The infectious hypothesis suggests that microbes like herpesviruses may play a role in the pathogenesis of Alzheimer's disease (AD) and other related dementias through methods that may include viral genome integration. The occurrence of herpesvirus genome integration in dementia patients has not been thoroughly characterized.

METHODS: Over 7500 total whole-genome sequences from control, frontotemporal dementia/amyotrophic lateral sclerosis spectrum, Lewy body dementia (LBD), multiple system atrophy (MSA), and AD cohorts were screened for the integration of pathogen genomes using the PathSeq computational tool.

RESULTS: Low PathSeq scores for human herpesvirus 6 (HHV-6) were consistent with the suspected integration of viral genome segments. The LBD and MSA cohorts had a significantly higher prevalence of this partial HHV-6 genome integration.

DISCUSSION: This higher prevalence in both synucleinopathies was not noted in other herpesviruses, suggesting that the integration of HHV-6 may play a role in a subset of these patients.

HIGHLIGHTS: Over 7500 whole-genome sequences from controls and dementia patients were analyzed. Sequences consistent with integrated herpesviruses were identified using PathSeq. Prevalence of partial HHV-6 integration was higher in synucleinopathies. Herpesviruses genome integration may play a role in subsets of dementia patients.}, } @article {pmid41854033, year = {2026}, author = {Fragkoudi, A and Stern, C and Pollock, D and Barker, TH and Semendric, I and Labra, J and Vucic, S and Whitehouse, J and Munn, Z}, title = {Identifying priorities for a national motor neurone disease (amyotrophic lateral sclerosis) guideline: results from an Australian online survey.}, journal = {Disability and rehabilitation}, volume = {48}, number = {19}, pages = {6308-6324}, doi = {10.1080/09638288.2026.2643544}, pmid = {41854033}, issn = {1464-5165}, mesh = {Humans ; Australia ; Caregivers/psychology ; Female ; Surveys and Questionnaires ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/psychology ; Male ; *Practice Guidelines as Topic ; Middle Aged ; Quality of Life ; Adult ; *Health Priorities ; Aged ; Palliative Care ; Motor Neuron Disease ; }, abstract = {PURPOSE: To identify the priorities of people living with motor neurone disease (MND), their carers, asymptomatic genetic carriers, and healthcare professionals (HCPs) in Australia, to inform the development of a national MND care guideline.

METHODS: An anonymous online survey was distributed via MND organisations and groups to the Australian MND community.

RESULTS: Two hundred and fourteen individuals completed the survey. Of those, 44.8% (n = 96) were HCPs, with the remaining consisting of people living with MND, genetic carriers, and carers. The following areas were rated as extremely important and should be included in the guideline: diagnosis, service delivery models, clinical care management, caregiver support, and palliative care; while views on genetic testing and cognitive assessment were mixed. Participants highlighted a need for holistic care which considered emotional/psychological and physical aspects of MND. People with MND and their carers want the Australian MND care guideline to highlight proactive and coordinated support prioritising quality of life, while maintaining independence for as long as possible.

CONCLUSIONS: Identifying priorities is a fundamental step that will shape the forthcoming Australian MND care guideline. This methodology ensures the voices of those with lived experience and interest holders are incorporated from the outset.}, } @article {pmid41854301, year = {2026}, author = {Walker, TB and Trowbridge, JW and McMahon, S and Marzano, NR and Rice, L and Yerbury, JJ and Ecroyd, H and McAlary, L}, title = {Small heat shock proteins HspB1 and HspB5 differentially alter the condensation and aggregation of the TDP-43 low-complexity domain.}, journal = {Protein science : a publication of the Protein Society}, volume = {35}, number = {4}, pages = {e70539}, pmid = {41854301}, issn = {1469-896X}, support = {//Motor Neurone Disease Australia/ ; //FightMND/ ; APP1194872//National Health and Medical Research Council/ ; }, mesh = {*DNA-Binding Proteins/chemistry/metabolism/genetics ; Humans ; Protein Domains ; *HSP27 Heat-Shock Proteins/metabolism/chemistry/genetics ; *Protein Aggregates ; Molecular Chaperones/metabolism ; Phosphorylation ; *Heat-Shock Proteins/metabolism/chemistry ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a nucleic acid-binding protein that regulates processes of mRNA metabolism, during which it undergoes condensation mediated by its C-terminal low-complexity domain (TDP-43[LCD]). TDP-43 aggregation and condensation are associated with neurodegenerative disease. However, the proteostasis mechanisms that regulate these processes remain elusive. Some evidence has shown that the molecular chaperone small heat shock protein HspB1 binds to and regulates the cytoplasmic phase separation of TDP-43, indicating that other small heat shock proteins may have similar effects. Here, we demonstrate divergent behaviors for HspB1 and its homolog HspB5 on TDP-43[LCD] condensation and aggregation. In addition to inhibiting TDP-43[LCD] aggregation, HspB1 partitions into TDP-43[LCD] condensates and increases the dynamic exchange of TDP-43[LCD] within condensates and with the surrounding solution. Phosphorylation-mimicking mutations within HspB1 enhance these effects. HspB5 inhibits TDP-43[LCD] aggregation more effectively than HspB1 and partitions into TDP-43[LCD] condensates, where it delays the pathological transition of the condensate to a gel/solid. We identify the N- and C-terminal regions of HspB1 and HspB5 to be crucial for the chaperone effects, and highlight the role of sequence diversity within these regions in defining small heat shock protein function. These findings demonstrate that HspB1 and HspB5 are regulators of TDP-43 phase separation and aggregation and may be potential therapeutic targets in mitigating toxic TDP-43 aggregation in neurodegenerative disease.}, } @article {pmid41854409, year = {2026}, author = {Shukla, A and Upadhyay, A and Qadeer, M and Thakur, AD and Raj, R}, title = {Eco-friendly Immersion-Coating Strategy for Scalable and Durable Superhydrophobic Aluminum Surfaces.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {42}, number = {12}, pages = {8343-8357}, doi = {10.1021/acs.langmuir.5c05945}, pmid = {41854409}, issn = {1520-5827}, abstract = {Superhydrophobic (SHPB) surfaces have strong potential to mitigate corrosion, fouling, and icing, yet conventional fabrication methods rely on fluorinated modifiers, toxic reagents, or multistep protocols that limit scalability and conformal coverage on complex geometries. Here, we report an eco-friendly, scalable, and fluorine-free immersion-coating strategy for developing SHPB aluminum (SHPB-Al) surfaces using an ionic liquid (IL, 1-ethyl-3-methylimidazolium chloride) and lauric acid (LA) as nontoxic precursors. The central novelty lies in generating the requisite hierarchical roughness via an ionic liquid adsorption-driven surface modification mechanism, rather than through conventional material-removal or etching processes, thereby minimizing substrate damage and preserving structural integrity. Specifically, the two-step protocol first forms an IL-derived adsorbed substrate layer that induces hierarchical topography and hydrophilicity, followed by lauric acid functionalization to reduce surface energy and induce superhydrophobicity. Systematic optimization of the precursor concentration and dip duration identifies an optimum condition that achieves a static contact angle (SCA) of ≈165° with contact angle hysteresis (CAH) of <5°. Microscopy and surface analyses confirm the presence of hierarchical textures and robust chemical grafting. Durability tests under harsh chemical, thermal, mechanical, and environmental conditions reveal minimal performance loss (SCA > 150° and CAH < 10°), underscoring the coating's reliability. Droplet dynamics exhibit ≥15 successive rebounds, a coefficient of restitution of ≈0.9, and contact times as short as ≈10 ms, demonstrating ultralow adhesion. Building on these insights, we introduce an improvised one-step IL-LA codeposition method that simplifies the fabrication route while retaining high performance (SCA of ≈160° and CAH of ≈5°) and prolonged durability under environmental exposure. Together, this fluorine-free immersion-coating framework offers durable, scalable, and nontoxic routes for producing SHPB-Als, enabling conformal coatings on complex geometries such as heat-exchanger fins and paving the way for industrial deployment in harsh service environments.}, } @article {pmid41854827, year = {2026}, author = {Calvache Anaya, JA and Urdiales Merino, A and Druetta, NN and Sanz Rigo, M and Cardona Monjo, AM}, title = {Nonlinear and Asymmetric Refractive Sensitivity to Effective Lens Position Errors in Pseudophakic Eye Models.}, journal = {Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists)}, volume = {46}, number = {3}, pages = {489-493}, pmid = {41854827}, issn = {1475-1313}, mesh = {Humans ; *Pseudophakia/physiopathology ; *Refraction, Ocular/physiology ; *Lenses, Intraocular ; *Refractive Errors/physiopathology ; Axial Length, Eye ; *Models, Biological ; Biometry ; Cornea/physiopathology ; }, abstract = {PURPOSE: To perform a theoretical analysis of refractive sensitivity to effective lens position (ELP) errors in pseudophakic eyes using an explicit vergence-based optical model, and to quantify how this sensitivity depends on axial length (AL) and corneal power across a wide biometric range.

METHODS: A paraxial two-lens thin-lens model of the pseudophakic eye was developed, explicitly parameterised by AL, total corneal power (TCP), intraocular lens (IOL) power and effective lens position (ELP). Refraction was calculated at the corneal plane using vergence propagation. For a fixed reference ELP, the emmetropic IOL power was derived analytically for each combination of AL and TCP, and subsequently held constant while ELP was perturbed by ±1.0 mm. Simulations were performed for ALs from 19 to 31 mm and corneal powers from 38 to 50 dioptres. Refractive changes were approximated using families of quadratic regression models as functions of AL.

RESULTS: Refractive sensitivity to ELP errors was dominated by AL. Short eyes exhibited large refractive changes per millimetre of ELP error, whereas long eyes showed markedly reduced sensitivity. The relationship between refractive error and ELP displacement was nonlinear, resulting in asymmetric refractive effects for equal-magnitude anterior and posterior ELP deviations. TCP continuously modulated refractive sensitivity indirectly through its influence on the emmetropic IOL power required for a given optical configuration.

CONCLUSIONS: Refractive sensitivity to ELP errors in pseudophakic eye models is inherently nonlinear and asymmetric. This sensitivity is primarily governed by AL, with TCP acting as a secondary but systematic modulator through its effect on emmetropic IOL power. By explicitly separating optical sensitivity from ELP prediction, this vergence-based framework provides a physical basis for understanding ELP-related refractive variability across the biometric spectrum.}, } @article {pmid41855303, year = {2026}, author = {Drouin, E and Pereon, Y}, title = {Historical and Clinical Analysis of a Case of Progressive Muscular Atrophy (1853-1871).}, journal = {European neurology}, volume = {89}, number = {3}, pages = {130-137}, doi = {10.1159/000550658}, pmid = {41855303}, issn = {1421-9913}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/history ; History, 19th Century ; Case Reports as Topic ; }, abstract = {BACKGROUND: Progressive muscular atrophy (PMA) emerged in the mid-19th century as a distinct clinical entity within the evolving field of French neurology, notably through the work of François Amilcar Aran, Duchenne de Boulogne, and later Jean-Martin Charcot. During this period, uncertainties persisted regarding its nosological status, pathophysiology, and relationship to amyotrophic lateral sclerosis (ALS). Longitudinal clinical observations from this era remain rare but are essential for understanding both the natural history of motor neuron diseases and the historical construction of neurological knowledge.

SUMMARY: This article presents a historical and clinical analysis of a unique case of PMA observed for over nearly 2 decades (1853-1871) in Parisian hospitals. The case concerns Auguste-Joseph Bellinghen, whose condition was first documented in an unpublished handwritten manuscript in 1853 and later published with photographic illustrations in 1871. Through a comparative analysis of these two observations, the study traces the slow, asymmetrical, and irreversible progression of muscular atrophy, marked by early fasciculations, the absence of sensory disturbances, and eventual severe motor disability. The case is examined within its institutional, nosological, and therapeutic contexts, highlighting hospital circulation, the role of medical interns, and the empirical treatments of the time, including electrotherapy and thermal baths. Reinterpreted in light of contemporary neurology, this historical observation likely corresponds to a spinal-onset motor neuron disease closely related to ALS. Beyond its clinical significance, the case illustrates the transition from descriptive clinical medicine to anatomoclinical correlation and contributes to the historiography of neurology by illuminating how individual patient trajectories shaped medical knowledge in the 19th century.

KEY MESSAGES: (1) Long-term historical clinical observations provide valuable insights into the natural history of PMA and motor neuron diseases. (2) The Bellinghen case illustrates the evolution of neurological semiology, particularly the early recognition of fasciculations and asymmetrical muscle wasting. (3) This case highlights the transition from Aran's initial clinical description of PMA to Charcot's anatomopathological framework linking PMA to ALS. (4) Historical medical archives offer not only scientific data but also a window into the social consequences of chronic neurological disease in the 19th century. (5) Integrating historical and clinical analysis enriches contemporary understanding of motor neuron disease nosology and medical memory.}, } @article {pmid41856038, year = {2026}, author = {Nguyen, L}, title = {Repeat expansion RNA elicits toxicity through hybrid G-quadruplexes with promoter DNA.}, journal = {Neuron}, volume = {114}, number = {6}, pages = {969-971}, doi = {10.1016/j.neuron.2026.02.018}, pmid = {41856038}, issn = {1097-4199}, mesh = {*G-Quadruplexes ; Humans ; *Promoter Regions, Genetic/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; *DNA Repeat Expansion/genetics ; *RNA/genetics ; C9orf72 Protein ; *Proteins/genetics ; RNA Polymerase II ; }, abstract = {In this Neuron issue, Liu et al.[1] show that the C9orf72 expanded G4C2 repeat RNA forms hybrid G-quadruplexes with CG-rich promoter regions, which impedes RNA polymerase II. This process causes global transcriptional dysregulation in C9orf72 amyotrophic lateral sclerosis patient-derived cells.}, } @article {pmid41856848, year = {2026}, author = {Wang, R and Chen, W}, title = {Comment on: "Clinical safety of ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis: Open-label extension of a phase 2/3 randomized controlled study".}, journal = {Journal of the neurological sciences}, volume = {484}, number = {}, pages = {125791}, doi = {10.1016/j.jns.2026.125791}, pmid = {41856848}, issn = {1878-5883}, } @article {pmid41858070, year = {2026}, author = {Zhang, Z and Fan, R and Jing, S and Liu, S and Liu, L and Que, W and Lu, D and Gan, Y and Xiao, F}, title = {Plasma proteomic trajectories before the onset of neurodegenerative diseases.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {5}, pages = {573-584}, pmid = {41858070}, issn = {1758-2032}, mesh = {Humans ; *Proteomics ; *Alzheimer Disease/blood/mortality/diagnosis ; *Amyotrophic Lateral Sclerosis/blood/mortality ; *Parkinson Disease/blood/mortality/diagnosis ; *Neurodegenerative Diseases/blood ; Female ; Male ; *Blood Proteins/metabolism ; Aged ; Biomarkers/blood ; }, abstract = {BACKGROUND: The study aimed to identify indicative proteins associated with the occurrence and mortality of three neurodegenerative diseases (NDDs) and track the changes of proteins before the onset of NDDs.

RESEARCH DESIGN AND METHODS: We analyzed plasma proteomic data from UK Biobank. Cox regression analyses were utilized to detect the relationship between plasma proteins and the risk of development and all-cause mortality of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Predictive models were established based on related proteins using Lasso regression.

RESULTS: We identified 14 disease-associated proteins for AD, 35 for PD, and one for ALS. The trajectory of plasma proteins before the onset of NDDs was portrayed. Neuroinflammation and the remodeling of the extracellular matrix might be common pathways for NDDs.

CONCLUSIONS: Our results highlighted that the landscape of plasma protein changes before the onset of NDDs.}, } @article {pmid41858090, year = {2026}, author = {Ellis, AC and Dobak, S and Pearson, K and McGuire, R and Sutton, T}, title = {Registered Dietitians' perspectives on nutrition management of persons living with amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {5}, pages = {545-553}, pmid = {41858090}, issn = {1758-2032}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy/complications ; *Nutritionists/psychology ; Female ; Male ; Nutritional Status ; Focus Groups ; Middle Aged ; Nutrition Therapy ; *Malnutrition/etiology ; *Attitude of Health Personnel ; }, abstract = {AIM: Persons with amyotrophic lateral sclerosis (PALS) are at high risk for malnutrition, which is a negative prognostic factor for disease progression and survival. This study explored the perspectives of Registered Dietitians (RDs) providing nutrition care to PALS, focusing on barriers and facilitators to optimal patient care.

METHODS: RDs from U.S. multidisciplinary ALS clinics participated in six virtual focus groups. Recordings were transcribed verbatim and independently coded by two researchers for deductive content analysis.

RESULTS: RDs highlighted the importance of using clinical judgment to assess nutrition status and individualizing recommendations to respect patient autonomy. The multidisciplinary team model was identified as a strong facilitator to optimal patient care, while insurance coverage for nutrition-related supplies was a common barrier. RDs reported having little prior knowledge of ALS before assuming their current roles and described the need to upskill through self-teaching and on-the-job experience.

CONCLUSIONS: Results emphasize the importance of clinical judgment with respect to patient autonomy in providing nutrition care to PALS. The barriers and facilitators identified across multiple levels provide insight for future interventions to improve patient care.}, } @article {pmid41858403, year = {2026}, author = {Chun, S and Woon Kim, G and Bit Kim, H}, title = {Association between on-scene cardiopulmonary resuscitation duration and outcomes in out-of-hospital cardiac arrest patients.}, journal = {World journal of emergency medicine}, volume = {17}, number = {2}, pages = {137-145}, pmid = {41858403}, issn = {1920-8642}, abstract = {BACKGROUND: Prolonged on-scene Advanced Life Support (ALS) in out-of-hospital cardiac arrest (OHCA) patients may enhance return of spontaneous circulation (ROSC), but the optimal duration of cardiopulmonary resuscitation (CPR) without initial prehospital ROSC remains unclear. We investigated the association between on-scene CPR duration and outcomes using nationwide data. METHODS: This prospective, multi-regional study (2015-2022) included medical cause OHCA patients who underwent Smart ALS (SALS). Data from emergency medical services (EMS) records, SALS logs, and hospital outcomes were analyzed. Logistic regression models were developed for prehospital ROSC, survival to discharge, and good neurological outcome (Cerebral Performance Category [CPC] 1-2). RESULTS: Among 98,569 patients, 34,989 were SALS-eligible and 16,052 received SALS. Predictors of ROSC included younger age, male sex, public arrest, witnessed arrest, bystander CPR, shockable rhythm, and shorter response/scene times. Longer on-scene CPR reduced probabilities of ROSC, survival, and neurological recovery at hospital discharge. Model AUROCs were 0.697 (95%CI 0.676-0.717) for ROSC, 0.836 (95%CI 0.810-0.861) for survival, and 0.925 (95%CI 0.904-0.946) for neurological outcome. CONCLUSION: On-scene CPR duration is a critical prognostic factor in OHCA. The proposed models highlight on-scene predictors that may inform decisions about CPR continuation and support individualized resuscitation strategies. External validation in other EMS systems is warranted.}, } @article {pmid41858506, year = {2026}, author = {Hier, DB and Carrithers, MD and Rodríguez-Fernández, JM and Kummer, B}, title = {Editorial: The digitalization of neurology-volume II.}, journal = {Frontiers in digital health}, volume = {8}, number = {}, pages = {1806851}, doi = {10.3389/fdgth.2026.1806851}, pmid = {41858506}, issn = {2673-253X}, } @article {pmid41858792, year = {2026}, author = {Raber, J and Sharpton, TJ}, title = {Diet, gut microbiome, and cognition in neurodegeneration: a review and methodological framework.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1771904}, pmid = {41858792}, issn = {1663-4365}, support = {R01 ES030226/ES/NIEHS NIH HHS/United States ; }, abstract = {The gut microbiome influences brain function through the gut-brain axis via synthesis of neurotransmitters, production of metabolites affecting epithelial barrier integrity and immune modulation and signaling through the vagus nerve. In humans, microbiome diversity reflects healthy aging and predicts survival, while dysbiosis is increasingly implicated in neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ALS. Fecal transplant studies in germ-free mice demonstrate that microbiome alterations are sufficient to induce cognitive and neuropathological phenotypes, supporting causality in preclinical models. Genetic risk factors and environmental exposures affect both neurodegeneration risk and microbiome composition. In this review, we synthesize evidence from human cohorts and preclinical models on the gut-brain axis in cognitive health and disease. We then present a methodological framework for diet-microbiome-cognition research, addressing causal inference through mediation analysis, supervised approaches for deriving diet scores, validation strategies, and individual heterogeneity. This framework can guide development of microbiome-targeted dietary interventions to improve cognitive outcomes.}, } @article {pmid41859232, year = {2026}, author = {Sharbafshaaer, M and Pirozzi, MA and Caiazzo, G and Canale, F and Silvestro, M and Russo, A and Tessitore, A and Esposito, F and Trojsi, F}, title = {Subcortical microstructural impairment in amyotrophic lateral sclerosis: clinical correlates of neurite orientation dispersion and density imaging (NODDI) changes.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1757470}, pmid = {41859232}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving widespread network disruption beyond the motor cortex. Deep gray matter (DGM) nuclei, crucial for motor and cognitive integration, remain underexplored in vivo. This study applied neurite orientation dispersion and density imaging (NODDI) to evaluate DGM microstructure and its relationship with clinical disability in ALS.

METHODS: Diffusion-weighted MRI data were acquired from 23 ALS patients and 24 age- and sex-matched healthy controls. Orientation dispersion index (ODI), neurite density index (NDI), and free water fraction (FWF) were extracted from the bilateral thalamus, caudate, putamen, pallidum, hippocampus, and amygdala using the Destrieux atlas. Group comparisons and partial correlations were adjusted for age, sex, and disease duration.

RESULTS: No significant group differences in DGM volumes or NODDI-derived metrics survived correction for multiple comparisons. Within the ALS group, several nominal (uncorrected) associations were observed between DGM microstructural metrics and ALSFRS-R subscores. Reduced respiratory subscores were associated with higher ODI in the left thalamus (ρ = 0.57, p = 0.0047, uncorrected). Fine-motor subscores showed nominal positive associations with ODI in the left (ρ = 0.48, p = 0.021, uncorrected) and right amygdala (ρ = 0.51, p = 0.012, uncorrected). Gross motor subscores were nominally associated with NDI in the right thalamus (ρ = 0.58, p = 0.004, uncorrected), left thalamus (ρ = 0.42, p = 0.047, uncorrected), left caudate (ρ = 0.52, p = 0.011, uncorrected), and right caudate (ρ = 0.57, p = 0.033, uncorrected). None of these associations survived false discovery rate correction and should therefore be interpreted as exploratory.

DISCUSSION: These findings suggest subtle and predominantly exploratory associations between DGM microstructural properties and clinical measures in ALS. NODDI derived metrics, particularly ODI and NDI, may provide sensitive indices of subcortical microstructural variation, warranting further investigation in larger cohorts.}, } @article {pmid41860162, year = {2026}, author = {Mak, SS and McManus, P and Greer, S and Haws, K and Carlson, CJ and Chandler, HK and Osinubi, O and Ash, GI}, title = {Deployment of an Activity Monitoring Program to Complement a Clinical Intervention for Veterans With Gulf War Illness: Qualitative Study.}, journal = {JMIR human factors}, volume = {13}, number = {}, pages = {e82177}, pmid = {41860162}, issn = {2292-9495}, support = {K01 DK129441/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Veterans/statistics & numerical data ; *Persian Gulf Syndrome/therapy ; Female ; Male ; Middle Aged ; Qualitative Research ; Adult ; Feasibility Studies ; Digital Health ; Gulf War ; Telemedicine ; }, abstract = {BACKGROUND: Many veterans who served in the Gulf experience Gulf War Illness (GWI), a chronic multisymptom condition associated with fatigue, pain, gastrointestinal problems and respiratory issues, mood/cognitive issues, and sleep difficulties. These symptoms contribute to decreased function, increased mental health needs, and poor quality of life. The Veterans Affairs War Related Illness and Injury Study Center in New Jersey developed a 26-week virtual health coaching intervention to support symptom management for veterans with GWI. In 2023, a consumer-grade smartwatch was added as part of an activity monitoring program to complement this program.

OBJECTIVE: The purpose of this project was to assess the feasibility and acceptability of including a smartwatch-based activity monitoring component to complement a virtual health coaching program for veterans with GWI.

METHODS: Twenty-four veterans enrolled in the health coaching program were invited to participate in the activity monitoring component. Participants attended a virtual orientation to set up the smartwatch, and verbal consent to share data through a Health Insurance Portability and Accountability Act (HIPAA)-compliant platform was obtained. Program feasibility was assessed by evaluating wear-time percentage and duration of use. Acceptability was assessed using two items from a monthly survey and through a midprogram semistructured interview. Quantitative data were summarized descriptively, and qualitative data were analyzed using a coding scheme adapted from Sekhon et al's Theoretical Framework for Acceptability (TFA).

RESULTS: Twenty veterans agreed to participate in the program (mean age 49 years; 7/20, 35% female; 19/20, 94% non-Hispanic White; 11/20, 55% first-time smartwatch users). Twelve participants (60%) wore the watch for the full 26 weeks. Among participants who completed 26 weeks, median daily wear-time completeness exceeded 80% for 25 weeks. Most participants (12/20, 60%) reported that wearing the smartwatch helped them achieve their wellness goals, and the majority (16/20, 80%) said they would recommend using the smartwatch for activity monitoring to other veterans. Qualitative findings supported acceptability across TFA domains. One adverse event was reported (minor skin irritation that resolved after changing the smartwatch band to a hypoallergenic watch band).

CONCLUSIONS: Within this clinical program, pairing a smartwatch with virtual health coaching for veterans with GWI was feasible and acceptable. Activity monitoring integrated into an existing intervention may support symptom self-management and augment patient education and engagement. As no prior activity monitoring programs specific to veterans with GWI have been described, these findings could inform future program development and implementation within this population.}, } @article {pmid41860208, year = {2026}, author = {Pirdankar, OH and Nene, AS and Thakur, R and Shah, S and Shenoy, P and Badole, P}, title = {Intravitreal Anti-vascular Endothelial Growth Factor in Retinopathy of Prematurity: A Bibliometric Analysis.}, journal = {Journal of pediatric ophthalmology and strabismus}, volume = {}, number = {}, pages = {1-10}, doi = {10.3928/01913913-20251106-02}, pmid = {41860208}, issn = {1938-2405}, abstract = {Retinopathy of prematurity (ROP) is one of the leading cause of blindness in premature infants. A bibliometric analysis on intravitreal anti-vascular endothelial growth factor (VEGF) in ROP was conducted. A comprehensive search of the article on the Scopus database was conducted with the terms related to "anti-vascular endothelial growth factor and retinopathy of prematurity." Only original research and review articles published in the English language were considered. VOSviewer version 1.6.20 was used for the visualization and analysis of the data. Publication trend, productive countries, researchers' details, commonly cited documents, source and influential journals, and keyword occurrence were analyzed. A total of 329 studies were considered, of which 270 were original articles and 59 were review articles. The highest numbers of publications were seen in the year 2022. The United States, China, Turkey, India, and Taiwan were the top 5 countries that published research on the use of anti-VEGF in ROP. The most documents were published by Wei-Chi Wu (22) and Chi-Chun Lai (14), and Falavarjani et al's article had the most citations (737). A total of 2,504 keywords were identified. All keyword analysis revealed the occurrence of "retinopathy of prematurity" and "human" as a keyword was 290 and 286 times, respectively. Most articles and citations were found in Retina. The use of anti-VEGF in ROP is constantly evolving and bibliometric analysis highlights a research trend and influential authors and journals that have published significant work on it. This article can serve as a guide to conduct a literature review for future researchers.}, } @article {pmid41860259, year = {2026}, author = {Burt-Oberecken, N and Megat, S and Rouaux, C}, title = {[Protective effect of a CREB3 gain-offunction variant in amyotrophic lateral sclerosis].}, journal = {Medecine sciences : M/S}, volume = {42}, number = {3}, pages = {234-237}, doi = {10.1051/medsci/2026027}, pmid = {41860259}, issn = {1958-5381}, } @article {pmid41861112, year = {2026}, author = {Fu, P and Zhang, X and Zhou, Y and Zheng, J and Sun, A and Zhuang, K and Bao, W and Gao, G}, title = {Embedded CRISPRi Enhances Gene-Silencing Efficiency in Drosophila.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {31}, pages = {e15849}, pmid = {41861112}, issn = {2198-3844}, support = {32500494//National Natural Science Foundation of China/ ; 32370631//National Natural Science Foundation of China/ ; //priority academic program development of jiangsu higher education institutions/ ; }, mesh = {Animals ; *Drosophila melanogaster/genetics ; *CRISPR-Cas Systems/genetics ; *Gene Silencing/physiology ; Drosophila Proteins/genetics ; RNA Interference ; *Amyotrophic Lateral Sclerosis/genetics ; Disease Models, Animal ; }, abstract = {CRISPR interference (CRISPRi), leveraging catalytically inactive Cas9 (dCas9), has transformed transcriptional silencing. However, its application in Drosophila melanogaster has been constrained by inconsistent efficiency and limited repression amplitude. Here, we present embedded CRISPR interference (emCRISPRi), an advanced gene-silencing platform that integrates transcriptional repression domains (Mxi and TRD) into a structurally flexible region of dCas9. This design significantly enhances silencing efficiency, enabling robust repression of coding genes and cis-regulatory elements, particularly at transcription start site (TSS)-proximal regions. emCRISPRi demonstrates improved gene-silencing activity compared to RNA interference (RNAi) at several tested loci and facilitates strong phenotypic rescue via unmodified cDNA. Its versatility is demonstrated through the dissection of Hippo pathway interactions and the mitigation of TDP-43-induced neurotoxicity in an amyotrophic lateral sclerosis (ALS) model. These findings position emCRISPRi as a transformative tool for functional genomics, enhancer studies, and disease modeling in Drosophila, with significant potential for cross-species adaptation and therapeutic innovation.}, } @article {pmid41861969, year = {2026}, author = {Kamar, N and Congy-Jolivet, N and Salhi, S and Darres, A and Colombat, M and Milhes, J and Esposito, L and Guy, P and Hebral, AL and Prudhomme, T and Sallusto, F and Pellegrini, J and Medrano, C and Marion, O and Del Bello, A}, title = {Anti-lymphocyte globulin versus anti-thymocyte globulin in kidney transplant patients with preformed donor specific antibodies.}, journal = {Transplant immunology}, volume = {96}, number = {}, pages = {102375}, doi = {10.1016/j.trim.2026.102375}, pmid = {41861969}, issn = {1878-5492}, mesh = {*Kidney Transplantation ; Humans ; *Antilymphocyte Serum/therapeutic use ; Female ; *Graft Rejection/immunology/prevention & control ; Middle Aged ; Animals ; Male ; Adult ; Retrospective Studies ; *Immunosuppressive Agents/therapeutic use ; Isoantibodies/blood ; Rabbits ; Graft Survival ; }, abstract = {State-of-the-art immunosuppressant therapies recommend the use of induction therapy after kidney transplantation. Anti-interleukin-2 receptor antibody (basiliximab) is used for low-risk patients whereas polyclonal anti-lymphocyte sera (ALS) are recommended for medium/high-risk patients. There are two commercially available rabbit-derived ALS, namely anti-thymocyte globulin (RATG; Thymoglobulin®) and anti-lymphocyte globulin (RATLG; Grafalon®). We retrospectively compared the efficacy and safety of RATG or RATLG induction therapy in high-risk kidney transplant recipients with preformed donor specific antibodies (DSAs; n = 124). Forty-seven recipients received 1.25 mg/kg RATG for 2 to 3 days. Seventy-seven recipients were treated with 9 mg/kg RATLG on day 0 followed by 4 mg/kg RATLG for 2 to 3 days (n = 21) or a single dose of 9 mg/kg RATLG on day 0 (n = 56). Overall there were no significant differences observed between patients treated with RATG and RATLG. Similarly, no difference was observed between patients who had been given a single dose of RATLG and multiple doses of RATLG or RATG. At one year, patient and graft survival rates, acute rejection rate and type of rejection, kidney function, infections and malignancies did not differ between groups. Kidney transplant patients with preformed DSA showed similar clinical outcomes when treated with RATG or RATLG induction therapy. Polyclonal antibodies in high immunological risk kidney transplant patients.}, } @article {pmid41862640, year = {2026}, author = {Onwunma, J and Binsabaan, S and Allen, SP and Thanthirige, SR and Gaur, D and Sankaran, B and Wohlever, ML}, title = {ALS mutations disrupt self-association between the ubiquilin STI1 hydrophobic groove and internal placeholder sequences.}, journal = {The EMBO journal}, volume = {45}, number = {8}, pages = {2694-2711}, pmid = {41862640}, issn = {1460-2075}, support = {P30 GM124169/GM/NIGMS NIH HHS/United States ; CAREER Award 2343131//National Science Foundation (NSF)/ ; R35 GM137904-01S2//HHS | National Institutes of Health (NIH)/ ; P30 GM124169-01//HHS | National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Autophagy-Related Proteins/genetics/metabolism/chemistry ; Humans ; Hydrophobic and Hydrophilic Interactions ; *Cell Cycle Proteins/genetics/chemistry/metabolism ; *Adaptor Proteins, Signal Transducing/genetics/chemistry/metabolism ; Protein Domains ; *Mutation ; Crystallography, X-Ray ; Models, Molecular ; Molecular Chaperones/metabolism/genetics/chemistry ; Protein Binding ; *Ubiquitins/genetics/metabolism/chemistry ; }, abstract = {Ubiquilins are molecular chaperones that play multifaceted roles in proteostasis, with point mutations in UBQLN2 leading to altered phase-separation properties and amyotrophic lateral sclerosis (ALS). Our mechanistic understanding of this essential process has been hindered by a lack of structural information on the STI1 domain, which is essential for ubiquilin chaperone activity and phase separation. Here, we present the first crystal structure of a ubiquilin-family STI1 domain bound to a transmembrane domain (TMD), and show that ALS mutations disrupt the STI1-TMD interaction. We further demonstrate that ubiquilins contain multiple conserved internal sequences that bind to the STI1 domain, including the PXX-repeat region that is a hotspot for ALS mutations. We propose that these placeholder sequences prevent solvent exposure of the STI1 hydrophobic groove and contribute to the multivalency that drives ubiquilin phase-separation. Together, this work provides a new paradigm for understanding how STI1 domains modulate ubiquilin chaperone activity and phase separation, and offers insights into the molecular basis of ALS pathogenesis.}, } @article {pmid41863273, year = {2026}, author = {Singh, DD}, title = {PROTAC-Based Therapeutics: From Design to Clinical Potential in Neurodegenerative Disease.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X438970260115164001}, pmid = {41863273}, issn = {1875-6190}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and ALS, are characterized by a progressive loss of neuronal function and a direct correlation between their progression and proteins with misfolded and aggregated structures. Although significant efforts have been made, and various therapies are available for their treatment, they show only a modest beneficial response to their progression. The main reasons for this phenomenon can be correlated with a loss of target specificity, low permeability in crossing the BBB, and their ineffectiveness in clearing proteins from neurons. Within this therapeutic paradigm, proteolysis-targeting chimaeras, or PROTACS, have been identified as a novel therapeutic strategy. Unlike traditional smallmolecule inhibitors, PROTACS take advantage of the natural ubiquitin proteasome system to specifically degrade target proteins. At a molecular level, PROTACS consist of a ligand that specifically recognizes a target protein, a linker, and an E3 ligand-recruiting ligand that specifically recruits an E3 ligase. At a therapeutic level, this offers the advantage of catalytic protein degradation that should allow for reduced dosing. Preclinical studies carried out using neurodegenerative disease models have shown the potential for selective targeting of major pathologic proteins, such as tau, α- synuclein, TDP-43, and mHTT, which are crucial for pathogenesis. In addition, developments in the formulation of brain-permeable PROTACS, understanding of E3 ligase expression levels in the central nervous system, and application of iPSC-derived neuronal systems have contributed to rapid developments in this area. Although pharmacokinetic modification and degradation-specific approaches are still required, evidence suggests a major therapeutic potential for PROTAC-based approaches for the treatment of neurodegenerative disorders.}, } @article {pmid41863275, year = {2026}, author = {Singh, AK and Kush, A and Bhushan, B and Dhanawat, M and Sharma, PK}, title = {Targeting Autophagy with Bioactive Compounds: Therapeutic Potential in Neurodegenerative Disorders.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X408653251130061347}, pmid = {41863275}, issn = {1875-6190}, abstract = {Neurodegenerative disorders (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by the accumulation of misfolded proteins and impaired cellular clearance mechanisms. Autophagy, a critical lysosomedependent degradative pathway, plays a vital role in maintaining proteostasis and neuronal health. Dysregulation of autophagy has been implicated in the pathogenesis of multiple NDs, making it a promising therapeutic target. This review comprehensively examines the molecular mechanisms of autophagy and its dysfunction across major NDs. Furthermore, it highlights the potential of bioactive compounds such as flavonoids, alkaloids, polyphenols, and terpenoids to modulate autophagic flux, thereby promoting the clearance of toxic protein aggregates like amyloid-β, tau, and α- synuclein. Emerging strategies, including nanotechnology-based delivery systems, are also discussed for enhancing the bioavailability and efficacy of these compounds. The evidence suggests that pharmacological or natural induction of autophagy may alleviate neurodegenerative pathology, though context- and stage-specific modulation is essential. This work underscores the therapeutic promise of autophagy-enhancing bioactives and calls for further research into their clinical applications.}, } @article {pmid41863659, year = {2026}, author = {Mullick, S and Chakraborty, A and Porel, P and Nath, R and Chaudhary, P and Islam, A and Das, J and Pramanik, S and Panigrahy, UP and Sridhar, SB and Mondal, M and Debnath, B and Ashique, S}, title = {Decoding Neuroinflammatory Pathways: The Role of the CXCL12-CXCR4/CXCR7 Axis in ALS-Related Cognitive Impairment.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41863659}, issn = {1559-1182}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/complications/pathology ; *Chemokine CXCL12/metabolism ; *Receptors, CXCR/metabolism ; Animals ; *Receptors, CXCR4/metabolism ; *Signal Transduction/physiology ; *Cognitive Dysfunction/metabolism/complications/pathology ; *Neuroinflammatory Diseases/metabolism/pathology ; Inflammation/pathology ; }, abstract = {Cognitive impairment (CI) and accelerating neuronal deterioration are hallmarks of amyotrophic lateral sclerosis (ALS). Under these circumstances a crucial molecular mechanism in the pathophysiology of CI has been identified: the CXC chemokine receptor type 7 (CXCR7)/CXC chemokine receptor type 4 (CXCR4)/Cysteine-X-cysteine chemokine ligand 12 (CXCL12) region. Research on ALS shows that the CXCR7/CXCR4/CXCL12 complex plays a role in the degeneration of motor neurons and the resulting cognitive decline. JAK/STAT, PI3K/AKT, MAPK, and other signaling pathways are among the ways the axis controls neuronal inflammation, synaptic remodeling, and neuronal maintenance in each of these scenarios. The CXC motif chemokine ligand 12 (CXCL12) and CXC chemokine receptor type 4 (CXCR4) axis is crucial for the start of the inflammatory mechanism because of their function in mediating the chemotaxis of inflammatory cells. By preventing the migration of inflammatory cells via CXCL12 in the inflammatory area, the response to inflammation can be prevented or reduced. Consequently, the development of CXCR4 antagonists has emerged as a cutting-edge strategy for inflammation treatment. Recent research suggests that managing this relationship could reduce cognitive deficits and offer neuroprotective benefits. According to the current review, the CXCL12/CXCR4/CXCR7 pathway may be a promising target for treating cognitive dysfunction in neurodegenerative disorder. It also emphasizes the need for additional research to completely comprehend its function and identify efficient treatments which may result in improved clinical treatment modalities for these debilitating illnesses.}, } @article {pmid41863721, year = {2026}, author = {Maidh, A and Kalra, P and Khan, H and Silakari, P and Grewal, AK}, title = {Circadian disruption as a driver and target in neurodegenerative diseases: from molecular mechanisms to chronotherapeutic strategies.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {41863721}, issn = {1573-7365}, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology/metabolism/therapy ; *Circadian Rhythm/physiology/drug effects ; Animals ; *Chronotherapy/methods ; Melatonin/metabolism ; }, abstract = {The Circadian System is a complex network of coordinated clocks that regulates the organism’s internal clock in synchronisation with the outside world. These rhythms are controlled by genetically controlled positive and negative transcriptional-translational feedback loops (TTFL) that generate 24-hour oscillations in the protein level and mRNA of core circadian components. Circadian disruption is recognised as a significant contributor to the molecular pathogenesis of neurodegenerative illnesses, as disease-specific alterations in clock gene expression and melatoninergic signalling have been identified as possible early-stage molecular indicators. Emerging evidence suggests a link between dysregulated circadian rhythms and neurodegenerative diseases, implying that the changes in circadian function may play a critical role in the development and progression of neurodegenerative diseases. The correlation between circadian rhythm and neurodegeneration is highly promising for developing treatment and promoting healthy lifestyle measures. This review article primarily focuses on how abnormalities in circadian rhythms may increase the risk of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Applying knowledge from pre-clinical and translational research on neurodegenerative diseases is crucial for lowering the risks of neurodegeneration and improving the symptoms and quality of life of people with neurodegenerative diseases through approaches that restore circadian rhythm in the context of precision medicine. Understanding this interaction holds promise for developing therapeutic approaches to support a healthy lifestyle.}, } @article {pmid41864292, year = {2026}, author = {Liu, H and Zhu, J and Chen, Y and Lin, X and Hua, C and Chen, H}, title = {Response to Jia et al's "Comment on the "Genetic classification helps with precise sirolimus treatment in slow-flow vascular malformations"".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {1}, pages = {e81-e83}, doi = {10.1016/j.jaad.2026.03.041}, pmid = {41864292}, issn = {1097-6787}, } @article {pmid41864411, year = {2026}, author = {Davias, A and Tang, IW and Hansen, J and Knekt, P and Rantakokko, P and Weisskopf, MG}, title = {Associations between pre-disease biomarkers of persistent organic pollutants and amyotrophic lateral sclerosis risk in four European cohorts.}, journal = {Environmental research}, volume = {299}, number = {}, pages = {124337}, pmid = {41864411}, issn = {1096-0953}, support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; R01 TS000315/TS/ATSDR CDC HHS/United States ; T32 ES007069/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/chemically induced/blood ; *Persistent Organic Pollutants/blood/toxicity ; Denmark/epidemiology ; Female ; Biomarkers/blood ; Male ; Cohort Studies ; Middle Aged ; Hydrocarbons, Chlorinated/blood ; Pesticides/blood ; Aged ; Finland/epidemiology ; Prospective Studies ; *Environmental Exposure ; Polychlorinated Biphenyls/blood ; Adult ; *Environmental Pollutants/blood ; Halogenated Diphenyl Ethers/blood ; }, abstract = {OBJECTIVES: Previous retrospective studies suggested that occupational exposures to persistent organic pollutants (POPs) may be associated with amyotrophic lateral sclerosis (ALS), but prospective studies with biomarker exposure assessment are scarce. This study aimed to prospectively investigate the relationship between POP exposures and ALS risk in the Danish Diet, Cancer and Health study (EPIC) cohort and to conduct a meta-analysis including results from the prior study of 3 small prospective Finnish cohorts in addition to the Danish EPIC cohort.

METHODS: We identified 166 incident ALS cases between 1993 and 1997 using the Danish National Patient Register and randomly selected 334 controls by individual matching on birth-year and sex. Levels of 13 polychlorinated biphenyls, 9 organochlorine pesticides and 3 polybrominated diphenyl ethers were assessed from baseline plasma samples. We employed conditional logistic regression models using exposure quartiles, and generalized additive models (GAMs), adjusting for confounders. We conducted a meta-analysis combining 3 Finnish prospective cohorts with the Danish data using a random-effects model.

RESULTS: The Danish results suggested generally inverse trends between several POPs and the predicted ALS risk; especially for chlordane-related compounds (co-pollutant quartile model, p-value<0.01). GAMs supported these trends, although most were not statistically significant. However, hexachlorobenzene was positively associated with ALS risk in co-pollutant GAM (p-value = 0.02). Additionally, the GAMs suggested higher ALS odds at the highest levels of exposure of some POPs, but the data at these levels was sparse. Meta-analysis results were mostly consistent with the Danish findings.

CONCLUSION: Our study suggested elevated ALS risk among those exposed to hexachlorobenzene when adjusting for co-pollutants. Higher level of some POPs suggested a positive association with ALS occurrence, but the data was scarce at these levels.}, } @article {pmid41864543, year = {2026}, author = {Wu, J and Ma, H and Niu, X and Zhang, Z and Guo, R and Shen, N and Tian, Y and Zhao, H and Yang, Y and Chen, Y}, title = {The p75NTR signaling axis: Bridging neurodevelopmental homeostasis, pathological mechanisms, and therapeutic strategies in neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {118}, number = {}, pages = {103105}, doi = {10.1016/j.arr.2026.103105}, pmid = {41864543}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; Animals ; *Signal Transduction/physiology ; *Receptors, Nerve Growth Factor/metabolism ; *Homeostasis/physiology ; Neurodevelopment ; *Nerve Tissue Proteins/metabolism ; }, abstract = {The neurotrophin receptor p75 (p75NTR) plays dual, context-dependent roles in the nervous system that are regulated by ligand binding, co-receptor interactions, and microenvironmental cues. During neurodevelopment, synaptic plasticity, and in neurodegenerative disorders, p75NTR orchestrates opposing cellular responses: it can support neuronal homeostasis through pro-survival pathways, while also initiating apoptotic and inflammatory cascades that exacerbate disease progression. In Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), activation of p75NTR drives pathological processes such as neuronal apoptosis and axonal degeneration, leading to impaired cognitive and motor function.Importantly, different structural domains of p75NTR have divergent effects. The extracellular domain (p75ECD) exhibits neuroprotective properties in AD models, in contrast with the pro-apoptotic activity associated with the full-length receptor. Therapeutic targeting of p75NTR with small-molecule ligands and ROCK inhibitors has shown efficacy in preclinical models, and some candidates have progressed to clinical trials. However, several challenges hinder clinical translation: (1) the mechanisms underlying p75NTR upregulation are not fully understood; (2) its downstream signaling network is highly complex; and (3) existing biomarker systems remain limited.A comprehensive understanding of p75NTR's role in neurodegeneration may clarify pathological mechanisms and reveal novel therapeutic targets. Achieving this will require multidisciplinary collaboration to bridge the gap between basic research and clinical applications.}, } @article {pmid41866066, year = {2026}, author = {Qian, J and Li, C and Wang, Y and Tong, J}, title = {Extracorporeal sliding knot technique for simplified hysteroscopic suture fixation of levonorgestrel-releasing intrauterine device.}, journal = {Journal of minimally invasive gynecology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jmig.2026.03.020}, pmid = {41866066}, issn = {1553-4669}, abstract = {OBJECTIVE: Approximately 20% of adenomyosis cases occur in women under 40 years of age [1]. Although LNG-IUD is the first-line medical therapy, its treatment failure is closely associated with uterine volume [2] with expulsion rates reported as high as 37.5% in uteri exceeding 12 gestational weeks [3]. Tong et al's hysteroscopic suture fixation technique (HCSS) reduced expulsion to 2.6% [4,5]. Although clinical studies have confirmed the safety and efficacy of this technique [5], its technical complexity and the requirement for repeated instrument exchanges have limited widespread adoption. We therefore developed an optimized extracorporeal sliding knot method to overcome these barriers.

SETTING: University hospital.

PARTICIPANTS: A 45-year-old woman diagnosed with adenomyosis and prior LNG-IUD expulsion.

INTERVENTIONS: The key modification involves three critical steps: Step 1) Construction of a secure multi-loop sliding knot using 2-0 Ethibond suture attached to the "T junction" of the LNG-IUD; Step 2) Introduction of the preformed knot into the uterine cavity in a single maneuver using a knot pusher; Step 3) Adjustment of the knot position under the hysteroscopic cold-knife surgery system (HCSS), achieving secure device fixation. The complete procedure obviates repeated instrument exchanges and intracavitary knot manipulation required by the original technique.

CONCLUSION: The extracorporeal sliding knot optimization preserves therapeutic efficacy while simplifying intrauterine manipulation, significantly enhancing surgical reproducibility and accessibility for widespread clinical adoption.}, } @article {pmid41866414, year = {2026}, author = {Li, X and Ding, W and Xu, E}, title = {Uncoupling of apnea-hypopnea index and oxygen desaturation in als: characterization and diagnostic implications of an "AHI-SpO2 dissociation" phenotype.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {4}, pages = {}, pmid = {41866414}, issn = {1590-3478}, support = {202610452//Health Commission of Jiangxi Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/diagnosis ; Polysomnography ; Female ; Retrospective Studies ; Male ; *Sleep Apnea Syndromes/diagnosis/physiopathology/etiology ; Phenotype ; Aged ; Middle Aged ; *Oxygen/blood ; }, abstract = {BACKGROUND: In Amyotrophic Lateral Sclerosis (ALS), sleep-disordered breathing (SDB) is primarily driven by neuromuscular hypoventilation. Traditional metrics like the Apnea-Hypopnea Index (AHI) may therefore lack sensitivity. This study aimed to characterize an “AHI-SpO2 Dissociation” phenotype—low event frequency despite significant desaturation—and explore its associations. METHODS: We retrospectively analyzed polysomnography and pulmonary function data from 43 ALS patients. The “AHI-SpO2 Dissociation” phenotype was defined as AHI < 5 events/h with Minimum SpO2 <90%. Spearman correlations assessed relationships between sleep parameters and Vital Capacity (VC) grade. RESULTS: The AHI-SpO2 Dissociation phenotype was identified in 32.6% (n = 14) of patients. Despite a “normal” AHI (2.8 vs. 2.1 events/h, p > 0.05 compared to controls), these patients exhibited nocturnal hypoxia comparable to the Obstructive Sleep Apnea group (Min SpO2 84.5% vs. 82.1%). Minimum SpO2 showed a strong positive correlation with VC impairment grade (ρ = 0.68, p < 0.001), while AHI did not (ρ=-0.15, p = 0.322). Relying solely on AHI ≥ 5 would have failed to classify 32.6% of the cohort (all AHI-SpO2 Dissociation patients) as having SDB. CONCLUSION: A dissociation between AHI and nocturnal oxygenation is prevalent in ALS. Minimum SpO2 correlates strongly with restrictive ventilatory deficit, suggesting it may complement AHI in identifying patients with significant respiratory compromise who might otherwise be missed. These findings highlight the need to integrate oximetry metrics into the diagnostic assessment of SDB in ALS.}, } @article {pmid41866449, year = {2026}, author = {Wang, Z and He, F and Li, L and Wang, W and Zhang, L and Tang, J and Le, W}, title = {Sleep Disorders in Neurodegenerative Diseases: Pathological Correlations and Underlying Mechanisms.}, journal = {Neuroscience bulletin}, volume = {42}, number = {9}, pages = {2101-2126}, pmid = {41866449}, issn = {1995-8218}, mesh = {Humans ; *Neurodegenerative Diseases/complications/pathology/physiopathology ; *Sleep Wake Disorders/pathology/physiopathology/etiology ; Animals ; Glymphatic System/physiopathology ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and others, represent an escalating public health burden in aging populations. NDDs are characterized by progressive neuronal loss and misfolded protein aggregation. Despite distinct clinical heterogeneity, these diseases universally present with debilitating non-motor symptoms, among which sleep-wake disorders are highly prevalent. Once considered secondary to neuronal damage, growing evidence now highlights a bidirectional interplay: sleep disruption is not only a consequence of neurodegeneration but also exacerbates its progression. This review synthesizes this complex interplay, outlining sleep phenotypes across major NDDs, dissecting key underlying mechanisms (impaired protein homeostasis, glymphatic dysfunction, chronic neuroinflammation, sleep-regulatory nucleus vulnerability, and circadian dysregulation), and summarizing current pharmacotherapeutic and non-pharmacological interventions. Attenuating sleep disorders may therefore provide symptomatic relief and disease‑modifying effects for NDDs.}, } @article {pmid41866924, year = {2026}, author = {Seyam, M and Morelli, KH and Waheed, W and van den Berg, LH and Tandan, R}, title = {Predicting Disease Progression and Survival in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {73}, number = {6}, pages = {961-965}, doi = {10.1002/mus.70198}, pmid = {41866924}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/physiopathology ; *Disease Progression ; Prognosis ; Phenotype ; }, abstract = {Amyotrophic lateral sclerosis (ALS) progresses relentlessly and is characterized by a median survival of 2-5 years from symptom onset with death from respiratory failure. ALS is a complex, multi-system neurodegenerative disorder with significant phenotypic heterogeneity and markedly variable disease progression. This variability presents challenges in determining the optimal timing for therapeutic interventions, complicates clinical trial design due to lack of effective stratification methods, and makes it difficult to reliably measure the longitudinal impact of specific interventions. Accurately capturing disease progression in ALS can be challenging. We propose that early respiratory phenotyping offers a promising approach to facilitate patient stratification, improve assessments of disease progression, and predict survival.}, } @article {pmid41867322, year = {2026}, author = {Alabdali, A and Alharkan, M}, title = {Comparative Cost Analysis of Ambulance Utilization: Advanced Life Support (ALS) vs Basic Life Support (BLS) at King Abdulaziz Medical City, Riyadh.}, journal = {ClinicoEconomics and outcomes research : CEOR}, volume = {18}, number = {}, pages = {570790}, pmid = {41867322}, issn = {1178-6981}, abstract = {PURPOSE: Unit-hour utilization (UHU) is the most common metric for evaluating the productivity of ambulances and crews for ambulance services. Calculating UHU is essential for maximizing profitability and evaluating the number of hours of ambulance utilization during a shift. This has not been examined previously at King Abdulaziz Medical City (KAMC). KAMC is a major tertiary-care medical center in Riyadh, Saudi Arabia, with dedicated ALS (Advanced Life Support) and BLS (Basic Life Support) ambulance units. This study aimed to determine the cost of operating the emergency calls (advanced life support [ALS]) unit and non-emergency calls (basic life support [BLS]) unit and compare the costs of emergency calls (ALS) and non-emergency calls (BLS). The study used a standardized institutional checklist that itemizes expenditures across logistics, equipment, maintenance, salary, pharmacy, and fuel cost components.

METHODS: This was a retrospective cross-sectional study. Institutional Review Board approval was obtained from King Abdullah International Medical Research Center. The study examined emergency and non-emergency calls for a period of 12 months. This study was based on a checklist assessing various expenditures to calculate the cost of ambulance utilization at KAMC in 2022.

RESULTS: The total average ambulance utilization cost per year for ALS was 4,806,245.7 SR, and the average ambulance utilization cost per hour was 548.65 SR; these costs were to operate the ALS crew for 24 hours, seven days a week. Conversely, the total average ambulance utilization cost per year for BLS was 3,934,156.92 SR, and the average ambulance utilization cost per hour was 449.10 SR. The main expenses concerned salaries and overhead costs for ALS and BLS.

CONCLUSION: This study provides insights into the cost of ambulance utilization between ALS and BLS. The higher cost of ALS calls may be attributed to the higher level of training, equipment, and staffing required.}, } @article {pmid41868729, year = {2026}, author = {Sethi, N and Levy, OA and Richardson, A and Harari, OA and Sellati, R}, title = {A Qualitive Investigation of Geographic Disparities in Genetic Testing and Care Access for Amyotrophic Lateral Sclerosis: Insights From Patient Journey Mapping.}, journal = {Patient preference and adherence}, volume = {20}, number = {}, pages = {566747}, pmid = {41868729}, issn = {1177-889X}, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that is associated with a high patient burden, reduced lifespan, and reduced quality of life. People living with ALS (PLwALS) often experience delays in diagnosis of ~1 year, and while current treatment options can slow disease progression, improve quality of life, and offer modest benefits in functional decline, they do not reverse neuronal damage. Defining and understanding the experiences of PLwALS can help identify gaps and barriers to optimal care.

PATIENTS AND METHODS: This non-interventional study was intended to obtain insights on the patient experience from the perspective of PLwALS. We sought to develop an ALS patient journey map from initial presentation through to end-of-life care for 4 regions (North America, Asia-Pacific, Latin America, and Europe/Middle East/Africa). The map was based on results from a global audit of data sources (including publications, patient narratives, society guidelines, academic reports, industry white papers [n=104]), and one-to-one, 60-minute, semi-structured interviews with PLwALS (n=12) or those caring for PLwALS (n=2). The initial patient journey map was subsequently reviewed during 2 advisory sessions with patient advocates (7 PLwALS and 2 caregivers) in September and November 2023.

RESULTS: We identified several barriers and challenges that most impact PLwALS, caregivers, and clinicians, with many similarities but also some differences across the regions.

CONCLUSION: These insights will enable targeted improvements in education, personalized care, resource allocation, care coordination, policy development, and funding, ultimately improving patient outcomes.}, } @article {pmid41870290, year = {2026}, author = {Narayan, A and Neupane, K and Woodside, MT}, title = {Scalable assay to identify inhibitors of prion-like propagation of protein misfolding as potential therapeutics for neurodegeneration.}, journal = {Protein science : a publication of the Protein Society}, volume = {35}, number = {4}, pages = {e70535}, pmid = {41870290}, issn = {1469-896X}, support = {PJT-185931/CAPMC/CIHR/Canada ; //NSERC Banting Postdoctoral Fellowship/ ; //Alberta Innovates Postdoctoral Fellowship/ ; }, mesh = {*Superoxide Dismutase-1/chemistry/antagonists & inhibitors/metabolism ; *Protein Folding/drug effects ; *Amyotrophic Lateral Sclerosis/drug therapy/enzymology ; Humans ; *Prions/chemistry/antagonists & inhibitors/metabolism ; }, abstract = {Protein misfolding is linked to many neurodegenerative diseases. In some cases, misfolding can propagate through a prion-like mechanism whereby natively folded molecules are converted into more copies of the misfolded isoform. Prion-like propagation of misfolding is an attractive therapeutic target, but difficulties with assaying conversion directly and simply have severely limited efforts to find drugs targeting conversion of disease-related proteins. Here, we demonstrate a scalable enzymatic assay for testing potential inhibitors of prion-like conversion in superoxide dismutase-1 (SOD1), whose misfolding is linked to amyotrophic lateral sclerosis (ALS). We tested several small-molecule inhibitors of SOD1 aggregation to determine if they also inhibited prion-like conversion. We found that some compounds, like telbivudine and cisplatin, did indeed significantly delay conversion, but others, like baicalein and quercetin, had little effect. Surprisingly, some compounds, like two statins tested, actually accelerated conversion, suggesting that they might act to promote ALS progression. These results underline the fact that conversion and aggregation are distinct biophysical processes. The ability of the assay to identify compounds effective at delaying prion-like conversion holds out promise for applications in future drug discovery efforts that target propagated misfolding specifically.}, } @article {pmid41870813, year = {2026}, author = {Upadhayay, S}, title = {Role of Pentacyclic Triterpenes in the Management of Neurological Disorders: An Insight into Molecular Mechanisms and Therapeutic Approaches.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41870813}, issn = {1559-1182}, mesh = {Humans ; *Pentacyclic Triterpenes/therapeutic use/pharmacology/chemistry ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Neurological disorders represent major public health concerns globally, as they profoundly affect motor function, memory, and cognitive abilities, thus compromising patients' independence and quality of life. Despite extensive research, current treatment approaches predominantly offer palliative care, failing to hinder disease progression. The rising incidence of these disorders underscores an urgent necessity for more efficacious and disease-modifying therapies. According to findings, pentacyclic triterpenoids exhibit neuroprotective properties by inhibiting neuronal oxidative stress, neuroinflammation, apoptosis, and degeneration, making them promising candidates for targeting the underlying causes of neurodegeneration. Therefore, in this review, we explore natural and synthetic pentacyclic triterpenoids that exhibit neuroprotective effects by modulating signaling pathways, such as HMGB1, TLR4, NLRP3, NF-κB, Nrf2, PI3K, Akt, and CREB, which play crucial roles in regulating cell proliferation, differentiation, and neuronal plasticity. The present literature survey is performed by searching various keywords with several combinations: "pentacyclic triterpenes", "neurological disorders", Parkinson's Disease", "Huntington's Disease", "Alzheimer's Disease", "Multiple sclerosis", "Amyotrophic Lateral Sclerosis" "Epilepsy", "mitochondria dysfunction", "oxidative stress", "preclinical studies", "molecular mechanisms", and "clinical studies". Studies indicates that pentacyclic triterpenoids have a wide range of therapeutic potentials, current findings summarizes existing knowledge and examines the neuroprotective properties and potential molecular mechanisms of pentacyclic triterpenoids related with health benefits and neurological diseases. Available evidence suggests that pentacyclic triterpenoids possess the capacity to impede disease progression and may be beneficial in the treatment of neurological disorders. This review strengthens the understanding of pentacyclic triterpenoids and their molecular mechanisms, while also facilitating pharmaceutical discovery and development for neurodegenerative disorders.}, } @article {pmid41870864, year = {2026}, author = {Gomez, R and Brown, T and Zarate, D and Houghton, S and Stavropoulos, V}, title = {A Network Approach to the Association Between Emotional Regulation and ADHD Symptoms in Adults: Pathways between Difficulties in Emotional Regulation and ADHD Dimensions.}, journal = {The Psychiatric quarterly}, volume = {97}, number = {2}, pages = {231-251}, pmid = {41870864}, issn = {1573-6709}, abstract = {UNLABELLED: Investigating the associations between emotional regulation difficulties and ADHD dimensions, this study employs network analysis to examine the interrelations among emotional regulation dimensions (as measured by the Emotional Regulation Strategies-36; DERS-36), affect lability (assessed using the Affect Lability Scale-18; ALS-18) and ADHD dimensions (Inattention, Hyperactivity, and Impulsivity, based on the Current Symptom Scale; CSS). Reflecting on the complexity of ADHD, this research contributes to the emerging discourse on the potential inclusion of emotional regulation difficulties within the ADHD diagnostic criteria, particularly in adult populations. A total of 532 adults [n man = 144; women = 388; mean age (SD) = 32.98 years (12.97 years)] from the general community were assessed. The network findings showed that the two highest values for strength centrality were DERS-36 strategies and ALS-18 depression. Within the DERS-36, ALS-18, and ADHD dimensions, 33%, 100%, and 11.11% of edges, respectively, were non-zero after regularisation, indicating significant connections, especially with Inattention. For edges involving the ADHD dimensions, only ALS-18 depression and DERS-36 goal showed non-zero unique associations with IA. This study is the first to examine DERS-36 and ALS-18 subdimensions alongside the three ADHD dimensions within a regularised partial correlation network. The results indicate that only a small number of emotion-related dimensions show direct associations with ADHD dimensions, suggesting selective rather than widespread associations among these constructs.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11126-026-10270-x.}, } @article {pmid41871620, year = {2026}, author = {Silva, DJD and Silveira, SCD and Souza, LC and Cruzeiro, MM and Vale, TC}, title = {Clinical and Sociodemographic Profile of Familial Amyotrophic Lateral Sclerosis Type 8 Compared to the Sporadic Form.}, journal = {Arquivos de neuro-psiquiatria}, volume = {84}, number = {3}, pages = {1-8}, pmid = {41871620}, issn = {1678-4227}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/epidemiology/physiopathology/genetics/diagnosis/classification ; Middle Aged ; Age of Onset ; Brazil/epidemiology ; Socioeconomic Factors ; Male ; Adult ; Aged ; Sociodemographic Factors ; Retrospective Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare degenerative disease of motor neurons, predominantly sporadic, with approximately 10% of the cases showing familial inheritance.To characterize the clinical and sociodemographic profile of patients with familial ALS type 8 (fALS8) and compare it with sporadic ALS (sALS).We reviewed the medical records (1997-2022) from a specialized Brazilian center. Patients with a confirmed diagnosis of ALSs were included, and sociodemographic and clinical data were collected.The sample was composed of 89 ALS patients, with a slight female predominance (53%) and a high frequency of fALS8 cases (45%). The fALS8 patients were diagnosed at a younger age, at approximately 50 years, compared to 53 years among the sALS patients (p = 0.043). Lower limb onset predominated in the fALS8 group (87%), while the sALS group showed more heterogeneous presentations, including bulbar onset (14%). The time until the diagnosis was significantly longer in the fALS8 group compared to the sALS group, both from symptom onset (approximately 51 versus 30 months respectively; p < 0.001) and after admission to a specialized center (7 versus 4 months respectively; p = 0.002). Dysphagia and gastrostomy were more frequent in the sALS group compared to the fALS8 group (p = 0.02 and p < 0.01 respectively), and older age at diagnosis was associated with worse functional scores.The fALS8 group presented with distinct clinical and demographic features compared to the sALS group, including younger age at diagnosis, more homogeneous symptom onset, and lower frequency of dysphagia and need for gastrostomy. The diagnosis was more delayed in the fALS8 group, and older age at diagnosis was associated with worse functional status. The current study contributes to the scarce data on fALS8 in South America.}, } @article {pmid41872337, year = {2026}, author = {Croteau, E and Rousseau, E and Tremblay, S and Rousseau, JF and Espinosa-Betancourt, E and Lavallée, E and Dubreuil, S and Ait-Mohand, S and Lareau-Trudel, É and Gosselin, S and Carrier, V and Côté-Bigras, S and Allard, C and Maier, M and Salzmann, M and Tétu, A and Houde, MP and Turcotte, É and Guérin, B}, title = {A phase I study to evaluate the dosimetry and safety of [[89]Zr]Zr-DFO-AP-101, a new antibody-based radiopharmaceutical to detect misfolded SOD1 in amyotrophic lateral sclerosis.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {53}, number = {7}, pages = {4639-4651}, pmid = {41872337}, issn = {1619-7089}, support = {Fonds d'accélération des collaborations en santé (FACS)//Ministère de la Santé et des Services sociaux/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Female ; Male ; *Zirconium ; Middle Aged ; *Radioisotopes/adverse effects ; Tissue Distribution ; *Superoxide Dismutase-1/metabolism/chemistry ; Radiometry ; Positron-Emission Tomography ; *Radiopharmaceuticals/adverse effects/pharmacokinetics ; Aged ; *Deferoxamine/adverse effects/pharmacokinetics/chemistry ; *Safety ; }, abstract = {PURPOSE: Misfolded superoxide dismutase-1 (mSOD1) is an abnormal protein observed in amyotrophic lateral sclerosis (ALS) and constitutes a therapeutic target. The present study evaluated the biodistribution, dosimetry, and safety of a new antibody-based radiopharmaceutical, [89Zr]Zr-DFO-AP-101, targeting mSOD1. METHODS: Seven control participants and one patient with ALS received 41 ± 3 MBq of [89Zr]Zr-DFO-AP-101. They were followed up with five whole-body positron emission tomography (PET) scans over 10 days. Semi-automatic segmentation was performed on the images to derive time-activity curves, radiotracer effective half-life and dose exposure. RESULTS: Total elimination of the radiotracer (urinary and hepatobiliary) was 25–30% after three days and reached a plateau after a week. At 2 h post-injection, ~ 60% of the radiopharmaceutical remained in the blood pool, with a biological half-life of 53 h. The liver was the dose-limiting organ with 0.84 mSv/MBq in males, 1.07 mSv/MBq in females, and 1.23 mSv/MBq in the female ALS patient. The spleen, adrenal glands, kidney, and heart wall were the other most irradiated organs. Average effective doses were 0.21 mSv/MBq for males, 0.28 mSv/MBq for females, and 0.31 mSv/MBq for the female ALS patient. Tracer uptake in the spinal cord and vertebrae of the ALS patient, on Days 7 and 10, was more than one standard deviation higher than for the control female participants. No serious adverse event was observed. CONCLUSIONS: The single dose of [89Zr]Zr-DFO-AP-101 was safe for all participants. It provided good image quality for the biodistribution and dosimetry analysis over 10 days. Further studies are needed to demonstrate the efficacy of ALS diagnosis through PET imaging. https://www.clinicaltrials.gov/study/NCT05974579.}, } @article {pmid41872984, year = {2026}, author = {Toomey, A and Kleinerova, J and Tan, EL and Siah, WF and Bede, P}, title = {Muscle MRI and Muscle Ultrasound Applications in MND/ALS: Academic Insights and Clinical Opportunities.}, journal = {European journal of neurology}, volume = {33}, number = {3}, pages = {e70582}, pmid = {41872984}, issn = {1468-1331}, support = {HRB JPND-Cofund-2025-3/HRBI_/Health Research Board/Ireland ; JPND-2025"Qual-Bulb-MND"//EU Joint Programme - Neurodegenerative Disease Research/ ; SFI-SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Ultrasonography/methods ; *Muscle, Skeletal/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; *Motor Neuron Disease/diagnostic imaging ; }, abstract = {BACKGROUND: There is an unmet need for the clinically relevant ALS biomarkers to facilitate an accurate diagnosis in suspected cases, monitor disease progression and evaluate response to therapy in clinical trials. While the MND/ALS literature is dominated by innovative brain studies, motor disability in ALS is primarily driven by neurogenic muscle change impacting mobility, dexterity, respiratory and bulbar function.

METHODS: With the intention of raising awareness of muscle-derived imaging markers in ALS, a systematic review has been conducted. Study designs, imaging methods, data interpretation frameworks, and cohort characteristics were systematically evaluated to identify innovative approaches and barriers to clinical implementation.

RESULTS: A total of 219 studies were screened and 73 original studies selected for systematic review; 37 muscle MRI studies and 36 studies using ultrasound, PET or CT. All of the selected studies successfully captured ALS-associated muscle degeneration and their methods included the evaluation of muscle dimensions (thickness/volumes n = 34), 'acute' denervation (water content, n = 15), fasciculation counts (n = 14), 'chronic' neurogenic change (fat content, n = 21), metabolic changes (n = 4), diffusion alterations (n = 8) and echo intensity changes (n = 13).

CONCLUSIONS: Despite the huge impact of lower motor neuron dysfunction on the patients' independence, survival and quality of life, muscle imaging is a glaringly overlooked frontier of MND/ALS research. This is a missed opportunity, as a variety of non-invasive quantitative muscle imaging techniques have been successfully used in other neurological conditions; these protocols are easy to implement on commercial MRI and ultrasound platforms and recent studies have demonstrated their ease of use and potential clinical utility.}, } @article {pmid41874673, year = {2026}, author = {Li, J and Gao, C and Wang, Q and Liu, J and Xie, Z and Zhao, Y and Yu, M and Zheng, Y and Lv, H and Zhang, W and Yuan, Y and Meng, L and Deng, J and Wang, Z}, title = {Aberrant SOD1 aggregates in skeletal muscle target fibers in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {151}, number = {1}, pages = {}, pmid = {41874673}, issn = {1432-0533}, } @article {pmid41875078, year = {2026}, author = {Mamede, LD and Hu, M and Vaquer-Alicea, J and Titus, AR and Passos, PM and Lantelme, E and French, RL and Kirschner, PA and Diamond, MI and Miller, TM and Ayala, YM}, title = {A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms.}, journal = {PLoS biology}, volume = {24}, number = {3}, pages = {e3003662}, pmid = {41875078}, issn = {1545-7885}, support = {T32 GM139774/GM/NIGMS NIH HHS/United States ; T32 NS121881/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; Neurons/metabolism/pathology ; *Protein Aggregation, Pathological/metabolism/genetics ; RNA Splicing ; Protein Aggregates ; Cell Nucleus/metabolism ; DNA Damage ; Exons/genetics ; TDP-43 Proteinopathies/metabolism/genetics/pathology ; Genes, Reporter ; Cell Line ; }, abstract = {TDP-43 pathology is a hallmark of fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43-encephalopathy (LATE). In affected patients, cytoplasmic TDP-43 aggregates are accompanied by disruption of its normal nuclear localization and function. Because TDP-43 is an RNA binding protein that controls transcript processing, including repression of cryptic exon splicing, its loss leads to dysregulation of gene expression. Despite its central significance in disease, the connection between TDP-43 aggregation and dysfunction remains poorly understood, and models to study the underlying mechanisms are limited. Here, we characterize a robust and quantitative cell-based reporter that captures both aggregation and the resulting loss of function. Using this human biosensor cell line, we show that aggregation initiated by prion-like seeding drives progressive depletion of nuclear TDP-43 and induces signature features of diminished TDP-43 activity, such as increased DNA damage and activation of cryptic exon splicing. We find that aggregate seeding also induces cryptic exon splicing in human neurons implying that this pathological link extends to disease-relevant models. The seeding model provides a platform for dissecting mechanisms that underlie TDP-43 pathology and for identifying factors that modulate the aggregation-to-dysfunction transition. Our data shows that aggregate seeding impacts TDP-43 autoregulation, initiating a toxic feed-forward mechanism that disrupts TDP-43 homeostasis. Furthermore, reducing ataxin-2 levels decreases aggregation and restores TDP-43 activity. Together, these findings reveal a molecularly guided strategy to directly impact TDP-43 activity by decreasing its misfolding and aggregation, highlighting approaches to prevent TDP-43 dysfunction and mitigate toxicity under pathological conditions.}, } @article {pmid41875115, year = {2026}, author = {Uversky, VN}, title = {Why is it so difficult to discover drugs for amyotrophic lateral sclerosis? A protein intrinsic disorder perspective.}, journal = {Expert opinion on drug discovery}, volume = {21}, number = {6}, pages = {553-573}, doi = {10.1080/17460441.2026.2648612}, pmid = {41875115}, issn = {1746-045X}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Humans ; Animals ; *Drug Discovery/methods ; *Intrinsically Disordered Proteins/metabolism ; Disease Models, Animal ; Drug Development/methods ; Drug Design ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is the most common adult motor neuron disease, now viewed as a spectrum disorder rather than a single entity. Because of the significant person-to-person variability in the disease's biology, driven by both genetic and environmental interactions, finding a single "magic bullet" drug is unlikely. Despite decades of research, only a few ALS drugs have being developed. Drug discovery has a 95% failure rate due to genetic complexity, lack of sensitive biomarkers, diagnostic delays, inadequate animal models, and poor clinical trial design.

AREAS COVERED: This article considers several aspects related to the prevalence of intrinsic disorder in ALS-related proteins and highlights how these features might hinder rational structure-based drug discovery.

EXPERT OPINION: There is a common oversight in current drug discovery methodologies, which is the neglect of intrinsically disordered proteins (IDPs) playing several crucial roles in the pathology of neurodegeneration in general and ALS in particular. Therefore, it seems that the 'one-size-fits-all' approach to ALS is hitting a wall because these 'shapeshifters' of the cellular world are ignored. Consequently, to be more successful in finding drugs treating ALS, gears should be shifted from rational structure-based models to intrinsic disorder-centric approaches.}, } @article {pmid41876403, year = {2026}, author = {Yan, K and Jiang, Y and Yong, Y and Zhang, T and Zhang, N and Zeng, Q and Gong, X and Meng, L and Bi, F and Liu, Y}, title = {ALDOA Promotes Glycolysis and NLRP3/GSDMD Pyroptosis to Accelerate ALS Progression.}, journal = {Annals of clinical and translational neurology}, volume = {13}, number = {9}, pages = {1903-1918}, pmid = {41876403}, issn = {2328-9503}, support = {81760238//National Natural Science Foundation of China/ ; 82171433//National Natural Science Foundation of China/ ; 2022JJ30918//Natural Science Foundation of Hunan Province/ ; 2023JJ30927//Natural Science Foundation of Hunan Province/ ; TSYC202401B119//Xinjiang Uygur Autonomous Region Health Commission "Tianshan Talent" High-Level Medical and Health Personnel Project/ ; 2025D01E38//Natural Science Foundation of Xinjiang Uygur Autonomous Region/ ; }, mesh = {Animals ; *Glycolysis/physiology/drug effects ; *Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; *Fructose-Bisphosphate Aldolase/metabolism ; Mice ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Pyroptosis/physiology ; Disease Progression ; Mice, Knockout ; Disease Models, Animal ; Motor Neurons/metabolism ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration. Glycolytic dysregulation is implicated in disease progression, yet the underlying mechanisms remain unclear. This study investigates how Aldolase A (ALDOA) drives ALS progression through glycolysis-mediated motor neuron pyroptosis.

METHODS: In vivo, tamoxifen-induced TDP-43 cKO mice were assessed for motor function (rotarod/suspension tests), motor cortex L-lactic acid, and ALDOA/NLRP3/GSDMD expression. The ALDOA inhibitor Aldometanib was administered. In vitro, TDP-43 KO NSC34 cells were used to measure viability, glucose uptake, and L-lactic acid.

RESULTS: ALS model mice exhibited significant motor deficits, progressive weight loss, and reduced survival. Their motor cortex showed elevated ALDOA expression, L-lactic acid accumulation, and NLRP3/GSDMD inflammasome activation. Aldometanib treatment suppressed glycolysis, prolonged survival, and slowed disease progression by inhibiting NLRP3/GSDMD-mediated pyroptosis. In vitro, TDP-43-deficient NSC34 cells displayed increased ALDOA levels, enhanced glycolytic flux, NLRP3/GSDMD pathway activation, and impaired proliferation.

CONCLUSION: We show that ALDOA-mediated glycolytic dysregulation activates the NLRP3/GSDMD inflammasome, leading to pyroptosis in motor neurons. Pharmacological inhibition of ALDOA alleviates glycolytic dysregulation and extends survival, identifying ALDOA as a potential therapeutic target.}, } @article {pmid41877227, year = {2026}, author = {Estiar, MA and Yu, E and Varghaei, P and Ross, JP and Ashtiani, S and Bayne, AN and Coarelli, G and Timmann, D and Klockgether, T and Beijer, D and Mengel, D and Coutelier, M and , and Dion, PA and Suchowersky, O and Ewenczyk, C and Goizet, C and Stevanin, G and Van Damme, P and Al-Chalabi, A and Zuchner, S and Synofzik, M and Veldink, JH and Trempe, JF and Durr, A and Rouleau, GA and Gan-Or, Z}, title = {Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {41877227}, issn = {1741-7015}, mesh = {Humans ; *Metalloendopeptidases/genetics ; *Mutation ; *ATPases Associated with Diverse Cellular Activities/genetics ; *Spastic Paraplegia, Hereditary/genetics ; *Motor Neuron Disease/genetics ; *ATP-Dependent Proteases/genetics ; Female ; *Cerebellar Diseases/genetics ; Heterozygote ; Male ; }, abstract = {BACKGROUND: Biallelic SPG7 mutations cause one of the most common forms of hereditary spastic paraplegia (HSP). Several reports have suggested that heterozygous SPG7 variants may also play a role in HSP, but also in amyotrophic lateral sclerosis (ALS). However, it remains controversial whether heterozygous SPG7 mutations are pathogenic on their own, or if other mechanisms are at play. We recently provided evidence for non-Mendelian inheritance in spastic paraplegia 7 (SPG7), as heterozygous carriers of SPG7 mutations often also carried mutations in other disease-related genes, including AFG3L2, more frequently than expected by chance. Given that SPG7 and AFG3L2 encode interacting subunits of the mitochondrial m-AAA protease complex, we hypothesized that combined heterozygous mutations in these genes may act synergistically to disrupt mitochondrial function and contribute to disease. In this study, we aimed to examine whether digenic heterozygous mutations in SPG7 and AFG3L2 can lead to a spectrum of neurodegenerative disorders.

METHODS: We first analyzed genome and exome sequencing data of 6644 unrelated individuals including 4817 motor neuron disorder (MND) and ataxia patients and 1827 controls. We next analyzed an additional 18,748 exome data from rare disease cohorts to further examine the occurrence of variants in SPG7 and AFG3L2.

RESULTS: Among the first 4817 MND and ataxia patients, we identified a total of 6 patients, 4 of whom were unrelated, who carried potentially pathogenic variants in both SPG7 and AFG3L2, in contrast to none in 1827 unrelated controls. Further analysis of the 18,748 additional patients with rare disease, as well as a comprehensive literature review, identified 6 more patients, 5 of whom were unrelated, who had digenic mutations in SPG7 and AFG3L2. In the two families we identified, digenic mutations in SPG7 and AFG3L2 perfectly segregated with the disease. The 12 patients reported here exhibited predominant signs of motor neuron and cerebellar involvement.

CONCLUSIONS: Our findings demonstrate that digenic inheritance of concurrent heterozygous mutations in SPG7 and AFG3L2 may cause motor neuron and cerebellar disorders. Screening of the entire SPG7 and AFG3L2 genes in genetically undiagnosed cases of MND and spastic ataxia may help to increase the diagnostic yield.}, } @article {pmid41877246, year = {2026}, author = {Shen, R and Sung, K and Ding, J and Wu, C}, title = {Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {41877246}, issn = {2047-9158}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/therapy/metabolism ; *Axons/pathology/metabolism ; Animals ; }, abstract = {Axons are unique structural and functional features of nerve cells, which play a critical role in regulating neuronal homeostasis. Dysfunction and degeneration of axons (axonopathy) has been established as an early and prominent contributing mechanism to the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In this review, we briefly summarize the structure and function of axons, and highlight recent advances in the understanding of the role of axons in health and disease. We argue that axons are a potential target for developing novel therapies for neurodegenerative diseases.}, } @article {pmid41879495, year = {2026}, author = {Singh, K and Sethi, P and Jain, D and Gupta, JK and Alsaidan, OA and Alzarea, SI and Kumar, A and Tabish, M and Sharma, MC}, title = {Emerging Roles of Small-molecule Derivatives in Modulating Neurodegenerative Pathways: From Molecular Targets to Therapeutic Applications.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575429412260112060311}, pmid = {41879495}, issn = {1875-5607}, abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease involve progressive neuronal dysfunction driven by mechanisms including protein aggregation, oxidative stress, mitochondrial impairment, and neuroinflammation. Current treatments are largely symptomatic, with limited disease-modifying options. Advances in medicinal chemistry have led to the development of small-molecule derivatives targeting specific pathological pathways, offering new therapeutic opportunities. This review summarizes recent progress in designing and optimizing such molecules to modulate amyloid-β metabolism, tau acetylation, α-synuclein aggregation, RNA-binding protein interactions, and NLRP3 inflammasome activation. Compounds acting on key signaling cascades, including PI3K/Akt, MAPK/ERK, Nrf2/ARE, and Wnt/β-catenin, are discussed, alongside drug repurposing strategies and preclinical-to-clinical translation. Special focus is given to microglial modulation, challenges in crossing the blood-brain barrier, and integration of precision medicine, metabolomics, and artificial intelligence into drug discovery. The review also highlights novel therapeutic concepts such as multi- target ligands, metal-chelation approaches, and modulation of neuroinflammatory pathways. Despite promising leads, significant challenges remain in optimizing pharmacokinetics, target selectivity, and delivery. Future directions include the identification of robust biomarkers, advanced imaging techniques, and computational tools to accelerate candidate validation. Collectively, smallmolecule therapeutics hold considerable promise in addressing unmet needs in neurodegenerative disease management, but their successful translation will require multidisciplinary approaches bridging molecular insights and clinical application.}, } @article {pmid41881396, year = {2026}, author = {Zhou, R and Lin, X and Lin, J and Liao, Z and Ni, H and Lin, X and He, Q and Ning, W}, title = {Cellular senescence in neurodegenerative diseases: A bibliometric analysis and mechanistic synthesis linking translational pathways to therapeutic implications.}, journal = {Ageing research reviews}, volume = {118}, number = {}, pages = {103110}, doi = {10.1016/j.arr.2026.103110}, pmid = {41881396}, issn = {1872-9649}, mesh = {*Neurodegenerative Diseases/pathology/metabolism/therapy/drug therapy ; Humans ; Bibliometrics ; *Cellular Senescence/physiology ; Animals ; Translational Research, Biomedical ; Senescence-Associated Secretory Phenotype ; }, abstract = {BACKGROUND: Cellular senescence is now recognized as a pivotal driver of neurodegenerative diseases (NDs). Despite advances in understanding senescence mechanisms, such as the p16[INK4A]/p53-p21[CIP1] pathways and the senescence-associated secretory phenotype (SASP), along with the development of therapeutic strategies like senotherapeutics, the research landscape remains fragmented.

OBJECTIVE: Systematically addresses the fragmentation characterizing current research on cellular senescence in NDs, integrating bibliometric analysis with a mechanistic synthesis of translational relevance and therapeutic implications.

METHODS: A comprehensive bibliometric analysis was performed. Literature retrieval on cellular senescence and four NDs (AD, PD, ALS, HD) was executed in Web of Science Core Collection (WoSCC) on April 30, 2025. CiteSpace V.6.4 R1 and VOSviewer 1.6.20 reconstructed networks for temporal trends, burst detection, and co-occurrence visualization. In addition to bibliometric mapping, we provide a mechanistic synthesis of emerging translational pathways.

RESULTS: Analysis included 269 relevant articles (2002-April 2025). Annual publications and cumulative citations increased markedly since 2018. The US led in output/influence, followed by China and Italy. Key collaborative institutions included Chinese Academy of Sciences, University of Texas System, and University of California System. Leading authors were Lorenz Studer, Judith Campisi, and Julie K. Andersen. Tyler J. Bussian and Peisu Zhang were highly co-cited. Top-cited journals were Nature, PNAS, and PLOS One. Research hotspots focus on abnormal tau protein in senescence and senescent microglia mediating chronic neuroinflammation, development of multi-target senomorphics targeting SASP is emerging as a promising therapeutic direction.

CONCLUSION: Cellular senescence research in NDs (notably AD, PD) shows broad promise from mechanisms to therapy. Future priorities include elucidating tau dysregulation's core role in senescence, developing specific biomarkers and targeted interventions. Senescent microglia are new therapeutic targets. Multi-target senomorphics modulating SASP offer new mechanisms for delaying ND progression. Understanding senescence mechanisms and precise interventions may provide novel ND therapies.}, } @article {pmid41882018, year = {2026}, author = {Lin, J and Agote-Aran, A and Liao, Y and Cloarec, M and Andronov, L and Schoch, RL and Ronchi, P and Cochard, V and Zhu, R and Grandgirard, E and Liu, X and Lemée, MV and Kleiss, C and Golzio, C and Ruff, M and Chevreux, G and Schwab, Y and Klaholz, BP and Sumara, I}, title = {RanBP2-dependent annulate lamellae drive nuclear pore assembly and nuclear expansion.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41882018}, issn = {2041-1723}, support = {ANR-22-CE13-0025//Agence Nationale de la Recherche (French National Research Agency)/ ; }, mesh = {*Nuclear Pore/metabolism ; *Nuclear Pore Complex Proteins/metabolism/genetics ; *Endoplasmic Reticulum/metabolism ; Humans ; *Molecular Chaperones/metabolism/genetics ; Animals ; Nuclear Envelope/metabolism ; *Cell Nucleus/metabolism ; Active Transport, Cell Nucleus ; Membrane Proteins/metabolism ; }, abstract = {Nuclear pore complexes (NPCs) enable nucleocytoplasmic transport. While NPCs primarily localize to the nuclear envelope (NE), they also appear in cytoplasmic endoplasmic reticulum (ER) membranes called annulate lamellae (AL). Though discovered in the mid-20th century, AL's function and biogenesis remain unclear. Previously considered exclusive to embryonic and malignant cells, we find AL in somatic mammalian cells. Under normal conditions, AL store pre-assembled AL-NPCs that integrate into the NE, producing approximately one-third of newly formed nuclear pores and supporting nuclear expansion during G1. Upon pathological stimuli, AL transfer to the NE is impaired, leading to their cytoplasmic accumulation. RanBP2 (Nup358) is essential for AL biogenesis, with its phenylalanine-glycine repeats promoting AL-NPC scaffold oligomerization. ER-associated Climp63 (CKAP4) directs AL-NPCs to ER sheets and the NE. This AL-driven nuclear pore formation is complementary to the canonical routes, constituting a distinct NPC assembly pathway. Our work uncovers the biogenesis mechanism of AL and the nuclear function of this key cellular organelle.}, } @article {pmid41883703, year = {2026}, author = {Nassan, M and Ayala, I and Sloan, J and Bonfitto, A and Stark, B and Song, S and Naymik, M and Geula, C and Gefen, T and Barbieri, E and Piras, I and Mesulam, MM and Huentelman, M}, title = {The Genetics of TDP-43 Type C Neurodegeneration: A Whole-Genome Sequencing Study and Literature Review.}, journal = {Neurology. Genetics}, volume = {12}, number = {2}, pages = {e200369}, pmid = {41883703}, issn = {2376-7839}, support = {P30 AG013854/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; R01 AG062566/AG/NIA NIH HHS/United States ; R01 AG077444/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Frontotemporal lobar degeneration TDP43 type C (TDP-C) is a rare and unique neurodegenerative disease that attacks the anterior temporal lobe. Recently, it was shown that Annexin-A11 and TDP-43 coaggregate specifically in TDP-C. Current literature on the genetic associations with TDP-C, reviewed here, lacks a discernible corpus of robust or replicated findings. In this study, using blood tissue, we completed whole genome sequencing to investigate ANXA11 and TARDBP genetic variants for their association with TDP-C. Then, we completed genome-wide hypothesis-free analyses using artificial intelligence to identify rare pathogenic variants associated with TDP-C.

METHODS: (1) We tested common variants in ANXA11 and TARDBP for their association with 37 TDP-C cases vs 290 controls. We attempted to replicate our findings in a different cohort of 467 TDP-C cases vs 3,153 controls and contrasted them with cohorts of TDP-A and TDP-B. (2) AI-guided analyses were completed to prioritize pathogenic rare variants associated with TDP-C in our cohort.

RESULTS: (1) Four common variants in ANXA11 (rs113772135, rs2789686, rs1079242, rs61860017) were significantly associated with TDP-C in the discovery cohort and replicated in the other cohort of TDP-C but not in TDP-A or TDP-B, providing evidence for ANXA11 specific association with TDP-C. Rs1079242-A showed the most robust replication (p = 7.35 × 10[-05]) and correlates with higher ANXA11 level in CSF (p = 4 × 10[-11]). No associations were found between TARDBP and TDP-C (p > 0.05). Using AI-guided rare variant analyses, we identified a pathogenic variant in FIG4, a gene that has been implicated in amyotrophic lateral sclerosis (ALS). Because of the observed potential genetic overlap between some ALS genes and TDP-C, we leveraged mendelian randomization and found that ALS genetic load is associated with TDP-C risk (p = 0.0046).

DISCUSSION: This study provides replicated evidence for the association between common variants in ANXA11 with TDP-C. Knowing rs1079242-A affects ANXA11 level in CSF, future studies may aim to investigate ANXA11 level as potential CSF biomarker for TDP-C. Moreover, FIG4 and ANXA11 have been implicated in the inositol pathway. Our results provide novel insights into the genetic risk of TDP-C and offer new clues about its underpinning mechanisms.}, } @article {pmid41884172, year = {2026}, author = {Seki, S and Enomoto, A and Tanaka, S}, title = {The mesencephalic trigeminal neuron: electrophysiological insights into function and dysfunction.}, journal = {Frontiers in cellular neuroscience}, volume = {20}, number = {}, pages = {1752701}, pmid = {41884172}, issn = {1662-5102}, abstract = {Mesencephalic trigeminal neurons (MTNs) are the sole primary afferent neurons with cell bodies located within the central nervous system. MTNs convey proprioceptive inputs from masticatory muscles and periodontal ligaments, thereby contributing to the precise regulation of jaw-oral motor functions. Through ionic mechanisms such as currents generated by the voltage-dependent sodium (Nav) channel isoform Nav1.6, hyperpolarization-activated currents, and persistent inward currents, MTNs generate sustained and burst firing that regulate masticatory rhythm and jaw-jerk reflex timing. Their activity is further modulated by neurotransmitters, including serotonin and norepinephrine, which provide flexibility in sensorimotor integration. Pathological conditions such as chronic stress and sodium channel dysfunction induce MTN hyperexcitability or irregular firing, contributing to bruxism, temporomandibular disorders, and feeding impairment in amyotrophic lateral sclerosis models. In addition, aging and tooth loss lead to Piezo2 downregulation and neuronal death, potentially resulting in masticatory dysfunction and cognitive decline. Recent findings suggest that interventions targeting vesicular glutamate transporter 1 projections, melanocortin 4 receptor signaling, and nitric oxide pathways represent novel therapeutic approaches. Taken together, MTNs have emerged as promising targets for treating conditions ranging from masticatory motor disorders to neurodegenerative diseases.}, } @article {pmid41884597, year = {2026}, author = {Milioto, C and Carcolé, M and Zanovello, M and Ahmed, M and Nirujogi, RS and Biggs, D and Roberts, MJ and Schweers, K and Cammack, AJ and Marchi, PM and Katona, E and Glaria, I and Santos, A and Devoy, A and Fratta, P and Alessi, DR and Davies, B and Greensmith, L and Fisher, EMC and Isaacs, AM}, title = {C9orf72 poly(glycine-alanine) knock-in mice exhibit mild rotarod and proteomic changes consistent with amyotrophic lateral sclerosis/frontotemporal dementia.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag087}, pmid = {41884597}, issn = {2632-1297}, abstract = {A GGGGCC repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeat expansion is translated into five different dipeptide repeat proteins: poly(glycine-alanine) (polyGA), poly(glycine-proline) (polyGP), poly(glycine-arginine) (polyGR), poly(alanine-proline) (polyAP) and poly(proline-arginine) (polyPR). To investigate the effect of polyGA, which is the most abundant dipeptide repeat protein in patient brains, we used clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated nuclease 9 (Cas9) to insert 400 codon-optimized polyGA repeats immediately downstream of the mouse C9orf72 start codon. This generated (GA)400 knock-in mice driven by the endogenous mouse C9orf72 promoter, coupled with heterozygous C9orf72 reduction. PolyGA remains soluble up to 18 months of age and (GA)400 mice develop subtle dysfunction characterized by impaired rotarod performance, without overt neuropathological alterations. Quantitative proteomics revealed polyGA expression caused protein alterations in the spinal cord, including changes in previously identified polyGA interactors. Our findings show that (GA)400 mice are a complementary in vivo model to better understand C9orf72 ALS/FTD pathology and determine the specific role of individual DPRs in disease.}, } @article {pmid41884646, year = {2026}, author = {Sudwarts, A and Thinakaran, G}, title = {Female-specific Cx3cr1-driven regulation of ALS and Alzheimer's risk genes in tauopathy.}, journal = {Molecular neurodegeneration advances}, volume = {2}, number = {1}, pages = {16}, pmid = {41884646}, issn = {3059-4944}, support = {R01 AG063175/AG/NIA NIH HHS/United States ; R01 AG077610/AG/NIA NIH HHS/United States ; R01 AG079141/AG/NIA NIH HHS/United States ; RF1 AG056061/AG/NIA NIH HHS/United States ; }, abstract = {UNLABELLED: By introducing haploinsufficiency of Cx3cr1 in the P301S (PS19) transgenic model of tau pathology, we report remarkable transcriptional changes, including crucial amyotrophic lateral sclerosis and Alzheimer's disease risk genes, several of which showed co-expression, suggesting gene-gene interactions among these genetic risk factors.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44477-026-00022-3.}, } @article {pmid41885541, year = {2026}, author = {Chen, RF and Liu, KF and Lee, CC and Li, YT and Chen, WY and Kuo, YR}, title = {Transcriptomic Analysis of Adipose-Derived Stem Cell Therapy Modulating B Cell Immune Tolerance in Vascularized Composite Allotransplantation.}, journal = {Plastic and reconstructive surgery}, volume = {}, number = {}, pages = {}, doi = {10.1097/PRS.0000000000013074}, pmid = {41885541}, issn = {1529-4242}, abstract = {BACKGROUND: Adipose-derived stem cells (ADSCs) have been shown to prolong vascularized composite allotransplantation (VCA) survival in rodent hindlimb transplantation. However, the mechanisms by which ADSCs modulate B cell responses and induce immune tolerance remain unclear. This study used next-generation sequencing (NGS) to investigate B cell gene expression after ADSC treatment.

METHODS: A rodent orthotopic hind-limb transplantation model was established using Brown-Norway to Lewis rats. The tolerance treatment group received a combination of ADSCs, short-term cyclosporine A (CsA) and anti-lymphocyte serum (ALS), while the control rejection group received no treatment. B cells were isolated from the spleens of rejection control group at 10-14 days post-transplantation when rejection was diagnosed, or tolerance group at least ≥100 days post-transplantation without rejection. RNA sequencing (RNA-Seq) was conducted to assess transcriptomic differences. Differentially expressed genes (DEGs) were analyzed using the EBSeq bioinformatics tool and pathway enrichment analyses, with validation by qPCR.

RESULTS: RNA-Seq identified 94 DEGs (out of 13,284 mRNAs) between the tolerance and rejection groups. Gene ontology and KEGG pathway analyses revealed significant enrichment in pathways associated with cytokine secretion, B cell receptor signaling, and humoral immunity. The tolerance group exhibited upregulation of key chemokines (e.g., Cxcl1, Cxcl2, Ccl4) and downregulation of pro-inflammatory genes (e.g., Tlr3, Siglec5, C3). qPCR validation confirmed the RNA-Seq findings. These results suggest that ADSCs modulate B cell-mediated immune responses and promote a shift toward an anti-inflammatory, tolerogenic profile.

CONCLUSIONS: ADSC-based therapy combined with short-term immunosuppression promotes immune tolerance in VCA by modulating B cell-related gene expression. These findings suggest that targeting B cell-mediated pathways may provide a novel approach may offer a novel therapeutic strategy for clinical application in VCA.}, } @article {pmid41885638, year = {2026}, author = {Sadhukhan, A and Chauhan, A and Kumar, M and Singh, TG and Mujwar, S and Awasthi, A}, title = {Cryptoxanthin as a multitarget neuroprotective agent: mechanistic and in silico perspectives.}, journal = {The Journal of pharmacy and pharmacology}, volume = {78}, number = {3}, pages = {}, doi = {10.1093/jpp/rgag029}, pmid = {41885638}, issn = {2042-7158}, mesh = {*Neuroprotective Agents/pharmacology/therapeutic use ; Humans ; Molecular Docking Simulation ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology ; *Beta-Cryptoxanthin/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; Computer Simulation ; }, abstract = {OBJECTIVES: Neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease (AD), and Amyotrophic lateral sclerosis (ALS) are complex disorders driven by multiple pathological processes, including oxidative stress, mitochondrial dysfunction, protein misfolding, and neuroinflammation. Due to this multifactorial nature, there is a growing interest in identifying natural compounds with multi-targeted neuroprotective properties. This review aims to evaluate the therapeutic potential of β-cryptoxanthin, a naturally occurring xanthophyll carotenoid, as a candidate molecule for mitigating neurodegenerative diseases.

METHODS: A comprehensive literature review was conducted to examine the neuroprotective mechanisms of β-cryptoxanthin, focusing on its antioxidant, anti-inflammatory, and immunomodulatory properties. In addition, in silico molecular docking studies were performed using AutoDock Vina to investigate the binding interactions of β-cryptoxanthin with key molecular targets associated with inflammation and neurodegenerative pathways.

KEY FINDINGS: β-Cryptoxanthin demonstrated strong neuroprotective potential due to its ability to scavenge reactive oxygen species (ROS) and modulate key molecular pathways involved in neuroinflammation and oxidative damage. Structurally characterized by a hydroxylated β-carotene backbone with 11 conjugated double bonds, β-cryptoxanthin showed favorable binding affinities with several inflammation- and neurodegeneration-related targets, including COX-2 (-11.6 kcal/mol), PI3K (-9.6 kcal/mol), mTOR1 (-9.2 kcal/mol), and GSK-3β (-8.7 kcal/mol). Additionally, interactions with JAK2, MAPK1, NF-κB, NRF2, and TLR4 suggest its involvement in regulating neuroimmune signalling pathways and inflammatory mediators.

CONCLUSIONS: The findings of this review highlight β-cryptoxanthin as a promising candidate for future neurotherapeutic investigation due to its multi-targeted mechanisms of action against key pathways implicated in neurodegeneration. Molecular docking results support its potential mechanistic role in modulating inflammation- and oxidative stress-related targets. However, these findings represent mechanistic plausibility rather than confirmed clinical efficacy, and further validation through preclinical and clinical studies is required.}, } @article {pmid41885937, year = {2026}, author = {Akiyama, T and Zeng, Y and Guo, C and Gautier, O and Koepke, L and Lyons, H and Molotsky, E and Bombosch, JS and Sianto, O and Ross, JP and Hoang, P and Zhao, L and Spencer, C and Sumner, CJ and Monje, M and Day, JW and Gitler, AD}, title = {KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS.}, journal = {JCI insight}, volume = {11}, number = {10}, pages = {}, pmid = {41885937}, issn = {2379-3708}, support = {R35 NS137159/NS/NINDS NIH HHS/United States ; R35 NS122306/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; T32 AG047126/AG/NIA NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Kinesins/genetics/metabolism ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Survival of Motor Neuron 1 Protein/genetics/metabolism ; *Muscular Atrophy, Spinal/genetics/metabolism/pathology ; Down-Regulation ; Disease Models, Animal ; *Axons/pathology/metabolism/physiology ; Motor Neurons/metabolism/pathology ; *Nerve Regeneration/genetics ; }, abstract = {Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene leading to decreased SMN protein levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. SMN deficiency resulted in downregulation of kinesin heavy chain isoform 5A (KIF5A) in human neurons and in a mouse model of SMA. SMN associated with KIF5A mRNA and contributed to its stability. Reduced SMN levels impaired axon regeneration, which was rescued by KIF5A overexpression. Because KIF5A has also been connected to ALS, these findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as an SMN-regulated factor. Our findings suggest that SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.}, } @article {pmid41888300, year = {2026}, author = {Sanchez-Mico, MV and Calvo-Rodriguez, M and Bacskai, BJ}, title = {Role of dysregulated calcium homeostasis in astrocytes in neurodegenerative disorders.}, journal = {Nature reviews. Neuroscience}, volume = {27}, number = {6}, pages = {377-394}, pmid = {41888300}, issn = {1471-0048}, mesh = {*Astrocytes/metabolism ; Humans ; *Homeostasis/physiology ; Animals ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Calcium/metabolism ; *Calcium Signaling/physiology ; Aging/metabolism ; Brain/metabolism ; }, abstract = {Calcium signalling in astrocytes is a fundamental mechanism for maintaining brain homeostasis, shaping neuronal activity, and coordinating vascular and immune responses. Once considered secondary to neuronal signalling, astrocytic Ca[2+] dynamics are now recognized as highly versatile, spatially compartmentalized and essential for regulating neurotransmitter uptake, ion buffering, metabolic support and mitochondrial function. Accumulating evidence shows that these Ca[2+] signalling pathways are progressively remodelled during ageing and become profoundly dysregulated in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis. Importantly, astrocyte Ca[2+] alterations are heterogeneous and context-dependent, ranging from aberrant spontaneous activity to loss of signalling in specific subcellular domains, reflecting the disease stage, brain region and molecular pathology. Disruption of astrocyte Ca[2+] homeostasis compromises core homeostatic functions and contributes to neuronal vulnerability, circuit dysfunction and impaired neurovascular regulation. By integrating current evidence across physiological, ageing and disease contexts, this Review highlights astrocytic Ca[2+] signalling as a central node in neurodegenerative pathophysiology and underscores its potential as a target for therapeutic intervention.}, } @article {pmid41888437, year = {2026}, author = {McLellan, C and Campos-Melo, D and Hammond, R and Strong, MJ}, title = {Preservation of miR-9-5p and miR-124-3p in ALS-resistant oculomotor neurons contrasts with their downregulation in vulnerable spinal motor neurons, irrespective of TDP-43 pathology.}, journal = {Acta neuropathologica}, volume = {151}, number = {1}, pages = {}, pmid = {41888437}, issn = {1432-0533}, support = {201806SOP-411481//CIHR/Canada ; }, mesh = {*MicroRNAs/metabolism ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; Humans ; *Motor Neurons/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Down-Regulation ; Female ; Spinal Cord/pathology/metabolism ; Male ; Aged ; Middle Aged ; *Oculomotor Nerve/pathology/metabolism ; }, abstract = {Selective vulnerability of motor neurons is a defining feature of amyotrophic lateral sclerosis (ALS) and provides a valuable framework for uncovering mechanisms that distinguish resilient from vulnerable neuronal populations. We investigated whether dysregulation of neuroprotective microRNAs (miRNAs), miR-9-5p and miR-124-3p, contributes to the differential susceptibility of motor neuron subtypes. We focused on cervical spinal motor neurons (SMNs), which undergo drastic degeneration in ALS, and oculomotor neurons (OMNs), which remain functionally intact and rarely degenerate, allowing preservation of eye movement in ALS patients. Using a modified multiplexed fluorescent in situ hybridization protocol combined with immunofluorescence, we quantified the expression of miR-9-5p and miR-124-3p in cervical SMNs and OMNs from ALS and control cases. We observed significant downregulation of both miRNAs in ALS SMNs, while their expression was maintained in ALS OMNs. Stratification of ALS SMNs by TDP-43 pathological status revealed similarly reduced miRNA expression in neurons with and without cytoplasmic inclusions, suggesting that miRNA downregulation occurs independently of visible TDP-43 pathology. We assessed the localization of the Dicer cofactor TRBP and found that it colocalized with TDP-43 inclusions in ALS SMNs, suggesting that TRBP sequestration could prevent proper miRNA processing. However, TRBP remained normally localized in neurons without cytoplasmic inclusions, indicating that sequestration cannot fully account for miRNA reduction across all ALS motor neurons. These findings support a model in which early or subtle disruptions, preceding visible pathology, may also contribute to miRNA downregulation in ALS. By identifying preserved miRNA networks as correlates of oculomotor neuron resilience in ALS, this work also exposes new therapeutic targets potentially capable of reinstating miRNA expression and reprogramming vulnerable SMNs.}, } @article {pmid41888964, year = {2026}, author = {Haddouali, K and Simma, K and Bellakhdar, S and El Otmani, H and El Moutawakil, B and Rafai, MA}, title = {Multifocal motor neuropathy secondary to gluten intolerance: a case report.}, journal = {Journal of medical case reports}, volume = {20}, number = {1}, pages = {}, pmid = {41888964}, issn = {1752-1947}, mesh = {Humans ; Middle Aged ; Male ; *Diet, Gluten-Free ; *Polyneuropathies/etiology/diagnosis/physiopathology ; Diagnosis, Differential ; *Celiac Disease/complications/diet therapy/diagnosis ; Nerve Conduction Studies ; Magnetic Resonance Imaging ; Treatment Outcome ; *Glutens/adverse effects ; }, abstract = {BACKGROUND: Peripheral nervous system manifestations of gluten sensitivity usually present as distal symmetric axonal polyneuropathy, small fiber neuropathy, or sensory neuropathy, often accompanied by ataxia or painful symptoms. By contrast, motor neuropathies are extremely rare, with only a few cases of multifocal motor neuropathy reported. Notably, the most recent guidelines of the European Society for the Study of Coeliac Disease do not recognize multifocal motor neuropathy as a classical neurological manifestation of gluten-related disorders. The main differential diagnoses include amyotrophic lateral sclerosis and chronic inflammatory demyelinating polyneuropathy. Currently, strict adherence to a gluten-free diet remains the only therapeutic option. Although clinical improvement is not universal, when observed, it strongly supports the causal role of gluten-related neurotoxicity.

CASE PRESENTATION: We report the case of a 50-year-old North African man with a history of dermatitis herpetiformis and persistent chronic diarrhea. Over the past 5 years, he developed progressive asymmetric motor weakness. Clinical examination revealed an asymmetric, pure motor, peripheral neurogenic syndrome, confirmed by nerve conduction studies, without evidence of proximal conduction block. Cerebrospinal fluid analysis showed elevated protein levels (0.75 g/L), and serum anti-GD3 IgM antibodies were positive. Brachial plexus magnetic resonance imaging revealed bilateral hypertrophy on T1-weighted sequences, with hyperintensity on short tau inversion recovery sequences but no contrast enhancement. The motor deficit gradually improved after the introduction of a gluten-free diet. The patient also received intravenous immunoglobulin without significant clinical benefit. On the basis of clinical, paraclinical, and follow-up findings, a diagnosis of multifocal motor neuropathy secondary to gluten intolerance was established.

CONCLUSION: This case highlights the importance of considering gluten intolerance as a potential etiology, particularly given the reversible nature of this neuropathy, which can otherwise be misdiagnosed as a more severe condition such as amyotrophic lateral sclerosis. Further studies are needed to better elucidate the pathophysiology of this rare gluten-related neurological phenotype.}, } @article {pmid41889878, year = {2026}, author = {Hines, TJ and Funke, JR and Pratt, SL and Rice, AD and Twiss, JL and Burgess, RW}, title = {A mouse model of autosomal dominant spastic ataxia and myopathy caused by a mutation in Tuba4a.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41889878}, issn = {2692-8205}, support = {K99 NS130151/NS/NINDS NIH HHS/United States ; R37 NS054154/NS/NINDS NIH HHS/United States ; }, abstract = {Hereditary ataxias are a heterogeneous group of neurodegenerative disorders characterized by impaired balance and coordination, often due to cerebellar dysfunction. Despite advances in identifying genetic causes, animal models remain essential for dissecting underlying mechanisms and testing therapeutic strategies. Here we describe a mouse model of spastic ataxia and myopathy caused by a missense mutation in Tuba4a (n.A626C, p.Gln176Pro). In an ENU mutagenesis screen, a male C57BL/6J mouse exhibiting muscle wasting and an intention tremor starting at approximately 4 weeks-of-age was identified. The male was bred by in vitro fertilization to BALB/cByJ oocyte donors. Genetic mapping determined dominant inheritance and localized the mutation to Chromosome 1. Genome sequencing revealed single nucleotide polymorphisms (SNPs) in serine threonine kinase 36 (Stk36 [Y1003N]) and alpha-tubulin 4A (Tuba4a [Q176P]) in the mapping interval. These SNPs were CRISPR-engineered into C57BL/6J mice, which confirmed the Tuba4a [Q176P] variant as the causative mutation. Mutant mice are normal at 3 weeks, except for decrement in muscle response following repetitive nerve stimulation. However, by 30 days these mice have ataxia, Purkinje neuron degeneration, and extensive skeletal muscle defects, which contribute to a decreased lifespan. Dominant TUBA4A mutations in humans are associated with spastic ataxia type 11 (SPAX11), congenital myopathy type 26 (CMYO26), and frontotemporal dementia/amyotrophic lateral sclerosis type 9 (FTDALS9). Our mice exhibit hallmark features of SPAX11 and CMYO26, but do not show motor neuron degeneration. This specificity makes this model a valuable tool for studying cell-type selective effects of TUBA4A mutations in neurodegeneration and myopathy.}, } @article {pmid41890126, year = {2026}, author = {Spence, H and Read, FL and Waldron, FM and Gregory, JM}, title = {Metabolic signatures of ferritin and TDP-43 co-pathology provide a mechanistic basis for stratified therapeutic approaches in ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41890126}, issn = {2692-8205}, support = {R01 NS127186/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: ALS is increasingly recognized as a biologically heterogeneous disease in which several molecular and pathological mechanisms converge on a similar clinical phenotype. One of these molecular markers is ferritin accumulation which is observed in a subset of ALS cases and has been shown to directly correlate with TDP-43 pathology in some brain regions. Additionally, TDP-43 proteinopathy is observed outside of ALS which may complicate the interpretation of case vs control approaches to target discovery. Here, we propose a pathology-stratified approach to empower targeted theranostics. We hypothesised that biologically distinct ALS subtypes may be defined by specific metabolic dysfunction linked to brain-accumulated ferritin and TDP-43 pathology.

METHODS: Post-mortem primary motor cortex tissue from 15 ALS cases and 20 age- and sex-matched controls was stratified, using immunohistochemistry, by single- or co-occurrence of ferritin accumulation, and pathological TDP-43. Untargeted metabolomics (>1,000 metabolites) was performed, and samples were stratified into dual positive (ferritin and TDP-43), single positive (either), or negative. Group-discriminating metabolites were identified using partial least squares discriminant analysis.

RESULTS: Dual ferritin and TDP-43 pathology reflected a distinct metabolomic profile, separable from single-pathology states. This dual positive metabolic signature was characterised by disruption of lysophospholipid, lysoplasmalogen, and fatty acid metabolism, consistent with impaired membrane and energy homeostasis. In contrast, pathological TDP-43 presence without ferritin, was characterised metabolically by significant depletion of secondary bile acids and increase in glycosylation markers, whilst ferritin accumulation alone reflected significant increase in oxidative stress and depletion of lipid peroxidation inhibition markers. The dual positive state suggests failure of compensatory metabolic responses present in single-pathology conditions.

CONCLUSIONS: Ferritin accumulation and TDP-43 pathology define biologically distinct subtypes associated with ALS with divergent metabolic vulnerabilities. The metabolic signature associated with dual pathology provides a mechanistic correlate to MRI-visible ferritin accumulated iron, supporting paired non-invasive biomarker and target discovery for pathology-dependent patient stratification. These findings argue for pathway-targeted, subtype-specific therapeutic strategies and highlight the necessity of precision medicine approaches in ALS.}, } @article {pmid41890230, year = {2026}, author = {Aguerd, A and Nouadi, B and Ezaouine, A and Fenjar, I and Bennis, F and Chegdani, F}, title = {An in silico protocol for predicting genetic biomarkers in rare diseases: a case study in sporadic amyotrophic lateral sclerosis.}, journal = {Frontiers in genetics}, volume = {17}, number = {}, pages = {1742595}, pmid = {41890230}, issn = {1664-8021}, abstract = {Studying the genetics of rare diseases is challenging because small sample sizes limit the statistical power of standard methods like Genome-wide association studies (GWAS). We created a new machine-learning approach to find candidate Single Nucleotide Polymorphisms (SNPs) when data is scarce. Our method trains a Random Forest model to spot similarities between SNPs. We used 189 known Sporadic Amyotrophic Lateral Sclerosis (sALS)-linked SNPs as positive examples and 938,544 unrelated SNPs as negatives. The model learns from genomic location, significance levels, nearby genes, and other features. When we tested it on sALS, it performed exceptionally well, with 93.8% accuracy and near-perfect AUC scores. The method uncovered 1,890 new SNP candidates for sALS. Among these, 209 reached genome-wide significance, and 50 appeared repeatedly in our analyses, making them strong candidates. Key genes like SARM1, OPHN1, and BPTF emerged from the results, all connected to neural health and survival pathways. Our examination revealed a notable excess of SNPs on chromosome 18 compared to expectations. This non-random distribution underscores the region's particular interest. Here, our approach demonstrates its ability to extract meaningful signals from a restricted sample. The results generated by this approach enable early diagnosis of the disease under study, explanation of its mechanism, and identification of therapeutic targets.}, } @article {pmid41890274, year = {2026}, author = {Silva-Hucha, S and Hernández, RG and Baena-López, D and Fernández de Sevilla, ME and Paradas, C and Morcuende, S}, title = {Excitotoxicity in amyotrophic lateral sclerosis: a key pathogenic mechanism.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag098}, pmid = {41890274}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a complex neurodegenerative disease affecting motor neurons, characterized by the involvement of various factors, including oxidative stress, inflammatory processes, glutamate excitotoxicity, mitochondrial dysfunction, protein aggregation, axonal transport abnormalities, and apoptosis. The complexity of amyotrophic lateral sclerosis arises from its multifactorial aetiology involving diverse genetic, protein, metabolic, and cellular alterations. Mutations of different genes, such as SOD1, C9ORF72, TARDBP, and FUS, have been identified as critical contributors to disease pathophysiology through their facilitation of aberrant protein misfolding and aggregation. All these factors disrupt glutamate homeostasis, leading to calcium-mediated neurotoxicity. Under oxidative stress, motor neurons exhibit a diminished capacity to regulate calcium influx, along with impaired functioning of the mitochondria and endoplasmic reticulum, further compromising cellular integrity. Dysregulation of glutamate signalling also triggers astrocytic stress responses, leading to reduced glutamate clearance, thus worsening neuronal damage through excitotoxic mechanisms. These factors contribute to the excessive production of reactive oxygen species, which exacerbates glutamate imbalance and establishes a detrimental cycle of neuronal damage and glial dysfunction, ultimately intensifying excitotoxicity. This review aims to highlight the role of excitotoxicity in motor neuronal degeneration and to explore the molecular mechanisms underlying the pathogenesis of amyotrophic lateral sclerosis. It also examines current therapeutic approaches, including approved treatments and ongoing clinical trials to reduce excitotoxicity, while emphasizing the urgent need for novel, targeted strategies. Given the lack of definitive diagnostic tools and curative therapies, advancing our understanding of the molecular mechanisms driving excitotoxicity and neurodegeneration is, therefore, crucial for the development of more effective, disease-modifying treatments to slow amyotrophic lateral sclerosis progression.}, } @article {pmid41890591, year = {2026}, author = {Gabbay, U}, title = {Axonal transport impairment as an upstream mechanism in amyotrophic lateral sclerosis pathogenesis.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1802313}, pmid = {41890591}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons. Despite marked genetic and pathological heterogeneity, a unifying pathogenic framework remains lacking. We propose that axonal transport impairment represents an early and convergent but genotype-modulated upstream vulnerability in ALS, contributing to distal synaptic failure, bioenergetic stress, protein aggregation, neuroinflammation, and neuronal death. Across many ALS models, including SOD1, TARDBP (TDP-43), FUS, and C9orf72, transport deficits are frequently detectable in presymptomatic stages, often preceding overt motor neuron loss or clinical manifestation, although temporal ordering varies by molecular subtype. Human data from induced pluripotent stem cell-derived motor neurons and neuroimaging in mutation carriers further support early transport dysfunction in both familial and sporadic ALS. We synthesize genetic, cellular, and systems-level evidence demonstrating that diverse ALS-associated mutations converge on intracellular trafficking machinery through distinct but interacting mechanisms, disrupting long-range cargo delivery and clearance in motor neurons. This framework provides a mechanistic basis for selective motor neuron vulnerability, the dying-back pattern of neuromuscular junction degeneration, and the emergence of downstream pathological hallmarks including mitochondrial dysfunction, excitotoxicity, aggregation, and inflammation. This model generates testable predictions regarding presymptomatic transport biomarkers and the timing of therapeutic intervention. We discuss implications for biomarker development and therapeutic strategy, proposing restoration of axonal transport as a central component of rational multimodal disease modification in ALS.}, } @article {pmid41892827, year = {2026}, author = {Pérez-Bonilla, M and Mora-Ortiz, M and Díaz-Borrego, P and Muñoz-Alcaraz, MN and Mayordomo-Riera, FJ and Girela-López, E}, title = {Biomechanical Voice Parameters as Potential Biomarkers for Phenotype Differentiation in Amyotrophic Lateral Sclerosis: A Cross-Sectional Study.}, journal = {Medical sciences (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, pmid = {41892827}, issn = {2076-3271}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Female ; Cross-Sectional Studies ; Male ; Middle Aged ; Aged ; Phenotype ; *Biomarkers ; Biomechanical Phenomena ; *Voice/physiology ; Adult ; }, abstract = {Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease in which bulbar involvement frequently affects speech and voice production. Although acoustic voice analysis can detect phonatory alterations in ALS, its ability to differentiate clinical phenotypes remains limited. This study investigated whether biomechanical voice parameters provide complementary information for characterizing bulbar involvement across bulbar-onset ALS (ALS-B) and spinal-onset ALS (ALS-S) and explored their association with clinical and functional measures. Methods: This cross-sectional observational study included 50 patients with ALS (20 ALS-B, 30 ALS-S) and 50 controls with non-neurological voice disorders. Sustained vowel phonation was analyzed using acoustic measures and biomechanical voice parameters derived from a standardized model of vocal fold vibration. Perceptual voice severity was assessed using the GRBAS scale, while functional status was evaluated with the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Barthel Index. Associations with clinical measures were explored in secondary analyses. Results: Compared with controls, ALS patients showed significant differences in acoustic measures and several biomechanical parameters related to glottal closure and vibratory stability. Biomechanical analysis revealed significant differences between ALS-B and ALS-S, particularly in parameters reflecting vibratory asymmetry, glottal tension and cycle-to-cycle instability. Unexpectedly, ALS-B showed greater perceptual voice severity and higher Barthel Index scores than ALS-S, while no differences were observed in global ALSFRS-R total scores. Conclusions: Biomechanical voice analysis appears to capture physiologically meaningful alterations in vocal fold function in ALS and provides complementary information for characterizing bulbar motor involvement across clinical phenotypes, particularly ALS-B disease. When combined with acoustic and clinical assessments, this approach may enhance the evaluation of bulbar involvement and functional status in ALS.}, } @article {pmid41893050, year = {2026}, author = {Duranti, E and Villa, C}, title = {Misfolded Proteins and Cognitive Decline: Mechanistic Insights into Neurodegenerative Disorders.}, journal = {Neurology international}, volume = {18}, number = {3}, pages = {}, pmid = {41893050}, issn = {2035-8385}, abstract = {Cognitive decline represents one of the most common clinical manifestations of neurodegenerative diseases (NDs), substantially affecting the quality of life of both patients and their families. Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are major NDs characterized by a progressive degeneration of the central nervous system, with functional impairments extending beyond motor symptoms to multiple cognitive domains, including memory, attention, language, and executive functions. Increasing evidence highlights misfolded protein accumulation as a key driver of neuronal dysfunction and cognitive deterioration. This narrative review examines the major cognitive deficits associated with these disorders, focusing on the underlying molecular mechanisms, particularly protein aggregation, as well as clinical manifestations and their effects on daily life. Furthermore, current diagnostic tools and emerging therapeutic options for mitigating cognitive decline will be further discussed.}, } @article {pmid41894075, year = {2026}, author = {Kuwar, OK and Tejpal, S and Sharma, V and Sharma, A and Rao, A and Attri, M and Pallavi, and Dhingra, MS}, title = {Therapeutic potential of sulforaphane in neurodegenerative diseases: mechanistic Insights into Nrf2, NF-κB, TrkB, SIRT1, MAPK, and JAK/STAT signalling pathways.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {41894075}, issn = {1573-4978}, mesh = {Humans ; *Isothiocyanates/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Sulfoxides/pharmacology/therapeutic use ; Signal Transduction/drug effects ; NF-E2-Related Factor 2/metabolism ; Animals ; Sirtuin 1/metabolism ; Oxidative Stress/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; NF-kappa B/metabolism ; Janus Kinases/metabolism ; STAT Transcription Factors/metabolism ; Receptor, trkB/metabolism ; }, abstract = {Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis, are chronic and progressive disorders distinguished by neuronal dysfunction, oxidative stress, neuroinflammation, and abnormal protein aggregation. Due to the multifactorial nature of these disorders, current pharmacotherapies provide limited symptomatic relief without altering disease progression. Sulforaphane, a naturally occurring isothiocyanate abundant in cruciferous vegetables like broccoli, has emerged as a potent neuroprotective compound owing to its pleiotropic effects on key cellular signalling pathways. This review provides a thorough overview of the mechanistic insights underlying SFN’s neuroprotective potential, with a focus on the modulation of key signalling pathways such as Nrf2/ARE, NFĸB, BDNF/TrkB, SIRT1, MAPK, and JAK/STAT. Through the activation of antioxidant defenses and suppression of inflammatory cascades, SFN effectively mitigates neuronal damage and supports cellular homeostasis. Preclinical studies consistently demonstrate SFN’s ability to attenuate oxidative stress, inhibit apoptosis, preserve mitochondrial function, and improve neurobehavioral outcomes. While limited clinical evidence supports its safety and bioactivity, further investigations are needed to establish its therapeutic utility in human populations. Overall, SFN represents a promising natural compound with significant potential for the prevention and management of neurodegenerative diseases through multi-targeted pathway modulation.}, } @article {pmid41894152, year = {2026}, author = {Kutahyalioglu, NS and Onan, N}, title = {The Relationship Between Academic Literacy and Critical Thinking Disposition on Nursing Students.}, journal = {The Journal of nursing education}, volume = {65}, number = {6}, pages = {339-347}, doi = {10.3928/01484834-20260317-02}, pmid = {41894152}, issn = {1938-2421}, mesh = {Humans ; *Thinking ; *Students, Nursing/psychology/statistics & numerical data ; Female ; Male ; Education, Nursing, Baccalaureate ; Nursing Education Research ; Young Adult ; Adult ; *Literacy ; Educational Status ; }, abstract = {BACKGROUND: Evidence-based nursing practice requires strong academic literacy (AL) and critical thinking (CT) skills, yet the link between these two competencies has not been adequately explored. This study aimed to assess nursing students' AL and CT levels and to examine the relationship between them.

METHOD: A descriptive and correlational design was used with 120 nursing students. Data was collected using a Socio-demographic Information Form, the Academic Literacy Scale (ALS), and the Critical Thinking Disposition Scale (CTDS), and analyzed through descriptive statistics and correlation analyses.

RESULTS: Students' mean ALS score was 86.54 (SD = 9.54), and the mean CTDS score was 3.85 (SD = 0.56). AL was strongly correlated with CT disposition (r = .641, p < .01). Regression analysis indicated that CT disposition explained 41% of the variance in AL (R[2] = .410).

CONCLUSION: Critical thinking significantly predicts academic literacy, underscoring the need for educational strategies that foster both skills.}, } @article {pmid41894255, year = {2026}, author = {Hirata, Y and Kobatake, Y and Koyama, H and Furuta, K and Takemori, H and Kamatari, YO}, title = {Destabilized Soluble SOD1 Species as Potential Determinants of Disease Severity in Familial Amyotrophic Lateral Sclerosis.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {8}, pages = {1469-1478}, doi = {10.1021/acschemneuro.5c00668}, pmid = {41894255}, issn = {1948-7193}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Superoxide Dismutase-1/metabolism/genetics ; Mice ; Humans ; *Superoxide Dismutase/genetics/metabolism ; Protein Folding ; Mutation/genetics ; Cell Line ; Hippocampus/metabolism ; Severity of Illness Index ; }, abstract = {Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are linked to familial amyotrophic lateral sclerosis (ALS), yet the identity of the toxic molecular species remains unclear. We investigated the relationship between protein misfolding and pathogenicity by expressing GFP-tagged wild-type and mutant SOD1 (A4V, H46R, G93A) in mouse hippocampal HT22 cells. Western blotting under nonreducing conditions suggested that A4V, associated with rapid disease progression, was largely depleted of properly folded soluble SOD1 and instead produced highly destabilized soluble species. In contrast, H46R, associated with a milder phenotype, showed a moderate reduction in properly folded soluble SOD1 and generated partially folded/native-like conformers. G93A exhibited biochemical characteristics intermediate between those of A4V and H46R. A4V also showed a pronounced loss of GFP fluorescence, indicating severe structural destabilization; the extent of fluorescence loss in A4V, G93A, and H46R broadly correlated with clinical severity. Neither CuATSM nor ebselen─targeting metal binding and disulfide formation, respectively─rescued fluorescence, suggesting broader defects in SOD1 maturation. Nevertheless, both compounds inhibited ferroptosis, a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation, in HT22 cells, indicating alternative neuroprotective mechanisms. These findings identify destabilized soluble SOD1 species as a key toxic entity in ALS and highlight the utility of GFP-tagged constructs for evaluating folding status and screening therapeutic candidates.}, } @article {pmid41895196, year = {2026}, author = {Schmidlin, D and Thaysen, EM and Platikanov, S and Xu, J and Chesa, MJ and Tauler, R and Vázquez-Suñé, E and Teixidó, M}, title = {Impact of the superblock model on key components of the urban water cycle: Trace metals and dissolved organic matter dynamics across the built environment.}, journal = {Journal of hazardous materials}, volume = {508}, number = {}, pages = {141867}, doi = {10.1016/j.jhazmat.2026.141867}, pmid = {41895196}, issn = {1873-3336}, abstract = {Climate change, growing urban pollution, and increasing water scarcity are forcing cities to adopt strategies that enhance resilience to both climatic and anthropogenic pressures. The Barcelona Superblock model is a novel urban planning strategy that highly restricts vehicle traffic, converts streets into pedestrian-priority corridors, and promotes green spaces. Within this framework, green infrastructures, also called sustainable urban drainage systems (SUDS), are implemented as local, site-specific measures to capture (i.e., flood control), treat, and infiltrate treated stormwater (i.e., aquifer recharge). To evaluate the Superblock model impact on urban water quality, we conducted seven sampling campaigns across three Barcelona districts, targeting rainfall, stormwater "first-flush" from roads and pedestrianized streets, as well as SUDS influent and effluent within and in the vicinity to Superblocks, with a focus on dissolved trace metals and dissolved organic matter (DOM). Results showed that Superblocks reduced pollutant loads and mitigated ecotoxicological risks. Trace metal and DOM concentrations followed the trend: Rain < SUDS effluent < Pedestrian Street runoff < Road runoff, highlighting traffic-related impacts and SUDS treatment capacity (23-70% in best case scenario). Risk assessment indicated episodic ecotoxicological risk in stormwater, especially in road runoff due to elevated concentrations of Cu and Zn, while SUDS consistently remained below risk thresholds. SUDS also transform DOM into more stable, humic-like forms. Trace metals and DOM emerged as biogeochemical proxies for stormwater quality, enabling more effective and sustainable urban water management. These findings support the integration of Superblock-like strategies into urban planning to control and reduce contaminant urban discharges.}, } @article {pmid41895273, year = {2026}, author = {Kim, D and Kondo, T and Inoue, H}, title = {Dissecting microglial contributions to neurodegenerative disease pathophysiology using human pluripotent stem cells.}, journal = {Stem cell reports}, volume = {21}, number = {4}, pages = {102866}, pmid = {41895273}, issn = {2213-6711}, mesh = {Humans ; *Microglia/metabolism/pathology/cytology ; *Neurodegenerative Diseases/physiopathology/pathology/metabolism ; Animals ; *Induced Pluripotent Stem Cells/metabolism/cytology ; Cell Differentiation ; *Pluripotent Stem Cells/metabolism/cytology ; }, abstract = {Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss. Microglia, the brain's resident macrophages, are key contributors to disease pathogenesis, with many genetic risk variants enriched in microglia-specific genes. While rodent models have provided valuable insights, human induced pluripotent stem cell (iPSC) and embryonic stem cell (ESC) technologies now enable the generation of human microglia-like cells, offering a physiologically relevant platform to study human microglial biology. This review discusses the developmental origins and functions of microglia, current differentiation approaches, and how these models help elucidate disease-relevant phenotypes and molecular mechanisms in neurodegeneration.}, } @article {pmid41895675, year = {2026}, author = {Barthes, R and Niérat, MC and Rivals, I and Gatignol, P and Raux, M and Faure, M and Bruneteau, G and Serresse, L and Morélot-Panzini, C and Similowski, T}, title = {Association between dyspnea and cognitive task performance in amyotrophic lateral sclerosis: An exploratory study.}, journal = {Respiratory physiology & neurobiology}, volume = {342}, number = {}, pages = {104566}, doi = {10.1016/j.resp.2026.104566}, pmid = {41895675}, issn = {1878-1519}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/psychology ; *Dyspnea/physiopathology/etiology/psychology/complications/therapy ; Male ; Female ; Middle Aged ; Electroencephalography ; Aged ; *Cognition/physiology ; Neuropsychological Tests ; *Cognition Disorders/etiology ; Noninvasive Ventilation ; Severity of Illness Index ; Respiratory Insufficiency/physiopathology ; }, abstract = {Dyspnea is a major sensory and emotional burden in patients with chronic respiratory insufficiency. While experimentally induced acute dyspnea has been shown to interfere with cognition in healthy participants, interferences between cognition and chronic clinical dyspnea have not been studied. We conducted an exploratory study to examine the association between dyspnea severity and cognitive performance in patients with amyotrophic lateral sclerosis (ALS) and chronic respiratory failure. Twenty patients were studied during unassisted breathing and during non-invasive ventilation (NIV). Dyspnea was assessed using the Multidimensional Dyspnea Profile, and cognitive performance was evaluated using the Paced Auditory Serial Addition Test (PASAT) and the Corsi block-tapping test. Respiratory-related cortical activity was assessed using electroencephalography. Linear mixed-effects models were used to examine associations between dyspnea descriptors and cognitive outcomes, adjusting for age, educational level, and disease severity. NIV markedly relieved dyspnea, anxiety, and respiratory-related cortical activity but was not associated with changes in cognitive performance. Dyspnea unpleasantness was independently associated with longer PASAT response time, whereas no associations were observed with PASAT accuracy measures or Corsi test outcomes. Neither ventilation condition nor respiratory-related cortical activity was associated with cognitive performance. These findings suggest that, in patients with ALS, dyspnea unpleasantness may be associated with slower PASAT response time without detectable relationships with other cognitive measures assessed in this study. Given the exploratory and focal nature of the study, further investigations are warranted to better characterize dyspnea-cognition interactions in this population.}, } @article {pmid41896845, year = {2026}, author = {Chang, J and Lipscombe, H and Lv, J and McCombe, PA and Henderson, RD and Ngo, ST and Steyn, FJ and Shaw, TB}, title = {White matter changes in reward circuits of amyotrophic lateral sclerosis: a fixel-based study of appetite loss.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {41896845}, issn = {1741-7015}, support = {UQ Graduate School Scholarship (RTP)//University of Queensland/ ; Scott Sullivan MND Research Fellowship//University of Queensland/ ; Faculty of Medicine//University of Queensland/ ; TU2201//Motor Neurone Disease Research Australia/ ; PDF2112//Motor Neurone Disease Research Australia/ ; Scott Sullivan MND Research Fellowship//Royal Brisbane and Women's Hospital Foundation/ ; Scott Sullivan MND Research Fellowship//MND and Me Foundation/ ; Scott Sullivan MND Research Fellowship//FightMND/ ; Collaborative Initiative Grant//FightMND/ ; 2017-07//Wesley Medical Research/ ; APP2029871//National Health and Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/pathology ; *White Matter/diagnostic imaging/pathology/physiopathology ; Case-Control Studies ; Female ; Male ; Middle Aged ; *Reward ; Aged ; Appetite ; }, abstract = {BACKGROUND: Non-motor symptoms such as appetite loss contribute to weight and fat mass reduction in people living with Amyotrophic Lateral Sclerosis (plwALS), both of which are strong prognostic factors in the disease. Consequently, understanding the neural mechanisms underlying appetite and other non-motor disturbances in ALS is of significant clinical concern. Previous studies highlight widespread grey and white matter involvement beyond the motor system, including hypothalamic volume loss and functional changes in reward-related regions. However, it remains unclear whether structural alterations in white matter tracts implicated in reward processing and behaviour contribute to the multisystem pathology of ALS.

METHODS: In this case-control study, we employ fixel-based analysis to examine changes in fibre characteristics of non-motor and motor tracts and their associations with clinical, anthropometric, and appetite-related measures within plwALS. Thirty-two plwALS and 24 non-neurodegenerative disease (NND) controls underwent multiband diffusion and structural imaging. Fixel-based analysis was conducted using MRtrix3 to model fibre pathways. For group-level statistical contrasts, fixels were generated in a common template space. We considered case-control differences, appetite, metabolism, body composition, and clinical measures.

RESULTS: Results reveal reductions in fibre density and cross-section in the corticospinal/corticobulbar and cerebellothalamic tracts. Exploratory analyses identified fibre density cross-section reductions throughout the temporo-ponto-cerebellar tract, the medial forebrain bundle, and the uncinate fasciculus. Though no direct associations were observed between fibre characteristics and measures of appetite or metabolism, we found significant correlation between fibre cross-section of the corticospinal/corticobulbar tracts and fat-free mass in NND controls, but not in plwALS. Furthermore, disease severity was associated with reduced fibre cross-section in the corticospinal/corticobulbar tract, medial forebrain bundle, uncinate fasciculus, and the temporopontine tract.

CONCLUSIONS: These findings highlight white matter fibre alterations in both motor and non-motor circuits in ALS. Although direct associations with appetite and metabolism were not observed, the results provide evidence of structural degeneration within reward- and behaviour-related pathways. Taken together, these findings reinforce that ALS is not confined to motor pathways but represents a multisystem neurodegenerative disease with both motor and extra-motor network involvement, offering important insights for future research into disease mechanisms and therapeutic targets.}, } @article {pmid41897327, year = {2026}, author = {Romano, R and Ruotolo, G and Perrone, F and Tomaselli, S and Mazzoni, M and Spataro, R and Conforti, FL and Rosati, J and Bucci, C}, title = {Selective Silencing of TDP-43 P. G376D Mutation Reverses Key Amyotrophic Lateral Sclerosis-Related Cellular Deficits.}, journal = {Biomolecules}, volume = {16}, number = {3}, pages = {}, pmid = {41897327}, issn = {2218-273X}, support = {PRIN2022 N. 2022XTM2S3//Ministero dell'università e della ricerca/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *DNA-Binding Proteins/genetics/metabolism ; Motor Neurons/metabolism/pathology ; RNA, Small Interfering/genetics ; Induced Pluripotent Stem Cells/metabolism ; *Mutation ; Oxidative Stress ; Cell Survival/genetics ; *Gene Silencing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease for which there is currently no cure. Dominant mutations in the TARDBP gene are causative of ALS. In particular, the p. G376D substitution in TDP-43 causes familial ALS and it is associated with TDP-43 mislocalization in the cytosol, increased presence of cytoplasmic aggregates, and lysosomal and mitochondrial dysfunction. We previously designed a small interfering RNA (siRNA) that specifically targets and silences the mutant allele and we demonstrated that, in patient-derived fibroblasts, it can reduce TDP-43 aggregation, decrease oxidative stress, and improve cell viability. Here, we investigated the ability of this siRNA to revert some ALS-associated pathological phenotypes in motor neurons derived from induced pluripotent stem cells (iPSCs), as motor neurons are the primary cells affected in ALS. siRNA treatment reduced TDP-43 mislocalization, enhanced lysosomal function and cell viability, and decreased oxidative stress. These findings indicate that this allele-specific siRNA effectively reverses key ALS-related cellular deficits in motor neurons, representing a promising candidate for targeted therapy in patients carrying the TDP-43 G376D mutation.}, } @article {pmid41898328, year = {2026}, author = {Nesci, S}, title = {Mitochondrial Dysfunction in the Inflammatory Process of Neurodegenerative Diseases.}, journal = {Biomedicines}, volume = {14}, number = {3}, pages = {}, pmid = {41898328}, issn = {2227-9059}, abstract = {Neurodegenerative diseases share a mitochondrial-immune axis in which impaired oxidative phosphorylation reshapes neuronal metabolism and drives chronic inflammation. Complex I play a redox gatekeeper role at the coenzyme Q (CoQ) junction: catalytic defects, misassembly, or reverse electron transport over-reduce the CoQ pool, increase electron leak, and elevate ROS. How respiratory supercomplex plasticity (CI-CIII2, CIII2-CIVn, or CI-CIII2-CIVn) modulates carrier channelling, flux control, and ROS propensity through dynamic reorganization of the electron transport chain is highlighted. Excess ROS damages lipids and mitochondrial DNA, promoting the release of mitochondrial damage-associated molecular patterns s that activate NLRP3 inflammasome signalling, cGAS-STING-dependent interferon programs, and endosomal TLR9 pathways, establishing feed-forward loops between mitochondrial injury and neuroinflammation. Disease-focused sections integrate evidence from Parkinson's, Alzheimer's, amyotrophic lateral sclerosis, and Huntington's models, and map these mechanisms onto therapeutic opportunities spanning electron transport chain support, supercomplex stabilization, and consider mtDNA-sensing inflammatory nodes.}, } @article {pmid41898412, year = {2026}, author = {Rakovskaya, A and Volkova, E and Pchitskaya, E}, title = {Neuronal Calcium Signaling and Cytoskeletal Dynamics in Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {27}, number = {6}, pages = {}, pmid = {41898412}, issn = {1422-0067}, support = {25-74-10019//Russian Science Foundation/ ; }, mesh = {Humans ; *Cytoskeleton/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Calcium Signaling ; *Neurons/metabolism/pathology ; Calcium/metabolism ; Dendritic Spines/metabolism ; }, abstract = {Neuronal function relies on the precise coordination between intracellular calcium (Ca[2+]) signaling and the cytoskeletal architecture that underpins synaptic transmission, plasticity, and structural stability. Disruption of this calcium-cytoskeleton interplay has been noted in numerous neurodegenerative diseases. We discuss how Ca[2+]-dependent cytoskeletal remodeling governs long-term potentiation and depression, dendritic spine morphology, and presynaptic function, highlighting the functions of end-binding proteins, STIM (Stromal Interaction Molecule)/Orai-mediated store-operated calcium entry, and the spine apparatus. Disease-specific manifestations of cytoskeletal-calcium dysregulation are reviewed across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, tauopathies, and prion disorders. Finally, we evaluate emerging therapeutic strategies targeting calcium homeostasis, cytoskeletal dynamics, and their downstream effectors, including multi-target approaches.}, } @article {pmid41898662, year = {2026}, author = {Katz, M and Robertson, T and Ngo, ST and Yarlagadda, S and Henderson, RD and McCombe, PA and Noakes, PG}, title = {Review of the Pathology of Muscle in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {6}, pages = {}, pmid = {41898662}, issn = {1422-0067}, support = {DIS-202403-01216//Fight MND/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Animals ; *Muscle, Skeletal/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Neuromuscular Junction/pathology/metabolism ; Disease Models, Animal ; }, abstract = {In amyotrophic lateral sclerosis (ALS), a central event is the withdrawal of the motor nerve terminal from its target muscle. Whether this defect is driven by faults in the motor neuron or faults that originate within the muscle remains an area of investigation. In this review, we focus on the pathological abnormalities that are found in skeletal muscle, focusing, when possible, on human ALS, with support from ALS animal models. We begin with an overview of skeletal muscle, including a review of muscle fiber type, motor units and the neuromuscular synapse. Next, we provide a description of the clinical and biomarker changes that occur in the muscles of patients with ALS. We provide an extensive account of the histopathological changes that are evident in ALS muscle, such as fiber type grouping, muscle inflammation, protein misfolding, mitochondrial dysfunction, and alterations in neuromuscular junctions and muscle satellite cells. Our review then concludes with an update of metabolic and molecular-genetic changes that are found in ALS muscle. The evidence shows that muscle can be an additional target for therapy in ALS, in combination with therapies targeting neurons and glia within the central nervous system (CNS).}, } @article {pmid41899342, year = {2026}, author = {Hermann, M and Stoiber, A and Schmid, A and Hamp, T and Santos, AA and Grassmann, D and Krammel, M and Lintschinger, JM and Ulbing, S and Stria, A and Hafner, C}, title = {Relevance of Reversible Causes of Out-of-Hospital Cardiac Arrest: The "REBECCA" Interactive Checklist.}, journal = {Journal of clinical medicine}, volume = {15}, number = {6}, pages = {}, pmid = {41899342}, issn = {2077-0383}, abstract = {Background/Objectives: Adequate cardiopulmonary resuscitation (CPR), defibrillation, and treatment of reversible causes are essential for improving the survival of patients suffering from out-of-hospital cardiac arrests (OHCAs). The Advanced Life Support (ALS) algorithm includes reversible causes for cardiac arrest. This study aimed to develop an interactive mobile checklist to identify reversible causes of OHCA (REBECCA) and evaluate their usability and usefulness among emergency physicians. Methods: This mixed-methods study was conducted at the Emergency Medical Service Vienna, Austria. All participants were emergency physicians from the Medical University of Vienna. An interactive mobile checklist was developed using a participatory design approach involving a focus group of 10 emergency physicians. Usability and applicability were assessed using structured questionnaires. Descriptive statistics were used to summarize participant characteristics and evaluation outcomes. Results: Among the included participants, 70% were specialists with a median prehospital experience of 2.0 (1.0-4.3) years. Although most participants were confident about their level of professional experience with OHCA, 85% still found the checklist to be helpful. The majority of the participants preferred the digital checklist over the paper-based checklist and appreciated its integration with the point-of-care ultrasound (POCUS) application. Although the participants did not communicate a significant need for further details on most causes, a small majority favored more information on intoxication and electrolyte disorders. Conclusions: The majority of the included emergency physicians found the REBECCA checklist helpful regardless of training level, whereas almost no physician needed further detailed information on the reversible causes. Our findings underscore the potential importance of future investigations aiming to reduce the cognitive load of emergency physicians during OHCA scenarios.}, } @article {pmid41900026, year = {2026}, author = {Jamerlan, A and Hulme, J}, title = {Chemical and Molecular Strategies in Restoring Autophagic Flux in TDP-43 Proteinopathy.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {6}, pages = {}, pmid = {41900026}, issn = {1420-3049}, support = {RS-2025-02292973//Korea Institute of Marine Science and Technology Promotion/ ; RS-2021-NR060117//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Autophagy/drug effects ; *TDP-43 Proteinopathies/metabolism/drug therapy/pathology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; Lysosomes/metabolism ; Proteolysis Targeting Chimera ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Oligonucleotides, Antisense/therapeutic use/pharmacology ; }, abstract = {The cytoplasmic accumulation of TDP-43 aggregates remains a persistent pathological hallmark of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The cell's natural clearance mechanisms, the Ubiquitin-Proteasome System (UPS) and the autophagy-lysosome pathway (ALP), are hypothesized to fail, at least in part, due to the sequestration of key components of these pathways by pathological TDP-43 species, thereby impairing autophagosome-lysosome fusion and lysosomal competence. Classical autophagic activators (e.g., rapamycin) can initiate upstream steps in the pathway but cannot address downstream flux bottlenecks, limiting their ability to restore effective TDP-43 clearance. This review revisits classical strategies and discusses newer approaches to modulate TDP-43 clearance, including transcription factor EB (TFEB) activators, proteolysis-targeting chimeras (PROTACs), and antisense oligonucleotides (ASOs). We propose that adopting multi-targeting strategies and developing better biomarkers are vital for clinical success.}, } @article {pmid41900140, year = {2026}, author = {Krzymiński, K and Zadykowicz, B and Czechowska, J and Rudnicki-Velasquez, P and Serdiuk, I and Sieradzan, AK and Holec-Gąsior, L}, title = {Acridinium Chemiluminogenic Labels-Synthesis, Analytical Performance, and Mechanism of Light Generation-A Comparison in View of Biomedical Diagnostics.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {6}, pages = {}, pmid = {41900140}, issn = {1420-3049}, support = {2011/03/D/ST4/02419//National Science Centre/ ; }, mesh = {Humans ; *Acridines/chemistry/chemical synthesis ; *Luminescent Measurements/methods ; Luminescence ; Surface-Active Agents/chemistry ; Immunoassay/methods ; Immunoglobulin G/chemistry ; }, abstract = {This paper presents the synthesis, physicochemical characterisation, and analytical applications of chemiluminescent (CL) labels based on acridinium salts (ALs) for biomedical diagnostics. These compounds emit light as a result of oxidative reactions and represent an established class of reagents widely employed in chemiluminescence immunochemical assays (CLIAs) today. A series of structurally differentiated acridinium labels (AL1-AL5) was synthesised applying mostly original synthetic routes and purified to chromatographic purity (>90%, RP-HPLC). The compounds, including a commercial product treated as a reference, were successfully conjugated to anti-human IgG, yielding stable immunochemical reagents suitable for immunoassays with CL detection. The chemiluminescence properties of the obtained labels and their protein conjugates were investigated in aqueous buffers and in the presence of surfactants. The emission profiles exhibited characteristic flash-type kinetics with emission maxima occurring within 0.15-0.25 s after reaction initiation. The presence of surfactants more or less significantly enhanced the emission intensity, with signal increases of up to approx. 2-fold compared to surfactant-free systems. Analytical calibration demonstrated a linear response of signal derived from native labels over at least one order of magnitude of concentration, with detection limits falling in the range of 10[-9]-10[-10] M, confirming the high sensitivity of the developed compounds. The experimental results were supported by theoretical studies using density functional theory (DFT), which confirmed the energetic feasibility of the CL reaction pathway and identified structural factors influencing activation barriers. Additional semiempirical calculations (PM7) indicated that the dielectric environment and proximity of ionic species can influence the reaction energetics, providing mechanistic support for the experimentally observed effects of surfactants. The results demonstrate that both molecular structure and microenvironment influence CL efficiency and kinetics of the investigated systems. The developed acridinium labels exhibit analytical performance better or comparable to commercial reagents and are fully compatible with standard immunodiagnostic conjugation protocols, confirming their suitability for use in modern chemiluminescent immunoassays.}, } @article {pmid41900340, year = {2026}, author = {Iungin, O and Potters, G and Kalinichenko, O and Prekrasna-Kviatkovska, Y and Moshynets, O and Kazakov-Kravchenko, O and Sidorenko, M and Okhmat, O and Mickevičius, S}, title = {Temperature-Dependent Biofilm Development in Antarctic Endophytic Microbial Communities.}, journal = {Microorganisms}, volume = {14}, number = {3}, pages = {}, pmid = {41900340}, issn = {2076-2607}, support = {0124U003829//National Antarctic Scientific Center of Ukraine/ ; 0125U003135//National Antarctic Scientific Center of Ukraine/ ; 984834//NATO SPS/ ; }, abstract = {Climate change is reshaping Antarctic ecosystems, where the resilience of Deschampsia antarctica and Colobanthus quitensis is mediated by endophytic microbial communities assembled under strong abiotic drivers. This study explores the temperature-dependent biofilm development in two Antarctic endophytic microbial communities (ALS and LS). Multivariate analysis revealed a fundamental trade-off between planktonic expansion and biofilm matrix investment as a function of thermal cues. While moderate warming (15-25 °C) optimized cell viability and turbidity, extreme thermal stress at 37-42 °C in nutrient-rich conditions triggered a significant shift toward a matrix-rich signature, characterized by a synergistic increase in total DNA and cellulose. Crucially, at the thermal extreme of 42 °C, we observed a decoupling of optical density from culturable biomass, where high turbidity did not translate into viable cells, signaling a state of severe environmental stress. These results identify 25 °C as the quantitative threshold for optimal growth, while temperatures of 37-42 °C act as a specific trigger for protective matrix production. Such thermal plasticity suggests that Antarctic endophytes are evolutionarily primed for persistence not only in cold native niches but also during bird-mediated dispersal at endothermic host temperatures.}, } @article {pmid41900568, year = {2026}, author = {Kostadinova-Slaveva, A and Savov, V and Antov, P and Malcheva, B and Todorova, E and Yusein, J and Dudeva, V and Ivanov, G}, title = {Aesthetic Profiling and Exploratory Composting Screening of Wood-Fiber Biocomposites Bonded with Spent Coffee Grounds and Ammonium Lignosulfonate.}, journal = {Materials (Basel, Switzerland)}, volume = {19}, number = {6}, pages = {}, pmid = {41900568}, issn = {1996-1944}, support = {BG16RFPR002-1.014-0015//European Regional Development Fund through Bulgarian Programme "Research, Innovation and Digitalisation for Smart Transformation"/ ; }, abstract = {Spent coffee grounds (SCGs) and lignin-derived binders, such as ammonium lignosulfonate (ALS), are increasingly being explored as renewable resources to reduce reliance on conventional formaldehyde-based resins in wood-fiber biocomposites. Although prior work has shown that SCG-ALS adhesive systems can achieve promising mechanical performance, two practical aspects essential for industrial applications and circular design remain insufficiently explored: a predictable and reproducible visual appearance and credible end-of-life options. In this study, sustainable wood-fiber biocomposites bonded with SCG and ALS were assessed from an aesthetic performance and end-of-life perspective. Color was quantified in the CIE L*a*b* (CIELAB) space and expressed as total color difference (ΔE*) relative to a reference panel. Increasing total SCG + ALS content from 40 to 75 wt.% based on oven-dry fibers produced pronounced darkening, with lightness decreasing from L* = 47.1 to 34.3 and ΔE* increasing from 18.38 to 32.51. Short-term composting behavior was explored by embedding fragments from formulations with 40-60 wt.% total SCG + ALS (based on oven-dry fibers; equal SCG/ALS shares) into a mixed organic substrate adjusted to an initial C/N ≈ 30 and monitored for 30 days in pots and trays. The process remained predominantly mesophilic (≈14-22 °C); nevertheless, visible microbial colonization and progressive surface degradation were observed, indicating susceptibility to biological activity under moist, nutrient-rich conditions. Overall, the results show that SCG-ALS content strongly governs the visual identity of the biocomposites and suggest composting-oriented routes as a potential end-of-life direction at an exploratory level, while highlighting the need for standardized compostability assessment and longer-term monitoring to substantiate circularity claims.}, } @article {pmid41900684, year = {2026}, author = {Pigato, M and Agresti, F and Benato, A and Bucci, C and Calliari, I and Cortis, D and D'Eramo, S and Fu, S and Giancarli, C and Pezzato, L and Zambon, A and D'Addabbo, A}, title = {Microstructural and Mechanical Characterization of Ultra-Pure Aluminum for Low-Amplitude-Vibration Cryogenic Applications.}, journal = {Materials (Basel, Switzerland)}, volume = {19}, number = {6}, pages = {}, pmid = {41900684}, issn = {1996-1944}, support = {2022KRKM2X//Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale/ ; }, abstract = {In fundamental physics, sensors operating below liquid helium temperatures are highly vulnerable to vibrations, which can affect the sensitivity, for example, of high-performance particle detectors. Pulse-tube refrigerators, while generating vibrations lower than those of conventional systems, may still introduce several disturbances. Hence, flexible thermal connections are a commonly used mechanical solution to mitigate these undesirable effects. Among the materials that can be used, ultra-high-purity aluminum (UHP-Al) has attracted the attention for low-amplitude-vibration cryogenic applications, including gravitational wave interferometry, quantum information systems, precision space instrumentation, and cryogenic resonators. Thus, the aim of the paper is the characterization of the mechanical and microstructure properties of three UHP-Als (i.e., 5N-99.999 wt%, 5N5-99.9995 wt% and 6N-99.9999 wt%) intended for the production of thermal flexible connections with low stiffness, specifically designed to reduce vibration transmission in cryogenic environments. Mechanical properties were evaluated through standard tensile tests from room (+25 °C) to low temperature (i.e., -150 °C), providing insights into yield strength, ultimate tensile strength, elongation and elastic modulus. In addition, the dynamic elastic modulus of material loads, at cryogenic conditions (i.e., about -180 °C), was determined by measuring the natural resonance frequency, thereby assessing the material's response to vibrational. Moreover, an extensive microstructural analysis was conducted using electron backscatter diffraction and x-ray diffraction. The correlation between the observed microstructure and the elastic properties was systematically examined. The results underscore the pivotal role of microstructural characteristics in dictating the elastic behavior of UHP Als. Eventually, the analysis provides valuable guidelines for the materials employment inside cryogenic systems, where severe vibration control is critical to maintain high operational performance.}, } @article {pmid41901170, year = {2026}, author = {Kwaśniewska, K and Fic, W and Polak-Szczybyło, E}, title = {Vitamins as Modulators of Neurodegenerative Disease Pathways: Mechanisms and Therapeutic Perspectives.}, journal = {Nutrients}, volume = {18}, number = {6}, pages = {}, pmid = {41901170}, issn = {2072-6643}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Vitamins/administration & dosage/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; *Dietary Supplements ; Antioxidants ; *Neuroprotective Agents ; Animals ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, currently represent one of the major challenges in contemporary medicine and geriatrics. Progressive degeneration of the nervous system affects not only patients' physical functioning but also their psychosocial well-being, often leading to social isolation and disruption of interpersonal relationships. These processes are most strongly associated with individuals over 65 years of age, in whom metabolic syndrome is frequently diagnosed and constitutes a significant factor predisposing them to the exacerbation of neuropathological changes. This review analyzes the role of selected vitamins in modulating the course of neurodegenerative disorders, with particular emphasis on their neuroprotective potential. Specific attention is given to their involvement in antioxidant defense mechanisms, regulation of inflammatory pathways, prevention of abnormal protein aggregation, participation in neurotransmitter synthesis, and support of mitochondrial function and cellular energy metabolism. The review also considers key interactions between vitamins and coenzyme Q10, which synergistically enhance neuroprotective mechanisms. Deficiencies in certain vitamins may exacerbate oxidative stress, impair synaptic transmission, and intensify neuroinflammatory responses, thereby contributing to disease progression. The study analyzes the available data on therapeutic doses of vitamins and compares them with the recommended dietary intake and the upper tolerable intake levels (UL). The available evidence suggests that personalized vitamin supplementation, when integrated with a well-balanced and nutrient-dense diet, may constitute a valuable adjunctive therapeutic strategy. Such an approach may help attenuate disease progression, support neuronal integrity, and improve functional outcomes. Ultimately, targeted nutritional interventions may enhance overall well-being and quality of life in patients affected by neurodegenerative diseases.}, } @article {pmid41903716, year = {2026}, author = {Alam, Z and Nguyen, KT and Lauck, KC and Malick, H and Tolkachjov, SN}, title = {Response to Newell et al's "commentary on 'DPP4 inhibitor use and skin cancer risk in type 2 diabetes'".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {2}, pages = {e157-e158}, doi = {10.1016/j.jaad.2026.03.073}, pmid = {41903716}, issn = {1097-6787}, } @article {pmid41903799, year = {2026}, author = {Chamorro-Muñoz, MI and Afkir-Ortega, MN and Aguilar-Monge, A}, title = {Impact of care by a multidisciplinary team on the assessment of cognitive aspects and decision-making at the end of life in a Spanish population with amyotrophic lateral sclerosis.}, journal = {Neurologia}, volume = {41}, number = {5}, pages = {501950}, doi = {10.1016/j.nrleng.2026.501950}, pmid = {41903799}, issn = {2173-5808}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; *Terminal Care/methods ; Spain ; Female ; Retrospective Studies ; *Patient Care Team ; *Decision Making ; Male ; Aged ; Middle Aged ; Longitudinal Studies ; *Cognition ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a disease with a fatal course, often associated with unassessed cognitive-behavioural disturbances, and very relevant end-of-life care decisions. The aim of this study is to verify whether multidisciplinary team care for ALS patients in our setting has modified the cognitive assessment and the end-of-life decision making, compared to a model of uncoordinated specialist care.

METHODS: An observational, longitudinal, retrospective study was conducted on a cohort of patients with probable or definite ALS, in a referral hospital, between 1 January 2000 and 31 December 2022, differentiating whether they were treated before or after the implementation of a multidisciplinary model. We analysed the performance of cognitive assessment, the use of riluzole, gastrostomy, non-invasive ventilation and invasive ventilation, and the recording of patients' decisions regarding the care they wished to receive. Comparisons between variables were performed using the chi-square test or Fisher exact test.

RESULTS: We evaluated 47 patients seen by uncoordinated specialists and 146 with a multidisciplinary model. Patients cared for using the multidisciplinary model were more frequently cognitively assessed (55.48% vs 12.8%, P < .001), diagnosed with dementia (11.6% vs 2.3%, P < .048), and had their advance directives recorded (56.8% vs 23.4%, P < .001). We found no differences in the use of advanced interventions, except for invasive ventilation, which was only performed in the context of multidisciplinary care.

CONCLUSIONS: The multidisciplinary model of care for ALS patients in our setting has improved cognitive assessment, promoted the registration of their advance directives, and thus helped to improve respect for their autonomous decisions and dignity.}, } @article {pmid41903869, year = {2026}, author = {Yang, Y and Yang, Y and Zhang, X and Ma, H and Ji, S and Zou, F and Yu, X and Du, G and Zhu, X and Tian, J}, title = {Targeting ME1 rescues redox-metabolic coordination in ALS: A core effector of NRF2-directed therapy.}, journal = {Neuropharmacology}, volume = {293}, number = {}, pages = {110940}, doi = {10.1016/j.neuropharm.2026.110940}, pmid = {41903869}, issn = {1873-7064}, mesh = {Animals ; *NF-E2-Related Factor 2/metabolism/agonists ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Mice, Transgenic ; Oxidative Stress/drug effects ; Mice ; Oxidation-Reduction/drug effects ; Kelch-Like ECH-Associated Protein 1/metabolism ; Disease Models, Animal ; Superoxide Dismutase-1/genetics ; Humans ; Mitochondria/drug effects/metabolism ; Neuroprotective Agents/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, muscle weakness, and respiratory failure, with dysregulated energy metabolism and oxidative stress representing core pathological features. Epidemiological studies indicate geographical variations in incidence, and recent multi-omics evidence identifies a hypermetabolic state and mitochondrial dysfunction as key drivers of disease progression. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), which regulates antioxidant response and metabolism, represents a promising therapeutic target; however, the exploration of specific activators remains insufficient. This study evaluated the efficacy and mechanism of a novel KEAP1-NRF2 activator, MKL01351, in SOD1 G93A transgenic mice and NSC-34 motor neuron-like ALS models. Behavioral analyses demonstrated that MKL01351 significantly delayed disease onset, improved motor coordination in the rotarod and hanging tests, and extended survival. The compound alleviated oxidative stress by reducing malondialdehyde (MDA) levels and restoring the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, while also ameliorating the energy deficit by modulating glycolytic and mitochondrial functions, as confirmed by Seahorse analysis. Mechanistic investigations revealed that MKL01351 activated the NRF2 pathway, upregulating downstream targets such as NQO1 and HO-1, and specifically enhanced the expression of malic enzyme 1 (ME1). Loss-of-function experiments confirmed that ME1 knockdown abolished the protective effects, indicating that the NRF2-ME1 axis is a central hub for the synergistic regulation of metabolic and oxidative homeostasis. In conclusion, MKL01351 concurrently ameliorates oxidative stress and metabolic dysregulation via the NRF2-ME1 signaling pathway, offering a novel neuroprotective strategy for ALS treatment.}, } @article {pmid41904003, year = {2026}, author = {Kinger, S and Choudhary, A and Kumar, P and Jagtap, YA and Sharma, V and Dhiman, R and Prasad, A and Verma, R and Chinnathambi, S and Mishra, A}, title = {Molecular chaperones mediated proteostasis depletion: A cause of neurodegeneration?.}, journal = {Advances in protein chemistry and structural biology}, volume = {150}, number = {}, pages = {181-219}, doi = {10.1016/bs.apcsb.2025.10.033}, pmid = {41904003}, issn = {1876-1631}, mesh = {Humans ; *Proteostasis ; *Neurodegenerative Diseases/metabolism/pathology ; *Molecular Chaperones/metabolism ; Animals ; Proteotoxic Stress ; }, abstract = {Protein homeostasis is a critical aspect of cellular homeostasis as proteins are one of the most diverse biomolecules, responsible for multiple molecular and cellular functions. Protein quality control machinery is essential for maintaining integrity of cellular proteome via regulating its synthesis, structure, function, and degradation. Molecular chaperones are central to the protein quality control apparatus of cells and assist in folding nascent polypeptides, maturation, sequestration, solubilisation, and degradation of proteins. The coordination and cooperation between multiple cellular chaperones and other quality control elements, such as ubiquitin-proteasome system and autophagy, form a network, critical for proteostasis. Disturbed proteostasis and protein aggregation are hallmark features of neurodegenerative diseases. Re-establishing cellular proteostasis and enhancing chaperones' levels and functions can alleviate protein aggregation and associated cytotoxicity. Here, we have explored the potential of abundant cellular chaperone Hsp90, large chaperone Hsp110, small chaperone Hsp27, and anti-oxidant and mitoprotective chaperone DJ-1 in the regulation of proteostasis, with implications for neurodegenerative diseases, Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis. We have focused on roles and mechanisms of function of these chaperones in countering disturbed proteostasis in neurodegenerative disorders.}, } @article {pmid41904009, year = {2026}, author = {Chinnathambi, S and Malik, S}, title = {Cytoskeltal intermediate filaments in Tau pathology and neurodegeneration.}, journal = {Advances in protein chemistry and structural biology}, volume = {150}, number = {}, pages = {351-376}, doi = {10.1016/bs.apcsb.2025.10.028}, pmid = {41904009}, issn = {1876-1631}, mesh = {Humans ; *Intermediate Filaments/metabolism/pathology ; *tau Proteins/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Intermediate Filament Proteins/metabolism ; *Alzheimer Disease/metabolism/pathology ; *Cytoskeleton/metabolism/pathology ; }, abstract = {Intermediate filaments are cytoskeletal proteins that are vital for proper cell structure formation and functioning. There are six types of these proteins. Type I includes acidic keratins, Type II includes basic and neutral keratins, both of which are present in epithelial cells. Type III includes vimentin, desmin, glial fibrillary acidic protein and peripherin, among which the last two are highly involved in neurodegenerative diseases. Type IV includes three types of neurofilament proteins, NF-L, NF-M and NF-H, where L signifies light, M signifies medium and H signifies heavy. The fourth protein in this category is α-internexin. All of these proteins are highly involved in neurodegenerative diseases, especially the neurofilament proteins. The type V intermediate filament proteins are lamins. The type VI intermediate filaments are nestins. Their involvement in a variety of neurodegenerative diseases has been observed, including Alzheimer's disease, Cerebral Ischemia, Multiple Sclerosis, Alexander Disease, Neuronal IF inclusion disease (NIFID) and Amyotrophic Lateral Sclerosis (ALS). Alzheimer's disease is a neurodegenerative disease in which two proteins are mainly involved, the Tau protein and the Amyloid-β protein. This review discusses the crosstalk of the intermediate filament proteins with the pathological proteins involved in the neurodegenerative diseases. For the case of the Alzheimer's disease, many of the intermediate filament proteins are involved in the disease pathology and are vital markers for the disease. One of the category of proteins involved is neurofilaments, among which NF-L is a marker for the disease. Keratin 9 and the glial fibrillary acidic protein (GFAP) are other intermediate filament proteins that are being explored as markers for the Alzheimer's disease.}, } @article {pmid41904011, year = {2026}, author = {Selvaraj, C and Desai, D and Sumitha, E}, title = {The quest to restore neuronal structure: Targeting cytoskeletal proteins in neurodegenerative diseases.}, journal = {Advances in protein chemistry and structural biology}, volume = {150}, number = {}, pages = {397-422}, doi = {10.1016/bs.apcsb.2025.10.026}, pmid = {41904011}, issn = {1876-1631}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/therapy/drug therapy ; *Neurons/metabolism/pathology ; *Cytoskeletal Proteins/metabolism/genetics ; Animals ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease are characterized by progressive neuronal dysfunction and loss. A growing body of evidence implicates cytoskeletal disruption as a central pathological mechanism in these conditions. Cytoskeletal proteins, including microtubules, actin filaments, tau, neurofilaments, and alpha-synuclein, not only provide structural integrity but also regulate axonal transport, synaptic connectivity, and neuroplasticity. Its dysfunction will lead to impaired intracellular trafficking, protein aggregation, and neuronal degeneration. This chapter explores clearly about the specific cytoskeletal abnormalities that are evident in major neurodegenerative disorders, highlighting the biological mechanisms such as tauopathy-induced microtubule instability in Alzheimer's, actin cytoskeleton dysregulation in Parkinson's, and neurofilament aggregation in ALS. Current therapeutic strategies aimed at the stabilizing cytoskeletal components, enhancing protein clearance, and restoring transport dynamics are examined, alongside the cutting-edge approaches including the gene therapy, CRISPR/Cas9 editing, and nanotechnology-based delivery systems. Challenges such as limited blood-brain barrier penetration, off-target toxicity, and patient heterogeneity are also discussed with the focus on need for precision medicine. Additionally, we have also explored the future directions that specifically focused on the biomarker development, combination therapies, and strategies to promote neuroregeneration and structural plasticity. Targeting cytoskeletal pathways holds significant promise not only for suppressing the disease progression but also for rebuilding the structural foundation of the nervous system, potentially reversing the neurodegenerative decline.}, } @article {pmid41904090, year = {2026}, author = {Haidar, M and Viden, A and Daniel, C and Cuic, B and Wang, T and Rosier, M and Tomas, D and Mills, SA and Govier-Cole, A and Djouma, E and Perera, ND and Luikinga, S and Rytova, V and Barton, SK and Gonsalvez, DG and Palmer, LM and McLean, C and Kiernan, MC and Vucic, S and Turner, BJ}, title = {Corrigendum to "Cortical hyperexcitability drives dying forward amyotrophic lateral sclerosis symptoms and pathology in mice"[Prog. Neurobiol. 252 (2025) 102809].}, journal = {Progress in neurobiology}, volume = {260}, number = {}, pages = {102910}, doi = {10.1016/j.pneurobio.2026.102910}, pmid = {41904090}, issn = {1873-5118}, } @article {pmid41905172, year = {2026}, author = {Balaji, R and Joshi, H and Patel, BK}, title = {Elucidating the conformational dynamics of the mitochondrial localization signal, M3, of TDP-43 and accessing potential binders using molecular docking and simulation.}, journal = {Computational biology and chemistry}, volume = {123}, number = {}, pages = {109029}, doi = {10.1016/j.compbiolchem.2026.109029}, pmid = {41905172}, issn = {1476-928X}, mesh = {*DNA-Binding Proteins/chemistry/metabolism ; *Molecular Docking Simulation ; *Molecular Dynamics Simulation ; Humans ; *Mitochondria/metabolism ; Protein Conformation ; }, abstract = {Aberrant mitochondrial localization of RNA/DNA-binding protein TDP-43 is implicated in amyotrophic lateral sclerosis (ALS), which may affect mitochondrial dynamics and contribute to neuronal toxicity. Inhibitors of the cytoplasmic aggregation of TDP-43 were reported previously, but their effect on the mitochondrial mislocalization of TDP-43 remains to be investigated. Three internal peptide sequences from TDP-43, M1, M3, and M5, were found to enable TDP-43's mitochondrial localization. The peptides carrying these sequences thwarted mitochondrial import of TDP-43 and rescued TDP-43-induced cytotoxicity to neurons. In the current study, we aimed to assess the repurposing potential of 2115 FDA-approved small molecules for binding to the M3 region of TDP-43 (aa: 146-150) through virtual screening. The M3 region is present in the RNA-recognition motif-1 (RRM-1); hence, multiple all-atom molecular dynamics (MD) simulations, with two different starting conformations, of the tandem RRM1-2 domains of TDP-43 in explicit solvent water were performed to understand the dynamics of the target M3 region. The analysis of the simulation trajectories suggests that the M3 region is relatively non-flexible and buried relative to the other regions of the tandem RRM1-2 domains. Cholecalciferol (Vitamin D3), as identified through virtual screening, consistently docked with the M3 region across various docking strategies, despite the region's poor accessibility in most conformations. Vitamin D3 also remained stably bound to the M3 region in most frames of four replica MD simulations, each of one microsecond. Taken together, our study proposes vitamin D3 as a potential binder to the M3 region, which may inhibit the pathogenic mitochondrial mislocalization of TDP-43.}, } @article {pmid41905471, year = {2026}, author = {Kuiper, MM and Cuppers, L and Sewell-Green, A and Kruithof, WJ and Visser-Meily, JMA and Beelen, A}, title = {Criterion validity of equations as alternatives to reference standards for assessing body composition and energy expenditure in amyotrophic lateral sclerosis - A systematic literature review.}, journal = {Clinical nutrition ESPEN}, volume = {73}, number = {}, pages = {103262}, doi = {10.1016/j.clnesp.2026.103262}, pmid = {41905471}, issn = {2405-4577}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Body Composition ; *Energy Metabolism ; Nutritional Status ; Reference Standards ; Reproducibility of Results ; Electric Impedance ; Nutrition Assessment ; Malnutrition/diagnosis/etiology ; Anthropometry/methods ; }, abstract = {BACKGROUND & AIM: People living with amyotrophic lateral sclerosis (ALS) are at high risk of malnutrition, making it essential to monitor their nutritional status through measurements of body composition and energy expenditure. However, validity of equations, as alternatives to reference standards for assessing these parameters in ALS, is unclear. This systematic review evaluates criterion validity of equations to estimate body composition and energy expenditure in ALS.

METHODS: Four electronic databases (EMBASE, MEDLINE, CINAHL and Cochrane) were systematically searched from inception until July 7th, 2025. Studies were included if criterion validity of an instrument or method for estimating body composition or energy expenditure was examined in people diagnosed with ALS. Methodological quality was assessed using the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) risk of bias checklist. Criterion validity was rated as sufficient (+), indeterminate (?) or insufficient (-) based on COSMIN criteria for good measurement properties. Results were qualitatively summarised.

RESULTS: Twelve studies were included: five evaluated the criterion validity of equations to estimate body composition using Bioelectrical Impedance Analysis (BIA) or anthropometry, and seven to estimate resting or total daily energy expenditure. No equation was rated as sufficient for criterion validity across studies.

CONCLUSION: Equations to estimate body composition and energy expenditure should be applied with caution, as no equation exhibited high criterion validity in ALS. ALS-specific equations require further validation, and ideally, new equations tailored to the unique physiological characteristics of ALS should be developed.

PROSPERO REGISTRATION NUMBER: CRD42024573509.}, } @article {pmid41905645, year = {2026}, author = {Martín-Sánchez, FJ and Marcos Sastre, MC and Muñoz de Maya, E and Sánchez-Pinto Pinto, B and Trueba Vicente, Á and Artero Ortiz, J and Arribas Guerrero, J and Soto Vargas, N and García Sánchez, IM and Marco Martínez, J and , }, title = {Six months of experience at a specialized daytime care center for people with amyotrophic lateral sclerosis (ALS) in the Community of Madrid.}, journal = {Neurologia}, volume = {41}, number = {5}, pages = {502006}, doi = {10.1016/j.nrleng.2026.502006}, pmid = {41905645}, issn = {2173-5808}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Spain ; Male ; Retrospective Studies ; Aged ; Female ; Middle Aged ; Quality of Life ; Patient Satisfaction ; Riluzole/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, leading to motor deterioration and a reduced quality of life. In the Community of Madrid, the ALS Network was established to improve patient care. In April 2024, the Specialised Day Care Centre for ALS (CEADELA) was inaugurated, complementing the care provided by the ALS Network. The aim of this study was to describe the experience of CEADELA during its first six months.

MATERIALS AND METHODS: A retrospective descriptive study was conducted on a cohort of CEADELA patients between April and October 2024. Clinical, functional, and therapeutic data were analysed, along with overall satisfaction levels.

RESULTS: A total of 91 patients were included, with a mean age of 65.2 years (SD 11); of these, 59 (64.8%) were men. Most had spinal-onset ALS and were receiving treatment with riluzole. A significant increase was observed in the use of physiotherapy, speech therapy, and occupational therapy after referral to the centre. Functionality significantly declined over six months. The mortality rate was 12.1% (18.2% opted for assisted dying). Overall, 76 patients (83.5%) responded to the survey, with 100% reporting satisfaction or high satisfaction with the centre (80.2% very satisfied and 18.4% satisfied).

CONCLUSIONS: CEADELA has improved access to specialised therapies with a high level of satisfaction, although disease progression remains a challenge. The need to continue developing integrated, evidence-based care models to optimise ALS management is highlighted.}, } @article {pmid41906032, year = {2026}, author = {Abdelaal, Z and Boya, BR and Lee, JH and Lee, J}, title = {Targeting Als3 adhesin of clinically relevant Candida species using natural carotenoids: an in-silico study.}, journal = {Molecular diversity}, volume = {30}, number = {4}, pages = {6221-6237}, pmid = {41906032}, issn = {1573-501X}, support = {RS-2025-00513239//the National Research Foundation of Korea (NRF)/ ; }, mesh = {Molecular Docking Simulation ; *Fungal Proteins/chemistry/metabolism/antagonists & inhibitors ; *Carotenoids/pharmacology/chemistry ; *Candida/drug effects/metabolism ; *Antifungal Agents/pharmacology/chemistry ; Protein Binding ; Candida albicans/drug effects ; Computer Simulation ; Binding Sites ; Biofilms/drug effects ; }, abstract = {Candidemia, caused by the opportunistic Candida spp., poses a severe global health threat, characterized by mortality rates reaching 75% and the increasing prevalence of multidrug-resistant biofilms. In this study, we targeted the Agglutinin-Like Sequence 3 (Als3) adhesin protein, the primary mediator of Candida species attachment, as a non-lethal strategy to inhibit biofilm formation. Using molecular docking, we screened a library of 1570 natural carotenoids against the conserved N-terminal domain of Als3 of Candida albicans and compared to five positive controls. Our virtual screening identified five compounds (mangicrocin, MODU, α-zeacarotene-3,17'-diol, BTTB, and (15Z)-zeaxanthin-3'-rhamnoside), with the best binding pose and the least binding energy. Among them, mangicrocin showed best binding affinity (docking score - 7.18 kcal/mol, ΔGbind - 35.23 kcal/mol) against C. albicans Als3, compared to the in vitro and in silico positive control, rutin (docking score - 5.772 kcal/mol, ΔGbind - 30.59). It consistently achieved the best docking scores across C. albicans Als family proteins (Als1 and Als5) and Als3 proteins of other species in the Candida genus like C. auris, C. tropicalis, C. parapsilosis, and C. dubliniensis. Molecular electrostatic potential (MESP) mapping analysis further clarified that the hydrophobic polyene backbone and the negative electrostatic potential of the OH groups on the aromatic rings aid in anchorage to the key cadherin-binding residues-Lys59 and Ser170 in the Als3 binding pocket. Density Functional Theory (DFT) analysis shows high electrophilicity and a narrow energy gap contributes to mangicrocin's interactions and chemical reactivity. Molecular dynamics simulations suggested stable retention of mangicrocin within the Als3 binding pocket, supported by stable structural parameters and favorable interaction energy profiles. In silico ADMET profiling concludes these top five hits had limited toxicity and are druggable. As this study is entirely computational, these findings are predictive and require future in vitro validation to confirm biological efficacy.}, } @article {pmid41906147, year = {2026}, author = {Zhou, X and Yu, P and Shen, X}, title = {m6A RNA methylation in neural plasticity, brain aging, and neurodegenerative vulnerability.}, journal = {Molecular brain}, volume = {19}, number = {1}, pages = {}, pmid = {41906147}, issn = {1756-6606}, support = {82471208 and 82171184//National Natural Science Foundation of China/ ; }, mesh = {*RNA Methylation ; Humans ; *Aging/genetics ; Animals ; *Neuronal Plasticity/genetics ; *Brain/pathology/metabolism/physiopathology ; *Neurodegenerative Diseases/genetics/pathology ; Epitranscriptome ; }, abstract = {m6A is a pervasive post-transcriptional RNA modification that regulates RNA splicing, stability, localization, and translation in the brain. In this review, we outline the core m6A regulatory machinery and summarize its spatial organization across neurons and glial cells, highlighting established roles in brain development, synapse formation, and axon growth. We then focus on experience-dependent plasticity, synthesizing evidence that neuronal activity and environmental inputs dynamically reshape m6A to regulate immediate-early transcription and local translation at synapses across sensory, cognitive, emotional, and motor domains. With aging, m6A programs are reconfigured in a cell-type-specific manner, a shift associated with reduced plasticity and increased vulnerability. We further survey disease-associated alterations in m6A across Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke-related cognitive impairment, ALS and FTD, as well as metal or toxin exposure, emphasizing convergent effects on dopaminergic and glutamatergic signaling, synaptic integrity, inflammation, and cellular stress responses. Finally, we discuss emerging opportunities and conceptual challenges in targeting m6A enzymes or reader proteins, and outline priorities for future work, including cell-type- and subcellular-resolved mapping, causal perturbation in defined circuits and life stages, and the development of biomarkers and selective modulators. Together, these observations position m6A as a molecular interface linking experience-dependent plasticity, brain aging, and neurodegenerative vulnerability.}, } @article {pmid41906403, year = {2026}, author = {Correale, J}, title = {Glial Plasticity and Dysfunction: Mechanistic Insights and Therapeutic Opportunities in Neurodegeneration.}, journal = {Journal of neurochemistry}, volume = {170}, number = {4}, pages = {e70414}, doi = {10.1111/jnc.70414}, pmid = {41906403}, issn = {1471-4159}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; *Neuroglia/metabolism/pathology ; *Neuronal Plasticity/physiology ; *Cell Plasticity/physiology ; }, abstract = {Recent advances, including single-cell transcriptomics, lineage tracing, and in vivo imaging, have unveiled the heterogeneity, plasticity, and functional versatility of astrocytes, microglia, oligodendrocytes, and Schwann cells. These cells respond to metabolic and immune cues, participate in synaptic regulation, and provide metabolic and trophic support to neurons. Their dual roles in neuroprotection and neurodegeneration underscore the complexity of their contributions across CNS disorders. This review examines the diverse physiological and pathological roles of glia, emphasizing their involvement in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Mechanisms including metabolic dysfunction, inflammatory polarization, glial-immune crosstalk, and extracellular vesicle-mediated signaling are critically discussed. Emerging therapeutic strategies, ranging from glial reprogramming and senolytic therapies to the use of engineered extracellular vesicles and metabolic modulators, are evaluated for their potential to harness glial plasticity and mitigate disease progression. The review also outlines current challenges in translating glial biology into clinical interventions, including cellular heterogeneity, delivery barriers, and the need for specific biomarkers. A glia-centered therapeutic paradigm offers promising avenues to restore CNS homeostasis and promote regeneration in neurodegenerative diseases.}, } @article {pmid41906714, year = {2026}, author = {Schellenberg, KL and Nataraj, R}, title = {Reviewer Comment on Li et al. "Nocturnal Hypoxia and Sleep-Disordered Breathing as Potential Early Biomarkers of Respiratory Progression in Mild ALS".}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1}, doi = {10.1017/cjn.2026.10558}, pmid = {41906714}, issn = {0317-1671}, } @article {pmid41907197, year = {2026}, author = {Elshony, H and Almuhanna, R and Albazli, KO and Muddassir, R}, title = {Hereditary transthyretin amyloidosis mimicking ALS: First genetically proven case report from Saudi Arabia.}, journal = {eNeurologicalSci}, volume = {43}, number = {}, pages = {100607}, pmid = {41907197}, issn = {2405-6502}, abstract = {BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is a systemic disorder that may mimic motor neuron disease (MND), leading to misdiagnosis and delayed access to disease-modifying therapies.

CASE REPORT: We report the first genetically confirmed case of ATTRv mimicking amyotrophic lateral sclerosis (ALS) in Saudi Arabia. A 47-year-old male presented with progressive right-sided limb weakness (proximal > distal) and dysarthria over 18 months. Neurological examination revealed fasciculations, distal atrophy, and brisk reflexes with normal muscle tone and no spasticity. Electrophysiological studies demonstrated a length-dependent sensorimotor axonal neuropathy with widespread denervation changes involving bulbar, cervical, and lumbosacral regions. Brain and spine MRI, along with whole-body CT, excluded structural or paraneoplastic causes. Genetic testing identified a pathogenic heterozygous variant in the TTR gene: NM_000371.4:c.424G > A (p.Val142Ile). Transthoracic echocardiography revealed mild concentric left ventricular hypertrophy. There was no clinical evidence of autonomic, renal, or ocular involvement.

DISCUSSION: This case underscores the importance of considering ATTRv in patients presenting with atypical MND, particularly when clinically significant sensory symptoms, absent upper motor neuron signs, or unexplained cardiac abnormalities are present. Early diagnosis enables access to targeted therapies such as TTR stabilizers and gene-silencing agents, which can alter disease trajectory.}, } @article {pmid41907482, year = {2026}, author = {Pham, N and Nguyen, CTH and Van, TT}, title = {Response to Brenaut et al., "Response to Pham et al's 'Sensory symptoms of scalp psoriasis are not sensitive scalp syndrome'".}, journal = {JAAD international}, volume = {25}, number = {}, pages = {139}, pmid = {41907482}, issn = {2666-3287}, } @article {pmid41907560, year = {2026}, author = {Ozgor, B and Goktas, OF and Baygin, M and Dogan, S and Tuncer, T}, title = {Differential quadruple pattern: A new EEG signal classification framework.}, journal = {IBRO neuroscience reports}, volume = {20}, number = {}, pages = {492-505}, pmid = {41907560}, issn = {2667-2421}, abstract = {EEG signals are the letters of the brain and reflect neural activity. Abnormal EEG patterns indicate brain disorders such as epilepsy. Recently, machine learning has enabled automated EEG interpretation with high accuracy. This study introduces an explainable EEG classification model based on feature engineering. A novel feature extractor, Differential Quadruple Pattern (DiffQuadPat), is proposed. DiffQuadPat computes relations between four channel values using difference-based transformations and combinational transition tables. Feature selection is performed by Cumulative Weight Neighborhood Component Analysis (CWNCA), and classification is achieved with t-algorithm-based k-Nearest Neighbors (tkNN). For interpretability, Directed Lobish (DLOB) is used to produce symbolic explanations. The proposed DiffQuadPat-centric XFE framework was validated on two EEG datasets: Amyotrophic Lateral Sclerosis (ALS) and neonatal epilepsy detection. The model achieved over 98% accuracy under 10-fold cross-validation. Furthermore, cortical and hemispheric connectome diagrams were generated, enabling transparent visualization of brain-level interactions.}, } @article {pmid41909467, year = {2026}, author = {Nagamatsu, Y and Umezu, T and Hong, T and Niijima, T and Ohno, SI and Harada, Y and Kanekura, K and Ochiya, T and Kuroda, M}, title = {Exosome-like nanovesicles from acerola for CRISPR-Cas9 ribonucleoprotein delivery to the central nervous system.}, journal = {Molecular therapy. Nucleic acids}, volume = {37}, number = {2}, pages = {102896}, pmid = {41909467}, issn = {2162-2531}, abstract = {An aberrant six-base repeat in intron 1 of C9orf72 is the most frequent cause of solitary and familial amyotrophic lateral sclerosis and frontotemporal dementia. This mutation is a potential target for CRISPR/Cas9-based genome editing. However, the blood-brain barrier and limitations of current viral or nanoparticle-based delivery systems to neurons significantly restrict the clinical application of CRISPR-Cas9 in the brain. To address these challenges, we developed a drug delivery system using acerola-derived exosome-like nanoparticles (AELNs), which may overcome several limitations associated with human exosomes. AELNs stably form complexes with ribonucleoproteins (RNPs) comprised of Cas9 proteins and guide RNAs (gRNAs). We improved the delivery efficiency and selectivity of AELN/RNP complexes in GLP2-receptor-expressing neurons by incorporating GLP2 peptides into the AELN/RNP complexes. Intranasal administration of peptide-tagged AELN/RNP complexes in vivo confirmed the successful genome editing of C9orf72, demonstrating the potential of this system for treating neurodegenerative diseases. This study presents a potentially innovative approach for in vivo genome editing using a noninvasive delivery system.}, } @article {pmid41909487, year = {2026}, author = {Gowdy, J and Ahn, J and Miller, RH and Islam, Y}, title = {Neurovascular dysfunction in the development and progression of neuroinflammatory diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {20}, number = {}, pages = {1741928}, pmid = {41909487}, issn = {1662-5102}, abstract = {The neurovascular unit (NVU) is critical for brain homeostasis through its roles in maintenance of an effective blood brain barrier (BBB) and regulation of cerebral blood flow. Perturbation of the NVU is a hallmark of the pathology of multiple neurodegenerative diseases resulting in loss of BBB integrity, neuroinflammation and neuronal dysfunction. The NVU is a complex structure composed of endothelial cells, pericytes, as well as central nervous system (CNS) glial and neuronal components. While the importance of the CNS vasculature in health and disease is well established, the mechanisms underlying vascular pathology and its contributions to neurodegenerative diseases are less well defined. Neuroinflammation and reactive gliosis occurs in the majority of neurodegenerative diseases and recent studies suggest that immune mediated disruption of the BBB contributes to the induction of reactive gliosis and neuronal dysfunction. Potential consequences of NVU disruption include immune-driven vascular inflammation and leukocyte infiltration in Multiple Sclerosis (MS), protease-mediated tight junction degradation in ischemic stroke (IS), α-synuclein-associated endothelial dysfunction in Parkinson's Disease (PD), amyloid-β- and tau-induced pericyte injury in Alzheimer's Disease (AD), and complement-mediated vascular damage in Amyotrophic Lateral Sclerosis (ALS). Here we review the nature of NVU perturbations in these common neurodegenerative diseases, with an emphasis on the contribution of immune modulation of BBB disruption in neuropathology and disease progression.}, } @article {pmid41910849, year = {2026}, author = {Akram, SW and K, C}, title = {Enhancing Parkinson's Disease Staging: An Integrative Deep Learning Framework for Multimodal Feature Selection.}, journal = {Journal of molecular neuroscience : MN}, volume = {76}, number = {2}, pages = {}, pmid = {41910849}, issn = {1559-1166}, mesh = {Humans ; *Parkinson Disease/diagnostic imaging/genetics/diagnosis/pathology ; *Deep Learning ; Neuroimaging/methods ; Multilayer Perceptrons ; Support Vector Machine ; Particle Swarm Optimization ; }, abstract = {Parkinson's disease (PD) affects 10 million globally, with accurate staging essential for personalized treatment planning. Current UPDRS assessments achieve < 93% accuracy due to subjective clinical judgment and unimodal data limitations, failing to capture complex genetic-neuroimaging-clinical interactions driving disease heterogeneity. This study introduces MAFNet, a novel deep learning framework pioneering Iterative Adaptive Vold-Kalman Filter (IAVKF) temporal denoising, Accelerated Binary Particle Swarm Optimization (ABPSO) swarm feature selection, Multilayer Perceptron-Lagrangian Support Vector Machine (MLP-LSVM) classification, and Graph-Attention Based Multimodal Fusion Network (GAMF). Applied to PPMI cohort (200 patients) with genetic SNPs (50), neuroimaging voxels (1,024), and UPDRS-III scores, the end-to-end pipeline delivers 97.6% accuracy, 98.2% precision, 96.8% recall, and 97.3% F1-score-outperforming CNN (92.4%), Autoencoder (90.8%), InceptoFormer (96.6%), and HCT (97.0%). IAVKF boosts SNR + 15.2dB (+ 2.9% accuracy vs. PCA/t-SNE); ABPSO reduces 1,276→340 features (73% reduction); regularization cuts overfitting gap to 0.9% (vs. 4.2% baseline). SHAP interpretability validates clinical plausibility (top predictors: LRRK2 SNPs, UPDRS-III tremor, hippocampal volume). Five-fold CV confirms stability with the Indian cohort external validation. Real-time inference (0.2s/patient, RTX 3090) enables clinical deployment. Future scope includes longitudinal temporal modelling, modality-agnostic fusion, edge deployment, federated learning, and extension to Alzheimer's/ALS. MAFNet transforms PD staging from subjective assessments to objective precision medicine, enabling biomarker discovery, progression forecasting, and personalized therapies across diverse global populations.}, } @article {pmid41910875, year = {2026}, author = {Rajagopalan, V and Pioro, EP}, title = {Diffusion network model analysis of multimodal neuroimaging reveals differential patterns of brain disease propagation in four subgroups of ALS patients.}, journal = {Brain imaging and behavior}, volume = {20}, number = {2}, pages = {}, pmid = {41910875}, issn = {1931-7565}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/physiopathology ; Female ; Male ; *Brain/diagnostic imaging/pathology ; Aged ; Middle Aged ; Disease Progression ; Multimodal Imaging/methods ; Gray Matter/diagnostic imaging/pathology ; Positron-Emission Tomography ; Neuroimaging/methods ; Magnetic Resonance Imaging ; White Matter/diagnostic imaging/pathology ; Frontotemporal Dementia/diagnostic imaging/pathology ; Cross-Sectional Studies ; Atrophy ; Diffusion Magnetic Resonance Imaging ; Pyramidal Tracts/diagnostic imaging/pathology ; }, abstract = {Four different subtypes of amyotrophic lateral sclerosis (ALS) were identified based on their clinical and magnetic resonance imaging (MRI) findings, including: (a) classic ALS (ALS-Cl) (b) upper motor neuron (UMN)-predominant ALS with corticospinal tract (CST) hyperintensity (ALS-CST+), (c) UMN-predominant ALS without CST hyperintensity (ALS-CST–), and (d) ALS with frontotemporal dementia (ALS-FTD). These phenotypes also showed differences in symptom duration, disease progression rate, revised ALS functional rating scale score and El Escorial score.Network diffusion model (NDM) is a computational approach that can identify disease epicenters based on brain gray matter (GM) atrophy and white matter (WM) structural connectome from cross-sectional MRI. Although previous NDM MRI studies have considered ALS patients as a single group, we examined whether the above-mentioned phenotypes display subgroup-specific site of disease onset, and whether the latter differs between positron emission tomography -revealed hypo- and hypermetabolic brain regions in ALS-FTD patients. Clinical evaluation and cross-sectional MRI of 83 patients with differing presentations of ALS were assigned into one of four subgroups, and NDM applied to the data.Both ALS-CST + and ALS-CST– subgroups showed the putamen as epicenter for GM atrophy and superior frontal gyrus (orbital part) as epicenter for WM disconnection. The ALS-Cl subgroup also showed the putamen as epicenter for GM degeneration but the inferior parietal gyrus (excluding supramarginal and angular gyri) for WM disconnection, the latter overlapping with ALS-FTD patients. However, epicenters for structural and functional GM degeneration in the ALS-FTD subgroup were different. These results suggest differential patterns of GM and WM degeneration onset between the four ALS subgroups.}, } @article {pmid41911331, year = {2026}, author = {Kwan, JY and Lantz, CI and Korobeynikov, VA and Snyder, A and Huang, X and Haselhuhn, T and Dore, KN and Madruga, A and Danielian, LE and Schindler, AB and Chia, R and Rasheed, M and Crook, J and Szabo, M and Portley, M and Sherer, CM and King, MC and Huang, TH and Kosa, P and Bielekova, B and Ward, ME and Grunseich, C and Shneider, NA and Traynor, BJ and Narendra, DP}, title = {Clinical and biochemical characterization of amyotrophic lateral sclerosis in a CHCHD10 R15L family.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag115}, pmid = {41911331}, issn = {1460-2156}, abstract = {Familial forms of ALS are potential candidates for gene-directed therapies, but many recently identified genes remain poorly characterized. Here, we provide a comprehensive clinical, neuropathological, and biochemical description of fALS caused by the heterozygous p.R15L missense mutation in the gene CHCHD10. Using a cross-sectional study design, we evaluated five affected and nine unaffected individuals from a large seven-generation pedigree with at least 68 affected members. The pedigree suggests a high (68 - 81%) but incomplete disease penetrance. Through cloning of the disease-allele from distant members of the family, we establish the disease haplotype in the family. Notably, the haplotype was distinct from that of a previously reported p.R15L mutation carrier with ALS, demonstrating that the variant is in a mutational hotspot. The clinical presentation was notable for being highly stereotyped; all affected individuals presented with the rare ALS variant Flail Arm Syndrome (FAS; also known as, brachial amyotrophic diplegia or Vulpian-Bernhardt Syndrome), suggesting greater involvement of the cervical spinal cord. Consistently, neuropathology from one family member demonstrated substantially increased CHCHD10 protein aggregation and neuronal loss (though absent TDP-43 pathology) in the cervical vs. lumbar spinal cord. This FAS phenotype could be captured by a simple timed finger tapping task, suggesting potential utility for this task as a clinical biomarker. Additionally, through analysis of fibroblast lines from 12 mutation carriers, isogenic iPSC cells, and a knockin mouse model, we determined that CHCHD10 with the R15L variant is stably expressed and retains substantial function both in cultured cells and in vivo, in contrast to prior reports. Conversely, we find loss of function (LoF) variants are more common in the population but are not associated with a highly penetrant form of ALS in the UK Biobank (31 in controls; 0 in cases). Together, this argues against LoF and in favor of toxic gain-of-function as the mechanism of disease pathogenesis, similar to the myopathy-causing variants in CHCHD10 (p.G58R and p.S59L). Finally, through proteomic analysis of CSF of variant carriers, we identify that CHCHD10 protein levels are elevated approximately 4-fold in mutation carriers, and that affected and unaffected individuals are differentiated by elevation of two neurofilaments: neurofilament light chain (NfL) and Peripherin (PRPH). Collectively, our findings help set the stage for gene-directed therapy for a devasting form of fALS, by establishing the likely disease mechanism and identifying clinical and fluid biomarkers for target engagement and treatment response.}, } @article {pmid41911483, year = {2026}, author = {Nusir, A and Anthony, SM and Zhou, W and Kabbani, N}, title = {Microglial Adaptations to Chronic Nicotine in the Cerebellum: Proteomic Evidence for Neuroimmune Vulnerability.}, journal = {Journal of proteome research}, volume = {25}, number = {5}, pages = {2359-2373}, pmid = {41911483}, issn = {1535-3907}, mesh = {Animals ; *Nicotine/pharmacology ; Male ; *Microglia/drug effects/metabolism/immunology ; Female ; *Cerebellum/drug effects/metabolism/immunology ; Mice ; Proteomics/methods ; *Proteome/drug effects/immunology/metabolism/genetics ; Mice, Inbred C57BL ; Adaptation, Physiological/drug effects ; }, abstract = {Smoking is a major public health concern with widespread effects on multiple organ systems, including the immune system. Chronic nicotine exposure can alter immune cell function through nicotinic receptors expressed on peripheral macrophages and microglia in the brain. Recent evidence indicates that the cerebellum is impacted by nicotine, contributing to motor and nonmotor outcomes, during drug use. In this study, we investigated the effect of chronic nicotine on microglia proteomes in the adult mouse cerebellum. Microglia were isolated by fluorescence-activated cell sorting (FACS) based on CD11b[high] CD45[low/intermediate] expression from male and female mice (n = 9 per group) exposed to 200 μg/mL nicotine (dissolved in 2% saccharin drinking water) for 30 days. Proteomic analysis was performed using liquid chromatography electrospray ionization (LC-ESI) mass spectrometry (MS) comparing the effect of nicotine relative to vehicle control. Our results reveal a sex-dependent effect of nicotine on microglial proteomes. While both males and females exhibited histone-related genomic responsiveness to nicotine, males demonstrated enrichment in cytoskeletal and metabolic proteins, and females showed complement-protein adaptations. The microglial proteome in male mice displayed nicotine-related adaptations in proteins that can contribute to neurodisorders including Huntington's disease and amyotrophic lateral sclerosis (ALS), of which smoking is a known risk factor. Together, these results highlight an effect of nicotine on the proteome of microglia providing insight into immune pathways that can contribute to smoking-related behavior and disease.}, } @article {pmid41911992, year = {2026}, author = {Di Napoli, G and Alfurno, L and Fissore, A and Raccuia, E and Olivieri, P and Marengo, M and Oliaro-Bosso, S and Piaz, FD and Catucci, G and Gilardi, G and Velazquez-Campoy, A and Prischi, F and De Simone, A and Spyrakis, F and Di Palma, F and Adinolfi, S}, title = {Calcium as a molecular switch that regulates Annexin A11 N- and C-terminal domains interaction and its role in ALS.}, journal = {International journal of biological macromolecules}, volume = {358}, number = {}, pages = {151719}, doi = {10.1016/j.ijbiomac.2026.151719}, pmid = {41911992}, issn = {1879-0003}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Calcium/metabolism ; Humans ; *Annexins/chemistry/metabolism/genetics ; Protein Binding ; Mutation ; Protein Domains ; Binding Sites ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive motor neuron loss, leading to muscle paralysis and respiratory failure. Genetic mutations, notably in the ANXA11 gene, have been implicated in both familial and sporadic ALS forms. ANXA11 functions as a cellular "tether," orchestrating the transport of RNA-protein complexes and lysosomes through its N-terminal (Nt) and C-terminal (Ct) domains, respectively. This study uncovers a novel calcium-dependent regulatory mechanism governing the intramolecular interaction between these domains. Using biochemical, biophysical, and computational approaches, we suggest that in the absence of calcium, ANXA11 adopts a closed conformation with stable Nt-Ct interactions. Elevated calcium levels induce a conformational shift, disrupting this interaction and exposing binding sites for RNA and membranes. Crucially, we show that the ALS-associated D40G mutation in the Nt domain impairs this calcium-regulated interaction, favoring a persistent open conformation that predisposes to toxic protein aggregation. These findings reveal that calcium acts as a molecular switch modulating ANXA11 conformation and function, providing new insights into its role in ALS pathogenesis and potential therapeutic targets.}, } @article {pmid41912102, year = {2026}, author = {Li, A and Xiao, X and Liu, G and Li, K and Ling, Y and Deng, S and Xu, C and Cao, SQ and Wen, J and Lu, G and Yang, G and Fang, EF and Qin, D and Su, H}, title = {Isoginkgetin protects against degeneration of ALS motor neurons via regulating the GSK-3β-TFEB signaling axis.}, journal = {Pharmacological research}, volume = {227}, number = {}, pages = {108172}, pmid = {41912102}, issn = {1096-1186}, mesh = {*Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Humans ; Signal Transduction/drug effects ; *Glycogen Synthase Kinase 3 beta/metabolism ; Animals ; *Motor Neurons/drug effects/pathology/metabolism ; Lysosomes/drug effects/metabolism ; *Neuroprotective Agents/pharmacology ; Induced Pluripotent Stem Cells/drug effects ; Mice ; }, abstract = {Lysosomal dysfunction is a core pathological driver of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Transcription factor EB (TFEB) serves as a master regulator of lysosomal biogenesis, and its pharmacological activation represents a strategy to restore lysosomal function in disease and aging. Here, using a series of artificial intelligence-powered computational virtual screening workflows, we have identified isoginkgetin (ISO), a small-molecule compound, as a potent TFEB activator that promotes mechanistic target of rapamycin complex 1 (mTORC1)-independent TFEB nuclear translocation to enhance lysosomal biogenesis and function. Mechanistically, ISO functions as an ATP-competitive inhibitor that binds to the key Lys85 residue within the ATP-binding pocket of glycogen synthase kinase 3β (GSK-3β), thereby regulating the GSK-3β-TFEB signaling axis to activate TFEB nuclear translocation. Functionally, ISO improves lysosomal function and protects motor neurons differentiated from induced pluripotent stem cells derived from patients with ALS from degeneration. Collectively, these results support the hypothesis that lysosomal dysfunction is a druggable target for ALS.}, } @article {pmid41912367, year = {2026}, author = {Garbey, M and Lesport, Q and Öztosun, G and Ghodasara, V and Kaminski, HJ and Bayat, E}, title = {Authors' Response to "Comment on 'Improving Care for Amyotrophic Lateral Sclerosis with Artificial Intelligence and Affective Computing'".}, journal = {Journal of the neurological sciences}, volume = {486}, number = {}, pages = {125885}, doi = {10.1016/j.jns.2026.125885}, pmid = {41912367}, issn = {1878-5883}, } @article {pmid41912662, year = {2026}, author = {Liu, Y and Huang, Z and Hsu, YW and Deme, P and Frankenfield, AM and Wu, S and Zhao, X and Liu, H and Zhang, T and Alexander, EJ and Liu, M and Zhang, Y and Wang, H and Zhou, Y and Monteiro, MJ and Hao, L and Haughey, NJ and Wang, J}, title = {UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration.}, journal = {Nature neuroscience}, volume = {29}, number = {4}, pages = {782-795}, pmid = {41912662}, issn = {1546-1726}, support = {NS128494//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS128494/NS/NINDS NIH HHS/United States ; NS110098//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS098243/NS/NINDS NIH HHS/United States ; NS089616//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS098243//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; FS-2023-SBF-S6//Target ALS (Target ALS Foundation)/ ; NS074324//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; RF1 NS098243/NS/NINDS NIH HHS/United States ; RF1 NS074324/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Lipid Metabolism/physiology ; Mice ; *Adaptor Proteins, Signal Transducing/genetics/metabolism ; Proteotoxic Stress ; *Autophagy-Related Proteins/genetics/metabolism ; *Cell Cycle Proteins/genetics/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Neurons/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/genetics ; Frontotemporal Dementia/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Mutation ; }, abstract = {Protein homeostasis and lipid metabolism are essential processes frequently disrupted in neurodegenerative diseases. However, their mechanistic intersection in disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. Ubiquilin 2 (UBQLN2) is a protein quality control factor linked to ALS/FTD. Through multi-omic analyses of induced pluripotent stem cell (iPSC)-derived neurons harboring disease-associated UBQLN2 mutations, we uncovered UBQLN2 as a molecular hub linking lipid dysregulation and proteostasis, the perturbation of which contributes to neurodegeneration. UBQLN2 mediated the degradation of ILVBL (acetolactate synthase-like protein) and ALDH3A2 (aldehyde dehydrogenase 3 family member A2), two enzymes essential for mitochondrial lipid catabolism associated with lipid droplets and neuronal viability. ALS/FTD-linked UBQLN2 mutations and TAR DNA-binding protein 43 (TDP-43) pathology impair the degradation of ILVBL and ALDH3A2, leading to metabolic dysfunction and neurodegeneration. Restoring the UBQLN2-ILVBL/ALDH3A2 axis attenuates neurodegenerative phenotypes in neurons, organoids and mice, establishing UBQLN2 as a critical regulator of metabolic homeostasis in ALS/FTD and other related neurodegenerative diseases.}, } @article {pmid41912988, year = {2026}, author = {Zheng, H and Yu, S and Zhou, T and Fu, S and Zhang, J and Zhang, N and Liu, Y and Huang, Y and He, Z and Zhang, J and Liu, P and Gong, M and Zhou, C}, title = {Distinct amino acid metabolic subtypes predict prognosis and stratify treatment response in acute-on-chronic liver failure: a multicenter prospective study.}, journal = {Hepatology international}, volume = {20}, number = {3}, pages = {864-874}, pmid = {41912988}, issn = {1936-0541}, support = {82305067//National Natural Science Foundation of China/ ; 2018ZX10725506-002//National Science and Technology Major Project of China during the 13th Five-Year Plan Period/ ; }, mesh = {Humans ; *Acute-On-Chronic Liver Failure/mortality/therapy/metabolism/blood ; Prospective Studies ; Prognosis ; *Amino Acids/metabolism/blood ; Female ; Male ; Middle Aged ; Liver, Artificial ; Metabolomics ; Treatment Outcome ; Adult ; Aged ; }, abstract = {BACKGROUND: Acute-on-chronic liver failure (ACLF) exhibits high mortality and heterogeneity, demanding precise risk stratification. We aimed to identify metabolic subtypes and explore their association with prognosis and real-world artificial liver support (ALS) responsiveness.

METHODS: This prospective, multicenter, observational cohort study enrolled 142 ACLF patients. Serum was collected at baseline, prior to ALS initiation. Patients were subtyped via metabolomics clustering. ALS exposure was analyzed using inverse probability of treatment weighting (IPTW) and Cox models to test for heterogeneity of treatment effect.

RESULTS: Two subtypes were identified (Cluster 1/2). Cluster 2 showed significantly higher 90 day mortality (p = 0.032) and severe amino acid metabolic reprogramming, particularly in branched-chain amino acid and glutamine pathways. Exploratory analysis suggested a differential association between ALS and survival across subtypes (interaction p = 0.12). ALS showed a weaker survival association in Cluster 2 after IPTW adjustment.

CONCLUSION: ACLF patients possess distinct amino acid-based metabolic subtypes that are potent prognostic indicators. Baseline metabolic profiling can serve as a stratification tool to identify patients who may derive the greatest clinical benefit from ALS therapy, guiding personalized treatment strategies.}, } @article {pmid41913878, year = {2026}, author = {Elfadil, U and Al-Majmuei, A and Alatoom, M and Juma, S and Shukralla, A}, title = {The Impact of Preoperative Nutritional Status on the Incidence of Anastomotic Leaks in Colorectal Surgery.}, journal = {Cureus}, volume = {18}, number = {2}, pages = {e104329}, pmid = {41913878}, issn = {2168-8184}, abstract = {Anastomotic leaks (ALs) are among the most serious complications following colorectal surgery, contributing to significant morbidity, reoperation, and prolonged hospitalisation. Poor preoperative nutritional status has been proposed as a modifiable risk factor; however, evidence from studies remains inconsistent. This systematic review, conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420251034523), synthesised findings from 32 eligible studies, including randomised controlled trials, cohort studies, and case-control designs, published between 2005 and 2025. Across 474 initially identified articles, nutritional status was assessed using serum albumin, body mass index (BMI), Subjective Global Assessment (SGA), Nutritional Risk Index (NRI), or Prognostic Nutritional Index (PNI). AL incidence ranged from 2.8% to 11.3%, with hypoalbuminaemia and low nutritional indices consistently associated with increased risk. Several studies have suggested that nutritional optimisation, particularly immunonutrition and enteral support initiated 7-14 days preoperatively, improves secondary outcomes, such as wound infection rates, hospital stay, and overall morbidity. However, reductions in leak incidence are less consistent. The certainty of evidence linking poor nutritional status to leak risk was rated as moderate, while the evidence for nutritional interventions was rated as low due to heterogeneity and small sample sizes. Perioperative factors, including operative time, intraoperative blood loss, transfusion, and steroid use, were also significant contributors to leak risk. Overall, nutritional status is a key, modifiable predictor of AL; however, integration with surgical and perioperative optimisation is essential. High-quality multicentre trials are needed to define optimal nutritional strategies and establish standardised risk assessment tools for clinical practice.}, } @article {pmid41914380, year = {2026}, author = {Chen, L and Chen, EW and Chen, BW and Wang, D}, title = {Retinol Taking a Detour Promotes Neural Stem Cell Self-Renewal In Vivo Accompanied by Down-Regulation of Some Retinoic Acid Receptors.}, journal = {Stem cells and development}, volume = {35}, number = {7-8}, pages = {144-151}, doi = {10.1177/15473287261436286}, pmid = {41914380}, issn = {1557-8534}, mesh = {Animals ; *Vitamin A/pharmacology ; *Neural Stem Cells/drug effects/cytology/metabolism ; Tretinoin/pharmacology ; *Down-Regulation/drug effects ; Mice ; *Receptors, Retinoic Acid/metabolism/genetics ; *Cell Self Renewal/drug effects ; Brain/metabolism/drug effects/cytology ; Cell Differentiation/drug effects ; }, abstract = {Since our previous studies have indicated retinol promotes self-renewal of embryonic stem cells in vitro culture, we speculate that retinol may be directly involved in regulating adult stem cell self-renewal or developmental function in vivo. Vitamin A or retinoic acid (RA) solution was first injected into the abdominal cavities of mice, and then self-renewal and development marker gene expressions were investigated. The in vivo effects of retinol and RA on RA receptor expressions were further examined. The results showed that retinol not only significantly promotes self-renewal of neural stem cells in vivo but also induces orientational development of neural stem cells in vivo and significantly downregulates the expression of some RA receptor gene expression in the brain. This study provides experimental and theoretical bases for elucidating the regulation mechanism of retinol-mediated cell development in vivo, especially in brain, and the development of therapeutic drugs for neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, and Huntington's disease.}, } @article {pmid41916622, year = {2026}, author = {Addington, C and Davies, N and Howell, P and Cruickshank, S and Hainsworth, E}, title = {Lived experiences of cancer care for people living with HIV who are treated for anal cancer: a scoping review.}, journal = {BMJ open}, volume = {16}, number = {3}, pages = {e114180}, pmid = {41916622}, issn = {2044-6055}, mesh = {Humans ; *Anus Neoplasms/therapy/psychology/complications ; *HIV Infections/complications/psychology ; Quality of Life ; }, abstract = {OBJECTIVE: This scoping review aims to identify existing evidence on the lived experiences of people living with HIV and treated for anal cancer, and to identify what aspects of health and well-being are addressed in clinical guidance.

DESIGN: A preregistered protocol (Open Science Framework, 2025) guided the review. We followed the Arksey and O'Malley framework, incorporating Levac et al's refinements around stakeholder consultation. Joanna Briggs Institute (JBI) guidance informed eligibility and data for charting, and reporting adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines.

DATA SOURCES: Systematic searches were performed across multiple databases, including CINAHL, MEDLINE, PsycINFO and Embase, using EBSCOhost and Ovid, supplemented handsearching reference lists. Two search strategies were used: one for research studies and one for clinical guidelines.

ELIGIBILITY CRITERIA: Sources included people living with HIV treated for anal cancer, capturing lived experiences directly through qualitative studies or indirectly via quantitative patient-reported outcomes and/or health-related quality of life. Guidelines addressing HIV or anal cancer were also included.

DATA CHARTING AND SUMMARIES: Data were charted to capture patient experiences and outcomes on living with and beyond cancer, and how these are addressed in clinical management and guidance, including biomedical, psychosocial, sexual and functional aspects, and patient-reported outcomes.

RESULTS: Of 945 records, three studies and four guidelines met criteria. No study focused exclusively on people living with HIV; findings reflect broader anal cancer populations with HIV-positive subsets. Studies addressed aspects of health-related quality of life which we mapped into physical, psychosocial and sexual domains. Clinical guidance prioritised treatment dosage and survival, with limited attention to broader effects. Stakeholders highlighted that existing research and guidance miss important nuances of lived experience and care needs.

CONCLUSIONS: No identified research solely explored the lived experiences of people living with HIV treated for anal cancer, leaving guidance non-specific and biomedical. The identified domains offer a starting point for future research; however, to inform patient-centred care, stakeholders emphasised the need to understand how living with HIV and anal cancer shapes health needs.}, } @article {pmid41916881, year = {2026}, author = {Calma, AD and Pavey, N and Silva, CS and Tsuji, Y and Ghapar, AA and Morris, K and Kiernan, MC and Farrar, MA and Menon, P and Vucic, S}, title = {Utility of Far-Field Potentials as a Biomarker of Neurodegeneration in Spinal Muscular Atrophy.}, journal = {Muscle & nerve}, volume = {73}, number = {6}, pages = {1089-1095}, pmid = {41916881}, issn = {1097-4598}, mesh = {Humans ; *Muscular Atrophy, Spinal/physiopathology/diagnosis ; Female ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Adult ; Ulnar Nerve/physiopathology ; Biomarkers ; Aged ; *Action Potentials/physiology ; Electromyography ; Muscle, Skeletal/physiopathology ; Nerve Conduction Studies ; *Nerve Degeneration/physiopathology/diagnosis ; Motor Neurons/physiology ; }, abstract = {INTRODUCTION/AIMS: Far field potentials (FFP) have been proposed as a reliable neurophysiological prognostic biomarker in amyotrophic lateral sclerosis (ALS). This study evaluated the utility of ulnar nerve FFP as a robust research biomarker of lower motor neuron degeneration in spinal muscular atrophy (SMA).

METHODS: Peripheral neurophysiological assessments were performed in 13 participants with SMA, 19 with amyotrophic lateral sclerosis (ALS), and 19 healthy controls. The ulnar nerve was stimulated at the wrist, and motor responses were recorded over the abductor digiti minimi (ADM) muscle. Recorded measures included compound muscle action potential (CMAP), FFP and near-field potential (NFP) amplitudes, and motor unit number index (MUNIX).

RESULTS: The FFP amplitude was significantly lower in SMA participants compared to healthy volunteers (p < 0.001), but comparable to ALS (p = 0.11). The FFP amplitude showed strong correlations with the Revised Upper Limb Module (RULM) (ρ = 0.92), ALS Functional Rating Score-Revised (ρ = 0.85), upper limb MRC score (ρ = 0.89), CMAP amplitude (ρ = 0.97), NFP amplitude (ρ = 0.88), and MUNIX values (ρ = 0.84), all of which were highly statistically significant. Multiple linear regression indicated that FFP amplitude was an independent predictor of RULM (p < 0.001).

DISCUSSION: FFP amplitude appears to be a promising neurophysiological biomarker for SMA, with potential utility for monitoring disease progression, particularly in a clinical trial setting.}, } @article {pmid41917183, year = {2026}, author = {Eom, E and Kim, J and Kim, J and Kang, SJ}, title = {STING is the scaffold protein for stress granule pre-condensation at the ER.}, journal = {Cell death and differentiation}, volume = {}, number = {}, pages = {}, pmid = {41917183}, issn = {1476-5403}, support = {RS-2024-00339685//National Research Foundation of Korea (NRF)/ ; RS-2024-00339685//National Research Foundation of Korea (NRF)/ ; }, abstract = {Stress granules (SGs) are dynamic, membraneless ribonucleoprotein condensates that assemble in response to cellular stress and coordinate diverse cellular stress responses and diseases. Although SG have been reported to associate with the endoplasmic reticulum (ER), how ER-localized stress granule assembly is organized and regulated remains unclear. STING (stimulator of interferon genes) is a central innate immune adaptor that has recently been implicated in diverse non-canonical cellular functions, yet its potential link to SG regulation has not been established. Independent of its canonical functions in innate immune signaling, we identified a novel role of STING as a regulator of SG formation. We found that prior to stress stimulation, STING interacts with key SG core components G3BP1 and UBAP2L via its C-terminal domain (CTD) at the ER, forming a pre-condensation complex that facilitates SG maturation in response to stress. Loss of STING reduces SG formation and increases stress-induced cell death, whereas ER-anchored STING CTD is sufficient to reverse them. Mechanistically, STING enhances basal interactions between G3BP1 and UBAP2L, lowering the threshold for SG maturation upon stress. In addition, STING promotes the pathologic effects of TDP-43 mutations associated with amyotrophic lateral sclerosis. Our findings implicate STING as an ER-resident regulator of SG dynamics that contributes to neurodegenerative pathology, highlighting it as a potential therapeutic target in diseases associated with aberrant SG assembly.}, } @article {pmid41917198, year = {2026}, author = {Yin, H and Ren, Z and Zhang, Y and Wang, Y and Sun, Y and Fu, X and Yan, W and Zhang, F and Zeng, L}, title = {Lisinopril activates BI1 to reprogram lipid metabolism and restore autophagy in ALS.}, journal = {Communications biology}, volume = {9}, number = {1}, pages = {}, pmid = {41917198}, issn = {2399-3642}, support = {20250206017ZP//Department of Science and Technology of Jilin Province (Jilin Province Science and Technology Department)/ ; }, mesh = {Animals ; *Lipid Metabolism/drug effects ; *Lisinopril/pharmacology ; *Autophagy/drug effects ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; Mice ; *Apoptosis Regulatory Proteins/metabolism/genetics ; Humans ; Signal Transduction/drug effects ; *Membrane Proteins/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) involves disrupted lipid metabolism. Bax inhibitor 1 (BI1), an endoplasmic reticulum protein downregulated in ALS neuroprotective, represents a therapeutic target, but its metabolic regulatory mechanisms are incompletely understood. Using transcriptomics in skeletal muscle of ALS mice pre- and post-BI1 treatment, we identified BI1-regulated pathways. Structure-based virtual screening of FDA-approved compounds nominated lisinopril as a BI1 activator. Lisinopril upregulated BI1 protein expression, stabilizing mitochondrial membrane potential and protecting against SOD1[G93A]-induced apoptosis in NSC34 cells. Concurrently, it regulated TGF-β1/mTOR-dependent autophagy, maintained NMJ integrity, and reshaped triglyceride/sphingolipid/glycerophospholipid metabolism to attenuate spinal cord pathology in ALS mice, promoting energy metabolism shift toward glucose oxidation. Additionally, lisinopril inhibited the TGF-β1/Smad2/3 pathway to alleviate muscle fibrosis, downregulate Acp5/FN expression, and reduce type I collagen deposition. In conclusion, this study provides evidence that pharmacological activation of BI1 by lisinopril suppresses TGF-β1, modulates lipid metabolism, and ameliorates ALS pathology, demonstrating promising therapeutic repurposing potential.}, } @article {pmid41917433, year = {2026}, author = {Hop, PJ and Kooyman, M and Kenna, BJ and Zwamborn, RAJ and van Eijk, KR and Wang, Y and van Dijk, CH and Bekema, E and van Rheenen, W and Beele, P and van Vugt, JJFA and , and , and , and , and Khleifat, AA and Iacoangeli, A and Cooper-Knock, J and Smith, BN and Topp, S and van der Kooi, AJ and Fominykh, V and Drory, V and Lerner, Y and Shovman, Y and Rowe, DB and Williams, KL and McLaughlin, RL and Hurt, J and Huang, Y and Chen, CY and Tsai, E and Runz, H and Aronica, E and Groen, EJN and van Es, MA and Pasterkamp, RJ and Farhan, SMK and Garton, FC and McRae, AF and McCombe, PA and Henderson, RD and Fan, D and Šlachtová, L and Høyer, H and Nishimura, AL and Cauchi, RJ and Brylev, L and Rogelj, B and Koritnik, B and Zidar, J and Salas, T and Mora Pardina, JS and Gotkine, M and Povedano, M and Corcia, P and Vourc'h, P and Couratier, P and Weber, M and Kiernan, MC and Pamphlett, R and Blair, IP and de Carvalho, M and Başak, NA and Ingre, C and Andersen, PM and Zinman, L and Rogaeva, E and MacKenzie, IR and Dupre, N and Rouleau, GA and Traynor, BJ and Ticozzi, N and Chiò, A and Silani, V and Hardiman, O and Phatnani, H and Harms, MB and Dalgard, CL and Glass, JD and Landers, JE and Van Damme, P and Morrison, KE and Shaw, PJ and Shaw, CE and Al-Chalabi, A and van den Berg, LH and Kenna, KP and Veldink, JH}, title = {Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis.}, journal = {Nature genetics}, volume = {58}, number = {4}, pages = {717-725}, pmid = {41917433}, issn = {1546-1718}, support = {19-SI-459//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; ZonMW-VIDI 91719350//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; ZonMW-VIDI 91719350//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; *Exome/genetics ; *Genetic Variation ; Exome Sequencing ; Polymorphism, Single Nucleotide ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heritable disorder where rare variants with low-to-moderate penetrance are thought to dominate genetic risk. To identify such rare variants, we harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases. Rare variant analyses identified several new risk genes, with replication confirming association of YKT6 and supporting HTR3C, GBGT1 and KNTC1. We also provide strong, independent validation for genes with limited previous evidence: ARPP21, DNAJC7 and CFAP410. Notably, in ARPP21, we identified a new high-effect variant (p.P747L) and confirmed that p.P563L is an ALS-associated variant leading to an aggressive disease course. Beyond new discoveries, our analyses largely recapitulated the known genetic architecture of ALS, identifying risk variants in over 20% of cases and supporting a cumulative oligogenic risk model. These findings highlight new translational targets and show that rare variant analyses capture substantially more genetic risk than common variant genome-wide association studies.}, } @article {pmid41917466, year = {2026}, author = {Liu, Y and Song, M and Wan, L and Guo, P and Han, D}, title = {Condensate protein aggregation in ALS/FTD is regulated by GGGGCC-repeat RNA scaffolds.}, journal = {Nature structural & molecular biology}, volume = {33}, number = {4}, pages = {641-651}, pmid = {41917466}, issn = {1545-9985}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; G-Quadruplexes ; *C9orf72 Protein/genetics/metabolism/chemistry ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Humans ; *RNA/chemistry/genetics/metabolism ; *Biomolecular Condensates/metabolism/chemistry ; *Protein Aggregates ; DNA Repeat Expansion ; Nucleic Acid Conformation ; *Protein Aggregation, Pathological/genetics ; }, abstract = {Biomolecular condensates regulate essential biological processes relevant to health and disease. However, the mechanisms driving pathogenic condensate formation and their therapeutic targeting have not been fully elucidated. In amyotrophic lateral sclerosis and frontotemporal dementia caused by C9orf72 GGGGCC repeat expansions (c9ALS/FTD), the expanded repeat RNA and repeat-associated non-AUG translation products are key pathogenic factors. Here, we show that the GGGGCC-repeat RNA and poly(GR) form cocondensates in vitro and in cellulo. The G-quadruplex and hairpin structures of GGGGCC-repeat RNA act as scaffolds to accelerate liquid-to-solid phase transition and aggregation of poly(GR), with the hairpin structure promoting amorphous solid-like condensates in vitro and reducing poly(GR) mobility. The cocondensation of GGGGCC-repeat RNA and poly(GR) exacerbates nucleolar stress and cellular toxicity. Targeting both G-quadruplex and hairpin structures of GGGGCC-repeat RNA with small molecules diminishes poly(GR) aggregation and ameliorates cellular dysfunction. These findings expand our understanding of poly(GR) aggregation in c9ALS/FTD, highlight the importance of RNA structure in regulating protein aggregation and suggest that targeting the RNA scaffold may expand the druggable space of pathogenic condensates.}, } @article {pmid41917768, year = {2026}, author = {Jiang, Z and Ren, YL and Gu, XJ and Su, WM and Duan, QQ and Yin, KF and Cao, B and Li, JY and Yan, B and Chen, YP}, title = {Integrative Multi-Omics Mendelian Randomization Highlights Causal Autophagy-Related Genes for Amyotrophic Lateral Sclerosis.}, journal = {Brain and behavior}, volume = {16}, number = {4}, pages = {e71366}, pmid = {41917768}, issn = {2162-3279}, support = {2022YFC2703101//National Key Research and Development Program of China/ ; 82371422//National Natural Science Fund of China/ ; 81971188//National Natural Science Fund of China/ ; 2022NSFSC0749//National Natural Science Fund of Sichuan/ ; 2023YFS0269//Science and Technology Bureau Fund of Sichuan Province/ ; //the National Natural Science Fund of China/ ; //the Science and Technology Bureau Fund of Sichuan Province/ ; //the National Natural Science Fund of Sichuan/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Autophagy/genetics ; Mendelian Randomization Analysis ; Quantitative Trait Loci ; Multiomics ; DNA Methylation ; Genetic Predisposition to Disease ; }, abstract = {BACKGROUND: Autophagy dysregulation has been implicated in the toxic protein aggregates of amyotrophic lateral sclerosis (ALS). However, the causal relationship between impaired autophagy and ALS remains ambiguous, necessitating further elucidation.

METHODS: This Mendelian randomization (MR) study employs a two-sample design, utilizing genetic instruments to proxy autophagy dysregulation as the exposure and ALS as the outcome. It incorporates summary statistics of ALS (27,205 cases, 110,881 controls), along with data on DNA methylation, RNA splicing, gene expression, and protein abundance quantitative trait loci (QTLs) in both blood and brain tissues (mQTL, sQTL, eQTL, and pQTL, respectively) sourced from European cohorts. Cis-variants situated proximal to or within the 604 autophagy-related genes, exhibiting robust associations with molecular alterations in autophagy, are employed as instrumental variables. Their causal links with ALS are assessed via summary-data-based MR (SMR) analyses, followed by Bayesian colocalization, sensitivity analyses, brain cell-specific MR analyses, protein-protein interaction (PPI), and druggable analyses.

RESULTS: Consistent evidence supported the causal effects of two lysosome genes (FNBP1 and IDUA), one autophagy core gene (C9orf72), and one mitophagy gene (USP35) on ALS risk. Specifically, brain FNBP1 splicing level (OR = 1.18, p = 3.38E-5) and blood USP35 expression level (OR = 1.17, p = 5.94E-5) were positively associated with higher ALS risk. In contrast, we found strong causal evidence of brain IDUA methylation level (OR = 0.96, p = 8.36E-6) and blood C9orf72 methylation level (OR = 0.55, p = 7.59E-12) with lower ALS risk. Cell-type-specific MR analyses, PPI, and druggable analyses further nominated the key brain cell type (astrocytes), potential interaction with known causative genes (SQSTM1 and PFN1), and promising druggability for FNBP1 in ALS.

CONCLUSIONS: This multi-omics MR study identified causal associations between the regulation of four autophagy-related genes and ALS risk, shedding light on autophagy-mediated mechanisms and offering early evidence of novel therapeutic targets for ALS.}, } @article {pmid41917957, year = {2026}, author = {Desnuelle, C and Couratier, P and Corcia, P and Arcelin, T and Nevoret, C and Duburcq, A and Baffert, S and Turgeman, S}, title = {The economic burden of amyotrophic lateral sclerosis for patients and families: a survey on out-of-pocket expenses and income loss in France.}, journal = {Orphanet journal of rare diseases}, volume = {21}, number = {1}, pages = {}, pmid = {41917957}, issn = {1750-1172}, support = {Association for Research on Amyotrophic Lateral Sclerosis and other Motor Neurone Diseases//Association for Research on Amyotrophic Lateral Sclerosis and other Motor Neurone Diseases/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/economics ; France ; Female ; Middle Aged ; Male ; Cost of Illness ; Aged ; Health Expenditures ; Caregivers ; Surveys and Questionnaires ; Income ; Adult ; }, abstract = {INTRODUCTION: Most published economic studies about the burden of amyotrophic lateral sclerosis (ALS) have measured direct and indirect costs but did not consider the perspective of patients and families. MATERIALS AND METHODS: The French ALS patient association, ARSLA, contacted 15 ALS reference centers to recruit a random sample of ALS patients stratified by age and severity accepting to participate in a structured interview survey. The objective was to document the out-of-pocket (OOP) expenses associated with ALS for patients and families in 2024. RESULTS: Fifty patients with a mean age 61.5 years (SD 12) participated in the survey. The average time since diagnosis was 28.9 months (SD 26.8). Most patients had disabling motor impairment, half of them (n = 26, 52%) affected 4 limbs, 27 (54%) required noninvasive respiratory support and 11 (22%) nutritional support. A proportion of 48% of patients or caregivers reported Out-of-Pocket (OOP) expenses for mobility equipment, 50% for home modifications, 40% for vehicle adaptations, and 54% for paying for paid caregivers. The mean annual OOP expenses was €7,764 (SD 9,776) in total of which home adaptations averaged €3,074 (SD 6,583), personal vehicle adaptation €2,774 (SD 5,239) and paid caregivers €1,279 (SD 3,351). The factors statistically significant for higher overall OOP expenses were the duration of ALS since diagnostic (p = 0.026) and use of paid caregivers (p = 0.005). The support of family caregivers was almost systematic (88%), involving spouses (95.5%), children (22.7%) and relatives (13.6%). The mean annual loss of family income associated with professional change of patients and family caregivers was €7,633. When added to the OOP, the mean total annual economic burden was €15,397. CONCLUSION: Despite the full coverage of all ALS-related health expenditures within the French healthcare system and additional associated financial support, it remains a substantial economic burden for patients and families to manage this condition. CLINICAL TRIAL REGISTRATION: Not applicable.}, } @article {pmid41919222, year = {2026}, author = {Spatafora, MG and Dubin, J and Domi, T and Lombardi, R and Cabras, P and Dalla Bella, E and Consonni, M and Quattrini, A and Verri, M and Lauria, G and Van Damme, P and Poesen, K and Riva, N and Peviani, M}, title = {Increased CSF levels of soluble AXL at diagnosis correlate with poor prognosis in patients affected by amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag086}, pmid = {41919222}, issn = {2632-1297}, abstract = {AXL, a receptor tyrosine kinase expressed in neurons and glial cells, involved in neuronal survival, myelination, and regulation of immune responses, can undergo shedding due to the activation of metalloproteases in neuroinflammatory conditions. Indeed, CSF and serum levels of soluble AXL (sAXL) have been correlated with neurodegeneration and cognitive decline in Alzheimer's disease (AD). Based on these observations, we explored whether sAXL is implicated in amyotrophic lateral sclerosis (ALS). sAXL levels were measured in biofluids (CSF and serum) from two biorepositories, totalling 107 ALS patients, 76 healthy controls, 25 AD patients, 22 patients with multiple sclerosis and 51 patients with ALS disease mimicking disorders (i.e. patients that displayed symptoms resembling ALS, in whom eventually ALS was excluded after a thorough clinical examination). Gender and age were considered as covariate in the statistical analyses. Our results provide the first evidence of sAXL alterations in the CSF and serum of ALS patients at diagnosis and demonstrate a significant association between CSF sAXL levels and disease progression, as well as its prognostic value in ALS. While these observations require validation through multicentre studies, they suggest the involvement of the AXL pathway in ALS pathology and pave the way for leveraging CSF sAXL levels as a biomarker to aid ALS disease stratification.}, } @article {pmid41919473, year = {2026}, author = {Cheng, Y and Qiu, M and Yu, Z and Tang, X and Zhang, J}, title = {Long non-coding RNAs in neurodegenerative diseases - Molecular mechanisms, liquid biopsy biomarkers, and therapeutic targets: A review.}, journal = {Biomolecules & biomedicine}, volume = {}, number = {}, pages = {}, doi = {10.17305/bb.2026.13978}, pmid = {41919473}, issn = {2831-090X}, abstract = {Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are age-related disorders characterized by progressive neuronal loss, cognitive decline, and limited options for disease-modifying treatments. Increasing evidence suggests that long non-coding RNAs (lncRNAs) play significant roles in neurodevelopment, neuronal homeostasis, and disease progression; however, their involvement in shared pathogenic pathways and clinical applications remains inadequately defined. This review consolidates recent experimental, transcriptomic, bioinformatic, and emerging clinical findings regarding the role of lncRNAs in NDDs. We examine how lncRNAs modulate common disease mechanisms, including protein misfolding and aggregation, neuroinflammation, mitochondrial dysfunction, ferroptosis, synaptic failure, and aging-related neurodegenerative processes. These regulatory functions occur through various mechanisms, including epigenetic modifications, transcriptional regulation, post-transcriptional processes, and RNA-protein interactions, as well as novel mechanisms such as liquid-liquid phase separation (LLPS), peptide coding, and exosome-mediated intercellular communication. Current evidence supports the potential of lncRNAs as minimally invasive liquid biopsy biomarkers, detectable in blood, cerebrospinal fluid (CSF), and extracellular vesicles. Additionally, lncRNAs may serve as therapeutic targets through antisense oligonucleotides (ASOs), gene editing, and engineered delivery platforms. Overall, lncRNAs have emerged as central molecular regulators and promising candidates for translation in NDDs. Nonetheless, challenges related to specificity, validation, delivery across the blood-brain barrier, and clinical standardization must be addressed before their routine application in precision neurology.}, } @article {pmid41919495, year = {2026}, author = {De Tito, S and Tooze, SA}, title = {Lysosomal homeostasis at the crossroads of neurodegeneration.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {7}, pages = {}, pmid = {41919495}, issn = {1558-8238}, mesh = {Humans ; *Lysosomes/metabolism/pathology/genetics ; *Homeostasis ; Animals ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Endosomal Sorting Complexes Required for Transport/metabolism/genetics ; Mitochondria/metabolism/pathology/genetics ; *Neurons/metabolism/pathology ; Endoplasmic Reticulum/metabolism/pathology/genetics ; }, abstract = {Lysosomes function as metabolic control centers that integrate degradation, nutrient sensing, and stress signaling. In neurons, which must maintain proteostasis and energetic balance throughout life, lysosomal homeostasis determines cellular resilience. Emerging evidence identifies lysosomal injury and defective repair as common denominators across neurodegenerative diseases. Damage to the lysosomal membrane caused by oxidative stress, lipid imbalance, or genetic mutations triggers a hierarchical quality control cascade. Early lesions recruit the endosomal sorting complex required for transport (ESCRT) machinery for mechanical resealing, while larger ruptures activate lipid-centered recovery modules. When repair fails, lysophagy eliminates irreparable organelles and a TFEB-dependent transcriptional program regenerates the lysosomal pool. These tightly coupled responses safeguard neurons from catastrophic proteostatic collapse. Their impairment, through mutations in lysosomal proteins, or through aging, produces the lysosomal fragility that underlies Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis/frontotemporal dementia, and Huntington disease. Crosstalk between lysosomes, mitochondria, and ER integrates local damage with systemic metabolic adaptation, while dysregulated lysosomal exocytosis and inflammation propagate pathology. Understanding how ESCRT complexes, lipid transport, and transcriptional renewal cooperate to preserve lysosomal integrity reveals unifying principles of neurodegeneration and defines molecular targets for intervention. Restoring lysosomal repair and renewal offers a rational path toward preventing neuronal loss.}, } @article {pmid41919981, year = {2026}, author = {Liampas, I and Kimiskidis, VK and Zouvelou, V and Veltsista, D and Moscholouri, A and Triantafyllou, E and Daponte, A and Xirou, S and Sterpi, AE and Salakou, S and Poulidou, V and Arnaoutoglou, M and Tsouris, Z and Ralli, S and Dardiotis, E and Papagiannopoulos, S and Zampetakis, A and Zaganas, Ι and Mitsias, P and Giannakis, A and Konitsiotis, S and Kefalas, F and Alexiou, E and Stoiloudis, P and Parissis, D and Kiamelidis, S and Terzoudi, A and Tsivgoulis, G and Rentzos, M and Chroni, E}, title = {Clinical parameters affecting the course of amyotrophic lateral sclerosis: a longitudinal analysis of the Greek registry for amyotrophic lateral sclerosis (ALS-GR).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2648293}, pmid = {41919981}, issn = {2167-9223}, abstract = {BACKGROUND: Reliable prognostic factors are essential for both clinical and research purposes in amyotrophic lateral sclerosis (ALS). The current study aimed to investigate the prognostic properties of clinical parameters regarding the course of ALS.

METHODS: A mixed retrospective-prospective cohort study was conducted in 11 specialized centers in Greece. Participants with ALS were assessed on the ALS functional rating scale-revised (ALSFRS-R) at baseline and follow-up (on 6-9-12-18-24 months). In case of dropouts, we elucidated whether death had occurred. Adjusted survival analyses were used to explore associations with mortality; adjusted generalized estimating equations were used to examine associations with the rate of functional decline.

RESULTS: A total of 165 individuals with an average follow-up of 12.6 ± 6.3 months were included in the current longitudinal analysis. Baseline ALSFRS-R was the strongest determinant of survival [Hazard-ratio; HR = 0.949 (0.921-0.977)], followed by age at diagnosis [HR = 1.043 (1.011-1.075)] and restrictive respiratory pattern [HR = 2.321(1.193-4.515)], while cramps [HR = 0.485 (0.249-0.946)] and pain [HR = 2.007 (1.041-3.868)] were the least influential. Regarding functional decline rates, the strongest predictor was dysphagia [β= -0.633 (-0.992, -0.274)], followed by pseudobulbar syndrome [β= -0.460 (-0.832, -0.088)], depression [β= -0.375 (-0.688, -0.062)], pain [β=-0.362 (-0.627, -0.096)]. fatigue [β= -0.338 (-0.644, -0.033)], spasticity [β= -0.362 (-0.644, -0.081)] and the interval between diagnosis and baseline visit to a specialized unit in months [β = 0.031 (0.013, 0.048)].

CONCLUSIONS: Lower baseline ALSFRS-R scores, older age at diagnosis, restrictive respiratory pattern, pain and absence of cramps were linked to shorter survival in ALS. Dysphagia, pseudobulbar syndrome, depression, pain, fatigue, spasticity and shorter intervals between diagnosis and baseline visit to specialized units were related to steeper functional decline.}, } @article {pmid41920737, year = {2026}, author = {Jude, JJ and Haro, S and Levi-Aharoni, H and Hashimoto, H and Acosta, AJ and Card, NS and Wairagkar, M and Brandman, DM and Stavisky, SD and Williams, ZM and Cash, SS and Simeral, JD and Hochberg, LR and Rubin, DB}, title = {Decoding intended speech with an intracortical brain-computer interface in a person with long-standing anarthria and locked-in syndrome.}, journal = {Cell reports}, volume = {45}, number = {4}, pages = {117162}, pmid = {41920737}, issn = {2211-1247}, support = {R25 NS065743/NS/NINDS NIH HHS/United States ; I50 RX002864/RX/RRD VA/United States ; I01 RX004820/RX/RRD VA/United States ; I01 RX002295/RX/RRD VA/United States ; DP2 DC021055/DC/NIDCD NIH HHS/United States ; K23 DC021297/DC/NIDCD NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; }, abstract = {Intracortical brain-computer interfaces (iBCIs) for decoding intended speech have provided individuals with ALS and severe dysarthria an intuitive method for high-throughput communication. These advances have been demonstrated in individuals who are still able to vocalize and move speech articulators. Here, we decoded intended speech from an individual with long-standing anarthria, locked-in syndrome, and ventilator dependence due to advanced symptoms of ALS. We found that phonemes, words, and higher order language units could be decoded well above chance. While sentence decoding accuracy was below that of demonstrations in participants with dysarthria, we attained an extensive characterization of neural signals underlying speech in a person with locked-in syndrome and identify directions for future improvement. These include closed-loop speech imagery training and decoding linguistic (rather than phonemic) units from neural signals in middle precentral gyrus to augment decoding at the sentence level. These results demonstrate that usable speech decoding from motor cortex may be feasible in people with anarthria and ventilator dependence.}, } @article {pmid41921453, year = {2026}, author = {Preuilh, A and Lackmy-Vallée, A and Béranger, B and Galléa, C and Bede, P and Querin, G and Pradat, PF and Pélégrini-Issac, M and Marchand-Pauvert, V}, title = {Impaired kinesthesia and cerebral integration during tendon vibration in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {187}, number = {}, pages = {2111864}, doi = {10.1016/j.clinph.2026.2111864}, pmid = {41921453}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Female ; *Vibration ; Male ; Middle Aged ; *Kinesthesis/physiology ; Aged ; *Tendons/physiopathology/physiology ; Magnetic Resonance Imaging/methods ; Adult ; Brain Mapping ; }, abstract = {OBJECTIVE: This study investigates the cortical processing of spindle input in patients with amyotrophic lateral sclerosis (ALS), hypothesizing that functional MRI (fMRI) activation elicited by muscle-tendon vibration would reveal specific disruptions in the integration of this sensory pathway.

METHODS: A block-designed fMRI protocol was used, consisting of 20-second periods of focal muscle-tendon vibrations (∼70-Hz frequency) applied to the first dorsal interosseous tendon, alternating with rest periods. Parametric brain activation maps were examined in 22 patients with ALS without clinically overt sensory deficits and in an age- and sex-matched group of 23 healthy controls. The relationship between task-related brain activations and clinical scores was assessed in patients reporting vibration-induced kinesthetic sensations.

RESULTS: Muscle-tendon vibration elicited activation of the precentral gyrus contralateral to the vibration site, in both ALS patients and healthy controls. Compared to controls, ALS patients exhibited reduced activation in prefrontal and cerebellar lobule VI regions. Notably, a greater proportion of ALS patients (41%) failed to perceive kinesthetic stimuli compared to controls (13%). Furthermore, activations in contralateral prefrontal and cerebellar areas were associated with hand motor disability and cognitive impairment.

CONCLUSION: It suggests that motor impairment in ALS is accompanied by disrupted perception of movement, and concomitant altered brain integration of proprioceptive inputs.

SIGNIFICANCE: ALS-related motor impairment extends beyond motor output, underscoring the need for assessing movement (body) awareness in clinical practice.}, } @article {pmid41921847, year = {2026}, author = {Dong, YR and Wang, JR and Yang, Y and Chen, QZ and Jiang, YQ and Yang, X and Zhou, MC and Cao, SP and Zeng, SX and Zang, CX and Li, FF and Bao, XQ and Zhang, D}, title = {Unveiling the UFMylation Pathway: Implications in Neurodegenerative Diseases.}, journal = {Journal of molecular biology}, volume = {438}, number = {12}, pages = {169772}, doi = {10.1016/j.jmb.2026.169772}, pmid = {41921847}, issn = {1089-8638}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Protein Processing, Post-Translational ; Ubiquitination ; Animals ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; *Proteins/metabolism ; }, abstract = {UFMylation is a recently characterized post-translational modification (PTM) system that conjugates Ubiquitin-Fold Modifier 1 (UFM1) to target proteins via a dedicated enzymatic cascade. This modification system regulates critical cellular processes by controlling protein subcellular localization, modulating protein-protein interactions, and coordinating with ubiquitination to regulate protein stability. Emerging evidence highlights UFMylation as a critical modifier of pathological proteins, including tau and α-synuclein, while impaired UFMylation pathways are observed in the brains of individuals with neurodegenerative disorders. In this review, we summarize the current role and mechanism of UFMylation in the pathogenesis of neurodegenerative diseases, offering the first comprehensive framework for targeting UFMylation in the treatment of neurodegenerative diseases.}, } @article {pmid41922953, year = {2026}, author = {Xing, Z and Cheng, Z and Yang, X and Hu, L and Wang, K and Wang, Y and Hu, D and Wang, YH and Du, J and Wang, L and Li, J}, title = {Integrated genomic and transcriptomic analysis reveals candidate genes underlying herbicide resistance in Sorghum.}, journal = {BMC plant biology}, volume = {26}, number = {1}, pages = {}, pmid = {41922953}, issn = {1471-2229}, support = {32372134//The National Natural Science Foundation of China/ ; }, mesh = {*Sorghum/genetics/drug effects ; *Herbicide Resistance/genetics ; Gene Expression Profiling ; *Herbicides/pharmacology ; Genes, Plant ; Genomics ; }, abstract = {BACKGROUND: Herbicide-resistant germplasms provide critical genetic resources for improving weed control and understanding resistance mechanisms in crops. OBJECTIVE: To screen sorghum accessions for tolerance to ACCase and ALS inhibitor herbicides at the seedling stage, identify the major locus and strong candidate gene associated with feproxydim resistance, and verify the gene expression pattern and genetic variation by quantitative real‑time PCR (qRT‑PCR) and KASP genotyping. METHOD: A total of 316 sorghum accessions were screened for seedling-stage herbicide tolerance using gradient herbicide treatments. Bulked segregant analysis sequencing (BSA-Seq) was performed on resistant and susceptible gene pools constructed from the F2 population derived from IS1219 × RTx430. Transcriptome sequencing (RNA-Seq) was conducted on leaf tissues after feproxydim treatment to identify candidate genes within the mapped interval. KASP markers were developed for the functional variation site of the key candidate gene for genotyping validation. Quantitative real‑time PCR (qRT-PCR) was used to measure the relative expression level of the target gene and compare it with the susceptible control line. Protein sequence comparison was used to detect variations in the key candidate gene between resistant and susceptible lines. RESULT: In the screening with the ACCase inhibitor 10% feproxydim, IS1219 exhibited high-level resistance. Preliminary screening under the ALS inhibitor mesosulfuron-methyl treatment identified only SJ304 with visible tolerance, which was not subjected to further mapping or validation. BSA-Seq identified a major feproxydim resistance QTL on chromosome 1. RNA-Seq revealed five co-expressed candidate genes in the target interval, among which Sobic.001G431500 (encoding carboxylesterase 17, an α/β‑hydrolase) was markedly upregulated in the resistant line IS1219 but not in the susceptible line RTx430. Quantitative real‑time PCR (qRT-PCR) analysis confirmed that Sobic.001G431500 was significantly upregulated in the resistant line IS1219 compared with the susceptible control. KASP genotyping demonstrated that the IS1219 allele cosegregated with feproxydim resistance. Protein sequence comparison showed that the IS1219 allele carried a missense mutation V300A and a deletion P301_P303 at and after position 300. CONCLUSION: These findings identify a major QTL and a strong candidate gene Sobic.001G431500 associated with feproxydim resistance in the sorghum line IS1219, based on differential expression, genetic variation, and genotype–phenotype cosegregation. This study provides valuable genetic resources and functional markers for marker-assisted selection and breeding of feproxydim-tolerant sorghum varieties.}, } @article {pmid41924615, year = {2026}, author = {Almalki, S and Salama, M and Taylor, MJ and Ahmed, Z and Tuxworth, RI}, title = {TDP-43 related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review and narrative synthesis.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1671909}, pmid = {41924615}, issn = {1662-5099}, abstract = {Mislocalization and aggregation of the DNA/RNA binding protein, TDP-43, is seen in most cases of amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Accumulating DNA damage in neurons is also a common feature of ALS-FTD. TDP-43 has several characterized roles in the regulation of the DNA damage response (DDR). This review systematically explored the relationship between TDP-43, DNA damage and the DNA damage response in various models of ALS-FTD, facilitating comparison of findings between studies using similar models. Twelve peer-reviewed papers, covering eight TDP-43 mutations out of nearly 40, were reviewed and five experimental models included: cell lines, patient-derived iPS cells, organoids, and rodent models, plus post-mortem cortex and spinal cord tissue from ALS-FTD patients. Across the studies and models, depletion of TDP-43 or ALS-linked mutations consistently increased genomic instability. Q331K-expressing cells showed a 2-3-fold reduction in DNA repair activity and a 4-6-fold increase in DDR activation, while TDP-43-depleted cells showed a 20-fold rise in double strand breaks. TDP-43 normally binds to damaged chromatin, participates in early DDR signaling and scaffolds core DNA damage repair factors, including Ku70, XRCC4 and DNA ligase 4. This systematic review and narrative synthesis sheds light on mechanisms that explain how TDP-43 dysfunction impairs genome maintenance. When TDP-43 is mislocalized, mutated or aggregated, these interactions are disrupted, resulting in impaired DNA repair. DNA damage is also caused by increasing R-loops, dysregulation of mismatch repair gene transcription, and sequestering of repair proteins into cytoplasmic inclusions. Upstream DNA damage can further drive TDP-43 mislocalisation, creating a feed-forward loop. Given the ubiquity of TDP-43 pathology across neurodegenerative diseases, targeting the DDR mechanisms affected by TDP-43 may offer new therapeutic opportunities.}, } @article {pmid41924700, year = {2026}, author = {McMackin, R and Tadjine, Y and Suleyman, N and Woods, E and Plaitano, S and Fasano, A and Awiszus, F and Hardiman, O and Carson, RG}, title = {Long-interval intracortical inhibition is similar in people with and without amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag091}, pmid = {41924700}, issn = {2632-1297}, abstract = {Long-interval intracortical inhibition, measured using transcranial magnetic stimulation, provides a non-invasive measure of spinal inhibition at interstimulus intervals below 100 ms and of GABA-B-mediated motor cortical inhibition at interstimulus intervals of 100-200 ms. To date, only a few small studies have investigated if long-interval intracortical inhibition is affected in amyotrophic lateral sclerosis. None have employed threshold tracking protocols or investigated multiple induced current directions. In this study, we aimed to determine if long-interval intracortical inhibition (i) differs between people with amyotrophic lateral sclerosis and healthy controls; (ii) relates to motor symptom severity, disease duration or survival time in those with amyotrophic lateral sclerosis; or (iii) relates to intracortical facilitation or short-interval intracortical inhibition. Employing automated threshold tracking during paired-pulse transcranial magnetic stimulation of the precentral gyrus, long-interval intracortical inhibition was recorded in 30 people with amyotrophic lateral sclerosis [9 female, 21 male, median (range) age: 63.5 (41-79) years] and 45 healthy controls [16 female, 29 male, median (range) age: 57 (34-76) years]. Long-interval intracortical inhibition was recorded with interstimulus intervals of 50, 100, 150 and 200 ms using posterior-to-anterior induced current (LICIPA), and with interstimulus intervals of 150 and 200 ms using anterior-to-posterior induced current (LICIAP). In subcohorts of both healthy controls and people with amyotrophic lateral sclerosis, short-interval intracortical inhibition was recorded with interstimulus intervals of 1 and 3 ms using posterior-to-anterior induced current and 3 ms using anterior-to-posterior current. Intracortical facilitation was recorded with an interstimulus interval of 10 ms using posterior-to-anterior induced current. No differences were found between those with and without amyotrophic lateral sclerosis in long-interval intracortical inhibition magnitude (P ≥ 0.44, Hedge's g ≤ 0.14) or in the interstimulus interval at which maximal long-interval intracortical inhibition occurs (P = 0.68, χ2 = 1.5). In those with amyotrophic lateral sclerosis, no statistically significant correlations were identified between long-interval intracortical inhibition measures and disease duration or functional rating scale scores. Statistically significant positive correlations were observed between LICIPA recorded with 100 and 150 ms interstimulus intervals, and between LICIPA recorded with 150 and 200 ms interstimulus intervals, but not between LICIPA and LICIAP measures or between long-interval intracortical inhibition and short-interval intracortical inhibition or intracortical facilitation. Our findings indicate that disinhibition manifested in this disease is primarily not mediated via changes in the cortical GABA-Bergic or spinal circuitry which underpins long-interval intracortical inhibition measures. As LICIPA and LICIAP measures show minimal covariation, it is possible that these measures are underpinned by distinct aspects of motor cortical inhibition.}, } @article {pmid41925063, year = {2026}, author = {Shtilbans, A and Lang, AE}, title = {Combination Disease-Modifying Therapy for Neurodegenerative Diseases Using Repurposed Drugs.}, journal = {Annals of neurology}, volume = {99}, number = {5}, pages = {1099-1112}, doi = {10.1002/ana.78190}, pmid = {41925063}, issn = {1531-8249}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/therapeutic use ; *Drug Repositioning/methods ; Drug Therapy, Combination/methods ; }, abstract = {We review the positive effects of several existing drugs from different classes, such as chemical chaperones, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), iron chelators, and cluster-Abelson tyrosine kinase inhibitors (c-Abl TKIs), in preclinical disease models and in available published human data following use of these drugs in individuals with common neurodegenerative diseases (NDs), including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). A concept of combinatory neuroprotective therapy using a drug-repurposing approach is then discussed. Finally, we propose a strategy to design an ideal combination of drugs able to address multiple pathogenic processes involved in neurodegeneration to achieve clinically meaningful results. ANN NEUROL 2026 ANN NEUROL 2026;99:1099-1112.}, } @article {pmid41925076, year = {2026}, author = {Krajewski, T and Koch, G}, title = {Randomization-Based Covariance Analysis for Confidence Intervals of Treatment Comparisons Based on Restricted Mean Survival Time With Categorized Time-to-Event Data.}, journal = {Statistics in medicine}, volume = {45}, number = {8-9}, pages = {e70422}, doi = {10.1002/sim.70422}, pmid = {41925076}, issn = {1097-0258}, support = {T32 ES007018/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; Survival Analysis ; Confidence Intervals ; Amyotrophic Lateral Sclerosis/drug therapy ; Analysis of Variance ; Double-Blind Method ; Models, Statistical ; Computer Simulation ; }, abstract = {This paper introduces a randomization-based method for covariate-adjusted comparisons of restricted mean survival time (RMST) between treatment arms in randomized controlled trials. Existing approaches for covariate-adjusted RMST analysis have model-based assumptions that may not be compatible with the complexity of survival data. We estimate the treatment difference in RMST using randomization-based analysis of covariance (RB-ANCOVA) for categorized time-to-event data by constraining the covariate mean differences between treatment groups to zero. Accordingly, we provide corresponding confidence intervals that offer greater precision than those based on unadjusted RMST differences. The methodology is detailed for comparing two treatment groups for a single or multiple time intervals, as well as for multiple treatment groups over a single interval. We demonstrate the application of these methods using data from a randomized, double-blind, placebo-controlled clinical trial evaluating three doses of a test treatment for ALS.}, } @article {pmid41925483, year = {2026}, author = {Kleinerova, J and Tahedl, M and Finegan, E and Siah, WF and Hengeveld, JC and Doherty, MA and Hardiman, O and McLaughlin, RL and Hutchinson, S and Tan, EL and Bede, P}, title = {Neuroimaging confirms selective cerebral involvement in primary lateral sclerosis and predilection to brain regions with high metabolic activity.}, journal = {Revue neurologique}, volume = {182}, number = {6}, pages = {514-527}, doi = {10.1016/j.neurol.2026.03.003}, pmid = {41925483}, issn = {0035-3787}, mesh = {Humans ; *Neuroimaging/methods ; *Brain/metabolism/pathology/diagnostic imaging ; Male ; Female ; *Motor Neuron Disease/pathology/diagnostic imaging/metabolism/genetics ; Middle Aged ; Mitochondria/pathology/metabolism ; Aged ; Prospective Studies ; Magnetic Resonance Imaging ; Adult ; }, abstract = {BACKGROUND: Primary lateral sclerosis (PLS) is a low incidence motor neuron disease manifesting in progressive limb spasticity, gait impairment, bulbar dysfunction and often in pseudobulbar affect. Varying degree of frontotemporal involvement has also been recently confirmed. Postmortem data is scarce in PLS and disease burden patterns are best characterised in vivo by purpose-designed neuroimaging protocols.

METHODS: A large prospective neuroimaging study has been undertaken to explore cerebral involvement patterns in PLS using a both structural T1-weighted data and diffusion MRI data. Neuroimaging data were complemented by genetic screening and comprehensive clinical profiling. Brain involvement patterns have been first characterised by standard morphometric and diffusivity analyses. Resulting disease burden maps were then correlated to physiological mitochondrial density (MitoD) maps. In an additional, region-of-interest analysis, brain regions with significant topological associations between neurodegeneration and MitoD were ranked based on their r-values.

RESULTS: Grey matter degeneration in PLS is not limited to the motor cortex, but also encompasses frontotemporal, caudate, thalamic, cerebellar and cingulate regions. Voxelwise statistics confirm topological associations between atrophy and physiological mitochondrial density. The most significant associations between neurodegeneration and MitoD were detected in the cerebellum, superior temporal lobe, precentral gyrus, inferior operculum, and orbitofrontal gyrus. Similarly, white matter degeneration is not limited to the corticospinal tracts, but includes the corpus callosum, frontotemporal association fibres, the cingulum, cerebellar peduncles, and the fornix. Anatomical associations were also detected between diffusivity alterations and focal MitoD.

DISCUSSION: PLS is associated with a selective disease burden pattern, and our data suggest that brain regions with high baseline metabolic activity are more likely to succumb to neurodegeneration. Cerebral areas showing the most significant anatomical associations between atrophy and mitochondrial density (precentral gyrus, cerebellum, frontotemporal regions) are pathognomonic brain regions of PLS driving its core clinical manifestations.}, } @article {pmid41925964, year = {2026}, author = {Oriquat, G and H, M and Maharana, L and Dhyani, A and Al-Hasnaawei, S and Singh-Chauhan, A and Arora, V and Sharma, J and Sadeghi-Samarjan, R}, title = {The Gut Microbiome in Amyotrophic Lateral Sclerosis: Emerging Mechanisms and Therapeutic Potential.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41925964}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/therapy ; Humans ; *Gastrointestinal Microbiome/physiology ; Animals ; Dysbiosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive loss of motor neurons and a median survival of 2 to 3 years after symptom onset. Despite advances in genetics, particularly the identification of mutations in C9ORF72, SOD1, and TDP 43, substantial variability in disease onset and progression remains unexplained. Mounting evidence points to the gut microbiome as a potential modifier of ALS biology. Microbial communities within the intestine influence systemic and central immune responses, energy metabolism, and the bioavailability of nutrients and therapeutic agents. Animal studies reveal that dysbiosis contributes to intestinal barrier dysfunction, immune activation, and altered metabolite production, while supplementation with beneficial metabolites such as butyrate or nicotinamide can delay disease progression and extend survival. Human studies, though inconsistent in their findings, consistently identify microbial imbalances and loss of diversity in subsets of patients. The gut-brain axis provides a plausible framework for these effects, as microbial products can signal through endocrine, neural, and immune pathways to influence central nervous system function. Beyond motor decline, microbiota alterations may also contribute to non-motor symptoms such as depression, anxiety, and gastrointestinal dysfunction, further shaping quality of life. While methodological variability complicates interpretation, integration of microbiome research with host genomics and metabolomics offers a path toward precision medicine. Targeting microbial composition and function may ultimately represent a novel therapeutic approach capable of modifying both disease biology and patient outcomes in ALS.}, } @article {pmid41926450, year = {2026}, author = {Christoforidou, E and Rowe, JS and Simoes, FA and Cassel, R and Dupuis, L and Leigh, PN and Hafezparast, M}, title = {Impaired dynein function preserves spinal interneuron survival and positioning in an ALS-like mouse model.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0346246}, pmid = {41926450}, issn = {1932-6203}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Interneurons/metabolism/pathology ; Mice ; Male ; *Spinal Cord/pathology/metabolism ; Disease Models, Animal ; *Cytoplasmic Dyneins/genetics/metabolism ; Cell Survival ; Mice, Transgenic ; }, abstract = {Impaired cytoplasmic dynein function has been implicated in amyotrophic lateral sclerosis (ALS) pathogenesis, yet the contributions of spinal interneurons to disease phenotypes remain unclear. We tested the hypothesis that hypomorphic dynein function in cholinergic neurons disrupts the development, survival, or positioning of inhibitory interneuron populations in the lumbar spinal cord. Using ChAT-Cre recombination, we generated four mouse genotypes with graded reductions in dynein activity in ChAT+ cells: Dync1h1+/+ (wildtype), Dync1h1-/+ (hemizygous wildtype), Dync1h1+/Loa (heterozygous Loa mutation), and Dync1h1-/Loa (hemizygous Loa). At 52 weeks of age, lumbar spinal cords (L3-L6) were harvested, cryosectioned, and immunostained for ChAT, GAD-67, Parvalbumin, and Calbindin. Cell counts were performed on confocal images from eight sections per mouse (N = 3 male mice/genotype), and radial distances from the central canal were normalised to gray matter width. Angular distributions were analysed via circular statistics. There were no significant genotype-dependent differences in the numbers of ChAT+, GAD-67+, Parvalbumin+, or Calbindin+ cells, nor in ChAT+ subpopulations (motor neurons versus interneurons) or double-positive interneuron subsets (e.g., ChAT+-GAD-67+, Parvalbumin+-GAD-67+, Parvalbumin+-Calbindin+). Radial positioning relative to the central canal was similarly preserved across all markers and genotypes. Circular-median tests revealed statistically significant shifts in mean angle for ChAT+, GAD-67+, and certain double-positive cells, but these amounted to only 5-10° displacements, translating to lateral shifts of ~10-20 µm, well within single laminar bands, and are unlikely to impact circuit connectivity. Despite substantial motor deficits and hallmark TDP-43 pathology previously seen in these models, impaired dynein function does not precipitate interneuron loss or gross migratory defects in the lumbar spinal cord. Instead, our findings suggest that the primary contributions of dynein to ALS-like phenotypes likely arise from functional disruptions in axonal transport, synaptic maintenance, and neuronal physiology rather than from structural alterations or loss of interneuron populations.}, } @article {pmid41926608, year = {2026}, author = {Mori, F and Kon, T and Itazawa, R and Akatsu, A and Miki, Y and Arai, A and Kurotaki, H and Tomiyama, M and Wakabayashi, K}, title = {Relationship between promyelocytic leukemia protein nuclear bodies and TAR DNA-binding protein-43 aggregation in spinal anterior horn cells in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {85}, number = {8}, pages = {903-912}, pmid = {41926608}, issn = {1554-6578}, support = {23K06802 (F.M.), 25K10784 (T.K.), 24K10654 (Y.M.), and 23K24209 (K.W.)//JSPS KAKENHI Grant/ ; 23K06802//JSPS KAKENHI/ ; 25K10784//JSPS KAKENHI/ ; 24K10654//JSPS KAKENHI/ ; 23K24209//JSPS KAKENHI/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Promyelocytic Leukemia Protein ; *Anterior Horn Cells/metabolism/pathology ; Female ; Male ; Aged ; Middle Aged ; Inclusion Bodies/pathology/metabolism ; *Intranuclear Inclusion Bodies/pathology/metabolism ; *Transcription Factors/metabolism ; *Nuclear Proteins/metabolism ; *Tumor Suppressor Proteins/metabolism ; Aged, 80 and over ; }, abstract = {Promyelocytic leukemia protein nuclear bodies (PML-NBs) and stress granules serve as deposition sites for stress-induced, aggregation-prone proteins. We previously reported that TAR DNA-binding protein 43 (TDP-43) colocalizes with stress granules during early aggregation in sporadic amyotrophic lateral sclerosis (ALS), and recent studies have noted PML-NB loss in familial ALS. To explore the role of PML-NBs in TDP-43 inclusion maturation, we analyzed spinal cord specimens from 12 patients with sporadic ALS and 5 controls using immunostaining for PML and TDP-43. PML-NB counts in anterior horn cells (AHCs) were significantly lower in patients with ALS than in controls (P < 0.05), especially in AHCs with TDP-43 inclusions (P < 0.01). Average numbers of PML-NB decreased progressively with inclusion type (3.1 in diffuse punctate cytoplasmic staining, 2.3 in round inclusions, and 0.8 in skein-like inclusions); all of these were significantly lower than those in inclusion-free AHCs (controls: 4.6; ALS: 5.5; P < 0.01). AHCs in ALS without inclusions showed higher PML-NB counts than in controls (P < 0.05), suggesting an early protective response. In contrast, reduced PML-NBs in mature inclusions may reflect diminished cellular defense. These findings implicate PML-NBs in the pathogenesis of sporadic ALS.}, } @article {pmid41928488, year = {2026}, author = {Andersen, B and Krarup, C}, title = {Reappraisal of the Diagnostic Significance of Transcranial Magnetic Stimulation and Triple Stimulation in Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {4}, pages = {e70560}, pmid = {41928488}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Transcranial Magnetic Stimulation/methods ; Female ; *Evoked Potentials, Motor/physiology ; Male ; Middle Aged ; Aged ; Electromyography ; Prospective Studies ; Adult ; Neural Conduction/physiology ; }, abstract = {OBJECTIVE: To reassess the importance of transcranial magnetic stimulation (TMS), including the triple stimulation technique (TST), to detect upper motor neuron (UMN) involvement in amyotrophic lateral sclerosis (ALS).

METHODS: In this single-center prospective study, 144 consecutive patients suspected of having motor neuron disease were included over 5 years at the time of diagnosis. All patients were examined clinically and with EMG to assess UMN and lower motor neuron (LMN) involvement, and survival was ascertained 2 years after inclusion of the last patient. Our TMS protocol consisted of TST in both arms and conventional motor evoked potentials (MEP) in arms and legs to assess central motor conduction time (CMCT).

RESULTS: The TST could be performed in 142 patients who showed central conduction failure in 63%, which was often markedly asymmetrical, and 50% had prolonged CMCT in the legs. Combining TST in the arms and conventional MEP in the legs showed central abnormalities in 77%. In 62 patients with only signs of LMN involvement at clinical and EMG assessment, the TST amplitude ratio was reduced in 45%, and combined TST to the arms and conventional MEP to the legs disclosed a central abnormality in 61%.

CONCLUSION: The main clinical significance was the subclinical corticospinal involvement at TMS with TST in a large proportion of patients without clinical UMN involvement. TMS with TST is a sensitive, non-invasive electrophysiological method to detect corticospinal dysfunction in ALS.}, } @article {pmid41928634, year = {2026}, author = {Dahshan, A and Khalil, MIM and Deraz, HADA}, title = {From theory to practice: physicians' knowledge, attitudes, and practices regarding amyotrophic lateral sclerosis in Egypt - a cross-sectional study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2652326}, pmid = {41928634}, issn = {2167-9223}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with heterogeneous presentations that often mimic other conditions, leading to frequent misdiagnosis and delayed recognition. Physician awareness and diagnostic confidence are critical for early detection, yet little is known about these factors in the Middle East and North Africa (MENA) region, where ALS services and specialized centers remain limited.

METHODS: We conducted a nationwide cross-sectional survey of 1,320 physicians in Egypt. A validated online questionnaire assessed demographics, knowledge, attitudes, and practice patterns regarding ALS. Data were analyzed using appropriate statistics, with multivariate regression to identify predictors of knowledge, attitudes, and practices.

RESULTS: Overall, 41.0% of physicians demonstrated poor knowledge of ALS, while only 8.8% achieved good knowledge. Nearly half (46.5%) reported little or no diagnostic confidence, and 93.7% expressed a strong need for additional educational programs. Most respondents identified MRI (78.3%) as the main diagnostic test, whereas only 2.0% selected electrophysiological studies. Nevertheless, practice scores were higher: 65.7% reported good practice levels and 48.4% indicated they would directly refer suspected cases to specialists. Knowledge strongly correlated with attitudes (r = 0.610, p < 0.001) and both were moderately correlated with practice. Multivariate analysis identified neurology specialty, postgraduate ALS training, and urban practice as independent predictors of better knowledge and attitudes, while greater experience predicted improved practice.

CONCLUSION: Egyptian physicians show limited ALS knowledge and low diagnostic confidence despite reasonable practice behaviors. Training and structured referral pathways are urgently needed to improve ALS preparedness in Egypt and the wider MENA region.}, } @article {pmid41928799, year = {2026}, author = {Ouyang, Z and Walmsley, K and Luo, S and Tippett, D and Wyse-Sookoo, K and Fifer, M and Vansteensel, MJ and Angrick, M and Ramsey, N and Crone, NE}, title = {Stable speech BCI performance during slow progression of ALS: A longitudinal ECoG study.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41928799}, issn = {2693-5015}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Electrocorticographic (ECoG) speech brain-computer interfaces (BCIs) show promise for restoring communication in amyotrophic lateral sclerosis (ALS), but the long-term stability of speech-related neural signals and decoding performance during disease progression remains unclear. We tracked signal characteristics and decoding over 25 months in a participant with ALS to determine how high-gamma (HG, 70-170 Hz) activity changes over time and whether these changes affect offline speech decoding.

METHODS: We implanted two 8×8 subdural ECoG grids over left sensorimotor cortex (SMC) in a participant with slowly progressive bulbar variant ALS. Across 25 months, the participant performed an overt syllable-repetition task (12 consonant-vowel tokens) during simultaneous ECoG and audio recording. We quantified HG activation ratio (ActR), spectral signal-to-noise ratio (SNR; HG/HF, where HF = 300-499 Hz), and peak z-scored HG responses. Speech acoustics were evaluated using first/second formants (F1/F2) and the triangular vowel space area (tVSA). Offline EEGNet-based decoders were assessed in two stages: models trained on post-implant months 1-6 were tested on months 7-25, while models trained on stabilized data (months 7-11) were tested on the remaining period (months 12-25). Electrode-level saliency assessed spatial contributions to decoding.

RESULTS: Acoustic analyses showed a significant reduction in tVSA over two years (-44.6 Hz[2]/day; P < 10[-7]), consistent with mild intelligibility decline. Neural metrics (ActR and SNR) followed a biphasic trajectory: increasing during the first 6 months, after which ActR stabilized (0.041%/day; P = 0.13), and SNR declined gradually (-0.46%/day, P < 10[- 4]). The model trained on months 1-6 achieved 55.7% accuracy (chance: 8.33%), but performance declined over time (-0.019%/day; P = 2.1×10[-4]). Conversely, the model trained on months 7-11 achieved higher accuracy (65.9%) on subsequent data with no significant temporal decline (P = 0.23).

CONCLUSIONS: Speech-related HG features exhibited an initial unstable period followed by a long-term gradual SNR reduction, potentially reflecting disease progression. Models trained after signal stabilization generalized robustly to data recorded over a year later. These findings confirm that despite reduced absolute HG power and mild acoustic degradation of speech, cortical features remain stable enough to support durable ECoG speech BCIs without frequent recalibration. These findings will motivate future adaptive calibration algorithms that account for slow signal changes while leveraging stable spatial representations in ventral SMC.

CLINICALTRIALSGOV IDENTIFIER: NCT03567213.}, } @article {pmid41928938, year = {2026}, author = {Michels, S and Chen, C and Ruf, WP and Garcia, MMG and Arnold, FJ and Wu, Z and Bennett, CL and Shams, D and Thompson, LM and Walker, AC and Dickson, DW and Petrucelli, L and Dorst, J and Prudencio, M and Li, W and La Spada, AR}, title = {Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41928938}, issn = {2692-8205}, support = {R35 NS122140/NS/NINDS NIH HHS/United States ; }, abstract = {The role of the epigenome in age-related neurodegenerative disorders remains understudied. Here, we analyzed circulating cell-free DNA (cfDNA) from blood to detect methylation changes as a liquid-biopsy for Amyotrophic Lateral Sclerosis (ALS). Our study included 20 patients with sporadic ALS, 10 patients with C9orf72-associated ALS, 10 asymptomatic carriers of the C9orf72 repeat expansion mutation, and 21 non-disease controls. Following targeted enzymatic methyl-sequencing (EM-seq) of ~4 million CpG sites, we detected numerous differentially methylated genes, including several implicated in ALS disease risk and pathogenesis. By integrating multiple epigenetic features, we delineated a distinct epigenetic signature, which achieved an average area under the curve (AUC) of 0.91 ± 0.10 upon receiver operator characteristic (ROC) analysis, which enabled detection of ~70% of ALS patients with close to 100% specificity. Furthermore, we also identified a set of genes whose methylation status significantly correlated with clinical disease progression and cerebrospinal fluid (CSF) neurofilament levels. Our results reveal the potential of cfDNA-based biomarkers to accurately diagnose ALS and potentially predict disease progression.}, } @article {pmid41929081, year = {2026}, author = {Fodder, K and Murthy, M and de Silva, R and Raj, T and Farrell, K and Humphrey, J and Bettencourt, C}, title = {Cross-disease genetic and epigenetic architecture of the MOBP locus shows convergence in ALS-PSP.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41929081}, issn = {2692-8205}, support = {R01 AG054005/AG/NIA NIH HHS/United States ; R01 AG065926/AG/NIA NIH HHS/United States ; R56 AG088669/AG/NIA NIH HHS/United States ; U01 AG068880/AG/NIA NIH HHS/United States ; S10 OD030463/OD/NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; S10 OD026880/OD/NIH HHS/United States ; R21 AG063130/AG/NIA NIH HHS/United States ; K01 AG070326/AG/NIA NIH HHS/United States ; UL1 TR004419/TR/NCATS NIH HHS/United States ; R01 NS116006/NS/NINDS NIH HHS/United States ; RF1 AG065926/AG/NIA NIH HHS/United States ; R01 NS146414/NS/NINDS NIH HHS/United States ; R21 AG091272/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; }, abstract = {Myelin oligodendrocyte basic protein (MOBP) is an abundant oligodendrocyte gene implicated in multiple neurodegenerative diseases. Genetic variation at the MOBP locus has been associated with risk for progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTD), corticobasal degeneration (CBD), Alzheimer's disease (AD), Lewy body dementia (LBD), and Creutzfeldt-Jakob disease (CJD). Epigenetically, MOBP promoter hypermethylation and reduced expression have been reported in multiple system atrophy (MSA). Although MOBP is thought to play a role in oligodendrocyte morphology and myelin structure, how genetic and epigenetic variation at this locus influences gene regulation and contributes to disease risk remains poorly understood across neurodegenerative disorders. Here, we investigated whether shared or disease-specific genetic mechanisms at MOBP converge on altered DNA methylation and expression across neurodegenerative disorders. We analysed MOBP variants using summary statistics from recent GWAS for ALS, PSP, FTD, LBD, PD, MSA, AD, and CJD. Colocalisation (COLOC and SuSiE-coloc) was used to test whether disease-associated variants overlapped between diseases, and with oligodendrocyte expression quantitative trait loci (eQTLs) and bulk brain methylation quantitative trait loci (mQTLs). To further investigate mQTL effects at this locus, rs1768208, a variant previously associated with PSP, was genotyped in an overlapping brain methylation cohort, allowing direct testing of genotype-methylation associations in frontal white matter tissue. ALS and PSP GWAS demonstrated strong association at MOBP, with most strongly associated SNPs (e.g. rs631312, rs616147, rs1768208) shared between both disorders. Colocalisation analyses indicated high posterior probability that ALS and PSP share the same causal variant, with weaker overlap with FTD. mQTL colocalisation highlighted cg15069948, located near an exon junction within MOBP, as strongly colocalising with the ALS/PSP risk variants. In complementary tissue analyses, rs1768208-T carriers showed hypomethylation at cg15069948 in PSP brains. No genotype-methylation effects were detected in MSA or Parkinson's disease. Together with prior evidence of promoter hypermethylation and reduced expression in MSA, our findings identify cg15069948 as a regulatory methylation site linking ALS/PSP risk variants to altered MOBP methylation, and support MOBP dysregulation as a shared feature of neurodegeneration. However, the underlying mechanisms appear disease-specific, highlighting the complexity of involvement of this gene across neurodegenerative disorders.}, } @article {pmid41929167, year = {2026}, author = {Mahrous, AA and Heit, BS and Heckman, CJ}, title = {Riluzole treatment paradoxically increases motoneuron excitability in ALS due to hyperactive homeostasis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41929167}, issn = {2692-8205}, support = {R01 NS110953/NS/NINDS NIH HHS/United States ; }, abstract = {Riluzole is the most commonly prescribed among the limited approved therapies for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive motoneuron loss and paralysis. It is thought to act by suppressing motoneuron excitability and glutamate release, but its clinical benefits are modest and often diminish over time. We previously showed that homeostatic mechanisms in the SOD1[G93A] (mSOD1) mouse model of ALS are hyperactive and prone to overcompensation. Here, we tested whether such dysregulated homeostasis antagonizes the effects of riluzole. Wild-type (WT) and presymptomatic mSOD1 mice received therapeutic doses of riluzole in drinking water for 10 days, with untreated littermates of both genotypes serving as controls. Motoneuron excitability and synaptic inputs were then examined using intracellular recordings from the isolated sacral spinal cord. The data showed that chronic riluzole treatment increased motoneuron excitability and polysynaptic inputs in mSOD1 mice but produced no detectable changes in WT motoneurons. These results suggest that hyperactive homeostatic mechanisms in ALS counteract the suppressive effects of riluzole. Notably, mSOD1 motoneurons exhibited larger membrane capacitance than WT, consistent with their increased cell size at this disease stage. Riluzole treatment reduced motoneuron membrane capacitance in mSOD1 mice to the range observed in WT animals, indicating normalization of cell size and potentially reduction in metabolic demand. Together, these findings help explain the limited clinical efficacy of riluzole while revealing a previously unrecognized neuroprotective mechanism of the drug in ALS.}, } @article {pmid41929296, year = {2026}, author = {Sebogo, MA and Frans, MC and Paulose, H and Rodriguez, CL and Hsiung, GY and Cashman, NR and Ly, CV and Leavens, MJ}, title = {Longitudinal Analysis of Superoxide Dismutase 1 Seeding Activity in Amyotrophic Lateral Sclerosis Cerebrospinal Fluid.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.03.20.26348753}, pmid = {41929296}, abstract = {Twenty percent of familial amyotrophic lateral sclerosis (fALS) cases are linked to mutations in the Superoxide Dismutase 1 (SOD1) gene and accumulation of misfolded SOD1 aggregates. SOD1 misfolding from the broader ALS population without SOD1 mutations is less clear. Here, we report SOD1 seeding activity in antemortem cerebrospinal fluid (CSF) from ALS participants with and without SOD1 mutations during ALS progression. Antemortem CSF from controls, SOD1- ALS, and sporadic ALS (sALS) patients was subjected to SOD1 seed amplification real-time quaking induced conversion (RT-QuIC) assays. SOD1 -ALS CSF exhibited shorter lag phase and increased ThioflavinT (ThT) fluorescence amplitude compared to healthy controls and those with spinal muscular atrophy. CSF from sALS participants, who had no mutations in SOD1 or nine other ALS risk genes, also displayed SOD1 seeding activity, indicating wild-type SOD1 is aggregate-prone in the broader ALS population. Longitudinal CSF data indicated that SOD1 seeding activity correlates with ALS progression via the ALS Functional Rating Scale Revised (ALSFRS-R) slope decline and CSF neurofilament light. Our sALS CSF cohort primarily comprised of participants less than 2 years from symptom onset, suggesting that SOD1 seeding activity is an early biomarker that may enable inclusion in clinical trials. With the FDA-approval of tofersen (Qalsody), a SOD1-lowering antisense oligonucleotide, new SOD1 diagnostic, prognostic and pharmacodynamic biomarkers may enable SOD1-targeting strategies that could benefit the broader ALS population.}, } @article {pmid41929582, year = {2026}, author = {Poyan Mehr, A and Sundang, A and Drasin, T and Bhalla, N and Zheng, S and Pravoverov, L}, title = {Comparison of peritoneal dialysis catheter placement outcomes: image-guided percutaneous technique versus advanced laparoscopic surgical technique.}, journal = {Clinical kidney journal}, volume = {19}, number = {4}, pages = {sfag048}, pmid = {41929582}, issn = {2048-8505}, abstract = {BACKGROUND: Peritoneal dialysis (PD) is an increasingly emphasized modality in nephrology care, due to patient autonomy, reduced healthcare cost and alignment with value-based care initiatives. A critical factor influencing successful PD uptake is the timely placement of peritoneal dialysis catheters (PDCs). Traditional advanced laparoscopic surgical (ALS) methods are effective but constrained by the need for general anesthesia and operating room access. The image-guided percutaneous (IGP) approach has emerged as a potentially safer and more accessible alternative.

METHODS: We conducted a retrospective study of adult patients who underwent PDC placement within Kaiser Permanente Northern California (KPNC) from 1 January 2018 to 31 December 2022. Patient characteristics, procedural variables, post-procedure length of stay, 90- and 180-day catheter intervention rates, 30-day readmission and mortality rates were compared between IGP and ALS techniques.

RESULTS: Among 3062 patients, 835 (27%) received PDCs via IGP and 2227 (73%) via ALS. While there were differences in patient characteristics due to selection biases, with the IGP group having higher prevalence of heart failure, and lower body mass index (BMI), estimated glomerular filtration rate, hemoglobin and albumin levels, IGP was associated with significantly shorter post-procedure length of stay among admitted outpatients (1.8 vs 3.1 days, P = .01) and lower catheter intervention rates at 90 days (1% vs 2.5%, P = .006) and 180 days (1.3% vs 4%, P < .0001). After adjustment for patient gender, race, BMI and polycystic kidney disease status, the ALS technique remained significantly associated with higher odds of catheter re-intervention compared with IGP at both 90 days [adjusted odds ratio (OR) 2.76, 95% confidence interval (CI) 1.30-5.85, P = .008] and 180 days (adjusted OR 3.16, 95% CI 1.67-5.96, P < .0004). Overweight BMI was independently associated with increased intervention risk.

CONCLUSIONS: Despite being applied to a potentially sicker patient cohort, IGP was associated with favorable short- and intermediate-term outcomes compared with ALS, including reduced catheter interventions, without compromising safety outcomes.}, } @article {pmid41929709, year = {2026}, author = {Gazwi, K and Zaza, T and Mitwally, H and Davda, N and Ganaw, A}, title = {Botulinum toxin injection induced autoimmune thyroiditis and myxedema coma: A case report.}, journal = {SAGE open medical case reports}, volume = {14}, number = {}, pages = {2050313X261430649}, pmid = {41929709}, issn = {2050-313X}, abstract = {This case describes a 28-year-old female with amyotrophic lateral sclerosis and recurrent urinary tract infections who developed myxedema coma following a botulinum toxin type-A (Btx) injection for muscle spasticity. On intensive care unit admission, she presented with hypothermia, bradycardia, and reduced consciousness. Laboratory evaluation revealed markedly elevated thyroid-stimulating hormone levels, confirming myxedema coma. Prompt treatment with intravenous levothyroxine and hydrocortisone resulted in rapid improvement in temperature and mental status. Further investigation showed elevated antithyroid peroxidase antibodies, suggesting drug-induced autoimmune thyroiditis triggered by Btx. This case highlights the potential link between Btx injection and thyroid autoimmunity, emphasizing the importance of early recognition and monitoring of thyroid function to prevent life-threatening complications in at-risk patients.}, } @article {pmid41930586, year = {2026}, author = {Pavithra, N and Begum, RF and Ashwini, ST and Nirenjen, S and Singh, A and Manisha, M and Sridevi, S and Singh, SA}, title = {AI-Driven Biomarker Discovery in Motor-Related Neurodegenerative Diseases.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273436955260126215111}, pmid = {41930586}, issn = {1996-3181}, abstract = {Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxias (SCAs) are examples of neurodegenerative disorders (NDDs) that share overlapping neuropathological processes and largely affect motor coordination. For early diagnosis, illness monitoring, and treatment targeting, it is essential to find trustworthy biomarkers that represent motor circuit dysfunction. The purpose of this study is to summarize the state of the art regarding molecular, neurochemical, and imaging biomarkers that are pertinent to motor impairment and to investigate the function of artificial intelligence (AI) in their identification and verification Methods: With an emphasis on biomarker discovery, validation, and AI/ML applications in PD, HD, ALS, and SCAs, a thorough literature search was carried out in the PubMed, Scopus, and Google Scholar databases for research published between 2015 and 2025. The motor-specific correlations of key molecular (α-synuclein, tau, neurofilament light chain, TDP-43, mutant huntingtin), neuroimaging, and digital biomarkers were carefully examined Results: AI-driven methods, such as deep learning and machine learning, have shown great promise in combining multimodal data from digital, fluid, and imaging sources. These techniques enhanced the detection of disease-specific biomarker signatures, especially those associated with deficiencies in motor coordination Discussion: Data heterogeneity, biomarker standardization, model interpretability, and limited cross-disease validation are still issues despite encouraging developments. Improving the clinical reliability of AI-based biomarker models requires filling in these gaps Conclusion: An effective foundation for deciphering intricate motor neurological pathways is provided by AI-assisted biomarker discovery. Transparent algorithms, multicenter data integration, and ethical frameworks should be given top priority in future research to guarantee clinical translation and better patient stratification.}, } @article {pmid41930760, year = {2026}, author = {Patel, S and Sood, R and Shrivastava, S and Jeengar, MK}, title = {Neuroprotective Mechanisms of Erucin: Therapeutic Pathways in Neurodegenerative Disorders.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X385491251208144807}, pmid = {41930760}, issn = {1875-6190}, abstract = {Neurodegenerative Disorders (NDDs), including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and other less prevalent conditions, represent a growing challenge in medical science due to their progressive nature and the absence of curative treatments. Cruciferous vegetables, such as those from the Brassicaceae family and other species in the Brassicales order, have been reported to offer potential benefits for treating and preventing NDDs. Their neuroprotective effects have been attributed to secondary metabolites, glucosinolates (GLs), and their hydrolytic products, isothiocyanates (ITCs). One of these ITCs is Erucin (ERU), chemically known as 4-isothiocyanatobutane, which is a specific type of ITC. ERU is the isothiocyanate derivative of erucic acid and is structurally related to sulforaphane (SFN), another well-known ITC. This review aims to synthesize current scientific knowledge on ERU's mechanisms of action in neurodegeneration, highlighting preclinical evidence supporting its neuroprotective effects in diseases such as AD and PD, and suggesting its potential as a treatment strategy for NDDs. Preliminary studies suggest that ERU may confer neuroprotection through antioxidative stress pathways, modulation of neuroinflammatory responses, and upregulation of neurotrophic factors. This article discusses ERU's chemical properties, pharmacokinetics, and observed impacts on neurodegenerative models, suggesting potential therapeutic pathways it may influence, thereby highlighting its promise as a future component of neuroprotective strategies against NDDs.}, } @article {pmid41931746, year = {2026}, author = {Chalitsios, CV and Rudolf, O and Gao, J and Turner, MR and Thompson, AG}, title = {Long-Term Exposure to Ambient Air Pollution and Incident Amyotrophic Lateral Sclerosis: A Prospective Cohort Analysis of the UK Biobank.}, journal = {Neurology}, volume = {106}, number = {8}, pages = {e214858}, pmid = {41931746}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/etiology ; Female ; Middle Aged ; United Kingdom/epidemiology ; Prospective Studies ; *Air Pollution/adverse effects ; Male ; Aged ; Gene-Environment Interaction ; *Environmental Exposure/adverse effects ; Adult ; Particulate Matter/adverse effects ; Incidence ; Biological Specimen Banks ; UK Biobank ; Nitrogen Oxides/adverse effects ; C9orf72 Protein/genetics ; Nitrogen Dioxide/adverse effects ; *Air Pollutants/adverse effects ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex etiology. Although a range of genetic and lifestyle factors have been implicated, the potential role of environmental airborne pollution exposure is uncertain. This study examined the association between long-term ambient exposure to air pollutants and the incidence of ALS in UK Biobank participants.

METHODS: This prospective cohort study was based on the UK Biobank participants aged 40-69 years. The analytical sample comprised participants free of ALS at baseline and had complete data on air pollution exposure. Long-term exposure (2006-2021) to nitrogen dioxide (NO2), nitrogen oxides (NOX), fine particulate matter (PM2.5; <2.5 µm), and coarse particulate matter (PM10; <10 µm) was assessed using data from the UK Department for Environment, Food and Rural Affairs at a spatial resolution of 1 × 1 km. To evaluate the association between these pollutants and ALS risk, we used multivariable time-varying Cox proportional hazards models. Several sensitivity analyses were conducted to assess the robustness of the results. We also examined for gene-environment interaction stratified by C9orf72 status and UNC13A genotype.

RESULTS: Among the 501,308 participants with a mean age of 56.5 (SD 8.1) years at baseline, 272,764 (54.4%) were female. Over a median follow-up of 8.4 years, 687 individuals developed ALS. We did not observe any associations for any of the examined pollutants and ALS risk. Specifically, the hazard ratios per SD increment for PM10, PM2.5, NOX, and NO2 were 1.03 (95% CI 0.92-1.15), 1.00 (95% CI 0.88-1.14), 1.01 (95% CI 0.90-1.13), and 1.00 (95% CI 0.89-1.12), respectively. Individuals living in areas with the highest tertile of air pollutant exposure, compared with those in the lowest tertile, did not show a higher risk of ALS across any of the pollutants examined (p for trend >0.05). Restricted cubic spline analyses revealed no nonlinear associations between air pollution and ALS risk (all p for nonlinearity >0.05). These results remained robust in various subgroup and sensitivity analyses. No evidence of gene-environment interaction was found.

DISCUSSION: In this large population-based study with high statistical power, ambient air pollution was not a risk factor for the development of ALS.}, } @article {pmid41932459, year = {2026}, author = {Biscardi, T and Pepe, R and Cortini, E and Luongo, D and Notariale, R and Sharbafshaaer, M and Trojsi, F and Bergamo, P}, title = {Supplementation with conjugated linoleic acid ameliorates the level of some Nrf2-activated systemic markers in patients with amyotrophic lateral sclerosis: a proof-of-principle study.}, journal = {Free radical biology & medicine}, volume = {250}, number = {}, pages = {312-320}, doi = {10.1016/j.freeradbiomed.2026.03.067}, pmid = {41932459}, issn = {1873-4596}, } @article {pmid41932651, year = {2026}, author = {Scaricamazza, S and Nesci, V and Fenili, G and Tiberi, M and Percio, A and Rosina, M and Salvatori, I and Riggio, F and Candelise, N and Pieroni, L and Greco, V and Chiurchiù, V and Ferri, A and Valle, C}, title = {The hypothalamus is an early site of mitochondrial failure and neuro-immune circuit disruption in amyotrophic lateral sclerosis.}, journal = {Molecular metabolism}, volume = {107}, number = {}, pages = {102360}, pmid = {41932651}, issn = {2212-8778}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/immunology ; *Hypothalamus/metabolism/immunology ; *Mitochondria/metabolism ; Mice ; Mice, Transgenic ; Energy Metabolism ; Disease Models, Animal ; Superoxide Dismutase-1/genetics/metabolism ; Male ; Humans ; Proteomics ; }, abstract = {BACKGROUND: Metabolic dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), emerging early and strongly associated with disease progression and prognosis. While systemic hypermetabolism is well documented, the central mechanisms underlying energy imbalance remain poorly understood. The hypothalamus, a key regulator of whole-body energy homeostasis, has recently been implicated in ALS, but its mechanistic contribution to metabolic failure and disease progression remains unclear.

METHODS: We analyzed the hypothalamus SOD1-G93A mouse model using proteomics (ProteomeXchange ID: PXD070931), mitochondrial bioenergetic assays, immunofluorescence, flow cytometry, and gene expression to assess hypothalamic mitochondrial function, glial activation, and melanocortin system integrity. Limited analyses in the hFUS model confirmed the presence of key hypothalamic alterations, supporting a shared vulnerability across ALS models. In SOD1-G93A mice, the metabolic modulator trimetazidine (TMZ) was administered presymptomatically to evaluate effects on hypothalamic pathology, metabolic regulation, disease onset, and survival.

FINDINGS: We provide the first evidence that mitochondrial bioenergetic defects arise specifically in the hypothalamus of ALS models before symptom onset. Proteomic profiling revealed dysregulation of mitochondrial pathways, while functional assays confirmed impaired bioenergetics in the hypothalamus. These deficits were accompanied by local pro-inflammatory activation of astrocytes and microglia, mitochondrial dysfunction in glial cells, and early disruption of the arcuate nucleus melanocortin system. Limited analyses in hFUS mice confirmed selective hypothalamic vulnerability. Early TMZ treatment in SOD1-G93A mice specifically restored hypothalamic bioenergetics, normalized local glial activation and melanocortin signaling, delayed disease onset, and extended survival.

INTERPRETATION: These findings establish the hypothalamus as an early and selectively vulnerable site in ALS, where region-specific mitochondrial dysfunction contributes to metabolic and neuroinflammatory alterations. Targeting hypothalamic bioenergetics represents a promising therapeutic strategy.}, } @article {pmid41935163, year = {2026}, author = {Sheikhpour, Z and Seyedalipour, B and Ataei, F and Baziyar, P and Akhlaghi, M and Hosseinkhani, S}, title = {Inhibitory effect of epigallocatechin-3-gallate as a potent anti-amyloidogenic agent against the G138E mutant of SOD1.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41935163}, issn = {2045-2322}, mesh = {*Catechin/analogs & derivatives/pharmacology/chemistry ; Humans ; *Superoxide Dismutase-1/genetics/chemistry/metabolism/antagonists & inhibitors ; *Mutation ; Protein Aggregates/drug effects ; Cell Line, Tumor ; Molecular Dynamics Simulation ; *Amyloid/metabolism ; Cell Survival/drug effects ; Protein Aggregation, Pathological ; }, abstract = {SOD1 misfolding leads to protein aggregation, which is a common feature of neurodegenerative diseases such as ALS. The effect of epigallocatechin gallate (EGCG) as a potent anti-amyloidogenic polyphenol on the G138E-SOD1 mutant was investigated using computational/experimental approaches. MD simulation results (RMSD, RMSF, Rg, SASA, PCA, and FEL) showed that EGCG binding stabilizes the mutant in a structure closer to the native structure, which was consistent with the FTIR and DSSP results. Intrinsic fluorescence spectroscopy calculated Ksv and Kq values as 1.8 × 10[4] M[-1] and 5.8 × 10[12] M[-1]s[-1], respectively, indicating the participation of a static quenching mechanism. TEM images provide compelling evidence for the potential inhibitory effect of EGCG on protein aggregates in the G138E mutant, confirming the results of the ThT assay. DLS results showed a reduction in the size of aggregated particles in the presence of 80 μM EGCG, confirming the inhibition of amyloid aggregation by this compound. Finally, MTT assay on SH-SY5Y cells showed that cell survival in the presence of SOD1-G138E aggregates was approximately 40%, which increased to 60% with the addition of 80 μM EGCG. Taken together, this study suggests that EGCG may inhibit amyloid aggregation and reduce cytotoxicity by affecting nucleation and structural stabilization, making it a promising compound for ALS therapeutic strategies.}, } @article {pmid41936785, year = {2026}, author = {Bao, A and Liu, J and Bian, B and Gao, T and Zhou, H}, title = {U-Mamba-Spectra: A novel generative and explainable framework for camel milk adulteration detection using near-infrared spectral learning.}, journal = {Food chemistry}, volume = {514}, number = {}, pages = {149054}, doi = {10.1016/j.foodchem.2026.149054}, pmid = {41936785}, issn = {1873-7072}, mesh = {Animals ; *Milk/chemistry ; Spectroscopy, Near-Infrared/methods ; *Food Contamination/analysis ; Camelus ; Machine Learning ; }, abstract = {Camel milk is vulnerable to adulteration due to its high value and limited supply. This study proposes an interpretable framework, U-Mamba-Spectra, for qualitative and quantitative detection of camel milk adulteration using near-infrared (NIR) spectroscopy. A total of 460 samples (0-100% adulteration) were analyzed within 780-1830 nm. The proposed U-Mamba classifier, integrating U-Net and Mamba modules to capture local and global spectral dependencies, achieved superior classification performance compared with conventional machine learning and deep learning models. SHAP analysis identified chemically meaningful bands associated with water, protein, and fat. For quantitative analysis, a two-stage MCR-ALS-RF model enabled accurate and chemically interpretable concentration prediction, with validation according to ICH Q2 (R1) demonstrating recoveries of 96.8-99.5%, RSD < 5%, and detection limits of 0.025-0.060 g/100 g. To improve robustness under limited sample conditions, a hybrid generative model (CVAE-CWGAN-GP-SAM) was introduced for spectral augmentation, increasing classification accuracy from 95.21% to 98.60%.}, } @article {pmid41937301, year = {2026}, author = {Laine, M and Raitanen, J and Auvinen, A}, title = {Mortality From Amyotrophic Lateral Sclerosis in Finland 1987-2022.}, journal = {European journal of neurology}, volume = {33}, number = {4}, pages = {e70586}, pmid = {41937301}, issn = {1468-1331}, mesh = {*Amyotrophic Lateral Sclerosis/mortality ; Finland/epidemiology ; Humans ; Female ; Male ; Aged ; Middle Aged ; Adult ; Aged, 80 and over ; Age Distribution ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. We assessed changes in the mortality from ALS in Finland from 1987 to 2022.

METHODS: Numbers of deaths caused by ALS (ICD-10 code G12.2) and population sizes by sex, age group, and year were obtained from Statistics Finland. Crude and age-standardized mortality rates were calculated. The annual percentage change was estimated using Poisson regression, and joinpoint regression was used to identify changes in trend during the study period.

RESULTS: Mortality from ALS increased in Finland from 1987 to 2022. The age-standardized ALS mortality in the entire population was 2.24/100,000 in 1987 and 4.21/100,000 in 2022. The male: female ratio in mortality was 1.18. The age-standardized mortality increased on average by 1.7% (95% CI 1.5%-2.0%) annually. In men, the age-standardized mortality increased on average by 1.2% (95% CI 0.9%-1.6%) annually and in women by 2.0% (95% CI 1.6%-2.3%). The largest increase occurred in the oldest age group (70+ years), with an average annual increase of 2.4% (95% CI 2.0%-2.8%). In joinpoint regression, no changes in trend were identified overall or in men, but in women, the annual percentage change (APC) was 5.5% (95% CI 3.0%-8.0%) in 1987-1997 and 1.0% (95% CI 0.5%-1.4%) during 1997-2022.

CONCLUSION: Similar to some other countries, mortality from ALS has increased in Finland, nearly doubling in 35 years. Further research on possible reasons is needed.}, } @article {pmid41938070, year = {2026}, author = {Samokhina, E and Buskila, Y}, title = {Astrocytic K[+] regulation during neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1782460}, pmid = {41938070}, issn = {1663-4365}, abstract = {Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in specific areas of the central nervous system. Historically, a "neurocentric" paradigm viewed glial cells, such as astrocytes, as cells that provided adequate support for neuronal energy metabolism and controlled local cerebral blood flow. However, studies from the past two decades found that astrocytes are involved in synaptic function through different mechanisms, including the uptake of extracellular glutamate molecules and potassium ions following synaptic neuronal transmission. Also, astrocytes respond to neurotransmitters and neuromodulators through alterations of intracellular ion concentrations (e.g., Na[+], Ca[2+], K[+]) and the release of gliotransmitters. Astrocytes play a pivotal role in preserving potassium homeostasis within the central nervous system through their potassium channels, a process known as "potassium clearance." Impaired astrocytic potassium clearance mechanisms can result in neuronal hyperexcitability, leading to increased glutamate release, overactivation of glutamate receptors, and cytotoxicity. Recent studies suggest that these factors can cause cell death and neurodegeneration, and further indicate a region-specific glial dysfunction in neurodegeneration, which reflects the heterogeneity of glial cell function and sensitivity across different brain regions. Overall, this manuscript offers novel insights into a relatively new concept that glial cells can actively shape neuronal activity and survival.}, } @article {pmid41940896, year = {2026}, author = {Tang, Z and Lei, Y and Huang, J and He, R and Wu, Y and Li, M and Ye, Z and He, X and Heng, H and Zha, Y and Wei, J}, title = {Accuracy of muscle ultrasonography in detecting fasciculations for the diagnosis of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology}, volume = {273}, number = {4}, pages = {}, pmid = {41940896}, issn = {1432-1459}, support = {2020ZYYD024//Local Development Project of Science and Technology guided by the Central Commission/ ; EWT201947//Hubei Province Leading Medical Talents and Hubei Province Famous Doctor Studio Program/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/complications ; Humans ; Ultrasonography/standards ; *Fasciculation/diagnostic imaging/etiology ; *Muscle, Skeletal/diagnostic imaging ; Sensitivity and Specificity ; }, abstract = {PURPOSE: This systematic review and meta-analysis aims to evaluate the diagnostic accuracy of muscle ultrasonography in detecting fasciculations for the diagnosis of amyotrophic lateral sclerosis (ALS).

METHODS: Following PRISMA-DTA guidelines, we systematically searched PubMed, Embase, Cochrane Library, Ovid Medline, Sinomed, Web of Science, CNKI and VIP for studies published up to July 8, 2025 that evaluated muscle ultrasonography to detect fasciculations for ALS diagnosis. The study protocol was registered in PROSPERO (CRD420251057866). Studies were screened using predefined inclusion and exclusion criteria and data were extracted. Risk of bias was assessed with QUADAS-2. Statistical analyses (Stata 16.0 and R 4.5.1 with the "midas," "metandi," and "mada" packages) were used to calculate pooled sensitivity (Sen), specificity (Spe), positive likelihood ratio (LR+), negative likelihood ratio (LR-), and diagnostic odds ratio (DOR). We constructed forest plots, hierarchical summary receiver operating characteristic (HSROC) curves, summary ROC (SROC) curves and calculated the area under the SROC curve (AUC). Univariate meta-regression and subgroup analyses explored sources of heterogeneity. Publication bias was assessed using Deeks' funnel plot asymmetry test. Fagan nomograms were also used to illustrate the changes from pre-test to post-test probability and to enhance clinical interpretability.

RESULTS: Thirteen studies involving 1176 participants met the inclusion criteria. Muscle ultrasonography for fasciculation detection in ALS yielded a pooled sensitivity of 0.87 (95% CI 0.83-0.91) and specificity of 0.91 (95% CI 0.86-0.94). The pooled LR+ was 9.81 (95% CI 6.25-15.40) and LR- was 0.14 (95% CI 0.10-0.19), with a DOR of 70.03 (95% CI 41.72-117.56). The area under the SROC curve was 0.94 (95% CI 0.91-0.95). Meta-regression identified scan duration as a primary factor influencing diagnostic accuracy, with scan durations ≥ 30 s associated with higher sensitivity but relatively lower specificity. Deeks' funnel plot showed no significant asymmetry (p = 0.61), indicating no notable publication bias. Fagan nomograms showed that, at a pre-test probability of 30%, the post-test probability increased to 81% after a positive MUS result and decreased to 6% after a negative result.

CONCLUSION: Muscle ultrasonography demonstrates good pooled diagnostic accuracy for detecting fasciculations in ALS and may serve as a useful adjunct to electrodiagnostic evaluation. Scan duration appears to significantly affect the diagnostic performance, with longer scanning improving sensitivity at the cost of reduced specificity. We speculate that prolonged scanning may be more useful in clinical scenarios where fasciculations are subtle or atypical, whereas shorter scanning may be sufficient when fasciculations are already readily apparent. Nevertheless, further large-scale prospective studies are needed to validate standardized scanning protocols and to better define the clinical role of MUS in ALS diagnostic pathways.}, } @article {pmid41941281, year = {2026}, author = {Subramanian, I and Surajambika, RR and Sekar, D and Natarajan, R and Nagarajan, NC}, title = {A Systematic Review on Isoquinoline Derivatives as Emerging Multi-target Agents in Alzheimer's and Parkinson's Disorder Therapy.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249401454260108062419}, pmid = {41941281}, issn = {1875-6166}, abstract = {INTRODUCTION: Neurodegenerative disorders, including Alzheimer's, Parkinson's, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease, are characterized by progressive neuronal loss driven by damage or apoptosis. Although their precise etiologies remain unclear, neuronal degeneration is a common pathological hallmark.

METHODS: This review compiles and critically evaluates studies investigating the potential of isoquinoline derivatives to mitigate neurodegeneration. Particular attention is given to their inhibitory effects on key enzymes implicated in these disorders and structural modifications aimed at improving potency and reducing toxicity.

RESULTS: Experimental findings demonstrate that isoquinoline derivatives exhibit significant inhibitory activity against several neurodegeneration-related enzymes. These compounds show promise in attenuating disease progression in preclinical models, supporting their potential as therapeutic leads.

DISCUSSION: Isoquinoline derivatives display multitarget properties, and structural optimization has enhanced their efficacy and safety profiles. Their multifunctional nature could offer advantages over current single-target therapies by improving efficacy and reducing adverse effects.

CONCLUSION: Isoquinoline derivatives represent promising scaffolds for developing novel therapeutics targeting neurodegenerative disorders. However, most data are limited to in vitro and earlystage preclinical studies. Comprehensive mechanistic investigations, standardized in vivo evaluations, and early-phase clinical trials are required to establish their pharmacokinetics, blood-brain barrier permeability, safety, and therapeutic potential.}, } @article {pmid41941533, year = {2026}, author = {Zhuolin, D and Chun, H and Su, X}, title = {Association between allostatic load and thyroid function in U.S. adults: a cross-sectional study based on NHANES data.}, journal = {Stress (Amsterdam, Netherlands)}, volume = {29}, number = {1}, pages = {2653858}, doi = {10.1080/10253890.2026.2653858}, pmid = {41941533}, issn = {1607-8888}, mesh = {Humans ; *Allostasis/physiology ; Male ; Female ; Cross-Sectional Studies ; Nutrition Surveys ; *Thyroid Gland/physiopathology/physiology ; Thyrotropin/blood ; Middle Aged ; Adult ; United States ; Biomarkers/blood ; Thyroxine/blood ; Triiodothyronine/blood ; *Stress, Psychological/physiopathology ; Thyroid Function Tests ; Aged ; }, abstract = {Chronic stress may contribute to endocrine dysregulation. The allostatic load (AL), an indicator of cumulative physiological burden across multiple systems, has unclear associations with thyroid function. We analyzed 5525 adults (2678 men and 2847 women) from NHANES 2007-2010. The participants were categorized into allostatic load score (ALS) quartiles: Q1 (n = 2582), Q2 (n = 1394), Q3 (n = 1003), and Q4 (n = 546). The ALS was constructed from eight cardiovascular, metabolic, and inflammatory biomarkers. Thyroid function was assessed (TSH, FT3, FT4, TgAb, and TPOAb) and categorized as thyroid dysfunction. Survey-weighted multivariable linear and logistic models estimated associations; trend tests and restricted cubic splines (RCS) assessed linearity. Subgroup and interaction analyses examined effect modification, and sensitivity analyses evaluated robustness. ALS was positively associated with higher TSH (β = 0.038, 95% CI: 0.019-0.057, p = 0.001) and FT3 (β = 0.005, 95% CI: 0.003-0.008, p < 0.001). No significant associations were observed for FT4, TPOAb, or TgAb. TSH increased linearly across ALS quartiles (p-trend < 0.001). Restricted cubic splines indicated no overall departure from linearity; in sex-stratified analyses, the association was linear in women and nonlinear in men. Significant interactions with age and race (p < 0.05) indicate that the ALS-TSH association differs by demographics. The results were consistent across the subgroup and sensitivity analyses. Our study suggested a significant positive association between AL and TSH levels. Further research is needed to clarify the mechanisms linking stress and thyroid function.}, } @article {pmid41941997, year = {2026}, author = {Cai, ZW and Zhuang, SP and Huang, ZY and Shi, JY and Huang, NX and Chen, S and Zou, ZY and Chen, HJ}, title = {Abnormal cortical hierarchy revealed by gradient dysfunction in patients with definite amyotrophic lateral sclerosis.}, journal = {Brain research bulletin}, volume = {239}, number = {}, pages = {111850}, doi = {10.1016/j.brainresbull.2026.111850}, pmid = {41941997}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Female ; Male ; Magnetic Resonance Imaging/methods ; Middle Aged ; *Cerebral Cortex/physiopathology/diagnostic imaging ; Brain Mapping/methods ; Aged ; Neural Pathways/physiopathology ; Adult ; Nerve Net/physiopathology/diagnostic imaging ; }, abstract = {PURPOSE: Cortical multisystem dysfunction in amyotrophic lateral sclerosis (ALS) has been investigated, but disruptions in unimodal-to-transmodal cortical hierarchy remained unexplored. We identified cortical hierarchy abnormalities using functional connectivity gradient (FCG) analysis and evaluated their clinical relevance in ALS.

METHODS: Resting-state functional MRI images were acquired from 17 definite ALS patients and 29 healthy controls. Unimodal-to-transmodal cortical gradient values were derived from functional connectivity matrices using diffusion map embedding, a nonlinear dimensionality reduction method. Intergroup differences were examined with two-sample t tests at the voxel and network levels.

RESULTS: Gradients primarily in transmodal areas (including the bilateral frontal and parietal cortex and anterior cingulate gyrus) decreased, and gradients primarily in unimodal areas (including the bilateral precentral and postcentral gyrus and occipital cortex) increased in ALS patients (false discovery rate (FDR)-corrected P < 0.05). Network-level gradients in ALS were elevated in the sensorimotor (SMN) and visual networks (VN) but reduced in the frontoparietal (FPN) and limbic networks (FDR-corrected P < 0.05). Among ALS patients, the gradient values in SMN (r = 0.506; P = 0.038), VN (r = 0.534; P = 0.027) and FPN (r = -0.792; P < 0.001) correlated with disease duration, and the gradient value in FPN correlated with disease severity (r = 0.532; P = 0.028). Gradient measures demonstrated moderate accuracy for diagnosing ALS (AUC = 0.712-0.866).

CONCLUSION: Aberrant cortical hierarchy may elucidate pathophysiological mechanisms of multisystem dysfunction in ALS. FCG analysis may provide biomarkers related to hierarchical functional systems for assessing ALS progression and diagnosis.}, } @article {pmid41942009, year = {2026}, author = {Song, L and Li, W and Li, H and Zhang, L}, title = {Comment on Gao et al's "Eggshell fragments as a high-yield diagnostic target in microscopic examination of scabies: a retrospective study".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {2}, pages = {e171-e172}, doi = {10.1016/j.jaad.2026.01.105}, pmid = {41942009}, issn = {1097-6787}, } @article {pmid41943205, year = {2026}, author = {Beers, DR and Lin, YY and Thonhoff, JR and Thome, AD and Faridar, A and Zhao, W and Wen, S and Appel, SH}, title = {Longitudinal Assessment of Biomarkers in ALS: Discriminative Biomarkers for Disease Progression and Survival.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, pmid = {41943205}, issn = {2328-9503}, abstract = {OBJECTIVE: To assess the association and discriminative performance of serum biomarkers with clinical disease progression and survival in patients with amyotrophic lateral sclerosis (ALS).

METHODS: This retrospective study, conducted at Houston Methodist Hospital, Houston, TX, used longitudinal serum samples collected between January 2018 and December 2022. A cohort of 100 patients with sporadic or familial ALS was randomly selected and assayed by ELISAs for biomarkers 4-hydroxy-2-nonenal (4-HNE), lipopolysaccharide binding protein (LBP), and neurofilament light chain (NfL) levels.

RESULTS: Each biomarker was increased in patients. 4-HNE and LBP were increased at diagnosis and continued to increase as the disease progressed; both correlated with progression rates and survival. NfL was increased at diagnosis, then plateaued relatively. LBP correlated with ALSFRS-R at diagnosis; NfL did not correlate. 4-HNE and LBP were increased in bulbar onset patients who survived a shorter period of time; NfL levels for bulbar/limb onsets were not different. Receiver operating characteristic analyses with apparent and optimism-adjusted area-under-the-curve (AUC) demonstrated that 4-HNE and LBP discriminated rapid progression and survival, whereas NfL showed modest discrimination for rapid progression. The combination of biomarkers yielded improved AUCs as depicted in Venn diagrams across individual and combined biomarkers.

INTERPRETATION: 4-HNE, LBP, and NfL are biomarkers of lipid peroxidation, systemic inflammation, and axonal integrity. 4-HNE and LBP correlated with disease burden, disease progression, and survival. In the bulbar onset, survival was shortened and associated with increased 4-HNE and LBP. This exploratory longitudinal study suggests the utility of combining biomarkers to discriminate disease progression and survival and monitor clinical trial outcomes.}, } @article {pmid41943580, year = {2026}, author = {Ye, Y and Zhang, Z and Xiao, Y and Zhu, C and Wright, N and Asbury, J and Huang, Y and Wang, W and Gomez-Isaza, L and Troncoso, JC and He, C and Sun, S}, title = {DCPS modulates TDP-43-linked neurodegeneration through P-body-mediated RNA decay.}, journal = {Neuron}, volume = {114}, number = {11}, pages = {1970-1985.e12}, pmid = {41943580}, issn = {1097-4199}, support = {R01 AG078948/AG/NIA NIH HHS/United States ; R01 NS127925/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; RM1 HG008935/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/genetics/metabolism ; *RNA Stability/genetics ; Neurons/metabolism ; *Processing Bodies/metabolism ; *Neurodegenerative Diseases/genetics/metabolism ; Animals ; *Endoribonucleases/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics ; RNA, Messenger/metabolism ; }, abstract = {The proteinopathy of the RNA-binding protein TDP-43, characterized by nuclear clearance and cytoplasmic inclusion, is a hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). Through CRISPR interference (CRISPRi) screening in human neurons, we identified the decapping scavenger enzyme (DCPS) as a novel genetic modifier of TDP-43 loss-of-function (LOF)-mediated neurotoxicity. Our findings reveal that TDP-43 LOF leads to aberrant mRNA degradation via dysregulating the properties and activity of processing bodies (P-bodies). TDP-43 interacts with P-body component proteins, potentially influencing their dynamic equilibrium and assembly into ribonucleoprotein (RNP) granules. Loss of TDP-43 hyperactivates P-bodies, increasing mRNA association and RNA decay. Reducing DCPS restores P-body integrity and RNA turnover, ultimately improving neuronal survival. Overall, this study highlights a novel role of TDP-43 in RNA processing through P-body regulation and identifies DCPS as a potential therapeutic target for TDP-43 proteinopathy-related neurodegenerative diseases.}, } @article {pmid41943810, year = {2026}, author = {Khandelwal, N and Geremakis, C and Riaz, F and Ryan, G and Saundankar, V and Sheer, R and Suehs, B}, title = {Epidemiology, Patient Characteristics, Real-World Treatment Patterns, and Healthcare Utilization and Spending for Patients with Multifocal Motor Neuropathy: A US Claims-Based Analysis.}, journal = {Journal of health economics and outcomes research}, volume = {13}, number = {1}, pages = {111-119}, pmid = {41943810}, issn = {2327-2236}, abstract = {BACKGROUND: Multifocal motor neuropathy (MMN) is a rare, progressive neurological disease characterized by asymmetrical limb weakness. The real-world healthcare burden of MMN is not well established.

OBJECTIVES: To characterize the epidemiology, diagnostic procedures, treatment patterns, healthcare resource utilization (HCRU), and healthcare spending associated with MMN in patients in the US.

METHODS: This retrospective, observational claims study extracted data from the Humana Healthcare Research Database, comprising US Medicare Advantage plan members. Eligible patients were aged 18-89 years, had ≥2 nondiagnostic medical claims (the first being the index date) associated with an MMN diagnosis code (January 1, 2017-June 30, 2022), and continuous enrollment for 12 months pre-index (baseline) and post-index (follow-up). Patients with amyotrophic lateral sclerosis, chronic inflammatory demyelinating neuropathy, or immunosuppressant use were excluded. Outcomes were assessed during the baseline and follow-up periods.

RESULTS: Deidentified data were extracted for 248 patients with MMN. Median (Q1, Q3) age at index was 70.0 (62.0, 77.0) years; most patients were male (53.6%) and White (78.2%). Diagnostic procedures included (baseline/follow-up periods) spinal magnetic resonance imaging (21.4%/18.1%), nerve conduction studies (19.8%/14.5%), and electromyography (17.7%/15.3%). Anticonvulsants, pain medications, corticosteroids, and central muscle relaxants were the most commonly used medications. Overall, 5.2% of patients had intravenous immunoglobulin (IVIG) during follow-up. Mean (standard deviation [SD]) time from index to IVIG initiation was 63.1 (52.2) days, with 6.5 (5.4) administrations, 28.7 (22.9) days between administrations, and 147.5 (133.9) days of total treatment. For all-cause HCRU, 23.8% of patients had ≥1 inpatient stay in the baseline period, with mean (SD) length of stay of 12.7 (14.5) days; during follow-up, 27.8% of patients had ≥1 inpatient stay (length of stay, 13.4 [16.2] days). During the baseline/follow-up periods, 43.1%/46.8% of patients had ≥1 emergency department visit, and 18.5%/28.6% used telehealth services. Median all-cause spending (baseline/follow-up) was 11   299 / 16 074 for total healthcare, 6745 / 10 630 for medical resources, and 1374 / 1701 for pharmacy.

DISCUSSION: Further studies are needed to enhance our understanding of the real-world diagnostic and treatment patterns associated with MMN and to determine long-term clinical outcomes.

CONCLUSION: These real-world data highlighted the considerable burden associated with MMN on the healthcare system and patients.}, } @article {pmid41944768, year = {2026}, author = {Pang, XY and Wang, HF and Bai, JM and Huang, XS}, title = {Integration of Single-cell RNA Sequencing and Mendelian Randomization Analysis for Identifying Potential Immune Therapeutic Targets in Amyotrophic Lateral Sclerosis.}, journal = {Biomedical and environmental sciences : BES}, volume = {39}, number = {3}, pages = {327-341}, doi = {10.3967/bes2026.011}, pmid = {41944768}, issn = {2214-0190}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/immunology ; Humans ; *Mendelian Randomization Analysis ; Sequence Analysis, RNA ; Single-Cell Analysis ; Genome-Wide Association Study ; Single-Cell Gene Expression Analysis ; Female ; }, abstract = {OBJECTIVE: Adaptive immune responses play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). In this study, we investigated the functional mechanisms of T cell subtypes and assessed the causal links between CD4+ cytotoxic T cell-related genes and ALS risk.

METHODS: Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from patients with ALS and healthy controls (HC) was used to identify differentially expressed genes (DEGs) in CD4+ cytotoxic T cells. Comprehensive analyses of CD4+ cytotoxic T cells, including pseudotemporal trajectory, intercellular communication, and metabolic pathway analysis, were performed. Mendelian randomization (MR) analysis evaluated the causal effects of DEGs on ALS risk, with validation using independent genome-wide association study (GWAS) data. Expression patterns of the causal genes were further verified using scRNA-seq, bulk-seq, and clinical samples.

RESULTS: CD4+ cytotoxic T cells were significantly expanded in patients with ALS. The upregulated genes S100A6, SERPINB6, SMAD7, and TPST2 were positively correlated with ALS susceptibility, whereas DIP2A showed a protective association.

CONCLUSION: S100A6, SERPINB6, SMAD7, TPST2, and DIP2A were identified as causal genes and potential therapeutic targets in ALS, implicating CD4+ cytotoxic T cells in the disease mechanisms. Further studies targeting these genes and neuroinflammatory pathways are warranted.}, } @article {pmid41945266, year = {2026}, author = {Pouliquen, O}, title = {Non-local rheology in granular media: a perspective on the 2015 EPJE Paper by Bouzid et al.}, journal = {The European physical journal. E, Soft matter}, volume = {49}, number = {4}, pages = {}, pmid = {41945266}, issn = {1292-895X}, support = {101097842//HORIZON EUROPE European Research Council/ ; }, abstract = {The study "Non-local rheology in dense granular flows: Revisiting the concept of fluidity," published in 2015 in The European Physical Journal E (vol. 38) by Mehdi Bouzid and collaborators, stands as an important contribution to the rheology of granular materials. In their work, the authors critically discuss the differences between proposed non-local models and provide clear pathways to discriminate between them. This perspective paper revisits the state of the art at the time of the Bouzid et al's publication, highlighting its role in inspiring subsequent research. We then explore recent advancements since 2015, which, while significant, have not yet fully resolve the questions originally raised by Bouzid et al.}, } @article {pmid41945652, year = {2026}, author = {Schmidt, J and Lampe, D and Poppe, A and Meyer, I and Söling, S and Köberlein-Neu, J and Grandt, D and Düvel, L and Greiner, W and , }, title = {Enhancing Continuous Medication Safety Through e-Prescription and Clinical Decision Support Systems in Outpatient Practices and Pharmacies: Protocol for a Multiperspective Study (eRIKA Study).}, journal = {JMIR research protocols}, volume = {15}, number = {}, pages = {e87277}, pmid = {41945652}, issn = {1929-0748}, mesh = {Humans ; *Decision Support Systems, Clinical/standards ; *Electronic Prescribing/standards/statistics & numerical data ; Pharmacies/statistics & numerical data ; Germany ; Polypharmacy ; Research Design ; Ambulatory Care ; Drug-Related Side Effects and Adverse Reactions/prevention & control ; }, abstract = {BACKGROUND: Increased life expectancy is associated with increasing multimorbidity and polypharmacy, leading to a heightened risk of drug-drug interactions and adverse events, especially when multiple health care providers are involved. To address the urgent need for safer medication management in this population, tools such as medication plans (MP), electronic prescriptions (e-prescriptions), and clinical decision support systems (CDSS) offer valuable support. These instruments have the potential to enhance medication safety by providing physicians and pharmacists with a comprehensive overview of a patient's overall medication regimen and by assisting health care professionals in making informed prescribing decisions.

OBJECTIVE: This study aims to improve medication therapy safety by combining e-prescriptions, the use of claims data, MPs, CDSS, and interprofessional communication. To comprehensively evaluate this complex intervention, a holistic multiphase study will be conducted, examining (1) the effectiveness of the intervention and (2) health-economic and (3) implementation-related aspects.

METHODS: A multiphase study design is used. In the first phase, the intervention is implemented in selected outpatient practices (n=10) and pharmacies (n=10) in 2 regions in Germany as part of a cluster-randomized controlled trial to assess process-related outcomes. The primary outcome is the congruence between the MP and claims data. In phase 2, the intervention is scaled up in 3 regions and evaluated in a quasi-experimental study. The required sample size for the intervention group is 3528 patients, with a synthetic control group matched from existing claims data. The primary outcome is a combined end point of all-cause mortality and hospitalization within 3 months of an index prescription. Quantitative methods (descriptive, regression-based methods using claims data, calculation of the incremental cost-effectiveness ratio, and survey-based analyses of implementation-related aspects) and qualitative methods (interviews and focus groups to capture experiences of health care professionals and patients) are used.

RESULTS: In phase 1, a total of 187 patients were recruited (74 in the intervention group and 113 in the control group) by June 2025. Phase 2 is currently ongoing, with data collection continuing through December 31, 2025. Final analyses are planned by March 2027.

CONCLUSIONS: Medication safety in polypharmacy remains a critical challenge in Germany. This study provides multiperspective evidence supporting the nationwide implementation of the eRIKA (e-prescription as an element of interprofessional care pathways for continuous medication therapy management [eRezept als Element interprofessioneller Versorgungspfade für kontinuierliche AMTS]) intervention.}, } @article {pmid41945799, year = {2026}, author = {Barnwal, N and Dubey, S and Tiwari, P}, title = {Benzimidazole as a Versatile Scaffold for Developing Neurotherapeutics Against Neurodegenerative Diseases.}, journal = {ChemMedChem}, volume = {21}, number = {7}, pages = {e202500869}, doi = {10.1002/cmdc.202500869}, pmid = {41945799}, issn = {1860-7187}, mesh = {Humans ; *Benzimidazoles/chemistry/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use/chemical synthesis ; Animals ; Molecular Structure ; Structure-Activity Relationship ; *Enzyme Inhibitors/chemistry/pharmacology ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss, leading to severe cognitive and motor dysfunction. Benzimidazole, a privileged heterocyclic scaffold, has emerged as a promising pharmacophore in modulating key pathological targets across these disorders. In AD, benzimidazole derivatives inhibit cholinesterases, glycogen synthase kinase-3β (GSK-3β), and glutaminyl cyclase (QC), thereby addressing cholinergic dysfunction, tau phosphorylation, and amyloid aggregation. In PD and HD, they act as monoamine oxidase-B (MAO-B) inhibitors, dopamine D1/D2 receptor modulators, and N-methyl D-aspartate receptor antagonists, improving dopaminergic signalling and reducing excitotoxicity. In ALS, benzimidazoles regulate acetylcholine dysfunction and inhibit receptor-interacting protein kinase 1 (RIPK1), limiting neuroinflammation and cell death. Preclinical studies demonstrate potent enzyme inhibition, often with IC50 values in the nanomolar to micromolar range, alongside favourable ADMET properties enabling blood-brain barrier penetration. Clinically, the glutaminyl cyclase inhibitor Varoglutamstat has advanced to Phase II trials for AD, while Riluzole remains the only food and drug administration (FDA)-approved benzimidazole drug for ALS. The structural versatility of benzimidazoles supports their development as multi-target-directed ligands, addressing overlapping mechanisms such as protein aggregation, oxidative stress, and neuroinflammation. Emerging strategies including hybrid molecules, nanocarrier delivery, and AI-driven design may accelerate their clinical translation.}, } @article {pmid41947659, year = {2026}, author = {Vaudroz, V and Hübers, A and Kiliaridis, S and Antonarakis, GS}, title = {The Repercussions of Amyotrophic Lateral Sclerosis on the Orofacial Sphere: A One-Year Prospective Longitudinal Study.}, journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry}, volume = {46}, number = {2}, pages = {e70170}, pmid = {41947659}, issn = {1754-4505}, mesh = {Humans ; Female ; Longitudinal Studies ; Male ; Prospective Studies ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Disease Progression ; *Malocclusion/etiology ; Middle Aged ; *Oral Health ; Aged ; Adult ; DMF Index ; }, abstract = {AIM: The aim of this longitudinal study was to evaluate the repercussions of amyotrophic lateral sclerosis (ALS) on orofacial function, dental health, and the development of malocclusions, in order to assess whether disease progression influences oral and craniofacial outcomes.

SUBJECTS AND METHODS: Thirteen patients diagnosed with ALS according to the Gold Coast criteria were enrolled to be examined at two time points (T1 and T2), with a one-year interval. The ALS Functional Rating Scale-Revised (ALS-FRS-R), the Nordic Orofacial Test Screening (NOT-S), the Decayed Missing and Filled Teeth (DMFT) index, Plaque Index, and standard orthodontic assessments were used to quantify changes in disease progression, orofacial function, dental health, and occlusal parameters, respectively. Statistical evaluation: Paired sample t-tests were performed to evaluate differences between T1 and T2 for continuous variables. Chi-square and Fisher's exact tests were used for categorical data. Multiple linear regression analyses were carried out to assess potential associations between general disease progression, ALS type, and orofacial functional or dental health decline. A significance level of p < 0.05 was adopted for all analyses.

RESULTS: Thirteen patients were examined at T1, 10 of whom completed both evaluations. A significant deterioration in the general disease condition was observed (ALS-FRS-R: mean difference -6.0 ± 6.98; p = 0.024). Orofacial function worsened significantly as reflected by an increase in NOT-S total score (+2.3; p = 0.001). Dental health also declined, with a significant increase in DMFT (+1.8; p = 0.014) and Plaque Index (+0.4; p = 0.004). However, occlusal parameters remained stable over the 12-month period, with no significant changes in overjet (p = 0.860) or overbite (p = 0.347). The bulbar type of ALS seems to show worse deterioration of orofacial function over time, and individuals with more significant general disease progression also showed worse orofacial functional decline.

CONCLUSIONS: ALS has a significant impact on orofacial function and dental health, characterized by neuromuscular deterioration, increased plaque accumulation, and a higher number of affected teeth. Despite this decline, dental occlusion appears to remain stable in the short term. These findings highlight the need for interdisciplinary and preventive oral care strategies in the management of patients with ALS, aiming to preserve oral function and quality of life in a progressively disabling disease.}, } @article {pmid41949165, year = {2026}, author = {Xu, X and Xu, J and Xue, F and Li, W and Liu, H and Zhang, Z and Chen, S}, title = {Isoform-specific function underlies differential herbicide resistance of the W574L mutation in peanut AhALS isozymes.}, journal = {Pest management science}, volume = {82}, number = {8}, pages = {7308-7320}, pmid = {41949165}, issn = {1526-4998}, support = {//S&T Program of Hebei/ ; //Shijiazhuang City Modern Agricultural Innovation Special Project of the Key R & D and Small and medium-sized enterprises Innovation Program/ ; //National Natural Science Foundation of China/ ; }, mesh = {*Herbicide Resistance/genetics ; *Acetolactate Synthase/genetics/metabolism ; *Arachis/genetics/drug effects/enzymology ; *Herbicides/pharmacology ; *Plant Proteins/genetics/metabolism ; Mutation ; Isoenzymes/genetics/metabolism ; Nicotinic Acids/pharmacology ; }, abstract = {BACKGROUND: Peanut (Arachis hypogaea) is an important cash crop with high oil yield per unit area; it is considered an excellent source for producing premium edible oil and a variety of processed foods. Weed infestation poses a critical challenge to peanut cultivation. Although the acetolactate synthase (ALS)-inhibiting herbicide imazethapyr is extensively applied for weed control in peanut fields, it also causes significant phytotoxicity to the crop. The development of herbicide-resistant varieties through gene editing represents a promising sustainable solution; however, the identification of efficient gene-editing targets for conferring high herbicide resistance in peanut remains limited. Plant resistance to imazethapyr arises primarily from mutations in the target gene ALS.

RESULTS: In this study, a total of four AhALS genes (AhALS1a, AhALS1b, AhALS2a and AhALS2b) with high homology were identified in cultivated peanut. Importantly, we demonstrated for the first time that all four AhALS proteins localize to the chloroplast. Using site-directed mutagenesis, we introduced mutations at position 574 (W574L) in AhALS1a, AhALS2a, AhALS1b and AhALS2b. Both petri-dish and whole-plant bioassays revealed that transgenic Arabidopsis thaliana expressing AhALS2b-W574L remained susceptible to imazethapyr. By contrast, lines expressing AhALS1a-W574L, AhALS2a-W574L or AhALS1b-W574L exhibited high herbicide resistance. The reduced binding ability of resistance AhALS isoforms to imazethapyr was mainly responsible for transgenic lines resistance to imazethapyr. Furthermore, enzymatic and molecular interaction analyses critically showed that the W574L mutation in AhALS2b, unlike its paralog AhALS1b, did not reduce binding affinity to imazethapyr and thus conferred no resistance.

CONCLUSIONS: This demonstrates marked functional divergence among peanut ALS isozymes, where an identical mutation yields different phenotypic outcomes depending on the protein structure. Consequently, position 574 in AhALS2b is an ineffective editing target, underscoring the need for isozyme-specific screening to develop herbicide-resistant peanut varieties. © 2026 Society of Chemical Industry.}, } @article {pmid41950410, year = {2026}, author = {Koyya, R and O'Brien, C and Drennan, IR and Cheskes, S and von Vopelius-Feldt, J}, title = {Paramedics' Decisions to Withhold Resuscitation in Traumatic Cardiac Arrest: Accuracy of Paramedic Assessments Compared with Autopsy Findings.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/10903127.2026.2655289}, pmid = {41950410}, issn = {1545-0066}, abstract = {OBJECTIVES: Trauma remains the leading cause of death among Canadians under 45, with over 70% of these deaths occurring in the prehospital setting. In Ontario, Canada, paramedics' decision to initiate or withhold resuscitation in traumatic cardiac arrest (TCA) is governed by basic life support (BLS) and advanced life support (ALS) patient care standards. This study explores paramedics' decisions to withhold cardiopulmonary resuscitation (CPR) in cases of prehospital TCA.

METHODS: We conducted a retrospective review of case files relating to coroner investigations of prehospital TCA across two emergency medical services (EMS) covering a mixed urban/suburban region in Ontario, Canada, with a population of approximately 4.3 million people, from January 2018 to July 2022. We reviewed all deaths where EMS records were available in the death investigation files and where paramedics did not provide CPR. Paramedics' documentation of reasons to withhold CPR was reviewed and compared to postmortem findings. Descriptive statistics were used to describe the findings.

RESULTS: We identified 90 cases of prehospital TCA where no CPR was provided by paramedics. Of these, 55 cases (61%) had documented, injuries incompatible with life (decapitation, open head or torso wounds with visible outpouring of brain or abdominal contents) or signs of irreversible death (rigor mortis, lividity, decomposition). Postmortem examination confirmed paramedics' findings of injuries incompatible with life in 29 cases (89%). For the remaining 35 cases (39%), CPR was withheld due to a combination of prolonged time from TCA to EMS contact, severity of injuries deemed non-survivable, significant external blood loss, and following remote physician agreement in 31 (89%) cases. Of these, 29 (83%) had postmortem findings demonstrating anatomical injuries that made the TCA irreversible.

CONCLUSIONS: The majority of decisions to withhold CPR in prehospital TCA cases are based on signs that are clearly incompatible with life, identified by paramedics with high specificity. In the absence of such findings, paramedics consider factors like prolonged time intervals, overall injury severity, and seek guidance through remote physician supervision before deciding whether to withhold resuscitation efforts.}, } @article {pmid41950600, year = {2026}, author = {Yoo, HE and Issenberg, SB and Roh, YS}, title = {Effects of distinct prebriefing and debriefing on learning outcomes in advanced life support training for ward nurses: A randomized controlled trial.}, journal = {Nurse education today}, volume = {163}, number = {}, pages = {107094}, doi = {10.1016/j.nedt.2026.107094}, pmid = {41950600}, issn = {1532-2793}, mesh = {Humans ; *Advanced Cardiac Life Support/education ; Self Efficacy ; Female ; Adult ; Clinical Competence ; *Learning ; Male ; *Nursing Staff, Hospital/education ; }, abstract = {BACKGROUND: Effective training in advanced life support (ALS) is crucial for improving ward nurses' ALS performance and patient outcomes during in-hospital cardiac arrest. However, the comparative effects of prebriefing and debriefing strategies in ALS education remain unclear.

OBJECTIVE: This study aimed to determine whether differences in prebriefing and debriefing strategies in ALS training result in significant variations in metacognition, self-efficacy, ALS performance, and learning satisfaction among novice ward nurses.

METHODS: In this randomized controlled trial, 205 novice ward nurses were assigned to four ALS training groups. Groups 1 and 2 received prebriefing with a role-modeling video, whereas Groups 3 and 4 received prebriefing with self-directed learning. Instructor-led (Groups 1 and 3) or peer-led (Groups 2 and 4) debriefings followed the prebriefing methods. Participants completed baseline and post-intervention assessments that measured metacognition, self-efficacy. ALS performance and learning satisfaction was measured only at the posttest.

RESULTS: All groups demonstrated improved self-efficacy following ALS training. However, Groups 1 and 2, who received prebriefing with a role-modeling video, achieved greater gains in both metacognition and self-efficacy than Groups 3 and 4, regardless of the debriefing method. Among all groups, Group 1 showed the highest ALS performance and learning satisfaction, followed by Group 2.

CONCLUSION: This study highlights the effectiveness of structured prebriefing using a role-modeling video for enhancing critical ALS competencies among novice ward nurses. These findings provide evidence to inform the design of more effective simulation-based resuscitation training programs in clinical settings.}, } @article {pmid41951265, year = {2026}, author = {Marques Couto, C and Gomes, SAMC and Carvalho, RS and Nascimento, OJ}, title = {Disappearing corticospinal tract on routine MRI: dynamic signal evolution in primary lateral sclerosis.}, journal = {BMJ case reports}, volume = {19}, number = {4}, pages = {}, pmid = {41951265}, issn = {1757-790X}, mesh = {Female ; Humans ; Middle Aged ; Disease Progression ; *Magnetic Resonance Imaging/methods ; *Motor Cortex/diagnostic imaging/pathology ; *Motor Neuron Disease/diagnostic imaging/physiopathology/pathology ; *Pyramidal Tracts/diagnostic imaging/pathology ; }, abstract = {Primary lateral sclerosis (PLS) may show corticospinal tract (CST) hyperintensity on fluid-attenuated inversion recovery and motor cortex hypointensity on susceptibility-weighted imaging (SWI); however, its longitudinal evolution remains poorly understood. Here, we describe two cases with definite PLS, who were followed up for 15 and 6 years and assessed using qualitative visual magnetic resonance imaging (MRI) scores. Both patients initially exhibited CST hyperintensity. Despite progressive clinical deterioration due to wheelchair/walker dependence, serial MRI demonstrated complete CST normalisation (score 0/16). Concurrently, SWI revealed progressive motor cortex hypointensity, consistent with iron deposition. These cases illustrate a possible dissociation between conventional and susceptibility-based MRI markers, suggesting dynamic pathophysiological processes and potentially early inflammation followed by gliotic remodelling, although technical factors cannot be excluded. A normal-appearing CST should not exclude advanced PLS, and progressive motor cortex hypointensity may provide a more stable marker. Prospective studies with standardised protocols are required to validate these observations.}, } @article {pmid41952193, year = {2026}, author = {Linse, K and Lulé, D and Schöberl, F and Reilich, P and Ilse, B and Metelmann, M and Eickhoff, C and Bublitz, S and Lorenzl, S and Boentert, M and Petri, S and Rödiger, A and Smesny, U and Wolf, J and Weyen, U and Zeller, D and Dorst, J and Maier, A and Meyer, T and Lingor, P and Hermann, A and Regensburger, M and Großkreutz, J and Runge, C and Lapp, HS and Freigang, M and Vidovic, M and Aust, E and Weber, C and Günther, R}, title = {Between guidelines and reality: expert neurologists' perspectives on structural resources for ALS care in Germany.}, journal = {Neurological research and practice}, volume = {8}, number = {1}, pages = {}, pmid = {41952193}, issn = {2524-3489}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, leading to an inexorable decline in voluntary muscle function, and finally to death within 2–4 years. The provision of professional ALS care is a multifaceted and continually evolving challenge, including the management of symptoms, advanced care planning, and the provision of psychosocial support. The core objective is to minimize suffering by optimizing symptom management and preserving quality of life. European and German guidelines recommend a specialized, multidisciplinary, and multiprofessional team, including collaborations with palliative care providers. While this is a validated approach to ensure optimal care and patient satisfaction, real-world experience suggests that the German healthcare system may not fully meet these requirements. METHODS: This study assessed resources of specialized ALS centres in Germany, focusing on the structural prerequisites for the provision of multidimensional care and collaboration with specialised palliative care (SPC) providers. A mixed methods design was used, comprising remote video interviews with neurologists specialized in ALS, including standardised questions and an open section. RESULTS: Sixteen neurologists representing their ALS centres were interviewed. The findings indicated a substantial discrepancy in the allocation of time and personnel resources among the centres. The majority of interviewees regarded resources to be inadequate and reported deficiencies in multidisciplinarity and networking. Consequently, certain components of ALS care - particularly psychosocial concerns - have been documented as being occasionally disregarded due to limitations in time or human resources. A number of interviewees expressed criticism regarding the inadequate access to and suboptimal collaboration with SPC providers. The compensation for patient care and interprofessional communication was not perceived as cost-effective. CONCLUSIONS: Our results suggest that limited resources may prevent the provision of guideline-based care for people living with ALS and their families, even in specialized outpatient clinics. To facilitate the delivery of comprehensive care by ALS centers throughout the entire disease course, the establishment of operational standards concerning their multi-professional staffing and adequate compensation is imperative. Further research is needed to develop feasible concepts of how specialized neurological palliative care can be made reliably accessible to all patients in need.}, } @article {pmid41952858, year = {2026}, author = {Calderón-Garcidueñas, L and Hernández-Luna, J and Galaz-Montoya, CI and Clouston, SAP and Aiello-Mora, MV and Amaro de Gante, J and Stommel, EW and Torres-Jardón, R and Nalbantoglu, OU}, title = {Cortical, subcortical, and cerebellar atrophy and cognition deficits in Metropolitan Mexico City teens and young adults exposed to fine particulate matter (PM2.5) - neurodegeneration is in progress.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1772916}, pmid = {41952858}, issn = {1664-2295}, abstract = {Exposure to environmental fine particulate matter (PM2.5), ultrafine PM (UFPM) and nanoparticles (NPs) are associated with accumulation of amyloid-β1-42 peptides, phosphorylated-Tau, alpha-synuclein and transactive response DNA binding-protein-43 misfolded aberrant proteins, consistent with the biological definitions of overlapping Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) in 99% of ≤40-year-old Metropolitan Mexico City (MMC) forensic autopsies. Structural and volumetric brain responses in vivo are critical in young MMC residents. We performed volumetric and whole-brain correlation analyses in 75 healthy volunteers: 45 MMC 31.2 ± 14.7 y old and 30 low-pollution 31.8 ± 4.8 y old controls, matched by ethnicity, socioeconomic status, nutrition, and BMI. MMC residents exhibited fronto-parietal and temporal lobes, precentral gyrus, hippocampi, basal ganglia, thalamus, amygdala and cerebellar atrophy. The most common atrophy pattern was cortical first parietal and fronto-parietal lobes, combined with gray matter (GM) atrophy in cerebellar lobules IV and V left and right III, IV and V and VI.MMC participants had mild cognitive impairment (Montreal Cognitive Assessment Score 22.8 ± 3.2). GM atrophy involving right globus pallidus and pulvinar and cerebellar white matter (WM) bilaterally were associated with lower cognitive performance and high BMI to subiculum, posterior orbital gyrus and insula, inferior temporal gyrus, supplementary motor cortex, and cuneus WM atrophy. PM2.5 exposure and BMI appear to play key roles in early neurodegenerative disease biology and may contribute to adverse effects on academic and occupational performance, neuropsychiatric disorders, behavioral regulation, risk of substance use initiation, and psychopathy. Neuroradiologists across the world need to know cortical and subcortical, including extensive hippocampal, stratium and cerebellar atrophy identifies overlapping patterns of regional atrophy associated with MCI, AD, bvFTD, PD and ALS, in young urbanites. There is an urgent need for early pediatric neuroprevention interventions, non-invasive AD, PD and TDP-43 biomarkers, in-depth characterization of emission pollutants exposures and their effective control. Denial is no longer an option.}, } @article {pmid41953830, year = {2026}, author = {Baby, P and John, J and Binesha, PB and Keerthipriya, MS and Ramazanu, S and Nashi, S and Menon, D and Vengalil, S and Thomas, PT and Nalini, A}, title = {Amyotrophic Lateral Sclerosis: A Cross-sectional Survey on Sialorrhoea.}, journal = {Indian journal of palliative care}, volume = {32}, number = {1}, pages = {85-90}, pmid = {41953830}, issn = {0973-1075}, abstract = {OBJECTIVES: One of the major distressing symptoms related to Amyotrophic Lateral Sclerosis (ALS) is excessive drooling of saliva, also termed sialorrhoea. Evaluating its prevalence and severity among Indian patients with ALS is essential for understanding the magnitude and impact of the problem. A cross-sectional survey was conducted to estimate the prevalence and severity of sialorrhoea among individuals diagnosed with ALS. We also intended to assess the current pharmacological management practice for sialorrhoea in ALS patients.

MATERIALS AND METHODS: Patients with ALS enrolled in the Neuropalliative Registry of a quaternary care centre for neurological disorders were included in the study. As part of routine follow-up, telephonic interviews were conducted with either the patients or their next of kin. The extent of sialorrhoea was assessed using the sialorrhoea scoring scale.

RESULTS: Seventy patients were included in the study. The mean age at presentation was 51.8 (standard deviation [SD]-12.8) years. The majority were males (74.3%). The mean duration of illness was 21.6 (SD 15.7) months. The majority (80%) had limb onset ALS. Forty per cent of the patients in the study had some degree of sialorrhoea. Mild drooling was present in 15 patients (21.4%), moderate in 9 (12.9%), severe in 2 (2.9%) and profuse drooling in another 2.9% of patients. A total of 9 patients (12.9%) were receiving anticholinergic medication. Patients diagnosed with bulbar onset ALS had a significantly greater degree of sialorrhoea than those with limb onset presentation (P = 0.008). In addition, a longer duration of illness showed a positive correlation with the severity of sialorrhoea (r = 0.30, P = 0.012).

CONCLUSION: Sialorrhoea is a prevalent and clinically significant symptom in individuals with ALS. The severity of sialorrhoea is greater in patients with bulbar onset ALS and tends to increase with longer illness duration. A substantial proportion of patients may benefit from recommended treatment for excessive salivation and saliva-related issues. This study underscores the need for screening of distressing symptoms as sialorrhoea, in ALS patients. The treating teams need to have a heightened awareness regarding the same so that treatment options can be offered to the patients.}, } @article {pmid41954708, year = {2026}, author = {Luo, S and Zheng, Q and Wang, M and Wang, X and Ma, B and Liu, D and Li, L and Lu, Y and Sang, D and Yang, L}, title = {Synergistic Neuroprotection of MFSD2A Overexpression and DHA Supplementation in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41954708}, issn = {1559-1182}, support = {202304295107020076//Clinical Medicine Research and Translational Project of Anhui Province/ ; 2022AH051480//University Natural Science Research Project of Anhui Province/ ; 2022//Anhui Province "Jianghuai Famous Doctors" Cultivation Project/ ; 2020byzd169//Natural Science Key Project of Bengbu Medical College/ ; BB21B032//Bengbu Think Tank Construction and Social Science Planning Project/ ; 20230131//Bengbu science and technology innovation guidance project/ ; BBWK2024B204//Bengbu Health and Health Research Project Intestinal Transplantation Technology Clinical Special General Project/ ; AHWJ2024Aa30089//Anhui Province Health and Health Research Project Youth Project/ ; }, mesh = {Animals ; *Docosahexaenoic Acids/pharmacology/therapeutic use/administration & dosage ; Male ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics/physiopathology ; *Neuroprotection/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Transgenic ; *Dietary Supplements ; *Symporters ; *Membrane Transport Proteins/metabolism/genetics/biosynthesis ; Humans ; Mice ; Oxidative Stress/drug effects ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss, with limited effective therapies. Docosahexaenoic acid (DHA) exhibits neuroprotective effects, but its limited transport across the blood-brain barrier (BBB) restricts clinical utility. Major facilitator superfamily domain-containing protein 2A (MFSD2A) is the primary transporter of DHA into the central nervous system, yet its role in ALS remains unclear. This study investigated the therapeutic potential and mechanisms of MFSD2A overexpression combined with DHA supplementation in male SOD1^G93A ALS mice. We found that MFSD2A expression was markedly reduced in ALS mice and correlated with impaired motor function and neuronal damage. DHA supplementation or MFSD2A overexpression partially improved behavioral deficits, while their combination produced synergistic benefits. Histological analyses revealed attenuated neuronal degeneration and reduced muscle fibrosis following combined treatment. Furthermore, MFSD2A physically interacted with the E3 ubiquitin ligase TRIM21, regulating glycolytic metabolism by modulating key enzymes (GLUT1, HK2, LDHA, PDK1) and products (lactate/pyruvate and NADH/NADPH ratio). TRIM21 knockdown reversed MFSD2A-mediated neuroprotection and impaired glycolytic metabolism, indicating its critical role in this pathway. The combined intervention also suppressed systemic inflammation and oxidative stress by decreasing pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and restoring antioxidant enzyme activities (GSH-Px), while reducing lipid peroxidation (MDA). These findings suggest that MFSD2A facilitates DHA's neuroprotective effects by enhancing glycolytic metabolism and mitigating neuroinflammation. This study highlights MFSD2A and DHA as promising therapeutic targets in ALS and provides novel insights into overcoming BBB transport limitations for neurodegenerative disease treatment.}, } @article {pmid41955555, year = {2026}, author = {Katzberg, HD and Bril, V and Zinman, L and Abrahao, A and Cherney, D and Shah, H and Mendoza, MG and Alfaidi, N and Alnajjar, S and Barnett-Tapia, C}, title = {The Muscle Cramp Impact Index: A Patient-Centered Scale for the Assessment of Muscle Cramps.}, journal = {Neurology}, volume = {106}, number = {9}, pages = {e214835}, doi = {10.1212/WNL.0000000000214835}, pmid = {41955555}, issn = {1526-632X}, mesh = {Humans ; *Muscle Cramp/diagnosis/psychology/physiopathology ; Female ; Middle Aged ; Male ; *Patient Reported Outcome Measures ; Reproducibility of Results ; Aged ; Prospective Studies ; Adult ; Psychometrics ; Severity of Illness Index ; Surveys and Questionnaires ; Quality of Life ; Symptom Burden ; }, abstract = {BACKGROUND AND OBJECTIVES: Muscle cramps are common, variably disabling, and lack a comprehensive validated tool to assess their multidimensional effect. Previous cramp studies have relied primarily on cramp frequency and intensity, despite qualitative work demonstrating that sleep disturbance, daytime functioning, and mental health are also important to patients. Guided by these findings, the aim of this study was to develop and validate a patient-reported outcome measure, the Muscle Cramp Impact Index (MCII), to assess the effect of muscle cramps across diverse etiologies and clinical settings.

METHODS: This was a multisite, prospective scale-development and validation study conducted in neuromuscular, amyotrophic lateral sclerosis, hepatology, and kidney clinics at the University Health Network/Mount Sinai Hospital and Sunnybrook Health Sciences Centre (2018-2022). MCII item generation was based on a previous qualitative study, literature review, and cognitive interviews with affected patients. Content validity was assessed through review by 27 international neuromuscular and muscle cramp experts. Adult patients experiencing muscle cramps within the preceding 2 weeks were enrolled. Draft items were evaluated for missing data, floor/ceiling effects, and exploratory factor analysis (EFA). Test-retest reliability was assessed in clinically stable patients over a 2-week interval using weighted κ and intraclass correlation coefficients (ICCs). Construct validity was examined through predefined hypotheses correlating MCII scores with established measures of sleep disturbance, mood, pain, stiffness, and quality of life.

RESULTS: A total of 105 patients (40% female individuals; mean age 60.0 ± 14.2 years) completed the field testing. Eighteen draft items were refined to 16 after patient and expert review. All items demonstrated low missingness (<6%). EFA identified 3 domains-cramp frequency/distribution, sleep interference, and interference with daily life-and 2 items were removed for floor effects or low factor loadings, yielding a final 14-item measure (score range 0-42). The MCII demonstrated moderate correlations with EuroQol 5 Dimension, Epworth Sleepiness Scale, Beck Depression Inventory, and Sleep Disturbance scores. Test-retest reliability was excellent (n = 57; ICC 0.83, 95% CI 0.72-0.89), confirming strong measurement stability.

DISCUSSION: The MCII is a patient-centered, psychometrically robust measure capturing the multidimensional effect of muscle cramps. Limitations include reliance on self-reported clinical stability and inability to verify respondent identity for mailed questionnaires. Further evaluation of responsiveness and validation in additional cramp populations is warranted to support broader implementation.}, } @article {pmid41955837, year = {2026}, author = {Song, Y and Zhao, Z and Dai, Y and Li, C and He, X and Wang, Y and Xu, ZD and Yang, Y}, title = {The m7G modification: An emerging player in neurological diseases.}, journal = {Pathology, research and practice}, volume = {282}, number = {}, pages = {156465}, doi = {10.1016/j.prp.2026.156465}, pmid = {41955837}, issn = {1618-0631}, mesh = {Humans ; RNA Methylation ; *Nervous System Diseases/genetics/metabolism ; *Guanosine/analogs & derivatives/metabolism/genetics ; Epitranscriptome ; Epigenesis, Genetic ; Animals ; }, abstract = {With the growing researches on RNA epigenetics, the importance of 7-methylguanosine (m7G) modification is increasingly recognized. The m7G modification is known as a kind of post-transcriptional modifications of RNA and present in many types of RNAs, including mRNAs, microRNAs, ribosomal RNA, and transfer RNAs. Increasing evidence indicates that m7G modifications are involved in a variety of critical biological processes through affecting the stability of RNA, nucleoplasmic transfer and translation efficiency. In the central nervous system (CNS), m7G modification is catalyzed by three major methyltransferase complexes: METTL1/WDR4, RNMT/RAM, and WBSCR22/TRMT112. Dysregulation of this modification is tightly associated with the pathogenesis of various neurological diseases, such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), epilepsy, glioblastoma, ischemic stroke (IS), etc. Here, we review the current knowledge regarding the latest findings on the distribution, regulatory factors, detection techniques and prediction methods of m7G. We further highlight critical knowledge gaps, especially the limited understanding of m7G "readers," the absence of validated "erasers," and the scarcity of cell-type-resolved profiling in the brain. In addition, we also discuss the translational opportunities and challenges, including biomarker discovery, therapeutic targeting of m7G regulators, and specificity concerns in precision neurological medicine.}, } @article {pmid41957276, year = {2026}, author = {Fang, L and Bai, Z and Yang, D and Sun, B and Zhao, X and Deng, J}, title = {Elimination of senescent cells fails to attenuate disease progression in an ALS mouse model.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {5}, pages = {}, pmid = {41957276}, issn = {1590-3478}, support = {2025NSFJQ0057//the Department of Science and Technology of Sichuan Province/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/therapy/physiopathology/genetics ; Mice, Transgenic ; Disease Models, Animal ; Disease Progression ; Humans ; Superoxide Dismutase-1/genetics/metabolism ; *Cellular Senescence/physiology ; Mice ; Spinal Cord/pathology ; NK Cell Lectin-Like Receptor Subfamily K/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving progressive motor neuron degeneration, resulting in muscle weakness and paralysis. Current therapeutic options provide only modest benefit, and the etiology of ALS remains incompletely understood. Emerging evidence implicates cellular senescence in the central nervous system (CNS) of ALS pathogenesis, with senescent astrocytes identified in both animal models and patients.

METHODS: We employed transgenic mice overexpressing the human superoxide dismutase 1 gene with a glycine-to-alanine substitution at codon 93 (hSOD1[G93A]) as the experimental model. To eliminate senescent cells, mouse-derived natural killer group 2, member D (NKG2D) chimeric antigen receptor T (CAR-T) cells were engineered to target NKG2D ligands (NKG2DLs) [+] senescent cells. The efficacy of senescent cell clearance was assessed by SA-β-gal staining on frozen tissue sections and by quantifying the expression of senescence-associated markers (e.g., p16[INK4a], p21). Disease progression in mice was evaluated by monitoring changes in body weight, behavioral performance, and motor function.

RESULTS: We found that NKG2DLs[+] senescent cells accumulate in symptomatic transgenic mice. NKG2D CAR-T cells can selectively eliminate senescent cell populations in symptomatic hSOD1[G93A] mice. A single infusion effectively reduced senescent cell burden and suppressed Senescence-Associated Secretory Phenotype (SASP) features within central nervous system tissues. However, no significant improvements in motor function or survival were observed.

CONCLUSION: These results indicate that while senescence is a pathogenic feature of ALS, it operates within an integrated disease network. Early senolytic intervention or combinatorial approaches may represent promising future strategies for ALS.}, } @article {pmid41957959, year = {2026}, author = {Jha, I and Arora, S and Ravi, SK}, title = {Comparison of Neurophysiological Parameters Between Menstruating and Menopausal Females at Different Frequencies.}, journal = {Annals of African medicine}, volume = {}, number = {}, pages = {}, doi = {10.4103/aam.aam_835_25}, pmid = {41957959}, issn = {0975-5764}, abstract = {INTRODUCTION: An important impact of gonadal hormones on the auditory pathway has been found. Few neurophysiological research study has been done during different phases of menstrual cycle and menopause. This study was conducted to compare the brainstem auditory evoked potential (BAEP) between menstruating females during the follicular phase and the menopausal group.

MATERIALS AND METHODS: This was a case-control study. Group 1 included n = 30 menstruating females in the follicular phase and aged between 18 and 25 years. Group 2 included 30 menopausal females and aged between 42 and 50 years. For analysis, Student's unpaired t-test and Chi-square test were applied. BAEP recording was done using standard protocol. Mean wave latencies: I, III, and V and interpeak latencies (IPLs): I-III, III-V, and I-V were recorded.

RESULTS: Mean ± standard deviation of absolute latencies (ALs) of brainstem auditory evoked potential (BERA) waves III and V and all IPL at 80 dB and 2, 4, 6 KHz in Group 2 menopausal females were delayed and significant as compared to Group 1 menstruating females. All parameters were highly significant at 6 KHz as compared to 2 KHz in menopausal Group 2.

CONCLUSION: Brainstem audiometry evoked potential detects hearing loss early in menopausal females at higher frequencies, i.e. at 6 KHz, due to a decrease in estrogen level.}, } @article {pmid41958917, year = {2026}, author = {Rifai, OM and Waldron, FM and O'Shaughnessy, J and Read, FL and Gilodi, M and Pastore, A and Shneider, NA and Tartaglia, GG and Zacco, E and Spence, H and Gregory, JM}, title = {Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag104}, pmid = {41958917}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 NS127186/NS/NINDS NIH HHS/United States ; }, abstract = {Cognitive and behavioural symptoms associated with amyotrophic lateral sclerosis and frontotemporal spectrum disorders (ALS-FTSD) are thought to be driven, at least in part, by the pathological accumulation of TDP-43. Here we examine post-mortem tissue from six brain regions associated with cognitive and behavioural symptoms in a cohort of 30 people with sporadic ALS (sALS), a proportion (12/30) of which underwent standardized neuropsychological behavioural assessment as part of the Edinburgh Cognitive ALS Screen (ECAS). Overall, the behavioural screen performed as part of the ECAS predicted accumulation of pathological phosphorylated TDP-43 (pTDP-43) with 100% specificity and 86% sensitivity in behaviour-associated brain regions. Notably, of these regions, pathology in the amygdala was the most predictive correlate of behavioural dysfunction in sALS. In the amygdala of sALS patients, we show variation in morphology, cell-type predominance and severity of pTDP-43 pathology. Further, we demonstrate that the presence and severity of intra-neuronal pTDP-43 pathology, but not astroglial pathology, or phosphorylated Tau pathology, is associated with behavioural dysfunction. Cases were also evaluated using a TDP-43 aptamer (TDP-43[APT]), which revealed that pathology was not only associated with behavioural symptoms, but also with ferritin levels, a measure of brain iron. Intra-neuronal pTDP-43 and cytoplasmic TDP-43[APT] pathology in the amygdala is associated with behavioural symptoms in sALS. TDP-43[APT] staining intensity is also associated with increased ferritin, regardless of behavioural phenotype, suggesting that ferritin increases may occur upstream of clinical manifestation, in line with early TDP-43[APT] pathology, representing a potential region-specific imaging biomarker (e.g. volumetric or susceptibility-weighted MR imaging) of early disease in ALS.}, } @article {pmid41959630, year = {2026}, author = {Renga, V and Jeffreys, CA and Kersey, GE and Stommel, EW}, title = {Connectivity in ALS II (CoALS II): a study of structural and functional connectivity in ALS.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1743723}, pmid = {41959630}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a network-level neurodegenerative disease involving distributed disruptions across structural and functional systems. While previous studies have often examined white matter integrity or functional connectivity in isolation, the nature of structure-function coupling and its reorganization in ALS remains poorly understood.

METHODS: We conducted a multimodal connectomic analysis in ALS patients and matched controls, integrating cortical thickness-based structural covariance networks, diffusion MRI tractography, and resting-state and task-based functional MRI. Graph-theoretical metrics were derived, and cross-modal structure-function correspondence was quantified using ROI-wise correlation analyses. A comprehensive 104-node parcellation scheme based on the Desikan-Killiany atlas was employed.

RESULTS: ALS participants showed preserved global network topology (p > 0.05 for efficiency and small-worldness) but evidence of selective reorganization, particularly within motor and interhemispheric pathways. Cortical covariance networks exhibited minimal association with functional dynamics, whereas diffusion-derived white matter connectivity remained closely aligned with functional organization. This structure-function coupling was maintained or even enhanced during task performance (p = 0.005), suggesting adaptive reconfiguration rather than uniform disconnection.

CONCLUSIONS: Structure-function coupling in ALS is not globally diminished but reorganized, with robust white matter-functional relationships coexisting alongside weak cortical covariance-functional associations. These findings refine the traditional disconnection model and highlight the utility of multimodal metrics for understanding disease mechanisms and developing biomarkers for progression and therapeutic response.}, } @article {pmid41960733, year = {2026}, author = {Han, JJ and Hayward, LJ and Adams, C and Perez-Ibarra, J}, title = {Reachable Workspace as a Clinical Outcome for Upper Extremity Function: A Narrative Review.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70190}, pmid = {41960733}, issn = {1097-4598}, support = {U01 AR065113/AR/NIAMS NIH HHS/United States ; //Fulcrum Therapeutics/ ; U01 AR065113-01/AR/NIAMS NIH HHS/United States ; }, abstract = {Motion sensing technology can be utilized to capture detailed upper extremity (UE) motion to reconstruct an individual's three-dimensional (3D) reachable workspace (RWS). The RWS can be quantified as relative surface area (RSA), providing an innovative surrogate measure to assess UE mobility and function. Numerous studies have shown that RSA can reliably distinguish between healthy and impaired UE function and also is able to detect clinically relevant longitudinal changes, with sufficient sensitivity to detect small differences even in slowly-progressive conditions. After more than a decade of experience in clinical studies, RWS has been shown to be a valid, reliable, and sensitive UE clinical outcome assessment (COA) tool, with clinical utility in various neuromuscular diseases in which UE impairment is significant, including facioscapulohumeral dystrophy (FSHD), Duchenne muscular dystrophy (DMD), and amyotrophic lateral sclerosis (ALS). RWS and its performance outcome (PerfO) measure RSA have demonstrated strong associations with established clinical measures of disease severity, patient-reported outcomes (PROs), and functional performance, further supporting its clinical relevance. As an UE functional assessment tool, RWS has also shown its generalizable application in various other conditions with UE impairment, such as stroke, orthopedic conditions, and other musculoskeletal disorders. With significant body of work supporting sensor-based RWS as a clinically useful assessment of UE function, future developments incorporating increasingly-capable mobile sensing technologies for remote monitoring and applying machine learning and artificial intelligence (AI) approaches to the sensor-acquired motion data promise further exciting possibilities to enhance clinical studies and patient care.}, } @article {pmid41961863, year = {2026}, author = {Emond, A and Laflamme, C and Therrien, M and Liao, M and Maios, C and Labarre, A and Drapeau, P and Parker, JA}, title = {Characterization of a C9orf72 Knockout Danio rerio model for ALS and cross-species validation of potential therapeutics screened in Caenorhabditis elegans.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0346613}, pmid = {41961863}, issn = {1932-6203}, mesh = {Animals ; *Zebrafish/genetics ; *Caenorhabditis elegans/genetics ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/pathology ; Disease Models, Animal ; Gene Knockout Techniques ; Motor Neurons/metabolism/pathology/drug effects ; Animals, Genetically Modified ; Humans ; }, abstract = {Intronic hexanucleotide repeat expansions in the C9orf72 gene represent the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. This expansion decreases C9orf72 expression in affected patients, indicating that loss of C9orf72 function (LOF) acts as a pathogenic mechanism. Several models using Danio rerio (zebrafish) for C9orf72 depletion have been developed to explore disease mechanisms and the consequences of C9orf72 LOF. However, inconsistencies exist in reported phenotypes, and many have yet to be validated in stable germline ablation models. To address this, we created a zebrafish C9orf72 knockout model using CRISPR/Cas9. The C9orf72 LOF model demonstrates, in a generally dose-dependent manner, increased larval mortality, persistent growth reduction, and motor deficits. Additionally, homozygous C9orf72 LOF larvae exhibited mild overbranching of spinal motoneurons. To identify potential therapeutic compounds, we performed a screen on an established Caenorhabditis elegans (C. elegans) C9orf72 homologue (alfa-1) LOF model, identifying 12 compounds that enhanced motility, reduced neurodegeneration, and alleviated paralysis phenotypes. Motivated by the shared motor phenotype, 2 of those compounds were tested in our zebrafish C9orf72 LOF model. Pizotifen malate was found to significantly improve motor deficits in C9orf72 LOF zebrafish larvae. We introduce a novel zebrafish C9orf72 knockout model that exhibits phenotypic differences from depletion models, providing a valuable tool for in vivo C9orf72 research and ALS therapeutic validation. Furthermore, we identify pizotifen malate as a promising compound for further preclinical evaluation.}, } @article {pmid41962593, year = {2026}, author = {Ran, X and Wang, M and Huang, J and Kuang, N and Tian, P and Wu, J and Feng, F and Luo, Y and Huang, N}, title = {Mechanistic research and therapeutic prospects of alternative splicing in neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {118}, number = {}, pages = {103133}, doi = {10.1016/j.arr.2026.103133}, pmid = {41962593}, issn = {1872-9649}, mesh = {Humans ; *Alternative Splicing/genetics ; *Neurodegenerative Diseases/genetics/therapy/metabolism ; Animals ; }, abstract = {One essential post-transcriptional regulatory mechanism that increases protein diversity in eukaryotes is alternative splicing. This process is crucial for maintaining nervous system function and is highly active in neurons. Dysregulation of alternative splicing is a common pathogenic factor in many neurodegenerative diseases. For example, splicing variants of tau protein and amyloid precursor protein are implicated in Alzheimer's disease; aberrant splicing of α-synuclein (SNCA) and upregulation of specific transcript variants of the Parkin (PARK2) gene occurs in Parkinson's disease; and aberrant splicing of Stathmin-2 (STMN2) pre-mRNA leads to the loss of axonal maintenance proteins in amyotrophic lateral sclerosis and frontotemporal dementia. This process is precisely regulated by trans-acting factors, a class of RBPs that specifically recognize and bind to cis-acting elements on precursor mRNA (pre-mRNA). These factors are primarily categorized into two major groups: serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs). Although hnRNPs and SR proteins have been shown to regulate neuronal alternative splicing, their complex regulatory networks and associated disease mechanisms remain incompletely understood, hindering the development of targeted therapies. This review summarizes the molecular mechanisms of alternative splicing and its regulatory features in neurodegenerative diseases. It also summarizes recent advances in splicing-based therapies and biomarkers, providing insights into disease mechanisms and therapeutic development.}, } @article {pmid41963814, year = {2026}, author = {Sýkora, R and Chvojka, J and Kukačková, N and Šimečková, V and Smetana, J}, title = {Early resuscitation priorities in two-provider EMS crews: an interpretive commentary.}, journal = {BMC emergency medicine}, volume = {26}, number = {1}, pages = {}, pmid = {41963814}, issn = {1471-227X}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy ; *Emergency Medical Services/standards/organization & administration ; *Cardiopulmonary Resuscitation/standards ; *Advanced Cardiac Life Support/standards ; Practice Guidelines as Topic ; Task Shifting ; Paramedicine ; }, abstract = {BACKGROUND: International resuscitation guidelines are grounded in physiological principles and outcome-based evidence, but they implicitly assume staffing levels that allow multiple time-critical interventions to be delivered in parallel. In many emergency medical systems, however, advanced life support is initially provided by a two-provider crew working alone for a substantial period. Under these conditions, the parallel task execution described in guidelines may become structurally impossible because of capacity constraints. This commentary therefore focuses on adult non-traumatic out-of-hospital cardiac arrest managed according to standard adult ALS guidelines. INTERPRETIVE FRAMEWORK: This article is presented as an interpretive commentary and is intended to provide an explanatory perspective on how early guideline-consistent care is enacted under conditions of limited personnel and cognitive capacity, rather than as a prescriptive care algorithm. It applies exclusively to the initial, transient phase of out-of-hospital resuscitation in which advanced life support is delivered by a two-provider professional crew working alone. Its applicability ends once additional trained personnel arrive, stable task allocation becomes possible, or the initial defibrillation cycles have been completed. Deviations from ideal task sequencing are conceptualised as forced deviations, an emergent property of system-level capacity limits rather than individual performance failure. Resuscitation actions are therefore considered in terms of their relative short-term physiological penalty when delayed or interrupted: (1) critical perfusion-dependent actions, where interruption is associated with immediate physiological harm; (2) actions with lower short-term physiological penalty when briefly deferred; and (3) bounded uncertainty domains, particularly ventilation, where physiological effects are non-linear and context dependent. CONCLUSION: This interpretive commentary does not modify existing resuscitation guidelines. Instead, it clarifies how their physiological intent may be understood and preserved during the earliest phase of two-provider advanced life support, when parallel task execution is not feasible. By providing a shared interpretive model for early resuscitation under capacity constraint, this approach may help reduce harmful variability, cognitive overload, and misinterpretation of performance at a system level in real-world emergency medical systems.}, } @article {pmid41964083, year = {2026}, author = {Viswanathan, M and Yin, L and Kurmi, Y and Chai, S and Jiang, X and Huo, Y and Xu, J and Chen, L and Gore, JC and Zu, Z}, title = {Enhanced Quantitative Phosphocreatine MR Imaging of Skeletal Muscle Using a Global-Local Two-Branch Deep Learning Model.}, journal = {Magnetic resonance in medicine}, volume = {96}, number = {2}, pages = {741-755}, pmid = {41964083}, issn = {1522-2594}, support = {R01NS140757/NH/NIH HHS/United States ; R01EB036574/NH/NIH HHS/United States ; R01EB029443/NH/NIH HHS/United States ; R01 NS140757/NS/NINDS NIH HHS/United States ; R01 EB036574/EB/NIBIB NIH HHS/United States ; R01 EB029443/EB/NIBIB NIH HHS/United States ; R21AG089699/NH/NIH HHS/United States ; R21 AG089699/AG/NIA NIH HHS/United States ; }, mesh = {*Phosphocreatine/chemistry/analysis/metabolism ; Animals ; *Muscle, Skeletal/diagnostic imaging ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; Rats ; Phantoms, Imaging ; *Image Processing, Computer-Assisted/methods ; Algorithms ; Rats, Sprague-Dawley ; Male ; }, abstract = {PURPOSE: Phosphocreatine (PCr) is an essential marker of muscle metabolism, and accurate quantification of its (fs) and its exchange rate (ksw) is essential for diagnosing various muscular and neuromuscular diseases. Although chemical exchange saturation transfer (CEST) MRI can detect the saturation transfer effect from PCr, quantification of the underlying PCr fs and ksw, particularly at low fields, remains challenging due to significant overlapping confounding effects in tissues when using conventional fitting approaches. Deep learning (DL) presents a promising alternative, yet traditional DL models often struggle to capture subtle PCr-specific variations induced by changes in fs or ksw. Furthermore, these models are typically trained on either fully synthetic data, which may not adequately mimic tissues, or in vivo data which lack ground truth.

METHODS: This study introduces a global-local two-branch DL model to effectively eliminate confounding effects and capture subtle variations in the PCr CEST effect. Furthermore, our model was trained on partially synthetic data that offers both simulation flexibility and fidelity. Model accuracy was evaluated by using both digital and physical phantoms, and the model was applied to skeletal muscle of healthy rats and rats with amyotrophic lateral sclerosis (ALS).

RESULTS: Phantom experiments demonstrate that our approach surpasses all fitting methods, the state-of-the-art model, and other combinations of DL models and training data. In vivo, the model identified a significant reduction in PCr fs in ALS rats, which other methods fail to detect.

CONCLUSIONS: Our global-local two-branch DL model trained using partially synthetic data enhances PCr quantification in skeletal muscle.}, } @article {pmid41964193, year = {2026}, author = {Grabarczyk, Ł}, title = {Comprehensive Review of Anesthetic Strategies for Patients With Neurodegenerative Diseases.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {32}, number = {}, pages = {e950453}, pmid = {41964193}, issn = {1643-3750}, mesh = {Humans ; *Neurodegenerative Diseases/surgery ; *Anesthetics/therapeutic use ; *Anesthesia/methods ; }, abstract = {Patients with neurodegenerative diseases (NDDs) represent a unique and challenging population from an anesthesiological perspective due to their neurological vulnerability. This issue is becoming increasingly relevant as the incidence of certain NDDs rises with population aging. Effective perioperative management in patients with NDDs requires detailed preoperative evaluation, with emphasis on neurological status, cardiopulmonary function, and a thorough review of current medications. Intraoperatively, careful selection of anesthetic agents and monitoring strategies is essential because of altered drug sensitivity, increased susceptibility to malignant hyperthermia, and potential drug interactions. Particular attention must be given to neuromuscular blockade. The use of nondepolarizing neuromuscular blocking agents is generally risky due to their potentially prolonged and unpredictable effects; their use may be considered under strictly controlled conditions. In contrast, propofol and inhalational agents have demonstrated safety and efficacy in this patient population. This article aims to review the perioperative anesthetic management of patients with NDDs, including Huntington disease, (spino)cerebellar ataxia, Friedreich ataxia, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis.}, } @article {pmid41964251, year = {2026}, author = {Anastasakis, DG and Hafner, M}, title = {RNA G-quadruplex-protein interactions: from nuclear RNA processing to cytoplasmic stress response and neurodegeneration.}, journal = {RNA biology}, volume = {23}, number = {1}, pages = {1-16}, pmid = {41964251}, issn = {1555-8584}, mesh = {*G-Quadruplexes ; Humans ; *Cytoplasm/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/genetics/pathology ; *Cell Nucleus/metabolism/genetics ; *Stress, Physiological ; *RNA-Binding Proteins/metabolism ; *RNA Processing, Post-Transcriptional ; *RNA/metabolism/chemistry/genetics ; Stress Granules/metabolism ; Protein Binding ; RNA Splicing ; }, abstract = {RNA G-quadruplexes (rG4s) are stable secondary structures formed by non-canonical Hoogsteen base-pairing of guanine-rich sequences in precursor and mature messenger and non-coding RNAs. We review evidence that rG4s exist in two functionally distinct worlds. In the nucleus, rG4s fold co-transcriptionally to regulate gene expression and RNA processing and organizing membraneless organelles through liquid-liquid phase separation. Splicing regulation by rG4s is restricted to vertebrates and co-evolved with transcriptome complexity. In the cytoplasm, rG4s are actively maintained in an unfolded state by dedicated helicases and RNA-binding proteins, but fold upon stress to nucleate stress granules, that sequester mRNAs and sustain cell survival. When compartmentalization of rG4-protein interactions fails, cells lose both nuclear RNA processing control and cytoplasmic translational regulation and proper stress response. The same biophysical properties that make rG4s effective scaffolds for reversible phase separation in RNA processing, proteostasis, and acute stress become liabilities under chronic conditions: in ageing neurons, failure of rG4-protein homoeostasis transforms protective condensates into irreversible aggregates associated with α-synuclein, tau, TDP-43, and FUS pathology. We discuss the implications of a dynamic equilibrium of folded and unfolded rG4s in health and disease, with particular focus on their emerging roles in neurodegeneration.}, } @article {pmid41964384, year = {2026}, author = {Hodgson, AKO and McDermott, CJ and Shaw, PJ and Alix, JJP}, title = {The Diagnostic Potential of Axon Excitability Is Consistent Across Hand Muscles in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {73}, number = {6}, pages = {1138-1145}, pmid = {41964384}, issn = {1097-4598}, support = {//NIHR Sheffield Biomedical Research Center (BRC)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Female ; Male ; *Muscle, Skeletal/physiopathology/innervation ; Electromyography ; *Hand/innervation/physiopathology ; Middle Aged ; *Axons/physiology ; Aged ; Prospective Studies ; Motor Neurons/physiology ; Action Potentials/physiology ; Adult ; ROC Curve ; Nerve Conduction Studies ; }, abstract = {INTRODUCTION/AIMS: Recent work suggests that nerve excitability testing has diagnostic potential in amyotrophic lateral sclerosis (ALS). The diagnostic performance of nerve excitability across hand muscles is currently unknown. This study aimed to assess if muscles of the so-called split hand (abductor pollicis brevis [APB], first dorsal interosseous [FDI], and abductor digiti minimi [ADM]) manifest differences in diagnostic performance.

METHODS: We prospectively recruited 60 consecutive patients investigated for ALS. Nerve excitability, motor unit number and size (MScanFit), needle electromyography (EMG), and standard clinical data were collected. ALS and non-ALS groups were compared using t tests, area under receiver operating characteristic curves (AUROC), and multivariate modeling.

RESULTS: Forty-eight patients completed testing of all three muscles, 25 were diagnosed with ALS. The most prominent nerve excitability changes were in superexcitability (APB p = 0.001, FDI p = 0.0001, ADM p = 0.002). Diagnostic performance with superexcitability was similar across the three muscles (p > 0.05). Reductions in motor unit number were observed in ALS patients. Changes in excitability were evident without loss of motor units, most frequently in APB (40% of recordings). Improvements to the AUROC were obtained using combined excitability/motor unit parameters from APB/FDI (AUROC 0.97, p = 0.01 vs. FDI superexcitability alone). Combined excitability and motor unit modeling outperformed detection of EMG abnormalities.

DISCUSSION: Disturbances to nerve excitability are similar across the split hand muscles at the time of ALS diagnosis. These occurred prior to motor unit loss and traditional EMG changes. Combining excitability and motor unit parameters in the lateral hand can identify early pathology and potentially lead to earlier diagnosis.}, } @article {pmid41964735, year = {2026}, author = {Matsuda, C and Nakayama, Y and Haraguchi, M and Morishima, R and Itagaki, Y and Bokuda, K and Hayashi, K and Takahashi, K and Shimizu, T}, title = {Weight maintenance following enteral nutrition is associated with prolonged survival in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {5}, pages = {}, pmid = {41964735}, issn = {1432-1459}, support = {Grant-in-Aid for Scientific Research [B] No. 23K24656//Japan Society for the Promotion of Science/ ; Grant-in-Aid for Scientific Research[C] No. 23K09948//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy/physiopathology ; *Enteral Nutrition ; Female ; Male ; Retrospective Studies ; Body Mass Index ; Middle Aged ; Aged ; *Energy Intake/physiology ; Kaplan-Meier Estimate ; *Body Weight/physiology ; Proportional Hazards Models ; }, abstract = {OBJECTIVE: To investigate the association between energy intake at the initiation of enteral nutrition (EN), subsequent changes in body mass index (BMI), and survival in patients with amyotrophic lateral sclerosis (ALS).

METHODS: This retrospective study included 121 patients with ALS who received EN. Annual BMI decline rates (∆BMI, kg/m[2]/year) were calculated for three periods: from symptom onset to diagnosis (T1-T2), from diagnosis to EN initiation (T2-T3), and from EN initiation to post-EN assessment (T3-T4). Energy intake per weight (E/W, kcal/kg/day) at EN initiation was also assessed. Survival after EN initiation was analyzed using Kaplan-Meier methods and Cox proportional hazards models.

RESULTS: Post-EN BMI decline (∆BMIT3-T4) showed a significant negative correlation with E/W at T3 (p < 0.001). Patients with lower post-EN BMI decline (∆BMI < 0.8 kg/m[2]/year) had significantly longer survival after EN initiation than those with greater BMI decline (p < 0.001). Multivariate Cox analysis identified ∆BMIT3-T4 and pre-EN respiratory decline as independent predictors of post-EN survival. Subgroup analyses demonstrated that patients who maintained body weight after EN had better survival irrespective of energy intake at EN initiation.

CONCLUSION: Weight maintenance following EN was associated with prolonged survival in ALS, whereas energy intake at EN initiation alone was not. These findings suggest that the survival benefit of nutritional intervention may be mediated through stabilization of body weight rather than caloric intake per se.}, } @article {pmid41965692, year = {2026}, author = {Vergano, M and Craxì, L and Zamperetti, N and Latronico, N}, title = {Sliding doors at the bedside: conditional outcomes and moral judgments in end-of-life care.}, journal = {Critical care (London, England)}, volume = {30}, number = {1}, pages = {}, pmid = {41965692}, issn = {1466-609X}, mesh = {Humans ; *Terminal Care/methods/ethics/psychology/standards ; *Judgment ; Decision Making ; Amyotrophic Lateral Sclerosis/complications/psychology ; Prognosis ; Advance Care Planning ; *Morals ; }, abstract = {BACKGROUND: Intensive care medicine has increasingly embraced shared decision-making and advance care planning as core components of good clinical practice. Nonetheless, clinical reasoning is sometimes implicitly framed as a linear, biologically driven process. In contexts of prognostic uncertainty, this framing risks obscuring a structural feature of decision-making: the constitutive role of value-based judgments in shaping prognosis and outcomes. MAIN BODY: This paper introduces the concept of conditional outcomes to clarify a structural feature of certain clinical situations, in which survival or death does not follow from biology alone but is co-determined within the range of biologically possible trajectories by value-based choices made by patients, families, and clinicians regarding whether and how to intervene. Using the case of Mrs. Elizabeth, a woman with advanced amyotrophic lateral sclerosis, we show how an identical clinical state may be framed as either terminal or amenable to escalation, not because it is assessed differently, but because values and goals are interpreted and enacted differently. Even when shared decision-making is practiced, the way value judgments shape prognostic determinations often remains implicit. Making these assumptions explicit complements shared decision-making and advance care planning, clarifying how clinical outcomes are logically dependent on prior value-based commitments that shape judgments about benefit, burden, and the goals of care. CONCLUSIONS: Making the conditional structure of outcomes explicit clarifies that value-based judgments are not ancillary to prognosis but structurally shape prognostic determinations and subsequent outcomes. Recognizing the conditional nature of prognostication strengthens clinical reasoning by integrating biological knowledge with ethical commitments in end-of-life care.}, } @article {pmid41966055, year = {2026}, author = {Russell, ND and Downie, JM and Bromberg, MB and Pulst, SM and Jorde, LB}, title = {Genetic contributions to mitochondrial dysfunction in amyotrophic lateral sclerosis etiology.}, journal = {HGG advances}, volume = {7}, number = {3}, pages = {100614}, pmid = {41966055}, issn = {2666-2477}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/etiology/pathology/metabolism ; *Mitochondria/genetics/metabolism/pathology ; *DNA Polymerase gamma/genetics ; DNA, Mitochondrial/genetics ; *Genetic Predisposition to Disease ; Mitophagy/genetics ; Female ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with multiple genetic causes. Given the strong evidence of mitochondrial dysfunction in ALS, this study aimed to identify genetic contributors to ALS by focusing on genes involved in mitochondrial function. Whole-genome and whole-exome sequencing data from 1,034 individuals with ALS were analyzed using two distinct computational tools, which ranked candidate genes based on functional relevance to ALS. POLG, the sole mitochondrial DNA (mtDNA) polymerase, emerged as a top candidate gene. RNA sequencing (RNA-seq) analysis revealed that among genes upregulated in samples with a POLG variant, there was an enrichment for mitochondrial pathways, including translation, localization, and mitophagy. It also revealed variants in POLG and SOD1, a well-known ALS gene, to be the most enriched in samples with expression profiles of mitochondrial-related genes that differed most from those of unaffected control subjects. POLG variant carriers also exhibited an increased burden of mitochondrial genome variants, a pattern shared by carriers of variants in other genes involved in mtDNA maintenance. Additionally, POLG variant carriers had elevated mtDNA copy number (mtDNA-CN), similar to carriers of variants in mitophagy-related genes, suggesting impaired mitophagy. Together, these findings implicate POLG as an ALS-associated gene and link mtDNA maintenance defects, altered expression of mitochondrial-related pathways, and impaired mitophagy to the ALS etiology.}, } @article {pmid41967177, year = {2026}, author = {Dhandapani, R and Bakavayev, S and Armoza, A and Bersudsky, M and Shlifer, A and Yehezkel, G and Tsitrina, A and Barak, Z and Sintov, AC and Engel, S}, title = {Nose-to-brain delivery of a SOD1-stabilizing small molecule ameliorates pathology in an ALS mouse model.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {3}, pages = {e00904}, pmid = {41967177}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/drug therapy/genetics ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Brain/drug effects/metabolism/pathology ; Administration, Intranasal ; Humans ; Spinal Cord/drug effects/pathology/metabolism ; Female ; }, abstract = {Exposure of a pathogenic β6/β7 loop neo-epitope has been proposed to contribute to the pathogenesis of misfolded Cu/Zn superoxide dismutase (SOD1) in amyotrophic lateral sclerosis (ALS) by mediating early events in its noxious structural transformation and prion-like activity. Antibody-mediated blockade of this epitope was shown to ameliorate disease phenotype in an ALS animal model. Here, as an alternative strategy, we sought to block this epitope using a small molecule designed to occupy the inter-subunit cavity framed by the two β6/β7 loops. Using a structure-based virtual screen targeting this cavity, we identified a small molecule, N-[3-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)phenyl]-4-sulfamoylbenzamide (C7), that preferentially bound the native-like conformation of SOD1, reduced β6/β7 loop epitope accessibility, and inhibited irreversible apo-SOD1 misfolding in vitro. Delivered to presymptomatic hSOD1[G93A] mice via a nanoparticle-based nose-to-brain delivery system, C7 significantly delayed the onset of motor abnormalities and modestly extended survival. At disease onset, spinal cord analysis revealed reduced misfolded SOD1 inclusions and attenuated astro- and microgliosis. Analysis of C7 concentrations in combined brain and spinal cord tissue indicated rapid but saturable nose-to-CNS uptake and slow clearance. Our findings demonstrate that targeting the surface cavity shaped by the β6/β7 loops of SOD1 with a reversibly-binding small molecule can ameliorate ALS-like disease in vivo, potentially by counteracting early misfolding events and/or limiting prion-like propagation of molecular pathology. However, saturable nose-to-CNS uptake of C7 restricts CNS exposure and likely constrains therapeutic efficacy, underscoring the need to define the rate-limiting pharmacokinetic step and to optimize the nanoparticle formulation and/or physicochemical properties of the C7 scaffold.}, } @article {pmid41967717, year = {2026}, author = {Erol Mart, HM and Akay, BN}, title = {Response to Navarrete-Dechent et al's "Ultraviolet-induced fluorescent dermoscopy for the diagnosis of skin tumors: A multicenter study".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {2}, pages = {e181-e182}, doi = {10.1016/j.jaad.2026.01.106}, pmid = {41967717}, issn = {1097-6787}, } @article {pmid41968313, year = {2026}, author = {Ghanem, HN and El-Zaher, AA and Taha, EA and Abbas, AEF and Mahmoud, ST}, title = {MATLAB-candexch algorithm-enhanced UV spectrophotometric-chemometric models for green, blue, and white determination of cinnarizine, domperidone, and carcinogenic impurity in pharmaceuticals: NQS assessment and UN-SDGs integration.}, journal = {BMC chemistry}, volume = {20}, number = {1}, pages = {}, pmid = {41968313}, issn = {2661-801X}, abstract = {Novel analytical methodologies integrating UV spectrophotometric techniques with chemometric models were developed for the simultaneous determination of cinnarizine (CIN), domperidone (DOM), and benzophenone (BNZ), a carcinogenic degradation product of CIN, without prior separation. Despite their clinical significance, no existing methods have been reported for their simultaneous quantification. This approach aligns with green and white analytical chemistry principles, offering an environmentally sustainable solution. Predictive models were constructed using Classical Least Squares (CLS), Partial Least Squares (PLS), and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). A key methodological advancement was the application of D-optimal design via MATLAB's Candexch algorithm, generating a strategically balanced validation dataset of 13 mixtures and overcoming limits of conventional data splitting in chemometric modelling. The methods demonstrated robust linearity across concentration ranges of 4-20 µg/mL for CIN, 3-15 µg/mL for DOM, and 1-5 µg/mL for BNZ. Calibration performance was excellent, with root mean square errors of calibration (RMSEC) values of 0.036-0.062 for CLS, 0.013-0.024 for PLS, and 0.009-0.012 for MCR-ALS. Notably, MCR-ALS exhibited the smallest and most consistent RMSEC range, demonstrating superior accuracy and stability compared to other chemometric models. Validation studies confirmed excellent method performance with recovery rates between 98 and 102%. The root mean square errors of prediction (RMSEP) for the validation set were 0.042-0.201 for CLS, 0.035-0.187 for PLS, and 0.022-0.154 for MCR-ALS, with MCR-ALS consistently exhibiting exceptional predictive capability. The environmental sustainability credentials of the methodology were comprehensively evaluated using nine distinct evaluation tools: NEMI, Complex GAPI, AGREE, BAGI, RGB12, SDAGI, Carbon Footprint Analysis, GSST, and NQS. These rigorous assessments confirmed the method's exceptional environmental compatibility while maintaining analytical excellence, positioning this approach as an ideal sustainable alternative for pharmaceutical quality control applications aligned with UN Sustainable Development Goals.}, } @article {pmid41968317, year = {2026}, author = {Algmaal, SE and Boltia, SA and El Saharty, YS and Ghoniem, NS}, title = {Chemometric and learning-based multivariate models for quantifying a challenging quaternary mixture of bupropion, dextromethorphan, and their related impurities by UV-Vis spectrophotometry.}, journal = {BMC chemistry}, volume = {20}, number = {1}, pages = {}, pmid = {41968317}, issn = {2661-801X}, abstract = {This study presents a robust, green, sustainable and time-efficient approach for the simultaneous determination of Bupropion HCl (BUP) and Dextromethorphan HBr (DEX) along with their related impurities 3-Chlorobenzoic acid and N, N-Dimethylaniline. Principal component regression (PCR) and partial least-squares (PLS), in addition to advanced chemometric models, namely multivariate curve resolution-alternating least squares (MCR-ALS), and artificial neural networks (ANN), are the four green smart multivariate spectrophotometric models that were proposed and validated. The suggested models were successful in examining the mixture of BUP and DEX in the presence of their impurities. Therefore, the suggested analytical methods can be applied to pharmaceutical formulation analysis without the need for a separation step. The proposed strategy offers a novel analytical platform for quality control laboratories to manage complex formulations involving interfering substances. To further ensure greenness and sustainability of the proposed approach, several assessment tools were applied, including the Modified National Environmental Methods Index (NEMI), Eco-Scale, the Analytical GREEnness (AGREE) metric, the Hexagon algorithm, the Green Analytical Procedure Index (GAPI), the Modified GAPI (MoGAPI), the Blue Applicability Grade Index (BAGI), White Analytical Chemistry (WAC), and the Click Analytical Chemistry Index (CACI). Many traditional analytical techniques pose undesirable dangers to the environment and the analyst, such as using hazardous solvents. This gave analysts the incentive to use green methodologies that take into account the use of safe chemicals, the production of the least amount of trash, substantial time savings, and enhanced analyst safety.}, } @article {pmid41968679, year = {2026}, author = {Li, A and Xiao, X and Qin, D and Su, H}, title = {Discovery of a novel TFEB activator targeting lysosomal dysfunction in amyotrophic lateral sclerosis using artificial intelligence-based virtual screening.}, journal = {Autophagy}, volume = {22}, number = {8}, pages = {2041-2042}, pmid = {41968679}, issn = {1554-8635}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; *Lysosomes/metabolism/drug effects ; *Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism/agonists ; Humans ; Animals ; *Artificial Intelligence ; Motor Neurons/drug effects/metabolism/pathology ; }, abstract = {Lysosomal dysfunction is a defining feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), yet effective pharmacological strategies to restore lysosomal homeostasis remain limited. Transcription factor EB (TFEB), a master transcriptional regulator of lysosomal biogenesis, has emerged as an attractive therapeutic target. In our recent study published in Pharmacological Research, we established a robust artificial intelligence (AI) - driven virtual screening pipeline and identified isoginkgetin (ISO) as a potent TFEB activator that effectively promotes lysosomal biogenesis and enhances lysosomal function. Importantly, ISO exhibits potent neuroprotective effects against motor neuron degeneration in ALS models. Using this AI-driven strategy, we identified a previously unrecognized neuroprotective mechanism by which ISO protects motor neurons through TFEB-dependent restoration of lysosomal function, validating lysosomal function as a promising therapeutic target for ALS. Collectively, this work establishes that AI-powered screening to identify mTORC1-independent TFEB agonists is a valuable paradigm for the discovery and development of therapeutic agents against ALS and other neurodegenerative diseases.}, } @article {pmid41969219, year = {2026}, author = {Byrd, EJ and Crossley, JA and Chau, CCC and Actis, P and Calabrese, AN}, title = {An ALS-associated mutation in the C-terminal α-helix of TDP-43 uncouples condensate formation and amyloid assembly.}, journal = {Protein science : a publication of the Protein Society}, volume = {35}, number = {5}, pages = {e70565}, pmid = {41969219}, issn = {1469-896X}, support = {BB/M012573/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; 220628/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; BB/X003086/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; WT104918MA/WT_/Wellcome Trust/United Kingdom ; RGS\R2\222357//Royal Society/ ; /WT_/Wellcome Trust/United Kingdom ; 090932/Z/09/Z/WT_/Wellcome Trust/United Kingdom ; BB/Y00034X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {*DNA-Binding Proteins/genetics/chemistry/metabolism ; Humans ; *Amyloid/chemistry/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Protein Conformation, alpha-Helical ; *Mutation ; Spectrometry, Mass, Electrospray Ionization ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) plays a critical role in RNA metabolism and is incorporated into biomolecular condensates called stress granules. In amyotrophic lateral sclerosis (ALS) and several other neurodegenerative disorders, TDP-43 undergoes aberrant phase transitions, forming insoluble amyloid aggregates, including fibrils composed of solely its intrinsically disordered C-terminal domain (CTD). Despite its central role in disease, the conformational dynamics of the CTD remain poorly understood due to its heterogeneous and transient conformational landscape. Here, we employ native ion mobility-mass spectrometry (IM-MS) using nanopipette sub-micron nano electrospray ionization (nanoESI) emitters to characterize the conformational landscape of wild-type and ALS-associated TDP-43 CTD variants (Q331K and R361S) under different solution conditions. Our data suggest that mutations and salt concentration modulate the CTD's conformations. Combined with thioflavin T fluorescence, light scattering, and microscopy, we reveal that these conformational shifts correlate with altered amyloid assembly kinetics and propensity to form condensates. Notably, the Q331K variant, which has a mutation in the transient α-helical region in the CTD, has reduced propensity to form biomolecular condensates but can undergo amyloid assembly in the absence of condensate formation, suggesting that sequence alterations in this α-helical region can tune the molecular mechanism of amyloid assembly. This study demonstrates the power of IM-MS in probing disordered proteins and reveals mechanistic insights into how disease-associated mutations differentially tune TDP-43 CTD amyloid assembly mechanisms.}, } @article {pmid41970050, year = {2026}, author = {Ren, Y and Han, X and Zhang, K and Niu, S and Chen, B and Wang, X and Jian, F and Pan, H and Zhang, Z and Chen, X}, title = {MRI abnormal patterns of lumbar paraspinal muscles in patients with amyotrophic lateral sclerosis and lumbosacral radiculopathy: a comparative study.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1751139}, pmid = {41970050}, issn = {1664-2295}, abstract = {BACKGROUND: Recent evidence highlights the potential predictive value of paraspinal muscle degeneration in amyotrophic lateral sclerosis (ALS). However, the magnetic resonance imaging (MRI) characteristics of degeneration in lumbar paraspinal muscles in ALS and lumbosacral radiculopathy (LR) remain unclear.

METHODS: Comparison of fatty infiltration (FI) and relative cross-sectional area (rCSA) of the paraspinal muscles was conducted between 38 ALS patients and 32 LR patients.

RESULTS: The mean rCSA of the multifidus (MF), erector spinae (ES), and psoas major (PM) muscles was lower on the symptomatic onset side compared to the contralateral side at the L3-L5 segments in patients with ALS. On the symptomatic onset side, the FI of the ES (L1-L4 segments), MF (L4 segment), and PM muscles (L1, L2, and L4 segments) was significantly higher in ALS patients who had pathological spontaneous activity (PSA) than in those without PSA. At the L3-L5 segments on the symptomatic onset side, the mean rCSA of the MF, ES, and PM muscles was significantly higher in LR patients compared to ALS patients (p < 0.01). Similar differences in the rCSA of the MF, ES, and PM muscles were observed between lower limb-onset ALS patients and LR patients (p < 0.05). In addition, mild associations were observed between declines in the ALS functional rating scale (ALSFRS)-lower score and decreases in the rCSA of MF and PM muscles, as well as increased FI of the MF and ES muscles.

CONCLUSION: The decrease in the rCSA of the paraspinal muscles on the symptomatic onset side suggests progressive involvement of muscle fibers in ALS patients. The presence of PSA in the paraspinal muscles appears to be more valuable and sensitive for evaluating fatty substitution than muscle atrophy in ALS. MRI parameters of the paraspinal muscles may be useful for monitoring disease progression in ALS and distinguishing ALS, especially lower limb-onset cases, from pauci-symptomatic LR.}, } @article {pmid41971996, year = {2026}, author = {Apostol, CV and Li, A and Daniels, P and Griffith, L and Cooper-Knock, J and Aguilar-Martinez, E and Yonchev, ID and Whelan, AGR and Shaw, PJ and Sudbery, IM and Wilson, SA}, title = {hnRNPUL1 has a dead polynucleotide kinase domain that regulates RNA and protein interactions.}, journal = {iScience}, volume = {29}, number = {4}, pages = {115360}, pmid = {41971996}, issn = {2589-0042}, abstract = {hnRNPUL1 is a nuclear RNA-binding protein involved in both pre-mRNA splicing and DNA double-strand break repair. Using AlphaFold, we show that hnRNPUL1 has a central folded region consisting of tightly juxtaposed SPRY and dead polynucleotide kinase (dPNK) domains flanked by intrinsically disordered regions (IDRs). The dPNK domain binds both nucleotides and RNA. Remarkably, polynucleotide kinase activity can be reactivated with a single amino acid substitution. Mutations altering nucleotide binding also change the ability of the entire protein to bind RNA and regulate homotypic versus heterotypic protein interactions driven by the IDRs. A mutation that prevents nucleotide binding also destabilizes the protein. In a small number of amyotrophic lateral sclerosis patients, we identify rare coding variants in the HNRNPUL1 gene, which alter the ability of hnRNPUL1 to bind nucleotides, RNAs, and FUS. Together, these data establish that hnRNPUL1 utilizes its dPNK domain to regulate interactions with itself, RNA, and other proteins.}, } @article {pmid41973722, year = {2026}, author = {Ge, D and Wu, L and Yang, J and Sun, J and Wang, J and Wang, J and Song, H and Wei, R and Xu, Z and Zhao, B and Sun, R and Wang, Y}, title = {Adverse events in different administration routes of Edaravone: A pharmacovigilance study based on the FDA adverse event reporting system.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0346797}, pmid = {41973722}, issn = {1932-6203}, mesh = {*Edaravone/adverse effects/administration & dosage ; United States ; Humans ; United States Food and Drug Administration ; *Adverse Drug Reaction Reporting Systems ; Administration, Oral ; *Pharmacovigilance ; Amyotrophic Lateral Sclerosis/drug therapy ; Administration, Intravenous ; Drug Administration Routes ; *Drug-Related Side Effects and Adverse Reactions/epidemiology ; }, abstract = {The U.S. Food and Drug Administration (FDA) approved intravenous edaravone for the treatment of amyotrophic lateral sclerosis (ALS) in 2017, followed by the approval of the oral formulation in 2022. This study aims to utilize the FDA#39;s Adverse Event Reporting System (FAERS) to investigate the spectrum and timing of adverse events (AEs) associated with edaravone administration, employing repeatability analysis, the Reporting Odds Ratio (ROR) approach, Weibull distribution, and stratification methods. The investigation focuses on data collected from the first quarter of 2017 through the fourth quarter of 2024, aiming to identify adverse event signals and their temporal patterns related to both intravenous and oral edaravone administration. In total, 3,262 records of edaravone-related adverse reactions were identified; among these, 1,534 incidents were associated with intravenous administration, while 453 incidents pertained to oral administration. The analysis revealed distinct adverse reaction profiles for the two routes of administration. Notably, the spectrum of adverse reactions resulting from oral administration predominantly involved the respiratory system, digestive system, and skin damage. In contrast, intravenous administration was more frequently linked to complications associated with invasive procedures and local tissue damage. Furthermore, the timing of adverse reactions exhibited significant variability between the two routes. Weibull distribution analysis indicated that the median onset time for adverse reactions following intravenous administration was 35 days, whereas for oral administration, it was 27 days. Both analytical approaches identified early failure signals, suggesting that the risk of adverse events diminishes over time.}, } @article {pmid41974001, year = {2026}, author = {Beaulieu, D and Smith, K and Ross, C and Yip, S and Felizardo, TC and Fournier, C and Glass, JD and Berry, JD and Fowler, DH and Ennist, DL and , }, title = {Development of a machine learning-based survival prediction model for ALS inclusive of the advanced-stage population.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {678-688}, pmid = {41974001}, issn = {2167-9223}, support = {U01 NS136020/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/physiopathology ; *Machine Learning ; Female ; Predictive Learning Models ; Male ; Middle Aged ; Aged ; Random Forest ; Boosting Machine Learning Algorithms ; Prognosis ; Kaplan-Meier Estimate ; Prediction Algorithms ; Classification Algorithms ; }, abstract = {OBJECTIVE: Develop a machine learning-based model for survival prediction in ALS, including advanced-stage patients (≤50% predicted normal vital capacity [VC50]).

METHODS: Training data from the PRO-ACT Database (n = 6896) was supplemented with advanced-stage ALS patients (n = 678), with model validation on distinct advanced-stage ALS patients (n = 403). Baseline patient characteristics, including slopes from symptom onset, were used to train a random forest model to identify parameters with the greatest relative importance (RI) for predicting survival outcomes. These parameters were used to train a gradient-boosting machine (GBM) model that generated patient-level survival predictions (log-hazard). Model discrimination and calibration were quantified by C-index and calibration-in-the-large plus calibration slope, respectively. Kaplan-Meier curves were generated, with patient stratification into tertiles based on the predicted survival risk score.

RESULTS: Baseline characteristics with the highest RI for driving survival predictions included: VC% slope (20.2%); age (12.4%); VC% (9.9%); VC(L) (7.5%); ALSFRS-R (6.6%); and ALSFRS-R slope (5.1%). Model performance upon external validation was satisfactory for both discrimination (C-index, 0.709 [95% CI, 0.671-0.746]) and calibration (calibration-in-the-large, 0.083 [95% CI, -0.073-0.232]; calibration slope, 0.992 [95% CI, 0.789-1.198]). At 8-months from baseline, the model successfully stratified patients by survival prognosis, with low-, average-, and high-risk population tertiles having observed median survival probabilities of 85, 69, and 43%, respectively.

CONCLUSIONS: This model accurately predicts survival prognosis in ALS, including patients with severely impaired respiratory function. This new understanding of patient-specific factors that drive survival prognostication will be invaluable for reducing patient heterogeneity in clinical trials evaluating novel therapeutic modalities in early- and advanced-stage ALS.}, } @article {pmid41974046, year = {2026}, author = {Willemse, SW and Hollak, CEM and Reijnhout, ND and Reparon-Schuijt, CC and Pisters-van Roy, AAMG and Demaegd, KC and van Eijk, RPA and van Den Berg, LH and van Es, MA}, title = {Fast and controlled access to tofersen for SOD1-related amyotrophic lateral sclerosis in The Netherlands; experiences using the orphan drug access protocol.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2026.2655738}, pmid = {41974046}, issn = {2167-9223}, } @article {pmid41974458, year = {2026}, author = {Facciabene, A and Ellsworth, SG}, title = {Gut-targeted strategies at the intersection of radiotherapy and immunotherapy.}, journal = {Journal for immunotherapy of cancer}, volume = {14}, number = {4}, pages = {}, pmid = {41974458}, issn = {2051-1426}, mesh = {Humans ; *Immunotherapy/methods ; *Gastrointestinal Microbiome/radiation effects/drug effects/immunology ; *Neoplasms/immunology/therapy/radiotherapy ; Animals ; *Radiotherapy/methods ; Host-Directed Therapy ; }, abstract = {The gut microbiota has emerged as a critical determinant of therapeutic immunity, shaping responses to immune checkpoint inhibitors, adoptive cellular therapies, and radiotherapy (RT). Interest has grown in whether interventions targeting the microbiota might deliberately amplify anticancer immunity.Chen and colleagues recently proposed an unconventional approach: using low-dose intestinal irradiation (ILDR) to remodel the gut microbiota and thereby enhance responsiveness to programmed death-ligand 1 blockade in patients with metastatic cancer. Their report, though preliminary, suggests that directed RT to the intestine can in fact act to favorably modulate the intestinal microbiota. Importantly, current evidence remains largely correlative and does not establish a causal relationship between ILDR, microbiota remodeling, and enhanced systemic antitumor immunity. This concept is provocative, but it raises fundamental questions: does gut-directed RT truly enhance systemic antitumor immunity, or might additional confounding variables, organ-specific effects, and potential toxicities influence the signal?In this Commentary, we balance enthusiasm with caution. We first outline the conceptual framework linking RT, microbiota, and immune activation; then highlight the specific pitfalls revealed by Chen et al's study, including challenges in attribution, heterogeneity, and immunosuppression. We also discuss complementary translational approaches, including direct microbiota modulation through targeted antibiotics and other gut-directed strategies, as potential tools to experimentally interrogate the microbiota-RT-immunotherapy axis in patients.}, } @article {pmid41975461, year = {2026}, author = {Abbas, AEF and Talib, NFA and Elghobashy, MR and Al Kamaly, O and Halim, MK}, title = {Candexch algorithm-enhanced chemometric determination of a novel anti-COVID-19 therapeutics in plasma and paxlovid formulation using advanced multivariate modeling: a sustainability-centered bioanalytical approach.}, journal = {BMC chemistry}, volume = {20}, number = {1}, pages = {}, pmid = {41975461}, issn = {2661-801X}, support = {PNURSP2026R917//Princess Nourah Bint Abdulrahman University/ ; }, abstract = {This work reports the development of an algorithm-assisted chemometric spectrophotometric method for the concurrent quantification of anti-COVID-19 therapeutics nirmatrelvir, ritonavir, and the active molnupiravir metabolite N4-hydroxycytidine in pharmaceutical formulations and human plasma. A structured fractional five-level factorial calibration design consisting of 25 mixtures was employed to construct the calibration dataset, while the external validation set was generated using D-optimal sample selection via the Candexch algorithm to ensure uniform coverage of the experimental domain and minimize sampling bias relative to random dataset partitioning. Quantitative modeling was performed using four multivariate regression strategies: Principal Component Regression (PCR), Genetic Algorithm-assisted Partial-Least Squares (GA-PLS), Firefly Algorithm-assisted Partial-Least Squares (FA-PLS), and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). Model optimization, including latent variable selection, wavelength selection, and parameter tuning, was performed exclusively using the calibration dataset through internal cross-validation (LOO-CV) based on minimum RMSECV, while the external validation set was kept completely independent and used only for final prediction. Among the models that were assessed, the MCR-ALS algorithm demonstrated the best overall predictive performance, yielding correlation coefficients exceeding 0.9997 and root mean square prediction errors ranging from 0.076 to 0.213 µg mL[-1]. NAS-based sensitivity assessment produced detection limits between 0.109 and 0.876 µg mL[-1], demonstrating adequate sensitivity within the investigated concentration ranges. Matrix-matched validation employing 25 calibration and 13 external validation mixtures prepared in fortified human plasma confirmed predictive robustness across both plasma and Paxlovid[®] dosage matrices. Multidimensional sustainability appraisal revealed favorable environmental and operational attributes. The method satisfied all National Environmental Methods Index criteria, achieved a Greenness Evaluation Metric for Analytical Methods score of 7.502, and displayed a calculated carbon footprint of 0.021 kg CO2/sample. Complementary operational and innovation assessments yielded Blue Applicability Grade Index and Violet Innovation Grade Index scores of 90.00 and 80.00, respectively, while the integrated Normalized Quality Score reached 83%. Collectively, the developed platform provides a cost-efficient and environmentally considerate analytical approach suitable for pharmaceutical quality control and preliminary bioanalytical screening in fortified plasma matrices, particularly in laboratories lacking access to advanced chromatographic instrumentation.}, } @article {pmid41975595, year = {2026}, author = {Tedeschi, V and Ciancio, R and Piccirillo, S and Preziuso, A and Serfilippi, T and Terenzi, V and Magi, S and Lariccia, V and Castaldo, P and Vinciguerra, A and Piccialli, I and Canzoniero, LMT and Pannaccione, A and Secondo, A}, title = {Organelles storing Ca 2+ in the brain cells: New druggable targets in neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {21}, number = {11}, pages = {5116-5125}, doi = {10.4103/NRR.NRR-D-25-01754}, pmid = {41975595}, issn = {1673-5374}, abstract = {Several lines of evidence suggest that targeting dysfunctional calcium (Ca 2+)-storing organelles and their defective connections may represent a promising therapeutic strategy counteracting neurodegeneration. Dysfunction in these compartments converges to promote oxidative and endoplasmic reticulum stress, energy failure, autophagy blockade or hyperactivation, and progressive neurodegeneration. Within the intracellular scenario, several dysfunctional organelles have been characterized in terms of their capability to hijack Ca 2+ signaling during neurodegeneration to deadly impact on neuronal tasks in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, brain ischemia, and neonatal hypoxic injury. This review has focused on the endoplasmic reticulum, mitochondria, and lysosomes, as well as their functional interconnection able to maintain the physiological processes such as lysosomal-dependent autophagy and function, lipid trafficking, and protein quality control. Clinically, looking ahead from the already existing therapies, drugs that enhance mitochondrial Ca 2+ efflux or modulate mitochondrial Ca 2+ uniporter regulation at mitochondria-associated membranes-endoplasmic reticulum sites represent innovative opportunities for next-generation strategies aimed at restoring mitochondrial homeostasis and protecting dopaminergic neurons in Parkinson's disease. Furthermore, functional stabilization of the lysosomal channel transient receptor potential mucolipin 1 by the lipid-based formulation of PI(3,5)P 2 may extend the lifespan of amyotrophic lateral sclerosis mice by stimulating the nuclear translocation of the master regulator of autophagy activated by lysosomal Ca 2+ release, namely transcription factor EB. Moreover, dysfunction of lysosomal-dependent autophagy can cause mutant huntingtin accumulation in Huntington's disease through the repression of transcription factor EB and lysophagy induction. Collectively, this growing focus may highlight a shift toward recognizing mitochondria, lysosomes, and endoplasmic reticulum, as well as their ionic machinery and interconnections, as a unifying strategy to maintain neuronal viability and mitigate the neurodegeneration progression in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, lysosomal storage diseases, brain ischemia, and neonatal hypoxic insult.}, } @article {pmid41975602, year = {2026}, author = {Szewczyk, B and Hermann, A and Zimyanin, V}, title = {From cell cycle re-entry to checkpoint failure: Rethinking DNA damage response in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01740}, pmid = {41975602}, issn = {1673-5374}, } @article {pmid41976821, year = {2026}, author = {Suzuki, H}, title = {Speculum-Induced Intraocular Pressure Elevation During Cataract Surgery and Its Association with Axial Length: A Retrospective Clinical Study.}, journal = {Journal of clinical medicine}, volume = {15}, number = {7}, pages = {}, pmid = {41976821}, issn = {2077-0383}, abstract = {Background/Objectives: This study aimed to characterize eyelid speculum-induced intraocular pressure (IOP) elevation during cataract surgery and identify ocular biometric factors that stratify susceptibility to this pressure response. This study was conducted at Zengyo Suzuki Eye Clinic, Kanagawa, Japan. Methods: In this retrospective observational study, we analyzed 100 eyes that underwent routine cataract surgery. IOP was measured immediately before and within 10 s of speculum opening in the seated position using a rebound tonometer. The eyelid speculum was opened to a maximal opening position, and the opening width was recorded. Biometric parameters included axial length (AL), central corneal thickness, white-to-white distance, anterior chamber depth, and temporal angle-opening distance. Associations between IOP elevation and biometric factors were analyzed. IOP elevation rate was quantified as the percentage increase from baseline. The discriminatory performance of axial length was evaluated using receiver operating characteristic (ROC) analysis. Results: Overall, 100 patients (100 eyes) were included in the analysis. Mean IOP increased significantly from 15.75 ± 2.77 mmHg before speculum placement to 21.42 ± 5.54 mmHg after placement. The mean IOP elevation rate was 36.0 ± 27.4%. Shorter AL was consistently associated with a greater proportional IOP elevation. ROC analysis demonstrated consistent stratification of IOP elevation susceptibility by AL (area under the curve [AUC] = 0.645), with eyes shorter than 23.84 mm showing greater pressure elevation (sensitivity, 73.1%; specificity, 56.0%). Eyes in the upper quartile of the IOP elevation rate exhibited relatively greater pressure elevation. Conclusions: Eyelid speculum placement imposes a clinically meaningful IOP load during cataract surgery, with shorter ALs making eyes more biomechanically susceptible to IOP elevation.}, } @article {pmid41977262, year = {2026}, author = {Mîndreanu, R and Chiș, IC and Sevastre-Berghian, A and Login, C and Stan, A and Stan, T and Clichici, S and Suciu, Ș}, title = {N-Acetylcysteine in Neurological Disorders: A Systematic Review of Clinical and Translational Evidence Across Seven Disorders.}, journal = {International journal of molecular sciences}, volume = {27}, number = {7}, pages = {}, pmid = {41977262}, issn = {1422-0067}, mesh = {*Acetylcysteine/therapeutic use/pharmacology ; Humans ; *Nervous System Diseases/drug therapy ; *Neuroprotective Agents/therapeutic use ; Alzheimer Disease/drug therapy ; Oxidative Stress/drug effects ; Animals ; Parkinson Disease/drug therapy ; Antioxidants/therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy ; Multiple Sclerosis/drug therapy ; Brain Injuries, Traumatic/drug therapy ; }, abstract = {N-acetylcysteine (NAC) is a glutathione precursor with established antioxidant and anti-inflammatory properties that has been investigated as a neuroprotective agent across multiple neurological conditions. This systematic review systematically mapped the clinical evidence for NAC across seven neurological disorders. PubMed and Cochrane Library were searched for studies published between 1 January 1995 and 31 December 2025. Twenty-three studies were included: traumatic brain injury (TBI, n = 6), Alzheimer's disease (AD, n = 5), Parkinson's disease (PD, n = 5), multiple sclerosis (n = 4), amyotrophic lateral sclerosis (n = 2), and migraine (n = 1); no eligible epilepsy studies were identified. The strongest evidence emerged for acute mild TBI, where early NAC administration significantly improved symptom resolution, and for PD, where combined intravenous/oral NAC improved dopamine transporter binding. In AD, nutraceutical formulations including NAC and other active compounds showed trends toward cognitive stabilization. Most included studies had a high or serious risk of bias, and only eight of 23 assessed oxidative stress biomarkers. NAC demonstrated a favorable safety profile across all conditions. Despite fragmented and heterogeneous evidence, the encouraging signals identified warrant large-scale randomized controlled trials with a standardized biomarker assessment.}, } @article {pmid41977439, year = {2026}, author = {Bougea, A}, title = {Targeting Non-Coding RNAs as a Potential Therapeutic and Delivery Strategy Against Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {27}, number = {7}, pages = {}, pmid = {41977439}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy ; Animals ; MicroRNAs/genetics ; *RNA, Untranslated/genetics ; Exosomes/metabolism/genetics ; CRISPR-Cas Systems ; RNA, Long Noncoding/genetics ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies-such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications-aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms.}, } @article {pmid41978251, year = {2026}, author = {Malmström, N and Ozanne, A and Nilsson, S and Öhlén, J and Jakobsson Larsson, B}, title = {Support interventions for families facing parental life-threatening illness - A scoping review.}, journal = {Palliative & supportive care}, volume = {24}, number = {}, pages = {e78}, pmid = {41978251}, issn = {1478-9523}, mesh = {Humans ; *Social Support ; *Parents/psychology ; Family Support ; Child ; }, abstract = {OBJECTIVES: Despite the urgent need for support interventions for families facing parental life-threatening illness, research is limited - particularly in progressive neurological diseases. This scoping review aimed to systematically map existing interventions to inform the development of tailored support in the neurological context.

METHODS: A scoping review was conducted, including articles published between 2013 and 2025, identified through searches in PubMed, CINAHL, PsycINFO, and Web of Science, along with manual screening of reference lists. Extracted data were systematically charted and descriptively summarized.

RESULTS: Of 5172 articles, 15 were included, describing 6 unique interventions aimed at supporting children (0-25 years) and/or parents in families where a parent had a life-threatening illness. While cancer was the predominant diagnosis among ill parents, progressive neurological diseases, such as amyotrophic lateral sclerosis (ALS) and Huntington's disease, were represented to a limited extent. The interventions targeted children (n = 4), parents in their parenting role (n = 4), or the entire family (n = 7) and were primarily based on psychosocial, psychoeducational, or peer support. Overall, the interventions were positively received by both children and parents and perceived as helpful in navigating their challenging life situations in various ways.

SIGNIFICANCE OF RESULTS: This review confirms a particular lack of knowledge and tailored support for families affected by progressive neurological diseases. While support interventions for other life-threatening illnesses are also limited, those that exist may offer valuable insights to inform the development of support within neurological care contexts. The findings underscore the need for early, proactive, and accessible approaches that address both individual and family needs across the disease trajectory, aligning with core principles of high-quality palliative care.}, } @article {pmid41978444, year = {2026}, author = {Stokholm, JB and Küchen, SHL and Møller, K and Gätke, MR and Svenstrup, K and Staehr-Rye, AK}, title = {Outpatient versus inpatient initiation of home mechanical ventilation in patients with amyotrophic lateral sclerosis - a protocol for a randomised trial.}, journal = {Danish medical journal}, volume = {73}, number = {4}, pages = {}, doi = {10.61409/A09250733}, pmid = {41978444}, issn = {2245-1919}, mesh = {Female ; Humans ; Male ; Middle Aged ; *Ambulatory Care ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Home Care Services ; *Hospitalization ; *Hypoventilation/therapy/etiology ; Inpatients ; *Noninvasive Ventilation/methods ; Patient Compliance ; Patient Satisfaction ; Quality of Life ; Remote Patient Monitoring ; *Respiration, Artificial/methods ; Telemedicine ; Randomized Controlled Trials as Topic ; Equivalence Trials as Topic ; }, abstract = {INTRODUCTION: In-home non-invasive ventilation (NIV) is associated with prolonged life and improved quality of life in patients with hypoventilation due to amyotrophic lateral sclerosis (ALS). The initiation of NIV is scheduled for a 1-2-night hospital stay. Telemedicine enables remote monitoring and adjustment of respiratory treatment. These possibilities should be examined to improve patients' experiences and adherence to treatment while freeing up resources in the healthcare system. We hypothesise that outpatient initiation of NIV combined with close telemonitoring in patients with ALS is non-inferior to standard initiation of NIV in adherence to treatment.

METHODS: This is a randomised, controlled, non-inferiority study. A total of 46 patients with ALS scheduled for initiation of NIV are randomised to start NIV either as an outpatient combined with close telemonitoring or during hospitalisation for 1-2 nights. The primary outcome is NIV adherence after three months, measured as minutes per day for the past seven days. Secondary outcomes are patient satisfaction with NIV treatment and its initiation after three months, assessed on a 1-5 rating scale.

CONCLUSIONS: The study is the first randomised, controlled study assessing the combination of outpatient initiation of NIV and close telemedical follow-up in patients with a progressive neuromuscular disease. The results may be applicable to other patient populations initiating NIV, e.g., patients with obesity hypoventilation syndrome.

FUNDING: The study was supported by grants from ALS-fonden and Muskelsvindfonden.

TRIAL REGISTRATION: NCT05829330.}, } @article {pmid41979429, year = {2026}, author = {Patel, J and Eisenberg-Godsey, SR and Tipton, PW}, title = {Exploring the phenotypic spectrum of frontotemporal lobar degeneration.}, journal = {Neurologia i neurochirurgia polska}, volume = {60}, number = {2}, pages = {138-152}, doi = {10.5603/pjnns.109796}, pmid = {41979429}, issn = {0028-3843}, mesh = {Humans ; *Frontotemporal Lobar Degeneration/diagnosis/genetics/physiopathology/pathology ; Phenotype ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; }, abstract = {Frontotemporal lobar degeneration (FTLD) refers to a spectrum of neuropathology preferentially affecting the frontal and temporal lobes manifesting with progressive behavioral, language, and motor impairment. These clinical symptoms linked to FTLD are collectively referred to as frontotemporal spectrum disorders (FTSD) and include behavioral-variant frontotemporal dementia, nonfluent/agrammatic primary progressive aphasia, semantic variant primary progressive aphasia, right temporal variant frontotemporal dementia, corticobasal syndrome, progressive supranuclear palsy, and amyotrophic lateral sclerosis-frontotemporal spectrum disorders. While some patients with FTLD present with a single, well-defined syndrome, others exhibit features of multiple syndromes, and clinical phenotypes frequently evolve over time. Moreover, there is substantial phenotypic overlap between FTSD and other neurological disorders, contributing to frequent misdiagnosis and diagnostic delays. To address these challenges, we provide a practical, clinically oriented framework for the diagnosis of FTSD. We review common and nuanced clinical features, pertinent diagnostic testing, and the role of genetic testing in the context of current understanding of neuropathological correlates. Despite the absence of disease-modifying therapies, we also outline evidence-informed strategies for the symptomatic management of FTSD.}, } @article {pmid41980219, year = {2026}, author = {Galizzi, G}, title = {MAMs as a promising therapeutic strategy for age-related neurodegenerative diseases.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2025.1342}, pmid = {41980219}, issn = {2152-5250}, abstract = {Aging is a natural process leading to the slow and progressive deterioration of numerous physiological functions. It is the main risk factor for several neurodegenerative diseases. Mitochondria-associated membranes (MAMs) or mitochondria-ER contacts (MERCs) are essential and dynamic sites of contact between mitochondria and the endoplasmic reticulum (ER) and are involved in numerous cellular processes, such as calcium (Ca[2+]) homeostasis, reactive oxygen species (ROS) production, autophagy, inflammation, mitochondrial dynamics, apoptosis, lipid biosynthesis, and trafficking. As a result, they play a significant role in maintaining cellular functionality regulating metabolism and ensuring proper stress responses. Recently, MAMs have been widely investigated to understand their critical role in cell physiology as well as in different pathological conditions. Increasing evidence indicates that alterations in ER-mitochondria communication contribute to aging and the development of age-related diseases. However, the cellular mechanisms underlying this link remain unclear. Understanding how these interactions change with age could provide further insights into the aging process and the mechanisms underlying age-related diseases, suggesting potential new therapeutic strategies. This review summarizes the current knowledge on MAM biology, focusing on their role in the pathogenesis of age-related brain disorders. Their therapeutic potential in limiting the progression of some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, and slowing the physiological aging process are also explored.}, } @article {pmid41980342, year = {2026}, author = {Dubbioso, R}, title = {Beyond motor output: disrupted kinesthesia reveals hidden sensory-cognitive dysfunction in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {187}, number = {}, pages = {2111885}, doi = {10.1016/j.clinph.2026.2111885}, pmid = {41980342}, issn = {1872-8952}, } @article {pmid41980818, year = {2026}, author = {Shah, NM and Kaltsakas, G}, title = {Non-invasive ventilation timing in ALS: one size does not fit all.}, journal = {Thorax}, volume = {81}, number = {10}, pages = {939-940}, doi = {10.1136/thorax-2026-224807}, pmid = {41980818}, issn = {1468-3296}, } @article {pmid41981045, year = {2026}, author = {Neumann, M and Kothare, H and Bartlett, M and Roesler, O and Suendermann-Oeft, C and Hosamath, A and Arbatti, L and Pautler, D and Suendermann-Oeft, D and Cadavid, D and Scannevin, RH and Hoffmann, I and Tarachandani, A and Haley, T and Raines, S and Damme, PV and Tienari, P and Solje, E and Jokela, M and Genge, A and O'Connell, C and Eijk, RPAV and Berg, LHVD and Ramanarayanan, V}, title = {Speech-based digital endpoints track ALS progression and align with standard clinical outcomes: evidence from the VRG50635 trial.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41981045}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology/diagnosis ; Disease Progression ; Female ; Male ; *Speech/physiology ; Middle Aged ; Aged ; Neurofilament Proteins/blood ; }, abstract = {We report on the utility of speech-based digital endpoints measured during a Phase 1b study of VRG50635 in Amyotrophic Lateral Sclerosis (ALS). Fifty-four participants with ALS were enrolled and participated in an 8-week pretreatment run-in, followed by three 8-week dosing periods and an 8-week follow-up. They completed a speech assessment every two weeks in the clinic or at home. We observed moderate to high correlations between digital measures of speech timing and articulatory motor function, and the ALS Functional Rating Scale-Revised, slow vital capacity and plasma neurofilament light chain. Furthermore, speech measures can show functional decline before the ALSFRS-R does, while also capturing differences between participants with bulbar symptoms and those without. The results support the feasibility and utility of digital speech endpoints to study disease impact in ALS clinical trials.}, } @article {pmid41981822, year = {2026}, author = {Luo, X and Alias, BS and Adnan, NH}, title = {Active learning strategies and student engagement in undergraduate medical education: A systematic review (2015-2025).}, journal = {Anatomical sciences education}, volume = {19}, number = {7}, pages = {1157-1169}, doi = {10.1002/ase.70231}, pmid = {41981822}, issn = {1935-9780}, support = {JYZ202412//Hubei Enshi College/ ; }, mesh = {*Education, Medical, Undergraduate/methods ; Humans ; *Problem-Based Learning/methods ; *Students, Medical/psychology/statistics & numerical data ; Curriculum ; Academia ; }, abstract = {Active learning strategies (ALS) are increasingly employed in undergraduate medical education to promote student engagement across behavioral, emotional, and cognitive dimensions; however, there remains limited integrative understanding of the pedagogical mechanisms through which ALS activate engagement and the contextual conditions shaping this process. This systematic review synthesized empirical studies published between 2015 and June 2025 to examine how ALS activate multidimensional student engagement and to develop an integrative, mechanism-oriented framework for engagement activation in undergraduate medical education. Following PRISMA 2020 guidelines, six academic databases were systematically searched for quantitative, qualitative, and mixed-methods studies involving undergraduate medical students, yielding 22 eligible studies. Thematic synthesis indicated that strategies such as gamification, scenario-based learning, team-based learning, and audience response systems demonstrated robust engagement activation when instructional designs integrated authentic tasks, structured collaboration, and timely feedback, rather than through instructional format alone. Across studies, discrepancies were frequently observed between perceived engagement and actual learning outcomes, highlighting the limitations of relying on self-report measures. Contextual moderators, including instructional culture, facilitation practices, and learning environments, further shaped how engagement was activated, expressed, and sustained across settings. These findings informed the development of the Active Learning Engagement Activation model, which conceptualizes engagement as a dynamic, context-sensitive process arising from interactions among instructional design features, learner-interface mechanisms, and contextual moderators, providing a mechanism-oriented framework to support engagement-informed curriculum design and future research in undergraduate medical education.}, } @article {pmid41981990, year = {2026}, author = {Vavers, E and Kopanchuk, S and Veiksina, S and Jonane, J and Mathur, C and Nasirova, N and Midekessa, G and Rinken, A}, title = {Simultaneous Expression of Sigma-1 Receptor and Tetraspanins Highlights Pathways of Receptor Sorting Into Extracellular Vesicles.}, journal = {Journal of neurochemistry}, volume = {170}, number = {4}, pages = {e70426}, doi = {10.1111/jnc.70426}, pmid = {41981990}, issn = {1471-4159}, support = {SJD34//Estonian Research Council/ ; }, mesh = {*Receptors, sigma/biosynthesis/genetics ; Sigma-1 Receptor ; Humans ; *Extracellular Vesicles/metabolism/genetics ; *Tetraspanins/biosynthesis/genetics/metabolism ; Protein Transport/physiology ; Animals ; }, abstract = {Sigma-1 receptor (Sig1R) is an endoplasmic reticulum (ER) chaperone protein involved in regulating ER function, cellular stress responses, and autophagy, and disturbed Sig1R function has been associated with neurodegenerative and neuropsychiatric disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. Although Sig1R has been implicated in secretory pathways and detected extracellularly, its direct presence in isolated extracellular vesicles (EVs) has not been clearly established. In this study, we aimed to confirm Sig1R in isolated EVs by co-expressing it alongside tetraspanin EV markers. Expression of fluorescently tagged Sig1R together with fluorescent protein-labeled tetraspanins CD9, CD63, and CD81 in both cells and isolated EVs was verified using live-cell imaging, emission spectrum measurements, and Western blotting. Efficient expression of these proteins in cells was achieved by using the MultiBacMam expression system and their presence in EVs was detected through advanced TIRF-based multi-well single-particle EV analysis. We observed significantly higher levels of Sig1R in CD63- and CD9-labeled EVs in comparison with CD81-labeled EVs. The obtained data suggest that Sig1R may be released into the extracellular space via exocytotic pathways linked to exosome secretion. The presence of Sig1R in exosomes underscores its potential as a biomarker in neurological disorders, emphasizing the need for further exploration of its diagnostic and other applications.}, } @article {pmid41983194, year = {2026}, author = {Qi, M and Hu, N and Ding, J and Niu, J and Long, B and Liu, M}, title = {Dynamic changes in excitability and viability of sporadic and SOD1-related amyotrophic lateral sclerosis iPSC-derived motor neurons.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1755814}, pmid = {41983194}, issn = {2296-634X}, abstract = {OBJECTIVE: To explore the dynamic changes in excitability and viability of induced pluripotent stem cells (iPSC)-derived motor neurons from sporadic amyotrophic lateral sclerosis (ALS) and compare them with SOD1-related ALS patients and healthy control.

METHODS: Peripheral blood samples were collected from ALS patients and healthy controls (HC) to establish the iPSC-derived motor neurons (MNs). Whole-cell patch-clamp recordings at different culture stages was made using an Axopatch 700B amplifier in combination with pClamp 11 software (Molecular Devices). The frequency of action potentials (APs) was recorded. Additionally, Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) Nick-End Labeling (TUNEL) was used to assess the apoptosis of MNs.

RESULTS: ALS patient-derived MNs exhibited significantly higher firing rates compared to HCs at both 4-7 weeks (p = 0.004) and 7-9 weeks (p = 0.009). Further analysis revealed that SOD1-derived MNs showed significantly higher firing frequencies than sALS (p = 0.009) and HCs (p < 0.001) in 4-7 weeks. In 7-9 weeks, it remained significant between SOD1 and HC-derived MNs (p = 0.015), but became insignificant between SOD1 and sALS (p = 0.855). The apoptotic rate of sALS (Day 30: 61.37% ± 9.63%; Day 60: 78.41% ± 6.63%) and SOD1 (Day 30: 73.69% ± 8.81%; Day 60: 60.37% ± 11.53%) -derived MNs was significantly higher than those of HCs at both Day 30 (30.72% ± 7.57%) and Day 60 (50.85% ± 19.36%) (p < 0.001).

CONCLUSION: MNs derived from both patients with mutant SOD1 and sporadic ALS exhibited increased excitability compared to HCs. The increased excitability of MNs derived from ALS patients with mutant SOD1 occurred earlier, and over time, became consistent with the excitability observed in MNs derived from sporadic ALS. The apoptosis rates of MNs showed similar trends. iPSC-derived MNs from both sporadic and mutant ALS may serve as useful cell models for ALS in future studies.}, } @article {pmid41983529, year = {2026}, author = {Nagasse, HY and Okuda, EK and Coltri, PP}, title = {TDP43 and hnRNP K Regulate Alternative Splicing of DNAJC5.}, journal = {Cell biology international}, volume = {50}, number = {4}, pages = {e70158}, pmid = {41983529}, issn = {1095-8355}, support = {2019/21874-5//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; }, mesh = {*Alternative Splicing/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Heterogeneous-Nuclear Ribonucleoprotein K/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; HEK293 Cells ; RNA, Messenger/metabolism/genetics ; }, abstract = {Alternative splicing is a finely regulated process which defines the final maturation of pre-mRNAs. Modulation of trans-acting spliceosome proteins changes specific patterns of splicing and contributes to the development of diseases. During Amyotrophic Lateral Sclerosis (ALS) disease progression, loss of nuclear trans-acting splicing protein TDP43 leads to accumulation of cryptic exons in mRNAs, which inhibits expression of proteins and aggravates the disease. One of the affected genes is DNAJC5, which codes for a protein responsible for clearance of misfolded proteins in the cytoplasm. We first observed that TDP43 knockdown regulates DNAJC5 transcript splicing. A similar phenotype was observed upon hnRNP K knockdown. We hypothesized canonical splicing of DNAJC5 is dependent on the activity of both TDP43 and hnRNP K. Our results confirmed TDP43 and hnRNP K interaction is dependent on RNA. We also confirmed that DNAJC5 canonical splicing is dependent on its internal TDP43 and hnRNP K binding sites. Taken together, our work enrolls both TDP43 and hnRNP K on splicing regulation of DNAJC5 transcript, affecting activity of the protein encoded by DNAJC5 on endosomal traffic. As a result, activity of both TDP43 and hnRNP K and their association are important for ALS progression.}, } @article {pmid41985161, year = {2026}, author = {Pervushina, EV and Rushkevich, YN and Turuspekova, ST and Kutlubaev, MA}, title = {Challenges in medical care for amyotrophic lateral sclerosis: a survey of physicians from Republic of Bashkortostan (Russia), Belarus, and Kazakhstan.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2652327}, pmid = {41985161}, issn = {2167-9223}, abstract = {OBJECTIVE: To identify and compare the main challenges in diagnosing and managing amyotrophic lateral sclerosis (ALS) from the perspective of neurologists in Republic of Bashkortostan (Russia), Belarus, and Kazakhstan.

METHODS: An anonymous online survey was distributed to neurologists via professional networks from May to October 2025. The questionnaire collected data on demographics, diagnostic and therapeutic approaches, barriers, and suggestions for improvement.

RESULTS: The survey included 294 neurologists. Over half (58.2%) diagnosed ALS less than once a year. Major diagnostic barriers were limited access to key investigations like electromyography (62.6%) and a lack of specialized ALS centers (37.8%). For treatment, 48% prescribed riluzole, while only 12.9% used edaravone. Critically low rates of gastrostomy placement and respiratory support provision (<10% of terminal patients) were noted by over 80% of respondents. Significant cross-country differences were found: neurologists in Kazakhstan utilized genetic testing and edaravone more frequently; neurologists in Belarus employed muscle/tongue ultrasound more often; neurologists in the Republic of Bashkortostan (Russia) reported higher use of speech therapy and gastrostomy. The most frequently proposed solutions were establishing specialized ALS centers (34%), enhancing physician training (20%), and improving palliative care services (16.5%).

CONCLUSIONS: This multinational survey provides important insights into ALS care in the studied countries, identifying key areas for further development. The results point to opportunities for enhancing diagnostic resources, therapeutic strategies, and palliative care approaches. Enhancing the quality of ALS care requires the development of specialized clinical pathways, the implementation of consensus-based protocols, and the expansion of professional education in multidisciplinary management.}, } @article {pmid41985299, year = {2026}, author = {Raka, RN and Zhang, Z and Xiao, J and Wu, H}, title = {Integrative network pharmacology delineates dual GPCR and non-GPCR mechanisms of blended and individual Taikong Blue lavender and Pingyin rose essential oils in neurodegenerative and psychiatric disorders.}, journal = {Computers in biology and medicine}, volume = {208}, number = {}, pages = {111681}, doi = {10.1016/j.compbiomed.2026.111681}, pmid = {41985299}, issn = {1879-0534}, mesh = {*Oils, Volatile/chemistry/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Lavandula/chemistry ; *Rosa/chemistry ; Humans ; *Network Pharmacology ; *Mental Disorders/drug therapy/metabolism ; Molecular Docking Simulation ; *Plant Oils/chemistry/pharmacology ; }, abstract = {Neurodegenerative and psychiatric disorders share overlapping molecular mechanisms, including neuroinflammation, oxidative stress, and neurotransmitter dysregulation. Essential oils from Lavandula angustifolia (TLEO) and Rosa rugosa (PREO) contain neuroactive compounds with therapeutic potential, but their mechanisms remain poorly defined. This study aimed to elucidate the shared and distinct molecular targets and pathways of TLEO and PREO using a multi-scale computational strategy. Compounds identified by GC-MS were evaluated through ADMET profiling, target prediction, and disease-target intersection analysis. Enrichment, network, docking, and dynamics analyses were performed on shared protein-coding targets between essential oils and twelve brain disorders, including seven neurodegenerative conditions (Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, spinal muscular atrophy) and five psychiatric disorders (autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia). A total of 110 compounds yielded 252 common targets, with CHRM2 (GPCR) and NR1H3 (non-GPCR) identified as key hubs. Docking suggested strong binding affinities for caryophyllene oxide at CHRM2 (-7.3 kcal/mol) and α-himachalene at NR1H3 (-8.5 kcal/mol). Molecular dynamics simulations confirmed stable, compact complexes with low RMSD and SASA values. MM/PBSA free energy calculations quantitatively validated these interactions, revealing favorable binding energetics driven predominantly by van der Waals and hydrophobic contributions, consistent with the terpenoid chemical profiles. Functional enrichment highlighted involvement in cholinergic signaling, lipid metabolism, and inflammatory regulation. This study demonstrates that PREO and TLEO can modulate multiple targets relevant to brain disorders through both GPCR and non-GPCR mechanisms. These findings provide a computationally inferred mechanistic framework for the potential neuroprotective synergy of these oils and highlight essential oil-derived compounds as promising leads for further experimental investigation.}, } @article {pmid41985558, year = {2026}, author = {Navarrete-Dechent, C and Pietkiewicz, P and Voloshynovych, M and Marghoob, AA}, title = {Authors' response to Mart et al's "Response to Navarrete-Dechent et al's 'Ultraviolet-induced fluorescent dermoscopy for the diagnosis of skin tumors: A multicenter study'".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {2}, pages = {e183-e184}, doi = {10.1016/j.jaad.2026.03.104}, pmid = {41985558}, issn = {1097-6787}, } @article {pmid41985725, year = {2026}, author = {Wintz, K and Lechtape, PL and Klenzendorf, J and Schemmert, S and Dingley, AJ and Willuweit, A and Kutzsche, J}, title = {Elucidation of the influence of the CaV2.2 calcium channel on ALS disease progression in the SOD1*G93A mouse model.}, journal = {Neurobiology of disease}, volume = {224}, number = {}, pages = {107396}, doi = {10.1016/j.nbd.2026.107396}, pmid = {41985725}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Mice, Transgenic ; *Calcium Channels, N-Type/metabolism/genetics ; Disease Progression ; Disease Models, Animal ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Motor Neurons/metabolism ; Humans ; *Superoxide Dismutase/genetics/metabolism ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal neurodegenerative disease affecting upper and lower motor neurons in the central nervous system. Drugs like riluzole, edaravone, and tofersen treat disease symptoms or are designed for a specific pathological mutation (e.g., SOD1), but they cannot prevent or halt the disease. For this reason, the search for new therapeutic strategies continues. The voltage-gated calcium channel CaV2.2 might be a novel target in ALS treatment as the channel was shown to be overexpressed in murine SOD1*G93A cortical neurons, resulting in higher mortality. Further, murine SOD1*G93A motor neurons showed increased calcium currents mainly by an increased expression of the CaV2.2 channel. In addition, inhibition of the channel was hypothesized as mode of action for the all-d-enantiomeric peptide RD2RD2, a novel drug candidate for the treatment of ALS, which already demonstrated its efficacy in SOD1*G93A mice. To investigate the influence of the CaV2.2 channel on the progression of disease symptoms in the SOD1*G93A mouse model, a new double-transgenic line was created, combining the ALS phenotype with a knockout of the CaV2.2 channel. The study showed that the CaV2.2 knockout on the SOD1*G93A background led to reduced SHIRPA and splay scores, and a delayed disease onset. Additionally, differences were detected between wildtype and single-transgenic CaV2.2 knockout mice. However, survival was not affected. Post mortem analysis of human tissue found more CaV2.2 in ALS cases in comparison to healthy control subjects confirming involvement of the channel in human ALS. These results indicate that the CaV2.2 calcium channel may play an influential role in early disease progression of ALS.}, } @article {pmid41986690, year = {2026}, author = {Zhou, Z and Kim, J and Huang, AY and Nolan, M and Park, J and Doan, R and Shin, T and Miller, MB and Bae, M and Zhao, B and Kim, J and Chhouk, B and Morillo, K and Yeh, RC and Kenny, C and Neil, JE and Lee, CZ and Ohkubo, T and Ravits, J and Ansorge, O and Ostrow, LW and Lagier-Tourenne, C and Lee, EA and Walsh, CA}, title = {Somatic mosaicism in ALS and FTD identifies focal mutations associated with widespread degeneration.}, journal = {Nature genetics}, volume = {58}, number = {5}, pages = {1019-1029}, pmid = {41986690}, issn = {1546-1718}, support = {R01 NS032457/NS/NINDS NIH HHS/United States ; R56 AG079857/AG/NIA NIH HHS/United States ; UH3 NS132138/NS/NINDS NIH HHS/United States ; W81XWH2010028//U.S. Department of Defense (United States Department of Defense)/ ; DP2 AG072437/AG/NIA NIH HHS/United States ; 23CDA1046074//American Heart Association (American Heart Association, Inc.)/ ; K08 AG065502/AG/NIA NIH HHS/United States ; K01 AG051791/AG/NIA NIH HHS/United States ; RS-2025-02215360//National Research Foundation of Korea (NRF)/ ; RS-2023-00217881//National Research Foundation of Korea (NRF)/ ; R01 AG070921/AG/NIA NIH HHS/United States ; UG3 NS132138/NS/NINDS NIH HHS/United States ; R01 AG088082/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; *Mutation ; *Mosaicism ; C9orf72 Protein/genetics ; Brain/pathology ; High-Throughput Nucleotide Sequencing ; }, abstract = {Although mutations in many genes cause familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), most cases are sporadic (sALS and sFTD) with unclear etiology. Here we tested whether somatic mutations contribute to sALS and sFTD by deep targeted sequencing of 88 neurodegeneration-related genes in postmortem brain and spinal cord samples from 399 sporadic cases and 144 controls. Predicted deleterious somatic variants in ALS/FTD genes were observed in 2.1% of sporadic cases lacking deleterious germline variants. These variants occurred at very low allele fractions (typically <2%) and were often focal and enriched in disease-affected regions. Analysis of bulk RNA-sequencing data from an additional cohort identified deleterious somatic variants in DYNC1H1 and LMNA, genes associated with pediatric motor neuron degeneration. Targeted long-read sequencing further identified one sFTD case with de novo somatic C9orf72 repeat expansions. Together, these findings suggest that rare, focal somatic variants can contribute to sALS and sFTD and drive widespread neurodegeneration.}, } @article {pmid41987036, year = {2026}, author = {Nagy, ZF and Géresi, A and Grosz, Z and Trombitás, B and Pál, M and Nagy, D and Salamon, A and Balicza, P and Dézsi, L and Klivényi, P and Széll, M and Molnár, MJ}, title = {Genetic epidemiology of C9orf72 repeat expansion associated amyotrophic lateral sclerosis in Hungary.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {32}, number = {1}, pages = {}, pmid = {41987036}, issn = {1528-3658}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/diagnosis ; *C9orf72 Protein/genetics ; Hungary/epidemiology ; *DNA Repeat Expansion ; Female ; Male ; Middle Aged ; Aged ; Genetic Predisposition to Disease ; Disease Progression ; Adult ; Retrospective Studies ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. The most common genetic cause of ALS is the hexanucleotide repeat expansion in the C9orf72 gene, which is associated with earlier disease onset, faster progression, and an increased frequency of cognitive and psychiatric involvement. Data on population-specific characteristics of C9orf72-associated ALS remains limited in Central and Eastern Europe.

METHODS: Between 2011 and 2024, a total of 959 ALS patients fulfilling established diagnostic criteria were screened for C9orf72 repeat expansions at two Hungarian centers. Hexanucleotide repeat expansions were analyzed using repeat-primed long-read PCR. Repeat numbers exceeding 30 were considered pathogenic. Clinical, demographic, and disease course data were retrospectively collected and analyzed.

RESULTS: Pathogenic C9orf72 repeat expansions were identified in 63 of 959 patients, corresponding to a prevalence of 6.57% among Hungarian ALS patients. Bulbar onset was the most common presentation and was associated with faster progression and shorter survival (mean survival: 27.8 months). Cognitive impairment and psychiatric comorbidities were present in a substantial proportion of patients and were associated with slower functional decline. Regional differences in survival were observed, likely reflecting disparities in healthcare access rather than biological factors.

CONCLUSIONS: This study provides the first comprehensive national characterization of C9orf72 repeat expansion-associated ALS in Hungary, based on a genetically defined cohort assembled over 13 years. Despite limitations related to retrospective data collection and cohort size, this ethnically homogeneous dataset offers valuable insight into population-specific clinical and epidemiological features and complements larger international studies. Systematic characterization and longitudinal follow-up of genetically defined, trial-ready ALS cohorts will be essential as targeted therapies for C9orf72-associated ALS approach clinical implementation.}, } @article {pmid41987206, year = {2026}, author = {Zheng, M and Li, M and Liu, S and Guan, R and Liu, X}, title = {RNA-binding proteins: a comprehensive review of multifaceted regulatory mechanisms in neuroinflammation and implications in the pathogenesis of neurological disorders.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {41987206}, issn = {1742-2094}, support = {82230063//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Animals ; *RNA-Binding Proteins/metabolism ; *Nervous System Diseases/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism/pathology ; }, abstract = {Neuroinflammation stands as a cornerstone pathological hallmark across a spectrum of neurological disorders, drawing intensified scientific scrutiny owing to its profoundly intricate and multi-layered regulatory networks. At the heart of this complexity, RNA-binding proteins (RBPs) emerge as masterful post-transcriptional orchestrators, exerting precise control over a vast array of neuroinflammatory cascades. Mounting evidence underscores that RBPs transcend their classical roles in RNA sensing and innate immune recognition, actively shaping pivotal biological pathways—ranging from inflammatory signal transduction and programmed cell death to metabolic reprogramming, epigenetic remodeling and dynamic crosstalk with non-coding RNAs. Furthermore, the functional versatility of RBPs is amplified by nuanced alterations in their nucleocytoplasmic trafficking, stress granule formation, post-translational modifications, and RNA-binding specificities, all of which intricately fine-tune their regulatory impact within the neuroinflammatory milieu. Strikingly, the cell type-specific actions of RBPs in neurons, microglia, and astrocytes unveil a sophisticated tapestry of molecular specialization, offering transformative insights into their context-dependent functions. Abnormal function of RNA-binding proteins is closely related to neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. In addition, RNA-binding proteins are involved in various pathological processes, including central nervous system infections, stroke, high-altitude cerebral hypoxia, and traumatic brain injury. This review systematically organizes the multifaceted regulatory mechanisms of RNA-binding proteins in neuroinflammation. It deeply explores their key roles in the occurrence and development of nervous system diseases. The review aims to construct a comprehensive theoretical framework and provide a scientific basis for developing new diagnostic methods and targeted therapeutic strategies.}, } @article {pmid41987881, year = {2026}, author = {Li, R and Wang, L and Bu, W and Zhang, X and Li, X and Li, J and Shen, J and Li, J and Cai, Z}, title = {Autologous SVF therapy modulates neuroinflammation in ALS: phase I trial demonstrating safety and CSF biomarker dynamics.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1784115}, pmid = {41987881}, issn = {1663-4365}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with limited treatments. Stromal vascular fraction (SVF), a cell population derived from autologous adipose tissue, exhibits multimodal immunomodulatory and neuroprotective properties, positioning it as a promising therapeutic candidate.

METHODS: This trial aimed to assess autologous stromal vascular fraction (SVF) safety and efficacy in patients with ALS. 26 patients received combined intravenous (0.5 × 106 cells/kg) and intrathecal (20 × 10[6] cells) autologous SVF (An exploratory second dose of SVF was administered intrathecally to three patients 45 days later). The trial is registered with the Chinese Clinical Trial Registry (ChiCTR2400091754).

RESULTS: SVF administration was well-tolerated. Five mild adverse events (adverse events, AEs) (subcutaneous bleeding, headache, and low-grade fever) occurred, with no serious AEs reported. Although ALSFRS-R scores showed non-significant improvement post-treatment, 15/26 participants (57.7%) self-reported symptomatic improvement after treatment. Critically, cerebrospinal fluid biomarker analysis revealed significant reductions in neurofilament light chain (NfL; Δ530.29 pg/mL, P = 0.039) and glial fibrillary acidic protein (GFAP; Δ622.23 pg/mL, P = 0.038), indicating attenuation of neuroaxonal degeneration and astroglial activation. While ALSFRS-R scores showed no significant change (Δ-0.53, P = 0.384), prognostic modeling identified female sex (OR = 0.011, P = 0.008) and shorter disease duration (OR = 1.35/month, P = 0.005) as predictors of response. Three patients who underwent the second treatment were well tolerated without any adverse events.

CONCLUSION: These findings indicate that Autologous SVF therapy might possess an acceptable safety profile for patients with ALS. The significant reduction in CSF NfL and GFAP levels provides objective evidence of their potential neuroprotective effects that modulates ALS-relevant neuroinflammation pathways. Female participants and those with shorter disease duration may derive greater benefits.}, } @article {pmid41988392, year = {2026}, author = {Khan, SF and Rasool, W and Khan, MH and Kumar, G and Ijaz, A and Amjad, M and Sheikh, MQ and Rath, S and Kunwar, D and Akbar, A}, title = {The Impact of Chemical Toxicants and Air Pollutants on Neurodegenerative Disorders and Their Underlying Potential Mechanisms: A Literature Review.}, journal = {Health science reports}, volume = {9}, number = {4}, pages = {e72256}, pmid = {41988392}, issn = {2398-8835}, abstract = {BACKGROUND AND AIMS: Neurodegenerative disorders are marked by progressive deterioration of neurons, affecting cognitive, memory, and motor functions. This decline creates substantial personal and social challenges, making early identification of risk factors essential for effective intervention. Environmental toxicants, such as chemicals and air pollutants, are suspected to negatively impact brain health. This review critically examines the relationship between environmental toxicants and neurodegenerative disorders, exploring their potential mechanisms and providing recommendations for future research.

METHODS: A PubMed search was performed for all available data until April 2024 using keywords related to environmental toxicants and neurodegenerative diseases. The search was limited to peer-reviewed articles in English, focusing on human studies that investigate the association between toxicants and neurodegenerative disorders. A narrative synthesis was conducted based on the neurodegenerative disorder, specific toxicants, and mechanisms of action.

RESULTS: This review highlights the detrimental effects of chemical toxicants and air pollutants on diseases, such as Parkinson's, Alzheimer's, multiple sclerosis, and Huntington's disease. Key mechanisms discussed include oxidative stress, protein aggregation, and mitochondrial dysfunction.

CONCLUSION: The findings emphasize the need to understand the mechanisms by which environmental toxicants contribute to neurodegenerative diseases. Early detection and management, including reduced exposure to harmful substances, are vital. Further research is essential for improving screening techniques and developing targeted interventions.}, } @article {pmid41989583, year = {2026}, author = {Wang, X and Wu, F and Zhang, J and Song, X and Liu, P and Liu, Z and Wang, J and Zhang, Y and Grecucci, A and Yi, X and Chen, BT}, title = {Cerebral metabolic patterns on [18]F-FDG PET are associated with clinical heterogeneity and prognosis in amyotrophic lateral sclerosis: a genetic and transcriptomic perspective.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {53}, number = {8}, pages = {5130-5145}, pmid = {41989583}, issn = {1619-7089}, support = {2024PT5109//the Scientific Research Program of FuRong Laboratory/ ; 2021YFA0805202//National Key R&D Program of China/ ; 2024ZZTS0954//Fundamental Research Funds for Central Universities of the Central South University/ ; 2020XJ88//Scientific research project of Xiangnan University/ ; 2023JJ50382//Natural Science Foundation of Hunan Province/ ; D202303077714//Scientific research project of Hunan Provincial Health Commission/ ; IIT2025-00111//the Joint Research Fund of Chongqing University Three Gorges Hospital-Peking University Human Dajiaweikang Pharmaceutical Industry Co.,Ltd./ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics/metabolism ; *Brain/diagnostic imaging/metabolism ; Case-Control Studies ; Fluorodeoxyglucose F18 ; *Positron Emission Tomography Computed Tomography ; Prognosis ; *Transcriptome ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. However, the neurobiological basis of disease heterogeneity and its prognostic relevance remain incompletely understood. METHODS: In this prospective study, 127 patients with ALS and 128 age- and sex-matched healthy controls underwent brain fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Clinical assessments included standardized evaluations of motor function, cognition, anxiety, and depression. Associations between regional cerebral metabolism and clinical variables were examined using linear regression, whereas survival outcomes were evaluated with Cox proportional hazards models. Whole-exome sequencing was performed to assess genetic mutation status and mutation burden, and a neuroimaging-transcriptomic association analysis was conducted to link regional metabolic alterations with spatial gene expression patterns. RESULTS: Compared with the healthy controls, patients with ALS exhibited a distinctive cerebral metabolic pattern characterized by coexisting hypometabolism and hypermetabolism within the fronto-striatal-limbic network. Significant hypometabolism was observed in the visual pathways, temporal lobes, and cerebellum (all p < 0.05). Hypermetabolism within the fronto-striatal-limbic circuit was associated with better motor and cognitive performance, and lower levels of anxiety and depression (all p < 0.05). Multivariate Cox regression identified hypermetabolism in the right inferior frontal gyrus (opercular part), cognitive impairment, and disease progression rate as independent predictors of survival (all p < 0.05). In addition, genetic mutation status and mutation burden were significantly associated with region-specific metabolic alterations, and neuroimaging-transcriptomic analysis revealed distinct transcriptional signatures underlying hypermetabolic and hypometabolic brain regions. CONCLUSION: Cerebral metabolic abnormalities in patients with ALS reflected a complex interplay between compensatory and degenerative processes, which were closely linked to clinical symptoms and prognosis. Integrating FDG-PET metabolic profiles with genetic and transcriptional information may improve understanding of disease heterogeneity and support personalized prognostic assessment for patients with ALS. CLINICAL TRIAL REGISTRATION: Clinical trial number: not applicable.}, } @article {pmid41989758, year = {2026}, author = {Ahmed, M and Volkening, K and Mclellan, C and Shoesmith, C and Balci, TB and Strong, MJ}, title = {Emerging strategies for interpreting variants of uncertain significance (VUS) in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/21678421.2026.2655734}, pmid = {41989758}, issn = {2167-9223}, abstract = {As the use of genetic testing for neurological diseases increases exponentially, interpreting variants of uncertain significance (VUS) has become a challenging problem. Nowhere has this become more evident than in amyotrophic lateral sclerosis (ALS) and the frontotemporal dementias (FTDs), both of which are complex heterogeneous disorders in which an increasing array of disease-causative and modifying genetic variants are observed. Moreover, while traditionally identified as distinct clinical syndromes, ALS and FTD are increasingly recognized to exist along a spectrum of clinical syndromes (termed the frontotemporal spectrum disorders of ALS; ALS-FTSD) with shared genetic risk. While VUS are generally not used in clinic for decision-making or counseling given their obvious limitations in being medically actionable, their correct interpretation is dynamic and rapidly evolving. VUS are increasingly the subject of intensive study as potential determinants of biological outcomes. It is timely therefore to review the current state of VUS interpretation and to critically evaluate how this can be applied to enhance both patient care and treatment decisions in the broader context of neurological disorders and more specifically in the context of ALS and ALS-FTSD. In doing so, we also explore the evolving challenge of defining pathogenicity of oligogenic inheritance in the context of multiple VUS detection in a single individual using an illustrative case example.}, } @article {pmid41991114, year = {2026}, author = {Zhang, W and Zhang, D and Han, L and Wang, D and Huo, D and Tan, X and Su, X and Wang, M and Xu, J and Cheng, J and Feng, H}, title = {The neuroprotective effect of guanabenz combined with α-lipoic acid in the hSOD1-G93A amyotrophic lateral sclerosis model.}, journal = {Brain research bulletin}, volume = {239}, number = {}, pages = {111890}, doi = {10.1016/j.brainresbull.2026.111890}, pmid = {41991114}, issn = {1873-2747}, mesh = {Animals ; *Thioctic Acid/pharmacology/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics/pathology ; *Neuroprotective Agents/pharmacology ; Mice, Transgenic ; *Guanabenz/pharmacology ; Disease Models, Animal ; Mice ; Endoplasmic Reticulum Chaperone BiP ; Humans ; Motor Neurons/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Spinal Cord/metabolism/drug effects ; Drug Therapy, Combination ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and although its pathogenesis is not yet clear, the multifactorial mechanisms that affect motor neuron death are intertwined, exacerbating the disease. Here, we explore the effectiveness and mechanism of a combination medication that combines guanabenz with α-lipoic acid in an in vitro as well as in vivo model of ALS. In this research, we initially determined the independent action targets and synergistic action targets of the two drugs through network pharmacology and molecular docking. Subsequently, we further investigated their specific action mechanisms in both in vivo and in vitro studies. In NSC34 cells transfected with hSOD1-G93A, we observed that the combined drugs could more effectively safeguard against cell damage and the production of reactive oxygen species (ROS) generated by mutant hSOD1, superior to monotherapy. This was achieved by upregulating the p-AKT/HO-1 pathway and synergistically suppressing the GRP78/CHOP pathway. Moreover, we found that combination drugs can effectively delay the decline in motor function of hSOD1-G93A transgenic mice by synergistically inhibiting GRP78/CHOP pathway. They can protect the motor neurons in the anterior horn of the spinal cord and suppress gliosis in hSOD1-G93A transgenic mice. In summary, our research indicates that the combination therapy of guanabenz and α-lipoic acid can serve as a viable treatment option for ALS.}, } @article {pmid41991228, year = {2026}, author = {Shukla, A and Jaiswal, P and Ashraf, F}, title = {Bannayan-Riley-Ruvalcaba syndrome with arteriovenous malformation.}, journal = {BMJ case reports}, volume = {19}, number = {4}, pages = {}, doi = {10.1136/bcr-2025-269126}, pmid = {41991228}, issn = {1757-790X}, mesh = {Humans ; Male ; *Arteriovenous Malformations/surgery/diagnosis/diagnostic imaging/complications ; *Hamartoma Syndrome, Multiple/diagnosis/complications/surgery/genetics ; *Femoral Artery/abnormalities/surgery/diagnostic imaging ; Skin Transplantation ; }, abstract = {Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare autosomal dominant PTEN hamartomatous tumour syndrome characterised by macrocephaly, genital lentiginosis and intestinal polyposis, often with mucocutaneous, skeletal and vascular anomalies. We report a preadolescent boy with macrocephaly, oral papillomatosis, palmar keratoses, penile lentiginosis, pectus excavatum, hepatosplenomegaly, gastrointestinal hamartomatous polyps and intracranial vascular changes. A large high-flow arteriovenous malformation (AVM) of the right superficial femoral artery was surgically excised with skin graft reconstruction, resulting in a viable graft and no complications. The diagnosis was made using Parisi et al's BRRS criteria and Pilarski's PTEN syndrome guidelines. AVMs are rare in BRRS, reported in ≤10% of cases, typically high-flow and limb-located. This case underscores the need for multidisciplinary evaluation and surveillance for PTEN-associated malignancies and highlights surgical intervention's role in preventing complications while expanding BRRS's recognised vascular phenotype. Early recognition facilitates timely, targeted management.}, } @article {pmid41992463, year = {2026}, author = {Veith, PD and Leeming, MG and Chen, YY and Reynolds, EC}, title = {Cargo Secreted by the Type IX Secretion System of Porphyromonas gingivalis Are Tethered to O-Lipopolysaccharides via a Pentasaccharide Linker.}, journal = {MicrobiologyOpen}, volume = {15}, number = {2}, pages = {e70296}, pmid = {41992463}, issn = {2045-8827}, support = {1123866//Australian National Health and Medical Research Council/ ; DP200100914//Australian Research Council/ ; 20080108//Australian Government Department of Industry, Innovation and Science/ ; }, mesh = {*Porphyromonas gingivalis/metabolism/chemistry ; *Lipopolysaccharides/chemistry/metabolism ; *Bacterial Secretion Systems ; *O Antigens/metabolism/chemistry ; Mass Spectrometry ; *Oligosaccharides/chemistry/metabolism ; Bacterial Proteins/metabolism ; Virulence Factors/metabolism ; }, abstract = {The Gram-negative oral pathogen, Porphyromonas gingivalis, uses the Type IX Secretion System (T9SS) to secrete major virulence factors (cargo proteins) and anchor them to the cell surface via a novel linking sugar, 2-N-seryl, 3-N-acetylglucuronamide (SAGA), which is a component of a specific type of lipopolysaccharide, A-LPS. The reported structure of the polysaccharide component (A-PS) was a repeating phosphorylated mannan whereas the PS of conventional O-LPS (O-PS) is a repeating Gal-Glu-Rha-GalNAc unit. Here, we have performed extensive mass spectrometric analyses of cargo protein-linked LPS with and without proteinase K treatment to determine the structure of A-LPS. Limited acid hydrolysis of the PS backbone with trifluoromethanesulfonic acid enabled long PS fragments linked to cargo-derived peptides to be identified for the first time. Unexpectedly, rather than finding A-PS units, up to eleven O-PS repeating units were found linked to cargo via a novel pentasaccharide linker designated A-LS, composed of SAGA-Hex-dHex(C4H4O3)(Pent)-Hex. In addition, samples from a wzzP/porT double mutant that produced free truncated O-PS were specifically hydrolyzed to cleave lipid A prior to MS analysis. In these samples A-LS was found attached to a limited number of O-PS repeating units that in turn were associated with a putative core oligosaccharide that included the LPS-specific sugar, 3-deoxy-d-manno-octulosonic acid (Kdo). The proposed structure of A-LPS explains all 11 genes specific to A-LPS biosynthesis, and provides the first structural evidence that cargo proteins such as the gingipains are anchored to the cell surface via a complete LPS molecule.}, } @article {pmid41992971, year = {2026}, author = {Cheng, H and Zheng, G and Yang, Y and Xu, C and Tang, G and Huang, C}, title = {Incorporating artificial intelligence into morphological diagnosis of acute leukemias: Current landscape, challenges and prospects (Review).}, journal = {Oncology reports}, volume = {55}, number = {6}, pages = {}, pmid = {41992971}, issn = {1791-2431}, mesh = {Humans ; *Artificial Intelligence ; *Leukemia/diagnosis/pathology ; Machine Learning ; Microscopy/methods ; Data Mining/methods ; }, abstract = {Acute leukemias (ALs) are a diverse group of hematological malignancies characterized by the abnormal proliferation of immature cells. Microscopic observation of cell morphology based on the French‑American‑British classification remains a fundamental diagnostic method for ALs. However, manual screening from bone marrow smear images is often inefficient, laborious and prone to subjective bias, leading to potential misdiagnosis or missed diagnosis. Artificial intelligence (AI), particularly machine learning (ML), has expanded human capabilities in analyzing complex datasets, leading to breakthroughs in multiple fields, including medical research and clinical practice. Increasingly, ML applications are being developed to diagnose hematological diseases by extracting and aggregating morphological characteristics from peripheral blood and bone marrow smears. However, applying ML methods to recognize cell morphology in hematological diseases presents unique challenges compared with other pathology subspecialties. The present review provided an overview of AI and ML applications in ALs diagnosis, focusing on cell segmentation and data mining methods from microscopy images, and highlights their advantages over manual microscopy.}, } @article {pmid41993388, year = {2026}, author = {Sahoo, BR and Bhattrai, J and Sharma, A and Jakob, U and Bardwell, JC}, title = {Microprotein Regulates G-quadruplex Driven RNA Aggregation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41993388}, issn = {2692-8205}, support = {R35 GM122506/GM/NIGMS NIH HHS/United States ; }, abstract = {Repeat expansions of the hexanucleotide GGGGCC in C9orf72 form aberrant phase transitions that have been linked to Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. RNA structures such as G-quadruplexes and hairpins play important roles in these processes. Here, we show that the human microprotein ZNF706 acts as a modulator of G-quadruplex formation and RNA phase behavior. ZNF706 antagonizes pathological gel-solid transitions by melting hexanucleotide repeat G-quadruplex structures converting gel-like aggregates into more dynamic condensates. Loss of ZNF706 enhances the cellular production clearance of hexanucleotide repeat-mediated dipeptide repeat proteins, while overexpression suppresses their production and promotes clearance. Mechanistically, ZNF706 influences hexanucleotide repeat condensate fluidity and viscoelasticity. We find ZNF706 acts as an RNA chaperone that remodels repeat RNA structures and solubilizes RNA aggregates. This activity represents one mechanism whereby cells can regulate G-quadruplex driven phase transitions linked to neurodegenerative diseases.}, } @article {pmid41993486, year = {2026}, author = {Ramos, MEP and Singh, BK and Shelest, O and Tindel, I and Zogu, B and Dawson, A and Mathkar, P and Bell, S and Ho, R}, title = {A region-delineated snRNA-seq atlas of mouse spinal cord across lifespan resolves the interaction of normative aging programs with SOD1-G93A ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41993486}, issn = {2692-8205}, abstract = {Aging is the strongest risk factor for amyotrophic lateral sclerosis (ALS), yet how normative aging programs intersect with disease mechanisms remain unclear. Here we generated a lifespan-resolved, cell type- and region-specific single-nucleus RNA-sequencing atlas of the mouse spinal cord spanning embryonic development through advanced age in WT mice and end-stage disease in the SOD1-G93A ALS model. This resource enabled systematic comparison of physiological aging trajectories with disease-associated transcriptional changes across spinal cord cell types and rostrocaudal regions. We found that SOD1-G93A transcript and protein states differed markedly across spinal regions during disease onset and progression, and these molecular patterns paralleled the relative resilience of cervical regions and the heightened vulnerability of lumbar regions to degeneration in this transgenic mouse model. Prior to disease onset, we identified reduced ubiquitin expression that primed region-specific disruption of proteostasis in the SOD1-G93A spinal cord. Despite these disease-associated changes, aging-related transcriptional programs were largely preserved across most cell types, arguing against a global acceleration of aging in ALS. Instead, microglia emerged as a key exception, exhibiting accelerated and rewired aging- and disease-associated gene expression modules regulated by MITF and NRF2. Together, these findings provide an anatomically, cellularly, and temporally resolved framework for understanding how aging programs interact with disease-specific pathways to shape regional dysfunction and neurodegeneration in ALS.}, } @article {pmid41993496, year = {2026}, author = {Chin, N and Zhang, Q and Zou, J and Cheng, KC and Zheng, W and Ye, Y}, title = {Nuclear export modulates TDP-43 phase transition and cytoplasmic aggregation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41993496}, issn = {2692-8205}, abstract = {RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like, nuclear assemblies whose phase behavior may influence its aggregation propensity and neurotoxic activity. The mechanism(s) that modulates the transition of TDP-43 from a liquid to solid phase is poorly defined. Here we combine chemical and genome-wide genetic screenings to identify cellular factors that modulate the phase behavior of an RNA-binding defective TDP-43 mutant that mimics an Amyotrophic Lateral Sclerosis (ALS)-associated variant. Our screens uncover multiple cellular processes including RNA splicing, protein translation, proteostasis imbalance and nuclear export as TDP-43 phase regulators. Importantly, TDP-43 phase transition can be dynamically recapitulated in vitro in a semi-permeabilized cell system, which reveals that the inhibition of nuclear export reshapes the nuclear environment in favor of an RNA-dependent TDP-43 liquid-liquid phase separation (LLPS) state, which mitigates cytoplasmic TDP-43 aggregation. We validated this mechanism in a brain organoid model bearing an ALS-associated mutation, showing that nuclear export deficiency can limit pathogenic phospho-TDP-43 accumulation. These findings establish nuclear export as a key regulator of TDP-43 phase transitions and define a mechanistic framework that links altered nuclear transport and phase dynamics to TDP-43 aggregation potential.}, } @article {pmid41993642, year = {2026}, author = {Zhou, H and Meng, T and Liang, D and Wang, Y}, title = {The effect of statins on the survival of patients with amyotrophic lateral sclerosis: a meta-analysis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1753992}, pmid = {41993642}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited disease-modifying therapies and a poor overall prognosis. Statins, are commonly used for dyslipidemia, and have been proposed to exert cholesterol-independent actions including anti-inflammatory and potential neuroprotective effects. Prior studies, However, existing studies offer conflicting results regarding their impact on ALS survival. This systematic review and meta-analysis aimed to evaluate the association between statin use and survival outcomes in patients with ALS.

METHODS: A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science from inception to September 2025. Studies were included if they reported survival outcomes for statin users vs. non-users among patients with ALS. Data on hazard ratios (HRs) were extracted and pooled using fixed- or random-effects models, depending on heterogeneity. Meta-regression and sensitivity analyses were performed to explore the influence of covariates such as age and gender.

RESULTS: Six studies with 3,739 participants (889 statin users) met the inclusion criteria. The pooled analysis showed no statistical significant association between statin use and ALS survival [Log(HR) = -0.04; 95% CI: -0.18 to 0.10], with moderate heterogeneity (I [2] = 24.85%).

CONCLUSION: The pooled estimate in this meta-analysis did not show a statistically significant association between statin use and ALS survival; however, the evidence is limited by heterogeneity in statin exposure definitions and likely residual confounding in predominantly observational data. Further high-quality studies with large sample sizes are needed to determine whether specific subgroups may benefit/harm from statin therapy.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251160344; PROSPERO: CRD420251160344.}, } @article {pmid41994333, year = {2026}, author = {Stein, DN and Gendelman, HE}, title = {CAR Treg therapies for neurodegenerative diseases.}, journal = {iScience}, volume = {29}, number = {3}, pages = {114988}, pmid = {41994333}, issn = {2589-0042}, support = {R01 NS036126/NS/NINDS NIH HHS/United States ; R01 AI145542/AI/NIAID NIH HHS/United States ; R01 AI158160/AI/NIAID NIH HHS/United States ; R01 MH121402/MH/NIMH NIH HHS/United States ; R01 NS126089/NS/NINDS NIH HHS/United States ; R01 NS034239/NS/NINDS NIH HHS/United States ; }, abstract = {Regulatory T cells (Tregs) promote immune tolerance by recognizing non-foreign self-antigens. Consequently, Tregs suppress chronic immune responses and prevent autoimmunity. Chimeric antigen receptor Tregs (CAR Tregs) enhance Treg responses by genetic modification for cell-specific targeting. This can lead to effective treatments for autoimmune diseases, transplant rejection, and graft-versus-host disease. An extension of CAR Tregs involves their potential ability to regulate immune responses to misfolded and aggregated proteins, which drive neurodegenerative diseases. These protein aggregates can trigger immune responses that lead to neural injury. Early preclinical and translational strategies suggest CAR Treg therapies can treat Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In each case, a Treg-based approach transforms a neurotoxic, inflammatory environment through neurotrophic responses. By doing so, CAR Tregs may restore brain balance and slow disease progression. This review highlights ongoing efforts to develop CAR Treg strategies as potential therapies for neurodegenerative disorders.}, } @article {pmid41995858, year = {2026}, author = {Miki, T and De Bertier, S and Amador, MD and Nicolas, M and Guissart, C and Deret, M and Teyssou, E and Muratet, F and Bohl, D and Lobsiger, CS and Boillée, S and Esselin, F and Salachas, F and Millecamps, S and Seilhean, D}, title = {Neuropathological analysis of an ALS patient carrying a SOD1 missense variant and a C9orf72 repeat expansion.}, journal = {Acta neuropathologica}, volume = {151}, number = {1}, pages = {}, pmid = {41995858}, issn = {1432-0533}, support = {EQU202103012581//the Fondation Recherche Médicale (FRM)/ ; #19466//the Association Française contre les Myopathies (AFM)/ ; }, } @article {pmid41995990, year = {2026}, author = {Simula, ER and Garcia-Montojo, M and Canu, M and Chessa, V and Ercoli, T and Ruiu, E and Solla, P and Nath, A and Sechi, LA}, title = {Downregulation of miRNAs Accompanies Increased HERV-K (HML-2) Expression in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41995990}, issn = {1559-1182}, support = {legge regionale 12 22 December 2022 n. 22//Regione Autonoma della Sardegna/ ; PNRR-MCNT1-2023-12376993//Ministero Della Salute/ ; 2022BP837R//PRIN 2022/ ; }, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/virology/blood ; *Down-Regulation/genetics ; *Endogenous Retroviruses/genetics/metabolism ; Female ; Male ; Middle Aged ; Case-Control Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease with limited treatments. Evidence suggests that reactivation of the HERV-K (HML-2) subgroup contributes to its pathogenesis. This study explores the role of microRNAs (miRNAs) in regulating HML-2 expression. We identified dysregulated miRNAs in ALS and, among them, those predicted to target the HML-2 transcript. The expression levels of selected miRNAs were validated in peripheral blood leukocytes of ALS individuals and healthy controls. Co-transfection experiments were then performed to determine the regulatory potential of these miRNAs on HML-2 expression. We found that the HML-2 envelope gene expression levels were elevated in peripheral blood mononuclear cells of ALS individuals compared to controls (p = 0.02), and they negatively correlated with the levels of previously identified miRNAs, which were downregulated in patients compared to healthy controls (miR-15a-3p, p = 0.04; miR-15a-5p, p = 0.01; miR-150-5p, p = 0.001; miR-182-5p, p = 0.012; miR-192-3p, p = 0.034; miR-221-3p, p = 0.011), except miR-181a-2-3p that was upregulated in ALS compared to controls (p = 0.006). Among these miRNAs, we found, by co-transfection, that miR-182-5p and miR-221-3p were capable of binding the HML-2 transcript. This interaction resulted in a significant downregulation of the expression of its genes, with a pronounced effect observed on the envelope gene. Our findings suggest a link between miRNAs and HML-2 expression. In particular, the observed increase in HML-2 levels in ALS may result from the downregulation of key miRNAs, such as miR-221, that normally help restrain HML-2 expression under physiological conditions.}, } @article {pmid41996350, year = {2026}, author = {Tendulkar, S and Wu, T and Strickland, A and Hackett, AR and Sato-Yamada, Y and Mao, X and Sasaki, Y and Milbrandt, J and Bloom, AJ and DiAntonio, A}, title = {Dysregulated lactate metabolism synergizes with ALS genetic risk factors to accelerate motor decline.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0347135}, pmid = {41996350}, issn = {1932-6203}, support = {R01 NS119812/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Lactic Acid/metabolism ; *L-Lactate Dehydrogenase/genetics/metabolism/deficiency ; Mice, Knockout ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/physiopathology ; Motor Neurons/metabolism/pathology ; Risk Factors ; Humans ; Superoxide Dismutase-1/genetics ; Schwann Cells/metabolism/pathology ; Genetic Predisposition to Disease ; Superoxide Dismutase/genetics ; Neuromuscular Junction/pathology/metabolism ; }, abstract = {Neurons rely on glial 'lactate shuttling' for metabolic support, which declines with aging and in neurodegenerative disease. Full disruption of lactate shuttling in peripheral nerves causes progressive axon degeneration, but we were interested to understand how partial disruption, a scenario more relevant to aging and disease, contributes to neurodegeneration risk. Pyruvate and lactate are interconverted by lactate dehydrogenases (LDHA and LDHB) in both lactate producing and consuming cells. We therefore began by investigating Ldhb knockout mice (loss of LDHA, the dominant LDH in liver and muscle, caused embryonic lethality), and discovered that they develop progressive neuromuscular junction atrophy and functional decline without axon degeneration. Because even Ldhb+/- heterozygosity significantly affects motor behavior, we also wondered about a potential link to congenital disease and pursued this by identifying rare loss-of-function LDHB variants among ALS patients. Next, to better understand how LDHB loss leads to motor decline, we selectively deleted it in defined cell types. Schwann cell (SC)-specific deletion caused robust motor defects, whereas motor neuron-specific deletion has little effect. Reasoning that neuronal LDHB deficiency could model age-associated decline in lactate metabolism, we asked whether it would interact with ALS genetic risk. Indeed, motor-neuron LDHB deficiency synergizes with relatively mild ALS risk variants- TDP43Q331K and Sod1D83G knock-in alleles-to produce early motor neuropathy, indicating that LDHB loss enhances disease risk. These findings establish lactate metabolism as a modifier of motor system vulnerability and highlight it as a therapeutic target in peripheral as well as central neurodegeneration.}, } @article {pmid41996956, year = {2026}, author = {Li, M and Han, M and Li, X and Yu, N and Zhang, X and Zhao, L and Liu, Q and Liu, H and Wu, J and Han, Z and Dong, H and Liu, Y}, title = {Sleep spindle alterations as a novel biomarker for phenotypic stratification in sporadic amyotrophic lateral sclerosis.}, journal = {Sleep medicine}, volume = {144}, number = {}, pages = {108961}, doi = {10.1016/j.sleep.2026.108961}, pmid = {41996956}, issn = {1878-5506}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Female ; Biomarkers ; Male ; Cross-Sectional Studies ; Middle Aged ; Electroencephalography ; Phenotype ; Aged ; Polysomnography ; *Sleep/physiology ; }, abstract = {OBJECTIVE: To quantitatively evaluate sleep spindle alterations in sporadic amyotrophic lateral sclerosis (ALS) and explore their potential as biomarkers for diagnosis and phenotypic stratification.

METHODS: In this cross-sectional study, overnight sleep electroencephalography was recorded in 97 sporadic ALS patients and 73 matched healthy controls. Sleep spindle parameters (amplitude, duration, density, frequency) were automatically analyzed at frontal leads. Multiple comparisons were controlled using the false discovery rate (FDR) approach. We used least absolute shrinkage and selection operator (LASSO) regression for diagnostic modeling and employed K-means clustering to define spindle-based subtypes. Bootstrap internal validation was performed to assess model optimism.

RESULTS: After FDR correction, ALS patients showed significant spindle abnormalities predominantly in the bipolar FP12 derivation, including reduced slow spindle density (p-FDR = 0.007), reduced overall spindle density (p-FDR = 0.007), and shortened slow spindle duration (p-FDR = 0.017). A diagnostic model incorporating Epworth Sleepiness Scale score, wake after sleep onset, sleep efficiency, FP12 slow spindle density, and education years showed promising discriminative ability (apparent AUC = 0.931; optimism-corrected AUC = 0.923). Unsupervised clustering consistently revealed two distinct spindle phenotypes. The "spindle-deficient" phenotype, characterized by poorer spindle integrity, was independently associated with lower ALSFRS-R scores (OR 1.101, 95% CI 1.024-1.202, p = 0.017), lower percentage of predicted forced vital capacity (OR 1.035, 95% CI 1.010-1.065, p = 0.011), and absence of drinking history (OR 3.03, 95% CI 1.02-9.46, p = 0.049).

CONCLUSIONS: Sleep spindle alterations may represent a core electrophysiological feature of ALS, potentially reflecting thalamocortical dysfunction. These exploratory findings suggest that spindle parameters could serve as candidate biomarkers for disease stratification, though validation in independent longitudinal cohorts is needed before clinical application.}, } @article {pmid41996987, year = {2026}, author = {Priya, R and Tanti, GK and Jain, BP}, title = {Decoding RNA splicing pathology: Alternative splicing in amyotrophic lateral sclerosis and its therapeutic potential.}, journal = {Biochemical and biophysical research communications}, volume = {818}, number = {}, pages = {153723}, doi = {10.1016/j.bbrc.2026.153723}, pmid = {41996987}, issn = {1090-2104}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/metabolism ; *Alternative Splicing ; Animals ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron loss, leading to muscle weakness, paralysis, and respiratory failure. Dysregulation of RNA metabolism and splicing has emerged as a central mechanism in ALS pathogenesis. TARDBP (TAR DNA-binding protein), FET family proteins (FUS, EWSR1, TAF15), SOD1 (Superoxide Dismutase 1), and C9orf72 (Chromosome 9 Open Reading Frame 72) are key genes associated with ALS that regulate RNA processing, alternative splicing, and nuclear-cytoplasmic transport. Mutations or mislocalization of these proteins result in nuclear loss-of-function and cytoplasmic gain-of-function toxicity, promoting protein aggregation, sequestering spliceosomal components, and impairing spliceosome assembly. This leads to the aberrant inclusion of cryptic exons in essential neuronal genes, such as STMN2 (Stathmin 2) and UNC13A (Unc-13 Homolog A), resulting in the production of truncated proteins, defective axonal maintenance, and impaired synaptic function. TDP-43 pathology, a hallmark of ALS, disrupts splicing and RNA transport, while C9orf72 repeat expansions and FET protein mutations exacerbate cytoplasmic aggregation and stress granule dynamics. Mutant SOD1 contributes via mitochondrial dysfunction, endoplasmic reticulum stress, and disrupted axonal transport. Therapeutic strategies targeting these mechanisms are advancing rapidly. Gene replacement therapy, which restores STMN2 expression, and antisense oligonucleotides (ASOs) targeting mutant transcripts show promise in preclinical and early clinical studies. Complementary approaches, including the inhibition of stress kinases and the activation of autophagy, reduce cytoplasmic protein aggregation and support neuronal homeostasis. This review provides a comprehensive overview of RNA splicing regulation, spliceosomal dysfunction, and cryptic exon incorporation in ALS. Understanding the interplay among splicing defects, RNA-binding protein pathology, and neuronal degeneration is critical for developing next-generation multimodal therapies to restore RNA processing, reduce toxic protein accumulation, and promote motor neuron survival.}, } @article {pmid41997149, year = {2026}, author = {Wu, T and Yuan, L and Sasaki, Y and Chen, SJ and Buchser, W and Bloom, AJ and DiAntonio, A and Milbrandt, J}, title = {SARM1 executes neuronal parthanatos and promotes excitotoxic cell death.}, journal = {Neuron}, volume = {114}, number = {16}, pages = {2975-2986.e5}, pmid = {41997149}, issn = {1097-4199}, support = {R01 NS065053/NS/NINDS NIH HHS/United States ; R01 NS087632/NS/NINDS NIH HHS/United States ; R01 NS133348/NS/NINDS NIH HHS/United States ; R37 NS065053/NS/NINDS NIH HHS/United States ; }, mesh = {*Armadillo Domain Proteins/metabolism ; Animals ; Humans ; *Cytoskeletal Proteins/metabolism ; *Cell Death/physiology/drug effects ; *Parthanatos/physiology ; *Neurons/metabolism ; DNA Damage ; }, abstract = {The nicotinamide adenine dinucleotide (NAD[+]) hydrolase sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is the central executioner of pathological axon degeneration and is allosterically activated by an increased nicotinamide mononucleotide (NMN)/NAD[+] ratio. DNA damage induces NAD[+] loss and an increased NMN/NAD[+] ratio by hyperactivating poly(ADP-ribose) polymerase 1 (PARP1), which triggers the parthanatos cell death pathway. Multiple mechanistically distinct DNA-damaging agents activate SARM1 and induce axon degeneration following PARP1 activation. Remarkably, SARM1 is required for key steps downstream of hyperactivated PARP1, which are pathognomonic of parthanatos, including mitochondrial depolarization, nuclear translocation of apoptosis-inducing factor (AIF), and cell death. Hence, SARM1 is an essential component of neuronal parthanatos. Moreover, complex neurodegenerative stimuli whose mechanisms include activation of parthanatos, such as 1-methyl-4-phenyl-pyridinium (MPP[+]) dopaminergic neuron toxicity and N-methyl-D-aspartate (NMDA) excitotoxicity, are potently protected by SARM1 inhibition. These findings place SARM1 at the nexus of multiple mechanisms driving neuronal cell death, thereby greatly expanding the potential clinical utility of SARM1 inhibitors beyond diseases of axon loss.}, } @article {pmid41998853, year = {2026}, author = {Qian, W and Zhu, D and Yang, S}, title = {Spray Coating of Thick Perovskite Films for Photodetectors: The Aerosol-Liquid-Solid Mechanisms and Sensing Applications.}, journal = {Chemical record (New York, N.Y.)}, volume = {26}, number = {6}, pages = {e202500358}, doi = {10.1002/tcr.202500358}, pmid = {41998853}, issn = {1528-0691}, support = {22261160370//National Natural Science Foundation of China/ ; U2001217//National Natural Science Foundation of China/ ; 22579004//National Natural Science Foundation of China/ ; 12505294//National Natural Science Foundation of China/ ; 2508085QA021//Natural Science Foundation of Anhui Province/ ; KQTD2016053015544057//Shenzhen Peacock Plan/ ; SYSRD20250529113001002//Shenzhen Key Lab of Glass-based Optoelectronic Thin Film Materials/ ; //Shenzhen Bay Lab Concept Validation Fund/ ; }, abstract = {Spray coating has emerged as a transformative technique for fabricating high-quality perovskite thick films, which are essential for advanced photodetectors such as X-ray and narrowband sensors. This review surveys and systematically elucidates the physicochemical mechanisms underlying the aerosol-liquid-solid (ALS) transformation during spray deposition, focusing on three core stages: aerosol generation (via pneumatic, electrospray, or ultrasonic methods), droplet deposition and wetting dynamics, and liquid-to-solid crystallization. The interplay among precursor properties, spray parameters, and substrate characteristics dictates film morphology, crystallinity, and defect density. We highlight optimization strategies, including solvent engineering, additive incorporation, and process control, that enable the growth of dense, vertically aligned, and large-grained perovskite films with thicknesses up to hundreds of micrometers. Furthermore, the integration of dimensional engineering and heterojunction design through sequential spray deposition enhances charge transport, suppresses ion migration, and improves detection performance. Applications of these films are demonstrated in direct X-ray detectors and filter-free narrowband photodetectors with high sensitivity, low detection limits, and excellent spatial resolution. Remaining challenges are also discussed in understanding dynamic phase transitions and ensuring large-area uniformity of the spray-deposited films. Advancing in situ characterization and intelligent process control will accelerate the transition of spray coating from a laboratory technique to a scalable precision-manufacturing platform for next-generation perovskite optoelectronics.}, } @article {pmid42000222, year = {2026}, author = {Thate, S and Lubasch, JS and Plata, C and Gülöz, K and Eisenreich, EW and Röhrig, R and Seeger, I}, title = {[Low-priority emergency calls: planned and actual dispatching of resources in a German Emergency Dispatch Center (EDC) following the introduction of a standardized emergency call query. A retrospective analysis of EDC data].}, journal = {Zeitschrift fur Evidenz, Fortbildung und Qualitat im Gesundheitswesen}, volume = {203}, number = {}, pages = {77-86}, doi = {10.1016/j.zefq.2026.03.006}, pmid = {42000222}, issn = {2212-0289}, mesh = {Humans ; Cross-Sectional Studies ; *Emergency Medical Dispatch/organization & administration/statistics & numerical data/standards ; *Emergency Medical Service Communication Systems/organization & administration/standards/statistics & numerical data ; *Emergency Medical Services/organization & administration/statistics & numerical data ; Germany ; *National Health Programs/organization & administration ; Paramedics ; Retrospective Studies ; *Triage/organization & administration/statistics & numerical data ; }, abstract = {BACKGROUND: A significant proportion of calls to Emergency Dispatch Centers (EDCs) are classified as low-priority calls (LPCs). This study examines LPCs detected in an EDC through a standardized emergency call query and the degree of fulfilment between planned and actual dispatching.

METHOD: This retrospective prevalence study uses descriptive and exploratory data analysis to examine data from the routine documentation of the emergency dispatch system (EDS) and the standardized emergency call system of an EDC. The primary endpoint of the study is the frequency of LPCs for assistance and their standardized assignment to the appropriate care structures of medical on-call services (provided by the Association of Statutory Health Insurance Physicians, ASHIP) and community paramedics (CPs).

RESULTS: Just under 10% of the calls handled with a standardized emergency call query were LPCs. Of these, 54.0% fell within the remit of the ASHIP and 41.1% within the remit of EMS. In areas without CPs, an ALS ambulance was dispatched twice as often as in areas with such a system (85.9% versus 41.6%). Also, a difference was found regarding the subsequent transport to a hospital (57.4% vs. 29%). There were only minor differences in utilization between day (49.2%) and night (50.8%).

CONCLUSION: The data examined support the current approach to reforming cross-sectoral emergency care services. Detecting LPCs will only lead to a needs-based care if suitable downstream resources are available at all times. The control of all outreach care resources by the EDC could prevent disruptions at sector boundaries.}, } @article {pmid42000269, year = {2026}, author = {Desnuelle, C and Couratier, P and Corcia, P and Duburcq, A and Torreton, E and Baffert, S and Nevoret, C and Turgeman, S}, title = {Treatment pathway, healthcare resource utilization and direct cost of ALS in France: A nationwide claims database study.}, journal = {Revue neurologique}, volume = {182}, number = {6}, pages = {528-538}, doi = {10.1016/j.neurol.2026.02.159}, pmid = {42000269}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy/epidemiology ; France/epidemiology ; Humans ; Female ; Retrospective Studies ; Male ; *Patient Acceptance of Health Care/statistics & numerical data ; *Health Care Costs/statistics & numerical data ; Databases, Factual ; Aged ; Middle Aged ; *Health Resources/statistics & numerical data/economics ; Cohort Studies ; Aged, 80 and over ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a severe, progressive disease, associated with high clinical burden. The aim of this study was to estimate ALS-related healthcare resource utilization (HCRU), associated direct costs and their determinants in France.

METHODS: A retrospective cohort study was conducted among newly diagnosed patients with ALS identified between 2012 and 2022 (11 years) in the French National Health Data System (SNDS) through a validated algorithm. This incident population was compared with non-ALS controls (1:2) matched on age, sex, and region. Direct all-cause healthcare reimbursable costs were estimated. Survival, HCRU and direct costs were analyzed over the first five years after diagnostic.

RESULTS: A total of 16,814 newly diagnosed ALS patients were identified who could be matched with 33,628 non-ALS controls. The median age was 68.0 year and 55.3% were males. Over the first year after diagnosis, the direct all-cause medical cost per patient was €19,497 of which 47.2% was related to inpatient care, compared to €4,921 for controls which led to an ALS-attributable cost of €14,474 per patient per year. ALS patients had significantly (P<0.0001) higher HCRU than controls in all items of inpatient and outpatient care but especially for utilization of medical devices, frequencies of nurse and physiotherapist visits and acute care hospitalizations. The annual direct cost per patient who survived the successive annual period after diagnosis increased during the second, third and fourth year to €22,358, €22,276 and €21,372 respectively and then declined in year 5 to €19,720. These results largely underestimated the real cost of the management of ALS by not considering the out-of-pocket expenses associated with informal care and home renovation as well as productivity loss.

CONCLUSIONS: Patients with ALS had higher HCRU and direct medical cost, compared with controls. The economic burden of ALS was substantial even when restricted to the medical costs covered by the public health insurance system. There is an important need for novel therapies that might lower disease progression in early disease stages.}, } @article {pmid42002556, year = {2026}, author = {Selvam, AK and Loganathan, A}, title = {An intelligent EEG-based ensemble framework for communication assistance in Locked-In Syndrome patients.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42002556}, issn = {2045-2322}, mesh = {Humans ; *Electroencephalography/methods ; *Brain-Computer Interfaces ; *Locked-In Syndrome/physiopathology ; Event-Related Potentials, P300/physiology ; Support Vector Machine ; Male ; Female ; Adult ; Random Forest ; Communication ; Communication Devices for People with Disabilities ; }, abstract = {Locked-In Syndrome (LIS) is a neurological condition in which patients experience complete motor paralysis while preserving cognitive function, severely restricting their ability to communicate. Electroencephalography (EEG)-based brain–computer interface (BCI) systems, particularly those utilizing the P300 event-related potential, offer a promising solution for enabling communication in such patients. Despite their potential, P300-based systems often suffer from low robustness due to noise, non-stationarity of EEG signals, and limitations of single-classifier approaches. This study addresses the problem of improving classification accuracy and reliability in EEG-based P300 speller systems for assistive communication. The scope of the work is focused on a visual P300 paradigm designed to represent a set of five basic communication phrases relevant to LIS patients. The primary objective of this paper is to develop an ensemble learning framework that enhances P300 detection by leveraging complementary strengths of multiple classifiers. EEG signals were recorded from 20 subjects during a visual P300 task. Discrete Wavelet Transform (DWT) was employed for effective time–frequency feature extraction. A soft-voting ensemble classifier combining Support Vector Machine (SVM) and Random Forest (RF) models was proposed and evaluated. The novelty of the proposed methodology lies in the integration of wavelet-based feature extraction with a soft-voting ensemble learning strategy to improve classification robustness and generalization. Experimental results demonstrate that the proposed ensemble achieved a classification accuracy of 97.5%, outperforming individual SVM (92.5%) and RF (89%) classifiers across multiple evaluation metrics, including precision, recall, F1-score, and Matthews Correlation Coefficient. These findings highlight the effectiveness of ensemble-based learning for enhancing the performance and reliability of P300-based EEG communication systems.}, } @article {pmid42006515, year = {2026}, author = {Cheung, N}, title = {Synaptic Plasticity Fragility Underlies a Microglial Pruning Continuum in Major Depressive Disorder and Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {18}, number = {4}, pages = {e107259}, pmid = {42006515}, issn = {2168-8184}, abstract = {Background Major depressive disorder (MDD) and amyotrophic lateral sclerosis (ALS) are clinically distinct yet show intriguing comorbidity, often early in the disease course. We hypothesized a shared microglia-mediated synaptic pruning vulnerability, amplified differently by disorder-specific pathways, autophagy collapse in ALS versus RNA processing and immune dysregulation in MDD, thereby creating a biological continuum. Methods Using large-scale genome-wide association study (GWAS) from the Psychiatric Genomics Consortium (PGC) (MDD, N=829,249) and Project MinE (ALS, effective N=87,381), we applied Multi-marker Analysis of GenoMic Annotation (MAGMA) for gene- and set-level associations, Gene Set Enrichment Analysis (GSEA)/Differential Gene Set Enrichment Analysis (DGSEA) for pathway enrichment and differential enrichment, S-PrediXcan transcriptome-wide association study (TWAS) across 14 GTEx tissues, and linkage disequilibrium score regression (LDSC) for partitioned heritability and cross-trait genetic correlation. Eight gene sets (housekeeping controls, monoaminergic, neurosteroid, glutamatergic, synaptic pruning, autophagy/protein quality, RNA processing, and immune/neuroinflammation) were tested for convergence and divergence. Results Synaptic pruning emerged as the sole consistent cross-disorder signal, with robust enrichment in MDD (LDSC 1.32×, GSEA NES=1.415, p=0.0001) and nominal but consistent signals in ALS (GSEA NES=1.40, p=0.011; TWAS HLA-B). Autophagy dominated ALS (LDSC 2.20×, TWAS C9orf72 Z=13.43, GSEA NES=1.94) but was depleted in MDD. RNA processing and immune pathways were prominent in MDD (LDSC 1.48× and 1.89×, respectively), with only nominal signals in ALS. Overall genetic correlation was near zero (rg=-0.044, p=0.196). Conclusions These findings support a microglial pruning continuum model: shared pruning liability as the foundation, with autophagy failure driving ALS neurodegeneration and RNA/immune dysregulation shaping MDD stress sensitivity. The low rg explains the modest overlap, while pathway specificity accounts for comorbidity and divergent progression. This framework offers testable predictions for polygenic risk score (PRS) stratification, complement modulators in ALS mood subsets, and microglial therapies in treatment-resistant MDD.}, } @article {pmid42006781, year = {2026}, author = {Raikes, AC and Garza, M and Murrell, AN and Brinton, RD}, title = {Meta analysis of glucose metabolism across Alzheimer's, Parkinson's and ALS Reveals emergence of adaptive brain glucometabolic responses and associated neurological functional profiles.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42006781}, support = {P01 AG026572/AG/NIA NIH HHS/United States ; R01 AG063826/AG/NIA NIH HHS/United States ; T32 AG061897/AG/NIA NIH HHS/United States ; }, abstract = {IMPORTANCE: Glucose metabolic dysregulation in brain is a common feature of late-onset age-associated neurodegenerative disease (A[2]ND). Prior meta-analyses have identified disease-specific effects compared to healthy, unimpaired individuals. Yet, a unifying A[2]ND glucose dysregulation spatial signature remains undescribed.

OBJECTIVE: To determine the common signature of dysregulated glucose metabolism on FDG-PET using activation likelihood estimation (ALE) meta-analyses across A[2]ND.

DATA SOURCES: Searches were conducted using MEDLINE, Embase, PsycINFO, Scopus, and Cochrane from inception through July 2025. The search terms included controlled vocabulary and keywords for four neurodegenerative diseases Parkinson Disease, Amyotrophic Lateral Sclerosis, Alzheimer Disease, and Multiple Sclerosis, Fluorodeoxyglucose F18, glucose, and positron-emission tomography (PET).

STUDY SELECTION: Studies comparing adults with late-onset neurodegenerative diseases to non-diseased controls using FDG-PET to quantify brain glucose uptake and reporting whole-brain coordinate findings in either Talairach or Montreal Neurological Institute space were included.

DATA EXTRACTION AND SYNTHESIS: Three researchers, assisted by an AI screening tool, screened 7275 potential titles and abstracts for inclusion. Full texts were then retrieved for potentially relevant articles and were evaluated by three researchers using prespecified inclusion/exclusion criteria.

MAIN OUTCOMES AND MEASURES: Cluster peak and subpeak coordinates, cluster-wise t- or Z- values, and annotations indicating the disease of interest, whether the outcome was for hyper- (disease group > control) or hypometabolism (disease group < control), were extracted from included texts and analyzed using ALE.

RESULTS: A total of 130 FDG-PET studies were included in the meta-analysis, with a combined sample of 5298 individuals with A[2]ND and 3499 controls. Meta-analyses revealed dysregulated glucose metabolism as a unifying feature across A[2]ND which included both hypo- and hypermetabolic patterns. Neuroanatomical metabolic pattern was unique and disease specific. Each A[2]ND metabolic phenotype was associated with unique and complex patterns of neurological functionalities.

CONCLUSIONS AND RELEVANCE: These data demonstrate dysregulated glucose metabolism as a common A[2]ND feature, suggesting responsive remodeling of neural bioenergetics. While hypometabolism is a common research focus, due to functional relevance, hypermetabolism may reflect a compensatory, maladaptive, or neuroinflammatory signal, that requires focused investigation. A[2]ND prevention and treatment efficacy may depend on addressing bidirectional metabolic dysregulation in addition to disease-specific drivers of pathology.}, } @article {pmid42007068, year = {2026}, author = {Li, Z and Catelli, E and Stergar, J and Milanič, M and Sáez-Hernández, R and Prati, S and Oliveri, P and Sciutto, G}, title = {Expanding the Capabilities of Portable Mapping in Macroscopic External Reflection FT-IR through a Targeted Data-Driven Spectral Enhancement and Denoising Strategy.}, journal = {ACS measurement science au}, volume = {6}, number = {2}, pages = {361-373}, pmid = {42007068}, issn = {2694-250X}, abstract = {Reliable spectral quality is essential for extracting meaningful information from infrared reflectance data, particularly when using portable systems with limited scan numbers. This study presents a data-driven spectral enhancement workflow designed to improve the interpretability of portable macroscopic external reflection Fourier Transform Infrared (MA-rFT-IR) mapping systems developed by the Authors, operating in the near- and mid-infrared (NIR-MIR) ranges. Despite the growing use of reflectance imaging spectroscopy, limited attention has been devoted to the development of robust denoising strategies capable of minimizing noise and unwanted variability while preserving spectral quality and enabling more reliable and accurate data analysis. This study proposes a broadly applicable processing framework aimed at enhancing the efficiency and performance of reflectance-based spectral analysis. Denoising methods including Savitzky-Golay filtering and wavelet- and PCA-based denoising were tested and evaluated individually and in combination. Quantitative performance was assessed using arccosine similarity (ACOS) and derivative-based root-mean-square error (dRMSE) metrics across selected spectral regions of interest, with a derivative ACOS (dACOS) index applied to monitor band-shape variations. The evaluation results were integrated through Pareto analysis to identify the optimal trade-off between noise reduction and spectral-feature preservation. Application of the proposed approach to a multilayered painting mock-up demonstrated that the enhancing spectral data workflow preserves key diagnostic features revealing subtle spectral bands. Furthermore, applying multivariate curve resolution-alternating least-squares (MCR-ALS) to the denoised data enabled chemically meaningful separation of complex overlapping signals, improving the interpretability of compositional information compared with traditional denoising methods and data processing. The workflow strengthens the analytical reliability of low-scan reflection-mode data and provides a transferable framework for optimizing denoising strategies in portable infrared applications.}, } @article {pmid42008451, year = {2026}, author = {Pena, C and Sinar, MK and Koza, LA and Boehler, N and Buechler, E and Smith, AC and McGarr, A and Baybayon-Grandgeorge, AN and Herda, MS and Jaques, S and Linseman, DA}, title = {Preclinical study of red dragon fruit (Hylocereus polyrhizus) betacyanins in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/1028415X.2026.2661760}, pmid = {42008451}, issn = {1476-8305}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of cortical and spinal motor neurons, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Betacyanins, betalain pigments found in red dragon fruit and beetroot, display powerful anti-inflammatory and free-radical scavenging properties which may help ameliorate ALS pathology and slow disease progression. The present study characterized the therapeutic effects of a betacyanin-rich red dragon fruit extract (DFE) in the G93A mutant hSOD1 transgenic mouse model of ALS. Mice were treated orally with 5% (v/v) DFE in drinking water ad libitum, from disease onset until end-stage. DFE treatment had a statistically significant effect on survival, with an approximate 13-day extension of median lifespan in the treated G93A mutant hSOD1 group. Treatment with DFE also significantly preserved muscle strength and endurance, as assessed by grip strength and rotarod behavioral testing. This was associated with a modest but statistically significant preservation of gastrocnemius muscle weight in the DFE-treated group. Histopathological analyses demonstrated improvements in NMJ size and complexity, an increase in surviving spinal cord motor neurons, and a reduction in spinal cord astrogliosis in G93A mutant hSOD1 mice treated with DFE, when compared to their untreated mutant littermates. Overall, these findings indicate that DFE, or purified betacyanin compounds, should be investigated further as potential therapeutic agents for patients with SOD1-related ALS. Additional preclinical studies in non-SOD1 models of ALS will need to be completed to determine the potential benefit of betacyanin compounds in sporadic ALS.}, } @article {pmid42008552, year = {2026}, author = {Sidibe, DK and Smith, EM and Spivey, ML and Vogel, MC and Maday, S}, title = {Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0345890}, pmid = {42008552}, issn = {1932-6203}, support = {F31 NS132431/NS/NINDS NIH HHS/United States ; F31 NS132453/NS/NINDS NIH HHS/United States ; R01 NS110716/NS/NINDS NIH HHS/United States ; }, mesh = {*Astrocytes/metabolism ; *Neurons/metabolism ; Animals ; Sequestosome-1 Protein/metabolism ; *Ubiquitin/metabolism ; *Stress, Physiological ; Lysosomes/metabolism ; Mice ; *Adaptor Proteins, Signal Transducing/metabolism ; Proteotoxic Stress ; }, abstract = {Sequestosome 1/p62 (hereafter referred to as p62) is a multifunctional protein that orchestrates various cellular stress response pathways including autophagy, proteasome-mediated degradation, antioxidant defense, nutrient sensing, and inflammatory signaling. Mutations in distinct functional domains of p62 are linked with the neurodegenerative disease amyotrophic lateral sclerosis (ALS), underscoring its importance in neural cells. Neurons and astrocytes, two key cell types in the brain, perform distinct roles in brain physiology and thus encounter a unique landscape of cellular stress. However, how p62 is regulated in these cell types in response to various stress modalities remains largely unexplored. Several functions for p62 depend on its engagement with ubiquitinated substrates. Thus, we investigated how the regulation of p62-ubiquitin conjugates differs between neurons and astrocytes exposed to two stress modalities: lysosomal membrane damage and metabolic stress. Lysosomal damage triggered ubiquitin-dependent assembly of p62 puncta in both neurons and astrocytes. In contrast, nutrient deprivation elicited different responses between neurons and astrocytes. Neurons formed p62-ubiquitin structures more prominently and displayed a greater dependence on ubiquitin for p62 clustering. Together, these findings reveal cell-type-specific and stress-specific regulation of p62-ubiquitin conjugates, indicating that neurons and astrocytes can deploy distinct quality control strategies.}, } @article {pmid42008764, year = {2026}, author = {Stone, AK and Veinot, TC}, title = {Access to Technology-Mediated Community Mental Health Care Among Low-Socioeconomic Status Consumers With Serious Mental Illness: Qualitative Study.}, journal = {JMIR formative research}, volume = {10}, number = {}, pages = {e79608}, pmid = {42008764}, issn = {2561-326X}, mesh = {Humans ; *Mental Disorders/therapy/psychology ; *Health Services Accessibility/standards/statistics & numerical data ; Qualitative Research ; Low Socioeconomic Status ; Female ; Adult ; *Community Mental Health Services/methods/statistics & numerical data ; Male ; Middle Aged ; Anthropology, Cultural/methods ; Digital Health ; Telemedicine ; }, abstract = {BACKGROUND: Access to mental health care is critical for the effective management of serious mental illness (SMI), but consumers with low socioeconomic status (SES) have lower rates of service usage and worse retention in care. Digital technologies are often lauded as a way to bridge access gaps; however, little is known about how technology-mediated care may influence care access among low-SES consumers and how consumers use technology in care access.

OBJECTIVE: This study aimed to examine the applicability of Levesque et al's access framework to technology-mediated care for SMI and analyze how low-SES consumers use technology to facilitate care access. Furthermore, the study assesses whether and how technologies are involved in care access at multiple points within the process of accessing care.

METHODS: This study used 2 qualitative methods: ethnographic observations at a mental health treatment court and interviews with low-SES consumers with SMI using community mental health care (n=14) and key informant interviews with health and service providers working with this population (n=14). Observations occurred from July 2022 through September 2023, and interviews occurred between January 2022 and May 2024. Data analysis involved both inductive and deductive coding approaches. Data from both the interviews and observations were analyzed in NVivo and further triangulated through analytic memos.

RESULTS: Levesque et al's framework required several extensions to accommodate technology-mediated care related to SMI for low-SES consumers: (1) a cyclical rather than linear trajectory; (2) simultaneous care acquisition from multiple health and service providers; (3) staying in care long-term; (4) identification of both one-time and ongoing health needs; and (5) an emergency pathway for entering care. Consumers often faced challenges related to the varied digital requirements of each provider and a dearth of integrative, patient-facing tools like portals. Within this context, some consumers use mobile apps, communication, and telehealth technologies across various care access stages. Consumers used technology by figuring out how to navigate technology-mediated care, especially by leaning on others, such as case managers, for support. These others provided consumers with temporary technologies, showed them how to use technologies, and accompanied them through the process of using technology for accessing care.

CONCLUSIONS: This study highlights that accessing care is iterative and ongoing, involving multiple forms of co-occurring service provision. A theoretical contribution of this work is its extension of Levesque et al's care access framework to better reflect technology-mediated care for SMI among low-SES consumers. This work also underscores ongoing challenges for accessing technology-mediated care and the importance of human support in addressing access difficulties. Clinical implications include incorporating digital readiness assessments and providing comprehensive guidance on how consumers can effectively use technologies for care. Future work should investigate how technology-mediated care can make care access easier rather than harder.}, } @article {pmid42009215, year = {2026}, author = {Nassar, JE and Knebel, A and Ammar, LA and Singh, M and Kuris, EO and Diebo, BG and Daniels, AH}, title = {Differentiating neurologic disorders from spinal conditions: Evidenced-based history and physical examination clues for the orthopedic clinic.}, journal = {The American journal of medicine}, volume = {139}, number = {9}, pages = {1128-1139}, doi = {10.1016/j.amjmed.2026.04.017}, pmid = {42009215}, issn = {1555-7162}, mesh = {Humans ; Diagnosis, Differential ; Physical Examination ; *Nervous System Diseases/diagnosis ; *Spinal Diseases/diagnosis ; Neurologic Examination ; Medical History Taking ; }, abstract = {This narrative review highlights neurologic disorders that mimic or worsen degenerative spine disease and provides key clinical clues for recognition in spine surgery practice. A focused review examined amyotrophic lateral sclerosis, normal pressure hydrocephalus, multiple sclerosis, Parkinson's disease, Guillain-Barré syndrome, peripheral neuropathies, and transverse myelitis. These conditions frequently overlap with structural spinal pathology through motor, sensory, and gait disturbances. Amyotrophic lateral sclerosis presents with combined upper and lower motor neuron signs. Normal pressure hydrocephalus is characterized by gait impairment, urinary incontinence, and cognitive decline. Multiple sclerosis often causes relapsing multifocal deficits that do not localize to a single spinal level. Parkinson's disease is identified by bradykinesia, rigidity, tremor, and progressive postural deformity. Other mimics including Guillain-Barré syndrome, small and large fiber neuropathies, and transverse myelitis further complicate evaluation. Careful history and neurologic examination remain central, while disease-specific tools such as the 2017 McDonald criteria and the Dubousset Functional Test improve recognition. Early identification is essential to avoid unnecessary surgery, guide multidisciplinary referral, improve risk stratification, and optimize patient outcomes.}, } @article {pmid42011674, year = {2026}, author = {Doyle, L and Galvin, M and Tague, AM and Meldrum, D and Murphy, D and Hardiman, O and Murray, D}, title = {Speech and swallow outcome measures for ALS and perspectives on remote monitoring: an international survey of speech & language therapists.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/21678421.2026.2655735}, pmid = {42011674}, issn = {2167-9223}, abstract = {OBJECTIVE: Dysarthria and dysphagia occur frequently in Amyotrophic Lateral Sclerosis (ALS). To manage these symptoms, speech & language therapists (SLTs) must identify relevant speech and swallow outcomes and select suitable outcome measurement instruments. Remote monitoring is an evolving mode of health status tracking. This survey aimed to establish SLT perspectives on ALS assessment regarding 1) the clinical meaningfulness of existing outcome measurement instruments 2) remote monitoring 3) usefulness of assessment devices for patient care and 4) bulbar function outcomes and measurement instruments useful for research studies.

METHODS: An online English-language survey was distributed internationally through gatekeepers and social media.

RESULTS: Sixty-six SLTs responded from 13 countries. Current outcome measurement instruments were regarded as clinically meaningful in ALS by 35% for speech and 41% for swallow. Only 12% had access to remote monitoring, but 77% would like to avail of it, with 58% perceiving its potential to enhance care. Eighty-two percent deemed remote monitoring using digital patient-reported outcome measures (PROMs) useful. Speech intelligibility measurement was selected as the most useful communication outcome for remote monitoring (92%) and research (94%). SLTs agreed that speech intelligibility test software (72%), smart device apps (70%) and tongue pressure measurement devices (54%) are useful assessment equipment.

CONCLUSIONS: SLTs want better measurement instruments for speech and swallow in ALS. They regarded technologies including remote monitoring incorporating digital PROMs as useful. Outcomes reflecting communication and swallow functional success level were deemed most useful. These survey findings can inform the selection of digital speech and swallow outcomes for ALS.}, } @article {pmid42011986, year = {2026}, author = {Palma, A and Stefanelli, R and Trenta, F and Projetti, C and Massa, G and Canterini, S and Fiorenza, MT}, title = {A Cross-Disease Microglial Transcriptional Program Characterizes Neurodegeneration and Highlights SPP1 as a Biomarker.}, journal = {Glia}, volume = {74}, number = {6}, pages = {e70163}, pmid = {42011986}, issn = {1098-1136}, support = {RM123188F700A7B2//Sapienza Università di Roma/ ; RG1221816B9646F5//Sapienza Università di Roma/ ; GSP20006_Covid050//Fondazione Telethon/ ; }, mesh = {*Microglia/metabolism/pathology ; Animals ; Humans ; *Neurodegenerative Diseases/metabolism/genetics/pathology ; Mice ; *Osteopontin/genetics/metabolism ; Biomarkers/metabolism ; Alzheimer Disease/metabolism ; Transcriptome ; }, abstract = {Microglial cells are key players in maintaining brain homeostasis and responding to pathological conditions. Their multifaceted roles in health and disease have garnered significant attention in the context of neurodegeneration. In recent years, single-cell transcriptomic techniques have provided unprecedented insights into microglial heterogeneity, revealing distinct subpopulations and gene expression patterns associated with neuroprotection or neurotoxicity. Here, we dissect the transcriptomic landscape of microglia by leveraging human single-nuclei RNA sequencing datasets from multiple neurodegenerative conditions, including Amyotrophic Lateral Sclerosis, frontotemporal dementia, Alzheimer's disease, aging, and Parkinson's disease. This integrative analysis identifies distinct microglial subpopulations, reflecting functional heterogeneity across diseases and reveals a shared cross-disease microglial transcriptional program associated with inflammatory and neurodegenerative processes. Using a machine learning framework, we further demonstrate that this transcriptional program enables robust discrimination between neurodegenerative and control samples. Experimental validation in primary microglia isolated from a mouse model of Niemann-Pick disease type C, also known as juvenile Alzheimer's disease, supports the conservation of key components of this program and highlights Spp1 as a biomarker of disease-associated microglia states. Overall, this study provides an improved portrait of microglia transcriptional remodeling across neurodegenerative disorders and offers a framework for identifying conserved molecular features that may inform therapeutic strategies aimed at modulating microglial activity to mitigate disease progression and foster neuroprotection.}, } @article {pmid42012311, year = {2026}, author = {Erol, ZY and Quintanilla, C and Ozdinler, PH}, title = {Bringing cellular clarity to the cortical component of ALS with a high-density multi-electrode array system.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.70552}, pmid = {42012311}, issn = {1742-4658}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; R01AG061708//NIH-NIA/ ; }, abstract = {There is selective vulnerability in diseases, requiring the understanding of cell-type specific aspects of neurodegeneration with cellular resolution. Single-cell electrophysiology enables direct investigation of neuronal excitability, ion-channel dynamics, and synaptic transmission with high temporal precision, which is crucial in understanding neuronal circuitries and how they are affected in diseases. Microelectrode arrays (MEAs) have emerged as powerful platforms enabling long-term, parallel, and non-invasive extracellular measurements. The advent of complementary-metal-oxide-semiconductor (CMOS)-based and high-density microelectrode arrays (HD-MEAs) has expanded the spatial and temporal resolution attainable both in vitro and ex vivo. Combined with acute slices, novel cell-culture approaches and three-dimensional (3D) brain organoids, these tools now expedite translational research in disease modeling, neurotoxicity, and pharmacology. Here, we summarise the significance of single-cell electrophysiology, the advantages of the MEA systems, and the latest biomedical and technological advances in this area of research.}, } @article {pmid42013251, year = {2026}, author = {Wu, ZC and Deng, LJ and Huang, TZ and Dou, HX and Vivone, G and Liu, Y}, title = {Tensor Wheel Decomposition: Theory and Application to Tensor Completion.}, journal = {IEEE transactions on image processing : a publication of the IEEE Signal Processing Society}, volume = {35}, number = {}, pages = {4237-4252}, doi = {10.1109/TIP.2026.3684420}, pmid = {42013251}, issn = {1941-0042}, abstract = {Recently, tensor network (TN) decompositions have gained prominence in computer vision and contributed promising results to tensor recovery for their capability of compactly and efficiently representing high-order tensors. However, current TN topologies are rather being developed towards more intricate structures to pursue incremental improvements, resulting in a drastically increased number of TN ranks, which requires laborious hyper-parameter selection, especially for higher-order cases. In this paper, we propose a novel TN decomposition, dubbed tensor wheel (TW) decomposition, in which a high-order tensor is represented by a set of latent factors mapped into a specific wheel topology. Such a decomposition is constructed starting from analyzing the graph structure, aiming to more accurately characterize the complex interactions inside objectives while maintaining a lower hyper-parameter scale, theoretically alleviating the above deficiencies. The comprehensive analysis of the mathematical properties fully demonstrates that TW decomposition can be more potential in representation capabilities and more flexible in controlling both parameter storage and computational costs. To compute the TW-format decomposition, the sequential singular value decomposition (SVD)-based and the alternating least squares (ALS)-based learning algorithms are developed. Furthermore, to investigate the validity of TW decomposition, we provide its one numerical application, i.e., tensor completion (TC), yet develop an efficient proximal alternating minimization-based solving algorithm with guaranteed convergence. Experimental results on both synthetic and real-world data reveal that TW decomposition significantly outperforms other state-of-the-art tensor decompositions for incomplete-tensor inference, especially under solely few observations, thus substantiating the superiority and reliability of TW decomposition.}, } @article {pmid42013406, year = {2026}, author = {Weemering, DN and van Unnik, JWJ and Genge, A and van den Berg, LH and van Eijk, RPA}, title = {Heterogeneity in the Analysis of the ALSFRS-R in ALS Clinical Trials and its Effect on the Validity and Precision of Trial Conclusions.}, journal = {Neurology}, volume = {106}, number = {9}, pages = {e214937}, pmid = {42013406}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/therapy ; *Randomized Controlled Trials as Topic/standards ; Reproducibility of Results ; *Disability Evaluation ; }, abstract = {BACKGROUND AND OBJECTIVES: Disability rating scales play a pivotal role in clinical trials, but there is a notable lack of guidance on how to analyze these scales. Using amyotrophic lateral sclerosis as a case study, our aim was to explore how disability rating scales have been analyzed in completed clinical trials and to assess how these different approaches influence both the risk of false-positive findings and the statistical power to detect true treatment effects.

METHODS: We searched PubMed and Embase to systematically identify randomized, placebo-controlled clinical trials using the revised ALS functional rating scale (ALSFRS-R) as primary end point, with ≥20 randomly assigned patients and ≥12-weeks of follow-up. Data were extracted on the statistical analysis approaches and strategies for handling missing data. Variability in statistical methods was mapped to the various research questions that the trials aimed to address. A simulation study assessed how each statistical method influenced validity (false-positive rate) and precision (statistical power), using the Ceftriaxone trial data set to model a realistic trial scenario.

RESULTS: Our analysis included 45 randomized clinical trials, comprising a total sample size of 7,338 patients, and identified 39 distinct statistical methods using a mixture of longitudinal and cross-sectional techniques. Most trials (55.6%) did not use all available (longitudinal) ALSFRS-R measurements, resulting in suboptimal utilization of patient data and reduced statistical precision. Applying the different statistical methods to the same trial data set resulted in large differences in the estimated treatment effect size, ranging from a negative 1.33 to a positive 2.33 SD difference. Among the methods used, 38.9% (95% CI 24.8%-55.1%) were at risk of increasing false-positive rates, potentially contributing to the erroneous advancement of ineffective treatments. Statistical power of valid strategies varied widely, ranging from 17.9% to 78.2%.

DISCUSSION: Our results demonstrate considerable variability in statistical methods, with the choice of method able to influence the estimated treatment effects, potentially resulting in misleading conclusions and uncertainty about treatment effects. This limits the interpretability and comparability of clinical trials and influences clinical decision-making and drug development. Establishing statistical consensus recommendations could improve the utility of disability scales in clinical trials and accelerate progress toward effective therapies for neurodegenerative diseases.}, } @article {pmid42013408, year = {2026}, author = {de Carvalho, M}, title = {The Cat is Out of the Bag: Confronting False-Positive Risks in Amyotrophic Lateral Sclerosis Clinical Trials.}, journal = {Neurology}, volume = {106}, number = {9}, pages = {e218029}, doi = {10.1212/WNL.0000000000218029}, pmid = {42013408}, issn = {1526-632X}, } @article {pmid42013466, year = {2026}, author = {Darke, A and Orsulak, C}, title = {How effective does a new drug for Amyotrophic Lateral Sclerosis need to be - the patient perspective: a letter in response to "Estimating the minimum important difference in the ALSFRS-R-instrument in people living with MND" published in vol. 26, pp. 249-258.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {485-486}, doi = {10.1080/21678421.2025.2589781}, pmid = {42013466}, issn = {2167-9223}, } @article {pmid42013476, year = {2026}, author = {El-Agamy, SE and Mattedi, F and Fratta, P}, title = {Cryptic Splicing in ALS: From Driving Disease Progression to Unlocking Novel Therapeutics.}, journal = {Annual review of genomics and human genetics}, volume = {27}, number = {1}, pages = {277-303}, pmid = {42013476}, issn = {1545-293X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *RNA Splicing/genetics ; Disease Progression ; Animals ; Proteostasis/genetics ; }, abstract = {TDP-43 is an RNA-binding protein that regulates multiple aspects of RNA processing, and its mislocalization from the nucleus to the cytoplasm is a defining feature of amyotrophic lateral sclerosis (ALS). While both loss- and gain-of-function mechanisms contribute to disease, the discovery of cryptic splicing has shed light on the downstream consequences of TDP-43 nuclear clearance for neuronal health. Here, we highlight how loss of nuclear TDP-43 can drive a cascade of events that lead to the impairment of cellular proteostasis and result in a positive feedback loop that perpetuates neuronal dysfunction. This sustains the appearance of cryptic splicing events in genes that are involved in key pathways for the maintenance of axonal homeostasis and synaptic transmission. In contrast to their detrimental effects on neuronal health, cryptic splicing mechanisms may be harnessed to develop novel therapeutic strategies, unprecedentedly expanding the availability of therapeutic avenues for TDP-43 proteinopathies.}, } @article {pmid42013513, year = {2026}, author = {Saldanha-Castro, P and Vyas, MV and Jain, D and Santos-Neto, D and Mirian, A and , and Zinman, L and Abrahao, A}, title = {Association between statin use and survival in patients with ALS: A propensity score-matched analysis.}, journal = {Journal of the neurological sciences}, volume = {486}, number = {}, pages = {125916}, doi = {10.1016/j.jns.2026.125916}, pmid = {42013513}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/drug therapy ; Female ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Propensity Score ; Male ; Middle Aged ; Retrospective Studies ; Aged ; Disease Progression ; Cohort Studies ; }, abstract = {OBJECTIVE: To evaluate the association between statin use, disease progression, and survival in patients with amyotrophic lateral sclerosis (ALS) using data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.

METHODS: We conducted a retrospective cohort study of adults (≥18 years) diagnosed with ALS and included in the PRO-ACT database. Statin exposure was defined as any statin use at cohort entry. Statin users were matched 1:1 to non-users using propensity score matching based on age, baseline ALS Functional Rating Scale (ALSFRS), disease duration, ethnicity, bulbar onset, riluzole use, and cardiovascular or metabolic comorbidities. Participants were followed from cohort entry or statin initiation until death, end of follow-up (36 months), or loss to follow-up. The primary outcome was all-cause mortality at three years. The secondary outcome was disease progression, defined as time to a four-point decline in ALSFRS score. Cox proportional hazards models were used to estimate hazard ratios (HRs).

RESULTS: Among 3439 eligible participants, 131 statin users (mean age 63.1 years; 34% female) were identified and matched to 131 non-users. Statin use was not associated with all-cause mortality at three years (HR 0.97; 95% CI 0.66-1.44; P = 0.89). Disease progression was also similar between statin users and non-users (HR 1.02; 95% CI 0.80-1.31; P = 0.90).

CONCLUSIONS: In this large observational cohort, statin use was not associated with survival or disease progression in ALS. These findings do not support statin initiation or discontinuation based solely on ALS diagnosis or disease course.}, } @article {pmid42013739, year = {2026}, author = {Mirveis, Z and Patil, N and Byrne, HJ}, title = {Evaluating data-mining strategies for label-free Raman microspectroscopic analysis of cellular processes in vitro: dynamic dimensionality reduction.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {359}, number = {}, pages = {127923}, doi = {10.1016/j.saa.2026.127923}, pmid = {42013739}, issn = {1873-3557}, mesh = {*Spectrum Analysis, Raman/methods ; Principal Component Analysis ; Least-Squares Analysis ; *Data Mining/methods ; Humans ; Dimensionality Reduction ; Kinetics ; Multivariate Analysis ; }, abstract = {Understanding dynamic intracellular metabolism is essential for elucidating cellular function and disease mechanisms. However, analysing time-resolved spectral data is challenging due to overlapping signals, high dimensionality, and biological variability. This study evaluates the applicability of Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) for resolving complex cellular spectral data and introduces a framework that integrates Principal Component Analysis (PCA) of sequential time points as a preprocessing step. PCA was used to extract dominant spectral variance associated with biological kinetics (PC1), and MCR-ALS was subsequently applied to the sequential PC1 loadings to enhance the recovery of kinetic trends. To validate the approach, simulated Raman datasets were generated by combining predefined component spectra with known kinetic profiles, representing sequential (glycolysis-like) and parallel (glycolysis + glutaminolysis) models. These signals were superimposed onto real cellular spectra ("Sim-Cell" data) to include intercellular variability and background interference. Standard MCR-ALS was first assessed to determine the optimal number of components and, when applied to cell-free datasets, resolved up to three components. It was then applied to Sim-Cell datasets to evaluate performance under simulated biological conditions. MCR-ALS resolved the sequential model up to a cellular background weight of 2 but failed for the parallel model, highlighting limitations in complex, overlapping systems. In contrast, PCA-MCR-ALS substantially improved performance under strong cellular background, maintaining accurate resolution up to weight = 5 for sequential and weight = 8 for parallel models. Overall, this study benchmarks chemometric performance in label-free Raman microspectroscopy and highlights PCA-assisted MCR-ALS for analysing time-resolved intracellular spectral data.}, } @article {pmid42013766, year = {2026}, author = {Kravitz, D and Saker, TS and Odess, N and Drory, VE and Abraham, A}, title = {Quantitative sonographic assessment of relaxed and contracted muscle thickness predicts survival in ALS.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {187}, number = {}, pages = {2111845}, doi = {10.1016/j.clinph.2026.2111845}, pmid = {42013766}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/mortality/physiopathology ; Female ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Ultrasonography/methods ; Male ; Aged ; Middle Aged ; *Muscle Contraction/physiology ; Prospective Studies ; Predictive Value of Tests ; }, abstract = {OBJECTIVES: To explore the ability of quantitative sonographic assessment of muscle thickness to predict mortality in amyotrophic lateral sclerosis (ALS) patients compared with manual muscle testing (MMT) and the ALS functional rating scale-revised (ALSFRS-R).

METHODS: 86 prospectively recruited ALS patients underwent clinical assessment and quantitative sonographic assessment of muscle thickness in 8 relaxed and 4 contracted limb muscles. Average monthly decline rates of MMT and ALSFRS-R scores and measured relaxed and contracted muscle thickness were calculated at study entry. The area under the curve (AUC), optimal cutoff points, and hazard ratio (HR) for 1 to 3-year mortality were calculated and adjusted for covariates.

RESULTS: Significant increased 1-year mortality was associated only with lower contracted muscle thickness (HR-8.1), while increased 3-year mortality was in greater correlation with a reduced contracted muscle thickness (HR-4.85) than with a decline in MMT (HR-3.31) and ALSFRS-R (HR-2.12) or a reduced relaxed muscle thickness (HR-2.65).

CONCLUSION: Reduced limb muscle thickness, especially in a contracted state, is associated with significantly increased mortality in ALS.

SIGNIFICANCE: Sonographic muscle measurement is a novel estimator of ALS mortality and has the potential to serve as an additional biomarker in future multi-variable prognostication models, clinical decision making and research.}, } @article {pmid42013845, year = {2026}, author = {Xu, Y and He, J and Wang, S and Ge, Y and Jia, Y and Guo, W and Lv, C and Yao, X and Mao, Y and Mei, F and Fan, D and Yuan, P and Lu, B}, title = {BDNF insufficiency exacerbates ALS progression.}, journal = {Cell reports. Medicine}, volume = {7}, number = {5}, pages = {102758}, pmid = {42013845}, issn = {2666-3791}, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/genetics/metabolism/deficiency ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism/drug therapy ; Receptor, trkB/metabolism/agonists ; Motor Neurons/metabolism/pathology/drug effects ; Humans ; Mice ; Disease Progression ; Disease Models, Animal ; Mutation ; Mice, Transgenic ; RNA-Binding Protein FUS/genetics/metabolism ; Riluzole/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive loss of motor neurons. Insufficiency of neurotrophic factors is suspected to underlie the disease, but direct evidence remains scarce. In this study, we discover that brain-derived neurotrophic factor (BDNF) val/met mutation, which results in a decrease in BDNF secretion, reduces survival time of ALS patients in two separate cohorts. Using a knockin mouse model of the ALS causal gene FUS[R521C], we demonstrate that BDNF haploinsufficiency leads to shortened lifespan, accelerated motor dysfunctions, and exacerbated motor neuron death. Importantly, activation of the BDNF receptor TrkB by an agonistic antibody effectively rescues these ALS-associated phenotypes. In additional ALS mouse models, TrkB activation antibody also shows superior therapeutic effects compared to current ALS medication riluzole. Our data indicate that insufficient BDNF could be a crucial contributing factor for ALS progression, and activation of BDNF-TrkB pathway may represent a promising therapeutic strategy against ALS.}, } @article {pmid42014727, year = {2026}, author = {Guo, X and Hu, J and Kanwal, S and Yuan, J and Tariq, M and Zheng, J and Sun, M and Lu, Y and Wang, J and Jiang, M and Wang, A and Castells-Garcia, A and Zheng, X and Peng, B and Wang, D and Wei, X and Yang, T and Volpe, G and Wu, L and Mazid, MA and Li, W and Lai, Y and Qin, D and Aguilo, F and Zhou, Y and Liu, C and Cosma, MP and Xu, X and Lundberg, E and Mulder, J and Hutchins, AP and Maxwell, PH and Di Croce, L and Zhang, X and Esteban, MA and Lv, Y}, title = {A framework for the exploration of subcellular compartmentalization of RNA-binding proteins.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42014727}, issn = {2041-1723}, mesh = {*RNA-Binding Proteins/metabolism/genetics ; Humans ; DNA Damage ; Protein Binding ; Subcellular Fractions/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Animals ; *Cell Compartmentation ; }, abstract = {The ability of RNA-binding proteins to form complexes with other biomolecules underpins a broad range of structural properties and functions. Understanding the subcellular distribution of RNA-binding proteins and their interacting partners in the steady state and upon perturbation can therefore shed light on these aspects. Here, we present the compartmentalized RNA-Binding Protein (or coRBP) map, an experimental resource and analytical pipeline to study subcellular RNA-binding proteins through multimodal dataset integration and machine learning. Using this approach, we generate a dataset of 1,768 known and putative RNA-binding proteins distributed in a broad panel of subcellular compartments and delineate their intermolecular and intercompartmental relationships. We also establish a hierarchy of RNA-binding protein-containing complexes at multiple scales across the cell, which suggests additional functions for multiple RNA-binding proteins. Furthermore, we investigate changes in RNA-binding protein complex composition and subcellular distribution in response to C9ORF72-associated amyotrophic lateral sclerosis/frontotemporal dementia dipeptide repeats and DNA damage stress. The coRBP map provides a resource to study the roles of RNA-binding proteins in homeostasis and disease.}, } @article {pmid42014913, year = {2026}, author = {Cai, F and Xu, D and Yang, D and Huang, F and Song, X and Jiang, Q and Wan, S and Zhao, Y and Zhou, J}, title = {Correction: Multidimensional predictors of fatigue in amyotrophic lateral sclerosis: a cross-sectional study in China.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, doi = {10.1038/s41598-026-49397-z}, pmid = {42014913}, issn = {2045-2322}, } @article {pmid42015194, year = {2026}, author = {Luo, J and Li, K and Yang, R and Tang, M and Ge, J}, title = {Whole-exome sequencing identifies PRSS56 variants in Chinese patients with microphthalmia.}, journal = {BMC medical genomics}, volume = {19}, number = {1}, pages = {}, pmid = {42015194}, issn = {1755-8794}, support = {A1515010914//Guangdong Basic and Applied Basic Research Foundation/ ; 82271083//National Natural Science Foundation of China/ ; 2018YFA0108304//National Key Research and Development Program of China/ ; 2025QZSPT46//State Key Laboratory of Ophthalmology/ ; }, mesh = {Child ; Child, Preschool ; Female ; Humans ; Male ; China ; *Exome Sequencing ; Genetic Association Studies ; *Microphthalmos/genetics/pathology ; *Mutation ; Pedigree ; Phenotype ; *Serine Proteases/genetics/chemistry ; East Asian People ; }, abstract = {PURPOSE: This study aimed to elucidate the genetic and clinical profiles of Chinese patients with microphthalmia harbouring PRSS56 variants and investigate the genotype‒phenotype correlation. METHODS: Whole-exome sequencing (WES) was performed in patients with microphthalmia and available family members to assess coding regions and adjacent intronic splice boundaries for variant detection and downstream interpretation. The axial lengths (ALs) of all the probands and available family members were measured. The genotype‒phenotype correlation was explored by statistical analysis, and protein structure prediction was analysed in silico. RESULTS: Seven PRSS56 variants were detected across four of the seven families, including two novel candidate variants (c.175G > A:p.E59K and c.1030 C > A:p.P344T) and five previously reported variants. Variant p.Q356Pfs152 was found in two unrelated families and was the most frequent. The mutational spectrum frequency in the Chinese population differed from that in other ethnic groups worldwide. The average AL was 17.82 ± 1.51 mm. In an exploratory pooled analysis combining the current cohort with previously published cases, eyes with biallelic LoF variants showed shorter ALs than eyes with missense variants. Variants p.G107V and p.E396K, which were reported exclusively in Chinese microphthalmia cases, were predicted to destabilize the PRSS56 protein. CONCLUSIONS: Among nine individuals from seven families, seven PRSS56 variants were identified in four families, underscoring the significant genetic diversity within the Chinese population. The reported variant p.Q356Pfs*152 had the highest frequency in our cohort. Our findings expand current understanding of PRSS56-associated microphthalmia and provide valuable information for prenatal diagnosis and future therapeutic strategies.}, } @article {pmid42015728, year = {2026}, author = {Wang, H and Li, G and Liang, F and Xia, X and Zhang, W and Fan, Z}, title = {A nomogram for estimating baseline respiratory insufficiency in patients with amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {58}, number = {1}, pages = {2654938}, pmid = {42015728}, issn = {1365-2060}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Nomograms ; Female ; *Respiratory Insufficiency/etiology/diagnosis/physiopathology/epidemiology ; Retrospective Studies ; Male ; Vital Capacity ; Middle Aged ; Respiratory Function Tests ; Aged ; ROC Curve ; Muscle Strength/physiology ; }, abstract = {OBJECTIVES: To develop and validate a nomogram for estimating the risk of baseline respiratory insufficiency in patients with amyotrophic lateral sclerosis (ALS). This also aims to analyze the association between readily available clinical predictors and pulmonary function.

MATERIALS AND METHODS: This retrospective study assessed 142 ALS patients treated at the First Hospital of Shanxi Medical University from August 2020 to June 2023. ALS was diagnosed based on revised El Escorial criteria with Awaji modifications. Clinical data and pulmonary function tests (PFTs) were performed during a single hospital stay. Respiratory insufficiency was marked as forced vital capacity (FVC) < 80% of predicted. Muscle strength of neck and limbs was measured with the Medical Research Council (MRC) scale. Multivariable logistic regression evaluated independent predictors of respiratory insufficiency. A nomogram was created and internally validated using bootstrap resampling (1,000 iterations). Model performance was assessed with ROC curve analysis, calibration curve analysis, and decision curve analysis (DCA).

RESULTS: Of the 142 patients, 30 (21.1%) presented with baseline respiratory insufficiency. In the multivariable analysis, neck flexor muscle strength (OR = 0.497, 95% CI: 0.321-0.769; p = 0.002) and bulbar onset (OR = 4.392, 95% CI: 1.674-11.521; p = 0.003) were independent predictors in the multivariable analysis. The nomogram showed good discrimination and calibration (AUC = 0.823, 95% CI: 0.739-0.907).

CONCLUSIONS: Weakness of neck flexors and bulbar onset are independently associated with baseline respiratory insufficiency in ALS patients. The proposed nomogram may serve as a useful tool for baseline screening and risk stratification. External validation in larger multicenter cohorts is warranted before clinical application.}, } @article {pmid42016758, year = {2026}, author = {Liu, Y and Xia, X and Chen, Y and Yang, H and Chen, X and Cai, L and Shi, B}, title = {When Rare Is Not Small: Amyotrophic Lateral Sclerosis Initiatives and Therapy.}, journal = {Exploration (Beijing, China)}, volume = {6}, number = {2}, pages = {70114}, pmid = {42016758}, issn = {2766-2098}, abstract = {In the precision-medicine era, rare diseases must not be sidelined in translational infrastructure. The Mr. Cai Lei-led "Ice-Breaking Team" turns an amyotrophic lateral sclerosis patient community into a sustainable ecosystem, realigning philanthropy, data, and research and development to reshape rare-disease pipelines and guide precision therapies, offering a replicable blueprint for rare-disease strategies.}, } @article {pmid42016770, year = {2026}, author = {Cao, L and Chen, G and Zhou, J and Huang, H and Xu, A and Zhan, T and Zhao, Y and Liu, H}, title = {Subtype-specific associations between serum lipid profiles and disease severity in patients with amyotrophic lateral sclerosis.}, journal = {Biomedical reports}, volume = {24}, number = {6}, pages = {68}, pmid = {42016770}, issn = {2049-9442}, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disorder. Notably, the differences in lipid metabolism between bulbar- and limb-onset subtypes of ALS remain unclear, particularly in non-Western populations. The present study investigated serum lipid profiles in a Chinese cohort of patients with ALS to explore their associations with disease severity and clinical subtypes. A retrospective, cross-sectional study was conducted, involving 158 patients with ALS and 62 matched healthy controls. Serum lipid parameters, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), small dense LDL cholesterol (sdLDL-c), apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB) and the TG/HDL ratio, were compared between the groups. Correlation analyses and multivariable linear regression models incorporating phenotype x lipid interaction terms were conducted after adjusting for age, sex, body mass index and disease duration. Patients with ALS exhibited significantly higher TC, TG, LDL, sdLDL-c, ApoA1, ApoB and TG/HDL ratios than controls. Subtype-specific analyses revealed different associations; in bulbar-onset ALS, higher sdLDL-c and TG/HDL ratios were associated with better functional status, whereas higher HDL and ApoA1 levels were negatively correlated with functional status. By contrast, in limb-onset ALS, higher sdLDL-c and ApoB levels were associated with worse function. Interaction analyses confirmed significant phenotype modification for sdLDL-c, TG/HDL ratio, HDL and ApoA1. These results suggest that lipid-severity relationships in ALS vary by subtype, indicating metabolic heterogeneity across phenotypes and supporting the potential of specific lipid parameters as exploratory markers for disease monitoring.}, } @article {pmid42018749, year = {2026}, author = {Niu, RZ and Zhang, MY and Yang, HH and Zeng, XF and Liu, J and Bao, TH}, title = {Single-cell multiregion dissection of central nervous system aging.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {81}, number = {5}, pages = {}, doi = {10.1093/gerona/glag103}, pmid = {42018749}, issn = {1758-535X}, support = {82501796//National Natural Science Foundation of China/ ; 82160269//National Natural Science Foundation of China/ ; 82360275//National Natural Science Foundation of China/ ; 82160272//National Natural Science Foundation of China/ ; 82560282//National Natural Science Foundation of China/ ; //Kunming Health Science and Technology Talent Training Project/ ; 2024YNLCYXZX0278//Research Project of Yunnan Provincial Clinical Medical Center/ ; 2024YNLCYXZX0280//Research Project of Yunnan Provincial Clinical Medical Center/ ; 202405AC350104//Yunnan Provincial Department of Science and Technology Science and Technology/ ; }, mesh = {Humans ; *Aging/genetics/pathology ; *Central Nervous System/metabolism/pathology ; Aged ; Aged, 80 and over ; Adult ; Middle Aged ; Female ; *Transcriptome ; Male ; Young Adult ; *Single-Cell Analysis ; Astrocytes ; }, abstract = {Central nervous system (CNS) aging is a major risk factor for many disorders, including cerebrovascular disease, neurodegeneration, and amyotrophic lateral sclerosis, yet the cellular pathways driving its progression across CNS regions remain poorly defined. Here we present a single-nucleus transcriptomic atlas spanning 7 human CNS regions, comprising ∼1.0 million nuclei from 235 postmortem samples derived from 200 neurologically and psychiatrically normal donors aged 19-101 years. Across regions, we delineate both shared and region-specific features of CNS aging, integrating analyses of transcriptional noise, programmed cell-death signatures, disease associations, metabolic reprogramming, and transcriptomic remodeling. We identify cross-regional vulnerability of astroglia, oligodendrocytes, and excitatory and inhibitory neurons, and show that microglial and astrocytic activation represents a broadly conserved aging response across the CNS, highlighting potential targets for intervention. Finally, we present within-dataset proof-of-concept predictive modeling use cases based on aging-associated gene signatures, providing a resource for within-atlas prioritization and hypothesis generation of candidate biomarkers of CNS aging. Together, this work offers a region-by-region map of the aging human CNS and informs the selection of specific cell types and/or regions for future anti-aging strategies.}, } @article {pmid42020473, year = {2026}, author = {García-Camacho, M and Martínez-Subiela, S and Tvarijonaviciute, A and Cerón, JJ and Rubio, CP and Muñoz-Prieto, A}, title = {Analytical validation of aldolase, microalbumin and myeloperoxidase in canine saliva and their evaluation in canine gingivitis.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42020473}, issn = {2045-2322}, support = {22724/FPI/24//Fundación Séneca/ ; PID2023-149944OB-I00//Agencia Estatal de Investigación/ ; PID2023-149944OB-I00//FEDER, EU/ ; RYC2021-034764-I//Ramón y Cajal/ ; RYC2021-033660-I//Ramón y Cajal/ ; }, mesh = {Animals ; Dogs ; *Gingivitis/veterinary/metabolism/diagnosis ; *Peroxidase/metabolism/analysis ; *Saliva/metabolism/chemistry ; *Fructose-Bisphosphate Aldolase/metabolism/analysis ; Biomarkers/metabolism/analysis ; Female ; *Dog Diseases/metabolism/diagnosis ; Male ; *Albumins ; }, abstract = {Saliva is a biological fluid that offers potential practical advantages for biomarker assessment in dogs due to its non-invasive nature. This study evaluated aldolase (ALS), microalbumin (mALB), and myeloperoxidase (MPO) in canine saliva using automated assays. All assays showed acceptable analytical performance, with adequate precision (coefficients of variation < 15%), accuracy (coefficients of determination close to 1 after serial sample dilutions), and sensitivity (lower limits of quantification of 5.6 IU/L, 2.05 mg/dL, and 26.3 IU/L for ALS, mALB and MPO, respectively). The effect of gingivitis on these salivary analytes was also assessed. Dogs with gingivitis showed significantly higher salivary ALS and mALB results — ALS, 21.9 (14.2–37.3) IU/L; mALB, 13.15 (5.89–25.71) mg/dL — compared with controls — ALS, 7.65 (2.2-12.23) IU/L; mALB, 3.51 (2.32–5.21) mg/dL— (p < 0.0001). Moreover, increasing gingivitis severity was associated with progressively higher levels of ALS and mALB. In contrast, no significant differences were observed in MPO activity between groups. These findings suggest that ALS and mALB may serve as salivary biomarkers for gingivitis assessment. Further studies are warranted to explore their potential applicability in other local and systemic inflammatory conditions in dogs.}, } @article {pmid42020605, year = {2026}, author = {}, title = {Somatic mutations link focal onset to widespread neurodegeneration in ALS and FTD.}, journal = {Nature genetics}, volume = {58}, number = {5}, pages = {958-959}, pmid = {42020605}, issn = {1546-1718}, } @article {pmid42020662, year = {2026}, author = {Abati, E and Saccomanno, D and Alberti, C and Anastasia, A and Gagliardi, D and Ferri, E and Arosio, B and D Angelo, G and Cima, R and Bassi, MT and Oldoni, S and Comi, GP and Rizzo, F and Corti, SP}, title = {Investigating the role of serum NfL, FGF21, NCAM1 and GDF15 as disease biomarkers for Charcot-Marie-Tooth type 2A.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42020662}, issn = {2045-2322}, support = {GMR23T2153//Fondazione Telethon/ ; Ricerca Corrente 2024 MoH//Ministero della Salute/ ; GR-2018-12365358//Ministero della Salute/ ; }, mesh = {*Charcot-Marie-Tooth Disease/blood/diagnosis/genetics ; Humans ; Biomarkers/blood ; *Growth Differentiation Factor 15/blood ; Female ; *Fibroblast Growth Factors/blood ; Male ; Animals ; Middle Aged ; Adult ; *Neurofilament Proteins/blood ; Mice ; Mice, Transgenic ; Aged ; Case-Control Studies ; Neural Cell Adhesion Molecules/blood ; }, abstract = {Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal form of inherited peripheral neuropathy, caused by mutations in the mitofusin 2 (MFN2) gene that impair mitochondrial fusion and axonal transport, ultimately leading to progressive neurodegeneration. The identification of accessible molecular biomarkers may improve diagnostic accuracy, enable patient stratification, and support the development and monitoring of emerging therapies. We investigated serum levels of neurofilament light chain (NfL), neural cell adhesion molecule 1 (NCAM1), growth differentiation factor 15 (GDF15), and fibroblast growth factor 21 (FGF21) in CMT2A patients (n = 15), healthy controls (n = 10), and neurological disease controls (n = 16; amyotrophic lateral sclerosis [ALS], n = 10, spinal muscular atrophy type 3 [SMA3], n = 6), evaluating their utility as diagnostic and monitoring biomarkers. In parallel, serum NfL levels were assessed in transgenic Thy1-MFN2*R94Q mice, a validated preclinical model of CMT2A. Serum NfL levels were significantly elevated in CMT2A patients compared to healthy controls, a finding corroborated in transgenic mice. Notably, NfL levels in CMT2A patients were higher than in SMA3 but lower than in ALS patients, supporting the ability of this biomarker to discriminate between clinically overlapping neuromuscular conditions. Higher NfL levels were associated with younger age, earlier disease onset, and shorter disease duration, suggesting a role as a marker of early disease burden. However, no significant correlation was observed with clinical severity scores or electrophysiological measures. Serum FGF21 levels were also significantly elevated in CMT2A patients compared to controls, whereas NCAM1 and GDF15 levels did not differ significantly between groups. These findings support the role of serum NfL as a translational biomarker of axonal damage in CMT2A, capable of distinguishing affected individuals from both healthy and neurological disease controls. The concomitant elevation of FGF21 further underscores the contribution of mitochondrial dysfunction to CMT2A pathophysiology. Together, these results highlight the potential of serum biomarkers to refine diagnostic workflows and facilitate therapeutic development and future clinical trials for CMT2A.}, } @article {pmid42020791, year = {2026}, author = {Tsagkas, C and Donadieu, M and Sun, R and Bujak, B and Hu, K and Rood, C and Cameron, K and Dodd, S and Reich, DS and Nair, G}, title = {A pipeline to characterize spinal cord pathology in neurological disorders combining magnetic resonance microscopy and histopathology.}, journal = {Communications medicine}, volume = {6}, number = {1}, pages = {}, pmid = {42020791}, issn = {2730-664X}, abstract = {BACKGROUND: The length, shape, and size of the spinal cord (SC) present unique challenges for MRI, including the need for high resolution to distinguish anatomical and pathological features along its span. Postmortem MRI offers an opportunity to map SC tissue abnormalities and investigate their histological correlates.

METHODS: We developed a pipeline combining postmortem microscopic resolution MRI (MR microscopy; MRM) of whole formalin-fixed SC specimens with targeted histopathological analysis. A gadolinium-based tissue preparation protocol was optimized using SC tissue from common marmosets with experimental autoimmune encephalomyelitis. A custom tissue holder and container were designed to enable postmortem MRI of the entire human SC. Human SC samples from individuals with multiple sclerosis, amyotrophic lateral sclerosis, and intracranial hemorrhage were scanned at 75 μm isotropic resolution on a 9.4 T Bruker system after gadolinium preparation.

RESULTS: MRM after gadolinium-based tissue preparation yields images with high signal- and contrast-to-noise ratio while minimizing acquisition times. MRI demonstrates fine anatomical detail and pathological features, including demyelination and neurodegeneration throughout the SC. A complementary custom-made cutting rack enables targeted histological sectioning of MRI-identified regions. This approach provides precise spatial correspondence between imaging and histological findings, demonstrating strong agreement across modalities.

CONCLUSIONS: In summary, this pipeline facilitates comprehensive SC assessment by integrating MRM with histology. It enables accurate localization of both subtle and widespread SC pathology and enhances interpretation of MRI signals in the context of neurodegenerative and inflammatory diseases.}, } @article {pmid42021292, year = {2026}, author = {Yang, T and Wang, Y and Dong, N and Ding, J and Yan, X and Luo, J and Chen, P and Qiu, Y and Lin, T and Tong, J and Mao, J and Dai, Y and Shentu, H and Tang, S and Sheng, L and Zhao, M and Yang, G}, title = {Predicting amyotrophic lateral sclerosis stage based on multi-parameter ultrasound: development and validation of an interpretable machine learning model.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {42021292}, issn = {1741-7015}, support = {2025HZZD09//The Construction Fund of Key Medical Disciplines of Hangzhou - Rare Disease (Motor Neuron Disease)/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Muscle, Skeletal/diagnostic imaging ; *Predictive Learning Models/standards ; *Ultrasonography/methods ; *Image Interpretation, Computer-Assisted/methods/standards ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) lacks sensitive, objective staging tools to guide clinical management and trials. Existing methods have limited granularity and rely on subjective assessment, while biomarker and imaging approaches can be invasive or impractical for serial use. Ultrasound is a safe, portable imaging modality that can detect neuromuscular changes, but it has not yet been applied to ALS staging. We developed and validated an interpretable ultrasound model for clinical staging and risk stratification in ALS.

METHODS: We enrolled 300 ALS patients, classified as early-stage (King's stages 1-2; n = 148) or late-stage (3-4; n = 152). Each patient underwent ultrasound of key muscle groups, including the diaphragm (excursion and thickening), geniohyoid (shear-wave velocity), and peripheral skeletal muscles (thickness and cross-sectional area). Six machine learning models were trained to predict early vs late stage from these ultrasound metrics combined with clinical factors. Performance was evaluated on a test set using area under the curve (AUC), F1 score and Brier score. Feature importance was analyzed with SHapley Additive exPlanation (SHAP) values.

RESULTS: In the test set, the random forest achieved an AUC of 0.843, an F1 score of 0.727, and a Brier score of 0.177, with sensitivity 0.80 and specificity 0.68. SHAP analysis identified diaphragm excursion during deep breathing (DEDB) as the top predictor, followed by masseter muscle thickness (MMT) and geniohyoid shear-wave velocity (GHSWVmean). Higher DEDB, MMT and GHSWVmean values predicted earlier stage, whereas lower peripheral muscle thickness and older age indicated late-stage disease.

CONCLUSIONS: Multiparameter ultrasound combined with machine learning offers a non-invasive, bedside tool for ALS staging. The model's accuracy and interpretability enable objective tracking of disease progression and may support timely interventions and patient stratification in clinical practice and trials. Leveraging widely accessible ultrasound technology, this approach is feasible for routine ALS care and research.}, } @article {pmid42021677, year = {2026}, author = {Mukhija, S and Lehner, F and Jung, HH}, title = {[Amyotrophic lateral sclerosis (ALS): current perspectives and the Swiss ALS Registry].}, journal = {Praxis}, volume = {115}, number = {4}, pages = {100-106}, doi = {10.23785/PRAXIS.2026.04.003}, pmid = {42021677}, issn = {1661-8157}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy/epidemiology ; *Registries ; Switzerland ; Disease Progression ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease leading to muscle weakness, atrophy, and ultimately death. In addition to mutations in ALS-related genes, environmental and lifestyle factors may increase disease risk. Diagnosis is based on clinical evaluation, supplemented by electroneuromyography, imaging, and molecular genetic testing. No curative therapy exists, but Riluzole and Edaravone can slow progression, and genetic therapies offer promising perspectives in certain genetically determined forms. In practice, diagnosis is often delayed. The Swiss ALS Registry collects comprehensive data on environmental, lifestyle, clinical, genetic, and biomarker factors, aiming to improve understanding of risk, disease progression, and therapeutic approaches.}, } @article {pmid42021792, year = {2025}, author = {Iztleuov, M and Abugaliyeva, N and Ryzhkin, S and Iztleuov, Y and Saparbaev, S and Smagulova, G}, title = {Current Insights into Plausible Mechanisms of Chromium (VI) Neurotoxicity in the Brain and Future Perspectives.}, journal = {Medical journal of the Islamic Republic of Iran}, volume = {39}, number = {}, pages = {157}, pmid = {42021792}, issn = {1016-1430}, abstract = {BACKGROUND: Hexavalent chromium (Cr (VI)) is a known neurotoxin and environmental contaminant. Despite its recognition, the underlying mechanisms by which Cr (VI) induces neurological damage remain insufficiently explored. The complexities of the Central Nervous System (CNS), including the Blood Brain Barrier (BBB) and supporting brain cells, contribute to regions-specific susceptibility within the brain. Understanding Cr (VI) neurotoxicity is crucial for its potential role in neurodegenerative diseases.

METHODS: A Systematic Review was conducted using international databases (PubMed, Medline, Scopus, and Web of Science) and Google Scholar. Only open-access, free full-text articles published in English between 2010 and 2025 were included. Following PRISMA 2020 guidelines, a total of 19 relevant studies were selected, comprising 12 animal-based and 7 human cohort studies.

RESULTS: Animal studies investigated the effects of Cr (VI) via various administration methods and doses, revealed evidence of oxidative stress, inflammatory markers, and apoptotic changes in the brain. Interventional studies showed delayed toxicity when antioxidant agents were used prior to Cr (VI) exposure, including PDC (Potassium Dichromate), SA (Sodium Alginate), and TNG (Tangeretin). Human studies, including autopsies and cell culture analyses, demonstrated neurotoxic effects in conditions such as ALS (Amyotrophic Lateral Sclerosis), nAMD (Neovascular Age-Related Macular Degeneration).

CONCLUSION: Animal studies have clarified the role of oxidative stress in Cr (VI)-induced neurotoxicity. Human cohort studies have identified Cr (VI) as an environmental risk factor for both neurodegenerative and neurobehavioral disorders. Future research should focus on defining harmful levels of Cr (VI) and exploring potential antioxidant therapies.}, } @article {pmid42022335, year = {2026}, author = {Cutti, L and Turra, GM and Machado, FM and Sulzbach, E and Angonese, PS and Markus, C and Gaines, TA and Merotto, A}, title = {Subgenomic Distribution and Herbicide Cross-Resistance of ALS Gene Mutations in Allohexaploid Echinochloa crus-galli.}, journal = {Plant direct}, volume = {10}, number = {}, pages = {e70168}, pmid = {42022335}, issn = {2475-4455}, abstract = {Herbicide target site resistance in polyploid species is more complex than in diploids due to potential subgenome interactions. This study characterized mutations in the ALS gene across distinct subgenomes of hexaploid Echinochloa crus-galli and evaluated the cross-resistance patterns conferred by each mutation to various ALS-inhibiting herbicides. E. crus-galli populations were screened, and dose-response curves were performed with ALS inhibitors from different chemical groups. The ALS gene copies of each subgenome (A, B, and C) were sequenced. Copy number variation, global relative expression, and the specific relative expression of ALS gene from each subgenome were performed. The mutations Ala122Thr, Ala205Asn, and Ser653Asn conferred resistance only to imazethapyr, whereas Trp574Leu to imazethapyr, penoxsulam, bispyribac-sodium, and nicosulfuron, when considered the label rate. ALS mutations were more frequent in subgenome A, but ALS from subgenome C had the highest expression. Biotypes with the same mutation showed different resistance level to herbicides. The biotype SAOJER-01 had Trp574Leu mutation in subgenome C and was 22 times more resistant to imazethapyr and penoxsulam than CAMAQ-01, which had the same Trp574Leu mutation in subgenome A. Both SAOJER-01 and CAMAQ-01 biotypes showed CYP450 metabolism mediating penoxsulam resistance in addition to the target site mutation. In conclusion, the mutations Ala122Thr, Ala205Asn, Trp574Leu, and Ser653Asn confer resistance to imazethapyr, but only Trp574Leu confers resistance to the other chemical groups. The herbicides penoxsulam, bispyribac-sodium, and nicosulfuron are effective in controlling three out of four mutations. CYP450-mediated metabolism coexists in biotypes carrying the Trp574Leu mutation. The subgenome location of the ALS mutation may result in variable levels of resistance.}, } @article {pmid42023099, year = {2026}, author = {Galluzzi, G and Ruocco, G and Fornetti, E and Genovese, I}, title = {Modeling ALS in a dish: how organoids are transforming research.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1792336}, pmid = {42023099}, issn = {2296-858X}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the selective loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. The multifactorial etiology of ALS, encompassing genetic mutations, protein aggregation, oxidative stress, excitotoxicity, and dysregulated RNA metabolism, has hindered the development of effective therapies. Traditional animal and 2D cell models have provided important mechanistic insights but often fail to fully capture the human-specific and multicellular aspects of disease pathophysiology. Recent advances in induced pluripotent stem cell (iPSC)-derived organoids offer a promising human-based platform for ALS research, enabling the generation of disease-relevant neural and neuromuscular subtypes in three-dimensional architectures. These models recapitulate key pathological features, including protein mis-localization, neuromuscular junction defects, synaptic impairments, and glial contributions to motor neuron degeneration, while also serving as platforms for drug screening and mechanistic studies. Importantly, spinal and neuromuscular organoids bridge the gap between simplified in vitro systems and the complex human nervous system, providing a unique framework to study ALS pathogenesis. This review provides a comprehensive overview of the various differentiation protocols, experimental strategies and key results obtained to date, with a primary focus on validating and benchmarking organoid models, while also highlighting their limitations, emerging clinical applications, translational potential, and opportunities for personalized therapeutic discovery.}, } @article {pmid42024796, year = {2026}, author = {Mei, J and Xia, M and Peng, L and Li, X}, title = {Alcohol and neurodegenerative diseases: a review of mechanistic insights and disease specific effects.}, journal = {The American journal of drug and alcohol abuse}, volume = {52}, number = {3}, pages = {287-302}, doi = {10.1080/00952990.2026.2645215}, pmid = {42024796}, issn = {1097-9891}, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology/etiology/epidemiology ; Animals ; *Alcohol Drinking/adverse effects ; Oxidative Stress/drug effects ; Disease Progression ; *Ethanol/adverse effects ; Brain/drug effects ; Risk Factors ; }, abstract = {Background: Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) represent a significant global public health problem. Alcohol consumption is a common lifestyle factor that has been implicated as both a risk factor and potential modifier of disease progression.Objectives: This review integrates evidence from human and experimental studies to characterize the effects of alcohol consumption on the onset and progression of major neurodegenerative diseases.Methods: A narrative review was undertaken examining the pathophysiological effects of alcohol on the brain and its disease-specific effects on neurodegenerative disorders, integrating findings from human cohort studies and mechanistic investigations in preclinical models.Results: Experimental evidence indicates that chronic alcohol consumption exacerbates neurodegeneration through multiple converging mechanisms, including oxidative stress, mitochondrial dysfunction, lipid peroxidation, inflammatory signaling, disruption of neurotrophic pathways, impairment of dopaminergic neurotransmission, and alcohol-induced gut microbiota dysbiosis with blood-brain barrier compromise. Epidemiological data suggest dose-dependent and disease-specific associations, with heavy and sustained consumption more consistently linked to increased risk or accelerated progression of AD and PD, while evidence in ALS and HD remains inconsistent.Conclusion: Alcohol exerts a multifaceted and context-dependent influence on neurodegenerative diseases. Accumulating evidence supports that long-term heavy alcohol consumption is associated with enhanced neurodegeneration. Minimizing alcohol consumption may present a pragmatic opportunity to reduce neurodegenerative risk.}, } @article {pmid42025804, year = {2026}, author = {Woodard, GE}, title = {C3 and C5 complement cascade activation in brain injury and disease: Molecular mechanisms, pathological roles, and therapeutic implications.}, journal = {Neurochemistry international}, volume = {196}, number = {}, pages = {106161}, doi = {10.1016/j.neuint.2026.106161}, pmid = {42025804}, issn = {1872-9754}, mesh = {Humans ; Animals ; *Complement Activation/physiology/drug effects ; *Brain Injuries/metabolism/pathology/drug therapy/immunology ; *Complement C3/metabolism ; *Complement C5/metabolism ; Neurodegenerative Diseases/metabolism/pathology/drug therapy ; Brain/metabolism/pathology ; }, abstract = {The complement system represents a crucial component of innate immunity with increasingly recognized roles in central nervous system pathology and homeostasis. Complement components C3 and C5 serve as central molecular hubs in the complement cascade, orchestrating inflammatory responses, synaptic pruning, and neuronal injury across diverse neurological conditions. This comprehensive review examines the molecular mechanisms underlying C3 and C5 activation in the brain, their pathological contributions to acute brain injuries including traumatic brain injury and ischemic stroke, and their complex involvement in chronic neurodegenerative diseases such as Alzheimer disease, multiple sclerosis, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis. Emerging evidence demonstrates that complement activation in the central nervous system extends beyond traditional immune functions to encompass critical roles in neurodevelopment, synaptic plasticity, and neural circuit refinement. The dual nature of complement function in the brain, exhibiting both neuroprotective and neurodegenerative properties depending on context and activation levels, presents unique therapeutic challenges and opportunities. This review synthesizes current understanding of complement-mediated neuroinflammation, discusses validated and emerging therapeutic strategies targeting C3 and C5, evaluates complement biomarkers for disease diagnosis and monitoring, and identifies critical knowledge gaps requiring future investigation. Understanding the nuanced roles of C3 and C5 in neurological disease provides essential foundations for developing targeted immunomodulatory therapies that preserve beneficial complement functions while mitigating pathological activation.}, } @article {pmid42025938, year = {2026}, author = {McColgan, L and Evans, TV and Marku, RN and Perim, RR and Xu, G and Amorim, IP and Urdaneta, M and Mitchell, GS}, title = {Physiological predictors of respiratory motor plasticity: A machine-learning reappraisal of phrenic motor facilitation.}, journal = {Respiratory physiology & neurobiology}, volume = {343}, number = {}, pages = {104574}, pmid = {42025938}, issn = {1878-1519}, support = {R01 HL148030/HL/NHLBI NIH HHS/United States ; R01 HL149800/HL/NHLBI NIH HHS/United States ; }, mesh = {*Phrenic Nerve/physiology ; Animals ; *Hypoxia/physiopathology ; *Long-Term Potentiation/physiology ; *Neuronal Plasticity/physiology ; *Machine Learning ; Predictive Learning Models ; *Respiration ; Rats ; }, abstract = {Acute intermittent hypoxia (AIH)-induced phrenic long-term facilitation (pLTF) is a well-established form of respiratory motor plasticity and a subtype of phrenic motor facilitation (pMF), which also includes pharmacologically induced plasticity. Understanding the mechanisms of pLTF and pMF represents opportunities for therapeutic targets for spinal cord injury, amyotrophic lateral sclerosis and other neurological disorders. Here, we performed a secondary analysis of previously generated experimental datasets to reassess physiological predictors of pLTF and pMF. Given the limitations of expressing pMF as a percent, and to systematically evaluate complex and potentially nonlinear relationships among physiological variables, we employed a supervised machine learning approach using Gradient Boosted Decision Trees and Shapley Additive Explanations (SHAP) analysis to identify and rank both established and novel determinants of respiratory plasticity via percent-based (%) and absolute (Δ) changes in pLTF and pMF. Gradient Boosted Decision Trees models were trained to predict Δ and % outcomes using baseline physiological variables and AIH- or drug-evoked responses as input features, and model interpretability was achieved using SHAP to quantify the contribution of each predictor. The pooled datasets included experiments in which pLTF was induced via AIH (n = 75) and pMF via pharmacologic intervention (n = 39) using established experimental protocols. All animals underwent standardized measurement of phrenic nerve activity, respiratory frequency, arterial blood pressure, and evoked hypoxic responses, which were incorporated into the predictive models. Hypoxia-induced phrenic nerve response (ΔHypoxicPNA) was the primary predictor of ΔpLTF, while ΔMaximalPNA exerted a lesser influence in our analysis. Similarly, %pLTF was most strongly influenced by %HypoxicPNA but was also influenced by baseline phrenic nerve activity (BL PNA) and the hypoxia-evoked blood pressure response (ΔHypoxicBP). Notably, calculating percent change in pLTF versus absolute change in pLTF presents certain limitations. Each animal has a unique level of baseline phrenic nerve activity, so calculation via percent change can conceal or misrepresent the overall magnitude of respiratory motor plasticity. For ΔpMF, BL PNA was the strongest positive correlate, while body mass, which strongly correlates with age in laboratory rats, was inversely correlated to ΔpMF. Rat body mass was strongly inversely correlated with %pMF, while BL PNA and BL respiratory frequency (RF) exerted some influence. Similarities in determinant variables for pMF and pLTF indicate the two phenomena exhibit overlapping mechanisms of action, while the differing variables in each measure of respiratory motor plasticity demonstrate the unique sensitivities of pLTF and pMF. This study provides a comprehensive evaluation of respiratory motor plasticity, discovering new determinants while validating previous research regarding pLTF. Better understanding its mechanism could further research into new therapies for increasing respiratory drive.}, } @article {pmid42026110, year = {2026}, author = {Trad, G and Lenglet, T and Ledoux, I and Querin, G and Blancho, S and Marchand-Pauvert, V and Pradat, PF and Hogrel, JY}, title = {Exploring the interplay between quantitative muscle strength, functional performance, and patient-reported outcomes in amyotrophic lateral sclerosis: a cross-sectional pilot study.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42026110}, issn = {2045-2322}, support = {ANR-23-BIOC-0003//Agence Nationale de la Recherche/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology ; Cross-Sectional Studies ; Fatigue/physiopathology ; *Muscle Strength/physiology ; *Patient Reported Outcome Measures ; Physical Functional Performance ; Pilot Projects ; Severity of Illness Index ; Walk Test ; }, abstract = {Amyotrophic lateral sclerosis (ALS) shows marked clinical heterogeneity, while standard clinical assessments may fail to capture its multidimensional burden. Integrating quantitative muscle strength, functional tests and patient-reported outcomes (PROs) may improve disease characterization. Ten ambulant adults with ALS were enrolled in a cross-sectional pilot study. Functional performance was assessed with the Revised ALS Functional Rating Scale (ALSFRS-R), Six-Minute Walk Test (6MWT), Ten-Meter Walk Test, Timed Up and Go, Berg Balance Scale and a fatigability index, lower-limb strength with dynamometry, and PROs with ALS Assessment Questionnaire-40 (ALSAQ-40), Hospital Anxiety and Depression Scale, Fatigue Severity Scale and Modified Fatigue Impact Scale (MFIS). Despite relatively preserved ALSFRS-R scores (40.6 ± 2.8), participants showed reduced 6MWT (61.3 ± 21.7% predicted), marked fatigability (- 47.3 ± 112.3%) and a lower-limb strength index of 58.2 ± 13.8% predicted. The ALSAQ-40 score averaged 183.1 ± 59.5. Fatigue was prominent, while anxiety and depression remained mild. Muscle strength correlated positively with ALSFRS-R gross motor score and inversely with anxiety. ALSAQ-40 and MFIS components showed significant associations with both functional and walking performance. Even at ambulant stages, measurable muscle weakness and fatigability co-occur with functional and PROs changes in ALS, supporting the use of multidomain, sensitive clinical assessment. The trial was registered at ClinicalTrials.gov (NCT06199284) on 29/12/2023.}, } @article {pmid42026661, year = {2026}, author = {Kuppens, A and Rogister, B and Neirinckx, V}, title = {Pharmacological modulation of CXCL12/CXCR4/ACKR3 for brain disorders - an overview.}, journal = {Cell communication and signaling : CCS}, volume = {24}, number = {1}, pages = {}, pmid = {42026661}, issn = {1478-811X}, support = {7.6518.24//Fonds De La Recherche Scientifique - FNRS/ ; }, mesh = {Humans ; *Chemokine CXCL12/metabolism ; *Receptors, CXCR4/metabolism ; *Receptors, CXCR/metabolism ; Animals ; *Brain Diseases/drug therapy/metabolism ; Signal Transduction/drug effects ; }, abstract = {The CXCL12/CXCR4/ACKR3 axis is essential for brain development and homeostasis. Dysregulation of CXCL12 or its receptors has been associated with various CNS disorders related to neurodevelopmental defects, neuroinflammation, neurodegeneration and brain tumors. This signaling axis represents an attractive therapeutic target, and large efforts have led to the development and use of specific pharmacological modulators for brain diseases. While pharmacological modulation of CXCR4 has extensively been studied in the last decades, targeting ACKR3 has only recently emerged as a critical component of the CXCL12 signaling network, driving growing interest in the development of ACKR3-specific modulators.This review synthesizes CXCL12-induced distinct signaling mechanisms downstream of the receptors: G protein-dependent for CXCR4, and β-arrestin-biased for ACKR3, which acts as a scavenger. We also describe the expression and function of CXCL12, CXCR4 and ACKR3 under physiopathological conditions in the CNS. We exhaustively depict the current status of specific modulators of CXCL12 and its receptors, from in vitro testing to preclinical studies and clinical trials, through exploring various neuropathological contexts, e.g. multiple sclerosis, Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis or cancer. We highlight how pharmacological modulation of one or another triad component drives context-dependent outcomes, and we point out the limitations that should carefully be addressed in the future, to advance CXCL12/CXCR4/ACKR3 targeting approaches for CNS pathologies.}, } @article {pmid42026720, year = {2026}, author = {Kamal, S and Kennel, N and Li, AM and Gale, S and Hennessey, EL and Rodriguez, BN and Feany, MB and Stern, AM and Ganesh, VS and Schildkrout, B and Daffner, K and Silbersweig, DA and Singhal, T and Kletenik, I and Miller, MB}, title = {Case Study 11: A 67-Year-Old Man With Behavioral Disturbances and Frequent Falls.}, journal = {The Journal of neuropsychiatry and clinical neurosciences}, volume = {}, number = {}, pages = {appineuropsych20250213}, doi = {10.1176/appi.neuropsych.20250213}, pmid = {42026720}, issn = {1545-7222}, support = {T32 GM007748/GM/NIGMS NIH HHS/United States ; }, } @article {pmid42027125, year = {2026}, author = {Aiello, EN and De Luca, G and Curti, B and Torre, S and Gendarini, C and Cocuzza, A and Colombo, E and De Sandi, A and Mellace, D and Ferrucci, R and Barbieri, S and Maranzano, A and Verde, F and Messina, S and Doretti, A and Morelli, C and Silani, V and Ticozzi, N and Poletti, B}, title = {Prevalence and determinants of anxiety in amyotrophic lateral sclerosis.}, journal = {BJPsych open}, volume = {12}, number = {3}, pages = {e114}, pmid = {42027125}, issn = {2056-4724}, abstract = {BACKGROUND: Clinically relevant anxiety can be detected in patients with amyotrophic lateral sclerosis (ALS), but its prevalence and determinants have not yet been fully assessed.

AIMS: This study aimed at assessing the prevalence and clinical underpinnings of anxiety in ALS.

METHOD: Non-demented ALS patients (N = 433) and healthy controls (N = 313) were administered the State- and Trait-Anxiety Inventory - Form Y (STAI-Y1 for state-anxiety and STAI-Y2 for trait-anxiety) and the Beck Depression Inventory (BDI). Patients were further assessed for cognition (Edinburgh Cognitive and Behavioural ALS Screen), behaviour (Frontal Behavioural Inventory) and motor status (disease duration, ALS Functional Rating Scale-Revised and progression rate). The prevalence of clinically significant state- and trait-anxiety were estimated by applying age-stratified cut-offs to STAI-Y1/-Y2 t-scores. Linear and logistic regressions were run to test the determinants of STAI-Y1/-Y2 scores.

RESULTS: STAI-Y1 and -Y2 scores above cut-off were detected in 18.2 and 13.9% of patients, respectively - with proportions being higher in cases versus controls (ps < 0.001). BDI, but neither cognitive/behavioural nor motor variables, was identified as a significant predictor of STAI-Y1/-Y2 scores (ps < 0.003). The cognitive-affective subscale of BDI was the sole predictor of scores above cut-off on both STAI-Y1 and STAI-Y2 (ps < 0.001).

CONCLUSIONS: Clinically significant levels of state- and trait-anxiety occur in ∼18 and ∼14% of non-demented ALS patients, respectively, mostly driven by cognitive and affective facets of depression, and are independent of motor and cognitive/behavioural features.}, } @article {pmid42029573, year = {2026}, author = {Kuroiwa, N and Sakaue, F and Miura, M and Go, A and Iwase, R and Iwata Hara, R and Sanjo, N and Ui-Tei, K and Yokota, T}, title = {Rational Design of a Multivalent RNA Combining Structural Motifs Tailored to Multiple Domains of Fused in Sarcoma for Potent Inhibition of Aggregation.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {27}, number = {8}, pages = {e202500568}, doi = {10.1002/cbic.202500568}, pmid = {42029573}, issn = {1439-7633}, support = {KKCS20220502009//Kyowa Hakko Kirin/ ; }, mesh = {*RNA-Binding Protein FUS/metabolism/chemistry/antagonists & inhibitors ; *RNA/chemistry/pharmacology/metabolism/chemical synthesis ; Humans ; G-Quadruplexes ; Protein Aggregates/drug effects ; Protein Domains ; }, abstract = {Fused in sarcoma (FUS) is an RNA-binding protein whose pathological aggregation, driven by aberrant phase separation, is implicated in amyotrophic lateral sclerosis (ALS). Although RNA molecules can modulate the FUS phase behavior, identifying highly effective sequences remains challenging because of FUS's multiple low-specificity RNA-binding domains. In this study, we rationally designed a 65-mer RNA, U1'+TERRA, by combining a stem-loop-GGU motif and a G-quadruplex (G4) structure, each known to interact with distinct FUS domains. U1'+TERRA exhibited strong binding affinity and effectively inhibited FUS aggregation in vitro. We introduced 2'-O-methyl modifications, generating (U1'+TERRA)-2'-OMe, which retained structural integrity and demonstrated resistance to nuclease degradation to enhance biological stability. Notably, (U1'+TERRA)-2'-OMe suppressed FUS aggregation even at a low concentration. These findings suggested that multivalent RNA constructs with rationally arranged motifs can serve as potent inhibitors of FUS aggregation. Our approach highlights the potential of structure-guided RNA engineering for the development of nucleic acid therapeutics targeting RNA-binding proteins involved in neurodegenerative diseases, such as ALS.}, } @article {pmid42029829, year = {2026}, author = {Bordoni, M and Scarian, E and Messa, L and Garofalo, M and Jacchetti, E and Raimondi, MT and Diamanti, L and Gagliardi, S and Carelli, S and Cereda, C and Pansarasa, O}, title = {Development and characterization of 3D spinal cord organoids to advance the study of amyotrophic lateral sclerosis.}, journal = {Molecular biomedicine}, volume = {7}, number = {1}, pages = {}, pmid = {42029829}, issn = {2662-8651}, support = {Starting Grant//BraYn Association/ ; RC2025-2027//Ministero della Salute/ ; }, } @article {pmid42030003, year = {2026}, author = {Arslan, HN and Bozkul, G and Çelik, SŞ}, title = {Emotional, Ethical and Cultural Challenges in Percutaneous Endoscopic Gastrostomy (PEG) Decision-Making: A Systematic Review and Meta-Synthesis.}, journal = {Health expectations : an international journal of public participation in health care and health policy}, volume = {29}, number = {2}, pages = {e70294}, pmid = {42030003}, issn = {1369-7625}, support = {//The authors received no specific funding for this work./ ; }, mesh = {Humans ; *Gastrostomy/psychology/methods/ethics ; *Decision Making/ethics ; *Emotions ; Qualitative Research ; }, abstract = {BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is a critical intervention for patients with neurological and gastrointestinal conditions affecting oral intake. While clinical guidelines emphasise medical indications, they often overlook the intricate emotional, ethical and cultural concerns that shape decision-making. This gap in understanding leads to variability in clinical recommendations and uncertainty among patients and their families. A deeper exploration of these factors is necessary to support informed, patient-centred decision-making.

AIM: This systematic review and meta-synthesis aimed to explore the emotional, ethical and cultural challenges influencing PEG decision-making, while also considering the broader context of shared decision-making.

DESIGN: A systematic review and meta-synthesis of qualitative studies.

METHODS: The review was conducted by systematically searching six databases, including CINAHL, Scopus, Web of Science, MEDLINE, PubMed and TRDizin. Only qualitative studies published between 2004 and 2024 were included to capture subjective experiences related to PEG decision-making. Studies focusing only on clinical outcomes or utilising quantitative methodologies were excluded. The review considered perspectives from adult patients, family members, caregivers and healthcare professionals while paediatric studies were excluded due to differences in decision-making dynamics. Data were synthesised using thematic analysis to organise findings into main themes and sub-themes.

RESULTS: A total of 15 studies representing a variety of clinical settings and patient conditions, such as amyotrophic lateral sclerosis, advanced dementia and stroke, were included. These studies involved 141 patients (41.1%), 62 caregivers (18.1%) and 140 healthcare professionals (40.8%), ensuring a comprehensive analysis of perspectives on PEG decision-making. Seven major themes were identified: (1) emotional and psychological impact of decision-making, (2) ethical and moral considerations both patients and caregivers, (3) communication challenges and information gaps, (4) impact of healthcare professionals on decision-making, (5) ethical and emotional challenges in decision-making, (6) communication barriers and conflicting advice and (7) professional responsibility and advocacy. Family members and caregivers reported feelings of anxiety, guilt and regret, often due to uncertainty and inadequate communication. Healthcare professionals also faced challenges, including conflicting messages and a lack of comprehensive information.

CONCLUSION: Emotional, ethical and cultural factors significantly impact the PEG decision-making process involving patients, caregivers and healthcare professionals. Improving healthcare professionals' communication skills, developing decision aids and encouraging interdisciplinary collaboration are crucial for supporting informed and shared decision-making.

IMPLICATIONS FOR NURSING: Nurses play a central role in the PEG decision-making process, as they are the healthcare professionals with the most frequent and direct contact with patients and their family support networks. Addressing the gaps in communication and emotional support can help improve the quality of care provided to patients undergoing PEG. Implementing structured emotional support programmes, integrating psychological counselling into routine care and training healthcare professionals in empathetic communication strategies can significantly reduce patient and caregiver distress. Beyond providing clinical care, nurses act as essential advocates, educators and emotional support providers, ensuring that patients and families receive clear, consistent and compassionate guidance throughout the decision-making process. Their involvement in interdisciplinary collaboration and shared decision-making frameworks is crucial for aligning PEG decisions with patient values and preferences.

This review synthesised findings from studies capturing the experiences of patients, families, caregivers and healthcare professionals involved in PEG decision-making, ensuring their perspectives were represented.}, } @article {pmid42030149, year = {2026}, author = {Varela, V and Garcimartín, S and Trias, E and Zeida, A and Richter, M and de León, A and Miquel, E and King, PH and Vulliez-Le Normand, B and Martinez, M and Alzari, PM and Bartesaghi, S and Radi, R and Barbeito, L}, title = {Monoclonal antibodies against nitrated nerve growth factor reveal an oxidation-dependent pathogenic hallmark in ALS.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {17}, pages = {e2536562123}, pmid = {42030149}, issn = {1091-6490}, support = {EI_2020//Universidad de la República Uruguay (UdelaR)/ ; CSIC I + D _ 2022//UdelaR | Comisión Sectorial de Investigación Científica (CSIC)/ ; CSIC I _ 2023//UdelaR | Comisión Sectorial de Investigación Científica (CSIC)/ ; }, mesh = {Animals ; *Nerve Growth Factor/immunology/metabolism/chemistry ; *Antibodies, Monoclonal/immunology/chemistry ; *Amyotrophic Lateral Sclerosis/immunology/metabolism/pathology ; Humans ; Oxidation-Reduction ; Motor Neurons/metabolism/pathology ; Mice ; Epitope Mapping ; Rats ; }, abstract = {Nerve growth factor (NGF) is a member of the neurotrophin family, essential for neuronal survival and phenotypic maintenance. However, in vitro, its function can be disrupted by oxidative posttranslational modifications such as tyrosine nitration. Nitrated NGF (NO2NGF) has been shown to have a gain-of-toxic, pro-apoptotic, activity in motoneuron cultures. Herein, we report the generation and characterization of monoclonal antibodies (mAbs) that specifically recognize NO2NGF to unravel its formation in vivo. Using hybridoma technology, we produced mAbs with high affinity and selectivity for NO2NGF, as demonstrated immunochemically and by surface plasmon resonance. The antibodies elicit neutralizing capacity to NO2NGF in neuronal cells. Nitrated Tyr52 within the NGF48-58 sequence was identified as the primary antigenic determinant by crystallographic analysis of antibody:peptide complexes at atomic resolution, peptide-based epitope mapping and molecular dynamics simulations, whereas local sequence NGF motifs around the nitrated tyrosine are important for protein specificity. The antibodies revealed NO2NGF accumulation in amyotrophic lateral sclerosis (ALS) rodent models and human subjects. Indeed, immunofluorescence showed selective accumulation of NO2NGF in spinal cord regions undergoing motor neuron degeneration, as well as in sciatic nerves and neuromuscular junctions. Our findings establish NGF nitration as an oxidative hallmark in ALS and demonstrate that monoclonal antibodies targeting this chemical modification are powerful tools for both mechanistic studies and biomarkers development. This work proposes a link between neurotrophin nitration and neurodegenerative disease progression and opens avenues for therapeutic exploration along the peroxynitrite-tyrosine nitration pathway.}, } @article {pmid42031063, year = {2026}, author = {Shi, C and Jia, K and Guo, Y and Qian, S and Wang, B and Qiu, Y and Dan, L and Dang, Z and Xue, K and Gao, F and Zhao, L}, title = {Disulfidptosis in neurodegenerative diseases: From redox imbalance to neuronal dysfunction.}, journal = {Behavioural brain research}, volume = {509}, number = {}, pages = {116242}, doi = {10.1016/j.bbr.2026.116242}, pmid = {42031063}, issn = {1872-7549}, mesh = {*Disulfidptosis/physiology ; *Neurodegenerative Diseases/metabolism/physiopathology ; Humans ; Animals ; *Neurons/metabolism ; Oxidation-Reduction ; Oxidative Stress/physiology ; }, abstract = {Disulfidptosis is a recently identified form of regulated cell death driven by disulfide stress and cytoskeletal collapse under conditions of impaired reducing capacity. Neurodegenerative diseases (NDs), including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by oxidative stress, mitochondrial dysfunction, metabolic impairment, protein aggregation, and cytoskeletal instability-features that may provide a permissive intracellular context for disulfidptosis. However, its occurrence and pathological relevance in these disorders remain incompletely understood. In this review, we examine the potential involvement of disulfidptosis in neurodegenerative diseases from a disease-centered perspective. We emphasize that current evidence is largely indirect and based on mechanistic overlap rather than direct experimental validation in neural systems. Accordingly, we distinguish between direct evidence, indirect mechanistic support, and pathophysiological plausibility. We further discuss cell-type-specific susceptibility across neurons and glial cells, analyze its relationship with other cell death pathways, and consider potential therapeutic implications. Overall, disulfidptosis is best regarded as a context-dependent and emerging mechanism that may contribute to neuronal vulnerability under specific metabolic and redox constraints. Clarifying its disease relevance will be essential for determining its significance in neurodegeneration and its potential as a therapeutic target.}, } @article {pmid42031611, year = {2026}, author = {Etik, DÖ and Dişibeyaz, S and Özmert, EH}, title = {Pancreatitis due to afferent loop syndrome: A case report and a brief review of the literature.}, journal = {Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology}, volume = {27}, number = {3}, pages = {438-442}, doi = {10.1016/j.ajg.2026.02.003}, pmid = {42031611}, issn = {2090-2387}, mesh = {Humans ; Male ; *Afferent Loop Syndrome/complications/diagnosis ; Adult ; *Pancreatitis/etiology/diagnosis/therapy ; Gastric Bypass/adverse effects ; Gastrectomy/adverse effects ; Abdominal Pain/etiology ; Diagnosis, Differential ; }, abstract = {Afferent loop syndrome (ALS) should be a part of the differential diagnosis in a patient with acute pancreatitis with a history of gastric surgery. Although it is a rare clinical entity, association of ALS with acute pancreatitis can lead to poor clinical outcomes. Herein, we report the case of a 41-year-old man with a history of subtotal gastrectomy and Roux-en-Y gastric bypass who presented with abdominal pain and tenderness. Treatment of choice in this case was purely medical. A brief review of similar cases in the literature highlights the wide array of etiologies of acute pancreatitis due to ALS and reveals a broad spectrum of treatment options from medical to surgical.}, } @article {pmid42032949, year = {2026}, author = {Sipilä, J and Solje, E and Ahola, S and Surakka, L and Jokela, M}, title = {Death certificate data of patients with amyotrophic lateral sclerosis in easternmost Finland.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2026.2662015}, pmid = {42032949}, issn = {2167-9223}, abstract = {Objective: Topical data on causes of death and death certificate (DC) accuracy in patients with amyotrophic lateral sclerosis (ALS) are constantly needed. Methods: Data on a previously published ALS cohort from North Karelia in easternmost Finland was updated by extracting DC information from the electronic health records. Results: Death certificate data were available for 91% of the deceased. In all cases, ALS had been coded as a cause of death. In four cases, it had been inserted as a contributory cause of death. In three cases, ALS was indicated but incorrect coding was used. Three of the four cases in which ALS had not been deemed the underlying or immediate cause of death were cardiovascular deaths. One or more contributory causes of death had been recorded in 28% of DCs (54% of these were cardiovascular disorders), although comorbidities had not always been coded in the DC. In individual cases, the death had been sudden and unexpected, resembling a cardiovascular death, but this had not been coded. Conclusion: Finnish DC data remain a very reliable data source for ALS epidemiology, albeit with the caveat that data need to be obtained rigorously. Comorbidities are incompletely recorded as may be some immediate causes of death.}, } @article {pmid42033202, year = {2026}, author = {Yusuf, S and Allen, MD and Kang, H and Phillips, DE and Genge, A}, title = {Opportunities and challenges related to participant stratification and cohort enrichment in ALS clinical trials.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2659128}, pmid = {42033202}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is marked by substantial clinical heterogeneity. This heterogeneity has impacted clinical trials by obscuring treatment effects and causing inefficiency. In this review, we summarize potential approaches for addressing heterogeneity in ALS via patient stratification and cohort enrichment methods and highlight potential challenges and limitations. These categories include stratification based on genetics, clinical characteristics (e.g. pattern of weakness, ALS Functional Rating Scale rates of progression), wet biomarkers (e.g. neurofilament light chain), neuroimaging, and novel methods employing statistical modeling or machine learning. These stratification methods have yet to be fully leveraged in clinical trial design. But these strategies must be employed thoughtfully and judiciously due to potential issues stratification can introduce. Future clinical trials should explore how participant stratification and cohort enrichment strategies may improve our ability to identify treatment effects, which may ultimately aid in the quest to establish more personalized medicine for persons with ALS.}, } @article {pmid42033225, year = {2026}, author = {Barber, HM and Parasrampuria, MA and Jurado-Arjona, J and Gamir-Morralla, A and Berninger, B and González, C and Gagnon, KT and Damha, MJ and Garavís, M}, title = {Direct targeting of C9ORF72 repeat RNA with fluorinated antisense oligonucleotides.}, journal = {Nucleic acids research}, volume = {54}, number = {8}, pages = {}, pmid = {42033225}, issn = {1362-4962}, support = {MSCA-IF-799693//European Union Marie Skłodowska-Curie Actions/ ; MSCA-IF-841260//European Union Marie Skłodowska-Curie Actions/ ; MSCA-IF-750624//European Union Marie Skłodowska-Curie Actions/ ; RYC2023-043599-I//CSIC/ ; 1R01GM135646-01/NH/NIH HHS/United States ; #2022-03372//Natural Sciences and Engineering Research Council of Canada/ ; PID2023-146366NB-I00//Ministerio de Ciencia e Innovación/ ; P2024-02-015//ERA-NET Neuron/ ; //Fonds de Recherche du Québec/ ; }, mesh = {Humans ; *Oligonucleotides, Antisense/chemistry ; *C9orf72 Protein/genetics ; *Fluorine/chemistry ; *DNA Repeat Expansion ; *RNA/chemistry/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Nucleic Acid Conformation ; }, abstract = {Hexanucleotide repeat expansions in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. These expansions give rise to pathogenic sense and antisense repeat RNAs that form nuclear foci and undergo repeat-associated non-AUG translation, producing dipeptide repeat proteins with cellular toxicity. Directly targeting the causative repeat RNAs with antisense oligonucleotides represents a promising therapeutic strategy. One barrier to further development is the propensity of this G-rich repeat-containing RNA target to form stable secondary structures, which may hinder efficient hybridization. In this study, we designed a panel of fluorine-modified ASOs that target the sense repeat expansions. We identified C-rich F-ASO gapmers that reduced translation from sense repeat RNAs in a cell-based reporter assay and lowered the RNA foci burden in patient-derived cells. Structural analyses in vitro revealed that the 2'F-RNA gapmer formed a stable hairpin structure. Our results demonstrate that structural properties of fluorine modifications can be leveraged for effective binding of repeat RNA and highlight the potential for F-ASOs to serve as therapeutic tools when targeting toxic repeat RNAs in C9ORF72-mediated FTD/ALS and other repeat expansion diseases.}, } @article {pmid42033865, year = {2026}, author = {Wang, F}, title = {Polyphenols and physical activity stimulate gut microbiota mediated Nrf2 signaling to combat neurodegeneration.}, journal = {Pathology, research and practice}, volume = {283}, number = {}, pages = {156478}, doi = {10.1016/j.prp.2026.156478}, pmid = {42033865}, issn = {1618-0631}, mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Polyphenols/pharmacology ; Signal Transduction/drug effects ; Animals ; *Gastrointestinal Microbiome/drug effects/physiology ; *Neurodegenerative Diseases/metabolism/prevention & control/microbiology ; *Exercise/physiology ; Oxidative Stress ; }, abstract = {Polyphenols and regular physical activity are increasingly recognized as complementary lifestyle interventions that influence the gut-brain axis and contribute to neuroprotection. Emerging evidence highlights the central role of the gut microbiota in mediating these effects by transforming dietary and host-derived substrates into bioactive metabolites. These metabolites can activate the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, a key regulator of cellular antioxidant defenses, mitochondrial function, and anti-inflammatory responses processes that are critically impaired in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review synthesizes current mechanistic insights into how polyphenol-derived metabolites and exercise-induced alterations in gut microbial composition converge to modulate Nrf2 signaling. We discuss the roles of key microbiota-derived metabolites, including short-chain fatty acids, urolithins, and indole derivatives, in regulating oxidative stress, neuroinflammation, and synaptic function. Furthermore, we examine evidence from preclinical models supporting the synergistic effects of dietary polyphenols and physical activity on gut microbiota-mediated neuroprotection. Finally, we address translational challenges and highlight the potential of integrating dietary and exercise-based strategies to harness microbiota-dependent Nrf2 activation. This integrative framework provides a basis for developing personalized, microbiome-informed interventions aimed at delaying or mitigating neurodegeneration.}, } @article {pmid42034127, year = {2026}, author = {Ghaderi, S and Mohammadi, S and Kalra, S and Batouli, SAH}, title = {Functional adaptive longitudinal reorganization of superior parietal lobule networks in amyotrophic lateral sclerosis: Evidence suggesting compensatory mechanisms.}, journal = {Brain research bulletin}, volume = {240}, number = {}, pages = {111900}, doi = {10.1016/j.brainresbull.2026.111900}, pmid = {42034127}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Female ; Male ; *Parietal Lobe/physiopathology/diagnostic imaging ; Magnetic Resonance Imaging/methods ; Middle Aged ; Aged ; *Nerve Net/physiopathology/diagnostic imaging ; Longitudinal Studies ; Brain Mapping/methods ; Neural Pathways/physiopathology ; Adult ; Neuronal Plasticity/physiology ; }, abstract = {PURPOSE: To investigate longitudinal changes in resting-state functional connectivity (rs-FC) of the superior parietal lobule (SPL) in limb-onset amyotrophic lateral sclerosis (ALS).

METHODS: Resting-state fMRI was used to compare SPL connectivity between 14 ALS patients and 14 healthy controls (HCs) at baseline and during a 5-month follow-up (n = 10 ALS patients). Imaging sequences were acquired using a 3-Tesla scanner equipped with a 64-channel head coil. The data were preprocessed and analyzed using CONN and SPM12, employing FDR correction (p < 0.05) to identify significant resting-state functional connectivity (rs-FC) alterations.

RESULTS: ALS patients showed significant FC alterations in both right and left SPL compared to HCs. At baseline, the right SPL exhibited increased FC with the right Lateral Visual Network, Medial Visual Network (MVN), right Occipital Fusiform Gyrus (OFG), and left Lingual Gyrus (LG). At follow-up, these increases persisted and expanded, notably to the Occipital Visual Network and left LVN. For several connections, including the right OFG and MVN, the corresponding beta values were descriptively larger at follow-up than at baseline. Conversely, at follow-up, the right SPL showed decreased FC with the left Salience Network (SN). The left SPL showed no baseline changes but, at follow-up, exhibited increased FC with visual networks and the Default Mode Network, alongside decreased FC with the SN.

CONCLUSION: These findings may be suggestive of adaptive reorganization of SPL-related brain networks in response to neurodegeneration in ALS.}, } @article {pmid42035155, year = {2026}, author = {Pedde, M and Adar, SD and Jang, DG and Feldman, EL and Goutman, SA}, title = {Air pollution and mortality in a University of Michigan amyotrophic lateral sclerosis cohort: a survival analysis.}, journal = {Environmental health : a global access science source}, volume = {25}, number = {1}, pages = {}, pmid = {42035155}, issn = {1476-069X}, support = {R01TS000327/TS/ATSDR CDC HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/mortality ; Humans ; Michigan/epidemiology ; *Air Pollutants/analysis/adverse effects ; *Air Pollution/adverse effects/analysis ; Female ; Particulate Matter/analysis/adverse effects ; Male ; Middle Aged ; Survival Analysis ; Prospective Studies ; Aged ; *Environmental Exposure/adverse effects ; Nitrogen Dioxide/analysis ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare, fatal, neurodegenerative disease. With limited treatment options, identifying modifiable risk factors that impact ALS survival is an important goal. Air pollution may be one such risk factor, yet the research on this topic is limited. METHODS: We assessed survival for ALS patients at the University of Michigan Pranger ALS Clinic who were recruited to participate in a prospective cohort study between 2009 and 2022. Participants’ personal characteristics were linked with residential air pollutant levels of fine particulate matter mass (PM2.5), nitrogen dioxide (NO2), and ozone (O3), as well as several particle components, including black carbon (BC), nitrate, sulfate, and sea-salt (as a negative control) over follow-up. To assess the role of air pollution on ALS mortality we used time-dependent Cox proportional hazards models with days from diagnosis as the time axis, adjusted for potential confounders and co-pollutants. RESULTS: Across the 1,276 total years of person-time during follow-up (2.7 ± 2.5 years per participant) there were 329 deaths. In fully adjusted multi-pollutant models, one interquartile range (IQR) (2.1 µg/m3) higher 1-year average PM2.5 was associated with a 66% (HR 1.66 per IQR; 95% CI 1.03–2.68) increase in the hazard of death. The other pollutants were not associated with death in participants with ALS . CONCLUSIONS: This finding suggests a seven month longer median survival for a 2.1 µg/m3 decrease in 1-year average PM2.5, which is significant given that ALS lacks a cure and that existing treatments only extend survival by a few months.}, } @article {pmid42035914, year = {2026}, author = {Li, F and Tao, S and Wang, S and Ren, T and Qiu, M and Xu, X}, title = {New Perspectives on oligodendrocytes: Guardians of iron homeostasis and defenders against ferroptosis.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2026.04.052}, pmid = {42035914}, issn = {2090-1224}, abstract = {BACKGROUND: Oligodendrocytes (OLs) play a pivotal role in preserving iron homeostasis within the central nervous system (CNS), as they harbor the largest cellular iron reservoir essential for myelination. However, this indispensable function places OLs at heightened risk of ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation. The susceptibility of OLs to ferroptosis has significant implications for CNS health, particularly in the context of neurodegenerative diseases where OL dysfunction exacerbates demyelination and accelerates disease progression.

AIM OF REVIEW: This review aims to systematically elucidate the mechanisms by which mature OLs balance their dual roles as guardians of iron homeostasis and defenders against ferroptosis. Furthermore, it aims to underscore the ramifications of impaired OL iron regulation in prominent neurodegenerative conditions and to investigate potential therapeutic interventions aimed at bolstering OL resilience.

Mature OLs employ a sophisticated, multi-layered defense system to maintain iron homeostasis and prevent ferroptosis, encompassing precise metabolic regulation of iron uptake and storage, alongside a specialized antioxidant network centered on selenoprotein synthesis. Disruption of this delicate balance renders OLs vulnerable in diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD), leading to a vicious cycle of OL death, iron dysregulation, and demyelination. Targeting OL iron homeostasis and anti-ferroptotic pathways through iron modulation, antioxidant reinforcement, or direct ferroptosis inhibition represents a promising strategy to promote remyelination and mitigating neurodegeneration.}, } @article {pmid42035928, year = {2026}, author = {Codron, P and Desquiret, V and Prunier, D and Amati-Bonneau, P and Nguefackngoune, V and Rapenne, C and Legoff, L and Cassereau, J and Procaccio, V}, title = {Analysis of mitochondrial DNA heteroplasmy in sporadic ALS suggests technical limitations rather than disease association.}, journal = {Neurobiology of disease}, volume = {224}, number = {}, pages = {107412}, doi = {10.1016/j.nbd.2026.107412}, pmid = {42035928}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *DNA, Mitochondrial/genetics ; *Heteroplasmy/genetics ; Female ; Male ; Middle Aged ; Aged ; High-Throughput Nucleotide Sequencing ; }, abstract = {Mitochondrial DNA (mtDNA) has received increasing attention in amyotrophic lateral sclerosis (ALS) following the recent report of recurrent low-heteroplasmy mtDNA variants in patients. Here, we performed mtDNA analysis on an independent cohort of 20 sporadic ALS patients using an in-house next-generation sequencing pipeline designed for diagnostics. Using standard filters, none of the previously reported low-heteroplasmy mtDNA variants were detected. These variants only appeared in the low-quality data and were present at similar rates in a large reference population without ALS, localizing to homopolymeric regions that are prone to sequencing errors. Our findings suggest that these low-level mtDNA variants are a result of the technical limitations of short-read next-generation sequencing rather than being associated with the disease.}, } @article {pmid42036021, year = {2026}, author = {Kim, YH and Jing, FZ and Brewer, JD and Demer, AM}, title = {Response to O'Neill et al's "Disparities in melanoma survival in Asian American and Pacific Islander patients: A Surveillance, Epidemiology, and End Results (SEER) program-based analysis".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {2}, pages = {e219-e221}, doi = {10.1016/j.jaad.2026.03.112}, pmid = {42036021}, issn = {1097-6787}, } @article {pmid42036719, year = {2026}, author = {Lin, CY and Hsieh, WC and Wang, SM}, title = {Poly-GR promotes ferroptosis-associated vulnerability in C9orf72-ALS.}, journal = {Cell & bioscience}, volume = {16}, number = {1}, pages = {}, pmid = {42036719}, issn = {2045-3701}, support = {MOST 111-2628-B-039- 006-MY3//National Science and Technology Council/ ; CMU114-MF-04//China Medical University, Taiwan/ ; }, abstract = {Ferroptosis, an iron-dependent form of oxidative cell death driven by uncontrolled lipid peroxidation, has been increasingly implicated in neurodegeneration. However, its involvement and the underlying regulatory mechanism in C9orf72-linked amyotrophic lateral sclerosis (ALS), the most common genetic form of the disease, remain incompletely understood. Here, we show that the arginine-rich dipeptide repeat protein poly-GR promotes ferroptosis-associated molecular and biochemical features in motor neuron-like NSC34 cells. Poly-GR expression significantly increased lipid peroxidation, intracellular ferrous iron, and reactive oxygen species, indicating a cellular environment permissive for ferroptotic vulnerability. Mechanistically, poly-GR suppresses the Nrf2/Slc7a11 antioxidant defense axis by reducing Nrf2 nuclear localization and its occupancy at the Slc7a11 promoter, resulting in decreased Slc7a11 transcription. Restoration of Nrf2 or Slc7a11 expression attenuated lipid peroxidation and oxidative stress, while the iron chelator deferiprone effectively reduced Fe[2+] accumulation and ferroptosis-associated injury. Functionally, poly-GR sensitized neuronal cells to erastin-induced ferroptotic stress-associated cell death, an effect reversed by Nrf2 or Slc7a11 overexpression and iron chelation. Together, these findings indicate that poly-GR disrupts redox homeostasis and iron metabolism to increase susceptibility to ferroptosis, highlighting the Nrf2/Slc7a11 pathway and labile iron regulation as potential therapeutic targets in C9orf72-associated ALS.}, } @article {pmid42037134, year = {2026}, author = {Classen, S and Del Mundo, J and Kulkarni, D and Prabhakar, S and Hicks, A and Hammel, M}, title = {BilboMD: a web-accessible SAXS and AlphaFold-guided modeling pipeline.}, journal = {Nucleic acids research}, volume = {54}, number = {W1}, pages = {W216-W225}, pmid = {42037134}, issn = {1362-4962}, support = {CA92584/CA/NCI NIH HHS/United States ; P30 GM124169/NH/NIH HHS/United States ; P30 GM124169/GM/NIGMS NIH HHS/United States ; //National Energy Research Scientific Computing Center/ ; //Office of Biological and Environmental Research/ ; DDR-ERCAP0031203//Department of Energy User Facility/ ; P01 CA092584/CA/NCI NIH HHS/United States ; //Advanced Research Projects Agency for Health/ ; }, mesh = {*Scattering, Small Angle ; *X-Ray Diffraction ; *Software ; Internet ; Molecular Dynamics Simulation ; Protein Conformation ; Models, Molecular ; Neutron Diffraction ; }, abstract = {BilboMD is a web-accessible platform that facilitates integrative modeling of flexible macromolecules using experimental small-angle X-ray and neutron scattering data. BilboMD combines a browser-based interface with high-performance back-end services hosted locally at the SIBYLS beamline and at the National Energy Research Scientific Computing Center (NERSC). BilboMD guides users through a workflow that includes preparing compatible input files, conformational sampling through molecular dynamics (MD) simulations, small-angle X-ray scattering (SAXS) fitting with FoXS, and establishing multi-state models with MultiFoXS. Input assistants (Inp Jiffy and PAE Jiffy) streamline the process of defining rigid and flexible regions for conformational sampling, including automatic inference from AlphaFold PAE matrices. All analyses are containerized to ensure reproducibility, with job metadata and provenance stored in a central database. By leveraging GPU-enabled MD engines, such as OpenMM (on NERSC resources), BilboMD significantly accelerates conformational sampling and expands the set of models used for SAXS fitting. The platform reduces technical barriers for non-specialists while providing API access for advanced users to automate and integrate with custom workflows. Thus, BilboMD democratizes ensemble-based SAXS modeling, accelerates high-throughput SAXS/small-angle neutron scattering analysis, and lays the groundwork for future integration of AI-driven structure prediction with experimental scattering data. It is freely available without a login requirement at https://bilbomd.bl1231.als.lbl.gov.}, } @article {pmid42037681, year = {2026}, author = {Wölk, SA and Prudlo, J and Walter, U and Patejdl, R}, title = {Augmented and prematurely occurring H-reflex recovery curve shows enhanced spinal network excitability in ALS patients when employing the double stimulation paradigm.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1790581}, pmid = {42037681}, issn = {1664-2295}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder in which motoneuron loss in the brain and spinal cord induces complex neuroplastic changes. Although these alterations hold considerable potential for clinical diagnosis and disease monitoring, they remain underutilized due to the lack of sensitive and non-invasive assessment methods. The H-reflex is a monosynaptic spinal reflex arc and represents the neurophysiological analog of the Achilles tendon reflex. A modified H-reflex double-stimulation paradigm enables differentiation of the temporal dynamics of spinal inhibitory and excitatory mechanisms. In ALS, this approach may provide clinically relevant insights into motor system dysfunction. Furthermore, this approach may contribute to a better understanding of the pathophysiology of spinal network plasticity associated with this disease, reflecting the complex interplay between spinal and supraspinal pathways. We assessed H-reflex recovery in 15 ALS patients and 82 non-ALS subjects, including 12 age-matched healthy controls (HC). The protocol included 14 interstimulus intervals (ISI) within a timeframe of up to one second. In contrast to the HCs, ALS patients exhibited recovery at ISIs of 30 or 50 ms. At interstimulus intervals ranging from 50 to 200 ms, the extent of recovery was significantly elevated in the ALS group compared to the age-matched HCs. ALS patients thus demonstrate heightened spinal network excitability as evidenced by an augmented and prematurely occurring H-reflex recovery measurement. These alterations likely reflect changes in neuronal network activity and can be attributed to modifications in both segmental spinal circuits and supraspinal regulatory pathways.}, } @article {pmid42037767, year = {2026}, author = {McGee, SB and Stanisheuski, S and Mehl, RA and Cooley, RB}, title = {Efficient and Site-Specific Incorporation of 3-Nitro-Tyrosine Into Recombinant Proteins in Escherichia coli.}, journal = {Bio-protocol}, volume = {16}, number = {8}, pages = {e5674}, pmid = {42037767}, issn = {2331-8325}, support = {R01 GM114653/GM/NIGMS NIH HHS/United States ; RM1 GM144227/GM/NIGMS NIH HHS/United States ; }, abstract = {3-nitro-tyrosine (nitroTyr) is one of numerous oxidative protein modifications implicated in diseases such as cardiovascular disease, cancer, and amyotrophic lateral sclerosis (ALS). Because of this, the ability to site-specifically encode nitroTyr into recombinant proteins is a powerful approach for studying these disease pathways. However, producing proteins with defined nitration sites is technically challenging due to the limitations of traditional chemical nitration via peroxynitrite, which lacks residue and site-specificity. Genetic code expansion (GCE) offers a solution by enabling precise incorporation of nitroTyr at designated TAG codons using engineered aminoacyl-tRNA synthetase/tRNA pairs from Methanocaldococcus jannaschii and Methanomethylophilus alvus. This protocol provides a reliable, optimized workflow for incorporating nitroTyr into proteins in E. coli using GCE. It guides users through key considerations in selecting cell lines, media conditions, and GCE systems to minimize off-target effects such as release factor 1 competition, near-cognate suppression, and chemical reduction of nitroTyr. The method is demonstrated using wild-type and TAG-containing superfolder GFP but is broadly applicable to other proteins of interest. Key features • This protocol offers a practical guide for the recombinant expression of proteins containing site-specific 3-nitro-tyrosine in E. coli. • These methods should be used to characterize the functional and structural consequences of site-specific tyrosine nitration on proteins without having to modify any other residues. • This protocol avoids the use of peroxynitrite as a method to nitrate proteins, which modifies all solvent accessible tyrosine residues to different extents. • Users are guided through the advantages and disadvantages of using different expression strains and genetic code expansion systems depending on specific needs.}, } @article {pmid42038083, year = {2026}, author = {MacMillan, C and Gogtay, N and Gibson, D and Qian, JJ and Sauve, WM and Shih, E}, title = {Psychometric evaluation of the DSM-5-TR-Level 1 Cross-Cutting Symptom Measure: transdiagnostic factor analysis in a real-world psychiatric outpatient sample.}, journal = {Frontiers in psychiatry}, volume = {17}, number = {}, pages = {1680352}, pmid = {42038083}, issn = {1664-0640}, abstract = {BACKGROUND: Dimensional approaches to psychiatric assessment are increasingly used to complement categorical diagnoses. The DSM-TR Level 1 Cross-Cutting Symptom Measure (DSM-XC) assesses symptoms across psychopathology domains, but its latent structure remains unexplored in large, real-world psychiatric outpatient populations, limiting guidance on how clinicians interpret and apply results.

METHODS: We analyzed real-world data from patients (N = 3,101) using the Osmind platform who completed the DSM-XC as part of measurement-based care (the systematic collection of patient-reported outcomes to guide clinical decision-making). Exploratory factor analysis was conducted in half of the sample, and confirmatory factor analysis tested two models in the remaining half: a 6-factor general model, a 5-factor bifactor model with a general psychopathology factor. A third confirmatory model based on Caspi et al's framework was also evaluated using the full sample.

RESULTS: The 6-factor general model identified domains of 'Mood', 'Anxiety', 'Depression', 'Psychosis', 'Substance Use', and 'Distress and Disconnection'. The 5-factor bifactor model demonstrated a strong general psychopathology factor. The Caspi-inspired model showed acceptable fit but weaker support for the specific dimensions. These results underscore the DSM-XC's capacity to capture both shared and domain-specific dimensions of psychopathology, highlighting its relevance for dimensional assessment.

CONCLUSION: By clarifying its latent structure, this study identified clinically meaningful symptom dimensions which helps facilitate interpretation and application of the DSM-XC in the real-world. As dimensional and measurement-based approaches continue to expand in psychiatry, clearer understanding of tools such as the DSM-XC may support their integration into clinical practice and future research.}, } @article {pmid42038869, year = {2025}, author = {Behroozinia, M and Khosrawi, S}, title = {Rehabilitation Interventions in Adults with Amyotrophic Lateral Sclerosis: A Review :.}, journal = {Galen medical journal}, volume = {14}, number = {}, pages = {e3708}, pmid = {42038869}, issn = {2322-2379}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common and rapidly devastating neurodegenerative disease, which causes impairment of motor neurons in the upper and lower limbs, as well as in the bulbar muscles among adults. This leads to progressive weakness of voluntary muscles. The median survival after the emergence of initial symptoms is typically three years. During this period, due to the worsening of general well-being and independence, patients and their caregivers experience significant emotional stress. Furthermore, there is currently no definitive treatment for ALS. Consequently, patients face various challenges associated with motor impairment, including mobility disturbances, respiratory dysfunction, speech difficulties, and limitations in activities of daily living. Therefore, rehabilitation plays a vital role as a component of multidisciplinary care for managing these issues and reducing the impact of the disease on patients and their families. It is considered the optimal choice for alleviating the discomfort of ALS patients until a curative treatment is discovered.This narrative review aims to provide an overview of different aspects of rehabilitation, including physical therapy, occupational therapy, speech therapy, and respiratory strategies focused on enhancing independence, functional abilities, and overall quality of life while minimizing disabilities and complications in patients coping with this debilitating condition.}, } @article {pmid42039076, year = {2026}, author = {Tao, Y and Xiao, M and Mofreh, SAM and Salem, S}, title = {The effect of EFL learners' identity on English speaking proficiency and autonomous learning skills among university students: the mediating role of speaking anxiety.}, journal = {Frontiers in psychology}, volume = {17}, number = {}, pages = {1773756}, pmid = {42039076}, issn = {1664-1078}, abstract = {INTRODUCTION: As a Foreign Language (EFL) learner identity constitutes a pivotal sociopsychological factor in higher education; however, empirical research on how learner identity relates to speaking proficiency (SP) and autonomous learning skills (ALS) remains limited, particularly regarding the affective mechanism through speaking anxiety (SA).

METHODS: Drawing on Identity Theory and the Affective Filter Hypothesis, the present study examined the effect of EFL learner identity, modeled as a second order latent construct indicated by identity belongingness (IDB) and identity expectations (IDE), on SP and ALS among 392 Chinese non-English major sophomores, and tested speaking anxiety (SA) as a mediator using structural equation modeling (SEM).

RESULTS: The results showed that overall learner identity significantly predicted both SP and ALS, and that SA served as a meaningful affective pathway, accounting for approximately 36% of the total effects on learning outcomes.

DISCUSSION: These findings highlight the importance of fostering an identity-supportive learning environment that reduces the "affective filter" and strengthens university students' oral communication and learner autonomy in EFL contexts.}, } @article {pmid42039423, year = {2026}, author = {Rout, SR and Kulke, M and Droemer, M and Wendel, M and Cheng, TC and Mauck, TA and Asgari, S and Nemec, AA and Shein, M and Sato, Y and Fukai, S and Witte, G and Tomko, RJ and Stengel, F and Zacharias, M and Schuetz, AK and Sakata, E}, title = {The vacuolar tauopathy-associated mutation D395G confers redox sensitivity to p97/VCP.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42039423}, issn = {2692-8205}, support = {R01 GM118600/GM/NIGMS NIH HHS/United States ; }, abstract = {The multifunctional AAA+ ATPase p97/VCP is a pivotal regulator of cellular proteostasis, extracting polyubiquitinated substrates from protein complexes or organelle membranes for proteasomal degradation. Mutations in p97 are linked to a broad spectrum of neurodegenerative disorders, including multisystem proteinopathy and amyotrophic lateral sclerosis. Here, we provide insights into the basis of dysfunction in p97[D395G], implicated in vacuolar tauopathy, using an integrated structural approach. The mutation destabilizes the interaction network in the transient ADP.Pi state previously identified in p97[WT] and alters the dynamics of the linker between the tandem ATPase domains, resulting in decreased ATPase activity. We further demonstrate that the D395G mutation sensitizes p97 to oxidative stress by enhancing C522 oxidation, thereby perturbing nucleotide binding in D2, and define the functional basis of this oxidative inactivation of p97. These findings reveal redox control as a key regulatory layer of the p97 ATPase cycle and provide a mechanistic framework for how oxidative stress contributes to p97-associated neurodegeneration.}, } @article {pmid42039583, year = {2026}, author = {Sowoidnich, L and Norman, AL and Gerstner, F and Siemund, JK and Buettner, JM and Pagiazitis, JG and Dreilich, V and Pilz, K and Tian, D and Sumner, CJ and Paradis, A and Mentis, GZ and Simon, CM}, title = {A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42039583}, issn = {2692-8205}, support = {R01 NS078375/NS/NINDS NIH HHS/United States ; R01 NS125362/NS/NINDS NIH HHS/United States ; R35 NS122306/NS/NINDS NIH HHS/United States ; }, abstract = {Motor neuron (MN) loss is a hallmark of neurodegenerative disorders, yet its assessment remains variable, confounding mechanistic and therapeutic interpretation. To address this, we conducted a systematic review and meta-analysis of spinal muscular atrophy (SMA) mouse studies, revealing 60% variability in reported MN loss, largely attributable to nonspecific spinal cord sampling. Using a whole-segment approach with tissue clearing, MN tracing, and multimodal imaging, we confirmed segment-dependent differences in MN counts. Common MN markers (SMI-32, Nissl) lacked specificity, whereas choline acetyltransferase (ChAT) provided robust labeling in murine and human spinal cords. Deep learning-based whole-mount segmentation enabled unbiased MN quantification and validated manual counts. Integrating analysis with computational modeling established segment sampling as a key driver of variability and revealed degeneration patterns: widespread MN loss in amyotrophic lateral sclerosis (ALS), selective MN loss in severe SMA, and preservation in mild SMA models. These findings establish a framework for reproducible MN quantification.}, } @article {pmid42040341, year = {2026}, author = {Rong, P and Heidrick, L and Pattee, G}, title = {Translation of surface electromyography into a clinically applicable objective bulbar assessment tool to improve measurement-based care in amyotrophic laterals sclerosis.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1784520}, pmid = {42040341}, issn = {1662-4548}, abstract = {OBJECTIVE: This study aims to translate surface electromyography (sEMG) into a clinically applicable, objective tool for assessing bulbar involvement in amyotrophic lateral sclerosis (ALS).

METHODS: A clinically grounded sEMG framework was developed, integrating a standardized, repeatable protocol with a novel analytic pipeline, to automatically extract 60 features from six craniofacial muscle groups during a set of motorically demanding but cognitively and linguistically less challenging oral diadochokinetic (DDK) tasks. Using this framework, 104 oral DDK recordings were acquired from 16 individuals with ALS-nine with overt bulbar symptoms (ALS+B) and seven without (ALS-B)-and 10 healthy controls (HCs). The sEMG features were clustered into 10 interpretable composite measures and validated by evaluating their (1) internal consistency using Cronbach's α ; (2) associations with standardized functional outcomes and a biomechanical metric-stiffness-via mediation analysis; (3) discriminatory efficacy in distinguishing ALS+B and ALS-B from HC, as well as from each other, using machine learning classifications; and (4) robustness to common nonmotor confounders, including age, sex, and cognitive-linguistic impairments, through a comparison of discriminatory performance before and after adjustment for these factors.

RESULTS: All composite measures exhibited (1) high internal consistency (Cronbach's α = 0.89 ± 0.071), (2) significant (or marginally significant) direct or stiffness-mediated indirect associations with the functional outcomes, and (3) consistently high discriminatory accuracy (0.82-0.85), both before and after adjustment for confounders.

CONCLUSION: The sEMG framework demonstrates strong potential as a reliable, valid, and robust objective tool to detect subclinical neuromuscular changes throughout the prodromal and symptomatic phases of bulbar involvement in ALS, while remaining resistant against disease-related cognitive-linguistic impairments and disease-unrelated confounders. This tool may augment standard clinical evaluations, enabling earlier detection of bulbar involvement and measurement-based care in ALS.}, } @article {pmid42040397, year = {2026}, author = {Maia, ME and Carvalho, M and Sousa Gomes, C and Arruda, M and Antunes de Magalhães, AJ and Farias, D}, title = {Plant-Derived Peptides with Neuroprotective Activity: Advances and Perspectives in the Prevention of Neurodegenerative Diseases.}, journal = {ACS omega}, volume = {11}, number = {15}, pages = {22458-22478}, pmid = {42040397}, issn = {2470-1343}, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, represent an increasing global public health challenge, driven by population aging and the lack of effective curative therapies. In this context, plant-derived peptides have emerged as promising bioactive compounds due to their multitarget neuroprotective properties and favorable safety profiles. This review provides a comprehensive overview of plant peptides with reported activity against neurodegeneration, highlighting their natural sources, biological activities, and mechanisms of action. Evidence from in vitro and in vivo models indicates that these peptides act through multiple complementary pathways, including attenuation of oxidative stress, modulation of neuroinflammation, regulation of apoptosis, preservation of mitochondrial function, and inhibition of toxic protein aggregation. Additionally, several peptides have been shown to enhance synaptic plasticity, modulate neurotransmission, and regulate ion channel activity, suggesting beneficial effects on neuronal communication and cognitive function. Some studies explored structural modifications, such as the introduction of specific residues or glycosylation, which have resulted in greater stability and enhanced efficacy against oxidative insults. Overall, plant-derived peptides demonstrate consistent neuroprotective effects and low toxicity; however, challenges related to the blood-brain barrier, bioavailability, and the understanding of molecular mechanisms must still be overcome to enable their clinical application.}, } @article {pmid42041525, year = {2026}, author = {Bertoni, G and Ristori, S and Monti, D}, title = {Immunosenescence and Inflammaging as Drivers of Neurodegeneration: Cellular Mechanisms, Neuroimmune Crosstalk, and Therapeutic Implications.}, journal = {Cells}, volume = {15}, number = {8}, pages = {}, pmid = {42041525}, issn = {2073-4409}, support = {DM 1557 11.10.2022//Next Generation EU/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/immunology/pathology/therapy ; *Immunosenescence/immunology ; Animals ; *Inflammation/immunology/pathology ; *Aging/immunology ; *Neuroimmunomodulation ; }, abstract = {Aging is accompanied by profound alterations in immune function, termed immunosenescence, and by a chronic, low-grade inflammatory state known as inflammaging. These processes are increasingly recognized as central drivers of age-related neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis and Multiple Sclerosis. In the central nervous system, senescent microglia and astrocytes lose their homeostatic and neuroprotective functions, while systemic immune aging and blood-brain barrier dysfunction further amplify neuroinflammation and impair protein aggregate clearance. This sustained pro-inflammatory environment promotes synaptic dysfunction, neuronal loss and cognitive decline. Here, we synthesize current knowledge of the mechanistic links among immunosenescence, inflammaging, and neurodegeneration, highlighting innate and adaptive immune dysregulation, mitochondrial impairment, and failed resolution pathways. We further discuss emerging therapeutic strategies, including senolytics, immunoceuticals, microbiome-based interventions and advanced drug delivery systems, aimed at restoring immune homeostasis and enhancing brain resilience. By integrating mechanistic and translational insights, this review provides a framework for developing novel interventions to target immune aging in neurodegenerative diseases.}, } @article {pmid42041567, year = {2026}, author = {Auburger, G and Kandi, AR and Vutukuri, R and Almaguer-Mederos, LE and Gispert, S and Sen, NE and Key, J}, title = {Astro-Versus Microglia-Enriched Transcriptomes from Aged Atxn2-CAG100-Knockin Mice Suggest Underlying Pathology of RNA Processing at Ribosomes, and Possibly at U-Bodies.}, journal = {Cells}, volume = {15}, number = {8}, pages = {}, pmid = {42041567}, issn = {2073-4409}, support = {AU96/21-1//Deutsche Forschungsgemeinschaft/ ; SFB1039//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Animals ; *Microglia/metabolism/pathology ; Mice ; *Transcriptome/genetics ; *Ribosomes/metabolism/genetics ; *Ataxin-2/genetics/metabolism ; *Aging/genetics/pathology ; }, abstract = {Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis type 13 (ALS13) are triggered by polyglutamine expansion in Ataxin-2 (ATXN2). To understand these neurodegenerative disorders at the molecular level, the brains of 10-month-old Atxn2-CAG100-knockin mice were analyzed as microglial, astroglial and neuronal fractions via global RNA sequencing. Data were validated by comparison with the spinal cord oligonucleotide microarray profile or filtered by RNA-seq consistency. Here, we show that the mutation causes a massive inflammatory response in microglia and a reciprocal loss of neuronal transcripts in glial fractions, suggesting severe synapse loss. Beyond these general neurodegenerative signs, we identify pathognomonic changes in the machinery for protein translation and RNA splicing. Glial fractions showed upregulation of Gpnmb (to 2082%), Cst7, Clec7a, Axl, Csf1, Lgals3, Lgals3bp, Slc11a1, and Usp18 as an unspecific neuroinflammatory signature, versus downregulation of axonal Nefh (to <19%), and synaptic Scn4b, Camk2b, Rab15, and Grin1 mRNAs correlating with circuit disconnection. In all fractions, reductions in Kif5a, Rph3a, and Cplx1 were noted versus disease-specific inductions of ribosomal subunits, presumably mirroring the partial loss-of-function of ATXN2 as RNA translation modulator. Selective accumulations of embryonic factors Rnu1b2 and Eef1a1 versus downregulation of adult Eef1a2 specify the mutation impact on splicing and translation elongation. As a potential underpinning of toxic gain-of-function, the proteostasis transcript Rnf213 appeared increased in astroglial and microglial fractions. These transcriptome data suggest altered ribosomal and spliceosome machinery, with massive microgliosis versus mild astrogliosis, at the core of SCA2 and ALS13.}, } @article {pmid42041816, year = {2026}, author = {Kleinerova, J and Tully, J and Lope, J and Tan, EL and Toomey, A and Siah, WF and Bede, P}, title = {Driving with Motor Neuron Disease: Disease-Specific Considerations, Multi-Domain Assessments and Support Strategies.}, journal = {Brain sciences}, volume = {16}, number = {4}, pages = {}, pmid = {42041816}, issn = {2076-3425}, support = {HRB JPND-Cofund-2025-3/HRBI_/Health Research Board/Ireland ; JPND - 2025 "Qual-Bulb-MND"//EU Joint Programme - Neurodegenerative Disease Research/ ; SFI SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; }, abstract = {Motor neuron diseases (MNDs) encompass a clinically heterogeneous group of neurodegenerative conditions with varying impact on dexterity, mobility, decision making, respiratory and bulbar dysfunction. While consensus best-practice recommendations exist for genetic screening, diagnostic work-up, pharmacological and respiratory management, disease-specific facets of driving safety, assessment approaches and intervention strategies to support patients for safe driving have not been comprehensively reviewed. MNDs have unique, phenotype-specific clinical features, which are distinct form other neuromuscular conditions which necessitate a careful and systematic approach to evaluate driving safety. While MNDs are primarily associated with progressive motor impairment, extrapyramidal, cerebellar, cognitive, behavioural, and respiratory manifestations of the disease also affect driving safety and necessitate comprehensive driving assessments and individualised strategies to enable patients to continue to drive. The majority of existing papers focus on amyotrophic lateral sclerosis, and low-incidence MND phenotypes, such as PLS, SBMA, PPS, are glaringly understudied from a driving safety perspective despite the relatively slower progression of these conditions. Beyond the review of specific aspects of driving in MNDs, the main objective of this review paper is to raise awareness of non-motor aspects of MNDs with regard to driving safety and to explore viable strategies to support patients to maintain their independence. Despite the considerable differences in driving regulations around the globe, there are core, disease-specific aspects of MND which are universal. The careful consideration of these clinical factors, comprehensive domain-by-domain assessments, and the implementation of practical, individualised adaptations may enable patients to continue driving safely, maintain their independence and enhance their quality of life.}, } @article {pmid42042751, year = {2026}, author = {Aguilera-Méndez, A and Aguilera-Manuel, K and Saavedra-Molina, A and Ríos-Chávez, P and Villafaña, S and Nieto-Aguilar, R and Godínez-Hernández, D and Ortega-Cuellar, D and Palomera-Sanchez, Z and Gauthereau-Torres, M}, title = {Alpha-Lipoic Acid and Biotin in Neurodegenerative Diseases: Convergent Mechanistic Insights from Preclinical Models to Clinical Perspectives.}, journal = {Neurology international}, volume = {18}, number = {4}, pages = {}, pmid = {42042751}, issn = {2035-8385}, support = {CIC-19443//CIC-UMSNH/ ; }, abstract = {BACKGROUND: Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, represent a major global health burden and share convergent pathogenic mechanisms, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, calcium imbalance, and neuronal loss. Despite advances in symptomatic management, effective disease-modifying therapies remain limited.

OBJECTIVES: This review aims to critically synthesize mechanistic, preclinical, and clinical evidence on α-lipoic acid and biotin as candidate neuroprotective agents in neurodegenerative diseases, with emphasis on shared signaling pathways, therapeutic potential, generally favorable safety profiles, and translational limitations.

METHODS: A narrative and integrative review was conducted, encompassing mechanistic studies, preclinical experimental models, and clinical trials and observational studies evaluating ALA and biotin in neurodegenerative diseases. The evidence was qualitatively analyzed with attention to biological plausibility, consistency across models, and clinical relevance.

RESULTS: ALA and biotin modulate key cellular pathways implicated in neurodegeneration, including mitochondrial metabolism, redox homeostasis, inflammatory signaling, and neurovascular function. Preclinical studies consistently report beneficial effects on mitochondrial efficiency, oxidative stress, and neuroinflammatory markers. In contrast, clinical evidence remains heterogeneous, with more extensive evaluation of biotin in progressive multiple sclerosis and more limited or exploratory findings for ALA across neurodegenerative disorders.

CONCLUSIONS: ALA and biotin exhibit mechanistic convergence across pathways relevant to neurodegeneration and generally favorable safety profiles. Although current evidence supports their biological plausibility as adjunctive or exploratory therapeutic strategies, clinical outcomes remain inconsistent and appear to be influenced by dosing regimens, disease stage at intervention, and endpoint selection. Well-designed clinical studies are required to define their efficacy, optimal dosing, and disease-specific applicability.}, } @article {pmid42043421, year = {2026}, author = {Cheng, T and Li, M and Yang, Y and Rao, Z and Yang, W}, title = {Glycolysis as a central pathological axis in neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {37}, number = {6}, pages = {577-591}, pmid = {42043421}, issn = {2191-0200}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Glycolysis/physiology ; Animals ; *Brain/metabolism/pathology ; Neurons/metabolism ; Energy Metabolism/physiology ; Astrocytes/metabolism ; Microglia/metabolism ; }, abstract = {Glycolysis is increasingly recognized as a pathological backbone in neurodegenerative diseases rather than merely an accompanying epiphenomenon. This article first delineates the division of metabolic labor among neurons, astrocytes, microglia, and oligodendrocytes in the brain, with particular emphasis on cell type-specific glycolytic flux, lactate shuttling, and an integrated brain-periphery framework of energy metabolism. It then systematically compares alterations in glucose uptake, glycolytic intermediates, and lactate metabolism across Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Wilson disease (WD), Huntington's disease (HD), and multiple sclerosis (MS), highlighting pronounced heterogeneity across cell types, disease stages, and brain regions. These metabolic disturbances encompass not only global cerebral hypometabolism and an energy crisis, but also compensatory hyperglycolysis and inflammation-associated metabolic reprogramming in astrocytes and microglia, and extend further to systemic metabolic phenotypes involving peripheral blood cells, muscle, and liver. The article summarizes recent methodological advances for characterizing glycolytic reprogramming, including fluorodeoxyglucose positron emission tomography (FDG-PET), hyperpolarized carbon-13 magnetic resonance spectroscopy(ˆ13C-MRS), metabolomics, single-cell and spatial transcriptomics, genetically encoded metabolic sensors, and Seahorse assays. In addition, potential therapeutic strategies are discussed, focusing on targets such as 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3), the astrocyte-neuron lactate shuttle (ANLS), microglial glycolysis and lactylation, as well as systemic metabolic modulation and nanodelivery approaches. Finally, key challenges are highlighted, including unclear causal relationships, biphasic and cell type-specific effects, insufficient brain-periphery integration, and the lack of standardized metrics, underscoring the need for longitudinal, multimodal, and stage-specific strategies to reposition glycolysis as a targetable therapeutic dimension in neurodegenerative diseases.}, } @article {pmid42043709, year = {2026}, author = {Umar, M and Franjieh, K and White, AL and Ward-Dones, E and Ismael, S and Roskey, RC and Courseault, J and Bix, GJ}, title = {Role of Folate Metabolism in Neurodegenerative Diseases: Insight from Experimental and Clinical Studies.}, journal = {Current nutrition reports}, volume = {15}, number = {1}, pages = {}, pmid = {42043709}, issn = {2161-3311}, mesh = {Humans ; *Folic Acid/metabolism ; *Neurodegenerative Diseases/metabolism ; Animals ; Oxidative Stress ; Folic Acid Deficiency/metabolism/complications ; Brain/metabolism ; Alzheimer Disease/metabolism ; Parkinson Disease/metabolism ; Homocysteine/metabolism ; Hyperhomocysteinemia/metabolism ; }, abstract = {PURPOSE OF REVIEW: Folate is a key regulator of one-carbon metabolism (OCM), which supports essential physiological processes, including DNA synthesis, repair, methylation, amino acid homeostasis, and redox balance. It is also crucial for brain health throughout life, from neural tube formation during early development to neurotransmitter synthesis, myelination, neuronal development, synaptic plasticity and cognitive function during later stages of life. Disruption of folate-mediated OCM (FOCM) can adversely affect brain health and contribute to neurodegeneration. In this review, we summarize current evidence linking FOCM dysregulation to neurodegenerative diseases, emphasizing disease-specific mechanisms and the therapeutic potential of modulating folate metabolism, as evidenced by experimental and clinical studies. RECENT FINDINGS: Disruption of FOCM can lead to oxidative stress, impaired methylation, excitotoxicity, and neuroinflammation, thereby contributing to neurodegenerative diseases. In Alzheimer’s disease, impaired FOCM promotes amyloid-β accumulation, tau pathology, cognitive decline, and vascular dysfunction, consistent with low folate and elevated homocysteine observed clinically, though supplementation outcomes remain mixed. In Parkinson’s disease, folate deficiency and hyperhomocysteinemia exacerbate motor deficits and dopaminergic neurodegeneration via oxidative stress, mitochondrial dysfunction, and NLRP3-mediated inflammation and combined folate and vitamin B12 supplementation may reduce levodopa-associated risks. Elevated homocysteine and aberrant FOCM have also been reported in Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Huntington’s disease and are associated with neuroinflammation, demyelination, neuronal loss, and severe disease phenotypes in these conditions. Overall, maintaining optimal folate levels may be a promising strategy to support brain health and reduce the risk of neurodegenerative disorders.}, } @article {pmid42043769, year = {2026}, author = {Raafat, MA and Al-Hasnaawei, S and Mousa, HM and Hanumanthayya, M and Sahoo, S and Prathiba, S and Singh, G and Sinha, A}, title = {The central role of mitochondrial dysfunction in neurodegeneration: implications for therapy.}, journal = {Molecular and cellular biochemistry}, volume = {481}, number = {8}, pages = {3215-3249}, pmid = {42043769}, issn = {1573-4919}, mesh = {Humans ; *Mitochondria/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; Animals ; Reactive Oxygen Species/metabolism ; DNA, Mitochondrial/metabolism ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, remain leading causes of disability and premature death. Although they present with distinct clinical phenotypes, they converge on several pathogenic processes. Among these, mitochondrial dysfunction has emerged as a key driver of neurodegeneration, encompassing impaired bioenergetic capacity, disturbed calcium handling, altered mitochondrial dynamics, insufficient mitophagy, and excessive production of reactive oxygen species (ROS). This review provides a focused synthesis of the ways in which mitochondrial pathology contributes to neurodegeneration across major neurodegenerative disorders and summarizes therapeutic strategies designed to target mitochondria. We outline disease-relevant mitochondrial abnormalities and connect them to neuronal loss, synaptic failure, and neuroinflammatory cascades, with particular attention to mitochondrial ROS and inflammatory signaling linked to mitochondrial DNA. The manuscript further evaluates current and emerging interventions, including mitochondria-targeted antioxidants, mitochondrial transfer/transplantation, exercise, dietary approaches, and nanotechnology-enabled delivery systems. For each strategy, we consider the mechanistic rationale, key preclinical findings, and barriers to translation. Across experimental models, many of these approaches confer measurable neuroprotection-often reflected by lower oxidative burden, stabilization of mitochondrial membrane potential, and partial restoration of ATP production. However, clinical findings have been inconsistent, suggesting that efficacy depends strongly on disease stage, patient heterogeneity, and the specific mitochondrial defect being targeted. By integrating mechanistic insights with therapeutic evidence, this review offers a structured perspective on shared and disease-specific features of mitochondrial dysfunction and highlights priorities for advancing mitochondria-centered interventions toward meaningful clinical benefit.}, } @article {pmid42044891, year = {2026}, author = {Spons, R}, title = {Reversible Dropped Head Syndrome Due to Olanzapine-Associated Cervical Dystonia in a Patient With C9orf72-Associated bvFTD Within the FTD-ALS Spectrum.}, journal = {Journal of movement disorders}, volume = {19}, number = {3}, pages = {341-343}, pmid = {42044891}, issn = {2005-940X}, } @article {pmid42045773, year = {2026}, author = {Rana, R and Mehan, S and Mukherjee, R and Khan, MDN and Das Gupta, G and Narula, AS}, title = {Caffeic Acid Phenethyl Ester Enhanced the Klotho/SIRT1/Nrf2/HO-1 Axis to Protect Against Methylmercury-Induced ALS-Like Neurodegeneration.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42045773}, issn = {1559-1182}, support = {DST-SERB, Govt. of India (Grant Number: CRG/2021/001009).//Science and Engineering Research Board/ ; }, mesh = {Animals ; *Caffeic Acids/pharmacology/therapeutic use ; *Phenylethyl Alcohol/analogs & derivatives/pharmacology/therapeutic use ; *NF-E2-Related Factor 2/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/chemically induced/prevention & control ; Male ; Klotho Proteins ; Methylmercury Compounds/toxicity ; *Sirtuin 1/metabolism ; *Glucuronidase/metabolism ; *Signal Transduction/drug effects ; Oxidative Stress/drug effects ; Antioxidants/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by motor neuron degeneration, oxidative stress, and neuroinflammation. This study evaluated the neuroprotective potential of caffeic acid phenethyl ester (CAPE) against MTME + 5-induced neurotoxicity in an ALS-like pathology model. CAPE (50 and 100 mg/kg., p.o.) demonstrated significant therapeutic efficacy by improving motor and cognitive deficits, restoring oxidative balance, and mitigating neuroinflammatory and apoptotic pathways. Behavioral assessments, including the open field, grip strength, forced swim, and Morris water maze, highlighted CAPE's ability to restore neuromuscular coordination and cognitive function in a dose-dependent manner. Cellular and Molecular analyses revealed that MTME[+]5 exposure significantly disrupted Klotho/SIRT-1/Nrf2/HO-1 antioxidant signaling, increased pro-inflammatory cytokines (TNF-α, IL-1β), and elevated apoptotic markers (Bax, caspase-3) while depleting anti-inflammatory cytokines (IL-10) and neuroprotective proteins. Furthermore, CAPE treatment restored these parameters, reduced oxidative stress, and enhanced antioxidant defenses (SOD, CAT, r-GSH). Furthermore, CAPE normalized neurotransmitter imbalances, including acetylcholine, dopamine, GABA, serotonin, and glutamate, alleviating excitotoxicity. Histopathological and gross morphological analyses confirmed CAPE50 and CAPE100 ability to preserve neuronal and myelin integrity across key brain regions, including the cerebral cortex, hippocampus, striatum, midbrain, and cerebellum. CAPE also reduced methylmercury accumulation in the brain and cerebrospinal fluid, indicating detoxifying effects. Co-administration of vitamin B1 (VTB1(200)) further amplified CAPE's therapeutic efficacy. Complete blood count (CBC) analysis demonstrated MTME[+]5-induced hematological abnormalities, including reduced RBCs, hemoglobin, WBCs, and platelets, alongside elevated eosinophils and basophils. CAPE treatment normalized these parameters, indicating systemic recovery. These findings establish CAPE as a promising neuroprotective agent for ALS, capable of targeting neurocomplications.}, } @article {pmid42046889, year = {2026}, author = {Martinez-Gonzalez, L and Sanchez-Santos, C and Huang, CS and Gil, C and Martinez, A}, title = {Innovative therapies under clinical development for ALS treatment: small molecules.}, journal = {Expert opinion on investigational drugs}, volume = {35}, number = {5}, pages = {351-367}, doi = {10.1080/13543784.2026.2667249}, pmid = {42046889}, issn = {1744-7658}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; *Drug Development/methods ; Clinical Trials as Topic/methods ; Precision Medicine/methods ; Patient Selection ; Molecular Targeted Therapy ; }, abstract = {INTRODUCTION: The clinical trial landscape for Amyotrophic Lateral Sclerosis (ALS) is a rapidly evolving field, characterized by significant obstacles but also by an increasing volume of novel therapeutics entering clinical research. Expanding on our 2022 work, this review examines the current state of the ALS clinical pipeline. Given the high volume of ongoing trials, the diversity of their biological targets and the nature of their therapeutic approaches, we focus this comprehensive update in providing a comprehensive overview of the current state of small-molecule development, focusing on agents that have entered or progressed through clinical evaluation since 2022 to the end of 2025.

AREAS COVERED: Clinical trials for ALS registered within the United States (ClinicalTrials.gov) and European Union (EU Clinical Trials Register/CTIS) databases have been systematically reviewed and are detailed in this report.

EXPERT OPINION: The implementation of advanced clinical trial platforms has introduced more efficient, adaptive strategies, leading to a significant increase in the breadth of explored therapies for ALS. Furthermore, the advent of precision medicine, powered by Artificial Intelligence (AI) for enhanced patient selection and stratification, offers a critical pathway toward overcoming the challenges posed by this severe and heterogeneous disease.}, } @article {pmid42047551, year = {2026}, author = {Zeng, Y and Qian, H and Zhao, H and Fu, M and Pan, L and Liu, M}, title = {LrGSTU181 Contributes to Glufosinate Resistance in the Multiple Resistant Lolium rigidum Populations.}, journal = {Journal of agricultural and food chemistry}, volume = {74}, number = {18}, pages = {14322-14334}, doi = {10.1021/acs.jafc.5c17635}, pmid = {42047551}, issn = {1520-5118}, mesh = {*Aminobutyrates/pharmacology ; *Herbicide Resistance ; *Herbicides/pharmacology ; *Plant Proteins/genetics/metabolism ; *Lolium/genetics/drug effects/enzymology/metabolism ; *Plant Weeds/drug effects/genetics/enzymology/metabolism ; *Glutathione Transferase/genetics/metabolism ; Cytochrome P-450 Enzyme System/metabolism/genetics ; Glyphosate ; Plants, Genetically Modified/genetics/drug effects ; }, abstract = {Glufosinate is increasingly applied alongside glyphosate to control glyphosate-resistant weeds, a practice that has led to emerging resistance issues. Here, glufosinate resistance was confirmed in two multiple-resistant Lolium rigidum (glyphosate, ALS- and ACCase inhibitors) populations, NLR70 and WALR70 (RIs of 4.47 and 2.17, respectively), with no target-site GS resistance mutations. GST and P450 inhibitor studies identified distinct mechanisms: NBD-Cl reversed glufosinate resistance in both populations, while malathion reversed resistance only in population NLR70. Resistance in population NLR70 involved both the overexpression of LrGS1-2 and LrGS2 and the upregulation of LrGSTU181, CYP94B3, and possibly other GSTs and P450s. Whereas in population WALR70, resistance likely involved LrGSTU181 and possibly other GSTs. Transgenic validation demonstrated that LrGSTU181 contributes to glufosinate resistance and clodinafop-propargyl. These findings suggest a possible preadaptation scenario wherein detoxification genes selected under long-term herbicide pressure contribute to the evolution of resistance to chemically distinct herbicides.}, } @article {pmid42047858, year = {2026}, author = {Hu, N and Liu, M and Cui, L}, title = {Slowly progressive amyotrophic lateral sclerosis associated with a rare SOD1 Pro67Arg mutation: a case report.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {5}, pages = {}, pmid = {42047858}, issn = {1590-3478}, } @article {pmid42049092, year = {2026}, author = {Liu, C and Meng, L and Zhang, Z}, title = {Physiological and pathological functions of TAF15 in neurodegenerative diseases and cancers.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2026.04.066}, pmid = {42049092}, issn = {2090-1224}, abstract = {BACKGROUND: TATA-box binding protein associated factor 15 (TAF15) is a multifunctional DNA/RNA-binding protein that plays pivotal roles in transcription regulation, precursor mRNA splicing, and cellular stress responses. Accumulating evidence demonstrates that TAF15 is strongly implicated in two distinct pathological classes: neurodegenerative diseases and cancers. In neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), TAF15 undergoes abnormal cytoplasmic aggregation and mislocalization in neurons and glia, and TAF15 has been established as a candidate disease gene for ALS. In a wide range of cancers, TAF15 drives oncogenic transcriptional dysregulation either via wild-type protein dysfunction or the formation of oncogenic fusion proteins derived from chromosomal translocations.

AIM OF REVIEW: A central unresolved question is how TAF15 contributes to two mechanistically distinct disease entities. This review aims to provide a mechanistically integrated analysis of the physiological and pathological functions of TAF15. We use TAF15's intrinsic molecular properties as a unifying framework to connect its roles in neurodegeneration and cancer. We also summarize key pathogenic mechanisms and emerging therapeutic strategies targeting TAF15, with the goal of proposing a novel conceptual perspective to guide future research. Key scientific concepts of review. TAF15 may act as a biologically relevant molecular link between neurodegeneration and cancer through its intrinsic molecular characteristics, such as nucleic acid binding, phase separation, and nucleocytoplasmic shuttling. The "localization determines outcome" hypothesis offers a unifying framework to explain the connection between the two diseases. TAF15 holds promise as a target for novel biomarkers and precision therapeutics across both disease areas. Deepening mechanistic studies of TAF15 will not only advance understanding of its dual pathological roles but also illuminate the largely unexplored molecular link between neurodegenerative diseases and cancers.}, } @article {pmid42049146, year = {2026}, author = {Senerchia, G and Iuzzolino, VV and Spisto, M and Panico, F and Polito, C and Aruta, L and Fiorenza, M and Sirica, R and Terracciano, D and Dubbioso, R}, title = {Plasma NfL, GFAP and pTau181 define distinct biological axes in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {224}, number = {}, pages = {107415}, doi = {10.1016/j.nbd.2026.107415}, pmid = {42049146}, issn = {1095-953X}, mesh = {Humans ; *Glial Fibrillary Acidic Protein/blood ; Male ; *Amyotrophic Lateral Sclerosis/blood/physiopathology/diagnosis ; Female ; *Neurofilament Proteins/blood ; Biomarkers/blood ; Middle Aged ; Aged ; *tau Proteins/blood ; Phosphorylation ; Motor Neurons/pathology ; }, abstract = {Amyotrophic lateral sclerosis is biologically heterogeneous, and blood biomarkers may reflect distinct pathological mechanisms. We investigated whether plasma neurofilament light chain (NfL), phosphorylated tau at threonine 181 (pTAU181), and glial fibrillary acidic protein (GFAP) capture complementary biological domains in amyotrophic lateral sclerosis. Plasma biomarkers were measured using a fully automated chemiluminescent immunoassay platform in patients with amyotrophic lateral sclerosis and control groups. Upper motor neuron burden was quantified using transcranial magnetic stimulation and the Penn Upper Motor Neuron Score. Lower motor neuron involvement was assessed by electromyography and Medical Research Council strength scores. Associations were tested using multivariable models adjusted for age, sex, disease progression rate, and phenotype. Latent profile analysis was applied to identify biomarker-defined subgroups. NfL levels increased with greater upper motor neuron burden across both neurophysiological and clinical measures. In contrast, pTAU181 selectively reflected lower motor neuron degeneration, particularly chronic denervation severity. GFAP levels were strongly associated with age and showed no relationship with motor neuron involvement. After adjustment for age and other covariates, higher GFAP levels were independently associated with behavioural lability. Biomarker levels did not differ across cognitive classes. Latent profile analysis identified three biologically distinct clusters characterized by selective pTAU181 elevation, progressive NfL increase, or prominent glial activation. Cluster membership independently predicted disease aggressiveness. These findings demonstrate that plasma NfL, pTAU181, and GFAP capture complementary biological processes in amyotrophic lateral sclerosis and support combined biomarker profiling for mechanistically informed patient stratification.}, } @article {pmid42049669, year = {2026}, author = {Vrana, KE}, title = {Are Cannabis and/or Cannabinoids a Potential Therapy for ALS?.}, journal = {Muscle & nerve}, volume = {74}, number = {1}, pages = {5-7}, doi = {10.1002/mus.70262}, pmid = {42049669}, issn = {1097-4598}, support = {R01 AT012053/AT/NCCIH NIH HHS/United States ; R01 AT012053/GF/NIH HHS/United States ; }, } @article {pmid42050008, year = {2026}, author = {Gascón, E and Calvo, AC and Zaragoza, P and Osta, R}, title = {Unveiling an ALS Blood Transcriptomic Signature: A Machine Learning Classifier Distinct from Neurodegenerative Controls.}, journal = {Neuroinformatics}, volume = {24}, number = {2}, pages = {}, pmid = {42050008}, issn = {1559-0089}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/diagnosis ; *Transcriptome ; *Machine Learning ; Biomarkers/blood ; Alzheimer Disease/blood/genetics ; Gene Expression Profiling ; Parkinson Disease/blood/genetics ; Female ; Male ; *Neurodegenerative Diseases/blood/genetics ; Classification Algorithms ; Predictive Learning Models ; }, abstract = {The absence of accessible and reliable biomarkers constitutes a critical barrier for the early diagnosis and stratification of neurodegenerative diseases. While peripheral blood offers a minimally invasive window into systemic pathophysiology, identifying molecular signatures that survive biological heterogeneity and technical noise remains an unresolved challenge. In this study, this issue was addressed through a comparative systemic transcriptomic analysis of Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease (AD), and Parkinson’s disease (PD) in whole blood, implementing a comprehensive workflow integrating unsupervised network analysis and supervised machine-learning methods. By employing LASSO regression and cross-validation across independent external cohorts, a stable and specific transcriptomic signature for ALS was identified, comprising key crosstalk genes involved in systemic immune dysregulation and microglial function, including CTSS, PTEN, IL18, PTPRC, and CSF1R. In contrast, AD and PD exhibited weak transcriptomic signatures with poor predictive reproducibility, suggesting a distinctive systemic pathology in ALS. In addition, the study confirms the superiority of linear modeling for this genomic signature: while complex non-linear algorithms, specifically Radial Basis Function (RBF) kernel Support Vector Machine (SVM) and Random Forest, displayed high initial performance, they collapsed due to overfitting during external validation. Conversely, the linear LASSO model demonstrated superior robustness and generalizability (AUC 0.74). In conclusion, this study not only defines a unique systemic immunotranscriptomic signature for ALS, distinguishable from other neurodegenerative pathologies, but also establishes interpretability and linear simplicity as essential factors for developing reproducible blood-based biomarkers with clinical translational potential.}, } @article {pmid42051098, year = {2026}, author = {Khan, N and Doshi, G}, title = {Zebrafish (Danio rerio) as a Model for Neurodegenerative Disease Research: Mechanisms, Biomarkers, and Translational Promise.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273442688260330060220}, pmid = {42051098}, issn = {1996-3181}, abstract = {Zebrafish (Danio rerio) have gained prominence as a versatile vertebrate model for studying neurodegenerative disorders due to their genetic similarity to humans, rapid development, transparency, and suitability for high-throughput drug screening. The usefulness of zebrafish in modelling human neurological disorders is supported by the similarity of their brains' anatomical and neurochemical characteristics, including comparable divisions of the forebrain, midbrain, and hindbrain, as well as dopaminergic, serotonergic, glutamatergic, and GABAergic pathways. Zebrafish have been used to successfully model several neurodegenerative diseases, including Alzheimer's disease (via tau phosphorylation and amyloid-beta aggregation), Parkinson's disease (via dopaminergic neuronal loss and alpha-synuclein pathology), Huntington's disease (via polyglutamine-expanded huntingtin), and amyotrophic lateral sclerosis (via mutant SOD1 and TDP- 43 transgenes). They have also been used to study multiple sclerosis, spinocerebellar ataxias, and Rett syndrome, enabling mechanistic exploration and preclinical drug discovery. This review crucially depicts how zebrafish models provide an affordable, morally acceptable, and scalable platform for early-stage neurodegeneration research. These models complement, rather than replace, rodent- and human-derived systems. Additionally, we will review how to bridge the gap between therapeutic screening and basic mechanistic findings, highlighting their increasing significance in the neuroscience research continuum.}, } @article {pmid42051315, year = {2026}, author = {Nolan, M and Aryal, S and Ndayambaje, IS and Cao, M and Lee, P and Hovde, M and Yun, S and Wlaschin, J and Held, A and Beaussant, H and Wymann, B and Zong-Lee, C and Lim, SM and Jiang, X and Ramesh, N and Agra Almeida Quadros, AR and Boulos, A and Zinter, N and Salem, S and El-Tayar, L and Beccari, M and Presa, M and Jourdan Ferreras Reyes, C and Ruan, YY and Griesman, G and Aguilar, C and Hawrot, J and Wheeler, H and Melamed, Z and Kleinstiver, BP and Albers, M and Cleveland, DW and Tanzi, RE and Lutz, CM and Hubbard, RD and Kobayashi, D and Ward, M and R R Alves, C and Wainger, B and Pichon, CL and Lagier-Tourenne, C}, title = {Statins and genetic inhibition of the mevalonate pathway activate an ATF3-STMN2 regenerative program.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42051315}, issn = {2692-8205}, support = {T32 AG066596/AG/NIA NIH HHS/United States ; DP2 CA281401/CA/NCI NIH HHS/United States ; R01 NS112503/NS/NINDS NIH HHS/United States ; RM1 NS133601/NS/NINDS NIH HHS/United States ; K01 NS134784/NS/NINDS NIH HHS/United States ; ZIA HD008966/ImNIH/Intramural NIH HHS/United States ; RF1 NS124203/NS/NINDS NIH HHS/United States ; }, abstract = {Loss of neuronal regenerative capacity is a common feature of neurodegenerative disease and axonal injury, yet the transcriptional programs governing this state remain poorly defined. Stathmin-2 (STMN2), a tubulin-binding protein essential for axon maintenance and repair, is profoundly depleted following loss of nuclear TDP-43 in neurodegenerative disease. Here, we identify statins as potent inducers of STMN2 expression. Pharmacological and genetic suppression of the mevalonate pathway, and subsequent prevention of protein geranylgeranylation, restored STMN2 levels in TDP-43 deficient cells and promoted neurite growth. STMN2 induction was abrogated when using a statin analogue unable to interact with HMG-CoA reductase, and through co-administration of mevalonate or geranylgeranyl diphosphate substrates. RNA-seq revealed that statins induce a coordinated pro-regenerative transcriptional response, including activation of the AP-1 transcription factor complex gene, ATF3. Loss of ATF3 attenuated STMN2 induction in vitro, and diminished injury-induced Stmn2 upregulation in spinal motor neurons in vivo. These results demonstrate statins as modulators of ATF3 and STMN2 expression and highlight their therapeutic potential in neurodegenerative disease.}, } @article {pmid42051550, year = {2026}, author = {Chakraborty, DK and Roy, T and Ngo, ST and Al-Chalabi, A and Al Khleifat, A}, title = {Gut microbiota and ALS: cause, consequence or correlation? - a systematic review.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1774417}, pmid = {42051550}, issn = {1662-4548}, abstract = {BACKGROUND: Gut microbiome disturbances have been proposed as contributors to amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disorder characterised by motor neuron loss, extra-motor symptoms, and rapid progression. Mechanistic links between dysbiosis, epithelial and blood-brain barrier dysfunction, metabolic imbalance, and immune activation have been suggested, but causality remains unresolved. We conducted a systematic review to evaluate the evidence supporting microbiome involvement in ALS pathogenesis.

METHODS: We searched PubMed, Medline, Embase, Scopus, Semantic Scholar, and Google Scholar (Nov 23, 2025) for human and ALS-relevant animal studies assessing bacterial microbiota, gut or blood-brain barrier integrity, microbial metabolites, or immune pathways. No language or date restrictions were applied. Studies were screened according to predefined criteria, and quality was assessed using QUADAS-2. Owing to the heterogeneity of study designs and sequencing approaches, findings were synthesised narratively.

FINDINGS: 61 of 2,397 studies met inclusion criteria. Across human cohorts, ALS was consistently associated with reduced microbial diversity, shifts in key taxa, and disruption of microbial pathways regulating short-chain fatty acids, nicotinamide metabolism, and inflammatory signalling. Several mechanistic animal studies demonstrated that microbiota manipulation, through antibiotics, faecal microbiota transfer, or supplementation with protective taxa, modulated motor function, microglial activation, gut permeability, and survival, indicating that dysbiosis can influence disease trajectories. Conversely, longitudinal human data showed that dysbiosis often emerged alongside worsening physical function, gastrointestinal dysmotility, weight loss, and changes in dietary intake, suggesting secondary effects of disease progression. Integrative multi-omics studies linked microbial alterations with systemic cytokine profiles, metabolic stress pathways, and CNS immune phenotypes, reinforcing a bidirectional gut-brain axis. However, the predominance of cross-sectional designs and small sample sizes substantially limits causal inference.

INTERPRETATION: Current evidence supports a model in which gut dysbiosis interacts with ALS via barrier failure, metabolic disruption, and immune dysregulation, but does not establish dysbiosis as a primary cause of disease. Preclinical findings highlight microbiome-derived mechanisms with disease-modifying potential, yet human data largely indicate association rather than initiation. Clarifying temporal relationships will require longitudinal, multi-modal studies, integration with pre-symptomatic cohorts, and controlled interventional trials. Microbiome-targeted therapies remain a promising but unproven avenue for ALS.}, } @article {pmid42051853, year = {2026}, author = {Eissazade, N and Nazemi, L and Haghi Ashtiani, B and Moradi-Lakeh, M}, title = {Neutrophil-to-lymphocyte ratio in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag132}, pmid = {42051853}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited diagnostic and prognostic biomarkers. The neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, has been proposed as a potential indicator. This systematic review and meta-analysis assesses the diagnostic and prognostic value of NLR in ALS. We searched PubMed, Scopus, Embase and Web of Science through June 2025 for peer-reviewed studies evaluating NLR in adults with ALS diagnosed by established criteria. Eligible studies reported validated measurements of NLR and diagnostic or prognostic outcomes. Two reviewers independently extracted data and assessed quality. Random-effects meta-analyses were performed, with heterogeneity, publication bias, evidence certainty and sources of heterogeneity evaluated using meta-regression. Sixteen studies from 12 countries including 357 044 participants met inclusion criteria, comprising 8710 ALS patients (mean age 60.3 years; 59.1% male) and 348 334 controls (mean age 57.8 years; 47.6% male). Meta-analysis of 11 studies showed a pooled mean NLR of 2.74 in ALS patients [95% CI (2.42, 3.10); I [2] = 95.4%], while three control studies yielded a pooled mean NLR of 1.94 [95% CI (1.55, 2.43); I [2] = 94.7%]. Comparison of three studies demonstrated a 35% higher NLR in ALS patients than controls [95% CI (1.03, 1.76); I [2] = 88.3%], with low certainty according to GRADE due to observational design and substantial heterogeneity. Elevated NLR was consistently associated with worse clinical outcomes, including faster disease progression, lower ALSFRS-r scores, reduced forced vital capacity, shorter survival and increased mortality. Pooled univariate analyses from four studies showed that higher NLR predicted mortality [HR = 1.16; 95% CI (1.04, 1.29); I [2] = 93.8%]. Multivariable-adjusted analyses from six studies confirmed NLR as an independent predictor of poorer survival (HR = 1.13; 95% CI (1.06, 1.21); I [2] = 86.5%), with heterogeneity modestly reduced after adjustment for age and sample size. Certainty of evidence for prognostic outcomes was rated low to moderate. Associations between higher NLR and age at onset, sex and classical ALS phenotype were inconsistent. NLR correlated with inflammatory markers and gut microbiota features, supporting a potential mechanistic link between systemic inflammation and ALS disease progression. Elevated NLR is associated with ALS diagnosis and poorer prognosis, including faster disease progression and reduced survival. Despite heterogeneity and potential bias, NLR appears to be a readily accessible biomarker for disease monitoring and risk stratification in ALS, warranting validation in large, longitudinal studies.}, } @article {pmid42051912, year = {2026}, author = {File, C and Price, AM and Ahmad, R and Shanina, E and Sun, RL}, title = {Amyotrophic lateral sclerosis and chronic inflammatory demyelinating polyneuropathy coexistence in a patient with a C9orf72 variant: case report.}, journal = {Frontiers in dementia}, volume = {5}, number = {}, pages = {1785124}, pmid = {42051912}, issn = {2813-3919}, abstract = {BACKGROUND: The C9orf72 variation has been strongly implicated in the inheritance of familial ALS, frontotemporal dementia (FTD), and combined ALS-FTD cases. Increasing evidence implicates immune changes and inflammation in some ALS patients. Several studies demonstrated that ALS coexists with CIDP or polyneuropathy. Mouse models of C9orf72 loss-of-function mutations exhibit fatal immune dysregulation.

CASE SUMMARY: A 62-year-old Caucasian man developed right foot drop, and he underwent fibular nerve release without significant improvement. At the same time, he developed progressive weakness and numbness in his bilateral hands. MRI revealed cervical canal stenosis and neuroforaminal narrowing that prompted neurosurgical decompression without clinical improvement. Subsequently, he developed left foot drop. At the clinic presentation, he exhibited dysarthria, tongue fasciculations, weakness in all extremities, muscle atrophy, widespread fasciculations, and upper extremity hyperreflexia, meeting clinical criteria for ALS. Genetic testing identified a pathogenic variant in the C9orf72 gene, confirming a C9orf72 variant, commonly linked to familial ALS. Brain MRI demonstrated the motor band sign. Although EMG/NCS findings were consistent with lower motor neuron disease, he also had signs of demyelinating polyneuropathy based on conduction parameters. Neuromuscular ultrasound showed significant multifocal nerve enlargement typical of immune-mediated neuropathy. CSF studies revealed albuminocytologic dissociation (protein: 112 mg/dL, with normal cell count) and high albumin quotient and index. He fulfilled the 2021 EAN/PNS criteria for possible typical CIDP. He was treated with intravenous immunoglobulin in addition to riluzole with temporary improvement.

CONCLUSION: This is the first case of the co-existence of CIDP and ALS in the setting of a pathogenic C9orf72 variant.}, } @article {pmid42052844, year = {2026}, author = {Chen, W and Wang, J and Li, Q and Zhang, L and Wu, X and Luo, S and Xie, Y and Guo, P}, title = {Keap1-Nrf2 Signaling Pathway-Mediated Antioxidant Defense in Neurodegenerative Diseases: Mechanisms and Traditional Chinese Medicine Therapeutic Strategies.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {31}, number = {4}, pages = {45233}, doi = {10.31083/FBL45233}, pmid = {42052844}, issn = {2768-6698}, support = {81660671//National Natural Science Foundation of China/ ; 202101AZ070001-172//Yunnan Provincial Science and Technology Department-Applied Basic Research Joint Special Funds of Chinese Medicine/ ; 202105AG070014//Yunnan Provincial Key Laboratory of Formula Granules/ ; zyzdxk-2023192//High-level Discipline Construction Project of Dai Medicine, National Administration of Traditional Chinese Medicine/ ; 2024SS24045//Yunnan Key Laboratory for Dai and Yi Medicines/ ; }, mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *Signal Transduction/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Antioxidants/metabolism ; *Medicine, Chinese Traditional/methods ; Oxidative Stress/drug effects ; Animals ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases (NDs) are incurable, progressively disabling disorders marked by sustained neuronal degeneration and loss. Their molecular basis involves intricate regulatory networks, while current therapeutic strategies remain inadequate. Oxidative stress (OS) constitutes a major driver in the initiation and progression of age-related pathologies. Kelch-like enoyl-CoA hydratase-associated protein-1 (Keap1)-Nuclear factor Erythroid 2-related factor 2 (Nrf2) signaling pathway, an essential antioxidant system, exerts protective effects by limiting OS-mediated cellular injury. Extensive evidence demonstrates a close association between Nrf2 signaling and the pathological processes of NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Traditional Chinese medicine, characterized by multi-target and multi-pathway regulatory actions of its bioactive constituents, offers distinctive therapeutic potential for NDs. This review provides an integrated analysis of current advances of Nrf2 involvement in NDs and evaluates therapeutic strategies based on traditional Chinese medicine and its active components, with the aim of guiding future clinical translation.}, } @article {pmid42053785, year = {2026}, author = {Fernandes, JMA and Dutra Junior, AM and Thomas, FP and Gondim, FAA}, title = {Evolving 10-year epidemiological landscape of amyotrophic lateral sclerosis (ALS) in Ceará, Brazil.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2026.2663916}, pmid = {42053785}, issn = {2167-9223}, abstract = {Objective: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects upper and lower motor neurons with variable cognitive impairment. Despite its rarity, ALS has a major social and economic impact and increasing incidence worldwide. There are few population-based studies of ALS in Brazil. Methods: We present a descriptive and quantitative study, with a retrospective and prospective design, of patients with ALS followed at the Walter Cantídio University Hospital (HUWC) from January 2013 to December 2023, with the aim of describing the clinical, epidemiological, and genetic aspects of ALS in this population, as well as the ALS epidemiology within the state of Ceará, Brazil. Results: Two hundred and forty patients had their medical records analyzed. One hundred and thirty-four (55.8%) cases were male, with a male to female ratio of 1.3:1. The mean age of symptom onset was 56.39 ± 13.05 years. 92.1% (221) of cases were sporadic, 7.9% (19) were familial. Spinal onset was most common (72.1%). Genetic mutations were found in 10 patients, with SOD1 mutations (variant: c.358G > C; p.Val120Leu) being the most common. Using riluzole prescription data, the prevalence and incidence of ALS in 2022 were estimated at 2.32 and 0.8/100.000/inhabitants, respectively. Conclusion: The epidemiology of ALS in the state of Ceará is similar to what has been reported in prior studies from Brazil and other developing countries; SOD1 mutations were the most prevalent genetic subtype.}, } @article {pmid42054542, year = {2026}, author = {Gu, T and Xue, J and Zhang, Z and Cao, J and Song, J and Li, G and Ming, L and Zhu, Z and Wang, H}, title = {Mechanisms of Resistance to ALS Inhibitors and Bentazone in Fimbristylis littoralis and Rapid Identification of the ALS Trp-574-Leu Mutation Using LAMP-CRISPR/Cas12a.}, journal = {Journal of agricultural and food chemistry}, volume = {74}, number = {18}, pages = {14311-14321}, doi = {10.1021/acs.jafc.5c17149}, pmid = {42054542}, issn = {1520-5118}, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Herbicides/pharmacology ; *Herbicide Resistance ; Mutation ; *Plant Proteins/genetics/metabolism/antagonists & inhibitors/chemistry ; *Benzothiadiazines/pharmacology ; CRISPR-Cas Systems ; *Enzyme Inhibitors/pharmacology ; Plant Weeds/drug effects/genetics/enzymology ; Nucleic Acid Amplification Techniques/methods ; *Poaceae/drug effects/genetics/enzymology ; }, abstract = {Fimbristylis littoralis Gaudich., a harmful sedge weed in Chinese rice paddy, impairs rice productivity and quality. In this study, we identified a resistant population (FL2) displaying multiple resistance to pyrazosulfuron-ethyl and bentazone, alongside cross-resistance to other acetolactate synthase (ALS)-inhibiting herbicides. The other population (FL6) showed exclusive resistance to bensulfuron-methyl. Sequencing demonstrated that FL2 carried a Trp-to-Leu mutation at codon 574 of ALS, whereas no mutations were detected in the psbA gene of bentazone-resistant FL2 or the ALS gene of bensulfuron-methyl-resistant FL6. Studies on nontarget-site resistance (NTSR) mechanisms indicated that FL2's resistance to pyrazosulfuron-ethyl was associated with neither PBO-inhibited P450s nor NBD-Cl-inhibited GSTs. In contrast, FL6's resistance to bensulfuron-methyl and FL2's resistance to bentazone were linked to P450 activity. A loop-mediated isothermal amplification (LAMP) coupled with CRISPR/FnCas12a assay was established for rapid detection of the Trp-574-Leu mutation, facilitating resistance management. These findings provide insights for managing resistant F. littoralis populations.}, } @article {pmid42054746, year = {2026}, author = {Biscetti, L and Gambuzza, ME and Princiotto, M and Sabbatinelli, J and Olivieri, F and Fiorillo, M and Chinigò, C and Muglia, L and Cozza, A and Beccacece, A and Gembillo, G and Bruschetta, G and Villalta Savedra, E and Lattanzio, F and Corsonello, A and Soraci, L}, title = {From necroptosis to neuroinflammation: Unraveling mechanisms and therapeutic targets in age-related cognitive decline.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {199}, number = {}, pages = {119326}, doi = {10.1016/j.biopha.2026.119326}, pmid = {42054746}, issn = {1950-6007}, mesh = {Humans ; *Necroptosis/drug effects/physiology ; Animals ; *Neuroinflammatory Diseases/metabolism/drug therapy/pathology ; *Aging/pathology/metabolism ; *Cognitive Dysfunction/metabolism/drug therapy/pathology ; Signal Transduction ; *Brain/metabolism/pathology/drug effects ; Inflammation ; }, abstract = {Aging is the major risk factor for several chronic conditions, including cognitive decline and dementia. It is accompanied by profound immune alterations characterized by a progressive decline in immune competence, a process known as immunosenescence. The resulting dysregulation of immune function leads to the overproduction of proinflammatory cytokines and fuels a persistent, low-grade inflammatory state termed inflammaging. This chronic inflammation contributes to dysfunction across the central and peripheral nervous systems, promoting neuronal damage and accelerating neurodegenerative processes such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other age-related cognitive disorders. Within this framework, prolonged activation of inflammatory pathways can trigger regulated forms of cell death. Among these, necroptosis has recently emerged as a potential mediator linking inflammaging to neurodegeneration. Its core molecular effectors, including the receptor-interacting protein kinases RIPK1 and RIPK3 and the mixed-lineage kinase domain-like protein (MLKL), are increasingly expressed in aged neural tissues, promoting the release of damage-associated molecular patterns (DAMPs) that amplify glial activation, oxidative stress, and blood-brain barrier disruption. Growing evidence suggests that necroptotic signaling may be upregulated in the aging brain and in neurodegenerative disorders, where it could contribute to neuronal loss and cognitive impairment. This review discusses the potential role of necroptosis in the continuum between inflammation and neurodegeneration, highlighting emerging diagnostic and therapeutic perspectives. Epigenetic and circulating biomarkers, such as phosphorylated MLKL and specific microRNAs, may support early detection, while pharmacological and nutraceutical strategies targeting necroptosis show promising neuroprotective effects in preclinical studies.}, } @article {pmid42055109, year = {2026}, author = {Zhu, Y and Zhang, H and Zhang, Z and Song, G and Fu, J and Wang, H}, title = {The role of ultrasound in addressing neurodegenerative diseases: A review of mechanisms, applications, and challenges.}, journal = {Neuroscience}, volume = {606}, number = {}, pages = {126-137}, doi = {10.1016/j.neuroscience.2026.04.024}, pmid = {42055109}, issn = {1873-7544}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Blood-Brain Barrier/metabolism ; Animals ; *Ultrasonic Therapy/methods ; }, abstract = {With the aging of the global population, neurodegenerative diseases have become a major public health challenge. Currently, there are many limitations in the traditional treatment of neurodegenerative diseases, such as medicine, deep brain stimulation, transcranial magnetic stimulation, and transcranial direct current stimulation, including the inability to penetrate the blood-brain barrier (BBB) accurately and challenges in achieving precise and quantitative control during the treatment process. Ultrasound is an emerging neural modulation technology that stands out for its non-invasive nature, precise targeting, and unique ability to penetrate the BBB, demonstrating tremendous application potential. In this review, we summarized the common types of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS), and the limitations of traditional treatments. It delves into the physical principles, classification, mechanisms, and unique advantages of ultrasound therapy in neuromodulation. It provides a detailed account of the current status of application of ultrasound in neurodegenerative diseases, and represents the advantages and challenges currently faced by ultrasound therapy, which offers insights into future research directions and technological improvements.}, } @article {pmid42055490, year = {2026}, author = {Banerjee, C and Singh, RK and Mehan, S}, title = {Raloxifene Beyond Osteoporosis: Unlocking Neurorestoration Through Remyelination, Inflammatory Regulation, and Neuroimmune Modulation in CNS Pathologies.}, journal = {International immunopharmacology}, volume = {181}, number = {}, pages = {116668}, doi = {10.1016/j.intimp.2026.116668}, pmid = {42055490}, issn = {1878-1705}, mesh = {Humans ; *Raloxifene Hydrochloride/therapeutic use/pharmacology ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Selective Estrogen Receptor Modulators/therapeutic use/pharmacology ; Remyelination/drug effects ; Neuroimmunomodulation/drug effects ; *Central Nervous System Diseases/drug therapy/immunology ; }, abstract = {Raloxifene, a selective estrogen receptor modulator (SERM), has emerged as a promising candidate for repurposing in neurodegenerative and neuropsychiatric disorders. Traditionally approved for osteoporosis and breast cancer prevention, its tissue-selective estrogen receptor modulation underpins its potential therapeutic applications. This review critically examines the pharmacological, preclinical, and clinical evidence supporting raloxifene's neuroprotective and neuropsychiatric effects, as well as its mechanisms of action, safety profile, and clinical limitations. Raloxifene exerts neuroprotective effects by targeting estrogen receptors, including ERα, ERβ, and GPER, modulating genomic and non-genomic pathways. These pathways regulate oxidative stress, mitochondrial stability, neuroinflammation, and apoptosis-core features of neurological disorders such as Alzheimer's (AD), Parkinson's (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Preclinical studies demonstrate raloxifene's ability to reduce amyloid-β aggregation in AD, protect dopaminergic neurons in PD, mitigate demyelination in MS, and decrease protein aggregation in ALS. Additionally, raloxifene exhibits positive effects on memory, attention, and negative symptoms in schizophrenia, alongside antidepressant and anxiolytic properties. Although promising, raloxifene's clinical translation faces challenges. Existing trials are limited by small sample sizes, heterogeneous designs, and a lack of long-term data. Most studies focus on postmenopausal women, leaving gaps regarding effects in men, premenopausal women, and younger populations. Furthermore, discrepancies between preclinical and clinical dosing complicate its therapeutic optimization. Future research should explore sex-specific effects, optimize CNS-targeted dosing strategies, and employ biomarkers for neuroprotection and inflammation. Long-term trials are essential to evaluate its disease-modifying potential. Raloxifene represents a promising repurposing candidate for CNS disorders, however, its therapeutic role remains to be established through robust clinical validation.}, } @article {pmid42055632, year = {2026}, author = {Alhadidy, MM and Hinton, TV and Ernst, KN and Yang, Y}, title = {Amyloid extraction from neurodegenerative disease tissues for structural studies.}, journal = {Methods in enzymology}, volume = {729}, number = {}, pages = {1-33}, doi = {10.1016/bs.mie.2026.01.032}, pmid = {42055632}, issn = {1557-7988}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism ; *Amyloid beta-Peptides/isolation & purification/chemistry ; Cryoelectron Microscopy/methods ; *Brain/pathology/metabolism ; alpha-Synuclein/isolation & purification/chemistry ; tau Proteins/isolation & purification/chemistry ; Amyotrophic Lateral Sclerosis/pathology ; Alzheimer Disease/pathology/metabolism ; DNA-Binding Proteins/isolation & purification ; }, abstract = {Amyloid aggregates are hallmarks of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Yet structural analysis of these brain-extracted filaments requires specialized extraction protocols that minimize structural perturbation while removing tissue matrix components. This chapter focuses on amyloid-β (Aβ) filaments, the primary component of senile plaques in AD, and presents three complementary methods for isolating these filaments from human brain tissues suitable for cryo-electron microscopy analysis. These methods have enabled high-resolution structural studies reaching 2.0-3.5 Å resolution and revealed distinct conformational polymorphs in AD and other neurodegenerative diseases. Method selection depends on tissue type, target filaments, and downstream analysis requirements, with comprehensive guidance provided for optimal protocol choice and implementation. The protocols demonstrate broad applicability beyond Aβ extraction, with successful adaptations provided for tau, α-synuclein, and TDP-43 extraction. Understanding these filamentous structures extracted with minimal perturbation is essential for developing targeted therapeutics and advancing structure-based drug design approaches for AD, PD, ALS, FTD, and other neurodegenerative diseases.}, } @article {pmid42057546, year = {2026}, author = {Jha, NK and Chauhan, P and Abomughaid, MM and Avinash, D and Almutary, AG and Lakhanpal, S and Singh, A and Sulaimani, GM and Al-Kuraishy, HM and Mohammed, HA and Misra, J and Thakur, K and Kumar, D}, title = {mTOR Signalling in Neurodegenerative Disorders: Unveiling Key Factors, Mechanistic Insights, and Possible Therapeutic Interventions.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {60}, number = {2}, pages = {136-174}, doi = {10.33594/000000858}, pmid = {42057546}, issn = {1421-9778}, mesh = {*TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors ; Humans ; *Signal Transduction/drug effects ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; Animals ; Autophagy/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Apoptosis/drug effects ; Sirtuin 1/metabolism ; }, abstract = {Neurodegenerative diseases (NDDs) are defined by the gradual degeneration of neuronal cells, wherein the accumulation of misfolded proteins can lead to memory impairments, motor dysfunctions, and other deteriorations. Despite the widespread impact, there are currently no viable pharmaceuticals to treat these disorders. The mTOR protein is a crucial regulator of cell survival, growth, autophagy, and apoptosis. Targeted modulation of mTOR signaling holds promise for mitigating neurodegeneration in Alzheimer's, Huntington's, ALS, and Parkinson's disease. Understanding its interactions with pathways such as PI3K/Akt, AMPK, and SIRT1 is essential for developing effective therapeutics.}, } @article {pmid42057560, year = {2026}, author = {Turner, N and Wilson, E and Faull, C and Palmer, J and Davidson, S and Turner, MR}, title = {A qualitative exploration of how people with motor neurone disease who use tracheostomy ventilation understand and experience quality of life.}, journal = {Disability and rehabilitation}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/09638288.2026.2658439}, pmid = {42057560}, issn = {1464-5165}, abstract = {PURPOSE: This qualitative study aimed to increase awareness of how people with motor neurone disease (pwMND) who use tracheostomy ventilation (TV) understand quality of life.

METHODS: Semi-structured interviews were conducted with 14 pwMND (age 36-76 years) who had used TV for 3 months-12 years.

RESULTS: Five themes were identified following thematic analysis. PwMND who use TV associated quality of life with: i) Extending life; ii) Improving symptom management; iii) Adapting to living with MND; iv) Finding purpose; v) Staying positive. TV extended survival and improved management of symptoms such as breathlessness and secretions. Psychological adaptation and acceptance supported pwMND to focus on remaining abilities and sources of enjoyment, whilst the pursuit of meaning and purpose sustained a positive outlook.

CONCLUSIONS: Quality of life for pwMND who use TV is multidimensional, encompassing physical, psychological, and existential domains. Findings underscore the value of a person-centred approach, recognising that pwMND can maintain a positive outlook despite significant limitations. A holistic assessment of quality of life is recommended, addressing not only physical health but also psychological and social well-being. Effective communication is required to ensure pwMND consider all implications of TV, including costs of adapting the home and demands of living with paid carers.}, } @article {pmid42058164, year = {2026}, author = {Park, S and Song, Y}, title = {Development and implementation of a student-led, project-based, community health nursing clinical placement focused on health promotion for nursing students in Korea.}, journal = {Journal of research in nursing : JRN}, volume = {}, number = {}, pages = {17449871261427312}, pmid = {42058164}, issn = {1744-988X}, abstract = {PURPOSE: This study aimed to develop and implement a community health nursing clinical placement focused on a health promotion project for nursing students in Korea.

METHODS: This quantitative descriptive study developed and implemented a community health nursing clinical placement curriculum based on a health promotion project.

RESULTS: In this study, Jalinus et al's seven steps for project-based learning were applied: formulation of expected learning outcomes through community health promotion projects, understanding the concept of teaching materials, skill training, designing the community health promotion project theme, developing the community health promotion project proposal, executing the community health promotion project, and presenting the community health promotion project outcomes. Nursing students demonstrated positive satisfaction scores with the clinical placement.

CONCLUSIONS: The community health nursing clinical placement focused on a health promotion project demonstrated a high level of student satisfaction. The nursing students actively engaged in the clinical placement and expressed strong satisfaction with the acquisition of new knowledge and the development of competencies to assess community health issues. Locally co-designed clinical placements that reflect regional characteristics may contribute to improved student satisfaction, and there is a need to include student participation in the future design of learner-driven, problem-solving-oriented curriculum.}, } @article {pmid42058282, year = {2026}, author = {Kalyani, A and Northall, A and Schreiber, S and Brüggemann, J and Vielhaber, S and Al Dubai, M and Bin Ramadan, A and Mattern, H and Speck, O and Reichert, C and Kuehn, E}, title = {Individualized phenotyping of functional amyotrophic lateral sclerosis pathology in sensorimotor cortex.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag127}, pmid = {42058282}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons in primary motor cortex, leading to muscle weakness, atrophy and death within a median of 3 years. Even though ALS is characterized by different disease subtypes affecting different body parts, individualized phenotyping of functional ALS pathology has so far not been achieved. We recorded 7 Tesla functional MRI data while ALS patients and matched controls moved affected and non-affected body parts in the MR scanner. We applied robust Shared Response Modelling for capturing ALS-specific shared responses for group classification, and Partial Least Squares regression for relating the latent variables to clinical subtypes and the degree of disease progression. We show that disease onset and severity can be best modelled by functional connectivity rather than local activation changes. We also show that functional disease-defining information in primary motor cortex is not the strongest in the area that is behaviourally first-affected, deviating from the behavioural phenotype of the patients. When computing the model's weight distribution of the King stage classification and projecting them back into voxel space, the highest mean weights are present in the foot and tongue/face regions. Our data highlight the importance of 7 Tesla functional MRI task-based functional connectivity measures for classifying ALS patients in addition to structural readouts and provides evidence that a 7 Tesla functional MRI can be used for identifying a disease signature of each individual ALS patient.}, } @article {pmid42058985, year = {2026}, author = {Balusamy, S and Sivalingam, R and Rooben, S and Helen, S}, title = {RES-MND: Motor neuron disease detection using Res4Net-convolutional block attention module.}, journal = {Turkish journal of medical sciences}, volume = {56}, number = {2}, pages = {426-438}, pmid = {42058985}, issn = {1303-6165}, mesh = {Humans ; *Motor Neuron Disease/diagnostic imaging/diagnosis ; Convolutional Neural Networks ; Algorithms ; *Multimodal Imaging/methods ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND/AIM: Motor neuron diseases (MNDs) are progressive neurological disorders that cause muscle weakness and wasting as a result of ongoing neurodegeneration. MNDs require comprehensive diagnostic approaches that integrate clinical symptoms, laboratory findings, and multimodal imaging data.

MATERIALS AND METHODS: In this study, a novel residual network for motor neuron disease detection (RES-MND) framework is proposed for detecting MNDs using multimodal imaging data. Initially, the input multimodal images, including MRI, CT, PET, and DTI, are preprocessed using adaptive dynamic histogram equalization and the total variation bilateral filter. The preprocessed multimodal images are processed through Res4Net-CBAM for feature extraction to enhance image recognition performance. A dove swarm optimization algorithm is employed to select the most relevant features from the multimodal images. Finally, the deep belief network (DBN) classifies five categories, including one control group (normal) and four MND types: ALS, PLS, PBP, and PMA.

RESULTS: The performance of the proposed RES-MND method is evaluated using standard metrics such as accuracy, precision, recall, and F1-score. According to the results, the proposed RES-MND method achieved the highest accuracy rate of 99.65%, outperforming existing methods.

CONCLUSION: The proposed DBN achieved 0.68%, 0.41%, and 0.9% higher accuracy than SNN, DNN, and CNN, respectively. The proposed RES-MND method achieved 1.08%, 2.18%, and 1.7% higher overall accuracy compared to existing methods such as miRNA, vGRF, and SVM-RFE, respectively.}, } @article {pmid42059647, year = {2026}, author = {Ma, X and Jiang, Z and Yang, T and Zhang, H and Lu, W and Liu, K and Fan, X and Yang, G and Wu, S}, title = {Integrated multi-omics analysis reveals gut dysbiosis and altered energy metabolism in Chinese ALS patients.}, journal = {Microbiology spectrum}, volume = {14}, number = {6}, pages = {e0060926}, pmid = {42059647}, issn = {2165-0497}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/microbiology/metabolism ; Multiomics ; *Energy Metabolism ; *Dysbiosis/microbiology/metabolism ; *Gastrointestinal Microbiome ; Bacteria/classification/genetics/isolation & purification/metabolism ; China ; Metabolome ; Oxidative Stress ; Metabolomics ; Female ; Virome ; Male ; Middle Aged ; Feces/microbiology ; East Asian People ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a complex etiology. Emerging evidence implicates gut microbiota dysbiosis in ALS pathology via the gut-brain axis, yet the specific integrative profile of the gut microbiome, virome, and metabolome, particularly in Chinese patients, remains incompletely characterized. Although global diversity indices showed no significant differences, taxonomic analysis revealed distinct compositional shifts. The ALS microbiome was characterized by a significant depletion of beneficial anti-inflammatory genera, specifically Akkermansia and Faecalibacterium, and an expansion of opportunistic pathogens such as Escherichia and oral-associated taxa (e.g., Streptococcus). We also observed a specific alteration in the gut virome, with viral genera including Puppervirus and Donellivirus enriched in ALS patients. Functionally, the ALS microbiome exhibited a marked upregulation of pathways involved in L-ascorbate (vitamin C) degradation and fatty acid biosynthesis, suggesting a microbial contribution to systemic oxidative stress. Metabolomic analysis corroborated these findings, identifying 271 differentially expressed metabolites. ALS patients showed elevated levels of inflammatory lipids (e.g., LysoPC) and metabolic intermediates of the tricarboxylic acid (TCA) cycle, alongside a downregulation of antioxidants. Integrative analysis highlighted profound dysregulation in porphyrin metabolism, oxidative phosphorylation, and energy homeostasis. Our findings demonstrate that ALS is associated with a specific dysbiotic gut ecosystem characterized by the loss of protective commensals, unique viral signatures, and functional metabolic reprogramming that exacerbates host oxidative stress and energy deficits. These results provide new insights into gut-brain interactions and highlight microbial antioxidant depletion as a potential therapeutic target.IMPORTANCEAmyotrophic lateral sclerosis (ALS) is a devastating disease with no cure. While gut bacteria are known to influence brain health, we still do not understand exactly how they contribute to ALS progression. In this study, we used advanced DNA sequencing and chemical analysis to deeply examine the gut ecosystem of ALS patients. Beyond just cataloging which bacteria are present, we discovered what they are doing: the ALS microbiome actively breaks down vitamin C (a critical antioxidant) and disrupts energy metabolism. We also found a loss of protective bacteria that maintain the gut barrier. These findings are significant because they suggest that the gut microbiome in ALS patients may be actively fueling the disease by depleting the body's antioxidant reserves. This points to a new potential treatment strategy: targeting these specific bacterial functions or replenishing specific metabolites to protect motor neurons.}, } @article {pmid42059992, year = {2026}, author = {Ghiyamihoor, F and Asemi Rad, A and Hassanifar, P and Kaur, R and Patel, JH and Kim, I and Marzban, A and Mehdizadeh, M and Levin, DB and Ghavami, S and Toncheva, A and Benali, S and Dubois, P and Balci, F and Habibi, HR and Manto, M and Marzban, H}, title = {Micro- and Nanoplastics in the Human Brain: Mechanistic Plausibility, Translational Challenges, and Links to Neurological Disease Trends.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42059992}, issn = {1559-1182}, mesh = {Humans ; *Brain/metabolism/pathology ; *Nervous System Diseases/metabolism/pathology ; Animals ; *Microplastics/adverse effects/metabolism ; Blood-Brain Barrier/metabolism ; *Translational Research, Biomedical ; *Nanoparticles ; }, abstract = {The exponential growth in plastic production since the mid-twentieth century has led to the pervasive presence of micro- and nanoplastics (MNPs) across ecosystems and human exposure pathways, coinciding with a rising global burden of neurological disorders. Increasing evidence demonstrates that MNPs are not confined to peripheral tissues but can accumulate even in the human brain, raising concerns about their potential contribution to neurological disease. This structured review synthesizes global trends in plastic production, environmental MNP burden, and human exposure, together with emerging data on brain accumulation, entry pathways, neurotoxic mechanisms, and key translational challenges. We present evidence showing that MNPs may cross brain barriers via multiple routes, including the blood-brain barrier, blood-cerebrospinal fluid barrier, olfactory, and circumventricular pathways, particularly under conditions of barrier vulnerability. Experimental studies reveal that once in neural tissue, MNPs may disrupt synaptic function, mitochondrial homeostasis, autophagy, and redox balance, while activating neuroinflammatory and gut-brain axis-mediated pathways. These mechanisms intersect with disease-relevant processes implicated in multiple neurological disorders whose global prevalence and societal burden have sharply increased over recent decades, including stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, mood disorders, and neurodevelopmental conditions. Despite growing mechanistic plausibility, translational and human epidemiological evidence remains limited by methodological heterogeneity, a lack of standardized detection methods, and the absence of longitudinal clinical data/studies. We highlight critical analytical and translational gaps, public health implications, and priorities for longitudinal, biomarker‑driven studies needed to rigorously test whether MNPs may contribute to population‑level risk of neurological disease.}, } @article {pmid42060866, year = {2026}, author = {Kiernan, MC and Genge, A and Grosskreutz, J and Kuwabara, S and Lillo, P and Rosenfeld, J and Cummings, C}, title = {The World Federation of Neurology Specialty Group in ALS/MND: toward strategic partnership and new frontiers.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {501-503}, doi = {10.1080/21678421.2026.2663915}, pmid = {42060866}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/epidemiology ; *Neurology/organization & administration ; *Societies, Medical ; *International Cooperation ; *Motor Neuron Disease/therapy/diagnosis/epidemiology ; }, abstract = {A memorandum of understanding was recently established between the World Federation of Neurology Specialty Group and the International Alliance of ALS/MND Associations. This new strategic partnership brings together leading clinicians and researchers with national and regional organizations dedicated to supporting ALS patients, their families, and caregivers. The purpose of partnership is to strengthen global coordination in research, education, advocacy, and clinical care for people living with MND. The agreement outlines shared priorities, including promoting equitable access to diagnosis and treatment, supporting capacity building in low- and middle-income regions, and facilitating the exchange of scientific knowledge and best practice. Both parties commit to joint initiatives such as international meetings, guideline development, clinical trials and data-sharing efforts that advance understanding of disease mechanisms and therapeutic approaches. Together, these organizations represent the scientific and human dimensions of the ALS challenge. Through partnership, the WFN Specialty Group and the International Alliance aim to accelerate progress toward improved outcomes and, ultimately, effective treatments for MND worldwide.}, } @article {pmid42060880, year = {2026}, author = {, }, title = {Retirement of Guidelines: Practice Parameter Update: The Care of the Patient With Amyotrophic Lateral Sclerosis: Drug, Nutritional, and Respiratory Therapies (An Evidence-Based Review): Report of the Quality Standards Subcommittee of the American Academy of Neurology.}, journal = {Neurology}, volume = {106}, number = {10}, pages = {e218083}, doi = {10.1212/WNL.0000000000218083}, pmid = {42060880}, issn = {1526-632X}, } @article {pmid42060881, year = {2026}, author = {Nolano, M and Provitera, V and Caporaso, G and Areniello, AR and Borreca, I and Stancanelli, A and Senerchia, G and Iuzzolino, VV and Fasolino, I and Vitale, F and Ciccarelli, G and Dell'Aversana, D and Masciarelli, F and Tozza, S and Iodice, R and Santoro, L and Manganelli, F and Dubbioso, R}, title = {Phosphorylated TDP-43 Pathology in Skin and Muscle Tissue of Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {106}, number = {10}, pages = {e214940}, doi = {10.1212/WNL.0000000000214940}, pmid = {42060881}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Female ; *DNA-Binding Proteins/metabolism ; Male ; Middle Aged ; Cross-Sectional Studies ; Aged ; Case-Control Studies ; *Skin/metabolism/pathology ; Phosphorylation ; *Tongue/metabolism/pathology ; }, abstract = {BACKGROUND AND OBJECTIVES: Phosphorylated TAR DNA-binding protein 43 (pTDP-43) is the pathologic hallmark of amyotrophic lateral sclerosis (ALS), yet no peripheral premortem biomarker is available. We evaluated pTDP-43 distribution in skin and tongue tissues and its association with ALS and clinical stage.

METHODS: This cross-sectional case-control study included patients with ALS meeting revised El Escorial criteria who underwent skin and tongue biopsies. Control groups included healthy controls (HC), patients with non-ALS neuropathy or neuronopathy (NANN), and patients with burning mouth syndrome (BMS). pTDP-43 was quantified in Meissner corpuscles (MC) and keratinocytes using standardized immunofluorescence. In MC, PGP (%), pTDP-43 (%), and the pTDP-43/PGP ratio were assessed. A subset of skin samples underwent western blot analysis. ALS severity was classified using King's staging system. Diagnostic performance was evaluated using receiver operating characteristic analysis.

RESULTS: Fifty patients with ALS were included, median age 66.5 years, 36% female. Control groups included 20 HC, median age 60 years, 20% female, and 20 patients with NANN, median age 60 years, 50% female. Tongue biopsy was performed in 10 patients with ALS and 10 patients with BMS. pTDP-43 deposits were detected in ALS across epidermis and dermis structures, whereas they were almost absent in HC and low in NANN. Accordingly, MC pTDP-43% differed across groups (H = 53.30; p < 0.001), with median values of 0.35 (interquartile range [IQR] 0.39) in ALS, 0.04 (IQR 0.03) in NANN, and 0.00 in HC. The pTDP-43/PGP ratio increased with clinical stage at subject level (Z = 2.20, p = 0.028) and single-corpuscle level (H = 21.72, p < 0.001). Western blot showed higher pTDP-43/GAPDH ratio in ALS skin than in HC (median 3.45, IQR 7.23 vs 1.30, IQR 0.80; p = 0.007). Nonphosphorylated TDP-43 did not differ across groups. In keratinocytes, pTDP-43 was higher in ALS than in NANN and HC (median 0.047, IQR 0.023; 0.019, IQR 0.049; and 0.005, IQR 0.047; p < 0.001). Combined cutaneous pTDP-43 measures discriminated ALS from HC (area under the curve [AUC] 0.94, p < 0.001) and from NANN (AUC 0.90, p < 0.001). Tongue biopsies showed pTDP-43 aggregates in intramuscular nerves, denervated endplates, and muscle fibers.

DISCUSSION: Peripheral pTDP-43 deposition distinguishes ALS from controls and reflects disease stage, supporting its potential role as a biomarker of ALS and disease severity. Larger and longitudinal studies are required for validation.}, } @article {pmid42061283, year = {2026}, author = {Banerjee, S and Panjwani, D and Singh, S and Singh, TG}, title = {TGR5 and FXR receptors in motor degeneration: Molecular mechanism, crosstalk pathways and therapeutic prospects.}, journal = {Journal of neuroimmunology}, volume = {417}, number = {}, pages = {578942}, doi = {10.1016/j.jneuroim.2026.578942}, pmid = {42061283}, issn = {1872-8421}, mesh = {Humans ; Animals ; *Receptors, Cytoplasmic and Nuclear/metabolism ; *Receptors, G-Protein-Coupled/metabolism ; Receptor, Farnesoid X-Activated ; Signal Transduction/physiology ; *Motor Neuron Disease/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; *Receptor Cross-Talk/physiology ; }, abstract = {Motor neuron degeneration in disorders such as amyotrophic lateral sclerosis, spinal muscular atrophy, and Parkinson's disease is increasingly recognized as a consequence of disrupted metabolic, mitochondrial, and inflammatory balance. There is emerging data that bile acid receptors - Takeda G-protein-coupled receptor 5 (TGR5) and Farnesoid X receptor (FXR) are key regulators that combine systemic metabolism with neuronal survival. These receptors modulate the mitochondrial biogenesis, oxidative stress responses, and glial inflammatory signaling and coordinate gut-liver-brain crosstalk. Their malfunction leads to an unaffected energy metabolism, increased reactive oxygen species, and neuroinflammation, thereby accelerating the death of motor neurons. Their dysfunction results in impaired energy metabolism increased reactive oxygen species and neuroinflammation, accelerating motor neuron death. Pharmacological activation of TGR5 and FXR improves mitochondrial integrity reduces cytokines driven toxicity and preserves neuromuscular junction stability in preclinical models. However, translational opportunities are dampened by some factors such as restriction of bioavailability of the central nervous system, receptor variation and metabolic systemic interactions. To clarify, the TGR5 -FXR signaling axis would provide a mechanistic model of how to develop metabolism-based therapeutics that can simultaneously supplement mitochondrial protection, immunologic mangling, and neuro-specific to energetic homeostasis in motor neuron disease.}, } @article {pmid42061810, year = {2026}, author = {Arasmou-Idrovo, MS and Marín-Rodríguez, B and Gironda-Martínez, A and García, AG and León, R and Pascual-Guerra, J and Torres-Rico, M}, title = {Unexpected mechanisms of repurposed drugs in the pathogenic pathways of neurodegenerative diseases. Discovering new neuroprotective therapies in cellular models.}, journal = {Neuropharmacology}, volume = {295}, number = {}, pages = {110994}, doi = {10.1016/j.neuropharm.2026.110994}, pmid = {42061810}, issn = {1873-7064}, mesh = {Humans ; *Neuroprotective Agents/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Drug Repositioning/methods ; HEK293 Cells ; Cell Line, Tumor ; }, abstract = {Advances in biomedicine have increased life expectancy, leading to a growing prevalence of age-related neurodegenerative diseases such as Alzheimer's and Parkinson's disease, alongside disorders of genetic or environmental origin including multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. Despite their diverse etiologies, these conditions share convergent pathogenic mechanisms-calcium overload, neuroinflammation, and oxidative stress-that drive neuronal apoptosis and progressive neurodegeneration. Developing therapies that effectively target these interconnected pathways remains a major challenge. Here, we applied a drug-repurposing pipeline integrating computational chemistry, calcium channel affinity prediction, and in vitro validation in SH-SY5Y and HEK293 cells. Eight clinically approved CNS drugs were screened for activity against Caᵥ1, Orai1, and P2X7 channels, and subsequently evaluated in neuroprotection assays. Several compounds demonstrated significant efficacy, with chlorpromazine showing broad-spectrum activity (neuroprotection, Caᵥ1.2 and P2X7 antagonism, anti-inflammatory effects), trimipramine emerging as a potent antioxidant, and vilazodone displaying synergistic neuroprotection in combination with procyclidine. These findings reveal multi-target pharmacological profiles in well-tolerated drugs not currently used for neurodegenerative indications. By highlighting both individual and combinatorial strategies, this work provides a foundation for translational studies aimed at repurposing approved agents for complex neurological disorders, with particular relevance to Parkinson's disease.}, } @article {pmid42062527, year = {2026}, author = {Azzolino, D and Zulueta, A and Piras, R and Mariani, P and Sideri, R and Lucchi, T and Lunetta, C}, title = {Agreement between bioimpedance-measured and calf-derived appendicular skeletal muscle mass in amyotrophic lateral sclerosis patients.}, journal = {European journal of clinical nutrition}, volume = {80}, number = {8}, pages = {846-850}, pmid = {42062527}, issn = {1476-5640}, support = {Ricerca Corrente//Ministero della Salute (Ministry of Health, Italy)/ ; }, mesh = {Humans ; Female ; Male ; *Electric Impedance ; *Muscle, Skeletal/physiopathology ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Body Composition ; *Sarcopenia/etiology/diagnosis/physiopathology ; Aged ; Middle Aged ; Leg ; ROC Curve ; }, abstract = {BACKGROUND: Over time, amyotrophic lateral sclerosis (ALS) has been considered an accelerated model of sarcopenia. However, muscle mass is rarely assessed in ALS patients. The aim of this study was to explore the agreement between bioelectrical impedance analysis (BIA)-measured and calf circumference (CC)-derived appendicular skeletal muscle mass index (ASMMI) in ALS patients.

METHODS: Body composition was assessed using anthropometric measures and BIA. Pearson analyses were used to assess correlations and Kappa (κ) statistics were used to evaluate agreement between BIA-measured and CC-derived ASMMI. CC predictive ability was assessed through the area under the receiver operating characteristic curve.

RESULTS: A total of 61 ALS patients were included. The CC-ASMM was highly correlated with the BIA-ASMM (r = 0.830, p < 0.001) and CC-ASMMI was moderately correlated with BIA-ASMMI (r = 0.62, p < 0.001). Low CC-derived and BIA-derived ASMMI presented a moderate degree of agreement in the overall sample (k = 0.546, 95% CI 0.325-0.767) and in men (k = 0.432, 95% CI 0.056-0.809), while a substantial agreement was observed in women (k = 0.613, 95% CI 0.344-0.883). The optimal cut-off values for CC in identifying low ASMMI from the ROC analysis, were 34 cm for both sexes with an area under the curve (AUC) of 0.818 for men (sensitivity 80%, specificity 78.3%) and of 0.841 (sensitivity 83.3%, specificity 72.7%) for women.

CONCLUSION: Our preliminary study showed a good predictive ability of the CC, an anthropometric parameter significantly associated with sarcopenia, in reflecting the ASMM. The best performance was found for a CC cut-off point of ≤34 cm in both sexes.}, } @article {pmid42063547, year = {2026}, author = {Demaegd, KC and Kool, L and Baindoor, S and Donovan, PD and Su, J and Westeneng, HJ and van Eijk, RPA and Geoghegan, G and Perez Morrissey, E and Halang, L and Poesen, K and Masrori, P and Gibriel, HAY and Jirström, E and Venø, MT and Kjems, J and Hardiman, O and Veldink, JH and Kenna, K and van den Berg, LH and Van Damme, P and Prehn, JHM and van Es, MA}, title = {Small RNA sequencing identifies serum tDR-1:34-Gly-GCC tiRNA levels as a biomarker for survival in amyotrophic lateral sclerosis.}, journal = {iScience}, volume = {29}, number = {5}, pages = {115636}, pmid = {42063547}, issn = {2589-0042}, abstract = {Survival is highly variable in amyotrophic lateral sclerosis (ALS), complicating prognosis and clinical trial design. Despite advances in biomarker development, accessible prognostic tools are limited. Small non-coding (snc) RNAs are a recently discovered biomarker class showing differential regulation across neurodegenerative diseases, including ALS. Here, we explored changes in sncRNAs over time in ALS. We performed small RNA sequencing in a discovery cohort of 116 longitudinal serum samples from ALS 40 patients collected at 3- to 4-month intervals and identified tRNA-derived stress-induced RNA (tiRNA) tDR-1:34-Gly-GCC as the top sncRNA to increase over time. The finding was validated using TaqMan PCR and replicated in an independent cohort of 35 patients. Both univariate and joint model analyses showed that higher tDR-1:34-Gly-GCC levels correlated with shorter survival. Given that the translation of mRNAs and stress-induced translation inhibition are dysregulated in ALS and linked to familial ALS genes, combined with these findings, serum tDR-1:34-Gly-GCC tiRNA levels hold potential as a prognostic biomarker and outcome measure in clinical trials.}, } @article {pmid42063613, year = {2025}, author = {van der Putten, TAW and Verhees, JJF and Koma, Z and van Hoof, PH and Heijkers, D and de Boer, WF and Esser, HJ and Hoogerwerf, G and Lemmers, P}, title = {Insights into the fine-scale habitat use of Eurasian Water Shrew (Neomys fodiens) using radio tracking and LiDAR.}, journal = {Journal of mammalogy}, volume = {106}, number = {3}, pages = {549-560}, pmid = {42063613}, issn = {0022-2372}, abstract = {The Eurasian Water Shrew (Neomys fodiens) is one of the largest shrew (Soricidae) species in Eurasia. In Western Europe, this semiaquatic species often occurs in riparian and marshland habitats that have a high degree of naturalness, but is being threatened by habitat degradation and other anthropogenic factors. The species mostly occurs in low abundance and is elusive. Therefore, understanding its habitat use is challenging, yet imperative for establishing species-specific conservation measures. Technological developments in radio tracking and high-resolution remote sensing such as Light Detection And Ranging (LiDAR) now enable the quantification of ecological niches and provide insight into habitat requirements for a species. Here, we combined radio tracking and LiDAR to quantify habitat use by Eurasian water shrews. Alongside a lowland brook in the Netherlands, 20 individuals were tracked between September and October 2022, resulting in 332 unique locations of Eurasian water shrews. For each of these locations, 11 LiDAR-derived variables were calculated and subsequently analyzed in a species distribution model (SDM). The SDM yielded a model with a high accuracy (predictive performance AUC = 0.93). The variable of highest importance was dense and relatively short vegetation <1 m, which had a positive effect on Eurasian Water Shrew occurrence. Open areas seem to be avoided. Vegetation of heights between 1 and 15 m were found to be less important for the occurrence. The probability of occurrence decreased with increasing distance to water, indicating that the species occurs in the proximity of water, although vegetation-related variables were more important. The obtained detailed knowledge of fine-scale habitat use can be used to improve habitat conservation, restoration, and management for the species. Combining radiotelemetry data with LiDAR data is a promising approach to identifying species-habitat relationships of elusive species such as the Eurasian Water Shrew.}, } @article {pmid42064053, year = {2026}, author = {Chen, Y and Kang, Q and Nie, D and Zhang, P and Zhou, X and Li, Z and Hu, Y and Xin, T and Gong, H}, title = {Combination of albumin-lymphocyte score and skeletal muscle index predicts prognosis of patients with ovarian cancer after primary debulking surgery.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1781291}, pmid = {42064053}, issn = {1664-3224}, mesh = {Humans ; Female ; *Ovarian Neoplasms/surgery/blood/mortality/diagnosis/pathology ; *Muscle, Skeletal/pathology ; *Cytoreduction Surgical Procedures ; Prognosis ; Retrospective Studies ; Middle Aged ; *Lymphocytes ; Aged ; Adult ; }, abstract = {PURPOSE: Accumulating evidence underscores the significance of inflammation and nutrition in tumor progression. Although low albumin-lymphocyte score (ALS) and skeletal muscle index (SMI) are known to be associated with negative outcomes in patients with ovarian cancer (OC) undergoing primary debulking surgery, the usefulness for predicting prognosis remains unclear. We aimed to assess the relevant preoperative prognostic variables and their combined impact on patients with OC.

METHODS: This retrospective study included 347 patients with primary OC from multiple medical centers. The patients were divided into discovery (237 patients) and validation (110 patients) cohorts. Serological tests and plain computed tomography were performed to quantify the ALS and SMI. We investigated the preoperative prognostic ability of a unique index based on a combination of ALS and SMI, the CAS grade.

RESULTS: Patients with a lower ALS and a higher SMI showed improved overall survival (OS) and recurrence-free survival (RFS). Upon stratification by CAS grade, grade 1 patients demonstrated the highest body mass index and the most favorable survival prognosis, whereas grade 3 patients demonstrated the poorest OS and RFS. The independent variables for OS and RFS included residual disease and elevated CAS grade. These findings were validated in an independent cohort study.

CONCLUSION: The CAS grade, a combination of ALS and SMI, is a meaningful and independent predictor of prognosis in patients with OC.}, } @article {pmid42065104, year = {2025}, author = {Doherty, AJ and Howarth, JL}, title = {The Simplified BrainTower and Pipe Cleaners: Model Building as a Learning Tool in Neuroscience.}, journal = {Journal of undergraduate neuroscience education : JUNE : a publication of FUN, Faculty for Undergraduate Neuroscience}, volume = {24}, number = {1}, pages = {27-37}, pmid = {42065104}, issn = {1544-2896}, abstract = {Models have a long history of use in helping students to understand the three-dimensional organisation of biological structures. This is particularly true of neuroanatomical teaching where it is often difficult to distinguish grey and white matter in the fixed prosections often used in dissection rooms. A model system designed to help medical students understand the anatomy of the ascending and descending white matter tracts through the brain and spinal cord had the opposite effect: it made the task of learning these tracts more difficult. The model was complex and difficult for students to engage with. The aim of this study was to introduce a simplified version of this modelling system that was interactive and intuitive, to enable students to build a model in a single workshop session and to assess how the modeling activity impacted on students' learning. Students were asked to build a model of either the anterolateral/spinothalamic tracts (ALS), the dorsal column/medial lemniscus tract (DCML) or the corticospinal tracts (CST) using pipe-cleaners to represent the route of the pathway, including the number of neurons. We found that students were easily able to build a representation of one of these tracts and that they could answer questions on the structure and function of the tract they built significantly better than similar questions related to the other tracts. This enhancement in knowledge was maintained through to end of unit exams eleven weeks after the modelling activity, demonstrating that actively building a model contributes to deep rather than superficial learning.}, } @article {pmid42067481, year = {2026}, author = {Adhyapak, SU and Mishra, P and Basavaraj, M}, title = {Comment on "Improving care for amyotrophic lateral sclerosis with artificial intelligence and affective computing".}, journal = {Journal of the neurological sciences}, volume = {486}, number = {}, pages = {125886}, doi = {10.1016/j.jns.2026.125886}, pmid = {42067481}, issn = {1878-5883}, } @article {pmid42067845, year = {2026}, author = {Sawada, J and Nakayama, Y and Shimatani, K and Matsuda, C and Haraguchi, M and Itagaki, Y and Bokuda, K and Hayashi, K and Morishima, R and Shinba, T and Fukui, S and Shimizu, T}, title = {Cluster analysis of heart rate variability reveals subgroups with preserved and early-impaired autonomic regulation in amyotrophic lateral sclerosis.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {}, pmid = {42067845}, issn = {1471-2377}, support = {Grant-in-Aid for Scientific Research [B] 22H03398 and 23K24656//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Heart Rate/physiology ; *Amyotrophic Lateral Sclerosis/physiopathology ; Female ; Cluster Analysis ; Male ; Middle Aged ; *Autonomic Nervous System/physiopathology ; Aged ; Disease Progression ; *Autonomic Nervous System Diseases/physiopathology/etiology ; Adult ; Clustering Algorithms ; }, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) occasionally exhibit autonomic nervous system dysregulation. We examined whether autonomic regulation differed across patients with ALS with varying severity and progression.

METHODS: A total of 45 patients with ALS were enrolled and classified into three subgroups using cluster analysis. Heart rate variability was assessed using the maximum entropy method. The low-frequency (LF) and high-frequency (HF) components, LF/HF ratio (LF/HF), and heart rate (HR) were measured. Temporal changes in each parameter during rest, mental tasks, and post-task rest were evaluated. The values for all patients and subgroups were compared with those of 11 healthy control subjects. Between-group differences were evaluated at rest and using the Task/Rest and After/Task ratios, and within-group changes across the three phases were also analyzed, with non-parametric statistical tests applied.

RESULTS: Cluster analysis classified the patients into three groups: "Group 1: early-preserved group", "Group 2: late-preserved group", and "Group 3: late-impaired group". Overall, the patients showed lower HF and higher LF/HF at rest than the controls, indicating parasympathetic hypoactivity and sympathetic predominance. Abnormalities were more prominent in Groups 1 and 3 than in Group 2. The former two groups showed blunted HF, LF/HF and HR responses during the tasks. The late-preserved group (Group 2) showed no difference in the Task/Rest ratios of HF, LF/HF and HR compared with the controls.

CONCLUSION: Autonomic regulatory functions differ depending on the severity and progression of ALS. The presence of HRV abnormalities in early-preserved patients suggests that autonomic dysregulation in ALS may not be limited to a late-stage secondary complication but may also be present earlier stages. Recognizing HRV abnormalities from early stages may help identify patients at risk of faster progression. Future longitudinal studies in larger cohorts are needed to establish the pathophysiological significance of HRV abnormalities.}, } @article {pmid42068244, year = {2026}, author = {Chevet, E}, title = {Exploring the role of phase separation in TDP-43 pathogenesis with ArtiTDP43.}, journal = {The FEBS journal}, volume = {293}, number = {14}, pages = {4145-4148}, pmid = {42068244}, issn = {1742-4658}, mesh = {Phase Separation ; Humans ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; Oxidative Stress ; Stress Granules/metabolism ; Cytoplasm/metabolism ; Phosphorylation ; Protein Aggregates ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; }, abstract = {TDP-43 is a nuclear RNA-binding protein implicated in neurodegenerative diseases such as ALS and FTLD, where it becomes mislocalized to the cytoplasm and forms pathological aggregates. These aggregates are thought to arise through liquid-liquid phase separation, a process by which proteins form dynamic, membrane-less condensates that can mature into solid structures. To better understand this process, the authors developed ArtiTDP43, a chemically controllable system that enables reversible formation of TDP-43 condensates in cells. Using this tool, they showed that TDP-43 forms different structures depending on its concentration: small liquid-like puncta, intermediate condensates associated with stress granules, and large solid aggregates resembling disease pathology. These transitions are reversible at early stages but become irreversible as aggregates solidify. The study by Combe et al. demonstrates that increasing cytoplasmic TDP-43 concentration drives a liquid-to-solid transition, while oxidative stress accelerates this process and promotes pathological features such as phosphorylation and p62 recruitment. Importantly, formation of cytoplasmic aggregates leads to depletion of nuclear TDP-43 and increased cell death, indicating toxicity. Overall, the findings establish a mechanistic link between phase separation, aggregation, and cytotoxicity in TDP-43 proteinopathies. ArtiTDP43 provides a powerful tool to study early disease mechanisms and explore therapeutic strategies aimed at preventing pathological aggregation or maintaining normal TDP-43 dynamics.}, } @article {pmid42069087, year = {2026}, author = {Zecca, C and Urso, D and Dell'Abate, MT and Borlizzi, F and Rollo, E and Logroscino, G}, title = {Neurofilament light and GFAP predict survival in frontotemporal dementia spectrum: A population-based study.}, journal = {Neurobiology of disease}, volume = {225}, number = {}, pages = {107421}, doi = {10.1016/j.nbd.2026.107421}, pmid = {42069087}, issn = {1095-953X}, mesh = {Humans ; *Glial Fibrillary Acidic Protein/blood ; Female ; Male ; Biomarkers/blood ; *Neurofilament Proteins/blood ; Aged ; Middle Aged ; *Frontotemporal Dementia/mortality/blood/diagnosis ; Prognosis ; Registries ; }, abstract = {BACKGROUND: Survival estimates for frontotemporal lobar degeneration (FTLD)-related syndromes by incorporating fluid biomarkers are essential to better assess their prognostic value and explore how they might inform long-term outcomes in FTLD. Population-based registries provide valuable data for these predictions. The aim of the present study was to assess whether NfL and GFAP levels correlate with mortality risk in a population-based registry of incident FTLD.

METHODS: Incident cases with FTLD-spectrum, occurring between 2018 and 2020, were followed for up to six years. Survival and hazard analysis according to biomarkers levels were conducted.

RESULTS: Median survival was 6 years from symptom onset and 3 years from diagnosis. While FTD-ALS phenotype showed significantly shorter survival, no differences were observed among bvFTD, PPAs, and CBS/PSP. Biomarkers were significantly associated with survival. Higher plasma GFAP (HR = 1.006, 95%CIs 1.001-1.012; p = 0.026) and plasma NfL (HR = 1.027, 95%CIs 1.003-1.053; p = 0.025) were associated with increased mortality risk in bvFTD, PPAs, and CBS/PSP.

CONCLUSIONS: These results highlight the potential of NfL and GFAP as valuable biomarkers for assessing prognosis in FTLD and underscore the importance of incorporating biomarker analysis into clinical practice for more accurate patient management. Further studies are needed to refine prognostic models for FTLD.}, } @article {pmid42069088, year = {2026}, author = {Senerchia, G and Iuzzolino, VV and Spisto, M and Panico, F and Polito, C and Aruta, L and Fiorenza, M and Sirica, R and Terracciano, D and Dubbioso, R}, title = {Elevated plasma sTREM2 reflects microglial activation but lacks diagnostic and clinical relevance in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {224}, number = {}, pages = {107430}, doi = {10.1016/j.nbd.2026.107430}, pmid = {42069088}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; Female ; Male ; *Microglia/metabolism ; Middle Aged ; *Membrane Glycoproteins/blood ; Biomarkers/blood ; *Receptors, Immunologic/blood ; Aged ; tau Proteins/blood ; Adult ; }, abstract = {Microglial activation contributes to the neuroinflammatory response in amyotrophic lateral sclerosis (ALS). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) reflects microglial activity in several neurodegenerative disorders, but its role in ALS remains unclear. We evaluated plasma sTREM2 as a marker of microglial activation in ALS and compared its diagnostic performance with established blood biomarkers of neurodegeneration. Plasma sTREM2, neurofilament light chain (NfL), phosphorylated tau181 (Ptau181), and glial fibrillary acidic protein (GFAP) were measured in 100 patients with ALS, 30 healthy controls, and 30 disease mimics. Group differences were assessed using general linear models adjusted for age and sex. Associations with clinical variables and inflammatory markers were tested using Spearman correlation, and diagnostic performance was evaluated using receiver operating characteristic curves. Plasma sTREM2 differed across groups (p = 0.016), with higher levels in ALS compared with healthy controls (p = 0.013) and in mimics compared with healthy controls (p = 0.007), but no difference between ALS and mimics (p = 0.394). Discrimination between ALS and healthy controls was modest (area under the curve 0.677), with no discrimination between ALS and mimics (area under the curve 0.512). No association was found between sTREM2 and disease severity or inflammatory markers (all p > 0.10). Plasma sTREM2 increases in ALS but lacks diagnostic specificity and clinical associations, supporting its role as a nonspecific marker of neuroimmune activation rather than a biomarker of disease-related neurodegeneration.}, } @article {pmid42069252, year = {2026}, author = {Zi, X and Li, H and Fan, H}, title = {Considerations on Sayed et al's bimekizumab trial: Definitions, bias, and risk.}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {3}, pages = {e275-e276}, doi = {10.1016/j.jaad.2026.04.1974}, pmid = {42069252}, issn = {1097-6787}, } @article {pmid42069601, year = {2026}, author = {Robinson, L and Do-Ha, D and Cheng, F and Stevens, CH and Rosa Porto, R and Coles, M and Subachandran, J and Kalajdzic, P and Lui, J and Balez, R and Sanz Muñoz, S and Cabral-da-Silva, MC and Berg, T and Morsch, M and Lisowski, L and Tan, RH and Burgio, G and Karl, T and Lee, A and Chung, RS and Blair, I and Ooi, L}, title = {ALS-FTD-linked CCNF[S621G] drives increased hippocampal astrocyte ramification and mitochondrial dysfunction and impairs motor neuron excitability.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {42069601}, issn = {1742-2094}, support = {APP1107644//National Health and Medical Research Council/ ; APP1135720//National Health and Medical Research Council/ ; CE230100021//Australian Research Council/ ; }, mesh = {Animals ; *Astrocytes/pathology/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Motor Neurons/pathology/metabolism ; Mice ; *Hippocampus/pathology/metabolism ; Humans ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Mice, Transgenic ; Female ; *Mitochondria/pathology/metabolism ; Male ; Mice, Inbred C57BL ; Disease Models, Animal ; Cells, Cultured ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping pathology. Mutations in CCNF, encoding the E3 ubiquitin ligase, Cyclin F, can cause ALS, FTD, or both, even within the same family. Most prior studies of CCNF[S621G] have relied on overexpression systems, potentially confounding outcomes through disruption of endogenous Cyclin F. Here, we generated the first knock-in mouse model of endogenous Ccnf[S621G] using CRISPR/Cas9. Heterozygous and homozygous Ccnf[S621G] mice showed no motor decline or neuronal loss after 18 months, however immunohistochemistry revealed increased hippocampal astrocyte ramification, with sex-, age, and subfield-dependent effects. These data indicate that endogenous Ccnf[S621G] may prime early astrocyte alterations in the absence of overt neurodegeneration. Similar astrocyte morphological changes were observed in canonically affected regions of sporadic ALS and FTD-ALS patients post mortem, as well as in CCNF[S621G] iPSC-derived astrocytes following inflammatory stimulation. Proteomics on Ccnf mice identified early dysregulation of pathways related to translation, mitochondrial function, cytoskeletal remodelling, synaptic transmission and neuroinflammation. Correspondingly, CCNF[S621G] iPSC-derived astrocytes displayed impaired mitochondrial membrane potential and altered network morphology under both basal and inflammatory stimuli. As altered neuronal excitability is a hallmark of ALS, we examined astrocyte-driven changes to neuronal excitability. CCNF[S621G] iPSC-derived motor neurons cultured alone were hyperexcitable, firing more action potentials than isogenic controls. Remarkably, co-culture with CCNF[S621G] astrocytes, but not isogenic control astrocytes, abolished repetitive firing, increased the proportion of neurons unable to generate action potentials, and reduced voltage-gated sodium currents in CCNF[S621G] and isogenic control neurons. Together, these findings identify astrocyte alterations as an early feature of CCNF[S621G]-mediated disease, in the absence of neuronal loss. Moreover, the combination of astrocytic mitochondrial dysfunction and the ability of CCNF[S621G] astrocytes to suppress repetitive neuronal firing suggests a critical astrocyte-driven non-cell autonomous mechanism that may contribute to an oligogenic role for CCNF in ALS/FTD pathogenesis.}, } @article {pmid42070160, year = {2026}, author = {Abdel Mageed, SS and Sayed, GA and Mahdy, A and El-Dakroury, WA and Abdulkader, AO and Moustafa, HAM and Mansour, RM and Mohammed, OA and Elballal, MS and Elesawy, AE and Doghish, AS}, title = {miRNAs in Amyotrophic Lateral Sclerosis: Tiny Molecules, Tremendous Impact.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42070160}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/diagnosis/metabolism ; Humans ; *MicroRNAs/genetics/metabolism ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder distinguished by progressive motor neuron degeneration, with diverse clinical manifestations and complex genetic and environmental triggers. The variability in disease progression underscores the necessity for tailored diagnostic and therapeutic approaches. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising biomarkers and therapeutic targets in ALS. Dysregulation of specific miRNAs has been linked to mechanisms of ALS, including neuromuscular dysfunction, neuroinflammation, and neuronal survival/apoptosis. The potential of miRNA-based therapies, such as mimics and inhibitors, offers a more integrated approach by modulating entire disease networks, rather than targeting isolated pathways. However, challenges persist, particularly in delivering these therapies efficiently across the blood-brain barrier and minimizing off-target effects. Current delivery strategies involving nanoparticles, viral vectors, and exosome-based approaches require optimization for clinical use. This review synthesizes the latest research on miRNA-mediated mechanisms in ALS, evaluating their diagnostic, prognostic, and therapeutic potential, while highlighting the current limitations in clinical validation. It underscores the importance of standardized methodologies, multi-omics integration, and rigorous validation to facilitate the clinical translation of miRNA-based strategies. Standardized protocols and multicenter validation in large cohorts are essential to confirm the diagnostic accuracy of miRNAs, paving the way for their clinical application in ALS precision medicine.}, } @article {pmid42070757, year = {2026}, author = {Liu, JY and Liu, SY and Ran, LX and Qiao, WH and Zhang, F and Zhang, KS and Liang, XX and Liu, MY and Yu, ZH and Wei, MJ and Zhong, X}, title = {Organelle-orchestrated cGAS-STING signaling and its role in neurodegeneration.}, journal = {Pharmacological research}, volume = {228}, number = {}, pages = {108216}, doi = {10.1016/j.phrs.2026.108216}, pmid = {42070757}, issn = {1096-1186}, mesh = {Humans ; Animals ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; cGAS-STING Signaling Pathway ; *Organelles/metabolism ; *Membrane Proteins/metabolism ; *Nucleotidyltransferases/metabolism ; STING Protein ; Signal Transduction ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; Mitochondria Associated Membranes ; }, abstract = {The cGAS-STING signaling pathway serves as a central signalling axis of the innate immune system, and its aberrant activation plays a pivotal role in inflammatory responses. Recent studies have demonstrated that its regulation depends not only on individual organelles but also on a coordinated interorganelle network. This review systematically analyze how mitochondria, centrosomes, the endoplasmic reticulum (ER), membrane contact sites (MCSs), the Golgi apparatus, endosomes, and lysosomes collectively orchestrate cGAS-STING signaling. Mitochondria initiate signaling by releasing mitochondrial DNA; centrosomes serve as platforms for double-stranded DNA accumulation to potentiate cGAS activation; the ER anchors STING in a calcium homeostasis-dependent manner; mitochondrial-associated ER membranes (MAMs) integrate calcium and lipid signaling as regulatory checkpoints governing STING trafficking to the Golgi apparatus; the Golgi amplifies downstream signaling through site-specific post-translational modifications of STING; finally, the endosome-lysosome system, together with ER-lysosome MCSs, acts as a coordinated hub for STING sorting, lysosomal degradation and signal termination. Consequently, disruption of organelle homeostasis leads to persistent STING activation. In neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and Huntington's disease, organelle dysfunction resulting from calcium overload, impaired organelle clearance, proteolytic cleavage of tethering proteins or multi-source attacks drives aberrant STING signaling. Sustained STING activity exacerbates pathological cascades such as protein misfolding, chronic neuroinflammation, and progressive neuronal loss. Therefore, therapeutic strategies targeting key regulatory nodes of the STING pathway, from upstream organelle repair to direct pharmacological inhibition, offer significant potential to mitigate disease-associated pathological progression and constitute a promising foundation for precision therapeutics in neurodegenerative disorders.}, } @article {pmid42071322, year = {2026}, author = {Buttifant, E and Allogmanny, S and Probst, Y}, title = {Investigating Disordered Eating Behaviours Among Individuals Living With Neurodegenerative Disease: A Scoping Review.}, journal = {Journal of human nutrition and dietetics : the official journal of the British Dietetic Association}, volume = {39}, number = {3}, pages = {e70250}, pmid = {42071322}, issn = {1365-277X}, mesh = {Humans ; *Neurodegenerative Diseases/psychology/complications ; *Feeding and Eating Disorders/psychology/epidemiology/etiology ; *Feeding Behavior/psychology ; Alzheimer Disease/complications/psychology ; Female ; Food Addiction ; Bulimia ; Anorexia ; Hyperphagia ; Male ; Middle Aged ; }, abstract = {AIM: Neurodegenerative diseases and disordered eating have become rapidly expanding areas of research. However, research addressing the relationship between the two is lacking.

METHODS: A scoping review guided by the Joanna Briggs Institute methodological framework was completed to synthesise the evidence related to disordered eating behaviours among individuals living with neurodegenerative disease. A systematic search strategy was applied across four scientific databases. A narrative descriptive analysis was conducted to identify key patterns in the studies categorised by the type of eating behaviour. The types of tools used within studies were explored.

RESULTS: Thirty-six evidence sources were included in this review. Overeating-related issues such as hyperphagia were identified (n = 5, 25%) for dementia and Alzheimer's disease-related studies. Appetite-related changes were prevalent across amyotrophic lateral sclerosis (n = 1, 100%) and dementia and Alzheimer's disease-related studies (n = 6, 30%). Food addiction and binge eating were reported in all Parkinson's disease studies (n = 9, 100%), and in one case report for dementia. Eating disorders such as anorexia, bulimia and binge eating disorder were identified in all multiple sclerosis-related studies (n = 6, 100%). Validated and unvalidated tools (53%, n = 19) were used to identify eating behaviours.

CONCLUSIONS: This review revealed reports of disordered eating behaviours among various neurodegenerative disease types. Additional research is required to understand the aetiology and mechanisms behind disordered eating behaviours in these populations. Standardised tools to assess eating behaviours for people living with a neurodegenerative disease are needed. Eating behaviours should be screened upon neurodegenerative disease diagnosis and monitored as part of routine care.}, } @article {pmid42072614, year = {2026}, author = {Ferreon, JC and Choi, KJ and Quan, MD and Tsoi, PS and Ferreon, CC and Coskun, U and Liao, SJ and Ferreon, ACM}, title = {Modulation of Biomolecular Aggregate Morphology and Condensate Infectivity.}, journal = {Biomolecules}, volume = {16}, number = {4}, pages = {}, pmid = {42072614}, issn = {2218-273X}, support = {R01 GM122763/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Heterogeneous Nuclear Ribonucleoprotein A1/chemistry/metabolism/genetics ; Phase Separation ; *Biomolecular Condensates/chemistry/metabolism ; *Protein Aggregates ; Amyloid/metabolism/chemistry ; Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Prions/chemistry/metabolism ; Protein Domains ; *Protein Aggregation, Pathological/metabolism ; }, abstract = {Neurodegenerative diseases feature diverse pathological protein aggregates, including Lewy bodies in Alzheimer's disease (AD) and skein-like filaments in amyotrophic lateral sclerosis (ALS). The physical mechanisms underlying this morphological diversity remain unclear. Here, we demonstrate that aggregation of the prion-like domain of hnRNPA1 (A1PrD), implicated in AD and ALS, is driven by solution composition and phase transition dynamics. Utilizing 3D timelapse and fluorescence lifetime imaging microscopy, we show that solution conditions modulate phase separation, gelation, and fibrillation, resulting in distinct structures such as fibril, gel, and starburst morphologies. Homotypic and heterotypic interactions between A1PrD and RNA were observed to shift the balance between pathological and physiological condensates. Importantly, amyloid-rich starbursts displayed prion-like infection capabilities toward amyloid-poor condensates. Our findings highlight how the interplay between solution composition and kinetic balances of liquid-liquid phase separation, gelation, and fibrillation shapes the diverse pathological aggregate morphologies characteristic of neurodegenerative diseases.}, } @article {pmid42072687, year = {2026}, author = {Fiorucci, C and Rossi, MN and Di Santo, R and Salvatori, I and Scaricamazza, S and Giuliani, S and Carletta, O and Filomena, E and Laurenti, D and Mattioli, R and Mosca, L and Valle, C and Ferri, A and D'Erchia, AM and Cervelli, M}, title = {Transcriptomic Analysis Reveals the Beneficial Effects of Spermidine in an ALS Mouse Model.}, journal = {Biomolecules}, volume = {16}, number = {4}, pages = {}, pmid = {42072687}, issn = {2218-273X}, support = {LSH-Puglia, T4-AN-01 H93C22000560003//INNOVA - Italian network of excellence for advanced diagnosis/ ; Grant Code IR0000010//ELIXIR-IT/ ; MAE0067342//Protocols of Scientific and Technological Bilateral Cooperation funded by the Ministry of Health/ ; L. 232/2016-art.1 cc. 314-337 awarded to the Department of Science of Roma Tre University (2023-2027)//MIUR-Italy Grants of Departments of Excellence/ ; CUP B83C22002820006//Progetto ECS 0000024 Rome Technopole/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Spermidine/pharmacology/therapeutic use ; Disease Models, Animal ; Mice ; Muscle, Skeletal/metabolism/drug effects ; Mitochondria/metabolism/drug effects ; Mice, Transgenic ; *Gene Expression Profiling ; Spinal Cord/metabolism/drug effects ; Humans ; Superoxide Dismutase-1/genetics ; *Transcriptome/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive degeneration of motor neurons and skeletal muscle. Gene expression analysis of the spinal cord and gastrocnemius of the SOD1-G93A ALS mouse model revealed a strong increase in inflammatory pathways and, specifically in the ALS gastrocnemius, a decrease in mitochondrial transcription and an increase in ribosomal protein expression. Treatment of ALS mice with the polyamine spermidine (SPD), a promising molecule in combating neurodegeneration and muscle atrophy, is able to partially restore the expression of more than four thousand genes in gastrocnemius tissue, including the mitochondrial regulator Pgc1α, as well as all the mitochondrial encoded genes and a large class of ribosomal proteins. SPD enhanced mitochondrial bioenergetics, as evidenced by Seahorse experiments, and delayed muscle weakness in vivo, as shown by grip strength records. These findings suggest that SPD can act as a potential supplement in the therapeutic strategy for ALS, offering a foundation for further research to improve patient outcomes.}, } @article {pmid42073390, year = {2026}, author = {Hossain, R and Surinkaew, S and Sompol, P and Bastaki, NK and Jafrin, R and Sekeroglu, N and Tangpong, J}, title = {Mapping the Polar Neuro-Interactome of Garcinia mangostana Against the AD-PD-ALS Nexus.}, journal = {Life (Basel, Switzerland)}, volume = {16}, number = {4}, pages = {}, pmid = {42073390}, issn = {2075-1729}, support = {WU69203//Walailak University under the New Researcher Development scheme/ ; }, abstract = {Background/Objectives: Neurodegenerative diseases like Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis (ALS) share common molecular pathways, including neuroinflammation and oxidative stress, which complicate the effectiveness of single-target treatments. Garcinia mangostana L. (mangosteen) has shown neuroprotective properties, but previous studies focused on lipophilic xanthones, which have poor bioavailability and uncertain blood-brain barrier permeability. Methods: In the current study, polar metabolites from G. mangostana peel aqueous extract (GMPE) were assessed for potential multi-target interactions via UHPLC-QTOF-MS-based metabolomics, systems pharmacology, and molecular docking analysis. Further, in silico ADMET screening and network-based analyses assessed for overlap between GMPE compounds and genes associated with neurodegeneration (AD, PD, ALS). Results: Analysis of genes linked to AD, PD, and ALS revealed 121 common molecular targets influenced by GMPE metabolites. Network and enrichment analyses indicated that the compounds derived from GMPE may be involved in common pathways related to oxidative stress, neuroinflammation, and neuronal survival. Molecular docking analyses suggest that selected metabolites are likely to exhibit moderate binding affinities to their respective protein targets. Conclusions: The results presented in this study provide evidence that GMPE may possess potential multi-target interactions within common neurodegenerative pathways. However, since the data are based on computational and predictive approaches, these results should be considered hypothesis-generating and warrant further experimental validation.}, } @article {pmid42073997, year = {2026}, author = {Rafique, A and Junaid, A and Bakovic, M}, title = {Impact of Oxidative Stress-Driven Ferroptosis in Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {27}, number = {8}, pages = {}, pmid = {42073997}, issn = {1422-0067}, support = {APP465536/CAPMC/CIHR/Canada ; }, mesh = {*Ferroptosis ; Humans ; *Oxidative Stress ; *Neurodegenerative Diseases/metabolism/pathology ; Iron/metabolism ; Animals ; Lipid Peroxidation ; Reactive Oxygen Species/metabolism ; }, abstract = {Ferroptosis is an iron-dependent cell death driven by lipid peroxidation and failure of cellular antioxidant defenses. It is triggered by oxidative stress and can be aggravated by aging, inflammation, and dysregulation of iron homeostasis. In the central nervous system, iron dyshomeostasis, mitochondrial dysfunction, and membrane lipid remodeling can amplify oxidative injury and increase susceptibility to ferroptotic damage, particularly in vulnerable neurons. There is growing evidence that ferroptosis-related processes are linked to Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. This review addresses novel approaches to track ferroptosis in vivo, such as imaging and biomarker techniques, and important molecular mechanisms linking iron metabolism, reactive oxygen species, and PUFA-driven lipid peroxidation to neuronal damage. We also explore upstream transcriptional control via NRF2, iron chelation and iron-handling modulation, inhibition of lipid peroxidation, and reinforcement of the System Xc-GSH-GPX4 and CoQ10-linked defense pathways. Subsequently, we highlight translational issues that need attention to further progress ferroptosis-targeted therapies for neurodegenerative disease.}, } @article {pmid42074010, year = {2026}, author = {Goloborshcheva, VV and Kostikova, YS and Kucheryanu, VG and Morozov, SG and Kokhan, VS}, title = {Insights into the Impact of Low-Dose Ionizing Radiation on Neurodegenerative Disease Progression in In Vivo Models.}, journal = {International journal of molecular sciences}, volume = {27}, number = {8}, pages = {}, pmid = {42074010}, issn = {1422-0067}, support = {FGFU-2025-0004//Russian state contract/ ; }, mesh = {Animals ; *Neurodegenerative Diseases/radiotherapy/pathology/metabolism ; Humans ; *Radiation, Ionizing ; Disease Progression ; Disease Models, Animal ; Autophagy/radiation effects ; DNA Repair/radiation effects ; }, abstract = {The effective treatment of neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, remains a critical challenge in modern medicine. Given the limitations of current therapies, alternative strategies to slow neurodegeneration are urgently needed. This study presents a critical review of the current evidence regarding low-dose ionizing radiation (IR) as a promising modality for modulating neurodegenerative processes. This study examines current experimental data on the effects of low-dose IR (LDIR) on cellular protective and compensatory mechanisms, including evidence from in vivo models of NDDs. Our analysis demonstrates that LDIR enhances antioxidant activity and DNA repair, stimulates autophagy and neuroplasticity, and modulates neuroinflammatory signaling. Collectively, these findings support the hypothesis of the neuroprotective potential of LDIR, underscoring its translational viability provided that strict dosimetric guidelines are followed and individual biological responses are rigorously monitored.}, } @article {pmid42074053, year = {2026}, author = {Ribeiro, GD and Queiroz, DD and Monteiro-Neto, JR and Gerhardt, E and de Souza, GF and Albino, PCSC and Paranhos, LH and Outeiro, TF and Eleutherio, ECA}, title = {Molecular Modulation of the Crosstalk Between TDP-43 and SOD1.}, journal = {International journal of molecular sciences}, volume = {27}, number = {8}, pages = {}, pmid = {42074053}, issn = {1422-0067}, support = {CNE 201.174/2022//FAPERJ/ ; PROBRAL 88881.986154/2024-01//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; PQ 309635/2023-3//National Council for Scientific and Technological Development/ ; CNPq Universal 401780/2023-6//National Council for Scientific and Technological Development/ ; 210.034/2026//FAPERJ/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; *Superoxide Dismutase-1/metabolism/genetics ; Humans ; Phosphorylation/drug effects ; Pyruvaldehyde/pharmacology ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Cytosol/metabolism ; Mutation ; Glycosylation ; Cell Line ; Protein Binding ; Cell Nucleus/metabolism ; }, abstract = {Glycation of superoxide dismutase 1 (SOD1) has been shown to modulate the cytosolic levels of phosphorylated TAR DNA-binding protein 43 (TDP-43), a hallmark of amyotrophic lateral sclerosis (ALS) pathology. In this study, we investigated the interaction between TDP-43 and SOD1 and assessed how methylglyoxal (MGO)-induced glycation and the ALS-associated G93A SOD1 mutation affect this interplay in H4 cells. MGO exposure reduced SOD1 activity and TDP-43 phosphorylation in cells expressing WT SOD1, but not in those expressing G93A SOD1. Both WT and mutant SOD1 interacted with TDP-43 in the nucleus and cytosol; however, cytosolic interactions were more prevalent in G93A-expressing cells. Although MGO did not significantly alter the overall interaction between TDP-43 and WT SOD1, it induced cytosolic inclusion formation at 0.4 mM, a concentration associated with reduced cell viability. These inclusions did not colocalize with stress granules, indicating alternative aggregation pathways. Treatment with cyclosporin A, which inhibits the phosphatase calcineurin, decreased both TDP-43-WT SOD1 inclusions and cytosolic interactions between TDP-43 and G93A SOD1. Together, these findings suggest that SOD1 damage, induced by glycation or ALS-linked mutation, may affect TDP-43 phosphorylation status and promote its cytosolic mislocalization and aggregation, providing new insights into ALS-associated proteinopathy.}, } @article {pmid42074133, year = {2026}, author = {Meltzer, M and Zamir, MS and Tzuri, N and Tan, AM and Geva, M and Hayden, MR and Lichtenstein, RG}, title = {Pridopidine Protects ALS Patient-Derived Neural Progenitor Cells via Sigma-1 Receptor Activation.}, journal = {International journal of molecular sciences}, volume = {27}, number = {8}, pages = {}, pmid = {42074133}, issn = {1422-0067}, mesh = {*Receptors, sigma/metabolism/agonists ; Humans ; Sigma-1 Receptor ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy ; *Neural Stem Cells/metabolism/drug effects ; *Piperidines/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Endoplasmic Reticulum Stress/drug effects ; Apoptosis/drug effects ; Cell Survival/drug effects ; Induced Pluripotent Stem Cells/metabolism/drug effects ; Tunicamycin/pharmacology ; Mitochondria/metabolism/drug effects ; Transcription Factor CHOP/metabolism ; Neuroprotective Agents/pharmacology ; }, abstract = {The sigma-1 receptor (S1R) is an endoplasmic reticulum (ER)-resident protein enriched at the mitochondria-associated ER membranes (MAMs) that supports ER homeostasis, preserves mitochondrial function, and enhances cell survival under stress. Disruptions of MAM integrity and prolonged ER stress are well-recognized pathological features of amyotrophic lateral sclerosis (ALS), contributing to motor neuron dysfunction and degeneration. In this study, we evaluated the protective effects of pridopidine, a highly selective and potent S1R agonist currently in clinical development for Huntington's disease (HD) and ALS, using neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs) from a patient with sporadic ALS. Exposure of ALS NPCs to the ER stressor tunicamycin increased the ER stress markers binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP), disrupted mitochondrial membrane potential, upregulated expression of the mitochondrial apoptotic marker, BAX, increased caspase-3 activation, and reduced cell viability. Pridopidine significantly attenuated tunicamycin-induced BiP and CHOP expression in a biphasic, dose-dependent manner (with maximal efficacy at 1 µM), consistent with the typical pharmacology of S1R agonists. Pridopidine restored mitochondrial membrane potential, reduced mitochondrial apoptotic signaling, shown by decreased BAX expression and caspase-3 activation, and improved survival of ALS-NPCs under ER stress. Co-treatment with the selective S1R antagonist, NE-100, attenuated these effects, supporting an S1R-mediated mechanism of action for pridopidine. Together, these results demonstrate that S1R activation by pridopidine mitigates ER-stress-induced mitochondrial dysfunction and cell loss in ALS-NPCs, resulting in enhanced survival of NPCs supporting the therapeutic potential of pridopidine in ALS.}, } @article {pmid42074537, year = {2026}, author = {Yesbek Kaymaz, A and Bora-Akoğlu, G and Erdem Yurter, H and Grunseich, C}, title = {Gene Targeted Therapies for Neurodegenerative Disorders: Strategies and Implications in ALS and SMA.}, journal = {Genes}, volume = {17}, number = {4}, pages = {}, pmid = {42074537}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Genetic Therapy/methods ; *Muscular Atrophy, Spinal/genetics/therapy ; Animals ; Genetic Vectors ; *Neurodegenerative Diseases/genetics/therapy ; Gene Editing ; *Gene Targeting/methods ; Gene Therapy Agents ; }, abstract = {Advances in technology have provided a better understanding of the genetic basis of neurodegenerative disorders and their underlying molecular pathophysiology. However, treating these disorders with conventional strategies is a major challenge. The approval of gene targeted therapy for spinal muscular atrophy (SMA) has laid the foundation for developing highly personalized therapies for other neurodegenerative disorders. As intensive research and efforts to advance gene targeted therapies continue, this review provides an overview of viral and non-viral vectors and delivery methods, as well as treatment strategies, including gene addition, replacement, editing, silencing, and splice modulation. Gene targeted approaches and clinical trials for SMA and amyotrophic lateral sclerosis (ALS) have demonstrated success, and additional studies are in progress. The design of efficient clinical trials which facilitate successful translation into clinical practice is of critical importance. Key considerations include the selection of appropriate disease models, understanding the natural history of the disease, and establishing well-defined outcome measures to assess prognosis of the disease and therapeutic efficacy. Finally, the precision of CRISPR-based gene editing offers the potential for one-time corrective therapies for monogenic disorders like SMA and SOD1-ALS.}, } @article {pmid42074613, year = {2026}, author = {Quak, ZX and Wang, F and Tay, SKH and Koh, PL and Yap, ES and Ng, KWP}, title = {Thrombosis in Neuromuscular Medicine: Current Evidence, Unmet Needs, and Future Directions.}, journal = {Journal of clinical medicine}, volume = {15}, number = {8}, pages = {}, pmid = {42074613}, issn = {2077-0383}, abstract = {Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is an important but under-recognised complication in neuromuscular diseases. In adults, emerging epidemiological data suggests increased VTE occurrence in conditions such as Amyotrophic Lateral Sclerosis, myotonic dystrophy, myasthenia gravis, inflammatory neuropathies, inflammatory myopathies, and POEMS syndrome. This heightened risk reflects not only disease-related immobility but also disorder-specific biological mechanisms, including inflammation, endothelial dysfunction and cardiomyopathy-related stasis. Therapies such as corticosteroids, IVIG-related hyperviscosity, long-term central venous access, perioperative immobility, critical illness, and complex orthopaedic procedures have prothrombotic effects. Despite this multifactorial risk profile, disease-specific guidance for thromboprophylaxis is lacking, and current practice relies heavily on extrapolation from general medical and surgical recommendations rather than data derived from neuromuscular cohorts. In children and adolescents, the VTE burden is less well-characterised, but events have been reported in Duchenne and Becker muscular dystrophy, congenital myopathies, and spinal muscular atrophy particularly with advanced motor impairment, severe cardiomyopathy, ventilatory insufficiency, and prolonged hospitalisation. Beyond venous events, selected neuromuscular disorders also exhibit increased arterial thrombosis risk. Myotonic dystrophy and dystrophinopathies are associated with cardiomyopathy and arrhythmia that predispose to systemic embolism and stroke, while inflammatory myopathies may demonstrate arterial events related to vasculitic or endothelial processes, although overall evidence remains limited. This review summarises available empirical and epidemiological evidence on venous and arterial thrombosis across adult and paediatric neuromuscular disorders, outlines disease-specific mechanistic pathways, examines treatment-related contributors, and highlights key evidence gaps that must be addressed to guide rational and targeted prophylaxis strategies in this complex, heterogeneous population.}, } @article {pmid42074898, year = {2026}, author = {Shovman, Y and Lerner, Y and Gotkine, M}, title = {Slower Progression Rates in Lower Limb-Onset ALS.}, journal = {Journal of clinical medicine}, volume = {15}, number = {8}, pages = {}, pmid = {42074898}, issn = {2077-0383}, support = {//Perner Yaacov memorial fund/ ; }, abstract = {Objectives: The aim of this study was to assess the differences in diagnostic delay and disease progression in people with ALS (PALS) based on site of onset. Methods: A retrospective analysis of prospectively collected data was performed, including all PALS seen in the ALS clinic in the Hadassah Medical Center between January 2009 and March 2022. PALS were divided to three groups based on site of onset (upper limb onset-ULO, lower limb onset-LLO, or bulbar onset-BO). A linear mixed-effects model was constructed with the following variables: diagnostic delay, site of onset, age of onset and time since the initial visit. The model was applied to the ALSFRS-R total score and the bulbar and motor subscales. Results: Data from 1255 visits of 281 PALS were included in the study. PALS with LLO had longer diagnostic delays than PALS in the BO group. Slower decline of total ALSFRS-R score was observed in younger PALS, and in PALS with LLO when compared with PALS with BO or ULO. The slower decline of ALSFRS-R in PALS with LLO was due to a slower decline in the motor subscale. Longer diagnostic delays were associated with lower total ALSFRS-R scores at the initial visit and with slower rates of decline. Conclusions: Comparison among PALS with ULO, LLO and BO revealed differences in the diagnostic delay and in the rate of functional decline, suggesting that differentiating between ULO and LLO ALS may be useful in the stratification of PALS in clinical trials.}, } @article {pmid42076023, year = {2026}, author = {Rodkin, S and Gasanov, M and Tushev, A and Belousova, E and Gordeeva, Y and Nwosu, C and Tolmacheva, A}, title = {The Dual Role of Connexins in Stroke, Neurotrauma, Neurodegenerative and Psychiatric Disorders: A Global Systematic Review.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {8}, pages = {}, pmid = {42076023}, issn = {1420-3049}, support = {25-75-10137//Russian Science Foundation/ ; }, mesh = {Humans ; *Connexins/metabolism/genetics ; *Mental Disorders/metabolism ; *Neurodegenerative Diseases/metabolism ; Animals ; *Stroke/metabolism ; }, abstract = {Background: Connexins (Cx) are a family of transmembrane proteins that form gap junctions and connexin hemichannels (HCs), enabling direct intercellular communication within the nervous system. Connexin 43 (Cx43), the principal astrocytic connexin, exhibits a context-dependent dual role: under physiological conditions it maintains tissue homeostasis and metabolic support, whereas under pathological conditions excessive activation of Cx43 hemichannels promotes neuroinflammation, excitotoxicity, blood-brain barrier disruption, and secondary neural tissue damage. Other connexin isoforms also contribute to the pathogenesis of neurological and psychiatric disorders through alterations in neuronal synchronization, glial signaling, and myelin integrity. Objective: To systematize current evidence on the role of key connexin isoforms in acute nervous system injuries-including stroke, traumatic brain injury, spinal cord injury, and peripheral nerve injury-as well as chronic disorders such as neurodegenerative diseases, epilepsy, and psychiatric disorders, with particular emphasis on the functional duality of connexin channels and the therapeutic potential of their selective modulation. Methods: A systematic literature search was conducted in the PubMed, Scopus, and Web of Science databases in accordance with the PRISMA framework and the PRISMA Extension for Scoping Reviews guidelines. The review included data from experimental models, postmortem brain studies, genetic association analyses, and pharmacological intervention studies. The retrieved studies were screened, assessed for eligibility, and integrated using a qualitative narrative synthesis approach. Results: In acute neural injuries, hyperactivation of Cx43 hemichannels amplifies inflammatory signaling, edema formation, and neuronal death, whereas selective HCs inhibitors reduce lesion volume and improve functional outcomes in experimental models. Connexin 36 (Cx36) contributes to cortical spreading depolarization and seizure propagation, while Connexin 32 (Cx32) and Connexin 47 (Cx47) are critically involved in oligodendrocyte function and white-matter demyelination. In PNI, Cx43 upregulation contributes to neuropathic pain, whereas mutations in Cx32 cause hereditary demyelinating neuropathies. In neurodegenerative diseases-including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis-Cx43 hemichannel activity promotes neuroinflammation and pathological protein accumulation, while reduced Cx32/Cx47 expression disrupts metabolic support of axons. In psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia, decreased astrocytic connexin expression (Cx43 and Cx30) has been associated with impaired glial-neuronal communication and cognitive-emotional dysfunction. In epilepsy, increased Cx43/Cx30 expression contributes to neuronal hypersynchronization and blood-brain barrier dysfunction, whereas selective hemichannel blockade suppresses seizure activity. Conclusions: Cx-particularly Cx43-occupies a central position in the molecular mechanisms of secondary neural injury and network dysfunction. The dual functional properties of gap junctions and hemichannels determine their context-dependent effects across neurological and psychiatric diseases. Selective inhibition of pathological HCs activity shows significant neuroprotective and anticonvulsant potential and represents a promising direction for the development of targeted therapeutic strategies. Further studies are required to determine optimal therapeutic time windows, tissue-specific effects, and the long-term safety of Cx modulation.}, } @article {pmid42076656, year = {2026}, author = {Manavalan, G and Arnon, Y and Nithyaa, AN and Arnon, S}, title = {Smart Sensor-Driven Gait Rehabilitation Walker Using Machine Learning for Predictive Home-Based Therapy.}, journal = {Sensors (Basel, Switzerland)}, volume = {26}, number = {8}, pages = {}, pmid = {42076656}, issn = {1424-8220}, mesh = {Humans ; *Gait/physiology ; *Machine Learning ; *Walkers ; Electromyography ; Female ; Male ; Biomechanical Phenomena ; Pilot Projects ; Arthritis, Rheumatoid/rehabilitation/physiopathology ; Middle Aged ; Aged ; }, abstract = {Abnormal gait associated with neuromuscular and musculoskeletal disorders represents a growing clinical burden, particularly in aging populations. This study presents a modular, low-cost Smart Rehabilitation Walker (SRW) that integrates multimodal sensing and real-time haptic feedback to enable simultaneous gait monitoring and corrective intervention in both clinical and home environments. The system combines force-sensing resistors for bilateral load symmetry assessment, inertial measurement units for fall detection, and surface electromyography (sEMG) for neuromuscular activity monitoring within a closed-loop assistive feedback architecture. A 15-day pilot study involving ten individuals with rheumatoid arthritis and clinically observed neurological gait abnormalities demonstrated measurable improvements in gait biomechanics. The Force Symmetry Index (FSI), calculated using the Robinson symmetry metric, decreased from an average of 0.9691 to 0.2019, corresponding to a 79.26% average reduction in inter-limb load asymmetry. Concurrently, sEMG measurements showed a substantial increase in neuromuscular activation (ΔEMG = 4.28), with statistical analysis confirming a significant improvement across participants (paired t-test: t(9) = 13.58, p < 0.001). To model rehabilitation trajectories, a nonlinear predictive framework based on Gaussian Process Regression achieved high predictive accuracy (R[2] ≈ 0.9, with a mean RMSE of 0.0385), while providing uncertainty-aware trend estimation. Validation using an independent amyotrophic lateral sclerosis gait dataset further demonstrated the transferability of the analytical pipeline. These results highlight the potential of sensor-enabled assistive walkers as scalable platforms for quantitative gait rehabilitation, adaptive feedback, and long-term mobility monitoring.}, } @article {pmid42076823, year = {2026}, author = {Petrozziello, T and Mizerak, E and Krishnamoorthy, A and Donahue, RA and Castillo Torres, AL and Monsanto, RZB and Hammerschlag, BL and Webster, HA and Fillingham, B and Kivisäkk, P and Timmons, J and Fox, K and Arnold, SE and Cohen, J and Klee, J and Paganoni, S and Cudkowicz, ME and Chibnik, LB and Berry, JD and Sadri-Vakili, G}, title = {Phosphorylated Tau at Threonine 181 Is Elevated in Amyotrophic Lateral Sclerosis Plasma.}, journal = {Muscle & nerve}, volume = {74}, number = {1}, pages = {139-148}, doi = {10.1002/mus.70266}, pmid = {42076823}, issn = {1097-4598}, support = {//Linda and Mike Mussallem Foundation/ ; //Andre Family/ ; P30AG062421//National Institute of Aging (NIA)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood ; *tau Proteins/blood ; Phosphorylation ; Male ; Middle Aged ; Female ; Biomarkers/blood ; *Threonine/metabolism ; Disease Progression ; Aged ; Cohort Studies ; Cross-Sectional Studies ; Adult ; Longitudinal Studies ; }, abstract = {INTRODUCTION/AIMS: Reliable biomarkers for amyotrophic lateral sclerosis (ALS) remain limited. Although previous studies have shown altered cerebrospinal fluid (CSF) tau measures in ALS, the clinical relevance of plasma tau species as biomarkers remains unclear. Here, we sought to determine whether total tau, tau phosphorylated at T181 (pTau-T181), and their ratio are altered in ALS and whether these measures correlate with disease progression.

METHODS: Plasma samples were obtained from two independent cohorts from the Northeast ALS Consortium (NEALS) Biofluid Repository (cohort 1: n = 76 ALS and n = 52 healthy controls [HC]; cohort 2: n = 98 ALS and n = 90 HC). Cohort 1 (mean age ALS 61.8 years; 63% male) included longitudinal samples; cohort 2 (mean age ALS 45.8 years; 51% male) was cross-sectional. Tau measures were quantified using Quanterix Simoa (cohort 1) and Meso Scale Discovery (MSD) (cohort 2) platforms.

RESULTS: In cohort 1, total tau was lower in ALS versus HC (0.88 vs. 1.49 pg/mL), whereas pTau-T181 (30.29 vs. 12.97 pg/mL) and pTau-T181:tau ratio (52.07 vs. 13.18 pg/mL) were higher. In cohort 2, total tau (40.07 vs. 25.85 pg/mL), pTau-T181 (6.77 vs. 2.18 pg/mL), and their ratio (0.37 vs. 0.098 pg/mL) were elevated in ALS. Plasma measures in cohort 1 did not correlate with decline on the revised ALS Functional Rating Scale (ALSFRS-R). Brain-derived tau (BD-tau) was elevated in ALS (10.07 vs. 5.65 pg/mL) in a subset of samples from cohort 1.

DISCUSSION: Collectively, plasma pTau-T181 levels are consistently elevated in ALS, supporting future studies to define its potential utility as an ALS biomarker.}, } @article {pmid42079104, year = {2026}, author = {Kaye, J and Amirani, N and Chan, Ú and Al Bistami, N and Faghihmonzavi, Z and Ahirwar, M and Thomas, R and Robinson, W and Vertudes, E and Raja, K and Barch, M and Linsley, D and Jovicic, A and Finkbeiner, S}, title = {Predictive Cellular Signatures from Live Human Motor Neurons Distinguish TDP-43 ALS and Enable ALS Subtype Stratification.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42079104}, issn = {2692-8205}, support = {P01 AG073082/AG/NIA NIH HHS/United States ; R01 LM013617/LM/NLM NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive, rapid deterioration of motor neurons (MNs). Rare mutations in a handful of genes are sufficient to cause ALS; however, 90% of ALS cases are not linked to these genes and their underlying cause remains unknown. Abnormal subcellular distribution, structure or aggregation of the TDP-43 protein are nearly universal hallmarks of the disease, suggesting a shared molecular mechanism across both genetic and sporadic ALS (sALS). However, the heterogeneity of the ALS clinical syndrome suggests that the underlying mechanisms culminating in ALS and TDP-43 pathology may partly differ among individuals and may need to be understood to develop successful therapies that target subgroups of patients. Here, we harnessed the power of machine learning (ML) to begin to decode, in a systematic and unbiased fashion, the cellular signatures of ALS. We used high-content imaging of live, human iPSC-derived motor neurons (iMNs) from ALS patients or gene-edited and gene-corrected TDP-43 mutant lines to train shallow connected ML algorithms (SMLs) and deep convolutional neural networks (DNNs). Our models identified and distinguished mutant and control iMNs with moderately high accuracy. We then used explainability methods to uncover the discriminating cellular signals and found that the strongest ones mapped to the nuclear area, suggesting underlying alterations within the nucleus. We validated this finding by revealing that TDP-43 mutant iMNs display alterations in nucleocytoplasmic shuttling and cellular integrity. Further, a time-interaction ML model uncovered dynamic morphological transitions preceding degeneration, offering a window into early pathogenic events as well as neurodevelopmental changes. Extending our ML pipeline to iMNs with mutations in the ALS gene C9orf72 or derived from sALS revealed both overlapping and distinguishable signatures, suggesting shared yet distinct mechanistic pathways. Together, these findings establish ML-driven phenotypic profiling as a powerful approach to stratify people with ALS, help disentangle the molecular heterogeneity of ALS and produce a more holistic phenotypic definition in cell-based models, and ultimately find causes and treatments. This strategy offers a scalable and innovative paradigm for uncovering early disease mechanisms not only in ALS but potentially across a spectrum of neurodegenerative and sporadic disorders.}, } @article {pmid42080410, year = {2026}, author = {Kasper, E and Lehto, A and Nordmann, N and Peters, O and Hellmann, J and Priller, J and Spruth, EJ and Petzold, GC and Vogt, I and Weydt, P and Bernsen, S and Dinter, E and Falkenburger, B and Günther, R and Düzel, E and Glanz, W and Synofzik, M and Beichert, L and Spottke, A and Wagner, M and Brosseron, F and Schmid, MC and Schneider, A and Teipel, S and Prudlo, J and Hermann, A}, title = {Impact of Plasma p-tau181 on Cognition, Motor Phenotypes, and Disease Course in ALS.}, journal = {Annals of clinical and translational neurology}, volume = {13}, number = {8}, pages = {1711-1718}, pmid = {42080410}, issn = {2328-9503}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/physiopathology/complications ; *tau Proteins/blood ; Female ; Disease Progression ; Male ; Aged ; Middle Aged ; Biomarkers/blood ; Phosphorylation ; *Frontotemporal Dementia/blood/physiopathology/complications ; Neurofilament Proteins/blood ; Longitudinal Studies ; *Cognitive Dysfunction/etiology/blood/physiopathology ; }, abstract = {Phosphorylated tau181 (p-tau181), an Alzheimer's disease biomarker, was recently evaluated in amyotrophic lateral sclerosis (ALS). We investigated plasma p-tau181 in 202 ALS/ALS-FTD patients and 94 healthy controls, assessing cognitive performance, motor function, and longitudinal dynamics. Plasma p-tau181 and NfL were significantly elevated in ALS, with p-tau181 increasing over 1 year while NfL remained stable. Neither marker correlated with cognitive performance, and only NfL was associated with disease severity and progression. Plasma p-tau181 was higher in patients with predominant lower motor neuron involvement. The results indicate that p-tau181 reflects peripheral processes in ALS, providing a complementary, mechanistically distinct biomarker from NfL.}, } @article {pmid42081010, year = {2026}, author = {Li, J and Yang, X and Liu, J and Zhao, K}, title = {Unraveling the Pathophysiological Link Between ALS and SCA: The Role of Ischemic Cerebral Vascular Dissection and the Efficacy of Endovascular Therapy.}, journal = {Cerebellum (London, England)}, volume = {25}, number = {3}, pages = {}, pmid = {42081010}, issn = {1473-4230}, support = {YXJL-2022-00351-0183//Neuroscience Innovation Development Research Project/ ; PW2022A-28//Pudong New Area Health Commission/ ; }, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/complications/genetics ; *Spinocerebellar Ataxias/physiopathology/diagnostic imaging/complications/genetics ; Young Adult ; *Endovascular Procedures/methods ; *Brain Ischemia/diagnostic imaging/physiopathology/complications/therapy ; Treatment Outcome ; Dissection, Blood Vessel ; }, abstract = {To explore the role of ischemic cryptogenic vascular dissection (CVD) in a patient presenting with overlapping symptoms of amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia (SCA), and the impact of endovascular treatment on posterior circulation hypoperfusion, cerebellar atrophy, and clinical symptoms. A 22-year-old male patient with progressive neurological symptoms underwent MRI, CTA, and genetic testing, revealing cerebellar atrophy, a novel TGM6 gene variation associated with SCA type 35, and SETX gene deletions linked to ALS type 4. Ischemic CVD was diagnosed via dynamic contrast-enhanced CT (DCE-CT) and treated with endovascular stent repair followed by dual antiplatelet therapy. Following endovascular treatment, posterior circulation hypoperfusion and cerebellar atrophy were significantly improved. MRI follow-up showed increased cerebellar size and reduced interlobar spacing, with cerebellar dimensions expanding by up to 26.98% and interlobar spacing narrowing by up to 27.14%. Concurrently, the patient experienced marked improvement in clinical symptoms. At the 21-month follow-up, the patient's Modified Rankin Scale (MRS) score was rated as favorable. Ischemic CVD may underlie overlapping ALS and SCA symptoms, suggesting a genetic-vascular link. Endovascular treatment of CVD led to improvements in posterior circulation hypoperfusion, cerebellar atrophy, and clinical symptoms, supporting further investigation into this potential pathogenic nexus.}, } @article {pmid42081784, year = {2026}, author = {Zhu, RH and Kalra, S and Dobrowolski, P and Fok, D and DuVal, M and Putko, BN and Johnston, W and Beecher, G}, title = {Medical Assistance in Dying in ALS: Frequency, Survival, and Associations With Patient Characteristics in a Canadian Clinic.}, journal = {Neurology}, volume = {106}, number = {10}, pages = {e218032}, doi = {10.1212/WNL.0000000000218032}, pmid = {42081784}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy ; Female ; Retrospective Studies ; Canada/epidemiology ; Aged ; Male ; Middle Aged ; *Suicide, Assisted/statistics & numerical data ; Gastrostomy ; }, abstract = {OBJECTIVES: Medical assistance in dying (MAiD) has been available across Canada since 2016 for patients with amyotrophic lateral sclerosis (ALS). We aimed to characterize MAiD use, identify associated factors, and compare survival and location of death in a Canadian ALS cohort.

METHODS: We retrospectively reviewed patients with ALS followed at a Canadian multidisciplinary clinic who died between January 1, 2019 and December 31, 2024. Patient characteristics were described by MAiD status. Factors associated with MAiD utilization were evaluated using regression analyses, and survival and location of death were compared between patients who did and did not pursue MAiD.

RESULTS: Of 255 patients (median age 67 years [IQR 60-75]; 42% female), 55 (21.6%) underwent MAiD. Percutaneous endoscopic gastrostomy (PEG) use was inversely associated with MAiD utilization (OR 0.34, 95% CI 0.15-0.78), whereas demographic and disease characteristics were not associated with MAiD. Survival from diagnosis to death was shorter among patients who underwent MAiD (median 12 vs 14 months; p = 0.019), with no difference from symptom onset. Death at home was more frequent with MAiD (62% vs 35%; p < 0.001).

DISCUSSION: MAiD is a common end-of-life option in ALS, reflecting patient values and is associated with lower PEG use, shorter postdiagnosis survival, and more frequent death at home.}, } @article {pmid42081880, year = {2026}, author = {Schnieders, C and Scholl, C and Hoeflich, A and Schmicke, M}, title = {A pilot study on the influence of early pregnancy interferon τ to the expression of IGF-binding proteins in primary bovine hepatocytes.}, journal = {Domestic animal endocrinology}, volume = {96}, number = {}, pages = {107018}, doi = {10.1016/j.domaniend.2026.107018}, pmid = {42081880}, issn = {1879-0054}, mesh = {Animals ; Cattle ; Female ; *Hepatocytes/metabolism/drug effects ; *Interferon Type I/pharmacology ; Pregnancy ; *Pregnancy Proteins/pharmacology ; *Insulin-Like Growth Factor Binding Proteins/genetics/metabolism ; Cells, Cultured ; *Gene Expression Regulation/drug effects ; Pilot Projects ; RNA, Messenger/genetics/metabolism ; }, abstract = {The implantation period is crucial for the establishment of pregnancies in cows. Interferon τ (IFNτ) is produced during early implantation and acts in autocrine, paracrine and endocrine fashions on other endocrine systems. One of these is the insulin-like growth factor 1 (IGF-1) system, which is important for cell growth, proliferation, and therefore pregnancy establishment. This study investigated the effect of IFNτ on the expression of hepatic IGF-binding proteins (IGFBPs) in vitro. Primary bovine hepatocytes in a 2D sandwich culture model were stimulated with recombinant bovine IFNτ (rbIFNτ; 0.1-10.0 ng/mL) for six hours. The mRNA expression of IGFBP-1 to -7 and acid labile subunit (ALS) was measured using qRT‒PCR, and protein production was confirmed using western ligand blotting. All the IGFBPs (1-7) and ALS were expressed at basal levels in primary bovine hepatocytes, with IGFBP-2 to -4 secreted at appreciable concentrations in the medium. The expression of IGFBP-2 to -6 was stimulated by IFNτ, (treatment with rbIFNτ vs. control; IGFBP-2: for 0.5 ng/mL rbIFNτ, p = 0.0166; IGFBP-3: for 0.5 ng/mL, 5.0 ng/mL, and 10.0 ng/mL rbIFNτ, p = 0.0293, p = 0.0252, and p = 0.0099; IGFBP-4: for 0.5 ng/mL rbIFNτ, p = 0.0024; IGFBP-5: for 0.5 ng/mL and 10 ng/mL rbIFNτ, p = 0.0008 and p = 0.0421; IGFBP-6: for 0.1-10.0 ng/mL rbIFNτ, p = 0.0498-0.0022). These results indicate modulation of the IGF-system through IFNτ, which may contribute to adaptations supporting the early establishment of pregnancies in cattle.}, } @article {pmid42082278, year = {2026}, author = {Zhu, Z and Yuan, L and Yang, J and Jiang, S and Cao, Y and Yang, J and Zhang, Y and Mo, Y and Chen, C and Zhang, H and Zhou, J and , }, title = {Healthcare burden of bronchopulmonary dysplasia among very preterm infants in China: a cohort study.}, journal = {BMJ paediatrics open}, volume = {10}, number = {1}, pages = {}, pmid = {42082278}, issn = {2399-9772}, mesh = {Humans ; *Bronchopulmonary Dysplasia/epidemiology/mortality/economics/therapy ; China/epidemiology ; Infant, Newborn ; Prospective Studies ; Female ; Male ; Intensive Care Units, Neonatal ; Length of Stay/statistics & numerical data ; Gestational Age ; *Cost of Illness ; Infant, Extremely Premature ; Severity of Illness Index ; }, abstract = {OBJECTIVE: To assess the healthcare burden of bronchopulmonary dysplasia (BPD) among very preterm infants in China.

DESIGN: A prospective cohort study between 2022 and 2023.

SETTING: Chinese Neonatal Network (CHNN) participating centres.

PATIENTS: Infants with gestational age <32 weeks admitted to CHNN neonatal intensive care units.

MAIN OUTCOME MEASURES: A composite rate of BPD or mortality at 36 weeks' postmenstrual age (PMA), major comorbidities, clinical resources utilisation and outcome at discharge. BPD severity was classified by Jensen et al's criteria.

RESULTS: Among 17 793 eligible infants, 568 (3.2%) infants died before 36 weeks' PMA, 1729 (9.7%) were discharged against medical advice before 36 weeks' PMA, 9895 (55.6%) were classified as no BPD, 2751 (15.5%) developed Grade 1 BPD, 2634 (14.8%) developed Grade 2 BPD and 216 (1.2%) developed Grade 3 BPD. Infants with BPD had significantly longer hospital stays than those without BPD (median (IQR), 67 (52-84) vs 44 (34-56) days) and incurred higher total hospitalisation charges (median (IQR), 127 (91-177) vs 73 (52-103) thousand CNY) and charge per day (median (IQR), 1975 (1638-2361) vs 1714 (1409-2048) CNY). Mortality at discharge increased with BPD severity, with rates of 0.2% (18/9895) for infants without BPD, 0.5% (15/2751) for Grade 1 BPD, 2.1% (56/2634) for Grade 2 and 26.9% (58/216) for Grade 3. Similarly, the rates of major comorbidities and the need for home oxygen therapy increased with BPD severity.

CONCLUSIONS: Greater BPD severity was associated with increased comorbidities, higher in-hospital mortality and greater utilisation of healthcare resources. These findings emphasised the ongoing need to develop cost-saving strategies to reduce the risk and severity of BPD in this vulnerable population and improve overall care.}, } @article {pmid42082894, year = {2026}, author = {Kipourgos, G and Bakalis, N and Albani, E and Stefanopoulos, N and Lakoumentas, J and Tzenalis, A}, title = {Expert Consensus on Key Attributes of Nurses in Resuscitation Teams: Findings From a Delphi Study.}, journal = {Nursing in critical care}, volume = {31}, number = {3}, pages = {e70506}, pmid = {42082894}, issn = {1478-5153}, mesh = {Humans ; *Cardiopulmonary Resuscitation/nursing ; *Clinical Competence ; Delphi Technique ; Greece ; *Heart Arrest/nursing/therapy ; *Patient Care Team ; *Resuscitation ; }, abstract = {BACKGROUND: In-hospital cardiac arrest (IHCA) requires coordinated interdisciplinary action. Nurses are often first responders and essential members of resuscitation teams, yet the attributes that define their effectiveness remain unclear. Although team performance has been widely studied, few works have systematically examined nursing competencies in this context. This is the first Delphi-based study in Greece defining key nursing attributes within in-hospital resuscitation teams.

AIM: To achieve expert consensus on the key attributes characterizing effective nursing participation in IHCA teams.

STUDY DESIGN: A two-round Delphi study was conducted with experts in resuscitation and critical care. Round one involved thematic analysis of semi-structured interviews. In round two, experts rated attributes on a 10-point Likert scale. Consensus was defined as mean (M) > 8 and coefficient of variation (CV) < 20%. Descriptive statistics and Kendall's W assessed agreement across domains.

RESULTS: Thirty-nine attributes were identified and grouped into seven domains: education, experience, physical condition, psychological resilience, technical skills and non-technical skills. Thirty-five attributes met the consensus criteria. Highest agreement was observed for ALS certification, stress resilience, closed-loop communication, adaptability and teamwork. Strongest consensus emerged in non-technical (M = 9.75, CV = 3.79%) and technical (M = 9.61, CV = 5.62%) domains.

CONCLUSIONS: This study provides an evidence-informed framework of competencies and personal qualities underpinning nurses' effectiveness in resuscitation teams, emphasizing both technical expertise and non-technical skills-especially closed-loop communication, composure and collaboration.

The framework supports clearer role delineation, structured competency development and enhanced team effectiveness in IHCA management.}, } @article {pmid42082968, year = {2026}, author = {Terrin, F and Faggin, S and Bizzotto, E and Santinello, D and Cerantola, S and Borsato, G and Fabris, F and Scarso, A and Licitra, R and Guella, G and Sales, G and Cagnin, S and Treu, L and Bubacco, L and Giron, MC and Plotegher, N and Dalla Valle, L}, title = {β-Sitosterol β-D-glucoside (BSSG) triggers intestinal inflammation in zebrafish and mouse models prior to neurodegeneration onset.}, journal = {Journal of biomedical science}, volume = {33}, number = {1}, pages = {}, pmid = {42082968}, issn = {1423-0127}, support = {PhD Fellowship 2020//MUR/University of Padova/ ; PostDoc Fellowship 2024//Department of Biology/ ; PostDoc Fellowship ARD-B 2023//Department of Pharmaceutical and Pharmacological Sciences/ ; PostDoc Fellowship ARD-B 2020//Department of Pharmaceutical and Pharmacological Sciences/ ; Seed 2020//Department of Biology Intramural Grant/ ; Seed 2022//Department of Biology Intramural Grant/ ; Project ID: CN00000041 - SP. 3//National Center For Gene Therapy And Drugs Based On RNA Technology Neurodegeneration/ ; UNIPD-DSF-PRID-2023//San Camillo Hospital Grant, Treviso, Italy/ ; }, mesh = {Animals ; Zebrafish ; Mice ; Disease Models, Animal ; *Inflammation/chemically induced ; *Sitosterols/adverse effects/toxicity ; Gastrointestinal Microbiome/drug effects ; *Intestines/drug effects ; *Glucosides/adverse effects ; *Neurodegenerative Diseases/chemically induced ; }, abstract = {BACKGROUND: Glucosylated-sterols can be synthetized endogenously, absorbed through the diet or derive from bacterial infection. Their clinical relevance is currently underestimated, even though their imbalance has been associated with an increased risk of neurodegeneration over the lifespan. We studied the detrimental effects elicited by dietary consumption of the plant-derived β-sitosterol β-D-glucoside (BSSG), known to be associated with the occurrence of ALS-PDC, to elucidate its potential mechanism of action.

METHODS: Zebrafish larvae and adults, as well as mice, were treated with BSSG administered directly in the water or via customized food pellet, respectively. Since the intestine was identified as the primary target tissue, its morphological and functional characteristics were assessed, together with transcriptional profiling and gut microbiota sequencing. Ex vivo analysis of zebrafish gut contractility was applied to evaluate intestinal neuromuscular responses. Mutant and transgenic zebrafish lines were used to explore a potential BSSG mechanism of action.

RESULTS: BSSG induced intestinal inflammation in both zebrafish and mouse models. This previously unknown effect was evidenced by gut dysmotility and inflammatory response. Transcriptomic analyses revealed increased expression of inflammation-related genes in the intestine of both zebrafish and mice, while preliminary gut microbiota analyses suggested the onset of dysbiosis. Transgenic and mutant zebrafish lines, depleted of genes involved in glucocorticoids synthesis and activity, evidenced that BSSG likely interacts with the glucocorticoid receptor, potentially impairing its canonical anti-inflammatory activity.

CONCLUSIONS: We identified novel pathways altered by dietary BSSG exposure. This molecule appears to initially induce gut inflammation, leading to changes in intestinal morphology and function, and may contribute to neurodegeneration through disruption of the well-known gut-brain axis.}, } @article {pmid42083136, year = {2026}, author = {O'Reilly, ÉJ and Bjornevik, K and Furtado, JD and Patel, AV and Wang, Y and Kolonel, LN and Le Marchand, L and Ascherio, A}, title = {Pre-Diagnostic Plasma Carotenoids, Tocopherols and Retinol Levels, and Risk of Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {100}, number = {2}, pages = {426-435}, pmid = {42083136}, issn = {1531-8249}, support = {U01 CA167552/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; R01 NS045893/NS/NINDS NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; R01 CA49449//Common Fund/ ; R01 NS045893/NS/NINDS NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/epidemiology/diagnosis ; Female ; *Carotenoids/blood ; Male ; *Vitamin A/blood ; *Tocopherols/blood ; Case-Control Studies ; Middle Aged ; Aged ; Cohort Studies ; Risk Factors ; beta Carotene/blood ; }, abstract = {OBJECTIVE: Our goal was to examine whether pre-diagnostic plasma carotenoids and tocopherols are associated with amyotrophic lateral sclerosis (ALS).

METHODS: A nested case-control study within 4 United States cohorts, where 154 participants with pre-diagnostic blood-draw, were diagnosed during follow-up with amyotrophic lateral sclerosis (ALS). Controls were randomly selected from participants alive on the date a case was diagnosed, matched 2:1 by cohort, sex, age, race/ethnicity, fasting-status, time of blood-draw. Carotenoid and tocopherol levels were quantified by high-performance liquid-chromatography with diode array-detector. ALS incidence or death rate ratios (RR) were estimated using conditional logistic regression adjusting for body mass index, smoking status, physical activity, cholesterol, and urate levels.

RESULTS: The association between beta-carotene and ALS varied by sex (p-for-interaction = 0.007). After matched- and multivariable-adjustment, women with higher cis-, trans- and total beta-carotene had lower incidence of ALS (RR for 1-standard deviation [SD] increase in total beta-carotene: 0.68; 95% CI: 0.48-0.98; p = 0.038), whereas a positive association was seen in men (1-SD increase: RR = 1.44; 95% CI: 1.03-2.01; p = 0.033). However, after further adjustment for other correlated carotenoids, the association in men was attenuated, whereas it remained significant in women. Women with higher beta-cryptoxanthin, but not men, had a lower risk of ALS (1-SD increase: RR = 0.67; 95% CI: 0.48-0.94; p = 0.02; p-for-interaction = 0.12). Alpha-carotene, lutein-zeaxanthin, lycopene, retinol, and tocopherols were not associated with ALS, except for a borderline inverse association of gamma-tocopherol in men (RR = 0.74; 95% CI: 0.54-1.01; p = 0.059).

INTERPRETATION: Higher pre-diagnostic plasma levels of beta-carotene and beta-cryptoxanthin in women and gamma-tocopherol in men were suggestively associated with lower ALS risk. Other carotenoids or tocopherols were not clearly associated with ALS. ANN NEUROL 2026;100:426-435.}, } @article {pmid42084479, year = {2026}, author = {Liu, X and Dhakal, D and Gu, S and Li, G and Jing, M and Zhang, G and Wang, Y and Zhang, Z and Fan, D}, title = {Relationship between grip strength, functional outcome, and health-related quality of life measurements in amyotrophic lateral sclerosis patients.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/17582024.2026.2667425}, pmid = {42084479}, issn = {1758-2032}, abstract = {AIM: To explore how grip strength is related to functional status and health-related quality of life (HRQoL) in amyotrophic lateral sclerosis (ALS) patients.

METHODS: In the phase 2 trial of TBN for treatment of ALS, 148 patients in full analysis set received TBN (600 mg or 1200 mg) or a placebo for 180 days. Outcome measurements included ALS Functional Rating Scale-Revised (ALSFRS-R), 40-item ALS Assessment Questionnaire (ALSAQ-40), grip strength, and forced vital capacity (FVC). Spearman's rank correlation was used to examine associations between grip strength, ALSFRS-R and ALSAQ-40. A principal component analysis-ANCOVA model adjusted for sex was used to further explore the associations.

RESULTS: Grip strength was strongly correlated with ALSFRS-R fine motor function domain (rs = 0.740) and moderately correlated with ALSAQ-40 activities of daily living (ADL) domain (rs = -0.637) (p < 0.05). Weak correlations were observed between FVC and both ALSFRS-R total score (rs = 0.355) and respiratory domain (rs = 0.229) and ALSAQ-40 domains. Grip strength was a strong predictor of ALSFRS-R fine motor and ALSAQ-40 ADL domains.

CONCLUSION: Grip strength was associated with functional status and HRQoL, supporting its potential role as a meaningful clinical outcome measure in patients with ALS.}, } @article {pmid42084503, year = {2026}, author = {Shino, Y and Muraki, N and Kobatake, Y and Kamishina, H and Kosuge, H and Nakakido, M and Tsumoto, K and Furukawa, Y}, title = {Structural analysis of Cu/Zn-superoxide dismutase linked to neurodegenerative disease by antibody-guided cryo-EM.}, journal = {Protein science : a publication of the Protein Society}, volume = {35}, number = {6}, pages = {e70615}, pmid = {42084503}, issn = {1469-896X}, support = {19H05765//Ministry of Education, Culture, Sports, Science and Technology/ ; 22H02768//Ministry of Education, Culture, Sports, Science and Technology/ ; 22K19389//Ministry of Education, Culture, Sports, Science and Technology/ ; }, mesh = {Animals ; Dogs ; Cryoelectron Microscopy ; *Superoxide Dismutase-1/chemistry/metabolism/genetics ; *Antibodies, Monoclonal/chemistry/metabolism/immunology ; Humans ; Amyotrophic Lateral Sclerosis ; Models, Molecular ; *Neurodegenerative Diseases/veterinary/enzymology ; }, abstract = {Accumulation of misfolded proteins is a hallmark of many neurodegenerative diseases. To characterize such misfolded species in vivo, conformation-specific antibodies are widely used; however, limited knowledge of antibody-epitope interactions often hampers mechanistic insight. To address this, we determined the cryo-electron microscopy structure of the complex between a monoclonal antibody, 19A9, and Cu/Zn-superoxide dismutase (SOD1), a protein associated with canine degenerative myelopathy (DM), which is related to human amyotrophic lateral sclerosis. Biochemical analyses confirmed that 19A9 specifically recognizes monomeric SOD1, and the structure revealed binding near the interface normally used for homodimerization in native SOD1, with steric hindrance preventing interaction when the protein is in its homodimeric form. Immunofluorescence staining of spinal cord sections revealed that 19A9 stained a subset of motoneurons in DM-affected dogs, but not in asymptomatic controls. Structural characterization of the 19A9-monomeric SOD1 complex enabled us to propose that SOD1 monomers can arise in vivo under pathological conditions.}, } @article {pmid42084731, year = {2026}, author = {Pendergast, TH and Maddali, S and Chaluvadi, SR and Qi, P and Vencill, WK and Bennetzen, JL and Devos, KM}, title = {Widespread non-target-site resistance in Setaria viridis to four classes of herbicide.}, journal = {TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik}, volume = {139}, number = {6}, pages = {}, pmid = {42084731}, issn = {1432-2242}, support = {0952177//Directorate for Biological Sciences/ ; }, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Setaria Plant/genetics/drug effects ; Acetyl-CoA Carboxylase/genetics ; Genotype ; Acetolactate Synthase/genetics ; Mutation ; Polymorphism, Single Nucleotide ; Plant Proteins/genetics ; 3-Phosphoshikimate 1-Carboxyvinyltransferase/genetics ; Glutamate-Ammonia Ligase/genetics ; }, abstract = {Although herbicide resistance in Setaria is rampant and cosmopolitian across four herbicide families, we encountered little evidence of target-site resistance, indicating diverse non-target mechanisms of metabolizing, sequestering, and overwhelming herbicides. Setaria viridis is a cosmopolitan weed and model genetic system with increasing reports of resistance to multiple classes of herbicides. Our goal was to assess the herbicide resistance and allelic diversity in herbicide target genes in a collection of Setaria genotypes from North America and Eurasia, and identify the occurrence of novel and known target-site mutations that led to resistance. A total of 214 Setaria genotypes were exposed to commonly used herbicides that inhibit specific genes: herbicide action class (HRAC) group 1 herbicides targeting acetyl-CoA carboxylase (ACCase), HRAC 2 targeting acetolactate synthase (ALS), HRAC 9 targeting 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase, and HRAC 10 targeting glutamine synthetase. ACCase and ALS genes in 53 accessions were PCR-amplified and sequenced. Whole-genome sequencing reads covering the target genes were analyzed for an additional 98 genotypes. Herbicide trials showed that 30% of our accessions set seed following application of at least one herbicide, and 13 accessions were resistant to multiple classes of herbicides. Although there were numerous SNPs, including some known to lead to resistance, in our target genes, SNPs found predominantly in herbicide-resistant genotypes were largely intronic or synonymous. A small number of amino acid substitutions in ALS and ACCase indicated potential and incomplete resistance to HRAC 1 and 2 herbicides, but no SNPs putatively associated with herbicide resistance were identified in the other 6 target-site genes. The broader pattern of herbicide resistance in S. viridis is likely driven by non-target mutations that detoxify or compartmentalize applied herbicides.}, } @article {pmid42085565, year = {2026}, author = {Singh, K and Ahmad, I and Jain, D and Mim, TJ and Noman, AA and Shihab, MPR and Kondaveeti, SB and Gupta, JK and Wal, P}, title = {Novel Cellular Signalling Axes in Neurodegenerative Diseases: From NLRP3 Inflammasome to Wnt/β-Catenin and Hippo-YAP Pathways.}, journal = {Journal of biochemical and molecular toxicology}, volume = {40}, number = {5}, pages = {e70880}, doi = {10.1002/jbt.70880}, pmid = {42085565}, issn = {1099-0461}, mesh = {Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Inflammasomes/metabolism ; Animals ; *Wnt Signaling Pathway ; *Protein Serine-Threonine Kinases/metabolism ; Hippo Signaling Pathway ; *Adaptor Proteins, Signal Transducing/metabolism ; YAP-Signaling Proteins ; *Transcription Factors/metabolism ; *Signal Transduction ; }, abstract = {Neurodegenerative diseases (NDs), including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), are characterised by impaired cellular homeostasis and progressive neuronal loss. Emerging evidence highlights the critical role of cellular signalling pathways in the progression and pathogenesis of these disorders. With a focus on the NLRP3 inflammasome, Wnt/β-catenin, and Hippo-YAP cascades, this review focuses on new signalling pathways linked to neurodegenerative disorders. Among them, the NLRP3 inflammasome is a crucial mediator of neuroinflammation, causing neuronal damage and persistent immune activation. In contrast, these pathways regulate neurogenesis, synaptic plasticity, and cell survival, offering potential neuroprotective functions. Dysregulation of these pathways disrupts cellular integrity, exacerbates disease progression, and represents a convergence point for therapeutic intervention. In NDs, knowing how these pathways interact offers fresh perspectives on disease processes and finds new targets for the creation of disease-modifying treatments.}, } @article {pmid42086102, year = {2026}, author = {Chen, M and Huang, X and Li, Y and Hu, L and Lu, R and Li, L}, title = {Microplastics as an emerging environmental pollutant potentially leading to neurodegenerative diseases.}, journal = {Neuroscience}, volume = {607}, number = {}, pages = {63-75}, doi = {10.1016/j.neuroscience.2026.04.033}, pmid = {42086102}, issn = {1873-7544}, mesh = {Humans ; *Neurodegenerative Diseases/chemically induced/metabolism ; *Microplastics/adverse effects/toxicity ; *Environmental Pollutants/adverse effects/toxicity ; Animals ; }, abstract = {Microplastics (MPs), defined as plastic fragments less than 5 mm in diameter, are ubiquitous in the environment. As an emerging environmental pollutant, MPs can infiltrate the human body through multiple pathways, including inhalation, ingestion, dermal contact and bloodborne transmission.Correspondingly, MPs, which can penetrate the blood-brain barrier and enter the central nervous system (CNS), have been linked to the development of neurodegenerative diseases (NDs).In this review, we provide a comprehensive analysis of the environmental distribution of MPs, the pathways of entry into the human body, and the distribution within the CNS. Furthermore, we explore intrinsic factors influencing the neurotoxicity of MPs and elucidate the mechanisms underlying MPs-induced NDs, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Beyond mechanistic insights, we offer a novel perspective by exploring the potential adaptation of emerging environmental MPs detection and removal technologies for CNS applications. Ultimately, elucidating these mechanisms positions the reduction of MPs accumulation as a critical intervention point, highlighting the adaptation of environmental technologies as a promising strategy for the prevention and management of NDs.}, } @article {pmid42086408, year = {2026}, author = {Ibrahim, M and Hossain, MS and Ooi, L and Hasan, MM and Ahsan, S and Salem, AK and Piazza, GA and Feng, X and Ahsan, F}, title = {Targeting the NAD[+]-PARP1-XRCC1 axis in ALS.}, journal = {Trends in molecular medicine}, volume = {}, number = {}, pages = {}, pmid = {42086408}, issn = {1471-499X}, support = {R01 HL144590/HL/NHLBI NIH HHS/United States ; R43 HL169134/HL/NHLBI NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) remains a fatal neurodegenerative disease with few effective therapies. Emerging evidence indicates that oxidative DNA damage, defective base excision and single-strand break repair, and progressive NAD[+] depletion contribute to motor neuron degeneration. The NAD[+]-PARP1-XRCC1 axis sits at the intersection of genome maintenance and metabolic control, linking DNA damage signaling to cellular bioenergetics. When dysregulated, this pathway may drive persistent PARP1 activation, failed repair, and energetic collapse. In this review, we integrate mechanistic and translational evidence supporting this axis as a therapeutic target in ALS. We propose a staged translational framework that prioritizes repurposable low-trapping PARP1 inhibitors combined with NAD[+] support, followed by central nervous system-directed RNA-lipid nanoparticle delivery of repair factors, with poly(ADP-ribose) and NAD[+] metabolites as pharmacodynamic biomarkers.}, } @article {pmid42086533, year = {2026}, author = {Modafferi, S and Silenzi, V and Garbelli, A and Lazoi, G and Scarian, E and D'Uva, S and Santini, T and Riccardi, A and Cozzolino, M and Pansarasa, O and D'Ambrosi, N and Sabbioneda, S and Morlando, M and Francia, S}, title = {Proteasomal-dependent CHK1 degradation leads to DNA damage accumulation in ALS cellular model systems.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {}, pmid = {42086533}, issn = {2041-4889}, support = {PNRR-CN3 642 "National Center for Gene Therapy and Drugs based on RNA Technology"//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; 2017NWEXEP//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; 2020CXFL4T//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; 2022R7LH5T//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; DN. 1553 11.10.2022//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; 2017KSZZJW//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; 2022JA8JY5//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; DSB.AD004.294//Regione Lombardia (Region of Lombardy)/ ; FOE-2021 DBA.AD005.225//Consiglio Nazionale delle Ricerche (National Research Council)/ ; DBA.AD005.225-NUTRAGE-FOE2021//Consiglio Nazionale delle Ricerche (National Research Council)/ ; RIPREI2023_7c8ae10d783c//Istituto Superiore di Sanità (ISS)/ ; IG2022-27833//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; IG-2020-24316//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; Ricerca Corrente 2025 - 2027//Ministero della Salute (Ministry of Health, Italy)/ ; RG12419107CD28D5//Sapienza Università di Roma (Sapienza University of Rome)/ ; }, mesh = {*Checkpoint Kinase 1/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Animals ; Humans ; *Proteasome Endopeptidase Complex/metabolism ; *DNA Damage ; Mice ; RNA-Binding Protein FUS/metabolism/genetics ; Proteolysis ; Motor Neurons/metabolism/pathology ; DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; DNA Repair ; Histone Chaperones/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterised by the aggregation of TDP-43 and mutant FUS in the cytoplasm of affected motor neurons. Accumulation of DNA damage is emerging as a novel correlative trait of ALS. We recently showed that formation of TDP-43 and FUS cytoplasmic inclusions (CIs) lead to DNA damage accumulation through dysregulation of the DNA damage response (DDR). However, the multiple molecular mechanisms contributing to DNA damage accumulation in affected motor neurons in ALS have not been fully elucidated. In recent years, chemical inhibition of the serine/threonine kinase CHK1 was shown to lead to accumulation of DNA breaks as well as increased apoptosis, in differentiated cortical neurons. Notably, CHK1 has been involved in DNA double-strand break repair in non-dividing cells, by acting through the histone chaperone ASF1A. In this article, we show that cells bearing FUS and TDP-43 CIs show downregulation of the protein levels of CHK1 and ASF1A. We observe CHK1 protein downregulation in neuronal cell lines, as well as in patient-derived motor neurons progenitors and in the spinal cord of a FUS-ALS mouse model. Restoration of the nuclear levels of CHK1 and ASF1A via transient overexpression, is sufficient to reduce DNA damage signal accumulation and rescues DDR defects. Importantly, we show that the ubiquitin-proteasome pathway is responsible for CHK1 degradation in cells bearing FUS CI, since its inhibition restores CHK1 and ASF1A protein levels. Our study demonstrates that proteasomal-dependent CHK1 and ASF1A downregulation contributes to accumulation of DNA damage in cells affected by ALS-linked protein aggregates.}, } @article {pmid42087223, year = {2026}, author = {Brede, JR and Farbu, BH and Gamberini, L and Thorsen, K and Rehn, M and Rognås, L and Tønsager, K and Sunde, GA and Lauritzen, M and Lupi, C and Tartaglione, M and Skjaerseth, EÅ and Aaen, M and Wiseth, R and Krüger, AJ}, title = {Prehospital resuscitative endovascular balloon occlusion of the aorta in non-traumatic out-of-hospital cardiac arrest (REBOARREST): an international, multicentre, open label, pragmatic, randomised, controlled trial.}, journal = {Critical care (London, England)}, volume = {30}, number = {1}, pages = {}, pmid = {42087223}, issn = {1466-609X}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy ; *Balloon Occlusion/methods/standards ; Male ; Middle Aged ; *Emergency Medical Services/methods ; Female ; Aged ; Adult ; Aged, 80 and over ; *Cardiopulmonary Resuscitation/methods/standards ; *Aorta ; Denmark ; *Resuscitation/methods/standards ; Italy ; }, abstract = {BACKGROUND: Most patients with out-of-hospital cardiac arrest do not achieve sustained return of spontaneous circulation (ROSC). Resuscitative endovascular balloon occlusion of the aorta (REBOA) may increase blood pressure proximal to the ballon. If this technique is used during advanced life support (ALS), and occlusion is performed in the thoracic aorta, it may augment aortic pressure and coronary perfusion pressure. We investigated whether prehospital REBOA as an adjunct to ALS increased the rate of ROSC.

METHODS: REBOARREST was a pragmatic, parallel-group, multicentre, randomised controlled trial conducted at 12 sites in Norway, Denmark, and Italy. Adult patients (18-80 years) with non-traumatic out-of-hospital cardiac arrest were randomly assigned (1:1) to either a control group that received ALS or to an intervention group that received ALS combined with REBOA as an adjunct. Fulfilment of eligibility criteria was determined by the physician on scene and sealed envelopes were used to allocate patients. The statistician that performed the analyses was blinded for group allocation. The primary outcome was sustained ROSC, defined as lasting ≥ 20 min, assessed in the intention-to-treat population.

RESULTS: From June 7, 2021, to June 28, 2025, 200 patients were randomly assigned to the study groups. Due to lack of consent 21 patients dropped out of the trial, hence data from 179 patients are presented, 88 in the intervention group and 91 in the control group. Most patients were male (76%), with median age of 68 years (IQR 58-74). Median time from arrest to randomisation was 33 min (IQR 23-39) in the intervention group and 29 min (IQR 23-38) in the control group. Twenty-five of 88 patients (28%) in the intervention group and 24 of 91 patients (26%) in the control group achieved sustained ROSC (adjusted risk difference 1.8% [-11, 15, 95% CI], p = 0.78). Adverse events were registered in 19 patients.

CONCLUSIONS: Among patients with non-traumatic out-of-hospital cardiac arrest, a strategy of prehospital deployment of REBOA as an adjunct to ALS was feasible but did not significantly improve rates of sustained ROSC compared to ALS alone. Deployment of prehospital REBOA is safe and manageable in a two-person team with low procedure time.

TRIAL REGISTRATION: Clinicaltrials.gov ID NCT04596514. Registered 22.10.2020.}, } @article {pmid42087256, year = {2026}, author = {Harper, NS and Sharpe, JL and Speranza, J and Gulia, R and Chen, JX and Allen, SP and Atwal, MS and Pickering-Brown, S and Livesey, MR and Bennett, CL and Prokop, A and La Spada, AR and West, RJH}, title = {Targeting the integrated stress response or Ataxin-2 alleviates neurodegeneration in PolyGR models of C9orf72 associated frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42087256}, issn = {2051-5960}, support = {630//Alzheimer's Society and The Heather Corrie Impact Fund/ ; NIH R35 NS122140//National Institutes of Health (NIH)/ ; Livesey/Oct20/900-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; Livesey/Oct20/900-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; 510/ALZS_/Alzheimer's Society/United Kingdom ; R35 NS122140/NS/NINDS NIH HHS/United States ; P40 OD018537/OD/NIH HHS/United States ; 087742/Z/08/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Integrated Stress Response ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *Ataxin-2/genetics/metabolism ; Disease Models, Animal ; Humans ; DNA Repeat Expansion ; Animals, Genetically Modified ; Drosophila ; Drosophila Proteins/genetics/metabolism ; Stress Granules/metabolism ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal, early-onset neurodegenerative diseases. The most common genetic cause of FTD and ALS is a G4C2 hexanucleotide repeat expansion in the C9orf72 gene. This mutation leads to the production of toxic dipeptide repeat proteins (DPRs), via repeat-associated non-AUG (RAN) translation. These DPRs disrupt stress granule (SG) dynamics, with SG regulators such as Ataxin-2 (ATXN2) implicated in disease risk. The integrated stress response (ISR), a key driver of SG formation via eIF2α phosphorylation, has been linked to C9orf72 expansions, but the role of individual DPRs in ISR activation remains unclear. Here, using Drosophila models expressing physiologically relevant repeat length DPRs, we identify poly(GR) as a novel activator of the ISR, inducing early and sustained eIF2α phosphorylation and SG accumulation prior to motor decline. Genetic inhibition of the ISR or knockdown of ATX2, the Drosophila orthologue of ATXN2, rescues motor deficits in these models. ATXN2 knockdown also reduces poly(GR) toxicity in mouse primary neurons. These findings position poly(GR) as a key driver of ISR activation and highlight ATXN2 and the ISR as promising therapeutic targets in C9orf72-associated FTD/ALS.}, } @article {pmid42087754, year = {2026}, author = {van Selms, MKA and Lobbezoo, F and Verhoeff, MC}, title = {[A personal exploration of oral health in amyotrophic lateral sclerosis].}, journal = {Nederlands tijdschrift voor tandheelkunde}, volume = {133}, number = {5}, pages = {232-238}, doi = {10.5177/ntvt.2026.05.26012}, pmid = {42087754}, issn = {0028-2200}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Oral Health ; *Oral Hygiene ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease impairing motor functions, including those of the oral muscles. As a result, oral hygiene and oral care become challenging. Nonetheless, oral health in patients with amyotrophic lateral sclerosis often remains under-addressed. On the basis of interviews with Dr M.K.A. van Selms dental researcher and patient oral health in amyotrophic lateral sclerosis was explored, highlighting care, research and education. Dr van Selms identifies the neglect of oral hygiene in the care of patients with amyotrophic lateral sclerosis, and advocates for patient-informed, functionally tailored guidelines, interdisciplinary collaboration, and improved access to dental services. He also calls for ethically sensitive, patient-centred research; he stresses the relevance of inclusive training for all involved; and recommends developing instructional material for carers and patients. Dr van Selms unique perspective reveals the necessity to integrate oral health into the care for this patient group and offers starting points for improving oral health and quality of life in amyotrophic lateral sclerosis and similar diseases.}, } @article {pmid42088060, year = {2026}, author = {Hou, DL and Ho, J and Guan, T and Dong, XX and Zeng, L and Sanders, LH and Wu, YC and Tan, EK and Zhou, ZD}, title = {E3 ubiquitin ligases in neurodegenerative diseases.}, journal = {Military Medical Research}, volume = {13}, number = {1}, pages = {100032}, pmid = {42088060}, issn = {2054-9369}, mesh = {Humans ; *Ubiquitin-Protein Ligases/therapeutic use/metabolism ; *Neurodegenerative Diseases/physiopathology/enzymology ; Animals ; Proteolysis Targeting Chimera ; Ubiquitination ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss and proteostatic failure, driven by impaired clearance of misfolded proteins via the ubiquitin-proteasome system (UPS) and autophagy. In UPS, E3 ubiquitin ligases are crucial for regulating protein ubiquitination and degradation. Mutations in E3 ligases, along with dysfunctions of specific ligases such as Parkin, the C-terminus of HSC70-interacting protein (CHIP), and tripartite motif-containing proteins, have been identified as key factors in the buildup of amyloid-β, α-synuclein, tau, trans-active response DNA-binding protein 43, and mutant huntingtin. These accumulations are associated with NDs like Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Therapeutic strategies targeting E3 ligases, particularly proteolysis-targeting chimeras (PROTACs), are being developed for ND treatment and are currently in clinical trials. These approaches aim to enhance E3 ligase activity and promote selective protein degradation. Here, we examine how individual E3 ligases influence cell-fate decisions in NDs, showing that their substrate selection determines whether neurons survive or die. Building on this knowledge, we present an innovative therapeutic pipeline that includes ligase activators, PROTAC degraders, and miRNA switches, which are molecules designed to transition from research to clinical application.}, } @article {pmid42091241, year = {2026}, author = {Pronto-Laborinho, AC and Carvalho, M}, title = {Interleukin-6 in ALS: metabolic mediator or marker of ventilatory decline?.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {715-716}, doi = {10.1080/21678421.2026.2667283}, pmid = {42091241}, issn = {2167-9223}, } @article {pmid42091714, year = {2026}, author = {Motta, S and Quaremba, G and Aruta, L and Allosso, S and Senerchia, G and Iuzzolino, VV and Dubbioso, R}, title = {The Dysphagia Outcome and Severity Scale (DOSS) and non-instrumental swallowing measures in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {6}, pages = {}, pmid = {42091714}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/diagnosis ; *Deglutition Disorders/diagnosis/etiology/physiopathology ; Female ; *Severity of Illness Index ; Male ; Middle Aged ; Aged ; Reproducibility of Results ; Deglutition/physiology ; Adult ; }, abstract = {PURPOSE: To evaluate reliability of the Dysphagia Outcome and Severity Scale (DOSS) in Amyotrophic Lateral Sclerosis (ALS) patients, and to assess diagnostic accuracy of selected non-instrumental measures in defining swallowing safety in this population.

METHODS: One hundred and thirteen consecutive ALS patients underwent comprehensive dysphagia evaluation with fiberoptic endoscopic evaluation of swallowing (FEES) and were classified according to DOSS. Safe and unsafe swallowing were defined by DOSS levels 7-6 and 5-1, respectively. Patient-reported measures included ALS Functional Rating Scale-Revised swallow item (I-3) and Eating Assessment Tool-10 (EAT-10). Non-instrumental clinical measures were hyolaryngeal excursion, voluntary cough (VC), voice quality and reflexive cough/throat clearing (VRC), and maximum phonation time (MPT). Inter- and intra-rater reliability were assessed using weighted Cohen's kappa and Fleiss' kappa coefficients. Non-instrumental measures diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis.

RESULTS: Twenty-six of 113 patients (23%) exhibited an unsafe swallowing. Inter- and intra-rater agreement for DOSS classification was excellent across raters. EAT-10 and a composite clinical index derived from VC, VRC, and MPT showed the highest diagnostic accuracy with area under the curve values of 0.790 and 0.832, respectively. Other non-instrumental measures demonstrated lower discriminative performance.

CONCLUSIONS: The DOSS showed an excellent reliability when applied to FEES in patients with ALS, supporting its use as a functional classification tool with direct nutritional and management implications. Non-instrumental measures should be interpreted with caution and confined to a triage role rather than diagnostic decision-making, particularly in light of the rapid progression of dysphagia in ALS.}, } @article {pmid42091757, year = {2026}, author = {Puthusseri, SP and Ravivarma, S and Johny, M and Vengellur, A}, title = {Hypoxia-inducible factor-1α: Dual roles in maintaining neuronal homeostasis and neuronal degeneration via regulation of oxidative stress, mitochondrial dynamics, and bioenergetics.}, journal = {Journal of physiology and biochemistry}, volume = {82}, number = {1}, pages = {}, pmid = {42091757}, issn = {1877-8755}, mesh = {*Oxidative Stress ; Humans ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Animals ; *Energy Metabolism ; *Neurons/metabolism/pathology ; Homeostasis ; *Mitochondrial Dynamics ; Mitochondria/metabolism/pathology ; Neurodegenerative Diseases/metabolism/pathology ; Signal Transduction ; }, abstract = {Hypoxia-inducible factor-1α (HIF-1α) is an oxygen-sensitive transcription factor with an inherently paradoxical biology: under mild-to-moderate hypoxic stress, it functions as a pro-survival regulator, yet under severe or prolonged hypoxia, the same signalling axis promotes apoptotic and autophagic cell death. This duality carries particular significance in neurons, where HIF-1α serves as a critical nexus among neuronal survival, metabolic adaptation, and mitochondrial integrity, and where the consequences of its dysregulation are most profound given their exceptional metabolic demands and limited regenerative capacity. This review examines the molecular determinants governing this protective-to-detrimental switch, integrating key interconnected dimensions: the context-dependent regulation of oxidative stress, the control of mitochondrial bioenergetics, dynamics, mitophagy, and axonal transport; the dual role of HIF-1α in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and cerebral ischemia; and the therapeutic implications of precision-targeted HIF-1α modulation. Across all these contexts, a consistent pattern emerges: early or acute HIF-1α activation is broadly neuroprotective, while chronic or severe hypoxic stress converts the same pathway into a driver of neurodegeneration. Understanding the determinants of this switch, including hypoxia duration, severity, and cell-type specificity, provides a framework for designing temporally precise therapeutic interventions for hypoxia-related neurological disorders.}, } @article {pmid42092055, year = {2026}, author = {Azizzadeh, M and Wouters, EFM and Karimi, A and Janssen, DJA and Spaetgens, B and Hartl, S and Breyer-Kohansal, R and Breyer, MK}, title = {Integration of lung function in allostatic load scoring and its impact on mortality prediction.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42092055}, issn = {2045-2322}, mesh = {Humans ; Female ; *Allostasis/physiology ; Aged ; Male ; Middle Aged ; Aged, 80 and over ; *Lung/physiology/physiopathology ; Proportional Hazards Models ; Respiratory Function Tests ; *Mortality ; Forced Expiratory Volume ; Vital Capacity ; Austria/epidemiology ; }, abstract = {Allostatic load refers to the physiological "wear and tear" that results from adaptation to stressors over the lifespan. In this study, we integrated lung function (LF) parameters into the calculation of the allostatic load score (ALS) to evaluate changes in its performance for predicting all-cause mortality. Data from 8,775 participants (aged 25-82 years; 52% female) who participated in the first wave of the Austrian LEAD cohort were used. "ALS without LF" was calculated using 12 parameters, including cardiovascular, metabolic, body composition, and bone mineral density measures. Z-scores of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were integrated with the aforementioned parameters for the calculation of "ALS with LF". Participants scored 1 point for each at-risk marker and 1 point for medication use for hypertension, diabetes, and dyslipidaemia. The total points constituted the ALS. Participants were followed-up for death for an average of 7.7 years. The association of ALS, with and without LF, with mortality was investigated using Cox proportional hazards models. ALS increased with age and was higher in males compared to females across all age categories. ALS (as a continuous variable) with LF [hazard ratio (HR): 1.19 (95% confidence interval (CI) 1.14-1.24)] and without LF [HR: 1.16 (95% CI 1.11-1.21)] showed a significant association with mortality in sex- and age-adjusted models. The adjusted models incorporating ALS as a categorical variable showed that individuals with high ALS, with [HR: 2.44 (95% CI 1.41-4.20)] and without [HR: 2.47 (95% CI 1.46-4.80)] LF parameters, had a higher risk of mortality compared to those in the low ALS group. Cox models incorporating "ALS with LF" parameters exhibited higher concordance index and R[2] values, along with a lower Akaike's information criterion indicating superior predictive power compared to models that included "ALS without LF". ALS is strongly associated with mortality, with higher ALS linked to an increased risk of mortality across both continuous and categorical analyses. Models that incorporate ALS with LF parameters demonstrated superior predictive performance and greater robustness, underscoring the added value of including LF in the models.}, } @article {pmid42092406, year = {2026}, author = {Chen, Q and Zhou, Y and Peng, Y and Lan, J and Kang, Y and Wu, L and Liu, J and Tang, J and Peng, Y}, title = {TRIM16 attenuates TDP43-mediated oxidative injury by coordinating Nrf2 activation and TFR1 autophagic degradation.}, journal = {Free radical biology & medicine}, volume = {252}, number = {}, pages = {132-149}, doi = {10.1016/j.freeradbiomed.2026.05.014}, pmid = {42092406}, issn = {1873-4596}, mesh = {*NF-E2-Related Factor 2/metabolism/genetics ; *Oxidative Stress ; Humans ; *Receptors, Transferrin/metabolism/genetics ; Autophagy ; *DNA-Binding Proteins/genetics/metabolism ; *Tripartite Motif Proteins/metabolism/genetics ; *Ubiquitin-Protein Ligases/metabolism/genetics ; Ubiquitination ; Kelch-Like ECH-Associated Protein 1/metabolism/genetics ; Animals ; Iron/metabolism ; *Antigens, CD/metabolism/genetics ; Mice ; Ferroptosis ; Proteolysis ; Mitochondria/metabolism ; *Transcription Factors/metabolism/genetics ; }, abstract = {TAR DNA-binding protein 43 (TDP43) aggregation is a well-established pathological hallmark of amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders, contributing significantly to oxidative stress and neuronal injury. Here, we report that the M337V mutation in TDP43 exacerbates its proteotoxicity relative to the wild-type protein. Concurrently, multi-omics analysis revealed a pronounced downregulation of TRIM16 in motor neuron-like cells expressing either wild-type or M337V mutant TDP43. Functional studies demonstrated that TRIM16 overexpression effectively mitigated oxidative stress, restored mitochondrial integrity, and suppressed ferroptosis. Mechanistically, TRIM16 promoted the ubiquitination and degradation of Keap1, thereby facilitating the activation of Nrf2-mediated antioxidant genes. Furthermore, we identified the iron import receptor TFR1 as a novel ubiquitination substrate of TRIM16. TRIM16 mediated the ubiquitination of TFR1 and targeted it for p62-dependent autophagic degradation, which in turn reduced iron accumulation and lipid peroxidation. Collectively, our findings establish TRIM16 as a pivotal suppressor of TDP43-induced toxicity by orchestrating dual cytoprotective pathways to enhance cellular resilience, highlighting its promising therapeutic potential for TDP43 proteinopathy.}, } @article {pmid42092970, year = {2026}, author = {Liu, H and Hu, C and Liu, H and Gong, Z and Jiang, S and Xie, J and Li, Y and Liu, C and Wang, Y and Zou, C and Yang, G}, title = {Mechanistic insights and therapeutic potential of targeting the cGAS-STING pathway in neurodegenerative diseases.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {42092970}, issn = {1742-2094}, support = {2023JJ40952//the Natural Science Foundation of Hunan Province/ ; 2024JJ6618//the Natural Science Foundation of Hunan Province/ ; 82204733//Foundation for Innovative Research Groups of the National Natural Science Foundation of China/ ; 20254677//Health Research Project of Hunan Provincial Health/ ; 82474009//the National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; cGAS-STING Signaling Pathway ; *Membrane Proteins/metabolism ; *Nucleotidyltransferases/metabolism ; Animals ; *Signal Transduction/physiology/drug effects ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; }, abstract = {The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA-sensing module that links DNA damage and mitochondrial dysfunction to innate immune activation. Here, we focus on canonical cGAS-STING signaling in the central nervous system (CNS) and discuss non-canonical branches only when directly relevant to neurodegeneration. We summarize structural and activation-termination mechanisms and synthesize cell-type-biased outputs across microglia, astrocytes, neurons, and oligodendroglial lineage cells. We then integrate Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease by mapping shared DNA-stress triggers to multicellular amplification loops and by grading causal evidence from genetic perturbation, pharmacological pathway interference, and correlative human datasets. Finally, we classify inhibitor modalities and emerging enabling technologies while emphasizing translational constraints, including blood-brain barrier (BBB) delivery, long-term safety, human STING-allele diversity, and pharmacodynamic biomarkers. Collectively, we propose an evidence-calibrated framework for judging when cGAS-STING is most plausibly positioned as a causal node, a permissive amplifier, or a secondary correlate in neurodegenerative disease, and where therapeutic translation should proceed cautiously.}, } @article {pmid42093061, year = {2026}, author = {Abbasi, H and Rasekhi, H and Shafaatdoost, M and Mohajerani, A and Asadollahi, M and Rashidi, M and Malekahmadi, M and Sarraf, P}, title = {Association of dietary inflammatory index with body composition and disease progression in adults with amyotrophic lateral sclerosis: evidence from a cross-sectional study.}, journal = {BMC nutrition}, volume = {12}, number = {1}, pages = {}, pmid = {42093061}, issn = {2055-0928}, support = {IR. TUMS.NI.REC.1401.059//Tehran University of Medical Sciences and Health Services/ ; }, abstract = {BACKGROUND: For decades, diet's pro-inflammatory properties have been considered a potential risk factor in the onset of amyotrophic lateral sclerosis (ALS). This study aimed to explore the association of dietary inflammatory index (DII) with body composition and disease progression in adult individuals with ALS.

METHODS: Clinically stable adults aged 18 years and older were enrolled for this study from the neuromuscular disorders clinic at Imam Khomeini Hospital. All participants met the EI Escorial criteria for ALS. Participants completed a 153-item dish-based semi-quantitative food frequency questionnaire (FFQ), which was developed and validated for Iranian adults. Multiple linear regression analyses were performed to examine the association between DII and the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), Medical Research Council (MRC) score, disease progression rate (DPR), and body composition among adult participants with ALS.

RESULTS: This cross-sectional study involved 93 adult participants with ALS, comprising 29 women and 64 men (aged 56.95 ± 12.05 years). Participants in the third DII tertile had significantly reduced consumption of several nutrients, comprising vitamin E (P < 0.001), vitamin A (P < 0.001), vitamin B6 (P < 0.001), folic acid (P = 0.006), vitamin K (P < 0.001), fluoride (P = 0.009), potassium (P < 0.05), and selenium (P = 0.003). DPR displayed a significant negative association with the third tertile of DII (β T3 vs. T1= -1.1, 95CI%:-2.2, -0.04; Ptrend= 0.04), signifying a significant relationship after accounting for confounders, including age, gender, BMI, physical activity, and history of ALS.

CONCLUSION: Our findings suggest that higher inflammatory dietary patterns might be associated with a slower rate of disease progression in adults suffering from ALS. To elucidate these findings, randomized controlled trials are warranted.}, } @article {pmid42093242, year = {2026}, author = {Torgeman, S and Pincot, DDA and Bjornson, M and Famula, RA and Skillin, P and Krill-Brown, A and Feldmann, MJ}, title = {Genetic architecture of angular leaf spot resistance in cultivated strawberry shaped by epistasis and genotype-by-environment interactions.}, journal = {The plant genome}, volume = {19}, number = {2}, pages = {e70246}, pmid = {42093242}, issn = {1940-3372}, support = {//California Strawberry Commission/ ; FI- 642-24//United States - Israel Binational Agricultural Research and Development Fund/ ; 2024-67013-42591//Agricultural Research Service/ ; 2022-51181-38328//National Institute of Food and Agriculture/ ; }, mesh = {*Epistasis, Genetic ; *Fragaria/genetics/microbiology ; *Plant Diseases/microbiology/genetics ; *Disease Resistance/genetics ; *Xanthomonas/physiology ; *Gene-Environment Interaction ; Genotype ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; Phenotype ; Quantitative Trait Loci ; }, abstract = {Angular leaf spot (ALS), caused by Xanthomonas fragariae, is a bacterial disease that limits strawberry (Fragaria × ananassa) productivity worldwide. Although major resistance loci have been identified in wild Fragaria species, their introgression into elite germplasm remains constrained by linkage drag and inconsistent inheritance. To dissect the genetic architecture of ALS resistance, we evaluated a diverse panel of n = 241 greenhouse-tested and n = 468 field-tested strawberry accessions representing elite cultivars, breeding materials, and heirloom varieties of cultivated strawberry (F. × ananassa). Plants were evaluated under controlled inoculations and natural field infection using a standardized phenotypic scale and genotyped with 50K single nucleotide polymorphism array. Broad-sense heritability was moderate (H[2] = 0.45), whereas narrow-sense heritability was low (h[2] = 0.10), reflecting the contribution of nonadditive genetic effects such as epistasis. Genome-wide association studies (GWAS) identified two loci on chromosomes 1D and 2D, explaining 4%-5% of phenotypic variance, respectively. A segregating F1 population validated the 2D locus, confirmed by co-localization with the GWAS signal explaining 11.3% of the phenotypic variance. Two-dimensional genome wide scan in this F1 population revealed a significant epistatic interaction between locus on chromosome 2D and an additional locus on chromosome 6B, collectively explaining 27% of the phenotypic variance. Together, these results demonstrate that nonadditive effects in these populations control ALS resistance. Understanding this complexity provides a foundation for developing elite cultivars with durable resistance, such as UCD Royal Royce. Our findings underscore the need for predictive breeding strategies that capture epistatic and environmental variance to accelerate genetic gain for ALS resistance in strawberry.}, } @article {pmid42093345, year = {2026}, author = {Griffiths, AW and White, S and Norman, P and Coates, E and Hartley, H and Williams, IA and Halliday, V and Beever, D and Hackney, G and Stavroulakis, T and , and McDermott, C}, title = {Development of a Complex Intervention to Support High Calorie Diets for People With Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {74}, number = {1}, pages = {149-158}, doi = {10.1002/mus.70269}, pmid = {42093345}, issn = {1097-4598}, support = {RP-PG-1016-20006//National Institute for Health and Care Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy ; Female ; Male ; Middle Aged ; *Energy Intake/physiology ; Aged ; Caregivers ; Adult ; Focus Groups ; Motivation ; }, abstract = {INTRODUCTION: Weight loss in people with amyotrophic lateral sclerosis (pwALS) is a poor prognostic factor. We aimed to develop an intervention to support pwALS to increase calorie intake and explore feasibility and acceptability.

METHODS: Intervention development was underpinned by the Capability, Opportunity and Motivation (COM-B) model and Person Based Approach (PBA). Phase 1: healthcare professional (HCP) focus groups (n = 47), national survey (n = 281), mapping review and National Health Service (NHS) organization Freedom of Information requests (n = 251) charted current nutritional support. Systematic reviews of correlates (65 studies) and interventions supporting nutritional behaviors (14 studies), and interviews/focus groups with pwALS (n = 18), carers (n = 18) and HCPs (n = 51) identified barriers/facilitators. Phase 2: Think Aloud interviews (verbalizing thoughts whilst using the intervention) with pwALS (n = 12), carers (n = 10) and HCPs (n = 10). Phase 3: three pilot cycles, interviews with pwALS (n = 9), carers (n = 6) and HCPs (n = 5).

RESULTS: Limited evidence-based nutritional guidelines, late dietetic referral post-diagnosis, little HCP training, and few effective interventions were identified. Key facilitators/barriers included capabilities (physical ability), opportunities (social support), and motivations (dietary beliefs). The intervention was developed and piloted to refine content, presentation, and functionality. Concerns around high calorie diets and increasing intake were addressed. The final intervention comprises: (1) interventionist training, (2) calorie target setting, (3) food diaries, (4) feedback provision, (5) online resources, and (6) oral nutritional supplements. User feedback indicates high usability, acceptability, and feasibility.

DISCUSSION: The theoretically grounded intervention targets calorie intake through tailored behavior change techniques to support dieticians in practice to deliver personalized care and oral nutritional support for pwALS.}, } @article {pmid42093834, year = {2026}, author = {Martinez-Nunez, AE and Guo, J and Dorsey, ER and Ruffing, KW and Wymer, J and Okun, MS}, title = {Head trauma and environment progression of amyotrophic lateral sclerosis: long-term data from the National ALS Registry.}, journal = {BMJ neurology open}, volume = {8}, number = {1}, pages = {e001574}, pmid = {42093834}, issn = {2632-6140}, abstract = {BACKGROUND: Environmental exposures have been linked to increased risk of amyotrophic lateral sclerosis (ALS); however, their impact on disease progression remains unclear. This study examined whether prior environmental and occupational exposures influenced functional decline in patients with an established ALS diagnosis.

METHODS: We conducted a retrospective cohort analysis using the National ALS Registry from 2010 to 2024. Participants with complete exposure histories were included. Disease progression was measured with the ALS Functional Rating Scale-Revised (ALSFRS-R) at baseline and every 3 months. Mixed-effects linear regression models assessed associations between exposures and ALSFRS-R decline, adjusting for age, sex and time since diagnosis.

RESULTS: The cohort included 8618 participants with ALS. The median time from diagnosis to enrolment was 2 years (IQR= 1.1-2.9), with a median of 1 year of follow-up (IQR=1-4). Exposure to herbicides (β=-0.57. IC95%=-0.86 to -0.28, p<0.001), metal dust and fumes (β=-0.28, IC95%=-0.51 to -0.04, p=0.020) and oil paint (β=-0.27, IC95%=-0.48 to -0.06, p=0.011) prior to diagnosis were each associated with accelerated decline. Head injury was associated with an overall lower ALSFRS-R score (β=-1.74, IC95%=-2.21 to -1.27, <0.001), based on our non-linear mixed effects model.

CONCLUSION: Environmental and occupational exposures, particularly herbicides, metal dust/fumes and oil-based paints, were associated with faster ALS progression, and head injury was associated with overall worse function.}, } @article {pmid42094407, year = {2026}, author = {Flax, R and Lacigová, A and Howell, S and Li, H and Bashore, FM and Čajánek, L and Axtman, AD}, title = {Development of Potent and Cell Active 5-Azaindole-Based Tau Tubulin Kinase Inhibitors.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42094407}, issn = {2692-8205}, support = {S10 OD032476/OD/NIH HHS/United States ; U24 DK116204/DK/NIDDK NIH HHS/United States ; }, abstract = {We have developed and characterized a potent and cell active tau tubulin kinase 1 and 2 (TTBK1 and TTBK2) inhibitor, 13. Compound 13 demonstrates in-cell, kinome-wide selectivity, and potently inhibits both TTBK1 and TTBK2. As part of our medicinal chemistry campaign, we also identified a structurally similar negative control, compound 5, which lacks in-cell affinity for TTBK1 and TTBK2. Based on their substrates, which include TDP-43, tau, and tubulin, TTBK1 and TTBK2 inhibition has been pursued as a therapeutic approach for Alzheimer's disease, frontotemporal lobe dementia, and amyotrophic lateral sclerosis. TTBK2 is also an effector of ciliogenesis, acting in concert with CEP164, CP110, and CEP83 to initiate the biogenesis of primary cilia. The development of selective chemical tools for these kinases facilitates investigation into TTBK1/2-mediated pathways and potential disease-altering ramifications linked to their pharmacological perturbation.}, } @article {pmid42094412, year = {2026}, author = {Tilahun, K and Parameswaran, J and Dudley, M and Pun, D and Ma, F and Zhang, J and Bold, T and Jiang, J}, title = {TMEM106B C-terminal fragments drive nucleocytoplasmic transport failure and TDP-43 mislocalization in the aging human brain.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42094412}, issn = {2692-8205}, support = {R01 AG068247/AG/NIA NIH HHS/United States ; R01 NS138605/NS/NINDS NIH HHS/United States ; R36 AG088283/AG/NIA NIH HHS/United States ; }, abstract = {TMEM106B is a lysosomal membrane protein and major genetic modifier of multiple neurodegenerative diseases, including frontotemporal lobar degeneration, Alzheimer's disease, and amyotrophic lateral sclerosis. Proteolytically generated C-terminal fragments of TMEM106B assemble into amyloid fibrils that accumulate in the brains of individuals with neurodegenerative disease and in cognitively normal aged adults, yet how these fibrils produce neuronal dysfunction has remained unclear. Here, we show that cytosolic and lysosome-directed TMEM106B C-terminal fragments (CTF and gCTF) form detergent-insoluble amyloid aggregates, drive redistribution of endogenous TDP-43 from the nucleus to the cytoplasm, and accelerate neuronal death. Unbiased proximity proteomics identified the inner nuclear membrane LAP1-TorsinA axis as a fragment-specific interactome, and co-immunoprecipitation confirmed a direct physical interaction between gCTF and LAP1 that was not observed with full-length TMEM106B. Fragment expression disrupted Lamin B1 organization, mislocalized the nuclear import machinery KPNB1 and RanGAP1, and impaired importin-dependent nuclear transport in primary cortical neurons. Critically, neurons harboring endogenous TMEM106B fibrillar pathology in aged human frontal cortex exhibited the same phenotypes, namely disrupted Lamin B1 and LAP1 localization and cytoplasmic redistribution of TDP-43, whereas fibril-negative neurons from the same cases and younger control tissue retained intact nuclear envelope organization. These findings define TMEM106B proteinopathy as an upstream driver of nuclear envelope disruption and nucleocytoplasmic transport failure, linking a widespread feature of brain aging to a central mechanism of neurodegeneration.}, } @article {pmid42095061, year = {2026}, author = {Hu, Z and Wan, JJ and Yan, QQ and Fan, Y and Liu, J}, title = {Systematic proteomics reveals plasma NEFL as a robust predictor and pathological associate in C9ORF72-related neurodegeneration.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1792887}, pmid = {42095061}, issn = {1663-4365}, abstract = {BACKGROUND: The C9ORF72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While neurofilament light chain (NEFL) is an established biomarker of neuroaxonal damage, its specific dose-response relationship with the C9ORF72 expansion and its potential role beyond a passive bystander require systematic investigation. We performed a proteome-wide screen to identify plasma proteins linked to the C9ORF72 expansion and evaluated their predictive value for motor neuron disease (MND).

METHODS: We utilized whole-genome sequencing and plasma proteomics from the UK Biobank, analyzing 106 individuals with C9ORF72 expansions (defined as >30 repeats) and 212 age- and sex-matched controls. We screened ~3,000 proteins for associations with the continuous repeat count. The top candidate was evaluated using restricted cubic splines (RCS) to assess non-linearity and threshold effects. Its ability to independently predict MND risk was tested using regression models and a machine learning approach.

RESULTS: Our unbiased screen identified NEFL as the sole protein significantly associated with the C9ORF72 repeat count (FDR-adjusted P = 8.39 × 10[-4]). NEFL levels demonstrated a step-wise increase with expansion size, which followed a stable linear trajectory across the repeat spectrum (P non - linear = 0.4435). Elevated NEFL independently predicted MND risk (OR = 2.42; HR = 2.90), even after adjusting for the C9ORF72 repeat count. Our predictive model, combining NEFL and repeat count, achieved an AUC of 0.941 with 100% sensitivity. These findings align with emerging evidence that secreted NEFL may actively modulate neuroinflammation.

CONCLUSIONS: NEFL emerges as a robust and specific plasma biomarker for C9ORF72-related neurodegeneration. Its strong linear association with repeat burden and independent predictive power, contextualized within its potential role in immune activation, suggest that NEFL is deeply integrated into the C9ORF72 pathological landscape. These findings support NEFL-based screening and monitoring strategies for early intervention in C9ORF72 carriers.}, } @article {pmid42095090, year = {2026}, author = {Tremblay, E and Arbour, D and Vallée, J and Piovesana, R and Vallières, G and Mechichi, E and Robitaille, R}, title = {Neuromuscular junction innervation and motor function are preserved by restoring muscarinic signaling in perisynaptic glia in ALS.}, journal = {iScience}, volume = {29}, number = {5}, pages = {115565}, pmid = {42095090}, issn = {2589-0042}, abstract = {Neuromuscular junction (NMJ) denervation is an early pathological event in amyotrophic lateral sclerosis (ALS) causing motor dysfunction and paralysis. Glial cells at the NMJ, perisynaptic Schwann cells (PSCs), ensure a balance between maintenance and repair via muscarinic receptor signaling. However, in ALS mouse models, PSCs show an aberrant muscarinic hyperactivation. We posited that this excessive activation impairs the PSC capacity to support NMJ repair in ALS. Beginning at symptoms onset, SOD1 [G37R] mice received daily oral administration of darifenacin, a clinically approved type 3 muscarinic receptor antagonist, to reduce PSC hyperactivation. The treatment improved locomotion and preserved NMJ innervation in male mice, with comparable effects observed in females, and extended survival in males. Functional benefits were supported by signs of glial repair and enhanced survival of lumbar motor neurons. These preclinical data indicate that pathological PSC hyperactivity contributes to NMJ denervation in ALS and support therapeutic strategies targeting NMJs in ALS.}, } @article {pmid42095783, year = {2026}, author = {Gupta, S and Russell, B and Kristensen, LG and de Chant, J and Lu, A and Obst-Huebl, L and Rad, B and Tyler, J and Subramanian, S and Kidd, S and Paul, S and Chen, Y and Petzold, CJ and Kahan, DN and Costello, SM and Nakamura, K and Inman, JL and MacDowell, AA and Spucces, A and Ralston, CY}, title = {Design and commissioning of a new synchrotron beamline dedicated to X-ray footprinting mass spectrometry.}, journal = {Journal of synchrotron radiation}, volume = {33}, number = {Pt 4}, pages = {1206-1218}, pmid = {42095783}, issn = {1600-5775}, support = {P30 GM124169/GM/NIGMS NIH HHS/United States ; R01 GM126218/GM/NIGMS NIH HHS/United States ; R01GM126218//National Institutes of Health, National Institute of General Medical Sciences/ ; P30GM124169//National Institutes of Health, National Institute of General Medical Sciences/ ; }, mesh = {*Synchrotrons/instrumentation ; *Mass Spectrometry/instrumentation/methods ; Equipment Design ; *Protein Footprinting/instrumentation ; X-Rays ; *Proteins/chemistry ; }, abstract = {The structural biology method of X-ray footprinting mass spectrometry (XFMS) is available at two national synchrotron beamlines in the USA: one at the Advanced Light Source (ALS) on the West Coast and the other at the National Synchrotron Light Source II on the East Coast. XFMS is a solution-state technique that utilizes oxidative modifications of proteins at micromolar concentrations in aqueous buffer to extract structural information. X-rays are employed to generate hydroxyl radicals in situ, which covalently modify specific protein side chains. These modifications are subsequently quantified using liquid chromatography and mass spectrometry. Ratiometric changes in modification levels between two protein states (e.g. with and without ligand) generate a relative solvent accessibility map of the protein pairs, which serves to reveal structural features. Up until recently, the XFMS capability was available as part of a shared program at the ALS without a dedicated beamline. In this article, we describe the commissioning of ALS beamline 3.3.1, dedicated to XFMS, including the installation of a new focusing mirror, the design and construction of a new endstation with automated sample handling and exposure capabilities, and the use of accurate empirical dose calculations using Gafchromic film. Finally, we showcase the new beamline capabilities using two protein systems.}, } @article {pmid42096556, year = {2026}, author = {Copley, KE and Mauna, JC and Danielson, HL and Chen, Q and Ozguney, B and Ngo, M and Xie, L and Smirnov, A and Davis, M and Mayne, L and Linsenmeier, M and Rubien, JD and Bergmann, CA and Portz, B and Lee, BL and Odeh, HM and Lai, L and Chang, YW and Hallegger, M and Ule, J and Pasinelli, P and Poon, Y and Mittal, J and Fawzi, NL and Black, BE and Donnelly, CJ and Jensen, BK and Shorter, J}, title = {Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration.}, journal = {Science (New York, N.Y.)}, volume = {392}, number = {6798}, pages = {eadv3301}, pmid = {42096556}, issn = {1095-9203}, support = {R35 GM156396/GM/NIGMS NIH HHS/United States ; RF1 AG090910/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/chemistry/genetics/metabolism ; Motor Neurons/metabolism/pathology ; *Protein Aggregation, Pathological/genetics ; *RNA/metabolism/chemistry ; RNA Recognition Motif ; *TDP-43 Proteinopathies/genetics/metabolism/pathology ; }, abstract = {Aberrant aggregation of the prion-like RNA binding protein TDP-43 drives several fatal neurodegenerative proteinopathies, including amyotrophic lateral sclerosis (ALS). In this work, we define how short, specific RNAs solubilize TDP-43. These short RNAs engage and stabilize the TDP-43 RNA recognition motifs, which allosterically destabilizes a conserved helical region in the prion-like domain, thereby promoting aggregation-resistant conformers. Sequence-space mining identified short RNA chaperones with enhanced activity against TDP-43 and disease-linked variants. Enhanced short RNA chaperones mitigated aberrant TDP-43 phenotypes in optogenetic models and in ALS patient-derived and control motor neurons. In mice with cytoplasmic TDP-43 aggregation and motor neuron loss, an enhanced short RNA chaperone reduced pathological aggregation, restored TDP-43 function, and conferred neuroprotection. These results define a mechanistic and therapeutic framework for RNA-based strategies to counter TDP-43 proteinopathies.}, } @article {pmid42096854, year = {2026}, author = {De Avila-Arias, M and Fang, L and Hoyos-Hoyos, V and Harris Ricardo, J and Cadena-Cruz, C and Villarreal-Camacho, JL and Fortich Mesa, N}, title = {Candida-bacteria interactions in peri-implantitis: A narrative review of evidence, mechanisms, and clinical implications.}, journal = {Archives of oral biology}, volume = {188}, number = {}, pages = {106603}, doi = {10.1016/j.archoralbio.2026.106603}, pmid = {42096854}, issn = {1879-1506}, mesh = {Humans ; *Peri-Implantitis/microbiology ; Biofilms ; *Candida albicans/physiology ; *Microbial Interactions ; *Candida/physiology ; *Bacteria ; }, abstract = {OBJECTIVE: To critically synthesize clinical, molecular, and mechanistic evidence on the contribution of the oral mycobiome, particularly Candida albicans, to peri-implantitis, and to evaluate how fungal-bacterial interactions influence biofilm pathogenicity, host responses, and potential therapeutic implications.

DESIGN: Narrative review of peer-reviewed studies including clinical and epidemiological investigations, molecular analyses (quantitative polymerase chain reaction [qPCR] and next-generation sequencing [NGS] targeting the internal transcribed spacer [ITS] region for fungal profiling and the 16S ribosomal RNA [16S rRNA] gene for bacterial profiling), in vitro and in vivo interkingdom biofilm models, and immunological mechanistic studies. Evidence was evaluated qualitatively, with emphasis on detection methods, study design, and translational relevance.

RESULTS: Molecular studies detect Candida spp. in a notable fraction of peri-implantitis sites, with higher detection by qPCR/NGS than by culture. Co-occurrence of C. albicans with periodontopathogens (e.g., Porphyromonas gingivalis, Fusobacterium nucleatum) is frequently reported. Mechanistic studies show that C. albicans forms hyphal scaffolds, consumes oxygen to create microanaerobic niches, mediates bacterial adhesion via Als adhesins, and participates in metabolic exchange and cooperative proteolysis. These processes enhance biofilm resilience, promote inflammatory signalling pathways (nuclear factor kappa B [NF-κB] and mitogen-activated protein kinase [MAPK]), activate the NLRP3 inflammasome, and increase antimicrobial tolerance. No randomized controlled trials of antifungal or interkingdom-directed therapies are currently available.

CONCLUSIONS: Evidence supports an interkingdom, polymicrobial model of peri-implantitis in which fungi contribute to biofilm stability and inflammation. However, heterogeneity in definitions, sampling, and detection methods limits causal inference. Longitudinal and interventional studies are required before mycobiome-directed therapies can be recommended.}, } @article {pmid42097486, year = {2026}, author = {Deloncle, R}, title = {Conjecture for a free radical epimerization process in Alzheimer, Parkinson, Lewy body, amyotrophic lateral sclerosis, progressive Supranuclear Palsy and Creutzfeldt Jakob diseases.}, journal = {Experimental neurology}, volume = {403}, number = {}, pages = {115812}, doi = {10.1016/j.expneurol.2026.115812}, pmid = {42097486}, issn = {1090-2430}, mesh = {Humans ; Animals ; *Creutzfeldt-Jakob Syndrome/metabolism/pathology ; Free Radicals/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; *Supranuclear Palsy, Progressive/metabolism/pathology ; Lewy Body Disease/metabolism/pathology ; *Alzheimer Disease/metabolism ; Copper/metabolism ; Brain/metabolism ; Parkinson Disease/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; }, abstract = {Brain protease-resistant misfolded proteins have been described in Alzheimer (AD), Parkinson (PD), Lewy Body (LBD), Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy (PSP) and Creutzfeldt Jakob (CJD) diseases. The role of free radicals in generating these protease resistant structures has been experimentally demonstrated in prion bovine spongiform encephalopathy (BSE), when manganese is substituted for copper (Cu), in bovine brain homogenates in reductive medium, while Cu protective effect against free radicals can be restored by Cu supplementation in oxidative medium. These facts can suggest a free radical-induced epimerization process in neuroprotein misfolding leading to the transformation of physiological L-amino acid brain proteins into abnormal D-structures which will be deposited in the brain as observed in neurodegenerative diseased brains. A blood Cu increase, not ceruloplasmin (CP) bound correlated with a Cu increase in the cerebrospinal fluid (CSF) and a Cu decrease in the brain have been described in AD, PD, ALS, or CJD. This indicates that following neuronal death, Cu might be expelled from brain proteins and subsequent to redistribution between brain, CSF and blood, it will result a brain Cu deficiency and a decrease in Cu brain protection against free radicals. In the aim of repairing this deficiency and slow down the neurodegenerative disease process, a brain Cu complexes vectorization through the blood-brain barrier might restore brain Cu homeostasis.}, } @article {pmid42099046, year = {2026}, author = {Yang, X and Taghavi, A and Akahori, Y and Pedrini, M and Ishii, T and Disney, MD}, title = {An RNA-Focused DNA-Encoded Library Platform for Discovering Ligands of Pathogenic r(G4C2)[exp] RNA.}, journal = {ACS chemical biology}, volume = {21}, number = {6}, pages = {1562-1575}, doi = {10.1021/acschembio.6c00337}, pmid = {42099046}, issn = {1554-8937}, support = {R35 NS116846/NS/NINDS NIH HHS/United States ; }, mesh = {Ligands ; *RNA/chemistry/metabolism/genetics ; *DNA/chemistry ; *Small Molecule Libraries/chemistry/pharmacology ; Molecular Docking Simulation ; Humans ; Structure-Activity Relationship ; Gene Library ; }, abstract = {Disease-associated RNAs are increasingly recognized as promising therapeutic targets for small-molecule intervention. While DNA-encoded libraries (DELs) have long been established for protein ligand discovery, recent studies have demonstrated their feasibility for identifying RNA-binding small molecules. To further advance RNA-targeted ligand discovery, a diverse, solid-phase DEL enriched in privileged RNA-binding scaffolds was constructed and applied to identify ligands of r(G4C2)[exp], a toxic RNA repeat expansion implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). DEL selection outcomes were analyzed through large-scale molecular docking integrated with physicochemical and structure-activity relationship (SAR) analyses. Correlations were observed between docking predictions and experimental enrichment trends, supporting lead identification. The lead compound was subsequently optimized based on rational design, resulting in analogues with enhanced binding affinity and bioactivity. These findings demonstrate that RNA ligand identification can be effectively achieved by combining DNA-encoded library technology with computational approaches for rational design and analysis and highlight a broadly adaptable platform for RNA-targeted small-molecule discovery.}, } @article {pmid42099104, year = {2026}, author = {Oriquat, G and Jasim, IK and Gajjar, TB and Hanumanthayya, M and Abdulhameed Ahmad, I and Singh, G and Maharana, L and Bainsal, N}, title = {SUMOylation in Neural Health and Disease: From Cellular Homeostasis to Neurodegeneration.}, journal = {DNA and cell biology}, volume = {45}, number = {7}, pages = {299-316}, doi = {10.1177/10445498261444640}, pmid = {42099104}, issn = {1557-7430}, mesh = {Humans ; *Sumoylation ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Homeostasis ; Animals ; *Neurons/metabolism/pathology ; Small Ubiquitin-Related Modifier Proteins/metabolism ; }, abstract = {Neurodegenerative diseases (NDDs) represent a growing global health burden, particularly in aging populations. These disorders primarily affect neurons and are characterized by progressive neuronal dysfunction and loss within specific regions of the central nervous system. Major NDDs include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and stroke. Although each disorder exhibits distinct genetic backgrounds and pathological protein aggregates, they share common pathogenic mechanisms, including chronic neuroinflammation, impaired autophagy and mitophagy, disrupted proteostasis, telomere instability, and epigenetic alterations. A hallmark feature across NDDs is the accumulation of misfolded proteins, leading to synaptic dysfunction and neuronal degeneration. Small ubiquitin-like modifiers (SUMOs) are a family of ∼100 amino acid proteins, including SUMO1 and the closely related SUMO2/3 isoforms. SUMOylation is a dynamic posttranslational modification that regulates protein function through the covalent attachment or removal of SUMO moieties. This reversible process is mediated by SUMO-specific E1 activating, E2 conjugating, and E3 ligating enzymes and is counterbalanced by SUMO/Sentrin-specific proteases. The SUMOylation status of target proteins depends on the tightly controlled balance between conjugation and deconjugation systems. Acting as a molecular switch, SUMOylation modulates diverse cellular processes such as DNA damage repair, RNA metabolism, transcriptional regulation, and protein quality control, all of which are essential for maintaining cellular homeostasis. Accumulating evidence links dysregulated SUMOylation to the pathogenesis of multiple neurological disorders, including polyglutamine and synucleinopathies. SUMOylation influences neuroinflammation, oxidative stress, protein aggregation, neuroangiogenesis, ischemic injury, and demyelination. This review highlights recent advances in understanding the role of SUMOylation in NDDs and explores its potential as a promising therapeutic target.}, } @article {pmid42099653, year = {2026}, author = {Zhang, W and Zhao, Y and Ge, N and Hou, F and Li, X and Zhao, C and Fei, H and Shi, X and Wang, W and Wang, S and Liu, X}, title = {Pediatric diamond-blackfan anemia after hematopoietic stem cell transplantation complicated by bronchiolitis obliterans and air-leak syndrome leading to lung transplantation: a case report with multimodal follow-up.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1782188}, pmid = {42099653}, issn = {1664-3224}, mesh = {Humans ; Female ; Child ; *Anemia, Diamond-Blackfan/therapy ; *Bronchiolitis Obliterans/etiology/surgery ; *Lung Transplantation/methods ; Follow-Up Studies ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Syndrome ; *Lung Diseases/etiology/surgery ; Treatment Outcome ; }, abstract = {INTRODUCTION: Bronchiolitis obliterans syndrome (BOS) is a severe, often fatal pulmonary manifestation of chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Its progression to air-leak syndrome (ALS) signifies a critical deterioration with exceedingly high mortality. Lung transplantation (LTx) remains a rare salvage option, especially in children, with scarce reports of successful outcomes in those with this complication cascade.

CASE PRESENTATION: We report the case of a 7-year-old girl with Diamond-Blackfan anemia (DBA) who developed BOS complicated by ALS after allo-HSCT. She developed acute GVHD involving the skin and liver on +100d, which improved following immunosuppressive therapy. On +231d, pulmonary function tests showed severe mixed ventilatory dysfunction (FEV1 37% of predicted value, FEV1/FVC 52%), and high-resolution computed tomography (HRCT) revealed mosaic perfusion and bronchial wall thickening, contributing to the diagnosis of BOS. Despite intensive immunosuppressive therapy, she developed ALS on +360d and type II respiratory failure on +475d. Sequential bilateral LTx was performed on October 28, 2025. Postoperatively, the patient recovered following the management of multidrug-resistant bacterial infections and respiratory complications, with no rejection or recurrence of cGVHD during follow-up.

CONCLUSION: This report presents the youngest documented DBA case of successful LTx for BOS complicated by ALS after allo-HSCT globally. It demonstrates that dynamic multimodal monitoring is crucial for early BOS detection. LTx is a viable therapy for end-stage pulmonary cGVHD in children. This case underscores the need for proactive monitoring in high-risk patients and provides a paradigm for managing this complex complication.}, } @article {pmid42101064, year = {2026}, author = {Chae, J and Yoo, SH and Lee, SY and Kim, JS and Sung, JJ and Choi, SJ}, title = {Factors Impacting Tracheostomy Decisions in Korean Individuals With Amyotrophic Lateral Sclerosis: A Cross-Sectional Survey.}, journal = {Muscle & nerve}, volume = {74}, number = {1}, pages = {159-172}, doi = {10.1002/mus.70270}, pmid = {42101064}, issn = {1097-4598}, support = {RS-2025-02216164//Korea Health Industry Development Institute/Republic of Korea ; RS-2025-02215165//Korea Health Industry Development Institute/Republic of Korea ; RS-2025-00553428//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/surgery/therapy/epidemiology ; *Tracheostomy/psychology ; Male ; Female ; Cross-Sectional Studies ; Middle Aged ; *Decision Making ; Aged ; Republic of Korea/epidemiology ; Surveys and Questionnaires ; Quality of Life ; Adult ; Patient Preference ; }, abstract = {INTRODUCTION/AIMS: Decisions regarding tracheostomy are often made under emergent circumstances, although they require complex considerations of patient preferences, quality of life, and prognosis. This study investigated decision-making surrounding tracheostomy in Korean people with amyotrophic lateral sclerosis (pwALS) and factors influencing these decisions.

METHODS: Eighty participants were recruited from the Korean ALS Association and categorized into those who underwent tracheostomy-invasive ventilation (TIV) and those who did not. Participants completed the Hospital Anxiety and Depression Scale (HADS), the Decisional Conflict Scale (DCS), and the Control Preference Scale (CPS), as well as 27 modified questions from the Columbia University TIV study assessing demographics, disease characteristics, preferences, and reasons for undergoing or declining tracheostomy.

RESULTS: Forty-two patients underwent TIV. The TIV and non-TIV groups were similar in age and sex, whereas disease duration was longer in the TIV group. Among those in the non-TIV group, King's stage 4a was the most frequent (n = 13). Fourteen patients (33%) who underwent TIV reported that they received information about tracheostomy at the time of the procedure, whereas 22 patients in the non-TIV group (58%) reported no prior discussion. DCS and HADS scores did not differ significantly between groups; however, high decisional conflict (DCS ≥ 25) was associated with higher HADS scores.

DISCUSSION: Tracheostomy decision-making among Korean pwALS is frequently crisis-driven, limiting opportunities for advance discussion. Timely and structured discussions about end-of-life care are essential for supporting informed, preference-aligned decisions and reducing psychological burden. Using simple, validated questionnaires may help identify decisional uncertainty and clarify patients' preferred roles in decision-making.}, } @article {pmid42101470, year = {2026}, author = {Panchal, D and Solanki, D and Solanki, R and Yadav, AK and Bhatia, D and Yadav, P}, title = {Biomaterials and Nanoparticle-Based Therapeutics in Neurodegenerative Diseases: Bridging the Gap Between Innovation and Translation.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {10}, pages = {1824-1869}, doi = {10.1021/acschemneuro.6c00245}, pmid = {42101470}, issn = {1948-7193}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Blood-Brain Barrier/metabolism/drug effects ; *Nanoparticles/administration & dosage ; *Biocompatible Materials/administration & dosage ; *Drug Delivery Systems/methods ; *Translational Research, Biomedical/methods ; Nanoparticle Drug Delivery System ; }, abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and multiple sclerosis, represent a growing global health crisis characterized by irreversible neuronal loss, protein aggregation, chronic neuroinflammation, and mitochondrial dysfunction. Central to their therapeutic intractability is the blood-brain barrier (BBB), a highly selective neurovascular interface that excludes nearly 98% of conventional pharmacological agents from the central nervous system (CNS). Nanoparticle- and biomaterial-based delivery platforms have emerged as promising strategies to overcome these barriers, encompassing liposomes, polymeric nanoparticles, engineered exosomes, inorganic nanoparticles, and hydrogel scaffolds capable of enabling targeted CNS drug delivery. This Review systematically evaluates the landscape of nanomaterial-based neurotherapeutics across disease-specific pathological contexts, critically analyzing translational failure mechanisms including limited parenchymal brain exposure, receptor saturation during transcytosis, protein corona-mediated immune clearance, and nanoscale toxicity in postmitotic neural tissue. Preclinical-to-clinical translational gaps arising from interspecies BBB transporter heterogeneity and pharmacokinetic divergence are examined alongside manufacturing and regulatory barriers impeding Good Manufacturing Practice (GMP)-scale production. Emerging convergence strategies─including AI-integrated design, hybrid physiologically based pharmacokinetic modeling, theranostic nanoplatforms, and wearable bioresponsive delivery systems─are evaluated for their capacity to address these limitations. The review concludes by proposing a framework for developing clinically viable, disease-modifying CNS nanomedicines.}, } @article {pmid42102048, year = {2026}, author = {Bombaci, A and Giordano, A and Lavalle, I and Magnino, A and Calvo, A and Chiò, A and Cicolin, A}, title = {"Silent Echoes of the Day: Dream Content Analysis in Amyotrophic Lateral Sclerosis".}, journal = {Brain and behavior}, volume = {16}, number = {5}, pages = {e71387}, pmid = {42102048}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/physiopathology ; Female ; *Dreams/psychology/physiology ; Male ; Middle Aged ; Aged ; Adult ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to muscle atrophy, weakness, and respiratory failure. Numerous studies evaluated the impact of diseases on dream content, and the dream content analysis may be considered an interesting tool in the study of the internalization of the consequences of significant life changes. The study of ALS patients' dream content has been mostly neglected in the literature. This study investigated the dream content in a population affected by ALS.

MATERIAL AND METHODS: We evaluated all consecutive outpatients referred to our ALS Centre using a weekly diary of dreams. Dream contents were coded according to the Hall and Van de Castle coding system.

RESULTS: Sixty-eight patients completed the study. We collected 127 dreams (females 39.4%) (males 60.6%). Males showed a reduced presence of friends, anatomical elements, aggression, friendship, and sexuality. Instead, we found an increased presence of family members, situations in which the dreamer initiates aggressive action and familiar settings. In the female sample, we found a decreased presence of friends, aggressive and friendly elements, sex-related content, and misfortune, while an increase in animal content.

CONCLUSIONS: Our results demonstrate that dream content in ALS patients differs from that of healthy subjects, and we noticed some gender differences among ALS patients. The dream content can offer insights into ALS patients' mental state and may improve clinicians' ability to support their patients during their therapeutic course.}, } @article {pmid42102258, year = {2026}, author = {Di Pede, F and Cabras, S and Manera, U and Vasta, R and Zocco, G and Minerva, E and Matteoni, E and De Mattei, F and Pellegrino, G and Palumbo, F and Pascariu, D and Callegaro, S and Maccabeo, A and Polverari, G and Martino, A and Giuliani, A and Moglia, C and Calvo, A and Chiò, A and Pagani, M and Canosa, A}, title = {King's stages of amyotrophic lateral sclerosis: an 18F-FDG-PET study of brain connectivity.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {7}, pages = {2495-2504}, pmid = {42102258}, issn = {1460-2156}, support = {2017SNW5MB//Progetti di Rilevante Interesse Nazionale (PRIN)/ ; //Joint Programme-Neurodegenerative Disease Research/ ; //Italian Ministry of Education, University and Research/ ; //Thierry Latran Foundation/ ; RF-2016-02362405//Italian Ministry of Health/ ; FP7/2007-2013//European Commission's Health Seventh Framework Programme/ ; 259867//European Commission's Health Seventh Framework Programme/ ; GA101017598//European Union's Horizon 2020 research and innovation programme/ ; 101137074//European Union's Horizon 2020 research and innovation programme/ ; //A.S.D. Polisportiva U.I.C.I Torino Onlus/ ; //Department of Excellence/ ; //Department of Neuroscience, University of Turin/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/physiopathology ; Positron-Emission Tomography/methods ; Fluorodeoxyglucose F18 ; Female ; *Brain/diagnostic imaging/metabolism ; Male ; Cross-Sectional Studies ; Middle Aged ; Aged ; Severity of Illness Index ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons. TAR DNA-binding protein 43 (TDP-43) proteinopathy is the neuropathological signature of the disease, and 18F-fluorodeoxyglucose PET (18F-FDG-PET) serves as a marker of neurodegeneration in vivo. The aim of the present cross-sectional study was to disentangle 18F-FDG-PET correlates of disease severity assessed through the King's staging system, by exploring connectivity changes across motor stages. Patients with ALS classified as King's stage 1, 2 or 3, who underwent brain 18F-FDG-PET at diagnosis from 2008 to 2022 at the ALS Centre of Turin, were included. A multiple regression analysis to evaluate the relationship between brain metabolism and King's stage was performed. The clusters showing significant results were used as seed regions in an interregional correlation analysis (IRCA), performed for each stage. Of a total of 832 patients with ALS, 337 were classified as King's stage 1, 274 as stage 2 and 221 as stage 3. The three groups significantly differed in age at PET, disease duration and total ALS Functional Rating Scale Revised (ALSFRS-R) score at the time of PET, C9orf72 status and the distribution of cognitive categories. We found a decreasing metabolic gradient from King's stage 1 to King's stage 3 in a cluster encompassing motor and cognitive areas. As King's stage increases, we found a decrease of connectivity within the sensorimotor and cognitive areas. The IRCA also showed the connectivity of motor and cognitive regions with temporal and cerebellar regions. The connectivity with temporal regions found in King's stage 1 decreases in King's stage 2 and finally, disappears in King's stage 3. The connectivity with the cerebellum occurs in King's stage 2 and decreases in King's stage 3. The changes of connectivity of motor and cognitive areas with temporal and cerebellar regions among different King's stages might reflect the spread of TDP-43 proteinopathy or a compensatory mechanism, respectively. The present study suggests that 18F-FDG-PET imaging of the brain may be integrated with the King's staging system to assess the extent of the pathogenic process in the context of clinical trials.}, } @article {pmid42102977, year = {2026}, author = {Zhang, J and Wang, C and Li, Y and Xiao, Z and Cai, Z and Qian, Y and Shi, L and Zhang, Q}, title = {Lipid dysregulation as a central contributor of neurodegenerative diseases: Emerging therapeutic targets and strategies.}, journal = {Ageing research reviews}, volume = {119}, number = {}, pages = {103159}, doi = {10.1016/j.arr.2026.103159}, pmid = {42102977}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy/therapy ; *Lipid Metabolism/physiology/drug effects ; Animals ; *Brain/metabolism/pathology ; }, abstract = {Lipid homeostasis is essential for preserving the structural integrity and functional capacity of the brain. A diverse array of lipids, including cholesterol, phospholipids, and sphingolipids, has been identified as playing pivotal roles. Dysregulation of lipid metabolism is increasingly recognized as a central pathological mechanism in neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Cerebrotendinous Xanthomatosis, though much of the existing evidence comes from associative studies, and causal relationships still need to be further validated through interventional studies. Here we systematically review the metabolic pathways and regulatory networks of major brain lipids, with a focus on delineating disease-specific alterations and summarizing emerging therapeutic strategies targeting lipid metabolism. These strategies encompass the modulation of cholesterol homeostasis, sphingolipid metabolism, phospholipid signaling, and fatty acid oxidation, alongside approaches that enhance lipid clearance and neural repair. Preclinical advances and ongoing clinical trials underscore the translational potential of lipid-targeted interventions. In conclusion, we emphasize the potential of lipid metabolism as a promising avenue for developing novel treatments, offering insights to guide future research and therapeutic innovation in neurodegeneration.}, } @article {pmid42103041, year = {2026}, author = {López-Blanch, R and Oriol-Caballo, M and Estrela, JM and Obrador, E}, title = {Multimodal strategies for diagnosis, stratification, and therapeutic monitoring in ALS.}, journal = {Neuroscience and biobehavioral reviews}, volume = {187}, number = {}, pages = {106727}, doi = {10.1016/j.neubiorev.2026.106727}, pmid = {42103041}, issn = {1873-7528}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy/physiopathology/genetics ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of motor neurons (MN) that is currently diagnosed through a prolonged process of exclusion, often delaying intervention. This review provides an overview of fluid, imaging, electrophysiological, and genetic biomarkers, explicitly linking each modality to early detection, patient stratification, disease monitoring, therapeutic development, and clinical trial design. Fluid biomarkers (i.e., neurofilament light chain, phosphorylated neurofilament heavy chain, inflammatory cytokines, microRNAs, and proteins in blood or cerebrospinal fluid) reflect neuronal injury and/or disease activity, enabling early identification of pres-ymptomatic individuals and longitudinal tracking of neurodegeneration. Imaging biomarkers, such as structural and diffusion MRI of the motor cortex, corticospinal tracts, and spinal cord, as well as PET imaging neuroinflammation or metabolism, provide objective measures of MN degeneration and extra-motor involvement. Electrophysiological biomarkers, including high-density electromyography, motor unit number, transcranial magnetic stimulation, and electrical impedance myography, quantitatively assess upper and lower MN loss and functional reserve. Genetic biomarkers, encompassing variants in genes such as C9orf72, SOD1, FUS, and TARDBP, enable presymptomatic screening and molecular stratification. In this context, transposable elements have emerged as an additional layer linking genomic variation and RNA dysregulation. We highlight the importance of multimodal and stage-specific biomarker integration to improve diagnostic accuracy and illuminate distinct disease phases. This approach supports stratification by progression rate or molecular subtype, enrichment of clinical trial cohorts, and the development of surrogate endpoints. We conclude by discussing current challenges, including disease heterogeneity and assay standardization, and outline future directions toward biomarker-driven precision medicine in ALS.}, } @article {pmid42104039, year = {2026}, author = {Jantrapirom, S and Sangphukieo, A and U-On, N and Poonsawas, P and Wongkumool, W and Yeewa, R and Panto, C and Poound, P and Zito, E and Marrazza, A and Lo Piccolo, L}, title = {Discovery of a pyrazolopyridine alkaloid that mitigates neuronal ER stress and age-related decline.}, journal = {Communications biology}, volume = {9}, number = {1}, pages = {}, pmid = {42104039}, issn = {2399-3642}, support = {FF66/061//Chiang Mai University (CMU)/ ; FF67/044//Chiang Mai University (CMU)/ ; FF68/207569//Chiang Mai University (CMU)/ ; 66-124//Health Systems Research Institute (HSRI)/ ; 68-060//Health Systems Research Institute (HSRI)/ ; N42A670768//National Research Council of Thailand (NRCT)/ ; 139/2567//CMU | Faculty of Medicine, Chiang Mai University/ ; }, mesh = {Animals ; Humans ; *Pyrazoles/pharmacology/chemistry ; *Pyridines/pharmacology/chemistry ; *Neurons/drug effects/metabolism ; *Aging/drug effects ; *Endoplasmic Reticulum Stress/drug effects ; *Alkaloids/pharmacology/chemistry ; }, abstract = {Endoplasmic reticulum (ER) stress contributes to the pathogenesis of neurodegenerative and age-associated diseases, motivating the search for compounds that enhance ER-stress resilience. Modulation of ER-redox pathways, including those associated with the oxidase ERO1A, can attenuate maladaptive unfolded protein response (UPR) signaling and improve cellular stress tolerance. Here we develop an integrative discovery strategy to identify natural compounds that mitigate ER-stress-associated phenotypes across cellular and organismal models. Structure-informed virtual screening guided by ERO1A biology prioritized the pyrazolopyridine alkaloid S88. In human SH-SY5Y-derived neurons, S88 improves survival and reduces tunicamycin-induced ER-stress markers. In Drosophila, S88 ameliorates neuromuscular and locomotor phenotypes in a UBQLN2-associated ALS model and improves aging-related outcomes. Biochemical assays did not detect inhibition of ERO1A or radical scavenging activity by S88, indicating that its molecular target remains to be identified. Together, these findings identify S88 as a natural-product scaffold that enhances ER-stress resilience across neuronal and in vivo models.}, } @article {pmid42105306, year = {2026}, author = {Flores, SV and Lillo, P and Briceño-Moya, J and Pedro, AP}, title = {Molecular and genetic landscape of amyotrophic lateral sclerosis in Latin America: a scoping review of pathogenic hypotheses and ancestral heterogeneity.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2668070}, pmid = {42105306}, issn = {2167-9223}, abstract = {Background: The genetic architecture of amyotrophic lateral sclerosis (ALS) has been predominantly characterized in populations of European ancestry, while Latin American populations remain underrepresented despite their complex admixture. Objective: To map the molecular hypotheses explored in ALS research conducted in Latin American populations and identify key methodological and structural gaps. Methods: A scoping review was conducted following Joanna Briggs Institute methodology and reported according to PRISMA-ScR guidelines. Searches were performed in Web of Science, Scopus, PubMed/MEDLINE, SciELO, and LILACS. Studies investigating genetic or molecular aspects of ALS or the ALS-FTD spectrum in Latin American populations were included. Data were extracted using a standardized matrix and synthesized descriptively. Results: Nineteen studies met inclusion criteria. Most were small, single-center investigations employing targeted candidate-gene approaches, predominantly focused on C9orf72 expansions and SOD1 mutations. Reported C9orf72 frequencies varied substantially across countries, indicating population-specific genetic heterogeneity. Only one study incorporated explicit ancestry inference, and no genome-wide association studies or large multicenter ALS genomic cohorts were identified. Conclusions: ALS research in Latin America remains limited, fragmented, and largely candidate-gene driven, with minimal integration of ancestry-informed approaches. The absence of large-scale genomic studies, despite existing regional sequencing capacity, highlights the need for coordinated multicenter initiatives to enable equitable implementation of precision medicine.}, } @article {pmid42105767, year = {2026}, author = {Sivasubramanian, R and Sterneckert, J}, title = {Restoring miRNA biogenesis in ALS: Enoxacin enhances DICER activity in a first-in-human trial.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {34}, number = {6}, pages = {3147-3148}, pmid = {42105767}, issn = {1525-0024}, } @article {pmid42106156, year = {2026}, author = {Wang, J and Hu, M and Meng, W and Zhang, M and Yuan, Z and Wang, F and Li, S}, title = {Suppressing isovaleric acid off-flavor in Bacillus subtilis fermentation and its consequential effects on secondary metabolism.}, journal = {Bioresource technology}, volume = {455}, number = {}, pages = {134803}, doi = {10.1016/j.biortech.2026.134803}, pmid = {42106156}, issn = {1873-2976}, mesh = {*Bacillus subtilis/metabolism/genetics ; *Fermentation ; *Taste ; Soy Milk/metabolism ; *Hemiterpenes/metabolism ; *Pentanoic Acids/metabolism ; }, abstract = {Bacillus subtilis-fermented soybean foods (BFSFs) are nutritious East Asian staples. However, off-flavors dominated by isovaleric acid (IVA), a branched-chain fatty acid, limit consumer acceptance and industrial adoption. Although leucine- and acetolactate-derived pathways have been proposed, key regulatory nodes for IVA in soymilk remain unclear. This study systematically evaluated the key gene nodes controlling IVA biosynthesis during soymilk fermentation by B. subtilis, including bcd (leucine dehydrogenase, Bcd), bkdAB (branched-chain α-keto acid dehydrogenase complex, Bkd), ptb (phosphotransbutyrylase, Ptb), and alsS (acetolactate synthase, ALS). This study utilized B. subtilis 168 (BS168) and a gene-editing approach to construct BS168 mutants lacking bkdAB and alsS, which were combined with previously generated BS168Δbcd and BS168Δptb. IVA was significantly reduced in all mutants, most markedly in BS168Δbcd (-81.85%) and BS168ΔbkdAB (-70.31%). The volatile profile shifted toward higher levels of fruity esters and alcohols and lower levels of acids and ketones, with improved sensory acceptability, particularly in BS168ΔbkdAB. Enzyme assays confirmed Bcd, Bkd, and Ptb as key pathway nodes, while ALS modulated upstream pyruvate flux toward branched-chain amino acid (BCAAs) biosynthesis. Collectively, this work genetically validates IVA pathway control in a real food matrix and shows that targeted disruption of bcd, bkdAB, and ptb is an effective strategy to suppress IVA off-flavor and improve sensory acceptability in B. subtilis-fermented soymilk, providing mechanistic targets for subsequent development and evaluation in food-grade or industrial strains.}, } @article {pmid42107892, year = {2026}, author = {Chen, G and Zhao, C and Wang, C and Chen, G and Shi, J and Chen, H}, title = {Microglia crosstalk with T cells in neurodegenerative diseases: pathogenesis and treatment targets.}, journal = {International immunopharmacology}, volume = {182}, number = {}, pages = {116781}, doi = {10.1016/j.intimp.2026.116781}, pmid = {42107892}, issn = {1878-1705}, mesh = {Humans ; *Microglia/immunology ; *Neurodegenerative Diseases/immunology/therapy ; Animals ; *T-Lymphocytes/immunology ; }, abstract = {Immune cells play a central role in driving inflammation and neurodegeneration across various neurological disorders. Central nervous system (CNS)-resident microglia and infiltrating T cells represent the innate and adaptive immune systems, respectively, and have been reported to contribute to the pathogenesis of neurodegenerative diseases individually. Growing evidence suggests that the encounter between activated microglia and infiltrating T cells amplifies their neurotoxic potential. In this review, we discussed alterations in microglial phenotype and function, and the contributions of different T cell subsets in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS) and glaucoma. We emphasized the crosstalk between microglia and T cells via antigen presentation, chemotactic signals, and pro-inflammatory mediators. We also explored emerging therapeutic strategies aimed at modulating T cell and microglial responses, as well as their interactions, for the treatment of neurodegenerative diseases.}, } @article {pmid42108848, year = {2026}, author = {Jung, YH and Seok, HY and Kang, M and Do, YW and Park, JO and Kim, JH and Park, JS}, title = {Clinical Significance of Plasma Sphingosine-1-Phosphate Decline in Progression of Spinal and Bulbar Muscular Atrophy.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {22}, number = {3}, pages = {327-337}, pmid = {42108848}, issn = {1738-6586}, support = {NRF-2022R1C1C1009723/NRF/National Research Foundation of Korea/Korea ; RS-2025-25424215/NRF/National Research Foundation of Korea/Korea ; }, abstract = {BACKGROUND AND PURPOSE: Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked neuromuscular disorder characterized by slowly progressive motor decline. However, there is no specific fluid marker that reflects the severity or progression of the disease. Therefore, identifying measurable markers that reflect disease progression remains a major unmet need in SBMA management.

METHODS: Plasma samples from 21 Korean patients with SBMA were collected at baseline and after 3 years. Untargeted and targeted metabolomics profiling was performed, and plasma sphingosine-1-phosphate (S1P) was the final candidate biomarker. S1P was then quantified using liquid chromatography-mass spectrometry. Associations between longitudinal S1P changes and clinical parameters, including the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), serum creatine kinase (CK), 6-minute walk test (6MWT), and forced vital capacity (FVC), were examined.

RESULTS: Plasma S1P levels significantly declined in the fast progression group over 3 years, while remaining relatively stable in the slow progression group. Longitudinal changes in plasma S1P showed weak-to-moderate positive trends with clinical measurements, including ALSFRS-R, FVC, and 6MWT, and a negative trend with serum CK at follow-up.

CONCLUSIONS: Plasma S1P represents a promising quantitative biomarker for monitoring SBMA progression. Validation in larger cohorts and mechanistic studies of S1P regulation are warranted to establish its role in clinical management.}, } @article {pmid42111077, year = {2026}, author = {Zhou, S and Li, X and Jiao, Y and Wu, J}, title = {Efficacy and safety of pharmacological and biological therapies for amyotrophic lateral sclerosis: a network meta-analysis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1754716}, pmid = {42111077}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder for which disease-modifying treatment options remain limited. This study aimed to systematically assess the efficacy and safety of pharmacological and biological therapies for ALS via a network meta-analysis (NMA).

METHODS: PubMed, EMBASE, Cochrane, and Web of Science were searched until February 25, 2025. Randomized controlled trials (RCTs) evaluating any pharmacological or biological intervention in ALS were eligible. Risk of bias was assessed using the Cochrane RoB 2 tool. A Bayesian NMA was performed in R (gemtc package). Effect estimates were expressed as mean differences (MDs) or risk ratios (RRs) with 95% credible intervals (CrIs). Interventions were ranked using the surface under the cumulative ranking curve (SUCRA). Publication bias was explored with funnel plots (Stata 18.0). Subgroup analyses were conducted for drug classes demonstrating significant efficacy and including at least three RCTs.

RESULTS: 109 trials involving 16,353 participants were included. The primary outcome was the ALS Functional Rating Scale-Revised (ALSFRS-R); secondary outcomes included forced vital capacity (FVC), mortality, and serious adverse events (SAEs). Compared with placebo, the combination of cell therapy and neuroprotective agents produced the greatest attenuation of ALSFRS-R decline (MD: 3.65, 95% CrI: 1.27-6.05) and was associated with the lowest SAE risk. Receptor agonists ranked highest for preservation of FVC, whereas alkaloids ranked first for mortality reduction; however, no intervention demonstrated a statistically significant survival benefit versus placebo. Within-class subgroup analyses further identified several specific agents, such as masitinib, talampanel, and EH301, as demonstrating relatively consistent efficacy, although substantial heterogeneity remained among enzyme inhibitors.

CONCLUSION: Cell therapy combined with neuroprotective agents may slow functional decline in ALS. Receptor agonists may help preserve respiratory function. Survival benefits remain inconclusive, underscoring the continued importance of comprehensive supportive care.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251000672, identifier CRD420251000672.}, } @article {pmid42111176, year = {2026}, author = {Li, Y and Yao, Z and Song, Z and Yang, P and Huang, J and Lei, K and Xu, Y}, title = {The intrinsic disorder challenge for AlphaFold: A case study of G3BP1 and pathogenic peptide.}, journal = {iScience}, volume = {29}, number = {5}, pages = {115737}, pmid = {42111176}, issn = {2589-0042}, abstract = {The dipeptide repeat protein GR20 in amyotrophic lateral sclerosis (ALS) exerts neurotoxicity in part by binding to the stress granule protein G3BP1 and disrupting liquid-liquid phase separation (LLPS). However, the structural basis of this interaction remains elusive due to the pervasive intrinsic disorder in both partners. Here, we combine biochemical assays and structure prediction to characterize the G3BP1-GR20 complex. GR20 has high-affinity binding to G3BP1 and modulates LLPS in a concentration-dependent manner. Since the standard AlphaFold (AF) pipeline failed to predict credible models, we employed a constraint-based method AFEX to generate a G3BP1-GR20 complex model with improved confidence and structural plausibility. Our work underscores the necessity of extra efforts for AF predictions on disordered complexes and demonstrates the value of integrative and knowledge-guided approaches for exploring the "invisible proteome" of biomolecular condensates.}, } @article {pmid42112660, year = {2026}, author = {Kasper, E and Lehto, A and Jürs, A and Nordmann, N and Peters, O and Hellmann, J and Priller, J and Spruth, EJ and Petzold, GC and Voigt, I and Weydt, P and Bernsen, S and Dinter, E and Falkenburger, B and Günther, R and Düzel, E and Glanz, W and Synofzik, M and Beichert, L and Spottke, A and Wagner, M and Brosseron, F and Schmid, MC and Halle, A and Herms, J and Schneider, A and Teipel, S and Prudlo, J and Neumann, M and Hermann, A}, title = {Alzheimer's Disease Co-Pathology and Cognitive Impairment in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {100}, number = {1}, pages = {123-138}, pmid = {42112660}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/complications/cerebrospinal fluid/psychology ; Female ; Male ; *Alzheimer Disease/pathology/complications/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Aged ; *Cognitive Dysfunction/pathology/cerebrospinal fluid ; DNA-Binding Proteins/blood/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; Biomarkers/cerebrospinal fluid/blood ; Neurofilament Proteins/cerebrospinal fluid/blood ; Frontotemporal Dementia/pathology ; }, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) share neuropathological features, including tau, amyloid, and TDP-43 pathology. This study investigated whether AD-related pathological changes are associated with cognitive impairment ALS.

METHODS: Cerebrospinal fluid (CSF total-tau, phosphorylated-tau, beta-amyloid) and plasma biomarkers (TDP-43; neurofilament light chain [NfL]) were analyzed in 192 individuals with ALS or ALS with frontotemporal dementia (ALS-FTD) and 100 healthy controls. Cognitive performance was assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Group comparisons and regression analyses examined associations between biomarker profiles and cognitive status. Autopsy data were available for a subset of participants.

RESULTS: Compared with healthy controls, patients with ALS - particularly those with cognitive impairment (ALSci) or ALS-FTD - showed elevated AD-related biomarkers. Significant differences in beta-amyloid levels were observed between healthy controls (HCs) and patients with ALSci, but not between controls and cognitively unimpaired patients. CSF p-tau and total-tau levels were strongly associated with domain-specific cognitive performance. In contrast, plasma extracellular vesicle TDP-43 and NfL showed weak or no association with cognition. In vivo biomarkers alone reliably distinguished cognitive impairment only in ALSci and ALS-FTD. Postmortem analyses showed no strong association between ABC scores or overall TDP-43 burden and cognitive state; however, temporal and hippocampal TDP-43 burden was associated with cognitive dysfunction.

INTERPRETATION: Our findings suggest that tau-related CSF biomarkers, particularly p-tau and total-tau, are associated with cognitive deficits in ALS, indicating that AD-related pathology might be associated to cognitive decline in ALS. However, postmortem data showed even stronger relation of TDP43 pathology to cognitive deficits in ALS. ANN NEUROL 2026;100:123-138.}, } @article {pmid42112934, year = {2026}, author = {Melechovsky, J and Novotny, M and Tykalova, T and Klempir, J and Herremans, D and Rusz, J}, title = {Development of an Interpretable Deep Learning-Based Segmentation Algorithm for Automated Assessment of Oral Diadochokinesis in Progressive Neurological Diseases.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {69}, number = {6}, pages = {2437-2453}, doi = {10.1044/2026_JSLHR-25-00453}, pmid = {42112934}, issn = {1558-9102}, mesh = {Humans ; *Deep Learning ; *Algorithms ; *Dysarthria/diagnosis/etiology/physiopathology ; Female ; *Nervous System Diseases/complications/physiopathology ; Male ; Convolutional Neural Networks ; Middle Aged ; Aged ; Signal Processing, Computer-Assisted ; }, abstract = {PURPOSE: We aimed to develop a universal, fully automated segmentation algorithm that allows robust analysis of oral diadochokinesis across various neurological diseases, dysarthria types, and dysarthria severities.

METHOD: Recordings of sequential motion rates were collected from 231 subjects, including 80 healthy controls and 151 patients with neurological diseases such as amyotrophic lateral sclerosis, essential tremor, Huntington's disease, multiple sclerosis, multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and cerebellar ataxia. A robust automatic segmentation algorithm utilizing convolutional neural networks and rule-based postprocessing was developed and evaluated across disease type, dysarthria type, and dysarthria severity. The performance of the developed artificial intelligence-based algorithm was compared with a traditional signal processing-based segmentation approach.

RESULTS: Our deep learning-based algorithm was able to correctly identify the position of individual syllables with a very high F1 score of 99.1%, compared to a signal processing-based approach with an F1 score of 97.7%. Using a 10-ms tolerance window, the deep learning-based algorithm achieved an average accuracy of 92.0% for the temporal detection of individual phoneme positions. Performance was strongly influenced by dysarthria severity, with accuracy reaching 94.7% in mild, 91.0% in moderate, and 83.1% in severe dysarthria. Disease and dysarthria type did not appear to have a substantial effect on algorithm performance.

CONCLUSIONS: Our proposed deep learning-based algorithm provides reliable segmentation of syllable and individual phoneme positions during oral diadochokinesis across various disease types, dysarthria types, and dysarthria severities. The deep learning-based segmentation approaches have the potential to outperform the traditional signal processing methods for assessing oral diadochokinesis.}, } @article {pmid42113315, year = {2026}, author = {Mishra, R and Upadhyay, A}, title = {Exosomes in Amyloid Propagation-Roles in Neurodegeneration.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42113315}, issn = {1559-1182}, mesh = {*Exosomes/metabolism ; Humans ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Amyloid/metabolism ; }, abstract = {Extracellular vesicle (EVs)-mediated cell-to-cell communication is crucial for cell growth, signaling, and metabolism. Exosomes are a subtype of EVs originating from endosomal cellular machinery and have a relatively smaller size (30-150 nM). They carry nucleic acids, proteins, miRNA, lipids, metabolites, and growth factors, making them an exciting research tool for understanding the pathophysiology of complex human diseases. Different brain cells also communicate with themselves by the release of exosomes which helps in overall brain growth and in cell signaling. Recent studies have highlighted the importance of exosomes in neurodegenerative diseases (NDDs) of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), prion, and Huntington's disease (HD). Exosomes are involved in the spread of amyloid-like protein aggregates formed in these diseases, but a comprehensive understanding of this spread mechanism is limited. In this article, we have analyzed the roles of exosomes in the spread of amyloid protein aggregates in the NDDs. Furthermore, we have discussed possible measures to address several gaps in our current understanding of cross talks between exosomes and protein aggregates in neurodegenerative disorders (NDDs). We have also discussed the therapeutic opportunities to delay or prevent pathogenic amyloid aggregate spread by exploiting exosomal transport. Overall, the review will contribute to develop a better understanding vesicular transport of amyloids and will help contend their propagation in different NDDs.}, } @article {pmid42113599, year = {2026}, author = {Ravits, J and Ferrey, D and Gundogdu, B and Qayoumi, W and Zale, C}, title = {Amyotrophic Lateral Sclerosis: A Review.}, journal = {JAMA}, volume = {335}, number = {22}, pages = {1970-1982}, doi = {10.1001/jama.2026.6385}, pmid = {42113599}, issn = {1538-3598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/mortality/therapy ; Genetic Therapy/methods ; Riluzole/therapeutic use ; Superoxide Dismutase-1/genetics ; *Motor Neurons/pathology/physiology ; *Muscle Weakness/diagnosis/genetics/physiopathology/therapy ; Electromyography ; C9orf72 Protein/genetics ; Quality of Life ; Edaravone/therapeutic use ; Neuroprotective Agents/therapeutic use ; Oligonucleotides/administration & dosage ; Gene Therapy Agents ; Patient Care Team ; Disease Progression ; Injections, Spinal ; }, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive weakness due to degeneration of upper motor neurons in the brain and lower motor neurons in the brainstem and spinal cord. It affects approximately 25 000 individuals in the United States.

OBSERVATIONS: Amyotrophic lateral sclerosis is characterized by progressive painless muscle weakness that typically begins in a focal region of the body, such as limb muscle weakness causing hand weakness or foot drop (65%), cranial muscle weakness causing speech or swallowing problems (20%-25%), or axial muscle weakness causing bent posture (5%-10%), and spreads to other body regions over time. The disease usually manifests with dysfunction indicative of both upper motor neurons (causing muscle stiffness and spasticity) and lower motor neurons (causing weakness, fasciculations, atrophy, and flaccidity). After onset, weakness spreads through the musculature and typically causes death due to respiratory muscle weakness. Among people with ALS, approximately 85% have sporadic ALS, which is not associated with known environmental or genetic factors, and 15% have familial ALS. Amyotrophic lateral sclerosis is diagnosed based on clinical features, which can be supported by results of electromyography. More than 60 genes have been associated with ALS, and most are autosomal dominant. Pathogenic variants in chromosome 9 open reading frame 72 (C9orf72) are found in 40% of all familial ALS cases, and pathogenic variants in superoxide dismutase 1 (SOD1) are found in 20% of patients with familial ALS. Patients with ALS survive a mean of 3 to 5 years after diagnosis, and there are currently no curative therapies. Clinical care primarily focuses on symptom management and quality of life. Three US Food and Drug Administration (FDA)-approved disease-modifying therapies are available in the United States. Riluzole and edaravone are oral medications that slow ALS progression by up to 2 to 4 months, and tofersen is an intrathecally administered gene therapy for patients with SOD1 gene variants. Specialized multidisciplinary teams, comprising neurologists, nurses, therapists, dietitians, and social workers, are associated with improved survival (4-7 months) and quality of life.

CONCLUSIONS AND RELEVANCE: Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disorder of upper and lower motor neurons. No curative therapies exist. Two oral medications, riluzole and edaravone, are approved by the FDA and modestly decrease disease progression in sporadic ALS. Tofersen, an intrathecally administered gene-based therapy, is also FDA approved and slows disease progression in patients with SOD1 pathogenic gene variants.}, } @article {pmid42114078, year = {2026}, author = {Bareamichael, PI and Babu, S and Hoang, T and Socal, MP}, title = {Bridging the Funding Gap in Drug Development for Amyotrophic Lateral Sclerosis.}, journal = {Neurology. Clinical practice}, volume = {16}, number = {3}, pages = {e200623}, pmid = {42114078}, issn = {2163-0933}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/economics ; Humans ; *Drug Development/economics ; United States ; Clinical Trials as Topic/economics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with few effective treatments and high clinical trial failure rates. Since 1995, only 3 drugs riluzole, edaravone, and tofersen have gained approval from the Food and Drug Administration, all offering modest benefits. Challenges in ALS drug development include poor translational preclinical models, underpowered early-phase trials, and the high cost of late-stage development. Despite federal initiatives such as the Accelerating Access to Critical Therapies for ALS Act and the ALL ALS Consortium, critical gaps remain in funding large multisite trials and sustaining research networks. Accelerating progress requires strengthening national registries, expanding adaptive trial platforms, integrating existing networks, and adopting innovative funding models such as milestone-based public-private partnerships and reinvestment of licensing revenues. A coordinated, sustainable research and funding ecosystem could transform ALS therapy development and serve as a model for advancing treatments for other rare neurodegenerative and neurogenetic disorders.}, } @article {pmid42114311, year = {2026}, author = {Shubham, and Mathur, A}, title = {Comment on "profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis".}, journal = {Journal of the neurological sciences}, volume = {487}, number = {}, pages = {125920}, doi = {10.1016/j.jns.2026.125920}, pmid = {42114311}, issn = {1878-5883}, } @article {pmid42114427, year = {2026}, author = {Ritu, JR and Uddin, MH and Ferrari, MCO and Chivers, DP}, title = {Ecotoxicological implications of environmental neurotoxin β-N-methylamino-L-alanine (BMAA) in fishes: An emerging concern.}, journal = {Ecotoxicology and environmental safety}, volume = {318}, number = {}, pages = {120252}, doi = {10.1016/j.ecoenv.2026.120252}, pmid = {42114427}, issn = {1090-2414}, mesh = {*Amino Acids, Diamino/toxicity ; Cyanobacteria Toxins ; Animals ; *Fishes/growth & development ; *Neurotoxins/toxicity ; *Water Pollutants, Chemical/toxicity ; Harmful Algal Bloom ; Humans ; Ecotoxicology ; Food Chain ; }, abstract = {Harmful algal blooms (HABs), intensified by climate change, eutrophication, and altered hydrological regimes, are expanding globally, releasing cyanotoxins that threaten aquatic ecosystems and human health. β-N-methylamino-L-alanine (BMAA), a non-protein amino acid with neurotoxic potential, has been recognized as a global emerging concern. Following exposure, BMAA is present in both free and protein-bound forms, forming an endogenous toxin reservoir that exacerbates potential neurotoxicity in aquatic organisms and humans. Its presence in aquatic food webs not only elevates ecological risks for wildlife but also raises potential human health concerns, particularly its potential association with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and the ALS/Parkinsonism-dementia complex. This review aims to explore current knowledge of the ecotoxicological impacts of BMAA in fishes, focusing on developmental, behavioural and cognitive perturbations, along with their mechanistic underpinnings. BMAA exposure induces developmental abnormalities, including convulsions, spinal axis malformations, pericardial edema, and altered heart rate, as well as neurodevelopmental impairments, such as reduced motor neuron length and altered neuromuscular colocalization in fishes. Additionally, BMAA exposure affects a wide array of behaviours in fishes, including motor coordination, locomotion, feeding, startle responses, anxiety-like behaviours, and cognitive performance, primarily through excitotoxicity, oxidative stress, apoptosis, metabolic disruption, neuroendocrine modulation, and dysregulated neurotransmitter signalling. Future research should focus on more environmentally relevant exposure scenarios, elucidating BMAA toxicokinetics, and investigating cyanotoxin co-exposure toxicity in fishes. Advancing integrative phenotypic endpoints and knowledge of molecular mechanisms of BMAA toxicity in aquatic organisms is essential for effective ecological risk assessments and for developing regulatory standards to safeguard aquatic ecosystems and human health.}, } @article {pmid42115692, year = {2026}, author = {Yada, Y and Naoki, H}, title = {Decomposing heterogeneity in disease progression speeds and pathways.}, journal = {NPJ digital medicine}, volume = {9}, number = {1}, pages = {}, pmid = {42115692}, issn = {2398-6352}, support = {JP23K16994//JSPS Grant-in-Aid for Early-Career Scientists/ ; JP24wm0625416//AMED Brain/MINDS 2.0/ ; JP25wm0625322//AMED Brain/MINDS 2.0/ ; JPMJMS2024//JST Moonshot R D-MILLENNIA Program/ ; JPMJCR25Q2//Japan Science and Technology Agency/ ; }, abstract = {Understanding why patients with the same diagnosis exhibit markedly different disease progression-some rapidly, others slowly, with distinct symptom patterns-remains a major challenge in medicine. Here, we developed a machine learning framework called DiSPAH (Disease-progression Speed and Pathway Analysis based on a Hidden Markov model) to estimate both the pathway and speed of disease progression in individual patients. DiSPAH models disease progression as continuous-time transitions among latent disease states with a patient-specific progression speed. We applied DiSPAH to longitudinal clinical scores from an amyotrophic lateral sclerosis (ALS) cohort and inferred each patient's trajectory of the latent disease states and progression speed. These dynamics were associated with baseline clinical features and enabled prediction of future course from first-visit data. Our results highlight that jointly modeling progression pathway and speed improves prediction of heterogeneous disease courses, offering a powerful tool for personalized care and research in ALS and other chronic conditions.}, } @article {pmid42115814, year = {2026}, author = {Fang, SY and Jih, KY and Chao, YC and Sytwu, HP and Shih, YC and Liao, YC and Lee, YC}, title = {Clinical and electrophysiological features for differentiating MMN from hand-onset ALS.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {89}, number = {6}, pages = {437-444}, pmid = {42115814}, issn = {1728-7731}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Creatine Kinase/blood ; Diagnosis, Differential ; *Hand ; Nerve Conduction Studies ; Neural Conduction ; *Polyneuropathies/diagnosis/physiopathology ; Retrospective Studies ; }, abstract = {BACKGROUND: Multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis (ALS) can be difficult to differentiate, particularly at early disease stages for patients with hand-onset weakness and without upper motor neuron (UMN) signs. This study aimed to identify clinical and electrophysiological features that may facilitate early differentiation between MMN and ALS.

METHODS: We retrospectively analyzed the clinical, laboratory, and electrophysiological characteristics of patients diagnosed with MMN and ALS who underwent an identical nerve conduction study protocol comprising extended motor stimulation.

RESULTS: A total of 125 patients (74 men and 51 women) were included, consisting of eight patients with MMN and 117 patients with ALS, including 42 with hand-onset ALS. The patients with MMN had a significantly younger mean age at symptom onset than those with ALS (43.1 vs 58.7 years, p = 0.004). The patients with ALS had greater muscle weakness, more frequent muscle atrophy and fasciculation, UMN signs, and body weight loss. Compared with both the overall ALS and hand-onset ALS groups, the MMN group had significantly lower serum creatine kinase (CK) levels and higher serum IgM levels. Elevated CK levels were observed in approximately one-third of patients with hand-onset ALS, whereas none of the MMN patients had elevated CK levels. Conduction blocks (CB) on nerve conduction studies were more common in the MMN group (87.5%) than in the overall ALS (19.7%, p < 0.001) and hand-onset ALS groups (31.0%, p = 0.005). MMN patients more frequently exhibited definite CBs involving multiple nerves (85.7%) compared with the overall ALS (17.4%, p = 0.002) and hand-onset ALS groups (7.7%, p = 0.001).

CONCLUSION: Our findings suggest that a combination of clinical features, serum CK and IgM levels, and electrophysiological evidence of CB provides valuable clues for distinguishing MMN from ALS.}, } @article {pmid42116144, year = {2026}, author = {Li, M and Jin, H and Meng, L and Altay, O and Yuksel, B and Zhang, C and Uhlen, M and Turkez, H and Mardinoglu, A}, title = {WBT-DC pipeline: a cross-cohort and cross-platform disease classification pipeline based on whole-blood transcriptomics.}, journal = {Journal of translational medicine}, volume = {24}, number = {1}, pages = {}, pmid = {42116144}, issn = {1479-5876}, mesh = {Humans ; *Transcriptome/genetics ; Cohort Studies ; *Gene Expression Profiling ; *Disease/genetics/classification ; Reproducibility of Results ; Machine Learning ; ROC Curve ; Female ; Area Under Curve ; Classification Algorithms ; }, abstract = {BACKGROUND: Machine-learning models based on tissue transcriptomic data are powerful tools for disease classification. However, their clinical adoption is limited by the invasive nature of tissue sampling. Furthermore, transcriptomic datasets are often affected by batch effects and gene-level noise, which compromise model generalizability across platforms and clinical cohorts.

METHODS: We developed WBT-DC (Whole Blood Transcriptomics-based Disease Classification), a computational pipeline designed to overcome these challenges. WBT-DC integrates rank-based feature extraction to mitigate batch effects with an ensemble machine-learning framework that incorporates cross-validation and hyperparameter optimization. Its performance was systematically evaluated across five independent cohorts involving 2,164 participants and three disease contexts: Crohn's disease (CD), ulcerative colitis (UC), and amyotrophic lateral sclerosis (ALS). We tested the model's robustness across RNA-sequencing and microarray platforms. Additionally, an internal rheumatoid arthritis (RA) cohort (n = 165) was utilized for real-world prospective validation.

RESULTS: WBT-DC demonstrated high accuracy, achieving ROC-AUC values of 0.90-0.94 in independent datasets when training and testing were conducted on the same platform. In cross-platform evaluations, the pipeline maintained robust performance with ROC-AUC values ranging from 0.71 to 0.84, consistently outperforming conventional gene expression-based models. In the RA validation cohort, WBT-DC achieved an ROC-AUC of 0.81, supporting its applicability in a real-world clinical setting.

CONCLUSIONS: WBT-DC provides a robust, non-invasive, and platform-agnostic framework for disease classification using whole-blood transcriptomics. By effectively addressing batch effects and platform variability, this pipeline offers a scalable solution for translating systems-level transcriptomic insights into applications.}, } @article {pmid42116550, year = {2026}, author = {Bae, JH and Kwak, S}, title = {Emergency department visits among patients with neuromuscular diseases receiving home mechanical ventilation: a nationwide population-based study.}, journal = {Journal of Yeungnam medical science}, volume = {43}, number = {}, pages = {32}, pmid = {42116550}, issn = {2799-8010}, abstract = {BACKGROUND: Population-level data on emergency department (ED) utilization in patients with neuromuscular disease (NMDs) receiving home mechanical ventilation (HMV) remain limited. This study investigated the frequency, outcomes, and associated factors of ED visits using a nationwide administrative database.

METHODS: Using the Health Insurance Review and Assessment Service database, we identified patients with NMDs who received HMV between January 2016 and October 2021, based on diagnostic codes and the MM441 procedure code. ED visits and outcomes were analyzed using claims data. Associations between ED visits and tracheostomy or gastrostomy were evaluated using the chi-square test.

RESULTS: A total of 1,569 patients were identified; amyotrophic lateral sclerosis (39.7%) and muscular dystrophy (31.0%) were the most common diagnoses. During the study period, 1,009 patients (64.3%) visited the ED at least once, accounting for 5,159 visits (mean 5.1 visits per patient). Among these visits, 36% resulted in hospitalization and 3% resulted in death in the ED. ED visits were more frequent among patients with tracheostomy than in those without tracheostomy (76.6% vs. 59.0%; relative risk [RR], 1.30; 95% confidence interval [CI], 1.21-1.39; p<0.001). In contrast, patients with gastrostomy had a lower proportion of ED visits than those without gastrostomy (22.6% vs. 55.1%; RR, 0.41; 95% CI, 0.35-0.48; p<0.001).

CONCLUSION: ED utilization is common among patients with NMDs receiving HMV and is frequently associated with hospitalization, highlighting a substantial acute healthcare burden. These findings highlight the need for improved long-term respiratory care and outpatient management.}, } @article {pmid42116584, year = {2026}, author = {Bala, VC and Singh, MK and Kumar, A and Tiwari, SK and Gupta, AK and Chawla, R and Kumar, S}, title = {Targeting α-Synuclein: Current Strategies and Emerging Therapies for Synucleinopathies.}, journal = {Protein and peptide letters}, volume = {33}, number = {1}, pages = {258-274}, doi = {10.2174/0109298665429866260217115717}, pmid = {42116584}, issn = {1875-5305}, mesh = {Humans ; *alpha-Synuclein/metabolism/antagonists & inhibitors/genetics ; *Synucleinopathies/metabolism/drug therapy/therapy/pathology ; *Parkinson Disease/metabolism/drug therapy/pathology ; Animals ; Autophagy ; Oxidative Stress/drug effects ; }, abstract = {Alpha-synuclein (α-syn) is a crucial protein involved in the pathogenesis of Parkinson's Disease (PD) and other synucleinopathies. It is important with respect to neuron health, regulation of α-syn protein synthesis, and its degradation. Numerous cellular pathways implicated in the process of autophagy, chaperone, and proteolysis play a vital role in the maintenance of α-syn protein homeostasis. Autophagy dysfunction defeats α-syn protein accumulation and neuroinflammation, as present in dementia with Lewy bodies and sporadic PD. Oxidative stress is another key factor that intensifies α-syn protein misfolding and aggregation, thereby leading to neurodegeneration. Involvement in the treatment of α-syn related disorders includes passive and active immunization, inhibitors of protein aggregation, gene silencing technology, modulators of synaptic function, and target drug delivery systems. Other α-syn related therapy approaches include the development of a novel herbal formulation focusing on the gut-brain axis and interventions designed to enhance protein quality control. As clinical trials move forward, minimizing challenges related to the target involved, biomarkers, and patient stratification is crucial to decoding these therapies into effective management. These insights not only advance our understanding of α-syn biology but also highlight the urgency of early and multi-targeted therapeutic interventions.}, } @article {pmid42116669, year = {2026}, author = {Shimizu, T and Myojin, H and Bokuda, K and Kawazoe, T and Morishima, R and Kimura, H and Takahashi, K and Nakayama, Y}, title = {Offset Conduction Velocity Reveals Prognostic Slowing of Motor Axons in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {74}, number = {1}, pages = {207-215}, doi = {10.1002/mus.70273}, pmid = {42116669}, issn = {1097-4598}, support = {25293449//Japan Society for the Promotion of Science/ ; 16H05583//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/mortality ; Female ; *Neural Conduction/physiology ; Male ; Nerve Conduction Studies ; Aged ; Middle Aged ; *Motor Neurons/physiology ; Prognosis ; *Axons/physiology ; Action Potentials/physiology ; Tibial Nerve/physiopathology ; Adult ; Median Nerve/physiopathology ; }, abstract = {INTRODUCTION/AIMS: Slowing of motor nerve conduction is not classically regarded as a feature of amyotrophic lateral sclerosis (ALS). We introduce a novel electrophysiological parameter, offset motor conduction velocity (offset-MCV), to assess conduction in relatively slower motor axons and investigate its association with survival in ALS.

METHODS: Motor nerve conduction studies of the median and tibial nerves were performed in 145 patients with ALS and 70 healthy controls. Onset and offset latencies of compound muscle action potentials were measured, and onset- and offset-MCVs were calculated. Patients were followed until death or tracheostomy, and associations between MCV parameters and survival were analyzed.

RESULTS: Both onset- and offset-MCVs were significantly reduced in patients with ALS compared with controls for the median and tibial nerves (all p < 0.0001). Onset-MCVs were not associated with survival. In contrast, reduced offset-MCVs in both nerves were associated with short survival (log-rank test: median nerve, p = 0.009; tibial nerve, p = 0.021). Multivariate Cox regression analysis identified tibial nerve offset-MCV as an independent prognostic factor (p = 0.029).

DISCUSSION: Pathological slowing of motor nerve conduction occurs in ALS and is associated with poor survival. Offset-MCV may reflect disease-related changes in slower α-motor axons and represents a potential prognostic biomarker in ALS.}, } @article {pmid42117108, year = {2026}, author = {Jiang, A and Huang, Y and Que, X and Li, C and Lin, Z and Huang, W}, title = {Integrative Transcriptomics Identifies Ubiquitination-Related Genes BIRC2, COPS5, and TBK1 as Novel Biomarkers of T-Cell Dysregulation in Amyotrophic Lateral Sclerosis.}, journal = {Journal of inflammation research}, volume = {19}, number = {}, pages = {585872}, pmid = {42117108}, issn = {1178-7031}, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is marked by immune dysregulation; however, the role of T cell-ubiquitination-related genes (TURGs) in its pathogenesis remains unclear. This study aimed to investigate the contribution of TURGs to T-cell dysfunction and ubiquitination imbalance in ALS.

PATIENTS AND METHODS: Differentially expressed genes were identified through analysis of bulk transcriptomes (GSE112680). CIBERSORT deconvolution and weighted gene co-expression network analysis were employed to define T-cell-associated modules. Integration with ubiquitination-related gene sets yielded T cell-ubiquitination-related differentially expressed genes (TURDEGs). Functional enrichment analysis and protein-protein interaction network construction, combined with multi-algorithm selection, facilitated the development of a risk-prediction model. Mechanistic insights were derived from Gene Set Enrichment Analysis, immune profiling, co-expression and regulatory network analyses, and drug-target prediction. Single-cell transcriptomic analysis provided insights into cellular-level pathogenic mechanisms in ALS. qPCR was used to validate core TURDEGs expression in peripheral blood samples from patients with ALS.

RESULTS: Thirty-nine TURDEGs were identified and exhibited significant enrichment in pathways related to ubiquitination, immune activation, autophagy, and NOD-like receptor signaling. BIRC2, COPS5, and TBK1 were identified as core genes. The resulting risk-prediction model demonstrated significant potential for clinical application. Immune infiltration analysis revealed positive correlations between core genes and CD4⁺ resting memory T cells, as well as negative correlations between COPS5, TBK1, and regulatory T cells. Adavosertib and MRS2211 were identified as potent modulators of TBK1 and BIRC2, respectively. Single-cell transcriptomics highlighted enhanced T cell-neutrophil interactions, suggesting a remodeling of the immune communication network in ALS. qPCR validation confirmed significantly increased expression of these genes in patients with ALS (p<0.05).

CONCLUSION: TURDEGs-mediated T cell dysfunction and ubiquitination imbalance play critical roles in ALS pathogenesis, unveiling novel biomarkers and potential personalized therapeutic targets.}, } @article {pmid42118126, year = {2026}, author = {Ghiasi, S and Röder, T and Schunk, S and Parastar, H and Weller, P}, title = {Separation of Ammonia Isotopologues by Benchtop Drift Tube Ion Mobility Spectrometry and Chemometric Modeling.}, journal = {Journal of the American Society for Mass Spectrometry}, volume = {37}, number = {6}, pages = {1353-1365}, doi = {10.1021/jasms.5c00434}, pmid = {42118126}, issn = {1879-1123}, abstract = {This research study assesses the applicability of drift tube ion mobility spectrometry (DTIMS) to resolve ammonia (NH3) from its isotopologue, ammonia-d3 (ND3). DTIMS, known for its rapid response at ambient pressure, was employed to conduct real-time analysis of gaseous samples. Two ammonia introduction methods were evaluated, evaporation of a 3 ppm(v) aqueous ammonia solution and dry gas synthesis. The study tested these methods for the mixture analysis of ammonia and examined their impact on resolution. The resolution of isotopologues and the influence of moisture in the carrier gas on separation were assessed. Individual analysis by evaporation method provided drift times of 6.03 ms for NH3 and 6.17 ms for ND3, from which reduced mobility (K0) values of 2.52 cm[2] V[-1] s[-1] and 2.46 cm[2] V[-1] s[-1] were calculated, respectively. The presence of moisture in the carrier gas was found to significantly reduce the resolution of isotopologue separation. To address this limitation and enhance signal clarity, the application of wavelet denoising was conducted, with universal thresholding based on Symlet, Daubechies, and Coiflet wavelet families systematically evaluated. The Daubechies wavelet (db9) at level 9 was identified as the optimal denoising approach. Following this, multivariate curve resolution alternating least-squares (MCR-ALS) was employed for the decomposition of the complex overlapping signals into their pure ion mobility spectra and corresponding concentration profiles over time. The integration of wavelet-based denoising and MCR-ALS offers a practical strategy for the enhancement of DTIMS performance in complex isotopologue separation, particularly for future studies focused on quantitative analysis. Future work will involve the integration of steady-state isotopic transient kinetic analysis (SSITKA) for a comprehensive kinetic framework for kinetic models.}, } @article {pmid42118400, year = {2026}, author = {Pi, C and Liu, Y and Jia, Z and Zhang, M and Wang, X and Zhao, H and Dong, Z and Yu, S and Liu, R}, title = {Mechanism of the N87D mutation in SOD1-atypical amyotrophic lateral sclerosis case report and literature review molecular mechanism of N87D mutation in SOD1.}, journal = {Neurogenetics}, volume = {27}, number = {1}, pages = {}, pmid = {42118400}, issn = {1364-6753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Superoxide Dismutase-1/genetics ; Molecular Dynamics Simulation ; *Mutation ; *Superoxide Dismutase/genetics/chemistry ; Models, Molecular ; Female ; Protein Conformation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unclear pathogenesis. This study aimed to investigate the possible molecular mechanisms of ALS by analyzing protein structure and dynamics in a rapidly progressing ALS patient carrying the N87D mutation. A patient with the N87D mutation experienced rapid disease progression and died within one year. We reviewed all known mutations at the 87th position of the superoxide dismutase (SOD1) gene and the clinical characteristics. To investigate the molecular basis of the severe phenotype, we performed protein structure modeling and molecular dynamics (MD) simulations, and compared wild type homodimers, mutant homodimers, and heterodimers in terms of energy, residue fluctuation, number of hydrogen bonds, radius of gyration (Rg), principal component analysis (PCA), free energy landscape (FEL), the contribution of dimer interface residues, solvent-accessible surface area, and metal ion coordination. Our analysis revealed that patients with mutations at the 87th position of the SOD1 gene typically exhibited rapid disease progression. Protein structure modeling and MD simulations demonstrated that the N87D mutation significantly increased the energy and RMSF of SOD1 heterodimers compared to homodimers. Furthermore, Rg, FEL and PCA analyses showed that the heterodimers had a broader and more unstable conformational energy distribution, along with a stronger tendency for aggregation. Additionally, the N87D mutation disrupted metal ion coordination, further destabilizing the heterodimer and promoting protein misfolding. These findings suggest a potential molecular mechanism underlying ALS and support a protein structure based approach for investigating the pathogenic mechanisms of disease causing mutations.}, } @article {pmid42119241, year = {2026}, author = {Toubasi, AA and Al-Sayegh, TN}, title = {Head injuries as a risk factor for amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Clinical neurology and neurosurgery}, volume = {267}, number = {}, pages = {109466}, doi = {10.1016/j.clineuro.2026.109466}, pmid = {42119241}, issn = {1872-6968}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/etiology ; Risk Factors ; *Craniocerebral Trauma/epidemiology/complications ; Female ; Male ; }, abstract = {BACKGROUND: Previous studies have suggested that traumatic head injury (THI) is associated with amyotrophic lateral sclerosis (ALS). However, the evidence remains limited and inconsistent, partly due to small sample sizes.

OBJECTIVES: In this meta-analysis, we aimed to investigate the association between THI and the risk of ALS.

METHODS: We conducted a systematic review and meta-analysis of studies assessing the relationship between THI and ALS. The exposure of interest was THI, and the outcome of interest was ALS development. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used as effect measures.

RESULTS: Eighteen studies comprising 578,815 participants were included. THI was associated with an increased risk of ALS (OR = 1.47; 95% CI: 1.23-1.76). The association was consistent across studies conducted in Europe (OR = 1.60; 95% CI: 1.19-2.15) and the Americas (OR = 1.27; 95% CI: 1.12-1.43). Subgroup analysis by sex showed a significant association among males (OR = 2.27; 95% CI: 1.41-3.66) but it was less significant among females (OR = 1.30; 95% CI: 0.78-2.17). Both single (OR = 1.48; 95% CI: 1.18-1.85) and multiple THIs (OR = 1.34; 95% CI: 1.15-1.56) were associated with ALS. Funnel and doi plots demonstrated asymmetry indicating significant publication bias.

CONCLUSIONS: Our analysis demonstrated an association between THI and ALS, however the lack of dose-response relationship suggests it is less likely to be causative.}, } @article {pmid42121359, year = {2026}, author = {Goto, S and Singh, S and Zhu, Q and Vyas, SA and Wildsoet, C}, title = {Development of an Optical Defocus-Induced Myopia Model for Guinea Pigs Using Rigid Gas Permeable Contact Lenses.}, journal = {Eye & contact lens}, volume = {52}, number = {7}, pages = {306-314}, doi = {10.1097/ICL.0000000000001279}, pmid = {42121359}, issn = {1542-233X}, support = {Loris and David Rich Postdoctoral Scholar//International Retina Research Foundation/ ; T32 EY007043/EY/NEI NIH HHS/United States ; R01 EY012392/EY/NEI NIH HHS/United States ; T32 EY007043/EY/NEI NIH HHS/United States ; R01 EY012392/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Guinea Pigs ; *Myopia/physiopathology/therapy/etiology ; *Disease Models, Animal ; *Refraction, Ocular/physiology ; *Contact Lenses ; Tomography, Optical Coherence ; Axial Length, Eye ; Male ; }, abstract = {OBJECTIVES: Guinea pigs are a widely used mammalian model for studies of myopia and early ocular growth regulation more generally. The study reported here covers the development of rigid gas permeable (RGP) contact lenses (CLs) for guinea pigs, as an alternative to spectacle lenses for imposing optical defocus, recognized as an important modulator of eye elongation in young animals.

METHODS: New Zealand pigmented guinea pigs (Cavia porcellus) were used in this study, with the RGP lens design based on developmental corneal shape profiles derived from anterior segment optical coherence tomography data collected across a range of ages, as typically encountered in such studies. The validity of this CL-based approach was examined in a follow-up study, in which the ocular effects of -10, 0, and +5 diopters [D] RGP lenses, applied as continuous monocular optical defocus treatments, were tracked over 2 weeks, with the fellow untreated eyes of experimental animals serving as contralateral controls. Pretreatment baseline spherical equivalent refractive errors (RE) and axial length (AL) of both eyes were measured, along with follow-up weekly measurements over the wearing period.

RESULTS: There were no differences in any of the ocular parameters between the three groups at baseline, while after two weeks of lens wear, there were significant differences between the -10 D group compared with 0 D and +5 D groups in both RE (P <0.001) and AL (P <0.05). Importantly, myopia was observed in all of the guinea pigs fitted with -10 D lenses, and overall, eyes fitted with -10 D lenses showed increased ALs and relative myopia compared with their fellows, while those fitted with +5 D lenses showed reduced ALs and relative hyperopia; the plano lens group fell in between (treated-fellow eyes: -10, 0, and +5 D lenses: -8.25, -1.0, and +0.5 D, and +0.16, +0.08, and -0.02 mm, respectively). Also importantly, no significant CL-related adverse ocular effects were observed.

CONCLUSIONS: This study provides proof of principle that defocusing RGP CLs are a feasible alternative to spectacle lenses for studies of eye growth regulation in young guinea pigs and experimental myopia specifically, with potential application in investigations into novel approaches for controlling myopia progression and underlying mechanisms.}, } @article {pmid42123994, year = {2026}, author = {Christodoulou, RC and Lorentzen, L and Eller, D and Vassiliou, E}, title = {Long-Chain Fatty Acids as Drivers of Neuroinflammation in Neurodegeneration: Mechanistic Links to Lipid Peroxidation, Ferroptosis, and Mitochondrial Dysfunction.}, journal = {Nutrients}, volume = {18}, number = {9}, pages = {}, pmid = {42123994}, issn = {2072-6643}, mesh = {Humans ; *Ferroptosis ; *Lipid Peroxidation ; *Fatty Acids/metabolism ; *Mitochondria/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism ; *Neuroinflammatory Diseases/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; }, abstract = {Background: Neurodegenerative diseases (NDs) are mainly considered disorders marked by severe immunometabolic imbalance, characterized by ongoing neuroinflammation and glial activation. While mitochondrial dysfunction and oxidative stress are well-known features, the upstream metabolic factors linking these pathological processes remain poorly understood. Methods: In this review, we examined recent preclinical and clinical studies exploring the connections between lipid metabolism, glial immunometabolism, and regulated cell death pathways. Our focus was on how long-chain fatty acids (LCFAs) facilitate communication among mitochondria, reactive oxygen species (ROS), and ferroptosis in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Results: New evidence shifts LCFAs from merely being passive indicators of cellular damage to active, upstream regulators of the neuroimmune response. Existing research shows that excess LCFA intake can overload astrocytic mitochondrial oxidative phosphorylation, leading to abnormal lipid droplet buildup and reactive astrogliosis. This lipid-driven reactivity promotes microglial polarization toward a persistent pro-inflammatory state. Notably, high levels of specific LCFAs, especially arachidonic acid, increase ROS production and lipid peroxidation. This lipotoxic environment ultimately triggers ferroptosis, an iron-dependent form of cell death shared across multiple NDs. Conclusions: The harmful interaction among mitochondrial dysfunction, lipid peroxidation, and ferroptosis is driven by an imbalance in LCFA levels. Addressing current challenges, such as the complex effects of polyunsaturated fatty acid supplementation, requires advanced techniques like single-cell multi-omics and artificial intelligence. Understanding this intricate lipidomic-transcriptomic crosstalk is crucial for moving toward personalized neuroimmunometabolism and developing new treatments to prevent ferroptosis.}, } @article {pmid42125740, year = {2026}, author = {Tranoulis, I and Stefanakis, A and Giannoudi, M and Ioannidis, K}, title = {Basic life support and use of automated external defibrillator by dentists in Greece: a questionnaire-based cross-sectional study.}, journal = {Resuscitation plus}, volume = {29}, number = {}, pages = {101341}, pmid = {42125740}, issn = {2666-5204}, abstract = {BACKGROUND: Cardiac arrest is a leading cause of death; timely intervention with basic life support (BLS) is crucial for healthcare providers, including dentists. This study aimed to assess awareness, educational level, and knowledge regarding the application of BLS and the use of an automated external defibrillator (AED) among dentists in Greece.

METHODS: A cross-sectional survey using an online questionnaire was conducted to collect demographic data, knowledge of BLS/Advanced Life Support (ALS), and experience in managing medical emergencies in dental practices. The results were statistically analysed, with the level of significance set at P < 0.05.

RESULTS: Overall, the national response rate among Greek dentists was 2.5%. A total of 354 dentists across Greece participated in the study. Attendance at CPR/AED courses was recorded for 67.5% of participants, while 29.4% reported holding active certification. A small proportion of the surveyed dentists had an AED in their dental practices (8.5%), and 47.4% did not possess a self-injectable adrenaline. Syncope was the most common medical emergency during dental procedures (50.3%). Dentists who attended BLS training sessions demonstrated more appropriate practice in managing medical emergencies (P < 0.05).

CONCLUSIONS: Continuous training and ongoing professional development for dentists are essential for effectively handling medical emergencies. This study promotes a more proactive approach to enhancing competency in emergency care and the appropriate management of medical emergencies in dental practices.}, } @article {pmid42126073, year = {2026}, author = {Razlan, AN and Ma, W and Dickie, AC and Polgar, E and McFarlane, AG and Yadav, M and Cooper, AH and Strathdee, D and Watanabe, M and Bell, AM and Todd, AJ and Hachisuka, J}, title = {Characterisation of cold-selective lamina I spinal projection neurons in the mouse.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {42126073}, issn = {2050-084X}, support = {10.35802/219433/WT_/Wellcome Trust/United Kingdom ; MR/V033638/1/MRC_/Medical Research Council/United Kingdom ; 10.35802/304005/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; *Cold Temperature ; Mice ; TRPM Cation Channels/metabolism/genetics ; *Neurons/physiology ; *Spinal Cord/physiology ; Optogenetics ; Calbindins/metabolism ; *Thermosensing ; }, abstract = {Skin cooling is detected by primary afferents that express the Trpm8 channel, but how this information is conveyed to the brain remains poorly understood. We have previously identified a population of lamina I projection neurons belonging to the anterolateral system (ALS) that receive numerous contacts from Trpm8-expressing primary afferents. Here, using a semi-intact somatosensory preparation, we provide evidence that these cells correspond to the cold-selective ALS neurons identified in previous physiological studies. We also confirm the presence of synapses from Trpm8 afferents onto these cells at the ultrastructural level and with optogenetics. Based on our previous transcriptomic findings, we identify calbindin as a molecular marker, and show that this can be used to target the cold-selective ALS neurons for anterograde tracing studies. We provide evidence that they project to brain regions that have been implicated in thermosensation: the rostralmost part of the lateral parabrachial area, the caudal part of the periaqueductal grey matter, and the posterior triangular and ventral posterolateral nuclei of the thalamus. Our findings provide important insights into the organisation of neuronal circuits that underlie thermoregulation and the perception of cold stimuli applied to the skin.}, } @article {pmid42127155, year = {2026}, author = {Sunindyo, WD and Anshori, I and Wiguna, KA and Kahari, MMH and Syafalni, I and Dwiyanti, L and , }, title = {Algorithm-assisted interpretation of cyclic and differential pulse voltammetry for cardiac troponin detection.}, journal = {PloS one}, volume = {21}, number = {5}, pages = {e0348348}, pmid = {42127155}, issn = {1932-6203}, mesh = {*Algorithms ; *Electrochemical Techniques/methods ; *Troponin/analysis ; Biomarkers/analysis ; Humans ; Biosensing Techniques/methods ; Electrodes ; Reproducibility of Results ; }, abstract = {Cardiovascular disease remains a leading cause of mortality worldwide, and rapid identification of cardiac biomarkers is essential for early detection. Electrochemical voltammetry techniques, particularly cyclic voltammetry (CV) and differential pulse voltammetry (DPV), are widely used for detecting cardiac troponin; however, interpretation of raw voltammetric signals is often affected by baseline drift, signal noise, and operator-dependent analysis. This study proposes an algorithm-assisted analytical framework for automated interpretation of voltammetric data obtained from a screen-printed carbon electrode potentiostat. Polynomial fitting was applied for baseline correction in CV signals, while asymmetric least squares (ALS) was employed for DPV data. Peak-to-baseline current response was extracted as a quantitative indicator of biomarker presence. The proposed method successfully identified characteristic voltammetric peaks and distinguished samples with higher and lower cardiac biomarker responses relative to a predefined detection threshold. The analysis showed close agreement with reference electrochemical analysis software, demonstrating reliable peak detection and baseline estimation. By reducing manual interpretation and improving signal clarity, the framework enhances the reproducibility and accessibility of electrochemical biosensor measurements and supports early screening of cardiac biomarkers.}, } @article {pmid42127907, year = {2026}, author = {Xu, W and Li, H and Zhang, W and Bai, G and Shen, C and Zhang, K}, title = {S-acylation of TDP43 regulates its condensation in amyotrophic lateral sclerosis.}, journal = {Molecular cell}, volume = {86}, number = {11}, pages = {2191-2206.e8}, doi = {10.1016/j.molcel.2026.04.016}, pmid = {42127907}, issn = {1097-4164}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; Humans ; Acylation ; Acyltransferases/metabolism/genetics ; Mice ; Induced Pluripotent Stem Cells/metabolism/pathology ; Mutation ; Mice, Transgenic ; Inclusion Bodies/metabolism/pathology/genetics ; Neurons/pathology/metabolism ; Disease Models, Animal ; HEK293 Cells ; }, abstract = {TDP43 inclusion bodies are widely present in the majority of patients with familial and sporadic amyotrophic lateral sclerosis (ALS). The mechanisms regulating TDP43 solubility remain incompletely understood. Here, we report that TDP43 undergoes S-acylation primarily at the Cys244 residue by the S-acyltransferase zDHHC23. This S-acylation maintains the liquid-like properties of TDP43 by reducing the aberrant interaction with poly(ADP-ribose) polymerase 1 (PARP1) and PARylated proteins, thereby countering the pathological condensation of TDP43. S-acylation-deficient TDP43 inclusions sequester the translational machinery and inhibit cytoplasmic protein translation, ultimately resulting in neurotoxicity. Importantly, TDP43 S-acylation is decreased in the familial ALS-associated TDP43 mutants as well as in SOD1-G93A mice and C9orf72-ALS induced pluripotent stem cell (iPSC)-derived neurons, suggesting the widespread involvement of TDP43 S-acylation in ALS pathogenesis. Our findings reveal an undescribed modification of TDP43 and provide deeper insight into the regulation of TDP43 pathological condensation in ALS.}, } @article {pmid42129145, year = {2026}, author = {Pulst, SM and Paul, S and Nguyen, H and Dansithong, W and Figueroa, KP and Gandelman, M and Bonini, NM and Scoles, DR}, title = {A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {}, pmid = {42129145}, issn = {2041-4889}, support = {R61/R33NS124965//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35NS127253//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35NS097275//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS137233/NS/NINDS NIH HHS/United States ; R21NS127028//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS128630//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS097903//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R37NS033123//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS137233//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R56NS033123//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; Humans ; Mice, Transgenic ; *RNA-Binding Proteins/genetics/metabolism ; *Autophagy/genetics ; *Cytoskeletal Proteins/genetics/metabolism ; Mice ; Disease Models, Animal ; Neurons/metabolism/pathology ; Astrocytes/metabolism/pathology ; *Nerve Degeneration/pathology/genetics/metabolism ; Spinal Cord/metabolism/pathology ; }, abstract = {RNA-binding proteins (RBPs) play an essential role in development, normal functioning, and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire human STAU1 gene (hSTAU1) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum, and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes, and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene.}, } @article {pmid42130389, year = {2026}, author = {Thurn, T and Chiò, A and Galvin, M and Stavroulakis, T and Anneser, J}, title = {Beyond the surface: Exploring differing aspects of wishes to hasten death in patients with amyotrophic lateral sclerosis.}, journal = {Palliative & supportive care}, volume = {24}, number = {}, pages = {e147}, pmid = {42130389}, issn = {1478-9523}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Female ; Cross-Sectional Studies ; Male ; *Attitude to Death ; Aged ; Middle Aged ; Longitudinal Studies ; Quality of Life/psychology ; Europe ; Surveys and Questionnaires ; }, abstract = {OBJECTIVES: This study investigates differing aspects of wishes to hasten death (WTHD) distinguished by the extent to which WTHD were linked to patients' agency: desire for hastened death (DHD), defined as general wishes for death to come sooner, and hastening death intentions (HDI), defined as thoughts about ending one's life. In particular, this study aims to examine the differences between DHD and HDI in patients with amyotrophic lateral sclerosis (pALS) and identify predictive factors for both.

METHODS: A cross-sectional nested study was conducted within a multi-center longitudinal study involving pALS from 5 European countries. Data collected included DHD (Schedule of Attitudes toward Hastened Death), HDI ("could you currently imagine ending your life?"), sociodemographic and clinical characteristics, psychological distress, quality of life, and social and spiritual-existential aspects.

RESULTS: In our sample of 121 pALS, 12.4% (15/121) expressed DHD, and 28.1% (34/121) expressed HDI. Of the 38 patients reporting any WTHD, only 11 experienced both DHD and HDI simultaneously. 23 patients reported HDI without DHD, while 4 patients expressed DHD without HDI. Multivariable logistic regression identified loneliness (OR = 1.33, 95% CI 1.03-1.71, p = 0.028) and reduced meaning in life (OR = 0.89, 95% CI 0.84-0.95, p < 0.001) as independent predictors of DHD. For HDI, independent predictors were female gender (OR = 3.31, 95% CI 1.37-7.98, p = 0.008) and lower spirituality (OR = 0.92, 95% CI 0.88-0.95, p < 0.001).

SIGNIFICANCE OF RESULTS: One in 3 pALS expressed WTHD. Our separate analysis of DHD and HDI supports the existence of distinct manifestations of WTHD and varying underlying factors. While DHD and HDI were associated with different predictors, our results point to the crucial role of spiritual-existential factors in the experience of WTHD, identifying these aspects as target points for intervention. This study highlights the importance of a nuanced understanding and communication regarding WTHD.}, } @article {pmid42131110, year = {2026}, author = {Zhang, M and Su, L and Han, W and Song, F and Fu, Y and Chi, MB and Chen, X and Wu, YH and Gao, SJ}, title = {Single cell Raman spectroscopic profiles predict treatment responses in patients with de novo acute myeloid leukemia.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1767226}, pmid = {42131110}, issn = {2296-634X}, abstract = {INTRODUCTION: Leukemia is a clonal malignant proliferative disease originating from hematopoietic stem cells. Although its treatment strategy has gradually developed from traditional chemotherapy to a multimodal treatment system including novel targeted therapy and immunotherapy, primary drug resistance in particular remains the core clinical problem leading to poor patient prognosis. This clinical dilemma indicates that the traditional genotyping system based on genomics has not been able to fully resolve the molecular heterogeneity of acute myeloid leukemia (AML), and it is urgent to establish a precise stratified model that can dynamically reflect the functional status of tumor cells in the initial stage of treatment.

METHODS: In this study, Raman spectroscopy (RS) combined with machine learning algorithm was used to construct a metabolic prognosis prediction model for AML chemotherapy response. Bone marrow single cell Raman spectroscopy data of newly diagnosed AML patients were collected, and the molecular fingerprint was analyzed by principal component analysis linear discriminant analysis (PCA-LDA) and multivariate curve resolute alternating least square method (MCR-ALS).

RESULTS: The results showed that the PCALDA model achieved complete remission or non-remission (CR/NR) classification through 24 principal components (cumulative variance contribution of 90.1%), the accuracy of external validation was 94.8% (sensitivity 97.9%, specificity 92.0%), and the AUC reached 96.27%. Protein, lipid, nucleic acid and mixed components were decomposed by MCR-ALS, and lipid and nucleic acid metabolic pathways were enriched in NR group (P < 0.001).

DISCUSSION: Studies have shown that RS single-cell metabolic fingerprint can decode the metabolic reprogramming features associated with chemotherapy resistance in AML, providing a new marker-free and highly sensitive tool for real-time prognostic stratification and targeted intervention.}, } @article {pmid42131356, year = {2026}, author = {Macchietti, L and Carta, M and Delogu, F and Grepioni, F and Emmerling, F and Casali, L}, title = {Scaling up mechanochemical reactions: linking crystalline phase evolution studied via in situ PXRD with kinetics from MCR-ALS.}, journal = {Chemical science}, volume = {17}, number = {24}, pages = {12047-12054}, pmid = {42131356}, issn = {2041-6520}, abstract = {This work addresses a key challenge in scaling up mechanochemical synthesis: deriving a kinetic model when unpredictable formation and intricate interaction of multiple crystalline phases occur during solid-state transformations. Reaction kinetics translate our understanding of chemical processes into mathematical rate expressions used for reactor design and evaluation, thus representing a challenge to be addressed for the scale up at the industrial level. Choosing co-crystallization of chloro-3-sulfamoylbenzoic acid (CSBA) and isonicotinamide (INA) as a model system, at first we employ time-resolved in situ powder X-ray diffraction (PXRD) and multivariate curve resolution-Alternating Least Squares (MCR-ALS) analysis to quantify and resolve the evolution of crystalline intermediates under varying methanol-assisted conditions. Our data show that even small changes in the amount of methanol can dramatically alter the kinetic profile, stabilise transient phases (including some that were previously unreported) and alter the overall reaction pathway. We then demonstrate the robust deconvolution of overlapping phases and the extraction of quantitative rate parameters that rationalize the observed behaviour by integrating kinetic modelling as a soft-hard constraint in the MCR-ALS workflow. The validation of the established MCR-ALS workflow is achieved by applying a phenomenological kinetic modelling tailored to rationalize the mechanochemical reaction rates. These results establish a broadly applicable platform for analysing and controlling the complex phase evolution, along with the derivation of a kinetic model instrumental to mechanochemical process development and scaling up, thereby supporting the transition of sustainable solid-state syntheses from the laboratory to industry.}, } @article {pmid42133017, year = {2026}, author = {Svihlik, J and Rusz, J}, title = {Screening speech disorders in progressive neurological diseases via long-term average spectrum.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {42133017}, issn = {1435-1463}, abstract = {The long-term averaged spectrum (LTAS) may provide a universal method for capturing distinct patterns of dysarthria. This study aimed to evaluate the sensitivity of LTAS descriptors in a broad range of neurological diseases and various types and severities of dysarthria. Four spectral moments of spectral mean, spectral standard deviation, spectral skewness and spectral kurtosis based on LTAS were computed for reading passage collected from 461 speakers, including 306 healthy controls and 155 neurological patients secondary to Parkinson's disease (PD), progressive supranuclear palsy, multiple system atrophy (MSA), Huntington's disease, essential tremor, cerebellar ataxia (CA), multiple sclerosis (MS), and amyotrophic lateral sclerosis. Compared to controls, the spectral mean was significantly lower in PD and MS while elevated in CA. Significantly changed LTAS features were observed only in hypokinetic dysarthria and in mixed dysarthrias manifesting hypokinetic elements. Although LTAS features differed between controls and patients with varying degrees of dysarthria, there was no progressive increase in dysarthria severity. Our findings suggest that LTAS-based speech analysis may provide valuable cues to aid differential diagnosis among neurological diseases with overlapping clinical features. LTAS appears more informative when applied to specific diseases than to pooled dysarthria types arising from diverse neurological etiologies.}, } @article {pmid42134656, year = {2026}, author = {Vassallu, F and López, M and López Ambrosioni, F and Casal, J and Caltana, L and Igaz, LM}, title = {TDP-43 expression in the cytoplasm leads to early synaptic and mitochondrial abnormalities in an inducible mouse model of ALS/FTD.}, journal = {Neurochemistry international}, volume = {197}, number = {}, pages = {106180}, doi = {10.1016/j.neuint.2026.106180}, pmid = {42134656}, issn = {1872-9754}, mesh = {Animals ; *DNA-Binding Proteins/genetics/biosynthesis ; *Mitochondria/metabolism/pathology/genetics/ultrastructure ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Synapses/metabolism/pathology/genetics/ultrastructure ; Mice ; *Frontotemporal Dementia/pathology/metabolism/genetics ; Disease Models, Animal ; *Cytoplasm/metabolism/genetics/pathology ; Humans ; }, abstract = {TDP-43 proteinopathy is the primary pathology associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), indicating that these neurodegenerative diseases have common underlying mechanisms. We have previously shown that transgenic (Tg) mice conditionally overexpressing a cytoplasmic form of human TDP-43 protein (TDP-43-ΔNLS) in forebrain neurons replicate key features of FTD/ALS, including altered cognitive, motor and social behaviors. These behavioral phenotypes and changes in plasticity-related gene expression can be detected as early as 1 month after Tg induction, before overt neurodegeneration occurs. To assess early ultrastructural features in this model, we performed Transmission Electron Microscopy (TEM) analysis in the cortex (Ctx) and hippocampus (Hp) of Tg animals and their non-Tg controls. TEM evaluation of Ctx and Hp revealed that synaptic density was significantly decreased and synapse length was increased in both regions of Tg animals. Synaptic cleft thickness was increased and post-synaptic density thickness was decreased only in the Ctx of Tg mice, revealing differential regional effects in synaptic morphology. We analyzed mitochondrial density and we found an increase in the Ctx and a decrease in the Hp of Tg animals, with preserved individual mitochondrial area. Lastly, transcriptomic and proteomic analysis from both Tg TDP-43-ΔNLS mice and human proteinopathy showed widespread decreased expression of synaptic structure and function genes. The alterations in synaptic density and architecture reported here, combined with the mRNA/protein expression data, suggest that TDP-43-ΔNLS mice may exhibit abnormal synaptic transmission and that ultrastructural changes play a role in the early behavioral deficits observed in this model.}, } @article {pmid42134658, year = {2026}, author = {Purushotham, SS and Chesworth, R and Keembiyage, N and Münch, G and Gyengesi, E and Buskila, Y}, title = {The impact of long-term feeding with curcuminoids phospholipids enriched diet on disease progression of fALS.}, journal = {Neurochemistry international}, volume = {197}, number = {}, pages = {106183}, doi = {10.1016/j.neuint.2026.106183}, pmid = {42134658}, issn = {1872-9754}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/diet therapy/genetics/drug therapy/pathology ; *Curcumin/administration & dosage ; Female ; *Disease Progression ; Male ; *Phospholipids/administration & dosage ; Mice ; Mice, Transgenic ; *Diet ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal neurodegenerative disease characterised by the progressive loss of motor functions affecting both upper and lower motor neurons. Although considered multifactorial with an unclear aetiology, it is believed that the interplay between genetic and environmental factors, with neuroinflammation playing a key role in disease progression, contributes to its development. There is currently no effective treatment for ALS. Curcumin has been recently highlighted for its potential therapeutic role in treating neurodegenerative diseases. Curcumin phospholipids, a highly bioavailable form of curcumin that allow the curcumin to be absorbed into the bloodstream more effectively than standard curcumin extracts, is considered as a natural cytokine-suppressive anti-inflammatory compound (CSAID) that is well-known for its therapeutic properties and is considered safe for humans and rodents at low to moderate concentrations. In this study, we investigated whether a long-term feeding regimen incorporating curcuminoids phospholipids-enriched diet early in disease progression could mitigate motor deficits and affect the lifespan of the SOD1 mouse model of familial ALS (fALS). Our results indicate sex-differences regarding the effect of curcumin supplementation on motor deficits and anxiety-like behaviour. While long-term feeding with curcuminoids phospholipids enriched diet had a complex effect on SOD1 female mice expressed as reduced anxiety like behaviour and motor deficits at the walking beam test, it had no effect on SOD1 male mice. Moreover, curcuminoids supplementation had a limited effect on disease onset and progression in SOD1 mice model for fALS.}, } @article {pmid42134762, year = {2026}, author = {Song, J and Lee, S and Lee, J and Gil, Y and Kim, T and Kim, SY and Cha, SJ and Kim, HJ and Kim, K}, title = {Carboplatin alleviates astrocytic TDP-43 neurotoxicity by inhibiting NF-κB activation.}, journal = {European journal of pharmacology}, volume = {1026}, number = {}, pages = {178968}, doi = {10.1016/j.ejphar.2026.178968}, pmid = {42134762}, issn = {1879-0712}, mesh = {*Astrocytes/drug effects/metabolism/pathology ; Animals ; *DNA-Binding Proteins/metabolism/genetics/toxicity ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Carboplatin/pharmacology/therapeutic use ; Humans ; Mitochondria/drug effects/metabolism ; Neurons/drug effects/metabolism/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Phosphorylation/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare and progressive motor neuron disease; however, its exact pathogenic mechanisms remain unclear. Currently, no effective treatments are available for this disease. Therefore, in this study, we investigated the anti-inflammatory effects of the anti-cancer agent, carboplatin, on neuronal cells and its potential therapeutic effects against ALS. Carboplatin inhibited NF-κB phosphorylation in the transactive response DNA-binding protein (TDP)-43-transfected astrocytes, reducing pro-inflammatory cytokine levels, without affecting the TDP-43 protein levels. In neuron-astrocyte co-culture models, carboplatin effectively alleviated TDP-43-induced toxicity by restoring mitochondrial integrity, specifically rescuing basal respiration, ATP production, and maximal respiratory capacity. In vivo, carboplatin rescued the locomotor deficits in glial-specific TDP-43-expressing Drosophila, without altering TDP-43 protein levels and subcellular localization. These findings suggest that TDP-43-induced astrocytic damage compromises mitochondrial functions in adjacent neurons, and that carboplatin-mediated restoration of TDP-43-mediated astrocyte damage is critical for neuronal survival and functions. Therefore, carboplatin, a chemotherapeutic agent, represents as a potential therapeutic candidate for TDP-43-associated proteinopathies.}, } @article {pmid42135015, year = {2026}, author = {Bate, J and Fealey, J and Young, C and McArdle, A and Staunton, CA and Close, GL}, title = {Sport-related trauma and motor neurone disease: a scoping review of epidemiology, mechanisms and future directions.}, journal = {British journal of sports medicine}, volume = {60}, number = {12}, pages = {900-908}, doi = {10.1136/bjsports-2025-111410}, pmid = {42135015}, issn = {1473-0480}, mesh = {Humans ; *Athletic Injuries/epidemiology/complications ; *Motor Neuron Disease/epidemiology/etiology ; Risk Factors ; *Amyotrophic Lateral Sclerosis/epidemiology ; }, abstract = {OBJECTIVE: To map existing epidemiological evidence assessing the relationship of sport-related trauma and Motor Neurone Disease/Amyotrophic Lateral Sclerosis (MND/ALS), identify potential mechanistic pathways through which athletic exposures may influence disease risk and highlight gaps informing future research priorities.

DESIGN: Scoping Review. Online databases were used to retrieve data from available sources to 25 September 2025.

DATA SOURCES: Published and grey literature in English were identified through searches of ProQuest Central, Web of Science, Scopus, Sport Discus and PubMed. Studies were deemed eligible if they examined MND/ALS in the context of sport-related physical trauma.

METHODS: The scoping review was carried out in accordance with Preferred Reporting Items for Systematic reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. A three-step search strategy identified primary studies, secondary literature and grey literature. Following screening, data were extracted using a standardised charting tool to develop a descriptive analysis and thematic synthesis.

RESULTS: The search identified 3307 records, with 45 studies meeting inclusion criteria. General physical activity does not elevate MND/ALS risk; however, professional participation in high-impact sports, particularly those involving repetitive head impacts, has been associated with a 4-15-fold increased risk of MND/ALS. However, current evidence is largely descriptive, correlative and lacks mechanistic insights to verify causation.

CONCLUSION: This scoping review highlights a plausible association between repeated physical trauma in sport and MND/ALS, particularly in professional sports with high exposure to repeated head impacts. Future research should identify biological mechanisms linking trauma exposure with MND/ALS, integrating biomarker, experimental and longitudinal study designs to clarify causal mechanisms and inform risk mitigation in sport.}, } @article {pmid42135109, year = {2026}, author = {Yin, X and Zhang, H and Zhang, R and Xue, J and Hou, Y}, title = {Epigenetic noise in the aging brain: tuning neuronal vulnerability to neurodegeneration.}, journal = {Trends in neurosciences}, volume = {49}, number = {6}, pages = {481-499}, doi = {10.1016/j.tins.2026.04.006}, pmid = {42135109}, issn = {1878-108X}, mesh = {Humans ; *Aging/genetics/pathology ; *Epigenesis, Genetic ; Animals ; *Neurodegenerative Diseases/genetics/pathology ; *Brain/metabolism/pathology ; *Neurons/pathology/metabolism ; DNA Methylation ; }, abstract = {Aging is the predominant risk factor for neurodegenerative diseases, yet the mechanisms linking biological aging to selective neuronal degeneration remain incompletely understood. Accumulating evidence indicates that aging progressively disrupts epigenetic regulation, manifested as increased epigenetic noise in DNA methylation, histone modifications, and chromatin accessibility, which undermines transcriptional precision and the stability of neuronal identity. Recent advances in single-cell and spatial epigenomics further suggest that these age-associated epigenetic alterations are not merely correlative but can actively shape neuronal vulnerability across brain regions and cell types. In this review, we synthesize emerging evidence showing how epigenetic noise contributes to selective neurodegeneration across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, and discuss emerging strategies aimed at stabilizing the aging neuronal epigenome.}, } @article {pmid42135512, year = {2026}, author = {Zhang, Z and van Olst, L and Alessandrini, F and Wright, M and Edwards, AJ and Boles, J and Nalbandian, A and Forsyth, AV and Shepard, N and Watson, T and Kaspi, E and Mittal, A and Kuruvilla, J and Piehl, N and Ramakrishnan, A and Appel, S and Kiskinis, E and Gate, D}, title = {Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration and reprogramming.}, journal = {Nature neuroscience}, volume = {29}, number = {7}, pages = {1735-1748}, pmid = {42135512}, issn = {1546-1726}, support = {R01AG078713//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/genetics/pathology ; Humans ; Spinal Cord/immunology/pathology ; Spatial Transcriptomics ; C9orf72 Protein/genetics ; Motor Neurons/pathology/immunology ; Single-Cell Gene Expression Analysis ; Single-Cell Analysis/methods ; Transcriptome ; Gene Expression Profiling ; CD8-Positive T-Lymphocytes/immunology ; DNA-Binding Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron (MN) degeneration in the brain and spinal cord. Although neuroinflammation is increasingly recognized as a hallmark of ALS, the precise molecular programs linking immune responses to MN pathology remain poorly defined. Using an integrated approach that combines single-cell and bulk RNA sequencing with spatial proteogenomics, we characterized both shared and distinct immune dynamics in peripheral blood and spinal cord tissues from patients with sporadic ALS and those carrying C9orf72 repeat expansions. Our analysis revealed broad immune remodeling in C9orf72 ALS, ALS subtype-specific and progression-associated differences in monocyte activation and antigen-experienced CD8 effector memory T cells with clonal features consistent with antigen-driven responses. Spatial mapping revealed complement activation and lipid-programmed myeloid states converging at sites of MN loss and TDP-43 pathology. Together, these findings connect peripheral and central immune alterations to ALS heterogeneity and highlight stratified immunomodulation as a potential therapeutic strategy.}, } @article {pmid42135750, year = {2026}, author = {Tamaki, Y and Kaneko, S and Urushitani, M}, title = {Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {42135750}, issn = {1741-7015}, support = {24K18702//Japan Society for the Promotion of Science/ ; 23K24211//Japan Society for the Promotion of Science/ ; 25wm0625522h0001//Japan Agency for Medical Research and Development/ ; }, mesh = {*DNA-Binding Proteins/chemistry/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Frontotemporal Lobar Degeneration/metabolism/genetics ; *Protein Multimerization ; }, abstract = {BACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) is an essential regulator of RNA metabolism, playing a pivotal role in splicing, transport, and stability. While its cytoplasmic aggregation is the pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), recent evidence suggests that the earliest pathogenic event is the disruption of its physiological homodimeric structure. Under healthy conditions, TDP-43 forms dimers via its N-terminal domain, a configuration that is crucial for its nuclear solubility and cooperative RNA binding. In this review, we propose the "Molecular Zipper" hypothesis to describe the maintenance of TDP-43 structural homeostasis. In this framework, the N-terminal domain acts as a stabilizing "NTD-mediated anchor" that keeps the protein in a functional, "zipped" dimeric state, effectively sequestering its aggregation-prone C-terminal regions. Pathogenic triggers-including genetic mutations, aberrant post-translational modifications such as phosphorylation and acetylation, and environmental stressors-can "unzip" this structure, leading to the formation of pathogenic monomers. These pathogenic monomers show increased propensity for cytoplasmic mislocalization and recruit wild-type protein into aggregates through a prion-like seeded aggregation mechanism, culminating in nuclear functional loss and cytoplasmic gain-of-toxicity. We further evaluate the emerging diagnostic landscape, focusing on methods to monitor the dimer-to-monomer ratio.

SHORT CONCLUSION: Integrating prior biochemical data on TDP-43 dimerization with structural modeling enables a more coherent account of the transition from the physiological dimer to pathological conformers. The Molecular Zipper framework offers a conceptual foundation for reconciling existing experimental findings and for guiding future studies on early structural changes in TDP-43 proteinopathy.}, } @article {pmid42135847, year = {2026}, author = {Sinha, IR and Atkinson, AL and Irwin, KE and Ling, JP and Wong, PC}, title = {TDP-43: [GU]-ardian of the transcriptome.}, journal = {Molecular neurodegeneration}, volume = {21}, number = {1}, pages = {}, pmid = {42135847}, issn = {1750-1326}, support = {DGE2139757//National Science Foundation/ ; }, mesh = {Humans ; *DNA-Binding Proteins/genetics/metabolism ; Animals ; *Transcriptome/genetics ; *Neurodegenerative Diseases/genetics/metabolism ; }, abstract = {TDP-43 is a ubiquitously expressed, primarily nuclear DNA/RNA-binding protein implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). In this review, we examine the structure and regulation of TDP-43, how these features influence its localization and functional activity, and how their disruption may contribute to disease. Among TDP-43's diverse functions, splicing repression of nonconserved RNA sequences termed cryptic exons has emerged as especially central to human disease. TDP-43 nuclear depletion and cytoplasmic aggregation are well-established pathological features in affected neurons and glia of neurodegenerative diseases, and accumulating evidence suggests that loss of TDP-43-mediated splicing repression occurs presymptomatically in disease. Advances in RNA-sequencing have enabled systematic identification of cryptic exon inclusion as a sensitive marker of TDP-43 dysfunction. Here, we synthesize current knowledge of TDP-43 biology and curate datasets from human tissues and experimental models, focusing on cryptic splicing to provide a resource for leveraging cryptic exon biology to better understand, detect, and target TDP-43 dysfunction.}, } @article {pmid42135897, year = {2026}, author = {Kawazoe, T and Sugaya, K and Hayashi, K and Hino, K and Nakata, Y and Bokuda, K and Shimizu, T and Takahashi, K}, title = {Sex-Stratified Association of Regional Dopamine Transporter Binding With Disease Progression in Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, pmid = {42135897}, issn = {2328-9503}, support = {R051201013//Tokyo Metropolitan Hospital Organization/ ; }, abstract = {OBJECTIVE: To clarify the clinical relevance of dopamine transporter single-photon emission computed tomography (DAT-SPECT) abnormalities in amyotrophic lateral sclerosis (ALS), with a prespecified focus on sex-stratified associations with disease progression and short-term prognosis.

METHODS: Fifty-eight consecutive patients with ALS were prospectively enrolled and underwent [123]I-ioflupane DAT-SPECT, and DAT-SPECT data from 30 patients with essential tremor were analyzed as a reference group. We quantified the specific binding ratio (SBR) and the caudate-to-putamen binding ratio (BR-C/P) as age-adjusted Z-scores. Associations with functional decline (ΔALSFRS-R), respiratory function (forced vital capacity), neuropsychiatric measures, and a 6-month composite endpoint of death or ventilator support were examined using correlation and logistic regression analyses, with prespecified sex-stratified evaluation.

RESULTS: A significant sex difference in BR-C/P Z-scores prompted sex-stratified analyses. SBR Z-scores were not associated with clinical or neuropsychiatric variables in either sex. In women, lower BR-C/P Z-scores correlated with faster functional decline and were independently associated with a higher risk of death or ventilator support within 6 months (odds ratio per 1-unit increase, 0.31; 95% confidence interval, 0.12-0.83). In men, BR-C/P Z-scores correlated with forced vital capacity and respiratory decline. Exploratory voxel-based morphometry suggested limbic and striatal gray matter correlates in women with lower BR-C/P Z-scores.

INTERPRETATION: Regional dopaminergic imbalance captured by BR-C/P, rather than global SBR, demonstrated sex-stratified associations with disease progression in ALS. These findings support sex-specific interpretation of dopaminergic imaging biomarkers and suggest that BR-C/P may complement clinical measures for identifying higher-risk trajectories, particularly in women. Validation in larger, longitudinal cohorts is required.}, } @article {pmid42135919, year = {2026}, author = {Baird, LA and McQuown, H and Park, J and Teener, SJ and Webber-Davis, IF and Carter, AD and Jang, DG and Feldman, EL and Goutman, SA and Murdock, BJ}, title = {Peripheral Neutrophil Activation and Extracellular Trap Formation in Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, pmid = {42135919}, issn = {2328-9503}, support = {//Scott Pranger ALS Center, the Dr. Randall Whitcomb Fund for ALS Genetics, the Coleman Therapeutic Discovery Fund, James and Margaret Hiller, Eric and Linda Novak/ ; //Peter R. Clark Fund for ALS Research/ ; R01NS120926/NH/NIH HHS/United States ; //Stanford Morris ALS Research Fund/ ; F31NS139629/NH/NIH HHS/United States ; //Richard Stravitz Foundation/ ; //NeuroNetwork for Emerging Therapies/ ; T32AI007413/NH/NIH HHS/United States ; F31 NS139629/NS/NINDS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; //Michael R. Johns Fund/ ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; T32 AI007413/AI/NIAID NIH HHS/United States ; //Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund/ ; U01TS000351/ACL/ACL HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; //Coleman Therapeutic Discovery Fund/ ; R01TS000339/ACL/ACL HHS/United States ; }, abstract = {OBJECTIVES: Peripheral neutrophil levels in amyotrophic lateral sclerosis (ALS) inversely correlate with survival, suggesting a role for neutrophils in disease progression. Here, we characterize markers of several neutrophil activation pathways and evaluate their associations with survival to identify potential mechanisms of disease.

METHODS: Blood samples were obtained from participants at the University of Michigan ALS Clinic or from healthy controls. Ex vivo neutrophil extracellular trap (NET) formation was quantified via image analysis of primary neutrophils. Neutrophil function markers of general activation (calprotectin), migration (matrix-metalloproteinase 9 [MMP9]), and degranulation (neutrophil gelatinase-associated lipocalin [NGAL]) were then quantified in plasma via ELISA; NET formation (double-stranded DNA [dsDNA]) was assessed via fluorescence assay. These markers were then associated with ALS survival using Cox proportional hazard regression models, and analyses were stratified by sex.

RESULTS: Spontaneous ex vivo NET formation (N = 20 controls, 66 ALS) was increased in ALS (1.0% vs. 9.7%; p = 0.017). In plasma (N = 233 controls, 178 ALS), calprotectin (294 vs. 372 ng/mL; p < 0.001), MMP9 (106 vs. 152 ng/mL; p < 0.001), and NGAL (61 vs. 66 ng/mL; p = 0.01) were elevated in ALS. Calprotectin, MMP9, and NGAL levels were not associated with ALS survival; however, dsDNA was associated with poorer ALS survival but only in females (HR = 1.77 [95% CI, 1.20-2.61]; p = 0.004).

INTERPRETATION: Neutrophil function is altered in ALS, and NET formation is a potential mechanism by which neutrophils contribute to ALS, particularly in females.}, } @article {pmid42136278, year = {2026}, author = {Sharma, A and Mittal, V and Sharma, D and Deswal, G and Das, A and Guarve, K and Grewal, AS}, title = {Therapeutic Insights into Natural Products for Modulating Neurodegenerative Disease Pathways.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249405308251210104405}, pmid = {42136278}, issn = {1875-6166}, abstract = {INTRODUCTION: Neurodegenerative Disorders (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS), are chronic and progressive conditions marked by the gradual loss of neuronal structure and function. These disorders lead to cognitive, motor, and sensory decline, significantly reducing quality of life and posing a major global health burden due to rising healthcare costs and the absence of curative therapies. This review aims to comprehensively explore the therapeutic potential of natural products in targeting cellular and molecular mechanisms underlying NDs, highlighting their neuroprotective roles and potential for disease modification.

METHODS: A comprehensive literature review was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trials, and experimental studies were analyzed to evaluate the therapeutic potential of natural products and their bioactive compounds in the management of NDs.

RESULTS: ND pathogenesis involves oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation, ultimately leading to neuronal death. Current therapies largely provide symptomatic relief without altering disease progression. Natural products from plants, fungi, and marine sources demonstrate strong neuroprotective potential through multitargeted mechanisms. Bioactive compounds such as flavonoids, alkaloids, terpenoids, and polyphenols exhibit antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective activities. Key molecules, including curcumin, resveratrol, luteolin, quercetin, and catechins, modulate signaling pathways such as NF-κB, MAPK, PI3K/AKT, Nrf2, apoptosis, and autophagy, thereby reducing amyloid-beta aggregation, protecting dopaminergic neurons, improving mitochondrial function, and enhancing cognition in preclinical and clinical studies.

DISCUSSION: Natural products represent promising candidates for disease modification in NDs due to their multi-pathway actions and relatively low toxicity. However, major limitations, such as poor bioavailability, pharmacokinetic variability, and the lack of standardized formulations, hinder clinical translation. Innovative strategies, including advanced drug-delivery systems, structural modifications, and synergistic formulations, are needed to overcome these barriers.

CONCLUSION: Natural products hold significant therapeutic potential in managing neurodegenerative diseases by targeting multiple pathological mechanisms. Their integration into ND treatment could provide safer and more effective alternatives, but further well-designed clinical trials are essential to establish their efficacy and facilitate clinical application.}, } @article {pmid42136293, year = {2026}, author = {Ramesh, J and Jayanthi, B and Mohan, VK and Srinivasan, S and Vijayalakshmi, MK and Mohan, M}, title = {Targeted Nanotechnology Approaches to Bypass the Blood-brain Barrier in Neurodegenerative Disorders.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273444679260416064255}, pmid = {42136293}, issn = {1996-3181}, abstract = {Neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) are a growing health burden across the world because of the progressive loss of brain cells and the ineffective nature of the available treatment. One significant challenge in the treatment of these conditions is the Blood- -Brain Barrier (BBB), a highly selective interface that limits the access of most therapeutic molecules to the central nervous system. Nanotechnology has become an attractive approach to addressing this difficulty, as it enables the delivery of drugs with high accuracy and actively engages in the repair of the BBB. This review provides an overall synthesis of focused nanotechnology solutions aimed at both circumventing and restoring BBB function in neurodegenerative illnesses. It discusses various nanoparticle (NP) platforms such as polymeric, lipid-based, micellar, metallic, and carbon-derived systems in the light of their physicochemical aspects, transport across the BBB, and therapeutic efficacy. Particular emphasis is put on the receptor-mediated transcytosis, neurovascular unit modulations, and the regulation of Wnt, Shh, and Tie-2 signalling pathways, which are BBB integrity pathways. The review incorporates mechanisms of BBB repair in combination with neuroprotective nanotherapies, rather than focusing solely on end repair. This review covers the role of targeted nanotechnology in the future of therapeutic approaches for neurodegenerative diseases. By connecting materials science, molecular neuroscience, and clinical innovation, it demonstrates how next-generation brain-targeted therapies can be developed using targeted nanotechnology.}, } @article {pmid42136304, year = {2026}, author = {Anjukandan, A and Kaliyaperumal, R}, title = {Challenges in Brain Drug Delivery for Neurodegenerative Disorders and Recent Trends: A Review.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273453002260416115852}, pmid = {42136304}, issn = {1996-3181}, abstract = {INTRODUCTION: Age-related disorders known as neurodegenerative illnesses are defined by uncontrolled neuronal loss that gradually impairs brain function. The majority of age-related neurodegenerative disorders are caused by dementias, in particular. Nowadays, the neurodegenerative disorders are not limited to age and are reported in all age groups. The drug delivery to treat the neurodegenerative disorders is challenging due to the presence of the blood-brain barrier (BBB).

METHOD: A critical literature review has been conducted across databases such as Scopus, Embase, Cochrane, and PubMed. Blood-brain barrier, neurodegenerative disorders, novel drug delivery system, and targeted drug therapy were the search terms.

RESULTS: Neurodegenerative Diseases (NDD) impact the peripheral nervous system, nerve cells, muscles, and the nerve-muscle junction. This term broadly encompasses cognitive disorders, such as Alzheimer's disease, Lewy body dementia, frontotemporal dementia, and vascular dementia. Additionally, other neurodegenerative conditions such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and spinocerebellar ataxias predominantly impair motor system function and nerves in the limbs. The existing therapeutic approaches to treat neurological diseases exhibit limited efficacy due to the BBB. This highly selective semipermeable membrane permits vital nutrients to enter the brain while blocking the potentially harmful toxins. It makes it very challenging to get medications into the brain. There are several effective approaches to deliver drugs to the brain (nanocarrier systems, intranasal administration, and focused ultrasound) to address the limitations of conventional treatments.

CONCLUSION: This review discusses neurodegenerative disorders, brain anatomy/physiology, barriers to drug delivery, and strategies to overcome these limitations.}, } @article {pmid42136825, year = {2026}, author = {Pan, J and Zhang, C and Li, J and Ma, L}, title = {Neurocritical progression in amyotrophic lateral sclerosis: pathological relevance and validation.}, journal = {Open life sciences}, volume = {21}, number = {1}, pages = {20251323}, pmid = {42136825}, issn = {2391-5412}, abstract = {Evidence from multiple clinical studies indicates that amyotrophic lateral sclerosis (ALS) frequently evolves into a condition requiring neurocritical care. In advanced stages or during acute complications, ALS can rapidly transition into a neurocritical state characterized by respiratory insufficiency, systemic dysfunction, and accelerated neurological decline. Although current management strategies for advanced-stage ALS are relatively well established, there remains a significant lack of targeted interventions aimed at preventing or attenuating neurocritical deterioration. This review systematically examines the pathophysiological mechanisms underlying neurocritical progression in ALS, including respiratory failure, metabolic imbalance, autonomic dysfunction, and multisystem involvement. We further evaluate emerging and potential therapeutic strategies designed to mitigate disease severity and stabilize critical neurological function. In addition, we analyze clinical and biological factors that increase susceptibility to neurocritical states and discuss evidence-based approaches to delay disease progression. By integrating clinical observations with mechanistic insights, this review aims to improve early recognition, optimize neurocritical management, and ultimately enhance outcomes for patients with ALS.}, } @article {pmid42137032, year = {2026}, author = {Miura, K and Nishimura, H and Ito, Y}, title = {Enhanced saccharification yields from rice straw by senescence-induced expression of a cytokinin biosynthesis gene in intragenic rice plants.}, journal = {Plant biotechnology (Tokyo, Japan)}, volume = {43}, number = {1}, pages = {145-149}, pmid = {42137032}, issn = {1342-4580}, abstract = {Controlling the digestibility of cellulosic biomass is important for its efficient use. We generated intragenic rice plants showing enhanced saccharification yield of rice straw. The rice cytokinin biosynthesis gene, LONELY GUY, under the control of the rice senescence-inducible STAY GREEN promoter, was introduced into the rice genome via particle bombardment. The rice-derived herbicide resistance gene ALS(G95A) was used as a selection marker gene. Regenerated intragenic rice plants with no foreign sequences showed enhanced saccharification yields from the leaves at harvest, whereas no significant differences were observed at the heading stage. Because the saccharification yields of rice straw are reduced after senescence, which is suppressed by cytokinin, we propose that the enhanced saccharification yields of intragenic rice plants are caused by the delay in senescence of the rice leaves due to the expression of the introduced cytokinin biosynthesis gene upon senescence.}, } @article {pmid42137113, year = {2026}, author = {Rong, P and Heidrick, L}, title = {An interpretable, clinically grounded framework for digital speech biomarker development in neurodegenerative diseases.}, journal = {Frontiers in digital health}, volume = {8}, number = {}, pages = {1794169}, pmid = {42137113}, issn = {2673-253X}, abstract = {INTRODUCTION: Communication ability-a key determinant of quality of life-is frequently affected and progressively declines in neurodegenerative diseases. Effective management of progressive communication disorders requires a personalized approach to deliver timely interventions tailored to the evolving profiles of communicative impairment, thereby supporting functional communication throughout the disease course. To this end, reliable tools capable of detecting and quantifying both disease-specific patterns of communicative impairment and within-disease phenotypic variability are urgently needed. This study leverages Artificial Intelligence and advanced data analytics to develop an acoustic-based framework for automated extraction of interpretable, clinically grounded speech markers to enable objective assessment and phenotyping of progressive communication disorders.

METHODS: Three groups of participants, including 14 individuals with amyotrophic lateral sclerosis (ALS) and 15 individuals with Parkinson's disease (PD), alongside 10 neurologically healthy controls, performed a standardized oral passage reading task, yielding 739 speech samples. Fifty acoustic features were extracted using an automated analytic pipeline and subsequently clustered into six interpretable composite markers. The clinical utility of these markers was evaluated with the recorded speech samples by examining their (1) associations with standardized metrics of cognitive, motor speech, and overall communicative functions, (2) efficacy for detecting and differentiating disease-specific communicative impairment patterns in ALS and PD using supervised machine learning, and (3) utility for within-disease phenotyping and stratification using unsupervised clustering analysis.

RESULTS: The markers effectively (1) detected subtle subclinical changes across multiple domains prior to substantial declines in functional communication outcomes; (2) differentiated disease-specific patterns of communicative impairment (multiclass area under the curve > 0.90); and (3) identified subgroups with distinct speech profiles within each disease.

DISCUSSION: The findings support the potential of the proposed framework as a clinically translatable, objective tool to facilitate early detection, differential diagnosis, and phenotyping of progressive communication disorders, ultimately advancing personalized, measurement-based care in neurodegenerative diseases.}, } @article {pmid42139128, year = {2026}, author = {Hong, J and Rao, P and Wang, W and Najafizadeh, L}, title = {ChatBCI-Assist: An Intent-Based P300 Speller With A Locally Deployed LLM and Adaptive Stopping Strategy Enabling Record Online Spelling Performance.}, journal = {IEEE transactions on bio-medical engineering}, volume = {73}, number = {8}, pages = {2876-2888}, doi = {10.1109/TBME.2026.3693965}, pmid = {42139128}, issn = {1558-2531}, mesh = {Humans ; Large Language Models ; *Brain-Computer Interfaces ; *Event-Related Potentials, P300/physiology ; *Signal Processing, Computer-Assisted ; Amyotrophic Lateral Sclerosis/physiopathology ; Electroencephalography/methods ; *Communication Devices for People with Disabilities ; User-Computer Interface ; }, abstract = {P300-based speller brain computer interfaces (BCIs) provide promising communication solutions for individuals with severe motor impairments, such as those with amyotrophic lateral sclerosis (ALS). However, existing P300 spellers are constrained by slow typing speed and limited efficiency. Here, we present ChatBCI-Assist, an intent-based P300 speller that integrates a locally deployed large language model (LLM), fine-tuned for the task at hand, and a graphical user interface (GUI) designed for efficient message composition, while incorporating an adaptive stopping strategy for key selection, to achieve record online spelling performance. The LLM, trained on an ALS-specific communication corpus using low-rank adaptation (LoRA), produces context-aware, prefix-constrained word and phrase predictions in real time. The proposed GUI enables efficient, user-adaptive interaction with these predictions and facilitates semantically driven message composition, where suggestions can reflect the user's intended message. To evaluate intent-based communication, we introduce semantic spelling tasks (beyond traditional copy-spelling), where users convey intended meaning rather than reproduce text verbatim, along with metrics to assess communication based on semantic similarity. Results from online experiments show that ChatBCI-Assist achieves record performance, with an average (estimated) information transfer rate (ITR) of 105.2 bits/min, an overall character-level mutual information rate (MIR) of 52.9 bits/min, and average values of 19.7 characters per minute (CPM) in copy-spelling tasks and 30.7 CPM in semantic spelling tasks. Evaluated using semantic ITR (SITR), a metric proposed to characterize semantic communication efficiency, ChatBCI-Assist achieves an SITR of 147.1 bits/min. User experience evaluations further indicate reduced workload and improved usability compared to traditional copy-spelling paradigms. These results demonstrate that integrating locally-adapted LLMs with intent-driven design and subject-specific decoding optimization can substantially improve the speed, efficiency, and user experience of BCI-based communication systems.}, } @article {pmid42141072, year = {2026}, author = {Cropper, HC and Mir, F and Liu, J and Dachet, F and Srivastava, VR and Ramizuddin, M and Kopecky, K and Mocanu, E and Jiang, QL and Soni, M and Valyi-Nagy, T and Mnatsakanova, D and Abrams, CK and Song, F and Loeb, JA}, title = {Axonal dying back of upper motor neurons in human ALS.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42141072}, issn = {2045-2322}, support = {T32 AG057468/AG/NIA NIH HHS/United States ; T32AG057468/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *Motor Neurons/pathology/metabolism ; Male ; Female ; *Axons/pathology/metabolism ; Aged ; Middle Aged ; Spinal Cord/pathology/metabolism ; Motor Cortex/pathology/metabolism ; Microglia/pathology/metabolism ; Brain Stem/pathology ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) typically present with arm, leg, or bulbar weakness. While genetics plays a clear role, it cannot explain why symptoms start focally or how upper (UMN) and lower motor neuron (LMN) systems are linked. In this clinicopathological case series, we examined the relationships between UMN/LMN disease in ten ALS patients. Detailed clinical assessments and motor cortex, brainstem, and spinal cord tissues were collected via rapid autopsy. Tissues were stained for UMN/LMN, myelin, axons, microglia, and pTDP43, and RNA-sequencing was performed. None of the patients had symptoms of frontotemporal dementia (FTD), but all had focal sites of clinical onset and both UMN/LMN involvement. LMN degeneration and microglial activation were highest at disease onset sites. UMN degeneration was present at all spinal cord levels through the medulla, regardless of onset site. Surprisingly, there was no evidence of UMN axonal degeneration above the brainstem. While extensive pTDP43 aggregates were seen in degenerating LMNs, no pTDP43 aggregates were seen in UMN cell bodies or their axons. RNA-sequencing implicated inflammatory pathways at sites of disease onset. Our findings suggest that some ALS patients without FTD have a dying back of UMN axons rather than a primary upper neuronopathy of neurons.}, } @article {pmid42141160, year = {2026}, author = {Hatano, Y and Nakahara, A and Tada, M and Kakita, A and Onodera, O and Ishihara, T}, title = {APOE ε4 influences the widespread TDP-43 pathological subtype in sporadic amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {151}, number = {1}, pages = {}, pmid = {42141160}, issn = {1432-0533}, support = {23K14771//Japan Society for the Promotion of Science/ ; 21K07272//Japan Society for the Promotion of Science/ ; JPJS00420240016//JSPS J-PEAKS Program/ ; JP22jm0210097//the AMED-SICORP program/ ; JPMH23FC1008//the Ministry of Health, Labour and Welfare (Research on Rare and Intractable Diseases Program)/ ; JP24zf0127012//AMED MoonShot Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Female ; *Apolipoprotein E4/genetics ; Male ; Aged ; Middle Aged ; Aged, 80 and over ; *Brain/pathology/metabolism ; Genotype ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, most sporadic cases exhibiting TAR DNA-binding protein 43 (TDP-43) pathology. The anatomical distribution of TDP-43 pathology varies among patients; however, factors contributing to this heterogeneity remain unclear. Apolipoprotein E (APOE) ε4 is known to influence the spread of pathological protein in several neurodegenerative diseases, raising the possibility that it also modulates the pathological distribution of TDP-43 inclusions in ALS. We investigated this hypothesis in a cohort of 145 autopsy-confirmed sporadic ALS cases. ALS-associated TDP-43 pathology was classified into two subtypes: type 1 - largely restricted to motor regions - and type 2 - characterized by widespread cortical involvement. APOE genotypes and rare variants in known ALS-associated genes were determined by exome sequencing. Amyloid-β and tau pathologies were assessed neuropathologically using established staging systems. Structural equation modeling (SEM) was applied to disentangle direct and indirect relationships among APOE ε4, temporal clinical parameters, Alzheimer's disease-related pathologies, and ALS TDP-43 subtype. Furthermore, we also performed an unbiased evaluation using random forest model. APOE ε4 carriers showed a significantly higher proportion of type 2 pathology than non-carriers. Bayesian SEM demonstrated that APOE ε4 was directly associated with the type 2, widespread TDP-43 subtype, independent of amyloid-β and tau pathology, while also reproducing the canonical cascade linking APOE ε4 to amyloid-β and tau. Rare variants in ALS-associated genes showed no clear effect on TDP-43 subtype. These findings indicate that APOE ε4 modifies the anatomical distribution of TDP-43 pathology in sporadic ALS through mechanisms independent of classical Alzheimer's disease pathology. Incorporation of APOE genotype into ALS stratification may be informative for biologically grounded subtype-specific therapeutic approaches.}, } @article {pmid42141322, year = {2026}, author = {Slaghekke, HMJ and Govaarts, R and Mesarosova, L and Mühlebner, A and Beeldman, E and de Visser, M and van Es, MA and van den Berg, LH and van der Kooi, AJ and Pijnenburg, YAL and Aronica, E and Raaphorst, J}, title = {Associations of cognitive and behavioural impairment in ALS with brain pathology: pTDP-43 versus microglial activation.}, journal = {Journal of neurology}, volume = {273}, number = {6}, pages = {}, pmid = {42141322}, issn = {1432-1459}, support = {2013-19//Stichting ALS Nederland/ ; 023.012.055//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/complications/psychology/metabolism ; Female ; Male ; *Microglia/pathology/metabolism ; *Brain/pathology/metabolism ; Aged ; Neuropsychological Tests ; Middle Aged ; *DNA-Binding Proteins/metabolism ; Frontotemporal Dementia/pathology ; *Cognition Disorders/etiology/pathology ; }, abstract = {OBJECTIVE: Investigate associations between brain pathology (pTDP-43 inclusions and microglial activation) and cognitive and behavioural impairment in patients with amyotrophic lateral sclerosis (ALS).

METHODS: Based on comprehensive neuropsychological examination and behavioural assessment, 21 ALS patients of whom post mortem brain tissue was obtained, were classified as having 1) no cognitive and/or behavioural impairment (pure motor ALS), 2) mild cognitive and/or behavioural impairment (ALSci/bi), and 3) ALS with behavioural variant frontotemporal dementia (ALS-bvFTD). Immunohistochemical staining of pTDP-43 and HLA-DR-defined microglial activation was semi-quantitatively assessed in grey and/or white matter of the prefrontal cortex, thalamus, hippocampus, and motor cortex.

RESULTS: Fourteen patients had pure motor ALS, four patients had ALSci/bi, and three patients had ALS-bvFTD. pTDP-43 pathology in the grey matter of the prefrontal cortex and gyrus dentatus differed between groups, especially between pure motor ALS and ALS-bvFTD. For each extra-motor brain region, pTDP-43 severity was highest in patients with ALS-bvFTD and lowest in patients with pure motor ALS, with ALSci/bi in between. This pattern was not observed for microglial activation. Associations between white matter pTDP-43 severity and cognitive/behavioural impairment were less robust than those in grey matter.

CONCLUSION: Severity of cognitive and/or behavioural impairment in ALS is related to severity of pTDP-43 pathology, in particular in the grey matter of extra-motor brain regions; we did not detect a clear association with microglial activation.}, } @article {pmid42141969, year = {2026}, author = {Olesen, L and Moèll, SK and Knudsen, L}, title = {Living Outside the ALS Home - Everyday Experiences, Challenges and Needs of Adult Children with a Parent with ALS.}, journal = {Journal of social work in end-of-life & palliative care}, volume = {22}, number = {3}, pages = {241-267}, doi = {10.1080/15524256.2026.2672970}, pmid = {42141969}, issn = {1552-4264}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; *Adult Children/psychology ; Female ; Male ; Adult ; Focus Groups ; Middle Aged ; *Child of Impaired Parents/psychology ; Qualitative Research ; Adaptation, Psychological ; Social Support ; Parent-Child Relations ; *Parents/psychology ; Aged ; Family Support ; }, abstract = {Adult children of a parent with ALS may be highly burdened and in need of support, but studies of their experiences and needs are scarce. The aim of this study was to explore everyday experiences, challenges and needs of adult children living outside the home of a parent with amyotrophic lateral sclerosis (ALS). The design was qualitative using Interpretive Description methodology and Sense of Coherence as framework. Focus group interviews were conducted with 16 adult children. Participants experienced changes in relationship and roles with siblings and parents when ALS moved into the family. Their parents' disease evoked a need for understanding ALS and its trajectory as the disease raised questions, concerns, and sorrow. Furthermore, having a parent with ALS led to strong and mixed emotions and dilemmas like bad conscience, self-blame, gratitude and closeness and wanting to be there but also not being able to bear witnessing the deterioration of their parent. Adult children experience profound challenges and needs related to their parent's disease. They need information and support from professionals and peers as they struggle to balance the demands related to ALS and everyday life with family, work and leisure. Professionals should provide support for this vulnerable group who appear highly burdened practically and emotionally by the situation.}, } @article {pmid42142504, year = {2026}, author = {Abd-Eldayem, AM and Mohammed, RA}, title = {Riluzole in neuroinflammation and neurodegeneration: Mechanistic insights and experimental validation.}, journal = {Current opinion in pharmacology}, volume = {88}, number = {}, pages = {102632}, doi = {10.1016/j.coph.2026.102632}, pmid = {42142504}, issn = {1471-4973}, mesh = {Humans ; Animals ; *Riluzole/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism ; }, abstract = {Neuroinflammation and neurodegeneration are tightly interconnected processes that drive the progression of multiple central nervous system (CNS) disorders. Riluzole, a benzothiazole derivative approved for amyotrophic lateral sclerosis (ALS), has been widely investigated for its broader neuroprotective potential. Its actions include modulation of glutamatergic transmission through presynaptic inhibition and upregulation of excitatory amino acid transporters. Additionally, Riluzole inhibits voltage-gated sodium channels, thereby reducing neuronal hyperexcitability and excitotoxicity. Its anti-inflammatory properties are mediated through the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and the attenuation of microglial activation, while its antioxidant effects involve the activation of the nuclear factor erythroid 2-related factor 2/heme Oxygenase-1 (Nrf2/HO-1) pathway and the preservation of mitochondrial function. These mechanisms have been supported by preclinical evidence across models of ALS, Alzheimer's disease (AD), Huntington's disease (HD), and spinal cord injury (SCI), with emerging clinical data supporting its broader therapeutic relevance. Although clinical findings remain limited and disease-specific, the mechanistic breadth of Riluzole continues to motivate interest in its potential utility across neuroinflammatory and neurodegenerative conditions. This review synthesizes recent advances in Riluzole pharmacology and outlines key considerations for future mechanistic and translational research.}, } @article {pmid42143042, year = {2026}, author = {Ferrari, V and Tedesco, B and Cozzi, M and Pramaggiore, P and Gagliani, MC and Magdalena, R and Cornaggia, L and Casarotto, E and Chierichetti, M and Mohamed, A and Brodnanovà, M and Milioto, C and Piccolella, M and Galbiati, M and Crippa, V and Provenzani, A and Cortese, K and Rusmini, P and Cristofani, R and Poletti, A}, title = {VCP modulation ameliorates pathological features in C9orf72 models.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {}, pmid = {42143042}, issn = {2041-4889}, support = {23236//AFM-Téléthon (French Muscular Dystrophy Association)/ ; 29514//AFM-Téléthon (French Muscular Dystrophy Association)/ ; GGP19128//Fondazione Telethon (Telethon Foundation)/ ; GMR25T1103//Fondazione Telethon (Telethon Foundation)/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2022EFLFL8//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; National Center for Gene Therapy and Drugs Based on RNA Technology (CN3) CN00000041//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2020PBS5MJ//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n.//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2022KSJZF5//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n. P2022B5J32//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; piano di sviluppo della ricerca (PSR) UNIMI -linea B//Università degli Studi di Milano (Universitas Studiorum Mediolanensis)/ ; 2025-0708//Fondazione Cariplo (Cariplo Foundation)/ ; 2021-1544//Fondazione Cariplo (Cariplo Foundation)/ ; Grant 2020//Kennedy's Disease Association (KDA)/ ; Grant 2018//Kennedy's Disease Association (KDA)/ ; }, mesh = {*Valosin Containing Protein/metabolism/genetics ; *C9orf72 Protein/metabolism/genetics ; Humans ; Autophagy ; Lysosomes/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Ubiquitin/metabolism ; Mutation ; Motor Neurons/metabolism ; Neurons/metabolism ; Frontotemporal Dementia/genetics/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases linked by similar pathological mechanisms, which, in some familial forms, may be associated with the same genetic alterations. Among them, the most common is the C9ORF72 (C9) mutation. The C9 mutation consists in an aberrant expansion of the hexanucleotide repeat (G4C2)n that leads to the production and accumulation of toxic dipeptide repeat proteins (DPRs). Some of these C9-DPRs contribute to neuronal dysfunction and degeneration through different mechanisms. One of these involves alterations in the protein quality control (PQC) system, specifically in the autophagy-lysosomal pathway. Valosin-containing protein (VCP) is a critical component of the PQC system, assisting the degradation of misfolded proteins and damaged organelles and the maintenance of cellular homeostasis. In this study, we investigated the role of VCP in modulating pathological features associated with C9 mutation. Using neuronal cell models, we demonstrated that VCP overexpression significantly reduced C9-DPRs levels. This reduction is mediated by mechanisms involving both the ubiquitin-proteasome system (UPS) and autophagy. Additionally, we also observed that C9-DPRs induce lysosomal damage, which is counteracted by VCP overexpression, as indicated by decreased galectin-3 puncta and restored lysosomal pH. We then pharmacologically activated VCP-mediated clearance through SMER28, increasing the clearance of the most toxic DPR, the polyPR. We also determined that in this model, SMER28 activity is mediated by the UPS and is associated with the mitigation of DPR-induced lysosome damage. Additionally, using motor neurons derived from induced pluripotent stem cells (iPSC-MNs) from C9-ALS mutation carriers, we demonstrated that SMER28 treatment significantly decreased polyGA levels, a marker for C9-DPR accumulation. Moreover, SMER28 rescued C9-MNs commitment to differentiation and the alteration in the expression of autophagy-related genes. Taken together, our findings strongly support VCP as a modulator of C9 pathology and highlight its potential as a therapeutic target.}, } @article {pmid42143797, year = {2026}, author = {Tribhuvan, M and Phatke, SN}, title = {Comment on "Head injuries as a risk factor for amyotrophic lateral sclerosis: A systematic review and meta-analysis".}, journal = {Clinical neurology and neurosurgery}, volume = {268}, number = {}, pages = {109480}, doi = {10.1016/j.clineuro.2026.109480}, pmid = {42143797}, issn = {1872-6968}, } @article {pmid42145633, year = {2026}, author = {Sonkar, KS and D'Ancona, VL and Cramp, J and Shilling, H and Giles, E and Howell-Bray, T and Fillingham, B and Cudkowicz, ME and Nath, A and Rothstein, JD and Bowser, R and Borroni, B and Padovani, A and Berry, JD and Vakili, GS and Buratti, E and Thrippleton, IP}, title = {Functional Activity of TDP 43: A Direct Biomarker for ALS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.04.26352054}, pmid = {42145633}, abstract = {TDP-43 dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), yet no biofluid biomarker directly measures its functional activity. We developed a serum-based homogeneous time-resolved FRET (hTR-FRET) assay that quantifies TDP-43 RNA binding activity using synthetic UU-rich RNA probes. We analyzed 1,080 serum samples from controls, sporadic ALS, and genetic subgroups (C9orf72, SOD1) across multiple biorepositories. Cross-sectionally, TDP-43 functional activity was elevated in ALS (mean 390 a.u.) versus controls (304 a.u.), yielding AUC = 0.79. Genotype means were 392 a.u. (sporadic), 382 a.u. (C9orf72), and 323 a.u. (SOD1); a 366 a.u. threshold achieved 95% specificity against controls. Longitudinally, Target ALS showed a modest but significant inverse correlation between TDP-43 activity and ALSFRS-R, while other cohorts exhibited similar non-significant trends. Elevated signal in serum likely reflects increased extracellular, probe-competent TDP-43 species. This assay provides a proof-of-concept platform for the direct functional measurement of probe-competent TDP-43 species in serum. While it demonstrates moderate group-level discrimination, individual diagnostic performance requires prospective validation. The assay may support exploratory applications in genotype stratification and progression monitoring in future clinical studies.}, } @article {pmid42145639, year = {2026}, author = {Humphrey, J and Oku, A and Byrska-Bishop, M and Basile, AO and Evani, US and Corvelo, A and Tokolyi, A and Bp, K and Réal, A and Kim, Y and Bond, ML and Clarke, WE and Fu, R and Geiger, H and Chang, S and Naito, T and Jang, B and Musunuri, R and Dredge, WH and Al-Abri, R and Hoover, BN and Manaa, D and McClintock, J and Singh, FP and Pedersen, MH and Runnels, A and Propp, N and Fennessey, S and Won, HH and Zody, MC and Narzisi, G and Robine, N and Lappalainen, T and Fagegaltier, D and Gürsoy, G and Knowles, DA and Raj, T and , and Harms, MB and Phatnani, H}, title = {The New York Genome Center ALS Consortium resource integrates postmortem tissue transcriptomics and whole genome sequencing to empower biological discovery.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.29.26350889}, pmid = {42145639}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with substantial genetic and clinical heterogeneity that impedes therapeutic development. Large-scale multi-tissue genomic resources have transformed the study of neuropsychiatric and neurodegenerative diseases, but no equivalent resource exists for ALS. Here we present the full NYGC ALS Consortium dataset, combining whole-genome sequencing from 4,746 donors and bulk RNA-seq from 2,574 samples across 8 brain and spinal cord regions from 695 donors across the ALS disease spectrum. Our catalogue of small variants, structural variants, and short tandem repeats identified likely pathogenic mutations in 15.6% of ALS cases. Gene expression and mRNA splicing analysis across 5 major tissues reveals shared and region-specific features, highlighting microglial and T-cell dysregulation in the spinal cord. Mapping the genetic regulation of expression and splicing across tissues identified associations with 6 ALS risk loci, whereas allele-specific rare variant analysis detected expression effects for C9orf72 and OPTN . All data are immediately publicly available.}, } @article {pmid42146463, year = {2026}, author = {Chen, X and Yan, H and Wei, H and Sajadi, S and Hu, J and Vasconcellos, V and Kim, A and Shriram, T and Tan, H and Keum, K and Wu, J and Paukert, M and Yang, Y}, title = {Genetic suppression of myeloid receptor Clec7a attenuates microglia neuroinflammation and promotes microglial phagocytosis to delay disease progression in ALS models.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42146463}, issn = {2692-8205}, support = {R01 AG078728/AG/NIA NIH HHS/United States ; R01 NS125490/NS/NINDS NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; }, abstract = {Microglial activation has been closely associated with accelerated ALS disease progression. However, specific microglial pathways that regulate microglial activation and ALS disease progression remain limitedly understood. Here, we determined the role of Clec7a (or Dectin-1), a core signature gene of disease-associated microglia (DAM) in ALS, in regulating microglial activation and ALS disease progression. Our spinal cord scRNA-Seq results found that Clec7a deficiency specifically attenuated microglial neuroimmune gene expression in SOD1G93A mice and human ALS. In addition, in vivo two-photon imaging of human (h) TDP43 phagocytosis by microglia in the cortex showed that Clec7a deficiency promotes microglial phagocytosis of pathological hTDP43 by enhancing microglial process dynamics. Subsequent survival analysis further showed that selective deletion of Clec7a in microglia mitigates motor neuron degeneration and delays disease progression in SOD1G93A ALS mice. Together, our results establish that Clec7a is a key regulator in shaping disease microglial functions and promotes disease progression in ALS.}, } @article {pmid42146521, year = {2026}, author = {Shahani, N and Banerjee, R and MacMullen, C and Sharma, N and Habibi, M and Wasserman, HD and Noyes, NC and Zhao, P and Elgendy, B and Cameron, MD and Bannister, TD and Hegazy, L and Finck, BN and Davis, RL}, title = {Pharmacological rescue of mitochondrial dysfunction, neurite degeneration, and premature death of ALS and AD iPSC-derived neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42146521}, issn = {2692-8205}, support = {R35 NS097224/NS/NINDS NIH HHS/United States ; RF1 AG077160/AG/NIA NIH HHS/United States ; R33 AG068887/AG/NIA NIH HHS/United States ; P30 DK056341/DK/NIDDK NIH HHS/United States ; S10 OD030332/OD/NIH HHS/United States ; R01 DK104735/DK/NIDDK NIH HHS/United States ; }, abstract = {Mitochondrial (MT) dysfunction is a key driver of ALS pathology. Without a healthy MT system, motor neurons (MN) function at sub-optimal levels and die. In addition, other effects of ALS, like axon/dendrite degeneration, may occur from a pathophysiological cascade spurred by MT dysfunction. A phenotypic screen identified Dipyridamole (DPM), an FDA-approved and safe drug, as having extraordinary effects on ALS patient induced pluripotent stem cell (iPSC)-derived MNs. The drug prevented MT fragmentation, loss of MT content, impaired MT bioenergetics, axon/dendrite degeneration, and premature MN death, extending neuronal survival by more than fivefold. Importantly, its efficacy extended across iPSC-derived neurons representing two different familial forms of ALS (C9orf72, TDP43) and Alzheimer's disease (PSEN1), implying broad neuroprotection across ALS forms and other neurodegenerative diseases. DPM increased MT respiration and pyruvate uptake in a mechanism requiring the Mitochondrial Pyruvate Carrier (MPC), mechanistically explaining its biological activities. Thus, DPM is a promising drug to repurpose or refine for treating neurodegenerative diseases or other diseases that would benefit by augmenting pyruvate uptake into MT.}, } @article {pmid42147178, year = {2026}, author = {Gough, E and Basu, S and Brubaker, J and DeNeraing, B and Sack, D and Bourgeois, AL and Walker, R and Harro, CD and Chakraborty, S}, title = {Influence of Gut Microbiota on Immune Responses and Protection in Volunteers Receiving the Live Attenuated Oral ETEC Vaccine ACE257 followed by Virulent ETEC H10407 Challenge.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {42147178}, issn = {2693-5015}, support = {R01 AI153399/AI/NIAID NIH HHS/United States ; R56 AI168316/AI/NIAID NIH HHS/United States ; }, abstract = {Enterotoxigenic Escherichia coli (ETEC) remains a major cause of diarrheal morbidity with no licensed vaccines. Role of gut microbiota in vaccine immunogenicity and protection was investigated using 16S rRNA sequencing from the stool samples of 27 volunteers receiving two doses of the live attenuated oral ETEC vaccine ACE527 followed by virulent ETEC H10407 challenge. Systemic and mucosal IgG and IgA responses to heat-labile toxin-B (LTB) and colonization-factor-antigen-I (CFA/I) were quantified by ELISA in serum and antibody-in-lymphocyte-supernatant (ALS). Microbiome α-diversity, β-diversity, and taxa-immune associations were evaluated using regression models, MiRKAT, and relaxed LASSO. Vaccination increased (~ 25-30%) Eubacterium_brachy_group, Family_XIII_AD3011 and Actinomyces. Higher α-diversity (inverse-Simpson) was associated with reduced ALS anti-LTB and CFA/I IgA responses, whereas β-diversity correlated with increased serum anti-CFA/I IgA. Members of Anaerovoraceae, Peptostreptococcaceae, Oscillospiraceae, and Veillonellaceae enhanced immune responses and protection against severe diarrhea and ETEC colonization, while Ruminococcaceae, Sutterellaceae, Coriobacteria, Clostridia, and Actinobacteria showed antagonistic associations.}, } @article {pmid42147445, year = {2026}, author = {Arogundade, OA and Lam, KJK and Brown, KA and Jain, T and Issagholian-Lewin, PO and Huang, C and Rae-Hudson, T and Briseno, K and Wyman, SK and Krishnappa, N and George, CA and O'Dare, K and Wilson, RHC and van Eijk, P and Reed, SH and Giannikopoulos, P and Clelland, CD}, title = {Arrayed dual-gRNA CRISPR screening platform for C9orf72 repeat expansion excision in patient iPSCs.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {2}, pages = {201741}, pmid = {42147445}, issn = {3117-387X}, support = {K08 NS112330/NS/NINDS NIH HHS/United States ; R01 AG072052/AG/NIA NIH HHS/United States ; U01 NS134062/NS/NINDS NIH HHS/United States ; U19 NS132303/NS/NINDS NIH HHS/United States ; }, abstract = {An intronic hexanucleotide repeat expansion in C9orf72 is the leading genetic cause of both frontotemporal dementia and amyotrophic lateral sclerosis (C9-FTD/ALS). We have previously demonstrated that CRISPR-Cas9 excision of the repeat expansion in patient iPSCs reverts pathological hallmarks of C9-FTD/ALS. Here, we aim to identify efficient and safe gRNAs for CRISPR-spCas9 dual-gRNA excision of the C9-repeat expansion. Utilizing novel ddPCR and single-molecule sequencing assays, we screened 120 gRNA pairs, comparing 64 bi-allelic, intronic excisions of the repeat region to 56 allele-specific excisions of the mutant allele in patient iPSCs, ranking them by efficiency. Bi-allelic excisions of the intronic repeat region were more efficient than excisions of the mutant allele. Single gRNA indel rates can nominate likely efficient gRNA pairs, but these pairs must be tested empirically. The length of the repeat expansion did not impact excision efficiency; rather, the activity of individual gRNAs drove excision efficiencies. Using whole genome sequencing and INDUCE-seq, we found only one detectable off-target of those nominated by Cas-OFFinder and CHANGE-seq across 4 of the most efficient gRNAs. This study advances the development of targeted therapies for C9-FTD/ALS and establishes a framework for dual-gRNA screening in patient iPSCs applicable to other repeat expansions.}, } @article {pmid42148083, year = {2026}, author = {Li, L and Wang, S and Duan, L and Zhang, L and Yan, H and Chen, X and Tao, L and Gao, Y}, title = {Ferroptosis-immune crosstalk in CNS diseases: mechanisms and translational insights.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1807104}, pmid = {42148083}, issn = {1664-3224}, mesh = {Humans ; *Ferroptosis/immunology ; Animals ; *Central Nervous System Diseases/immunology/metabolism ; Iron/metabolism ; Neuroimmunomodulation ; Neuroinflammatory Diseases ; }, abstract = {Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation, which plays a pivotal role in regulating the inflammatory-immune microenvironment of central nervous system (CNS) diseases. Mounting evidence indicates that dysregulated iron metabolism and an imbalance in antioxidant defenses can induce ferroptosis in neurons and glial cells while simultaneously remodeling immune cell function, thereby establishing a bidirectional feedback loop that amplifies neuroinflammation and tissue damage. In neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), pro-inflammatory cytokines such as TNF-α and IL-1β released by activated microglia upregulate neuronal iron transporters (e.g., DMT1 and TfR1), promoting iron accumulation and ferroptotic cell death. In turn, damage-associated molecular patterns released from ferroptotic cells further potentiate immune activation, forming a self-amplifying cycle. In contrast, within the glioma microenvironment, CD8[+] T cell-derived IFN-γ suppresses SLC7A11 expression in tumor cells, leading to glutathione depletion and glutathione peroxidase 4 inactivation, thereby triggering ferroptosis and modulating anti-tumor immunity. Although targeting ferroptosis or neuroimmune pathways has shown therapeutic promise in mitigating neurological deficits and enhancing anti-tumor responses, the underlying mechanisms governing ferroptosis-immune crosstalk remain inadequately characterized. Herein, this review systematically summarizes the key biological characteristics of ferroptosis and immune responses, with particular emphasis on their interplay across major CNS disorders (i.e., AD, PD, ALS, multiple sclerosis, stroke, and glioma). Furthermore, we discuss emerging therapeutic strategies encompassing small molecules, immunomodulatory approaches, and nanotechnology-based interventions, highlighting the ferroptosis-immune axis as a promising therapeutic target for CNS diseases.}, } @article {pmid42148235, year = {2025}, author = {Naserzadeh, E and Olfati, N and Akhlaghi, S and Emadzadeh, M and Rashidnezhad, A and Nafissi, S and Fatehi, F and Sarraf, P and Haghi-Ashtiani, B and Ziaadini, B and Ansari, B and Okhovat, AA and Basiri, K and Boostani, R}, title = {Translation and psychometric validation of the Persian version of amyotrophic lateral sclerosis cognitive behavioral screen (ALS-CBS) and revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R).}, journal = {Current journal of neurology}, volume = {24}, number = {1}, pages = {16-22}, pmid = {42148235}, issn = {2717-011X}, abstract = {Background: The Amyotrophic Lateral Sclerosis Cognitive Behavioral Screen (ALS-CBS) and the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) are widely recognized tools for evaluating cognitive, behavioral, and functional changes in patients with amyotrophic lateral sclerosis (ALS). Given the increasing number of ALS cases in Persian-speaking communities, there is a critical need for culturally and linguistically adapted versions of these instruments. The objective of this study was to translate the ALS-CBS and ALSFRS-R into Persian and evaluate their validity and reliability to ensure their applicability in clinical practice and research. Methods: The Persian versions of the ALS-CBS and ALSFRS-R questionnaires were developed using the translation-back translation method. The translated questionnaires were administered to 36 individuals diagnosed with ALS. To assess content validity, neuromuscular specialists evaluated each item based on relevance, clarity, simplicity, necessity, and comprehensiveness, using content validity ratio (CVR) and content validity index (CVI) measures. Internal consistency reliability was assessed using Cronbach's alpha coefficient. Test-retest reliability was evaluated using the intra-class correlation coefficient (ICC). Statistical analysis was conducted using SPSS software. Results: All questionnaire items demonstrated satisfactory face validity after expert-guided revisions. The minimum acceptable values for CVI (≥ 0.78) and CVR (≥ 0.62) were achieved by correcting items that initially scored below the threshold. Reliability analysis revealed ICC values of 0.969 and 0.816 for the cognitive and behavioral sections of the ALS-CBS, respectively, and 0.909 for the ALSFRS-R. Cronbach's alpha coefficients were 0.791 for the ALS-CBS behavioral section and 0.825 for the ALSFRS-R, indicating acceptable internal consistency. Conclusion: The Persian versions of the ALS-CBS and ALSFRS-R have been shown to be both valid and reliable. These adapted tools provide valuable resources for assessing the cognitive, behavioral, and functional status of patients with ALS in Persian-speaking populations, ultimately supporting more accurate diagnosis, monitoring, and disease management.}, } @article {pmid42148602, year = {2026}, author = {Du, W and Wu, T and Fan, Y and Zhao, M}, title = {When copper turns killer: Decoding copper dyshomeostasis and cuproptosis in neurodegenerative pathogenesis and precision metal interventions.}, journal = {Neural regeneration research}, volume = {21}, number = {9}, pages = {3964-3976}, pmid = {42148602}, issn = {1673-5374}, abstract = {Copper is an essential cofactor for neuronal metabolism, enzymatic functions, and neurotransmission. However, copper dyshomeostasis-induced redox activity makes the brain vulnerable to oxidative and proteostatic stress. Cuproptosis, a recently characterized form of programmed cell death, is triggered by copper binding to lipoylated enzymes of the tricarboxylic acid cycle, resulting in proteotoxic stress, mitochondrial dysfunction, and cell death. Given that mitochondria are central to copper handling and the primary site of cuproptosis, we examine mitochondrial pathways and key cuproptosis-related genes. We also assess disease-specific signatures of copper imbalance. In Alzheimer's disease, excess copper binds to amyloid-β, promoting aggregation and neurotoxicity. In Parkinson's disease, copper-bound α-synuclein fosters aggregation, while copper-driven redox cycling elevates reactive oxygen species. Cuproptosis worsens mitochondrial vulnerability in Parkinson's disease and impairs cellular stress responses in Huntington's disease. In amyotrophic lateral sclerosis, superoxide dismutase 1-related defects compromise antioxidant defenses alongside copper-dependent mitochondrial dysfunction. In prion diseases, copper facilitates prion protein misfolding and toxicity. Across these disorders, common features include mitochondrial dysfunction and cuproptosis hallmarks-such as enhanced protein lipoylation, elevated reactive oxygen species, impaired electron transport chain activity, fragile Fe-S clusters, and increased reliance on the tricarboxylic acid cycle-which collectively increase neuronal susceptibility to copper dyshomeostasis. Clarifying and understanding the critical roles of copper metabolism not only elucidates the pathogenesis of neurodegenerative diseases but also offers alternative therapeutic strategies. This review uniquely integrates the mitochondria-centered cuproptosis axis with copper dyshomeostasis across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases, mapping convergent vulnerabilities to mechanism-grounded interventions and outlining testable translational routes.}, } @article {pmid42149283, year = {2026}, author = {Dey, A and Baumeister, TR and Evans, KC and Koppelmans, V and Luk, C and McLaren, DG and Parnianpour, P and Seres, P and , and Kalra, S}, title = {Correction: Data-driven disease subgrouping in ALS: a multicenter cerebral functional connectivity study.}, journal = {Journal of neurology}, volume = {273}, number = {6}, pages = {}, doi = {10.1007/s00415-026-13768-3}, pmid = {42149283}, issn = {1432-1459}, } @article {pmid42149299, year = {2026}, author = {Morimoto, S and Takahashi, S and Okano, H}, title = {Human iPSC‑based translational and reverse translational research for neurodegenerative diseases: emphasis on ALS and key advances.}, journal = {Japanese journal of radiology}, volume = {44}, number = {9}, pages = {1576-1587}, pmid = {42149299}, issn = {1867-108X}, support = {JP21H05278, JP22K15736, JP25H00007//Japan Society for the Promotion of Science/ ; JP26K10434//Japan Society for the Promotion of Science/ ; JP26H02431//Japan Society for the Promotion of Science/ ; JP23bm1123046, JP23kk0305024, JP25ek0109811//Japan Agency for Medical Research and Development/ ; JP21wm0425009, JP22bm0804003, JP22ek0109616, JP23bm1423002, JP25wm0625519//Japan Agency for Medical Research and Development/ ; UBE Academic Foundation//UBE Academic Foundation/ ; the Kato Memorial Trust for Nambyo Research//the Kato Memorial Trust for Nambyo Research/ ; 2024A04//Japan Intractable Diseases Research Foundation/ ; Inamori Foundation//Inamori Foundation/ ; Kanagawa Institute of Industrial Science and Technology (KISTEC)e and Technology//Kanagawa Institute of Industrial Science and Technology (KISTEC)e and Technology/ ; Ono Medical Research Foundation//Ono Medical Research Foundation/ ; Nakatomi Foundation//Nakatomi Foundation/ ; }, mesh = {Humans ; *Induced Pluripotent Stem Cells ; *Translational Research, Biomedical/methods ; *Neurodegenerative Diseases/therapy ; *Amyotrophic Lateral Sclerosis/therapy ; }, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) cause progressive loss of specific neuronal populations and currently lack curative therapies. Animal models and immortalized cell lines incompletely recapitulate human pathology and genetic heterogeneity, limiting drug discovery. Human induced pluripotent stem cells (iPSCs) provide a patient‑specific platform for disease modelling, drug screening and studying individual responses. Translational research (TR) uses iPSC models to identify candidate therapies that are subsequently tested in clinical trials, while reverse translational research (rTR) feeds clinical observations back to the bench by analyzing iPSCs derived from trial participants and integrating molecular data with patient phenotypes. This review summarizes recent advances in iPSC‑based TR and rTR for ALS and extends the discussion to other neurodegenerative diseases. Key clinical trials launched from iPSC screens-ropinirole, retigabine and bosutinib-are reviewed alongside emerging rTR efforts that use patient‑derived iPSCs to identify biomarkers and therapeutic mechanisms. We also survey iPSC models for AD, PD and HD, highlighting applications of three‑dimensional (3D) brain organoids and gene‑editing technologies. Finally, we discuss future directions for precision medicine, multimodal integration and technological challenges, with particular attention to how imaging biomarkers may complement iPSC-based TR/rTR frameworks in neurodegenerative diseases.}, } @article {pmid42151714, year = {2026}, author = {Zwicker, J and Smith, IC and Bush, SH and Rice, J and Murphy, R and Breiner, A and Buenger, U and Zehrt, B and Warman-Chardon, J and Watt, CL}, title = {Lessons Learned From a Feasibility Study of Longitudinal Palliative Care for Patients With Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {74}, number = {1}, pages = {225-232}, doi = {10.1002/mus.70283}, pmid = {42151714}, issn = {1097-4598}, support = {//ALS Society of Canada/ ; //Eric Poulin Centre for Neuromuscular Disease/ ; //University of Ottawa/ ; INS-464765/CAPMC/CIHR/Canada ; 932196//Muscular Dystrophy Canada/ ; INS-464765/CAPMC/CIHR/Canada ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Palliative Care/methods ; Female ; Male ; Middle Aged ; Aged ; Feasibility Studies ; Longitudinal Studies ; Referral and Consultation ; }, abstract = {INTRODUCTION/AIMS: The benefits of initial palliative care (PC) consultation for patients with amyotrophic lateral sclerosis (ALS) have been previously described. The aim of this study was to explore the evolution of PC needs of patients with ALS over time through analysis of PC follow-up visits.

METHODS: Patients followed at a multidisciplinary ALS clinic received PC consultations and follow-ups between October 2020 and April 2022. All patients who received at least one PC follow-up visit were included in this study. Physician documentation of the visits was analyzed for sub-themes and topics. Topics discussed during visits and visit frequency were examined in the context of patient variables.

RESULTS: The 26 patients had at least one PC follow-up visit (range 1-12 visits). Topics of discussion varied by individual rather than disease status and were often discussed repeatedly. Compared to initial consultations, follow-up visits featured more frequent discussion of sialorrhea and less frequent discussion of constipation, pain, and prognosis (all p < 0.05). Care coordination was discussed in 82% of follow-ups. Time between follow-up visits shortened as the disease progressed. Medical assistance in dying (MAID) was discussed by 31% of patients either at initial consultation or follow-up.

DISCUSSION: Each individual with ALS has unique PC needs. PC specialist resource planning should anticipate higher frequency visits for patients later in the disease course. Given the importance of care coordination and the scarcity of PC specialists, we recommend further study of effective models of care coordination. We recommend that PC specialists be comfortable counseling patients on MAID.}, } @article {pmid42151746, year = {2026}, author = {Best, JD and Landera, MA and Ma, R and Perry, BJ}, title = {Perceptions of Speech-Language Pathology Care in Amyotrophic Lateral Sclerosis: A Patient-Centered Exploratory Study.}, journal = {Muscle & nerve}, volume = {74}, number = {1}, pages = {216-224}, doi = {10.1002/mus.70286}, pmid = {42151746}, issn = {1097-4598}, support = {K23NS123369/NH/NIH HHS/United States ; //MGH Institute of Health Professions/ ; K23NS123369/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology/complications ; *Speech-Language Pathology ; Cross-Sectional Studies ; Female ; Male ; Middle Aged ; Aged ; *Patient Satisfaction ; Surveys and Questionnaires ; Adult ; Patient-Centered Care ; Caregivers ; Perception ; }, abstract = {INTRODUCTION/AIMS: Given limited research on patient perspectives of speech-language pathology (SLP) services in ALS care, this study aimed to assess the satisfaction with, and understanding of, SLP services by people with ALS (pwALS) and to examine the alignment between services received and patient-reported impairments.

METHODS: A cross-sectional survey assessing pwALS' perceptions of SLPs was distributed from October 2024 to January 2025 through electronic mailing lists of relevant professional organizations. A questionnaire examined pwALS' understanding of the SLP role, satisfaction levels, alignment between patient-reported impairments and SLP interventions, and perceived gaps in care. Responses were analyzed using descriptive statistics, with open-ended items analyzed using qualitative analysis.

RESULTS: The 81 survey respondents consisted of pwALS (81.5%), caregivers (11.1%), family members (4.9%), and others (2.5%). Overall satisfaction with SLP care was high, though open-ended responses revealed gaps in understanding. Many were unaware of the full scope of SLP services; only 17.3% recognized cognitive evaluation and 8.6% cognitive therapy, compared with speech (77.8%) and swallowing (81.5%) evaluations. Reported services often did not align with communication and swallowing needs, but patients educated about a service were significantly more likely to use it.

DISCUSSION: Overall satisfaction with SLP care was high; however, open-ended responses revealed gaps in understanding, unmet needs, and limited awareness of the full scope of SLP services. This misalignment highlights the need for improved patient and caregiver education regarding the role and timing of SLP involvement to enhance engagement, appropriate service use, and outcomes in ALS care.}, } @article {pmid42152795, year = {2026}, author = {Hu, N and Qi, M and Su, N and Zhang, D and Zhang, J and Xu, Y and Wang, K and Xu, Y and Li, Z and Hu, B and Wang, L and Wu, B and Chu, L and Wang, Y and Jiang, H and Lu, Z and Wu, J and Fan, X and Han, F and Tian, F and Yuan, J and Liu, M and Zhu, Y}, title = {Quantitative Gait Analysis Reveals Distinct Patterns Associated With Pyramidal Involvement in Amyotrophic Lateral Sclerosis: A Cross-Sectional Study.}, journal = {Brain and behavior}, volume = {16}, number = {5}, pages = {e71498}, pmid = {42152795}, issn = {2162-3279}, support = {//National Science and Technology Major Project/ ; CIFMS 2021-I2M-1-003//CAMS Innovation Fund for Medical Sciences/ ; //Ministry of Industry and Information Technology of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Female ; Cross-Sectional Studies ; Male ; Middle Aged ; *Gait Analysis/methods ; Aged ; Motor Neurons/physiology ; Severity of Illness Index ; Adult ; *Gait Disorders, Neurologic/physiopathology/etiology ; }, abstract = {OBJECTIVE: To dissect specific gait abnormalities associated with upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis (ALS) by controlling for overall disease severity and to develop a multivariate classification model.

METHODS: We performed 3D gait analysis on 118 ALS patients and 1796 healthy controls (HC). ALS patients were categorized into those with ALS with UMN dysfunction((ALS-UMN), n = 70) and those without ALS without UMN signs ((ALS-Numn), n = 48) lower limb UMN signs based on neurological examination. Gait parameters were compared, and their association with UMN involvement was analyzed using partial correlation (controlling for ALSFRS-R score) and machine learning models (Random Forest and Least Absolute Shrinkage and Selection Operator (Lasso) regression).

RESULTS: Compared with HC, ALS patients exhibited widespread gait deterioration (e.g., reduced speed, increased step width, p < 0.001). After controlling for ALSFRS-R, specific parameters, including reduced stride, increased step width, prolonged double support, and elevated gait cycle time asymmetry, remained independently associated with UMN severity (PENN score, p < 0.01). A multivariate model incorporating key features demonstrated fair discriminative ability for identifying ALS-UMN patients, with an area under the curve (AUC) of 0.690, a sensitivity of 0.816, and a specificity of 0.418.

CONCLUSION: Quantitative gait analysis reveals a distinct spatiotemporal pattern linked to UMN dysfunction in ALS. A model based on gait features shows potential, particularly high sensitivity, for identifying patients with pyramidal signs, supporting the exploratory utility of objective gait metrics for motor phenotyping in ALS, pending external validation.}, } @article {pmid42152867, year = {2026}, author = {Cho, Y and Won, SY and Kim, H and Lee, HK and Cho, SR}, title = {The effects of a mobile healthcare application on speech and swallowing in amyotrophic lateral sclerosis.}, journal = {Digital health}, volume = {12}, number = {}, pages = {20552076261452405}, pmid = {42152867}, issn = {2055-2076}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) impairs oral motor function, negatively affecting patients' speech and swallowing abilities, as well as quality of life.

OBJECTIVE: This study aims to evaluate the effectiveness of A Successful Swallowing with Effortful Training (ASSET) program, included in the 'The 365 Healthy Swallow Health Coach application' in preserving speech and swallowing abilities in ALS patients through self-training.

METHODS: In this 8-week quasi-experimental study, 13 participants were allocated to either the app-guided ASSET training group (n=7; three sessions per day, five days per week) or a usual-care control group (n=6) based on their clinical visit schedules. To evaluate changes over time and compare the two groups, linear mixed models were employed. Changes in ALS severity scale (ALSSS), Diadochokinetic (DDK) task, speech intensity, Speech Handicap Index-15, Dysphagia Handicap Index, Swallowing Quality of Life (SWAL-QOL), and Brief Inventory of Swallowing Assessment-15 were assessed.

RESULTS: ALSSS speech scores was relatively preserved from 5.43 (95% CI 3.01-7.84) to 5.29 (95% CI 2.87-7.70) in the ASSET treatment group, but declined from 6.33 (95% CI 3.73-8.94) to 4.83 (95% CI 2.23-7.44) in the control group, with a significant group-by-time interaction (p=.017). DDK/tuh/and/kuh/were relatively preserved from 11.86 to 11.71 and from 12.29 to 11.57 respectively in ASSET group, but declined from 11.67 to 7.50 and from 11.83 to 7.17 in the control group, with significant interactions in/tuh/(p=.032) and/kuh/(p=.044). SWAL-QOL total score was relatively preserved from 155.86 to 149.71 in ASSET group, but declined from 154.67 to 125.17 in the control group, with a significant interaction (p=.011).

CONCLUSIONS: The findings suggest that ASSET program may help preserve speech and swallowing function in patients with ALS. Future research should validate the ASSET program with a larger, adequately powered sample size.}, } @article {pmid42153537, year = {2026}, author = {Shi, J and Wu, Y and Liu, X and Xia, W and Wu, J and Lou, J and Zhang, X and Zhang, J and Yang, N and Chi, W and Xiang, L and Zhang, Y and Shu, Y and Miao, R and Zhao, J and Zhu, X and Qi, J and Xiao, J and Zhou, K}, title = {MOTS-c, a mitochondrial-derived peptide, ameliorates lysosomal membrane permeability and improves survival of soft tissue transplantation.}, journal = {Autophagy}, volume = {22}, number = {10}, pages = {2695-2724}, doi = {10.1080/15548627.2026.2677180}, pmid = {42153537}, issn = {1554-8635}, mesh = {*Lysosomes/metabolism/drug effects ; Animals ; Humans ; Autophagy/drug effects ; *Intracellular Membranes/metabolism/drug effects ; *Mitochondrial Proteins/pharmacology ; Mitochondria/metabolism ; Permeability/drug effects ; Mice ; Ischemia/pathology ; Mice, Inbred C57BL ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Male ; }, abstract = {Distal ischemic necrosis remains a major challenge in reconstructive surgery. Mitochondria and lysosomes interact via signaling and membrane contacts to maintain cellular homeostasis. Mitochondrial-derived peptide MOTS-c, encoded by the MT-RNR1/12S rRNA open reading frame, enhances mitochondrial function by reducing reactive oxygen species (ROS) and stabilizing the membrane potential, potentially preserving lysosomal integrity and reducing lysosomal membrane permeabilization (LMP). This study investigated the protective effects and underlying mechanisms of MOTS-c in ischemic flaps. RNA sequencing explored MOTS-c mechanisms in ischemic flaps. Tissue clearing, laser speckle contrast imaging and Doppler analyses revealed improved blood flow perfusion following MOTS-c treatment. Histological staining (HE, Masson, F-CHP) demonstrated enhanced angiogenesis and collagen remodeling. Western blotting, ELISA, and immunofluorescence were used to assess pyroptosis, macroautophagy/autophagy, LMP, and MAPK1/ERK2-MAPK3/ERK1-NFKB/NF-κB pathway-related proteins. MOTS-c reduced endothelial pyroptosis, enhanced autophagy, and attenuated LMP in ischemic flaps. Mechanistically, in vivo overexpression of PLA2G4A/cPLA2 (phospholipase A2, group IVA (calcium, calcium dependent)) via AAV confirmed that MOTS-c enhances autophagy and reduces pyroptosis and LMP by suppressing PLA2G4A phosphorylation. Furthermore, MOTS-c inhibited PLA2G4A via the MAPK1-MAPK3-NFKB signaling cascade, thereby reducing LMP and enhancing flap survival. These findings suggest that MOTS-c restores cellular homeostasis by targeting the PLA2G4A-LMP axis, representing a promising therapeutic strategy for improving outcomes in ischemic flap surgery.Abbreviations: AA = arachidonic acid, AAV = adeno-associated virus, ACTA2/α-SMA = actin alpha 2, smooth muscle, aorta, ALs = autolysosomes, BECN1 = beclin 1, CASP1 = caspase 1, CQ = chloroquine, CTSB = cathepsin B, CTSD = cathepsin D, CTSL = cathepsin L, Co-IP = co-immunoprecipitation, DEGs = differentially expressed genes, ELISA = enzyme-linked immunosorbent assay, F-CHP = 5-FAM-conjugated collagen hybridizing peptide staining, GSDMD = gasdermin D, GO = gene Ontology, GPT/ALT = glutamic pyruvic transaminase, soluble, GOT1/AST = glutamic-oxaloacetic transaminase 1, soluble, HE = hematoxylin-eosin, HUVECs = human umbilical vein endothelial cells, IP/MS = immunoprecipitation coupled with mass spectrometry, IL1B/IL-1β = interleukin 1 beta, IL18 = interleukin 18, IP = intraperitoneal injection, IV = intravenous injection, LDBF = laser Doppler blood flow, LMP = lysosomal membrane permeability, MAP1LC3/LC3 = microtubule-associated protein 1 light chain 3, MAPK = mitogen-activated protein kinase, NAGLU = alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB), NFKB/NF-κB = nuclear factor kappa B, NLRP1 = NLR family pyrin domain containing 1, NLRP3 = NLR family pyrin domain containing 3, PECAM1/CD31 = platelet/endothelial cell adhesion molecule 1, PLA2G4A/cPLA2 = phospholipase A2, group IVA (cytosolic, calcium-dependent), PYCARD/ASC = PYD and CARD domain containing, PIK3C3/VPS34 = phosphatidylinositol 3-kinase catalytic subunit type 3, PMA = phorbol 12-myristate 13-acetate, ROS = reactive oxygen speciesSQSTM1/p62 = sequestosome 1, SPR = surface plasmon resonance, scRNA-seq = single-cell RNA sequencing, UMAP = uniform manifold approximation and projection, WB = western blotting.}, } @article {pmid42155171, year = {2026}, author = {Czuba, M and Szafrańska, K and Kolaczkowski, M and Marcinkowska, M}, title = {Targeting lysosomal dysfunction with small-molecule TRPML1 ligands: Therapeutic opportunities in lysosomal storage disorders, neurodegeneration and beyond.}, journal = {European journal of medicinal chemistry}, volume = {315}, number = {}, pages = {118951}, doi = {10.1016/j.ejmech.2026.118951}, pmid = {42155171}, issn = {1768-3254}, mesh = {Humans ; *Transient Receptor Potential Channels/metabolism/antagonists & inhibitors/agonists ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Lysosomal Storage Diseases/drug therapy/metabolism ; *Small Molecule Libraries/pharmacology/chemistry ; Ligands ; *Lysosomes/drug effects/metabolism ; Animals ; Molecular Structure ; }, abstract = {TRPML1, a lysosomal Ca[2+] channel, has emerged as a clinically relevant target due to its genetic and mechanistic links to lysosomal storage disorders and neurodegenerative diseases, including Gaucher disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This evidence has prompted TRPML1 drug discovery efforts across academia and industry, with several small-molecule agonists advancing toward clinical development. In this review, we provide a comprehensive overview of the therapeutic potential of TRPML1 as a molecular target from a medicinal chemistry perspective. We summarize the structural basis of channel activation and inhibition, highlighting insights from recent cryo-EM studies that define the principal ligand-binding sites and mechanisms of allosteric modulation. We systematically survey the chemical space of TRPML1 ligands reported to date, including diverse agonist and antagonist chemotypes, and extend this analysis to encompass undisclosed or recently disclosed compounds emerging from industry pipelines. Furthermore, we discuss key determinants of ligand design and developability, including the challenges associated with targeting a deeply embedded, lipophilic binding pocket within the membrane. Overall, the available evidence positions TRPML1 as a promising target for small-molecule drug discovery and provides a framework for the rational design of next-generation lysosome-directed therapeutics.}, } @article {pmid42155219, year = {2026}, author = {He, L and Zhu, Z and Liu, W and Lan, J and Lin, S and Shang, J}, title = {A Y-γ segmented linear framework for non-equilibrium UV-Vis titration: stage-resolved exploratory analysis of a chemically evolving EGCG-iron system.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {361}, number = {}, pages = {128073}, doi = {10.1016/j.saa.2026.128073}, pmid = {42155219}, issn = {1873-3557}, abstract = {Non-equilibrium UV-Vis titration data are difficult to interpret when multiple processes overlap and strict equilibrium assumptions no longer hold. We propose a non-equilibrium titration framework that transforms UV-Vis matrices into reaction-progress space using a dimensionless γ and a volume-corrected absorbance Y. Under mass and proton-balance constraints, locally single-process intervals obey Yλ = aλ + bλγ; segmented linear regression then yields wavelength-dependent slope fingerprints (bλ) that delineate coordination stages. In the EGCG-iron system, the Y-γ analysis resolves a progression from low-coordination mononuclear species to higher-coordination complexes, multinuclear/bridged units, and iron-rich aggregates across metal-to-ligand ratios and pH. Single-wavelength initial-rate measurements and solid-state characterization support rapid deprotonation-coordination coupling and the formation of cross-linked multinuclear networks at high γ. To benchmark soft-modeling, we performed MCR-ALS decompositions under weak constraints (post-normalized closure) and strong constraints (iterative simplex projection plus monotonic decay-to-zero of the initial dominant component). Both fits achieve similar residual levels, yet the recovered spectra/concentration profiles differ, evidencing rotational ambiguity and emphasizing the dependence of chemometric solutions on constraint choice. In contrast, the Y-γ segmented linear model relies on explicit stoichiometric/proton-balance transformations, providing robust stage boundaries and compact spectral descriptors while remaining computationally simple. This combined hard/soft analysis offers a practical route to mechanistic interpretation of complex titration spectra and motivates future integration of Y-γ descriptors with advanced chemometrics and hybrid hard-soft modeling.}, } @article {pmid42155417, year = {2026}, author = {Simpson, J and Zarotti, N}, title = {Distress, not symptoms: Reframing psychological difficulties in neurodegenerative diseases of the motor system.}, journal = {Cortex; a journal devoted to the study of the nervous system and behavior}, volume = {200}, number = {}, pages = {262-271}, doi = {10.1016/j.cortex.2026.05.004}, pmid = {42155417}, issn = {1973-8102}, mesh = {Humans ; *Neurodegenerative Diseases/psychology ; *Psychological Distress ; *Stress, Psychological/psychology ; *Motor Neuron Disease/psychology ; Huntington Disease/psychology ; Parkinson Disease/psychology ; Anxiety/psychology ; }, abstract = {Psychological distress is common among people living with neurodegenerative diseases of the motor system (NDMS) such as Parkinson's disease, motor neurone disease/amyotrophic lateral sclerosis, and Huntington's disease. Yet the way psychological difficulties are conceptualised in these populations is heavily shaped by medicalised language. Terms such as 'non-motor symptoms' and 'neuropsychiatric manifestations' were originally introduced to draw attention to difficulties beyond movement changes but they now risk positioning mood, anxiety, apathy, and related experiences solely as direct manifestations of neurological degeneration. This framing can obscure the rich psychosocial contexts in which distress arises, blur distinctions between emotional responses and disease processes, and reinforce deficit-based and disease-focused understandings that privilege biological explanations over person-centred ones. It may also influence clinical communication, treatment decisions, help-seeking behaviour, and access to psychological therapy and psychosocial interventions, contributing to inequities in care. This article argues that linguistic choices are not neutral: they construct the boundaries of what counts as legitimate knowledge, shape expectations about causality, and delimit the interventions considered appropriate. Without critical attention to these assumptions, individuals may experience distress as biologically inevitable and clinicians may overlook psychosocial contributors that are amenable to change. We propose that greater awareness of the power of language, coupled with empirical investigation into its effects, is essential for developing a linguistic reformulation of psychological distress in NDMS and more holistic, contextually grounded approaches to supporting psychological wellbeing.}, } @article {pmid42156174, year = {2026}, author = {Su, X and Tan, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Wang, S and Wang, J and Feng, H}, title = {COMMD1 Induces Copper Deficiency of SOD1 by Inhibiting the Palmitoylation of CCS in ALS.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {46}, number = {24}, pages = {}, pmid = {42156174}, issn = {1529-2401}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; *Superoxide Dismutase-1/metabolism/genetics ; Mice ; *Lipoylation/physiology ; Male ; *Copper/deficiency/metabolism ; *Adaptor Proteins, Signal Transducing/genetics/metabolism ; Mice, Transgenic ; *Molecular Chaperones/metabolism ; }, abstract = {Mutations in superoxide dismutase 1 (SOD1) compromise its metal-binding capacity, resulting in protein misfolding and aggregation, which ultimately induces cellular apoptosis in amyotrophic lateral sclerosis (ALS). Copper metabolism domain containing 1 (COMMD1), a gene implicated in copper homeostasis, has not been thoroughly characterized in the context of ALS pathogenesis. In this study, we identified elevated COMMD1 expression in ALS, potentially contributing to diminished copper incorporation into SOD1. Knockdown of COMMD1 enhanced palmitoylation of the copper chaperone for SOD1 (CCS), facilitating its membrane translocation and promoting copper loading into SOD1, thereby conferring neuroprotection in ALS. Mechanistically, we established that COMMD1 knockdown augments CCS palmitoylation via activation of the hypoxia-inducible factor 1 subunit alpha (HIF-1α)/fatty acid synthase (FASN) signaling axis. In vivo investigations utilizing male hSOD1[G93A] transgenic mice demonstrated that COMMD1 deficiency markedly ameliorated the deterioration of motor function and prolonged survival duration. These findings collectively suggest that COMMD1 represents a potential therapeutic target for ALS intervention.}, } @article {pmid42156213, year = {2026}, author = {Nalepa, M and Skweres, A and Węgrzynowicz, M}, title = {Dysregulation of arginase and arginine pathways in neurodegenerative diseases: Metabolic and cellular dysfunction and therapeutic implications.}, journal = {Free radical biology & medicine}, volume = {252}, number = {}, pages = {559-579}, doi = {10.1016/j.freeradbiomed.2026.05.285}, pmid = {42156213}, issn = {1873-4596}, mesh = {Humans ; *Arginase/metabolism/genetics ; *Arginine/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; Animals ; Metabolic Networks and Pathways ; Oxidative Stress ; Neurons/pathology/metabolism ; Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; }, abstract = {Neurodegenerative diseases are increasingly recognized as disorders associated with metabolic dysfunction with arginine metabolism emerging as a significant contributor. Arginase, by regulating the balance between arginine and ornithine, is positioned at the crossroads of multiple arginine metabolic pathways, thereby controlling a variety of cellular processes essential for proper brain homeostasis. Chronic disruption of these pathways may lead to dysfunction of neurons and glia ultimately resulting in the induction of neurodegenerative processes. In this review, based on data from patients and experimental models, we synthesize and critically evaluate evidence demonstrating alterations in arginase isoenzymes and associated metabolic pathways in Alzheimer's Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis. We discuss mechanisms through which dysregulation of arginase and arginine metabolism may contribute to neurodegeneration, including disturbances in nitrogen metabolism, oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Based on this body of evidence, we propose therapeutic strategies targeting arginase-related pathways, with the aim of preserving cellular metabolic homeostasis to ameliorate disease progression. Finally, we outline directions for future research, emphasizing that a proper understanding of the physiological roles of arginase isoenzymes and their disease-, stage-, and cell-specific dysregulation will be essential for the development of effective metabolically targeted therapies against neurodegenerative diseases.}, } @article {pmid42156505, year = {2026}, author = {Kerins, C and Lieberam, I and Gentleman, E}, title = {ALS mutations do not alter perineuronal net formation in human stem cell-derived motor neurons.}, journal = {Communications biology}, volume = {9}, number = {1}, pages = {}, pmid = {42156505}, issn = {2399-3642}, support = {/WT_/Wellcome Trust/United Kingdom ; 218452/Z/19/Z//Wellcome Trust (Wellcome)/ ; MR/N025865/1//RCUK | Medical Research Council (MRC)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Motor Neurons/metabolism/pathology ; *Mutation ; *Perineuronal Nets ; Astrocytes/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Coculture Techniques ; }, abstract = {Perineuronal nets (PNNs) are extracellular matrix structures that stabilise synaptic inputs and play a role in regulating neuronal plasticity. Although PNN dysregulation is observed in several neurological disorders, their relevance to amyotrophic lateral sclerosis (ALS) remains unclear. In particular, the extent to which PNN alterations reported in ALS animal models are motor neuron (MN)-intrinsic is unknown. We investigated whether human pluripotent stem cell-derived MNs form PNN-like structures in vitro, and whether ALS-associated mutations alter this process. We show that PNN-like structures containing hyaluronan, tenascin-R, and aggrecan form in in vitro co-cultures of iPSC-derived MNs and astrocytes, and that their formation and gene expression were not altered by ALS mutations. To explore whether PNN dysregulation reflects contributions from other cell types or selective MN vulnerability, we conducted meta-analyses of transcriptomic datasets from pluripotent stem cell-derived astrocytes carrying ALS-associated mutations, as well as datasets comparing MN populations with differential susceptibility to ALS. These analyses revealed no consistent differences in PNN-related gene expression within human stem cell-derived MNs. In contrast, transcriptomic analyses of human post-mortem ALS tissues revealed dysregulation of PNN-related genes, including core PNN components. Taken together, these findings indicate that PNN-related alterations described in ALS animal models are not reproduced by ALS-associated mutations in MNs alone, and instead point to a role for additional cellular components within the central nervous system.}, } @article {pmid42156779, year = {2026}, author = {Shaw, TB and Al Najjar, A and Barth, M and Bollmann, S and Bourgeat, P and Chang, J and Dempsey-Jones, H and Fazlollahi, A and Fripp, J and Garden, N and Guo, CC and Henderson, RD and Kuan, E and Lv, J and McCombe, PA and Narayanan, A and Ngo, ST and Nguyen, V and O'Brien, K and Robinson, G and Robinson, S and Salvado, O and Stewart, A and Steyn, FJ and Bollmann, S}, title = {Multimodal ultra-high-field MRI, clinical, cognitive, and genetic profiles across the ALS-FTD spectrum.}, journal = {Scientific data}, volume = {13}, number = {1}, pages = {}, pmid = {42156779}, issn = {2052-4463}, support = {PDF2112//Motor Neurone Disease Research Australia/ ; TU2201//Motor Neurone Disease Research Australia/ ; APP2029871//National Health and Medical Research Council/ ; Boosting Dementia Research Leadership Fellowship (APP1135769)//National Health and Medical Research Council/ ; ECR-202503-01848//FightMND/ ; Mid-Career Research Fellowship//FightMND/ ; APP 1088419, DP250103627//National Health and Medical Research Council, Australia/ ; FT140100865, IC170100035, DP200103386, DP250103627//Australian Research Council/ ; DP250103627//Australian Research Council/ ; DP240102161//Australian Research Council/ ; Linkage Grant LP200301393//Australian Research Council, Australia/ ; RTP//University of Queensland Graduate School/ ; Research Development Grant//Brain and Mind Centre, University of Sydney/ ; Fudan Brain and Intelligence Science Alliance Flagship Research Program, Moyira Elizabeth Vine Fund for Research into Schizophrenia Program//University of Sydney/ ; 10.55776/PAT3786024//Austrian Science Fund/ ; 794298//Marie Sklodowska-Curie Actions, European Union/ ; }, mesh = {Humans ; *Magnetic Resonance Imaging ; *Frontotemporal Dementia/genetics/diagnostic imaging/physiopathology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; Cognition ; }, abstract = {This dataset was acquired and curated to explore the spectrum of Motor Neuron Disease (MND) and Fronto-Temporal Dementia (FTD) with Ultra-High Field Magnetic Resonance Imaging (7 Tesla) and compare these to non-neurodegenerative disease controls (known colloquially as "The 7 T hEalthy Ageing study [7TEA]"). Twenty people living with neurodegenerative disease and 14 non-neurodegenerative controls underwent a comprehensive multimodal MRI protocol including structural, diffusion, quantitative MRI, resting state, and task fMRI, alongside cognitive testing and genetic screening. This dataset combines detailed imaging phenotypes with extensive clinical characterisations. It facilitates investigations into the spectrum of MND and FTD, has provided a basis for developing novel quantitative biomarkers, and supports the exploration of interactions between imaging features and clinical progression. The availability of this dataset supports various research avenues, from detailed hippocampal subfield analyses, network connectivity assessments, and multimodal genetic, cognitive, and imaging studies. The dataset is published on OpenNeuro (dataset ds007036) and is curated in the Brain Imaging Data Structure (BIDS) standard.}, } @article {pmid42157222, year = {2026}, author = {Bayer, PA and O'Bryan, SJ and Thomas, HJ and Del Vecchio, A and Jain, G and Farina, D and Ferri, A}, title = {The use of high-density surface electromyography in amyotrophic lateral sclerosis: a scoping review.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {23}, number = {1}, pages = {}, pmid = {42157222}, issn = {1743-0003}, support = {GNT2021176//National Health and Medical Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Humans ; *Electromyography/methods ; Motor Neurons/physiology ; Action Potentials/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of motor neurons, resulting in muscle weakness and atrophy. This neuronal loss is partially compensated for by the collateral sprouting of surviving motor neurons, leading to the formation of enlarged motor units (MUs). These MU adaptations, together with hyperexcitability and altered descending messages from the brain, lead to altered characteristics of the MU action potential shape and discharge pattern, that can be captured using high-density surface electromyography (HDsEMG). The aim of this review is to survey all available literature, investigating how HDsEMG has been used in ALS, and highlight differences in methods and outcomes to allow comparison between studies.

METHODS: A systematic literature search was conducted using four databases (PubMed, Scopus, IEEE Xplore, and Academic Search Ultimate) to identify studies employing HDsEMG in individuals diagnosed with ALS. Eligible studies were reviewed to examine experimental protocols, hardware and software configurations and reported outcome measures.

RESULTS: Out of 168 identified articles, 26 were included in this review. High heterogeneity was observed in recording methods, analysis, and reporting strategies. Based on measurable features of MU behaviour and morphology, the outcomes reported in the studies were grouped into five main categories: fasciculations, MU properties, MU discharge characteristics, multiple discharges and number of MUs.

CONCLUSIONS: HDsEMG represents a promising non-invasive technique that allows for repeated, longitudinal measurements as well as the detection of multiple MUs and their individual analysis, the potential of which has not been fully explored. HDsEMG has a strong potential for clinical use in ALS, but its application should first be based on a clear understanding of disease pathophysiology. The findings of this review highlight the urgent need for a consensus on standardised protocols and reporting practices for the application of HDsEMG in ALS research, along with the development of methods that can sensitively indicate disease-specific physiological changes to improve comparability, reproducibility. This understanding will improve how HDsEMG findings are interpreted and support the translation of HDsEMG into a diagnostic tool.}, } @article {pmid42158589, year = {2026}, author = {Tran, CM and Reddy, N and Thomas, JK and Venugopal, V and Bowser, R}, title = {CHI3L1 (YKL-40) and Chit-1 expressing glia in the white matter of ALS, FTLD and AD: correlations to pathology and disease duration.}, journal = {BMJ neurology open}, volume = {8}, number = {1}, pages = {e001225}, pmid = {42158589}, issn = {2632-6140}, abstract = {BACKGROUND: Chitotriosidase (Chit-1) and chitinase-3-like protein 1 (CHI3L1) protein levels are increased in the cerebrospinal fluid (CSF) of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). Few studies have examined the spatial expression of chitinase-expressing cells with respect to neuropathologic hallmarks of disease.

METHODS: RNA sequencing was used to examine Chit-1 and CHI3L1 gene expression in the spinal cord and motor cortex. Immunohistochemistry was used to characterise the distribution of Chit-1 and CHI3L1 expressing cells in ALS, C9-ALS, FTLD, AD and non-neurologic disease controls. Immunofluorescence confocal microscopy was used to correlate distribution of Chit-1 and CHI3L1 expressing cells to TDP-43 pathology.

RESULTS: Chit-1 gene expression was increased in the spinal cord, and CHI3L1 expression was increased in both the spinal cord and motor cortex of patients with sALS and C9-ALS when compared with controls. Highest levels of Chit-1[+] glia were in cortical regions that contain hallmark neuropathology for each neurodegenerative disease. CHI3L1[+] glia were only significantly increased in sALS. Neither Chit-1[+] nor CHI3L1[+] glia was in close proximity to phosphorylated TDP-43 (pTDP) containing neurons in the motor cortex grey matter; however, there was a significant co-localisation of glial pTDP with Chit-1 and CHI3L1 in the motor cortex white matter.

CONCLUSIONS: Chit-1 and CHI3L1 expressing cells were most abundant in the white matter of cortical regions affected by each neurodegenerative disease and the spinal cord. Chit-1 or CHI3L1 expressing cells in the white matter often contained pTDP. We also observed correlations between levels of Chit-1 or CHI3L1 expressing cells in the white matter to disease duration.}, } @article {pmid42159474, year = {2026}, author = {Mueller, A and Vallejo, V and Panadés, MP and Hardiman, O and Danel-Brunaud, V and Ajroud-Driss, S and Couratier, P and Shefner, J and Gokey, A and DiCesare, M and Lennox, E and Praestgaard, J and Brujin, L and Allred, P and Miller, R}, title = {Evaluation of Digital Technologies for Home-Based Assessment in People With Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, pmid = {42159474}, issn = {2328-9503}, support = {//Novartis Pharma AG/ ; }, abstract = {OBJECTIVE: Digital technologies hold promise for transforming healthcare by enhancing personalized treatments and offer valuable opportunities to improve patient care. Here, we evaluated several novel, self-administered, home-based, digital endpoints for their association with corresponding conventional standard clinical measures (primary) in people living with Amyotrophic Lateral Sclerosis (ALS).

METHODS: This was a longitudinal study in people with ALS who were followed up to 9 months. A total of 33 participants were enrolled in the study. At each of six visits, participants were evaluated with a battery of conventional standard measurements to determine ALS disease progression and quality of life. Between visits, participants performed weekly home-based self-assessments with digital health technologies (DHT) and self-administered ALSFRS-R. Cross-sectional analysis of DHTs anchored to ALSFRS-R and longitudinal analyses were performed and compared to standard clinical measures.

RESULTS: Of the 33 participants, 20 completed the study, and 13 discontinued before completing the planned 9-month follow-up mainly due to disease progression. The distribution of various digital metrics in home-based assessments corresponded well with the sub-scores of ALSFRS-R in the cross-sectional analyses, with the strongest construct validity for digital speaking rate. In the longitudinal analysis, a weak but significant trend in most metrics was observed, with the strongest trend in the duration of the Timed Up and Go (high variability between participants).

INTERPRETATION: The findings from this study provide insights into the potential of digital endpoints to evaluate people living with ALS with the goal of reducing the burden of study participation and improving the efficiency of ALS clinical trials.}, } @article {pmid42159475, year = {2026}, author = {Sewak, A and Inácio, V and Wuu, J and Benatar, M and Hothorn, T}, title = {Likelihood-based modeling of covariate-specific time-dependent receiver operating characteristic curves.}, journal = {Statistical methods in medical research}, volume = {35}, number = {6}, pages = {1325-1346}, doi = {10.1177/09622802261445416}, pmid = {42159475}, issn = {1477-0334}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/blood/diagnosis ; Biomarkers/blood ; *ROC Curve ; Prognosis ; Neurofilament Proteins/blood ; Likelihood Functions ; *Models, Statistical ; Time Factors ; }, abstract = {Identifying reliable biomarkers for predicting clinical events in longitudinal studies is important for accurate disease prognosis and for guiding development of new treatments. However, prognostic studies are often observational, making it difficult to account for patient heterogeneity. In amyotrophic lateral sclerosis (ALS), factors such as age, site of onset and genetic status influence both survival and biomarker levels, yet their impact on the prognostic accuracy of biomarkers over time remains unclear. While time-dependent receiver operating characteristic methods have been developed to handle censored time-to-event outcomes, most do not adjust for covariates. To address this, we propose the nonparanormal prognostic biomarker framework, which models the joint distribution of the biomarker and event time while accounting for covariates. This allows estimation of covariate-specific time-dependent receiver operating characteristic curves and related summary measures. We apply the NPB framework to evaluate serum neurofilament light as a prognostic biomarker in ALS, showing that its accuracy varies over time and with patient characteristics. By capturing these covariate-specific effects, the NPB framework supports more targeted risk stratification and can potentially improve the design of clinical trials for new ALS treatments.}, } @article {pmid42160473, year = {2026}, author = {Kim, S and Curtis, SE and Iacono, D and Mehdiyoun, NF and Mitchell, L and Genge, A and Brandt, AU and , and Mancini, M}, title = {Types and frequencies of adverse events across clinical trials for patients with amyotrophic lateral sclerosis: an analysis of the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2026.2667290}, pmid = {42160473}, issn = {2167-9223}, abstract = {OBJECTIVE: Symptoms of amyotrophic lateral sclerosis (ALS) may present as adverse events (AEs) in ALS clinical trials. Identifying anticipated AEs independent of investigational drug is crucial for trial design and required by the FDA for safety reporting and assessment in drug development. This study describes anticipated AEs and their predicted incidence in ALS trials, leveraging data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.

METHODS: Placebo-treated people living with ALS (age ≥18 years, disease duration ≤36 months, ≥50% of predicted vital capacity at screening) were included. A confirmed diagnosis per the El Escorial criteria was required for a sensitivity analysis. Reported AEs were grouped based on pathophysiology and implications in clinical management and safety monitoring. AEs were further consolidated, with seven anticipated groups pre-specified for analysis. AE incidence proportions (IPs) and rates in person-years were estimated.

RESULTS: The analysis included 1,388 participants (mean [SD] age: 56.8 [11.3] years; mean [SD] disease duration: 1.4 [0.6] years). IP was ≥5% for 24 AE groups, highest for falls and injuries (18.8%), headaches (13.5%), muscle weakness (13.1%), and gastrointestinal signs and symptoms (13.1%). Of seven pre-specified AE groups, falls, injuries, and fractures were the most frequent (23.0%), followed by severe respiratory failure and disorders including dyspnea (19.1%) and dysphagia (10.5%). Sensitivity analysis results were comparable (n = 931), although IPs were generally lower.

CONCLUSIONS: These new findings will facilitate a systematic approach for safety monitoring and reporting in ALS trials, enable detection of true safety signals that may be obscured by these events, and support clinical development.}, } @article {pmid42160478, year = {2026}, author = {Cosijn, FS and van Unnik, JWJ and Exalto, LG and de Groot, LN and Weemering, DN and van Rijssen, RC and Vink, RG and van den Berg, LH and van Eijk, RPA}, title = {Clinical drug development in amyotrophic lateral sclerosis: industry-reported challenges and opportunities.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2671167}, pmid = {42160478}, issn = {2167-9223}, abstract = {OBJECTIVE: The pharmaceutical industry plays a pivotal role in amyotrophic lateral sclerosis (ALS) drug development, yet the challenges and priorities remain largely unexplored. This study aims to identify industry-perceived opportunities for ALS and examine industry perspectives on trial design.

METHODS: A survey study was conducted among pharmaceutical companies involved in ALS drug development. The survey was based on literature review and interviews with industry experts. Final survey topics included scientific and operational challenges as well as preferred design settings for phase 2 and 3 clinical trials. Respondents were asked to rank trial-related topics using Likert scales.

RESULTS: In total, 53 industry professionals responded, representing 42 international companies. Respondents identified three major scientific challenges: heterogeneity in disease progression, lack of reliable biomarkers, and insensitive efficacy measures. Insufficient funding, high dropout rates, and staffing shortages emerged as main operational barriers. For phase 2 trials, neurofilament light chain was most often prioritized as primary outcome, whereas the ALS Functional Rating Scale-Revised was prioritized for phase 3, although priority rankings varied considerably among respondents. Expected median sample sizes were 100 patients (range 20-300) for phase 2 and 300 patients (range 60-800) for phase 3. Overall, 58% of the respondents indicated that standardizing aspects of trial design could enhance trial quality and success rates.

CONCLUSIONS: This study provides an overview of the industry-perceived challenges, exposing strategic knowledge gaps related to disease and clinical heterogeneity. Standardization of key trial design elements may help mitigate these challenges and better align ALS drug development efforts.}, } @article {pmid42160479, year = {2026}, author = {Catley, CS and Hoedt, EC and Pockney, P and Keely, S and Hedley, KE}, title = {Unraveling anastomotic leak: biological mechanisms underlying intestinal healing after resection.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {331}, number = {1}, pages = {G1-G11}, doi = {10.1152/ajpgi.00071.2026}, pmid = {42160479}, issn = {1522-1547}, support = {//University of Newcastle Australia (UON)/ ; //Australian Government (Federal Government)/ ; G2300020//nswgov | NSW Health (The NSW Health)/ ; }, mesh = {Humans ; *Wound Healing/physiology ; *Anastomotic Leak/metabolism/pathology/physiopathology/etiology/microbiology ; Animals ; Anastomosis, Surgical/adverse effects ; *Intestines/surgery/pathology ; *Intestinal Mucosa/metabolism/pathology ; Gastrointestinal Microbiome ; }, abstract = {Understanding intestinal healing following resection and anastomosis is a challenging topic due to the complexity of underlying mechanisms. Anastomotic healing follows the fundamental phases of normal wound repair; however, the intestinal anastomosis represents a unique biological environment in which factors such as the structure of the intestines, as well as the microbiome, may modify the healing process. Disruptions in any of the healing phases, such as the inflammatory, proliferative, and remodeling phase, may result in severe complications, characterized by the intraluminal contents leaking out into the extraluminal space, termed an anastomotic leak (AL). Despite decades of surgical advancements, we are still no closer to understanding the underlying AL etiology. It is clear that ALs are multifactorial in nature and contribute to by patient-, technical-, and biological-related factors; however, emerging evidence suggests that biological mechanisms may play a more significant role in AL pathology than originally believed. Evidence points to an interplay between epithelial healing, tissue oxygenation, and the resident microbiome in influencing mucosal healing at the anastomotic site. However, the precise contribution of these factors to failed anastomotic healing and AL etiology remains unclear. In this review, we examine the phases of healing, discuss the existing literature on biological factors affecting anastomotic healing, and describe the advancements made to improve AL rates by targeting the healing response.}, } @article {pmid42160515, year = {2026}, author = {Zhang, M and Yang, W and Wang, J and Zou, B and Zheng, JC and Wu, Q and Gao, G}, title = {Immunotherapeutic landscape of amyotrophic lateral sclerosis: A bibliometric analysis of research trends, translational priorities, and collaboration networks (2006-2025).}, journal = {Human vaccines & immunotherapeutics}, volume = {22}, number = {1}, pages = {2664985}, pmid = {42160515}, issn = {2164-554X}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy/immunology ; *Bibliometrics ; C9orf72 Protein/genetics/immunology ; *Immunotherapy/methods/trends ; Microglia/immunology ; Superoxide Dismutase-1/immunology ; *Translational Research, Biomedical/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) remains a major therapeutic challenge, with immune dysregulation increasingly recognized as a critical driver of disease progression. Despite extensive mechanistic research, no immunotherapeutic approach has achieved consistent disease-modifying effects, raising questions about whether this translational gap reflects biological complexity or structural misalignment within the research ecosystem. To characterize the intellectual evolution of ALS immunotherapeutics research, identify immune targets with translational potential, and evaluate collaboration patterns that may influence translational efficiency, we performed a bibliometric analysis of 2,256 publications indexed in Web of Science and Scopus using network-based approaches including co-citation clustering, keyword co-occurrence, and citation burst detection implemented in CiteSpace, VOSviewer, and R-Bibliometrix. Publication output increased 8.4-fold over the study period, delineating three developmental phases. Thematic analyses revealed a shift from early emphasis on microglial biology and SOD1-based models toward recent focus areas including the gut-brain axis, C9orf72-associated immune dysregulation, and advanced immunomodulatory strategies. Collaboration networks remain predominantly regional despite strong contributions from the United States, Europe, and Asia, with limited integration between mechanistic research groups and clinical trial consortia. Among immune-directed therapeutic strategies, regulatory T cell modulation and microglial-targeted approaches exhibit the highest translational readiness. These findings suggest that the lack of effective ALS immunotherapeutics reflects not only biological complexity but also structural and strategic misalignment within the research ecosystem. This bibliometric analysis provides a systems-level framework to guide more integrated translational strategies in ALS immunotherapeutics development.}, } @article {pmid42161327, year = {2026}, author = {Vallikivi, JK and Kooyman, M and , and Kirby, J and Nigel Leigh, P and Iacoangeli, A and Al-Chalabi, A and Al Khleifat, A}, title = {CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag178}, pmid = {42161327}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. Riluzole remains the only widely available disease-modifying treatment for ALS, yet its survival benefit is modest and likely to vary substantially between patients. Cytochrome P450 2D6 (CYP2D6), is a highly polymorphic enzyme that contributes to interindividual variability in the metabolism of many drugs. CYP2D6 is also expressed in the brain, and experimental and translational studies indicate that brain CYP2D activity can influence local metabolism of neuroactive compounds. Accordingly, CYP2D6 poor function variants have been examined as susceptibility modifiers in the development of other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, with heterogenous evidence; however, the role of CYP2D6 in ALS has not been established.}, } @article {pmid42161891, year = {2026}, author = {Liu, Y and Shi, K and Zhang, M and Wei, J and Feng, M and Dayan, FE and Tao, X and Feng, Z}, title = {Establishment of a versatile virus-based system for elucidating herbicide resistance in Galium aparine.}, journal = {Plant physiology}, volume = {201}, number = {2}, pages = {}, pmid = {42161891}, issn = {1532-2548}, support = {2023YFD1400500//National Key R & D Program of China/ ; 32372567//National Natural Science Foundation of China/ ; KYCX25-0990//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; }, mesh = {*Herbicide Resistance/genetics ; *Tobacco Mosaic Virus/genetics ; *Herbicides/pharmacology ; *Galium/genetics/drug effects/virology ; Plants, Genetically Modified ; Plant Weeds/genetics/drug effects/virology ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Plant Proteins/genetics/metabolism ; }, abstract = {Herbicide resistance challenges sustainable weed management in crop fields. However, the lack of gene manipulation tools for weeds hinders studies of herbicide resistance evolution and regulation. Here, we identified that tobacco mosaic virus (TMV) can systemically infect Galium aparine, a noxious broadleaf weed common in wheat and rapeseed fields, among 13 broadleaf weeds. The TMV-based expression system can be used to elucidate herbicide resistance in G. aparine. We demonstrated that virus-based expression of BAR, ALS, and its site-directed mutagenized form in G. aparine plants can impart herbicide resistance. To expand the application of this system in metabolic resistance studies, 10 upregulated P450 genes in the tribenuron-methyl-resistant G. aparine population plants were identified. Expression of these P450 genes in G. aparine via this system enhanced tribenuron-methyl resistance in G. aparine plants. Additionally, we confirmed Eleusine indica CYP81A104 functions in herbicide resistance through heterologous expression in G. aparine plants, suggesting that this system can be used to investigate the roles of genes from other weed species. The TMV vector-based assay system enabled the functional validation of weed genes within 2 months, which is shorter than the time required in other heterologous expression systems (ie, stable expression of weed genes in rice or Arabidopsis). Thus, this virus-based system provides insights into target-site and/or metabolic-based resistance mechanisms to herbicides in G. aparine and possibly in other weed species.}, } @article {pmid42162572, year = {2026}, author = {Mehta, AK and Steele, SU and Shah, I and Wang, K and Booth, A and Swain, C and Desai, A and Popli, KA and Maragakis, NJ and Wright, R}, title = {Improving ALS Clinic Care Through Experience-Based Co-Design: A Participatory Action Research Study.}, journal = {Muscle & nerve}, volume = {74}, number = {2}, pages = {349-356}, doi = {10.1002/mus.70279}, pmid = {42162572}, issn = {1097-4598}, support = {//Harold Young Scholarship/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Health Services Research ; Female ; *Ambulatory Care Facilities ; *Quality Improvement ; }, abstract = {INTRODUCTION/AIMS: Multidisciplinary clinics (MDCs) are the standard of care for amyotrophic lateral sclerosis (ALS), yet little is known about how well they meet patient and care partner needs, or how stakeholder engagement can be used to strengthen these services. The aim of this study was to explore the experiences of people living with ALS (pALS), care partners (cALS), and staff in an ALS MDC to identify care gaps and collaboratively develop improvement strategies.

METHODS: We conducted a six-stage experience-based co-design (EBCD) study comprising narrative interviews with pALS, cALS, and ALS clinic staff, followed by validation events and co-design workshops. Data were analyzed using reflexive thematic analysis. Priority areas for improvement were identified through collaborative ranking and translated into actionable interventions through iterative working groups.

RESULTS: A total of 11 pALS, eight cALS, and 10 clinic staff participated. Two shared priority domains were identified: (1) communication and relationships across the care continuum, and (2) navigational and supportive resources. Stakeholders unanimously identified communication and relationships between cALS and staff as the highest priority for improving MDC care delivery. Key strategies included pre-visit orientation materials, pacing information delivery aligned with patient readiness, and incorporating digital tools to enhance flexible access to resources.

DISCUSSION: Curated, iterative education is essential for pALS and cALS across the disease trajectory. Improvement strategies developed through equitable stakeholder partnership may yield different, and potentially more patient-centered priorities for ALS MDC care delivery than strategies developed by any single stakeholder group alone.}, } @article {pmid42162905, year = {2026}, author = {Alamri, MA and Afzal, M and Pandey, SN and Afzal, O and Akela, MA and Rekha, A}, title = {Exosomal miRNA in cerebrospinal fluid as biomarkers for neurodegenerative disease.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {590}, number = {}, pages = {121094}, doi = {10.1016/j.cca.2026.121094}, pmid = {42162905}, issn = {1873-3492}, mesh = {Humans ; *MicroRNAs/cerebrospinal fluid/genetics ; *Exosomes/genetics/metabolism ; Biomarkers/cerebrospinal fluid ; *Neurodegenerative Diseases/cerebrospinal fluid/diagnosis/genetics ; }, abstract = {Cerebrospinal fluid protein biomarkers, such as the Aβ42/Aβ40 ratio, phosphorylated tau, and neurofilament light chain, have significantly advanced the diagnostic process for Alzheimer's disease. Nonetheless, these biomarkers face challenges in effectively distinguishing Alzheimer's disease from frontotemporal dementia or Parkinson's disease from dementia with Lewy bodies. This limitation arises from overlapping protein profiles and the variability inherent in immunoassay techniques. A complementary class of analytes is exosomal microRNAs in cerebrospinal fluid, where these non-coding RNAs are secreted by neurons, astrocytes, and microglia, are resistant to RNase degradation, and have a disease-specific expression pattern. This review critically evaluates the existing evidence of cerebrospinal fluid exosomal miRNAs as diagnostic biomarkers in Alzheimer's disease, frontotemporal dementia, Parkinson's disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis. Exosome isolation techniques and detection platform characteristics were compared using RT-qPCR, droplet digital PCR, and small RNA sequencing. Pre-analytical factors, such as collection protocols, hemolysis contamination, freeze-thaw cycling, and circadian sampling variation, were assessed. miRNA profiling data based on disease stratification, receiver operating characteristic performance of the combinatorial panel, and strategies combining exosomal miRNAs with core cerebrospinal fluid proteins were synthesized. This article brings together disease-specific miRNA signatures, pre-analytical standardization needs, and diagnostic accuracy analyses in a translational model to fill the literature gap and form the basis for developing exosomal miRNA panels for rigorously validated clinical laboratory practice.}, } @article {pmid42163674, year = {2026}, author = {Qi, M and Fei, L and Cui, W and Ho, PW and Lee, SM and Li, J and Zhang, Z}, title = {Unraveling the Pathological Mechanisms and Biomarkers of Amyotrophic Lateral Sclerosis: A Comprehensive Review.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X431460260227095109}, pmid = {42163674}, issn = {1875-6190}, abstract = {Amyotrophic lateral sclerosis (ALS) is an devastating neurodegenerative disorder with a very fast course and a very high fatality rate. The review discusses the intricate pathophysiology of ALS, such as the alterations caused by the genetic mutations of the C9orf72 and SOD1 genes, the misfolding and aggregation of proteins, oxidative stress, the excitotoxicity of glutamate, neuroinflammation, malfunctions in mitochondria, and axonal transport. Heterogeneity of the disease makes the development of biomarkers in ALS challenging; however, some promising candidates have been identified. Protein aggregation markers, including TDP-43 and SOD1, oxidative stress markers, such as 8-oxodG, neuroinflammatory markers, such as CRP and MCP-1, and neurological injury markers, such as NfL and pNfH, have potential in diagnosis, monitoring, and prediction. The miRNAs and particular metabolites can also provide clues to the molecular basis of ALS. The creation of biomarkers is challenged by the presence of a significant amount of disease heterogeneity and the lack of animal model reliability. The review highlights the importance of further research on biomarkers aimed at improving the diagnosis, treatment, and development of drugs for ALS. It supports the concept of a systematic biomarker development process, including genetic testing and molecular subgroup analysis, to enhance diagnostic accuracy and prognostic prediction capabilities. Exploring the interrelationship between the pathological process of ALS and the treatment based on multi-biomarker strategies is crucial for achieving effective management of this disease. As our understanding of ALS deepens, we expect to discover more new biomarkers in the future. This will significantly improve the diagnosis, treatment, and overall management of this devastating diseas.}, } @article {pmid42163677, year = {2026}, author = {Tiwari, D and Mukherjee, A and Singh, S}, title = {Interplay of NMDAR and AMPAR in the Pathophysiology of Alzheimer's, Parkinson, ALS, Huntington's, and Epilepsy: An Update in Therapeutic Perspective.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X466249260418090832}, pmid = {42163677}, issn = {1875-6190}, abstract = {Glutamate-mediated excitotoxicity is a central driver of neurodegeneration and represents a shared pathogenic mechanism across neurodegenerative diseases and epilepsy, with N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid recep-tors (AMPARs) occupying central roles in synaptic plasticity, Ca[2+] signalling, and neuronal survival. Dysregulation of these receptors disrupts the balance between pro-survival and pro-death pathways, accelerating neuronal loss in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lat-eral sclerosis (ALS), Huntington's disease (HD), and epilepsy. Disease-specific triggers converge on common patterns of receptor dysregulation, including a shift toward extrasynaptic NMDAR signal-ling and the pathological emergence of Ca[2+]-permeable AMPARs (CP-AMPAR), ultimately driving synaptic failure and neuronal loss. Although numerous NMDAR and AMPAR-directed modulators have demonstrated neuroprotective efficacy in preclinical models, clinical translation has been lim-ited by inadequate spatial, kinetic, and subunit selectivity, as well as adverse effects arising from the disruption of physiological glutamatergic transmission. In this review, we synthesize the literature published between June 1990 and March 2025 to develop an integrative framework that links recep-tor localization, downstream Ca[2+]-dependent signalling, astrocytic regulation, mitochondrial dys-function, and disease progression across these disorders. By critically evaluating both successful and failed therapeutic strategies, we provide insight into evident research gaps in the field and the neces-sity of addressing them to develop precise multi-target approaches at both the genetic and cellular levels as next-generation therapeutics. Such an approach would be essential to move beyond indis-criminate receptor blockade strategies, which have repeatedly proven ineffective over the decades, and towards a future of durable neuroprotection.}, } @article {pmid42164014, year = {2026}, author = {Cheung, N}, title = {Symptom-Level Precision Neurology in Amyotrophic Lateral Sclerosis (ALS): Linking Microglial Pruning, Mitochondrial Nicotinamide Adenine Dinucleotide (NAD+) Compensation, and Autophagy Failure Across the Aging Spectrum.}, journal = {Cureus}, volume = {18}, number = {5}, pages = {e109147}, pmid = {42164014}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurological disease with limited disease-modifying treatment options and, for many patients, a short survival window. The clinical course varies widely. Limb weakness, bulbar impairment, respiratory decline, fine-motor dysfunction, cognitive change, mood symptoms, and fatigue may each appear at different times and progress at different rates. This variability suggests that motor neuron loss alone may not fully explain the patient-level pattern of symptoms. This article is a narrative hypothesis framework, not a clinical guideline or a validated stratification tool. Established ALS biology, associative genomic findings, preclinical observations, computational predictions, and author-derived hypotheses are therefore separated throughout the article. This review brings together four interlinked studies by the current author as a primary hypothesis-generating corpus, which proposes that synaptic plasticity fragility may initiate a microglial pruning continuum shared by major depressive disorder and ALS, while ALS-specific progression may depend on mitochondrial stress, oxidized nicotinamide adenine dinucleotide (NAD+) compensation failure, and collapse of autophagy under aging-related limits. The model presented here maps symptom domains to vulnerable circuit compartments and separates three broad biological states: compensated plasticity, fragile plasticity, and network collapse. A compact mechanistic formulation is used to describe the balance between pruning pressure, glutamatergic burden, and aging stress on one side, and oxidative phosphorylation capacity, NAD+ reserve, and autophagic clearance on the other. The framework also incorporates opposing phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) pathway patterns that may distinguish ALS from frontotemporal dementia (FTD) within an aging context. The result is a falsifiable, biomarker-oriented hypothesis model for future studies, not an evidence-based diagnostic or therapeutic algorithm.}, } @article {pmid42164629, year = {2026}, author = {Akan, T and Aishwarya, R and Bhuiyan, MS and Conrad, SA and Vanchiere, JA and Bhuiyan, MAN}, title = {Computational pathology with dynamic convolutional and adaptive kernels.}, journal = {Journal of pathology informatics}, volume = {21}, number = {}, pages = {100662}, pmid = {42164629}, issn = {2229-5089}, abstract = {Data processing and learning have become essential to the advancement of medicine, with pathology and lab medicine being no exception. Integrating scientific research with clinical informatics into clinical practice facilitates novel methodologies for patient care. Computational pathology is a burgeoning subspecialty in pathology that promises a better-integrated solution to histopathological images and clinical informatics. Deep-learning methods in computational pathology have demonstrated considerable advances in automated histopathological image analysis. However, convolutional neural networks (CNNs) face fundamental limitations when dealing with the significant morphological heterogeneity present in disease tissues. Conventional CNNs use fixed convolutional kernels, which restrict their effectiveness in adaptively extracting features from histopathological images that exhibit diverse pathological patterns, staining intensities, and tissue architecture. To address this substantial limitation, we present an optimized variant of Omni-Dimensional Dynamic Convolution (ODConv) networks for distinguishing diseased tissue from healthy tissue. Compared with prior dynamic convolution methods that attend to a single kernel dimension, ODConv applies multi-dimensional attention across spatial positions, input channels, output channels, and kernel candidates, enabling more flexible and adaptive feature extraction. We evaluated our approach on wheat-germ agglutinin-stained and hematoxylin and eosin-stained skeletal muscle images from multiple disease models, including G93A*SOD1 transgenic mice (amyotrophic lateral sclerosis) and Akita mice (Type I diabetes). ODConv, trained entirely from scratch without ImageNet pretraining, achieved competitive classification performance relative to seven fine-tuned pretrained architectures across both staining modalities, demonstrating the effectiveness of omni-dimensional dynamic kernels in learning discriminative morphological representations directly from domain data. The study reports strong statistical agreement metrics, proving effective class balance handling and stable decision boundaries. These findings confirm ODConv as a strong computational pathology framework that advances automated diagnosis of neurodegenerative and metabolic skeletal muscle disorders.}, } @article {pmid42165374, year = {2026}, author = {Fernández-Gómez, P and Tosat-Bitrián, C and Marugán, T and Fernández-Hernández, L and Cano, A and Martinez-Mulero, JA and López-Carbonero, JI and Pignatelli, J and Corrochano, S and Palomo, V}, title = {Lighting Up Mislocalized Proteins: Quantum Dot Probes for Multiplexed Cytoplasm-Selective Cell Profiling in Neurodegeneration.}, journal = {ACS sensors}, volume = {11}, number = {6}, pages = {4285-4296}, doi = {10.1021/acssensors.5c01941}, pmid = {42165374}, issn = {2379-3694}, mesh = {*Quantum Dots/chemistry ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *DNA-Binding Proteins/metabolism/analysis ; *Cytoplasm/metabolism/chemistry ; Mice ; Biomarkers/analysis ; }, abstract = {Semiconductor quantum dots (QDs) provide unique stability, brightness, and multiplexed capacity for biomarker detection in complex diseases; however, their distinctive intracellular distribution has rarely been leveraged for spatially resolved diagnostics. Here, we show how QD-based sensors enable selective detection of cytoplasmic proteins and can quantify nucleo-cytoplasm protein mislocalization in patient-derived samples. We validated this approach labeling TAR DNA-binding protein 43 (TDP-43), a key mislocalized protein in amyotrophic lateral sclerosis (ALS). Spatial resolution is achieved in several patient-derived models and mouse brain tissue, underscoring the nanosensor's versatility across biological systems. Multiplexed QD-based immunolabeling, combined with confocal imaging and high-throughput flow cytometry, enables the detection of distinct cytoplasmic biomarker signatures that discriminate ALS patients from healthy controls. These signatures include variations in TDP-43 mislocalization and protein coexpression patterns, which were further modulated by pharmacological treatment. This work establishes QDs as spatially selective, multiplexable nanosensors capable of resolving subtle yet disease-relevant intracellular phenotypes in patient-derived samples. Compared to organic fluorophores, QDs enhance sensitivity, improve signal stability, and enable simultaneous spatially resolved biomarker quantification, broadening their potential for clinical diagnostics and personalized medicine. These findings establish QDs as powerful tools for neurodegeneration research, disease monitoring, and early biomarker discovery, with potential applications in translational neuroscience and precision medicine.}, } @article {pmid42166253, year = {2026}, author = {Fung, WY and Agustini, S and Amornvit, J and Chai, J and Damian, LF and Fadli, N and Pg Hj Mohd Yassin, DHN and Keovilayhong, S and Krishnan, D and Kulkantrakorn, K and Nguyen Tran, MD and Ng, K and Nghia, HTT and Ohnmar, O and Pengiran Tengah, DSNA and Prado, M and Remli, R and Rojana-Udomsart, A and Le Tuan, TQ and Yanuar, A and Shahrizaila, N}, title = {Strengthening care and research in ALS in Southeast Asia: a call for action.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/21678421.2026.2671159}, pmid = {42166253}, issn = {2167-9223}, abstract = {In Southeast Asia (SEA), healthcare resources, infrastructure, and access to therapies in amyotrophic lateral sclerosis (ALS) remain limited compared to other parts of the Asia-Pacific region. Many SEA countries continue to face delays in diagnosis, fragmented care pathways, and limited representation in international research. Beyond health system challenges, ALS in SEA may also differ biologically. Emerging studies suggest that genetic variants and clinical phenotypes in Asian populations are not fully mirrored in Western cohorts. In this report, the authors summarize their country-specific background and status of care in ALS as well as their consensus on future strategies and actions. Key short- and long-term strategies are proposed, highlighting the critical need for regional collaboration and patient engagement to advance ALS care and research in the region.}, } @article {pmid42166520, year = {2026}, author = {Marques Couto, C and De Melo Queiroz, E and Souza Lima, W and Camilla De Lima Santos, S and José Moreira Nascimento, O}, title = {Clinical characterization and natural history of ALS8/VAPB p.Pro56Ser: upper motor neurone signs, survival, and functional milestones in 78 patients.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2674020}, pmid = {42166520}, issn = {2167-9223}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis type 8 (ALS8), caused by the VAPB p.Pro56Ser mutation, is a rare familial motor neurone disease with an incompletely characterized profile. We aimed to characterize the clinical phenotype, upper motor neurone (UMN) sign prevalence, survival, and functional milestones.

METHODS: We retrospectively analyzed 78 patients with ALS8 confirmed via molecular testing or familial linkage analysis from 57 apparently unrelated families. UMN signs were assessed using a five-item composite of pyramidal signs. Survival and milestones were estimated using Kaplan-Meier analysis.

RESULTS: Median age at onset was 44.9 years; 51% were men. Onset was lumbar in 94%, proximally predominant. UMN signs were present in 53 patients; none exhibited clonus. At admission, 51% had spinal-onset ALS, 42% progressive muscular atrophy (PMA) and 6% flail leg; 30% of patients with PMA subsequently developed UMN signs. Survival was 21.9 years; times to wheelchair dependence and noninvasive ventilation were 7.0 and 10.0 years, respectively. Bulbar involvement occurred in 17 (21.8%) patients, predominantly as dysphonia. UMN status did not affect survival (p = 0.312). The standardized mortality ratio was 4.54 (95% CI 2.77-7.01), supporting disease-related excess mortality.

CONCLUSIONS: ALS8 is a slowly progressive motor neurone disease with lumbar onset, ascending progression, and frequent but subtle UMN signs. Survival was markedly prolonged but functional decline followed a predictable sequence. These findings expand the phenotypic characterization of ALS8 and support genetic counseling and anticipatory management.}, } @article {pmid42167402, year = {2026}, author = {Ballesteros, AL and Rodriguez-Cañamero, S and Martín-Conty, JL and Polonio-López, B and Pozo-Vegas, CD and López-Izquierdo, R and Martín-Rodríguez, F and Sanz-García, A}, title = {Effect of Glycemia and Diabetes on Early Warning Scores Performance in Prehospital Patients With Acute Illness: Multicenter, Prospective, Cohort Study.}, journal = {Mayo Clinic proceedings}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.mayocp.2026.05.008}, pmid = {42167402}, issn = {1942-5546}, abstract = {OBJECTIVE: To determine how glycemia and diabetes affect the performance of the NEWS and mSOFA scores to predict 30-day mortality in patients with acute illnesses requiring EMS assistance.

PARTICIPANTS AND METHODS: This prospective, multicenter cohort study evaluated 14,726 adults with acute illness attended by advanced life support (ALS) units and helicopter emergency medical services (HEMS) between January 1, 2019, and December 1, 2025. Associations between glucose levels (hypoglycemia, normoglycemia, hyperglycemia), diabetic status, and 30-day mortality were analyzed. Predictive capacity (area under the receiver operating characteristic curve, AUC-ROC) of NEWS and mSOFA stratified by metabolic groups was assessed and compared.

RESULTS: A nonlinear U-shaped relationship was observed between glycemia and mortality. mSOFA outperformed NEWS (AUC-ROC 0.877 vs 0.822). Under hyperglycemia, NEWS performance decreased (AUC-ROC 0.764), while mSOFA remained more stable (AUC-ROC 0.815). Both scores performed better in nondiabetic patients (AUC-ROC >0.82) than in diabetics with complications, suggesting stress hyperglycemia in nondiabetics reflects greater acute severity.

CONCLUSIONS: mSOFA showed greater robustness and more stable predictive performance than NEWS with glycemic variability, particularly in nondiabetic patients with stress hyperglycemia, suggesting glucose serves as a universal biomarker of acute severity across prehospital acute illness. These findings support potential value of prehospital POCT to improve critical patient identification and risk stratification where resources and infrastructure allow.}, } @article {pmid42168009, year = {2026}, author = {Corcia, P and Bernard, E and de la Cruz, E and Danel, V and Soriani, MH and Guy, N and Esselin, F and Bruneteau, G and Pradat, PF and Goutines, V and Catherine, J and Eyraud, N and Cheve, P and Fernandez, A and Erazo, D and Couratier, P}, title = {Primary Lateral Sclerosis French National Diagnostic and Care Protocol.}, journal = {Revue neurologique}, volume = {182}, number = {6}, pages = {555-562}, doi = {10.1016/j.neurol.2026.04.006}, pmid = {42168009}, issn = {0035-3787}, mesh = {Humans ; France/epidemiology ; *Motor Neuron Disease/diagnosis/therapy/epidemiology ; Diagnosis, Differential ; Clinical Protocols ; Amyotrophic Lateral Sclerosis/diagnosis ; }, abstract = {Primary lateral sclerosis (PLS) is a rare neurodegenerative motor neuron disease characterized by progressive and selective involvement of the central motor neuron within the bulbar and spinal regions. It is estimated to account for 1-5% of motor neuron diseases and typically presents in the fifth or sixth decade of life, with a slight male predominance. According to current consensus criteria, the diagnosis relies on the demonstration of progressive upper motor neuron dysfunction in the absence of lower motor neuron involvement, with persistence of isolated upper motor neuron signs for at least four years in order to exclude a slowly progressive upper motor neuron-predominant form of amyotrophic lateral sclerosis (ALS). The French Motor Neuron Disease Network (FILSLAN) developed a National Diagnostic and Care Protocol (PNDS) with the aim of standardizing diagnostic criteria, optimizing differential diagnosis, and providing evidence-based recommendations for therapeutic management and follow-up across the national territory. These recommendations were elaborated in accordance with the methodological framework of the French National Authority for Health for rare diseases. The protocol provides practical guidance for establishing PLS as a diagnosis of exclusion, distinguishing it from ALS and hereditary spastic paraplegias, and organizing appropriate clinical and paraclinical investigations. It also outlines indications for genetic testing in selected cases and defines a multidisciplinary management strategy centered on symptomatic treatment, early rehabilitation, respiratory and nutritional surveillance, and psychosocial support. Given the slower progression of PLS compared with ALS, biannual multidisciplinary follow-up is generally appropriate. This protocol aims to harmonize clinical practice and improve patient care while acknowledging the current absence of disease-modifying therapies.}, } @article {pmid42168859, year = {2026}, author = {Levin, AB and Joshi, Y and Vaidhya, N and Kantianis, J and Macdonald, PS}, title = {Anaesthetics considerations for organ retrieval in the voluntary assisted dying patient - case report.}, journal = {BMC anesthesiology}, volume = {26}, number = {1}, pages = {}, pmid = {42168859}, issn = {1471-2253}, mesh = {Humans ; Middle Aged ; Male ; *Suicide, Assisted ; Amyotrophic Lateral Sclerosis ; *Tissue and Organ Procurement/methods ; *Anesthesia/methods ; *Anesthetics/administration & dosage ; *Tissue and Organ Harvesting/methods ; }, abstract = {BACKGROUND: Voluntary assisted dying (VAD) is now legalised in several countries. Organ donation after VAD provides unique moral and logistical challenges. This report highlights the role of the anaesthetist in such cases.

CASE PRESENTATION: A 50-year-old man with end-stage amyotrophic lateral sclerosis underwent VAD and became an organ donor. Anaesthetic and logistical considerations during procurement are described. Advances in organ retrieval after VAD and psychosocial implications are briefly outlined.

CONCLUSIONS: Organ donation after VAD presents unique opportunities and challenges. The anaesthetist plays a key role in ensuring both dignity for the patient and optimal conditions for organ retrieval.}, } @article {pmid42169130, year = {2026}, author = {Sarti, A and Mandrioli, J and Costanzini, S and Balbo, GX and Malagoli, C and Martini, N and Despini, F and Violi, F and Malavolti, M and Martinelli, I and Giacchino, M and Donelli, G and Canali, E and Zinno, L and Teggi, S and Vinceti, M and Filippini, T}, title = {Green space exposure and risk of amyotrophic lateral sclerosis: a population-based case-control study in Northern Italy.}, journal = {Environmental health : a global access science source}, volume = {25}, number = {1}, pages = {}, pmid = {42169130}, issn = {1476-069X}, support = {"PRIN 2022" (No. 2022MHMRPR)//Ministero dell'Università e della Ricerca/ ; "UNIMORE FAR 2023"//Università Degli Studi di Modena e Reggio Emilia/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/etiology ; Humans ; Italy/epidemiology ; Case-Control Studies ; Female ; *Environmental Exposure/adverse effects ; Male ; Middle Aged ; Aged ; Adult ; Risk Factors ; *Environment ; }, abstract = {BACKGROUND: The contribution of environmental determinants in the etiology of amyotrophic lateral sclerosis (ALS) is still unclear. Among the various environmental factors, exposure to green spaces, also known as greenness, is attracting considerable interest as many studies have reported its beneficial associations to health outcomes, particularly to neurodegenerative diseases.

METHODS: To investigate the relation between greenness and ALS risk, we conducted a population-based case-control study in a Northern Italy population (from Modena, Reggio Emilia and Parma provinces), including 499 cases of ALS newly-diagnosed from 1998 to 2011 and 1,935 sex-, age-, and province-matched controls randomly selected from study provinces residents. We evaluated the association between greenness in the proximity of residence and ALS risk, assessing exposure through multiple satellite-based and land-use derived indices, both conventional and novel devised, for a total of six indices, each providing specific information, including annual and seasonal Normalized Difference Vegetation Index (NDVI), NDVI-weighted to green areas, green cover ratio, accessibility index, and their combined Green Exposure Index (GEI). We used conditional logistic regression models to evaluate disease risk for increasing exposure through both fixed-categories and non-linear restricted cubic splines.

RESULTS: We observed a non-linear U-shaped association between greenness and ALS risk with increased odds ratios at both low and high levels. Results were more defined when using NDVI-based indices, while the associations were smoother when considering GEI. The higher risk at low levels may be related to lower accessibility to green spaces with lower physical activity and higher exposure to outdoor air pollutants, whilst elevated greenness may reflect higher exposure to neurotoxic pesticides. These results were confirmed also after adjustment for potential confounders, namely magnetic fields and light at night. Sex stratified analysis yielded similar results, except for more distinct associations in females for GEI.

CONCLUSIONS: Despite the limitations due to possible unmeasured confounding and exposure misclassification related to the use of residential data, our results provide evidence of an inverse association between intermediate residential greenness and ALS risk, and may have public health implications including disease prevention and urban planning.}, } @article {pmid42170697, year = {2026}, author = {Prasun, P and Rasberry, M}, title = {Expanding Spectrum of FIG4-Related Neurological Disorders of Lysosomal Homeostasis: Case Report and Overview of the Potential Genotype-Phenotype Correlations.}, journal = {Clinical genetics}, volume = {110}, number = {3}, pages = {363-368}, pmid = {42170697}, issn = {1399-0004}, mesh = {Humans ; *Genetic Association Studies ; Homeostasis/genetics ; *Lysosomes/genetics/metabolism/pathology ; *Charcot-Marie-Tooth Disease/genetics/pathology ; *Flavoproteins/genetics ; *Cleidocranial Dysplasia/genetics/pathology ; Male ; Phenotype ; *Micrognathism/genetics/pathology ; Female ; Ectodermal Dysplasia ; Phosphoric Monoester Hydrolases ; Limb Deformities, Congenital ; }, abstract = {Biallelic loss-of-function variants in FIG4 are associated with Charcot-Marie-Tooth disease type 4J, a progressive peripheral sensorimotor demyelinating polyneuropathy. Biallelic null FIG4 variants cause Yunis-Varon syndrome, a severe neurological disorder characterized by global developmental delay, hypotonia, brain malformations, skeletal defects, dysmorphic facial features, and juvenile lethality. In the past few years, many individuals with combined central and peripheral nervous system disease associated with biallelic FIG4 variants have been described. In addition, certain heterozygous FIG4 variants are associated with amyotrophic lateral sclerosis. We describe an individual with global developmental delay, hypotonia, cerebral hypomyelination, peripheral hypomyelinating polyneuropathy, frequent fractures, and juvenile ossifying fibroma. The spectrum of clinical presentation of FIG4-related disorders is increasingly being recognized. Our observations expand the phenotypic spectrum of FIG4-related neurological disorders. In addition, we provide an overview of the potential genotype-phenotype correlations of this expanding group of disorders of lysosomal homeostasis.}, } @article {pmid42170793, year = {2026}, author = {Michelon, H and Lefèvre-Dognin, C and Paquereau, J and Guidoni, R and Boudy, V and Ruiz, F and Vallet, T}, title = {Acceptability of Atropine Eyedrops Administered Sublingually for Sialorrhea Treatment Related to Neurological Conditions.}, journal = {Pharmacology research & perspectives}, volume = {14}, number = {3}, pages = {e70250}, pmid = {42170793}, issn = {2052-1707}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Administration, Oral ; Administration, Sublingual ; *Atropine/administration & dosage ; Cross-Sectional Studies ; France ; *Nervous System Diseases/complications ; Off-Label Use ; Ophthalmic Solutions/administration & dosage ; *Patient Acceptance of Health Care ; *Sialorrhea/drug therapy/etiology ; }, abstract = {Off-label use of anticholinergic agents (atropine eye drops) administered sublingually are a first-line treatment in standard clinical practice in France to treat sialorrhea in patients with neurological conditions. The ability and willingness to using and administering such medication have become key factors to ensure safe and effective therapy. Given that the critical aspects for ophthalmic product development differ from those for oral medicine, the objectives of this study were to investigate patient acceptability of atropine eye drops for treating sialorrhea. A multi-centric, cross-sectional study using the CAST-ClinSearch Acceptability Score Test methodology was conducted in France between February 2021 and April 2023. In total, 31 evaluations were collected. Most patients were males (74.2%) and the mean age was 51.6 ± 20 years. Poor acceptability was reported in real-life settings. A lack of a suitable administration device combined with excessive saliva flow and patient disabilities made it difficult to ensure the required dose intake. Due to the bitter taste of the drug, poor palatability of the product appeared to be a key concern for oral administration. Designing a suitable form of atropine in accordance with the specificities of patients with neurological disabilities is needed to ensure the effective treatment of sialorrhea.}, } @article {pmid42171198, year = {2026}, author = {Tian, J and Jin, Z and Chi, Y and Wang, P and Sun, H}, title = {Targeting lipid nanoparticle mediated co-delivery of edaravone and kaempferol for amyotrophic lateral sclerosis therapy.}, journal = {Nanoscale}, volume = {18}, number = {24}, pages = {12930-12941}, doi = {10.1039/d6nr00300a}, pmid = {42171198}, issn = {2040-3372}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; *Edaravone/chemistry/pharmacology/therapeutic use ; *Kaempferols/chemistry/pharmacology/therapeutic use ; Mice ; *Nanoparticles/chemistry ; Mice, Transgenic ; Humans ; Liposomes/chemistry ; Blood-Brain Barrier/metabolism ; Ferroptosis/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by a progressive and selective loss of motor neurons in the central nervous system, particularly in the brain and spinal cord. However, the main cellular mechanisms and cell death pathways leading to motor neuron degeneration have not yet been clarified. Research indicates evidence of ferroptosis in ALS, and the natural compound kaempferol has been demonstrated to inhibit neuronal ferroptosis. However, damage to the blood-brain barrier (BBB) prevents the drug from penetrating the central nervous system, which significantly reduces its therapeutic efficacy. Here, we developed a targeted delivery system named Eda/Kae@Lip-RGD (EKLR), which consisted of liposome-grafted RGD peptides for the co-delivery of the drugs kaempferol and edaravone, capable of crossing the BBB to provide co-delivery of kaempferol and edaravone for combined treatment of ALS. As expected, treatment with EKLR for one month significantly slowed down weight loss and improved athletic performance in SOD1[G93A] transgenic mice. Mechanistically, this nanomedicine suppressed ferroptosis by upregulating the antioxidant proteins GPX4 and SLC7A11, alongside the downregulation of Nrf2 and ACSL4 levels, thus collectively preserving neuronal integrity. Meanwhile, EKLR restored the normal morphology and the survival rate of neurons and maintained the mitochondrial structure and morphological integrity. Accordingly, this nanoplatform may represent a distinctive and potentially effective strategy for achieving neuroprotection in ALS as well as in other disorders of the central nervous system.}, } @article {pmid42171508, year = {2026}, author = {Ramos, S and Watson, MD and Lee, JC}, title = {Kinetics and Spatial Distribution of β-Sheet Development in TDP-43CTD Condensate Maturation.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {11}, pages = {2219-2228}, pmid = {42171508}, issn = {1948-7193}, mesh = {Kinetics ; Mutation ; Protein Conformation, beta-Strand ; *DNA-Binding Proteins/chemistry/genetics/metabolism ; Spectrum Analysis, Raman ; }, abstract = {Cytosolic inclusions of aggregated TAR DNA-binding protein 43 (TDP-43) are hallmarks of neurodegenerative disorders such as amyotrophic lateral sclerosis and frontotemporal lobar dementia. A prevailing hypothesis suggests that TDP-43 condensates undergo a liquid-to-solid transition during maturation, involving the formation of β-sheet-rich, amyloid-like aggregates. To test this hypothesis, we sought to study the temporal and spatial evolution of protein secondary structure within individual condensates by Raman spectroscopy. We measured in vitro β-sheet development of the C-terminal domain of TDP-43 (TDP-43CTD) at the single-condensate level under physiological solution conditions. All condensates showed apparent single-exponential kinetics (k = 1.6 × 10[-5] s[-1]) for the disordered-to-β-sheet transformation, as indicated by increased amide-I intensity and a shift of the amide-III band to lower energy. Interestingly, the water bend-libration band exhibited a slower rate (k = 4.0 × 10[-6] s[-1]), suggesting that changes in the water environment lag behind protein conformational rearrangement. Further, Raman maps revealed that protein density is highest near the condensate center, whereas β-sheet content is mostly uniform in the interior of the condensate. The unexpected difference between the spatial distributions of β-sheet content and protein density challenges the typical concentration-dependent model of protein aggregation. Importantly, rare events were captured where condensates exhibited spatially asymmetric β-sheet development, revealing localized structural heterogeneity not detectable by ensemble measurements. Collectively, these results provide insight into the temporal and spatial dynamics of protein structure within TDP-43CTD condensates and demonstrate the utility of Raman spectral imaging for tracking condensate maturation.}, } @article {pmid42171861, year = {2026}, author = {Condorelli, GA and Iozzia, A and Bonifacio, D and Pelin, A}, title = {TDP-43 Acetylation at the Neuroimmune Interface: A Hypothesis-Driven Framework for Peripheral Inflammatory Stratotypes in ALS.}, journal = {Neurochemical research}, volume = {51}, number = {3}, pages = {}, pmid = {42171861}, issn = {1573-6903}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/immunology ; Acetylation ; *DNA-Binding Proteins/metabolism/immunology ; Animals ; Inflammation/metabolism/immunology ; *Neuroimmunomodulation/physiology ; }, abstract = {Transactive Response Deoxyribonucleic Acid-Binding Protein-43 (TDP-43) acetylation may couple motor-neuron degeneration to systemic immune orchestration in Amyotrophic Lateral Sclerosis (ALS). Upon nuclear clearance and mislocalisation, TDP-43 enters the periphery; acetylation shapes its conformation, trafficking and immunogenicity. This narrative review synthesises single-cell transcriptomics, proteomic immunoprofiling and clinical inflammatory phenotyping to examine whether site-specific acetylated TDP-43 species may be associated with peripheral inflammatory signatures relevant to ALS immunopathology. By integrating separate datasets on acetylated TDP-43, monocyte phenotypes and cytokine modules, we propose two provisional endotypes characterised by monocyte reprogramming, cytokine modules and Blood-Brain Barrier (BBB) dysfunction-each representing clinically actionable pathways. Framed as a provisional neuroimmune interface, the acetylation state is considered here as a plausible molecular correlate and potential therapeutic entry point: a measurable clue to inform pharmacological targeting and, potentially, a modifiable target via p300CREB-Binding Protein (CBP)-Histone Deacetylase (HDAC) axes or sirtuin activity. Recasting TDP-43 from neuropathological hallmark to immunoactive sentinel supports a shift from descriptive nosology to stratified immunotherapy, in which treatment allocation is informed by acetylation-defined peripheral signatures.}, } @article {pmid42172922, year = {2026}, author = {Myers, S and Kraus, E and Davis, ES and Murillo, A and Ng, SC and Sachs, T and Davids, JS and Kenzik, KM}, title = {Ostomy and Anastomotic Leak Differences Among Rural and Urban Surgical Colon Cancer Patients.}, journal = {The Journal of surgical research}, volume = {324}, number = {}, pages = {59-66}, pmid = {42172922}, issn = {1095-8673}, support = {R37 CA266193/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Aged ; Male ; Aged, 80 and over ; *Colonic Neoplasms/surgery ; *Anastomotic Leak/epidemiology/etiology ; Rural Population/statistics & numerical data ; United States/epidemiology ; SEER Program/statistics & numerical data ; *Ostomy/statistics & numerical data/adverse effects ; Urban Population/statistics & numerical data ; *Colectomy/adverse effects/statistics & numerical data ; Patient Readmission/statistics & numerical data ; Retrospective Studies ; Colorectal Surgical Procedures ; }, abstract = {INTRODUCTION: Rural populations experience higher morbidity and mortality after resection of colon cancer (CC) than urban populations. Ostomy creation may obviate or reduce the severity of anastomotic leaks (ALs); however, this practice is surgeon-dependent. Differences in rural-urban ostomy practices and AL following CC resection are unknown.

METHODS: We identified patients who underwent CC resection between 2014 and 2019 from the Surveillance, Epidemiology, and End Results-Medicare database and characterized ostomy practices. We used multivariable logistic regression to evaluate rural-urban differences in AL and readmissions, with and without ostomies. Oaxaca-Blinder nonlinear effect decomposition was used to analyze the proportion of rural-urban difference in AL explained by age, sex, race, Charlson Comorbidity Index, stage of cancer, surgical approach, surgeon specialty, and ostomy creation.

RESULTS: Among 28,031 individuals (17.9% rural), rural patients underwent ostomy surgery less often than urban (47.6% versus 52.4%, P < 0.0001). The rate of AL was higher among rural patients with ostomies (8.6% versus 7.0%, P = 0.0069), and rural ostomy patients were discharged with postacute care services less often (43.8% versus 47.3%, P = 0.0034). Resection by a general surgeon was associated with higher odds of AL only among urban patients (versus colorectal, OR = 1.27; 95% CI = 1.13-1.42). Surgical approach explained 37.5% of the rural-urban AL disparity, surgeon specialty explained 21.5%, and ostomy surgery only explained 2.6% of the difference.

CONCLUSIONS: Ostomy surgery explained a small proportion of the rural-urban AL disparity, while surgical approach explained over a third of the higher AL risk among rural populations. Surgical approach should be prioritized in interventions to improve CC surgical outcomes among rural populations.}, } @article {pmid42173382, year = {2026}, author = {Braza, AJ and Viñas-Bastart, M and Sureda-Rosich, M and García-Parra, B and Guiu-Segura, JM and Modamio, P}, title = {Tofersen in SOD1-associated amyotrophic lateral sclerosis: From molecular mechanisms to regulatory milestones.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {223}, number = {}, pages = {107563}, doi = {10.1016/j.ejps.2026.107563}, pmid = {42173382}, issn = {1879-0720}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Humans ; *Superoxide Dismutase-1/genetics/metabolism ; Animals ; *Oligonucleotides, Antisense/therapeutic use/pharmacology ; Mutation ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disorder characterized by degeneration of upper and lower motor neurons. Mutations in the superoxide dismutase 1 (SOD1) gene account for approximately 2% of ALS cases and are associated with toxic protein misfolding and aggregation. Tofersen is an antisense oligonucleotide therapy designed to reduce the synthesis of mutant SOD1 protein through targeted mRNA degradation. While this strategy represents a gene-specific therapeutic approach for a subset of ALS patients, evidence regarding its efficacy, effectiveness and long-term outcomes continues to be evaluated in clinical trials and post-marketing studies.

OBJECTIVE: First, to describe the molecular mechanisms underlying SOD1-associated ALS and second, to analyze the therapeutic development, clinical outcomes, and regulatory evolution of tofersen.

METHODS: A narrative review was conducted in PubMed on preclinical and clinical studies published from 2016 through late 2025, complemented by an analysis of public registries and regulatory documentation. Clinical trials were identified through ClinicalTrials.gov and the Clinical Trials Information System (CTIS), and official reports from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were reviewed to contextualize their development and regulatory evaluation.

RESULTS: Fifty-three publications were identified, of which 20 met predefined inclusion criteria after screening and full-text review. Preclinical studies showed reduced mutant SOD1 expression and prolonged survival in transgenic models. Phase I-II trials demonstrated safety, favorable pharmacokinetics, and dose-dependent reductions in SOD1 in the cerebrospinal fluid and plasma neurofilament light chain (NfL) levels. Although the phase III VALOR trial did not meet the primary ALSFRS-R endpoint (a validated questionnaire-based functional rating scale-revised for determining ALS disease progression) at 28 weeks, significant reductions in the surrogate biomarker NfL indicated target engagement and supported accelerated regulatory approval. Extension data suggested potential clinical benefit with early treatment. Ongoing studies, including ATLAS in presymptomatic carriers, and real-world European data support continued evaluation, alongside accelerated regulatory approvals by FDA and EMA.

CONCLUSION: Tofersen marks a paradigm shift in ALS management, establishing the foundation for precision medicine in neurodegenerative diseases. Its ongoing evaluation in the ATLAS trial will determine whether early intervention can prevent or delay disease onset in presymptomatic SOD1 mutation carriers.}, } @article {pmid42174751, year = {2026}, author = {Grouls, A and Leavell, YL and Mehta, AK and Kojimoto, G and O'Riordan, DL and Maiser, S and Kluger, BM and Pantilat, SZ and Bischoff, KE}, title = {Embedding Palliative Care Clinicians in ALS Teams Improves ALS Clinicians' Confidence in Their Patient Management and Satisfaction With Palliative Care.}, journal = {Muscle & nerve}, volume = {74}, number = {2}, pages = {427-432}, pmid = {42174751}, issn = {1097-4598}, support = {A142921//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Palliative Care/methods ; Female ; Male ; *Patient Care Team ; Middle Aged ; Surveys and Questionnaires ; Adult ; *Personal Satisfaction ; Referral and Consultation ; }, abstract = {INTRODUCTION/AIMS: Specialty palliative care (SPC) can improve symptoms and well-being for people living with ALS. Few studies capture how ALS clinicians utilize or are impacted by SPC. We sought to understand how the presence of SPC clinicians on ALS teams impacts ALS clinicians' referrals to and satisfaction with SPC.

METHODS: We conducted a survey of interdisciplinary ALS clinicians to understand their confidence in their team's care, SPC referral patterns, and satisfaction with SPC. We compared responses from ALS clinicians with and without SPC in their team.

RESULTS: 141 ALS clinicians completed the survey, having primarily neurology, nursing, and therapy backgrounds. ALS clinicians who had SPC embedded in their team reported more confidence in their team's ability to address pain (63.3% v 37.4%, p < 0.001), dyspnea (88.8% v 70.8%, p = 0.05), and end-of-life needs (71.4% v 52.1%, p = 0.005). They reported fewer SPC referral barriers and referred to SPC for different reasons. ALS clinicians with SPC on their team were more satisfied with SPC's ability to help with motor symptoms (92.7% v 71.4%, p = 0.02), dyspnea (98.3% v 86.7%, p = 0.04), and care coordination (90.0% v 73.5%, p = 0.04).

DISCUSSION: The presence of SPC embedded within multidisciplinary ALS teams is associated with ALS clinicians feeling more confident in their team's ability to address certain care needs, more satisfied with the care provided by SPC, and experiencing fewer barriers to involving SPC. Additional research should explore how embedding SPC on ALS teams impacts patient outcomes.}, } @article {pmid42174808, year = {2026}, author = {Bosoni, P and Vazifehdan, M and Aidos, H and Alves, I and Birolo, G and Faggioli, G and González-Martínez, S and Gromicho, M and Jovanović, A and Kostić, B and Longato, E and Manera, U and Tavazzi, E and Tavazzi, E and Bellazzi, R and Bergamaschi, R and Fernanda Cabrera, M and Chiò, A and de Carvalho, M and di Camillo, B and Fariselli, P and Ferro, N and Madeira, SC and Dagliati, A}, title = {Environmental Personal Exposure Clusters to Investigate Multiple Sclerosis and Amyotrophic Lateral Sclerosis Progression.}, journal = {Studies in health technology and informatics}, volume = {336}, number = {}, pages = {173-177}, doi = {10.3233/SHTI260131}, pmid = {42174808}, issn = {1879-8365}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Multiple Sclerosis/diagnosis/physiopathology ; *Environmental Exposure/analysis ; Disease Progression ; Female ; Male ; Prognosis ; Clustering Algorithms ; Wearable Electronic Devices ; Middle Aged ; Cluster Analysis ; }, abstract = {Reliable prognosis in Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS) is hampered by data scarcity and variability. Beyond clinical variables, evidence suggests that environmental data can help capture disease trajectories. We investigated whether personal environmental measures can be organized into stable patterns that inform prognosis. In a multicenter cohort, 293 patients with MS or ALS were equipped with Atmotube air-quality sensors. We normalized volatile organic compound (VOC) time series and computed Dynamic Time Warping distances to capture temporal similarity. Hierarchical clustering yielded five daily exposure clusters, which were profiled using Atmotube variables (season, day type, humidity, temperature) and patient self-reports (work status, time outdoors), and evaluated by day-level differences between personal and fixed-station variables. These clusters can support interpolation of missing wearable intervals and generation of context-aware exposure estimates, thereby strengthening environmental inputs for prognostic modeling in MS and ALS.}, } @article {pmid42174849, year = {2026}, author = {Ferraro, PM and Narteni, S and Lenatti, M and Oliveri, F and Gemelli, C and Cabona, C and Uccelli, A and Paglialonga, A and Mongelli, M and Schenone, A}, title = {A Consensus Clustering Approach to Amyotrophic Lateral Sclerosis Phenotyping.}, journal = {Studies in health technology and informatics}, volume = {336}, number = {}, pages = {338-342}, doi = {10.3233/SHTI260173}, pmid = {42174849}, issn = {1879-8365}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/classification ; Humans ; Clustering Algorithms ; *Phenotype ; Cluster Analysis ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) phenotyping is a challenging task due to its heterogeneous nature and low prevalence. In this paper, we introduce a data-driven approach to support the characterization of ALS phenotypes based on clinical data from a battery of examinations. A consensus clustering method is proposed to identify stable clusters across multiple random data sub-samples, with the objective of discovering whether the retrieved patients' groups and related features align with clinical phenotypes and medical knowledge. Results suggest consistent profiles for bulbar onset ALS patients, driven by onset characteristics, whereas spinal onset ALS patients exhibit greater within-phenotype heterogeneity.}, } @article {pmid42174979, year = {2026}, author = {Faujour, C and Bouee, S and Emery, C and Jannot, AS}, title = {Evaluating the Role of Order and Time Information for Classifying Sequences of Healthcare Events Derived from Claims Data.}, journal = {Studies in health technology and informatics}, volume = {336}, number = {}, pages = {879-883}, doi = {10.3233/SHTI260305}, pmid = {42174979}, issn = {1879-8365}, mesh = {Humans ; *Neural Networks, Computer ; Classification Algorithms ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Insurance Claim Review/statistics & numerical data ; Long Short Term Memory ; Predictive Learning Models ; Computer Simulation ; Prediction Algorithms ; Female ; }, abstract = {Sequences of healthcare events from claims data are increasingly used for predictive modeling. Despite the rise in popularity of neural networks, the benefit of modeling event order and timing remains underexplored. We simulated patient trajectories using parameters estimated from claims data including 22,000 amyotrophic lateral sclerosis (ALS) cases and 22,000 age and gender-matched controls. The simulation reproduced irregular event timing and condition-related activity that increased near an incident diagnosis. We compared three model families for population classification: frequency-based models, sequential models (long short-term memory and Transformer architectures) capturing event order, and sequential models incorporating temporal information. Performance was evaluated using the area under the ROC curve (AUC) at multiple time points before diagnosis. Sequential models outperformed frequency-based baselines by about +0.06 AUC on average, confirming the benefit of modeling event order. Adding time information provided no noticeable improvement, and results were stable across different time encoding and scaling methods. These findings suggest that, in claims-based classification tasks, event order captures most of the useful temporal signal, while explicit time encoding offers limited additional benefit under similar conditions.}, } @article {pmid42175187, year = {2026}, author = {Yadav, R and Pragya, P and Agastinose Ronickom, JF}, title = {Identification of Reliable Biomarkers for ALS Through Machine Learning Approach.}, journal = {Studies in health technology and informatics}, volume = {336}, number = {}, pages = {1705-1709}, doi = {10.3233/SHTI260516}, pmid = {42175187}, issn = {1879-8365}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Humans ; *Biomarkers/analysis ; *Machine Learning ; Boosting Machine Learning Algorithms ; Random Forest ; Gene Expression Profiling/methods ; Transcriptome ; Predictive Learning Models ; Classification Algorithms ; Sensitivity and Specificity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and limited diagnostic biomarkers. Identifying robust molecular biomarkers for ALS remains a major challenge due to disease heterogeneity and high-dimensional gene expression data. In this study, we developed a machine learning (ML) based pipeline integrating transcriptome data and feature selection to identify potential ALS biomarkers. RNA-Seq data of motor neuron disease patients and healthy controls were obtained from publicly available GEO datasets, followed by preprocessing was performed. We implemented two ensembled ML models such as eXtreme gradient boosting (XGBoost) and random forest (RF) algorithms under a five-fold stratified cross-validation framework to identify the differentially expressed genes. These models were evaluated using the performance metrics. We identified top 10 genes ranked by feature importance from the XGBoost and RF models. Notably, the DCN (Decorin) gene appears consistently in the top 10 features of both models, underscoring its stability and biological relevance. Both ML models exhibited excellent classification performance, with RF achieving 98.8% accuracy and XGBoost achieving 97.6% accuracy, alongside consistently high sensitivity, specificity, precision, and F1-score values. This work highlights the utility of transcriptomic data and ML in identifying key genes as biomarkers for diagnostic and therapeutic potential in ALS.}, } @article {pmid42177561, year = {2026}, author = {Sharma, S and Cortés-Pérez, C and Bird, S and Di Curzio, D and Vandenakker, A and Schellenberg, K and Douville, RN}, title = {ERVK activity in CD8[+] T cell immune cell compartment in patients with ALS.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {42177561}, issn = {1742-2094}, support = {19-IIA-489//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/pathology ; *CD8-Positive T-Lymphocytes/metabolism/immunology/enzymology ; Male ; Female ; Middle Aged ; *Endogenous Retroviruses/immunology ; Aged ; DNA Damage ; Leukocytes, Mononuclear/metabolism ; Adult ; }, abstract = {Endogenous retrovirus-K (ERVK) expression has been associated with Amyotrophic Lateral Sclerosis (ALS), and its viral proteins can be detected in affected brain and spinal cord tissues. Despite confirmation of ERVK load in the blood of patients with ALS, few studies have examined ERVK protein expression in immune cells. ERVK produces an enzyme called integrase (IN), which can cause DNA damage during the integration of viral DNA into the host genome. Given that genomic instability is a hallmark of ALS, we hypothesized that the ERVK IN enzyme may also be expressed in lymphoid and myeloid-derived immune cells of patients. Peripheral blood mononuclear cells (PBMC) were isolated from blood specimens using Ficoll isolation, and either flash-frozen for western blot analyses or affixed onto slides using the cytospin technique for subsequent confocal microscopy analysis. Image analysis of confocal micrographs revealed that ERVK IN expression was significantly elevated in CD3[+]CD8[+] T cells from a subset of patients with ALS as compared to controls. CD3[+]CD8[+] T cells in ALS exhibit enhanced number and size of ERVK IN puncta within the nucleus and at the plasma membrane. The DNA damage load, as measured by marker γH2AX, was strongly associated with ERVK IN levels in both controls and patients with ALS. Stratification of molecular data based on clinical parameters showed an association of elevated ERVK IN load in CD8[+] T cells from patients with ALS with lower ALSFRS-R and higher King's scores, as well as a significant decline in lung function metrics. In bulk PBMC from patients with ALS, ERVK IN was associated with expression of immune checkpoint marker PD-1, but not T cell exhaustion marker TOX. ERVK IN in CD14[+]CD11b[+] myeloid cells was also elevated, with ERVK[+] cells exhibiting notable membrane ruffling typical of immune cell activation and increased expression of HLA-DR. However, ERVK IN expression in monocytes was not correlated with clinical metrics in patients with ALS. This work points to the use of ERVK IN in CD8[+] cytotoxic T cells as a blood biomarker for ALS clinical trials, especially those focused on testing the efficacy of antivirals as a therapeutic strategy for ALS.}, } @article {pmid42178739, year = {2026}, author = {Paquet, A and Touzel-Deschênes, L and Roy, V and Saikali, S and Dupré, N and Gros-Louis, F}, title = {Proteomic Analysis of Corpora Amylacea Extracted From Post-mortem Brain of MAiD-end-of-life Sporadic ALS Patients.}, journal = {Brain and behavior}, volume = {16}, number = {5}, pages = {e71486}, pmid = {42178739}, issn = {2162-3279}, support = {//tier-1 Canada Research Chair/ ; //CHU de Québec Foundation-Desjardins/ ; /CAPMC/CIHR/Canada ; //Canada Foundation for Innovation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Proteomics/methods ; *Brain/metabolism/pathology ; Female ; *Inclusion Bodies/metabolism/pathology ; Aged ; Male ; Middle Aged ; Biomarkers/metabolism ; Proteome/metabolism ; Aged, 80 and over ; }, abstract = {PURPOSE: Corpora amylacea (CA) are starch-like inclusions that accumulate in the central nervous system (CNS) with aging and are enriched in neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS). Although often regarded as waste reservoirs, their cellular origins, molecular composition, and pathological significance remain poorly understood.

METHODS: Here, we performed an unbiased proteomic analysis of purified CAs isolated from post-mortem brains of sporadic ALS patients and controls.

FINDINGS: In-depth mass spectrometry identified 4,470 proteins, of which 658 were quantified, revealing distinct ALS-specific proteomic signatures. Enriched proteins included markers of cytoskeletal remodeling, mitochondrial dysfunction, and proteostasis disruption, as well as known ALS-associated proteins such as TDP-43 and neurofilament proteins. These findings demonstrate that CAs serve as reservoirs of dysfunctional, disease-relevant proteins and capture key pathological processes in ALS.

CONCLUSION: By applying an unbiased proteomic approach to purified CAs, this study provides the first comprehensive map of their protein content in ALS, supporting their potential as biomarker sources and as a source of mechanistic insights into neurodegeneration.

SIGNIFICANCE: Unbiased analyses of CAs in the context of ALS have yet to be undertaken. This study provides the first proteomic profiling of purified CAs, isolated from ALS patient brains using biochemical methods, revealing that CAs harbor disease-relevant proteins implicated in sporadic ALS. By demonstrating that CAs act as reservoirs of dysfunctional proteins related to metabolism, cytoskeletal organization, and proteostasis, our findings highlight their potential as a novel source of ALS-specific mechanistic insight into disease pathology.}, } @article {pmid42178909, year = {2026}, author = {Debnath, J and Leidal, AM}, title = {Membrane ATG8ylation in secretory autophagy.}, journal = {Autophagy}, volume = {22}, number = {10}, pages = {2522-2537}, doi = {10.1080/15548627.2026.2676796}, pmid = {42178909}, issn = {1554-8635}, mesh = {*Autophagy/physiology ; Humans ; Animals ; *Autophagy-Related Protein 8 Family/metabolism ; *Cell Membrane/metabolism ; }, abstract = {Mammalian Atg8-family (ATG8) proteins are crucial for macroautophagic/autophagic degradation in the lysosome and facilitate non-degradative processes including multiple distinct forms of unconventional protein secretion. These secretion pathways, collectively termed secretory autophagy, depend upon ATG8 conjugated to membranes to both specify and traffic molecules for extracellular release. Here, we review the current understanding of how membrane ATG8ylation supports secretory autophagy, and propose a cell biological framework for classifying the growing repertoire of secretory autophagy pathways based on membrane ATG8ylation at discrete intracellular vesicular intermediates. Finally, we detail the emerging roles of these pathways in physiology and disease.Abbreviations: Aβ, amyloid-β; Acb1, acyl-coA-binding 1; ALS, amyotrophic lateral sclerosis; APP, amyloid beta precursor protein; APEX2, ascorbate peroxidase; ATG, autophagy related; AWOL, autophagosome-mediated exit without lysis; BafA1, bafilomycin A1; BirA*, mutant BirA biotin ligase; BMI, body-mass index; CASM, ATG8 conjugation at single membranes; DAMPs, danger/damage-associated molecular patterns; DBI, diazepam binding inhibitor, acyl-CoA binding protein; DSS, dextran sodium sulfate; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum intermediate compartment; ESCRT, endosomal complexes required for transport; EVs, extracellular vesicles; EVPs, extracellular vesicles and particles; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IFNB, interferon beta; ILV, intralumenal vesicles; LANDO, LC3-associated endocytosis; LAP, LC3-associated phagocytosis; LIR, LC3 interacting region; LDELS, LC3-dependent EV loading and secretion; LLOMe, L-leucyl-L-leucine methyl ester hydrobromide; M2, influenza A virus matrix 2, MAD, migratory autolysosome disposal; miRNAs, microRNAs; M-MDSC, monocytic myeloid derived suppressor cells; MVEs, multivesicular endosomes; PAMPs, pathogen-associated molecular patterns; P-bodies, processing bodies; PE, phosphatidylethanolamine; PD, Parkinson disease; PS, phosphatidylserine; RBPs, RNA binding proteins; R-EV, RAB22A-induced extracellular vesicle; SLC2A1, solute carrier family 2 member 1; TFRC, transferrin receptor; TGN, trans-Golgi network; TMED10, transmembrane p24 trafficking protein 10; THU, TMED10-channeled unconventional secretion; SALI, secretory autophagy during lysosome inhibition; SCF, SKP1-CUL1-F-box; SNAREs, soluble NSF attachment protein receptors.}, } @article {pmid42178983, year = {2026}, author = {Liu, JQ and Liu, H and Sun, YX and Li, Y and Liu, X and Wang, LQ and Yang, Z and Fu, Q and Xu, X and Chen, J and Zhang, Y and Zhou, J and Le, W and Cui, M and Liang, Y}, title = {Protein Disulfide Isomerase Disassembles TDP-43/G3BP1 Condensates and Antagonizes TDP-43 Pathological Aggregates.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {38}, pages = {e16846}, pmid = {42178983}, issn = {2198-3844}, support = {U1967221//National Natural Science Foundation of China/ ; 32071212//National Natural Science Foundation of China/ ; 22022601//National Natural Science Foundation of China/ ; 2024YFA1307300//National Key Research and Development Program of China/ ; 2023ZD0507202//National Major Science and Technology Projects of China/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; Humans ; *Protein Disulfide-Isomerases/metabolism/genetics ; *RNA Recognition Motif Proteins/metabolism/genetics ; *DNA Helicases/metabolism/genetics ; *RNA Helicases/metabolism/genetics ; *Protein Aggregation, Pathological/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Mitochondria/metabolism ; Animals ; Poly-ADP-Ribose Binding Proteins ; }, abstract = {Cytoplasmic mislocalization and aggregation of transactive response DNA-binding protein-43 (TDP-43) is a common pathological feature of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease with TDP-43 pathology (AD-TDP); the exact role of protein disulfide isomerase (PDI), an enzyme with chaperone activity, in modulating the pathological behavior of TDP-43 is unknown. In this study, we report that wild-type PDI, through its specific interaction with TDP-43, markedly attenuates phase separation of TDP-43, competitively displaces G3BP1 to disassemble TDP-43/G3BP1 condensates, and further counteracts the pathological mislocalization, abnormal phosphorylation, and pathological aggregation of TDP-43 through the b' domain of the enzyme. Ultimately, this alleviates mitochondrial damage and neuronal toxicity caused by TDP-43 aggregation and suppresses UNC13A cryptic splicing in stressed cells. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS and AD-TDP patients. These findings not only provide new insights into the pathogenic mechanisms of TDP-43 in neurodegenerative diseases such as ALS and AD-TDP, but also propose PDI as a potential therapeutic target.}, } @article {pmid42180530, year = {2026}, author = {Zhao, W and Lai, Y and Li, Z and Yuan, Z and Wen, Z and Zhang, L}, title = {Targeting non-apoptotic regulated cell death (RCD) to treat neurodegenerative diseases.}, journal = {Acta pharmaceutica Sinica. B}, volume = {16}, number = {5}, pages = {2601-2644}, pmid = {42180530}, issn = {2211-3835}, abstract = {Regulated cell death (RCD) is well-known as a controlled form of cell death regulated by one or more cascading signaling pathways. Over the past few decades, increasing evidence has implicated various non-apoptotic forms of RCD in neurons-including ferroptosis, parthanatos, necroptosis, pyroptosis, autophagic cell death, paraptosis, and cuproptosis-in the pathogenesis of neurodegenerative diseases (NDs) and their associated clinical manifestations. We provide an in-depth analysis of the associations between these RCDs and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), and highlight the potential of modulating non-apoptotic RCD subtypes as neuroprotective targets. Besides, we highlight the crosstalk mechanisms among different non-apoptotic RCDs in NDs and the key targets regulating the crosstalk, which hold significant promise for developing dual-functional inhibitors that precisely modulate the pathological microenvironment and overcome drug resistance. As our understanding of death signaling networks deepens, such strategies may lead to breakthrough therapies for multiple NDs. Moreover, we further discuss the emerging small molecule compounds targeting non-apoptotic RCDs and their current research progress in clinical trials for the treatment of NDs, which may provide novel directions for related drugs. This comprehensive analysis paves the way for future research and therapeutic strategies aimed at harnessing non-apoptotic RCD pathways to mitigate neurodegeneration and improve patient outcomes.}, } @article {pmid42181829, year = {2026}, author = {Kuru Çolak, T and Akçay, B and Weiss, HR and Nan, X and Elliott, L and Akkoyunlu, SZ and Borysov, M}, title = {Treatment outcomes across curve patterns and severities in adolescent idiopathic scoliosis treated with a pattern-specific CAD-CAM brace.}, journal = {Frontiers in rehabilitation sciences}, volume = {7}, number = {}, pages = {1826976}, pmid = {42181829}, issn = {2673-6861}, abstract = {BACKGROUND: Whether treatment outcomes differ according to curve pattern or baseline severity in adolescents with idiopathic scoliosis (AIS) remains a subject of debate. In particular, it is unclear whether pattern-specific, CAD-CAM-designed brace systems provide comparable effectiveness across different curvature types. This study aimed to evaluate the influence of curve pattern and initial curve magnitude on treatment outcomes in AIS patients treated with a pattern-specific CAD-CAM-designed brace.

METHODS: A retrospective analysis was conducted on female AIS patients aged 10-14 years (Risser 0-2) treated between 2015 and 2024. Cobb angle and angle of trunk rotation (ATR) were used as primary outcome measures. Data from four international clinics were analyzed for changes in spinal curvature and curve pattern.

RESULTS: A total of 145 patients were included (mean age 12.2 years; mean Cobb angle 38.4° ± 11.4°). Post-treatment, mean Cobb angle and ATR values decreased significantly (p < 0.001). The overall treatment success rate was 91%, with no significant differences based on apex vertebra location (p = 0.459), ALS patterns (p = 0.705), or baseline curve severity (p = 0.274).

CONCLUSION: In this multicenter cohort of skeletally immature adolescents with idiopathic scoliosis, pattern-specific brace treatment was associated with significant reductions in both radiographic curvature and trunk rotation. Improvements were observed across different curve patterns and baseline severities. However, given the retrospective design and absence of a comparison group, these findings should be interpreted with caution. Prospective controlled studies are warranted to further validate these observations.}, } @article {pmid42182254, year = {2026}, author = {Fonda, BD and Murray, DT}, title = {Phosphorylation Mimicking Mutations Cause TDP-43 to Adopt Different Fibril Conformations.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42182254}, issn = {2692-8205}, support = {R35 GM142892/GM/NIGMS NIH HHS/United States ; }, abstract = {The Tar-DNA Binding Protein-43 C-terminal region, TDP43LC, has been previously shown to form amyloid-like fibrils with distinct folds in ALS and FTD. In both diseases, proteinaceous inclusions contain TDP43 C-terminal protein fragments as well as phosphorylated TDP43. Here, we use solution NMR to show that soluble phosphomimetic TDP43LC, P-TDP43LC, is structurally similar to wild-type TDP43LC. Disperse P-TDP43LC, like wild-type protein, contains a central helical region flanked by long disordered regions. Despite this similarity, our turbidity measurements, imaging, and kinetic assays show that P-TDP43LC has different aggregation behavior than wild-type protein. Using solid state NMR measurements we find that that phosphomimetic mutations alter the wild-type fibril conformation. Electrostatic repulsion from negatively charged sidechains, despite having little effect on the soluble protein's structure, perturbs amyloid-like fibril formation and selects for a different conformation in vitro. These results shed light on the structural role of TDP43LC phosphorylation in fibril formation in disease.}, } @article {pmid42182325, year = {2026}, author = {Chauhan, BS and Brennan, MA and Forstmeier, PC and Yifu, H and Godfrey, RK and Van Keuren-Jensen, K and Sattler, R and Ichida, J and Zarnescu, DC}, title = {C9orf72 -associated G4C2 hexanucleotide repeat expression in Drosophila mushroom bodies causes age dependent TDP-43 pathology and dementia relevant phenotypes mediated in part by the glypican Dlp/GPC6.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.08.723849}, pmid = {42182325}, issn = {2692-8205}, abstract = {Hexanucleotide repeat expansions (HREs) in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet the age-, sex-, repeat-length-, and circuit-specific influence on the pathology of neurons remains incompletely understood. Here, we established a Drosophila model of C9orf72 -associated dementia by expressing G4C2 repeats in mushroom body neurons (MBNs), a brain region critical for memory, locomotion, and sleep. Expression of 44X G4C2 repeats ((G4C2) 44X) led to progressive axonal thinning, age-dependent accumulation of Repeat Associated Non-AUG (RAN) translated GR-GFP dipeptide repeat (DPR) puncta, premature nuclear-to-cytoplasmic mislocalization of endogenous TDP-43, increased caspase, reduced lifespan and a loss of presynaptic active zones. Behaviorally, (G4C2) 44X expression caused locomotor hyperactivity, altered spatial working memory, and fragmentation of sleep architecture in an age- and sex-dependent manner, recapitulating core features of FTD. Surprisingly, the shorter (G4C2) 12X repeat, traditionally considered a control, also produced detectable RAN translation and intermediate phenotypes in aging MBNs, suggesting that length- and tissue-associated factors modulate repeat toxicity. We further identified a repeat-length- and age-dependent reduction of the glypican Dally-like protein (Dlp) in (G4C2) 44X consistent with disrupted Wnt-related signaling linked to TDP-43 proteinopathies. Restoring Dlp expression in MBNs mitigated locomotor and working-memory alterations, and loss of presynaptic active zones. In contrast, axonal degeneration, TDP-43 mislocalization, and lifespan were not significantly improved by restoring Dlp, suggesting that multiple mechanisms contribute to G4C2-induced toxicity. Supporting our findings in Drosophila MBNs, a CRISPRi screen in TDP-43 knock-down iNeurons identified GPC6, a human ortholog of Dlp, as a significant contributor to TDP-43 dependent synaptic loss. Together, our findings reveal an aging-sensitive, circuit-specific model of C9orf72 -associated neurodegeneration and highlight roles for DPR accumulation and Dlp/GPC6 dependent synaptic loss in FTD pathomechanisms.}, } @article {pmid42183197, year = {2026}, author = {Dashti, M and AlAbdulghafour, F and AlMutairi, O and Mohammad, A and Malik, MZ and AlRefaie, K and Nizam, R and Jacob, S and Chalabi, A and Al Khleifat, A and Al-Mulla, F}, title = {Classical HLA class II associations with ALS in Kuwait reveal a DR7-DQ2.2 risk haplotype.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1820694}, pmid = {42183197}, issn = {1664-3224}, mesh = {Humans ; Kuwait ; *Haplotypes ; Male ; *Genetic Predisposition to Disease ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/genetics/immunology ; *Histocompatibility Antigens Class II/genetics ; Alleles ; Aged ; Genome-Wide Association Study ; *HLA-DQ Antigens/genetics ; Gene Frequency ; }, abstract = {BACKGROUND: Genome-wide association studies have implicated the human leukocyte antigen/major histocompatibility complex (HLA/MHC) region in amyotrophic lateral sclerosis (ALS) susceptibility, and immune dysregulation is increasingly recognised as a modifier of disease course. High-resolution HLA data for ALS remain confined to European and East Asian ancestries. We tested whether classical HLA class I and class II variation contributes to ALS susceptibility in a Kuwaiti cohort.

METHODS: We analysed 38 unrelated ALS cases (mean age, 57.4 years; 63.2% male) and 150 population-matched controls (mean age, 57.0 years) from Kuwait. HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 alleles were typed at two-field resolution using HLA-HD from next-generation sequencing (NGS) data. Allele, haplotype, and amino-acid residue associations were tested in BIGDAWG with locus-specific Bonferroni correction, with additional across-locus sensitivity analysis. Significant class II residues were mapped onto AlphaFold 3 structural models and interpreted alongside published class II crystal structures.

RESULTS: No class I allele, haplotype, or residue remained significant after correction. In class II, DQA1*02:01 [odds ratio (OR) = 3.18, 95% confidence interval (CI) 1.67 to 5.95, p c = 0.0007], DRB1*07:01 (OR = 3.00, 95% CI: 1.58-5.59, p c = 0.001), and DQB1*02:02 (OR = 2.48, 95% CI: 1.28-4.69, p c = 0.03) were enriched in cases. The extended haplotype DQA1*02:01~DQB1*02:02~DRB1*07:01 (DR7-DQ2.2) conferred increased odds of ALS (OR = 3.11, 95% CI: 1.53-6.19, p c = 0.002). Amino-acid residue analysis identified convergent risk positions in DQα1 (positions 47, 52, and 54; OR = 3.18, p c = 0.006) and DRβ1 (positions 11, 13, 14, 25, and 30; OR = 2.84, p c = 0.03) that map to the peptide-binding groove and correspond to the defining motifs of DQA1*02:01 and DRB1*07:01.

CONCLUSION: Using high-resolution NGS-based HLA typing in a Kuwaiti cohort, we identified a class II risk signal for ALS centred on the DR7-DQ2.2 haplotype with convergent residue-level support in the peptide-binding domains. These findings support a contribution of class II-restricted antigen presentation to ALS susceptibility and warrant functional validation and replication in larger, independent Middle Eastern cohorts.}, } @article {pmid42183611, year = {2026}, author = {Ji, F and Dai, M and Wang, Z and Dai, E and Kang, R and Klionsky, DJ and Tang, D and Huang, Y and Sun, Y and Liu, T}, title = {Mammalian lysophagy: mechanisms and pathophysiological implications.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/15548627.2026.2679642}, pmid = {42183611}, issn = {1554-8635}, abstract = {Lysophagy is a form of selective macroautophagy/autophagy that preserves lysosomal integrity by eliminating damaged lysosomes. Lysosomal membrane permeabilization can arise from diverse physiological and pathological insults, including proteotoxic stress, crystalline particles, pathogens and chemical perturbations, and occurs along a continuum ranging from transient nanoscale lesions to catastrophic rupture. Cells respond to lysosomal injury through a hierarchical quality-control network in which membrane repair, lysophagic removal and lysosomal regeneration operate in a coordinated manner. Damage recognition involves sensing of exposed lumenal glycans and membrane lipids, followed by ubiquitin-dependent tagging that recruits selective autophagy receptors and activates the core autophagy machinery to form lysophagosomes. Lysophagy is closely integrated with membrane repair pathways, metabolic signaling and innate immune responses that together determine lysosomal fate. Dysregulated lysosomal quality control has been implicated in diverse diseases, including neurodegeneration, infection, cancer and chronic inflammatory disorders. In this review, we summarize current mechanistic insights and emerging experimental approaches for studying lysosomal quality control and lysophagy in mammalian cells.Abbreviations: ALR, autophagic lysosome reformation; ALS, amyotrophic lateral sclerosis; ATG8, mammalian Atg8-family protein; ER, endoplasmic reticulum; ESCRT, endosomal sorting complexes required for transport; LAMPs, lysosome associated membrane proteins; LIR, LC3-interacting region; LLOMe, L-leucyl-L-leucine methyl ester; LMP, lysosomal membrane permeabilization; PITT, phosphoinositide-initiated membrane tethering and lipid transport; PtdIns3K, class III phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; PtdIns4P, phosphatidylinositol-4-phosphate; ROS, reactive oxygen species; V-ATPase, vacuolar-type H[+] -ATPase.}, } @article {pmid42183628, year = {2026}, author = {Zhou, W and Zhang, MM and Tang, W and Singh, BK and Zhang, Z and Zhou, L and Goh, JKW and Tan, FRE and Huang, J and Sun, Q and Xiao, B and Priyanka, G and Sun, AX and Zeng, L and Shen, HM and Tan, EK}, title = {CHCHD2 and CHCHD10 promoted autophagic clearance of protein aggregates via GABARAPs.}, journal = {Autophagy}, volume = {22}, number = {10}, pages = {2947-2976}, doi = {10.1080/15548627.2026.2678427}, pmid = {42183628}, issn = {1554-8635}, mesh = {Humans ; *Autophagy/genetics/physiology ; *Mitochondrial Proteins/metabolism/genetics ; Animals ; *Transcription Factors/metabolism/genetics ; *Microtubule-Associated Proteins/metabolism ; *Protein Aggregates ; DNA-Binding Proteins/metabolism ; Mice ; *Apoptosis Regulatory Proteins/metabolism ; Mutation/genetics ; }, abstract = {Mutations in mitochondrial protein CHCHD2 and its paralog CHCHD10 were identified in patients with Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) or Alzheimer disease (AD). CHCHD2 and CHCHD10 mutations caused neurodegeneration in model animals as seen in patients, but their pathophysiological roles remain elusive. Here we reported a direct role of CHCHD2 and CHCHD10 in autophagy. We identified a protein complex composing of CHCHD2-CHCHD10-C1QBP/p32-Atg8-family proteins (ATG8s), in which each molecule interacted with another. CHCHD2, CHCHD10 and C1QBP/p32 associated with ATG8s, preferentially, GABARAPs. Disease-associated CHCHD2 and CHCHD10 mutations exhibited varied interaction with ATG8s. By binding to GABARAPs, CHCHD2 and CHCHD10 underwent autophagic degradation, and recruited the ULK1 complex. Autophagy initiation defects occurred upon transient knockdown of CHCHD2, and also in human iPSC-derived CHCHD2[-/-] or CHCHD2[T61I] dopaminergic neurons. Importantly, CHCHD2 and CHCHD10 promoted autophagy. CHCHD2 reduced protein aggregates in cells and toxic SNCA/α-synuclein species in mouse striatum. Our study thus revealed mitochondrial proteins CHCHD2 and CHCHD10 as both autophagy substrates and autophagy activators and laid groundwork for therapy targeting patients with neurodegeneration.Abbreviations: AA: amino acid; AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG8: mammalian Atg8-family protein; ATG13: autophagy related 13; bafA1: bafilomycin A1; C1QBP/p32/gC1qR/HABP1: complement component 1, q subcomponent binding protein; CHCHD2/MNRR1/MIX17B: coiled-coil-helix-coiled-coil-helix domain containing 2; CHCHD10/MIX17A: coiled-coil-helix-coiled-coil-helix domain containing 10; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CRISPR: clustered regularly interspaced short palindromic repeats; CQ, chloroquine; DA: dopaminergic; DMSO: dimethyl sulfoxide; EBSS: Earle's balanced salt solution; RB1CC1/FIP200: RB1 inducible coiled-coil 1; FTD: frontotemporal dementia; GABARAP: gamma-aminobutyric acid receptorbassociated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; hESC: human embryonic stem cells; iPSC: induced pluripotent stem cell; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; LIR: LC3-interacting region; PD: Parkinson disease; SQSTM1/p62: sequestosome 1; TARDBP/TDP-43: TAR DNA binding protein; TH: tyrosine hydroxylase; TMR, tetramethylrhodamine; WT: wild type; UB: ubiquitin; ULK1: unc-51 like kinase 1.}, } @article {pmid42183665, year = {2026}, author = {Tavaglione, L and Madonia, N and Corrado, L and Comi, C and D'Alfonso, S and Mazzini, L and De Marchi, F}, title = {Expanding the phenotypic spectrum of SOD1‑related ALS: upper motor neuron predominance in a p.D91A case.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/17582024.2026.2676822}, pmid = {42183665}, issn = {1758-2032}, abstract = {Mutations in superoxide dismutase 1 SOD1 are the second most common genetic cause of ALS, usually associated with prevalent lower motor neuron phenotypes. We describe a 66-year-old woman with slowly progressive spastic paraparesis, initially diagnosed as primary lateral sclerosis, who carried a heterozygous p.D91A mutation. Clinical and neurophysiological findings indicated predominant upper motor neuron involvement, an unusual presentation for this mutation. This case broadens the SOD1 phenotypic spectrum and highlights the importance of early genetic testing in atypical motor syndromes, given the availability of targeted therapies where diagnostic delay may limit benefit.}, } @article {pmid42183747, year = {2026}, author = {Ma, G and Shi, Y and Qiu, J and Ren, C and Shao, K and Shu, X}, title = {Cumulative environmental burden and neurodegenerative disease mortality: a national ecological study in the United States.}, journal = {American journal of epidemiology}, volume = {195}, number = {9}, pages = {2440-2449}, doi = {10.1093/aje/kwag114}, pmid = {42183747}, issn = {1476-6256}, support = {//Project of Jiangsu Province Engineering Research Center of Molecular Target Therapy and Companion Diagnostics in Oncology/ ; //Wu Jieping Medical Foundation-Clinical Research Special Grant/ ; //Suzhou Applied Basic Research Program (Medical and Health Care)-Science and Technology Innovation Project/ ; //Outstanding Young Talents Project in Health of Qilu; the Youth Talent Training Program from Qingdao Medical College of Qingdao University/ ; //Taishan Scholar Project/ ; //Key Project of Shandong Provincial Natural Science Foundation/ ; //Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions, China; the Shandong Provincial Postdoctoral Foundation Project/ ; //Nuclear Energy Development Project, China/ ; //Suzhou Clinical Trial Institution Capacity Enhancement Project/ ; //Suzhou Medical and Industrial Integration Collaborative Innovation Research Project/ ; //Social Development-Clinical Frontier Technology Project of the Science and Technology Department of Jiangsu Province/ ; //Scientific Research Foundation for Talented Scholars in Soochow University, China/ ; }, mesh = {Humans ; United States/epidemiology ; *Neurodegenerative Diseases/mortality ; *Environmental Exposure/adverse effects/statistics & numerical data/analysis ; Female ; Male ; Aged ; Bayes Theorem ; }, abstract = {Neurodegenerative diseases (NDDs) represent a growing cause of mortality and disability among aging populations worldwide. However, the relationship between cumulative, multidomain environmental exposures, and NDD mortality remains poorly characterized. This study aimed to examine the association between comprehensive environmental quality and NDD mortality in the United States. We used the environmental quality index (EQI) from 2000 to 2005 to characterize cumulative environmental exposure. Associations between EQI quintiles and NDD mortality, including dementia, Parkinson's disease (PD), amyotrophic lateral sclerosis, and Huntington's disease, were examined using Bayesian interval-censored mixed-effects models. During 2006-2020, among 3.66 million NDD deaths, poorer environmental quality (Q5 vs Q1) was associated with mortality rate differences of 24.72 (95% credible intervals [CrI]: 22.43, 27.06) per 100 000 at 5-year lag, 26.74 (95% CrI: 24.34, 29.21) at 10-year lag, and 22.74 (95% CrI: 20.49, 25.13) at 15-year lag. Within each lag period, a clear dose-response pattern was consistently observed across EQI quintiles. Furthermore, associations were most pronounced for the air quality, followed by sociodemographic disadvantage. In addition, demographic and geographic heterogeneity was observed across sex, race, census regions, urbanicity, climate zone, and county economic type. These findings underscore the need for integrated, place-based environmental health policies targeting neurodegeneration prevention.}, } @article {pmid42183749, year = {2026}, author = {Trad, G and Lenglet, T and Querin, G and Blancho, S and Marchand-Pauvert, V and Hogrel, JY and Pradat, PF}, title = {Beyond outcomes: patients' lived experience of exoskeleton-assisted gait training in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2674021}, pmid = {42183749}, issn = {2167-9223}, abstract = {OBJECTIVES: To explore patients' expectations and lived experience of Atalante exoskeleton-assisted gait training in amyotrophic lateral sclerosis (ALS).

METHODS: In the EXALS study (NCT06199284), 10 ambulatory ALS participants completed 18 sessions of Atalante exoskeleton-assisted gait training. After completion of the intervention phase, post-training semi-structured interviews were audio-recorded, transcribed verbatim, and analyzed using inductive qualitative content analysis approach. Structured interview items were summarized descriptively.

RESULTS: Ten participants reported positive expectations and experiences. Initial expectations most often included contributing to research (5/10), maintaining walking ability (4/10), and improving gait quality/balance (3/10). Expectation fulfillment was high (very satisfied: 7/10). The rehabilitative aspect was most frequently ranked as most reflective of the experience (rank 1: 4/10), followed by motivational/recreational (rank 2: 4/10), psychological/emotional was most often ranked last (rank 5: 5/10). Participants described perceived benefits including improved upright posture, stability, reduced stiffness, smoother gait, and reduced fear of falling, though some effects were described as short-lived. Three-word summaries were predominantly positive (8/10), commonly "interesting" and "motivating," with occasional negatives (tiring/heavy/repetitive/disappointing; 2/10). Compared with conventional physiotherapy, sessions were perceived as more dynamic and walking-focused, with a structured, innovative, closely supervised set-up. Suggested improvements centered on increasing access/dose, expanding walking space and training content, and enhancing safety/user control. Most participants would continue training if available (8/10), most commonly preferring two sessions per week (4/8).

CONCLUSIONS: Exoskeleton-assisted gait training was experienced as acceptable and meaningful. Translating this into practice will require aligning future protocols with patient priorities, autonomy/safety, access and delivery logistics, and broader functional content alongside quantitative evaluation.}, } @article {pmid42185781, year = {2026}, author = {Fujiwara, Y and Hashiguchi, A and Yamashiro, S and Seno, H and Ohya, Y and Yasutomi, D and Fujisaki, N and Kido, M and Suwazono, S and Tokashiki, T}, title = {Association between creatinine-to-cystatin C ratio and ALSFRS-R across clinical phenotypes.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {}, pmid = {42185781}, issn = {1471-2377}, mesh = {Humans ; *Cystatin C/blood ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; *Creatinine/blood ; Male ; Female ; Retrospective Studies ; Cross-Sectional Studies ; Biomarkers/blood ; Aged ; Phenotype ; Middle Aged ; }, abstract = {BACKGROUND: Reliable and accessible biomarkers for amyotrophic lateral sclerosis (ALS) are scarce. Creatinine (Cre) reflects muscle mass, whereas cystatin C (CysC) may reflect neurodegeneration without being directly influenced by muscle mass; however, both have limitations. We aimed to investigate whether the creatinine-to-cystatin C ratio (Cre/CysC) was cross-sectionally associated with functional status in patients with ALS.

METHODS: We retrospectively analyzed 30 patients diagnosed with ALS at the National Organization Hospital Okinawa Hospital between 2021 and 2024. Baseline ALS Functional Rating Scale-Revised (ALSFRS-R) scores and serum Cre and CysC levels were recorded. Associations with the ALSFRS-R were assessed using Spearman's correlation, with subgroup analyses by sex, site of onset, age at diagnosis, body mass index (BMI), and diagnostic delay. Multivariable analyses were performed to examine the independent association between Cre/CysC and ALSFRS-R while accounting for relevant clinical covariates.

RESULTS: Cre/CysC showed a stronger cross-sectional correlation with ALSFRS-R (rs=0.648, p = 0.0001) than Cre alone (rs =0.427) or CysC (rs =-0.119). Exploratory subgroup analyses showed generally positive associations in several subgroups, although no statistically significant association was observed in the small bulbar-onset subgroup. In multivariable analysis adjusted for age at onset and diagnostic delay, Cre/CysC remained independently associated with ALSFRS-R (β = 20.1, 95% CI 6.41-33.9, p = 0.006). Given the small sample size and cross-sectional design, these findings should be interpreted as exploratory.

CONCLUSIONS: Cre/CysC showed a stronger cross-sectional association with functional status than either marker alone. Because it is derived from routine laboratory tests, Cre/CysC may represent a simple exploratory measure associated with functional status in ALS. However, the present findings do not establish prognostic utility or fully account for disease stage and biological heterogeneity. Prospective longitudinal studies incorporating disease progression measures and broader clinical and genetic characterization are warranted.}, } @article {pmid42186042, year = {2026}, author = {Salgueiro, AM and Ferreira-Marques, M and Ribeiro, RFN and Lopes, SM and Pereira, D and Costa, DG and Santana, MM and de Almeida, LP and Cavadas, C}, title = {Ketogenic diet as a therapeutic strategy for neurodegenerative diseases: from mechanisms to translational challenges.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {42186042}, issn = {2047-9158}, support = {UIDB/04539/2020//Fundação para a Ciência e a Tecnologia/ ; UIDP/04539/2020//Fundação para a Ciência e a Tecnologia/ ; LA/P/0058/2020(JPND/ 0001/2022//Fundação para a Ciência e a Tecnologia/ ; DOI: 10.54499/JPND/0001/2022; JPND/0002/2022//Fundação para a Ciência e a Tecnologia/ ; DOI: 10.54499/JPND/0002/2022//Fundação para a Ciência e a Tecnologia/ ; SFRH/BD/120023/2016; 2020.04850.BD//Fundação para a Ciência e a Tecnologia/ ; 2022.11293.BD//Fundação para a Ciência e a Tecnologia/ ; GeneT project-The Gene Therapy CoE at the Center of Portugal (Project ID: 101059981//HORIZON EUROPE Widening participation and spreading excellence/ ; DOI: 10.3030/101059981); GCure - From Gene to Cure//HORIZON EUROPE Widening participation and spreading excellence/ ; ID: 101186929//HORIZON EUROPE Widening participation and spreading excellence/ ; DOI:10.3030/101186929; GeneH - Excellence Hub for Advancing Innovation in Gene Therapy//HORIZON EUROPE Widening participation and spreading excellence/ ; ID: 101186939//HORIZON EUROPE Widening participation and spreading excellence/ ; DOI: 10.3030/101186939//HORIZON EUROPE Widening participation and spreading excellence/ ; }, mesh = {Humans ; *Diet, Ketogenic/methods ; *Neurodegenerative Diseases/diet therapy/metabolism ; Animals ; Oxidative Stress/physiology ; *Translational Research, Biomedical/methods ; }, abstract = {The ketogenic diet (KD) is increasingly recognized as a promising therapeutic strategy for neurodegenerative disorders because of its multifaceted impacts on key pathophysiological mechanisms. This review explores the molecular pathways through which KD may protect against neurodegeneration, including the use of ketone bodies as alternative energy substrates, reduction of oxidative stress and inflammation, modulation of autophagy and protein aggregation, and impact on the gut microbiome. The potential benefits of KD are explored across neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, based on both preclinical and clinical evidence that supports its feasibility. However, challenges in long-term safety, patient adherence, and clinical practicality limit its widespread adoption. This review underscores the potential of KD for treating neurodegeneration on the basis of current scientific evidence while highlighting the need for further research to optimize its application and address existing gaps.}, } @article {pmid42186501, year = {2026}, author = {AlSabah, AA and Reda, H}, title = {SOD1 amyotrophic lateral sclerosis associated with Neurosarcoidosis: a case report and review of the literature.}, journal = {Oxford medical case reports}, volume = {2026}, number = {5}, pages = {omag078}, pmid = {42186501}, issn = {2053-8855}, abstract = {We describe a 37-year-old man with coexisting amyotrophic lateral sclerosis (ALS) caused by a mutation in superoxide dismutase 1 (SOD1) and probable neurosarcoid myeloradiculitis. The concurrence of the two rare conditions posed significant diagnostic and therapeutic challenges. We discuss the diagnostic timeline, therapeutic interventions, outcomes over half a decade of care, and a review of relevant literature.}, } @article {pmid42186604, year = {2026}, author = {Albadri, Z and Häbel, H and Thorslund, K and Grönhagen, C and Seifert, O}, title = {Associations between bullous pemphigoid and comorbidities: A Swedish nationwide cohort study of 5,738 patients.}, journal = {Journal of multimorbidity and comorbidity}, volume = {16}, number = {}, pages = {26335565261455676}, pmid = {42186604}, issn = {2633-5565}, abstract = {BACKGROUND: Bullous pemphigoid (BP) has been linked to neurological and psychiatric disorders, but no nationwide population-based study has comprehensively examined the association of various comorbidities in BP patients in Sweden.

OBJECTIVES: To investigate the associations between BP and various comorbidities, comparing these conditions before and after BP diagnosis with a matched control group.

METHODS: A nationwide cohort study was conducted in Sweden from 2005 to 2016, including 5,738 BP cases and 17,167 age, sex and county of residence matched controls. Multivariable Cox proportional hazard regression models were used to calculate hazard ratios (HR). Univariable logistic regression assessed pre-diagnosis comorbidities, generating prevalence odds ratios (POR) with 95% confidence intervals (CI).

RESULTS: BP was associated with a significantly higher overall HR for comorbidity (HR: 2.20, 95% CI: 2.08-2.33). Before BP diagnosis, the overall comorbidity was significantly increased POR 2.72 (95% CI: 2.56-2.90). Pre-diagnosis association included dementia, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia, unipolar/bipolar disorders, suicide, diabetes, stroke, systemic lupus erythematosus, systemic sclerosis, psoriasis, lichen planus, alopecia areata, and vitiligo. After diagnosis, the overall hazard ratio (HR) for comorbidities was highest within the first year (HR 2.88, 95% CI: 2.68-3.10) and remained elevated beyond one year (HR 1.57, 95% CI: 1.44-1.71). Post-diagnosis associations remained elevated for dementia, Parkinson's disease, epilepsy, schizophrenia, unipolar/bipolar, diabetes, psoriasis, lichen planus and autoimmune diseases such as systemic sclerosis and Sjögren's syndrome.

CONCLUSION: BP is strongly associated with neurodegenerative, psychiatric, autoimmune, and metabolic comorbidities before and after diagnosis, highlighting their clinical significance as predisposing and prognostic factors in BP patients.}, } @article {pmid42187452, year = {2026}, author = {Kolukisa Birgec, B and Toprak, B and Mullen, AB}, title = {Assessment of Respiratory Rate and Simulated Apnea Utilizing the PneumoWave Biosensor: In Vitro and In Vivo Validation.}, journal = {Biosensors}, volume = {16}, number = {5}, pages = {}, pmid = {42187452}, issn = {2079-6374}, support = {YLSY2018/YLSY2020//Mi̇lli̇ Eği̇ti̇m Bakanliği/ ; }, mesh = {Humans ; *Biosensing Techniques ; *Respiratory Rate/physiology ; *Apnea/diagnosis/physiopathology ; Monitoring, Physiologic ; Male ; Adult ; Female ; Manikins ; }, abstract = {Accurate monitoring of respiratory rates is critical for early detection of a range of clinical conditions. However, standard manual counting or inadequate clinical monitoring often fails to provide reliable measurements. This study evaluated and validated the PneumoWave biosensor for respiratory rate measurement across a broad physiological range and different body postures (45°, 90°, and 180°) in both in vitro and in vivo settings. In vitro validation was performed using a SimMan ALS manikin operated at respiratory settings of 6-30 breaths per minute, with 10 s periods of simulated apnea. In vivo validation involved 20 healthy volunteers performing metronome-guided breathing while wearing bilateral PneumoWave biosensors. In vitro results demonstrated an excellent correlation between biosensors and manikin respiratory settings and captured all apnea events (r = 0.99, ICC = 0.99). In vivo findings showed good agreement with direct observational count (r = 0.99, R[2] = 0.99, ICC = 0.99), with 97% of apnea events captured by both devices in all positions. Body postures had no significant impact on biosensor accuracy. These findings demonstrate that the PneumoWave biosensor provides accurate and reliable respiratory monitoring and supports its potential as a robust, non-invasive tool for continuous clinical and remote patient monitoring.}, } @article {pmid42187823, year = {2026}, author = {Hayden, E and Kebe, A and Chen, S and Chumley, A and Xia, C and El-Zein, W and Zhong, Q and Ju, S}, title = {RNA-Binding Protein TAF15 Suppresses Toxicity in a Yeast Model of FUS Proteinopathy.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {42187823}, issn = {2309-608X}, support = {R15 NS109804/NS/NINDS NIH HHS/United States ; 1R15NS109804-01A1/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in an RNA-binding protein FUS are known to cause familial amyotrophic lateral sclerosis (ALS). Since this discovery, mutations in several other RNA-binding proteins (RBPs) have also been linked to ALS. Some of these ALS-associated RBPs have been shown to colocalize with ribonucleoprotein (RNP) granules such as stress granules and processing bodies (p-bodies). Increasing evidence has emerged supporting a hypothesis that the impaired clearance, inappropriate assembly, and dysregulation of RNP granules play a role in ALS. Through the genome-scale overexpression screening of a yeast model of FUS toxicity, we found that TAF15, a human RBP with a similar protein domain structure and belonging to the same FET protein family as FUS, suppresses FUS toxicity in yeast. The suppression by TAF15 is specific to FUS and not found in other yeast models of neurodegenerative disease-associated proteins. We showed that the RNA recognition motif (RRM) of TAF15 is required for its suppression of FUS toxicity. Furthermore, FUS and TAF15 physically interact, and the C-terminus of TAF15 is required for both the physical protein-protein interaction and its protection against FUS toxicity. Finally, while FUS induces and colocalizes with both stress granules and p-bodies, TAF15 only induces and colocalizes with p-bodies. Importantly, the co-expression of FUS and TAF15 induces more p-bodies than individually expressing each gene alone, and FUS toxicity is exacerbated in yeast that is deficient in p-body formation. Overall, our findings suggest a role of increased p-body formation in the suppression of FUS toxicity by TAF15.}, } @article {pmid42188341, year = {2026}, author = {Buccarello, L and Montagna, C and Di Matteo, S and Mangione, R and Carota, G and Sibbitts, J and Jarosova, R and Lunte, SM and Lazzarino, G and Caruso, G}, title = {The Bright and Dark Sides of Nitric Oxide in Neurodegenerative Diseases.}, journal = {Journal of personalized medicine}, volume = {16}, number = {5}, pages = {}, pmid = {42188341}, issn = {2075-4426}, abstract = {Nitric oxide (NO) plays an important role in neuronal communication, synaptic plasticity and vascular regulation. Due to its important function in neuronal homeostasis, NO imbalance is associated with neurodegeneration. Specifically, in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and frontotemporal lobar degeneration (FTLD), an excessive amount of NO, mostly produced by inducible NO synthase (iNOS), reacts with superoxide to form peroxynitrite, driving oxidative/nitrosative stress, mitochondrial dysfunction, and aberrant protein modifications. In AD, NO dysregulation promotes amyloid-β (Aβ) accumulation, tau hyperphosphorylation and synaptic loss, creating a self-perpetuating cycle of neuronal damage. NO's dual role, protective at physiological levels but harmful if overproduced, underscores the therapeutic potential of antioxidant compounds that restore the balance of NO/NOS (especially iNOS) while preserving physiological functions. However, despite the emerging role of antioxidant-based therapeutic approaches, clinical translation is limited by the complexity of NO signaling and the absence of safe, specific NOS inhibitors. By targeting the molecular switch from protective to toxic, NO activity may offer new personalized treatment avenues for neurodegenerative diseases.}, } @article {pmid42188687, year = {2026}, author = {Fajkić, A and Belančić, A and Pilipović, K and Rački, V and Mežnarić, S and Janković, T and Gkrinia, EMM and Vitezić, D and Mršić-Pelčić, J}, title = {Nanotube-Assisted Motor Neuron and Neuromuscular Junction Stabilization in Spinal Muscular Atrophy: A Hypothesis for Adjunctive Therapy.}, journal = {Neurology international}, volume = {18}, number = {5}, pages = {}, pmid = {42188687}, issn = {2035-8385}, abstract = {Spinal muscular atrophy (SMA) therapies that restore SMN expression improve survival and motor function but often fail to fully stabilize distal motor units or sustain endurance. We propose a hypothesis-driven adjunctive approach, intended to complement SMN-restoring therapies, in which localized nanotube-enabled interfaces acting at or near the distal motor unit and neuromuscular junction enhance neuromuscular transmission reliability in surviving, remodeled motor units. The model predicts a temporal cascade: improved junctional reliability and reduced activity-dependent failure, followed by consistent motor unit output across repeated activation, and ultimately, enhanced endurance and functional reserve. Phenotype-specific responsiveness identifies patients most likely to benefit, specifically those with preserved-but-limited residual motor unit substrate accompanied by measurable neuromuscular junction instability. Drawing on shared mechanisms from ALS, spinal cord injury, and other neuromuscular disorders, we discuss mechanistic, translational, safety, regulatory, and ethical considerations. This framework links objective physiological constructs to functional outcomes, offering a mechanistically grounded path for adjunctive therapy development in SMA and related conditions.}, } @article {pmid42190746, year = {2026}, author = {Zheng, P and Chen, L}, title = {Comments on Wu et al's "The efficacy and adverse reactions of 755 nm picosecond alexandrite laser on the treatment of nevus of Ota at different endpoints".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {4}, pages = {e355-e356}, doi = {10.1016/j.jaad.2026.03.126}, pmid = {42190746}, issn = {1097-6787}, } @article {pmid42190754, year = {2026}, author = {Wu, X and Wang, X and Zhang, Z}, title = {Response to Chen et al, "Comments on Wu et al's 'The efficacy and adverse reactions of 755 nm picosecond alexandrite laser on the treatment of nevus of Ota at different endpoints'".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {4}, pages = {e357-e358}, doi = {10.1016/j.jaad.2026.05.061}, pmid = {42190754}, issn = {1097-6787}, } @article {pmid42190894, year = {2026}, author = {Oriquat, G and Abdulqader, AF and Farid, H and Ashurov, Z and Sottarov, A and Ghafl, NY and Bainsal, N and Singh, R}, title = {From protector to perpetrator: The cGAS-STING pathway at the intersection of neurodegeneration and neuroinflammation.}, journal = {Brain research bulletin}, volume = {241}, number = {}, pages = {111963}, doi = {10.1016/j.brainresbull.2026.111963}, pmid = {42190894}, issn = {1873-2747}, mesh = {Animals ; Humans ; *cGAS-STING Signaling Pathway ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase/metabolism ; Immunity, Innate ; *Neurodegenerative Diseases/metabolism ; *Neuroinflammatory Diseases/metabolism ; *Nucleotidyltransferases/metabolism ; STING Protein/metabolism ; }, abstract = {The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cornerstone of the innate immune system designed to combat pathogens, is now implicated as a critical driver of sterile inflammation in the brain. This review synthesizes compelling evidence that in the aging and diseased central nervous system, endogenous cytosolic DNA, sourced from genomic instability, mitochondrial dysfunction, and activated retrotransposons, hijacks this pathway. Chronic cGAS-STING activation transforms microglia into inflammatory amplifiers, instigates neurotoxic astrocyte programs, and directly compromises neuronal health, creating a self-perpetuating cycle of neuroinflammation. We dissect the cell-type specific consequences within the neurovascular unit and establish the pathway's role in the pathogenesis of ALS/FTD, Alzheimer's, Parkinson's, and Huntington's diseases. Crucially, we evaluate the therapeutic potential of targeting this axis, discussing small-molecule inhibitors, oligonucleotide therapies, and upstream interventions to quell the source of immunogenic DNA. We also explicitly examine contradictory preclinical data, including the retracted PINK1-Parkin-STING report and context-dependent neurovascular findings, to provide a balanced appraisal of STING biology in the CNS. By reconciling its dual protective and pathogenic roles, this review posits cGAS-STING as a pivotal mechanism-based therapeutic node for halting the progression of neurodegenerative disorders.}, } @article {pmid42191539, year = {2026}, author = {Pérez-Bonilla, M and Díaz-Borrego, P and Mora-Ortiz, M and Mayordomo-Riera, FJ and Girela-López, E}, title = {Discovering Hidden Vocal Subtypes: An Unsupervised Acoustic-Biomechanical Exploration of Voice Profiles.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2026.05.002}, pmid = {42191539}, issn = {1873-4588}, abstract = {OBJECTIVE: This study aims to explore latent acoustic-biomechanical patterns of voice production using an unsupervised multivariate approach, and to identify data-driven vocal profiles across individuals with amyotrophic lateral sclerosis (ALS) and nonneurological dysphonia.

METHODS: A cross-sectional sample of 100 individuals, including patients with ALS and individuals with nonneurological dysphonia, was analyzed. Sustained vowel phonation was recorded and characterized using 26 variables, including standard acoustic measures (fundamental frequency -fo-, jitter, shimmer, and harmonics-to-noise ratio (HNR)) and 22 biomechanical parameters. Principal component analysis was applied to investigate relationships among variables and reduce dimensionality. Unsupervised clustering was performed at both the variable level to identify functional groupings and the participant level to derive data-driven voice profiles. Cluster validity was assessed using internal indices. Post hoc statistical comparisons and chi-square tests were used descriptively to characterize between-cluster differences and their relationship with clinical categories.

RESULTS: The first five principal components explained 70.7% of the total variance, revealing structured relationships between acoustic and biomechanical features. Participant level clustering consistently supported a two-profile solution. Fifteen voice parameters differed significantly between profiles after false discovery rate correction, with the largest effects observed for shimmer, HNR, and the biomechanical parameter Pr11, reflecting differences in vocal stability and noise-related characteristics. The identified profiles were not significantly associated with clinical diagnostic categories.

CONCLUSIONS: An unsupervised multimodal analysis of sustained phonation revealed two coherent vocal profiles that transcend traditional diagnostic labels. These data-driven voice phenotypes may capture functional patterns of voice production and support future efforts toward more refined and personalized characterization of voice disorders.}, } @article {pmid42191846, year = {2026}, author = {Zhang, J and Tian, M and Niu, T and Li, R and Liu, Q and Liu, M and Zhou, X and Dong, H and Liu, Y}, title = {The role of adiponectin and cytokines in Amyotrophic lateral sclerosis: assessment of disease progression and survival status.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42191846}, issn = {2045-2322}, support = {H2023206055//Key Project of Natural Science Foundation of Hebei Province/ ; 20240391//Scientific Research Foundation of Health Commission of Hebei Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/metabolism/pathology/blood ; *Adiponectin/blood/metabolism ; Disease Progression ; Female ; Prognosis ; Male ; *Interleukin-10/blood ; Middle Aged ; *Cytokines/blood/metabolism ; Aged ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disorder. ALS typically progresses rapidly, leading to respiratory failure within 3 to 5 years of symptom onset. Identifying risk factors that influence disease progression and survival is critical for enhancing management strategies. The present study therefore investigated the roles of inflammatory factors and adipokines (especially adiponectin) in the progression and prognosis of ALS. The study included 80 ALS patients, with a follow-up period of 1.5 years. Survival analysis was performed using a Cox regression, with hazard ratios (HR) and 95% confidence intervals (CI) presented via forest plots. Our results indicated that ALS patients in the fast-progressing group exhibited lower levels of adiponectin (p < 0.001) and IL-10 (p < 0.001). The Cox regression and forest plot results suggest the potential of adiponectin (HR = 0.905, 95%CI: 0.866-0.946, p < 0.001), IL-10 (HR = 0.968, 95%CI: 0.951-0.986, p < 0.001), δFS (HR = 1.234, 95%CI: 1.065-1.430, p = 0.005) and ALSFRS-R (HR = 0.820, 95%CI: 0.765-0.878, p < 0.001) as potential risk factors. In addition, these risk factors are significantly associated with poor survival prognosis in high-risk populations (all p < 0.001). This study identifies adiponectin, IL-10, ALSFRS-R, and δFS as key risk factors influencing ALS progression and prognosis.}, } @article {pmid42191932, year = {2026}, author = {Heckmann, JM and Floudiotis, N and Makanjuola, A and Ogunniyi, A and Mochan, A and Mongwe, RR and Sokhi, DS and Nel, M}, title = {Motor neuron disease in Africa: a critical appraisal of the literature.}, journal = {Nature reviews. Neurology}, volume = {22}, number = {7}, pages = {428-438}, pmid = {42191932}, issn = {1759-4766}, mesh = {Humans ; *Motor Neuron Disease/epidemiology/genetics/diagnosis/therapy ; Africa/epidemiology ; Amyotrophic Lateral Sclerosis/epidemiology/genetics ; HIV Infections/epidemiology/complications ; }, abstract = {Motor neuron disease (MND) refers to a group of neurodegenerative diseases that cause motor neuron degeneration and death. The most common subtype, amyotrophic lateral sclerosis (ALS), is characterized by both upper and lower motor neuron impairment, which can manifest clinically in the bulbar region or asymmetrically in a limb. Typically, the disease progresses over several months, and death from respiratory failure occurs within 2-5 years of onset. As we highlight in this Review, data on MND in Africa are sparse, although common observations in this region - and in other populations with relatively low life expectancy - include apparent earlier disease onset and lower disease incidence compared with the rest of the world. In view of the HIV epidemic in Africa, we critically examine the evidence for an association between ALS and HIV infection. We briefly discuss conditions that might be regarded as ALS mimics and summarize the limited data on MND genetics in this region. Other issues pertinent to people living with MND in Africa include the absence of cognitive and behavioural data and the limited access to multidisciplinary clinics, therapies and palliative care. We share our perspective on how the ALS Africa Network is coordinating a shift in the African MND landscape to improve patient care.}, } @article {pmid42192558, year = {2026}, author = {Aggad, WS and Ghosh, R and Almohaimeed, HM and Mohammedsaleh, ZM and Saleh, FM and Almars, AI and Jyothi, SR and Panigrahi, R and Kumer, A and Dhara, B}, title = {Exosome-mediated gut-brain axis signaling in neurodegenerative diseases: Mechanisms, experimental evidence, and therapeutic perspectives-A narrative review.}, journal = {Animal models and experimental medicine}, volume = {9}, number = {8}, pages = {1527-1538}, pmid = {42192558}, issn = {2576-2095}, support = {PNURSP2026R213//Princess Nourah Bint Abdulrahman University/ ; }, mesh = {*Exosomes/metabolism/physiology ; *Neurodegenerative Diseases/therapy/physiopathology ; Animals ; Humans ; *Brain/metabolism ; Signal Transduction ; *Gastrointestinal Microbiome/physiology ; *Brain-Gut Axis/physiology ; Blood-Brain Barrier ; }, abstract = {The stomach and the brain are connected by a sophisticated two-way communication mechanism called the gut-brain axis. Extracellular vesicles, particularly exosomes, that move bioactive substances between the stomach and the brain, such as proteins, lipids, metabolites, and microRNAs, may improve the gut-brain axis. In the past years, the role of exosome-mediated communication has been recognized as significant in relation to the etiology, continued progression, and potential treatment of neurodegenerative disorders. The authors of this review article present a summary of the current understanding of the relationship of gut microbiome, exosome biogenesis, and the pathophysiological development of neurodegenerative diseases. Evidence from laboratory studies, animal studies, and newly emerging human studies suggests that microbiome-based metabolites and inflammatory mediators may modulate how exosomes are produced, what they carry, and how they interact with the blood-brain barrier. These exosomal signals may impact neuroinflammation, neuronal signaling, and the spread of pathological proteins of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. In addition, they examine some possible ways to target the gut-brain axis from a therapeutic perspective, including manipulating the gut microbiome, providing probiotics and/or prebiotics, performing fecal microbiota transplantation, and/or using engineered extracellular vesicles as vehicles for drug delivery. The authors also outline some of the methodological differences that make it difficult to assess the effects of exosomes.}, } @article {pmid42193936, year = {2026}, author = {Sepehrimanesh, M and Melen, SV and Yeasmin, F and Ojo, VA and Walden, F and Urmee, H and Etheridge, J and Nasu, AK}, title = {Emerging Therapeutic Strategies for Neurodegenerative Diseases: A Comprehensive Review of Recent Advances and Future Directions.}, journal = {Cells}, volume = {15}, number = {10}, pages = {}, pmid = {42193936}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Animals ; Neuroprotective Agents/therapeutic use ; Genetic Therapy ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the urgent need for innovative therapeutic strategies. This review highlights recent advances in the understanding of disease etiology and emerging treatment approaches, with a particular focus on modalities with translational potential. We discussed novel disease-modifying interventions, including gene and cell therapies, RNA-targeting strategies, and immunotherapies aimed at clearing misfolded proteins such as amyloid-β, tau, and α-synuclein. In parallel, we examined the evolving recognition of neuroinflammation and mitochondrial dysfunction as actionable therapeutic targets, alongside progress in precision medicine and biomarker-guided approaches that enable early diagnosis and individualized treatment. Additionally, we summarized developments in repurposed pharmacological agents, neuroprotective compounds, and lifestyle interventions, emphasizing the importance of integrative, multimodal strategies. Across AD, PD, and ALS, convergent molecular mechanisms, including protein misfolding, oxidative stress, and disrupted proteostasis, present opportunities for cross-disease therapeutic targeting. Finally, we addressed key challenges and future directions, including translating preclinical efficacy into clinical success, optimizing CNS-targeted delivery systems, and navigating ethical considerations surrounding gene editing and stem cell therapies.}, } @article {pmid42194069, year = {2026}, author = {Malá, P and Váňová, N and Malý, O and Vyšata, O}, title = {Oxidative-Nitrosative Stress and Routine Biochemical Parameters in Amyotrophic Lateral Sclerosis: Associations with Clinical Status and Disease Duration-A Pilot Study.}, journal = {Biomolecules}, volume = {16}, number = {5}, pages = {}, pmid = {42194069}, issn = {2218-273X}, support = {Cooperatio Program, research area NEUR//Charles University/ ; Grant No. DRO-UHHK 00179906//Ministry of Health of the Czech Republic/ ; }, mesh = {Humans ; Pilot Projects ; *Amyotrophic Lateral Sclerosis/blood/metabolism/pathology ; *Nitrosative Stress ; *Oxidative Stress ; Female ; Biomarkers/blood ; Middle Aged ; Male ; Tyrosine/analogs & derivatives/blood ; Aged ; 8-Hydroxy-2'-Deoxyguanosine/blood ; Glutathione/blood ; Malondialdehyde/blood ; }, abstract = {BACKGROUND: This pilot study examined whether oxidative-nitrosative stress is associated with clinical status in amyotrophic lateral sclerosis (ALS). We analyzed associations between plasma markers of oxidative-nitrosative imbalance and ALSFRS-R, disease duration, survival, and routine biochemical parameters.

METHODS: Twenty-nine ALS patients fulfilling the Gold Coast diagnostic criteria were enrolled. Plasma levels of 3-nitrotyrosine (3-NT), 8-oxo-2'-deoxyguanosine (8-oxodG), malondialdehyde (MDA), glutathione (GSH), non-protein thiols (NP-SH), and non-protein disulfides (NP-SS-NP), as well as creatinine, urea, uric acid and BMI, were measured. Associations with ALSFRS-R and disease duration were evaluated using non-parametric correlation analyses and second-order polynomial regression (adjusted R[2]), while survival was explored using Kaplan-Meier analysis and multivariable Cox regression. Given the modest sample, we considered statistical power and applied Benjamini-Hochberg false discovery rate (FDR) correction within marker families.

RESULTS: At the uncorrected significance level, 3-NT showed a positive correlation with ALSFRS-R and a negative correlation with disease duration, and NP-SH correlated negatively with disease duration; however, these associations did not remain significant after FDR correction (FDR-adjusted p ≥ 0.099). Other oxidative-nitrosative markers and biochemical parameters showed no robust relationships with clinical measures. In Cox models, 3-NT was not significantly associated with survival (HR 3.44 per 1 nM, 95% CI 0.25-47.97, p = 0.358), whereas older age predicted higher mortality (HR 1.05 per year, 95% CI 1.00-1.10, p = 0.036).

CONCLUSIONS: 3-NT and NP-SH exhibited the strongest trends among the investigated markers, but their clinical associations in this small cross-sectional cohort remain exploratory and require confirmation in larger longitudinal studies.}, } @article {pmid42195033, year = {2026}, author = {Richard, E and Al-Hajj Vourc'h, S and Marouillat, S and Beltran, S and Blasco, H and Corcia, P and Vourc'h, P}, title = {From Mutation to Manifestation: Penetrance in Amyotrophic Lateral Sclerosis.}, journal = {Genes}, volume = {17}, number = {5}, pages = {}, pmid = {42195033}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Penetrance ; *Mutation ; Superoxide Dismutase-1/genetics ; RNA-Binding Protein FUS/genetics ; C9orf72 Protein/genetics ; Genetic Counseling ; DNA-Binding Proteins/genetics ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord. While most cases are sporadic, around 10% are familial. Recent genetic studies show that many apparently isolated cases carry pathogenic mutations, highlighting the importance of penetrance, the probability that a causal mutation manifests clinically. This review focuses on mutation penetrance in ALS (C9orf72, SOD1, TARDBP, FUS genes), its variability across genes, age, and environmental or genetic modifiers, and its implications for genetic counseling. Identification of pathogenic mutations informs the monitoring of relatives and, in some cases, gives access to targeted therapies or clinical trials. Counseling of asymptomatic relatives must consider incomplete penetrance, which can lead to delayed or absent disease manifestation. ALS exists on a clinical and genetic continuum including related disorders, such as frontotemporal dementia, further influencing risk interpretation. Advances in panel, whole-exome and whole-genome sequencing refine our understanding of penetrance and enable precise diagnostics, and potential tailored therapies. Understanding penetrance is therefore essential to translate mutation discovery into informed clinical decisions and genetic counseling in ALS.}, } @article {pmid42196191, year = {2026}, author = {Giordano, A and Mandrioli, J and Cerri, F and Lunetta, C and Saebfar, H and Catania, M and Battipaglia, C and Leone, L and Trojsi, F and Vizziello, M and Gerardi, F and Farè, M and Zulueta, A and Piras, R and Giacchino, M and Gianferrari, G and Dalla Bella, E and Domi, T and Bonanomi, D and Ganci, G and Lombardi, R and Lauria, G and Riva, N}, title = {Longitudinal CSF and Serum Biomarker Dynamics in Tofersen-Treated SOD1-ALS: A Real-World Multicentre Cohort Study.}, journal = {International journal of molecular sciences}, volume = {27}, number = {10}, pages = {}, pmid = {42196191}, issn = {1422-0067}, support = {IDEALS//AriSLA/ ; RF-2021-12373036//Ministero della salute Ricerca Finalizzata bando 2021/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; Giovanni Marazzina Project//Giovanni Marazzina Foundation/ ; }, mesh = {Humans ; *Biomarkers/blood/cerebrospinal fluid ; *Superoxide Dismutase-1/genetics ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy/blood/cerebrospinal fluid/genetics ; Longitudinal Studies ; tau Proteins/blood/cerebrospinal fluid ; Ubiquitin Thiolesterase/blood/cerebrospinal fluid ; Male ; Glial Fibrillary Acidic Protein/blood/cerebrospinal fluid ; Middle Aged ; Neurofilament Proteins/blood/cerebrospinal fluid ; Retrospective Studies ; Aged ; }, abstract = {Tofersen is a gene-targeted therapy for superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS), but neurofilament light chain (NfL) may not fully capture the biological response to treatment. We performed a multicentre retrospective longitudinal study including 24 patients with SOD1-ALS treated with intrathecal tofersen at four Italian referral centres between 2022 and 2025. Cerebrospinal fluid (CSF) and serum biomarkers were assessed at baseline, month 3, month 6, and last available administration using single-molecule array assays to quantify NfL, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL-1), and total Tau. NfL decreased after treatment initiation in both CSF and serum, providing the clearest pharmacodynamic signal. In contrast, CSF GFAP increased progressively over follow-up, while CSF total Tau and UCHL-1 rose mainly at later timepoints; serum GFAP, total Tau, and UCHL-1 also showed increases during follow-up. ALS Functional Rating Scale-Revised trajectories were broadly stable, whereas disease progression rate was lower at last follow-up than at baseline. Greater reductions in CSF NfL were observed in pathogenic versus uncertain SOD1 variants, and early serum NfL and UCHL-1 changes were associated with longer-term changes in disease progression. These findings suggest that longitudinal multi-analyte profiling may refine biological response stratification beyond NfL alone in tofersen-treated SOD1-ALS.}, } @article {pmid42196458, year = {2026}, author = {Prodromos, CC and Del Villar, R and Striegel, A and Pena, G and Dixit, R}, title = {The Molecular Basis of Partial Reversal or Significant Slowing of ALS, Parkinson's Disease, and Lewy Body Dementia by Mesenchymal Exosomes/Secretome.}, journal = {International journal of molecular sciences}, volume = {27}, number = {10}, pages = {}, pmid = {42196458}, issn = {1422-0067}, mesh = {Humans ; *Exosomes/metabolism/transplantation ; *Amyotrophic Lateral Sclerosis/therapy/metabolism ; *Parkinson Disease/therapy/metabolism ; Female ; Male ; *Lewy Body Disease/therapy/metabolism ; Aged ; *Mesenchymal Stem Cells/metabolism ; Middle Aged ; *Secretome/metabolism ; Case-Control Studies ; Administration, Intranasal ; }, abstract = {Neuromuscular and neurodegenerative (NMND) disorders are diseases that cause progressive damage to the central nervous system leaving patients with symptoms that negatively affect everyday living with death almost inevitable. These include amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), and Parkinson's disease (PD) with cases expected to increase in the future. Intranasally administered stem cell-derived exosomes/secretome have been seen as potential therapeutic options for these disorders in preclinical animal models. This study sought to observe the efficacy of mesenchymal stem cell-derived exosomes/secretome in patients with ALS, LBD, and PD. Based off these preclinical studies, we conducted a case-controlled series experiment with 86 patients with ALS, LBD, or PD, with the independent variable being the treatment and the dependent variable being the clinical response. These patients were recruited and given intranasal instillations of various MSC-derived exosome/secretome products. Subsequent treatments were given to patients who did not have a response to one product. Patients were followed up at one week, one, two, three, and six months post-treatment. Historical external controls were used for comparison to clinical outcomes. There were no serious adverse events in any patient. A total of 67 of 86 (77%) patients showed a positive clinical response to at least one product. Outcomes were strongly associated with greater treatment frequency for ALS and LBD. Intranasal administration of MSC-derived exosome/secretome products were safe, and most patients showed overall improvement with at least one product. Some patients also saw a substantial decrease in the rate of decline compared to historical controls. These results also give rise to the hypothesis: do MSC-derived exosomes/secretome treatments show efficacy in other NMND disorders? The primary limitation of this study is the 6-month follow-up.}, } @article {pmid42197088, year = {2026}, author = {Herrmann, C and Satari, S and Weber, A and Ruschitzka, T and Jagodzinski, L and Elmas, Z and Becker, F and Richter, L and Wiesenfarth, M and Michels, S and Weishaupt, JH and Schuster, J and Dorst, J}, title = {Feasibility and Tolerability of Ketogenic Interventions in Amyotrophic Lateral Sclerosis-A Dose-Finding Case Series.}, journal = {Nutrients}, volume = {18}, number = {10}, pages = {}, pmid = {42197088}, issn = {2072-6643}, support = {N/A//Nutricia (Germany)/ ; N/A//KetoneAid/ ; N/A//KetoForce/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy/blood ; *Diet, Ketogenic/methods/adverse effects ; Female ; Male ; Middle Aged ; Feasibility Studies ; Aged ; Adult ; 3-Hydroxybutyric Acid/blood/administration & dosage ; Ketone Bodies/administration & dosage/blood ; Treatment Outcome ; }, abstract = {Background/Objectives: Weight loss and hypermetabolism are negative prognostic factors in amyotrophic lateral sclerosis (ALS). Ketone bodies (β-hydroxybutyrate, βHB) as high-energy substrates may compensate for this energy deficit, since a ketogenic diet (KD) has been shown to increase survival and stabilize body weight in the SOD1 mouse model. In this case series, we tested exogenous ketone salts (KS), ketone esters (KE), and a KD, in patients with ALS and in healthy subjects to identify novel therapeutic interventions for subsequent clinical studies. Methods: KS (KetoForce[®] (KetoSports, Frisco, TX, USA)) were tested in healthy subjects (11.7 g and 15.6 g βHB) and patients (15.6 g βHB 3×/day over 3 days). KE (KE4[®] (KetoneAid, Falls Church, VA, USA)) containing 10.0 g βHB were applied in healthy subjects (once) and in patients (3×/day over 2 days). For the KD, KetoCal[®] 2.5:1 LQ MCT MF Vanilla (Nutricia, Frankfurt, Germany) was applied via percutaneous endoscopic gastrostomy over four weeks. Regular capillary βHB measurements were conducted, and adverse events were recorded. Results: Between January 2021 and March 2025, we treated nine patients with ALS and two healthy subjects at the Department of Neurology of Ulm University, Germany. KE and KS increased βHB temporarily. However, the elevation was more pronounced following KE (maximum 2.2-2.7 mmol/L vs. 0.8-1.2 mmol/L). The KD increased βHB levels continuously with nighttime fluctuations. No adverse events occurred under KE. KS caused diarrhea in 3/5 patients and 1/2 healthy subjects. The KD was well tolerated, with mild gastrointestinal symptoms occurring in all patients. Conclusions: All ketogenic approaches increased βHB blood levels. While the KD and KE provided good tolerability, KS caused significant gastrointestinal side effects. KD seems to be an interesting candidate for future clinical studies, as it prompted a long-term increase in βHB while providing satisfying tolerability. Since maintaining a KD long-term is difficult for oral-feeding patients, KE may constitute a feasible alternative.}, } @article {pmid42197516, year = {2026}, author = {Tavares, GC and Carneiro, SP and Barbanti, ACC and Rosário, AECD and Matos, HC and Maia, CRMDS and Costa, HL and Egger, RC and Nogueira, LFF and Rosa, JCC and Pereira, FL and Pilarski, F and Gallani, SU and Soto, E and Leal, CAG and Figueiredo, HCP}, title = {Multilocus Sequence Typing Reveals New Insights into the Population Structure and Genetic Diversity of Lactococcus spp. from Brazilian Fish.}, journal = {Microorganisms}, volume = {14}, number = {5}, pages = {}, pmid = {42197516}, issn = {2076-2607}, support = {88881.200614/2018-01//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; APQ-01227-22, APQ-04309-22 and PPM-00779-18//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; 01.02.016301.03071/2022-11//Fundação de Amparo à Pesquisa do Estado do Amazonas/ ; }, abstract = {Lactococcosis has emerged as an economically and ecologically significant disease in aquatic animals worldwide. This study employed multilocus sequence typing (MLST) to investigate the genetic diversity of Lactococcus spp. strains from Brazilian fish species and evaluate their phylogenetic relationships with global isolates to elucidate potential epidemiological connections involving multiple host species and distinct geographic regions. A total of 55 isolates from different laboratories had their DNA extracted, followed by the amplification and sequencing of the internal fragments of seven housekeeping genes (als, atpA, tuf, gapC, gyrB, rpoC and galP). Sequence types (STs) and clonal complexes (CCs) were defined. An unrooted neighbor-joining phylogenetic tree was generated using allele profiles from this study and those previously reported from other aquatic animal species. The isolates comprised 29 STs (11 previously reported, 18 novel ones), which were grouped into species-specific CCs: CC5 (L. formosensis); CC4, CC17, CC62 (L. garvieae); CC24, CC29, CC97 (L. petauri). Considerable genetic divergence was observed, with L. formosensis and L. garvieae forming heterogeneous populations, while L. petauri was more homogeneous. These findings describe the MLST structure of the sampled isolates and should be interpreted as hypothesis-generating rather than population-level estimates of genotype prevalence. Phylogenetics confirmed groupings within the CCs and revealed additional phylogenetic clustering patterns. In conclusion, the Brazilian Lactococcus spp. strains analyzed in this study constitute a genetically diverse population based on their STs. MLST and phylogenetic analysis demonstrated genetic relatedness between the L. garvieae and L. formosensis isolates from this study and those from other aquatic animal species. In contrast, all the STs identified for L. petauri in this study were unrelated to the MLST lineages responsible for outbreaks in Brazilian Nile tilapia (Oreochromis niloticus) and North American rainbow trout (Oncorhynchus mykiss). This suggests that piscine L. petauri populations in the Americas evolved from distinct ancestral origins.}, } @article {pmid42198024, year = {2026}, author = {Aminfar, K and Scafide, K and Wojtusiak, J and Lattanzi, D}, title = {Evaluation Framework for Bruise Detection: Systematic ALS/White-Light Training and Skin-Tone Balancing with Deep Learning.}, journal = {Sensors (Basel, Switzerland)}, volume = {26}, number = {10}, pages = {}, pmid = {42198024}, issn = {1424-8220}, support = {1625039//National Science Foundation/ ; 2018631//National Science Foundation/ ; 15PNIJ-21-GG-04145-SLFO//National Institute of Justice/ ; }, mesh = {Humans ; *Deep Learning ; *Contusions/diagnosis/diagnostic imaging ; Image Processing, Computer-Assisted/methods ; Forensic Imaging ; *Skin Pigmentation/physiology ; Algorithms ; Lighting ; }, abstract = {Accurate and consistent forensic bruise assessment is critical in ensuring positive clinical and legal outcomes for victims of violence. In this study, a framework for automated bruise detection is presented that, for the first time, integrates narrowband alternate-light-source (ALS) forensic imaging and ambient white light imaging. This evaluation framework is designed to address long-standing issues with respect to equitable performance across skin tones and lighting scenarios via a combination of novel model diagnostic strategies. In particular, skin-tone balancing during training and testing, threshold-sensitivity analysis, and embedding-similarity partitioning are employed to quantify the model robustness and deployment trade-offs that arise in forensic image analysis. Models were implemented with ImageNet-pretrained backbones and trained on a unique, multi-annotator full-consensus dataset comprising both white-light and ALS (415 nm and 450 nm) images. The protocol emphasizes three axes of operational relevance: (1) illumination composition in training (W/ALS ratio); (2) subgroup fairness via targeted balancing; and (3) model operating-point selection (confidence and IoU thresholds) informed by confidence-stability metrics and bootstrapped uncertainty estimates. Systematic W/ALS ratio sweeps indicate peak accuracy under ALS-dominant training and declining performance as the proportion of white-light images increases within the training set. Skin-tone balancing reduced failure rates for darker skin tones but increased overprediction in some demographic subgroups. Embedding-similarity and seen/unseen injury analyses demonstrate inflated generalization under image-level partitioning. Ultimately, the findings suggest that future researchers and developers should employ injury-level data partitioning and ensure a weighted balance of ALS images during training.}, } @article {pmid42199117, year = {2026}, author = {Zhou, Q and Gong, T and Liu, J and Ma, J and Zheng, M and Zhong, Z and Deng, H and Lin, H and Feng, N and Lei, X and Zhang, C}, title = {An integrated single-nucleus ribonucleic acid sequencing and spatial transcriptomic atlas reveals stage-specific neuronal and glial trajectories in a mouse model of amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {21}, number = {11}, pages = {5649-5661}, doi = {10.4103/NRR.NRR-D-25-00859}, pmid = {42199117}, issn = {1673-5374}, } @article {pmid42199142, year = {2026}, author = {Gerbino, V}, title = {Targeting the type-I interferon response in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-26-00133}, pmid = {42199142}, issn = {1673-5374}, } @article {pmid42200208, year = {2026}, author = {Peerbhai, N and Ramsunder, N and Europa, T and Heckmann, J and Nel, M}, title = {Expanding African contributions to ClinVar through genetic counselor-led variant curation.}, journal = {Journal of genetic counseling}, volume = {35}, number = {3}, pages = {e70235}, doi = {10.1002/jgc4.70235}, pmid = {42200208}, issn = {1573-3599}, support = {226519/Z/22/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Genetic Counseling ; *Genetic Variation ; *Databases, Genetic ; African People ; *Black People/genetics ; *Data Curation ; }, abstract = {Global variant databases such as ClinVar are vital in linking genetic variation to clinical significance and enabling shared interpretation across laboratories. However, African genetic variants remain underrepresented, comprising under 2% of global ClinVar submissions. This gap reflects inequities in access to genome sequencing, workforce capacity, and data-sharing systems, which limit visibility, contextual interpretation, and re-evaluation of African genetic variation. We describe our experiences of genetic counselor-led variant curation, ClinVar submissions, and ongoing monitoring of germline genetic variants identified in African neuromuscular and amyotrophic lateral sclerosis research cohorts. Between March 2023 and August 2025, the Clinical Omics and Informatics Unit (University of Cape Town) submitted 93 DNA sequence variants to ClinVar spanning 58 genes, including 27 first-time submissions to the database. ClinVar submissions require valid Monarch Disease Ontology (Mondo) identifiers; gaps or inaccuracies were identified (n = 3) and updated, or Mondo disease entities were created to ensure gene-disease pairs were correctly represented. Using African Genome Variation Database frequencies to guide variant classification provided sub-regional context, highlighting population differences and refining interpretations. Furthermore, we maintained a structured follow-up of variant records using ClinVar's "follow" feature. This enabled passive monitoring of new submissions or classification changes, which were evaluated to assess whether reinterpretation or resolution of variants of uncertain significance or those with conflicting assertions were warranted. This work highlights the critical role that African genetic counselors can play as contributors to variant curation in an underrepresented geography, given their expertise in human genetics and clinical reasoning. By embedding African-specific frequency data and locally trained expertise into variant curation pipelines, a sustainable, equity-driven model for genomic knowledge production in Africa is developed. African-led ClinVar contributions can strengthen interpretative accuracy, foster collaborative curation, and position genetic counselors as active agents in global genomic data sharing and interpretation.}, } @article {pmid42200920, year = {2026}, author = {An, Y and Lan, H and Xiong, J and Jing, R and Gu, D and Zhang, H and Liu, X and Zhao, Q and Wang, F}, title = {From Axonal Growth to Neurodegeneration: The Dual Role of Neurofilament Dynamics in Health and Disease.}, journal = {NeuroSci}, volume = {7}, number = {3}, pages = {}, pmid = {42200920}, issn = {2673-4087}, support = {ZR2025MS434//Natural Science Foundation of Shandong Province/ ; }, abstract = {Neurofilaments (NFs) are the predominant type IV intermediate filaments in differentiated neurons, functioning not just as static scaffolds, but as active drivers of radial axonal growth and nerve conduction velocity. While their physical properties are well characterized, a critical gap remains in synthesizing how their dynamic assembly and developmental subunit switching directly dictate neurodegenerative outcomes. This review breaks down the molecular architecture and stepwise kinetic assembly of NFs, detailing their role in polarized transport and the formation of a protective viscoelastic gel network within axons. We specifically highlight the physiological expression switching of early subunits, such as alpha-internexin and peripherin, during neuronal maturation, a process often overlooked in traditional structural reviews. By examining how specific gene mutations and aberrant hyperphosphorylation trigger axonal transport jams and protein aggregation, we map the direct pathways leading to amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth (CMT) disease. Finally, we emphasize that a precise mechanistic decoding of NF structural dynamics and their pathological disruption is essential for understanding the fundamental etiology of these neurodegenerative conditions.}, } @article {pmid42201810, year = {2026}, author = {Gibbons, GM and Fuchsberger, T and Abdelgawad, M and Giandomenico, SL and Szebényi, K and Petrova, V and Wenger, LMD and Olschewski, DN and Chabros, J and Muresan, L and Feord, RC and Asif, M and Fawcett, JW and Mierau, SB and Paulsen, O and Lancaster, MA and Lakatos, A}, title = {A human corticospinal organoid-slice connectoid model informs enhancer strategies for post-injury axon regrowth.}, journal = {Cell reports}, volume = {45}, number = {6}, pages = {117399}, pmid = {42201810}, issn = {2211-1247}, mesh = {Humans ; *Axons/metabolism/pathology/physiology ; *Organoids/metabolism ; *Pyramidal Tracts ; *Nerve Regeneration ; }, abstract = {Axon elongation in the mammalian central nervous system (CNS) declines during development, limiting regenerative capacity after birth. Intrinsic regulators of this process are promising repair targets, as immature axons can regrow in tissues otherwise not conducive to regeneration. Yet the precise timing and mechanisms underlying the cessation of axon growth in the human CNS remain unresolved. Here, we developed a three-dimensional human corticospinal motor organoid-slice connectoid platform mimicking the developmental axon elongation program and its subsequent restriction through maturation. Cortical and spinal slices establish functional connections while remaining spatially segregated, enabling cortical cell-type-specific observations without direct confounding effects by spinal cells. Using single-cell transcriptomics, computational analyses, axon regrowth assays, and live imaging, we identified transcriptional alterations contributing to decreased axon growth in maturing human cortical projection neurons. We further demonstrate that this decline can be reversed using compounds and repurposable drugs targeting a maturation-associated transcriptional shift, promoting post-injury axon repair.}, } @article {pmid42202251, year = {2026}, author = {Ronquillo, CE}, title = {Beyond Time Saved: Implementation, Equity, and the Utility Threshold for Nursing AI Scribes.}, journal = {Journal of medical Internet research}, volume = {28}, number = {}, pages = {e101190}, pmid = {42202251}, issn = {1438-8871}, mesh = {Humans ; *Artificial Intelligence ; *Documentation ; Long-Term Care ; }, abstract = {Schwabe et al's pre-post time-motion study of a domain-specific artificial intelligence (AI) speech assistant used by nurses in German long-term care provides one of the few real-world, full-shift evaluations of an AI scribe deployed to a nonphysician workforce, with paired objective observation and self-reported outcomes. This commentary points to the implications of these findings that extend well beyond the time savings headline. The study reports substantial reduction in self-reported documentation time and increased satisfaction with the documentation system, yet workplace satisfaction and the perception that AI scribes are "a good idea to implement" did not improve. Taken together, these findings show three undertheorized issues for AI scribe implementation in nursing and long-term care. First, postimplementation increases in time spent reviewing entries and retrieving information indicate that AI scribes redistribute cognitive effort from authoring to verification, with unknown consequences for satisfaction, mastery, and error detection. Second, the apparent paradox of rising documentation satisfaction alongside falling expectations of AI quality represents user calibration. Third, the substantial equity considerations of automatic speech recognition documentation reflect a broader trend of AI scribe studies that treat equity as a caveat, rather than treating equitable performance as empirically measurable and testable across variations in linguistic styles, dialects, and social linguistic dimensions. To advance the field, the next generation of nursing AI scribe research must treat documentation as a heterogeneous bundle of authoring, reviewing, retrieving, and verifying activities with distinct satisfaction and error profiles; specify and validate end-user-defined anchor utilities, rather than having a narrow focus on diffuse improvement; and treat equity testing and reporting of both automatic speech recognition systems and workforce adoption as standard reporting expectations, rather than caveats.}, } @article {pmid42202610, year = {2026}, author = {Doğan, V and Sinanoğlu, GK}, title = {2D:4D ratio, affective lability, and impulsivity in men with cannabinoid and methamphetamine use disorders: A comparative analysis with healthy controls.}, journal = {Early human development}, volume = {221}, number = {}, pages = {106587}, doi = {10.1016/j.earlhumdev.2026.106587}, pmid = {42202610}, issn = {1872-6232}, mesh = {Humans ; Male ; Adult ; *Impulsive Behavior ; Case-Control Studies ; *Amphetamine-Related Disorders/psychology/epidemiology ; *Fingers/anatomy & histology ; Methamphetamine/adverse effects ; Cross-Sectional Studies ; *Marijuana Abuse/psychology/epidemiology ; }, abstract = {The second-to-fourth digit ratio (2D:4D) is considered a non-invasive marker of prenatal androgen exposure and has been proposed as a developmental indicator of behavioral vulnerability; however, findings in substance use disorders remain inconsistent. This study aimed to examine whether 2D:4D ratios are associated with substance use disorders and to compare their relative contribution with psychological factors, including affective lability, impulsivity, and anxiety. In this cross-sectional case-control study, male participants with cannabinoid use disorder (CUD; n = 47), methamphetamine use disorder (MUD; n = 48), and healthy controls (n = 53) were included. The mean age of participants was 32.7±8.95 years. All participants were assessed using the Structured Clinical Interview for DSM-5 (SCID-5), Affective Lability Scale-18 (ALS-18), Barratt Impulsiveness Scale-11 (BIS-11), and Generalized Anxiety Disorder-7 (GAD-7). The 2D:4D ratio was measured with a digital caliper by two trained psychiatrists, and 2D:4D ratios and right-left differences (Dr-I) were calculated. No significant group differences were observed in left or right 2D:4D ratios or Dr-I; however, a consistent trend toward lower 2D:4D values, particularly for right-hand 2D:4D, was observed in the CUD and MUD groups compared with controls. In contrast, affective lability, impulsivity, and anxiety scores were significantly elevated in both patient groups (p <0.05). In univariate logistic regression analyses, affective lability, impulsivity, anxiety, and lower right-hand 2D:4D were associated with substance use disorder; however, right-hand 2D:4D showed the weakest association among these predictors. In the multivariate model, lower right-hand 2D:4D, impulsivity, lower educational attainment, and smoking remained independently associated with substance use disorder. These findings suggest that while 2D:4D may reflect a distal developmental vulnerability, psychological factors, particularly impulsivity, have a more direct and clinically relevant role in substance use disorders. Incorporating the assessment of impulsivity into clinical evaluation and intervention strategies may improve risk identification and treatment planning.}, } @article {pmid42202831, year = {2026}, author = {Gorenshtein, A and Omar, M and Barash, Y and Nadkarni, GN and Klang, E}, title = {Large language models integrated into brain-computer interfaces for communication and control: a systematic review.}, journal = {Biomedical physics & engineering express}, volume = {12}, number = {3}, pages = {}, doi = {10.1088/2057-1976/ae737b}, pmid = {42202831}, issn = {2057-1976}, mesh = {*Brain-Computer Interfaces ; Humans ; *Large Language Models ; Electroencephalography ; *Communication ; *Brain/physiology ; Event-Related Potentials, P300 ; }, abstract = {Large language models (LLMs) are starting to be coupled with brain-computer interfaces (BCIs) for assistive communication, but the resulting systems differ widely in where the model sits in the pipeline and in what they actually measure. We performed a systematic review, prepared according to PRISMA, of eleven studies that combine an LLM with a BCI for communication or control. The included work covers P300, SSVEP, cVEP, passive affective and auditory paradigms, and five integration patterns: autocomplete, post-edit correction, intent expansion, dynamic interface generation and affective support. For each study we extracted the hardware and decoding pipeline, the LLM and prompting strategy, latency reporting and outcomes; we used scenario-appropriate metrics rather than a single common metric. Risk of bias was judged with an adapted ROBINS-I framework that stratified studies into online, offline-simulation and system-proposal categories. In the copy-spelling scenario, two studies that measured keystroke savings directly reported values above 50%, with one study exceeding 60% in a multi-turn condition; on an intent-based ALS message-bank task, one online study reached 42 characters per minute with a semantic accuracy of 88%. None of the eleven studies enrolled motor-impaired patients, seven of eleven relied on remote OpenAI endpoints, and reporting of end-to-end latency and failure modes was sparse. We propose a five-category taxonomy of BCI/LLM integration, separate findings that are supported from those that are still speculative, and give a checklist of metrics that should be reported by future studies. The taxonomy and the reporting checklist are the main contributions; clinical benefit for the target population remains to be shown.}, } @article {pmid42204151, year = {2026}, author = {Jia, Q and Zhu, L and Li, D and Nan, Z and Hou, J and Zhao, Y and Zhu, G and Ou, K and Guo, M and Dui, H and Liu, X and Yan, XX and Yang, S and Huang, L and Fan, D and Li, S and Li, XJ and Yin, P}, title = {Caspase-4 transgenic mice exhibit cytoplasmic TDP-43 accumulation and age-dependent neuropathology.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42204151}, issn = {2041-1723}, support = {32270564//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; Mice, Transgenic ; Humans ; *Cytoplasm/metabolism ; Mice ; *Caspases, Initiator/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Aging/pathology/metabolism ; Disease Models, Animal ; Male ; }, abstract = {TAR DNA-binding protein (TDP-43) is a multifunctional protein that binds DNA and RNA within the nucleus. In neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), TDP-43 is mislocalized to the cytoplasm, forming inclusions. Current TDP-43 transgenic mouse models generally fail to exhibit significant cytoplasmic accumulation and loss of nuclear TDP-43, which hampers the investigation of cytoplasmic TDP-43 pathology. We previously discovered that primate-specific caspase-4 (CASP4) can cleave TDP-43, producing truncated fragments that are mislocalized to the cytoplasm. Here we show that a transgenic mouse model that expresses human CASP4 and recapitulates the cytoplasmic mislocalization of endogenous TDP-43 and motor dysfunction in an age-dependent manner. Moreover, CASP4 mice exhibited gene expression changes and neuropathology similar to patients with sporadic ALS. Inhibition of CASP4 by its antisense oligonucleotide ameliorated TDP-43 pathology and subsequent neurotoxicity in CASP4 mice. Thus, CASP4 mice present a valuable animal model for exploring endogenous TDP-43-mediated pathogenesis and therapeutics.}, } @article {pmid42204279, year = {2026}, author = {Fowler, M and Carr, JM and Gold, J and Walker, A and Rogers, ML}, title = {Evaluation of triumeq treatment on a TDP-43 mouse model of amyotrophic Lateral sclerosis.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42204279}, issn = {2045-2322}, support = {DIS-202303-00932//FightMND/ ; IG1950//Motor Neurone Disease Research Australia/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the accumulation of TAR DNA Binding Protein (43 kDa; TDP-43) within the cytoplasm of neurons. Endogenous retroviruses (ERVs) have been implicated in ALS pathology and the application of antiretroviral therapy, specifically Triumeq, has been proposed for treatment of ALS. However, evidence to support the actions of Triumeq in ALS is lacking. This study investigates the effects of the antiretroviral treatment Triumeq on ALS disease that occurs through TDP-43 pathology by utilising the doxycycline (Dox)-suppressible rNLS8 TDP-43 expression mouse model. In this model, TDP-43 accumulation in the cytoplasm is induced after removal of Dox. Disease was assessed through measures of body weight, neurological score, motor function, urinary p75[ECD] and inflammatory marker expression. Mice were treated with Triumeq and TDP-43 pathology and inflammatory marker expression examined. Triumeq treatment significantly improved motor function early on in the disease course but did not impact other disease progression markers or disease endpoint. In this TDP-43 ALS mouse model, there was a positive association of TDP-43 mRNA levels with transcription factor ATF4, and inflammatory markers CXCL10 and IRF-1, and Triumeq treatment negated this association. Triumeq treatment transiently and modestly improved motor function and influenced TDP-43 associated inflammatory gene expression in an ALS mouse model. These findings support the potential use of Triumeq in treating TDP-43-associated ALS and supports further investigation to better understand if the beneficial actions of Triumeq are via disruption of TDP-43-driven inflammation in ALS.}, } @article {pmid42204548, year = {2026}, author = {Jin, X and Fu, Y and Qiu, T and Li, J and Zhang, H and Chen, Y and Chen, K and Zhang, Y and Wang, J and Yi, X and Palaniyappan, L and Braden, BB}, title = {Putative glymphatic dysfunction links extracellular fluid dysregulation to white matter degeneration and clinical impairment in amyotrophic lateral sclerosis.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {42204548}, issn = {1741-7015}, support = {No. 2022LNJJ09//Project Program of National Clinical Research Center for Geriatric Disorders/ ; 2024ZZTS0954//Fundamental Research Funds for the Central Universities of Central South University/ ; U22A20377//National Natural Science Foundation of China/ ; No.2024PT5109//Scientific Research Program of FuRong Laboratory/ ; CB-C2022//Santé/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; *Extracellular Fluid/metabolism ; *White Matter/diagnostic imaging/pathology/physiopathology ; Female ; *Glymphatic System/physiopathology/diagnostic imaging ; Diffusion Tensor Imaging ; Male ; Middle Aged ; Aged ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and prominent extra-motor involvement. Impaired clearance of neurotoxic proteins has led to increasing interest in the brain glymphatic system; however, its in vivo associations with brain microstructure and clinical heterogeneity remain incompletely understood.

METHODS: One hundred forty-six patients with ALS and 149 demographically matched healthy controls (HCs) underwent multimodal MRI and comprehensive clinical assessments. Putative glymphatic function was quantified using diffusion tensor imaging along perivascular space (DTI-ALPS). Extracellular free water fraction (FWF) and free-water-corrected fractional anisotropy (fwcFA) were derived to characterize extracellular fluid and white matter microstructure. Group differences were assessed using vertex-wise and voxel-wise analyses with correction for multiple comparisons. Associations among imaging metrics and clinical measures were evaluated using correlation and serial mediation analyses.

RESULTS: Compared with HCs, patients with ALS exhibited significantly reduced DTI-ALPS index, widespread increases in cortical FWF, bidirectional alterations in white matter FWF, and extensive reductions in fwcFA across major white matter tracts. Reduced DTI-ALPS was associated with changes in extracellular free water and white matter microstructural integrity, whereas FWF and fwcFA measures were associated with functional, cognitive, and emotional outcomes. Mediation analyses identified significant indirect associations between DTI-ALPS and both functional and cognitive measures through a pathway involving cortical FWF, white matter FWF, and fwcFA, although direct associations were not observed.

CONCLUSIONS: These findings provide in vivo evidence that putative glymphatic dysfunction co-occurs with extracellular fluid alterations, white matter microstructural changes, and clinical impairment in ALS. Multi-compartment diffusion imaging may offer complementary markers for characterizing brain microstructure and its clinical relevance in ALS.}, } @article {pmid42204729, year = {2026}, author = {Pasetto, L and Callegaro, S and Corbelli, A and Fiordaliso, F and Ferrara, D and Brunelli, L and Sestito, G and Pastorelli, R and Bianchi, E and Cretich, M and Chiari, M and Potrich, C and Moglia, C and Corbo, M and Sorarù, G and Lunetta, C and Calvo, A and Chiò, A and Mora, G and Pennuto, M and Quattrone, A and Rinaldi, F and D'Agostino, VG and Basso, M and Bonetto, V}, title = {Correction: Decoding distinctive features of plasma extracellular vesicles in amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {21}, number = {1}, pages = {}, doi = {10.1186/s13024-026-00955-z}, pmid = {42204729}, issn = {1750-1326}, } @article {pmid42205021, year = {2026}, author = {Sun, QH and Xuan, X and Du, YG and Zhai, YC and Ma, T and Duan, F and Xia, CQ and Huang, XS and Huang, YH and Wang, HF}, title = {APOE ε4 Allele is Associated with Cognitive Impairment in Chinese Sporadic ALS: A Retrospective Cohort Study.}, journal = {Biomedical and environmental sciences : BES}, volume = {39}, number = {5}, pages = {564-571}, doi = {10.3967/bes2026.038}, pmid = {42205021}, issn = {2214-0190}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Alleles ; *Amyotrophic Lateral Sclerosis/genetics/complications ; *Apolipoprotein E4/genetics/blood ; China ; *Cognitive Dysfunction/genetics/etiology ; Genotype ; Retrospective Studies ; East Asian People/genetics ; }, abstract = {OBJECTIVE: To evaluate the effects of apolipoprotein E (APOE) genotype and serum APOE levels on cognitive and motor phenotypes in Chinese patients with sporadic amyotrophic lateral sclerosis (ALS).

METHODS: APOE genotypes were determined in 289 patients with sporadic ALS, and serum APOE levels were measured in a subset of 222 patients. Cognitive function was assessed using the Edinburgh Cognitive and Behavioural ALS Screen. We examined the association of APOE genotype and serum levels with age at onset, site of onset, disease progression rate (DPR), time to generalization of symptoms (TTG), and cognitive performance.

RESULTS: No significant differences were observed in sex, age at onset, site of onset, DPR, or TTG among patients with different APOE genotypes. Similarly, serum APOE levels did not correlate with these clinical variables. However, the APOE-ε4 allele was associated with lower ALS-specific cognitive scores, particularly in the domain of verbal fluency.

CONCLUSION: Our study provides preliminary evidence linking the APOE-ε4 allele to cognitive impairment, particularly in language fluency, among Chinese patients with ALS. These findings support the hypothesis that APOE genotype contributes to ALS etiology and suggest its role in shaping distinct cognitive phenotypes in the disease.}, } @article {pmid42206537, year = {2026}, author = {Pulecio, J and Parra, S and Quiroz, W and Bravo, MA}, title = {Chemometric-Assisted Determination of Benzo[a]pyrene (BaP) and Benzo[a]anthracene (BaA) in Water Samples Using Fluorescence and Commercial Membranes: A White Analytical Chemistry Approach.}, journal = {Luminescence : the journal of biological and chemical luminescence}, volume = {41}, number = {6}, pages = {e70523}, doi = {10.1002/bio.70523}, pmid = {42206537}, issn = {1522-7243}, support = {Fondecyt Regular 1240296//Agencia Nacional de Investigación y Desarrollo, ANID/ ; ANID-PFCHA/Doctorado nacional/2024-21242116//Agencia Nacional de Investigación y Desarrollo, ANID/ ; }, mesh = {*Benzo(a)pyrene/analysis ; *Benz(a)Anthracenes/analysis ; *Water Pollutants, Chemical/analysis ; Spectrometry, Fluorescence ; *Membranes, Artificial ; Fluorescence ; }, abstract = {This study evaluates different solid membranes to develop an analytical method for the immobilization of two priority PAHs, benzo[a]pyrene (BaP) and benzo[a]anthracene (BaA), followed by the measurement of excitation-emission fluorescence matrices (directly measured over the membrane) coupled to second-order multivariate calibration. Commercially available membranes, such as nylon and C18, proved to be suitable supports for these purposes, especially for aqueous samples. The multivariate curve resolution-alternating least squares (MCR-ALS) algorithm showed adequate flexibility to fit the data and achieve the second-order advantage, even in the presence of unmodeled interferences. Even though both membranes showed different selectivity, the developed method allows quantification of PAH at ng L[-1] levels with a prediction error below 10%. The proposed methodology was successfully applied to spiked real water samples, demonstrating its suitability for detecting PAHs at trace levels. Finally, the proposed method was evaluated and compared with reported analytical approaches based on white analytical chemistry principles, showing remarkable analytical performance for monitoring PAHs in natural water samples.}, } @article {pmid42206648, year = {2026}, author = {Pupillo, E and Bianchi, E and Diamanti, L and Bergamaschi, R and Pisoni, E and Riva, N and Lunetta, C and Filosto, M and Padovani, A and Tremolizzo, L and De Lodovici, ML and Leone, MA and , }, title = {Air pollutants and amyotrophic lateral sclerosis in a population-based registry: investigating disease susceptibility, progression and survival.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2677537}, pmid = {42206648}, issn = {2167-9223}, abstract = {Objective: to investigate the association between long-term exposure to fine particulate matter (PM2.5) and nitrogen oxides (NOx) with ALS risk, progression, and survival. Methods: We conducted a population-based study in Lombardy, Italy. A case-control analysis included 161 incident ALS cases (2011-2014) and 161 age-, sex-, and province-matched controls. Average residential exposures to PM2.5 and NOx over the 20 years before diagnosis were estimated using European Monitoring and Evaluation Programme data and analysed with conditional logistic regression. A retrospective cohort of 135 ALS cases was used to assess associations with disease progression (ΔFS) and mortality using logistic and Cox regression models, adjusting for demographic and lifestyle factors. Results: Higher PM2.5 exposure in the 20 years preceding diagnosis was associated with increased ALS risk (adjusted OR per 5 µg/m[3] increase 1.19; 95% CI 1.01-1.40), with consistent findings across sensitivity analyses. NOx was not associated with ALS incidence. In contrast, NOx exposure in the 5 years before diagnosis was marginally associated with increased mortality (adjusted HR 1.12; 95% CI 1.00-1.26), whereas PM2.5 was not. Neither pollutant was significantly associated with disease progression rate. Conclusions: Long-term PM2.5 exposure was associated with higher ALS risk, while NOx showed a modest association with mortality. These findings support a role of air pollution in ALS susceptibility and highlight the need for integrated environmental prevention strategies to mitigate the burden of neurodegenerative diseases.}, } @article {pmid42207242, year = {2026}, author = {Alarcan, H and Veyrat-Durebex, C and Pradat, PF and Cassereau, J and Destee, A and Couratier, P and Camu, W and Neau, JP and Fleury-Lesaunier, MC and Emond, P and Dufour, D and Al Ojaimi, Y and Lefèvre, A and Vourc'h, P and Corcia, P and Andres, CR and Blasco, H}, title = {Anchoring ALS Prognosis: Neurofilament Light Chain Outperforms Inflammatory, Metabolic, and CNS Barrier Biomarkers in the METABALS Cohort.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42207242}, issn = {1559-1182}, mesh = {Humans ; *Neurofilament Proteins/blood/metabolism/cerebrospinal fluid ; Biomarkers/metabolism/blood ; *Amyotrophic Lateral Sclerosis/metabolism/blood/diagnosis/pathology ; Female ; Male ; Prognosis ; Middle Aged ; Cohort Studies ; *Inflammation/metabolism/blood ; *Blood-Brain Barrier/metabolism ; *Blood-Spinal Cord Barrier/metabolism ; *Metabolomics/methods ; Aged ; Kynurenine/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder with marked biological heterogeneity. Despite extensive research, reliable prognostic biomarkers remain limited, with neurofilament light chain (NfL) being the only marker increasingly implemented in clinical practice. The objective of this study is to assess and compare the prognostic value of NfL, circulating markers of central nervous system (CNS) barrier dysfunction, inflammatory mediators, kynurenine pathway metabolites, and global metabolomic profiles in patients with ALS. Seventy-two patients with ALS from the prospective multicenter METABALS cohort were included. Serum, cerebrospinal fluid (CSF), and urine samples were collected at diagnosis. NfL concentrations, markers of blood-brain and blood-spinal cord barrier permeability (albumin quotient, S100B, neuron-specific enolase [NSE]), 48 inflammatory mediators, kynurenine pathway metabolites, and untargeted metabolomic profiles were measured. Associations with clinical features, disease progression, and survival were investigated using univariate analyses and multivariate models. Serum and CSF NfL concentrations were strongly associated with ALS Functional Rating Scale-Revised scores, respiratory function, diagnostic delay, and survival. Higher serum NfL concentrations at diagnosis predicted shorter survival (ROC AUC = 0.86). In all multivariate and multi-block models, serum NfL was the only biomarker independently associated with survival. Markers of CNS barrier integrity, inflammatory mediators, and metabolomic signatures showed limited prognostic value but provided insights into metabolic remodeling and barrier dysfunction. In this integrated multi-omics study, serum NfL clearly outperformed inflammatory, metabolic, and CNS barrier markers as a prognostic biomarker in ALS, supporting its central role in clinical stratification while complementary biological markers highlighted several relevant pathophysiological mechanisms.}, } @article {pmid42207631, year = {2026}, author = {Valenti, D and Joshi, V and Pankivskyi, S and Cai, HH and Hamon, L and Desforges, B and Molliex, A and Duez, J and Bursztyka, J and Davignon, L and Maucuer, A and Bollot, G and Pastré, D}, title = {RNA-binding protein diversity and NLS arginines regulate FUS mixing in mRNA-rich compartments.}, journal = {Cell reports}, volume = {45}, number = {6}, pages = {117430}, doi = {10.1016/j.celrep.2026.117430}, pmid = {42207631}, issn = {2211-1247}, mesh = {*RNA-Binding Protein FUS/metabolism/genetics/chemistry ; *RNA, Messenger/metabolism/genetics ; *Arginine/metabolism ; Humans ; *Nuclear Localization Signals/metabolism ; *RNA-Binding Proteins/metabolism ; Biomolecular Condensates/metabolism ; Protein Binding ; Mutation ; Animals ; HeLa Cells ; }, abstract = {Despite being prone to condensation, many RNA-binding proteins (RBPs) do not form large condensates in cells. This issue is still widely researched, particularly because aggregation of RBPs, such as FUS, is the hallmark of some neurodegenerative diseases. Elevated RNA levels and protein chaperone activity have already emerged as key factors preventing aberrant phase separation. Here, we explored the role of RBP diversity in mRNA-rich condensates. While FUS and its partners form distinct compartments when probed one by one, increasing RBP diversity buffers FUS spatial segregation. In addition, we found that frequently mutated arginine residues in the nuclear localization signal (NLS) at the C-terminal end promote FUS mixing with multiple RBPs. Therefore, we anticipate that pathological NLS mutations in FUS not only alter its active nuclear import but also regulate FUS interactions with its partners in mRNA-rich compartments with putative consequences for the onset and progression of FUS-related neurodegenerative diseases.}, } @article {pmid42207731, year = {2026}, author = {Queiroz, EM and Couto, CM and Ferreira, AR and de Souza, LC and Caramelli, P}, title = {Clinical Presentation and Diagnostic Challenges of Frontotemporal Dementia in Brazil: A 15-Year Cohort Study.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-12}, doi = {10.1159/000552730}, pmid = {42207731}, issn = {1423-0208}, abstract = {INTRODUCTION: Frontotemporal dementia (FTD) comprises heterogeneous neurodegenerative syndromes with limited data from low- and middle-income countries, where diagnostic delay and misdiagnosis are common.

METHODS: A retrospective cohort study was conducted of 190 patients with FTD meeting criteria for behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), or FTD-amyotrophic lateral sclerosis (FTD-ALS) who were evaluated at a publicly funded Brazilian tertiary referral center (2009-2024). Clinical features, diagnostic trajectories, neuroimaging, genetic testing, and survival outcomes were analyzed. Standardized mortality ratios (SMRs) were calculated using IBGE 2017 life tables as a reference.

RESULTS: The cohort comprised 95 bvFTD (50.0%; 73 probable and 22 possible), 79 PPA (41.6%), and 16 FTD-ALS (8.4%) patients. Accurate initial diagnosis was achieved in only 15.8% of bvFTD patients and 17.7% of PPA patients, with Alzheimer's disease being the most common misdiagnosis (36.8% and 34.2%, respectively). Survival differed significantly between subtypes (p < 0.001), with FTD-ALS having the shortest median survival (79.0 months) compared with PPA (119.0 months) and bvFTD (144.0 months). Compared with PPA, FTD-ALS was associated with increased mortality risk (HR: 4.01; 95% CI: 1.94-8.31; p < 0.001). FTD patients had approximately twice the expected mortality for age- and sex-matched individuals in the general population (SMR: 1.97; 95% CI: 1.59-2.38), with the highest excess mortality in FTD-ALS patients (SMR: 4.08).

DISCUSSION: This Brazilian hospital-based cohort reveals alarming diagnostic delays despite typical clinical phenotypes and high mortality across all FTD subtypes relative to the general population. These findings highlight the need for improved FTD awareness and specialized training among healthcare providers in Brazil and similar Latin American countries, underscoring the value of hospital-based cohort studies in characterizing FTD in low- and middle-income countries.}, } @article {pmid42210413, year = {2026}, author = {Tripathi, P and Guo, H and Yamoah, A and Mathur, R and Doukas, P and Dreser, A and Jesse, CM and Aronica, E and Hermann, A and Steinbusch, H and Brook, GA and Weis, J and Goswami, A}, title = {VAPB confers selective neuroprotection by driving autophagic degradation of pathogenic aggregates in ALS.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42210413}, issn = {2051-5960}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Autophagy/physiology ; Humans ; Animals ; *Vesicular Transport Proteins/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; Spinal Cord/pathology/metabolism ; *Neuroprotection/physiology ; Female ; Mice ; Male ; Brain/pathology/metabolism ; Mice, Transgenic ; *Protein Aggregation, Pathological/metabolism/pathology ; }, abstract = {During the progression of amyotrophic lateral sclerosis (ALS), only specific motor neurons (MNs) preferentially deteriorate, while others are spared until the disease reaches its end stage. Resilient MNs possess several protective factors, yet the precise molecular mechanism(s) underlying selective neuronal vulnerability remains poorly understood. Vesicle-associated membrane protein (VAMP)-binding protein B (VAPB) is an endoplasmic reticulum (ER) protein involved in protein quality control (PQC) mechanisms, including unfolded protein response (UPR) as well as autophagy. A dominantly inherited P56S mutation in the VAPB gene has been linked to ALS8, atypical ALS, and late-onset spinal muscular atrophy (SMA). The P56S VAPB mutation causes ER-associated inclusions, disorganization, and ER stress, contributing to MN degeneration through toxic gain and loss of function. Over-expression of VAPB protein confers neuroprotection in a mouse model of ALS, and increased levels of neuronal VAPB inversely correlate with the absence of pathological aggregates. We hypothesize that VAPB is crucial for motor neuron survival by promoting autophagic degradation of ALS-associated aggregates, while lack of VAPB confers neuronal vulnerability. We analyzed the brain and spinal cord from sporadic (s) and familial (f) ALS patients, comparing patterns of VAPB immunoreactivity using immunohistochemistry, complemented by Western and dot blot analysis. Pathophysiological insights from these studies were further explored using cell culture models, including MNs derived from induced pluripotent stem cells (iPSCs). Consistent with our hypothesis we observed that MNs/neurons resistant to ALS exhibited elevated levels of VAPB and were devoid of pathogenic aggregates. Similarly, ALS-resistant oculomotor neurons showed increased VAPB immunoreactivity compared to normal controls. VAPB was often found to be sequestered within toxic aggregates alongside autophagy-related proteins in the lumbar spinal cord MNs. Notably, a compensatory increase in VAPB immunoreactivity was observed at the C-bouton synapse, suggesting a potential alternative mechanism of neuroprotection. Supporting these findings, in vitro experiments indicated that VAPB overexpression promoted autophagy and assisted in clearing ALS-associated RNA-binding protein aggregates. In summary, VAPB promotes selective neuronal survival by facilitating the autophagic clearance of toxic aggregates. Abnormal VAPB accumulations likely disrupt these neuroprotective processes.}, } @article {pmid42211895, year = {2026}, author = {Yang, X and Yang, J and Li, R and Dong, H and Liu, Y}, title = {Peripheral immune cells and glycation indices as potential diagnostic biomarkers in amyotrophic lateral sclerosis.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {251}, number = {}, pages = {10987}, pmid = {42211895}, issn = {1535-3699}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/blood/immunology ; *Biomarkers/blood ; Female ; Male ; Glycosylation ; Retrospective Studies ; Middle Aged ; Glycated Hemoglobin/analysis ; ROC Curve ; Monocytes ; Aged ; Leukocytes ; }, abstract = {The diagnosis of amyotrophic lateral sclerosis (ALS) mainly relies on clinical symptoms and the exclusion of other diseases, with a lack of specific biomarkers, leading to delayed diagnosis and a high rate of misdiagnosis. This study aims to explore the utility of peripheral immune cells and glycosylation indices as potential diagnostic biomarkers for ALS to enhance the accuracy and efficiency of early ALS diagnosis. This retrospective study included 54 ALS patients diagnosed in our hospital from June 2023 to October 2024, along with 54 healthy controls. Blood samples and laboratory data, including levels of peripheral immune cells and glycosylation indices, were collected from both groups. Through logistic regression, random forest models, receiver operating characteristic (ROC) curve analysis, and SHAP interpretability analysis, the predictive abilities and clinical significance of each candidate indicator were screened and evaluated. Notable disparities were detected in age, leukocyte count, monocyte levels, glycated haemoglobin A1c (HbA1c), and haemoglobin glycation index (HGI) between the control and ALS groups (all P < 0.05). Logistic regression analysis revealed that age (OR = 1.114) and monocyte (OR = 3.174) were risk factors for ALS, while leukocyte (OR = 0.533) and HbA1c (OR = 0.069) were protective factors. The random forest algorithm, ranked by decreasing importance, showed that leukocyte, HGI, monocyte, and HbA1c level all influenced ALS. Using these indicators to predict ALS resulted in a false-positive rate of 18% and a false-negative rate of 6%. ROC curve analysis indicated that the combined use of leukocyte, monocyte, HbA1c level, and HGI provided the highest diagnostic value for ALS (AUC = 0.774), which was higher than that of any individual indicator (all P < 0.05). SHAP analysis visualization demonstrated that increased monocyte and decreased leukocyte, HGI, and HbA1c level were all associated with an increased risk of ALS onset, ranked in descending order of feature importance as monocyte, leukocyte, HGI, and HbA1c. Peripheral blood white blood cells, monocytes, HbA1c, and HGI can serve as potential diagnostic biomarkers for ALS. Combined detection can improve the diagnostic accuracy of ALS, facilitating early diagnosis and intervention, and ultimately improving patient prognosis. Further validation in cohorts including disease controls is required to confirm specificity.}, } @article {pmid42212627, year = {2026}, author = {Raymond, J and Larson, T and Mohidul, S and Martin-Greene, D and Love, K and Mehta, V and Wymer, J and Howard, I and Horton, DK and Mehta, P}, title = {Diagnostic differences between military veterans and non-veterans: data from the United States National ALS Registry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2677528}, pmid = {42212627}, issn = {2167-9223}, abstract = {Background and Aim: Veterans in the U.S. have been reported to have a higher risk of developing amyotrophic lateral sclerosis (ALS) than the general population. However, it is unclear whether veterans experience differences in symptom recognition, diagnostic timing or access to care. This study examined differences reported in clinical characteristics and diagnostic trajectories between male veteran (MV) and non-veteran male (NVM) ALS patients enrolled in the U.S. National ALS Registry. Methods: We conducted a propensity score-matched analysis using self-administered military and clinical surveys from 2014 to 2024. Among 2,891 male ALS patients, MV were matched 1:1 with NVM on smoking history, birth year, head injury history, and region of residence at diagnosis. Outcomes included reported symptoms, time from symptom onset to diagnosis, and time to selected interventions. Results: Overall, 802 MV were matched to 802 NVM. Veterans were older at and reported longer intervals from symptom onset to ALS diagnosis (20.8 vs 16.7 months, p = 0.0004). MV were more likely to report difficulty swallowing and falls. Veterans were also more likely to use noninvasive breathing equipment (p = 0.0322). Findings from time-to-event analyses showed MV received wheelchairs or scooters statically earlier than NMV (log-rank p = 0.0028). Conclusions: Among participants in the Registry, MV reported differences in diagnostic timing, symptoms, and the use of supportive interventions compared to NVM. These findings may reflect differences in healthcare access, care pathways, and disease recognition over intrinsic differences in ALS biology. Because Registry participation is voluntary and data are self-reported, the result may not be generalizable to the broader ALS population.}, } @article {pmid42212756, year = {2026}, author = {Zhou, L and Li, M and Dai, Q and Liu, X and Li, C and Jiao, H and Pan, H and Xu, R}, title = {5-Hydroxytryptamine Distribution Alteration in Both Neuron and Synapse of Tg(SOD1*G93A)1gur Mice: A Potential Intervention Candidate Strategy for Amyotrophic Lateral Sclerosis.}, journal = {CNS neuroscience & therapeutics}, volume = {32}, number = {6}, pages = {e70946}, pmid = {42212756}, issn = {1755-5949}, support = {30560042//National Natural Science Foundation of China/ ; 81160161//National Natural Science Foundation of China/ ; 81360198//National Natural Science Foundation of China/ ; 82160255//National Natural Science Foundation of China/ ; GJJ13198//Education Department of Jiangxi Province/ ; GJJ170021//Education Department of Jiangxi Province/ ; 20142BBG70062//Jiangxi Provincial Department of Science and Technology/ ; 20171BAB215022//Jiangxi Provincial Department of Science and Technology/ ; 20192BAB205043//Jiangxi Provincial Department of Science and Technology/ ; 20212BAB216026//Jiangxi Provincial Department of Science and Technology/ ; 20181019//Health and Family Planning Commission of Jiangxi Province/ ; 202110016//Health and Family Planning Commission of Jiangxi Province/ ; 202310119//Health and Family Planning Commission of Jiangxi Province/ ; 2024SSY06081//Jiangxi Province Key Laboratory of Neurology/ ; 2024A0159//Science and Technology Plan Project of Jiangxi Provincial Administration of Traditional Chinese Medicine/ ; 20243BBI91030//Key Research and Development Project of Jiangxi Provincial Department of Science and Technology/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Serotonin/metabolism ; *Synapses/metabolism/pathology ; *Spinal Cord/metabolism/pathology ; Mice, Transgenic ; Mice ; *Neurons/metabolism/pathology ; Brain Stem/metabolism/pathology ; Receptor, Serotonin, 5-HT2A/metabolism ; Superoxide Dismutase-1/genetics ; Tryptophan Hydroxylase/metabolism ; Male ; Receptor, Serotonin, 5-HT1A/metabolism ; Disease Models, Animal ; Female ; Superoxide Dismutase/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; the precise pathogenesis of sporadic ALS (sALS) has not yet been elucidated up to now. Previous studies revealed that the abnormal alterations of some non-motor neurons (non-MN) were a potential pathogenesis of sALS. Therefore, this study aims to search the potential evidences of non-MN in the pathogenesis of ALS via exploring potential relationships between 5-hydroxytryptamine (5-HT) neurons and the development of ALS.

METHODS: We employed fluorescent immunohistochemistry to investigate the altered distribution patterns of 5-HT and tryptophan hydroxylase 2 in the spinal cord and brainstem of Tg(SOD1*G93A)1Gur (TG) and wild-type (WT) mice. Additionally, we used western blot to analyze the expression levels of 5-hydroxytryptamine receptor 1A (5-HTR1A) and 5-HTR2A.

RESULTS: Our findings revealed that 5-HT synapses were primarily distributed in the funiculus lateralis, anterior horn, posterior horn, central lateral column, and the area around the central canal of cervical, thoracic, and lumbar segments, and raphe nucleus as well as lateral paragigantocellular nucleus, and gradually reduced following age increase in WT mice. However, 5-HT synapses in the spinal cord and 5-HT neurons in the brainstem gradually increased following the progression of disease and presented a significantly negative correlation between the increased distribution of 5-HT synapses and neurons and the reduction of neural cell number (positively correlated with the increase in neural cell death) at the onset and/or progression stage of TG mice. 5-HTR1A significantly increased, while 5-HTR2A significantly decreased at the onset stage of TG mice.

CONCLUSION: Our study speculated that the distribution changes of 5-HT synapses in the spinal cord and 5-HT neurons in the brainstem play a potential protective role in the pathogenesis of sALS through a compensatory 5-HT increase.}, } @article {pmid42212889, year = {2026}, author = {Sommers-Spijkerman, M and Müller, F and Kruitwagen-Van Reenen, E and Visser-Meily, JMA and Uitslag, R and Beelen, A}, title = {Understanding psychological adjustment in patients with amyotrophic lateral sclerosis and their caregivers: a scoping review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/21678421.2026.2671166}, pmid = {42212889}, issn = {2167-9223}, abstract = {OBJECTIVE: Psychological adjustment is a major focus in the care of people with amyotrophic lateral sclerosis (ALS) and their caregivers, given its critical role in maintaining quality of life (QoL). This scoping review aimed to gain a better understanding of ALS patients' and caregivers' psychological adjustment, to inform future care and research.

METHODS: PubMed, Web of Science, PsycINFO, Embase and CINAHL were searched for peer-reviewed studies reporting associations of psychological factors with patient/caregiver QoL. Psychological factors were categorized by type (cognitive, emotional or behavioral responses), and by strength (weak, moderate, strong) and direction (positive, negative) of their association with patient/caregiver QoL.

RESULTS: Twenty-nine studies were included, identifying twelve cognitive responses (hope, positive thinking/reframing, psychological flexibility, resilience, coping/pain self-efficacy, helplessness, hopelessness, pain catastrophizing, rumination, self-perceived burden, self-stigma), two emotional responses (emotional support, venting) and three behavioral responses (independence, positive action, substance use) associated with patient QoL. Five cognitive responses (resilience, mindfulness, hopelessness, passive reaction coping, psychological inflexibility) and one behavioral response (positive action) were found associated with caregiver QoL.

CONCLUSIONS: A range of cognitive, emotional and behavioral responses, most notably cognitive responses, were found to shape patient and/or caregiver psychological adjustment, hence may serve as potential targets in ALS clinical practice. Nonetheless, empirical evidence is limited by heterogeneity in outcomes and measures and a lack of longitudinal, multivariable, and caregiver-oriented research. More systematic, standardized and longitudinal data collection is needed to clarify how psychological adjustment processes evolve throughout the disease trajectory and to identify modifiable targets for psychological supportive care.}, } @article {pmid42212970, year = {2026}, author = {Kallambettu, V and Maureen, F and Chapin, J and Hutcheson, K and Plowman, E}, title = {DIGEST Grades Remain Stable With Inclusion of Moderately Thickened Liquids in the Videofluoroscopic Examination in Individuals With Amyotrophic Lateral Sclerosis.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {69}, number = {6}, pages = {2475-2480}, pmid = {42212970}, issn = {1558-9102}, support = {R01 CA271223/CA/NCI NIH HHS/United States ; R01 NS100859/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/diagnostic imaging ; *Deglutition Disorders/diagnostic imaging/etiology/physiopathology ; Fluoroscopy/methods ; Longitudinal Studies ; Female ; Prospective Studies ; Male ; Middle Aged ; *Deglutition/physiology ; Video Recording ; Aged ; Severity of Illness Index ; Reproducibility of Results ; Pharynx/diagnostic imaging/physiopathology ; }, abstract = {PURPOSE: The Dynamic Imaging Grade of Swallowing Toxicity (Version 2; DIGESTV2) is a videofluoroscopy (VF) scale that measures pharyngeal swallowing severity based on functional measures of swallowing safety and efficiency. Original validation is based on a standard VF testing protocol including thin liquid, puree, and solid consistencies. Given that thickened liquid bolus trials are common in VF clinical testing protocols, we sought to determine the agreement in DIGESTV2 grades with and without the inclusion of moderately thick liquid bolus trials on DIGESTV2 outcomes in people with amyotrophic lateral sclerosis (pALS).

METHOD: This study represents a secondary analysis of VF examinations from a prospective longitudinal study conducted in 109 pALS. VF evaluations contained 10 barium trials spanning three International Dysphagia Diet Standardisation Initiative (IDDSI) levels (0-7). Duplicate, independent, and blinded ratings were completed. DIGESTV2 Efficiency and Safety grading was then completed under two conditions-with and without the inclusion of moderately thick liquid bolus trials into DIGESTV2 grading-to produce two sets of DIGESTV2 ratings for each VF study. Descriptives, percent agreement, and a weighted Cohen's kappa were performed on DIGESTV2 grades.

RESULTS: A total of 373 VF examinations were included in this analysis. DIGESTV2 grade percent agreement with and without IDDSI Level 3 was excellent for Safety (98.1%), Efficiency (93.8%), and Total (94.1%) grades. Kappa values for Safety, Efficiency, and Total grades were .96, .89, and .91, respectively, indicating excellent agreement across bolus trial inclusion methods.

CONCLUSIONS: Standard inclusion of moderately thick liquid bolus trials did not significantly impact DIGESTV2 grading in this data set. These results add to the preliminary but growing evidence suggesting stability of DIGEST grading with alternate bolus protocols in another patient population.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.32348451.}, } @article {pmid42213237, year = {2026}, author = {Leboeuf, M and Nijssen, J and Comley, LH and Aguila Benitez, JC and Mei, I and Gómez Alcalde, S and Muñoz de Bustillo-Alfaro, RA and Radoi, V and Nichterwitz, S and Schweingruber, C and Acevedo Arozena, A and Hedlund, E and Cullheim, S}, title = {Reevaluating the role of beta2-microglobulin: new insights on selective vulnerability in ALS pathology.}, journal = {Acta neuropathologica}, volume = {151}, number = {1}, pages = {}, pmid = {42213237}, issn = {1432-0533}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *beta 2-Microglobulin/metabolism/genetics ; Animals ; Humans ; *Motor Neurons/pathology/metabolism ; Mice ; Female ; Spinal Cord/pathology/metabolism ; Male ; Mice, Transgenic ; Superoxide Dismutase-1/genetics ; HLA Antigens/metabolism/genetics ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the selective loss of motor neurons (MNs). Why these neurons are particularly vulnerable in ALS remains unclear, as does why certain MN groups remain resistant throughout the disease course. We investigated the role of the human leukocyte antigens (HLAs) and beta2-microglobulin (β2m) in MN susceptibility to ALS, given their reported involvement in both prolonging and shortening disease progression. Loss of HLAs in ALS has also been shown to increase MNs vulnerability to toxicity exerted by activated astrocytes. RNA sequencing of control tissues demonstrated that disease-resistant oculomotor neurons (OMNs) and Onuf's MNs exhibited β2m and HLA mRNA levels comparable to those of vulnerable spinal MNs, suggesting that baseline differences in these transcripts do not explain the differential vulnerabilities of these MN groups. However, HLA protein levels showed an inverse correlation with spinal MN size, with the large MNs, those lost early in ALS, displaying the lowest HLA expression. HLA protein levels were also reduced in spinal MNs from end-stage ALS patient tissues, while remaining relatively unchanged in OMNs. In contrast, spinal MNs uniquely exhibited significant upregulation of β2m and HLA-C transcripts during disease, likely reflecting a protective compensatory response. Together, these findings suggest that β2m and HLAs may contribute to spinal MN vulnerability in ALS. To assess their functional role, β2m knockout mice were crossbred with SOD1G93A ALS mice. Loss of β2m did not alter life span of the ALS mice, but led to partial preservation of lumbrical muscle innervation that was insufficient to maintain motor function. Analysis of GFAP immunoreactivity revealed marked neuroinflammation activation in the spinal cords of β2m knockout mice. As these mice retain normal MN numbers and life-span, this indicates that loss of functional MHC-I, even in the presence of astrocyte activation, is insufficient to cause MN disease. Furthermore, β2m knockout significantly increased GFAP activation in SOD1G93A mice, but did not further exacerbate disease progression, suggesting that loss of functional MHC-I does not necessarily render MNs more vulnerable to astrocyte toxicity. Overall, these findings indicate that β2m and HLAs are dynamically regulated in ALS, and may influence MN vulnerability, but they are not major disease modifiers in ALS.}, } @article {pmid42214007, year = {2026}, author = {Bracaval, K and De Vocht, J and Ombelet, F and Den Bulcke, LV and Peeters, AM and Deleu, B and Vrijsen, B and Kalkanis, A and Buyse, B and Testelmans, D and Van Den Bossche, M and Van Damme, P}, title = {Sleep disturbances and respiratory dysfunction in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2026.2671162}, pmid = {42214007}, issn = {2167-9223}, abstract = {OBJECTIVE: To investigate how respiratory dysfunction and site of onset influences changes in sleep architecture in people with ALS (pwALS).

METHODS: We conducted a retrospective observational study, analyzing demographic data, lung function tests, and polysomnography (PSG) measures. Descriptive statistics, correlation analyses, and survival analyses were performed.

RESULTS: Our cohort had 240 pwALS, 63% male, median age at onset 59.3 (IQR 16.5) years. Median time from onset to PSG was 27.5 (IQR 25) months. Most pwALS had spinal onset (79%). Spirometry at time of PSG showed a reduced Forced Vital Capacity (FVC) (58; (IQR 26) %). We saw a significant FVC decline (3.9; (IQR 4) % per month) in the months before PSG. The sleep quality assessment in pwALS revealed a reduced total sleep time (339; (IQR 144.7) minutes), diminished sleep efficiency (62.8; (IQR 26.5)%) and increased wake after sleep onset (172; (IQR 130.2) minutes) when compared to normal values of healthy age-matched adults. The spinal onset group had a higher number of arousals. In the multivariate linear regression model adjusted for age and sex, FVC is a significant predictor for sleep efficiency (β = 3.359, p = 0.0059). Spinal onset, a slower rate of FVC decline in the months preceding PSG and a preserved FVC (≥ 70%) at the time of PSG were associated with improved survival.

CONCLUSION: We observed substantial sleep disturbances in our cohort overall with substantially increased arousals in the spinal group. FVC is a significant predictor for sleep efficiency and the decline in FVC is linked to survival.}, } @article {pmid42214042, year = {2026}, author = {de Boer, EMJ and Willemse, SW and Veldink, JH and Goedee, HS and Vrancken, AFJE and van Rheenen, W and Westeneng, HJ and van den Berg, LH and van Es, MA}, title = {Diagnostic Revision From Primary Lateral Sclerosis to Amyotrophic Lateral Sclerosis: A Cohort Study.}, journal = {Neurology}, volume = {106}, number = {12}, pages = {e218055}, pmid = {42214042}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Female ; *Motor Neuron Disease/diagnosis/physiopathology/epidemiology ; Male ; Middle Aged ; Aged ; Disease Progression ; Cohort Studies ; Retrospective Studies ; Registries ; Netherlands ; Electromyography ; }, abstract = {BACKGROUND AND OBJECTIVES: Primary lateral sclerosis (PLS) is defined as a pure upper motor neuron syndrome and is a diagnosis of exclusion, amyotrophic lateral sclerosis (ALS) being the most likely alternative diagnostic consideration. A minimum disease duration of 2 years is required for the diagnosis of PLS, after which patients are classified as probable PLS (P-PLS) and subsequently as definite PLS (D-PLS) after 4 years. Our aim is to apply the current diagnostic criteria to a population-based cohort and investigate which clinical characteristics are associated with a diagnostic revision to ALS.

METHODS: This cohort study included patients meeting the current diagnostic criteria for PLS retrospectively from the Dutch Motor Neuron Disease Registry. Diagnostic revision to ALS was based on clinical assessment, EMG findings according to the revised El Escorial Criteria, or if patients had died from disease progression within 4 years of disease onset. Clinical characteristics were compared for patients who underwent diagnostic revision with ALS vs true PLS. Subdistribution hazard ratios (SHRs) for characteristics associated with diagnostic revision were determined using Fine-Gray regression.

RESULTS: We included 478 patients (median age of onset 59.3 years, interquartile range 50.8-67.0, 47.9% female), of whom 311 (65.1%) met criteria for P-PLS and 167 (34.9%) for D-PLS at diagnosis. Eighty-eight patients (18%) underwent diagnostic revision to ALS, 76 cases (86%) before 4 years of disease duration. Patients whose diagnosis was revised to ALS had higher median age at onset (63.4 vs 58.0 years, p = 5.20 × 10[-4]), more often had bulbar onset (38.6% vs 19.7%, p = 6.19 × 10[-4]), and faster progression (median ALS Functional Rating Scale-revised slope 0.43 vs 0.18, p = 6.05 × 10[-11]). The risk of diagnostic revision increased if progression rate was faster (SHR 3.08 95% CI 1.69-5.60, p = 2.35 × 10[-4]) and if diagnosis was P-PLS compared with D-PLS (SHR 3.08, 95% CI 1.65-5.74, p = 3.96 × 10[-4]).

DISCUSSION: In our cohort, most diagnostic revisions from PLS to ALS were in patients with a disease duration of less than 4 years. Besides disease duration, a faster progression rate was associated with diagnostic revision from PLS to ALS. Adding progression rate to the current diagnostic criteria could increase accuracy and help identify patients at higher risk of developing ALS.}, } @article {pmid42214472, year = {2026}, author = {Garrett, TL and Wintermute, L and Armitage, M and Ward, S and Gerber, K and Elbasiouny, SM}, title = {Optimized multiplex immunofluorescent protocols for simultaneous in situ identification of α-motoneuron subtypes.}, journal = {Journal of neuroscience methods}, volume = {433}, number = {}, pages = {110815}, doi = {10.1016/j.jneumeth.2026.110815}, pmid = {42214472}, issn = {1872-678X}, support = {R01 NS091836/NS/NINDS NIH HHS/United States ; R01 NS131816/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Female ; *Spinal Cord/cytology ; *Motor Neurons/classification/cytology/metabolism/physiology ; Male ; *Fluorescent Antibody Technique/methods ; Mice, Inbred C57BL ; Mice, Transgenic ; Amyotrophic Lateral Sclerosis/pathology ; Mice ; Disease Models, Animal ; }, abstract = {BACKGROUND: Accurate identification of α-motoneuron (α-MN) subtypes - slow (S), fast fatigue-resistant (FR), fast fatigue-intermediate (FI), and fast fatigable (FF) - is essential for studying motor circuit organization and selective vulnerability in neurodegenerative disease. While electrophysiological approaches can distinguish these subtypes, existing immunohistochemical (IHC) methods lack the ability to simultaneously identify all four α-MN classes in situ, particularly the FI subtype, limiting their utility for large-scale or tissue-based analyses.

NEW METHOD: Here, we present novel multiplex immunofluorescent strategies that enables simultaneous in situ identification of S, FR, FI, and FF α-MN subtypes, including intermediate populations, within single sections of mouse lumbar spinal cord. This approach integrates a combinatorial marker framework with optimized co-labeling conditions to resolve subtype-specific molecular signatures, including FI MNs, which have not been previously distinguishable using standard IHC methods.

RESULTS: We establish a systematic validation pipeline demonstrating robust and reproducible subtype classification across multiple protocols, sexes, mouse strains, and disease conditions, including the G93A-SOD mouse model of amyotrophic lateral sclerosis. Labeled populations recapitulate known size distributions and exhibit consistent subtype-specific patterns across lumbar segments, supporting both the accuracy and reproducibility of the method.

CONCLUSIONS: By enabling comprehensive in situ classification of all major α-MN subtypes, this approach represents a substantive refinement of multiplex IF, overcoming key limitations of existing IF methods and enabling analyses of α-MN subtype organization and selective vulnerability that were previously not feasible with standard histological techniques. This framework is broadly applicable to studies of motor system organization, aging, and neurodegenerative disease.}, } @article {pmid42214970, year = {2026}, author = {Franzoia, B and de Diego-Balaguer, R}, title = {The beat in speech: A window into the attentional mechanisms supporting the detection of non-adjacent dependencies.}, journal = {Cognition}, volume = {274}, number = {}, pages = {106596}, doi = {10.1016/j.cognition.2026.106596}, pmid = {42214970}, issn = {1873-7838}, mesh = {Humans ; *Attention/physiology ; *Speech Perception/physiology ; *Music ; Female ; Adult ; Male ; Young Adult ; *Learning/physiology ; *Speech ; }, abstract = {Converging evidence suggests that musical training can elicit positive transfer effects across multiple domains of language processing, including grammar. In humans, exposure to musical rhythm induces beat and meter perception, which has been shown to enhance attentional allocation and temporal prediction. Theories hypothesize that the predictive gains intrinsic to music rhythmicity may exert cascading effects on syntactic processing by modulating sensitivity to speech prosody. From this perspective, learning should also be boosted insofar as prosody tends to align with grammatical structure. In the present study, we introduce a novel behavioural paradigm to investigate the link between rhythmicity and grammar learning by testing whether the rhythmic beat facilitates the detection of grammar-like structures in artificial languages (ALs), implemented as non-adjacent dependencies (NADs) between variable syllables forming a speech stream (e.g., PU reliably predicts KI in PUlaruKI). A total of 147 participants were exposed to four ALs that varied in rhythmic, grammatical structure, and the alignment between the two: (i) a beat-inducing rhythm with no NADs; (ii) a beat-hindering rhythm with NADs; (iii) a beat-inducing rhythm with embedded NADs temporally misaligned, and (iv) NADs aligned with beat time-points. Results of the implicit and, after exposure, explicit learning measures demonstrate enhanced learning when NADs are embedded within beat-inducing rhythmic structures. Together, these findings suggest that rhythm enhances predictive and attentional mechanisms implicated in grammar learning, underscoring their role in its acquisition.}, } @article {pmid42215790, year = {2026}, author = {Li, S and Xu, S and Li, F and Zhao, Q and Zhang, P and Guan, Q and Sun, X and Bi, J and Xiao, H and Tang, Y and Peng, C and Chen, Q and Wang, Y and Yang, M}, title = {The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.}, journal = {The EMBO journal}, volume = {45}, number = {13}, pages = {4531-4568}, pmid = {42215790}, issn = {1460-2075}, support = {32070743//MOST | National Natural Science Foundation of China (NSFC)/ ; 32560156//MOST | National Natural Science Foundation of China (NSFC)/ ; 202401BF070001-015//Yunnan Provincial Science and Technology Department ()/ ; 202401AS070131//Yunnan Provincial Science and Technology Department ()/ ; C619300A142//Yunnan Provincial Science and Technology Department ()/ ; C1762201000139//Yunnan University (YNU)/ ; KC-242410334//Yunnan University (YNU)/ ; }, mesh = {Animals ; *Microglia/metabolism/pathology ; *rab GTP-Binding Proteins/metabolism/genetics ; *Lysosomes/metabolism/pathology ; Mice ; *C9orf72 Protein/metabolism/genetics ; Homeostasis ; Mice, Knockout ; *Carrier Proteins/metabolism/genetics ; Humans ; }, abstract = {Microglia are critical regulators of neuroinflammation and neurodegeneration. Haploinsufficiency of C9orf72, the most frequently mutated gene in amyotrophic lateral sclerosis and frontotemporal dementia, has been linked to autophagy-lysosomal pathway defects, but the role of C9orf72 in microglia remains unclear. Here, we identify the C9orf72/SMCR8 complex as a key regulator of microglial homeostasis through promoting lysosomal membrane repair. Loss of C9orf72 and SMCR8 in mice causes age‑dependent neuroinflammation and microgliosis, with microglia adopting a disease-associated state. In aged brain and spinal cord tissue, microglia display lysosomal damage marked by galectin‑3 accumulation. Using a lysosomotropic agent to induce lysosomal damage in microglia, we find that C9orf72/SMCR8-deficient cells accumulate damaged lysosomes and show defective recruitment of phosphorylated RAB8A and the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery to damaged lysosomes. Notably, mutant microglia accumulate GTP‑bound RAB8A, which becomes hyperphosphorylated and mislocalized to RAB7-positive, LAMP1-negative vesicles. The GTPase-activating activity of the C9orf72/SMCR8 complex is essential for lysosomal repair. Our findings reveal that the C9orf72/SMCR8 complex coordinates RAB8A-ESCRT-mediated lysosomal repair to safeguard microglial homeostasis and limit neuroinflammation.}, } @article {pmid42215859, year = {2026}, author = {La Cognata, V and Gentile, G and Morello, G and Guarnaccia, M and Cavallaro, S}, title = {RNA-centric approaches in amyotrophic lateral sclerosis: prospects for future therapeutics.}, journal = {Expert opinion on therapeutic targets}, volume = {30}, number = {6}, pages = {571-583}, doi = {10.1080/14728222.2026.2682782}, pmid = {42215859}, issn = {1744-7631}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/drug therapy/therapy ; Animals ; Artificial Intelligence ; Drug Discovery/methods ; Molecular Targeted Therapy ; RNA/genetics ; Gene Expression Profiling/methods ; Transcriptome/genetics ; Algorithms ; Drug Repositioning ; Drug Development ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by profound clinical and molecular heterogeneity, which has substantially hindered the development of effective therapies. Significant advances in ALS research have been driven by the study of RNA biology, together with the implementation of advanced transcriptomic technologies and artificial intelligence-based algorithms, which are assuming a transformative role in reshaping the field.

AREAS COVERED: We discuss how genome-wide expression profiling enables the identification of molecular signatures for drug discovery and repurposing, facilitates the stratification of patients into biologically distinct subtypes for more refined clinical trials, and guides the development of novel nucleic acid-based therapies. Furthermore, we explore the potential of transcriptomics to identify molecular vulnerabilities during pre-symptomatic stages, paving the way for early intervention.

EXPERT OPINION: The convergence of transcriptomics and artificial intelligence is poised to fundamentally redefine ALS, transforming it from a single clinical entity into a spectrum of molecularly defined disorders, each potentially amenable to targeted therapeutic intervention. While challenges in translating high-dimensional data into clinical practice remain, the integration of transcriptomics with advanced computational tools promises to accelerate the transition toward a new era of personalized medicine in ALS.}, } @article {pmid42216417, year = {2026}, author = {Curman, P and Alam, U and Ludwig, RJ}, title = {Response to Meisenheimer et al's "Behind the data: Pitfalls and bias in database research".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {2}, pages = {e135-e136}, doi = {10.1016/j.jaad.2025.09.108}, pmid = {42216417}, issn = {1097-6787}, } @article {pmid42217760, year = {2026}, author = {Jiang, Y and Hu, S and Yang, B and Zhang, L and Wang, Y and Yang, G and Zhang, H}, title = {Fluid-based biomarkers of amyotrophic lateral sclerosis: recent advances and future prospects.}, journal = {Brain research}, volume = {1888}, number = {}, pages = {150395}, doi = {10.1016/j.brainres.2026.150395}, pmid = {42217760}, issn = {1872-6240}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism/cerebrospinal fluid ; *Biomarkers/metabolism/analysis/cerebrospinal fluid ; Saliva/metabolism ; Animals ; Tears/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with no definitive cure. The absence of specific diagnostic biomarkers leads to diagnostic delays, hindering early intervention and management. This review provides a critical appraisal of fluid-based biomarkers for ALS across multiple sources-cerebrospinal fluid (CSF), blood, urine, saliva, and tears-with emphasis on their diagnostic and prognostic potential, limitations, and readiness for clinical translation. While neurofilaments (NfL, pNfH) are well-established as sensitive indicators of neuroaxonal injury and are increasingly used as prognostic and pharmacodynamic markers in clinical trials, they lack disease specificity. Biomarkers reflecting ALS-specific pathology, such as TDP-43 species and C9orf72 dipeptide repeat proteins (DPRs), show promise but remain in early validation stages with limited multicenter data. Emerging markers from non-invasive sources (urine p75ECD, salivary chromogranin A, tear metabolomics) offer potential for repeated sampling but require rigorous external validation before clinical adoption. To address current gaps, we introduce a standardized evidence grading framework (Tier 1-3) and a comprehensive reporting template for biomarker studies, including explicit performance metrics (AUC, sensitivity, specificity, confidence intervals) and validation status. We also propose minimum reporting standards for study design, pre-analytical variables, and statistical rigor, modeled on REMARK guidelines. A roadmap for biomarker validation and a cross-fluid comparison matrix are provided to guide future research. Despite considerable progress, significant challenges remain, including biological heterogeneity, pre-analytical variability, and insufficient external validation. Future efforts should prioritize multicenter prospective studies, assay harmonization, ethical frameworks for early diagnosis, and integration of emerging technologies such as artificial intelligence and digital twins. Fluid-based biomarkers, while not yet replacing clinical evaluation, are essential tools for accelerating drug development, enabling patient stratification, and moving toward personalized medicine in ALS.}, } @article {pmid42218400, year = {2026}, author = {Abbasi, H and Shafaatdoost, M and Mohajerani, A and Asadollahi, M and Rashidi, M and Malekahmadi, M and Sarraf, P}, title = {Association between body composition and disease progression in adults with amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {}, pmid = {42218400}, issn = {1471-2377}, support = {IR. TUMS.NI.REC.1401.059//Tehran University of Medical Sciences and Health Services/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Female ; Cross-Sectional Studies ; Male ; *Body Composition/physiology ; *Disease Progression ; Middle Aged ; Aged ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration, muscle wasting, and respiratory failure, with a median survival of 30 months. Due to the strong link between dysphagia, weight loss, and disease progression, this study investigates the relationship between body composition and clinical outcomes in ALS adults. This cross-sectional study involved 93 ALS adults (29 females, 64 males) from Imam Khomeini Hospital in Tehran, selected based on EI Escorial criteria. Researchers assessed body composition, functional abilities, and disease progression using ALSFRS-R, MRC scores, and DPR, analyzing associations through linear regression models with RStudio in conjunction with R software. In this study, significant differences were found between the third and first tertiles for various measures. Significant associations were observed between body composition and ALSFRS-R for MAC (β: 3.0; P = 0.006), with underweight and moderately active adults exhibiting notable differences. The MRC score was positively associated with FFM (β: 5.8; P = 0.002), SLM (β: 5.6; P = 0.002), SMM (β: 3.8; P = 0.001), MAC (β: 3.2; P = 0.002), ICW (β: 2.7; P = 0.002), and ECW (β: 1.5; P = 0.003), while underweight and low-to-moderate physical activity adults indicated inverse associations. For DPR, significant relationships were noted for weight (β: 4.5; 95% CI: 0.02, 9.3; P = 0.002) and FFM (β: 11; P < 0.001), influenced by gender and physical activity. The findings highlight the role of gender, weight, and activity in ALS management, suggesting that maintaining a healthy weight along and muscle mass along with regular activity is associated with better outcomes. This can inform personalized treatment strategies for better patient care.}, } @article {pmid42218846, year = {2026}, author = {Bridge, F and Thevathasan, W and Schultz, D and Zhang, W and Wright, E and Yeh, WZ}, title = {Neurosymptomatic HIV CSF viral escape with parkinsonism and amyotrophic lateral sclerosis-like syndrome: a case report.}, journal = {Journal of neuroimmunology}, volume = {418}, number = {}, pages = {578992}, doi = {10.1016/j.jneuroim.2026.578992}, pmid = {42218846}, issn = {1872-8421}, mesh = {Humans ; Male ; Adult ; *HIV Infections/cerebrospinal fluid/complications/drug therapy ; *Parkinsonian Disorders/cerebrospinal fluid/virology ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/virology/diagnostic imaging ; Viral Load ; }, abstract = {Human immunodeficiency virus (HIV) infection can lead to various neurologic complications affecting central and peripheral nervous systems. Rarely, patients on combined anti-retroviral therapy (CART) with peripheral virologic suppression may develop compartmentalised central nervous system infection with cerebrospinal fluid (CSF) viral escape. We report the case of a 42-year-old man with chronic HIV infection and a previous diagnosis of Parkinson's disease referred for neurologic evaluation with diffuse hyperreflexia including brisk jaw jerk. He was adherent to combined anti-retroviral therapy (CART). During follow-up, he developed mild upper and lower limb weakness and gait instability. Electromyography was consistent with a motor neuropathy or neuronopathy. Neuraxial MRI showed non-specific supratentorial white matter lesions. Plasma HIV viral load was suppressed (<20 copies/mL) whereas CSF viral load was 35 copies/mL, consistent with CSF viral escape. CSF neopterin level was elevated indicating neuroinflammation. HIV-associated neurological overlap syndrome, with parkinsonism and an amyotrophic lateral sclerosis-like syndrome, in the context of neurosymptomatic CSF escape was diagnosed. The patient's HIV CART regime was adjusted to improve CNS penetration. Neurosymptomatic HIV CSF escape is a rare and likely under-recognised complication which can occur despite compliance with CART. When suspected, CSF viral load should be tested. CART optimisation to improve CNS penetration may be potentially beneficial in neurosymptomatic CSF viral escape and to reduce HIV-associated neurotoxicity, but these require further study to confirm.}, } @article {pmid42219148, year = {2026}, author = {Martin, R and Beauchamp-Chalifour, P and Rayes, J and Matovinovic, K and Schneider, PS}, title = {Incidence and strategies for prevention of adjustable loop suspensory fixation maldeployment in multiligament knee reconstruction.}, journal = {Journal of ISAKOS : joint disorders & orthopaedic sports medicine}, volume = {19}, number = {}, pages = {101151}, doi = {10.1016/j.jisako.2026.101151}, pmid = {42219148}, issn = {2059-7762}, mesh = {Humans ; Male ; Incidence ; Adult ; Female ; Reoperation/statistics & numerical data ; Range of Motion, Articular ; *Postoperative Complications/epidemiology/prevention & control/etiology ; *Knee Joint/surgery ; Retrospective Studies ; *Knee Injuries/surgery ; }, abstract = {INTRODUCTION/OBJECTIVES: Adjustable loop suspensory (ALS) fixation offers the ability to re-tension grafts in complex multiligament knee reconstruction. A frequent complication of adjustable loop fixation is implant maldeployment. This study's primary objective was to determine the incidence of implant maldeployment associated with ALS fixation in a cohort of patients who underwent multiligament knee reconstruction and to identify the most at-risk tunnel(s). Our secondary objective was to determine the clinical impact of implant maldeployment.

METHODS: Demographic, radiological, and clinical data were collected from adult patients who underwent multiligament knee reconstruction using ALS fixation between January 1, 2018, and January 1, 2020. The primary outcome measure was the incidence of implant maldeployment, as defined by radiologic soft-tissue interposition of >5 mm or radiologic intraosseous button flip. Secondary outcomes were the rate of reoperation, postoperative Lysholm and Tegner scores, and postoperative knee range of motion. Statistical analyses were conducted using univariate logistic regression, and odds ratio (OR) with 95% confidence interval (CI) were reported.

RESULTS: A total of 241 ALS buttons were included in 56 patients, predominantly male patients (N = 39, 70%), with a median age of 32 [26.0-42.0] years. The incidence of ALS implant maldeployment was 5% (N = 11/241). Soft-tissue interposition maldeployment only occurred for the femoral medial collateral ligament (MCL) and the femoral posterior cruciate ligament posteromedial bundle fixation (PCL PM). Reoperation occurred in five out of nine (56%) patients with maldeployment, and six out of 34 (18%) in patients with well deployed implants (OR 6.8, 95% CI 1.1 to 49, p = 0.022). Maldeployment did not appear to impact postoperative knee patient reported outcomes or range of motion (p ≥ 0.05). The median follow-up duration was 9.1 [7.4-13.6] months.

CONCLUSION: This cohort demonstrates a 5% incidence of maldeployment when using ALS fixation. Despite maldeployment, ALS fixation demonstrated similarly favorable clinical outcomes, but a higher rate of reoperation. In multiligament reconstructions, surgeons should be particularly attentive to femoral ALS button deployment for PCL and MCL grafts.

LEVEL OF EVIDENCE: IV.}, } @article {pmid42219616, year = {2026}, author = {Busi, R and Goggin, D and Eyres, N and Runge, F and Porri, A and Flower, K}, title = {A Trp574-Leu substitution confers resistance to three classes of acetolactate synthase inhibitors in Australian brome grass (Bromus diandrus).}, journal = {Pest management science}, volume = {82}, number = {10}, pages = {9437-9443}, pmid = {42219616}, issn = {1526-4998}, support = {UWA2007-002RTX//Grains Research and Development Corporation/ ; }, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Bromus/genetics/drug effects/enzymology ; Australia ; *Plant Proteins/genetics/metabolism/antagonists & inhibitors ; Amino Acid Substitution ; Imidazoles/pharmacology ; *Enzyme Inhibitors/pharmacology ; }, abstract = {BACKGROUND: Brome grass (Bromus diandrus) is a prevalent weed in southern Australian cropping regions which causes significant economic damage in crops and pastures. Before harvest 2023, two populations (named 6-24 and 7-24) suspected of resistance to imidazolinone herbicides were collected from separate fields. Preliminary screening indicated that these populations were resistant to several different acetolactate synthase (ALS)-inhibiting herbicides. Therefore, further characterisation of the level and mechanism of resistance was carried out.

RESULTS: There was high survival of the resistant populations at the maximum tested rates of sulfometuron (600 g ha[-1]) and imazamox + imazapyr (74 + 34 g ha[-1], 2× the label rate for use in imidazolinone-tolerant crops). All examined individuals (15 from each population) carried the same point mutation causing a tryptophan-to-leucine substitution at position 574 in the ALS protein. Application of the cytochrome P450 inhibitor malathion prior to herbicide treatment did not affect survival rates.

CONCLUSIONS: This is the first study reporting a Trp574-Leu mutation as the basis for cross-resistance to ALS-inhibiting herbicides (sulfonylureas, imidazolinones and triazolopyrimidines) in Australian populations of B. diandrus. Control of these populations will require strategic use of pre-emergence herbicides and herbicide-tolerant crops in combination with harvest weed seed control. © 2026 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid42221419, year = {2019}, author = {Kocia, L and Love, P}, title = {The non-disjoint ontic states of the Grassmann ontological model, transformation contextuality, and the single qubit stabilizer subtheory.}, journal = {Journal of physics. A, Mathematical and theoretical}, volume = {52}, number = {9}, pages = {}, pmid = {42221419}, issn = {1751-8113}, support = {9999-NIST/ImNIST/Intramural NIST DOC/United States ; }, abstract = {We show that it is possible to construct a preparation non-contextual ontological model that does not exhibit 'transformation contextuality' for single qubits in the stabilizer subtheory. In particular, we consider the 'blowtorch' map and show that it does not exhibit transformation contextuality under the Grassmann Wigner-Weyl-Moyal (WWM) qubit formalism. Furthermore, the transformation in this formalism can be fully expressed at order ℏ 0 , where it satisfies all of Kolmogorov's axioms of classical probability theory, and so does not qualify as a candidate quantum phenomenon. In particular, we find that the Grassmann WWM formalism at order ℏ 0 corresponds to an ontological model governed by an additional set of constraints arising from the relations defining the Grassmann algebra. Due to this additional set of constraints, the allowed probability distributions in this model do not form a single convex set when expressed in terms of disjoint ontic states and so cannot be mapped to models whose states form a single convex set over disjoint ontic states. However, expressing the Grassmann WWM ontological model in terms of non-disjoint ontic states corresponding to the monomials of the Grassmann algebra results in a single convex set. We further show that a recent result by Lillystone et al that proves a broad class of preparation and measurement non-contextual ontological models must exhibit transformation contextuality lacks the generality to include the ontological model considered here; Lillystone et al's result is appropriately limited to ontological models whose states produce a single convex set when expressed in terms of disjoint ontic states. Therefore, we prove that for the qubit stabilizer subtheory to be captured by a preparation, transformation and measurement non-contextual ontological theory, it must be expressed in terms of non-disjoint ontic states, unlike the case for the odd-dimensional single-qudit stabilizer subtheory.}, } @article {pmid42221822, year = {2026}, author = {Sreeram, A and Baron, DM and Brusati, A and Stallworth, K and Humphrey, J and Landers, JE}, title = {Global transcriptional changes across multiple isogenic C9orf72 patient iPSC-derived neurons.}, journal = {iScience}, volume = {29}, number = {6}, pages = {116054}, pmid = {42221822}, issn = {2589-0042}, abstract = {Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD); yet, mechanisms underlying selective neuronal vulnerability remain unclear. A major challenge in identifying consistent transcriptomic changes across C9orf72 patient-derived neuron lines has been heterogeneous differentiations, lack of isogenic controls and low sequencing depth. To overcome these challenges, we generated homogeneous cortical neuron (iCNs) cultures from multiple isogenic C9orf72 patient iPSC pairs and performed RNA deep sequencing. We identified robust and reproducible gene expression and splicing alterations in pathways related to cytoskeletal organization, extracellular matrix adhesion and synaptic signaling. Notably, we observed exon 30 skipping in the cytoskeletal regulator filamin B (FLNB), resulting in loss of its hinge domain. This was accompanied by altered FLNB localization, disrupted actin crosslinking, and mechanotransduction signaling. These findings reveal convergent transcriptomic and functional disruptions across multiple isogenic C9orf72 patient-derived iCNs offering insights into ALS/FTD pathogenesis.}, } @article {pmid42222887, year = {2026}, author = {Michels, S and Chen, C and Ruf, WP and Garcia Garcia, MM and Arnold, FJ and Wu, Z and Bennett, CL and Shams, D and Thompson, LM and Walker, AC and Dickson, DW and Petrucelli, L and Dorst, J and Prudencio, M and Li, W and La Spada, AR}, title = {Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {11}, pages = {}, pmid = {42222887}, issn = {1558-8238}, support = {R35 NS122140/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood ; *Cell-Free Nucleic Acids/genetics/blood/cerebrospinal fluid ; Female ; *Epigenesis, Genetic ; *DNA Methylation ; Male ; Biomarkers/blood/cerebrospinal fluid ; C9orf72 Protein/genetics ; Disease Progression ; Middle Aged ; Aged ; Neurofilament Proteins/cerebrospinal fluid ; Adult ; }, abstract = {The role of the epigenome in age-related neurodegenerative disorders remains understudied. Here, we analyzed circulating cell-free DNA (cfDNA) from blood to detect methylation changes as a liquid biopsy for Amyotrophic Lateral Sclerosis (ALS). Our study included 20 patients with sporadic ALS, 10 patients with C9orf72-associated ALS, 10 asymptomatic carriers of the C9orf72 repeat expansion mutation, and 21 nondisease control individuals. Following targeted enzymatic methyl-sequencing (EM-seq) of approximately 4 million CpG sites, we detected numerous differentially methylated genes, including several implicated in ALS disease risk and pathogenesis. By integrating multiple epigenetic features, we delineated a distinct epigenetic signature, which achieved an average area under the curve (AUC) of 0.91 ± 0.10 upon receiver operator characteristic (ROC) analysis, which enabled detection of approximately 70% of patients with ALS with close to 100% specificity. Furthermore, we also identified a set of genes whose methylation status significantly correlated with clinical disease progression and cerebrospinal fluid (CSF) neurofilament levels. Our results reveal the potential of cfDNA-based biomarkers to accurately diagnose ALS and potentially predict disease progression.}, } @article {pmid42222897, year = {2026}, author = {Inoue, H and Horimoto, Y and Tsuda, Y and Madokoro, Y and Kawashima, S and Akagi, A and Iwasaki, Y and Matsukawa, N}, title = {Visible Tongue Fasciculations With Electromyographic Denervation in Autopsy-Proven Progressive Supranuclear Palsy Mimicking Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {74}, number = {2}, pages = {496-499}, pmid = {42222897}, issn = {1097-4598}, } @article {pmid42223083, year = {2026}, author = {Zhang, Q and Valério, M and Grünewald, L and Borges-Araújo, L and Grünewald, F and Wang, S and Marrink, SJ and Gong, Y and Souza, PCT}, title = {Coarse-Grained Simulations Reveal Salt- and Length-Dependent Condensation of G4C2 RNA Repeats.}, journal = {The journal of physical chemistry letters}, volume = {17}, number = {23}, pages = {6445-6454}, doi = {10.1021/acs.jpclett.6c00916}, pmid = {42223083}, issn = {1948-7185}, mesh = {*Molecular Dynamics Simulation ; Nucleic Acid Conformation ; Osmolar Concentration ; Phase Separation ; *RNA/chemistry ; Salts/chemistry ; *G-Quadruplexes ; }, abstract = {RNA-RNA interactions drive the formation of biomolecular condensates via liquid-liquid phase separation (LLPS), but their underlying molecular mechanisms remain poorly understood. Here, we employ Martini 3 coarse-grained molecular simulations to investigate phase transitions of G4C2 RNA repeats─sequences implicated in neurodegenerative disorders such as ALS and FTD─across varying salt concentrations. The model captures salt-dependent transitions from dispersed to condensed-like states and suggests that dominant interaction patterns, including Watson-Crick-like and G-G contacts, shift with ionic strength. Notably, longer RNA sequences maintain phase-separated states at salt concentrations that dissolve shorter ones, in line with experimental observations. Our findings demonstrate the ability of the Martini coarse-grained model to reproduce key biophysical features of RNA LLPS, including sequence-length dependence and interaction specificity. This work provides molecular-level insight into RNA-driven phase separation and reveals how sequence composition and ionic strength govern the emergence and stability of RNA-rich assemblies.}, } @article {pmid42223334, year = {2026}, author = {He, C and Liu, Z and Yuan, Y and Tang, L and Wang, M and Li, Y and Zhao, Q and Weng, L and Du, J and Wu, H and Hu, F and Xu, R and Guo, J and Shen, L and Tang, B and Wang, J}, title = {Distinct UNC13A Haplotype Blocks Define Disease Severity and Survival in Chinese Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {6}, pages = {e70653}, pmid = {42223334}, issn = {1468-1331}, support = {2021YFA0805202//the National Key R&D Program of China/ ; STI2030‑MajorProjects2021ZD0201803//National Science and Technology Innovation 2030 Major Program/ ; 82371445//the National Natural Science Foundation of China/ ; 82171431//the National Natural Science Foundation of China/ ; 20242BAB26135//the Jiangxi Provincial Natural Science Foundation/ ; 20243BCE51002//the Ganpo Outstanding Talents Support Program-Cultivation Project for Academic and Technical Leaders in Key Disciplines/ ; gpyc20240194//the Ganpo Talents Program-Innovation Leading Talent Project (Medical and Health Care Category)/ ; 202510014//the Jiangxi Provincial Health Technology Project/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/mortality/diagnosis ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Haplotypes ; *Nerve Tissue Proteins/genetics ; Polymorphism, Single Nucleotide ; Severity of Illness Index ; East Asian People/genetics ; }, abstract = {BACKGROUND: UNC13A is a genetic modifier of amyotrophic lateral sclerosis (ALS) in European populations, but its role in Chinese patients remains incompletely characterized. We investigated the spectrum of UNC13A variation and its impact on disease risk and progression in a Chinese ALS cohort.

METHODS: We performed an integrated genetic analysis of 1,533 Chinese ALS patients and 1,405 controls, including rare variant burden testing, genome-wide survival analysis, haplotype mapping, and conditional analyses. An integrated clinical-genetic prognostic score was developed and validated.

RESULTS: Rare deleterious UNC13A variants were not associated with ALS risk. We identified two independent haplotype blocks with distinct clinical impacts. Block 1 (tagged by rs75421007) was associated with reduced baseline muscle strength (p = 0.030), while Block 2 (tagged by rs78549703), a brain-specific splicing QTL, was the primary driver of survival heterogeneity. The European variant rs12608932 showed a survival association in single-marker analysis (p = 0.024), but conditional analyses revealed its effect was not independent of Block 2. An integrated prognostic score combining clinical factors and Block 2 haplotype stratified patients into low-, intermediate-, and high-risk groups (median survival: 52.6, 37.1, and 32.0 months; p < 0.001), with decision curve analysis confirming clinical utility.

CONCLUSIONS: This study delineates UNC13A genetic architecture in Chinese ALS, identifying two independent haplotype blocks that differentially influence disease severity and survival. The Block 2 haplotype, which includes a brain sQTL, is a major determinant of survival heterogeneity and may inform patient stratification in future studies.}, } @article {pmid42224592, year = {2026}, author = {Galloway, DA and Patterson, HL and Hoye, ML and Shen, T and Shabsovich, M and Schoch, KM and Ly, CV and Miller, TM}, title = {miR-146a is a pleiotropic regulator of motor neuron degeneration.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {23}, pages = {e2526314123}, pmid = {42224592}, issn = {1091-6490}, support = {R01NS078398//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; F31NS092340//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *MicroRNAs/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Motor Neurons/pathology/metabolism ; Mice ; Mice, Knockout ; Superoxide Dismutase-1/genetics ; Spinal Cord/pathology/metabolism ; *Nerve Degeneration/genetics/pathology ; Disease Models, Animal ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Here, we have profiled motor neuron microRNAs (miRNAs) during motor neuron degeneration in vivo to gain a better understanding of ALS pathophysiology. We demonstrate that one miRNA, miR-146a, is downregulated in diseased motor neurons despite upregulation in bulk tissue. Genetic deletion of miR-146a significantly extended survival in SOD1[G93A] mice with heterozygous animals demonstrating the largest benefit. A corresponding reduction in spinal cord gliosis but not motor neuron loss was observed. Finally, we observed that a proportion of miR-146a knockout animals develop spontaneous paralysis, motor neuron loss and chronic neuroinflammation with advanced age. Together these findings demonstrate that a single miRNA influences multiple aspects of motor neuron disease and highlights the complex role for neuroinflammation in ALS pathogenesis.}, } @article {pmid42225765, year = {2026}, author = {Costello, E and Kiyui, K and Brennan, C and Obain, NN and Leonard, S and Heverin, M and Barbey, F and Dyer, J and Rueda-Delgado, L and Diggin, S and Tunbridge, E and Marston, H and Lai, RYK and Hargreaves, R and Shinobu, L and Nguyen, V and Hake, AM and Dawson, G and Latzman, R and Buick, A and Murphy, B and Hardiman, O and Pender, N}, title = {Longitudinal cognitive assessment using the Cumulus NeuLogiq platform in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42225765}, issn = {2045-2322}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/psychology/physiopathology/diagnosis ; *Neuropsychological Tests ; *Cognition/physiology ; *Frontotemporal Dementia/psychology/diagnosis/physiopathology ; Middle Aged ; Aged ; Longitudinal Studies ; Case-Control Studies ; }, abstract = {People living with ALS (plwALS) and/or FTD (plwFTD) often experience cognitive and behavioural changes. However, detection can be confounded due to factors like fatigue and testing anxiety. Cumulus neuroscience developed NeuLogiq[(R)], a multi-modal neurocognitive platform that can be used in clinic or at home, providing an ecologically valid measure of cognition. This study examined the feasibility and usability of NeuLogiq in plwALS, plwFTD, and controls, and compared performance on gold standard neuropsychological assessments with corresponding NeuLogiq digital assessments. Over 8 months, plwALS (n = 11), plwFTD (n = 7), and matched healthy controls (n = 10) completed longitudinal full neuropsychological assessment, as well as three 25-minute NeuLogiq Platform sessions every 2 weeks in their homes. Participants adhered well to the study schedule, conducting over 32/54 sessions on average. All groups rated usability in the 'good' or 'excellent' range and had > 80% complete data. Baseline group differences were detectable on both NeuLogiq digital assessments and benchmark neuropsychological assessments of similar cognitive domains. Longitudinal mixed effects models found that the ALS group showed decline on NeuLogiq measures of emotion recognition and speech fluency. These findings suggest that the NeuLogiq platform is feasible and usable for plwALS and plwFTD, and can identify cognitive deficits to a similar extent as benchmark assessments over time.}, } @article {pmid42225893, year = {2026}, author = {Pervaiz, I and Blazier, AS and Nyarko-Danquah, I and Wesseling, H and Ramos, A and Woodworth, L and Taksir, TV and Ryan, SK and Wirak, G and Zhao, Z and Hammond, TR and Morel, C and Bangari, DS and Ofengeim, D and Rapino, F and Hagan, N}, title = {Targeting MAPK-dependent pathways to modulate reactive astrocyte pathology in neurodegeneration.}, journal = {Communications biology}, volume = {9}, number = {1}, pages = {}, pmid = {42225893}, issn = {2399-3642}, mesh = {*Astrocytes/pathology/metabolism/drug effects ; Humans ; *MAP Kinase Signaling System/drug effects ; *Neurodegenerative Diseases/pathology/metabolism ; Cells, Cultured ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Proteomics ; Intercellular Adhesion Molecule-1/metabolism ; *Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Reactive astrocytes play a crucial role in the pathogenesis of neurodegenerative diseases; however, the mechanisms underlying glial cell interactions remain poorly understood. Here, we show that human primary astrocytes and iPSC-derived astrocytes in a tri-culture system adopt a reactive state with a distinct molecular phenotype overlapping with transcriptomic signatures observed in ALS astrocytes. Integrated proteomic and phosphoproteomic analyses revealed dysregulated cytoskeletal remodeling and kinase signaling in reactive astrocytes. Surface marker screening identified ICAM-1 as a novel in-vitro marker, validated in ALS spinal cord. Functionally, reactive astrocytes induced neurotoxicity and altered neuronal activity. To elucidate mechanisms regulating neurotoxicity, a phenotypic small molecule screen identified MAP kinase as a functional regulator, with subsequent single-nucleus RNA sequencing uncovering dysregulated signaling pathways modulated by MAPK inhibition in the tri-culture system. Together, these complementary approaches define the molecular landscape of reactive astrocytes, providing a systems-level framework for exploring disease mechanisms and therapeutic strategies in neurodegeneration.}, } @article {pmid42226981, year = {2025}, author = {Romina, A and Mohaddeseh, L and Mansour, B}, title = {Fabrication and Evaluation of PVA-NYS-THY Nanofiber Scaffolds as Antifungal Agents Against Fluconazoleresistant Candida glabrata.}, journal = {Archives of Razi Institute}, volume = {80}, number = {5}, pages = {1229-1238}, pmid = {42226981}, issn = {2008-9872}, mesh = {*Antifungal Agents/pharmacology/chemistry ; *Polyvinyl Alcohol/chemistry/pharmacology ; *Nanofibers/chemistry ; *Candida glabrata/drug effects ; *Fluconazole/pharmacology ; *Drug Resistance, Fungal ; *Nystatin/pharmacology/chemistry ; Microbial Sensitivity Tests ; }, abstract = {INTRODUCTION: The emergence of fluconazole-resistant Candida glabrata presents a significant challenge in antifungal therapy, necessitating the development of alternative treatment strategies. C. glabrata, an opportunistic yeast, is increasing resistance to common antifungals like fluconazole, often due to efflux pump overexpression, leading to compromised treatment efficacy, higher mortality, prolonged hospital stays, and increased healthcare costs. This study focused on fabricating and evaluating polyvinyl alcohol-nystatin-thymol (PVA-NYS-THY) nanofibrous scaffolds as a novel antifungal approach against fluconazole-resistant C. glabrata.

MATERIALS & METHODS: Clinical isolates were identified and assessed for resistance using culture methods, molecular assays, and antifungal susceptibility testing. PVA-NYS-THY nanofibers, produced via electrospinning, exhibited uniform fibers with an average diameter of ~100 nm as confirmed by scanning electron microscopy (SEM). Fourier transform infrared spectroscopy confirmed the successful incorporation of functional groups. Real-time polymerase chain reaction (PCR) was employed to evaluate the nanofibers' effect on the expression of secreted aspartyl proteinases (SAP) and agglutinin-like sequence (ALS) gene. Scaffold release kinetics were characterized, and antifungal efficacy was assessed using minimum inhibitory concentration (MIC) assays.

RESULTS: PVA-NYS-THY scaffolds showed favorable release profiles and significantly downregulated ALS and SAP gene expression. MIC values for PVA-NYS-THY, PVA-NYS, and PVA-THY were 7.81, 15.62, and 62.5 µg/mL, respectively, demonstrating superior antifungal activity of the PVA-NYS-THY formulation.

CONCLUSION: These findings suggest PVA-NYS-THY nanofibrous scaffolds offer a promising therapeutic strategy for combating fluconazole-resistant C. glabrata, providing a novel solution to overcome current limitations in antifungal treatment.}, } @article {pmid42227472, year = {2026}, author = {Amin, MA and Zehravi, M and Sweilam, SH and Darwin, R and Gupta, JK and Bhargav, E and Dharmamoorthy, G and Kumar, VV and Rao, AA and Suliman, M and Periyasamy, T and Emran, TB}, title = {Fisetin and Neurodegeneration: From Preclinical Studies to Potential Clinical Applications.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273427644251204045253}, pmid = {42227472}, issn = {1996-3181}, abstract = {Neurodegenerative diseases (NDs), like Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, pose significant challenges due to their gradual deterioration and limited available treatments. Fisetin, a naturally occurring flavonoid, has gained attention for its neuroprotective properties. This review explores the therapeutic potential of fisetin in NDs, focusing on its molecular processes and signaling pathways. Additionally, fisetin exhibits significant protective properties, particularly in reducing oxidative stress, neuroinflammation, and apoptosis. It enhances neuronal survival and reduces neuroinflammation by regulating key pathways, such as Nrf2/ARE, PI3K/Akt, and NF-κB. It also has anti-inflammatory, anti-apoptotic, and antioxidant actions. It stimulates autophagic processes, aiding in the removal of harmful protein aggregates, like tau tangles and amyloid plaques, which are hallmarks of NDs. Fisetin, as demonstrated through behavioral evaluations in animal models, has been found to improve motor coordination, synaptic plasticity, and cognitive function. Furthermore, fisetin's potential as a neuroprotective drug is emphasized by its role in enhancing autophagy and reducing tau and amyloid pathology. Research has shown its efficacy in enhancing neural resilience, synaptic plasticity, and cognitive function in both preclinical and in vitro settings. However, clinical translation remains limited due to challenges in pharmacokinetics and bioavailability, despite robust experimental evidence. Further clinical trials are needed to evaluate the safety and efficacy of fisetin, especially in early-stage NDs, explore potential synergistic effects, and understand the molecular interactions. The review demonstrates fisetin's therapeutic potential, recent research, and future strategies for NDs, highlighting bioavailability limitations and the need for new formulations or delivery systems.}, } @article {pmid42227825, year = {2026}, author = {Watson, MD and Lee, JC}, title = {Site-Specific Raman Probes Reveal Droplet Aging and Residue-Level Fibril Polymorphism in TDP-43CTD.}, journal = {Journal of the American Chemical Society}, volume = {148}, number = {23}, pages = {23494-23498}, pmid = {42227825}, issn = {1520-5126}, mesh = {Spectrum Analysis, Raman ; *DNA-Binding Proteins/chemistry ; Humans ; *Amyloid/chemistry ; Phase Separation ; }, abstract = {The C-terminal domain of TAR DNA-binding protein 43 (TDP-43CTD) drives both liquid-liquid phase separation (LLPS) and amyloid formation. Understanding how TDP-43CTD droplets convert into amyloid aggregates, a process implicated in amyotrophic lateral sclerosis and frontotemporal dementia, requires methodology capable of site-specific structural characterization with spatial resolution. Here, we used confocal Raman spectroscopy in conjunction with an alkyne-modified amino acid (4-ethynyl-l-phenylalanine, FCC) to probe aging in individual TDP-43CTD droplets at seven aromatic sites. While nascent droplets are composed of disordered proteins, β-sheet conformers develop in aged droplets and amyloid aggregates. All three states are spectrally distinct via the alkyne stretching band, with sensitivity that varies depending on the aromatic site probed. C-terminal sites (Y374FCC, W385FCC, and F397FCC) are highly sensitive amyloid probes, revealing multiple polymorphs at the single-residue level that are not resolvable by global secondary structure or morphological characterization alone. Strikingly, while W334FCC abolishes β-sheet formation in droplets, de novo aggregation still occurs, demonstrating that droplet aging is not required for amyloid formation. Given its broad applicability to other proteins and compatibility with cellular imaging, this work establishes a generalizable approach for investigating conformational changes underlying LLPS and amyloid formation in cellulo.}, } @article {pmid42228326, year = {2026}, author = {Dey, A and Das, R and Uppal, S}, title = {FUS modulates R-loops by functionally interacting with RNase H1.}, journal = {Human cell}, volume = {39}, number = {6}, pages = {}, pmid = {42228326}, issn = {1749-0774}, mesh = {*RNA-Binding Protein FUS/physiology/metabolism/genetics ; Humans ; *Ribonuclease H/metabolism ; *R-Loop Structures/genetics/physiology ; HeLa Cells ; Transcription, Genetic/genetics ; RNA/metabolism/genetics ; DNA Damage/genetics ; RNA Polymerase II/metabolism ; }, abstract = {R-loops are three-stranded nucleic acid structures consisting of an RNA:DNA hybrid and a displaced single-stranded DNA, typically formed during transcription. Emerging evidence indicates that R-loops are not merely transcriptional byproducts, but serve as functional regulatory structures that influence chromatin organization, transcriptional pausing, and RNA processing. However, dysregulated accumulation of R-loops can induce DNA damage and genomic instability, necessitating precise mechanisms for their regulation. This study aims to elucidate the role of the RNA-binding protein FUS (Fused in Sarcoma), a protein mutated in Amyotrophic Lateral Sclerosis (ALS) and cancer, in modulating R-loop dynamics. Knockdown of FUS in HeLa cells resulted in a significant increase in global R-loop levels, as assessed by immunofluorescence and dot blot assays. Proximity ligation assay (PLA) demonstrated that FUS is in close proximity to R-loops and nascent RNA. Further, FUS was found to interact with RNase H1, a key endonuclease involved in R-loop resolution, in an R-loop dependent manner, as demonstrated by PLA and co-immunoprecipitation assay. Importantly, in vitro assays show that FUS enhances RNase H1-mediated degradation of RNA:DNA hybrids. Moreover, FUS depletion reduces RNase H1 proximity to elongating RNA polymerase II, suggesting altered engagement of RNase H1 with the transcription machinery. These findings highlight a crucial role for FUS-RNase H1 axis in regulating R-loop levels, providing insights into the potential mechanisms underlying R-loop-associated pathologies in neurodegenerative diseases linked to FUS.}, } @article {pmid42229207, year = {2026}, author = {Pavey, N and Tu, S and Foster, S and Geevasinga, N and Calma, A and Tsuji, Y and Kiernan, MC and Vucic, S and Menon, P}, title = {Cortical changes in amyotrophic lateral sclerosis: comparing biomarkers of glymphatic flow and cortical excitability.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {190}, number = {}, pages = {2111949}, doi = {10.1016/j.clinph.2026.2111949}, pmid = {42229207}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; *Glymphatic System/physiopathology/diagnostic imaging ; Male ; Female ; Middle Aged ; Aged ; Transcranial Magnetic Stimulation/methods ; *Cortical Excitability/physiology ; Diffusion Tensor Imaging/methods ; *Cerebral Cortex/physiopathology/diagnostic imaging ; Biomarkers ; *Motor Cortex/physiopathology/diagnostic imaging ; Evoked Potentials, Motor/physiology ; }, abstract = {OBJECTIVE: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves a multistep process, with a central role for cortical hyperexcitability and misfolded protein accumulation. The glymphatic system mediates clearance of misfolded proteins, yet its role in modulating cortical excitability is unknown. This study aims to determine whether glymphatic dysfunction is associated with cortical hyperexcitability, thereby linking impaired protein clearance to excitotoxic neurodegeneration in ALS.

METHODS: Glymphatic function was assessed using diffusion tensor imaging analysis along perivascular spaces (DTI-ALPS) and correlated with measures of corticomotoneuronal function assessed by transcranial magnetic stimulation (TMS). The DTI-ALPS index and cortical excitability testing were performed in 35 ALS patients and compared to 25 age-matched controls. The DTI-ALPS index was correlated with TMS and clinical measures.

RESULTS: A significant reduction in the DTI-ALPS index was observed in ALS (p = 0.016), along with cortical hyperexcitability evident as shortened cortical silent period (CSP) duration (p = 0.001) and reduced short interval intracortical inhibition (p < 0.001). The DTI-ALPS index significantly correlated with CSP duration (R = 0.48, p = 0.027). The DTI-ALPS index was significantly reduced in ALS participants with mild functional impairment. The possibility that reduced DTI-ALPS index represents an epiphenomenon of tract degeneration cannot be completely excluded.

CONCLUSION: This study identified a potential association between impaired glymphatic clearance and disrupted GABAB-mediated cortical inhibition, suggesting that glymphatic dysfunction may play a role in the neurodegenerative cascade in ALS.

SIGNIFICANCE: Glymphatic dysfunction may be associated with impaired cortical inhibition, thereby contributing to cortical hyperexcitability in ALS and providing further mechanistic insight.}, } @article {pmid42229507, year = {2026}, author = {Swanson, E and Dohle, E and Bashford, L and Horsfall, HL and Jovanovic, L and Muirhead, WR and Brannigan, JFM}, title = {Recalibration of implantable brain-computer interfaces to enable long-term independent use-a systematic review.}, journal = {Journal of neural engineering}, volume = {23}, number = {3}, pages = {}, doi = {10.1088/1741-2552/ae7694}, pmid = {42229507}, issn = {1741-2552}, mesh = {Humans ; *Brain-Computer Interfaces/standards ; Calibration ; *Electrodes, Implanted/standards ; }, abstract = {Background.Implantable brain-computer interfaces (iBCIs) decode neural signals to generate command signals for effector devices to restore lost functions, such as movement or speech. However, maintaining device performance over time requires recalibration of decoding algorithms due to inherent instability in neural signals.Objective.To systematically review recalibration procedures in iBCIs for patients with motor impairments, focusing on the clinical implications of recalibration requirements and strategies which can enable long-term, independent use.Approach.A systematic search was conducted across EMBASE, MEDLINE, and CINAHL databases to identify studies involving recalibration of iBCIs. Data on recalibration frequency, duration, staff requirements, and location were extracted and analyzed.Main results.Recalibration practices varied widely amongst studies and were typically performed according to predetermined study protocols, rather than practical need following deteriorating device performance. Common practices include manual recalibration requiring a specialist research team, semi-automatic recalibration which could be performed by a non-specialist caregiver, and automatic recalibration methods whereby patients did not require assistance. Devices utilizing electrocorticography (ECoG) recording arrays generally required less frequent recalibration compared to those using microelectrode arrays (MEAs). Extended independent use was more frequently reported with ECoG-based iBCIs.Significance.Reducing recalibration frequency or complexity can improve patient autonomy, which is crucial for enhancing long-term independent iBCI use in home and clinical settings. ECoG iBCIs typically have a low recalibration burden due to inherent signal stability. Conversely, MEA iBCIs typically involve a higher recalibration burden, though recent studies have reduced this by incorporating spectral data and continuously updating models. Despite this progress, recalibration procedures are often not fully defined in iBCI studies, and where they are, they usually relate to the study protocol rather than the clinically meaningful recalibration requirement due to worsening device performance. Future studies should continue to develop user-friendly recalibration procedures and outline the clinically relevant recalibration requirements where possible.}, } @article {pmid42229706, year = {2026}, author = {Alqahtani, SM and Afzal, M and Afzal, O and Alabbas, A and Phalak, P and Goyal, K}, title = {Platelet-derived extracellular vesicles as neurodegenerative disease biomarkers.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {591}, number = {}, pages = {121130}, doi = {10.1016/j.cca.2026.121130}, pmid = {42229706}, issn = {1873-3492}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; Biomarkers/blood ; *Neurodegenerative Diseases/diagnosis/blood/metabolism ; *Blood Platelets/metabolism ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are increasingly prevalent worldwide and have not yet been adequately diagnosed, especially because they require minimally invasive, non-invasive techniques. Although established blood-based biomarkers, such as plasma p-tau217, neurofilament light chain (NfL), and GFAP, have shown clinical utility, limitations in sensitivity and scalability remain. Platelets, anucleate cytoplasmic fragments originating from megakaryocytes, are the primary producers of extracellular vesicles in the peripheral blood. These vesicles contain disease-specific cargo, including amyloid-β, α-synuclein, tau, disease-associated glycoproteins, and microRNAs (miRNAs) derived from platelets. Recent findings suggest that the cargo of platelet-derived extracellular vesicles (pEVs) may be associated with neurodegenerative changes linked to disease severity. However, validation through a prospective multicenter study is necessary. A systematic narrative review was performed by searching the PubMed, Scopus, and Web of Science databases with the keywords "platelet-derived extracellular vesicles," "platelet microvesicles," "neurodegeneration," and "biomarkers" (inception through April 2026). This review discusses the biogenesis of pEV, their composition in relation to blood markers, and their pathomechanistic roles, such as platelet-mediated blood-brain barrier disruption, neuroinflammation, and misfolded protein seeding. The diagnostic evidence of pEV-associated cargo in neurodegenerative diseases is critically evaluated and contextualized with current blood markers. Key preanalytical considerations, including the selection of anticoagulants, isolation procedures, storage conditions, and the number of freeze-thaw cycles, as well as analytical considerations, such as flow cytometric calibration, single-vesicle resolution, and multiplexed platforms, are examined for their applicability in clinical laboratory settings. The emphasis is on reporting according to the MISEV and the harmonization between laboratories. The limitations of this study are the small heterogeneous cohorts, lack of preanalytical handling standardization, ex vivo platelet activation artifact, and lack of external validation.}, } @article {pmid42230361, year = {2026}, author = {Barba, L and Steinacker, P and Halbgebauer, S and Oeckl, P and Landwehrmeyer, B and Weishaupt, J and Verde, F and Ticozzi, N and Silani, V and Levin, J and Schönecker, S and Kornhuber, J and Prudlo, J and Schroeter, ML and Fassbender, K and Fliessbach, K and Diehl-Schmid, J and Jahn, H and Lauer, M and Dorst, J and Rosenbohm, A and Abu-Rumeileh, S and Anderl-Straub, S and Söntgerth, M and Böhm, F and Wiltfang, J and Otto, M}, title = {Serum neurofilaments for motoneuron and dementia diseases: a German multicenter cohort study.}, journal = {Journal of neurology}, volume = {273}, number = {6}, pages = {}, pmid = {42230361}, issn = {1432-1459}, support = {JCS24/02//Martin Luther Christian University/ ; CS22/06//Martin-Luther-University Halle-Wittenberg/ ; RF-2021-12374238)//Ministero della Salute/ ; TelDem//Sächsische Aufbaubank/ ; 100757914//EFRE InfraProNet/ ; }, mesh = {Humans ; Female ; Male ; Germany ; Aged ; *Neurofilament Proteins/blood ; Biomarkers/blood ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; *Dementia/blood/diagnosis ; Cohort Studies ; Middle Aged ; }, abstract = {BACKGROUND: Serum neurofilament light and heavy chains (sNfL and sNfH) have been assessed as neuronal markers for amyotrophic lateral sclerosis (ALS) and dementias. Whereas sNfL has robust literature, systematic studies on sNfH are lacking. Here, we aimed to assess the diagnostic value of sNfH in comparison to sNfL in a broad range of neurodegenerative disorders.

METHODS: We measured with immunoassays sNfH and sNfL in patients recruited in the multicenter German Frontotemporal Lobar Degeneration (FTLD) Consortium (n = 340) and in a single-center German cohort (n = 290). We assessed the diagnostic accuracy of serum biomarkers for ALS and dementia subtypes and their relationship with cognitive impairment.

RESULTS: sNfH and sNfL were significantly increased in ALS (n = 90) vs. controls (n = 109) and ALS mimics (n = 56, p < 0.001), with sNfL showing higher discriminative accuracy (AUC = 0.94-0.95) than sNfH (AUC = 0.87-0.88). sNfH/sNfL ratio did not improve the diagnostic performance. Both markers were elevated in patients with dementia (n = 289) vs. controls (p < 0.001). sNfL was higher in behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA) and Creutzfeldt-Jakob disease (CJD) than in Alzheimer's disease (AD), whereas sNfH was similar in AD, PPA and bvFTD. sNfL, but not sNfH, was correlated with cognitive impairment at baseline and cognitive decline at follow-up in AD and bvFTD.

CONCLUSIONS: sNfH and sNfL are elevated in motoneuron and dementia disorders. sNfH showed good discriminative accuracy for ALS, which was slightly lower than that of sNfL. sNfL, but not sNfH, showed prognostic value for assessing cognitive decline in dementia.}, } @article {pmid42230882, year = {2026}, author = {Morishita, H and Umezawa, K and Kojima, M}, title = {Alkyl shikimates promote proliferation of human dermal fibroblasts and exhibit structure-activity relationships.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42230882}, issn = {2045-2322}, mesh = {Humans ; *Fibroblasts/drug effects/cytology/metabolism ; *Cell Proliferation/drug effects ; Structure-Activity Relationship ; *Shikimic Acid/pharmacology/chemistry/analogs & derivatives/chemical synthesis ; Cells, Cultured ; Cell Survival/drug effects ; *Dermis/cytology ; *Skin/cytology ; }, abstract = {Alkyl shikimates (SAEs) bearing linear and branched alkyl groups (R) ranging from CH3 to C5H11 were synthesized and assayed for proliferative activity toward human dermal fibroblasts; proliferation increase (PRA), measured using a CCK-8 assay kit, was used as the primary endpoint. Several SAEs exhibited significant PRA, depending on the concentration added to the culture medium and alkyl group structure. However, shikimic acid (SA) added to the culture medium did not induce fibroblast proliferation. SAEs with CH3, C2H5, and C3H7 alkyl groups (SAE-1, SAE-2, and SAE-3a,b) induced a 30-50% increase in cell proliferation at a concentration of 5.5 mM, while SAEs with a C4H9 groups (SAE-4a,b,c) showed low PRA and those with a C5H11 groups (SAE-5a,b,c) exhibited strong cytotoxicity (CYT: decrease in cell viability) at this concentration. The proliferation rates of SAEs at 5.5 mM correlated significantly with their calculated log P (ClogP) values, which reflect hydrophobicity and cell membrane permeability (quadratic regression; coefficient of determination, r[2] = 0.977-0.953. Based on these results, we proposed a mechanism in which membrane-permeable SAEs could form complexes with carboxylesterase (CES) present in dermal fibroblasts and be subsequently hydrolyzed into SA and alcohols (ALs) intracellularly, with the resulting SA potentially inducing PRA. In contrast, SA added extracellularly cannot enter cells due to its high hydrophilicity and therefore cannot induce PRA. In order to evaluate the stability of the proposed complexes, we estimated binding energies between CES and SAEs by quantum mechanical methods; however, the results showed no significant differences in binding energy attributable to alkyl chain length or steric effects of the SAE alkyl groups. The most plausible explanation for the differences in PRA among SAEs is that intracellularly regenerated SA promotes fibroblast proliferation, whereas the regenerated ALs may cause CYT. Alkyl group-dependent differences in AL toxicity may account for the concentration-dependent variation in SAE-induced PRA. In fact, when the CYT of linear alkyl alcohols (ALs-1, 2, 3a, 4a, and 5a) was measured by CCK-8 at a concentration of 100 mM, the results showed that differences in AL alkyl chain length significantly influenced cell viability, which was consistent with their ClogP values (CYT order; R = C5H11 > C4H9 > C3H7 > C2H5 ≥ CH3).}, } @article {pmid42232224, year = {2026}, author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD}, title = {Anti-inflammatory and immunomodulatory therapies are associated with reduced risk of age-associated neurodegenerative diseases: impact of sex and treatment duration.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1818660}, pmid = {42232224}, issn = {1663-4365}, abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and non-AD dementias share chronic neuroinflammatory mechanisms that contribute to neuronal injury and disease progression. While anti-inflammatory therapies (AITs) are associated with reduced neurodegenerative disease risk, knowledge regarding the impact of biological sex and treatment duration across multiple NDDs remains limited.

METHODS: We conducted a retrospective cohort analysis using a large propensity-score-matched population (n = 190,308; 95,154 treated vs. 95,154 untreated) to evaluate associations between long-term AIT exposure and incidence of major NDDs. Disease-specific and combined outcomes were assessed across drug classes (NSAIDs, corticosteroids, immunomodulators), sex, age, and therapy duration.

RESULTS: AIT exposure was associated with a significantly lower risk of developing any NDD (RR = 0.47, 95% CI 0.43-0.48, p < 0.0001) and was equally effective in both sexes. Risk reduction was observed for each age-associated disease: AD (RR = 0.40), non-AD dementia (RR = 0.51), PD (RR = 0.43), MS (RR = 0.25), and ALS (RR = 0.48). Among drug classes, immunomodulators conferred the greatest reduction (RR = 0.19), followed by corticosteroids (RR = 0.41) and NSAIDs (RR = 0.42). Duration analyses revealed a graded benefit, with RR declining from 0.94 (< 1 year) to 0.25 (> 6 years). Risk reduction was greatest in older participants (75-79 years).

DISCUSSION: Chronic use of anti-inflammatory or immunomodulatory therapies was associated with significantly reduced incidence of multiple neurodegenerative diseases in both sexes. The strongest effects were observed with immunomodulator use and prolonged therapy duration, suggesting that sustained modulation of systemic inflammation confers broad neuroprotective effects in both sexes. These findings highlight the potential of targeting immune-inflammatory pathways for neurodegenerative disease prevention and can inform prospective mechanistic and interventional studies.}, } @article {pmid42232333, year = {2026}, author = {Chalitsios, CV and Turner, MR}, title = {Considering prediagnostic environmental modifiers of progression in amyotrophic lateral sclerosis.}, journal = {BMJ neurology open}, volume = {8}, number = {1}, pages = {e001702}, pmid = {42232333}, issn = {2632-6140}, } @article {pmid42234776, year = {2026}, author = {Guo, C and Chen, K and Vatsavayai, S and Akiyama, T and Liu, C and Zeng, Y and Sianto, O and Yang, E and Bombosch, J and Powell, R and Zhen, S and Mekhoubad, S and Morrie, RD and Miller, G and Ilic, D and Boll, M and Parnell, E and Penzes, P and Lipstein, N and Green, EM and Petrucelli, L and Seeley, WW and Gitler, AD}, title = {Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction.}, journal = {Science translational medicine}, volume = {18}, number = {852}, pages = {eaeb8517}, doi = {10.1126/scitranslmed.aeb8517}, pmid = {42234776}, issn = {1946-6242}, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Neurons/metabolism/pathology ; *RNA Splicing/genetics ; *Synapses/metabolism/genetics ; *Cell Membrane/metabolism ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Frontotemporal Dementia/genetics/pathology ; Synaptic Transmission/genetics ; Animals ; }, abstract = {TAR DNA binding protein 43 (TDP-43) pathology is a defining pathological hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major feature of TDP-43 pathology is its nuclear depletion, leading to the aberrant inclusion of cryptic exons during RNA splicing. STMN2 and UNC13A have emerged as prominent TDP-43 splicing targets, but the broader impact of TDP-43-dependent cryptic splicing on neuronal function remains unclear. Here, we report previously unidentified TDP-43 splicing targets critical for membrane excitability and synaptic function, including KALRN, RAP1GAP, SYT7, and KCNQ2. Using human stem cell-derived neurons, we showed that TDP-43 reduction induces cryptic splicing and down-regulation of these genes, resulting in impaired excitability and synaptic transmission. In postmortem brains from patients with FTD, these cryptic splicing events occurred selectively in neurons with TDP-43 pathology. Suppressing individual cryptic splicing events using antisense oligonucleotides partially restored neuronal function, and combined targeting almost fully rescued the synaptic deficit caused by TDP-43 loss. Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD.}, } @article {pmid42235092, year = {2026}, author = {Wolff, AW and Leha, A and Koch, JC and Demleitner, AF and Neuwirth, C and Friede, T and Weber, M and Lingor, P}, title = {Effects of fasudil on disease spreading in ALS - A MUNIX-based post-hoc analysis of the ROCK-ALS trial.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {4}, pages = {e00936}, pmid = {42235092}, issn = {1878-7479}, mesh = {Humans ; *1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Female ; Male ; Middle Aged ; Double-Blind Method ; *Protein Kinase Inhibitors/therapeutic use ; *rho-Associated Kinases/antagonists & inhibitors ; Aged ; *Motor Neurons/drug effects/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the spread of muscle weakness across body regions. ROCK-ALS was a multicenter, placebo-controlled phase 2 trial assessing the safety, tolerability, and efficacy of the Rho kinase inhibitor fasudil in ALS patients. A key exploratory objective was to evaluate fasudil's effect on the spread of muscle weakness using the Motor Unit Number Index (MUNIX), an established, quantitative electrophysiological biomarker of lower motor neuron integrity. MUNIX was assessed in 10 muscles at baseline, day 26, day 90, and day 180. In the present post-hoc analysis, correlations were assessed between baseline serum biomarkers-neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP)-and baseline clinical measures (ALSFRS-R, slow vital capacity, and MUNIX-10 sum scores) as well as their monthly rates of change, to explore potential prognostic relationships. For the analysis of disease spreading, muscles were classified as newly affected based on MUNIX decline relative to contralateral values or prior measurements, using thresholds of ≥10%, ≥20%, or ≥30%. Out of 118 participants included in the intention-to-treat population, 78 had full MUNIX datasets at baseline, and 67 had at least one follow-up. Baseline MUNIX-10 sum scores correlated with subsequent ALSFRS-R decline, suggesting prognostic value. Additionally, at day 90, fasudil significantly reduced the number of newly affected muscles compared to placebo in a dose-dependent manner over different thresholds. This supports MUNIX as a sensitive biomarker for monitoring disease spreading and demonstrates that fasudil may attenuate the progression of lower motor neuron involvement in ALS. Trial registration number: NCT03792490 (ClinicalTrials.gov); 2017-003676-31 (Eudra-CT).}, } @article {pmid42235125, year = {2026}, author = {Talbot, K}, title = {Celebrating a breakthrough for amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {6}, pages = {1799-1800}, doi = {10.1093/brain/awag174}, pmid = {42235125}, issn = {1460-2156}, } @article {pmid42235808, year = {2026}, author = {De Mori Bajolin, F and Tavazzi, E and Bianchi, AM and Mendez, MO}, title = {Robust end-to-end stratification of amyotrophic lateral sclerosis patients via recurrent variational autoencoder and consensus clustering.}, journal = {Journal of biomedical informatics}, volume = {180}, number = {}, pages = {105059}, doi = {10.1016/j.jbi.2026.105059}, pmid = {42235808}, issn = {1532-0480}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/classification ; Humans ; Autoencoder ; Clustering Algorithms ; Cluster Analysis ; Deep Learning ; Disease Progression ; Long Short Term Memory ; Female ; Algorithms ; Male ; Computer Simulation ; }, abstract = {OBJECTIVE: This study aims to develop a data-driven methodology for stratifying Amyotrophic Lateral Sclerosis (ALS) patients based on longitudinal disease progression patterns, using a novel deep learning framework that combines a Recurrent Variational Autoencoder (RVA) with consensus clustering to identify clinically meaningful subgroups.

METHODS: The RVA integrates Peephole Long Short-Term Memory networks within the Variational Deep Embedding (VaDE) architecture to simultaneously learn latent representations and cluster assignments from multivariate time-series data. The approach incorporates hyperparameter optimization via prediction strength with two-fold cross-validation, consensus clustering, and internal validation metrics (Silhouette Coefficient, Davies-Bouldin index, Calinski-Harabasz index) for optimal cluster selection. The methodology was validated on simulated data and applied to 3076 ALS patients from the PRO-ACT dataset, using ALSFRS-R total scores, domain subscores, and MiToS staging from the first six months of observation.

RESULTS: Simulation experiments demonstrated that consensus clustering consistently outperformed single-model predictions across all noise levels. Applied to the PRO-ACT real data, the framework identified five distinct patient subgroups. These clusters exhibited distinct progression patterns and statistically significant differences in baseline clinical features, disease onset characteristics, and survival outcomes, with median survival ranging from 12.8 months to 27.5 months.

CONCLUSION: The proposed deep learning framework effectively captures the heterogeneous nature of ALS progression and identifies clinically relevant patient subgroups using routine clinical assessments. The stratification provides a foundation for personalized prognosis, optimized clinical trial design, and tailored therapeutic strategies, representing a practical tool for improving ALS patient management.}, } @article {pmid42236288, year = {2026}, author = {Chinoy, A and Soo, A}, title = {Effectiveness of Surgical Sealants in Reducing Prolonged Air Leaks After Pulmonary Resection: A Systematic Review.}, journal = {Interdisciplinary cardiovascular and thoracic surgery}, volume = {41}, number = {7}, pages = {}, pmid = {42236288}, issn = {2753-670X}, mesh = {Humans ; *Pneumonectomy/adverse effects ; *Tissue Adhesives/therapeutic use/adverse effects ; *Surgical Stapling/adverse effects ; Treatment Outcome ; *Fibrin Tissue Adhesive/therapeutic use ; *Anastomotic Leak/prevention & control/etiology ; Time Factors ; }, abstract = {OBJECTIVES: Prolonged air leak (PAL) is the most common complication following pulmonary resection, leading to increased morbidity, hospital stay, and healthcare costs. Although staplers are currently the standard for lung parenchymal closure, ALs remain frequent. Surgical sealants have been introduced as adjuncts to staplers to reduce PAL, but evidence remains inconsistent. Prior systematic reviews frequently pooled together stapled and sutured resections, limiting applicability to contemporary practice. This review specifically evaluates whether surgical sealants reduce the incidence and duration of PAL when used with staplers in adult patients.

METHODS: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420251064592). A literature search was conducted in PubMed, Ovid MEDLINE, and Cochrane Library for studies published between 2005 and June 2025. Eligible studies included adult patients undergoing stapler-based pulmonary resection comparing sealants plus staplers versus staplers alone. Risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials (RoB2) and risk of bias in non-randomized studies of interventions (ROBINS-I) tools.

RESULTS: Eight studies were included. Surgical sealants studied included fibrin-based (autologous fibrin sealant (FS), FS patch, human FS) and synthetic polymers (polyethylene glycol hydrogel sealant, cyanoacrylate-based sealant). Most studies reported a statistically significant reduction in PAL incidence and/or duration with sealant use. Some also showed reduced chest tube duration and hospital stay, though not always statistically significant. One study showed worse outcomes in the sealant group. No study reported increased complications. Subgroup analyses were limited.

CONCLUSIONS: Sealants used with staplers may reduce PAL incidence and duration, particularly in high-risk patients, without increased complications. However, variability in study design and limited subgroup data weaken current evidence. Larger, standardized randomized controlled trials are needed to confirm clinical benefit and inform routine use.}, } @article {pmid42236740, year = {2026}, author = {Moro-Velazquez, L and Wang, H and Gunzler, A and Rao, M and Butala, AA and Clawson, L and Ravichandran, V}, title = {HeyJay! A corpus of atypical speech for spoken language understanding and automatic speech recognition.}, journal = {Scientific data}, volume = {13}, number = {1}, pages = {}, pmid = {42236740}, issn = {2052-4463}, support = {No grant number//JHU+Amazon ai2ai faculty award/ ; }, mesh = {Humans ; *Speech Recognition Software ; *Speech ; Amyotrophic Lateral Sclerosis/physiopathology ; Parkinson Disease/physiopathology ; Dysarthria ; }, abstract = {Speech technologies, such as automatic speech recognition or spoken language understanding, are not usually adapted to atypical speech, i.e., the speech of people with dysarthria, dysphonia, or another type of speech impairment. That prevents atypical speakers from leveraging speech assistants or other human-machine-interaction-powered platforms, which could make their lives easier or increase their independence. In this article, we present HeyJay!, a new corpus of atypical speech in English language from participants with neurodegenerative disorders, including Parkinson's Disease, or Amyotrophic Lateral Sclerosis. The current corpus version comprises 8,669 utterance recordings, including supervised transcriptions and intent annotations. In this study, we demonstrate the validity of the corpus by applying it to automatic speech recognition, spoken language understanding, and data augmentation tasks. Additionally, the dataset includes speech quality ratings for each participant, performed by expert speech and language pathologists. This corpus, the first one with intent annotation of atypical speech that is publicly available, is intended to create more fair speech technologies for atypical speakers by adapting and improving the state of the art, and to facilitate further research in the field.}, } @article {pmid42236747, year = {2026}, author = {Yang, J and Li, J and Hou, X and Zheng, Y and Zhao, Z and Zhou, T and Jing, T and Kong, J and Zhang, G and Guo, Y}, title = {Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.}, journal = {npj aging}, volume = {12}, number = {1}, pages = {}, pmid = {42236747}, issn = {2731-6068}, support = {CSTB2023NSCQ-BHX0119//the Postdoctoral Science Founation Project of the Chongqing Natural Science Foundation/ ; C2024405023//the Natural Science Foundation of Hebei Province/ ; }, abstract = {Mitochondria are essential for neuronal energy production, cellular homeostasis, and overall neuronal function. Due to their high metabolic demands and limited regenerative capacity, neurons are particularly vulnerable to mitochondrial dysfunction, which leads to ATP depletion, excessive reactive oxygen species (ROS) production, and calcium imbalance-ultimately causing oxidative stress, metabolic disruption, and neuronal death. Mitophagy is a selective process that removes damaged mitochondria through the autophagy-lysosome pathway. As a key mechanism of mitochondrial quality control, mitophagy preserves energy production, limits oxidative damage, and maintains mitochondrial network integrity. This process is regulated by pathways such as PINK1-Parkin and receptor-mediated mechanisms involving BNIP3 and FUNDC1, all of which help sustain cellular health by preventing mitochondrial dysfunction. Impaired mitophagy is a common feature of several neurodegenerative diseases, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease, exacerbating mitochondrial damage and neuronal stress. Emerging therapeutic strategies that target mitophagy-ranging from pharmacological agents and gene therapies to dietary interventions-show promise in restoring mitochondrial quality and protecting neurons from degeneration. Nevertheless, challenges remain in translating these findings into effective clinical treatments. Mitophagy represents a critical mechanism for preserving neuronal integrity and offers a compelling target for innovative therapies against neurodegenerative disorders.}, } @article {pmid42237462, year = {2026}, author = {Iftesum, M and Sahoo, GR and Sheikh, E and Srivastava, M and Roy, S and Shukla, HD and Biswal, NC and Gartia, MR}, title = {Machine Learning-Integrated Raman Spectroscopy Identifies Race-Associated Biochemical Signatures in Prostate Cancer.}, journal = {Journal of biophotonics}, volume = {19}, number = {6}, pages = {e70293}, doi = {10.1002/jbio.70293}, pmid = {42237462}, issn = {1864-0648}, support = {2045640//National Science Foundation/ ; R24GM146107/GM/NIGMS NIH HHS/United States ; R35GM151218/GM/NIGMS NIH HHS/United States ; R35 GM150564/GM/NIGMS NIH HHS/United States ; R35GM150564/GM/NIGMS NIH HHS/United States ; }, mesh = {*Spectrum Analysis, Raman ; *Prostatic Neoplasms/metabolism/ethnology/diagnosis ; Humans ; Male ; *Machine Learning ; Random Forest ; }, abstract = {Black men experience disproportionately higher prostate cancer incidence and mortality, yet the underlying biochemical contributors remain unclear. In this study, we integrate Raman spectroscopy with advanced multivariate and machine-learning methods to characterize molecular differences in clinical formalin-fixed, paraffin-embedded (FFPE) prostate tissues from Black and White patients. Raman spectra were corrected using ICA-PLS, wavelet-denoised, and unmixed with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to quantify cellular components. Random forest (RF) models were trained on denoised spectra to classify cancer versus control tissues. MCR-ALS revealed elevated protein, collagen, lipid, and nucleic acid signatures in tumors from Black patients, aligning with clinically observed aggressive disease phenotypes. RF classification achieved > 90% accuracy, 95% sensitivity, 85% specificity, and an AUC > 0.96, demonstrating robust diagnostic performance. These findings show that Raman spectroscopy integrated with computational analysis provides a powerful label-free approach to probe biochemical drivers of racial disparities in prostate cancer.}, } @article {pmid42237527, year = {2026}, author = {Zoubi, M and Weydt, P and Kobeleva, X}, title = {Attentional Function in Patients With Amyotrophic Lateral Sclerosis is Moderated by Age and Education.}, journal = {Brain and behavior}, volume = {16}, number = {6}, pages = {e71511}, pmid = {42237527}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology ; Female ; Male ; *Executive Function/physiology ; Middle Aged ; *Attention/physiology ; Aged ; Educational Status ; Age Factors ; Reaction Time/physiology ; Neuropsychological Tests ; Adult ; }, abstract = {PURPOSE: Besides motor brain regions, amyotrophic lateral sclerosis (ALS) affects non-motor regions such as front temporal regions, affecting various cognitive domains.

METHOD: We performed a behavioral study using the attention network test (ANT) to examine two components of attention (alerting, executive condition) and two degrees of difficulty (conflict condition) in 27 patients with ALS with no reported symptoms suggestive of cognitive impairment and 26 matched control participants.

FINDINGS: Using a modified ANT that accounted for ALS-induced motor impairment by focusing on relative reaction times, we could demonstrate its feasibility even in severely paralyzed patients. Relative reaction time differences were comparable to controls, demonstrating the task's ability to correct for motor bias. When focusing on relative reaction times, in both groups we found intact executive and conflict effects. Furthermore, ALS patients had comparable task accuracies when reacting to congruent and incongruent easy targets. However, the task accuracy of ALS patients was significantly lower compared to controls when reacting to the incongruent hard target. This effect was enhanced by the interaction effect of ALS diagnosis and age.

CONCLUSION: Our results suggest a significant interaction between age and ALS pathology, potentially leading to a breakdown of cognitive resources at higher levels of executive demand. We hypothesize that subclinical executive vulnerability in ALS patients becomes apparent when additional detrimental factors, such as aging, are present in patients. While we did not test co-pathologies in our cohort, co-occurring neurodegenerative or vascular processes might have contributed to this result. Our findings highlight the importance of cognitive screening for ALS patients above 60 years, even in the absence of subjective and collateral history of cognitive impairment.}, } @article {pmid42237658, year = {2026}, author = {Vesevick, DR and Ghosh, S and Kalmes, A and Ozdinler, PH and Gautam, M}, title = {Neuroprotective Effects of RNS60 in TDP-43 Pathology-Associated Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {74}, number = {2}, pages = {463-473}, pmid = {42237658}, issn = {1097-4598}, support = {//Revalesio/ ; //Queen B Foundation/ ; //A Long Swim/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/drug therapy/genetics/metabolism ; Mice ; Mice, Transgenic ; Mitochondria/drug effects/ultrastructure/metabolism/pathology ; *Neuroprotective Agents/therapeutic use/pharmacology ; *DNA-Binding Proteins/genetics/metabolism ; Motor Neurons/drug effects/pathology ; Disease Models, Animal ; Spinal Cord/pathology/drug effects ; Neuromuscular Junction/drug effects/pathology ; Green Fluorescent Proteins/genetics/metabolism ; Male ; Muscle, Skeletal/drug effects ; Female ; }, abstract = {INTRODUCTION: TDP-43 pathology is broadly observed in the cerebral cortex of patients with amyotrophic lateral sclerosis (ALS). RNS60, an experimental treatment for acute ischemic stroke and ALS, enhanced mitochondrial biogenesis and function in other preclinical models. We investigated whether RNS60 improved mitochondrial stability and upper motor neuron (UMN) health in a TDP-43 mouse model of ALS.

METHODS: prpTDP-43[A315T]-UeGFP mice, in which UMNs express green fluorescent protein (eGFP), and WT-UeGFP mice were treated with RNS60 or placebo intraperitoneally every other day from post-natal day (P) 30 until P90. Astrogliosis and microgliosis in brain and spinal cord were quantified by immunocytochemistry. Mitochondrial ultrastructure was studied via electron microscopy, and mitochondrial function was assessed using flow cytometry. Neuromuscular junction (NMJ) integrity was assessed in gastrocnemius, tibialis, and diaphragm muscles.

RESULTS: RNS60 treatment reduced defective mitochondria in UMNs (prpTDP-43[A315T] + vehicle: 53.2% ± 0.71%; prpTDP-43[A315T] + RNS60: 19.6% ± 1.4%, p = 0.0001) and spinal motor neurons (prpTDP-43[A315T] + vehicle: 70.1% ± 0.4.48%; prpTDP-43[A315T] + RNS60: 33.5% ± 4.43%, p = 0.001). It increased mitochondrial membrane polarization (prpTDP-43[A315T]-UeGFP + vehicle: 7184 ± 1689 mean intensity; prpTDP-43[A315T]-UeGFP+RNS60: 22120 ± 4818 mean intensity, p = 0.032), reduced the extent of astrogliosis and microgliosis in motor cortex and spinal cord, protected UMNs compared to placebo, and enhanced the proportion of intact NMJs in leg and diaphragm muscles (prpTDP-43[A315T]-UeGFP + vehicle: 29.6% ± 3.6%; prpTDP-43[A315T]-UeGFP + RNS60: 64.3% ± 4.4%, p = 0.0002).

DISCUSSION: These results suggest that RNS60 treatment promotes motor neuron health in ALS by protecting mitochondrial structure and function, preserving NMJ integrity, and reducing gliosis.}, } @article {pmid42237814, year = {2026}, author = {Kulkarni, NP and Thulasidharan, A and Soory, A and Goel, P and Sarkar, S and Kelkar, V and Ratnaparkhi, GS}, title = {Fos regulates age-dependent neuroinflammation in a VAPP58S model of amyotrophic lateral sclerosis.}, journal = {Disease models & mechanisms}, volume = {19}, number = {7}, pages = {}, pmid = {42237814}, issn = {1754-8411}, support = {//Indian Institute of Science Education and Research Pune/ ; 2023/SL03//EMSTAR/ ; BT/INF/22/SP17358/2016//Department of Biotechnology, Ministry of Science and Technology, India/ ; P40 OD018537/OD/NIH HHS/United States ; //Council of Scientific and Industrial Research, India/ ; EMSTAR/2023/SL03//Indian Institute of Science/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology/genetics/metabolism ; *Aging/pathology/metabolism ; Disease Models, Animal ; Neuroglia/metabolism/pathology ; *Drosophila Proteins/metabolism/genetics ; *Drosophila melanogaster/metabolism/genetics ; *Neuroinflammatory Diseases/pathology/genetics ; *Proto-Oncogene Proteins c-fos/metabolism ; Humans ; Motor Activity ; Brain/pathology/metabolism ; Signal Transduction ; Inflammation/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor function. Here, we developed a Drosophila model of ALS8 (VAPBP58S) using CRISPR/Cas9 genome editing. VAPB is an endoplasmic reticulum-based adapter protein associated with and regulating intracellular membrane:membrane contact sites. VAPBP58S flies showed progressive age-dependent motor deficits and a shortened lifespan, paralleling features of the human disease. VAPBP58S brains exhibited age-dependent neuroinflammation, as measured by whole-transcriptome quantitative mRNA sequencing, suggesting a broad, low-grade enhancement of signalling across multiple immune pathways (Toll, Imd, Jak-STAT and c-Jun). Our results indicated that glial cells in the brain are the site of brain inflammation and identified the Drosophila orthologue of Fos (Kayak) as a key modulator of age-dependent inflammation. In accordance, we found that overexpression of wild-type kayak or its dominant-active variant kayakK357R in glia reduced inflammation and, concomitantly, improved motor function. In contrast, knockdown of glial kayak accelerated age-dependent deterioration of motor function and enhanced neuroinflammation. Our study underscores the roles of glial-modulated brain inflammation in dictating ALS8 progression and identifies kayak as a central negative regulator of neuroinflammation in disease.}, } @article {pmid42237817, year = {2026}, author = {Biondi, A and Gray, E and Aggreh, M and Jones, E and Collingwood, A and Knox, L and Bredin, A and Setters, D and Talbot, K and Al-Chalabi, A}, title = {The Motor Neuron Disease Register for England, Wales, and Northern Ireland: Protocol for a Population Register.}, journal = {JMIR research protocols}, volume = {15}, number = {}, pages = {e86458}, pmid = {42237817}, issn = {1929-0748}, mesh = {Humans ; *Motor Neuron Disease/epidemiology ; *Registries/statistics & numerical data/standards ; Northern Ireland/epidemiology ; Wales/epidemiology ; England/epidemiology ; Incidence ; Prevalence ; Female ; }, abstract = {BACKGROUND: Despite the existence of several regional registries in the United Kingdom, gaps in geographic coverage have limited the ability to produce accurate national estimates of incidence, prevalence, and regional variation for motor neuron disease (MND). To address these challenges, a comprehensive national register encompassing England, Wales, and Northern Ireland was established to support epidemiological studies, health care planning, and clinical research.

OBJECTIVE: The primary objective of the MND Register is to provide a centralized research database aggregating clinical and demographic data to facilitate high-quality research. Secondary objectives include estimating disease incidence and prevalence, identifying regional differences in care and survival, evaluating potential disease clustering, and supporting data linkage and clinical trial recruitment.

METHODS: Eligible patients are those aged 16 years or older with a confirmed MND diagnosis made by a consultant neurologist. Data are collected prospectively and retrospectively through standardized templates, available via Microsoft Access, Microsoft Excel, or the REDCap (Research Electronic Data Capture; Vanderbilt University) web platform, and include up to 34 demographic and clinical variables. Additional self-reported data can be contributed through the Telehealth in MND-Research platform. All data are securely stored in the King's College London Trusted Research Environment, undergo standardized preprocessing, and may be linked to National Health Service and national datasets for epidemiological analyses.

RESULTS: The register includes data on over 11,000 individuals with MND, of whom nearly 7000 are currently alive. Postcode data are available for more than 4300 patients, enabling future geospatial analyses. By October 2025, 60 clinical sites were participating in the register, with around 50 actively submitting data.

CONCLUSIONS: The MND Register represents one of the largest national registries for MND worldwide, providing a robust foundation for epidemiological modeling, clinical research, and health care planning. Ongoing efforts to expand prospective data collection, improve completeness, and integrate digital tools will further enhance its impact and support national and international MND research collaborations.}, } @article {pmid42238865, year = {2026}, author = {Bouras, A and Adio, AA and Kumar, R and Phadke, R and Rice, SW and Mody, K and Ndu, A}, title = {Primary Tibiotalocalcaneal Nailing vs Open Reduction and Internal Fixation for Fragility Ankle Fractures in Older Adults: A Markov Model.}, journal = {Foot & ankle orthopaedics}, volume = {11}, number = {2}, pages = {24730114261450956}, pmid = {42238865}, issn = {2473-0114}, abstract = {BACKGROUND: Fragility ankle fractures are common in the elderly population. The cost-effectiveness of primary tibiotalocalcaneal (TTC) nailing compared with open reduction and internal fixation (ORIF) in this population remains unclear.

METHODS: We constructed a Markov cohort model with a 4-year time horizon to compare TTC nailing vs ORIF for fragility ankle fractures in patients aged 75 years and older. All complication rates were derived from the McDonald et al's (2025) systematic review and meta-analysis. Costs were in 2024 US dollars with 3% annual discounting for costs and outcomes. Probabilistic and deterministic sensitivity analyses were performed.

RESULTS: In the base case, ORIF yielded 3.210 quality-adjusted life years (QALYs) (95% credible interval [CrI] 2.785-3.584) at $30 091 (95% CrI $21 426-$40 852) compared with 3.207 QALYs (95% CrI 2.783-3.581) at $33 583 (95% CrI $23 741-$45 447) for TTC nailing. ORIF dominated incremental cost (+$3492, 95% CrI -$11 467 to +$18 273) and incremental QALYs (-0.003, 95% CrI -0.009 to +0.002). The cost differential was driven by the $3000 higher index procedure cost for TTC, partially offset by lower superficial infection (2.1% vs 10.2%). Probabilistic sensitivity analysis demonstrated 33% probability of cost-effectiveness at $100 000/QALY. All 4 scenario analyses confirmed that ORIF dominated.

CONCLUSION: Under McDonald's pooled estimates, TTC nailing is dominated by ORIF for fragility ankle fractures in older adults. The lower superficial infection rate with TTC does not offset its higher procedure cost and higher rates of nonunion and hardware failure. These findings support ORIF as the preferred strategy from a cost-effectiveness standpoint, although the small incremental differences should be considered alongside clinical factors when selecting treatment.

LEVEL OF EVIDENCE: Level IV, economic modeling.}, } @article {pmid42239172, year = {2026}, author = {Matthews, AM and Whiteley, AM}, title = {The retroelement-derived human protein PEG10 is a regulator of mRNA splicing in neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42239172}, issn = {2692-8205}, support = {R01 NS131660/NS/NINDS NIH HHS/United States ; S10 OD034320/OD/NIH HHS/United States ; T32 GM142607/GM/NIGMS NIH HHS/United States ; }, abstract = {Retroelements, including retrotransposons, endogenous retroviruses, and their fragments, as well as rare co-opted or domesticated retroelements, can contribute to neurodegenerative disorders and aging through modulation of gene expression and induction of neuroinflammation. Paternally Expressed Gene 10 (PEG10) is a retroelement-derived human gene that has recently been identified as a putative driver of Amyotrophic Lateral Sclerosis (ALS) and Angelman's Syndrome. PEG10 has been reported to bind nucleic acid and undergoes a complex self-processing pathway that results in gene expression changes when the protein accumulates in cells. Here, we report that PEG10 has selectivity for binding U/G-rich RNAs and influences widespread gene expression changes. PEG10 overexpression mimics the loss of TDP-43 in broad changes to gene expression, including dysregulation of mRNA splicing pathways. Specific changes to mRNA splicing were largely unique between TDP-43 knockdown and PEG10 overexpression, as classic TDP-43 targets including STMN2 were not altered by PEG10. Instead, we identified a unique role for PEG10 in regulating splicing of neuregulin 3 (NRG3), a ligand for the neuronal receptor ERBB4. In SH-SY5Y cells and in human neurons overexpressing PEG10, NRG3 protein levels were decreased along cellular processes, suggesting that these cells are less competent at signaling through the NRG3/ERBB4 axis. Using human patient data, we observed similar changes to NRG3 splicing in UBQLN2-mediated ALS, where PEG10 is accumulated, as well as in some cases of sporadic ALS. In conclusion, the retroelement-derived gene PEG10 plays an unexpected role in regulating splicing of neuronal transcripts, which mimics some of the transcript changes observed in human ALS patient samples. Ultimately, this work has implications for the study of PEG10, and mRNA splicing in neurological diseases associated with elevated PEG10 abundance.}, } @article {pmid42239283, year = {2026}, author = {Reedich, E and Chen, YT and Imhoff-Manuel, R and Li, D and Manuel, M}, title = {Chronic diazepam reveals excessive homeostatic gain in SOD1[G93A] mouse spinal motoneurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42239283}, issn = {2692-8205}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; R01 NS110953/NS/NINDS NIH HHS/United States ; }, abstract = {Motoneurons are under strong pressure to maintain stable motor output throughout an individual life, through homeostatic regulation of their electrical properties. Dysregulated spinal motoneuron excitability has long been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Recent work in SOD1[G93A] mice suggests that the homeostatic response of motoneurons becomes dysregulated as cellular processes are disrupted by the disease, causing fluctuations in motoneuron electrical properties. Yet, few studies directly test whether ALS motoneurons respond differently than wild type motoneurons to a common chronic perturbation. Here, we used in vivo electrophysiology to test whether motoneurons from pre-symptomatic SOD1[G93A] mice modulate excitability differently than wild type motoneurons in response to the same homeostatic perturbation: chronic inhibition exerted by the benzodiazepine diazepam. Using linear mixed-effects statistical models, we assessed whether diazepam treatment differentially modulated passive properties, firing behavior, spike properties, and/or synaptic inputs in SOD1[G93A] versus wild type motoneurons. We identified a significant genotype × treatment interaction effect selectively for properties related to passive membrane integration and spike initiation, including membrane time constant, peak input resistance, and recruitment current. In contrast, firing gain, spike waveform characteristics, and synaptic inputs were largely unaffected. These findings indicate that sustained inhibitory perturbation selectively triggered overactive intrinsic compensatory mechanisms in SOD1[G93A] motoneurons rather than inducing widespread changes in firing or synaptic transmission. Together, our results provide direct evidence for over-active homeostatic control of motoneuron excitability and support a view of motoneuron dysfunction in ALS as a problem of altered feedback regulation rather than simply hyper- or hypo-excitability.}, } @article {pmid42240799, year = {2026}, author = {Saadat, A and Jasińska, M and Cedro, B and Piekarska, A and Flis, DJ and Ziółkowski, W and Pyza, E}, title = {Synaptic Plasticity Changes in the Somatosensory Cortex During Amyotrophic Lateral Sclerosis Progression and After Swim Training in SOD1-G93A Mice.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42240799}, issn = {1559-1182}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology ; *Somatosensory Cortex/physiopathology/pathology/ultrastructure ; *Neuronal Plasticity/physiology ; *Swimming/physiology ; Mice, Transgenic ; Female ; *Disease Progression ; Synapses/ultrastructure ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; *Superoxide Dismutase/metabolism/genetics ; Dendritic Spines ; *Physical Conditioning, Animal ; Disease Models, Animal ; }, abstract = {Somatosensory cortex hyperexcitability is present in the pre-symptomatic stage of amyotrophic lateral sclerosis (ALS) as evidenced by brain recordings, but its synaptic basis remains unclear. We examined synaptic plasticity, the density of asymmetric (putative excitatory) and symmetric (putative inhibitory) synapses, dendritic spine morphology, and the putative excitatory/inhibitory (E/I) ratio in the B2 barrel of the somatosensory cortex in female mice of an ALS mouse model. Transgenic mice, B6SJL-Tg (SOD1*G93A)1Gur/J, were used as the ALS model, and wild-type (WT) B6SJL/F1 mice served as controls. ALS mice were allocated to experimental groups based on disease stage (pre-symptomatic, onset, or terminal) and training condition (swim-trained or untrained). Swim training was applied after the first onset of symptoms (clinical score 1). We analyzed and quantified the density of asymmetric (putative excitatory) and symmetric (putative inhibitory) synapses and E/I ratios using serial electron micrographs to understand how these parameters change during disease progression and whether swim training influences this process. Our results showed stage-dependent alterations in asymmetric (putative excitatory) and symmetric (putative inhibitory) synaptic architecture in ALS. The obtained data showed an increase in the excitatory synaptic density in the presymptomatic ALS mice. This finding is consistent with previous reports of early cortical hyperexcitability and may reflect structural alterations associated with an initial increase in excitatory synapses before disease onset. Importantly, we report here an increase in inhibitory synapses at disease onset. TEM-based synaptic density quantification revealed reduced excitatory synapse density in the B2 barrel of the somatosensory cortex of trained ALS mice compared to WT controls, alongside a trend toward a reduced putative excitatory/inhibitory synaptic ratio. However, as no significant differences were detected between trained and untrained ALS mice, the contribution of swim training to these alterations remains unclear. Notably, swim training was not associated with detectable adverse effects on somatosensory cortex ultrastructure, excitatory synapse density, or the putative excitatory/inhibitory ratio, supporting previous observations that swim training is well tolerated under these experimental conditions. To our knowledge, these results provide the first TEM-based ultrastructural characterization of synaptic architecture in swim-trained SOD1-G93A mice, although further studies are needed to establish the underlying mechanisms and therapeutic relevance in ALS.}, } @article {pmid42241188, year = {2026}, author = {Chikktimmegowda, D and Keerthipriya, MS and Vengalil, S and Nashi, S and Baskar, D and Mol, JJ and Joseph, S and Aishwarya, SY and Binesha, PB and Kumar, BD and Chandrika, H and Mehta, M and Roshan, A and Belur, YK and Nalini, A and Thomas, PT}, title = {The Unfinished Breath: Caregiver Perceptions of Terminal Events and Gaps in Amyotrophic Lateral Sclerosis Care in India.}, journal = {Annals of Indian Academy of Neurology}, volume = {29}, number = {3}, pages = {386-391}, pmid = {42241188}, issn = {0972-2327}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with a high symptom burden and limited survival. Little is known about the terminal phase experiences, symptom prevalence, and end-of-life care patterns of people with ALS (PALS) in India. This study aimed to assess terminal events and caregiver-reported outcomes in PALS to identify gaps in ALS care delivery in India.

METHODS: A cross-sectional telephonic survey was conducted among bereaved caregivers of PALS enrolled in the Neuropalliative and Supportive Care project between December 2021 and May 2024. A structured, validated questionnaire was used to collect data on demographics, terminal-phase symptoms, medical interventions, and the nature of death as perceived by primary caregivers. Descriptive statistics and appropriate statistical analyses were performed.

RESULTS: A total of 130 caregivers participated in the survey; the majority (57.7%) were sons or daughters. Among the 130 PALS, 76 (58.5%) were men; 56.2% had limb onset and 43.8% had bulbar onset. The mean age at death was 53.5 ± 11.4 years. Most patients (57.7%) died at home, and 29.2% experienced sudden death. Patients who died in the hospital were more likely to be on invasive mechanical ventilation (P < 0.001). The most common terminal symptoms were breathlessness (79.2%), excessive oral secretions (54.6%), followed by anxiety or restlessness (44.6%). Only 20% received bilevel positive airway pressure, and 25.4% were on percutaneous endoscopic gastrostomy. A significant association was found between bulbar onset and assisted feeding (P = 0.002).

CONCLUSIONS: This study highlights the need for proactive, community-integrated palliative care services and emphasizes the urgency of early intervention and caregiver support to improve end-of-life experiences in PALS in India.}, } @article {pmid42242586, year = {2026}, author = {Wong, B and Payne, M and Silva, A and Kurniawan, E and Eidman, AS and Pizzo, D and Rajupalem, R and Lenk, GM and Paulo, JA and Khan, T and Eskelinen, EL and Gygi, SP and Brown, NG and Meisler, MH and Mendiola, AS and Gassaway, BM and Ferguson, CJ}, title = {Early-onset neuroinflammation drives neurodegeneration caused by lysosomal PI(3,5)P2 insufficiency.}, journal = {Neurobiology of disease}, volume = {226}, number = {}, pages = {107467}, doi = {10.1016/j.nbd.2026.107467}, pmid = {42242586}, issn = {1095-953X}, support = {R35 GM128855/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Neuroinflammatory Diseases/metabolism/pathology/genetics ; Mice ; *Lysosomes/metabolism/pathology ; *Phosphatidylinositol Phosphates/deficiency/metabolism ; *Flavoproteins/genetics/metabolism ; Microglia/metabolism/pathology ; *Brain/metabolism/pathology ; Membrane Proteins/genetics ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Neurons/metabolism/pathology ; Phosphoinositide Phosphatases ; Intracellular Signaling Peptides and Proteins ; }, abstract = {Phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is a lysosomal signaling lipid whose deficiency, caused by mutations in the PIKfyve complex subunits FIG4 or VAC14, underlies a spectrum of fatal neurologic diseases including Charcot-Marie-Tooth type 4J (CMT4J) and amyotrophic lateral sclerosis (ALS). To map the molecular consequences of PI(3,5)P2 insufficiency in the brain, we performed quantitative proteomic and transcriptomic analyses of three mouse lines bearing distinct loss-of-function mutations in Fig4 or Vac14, examining the brain at the presymptomatic and end stages. Strikingly, profound neuroinflammation was already present at postnatal day 5 (before significant neurodegeneration), characterized by complement activation, interferon signaling, and parenchymal infiltration of peripheral myeloid cells and T-cells. Isolated mutant microglia exhibited a markedly pro-oxidative transcriptional state with elevated reactive oxygen species, a partly non-cell-autonomous phenotype, being present in microglia from mice with conditional Fig4 inactivation in just neurons and astrocytes. Comparison of early (P5) and late (P25) proteomics data revealed that PI(3,5)P2 insufficiency impairs developmental remodeling of the brain proteome: proteins typically upregulated during postnatal maturation failed to accumulate, implicating lysosomal function in neurodevelopment. We identify coordinated elevation of p53, Fas receptor, inflammatory caspases, Gasdermin D, RIPK1, and ZBP1, consistent with multifactorial inflammatory cell death with features of apoptosis, pyroptosis, and necroptosis. Many of the dysregulated proteins are encoded by genes mutated in lysosomal storage disorders, ALS, CMT, Alzheimer's and Parkinson diseases, extending the pathogenic relevance of PI(3,5)P2 insufficiency. Together, these findings establish that early neuroinflammation is a defining - and likely initiating - feature of neurodegeneration caused by disruption of lysosomal PI(3,5)P2.}, } @article {pmid42243993, year = {2026}, author = {Hsieh, WC and Lin, CY and Wu, HC and Weng, EF and Wang, SM}, title = {Hyperoside protects against poly-GR-mediated neurodegeneration via regulation of mitochondrial fission and oxidative stress in C9orf72-associated ALS.}, journal = {Chinese medicine}, volume = {21}, number = {1}, pages = {}, pmid = {42243993}, issn = {1749-8546}, support = {MOST 111-2628-B-039- 006-MY3//National Science and Technology Council/ ; CMU114-MF-04//China Medical University, Taiwan/ ; }, abstract = {BACKGROUND: Arginine-rich poly-glycine-arginine (poly-GR), a toxic dipeptide repeat protein generated from C9orf72 hexanucleotide repeat expansion, drives mitochondrial dysfunction, oxidative stress, and neuronal loss in amyotrophic lateral sclerosis (ALS). Hyperoside, a bioactive flavonoid, exhibits antioxidant and cytoprotective properties, but its therapeutic relevance to C9orf72-associated ALS remains unclear.

PURPOSE: To determine whether hyperoside attenuates poly-GR-induced mitochondrial and oxidative injury and improves neuronal survival in cellular and animal models of C9orf72-ALS.

METHODS: A combined in vitro and in vivo experimental study using motor neuron-like cells and an AAV-mediated neonatal mouse model of poly-GR toxicity. NSC34 cells expressing EGFP-GR50 were analyzed for mitochondrial morphology, membrane potential, ROS generation, antioxidant signaling, and apoptosis using confocal microscopy, CellROX/MitoTracker assays, Western blot analysis, and viability testing. For in vivo assessment, neonatal mice received intracerebroventricular AAV9-EGFP-GR50 followed by intraperitoneal hyperoside (10 mg/kg). Survival, cerebral hemisphere length, and cortical NeuN⁺ neuron numbers were quantified.

RESULTS: Poly-GR expression induced pronounced mitochondrial fragmentation, reduced membrane potential, elevated ROS, and suppressed Nrf2/HO-1/GPx4 signaling, accompanied by increased Drp1 and reduced Opa1 expression. Hyperoside reversed these abnormalities by restoring mitochondrial integrity, normalizing the Drp1/Opa1 balance, enhancing Nrf2 nuclear accumulation, and increasing the expression of HO-1 and GPx4. Hyperoside also reduced cleaved caspase-3 and corrected the Bax/Bcl-2 ratio, improving cell viability under basal and oxidative stress conditions. In vivo, hyperoside modestly prolonged survival, increased cerebral hemisphere length, and significantly preserved cortical neuronal numbers in AAV9-EGFP-GR50 mice.

CONCLUSION: Hyperoside mitigates poly-GR-induced neurotoxicity by alleviating excessive mitochondrial fission, strengthening Nrf2-dependent antioxidant defenses, and suppressing apoptosis. These findings support hyperoside as a promising multi-target therapeutic candidate for C9orf72-associated ALS.}, } @article {pmid42244138, year = {2026}, author = {Subbotin, D and Voskanyan, A and Borovikov, A and Marakhonov, A and Bobreshova, A and Rosales-Sabino, M and Murtazina, A}, title = {FLNC Complex Structural Variant Causing Distal Myopathy Identified by Family-Based Genome Sequencing.}, journal = {American journal of medical genetics. Part A}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajmg.a.70223}, pmid = {42244138}, issn = {1552-4833}, support = {25-65-00031//Russian Science Foundation/ ; }, abstract = {Distal myopathies (DM) are clinically and genetically heterogeneous neuromuscular disorders, and identifying a molecular genetic cause may remain challenging in a subset of cases. Moreover, DM may be misdiagnosed as hereditary neuropathies due to overlapping clinical features. Here, we report a novel structural variant in FLNC associated with DM identified through genome sequencing (GS). Two affected relatives initially presented independently with referral diagnoses of Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. Clinical re-evaluation led to a change of the diagnosis to DM. Muscle MRI revealed a consistent pattern of selective muscle involvement characteristic of DM, enabling identification of six affected individuals within the family. GS was performed in seven family members, including six affected individuals and one unaffected relative. The analysis identified an insertion of two inverted fragments derived from the adjacent intron 2 into exon 3 of the FLNC gene. This complex rearrangement was accompanied by short non-templated nucleotide insertions at the junctions and a 3-bp exonic deletion at the insertion site, ultimately resulting in a frameshift. The structural variant was segregated with disease and was confirmed by Sanger sequencing and one Oxford nanopore long-read sequencing. Our findings expand the mutational spectrum of FLNC-associated disorders and highlight the importance of GS combined with a detailed clinical examination for the diagnosis of DM.}, } @article {pmid42245509, year = {2026}, author = {Wang, Z and Li, L and Dong, Y and Zhang, Y}, title = {The microbiota-tryptophan-brain axis in neurodegenerative diseases: pathogenic mechanisms, disease-specific roles, and translational therapeutics.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1820111}, pmid = {42245509}, issn = {1664-302X}, abstract = {The pathogenesis of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) is very complex. Recent studies have shown that gut microbiota and their metabolites play a key role in the progression of these diseases. Tryptophan (Trp) is an essential amino acid, which mainly produces a variety of biologically active compounds in the intestine through the metabolism of indole pathway, Kynurenine pathway (KP) and serotonin pathway, including indole derivatives, Kynurenine (KYN) and serotonin (5-HT). These metabolites affect the central nervous system (CNS) through the Microbiota-gut-brain axis (MGBA) and affect CNS in a variety of mechanisms, including immune regulation, neuroprotection and maintenance of intestinal barrier function. They are involved in key pathological processes such as neuroinflammation, oxidative stress and pathological protein aggregation. This paper systematically reviews the mechanism of the role of Trp metabolites derived from gut microbiota in NDDs, and explores their specific roles in AD, PD, Amyotrophic Lateral Sclerosis (ALS) and Huntington's disease (HD), and summarizes the potential therapeutic value of the current pathway strategy. These strategies include nutritional intervention, targeted microbiome therapy [such as probiotic and fecal microbiota transplantation (FMT)], and metabolite-derived drugs. Future research must clarify its dynamic mechanism in the human body, develop relevant biomarkers, and promote personalized prevention and treatment strategies through clinical transformation, so as to provide a new direction for early intervention and treatment of NDDs.}, } @article {pmid42246025, year = {2026}, author = {Pu, H}, title = {Editorial: Regulated cell death and neurological diseases.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1842251}, pmid = {42246025}, issn = {1662-4548}, } @article {pmid42247870, year = {2026}, author = {Aprile, FA and Pastore, A}, title = {Ribonucleic acid as an active driver of protein aggregation in neurodegeneration.}, journal = {Current opinion in structural biology}, volume = {99}, number = {}, pages = {103298}, doi = {10.1016/j.sbi.2026.103298}, pmid = {42247870}, issn = {1879-033X}, mesh = {Humans ; *RNA/metabolism/chemistry ; *Neurodegenerative Diseases/metabolism/pathology ; *Protein Aggregates ; Animals ; RNA-Binding Proteins/metabolism ; *Protein Aggregation, Pathological/metabolism ; }, abstract = {Neurodegeneration has traditionally been largely attributed to protein aggregation, yet ribonucleic acid (RNA) has emerged as an active driver of pathology. Expanded repeat RNAs, misregulated RNA-binding proteins, and aberrant RNA-protein interactions can directly or indirectly trigger neuronal dysfunction, although the distinction between the two mechanisms might, in some cases, be loose. RNA modulates prion-like aggregation, scaffolds liquid-liquid phase separation, and either promotes or inhibits protein assembly, depending on RNA sequence and structure. The aim of this review is to discuss our current understanding of RNA's dual role-as a facilitator of aggregation or as a potential therapeutic target-revealing new mechanistic insights into diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and spinocerebellar ataxias. We highlight RNA metabolism as a central determinant of neuronal vulnerability.}, } @article {pmid42248860, year = {2026}, author = {Ball, HE and Woods, AC and Wong, YC}, title = {TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42248860}, issn = {2041-1723}, support = {DP2 GM146322/GM/NIGMS NIH HHS/United States ; P30 CA060553/CA/NCI NIH HHS/United States ; DP2GM146322//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {*Mitochondria/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Oxidation-Reduction ; Humans ; *RNA/metabolism ; Reactive Oxygen Species/metabolism ; *Protein Phosphatase 1/metabolism/genetics ; *Cytoplasmic Granules/metabolism ; Oxidative Phosphorylation ; Animals ; Cysteine/metabolism ; }, abstract = {Inter-organelle contact sites are key hubs for organelle bidirectional crosstalk. However, how mitochondria and RNA granules interact at contact sites and its regulation by mitochondrial oxidative phosphorylation (OXPHOS) remain unclear. Here, using Super-Resolution live microscopy, we identify RNA granule-mitochondria contact site formation in OXPHOS conditions. Reactive oxygen species (ROS) generated by mitochondrial OXPHOS promotes TDP-43 localization to cytoplasmic RNA granules via TDP-43 cysteine oxidation at Cys173/Cys175. Mechanistically, RNA granule-mitochondria contact tethering is mediated by TDP-43 on RNA granules binding to GADD34 on mitochondria, while contact untethering is regulated by TDP-43 oxidation. Functionally, this allows for GADD34 and its binding partner PP1 to regulate TDP-43 RNA granule dynamics, and conversely, for TDP-43 oxidation to regulate the ability of the phosphatase PP1 to form granules. Finally, disease-associated mutant TDP-43 misregulates this pathway, ultimately leading to PP1 granules lacking TDP-43. This dynamic crosstalk between TDP-43 oxidation and PP1 has significant consequences for TDP-43-associated diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).}, } @article {pmid42248993, year = {2026}, author = {Gad, AG and Kelani, KM and Mahmoud, AM and Arafa, RM and Abbas, AEF}, title = {Fedorov algorithm-optimized chemometric spectrophotometry for cefepime-tazobactam microanalysis in plasma and pharmaceuticals with integrated MA and NQS sustainability assessment.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42248993}, issn = {2045-2322}, mesh = {Humans ; *Algorithms ; *Anti-Bacterial Agents/blood/analysis ; Calibration ; *Cefepime/blood/analysis ; Cephalosporins ; Least-Squares Analysis ; Spectrophotometry/methods ; Spectrophotometry, Ultraviolet/methods ; *Tazobactam/blood/analysis ; }, abstract = {A green, sustainability-oriented chemometric-assisted UV spectrophotometric platform was developed for the simultaneous determination of Cefepime (CFPM) and Tazobactam (TAZO) in pharmaceutical formulations and human plasma. Water served as the sole diluent, eliminating hazardous organic solvents and substantially reducing the environmental impact of the analytical procedure. Calibration and validation sets were efficiently constructed using the Fedorov exchange algorithm within Brereton's multilevel design framework, yielding 25 calibration and 13 validation mixtures and reducing experimental workload by approximately 70% compared with conventional designs. Three complementary chemometric models were evaluated: Principal Component Regression (PCR), Firefly Algorithm-assisted Partial Least Squares (FA-PLS), and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). Among them, MCR-ALS demonstrated superior predictive performance, with correlation coefficients exceeding 0.9998 for both analytes, minimal systematic bias confirmed by Elliptical Joint Confidence Region analysis, and high robustness across pharmaceutical and plasma matrices. Limits of detection were 0.0487 and 0.0396 µg mL[-1], while limits of quantification were 0.1476 and 0.1200 µg mL[-1] for CFPM and TAZO, respectively. The method was validated in accordance with ICH guidelines and successfully applied to CEFE-MAX™ powder for injection and fortified human plasma. Matrix effect evaluation showed negligible signal suppression (- 2.35% to - 1.27%), indicating strong matrix tolerance and calibration transferability. Comparative benchmarking against reported HPLC-UV, LC-MS/MS, capillary zone electrophoresis, and UV spectrophotometric methods demonstrated that the proposed approach achieves an optimal balance of sensitivity, simplicity, and environmental sustainability. Sustainability assessment using the Multi-Color Assessment (MA), carbon footprint analysis, and the Need-Quality-Sustainability (NQS) index yielded a Whiteness Score of 83.6%, an NQS score of 90, and a low carbon footprint of 0.032 kg CO2-eq per analysis. Overall, the developed platform provides a rapid, cost-effective, and environmentally responsible alternative for routine quality control and preliminary therapeutic monitoring of the CFPM-TAZO combination.}, } @article {pmid42250142, year = {2026}, author = {Jalaiei, A and Kiani Darabi, AH and Sakkaki, E and Rezazadeh, M and Ghafouri-Fard, S}, title = {Molecular interplay between Non-coding RNAs and BDNF in Neurodegenerative Disorders: a systematic review.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42250142}, issn = {1573-4978}, mesh = {*Brain-Derived Neurotrophic Factor/genetics/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/metabolism ; MicroRNAs/genetics/metabolism ; *RNA, Untranslated/genetics/metabolism ; Animals ; Gene Expression Regulation ; RNA, Long Noncoding/genetics/metabolism ; }, abstract = {Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays essential roles in nervous system development, neuronal maintenance, and neurogenesis. Aberrant BDNF concentrations, observed both peripherally and within the central nervous system (CNS), have been consistently implicated in the pathogenesis of a spectrum of neurodegenerative disorders (NDDs), including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and Multiple sclerosis. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), regulate gene expression and are critical factors in cellular processes relevant to neurodegenerative disease pathobiology. Consequently, ncRNAs are posited as promising biomarkers and potential therapeutic modalities for CNS-related pathologies. However, robust empirical evidence substantiating ncRNA-mediated, post-transcriptional regulation of BDNF expression in the context of neurodegeneration remains relatively scarce. The objective of this systematic review is to provide a critical synthesis of the current literature on the diagnostic and prognostic utility of ncRNAs that modulate BDNF expression, specifically within the scope of neurodegenerative disorders. Furthermore, we will explore innovative therapeutic strategies centered on targeting BDNF-associated miRNAs for the treatment of these disorders.}, } @article {pmid42250707, year = {2026}, author = {Hosseinpoor, Z and Seyedalipour, B and Behjou, NK and Hosseinkhani, S and Baziyar, P}, title = {Inhibitory effect of silymarin on amyloid formation in ALS-associated hSOD1 P66R mutant.}, journal = {International journal of biological macromolecules}, volume = {370}, number = {}, pages = {152922}, doi = {10.1016/j.ijbiomac.2026.152922}, pmid = {42250707}, issn = {1879-0003}, mesh = {*Silymarin/pharmacology/chemistry ; Humans ; *Amyloid/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; *Mutation ; Molecular Docking Simulation ; Protein Aggregates/drug effects ; Protein Aggregation, Pathological ; }, abstract = {The aberrant aggregation of human superoxide dismutase 1 (hSOD1) into β-sheet-rich amyloid fibrils is a crucial process in the pathogenesis of amyotrophic lateral sclerosis (ALS), enhancing motor neuron degeneration and disease progression. The P66R mutation in SOD1 destabilizes local structure and promotes β-sheet-driven fibrillation, which makes it a suitable model for exploring approaches for reducing pathogenic aggregation. Here, we evaluate silymarin, a polyphenolic compound with known antioxidant and neuroprotective properties, for its potential to inhibit P66R-hSOD1 aggregation. ThT fluorescence and transmission electron microscopy analyses demonstrate a significant decrease in amyloid fibril formation in the presence of silymarin; in addition, FTIR spectroscopy confirms the suppression of β-sheet formation. Fluorescence quenching and ANS binding assays indicate a moderate-affinity binding between silymarin and the mutant protein, along with a reduction in surface hydrophobicity. Hemolysis assays confirm its protective effect against membrane damage induced by aggregates, while molecular docking and dynamic simulations indicate that silymarin stabilizes aggregation-prone areas with hydrogen bonding and hydrophobic interactions, thereby promoting compact conformations and reducing solvent-exposed surfaces. The findings identified silymarin as an effective anti-amyloidogenic agent that reduces β-sheet accumulation and fibril formation while also decreasing cytotoxicity, highlighting its potential as a therapeutic candidate for ALS.}, } @article {pmid42251349, year = {2026}, author = {Masrori, P and Amado, DA}, title = {RAN translation as a dominant pathogenic axis in C9ORF72-associated ALS and FTD models.}, journal = {Molecular neurodegeneration}, volume = {21}, number = {1}, pages = {}, pmid = {42251349}, issn = {1750-1326}, } @article {pmid42251967, year = {2026}, author = {Manchinu, MF and Congiu, M and Massidda, M and Borghero, G and Marongiu, J and Marzi, I and Maschio, A and Rallo, V and Serra, M and Porcedda, C and Etzi, M and Palmas, MF and Angius, A and Sogos, V and Pateri, MI and Steri, M and Coroneo, V and De Simone, A and Cossu, G and Chiti, F and Carta, AR}, title = {PBMC DEG/miRNA biomarkers of TDP-43 pathology in ALS.}, journal = {Neurobiology of disease}, volume = {226}, number = {}, pages = {107473}, doi = {10.1016/j.nbd.2026.107473}, pmid = {42251967}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/blood ; Animals ; *MicroRNAs/metabolism/genetics ; *DNA-Binding Proteins/genetics/metabolism ; Humans ; *Leukocytes, Mononuclear/metabolism ; Rats ; Male ; Biomarkers/blood/metabolism ; Female ; Middle Aged ; Aged ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) lacks reliable, disease-specific, and minimally invasive biomarkers, representing a major barrier to early diagnosis and patient stratification. The primary aim of this translational pilot study was to identify a disease-specific, TDP-43-related, gene-microRNA (miRNA) signature in peripheral blood mononuclear cells (PBMCs) of ALS patients with potential diagnostic value. To this end, we first identified differentially expressed disease-specific genes (dsDEGs) using a TDP-43-based rat model of ALS, generated by stereotaxic infusion of full-length (FL) TAR DNA-binding protein 43 (TDP-43) into the motor cortex. Transcriptomic profiling of the motor cortex revealed candidate dsDEGs, which were subsequently validated by RT-qPCR in motor cortex, spinal cord, and PBMCs from the same animals. To assess translational relevance, expression levels of these dsDEGs were analyzed in PBMCs from early- to mid-stage ALS patients and matched healthy controls, while disease specificity was evaluated using Parkinson's disease (PD) samples. In parallel, conserved miRNAs predicted to target the identified dsDEGs were examined in both rat and human PBMCs. Five dsDEGs, Mctp1, Penk, Mt2A, Drd1, and Rasgrp2, were consistently dysregulated across central and peripheral tissues in the TDP-43 rat model. RT-qPCR analysis of human PBMCs confirmed significant and selective dysregulation of these genes in ALS, but not in PD, supporting disease specificity. Moreover, exposure of human neuroblastoma cells and healthy PBMCs to TDP-43 recapitulated the ALS-like expression changes. Computational and experimental analyses identified seven conserved miRNAs targeting these dsDEGs, of which four were significantly downregulated in ALS PBMCs, supporting a coordinated regulatory network. Receiver operating characteristic (ROC) analyses demonstrated strong discriminative performance for both the gene signature (AUC 0.87-1.00) and the associated miRNAs (AUC 0.95-1.00). Together, these findings define a novel PBMC-based gene-miRNA signature that mirrors central ALS pathology and shows high diagnostic accuracy and disease specificity, highlighting its potential as a minimally invasive biomarker for ALS.}, } @article {pmid42252093, year = {2026}, author = {Arlt, FA and Miske, R and Appeltshauser, L and Zinnow, V and Borowski, K and Stenzel, W and Radbruch, H and Meisel, A and Ruprecht, K and Endres, M and Blau, I and Kirchner, M and Mertins, P and Sanchez-Sendin, E and Wernick, S and Pressler, H and Stascheit, F and Linke, J and Hümmert, S and Werner, HB and Wibisono, EA and Doppler, K and Komorowski, L and Spiliotis, ET and Dubey, D and Zeckeridou, A and Pittock, SJ and Mills, JR and McKeon, A and Scharf, M and Prüss, H}, title = {Septin multimer autoantibodies in severe motor neuropathy mimicking lower motor neuron disease.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {8}, pages = {2731-2746}, pmid = {42252093}, issn = {1460-2156}, support = {EN343/16-1//University of Würzburg/ ; R01 NS126227/NS/NINDS NIH HHS/United States ; //NIH/ ; R35 GM136337/GM/NIGMS NIH HHS/United States ; 295-424778381//University of Würzburg/ ; WE 2720/2-2//University of Würzburg/ ; FOR3004//German Research Foundation/ ; PR1274/5-1//German Research Foundation/ ; RO1NS126227//University of Würzburg/ ; 821283-2//University of Würzburg/ ; EXC-2049-390,688,087//University of Würzburg/ ; Connect-Generate 01GM1908D//German Federal Ministry of Education and Research/ ; 504745852//German Research Foundation/ ; 2R35GM136337-07//University of Würzburg/ ; PR1274/9-1//German Research Foundation/ ; HIL-A03 BaoBab//Helmholtz Association/ ; }, mesh = {*Autoantibodies/immunology/blood ; Humans ; Male ; Female ; *Motor Neuron Disease/immunology/diagnosis ; Animals ; *Septins/immunology ; Retrospective Studies ; Middle Aged ; Mice ; Aged ; Sciatic Nerve/immunology ; Adult ; }, abstract = {Severe neuropathies with predominant involvement of motor fibres can resemble lower motor neuron disease (LMND) phenotypes. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to provide treatment options to patients. We investigated a novel autoantibody binding pattern observed on murine teased sciatic nerve fibres. Target antigens were identified using immunoprecipitation combined with mass spectrometry. Target specificity of these autoantibodies was validated in cell-based assays, neutralization assays and knock-out models. A retrospective study cohort consisting of different neuropathies (chronic inflammatory demyelinating polyradiculopathy n = 86, Guillain-Barré syndrome n = 37, multifocal motor neuropathy n = 18, diabetic neuropathy n = 30, other inflammatory neuropathies n = 10), amyotrophic lateral sclerosis (n = 50), multiple sclerosis (n = 50) and healthy controls (n = 50) was negative for septin multimer autoantibodies. Histopathological analysis of skin and the sural nerve including electron microscopy was performed in one seropositive patient, and autoantibody binding was characterized in vitro. Extensive immunotherapy was initiated in one patient, with clinical and serological follow-up over 4 years. Among 3543 total samples tested, three patients (two male, one female)-diagnosed with the LMND variant of amyotrophic lateral sclerosis (aged 65, 72 and 79 years, respectively)-showed a novel and distinct autoantibody binding pattern of indirect immunofluorescence staining on peripheral nerves, targeting Schmidt-Lanterman incisures (SLIs), paranodes and the abaxonal myelin. Target identification and validation revealed septin multimers as autoantibody epitopes. Despite the primarily intracellular location of septins, autoantibody binding was evident in living myelinated dorsal root ganglia, primarily at SLIs ('incisuropathy'). Septin multimer autoantibodies further initiated complement deposition on fixed and permeabilized cell-based assays. Sural nerve and skin biopsies showed inflammation, myelin and axonal pathology. Extensive immunotherapy in one patient was followed by disease stabilization over 3 years. The other two patients died of rapid disease progression: one of them received no immunotherapy while the other had ineffective treatments with single administrations of intravenous immunoglobulin and rituximab. Our data suggest that septin multimer autoimmunity occurs in severe motor-predominant neuropathies which can clinically resemble a neurodegenerative LMND. Screening for septin multimer autoantibodies should be considered in patients presenting with this phenotype. Follow-up studies need to determine the direct pathogenicity of septin multimer autoantibodies, their potential as a biomarker of an autoimmune syndrome and responses to immunotherapy in larger cohorts.}, } @article {pmid42252583, year = {2026}, author = {Melone, M and Di Palma, M and Scimemi, A and Conti, F}, title = {Organization of Astrocytic GLT-1 at Cortical Inhibitory Synapses.}, journal = {Glia}, volume = {74}, number = {8}, pages = {e70180}, pmid = {42252583}, issn = {1098-1136}, support = {PRIN2022BZWEKA//Italian Ministry of University and Reearch/ ; R56NS12955601/NH/NIH HHS/United States ; }, mesh = {*Astrocytes/metabolism/ultrastructure ; Animals ; *Excitatory Amino Acid Transporter 2/metabolism ; *Synapses/metabolism/ultrastructure ; Humans ; *Cerebral Cortex/metabolism/ultrastructure/cytology ; Rats ; Male ; Female ; Rats, Sprague-Dawley ; Glutamic Acid/metabolism ; *Neural Inhibition/physiology ; }, abstract = {Glutamate spillover from excitatory synapses modulates neighboring inhibitory synapses, yet the ultrastructural organization of the major glutamate transporter GLT-1 at these sites remains poorly defined. Using quantitative pre-embedding electron microscopy in rat and human cortex, we found that GLT-1-positive astrocytic leaflets (ALs) were frequently juxtaposed to morphologically identified symmetric synapses, with similar prevalence across axo-somatic, proximal axo-dendritic, and distal axo-dendritic subtypes. Because inhibitory synapses are embedded in a dense excitatory neuropil, we applied distance-based phenotyping relative to the nearest asymmetric synapse to define symmetric-associated GLT-1+ ALs. Within this population, distal axo-dendritic symmetric synapses showed shorter AL-to-synaptic-edge distances and were embedded in a tighter local excitatory microenvironment. Post-embedding immunogold further showed that GLT-1 was enriched at the plasma membranes of ALs and localized extrasynaptically relative to symmetric synapses. Consistently, symmetric-associated membrane GLT-1 and closely spaced GLT-1/α2 couples (with an interdistance ≤ 50 nm) were preferentially localized within 1000 nm of distal symmetric synapses compared to proximal. Similar organizational features of membrane GLT-1/α2 couples were observed in human cortex. These findings identify a subtype-dependent extrasynaptic astrocytic GLT-1 organization at cortical inhibitory synapses and provide a morphological framework for glutamate-dependent modulation of inhibitory signaling.}, } @article {pmid42252587, year = {2026}, author = {Jin, H}, title = {PET Molecular Probes for Neuroinflammation in Neurodegenerative Diseases: Progress and Prospects.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {12}, pages = {2229-2237}, doi = {10.1021/acschemneuro.6c00338}, pmid = {42252587}, issn = {1948-7193}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; *Positron-Emission Tomography/methods ; Animals ; *Neuroinflammatory Diseases/diagnostic imaging/metabolism ; Receptors, GABA/metabolism ; *Molecular Probes/metabolism ; *Brain/metabolism/diagnostic imaging ; }, abstract = {Neuroinflammation is a central pathological process underlying neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis. Positron emission tomography (PET) molecular probes now enable the noninvasive, quantitative visualization of neuroinflammatory processes in the living brain. This review surveys recent advances in PET probes targeting microglial activation markers─including the 18 kDa translocator protein (TSPO), the purinergic P2X7 receptor (P2X7R), colony-stimulating factor 1 receptor (CSF1R), and sphingosine-1-phosphate receptor 1 (S1PR1)─as well as astrocyte reactivity markers such as monoamine oxidase B (MAO-B) and imidazoline-2 binding sites (I2BS). I discuss the evolution from first-generation TSPO ligands to polymorphism-insensitive third-generation tracers, highlight emerging targets beyond TSPO, and evaluate the translational value of these probes for early diagnosis, disease staging, treatment monitoring, and drug development. Current challenges-including limited cellular specificity, genetic polymorphism effects, quantification difficulties, and clinical accessibility barriers─are analyzed alongside promising solutions. Integrating neuroinflammation PET into multimodal biomarker frameworks will be essential for advancing precision medicine in neurodegenerative diseases.}, } @article {pmid42253115, year = {2026}, author = {Orzechowski, K and Wasiluk, M and Milewska, W and Kowalska, N and Chuang, YT and Cao, JY and Wang, CT and Neumann, A and Strzeżysz, O and Kozanecka-Szmigiel, A and Konieczkowska, J and Schab-Balcerzak, E and Lewandowski, W and Woliński, TR}, title = {Synergistic Effects of Nanoparticles and Surface Anchoring on Fine-Tuning the Photonic Bandgap in Blue Phase Liquid Crystals.}, journal = {ACS nano}, volume = {20}, number = {24}, pages = {17286-17302}, pmid = {42253115}, issn = {1936-086X}, abstract = {Precise control over the photonic bandgap in Blue Phase Liquid Crystals (BPLCs) remains challenging due to the inherent limitations of existing tuning methods. Here, we present a 2-fold approach that synergistically combines internal and external effectors to enable controlled, fine modulation of the photonic bandgap across a wide spectral range of 200 nm. Internally, nanoparticles (NPs) embedded within the BPLC lattice enhance the thermal stability of the blue phase and reduce the cubic unit cell size, thereby shifting the reflection bandgap toward shorter wavelengths. Externally, the chemical structure of homogeneous alignment layers (ALs) affects the spectral position of the Bragg reflection. By systematically varying four ALs and three NP doping levels (0, 0.5, and 2 wt %), a cooperative influence of both effectors on spectral tuning is observed. These interactions are qualitatively explained by contact-angle measurements and chemical interactions at the LC-AL and LC-NP interfaces. Kossel diagram analysis, together with a factor based on the total tuning range and associated statistical descriptors, is used to confirm and quantify Bragg wavelength shifts. The results demonstrate that combined internal and external control provides an effective strategy for adjusting the optical response and thermal behavior of BPLCs, supporting their application in photonic devices.}, } @article {pmid42253371, year = {2026}, author = {Chen, X and Mo, Y and Jiang, H}, title = {NEK1 variants and reduced protein levels in Chinese ALS patients: a descriptive study.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1831861}, pmid = {42253371}, issn = {1663-4365}, abstract = {OBJECTIVE: NIMA-related kinase 1 (NEK1) have been implicated in amyotrophic lateral sclerosis (ALS). But genetic spectrum and clinical presentation have not been systematically defined.

METHODS: We screened 378 ALS patients and identified NEK1 variant carriers. Clinical records were reviewed retrospectively to characterise phenotypes. Leukocytes were isolated after routine testing and NEK1 protein abundance was quantified by western blot to assess the relationship between NEK1 protein levels and the rate of clinical progression. In parallel, we conducted a structured narrative review of published NEK1-ALS cases based on a systematic search of PubMed, Embase, and Web of Science. We extracted genetic and clinical information to summarise the variant spectrum, co-mutation profiles, and phenotype differences across populations.

RESULTS: NEK1 variants were identified in 8 of 378 patients (2.12%). Protein analysis showed lower peripheral NEK1 levels among carriers than among controls in this small exploratory sample. An exploratory analysis further suggested that lower systemic NEK1 protein levels may be associated with faster disease progression; however, because these measurements were obtained from peripheral leukocytes at highly heterogeneous sampling times and without adjustment for major clinical confounders, they should be interpreted strictly as descriptive observations and do not support biomarker claims. While phenotypic heterogeneity and population-specific variant distributions were observed, these findings remain descriptive due to the small sample size.

CONCLUSION: This regional case series provides a descriptive overview of NEK1 variants in a Chinese ALS cohort and offers preliminary exploratory evidence consistent with reduced peripheral NEK1 protein levels in variant carriers. The observed inverse relationship between lower measured protein levels and faster clinical decline should be regarded as hypothesis-generating only. Given the small sample size, highly heterogeneous sampling times, use of peripheral leukocytes, and lack of adjustment for major clinical confounders, these protein data do not support biomarker claims at this stage. Validation in larger, prospective multi-center cohorts with standardized longitudinal sampling is required.}, } @article {pmid42253609, year = {2026}, author = {Lajoie, I and Kalra, S and Dadar, M}, title = {Data-driven subtyping and staging of ALS: A multicenter, longitudinal, deformation-based morphometry study.}, journal = {Imaging neuroscience (Cambridge, Mass.)}, volume = {4}, number = {}, pages = {}, pmid = {42253609}, issn = {2837-6056}, abstract = {Amyotrophic lateral sclerosis (ALS) is clinically and biologically heterogeneous, yet data-driven imaging subtyping approaches have rarely been validated longitudinally or linked to clinical and survival outcomes. We aimed to identify and validate distinct ALS subtypes and disease stages using deformation-based morphometry (DBM) and the Subtype and Stage Inference (SuStaIn) model, and to characterize their cross-sectional and longitudinal imaging, clinical, cognitive, and survival profiles. Data from 198 ALS patients and 144 healthy controls in the Canadian ALS Neuroimaging Consortium (CALSNIC) multicenter cohort were analyzed. Baseline regional DBM w-scores from 14 ALS-relevant regions served as input to SuStaIn to infer subtypes and stages. Longitudinal consistency of subtype and stage assignments (e.g. adherence to the expected disease evolution) was assessed using follow-up visits. Imaging and clinical trajectories were compared across subtypes using linear mixed-effects models incorporating stage and elapsed time. Associations between longitudinal variables and SuStaIn stage were estimated using mixed models, while baseline clinical and cognitive differences were assessed with ordinary least squares regression. Survival differences were evaluated using Kaplan-Meier curves and log-rank tests. SuStaIn identified one normal-appearing group (S0) and three ALS atrophy subtypes. S0 showed no baseline atrophy but exhibited longitudinal motor decline and the most favorable survival (log-rank p < 0.05 to p < 0.01). S1 exhibited classical motor/corticospinal tract-dominant degeneration, greater lower motor neuron burden, and intermediate survival. S2 showed limbic-onset atrophy progressing toward motor pathways, with preserved cognition and a milder course. S3 demonstrated extensive fronto-parietal and striatal atrophy, longitudinal motor-thalamic degeneration, and the shortest survival. Subtype and stage assignments demonstrated high longitudinal consistency (>90%). SuStaIn stage was strongly associated with widespread brain atrophy (and ventricular expansion), with the strongest effects in limbic-subcortical regions. Stage also correlated with ALS Functional Rating Scale-Revised (ALSFRS-R) decline and forced vital capacity (FVC) reduction, indicating that stage reflects disease-linked progression. This study establishes a robust, longitudinally validated model of ALS heterogeneity, showing that SuStaIn-derived subtypes define distinct disease trajectories, whereas the normal-appearing group reflects an early, structurally preserved state with a more favorable survival profile. By integrating probabilistic staging with longitudinal modeling, these findings clarify dynamic subtype-specific progression patterns and support the use of SuStaIn for biologically informed patient stratification, prognostication, and clinical trial enrichment in ALS.}, } @article {pmid42253794, year = {2026}, author = {Melby, SR and Asok Kumar, JN and Bigus, ER and Kellis, S}, title = {Clinical evaluation of communication brain computer interfaces in amyotrophic lateral sclerosis: a landscape analysis.}, journal = {Frontiers in human neuroscience}, volume = {20}, number = {}, pages = {1771146}, pmid = {42253794}, issn = {1662-5161}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that leads to severe motor impairment, including loss of communication ability, and ultimately death. Communication brain computer interfaces (cBCIs) have the potential to restore communication without reliance on motor function, thereby improving quality of life, independence, and palliative care. However, standardized methods to evaluate cBCI efficacy necessary for clinical implementation are not yet established.

METHODS: We conducted a systematic literature review, semi structured interviews with key opinion leaders (KOLs), and a clinical assessment review panel to (1) identify clinical outcome assessments (COAs) relevant to cBCIs in ALS, (2) obtain expert feedback, and (3) synthesize the current clinical and scientific landscape.

RESULTS: A total of 21 COAs were identified as potentially relevant and may serve as a foundation for cBCI specific measures. However, no existing COA was found to comprehensively capture the clinical benefit or functional impact of cBCIs in ALS.

DISCUSSION: Current COAs are insufficient to evaluate cBCIs in ALS, highlighting a critical gap. Development of cBCI specific outcome measures is needed to support clinical validation, regulatory evaluation, and adoption.}, } @article {pmid42253845, year = {2026}, author = {Maslać, I and Palić, B and Kljakić, M and Puljić, M and Opančar, M and Kljakić, M and Opančar, B}, title = {Impact of dispatcher-assisted cardiopulmonary resuscitation, advanced life support training, and physician experience on out-of-hospital cardiac arrest outcomes in Mostar: a 10-year retrospective cohort study.}, journal = {Resuscitation plus}, volume = {28}, number = {}, pages = {101253}, pmid = {42253845}, issn = {2666-5204}, abstract = {BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a major public health challenge, with survival to hospital discharge rarely exceeding 10%. This study evaluated the association of dispatcher-assisted CPR (DA-CPR), advanced life support (ALS) training, and physician experience with OHCA outcomes in Mostar, Bosnia and Herzegovina, a resource-limited emergency medical service (EMS) system.

METHODS: We conducted a retrospective cohort study encompassing all OHCA cases recorded in the Mostar region between 2013 and 2022. Dispatcher-assisted CPR was formally implemented in early 2018. Accordingly, patients were stratified into two groups: the pre-implementation period (2013-2017) and the post-implementation period (2018-2022). The primary outcome was return of spontaneous circulation (ROSC) and the secondary outcome was survival to hospital discharge.

RESULTS: A total of 308 OHCA cases were included. ROSC was achieved in 88 patients (28.6%), and 14 patients (4.5%) survived to hospital discharge. Following DA-CPR implementation, ROSC increased from 22.7% to 33.5%. In adjusted logistic regression DA-CPR (OR = 1.857, 95% CI 1.075-3.208) and ALS-trained physician involvement (OR = 1.802, 95% CI 1.045-3.105) were independently associated with ROSC. Physician experience was not associated with ROSC or survival to hospital discharge, and no examined exposures were associated with survival to hospital discharge.

CONCLUSIONS: Dispatcher-assisted CPR and ALS-trained physician involvement were associated with higher odds of ROSC, while none of the examined variables showed an association with survival to hospital discharge. Early resuscitation gains did not translate into final outcomes in this resource-limited EMS system. Improving survival will require coordinated system strengthening, particularly public-access defibrillation and standardized post-resuscitation care.}, } @article {pmid42254255, year = {2026}, author = {Beniwal, SS and Rawat, A and Sharma, N and Calderón, DC and Mwaanga, C and Mora, VA and Saini, P and da Costa, REAR and Mushir Ali, AS and Kumar, A and Dwivedi, A and Mehta, SP and Patel, DR and Danda, P}, title = {Translating potential into practice: the evolving landscape of neural stem cell therapeutics in clinical applications.}, journal = {Annals of medicine and surgery (2012)}, volume = {88}, number = {6}, pages = {3284-3295}, pmid = {42254255}, issn = {2049-0801}, abstract = {BACKGROUND: Neural stem cell (NSC) therapeutics have emerged as a promising approach for addressing neurological disorders due to their inherent ability to self-renew, differentiate into neural lineages, and secrete neurotrophic factors.

METHODS: This narrative review explores the evolving clinical landscape of NSC applications, highlighting their therapeutic potential in neurodegenerative diseases, ischemic stroke, and spinal cord injuries.

FINDINGS: Recent clinical advancements demonstrate the safety and preliminary efficacy of NSC-based therapies in conditions like Parkinson's disease and amyotrophic lateral sclerosis. NSCs' capacity to promote neuroplasticity and tissue restoration underscores their potential in reversing synaptic and neuronal damage. Despite these advancements, significant challenges remain. Ethical considerations, particularly concerning cell sourcing and patient consent, must be carefully navigated. Technical barriers, including cell delivery, survival, and long-term integration, require innovative solutions. Furthermore, safety concerns such as tumor formation and immune rejection necessitate rigorous preclinical and clinical assessments. Regulatory challenges, including the standardization of manufacturing processes and international harmonization, are essential for widespread adoption.

CONCLUSION: Looking ahead, the integration of precision medicine, advanced biomaterials, and patient-specific-induced pluripotent stem cells offers promising approaches to enhance NSC therapeutics. Collaborative efforts between researchers, clinicians, and regulatory agencies are crucial for overcoming existing barriers and translating NSC research into clinical practice, offering new hope for patients with complex neurological conditions.}, } @article {pmid42254864, year = {2026}, author = {Yokoi, S and Iguchi, Y and Katsuno, M}, title = {Human iPSC-derived motor neurons as a platform for elucidating TDP-43-related amyotrophic lateral sclerosis pathogenesis: a mini review.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1864964}, pmid = {42254864}, issn = {1662-5099}, abstract = {TAR DNA-binding protein 43 (TDP-43) is a major pathogenic RNA-binding protein associated with amyotrophic lateral sclerosis (ALS). Heterozygous mutations in TDP-43 cause familial ALS, known as ALS10. TDP-43 is predominantly localized in the nucleus under physiological conditions. Not only ALS patients with TARDBP mutations but also the majority of sporadic ALS patients exhibit TDP-43 pathology, which is defined by nuclear clearance and cytoplasmic aggregation. The inclusion of cryptic exons in genes such as STMN2 and UNC13A has emerged as a hallmark of TDP-43 loss of function, as demonstrated in TDP-43 knockdown models and postmortem analyses. However, it is not yet clear how TDP-43 levels and location change from healthy to pathological conditions in ALS. Motor neurons derived from induced pluripotent stem cells (iPSCs) have been widely used in ALS research and provide a promising platform to investigate early-stage disease mechanisms. However, challenges remain in generating models that faithfully recapitulate ALS pathogenesis. In this review, we summarize recent advances in TDP-43-related iPSC-derived motor neuron models and discuss future perspectives for elucidating ALS pathogenesis. We propose that longitudinal analyses of TDP-43 dynamics and co-culture systems will be essential to better model early ALS pathogenesis.}, } @article {pmid42255926, year = {2026}, author = {}, title = {Correction to: C9orf72 poly(glycine-alanine) knock-in mice exhibit mild rotarod and proteomic changes consistent with amyotrophic lateral sclerosis/frontotemporal dementia.}, journal = {Brain communications}, volume = {8}, number = {3}, pages = {fcag208}, doi = {10.1093/braincomms/fcag208}, pmid = {42255926}, issn = {2632-1297}, abstract = {[This corrects the article DOI: 10.1093/braincomms/fcag087.].}, } @article {pmid42256556, year = {2026}, author = {Xiao, X and Hao, G and Wan, P and Hou, W}, title = {Safety evaluation of Tofersen in amyotrophic lateral sclerosis based on the FAERS database.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1843630}, pmid = {42256556}, issn = {1664-2295}, abstract = {BACKGROUND: This study utilizes data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) to conduct a post-marketing safety evaluation of Tofersen.

METHODS: A systematic search of the FAERS database was performed to identify adverse event (AE) reports from Q1 2023 to Q4 2025 was performed. Multi-dimensional disproportionality analyses were conducted using the ROR, PRR, BCPNN, and MGPS method.

RESULTS: A total of 409 Tofersen-related reports were identified, revealing significant signals across 22 System Organ Class (SOC) categories and 369 Preferred Terms (PTs). At the SOC level, the most prominent safety signals were observed in injury, poisoning and procedural complications, nervous system disorders, and musculoskeletal and connective tissue disorders. In contrast, ear and labyrinth disorders, as well as respiratory, thoracic and mediastinal disorders, were not listed in the current product labeling and may warrant further investigation. At the PT level, neurological procedural complication, CSF red blood cell count positive, CSF white blood cell count increased, and CSF cell count increased exhibited the strongest signals, primarily reflecting cerebrospinal fluid cytological and biochemical abnormalities, as well as procedural-related adverse events such as post-lumbar puncture syndrome, procedural pain, and procedural headache. Although central nervous system-related events (e.g., increased intracranial pressure, peroneal nerve palsy, papilloedema, and facial paralysis) and infectious or inflammatory events (e.g., radiculopathy, myelitis, aspiration pneumonia, and meningitis) were less frequently reported, their relatively high disproportionality signals warrant clinical attention and systematic monitoring. Notably, a newly identified signal of pulmonary embolism suggests a potential thromboembolic risk in specific patient populations.

CONCLUSION: These findings provide real-world evidence to inform the balance between the therapeutic potential and safety profile of Tofersen. Future clinical strategies should focus on mitigating central nervous system-related and procedure-related adverse events. Further mechanistic studies are crucial.}, } @article {pmid42257176, year = {2026}, author = {Villasi, W and Frederic, R and Qureshi, S and Zheng, B and Torrente, MP and Fisher, RMA}, title = {Histone H3 Post-Translational Modification Changes are Linked to Manganese and Copper Exposure in Saccharomyces cerevisiae.}, journal = {microPublication biology}, volume = {2026}, number = {}, pages = {}, pmid = {42257176}, issn = {2578-9430}, abstract = {Prolonged exposures to heavy metals are risk factors for chronic diseases, such as Amyotrophic Lateral Sclerosis and Frontotemporal dementia (ALS/FTD). ALS/FTD comprises a fatal neurodegenerative disease continuum and is linked to disruptions in the levels of histone post-translational modifications (PTMs). Epigenetic mechanisms can connect environmental exposures to disease occurrences. Here, we examine the effects of manganese and copper exposure on the H3 PTM landscape in yeast. Manganese exposure decreases H3K9ac, H3K14ac, and H3S10ph levels. Copper exposure increases H3S10ph and H3K14ac levels and decreases H3K36me3 levels. This provides a basis for linking environmental exposure to biological mechanisms of disease.}, } @article {pmid42257870, year = {2026}, author = {Nguyen, N and Lauinger, AR and Naik, A and Liu, R and Yolcu, Y and Arnold, PM}, title = {Clinical Research for the Use of 7 T Magnetic Resonance Imaging for Spinal Pathologies: a Scoping Review.}, journal = {Clinical neuroradiology}, volume = {}, number = {}, pages = {}, pmid = {42257870}, issn = {1869-1447}, abstract = {PURPOSE: Magnetic resonance imaging (MRI) at 7 T (7T) offers higher signal-to-noise ratio and improved spatial resolution compared to lower magnetic field strengths such as 1.5T and 3T, which may improve lesion detection and anatomical visualization for spinal cord pathology. This review summarizes current techniques and achievements in 7T spinal imaging and outlines associated technical barriers and future directions.

METHODS: A scoping review in accordance with PRISMA extension for scoping reviews guidelines was performed utilizing PubMed, Scopus, and Web of Science. Only studies related to 7T MRI of human subjects were included, after removing unrelated studies and those of non-human subjects.

RESULTS: Twenty-nine studies were included. Current literature supports 7T's superior resolution and signal-to-noise ratio in comparison to 1.5T and 3T MRI. These studies reported improved lesion detection and staging in multiple sclerosis (MS), spinal cord injury (SCI), and amyotrophic lateral sclerosis (ALS); however, the implications of results are limited by small sample sizes, technical heterogeneity, and inconsistent outcome measures. Additionally, the use of 7T spinal imaging remains limited by radiofrequency coil design, susceptibility artifacts, physiological noise, lack of FDA-clearance for spinal indications, and an absence of standardized imaging protocols. Future research aims to address these limitations.

CONCLUSION: Spinal cord imaging at 7T is challenging due to technical constraints and higher susceptibility to artifacts as a result of physiological noise (respiration, swallowing, and bulk movement). However, early studies' results using 7T imaging support improved ability, compared to 3T, to provide enhanced visualization of fine anatomical structures, such as nerve roots, and to improve spinal cord lesion detection.}, } @article {pmid42257902, year = {2026}, author = {Horiuchi, K and Nakamura, S and Ishikawa, K and Nunomura, S and Yamada, K and Inoue, T and Oiwa, K and Fujii, S and Oshima, Y and Kudo, A and Yabe, I}, title = {Early respiratory decline around diagnosis and short-term post-landmark outcomes in amyotrophic lateral sclerosis: a 6-month landmark cohort study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {7}, pages = {}, pmid = {42257902}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications/mortality ; Female ; Male ; Retrospective Studies ; Middle Aged ; Aged ; Cohort Studies ; Prognosis ; Disease Progression ; Vital Capacity ; }, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS), respiratory decisions rely on serial trends rather than a single value. We evaluated whether early respiratory decline around diagnosis provides prognostic information in a real-world landmark framework.

METHODS: This single-center retrospective cohort screened 94 consecutive patients diagnosed between April 2019 and December 2025. A 6-month landmark was used. Early decline was estimated from %FVC values between - 30 and + 180 days around diagnosis. The primary model included age and early %FVC decline; robustness analyses included time-varying Cox, piecewise Cox, RMST, included-vs-excluded comparison, death-only analysis, and slope-quality filtering.

RESULTS: Of 94 screened patients, 62 met baseline eligibility, 56 had calculable early slope, and 45 entered the landmark cohort; 28 post-landmark composite events occurred. In the Cox model, faster early %FVC decline was associated with higher hazard of death or invasive mechanical ventilation via tracheostomy (HR 1.33 per 1%/month faster decline, 95% CI 1.14-1.55, p < 0.001). PH diagnostics suggested non-proportionality (%FVC p = 0.031; NIV p = 0.034 in the expanded model), so this HR was interpreted as an average follow-up association and complemented by PH-robust analyses. The signal was stronger early than late, remained consistent in a death-only analysis, and favored the slower-decline group by RMST at 24 and 36 months.

CONCLUSIONS: In this selected measurement-capable landmark cohort, early respiratory decline provided a clinically meaningful short-to-medium term prognostic signal for post-landmark adverse outcomes. External validation is required before broader generalization beyond measurement-capable landmark populations.}, } @article {pmid42259179, year = {2026}, author = {Nakasako, J and Yaguchi, R and Terayama, A and Kuwahara, M and Nishimoto, Y}, title = {Association of anti-glycolipid IgG with respiratory function decline in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {488}, number = {}, pages = {126039}, doi = {10.1016/j.jns.2026.126039}, pmid = {42259179}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/physiopathology/blood/complications ; Female ; Male ; Retrospective Studies ; *Immunoglobulin G/blood ; Middle Aged ; Aged ; Cohort Studies ; *Glycolipids/immunology ; Kaplan-Meier Estimate ; Immunoglobulin M/blood ; Proportional Hazards Models ; }, abstract = {OBJECTIVE: Effective treatments for amyotrophic lateral sclerosis (ALS) remain limited, underscoring the need to identify robust biomarkers associated with disease severity and prognosis. This study investigated whether immunoglobulin G (IgG) and immunoglobulin M (IgM) anti-glycolipid antibodies are associated with clinical manifestations of ALS, particularly decline in respiratory function.

METHODS: This was a retrospective observational cohort study of the patients with ALS. Among patients with definite or probable limb-onset ALS, 11 patients in the glycolipid IgG-positive group were compared with 15 patients in the IgG-negative group, and 5 patients in the glycolipid IgM-positive group were compared with 9 patients in the IgM-negative group, with adjustment for age. Associations between anti-glycolipid antibody status and respiratory function were assessed using Kaplan-Meier survival analysis and Cox proportional hazards models.

RESULTS: The time to decline of percent forced vital capacity (%FVC) below 80% and 60% was significantly shorter in the IgG-positive group than in the IgG-negative group (p = 0.002 and p = 0.025, respectively). Cox proportional hazards analysis demonstrated that IgG antibody positivity was an independent risk factor for earlier decline in %FVC to 80%.

INTERPRETATION: These findings suggest that anti-glycolipid IgG antibodies may be associated with respiratory function decline in ALS. Larger comprehensive studies will be required to validate these results and to elucidate the underlying pathophysiological mechanisms.}, } @article {pmid42259394, year = {2026}, author = {Zhang, K and Kong, S and Ma, Y and Kan, C and Zheng, T and Sun, X}, title = {Natural monomer compounds in neurodegenerative diseases: Targeting ferroptosis and neuroinflammation.}, journal = {Behavioural brain research}, volume = {513}, number = {}, pages = {116319}, doi = {10.1016/j.bbr.2026.116319}, pmid = {42259394}, issn = {1872-7549}, mesh = {*Ferroptosis/drug effects ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss driven by oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Ferroptosis, an iron-dependent and lipid peroxidation-associated form of regulated cell death, has recently been identified as a key contributor to neuronal vulnerability. Emerging evidence demonstrates that purified natural monomer compounds derived from medicinal plants exert potent neuroprotective effects by targeting ferroptosis and neuroinflammatory pathways. Representative agents such as curcumin, baicalin, resveratrol, and ginsenoside Rg1 activate nuclear factor E2-related factor-2 and glutathione peroxidase 4 signaling to preserve redox balance, while suppressing microglia-mediated inflammation through inhibition of toll-like receptor 4 pathways. This review highlights the interplay between ferroptosis and neuroinflammation in NDDs, summarizes the regulatory effects of bioactive herbal monomer compounds, and discusses recent advances in multi-omics profiling, nano-delivery strategies, and translational research. By modulating the ferroptosis-neuroinflammation axis, these compounds may represent promising therapeutic candidates for NDDs.}, } @article {pmid42260986, year = {2026}, author = {Sun, X and Dong, J and Liang, X and Peng, J and Chen, Y and Yin, R and Tan, T and Bai, L and Lan, K}, title = {PFN1 inhibits lytic replication of Kaposi sarcoma-associated herpesvirus through SQSTM1/p62-mediated selective autophagy targeting the KSHV helicase.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/15548627.2026.2686417}, pmid = {42260986}, issn = {1554-8635}, abstract = {Kaposi sarcoma-associated herpesvirus (KSHV), an oncogenic virus associated with several malignancies, including Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease, harbors a DNA replication helicase encoded by ORF44 that is crucial for viral replication and pathogenesis. In this study, we identified the host PFN1 (profilin 1), a well-known actin-binding factor, as an inhibitor of KSHV lytic replication functioning via the macroautophagy/autophagy-lysosomal degradation pathway targeting ORF44. Mechanistic analyses revealed that PFN1 interacts with ORF44, leading to enhanced polyubiquitination of PFN1. Notably, the E3 ubiquitin ligase TRIM37 (tripartite motif containing 37) facilitates the polyubiquitination of lysine residues at position 116 of PFN1, which serves as a critical recognition motif for the cargo receptor SQSTM1/p62 (sequestosome 1), which is pivotal for the subsequent autophagic degradation of ORF44. Overall, our findings revealed a previously uncharacterized antiviral function of PFN1, highlighting its potential as a novel therapeutic avenue for the treatment of KSHV-associated malignancies.Abbreviations: ALS: amyotrophic lateral sclerosis; Baf A1: bafilomycin A1; co-IP: co-immunoprecipitation; KSHV: Kaposi sarcoma-associated herpes virus; LIR: LC3-interacting region; PFN1: profilin 1; SQSTM1/p62: sequestosome 1; TRIM37: tripartite motif containing 37; UBA: ubiquitin-associated domain.}, } @article {pmid42261056, year = {2026}, author = {Bromberg, MB}, title = {The Flail Limb Syndrome.}, journal = {Muscle & nerve}, volume = {74}, number = {2}, pages = {281-292}, pmid = {42261056}, issn = {1097-4598}, mesh = {Humans ; *Motor Neuron Disease/physiopathology/diagnosis/genetics ; *Muscle, Skeletal/physiopathology ; *Arm/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Syndrome ; *Leg/physiopathology ; }, abstract = {The flail limb syndrome is primarily a lower motor neuron disorder that initially affects proximal arm muscles (flail arm syndrome-FAS) or distal leg muscles (flail leg syndrome-FLS). Both were recognized early on (1886 for FAS and 1918 for FLS) as somewhat distinct from classic amyotrophic lateral sclerosis (ALS). Descriptions in the literature are case series with limited information on electrophysiologic features (central and peripheral), cognitive involvement, and genetic mutations. What follows is a compilation of these features. The flail limb syndromes are rare, representing ~7%-8% of ALS. They have a higher ratio of males to females compared to classic ALS. Both are defined by predominant focal arm or leg weakness for ~2 years before progression to other regions, although there can be early and mild clinical or electrophysiologic evidence for denervation and reinnervation in other regions during the initial period. Ultimately, there is progression to respiratory failure, but at a slower rate compared to classic ALS. Upper motor neuron clinical signs are variable, but transcortical magnetic stimulation paradigms and magnetic resonance imaging tractography support upper motor neuron loss. Tests of the split hand pattern show it is rare compared to ALS. Dementia is also rare. Genetic testing supports a spectrum of ALS-related gene mutations but at a lower frequency than with classic ALS, and no gene mutation is predominant. Diagnosis requires ~2 years of regional stability to predict the better prognosis for the flail limb syndromes.}, } @article {pmid41135633, year = {2025}, author = {Vu, TD and Sung, H}, title = {Endoplasmic reticulum in the axon: Insights into structural dynamics and implications in neurodegeneration.}, journal = {Neurobiology of disease}, volume = {216}, number = {}, pages = {107152}, doi = {10.1016/j.nbd.2025.107152}, pmid = {41135633}, issn = {1095-953X}, support = {//Pusan National University/ ; }, mesh = {Humans ; *Endoplasmic Reticulum/pathology/metabolism ; *Axons/pathology/metabolism ; Animals ; *Neurodegenerative Diseases/pathology/metabolism ; }, abstract = {The endoplasmic reticulum (ER) is an interconnected and highly dynamic organelle essential for multiple cellular functions. In neurons, the ER extends into axons, where it plays a pivotal role in maintaining neuronal polarity. The unique structural and dynamic adaptations of the axonal ER enable it to meet the specialized demands of neurons, ranging from compartmentalized physiological regulation to long-distance intracellular communication. Recent studies have shown that axonal ER supports the regulation of organelle remodeling and trafficking in a spatiotemporal manner, processes that become compromised in aged neurons. Moreover, disruptions in the structure and dynamics of the axonal ER have increasingly become associated with neurodegenerative diseases, including hereditary spastic paraplegia, amyotrophic lateral sclerosis, and peripheral neuropathies. This review synthesizes current knowledge of axonal ER biology, highlighting its structural and dynamic characteristics, its impact on organelle arrangement and distribution, and its pathological implications in neurodegeneration. By consolidating recent advances, this review outlines emerging questions and future directions in axonal ER research, a field gaining recognition for its contribution to neuronal dysfunction and neurodegenerative pathomechanisms.}, } @article {pmid41135683, year = {2025}, author = {Yeo, KH and Kong, JH and Ng, QH and Yoon, MJ and Agatha, O and Chae, E and Lee, HO and Je, HS and Choe, YJ}, title = {J-domain proteins cooperate with Hsp70 to drive multiphase separation of RNA-binding-deficient TDP-43.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {12}, pages = {110854}, pmid = {41135683}, issn = {1083-351X}, mesh = {*HSP70 Heat-Shock Proteins/metabolism/genetics ; *Saccharomyces cerevisiae Proteins/metabolism/genetics/chemistry ; *Saccharomyces cerevisiae/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; *HSP40 Heat-Shock Proteins/metabolism/genetics ; Protein Domains ; *RNA-Binding Proteins/metabolism/genetics ; Molecular Chaperones/metabolism/genetics ; }, abstract = {RNA-free TDP-43, resulting from mutations or post-translational modifications in its RNA-binding domain, forms multiphase condensates with Hsp70 chaperones enriched in the core. The presence of this structure in the nucleus is thought to be associated with disease states. However, the mechanisms underlying its formation remain poorly understood. In particular, it is unclear whether J-domain proteins (JDPs), critical co-chaperones of Hsp70, are incorporated into multiphase condensates, and if so, how they contribute to the phase separation process. Using yeast as a model organism with a relatively small JDP family, we identified Sis1, but not Ydj1, as an important factor in TDP-43 multiphase separation. RNA-binding-deficient TDP-43 initially forms uniform condensates enriched with the JDP Sis1 but not with Hsp70. Subsequent recruitment of Hsp70 transforms these uniform structures into multiphase condensates, with both Sis1 and Hsp70 enriched in the core. This transition requires a functional J-domain, which stimulates Hsp70 ATPase activity. These findings reveal a key role for JDPs in TDP-43 multiphase separation and highlight JDP specificity in this process.}, } @article {pmid41135686, year = {2026}, author = {Columbro, SF and Tortarolo, M and Re Cecconi, AD and Piccirillo, R and Bendotti, C and Biasini, E and Pasetto, L and Bonetto, V}, title = {Beneficial effects of synthetic torpor in a fast-progressing mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {396}, number = {}, pages = {115521}, doi = {10.1016/j.expneurol.2025.115521}, pmid = {41135686}, issn = {1090-2430}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/pathology/genetics/metabolism ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Torpor/physiology ; Disease Progression ; Superoxide Dismutase-1/genetics ; Motor Neurons/pathology/metabolism ; Male ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss, muscle atrophy, and progressive paralysis. Currently approved treatments provide only limited benefits. Due to the complex and multifactorial nature of ALS pathology, therapies targeting multiple pathways may prove more effective. Synthetic torpor, a state that mimics natural hibernation, has shown promise in promoting neuroprotection by modulating metabolism, reducing inflammation, and preserving both neurons and muscles. In this study, synthetic torpor was induced using 5'AMP combined with environmental cooling in the fast-progressing SOD1[G93A] ALS mouse model on the 129SvHsd genetic background, known for its aggressive disease course, early metabolic dysfunction and unresponsiveness to treatments. Synthetic torpor was highly effective in preserving motor neurons. The treatment significantly delayed disease onset and extended survival, although mildly, without altering overall disease duration. In the spinal cord, synthetic torpor increased glucose transporters, reduced markers of oxidative stress, decreased glial activation and sustained upregulation of neuroprotective proteins, such as RBM3 and PPIA. This occurred despite an increased SOD1 aggregation in a later phase of the disease. Muscles display clear protective effects across disease progression with preservation of mass, reduced atrogin-1, lower PDK4 and oxidative stress markers, associated with improvements in markers of axonal integrity and muscle denervation. This study provides proof-of-concept that activating multiple protective molecular pathways, particularly those involved in glucose metabolism and protein folding, can mitigate the pathological processes in ALS, especially in rapidly progressing forms of the disease.}, } @article {pmid41135742, year = {2025}, author = {Hu, T and Xi, J and Xie, N and Zhang, X and Huang, N and Cheng, Y}, title = {Multi-omics analysis reveals the protective role of transcriptional enhancer factor and the pathogenic mechanism of monocytes in Parkinson's disease.}, journal = {Brain research bulletin}, volume = {232}, number = {}, pages = {111594}, doi = {10.1016/j.brainresbull.2025.111594}, pmid = {41135742}, issn = {1873-2747}, mesh = {Animals ; *Parkinson Disease/genetics/metabolism ; Humans ; *Monocytes/metabolism/pathology ; Mice ; Mendelian Randomization Analysis ; *Transcription Factors/metabolism/genetics ; Male ; Mice, Inbred C57BL ; Cell Line, Tumor ; Multiomics ; }, abstract = {Parkinson's disease (PD) is a multifactorial neurodegenerative disorder whose pathogenic mechanisms remain incompletely elucidated. This study aimed to systematically identify key regulatory factors involved in PD at the genetic, cellular, and molecular levels. Using univariate Mendelian randomization (UVMR), we identified plasma proteins and genes associated with Alzheimer's disease (AD), PD, and amyotrophic lateral sclerosis (ALS), and validated their causal relationships through colocalization analysis. Cross-validation across multi-omics datasets revealed transcriptional enhancer factor (TEF) as a protective factor for PD, whereas increased counts of CD14[+]CD16[+] monocytes were identified as a risk factor. Single-cell analysis and multivariate Mendelian randomization (MVMR) further suggested potential mediating roles of these factors in PD pathogenesis. In vitro experiments demonstrated that TEF overexpression significantly enhanced the resistance of neuroblastoma cells to rotenone-induced damage, inhibited apoptosis, and preserved tyrosine hydroxylase (TH) expression. In vivo, TEF notably improved motor coordination and exploratory behavior in PD mouse models. Collectively, these findings suggest that TEF may exert neuroprotective effects by modulating immune and neuronal pathways, offering a novel therapeutic target for the prevention and treatment of Parkinson's disease.}, } @article {pmid41135993, year = {2025}, author = {Pahlevan, A and Khodadadi Karimvand, S and Abdollahi, H}, title = {Matrix effect assessment via matrix matching strategy using multivariate curve resolution methods.}, journal = {Analytica chimica acta}, volume = {1378}, number = {}, pages = {344692}, doi = {10.1016/j.aca.2025.344692}, pmid = {41135993}, issn = {1873-4324}, abstract = {BACKGROUND: Multivariate calibration models in analytical chemistry often suffer from matrix effects due to variations in sample composition and instrumental conditions. These effects present a major challenge, often resulting in inaccurate predictions due to spectral differences and concentration mismatches between unknown samples and calibration datasets. Existing strategies, such as standard addition and local modeling, are limited in addressing both aspects simultaneously. There is a critical need for a systematic approach that enhances calibration model robustness by ensuring spectral similarity and concentration alignment, thereby improving prediction accuracy across diverse sample matrices.

RESULTS: We developed a matrix-matching procedure using Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to enhance the accuracy and robustness of multivariate calibration models. Spectral matching is assessed via net analyte signal (NAS) projections and Euclidean distance, isolating analyte and non-analyte contributions. Additionally, concentration matching is performed by evaluating the alignment of predicted concentration ranges between unknown samples and calibration sets, ensuring consistency across varying sample compositions. The method was rigorously validated using both simulated datasets and real-world analytical data, including near-infrared (NIR) spectra of corn and nuclear magnetic resonance (NMR) spectra of alcohol mixtures. In all tested scenarios, the matrix-matching procedure successfully identified optimal calibration subsets that minimized matrix effects. This approach led to substantially improved prediction performance by effectively reducing errors caused by spectral shifts, intensity fluctuations, and concentration mismatches, outperforming conventional calibration strategies in diverse and complex matrices.

SIGNIFICANCE: This MCR-ALS-based matrix-matching framework enhances multivariate calibration by systematically selecting calibration sets that match spectrally and in concentration with unknown samples. By minimizing matrix-induced errors, it ensures robust and accurate predictions. Its versatility across analytical platforms and ability to handle diverse matrix effects make it a valuable tool for analytical chemistry, with potential for broad application in real-world analytical challenges.}, } @article {pmid41136086, year = {2025}, author = {Tran, K and Lussier, BL}, title = {Noninvasive Ventilation in Amyotrophic Lateral Sclerosis.}, journal = {Sleep medicine clinics}, volume = {20}, number = {4}, pages = {547-555}, doi = {10.1016/j.jsmc.2025.07.007}, pmid = {41136086}, issn = {1556-4088}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/complications ; Humans ; *Noninvasive Ventilation/methods ; *Respiratory Insufficiency/therapy/etiology ; }, abstract = {This article explores the role of early noninvasive ventilation in improving the quality of life and survival rates in patients with amyotrophic lateral sclerosis (ALS). It discusses how the goals of ventilatory support may vary depending on whether hospitalization is elective or emergent. The article emphasizes the importance of protocol-based optimization of nocturnal noninvasive positive pressure ventilation, focusing on patient tolerance and neuromuscular considerations. Additionally, it highlights the different approaches required for nocturnal and daytime ventilatory support, underscoring the need for tailored management strategies in ALS care.}, } @article {pmid41136425, year = {2025}, author = {Vokali, E and Chevalier, E and Dreyfus, N and Charmey, D and Melly, T and Kocher, J and Ratnam, M and Serra, AM and Jaquier, T and Delgado, C and Ravache, M and Scialò, C and Cappelli, S and Kroth, H and Capotosti, F and Luthi-Carter, R and Afroz, T and Derouazi, M and Constantinescu, CC and Seelaar, H and Buratti, E and Nelson, PT and Polymenidou, M and Pfeifer, A and Kosco-Vilbois, M and Seredenina, T}, title = {Development of [[18]F]ACI-19626 as a first-in-class brain PET tracer for imaging TDP-43 pathology.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {9358}, pmid = {41136425}, issn = {2041-1723}, support = {P01 AG019724/AG/NIA NIH HHS/United States ; P30 AG028383/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; }, mesh = {*Positron-Emission Tomography/methods ; *Brain/diagnostic imaging/metabolism/pathology ; Humans ; *DNA-Binding Proteins/metabolism ; Animals ; *Radiopharmaceuticals/pharmacokinetics/chemistry ; Fluorine Radioisotopes ; *TDP-43 Proteinopathies/diagnostic imaging/metabolism/pathology ; Mice ; Male ; Frontotemporal Dementia/diagnostic imaging/metabolism/pathology ; Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/pathology ; Female ; }, abstract = {Aggregated TDP-43 is a hallmark of frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and limbic-predominant age-related TDP-43 encephalopathy (LATE), and a common co-pathology in other neurodegenerative diseases. Currently, no specific biomarkers exist to assess TDP-43 pathology in vivo. We developed two small-molecule radiopharmaceuticals, [[18]F]ACI-19278 and [[18]F]ACI-19626, for visualizing TDP-43 inclusions by positron emission tomography (PET). Both ligands bind with high affinity to aggregated, but not soluble, TDP-43 in patient brain samples from diverse TDP-43 proteinopathies, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), ALS, and LATE, and in cell models. Both compounds display excellent selectivity for TDP-43 over Aβ, Tau, and α-synuclein aggregates. In non-human primates, [[18]F]ACI-19278 and [[18]F]ACI-19626 show a pharmacokinetic profile suitable for brain PET imaging (rapid brain uptake; fast and complete washout). ACI-19278 and ACI-19626 are promising first-in-class TDP-43 PET tracers with the potential to revolutionize the diagnosis and treatment of neurodegenerative proteinopathies, enabling a precision medicine approach.}, } @article {pmid41137727, year = {2026}, author = {Reza, S and Handique, J and Sharma, P and Mathew, S and Bari, S and Tyagi, N and Sharma, C and Panda, S and Chowdhury, D and Laskar, S and Shaji, CV and Joshi, D and Kp, D and Cherian, A and Desai, S and Gourie Devi, M and Srivastava, AK and Faruq, M}, title = {Deciphering ALS-linked genetic variants in indian patients using targeted and exome sequencing approaches.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {163-174}, doi = {10.1080/21678421.2025.2574681}, pmid = {41137727}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; India/epidemiology ; Male ; Female ; Middle Aged ; *Exome Sequencing/methods ; Adult ; *Mutation/genetics ; Aged ; *Genetic Variation/genetics ; *Genetic Predisposition to Disease/genetics ; Superoxide Dismutase-1/genetics ; Cohort Studies ; Genetic Testing ; Transcription Factor TFIIIA/genetics ; Cell Cycle Proteins ; DNA-Binding Proteins/genetics ; Membrane Transport Proteins ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with marked clinical and genetic heterogeneity. Data from India remain scarce, although unique survival patterns and regional genetic variation have been suggested. Objective: To define the genetic spectrum of ALS in an Indian cohort and assess the contribution of known and novel variants. Methods: We recruited 238 patients with clinically confirmed ALS from across India, all negative for C9orf72 repeat expansions. Genetic testing included targeted panels, whole exome sequencing, and screening of ALS-associated gene curated panels. Variants were prioritized using allele frequency thresholds, in silico prediction, and ACMG criteria. Results: Pathogenic or likely pathogenic variants were identified in 13 patients (6.8%). SOD1 mutations were the most frequent, followed by TARDBP, OPTN, and NEK1. Variants of uncertain significance were more common, with recurrent SQSTM1 changes suggesting a potential modifier role. Additional rare or novel variants were detected in genes including SETX, ALS2, DISC1, CNTN4, and MATR3. Conclusion: This is among the largest genetic studies of ALS in India. The predominance of SOD1 mutations underscores population-specific differences and highlights the clinical importance of early genetic testing, particularly as gene-targeted therapies become available. The recurrent identification of SQSTM1 variants suggests modifier effects that require functional validation. These findings expand the genetic landscape of ALS in an underrepresented population and provide a foundation for precision medicine approaches in India.}, } @article {pmid41137739, year = {2026}, author = {van Wijk, IF and Kraneburg, L and van Eijk, RPA and Veldink, JH and van Es, MA and Westeneng, HJ and van den Berg, LH}, title = {Prodromal symptoms in amyotrophic lateral sclerosis from the perspective of the patient and of the caregiver.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {263-273}, doi = {10.1080/21678421.2025.2574687}, pmid = {41137739}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology/physiopathology ; Male ; Female ; *Caregivers/psychology ; Middle Aged ; *Prodromal Symptoms ; Aged ; Adult ; Surveys and Questionnaires ; Registries ; }, abstract = {OBJECTIVE: Clinically manifest ALS is preceded by a prodromal phase in gene mutation carriers, characterized by mild motor impairment. A well-defined prodromal phase could enable earlier diagnosis and treatment. We investigated the presence of a prodromal phase in sporadic ALS, from the perspective of patients and caregivers.

METHODS: A survey was conducted of symptom onset in 279 ALS patients from a population-based registry and 150 caregivers. 244 patients and 123 caregivers were included in the primary qualitative analysis, followed by quantitative analysis of identified themes. A prodromal phase was defined as symptoms, in response to open-ended questions, before onset of recorded weakness, bulbar complaints or shortness of breath. Mild motor symptoms were defined as fasciculations, cramps, stiffness, atrophy, reduced sports performance, or mobility issues.

RESULTS: 26.6% of patients and 17.5% of caregivers reported a prodromal phase, primarily with mild motor symptoms (patients 23.0%; caregivers 11.4%). Prodromal symptoms occurred a median of 6.0 months (IQR 2.8-11.8 months) before recorded disease onset. In closed-ended questions, 19.2% of patients and 22.2% of caregivers reported cognitive or behavioral symptoms before weakness onset, compared to only 0.6% and 1.8% in open-ended questions.

CONCLUSIONS: In sporadic ALS, approximately a quarter of patients report a prodromal phase characterized primarily by mild motor symptoms. However, mild motor symptoms alone are unlikely to contribute to earlier disease recognition. Cognitive or behavioral symptoms are often not recognized as part of the clinical spectrum. These findings emphasize the need for reliable biomarkers to detect ALS pathology at an early stage.}, } @article {pmid41140053, year = {2025}, author = {Obara, K and Ito, D and Nilsson, C and Janelidze, S and Santillo, A and Katsuno, M and Mattsson-Carlgren, N}, title = {Diagnostic and Prognostic Value of Blood and Cerebrospinal Fluid Biomarkers in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {European journal of neurology}, volume = {32}, number = {10}, pages = {e70382}, pmid = {41140053}, issn = {1468-1331}, support = {//Elsa Schmitz stiftelse för neurologisk och neurokirurgisk forskning/ ; JPMJSP2125//Japan Science and Technology Agency (JST) SPRING/ ; //Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood/diagnosis ; Biomarkers/cerebrospinal fluid/blood ; Prognosis ; Neurofilament Proteins/cerebrospinal fluid/blood ; }, abstract = {BACKGROUND: Reliable biomarkers for amyotrophic lateral sclerosis (ALS) are urgently needed due to diagnostic and prognostic challenges. This systematic review and meta-analysis aimed to synthesize recent evidence on the utility of blood and cerebrospinal fluid (CSF) biomarkers for ALS.

METHODS: We systematically reviewed studies published from January 1, 2019 to March 25, 2025, that evaluated blood or CSF biomarkers for ALS. Eligible studies reported diagnostic performance, group-level biomarker values, hazard ratios (HRs) for survival, or correlations with functional rating scales or disease progression rates. Study quality was assessed using the QUADAS-2 and QUIPS frameworks. Random-effects models were employed to pool summary receiver operating characteristic (SROC) curves, HRs, standardized mean differences, and correlation coefficients.

RESULTS: We included 47 studies in the SROC analysis and 27 in the HR analysis, covering 9078 participants (5556 ALS and 3522 controls). Neurofilament light chain (NfL) consistently demonstrated the highest diagnostic accuracy (sensitivity/specificity: 0.81-0.87 vs. ALS mimics) and high prognostic value (pooled HRs: 2.8-4.3) in both blood and CSF. CSF chitinases and the p-tau/t-tau ratio showed moderate utility. Other biomarkers, including interleukins, had limited clinical relevance. Most studies showed moderate to high risk of bias, with methodological heterogeneity and limited transparency.

CONCLUSIONS: NfL is the most validated biomarker for ALS diagnosis and prognosis, in both blood and CSF. However, its limited accuracy when used alone carries a considerable risk of misclassification. Future studies should adopt prevalence-specific strategies and integrate biomarkers within multimodal frameworks to enhance diagnostic and prognostic precision.}, } @article {pmid41140080, year = {2025}, author = {Singh, M and Kaur, M and Dogra, G and Awasthi, V and Dua, A}, title = {A Case of Prolonged SARS-CoV-2 Shedding and HIV Co-infection: Clinical and Diagnostic Challenges.}, journal = {Infectious disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715265388132251014105118}, pmid = {41140080}, issn = {2212-3989}, abstract = {BACKGROUND: Co-infection of SARS-CoV-2 and HIV presents unique challenges for patients, including potential barriers to accessing care and social support. In the present case report, an unexpected revelation of HIV status was made in an asymptomatic individual who was concurrently infected with SARS-CoV-2. There is insufficient information on asymptomatic but SARS-CoV-2-positive carriers, who have been identified only because of contact tracing and surveillance. Asymptomatic individuals co-infected with SARS-CoV-2 and HIV pose a significant challenge, not only for the patients and their families, but also for the broader community, highlighting the need for enhanced awareness, testing, and contact tracing strategies.

CASE PRESENTATION: This study reports a case of a routine surveillance-based asymptomatic patient who was consistently SARS-CoV-2 positive from June to August 2021 by real-time PCR. Clinical investigations revealed that all vital parameters and laboratory tests were within normal limits, except for a notable elevation in D-dimer levels. The patient was vaccinated with two doses of Covishield, with the second dose administered during the quarantine period. The patient was followed up after six months, and we came to know that the patient's condition deteriorated in the month of November 2021, and he was tested HIV positive during his admission to a tertiary care hospital. Later on, he died in March 2022.

CONCLUSION: To our knowledge, this is the first study reporting accidental finding of HIV in a SARS-CoV-2 asymptomatic patient who was previously false negative. The persis-tence of SARS-CoV-2 in this case highlights the importance of comprehensive diagnostic workups and careful clinical management in patients with co-infections. This report also highlights the high risk of silent transmission of SARS-CoV-2 by asymptomatic individu-als, emphasizing the need to include such cases in dynamic surveillance strategies to pre-vent further spread. Along with this, the study highlights the need for further investigation into the interplay between HIV co-infection, COVID-19 vaccination outcomes, and the dynamics of SARS-CoV-2 shedding.}, } @article {pmid41141079, year = {2025}, author = {Jeong, E and Li, D}, title = {Antisense Oligonucleotide Therapy for Amyotrophic Lateral Sclerosis (ALS): An Umbrella Review.}, journal = {Cureus}, volume = {17}, number = {9}, pages = {e93140}, pmid = {41141079}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease, is a fatal neurodegenerative disease prominent in the elderly population. To this point, no completely effective treatments have been procured; however, antisense oligonucleotide therapies, or ASOs, are a promising venue. In order to investigate the efficacy of ASOs in the treatment of ALS by targeting specific genetic mutations, we conducted an umbrella review utilizing keywords such as "ALS" and "ASO" in the PubMed database, excluding sources published more than 10 years ago for relevance. Results revealed that of multiple tentative ASO treatments, for multiple specific gene mutations, only one, Tofersen, was approved for the wider population. The main cause of failure was an inability to meet efficacy endpoints, resulting in the discontinuation of the product. Tofersen is able to treat mutations in the SOD1 gene, but not any others. While initially discouraging, the production of ASOs is a relatively new and advanced process, and slow progress is expected. However, there remains the problem of identifying and treating the much more prevalent sporadic ALS, which is much more common compared to familial ALS.}, } @article {pmid41141812, year = {2025}, author = {Cobos, SN and Fisher, RMA and Bennett, SA and Janani, C and Dansu, DK and Cleere, MM and Yeasmin, A and Cruz, G and Qureshi, S and Villasi, W and Frederic, R and Chen, K and Mirzakandova, M and Angelakakis, G and Son, E and Elgendy, A and Torrente, MP}, title = {C9orf72 Dipeptide Repeat Proteinopathy Is Linked to Increased Histone H3 Phosphorylation on Serine 10.}, journal = {ACS omega}, volume = {10}, number = {41}, pages = {48395-48411}, pmid = {41141812}, issn = {2470-1343}, support = {K12 GM102778/GM/NIGMS NIH HHS/United States ; R15 NS125394/NS/NINDS NIH HHS/United States ; T34 GM149490/GM/NIGMS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal illnesses forming a neurodegenerative disease continuum. While most ALS/FTD cases are sporadic, a small proportion of cases are linked to mutations in many genes. Among these, hexanucleotide repeat expansions in the C9orf72 gene are the most common and lead to the formation of dipeptide repeat proteins (DPRs), including a proline-arginine dipeptide (PR), which aggregate in the cytoplasm of decaying neurons. As genetics alone fails to explain the etiology of ALS/FTD, it is possible that epigenetic mechanisms - such as histone post-translational modifications (PTMs) - are involved in disease processes. A Saccharomyces cerevisiae (PR)50 overexpression model displays overt growth suppression and aggregation. Here, we exploit this model as a discovery platform to comprehensively characterize changes in the levels of PTMs on Histones H3 and H4. We find that overexpression of (PR)50 is associated with increased levels of phosphorylation on Histone H3 at Serine 10 (H3S10ph). Furthermore, (PR)50 overexpression revealed modest increases in the levels of other marks associated with increased gene expression. Remarkably, decreased abundance of Ipl1, the kinase responsible for phosphorylating H3S10 in yeast, leads to amelioration of the growth suppression phenotype and restores H3S10ph levels even in the context of (PR)50 overexpression. Recapitulating our results in yeast, several c9orf72 ALS patient-derived fibroblasts and induced pluripotent stem cell (iPSCs) lines display similar increases in H3S10ph levels. Altogether, these findings reveal a previously undiscovered connection between H3S10ph and c9 ALS/FTD proteinopathy that could reveal novel targets for the treatment of this disease.}, } @article {pmid41143669, year = {2025}, author = {Morley, M and Aurora, M and Gustafson, K and Seals, CS and Feuer, A and Datar, S and Parvanta, S and Thakur, N and Dave, KD}, title = {Medicare expenditures in the first year of amyotrophic lateral sclerosis diagnosis.}, journal = {The American journal of managed care}, volume = {31}, number = {10}, pages = {e308-e312}, doi = {10.37765/ajmc.2025.89813}, pmid = {41143669}, issn = {1936-2692}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/economics/therapy ; *Health Expenditures/statistics & numerical data ; *Medicare/economics/statistics & numerical data ; *Fee-for-Service Plans/economics/statistics & numerical data ; Edaravone/economics/therapeutic use ; Riluzole/economics/therapeutic use ; Neuroprotective Agents/economics/therapeutic use ; Drug Costs/statistics & numerical data ; Administrative Claims, Healthcare/economics/statistics & numerical data ; Financial Stress/epidemiology ; Cost of Illness ; Retrospective Studies ; Hospitalization/economics/statistics & numerical data ; Humans ; Male ; Female ; Aged ; }, abstract = {OBJECTIVES: To determine Medicare expenditures and potential beneficiary out-of-pocket liability for Medicare beneficiaries with amyotrophic lateral sclerosis (ALS), including costs related to drug treatments.

STUDY DESIGN: This cohort study utilized the 100% Medicare fee-for-service claims for 2017-2021, including Part A and Part B medical claims and Part D prescription drug event data.

METHODS: Eligible Medicare beneficiaries with ALS were identified based on 1 or more inpatient or 2 or more outpatient claims with an International Statistical Classification of Diseases, Tenth Revision diagnosis code for ALS (G12.21) between 2017 and 2020. Health care expenditures and beneficiary liability were assessed for the 12-month study period.

RESULTS: At 1 year post index, Medicare beneficiaries with ALS had more than 3 times the Medicare expenditures of beneficiaries without ALS ($47,450 vs $13,889, respectively). Similar patterns were observed for beneficiary liability. Approximately one-third of Medicare beneficiaries used either edaravone or riluzole in the first 12 months following ALS diagnosis. The cost of care for beneficiaries using these drugs was notably higher than for beneficiaries with ALS overall.

CONCLUSIONS: Approximately one-third of people with ALS on Medicare receive disease-modifying medication. ALS is a burdensome disease with significant financial implications for people with ALS and the Medicare program. Treatment for ALS presents affordability challenges, and policy makers must consider how current Medicare policy addresses the costs of care.}, } @article {pmid41144002, year = {2025}, author = {Vidovic, M and Lapp, HS and Dittes, I and Leuchten, N and Aringer, M and Günther, C and Günther, R}, title = {Methotrexate therapy as a promising long-term treatment approach for immune-mediated adverse reactions of tofersen in SOD1-ALS: a case report.}, journal = {Journal of neurology}, volume = {272}, number = {11}, pages = {732}, pmid = {41144002}, issn = {1432-1459}, } @article {pmid41144030, year = {2025}, author = {Yang, D and Lei, X and Yang, L and He, D}, title = {A novel frameshift mutation in the NEK1 gene causing amyotrophic lateral sclerosis: A case report and literature review.}, journal = {Neurogenetics}, volume = {26}, number = {1}, pages = {75}, pmid = {41144030}, issn = {1364-6753}, mesh = {Humans ; *NIMA-Related Kinase 1/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; *Frameshift Mutation ; Male ; Aged ; Female ; Middle Aged ; }, abstract = {To investigate a novel NIMA Related Kinase 1 (NEK1) frameshift mutation in amyotrophic lateral sclerosis (ALS), assess its pathogenicity using computational algorithms and genetic databases, and analyze the clinical manifestations of cases carrying the NEK1 genetic mutation. A 65-year-old man with sporadic ALS (sALS) carrying a NEK1 c.2413dup (p.Thr805Asnfs*7) mutation was studied. Clinical and genetic data were evaluated using Mutation Taster and ACMG guidelines. A literature review was conducted in PubMed and CNKI to identify ALS cases with NEK1 mutations. Whole-exome sequencing identified a NEK1 mutation, c.2413dup (p.Thr805Asnfs*7),which is predicted to lead to a truncated protein. A literature review found 19 articles covering 89 mutation sites. Among the recorded cases, sex was reported for 79 cases (47 male,32 female), and age of onset was available for 80 cases, with an average of 56.94 ± 11.88 years. Onset type data were available for 77 cases, of which 49.35% (38/77) had lower motor neuron onset,41.56% (32/77) had upper motor neuron onset, and 9.09% (7/77) had both. Among those with lower motor neuron onset (n = 38),28.95% (11/38) had bulbar onset, and 2.63% (1/38) had respiratory onset. The c.2413dup (p.Thr805Asnfs*7) frameshift mutation in the NEK1 gene is likely pathogenic and may contribute to the onset of ALS. ALS associated with NEK1 mutations appears to be more common in men than women and typically affects individuals in late middle age.}, } @article {pmid41145462, year = {2025}, author = {Gandelman, M and Paul, S and Figueroa, KP and Sundrud, J and Dansithong, W and Scoles, DR and Pulst, SM}, title = {Targeting STAU1 prevents p53 apoptotic signaling in neurodegeneration.}, journal = {Cell death & disease}, volume = {16}, number = {1}, pages = {761}, pmid = {41145462}, issn = {2041-4889}, support = {R01 NS137233/NS/NINDS NIH HHS/United States ; R35 NS127253/NS/NINDS NIH HHS/United States ; }, mesh = {*Tumor Suppressor Protein p53/metabolism/genetics ; Humans ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; *Apoptosis/drug effects/genetics ; Signal Transduction/drug effects ; Mice ; *Cytoskeletal Proteins/metabolism/genetics ; Neurons/metabolism/pathology/drug effects ; Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; DNA Damage ; Induced Pluripotent Stem Cells/metabolism ; Frontotemporal Dementia/pathology/metabolism/genetics ; }, abstract = {Stress responses and neuronal death mediated by the p53 pathway play a central role in the progression of neurodegenerative disease, constituting a common target to extend neuronal function and survival. Interaction of p53 and its signaling network with RNA-binding proteins (RBPs) helps fine-tune its activation and the resulting cell fates. Preclinical therapeutics based on depletion of the RBP STAUFEN-1 (STAU1) protein successfully prevent neurodegeneration, however, the specific mechanisms are not fully understood. STAU1 is pathologically overabundant in multiple neurological disorders and contributes to neurodegeneration by exacerbating autophagy dysfunction, endoplasmic reticulum stress, and RNA-protein condensate accumulation. We previously showed that lowering STAU1 levels mitigates these disease-related features and prevents neuronal death in animal models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) and spinocerebellar ataxia type 2 (SCA2). Here, we show by combined transcriptomic and functional analyses that STAU1 reduction results in the inhibition of apoptosis through the p53 pathway. In both proliferating and post-mitotic cell types-human iPSC-derived neurons, mouse cortical neurons, SH-SY5Y cells, and fibroblasts-STAU1 reduction effectively prevented p53-mediated apoptosis and DNA damage induced by Nutlin-3 and etoposide. Further examination in C9orf72-expanded patient-derived fibroblasts and a C9orf72 mouse model of ALS/FTD, which exhibit baseline overabundance of STAU1 and activation of the p53 pathway, confirmed that STAU1 reduction also prevented p53-driven pro-apoptotic signaling. These findings establish STAU1 as a novel modulator of DNA damage and p53-dependent apoptosis, suggesting that targeting STAU1 could be a promising approach to prevent neurodegeneration in ALS/FTD.}, } @article {pmid41145518, year = {2025}, author = {Asakawa, K and Tomita, T and Shioya, S and Handa, H and Saeki, Y and Kawakami, K}, title = {Intrinsically accelerated cellular degradation is amplified by TDP-43 loss in ALS-vulnerable motor neurons in a zebrafish model.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {9213}, pmid = {41145518}, issn = {2041-1723}, mesh = {Animals ; Zebrafish ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Disease Models, Animal ; *Zebrafish Proteins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Spinal Cord/metabolism/pathology ; Autophagy ; Humans ; Proteasome Endopeptidase Complex/metabolism ; Unfolded Protein Response ; Proteolysis ; }, abstract = {Selective neuronal vulnerability is a defining feature of neurodegenerative disorders, exemplified by motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The nature of motor neurons underlying this selectivity remains unresolved. Here, by monitoring autophagy at single-cell resolution across the translucent zebrafish spinal cord, we identify motor neurons as the cell population with the highest autophagic flux. Large spinal motor neurons (SMNs), most susceptible to ALS, exhibit higher flux compared to smaller SMNs and ALS-resistant ocular motor neurons. Notably, large SMNs accelerates both autophagy and proteasome-mediated degradation, which are further augmented by TDP-43 loss. Additionally, acceleration of multiple unfolded protein response pathways indicates their innate tendency to accumulate misfolded proteins. Enhanced cellular degradation in large SMNs is neuroprotective as its inhibition halts axon outgrowth. These findings propose that cell size-associated degradation load underlies selective neuronal vulnerability in ALS, highlighting the alleviation of catabolic stress as a target of therapy and prevention.}, } @article {pmid41147458, year = {2025}, author = {}, title = {Correction to "TSPO Expression and [18F]DPA-714 PET/CT Imaging as Pathogenetic and Diagnostic Biomarkers in Symptomatic Stages of Skeletal Muscle Fiber Degeneration in SOD1-G93A ALS Mice".}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {39}, number = {21}, pages = {e71204}, pmid = {41147458}, issn = {1530-6860}, } @article {pmid41147470, year = {2025}, author = {van Alphen, CMJ}, title = {[Diagnostiek als startpunt voor groei en herstel].}, journal = {Tijdschrift voor psychiatrie}, volume = {67}, number = {8}, pages = {430}, pmid = {41147470}, issn = {0303-7339}, } @article {pmid41148120, year = {2025}, author = {Chan, TK and Wei, X and Ma, L and Wang, H and Liao, P and Matsuda, Y}, title = {Resistance Gene-Guided Discovery of a Fungal Spirotetramate as an Acetolactate Synthase Inhibitor.}, journal = {Journal of the American Chemical Society}, volume = {147}, number = {45}, pages = {42100-42109}, pmid = {41148120}, issn = {1520-5126}, mesh = {*Acetolactate Synthase/antagonists & inhibitors/metabolism/genetics ; *Spiro Compounds/pharmacology/chemistry ; *Enzyme Inhibitors/pharmacology/chemistry ; Multigene Family ; *Antifungal Agents/pharmacology/chemistry ; *Drug Discovery ; }, abstract = {Biosynthetic gene clusters (BGCs) of bioactive natural products occasionally encode resistant versions of the proteins they inhibit, offering opportunities for resistance gene-guided genome mining to uncover natural products with predictable modes of action. In this study, we developed a genome mining tool designed to identify fungal BGCs harboring putative resistance genes. Applying this tool to approximately 2500 fungal genomes, we identified a BGC designated as the pts cluster, which encodes an acetolactate synthase (ALS) homologue. Functional characterization of the pts cluster resulted in the identification of pterrespiramide A (1), featuring unique spirotetramate and cis-decalin moieties. Consistent with the predicted activity, 1 was confirmed as an ALS inhibitor and exhibited both antifungal and herbicidal activities. This study illuminates the potential of resistance gene-guided genome mining as a powerful strategy for accelerating the discovery of previously undescribed bioactive natural products.}, } @article {pmid41148458, year = {2025}, author = {Goel, F and Kumar, D and Singh, P and Rai, SN and Yadav, DK}, title = {Molecular crosstalk between miRNAs and lncRNAs in neurodegenerative disease pathways.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {16}, pmid = {41148458}, issn = {1573-4978}, mesh = {Humans ; Animals ; *MicroRNAs/genetics/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/therapy ; Signal Transduction ; Gene Regulatory Networks ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal degeneration and dysfunction. Of recent interest, a series of studies have been targeting the role of non-coding RNAs, particularly miRNAs and lncRNAs, in regulating gene expression and influencing cellular pathways that may play a critical role in the pathogenesis of these diseases. miRNAs regulate many biological processes by degrading or repressing the translation of target mRNAs, whereas lncRNAs act as scaffolds, sponges, and guides to control gene expression and cellular activities. Both miRNAs and lncRNAs participate in neurodegenerative mechanisms such as protein aggregation, inflammation, oxidative stress, and neuroinflammation. While targeting miRNAs and lncRNAs holds promise for potential therapeutic benefits, problems persist with their efficient delivery, specificity, and off-target effects. New techniques like viral vectors, lipid nanoparticles, and CRISPR-based gene editing will further enhance the development of therapies based on miRNA and lncRNA. Moreover, their interaction with regulatory networks may present new avenues toward understanding disease mechanisms and guiding therapeutic design. This review covers the role of miRNAs and lncRNAs in neurodegenerative disorders, their therapeutic potential, challenges, and future directions in ncRNA-based treatment approaches.}, } @article {pmid41148800, year = {2025}, author = {Salmaso, V and Menin, S and Moro, S and Spalluto, G and Federico, S}, title = {Adenosine Receptors in Neuroinflammation and Neurodegeneration.}, journal = {Cells}, volume = {14}, number = {20}, pages = {}, pmid = {41148800}, issn = {2073-4409}, mesh = {Humans ; *Receptors, Purinergic P1/metabolism ; *Neurodegenerative Diseases/metabolism ; Animals ; *Neuroinflammatory Diseases/metabolism ; Adenosine/metabolism ; *Inflammation/metabolism ; }, abstract = {Adenosine plays a crucial role in various pathophysiological conditions, including neuroinflammation and neurodegeneration. Neuroinflammation can be either beneficial or detrimental to the central nervous system, depending on the intensity and duration of the inflammatory response. Across a wide range of brain disorders, neuroinflammation contributes to both the onset and progression of disease. Notably, neuroinflammation is not limited to conditions primarily classified as neuroinflammatory but is also a key factor in other neurological disorders, including life-threatening neurodegenerative diseases. All four adenosine receptor subtypes (A1, A2A, A2B, and A3) are implicated, to varying degrees, in these conditions. This review aims to summarize the roles of individual adenosine receptor subtypes in neuroinflammation and neurodegenerative diseases, emphasizing their therapeutic potential. While some therapeutic applications are well-established with clinically approved drugs, others warrant further investigation due to their promising potential.}, } @article {pmid41149102, year = {2025}, author = {Mauriello, L and Cuozzo, A and Pezzella, V and Isola, G and Spagnuolo, G and Iorio-Siciliano, V and Ramaglia, L and Blasi, A}, title = {Oral Health Status in Patients with Amyotrophic Lateral Sclerosis: A Scoping Review.}, journal = {Dentistry journal}, volume = {13}, number = {10}, pages = {}, pmid = {41149102}, issn = {2304-6767}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative syndrome which often leads to progressive muscular dysfunction and therefore oral health deterioration. The aim of this scoping review is to evaluate oral health status in ALS patients focusing on the importance of dental care in improving patient's quality of life. Methods: A comprehensive literature search was conducted on PubMed, Scopus, Web of Science, and Embase databases until June 2025 using a combination of keywords and MeSH terms related to ALS and oral health. Studies were screened and selected based on inclusion and exclusion criteria, focusing on human clinical data reporting oral health outcomes in ALS. Results: Eight studies met the inclusion criteria. The findings showed a high prevalence of oral complications in bulbar-onset ALS patients. Common issues included reduced tongue mobility, poor oral hygiene, sialorrhea, and decreased masticatory function were evaluated. Conclusions: Oral health impairment in ALS patients frequently contributes to systemic risks and reduced quality of life. A dental expert may play an important role in multidisciplinary care teams in terms of early diagnosis and conservative treatment of oral diseases ranging from periodontal disease to temporomandibular disorders (TMD). Personalized oral hygiene strategies and adjunctive therapies may serve as key elements in maintaining overall health and patient comfort in ALS. Therefore, the objective of the following review was to evaluate oral health complication in patients with ALS, highlighting the impact of oral care on patients' quality of life.}, } @article {pmid41149812, year = {2025}, author = {Marjanovic, A and Stefanova, E and Viric, V and Palibrk, A and Mandić Stojmenović, G and Stojković, T and Stojadinovic, L and Basta, I and Novakovic, I and Stević, Z and Jankovic, M}, title = {Genetic and Clinical Insights into ALS/FTD: Profiling a Rare Cohort to Explore Spectrum Heterogeneity.}, journal = {Journal of personalized medicine}, volume = {15}, number = {10}, pages = {}, pmid = {41149812}, issn = {2075-4426}, support = {200110/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are recognized as a spectrum of neurodegenerative disorders with overlapping clinical, pathological, and genetic features. The identification of C9orf72 hexanucleotide repeat expansion as the most common genetic cause of both conditions has prompted further investigation of genetic modifiers that may contribute to disease heterogeneity. We aimed to analyze the frequency of C9orf72 repeat expansions and potential modifying roles of APOE, ATXN1, and ATXN2 in Serbian ALS/FTD patients. Methods: Our study included an ALS/FTD cohort (n = 22) and healthy controls (n = 94). Repeat sizing in C9orf72, ATXN1 and ATXN2 was performed by fluorescent polymerase chain reaction (PCR) and capillary electrophoresis, while repeat-primed PCR was used to confirm C9orf72 expansions. APOE genotyping was conducted using real-time PCR assays targeting SNPs rs429358 and rs7412. Results: In the ALS/FTD cohort, 31.82% of the patients had heterozygous C9orf72 repeat expansion. The most common APOE genotype among patients was ε3/ε3 (72.73%). Intermediate-length ATXN1 alleles (32-44 repeats) were detected in 13.64% of patients and ATXN2 intermediate-length alleles (27-33 repeats) were found in 9% of patients. No significant differences were observed between ALS/FTD patients and controls in APOE ε4 frequency or intermediate ATXN1/ATXN2 repeats. Conclusions: Larger, population-specific studies and meta-analyses are needed to better understand the role of genetic modifiers in ALS/FTD pathogenesis and their influence on clinical heterogeneity. By integrating genetic and clinical data, this study represents a step toward the development of precision medicine strategies for ALS/FTD.}, } @article {pmid41149991, year = {2025}, author = {Kwiatkowska, A and Grzeczkowicz, A and Lipko, A and Kazimierczak, B and Granicka, LH}, title = {Emerging Approaches to Mitigate Neural Cell Degeneration with Nanoparticles-Enhanced Polyelectrolyte Systems.}, journal = {Membranes}, volume = {15}, number = {10}, pages = {}, pmid = {41149991}, issn = {2077-0375}, abstract = {Counteracting neurodegenerative diseases (NDs) presents a multifaceted challenge in the aging societies of Western countries. Each year, millions of people worldwide are affected by such ailments as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), spinal cord injury, ischemic stroke, motor neuron disease, spinal muscular atrophy, spinocerebellar ataxia, and amyotrophic lateral sclerosis (ALS). Advancements in modern biomaterial technologies present substantial opportunities for the field of regenerative medicine. Nevertheless, limitations arise from the requirement that biomaterial design be tailored to the specific biological parameters of the target cell types with which they are intended to interact. Such an opportunity creates nanomaterials involving nanoparticles. The surface chemistry of nanoparticles, especially when functionalized with bioactive agents, enhances biocompatibility and facilitates interactions with nervous cells. Herein, we review contemporary strategies in the application of biomaterials for nerve regeneration, with particular emphasis on nanomaterials and biocompatible polyelectrolyte layers, which the authors identify as having the most significant potential to drive transformative advances in regenerative medicine in the near future.}, } @article {pmid41151289, year = {2025}, author = {Gao, Y and Zheng, B and Peng, X and Ma, N and Qi, Y and Lan, X and Wang, Y and Zha, H and Zhou, C and Liu, F and Zhao, Q and Cao, H and Wang, L and Qiu, Y and Zheng, J and Guo, J}, title = {Lead exposure induces ferroptosis in ALS cell models by activating the MAPK/ERK signaling pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {306}, number = {}, pages = {119301}, doi = {10.1016/j.ecoenv.2025.119301}, pmid = {41151289}, issn = {1090-2414}, mesh = {*Ferroptosis/drug effects ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *MAP Kinase Signaling System/drug effects ; *Lead/toxicity ; Reactive Oxygen Species/metabolism ; Cell Line ; }, abstract = {Lead is a potent toxicant that exerts deleterious effects on multiple organ systems within the human body. Existing evidence suggests that lead exposure may contribute to the progression of amyotrophic lateral sclerosis (ALS). However, the precise mechanism remains unclear and the experimental evidence is currently lacking. This study establishes an ALS cell model exposed to lead to investigate the potential relationship between lead exposure and ALS, and targets ferroptosis to elucidate the possible mechanism of lead exposure in ALS pathogenesis. Our findings demonstrate that lead exposure results in the accumulation of ROS and MDA in hSOD1[G93A] cells, accompanied by increased iron content, reduced GSH levels, mitochondrial vacuolization, and disruption of the cristae structure, upregulationation of ACSL4 protein levels, and inactivation of SLC7A11 and GPX4, ultimately triggering ferroptosis. The bioinformatics analyses and cellular experiments of the present study suggest that activation of the MAPK/ERK signaling pathway plays a crucial role in the ferroptosis process of ALS cells induced by lead exposure. This study not only provides new experimental evidence of the link between lead exposure and ALS but also elucidates the possible mechanism by which lead exposure contributes to the pathogenesis of ALS, demonstrating that the prevention of ferroptosis through targeting the MAPK/ERK signaling pathway may offer a promising intervention strategy for addressing lead-related ALS pathogenesis issues.}, } @article {pmid41151740, year = {2025}, author = {Bhatia, T and Godad, A}, title = {Disrupted proteostasis and ionic imbalance in TDP-43 and tauopathies: Dual drivers of neurodegeneration.}, journal = {Life sciences}, volume = {382}, number = {}, pages = {124055}, doi = {10.1016/j.lfs.2025.124055}, pmid = {41151740}, issn = {1879-0631}, mesh = {Humans ; *Proteostasis/physiology ; Animals ; *Tauopathies/metabolism/pathology ; *TDP-43 Proteinopathies/metabolism/pathology ; *DNA-Binding Proteins/metabolism ; *Neurodegenerative Diseases/metabolism ; tau Proteins/metabolism ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's Disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuronal dysfunction and protein aggregation. There is a growing body of evidence suggesting that the collapse of proteostasis, the failure of protein homeostasis, is an important contributor to neurotoxicity. In this review, we suggest that this collapse is exacerbated by ionic dysregulation, an important but under-addressed cause of neurodegeneration. Importantly, breakdowns in chloride, bicarbonate, sodium, and calcium homeostasis alter fundamental aspects of cellular physiology, including important aspects of TDP-43 phase separation and tau hyperphosphorylation and aggregation. We suggest that the relationship of proteostasis failure and ionic dysregulation is a bidirectional feedback loop that accelerates the progression of neurodegeneration. Some therapeutic strategies aimed at correcting these mechanisms-including small-molecule chaperone inducers, autophagy inducers, and ion-channel modulators-might hold the potential for disease modification. In this review, we document the complex intersections of proteostasis failure and ionic dysregulation in TDP-43 and tauopathies and provide new ideas for therapies and future studies.}, } @article {pmid41152189, year = {2025}, author = {Snyder, A and Samra, K and Wu, T and Russell, LL and Farren, J and Crook, J and Haselhuhn, T and Porter, K and Szabo, M and Duckett, A and Lin, F and Danielian, L and Traynor, BJ and Scholz, SW and Boeve, BF and Rosen, HJ and Rohrer, JD and Kwan, JY}, title = {Integrating a motor domain enhances disease severity scales in an FTD-ALS spectrum cohort.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70786}, pmid = {41152189}, issn = {1552-5279}, support = {U19 AG063911/AG/NIA NIH HHS/United States ; U19AG063911//The National Institute on Aging/ ; U01AG045390//The National Institute on Aging/ ; U54NS092089//The National Institute on Aging/ ; U01 AG045390/AG/NIA NIH HHS/United States ; //The Intramural Research Program of the National Institutes of Health/ ; U54 NS092089/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; *Severity of Illness Index ; Female ; *Frontotemporal Dementia/diagnosis/physiopathology ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Aged ; Longitudinal Studies ; Cohort Studies ; Neuropsychological Tests ; }, abstract = {INTRODUCTION: The Genetic Frontotemporal Initiative (GENFI) and Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)-Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Longitudinal Frontotemporal Lobar Degeneration Study (ALLFTD) consortia developed Clinical Dementia Rating (CDR)-derived scales with a motor domain to overcome systematic underestimation of disease severity by the CDR. We calculated disease severity scores using these scales in a mixed neurodegenerative cohort and correlated them with objective motor measures.

METHODS: The CDR plus National Alzheimer's Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD), CDR + NACC FTLD-M (Motor), and Multidomain Impairment Rating (MIR) scores and motor measures were determined and correlated in 242 participants.

RESULTS: Both CDR + NACC FTLD-M and MIR showed increased disease severity scores and correlated with motor measures. These findings were held in 81 amyotrophic lateral sclerosis (ALS) participants and correlated with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Including a motor domain required fewer study participants in a simulated clinical trial sample size calculation.

DISCUSSION: With a motor domain, CDR + NACC FTLD-M and MIR improve disease severity classification and correlate with quantitative motor assessments. This addition more fully captures the extent of symptoms across the FTD-ALS spectrum and improves clinical trial efficiency.

HIGHLIGHTS: CDR + NACC FTLD-M and MIR strongly correlate with objective motor measures. The enhanced scales improve disease severity classification in FTD and ALS. Greater clinical trial efficiency is achieved using these enhanced scales.}, } @article {pmid41152540, year = {2025}, author = {Yan, C and Zhang, J and Yang, Y and Zeng, X and Xiao, G}, title = {Virulence factors, biofilm formation and antifungal resistance in Candida albicans from recurrent vulvovaginal candidiasis patients: a comparative study.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {37557}, pmid = {41152540}, issn = {2045-2322}, mesh = {*Biofilms/drug effects/growth & development ; Humans ; *Candidiasis, Vulvovaginal/microbiology/drug therapy ; *Candida albicans/drug effects/genetics/physiology/pathogenicity/isolation & purification ; *Virulence Factors/genetics/metabolism ; Female ; *Drug Resistance, Fungal/genetics ; *Antifungal Agents/pharmacology ; Microbial Sensitivity Tests ; Fungal Proteins/genetics/metabolism ; Adult ; Fluconazole/pharmacology ; Gene Expression Regulation, Fungal ; }, abstract = {Recurrent vulvovaginal candidiasis (RVVC) is a common, refractory fungal infection affectingwomen, primarily caused by Candida albicans. The interplay among fungal virulence factors, biofilm formation, and antifungal resistance is crucial in the pathogenesis of RVVC. This study compared 50 Candida albicans isolates from RVVC patients and 50 from asymptomatic vaginal colonizers. Antifungal susceptibility testing was performed using the broth microdilution method. Biofilm formation was assessed via crystal violet staining, and the expression levels of virulence factor hydrolases (SAP, PL, Lip) and cell wall protein genes (ALS1, ALS3, HWP1) were analyzed using phenotypic assays and quantitative real-time PCR (qRT-PCR). Pearson correlation analysis was used to evaluate the relationships among these parameters and antifungal resistance. RVVC isolates exhibited significantly higher MICs for fluconazole, voriconazole, and itraconazole. Biofilm formation ability and the expression levels of SAP, PL, Lip, ALS1, ALS3, and HWP1 were also significantly higher in RVVC isolates. A moderate correlation was observed between antifungal drug MIC values and biofilm OD, while a weak correlation existed between MIC values and ALS/HWP1 gene expression. Notably, hydrolase expression showed no significant correlation with resistance. Candida albicans from RVVC patients demonstrated enhanced biofilm formation, virulence factor expression, and antifungal resistance. Biofilm-mediated drug tolerance may be a key mechanism underlying the refractoriness of RVVC. Targeting biofilm formation and virulence factor genes may offer novel strategies for managing RVVC.}, } @article {pmid41153386, year = {2025}, author = {Papapanagiotou, AP and Vasilakoglou, I and Alvanou, MV and Giantsis, IA and Madesis, P and Eleftherohorinos, IG}, title = {Blackgrass (Alopecurus myosuroides Huds.) Multiple Resistance to ACCase- and ALS-Inhibitors and Its Competition with Winter Wheat.}, journal = {Genes}, volume = {16}, number = {10}, pages = {}, pmid = {41153386}, issn = {2073-4425}, mesh = {*Poaceae/genetics/drug effects/growth & development ; *Herbicide Resistance/genetics ; *Acetyl-CoA Carboxylase/antagonists & inhibitors/genetics ; Herbicides/pharmacology ; *Triticum/drug effects/genetics/growth & development ; *Acetolactate Synthase/antagonists & inhibitors/genetics ; *Plant Proteins/genetics/antagonists & inhibitors ; Plant Weeds/drug effects/genetics ; Heterocyclic Compounds, 2-Ring ; Propionates ; Pyridines ; }, abstract = {Background/Objectives: The herbicide resistance of blackgrass (Alopecurus myosuroides Huds.) is one of the most serious problems in the winter cereal monoculture in Europe. Recently, Greek farmers expressed complaints of reduced susceptibility of this weed to winter wheat herbicides. Keeping this in mind, this study focused on the investigation of blackgrass resistance to herbicides at both phenotypic and molecular levels. Methods: Whole-plant rate-response pot assays were conducted to study the possible evolution of resistance (cross- or multiple-resistance) in a blackgrass population to ACCase- and ALS-inhibiting herbicides. Analysis of the ACCase gene sequence, herbicide metabolism study and competition with winter wheat studies were also conducted. Results: High levels of cross-resistance mainly to the ACCase post-emergence clodinafop-propargyl, medium to fenoxaprop-P-ethyl, cycloxydim, pinoxaden, as well as lower levels of resistance to ALS-inhibitors (mesosulfuron-methyl + iodosulfuron-methyl-sodium and pyroxsulam) were confirmed. In addition, the pre-emergence soil-applied herbicides chlorotoluron + diflufenican and prosulfocarb provided excellent control of the S and R blackgrass populations. The analysis of the ACCase gene sequence revealed a point mutation at position 1781, resulting in an amino acid substitution from isoleucine (Ile) to leucine (Leu). Furthermore, the combined application of the herbicides with piperonyl butoxide (PBO, applied 2 h before herbicide application) indicated that there was herbicide metabolism, which may be mediated by cytochrome P450. The R blackgrass population, when grown in competitive interaction with winter wheat, produced more tillers and aboveground fresh weight compared to the S population and caused greater reduction in winter wheat. Conclusions: The results suggest that a blackgrass population has developed multiple resistance to ACCase- and ALS-inhibiting herbicides, due to ACCase gene mutation and herbicide metabolism. No fitness cost and no compromised competitive ability associated with the blackgrass resistance were observed.}, } @article {pmid41153395, year = {2025}, author = {De La Cerna, JLO and Talubo, NDD and Villanueva, BHA and Tsai, PW and Tayo, LL}, title = {Conserved Blood Transcriptome Patterns Highlight microRNA and Hub Gene Drivers of Neurodegeneration.}, journal = {Genes}, volume = {16}, number = {10}, pages = {}, pmid = {41153395}, issn = {2073-4425}, mesh = {*MicroRNAs/genetics/blood ; Humans ; *Neurodegenerative Diseases/genetics/blood ; *Transcriptome/genetics ; Gene Regulatory Networks ; Gene Expression Profiling ; RNA, Messenger/genetics ; Gene Expression Regulation ; }, abstract = {Background/Objectives: Neurodegenerative diseases (NDs) such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and Amyotrophic Lateral Sclerosis (ALS) are clinically distinct but share overlapping molecular mechanisms. Methods: To identify conserved systemic signatures, we analyzed blood RNA-Seq datasets using Weighted Gene Co-Expression Network Analysis (WGCNA), differential expression, pathway enrichment, and miRNA-mRNA network mapping. Results: Two modules, the red and turquoise, showed strong preservation across diseases. The red module was enriched for cytoskeletal and metabolic regulation, while the turquoise module involved immune, stress-response, and proteostatic pathways. Discussion: Key hub genes, such as HMGCR, ACTR2, MYD88, PTEN, EP300, and regulatory miRNAs like miR-29, miR-132, and miR-146a, formed interconnected networks reflecting shared molecular vulnerabilities. The absence of classical heat shock proteins in preserved blood modules highlights tissue-specific expression differences between blood and neural systems. Several hub genes overlap with known pharmacological targets, suggesting potential in translational relevance. Conclusions: Together, these findings reveal conserved blood-based transcriptional modules that suggest parallel central neurodegenerative processes and may support future biomarker development and possible therapeutic exploration.}, } @article {pmid41153670, year = {2025}, author = {Santurtún, A and Pérez-Soberón, L and Sedano, MJ and Riancho, J}, title = {Amyotrophic Lateral Sclerosis Patients Show Higher Urinary Levels of Lead and Copper: A Pilot Case-Control Study.}, journal = {Biomedicines}, volume = {13}, number = {10}, pages = {}, pmid = {41153670}, issn = {2227-9059}, support = {PI23/00905//Instituto de Salud Carlos III/ ; INT24/0060//Instituto de Salud Carlos III/ ; INT24/04//Instituto de Investigación Marqués de Valdecilla/ ; }, abstract = {Background/Objectives: Amyotrophic Lateral Sclerosis (ALS) is the most frequent neurodegenerative disease affecting motor neurons. Sporadic ALS cases, which represent over 90% of the total, result from the interaction between genetic predisposition, aging, and environmental factors. Regarding natural environmental risk factors, the analysis of the role of exposure to heavy metals is of particular interest due to the well-known neurological effects of certain compounds. This study aims to compare the levels of heavy metals in urine samples in a cohort of patients with ALS who have not changed their living environment with the levels found in healthy controls (HCs). Methods: A cross-sectional case-control (14 patients with ALS vs. 28 HC) observational study was conducted in which urine samples were analyzed for five heavy metals (lead, manganese, selenium, copper, and zinc) using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Results: The patients with ALS showed significantly higher urine levels of lead (p < 0.001) and copper (p = 0.007) and a subtle increase in manganese concentrations (p = 0.043). Urine samples reflect recent exposures, so if the source of metals was related to the residential environment (the patients in the present study had not moved), dietary habits, or certain activities or hobbies that had not changed since diagnosis, it would be representative. Conclusions: In this pilot study, patients with ALS presented higher urinary levels of lead, manganese, and copper. Future larger studies are needed to elucidate the precise role of these heavy metals in ALS pathogenesis.}, } @article {pmid41154611, year = {2025}, author = {Moțățăianu, A and Ion, V and Dumitreasă, M and Ormenișan, I and Farczadi, L and Andone, S and Bălașa, R and Roman, MM}, title = {Short-Chain Fatty Acid Profiles in Amyotrophic Lateral Sclerosis: Longitudinal Effects of Disease and Mediterranean Diet Intervention.}, journal = {Biomolecules}, volume = {15}, number = {10}, pages = {}, pmid = {41154611}, issn = {2218-273X}, support = {PN-III-P1-1.1-TE-2021-0960 within PNCDI III.//Ministerul Cercetării, Inovării și Digitalizării (Ministry of Research, Innovation, and Digitization) CNCS-UEFISCDI/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diet therapy ; *Diet, Mediterranean ; *Fatty Acids, Volatile/blood ; Male ; Female ; Middle Aged ; Aged ; Prospective Studies ; Gastrointestinal Microbiome ; Longitudinal Studies ; Adult ; Propionates/blood ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) evolution is influenced by many dietary factors, biochemical and hormonal inter-relations and gut microbiota. This study focuses on dynamics by conducting a plasmatic quantitative analysis of six of the main short-chain fatty acids (SCFAs) for ALS patients and the shifts in circulating SCFA profiles during ALS progression as well as their potential responsiveness or change due to dietary modulation. Methods: A 12-month prospective study in parallel with control group determinations was conducted. The patients diagnosed with ALS were evaluated at the start of the study (T0) followed by a six-month observation time frame (T1) and after another six months of a Mediterranean diet intervention (T2). Plasma SCFAs were determined using liquid chromatography coupled to mass spectrometry to showcase the plasmatic profiles. Correlation between plasma levels of SCFAs and patients' clinical characteristics next to correlations between plasma SCFA levels at T1 and T2 were performed. Results: A significant increase between control group and patients at T0 was observed for acetic, propionic, butyric and hydroxy-butyric acid. Hexanoic acid levels stagnated and 4-methyl-valeric acid concentrations decreased. Evolutions from T1 and T2 impacted acetate, propionate and 4-methyl-valerate. Conclusions: The study offers a better understanding regarding the differences in SCFA levels in ALS patients. The Mediterranean diet may impact the levels of acetic and propionic acid, indicating the modulation of SCFA production by gut microbiota.}, } @article {pmid41154657, year = {2025}, author = {Nhieu, J and Wei, LN}, title = {Targeting CRABP1 Signalosomes in Managing Neurodegeneration.}, journal = {Biomolecules}, volume = {15}, number = {10}, pages = {}, pmid = {41154657}, issn = {2218-273X}, support = {R01 DK054733/DK/NIDDK NIH HHS/United States ; R01 NS132277/NS/NINDS NIH HHS/United States ; R01NS132277//National Institute of Health/ ; }, mesh = {Humans ; Animals ; *Receptors, Retinoic Acid/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/drug therapy ; Signal Transduction/drug effects ; Tretinoin/metabolism/pharmacology ; }, abstract = {Retinoic acid (RA) binds RA (RAR) and Retinoid X (RXR) receptors to elicit biological effects by regulating transcription. RA is also known to have non-canonical activities mediated, primarily, by cellular retinoic acid-binding protein 1 (CRABP1) which forms protein complexes named "CRABP1 signalosomes" to regulate cytosolic signaling independent of RARs/RXRs. This review focuses on therapeutic applications in neurodegeneration by targeting CRABP1 signalosomes including CRABP1-MAPK, CRABP1-CaMKII, CRABP1-eIF2α, and others recently identified from our proteomic studies. The mouse Crabp1 gene is regulated by various epigenetic factors and is important for the health of multiple cell types including motor neurons (MNs). In humans, CRABP1 gene expression is reduced in ALS- and SMA-patient MNs. RA is a therapeutic agent for leukemias and dermatological disorders and is being investigated for managing neurodegenerative diseases, but its therapeutic effects are accompanied by RAR-mediated toxic effects. We have uncovered a novel class of synthetic retinoids that bind CRABP1 without acting on RARs, circumventing RAR-mediated toxic effects. These first-generation CRABP1-selective compounds C3, C4, and C32 target CRABP1-MAPK and/or CRABP1-CaMKII signalosomes. This knowledge, together with emerging structural information, sheds lights on the strategies in designing next-generation CRABP1-signalosome-selective retinoids for the management of neurodegenerative diseases.}, } @article {pmid41155167, year = {2025}, author = {Sharbafshaaer, M and Pepe, R and Notariale, R and Canale, F and Tedeschi, G and Tessitore, A and Bergamo, P and Trojsi, F}, title = {Beyond Antioxidants: The Emerging Role of Nrf2 Activation in Amyotrophic Lateral Sclerosis (ALS).}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155167}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *NF-E2-Related Factor 2/metabolism/genetics ; Animals ; *Antioxidants/metabolism ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving the progressive degeneration of upper and lower motor neurons. While oxidative stress, RNA-binding protein (RBP) pathology, mitochondrial dysfunction, and glial-neuronal dysregulation is involved in ALS pathogenesis, current therapies provide limited benefit, underscoring the need for multi-target disease-modifying strategies. Nuclear factor erythroid 2-related factor 2 (Nrf2), classically regarded as a master regulator of redox homeostasis, has recently emerged as a central integrator of cellular stress responses relevant to ALS. Beyond its canonical antioxidant function, Nrf2 regulates critical pathways involved in mitochondrial quality control, proteostasis, nucleocytoplasmic transport, RNA surveillance, and glial reactivity. Experimental models demonstrate that astrocyte-specific Nrf2 activation enhances glutathione metabolism, suppresses neuroinflammation, promotes stress granule disassembly, and reduces RBP aggregation. In C9orf72-linked ALS, Nrf2 activation mitigates dipeptide repeat protein toxicity and restores RNA processing fidelity via modulation of nonsense-mediated decay and R-loop resolution. Recent advances in Nrf2-targeted interventions including Keap1-Nrf2 protein-protein interaction inhibitors, dual Nrf2/HSF1 activators, and cell-type-selective Adeno-associated virus 9 (AAV9) vectors show promise in preclinical ALS models. These multimodal approaches highlight Nrf2's therapeutic versatility and potential to address the upstream convergence points of ALS pathogenesis. Taken together, positioning Nrf2 as a systems-level regulator offers a novel framework for developing precision-based therapies in ALS. Integrating Nrf2 activation with RNA- and glia-directed strategies may enable comprehensive modulation of disease progression at its molecular roots.}, } @article {pmid41155480, year = {2025}, author = {Turpo-Peqqueña, AG and Valencia-Arce, RJ and Del-Carpio-Carrazco, FL and Quispe-Ppacco, DJ and Carbajal-Llerena, PF and Loza-Chipa, HR and Vásquez-Macedo, AS and Gómez, B}, title = {Inhibition of Casein Kinase 1δ as a Novel Therapeutic Strategy for Amyotrophic Lateral Sclerosis: A Theoretical Study.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155480}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/enzymology ; *Casein Kinase Idelta/antagonists & inhibitors/chemistry/metabolism ; Molecular Docking Simulation ; Humans ; Molecular Dynamics Simulation ; *Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; Protein Binding ; }, abstract = {Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease characterized by the degeneration of motor neurons and the pathological accumulation of phosphorylated TDP-43. Casein kinase one delta (CK1δ) has been identified as a key regulator of this aberrant phosphorylation, making it a promising therapeutic target. In this theoretical study, 26 structurally diverse compounds were evaluated against CK1δ using molecular docking, molecular dynamics simulations, and binding free energy calculations. Among them, BZH exhibited the most stable interaction with CK1δ (-46.53±1.94 kcal/mol). An inverse correlation was observed between theoretical affinity and experimental IC50 values, supporting the predictive validity of the computational approach. Pharmacokinetic analysis indicated that IMF and BIP show good oral absorption and the ability to cross the blood-brain barrier. At the same time, the toxicological profile classified all compounds in toxicity Class IV (moderate risk). Additionally, dynamic migration toward an alternative pocket was observed during simulation, highlighting the importance of considering protein flexibility in drug design. This study proposes BZH, IMF, and BIP as promising CK1δ inhibitors for future experimental validation in the treatment of ALS.}, } @article {pmid41155507, year = {2025}, author = {Sonkodi, B and Nagy, ZF and Keller-Pintér, A and Klivényi, P and Molnár, MJ and Széll, M}, title = {Genetic Variants in SDC3, KCNA2, KCNK1, KCNK16, and Heat Shock Transcription Factor-1 Genes: An Exploratory Analysis Supporting the Piezo2 Channelopathy Hypothesis in Amyotrophic Lateral Sclerosis Onset.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155507}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Ion Channels/genetics ; *Kv1.2 Potassium Channel/genetics ; *Heat Shock Transcription Factors/genetics ; Female ; Male ; Middle Aged ; *Channelopathies/genetics ; Genetic Predisposition to Disease ; Adult ; Genetic Variation ; Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multisystem progressive neurodegenerative disease. A recent theory of ALS onsetting pathogenesis proposed that the initiating primary damage is an acquired irreversible intrafusal proprioceptive terminal PIEZO2 channelopathy with underlying genetic and environmental risk factors. This Piezo2 channelopathy may also disrupt the ultrafast proton-based oscillatory signaling to motor neurons through vesicular transporter 1 (VGLUT1) and to the hippocampus through VGLUT2. As a result, it may gradually degenerate motor neurons in which process Kv1.2 ion channels are gradually depleted. It also gradually depletes heat shock transcription factor-1 (HSF-1) in the hippocampus, hence negatively affecting adult hippocampal neurogenesis. Syndecans, especially syndecan-3 (SDC3) in the nervous system, may act as critical players in the maintenance of the crosstalk between Piezo ion channels. Hence, our goal was to reanalyze the potential pathogenic gene variants from the cohort of our previous ALS study with a special focus on the aforementioned genes. Reanalysis of data formerly acquired by whole-exome sequencing of 21 non-related adult ALS patients was carried out with a focus on 28 genes. Accordingly, we identified charge-altering variants of SDC3 in 13 patients out of 21 that may contribute to the impairment of the Piezo crosstalk, and the progressive loss of the proposed proton-based signaling to motor neurons and to the hippocampus. A variant of uncertain significance was identified in the KCNA2 gene that may facilitate the faster loss of Kv1.2 ion function on motor neurons when Piezo2 channelopathy prevails. Not to mention that one variant was identified in the potassium current rectifying ion channels encoding KCNK1 and KCNK16 genes that may also propel the ALS disease process and provide the autoimmune-like pathogenic background. Moreover, Piezo2 channelopathy likely promotes diminishing HSF1 function in the hippocampus in the presence of the identified HSF1 variant. The current findings may support the ALS onsetting acquired irreversible Piezo2 channelopathy-induced pathogenesis. However, the preliminary nature of these findings needs validation and further functional studies on cohorts with a larger sample size in the future.}, } @article {pmid41155541, year = {2025}, author = {Perez, DM}, title = {α1A-Adrenergic Receptor as a Target for Neurocognition: Cautionary Tale from Nicergoline and Quinazoline Non-Selective Blockers.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {10}, pages = {}, pmid = {41155541}, issn = {1424-8247}, support = {R01 AG066627/AG/NIA NIH HHS/United States ; RO1AG066627/GF/NIH HHS/United States ; }, abstract = {Decades ago, previous studies that used non-selective ergot derivatives suggested that blockage of the α1A-adrenergic receptor mildly increased cognition through increased blood flow to the brain due to vasodilation and, thus, could be used as a treatment for dementia. However, further studies indicated that nicergoline was non-specific and hit many different targets. Today, a similar scenario is developing with the use of non-selective α1-AR antagonists of the quinazoline class, referred to as "osins", as potential treatments for COVID-19/SARS, post-traumatic stress disorder, cancer, and neurodegenerative disorders, such as Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. While there is extensive evidence of neuroprotection from many clinical trials, the mechanism of action of quinazolines is often not α1-AR-mediated but keyed to its glycolysis-enhancing effects through activation of the enzyme phosphoglycerate kinase 1 (PGK1). These studies have incorrectly labeled the α1A-adrenergic receptor as an "old target" to treat Alzheimer's and other neurocognitive diseases, hampering drug development. This review will summarize these and other studies to indicate that activation, not blockage, of norepinephrine's actions, through α1A-AR, mediates cognitive, memory, and neuroprotective functions that may reverse the progression of neurocognitive diseases.}, } @article {pmid41155689, year = {2025}, author = {Ruffo, P and Perrone, B and Perrone, F and De Amicis, F and Iuliano, R and Bucci, C and Messina, A and Conforti, FL}, title = {The Other Side of the Same Coin: Beyond the Coding Region in Amyotrophic Lateral Sclerosis.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {10}, pages = {}, pmid = {41155689}, issn = {1424-8247}, support = {2022XTM2S3//Ministero dell'università e della ricerca/ ; P20225J5NB//Ministero dell'università e della ricerca/ ; }, abstract = {Transposable elements (TEs), once regarded as genomic "junk," are now recognized as powerful regulators of gene expression, genome stability, and innate immunity. In the context of neurodegeneration, particularly Amyotrophic Lateral Sclerosis (ALS), accumulating evidence implicates TEs as active contributors to disease pathogenesis. ALS is a fatal motor neuron disease with both sporadic and familial forms, linked to genetic, epigenetic, and environmental factors. While coding mutations explain a subset of cases, advances in long-read sequencing and epigenomic profiling have unveiled the profound influence of non-coding regions-especially retrotransposons such as LINE-1, Alu, and SVA-on ALS onset and progression. TEs may act through multiple mechanisms: generating somatic mutations, disrupting chromatin architecture, modulating transcriptional networks, and triggering sterile inflammation via innate immune pathways like cGAS-STING. Their activity is normally repressed by epigenetic regulators, including DNA methylation, histone modifications, and RNA interference pathways; however, these controls are compromised in ALS. Taken together, these insights underscore the translational potential of targeting transposable elements in ALS, both as a source of novel biomarkers for patient stratification and disease monitoring, and as therapeutic targets whose modulation may slow neurodegeneration and inflammation. This review synthesizes the current knowledge of TE biology in ALS; integrates findings across molecular, cellular, and systems levels; and explores the therapeutic potential of targeting TEs as modulators of neurodegeneration.}, } @article {pmid41156220, year = {2025}, author = {Pupillo, E and Bianchi, E and Leone, MA and Corbo, M and Filosto, M and Padovani, A and Risi, B and Vedovello, M and dell'Era, V and Cerri, F and Morelli, C and Diamanti, L and Ceroni, M and Falzone, Y and Rigamonti, A and Vitelli, E}, title = {Understanding Long-Term Survival in ALS: A Cohort Study on Subject Characteristics and Prognostic Factors.}, journal = {Journal of clinical medicine}, volume = {14}, number = {20}, pages = {}, pmid = {41156220}, issn = {2077-0383}, abstract = {Background: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with variable clinical progression. While median survival is 2-4 years, 5-15% of individuals survive for longer. Methods: We conducted a retrospective, observational study using a population-based ALS register in Lombardy, Italy, to identify the clinical characteristics of long-term ALS survivors (≥10 years). Incident cases included in two periods (1998-2002 and 2008-2012) were considered. Results: A total of 828 ALS cases were included. Median survival for the entire cohort was 2.2 years (IQR 1.1-4.4). However, long-term survival was observed in 7% of individuals at 10 years, and 3% at 15 years. Long-survivors had a median survival of 13.4 years, significantly longer than the 1.9 years of non-long-survivors (IQR 1.0-3.6). Long-survivors were younger at disease onset and diagnosis, had longer diagnostic delay, and were more likely to have had a spinal onset. The cohort also showed a higher proportion of males among long-term survivors (75% vs. 59%). No significant difference in survival was observed between the two examined periods. Conclusions: Our findings suggest that long-term ALS survival is likely influenced by a complex interplay of clinical, genetic, and environmental factors, along with the intrinsic rate of motor neuron degeneration.}, } @article {pmid41156446, year = {2025}, author = {Polit, M and Chmielewska-Walczak, J and Sobol, M and Domitrz, I and Niemczyk, K}, title = {Safety of FEES Performed by Speech-Language Pathologists and Physicians-Evidence Supporting Task Sharing from a Retrospective Observational Study of 964 Consecutive Examinations.}, journal = {Nutrients}, volume = {17}, number = {20}, pages = {}, pmid = {41156446}, issn = {2072-6643}, mesh = {Humans ; Retrospective Studies ; *Speech-Language Pathology ; Female ; Male ; *Deglutition Disorders/diagnosis ; Middle Aged ; Aged ; *Physicians ; Adult ; Deglutition ; Aged, 80 and over ; Young Adult ; }, abstract = {(1) Background: Fiberoptic Endoscopic Evaluation of Swallowing (FEES) is one of the two gold-standard tools for assessing oropharyngeal dysphagia (alongside Videofluoroscopic Swallowing Study). Although generally considered safe, concerns about complications persist, particularly in systems where FEES is not routine and professional roles differ. The aim of this study was to evaluate the safety of FEES performed by both speech-language pathologists (SLPs) and physicians, in order to provide evidence of its safety in a healthcare system where the procedure is not yet widely established and to identify patient subgroups potentially at higher risk of procedure-related complications. (2) Methods: This retrospective study analyzed 964 consecutive FEES procedures. Examinations were carried out by trained SLPs or physicians. Data included demographics, clinical status, operator qualifications, setting, and complications, classified as minor (vomiting, poor tolerance, early termination) or major (laryngospasm, epistaxis). (3) Results: The overall complication rate was 1.14% (11/964): 0.6% minor and 0.5% major. All events were self-limiting. Complication rates did not differ between SLPs (1.05%) and physicians (1.23%) or by experience, setting, drug use, penetration-aspiration scale score, or nasogastric tube. Four complications occurred in amyotrophic lateral sclerosis patients, suggesting higher risk. (4) Conclusions: FEES is safe and well tolerated when performed by either physicians or SLPs. These findings underscore the value of task sharing in dysphagia diagnostics, demonstrating that a shared model increases service capacity, reduces delays, and facilitates timely management of dysphagia.}, } @article {pmid41157172, year = {2025}, author = {Carata, E and Destino, M and Tenuzzo, BA and Panzarini, E}, title = {Inter-Organ Crosstalk in Neurodegenerative Disease.}, journal = {Life (Basel, Switzerland)}, volume = {15}, number = {10}, pages = {}, pmid = {41157172}, issn = {2075-1729}, abstract = {Inter-organ communication plays a vital role in the pathogenesis of neurodegenerative diseases (ND), including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS). Emerging research highlights the involvement of the gut-brain axis, immune system, and peripheral metabolic systems in modulating neuroinflammation, protein misfolding, and neuronal dysfunction by releasing cytokines, adipokines, growth factors, and other soluble factors, which in turn affect neuronal health and systemic inflammation. This review explores the complex bidirectional interactions between the brain and peripheral organs, including the gut, adipose tissue, liver, muscle, bone and immune system. Notably, the gut microbiome's role in neurodegenerative diseases through the gut-brain axis, the impact of adipose tissue in inflammation and metabolic regulation, and the muscle-brain axis with its neuroprotective myokines are also discussed. Additionally, we examine the neuro-immune axis, which mediates inflammatory responses and exacerbates neurodegeneration, and liver-brain axis that is implicated in regulating neuroinflammation and promoting disease progression. Dysregulation of inter-organ pathways contributes to the systemic manifestations of neurodegenerative diseases, offering insights into both potential biomarkers and therapeutic targets, and, in turn, promising strategies for preventing, diagnosing, and treating neurodegenerative diseases.}, } @article {pmid41158661, year = {2025}, author = {Tao, F and Lin, M and Meng, X and Huang, L and Zhuo, B and Jiang, S and Deng, S and Meng, Z and Shi, J}, title = {Copper homeostasis and cuproptosis: implications for neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1688554}, pmid = {41158661}, issn = {1663-4365}, abstract = {Copper (Cu) is a vital trace element required for sustaining life and is involved in numerous critical metabolic processes within the body. Cuproptosis, a newly recognized type of Cu-dependent cell death, is mechanistically distinct from apoptosis, autophagy, pyroptosis, and ferroptosis. It is characterized by abnormal Cu accumulation and aberrant interactions with key enzymes of the tricarboxylic acid (TCA) cycle, which lead to protein aggregation, loss of iron-sulfur cluster proteins, and proteotoxic stress, ultimately leading to cell death. Recent studies have revealed that Cu dyshomeostasis and cuproptosis are intricately linked to the pathological progression of several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Wilson's disease (WD), and Menkes disease (MD). In this review, we systematically elucidate the systemic Cu metabolism, the molecular mechanisms of cuproptosis, and its intricate interplay with different neurodegenerative disorders. We also examined the relationship between cuproptosis and other types of cell death. Finally, we discuss therapeutic strategies targeting cuproptosis and Cu dyshomeostasis to combat neurodegenerative diseases and propose potential directions for future research.}, } @article {pmid41160951, year = {2025}, author = {Madhavi, K and Kandadai, RM and Kola, S and Borgohain, R and Prasad, VVSRK}, title = {Unveiling a rare case: Novel TBK1 variant mimicking as multiple system atrophy-like phenotype.}, journal = {Parkinsonism & related disorders}, volume = {141}, number = {}, pages = {108102}, doi = {10.1016/j.parkreldis.2025.108102}, pmid = {41160951}, issn = {1873-5126}, } @article {pmid41162076, year = {2025}, author = {Guan, Y and Liu, L and Xiong, Z and Li, C and Liu, C and Sun, Y and Ji, M}, title = {Omics analysis reveals key genes mediating herbicide resistance in Digitaria sanguinalis.}, journal = {Pesticide biochemistry and physiology}, volume = {215}, number = {}, pages = {106693}, doi = {10.1016/j.pestbp.2025.106693}, pmid = {41162076}, issn = {1095-9939}, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Digitaria/genetics/drug effects/metabolism ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Plant Proteins/genetics/metabolism ; Proteomics ; Plant Weeds/genetics/drug effects ; Transcriptome ; Gene Expression Regulation, Plant/drug effects ; }, abstract = {Digitaria sanguinalis (L.) Scop is recognized as one of the most problematic agricultural weeds, with chemical control remaining a crucial management strategy. However, increased selection pressures have led to the emergence of resistant populations that reproduce and establish themselves as dominant communities, thereby severely jeopardizing crop yields. It is especially crucial to reveal the resistance mechanism of D.Sanguinalis, and the lack of weed histology resources has always been an obstacle to the study of resistance mechanism, nowadays, with the development of histology technology, the combination of multi-omics applied to the identification of weed resistance genes is becoming more and more perfect. In our previous study, we have preliminarily demonstrated that the resistance of D.Sanguinalis to ALS inhibitors is related to the increase of P450 enzyme activity. Here, we employed single-molecule real-time (SMRT) sequencing technology to obtain full-length transcripts of D. sanguinalis. Using DIA proteomics, we identified upregulated herbicide-metabolizing proteins, which were validated via PRM analysis. By integrating the transcriptomic and proteomic results, we identified CYP709B2 and CYP74B2 as key effector genes that mediate resistance in D. sanguinalis. We elucidated the resistance patterns and specific genes associated with D. sanguinalis, thereby enriching the bioinformatics resources available for this species and providing a foundation for herbicide-resistant weed management.}, } @article {pmid41164053, year = {2025}, author = {Luan, Z and Narvaez-Correa, IV and Kandimalla, J and Valles, RG and Piriyawat, P}, title = {Clinical Reasoning and Diagnostic Challenge in a 23-Year-Old Man With Rapidly Progressive Dysphagia and Hypophonia: Juvenile-Onset Amyotrophic Lateral Sclerosis Caused by a FUS Gene Mutation.}, journal = {Cureus}, volume = {17}, number = {9}, pages = {e93369}, pmid = {41164053}, issn = {2168-8184}, abstract = {Dysphagia and dysphonia of unclear etiology in young adults pose a significant diagnostic challenge, as these symptoms are more commonly attributed to benign or structural causes rather than serious neurodegenerative disease. The absence of classic neuromuscular signs such as limb weakness, hyperreflexia, or fasciculations can delay consideration of motor neuron disease, particularly when bulbar symptoms occur in isolation. We describe a previously healthy 23-year-old man who presented with rapidly progressive dysphagia and hypophonia, initially misattributed to infectious causes. Despite an extensive workup for structural, autoimmune, and infectious causes, no clear etiology was identified. Neurologic examination revealed predominantly bulbar dysfunction, and electrodiagnostic studies showed acute to subacute denervation changes in the tongue and trapezius muscles. Genetic testing confirmed juvenile-onset amyotrophic lateral sclerosis due to a pathogenic FUS gene mutation (p.Pro525Leu). This case highlights the importance of including motor neuron disease in the differential diagnosis of rapidly progressive bulbar symptoms of unknown origin. It highlights the importance of early electrodiagnostic testing and genetic evaluation in establishing a diagnosis.}, } @article {pmid41164103, year = {2025}, author = {}, title = {Edaravone for amyotrophic lateral sclerosis.}, journal = {Australian prescriber}, volume = {48}, number = {5}, pages = {182-183}, pmid = {41164103}, issn = {0312-8008}, } @article {pmid41165081, year = {2026}, author = {Chalitsios, CV and Gao, J and Coupland, CAC and Cox, JH and Turner, MR and Thompson, AG}, title = {Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Have Distinct Prediagnostic Blood Biochemical Profiles.}, journal = {Annals of neurology}, volume = {99}, number = {4}, pages = {844-856}, pmid = {41165081}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/epidemiology/genetics ; *Frontotemporal Dementia/blood/diagnosis/epidemiology/genetics ; Male ; Female ; Middle Aged ; Biomarkers/blood ; Aged ; Cohort Studies ; Cholesterol/blood ; Cholesterol, LDL/blood ; United Kingdom/epidemiology ; Triglycerides/blood ; Adult ; Glycated Hemoglobin/metabolism/analysis ; Creatinine/blood ; Mendelian Randomization Analysis ; Creatine Kinase/blood ; }, abstract = {OBJECTIVE: Identifying modifiable factors influencing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) risk is important for prevention. Blood biomarkers, particularly cholesterol, have been associated with neurodegenerative risk, but findings in ALS are inconsistent, and data on FTD are limited.

METHODS: We conducted a population-based cohort study using UK primary care records from QResearch linked with Hospital Episode Statistics. Adults with biomarker data recorded between 1998 and 2023 were included. We examined associations of low- and high-density lipoprotein cholesterol (LDL-C and HDL-C), total cholesterol, triglycerides, creatinine, creatine kinase, and HbA1c with ALS and FTD risk. Cox proportional hazards models were used to estimate associations. Two-sample Mendelian randomization (MR) was applied to explore genetically predicted associations of selected biomarkers.

RESULTS: There were up to 2,695 ALS and 781 FTD diagnoses, with a median follow-up duration of 9.4 and 10.5 years, respectively. Higher LDL-C (hazard ratio [HR]per 1-SD = 1.07, 95% confidence interval [CI] = 1.02-1.11) and total cholesterol levels (HRper 1-SD = 1.06, 95% CI = 1.02-1.10) were linearly associated with higher ALS risk. Age-stratified analysis showed a stronger association for total cholesterol in those ≥ 60 years (HRper 1-SD = 1.08, 95% CI = 1.04-1.13, Pinteraction = 0.003). Higher creatinine was inversely associated with FTD risk (HRper 1-SD = 0.90, 95% CI = 0.83-0.97), supported by MR (odds ratio [OR] inverse variance weighted (IVW), per 1-SD = 0.73, 95% CI = 0.56-0.96). HbA1c showed a U-shaped association with FTD (Pnon-linearity = 0.006).

INTERPRETATION: LDL and total cholesterol may provide insights into early disease changes or the etiology of ALS, whereas creatinine and HbA1c may be relevant for FTD. Research in monogenic ALS and FTD is needed to determine whether these biomarkers inform targeted prevention or intervention strategies. ANN NEUROL 2026;99:844-856.}, } @article {pmid41165282, year = {2025}, author = {Roedl, K and Genbrugge, C}, title = {Managing cardiac arrest in the intensive care unit.}, journal = {Current opinion in critical care}, volume = {31}, number = {6}, pages = {729-734}, doi = {10.1097/MCC.0000000000001319}, pmid = {41165282}, issn = {1531-7072}, mesh = {Humans ; *Heart Arrest/therapy/epidemiology/etiology/mortality ; *Intensive Care Units ; *COVID-19/epidemiology ; *Cardiopulmonary Resuscitation/methods ; SARS-CoV-2 ; *Critical Care/methods ; }, abstract = {PURPOSE OF REVIEW: This review aims to explore the distinct clinical characteristics, epidemiology, treatment approaches, and research needs concerning cardiac arrest in the intensive care unit (ICU-CA), a specific subset of in-hospital cardiac arrest (IHCA). While IHCA remains a major cause of mortality, recent data indicate improved outcomes, with a notable variation in incidence and survival depending on the location, particularly within the ICU setting.

RECENT FINDINGS: Recent studies underscore that ICU-CA differs significantly from general IHCA in etiology, monitoring, and treatment environment. Although incidence rates vary widely (4-78 per 1000 ICU admissions), recent data suggest a stabilization. Causes of ICU-CA often involve noncardiac factors such as septic shock and respiratory failure. Treatment is typically guided by general advanced life support (ALS) protocols, but ICU-specific resources such as real-time monitoring, invasive pressure measurements, transesophageal echocardiography, and the potential for extracorporeal cardiopulmonary resuscitation offer unique advantages. The COVID-19 pandemic highlighted the vulnerability of ICU patients, with respiratory causes dominating and extremely poor outcomes reported.

SUMMARY: In summary, ICU-CA represents a distinct clinical entity requiring tailored research. Future directions should prioritize international registries, validation of predictive models using artificial intelligence, and clarification of do-not-resuscitate practices to improve outcomes and resource allocation in this critically ill population.}, } @article {pmid41165792, year = {2025}, author = {Goerdt, LA and Brandl, C and Schuster, AK and Rauscher, FG and Finger, RP and Mauschitz, MM}, title = {[Neurodegeneration and retinal changes-A literature overview].}, journal = {Zeitschrift fur Gerontologie und Geriatrie}, volume = {58}, number = {8}, pages = {645-651}, pmid = {41165792}, issn = {1435-1269}, mesh = {Humans ; *Tomography, Optical Coherence/methods ; *Neurodegenerative Diseases/pathology/diagnostic imaging ; *Retina/pathology/diagnostic imaging ; Aged ; Biomarkers ; }, abstract = {BACKGROUND: The eyes and the central nervous system (CNS) develop from the same embryonic tissue which explains why retinal changes have been observed in various neurological and neurodegenerative diseases. These changes can be visualized in vivo on a cellular and subcellular level using optical coherence tomography (OCT). This article summarizes which retinal changes occur and how these could be used as potential biomarkers of neurodegenerative diseases.

OBJECTIVE: The article gives an overview of the literature on the relationship between neurodegeneration, OCT-based retinal characteristics and cognitive functions.

METHODS: A literature search was carried out in PubMed until February 2025. The search terms "neurodegeneration", "dementia", "mild cognitive impairment", "mild neurocognitive disorder", "OCT", "OCT angiography (OCT-A)", "retinal biomarkers", "retinal layer", "RNFLT", and "GCL" were used. Relevant publications were reviewed, analyzed and summarized.

RESULTS: In OCT‑A Alzheimer's disease, frontotemporal dementia, vascular dementia, amyotrophic lateral sclerosis, multiple sclerosis (MS) and Parkinson's disease demonstrate an association with a reduced retinal nerve fiber layer (RNFL) and the ganglion cell layer (GCL) thickness as well as an enlarged foveal avascular zone.

CONCLUSION: So far retinal changes could not be specifically assigned to a particular form of neurodegenerative disease,; however, they could be meaningful in neuropsychological/radiological examinations and for longitudinal monitoring, as already recommended for MS. Further longitudinal studies are needed to identify and validate retinal biomarkers (patterns).}, } @article {pmid41166771, year = {2025}, author = {Shibuya, E and Miki, Y and Tanaka, MT and Ueno, T and Shimoyama, S and Tatara, Y and Nishijima, H and Arai, A and Suzuki, C and Mori, F and Wakabayashi, K and Tomiyama, M}, title = {Cerebrospinal fluid-driven extracellular vesicle as a potential diagnostic biomarker for multiple system atrophy.}, journal = {Journal of the neurological sciences}, volume = {478}, number = {}, pages = {123738}, doi = {10.1016/j.jns.2025.123738}, pmid = {41166771}, issn = {1878-5883}, mesh = {Humans ; *Multiple System Atrophy/cerebrospinal fluid/diagnosis ; *Extracellular Vesicles/metabolism ; Male ; Female ; Middle Aged ; Biomarkers/cerebrospinal fluid ; Aged ; Parkinson Disease/cerebrospinal fluid/diagnosis ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; }, abstract = {Given that Parkinsonian disorders, including Parkinson's disease (PD) and multiple system atrophy-parkinsonism (MSA-P), often have similar clinical presentations, making a clinical diagnosis can be challenging. In the present study, we extracted and analyzed extracellular vesicles (EVs) from the cerebrospinal fluid of individuals diagnosed with PD (N = 16), MSA-P (N = 16), and amyotrophic lateral sclerosis (ALS) (N = 16), with the latter serving as the control group. Transcriptomic analysis identified 7426 and 8003 differentially expressed RNAs between MSA and ALS, and MSA and PD, respectively. Four transcripts (RN7SL3, RN7SL1, MIR19B2, and SYF2P2) were among the top six transcripts upregulated in MSA-P compared with both ALS and PD. Proteomic analysis revealed notable changes in the levels of corneodesmosin, psoriasin (S100A7), and dystroglycan1 in MSA-P compared with ALS and PD. Notably, S100A7 mRNA levels were also significantly lower in MSA than in the other diseases examined. Furthermore, we found a positive correlation between S100A7 mRNA levels and the heart mean/mediastinum mean ratio on [123]I-metaiodobenzylguanidine myocardial scintigraphy, whereas SYF2P2 mRNA levels were negatively correlated with both the asymmetry index on dopamine transporter scans and Mini Mental State Examination scores. A positive correlation was found between S100A7 levels and motor symptoms. In distinguishing MSA-P from PD, MIR19B2 exhibited the highest Area Under Curve (AUC) of 0.867, demonstrating 100 % sensitivity and 68.7 % specificity. Conversely, the results for CDSN showed an AUC value of 0.847, with 58.3 % sensitivity and 100 % specificity. These combined transcriptomic and proteomic biomarkers could serve as valuable diagnostic tools for MSA.}, } @article {pmid41167574, year = {2026}, author = {Rush, CL and Lester, EG and Mehta, K and Seward, M and Vranceanu, AM}, title = {Patient and Care-Partner Voices in ALS: Shaping Behavioral Health and Collaborative Care.}, journal = {Journal of pain and symptom management}, volume = {71}, number = {2}, pages = {e145-e155}, doi = {10.1016/j.jpainsymman.2025.10.020}, pmid = {41167574}, issn = {1873-6513}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; Male ; Female ; Middle Aged ; Aged ; *Caregivers/psychology ; Psychological Distress ; Adult ; Surveys and Questionnaires ; Health Services Accessibility ; }, abstract = {CONTEXT: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease. Nearly half of people with ALS (pALS) and their care partners experience significant emotional distress, particularly around the time of diagnosis, yet behavioral health needs are inconsistently addressed.

OBJECTIVES: To explore perspectives of pALS and care partners regarding emotional distress, behavioral health needs and preferences, and access to behavioral health resources within their clinics and communities.

METHODS: 134 participants (88 pALS and 46 care partners) were recruited through ALS Y nonprofit listservs to complete an online survey developed by the study team. The survey included closed- and open-ended questions assessing behavioral health history, current needs, access to services, and preferred care approaches.

RESULTS: Participants (59.7%, n = 80) self-reported lack of behavioral health screening, 47.7% (n = 42) of pALS reported new behavioral health diagnoses after ALS diagnosis. 46 (52.3%) of pALS and 32 (69.6%) of care partner proxies expressed a need for behavioral health care at time of ALS diagnosis and were open to a range of provider types. Open-ended responses noted limited time, need for ALS-tailored behavioral health care, and feeling overwhelmed postdiagnosis.

CONCLUSION: Findings highlight current gaps and opportunity to enhance behavioral health within interdisciplinary care. Embedding brief, flexible interventions delivered by a range of trained providers-particularly at key transitions-may support emotional well-being, care engagement, and quality of life for pALS and care partners.}, } @article {pmid41169204, year = {2026}, author = {Setsu, S and Okano, H and Morimoto, S}, title = {Advancements in differentiation of induced pluripotent stem cells into specialized neuronal subtypes.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {4680-4689}, pmid = {41169204}, issn = {1673-5374}, abstract = {The ability to generate specialized human neurons from induced pluripotent stem cells has revolutionized neuroscience, regenerative medicine, and drug discovery. Since their discovery, induced pluripotent stem cells have emerged as an ethically favorable and versatile platform to model human neurological diseases, offering new insights beyond traditional animal models. In the past decade, rapid advances have enabled the efficient differentiation of induced pluripotent stem cells into diverse neuronal subtypes, including glutamatergic neurons, GABAergic neurons, dopaminergic neurons, serotonergic neurons, motor neurons, sensory neurons, Purkinje cells, sympathetic neurons, parasympathetic neurons, and noradrenergic neurons. Tailored combinations of developmental signaling molecules, transcription factor programming, and small molecule modulation have dramatically improved the reproducibility, scalability, and functional maturity of these differentiated neurons. These advancements are particularly timely as they underpin the next generation of disease modelling platforms, high-throughput drug screening systems, and emerging cell-based therapies for conditions such as Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and Alzheimer's disease. Moreover, the field is moving toward standardized, chemically defined protocols and improved validation pipelines, including electrophysiological assays and molecular profiling, to ensure the authenticity and maturity of induced pluripotent stem cell-derived neurons. Notably, recent breakthroughs in sympathetic and parasympathetic neuron derivation are expanding the scope of induced pluripotent stem cell technology into autonomic nervous system research and cardiac neuromodulation studies. However, challenges remain, including variability across induced pluripotent stem cell lines, incomplete neuronal maturation, and scalability constraints for clinical-grade applications. Addressing these hurdles through optimization of patterning cues, co-culture systems, and advanced bioprocessing strategies will be crucial to realizing the full translational potential of induced pluripotent stem cell-derived neurons. Collectively, the methodologies and developments summarized here mark a major step toward achieving faithful, efficient, and scalable generation of human neurons in vitro , laying the foundation for personalized neurology and regenerative medicine.}, } @article {pmid41169216, year = {2026}, author = {Chisholm, CG and McAlary, L and Lum, JS}, title = {From translation to stabilization and degradation: A multifaceted approach for the treatment of superoxide dismutase 1-associated amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {21}, number = {7}, pages = {2946-2947}, pmid = {41169216}, issn = {1673-5374}, } @article {pmid41169217, year = {2026}, author = {Mirshahvaladi, S and Gaire, BP and Kashani, SA and Guha, A and Koronyo, Y and Fuchs, DT and You, Y and Black, KL and Paulo, JA and Graham, SL and Gupta, V and Mirzaei, M and Koronyo-Hamaoui, M}, title = {Retinal proteomics in neurodegeneration: Insights into ocular and brain disorders.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {4690-4703}, pmid = {41169217}, issn = {1673-5374}, support = {R01 AG055865/AG/NIA NIH HHS/United States ; R01 AG056478/AG/NIA NIH HHS/United States ; R01 AG075998/AG/NIA NIH HHS/United States ; }, abstract = {Dysregulated proteome in the retina represents a promising avenue for discovering novel therapeutic targets and noninvasive diagnostic biomarkers for neurodegenerative diseases with ocular manifestations. Advanced mass spectrometry-based proteomics techniques have shown considerable potential in investigating the retinal proteome in diseases such as glaucoma, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, as well as Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Recent proteomics innovations are overcoming challenges such as limited sample size and protein coverage that previously hindered comprehensive retinal proteome analysis. Notably, the incorporation of artificial intelligence-driven computational pipelines, including Graphics Processing Unit-accelerated deep learning architectures, has markedly enhanced the precision and effectiveness of retinal proteomics. These advances facilitate high-resolution identification of novel protein signatures within large-scale multi-omics datasets. Furthermore, the integration of advanced artificial intelligence with state-of-the-art big data infrastructures supports the early detection of biomarkers and therapeutic targets in neurodegenerative diseases with ocular involvement, offering unprecedented disease specificity and sensitivity. In addition to these computational strides, emerging complementary and alternative technologies continue to provide valuable tools for retinal analysis, expanding the potential for identifying biomarker and therapeutic targets in both ophthalmic and neurodegenerative disorders. This review summarizes recent advancements in retinal proteomics, with a particular focus on neurodegenerative and ocular diseases.}, } @article {pmid41169507, year = {2025}, author = {Shao, W and Albagli, EA and Jansen-West, K and Daughrity, LM and Tong, J and Hysi, A and Jiang, P and Todd, TW and Lee, E and Alepuz, DZ and Carlomagno, Y and Yue, M and Dunmore, JA and Castanedes-Casey, M and Otero, PC and Kurti, A and Prudencio, M and Cook, CN and Dickson, DW and Gendron, TF and Petrucelli, L and Zhang, YJ}, title = {Endolysosomal dysfunction impairs proteostasis and induces neurodegeneration in vivo.}, journal = {iScience}, volume = {28}, number = {10}, pages = {113460}, pmid = {41169507}, issn = {2589-0042}, support = {R01 AG065219/AG/NIA NIH HHS/United States ; R01 AG063780/AG/NIA NIH HHS/United States ; R01 NS120992/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R01 NS117461/NS/NINDS NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; R01 AG071513/AG/NIA NIH HHS/United States ; }, abstract = {Transactive response (TAR) DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of the frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) spectrum. Dysfunction of the endolysosomal system, which plays a crucial role in protein trafficking and maintaining proteostasis, has been implicated in FTD-ALS pathogenesis. While the impact of endolysosomal dysfunction on TDP-43 pathology remains unclear, we demonstrated that disrupting the endolysosomal pathway by expressing the constitutively active endosomal protein, Rab5[Q79L], induces TDP-43 aggregation in cultured cells. Here, we generated a mouse model expressing GFP-tagged Rab5[Q79L], demonstrating that GFP-Rab5[Q79L] mice exhibit early motor deficits and endolysosomal dysfunction, including enlarged endosomes, abnormal lysosome morphology, and p62- or ubiquitin-positive inclusions. These mice also developed significant neuronal loss, neuroinflammation, phosphorylated TDP-43 (pTDP-43) inclusions, and nuclear envelope and nuclear pore structural defects reminiscent of FTD-ALS. Accordingly, GFP-Rab5[Q79L] mice will prove useful in expanding our understanding of endolysosomal dysfunction in proteostasis and pTDP-43 pathology.}, } @article {pmid41169598, year = {2025}, author = {Yip, MK and Au Yeung, M and Poon, WT}, title = {Two Families With Amyotrophic Lateral Sclerosis Founder Mutation TARDBP p.G298S in Hong Kong.}, journal = {Cureus}, volume = {17}, number = {10}, pages = {e95667}, pmid = {41169598}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS), which is characterized by progressive deterioration of upper and lower motor neurons resulting in severe muscle atrophy, respiratory failure, and death, is a rare and fatal neurodegenerative disease. TARDBP p.G298S was recently identified as a founder mutation in southern Chinese. This article first presented case summaries of three ALS patients: two families with TARDBP p.G298S presenting with heterogeneous clinical phenotypes, including a case with an unusual extraocular muscle onset. A review of TARDBP p.G298S cases reported worldwide was conducted, surveying the age and site of onset, disease duration, and motor neuron involvement. Finally, an overview of genetic mutations reported locally for ALS was presented, showing that TARDBP p.G298S is a common mutation detected in this locality. This article highlighted the distinct clinical manifestations and genetic background in ALS patients and will be useful for developing genetic screening and counseling strategies in Hong Kong and southern China.}, } @article {pmid41170888, year = {2025}, author = {Geoffrion, D and Mikhail, D and Rizk, M and Harissi Dagher, M}, title = {Letter to the Editor: Comment on Adamovich-Zeitlina et al's "Clinical Outcomes of Boston Type 1 Keratoprosthesis With and Without Endophthalmitis During the Covid-19 Pandemic".}, journal = {Ocular immunology and inflammation}, volume = {33}, number = {10}, pages = {2581-2582}, doi = {10.1080/09273948.2025.2583219}, pmid = {41170888}, issn = {1744-5078}, mesh = {Humans ; *COVID-19/epidemiology ; *Endophthalmitis/epidemiology/etiology ; *SARS-CoV-2 ; *Corneal Diseases/surgery ; *Cornea/surgery ; Visual Acuity ; Incidence ; *Eye Infections, Bacterial/epidemiology ; *Artificial Organs ; }, abstract = {Authors reported an 18% rate of endophthalmitis in Boston type 1 keratoprosthesis (KPro) patients, higher than previously reported rates. Most cases occurred during the COVID-19 pandemic, likely due to reduced access to care. Bandage contact lens wear was found to be protective, supporting its role as standard of care in KPro eyes. Black patients experienced higher rates of endophthalmitis, highlighting disparities in eye care. Vancomycin prophylaxis did not reduce the risk of endophthalmitis in KPro eyes and may increase the number of fungal cases, supporting the selective use of topical antibiotics. Despite the higher incidence of endophthalmitis in this study, visual outcomes remained stable, emphasizing the importance of lifelong follow-up and equitable access to care for all KPro patients.}, } @article {pmid41171075, year = {2025}, author = {Cazzola, J and Talpo, F and Faravelli, G and Donati, C and Maramai, S and Saletti, M and Giuliani, G and Paolino, M and Cappelli, A and Anzini, M and Sommi, P and Vitali, A and Sala, A and Trucco, A and Biella, GR and Spaiardi, P}, title = {Evaluation of a New Riluzole-Based Compound VA945 on Sodium and Potassium Conductances Expressed by SH-SY5Y- Derived Neurons.}, journal = {Journal of neurochemistry}, volume = {169}, number = {11}, pages = {e70280}, pmid = {41171075}, issn = {1471-4159}, mesh = {*Riluzole/pharmacology/analogs & derivatives ; Humans ; *Neurons/drug effects/metabolism ; *Neuroprotective Agents/pharmacology ; Cell Line, Tumor ; Potassium/metabolism ; *Potassium Channels ; Sodium/metabolism ; Membrane Potentials/drug effects ; Patch-Clamp Techniques ; *Sodium Channels ; Dose-Response Relationship, Drug ; }, abstract = {Riluzole (Rilutek), a derivative of benzothiazole, acts as a neuroprotective agent by inhibiting voltage-dependent sodium (Na[+]) and delaying rectifier potassium (K[+]) currents. By doing so, it helps reduce excitotoxicity, a key pathogenetic mechanism in various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although riluzole is a clinically approved treatment for ALS, it is not fully effective, particularly in advanced stages of the disease. In this study, we functionally characterized a newly synthetized riluzole-based compound, VA945, with potentially enhanced neuroprotective effects. By means of SH-SY5Y human neuroblastoma cells differentiated into neurons, we assessed using whole-cell patch-clamp techniques the effects of VA945 on voltage-dependent Na[+] and K[+] currents at extracellular concentrations of 5, 50, and 100 μM. The compound reduced maximal activation and inactivation of Na[+] conductance, as well as maximal activation of K[+] conductance, across all tested concentrations. We also observed shifts of the activation and inactivation curves to more hyperpolarized potentials along with changes in the slope factor (k), indicating an altered voltage sensitivity of voltage-dependent K[+] and Na[+] channels. While the activation kinetics of both channels remained unaffected, and the inactivation kinetics of Na[+] were unchanged, we noted a slowdown in the deactivation kinetics of the K[+] channels. Altogether, these findings suggest that VA945 exerts multi-target pharmacological effects on neuronal voltage-dependent ion currents critically involved in excitotoxicity and neurodegeneration, across a wide range of concentrations. This warrants further ex vivo and/or in vivo studies to explore its potential as a neuroprotective agent.}, } @article {pmid41171096, year = {2025}, author = {Deng, X and Bradshaw, GA and Kalocsay, M and Mitchison, T}, title = {Tubulin regulates stability and localization of STMN2 by binding preferentially to its soluble form.}, journal = {The Journal of cell biology}, volume = {224}, number = {12}, pages = {}, pmid = {41171096}, issn = {1540-8140}, support = {R35 GM131753/GM/NIGMS NIH HHS/United States ; RR220032//Cancer Prevention and Research Institute of Texas/ ; R35GM131753/GM/NIGMS NIH HHS/United States ; }, mesh = {*Tubulin/metabolism ; Humans ; Protein Binding ; Animals ; Protein Stability ; Proteasome Endopeptidase Complex/metabolism ; trans-Golgi Network/metabolism ; Proteolysis ; Cell Membrane/metabolism ; HEK293 Cells ; Protein Transport ; Solubility ; }, abstract = {The small, tubulin-binding protein STMN2 is highly expressed in neurons and is implicated in amyotrophic lateral sclerosis. STMN2 degrades rapidly and accumulates at axotomy sites, suggesting fast turnover is crucial for its neuroprotective function. We show that STMN2 was primarily degraded by the ubiquitin-proteasome system. Its membrane-targeting N-terminal domain promoted fast turnover, whereas its tubulin-binding domain promoted stabilization. Proximity labeling and imaging showed that tubulin binding reduced STMN2 targeting to trans-Golgi network membranes. Pull-down assays showed that tubulin binds preferentially to soluble over membrane-bound STMN2. Our observations suggest that STMN2 interconverts between a soluble, tubulin-bound form and a membrane-bound, tubulin-free form, and is rapidly degraded when released from both membranes and tubulin. We propose that tubulin binding sequesters and stabilizes STMN2, while its neuroprotective function involves an unknown membrane activity.}, } @article {pmid41171761, year = {2025}, author = {Smeyers, J and Oses-Prieto, JA and Yadanar, L and Wang, M and Iadarola, M and Lu, S and Wang, KS and Watanabe, TH and Debnath, J and Burlingame, AL and Mordes, DA}, title = {Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks.}, journal = {Cell reports}, volume = {44}, number = {11}, pages = {116494}, pmid = {41171761}, issn = {2211-1247}, support = {R01 AG089849/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Protein Serine-Threonine Kinases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Neurons/metabolism ; *Autophagy ; Induced Pluripotent Stem Cells/metabolism ; Phosphorylation ; *Frontotemporal Dementia/metabolism/pathology/genetics ; *Proteome/metabolism ; Cell Cycle Proteins/metabolism ; Proteomics/methods ; Transcription Factor TFIIIA/metabolism ; Membrane Transport Proteins/metabolism ; *Phosphoproteins/metabolism ; }, abstract = {Loss-of-function variants in TBK1, encoding a protein kinase, are strongly associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, how haploinsufficiency for TBK1 leads to age-related neurodegeneration remains unresolved. Here, we utilize sets of isogenic induced pluripotent stem cells (iPSCs) with loss of TBK1 or loss of optineurin (OPTN) for quantitative global proteomics and phospho-proteomics in both stem cells and excitatory neurons. We found that TBK1 sustains the abundance and phosphorylation of its interacting adapter proteins, AZI2/NAP1, TANK, and TBKBP1/SINTBAD. Moreover, TBK1 regulates the phosphorylation of endo-lysosomal proteins, such as GABARAPL2, the late-endosome GTPase RAB7A, and selective autophagy cargo receptor proteins-including novel phospho-sites in p62/SQSTM1-in neurons. Finally, we provide a census of the phospho-proteome in nascent human neurons for further studies. Overall, TBK1 serves as a point of convergence in ALS/FTD-linked endo-lysosomal networks that act in a cell-autonomous manner to maintain protein homeostasis in neurons.}, } @article {pmid41173461, year = {2026}, author = {Gunderson, R and Smith, L and Cornell, PY and Carder, P and Thomas, K}, title = {Medicaid Mechanisms and State Licensure: Pathways to Payment in Assisted Living.}, journal = {Journal of the American Medical Directors Association}, volume = {27}, number = {1}, pages = {105961}, pmid = {41173461}, issn = {1538-9375}, support = {R01 AG057746/AG/NIA NIH HHS/United States ; R01 AG082308/AG/NIA NIH HHS/United States ; RF1 AG082308/AG/NIA NIH HHS/United States ; }, mesh = {*Medicaid/economics ; United States ; Humans ; *Licensure ; *Assisted Living Facilities/economics/legislation & jurisprudence ; *Reimbursement Mechanisms ; State Government ; }, abstract = {OBJECTIVES: To document and highlight the variation in the types of assisted living (AL) licensed settings eligible for Medicaid home and community-based services (HCBS) payment.

DESIGN: Observational descriptive study.

SETTING AND PARTICIPANTS: We examined 32,991 licensed AL communities across all 50 states and the District of Columbia, representing 215 unique license combinations operating in 2019. We analyzed 6 Medicaid mechanisms: 1915(b), 1915(c), and 1115 waivers, and 1905(a), 1915(i), and 1915(k) state plan amendments.

METHODS: We empirically reviewed the waivers and state plans active in 2019 providing Medicaid-paid care and documented any eligible AL licenses. We compared the characteristics of eligible and ineligible AL licenses, including geography, number of AL communities represented, and AL capacity.

RESULTS: Overall, 89% of AL communities operated under a license type that is eligible for Medicaid payment through a waiver, state plan amendment, or other contracting mechanism. Forty-five states and DC employed a mechanism to reimburse care in AL with Medicaid payments, most having a 1915(c) waiver; 13 states that authorized Medicaid-reimbursed care in AL limited this benefit to a subset of licenses. AL communities operating under a license type that granted Medicaid contract eligibility had a smaller average capacity than those operating under licenses that did not allow for Medicaid payment.

CONCLUSIONS AND IMPLICATIONS: This paper builds on previous research that found associations between the percentage and concentration of dually enrolled residents in AL and state-level Medicaid payment mechanisms. We found that although most AL communities are eligible to accept Medicaid payment, the proportion of eligible ALs differs across states. Our research suggests that Medicaid policy may affect the accessibility of AL not only at the state level but also based on the type of license, which determines the type of care and services an AL can provide.}, } @article {pmid41173878, year = {2025}, author = {Sharaireh, A and Guevara-Ferrer, M and Ludlaim, AM and Humphries, JD and Phillips, AM and Dowsey, AW and Zhang, Z and Counsell, JR and Unwin, RD and Mole, SE and Rahim, AA and McKay, TR}, title = {CLN7 protein functions at the interface between endolysosomes and stress granules to promote cell survival.}, journal = {Cell death & disease}, volume = {16}, number = {1}, pages = {772}, pmid = {41173878}, issn = {2041-4889}, mesh = {Humans ; *Lysosomes/metabolism ; *Neuronal Ceroid-Lipofuscinoses/metabolism/pathology/genetics ; Cell Survival ; *Stress Granules/metabolism ; Induced Pluripotent Stem Cells/metabolism ; *Endosomes/metabolism ; Neural Stem Cells/metabolism ; Mitochondria/metabolism ; }, abstract = {Inherited biallelic mutations in the CLN7 gene result in the variant late infantile onset neuronal ceroid lipofuscinosis, a subtype of Batten disease (BD), a severe and fatal childhood neurodegenerative disease. Intriguingly, CLN7 genetic variants have also been associated with retinopathies, amyotrophic lateral sclerosis, and frontotemporal dementia. CLN7 encodes a transmembrane protein localizing to endolysosomal membranes with outward-facing chloride channel activity. Loss of CLN7 function results in cortical neurons accumulating swollen lipofuscin-containing lysosomes, leading to neuroinflammation and neurodegeneration. The molecular mechanisms underlying CLN7 BD neuropathology are not completely understood. We have generated iPSC lines from two CLN7 BD patients and age-matched unaffected controls to interrogate intracellular molecular phenotypes in iPSC-derived neural progenitor cells (iNPC). Taking a multi-omics approach we have identified disease-modified activities in endolysosomal transport in iNPC[BD] that lead to lysosomal dysfunction and decreased mitophagy, resulting in the accumulation of metabolically defective mitochondria. We further observe a breakdown in nuclear functions that centre on RNA processing and nuclear export, linking to CLN7 protein interactions at the stress granule. We have identified dual and distinct functions for CLN7, promoting cell survival during the cellular stress response. CLN7 loss of function in BD results in neuronal apoptosis.}, } @article {pmid41173979, year = {2025}, author = {Zhao, Y and Savelieff, MG and Li, X and Guo, K and Wang, K and Li, M and Li, B and Iyer, G and Sakowski, SA and Zhao, L and Teener, SJ and Bakulski, KM and Dou, JF and Traynor, BJ and Karnovsky, A and Batterman, SA and Hur, J and Goutman, SA and Sartor, MA and Feldman, EL}, title = {Gene expression signatures from whole blood predict amyotrophic lateral sclerosis case status and survival.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {9631}, pmid = {41173979}, issn = {2041-1723}, support = {20-IIA-532//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; P30ES017885//U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)/ ; R01NS127188//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS120926//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01ES030049//U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)/ ; P30 ES017885/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/mortality/diagnosis ; Male ; Female ; Middle Aged ; *Transcriptome ; Prognosis ; Gene Expression Profiling ; Case-Control Studies ; Machine Learning ; Aged ; Adult ; ROC Curve ; Sequence Analysis, RNA ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disease with a median survival of only 2 to 4 years from diagnosis. Improved tools are needed to shorten diagnostic delays and improve prognostication to benefit clinical care. Herein, we profiled whole blood gene expression by RNA sequencing in a large cohort of ALS participants (n = 422) versus controls (n = 272). Several machine learning classifiers trained on our detailed gene expression dataset accurately predicted case-control status, including in a fully independent external test cohort, achieving an area under the receiver operating characteristic curve of 0.894 with the best performing model. Integrating gene expression features with clinical variables improved our ability to discriminate ALS cases into shorter, intermediate, and longer survival in an external dataset. Finally, we identified ALS-relevant pathways in our blood transcriptomics dataset as well as "core genes" that overlapped with gene expression changes occurring in the primary disease tissue, facilitating a drug perturbation analysis that identified several candidates. Overall, our results highlight the potential diagnostic and prognostic applications of whole blood gene expression data, with important implications for improving ALS clinical care.}, } @article {pmid41174170, year = {2025}, author = {Joseph, BJ and Marshall, KA and Harley, P and Mann, JR and Alessandrini, F and Vanoye, CG and Chi, W and Prudencio, M and Simkin, D and Kao, TT and Desai, RR and Keuss, MJ and Barattucci, S and Zanovello, M and Mehta, PR and DeKeyser, JM and Limone, F and Lee, J and Brown, AL and Leyton-Jaimes, MF and Nash, LA and Juan, IGS and Aronica, E and Wainger, BJ and Shah, M and Goswami, A and Shneider, NA and Dickson, DW and Burrone, J and Zhang, C and Wichterle, H and Petrucelli, L and Watts, JK and George, AL and Fratta, P and Eggan, K and Kiskinis, E}, title = {TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD.}, journal = {Nature neuroscience}, volume = {28}, number = {12}, pages = {2476-2492}, pmid = {41174170}, issn = {1546-1726}, support = {U54 NS108874/NS/NINDS NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; R35GM145279//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; I01 BX002466/BX/BLRD VA/United States ; R35NS097273//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R01NS104219//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; T32 AG020506/AG/NIA NIH HHS/United States ; NS108874//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS125018/NS/NINDS NIH HHS/United States ; U54NS123743//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; S10 OD034362/OD/NIH HHS/United States ; R01NS125018//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; RF1 NS120992/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R35 GM145279/GM/NIGMS NIH HHS/United States ; R01 NS104219/NS/NINDS NIH HHS/United States ; RF1NS120992//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/physiopathology ; *KCNQ2 Potassium Channel/genetics/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology/physiopathology ; Induced Pluripotent Stem Cells ; *Motor Neurons/metabolism/physiology ; *RNA Splicing ; Neurons ; Male ; Female ; Animals ; }, abstract = {Motor neuron hyperexcitability is a broadly observed yet poorly understood feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Nuclear depletion and cytoplasmic aggregation of the RNA splicing protein TAR DNA-binding protein 43 (TDP-43) are observed in most ALS and FTD patients. Here we show that TDP-43 dysfunction causes mis-splicing of KCNQ2, which encodes a voltage-gated potassium channel (Kv7.2) that regulates neuronal excitability. Using iPSC-derived neurons and postmortem ALS/FTD brain and spinal cord tissue we find widespread, disease-specific and TDP-43-specific skipping of an exon encoding the KCNQ2 pore domain. The mis-spliced mRNA escapes degradation and is translated into a nonfunctional protein with severely reduced ion conductance that aggregates in the endoplasmic reticulum and causes intrinsic hyperexcitability in ALS neuronal models. This event, which correlates with higher phosphorylated TDP-43 levels and earlier age of disease onset in patients, can be rescued by splice-modulating antisense oligonucleotides that dampen hyperexcitability in induced pluripotent stem cell cortical neurons and spinal motor neurons with TDP-43 depletion. Our work reveals that nuclear TDP-43 maintains the fidelity of KCNQ2 expression and function and provides a mechanistic link between established excitability disruption in ALS/FTD patients and TDP-43 dysfunction.}, } @article {pmid41175111, year = {2026}, author = {Sewell-Green, AR and Kuiper, M and Holdom, CJ and Beelen, A and Ngo, ST and Steyn, FJ and Matthews-Rensch, KL}, title = {Examining the impact and role of lipid classes on the risk of amyotrophic lateral sclerosis (ALS) onset: a systematic review and GRADE analysis of the evidence.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {370-382}, doi = {10.1080/21678421.2025.2574685}, pmid = {41175111}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/epidemiology/diagnosis ; *Lipids/blood/classification ; Risk Factors ; }, abstract = {BACKGROUND: This study aimed to synthesize existing research on pre-diagnostic blood lipid levels and the risk of amyotrophic lateral sclerosis (ALS) onset in adults, and the quality of this evidence.

METHODS: A systematic review was conducted (8 March 2024, updated 19 June 2025) across six databases (PubMed, Embase, CINAHL, Scopus, Cochrane Library, and Web of Science) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, identifying adult clinical studies of blood lipids measured prior to ALS onset. Studies with high risk of bias, assessed using the Quality in Prognostic Studies tool, were excluded. Standardized mean difference and 95% confidence intervals were calculated. Study outcomes were categorized by lipid class as indicating reduced, no effect, or increased ALS risk. Certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.

RESULTS: Of 7222 studies identified, eight (n = 7 sterol lipids, n = 1 fatty acids) met inclusion. No significant differences in sterol lipids were observed between ALS cases and controls (I[2] = 69.9-77.3%). Most studies reported no association or increased risk between ALS onset and higher total cholesterol, triglycerides, LDL-C, HDL-C, or LDL/HDL ratio. For HDL-C, two studies showed protective associations. A single fatty acid study reported increased disease risk with higher arachidonic acid and reduced risk with higher alpha-linoleic acid. Certainty of evidence was low to very low.

CONCLUSION: Circulating sterol lipid levels were inconsistently associated with ALS risk. The overall low certainty of evidence, and variability of findings across studies call for research using standardized designs, high-resolution lipid profiling, and robust causal inference approaches to clarify the role of lipids in ALS risk.}, } @article {pmid41175163, year = {2026}, author = {Baindoor, S and Gibriel, HAY and Kool, L and Su, J and Demaegd, KC and Venø, MT and Van Den Berg, LH and Kjems, J and Van Es, MA and Prehn, JHM}, title = {Serum small non-coding RNA define molecular subtypes in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {383-392}, doi = {10.1080/21678421.2025.2574690}, pmid = {41175163}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/diagnosis/classification ; Male ; Female ; Middle Aged ; Biomarkers/blood ; Aged ; *RNA, Small Untranslated/blood/genetics ; *MicroRNAs/blood/genetics ; RNA, Transfer/genetics/blood ; Adult ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with variable site of onset, disease progression rates and survival times. Early-stage ALS characteristics are shared with other conditions, posing diagnostic challenges and resulting in diagnosis delays. We investigated tRNA-derived small RNAs (tsRNAs) and microRNAs (miRNAs) which are stable and abundantly expressed small non-coding RNAs (sncRNAs) as potential diagnostic serum biomarkers, comparing them to healthy controls and ALS mimics, and gained pathophysiological insights from dysregulated sncRNAs.

METHODS: We analyzed small RNA-seq data from 158 patients with ALS, 60 healthy controls and 39 patients with neurological conditions that mimic ALS to identify differentially expressed sncRNAs. A classifier was built to evaluate their diagnostic potential, followed by hierarchical clustering to identify ALS molecular subtypes. Finally, we performed gene ontology and pathway analysis to identify pathways disrupted within subtypes.

RESULTS: We identified several dysregulated tsRNAs and miRNAs and assessed their diagnostic potential using an extreme gradient boosting (XGBoost) classifier. Our models achieved an accuracy of 87.16% and 82.23% in classifying patients with ALS from healthy controls and ALS mimics, respectively. We identified four sncRNA expression-based ALS molecular subtypes with one C9orf72 enriched cluster. Further analysis of identified differentially expressed sncRNAs showed their involvement in neuronal pathways.

CONCLUSION: Our study identified potential sncRNA-based diagnostic serum biomarkers and associated molecular subtypes which can be further studied to match clinical parameters and develop subtype specific biomarkers and therapeutic strategies for ALS.}, } @article {pmid41175185, year = {2025}, author = {Yang, T and Wang, Y and Yan, X and Qiu, Y and Lin, T and Luo, J and Tong, J and Mao, J and Dai, Y and Yu, Y and Zhao, M and Yang, G}, title = {Association between Onodera's prognostic nutritional Index and ultrasound-measured muscle thickness in amyotrophic lateral sclerosis: a retrospective cross-sectional study.}, journal = {Annals of medicine}, volume = {57}, number = {1}, pages = {2578733}, pmid = {41175185}, issn = {1365-2060}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/complications/pathology/physiopathology ; Male ; Female ; Retrospective Studies ; Middle Aged ; Ultrasonography ; Cross-Sectional Studies ; Aged ; Prognosis ; *Nutritional Status ; *Nutrition Assessment ; *Muscle, Skeletal/diagnostic imaging/pathology ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) causes progressive muscle wasting. Ultrasound-measured thickness captures this loss. Nutritional status influences ALS prognosis, yet the link between Onodera's Prognostic Nutritional Index (OPNI) and muscle thickness is unclear.

OBJECTIVE: To assess whether OPNI correlates with thickness of the first dorsal interosseous (FDI), biceps brachii (BB) and masseter (MM) muscles, and to judge OPNI's utility as a practical nutrition marker in ALS.

METHODS: In this retrospective study of 150 ALS patients, ultrasound quantified FDI, BB and MM thickness. Patients were stratified by OPNI quartile. Group differences were tested with ANOVA/Kruskal-Wallis. Multivariable generalized linear models, adjusting for age, sex, ALSFRS-R, King's stage, comorbidities and lifestyle factors, examined independent associations; restricted cubic splines probed non-linearity.

RESULTS: Muscle thickness rose progressively across OPNI quartiles (p < 0.05 for trend). After full adjustment, each 1-point OPNI increase predicted 0.008 cm thicker FDI (95% CI 0.003-0.014; p = 0.004), 0.022 cm thicker BB (95% CI 0.005-0.039; p = 0.011) and 0.011 cm thicker MM (95% CI 0.002-0.020; p = 0.013). Spline analysis supported a linear relationship.

CONCLUSION: Higher OPNI independently predicts greater muscle thickness, indicating that better nutritional status parallels reduced muscle wasting in ALS. OPNI's low cost and rapid availability support its use to flag patients for early nutritional intervention.}, } @article {pmid41175647, year = {2025}, author = {Singh, A and Gupta, I and Saha, P and Hole, A and Anthony, F and Natu, A and Smoot, DT and Ashktorab, H and Chilakapati, MK and Gupta, S}, title = {Raman spectroscopy for detecting gastric and liver cancer cells that entered a tolerant persistence state to survive cisplatin chemotherapy.}, journal = {Biochemical and biophysical research communications}, volume = {790}, number = {}, pages = {152891}, doi = {10.1016/j.bbrc.2025.152891}, pmid = {41175647}, issn = {1090-2104}, mesh = {Humans ; *Cisplatin/pharmacology/therapeutic use ; *Stomach Neoplasms/drug therapy/pathology ; *Drug Resistance, Neoplasm/drug effects ; *Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; *Spectrum Analysis, Raman/methods ; *Liver Neoplasms/drug therapy/pathology ; Cell Survival/drug effects ; Neoplasm, Residual ; }, abstract = {The persistence of minimal residual disease (MRD), a small population of tumor cells that survive therapy but remain below the limit of conventional detection methods, often leads to relapse. The residual disease is attributed to drug-tolerant persister (DTP) cells at the cellular level. In the present study, the differences in drug-tolerant persister cells, which represent a transient, reversible survival state, and drug-resistant cells, which reflect a stable, fixed phenotype of gastric and liver cancer cell lines, were investigated. The ultramicroscopic and confocal studies revealed a phenotypic shift in DTP cells induced upon drug treatment, characterized by cytoplasmic expansion, enhanced mitochondrial biogenesis, and active intercellular communication, potentially contributing to the survival of the drug-tolerant cells. The observed morphological alterations in a cell's physical characteristics are associated with underlying biochemical changes. Further, Raman spectroscopy provides a non-invasive method for studying biochemical alterations; Raman spectral analysis demonstrated precision in distinguishing with significant accuracy between DTP cells compared to resistant and parental cells. Multivariate Curve Resolution-alternating least squares (MCR-ALS) analysis showed alteration of lipid, nucleic acid, and protein-related features. The accumulation of lipid vacuoles inside the cytoplasm of DTP cells, and gene set enrichment analysis (GSEA) showed significant downregulation of metabolic pathways purine and pyrimidine, highlighting the potential metabolic shift in imparting a survival advantage to DTP cells. Thus, Raman analysis has confirmed the biochemical changes and provides proof of concept for identifying cisplatin-induced DTP and resistant tumor cells for a better therapeutic approach in resistant and relapse management.}, } @article {pmid41175990, year = {2025}, author = {Konopka, A}, title = {Perspectives on the utilization of cell-free DNA in amyotrophic lateral sclerosis (ALS) diagnostics and prognostics - insight from cancer research.}, journal = {Neurobiology of disease}, volume = {217}, number = {}, pages = {107167}, doi = {10.1016/j.nbd.2025.107167}, pmid = {41175990}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/blood ; *Cell-Free Nucleic Acids/blood ; Prognosis ; Biomarkers/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) remains a devastating neurodegenerative disease with limited diagnostic and prognostic tools. In recent years, cell-free DNA (cfDNA) has emerged as a promising non-invasive biomarker in various clinical settings, particularly in oncology. Despite its potential, the application of cfDNA in ALS is still in its early stages, and several critical gaps must be addressed. This discussion article reviews the current knowledge about cfDNA in ALS and explores its potential applications for disease diagnosis, monitoring, and prognosis. Drawing on the advances made in cancer research, it also examines the challenges that ALS research may face in cfDNA utilization, highlighting lessons learned from oncology. Taken together, these insights point to the urgent need for a comprehensive understanding of cfDNA characteristics specific to ALS. Given the current lack of reliable diagnostic and prognostic biomarkers in ALS, further investigation into cfDNA represents a valuable and necessary scientific endeavor with the potential to transform patient care and disease management.}, } @article {pmid41176389, year = {2025}, author = {Shimazu, Y}, title = {Stratifying IL-2 therapy in ALS: integrating biomarkers.}, journal = {Lancet (London, England)}, volume = {406}, number = {10515}, pages = {2061}, doi = {10.1016/S0140-6736(25)01737-4}, pmid = {41176389}, issn = {1474-547X}, } @article {pmid41176390, year = {2025}, author = {Bensimon, G and Leigh, PN and Tree, T}, title = {Stratifying IL-2 therapy in ALS: integrating biomarkers - Authors' reply.}, journal = {Lancet (London, England)}, volume = {406}, number = {10515}, pages = {2061-2062}, doi = {10.1016/S0140-6736(25)01958-0}, pmid = {41176390}, issn = {1474-547X}, } @article {pmid41176929, year = {2025}, author = {Akan, T and Akan, S and Alp, S and Ledbetter, CR and Tafti, AP and Arevalo, O and Bhuiyan, MAN}, title = {Deep Learning in neuroimaging for neurodegenerative diseases: State-of-the art, Challenges, and Opportunities.}, journal = {Journal of the neurological sciences}, volume = {478}, number = {}, pages = {123735}, doi = {10.1016/j.jns.2025.123735}, pmid = {41176929}, issn = {1878-5883}, mesh = {Humans ; *Deep Learning/trends ; *Neurodegenerative Diseases/diagnostic imaging ; *Neuroimaging/methods/trends ; *Brain/diagnostic imaging ; }, abstract = {Neuroimaging is commonly used to diagnose neurodegenerative diseases (NDDs), providing crucial insights into brain changes before clinical symptoms manifest. Deep learning (DL) for neuroimaging can improve early diagnosis and disease monitoring. Clinical implementation of DL faces challenges in accurately representing real-world data. Recent models, particularly those focused on diagnostic categorization, have achieved high accuracy, but their applicability to patients is limited. Conflicting inferences have been reported, with findings from small cohorts generalizing conclusions without considering inter-scanner, intra- and inter-site variations. A theoretically feasible method involves gathering a comprehensive dataset that encompasses all patient demographics, but this presents practical challenges including harmonization, data incompleteness, class imbalance, and substantial costs. Existing research has also mostly focused on common NDDs like Alzheimer's Disease (AD) and Parkinson's Disease (PD). This contribution expands the literature by looking at a wider range of NDDs, exploring the latest advancements in applying deep learning algorithms to neuroimaging analysis for the diagnosis and monitoring of NDDs, including AD, Frontotemporal Dementia (FTD), Lewy Body Dementia, PD, Huntington's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. We emphasize how these approaches are handling spatial/temporal information available in brain volume imaging data. We conclude by discussing the challenges associated with the use of voxel-based, patch-based, ROI-based, and slice-based approaches in brain volume imaging. These challenges are further compounded by issues such as inter-site and inter-scanner variability, class imbalances in medical datasets, and the scarcity of accurately annotated data, all of which impact the performance and generalizability of deep learning models.}, } @article {pmid41177049, year = {2025}, author = {Varo-Martínez, MÁ and Navarro-Cerrillo, RM}, title = {Understanding defoliation of Pinus plantations in the Mediterranean mountains using tree segmentation and ALS time series.}, journal = {Journal of environmental management}, volume = {395}, number = {}, pages = {127837}, doi = {10.1016/j.jenvman.2025.127837}, pmid = {41177049}, issn = {1095-8630}, mesh = {*Pinus ; Forests ; Spain ; Trees ; Remote Sensing Technology ; Pinus sylvestris ; }, abstract = {Forest decline is observed across several spatial and temporal scales. Remote sensing studies have traditionally focused on severe, stand-replacing disturbances such as widespread tree mortality, whereas more gradual declines driven by drought or pest outbreaks have received less attention, largely due to their high spatial and temporal variability and the difficulty of detecting subtle changes in forest canopy and structure. In this study, we explored climatic-driven pine defoliation using time-series Airborne Laser Scanning (ALS) data (2008, 2013, 2018) in Pinus sylvestris and P. nigra plantations in south Spain. We derived three key forest attributes: tree segmentation, height, and defoliation from ALS point clouds using non-parametric methods (e.g., K-nearest neighbors k-NN, Random Forest RF and neural networks NN) and aggregated these at both tree and pixel scales. Then Kernel Density Estimation (SKDE) was used to characterize defoliation patterns. Based on these analyses, we identified temporal defoliation trends and their relationships with environmental and forest drivers. We obtained high accuracy values for tree segmentation, height estimation, and defoliation assessment. Considering the proportion of defoliated categories at tree- and stand-scale assessments, non-defoliated trees and defoliated tree were significantly related to forest attributes SKDE and climate variables. These findings demonstrate that ALS-based approaches can capture gradual forest decline, providing insights into ecological processes and supporting adaptive forest management strategies to adapt forests over space and time.}, } @article {pmid41177667, year = {2026}, author = {Dobak, S and Pearson, K and McGuire, R and Ellis, AC}, title = {Medical nutrition therapy for ALS: Dietitians' approaches to diagnosing malnutrition, facilitating feeding tube discussions, and mitigating refeeding syndrome risk.}, journal = {Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition}, volume = {41}, number = {2}, pages = {589-597}, pmid = {41177667}, issn = {1941-2452}, support = {//This research was supported by a quality of care research award from the ALS Association./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Refeeding Syndrome/prevention & control/etiology ; *Malnutrition/diagnosis/etiology/therapy ; *Enteral Nutrition/methods ; *Nutritionists ; Focus Groups ; Nutrition Assessment ; Female ; Male ; *Nutrition Therapy/methods ; Qualitative Research ; Gastrostomy ; United States ; Middle Aged ; }, abstract = {BACKGROUND: Persons living with amyotrophic lateral sclerosis (PALS) are at high risk for malnutrition because of disease-related factors such as dysphagia, self-feeding difficulty, and hypermetabolism. Nutrition interventions, including enteral nutrition (EN) initiation after gastrostomy tube (G-tube) placement, are integral to care but can introduce challenges, such as refeeding syndrome. This qualitative analysis explores how registered dietitians (RDs) at US-based outpatient amyotrophic lateral sclerosis (ALS) clinics assess malnutrition, facilitate discussions around G-tube placement, and mitigate refeeding syndrome risk.

METHODS: Six focus groups were conducted with 22 RDs from US ALS clinics. Audio files were transcribed verbatim, and data analyzed by deductive thematic analysis.

RESULTS: RDs reported widespread use of the Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition indicators for diagnosing malnutrition, with some using the Global Leadership Initiative on Malnutrition criteria. However, RDs described limitations in using these tools for PALS, particularly in differentiating disease-related from malnutrition-related muscle loss. When discussing G-tube placement, RDs described themselves as key informants in multidisciplinary teams, with timing of counseling typically based on symptoms and clinical progression. For refeeding syndrome, most clinics lacked formal protocols, although RDs used preventative practices, including slow initiation and advancement of EN and proactive communication with the care team.

CONCLUSIONS: ALS RDs play a critical and multifaceted role in managing nutrition-related ALS care. There is a need for ALS-specific malnutrition criteria and standard protocols to manage refeeding syndrome in the outpatient setting. RDs' involvement in G-tube discussions underscores their role in supporting patients in medical decision-making.}, } @article {pmid41178159, year = {2026}, author = {Mosna, S and Dormann, D}, title = {TDP-43 Phosphorylation: Pathological Modification or Protective Factor Antagonizing TDP-43 Aggregation in Neurodegenerative Diseases?.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {48}, number = {1}, pages = {e70084}, pmid = {41178159}, issn = {1521-1878}, support = {//Deutsche Forschungsgemeinschaft (DFG)/ ; //VERUM Foundation/ ; }, mesh = {Humans ; Phosphorylation ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; *Neurodegenerative Diseases/metabolism/pathology ; Protein Processing, Post-Translational ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; *Protein Aggregation, Pathological/metabolism ; Frontotemporal Dementia/metabolism/pathology ; }, abstract = {TDP-43 is a ubiquitously expressed RNA-binding protein that aggregates in the brains of patients suffering from neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease. Aggregated TDP-43 in these diseases is hyperphosphorylated in its C-terminal intrinsically disordered region, while physiological TDP-43 is normally unphosphorylated. Whether TDP-43 phosphorylation is a pathological driver, or rather a protective antagonist of TDP-43 aggregation and consequently neurodegeneration, is still debated and a matter of ongoing research. Here, we review current knowledge about TDP-43 phosphorylation in disease and the kinases and phosphatases that regulate this post-translational modification. We discuss how TDP-43 phosphorylation is thought to shape TDP-43's phase separation, aggregation and toxicity in neurodegenerative diseases. We highlight recent research that provides evidence that hyperphosphorylation antagonizes TDP-43 phase separation and aggregation, and speculate about a potential role of condensates in TDP-43 phosphorylation.}, } @article {pmid41178766, year = {2026}, author = {Wang, Y and Hu, J and Zhu, Q and Wang, S and Yu, S}, title = {Emerging Potential of Ras-proximate-1 (Rap1) in Mediating Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {24}, number = {6}, pages = {804-816}, pmid = {41178766}, issn = {1875-6190}, mesh = {Humans ; Animals ; *Neurodegenerative Diseases/metabolism ; *rap1 GTP-Binding Proteins/metabolism ; Signal Transduction/physiology ; }, abstract = {Neurodegenerative diseases have posed a rising global threat to the aging population, presenting structural and functional impairments in the central nervous system. These progressive disorders, which affect the brain and spinal cord, develop due to the continuous loss of neurons and myelin sheaths. Such specific pathophysiological changes lead to neurological dysfunction in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, resulting in typical motor dysfunctions and cognitive disorders, as well as symptoms like behavioral abnormalities and personality changes. To date, despite various treatments attempting to manage these symptoms, patients' quality of life remains severely deteriorated. A few effective therapeutics are available to mitigate the progression of neurodegenerative injuries. Increasing attention is now focused on molecular regulatory mechanisms, particularly the association between immune regulation and the neurovascular unit. A critical component in this process is Ras-proximate-1 (Rap1), a small Guanosine Triphosphatase (GTPase). Rap1 is determined to regulate glia-mediated immunoinflammatory responses, vascular endothelial function, and neuronal activity. It also modulates synaptic plasticity and mitochondrial function via autophagy-dependent modulation, which are significantly impacted during neuronal degeneration. Additionally, signaling pathways, including PI3K/Akt and ERK, are identified as its downstream effectors. Furthermore, by mediating the permeability of the blood-brain barrier, Rap1 probably influences neuroimmune-vascular modulation throughout the development of neurological disorders. In this review, we investigate recent studies to explore the emerging therapeutic potential of Rap1 in the inflammation-related regulation within neurodegenerative diseases. We also discuss novel treatments and possible targets, including natural medicines and genetic modulation, to enhance therapeutic effects and improve prognosis.}, } @article {pmid41178826, year = {2026}, author = {Stern, C and Semendric, I and Shrestha, N and Beasley-Hall, J and Hasanoff, S and Barker, T and Pollock, D and Schubert, C and Giles, L and Vucic, S and Merlin, T and Munn, Z}, title = {Guidelines addressing Motor Neurone Disease (MND): a scoping review.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {5}, pages = {603-618}, pmid = {41178826}, issn = {1758-2032}, mesh = {*Motor Neuron Disease/therapy ; Humans ; *Practice Guidelines as Topic ; Australia ; }, abstract = {INTRODUCTION: Motor Neurone Disease (MND) is a debilitating neurodegenerative condition affecting individuals, families, and carers. Evidence-informed care can improve outcomes, and guidelines play a key role in supporting this. A preliminary search showed limited guidelines exist, with none developed for the Australian context. This review aimed to identify existing health and social care guidelines for MND.

METHODS: A scoping review was conducted using Joanna Briggs Institute (JBI) methodology. Guidelines addressing health and social care for people with MND, gene carriers, family members, or carers were included regardless of publication status. Five databases and additional sources were searched. Two reviewers independently screened citations, and data were extracted and analysed descriptively, with qualitative content analysis grouping guideline questions. Reporting followed PRISMA-ScR.

RESULTS: Forty-two guidelines covering 133 questions were included. Most focused on symptom management for people with MND and were produced by professional bodies. Few used GRADE methodology or systematic reviews, and only seven assessed risk of bias. No guideline was developed for Australia.

CONCLUSIONS: A high-quality, evidence-based MND guideline following best practice development methods is needed.}, } @article {pmid41178854, year = {2025}, author = {Chen, GB and Wang, ZL and Sha, YG and Tang, RM and Liu, ZG and Chen, LJ}, title = {Closing infection pathways: Multidisciplinary disinfection measures reshape gastrointestinal surgical outcomes.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {10}, pages = {108505}, pmid = {41178854}, issn = {1948-9366}, abstract = {Surgical site infections remain a significant challenge in gastrointestinal surgery, despite advances in surgical techniques and antimicrobial therapy. Wang et al's retrospective analysis highlights the transformative potential of comprehensive perioperative disinfection and isolation protocols in gastrointestinal surgery, demonstrating a 55% reduction in postoperative infection rates and attenuation of systemic inflammation. Their findings underscore the critical role of multidisciplinary strategies-such as preoperative povidone-iodine decolonization, intraoperative laminar airflow systems, and strict postoperative wound care-in mitigating infection risk and preserving organ function. However, the study revealed persistent gaps in protocol standardization and compliance monitoring, particularly in resource-limited settings. Although these measures reduce reliance on antibiotics and align with global antimicrobial resistance containment efforts, challenges such as the high cost of technology and issues with contextual adaptability warrant urgent attention. This study conclusively demonstrated that structured perioperative disinfection protocols significantly transform surgical outcomes by creating comprehensive infection barriers that extend beyond traditional antibiotic prophylaxis. Future priorities include prospective multicenter trials to validate efficacy, cost-benefit analyses for equitable implementation, and integration of artificial intelligence-driven innovations to optimize infection prevention. This study redefines infection control as a cornerstone of surgical quality, urging collaborative action to bridge the gap between clinical evidence and real-world practice.}, } @article {pmid41178869, year = {2025}, author = {Shamoon, R and Nashwan, AJ}, title = {Survival outcomes after laparoscopic gastric cancer surgery: The need for stage-specific insights.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {10}, pages = {110668}, pmid = {41178869}, issn = {1948-9366}, abstract = {Gastric cancer remains one of the leading causes of cancer-related mortality worldwide. Advances in surgical techniques, especially laparoscopic surgery, have revolutionized the management of gastric cancer by reducing perioperative morbidity and enabling faster recovery. However, medium- to long-term survival remains understudied, and identifying factors that influence outcomes is essential for improving care. Gan et al's study analyzes the 3-year survival outcomes and prognosis in patients with primary gastric cancer undergoing laparoscopic surgery. The study identifies the important variables associated with survival, including age, tumor node metastasis stage, tumor characteristics, surgical factors, and postoperative complications. While the study provides important data for clinical practice, further research is warranted to refine risk stratification and explore the role of emerging therapies.}, } @article {pmid41179113, year = {2025}, author = {Luo, Y and Xu, Z and Li, Z}, title = {Advances in Induced Pluripotent Stem Cell Reprogramming and Its Application in Amyotrophic Lateral Sclerosis: A Review.}, journal = {FASEB bioAdvances}, volume = {7}, number = {11}, pages = {e70065}, pmid = {41179113}, issn = {2573-9832}, abstract = {Since Yamanaka's landmark achievement in reprogramming somatic cells into induced pluripotent stem cells (iPSCs) using the four key transcription factors-OCT4, SOX2, KLF4, and c-Myc (OSKM)-iPSC technology has made significant strides. Notable advancements include refining reprogramming factors, delivery systems, somatic cell selection, and optimization of reprogramming conditions, along with developing chemical reprogramming methods. With their unparalleled proliferative capacity and near-pluripotent differentiation potential, iPSCs have become invaluable tools for investigating neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Neuronal models derived from ALS patient-specific iPSCs, particularly iPSC-derived motor neurons (iPSC-MNs), offer a robust platform to recapitulate disease-specific pathology and investigate the molecular mechanisms underpinning ALS, thereby accelerating the discovery of novel therapeutic strategies. This review highlights the evolution of iPSC technology and its transformative applications in ALS modeling, drug discovery, and therapeutic development.}, } @article {pmid41180289, year = {2025}, author = {}, title = {Corrigendum to "Predicting Factors Affecting the Behavior of Healthcare Employees in the Use of Personal Protective Equipment During Epidemics Based on Godin et al's Model: A Study in Iran".}, journal = {Health services insights}, volume = {18}, number = {}, pages = {11786329251395188}, doi = {10.1177/11786329251395188}, pmid = {41180289}, issn = {1178-6329}, abstract = {[This corrects the article DOI: 10.1177/11786329251316668.].}, } @article {pmid41180498, year = {2025}, author = {Shamsi, A and Alrouji, M and AlOmeir, O and Tasqeruddin, S and Dinislam, K and Zuberi, A}, title = {CRISPR-Cas9: bridging the gap between aging mechanisms and therapeutic advances in neurodegenerative disorders.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1681891}, pmid = {41180498}, issn = {1662-5102}, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, ALS, and spinocerebellar ataxia are becoming more prevalent as populations age, posing major global health challenges. Despite decades of research, effective treatments that halt or reverse these conditions remain elusive. Aging is the most significant risk factor in the development of these diseases, intertwining with molecular processes like DNA damage, mitochondrial dysfunction, and protein aggregation. Recent advances in gene-editing technologies, particularly CRISPR-Cas9, are beginning to shift the therapeutic landscape. This revolutionary tool allows for precise correction of genetic mutations associated with neurodegeneration, offering the potential for disease modification rather than symptom management alone. In this review, we explore how CRISPR-Cas9 is being leveraged to target key genes implicated in various neurodegenerative conditions and how it may overcome barriers posed by aging biology. We also examine the delivery systems and safety challenges that must be addressed before clinical application. With continued progress, CRISPR-Cas9 could mark a turning point in our ability to treat or even prevent age-related neurological decline.}, } @article {pmid41180593, year = {2025}, author = {La Civita, E and Nicolella, V and Fiorenza, M and Cosimato, V and Castaldo, G and Morra, VB and Moccia, M and Terracciano, D}, title = {Advancing Clinical Use of Neurofilament Light Chain: Translational Insights From Research to Routine Practice.}, journal = {Biomarker insights}, volume = {20}, number = {}, pages = {11772719251364018}, pmid = {41180593}, issn = {1177-2719}, abstract = {Neurofilament Light Chain (NfL) has emerged as a promising biomarker for neurological diseases. NfL, a structural component of axons, is released into cerebrospinal fluid (CSF) and blood following neuro-axonal damage. Highly sensitive immunometric assays have enabled its reliable quantification in blood, facilitating non-invasive monitoring. Several studies demonstrated strong correlations between NfL levels and the risk of developing different neurological diseases and, in individuals already living with a neurological disease, with the risk of worsening. However, interpretation is affected by factors like age, BMI, renal function, and comorbidities. NfL is already utilized as a diagnostic and prognostic biomarker in clinical practice, particularly in specialized centers and research settings, although no FDA-cleared assay is currently available for routine use. Recent research has highlighted that NfL may represent the first of a new generation of neurological biomarkers, with many more ready to come, such as glial fibrillary acidic protein (GFAP), further improving diagnostic and prognostic accuracy. Despite its promising role in the landscape of biomarkers, challenges remain to implement NfL in daily clinical practice, including standardization of assays, defining reference values, and ensuring methodological consistency. Addressing these limitations will be essential for integrating NfL into routine clinical practice, ultimately advancing precision medicine in neurology.}, } @article {pmid41181712, year = {2025}, author = {Colaianni, D and Ceccato, N and Antolini, P and Conte, C and De Pittà, C and Feiguin, F and Mazzotta, GM}, title = {TDP-43-mediated amyotrophic lateral sclerosis: new/hidden insights from Drosophila.}, journal = {Frontiers in cell and developmental biology}, volume = {13}, number = {}, pages = {1677090}, pmid = {41181712}, issn = {2296-634X}, abstract = {Transactive response DNA-binding protein 43 (TDP-43) is a key factor in motor neurons and related neurodegenerative disorders, and the presence of cytoplasmic aggregates of TDP-43 is a major hallmark of diseases such amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Nevertheless, little is known about early developmental effects or the systemic nature of TDP-43-mediated pathology. Drosophila melanogaster is acknowledged as a powerful genetic model for studying the genetic inheritance and the behavioral and developmental processes associated with human neurodegenerative diseases, including ALS. To better understand the possible roles and potential pathogenic mechanisms of TDP-43 protein in the pathogenesis of ALS, we performed a transcriptomic analysis of larvae from a Drosophila model knock-out (KO) for the TBPH gene, the fly TDP-43 ortholog. Interestingly, the Gene Ontology (GO) analysis highlighted some pathways not yet associated with this pathology and this model. We identified several genes encoding for serine proteases, a class of enzymes that in the central nervous system (CNS) play important roles in neural development, synaptic plasticity, and neurodegeneration. Our work provides insights into novel pathological mechanisms underlying the disease, thereby opening new pathways for drug discovery.}, } @article {pmid41181835, year = {2025}, author = {Keritam, O and Erdler, M and Fasching, B and Zulehner, G and Rath, J and Krenn, M and Waldhör, T and Gruber, VA and Langweil, N and Kiss, C and Griedl, TA and Gold, V and Wanschitz, J and Hotter, A and Kleinveld, VEA and Horlings, CGC and Erber, A and Schernhammer, E and Troger, J and Grinzinger, S and Müller, P and Langenscheidt, D and Rappold, M and Wiesenhofer, A and Gosk-Tomek, M and Knipp, F and Mahal, S and Bernert, G and Baumann, M and Zimprich, F and Topakian, R and Eggers, C and Quasthoff, S and Löscher, W and Cetin, H}, title = {Efficacy and safety of risdiplam in adults with 5q-associated spinal muscular atrophy: a nationwide observational cohort study in Austria.}, journal = {EClinicalMedicine}, volume = {88}, number = {}, pages = {103536}, pmid = {41181835}, issn = {2589-5370}, abstract = {BACKGROUND: Spinal muscular atrophy (SMA) is a genetic motor neuron disease marked by the progressive decline of motor function. Risdiplam, an orally administered SMN2 splicing modifier, was approved for the treatment of 5q-associated SMA (5q-SMA) across all age groups. However, clinical trial data have primarily focused on paediatric populations, with limited evidence available for adult patients. This study aimed to evaluate the efficacy and safety of risdiplam in treatment-naïve adults with 5q-SMA in a real-world, multicentre setting.

METHODS: We conducted a nationwide, observational cohort study across eight neuromuscular centres in Austria. Patients aged ≥16 years at treatment initiation with genetically confirmed 5q-SMA, who were previously untreated and initiated risdiplam between December 2020 and September 2024 were eligible for inclusion if they had received risdiplam for ≥3 months and had functional motor assessments available at baseline (T0) and at least one follow-up. Functional outcomes were assessed at four predefined intervals after baseline: 3-<6 months (T1), 6-<12 months (T2), 12-<18 months (T3), and ≥18 months (T4). The primary outcome was the change from baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE). Secondary outcomes included changes in the Revised Upper Limb Module (RULM), Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), and 6-min walk test (6MWT). Adverse events were extracted from medical records.

FINDINGS: A total of 87 patients had received risdiplam, of whom 57 fulfilled the inclusion criteria and were included in this study. The median age at treatment initiation was 35.7 years (IQR 28.8-43.4), with a median disease duration of 29.6 years (IQR 24.2-36.3). Most individuals had SMA type II (40.4%) or III (47.4%). Mean HFMSE changes from baseline were +1.00 (95% CI 0.05-1.95, p = 0.0100) at T1, +0.97 (95% CI 0.22-1.72, p = 0.0132) at T2, +1.78 (0.66-2.89, p = 0.0008) at T3, and +1.73 (0.49-2.97, p = 0.0049) at T4. Clinically meaningful improvements in motor function (≥3 points in HFMSE and/or ≥2 in RULM) were observed in 63.9% of patients at T4. Improvements were more pronounced in patients with higher baseline function, ambulatory status, or without a history of spinal surgery. Risdiplam was generally well tolerated, with predominantly mild and non-specific adverse events reported in 14.0% of patients.

INTERPRETATION: In this nationwide observational study in a real-world setting, adult patients with 5q-SMA demonstrated consistent and clinically meaningful functional improvements with risdiplam over time, particularly by 18 months and beyond. These findings support the long-term use of risdiplam in adults with SMA and help close a critical evidence gap in this underrepresented population.

FUNDING: This study was financially supported by F. Hoffmann-La Roche Ltd.}, } @article {pmid41182353, year = {2026}, author = {Cai, Y and Huang, S and Dong, Y and Li, S and Jin, X}, title = {PIWI-Interacting RNAs in brain health and disease: biogenesis, mechanisms, and therapeutic horizons.}, journal = {Psychopharmacology}, volume = {243}, number = {6}, pages = {1377-1396}, pmid = {41182353}, issn = {1432-2072}, support = {81971083//National Natural Science Foundation of China/ ; 25JCLZJC00190//Tianjin Natural Science Foundation Project/ ; }, mesh = {Humans ; *Piwi-Interacting RNA/genetics/metabolism ; Animals ; *Brain/metabolism ; *Brain Diseases/genetics/physiopathology/drug therapy ; }, abstract = {PIWI-interacting RNAs (piRNAs), a class of small non-coding RNAs originally identified for their role in transposon silencing in germ cells, have recently been recognized as pivotal regulators of gene expression in the central nervous system. Beyond their canonical functions in genome defense, emerging evidence highlights piRNAs as key modulators of neuronal development, synaptic plasticity, axonal regeneration, and neuroimmune interactions-processes central to brain function and dysfunction. This review provides a comprehensive overview of piRNA biogenesis, molecular mechanisms, and regulatory pathways relevant to neurobiology. We focus on the growing body of evidence implicating piRNA dysregulation in major neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, glioma, autism spectrum disorder, and schizophrenia. Importantly, we discuss the neuropharmacological implications of piRNA pathways as novel targets for therapeutic intervention and their potential utility as biomarkers for early diagnosis and treatment stratification. By integrating mechanistic insights with emerging translational evidence, this review highlights piRNAs as promising molecular targets in the development of next-generation neurotherapeutics aimed at modifying disease progression and improving brain health.}, } @article {pmid41183377, year = {2025}, author = {Morris, AC and Seker, A and Telesia, L and Wickersham, A and Ching, BC and Roy, R and Epstein, S and Matcham, F and Sonuga-Barke, E and Downs, J}, title = {Adherence to Actigraphic Devices in Elementary School-Aged Children: Systematic Review and Meta-Analysis.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e79718}, pmid = {41183377}, issn = {1438-8871}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; Child ; *Actigraphy/instrumentation ; *Patient Compliance/statistics & numerical data ; Child, Preschool ; Female ; Schools ; Male ; }, abstract = {BACKGROUND: Consistent wear is essential for valid and reliable actigraphy data. Adherence to actigraphy may be challenging in primary school children due to developmental and design considerations, yet no quantitative synthesis of adherence in this age group exists.

OBJECTIVE: The aim of this study was to provide the first pooled estimate of actigraphy adherence in primary school-aged children and examine the impact of individual, device, and study-specific factors on adherence.

METHODS: We searched seven electronic databases for studies reporting adherence to actigraphy in primary school-aged children. Searches were conducted in Embase, MEDLINE, PsycINFO, Social Policy and Practice via OVID, Education Resources Information Center, British Education Index, and CINAHL via EBSCO using database-specific search strategies conducted between January 2018 and January 24, 2023. Forward and backward citation searches were completed on the Web of Science Core Collection and Google Scholar. Gray literature searches were undertaken in PsycEXTRA and Healthcare Management Information Consortium. Empirical studies reporting quantitative data on adherence to community-based actigraphy in children aged 5-11 years (or if ≥50% of the average age fell within this range) were included. Eligible studies were written in English and could be published or unpublished. Risk of bias was assessed using an 8-item checklist adapted from Berger et al's actigraphy reporting standards. All included studies were narratively synthesized, and adherence data were pooled in a proportional meta-analysis. Adherence was calculated as the proportion of children meeting wear-time criteria to be included in the analysis compared to the number of children invited to use the device at baseline. Meta-regression was used to examine the impact of individual, device, and study-specific factors on adherence. Prediction intervals were calculated to estimate the range of adherence expected across future studies.

RESULTS: Data were extracted from 235 studies (N=148,161); of these, 135 studies (n=64,541) provided adherence data for proportional meta-analysis. Pooled adherence, measured across 1-140 days, was 81.6% (95% CI 78.7%-84.4%; I2=98.8%). The prediction intervals (42.8%-100%) indicated substantial variability in adherence estimates across studies. Meta-regression suggested that individual characteristics contributed to observed heterogeneity as children with a physical health diagnosis (b=0.236, 95% CI 0.009-0.464; P=.04) and those with neurodevelopmental or mental health diagnosis (b=0.395, 95% CI 0.125-0.665; P=.004) demonstrated higher adherence than undiagnosed children, though these effects were of modest magnitude. No significant effects were found for age, placement, protocol length, protocol deviation, or incentivization. Reporting quality was poor, with only 3.4% of studies satisfying all criteria.

CONCLUSIONS: This review demonstrates generally high actigraphy adherence in primary school-aged children, particularly those with health conditions. However, observed variability indicates that adherence was much lower in some contexts, underscoring that the reported pooled adherence cannot be assumed across future actigraphy applications within this age group. Future research should use standardized adherence reporting and should plan for adherence variability.}, } @article {pmid41183928, year = {2025}, author = {Hanada, K and Haji, S and Fukushima, K and Yamazaki, H and Osaki, Y and Takamatsu, N and Fujita, K and Izumi, Y}, title = {Increase in the amyotrophic lateral sclerosis age of onset:Analysis of cases originating in 2011-2020.}, journal = {The journal of medical investigation : JMI}, volume = {72}, number = {3.4}, pages = {286-289}, doi = {10.2152/jmi.72.286}, pmid = {41183928}, issn = {1349-6867}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Age of Onset ; Male ; Female ; Aged, 80 and over ; Aged ; Japan/epidemiology ; Middle Aged ; Adult ; }, abstract = {The onset age of amyotrophic lateral sclerosis (ALS) has been increasing, but recent trends remain unclear. This study examined changes in ALS onset age over the past decade. We analyzed 233 ALS patients diagnosed from 2011 to 2020 at Tokushima University Hospital. The Jonckheere-Terpstra test assessed the trend in onset age. We compared onset age between 2011-2015 (Group A) and 2016-2020 (Group B) using the Mann-Whitney U test. We also analyzed the annual proportion of patients with onset age ≥80 using Spearman's rank correlation. In Tokushima Prefecture, we evaluated annual increase rates of individuals aged ≥80 and ALS patients with onset age ≥80, using 2011 as baseline. Regression slopes were compared using a t test. Onset age showed a significant positive trend (p=0.04), and Group B had older onset age than Group A (p=0.048). The proportion of patients with onset age ≥80 increased significantly (ρ=0.69, p=0.03). No significant difference was found between regression slopes for the general elderly population and ALS patients with onset age ≥80 (p=0.49). These findings suggest that the onset age of ALS at Tokushima University Hospital has increased over the past decade. J. Med. Invest. 72 : 286-289, August, 2025.}, } @article {pmid41184709, year = {2025}, author = {Kiecka, A and Szczepanik, M}, title = {Dietary modulation of the gut microbiome as a supportive strategy in the treatment of amyotrophic lateral sclerosis - a narrative review.}, journal = {Pharmacological reports : PR}, volume = {77}, number = {6}, pages = {1514-1526}, pmid = {41184709}, issn = {2299-5684}, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/therapy/diet therapy ; Humans ; *Gastrointestinal Microbiome/physiology ; Probiotics/therapeutic use/administration & dosage ; Fecal Microbiota Transplantation/methods ; Animals ; Prebiotics/administration & dosage ; *Diet ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to permanent damage to the central and peripheral motor neurons. Currently, there is no effective treatment for ALS, and therapy focuses solely on slowing the progression of the disease. Recent studies show that gut microbiota plays an important role in the development of neurodegenerative diseases. Altered gut microbiota has also been found in ALS. These changes have prompted the search for alternative forms of ALS treatment, focusing on changing the microbial composition of the gut. It has been noted that diet, probiotics, prebiotics and vitamins can all influence the course of ALS. Another interesting issue is fecal microbiota transplantation, which is already used in the treatment of certain intestinal diseases and could potentially be useful in the treatment of ALS. This review summarizes current knowledge on the impact of gut microbiota on the neurodegenerative process in ALS, with particular emphasis on the role of diet and probiotics. It also discusses potential mechanisms and highlights future research directions in this emerging field.}, } @article {pmid41185046, year = {2025}, author = {Zhou, Y and Huang, J and Xu, L and Zhang, F and Bai, C and Fan, F and Wang, Y and Fang, B and Wang, T and Mu, X and Li, J}, title = {Genomic structural equation modeling decodes skeletal aging: novel loci discovery and multisystem genetic crosstalk.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {1206}, pmid = {41185046}, issn = {1479-5876}, support = {82222076//Excellent Young Scientists Fund of the National Natural Science Foundation of China (NSFC)/ ; DZMG-LJRC0013//Talent Development Program of Dongzhimen Hospital, Beijing University of Chinese Medicine/ ; C2015//Clinical Research Funding for Central Government-Supported High-Level Traditional Chinese Medicine (TCM) Hospitals/ ; }, mesh = {Humans ; Genome-Wide Association Study ; *Aging/genetics ; Polymorphism, Single Nucleotide/genetics ; *Bone and Bones/physiology ; *Models, Genetic ; *Genomics ; *Genetic Loci ; Quantitative Trait Loci/genetics ; }, abstract = {OBJECTIVE: Skeletal aging, a core determinant of systemic aging, poses a global public health challenge due to its association with chronic diseases and functional decline. This study aimed to decode the genetic architecture of skeletal aging by identifying novel loci and multi-system crosstalk using genomic structural equation modeling (Genomic SEM).

METHODS: We integrated genome-wide association study (GWAS) data from five musculoskeletal-related traits (osteoporosis [OP], osteoarthritis [OA], lumbar spinal stenosis [LSS], telomere length [TL], and low back pain [LBP]) across 462,933 to 472,174 European individuals. Genomic SEM, FUMA, FUSION, and fine-mapping tools (SuSIE/FINEMAP) were applied to model latent skeletal aging ("mvSAge") and identify causal variants, enriched pathways, and tissue-specific gene expression.

RESULTS: The latent factor model (CFI = 0.993, SRMR = 0.065) revealed shared genetic architecture among OP, OA, LSS, TL, and LBP. We identified 514 lead SNPs (P < 5 × 10⁻[12]), including 136 novel loci enriched in regulatory regions (e.g., brain putamen, frontal cortex). Fine-mapping prioritized causal variants (posterior probability > 0.95) near MTPAP, GRAMD4, and DPP8, implicating mitochondrial function and immune regulation. Transcriptome-wide analyses highlighted PPP6R3 (bone mineral density) and SLC33A1 (anticancer target) as key genes. Enrichment analyses linked mvSAge to Wnt signaling, ER stress, and Mendelian disorders (e.g., ALS). Chromosomes 1, 2, and 4 showed elevated heritability contributions, driven by conserved regulatory elements (RUNX2, SP7) and chromatin accessibility hotspots.

CONCLUSION: This study establishes mvSAge as a genetically cohesive construct and uncovers novel loci, pathways, and multi-system interactions underlying skeletal aging. These findings advance precision medicine strategies for aging-related musculoskeletal disorders.}, } @article {pmid41186720, year = {2026}, author = {Aijaz, M and Ahmad, M and Ahmad, S and Afzal, M and Kothiyal, P}, title = {The gut-brain axis: role of gut microbiota in neurological disease pathogenesis and pharmacotherapeutics.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {399}, number = {4}, pages = {4879-4905}, pmid = {41186720}, issn = {1432-1912}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology/drug effects ; Animals ; *Brain/metabolism/drug effects ; Dysbiosis ; *Nervous System Diseases/microbiology/therapy/drug therapy/physiopathology ; Probiotics/therapeutic use ; *Brain-Gut Axis ; }, abstract = {The gut-brain axis is a highly complex, bidirectional communication link between the gut and the central nervous system (CNS), mainly through neural, endocrine, immunological, and metabolic pathways. This review outlines the growing contribution of gut microbiota in the remediation of neurological health and also emphasizes the controlling role of gut microbiota on the synthesis of neurotransmitters. Emerging evidence indicates that dysbiosis of the gut is related to a variety of neurodegenerative and neuropsychiatric diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), autism spectrum disorders (ASD), depression, and glioblastoma. Mechanistic understandings show that gut microbes critically contribute to neuroimmune and blood-brain barrier (BBB) signaling. The peripheral association of gut microflora, networked with inflammasome activation, nuclear factor kappa B (NF-κB), and type-I IFN pathways highlights their role in CNS inflammation. Microbiota-targeted interventions with probiotics, prebiotics, synbiotics, antibiotics, dietary modifications, and fecal microbiota transplantation are examined for their therapeutic potential. These strategies appear to be promising to reinstate microbial balance, enhance neuroplastic responses, and ameliorate the disease symptoms. The review highlights personalized microbiome-based algorithms, underpinned by integrated multi-omics technologies and machine-learning-driven diagnostics. Future research should address underlying microbial mechanisms and perform large, randomized controlled trials in order to establish microbiota-based therapies for neurological disorders.}, } @article {pmid41187881, year = {2026}, author = {Ge, TQ and Wang, P and Guan, PP}, title = {Targeting the C5-C5aR1 axis: A promising therapeutic strategy for Alzheimer's disease and amyotrophic lateral sclerosis by unlocking neuroprotection.}, journal = {Biochemical pharmacology}, volume = {243}, number = {Pt 1}, pages = {117518}, doi = {10.1016/j.bcp.2025.117518}, pmid = {41187881}, issn = {1873-2968}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *Alzheimer Disease/metabolism/drug therapy ; Humans ; *Receptor, Anaphylatoxin C5a/metabolism/antagonists & inhibitors ; Animals ; *Neuroprotection/drug effects/physiology ; *Neuroprotective Agents/administration & dosage/pharmacology/therapeutic use ; *Complement C5/metabolism/antagonists & inhibitors ; *Drug Delivery Systems/methods ; }, abstract = {C5aR1 is a G protein-coupled receptor (GPCR) which is involved in exacerbating neurodegenerative diseases, including Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS). This review highlights the critical role of the C5-C5aR1 axis, in the pathogenesis of neurodegenerative diseases such as AD and ALS. In AD and ALS, abnormal protein aggregates activate the complement system (CS), leading to increased production of C5a. C5a activates C5aR1 on microglia, triggering the release of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) that induce synaptic loss. Concurrently, the C5-C5aR1 axis impairs microglial phagocytic capacity, promoting damage-associated molecular patterns (DAMPs) accumulation and forming a vicious cycle of inflammation and complement activation. Additionally, excessive complement molecule assembles into the terminal complement complex (TCC), which exerts direct neurotoxic effects and drives neuronal apoptosis. Preclinical studies show that C5aR1 antagonists, such as PMX205, mitigate disease progression in AD and ALS animal models by reducing neuroinflammation and preserving synaptic function. These findings underscore the C5-C5aR1 axis as a promising target for neurodegenerative disease therapy and highlight the need for further development of potential antagonists of C5aR1.}, } @article {pmid41187939, year = {2025}, author = {Reis, AHO and Magno, GPO and Costa, BGF and Figalo, LB and Orsini, M}, title = {Genetic and clinical insights into ALS8: exploring the impact of VAPB pathogenic variants in familial amyotrophic lateral sclerosis.}, journal = {Arquivos de neuro-psiquiatria}, volume = {83}, number = {11}, pages = {1-5}, pmid = {41187939}, issn = {1678-4227}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; Adult ; Pedigree ; *Vesicular Transport Proteins/genetics ; Brazil ; Disease Progression ; Aged ; Mutation/genetics ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to progressive muscle weakness and paralysis. Approximately 10% of ALS cases are familial (FALS), with the VAPB gene's P56S pathogenic variant being notably prevalent in Brazilian families, contributing to the rare ALS8. This variant progresses more slowly than typical ALS, with distinct clinical features.To identify VAPB gene pathogenic variants in Brazilian FALS patients, particularly the P56S pathogenic variant associated with ALS8 and explore its clinical presentation and progression.Twelve FALS patients from 12 unrelated families in Rio de Janeiro were included in the study between 2023 and 2024. Clinical, laboratory, and electrophysiological data were reviewed. Collection of DNA samples happened via oral swabs, and VAPB gene sequencing was performed to identify pathogenic variants, specifically the P56S variant linked to ALS8.There were 3 cases of the P56S pathogenic variant, all presenting ALS8 with symptom onset in the lower limbs and slower disease progression. A family with 11 affected members across four generations showed an autosomal dominant inheritance pattern, with varying survival rates, highlighting its clinical variability.The present study underscores the importance of genetic screening for ALS subtypes, particularly ALS8, in Brazil. Identifying the P56S pathogenic variant enhances our understanding of ALS's genetic diversity and clinical presentation, offering a foundation for improved diagnostic practices and personalized care.}, } @article {pmid41188020, year = {2026}, author = {Parra-Torres, M and Dissanayake, K and Gray, JA and Langlands, AJ and Kucuk, R and Gierlinski, M and Troakes, C and King, A and McGurk, L}, title = {Aberrant NSUN1 activity connects m[5]C-RNA modification to TDP-43 neurotoxicity in ALS/FTD.}, journal = {Life science alliance}, volume = {9}, number = {1}, pages = {}, pmid = {41188020}, issn = {2575-1077}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Frontotemporal Dementia/metabolism/genetics/pathology ; *Methyltransferases/metabolism/genetics ; *5-Methylcytosine/metabolism ; *RNA/metabolism/genetics ; Disease Models, Animal ; Cell Line, Tumor ; Drosophila melanogaster ; Methylation ; Drosophila Proteins/metabolism/genetics ; Drosophila ; }, abstract = {In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the nuclear RNA-binding protein TDP-43 mislocalises to the cytoplasm and forms insoluble aggregates, but the mechanisms controlling this remain unclear. We define a native TDP-43 interactome in human SH-SY5Y cells and identify proteins linked to the 5-methylcytosine (m[5]C) RNA modification as highly enriched. Using a Drosophila model of TDP-43 pathology, we show that aberrant activity of m[5]C-RNA methyltransferases Nsun1 drives TDP-43-induced m[5]C-RNA hypermethylation, whereas Nsun1 down-regulation alleviates TDP-43-induced degeneration, lifespan deficits, and cytoplasmic accumulation. In human cells, TDP-43 selectively interacts with NSUN1 isoform 3 independently of RNA. Furthermore, NSUN1 is nucleolar and TDP-43 is largely nucleoplasmic, yet they interact in both compartments, suggesting functional roles beyond their predominant localisations. In ALS/FTD postmortem frontal cortex, NSUN1 isoform 3 persists, whereas the shorter isoform is reduced, suggesting that a pool of NSUN1 capable of contributing to pathological TDP-43 interactions remains in disease. These findings suggest that TDP-43 neurotoxicity is coupled to NSUN1 activation and m[5]C-RNA methylation, revealing a potential therapeutic axis in ALS/FTD.}, } @article {pmid41188562, year = {2025}, author = {Wright, R}, title = {Autoimmune target in ALS.}, journal = {Nature neuroscience}, volume = {28}, number = {11}, pages = {2175}, doi = {10.1038/s41593-025-02122-x}, pmid = {41188562}, issn = {1546-1726}, } @article {pmid41188584, year = {2025}, author = {Wang, S and Li, Y and Xing, X and Man, X and Chen, Y and Wang, G}, title = {DTI changes of brachial plexus nerve roots in amyotrophic lateral sclerosis and their correlation with electrophysiology.}, journal = {European radiology experimental}, volume = {9}, number = {1}, pages = {107}, pmid = {41188584}, issn = {2509-9280}, support = {2024FY135//Scientific Research Incubation Fund of Shandong Provincial Hospital/ ; 201912004//Jinan Clinical Research Center for Neurological Disease Imaging Monitoring/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; *Diffusion Tensor Imaging/methods ; Middle Aged ; *Brachial Plexus/diagnostic imaging/physiopathology ; Anisotropy ; Aged ; Adult ; Case-Control Studies ; Neural Conduction ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with peripheral nerve involvement, but current diagnostics are limited. Diffusion tensor imaging (DTI) may improve microstructural assessment and correlate with clinical markers. We investigated the diffusion properties of the brachial plexus in ALS and examined their relationships with electrophysiological parameters of upper limb nerves.

MATERIALS AND METHODS: We enrolled 25 ALS patients and 22 age- and sex-matched healthy controls. DTI of the brachial plexus was conducted to measure fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Differences in DTI parameters between the two groups were analyzed. Correlations between DTI parameters and ALS Functional Rating Scale-Revised (ALSFRS-R) scores, along with electrophysiological measurements, were assessed.

RESULTS: In ALS patients compared to controls, FA and AD values were significantly lower (p ≤ 0.002), while the RD value was significantly higher (p = 0.002). There were no statistically significant differences in MD (p = 0.540). Both FA and AD showed a positive correlation with ALSFRS-R score, ALSFRS-upper limb score, and compound muscle action potential amplitude of median, ulnar, and radial nerves (r ≥ 0.480; p ≤ 0.015). The RD values showed a negative correlation with ALSFRS-upper limb score and motor nerve conduction velocity of median, ulnar, and radial nerves (r ≤ -0.415; p ≤ 0.039).

CONCLUSION: FA, AD, and RD values of DTI showed the potential to identify microstructural changes in the brachial plexus nerve roots of ALS patients and may serve as potential indicators of nerve conduction function in the upper extremities.

RELEVANCE STATEMENT: DTI may reveal microstructural changes in ALS brachial plexus, correlating with nerve dysfunction, offering novel biomarkers for evaluation of upper limb neurodegeneration.

KEY POINTS: Lower Fractional anisotropy (FA) and axial diffusivity (AD), and higher radial diffusivity (RD) were shown in amyotrophic lateral sclerosis (ALS) brachial plexus. Diffusion tensor imaging (DTI) parameters correlated with clinical and electrophysiological parameters. FA, AD, and RD detected ALS nerve microstructural changes, indicating abnormal conduction function.}, } @article {pmid41188870, year = {2025}, author = {Keerie, AF and Martins, RR and Allen, CF and Bowden, K and Al Mashhadi, S and Marlow, T and Myszczynska, M and Thakur, N and Beal, SN and Shaw, A and Suresh, S and McKinnon, SN and Cooper-Knock, J and West, RJH and Bonsall, S and Daniel, A and Wells, T and Kumar, V and Ellis, BCS and Higgins, M and Dinkova-Kostova, AT and Shelkovnikova, TA and Kalfus, IN and Shan, N and Shaw, PJ and Ferraiuolo, L and Mead, RJ}, title = {M102 activates both NRF2 and HSF1 transcription factor pathways and is neuroprotective in cell and animal models of amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {118}, pmid = {41188870}, issn = {1750-1326}, support = {MR/V027735/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *NF-E2-Related Factor 2/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Mice ; Motor Neurons/drug effects/metabolism ; *Neuroprotective Agents/pharmacology ; *Heat Shock Transcription Factors/metabolism ; Humans ; Signal Transduction/drug effects ; }, abstract = {M102 is a central nervous system (CNS) penetrant small molecule electrophile which activates in vivo the NF-E2 p45-related factor 2-antioxidant response element (NRF2-ARE) pathway, as well as transcription of heat-shock element (HSE) associated genes. In the TDP-43[Q331K] transgenic mouse model of ALS dosed subcutaneously at 5 mg/kg OD or 2.5 mg/kg BD with M102, significant improvements in compound muscle action potential (CMAP) amplitude of hind limb muscles and gait parameters were observed at 6 months of age, with associated target engagement. An oral dose response study of M102 in SOD1[G93A] transgenic mice showed a dose-dependent improvement in CMAP of hindlimb muscles which correlated with preservation of lumbar spinal motor neurons at the same time point. These data enabled prediction of human efficacious exposures and doses, which were well within the safety margin predicted from Good Laboratory Practice (GLP) toxicology studies. A parallel program of work in vitro showed that M102 rescued motor neuron survival in co-culture with patient-derived astrocytes from sporadic, C9orf72 and SOD1 ALS cases. Markers of oxidative stress, as well as indices of TDP-43 proteinopathy were also reduced by exposure to M102 in these in vitro models. This comprehensive package of preclinical efficacy data across two mouse models as well as patient-derived astrocyte toxicity assays, provides a strong rationale for clinical evaluation of M102 in ALS patients. Combined with the development of target engagement biomarkers and the completed preclinical toxicology package, a clear translational pathway to testing in ALS patients has been developed.}, } @article {pmid41190025, year = {2025}, author = {Alhassan, HH and Janiyani, K and Surti, M and Adnan, M and Patel, M}, title = {The dual role of glycogen synthase kinase-3 beta (GSK3β) in neurodegenerative pathologies: interplay between autophagy and disease progression.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1693805}, pmid = {41190025}, issn = {1663-9812}, abstract = {Glycogen Synthase Kinase-3 Beta (GSK3β), a multifunctional serine/threonine kinase, plays a central role in cellular signaling pathways and autophagy regulation, processes critical to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (ALS). Dysregulation of autophagy leads to the toxic accumulation of misfolded proteins and damaged organelles, contributing to neuronal loss in these disorders. This review explores the mechanistic interplay between GSK3β and autophagy, highlighting its modulation through key pathways, including mTOR, AMPK and Bcl-2 and its direct impact on autophagy-related proteins such as Beclin-1 and LC3. This review systematically discusses the disease-specific roles of GSK3β in autophagy dysregulation and protein aggregation, providing evidence from recent studies on neurodegenerative models. Additionally, therapeutic approaches targeting GSK3β are evaluated, including preclinical and clinical trials of GSK3β inhibitors and combination therapies with autophagy modulators, emphasizing their potential for improving neuroprotection and cellular homeostasis. Despite its promise, challenges such as off-target effects and pathway complexity remain significant. This review highlights the importance of GSK3β as both a therapeutic target and a biomarker, offering avenues for future research into selective GSK3β modulators that enhance autophagy and mitigate ND progression.}, } @article {pmid41191158, year = {2025}, author = {Pal, B and Panda, S and Bashir, B and Vishwas, S and Chaitanya, M and Hussain, MS and Gupta, G and Kumbhar, P and Gupta, S and Singh, SK}, title = {Nanomedicine-enabled neuroprotection: therapeutic role of berberine in neurodegenerative diseases.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {49}, pmid = {41191158}, issn = {1573-4978}, mesh = {Humans ; *Berberine/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nanomedicine/methods ; Animals ; *Neuroprotection/drug effects ; Nanoparticles/chemistry ; Oxidative Stress/drug effects ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Amyotrophic lateral sclerosis, Huntington's, and Parkinson's, present an increasingly widespread health burden globally with limited curative or treatment modalities, mostly having symptomatic attenuation. Berberine (BBR) is an isoquinoline alkaloid that occurs naturally and has been proposed as a potential neuroprotectant, since it has been found to exert multiple effects to modulate most of the pathological hallmarks of NDs, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and protein aggregation. Although it shows promise, the practical utilization of BBR is marred by low oral bioavailability, high rate of oxidation, and low blood-brain barrier permeability. To combat these issues, recent developments in nanotechnology, especially in the use and creation of lipidic, inorganic, and polymeric nano-particles, have dramatically altered the pharmacokinetics and pharmacodynamics of BBR. This article summarizes recent advances in BBR-based nanoformulations and emphasizes the translational potential of BBR-based nanopreparations to improve treatment response in NDs. It also describes the molecular foundation of the neuroprotective effects of BBR and its possible place in clinical practice. Future nanocarrier development and investigation of BBR mechanisms will be essential to the development of the next generations of therapeutics in NDs.}, } @article {pmid41191168, year = {2025}, author = {Bhore, N and Sarkar, A and Yao, Z and Herbst, S and Lewis, PA}, title = {Glutamic Acid at Position 168 Is a Constitutive Activator of Tank Binding Kinase 1 Catalytic Function.}, journal = {Neuromolecular medicine}, volume = {27}, number = {1}, pages = {73}, pmid = {41191168}, issn = {1559-1174}, support = {MN5DF/CAAu23/100008//My name'5 doddie foundation/ ; MN5DF/CAAu23/100008//My name'5 doddie foundation/ ; MN5DF/CAAu23/100008//My name'5 doddie foundation/ ; MN5DF/CAAu23/100008//My name'5 doddie foundation/ ; IF\R2\222002//Royal Society/ ; IF\R2\222002//Royal Society/ ; }, mesh = {*Protein Serine-Threonine Kinases/genetics/chemistry/metabolism/physiology ; Humans ; *Glutamic Acid/physiology/chemistry/genetics ; Catalytic Domain/genetics ; HEK293 Cells ; Enzyme Activation/genetics ; Codon ; Amyotrophic Lateral Sclerosis/genetics ; Amino Acid Substitution ; Biocatalysis ; }, abstract = {TANK binding kinase 1 (TBK1) is serine/threonine protein kinase member of the inhibitor of nuclear factor-kB kinase family, with links to the etiology of familial as well as idiopathic Amyotrophic Lateral Sclerosis. It contributes to several regulatory cellular processes such as autophagy, inflammation and apoptosis. Reduction or loss of TBK1 kinase activity is associated with increased risk of ALS, and so understanding the molecular basis of this activity is an important research priority. In this current study, the role of the E168 residue, located adjacent to the active site of TBK1, has been assessed using a combination of artificial and naturally occurring variants found at this codon - evaluated using multiple readouts for TBK1 kinase activity. The results suggest that the negative charge resulting from the presence of a glutamic acid at this codon is a constitutive activator of TBK1 activity.}, } @article {pmid41191543, year = {2025}, author = {}, title = {Erratum.}, journal = {Neuro-degenerative diseases}, volume = {25}, number = {4}, pages = {227}, doi = {10.1159/000548749}, pmid = {41191543}, issn = {1660-2862}, abstract = {In the article “Characteristics of Neuromuscular Ultrasound in Patients with Amyotrophic Lateral Sclerosis” [Neurodegener Dis. 2025; https://doi.org/10.1159/000546425] by Wu et al., the wrong copyright license was displayed. It has been corrected to a CC-BY 4.0 license. The original online article has been updated to reflect this.}, } @article {pmid41191764, year = {2025}, author = {Qian, Y and Liu, C and Yu, P and Ran, X and Li, S and Yang, Q and Liu, Y and Xia, L and Wang, Y and Qi, J and Zhou, E and Lu, J and Li, Y and Tao, TH and Zhou, Z and Wu, J}, title = {Real-time decoding of full-spectrum Chinese using brain-computer interface.}, journal = {Science advances}, volume = {11}, number = {45}, pages = {eadz9968}, pmid = {41191764}, issn = {2375-2548}, mesh = {*Brain-Computer Interfaces ; Humans ; Language ; Male ; *Speech/physiology ; Female ; Adult ; Electroencephalography ; China ; East Asian People ; }, abstract = {Speech brain-computer interfaces (BCIs) offer a promising means to provide functional communication capacity for patients with anarthria caused by neurological conditions such as amyotrophic lateral sclerosis (ALS) or brainstem stroke. Current speech decoding research has predominantly focused on English using phoneme-driven architectures, whereas real-time decoding of tonal monosyllabic languages such as Mandarin Chinese remains a major challenge. This study demonstrates a real-time Mandarin speech BCI that decodes monosyllabic units directly from neural signals. Using the 256-channel microelectrocorticographic BCI, we achieved robust decoding of a comprehensive set of 394 distinct syllables based purely on neural signals, yielding median syllable identification accuracy of 71.2% in a single-character reading task. Leveraging this high-performing syllable decoder, we further demonstrated real-time sentence decoding. Our findings demonstrate the efficacy of a tonally integrated, direct syllable neural decoding approach for Mandarin Chinese, paving the way for full-coverage systems in tonal monosyllabic languages.}, } @article {pmid41192771, year = {2025}, author = {Shima, S and Kondo, T and Inoue, H}, title = {iPSC-derived neural organoids in dementia research: Recent advances and future directions.}, journal = {Neuroscience research}, volume = {221}, number = {}, pages = {104980}, doi = {10.1016/j.neures.2025.104980}, pmid = {41192771}, issn = {1872-8111}, mesh = {Humans ; *Organoids ; *Induced Pluripotent Stem Cells/physiology ; *Dementia/therapy/pathology ; Animals ; *Neurons ; }, abstract = {Neural organoids are self-assembled three-dimensionally shaped aggregates generated from pluripotent stem cells for the purpose of generating brain-like structures. The features of the disease, from molecular to functional levels, can be recapitulated by neural organoids derived from patient induced pluripotent stem cells (iPSCs). These features are not fully reproduced by other culture systems or in vivo models. Neural organoids have been applied to model dementia including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia, and they have recapitulated aspects of their complex pathophysiology, including neuronal network dysfunction and accumulation of pathogenic proteins. Although research using neural organoids still faces challenges such as heterogeneity and the absence of non-neural lineage cells, these limitations are being progressively addressed. Recent advances, including the integration of gene-editing technologies and the co-assembly of organoids with specific cell types, have demonstrated the remarkable potential of this approach. This article reviews current research on iPSC-derived neural organoids for dementia, discussing both the technical hurdles and the potential for translational applications.}, } @article {pmid41194479, year = {2025}, author = {Das, S and Patel, M and Khandelwal, S and Rawat, R and Shukla, S and Kumari, AP and Singh, K and Kumar, A}, title = {From Mutations to Microbes: Investigating the Impact of the Gut Microbiome on Repeat Expansion Disorders.}, journal = {Journal of neurochemistry}, volume = {169}, number = {11}, pages = {e70278}, doi = {10.1111/jnc.70278}, pmid = {41194479}, issn = {1471-4159}, mesh = {*Gastrointestinal Microbiome/physiology/genetics ; Humans ; Animals ; *Mutation/genetics ; Dysbiosis/genetics ; *DNA Repeat Expansion/genetics ; }, abstract = {Repeat expansion disorders (REDs) are a diverse array of genetic disorders characterized by the expansion of specific DNA sequences. These expansions are frequently dynamic and are susceptible to further expansion across generations. They contribute to disease progression by leading symptoms to become more severe and manifest earlier in subsequent generations. Despite a substantial understanding of their molecular mechanisms, the exact etiology of REDs remains tricky. Emerging evidence indicates that gut microbiome dysbiosis significantly impacts REDs by regulating various biochemical pathways. Alterations in microbial diversity and composition have been observed across multiple REDs; however, a comprehensive understanding of the complete scenario remains a significant challenge. To elucidate these dynamic interactions, future research should utilize multifaceted approaches. This review focuses on the key modifications in the gut microbiome that contribute to the pathogenesis of REDs and discusses potential gut microbiome-targeted therapeutic strategies that could be effectively employed to treat these disorders.}, } @article {pmid41194593, year = {2026}, author = {Levine, MP and Chung, SY and Quigg, KH and Carey, J and Babu, S and Paganoni, S and Berry, JD}, title = {Participation in U.S.-Based ALS Clinical Trials by Sex and Race.}, journal = {Muscle & nerve}, volume = {73}, number = {1}, pages = {50-55}, pmid = {41194593}, issn = {1097-4598}, support = {1OT2NS136939-01/NS/NINDS NIH HHS/United States ; OT2 NS136938/NS/NINDS NIH HHS/United States ; OT2 NS136939/NS/NINDS NIH HHS/United States ; 1OT2NS136938-01/NS/NINDS NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology/ethnology ; *Clinical Trials as Topic/statistics & numerical data ; *Patient Participation/statistics & numerical data ; Patient Selection ; *Racial Groups ; Registries ; United States/epidemiology ; *Sex Distribution ; }, abstract = {INTRODUCTION/AIMS: In global amyotrophic lateral sclerosis (ALS) trials, women and men appear to be proportionately enrolled, but quantification of enrollment by sex and race in U.S.-based ALS trials is limited. The objective of this study was to evaluate the sex and race of participants enrolled in U.S.-based ALS clinical trials.

METHODS: Participant demographics were extracted from recent U.S.-based Phase 2 and 3 ALS trials identified in literature and on ClinicalTrials.gov. The Centers for Disease Control and Prevention (CDC) National ALS Registry and a 2014 State Surveillance Project were used as proxies for prevalence. Participation-to-prevalence (PPR) ratios were calculated for sex and race. A modified time-trend analysis was performed for race for participants enrolled before and after 2020.

RESULTS: A total of 11 trials met criteria for inclusion with a total of 1153 patients enrolled. Compared to the CDC Registry, the PPR was 0.76 (95% CI: 0.63-0.90) for women, 1.26 (95% CI: 1.23-1.29) for White participants, 0.34 (95% CI: 0.17-0.51) for Black participants, and 0.35 (95% CI: 0.14-0.56) for all other races/multiracial. The modified time trend analysis showed no significant difference in the PPRs before and after 2020 (White: t = 1.44, p = 0.22; Black: t = -0.99, p = 0.37; Other races/multiracial: t = -1.50, p = 0.21). The comparison to the 2014 State Surveillance Project yielded similar findings.

DISCUSSION: U.S.-based ALS trials significantly under-enroll non-White participants, and there are trends toward slight underrepresentation of women. Efforts to broaden trial enrollment amongst people with ALS will help with the generalizability of trial results and hasten trial completion.}, } @article {pmid41194800, year = {2025}, author = {Su, Z and Xiang, L}, title = {Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1639114}, pmid = {41194800}, issn = {1662-5099}, abstract = {The pathophysiology of neurodegenerative diseases is largely driven by ER stress, contributing to cellular dysfunction and inflammation. Chronic ER stress in skeletal muscle is associated with a deterioration in muscle function, particularly in diseases such as ALS, PD, and AD, which are often accompanied by muscle wasting and weakness. ER stress triggers the UPR, a cellular process designed to restore protein homeostasis, but prolonged or unresolved stress can lead to muscle degeneration. Recent studies indicate that exercise may modulate ER stress, thereby improving muscle health through the enhancement of the adaptive UPR, reducing protein misfolding, and promoting cellular repair mechanisms. This review examines the influence of exercise on the modulation of ER stress in muscle cells, with a particular focus on how physical activity influences key pathways contributed to mitochondrial function, protein folding, and quality control. We discuss how exercise-induced adaptations, including the activation of stress-resilience pathways, antioxidant responses, and autophagy, can help mitigate the negative effects of ER stress in muscle cells. Moreover, we examine the potential therapeutic implications of exercise in neurodegenerative diseases, where it may improve muscle function, reduce muscle wasting, and alleviate symptoms associated with ER stress. By integrating findings from neurobiology, muscle physiology, and cellular stress responses, this article highlights the therapeutic potential of exercise as a strategy to modulate ER stress and improve muscle function in neurodegenerative diseases.}, } @article {pmid41195023, year = {2025}, author = {Furuya, K and Itoh, N}, title = {Red urine in a 68-year-old man with amyotrophic lateral sclerosis.}, journal = {Journal of general and family medicine}, volume = {26}, number = {6}, pages = {659-660}, pmid = {41195023}, issn = {2189-7948}, } @article {pmid41195301, year = {2025}, author = {Dijkstra, JIR and Hulsman, M and Waterink, L and Holstege, H and Teunissen, CE and Christiaansen, WFL and de Jong, BA and Kochunov, P and Donohue, B and Zwan, MD and den Braber, A and Vermunt, L and van der Lee, SJ}, title = {Heritability and shared environmental effects of brain diseases in 12,040 extended families.}, journal = {NPJ dementia}, volume = {1}, number = {1}, pages = {34}, pmid = {41195301}, issn = {3005-1940}, support = {R01 EB015611/EB/NIBIB NIH HHS/United States ; RF1 MH123163/MH/NIMH NIH HHS/United States ; S10 OD023696/OD/NIH HHS/United States ; }, abstract = {Brain diseases have complex patterns of genetic and environmental risk factors, and better understanding of these risks is required for more effective prevention strategies. Participants of the Dutch Brain Research Registry provided detailed information on family structure and occurrence of brain diseases. A total of 12,040 participants (73% female, aged 64.9 ± 11 years) provided information on 101,379 family members (53% female, aged 62 ± 25 years). We estimated heritability (h [2]) of the nine most common brain diseases using polygenic modeling in SOLAR and assessed variations in h [2] through bootstrapping; Alzheimer's disease (AD) (h [2] = 73, range 53-86, P fdr < 0.001), ALS (h [2] = 72, range 10-98, P fdr = 0.030), frontotemporal dementia (FTD) (h [2] = 48, range 0-97, P fdr = 0.132), vascular dementia (VaD) (h [2] = 41, range 7-64, P = 0.003), Lewy Body dementia (h [2] = 34, range 0-58, P = 0.132), iCVA (h [2] = 27, 6-59, P fdr = 0.013), hCVA (h [2] = 29, 8-57, P fdr = 0.007), Parkinson's disease (PD) (h [2] = 38, 6-66, P fdr = 0.013), and multiple sclerosis (h [2] = 10, 10-97, P fdr < 0.001). Shared environmental effects could be estimated for AD (c [2] = 5.8%, P fdr = 0.011), VaD (c [2] = 9.0%, P fdr = 0.021), FTD (c [2] = 9.7%, P fdr = 0.33), iCVA (c [2] = 15.9%, P fdr < 0.001), hCVA (c [2] = 14.9%, P fdr = 0.005), and PD (c [2] = 7.5%, P fdr = 0.25). These findings underscore the significance of genetic contribution to most brain diseases and the important role of shared environments in AD and vascular-related conditions, highlighting initiatives to mitigate modifiable risk factors.}, } @article {pmid41196018, year = {2026}, author = {Magara, J and Suzuki, T and Yoshihara, M and Onuki, W and Sasa, A and Tsujimura, T and Inoue, M}, title = {Lingual pressure as a physiological indicator for dysphagia in amyotrophic lateral sclerosis and multiple system atrophy.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {4}, pages = {391-400}, pmid = {41196018}, issn = {1758-2032}, mesh = {Humans ; *Deglutition Disorders/diagnosis/physiopathology/etiology ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Multiple System Atrophy/complications/physiopathology ; *Tongue/physiopathology ; Pressure ; Female ; Male ; Middle Aged ; Aged ; }, abstract = {BACKGROUND: This study aimed to characterize lingual pressure (LP) and clarify its association with dysphagia in patients with amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA).

METHODS: We examined 52 patients with ALS (Spinal-onset, 39; bulbar-onset, 13) and 36 patients with MSA (MSA-C, 26; MSA-P, 10). LP was measured using a balloon-type instrument during isometric contractions. Maximum LP (MLP) and 80% endurance of LP (ELP; duration above 80% of MLP during 7 seconds) were analyzed against videofluoroscopic findings of dysphagia.

RESULTS: Both parameters significantly correlated with food intake scales, especially in ALS. Liquid aspiration was predicted in ALS with 80.8% accuracy (AUC = 0.794, p < 0.001) using MLP cutoff of 20.5 kPa, and in MSA with 75.0% accuracy (AUC = 0.786, p < 0.01) using an ELP cutoff of 1.68 second. Predictive accuracy improved in spinal-onset ALS and MSA-C.

CONCLUSION: LP thus may represent a physiological indicator for dysphagia detection and management.}, } @article {pmid41196032, year = {2026}, author = {Mansoor, N and Heiman-Patterson, T and Feldman, EL and Wicks, P and Benatar, M and Vieira, F and Glass, J and Levine, T and Bertorini, T and Barkhaus, P and Mascias Cadavid, J and Jackson, C and Jhooty, S and Brown, A and Pattee, G and Sane, H and Mcdermott, CJ and Carter, G and Beauchamp, M and Wang, O and Ratner, D and Bedlack, R and Li, X}, title = {ALSUntangled #81: Pyridostigmine (mestinon[®]).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {487-491}, doi = {10.1080/21678421.2025.2582830}, pmid = {41196032}, issn = {2167-9223}, mesh = {Humans ; *Pyridostigmine Bromide/therapeutic use/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; Neuromuscular Junction/drug effects ; Animals ; Disease Progression ; }, abstract = {Pyridostigmine (Mestinon[®], Bausch Health, Canada Inc.) increases acetylcholine availability at the neuromuscular junction, enhancing transmission. Preclinical studies suggest that neuromuscular junction dysfunction develops early in ALS, and pyridostigmine may temporarily improve neuromuscular transmission. However, altered neuromuscular junction transmission has uncertain benefits in ALS progression. Pyridostigmine does not have other plausible mechanisms that truly modify ALS pathophysiology. People with ALS (PALS) who have positive acetylcholine receptor autoantibodies and no myasthenia symptoms are unlikely to respond to pyridostigmine treatment. Clinical trials on pyridostigmine in PALS are lacking, but two clinical trials of other similar anticholinesterase agents did not effectively slow ALS progression. Muscarinic cholinergic side effects, including gastrointestinal symptoms, are common. Given the lack of mechanistic plausibility and efficacy, we do not support the use of pyridostigmine for slowing ALS progression.}, } @article {pmid41196070, year = {2026}, author = {Kartanou, C and Kontogeorgiou, Z and Loupis, T and Vrachnos, DM and Ragazos, N and Spyropoulou, I and Petraki, M and Koniari, C and Aristeidou, S and Koropouli, E and Daponte, A and Rentzos, M and Kapaki, E and Panas, M and Makrythanasis, P and Stefanis, L and Koutsis, G and Karadima, G}, title = {Unraveling the genetic landscape of ALS in Greece: identification of known and novel causative variants in a 353-patient cohort.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {318-327}, doi = {10.1080/21678421.2025.2582828}, pmid = {41196070}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Greece/epidemiology ; Male ; Female ; Middle Aged ; *C9orf72 Protein/genetics ; Aged ; Cohort Studies ; Ataxin-2/genetics ; Adult ; DNA Repeat Expansion/genetics ; *Genetic Predisposition to Disease/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive, fatal neurodegenerative disorder characterized by progressive loss of motor neurons. Approximately 15% of individuals diagnosed with ALS have a known genetic variant that contributes to disease. Herein, we present clinical and genetic data of a large Greek ALS cohort.

PATIENTS AND METHODS: The cohort consisted of 353 Greek consecutive index patients with ALS, including 16 patients with related motor neuron disease (MND) subtypes (nine with PLS, four with PBP, and three with PMA). Next generation sequencing raw data (obtained from the NYGC ALS Consortium) were further analyzed and used to screen for causative variants in known implicated genes. Repeat expansions in C9ORF72 and ATXN2 were investigated using ExpansionHunter software, repeat-primed PCR and fragment analysis.

RESULTS: Pathogenic repeat expansions in C9ORF72 were detected in 41 patients (11.6%). In addition, 30 patients (8.5%) carried a causative variant in one of the genes studied. Known causative variants were identified in 27 cases (nine in SQSTM1, seven in TARDBP, five in SOD1, three in NEK1 and one each in SETX, VCP, FUS), whereas novel causative variants were identified in three cases (SOD1, FIG4, TBK1). In total, 71 cases received a molecular genetic diagnosis (20.1%). Additionally, seven cases (2.0%) carried an intermediate repeat expansion (30-33 CAG) in ATXN2.

CONCLUSION: Our results reveal the distinct genetic profile of Greek ALS patients. These findings will have an impact on genetic counseling, the design of diagnostic gene panels for the Greek population and on genotype-specific therapeutic interventions. Understanding the genetic causes of ALS in different populations is becoming increasingly important, especially with the advent of personalized medicine.}, } @article {pmid41196279, year = {2026}, author = {Han, J and Xu, X and Zhao, Y and Xiao, Y and Huang, F and Zhou, J and Huang, H and Wang, G}, title = {Tui Na Acupressure Modulates Treg Immunosuppression via FoxP3/mTORC1 Signalling in ALS Mice.}, journal = {Immunology}, volume = {177}, number = {3}, pages = {481-500}, pmid = {41196279}, issn = {1365-2567}, support = {//Hubei Provincial Natural Science Foundation's Innovation/ ; 2023AFD171//Development Joint Fund Project/ ; 2023AFD128//Development Joint Fund Project/ ; 2023AFD170//Development Joint Fund Project/ ; 2025AFD535//Development Joint Fund Project/ ; GZY-KJS-2025-008//Science and Technology Special Project of the State Administration of Traditional Chinese Medicine/ ; }, mesh = {Animals ; *T-Lymphocytes, Regulatory/immunology/metabolism ; *Mechanistic Target of Rapamycin Complex 1/metabolism ; Signal Transduction/immunology ; Mice ; *Amyotrophic Lateral Sclerosis/immunology/therapy/metabolism ; *Forkhead Transcription Factors/metabolism ; Disease Models, Animal ; *Acupressure/methods ; Cytokines/metabolism ; Immune Tolerance ; Male ; Mice, Transgenic ; Cell Proliferation ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease driven by neuroinflammation, where regulatory T cell (Treg) dysfunction exacerbates immune imbalance. This study explores whether Tui Na acupressure, a traditional Chinese therapy, can restore Treg immunosuppressive function through the FoxP3/mTORC1 signalling pathway to mitigate ALS pathology. In SOD1G93A ALS mice, Tui Na was applied at the Shenshu acupoint, with motor and cognitive functions assessed via rotarod, tail suspension, novel object recognition, and Y-maze tests. Multi-omics (transcriptomics, proteomics), flow cytometry, ELISA, and Western blot analysed Treg proportions, cytokine profiles, and pathway activation. In vitro assays evaluated Treg proliferation and immunosuppression. Tui Na significantly enhanced motor and cognitive performance, increased Treg proportions in spleen, lymph nodes, and blood, and elevated anti-inflammatory cytokines (IL-10, TGF-β) while reducing pro-inflammatory markers (IL-6, TNF-α). Transcriptomic and proteomic analyses revealed upregulated FoxP3, Mtor, and Raptor, with enhanced Treg proliferation and immunosuppression confirmed in vitro. Pathway inhibitors (GSK126, rapamycin) reversed these effects, confirming FoxP3/mTORC1 dependency. Tui Na also reduced apoptosis and oxidative stress, supporting immune regulation. These findings highlight Tui Na's potential to restore Treg-mediated immune balance in ALS, offering a non-pharmacological therapeutic strategy. This study provides novel immunological insights into Tui Na's mechanisms, advocating its clinical evaluation for ALS and related immune-driven disorders.}, } @article {pmid41196652, year = {2026}, author = {Lang, C and Guillot, SJ and Lule, D and Balz, LT and Knehr, A and Weydt, P and Dorst, J and Kandler, K and Muller, HP and Kassubek, J and Wassermann, L and Da Cruz, S and Roselli, F and Ludolph, AC and Bolborea, M and Dupuis, L}, title = {Early brain-wide disruption of sleep microarchitecture in amyotrophic lateral sclerosis.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {1}, pages = {}, pmid = {41196652}, issn = {1558-8238}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/genetics/pathology/metabolism ; Humans ; Animals ; Male ; Female ; Mice ; Middle Aged ; *Brain/physiopathology/pathology/metabolism ; Aged ; Superoxide Dismutase-1/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; *Sleep ; Adult ; Polysomnography ; Mice, Transgenic ; Disease Models, Animal ; }, abstract = {BACKGROUNDAmyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, is preceded by an early period unrelated to motor symptoms, including altered sleep, with increased wakefulness and decreased deep nonrapid eye movement (NREM). Whether these alterations in sleep macroarchitecture are associated with - or even precede - abnormalities in sleep-related EEG features remains unknown.METHODSHere, we characterize sleep microarchitecture using polysomnography for patients with ALS (n = 33) and controls (n = 32) as well as for asymptomatic carriers of superoxide dismutase 1 (SOD1) or C9ORF72 mutations (n = 57) and noncarrier controls (n = 30). Patients and controls with factors that could confound sleep structure, including respiratory insufficiency, were prospectively excluded. The results were complemented in 3 ALS mouse models (Sod1G86R, FusΔNLS/+, and TDP-43Q331K).RESULTSWe observed a brain-wide reduction in the density of sleep spindles, slow oscillations, and K-complexes in patients with early-stage ALS and in presymptomatic gene carriers. These defects in sleep spindles and slow oscillations correlated with cognitive performance in both cohorts, particularly with scores on memory, verbal fluency, and language function. Alterations in sleep microarchitecture were replicated in 3 mouse models, and decreases in sleep spindles were rescued following intracerebroventricular supplementation of melanin-concentrating hormone (MCH) or by oral administration of a dual orexin receptor antagonist.CONCLUSIONSleep microarchitecture was associated with cognitive deficits and causally linked to aberrant MCH and orexin signaling in ALS.FUNDINGAgence Nationale de la Recherche (ANR); Fondation Thierry Latran; Association Francaise de Recherche sur la sclérose latérale amyotrophique; Association Française contre les myopathies; TargetALS; and Joint Program on Neurodegenerative Diseases Research (JPND).}, } @article {pmid41198658, year = {2025}, author = {Volik, PI and Kopeina, GS and Zhivotovsky, B and Zamaraev, AV}, title = {p62-dependent caspase-2 activation governs TDP-43 clearance and neuronal fate in ALS.}, journal = {Cell death & disease}, volume = {16}, number = {1}, pages = {801}, pmid = {41198658}, issn = {2041-4889}, support = {222013//Cancerfonden (Swedish Cancer Society)/ ; 181301//Radiumhemmets Forskningsfonder (Cancer Research Foundations of Radiumhemmet)/ ; 23-74-30006//Russian Science Foundation (RSF)/ ; }, } @article {pmid41199372, year = {2025}, author = {Xu, L and Huang, B and Zhou, Y and Liao, X and Chen, T and He, H}, title = {Multi-omics-based decoding of circulating biomarkers in amyotrophic lateral sclerosis and risks in environmental toxins.}, journal = {BMC pharmacology & toxicology}, volume = {26}, number = {1}, pages = {186}, pmid = {41199372}, issn = {2050-6511}, support = {2024Y389//Scientific Research Foundation of Yunnan Provincial Education Department/ ; 2024Y392//Scientific Research Foundation of Yunnan Provincial Education Department/ ; 2024JJ7319//Natural Science Foundation of Hunan Province/ ; 2025JJ70442//Natural Science Foundation of Hunan Province/ ; 2025JJ70465//Natural Science Foundation of Hunan Province/ ; 202412//Doctoral research project initiation fund at Hunan University of Medicine/ ; 202401001789//Reform Project of Hunan Provincial Education Department/ ; 2541STC72898//International Cooperative Project of Traditional Chinese Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/blood/genetics/diagnosis ; Humans ; Biomarkers/blood ; Proteomics ; Genome-Wide Association Study ; Transcriptome ; *Environmental Pollutants/toxicity ; Machine Learning ; Mendelian Randomization Analysis ; Multiomics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the interplay of genetic and environmental factors, and currently, there there is a lack of effective diagnostic or therapeutic strategies available. This study aims to identify circulating biomarkers for ALS and investigate their interactions with environmental toxins.

METHODS: This research utilizes plasma proteomic genome-wide association study (GWAS) data and whole blood transcriptomic data from ALS patients to screen for potential circulating biomarkers through Mendelian randomization (MR). Subsequently, functional enrichment analysis and immune infiltration analysis were performed. An integrated machine learning approach will be used to construct a diagnostic model, with hub genes selected based on SHAP values. The model's performance will be validated using receiver operating characteristic (ROC) curves, nomogram, and decision curve analysis (DCA). Finally, reverse network toxicology will be used to explore the interaction mechanisms between hub genes and environmental toxins.

RESULTS: Based on a MR analysis of plasma proteomics, we identified 68 plasma proteins significantly associated with the risk of ALS. By integrating differentially expressed genes (DEGs) from whole blood transcriptomics (1,116 DEGs), we selected four potential circulating biomarkers: FCRL3, HTATIP2, RNASE6, and SF3B4. Functional enrichment analysis indicated that the pathogenesis of ALS is closely related to autophagy, apoptosis, the endoplasmic reticulum unfolded protein response, and the NF-κB signaling pathway. Immune infiltration analysis revealed a disruption of the immune microenvironment mediated by T cells/myeloid cells in ALS patients. Validation through 113 machine learning algorithms showed that the random forest model exhibited the best diagnostic performance (AUC = 0.786), while SHAP analysis confirmed the contribution ranking of hub biomarkers: RNASE6 > FCRL3 > HTATIP2 > SF3B4. Further validation of their diagnostic value was performed using ROC curves, nomograms, and DCA. Environmental toxins analysis revealed that substances such as benzo(a)pyrene exhibit significant neurotoxicity, and molecular docking confirmed that they can interfere with the function of hub biomarkers through strong binding (∆G < -5 kcal·mol⁻¹), suggesting potential environmental pathogenic mechanisms in ALS.

CONCLUSIONS: This study not only highlights the value of FCRL3, HTATIP2, RNASE6, and SF3B4 as potential diagnostic biomarkers and therapeutic targets for ALS but also provides new evidence for the involvement of environmental toxins, particularly benzo(a)pyrene, in the pathogenesis of ALS through gene-environment interactions.}, } @article {pmid41199620, year = {2026}, author = {Zelikovich, AS and Ackrivo, J}, title = {Acoustic Features in ALS: Taking a Pause to Appreciate a Novel Remote Respiratory Monitoring Strategy.}, journal = {Muscle & nerve}, volume = {73}, number = {1}, pages = {5-6}, pmid = {41199620}, issn = {1097-4598}, support = {K23 HL151879/HL/NHLBI NIH HHS/United States ; HT9425-25-1-0154//Department of Defense ALS research program/ ; K23 HL-151879/HL/NHLBI NIH HHS/United States ; }, } @article {pmid41200140, year = {2025}, author = {Bourke, CA}, title = {Decreased purine ingestion, increased molybdenum ingestion, and the decline in amyotrophic lateral sclerosis on Guam.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1618834}, pmid = {41200140}, issn = {2296-861X}, } @article {pmid41201205, year = {2025}, author = {Canosa, A and Callegaro, S and Manera, U and Vasta, R and Cabras, S and Di Pede, F and De Mattei, F and Palumbo, F and Iazzolino, B and Giudici, AD and Matteoni, E and Zocco, G and Minerva, E and Maccabeo, A and Pellegrino, G and Pascariu, D and Grassano, M and Ciresi, F and Testa, M and Polverari, G and Salamone, P and De Marco, G and Paolantonio, C and Marchese, G and Moglia, C and Calvo, A and Chiò, A and Pagani, M}, title = {Cognitive Reserve in Amyotrophic Lateral Sclerosis: A 2-[[18]F]FDG-PET Study on Sex-Related Differences.}, journal = {European journal of neurology}, volume = {32}, number = {11}, pages = {e70412}, pmid = {41201205}, issn = {1468-1331}, support = {PRIN 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; //Fondation Thierry Latran/ ; RF-2016-02362405//Ministero della Salute/ ; 259867//Seventh Framework Programme/ ; GA101017598//Horizon 2020 Framework Programme/ ; 101137074//Horizon 2020 Framework Programme/ ; //A.S.D. Polisportiva U.I.C.I Torino Onlus/ ; //Ministry of Education, University and Research of Italy/ ; //Ministry of Health/ ; }, mesh = {Humans ; *Cognitive Reserve/physiology ; Male ; Female ; Positron-Emission Tomography ; Fluorodeoxyglucose F18 ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/psychology/complications ; Middle Aged ; Aged ; *Brain/diagnostic imaging/metabolism ; *Sex Characteristics ; Radiopharmaceuticals ; }, abstract = {BACKGROUND: Cognitive reserve (CR) applies to ALS-related cognitive impairment and education is a CR proxy. The influence of sex on CR in ALS is unclear.

METHODS: We compared brain 2-[[18]F]FDG-PET metabolism of male (m-ALS, n = 95) and female (f-ALS, n = 95) patients, matched for age, education, onset, and King's stage, with no significant difference in ECAS scores. In each group, clusters showing a negative/positive correlation with education were used as seed regions in an interregional correlation analysis (IRCA) to evaluate connectivity. We identified the seed regions including age, onset, King's stage and ECAS as covariates.

RESULTS: M-ALS showed a relative hypometabolism compared to f-ALS in bilateral frontotemporal regions. In f-ALS brain metabolism positively correlated with education in the left fusiform gyrus, cerebellum and pons. The IRCA showed a positive correlation of the seed region with the cerebellum, pons, right fusiform gyrus and cuneus, and the left precuneus, and a negative correlation with the frontal lobes and caudate nuclei. In m-ALS brain metabolism negatively correlated with education in the left frontotemporal and insular cortices. The IRCA showed a positive correlation of the seed region with bilateral frontotemporal and cingulate cortices, and the right parietal cortex, and a negative correlation with bilateral cerebellum and motor cortex, and the left lingual gyrus.

CONCLUSIONS: M-ALS showed relative frontotemporal hypometabolism compared to f-ALS, suggesting a male prevalence of CR. In m-ALS the negative correlation of education with left frontotemporal and insular metabolism supports the CR hypothesis. In f-ALS the positive correlation of cerebellar metabolism with education suggests compensatory mechanisms, also supported by the IRCA.}, } @article {pmid41201375, year = {2026}, author = {Tomlinson, J and Roberson, E and Klee, V and Ma, J and Roggenbuck, J}, title = {A study of patient recall and comprehension of genetic testing results in amyotrophic lateral sclerosis (ALS).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {363-369}, doi = {10.1080/21678421.2025.2582829}, pmid = {41201375}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology/diagnosis ; Female ; Male ; *Genetic Testing ; Middle Aged ; *Comprehension/physiology ; Aged ; *Mental Recall/physiology ; Adult ; Health Literacy ; Registries ; }, abstract = {Objective: Assess the accuracy of ALS patient recall of genetic testing results and evaluate comprehension of key implications of results. Methods: Participants were recruited from the Center for Disease Control's National ALS Registry. A survey collected participant demographics, their recollection of their genetic test result, and their understanding of the implications of their result. Comprehension was scored based on responses to key questions. Whenever possible, patient-reported test results were confirmed by review of their test report. Results: Most participants (n = 246) were white (n = 238, 96.7%) with high health literacy. Among participants whose self-reported result could be validated, most 93/98 (94.9%) accurately recalled whether they received a positive, negative, or uncertain result. Among participants who reported positive results, 32/50 (64.0%) demonstrated understanding that their genetic testing results explained their ALS, while 38/50 (76.0%) accurately characterized the risk that first degree relatives carried the same variant. Among participants who reported negative results, 100/142 (70.4%) incorrectly indicated that their result ruled out a genetic cause. When asked about the risk for family members to develop ALS, 98/142 (69.0%) correctly characterized this residual risk. However, only 12/142 (8.5%), answered both questions correctly. Overall, participants who saw a genetic counselor were more likely to demonstrate high comprehension (p = 0.022). Conclusions: The majority of participants demonstrated accurate recall of their ALS genetic testing result. However, deficits in understanding of key implications were identified, particularly among those with negative results. Participants who saw a genetic counselor had significantly better comprehension of their test results than those who did not.}, } @article {pmid41201719, year = {2025}, author = {Gautam, P and Vishwakarma, RK and Nath, M and Nath, G and Pathak, A}, title = {Microbiota Dysbiosis in Amyotrophic Lateral Sclerosis: A Systematic Review of Human Studies.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {10}, pmid = {41201719}, issn = {1559-1182}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/microbiology/complications ; *Dysbiosis/microbiology/complications ; *Gastrointestinal Microbiome/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration. Despite intensive research, its pathogenesis remains poorly understood. Recent insights suggest a pivotal role of the gut microbiota in modulating neuroinflammation and neurodegeneration via the gut-brain axis. This systematic review aims to synthesize clinical evidence on gut microbiota dysbiosis in ALS, exploring microbial and metabolic alterations and their associations with disease progression and severity. A comprehensive literature search was conducted across PubMed, Embase, Scopus, Web of Science, and other databases up to May 10, 2024, adhering to PRISMA 2020 guidelines. Eighteen eligible human studies were selected based on predefined inclusion criteria. Data on microbial diversity, taxonomic shifts, metabolite profiles, and clinical correlations were extracted and assessed using a modified Newcastle-Ottawa Scale. Most studies reported altered microbial diversity, reduced butyrate-producing bacteria (e.g., Faecalibacterium, Roseburia), and increased pro-inflammatory taxa (e.g., Escherichia coli, Bacteroides) in ALS. Integrated microbiome-metabolome analyses revealed disruptions in SCFAs, bile acids, and lipid metabolism, some correlating with ALSFRS-R scores and cognitive impairment. Although some studies showed minimal or no differences, the overall evidence supports a link between dysbiosis and ALS pathophysiology. Probiotic trials demonstrated limited efficacy, highlighting the need for targeted, patient-specific interventions. Gut microbiota dysbiosis is increasingly recognized as a contributor to ALS progression. However, methodological variability, small sample sizes, and limited longitudinal data restrict definitive conclusions. Future research should employ standardized, multi-omics approaches and larger cohorts to clarify causal links and develop microbiome-informed diagnostics and therapies for ALS.}, } @article {pmid41202295, year = {2025}, author = {Sales de Campos, P and Smith-Hublou, M and Olsen, WL and Souza Leite, W and Wymer, JP and Napoli, NJ and Vose, AK and Pulley, MT and Mitchell, GS and Smith, BK}, title = {Acute Adenosine Receptor Antagonism in Combination With Acute Intermittent Hypoxia to Promote Breathing Plasticity in Amyotrophic Lateral Sclerosis: Protocol for a Randomized, Double-Blinded, Placebo-Controlled Trial.}, journal = {JMIR research protocols}, volume = {14}, number = {}, pages = {e76105}, pmid = {41202295}, issn = {1929-0748}, support = {T32 HL134621/HL/NHLBI NIH HHS/United States ; 22-CTA-611//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/drug therapy/therapy ; Double-Blind Method ; *Hypoxia/physiopathology ; Purines/therapeutic use/pharmacology ; *Respiration/drug effects ; *Neuronal Plasticity/drug effects ; *Purinergic P1 Receptor Antagonists/therapeutic use ; Randomized Controlled Trials as Topic ; Male ; Adult ; Middle Aged ; Female ; }, abstract = {BACKGROUND: Respiratory impairment is a major concern in amyotrophic lateral sclerosis (ALS), shortening survival and lowering quality of life. One therapy with promise to delay respiratory decline in ALS is acute intermittent hypoxia (AIH), consisting of alternating periods of breathing mildly hypoxic (9%-12% O2) and normoxic (21% O2) gas. AIH stimulates spinal, serotonin-dependent neuroplasticity in rodent models, conferring functional benefits in diverse physiological systems without detectable pathology. However, in rodent models, AIH-induced neuroplasticity is constrained by distinct signaling cascades initiated by spinal adenosine.

OBJECTIVE: We propose to investigate a therapeutic strategy to delay breathing compromise in those living with ALS by combining a selective adenosine 2A (A2A) receptor inhibitor (istradefylline) with AIH. The fundamental hypothesis guiding this proposal is that a single AIH trial after pretreatment with istradefylline enhances respiratory neuroplasticity versus AIH or sham intervention.

METHODS: We propose to evaluate resting breathing, respiratory strength, and participant-reported symptoms in adults living with ALS after combined istradefylline plus AIH. A mixed within- and between-participant study design incorporates 4 test sessions, separated by approximately 2 weeks (±5 days). Testing conditions include single sessions of AIH + istradefylline, AIH + placebo, sham AIH (ie, normoxia) + placebo, and sham AIH + istradefylline. Safety and feasibility will be characterized using the rate of adverse events, changes in vital signs, and participant-reported breathing sensations (Aim 1). Neuroplasticity of breathing and motor function will be evaluated as changes in resting breathing, voluntary respiratory strength, respiratory control, and maximal pinch force (Aim 2).

RESULTS: As of January 2025, with a target sample of 16 participants in each group, 10 participants with ALS and 5 control participants completed study procedures. Recruiting is ongoing, and the final participant will complete the study by December 2025. Publication of results is expected by the end of 2026.

CONCLUSIONS: These aims will provide crucial data regarding the preliminary safety and feasibility of this paired intervention and help optimize therapeutic AIH as a rehabilitation strategy, thereby guiding further research concerning this novel treatment for ALS.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05377424; https://clinicaltrials.gov/study/NCT05377424.

DERR1-10.2196/76105.}, } @article {pmid41203507, year = {2025}, author = {Zhang, YP and Kedia, S and Klenerman, D}, title = {Rethinking neurodegeneration through a co-proteinopathy lens.}, journal = {Trends in neurosciences}, volume = {48}, number = {12}, pages = {952-963}, doi = {10.1016/j.tins.2025.10.006}, pmid = {41203507}, issn = {1878-108X}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; tau Proteins/metabolism ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {Neurodegenerative diseases have long been considered distinct proteinopathies: amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TDP-43 in amyotrophic lateral sclerosis. This single-protein paradigm has guided therapeutic development for decades; yet clinical outcomes remain modest. Mounting evidence, however, reveals that protein aggregates rarely occur in isolation; instead, they coexist, colocalise, and modulate each other's pathogenicity. Here, we propose a co-proteinopathy framework that views neurodegeneration as an interactive network of misfolded proteins rather than as isolated disorders. Adopting this framework demands multiplexed quantification of protein aggregates and disease models that better reflect the biological complexity of human neurodegeneration. The co-proteinopathy perspective offers a more realistic foundation for next-generation approaches to neurodegeneration research and treatment.}, } @article {pmid41204026, year = {2026}, author = {Seemikeri, C and Menon, D and Nashi, S and Arshad, F and Srijithesh, PR and Alladi, S}, title = {Facial onset sensory and motor neuronopathy: a diagnostic challenge.}, journal = {Acta neurologica Belgica}, volume = {126}, number = {1}, pages = {309-311}, pmid = {41204026}, issn = {2240-2993}, mesh = {Humans ; *Motor Neuron Disease/diagnosis/physiopathology/complications ; *Facial Nerve Diseases/diagnosis/physiopathology ; Male ; Middle Aged ; Female ; }, abstract = {Facial onset sensory and motor neuronopathy (FOSMN) is a rare neurological disorder that combines features of both sensory neuropathy and motor neuron disease. Its clinical resemblance to trigeminal neuralgia and amyotrophic lateral sclerosis (ALS) often leads to delayed or incorrect diagnosis. Recent evidence suggests that FOSMN may represent a sensory-onset variant within the ALS spectrum, characterised by the addition of cranial and limb sensory involvement. The present report highlights this diagnostic challenge and emphasises that FOSMN can occur with prominent sensory symptoms and cranial nerve dysfunction even in the absence of significant bulbar features. Recognising this pattern broadens the classical understanding of motor neuron diseases, which are traditionally viewed as purely motor disorders. Awareness of such presentations and the use of targeted neurophysiological tests, particularly blink reflex studies, are essential for accurate diagnosis and better characterisation of this rare and evolving disease spectrum.}, } @article {pmid41204694, year = {2026}, author = {Scirocco, E and Luppino, SD and Allen, MD and Giacomelli, E and Gelevski, D and Higgins, M and Scalia, JL and McCaffrey, AC and Sanders, DL and Ho, DT and Quarles, B and Dalamagas, H and Heintzman, S and Paganoni, S}, title = {Amyotrophic Lateral Sclerosis Clinical Research Site Operations: Emerging Challenges and Potential Solutions From Multiple Sites in the US.}, journal = {Muscle & nerve}, volume = {73}, number = {1}, pages = {28-33}, pmid = {41204694}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; United States ; *Biomedical Research/organization & administration ; *Clinical Trials as Topic ; Research Personnel ; }, abstract = {As the amyotrophic lateral sclerosis (ALS) clinical trial landscape continues to grow and evolve, optimization of research site efficiency is essential. Herein, we outline results from a formal discussion among multiple ALS research sites in the US to help establish and maintain efficient research site infrastructure. Ten ALS site managers collaborated over a 6-month period to develop a framework of operational strategies to support ALS clinical research sites. To address the evolving ALS research landscape, it was agreed that the traditional site operational model requires continuous evaluation and adaptation. Challenges, particularly affecting staff recruitment and retention (such as salary, burnout, and limited opportunities for professional growth for certain positions), were discussed. The group identified challenges related to increased burden to maintain staff training, evolving outcome measures, and limitations in available space. Sites agreed on the importance of well-trained and experienced site personnel, and the emergence of site research nurses and nurse practitioners as trial leaders. Successful strategies to address staffing barriers were discussed, recognizing the need for ongoing improvements and increased funding to support the research team. A centralized organizational approach, consisting of multiple specialized study teams supported by an overarching site operations infrastructure, was identified as a key driver to optimize staff performance, accelerate trial conduct, and streamline workflow. Future initiatives should include refining strategies to continuously enhance site operations, identify key metrics to quantify efficiency and ensure financial sustainability.}, } @article {pmid41205733, year = {2026}, author = {Hendricus Maes, KJ and Briedé, JJ}, title = {Repurposing immunomodulatory drugs targeting microglia for amyotrophic lateral sclerosis.}, journal = {Brain research}, volume = {1870}, number = {}, pages = {150032}, doi = {10.1016/j.brainres.2025.150032}, pmid = {41205733}, issn = {1872-6240}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/immunology ; Humans ; *Drug Repositioning/methods ; *Microglia/drug effects/immunology ; Animals ; *Immunomodulating Agents/pharmacology/therapeutic use ; *Immunologic Factors/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that progressively affects upper and lower motor neurons, leading to symptoms including dysarthria, muscle weakness, and paralysis. The disease is multifactorial, with a variety of contributing pathways, including excitotoxicity, oxidative stress, and neuroinflammation. Current treatments target only two of these pathways with limited efficacy, highlighting the need for alternative approaches. Increasing evidence highlights the involvement of immune dysregulation, particularly microglial-mediated neuroinflammation, in ALS pathology. Fortunately, many immunomodulatory drugs acting on microglia are already available for other diseases, indicating promising opportunities for drug repurposing. This literature review provides an overview of existing drugs under investigation for ALS, including those that have failed, and highlights microglia-targeting compounds with emerging repurposing potential. Compounds such as ibudilast, fingolimod, and modafinil have shown encouraging initial clinical results, whereas others were well-tolerated but underpowered or failed to demonstrate efficacy. New candidates, such as azithromycin, montelukast, doxycycline, tofacitinib, quercetin, belinostat, propranolol, and several kinase inhibitors, have demonstrated positive preclinical results, supporting their advancement toward clinical evaluation. Overall, these findings emphasize the potential of microglia-targeting therapies for ALS. To realize this potential, future studies must include larger cohorts, assess effects across different disease stages and patient subgroups, and examine sex differences. This is essential to address patient heterogeneity and improve personalized treatments for ALS patients.}, } @article {pmid41205804, year = {2026}, author = {Akan, T and Alp, S and Aishwarya, R and Xing, DG and Dicharry, D and Bhuiyan, MS and Bhuiyan, MAN}, title = {PathViT Model for Automated Disease Classification from Skeletal Muscle Histopathology.}, journal = {The American journal of pathology}, volume = {196}, number = {2}, pages = {505-514}, pmid = {41205804}, issn = {1525-2191}, support = {P20 GM121307/GM/NIGMS NIH HHS/United States ; R01 HL145753/HL/NHLBI NIH HHS/United States ; R01 HL149264/HL/NHLBI NIH HHS/United States ; R01 HL172970/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Muscle, Skeletal/pathology ; *Deep Learning ; *Amyotrophic Lateral Sclerosis/pathology/diagnosis/classification ; *Diabetes Mellitus, Type 1/pathology/classification/diagnosis ; Muscle Fibers, Skeletal/pathology ; }, abstract = {Analyzing skeletal muscle pathology from histological images is labor intensive (requiring manual cell counting, segmentation, and thresholding), time consuming, and prone to inter- and intrauser variability, influencing the accuracy and consistency of diagnoses. To address these difficulties, PathViT, a transformer-based deep-learning model, was designed to automatically distinguish between healthy and diseased muscle fibers, with the aims of reducing human intervention, minimizing subjectivity and variability, and significantly decreasing analysis time compared to conventional manual methods. Skeletal muscle pathology is characterized by changes in myofiber cross-sectional area, increased central nuclei, and structural disruptions in sarcomeres. To investigate these changes in myofiber size, wheat germ agglutinin staining and digital histopathology of skeletal muscle (quadriceps, gastrocnemius, tibialis anterior, extensor digitorum longus, and soleus) was utilized to classify diseased tissue [amyotrophic lateral sclerosis (SOD1∗G93A) and type 1 diabetes (Akita)] versus nondiseased controls. The performance of PathViT in distinguishing diseased versus nondiseased muscle fibers was compared with that of state-of-the-art deep-learning models. PathViT classified healthy and diseased muscle fibers with 96% accuracy, outperforming the other models. This approach enhanced scalability and diagnostic accuracy and decreased variability, making PathViT a potentially powerful biomedical research and clinical tool.}, } @article {pmid41205880, year = {2026}, author = {Cho, H and Lee, B and Son, C and Choi, J and Eom, S and Park, J}, title = {ERLIN1: A central regulator of protein quality control, lipid homeostasis, and cellular signaling at the endoplasmic reticulum.}, journal = {Cellular signalling}, volume = {138}, number = {}, pages = {112224}, doi = {10.1016/j.cellsig.2025.112224}, pmid = {41205880}, issn = {1873-3913}, mesh = {Humans ; *Endoplasmic Reticulum/metabolism ; *Membrane Proteins/metabolism/genetics ; Homeostasis ; *Signal Transduction ; Animals ; *Lipid Metabolism ; Endoplasmic Reticulum-Associated Degradation ; Cholesterol/metabolism ; Nerve Tissue Proteins ; }, abstract = {Endoplasmic reticulum lipid raft-associated protein 1 (ERLIN1) is an endoplasmic reticulum (ER)-resident stomatin/prohibitin/flotillin/HflK/C (SPFH) family protein that assembles into oligomeric complexes within detergent-resistant membrane domains. ERLIN1 regulates multiple cellular functions, including protein quality control, calcium signaling, and lipid metabolism. Together with ERLIN2, it forms ER-associated degradation (ERAD) nanodomains through interactions with RING finger protein 170 (RNF170) and transmembrane and ubiquitin-like domain-containing 1 (TMUB1). These specialized domains facilitate the degradation of inositol 1,4,5-trisphosphate receptor type 1 (IP3R) via the ERAD pathway. ERLIN1 also controls cholesterol metabolism by inhibiting sterol regulatory element-binding protein (SREBP) activation and promoting 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) degradation. In addition, it blocks cholesterol esterification, thereby enhancing cholesterol transport to the Golgi apparatus. ERLIN1 further regulates cell fate by promoting autophagy and suppressing apoptosis; in complex with ERLIN2, it interacts with activating molecule in Beclin 1-regulated autophagy protein 1 (AMBRA1) at mitochondria-associated membranes to initiate autophagy and binds phosphatidylinositol 3-phosphate to stabilize autophagy signaling. Its overexpression enhances tumor progression, whereas silencing triggers apoptosis in colorectal cancer. Mutations in ERLIN1 are linked to neurodegenerative diseases such as hereditary spastic paraplegia type 62 and atypical amyotrophic lateral sclerosis. The ERLIN1/2 complex also influences immune responses and viral replication through cholesterol regulation. Collectively, these diverse and integrated functions highlight the potential of ERLIN1 as a therapeutic target in cancer, metabolic, neurodegenerative, and infectious diseases.}, } @article {pmid41206134, year = {2025}, author = {Allel, K and Palmer, T and Abou Jaoude, GJ and Korotych, O and Yedilbayev, A and Vilc, V and Corloteanu, A and Macari, M and Evghenia, C and Laticevschi, D and Shakhimurat-Shaimovich, I and Anar-Saduakasovna, R and Gulzhan-Elbrusovna, T and Anatolievna-Ryazanet, D and Shahrizada-Yergalymovna, A and Yatskevich, N and Skrahina, A and Zhurkin, D and Avaliani, Z and Kiria, N and Lomtadze, N and Kiria, N and Avaliani, T and Khonelidze, I and Danelia, M and Maxim, C and Haghparast-Bidgoli, H and Skordis, J}, title = {Cost-effectiveness of modified fully oral 9-month treatment regimens for rifampicin-resistant tuberculosis in Belarus, Georgia, Kazakhstan and the Republic of Moldova.}, journal = {BMJ global health}, volume = {10}, number = {11}, pages = {}, pmid = {41206134}, issn = {2059-7908}, support = {001/WHO_/World Health Organization/International ; D43 TW007124/TW/FIC NIH HHS/United States ; }, mesh = {Humans ; Cost-Benefit Analysis ; *Tuberculosis, Multidrug-Resistant/drug therapy/economics ; Moldova ; Kazakhstan ; Quality-Adjusted Life Years ; Male ; *Rifampin/therapeutic use/administration & dosage ; Republic of Belarus ; Female ; Adult ; *Antitubercular Agents/economics/administration & dosage/therapeutic use ; Administration, Oral ; Georgia (Republic) ; Middle Aged ; }, abstract = {INTRODUCTION: Prior to 2020, treatment options for multidrug-resistant tuberculosis (MDR-TB) were limited and typically involved long treatment durations and high financial burdens. In the eastern European and central Asian (EECA) region, traditional inpatient tuberculosis (TB) care models, alongside high MDR-TB rates, escalate nosocomial transmission risks and treatment costs. Modified, fully oral, shorter treatment regimens (mSTR) implemented in the WHO European Region under operational research conditions offered a potential reduction in the burden of MDR-TB treatment for both patients and health systems.

METHODS: We conducted the first regional evaluation of the cost-effectiveness of the novel mSTR treatment regimen compared with the standard of care (SOC) in Belarus, Georgia, Kazakhstan and Republic of Moldova. We used cohort data on mSTR efficacy and WHO data on SOC in patients with MDR-TB. We used a Markov model, with treatment costs calculated from the provider perspective. Outcomes were measured in quality-adjusted life years (QALYs), with incremental cost-effectiveness ratios (ICER) calculated per QALY gained in each country. An annual 3% discount rate was used for both costs and outcomes. We performed univariate and probabilistic sensitivity analysis (PSA) to assess the robustness of our cost-effectiveness calculations under varying assumptions. Finally, we estimated potential cost savings if mSTR was implemented nationally and we evaluated the incremental net monetary benefit (iNMB) and willingness-to-pay (WTP) thresholds based on Wood et al's country-level cost-effectiveness thresholds. All costs were reported in 2022 USD.

RESULTS: We estimated that mSTR can reduce TB treatment costs by between 23% and 47% and drug costs by 39% to 74%, compared with SOC in the countries studied. mSTR resulted in cost savings of between $3596 and $8174 per patient and offered additional health gains of between 0.56 to 2.69 QALYs per patient. mSTR remained cost-effective (iNMB>0) compared with SOC in 78%, 85%, 91% and 92% of PSA simulations in Belarus, Georgia, Kazakhstan and Republic of Moldova, respectively, when compared with their country-level WTP threshold. Implementing mSTR in up to 80% of MDR/rifampicin-resistant TB patients may result in cost savings of $20.5, 2.5, 0.7 and 0.2 million in Kazakhstan, Belarus, Republic of Moldova and Georgia; equivalent to 17%, 3%, 4% and 1% of their national TB budgets, respectively.

CONCLUSIONS: Compared with SOC, mSTR is a more cost-effective treatment option for MDR/RR-TB, which should be considered by policymakers in the EECA region. Using insights from current implementations to scale up, plan operational changes and reallocate savings from mSTR could greatly enhance TB services and patient care.}, } @article {pmid41206819, year = {2025}, author = {Buonocore, J and Fratto, E and Arcuri, F and Vescio, B and Calomino, C and Talarico, M and Cristiani, CM and Quattrone, A and Quattrone, A}, title = {Plasma NfL and GFAP in the preclinical stages of neurodegenerative diseases: insights from the UK Biobank.}, journal = {Journal of neurology}, volume = {272}, number = {12}, pages = {755}, pmid = {41206819}, issn = {1432-1459}, mesh = {Humans ; *Glial Fibrillary Acidic Protein/blood ; Male ; Female ; United Kingdom/epidemiology ; *Neurofilament Proteins/blood ; Aged ; Middle Aged ; Biomarkers/blood ; Biological Specimen Banks ; *Neurodegenerative Diseases/blood/epidemiology/diagnosis ; *Prodromal Symptoms ; Amyotrophic Lateral Sclerosis/blood/epidemiology ; Alzheimer Disease/blood/epidemiology ; UK Biobank ; }, abstract = {BACKGROUND: Plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are promising blood-based biomarkers of neuroaxonal injury and astrocytic activation, relevant in neurodegeneration. We investigated their pre-diagnostic profiles across common neurodegenerative diseases, including Parkinson's disease (PD), atypical parkinsonian disorders (APD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS).

METHODS: Forty-eight thousand five hundred and twenty-four UK Biobank participants with baseline plasma proteomic data for NfL and GFAP were included. Incident diagnoses of PD, APD, AD, and ALS were identified through ICD-10-coded health records, after careful inclusion/exclusion procedures. Baseline plasma NfL and GFAP concentrations were standardized as z-scores adjusted for relevant covariates. The hazard ratio (HR) for incident neurodegenerative diseases was estimated using Cox regression models adjusted for demographic, clinical, socioeconomic and genetic factors.

RESULTS: The final sample included 1196 cases (505 PD, 26 APD, 476 AD, 189 ALS) and 44,107 control subjects. In Cox regression models, NfL was associated with higher risk of incident ALS (HR 1.69; 95% CI, 1.58-1.80, p < 0.001), APD (HR 1.51; 95% CI, 1.22-1.87, p < 0.001), AD (HR 1.31; 95% CI, 1.22-1.41, p < 0.001), and PD (HR 1.14; 95% CI, 1.05-1.23, p < 0.001). GFAP was independently associated with incident AD only (HR 1.72; 95% CI, 1.63-1.82, p < 0.001).

CONCLUSION: Plasma NfL and GFAP showed distinct pre-diagnostic profiles. NfL was associated with incident diagnosis of several neurodegenerative diseases, while GFAP was specific to AD, reinforcing its role in dementia. These results may help optimize the identification of target populations at risk of neurodegenerative diseases for future neuroprotective treatments.}, } @article {pmid41207217, year = {2025}, author = {Wu, Y and Huang, S and Sha, Q and Yu, J}, title = {Emerging and Re-emerging viruses as triggers of human endogenous retrovirus activation: Implications for aging and age-related pathologies.}, journal = {Molecular aspects of medicine}, volume = {106}, number = {}, pages = {101422}, doi = {10.1016/j.mam.2025.101422}, pmid = {41207217}, issn = {1872-9452}, mesh = {Humans ; *Endogenous Retroviruses/physiology/genetics ; *Aging/genetics ; Immunity, Innate ; Epigenesis, Genetic ; *Virus Activation ; Retroviridae Infections/virology ; }, abstract = {The human genome contains a substantial legacy of ancient retroviral infections known as Human Endogenous Retroviruses (HERVs), composing 8 % of our DNA. In healthy young individuals, these elements are kept dormant by robust epigenetic mechanisms, primarily DNA methylation and repressive H3K9me3 histone marks. However, this epigenetic silencing deteriorates with age, leading to the reactivation of HERVs, particularly the youngest HERV-K subfamily. This report posits that this HERV awakening is not a passive byproduct of aging but an active, transmissible driver of pathology. The reactivation of HERVs leads to the production of retrovirus-like particles (RVLPs) that can induce senescence in healthy neighboring cells, propagating a contagious aging phenomenon. Furthermore, the accumulation of HERV-derived dsRNA and reverse-transcribed DNA triggers chronic innate immune responses through pathways including cGAS-STING and IFIH1-MAVS, fueling the systemic, low-grade inflammation characteristic of inflammaging, catalytically accelerated by exogenous viral infections. Pathogens such as SARS-CoV-2, Epstein-Barr Virus (EBV), and Herpes Simplex Virus (HSV-1) can directly transactivate HERVs via their own viral proteins, overwhelming the already compromised epigenetic controls in an aging host. This mechanistic link between viral triggers and endogenous retroviral activity is strongly implicated in a range of age-related diseases, including neurodegenerative disorders such as Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS), where the HERV-K envelope protein is directly neurotoxic. It is also linked to autoimmune diseases like Multiple Sclerosis and various cancers. This report synthesizes these findings and identifies a novel mechanistic link between viral activity, chronic inflammation, and the onset of age-related diseases.}, } @article {pmid41208712, year = {2025}, author = {Godrich, D and Pasteris, J and Martin, ER and Kunkle, B and Naj, AC and Hamilton, K and Wang, H and Lee, WP and Dumitrescu, L and Hohman, TJ and Mayeux, R and Larson, EB and Crane, PK and Keene, CD and Latimer, C and Mukherjee, S and Kofler, J and Kamboh, MI and Bennett, DA and Molina-Porcel, L and Schellenberg, G and Pericak-Vance, MA and Cuccaro, M and Scott, WK and Rundek, T and Kukull, W and Montine, T and Beecham, GW and , }, title = {Genome-wide association studies of TDP-43 proteinopathy and hippocampal sclerosis reveal shared genetic associations with APOE and TMEM106B.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70760}, pmid = {41208712}, issn = {1552-5279}, support = {P30 AG013854/AG/NIA NIH HHS/United States ; P50 MH060451/MH/NIMH NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; RC2 HL102419/HL/NHLBI NIH HHS/United States ; R01 AG064877/AG/NIA NIH HHS/United States ; R01 AG022374/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; U01 HG006375/HG/NHGRI NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; U01 AG058654/AG/NIA NIH HHS/United States ; U54 AG052427/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; RC2 AG036528/AG/NIA NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; P30 AG028377/AG/NIA NIH HHS/United States ; RF1 AG015819/AG/NIA NIH HHS/United States ; P50 AG008671/AG/NIA NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; P50 AG005142/AG/NIA NIH HHS/United States ; R01 AG035137/AG/NIA NIH HHS/United States ; P20 AG068053/AG/NIA NIH HHS/United States ; R01 AG009029/AG/NIA NIH HHS/United States ; P50 AG005131/AG/NIA NIH HHS/United States ; R01 NS069719/NS/NINDS NIH HHS/United States ; P01 NS026630/NS/NINDS NIH HHS/United States ; P50 AG005128/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; R01 AG031581/AG/NIA NIH HHS/United States ; R01 AG009956/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P50 AG005146/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; U01 AG049507/AG/NIA NIH HHS/United States ; U01 AG052411/AG/NIA NIH HHS/United States ; R01-AG059716//ADSP Phenotype Harmonization Consortium (ADSP-PHC)/ ; R01 AG019085/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; RC2-AG036528//Alzheimer's Disease Genetics Consortium (ADGC)/ ; R01 AG013616/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; R01 AG030146/AG/NIA NIH HHS/United States ; U01-AG068057//ADSP Phenotype Harmonization Consortium (ADSP-PHC)/ ; P50 AG008702/AG/NIA NIH HHS/United States ; UL1 RR029893/RR/NCRR NIH HHS/United States ; U24-AG21886//National Cell Repository for Alzheimer's Disease (NCRAD)/ ; AG041718//University of Pittsburg/ ; U01 AG068057/AG/NIA NIH HHS/United States ; RF1 AG054074/AG/NIA NIH HHS/United States ; U01 AG016976/AG/NIA NIH HHS/United States ; P50 NS039764/NS/NINDS NIH HHS/United States ; P30-AG066468//University of Pittsburg/ ; P30 AG066508/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P30 AG008051/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG013846/AG/NIA NIH HHS/United States ; U24 AG056270/AG/NIA NIH HHS/United States ; RC2 AG036502/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; AG006781//Adult Changes in Thought (ACT)/ ; R01 AG017917/AG/NIA NIH HHS/United States ; RC2 HG005605/HG/NHGRI NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; R01 MH080295/MH/NIMH NIH HHS/United States ; R01 AG028786/AG/NIA NIH HHS/United States ; U54 HG003273/HG/NHGRI NIH HHS/United States ; UF1 AG047133/AG/NIA NIH HHS/United States ; U01 AG057659/AG/NIA NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; RF1 AG054023/AG/NIA NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG012300/AG/NIA NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; U01 AG062943/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; RF1 AG051504/AG/NIA NIH HHS/United States ; R01 AG012101/AG/NIA NIH HHS/United States ; AG074855//Primary Funding includes (additional funding in Acknowledgements)/ ; AG064877//University of Pittsburg/ ; R01-AG17917//Rush University (ROSMAP)/ ; RF1 AG058066/AG/NIA NIH HHS/United States ; P50 AG016570/AG/NIA NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30-AG010161//Rush University (ROSMAP)/ ; P30 AG008017/AG/NIA NIH HHS/United States ; U24 AG041689/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; R01 AG033193/AG/NIA NIH HHS/United States ; U01 AG058589/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; R37 AG015473/AG/NIA NIH HHS/United States ; U24 AG026395/AG/NIA NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; R01 AG059716/AG/NIA NIH HHS/United States ; U01 AG049508/AG/NIA NIH HHS/United States ; U01 AG052410/AG/NIA NIH HHS/United States ; R01 CA129769/CA/NCI NIH HHS/United States ; P50 AG005133/AG/NIA NIH HHS/United States ; U01 AG010483/AG/NIA NIH HHS/United States ; U01-AG032984//Alzheimer's Disease Genetics Consortium (ADGC)/ ; P30 AG066509/AG/NIA NIH HHS/United States ; P01 AG002219/AG/NIA NIH HHS/United States ; R01-AG062695//Primary Funding includes (additional funding in Acknowledgements)/ ; U01 AG006781/AG/NIA NIH HHS/United States ; R01 AG041797/AG/NIA NIH HHS/United States ; P50 AG005144/AG/NIA NIH HHS/United States ; K23 AG030944/AG/NIA NIH HHS/United States ; RC4 AG039085/AG/NIA NIH HHS/United States ; P20 AG068077/AG/NIA NIH HHS/United States ; P01 AG010491/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; R01 AG048927/AG/NIA NIH HHS/United States ; U54 HG003079/HG/NHGRI NIH HHS/United States ; U01 AG052409/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; R01 AG021547/AG/NIA NIH HHS/United States ; R01 AG041232/AG/NIA NIH HHS/United States ; R01 AG019757/AG/NIA NIH HHS/United States ; R01 AG020688/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; R56 AG064877/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R01 AG030653/AG/NIA NIH HHS/United States ; R01 AG027944/AG/NIA NIH HHS/United States ; P20 AG068024/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; R01 AG017173/AG/NIA NIH HHS/United States ; R01 AG025259/AG/NIA NIH HHS/United States ; RF1 AG057519/AG/NIA NIH HHS/United States ; RF1 AG015473/AG/NIA NIH HHS/United States ; U01 AG049506/AG/NIA NIH HHS/United States ; U01 HG004610/HG/NHGRI NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG010129/AG/NIA NIH HHS/United States ; U01-AG016976//National Alzheimer's Coordinating Center (NACC)/ ; P30 AG062715/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 AG011101/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P50 AG016582/AG/NIA NIH HHS/United States ; R01 AG041718/AG/NIA NIH HHS/United States ; AG066567//Adult Changes in Thought (ACT)/ ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; U01 AG058635/AG/NIA NIH HHS/United States ; R01-AG3014//Rush University (ROSMAP)/ ; R01 AG062695/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; U24-AG074855//ADSP Phenotype Harmonization Consortium (ADSP-PHC)/ ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; P30 AG028383/AG/NIA NIH HHS/United States ; U19 AG066567/AG/NIA NIH HHS/United States ; R01 AG026916/AG/NIA NIH HHS/United States ; P50 AG033514/AG/NIA NIH HHS/United States ; R01 NS059873/NS/NINDS NIH HHS/United States ; P50 NS071674/NS/NINDS NIH HHS/United States ; U24-AG041689//National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS)/ ; AG030653//University of Pittsburg/ ; R01-AG019085//Rush University (ROSMAP)/ ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; R01-AG15819//Rush University (ROSMAP)/ ; U01 AG049505/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Genome-Wide Association Study ; *Hippocampus/pathology ; *Membrane Proteins/genetics ; Sclerosis/genetics/pathology ; *Apolipoproteins E/genetics ; *TDP-43 Proteinopathies/genetics/pathology ; *Nerve Tissue Proteins/genetics ; *DNA-Binding Proteins/genetics ; Male ; Female ; Aged ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Progranulins ; Hippocampal Sclerosis ; }, abstract = {INTRODUCTION: Transactive response DNA binding protein 43 kDa (TDP-43) proteinopathy has been linked to cognitive decline and often co-occurs with hippocampal sclerosis (HS). To identify genetic markers of TDP-43 proteinopathy and HS, we performed genome-wide association studies (GWASs) of HS and TDP-43 inclusions.

METHODS: Genetic data were obtained through the Alzheimer Disease Genetics Consortium and collaborating sites (HS: N = 9509; TDP-43: N = 4669). Statistical analyses included association analysis with HS and TDP-43 inclusions and meta-analysis, a mediation analysis, and fine mapping of the transmembrane protein 106B (TMEM106B) region.

RESULTS: Two regions achieved genome-wide significance with TDP-43: apolipoprotein E (APOE) and TMEM106B. Three loci reached genome-wide significance with HS: APOE, TMEM106B, and granulin precursor (GRN). Fine mapping of TMEM106B identified 93 variants in the credible set. Mediation analyses showed that genetic effects on HS were partially mediated through TDP-43 proteinopathy.

DISCUSSION: We identified associations with TDP-43 inclusion and HS, showing shared genetic risk across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, Alzheimer's disease, and limbic-predominant age-related TDP-43 encephalopathy.

HIGHLIGHTS: HS and TDP-43 contribute to dementia and often co-occur. The etiology and relationship of HS and TDP-43 remains unclear. HS and TDP-43 share genetic risk factors in the genes APOE and TMEM106B. Genes have direct effects on HS, with additional effects mediated through TDP-43.}, } @article {pmid41209384, year = {2025}, author = {Han, K and Yan, SG and Liu, F and Li, L and Zhou, D and Li, L and Liu, N and Dong, J}, title = {The Alterations in the Osteoimmune Microenvironment of STZ-Induced Type 2 Diabetic Mice:A Single-Cell RNA Sequencing Analysis.}, journal = {Journal of inflammation research}, volume = {18}, number = {}, pages = {15309-15327}, pmid = {41209384}, issn = {1178-7031}, abstract = {BACKGROUND: This study aimed to delineate the single-cell transcriptome of bone marrow (BM) cells from wild-type (WT) and type 2 diabetic (T2D) mice, revealing distinct immune microenvironment features.

METHODS: Single high-throughput single-cell RNA sequencing dataset (GSE212726) from BM cells of WT and streptozotocin (STZ)-induced T2DM mice were analyzed. Uniform manifold approximation and projection (UMAP), pseudo-time analysis, gene enrichment studies, and CellphoneDB were employed to identify immune cell interactions within the osteoimmune microenvironment. Key gene expression was validated by quantitative real-time polymerase chain reaction (qRT-PCR).

RESULTS: After filtering low-quality cells and doublets, 9,360 cells (WT) and 10,885 cells (T2DM) were retained and classified into 12 clusters. Proportional analysis revealed a significant decrease in BM-neutrophils (66.56% → 54.73%) and an increase in B cells (9.16% → 19.78%) in the DM group. The DM/WT ratio for BM-neutrophils/T cells, BM-neutrophils/DCs, and monocytes/T cells increased, while the ratio for BM-neutrophils/Naïve_B decreased. KEGG pathway analysis highlighted enrichment of neurodegeneration, protein processing in the endoplasmic reticulum, and amyotrophic lateral sclerosis pathways in BM-neutrophils. Intercellular communication analysis indicated reduced incoming and outgoing interaction strength for B cells and T cells, while the T2D group showed enhanced THBS, VISFATIN, CLEC, IL4, and IL6 signaling. Notably, CLEC was specific to outgoing signaling in T cells, and THBS was specific to both outgoing and incoming signaling in monocytes, MSCs, and BM-neutrophils.

CONCLUSION: Single-cell RNA sequencing provides a comprehensive profile of bone marrow immune cells in T2D mice and has highlighted their heterogeneity, population shifts, and intercellular interactions. These findings highlight critical alterations in immune cell functions that may contribute to T2D progression and suggest possible avenues for future therapeutic investigation. Future research should continue to leverage scRNA-seq technology to refine treatment strategies and enhance patient outcomes by addressing immune dysfunction and chronic inflammation.}, } @article {pmid41210444, year = {2025}, author = {Khan, S and Wennberg, B and Hooda, F and Witkowska, M}, title = {Delayed treatment and diagnostic challenges in differentiating multifocal acquired demyelinating sensory and motor neuropathy from lupus: a case report and literature review.}, journal = {AME case reports}, volume = {9}, number = {}, pages = {111}, pmid = {41210444}, issn = {2523-1995}, abstract = {BACKGROUND: Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) is a rare autoimmune-mediated inflammatory response with negative antibodies which causes demyelination of multiple peripheral nerves in an asymmetric distribution with both motor and sensory deficits. Diagnosis for MADSAM can be clinically challenging, relies on a combination of clinical and electrodiagnostic studies, and symptoms can overlap with other neurological conditions such as systemic lupus erythematosus (SLE). MADSAM is typically asymmetric, demyelinating, and limited to peripheral nerves, whereas SLE is systemic, more commonly axonal, and has vasculitic features. SLE is treated with steroids and immunosuppressants while MADSAM is treated with intravenous immunoglobulin (IVIG), steroids, or plasmapheresis. There is a good short-term prognosis for MADSAM with early treatment, but prognosis can worsen with delayed or inappropriate therapy.

CASE DESCRIPTION: We describe a case of a woman in her 50s who presented with progressive generalized weakness, weight loss, muscle atrophy, and numbness. She was initially diagnosed with SLE, but deteriorated despite treatment. A broad differential was considered which included SLE, paraneoplastic syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Guillain-Barré syndrome. Serological studies, neuroimaging studies, nerve conduction studies, and electromyography (EMG) were performed. She was ultimately diagnosed with Lewis-Sumner syndrome, or MADSAM, a variant of CIDP.

CONCLUSIONS: The case highlights the importance of understanding the various causes of weakness and neuropathy, particularly with an atypical presentation, to pursue the correct diagnostic tests and treatment. The case particularly focuses on the difference between MADSAM and SLE. There is significant clinical overlap between the two, and a misdiagnosis can delay effective treatment and worsen outcomes by allowing progression to more debilitating stages of the illness.}, } @article {pmid41210976, year = {2025}, author = {Thapa, R and Adhikari, N and Gautam, S and Sun, M and McOmie, S and Davydzenka, V and Smith, D and Syring, J and Kaligis, H and Kosmicki, JM and Chen, R and Li, Y}, title = {Single-nucleus RNA sequencing reveals GABAergic vulnerability and reactive gliosis driven by loss of TDP-43.}, journal = {iScience}, volume = {28}, number = {11}, pages = {113745}, pmid = {41210976}, issn = {2589-0042}, support = {P20 GM121310/GM/NIGMS NIH HHS/United States ; R01 NS129878/NS/NINDS NIH HHS/United States ; }, abstract = {TDP-43 is an RNA-binding protein important for RNA processing, whose loss of function is involved in multiple neurodegenerative disorders, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer's disease (AD). We performed single-nucleus RNA-sequencing to study the convergent and divergent molecular signatures of short-term and long-term TDP-43 depletion in the medial prefrontal cortex (mPFC) using Tdp-43 [F/F] mice, compared with that of 5xFAD mice, a well-established AD mouse model with β-amyloid plaque pathology. Our results demonstrated a significant loss of GABAergic neurons in the mPFC after short-term TDP-43 depletion. This was accompanied by a remarkable reactive gliosis in the mPFC. Our results revealed a strong GABAergic and glial involvement during early stages of TDP-43 loss of function, suggesting that the GABAergic system is vulnerable to TDP-43 pathology and could be considered a potential target for developing therapeutic strategies and biomarkers for early detection in TDP-43 linked AD-related dementia.}, } @article {pmid41211682, year = {2026}, author = {}, title = {Correction to "Amyotrophic Lateral Sclerosis and Swim Training Affect Copper Metabolism in Skeletal Muscle in a Mouse Model of Disease".}, journal = {Muscle & nerve}, volume = {73}, number = {1}, pages = {110}, doi = {10.1002/mus.70053}, pmid = {41211682}, issn = {1097-4598}, } @article {pmid41212342, year = {2025}, author = {Zhong, R and Yang, H and Li, X and Wang, F and Zhai, L and Gao, J}, title = {Mitochondria-Mediated Mechanisms of Ferroptosis in Neurological Diseases.}, journal = {Neurochemical research}, volume = {50}, number = {6}, pages = {354}, pmid = {41212342}, issn = {1573-6903}, support = {202403070986//Health Science and Technology Project of Shandong Province/ ; RZ1900011598//post-doctoral foundation of Qingdao University/ ; }, mesh = {*Ferroptosis/physiology ; Humans ; *Mitochondria/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; Lipid Peroxidation/physiology ; Iron/metabolism ; Oxidative Stress/physiology ; }, abstract = {Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, is increasingly recognized as a critical contributor to the pathogenesis of various neurological disorders. Mitochondria, the powerhouses of cells, play dual roles as both initiators and mediators of ferroptosis by integrating lipid peroxidation cascades, oxidative stress responses, and iron homeostasis dysregulation. This review first comprehensively explores the multifaceted mechanisms by which mitochondria mediate ferroptosis in neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Friedreich's ataxia (FRDA), amyotrophic lateral sclerosis (ALS), epilepsy, stroke, and brain injury, with a focus on mitochondrial lipid peroxidation and iron metabolism dysregulation. Building on these mechanistic insights, we further discuss emerging evidence suggesting that targeting mitochondrial pathways may represent a promising therapeutic strategy for mitigating ferroptosis-associated neuronal damage. By synthesizing these findings, our review establishes a conceptual foundation for developing innovative neuroprotective interventions through precise modulation of mitochondrial function within ferroptotic pathways.}, } @article {pmid41213077, year = {2025}, author = {Cai, S and Liu, Y and Liu, B and Liao, H and Li, K}, title = {Hexokinase as a Central Hub in Neurodegeneration: From Metabolic Dysfunction to Therapeutic Innovation.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2025.0891}, pmid = {41213077}, issn = {2152-5250}, abstract = {Neurodegenerative diseases represent an escalating global health crisis affecting more than 55 million people worldwide; however, underlying mechanisms remain unclear, and therapeutic breakthroughs are elusive. Emerging evidence indicates that hexokinase (HK), the rate-limiting glycolytic enzyme, functions as a master regulator orchestrating neuronal survival through metabolic‒mitochondrial coupling. This review consolidates emerging paradigms revealing that HK maintains neuronal viability through its obligate interaction with mitochondrial VDAC1, forming a metabolic checkpoint that integrates energy status with survival signaling. Disease-specific HK dysfunction patterns precede clinical manifestations and drive pathological cascades across primary neurodegenerative conditions. Pathological proteins characteristic of neurodegeneration-amyloid-β in AD, α-synuclein in PD, mutant SOD1 in ALS, and huntingtin in HD-converge to disrupt the HK-VDAC1 axis through distinct molecular mechanisms, triggering mitochondrial permeabilization, bioenergetic collapse, and inflammatory activation. This uncoupling event promotes VDAC1 oligomerization, enabling the cytosolic release of mtDNA, which in turn activates the NLRP3 inflammasome while depleting antioxidant capacity, establishing self-perpetuating neuroinflammatory cycles. The literature reveals that HK functions as a molecular rheostat, determining neuronal fate through glucose-6-phosphate-mediated feedback control, modulation of growth factor signaling, and regulation of apoptosis/survival pathways. Therapeutic targeting of HK through peptide interventions, enzymatic modulation, and gene therapy demonstrates robust neuroprotective effects across multiple disease models. Meanwhile, combination strategies addressing metabolic-inflammatory networks show synergistic efficacy. These insights position HK as a convergent therapeutic nexus offering unprecedented opportunities for precision intervention in neurodegeneration, with potential for early diagnostic applications and preventive strategies that could transform treatment paradigms for conditions affecting millions worldwide.}, } @article {pmid41213224, year = {2025}, author = {Hokkoku, K and Inoue, M and Yamada, S and Namba, H and Matsukura, K and Mukai, T and Chiba, T and Hatanaka, Y and Kobayashi, S and Sonoo, M}, title = {Clinically visible but often unperceived: Low awareness of fasciculations in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {479}, number = {}, pages = {123764}, doi = {10.1016/j.jns.2025.123764}, pmid = {41213224}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Fasciculation/etiology/psychology/diagnosis/physiopathology ; Aged ; *Awareness/physiology ; Surveys and Questionnaires ; Prospective Studies ; Adult ; }, abstract = {BACKGROUND: Fasciculations are a key clinical sign of amyotrophic lateral sclerosis (ALS) but also occur in other conditions such as benign fasciculation syndrome. Patients often present with perceived twitching fearing ALS; however, the extent to which ALS patients themselves perceive fasciculations has not been systematically examined. We therefore aimed to clarify how often ALS patients are aware of fasciculations that are clinically visible.

METHODS: We prospectively studied 34 ALS patients. First, a structured questionnaire assessed initial symptoms, chief complaints, and awareness of twitching. Then, the frequency and concordance between objective fasciculations and subjective awareness of fasciculations (twitching) were analyzed across five body regions (bilateral upper and lower limbs and trunk) based on simultaneous visual observation and patient reports.

RESULTS: In the questionnaire, only one of the 34 patients (3 %) reported twitching as the initial symptom, and none presented with twitching as the chief complaint. More than half (19, 56 %) had never noticed twitching. In the fasciculation analysis, patients showing objective fasciculations without subjective awareness were most common (21/34, 62 %), whereas those with objective fasciculations accompanied by subjective awareness were fewer (10/34, 29 %), indicating relatively low concordance between visible fasciculations and patient awareness. No patient exhibited subjective awareness without objective fasciculations. These findings suggest that the majority of visible fasciculations in ALS are not perceived by patients.

CONCLUSION: Fasciculations in ALS are rarely the initial or presenting symptom and are often unperceived by patients despite being clinically visible.}, } @article {pmid41213329, year = {2026}, author = {Adachi, M and Banno, H and Inoue, H}, title = {Drug discovery research with iPSC models of neurodegenerative diseases.}, journal = {Neuroscience research}, volume = {222}, number = {}, pages = {104985}, doi = {10.1016/j.neures.2025.104985}, pmid = {41213329}, issn = {1872-8111}, mesh = {Humans ; *Induced Pluripotent Stem Cells/drug effects ; *Drug Discovery/methods ; *Neurodegenerative Diseases/drug therapy ; Animals ; Amyotrophic Lateral Sclerosis/drug therapy ; Alzheimer Disease/drug therapy ; }, abstract = {Induced pluripotent stem cells (iPSCs) are widely used in research because they can be used to create models of diseases with the same genomic background as in patients. iPSC-based screening is recognized as a valuable approach in drug discovery research. Additionally, efforts are underway to develop high-quality models for drug discovery and to better integrate translational research with clinical studies. This review focuses on neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), and provides a broad overview of research using iPSCs, ranging from studies of disease mechanisms to applications in drug discovery. Furthermore, several clinical trials based on iPSC research have been initiated, including those of bosutinib, ropinirole, and ezogabine for ALS, and WVE-004 and BII078 for ALS/FTD. Finally, we also wish to highlight screening studies that incorporate artificial intelligence (AI).}, } @article {pmid41213972, year = {2025}, author = {Chisholm, CG and Bartlett, R and Brown, ML and Proctor, EJ and Farrawell, NE and Gorman, J and Delerue, F and Ittner, LM and Vine-Perrow, KL and Ecroyd, H and Cashman, NR and Saunders, DN and McAlary, L and Lum, JS and Yerbury, JJ}, title = {Development of a targeted BioPROTAC degrader selective for misfolded SOD1.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {9713}, pmid = {41213972}, issn = {2041-1723}, mesh = {Animals ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/drug therapy ; Mice, Transgenic ; Mice ; Protein Folding ; Humans ; Disease Models, Animal ; Proteolysis ; Motor Neurons/metabolism/pathology ; Ubiquitin-Protein Ligases/metabolism/genetics ; CRISPR-Cas Systems ; Disease Progression ; HEK293 Cells ; }, abstract = {The accumulation of misfolded proteins underlies a broad range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Due to their dynamic nature, these misfolded proteins have proven challenging to target therapeutically. Here, we specifically target misfolded disease variants of the ALS-associated protein superoxide dismutase 1 (SOD1), using a biological proteolysis targeting chimera (BioPROTAC) composed of a SOD1-specific intrabody and an E3 ubiquitin ligase. Screening of intrabodies and E3 ligases for optimal BioPROTAC construction reveals a candidate capable of degrading multiple disease variants of SOD1, preventing their aggregation in cells. Using CRISPR/Cas9 technology to develop a BioPROTAC transgenic mouse line, we demonstrate that the presence of the BioPROTAC delays disease progression in the SOD1[G93A] mouse model of ALS. Delayed disease progression is associated with protection of motor neurons, a reduction of insoluble SOD1 accumulation and preservation of innervated neuromuscular junctions. These findings provide proof-of-concept evidence and a platform for developing BioPROTACs as a therapeutic strategy for the targeted degradation of neurotoxic misfolded species in the context of neurodegenerative diseases.}, } @article {pmid41214238, year = {2025}, author = {Mushtaq, U and Seh, BA and Khanday, FA and Ahmad, M}, title = {CHI3L1: An Emerging Player in Neuroinflammation and Neurodegeneration.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {23}, pmid = {41214238}, issn = {1559-1182}, mesh = {Humans ; Animals ; *Chitinase-3-Like Protein 1/metabolism ; *Neuroinflammatory Diseases/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Inflammation/metabolism/pathology ; *Nerve Degeneration/metabolism/pathology ; Astrocytes/metabolism/pathology ; Neurons/metabolism/pathology ; }, abstract = {Neuroinflammation is now being identified as the major factor in the development of various neurological disorders. It is a vital process in neurons and the brain that maintains homeostasis under normal and healthy conditions. However, in hyperactivated states, neuroinflammation can also go awry when microglia and astrocytes enter a toxic, reactive state that can release chemicals that damage neurons. When innate immune cells encounter pathogens, infection, cell debris, or misfolded proteins, they release certain chemokines and cytokines to eliminate the intruding particles and protect the brain. However, persistent inflammatory reactions are harmful and can lead to neurodegeneration by continuously releasing toxic chemicals and proteins. Chitinase-3-like protein 1 (CHI3L1), a secretory protein, is emerging as a key inflammatory molecule that is strongly upregulated during neuroinflammation and has been implicated in the pathogenesis of many diseases. The brain's activated astrocytes are the main source of CHI3L1 and are a dependable biomarker for inflammatory pathologies affecting the central nervous system (CNS), including neurodegeneration and autoimmune diseases. The protein has been implicated in many neurological disorders, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and others, mediating neuroinflammation and neurodegeneration. CHI3L1 has contrasting functions in the CNS and other tissues. While the protein promotes cell proliferation and migration in various non-neuronal cancers, at the same time, it simultaneously promotes neurodegeneration and apoptosis in the CNS. This paper reviews the current developments in our knowledge of the pathogenic role of the CHI3L1 protein in various neurological disorders.}, } @article {pmid41214888, year = {2026}, author = {Lin, H and Xie, X and Gao, R and Jing, Y and Chen, D and Zhang, J and Qiu, X and Zhang, J and Luo, L}, title = {Comparison of ocular biometry and refractive outcome between a new and classic optical biometer.}, journal = {Journal of cataract and refractive surgery}, volume = {52}, number = {4}, pages = {333-338}, pmid = {41214888}, issn = {1873-4502}, mesh = {Humans ; *Biometry/instrumentation ; Prospective Studies ; *Axial Length, Eye/pathology ; Male ; Female ; *Refraction, Ocular/physiology ; Middle Aged ; Aged ; Cataract ; Phacoemulsification ; Lens Implantation, Intraocular ; Reproducibility of Results ; Aged, 80 and over ; Visual Acuity/physiology ; Adult ; }, abstract = {PURPOSE: To compare the ocular biometry and refractive outcome between 2 optical biometers.

SETTING: Zhongshan Ophthalmic Center, Guangzhou, China.

DESIGN: Prospective observational study.

METHODS: 953 patients with cataract underwent preoperative biometry including ZW-30 sum-of-segments (SOS) method (ZW SM), ZW-30 composite method (ZW CM), and IOLMaster 700. Agreement of axial length (AL), with or without Cooke-modified AL (CMAL) adjustment, was analyzed using Bland-Altman 95% limits of agreement (LoA). Subgroup analysis was used based on ALs (short eyes: AL <22 mm; normal eyes: 22 mm ≤ AL <26 mm; long eyes: AL ≥26 mm). Refractive prediction accuracy was evaluated using the Emmetropia verifying optical (EVO) 2.0 formula and its SOS-optimized version (EVO 2.0 SOS).

RESULTS: In short and normal eyes, narrow 95% LoAs (<0.2 mm) were identified among 3 ALs. However, AL obtained by ZW SM was lower compared with this obtained by ZW CM and IOLMaster 700 (95% LoA -0.39 to 0.01 mm; -0.38 to 0.04 mm) in long eyes. CMAL adjustment enhanced the agreement of AL between ZW SM and ZW CM (95% LoA -0.01 mm to 0.02 mm), ZW SM and IOLMaster 700 (95% LoA -0.10 mm to 0.07 mm) in long eyes. Myopic prediction errors (PE) have been identified in the use of ocular biometric parameters obtained from ZW SM (mean PE [ME]: EVO 2.0, -0.19 diopters [D]; EVO 2.0 SOS , -0.18 D). After adjusting ME to zero, no difference was observed in PE calculated using any combination of formulas based on biometric measurements from 3 devices.

CONCLUSIONS: This new segmented biometer demonstrated excellent agreement with IOLMaster 700 in short and normal eyes. However, ALs obtained by IOLMaster 700 are not interchangeable with the SOS method and require CMAL adjustment in long eyes. The application of the SOS method's ocular biometric parameters in refractive prediction led to myopic errors, which suggests constant optimization.}, } @article {pmid41215674, year = {2025}, author = {Adeagbo, MJ and Kahler, J and Jones, D and Reisinger, HS and Swenson, A}, title = {'I want to be generous, but I only have limited energy': a qualitative study of amyotrophic lateral sclerosis patients' preferences for clinical trials participation.}, journal = {Annals of medicine}, volume = {57}, number = {1}, pages = {2586150}, pmid = {41215674}, issn = {1365-2060}, support = {UM1 TR004403/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Patient Preference/psychology ; Female ; Male ; Qualitative Research ; Middle Aged ; Aged ; *Clinical Trials as Topic/psychology ; Adult ; *Patient Participation/psychology ; Emotions ; }, abstract = {BACKGROUND AND OBJECTIVE: Research and decisions on health-related issues such as Amyotrophic Lateral Sclerosis (ALS) continue to evolve as the etiology of network degenerative disease remains indeterminate. Due to its heterogeneity, clinical trials (CTs) are continually being conducted for beneficial breakthroughs aimed at improving the lives of patients with ALS. However, there is a dearth of research on ALS patients' health-seeking decisions and preferences in CTs, particularly for patients living in rural areas. To bridge this important gap, we explored patients' subjective experiences and preferences in CT participation through their emotions.

MATERIALS AND METHODS: Seventeen participants (10 ALS patients, 6 healthcare professionals, and an advocacy group representative associated with ALS) affiliated with the University of Iowa ALS Multidisciplinary clinic were purposively selected and interviewed for the study. Qualitative descriptive data were analyzed using thematic content analysis to understand the patients' experiences and preferences.

RESULTS: Findings indicate key emotional and logistical challenges including fatigue, travel distance and constraints, limited trial availability, which are exacerbated by the disease's rapid progression and restrictive eligibility criteria. Participants' narratives highlighted frustration, anxiety, and fear as central emotional experiences influencing their health-seeking decisions. Conversely, expressions of hope and empathy emerged as significant motivators, with patients demonstrating a willingness to participate in CTs despite the known risk of limited personal benefits, while focusing on the need to benefit future ALS research. Patients prefer and desire more compensation, broader eligibility and inclusive criteria, trial availability and publicity, and access to telemedicine.

CONCLUSION: Given the multifaceted physical, and emotional challenges faced by ALS patients, this study recommends prioritizing patient preferences in future CTs and intervention designs, while advocating for targeted grants and sustained funding that supports ALS clinical trials. This will better align with the needs and expectations of ALS patients, thereby enhancing trial participation and overall patient satisfaction.}, } @article {pmid41216140, year = {2025}, author = {Spencer, BE and Xie, SX and Ohm, DT and Elman, L and Quinn, CC and Amado, DA and Baer, M and Lee, EB and Van Deerlin, VM and Dratch, L and Massimo, L and Irwin, DJ and McMillan, CT}, title = {Cumulative incidence of motor and cognitive features in the amyotrophic lateral sclerosis-frontotemporal degeneration spectrum.}, journal = {Brain communications}, volume = {7}, number = {6}, pages = {fcaf405}, pmid = {41216140}, issn = {2632-1297}, support = {F32 AG079618/AG/NIA NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 NS109260/NS/NINDS NIH HHS/United States ; }, abstract = {In frontotemporal degeneration and amyotrophic lateral sclerosis, subsequent motor or cognitive-behavioural features, respectively, are associated with shorter survival. However, factors influencing subsequent feature development remain largely unexplored. In this study, we examined whether the presence of a C9orf72 expansion or the initial clinical syndrome was associated with increased risk of subsequent feature development in individuals with amyotrophic lateral sclerosis and frontotemporal degeneration. We performed a retrospective evaluation of the entire disease course of individuals with an initial clinical syndrome of amyotrophic lateral sclerosis or frontotemporal degeneration who had neuropathological confirmation of TDP-43 proteinopathy at autopsy or a C9orf72 hexanucleotide repeat expansion. We examined the odds and hazard of subsequent feature development and assessed whether each was modified by the presence of a C9orf72 expansion or initial clinical syndrome. At autopsy, we evaluated the association between TDP-43 pathology burden in characteristic brain regions and features across this disease spectrum. For individuals with amyotrophic lateral sclerosis (n = 168) and frontotemporal degeneration (n = 73), binary logistic regression revealed increased odds (odds ratio = 3.49 [95% confidence interval 1.64-7.80], P = 0.002) and Cox proportional hazard analyses revealed an increased hazard (hazard ratio = 3.78 [95% confidence interval 1.86-7.65], P < 0.001) for developing subsequent features in those with a C9orf72 expansion compared to those without. Beyond C9orf72 expansion status, binary logistic regression revealed decreased odds (odds ratio = 0.25 [95% confidence interval 0.12-0.53], P < 0.001) and Cox proportional hazard analyses revealed a decreased hazard (hazard ratio = 0.48 [95% confidence interval 0.25-0.95], P = 0.03) for developing subsequent features in those with an initial amyotrophic lateral sclerosis clinical syndrome compared to those with an initial frontotemporal degeneration clinical syndrome. We observed a 94-month difference in the time after symptom onset of the initial clinical syndrome that a given person without a C9orf72 expansion reached the highest probability of developing subsequent features (0.12 [95% CI 0.03-0.19], 113.00 months) and a person with a C9orf72 expansion surpassed that probability (0.13 [95% CI 0.06-0.19], 19.00 months). The distribution of TDP-43 pathology across characteristic brain regions reflected both the initial clinical syndrome and subsequent features, with relatively preserved spinal cord only in frontotemporal degeneration cases without subsequent motor features (P < 0.0001) and relatively preserved neocortical regions only in amyotrophic lateral sclerosis cases without subsequent cognitive-behavioural features (P < 0.0001). These data highlight the need for clinician vigilance to detect the onset of subsequent motor and cognitive-behavioural features in patients carrying a C9orf72 expansion, regardless of initial clinical syndrome. C9orf72 clinical care can be enhanced through coordination between cognitive and neuromuscular clinics.}, } @article {pmid41216506, year = {2026}, author = {Wei, Y and Snow, BA and Stevenson, CC and Miao, H and Kaur, J and Lee, SG and Kim, NC and Kim, WJ}, title = {Surface glia for modeling ALS-FTD-associated mutant C9orf72 toxicity in the nervous system of Drosophila.}, journal = {Genes & diseases}, volume = {13}, number = {2}, pages = {101629}, pmid = {41216506}, issn = {2352-3042}, } @article {pmid41216790, year = {2025}, author = {Strell, P and Waldron, MA and Johnson, ST and Shetty, A and Crane, AT and You, Y and Steer, CJ and Low, WC}, title = {Characterization of the intraspecies chimeric mouse brain at embryonic day 12.5.}, journal = {Cell transplantation}, volume = {34}, number = {}, pages = {9636897251384571}, pmid = {41216790}, issn = {1555-3892}, support = {R01 AI173804/AI/NIAID NIH HHS/United States ; R01 DK117286/DK/NIDDK NIH HHS/United States ; RF1 AG077772/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Brain/embryology/cytology/metabolism ; Mice ; *Chimera ; Induced Pluripotent Stem Cells/cytology ; Female ; Neurons/cytology/metabolism ; Blastocyst/cytology ; Mice, Inbred C57BL ; }, abstract = {Incidence of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis have increased dramatically as life expectancy has risen year-over-year, and can lead to neurologic changes. Neurological changes within the central nervous system, specifically the brain, include cell loss and deterioration that impact motor function, memory, executive function, and mood. Available treatments are limited and often only address symptomatic manifestations of the disease rather than disease progression. Cell transplantation therapy has shown promise for treating neurodegenerative diseases, but a source of autologous cells is required. Blastocyst complementation provides an innovative method for generating autologous neural cells. By injecting mouse induced pluripotent stem cells into a wild type mouse blastocyst, we generated a chimeric mouse brain derived of both donor and host neuronal and non-neuronal cells. At embryonic day 12.5 (E12.5), automated image analysis of mouse-mouse chimeric brains showed the presence of GFP-labeled donor-derived dopaminergic and serotonergic neuronal precursors. GFP-labeled donor-derived cholinergic precursor neurons and non-neuronal microglia-like and macrophage-like cells were also observed using more conventional imaging analysis software. This work demonstrates that the generation of mouse-mouse chimeric neural cells is possible; and that characterization of early neuronal and non-neuronal precursors provides a first step toward utilizing these cells for cell transplantation therapies for neurodegenerative diseases.}, } @article {pmid41218062, year = {2026}, author = {Takeuchi, E and Yasumizu, Y and Morita, J and Ishikawa, M and Ogawa, K and Motooka, D and Okuzaki, D and Nagata, M and Ishihara, Y and Miyashita, Y and Asano, Y and Mori, K and Morii, E and Beck, G and Saito, Y and Murayama, S and Mochizuki, H and Nagano, S}, title = {Single-nucleus multiome shows motor neuron glutamate overactivation in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {7}, pages = {2480-2494}, pmid = {41218062}, issn = {1460-2156}, support = {JP21H02841//JSPS KAKENHI/ ; JP22H04811//JSPS KAKENHI/ ; JP23K18265//JSPS KAKENHI/ ; JP24K02370//JSPS KAKENHI/ ; JP20lm0203007//AMED/ ; JP21ek0109520//AMED/ ; JP21wm0525029//AMED/ ; //Integrated Frontier Research for Medical Science Division/ ; //Institute for Open and Transdisciplinary Research Initiatives/ ; //Research Institute for Microbial Diseases/ ; //Osaka University/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Motor Neurons/metabolism/pathology ; *Glutamic Acid/metabolism ; Spinal Cord/metabolism/pathology ; Motor Cortex/metabolism/pathology ; Genome-Wide Association Study ; Female ; Polymorphism, Single Nucleotide ; Male ; Middle Aged ; Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes motor neuron degeneration. However, the mechanisms underlying the selective vulnerability of motor neurons and the involvement of non-motor neuron cells in ALS remain unclear. To investigate ALS pathology at the cellular level, we performed a single-nucleus multiome analysis, including RNA sequencing and chromatin accessibility profiling, on the motor cortex (75 583 nuclei) and spinal cord (62 711 nuclei) from patients with ALS (n = 6) and controls (n = 6). Our results revealed significant gene expression changes specifically in spinal motor neurons, including upregulation of a metabotropic glutamate receptor, GRM5, and enhanced glutamate signalling. By integrating genome-wide association study data, we identified ALS-associated single nucleotide polymorphisms (SNPs) in regulatory regions, suggesting cell-type-specific enrichment of risk, especially in microglia. These findings suggest that changes in spinal motor neurons and their surrounding environment, including glutamate signalling, may be involved in ALS pathology. The study also provides valuable resources for future research on the underlying mechanisms and potential therapeutic targets.}, } @article {pmid41218158, year = {2025}, author = {Silva Sousa, LD and Bertuzzi, A and Rodrigues Fiuza, TE and Leite, ER and Benito, P and Ferri, D and Zanchet, D and Beale, AM}, title = {Identification of Transient Intermediates and Active Species in Atomic CZA Catalysts for CO2 Hydrogenation to Methanol.}, journal = {Journal of the American Chemical Society}, volume = {147}, number = {47}, pages = {43295-43316}, pmid = {41218158}, issn = {1520-5126}, abstract = {Direct hydrogenation of carbon dioxide to methanol is a promising strategy for carbon capture and utilization (CCU). Copper-zinc-alumina (CZA) catalysts are widely used for this transformation, yet the nature of the active Cu and Zn species and the reaction intermediates remains debated due to their sensitivity to feed composition and temperature. This challenge is compounded by the high metal loading in conventional CZA catalysts, which obscures active species signals with background contributions from spectator species. To address this, we synthesized model CuZn/Al2O3 catalysts using bimetallic coordination complexes, achieving low metal loadings that yield small Cu clusters and Cu[+] single atoms adjacent to isolated Zn[2+] sites. In situ XANES and UV-vis data were analyzed using multivariate curve resolution-alternating least-squares (MCR-ALS), revealing that Cu dispersion and reagglomeration─phenomena suspected in industrial systems─also occur at low loadings. Operando and modulation excitation with phase sensitive detection DRIFTS (ME-PSD-DRIFTS) showed: (a) Cu clusters dissociate H2 and activate CO2 via monodentate formate; (b) Al2O3 stabilizes Cu[+] under reducing conditions, with Cu content correlating with methanol productivity via CO hydrogenation; and (c) Zn in ZnAl2O4 promotes CO2 activation through reactive carbonate formation and enhances oxygenate conversion kinetics. ZnAl2O4 also acts as a structural promoter, facilitating CO2 conversion via reverse water gas shift (RWGS) and CO hydrogenation. These findings reveal new structure-activity relationships, highlighting the role of the mixed-metal interface in stabilizing transient intermediates and providing some guidance in the rational design of improved catalysts for CO2 valorization.}, } @article {pmid41218638, year = {2025}, author = {Wasicki, B and Zawistowski, P and Jankowiak, T and de Oliveira Pires, L and Fernandes, S and Bączyk, M}, title = {Acute Invasive Dorso-Ventral DCS Applied With a Ball Electrode Does Not Alter Spinal Motoneurons' Firing Characteristics in the SOD-1 G93A Mouse Model of ALS.}, journal = {The European journal of neuroscience}, volume = {62}, number = {9}, pages = {e70314}, doi = {10.1111/ejn.70314}, pmid = {41218638}, issn = {1460-9568}, support = {2017/26/D/NZ7/00728//Narodowe Centrum Nauki/ ; 2019/35/B/NZ4/02058//Narodowe Centrum Nauki/ ; 2022/04/Y/NZ4/00117//Narodowe Centrum Nauki/ ; 2024.00602.BD//Fundação para a Ciência e a Tecnologia/ ; JPND/0003/2022//Fundação para a Ciência e a Tecnologia/ ; UID/00645/2025//Fundação para a Ciência e a Tecnologia/ ; }, mesh = {Animals ; *Motor Neurons/physiology ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/genetics ; Mice ; Mice, Transgenic ; *Spinal Cord/physiopathology ; Disease Models, Animal ; Superoxide Dismutase-1/genetics ; *Action Potentials/physiology ; Superoxide Dismutase/genetics ; }, abstract = {In amyotrophic lateral sclerosis (ALS), alterations of spinal motoneurons' (MNs) excitability form the hallmark of their degeneration. Trans-spinal direct current stimulation (tsDCS) is based on the delivery of low-intensity DC to the spinal column in order to alter spinal circuit excitability. Recently, this technique was applied to the management of ALS in the SOD1 G93A mice and resulted in a reduction of disease biomarkers and extended mouse survival. While indirect evidence suggests that these effects can be linked to a decrease in MNs excitability following tsDCS, this has never been directly confirmed. Therefore, in this study, we have utilized in vivo sharp intracellular recordings of spinal MN to directly investigate the impact of DC on MN intrinsic excitability in SOD1 G93A mice. Electrophysiological properties of MNs recorded before DCS were compared to the properties of MNs recorded within 1 h after DCS application using linear mixed-effect models. We have found that direct DCS application significantly increases MN peak and plateau input resistance (by 31% and 35%, respectively); however, this was not linked to any significant change to MN threshold and firing properties. Both mathematical modelling and in vivo recordings of the electric field (EF) indicate that our results may be explained by the low density of the EF at the MN recording site. While our results indicate that invasive DCS is not efficient in modifying MN excitability, it may be effective in altering the excitability of afferent fibers traversing the dorsal column close to the DCS application site.}, } @article {pmid41219095, year = {2025}, author = {Pu, S and Sawyer, A and Levinson, C and Putrino, D and Kirke, DN}, title = {Exploring Voice Banking as an Alternative Augmentative Communication Strategy for Individuals with Dysphonia, Aphonia, and Dysarthria: A Scoping Review.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2025.10.018}, pmid = {41219095}, issn = {1873-4588}, abstract = {OBJECTIVES: This scoping review sought to: (i) review studies involving people diagnosed with dysphonia, aphonia, and dysarthria who have used voice banking technology in a hospital or community setting, and (ii) understand the scope of research surrounding existing voice banking technology and software in the clinical setting.

METHODS: This scoping review was conducted according to the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews. An electronic search of databases, including Ovid MEDLINE(R), Embase (Ovid), APA PsycINFO (Ovid), and CINAHL was conducted. Title, abstract, and full text screening were completed using Covidence (Veritas Health Innovation, Melbourne, Australia) by two reviewers.

RESULTS: After deduplication, 1336 studies underwent title and abstract screening. Of these, the full texts of 65 studies were reviewed, and 23 were included. Three distinct topics were identified in the search: (i) message banking, in which discrete messages or phrases are recorded for later use, without the ability to create novel phrases outside of those previously recorded; (ii) voice banking, in which all the necessary phonemes in the target language are captured, with the goal of generating a personalized synthetic voice that can generate novel phrases; (iii) and voice conversion or voice reconstruction, in which pathologic voices or speech are "converted" into a personalized synthetic voices.

DISCUSSION AND CONCLUSION: This scoping review summarized the evidence for voice banking technology use in people diagnosed with dysphonia and dysarthria and sought to understand the research landscape of existing types of voice banking technology and software use in a clinical setting. The included papers were highly heterogeneous in terms of the population and type (research vs clinical program vs review/other). There is a pressing need for the publication of clinical programs and models facilitating the adoption of voice banking, especially within populations affected by conditions such as amyotrophic lateral sclerosis and laryngectomy, to address existing gaps and foster broader implementation and accessibility.}, } @article {pmid41219399, year = {2025}, author = {Fyfe, I}, title = {Microglia response altered by ALS mutation.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {12}, pages = {667}, pmid = {41219399}, issn = {1759-4766}, } @article {pmid41220184, year = {2025}, author = {Lei, J and Gong, L and Wei, S and Deng, J}, title = {Causal Relationship Between Inflammatory Bowel Disease and Neuropsychiatric Disorders: A Bidirectional Mendelian Randomization Study.}, journal = {Brain and behavior}, volume = {15}, number = {11}, pages = {e71046}, pmid = {41220184}, issn = {2162-3279}, mesh = {Humans ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Inflammatory Bowel Diseases/genetics/epidemiology ; *Mental Disorders/genetics/epidemiology ; Crohn Disease/genetics ; Schizophrenia/genetics ; Major Depressive Disorder/genetics ; Colitis, Ulcerative/genetics ; Genetic Predisposition to Disease ; Bipolar Disorder/genetics ; }, abstract = {BACKGROUND: Observational studies have indicated a correlation between inflammatory bowel disease (IBD) and neuropsychiatric disorders, yet the causal relationship remains unclear.

OBJECTIVE: We aim to employ two-sample Mendelian randomization (MR) to ascertain the potential causal relationship between IBD and seven major neuropsychiatric disorders.

METHODS: We conducted a bidirectional two-sample MR analysis utilizing genome-wide association study (GWAS) summary statistics of European ancestry for IBD (31,665 cases and 33,977 controls) and its subtypes, ulcerative colitis (UC, 13,768 cases and 33,977 controls) and Crohn's disease (CD, 17,897 cases and 51,874 controls), along with seven major neuropsychiatric disorders: major depressive disorder (MDD, 135,458 cases and 344,901 controls), bipolar disorder (BD, 41,917 cases and 371,549 controls), schizophrenia (SCZ, 33,640 cases and 43,456 controls), Alzheimer's disease (AD, 39,106 cases and 46,828 controls), Parkinson's disease (PD, 33,674 cases and 449,056 controls), multiple sclerosis (MS, 14,498 cases and 24,091 controls), and amyotrophic lateral sclerosis (ALS, 27,205 cases and 110,881 controls).

RESULTS: Our analysis revealed potential positive causal effects of IBD and CD on MDD and SCZ. Similarly, SCZ was positively correlated with an increased risk of IBD and UC. There was a bidirectional positive association between IBD, UC, and MS, whereas CD showed a positive causal effect on MS. Similar to the investigation of the seven specified neuropsychiatric disorders on CD, we did not find evidence supporting causal effects of MDD, BD, AD, PD, or ALS on IBD or UC. Sensitivity analyses further reinforced the robustness of the MR estimates.

CONCLUSION: Our results support potential causal relationships between IBD (including its subtypes CD and UC) and several neuropsychiatric disorders, reinforcing the gut-brain axis concept and enhancing our understanding of extra-intestinal manifestations of IBD and neuropsychiatric manifestations in the context of IBD.}, } @article {pmid41220229, year = {2026}, author = {Sehgal, D and Martín-Sanz, A and Sayago, A and Perraki, A and Kaundun, SS}, title = {Prevalence of two acetolactate synthase target site resistance mutations in sunflower broomrape from Europe as determined by robust kompetitive allele-specific assays (KASP).}, journal = {Pest management science}, volume = {82}, number = {2}, pages = {2122-2131}, doi = {10.1002/ps.70355}, pmid = {41220229}, issn = {1526-4998}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Helianthus/genetics ; Mutation ; *Orobanche/genetics/enzymology/drug effects ; *Herbicide Resistance/genetics ; *Plant Proteins/genetics/metabolism ; Alleles ; Europe ; Genotype ; }, abstract = {BACKGROUND: Orobanche cumana is an important pest of sunflower crops in Europe and Asia. Recently, two highly virulent populations of sunflower broomrape from Greece were found to have evolved resistance to imazamox owing to the A205D and S653N acetolactate synthase (ALS) target-site mutations. We have developed two robust fluorophore-based kompetitive allele-specific (KASP) assays to cost-effectively genotype a large European collection of O. cumana for these two mutations.

RESULTS: The KASP assays were established using 94 tubercules from the two imazamox-resistant populations of sunflower broomrape from Orestiada (GR-ORE) and Drama (GR-DRA) regions in Greece, and two sensitive populations from Romania (RO-TUL) and Spain (SP-VIL). The genotype calls generated by the two KASP assays completely matched with those from sanger sequencing, demonstrating the reliability of the two assays developed here. Genotyping of 2114 individuals from 94 European O. cumana populations collected between 2014 and 2022 did not reveal the A205D mutation in any sample, whereas the S653N mutation, in the homozygous state, was present in a single population (OR-183) from the Drama region in Greece. Cluster analysis of ALS gene sequences suggests that resistance has evolved independently in the two geographically close populations GR-DRA and OR-183 from Drama.

CONCLUSION: The KASP assays developed here allowed high-throughput reliable genotyping of the A205D and S653N mutations in a large number of O. cumana samples from Europe. The study indicates that, so far, resistance to imazamox owing to the A205D and S653N mutations in sunflower broomrape is limited to only three populations from Greece. © 2025 Society of Chemical Industry.}, } @article {pmid41220958, year = {2025}, author = {Highlander, M and Elbasiouny, S}, title = {Methodological and analytical limitations undermine reported outcomes of spinal DC stimulation in ALS.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1706131}, pmid = {41220958}, issn = {1664-2295}, } @article {pmid41220979, year = {2025}, author = {Konopka, A}, title = {Colocalizing Telomeres With PML or γH2AX Foci by IF-FISH in Mouse Brain Neurons.}, journal = {Bio-protocol}, volume = {15}, number = {21}, pages = {e5485}, pmid = {41220979}, issn = {2331-8325}, abstract = {Telomere length maintenance is strongly linked to cellular aging, as telomeres progressively shorten with each cell division. This phenomenon is well-documented in mitotic, or dividing, cells. However, neurons are post-mitotic and do not undergo mitosis, meaning they lack the classical mechanisms through which telomere shortening occurs. Despite this, neurons retain telomeres that protect chromosomal ends. The role of telomeres in neurons has gained interest, particularly in the context of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), where aging is a major risk factor. This has sparked interest in investigating telomere maintenance mechanisms in post-mitotic neurons. Nevertheless, most existing telomere analysis techniques were developed for and optimized using mitotic cells, posing challenges for studying telomeres in non-dividing neuronal cells. Thus, this protocol adapts an already established technique, the combined immunofluorescence and telomere fluorescent in situ hybridization (IF-FISH) on mitotic cells to study the processes occurring at telomeres in cortical neurons of the mouse ALS transgenic model, TDP-43 rNLS. Specifically, it determines the occurrence of DNA damage and the alternative lengthening of telomeres (ALT) mechanism through simultaneous labeling of the DNA damage marker, γH2AX, or the ALT marker, promyelocytic leukemia (PML) protein, together with telomeres. Therefore, the protocol enables the visualization of DNA damage (γH2AX) or the ALT marker (PML) concurrently with telomeres. This technique can be successfully applied to brain tissue and enables the investigation of telomeres specifically in cortical neurons, rather than in bulk tissue, offering a significant advantage over Southern blot or qPCR-based techniques. Key features • This protocol enables the labeling of telomeres in mouse brain tissue prepared from paraffin-embedded brain sections. • This method facilitates concurrent labeling of proteins that are colocalized at telomere sites.}, } @article {pmid41221045, year = {2025}, author = {Zhang, D and Han, L and Zhang, W and Wang, D and Huo, D and Tan, X and Su, X and Wang, M and Xu, J and Cheng, J and Wang, J and Feng, H}, title = {Neuroprotective mechanisms of valproic acid and alpha-lipoic acid in ALS: a network pharmacology-based investigation.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1681929}, pmid = {41221045}, issn = {1663-9812}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, and its multi-mechanism pathology makes single-target therapy insufficient. Valproic acid (VPA) and alpha-lipoic acid (ALA) are known neuroprotective agents, but their combined therapeutic potential and mechanisms in ALS remain unclear.

METHODS: In this study, network pharmacology method was used to integrate the target data of VPA, ALA and ALS, and key targets and pathways were screened by function enrichment, protein-protein interaction (PPI), network analysis and molecular docking. Furthermore, Mendel randomization (MR) was used to analyze the causal relationship between targets and ALS risk. The synergistic neuroprotective effects of VPA and ALA were then validated in the hSOD1[G93A] ALS cell and mouse models.

RESULTS: In this study, four core targets-TNF, EGFR, MAPK1 and MAPK8-were identified for the first time. Genetic analysis indicated that higher TNF levels and reduced MAPK8 expression are linked to a greater risk of ALS. Molecular docking demonstrated strong binding affinities of both compounds to these targets. In vitro and in vivo experiments showed that the combined therapy significantly improved neuronal survival and motor function, inhibited inflammation and apoptosis by activating the PI3K/AKT/FoxO3a pathway, and yielded significantly better therapeutic effects compared to the single drug treatments.

DISCUSSION: VPA and ALA synergistically alleviate ALS by modulating multiple targets and activating the PI3K/AKT/FoxO3a pathway. These findings support their potential as a combinatorial therapeutic strategy for ALS.}, } @article {pmid41221610, year = {2025}, author = {}, title = {Platform Communications: Abstract Book 36th International Symposium on ALS/MND (Complete printable file).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {sup2}, pages = {1-78}, doi = {10.1080/21678421.2025.2564539}, pmid = {41221610}, issn = {2167-9223}, } @article {pmid41222474, year = {2026}, author = {Bagheri, S and Saboury, AA and Ahmad, O and Khan, RH and Ryszkiel, I and Stanek, A}, title = {Association of mercury exposure with neurodegenerative diseases - a reality or a misconception?.}, journal = {Neurologia i neurochirurgia polska}, volume = {60}, number = {1}, pages = {26-36}, doi = {10.5603/pjnns.108158}, pmid = {41222474}, issn = {0028-3843}, mesh = {Humans ; *Neurodegenerative Diseases/chemically induced/epidemiology ; *Mercury/toxicity ; *Environmental Exposure/adverse effects ; Risk Factors ; Animals ; }, abstract = {INTRODUCTION: Exposure to heavy metals has long been considered a potential risk factor for neurodegenerative diseases.

STATE OF THE ART: Most existing studies include in vitro and animal models, and research involving human subjects has yielded conflicting results, obscuring the overall understanding of this topic.

AIMS OF THE STUDY: In this article, the aim is to clarify the situation by carefully reviewing and categorizing the available body of knowledge in this field. Specifically, the focus is on research that explores the relationship between mercury exposure and common neurodegenerative diseases.

CONCLUSIONS: Despite its neurotoxic properties, results show that mercury is not associated with frequent neurodegenerative disorders.}, } @article {pmid41222589, year = {2026}, author = {Heyming, T and Knudsen-Robbins, C and Kain, A and Morphew, T and Ta-Perez, Z and Darabpour, A and Lee, H and Brukman, S and Shelton, SK}, title = {Prehospital Pediatric Assessment Triangle-Real World Data: Emergency Medical Services Use of the Pediatric Assessment Triangle in the Prehospital Environment.}, journal = {Prehospital emergency care}, volume = {30}, number = {6}, pages = {828-836}, doi = {10.1080/10903127.2025.2581753}, pmid = {41222589}, issn = {1545-0066}, mesh = {Humans ; *Emergency Medical Services/methods/statistics & numerical data ; Retrospective Studies ; Child, Preschool ; Female ; Infant ; Child ; Male ; Adolescent ; *Pediatrics/methods ; Infant, Newborn ; }, abstract = {OBJECTIVES: Emergency medical services (EMS) clinicians report lack of training and experience with children, leading to discomfort and uncertainty regarding assessment and treatment. The Pediatric Assessment Triangle (PAT) was designed to provide a rapid and standardized approach. Despite widespread adoption, literature examining EMS implementation of PAT remains limited. We examined EMS use of PAT and assessment of clinical stability and the association between EMS use of PAT and prehospital interventions, EMS transport decisions (advanced life support [ALS] vs basic life support [BLS]), emergency department (ED) interventions, and ED disposition.

METHODS: This was a retrospective cohort study of pediatric patients 0 to <15 years transported to a quaternary care pediatric ED via EMS between October 2022 and November 2023. Data were abstracted from EMS and ED electronic health records (EHRs) including PAT evaluation, demographics, EMS and ED interventions, and ED disposition. Data were analyzed using counts and percentages, logistic regression, chi-square, and McNemar's test.

RESULTS: A total of 2929 patients were included. Most patients, 65.9%, had a PAT score of 0; for those with non-zero PATs, abnormalities in the appearance domain were most prevalent, 50.7%. A PAT score of 1 or higher was associated with transport via ALS (OR 67.9; 95% CI 32.0, 144.1) compared to a PAT of 0. Most patients, 62.2%, received an EMS intervention; the most common was diagnostics (blood glucose or electrocardiogram [EKG]). The EMS administered medications to 22% of patients. PAT scores of ≥2 were associated with double the odds of admission to the floor (OR 2.09; 95% CI 1.4, 3.0) and quadruple the odds of admission to ICU level of care/direct to surgery/expired (OR 4.9; 95% CI 2.9, 8.3); PATs abnormal for work of breathing only were associated with increased odds of admission to the floor (OR 2.5; 95% CI 1.8, 3.6).

CONCLUSIONS: This study suggests that EMS PAT assessment in the field appropriately reflects patient stability and may be associated with EMS intervention en-route. The EMS PAT scores demonstrate promise as an adjunct to ED assessment, alerting clinicians to increased likelihood of admission. The PAT has potential to serve as a practical mechanism for EMS feedback and quality improvement studies.}, } @article {pmid41223590, year = {2025}, author = {Elmansy, MF and Soares, P and Dos Remedios, JRD and Nowar, R and Fox, SG and Yu, A and Klein, WL and Morimoto, RI and Silverman, RB}, title = {Modifications of NU-9, a potent protein aggregation inhibitor. Properties and activity in a cellular model of amyotrophic lateral sclerosis.}, journal = {Bioorganic chemistry}, volume = {167}, number = {}, pages = {109190}, pmid = {41223590}, issn = {1090-2120}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; S10 OD032367/OD/NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Rats ; *Protein Aggregates/drug effects ; PC12 Cells ; Humans ; Molecular Structure ; Structure-Activity Relationship ; Dose-Response Relationship, Drug ; Superoxide Dismutase-1/genetics/metabolism ; *Protein Aggregation, Pathological/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fast-progressing disease characterized by the loss of voluntary movements and death due to respiratory failure. The presence of protein aggregates is a major hallmark of the disease. Hence, targeting the pathological protein aggregation may provide more efficient therapeutics for ALS. Recently, we reported a cyclohexane-1,3-dione (NU-9) with in vitro anti-aggregation capacity and promising in vivo efficacy in ALS animal models, which validated our approach toward the development of novel and potentially more effective ALS therapeutics. Herein, we report the design and synthesis of a new series of small-molecule derivatives of NU-9 and the evaluation of their in vitro anti-aggregation activity in a PC12 cellular model containing an SOD1[G85R] familial ALS mutation. The most promising compound (20) presented an in vitro anti-aggregation potency comparable to that of NU-9. Moreover, the better in vitro BBB permeability, microsomal stability, and toxicity profile of 20 also suggests a potentially higher efficacy in vivo.}, } @article {pmid41223829, year = {2026}, author = {Patil, N and Mirveis, Z and Byrne, HJ}, title = {Exploration of multivariate curve resolution- alternating least squares (MCR-ALS) for datamining kinetically evolving complex cellular spectroscopic data (Spectralomics).}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {348}, number = {Pt 2}, pages = {127156}, doi = {10.1016/j.saa.2025.127156}, pmid = {41223829}, issn = {1873-3557}, mesh = {Least-Squares Analysis ; *Spectrum Analysis, Raman/methods ; Principal Component Analysis ; Kinetics ; Multivariate Analysis ; Humans ; Discriminant Analysis ; }, abstract = {Multivariate curve resolution- alternating least squares (MCR-ALS) approach for datamining the complex spectral fingerprints from kinetically evolving cellular Raman spectroscopy data was explored in this study. Principal components analysis and partial least squares- discriminant analysis indicated the metabolic changes were captured in individual metabolic conditions (Control, Stimulation and Inhibition) as a function of time; however, MCR-ALS could not resolve the spectral components accurately. Hence simulated datasets were generated to test the limit of resolution which revealed the significance of initial estimation of spectral components in the MCR, and the effect of equality constraints in the ALS was studied. The resolved rate constants for the time evolution of the components were not quantitatively accurate at higher cellular background overlayed on the evolving components, although they did exhibit a consistent qualitative trend across the modulated conditions. Hence, the cellular data was analysed qualitatively, and the initial estimates constraint in MCR along with a kinetic hard model constraint in ALS was deduced to be the best strategy for datamining complex cellular spectra. The spectral fingerprints of both glycolytic and non-glycolytic cellular processes were resolved in all the modulated conditions, highlighting the high-content insights from the label-free approach. The study demonstrates the potential of Raman spectroscopy coupled with a spectralomics approach for datamining of the complex spectral fingerprints as a function of time and highlights its limitations. This approach could potentially find applications in high-content drug screening, drug discovery, disease diagnostics and process analytical techniques for monitoring bioprocesses.}, } @article {pmid41223995, year = {2026}, author = {Michelerio, A and Tomasini, C and Brazzelli, V}, title = {Response to Gronbeck et al's "Dermatologic toxicities of antibody-drug conjugates": Why ado-trastuzumab emtansine-associated telangiectasias deserve clinical attention.}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {3}, pages = {e191-e192}, doi = {10.1016/j.jaad.2025.11.008}, pmid = {41223995}, issn = {1097-6787}, } @article {pmid41224202, year = {2026}, author = {Metelmann, M and Heyne, S and Peuker, M and Claßen, J and Mehnert-Theuerkauf, A and Esser, P}, title = {[Experiences with the Application of Short-Term Psychotherapy in Patients with Amyotrophic Lateral Sclerosis: What Can We Learn from It?].}, journal = {Psychotherapie, Psychosomatik, medizinische Psychologie}, volume = {76}, number = {2}, pages = {86-94}, doi = {10.1055/a-2711-2085}, pmid = {41224202}, issn = {1439-1058}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; Male ; Female ; Middle Aged ; Aged ; *Psychotherapy, Brief/methods ; Palliative Care ; Adult ; Feasibility Studies ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is associated with elevated distress, but evidence on psychosocial interventions is limited. We tested the feasibility of a psychotherapy for palliative cancer patients in ALS patients.We applied CALM (Managing Cancer and Living Meaningfully), an effective psychodynamic short-term therapy for advanced cancer patients, within a pre-post study among patients with ALS. We provided patient flow and formal treatment information. Based on the treatment protocols, the therapist reflected on the applicability of the treatment structure, specifics in the psychosocial work with ALS patients and suggestions for treatment modification.Among 15 eligible patients, five participated. Three patients completed the treatment, two patients provided complete study data. The trial was prematurely stopped due to issues in feasibility. Six (22%) sessions were conducted via telephone, 10 (37%) were attended by family caregivers. The structure showed limited applicability largely because fear-laden topics including suffering and death were extensively avoided. Compared to palliative cancer patients, ALS patients fluctuated more strongly in their psychological and physical symptom burden and were more strongly distressed by disease-related practical issues. Recommendations included a multi-professional team, booster sessions and a direct support for caregivers.A psychotherapy effective for cancer patients showed features that limit its applicability among ALS patients. Some of these limitations are treatment-inherent and thus hard to adapt. Rather than modifying the program, we suggest to develop a specific supportive psychotherapeutic intervention within a participatory approach.}, } @article {pmid41224274, year = {2026}, author = {Takubo, M and Matsumoto, Y and Sasaki, C and Ikeda, K and Sugeno, N and Warita, H and Aoki, M}, title = {Spinocerebellar Ataxia Type 3 Accompanied by Amyotrophic Lateral Sclerosis: A Case Report and Comprehensive Literature Review.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {65}, number = {13}, pages = {1810-1814}, pmid = {41224274}, issn = {1349-7235}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Male ; Middle Aged ; *Machado-Joseph Disease/complications/diagnosis ; }, abstract = {Spinocerebellar ataxia type 3 (SCA3) is a hereditary neurodegenerative disorder characterized by cerebellar ataxia, whereas amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease. We herein report a 62-year-old man with genetically confirmed SCA3 who subsequently developed rapidly progressive asymmetric muscle weakness, atrophy, and fasciculations. Clinical features, including preserved tendon reflexes and widespread denervation observed on electromyography, support the diagnosis of concomitant sporadic ALS. Our literature review revealed only a few similar cases, suggesting the under-recognition of this rare combination. This case underscores the importance of considering coexisting ALS in patients with SCA3 to enable a timely diagnosis and management.}, } @article {pmid41224659, year = {2025}, author = {Moss, KR and Darvishi, FB and Badawi, Y and Fish, LA and Funke, JR and Pedersen, TH and Robitaille, R and Arnold, WD and Burgess, RW and Meriney, SD and Nishimune, H and Saxena, S}, title = {The Neuromuscular Junction: A Shared Vulnerability in Aging and Disease.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {45}, number = {46}, pages = {}, pmid = {41224659}, issn = {1529-2401}, support = {K22 NS125057/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Neuromuscular Junction/pathology/physiopathology/physiology ; *Aging/pathology/physiology ; Animals ; *Neuromuscular Diseases/physiopathology/pathology ; Schwann Cells ; }, abstract = {The neuromuscular junction (NMJ) is a specialized synapse essential for effective motor neuron-muscle communication and is increasingly recognized as a vulnerable site in aging and neuromuscular disease. While traditionally considered a final common pathway for motor deficits, accumulating evidence demonstrates that NMJ dysfunction is an early and critical driver of disease onset and progression in conditions such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. This review highlights shared and disease-specific mechanisms contributing to NMJ impairment, including presynaptic, postsynaptic, and perisynaptic Schwann cell defects in these diseases. We also discuss age-related changes at the NMJ, emphasizing its role in sarcopenia and muscle weakness in older adults. Furthermore, we explore emerging molecular drivers of NMJ dysfunction uncovered through studies in congenital myasthenic syndromes, autoimmune disorders, and advanced omics approaches. By integrating insights across diseases and aging, we underscore the potential for shared therapeutic strategies aimed at stabilizing NMJ function. Promising interventions targeting presynaptic neurotransmitter release, postsynaptic excitability, and perisynaptic Schwann cells are discussed as avenues to improve neuromuscular transmission and maintain muscle strength. Finally, we discuss the challenges and opportunities in translating these mechanistic insights into clinical therapies and highlight how novel human neuromuscular organoid models and advanced molecular profiling can bridge this gap. Together, these insights establish the NMJ as a critical, modifiable target for preserving motor function across neuromuscular diseases and aging.}, } @article {pmid41225259, year = {2025}, author = {Ghayal, NB and Crook, RJ and Jain, A and Sachdeva, G and Jiang, P and Roemer, SF and Sekiya, H and DeTure, MA and Baker, MC and De Coster, W and Oskarsson, B and Josephs, KA and Rademakers, R and van Blitterswijk, MM and Dickson, DW}, title = {Expanding the spectrum of annexin A11 proteinopathy in frontotemporal lobar degeneration and motor neuron disease.}, journal = {Acta neuropathologica}, volume = {150}, number = {1}, pages = {52}, pmid = {41225259}, issn = {1432-0533}, support = {R01-AG037491//Foundation for the National Institutes of Health/ ; UG3 NS103870/NS/NINDS NIH HHS/United States ; G064223N//Fund for Scientific Research Flanders (FWO)/ ; P30 AG062677/AG/NIA NIH HHS/United States ; R01 AG037491/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Lobar Degeneration/pathology/genetics/metabolism ; *Motor Neuron Disease/pathology/metabolism/genetics ; Male ; Female ; Aged ; Middle Aged ; *Annexins/metabolism/genetics ; DNA-Binding Proteins/metabolism ; Aged, 80 and over ; TDP-43 Proteinopathies/pathology ; Brain/pathology/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; }, abstract = {Aggregation of TAR-DNA-binding protein 43 (TDP-43) is strongly associated with frontotemporal lobar degeneration (FTLD-TDP), motor neuron disease (MND-TDP), and overlap disorders like FTLD-MND. Three major forms of motor neuron disease are recognized and include primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), and progressive muscular atrophy (PMA). Annexin A11 (ANXA11) is understood to aggregate in amyotrophic lateral sclerosis (ALS-TDP) associated with pathogenic variants in ANXA11, as well as in FTLD-TDP type C. Given these observations and recent reports of ANXA11 variants in patients with semantic variant frontotemporal dementia (svFTD) and FTD-MND presentations, we sought to characterize ANXA11 proteinopathy in an autopsy cohort of 379 cases diagnosed with a primary TDP-43 proteinopathy, including FTLD-TDP, FTLD-MND, and MND-TDP. Cases with FTLD-MND and MND-TDP were classified further into PLS, ALS, and PMA based on the relative loss of upper and lower motor neurons. ANXA11 proteinopathy was present in over 40% of FTLD-MND cases. Further, ANXA11 colocalized with TDP-43 in the pathologic inclusions of all FTLD-TDP type C cases, as well as 38 out of 40 FTLD-PLS cases (95%), of which 84% had TDP type B or an unclassifiable TDP-43 proteinopathy and 16% had TDP type C. Genetic analysis excluded pathogenic ANXA11 variants in all ANXA11-positive cases. We thus demonstrated two novel ANXA11 proteinopathies strongly associated with FTLD-PLS, but not with TDP type C or pathogenic ANXA11 variants. Given the emerging relationship between TDP-43 and ANXA11 in neurodegenerative disease, we propose that TDP-43 and ANXA11 proteinopathy (TAP) comprises a distinct group of molecular pathologies and define three TAP types based on key clinical and neuropathologic characteristics.}, } @article {pmid41226260, year = {2025}, author = {Cutter, LR and Ren, AR and Banerjee, IA}, title = {Advances in Naturally and Synthetically Derived Bioactive Sesquiterpenes and Their Derivatives: Applications in Targeting Cancer and Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {21}, pages = {}, pmid = {41226260}, issn = {1420-3049}, support = {N/A//Henry Luce Foundation/ ; N/A//Fordham University/ ; }, mesh = {Humans ; *Sesquiterpenes/chemistry/pharmacology/therapeutic use/chemical synthesis ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neoplasms/drug therapy/metabolism ; Animals ; *Biological Products/chemistry/pharmacology/therapeutic use ; *Antineoplastic Agents/pharmacology/chemistry ; Antioxidants/chemistry/pharmacology ; }, abstract = {Sesquiterpenes are a diverse class of natural products that have garnered considerable interest for their potent bioactivity and structural variability. This review highlights advances in the derivatization of various sesquiterpene lactones, quinones, and alcohols, particularly in targeting cancer and neurodegenerative diseases. The structural modifications discussed include the incorporation of triazole, arylidene, or thiol moieties with eudesmane, guaiane, and germacranolide-type sesquiterpenes, among others. In addition, the conjugation with chemotherapeutics, as well as the development of nanoscale therapeutics, is also discussed. Such modifications have expanded the pharmacological potential, enabling improved specificity, cytotoxicity profiles, and sensitization toward tumor cells. Additionally, sesquiterpenes such as parthenolide (20), pterosinsade A (176), and cedrol (186) have demonstrated potential in mitigating neurodegeneration via anti-inflammatory and antioxidant signaling pathway-modulation mechanisms, with potential applications in Alzheimer's, Parkinson's, and ALS diseases. Mechanistic insights into redox signaling modulation, NF-κB inhibition, ROS regulation, and disruption of aggregation underscore their multifaceted modes of action. This review highlights the translational promise of sesquiterpene derivatives as dual-action agents for potential drug development in a plethora of diseases that are caused by inflammation and free-radical damage. It provides a framework for future rational design of multifunctional drug candidates and therapeutics.}, } @article {pmid41226363, year = {2025}, author = {Thakur, B and Tarazi, S and Doležalová, L and Behbahani, H and Darreh-Shori, T}, title = {Comparative Analysis of Cholinergic Machinery in Carcinomas: Discovery of Membrane-Tethered ChAT as Evidence for Surface-Based ACh Synthesis in Neuroblastoma Cells.}, journal = {International journal of molecular sciences}, volume = {26}, number = {21}, pages = {}, pmid = {41226363}, issn = {1422-0067}, support = {//Åhlén-Foundation/ ; //Frimurarna Foundation/ ; //Ulla-Carin Linquist Foundation for ALS research/ ; AARG-24-1310046//Alzheimer´s Association/ ; //Dementia Foundation (Demensfonden)/ ; //Foundation for Old Servants (Gamla Tjänarinnor)/ ; //Karolinska Institutet´s Research Foundations/ ; //Olle Engkvist Byggmästare Foundation/ ; //Magnus Bergvalls Foundation/ ; //Gun and Bertil Stohnes Foundation/ ; ALF Med N 20200330//grant from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement/ ; #CAN2021/1469, and # 24 3793//the Swedish Cancer Society/ ; #221212, #241282 and #221383//the Stockholm Cancer Society/ ; }, mesh = {Humans ; *Neuroblastoma/metabolism/pathology ; *Acetylcholine/biosynthesis/metabolism ; Cell Line, Tumor ; *Choline O-Acetyltransferase/metabolism ; Choline/metabolism ; Cell Membrane/metabolism ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Signal Transduction ; }, abstract = {The cholinergic system is one of the most ancient and widespread signaling systems in the body, implicated in a range of pathological conditions-from neurodegenerative disorders to cancer. Given its broad relevance, there is growing interest in characterizing this system across diverse cellular models to enable drug screening, mechanistic studies, and exploration of new therapeutic avenues. In this study, we investigated four cancer cell lines: one of neuroblastoma origin previously used in cholinergic signaling studies (SH-SY5Y), one non-small cell lung adenocarcinoma line (A549), and two small cell lung carcinoma lines (H69 and H82). We assessed the expression and localization of key components of the cholinergic system, along with the cellular capacity for acetylcholine (ACh) synthesis and release. Whole-cell flow cytometry following membrane permeabilization revealed that all cell lines expressed the ACh-synthesizing enzyme choline acetyltransferase (ChAT). HPLC-MS analysis confirmed that ChAT was functionally active, as all cell lines synthesized and released ACh into the conditioned media, suggesting the presence of autocrine and/or paracrine ACh signaling circuits, consistent with previous reports. The cell lines also demonstrated choline uptake, indicative of functional choline and/or organic cation transporters. Additionally, all lines expressed the ACh-degrading enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), as well as the alfa seven (α7) nicotinic and M1 muscarinic ACh receptor subtypes. Notably, flow cytometry of intact SH-SY5Y cells revealed two novel findings: (1) ChAT was localized to the extracellular membrane, a feature not observed in the lung cancer cell lines, and (2) BChE, rather than AChE, was the predominant membrane-bound ACh-degrading enzyme. These results were corroborated by both whole-cell and surface-confocal microscopy. In conclusion, our findings suggest that a functional cholinergic phenotype is a shared feature of several carcinoma cell lines, potentially serving as a survival checkpoint that could be therapeutically explored. The discovery of extracellular membrane-bound ChAT uniquely in neuroblastoma SH-SY5Y cells points to a novel form of in situ ACh signaling that warrants further investigation.}, } @article {pmid41226491, year = {2025}, author = {Cappelli, S and Peradinovic, J and Mohovic, N and Mandal, P and Stuani, C and Longo, A and Cannon, JR and Baloni, P and Leoni, B and Krsmanovic, T and Stojanov, K and Apic, G and Russell, RB and Romano, M and Buratti, E and Munitic, I}, title = {Optineurin Shapes Basal and LPS-Induced Transcriptomes in BV2 Microglia.}, journal = {International journal of molecular sciences}, volume = {26}, number = {21}, pages = {}, pmid = {41226491}, issn = {1422-0067}, support = {IP-2024-05-5814//Croatian Science Foundation/ ; IP-2018-01-8563//Croatian Science Foundation/ ; DOK-2018-09-7739//Croatian Science Foundation/ ; DOK-2020-01-8703//Croatian Science Foundation/ ; 861 329//SCiLS/ ; }, mesh = {*Lipopolysaccharides/pharmacology ; Animals ; *Microglia/metabolism/drug effects ; Mice ; *Transcriptome/drug effects ; Membrane Transport Proteins/genetics ; *Cell Cycle Proteins/genetics/metabolism ; *Transcription Factor TFIIIA/genetics/metabolism ; Cell Line ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; }, abstract = {The OPTN gene, which encodes the adaptor protein optineurin, is genetically linked to amyotrophic lateral sclerosis and frontotemporal dementia, diseases characterized by chronic microglial activation. Optineurin regulates inflammatory signaling, autophagy, and trafficking, but its role in microglia remains incompletely understood. Here, we used bulk RNA sequencing to profile CRISPR-Cas9-mediated optineurin knockout (KO) and wild-type BV2 microglia under basal conditions and upon LPS stimulation. At baseline, optineurin KO altered ~7% of the transcriptome, with a predominant downregulation of type I interferon and antiviral pathways, suggesting its role in maintaining basal immune readiness. LPS stimulation reprogrammed ~35% of genes in wild-type microglia, inducing immune effectors and suppressing cell cycle regulators, whereas in optineurin-deficient cells, the response was blunted with only ~16% of genes changing relative to the KO baseline. Furthermore, LPS-treated optineurin KO microglia notably diverged from LPS-treated wild-type cells, with ~26% differentially expressed genes (DEGs). This included impaired induction of inflammatory programs and persistence of cell cycle-associated transcripts. Most DEGs in LPS-treated KO cells were unique to this condition, highlighting optineurin-dependent pathways specific to inflammatory challenge. Overall, our study provides a systems-level framework for investigating optineurin in microglia and neurodegeneration, establishing it as a key regulator of the microglial transcriptome, with its loss reshaping innate immune and cell cycle programs.}, } @article {pmid41227379, year = {2025}, author = {Spedding, M}, title = {Does Amyotrophic Lateral Sclerosis (ALS) Have Metabolic Causes from Human Evolution?.}, journal = {Cells}, volume = {14}, number = {21}, pages = {}, pmid = {41227379}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Animals ; *Biological Evolution ; Mixed Function Oxygenases/metabolism/genetics ; }, abstract = {As so many drugs have failed in ALS a new approach is needed. The author proposes that recent human genetic variants may play major roles in the disease, changing metabolism. Evolution of hominins was accelerated 3-2.5 Mya, by cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) becoming a unitary pseudogene after a pathogenic infection, changing the sialome, and hence metabolism, brain development and neuromuscular junctions (NMJs). This was when hominins evolved to run in Africa and develop bigger brains. Deletion of CMAH in mice allows them to run for longer (~50%). The enzyme CMAH is critical for the sialome, particularly the neurotrophin GM1, a critical hub for viral infection and for NMJ stability, but which is lost from NMJs at the beginning of denervation, probably due a 10-fold increase in spinal cord glucosylceramidases (non-lysosomal GBA2). A GBA2 inhibitor, ambroxol, is currently in phase II for ALS. Human-specific GM1 may be critical for human evolution, lactate metabolism and ALS. Lipid/lactate metabolism changed to support these evolutionary changes and lactate is a major body/brain fuel, but compromised in ALS patients and a marker of disease progression. Recent progress in sports science involving lactate metabolism and human performance may also be relevant to ALS therapies, and incidence.}, } @article {pmid41227857, year = {2025}, author = {Ma, H and Zong, M and Cedrick, N and Sun, Y and Wang, W and Yan, X and Liu, H and Zhu, P and Hua, M}, title = {Influence Mechanism of Chemically Modified Alumina on the Hydration of Gypsum-Based Self-Leveling Mortar.}, journal = {Materials (Basel, Switzerland)}, volume = {18}, number = {21}, pages = {}, pmid = {41227857}, issn = {1996-1944}, support = {42202034//National Natural Science Foundation of China/ ; 52508248//National Natural Science Foundation of China/ ; BK20220626//Natural Science Foundation of Jiangsu Province/ ; }, abstract = {This study investigates the effect of γ-aminopropyltriethoxysilane (KH550)-functionalized nano-active Al2O3 (KH-Al) on the properties of gypsum-based self-leveling mortar (GSL) prepared from industrial by-product gypsum. First, the effects of incorporating KH-Al at dosages of 0.05%, 0.1%, 0.25%, 0.5%, and 1% on the fluidity, setting time, and mechanical properties of GSL were analyzed. Subsequently, using X-ray diffraction (XRD), hydration heat analysis, thermogravimetric analysis (TG), and scanning electron microscopy (SEM), the influences of the nanomaterial on the mortar's morphology, hydration characteristics, and crystal forms of hydration products were thoroughly examined. Finally, by comparing the modified GSL with ordinary GSL, the mechanism of KH-Al's action on GSL was elucidated. The results demonstrate that nano-active Al2O3 modified with KH550 exhibits excellent dispersibility in the GSL paste. As the dosage of KH-Al increases, both the fluidity and setting time of GSL decrease. Upon incorporating KH-Al, the mechanical properties of GSL initially improve and then decline, with optimal mechanical performance observed at a 0.5% KH-Al addition. However, when the KH-Al dosage exceeds 0.5%, excess nano-active Al2O3 causes nanoparticle agglomeration, which impedes the hydration process. The nucleation effect of KH-Al promotes the formation of CŜH2 and AFt, refines the crystals of hydration products, and enhances the phase transformation efficiency of the mortar. These findings indicate that KH-Al has significant potential to improve the mechanical strength and hydration kinetics of gypsum mortar and provide theoretical support for the application of nanomaterials in gypsum building materials.}, } @article {pmid41228121, year = {2025}, author = {Wityshyn, S and Sanghai, N and Tranmer, GK}, title = {My Amyotrophic Lateral Sclerosis (ALS) Journey from Weakness to Diagnosis: A Journey of Hope.}, journal = {Healthcare (Basel, Switzerland)}, volume = {13}, number = {21}, pages = {}, pmid = {41228121}, issn = {2227-9032}, support = {202210PJT-495295/CAPMC/CIHR/Canada ; }, abstract = {Amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease is a progressive neurodegenerative disease that attacks and kills motor neurons in the brain and spinal cord, leading to muscle weakness and atrophy, eventually causing respiratory failure and death within 2-5 years after diagnosis. By 2040, the global population of individuals living with ALS is projected to approach 400,000. Since ALS was discovered by Charcot 150 years ago, only two drugs (Edaravone and Riluzole) have been available, offering modest clinical benefits in slowing disease progression. The increasing number of cases, along with the high costs of treatment and care, creates a growing burden on communities and the healthcare system. However, despite this rising burden and the failure of most clinical trials, the ALS community remains hopeful because of the patients themselves. ALS patients are the beating heart of the ALS community. They engage in efforts to improve lives for others, raising awareness through their real-life experiences, participating in research activities, fundraising, providing samples for research, and advocating strongly in front of communities and governments to raise funds. Their engagement is highly valuable, and collaboration with the research community is essential to understanding the disease process and developing effective disease-modifying therapies. Here, we share the story of Mrs. Sherry Wityshyn, an ALS patient and a true ALS warrior from Winnipeg, Manitoba, Canada. We believe her story will inspire and motivate the entire community to learn more about ALS. Furthermore, her story gives hope to everyone impacted. In this manuscript, we also emphasize the different stages of Sherry's journey from weakness to diagnosis and our efforts to share her enduring words with policymakers in the government.}, } @article {pmid41228417, year = {2025}, author = {de la Rubia Ortí, JE and Bargues-Navarro, G and Privado, J and Menarques-Ramírez, R and Sanchis-Sanchis, CE and Sancho-Castillo, S and Rubio, CP and Pardo-Marin, L and Benlloch, M and Martín-Ruiz, J}, title = {Dietary Vitamin Intake and Blood Biomarkers in Relation to Muscle Activation in Amyotrophic Lateral Sclerosis: A Cross-Sectional Study.}, journal = {Nutrients}, volume = {17}, number = {21}, pages = {}, pmid = {41228417}, issn = {2072-6643}, support = {2021-203-003//Catholic University of Valencia San Vicente Mártir/ ; }, mesh = {Humans ; Cross-Sectional Studies ; Biomarkers/blood ; *Amyotrophic Lateral Sclerosis/blood/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Muscle, Skeletal/physiopathology ; *Diet ; Aryldialkylphosphatase/blood ; Muscle Strength ; *Vitamins/administration & dosage ; Butyrylcholinesterase/blood ; }, abstract = {Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor function, which affects mobility and leads to secondary complications, including altered dietary intake due to dysphagia, fatigue, and hypermetabolism, particularly affecting vitamin consumption, which are essential micronutrients for neuromuscular performance. The specific relationship between vitamin intake and muscle activation is not well understood in patients with ALS; thus, it is relevant to identify blood biomarkers that reflect muscle status. Methods: A cross-sectional study was conducted with 61 patients with bulbar- or spinal-onset ALS. The dietary intake of B vitamins (B1, B2, B6, B12, folate, and niacin); vitamins C, A, D, and E; and the B6/protein ratio were assessed using a seven-day dietary record and a Food Frequency Questionnaire. Blood concentrations of butyrylcholinesterase (BuChE), albumin, haptoglobin, C-reactive protein (CRP), and paraoxonase 1 (PON1) were determined. Basal muscle activation was measured using surface electromyography of the biceps brachii, triceps brachii, rectus femoris, and tibialis anterior muscles. Two confirmatory predictive models were developed to evaluate the effects of muscle damage and vitamin intake on muscle strength. Results: Arm muscle activation was negatively predicted by the B6/protein ratio (β = -0.33). Leg activation was positively predicted by vitamin B9 (β = 0.39) and B6/protein (β = 0.17) and negatively predicted by vitamin A (β = -0.24). For biomarkers, albumin (β = 0.18) and PON1 (β = 0.28) positively predicted activation. For legs, albumin predicted activation (β = 0.31), whereas BuChE and haptoglobin predicted negative activation (β = -0.32 and β = -0.15, respectively). Conclusions: Weak associations were observed in patients with ALS: vitamin B9 intake showed a modest association with leg activation, the B6/protein ratio exhibited inconsistent associations across muscle groups, and vitamin A showed a negative association with leg activation. Albumin demonstrated the most consistent association as a potential biomarker of muscle function. These findings are exploratory and require validation in larger, longitudinal studies.}, } @article {pmid41229135, year = {2025}, author = {Vacchiano, V and Ragucci, C and Rizzo, G and Di Stasi, V and Pastorelli, F and Rinaldi, R and Provini, F and Postiglione, E and Fiorentino, A and Carelli, V and Liguori, R}, title = {Nerve Root Enhancement and Elevated Cerebrospinal Fluid Protein in Four Patients With SOD1-Linked Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {32}, number = {11}, pages = {e70434}, pmid = {41229135}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/pathology/physiopathology/diagnosis ; Male ; *Superoxide Dismutase-1/genetics ; Middle Aged ; Female ; Magnetic Resonance Imaging ; Aged ; *Spinal Nerve Roots/pathology/diagnostic imaging ; Adult ; *Cerebrospinal Fluid Proteins/cerebrospinal fluid ; }, abstract = {INTRODUCTION: The superoxide dismutase type 1 (SOD1) gene has been implicated in both sporadic and familial forms of amyotrophic lateral sclerosis (ALS). We report four ALS cases carrying pathogenic or likely pathogenic SOD1 variants, characterized by albuminocytologic dissociation and nerve root enhancement.

METHODS: We present the results of the diagnostic work-up, including lumbosacral magnetic resonance imaging (MRI) with gadolinium, electromyography (EMG), and cerebrospinal fluid (CSF) analysis. We also assessed the relationship between the albumin quotient (Q-Alb)-an index of blood-brain barrier (BBB) dysfunction-and the disease progression rate (DPR) in 12 SOD1-linked ALS patients (including the four described above) and in a cohort of 137 non-genetic ALS (NgALS) cases.

RESULTS: The four patients presented with spinal onset (progressive lower limb weakness). The EMG ultimately showed diffuse subacute neurogenic changes, while CSF analysis revealed albuminocytologic dissociation. Lumbosacral MRI demonstrated contrast enhancement of the cauda equina roots. Immunomodulatory treatment was administered due to suspected immune-mediated neuropathy, but all patients continued to deteriorate. Genetic testing revealed pathogenic or likely pathogenic variants in the SOD1 gene, confirming the diagnosis of ALS. CSF Q-Alb and protein levels were similarly distributed between SOD1-linked and NgALS patients. Q-Alb and CSF protein levels showed a positive correlation with DPR in SOD1-linked patients (Rho = 0.625, p = 0.03; Rho = 0.755, p = 0.005), but not in NgALS patients.

CONCLUSION: Albuminocytologic dissociation and nerve root enhancement may occur in SOD1-related ALS, expanding the spectrum of atypical ALS phenotypes.}, } @article {pmid41229403, year = {2025}, author = {Ackrivo, J and Bracy, D and Elman, LB and Hansen-Flaschen, J and Simmons, Z and Pasinelli, P and Heiman-Patterson, T and Kawut, SM and Lane-Fall, MB}, title = {How Patients With Amyotrophic Lateral Sclerosis Perceive Respiratory Interventions: A Mixed-Methods Study to Inform Implementation Efforts.}, journal = {Neurology. Clinical practice}, volume = {15}, number = {6}, pages = {e200560}, pmid = {41229403}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that commonly leads to respiratory failure. Early respiratory interventions that may improve symptoms and outcomes are underused when prescribed. We sought to characterize patient perspectives and preferences for respiratory care to enable identification of implementation strategies to improve the uptake of ALS respiratory interventions.

METHODS: A prospective multicenter mixed-methods observational study was conducted using semistructured interviews of participants recently diagnosed with ALS at 4 academic centers in the United States. Eligible patients were those with an ALS diagnosis in the previous 12 months, forced vital capacity <80% predicted normal, or presence of dyspnea or orthopnea.

RESULTS: Twenty-four patients with ALS were interviewed. Ten participants were using some form of respiratory therapy, including 8 using noninvasive ventilation (NIV). The most endorsed factors related to openness to initiate respiratory therapy were a doctor's recommendation and abnormal pulmonary function test results. The most commonly endorsed preferences for learning about a respiratory device included kinesthetic and reading. Descriptions of lung volume recruitment were received with more openness than of NIV. For those not prescribed NIV, reasons for hesitancy to start NIV included fear of mask discomfort, claustrophobia, and lack of perceived benefit. Perceptions about NIV differed in participants identifying as "proactive" rather than "reactive" with their health.

DISCUSSION: Patients in the first year after ALS diagnosis have variable receptiveness to respiratory care. These patients place different weights on the factors supporting NIV and may have different educational needs about respiratory interventions. Implementation strategies for respiratory care interventions in ALS should consider patients' motivations for adopting interventions such as NIV, provide multiple educational formats, and identify barriers to incorporating home respiratory care.}, } @article {pmid41229731, year = {2025}, author = {Nasir, AR and Delpirou Nouh, C}, title = {TDP-43-proteinopathy at the crossroads of tauopathy: on copathology and current and prospective biomarkers.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1671419}, pmid = {41229731}, issn = {1662-5102}, abstract = {Though usually described as isolated models, neurodegenerative diseases exist in a significant proportion of cases as mixed pathologies, particularly in older adults. The presence of co-pathologies may influence phenotypes and progression, and the correct classification in vivo has proven to be challenging, particularly without proper biomarker panels. Recent breakthroughs in biomarkers, enabling earlier detection in Alzheimer's disease and, more recently, in synuclein-related diseases, are promising as a first step toward the wider detection of all other abnormal proteins involved in neurodegenerative diseases. Over the past decade, the growing body of research on TDP-43 pathology has led to considering TDP-43 as a potential major contributor to the neurodegenerative process. TDP-43's normal function is essential for neuronal survival and the regulation of RNA processing and cellular stress response; abnormal TDP-43 protein leads to altered cell function and survival. TDP-43 is notably the neuropathological hallmark of amyotrophic lateral sclerosis (ALS) as well as some form of frontotemporolobar degeneration (FTLD). Tauopathies, divided in primary or secondary tauopathies cover other forms of FTLD including Pick disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) but also non-FTLD diseases like Alzheimer's disease (AD) which can be classified as secondary tauopathy. As the importance of copathology is more and more recognized, TDP-43 is also frequently observed in conjunction with other proteinopathies, possibly with a synergistic or additive effect, although the exact mechanism is still unclear. In Alzheimer's disease, the limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) co-occurrence with Alzheimer's disease neuropathologic changes (ADNC) lead to a more rapid course. Although there are currently no approved and validated biomarkers for its early detection, several promising tools, including neuroimaging and biofluid biomarkers, are under development, offering hope for the earlier detection of TDP-43 pathology in vivo. Accurate identification of the underlying proteinopathies and pathological processes could lead to better diagnosis and classification, more precise selection of clinical trial candidates, and ultimately, disease-specific tailored treatments.}, } @article {pmid41231679, year = {2025}, author = {Wang, T and Yu, G and Wu, Y and Wang, S and Zhu, Y and Li, H and Li, H and Yu, G}, title = {A Chiral Electrocatalyst for High-Performance Aluminum-Sulfur Battery.}, journal = {Journal of the American Chemical Society}, volume = {147}, number = {50}, pages = {46136-46144}, doi = {10.1021/jacs.5c14506}, pmid = {41231679}, issn = {1520-5126}, abstract = {Aluminum-sulfur (Al-S) batteries are regarded as promising electrochemical energy storage systems due to their high energy density, cost-effectiveness, and environmental compatibility. However, their practical application is hindered by sluggish sulfur conversion kinetics. Although certain achievements have been made, conventional strategies for modulating the spin state of electrocatalysts, such as heteroatom doping or lattice strain engineering, exhibit inherent limitations in optimizing electron orbital interactions. Herein, we report a novel MoS2 electrocatalyst with spin orientation manipulation achieved through the chiral-induced spin selectivity (CISS) effect. This approach couples chiral molecules with layered MoS2 to regulate the spin polarization of molybdenum atoms, thereby enhancing the sulfur redox kinetics without relying on chemical modification. Electrochemical analyses demonstrated that the cathode with chiral MoS2 delivers a reversible specific capacity of ∼700 mAh g[-1] at 2 A g[-1] over 3000 cycles, accompanied by improved sulfur utilization efficiency. This work not only provides a paradigm for designing high-performance electrocatalysts in sulfur-based batteries but also highlights the critical role of spin effects in electrocatalytic systems, offering new perspectives for the innovation of electrocatalyst materials in batteries.}, } @article {pmid41231952, year = {2025}, author = {Lu, YN and Li, X and Hayes, L and Zhao, XF and Wang, J}, title = {MARK2 regulates C9orf72 repeat-associated non-AUG translation.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {46}, pages = {e2514182122}, pmid = {41231952}, issn = {1091-6490}, support = {R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS128494/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Protein Biosynthesis ; Frontotemporal Dementia/genetics/metabolism/pathology ; *Protein Serine-Threonine Kinases/metabolism/genetics ; DNA Repeat Expansion ; Eukaryotic Initiation Factor-2/metabolism/genetics ; Neurons/metabolism ; Signal Transduction ; Disease Models, Animal ; }, abstract = {Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the C9orf72 gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2α kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2α signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity.}, } @article {pmid41233143, year = {2026}, author = {Cook, BE and McLaren, DG and Sullivan, JM and El Fakhri, G and Yokell, DL and Freeman, MW and Currier, N and Oestergaard, ME and Dobson, H and Hesterman, J and Salem, N and Nestorov, I and Monine, M and Martarello, L and Evans, KC and Fradette, S and Ferguson, TA and Graham, D and Passamonti, L}, title = {Central Nervous System Biodistribution and Pharmacokinetics of Radiolabeled Tofersen in Rodents, Nonhuman Primates, and Humans.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {67}, number = {1}, pages = {139-144}, pmid = {41233143}, issn = {1535-5667}, mesh = {Animals ; Humans ; Tissue Distribution ; Rats ; Male ; Female ; Single Photon Emission Computed Tomography Computed Tomography ; *Central Nervous System/metabolism/diagnostic imaging ; Adult ; *Oligonucleotides, Antisense/pharmacokinetics/chemistry ; Isotope Labeling ; Rats, Sprague-Dawley ; }, abstract = {Antisense oligonucleotides (ASOs) are an important therapeutic modality across several therapeutic areas, offering currently available and potential future treatment options for patients. ASO pharmacokinetics, biodistribution, and regional brain uptake are not fully characterized, particularly in humans. Here, we report preclinical studies and the first-in-human imaging trial measuring the biodistribution of [[99m]Tc]Tc-MAG3-tofersen. The tracer was designed to be a proxy for tofersen (Qalsody; Biogen), an ASO approved for the treatment of amyotrophic lateral sclerosis in adults who have a variant in the SOD1 gene (SOD1-ALS). Methods: Tofersen was conjugated to a MAG3 moiety, which chelates [99m]Tc to yield [[99m]Tc]Tc-MAG3-tofersen. [[99m]Tc]Tc-MAG3-tofersen and unlabeled tofersen were intrathecally injected in rats, nonhuman primates (NHPs), and healthy human volunteers (n = 3) via lumbar puncture, followed by SPECT/CT imaging. Tofersen was coadministered at a therapeutic dose. The tracer [[99m]Tc]Tc-MAG3-tofersen was prepared with greater than 99% purity. Results: Findings in rats demonstrated that [[99m]Tc]Tc-MAG3-tofersen was a proxy measure of unlabeled tofersen, and dosimetry was calculated from NHP imaging data. In a clinical study, unlabeled tofersen coadministered with a microdose of [[99m]Tc]Tc-MAG3-tofersen (≤129.5 MBq [3.5 mCi]) was well-tolerated. Human dosimetry estimates were within safe radiation dose levels. Imaging showed consistent distribution of radiolabeled ASO throughout the spinal cord and brain across species, with clearance patterns diverging in humans. Although rats and NHPs demonstrated declining brain concentrations over the study duration, human brain uptake increased during the first 4 h after injection. Additionally, tracer clearance from the spine in rodents and NHPs plateaued after 6 h but continued to decrease in humans. Radiolabeled ASO clearance from the lumbar spine was observed across all species, with peripheral clearance mediated primarily through the liver and kidneys. Broad uptake of the ASO in the brain and spinal cord is consistent with the clinical effects of tofersen observed in individuals with the SOD1-ALS variation. Conclusion: In preclinical and human SPECT/CT studies, [[99m]Tc]Tc-MAG3-tofersen mirrored unlabeled drug distribution, showing broad spinal cord and brain uptake, with some differences in kinetics among species.}, } @article {pmid41233174, year = {2025}, author = {Uchihara, T}, title = {[Success and Failure during Three Centuries of Charcot's Clinical Neuropathology: From Amyotrophic Lateral Sclerosis to Functional Neurological Disorders].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {11}, pages = {1165-1175}, doi = {10.11477/mf.188160960770111165}, pmid = {41233174}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/history/pathology ; Humans ; History, 19th Century ; History, 20th Century ; *Nervous System Diseases/history/pathology ; Hysteria/history ; *Neuropathology/history ; }, abstract = {Clinical neuropathology was advanced by Charcot at la Salpêtrière Hospital in the 19th century. The lower and upper motor signs of amyotrophic lateral sclerosis were corroborated at autopsy by degeneration of the anterior horns and lateral columns, respectively. The redefinition of paralysis agitans as Parkinson's disease was substantiated in the 20th century through a series of pathological, biochemical, and genetic studies that provided definitive, museum-like evidence of neurological diseases. In contrast to these scientific achievements, the phenomenology of hysteria was publicly evaluated and recognized in front of the audiences that included non-medical professionals. This theater-like format, which encouraged interaction between patients and spectators, might have influenced the clinical presentation of hysteria and complicated its interpretation. Contrary to Charcot's expectations, attempts to identify the causative lesions of hysteria were unsuccessful. Paradoxically, however, this failure paved the way for the development of dynamic psychiatry by Freud and Janet, and later, the conceptualization of functional neurological disorders in the 21st century.}, } @article {pmid41233177, year = {2025}, author = {Ando, T and Fukutake, T}, title = {[Charcot and Spinal Cord Disease].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {11}, pages = {1194-1200}, doi = {10.11477/mf.188160960770111194}, pmid = {41233177}, issn = {1881-6096}, mesh = {Humans ; *Spinal Cord Diseases/history/pathology/diagnosis ; History, 19th Century ; *Arthropathy, Neurogenic/history ; }, abstract = {This paper outlines the contributions of Jean-Martin Charcot (1825-1893) to the study of spinal cord diseases. Charcot pioneered the anatomoclinical method, which correlated clinical symptoms with pathological findings through detailed observations and autopsies. He elucidated the dual structure of the motor system-gray and white matter-and established the clinical and pathological framework of amyotrophic lateral sclerosis, distinguishing it from other disorders. He also contributed to the understanding of tabes dorsalis by linking sensory ataxia to lesions of the dorsal columns and roots, and identified neurogenic joint disease (Charcot joint). Furthermore, Charcot described compressive myelopathy based solely on clinical signs and postmortem findings, highlighting the importance of symptom distribution, such as hand muscle atrophy, in the differential diagnosis. His legacy continues to influence modern neurology, reinforcing the value of precise clinical observation in the diagnostic process.}, } @article {pmid41233180, year = {2025}, author = {Fukutake, T}, title = {[Charcot and Sherlock Holmes: The Contemporary Rise of Neurodiagnostics and Detective Science and Its Significance].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {11}, pages = {1221-1229}, doi = {10.11477/mf.188160960770111221}, pmid = {41233180}, issn = {1881-6096}, mesh = {*Neurology/history/methods ; History, 19th Century ; *Nervous System Diseases/diagnosis ; Literature/history ; Humans ; }, abstract = {Jean-Martin Charcot (1825-1893) gradually shifted his medical interest from internal medicine to neurology. Furthermore, he established neurodiagnostic methods that emphasized observation, such as in tabes dorsalis, and summarized core neurological diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and multiple sclerosis in a clinical-anatomical/pathological manner. For his contributions, he is known as the father of neurology. He then worked to elucidate hysteria. Sir Arthur Conan Doyle (1859-1930), born more than 30 years later, opened an ophthalmology clinic after earning his doctorate in research on tabes dorsalis. However, he then changed direction to writing books, such as Sherlock Holmes stories, and created full-fledged detective studies. Later, he shifted his focus to spiritualism, with an interest in Charcot's hypnotism. Although their careers are similar, there is no direct connection between Charcot's neurological studies and Conan Doyle's detective stories. However, neurodiagnostic and detective studies emerged in the second half of the 19th century at the same time, although they shared a commonality in content, in that they both emphasized observation and deduction without preconceptions. This contemporaneity was inevitable, as the background to this was the emergence of a middle class and urbanization in the era of war and revolution under capitalism after the Industrial Revolution.}, } @article {pmid41233462, year = {2025}, author = {Cattaneo, M and Bonanomi, M and Chirizzi, C and Malacarne, C and Giagnorio, E and Farinazzo, G and Bonanno, S and Porro, D and Lauria, G and Metrangolo, P and Bombelli, FB and Gaglio, D and Marcuzzo, S}, title = {Metabolic reprogramming in amyotrophic lateral sclerosis ependymal stem cells by FM19G11 nanotherapy.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {39847}, pmid = {41233462}, issn = {2045-2322}, support = {1157625//Fondazione Regionale per la Ricerca Biomedica POR FESR/ ; IR0000010//Italian Ministry of University and Research (MIUR)-ELIXIR-IT through the empowering project ELIXIRNextGenIT/ ; T4-AN-09//CALabria HUB per Ricerca Innovativa ed Avanzata/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy ; Animals ; Mice ; Male ; *Nanoparticles/chemistry ; *Ependyma/metabolism/cytology/pathology/drug effects ; *Stem Cells/metabolism/drug effects ; Metabolomics ; Metabolome/drug effects ; Mice, Transgenic ; Disease Models, Animal ; *Cellular Reprogramming/drug effects ; Motor Neurons/metabolism ; Humans ; Metabolic Reprogramming ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons in the motor cortex, brainstem, and the spinal cord. In response to neurodegeneration, spinal cord exhibits ineffective regenerative attempt, thus suggesting that therapeutic strategies aimed at enhancing regenerative capacity of ependymal stem/progenitor cells (epSPCs), residing in the spinal cord, could promote neurogenesis. Dysregulated levels of metabolites might disturb epSPC differentiation, and their restoration might favour neurogenesis. This study aimed to investigate the metabolomic profile of epSPCs from ALS mice to identify altered metabolites as novel therapeutic targets for precision treatment. We performed a metabolome analysis to investigate changes in epSPCs from ALS compared to control male mice (B6SJL-Tg (SOD1*G93A)1Gur/J) and treated the epSPCs with FM19G11-loaded nanoparticles (NPs) to reestablish metabolic balance. Metabolomics analysis revealed significant changes in ALS epSPCs compared to controls. In vitro treatment with FM19G11-loaded nanoparticles (NPs) restored key metabolic networks, particularly in pathways related to glucose, glutamate and glutathione metabolism. These findings highlight the potential of FM19G11-loaded NPs to revert metabolic dysregulation in ALS epSPCs, providing a basis for innovative metabolic therapies and precision medicine approaches to counteract motor neuron degeneration in ALS and other motor neuron diseases.}, } @article {pmid41234489, year = {2025}, author = {Chan, JM and Romano, C and Lee, AY and Wang, S and Lombardo, D and Kamdar, F and Dora, M and Khan, S and Mammen, P and Kimonis, V}, title = {Cardiomyopathy in valosin-containing protein multisystem proteinopathy: Evaluation, diagnosis, and management.}, journal = {American heart journal plus : cardiology research and practice}, volume = {60}, number = {}, pages = {100644}, pmid = {41234489}, issn = {2666-6022}, support = {UM1 TR004927/TR/NCATS NIH HHS/United States ; }, abstract = {Valosin-containing protein (VCP)-associated multisystem proteinopathy is a rare, autosomal dominant disease that affects skeletal muscle, bone, central nervous system, and the heart. While VCP mutations are well established as causing inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis, their role in cardiomyopathy remains underrecognized. This review aims to evaluate the pathophysiology, diagnostic approach, and management of VCP-associated cardiomyopathy to provide a framework for clinical care and future research. Emerging evidence from animal models and human case studies suggests that VCP dysfunction disrupts cardiomyocyte homeostasis, impairs protein degradation, and alters mitochondrial function, leading to maladaptive cardiac remodeling and susceptibility to dilated or hypertrophic cardiomyopathy. Echocardiographic studies in patients with VCP variants reveal a significant prevalence of diastolic dysfunction, conduction abnormalities, and variable degrees of systolic impairment. Despite these findings, there are no standardized guidelines for the diagnosis and management of VCP-associated cardiomyopathy. Current treatment strategies are extrapolated from heart failure guidelines, incorporating neurohormonal blockades with angiotensin-converting enzyme inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. Our review highlights the need for systematic screening protocols, genotype-phenotype correlation studies, and the development of targeted therapies. Future research should focus on identifying biomarkers for early detection, elucidating the molecular mechanisms underlying cardiac dysfunction, and assessing the efficacy of novel treatment strategies. Recognizing VCP-associated cardiomyopathy as a distinct clinical entity will facilitate earlier diagnosis, improve patient outcomes, pave the way for disease-specific therapeutic interventions and insights into the mechanism for isolated cardiomyopathy.}, } @article {pmid41237982, year = {2025}, author = {Streltsov, VA and Ganio, KE and Nuttall, SD and Hernandez, JA and Dennys, CN and Crouch, PJ and Estevez, AG and Franco, MC and Beckman, JS and Roberts, BR}, title = {The structure, redox chemistry and motor neuron toxicity of heterodimeric zinc-deficient SOD1-implications for the toxic gain of function observed in ALS.}, journal = {Neurobiology of disease}, volume = {217}, number = {}, pages = {107189}, pmid = {41237982}, issn = {1095-953X}, support = {R01 AG070937/AG/NIA NIH HHS/United States ; R01 AG085587/AG/NIA NIH HHS/United States ; R01 NS102479/NS/NINDS NIH HHS/United States ; U01 AG061357/AG/NIA NIH HHS/United States ; //Emory start-up, National Health and Medical Research Council (NHMRC) project/ ; }, mesh = {*Motor Neurons/metabolism/drug effects/pathology ; *Superoxide Dismutase-1/chemistry/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Zinc/deficiency/metabolism ; Animals ; Humans ; Oxidation-Reduction ; *Superoxide Dismutase/chemistry/genetics/metabolism ; Rats ; Cells, Cultured ; Mutation ; Gain of Function Mutation ; }, abstract = {A subset of familial cases of amyotrophic lateral sclerosis (fALS) are caused by mutations to copper, zinc superoxide dismutase (Cu, Zn SOD1). Over 200 mutations to SOD1 that have been associated with fALS and the majority of these mutations are dominantly inherited. Thus, individuals are heterozygous and express both wild-type SOD1 and the mutant form of the protein. Paradoxically, the motor neuron disease accelerates in rodent models that mimic the co-expression of wild-type SOD1 with mutant fALS SOD1. Previously, we have shown that the loss of zinc from SOD1 triggers motor neuron death in culture due to a gained, redox activity catalyzed by the active-site copper. Furthermore, motor neuron toxicity of zinc-deficient SOD1 is enhanced by wild-type Cu, Zn SOD1. Because SOD1 exists as a non-covalent dimer, the enhanced toxicity might result from stabilization of the heterodimeric interface between zinc-deficient SOD1 and Cu, Zn-SOD1. However, experimentation with the heterodimer is difficult because SOD1 subunits exchange in minutes. To better characterize the role of dimer stabilization on the enhanced toxicity of fALS mutant SOD1 by wild type SOD1, we genetically tethered a zinc-deficient SOD1 subunit with a Cu, Zn SOD1 subunit with a 16-residue linker. The x-ray structure of the tethered heterodimer showed that the zinc-deficient subunit adopts a wild-type-like conformation and is not misfolded. The heterodimer intermediate also produced peroxynitrite from nitric oxide, and the tethered SOD1 was strikingly toxic to primary cultures of motor neurons. This work supports the concept that zinc-deficient SOD1 is a likely toxic intermediate in ALS. Furthermore, the wild-type allele in human familial-SOD1 ALS patients may physically contribute to the dominant inheritance of SOD1 mutations through heterodimer formation.}, } @article {pmid41238102, year = {2026}, author = {Long, J and Liu, S and Shi, Y and Zhang, C and Qin, L and Ai, Q}, title = {Targeting lipid metabolism in neurodegenerative diseases: From experimental to clinical.}, journal = {Metabolism: clinical and experimental}, volume = {175}, number = {}, pages = {156436}, doi = {10.1016/j.metabol.2025.156436}, pmid = {41238102}, issn = {1532-8600}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Lipid Metabolism/drug effects/physiology ; Animals ; Brain/metabolism ; }, abstract = {The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases-including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)-are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.}, } @article {pmid41238191, year = {2025}, author = {Yang, Y and Wang, Q and Wang, Z and Wang, Y and Liu, B and Zhang, Y and Mao, X and Sun, H}, title = {The role of fatty acids in neurodegenerative diseases: mechanistic insights and therapeutic strategies.}, journal = {Journal of lipid research}, volume = {66}, number = {12}, pages = {100944}, pmid = {41238191}, issn = {1539-7262}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; *Fatty Acids/metabolism/therapeutic use ; Animals ; Gastrointestinal Microbiome ; Blood-Brain Barrier/metabolism ; }, abstract = {FAs play multifaceted roles in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review systematically summarizes current understanding of FA metabolism and its diverse implications in neurodegenerative diseases pathology. Short-chain FAs, primarily generated by gut microbiota, regulate neuroinflammation, gut-brain communication, and blood-brain barrier integrity via epigenetic modifications and immune modulation. Medium-chain FAs exhibit therapeutic potential by improving energy metabolism and neuromuscular function, particularly in amyotrophic lateral sclerosis models. Long-chain PUFAs, notably DHA and EPA, contribute to neuronal membrane integrity, synaptic plasticity, and antioxidant defense, mitigating oxidative stress and neuroinflammation. Conversely, saturated and certain n-6 FAs may exacerbate neurodegeneration through proinflammatory and oxidative pathways. Emerging evidence highlights FA involvement in key pathological processes such as lipid peroxidation, mitochondrial dysfunction, ferroptosis, and blood-brain barrier disruption. Therapeutically, targeted supplementation, dietary modification, microbiome manipulation, and advanced nanotechnology-based delivery systems are promising strategies. Nevertheless, precise therapeutic efficacy depends critically on disease stage, dosage, genetic background, and individual metabolic context. Integrating personalized medicine with precision nutritional strategies and novel drug-delivery platforms offers promising avenues to translate FA-based interventions into clinical practice, potentially improving patient outcomes in the aging global population.}, } @article {pmid41238313, year = {2025}, author = {Rival, M and Thouvenot, E}, title = {Tracing Neurological Diseases in the presymptomatic phase: moving forward a detection panel.}, journal = {Revue neurologique}, volume = {181}, number = {9}, pages = {821-828}, doi = {10.1016/j.neurol.2025.08.004}, pmid = {41238313}, issn = {0035-3787}, mesh = {Humans ; Biomarkers/analysis ; *Nervous System Diseases/diagnosis ; Neurodegenerative Diseases/diagnosis ; Early Diagnosis ; Disease Progression ; *Prodromal Symptoms ; Asymptomatic Diseases ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) often exhibit a prolonged presymptomatic phase during which neuropathological changes silently progress. Recent advances in biomarker research have revealed molecular and imaging signatures that precede clinical onset by years, offering a critical window for early intervention. This review synthesizes current knowledge on the most promising presymptomatic biomarkers across these conditions, highlighting their biological origins, diagnostic performance, and clinical utility. Particular emphasis is placed on the development and validation of biomarker panels, which combine multiple markers to enhance diagnostic sensitivity and specificity, enabling more accurate detection of disease in its earliest stages. Minimally invasive approaches, such as blood-based assays, are also discussed for their potential to facilitate widespread screening and longitudinal monitoring. As these biomarkers begin to integrate into clinical workflows, particularly in AD and MS, international collaboration will be essential to standardize methodologies and ensure equitable implementation. Ultimately, presymptomatic biomarkers hold transformative potential for shifting neurology toward a proactive and precision-based paradigm.}, } @article {pmid41238318, year = {2025}, author = {Soriani, MH and Blasco, H and Corcia, P and Danel-Brunaud, V and Desmaison, A and Pradat, PF and Querin, G and Vourch, P and Guy, N}, title = {Markers of presymptomatic amyotrophic lateral sclerosis: State of the art, practical implications and perspectives.}, journal = {Revue neurologique}, volume = {181}, number = {9}, pages = {893-908}, doi = {10.1016/j.neurol.2025.07.008}, pmid = {41238318}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy/blood ; *Biomarkers/analysis/blood ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an identified genetic origin in 10-15% of cases, mainly involving C9orf72 and SOD1 mutations. The increasing number of genetically confirmed ALS cases has led to a growing identification of asymptomatic mutation carriers. While riluzole remains the standard treatment, mutation-specific therapies such as tofersen, that was recently approved in SOD1-ALS, are emerging. In this context, the identification of presymptomatic biomarkers is crucial for monitoring genetically at-risk individuals. Plasma neurofilament light chain can increase up to 3.5years before symptom onset in C9orf72 carriers. Metabolic and neuroimaging alterations together with cognitive or behavioral changes, that are sometimes detectable decades prior to diagnosis, have also been observed. These biomarkers may support early surveillance and intervention strategies. The present review provides an overview of current evidence on presymptomatic biomarkers in ALS mutation carriers and their potential role in genetic counseling, monitoring, and early therapeutic decisions.}, } @article {pmid41238422, year = {2026}, author = {Liguori, F and Amadio, S and Angioli, C and Ferriero, A and Passaro, I and Alberti, F and Vernì, F and Volonté, C}, title = {Validation in Drosophila of the in silico predicted clomipramine as repurposable for SOD1-ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {1}, pages = {e00793}, pmid = {41238422}, issn = {1878-7479}, mesh = {Animals ; *Clomipramine/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Superoxide Dismutase-1/genetics ; Humans ; *Drug Repositioning/methods ; Disease Models, Animal ; Drosophila ; *Computer Simulation ; Animals, Genetically Modified ; Drosophila melanogaster ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration and muscle weakness, generally leading to death due to respiratory failure within 2-5 years of symptom onset. Current Food and Drug Administration-approved drugs -riluzole, edaravone, and tofersen - offer limited clinical benefit due to ALS multifactorial etiology and high heterogeneity. To bypass this therapeutic letdown, we previously exploited network medicine and drug repurposing strategies. Leveraging the SAveRUNNER algorithm, we identified several potentially repurposable candidates, including clomipramine (Anafranil®), mianserin (Lantanon®/Tolvon®), and modafinil (Provigil®). Here, we evaluated the in vivo efficacy of these compounds in Drosophila models of ALS, precisely those expressing pan-neuronal human SOD1[A4V] or SOD1[G85R] mutations. Our results demonstrate that clomipramine is the most promising candidate, ameliorating lifespan reduction, improving climbing abilities, and mitigating both genomic instability and inflammation, key pathological hallmarks of these SOD1-ALS models. Despite needing further validation in higher organisms, our Drosophila findings represent preliminary yet significant support for clomipramine's action as an add-on treatment for SOD1-ALS.}, } @article {pmid41238595, year = {2025}, author = {Lee, SK and El Ghazaoui, E and Kweon, JJ and Lee, S and Parq, JH}, title = {Hyperconnected amorphous oxide networks under compression.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {9930}, pmid = {41238595}, issn = {2041-1723}, support = {NRF-2020R1A3B2079815/0409-20240067//National Research Foundation of Korea (NRF)/ ; }, abstract = {Irreversibly densified oxide glass under extreme deformation exhibits unexpected softening with plasticity, while the glass network typically becomes rigid as it densifies. These distinct mechanical responses in amorphous networks remain puzzling at the atomic level. Understanding this behavior requires knowledge of how the network entangles and connects under high pressure. Here, our measurements on densified amorphous oxides under irreversible densification via magnetic resonance spectroscopy provide evidence of enhanced network entanglement and, consequently, hyperconnectivity, as highlighted by an increase in highly coordinated Al's and their spatial proximity. The results reveal that configurational diversity in prototypical amorphous Al2O3 under irreversible densification is more prominent than those of other complex oxide glasses, reaching hyperconnected under much lower pressures. In general, attainment of configurational diversity at lower pressures is promoted by increasing field strength of non-network cations in glasses under irreversible densification. The enhanced connectivity with increasing densification allows us to postulate the origin of mechanical responses in glass networks. Particularly, attainment of hyperconnectivity under lower pressures may promote network flexibility during deformation. This conceptual protocol enables control of dual mechanical responses in glasses under extreme stress, guiding the discovery of super-hard densified glasses for technological innovation and accounting for the weakening of hyperconnected glasses in planetary interiors.}, } @article {pmid41238908, year = {2026}, author = {Le, Y and Liu, G and Wu, S and Nissenbaum, M and Kusnecov, AW and Furmanski, P and Birge, RB and Zhou, R}, title = {AAV-mediated BDNF and GAS6 muscle delivery delays disease onset in SOD1[G93A] ALS mice.}, journal = {Gene therapy}, volume = {33}, number = {4}, pages = {462-473}, pmid = {41238908}, issn = {1476-5462}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; Female ; Male ; *Genetic Therapy/methods ; Mice ; *Brain-Derived Neurotrophic Factor/genetics/metabolism ; *Dependovirus/genetics ; Genetic Vectors/administration & dosage ; Disease Models, Animal ; *Intercellular Signaling Peptides and Proteins/genetics/metabolism ; Muscle, Skeletal/metabolism ; Growth Arrest-Specific Protein 6 ; Gene Therapy Agents ; Motor Neurons/metabolism ; Superoxide Dismutase-1/genetics ; Mice, Transgenic ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, with limited treatments. Gene therapy offers an alternative strategy for treating a large portion of ALS patients, however, the disparate genetic alterations in ALS complicate the development of gene therapies. Tyrosine receptor kinase B (TRKB) and Tyro3 receptors are highly expressed in mouse spinal cord motor neurons, suggesting that their ligands, brain-derived neurotrophic factor (BDNF) and growth arrest-specific 6 (GAS6), respectively, are crucial for neuronal survival. In this study, we tested whether genetically induced and muscle tissue-specific expression of such survival-enhancing ligands would ameliorate symptom development in the SOD1[G93A] ALS mouse model. The therapeutic vectors (AAV-Pmus7-HuBDNF-teLuc or AAV-Pmus7-HuGAS6), or a control vector (AAV-Pmus7-teLuc) were injected intravenously via the retro-orbital route and intramuscularly into the hindlimb skeletal muscle of six-week-old mice. Treatment with the therapeutic vectors delayed disease onset and slowed progression in both male and female mice. Interestingly, a sex-specific response was observed, with female mice benefiting more from the treatments than males. Lumbar motor neuron survival was more sustained in the therapeutic vector-treated group compared to control vector group. No statistically significant extension of lifespan was observed in the treated groups.}, } @article {pmid41238911, year = {2026}, author = {Gao, G and Sumrall, ER and Walter, NG}, title = {Nanoscale domains govern local diffusion and ageing within fused-in-sarcoma condensates.}, journal = {Nature nanotechnology}, volume = {21}, number = {2}, pages = {249-258}, pmid = {41238911}, issn = {1748-3395}, support = {R35 GM131922/GM/NIGMS NIH HHS/United States ; GM131922//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; DGE2241144//National Science Foundation (NSF)/ ; NS097542//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; Diffusion ; *RNA-Binding Protein FUS/chemistry/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; *RNA/chemistry/metabolism ; *Biomolecular Condensates/chemistry/metabolism ; }, abstract = {Biomolecular condensates regulate cellular physiology by sequestering and processing RNAs and proteins, yet how these processes are locally tuned within condensates remains unclear. Moreover, in neurodegenerative diseases such as amyotrophic lateral sclerosis, condensates undergo liquid-to-solid phase transitions, but capturing early intermediates in this process has been challenging. Here we present a surface multi-tethering approach to achieve intra-condensate single-molecule tracking of fluorescently labelled RNA and protein molecules within liquid-like condensates. Using RNA-binding protein fused-in-sarcoma as a model for condensates implicated in amyotrophic lateral sclerosis, we discover that RNA and protein diffusion is confined within distinct nanometre-scale domains, or nanodomains, which exhibit unique connectivity and chemical environments. The properties of these nanodomains are tunable by guest molecules. As condensates age, nanodomains reposition, facilitating fused-in-sarcoma fibrilization at the condensate surface, a process further enhanced by anti-amyotrophic lateral sclerosis drugs. Our findings demonstrate that nanodomain formation governs condensate function by modulating the residence time and spatial organization of constituent biomolecules, providing previously unattainable insights into condensate ageing and mechanisms underlying disease.}, } @article {pmid41239785, year = {2025}, author = {Inoue, K and Fujimura, H and Ueda, K and Nishio, H and Naruse, H and Izumi, Y}, title = {An Autopsy Case of ALS Which Clinically Presented Sporadic Adult-Onset Lower Motor Neuron Disease and Genetically Had p. Leu127Ser (L126S) Variant in SOD1 and SMN2 Deletion.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {45}, number = {6}, pages = {e70032}, doi = {10.1111/neup.70032}, pmid = {41239785}, issn = {1440-1789}, support = {25wm0625126s0301//Japan Agency for Medical Research and Development/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Male ; Adult ; *Superoxide Dismutase-1/genetics ; Autopsy ; *Survival of Motor Neuron 2 Protein/genetics ; Middle Aged ; Motor Neurons/pathology ; }, abstract = {Herein, we report an autopsy case of sporadic amyotrophic lateral sclerosis (ALS) with a p. L127S (L126S) SOD1 variant, SMN2 deletion and one hybrid SMN. A 43-year-old Japanese man noticed muscle weakness in his left lower extremity. At the age of 51, his muscle strength was moderately diminished in the upper extremities and severely in the lower extremities with hyporeflexia. At the age of 55, he started noninvasive intermittent ventilation (NIV) during nighttime. At the age of 57, he developed dysphagia and died of pneumonia. The total clinical course was 14 years and 8 months (13 years 9 months until NIV). Pathologically we found severe loss of lower motor neurons, moderate neuronal loss in Clarke's nuclei and mild grumose degeneration of the dentate nucleus. The primary motor cortex was well preserved and the pyramidal tracts showed vague myelin pallor in the lumbar cord. There were a few conglomerate hyaline inclusions (CHIs) that were negative for Bodian staining. Immunohistochemically, CHIs were positive for phosphorylated neurofilament (pNF) and were stained with Uq and SOD1 to varying degrees. Some CHIs contained granular-like components positive for p62. A post-mortem genetic test revealed that the patient had 2 copies of SMN1, 0 copies of SMN2, and one hybrid gene with exon 1 to 7 of SMN2 and SMN1 exon 8. Additional gene research elucidated a heterozygous SOD1 p. Leu127Ser (L126S) mutation. Compared to previous reports of ALS with the same mutation, the distribution of degenerative lesions was similar. It has been suggested that SMN2 deletion may not be directly implicated in lower motor neuron pathology, but further research is needed to confirm this. Further accumulation of cases is necessary to determine the effect of SMN2 on SOD1-ALS.}, } @article {pmid41239791, year = {2025}, author = {Bassi, P and Rana, S and Sapra, V and Raina, A and Kumar, P and Devi, S}, title = {Exploring Novel Therapeutic Avenues: Drug Repurposing for Neurodegenerative Movement Disorders.}, journal = {Current drug research reviews}, volume = {17}, number = {3}, pages = {375-393}, pmid = {41239791}, issn = {2589-9783}, mesh = {Humans ; *Drug Repositioning/methods ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Movement Disorders/drug therapy ; }, abstract = {Neurodegenerative movement disorders, encompassing conditions such as Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, represent a significant burden on individuals, families, and healthcare systems globally. Traditional drug discovery approaches for these disorders have encountered challenges, including high costs and lengthy timelines. Drug repurposing has emerged in recent years as a promising approach to expedite the discovery of new treatments by leveraging existing drugs approved for other indications. This review explores the landscape of drug repurposed for neurodegenerative movement disorders, highlighting promising candidates, underlying mechanisms, and clinical implications. The rationale behind repurposing, including the advantages of utilizing existing pharmacological agents with established safety profiles and known pharmacokinetics, along with techniques utilized for repurposing (computational and experimental), have been elaborated. Several studies on the potential of pre-existing drugs such as isradipine, tetracycline, ambroxol, metformin, deferiprone, simvastatin, etc., which have been repurposed for neurodegenerative movement disorders, including Parkinson's disease, Huntington's disease, Alzheimer's disease, Multiple Sclerosis, etc. have been discussed. Further, the current scenario and future prospective of drug repurposing have also been touched upon.}, } @article {pmid41239797, year = {2025}, author = {Garg, N and Dhankhar, S and Dhariya, A and Parkash, C and Chauhan, S and Singh, TG}, title = {Role of Liposomes in the Treatment of Neurodegenerative Disorders: A Comprehensive Review.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {25}, number = {4}, pages = {496-512}, pmid = {41239797}, issn = {1875-6166}, mesh = {Humans ; *Liposomes/metabolism/chemistry ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Drug Delivery Systems/methods ; *Neuroprotective Agents/administration & dosage/therapeutic use ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {The complex etiology and limited therapy options of neurodegenerative illnesses pose daunting challenges to modern medicine. Nonetheless, novel treatment approaches have exciting new possibilities because of developments in nanotechnology. Liposomes have garnered a lot of interest as a potential treatment for neurological illnesses due to the fact that they are able to adapt to their role as nanocarriers. This review article discusses various uses of liposomes, including their ability to help treat neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, as well as their diagnostic and neuroprotective uses. Liposomes allow for the targeted delivery of medicines to specific brain areas with minimal systemic side effects since they encapsulate and carry therapeutic molecules across the blood-brain barrier. Due to the fact that they are biocompatible, have surface features that can be adjusted, and have the ability to co-deliver many drugs, liposomes are excellent candidates for combination therapy and personalized medicine procedures. In spite of this, there is a growing body of research that suggests liposomes could serve as a versatile platform for the improvement of neurodegenerative disease treatment. This is a positive sign for the future results of patients and their quality of life.}, } @article {pmid41240362, year = {2026}, author = {Cogan, G and Houot, M and Bogoin, J and Noël, S and Larcher, K and David, I and Moreau, P and Bensalah, M and Fauret-Amsellem, AL and Lamari, F and Khrouf, W and Etcharry-Bouyx, F and Didic, M and Lagarde, J and Jagot, CR and Sarazin, M and Boutoleau-Bretonniere, C and Pasquier, F and Bombois, S and Auriacombe, S and Pariente, J and Chaussenot, A and Levy, R and Wallon, D and Zarea, A and Le Ber, I and LeGuern, E and Clot, F}, title = {The genetic landscape of frontotemporal lobar degeneration: investigation of a diagnostic cohort of 2747 probands.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {7}, pages = {2438-2448}, doi = {10.1093/brain/awaf423}, pmid = {41240362}, issn = {1460-2156}, mesh = {Humans ; *Frontotemporal Lobar Degeneration/genetics/diagnosis/blood ; Progranulins/genetics/blood ; C9orf72 Protein/genetics ; Female ; Aged ; Cohort Studies ; Intercellular Signaling Peptides and Proteins/genetics/blood ; Male ; Middle Aged ; Genetic Testing/methods ; Age of Onset ; DNA Repeat Expansion ; Proteins/genetics ; Aged, 80 and over ; }, abstract = {Genetic factors play an important role in frontotemporal lobar degeneration (FTLD), with about 20 genes reported to be involved. Although it is known that genetic diagnostic yield depends on age at onset, clinical subtype and family history, there are no precise indication criteria for a cost-effective and efficient strategy in a clinical setting. We report the molecular diagnostic experience in a French clinical laboratory in a large cohort of 2747 probands with sporadic or familial FTLD. We used a three-step genetic screening strategy. First, plasma progranulin was measured in all cases (n = 2747), followed by screening for GRN when plasma progranulin was below the threshold. If GRN screening was negative, the second step was to investigate the G4C2 repeat expansion in C9orf72 (n = 2675). In a third step, targeted sequencing of 14 FTLD genes was performed in 1279 individuals depending on age at onset and family history. The diagnostic yield of this strategy was 12.2% (n = 334). GRN (n = 73) and C9orf72 (n = 200) represented 81.7% of genetic diagnoses. The diagnostic yield of the panel sequencing was 4.8% (62/1279). Family history was the strongest factor related to genetic diagnosis, with four to five times more genetic diagnoses in cases with a family history of FTLD (32.1%) compared with sporadic cases (7.2%). However, the clinical presentation was not significantly associated with a genetic mutation, the behavioural variant of frontotemporal dementia (bvFTD) associated with amyotrophic lateral sclerosis (FTD/ALS), or not produced at a higher diagnostic yield (15.5% and 13.3%, respectively) than the primary progressive aphasia subgroup (9.9% for semantic variant and 8.8% for non-fluent variant) and others (8.3% and 4.2% for progressive supranuclear palsy and corticobasal syndrome, respectively). Interestingly, the genetic distribution varied greatly between clinical subtypes. FTD/ALS and bvFTD were mostly driven by C9orf72 (82.1% and 63.5%, respectively). In contrast, GRN was shown to be the dominant gene in nfvPPA (41.2%). C9orf72, MAPT, GRN and TBK1 equally contributed to svPPA (around 20% each). These results allow us to show the phenotype-genotype architecture of FTLD and to provide data to establish a cost-effective genetic diagnostic strategy in clinical settings for FTLD.}, } @article {pmid41240557, year = {2026}, author = {Jia, H and Chang, Y}, title = {Real-time photoelectric sensing of edaravone for therapeutic efficacy in amyotrophic lateral sclerosis.}, journal = {Journal of colloid and interface science}, volume = {704}, number = {Pt 2}, pages = {139457}, doi = {10.1016/j.jcis.2025.139457}, pmid = {41240557}, issn = {1095-7103}, mesh = {*Edaravone/therapeutic use/analysis ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Electrochemical Techniques/methods ; Photochemical Processes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) requires precise therapeutic monitoring of Edaravone, but current methods lack real-time capability. Herein, we developed a photoelectrochemical (PEC) sensor using a Bi4Ti3O12/BiOBr heterojunction for ultrasensitive Edaravone detection. The heterojunction interface enables Type II band alignment, facilitating efficient charge separation through electron transfer from BiOBr conduction band to Bi4Ti3O12 and hole migration in reverse, synergistically suppressing recombination. XRD, XPS, and HRTEM confirm the composite's crystal structure and intimate interface. UV-Vis DRS shows redshifted absorption (470 nm) with enhanced visible-light utilization, while PL quenching verifies improved charge dynamics. Under optimized conditions (0.4 V, pH = 7), the sensor exhibits linear response (0.1-10 μM) with 0.031 μM detection limit, high stability (92 % retention over 1500 s), and reproducibility (RSD 2.8 %). DFT calculations reveal modified interfacial charge distribution and narrowed bandgap (2.197 eV), enhancing optical absorption and conductivity. While machine learning analysis of ALS clinical trial data identifies Edaravone's superior efficacy (ALSFRS-R decline -5.04 ± 1.27) and patient subgroup responsiveness, enabling personalized therapeutic prediction. This novel integrated platform bridges material engineering, real-time sensing, and data analytics for ALS precision medicine.}, } @article {pmid41241727, year = {2025}, author = {Sironi, F and Tortarolo, M and Mazzucchi, S and Camporeale, L and Freschi, M and Arcadipane, E and De Giovanetti, G and Kurosaki, M and Terao, M and Parlanti, P and Podini, P and Gentile, F and Bonetto, V and Cappello, V and Riva, N and Quattrini, A and Bendotti, C}, title = {Loss of C9orf72 impacts the peripheral neuromuscular system via immune dysregulation and accelerates the progression of amyotrophic lateral sclerosis in SOD-1 mutant mice.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {272}, pmid = {41241727}, issn = {1742-2094}, support = {Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/immunology/metabolism ; *C9orf72 Protein/genetics/deficiency/metabolism ; Mice ; *Superoxide Dismutase-1/genetics ; Disease Progression ; Mice, Transgenic ; *Neuromuscular Junction/pathology/metabolism/immunology ; Disease Models, Animal ; Mutation/genetics ; Motor Neurons/metabolism/pathology ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder where neuromuscular health is central to disease progression. The degeneration of motor neurons (MNs) leads to muscle weakness and paralysis, underscoring the critical importance of neuromuscular junctions (NMJs) and axonal integrity. Among the genetic contributors to ALS, mutations in the C9orf72 gene are the most common, accounting for both ALS and frontotemporal dementia (FTD). While the role of C9orf72 has been studied across various cells and compartments, its function in the peripheral nervous system (PNS), a compartment crucial for maintaining neuromuscular connectivity in ALS,remains largely unexplored.

MAIN BODY: Our study investigates the role of C9orf72 loss-of-function in ALS, focusing on its neuromuscular effects. C9orf72 expression is localized in MNs, microglia, oligodendrocytes, and Schwann cells (SCs) in the sciatic nerve (SN), but not in astrocytes. The absence of C9orf72 in mice is associated with hypomyelination and axonal sorting defect in the SN, but not with MNs loss in lumbar spinal cord. Additionally, we identified immune dysregulation, with elevated CD8+ T cells transcript and increased major histocompatibility complex I (MHCI) expression in SCs, in association with enhanced NMJ denervation in C9orf72-deficient ALS mice, suggesting a potential contribution of immune dysregulation to disease progression. These changes contributed to NMJ denervation characterized by increase in the expression of acetylcholine receptor gamma (AChRγ). The combination of C9orf72-deficiency with the ALS-linked SOD1G93A mutation resulted in a more severe phenotype and accelerated disease progression, despite no additional spinal MN loss.

CONCLUSION: Our findings underscore the critical role of C9orf72 in maintaining neuromuscular health through its influence on myelination, immune response regulation, and NMJ integrity. Loss of C9orf72 function exacerbates ALS progression by promoting SC dysfunction and immune dysregulation. This highlights the significance of preserving normal C9orf72 function in ALS therapies through antisense oligonucleotides strategies. Furthermore, targeting immune responses and myelination pathways may offer novel avenues for ALS treatment strategies.}, } @article {pmid41242038, year = {2026}, author = {Singh, A and Barasa, L and DeOrsey, L and O'Reilly, MD and Choudhary, S and Cahill, SE and Rossetti, T and Green, RM and Humphries, F and Thompson, PR}, title = {Triazole-based STING inhibitors.}, journal = {Bioorganic & medicinal chemistry}, volume = {132}, number = {}, pages = {118484}, pmid = {41242038}, issn = {1464-3391}, support = {R35 GM118112/GM/NIGMS NIH HHS/United States ; T32 AI095213/AI/NIAID NIH HHS/United States ; T32 AI132152/AI/NIAID NIH HHS/United States ; }, mesh = {*Triazoles/chemistry/pharmacology/chemical synthesis ; Humans ; *Membrane Proteins/antagonists & inhibitors/metabolism ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug ; Signal Transduction/drug effects ; STING Protein ; }, abstract = {Aberrant activation of the DNA sensing cGAS-STING pathway has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus (SLE), and autoinflammatory disorders such as Aicardi-Goutières syndrome (AGS) and STING-associated vasculopathy with onset in infancy (SAVI). Consequently, considerable efforts have been directed toward the development of STING inhibitors. We previously reported that BB-Cl-amidine and LB244 inhibit STING-dependent signalling with nanomolar potency both in vitro and in vivo. The nitrofuran warhead on LB244 provided superior potency and proteome-wide selectivity. Moreover, LB244 mirrored the efficacy of BB-Cl-amidinein vivo. Herein, we describe the development of a series of triazole-based analogues designed to inhibit STING signalling. These efforts led to the development of ASF24, a highly potent inhibitor of STING signalling (IC50 = 0.49 μM). In summary, our findings identify a novel triazole-based STING inhibitor and establish a promising scaffold for the development of therapeutics targeting STING-mediated inflammatory diseases.}, } @article {pmid41242173, year = {2025}, author = {McFarlane, R and Ross, R and Domhnaill, ÉM and Chiò, A and Corcia, P and Ingre, C and McDermott, CJ and Panadés, MP and Shaw, PJ and van Damme, P and van den Berg, L and Al-Chalabi, A and Walsh, C and Hardiman, O}, title = {Dynamic modelling of the ALSFRS-R: leveraging population-based scores using neural networks.}, journal = {EBioMedicine}, volume = {122}, number = {}, pages = {106029}, pmid = {41242173}, issn = {2352-3964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; *Neural Networks, Computer ; Male ; Female ; Middle Aged ; Aged ; Retrospective Studies ; Severity of Illness Index ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder with highly heterogeneous trajectories. The Revised ALS Functional Rating Scale (ALSFRS-R) is challenging to model due to irregularly spaced data and patient-level variability. Here we sought to develop and validate a short-horizon prediction tool leveraging a fully connected neural network (FCNN) to forecast individual ALSFRS-R trajectories, providing a natural history benchmark for trials and clinical practice.

METHODS: We retrospectively analysed 29,992 ALSFRS-R measurements from 5319 people living with ALS (plwALS) in the population-based PRECISION-ALS dataset. plwALS were randomised (80:20) into a training and test cohort using group-based splitting. A three-layer FCNN was built in TensorFlow to predict a third ALSFRS-R score given two historical scores and their respective time intervals. Performance was evaluated on the PRECISION-ALS test set and externally on the PROACT database. Linear extrapolation served as a baseline comparator.

FINDINGS: On the PRECISION-ALS test set, the FCNN achieved a mean absolute error (MAE) of 0.0552 (95% CI 0.0547-0.0576) on a normalised 0-1 scale, corresponding to 2.65 (2.63, 2.76) points on the 48-point ALSFRS-R. This remained consistent across all post-diagnostic periods. The model generalised well to the PROACT dataset, with an improved MAE of 0.0485 (95% CI 0.0481, 0.0489). Linear extrapolation performed significantly worse across all metrics. Error remained consistent across all clinical groups investigated, such as sex, genotype, site of onset, age at diagnosis, age at onset and diagnostic delay.

INTERPRETATION: A short-horizon FCNN can provide clinically interpretable, individualised ALSFRS-R forecasts from sparse, irregularly spaced data. By supporting rapid identification of those who step outside of the model, this approach holds promise for optimising patient counselling, clinical trial monitoring, and early intervention strategies. This approach allows us to better utilise our growing bank of ALS patient data to support decision making.

FUNDING: R McFarlane is supported by a grant from Target ALS, Precision ALS is funded by Taighde Éireann (Research Ireland, formerly Science Foundation Ireland).}, } @article {pmid41242668, year = {2026}, author = {Chethana, HP and Rathan Kumar, U and Chakraborty, G and Sidhu, A}, title = {L-arginine interferes with functional studies of amyloid proteins.}, journal = {Protein expression and purification}, volume = {239}, number = {}, pages = {106854}, doi = {10.1016/j.pep.2025.106854}, pmid = {41242668}, issn = {1096-0279}, mesh = {*Arginine/chemistry/metabolism ; *alpha-Synuclein/chemistry/genetics/isolation & purification/metabolism ; Humans ; Escherichia coli/genetics/metabolism ; Solubility ; *RNA-Binding Protein FUS/chemistry/genetics/isolation & purification/metabolism ; Protein Aggregates ; Recombinant Fusion Proteins/chemistry/genetics/isolation & purification ; }, abstract = {Intrinsically disordered proteins/regions are abundant in cancer signalling pathways and neurodegenerative diseases like Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, etc. Purification of intrinsically disordered proteins can be challenging due to their sticky nature. For intrinsically disordered amyloid proteins, in-vitro aggregation studies are ideal experiments to study their liquid to solid transition. However, over-expression of these proteins in E. coli often results in insoluble protein fraction that ends up in cell-pellet as inclusion bodies, on lysis and centrifugation. Supplementing purification buffers with l-arginine is known to increase the solubility of proteins. For most of the structured proteins increasing solubility translates into a higher yield of functional proteins. However, for aggregation prone proteins associated with neurodegenerative diseases, like α-synuclein (Parkinson's disease), Aβ (Alzheimer's disease), fused in sarcoma (amyotrophic lateral sclerosis), etc. inclusion of l-arginine might interfere with aggregation studies. To test our hypothesis, we purified aggregation prone α-synuclein and fused in sarcoma protein in the presence and absence of l-arginine and studied their fibrillization. While recombinant FUS is difficult to prepare, purification of α-synuclein is well established but in all the protocols a significant amount of protein remains as insoluble fraction in the pellet. Inclusion of l-arginine increases the yield of protein purification by about 3 folds for both the proteins, but the resulting protein does not aggregate into fibrils thus showing that increased solubility of amyloid proteins (α-synuclein and fused in sarcoma) in the presence of l-arginine is not suitable for aggregation studies.}, } @article {pmid41243850, year = {2025}, author = {Bao, W and Hao, Y and Wang, J and Hai, B and Wei, H}, title = {A cobalt-doped Prussian blue analogue as an efficient catalytic confinement matrix for high-performance aluminum-sulfur batteries.}, journal = {Chemical communications (Cambridge, England)}, volume = {61}, number = {98}, pages = {19457-19460}, doi = {10.1039/d5cc05539c}, pmid = {41243850}, issn = {1364-548X}, abstract = {The development of cathode materials that combine effective polysulfide anchoring, and structural robustness is critical for advancing aluminum-sulfur (Al-S) battery performance. Herein, we propose a cobalt-based Prussian blue analogue (CoPBA) with a metal-organic framework structure as a cathode material for Al-S batteries. The S@CoPBA cathode exhibits a discharge capacity exceeding 414.0 mA h g[-1] after 650 cycles at a current density of 100 mA g[-1].}, } @article {pmid41244707, year = {2025}, author = {Baeken, MW and Bekbulat, F and Körschgen, H and Clement, AM and Behl, C}, title = {The sigma-1 receptor as a neurohomeostatic decision hub for GABARAP-mediated receptor trafficking and macroautophagy.}, journal = {Frontiers in molecular biosciences}, volume = {12}, number = {}, pages = {1673249}, pmid = {41244707}, issn = {2296-889X}, abstract = {Gamma-aminobutyric acid receptor-associated protein (GABARAP) is a multifunctional member of the autophagy-related (ATG8) protein family, playing key roles in two distinct cellular pathways: macroautophagy and plasma membrane protein trafficking. In the context of autophagy, GABARAP modulates cargo recognition and supports the maturation and fusion of autophagosomes with lysosomes, a critical step in intracellular clearance and proteostasis. Separately, GABARAP also regulates vesicular receptor protein transport from the Golgi apparatus to the plasma membrane, contributing to proper surface localization and receptor recycling. Both tasks are especially vital for neurons, where protein turnover and receptor localization are tightly linked to synaptic plasticity and neuroprotection. We recently identified a direct interaction between GABARAP and the sigma-1 receptor (σ1R), an ER-resident receptor involved in diverse cellular stress responses, mitochondrial function, and protein homeostasis. Our findings suggest that σ1R acts as an upstream regulatory hub, influencing GABARAP's functional commitment to either membrane trafficking or autophagy. Specifically, we hypothesize that ligand-dependent σ1R activation promotes GABARAP's involvement in macroautophagy at the expense of its role in membrane transport. This regulatory switch may underline part of the neuroprotective effects observed with σ1R agonists in neurodegenerative disease models, where enhanced autophagy is often beneficial. Overall, we discuss the emerging molecular crosstalk between σ1R and GABARAP, its potential impact on neuronal homeostasis, and how σ1R's pharmacological modulation might be leveraged to bias GABARAP function toward autophagy in diseases such as amyotrophic lateral sclerosis, Huntington's, Parkinson's, and Alzheimer's disease.}, } @article {pmid41244779, year = {2025}, author = {Sun, Z and Liu, C and Liu, W and Zhang, M and Ren, S and Gao, L and Ji, Z}, title = {Surgical treatment of autosomal recessive bestrophinopathy with angle-closure glaucoma: vitreous liquefaction as the key to correcting postoperative malignant glaucoma-three case reports.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1560475}, pmid = {41244779}, issn = {2296-858X}, abstract = {PURPOSE: This study aimed to evaluate the surgical treatment of autosomal recessive bestrophinopathy (ARB) combined with angle-closure glaucoma (ACG) through a retrospective case series.

METHODS: The treatment of three patients with ACG secondary to ARB was reviewed. The patients were admitted to the Department of Ophthalmology of Jinan Second People's Hospital from April 2023 to January 2024. Their conditions, treatments, and outcomes were extracted from the medical records and analyzed.

RESULTS: The patients were 48, 48, and 35 years old at the time of surgery. All had bilateral ARB and underwent surgery in the eye more severely affected by ACG. Topical eye drops failed to control the intraocular pressure (IOP), which measured 27, 28, and 47 mmHg before the surgery. The affected eyes also exhibited a shorter axial length (AL) and shallower anterior chamber depth (ACD). The ALs of the surgical eyes measured 22.73 mm, 21.52 mm, and 20.96 mm, while the ACDs were 2.51 mm, 1.97 mm, and 2.19 mm, respectively. After receiving trabeculectomy, they all immediately developed malignant glaucoma, which could not be resolved by conservative treatment. Following a second surgery, which importantly included an anterior vitrectomy and posterior capsulotomy, the IOP was normal, the ACD was satisfactory, and visual function was preserved.

CONCLUSION: For ACG/ARB patients, the risk of developing malignant glaucoma after glaucoma surgery is very high. Surgical intervention, such as anterior vitrectomy, is needed to increase vitreous fluidity, eliminate vitreous block, assist the formation of the anterior chamber, and stabilize the IOP to save the patient's vision. Long-term, close follow-up is essential due to the risk of recurrence in the operated eye and occurrence in the non-operated eyes.}, } @article {pmid41245603, year = {2025}, author = {Almalki, S and Salama, M and Taylor, MJ and Ahmed, Z and Tuxworth, RI}, title = {FUS-related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1671910}, pmid = {41245603}, issn = {1662-5099}, abstract = {Mutations in Fused in Sarcoma (FUS) are associated with neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This systematic review examined the connections between DNA damage in the central nervous system (CNS), dysfunction of DNA repair processes and the FUS proteinopathy. Twelve peer-reviewed publications were analyzed, investigating this question across a range of models, including immortalized cell lines, ALS-FTD patient-derived induced pluripotent stem cells, mouse tissues and post-mortem samples from ALS-FTD patients. The studies also explored the impact of inducing DNA damage using several agents, including calicheamicin and etoposide, on FUS pathology. Our findings indicated that accumulated DNA damage was documented in all twelve studies, with a key finding being the disruption of interactions between FUS and the DNA damage response (DDR). FUS interactions with various DDR and DNA repair proteins involved in sensing DNA damage and executing the major repair pathways were impaired, resulting in elevated levels of DNA damage in both the nucleus and mitochondria. Therefore, FUS is an essential protein for the preservation of genomic integrity and this loss of genome stability is likely to be a key contributor to the neurodegeneration in ALS-FTD.}, } @article {pmid41246229, year = {2025}, author = {Şahin, TÖ and Cemali, Ö and Özdemir, M and Ayten, Ş and Ağagündüz, D}, title = {Flavonoids and phenolic compounds: a promising avenue for neurodegenerative disease therapy.}, journal = {Turkish journal of biology = Turk biyoloji dergisi}, volume = {49}, number = {5}, pages = {635-659}, pmid = {41246229}, issn = {1303-6092}, abstract = {BACKGROUND/AIM: Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are characterized by a progressive loss of nerve cells, for which no definitive cure currently exists. These conditions share common pathological mechanisms, including chronic neuroinflammation, oxidative stress, protein aggregation, and mitochondrial dysfunction. Flavonoids and other plant-derived phenolic compounds have recently attracted attention for the treatment of such conditions due to their antiinflammatory and antioxidant properties. This review explores the neuroprotective mechanisms of flavonoids and evaluates their potential for the prevention and treatment of neurodegenerative diseases.

MATERIALS AND METHODS: A literature search of the Web of Science, PubMed, and ScienceDirect databases was conducted to evaluate the therapeutic potential of flavonoids and phenolic compounds against neurodegenerative diseases. The search terms included "polyphenols", "flavonoids", and related compounds, along with "Alzheimer's", "Parkinson's", "Huntington's", and "Amyotrophic lateral sclerosis". Eligible studies included clinical trials, randomized controlled trials, and in vitro and in vivo research published in English. Priority was given to studies from the last decade, although older but significant publications were also included.

RESULTS: The findings of multiple studies report the ability of flavonoid compounds such as quercetin, myricetin, apigenin, and epigallocatechin gallate (EGCG) to modulate critical signaling pathways, reduce oxidative stress, prevent the accumulation of neurotoxic proteins, and support mitochondrial function. These bioactive molecules have exhibited significant potential in slowing disease progression and preserving neuronal integrity. Their therapeutic application, however, has been limited by their poor bioavailability, low stability, and rapid metabolism.

CONCLUSION: Flavonoids have shown promise as naturally derived agents with multi-targeted activity against neurodegenerative processes. Enhancing their absorption and stability through novel delivery systems and structural modifications could significantly improve their clinical efficacy. When administered early or as a complementary therapy, flavonoids can be considered a safe and effective approach to the management of neurodegenerative diseases.}, } @article {pmid41246746, year = {2025}, author = {Bethea, JP and Sharma, H and Doberstein, N and Shenker, T and Gregory, B and Hoffman, R and Aizenman, D and Guirguis, G and Hoffmann, J and Tazani, S and Harris, Z and Costin, J}, title = {Application of Osteopathic Manipulative Treatment (OMT) in Neurodegenerative Disorders: A Scoping Review.}, journal = {Cureus}, volume = {17}, number = {10}, pages = {e94748}, pmid = {41246746}, issn = {2168-8184}, abstract = {Neurodegenerative diseases are comprised of a host of chronic conditions that impair the central nervous system. Osteopathic manipulative treatment (OMT) consists of many non-invasive modalities that can be used to treat a wide variety of ailments and conditions. OMT is reported to increase the range of motion and lymphatic flow, as well as decrease pain in a wide array of disorders. However, the efficacy of using OMT in neurodegenerative disorders has not been well established. The objective of this scoping review is to map the evidence that pertains to the application of OMT in treating neurodegenerative disorders and identify the gaps in the literature on this subject. This study was designed according to the Joanna Briggs Institute (JBI) guidelines for scoping reviews to gather information on OMT's potential efficacy in managing Parkinson's disease (PD), Alzheimer's disease (AD) dementia, amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Peer-reviewed literature was collected through the Excerpta Medica database (EMBASE), Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), and Web of Science. The criteria were limited to papers in English published between 1999 and 2023. The following search string was utilized: "osteopathic manipulative treatment" OR "osteopathic manipulation" AND "neurodegenerative disorders" OR "Alzheimer's disease" OR "dementia" OR "amyotrophic lateral sclerosis" OR "Parkinson's disease" OR "Huntington's chorea". One hundred and forty-three articles were identified following final screening and critical appraisal, with eleven articles selected for analysis in this study. Data from the selected articles demonstrated that OMT can possibly attenuate symptoms in patients diagnosed with neurodegenerative diseases. Studies in rats showed that OMT techniques were found to alter cholinergic neuronal genes, improve spatial learning and memory, reduce amyloid β protein levels, modulate synaptic transmission, and increase levels of the cytokines IL-1, IL-10, IL-13, RANTES, IL-17A, and EOTAXIN effects in AD dementia. ALS patients demonstrated a high level of satisfaction with OMT and did not report any adverse effects, though there was no decrease in pain or increased quality of life reported. PD patients reported improved postural stability, balance, and gait after OMT. No results were returned regarding OMT's effects on HD. Preliminary results in human PD and ALS patients who received OMT as an adjunct to traditional treatment regimens showed promising results, though few studies were found that address the topic, and the sample sizes of the studies that were found were small. There were no studies of the effects of OMT on human patients with AD or HD found, though preclinical studies in rats supported their trial in subsequent human studies. While current research on the impact of OMT on these neurodegenerative diseases is promising, there remain large gaps in the literature. Further research is necessary to support the use of and long-term efficacy of OMT in neurodegenerative diseases.}, } @article {pmid41247844, year = {2026}, author = {Kawaguchi, T and Yorimoto, K and Kawakami, M and Hara, T and Hanai, A and Miyazaki, Y and Nishida, D and Takahashi, Y and Tsuji, T}, title = {Lung Volume Recruitment Slows Pulmonary Functional Decline and Prolongs Survival in ALS.}, journal = {Journal of neurologic physical therapy : JNPT}, volume = {50}, number = {2}, pages = {79-87}, pmid = {41247844}, issn = {1557-0584}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/therapy ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Vital Capacity/physiology ; }, abstract = {BACKGROUND AND PURPOSE: Few studies have examined the long-term effects of lung volume recruitment (LVR) in amyotrophic lateral sclerosis (ALS). This study aimed to clarify the impact of LVR on respiratory function (Aim 1) and survival (Aim 2).

METHODS: This retrospective cohort included hospitalized patients with ALS who underwent LVR from 2015 to 2020. For Aim 1, longitudinal changes in forced vital capacity (%FVC) were assessed every 3 months before and after LVR. For Aim 2, the survival study, data on sex, onset age, delay in diagnosis, duration of LVR, and subtype were also collected.

RESULTS: A total of 79 patients underwent LVR (Aim 2), 48 patients had %FVC data before and after LVR (Aim 1). Regarding long-term effects on respiratory function (Aim 1), %FVC declined at approximately 2% per month before LVR, with significant decreases observed at 12, 9, and 6 months relative to baseline (P < .001). After LVR, the decline slowed to less than 1% per month, and no significant decreases were observed at 3, 6, 9, or 12 months. In Aim 2, patients continuing LVR ≥6 months had longer survival than those with shorter use. Multivariate Cox regression identified LVR ≥6 months as a prognostic factor (hazard ratio [95% CI] = 0.42 [0.19-0.96], P = .04).

DISCUSSION AND CONCLUSIONS: These findings suggest a potential association between continued LVR and both a slower decline in %FVC and longer survival in patients with ALS. Further prospective studies are warranted to confirm these findings.

VIDEO ABSTRACT AVAILABLE: For more insights from the author (see the Video, Supplemental Digital Content Video, available at http://links.lww.com/JNPT/A552.}, } @article {pmid41248812, year = {2025}, author = {Di Nunzio, M and Mignogna, ML and Bacigaluppi, M and Panina-Bordignon, P and Ragonese, P and Muzio, L and Summa, V and Martino, G}, title = {The role of dopaminergic signalling from physiology to neuroprotection in acute and chronic disorders.}, journal = {Neurobiology of disease}, volume = {217}, number = {}, pages = {107194}, doi = {10.1016/j.nbd.2025.107194}, pmid = {41248812}, issn = {1095-953X}, support = {//European Union - Next Generation EU - NRRP M6C2 - Investmen/ ; }, mesh = {Humans ; Animals ; *Neuroprotection/physiology ; *Signal Transduction/physiology ; *Dopamine/metabolism ; *Neurodegenerative Diseases/metabolism/physiopathology ; Chronic Disease ; }, abstract = {The dopaminergic system plays a central role in neuromodulation, involving motor control, reward, and cognition, and exerting its effects through five G protein-coupled receptors (DRD1-DRD5) with distinct tissue distributions and signalling mechanisms. While dopaminergic alterations are known to be associated to neuropsychiatric and movement disorders such as schizophrenia, Parkinson's disease, and Huntington's disease, growing evidence highlights a broader role in neurological and neurodegenerative conditions. This review explores the dopaminergic system's pathophysiological involvement in acute and chronic diseases such as stroke, spinal cord (SCI), traumatic brain (TBI) injury, and amyotrophic lateral sclerosis (ALS). Beyond characterizing its dysfunction, we aim to examine how this disrupted signalling contributes to the neurodegeneration underlying the neurological and neurodegenerative disorders discussed here, along with the associated pathophysiological factors of inflammation and altered plasticity. We further discuss emerging data supporting the potential of dopamine-based interventions not only to modulate disease mechanisms, but also to confer neuroprotection and reduce tissue damage in both acute and progressive neurodegeneration, while also considering sex-related dopamine alterations. By integrating findings across diverse conditions, we underscore the importance of advancing dopaminergic research beyond classical disease models into novel therapeutic territory.}, } @article {pmid41249720, year = {2025}, author = {Cabras, S and Manera, U and Di Pede, F and Zocco, G and Vasta, R and Novara, A and Minerva, E and Matteoni, E and De Mattei, F and Pellegrino, G and Grassano, M and Iazzolino, B and Palumbo, F and Callegaro, S and Polverari, G and Morbelli, SD and Pardini, M and Chiaravalloti, A and Schillaci, O and Leenders, KL and Kogan, RV and Moglia, C and Calvo, A and Chiò, A and Pagani, M and Canosa, A}, title = {Role of 2-[[18]F]FDG-PET as a biomarker of upper motor neuron involvement in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {12}, pages = {766}, pmid = {41249720}, issn = {1432-1459}, support = {PRIN 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 20228N7573//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; JPND (Strength//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; ALS-Care//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; Brain-Mend)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; Department of Excellence grant//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; 101017598//Horizon 2020/ ; INSPIRED//Fondation Thierry Latran/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Male ; Female ; Middle Aged ; *Fluorodeoxyglucose F18 ; Cross-Sectional Studies ; Aged ; *Positron-Emission Tomography/methods ; *Motor Cortex/diagnostic imaging/metabolism ; *Motor Neurons/metabolism/pathology ; Adult ; Biomarkers/metabolism ; Radiopharmaceuticals ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) affects upper (UMN) and lower (LMN) motor neurons. ALS diagnosis is challenging, especially in predominant LMN phenotypes. Electromyography can disclose LMN damage, while UMN involvement is detectable by clinical examination, with possible support of magnetic resonance imaging (MRI) and transcranial magnetic stimulation. Our aim was to investigate the role of 2-[[18]F]FDG-PET as an UMN biomarker in ALS.

METHODS: In our cross-sectional study, we created an UMN burden score. Performing a multiple regression analysis in SPM12, we evaluated the relationship between UMNBS and brain metabolism. We split ALS cohort based on the UMN burden score median value (group A-under median, group B-above median). We ran a full factorial analysis including group A and B and healthy controls, followed by group comparisons.

RESULTS: We included 118 ALS patients (group A and B, N = 59), with a median UMN burden score of 9.50 and a left lateralization of UMN signs. We found a negative correlation between motor cortex metabolism and UMN burden score. Comparing each ALS group with healthy controls, we found relative hypometabolism in the left frontal lobe and relative bilateral, right-prevalent hypermetabolism of cerebellum and corticospinal tracts. The relative hypermetabolism in corticospinal tracts was more evident in the group with low UMN signs.

CONCLUSIONS: Motor cortex metabolism reflects UMN burden. Corticospinal tracts' metabolic changes could provide information about UMN involvement even in patients with predominant LMN phenotype, suggesting a possible role of brain 2-[[18]F]FDG-PET as an UMN biomarker in ALS patients.}, } @article {pmid41250117, year = {2025}, author = {Kulcsárová, K and Piel, JHA and Schaeffer, E}, title = {Environmental toxins in neurodegeneration - a narrative review.}, journal = {Neurological research and practice}, volume = {7}, number = {1}, pages = {93}, pmid = {41250117}, issn = {2524-3489}, abstract = {As the global incidence of neurodegenerative disorders rises at a rate beyond what can be attributed solely to population aging, the role of modifiable risk factors has come into research spotlight to inform preventive strategies. While many lifestyle interventions can be implemented at an individual level, addressing environmental pollutants that drive neurodegeneration requires a collective effort involving both public and political engagement. This narrative review summarizes current evidence on the role of selected environmental toxins-pesticides, solvents, air pollution, and heavy metals-in the development of Parkinson's Disease, Alzheimer's Disease, and Amyotrophic Lateral Sclerosis. Drawing from epidemiological and experimental studies, we highlight associations between these exposures and neurodegeneration, as well as potential converging pathophysiological mechanisms such as neuroinflammation and proteinopathy. Understanding these links may help inform public health measures aimed at reducing the burden of these diseases.}, } @article {pmid41250565, year = {2025}, author = {Serizawa, S}, title = {Clinical Care Experience of Multidisciplinary Professionals in Amyotrophic Lateral Sclerosis: A Cross-Sectional Study.}, journal = {The Tokai journal of experimental and clinical medicine}, volume = {50}, number = {3}, pages = {112-118}, pmid = {41250565}, issn = {2185-2243}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/psychology ; Humans ; Surveys and Questionnaires ; Cross-Sectional Studies ; *Patient Care Team ; Male ; Female ; *Health Personnel/psychology ; Japan ; Middle Aged ; Adult ; Attitude of Health Personnel ; }, abstract = {OBJECTIVE: To clarify the characteristics of medical care for amyotrophic lateral sclerosis (ALS) by examining the most memorable experiences of multidisciplinary medical professionals involved in patient care.

METHODS: In a questionnaire, "the most impressive thing about the experience" was efficiently categorized using inductive thematic coding. Responses were categorized using keywords, and similar content was categorized using codes. The instances of each quantified item were calculated by expressing them as numbers and frequencies. Furthermore, representative quotations and context-specific nuances were analyzed to investigate the emotional and ethical dimensions of each category.

RESULTS: Questionnaires were distributed to 269 medical professionals treating patients with ALS at three hospitals in the western region of Kanagawa Prefecture. Of these, 164 (60%) responded to the questionnaire, and 143 were included (valid response rate: 53%). Based on the questionnaire responses, the experiences of the medical professionals were classified into 27 categories. Medical professionals are continuously involved in fulfilling the wishes of patients as much as possible, realizing individuality and patient commitment, and intervening without giving up.

CONCLUSION: For multidisciplinary medical professionals involved in the care of patients with ALS in clinical practice, the most memorable experiences coincided with those associated with the challenges of ALS care.}, } @article {pmid41250892, year = {2026}, author = {Aliakbari, F and Volkening, K and Nayeri, Z and Polat, AY and Donison, N and Palik, J and Strong, MJ}, title = {Co-localization of tau and TDP-43 after extracellular vesicle delivery to cells.}, journal = {The FEBS journal}, volume = {293}, number = {5}, pages = {1495-1515}, pmid = {41250892}, issn = {1742-4658}, support = {201806SOP-411481//CIHR/Canada ; 201806SOP-411481//CIHR/Canada ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism/genetics ; *tau Proteins/metabolism/genetics/chemistry ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; HEK293 Cells ; Animals ; Rats ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; }, abstract = {Perturbations in the metabolism of microtubule-associated protein tau (tau) underlie the pathology of a broad array of dementias, including chronic traumatic encephalopathy, amyotrophic lateral sclerosis (ALS) with cognitive impairment (ALSci) and approximately half of the dementias associated with frontotemporal lobar degeneration. We recently observed significantly increased hippocampal tau pathology in rats injected with pseudophosphorylated human tau (2N4R tau[T175D]) co-expressing an ALS-associated TAR DNA-binding protein 43 (TDP-43) mutant (TDP-43[M337V]) when compared to wild-type rats. To understand this mechanism, we examined whether the extracellular vesicles (EVs) derived from wild-type TDP-43 (wtTDP-43) or tau-expressing cells could transfer expression of these proteins to recipient cells, and whether co-localization of these proteins occurs. mCherry-wtTDP-43 or EGFP-tau constructs were expressed in HEK293 or SH-SY5Y cells. The secretome and EV fractions contained wtTDP-43 or 2N4R tau protein and RNA, and could transfer proteins into nontransfected cells. Co-localization was also detected in the cytosol of recipient cells. In silico modeling of tau and TDP-43 interactions suggests hydrogen bonding underlies this interaction. These studies further our understanding of the interaction between tau and TDP-43 by demonstrating their ability to co-aggregate and in providing a mechanism by which cell-cell transfer of either protein via extracellular vesicles can lead to these synergistic interactions.}, } @article {pmid41250939, year = {2025}, author = {Ayvazian-Hancock, A and Butler, E and Meehan, CF and Miles, GB and Broadhead, MJ}, title = {Synaptopathy in the TDP-43ΔNLS Mouse Model of Sporadic Amyotrophic Lateral Sclerosis.}, journal = {The European journal of neuroscience}, volume = {62}, number = {10}, pages = {e70320}, pmid = {41250939}, issn = {1460-9568}, support = {R434-2023-347//The Lundbeck Foundation/ ; //Tenovus Scotland/ ; //RS Macdonald Charitable Trust/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *DNA-Binding Proteins/genetics/metabolism ; *Synapses/pathology/metabolism ; Disease Models, Animal ; Mice ; Spinal Cord/pathology/metabolism ; Mice, Transgenic ; Astrocytes/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Male ; }, abstract = {Sporadic cases of amyotrophic lateral sclerosis (sALS) represent the most common form of motor neuron disease. sALS is characterised by pathological cytoplasmic inclusions of TDP-43, so-called reactive astrocyte pathology and motor neuron degeneration. Alterations in certain subpopulations of synapses between neurons are thought to be a key driver of the pathological mechanisms of ALS. However, we do not have a clear understanding of which types of synapses are impacted in ALS. Identifying vulnerable synapses affected in sALS models may provide insights into the key sites of disease pathogenesis. In this study we have performed quantitative high-resolution microscopy to survey different synapse subtypes, including excitatory (glutamatergic), inhibitory (glycinergic) and modulatory (cholinergic C-Boutons) synapses, in the spinal cord of a mouse model of sALS showing inducible TDP-43 pathology (TDP43ΔNLS) restricted to neurons. We have identified changes in cholinergic synapses and a subpopulation of excitatory synapses. Mice display robust neuronal TDP-43 pathology and evidence of TDP-43 changes at cholinergic C-boutons. We also observe no evidence of astrocytic pathology nor changes in the fraction of synapses that are contacted by astrocytes. Overall, our findings highlight the selective vulnerability of distinct synapse populations in ALS.}, } @article {pmid41251124, year = {2026}, author = {Ozkose, GS and Topcu, Y and Ay, B and Ozdemir, O and Akgun-Dogan, O and Ng, OH and Alanay, Y}, title = {Expanding the Phenotypic Spectrum of ERLIN1-Related SPG62: Report of Two Siblings With Behavioral Features and Hyperacusis.}, journal = {Clinical genetics}, volume = {109}, number = {1}, pages = {149-154}, doi = {10.1111/cge.70006}, pmid = {41251124}, issn = {1399-0004}, support = {//Acibadem Mehmet Ali Aydinlar University BAP Coordination Unit/ ; }, mesh = {Humans ; Siblings ; *Spastic Paraplegia, Hereditary/genetics/physiopathology/diagnosis/pathology ; Male ; Female ; Phenotype ; Mutation ; *Membrane Proteins/genetics ; Pedigree ; Adult ; }, abstract = {Hereditary spastic paraplegia type 62 (SPG62) is a neurodegenerative disorder, with more than 20 individuals reported to date. This ultra-rare entity is inherited in an autosomal recessive manner and has been associated with ERLIN1 variants. In addition, ERLIN1-related biallelic variants have been linked to early-onset amyotrophic lateral sclerosis (ALS). We present two siblings with slowly progressive spastic paraplegia, with mild intellectual decline, behavioral findings, and hyperacusis. This study expands the clinical spectrum of hereditary spastic paraplegia associated with ERLIN1.}, } @article {pmid41251254, year = {2025}, author = {Staehr-Rye, AK and Küchen, SHL and Salvesen, L and Blicher, J and Strange, DG and Svenstrup, K}, title = {[Chronic respiratory insufficiency in amyotrophic lateral sclerosis].}, journal = {Ugeskrift for laeger}, volume = {187}, number = {44}, pages = {}, doi = {10.61409/V03250140}, pmid = {41251254}, issn = {1603-6824}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/physiopathology ; *Respiratory Insufficiency/therapy/etiology/physiopathology ; Respiration, Artificial/methods ; Chronic Disease ; Noninvasive Ventilation ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord. As the disease progresses, respiratory function becomes increasingly compromised. Supporting respiratory function is the treatment with the greatest potential impact on life expectancy and should align with the patient's wishes to ensure quality of life. Optimal secretion management is essential for effective non-invasive mechanical ventilation therapy, as argued in this review. Home invasive mechanical ventilation is reserved for a small subset of patients.}, } @article {pmid41252371, year = {2025}, author = {Lillelund, CM and Kalra, S and Greiner, R and , }, title = {A meaningful prediction of functional decline in amyotrophic lateral sclerosis based on multi-event survival analysis.}, journal = {PloS one}, volume = {20}, number = {11}, pages = {e0336476}, pmid = {41252371}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/drug therapy ; Male ; Female ; Survival Analysis ; Middle Aged ; Aged ; Kaplan-Meier Estimate ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of the motor neurons that causes progressive paralysis in patients. Current treatment options aim to prolong survival and improve quality of life. However, due to the heterogeneity of the disease, it is often difficult to determine the optimal time for potential therapies or medical interventions. In this study, we propose a novel method to predict the time until a patient with ALS experiences significant functional impairment (ALSFRS-R ≤ 2) for each of five common functions: speaking, swallowing, handwriting, walking, and breathing. We formulate this task as a multi-event survival problem and validate our approach in the PRO-ACT dataset ([Formula: see text]) by training five covariate-based survival models to estimate the probability of each event over the 500 days following the baseline visit. We then predict five event-specific individual survival distributions (ISDs) for a patient, each providing an interpretable estimate of when that event is likely to occur. The results show that covariate-based models are superior to the Kaplan-Meier estimator at predicting time-to-event outcomes in the PRO-ACT dataset. Additionally, our method enables practitioners to make individual counterfactual predictions-where certain covariates can be changed-to estimate their effect on the predicted outcome. In this regard, we find that Riluzole has little or no impact on predicted functional decline. However, for patients with bulbar-onset ALS, our model predicts significantly shorter time-to-event estimates for loss of speech and swallowing function compared to patients with limb-onset ALS (log-rank p < 0.001, Bonferroni-adjusted [Formula: see text]). The proposed method can be applied to current clinical examination data to assess the risk of functional decline and thus allow more personalized treatment planning.}, } @article {pmid41252681, year = {2026}, author = {Yoo, SH and Cho, B and Kim, KH and Hwang, IY and Cho, W and Choi, SJ and Sung, JJ and Lee, SY}, title = {Quality of life and care burden of people living with amyotrophic lateral sclerosis who need home-based medical care in Korea and their family caregivers.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {274-284}, doi = {10.1080/21678421.2025.2589780}, pmid = {41252681}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/epidemiology/nursing ; Male ; Female ; *Quality of Life/psychology ; *Caregivers/psychology ; Republic of Korea/epidemiology ; Aged ; Middle Aged ; *Home Care Services ; Prospective Studies ; *Cost of Illness ; Surveys and Questionnaires ; Adult ; Aged, 80 and over ; }, abstract = {Objective: Advanced neurodegenerative diseases (NDDs) lead to severe mobility limitations, creating significant challenges for patients and caregivers at home. We aimed to investigate the quality of life (QOL) and care burden of people living with amyotrophic lateral sclerosis (ALS, pALS) and other NDDs and their family caregivers in Korea. Methods: This prospective survey study included people living with NDDs with mobility restrictions and their caregiver enrolled in a home-based medical care (HBMC) program at one tertiary hospital in South Korea from 2022 to 2024. Data collected included demographics, clinical characteristics, care burden (the Zarit Caregiver Burden Interview Short Form, ZBI-12), QOL (EQ-5D-5L), and depression (Patient Health Questionnaire-9). The results were compared between ALS and other NDDs (non-ALS). Results: Of 44 patients requiring HBMC, 70.5% (31) were pALS. pALS were younger than non-ALS (median age, 65 vs. 79 years); more often, the caregiver was a spouse (64.5% vs. 46.1%, p = 0.30). One-fourth (25.8%) of pALS were on polypharmacy (>10 medications a day). One-third (29%) of pALS and 22.6% of their caregivers experienced moderate or severe depression. Half of pALS caregivers experienced high caregiving burden (ZBI-12 score ≥17). The mean EQ-5D-5L index score was 0.48 for pALS and 0.84 for their caregivers, which was lower than the results for the Korean general population. Conclusions: Patients with severe NDD and caregivers experienced low QOL and high caregiving burden, with pALS caregivers particularly vulnerable to depression and heavy burden. Designing optimal HBMC programs to support pALS and home caregivers is warranted.}, } @article {pmid41253081, year = {2026}, author = {Okagaki, N and Tsuboi, T and Chihara, Y and Sumi, K and Takeuchi, H and Yamamoto, K and Hajiro, T and Sato, A}, title = {Impact of pneumothorax on clinical course of patients with amyotrophic lateral sclerosis on long-term ventilation.}, journal = {Respiratory investigation}, volume = {64}, number = {1}, pages = {101329}, doi = {10.1016/j.resinv.2025.11.008}, pmid = {41253081}, issn = {2212-5353}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Pneumothorax/etiology ; Retrospective Studies ; Male ; Female ; Middle Aged ; Longitudinal Studies ; *Positive-Pressure Respiration/adverse effects ; Aged ; Prognosis ; Time Factors ; Tracheostomy ; Quality of Life ; Adult ; }, abstract = {BACKGROUND: Numerous clinical studies have shown that long-term positive pressure ventilation (PPV) improves quality of life and prognosis in patients with amyotrophic lateral sclerosis (ALS). Pneumothorax is an important complication of PPV; however, few studies investigated pneumothorax in patients with ALS on long-term PPV.

METHODS: This retrospective longitudinal cohort study included 85 patients with ALS treated from 2013 to 2024. We collected information from medical records on ALS and pneumothorax treatment, blood laboratory data, radiology data, equipment data, and mortality. Subsequently, we compared clinical parameters and prognosis between the pneumothorax and non-pneumothorax groups.

RESULTS: Of the 85 patients, 61 underwent long-term PPV. Nine patients developed pneumothorax following the initiation of long-term PPV. In contrast, 24 patients without long-term PPV did not experience pneumothorax. Among patients who received tracheostomy PPV as a maximum respiratory management, the pneumothorax group tended to have a poorer prognosis from ALS onset than the non-pneumothorax group. Moreover, the pneumothorax group had higher inspiratory positive airway pressure and support pressure of ventilator settings than the non-pneumothorax group. Among the nine pneumothorax cases, there were no deaths directly related to the complication, two patients who developed pneumothorax during non-invasive PPV transitioned to tracheostomy PPV as a result of the complication.

CONCLUSIONS: Pneumothorax should be recognized as a serious complication that can occur in patients with ALS on PPV. Higher inspiratory positive airway pressure and support pressure settings on long-term PPV may be significant risk factors for pneumothorax.}, } @article {pmid41253416, year = {2026}, author = {MacDonald, C and Barnum, E and Pradeep, M and Rivera, V and Smith, P and Dombrowski, M and Sparkman, J and Manero, A}, title = {Serious Game-Based Training for Improved Control of a Temporalis Electromyography Interface for Controlling Powered Wheelchairs.}, journal = {Games for health journal}, volume = {15}, number = {3}, pages = {137-143}, doi = {10.1177/2161783X251397932}, pmid = {41253416}, issn = {2161-7856}, mesh = {Humans ; *Electromyography/methods/instrumentation ; *Wheelchairs/standards ; *Video Games/standards/psychology ; Male ; Female ; Adult ; Amyotrophic Lateral Sclerosis ; Middle Aged ; User-Computer Interface ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by a significant decrease in mobility due to its neurodegenerative etiology. Throughout the progression of ALS, patients lose independence in their motor control. An electromyography (EMG) interface that enables control of a powered wheelchair can restore autonomous movement. The use of serious game-based training that mimics EMG-temporalis wheelchair controls can be used as training prior to wheelchair usage in the real world.

PURPOSE: Limbitless Runner, a forearm EMG training game, found improved player performance with no significant difference noted between the free and structured play training. This study aims to investigate the generalizability of this finding when applied to a temporalis EMG system.

METHODS: Participants were given Limbitless Runner's quantifiable, structured training mode, the "ring challenge," for a scored pretest. Participants were then assigned to one of three cohorts for training: Limbitless Journey, Limbitless Runner "free play mode," or the Limbitless Runner "ring challenge." To assess improvement in user's performance, the ring challenge was repeated and scored. Quantitative surveys, including the Game User Experience Satisfaction Scale (GUESS) and the System Usability Scale (SUS), were given to gauge users' perceptions of the games.

RESULTS: All cohorts showed a user score improvement; however, the ring challenge (Cohort 2) showed the highest improvement, from an average of 22.9 rings in the pretest to 31.1 rings posttraining. The SUS and GUESS scores were not significantly different between the two different video games, demonstrating that both versions can be satisfying or acceptable platforms for users.}, } @article {pmid41255457, year = {2025}, author = {Hu, Y and Lu, Y and Lan, D}, title = {Early Multidisciplinary Rehabilitation Improves Swallowing and Speech Function in a Patient With Amyotrophic Lateral Sclerosis.}, journal = {Clinical case reports}, volume = {13}, number = {11}, pages = {e71486}, pmid = {41255457}, issn = {2050-0904}, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic, progressive neurodegenerative disease for which there is a lack of effective treatment. This case report describes a 49-year-old male with ALS who presented with dysphagia, dysarthria, dyskinesia, sleep disorders, anxiety, and depression. Following 45 days of early multidisciplinary rehabilitation, the patient demonstrated significant improvement in swallowing and speech function, alleviation of non-motor symptoms, and maintenance of motor function. Notably, he retained the ability to consume soft foods at a two-year follow-up. This case highlights the vital role of early multidisciplinary rehabilitation in the comprehensive management of ALS.}, } @article {pmid41255704, year = {2025}, author = {von Kügelgen, N and Ludwik, K and Mendonsa, S and Römer, C and Becher, E and Breimann, L and Strauch, M and Mari, T and Mongellaz, S and Zuckerman, B and Efendic, F and Grexa, N and Oliveras-Martinez, A and Woehler, A and Selbach, M and La Bella, V and Ulitsky, I and Chekulaeva, M}, title = {Neuromuscular dysfunction in patient-derived FUS[R244RR]-ALS iPSC model via axonal downregulation of neuromuscular junction proteins.}, journal = {NAR molecular medicine}, volume = {2}, number = {2}, pages = {ugaf005}, pmid = {41255704}, issn = {2976-856X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by the progressive degeneration of motor neurons (MNs), ultimately resulting in death due to respiratory failure. A common feature among ALS cases is the early loss of axons, pointing to defects in axonal transport and translation as initial disease indicators. ALS is associated with mutations in RNA-binding proteins, such as FUS (Fused in Sarcoma). Here, we established a FUS[R244RR]-ALS hiPSC-derived model that recapitulates the MN survival and muscle contractility defects characteristic of ALS patients. Analysis of the protein and mRNA expression profiles in axonal and somatodendritic compartments of ALS-afflicted and isogenic control MNs revealed a selective downregulation of proteins essential for the neuromuscular junction function in FUS-ALS axons. Furthermore, analysis of FUS CLIP and RIP data showed that FUS binds mRNAs encoding these proteins. This work shed light on the pathogenic mechanisms of ALS and emphasized the importance of axonal gene expression analysis in elucidating the mechanisms of neurodegenerative disorders.}, } @article {pmid41255818, year = {2025}, author = {Doelemeyer, A and Vaishampayan, S and Zurbruegg, S and Morvan, F and Locatelli, G and Shimshek, DR and Beckmann, N}, title = {Deep learning-driven MRI for accurate brain volumetry in murine models of neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1632169}, pmid = {41255818}, issn = {1662-4548}, abstract = {Brain atrophy as assessed by magnetic resonance imaging (MRI) is a key measure of neurodegeneration and a predictor of disability progression in Alzheimer's disease and multiple sclerosis (MS) patients. While MRI-based brain volumetry is valuable for analyzing neurodegeneration in murine models as well, achieving high spatial resolution at sufficient signal-to-noise ratio is challenging due to the small size of the mouse brain. In vivo MRI allows for longitudinal studies and repeated assessments, enhancing statistical power and enabling pharmacological evaluations. However, the need for anesthesia necessitates compromises in acquisition times and voxel sizes. In this work we present the application of a deep-learning-based segmentation approach to the reliable quantification of total brain and brain sub region volumes, such as the hippocampus, caudate putamen, and cerebellum, from T2-weighted images with a pixel volume of 78x78x250 μm[3] acquired in 4.3 min at 7 Tesla using a conventional radiofrequency coil. The reproducibility of the fully automatic segmentation pipeline was validated in healthy C57BL/6 J mice and subsequently applied to models of amyotrophic lateral sclerosis, cuprizone-induced demyelination, and MS. Our approach offers a robust and efficient method for in vivo brain volumetry in preclinical mouse studies, facilitating the evaluation of neurodegenerative processes and therapeutic interventions. The dramatic reduction in acquisition time achieved with our AI-based approach significantly enhances animal welfare (3R). This advancement allows brain volumetry to be seamlessly integrated into additional analyses, providing comprehensive insights without substantially increasing study duration.}, } @article {pmid41256173, year = {2025}, author = {Candrea, DN and Angrick, M and Luo, S and Ganji, R and Coogan, C and Milsap, GW and Rosenblatt, KR and Uchil, A and Clawson, L and Maragakis, NJ and Vansteensel, MJ and Tenore, FV and Ramsey, NF and Fifer, MS and Crone, NE}, title = {Longitudinal study of gesture decoding in a clinical trial participant with ALS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41256173}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {Brain-computer interfaces (BCIs) have the potential to preserve or restore communication and device control in people with paralysis from a variety of causes. For people living with amyotrophic lateral sclerosis (ALS), however, the progressive loss of cortical motor neurons could theoretically pose a challenge to the stability of BCI performance. Here we tested the stability of gesture decoding with a chronic electrocorticographic (ECoG) BCI in a man living with ALS and participating in a clinical trial (ClinicalTrials.gov, NCT03567213). We evaluated offline decoding performance of attempted gestures over two periods: a 5-week period beginning roughly 2 years post-implant and a 6-week period ending roughly 5 months later. Decoder sensitivity was high in both periods (90 - 98%), while classification accuracy was 37 - 68% in the first period and worsened to 23 - 39% in the second. We investigated multiple frequency bands that were used as model features in both periods, and we observed reductions in high gamma band power (70 - 110 Hz) and between-class separation during the second period compared to the first. Over the 5-month period motor function did not appreciably decline. These results, albeit preliminary, suggest that declines in the neural population responses that drive ECoG BCI performance can occur without overt signs of disease progression in people living with ALS, and could serve as a biomarker for disease progression in the future.}, } @article {pmid41256347, year = {2025}, author = {Kanda, T and Sasaki-Tanaka, R and Kamimura, H and Terai, S}, title = {Is higher body mass index correlated with worse clinical outcomes in acute liver failure?.}, journal = {World journal of clinical cases}, volume = {13}, number = {32}, pages = {113514}, pmid = {41256347}, issn = {2307-8960}, abstract = {Krishnan et al's article is a comprehensive and vigorous retrospective cohort study regarding the association between obesity and clinical outcomes in acute liver failure (ALF). Among patients with ALF in the United States, mean body mass index (BMI) was significantly greater in those who underwent liver transplantation or who died than among survivors, although acetaminophen induced ALF was the most common etiology. A high BMI was associated with renal failure and high grades of hepatic encephalopathy. The prevalence of obesity and its related fatty liver diseases, such as metabolic dysfunction-associated fatty liver disease/ metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, has increased worldwide. Obesity is related to increased serum cytokines and immune abnormalities. These findings may explain why ALF in patients with high BMI is associated with worse clinical outcomes. Further studies are needed to determine the associations among BMI, ALF and acute-on-chronic liver failure.}, } @article {pmid41256466, year = {2025}, author = {Waldron, FM and Spence, H and Taso, OS and Read, FL and Sinha, IR and Irwin, KE and Wong, PC and Ling, JP and Gregory, JM}, title = {Brain Iron as a Surrogate Biomarker of Pathological TDP-43 Identifies Brain Region-Specific Signatures in Ageing, Alzheimer's Disease and Amyotrophic Lateral Sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41256466}, issn = {2692-8205}, support = {R01 NS127186/NS/NINDS NIH HHS/United States ; RF1 NS095969/NS/NINDS NIH HHS/United States ; U01 FD008129/FD/FDA HHS/United States ; }, abstract = {BACKGROUND: TDP-43 pathology is a defining feature of several neurodegenerative diseases, but its prevalence and regional distribution in ageing and disease are not well characterised. We investigated the burden of brain TDP-43 pathology across ageing, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS), and examined ferritin as a region-specific correlate of TDP-43 pathology.

METHODS: Pathological TDP-43 was detected using an HDGFL2 cryptic exon in situ hybridisation probe and a TDP-43 RNA aptamer, providing greater sensitivity and specificity than antibody-based approaches. Amygdala, hippocampus, and frontal cortex tissue was analysed from non-neurological controls (ages 40-80), AD cases, and ALS cases. Ferritin (as a proxy for iron accumulation) was quantified in parallel to assess its association with TDP-43 pathology.

FINDINGS: TDP-43 pathology was detectable from the fourth decade of life, with a 4.5-fold increase in hippocampal involvement after age 60 years. In AD, pathology was present in 90% of cases and distinguished from ageing by selective amygdala involvement. In ALS, TDP-43 pathology was nearly ubiquitous across all regions studied. Regional ferritin strongly predicted TDP-43 burden: amygdala ferritin explained 87% of TDP-43 variance in ALS and 66% in AD, while hippocampal ferritin differentiated AD from controls. Across AD, ferritin explained between 43-81% of regional TDP-43 variance.

INTERPRETATION: TDP-43 brain pathology emerges in midlife with increased involvement after age 60 years, exhibits disease-specific regional signatures in AD and ALS, and is closely linked to ferritin accumulation. As TDP-43 confers a worse prognosis in AD, the capacity of ferritin, detectable with iron-sensitive MRI, to serve as a proxy for regional TDP-43 burden highlights its promise as a biomarker for disease stratification and prognosis.}, } @article {pmid41256495, year = {2025}, author = {Waldron, FM and Langerová, T and Rahmanova, A and Read, FL and Spence, H and Roberts, K and Macleod, AD and Pattle, SB and Hanna, K and Gregory, JM}, title = {Skin TDP-43 pathology as a candidate biomarker for predicting amyotrophic lateral sclerosis decades prior to motor symptom onset.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41256495}, issn = {2692-8205}, support = {R01 NS127186/NS/NINDS NIH HHS/United States ; }, abstract = {The recognition that disease-associated proteinopathies can manifest in peripheral organs outside the central nervous system preceding the onset of neurological symptoms, has transformed our understanding of Parkinson's disease, in wide terms of pathogenesis, detection and diagnosis. For amyotrophic lateral sclerosis, non-motor symptoms, and non-central nervous system pathologies are gaining increased recognition but remain incompletely understood. Here, using a TDP-43 RNA aptamer and a Stathmin-2 cryptic exon transcript BaseScope™ ISH probe, we identify widespread peripheral organ TDP-43 pathology prior to motor symptom onset in a discovery cohort of ante-mortem tissues from people who went on to develop ALS. Peripheral organs exhibiting both TDP-43 toxic gain- and loss-of function include muscle, lymph node, gallbladder, colon and with notably high incidence, skin. Given the accessibility of skin as a readily biopsiable tissue, representing a promising substrate for the detection of disease-associated proteinopathies and the development of minimally invasive biomarkers, we established an extended cohort of ante-mortem skin samples for TDP-43 pathology validation and further investigation. In skin biopsies taken during life from 17 individuals who went on to develop ALS we identify TDP-43 pathology from all 17 individuals in a wide distribution of anatomical sites, up to 26.5 years before ALS diagnosis - a presymptomatic period comparable to that observed for skin α-synucleinopathy in Parkinson's disease. TDP-43 pathology was most abundant in skin biopsies from the back and shoulder, with sweat and sebaceous glands showing the highest involvement. TDP-43 pathology was also associated with structural changes. As skin α-synucleinopathy has been established as a biomarker for both the detection of Parkinson's disease and the differentiation of Parkinson's disease from multiple system atrophy, we propose that skin TDP-43 likewise holds diagnostic and discrimination potential for diseases characterised by TDP-43 proteinopathy.}, } @article {pmid41256508, year = {2025}, author = {Kozareva, V and Liu, Z and Blake, K and Qi, YA and Rollinson, S and Seddighi, S and Alsaidi, M and Tsitkov, S and Prudencio, M and Petrucelli, L and Dickson, DW and Brown, AL and Fratta, P and Kim, HJ and Taylor, JP and Ward, ME and Fraenkel, E and Kargbo-Hill, SE}, title = {Integrative multiomic analysis links TDP-43-driven splicing defects to cascading proteomic disruption of ALS/FTD pathways.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.09.29.679403}, pmid = {41256508}, issn = {2692-8205}, abstract = {Loss of nuclear TDP-43 is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is known to regulate RNA processing, including repression of cryptic exons, we currently lack a systems-level understanding of the consequences of TDP-43 loss. To address this, we generated multiomic datasets, including RNA-seq and proteomics, from human iPSC-derived neurons depleted of TDP-43. We found that differentially spliced genes, many expressing cryptic exons, had the greatest protein reductions. Surprisingly, nearly half of differentially expressed proteins were neither mis-spliced, nor differentially expressed genes; most of these also had no reported mis-splicing in seven additional post-mortem and iPSC-derived neuron datasets. Integrative network analysis identified a high-confidence disease-specific subnetwork of over 700 interacting proteins, enriched for mRNA processing, synaptic function, and autophagy. Comparison with post-mortem ALS and FTD samples revealed convergent protein and pathway disruptions. We experimentally validated network-predicted effects of cryptic splicing in ATG4B, STMN2, and DAPK1. Our analyses reveal new TDP-43-dependent molecular cascades and nominate central genes as potential ALS/FTD therapeutic targets.}, } @article {pmid41256634, year = {2025}, author = {Li, Y and Dou, X and Xiao, Y and Zhang, Z and Ye, Y and Wright, N and Chang, K and Liu, C and Troncoso, JC and He, C and Sun, S}, title = {LINE1 RNA dysregulation impairs chromatin accessibility in C9ORF72- and TDP-43-linked ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.09.30.679260}, pmid = {41256634}, issn = {2692-8205}, support = {R01 AG078948/AG/NIA NIH HHS/United States ; R01 NS127925/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; }, abstract = {The long interspersed element-1 (LINE1) retrotransposon RNAs are abnormally elevated in various neurodegenerative disorders, but their pathogenic roles remain unclear. Here we investigated the mechanism of LINE1 RNA accumulation and its function in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with C9ORF72 repeat expansion and TDP-43 loss-of-function, the leading causes of familial and sporadic forms of these neurodegenerative diseases. We show that LINE1 RNA is dysregulated due to an impaired nuclear exosome targeting (NEXT) degradation pathway. Its elevation epigenetically increases chromatin accessibility, enhancing global transcription via a retrotransposon-independent mechanism. Reducing LINE1 RNA mitigates chromosomal abnormalities and improves the survival of disease-relevant neurons. These findings uncover an essential noncoding RNA function and regulatory mechanism of LINE1 in neurons, providing insights into disease pathogenesis and highlighting potential therapeutic targets for neurodegenerative diseases.}, } @article {pmid41258169, year = {2025}, author = {Straczkiewicz, M and Burke, KM and Carney, KT and Calcagno, N and Mandepudi, S and Premasiri, A and Vieira, FG and Berry, JD}, title = {Analytical and clinical validation of step counting method in people living with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {40769}, pmid = {41258169}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Walking/physiology ; *Gait/physiology ; *Accelerometry/methods ; Algorithms ; Aged ; Adult ; Reproducibility of Results ; }, abstract = {Accelerometer-based digital measures offer a scalable and low-burden means of quantifying physical function, but existing processing algorithms may not quantify pathological gait correctly. In people living with amyotrophic lateral sclerosis (ALS), where gait patterns are slow, variable, and asymmetric, validated tools to quantify mobility are urgently needed. We proposed a step-counting algorithm designed for ankle-worn accelerometers that leverage wavelet-based decomposition to quantify heel strikes under heterogeneous gait patterns. We validated this method using five datasets comprising healthy individuals and those with ALS in controlled and semi-controlled activities, and we performed clinical validation in a free-living cohort of 305 people with ALS. We tested our method for accuracy in detecting steps and recognizing walking activity. Reference labels used for analytical validation were obtained from annotated studies or video-based ground truth. Step counting accuracy was assessed using Bland-Altman analysis while clinical validity was evaluated by comparing step counts to gross motor functioning on the ALS Functional Rating Scale-Revised (ALSFRS-R). Walking recognition was robust across walking conditions and body types; sensitivity ranged from 0.94 to 0.98, and specificity exceeded 0.95 across all evaluated datasets. The mean step counting bias was minimal (e.g., 0.44 steps), and the 95% limits of agreement were narrow (LoA = [-5.90, 5.40]) relative to reference standards, including video-annotated ground truth. Clinical validation indicated substantial differences between groups with various levels of gait impairment, e.g., participants who reported "walks with assist" on the ALSFRS-R accumulated a mean of 1283 (95% CI 1063, 1503) steps/day, while those reporting "normal" walking covered 3984 (95% CI 3537, 4432) steps/day. Our study covered analytical and clinical validation of a step-counting method developed for ankle-worn accelerometers and demonstrated its applicability to pathological gait. The method provides accurate quantification of walking activity in controlled and free-living environments, supporting its use as a digital endpoint in ALS research.}, } @article {pmid41258507, year = {2025}, author = {Hashizume, A and Hanazawa, R and Yamada, S and Ito, D and Kishimoto, Y and Komori, S and Kawase, T and Iida, M and Kondo, A and Mori, Y and Obara, K and Morita, M and Yamamoto, T and Sato, H and Hirakawa, A and Katsuno, M}, title = {Therapeutic impact of leuprorelin acetate on spinal and bulbar muscular atrophy: pre- and post-marketing observational study.}, journal = {Journal of neurology}, volume = {272}, number = {12}, pages = {772}, pmid = {41258507}, issn = {1432-1459}, support = {24ek0109588//Japan Agency for Medical Research and Development/ ; 24K10658//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Leuprolide/therapeutic use/pharmacology ; Male ; Middle Aged ; Female ; Aged ; Adult ; *Product Surveillance, Postmarketing ; Disease Progression ; *Bulbo-Spinal Atrophy, X-Linked/drug therapy ; Treatment Outcome ; *Muscular Atrophy, Spinal/drug therapy ; Japan ; }, abstract = {Although leuprorelin acetate, a luteinizing hormone-releasing hormone agonist, has been approved based on short-term clinical trials conducted in Japan, its long-term efficacy on physical function remains unclear. We aimed to evaluate the long-term therapeutic efficacy of leuprorelin acetate using real-world clinical data through a self-controlled trend-shift analysis. The analysis included 91 genetically confirmed patients with spinal and bulbar muscular atrophy, with follow-up data collected before and after treatment initiation. The functional outcomes assessed included the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and modified Norris scales, grip power, and serum creatinine levels. Leuprorelin acetate significantly slowed disease progression. For instance, the annual ALSFRS-R decline rate improved from approximately 0.5 points pre-treatment to 0.2 points post-treatment. The subgroup analysis supported the potential benefit of early intervention. These findings highlight the value of leveraging patient registries and post-marketing real-world data to evaluate treatment efficacy in slowly progressive diseases, such as SBMA, where traditional randomized controlled trials are often limited by insufficient statistical power to detect therapeutic efficacy. They also underscore the need for innovative methodologies to assess post-approval drug performance, paving the way for improved clinical outcomes for neurodegenerative diseases.}, } @article {pmid41259153, year = {2026}, author = {Acheampong, HO and Rozich, E and Haupt, Z and Tokarz, C and Khan, M and Ghosn, ZA and Insolera, R}, title = {Kenny mediates the recruitment of the phagophore for ubiquitin-dependent mitophagy in Drosophila neurons.}, journal = {Molecular biology of the cell}, volume = {37}, number = {2}, pages = {ar9}, pmid = {41259153}, issn = {1939-4586}, support = {R00 NS111000/NS/NINDS NIH HHS/United States ; R35 GM156765/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Mitophagy/physiology ; *Drosophila Proteins/metabolism/genetics/physiology ; Mitochondria/metabolism ; *Ubiquitin/metabolism ; Drosophila melanogaster/metabolism ; Neurons/metabolism ; Autophagy/physiology ; Motor Neurons/metabolism ; Ubiquitination ; Transcription Factor TFIIIA/metabolism ; Valosin Containing Protein ; }, abstract = {The maintenance of healthy mitochondria is essential to neuronal homeostasis. Mitophagy is a critical mechanism that degrades damaged mitochondria, and disruption of this process is associated with neurodegenerative disease. Previous work has shown that mammalian optineurin (OPTN), a gene mutated in familial forms of amyotrophic lateral sclerosis (ALS) and glaucoma, is an adaptor to recruit autophagy machinery to mitochondria for ubiquitin-dependent mitophagy in cultured cells. However, OPTN's role in neuronal mitophagy in vivo remains largely unknown. Here, we demonstrate that the Drosophila autophagy adaptor gene Kenny, a homologue of OPTN, mediates the recruitment of the phagophore to mitochondria undergoing ubiquitin-dependent mitophagy. We find that Kenny colocalizes with ubiquitinated mitochondria targeted for autophagic degradation in larval motoneurons, and is concentrated on the mitochondrial surface in areas opposed to the phagophore. Removal of Kenny in conditions of induced mitophagy eliminates the recruitment of the phagophore to ubiquitinated mitochondria and decreases mitophagic flux. In basal conditions, loss of Kenny causes accumulation of ubiquitinated mitochondria in neurons, indicative of stalled mitophagy. These phenotypes were reproduced in Kenny mutants, ablating the LC3-interacting region domain. Overall, this work establishes Kenny as a functional homologue of OPTN in flies and a mediator of neuronal mitophagy in vivo.}, } @article {pmid41259564, year = {2025}, author = {Araújo, RCP and Godoy, CMA and Ferreira, LMBM and Godoy, JF and Magalhães, H}, title = {Fiberoptic endoscopic evaluation of swallowing in amyotrophic lateral sclerosis: comparison with older people with dysphagia and relationship with time since diagnosis.}, journal = {CoDAS}, volume = {37}, number = {6}, pages = {e20240296}, pmid = {41259564}, issn = {2317-1782}, mesh = {Humans ; *Deglutition Disorders/physiopathology/etiology/diagnosis ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Cross-Sectional Studies ; Male ; Retrospective Studies ; Aged ; Female ; Middle Aged ; *Deglutition/physiology ; Time Factors ; Fiber Optic Technology ; Aged, 80 and over ; Severity of Illness Index ; }, abstract = {PURPOSE: (1) to compare the findings of the instrumental swallowing assessment between individuals with amyotrophic lateral sclerosis (ALS) and older dysphagic adults without neurological diagnosis; (2) to compare the onset of pharyngeal response, pharyngeal residues, and the level of oral intake in relation to the time since diagnosis in the ALS group.

METHODS: This cross-sectional, retrospective study collected data from medical records. Altogether, 101 individuals with dysphagia were included and stratified into two groups: the first had 56 patients diagnosed with ALS, and the second had 45 older adults. Dysphagia signs were analyzed through fiberoptic endoscopic evaluation of swallowing, using four food consistencies, classified by the International Dysphagia Diet Standardisation Initiative (IDDSI). Pharyngeal residues were classified by the Yale Pharyngeal Residue Severity Rating Scale (YPRSRS), and oral intake by the Functional Oral Intake Scale (FOIS).

RESULTS: The ALS group had differences in multiple swallows with one IDDSI consistency; posterior oral leakage, pharyngeal residues, and laryngeal penetration with three consistencies; and aspiration with one consistency. Individuals with more than 3 years since diagnosis had differences in the onset of the pharyngeal response in the pyriform sinuses, moderate pharyngeal residues, and oral intake.

CONCLUSION: The ALS group had significant differences in the occurrence of multiple swallows, posterior oral leakage, pharyngeal residues, penetration, and aspiration with three IDDSI consistencies. Furthermore, the time since diagnosis was a determining factor for all three parameters.}, } @article {pmid41259707, year = {2025}, author = {He, T and Lu, Y and Chen, Y and Wang, J and Zhang, H}, title = {Intelligent Microsphere Soil Conditioner Based on Aminated Lignosulfonate and Thermoresponsive Polymer.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {41}, number = {47}, pages = {32031-32043}, doi = {10.1021/acs.langmuir.5c04647}, pmid = {41259707}, issn = {1520-5827}, abstract = {In this research, a composite hydrogel microsphere material, SA/P(NVCL-ALS)-N-ZnO/A-Dol-urea (hereafter referred to as SA-PANZ), with dual responsiveness to temperature and pH, was developed by integrating aminated lignosulfonate sodium (ALS), poly(N-vinylcaprolactam) (PNVCL), nano zinc oxide (N-ZnO), and alkali-treated dolomite (A-Dol). The material exhibited excellent controlled-release performance, with a cumulative urea release rate of 67.22% at 40 °C and pH = 4. The Ritger-Peppas model fitted well with the release data, providing strong theoretical support for optimizing the microspheres. Compared to control groups, both the loading efficiency and encapsulation efficiency were significantly improved, achieving 38.50 and 12.83%, respectively. Water retention tests demonstrated that the microspheres maintained 39.92% of their moisture after 5 h, indicating an excellent water-holding capacity. Degradation experiments indicated a degradation rate of 60.14% under acidic conditions, demonstrating excellent biodegradability. Antibacterial assays revealed a clear inhibitory effect against Aspergillus niger, and plant cultivation experiments confirmed that the microspheres promoted pea growth under acidic and high-temperature stress. This research introduced a novel biodegradable microsphere-based soil conditioner with strong potential to improve nutrient use efficiency and soil quality in agricultural environments.}, } @article {pmid41260310, year = {2025}, author = {Alberti, C and Parente, V and Corti, S and Sansone, VA}, title = {From molecular convergence to clinical divergence: Comparative pathogenic mechanisms and therapeutic trajectories in C9orf72-ALS/FTD and myotonic dystrophy.}, journal = {Neurobiology of disease}, volume = {217}, number = {}, pages = {107192}, doi = {10.1016/j.nbd.2025.107192}, pmid = {41260310}, issn = {1095-953X}, support = {//framework of the National Recovery and Resilience Plan/ ; //European Union - Next Generation EU, Project/ ; }, mesh = {Humans ; *Myotonic Dystrophy/genetics/therapy/pathology ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology ; *C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics/therapy/pathology ; DNA Repeat Expansion ; Animals ; RNA-Binding Proteins/genetics ; }, abstract = {Short tandem repeat expansions in C9orf72, DMPK, and CNBP genes cause amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) and myotonic dystrophy types 1 and 2 (DM1/DM2), respectively. Despite distinct clinical phenotypes, these disorders share convergent molecular mechanisms with tissue-specific vulnerability, offering a framework to inform precision therapeutic strategies. Shared pathogenic features include nuclear RNA foci sequestering RNA-binding proteins that disrupt splicing, and repeat-associated non-AUG translation generating toxic dipeptide repeat proteins. In C9orf72, GGGGCC repeats form RNA-driven condensates, including protein-free condensates, via G-quadruplex formation. Evidence also implicates autophagy-lysosome and mitochondrial dysfunction, suggesting a potential "two-hit" loss/gain-of-function model. Clinically, C9orf72 expansions primarily affect motor neurons and frontotemporal circuits, with ALS progression typically occurring over 2-5 years. Conversely, myotonic dystrophy manifests as a muscle-predominant multisystem disorder progressing over decades. Genomic instability contributes to disease variability, with anticipation and parent-of-origin effects strongest in DM1, not confirmed in DM2 and controversial in C9orf72. Sequence interruptions modulate repeat stability and phenotype, influencing diagnostic interpretation. Therapeutic development has yielded contrasting outcomes. Antisense oligonucleotides targeting C9orf72 achieved target engagement and reduced dipeptide repeat proteins but failed clinically, potentially due to sense-strand selectivity and persistence of TDP-43 pathology. In contrast, RNA-targeting conjugates for DM1 (delpacibart etedesiran and DYNE-101) received FDA Breakthrough Therapy designation. Therapeutic success depends on tissue accessibility and addressing both shared and circuit-specific pathogenic cascades. While nuclear RNA targets appear druggable in myotonic dystrophy, the bidirectional transcription and compartmentalized pathology of C9orf72 ALS/FTD may require multi-targeted approaches for precision medicine.}, } @article {pmid41261122, year = {2025}, author = {Gobert, F and Merida, I and Maby, E and Seguin, P and Jung, J and Morlet, D and André-Obadia, N and Dailler, F and Berthomier, C and Otman, A and Le Bars, D and Scheiber, C and Hammers, A and Bernard, E and Costes, N and Bouet, R and Mattout, J}, title = {Disorder of consciousness rather than complete Locked-In Syndrome for end stage Amyotrophic Lateral Sclerosis: a case series.}, journal = {Communications medicine}, volume = {5}, number = {1}, pages = {482}, pmid = {41261122}, issn = {2730-664X}, abstract = {BACKGROUND: The end-stage of amyotrophic lateral sclerosis (ALS) is commonly regarded as a complete Locked-In Syndrome (cLIS). Shifting the perspective from cLIS (assumed consciousness) to Cognitive Motor Dissociation (potentially demonstrable consciousness), we aimed to assess the preservation of covert awareness (internally preserved but externally inaccessible) using a multimodal battery.

METHODS: We evaluate two end-stage ALS patients using neurophysiological testing, passive and active auditory oddball paradigms, an auditory Brain-Computer Interface (BCI), functional activation-task imaging, long-term EEG, brain morphology, and resting-state metabolism to characterize underlying brain function.

RESULTS: Patient 1 initially follows simple commands but fails twice at BCI control. At follow-up, command following is no longer observed and his oddball cognitive responses disappear. Patient 2, at a single evaluation, is unable to follow commands or control the BCI. Both patients exhibit altered wakefulness, brain atrophy, and a global cortico-subcortical hypometabolism pattern consistent with a disorder of consciousness, regarded as an extreme manifestation of ALS-associated fronto-temporal dementia.

CONCLUSIONS: Although it is not possible to firmly prove the absence of awareness, each independent measure concurred with suggesting that a "degenerative disorder of consciousness" rather than a cLIS may constitute the final stage of ALS. This condition appears pathophysiologically distinct from typical tetraplegia and anarthria, in which behavioural communication and BCI use persist to enhance quality of life. Identifying the neuroimaging signatures of this condition represents a substantial milestone in understanding end-stage ALS. Large-scale longitudinal investigations are warranted to determine the prevalence of this profile among patients whose communication appears impossible.}, } @article {pmid41261682, year = {2025}, author = {Huang, X and Wang, X and Yang, Y and Chen, H}, title = {Assessing the potential causal influence of myasthenia gravis on neurodegenerative diseases via multivariable Mendelian randomization.}, journal = {Medicine}, volume = {104}, number = {44}, pages = {e45340}, pmid = {41261682}, issn = {1536-5964}, mesh = {Humans ; Alzheimer Disease/epidemiology/genetics ; Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Myasthenia Gravis/epidemiology/genetics ; *Neurodegenerative Diseases/epidemiology/genetics ; Parkinson Disease/epidemiology/genetics ; Risk Factors ; }, abstract = {Myasthenia gravis (MG), an autoimmune condition known for impairing neuromuscular signaling, has increasingly been implicated in broader neurological dysfunctions. Recent studies point toward a possible connection between autoimmune and neurodegenerative processes. However, whether MG contributes causally to the onset of major neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) remains unclear. This study utilizes Mendelian randomization (MR) to explore the potential causal influence of MG on these disorders from a genetic standpoint. A univariable Mendelian randomization (UVMR) framework was employed using summary-level data from genome-wide association studies (GWAS) to evaluate the effect of MG on the risk of AD, PD, and ALS. To confirm the robustness of the association between MG and AD, 2 independent AD GWAS datasets were incorporated for external replication, followed by a meta-analysis to combine the evidence. Additionally, multivariable Mendelian randomization (MVMR) was conducted to adjust for smoking behavior as a potential confounding factor. The UVMR analysis revealed a statistically significant causal relationship between MG and increased susceptibility to AD (odds ratio (OR): 1.037; 95% confidence interval (CI): 1.007-1.068; P = .016). No significant causal effects were observed for PD (OR: 1.019; 95% CI: 0.964-1.077; P = .509) or ALS (OR: 1.055; 95% CI: 0.977-1.140; P = .171). The association between MG and AD was consistently validated in 2 independent datasets (ieu-a-297: OR = 1.084; 95% CI: 1.017-1.156; P = .013; ieu-b-2: OR = 1.054; 95% CI: 1.006-1.104; P = .027). Meta-analysis reinforced the evidence supporting MG as a risk factor for AD (OR: 1.047; 95% CI: 1.023-1.072; P < .001). Furthermore, MVMR adjusting for smoking confirmed that MG independently contributes to AD risk (OR: 1.037; 95% CI: 1.006-1.069; P = .020). This study provides robust genetic evidence suggesting that MG is a causal and independent risk factor for AD. These findings highlight a novel link between autoimmunity and neurodegeneration, offering new directions for mechanistic and therapeutic research.}, } @article {pmid41262008, year = {2025}, author = {Scott, MR and Sverdlov, O and Davis-Plourde, K and Tripodis, Y}, title = {Assessment of Wiener Process Degradation Models With Application to Amyotrophic Lateral Sclerosis Decline.}, journal = {Statistics in medicine}, volume = {44}, number = {25-27}, pages = {e70323}, doi = {10.1002/sim.70323}, pmid = {41262008}, issn = {1097-0258}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Monte Carlo Method ; *Models, Statistical ; Computer Simulation ; Likelihood Functions ; Disease Progression ; Longitudinal Studies ; Stochastic Processes ; }, abstract = {Degradation models are commonly used in engineering to analyze the deterioration of systems over time. These models offer an alternative to standard longitudinal methods as they explicitly account for within-subject temporal variability through a latent stochastic process, allowing random fluctuations within a patient to be captured. This work investigates Wiener process-based degradation models with linear drift (i.e., slope) while considering a diffusion term to represent within-subject temporal variability, a random-effects term to capture between-subject variability of the slope, and a time-invariant term to account for measurement error. First-difference estimators that stabilize covariance matrix inversion and remove the influence of time-invariant confounders are presented and validated in clinically relevant settings. Monte Carlo simulations assessing relative error and coverage probability demonstrate that these models yield consistent and stable estimates. Profile likelihood methods, which reduce the dimensionality of the parameter space, also performed reliably, but should be used with caution when follow-up times are highly clustered. As a proof of concept, we applied these models to amyotrophic lateral sclerosis (ALS) data from the Pooled Resource Open-Access ALS Clinical Trials Database (PRO-ACT). We observed steeper slopes of the revised ALS Functional Rating Scale (ALSFRS-R) in individuals who died compared to those who survived, indicating that degradation model estimates are consistent with expected patterns of ALS decline. Our results demonstrate that these stochastic models provide accurate and efficient estimates of longitudinal deterioration. Future work aims to incorporate Wiener process degradation models into a joint modeling framework.}, } @article {pmid41262412, year = {2025}, author = {Rajagopalan, V and Pioro, EP}, title = {Detour ahead: possible causes of corticospinal tract truncation in upper motor neuron-predominant amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {6}, pages = {fcaf419}, pmid = {41262412}, issn = {2632-1297}, abstract = {Clinical diagnosis of amyotrophic lateral sclerosis (ALS) depends on finding evidence of combined of upper motor neuron (UMN) and lower motor neuron degeneration. T2- and proton density (PD)-weighted images reveal intracranial corticospinal tract (CST) hyperintensity in some UMN-predominant ALS patients who also exhibit faster disease progression compared to those without CST hyperintensity. Our previous study identified CST fibre tract truncation in a subset of UMN-predominant ALS patients, both with and without CST hyperintensity. In this study, we investigated the underlying cause(s) of CST fibre tract truncation in such ALS patients. Routine clinical diffusion tensor imaging (DTI) scans were acquired in 14 neurologic controls and 45 ALS patients using a 1.5 T magnetic resonance imaging (MRI) scanner. UMN-predominant ALS patients were categorized into two subgroups based on their clinically-acquired conventional MRI findings. DTI reconstruction was performed using both single-exponential and bi-exponential fitting approaches (the latter for free water [FW] estimation). DTI along the perivascular space (ALPS) index was also measured. CST fibres were reconstructed using tractography in both control and ALS subgroups. In CST-truncated ALS patients, the fibres deviated from their normal trajectory and entered the superior longitudinal fasciculus (SLF) at the level of the centrum semiovale, resulting in apparent truncation and overlap with the SLF. Axial diffusivity, radial diffusivity, FW content, and mean diffusivity values were normal along the expected CST pathway in cases of truncation, suggesting that axonal or myelin degeneration, inflammation, or oedema were unlikely to be responsible for CST truncation. ALPS index was significantly increased in CST-truncated patients compared to those without CST truncation. Based on these results, we hypothesize that impaired axonal guidance mechanisms or dysfunction of the glymphatic system may contribute to CST fibre tract truncation in ALS.}, } @article {pmid41263806, year = {2025}, author = {Kalkowski, K}, title = {[Genetic and Molecular Pathomechanisms of Amyotrophic Lateral Sclerosis and Therapeutic Perspectives – Current State of Knowledge].}, journal = {Postepy biochemii}, volume = {71}, number = {3}, pages = {252-259}, doi = {10.18388/pb.2021_599}, pmid = {41263806}, issn = {0032-5422}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; Humans ; Genetic Therapy ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; Mutation ; RNA-Binding Protein FUS/genetics ; DNA-Binding Proteins/genetics ; Protein Serine-Threonine Kinases/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease leading to progressive degeneration of motor neurons, muscle weakness and respiratory failure. Despite intensive research, the pathomechanisms of ALS have not been fully elucidated. This article presents the current state of knowledge on the genetic and molecular mechanisms of this disease, with a focus on mutations in the SOD1, C9ORF72, TARDBP, FUS, TBK1 genes, as well as recent discoveries in this area. Key pathogenetic processes are discussed, including disruption of RNA homeostasis, oxidative stress, mitochondrial dysfunction and protein aggregation. In addition, current therapeutic strategies are reviewed, including both registered drugs, such as riluzole and edaravone, and modern approaches, such as gene therapy, antisense oligonucleotides, immunotherapy and gene editing technologies, including CRISPR/Cas9. Special attention was given to clinical trials and their potential impact on future treatment options for ALS.}, } @article {pmid41264881, year = {2026}, author = {Genuis, SK and Luth, W and Adams, B and Johnston, WS}, title = {Patient-based evidence for amyotrophic lateral sclerosis prognostic health communication: "the clock is ticking…how long do I have?".}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {301-311}, doi = {10.1080/21678421.2025.2589782}, pmid = {41264881}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Male ; Female ; Prognosis ; Middle Aged ; *Health Communication/methods ; Aged ; *Caregivers/psychology ; Adult ; Focus Groups ; Canada ; Disease Progression ; }, abstract = {Objectives: Prognostic health communication is a critical challenge for amyotrophic lateral sclerosis (ALS) health-care professions, however patient-based evidence for best practice remains limited. We investigated how the experiences of ALS patients and caregivers can inform prognostic communication and whether patient-based evidence supports clinical use of predictive tools. Methods: Data were drawn from ALS Talk, an asynchronous, online focus group study. Patients and family caregivers were recruited from across Canada. Seven groups interacted in a threaded web-forum structure. Sixty-four participants shared experiences and perspectives on prognostic communication. Data were qualitatively analyzed using conventional content analysis and the constant-comparative approach. Results: Primary themes were prognostic communication as an ongoing, evolving conversation; prognostic heterogeneity; progression as an embodiment of prognosis; and functional prognosis. The theme, information needs/wants, contributed to the primary themes. Participants highlighted the importance of stepwise discussions of general and personalized prognosis; prognostic heterogeneity as a source of hope and a potential communication barrier; and how progression facilitates material understanding of prognosis, adaptation, and future planning. Further, participants wanted more information about functional prognosis and the impact of interventions/therapies on function and survival. Conclusions: We discuss participants' central questions: "how long" and "how well," and provide recommendations for patient-centred ALS prognostic communication. Participants' embodied understanding of prognosis and desire for information that anticipates functional change, informs disease management, and facilitates timely planning suggests that clinical application of ALS staging systems may meet patient and caregiver need. Testing in real-world clinical settings is needed to ensure the development of patient-centred predictive tools.}, } @article {pmid41266705, year = {2025}, author = {Di Rienzo, L and Genovese, I and Galluzzi, G and Ruocco, G and Fornetti, E}, title = {Uncovering the molecular details of the 14-3-3 recruitment by mutant Sod1 species.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {41091}, pmid = {41266705}, issn = {2045-2322}, mesh = {*Superoxide Dismutase-1/genetics/metabolism/chemistry ; *14-3-3 Proteins/metabolism/chemistry ; Humans ; Molecular Dynamics Simulation ; *Mutation ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Molecular Docking Simulation ; Protein Binding ; }, abstract = {Mutations in superoxide dismutase 1 (SOD1) are a major cause of familial Amyotrophic Lateral Sclerosis (ALS), promoting disease progression through metal depletion, aggregation, and abnormal protein interactions. Among proteins interacting with pathological SOD1 aggregates, 14-3-3 proteins are involved in key cellular pathways often disrupted in ALS, such as cell survival, axonal growth, and DNA repair. Their sequestration by mutant SOD1 may impair their neuroprotective functions, exacerbating disease pathology. Despite this, 14-3-3 proteins remain understudied in ALS research, presenting an opportunity for novel insights. This study employs molecular dynamics simulations to investigate structural changes in two ALS-linked SOD1 mutations, A4V and L144F, compared to wild-type SOD1. A4V is associated with a severe disease form, while L144F leads to a slower progression, allowing an analysis of different ALS severities. Using Zernike polynomials and hydropathy assessments, we identified key structural alterations that promote aggregation and aberrant interactions. Large-scale docking simulations further suggest a stable complex between mutant SOD1 and 14-3-3 proteins, confirmed through molecular dynamics analyses. By elucidating structural features driving SOD1 aggregation and pathological interactions, our findings support targeting protein-protein interactions as a potential therapeutic strategy in ALS, offering an alternative to direct aggregate inhibition.}, } @article {pmid41267271, year = {2025}, author = {Xue, S and Wang, T and Zhou, J and Liu, S and Wang, C and Zhang, Y and Li, H and Chen, D and Lu, Y}, title = {Safety evaluation of aristolactams from the edible herb Houttuynia cordata: implications for dietary exposure and food safety.}, journal = {Food research international (Ottawa, Ont.)}, volume = {222}, number = {Pt 1}, pages = {117663}, doi = {10.1016/j.foodres.2025.117663}, pmid = {41267271}, issn = {1873-7145}, mesh = {Animals ; *Houttuynia/chemistry ; Mice, Inbred BALB C ; Mice ; *Aristolochic Acids/toxicity/pharmacokinetics ; *Food Safety ; Humans ; Male ; *Dietary Exposure/adverse effects ; Biological Availability ; Oxidative Stress/drug effects ; Kidney/drug effects ; Cell Line ; *Drugs, Chinese Herbal/toxicity ; Complement Activation/drug effects ; }, abstract = {Houttuynia cordata Thunb., a traditional edible and medicinal herb widely consumed in Asia, has raised concerns about food safety due to the presence of aristolactams (ALs), which are structural analogues of the nephrotoxic aristolochic acid I (AA I). This study investigated the subacute toxicity, metabolism and oral bioavailability of predominant ALs-aristolactam I (AL I), aristolactam BII (AL BII), and ALs fractions from H. cordata (HCA)-in BALB/c mice, with AA I as a positive control. The AL I, AL BII and HCA groups exhibited only modest elevations in body weight, serum renal indicators and urinary injury biomarkers. In contrast, AA I induced significant increases through oxidative stress and complement activation (C3a/C3aR and C5a/C5aR pathways). Although AL I demonstrated greater cytotoxicity to HK-2 cells (IC50 = 2.76 μM) than its metabolite AL Ia (IC50 = 35.41 μM) and even AA I (IC50 = 79.85 μM) in vitro, its in vivo toxicity was lower. This was attributed to the lower oral bioavailability of AL I (52.71 %) and AL BII (39.60 %) compared to AA I (99.83 %), combined with metabolism into less toxic derivatives. Furthermore, no parent ALs were detected in urine. These toxicokinetic properties limited renal exposure and reduced in vivo toxicity despite their notable cytotoxicity in vitro. These findings provided scientific support for the safe consumption of H. cordata at typical dietary levels, while emphasizing the importance of monitoring ALs content in edible herbs to ensure food safety and inform regulatory guidelines.}, } @article {pmid41267644, year = {2026}, author = {Tahedl, M and Siah, WF and Karavasilis, E and Hengeveld, JC and Doherty, MA and McLaughlin, RL and Hardiman, O and Tan, EL and Christidi, F and Kleinerova, J and Bede, P}, title = {Anatomical Associations Between Focal Mitochondrial Metabolism and Patterns of Neurodegeneration in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {99}, number = {3}, pages = {614-628}, pmid = {41267644}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/diagnostic imaging/genetics ; Male ; Female ; Middle Aged ; *Mitochondria/metabolism/pathology ; Aged ; *Brain/metabolism/pathology/diagnostic imaging ; Cohort Studies ; Adult ; C9orf72 Protein/genetics ; Magnetic Resonance Imaging ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) has a very specific neuroimaging signature, but the molecular underpinnings of the strikingly selective anatomic involvement have not elucidated to date. Accordingly, a large neuroimaging study was conducted with 258 participants to evaluate associations between patterns of neurodegeneration and focal metabolic metrics.

METHODS: Structural and diffusivity alterations were systematically evaluated in a genetically stratified cohort. Voxelwise associations between neurodegeneration and physiological mitochondrial indices were systematically evaluated over the entire brain and also examined in specific regions.

RESULTS: Significant topological associations were identified between physiological mitochondria tissue density, nicotinamide adenine dinucleotide (NADH)-ubiquinone oxidoreductase, succinate dehydrogenase, cytochrome c oxidase (COX), mitochondrial respiratory capacity (MRC), tissue respiratory capacity (TRC), and propensity to focal atrophy in ALS. Anatomic correlations between mitochondrial metrics and morphometric change were particularly strong in GGGGCC hexanucleotide repeat carriers in C9orf72. Diffusivity analyses also confirmed associations between brain metabolism and microstructural degeneration. Higher focal mitochondria tissue density was associated with higher likelihood of frontal, temporal, cerebellar, opercular, thalamic, cingulum, putamen, corpus callosum, and corona radiata degeneration. Uncinate fasciculus degeneration was associated with higher Complex I, II, COX, and TRC activity. Topological associations were readily replicated in an external validation cohort.

INTERPRETATION: Our data indicate that brain regions with high metabolic activity are particularly vulnerable to neurodegeneration in ALS. Anatomic associations between physiological cerebral metabolism and patterns of neurodegeneration implicate mitochondrial dysfunction in the pathophysiology of ALS. Although mitochondrial dysfunction may not be the primary etiological factor, it may represent a shared bottleneck of multiple converging molecular and genetic pathways, offering a potential opportunity for meaningful pharmacological intervention. ANN NEUROL 2026;99:614-628.}, } @article {pmid41268324, year = {2025}, author = {Thakur, DK and Padole, S and Sarkar, T and Arumugam, S and Chattopadhyay, S}, title = {Liquid-Liquid Phase Separation: Mechanisms, Roles, and Implications in Cellular Function and Disease.}, journal = {FASEB bioAdvances}, volume = {7}, number = {11}, pages = {e70054}, pmid = {41268324}, issn = {2573-9832}, abstract = {Liquid-liquid phase separation is a basic biophysical process that creates essential membraneless organelles that support different cellular activities, including chromatin organization and gene expression. The malfunction of liquid-liquid phase separation (LLPS) plays a critical role in numerous diseases, such as neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), which involve TDP-43 and Tau, various cancers that utilize SPOP and YAP/TAZ proteins, and viral infections where pathogens use LLPS to replicate and avoid immune detection. This review brings together the fast-growing knowledge about LLPS across multiple scientific fields. The paper examines the physiological functions of LLPS along with its disease pathogenesis mechanisms and presents various experimental techniques (e.g., advanced microscopy, FRAP, FCS) for its investigation. It introduces new therapeutic approaches such as PTM modulation, small molecules like 1,6-hexanediol and Lipoamide, and advanced genetic tools including CRISPR and PROTACs like PSETAC, which also explores diagnostic applications. The thorough integration of knowledge presented here is essential to connect separate scientific findings while propelling research forward and turning LLPS discoveries into new biomedical developments.}, } @article {pmid41268542, year = {2025}, author = {Baird, LA and Teener, SJ and Webber-Davis, IF and Carter, AD and Huang, F and Jang, DG and Famie, JP and Piecuch, CE and Guo, K and Feldman, EL and Murdock, BJ}, title = {Tofacitinib extends survival in a mouse model of ALS through NK cell-independent mechanisms.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1662197}, pmid = {41268542}, issn = {1664-3224}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology/mortality/pathology ; *Pyrimidines/pharmacology/therapeutic use ; *Piperidines/pharmacology/therapeutic use ; Disease Models, Animal ; Mice ; *Killer Cells, Natural/immunology/drug effects ; Mice, Transgenic ; *Protein Kinase Inhibitors/pharmacology ; Superoxide Dismutase-1/genetics ; Spinal Cord/drug effects/immunology ; Motor Neurons/drug effects/immunology ; Male ; Female ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease with few treatment options, rendering the development of new, effective therapeutics of critical importance. The immune system plays a substantial role in ALS pathology, with multiple cell populations implicated in disease progression. Natural killer (NK) cells are innate immune cells that accumulate in the brain and spinal cord during ALS, increasing neuroinflammation and killing motor neurons. Depleting NK cells extends survival in mouse models of ALS. Tofacitinib, an FDA-approved janus kinase (Jak) and signal transducer and activator (STAT) pathway inhibitor, reduces NK cytotoxicity and decreases overall levels in peripheral blood and may represent a potential ALS therapy. Therefore, we aimed to evaluate the effects of tofacitinib treatment on survival and phenotype in an ALS mouse model. Additionally, we sought to determine the impact of dose and regimen on efficacy.

METHODS: SOD1 [G93A] mice, the most used rodent model of ALS, were treated with low- (5 mg/kg) and high-dose (30 mg/kg) tofacitinib following a prevention regimen, an intervention regimen, or a drug-cycling regimen, with survival being the primary outcome. Symptom onset was assessed via body weight, agility, and grip strength measurements. At end-stage disease (i) motor neurons and neuromuscular junctions were counted, (ii) immune populations were quantified via flow cytometry in peripheral blood and spinal cord, (iii) microglial surface marker expression was quantified to assess neuroinflammation, and (iv) bulk RNA-seq was performed on spinal cord.

RESULTS: Low-dose, but not high-dose, tofacitinib significantly increased survival and delayed weight loss. Notably, beginning treatment before symptom onset (prevention) did not offer any survival advantage over the intervention nor cycling regimen; further analyses were pooled by dose. There were no differences in motor neuron or neuromuscular junction counts. Peripheral NK and CD8+ T cells were decreased dose-dependently. Interestingly, spinal cord infiltrating NK cells increased with low-dose tofacitinib, though no other changes in neuroinflammation were observed. RNA-seq revealed that low-dose tofacitinib treatment reversed the dysregulation of multiple immune and metabolic pathways.

CONCLUSIONS: These data support the repurposing of tofacitinib as a potential ALS treatment.}, } @article {pmid41269363, year = {2025}, author = {Schito, P and Domi, T and Russo, T and Pozzi, L and Falzone, YM and Pipitone, GB and Agosta, F and Carrera, P and Quattrini, A and Riva, N and Filippi, M}, title = {The genetic architecture of primary lateral sclerosis in a cohort of Italian patients.}, journal = {Journal of neurology}, volume = {272}, number = {12}, pages = {780}, pmid = {41269363}, issn = {1432-1459}, mesh = {Humans ; Italy ; Male ; Female ; Middle Aged ; Aged ; Cohort Studies ; Adult ; C9orf72 Protein/genetics ; *Motor Neuron Disease/genetics ; High-Throughput Nucleotide Sequencing ; Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {BACKGROUND AND PURPOSE: Recent studies suggest that primary lateral sclerosis (PLS) may have a genetic component. In this work, we performed a next-generation sequencing (NGS) analysis in order to explore the genetic architecture of PLS in a cohort of Italian patients.

METHODS: NGS was conducted to analyze 228 genes associated with amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP), and parkinsonian syndromes (PS) in a cohort of PLS patients diagnosed between 2003 and 2021 at our center. All patients were also screened for C9orf72 hexanucleotide repeat expansion (C9orf72-HRE) by repeat-primed PCR. Genetic variants were classified according to the ACMG criteria.

RESULTS: In our study, including 47 PLS patients, we detected 22 rare variants in 17 patients, including 8 likely pathogenic or pathogenic variants and 14 variants of uncertain significance. Four patients carried more than one variant. Among the variants identified, 18 (81.8%) were found in ALS-associated genes. Variants in TBK1 were associated with extra-motor involvement.

CONCLUSIONS: Although the majority of the PLS patients in our cohort tested negative for an expanded panel of genes associated with ALS, HSP and PS, in 36.2% of the cases, a genetic variant was identified and it mostly belongs to genes associated with ALS, including a C9orf72 expansion and a rare SOD1 variant. Based on these results, we emphasize the need for genetic screening in PLS patients. Further studies on the genetic background are necessary to better understand the complex pathomechanism of each phenotype within the MND-FTD spectrum disorder.}, } @article {pmid41269403, year = {2025}, author = {Jin, J and Hand, R and Meltzer, M and Abate, C and Geva, M and Hayden, MR and Ross, CA}, title = {Sigma-2 Receptor Antagonism Enhances the Neuroprotective Effects of Pridopidine, a Sigma-1 Receptor Agonist, in Huntington's Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {121}, pmid = {41269403}, issn = {1559-1182}, mesh = {*Receptors, sigma/antagonists & inhibitors/agonists/metabolism ; *Huntington Disease/drug therapy/pathology/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; Sigma-1 Receptor ; *Piperidines/pharmacology/therapeutic use ; Mice ; Humans ; Neurons/drug effects/metabolism/pathology ; Huntingtin Protein/metabolism ; }, abstract = {Pridopidine is a selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Activation of the S1R by pridopidine is neuroprotective in multiple preclinical models of neurodegenerative disease. The sigma-2 receptor (S2R) is evolutionarily and structurally unique from the S1R. Nevertheless, the S1R and S2R share an overlapping yet distinct ligand binding profile. Inhibition of the S2R is neuroprotective and S2R antagonists are in clinical development for Alzheimer's Disease (AD), ⍺-synucleinopathies, and dry age-related macular degeneration. In this study, we hypothesized that simultaneous activation of the S1R by pridopidine and inhibition of the S2R by the selective S2R antagonist FA10 might provide enhanced protection against mutant huntingtin (mHTT) expression in an in vitro model of neurodegeneration. Consistent with previous studies, pridopidine reduced neuronal cell death in a mouse primary neuron mHTT model. Similarly, we found that inhibition of the S2R by FA10 was also sufficient to protect against mHTT induced neurodegeneration in this model. The combination treatment of pridopidine and FA10 achieved greater efficacy than either compound alone, even at lower concentrations. The combination of these compounds may allow for lower efficacious doses leading to improved safety profiles and reduced off-target effects. This novel combinatorial approach, in which the S1R is activated while simultaneously inhibiting the S2R may prove to be a highly effective therapeutic strategy for HD and other neurodegenerative diseases.}, } @article {pmid41269421, year = {2025}, author = {Asadinejad, H and Taherkhani, S and Golboos, SM and Azizi, Y and Mohammadkhanizadeh, A}, title = {Targeting Neurodegeneration with SGLT2is: From Molecular Mechanisms to Clinical Implications.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {119}, pmid = {41269421}, issn = {1559-1182}, mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a class of antidiabetic drugs that have demonstrated significant cardiovascular and renal benefits. Accumulating evidence suggests that SGLT2is also exert neuroprotective effects and may influence the progression of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). SGLT2is modulate glucose metabolism, reduce oxidative stress, suppress inflammation, and enhance mitochondrial function. Beyond glycemic control, they show potential therapeutic effects in ameliorating the metabolic dysregulation associated with neurodegenerative pathologies. Current preclinical and clinical evidence including metabolic regulation, anti-inflammatory actions, and neuroprotective effects mediated through SGLT2is associated molecular pathways have been critically evaluated to delineate their therapeutic potential in neurodegenerative disorders. Although preclinical studies have shown promising results, more clinical trials are needed. This review highlights key research gaps and proposes future translational applications.}, } @article {pmid41269513, year = {2026}, author = {Jude, EB and Saluja, S and Mannan, F and Heagerty, A and Frier, B}, title = {UK Resuscitation Advanced Life Support Guidelines: Should the Paradigm be Extended?.}, journal = {Diabetes therapy : research, treatment and education of diabetes and related disorders}, volume = {17}, number = {1}, pages = {9-18}, pmid = {41269513}, issn = {1869-6953}, abstract = {Cardiac arrest continues to be a predominant cause of mortality worldwide, necessitating its rapid identification, and intervention by reversible aetiologies to optimise successful outcomes. The established 4H 4T framework has served as a foundational guide for advanced life support (ALS) protocols since its formal introduction in the 2000 International Guidelines on Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care (ECC), effectively targeting critical conditions such as hypoxia, hypothermia, hypo-/hyperkalaemia, hypovolaemia, tension pneumothorax, cardiac tamponade, thrombosis, and exposure to toxins. However, this framework inadequately addresses other significant factors: specifically hypoglycaemia and tachy- and bradyarrhythmias. Hypoglycaemia, a reversible and treatable metabolic state, poses substantial threats to cardiovascular stability, particularly in people with diabetes and in association with sepsis. It disrupts myocardial repolarisation, prolongs the QT interval, and may instigate the R-on-T phenomenon, which can precipitate life-threatening arrhythmias. Likewise, tachyarrhythmias and bradyarrhythmias often precipitate cardiac arrest, thereby warrant dedicated attention within ALS protocols. This paper advocates expanding the current 4H 4T framework to include hypoglycaemia and tachy- and bradyarrhythmias as critical and reversible causes of cardiac arrest (5H 5T). The rationale for such a paradigm shift is supported by evidence from clinical studies, case reports, and experimental models that demonstrate the adverse effect of these conditions on cardiovascular integrity and alert clinicians to look for these reversible factors. The inclusion of these factors into ALS protocols will necessitate revising resuscitation guidelines, modifying training for healthcare practitioners, and including systematic monitoring of blood glucose alongside routine assessment of cardiac rhythm during resuscitation procedures. Future research should focus on elucidating the pathophysiological mechanisms underlying these conditions, to establish operational thresholds for intervention, and validate their integration into resuscitation frameworks. By expanding the conceptualisation of reversible causes, the proposed 5H/5T framework would offer a more rational and practical approach to the management of cardiac arrest, to improve the survival and recovery of these critically ill patients.}, } @article {pmid41269662, year = {2025}, author = {Milella, G and Fiorella, ML and Velucci, V and Sciancalepore, D and Luisi, F and Fraddosio, A and D'Errico, E and Muroni, A and Defazio, G}, title = {Unrevealing the sequence of dysphagia progression in ALS: an event-based, FEES-driven staging approach.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {41269662}, issn = {1435-1463}, abstract = {Dysphagia drives morbidity and mortality in amyotrophic lateral sclerosis (ALS), yet staging systems treat it as a binary milestone and do not capture its trajectory. Reports diverge on the earliest abnormality, with some citing cohesive-bolus inefficiency and others thin-liquid impairment. Furthermore, how these findings relate to patient-perceived dysphagia remains unclear. In a prospective cohort, 78 incident ALS patients underwent one or more fiberoptic endoscopic evaluations of swallowing (FEES), yielding 108 assessments. Pharyngeal residue for four consistencies was rated with a validated scale. An event-based model (EBM) inferred the temporal order of abnormalities and defined a five-stage, FEES-based dysphagia staging system (DSS). Construct, convergent, discriminant, and prognostic validity were tested against established measures; responsiveness was assessed in patients with longitudinal FEES. The EBM identified a consistent sequence of swallowing impairment: solids, semisolids, liquids, saliva. Patient-perceived dysphagia occurred in 38% of DSS 1-2 evaluations versus 100% of DSS 3-4. The DSS showed construct validity by distinguishing bulbar- from spinal-onset ALS and convergent validity with the ALSFRS-R bulbar subscore and LMN bulbar score. Discriminant validity was supported by weak, non-significant associations with spinal/respiratory measures. Agreement with King's staging was moderate, and all King's stage IV patients mapped to DSS stages 3-4. The DSS was responsive to change (Stuart-Maxwell χ[2] = 11.034; p = 0.026). The EBM reconciles prior discrepancies: pathophysiology begins with solids, whereas symptom recognition typically coincides with liquid-phase residue. The FEES-based DSS is reproducible and clinically meaningful for tracking bulbar involvement and identifying higher-risk patients.}, } @article {pmid41269901, year = {2025}, author = {Peters, T and Yang, H and Zou, Z and Ye, W}, title = {Thyroid Disease and Amyotrophic Lateral Sclerosis.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-8}, doi = {10.1159/000549662}, pmid = {41269901}, issn = {1423-0208}, abstract = {INTRODUCTION: Thyroid disease has been implicated in the pathology of neurodegenerative diseases. However, its role in amyotrophic lateral sclerosis (ALS) is unclear. This study aimed to investigate the association between thyroid disease, including hypothyroidism and hyperthyroidism, and the risk of ALS.

METHODS: We used a matched cohort design to evaluate UK Biobank data on participants enrolled between 2006 and 2010 who were followed up until 2022. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS: The study cohort comprised 42,684 patients with thyroid disease (females: 80%). Thyroid disease was moderately associated with an increased risk of ALS development (HR: 1.44, 95% CI: 1.02-2.02), and this association remained similar following adjustment for comparative height at the age of 10 years (HR: 1.44, 95% CI: 1.03-2.03). Hyperthyroidism showed a potential association with an increased risk of ALS development among individuals aged ≤60 years (HR: 21.22, 95% CI: 1.64-274.46) and in females (HR: 3.02, 95% CI: 1.13-8.08).

CONCLUSION: Our findings demonstrate that thyroid disease is associated with a moderately increased risk of ALS development. Given the multifunctional role of the thyroid gland, further in-depth studies examining the relationship between thyroid conditions and ALS are warranted.}, } @article {pmid41271630, year = {2025}, author = {Woo, E and Tasnim, F and Kawamata, H and Manfredi, G and Konrad, C}, title = {Investigation of mitochondrial phenotypes in motor neurons derived by direct conversion of fibroblasts from familial ALS subjects.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {51}, pmid = {41271630}, issn = {2041-4889}, support = {R01NS139141//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; MDA602762//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; R01 NS139141/NS/NINDS NIH HHS/United States ; R35 NS122209/NS/NINDS NIH HHS/United States ; MDA961871//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; R35NS122209//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *Mitochondria/metabolism/pathology ; *Fibroblasts/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; Phenotype ; Membrane Potential, Mitochondrial ; Superoxide Dismutase-1/genetics/metabolism ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons, leading to fatal muscle paralysis. Familial forms of ALS (fALS) account for approximately 10% of cases. Alterations of mitochondrial functions have been proposed to contribute to disease pathogenesis. Here, we employed a direct conversion (DC) technique to generate induced motor neurons (iMN) from skin fibroblasts to investigate mitochondrial phenotypes in a patient-derived disease relevant cell culture system. We converted 7 control fibroblast lines and 17 lines harboring the following fALS mutations, SOD1[A4V], TDP-43[N352S], FUS[R521G], CHCHD10[R15L], and C9orf72 repeat expansion. We developed new machine learning approaches to identify iMN, analyze their mitochondrial function, and follow their fate longitudinally. Mitochondrial and energetic abnormalities were observed, but not all fALS iMN lines exhibited the same alterations. SOD1[A4V], C9orf72, and TDP-43[N352S] iMN had increased mitochondrial membrane potential, while in CHCHD10[R15L] cells membrane potential was decreased. TDP-43[N352S] iMN displayed changes in mitochondrial morphology and increased motility. SOD1[A4V], TDP-43[N352S], and CHCHD10[R15L] iMN had increased oxygen consumption rates and altered extracellular acidification rates. FUS[R521G] mutants had decreased ATP/ADP ratio, suggesting impaired energy metabolism. SOD1[A4V], C9orf72, and TDP-43[N352S] had increased, while FUS[R521G] had decreased mitochondrial reactive oxygen species production. We tested the viability of iMN and found decreases in survival in SOD1[A4V], C9orf72, and FUS[R521G], which were corrected by small molecules that target mitochondrial stress and worsened by bioenergetic stressors. Together, our findings reinforce the role of mitochondrial dysfunction in ALS and indicate that fibroblast-derived iMN may be useful to study fALS metabolic alterations. Strengths of the DC iMN approach include low cost, speed of transformation, and the preservation of epigenetic modifications. However, further refinement of the fibroblasts DC iMN technique is still needed to improve transformation efficiency, reproducibility, the relatively short lifespan of iMN, and the senescence of the parental fibroblasts.}, } @article {pmid41271702, year = {2025}, author = {Resnick, SJ and Qamar, S and Krishna, P and Korben, VA and Ausserwoger, H and Miller, A and Esposito, P and Varela, JA and Sheng, J and Huang, LH and Nixon-Abell, J and Melore, S and Chung, CW and Läubli, NF and Kapsiani, S and Li, X and Wang, J and Zhang, N and Alam, MM and Burguete, AS and Swayne, TC and Chen, Y and Liao, YC and Shneider, NA and Vendruscolo, M and Knowles, TPJ and Kaminski, CF and Ruggeri, FS and Kaminski Schierle, GS and St George-Hyslop, P and Chavez, A}, title = {Multiplex neurodegeneration proteotoxicity platform reveals DNAJB6 promotes non-toxic FUS condensate gelation and inhibits neurotoxicity.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {10285}, pmid = {41271702}, issn = {2041-1723}, support = {406915, Canadian Consortium on Neurodegeneration in Aging Grant//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; F31NS111851//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; /WT_/Wellcome Trust/United Kingdom ; 337969//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; AL190073//U.S. Department of Defense (United States Department of Defense)/ ; Career Awards for Medical Scientists//Burroughs Wellcome Fund (BWF)/ ; 5R01NS106236//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; MR/K02292X/1//RCUK | Medical Research Council (MRC)/ ; 203249/Z/16/Z//Wellcome Trust (Wellcome)/ ; R01 NS106236/NS/NINDS NIH HHS/United States ; R01 HG006137/HG/NHGRI NIH HHS/United States ; 2R01HG006137-10//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 804581//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; F31 NS111851/NS/NINDS NIH HHS/United States ; 21-IIA-571//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; P30 CA013696/CA/NCI NIH HHS/United States ; AS-PhD-19a-016/ALZS_/Alzheimer's Society/United Kingdom ; 10100161//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; 2113646//National Science Foundation (NSF)/ ; ZEN-18-529769/ALZ/Alzheimer's Association/United States ; }, mesh = {*HSP40 Heat-Shock Proteins/metabolism/genetics ; Humans ; Animals ; *Molecular Chaperones/metabolism/genetics ; Mice ; *RNA-Binding Protein FUS/metabolism/genetics/chemistry ; *Nerve Tissue Proteins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Frontotemporal Dementia/metabolism/genetics/pathology ; Saccharomyces cerevisiae/metabolism/genetics ; Disease Models, Animal ; *Neurodegenerative Diseases/metabolism/genetics ; }, abstract = {Neurodegenerative disorders (NDDs) are a family of diseases that remain poorly treated despite their growing global health burden. To gain insight into the mechanisms and modulators of neurodegeneration, we developed a yeast-based multiplex genetic screening platform. Using this platform, 32 NDD-associated proteins are probed against a library of 132 molecular chaperones from both yeast and humans, and an unbiased set of ~900 human proteins. We identify both broadly active and specific modifiers of our various cellular models. To illustrate the translatability of this platform, we extensively characterize a potent hit from our screens, the human chaperone DNAJB6. We show that DNAJB6 modifies the toxicity and solubility of multiple amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD)-linked RNA-binding proteins (RBPs). Biophysical examination of DNAJB6 demonstrated that it co-phase separates with, and alters the behavior of FUS containing condensates by locking them into a loose gel-like state which prevents their fibrilization. Domain mapping and a deep mutational scan of DNAJB6 revealed key residues required for its activity and identified variants with enhanced activity. Finally, we show that overexpression of DNAJB6 prevents motor neuron loss and the associated microglia activation in a mouse model of FUS-ALS.}, } @article {pmid41271780, year = {2025}, author = {Hou, X and Tang, X and Zhao, Y and Liu, Z and Zhang, J and Gong, Z and Kang, Z and Li, Z and Chen, H and Wang, J and Tang, B and Zhou, X and Lei, L}, title = {Characterization of the genetic and clinical landscapes of DCTN1 gene in neurodegenerative diseases: a series of large case-control study.}, journal = {NPJ genomic medicine}, volume = {10}, number = {1}, pages = {75}, pmid = {41271780}, issn = {2056-7944}, support = {2022JJ30879//the Natural Science Foundation of Hunan Province/ ; 2024JJ5509//the Natural Science Foundation of Hunan Province/ ; 2023SK2037//the Hunan Innovative Province Construction Project/ ; 81971086//the Program of the National Natural Science Foundation of China/ ; }, abstract = {Impairment of axonal transport has been emphasized as a common feature in a series of neurodegenerative diseases (NDs). Variations in DCTN1 have been reported in NDs such as Parkinson's disease (PD), Perry syndrome (PS) and Amyotrophic lateral sclerosis (ALS). The overall objective of this study was to investigate the contribution of DCTN1 variants in different NDs and to explore the correlation between DCTN1 variants and disease phenotypes. We identified a previously published mutation p.G71E in three unrelated PS families. In the PD cohort, 30 putative deleterious variants (PDVs) were identified in DCTN1. Gene-based burden analysis showed a nominal association between DCTN1 rare PDVs and PD (uncorrected p = 0.042); however, this association did not remain statistically significant after multiple testing correction (FDR-corrected p = 0.084). In the ALS cohort, 10 PDVs were all rare damaging missense variants, and the PDVs were not enriched in ALS patients. Our findings first provide the independent evidence that PDVs in DCTN1 may be a risk factor for PD, but do not support the genetic involvement of DCTN1 in ALS of Asian ancestry.}, } @article {pmid41271785, year = {2025}, author = {Faggioli, G and Menotti, L and Marchesin, S and Trescato, I and Ahmad, L and Aidos, H and Alungulese, AL and Bellazzi, R and Bergamaschi, R and Birolo, G and Bosoni, P and Cabrera-Umpiérrez, MF and Cavalla, P and Chió, A and Dagliati, A and de Carvalho, M and Fariselli, P and García Dominguez, JM and González Martínez, S and Gromicho, M and Guazzo, A and Jovanović, A and Kostić, B and Longato, E and Madeira, SC and Manera, U and Muñoz Blanco, JL and Tavazzi, E and Tavazzi, E and Trasobares Iglesias, E and Urošević, V and Vettoretti, M and Di Nunzio, GM and Silvello, G and Di Camillo, B and Ferro, N}, title = {The BRAINTEASER Datasets: Clinical, Wearable and Environmental Data for ALS & MS Progression Modeling.}, journal = {Scientific data}, volume = {12}, number = {1}, pages = {1854}, pmid = {41271785}, issn = {2052-4463}, support = {GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Disease Progression ; *Multiple Sclerosis/physiopathology ; *Wearable Electronic Devices ; Artificial Intelligence ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are debilitating diseases with unpredictable progression. Artificial Intelligence-based tools for modelling disease progression could significantly improve the quality of life for patients and caregivers while supporting clinicians in delivering more personalized and timely care. However, the limited availability of data hinders the development, testing, and reproducibility of such predictive tools. To address this challenge, we curated, in the context of the H2020 BRAINTEASER project, four datasets containing clinical data from a total of 2,290 ALS patients and 723 MS patients. These datasets also include environmental data and information collected through wearable devices. Unlike most existing resources, the BRAINTEASER datasets are gathered from clinical practice, offering a more accurate representation of the data that an AI progression prediction tool would encounter in real-world scenarios. In addition to manual and automated data quality checks, the research community has validated the datasets through three editions of the intelligent Disease Progression Prediction challenges held within the Conference and Labs of the Evaluation Forum (CLEF).}, } @article {pmid41272780, year = {2025}, author = {Kumar, A and Shukla, S and Rai, A and Pathak, P and Narayan, KP}, title = {Concurrent nanotherapeutics and regulatory updates for the management of amyotrophic lateral sclerosis: a focused review for orphan drug (Tofersen).}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {598}, pmid = {41272780}, issn = {1750-1172}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Genetic Therapy/methods ; Orphan Drug Production ; *Oligonucleotides/therapeutic use ; United States Food and Drug Administration ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting nerve cells in the brain and spinal cord. With a global incidence of 1.9 to 6 per 100,000 people, ALS is slightly more common in men and prevalent in individuals over 60. However, this review provides a concise update on the regulatory landscape and therapeutic advancements in managing ALS, focusing on the recent approval of Tofersen, the first gene therapy specifically targeting SOD1 mutation-related ALS.

RESULTS: It highlights Tofersen unique role as an orphan drug approved by the US FDA, emphasizing its mechanism of action, gene silencing and its impact on reducing neurodegeneration. Additionally, the review synthesizes data from ongoing clinical trials, pharmacovigilance reports, and case studies to comprehensively understand Tofersen's safety, efficacy and market exclusivity. Beyond this, it explores the emerging potential of nanotherapeutic approaches to ALS treatment, identifying critical research gaps and future directions.

CONCLUSION: Integrating regulatory updates, clinical evidence, and innovative therapeutic strategies, the review uniquely contributes to the ALS literature by bridging current treatment realities with potential future therapies, aiming to inform researchers, clinicians, and policymakers on optimizing ALS management.}, } @article {pmid41273593, year = {2026}, author = {Paplomatas, P and Nikolidaki, M and Vrahatis, A}, title = {Uncovering Key Genes in Neurodegenerative Diseases Through Unsupervised Learning: A Variance-Based LSTM and Enrichment Analysis Approach.}, journal = {Advances in experimental medicine and biology}, volume = {1487}, number = {}, pages = {559-568}, pmid = {41273593}, issn = {0065-2598}, mesh = {Humans ; *Unsupervised Machine Learning ; *Neurodegenerative Diseases/genetics ; Cluster Analysis ; Gene Expression Profiling/methods ; Neural Networks, Computer ; Parkinson Disease/genetics ; Gene Regulatory Networks ; Alzheimer Disease/genetics ; Computational Biology/methods ; }, abstract = {This study presents an integrated approach for discovering and clustering significant genes associated with neurodegenerative diseases using a combination of variance-based filtering, Long Short-Term Memory (LSTM) neural networks, and enrichment analysis. By first filtering genes based on their variance across samples, we retain genes with high biological relevance. These selected genes are then used to train an LSTM model, capturing complex interactions between gene expression patterns. Using Uniform Manifold Approximation and Projection (UMAP) for dimensionality reduction and K-Means for clustering, we group genes with similar expression profiles. The optimal number of clusters is determined using the Silhouette Score. To refine the model, we introduce a feedback loop where cluster labels are fed back into the LSTM as additional features, enhancing the model's ability to detect significant gene associations. We compare various network architectures to assess their impact on clustering performance. Finally, enrichment analysis reveals key biological pathways, such as immune regulation and protein signaling, related to Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Our approach demonstrates the potential of machine learning and clustering to uncover meaningful gene associations, offering insights into the molecular mechanisms underlying neurodegenerative diseases.}, } @article {pmid41273627, year = {2025}, author = {Wang, W and Tan, S and Zuo, X and Gao, X and Ma, L and Sun, R and Liang, G and Yin, L and Pu, Y and Zhang, J}, title = {Brain Organoids in Neurodegenerative Disease Modeling: Advances, Applications and Future Perspectives.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {142}, pmid = {41273627}, issn = {1559-1182}, mesh = {*Organoids/pathology ; Humans ; *Neurodegenerative Diseases/pathology ; *Brain/pathology ; Animals ; Disease Models, Animal ; *Models, Biological ; }, abstract = {Neurodegenerative diseases (NDDs) represent incurable and debilitating conditions characterized by progressive deterioration of neurological function. Investigating neurodegeneration remains a critical global challenge in aging societies. Brain organoids-self-organizing three-dimensional structures derived from human pluripotent stem cells-recapitulate cell types and cytoarchitectures of the developing human brain. This in vitro model system has advanced our bridge between conventional two-dimensional cultures and in vivo models. Brain organoids emulate early neural tube formation, neuroepithelial differentiation, and whole-brain regionalization. Furthermore, region-specific organoid models now facilitate mechanistic investigation into acquired and inherited NDDs' pathogenesis, alongside drug discovery and toxicity screening. In this review, we (i) delineate the epidemiology and pathobiology of major NDDs, (ii) analyze limitations of current animal models, (iii) critically evaluate brain organoid generation methodologies, and (iv) focus on organoid applications in modeling Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).}, } @article {pmid41274292, year = {2026}, author = {Cohen, Y and Sinai, I and Magen, I and Danino, YM and Wuu, J and Malaspina, A and Benatar, M and Hornstein, E}, title = {IsomiR utility in amyotrophic lateral sclerosis prognostication.}, journal = {Med (New York, N.Y.)}, volume = {7}, number = {2}, pages = {100928}, doi = {10.1016/j.medj.2025.100928}, pmid = {41274292}, issn = {2666-6340}, support = {U01 NS107027/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/mortality/diagnosis ; Prognosis ; Male ; Female ; Middle Aged ; *MicroRNAs/blood/genetics ; Biomarkers/blood ; Aged ; High-Throughput Nucleotide Sequencing ; Neurofilament Proteins/blood ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. IsomiRs are microRNA (miRNA) isoforms that arise from alternative processing or editing events during miRNA biogenesis. While isomiRs may carry distinct biological and clinical relevance, their potential as cell-free biomarkers in neurodegeneration remains largely unexplored.

METHODS: Here, we investigated the prognostic utility of plasma isomiRs in ALS, using next-generation sequencing and two orthogonal statistical approaches.

FINDINGS: We profiled cell-free isomiRs in 154 ALS patients from a British cohort and identified higher levels of one isomiR, let-7g-5p.t, to be associated with longer survival. This finding was independently validated in an international ALS cohort of 200 patients. let-7g-5p.t prognostic utility was comparable to that of neurofilament light chain (NfL) or miR-181.

CONCLUSIONS: These results establish isomiRs as a novel class of blood-based biomarkers in ALS with the potential to refine prognostication in clinical trials for neurodegenerative diseases.

FUNDING: This study was funded by Target ALS the Israel Science Foundation (3497/21, 424/22) and the CReATe Consortium. All additional funding can be found under the Acknowledgments.}, } @article {pmid41274565, year = {2026}, author = {Chen, SC and Lee, YT}, title = {Comments on Liu et al's "Caged-hypocrellin mediated antimicrobial photodynamic therapy as a dual-action strategy for fungal clearance and immune response regulation in drug-resistant Candida auris wound infections".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {3}, pages = {e195-e196}, doi = {10.1016/j.jaad.2025.10.152}, pmid = {41274565}, issn = {1097-6787}, } @article {pmid41274569, year = {2026}, author = {Liu, X and Guo, S and Wang, J and Zhang, L and Lin, Y and Liu, Y and Ouyang, J and Shi, D and Xu, B and Fang, W and Ran, Y}, title = {Reply to: "Comments on Liu et al's 'Caged-hypocrellin mediated antimicrobial photodynamic therapy as a dual-action strategy for fungal clearance and immune response regulation in drug-resistant Candida auris wound infections'".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {3}, pages = {e197-e198}, doi = {10.1016/j.jaad.2025.11.050}, pmid = {41274569}, issn = {1097-6787}, } @article {pmid41274655, year = {2026}, author = {Kaplan, J and Smith, R and Craig, T and Carder, P and Taylor, J and Gadkari, G and Pollack, CE and Thomas, KS}, title = {Using the Low-Income Housing Tax Credit to Fund Assisted Living: Mapping the Current Environment.}, journal = {Journal of the American Medical Directors Association}, volume = {27}, number = {2}, pages = {106008}, doi = {10.1016/j.jamda.2025.106008}, pmid = {41274655}, issn = {1538-9375}, mesh = {Humans ; *Poverty ; United States ; *Housing/economics ; *Assisted Living Facilities/economics ; *Taxes ; }, abstract = {OBJECTIVES: The Low-Income Housing Tax Credit (LIHTC) has been responsible for creating more units of affordable housing than any other federal program. However, the extent to which it has been used to finance the development of assisted living (AL) is unknown. The objective of this study is to understand the prevalence of LIHTC-funded AL and how ALs funded with LIHTC differ from other ALs.

DESIGN: We linked the Department of Housing and Urban Development's LIHTC database (1987-2022) and a national list of licensed ALs (2023) to identify LIHTC-funded ALs (LIHTC-ALs) operating in 2023.

SETTING: Nationwide study of the location of ALs funded by LIHTC.

METHODS: We used geospatial coordinates, street addresses, and property names to link the data. Characteristics of ALs were compared using descriptive statistics.

RESULTS: We identified 197 LIHTC-ALs out of 37,510 total ALs (0.53%) and 50,471 LIHTC properties (0.39%). LIHTC-ALs were highly concentrated in a handful of states including Massachusetts (n = 31), Indiana (n = 26), Iowa (n = 13), Colorado (n = 12), and Maine (n = 12). Thirteen states did not have any LIHTC-ALs. Compared with other ALs, LIHTC-ALs were significantly more likely to be in a medically underserved area (11.7% vs 5.8%, P < .001), less likely to be in a higher-income area (median income of $71,758 vs $87,164, P < .001), and more likely to be in an area with a higher proportion of White individuals (71.1% vs 66.9%, P = .005). In addition, when compared with non-AL LIHTC properties, LIHTC-ALs were more likely to be in a higher-income area (median income of $71,758 vs $59,659.49, P < .001).

CONCLUSIONS AND IMPLICATIONS: LIHTC has been used to fund a small proportion of total ALs, with a high degree of between-state variability. Compared with other ALs, LIHTC-ALs tend to be in areas of lower socioeconomic status and higher medical need, signaling they may serve a different population than other ALs.}, } @article {pmid41275793, year = {2025}, author = {Rezaei, K and Seyedalipour, B and Behjou, NK and Faradonbeh, SMH and Hosseinkhani, S}, title = {Modulation of amyloid formation in the hSOD1 R115G mutant by an ionic liquid ([BMIM][SCN]).}, journal = {Biochemical and biophysical research communications}, volume = {793}, number = {}, pages = {153017}, doi = {10.1016/j.bbrc.2025.153017}, pmid = {41275793}, issn = {1090-2104}, mesh = {*Ionic Liquids/pharmacology/chemistry ; Humans ; *Imidazoles/pharmacology/chemistry ; *Amyloid/chemistry/metabolism ; Molecular Dynamics Simulation ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; Mutation ; Amyotrophic Lateral Sclerosis/genetics ; *Thiocyanates/pharmacology/chemistry ; }, abstract = {Protein aggregation is crucial to the molecular pathogenesis of amyotrophic lateral sclerosis (ALS), particularly in cases involving superoxide dismutase 1 (hSOD1) mutants. There is increasing focus on the development of small-molecule modulators that can disrupt aggregation pathways. Recently, ionic liquids (ILs) have been recognized as effective modulators of protein aggregation due to their tunable physicochemical properties. This study employed a combined computational and experimental approach to assess the inhibitory efficacy of 1-butyl-3-methylimidazolium thiocyanate ([BMIM][SCN]) on amyloid formation induced by the ALS-associated R115G mutation in hSOD1. Molecular dynamics (MD) simulations were conducted to obtain atomic-level insight into the inhibitory mechanism, demonstrating that [BMIM][SCN] primarily interacts with aggregation-prone loop regions in the R115G mutant, diminishing local flexibility and stabilizing partially folded intermediates. These interactions likely disrupt early nucleation processes essential for fibril propagation. The anti-amyloidogenic effects of [BMIM][SCN] were further confirmed under aggregating conditions using Thioflavin T (ThT) fluorescence kinetics, which exhibited a significant, concentration-dependent decrease in fibril formation. This trend was confirmed by transmission electron microscopy (TEM), which demonstrated a distinct suppression of fibrillar structures. Furthermore, ANS binding assays indicated reduced exposure of hydrophobic regions, implying a shift toward more compact, less aggregation-prone conformations. Fourier-transform infrared (FTIR) spectroscopy supported these findings by demonstrating a decrease in β-sheet-rich secondary structures commonly linked to mature amyloids. These findings indicate that [BMIM][SCN] modulates aggregation of the R115G mutant, providing mechanistic insights into how [BMIM][SCN] influences amyloid formation. These results may guide the rational design of biocompatible ionic-liquid-based analogs with potential therapeutic applications for ALS.}, } @article {pmid41276413, year = {2026}, author = {Isik, FI and Pickford, R and Dzamko, N and Rye, KA and Kim, WS}, title = {Upregulation of sphingomyelin and ABCA8 in response to TDP-43 pathology in amyotrophic lateral sclerosis brain.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {36}, number = {3}, pages = {e70053}, pmid = {41276413}, issn = {1750-3639}, support = {IM-202303-00957//FightMND/ ; R28AA012725//National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Sphingomyelins/metabolism ; Male ; Female ; *DNA-Binding Proteins/metabolism ; Middle Aged ; Up-Regulation ; Aged ; *ATP-Binding Cassette Transporters/metabolism ; *Brain/pathology/metabolism ; Motor Cortex/metabolism/pathology ; Cerebellum/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by the degeneration of motor neurons and the presence of TAR DNA-binding protein 43 (TDP-43) aggregation in the brain. Dyslipidemia is a common feature of ALS, and increasing evidence indicates that lipid dysregulation in the central nervous system underlies ALS pathology. Sphingomyelin is a sphingolipid that is highly enriched in the human brain. However, very little is known about changes in sphingomyelin in the context of ALS brain. We therefore undertook a comprehensive analysis of sphingomyelin in the disease-affected motor cortex and disease-unaffected cerebellum in sporadic ALS with TDP-43 pathology using liquid chromatography-mass spectrometry. We found that sphingomyelin was significantly increased in the ALS motor cortex compared to controls and was strongly associated with disease duration. In contrast, sphingomyelin was unaltered in the cerebellum. The increase in sphingomyelin was associated with an upregulation of ATP-binding cassette subfamily A member 8 (ABCA8), a sphingomyelin transporter, only in the motor cortex of ALS. Importantly, both sphingomyelin and ABCA8 were associated with TDP-43 only in the motor cortex. These results suggest that increases in sphingomyelin and ABCA8 could be a protective response against TDP-43 pathology.}, } @article {pmid41276866, year = {2025}, author = {Raoufinia, R and Alyari, G and Nia, AT and Abbaszadegan, MR and Mahmoudi, A and Shafaeibajestan, S and Saburi, E and Tavakol-Afshari, J and Hassani, M and Jamali, F and Salari, S and Boroumand, AR and Rahimi, HR}, title = {Cutting-edge treatments in amyotrophic lateral sclerosis: the role of molecular pathogenesis in targeted therapies.}, journal = {Stem cell research & therapy}, volume = {16}, number = {1}, pages = {689}, pmid = {41276866}, issn = {1757-6512}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics/pathology ; *Genetic Therapy/methods ; Animals ; C9orf72 Protein/genetics ; Mutation ; Motor Neurons/metabolism/pathology ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective loss of motor neurons (MNs), leading to progressive muscle weakness, atrophy, and ultimately paralysis. This review provides a comprehensive overview of the molecular mechanisms underlying ALS pathogenesis, the genetic mutations associated with both familial and sporadic forms of the disease, and the latest therapeutic strategies aimed at mitigating disease progression. mutations in genes such as C9orf72, SOD1, TARDBP, and FUS have been implicated in ALS, with an intricate interplay of protein misfolding, oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation contributing to motor neuron degeneration. While current FDA-approved treatments such as Riluzole and Edaravone offer only modest benefits and do not significantly halt disease progression. Emerging therapies, including gene therapies (e.g., antisense oligonucleotides (ASOs) and CRISPR/Cas9, stem cell-based approaches, and neurotrophic factor supplementation, are demonstrating promising results in preclinical and early-phase clinical trials. novel approaches aim to target, modulate, and promote regeneration, renewed hope for future ALS treatments. However, several challenges remain, including effective delivery methods, safety concerns, and the inherent complexity of ALS pathology, ongoing research continues to explore these innovative interventions with the goal of improving clinical outcomes for patients. This review highlights the importance of personalized therapeutic approaches and underscores the necessity of continued innovation in ALS research, with the ultimate goal of developing disease-modifying therapies and, potentially, a cure for this fatal condition.}, } @article {pmid41276980, year = {2026}, author = {Patel, K and Sarathamani, T and Kothandasamy, K and Sethy, PK and Behera, SK and Nanthaamornphong, A}, title = {Computational Approaches to Neurological Disorder Diagnosis: An In-Depth Review of Current Methods and Future Prospects.}, journal = {Current medical imaging}, volume = {22}, number = {}, pages = {e15734056404224}, pmid = {41276980}, issn = {1573-4056}, mesh = {Humans ; *Nervous System Diseases/diagnostic imaging/diagnosis ; Neuroimaging/methods ; Machine Learning ; *Diagnosis, Computer-Assisted/methods ; Artificial Intelligence ; }, abstract = {The rapid advancement of computational technologies has significantly transformed medical diagnostics, particularly in the realm of neurological disorders. This review provides a comprehensive analysis of the current computational approaches employed for the diagnosis of five major neurological disorders: Alzheimer's disease, Parkinson's disease, Epilepsy, Huntington's disease, and Amyotrophic Lateral Sclerosis. By evaluating 140 peer-reviewed studies, we explored a diverse array of diagnostic methods, including machine learning algorithms, neuroimaging techniques, and electrophysiological signal analysis. Our review highlights the efficacy, accuracy, and limitations of these diagnostic methods, emphasizing their role in early detection and differential diagnosis. Furthermore, we discuss the integration of multimodal data and the potential of emerging technologies such as deep learning and artificial intelligence to enhance diagnostic practices. We also address the current challenges in clinical implementation and propose future research directions to improve diagnostic precision and patient outcomes. This review aims to serve as a valuable resource for researchers, clinicians, and stakeholders in the field of neurodiagnostics, fostering a deeper understanding of computational methodologies that shape the future of neurological disorder diagnosis.}, } @article {pmid41277110, year = {2026}, author = {Lu, J and Di Florio, DN and Boya, P and Maday, S and Springer, W and Chu, CT}, title = {Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.}, journal = {Autophagy}, volume = {22}, number = {1}, pages = {10-52}, pmid = {41277110}, issn = {1554-8635}, support = {R21 AG075814/AG/NIA NIH HHS/United States ; R21 AG088697/AG/NIA NIH HHS/United States ; T32 NS086749/NS/NINDS NIH HHS/United States ; R01 NS110085/NS/NINDS NIH HHS/United States ; R01 NS101628/NS/NINDS NIH HHS/United States ; U54 NS110435/NS/NINDS NIH HHS/United States ; RF1 NS085070/NS/NINDS NIH HHS/United States ; R01 AG026389/AG/NIA NIH HHS/United States ; R01 NS110716/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Mitophagy/physiology ; *Autophagy/physiology ; *Synapses/metabolism ; Animals ; *Learning/physiology ; *Nervous System Diseases/metabolism/pathology/physiopathology ; *Memory/physiology ; Mitochondria/metabolism ; Neurons/metabolism ; Neurodegenerative Diseases ; }, abstract = {The human brain is one of the most metabolically active tissues in the body, due in large part to the activity of trillions of synaptic connections. Under normal conditions, macroautophagy/autophagy at the synapse plays a crucial role in synaptic pruning and plasticity, which occurs physiologically in the absence of disease- or aging-related stressors. Disruption of autophagy has profound effects on neuron development, structure, function, and survival. Neurons are dependent upon maintaining high-quality mitochondria, and alterations in selective mitochondrial autophagy (mitophagy) are heavily implicated in both genetic and environmental etiologies of neurodegenerative diseases. The unique spatial and functional demands of neurons result in differences in the regulation of metabolic, autophagic, mitophagic and biosynthetic processes compared to other cell types. Here, we review recent advances in autophagy and mitophagy research with an emphasis on studies involving primary neurons in vitro and in vivo, glial cells, and iPSC-differentiated neurons. The synaptic functions of genes whose mutations implicate autophagic or mitophagic dysfunction in hereditary neurodegenerative and neurodevelopmental diseases are summarized. Finally, we discuss the diagnostic and therapeutic potentials of autophagy-related pathways.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; APP: amyloid beta precursor protein; ASD: autism-spectrum disorder; BDNF: brain-derived neurotrophic factor; BPAN: β-propeller protein associated neurodegeneration; CR: caloric restriction; ΔN111: deleted N-terminal region 111 residues; DLG4/PSD95: discs large MAGUK scaffold protein 4; ER: endoplasmic reticulum; FTD: frontotemporal dementia; HD: Huntington disease; LIR: LC3-interacting region; LRRK2: leucine rich repeat kinase 2; LTD: long-term depression; LTP: long-term potentiation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OMM: outer mitochondrial membrane; PD: Parkinson spectrum diseases; PGRN: progranulin; PINK1: PTEN induced kinase 1; PRKA/PKA: protein kinase cAMP-activated; PtdIns3P: phosphatidylinositol-3-phosphate; p-S65-Ub: ubiquitin phosphorylated at serine 65; PTM: post-translational modification; TREM2: triggering receptor expressed on myeloid cells 2.}, } @article {pmid41277170, year = {2025}, author = {Jiang, Y and Zhang, Y and Ma, L and Li, C}, title = {Comprehensive Genome-Wide Analysis of Shared Genetic Factors in Gastrointestinal and Neurodegenerative Diseases.}, journal = {Brain and behavior}, volume = {15}, number = {11}, pages = {e71029}, pmid = {41277170}, issn = {2162-3279}, support = {TSYC202401B119//Third Batch of "Tianshan Talent" High-Level Medical and Health Personnel Project/ ; }, mesh = {Humans ; Genome-Wide Association Study/methods ; *Neurodegenerative Diseases/genetics ; *Gastrointestinal Diseases/genetics ; Polymorphism, Single Nucleotide/genetics ; Mendelian Randomization Analysis ; Genetic Predisposition to Disease/genetics ; Genetic Pleiotropy ; }, abstract = {BACKGROUND: This study investigates the shared genetic basis between gastrointestinal (GI) diseases and neurodegenerative diseases (ND) using genome-wide association study (GWAS) data and statistical genetic methods.

METHODS: GWAS data, primarily from European populations, covered four types of GI diseases and three types of ND. Genetic correlations were assessed using Linkage Disequilibrium Score Regression (LDSC), High-Definition Likelihood (HDL), and Local Analysis of Covariant Annotation (LAVA). Pleiotropic and functional genetic overlaps were explored using the Genomic Partitioning Approach (GPA), pleiotropic analysis under the composite null hypothesis (PLACO), and Functional Mapping and Annotation of Genetic Associations (FUMA). Multi-marker analysis of genomic annotation (MAGMA) was used for biological annotation and enrichment analysis, while summary data-based Mendelian randomization (SMR) analysis linked pleiotropic genes with gene expression. Two-sample Mendelian randomization (TSMR) investigated potential causal relationships.

RESULTS: Significant genetic correlations and shared genetic features were identified. The research identified 1,457 pleiotropic single nucleotide variants(SNVs) distributed across 47 chromosomal regions and 74pleiotropic genes, predominantly involved in pathways related tosignal transduction, amyloid regulation, and lipid metabolism. Nine colocalization loci (PPH4 > 0.8) were identified, while SMR analysis linked 26 pleiotropic genes to disease expression levels. Key genes, including EP300, CHRNB1, KNOP1, P2RY14, and POLR2A, were significantly associated with both disease types. Drug-gene interaction analysis highlighted 8 genes with drug targets, among which EP300, PRKCB, VKORC1, and CHRNB1 were found to anchor enriched pathways including purinergic signaling, amyloid/protein aggregation, and cholesterol/lipoprotein transport. Mendelian randomization corroborated possible causal association.

CONCLUSION: This study confirms a shared genetic basis between GI and ND, emphasizing the gut-brain axis in their etiology. These findings offer clues about shared pathways, potential therapeutic targets, and future research directions.}, } @article {pmid41277873, year = {2026}, author = {}, title = {Correction to "Cerebellar neuronal loss in amyotrophic lateral sclerosis cases with ATXN2 intermediate repeat expansions".}, journal = {Annals of neurology}, volume = {99}, number = {1}, pages = {288}, doi = {10.1002/ana.78107}, pmid = {41277873}, issn = {1531-8249}, } @article {pmid41277874, year = {2025}, author = {Ferreira-Junior, JR and de Lima Camandona, V and Barros, MH}, title = {From Yeast to Therapeutics: Modeling Neurodegenerative Diseases in Saccharomyces cerevisiae.}, journal = {Yeast (Chichester, England)}, volume = {42}, number = {12}, pages = {283-302}, pmid = {41277874}, issn = {1097-0061}, support = {//This study was supported by grants and fellowships from Fundacao de Amparo a Pesquisa de Sao Paulo (FAPESP 2024/01152-3; 2023/14056-0), Conselho Nacional de Desenvolvimento Cientıfico e Tecnologico (CNPq 305054/2022-8), and Coordenacao de Aperfeicoamento de Pessoal de Nıvel Superior-Brasil (CAPES-Finance Code 001)./ ; }, mesh = {*Saccharomyces cerevisiae/genetics/metabolism/drug effects ; *Neurodegenerative Diseases/drug therapy/genetics/metabolism ; Humans ; Drug Discovery ; Amyloid beta-Peptides/metabolism/genetics ; alpha-Synuclein/metabolism/genetics ; *Models, Biological ; Huntingtin Protein/metabolism/genetics ; }, abstract = {Here, we review the use of Saccharomyces cerevisiae as a powerful model organism for studying cellular processes implicated in neurodegenerative disorders, including stress responses, proteostasis impairment, and vesicle trafficking defects. Over the last two decades, baker's yeast models have been developed for complex diseases such as Parkinson's, Alzheimer's, Huntington's, and Amyotrophic lateral sclerosis (ALS). Yeast cells expressing human proteins, such as amyloid-β, α-synuclein, huntingtin, and TDP-43, have become crucial tools for high-throughput drug screening aimed at counteracting disease progression. These yeast models have unveiled key components involved in the metabolism and toxicity of these proteins, enabling the identification of interacting partners and novel factors within each pathway. Importantly, these pathways were subsequently shown to be conserved in mammalian models. Furthermore, drug candidates identified using yeast models have provided significant leads for drug discovery, highlighting their potential for developing treatments for these neurodegenerative diseases.}, } @article {pmid41278139, year = {2025}, author = {Prodromos, CC and Del Villar, R and Jin, MY and Abd-Elsayed, A and Candido, K}, title = {Exosome-rich mesenchymal stem cell secretome improves strength in patients with amyotrophic lateral sclerosis, Kennedy disease, congenital myasthenic syndrome and Lewy body dementia.}, journal = {American journal of stem cells}, volume = {14}, number = {4}, pages = {217-229}, pmid = {41278139}, issn = {2160-4150}, abstract = {AIM: Amyotrophic lateral sclerosis (ALS), Lewy Body dementia (LBD), Kennedy disease (KD), and Congenital Myasthenic Syndrome (CMS) are progressive motor disorders for which no disease modifying treatment exists. ALS and LBD are uniformly, and often rapidly, fatal. No treatment of any kind has ever resulted in actual improvement for ALS patients; the best that has been achieved is minor slowing of their progression. Forty-one preclinical studies of intra-nasal instillation of mesenchymal stem cell exosomes have, however, demonstrated complete safety and efficacy for models of a variety of neurocognitive and motor disorders. We hypothesized that intranasal exosomes treatment in humans would be completely safe and also effective for the treatment of motor disorders such as ALS, LBD, KD and CMS.

METHODS: 18 patients with ALS, Kennedy Disease, Congenital Myasthenic Syndrome, or Lewy Body Dementia had 32 AlloEx Exosome[®] treatments to assess safety, attenuation of disease, and increase in strength and motor function. The study was conducted under the clinical trial NCT07105371 found at clinicaltrials.gov/study/NCT07105371.

RESULTS: There were no adverse events of any kind reported among these treatments. All patients, except for one, achieved some degree of clinical and strength improvement; the longest improvement was recorded at the 6-month follow-up.

CONCLUSION: Intranasally-instilled AlloEx Exosomes[®] are completely safe, attenuate progression, and improve strength in ALS, Kennedy Disease, CMS, and LBD.}, } @article {pmid41278665, year = {2025}, author = {Hubbard, I and Dubnau, J}, title = {Glial cell-intrinsic and non-cell autonomous toxicity in a Drosophila C9orf72 neurodegeneration model.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41278665}, issn = {2692-8205}, support = {R01 AG076493/AG/NIA NIH HHS/United States ; R01 AG078788/AG/NIA NIH HHS/United States ; }, abstract = {The most common genetic cause of both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G4C2 repeat in the first intron of the gene C9orf72. The C9orf72 repeat expansion is bidirectionally transcribed into sense and anti-sense RNA foci, and also produces dipeptide repeats (DPRs) via a non-canonical translation mechanism known as repeat-associated (RAN) translation. Each of these components of the G4C2 repeat expansion cause neurodegenerative effects in animal models when expressed in neurons, but impacts from glial expression are more poorly understood. Here, we use glial cell type-specific expression of individual DPRs, of RNA repeat-only, or of the G4C2 repeat that is capable of producing both DPRs and RNA repeats to systematically investigate both the glial cell-intrinsic and non-cell autonomous toxicity of each of these components. Our results show that as with neurons, the GR and G4C2 transgenes, produce the highest degree of cell-intrinsic toxicity when expressed in glia. Both of these transgenes are capable of producing the GR DPR, which is also typically found to be the most toxic factor in neurons. We demonstrate that both the GR and G4C2 transgenes cause activation of mdg4, an endogenous retrovirus (ERV). Such ERV expression is a hallmark of TDP-43 dysfunction that is commonly observed in C9orf72 patients and contributes to both cell intrinsic and non-cell autonomous toxicity. We find that only the G4C2 transgene produces measurable non-cell autonomous effects that result in loss of nearby neurons. But manipulations of apoptosis reveal non-cell autonomous or systemic effects from either GR or G4C2 expressing glia. Blocking apoptotic cell death of either GR or G4C2 expressing glia via the p35 caspase inhibitor further exacerbates effects on lifespan and ablating such glia via expression of the proapoptotic reaper gene partially ameliorates these effects.}, } @article {pmid41278912, year = {2025}, author = {Kim, SH and Boos, CE and Scalf, M and Wilkemeyer, AK and Smith, LM and Tibbetts, RS}, title = {Interactome screening implicates BAG6 as a suppressor of UBQLN2 misfolding in ALS-dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.10.15.682441}, pmid = {41278912}, issn = {2692-8205}, support = {S10 OD034394/OD/NIH HHS/United States ; }, abstract = {Ubiquilin-2 (UBQLN2) is a ubiquitin (Ub)-binding shuttle protein that is mutated in X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS/FTD-linked mutations in UBQLN2 disrupt its conformation, increasing its tendency to form cytoplasmic aggregates that may disrupt cellular regulation through loss-of-function (LOF) and gain-of-function (GOF) effects. To explore how ALS-associated mutations impact UBQLN2 function, we performed quantitative mass spectrometry (MS)-based interactome analysis using affinity-purified UBQLN2 from inducible pluripotent stem cells (iPSCs) and induced motor neurons (iMNs) expressing wild-type UBQLN2 (UBQLN2WT), a UBQLN2P497H clinical mutant, or a UBQLN24XALS allele harboring four disease mutations. Proteins showing enhanced association with ALS-mutant UBQLN2 proteins included PEG10, a known degradation target of UBQLN2, and BAG6, a chaperone involved in the triage of mislocalized proteins (MLPs). BAG6 knockdown inhibited the solubility recovery of both wild-type and ALS-mutant UBQLN2 proteins following heat stress (HS), suggesting it functions as a UBQLN2 holdase. In addition, knockdown of BAG6 or knockout of UBQLN2 led to PEG10 accumulation, implicating both in PEG10 turnover; however, neither BAG6 nor UBQLN2 was required for PEG10 degradation in response to HS. The aggregation prone UBQLN24XALS mutant showed increased PEG10 binding and modestly delayed PEG10 turnover while PEG10 degradation was not significantly different between UBQLN2WT and UBQLN2P497H iPSCs. The combined findings implicate BAG6 a UBQLN2 holdase and identify a suite of proteins whose altered binding may contribute to pathologic changes in UBQLN2-associated ALS/FTD.}, } @article {pmid41279504, year = {2025}, author = {Yang, X and Taghavi, A and Akahori, Y and Pedrini, M and Ishii, T and Disney, MD}, title = {RNA-Focused DNA-Encoded Library Construction, Screening, and Integration of Docking Identify Bioactive Ligands of Pathogenic r(G4C2)[exp] RNA.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279504}, issn = {2692-8205}, support = {R35 NS116846/NS/NINDS NIH HHS/United States ; }, abstract = {Disease-associated RNAs are increasingly recognized as promising therapeutic targets for small-molecule intervention. While DNA-encoded libraries (DELs) have long been established for protein ligand discovery, recent studies have demonstrated their feasibility for identifying RNA-binding small molecules. To further advance RNA-targeted ligand discovery, a diverse, solid-phase DEL enriched in privileged RNA-binding scaffolds was constructed and applied to identify ligands of r(G4C2)[exp], a toxic RNA repeat expansion implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). DEL selection outcomes were analyzed through large-scale molecular docking integrated with physicochemical and structure-activity relationship (SAR) analyses. Strong correlations were observed between docking predictions and experimental enrichment trends, supporting lead identification. The lead compound was subsequently optimized based on its docked pose to an NMR structure, resulting in analogs with enhanced binding affinity and bioactivity. These findings demonstrate that RNA ligand identification can be effectively achieved by combining DNA-encoded library technology with computational approaches for rational design and analysis, and highlight a broadly adaptable platform for RNA-targeted small molecule discovery.}, } @article {pmid41279722, year = {2025}, author = {Prova, NS and Elsayyid, M and Tanis, JE}, title = {Superoxide dismutase impacts extracellular vesicle biogenesis and uptake.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279722}, issn = {2692-8205}, support = {P40 OD010440/OD/NIH HHS/United States ; R01 GM135433/GM/NIGMS NIH HHS/United States ; P20 GM103446/GM/NIGMS NIH HHS/United States ; S10 OD030321/OD/NIH HHS/United States ; P20 GM139760/GM/NIGMS NIH HHS/United States ; }, abstract = {Extracellular vesicles (EVs), which transfer bioactive macromolecules between cells, play an important role in the pathogenesis of multiple neurodegenerative diseases. Focus has centered on how altered EV contents propagate disease and the potential for EVs as diagnostic biomarkers, while the effect of pathogenic factors on EV release is less understood. Here, we defined how the key antioxidant enzyme superoxide dismutase 1 (SOD-1) affects EV shedding from sensory neuron primary cilia, enrichment of ciliary proteins packaged into EVs, and uptake of EVs by surrounding glia in vivo by imaging C. elegans expressing fluorescent protein-tagged EV cargos. We discovered that loss of SOD-1, as well as the SOD-1(G85R) amyotrophic lateral sclerosis (ALS) pathogenic variant, increased EV shedding from the cilium distal tip, and this was associated with greater abundance of EV cargo in this ciliary compartment. In contrast, loss of SOD-1 reduced the glial uptake of a different cargo present in EVs shed from the ciliary base. Together, this suggests that redox balance has a subtype-specific effect on EV biogenesis, influencing neuron communication in vivo.}, } @article {pmid41279779, year = {2025}, author = {Chen, H and Wang, H and Lu, Y and Chen, P and Zheng, Z and Zhang, T and Wang, J}, title = {Noncanonical amino acid incorporation enables minimally disruptive labeling of stress granule and TDP-43 proteinopathy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279779}, issn = {2692-8205}, support = {R01 NS110098/NS/NINDS NIH HHS/United States ; }, abstract = {We report a minimally disruptive labeling strategy for stress granule protein G3BP1 and ALS-linked protein TDP-43 using the fluorescent noncanonical amino acid Anap. By integrating genetic code expansion with rational site selection, we achieved precise incorporation of Anap that preserves protein structure and function. In live cells and neurons, Anap labeling faithfully recapitulated localization, stress-induced dynamics, and recovery behavior, outperforming conventional fluorescent tags and enabling physiologically relevant visualization of protein pathobiology.}, } @article {pmid41279899, year = {2025}, author = {Le, P and Lal, NK and Xu, S and Mumford, S and Huang, M and Yang, D and Mizrahi, O and Hoover, B and Yee, B and Mei, Y and Rothamel, K and Her, HL and Blue, SM and Shneider, NA and Yeo, GW}, title = {KIF5A binds RNA to orchestrate synaptic mRNA localization and stress granules in ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.10.31.685813}, pmid = {41279899}, issn = {2692-8205}, abstract = {UNLABELLED: Neuronal health depends on the precise transport and local translation of mRNAs to maintain synaptic function across highly polarized cellular architecture. While kinesin motor proteins are known to mediate mRNA transport, the specificity and direct involvement of individual kinesins as RNA-binding proteins (RBPs) remain unclear. Here, we demonstrate that KIF5A, a neuron-specific kinesin implicated in amyotrophic lateral sclerosis (ALS), functions as an RBP. We show that KIF5A directly binds mRNAs encoding synaptic ribosomal proteins and is required for their synaptic localization and for maintaining normal synaptic composition and function. Additionally, we show ALS-linked KIF5A mutations confer gain-of-function properties, enhancing mRNA binding, increasing synaptic ribosomal protein accumulation, inducing neuronal hyperexcitability, and impairing stress responses. These findings reveal a previously unrecognized mechanism by which mutant KIF5A disrupts synaptic homeostasis. Our work positions a kinesin motor protein as an RBP with critical roles in mRNA transport, local translation, and stress response.

HIGHLIGHTS: KIF5A interacts with mRNA encoding synaptic ribosomal proteinsKIF5A is required for normal synaptic composition and functionKIF5A binds to G3BP1 and G3BP1 stress granule associated proteinsKIF5A mutant ALS patient-derived motor neurons have abnormal synaptic function and stress response.}, } @article {pmid41280004, year = {2025}, author = {Rao, PP and Herbert, C and Azeem, SM and Gary, E and Ho, G and Munira, R and Askarifirouzja, H and Haimovitz-Friedman, A and Mahajan, SS}, title = {Riluzole as a Dual-Targeted Radiosensitizer for Osteosarcoma: Targeting Tumor Cells and Angiogenic Vasculature to Enhance Single High Dose Radiotherapy Efficacy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41280004}, issn = {2692-8205}, support = {SC1 GM131929/GM/NIGMS NIH HHS/United States ; }, abstract = {Osteosarcoma is a highly aggressive bone malignancy primarily affecting children and young adults. It presents significant treatment challenges due to its inherent resistance to conventional fractionated radiotherapy (CFRT). Single high dose radiation therapy (SDRT) has promise for the treatment of radioresistant sarcomas, especially those characterized with extensive vascularity. However, its clinical application is severely constrained by toxicity to adjacent critical tissues. Radiosensitizers can enhance tumor cell susceptibility to radiation-induced DNA damage, improving therapeutic efficacy and potentially reducing collateral toxicity. Monotherapies targeting tumor vasculature alone in solid tumors have shown limited success as radiosensitizers in clinical settings. This highlights the importance of compounds that can simultaneously target both tumor cells and its associated microvasculature to maximize the therapeutic outcome to SDRT. Riluzole, the FDA-approved drug for Amyotrophic Lateral Sclerosis, is currently under investigation as a therapeutic agent for osteosarcoma. Riluzole acts to inhibit glutamate release, reduce glutathione levels in cancer cells, and mitigate tumor angiogenesis, positioning it as a potent radiosensitizing agent for the treatment of osteosarcoma. We hypothesize that Riluzole enhances osteosarcoma radiosensitivity to SDRT by simultaneously targeting intrinsic tumor radioresistance and pro-angiogenic signaling. Our findings demonstrate that Riluzole radiosensitizes osteosarcoma cells in vitro by reducing clonogenic survival and enhancing apoptosis. Mechanistically, Riluzole potentiates irradiation-induced reactive oxygen species (ROS) production, induces G2/M phase cell cycle arrest, inhibits DNA repair, and thereby amplifies radiation-induced DNA damage. Additionally, Riluzole suppresses radiation-induced Vascular Endothelial growth factor A (VEGFA) expression indicating its ability to overcome endothelial cell mediated radioresistance. Collectively, these results establish Riluzole as a promising radiosensitizer for osteosarcoma, with the potential to improve SDRT efficacy by overcoming both tumor-intrinsic and microvasculature-mediated radioresistance.}, } @article {pmid41280089, year = {2025}, author = {Rotunno, MS and Fowler-Magaw, M and Zhong, J and O'Hara, K and Wiggin, EA and Cameron, D and Stallworth, K and Bouley, J and McEachern, H and Anadolu, MN and Nickerson, JA and Tapper, AR and Molas, S and Massi, F and Henninger, N and King, OD and Bosco, DA}, title = {TDP-43 dysfunction leads to impaired proteostasis and predisposes mice to worse neurological outcomes after brain injury.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.10.20.683438}, pmid = {41280089}, issn = {2692-8205}, support = {T32 AI095213/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Pathological TAR DNA-binding protein 43 (TDP-43) dysfunction is associated with multiple neurodegenerative disorders. However, the mechanistic link between TDP-43 dysfunction and neurodegeneration is poorly understood and likely involves a combination of genetic and environmental risk factors. A major risk factor for neurodegenerative disease is exposure to traumatic brain injury (TBI). Here, we investigated the synergistic interplay between TDP-43 dysfunction and TBI in a murine model of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD).

METHODS: A model of TDP-43 dysfunction caused by a knock-in Q331K mutation in Tardbp was combined with a mild model of TBI. Control conditions included both WT mice and mice with sham surgery. Animals were evaluated for behavioral deficits at timepoints pre- and post-surgery. Additionally, post-mortem brain tissues were examined using RNA sequencing and mass spectrometry-based quantitative proteomics together with histological and biochemical analyses.

RESULTS: Expression of dysfunctional TDP-43 in vivo caused deficits in multiple branches of the proteostasis network, including protein folding, protein synthesis, and protein turnover. Examples include mis-expression of chaperones and genes within the ubiquitin-proteosome pathway in mutant TDP-43 versus WT mice. Further, mutant TDP-43 expression correlated with reduced thermostability of proteins associated with the ribosome and the chaperonin containing TCP-1 complex. In response to TBI, mutant TDP-43 mice exhibited significantly worse neurological outcomes relative to WT animals. Heightened neurological deficits in mutant TDP-43 mice following TBI coincided with a robust upregulation of proteostasis- and stress-related genes at the transcript level. However, this upregulation was not detected at the protein level.

CONCLUSIONS: Our data demonstrate that expression of dysfunctional TDP-43 leads to deficits within the proteostasis network in vivo at baseline. Despite an upregulation of proteostasis-related genes at the transcript level in mutant TDP-43 mice after TBI, mutant TDP-43 mice exhibit an impaired response to, and recovery from, brain trauma relative to their WT counterparts. Restoring proteostasis is expected to protect against the detrimental effects of TDP-43 dysfunction, especially under stress conditions that promote neurodegenerative disease.}, } @article {pmid41281478, year = {2025}, author = {Kumar, S}, title = {Artificial intelligence powered radiomics model for the assessment of colorectal tumor immune microenvironment.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {11}, pages = {108576}, pmid = {41281478}, issn = {1948-5204}, abstract = {Zhou et al's investigation on the creation of a non-invasive deep learning (DL) method for colorectal tumor immune microenvironment evaluation using preoperative computed tomography (CT) radiomics published in the World Journal of Gastrointestinal Oncology is thorough and scientific. The study analyzed preoperative CT images of 315 confirmed colorectal cancer patients, using manual regions of interest to extract DL features. The study developed a DL model using CT images and histopathological images to predict immune-related indicators in colorectal cancer patients. Pathological (tumor-stroma ratio, tumor-infiltrating lymphocytes infiltration, immunohistochemistry, tumor immune microenvironment and immune score) parameters and radiomics (CT imaging and model construction) data were combined to generate artificial intelligence-powered models. Clinical benefit and goodness of fit of the models were assessed using receiver operating characteristic, area under curve and decision curve analysis. The developed DL-based radiomics prediction model for non-invasive evaluation of tumor markers demonstrated potential for personalized treatment planning and immunotherapy strategies in colorectal cancer patients. The study, involving a small group from a single medical center, lacks inclusion/exclusion criteria and should include clinicopathological features for valuable therapeutic practice insights in colorectal cancer patients.}, } @article {pmid41281507, year = {2025}, author = {Lucke-Wold, B and Salam, HD and Karayi, G}, title = {Behavioral analysis of insomnia sufferers to acupuncture treatment.}, journal = {World journal of psychiatry}, volume = {15}, number = {11}, pages = {108630}, pmid = {41281507}, issn = {2220-3206}, abstract = {In this commentary, we respond to Zhao et al's recent paper which focuses on mechanisms underlying insomnia sufferers' engagement with acupuncture. Insomnia, a prevalent condition characterized by difficulty falling asleep and poor sleep quality, is associated with increased risk of cardiovascular disease, diabetes, and psychiatric illness. Acupuncture, a method involving the therapeutic placement of needles, has been widely accepted as a treatment for insomnia with minimal side effects. In fact, clinical trials suggest auricular acupuncture may improve sleep duration more than cognitive behavioral therapy. However, responses to acupuncture vary. Some patients find it extremely beneficial, while others view it as a routine treatment-or avoid it altogether due to needle phobia. Patient engagement is influenced by cultural beliefs, encouragement, motivation, prior experiences, and recommendations from peers or clinicians. Trust in the physician and testimonials from recovered patients are particularly important facilitators. Looking ahead, a holistic approach - integrating acupuncture with meditation, pranayama, yoga, and other restorative practices - may enhance treatment effectiveness and help patients achieve restorative sleep.}, } @article {pmid41281542, year = {2025}, author = {Wang, X}, title = {Childhood trauma and parenting in at-risk mental state: Clarifying pathways and expanding perspectives.}, journal = {World journal of psychiatry}, volume = {15}, number = {11}, pages = {112624}, pmid = {41281542}, issn = {2220-3206}, abstract = {Jovani et al's study contributes important evidence linking childhood trauma (CT) and parental socialization with at-risk mental state (ARMS) in non-clinical adolescents, demonstrating the mediating role of low levels of parental affection and communication in this relationship. This letter commends the study's strengths while also identifying key issues that warrant further attention, including the limitations of cross-sectional design, potential perceptual biases, conceptual overlap between CT and parenting, and limited cultural generalizability. We advocate for longitudinal, culturally sensitive, and multi-informant approaches to further refine ARMS risk models, strengthen theoretical distinctions between CT and parenting, and inform targeted prevention strategies across diverse populations. We also extend the discussion by highlighting promising directions for future research.}, } @article {pmid41282267, year = {2025}, author = {Fernandes, AR and Owen, AP and Faroqi, AH and Lee, J and Sachdeva, GS and Morderer, D and Hoffmann, C and Madden, B and Zhang, S and Ren, Y and Boschen, SL and Pandey, A and Rossoll, W and McLean, PJ}, title = {A Split Biotin Ligase Approach to Revealing Proteins Associated with Oligomeric Alpha-Synuclein During Aggregation.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41282267}, issn = {2693-5015}, support = {U01 CA271410/CA/NCI NIH HHS/United States ; RF1 AG068581/AG/NIA NIH HHS/United States ; R01 AG068581/AG/NIA NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; R01 AG077771/AG/NIA NIH HHS/United States ; R01 AG076122/AG/NIA NIH HHS/United States ; RF1 AG076122/AG/NIA NIH HHS/United States ; R21 AG085314/AG/NIA NIH HHS/United States ; }, abstract = {Lewy pathology can form over decades in patients with Lewy body diseases, but the causal cellular mechanisms associated with this process remain unclear. This project aims to discover proteins that associate with monomeric and/or oligomeric alpha-synuclein during early stages of the aggregation process. To mimic the aggregation processes, cells expressing a synuclein-biotin ligase fusion protein were treated human recombinant pre-formed fibrils and subjected to BioSITe and mass spectrometry. Using a novel split biotin ligase fused to alpha-synuclein facilitated the identification of proteins specifically associated with multimeric alpha-synuclein. A total of 581 proteins were differentiated into potential interactors of monomeric versus multimeric alpha-synuclein in physiological versus aggregated conditions. The data reveal important phosphorylation mechanisms, connections to insulin processing, and a potential interaction with ALS-associated FUS. Interestingly, we identified that loss of specific interactions may contribute to pathology in patients with sporadic onset of Lewy body diseases. Future studies will validate both true interaction of highlighted proteins with alpha-synuclein, and the impact of such proteins on alpha-synuclein aggregation.}, } @article {pmid41282495, year = {2025}, author = {Araújo, B and Serrenho, I and Valente da Silva, A and Marceta, BM and Baltazar, G}, title = {Mesenchymal stem cells in neurological disorders: Insights from clinical trials.}, journal = {Regenerative therapy}, volume = {30}, number = {}, pages = {1024-1035}, pmid = {41282495}, issn = {2352-3204}, abstract = {Mesenchymal stem cells (MSCs) exhibit unique properties that make them promising candidates for cell therapy, particularly in neurological disorders. They can be derived from various tissues, with bone marrow, adipose tissue, umbilical cord, and placenta being the most common sources. Evidence suggests that the tissue of origin significantly influences MSC characteristics, including secretome composition, proliferation rate, and adhesion capacity. Clinical trials have demonstrated the safety and therapeutic potential of MSCs in conditions such as spinal cord injury, multiple sclerosis, and stroke. MSC therapy has been associated with improvements in motor, sensory, and cognitive functions, as well as enhanced quality of life. Mechanistically, MSCs promote neuroprotection, reduce inflammation, and modulate immune responses. In spinal cord injury, intrathecal administration of adipose- and bone marrow-derived MSCs has led to significant functional recovery, with single high-dose treatments often yielding better outcomes than multiple lower doses. In amyotrophic lateral sclerosis, bone marrow-derived MSCs have shown potential in slowing disease progression, though higher doses do not always result in greater benefits. In multiple sclerosis, high doses of umbilical cord-derived MSCs improved quality of life and prevented disease progression, whereas lower doses of bone marrow-derived MSCs provided limited functional benefits. While MSC therapy is considered safe, patient responses vary, and a definitive correlation between administered dose and therapeutic effects remains elusive. The small number of studies using comparable protocols impedes comparison of other relevant factor, limits the drawing of conclusions and underscore the importance of developing standardized protocols to optimize MSC-based treatments and maximize their clinical efficacy.}, } @article {pmid41282964, year = {2025}, author = {Nachammai, KT and Sangavi, P and Sekar, C and Sangeetha, and Kulanthaivel, L}, title = {Targeting the core: C9ORF72 antagonists as pioneers in amyotrophic lateral sclerosis therapy-a computational and machine learning based approach.}, journal = {In silico pharmacology}, volume = {13}, number = {3}, pages = {188}, pmid = {41282964}, issn = {2193-9616}, abstract = {Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou Gehrig's disease, is a neurodegenerative condition characterized by the gradual deterioration of motor neurons in the brain and spinal cord, leading to muscle weakness, difficulty swallowing, speaking, and breathing. The normal ageing process has structural and functional effects on motor neurons, which may contribute to motor neuron pathology in ALS, either directly or indirectly. Although there are a few treatments available for ALS, their efficacy is limited. The objective of this study is to identify and screen potential C9ORF72 Agonists using High Throughput Virtual screening and Molecular Dynamics simulations. Using Edaravone and Riluzole as benchmark molecules, the study evaluated various chemical compounds from different databases against the target. Lead compounds from three databases (Specs_1289, Zinc_67912153 and Enamine_785152) showed binding affinity, stability and pharmacokinetic greater activity which is achieved through ML based tool; concluding that they could be used as a potential agonist for ALS-associated C9ORF72. The complexes have the highest docking scores of - 8.21, - 11.06, and - 6.934 kcal/mol with the lowest binding energy which aids the structural stability of the complex. HOMO and LUMO occupancy of the lead compounds deciphers the energy levels of the compounds with the lowest energy gap which was favorable for the chemical reactivity and chemical inertness of the molecule. Furthermore, ADME and Toxicity analysis of the compounds were evaluated through Machine Learning based tool, pkCSM. MD simulation concluded that the lead complexes showed lesser deviation and fluctuations with the higher number of hydrogen bond interactions which favors the structural stability and biological activity of the complex. This study concluded that the resultant leads from three different chemical libraries were considered as the potential therapeutic option for targeting ALS.}, } @article {pmid41283146, year = {2026}, author = {Chen, BP and Lee, CC and He, RY and Huang, AC and Huang, JR and Chan, JCC and Huang, JJ}, title = {Amyloidogenic oligomers derived from TDP-43 LCD promote the condensation and phosphorylation of TDP-43.}, journal = {Chemical science}, volume = {17}, number = {2}, pages = {1210-1222}, pmid = {41283146}, issn = {2041-6520}, abstract = {The aberrant aggregation of TAR DNA-binding protein 43 (TDP-43) is a hallmark of amyotrophic lateral sclerosis (ALS). While TDP-43 aggregation can occur via both classical amyloidogenesis and phase separation-mediated mechanisms, the role of amyloidogenic oligomers in modulating TDP-43 condensation remains unclear. Herein, we employ a reverse micelle method to prepare uniform oligomers derived from the low-complexity domain of TDP-43, termed D1core oligomers. These amyloidogenic oligomers are toxic, potently induce phase separation of recombinant TDP-43 C-terminal domains, and promote phosphorylation of cytosolic TDP-43 condensates in cells. Compared to monomeric or fibrillar forms, D1core oligomers uniquely enhance the condensation propensity of wild-type TDP-43 and further potentiate aggregation of the ALS-associated A315T mutant. Live-cell studies using fluorescence recovery after photobleaching reveal that oligomer-induced condensates are modulated by HSP70, which preserves their liquid-like properties. These findings provide new insights into the interplay between TDP-43 oligomers, phase separation, and aggregation, advancing our understanding of ALS-related proteinopathy.}, } @article {pmid41283303, year = {2025}, author = {Bartoshyk, P and O'Caoimh, R}, title = {Update on Disease-Modifying Pharmacological Treatments for Frontotemporal Dementia (FTD): A Scoping Review of Registered Trials.}, journal = {NeuroSci}, volume = {6}, number = {4}, pages = {}, pmid = {41283303}, issn = {2673-4087}, abstract = {Frontotemporal dementia (FTD) represents a cluster of adult-onset neurodegenerative diseases resulting from a combination of genetic and epigenetic factors. Currently, treatment is symptomatic and there are no licensed disease-modifying therapies available. The aim of this review was to provide an overview of ongoing or recently completed clinical studies targeting disease modification in FTD. A structured search of interventional trials of pharmacological compounds was conducted on three clinical trial registries (National Library of Medicine Clinical Trials, European Union Clinical Trials, and the Australian New Zealand Clinical Trials registries) up to September 2025. Twelve interventional trials were found. Half targeted autosomal-dominant progranulin (GRN) mutations (n = 6) and half examined therapies targeting neuroinflammatory-induced sporadic FTD (n = 6). The interim results of the early-phase (1/2) randomized controlled trials (RCTs), comprising three ongoing gene replacement studies (PROCLAIM, ASPIRE-FTD, upliFT-D) and one immune-modulating monoclonal antibody (INFRONT, now in phase 3)-all targeting the FTD-GRN mutation-show safety, tolerability, and effectiveness in restoring progranulin levels. Two recently completed phase 2 RCTs for sporadic FTD targeting neuroinflammation, the PEA-FTD and C9orf72 ALS/FTD trials, show disease-modifying potential. While interim results from six trials suggest clear mechanistic efficacy, prospective high-quality later-phase RCTs are required to ascertain long-term clinical efficacy. Since familial FTD encompasses less than half of the people with this disease, it is important to continue exploring the underlying pathophysiology, neuroimmunology, and treatment of epigenetic-induced sporadic FTD.}, } @article {pmid41283495, year = {2025}, author = {Capobianco, S and Bastiani, L and Forli, F and Fattori, B and Stomeo, F and Russo, M and Barillari, MR and Nacci, A}, title = {Acoustic Vowel Metrics as Correlates of Dysphagia and Dysarthria in Brainstem Neurodegenerative Diseases.}, journal = {Audiology research}, volume = {15}, number = {6}, pages = {}, pmid = {41283495}, issn = {2039-4330}, abstract = {Background/Objectives: Swallowing and speech rely on shared brainstem circuits coordinating oropharyngeal motor functions. In neurodegenerative diseases affecting the brainstem-such as progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS), and multiple system atrophy (MSA)-bulbar dysfunction often impairs tongue propulsion and motility, affecting both swallowing (dysphagia) and phonation (dysarthria). This study aimed to investigate whether vowel-based acoustic features are associated with swallowing severity in brainstem-related disorders and to explore their potential as surrogate markers of bulbar involvement. Methods: This was a cross-sectional observational study. Thirty-one patients (13 PSP, 12 ALS, 6 MSA) underwent clinical dysarthria assessment, acoustic analysis of the first (F1) and second (F2) formants during sustained phonation of /a/, /i/, /e/, and /u/, and swallowing evaluation using standardized clinical scales (DOSS, FOIS, ASHA-NOMS) and fiberoptic endoscopic evaluation (Pooling Score, Penetration-Aspiration Scale). The vowel space area (tVSA, qVSA) and Formant Centralization Ratio (FCR) were computed. Results: Significant correlations emerged between acoustic vowel metrics and dysphagia severity, especially for liquids. The FCR showed strong correlations with DOSS (ρ = -0.660, p < 0.0001), FOIS (ρ = -0.531, p = 0.002), ASHA-NOMS (ρ = -0.604, p < 0.0001), and instrumental scores for liquids: the Pooling Score (ρ = 0.538, p = 0.002) and PAS (ρ = 0.630, p < 0.0001). VSA measures were also associated significantly with liquid swallowing impairment. F2u correlated with dysarthria severity and all liquid-related dysphagia scores. Conclusions: Vowel-based acoustic parameters, particularly FCR and F2u, reflect the shared neuromotor substrate of articulation and swallowing. Acoustic analysis may support early detection and monitoring of bulbar dysfunction, especially where instrumental assessments are limited.}, } @article {pmid41283496, year = {2025}, author = {D'Alatri, L and Marchese, MR and Tizio, A and Galli, J}, title = {Pathophysiology and Etiology of Brainstem-Related Dysphagia.}, journal = {Audiology research}, volume = {15}, number = {6}, pages = {}, pmid = {41283496}, issn = {2039-4330}, abstract = {BACKGROUND: Brainstem-related dysphagia represents a complex and severe form of neurogenic dysphagia (ND) arising from lesions that disrupt the central pattern generator (CPG) for swallowing located in the medulla oblongata.

METHODS: This paper explores the physiological basis of swallowing and its disruption in various brainstem pathologies.

RESULTS: The clinical presentation and electrophysiological evaluation of dysphagia are discussed, with a focus on volitional and spontaneous swallowing (SS) and the use of electromyography (EMG)-based assessment techniques.

CONCLUSIONS: Finally, therapeutic strategies are reviewed, including conventional rehabilitative methods, neuromuscular electrical stimulation, non-invasive brain stimulation, and invasive procedures such as neurobotulinum toxin-A (BoNT-A) injections, balloon dilation, and CP myotomy.}, } @article {pmid41283823, year = {2026}, author = {Alshoshan, A and Aldubaiyan, AAR and Hakami, A and Alolayyan, A and Alqurishi, M and Alhazmi, OM and Abuzinadah, AR and Alshareef, AA and Alqahtani, HM and Alanazy, MH and Bushnag, A and Alkully, H and Beck, AA and Makkawi, S and Maglan, A and Al Hashim, S and Abulaban, AA and Almasood, AA and Alnasser, OI and Alyahya, M and Alsolaihim, A and Alshehri, A and , }, title = {Amyotrophic lateral sclerosis in Saudi Arabia: a multicenter descriptive study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {398-403}, doi = {10.1080/21678421.2025.2582835}, pmid = {41283823}, issn = {2167-9223}, mesh = {Humans ; Saudi Arabia/epidemiology ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/therapy/diagnosis ; Male ; Female ; Middle Aged ; Retrospective Studies ; Adult ; Aged ; Disease Progression ; Genetic Testing ; Cohort Studies ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease characterized by the progressive loss of muscle control, leading to paralysis and death. While ALS has been extensively studied globally, little research has focused on ALS in the Middle East, specifically Saudi Arabia. This study aims to investigate the demographic data, clinical characteristics, disease progression, and prognosis of ALS patients in Saudi Arabia to better understand region-specific disease patterns and potential therapeutic strategies.

METHODOLOGY: Retrospective multicenter cohort across five tertiary Saudi centers (2003-2022). The authors identified cases from neurology/neuromuscular clinics and neurophysiology laboratories; diagnoses followed revised El Escorial criteria with EMG confirmation where indicated. ALS variants and cases lacking sufficient longitudinal evidence were excluded. Clinical genetic testing was performed at the clinician's discretion; variants were classified per ACMG and only pathogenic/likely pathogenic results were counted; C9orf72 repeat-expansion testing was not systematically available. Prespecified variables included demographics, family history, initial phenotype, MRI/EMG, genetics, treatments (riluzole, edaravone, SPT, tofersen for SOD1), times to noninvasive ventilation (NIV), gastrostomy and invasive ventilation.

RESULTS: We included 270 patients (57% male). Mean age at first symptom was 51 years. Limb-onset occurred in 169/247 (68%) and bulbar-onset in 78/247 (32%). Among those with documented family history (97/270), 14% reported an affected relative. 37/270 underwent genetic testing; 56.7% were positive-most commonly OPTN (47.6.6% of positives) and SOD1 (38.1%). MRI brain/spine was normal in ∼53%. By 3 years from symptom onset, ∼80% of those who eventually required advanced support (NIV, invasive ventilation, and/or gastrostomy) had received it. Most patients were treated with riluzole.

CONCLUSION: This study provides valuable insights into ALS in Saudi Arabia, contributing to a better understanding of the disease in this region. The younger age of onset and the high familial prevalence are notable findings that warrant further investigation. Future studies focusing on genetic and environmental influences in Saudi Arabia may help improve diagnosis and therapeutic approaches.}, } @article {pmid41283860, year = {2026}, author = {Varline, J and Enfinger, M and Kavanaugh, MS}, title = {Mental health treatment of persons with ALS & their families: implementing an intervention to support practitioners.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {602-607}, doi = {10.1080/21678421.2025.2593304}, pmid = {41283860}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/complications ; *Caregivers/psychology/education ; *Family/psychology ; Female ; Male ; *Mental Health Services ; Surveys and Questionnaires ; Mental Health ; Middle Aged ; Adult ; *Mental Disorders/therapy/etiology ; }, abstract = {Objective: Given the limited education available to practitioners who provide mental health care for persons with amyotrophic lateral sclerosis (ALS) and their family members, a partnership between Mental Health America, Global Neuro YCare, and the ALS Association developed a web-based education programme providing discussions addressing ALS background, lived experience, and impact of caregiving, to increase confidence in care and access to resources when serving persons living with ALS and their caregivers. Methods: A pre/post survey was utilized to assess the webinar's impact on provider confidence in their knowledge and experience of ALS, access to ALS information and resources, and the ability to refer persons with ALS to care. The percentage change from pretest to post-test, frequency of knowledge, and qualitative analyses were conducted. Results: The findings indicated a 24% increase in practitioners' confidence in working with people with ALS and their family members, a 19% increase in providing mental health care to a family member, and a 20% increase in assessing resource information about ALS. Qualitative data highlighted several categories of responses, including increases in knowledge from the workshop, the need for individuals to be treated as more than just ALS, and a continuing need for training, and additional emotional support for practitioners. Conclusion: The online training increased confidence in providing mental health care to people living with ALS and their family members, adding to this understudied area. Still, additional research is needed to increase confidence in referring people to care, accessing information, and growing knowledge about ALS.}, } @article {pmid41285343, year = {2026}, author = {Pedde, M and Adar, SD and D'Souza, J and Feldman, EL and Goutman, SA}, title = {Air pollution and disease progression in a University of Michigan amyotrophic lateral sclerosis cohort.}, journal = {Environmental research}, volume = {289}, number = {}, pages = {123398}, doi = {10.1016/j.envres.2025.123398}, pmid = {41285343}, issn = {1096-0953}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/chemically induced ; Disease Progression ; Michigan/epidemiology ; Female ; Male ; Middle Aged ; *Air Pollution/adverse effects ; Particulate Matter/analysis/adverse effects ; Aged ; *Air Pollutants/analysis/adverse effects ; Cohort Studies ; *Environmental Exposure ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, fatal, neurodegenerative disease without effective treatments. Therefore, identifying modifiable risk factors to slow disease progression is important. We aimed to identify whether air pollution may be a modifiable risk factor associated with ALS progression. We recruited patients with ALS from the University of Michigan Pranger ALS Clinic from 2009 to 2022. Patient functional status was assessed at clinic evaluations approximately every three months using the ALS Functional Rating Scale Revised (ALSFRS-R); the change in total ALSFRS-R score over time was used to assess disease progression. The repeated ALSFRS-R overall scores were linked to spatiotemporal prediction model estimates of 3-month and 5-year average residential exposures to fine particulate matter mass (PM2.5) and components (sulfate, nitrate, black carbon), ozone, nitrogen dioxide, and sea salt (negative control expected to be nontoxic) before baseline and each clinical assessment. We used longitudinal linear mixed-effects models to assess associations between air pollution and the rate of disease progression, using the overall ALSFRS-R score, controlling for potential confounders. Among 469 participants with 3147 valid overall ALSFRS-R scores (44.8 % female; 62 ± 11 years at symptom onset; 3.6 ± 2.9 years follow-up) who resided in areas with PM2.5 levels near and below US regulatory standards, average rates of decline were 11.6 ± 24.0 ALSFRS-R points/year. In multi-pollutant models adjusted for potential confounders, one interquartile range (IQR) higher 5-year average black carbon (0.2 μg/m[3]) and nitrate (0.4 μg/m[3]) concentrations were associated with 2.4 (95 % CI: -3.4, -1.4) and 1.2 (95 % CI: -1.9, -0.5) ALSFRS-R points/year faster rates of decline, respectively. One IQR higher 3-month average ozone concentrations (1.4 ppb) were also associated with a faster rate of decline (-0.3 [95 % CI: -0.5, -0.1] ALSFRS-R points/year). Sea salt was not associated with ALS progression. These observed differences between high and low exposure participants reflected 3-21 % of the observed average annual ALSFRS-R decline.}, } @article {pmid41286090, year = {2025}, author = {Ariaei, A and Talebi, S and Ashtiani, BH and Hamblin, MR and Alipour Langouri, M and Ramezani, F}, title = {Distinguishing amyotrophic lateral sclerosis from radiculopathy using machine learning to analyze nerve conduction data.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {41633}, pmid = {41286090}, issn = {2045-2322}, support = {1402-4-4-27191//Iran University of Medical Sciences/ ; 43008282 -0//Shahid Beheshti University of Medical Sciences/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Radiculopathy/diagnosis/physiopathology ; *Machine Learning ; Male ; Female ; Middle Aged ; Diagnosis, Differential ; *Neural Conduction/physiology ; Algorithms ; Adult ; Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, fatal, and irreversible disease that shares some key clinical features with radiculopathy, including muscle atrophy, muscle cramps, and fasciculation. The aim of this study was to find a reliable method to differentiate these two diseases. Machine learning was used to discover new clinical biomarkers for the differential diagnosis of ALS from radiculopathy using nerve conduction study (NCS) data from patients. Data preparation and feature selection were performed by a random forest classifier algorithm, as well as a confusion matrix tool for model selection. After selecting the minimum number of features and the best algorithm, grid search cross-validation was used to optimize the hyperparameters of the chosen algorithm. 77 features were ranked according to their importance. The results of 20 algorithms acting on 8 different groups of features showed that the best performance (accuracy, precision, recall, f-1 score) was obtained using 35 important features and the XGB algorithm, particularly for the recall parameter. Using the XGB algorithm, ALS patients could be identified with accuracy = 0.871, precision = 0.923, recall = 0.850, and f-1 score = 0.857. The XGB algorithm using 35 NCS features could differentiate radiculopathy from ALS in patients with high accuracy.}, } @article {pmid41286450, year = {2026}, author = {Bye, CR and Qian, E and Lim, K and Daniszewski, M and Garton, FC and Trần-Lê, BC and Liang, HH and Lin, T and Lock, JG and Crombie, DE and Morgan, S and Hu, Y and Barton, SK and Palmer, LM and Djouma, E and Kodikara, S and Lê Cao, KA and Dharmadasa, T and Henders, AK and Ziser, LA and Kiernan, MC and Talbot, K and Needham, M and Fletcher, S and Talman, P and Mathers, S and Wray, NR and Hewitt, AW and Pebay, A and Turner, BJ}, title = {Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy.}, journal = {Nature neuroscience}, volume = {29}, number = {1}, pages = {40-52}, pmid = {41286450}, issn = {1546-1726}, support = {1137024//Department of Health | National Health and Medical Research Council (NHMRC)/ ; 2021//Department of Health | National Health and Medical Research Council (NHMRC)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; *Induced Pluripotent Stem Cells/drug effects/physiology ; *Motor Neurons/drug effects/pathology ; Riluzole/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Female ; Sulfonamides/pharmacology ; Drug Evaluation, Preclinical/methods ; Male ; Azetidines/pharmacology/therapeutic use ; Memantine/pharmacology ; Middle Aged ; Purines ; Pyrazoles/pharmacology ; Drug Therapy, Combination ; Aged ; }, abstract = {Heterogeneous and predominantly sporadic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), remain highly challenging to model. Patient-derived induced pluripotent stem cell (iPSC) technologies offer great promise for these diseases; however, large-scale studies demonstrating accelerated neurodegeneration in patients with sporadic disease are limited. Here we generated an iPSC library from 100 patients with sporadic ALS (SALS) and conducted population-wide phenotypic screening. Motor neurons derived from patients with SALS recapitulated key aspects of the disease, including reduced survival, accelerated neurite degeneration correlating with donor survival, transcriptional dysregulation and pharmacological rescue by riluzole. Screening of drugs previously tested in ALS clinical trials revealed that 97% failed to mitigate neurodegeneration, reflecting trial outcomes and validating the SALS model. Combinatorial testing of effective drugs identified baricitinib, memantine and riluzole as a promising therapeutic combination for SALS. These findings demonstrate that patient-derived iPSC models can recapitulate sporadic disease features, paving the way for a new generation of disease modeling and therapeutic discovery in ALS.}, } @article {pmid41287942, year = {2026}, author = {Kimachi, T and Kowa, H}, title = {Pneumothorax During Mechanical Ventilation in Patients With Amyotrophic Lateral Sclerosis: Incidence, Risk Factors, and Impact on Survival.}, journal = {Muscle & nerve}, volume = {73}, number = {2}, pages = {222-228}, doi = {10.1002/mus.70078}, pmid = {41287942}, issn = {1097-4598}, support = {JPMH23FC1008//MHLW Research on Rare and Intractable Diseases Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/mortality/complications ; Male ; Female ; *Pneumothorax/epidemiology/etiology/mortality/diagnostic imaging ; Middle Aged ; *Respiration, Artificial/adverse effects ; Risk Factors ; Incidence ; Retrospective Studies ; Aged ; Adult ; Body Mass Index ; }, abstract = {INTRODUCTION/AIMS: Pneumothorax is a complication of mechanical ventilation (MV) in patients with amyotrophic lateral sclerosis (ALS); however, its clinical features and risk factors are not well defined. This study aimed to characterize the incidence, risk factors, and prognostic impact of pneumothorax in patients with ALS undergoing MV.

METHODS: We retrospectively analyzed clinical data from patients with ALS admitted to our center between 2014 and 2024. Patient demographics and baseline characteristics, pneumothorax occurrence, MV details, chest computed tomography (CT) findings, and survival outcomes were reviewed. We analyzed independent risk factors for pneumothorax and evaluated cumulative incidence and survival.

RESULTS: Among the 131 patients with ALS, 95 underwent MV, 19 of whom developed pneumothorax. Only low body mass index (BMI) (< 18.5 kg/m[2]; p = 0.015) was identified as an independent risk factor. The cumulative incidence rates of pneumothorax at 1, 3, 5, and 10 years after MV initiation were 4.5%, 13.4%, 24.3%, and 32.0%, respectively. The median post-pneumothorax survival was 16 months (95% confidence interval [CI]: 6-67), with no significant difference in overall survival from the time of initiation of MV between patients with and without pneumothorax (p = 0.88).

DISCUSSION: This study identified low BMI as a potential risk factor for pneumothorax in ALS patients receiving MV. However, given the limited sample size, these findings should be interpreted with caution. Larger, multicenter studies are warranted to validate this association and to further elucidate long-term pulmonary effects and preventive strategies.}, } @article {pmid41288560, year = {2025}, author = {Jaecques, V}, title = {[Academische publicatie als toegangsticket tot het beroep: tijd voor een alternatief!].}, journal = {Tijdschrift voor psychiatrie}, volume = {67}, number = {9}, pages = {488-489}, pmid = {41288560}, issn = {0303-7339}, } @article {pmid41289739, year = {2026}, author = {Dakroub, F and Awada, B and Abdelhady, S and Shaito, AA and Eid, AH and Walker, J and Mondello, S and Bondi, CO and Moro, F and Elgendy, B and Wang, KK and Zanier, ER and Mechref, Y and Kobeissy, F}, title = {Edaravone: Advances on cytoprotective effects, pharmacological properties, and mechanisms of action.}, journal = {Pharmacological reviews}, volume = {78}, number = {1}, pages = {100101}, doi = {10.1016/j.pharmr.2025.100101}, pmid = {41289739}, issn = {1521-0081}, support = {1R01GM112490-08,/NH/NIH HHS/United States ; 1R01GM130091-05/NH/NIH HHS/United States ; 1U01CA225753-05/NH/NIH HHS/United States ; }, mesh = {Humans ; *Edaravone/pharmacology/therapeutic use/pharmacokinetics/chemistry ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/pharmacokinetics ; *Free Radical Scavengers/pharmacology/therapeutic use/pharmacokinetics ; Cytoprotection/drug effects ; *Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Neurological diseases often lead to life-altering consequences, underscoring the urgent need for therapies that can reverse or mitigate their effects. Effective management of neurological disorders necessitates a thorough understanding of the common pathological mechanisms driving their onset and progression. Mitochondrial dysfunction and oxidative stress stand out as critical contributors to neuronal damage, implicated in traumatic brain injury, stroke, and amyotrophic lateral sclerosis. Disruptions in energy metabolism lead to the accumulation of reactive oxygen species and elevate the level of neural injury. Moreover, these imbalances disrupt cellular homeostasis and activate apoptotic pathways, further exacerbating neuronal loss and ultimately worsening the clinical prognosis. In this context, edaravone (Eda), a Food and Drug Administration-approved free radical scavenger, has emerged as a compelling candidate for the treatment of neuropathologies. This review provides a comprehensive overview of Eda, detailing its chemical structure and pharmacokinetic profile, with a focus on strategies to enhance its delivery to the central nervous system by modulating blood-brain barrier permeability or employing delivery systems that facilitate central nervous system penetration. Moreover, the review examines Eda's pharmacodynamic properties, including the signaling pathways it influences. The neurotherapeutic potential of Eda is further examined through in vitro and in vivo models of neurological disease. Insights from clinical trials are discussed to bridge the gap between preclinical findings and patient outcomes. Finally, the review highlights the synergistic effects of combining Eda with other pharmacological agents or therapeutic interventions, underscoring its promise as a versatile and indispensable treatment for neurological disorders. SIGNIFICANCE STATEMENT: Edaravone, a Food and Drug Administration-approved free radical scavenger, shows broad neuroprotective potential by mitigating oxidative stress and mitochondrial dysfunction across diverse neurological disorders, including stroke, amyotrophic lateral sclerosis, and traumatic brain injury. By synthesizing preclinical and clinical evidence, this review highlights edaravone's pleiotropic therapeutic actions, identifies translational challenges, and underscores its promise as a versatile treatment strategy for neurodegenerative and acute and chronic brain conditions.}, } @article {pmid41290422, year = {2025}, author = {Morena, J and Hiana, J and Naum, R and Juel, V}, title = {Mills' syndrome and myasthenia gravis: a case report.}, journal = {Neuromuscular disorders : NMD}, volume = {56-57}, number = {}, pages = {106280}, doi = {10.1016/j.nmd.2025.106280}, pmid = {41290422}, issn = {1873-2364}, mesh = {Humans ; *Myasthenia Gravis/complications/diagnosis/physiopathology ; Male ; Middle Aged ; Magnetic Resonance Imaging ; Receptors, Cholinergic/immunology ; Diplopia ; Electromyography ; Syndrome ; }, abstract = {A 50-year-old man with hypothyroidism was referred for refractory myasthenia gravis (MG). He developed progressive, painless right-sided shoulder and leg weakness, dysphagia, and fatigable diplopia. Acetylcholine receptor (AChR) antibodies were positive. Immunosuppressive therapies provided only transient improvement in oculo-bulbar symptoms, while hemiparesis progressed. Examination showed fatigable ptosis with curtain sign, vertical gaze limitation, and diplopia localizing to left lateral rectus weakness. Upper motor neuron signs included brisk masseteric reflex, right spastic hemiparesis, and hyperreflexia. EMG demonstrated chronic reinnervation in right cervical and lumbosacral regions. MRI revealed T2 hyperintensity in the left upper cervical cord and adjacent medulla without enhancement. A diagnosis of AChR+ MG and Mills' syndrome was made. While MG has previously been reported to coexist with ALS, this is the first known case associated with Mills' syndrome. This highlights the importance of recognizing overlapping autoimmune and neurodegenerative disorders and the need for further research into shared mechanisms.}, } @article {pmid41290864, year = {2025}, author = {Kaur, P and Singh, G and Kaur, K and Kaur, N and Kumar, R and Bhullar, MS}, title = {Nanoemulsion of Apium graveolens essential oil as a natural pre-emergent herbicide.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {41963}, pmid = {41290864}, issn = {2045-2322}, mesh = {*Oils, Volatile/pharmacology/chemistry ; *Herbicides/pharmacology/chemistry ; Emulsions/chemistry ; *Apium/chemistry ; Germination/drug effects ; Limonene ; }, abstract = {Essential oils (EOs) are recognized for their potential as environmentally compatible alternatives to synthetic herbicides, often associated with a reduced risk of resistance development. However, their practical application faces challenges such as volatility and inconsistent efficacy. To address these limitations and enhance herbicidal potential, nanoemulsions (NEms) of Apium graveolens L. EO (celery) were formulated and assessed for their efficacy against Phalaris minor Retz. biotypes resistant (R) and sensitive (S) to ALS and ACCase-inhibiting herbicides, as well as Avena ludoviciana Durieu. The EO of A. graveolens had 37 compounds, with limonene (76.95%) as the main one. In the Petri plate bioassay emulsion of A. graveolens EO completely inhibited the germination of R and S P. minor biotypes and A. ludoviciana at 0.1%w/w. The individual components, R (+) limonene, S (-) limonene and their binary mixtures were less effective and reduced the germination of R and S P. Minor biotype and A. ludoviciana at comparatively higher concentrations. Individual components at concentration of 3 to 4%w/w were also toxic to Triticum aestivum. NEm of effective EO concentrations were fabricated by high frequency ultrasonic method and a phase diagram was mapped. The physicochemical properties indicated the formation of isotropic oil-in-water NEm. Transmission electron microscopy (TEM) and Dynamic Light scattering (DLS) studies indicated spherical nature of droplets with an average size > 21 nm. The prepared formulations were stable to storage as well as external forces. Emulsion and NEms each prepared at 0.05 and 0.1% w/w. A. graveolens EO concentrations completely inhibited the germination of R and S P. minor biotypes and A. ludoviciana by altering the physiological processes such as reduction in seed imbibition by 20% to 40% and causing up to a 13% increase in membrane leakage, without having adverse effects on T. aestivum.}, } @article {pmid41291238, year = {2025}, author = {Li, H and Yu, C and Markovic, T and Nestler, EJ and Dong, Y}, title = {Chemical strategies for brain delivery of genomic therapy.}, journal = {Nature reviews. Chemistry}, volume = {9}, number = {12}, pages = {841-854}, pmid = {41291238}, issn = {2397-3358}, support = {P01 DA047233/DA/NIDA NIH HHS/United States ; R01 DA007359/DA/NIDA NIH HHS/United States ; R35 GM144117/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Genetic Therapy/methods ; *Brain/metabolism ; Animals ; Nanoparticles/chemistry ; *Drug Delivery Systems/methods ; Lipids/chemistry ; Polymers/chemistry ; Oligonucleotides/chemistry ; *Gene Transfer Techniques ; }, abstract = {Genomic therapy has emerged as a transformative strategy for the prevention, diagnosis and treatment of a wide array of diseases, including Alzheimer's disease, amyotrophic lateral sclerosis and other CNS-related diseases. Recent developments in chemical strategies and delivery platforms have enhanced the potential of genomic therapies for brain disorders. In this Review, we summarize such strategies, focusing on advances in delivery platforms such as lipid nanoparticles, polymers and oligonucleotide conjugates to facilitate the brain delivery of DNA-based or RNA-based therapeutics into the CNS. We present an overview of the chemical structures and functional moieties of lipids, polymers and oligonucleotides used in these platforms. Lastly, we provide an outlook on future chemical directions to further improve the delivery of genomic medicines to the brain.}, } @article {pmid41292426, year = {2025}, author = {Menta, BW and Schueddig, E and Ranjan, A and Li, Y and Andrews, SJ and Wilkins, HM and Pei, D and Swerdlow, RH}, title = {MtDNA-depleted neuronal cell transcriptomes reveal Alzheimer's disease-related changes.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70929}, pmid = {41292426}, issn = {1552-5279}, support = {P30 CA168524/CA/NCI NIH HHS/United States ; T32 HD057850/HD/NICHD NIH HHS/United States ; //The Stop Alzheimer's Now Foundation/ ; P20 GM130423/GM/NIGMS NIH HHS/United States ; U54 HD090216/HD/NICHD NIH HHS/United States ; //The Institute for Neurological Discoveries Mabel A. Woodyard Memorial Fellowship Fund/ ; UL1 TR002366/TR/NCATS NIH HHS/United States ; S10OD021743//An NIH S10 High End Instrumentation award/ ; P30 GM122731/GM/NIGMS NIH HHS/United States ; P20 GM103418/GM/NIGMS NIH HHS/United States ; P30AG072973//The University of Kansas Alzheimer's Disease Research Center/ ; //The KUMC Neurological & Rehabilitation Sciences Training Program: NIHCHD T32HD057850/ ; P30 AG072973/AG/NIA NIH HHS/United States ; S10 OD021743/OD/NIH HHS/United States ; //The Ruble Family Foundation/ ; //The Clune Family Foundation/ ; UL1TR002366//The KUMC Frontiers CTSA/ ; //The KU Institute for Neurologic Discoveries/ ; //The Snyder Family Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/metabolism ; *DNA, Mitochondrial/genetics ; *Transcriptome/genetics ; *Neurons/metabolism ; Sequence Analysis, RNA ; Cell Line, Tumor ; }, abstract = {INTRODUCTION: We determined whether mitochondrial DNA (mtDNA) depletion induced Alzheimer's disease (AD)-relevant transcription changes.

METHODS: Following RNA sequencing (RNA-seq), we identified differentially expressed genes (DEGs) between SH-SY5Y or NT2 mtDNA-depleted (ρ0) and intact (ρ+) cell lines and quantified concordant DEG changes. Gene set enrichment analysis and over-representation analysis were used to determine the impact on the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD and other neurodegenerative disease pathways, ascertain pathway and term enrichment in the Reactome and Gene Ontology databases, and generate Ingenuity Pathway Analysis z-scores.

RESULTS: Relative to their ρ+ comparators, ρ0 lines differentially expressed >75% of their genes. The KEGG AD pathway was significantly enriched, and equivalently altered genes ranked the AD, Parkinson's disease, ALS, and Huntington's disease KEGG pathways among the most enriched gene sets. AD-related enriched pathways and terms reflected lipid, insulin signaling, synapse, inflammation/immune response, endosome/endocytosis, RNA, and proteostasis biology.

CONCLUSION: MtDNA depletion alters gene expression in ways that recapitulate or predictably promote AD molecular phenomena.

HIGHLIGHTS: MtDNA-depleted neuronal cell lines reshuffle nuclear gene expression. The KEGG AD pathway is enriched with DEGs. Transcription-defined pathways and terms relating to AD biology broadly change.}, } @article {pmid41292721, year = {2025}, author = {Buchholz, HE and Martin, SA and Dorweiler, JE and Prosser, DC and Sontag, EM and Manogaran, AL}, title = {Stress granules and protein aggregates reveal intracellular resource competition.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41292721}, issn = {2692-8205}, support = {R15 GM155860/GM/NIGMS NIH HHS/United States ; }, abstract = {Stress granules are biomolecular condensates that form in response to environmental stress and disassemble once normal conditions are restored. However, when disassembly fails, stress granules can persist and solidify. While stress granule solidification has been well documented, the cellular mechanisms underlying the transition from reversible to persistent stress granules remain unclear. Persistent stress granules can seed the formation of pathological aggregates, such as TDP-43 in amyotrophic lateral sclerosis[1, 2]. Although amyloid and tau aggregates are hallmarks of Alzheimer's disease, a subset of patients also develop TDP-43 deposits, suggesting a possible role for stress granule solidification in Alzheimer's disease progression[3-5]. Despite theoretical models explaining why persistence and ensuing solidification occurs, strong in vivo evidence is lacking[6]. Here we show that competition for limited chaperone resources drive stress granule persistence. In the presence of TDP-43 aggregates or yeast amyloid proteins called prions, stress granule disassembly is slowed or halted disassembly. Using yeast prions as a model, we show that the addition of chaperones, specifically the AAA+ ATPase molecular chaperone, Hsp104, resulted in resumption of stress granule disassembly. Our results demonstrate that the competition for shared resources, such as molecular chaperones, can limit stress granule disassembly. We suspect that the presence of pathological aggregates results in resource competition within the aging brain, contributing to the persistence of stress granules and their subsequent solidification and aggregation.}, } @article {pmid41292773, year = {2025}, author = {Linsenmeier, M and Shinn, MK and Mumford, TR and Liu, V and Bugaj, LJ and Pappu, RV and Shorter, J}, title = {Nuclear-import receptors remodel the dilute phase to suppress phase transitions of RNA-binding proteins with prion-like domains.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41292773}, issn = {2692-8205}, support = {K99 GM152778/GM/NIGMS NIH HHS/United States ; R01 AG077771/AG/NIA NIH HHS/United States ; R01 NS121114/NS/NINDS NIH HHS/United States ; R35 GM138211/GM/NIGMS NIH HHS/United States ; }, abstract = {RNA-binding proteins (RBPs) with prion-like domains, including FUS, hnRNPA1, and hnRNPA2, assemble into functional, metastable condensates that organize ribostasis, but can also transition into self-templating fibrils implicated in neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS). How nuclear-import receptors (NIRs) antagonize this pathological transition has remained unresolved. Here, we establish that NIRs regulate the phase behavior of prion-like cargos by remodeling the dilute phase. Quantitative analyses across length scales reveal that Karyopherin-β2 (Kapβ2) preferentially binds cargo in the dilute phase to lower the effective concentration of free RBPs thereby elevating the saturation concentration for phase separation and suppressing mesoscale clustering. ALS-linked FUS[P525L], which binds Kapβ2 weakly, evades this regulation to form pathogenic assemblies. Thus, NIRs harness polyphasic linkage, the thermodynamic relationship between ligand binding and phase equilibria, to reshape the landscape of prion-like RBP assembly states, establishing a paradigm for how ATP-independent chaperones regulate phase behavior to prevent disease-linked aggregation.}, } @article {pmid41292965, year = {2025}, author = {Zhang, Q and Liu, M and Fan, X and Chin, N and Xu, Y and Suh, J and Amniouel, S and Linask, K and Zou, J and Hafner, M and Ma, L and Zheng, W and Ye, Y}, title = {A human forebrain organoid model phenocopies dysregulated RNA and protein homeostasis in ALS/FTD-associated TDP-43 proteinopathies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41292965}, issn = {2692-8205}, abstract = {BACKGROUND: TAR DNA-binding protein 43 (TDP-43) proteinopathy is a central hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet current experimental models fail to reproduce the full pathological spectrum without external stress or TDP-43 overexpression. This study aims to establish a human induced pluripotent stem cells (iPSC)-derived system that spontaneously manifests TDP-43 pathology driven by an ALS-associated TDP-43 mutation.

METHODS: We generated forebrain 3-D organoid cultures from iPSC carrying the TDP-43 K181E patient mutation. Single-cell RNA sequencing was used to define transcriptional alterations across cell types, and enhanced crosslinking immunoprecipitation (eCLIP) was applied to examine the global RNA binding and splicing defects in mutant organoids. We further used immunostaining, RT-PCR and biochemical assays to confirm TDP-43 proteinopathy and validate findings from the multi-omics analyses.

RESULTS: The TDP-43 K181E organoids recapitulated key disease features, including cytoplasmic p-TDP-43 accumulation, RNA dysregulation, and cryptic exon inclusion. Single-cell analysis revealed a population of immature neurons with enhanced neuroinflammation and altered translation capacity. Comparative transcriptomics showed that the ALS mutation-induced transcriptional changes strongly overlap with those in ALS patient-derived brains. eCLIP analysis showed that mutant TDP-43 exhibited altered RNA-binding specificity, resulting in widespread RNA mis-splicing and cryptic exon inclusion. RT-PCR confirmed PRDM2, a gene regulating cell senescence, is mis-spliced in mutant cells. These defects collectively disrupt neuronal homeostasis and cell-cell communications.

CONCLUSIONS: Our iPSC-derived forebrain organoid model displays spontaneous TDP-43 proteinopathies and associated molecular dysfunctions without artificial manipulation. The model offers a robust platform for dissecting the mechanisms of TDP-43-mediated neurodegeneration and advancing therapeutic discovery in ALS and FTD.}, } @article {pmid41293411, year = {2025}, author = {Yang, D and Zhou, J and Zhao, Y and Nasb, M}, title = {Tuina combined with Riluzole in amyotrophic lateral sclerosis: protocol for a randomized controlled trial with clinical outcomes and synaptic PET biomarkers.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1705466}, pmid = {41293411}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration, leading to severe functional decline and limited therapeutic options. While current pharmacological interventions such as Riluzole offer only modest benefits, there is a growing imperative to explore complementary rehabilitation strategies. Preclinical and neuroimaging evidence suggests that Tuina, a traditional Chinese manual therapy, may influence synaptic plasticity and integrity, offering a biologically reasonable mechanism for therapeutic benefit.

METHODS: This randomized controlled trial, approved by the Ethics Committee of Hubei Provincial Hospital of Traditional Chinese Medicine (Approval No. HBZY2022-C42-01), will use a 1:1:1 allocation to enroll 135 participants. Participants will be assigned to: (i) Tuina therapy plus oral Riluzole, (ii) sham Tuina plus oral Riluzole, or (iii) Riluzole alone. Interventions will last for 1 year. The primary outcome is the change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Secondary outcomes include manual muscle test (MMT), modified Ashworth scale (MAS), forced vital capacity (FVC), vital capacity (VC), forced expiratory volume in 1 second (FEV1), FEV1/FVC ratio, peak expiratory flow (PEF), maximal voluntary ventilation (MVV), and ALS Assessment Questionnaire (ALSAQ-40). Outcomes will be assessed at baseline, 4 weeks, and every 6 months up to 24 months. A mechanistic substudy will employ presynaptic Synaptic vesicle protein 2A (SV2A) PET imaging to quantify synaptic changes associated with Tuina intervention.

DISCUSSION: This study is designed to evaluate the clinical efficacy of Tuina therapy combined with Riluzole and to investigate its potential to modulate synaptic integrity in patients with ALS. The findings are expected to provide evidence for integrating Tuina as an adjunctive, non-pharmacological therapy into comprehensive ALS management, linking functional improvements to underlying synaptic mechanisms.

CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn, identifier ChiCTR2300068650.}, } @article {pmid41293946, year = {2025}, author = {Xue, X and Xu, X and Lin, X and Wang, G and Dong, H}, title = {Optimizing the Diagnostic Assessment of Left Ventricular Noncompaction Cardiomyopathy: The Clinical Value of Cardiac Magnetic Resonance Imaging.}, journal = {Current medical imaging}, volume = {21}, number = {}, pages = {}, pmid = {41293946}, issn = {1573-4056}, abstract = {INTRODUCTION: The current diagnostic criteria for noncompaction of the ventricular myocardium (NVM) remain inconsistent, and comprehensive cardiac magnetic resonance (CMR) imaging data on the disease are limited. Therefore, the purpose of this study is to evaluate the clinical utility of CMR imaging in the diagnosis and functional assessment of patients with NVM.

MATERIALS AND METHODS: Twenty patients with NVM and twenty age- and sex-matched healthy controls (HC) underwent comprehensive CMR imaging. Postprocessing software was used to quantify left ventricular longitudinal strain, both global longitudinal strain (GLS) and strain in the basal, middle, and apical segments (BLS, MLS, and ALS, respectively). Statistical analyses were performed to assess group differences.

RESULTS: Compared with the HC group, patients with NVM presented significantly increased left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), stroke volume (LVSV), and myocardial mass index (LVMI) and a significantly reduced left ventricular ejection fraction (LVEF) (all P < 0.001). All NVM patients presented prominent trabeculations and deep intertrabecular recesses in the left ventricle during diastole. Cine imaging revealed direct blood flow communication between the recesses and the ventricular cavity. The myocardium exhibited a thin compacted outer layer (C) and a thickened noncompacted inner layer (NC), with an average NC/C ratio of 2.8 ± 0.5. For these patients, NVM primarily involved the apical and adjacent mid-ventricular free wall segments; in five patients, it also involved the basal segment. Right ventricular noncompaction was observed in five patients, and apical ventricular aneurysms were identified in two patients. Compared with the HC group, the NVM group presented a significantly lower ALS (P < 0.05); however, the BLS, MLS, and GLS values were not significantly different between the groups (P > 0.05).

DISCUSSION: Our study demonstrated the feasibility of using CMR imaging to quantitatively assess left ventricular systolic function in NVM patients. The choice of longitudinal strain as a primary parameter was driven by the fact that NVM predominantly affects the endocardial myocardium, particularly the subendocardial fibers, which are primarily longitudinal. As such, longitudinal strain is particularly sensitive for detecting myocardial contractile dysfunction in NVM. Our results indicated that ALS apical longitudinal strain is a more significant marker of contractile dysfunction in NVM than MLS, which was not significantly altered in NVM patients relative to HCs.

CONCLUSION: CMR imaging offers robust diagnostic capabilities for patients with NVM and, when combined with feature tracking, allows the quantitative assessment of left ventricular systolic function. The ALS may serve as a sensitive marker of early myocardial dysfunction and may be clinically important in guiding timely diagnosis and intervention.}, } @article {pmid41294071, year = {2026}, author = {Khan, H and Khan, MM}, title = {Extending the Interpretation of Biomarker Dynamics in SOD1-ALS Proteomics.}, journal = {Annals of neurology}, volume = {99}, number = {2}, pages = {545}, doi = {10.1002/ana.78089}, pmid = {41294071}, issn = {1531-8249}, } @article {pmid41294352, year = {2025}, author = {Aradhye, PD and Mandal, S and Gray, RD and Campbell, CJ}, title = {Adaptive Physics-Aware Raman Baseline Correction with Machine Learning Predicted Parameters.}, journal = {Analytical chemistry}, volume = {97}, number = {48}, pages = {26708-26719}, doi = {10.1021/acs.analchem.5c05185}, pmid = {41294352}, issn = {1520-6882}, abstract = {Accurate baseline correction is critical for reliable Raman spectral interpretation. Traditional algorithmic methods often require manual tuning of regularization parameters, while recent machine learning and neural network approaches automate correction but lack generalizability and user control. We have developed a new approach to baseline correction which adaptively resolves baseline distortions without manual intervention - DIRAS (Dynamic Iterative Reweighted Autoregressive Spectral baseline correction). DIRAS uses a fixed regularization parameter (λ), which performs robust batch correction by iteratively reweighting residuals. We further used Structural Similarity Index Measure (SSIM) as an objective for λ optimization and trained a deep learning model to learn the nonlinear mapping between raw spectral features and optimal regularization. The resulting framework (DIRAS+) was capable of real-time spectrum-specific λ prediction. Applied to two SERS data sets, DIRAS+ outperformed ALS and SEALS in preserving peak fidelity, reducing intraclass variability and minimizing baseline distortion. Importantly, in downstream chemometric workflows, DIRAS improved calibration and model performance, yielding lower errors and enhancing analytical sensitivity. DIRAS and DIRAS+ together provide robust, scalable, and user-adaptable solutions for high-throughput Raman spectroscopy applications.}, } @article {pmid41294799, year = {2025}, author = {Medigovic, G and Rachamala, HK and Dutta, SK and Pal, K}, title = {Structural and Functional Perspectives of Optineurin in Autophagy, Immune Signaling, and Cancer.}, journal = {Cells}, volume = {14}, number = {22}, pages = {}, pmid = {41294799}, issn = {2073-4409}, support = {R56 HL160545/HL/NHLBI NIH HHS/United States ; W81XWH-21-1-0678//Department of Defense Congressionally Directed Medical Research Program/ ; R56HL160545//The National Heart, Lung, and Blood Institute/ ; }, mesh = {Humans ; *Autophagy ; *Neoplasms/immunology/metabolism/pathology ; *Membrane Transport Proteins/chemistry/metabolism ; *Signal Transduction ; *Cell Cycle Proteins/chemistry/metabolism ; Animals ; *Transcription Factor TFIIIA/metabolism/chemistry/genetics ; }, abstract = {Optineurin (OPTN) is a multifunctional adaptor protein that regulates diverse cellular processes, including inflammatory signaling, autophagy, vesicular trafficking, and immune responses. This multifaceted role of OPTN is made possible by the presence of a complex structure comprising multiple domains that interact with different proteins to exert various functions important for modulating key signaling processes. Mutations in OPTN are linked with several human pathologies including glaucoma, Paget's disease of bone, Crohn's disease, and neurodegenerative diseases such as amyotrophic lateral sclerosis, and dementia. Emerging evidence suggests that OPTN has a complex and context-dependent role in cancer biology as well. It is upregulated in pancreatic ductal adenocarcinoma and hepatocellular carcinoma but downregulated in lung and colorectal cancers, indicating its dual role as a potential oncogene or tumor suppressor depending on the cellular environment. Additionally, OPTN plays a critical role in preventing immune evasion in colorectal cancer by maintaining interferon-gamma receptor 1 (IFNGR1) expression and supporting dendritic cell-mediated T-cell priming, thereby enhancing antitumor immune responses. Despite its significance in oncogenic pathways and immune regulation, the therapeutic potential of targeting OPTN in cancer remains largely unexplored. This review aims to provide a comprehensive understanding of OPTN's pleiotropic functions, highlighting its role in autophagy, inflammation, immune surveillance, and cancer progression. By elucidating its diverse regulatory mechanisms, we seek to encourage further research into the therapeutic implications of OPTN in cancer treatment and immunotherapy.}, } @article {pmid41294805, year = {2025}, author = {Xu, H and Zhou, K and Xia, L and Ren, K and Xu, Y}, title = {In-Depth Study of Low-Complexity Domains: From Structural Diversity to Disease Mechanisms.}, journal = {Cells}, volume = {14}, number = {22}, pages = {}, pmid = {41294805}, issn = {2073-4409}, support = {31972537//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Humans ; *Intrinsically Disordered Proteins/chemistry/metabolism ; Neurodegenerative Diseases/metabolism ; *Protein Domains ; }, abstract = {Low-complexity domains (LCDs) are protein regions characterized by a simple amino acid composition and low sequence complexity, as they are typically composed of repeats or a limited set of a few amino acids. Historically dismissed as "garbage sequences", these regions are now acknowledged as critical functional elements. This review systematically explores the structural characteristics, biological functions, pathological roles, and research methodologies associated with LCDs. Structurally, LCDs are marked by intrinsic disorder and conformational dynamics, with their amino acid composition (e.g., G/Y-rich, Q-rich, S/R-rich, P-rich) dictating structural tendencies (e.g., β-sheet formation, phase separation ability). Functionally, LCDs mediate protein-protein interactions, drive liquid-liquid phase separation (LLPS) to form biomolecular condensates, and play roles in signal transduction, transcriptional regulation, cytoskeletal organization, and nuclear pore transportation. Pathologically, LCD dysfunction-such as aberrant phase separation or aggregation-is implicated in neurodegenerative diseases (e.g., ALS, AD), cancer (e.g., Ewing sarcoma), and prion diseases. We also summarize the methodological advances in LCD research, including biochemical (CD, NMR), structural (cryo-EM, HDX-MS), cellular (fluorescence microscopy), and computational (MD simulations, AI prediction) approaches. Finally, we highlight current challenges (e.g., structural heterogeneity, causal ambiguity of phase separation) and future directions (e.g., single-molecule techniques, AI-driven LCD design, targeted therapies). This review provides a comprehensive perspective on LCDs, illuminating their pivotal roles in cellular physiology and disease, and offering insights for future research and therapeutic development.}, } @article {pmid41294820, year = {2025}, author = {Sironi, F and Parlanti, P and Margotta, C and Cassarà, J and Bonetto, V and Bendotti, C and Tortarolo, M and Cappello, V}, title = {C9ORF72 Is Pivotal to Maintain a Proper Protein Homeostasis in Mouse Skeletal Muscle.}, journal = {Cells}, volume = {14}, number = {22}, pages = {}, pmid = {41294820}, issn = {2073-4409}, support = {1157625//Regione Lombardia, Italy/ ; }, mesh = {Animals ; *Muscle, Skeletal/metabolism/ultrastructure/pathology ; Mice ; *C9orf72 Protein/metabolism/genetics ; *Proteostasis ; Mice, Knockout ; Mitochondria/metabolism/ultrastructure ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Autophagy ; Mitophagy ; *Homeostasis ; Male ; Ubiquitin-Protein Ligases/metabolism ; Mice, Inbred C57BL ; }, abstract = {The C9ORF72 gene mutation is a major cause of amyotrophic lateral sclerosis (ALS). Disease mechanisms involve both loss of C9ORF72 protein function and toxic effects from hexanucleotide repeat expansions. Although its role in neurons and the immune system is well studied, the impact of C9ORF72 deficiency on skeletal muscle is not yet well understood, despite muscle involvement being a key feature in ALS pathology linked to this mutation. This study examined skeletal muscle from C9ORF72 knockout mice and found a 19.5% reduction in large muscle fibers and altered fiber composition. Ultrastructural analysis revealed mitochondrial abnormalities, including smaller size, pale matrix, and disorganized cristae. Molecular assessments showed increased expression of Atrogin-1, indicating elevated proteasomal degradation, and markers of enhanced autophagy, such as elevated LC3BII/LC3BI ratio, Beclin-1, and reduced p62. Mitochondrial quality control was impaired, with a 3.6-fold increase in PINK1, upregulation of TOM20, reduced Parkin, and decreased PGC-1α, suggesting disrupted mitophagy and mitochondrial biogenesis. These changes led to the accumulation of damaged mitochondria. Overall, the study demonstrates that C9ORF72 is critical for maintaining muscle protein and mitochondrial homeostasis. While C9orf72-haploinsufficiency does not directly compromise muscle strength in mice, it may increase the vulnerability of skeletal muscle in C9ORF72-associated ALS.}, } @article {pmid41294873, year = {2025}, author = {Wang, S and Feng, Z and Wu, H and Wang, S and Qin, S and Wang, X and Zhou, F and Zheng, K and Huang, X and Liu, X}, title = {The m[6]A Modification in Neurodegenerative Disease: A Cellular Perspective.}, journal = {Cells}, volume = {14}, number = {22}, pages = {}, pmid = {41294873}, issn = {2073-4409}, support = {BK20231347//Natural Science Foundation of Jiangsu Province/ ; 81971179//National Natural Science Foundation of China/ ; Z2019035//Jiangsu Commission of Health/ ; 20KJA320004//Jiangsu Provincial Department of Education/ ; KC23242//Technology Innovation Foundation of Xuzhou City/ ; JBGS202202//Open Competition Grant of Xuzhou Medical University/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Adenosine/analogs & derivatives/metabolism/genetics ; Animals ; Neurons/metabolism ; }, abstract = {N6-methyladenosine (m[6]A) is the most abundant internal RNA modification in eukaryotes and plays a critical role in gene expression regulation by influencing RNA stability, splicing, nuclear export, and translation. Emerging evidence suggests that dysregulation of m[6]A contributes to neuroinflammation, neurotoxicity, and synaptic dysfunction-key features of neurodegenerative diseases. This review aims to examine the role of m6A modification in neurodegenerative diseases from a cell-type-specific perspective. We systematically reviewed recent studies investigating m[6]A modifications in neurons and glial cells. Data from transcriptomic, epitranscriptomic, and functional studies were analyzed to understand how m[6]A dynamics influence disease-related processes. Findings indicate that m[6]A modifications regulate neuroinflammation and immune responses in microglia, modulate astrocytic support functions, affect myelination through oligodendrocytes, and alter m[6]A patterns in neurons, impacting synaptic plasticity, stress responses, and neuronal survival. These cell-type-specific roles of m[6]A contribute to the progression of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). Understanding m[6]A-modulated mechanisms in specific neural cell types may facilitate the development of targeted interventions for neurodegenerative diseases.}, } @article {pmid41294911, year = {2025}, author = {Abreu, MM and Hosseine-Farid, M and Silverman, DG}, title = {Total Reversal of ALS Confirmed by EMG Normalization, Structural Reconstitution, and Neuromuscular-Molecular Restoration Achieved Through Computerized Brain-Guided Reengineering of the 1927 Nobel Prize Fever Therapy: A Case Report.}, journal = {Diseases (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {41294911}, issn = {2079-9721}, abstract = {BACKGROUND: Neurological disorders are the leading cause of disability, affecting over three billion people worldwide. Amyotrophic lateral sclerosis (ALS) is among the most feared and uniformly fatal neurodegenerative diseases, with no therapy capable of restoring lost function.

METHODS: We report the first application of therapeutic fever to ALS using Computerized Brain-Guided Intelligent Thermofebrile Therapy (CBIT[2]). This fully noninvasive treatment, delivered through an FDA-approved computerized platform, digitally reengineers the 1927 Nobel Prize-recognized malarial fever therapy into a modern treatment guided by the Brain-Eyelid Thermoregulatory Tunnel. CBIT[2] induces therapeutic fever through synchronized hypothalamic feedback, activating heat shock proteins, which are known to restore proteostasis and neuronal function.

CASE PRESENTATION: A 56-year-old woman was diagnosed with progressive ALS at the Mayo Clinic, with electromyography (EMG) demonstrating fibrillation and fasciculation indicative of denervation corroborated by neurological and MRI findings; the patient was informed that she had an expected survival of three to five years. A neurologist from Northwestern University confirmed the diagnosis and thus maintained the patient on FDA-approved ALS drugs (riluzole and edaravone). Her condition rapidly worsened despite pharmacological treatment, and she underwent CBIT[2], resulting in (i) electrophysiological reversal with complete disappearance of denervation; (ii) biomarker correction, including reductions in neurofilament and homocysteine, IL-10 normalization (previously linked to mortality), and robust HSP70 induction; (iii) restoration of gait, swallowing, respiration, speech, and cognition; (iv) reconstitution of tongue structure; and (v) return to complex motor tasks, including golf, pickleball, and swimming.

DISCUSSION: This case provides the first documented evidence that ALS can be reversed through digitally reengineered fever therapy aligned with thermoregulation, which induces heat shock response and upregulates heat shock proteins, resulting in the patient no longer meeting diagnostic criteria for ALS and discontinuation of ALS-specific medications. Beyond ALS, shared protein-misfolding pathology suggests that CBIT[2] may extend to Alzheimer's, Parkinson's, and related disorders. By modernizing this Nobel Prize-recognized therapeutic principle with computerized precision, CBIT[2] establishes a framework for large-scale clinical trials. A century after fever therapy restored lost brain function and so decisively reversed dementia paralytica such that it earned the 1927 Nobel Prize in Medicine, CBIT[2] now safely harnesses the therapeutic power of fever through noninvasive, intelligent, brain-guided thermal modulation. Amid a global brain health crisis, fever-based therapies may offer a path to preserve thought, memory, movement, and independence for the more than one-third of humanity currently affected by neurological disorders.}, } @article {pmid41295414, year = {2025}, author = {Favari, E and Parolini, C}, title = {Marine Bioactive Components and Chronic Neuroinflammation: Focus on Neurodegenerative Disease.}, journal = {Marine drugs}, volume = {23}, number = {11}, pages = {}, pmid = {41295414}, issn = {1660-3397}, support = {NA//MUR Progetto Eccellenza/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroinflammatory Diseases/drug therapy ; *Aquatic Organisms/chemistry ; Oxidative Stress/drug effects ; Inflammation/drug therapy ; }, abstract = {Advances in neuroscience, immunology, and neuroimmunology have revealed that the nervous and immune systems form a bidirectional integrated network, ranging from regulating inflammation to directing stress responses, pivotal for the maintenance of the brain-body physiology. Like peripheral inflammation, neuroinflammation is a conserved process aimed at activating innate/adaptive immune and non-immune cells to effectively deal with bacteria, viruses, toxins, and injuries, and eventually at removing the microbial pathogens and supporting tissue repair and recovery. A failure of this process or the permanent release of pro-inflammatory mediators causes a condition called "chronic low-grade neuroinflammation" resulting in tissue damage and an increased risk of developing neurodegenerative diseases (NDD), such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Marine-derived bioactive components are able to modulate lipid and glucose metabolism as well as inflammation and oxidative stress. In this review, we describe the neuroinflammatory process and its involvement in the pathogenesis and progression of AD, PD, MS, and ALS. Then, we discuss the potential therapeutic efficacy of select marine-derived bioactive components.}, } @article {pmid41295911, year = {2025}, author = {Warren, J and Bosson, N and Tolles, J and Wilhelm, K and Avakoff, E and Arase, M and Toy, J and Kim, M and Nulty, J and Roel, A and Mendoza, L and Cohen, M and Gausche-Hill, M and Whitfield, D}, title = {A Live Human Model Comparison Evaluating ThoraSite[®] Accuracy for Needle Thoracostomy.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/10903127.2025.2592880}, pmid = {41295911}, issn = {1545-0066}, abstract = {OBJECTIVES: Needle thoracostomy (NT) is a time-sensitive procedure infrequently performed by EMS clinicians with variable success rates. Our primary objective was to evaluate the accuracy of NT site selection by paramedics using ThoraSite[®] compared to traditional anatomic landmarks (ALs). Secondarily, we assessed paramedic-rated confidence and ease of ThoraSite[®] use.

METHODS: We conducted a randomized, two-arm crossover study including fire-based paramedics. Emergency physician investigators determined a NT placement zone for live human models in three size groups, confirming with ultrasound and demarcating the zone with "invisible" ultraviolet ink. Following training, paramedics performed NT site selection on the models using ThoraSite[®] and ALs by placing a sticker at the selected insertion site. Accuracy of placement was confirmed with ultraviolet flashlight. If placement was outside the demarcated zone (DZ), we identified underlying structures with ultrasound. We evaluated the effect of approach on placement accuracy and time-to-NT placement using linear models with covariates of paramedic, approach, and model size. For the outcome of accuracy, we used a log link function. For time-to-NT, we log-transformed the values for the parametric analysis allowing interpretation of the coefficients as percent differences. We compared paramedic confidence in performing the NT procedure and perceived ease of procedure using a 5-point Likert scale.

RESULTS: There were 112 paramedics that performed 223 ThoraSite[®] and 223 landmark attempts with 383 correct placements within the DZ: 198 attempts using ThoraSite[®] compared to 185 with ALs, odds ratio (OR) 1.91 (95%CI 1.01-3.62), p = 0.04. Placement accuracy by model size followed similar trends. Incorrect placement over critical structures occurred in 1 ThoraSite[®] and 3 AL attempts. The mean time for NT site selection was 14.3s (SD = 7.11) using ThoraSite[®] and 18.7s (SD = 7.40) using ALs (p < 0.01). Overall procedural confidence improved with training. However, there was no statistically significant difference in the change in confidence with ThoraSite[®] as compared to ALs (OR = 1.55 95%CI = 0.89-2.72). Paramedics rated ease of NT placement significantly higher using ThoraSite[®] (median = 5, IQR = 4-5) compared to ALs (median = 4, IQR = 4-5; p < 0.01).

CONCLUSIONS: ThoraSite[®] was associated with increased odds of NT site selection in the DZ, reduced time-to-NT site selection, and increased self-rated ease reported by paramedics.}, } @article {pmid41296103, year = {2025}, author = {Ge, TQ and Ma, XY and Guan, PP and Wang, P}, title = {Aspirin Attenuates the Pathogenesis of Amyotrophic Lateral Sclerosis by Inhibiting the Activities of Microglia in a NF-κB-dependent Complement System-deactivating Mechanism.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {180}, pmid = {41296103}, issn = {1559-1182}, support = {JYTMS20230628//Liaoning Provincial Department of Education Funding/ ; D2402007//Shenzhen Medical Research Fund/ ; GDRC202404//Natural Science Foundation of Top Talent of SZTU/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism ; *NF-kappa B/metabolism ; *Microglia/drug effects/metabolism/pathology ; Animals ; *Aspirin/pharmacology/therapeutic use ; Mice ; *Complement System Proteins/metabolism ; Apoptosis/drug effects ; Cell Line ; Lipopolysaccharides/pharmacology ; Signal Transduction/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which is pathologically characterized by impairing the motor neurons, leading to the disorders of motor function. Aspirin (ASP) has the ability to increase the survival time of SOD1[G93A] mice via concurrently reducing the activation of glial cells and restoring the number of neurons. Meanwhile, ASP treatment inhibited the activities of NF-κB pathway, which resulted in regulating the expression of complement system (CS), including C3, C1qb, and C4b in vivo. To reveal the inherent mechanisms, the in vitro experiments were carried out in SOD1[G93A] protein- and lipopolysaccharide (LPS)-treated BV2 cells. The results demonstrated that SOD1[G93A] protein or LPS induces the activation of NF-κB in BV2 cells, whose conditional medium induces the apoptosis of NSC34 cells. By blocking the activities of NF-κB by ASP, Bay 11-7082 or si NF-κB, the synthesis of CS molecules was suppressed, which results in alleviating the apoptosis of NSC34 cells. More importantly, Terminal complement complex (TCC) was identified to be the critical component of CS for mediating the effects of SOD1[G93A] protein or LPS on inducing the apoptosis of neurons, which was inhibited by the ASP or Bay 11-7082. On the basis of these observations, our findings novelly revealed that ASP delayed the progression of ALS via inhibiting the activities of microglia in a NF-κB-dependent CS-deactivating mechanisms.}, } @article {pmid41296954, year = {2025}, author = {Lu, Z and Kong, D and Zhou, H and Zhou, S and Chen, L and Tao, Y and Yang, G}, title = {A Unified Contrastive Learning Framework for Neurological Disease Diagnosis from VGRF and IMU Gait Data.}, journal = {IEEE journal of biomedical and health informatics}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/JBHI.2025.3637054}, pmid = {41296954}, issn = {2168-2208}, abstract = {Accurate early diagnosis of neurological diseases (NDs) can effectively facilitate intervention and help with neural healthcare. While wearable informatics like Vertical Ground Reaction Force (VGRF) and Inertial Measurement Unit(IMU) offer complementary gait insights, a key challenge is fusing these heterogeneous modalities, especially when the data are unaligned and scarce. In this study, our primary contribution lies in proposing a novel contrastive learning framework designed specifically to unify VGRF and IMU gait data for ND classification. This framework learns a shared representation space during training, enabling the final trained model to perform accurate diagnosis from data streams of either a single VGRF or a single IMU modality. We evaluated this approach on the classification of four NDs-Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke-against healthy controls using two public VGRF datasets and one real-world IMU dataset. As a key result, our model achieved 98.21% accuracy in the binary task (disease vs. healthy) and 96.99% accuracy in the multi-class classification. The high performance demonstrates the potential of our method to advance neural health diagnostics, providing a robust approach for gait-based neurological assessment using heterogeneous wearable sensors.}, } @article {pmid41297670, year = {2026}, author = {Matsumoto, C and Kabuta, T and Sano, T and Murayama, S and Saito, Y and Takahashi, Y}, title = {ERBB4 colocalizes with phosphorylated tau aggregates in multiple tauopathies.}, journal = {Neurochemistry international}, volume = {192}, number = {}, pages = {106093}, doi = {10.1016/j.neuint.2025.106093}, pmid = {41297670}, issn = {1872-9754}, mesh = {*Receptor, ErbB-4/metabolism ; Humans ; Phosphorylation/physiology ; *tau Proteins/metabolism ; *Tauopathies/metabolism/pathology ; Male ; Female ; Aged ; }, abstract = {The neuregulin-ERBB4 pathway is essential for maintaining cellular function. Upon stimulation by its ligand, neuregulin, ERBB4-a receptor tyrosine kinase-triggers multiple cellular responses, including proliferation, apoptosis, differentiation, and neuromuscular junction formation. Previous research has implicated dysregulated ERBB4 signaling in the pathophysiology of several neurodegenerative disorders, such as Alzheimer's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, and Parkinson's disease. In this study, we examined ERBB4 expression in diseases characterized by phosphorylated tau (MAPT) pathology. We found that ERBB4 colocalized with neuronal and glial phosphorylated tau-positive inclusions in multiple tauopathies, including Pick's disease, Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutation. Conversely, ERBB4 did not colocalize with α-synuclein aggregates in α-synucleinopathies (Parkinson's disease and multiple system atrophy) or with neuronal intranuclear inclusions in triplet repeat disorders (Huntington's disease and dentatorubral-pallidoluysian atrophy). A co-immunoprecipitation assay indicated that ERBB4 can interact with tau intracellularly. Notably, in corticobasal degeneration, we observed ectopic ERBB4 expression in astrocytes lacking apparent phosphorylated tau aggregates. These findings suggest a potential role for ERBB4 in the pathophysiology of tau-related neurodegenerative diseases.}, } @article {pmid41298223, year = {2026}, author = {Lin, CY and Lee, BC and Zhang, PH and Lu, SC and Chang, WZ and Wang, CC and Tsai, HJ}, title = {A 16-amino acid peptide delays the progression of motor neuron degeneration and pathogenic symptoms in ALS models.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {1}, pages = {e00806}, pmid = {41298223}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/drug therapy/genetics/metabolism ; *Motor Neurons/drug effects/pathology/metabolism ; Mice ; Disease Progression ; Mice, Transgenic ; Disease Models, Animal ; *Nerve Degeneration/pathology/drug therapy ; Zebrafish ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Peptides/pharmacology/therapeutic use ; Mice, Inbred C57BL ; Phosphoglycerate Kinase ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neurons (MNs) degenerative disease. Despite advancements in understanding ALS pathogenesis, drug development lags far behind. The reduced secretion of phosphoglycerate kinase 1 (Pgk1) by NogoA-overexpressing muscle cells inhibits neurite outgrowth of MNs (NOMNs). However, administration of extracellular Pgk1 (ePgk1) reduces phospho-Cofilin (p-Cofilin), a growth cone collapse marker, and mitigates MN degeneration. This improves NOMNs in NSC34 neural cells and locomotion in SOD1-G93A ALS-mice by suppressing the p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 signaling pathway. Here, we identified two Pgk1-based 16-amino acid (aa) short peptides, FD-1 and FD-2, with neuroprotective effects equivalent to those of full-length ePgk1. Administration of FD-1 or FD-2 (FD-1/-2) reduced p-Cofilin and promoted NOMNs in NSC34 cells cultured in conditioned medium obtained from NogoA-overexpressing muscle cells. Furthermore, we found that exogenous addition of FD-1/-2 to the culture medium attenuated the accumulation of phospho-Tau-S396 and the cytoplasmic mislocalization of transactive response DNA binding protein of 43 kDa (TDP-43) in oxidative-stressed ALS-like SOD1-G93A NSC34 cells. In FD-1/-2-injected zebrafish embryos, we observed increased caudal primary MNs branching. In C9orf72-knockdown and hTDP-43-G348C mRNA overexpressing zebrafish embryos injected with FD-1/-2, axonal growth and motor function were rescued. Moreover, intravenous injection of FD-1/-2 in SOD1-G93A ALS-mice delayed denervation of neuromuscular junction, preserved cell bodies of MNs in the ventral horn of spinal cord, increased grip strength, improved locomotion and prolonged survival. Therefore, both 16-aa short FD peptides are functionally equivalent to full-length 417-aa ePgk1 and thus promising therapeutic short peptides for the treatment of ALS.}, } @article {pmid41298366, year = {2025}, author = {Rizuan, A and Shenoy, J and Mohanty, P and Dos Passos, PM and Mercado Ortiz, JF and Bai, L and Viswanathan, R and Zaborowksy, J and Wang, SH and Johnson, V and Mamede, LD and Titus, AR and Ayala, YM and Ghirlando, R and Mittal, J and Fawzi, NL}, title = {Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {10528}, pmid = {41298366}, issn = {2041-1723}, support = {R01 NS114289/NS/NINDS NIH HHS/United States ; R01 NS116176/NS/NINDS NIH HHS/United States ; R01NS114289//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS116176//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {*DNA-Binding Proteins/chemistry/metabolism/genetics ; Humans ; Molecular Dynamics Simulation ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Protein Domains ; *Protein Multimerization ; Magnetic Resonance Spectroscopy ; Mutation ; Conserved Sequence ; Protein Conformation, alpha-Helical ; }, abstract = {Pathological inclusions of the C-terminal domain (CTD) of TAR DNA binding protein-43 (TDP-43) are neurodegenerative hallmarks in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, yet CTD's aggregation propensity complicates structural characterization of native TDP-43. Here we propose structural models for the physiological multimerization of TDP-43 CTD's conserved region (CR) essential for TDP-43 RNA processing. Using NMR spectroscopy, we establish that the native state of TDP-43 CR at physiological conditions is α-helical. Hydrophobic residues drive CR helix-helix assembly, phase separation, and TDP-43 nuclear retention, while polar residues down regulate these processes. An integrative approach combining analytical ultracentrifugation, NMR-derived contacts, AlphaFold2-Multimer modeling, and all-atom molecular dynamics simulations together suggest that TDP-43 CR forms dynamic, multimeric helical assemblies stabilized by a methionine-rich core with specific contributions from a tryptophan/leucine pair. These structures show how ALS-associated mutations disrupt TDP-43 function and provide pharmacologically targetable structures to prevent its conversion into pathogenic β-sheet aggregates.}, } @article {pmid41298695, year = {2025}, author = {Almaguer-Mederos, LE and Key, J and Sen, NE and Canet-Pons, J and Döring, C and Meierhofer, D and Gispert-Sánchez, S and Cuello-Almarales, D and Almaguer-Gotay, D and Osorio-González, LM and Aguilera-Rodríguez, R and Medrano-Montero, J and Auburger, G}, title = {Multiomics approach identifies SERPINB1 as candidate biomarker for spinocerebellar ataxia type 2.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {42559}, pmid = {41298695}, issn = {2045-2322}, mesh = {Animals ; Humans ; Biomarkers/blood/metabolism ; Mice ; *Spinocerebellar Ataxias/metabolism/genetics/blood ; Proteomics/methods ; Male ; Ataxin-2/genetics/metabolism ; Female ; *Serpins/blood/genetics/metabolism ; Cerebellum/metabolism ; Spinal Cord/metabolism ; Disease Models, Animal ; Middle Aged ; Multiomics ; }, abstract = {Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder, and variants in its disease protein Ataxin-2 act as modifiers in the progression of Amyotrophic Lateral Sclerosis. There are no reliable molecular biomarkers for SCA2. The aim of this study was to define novel molecular biomarker candidates for SCA2. Using cerebellar and cervicothoracic spinal cord RNA/protein from Atxn2-CAG100-KnockIn (KIN) and wildtype mice, a multi-omics study was conducted based on the integration of global transcriptomic, proteomic, and phosphoproteomic data, followed by validation in mice and humans. Venn diagram comparisons across all OMICS datasets indicated that only Serpinb1a-transcript, SERPINB1A-protein and -phosphopeptides were consistently downregulated at terminal stage in 14-month-old KIN mice. Expression studies in cerebellum and spinal cord from 10 weeks (pre-manifest), 6-month-old (early ataxic), and 14-month-old (late ataxic stage) mice confirmed this progressive decrease at mRNA and protein level. SERPINB1 plasma levels were significantly lower in early-stage SCA2 patients, and displayed a significant association with the CAG repeat length at expanded ATXN2 alleles, the age at onset and INAS count. However, these human data from this SCA2 founder population were not robust, so reappraisal in large international studies and at later disease stages of SCA2 is needed. SERPINB1 was identified as novel candidate progression biomarker for SCA2 pathomechanisms.}, } @article {pmid41300346, year = {2025}, author = {Yeasmin, A and Torrente, MP}, title = {Histone Post-Translational Modifications and DNA Double-Strand Break Repair in Neurodegenerative Diseases: An Epigenetic Perspective.}, journal = {Biology}, volume = {14}, number = {11}, pages = {}, pmid = {41300346}, issn = {2079-7737}, support = {R15 NS125394/NS/NINDS NIH HHS/United States ; 1R15NS125394-01/NH/NIH HHS/United States ; }, abstract = {DNA damage is a hallmark of the fatal process of neurodegeneration in the central nervous system (CNS). As neurons are terminally differentiated, they accumulate metabolic and oxidative burdens over their whole life span. Unrepaired DNA develops into DNA double-strand breaks (DSBs), which are repaired through homologous recombination (HR) or non-homologous end joining (NHEJ). Being post-mitotic and unable to normally undergo HR, damage and defective repair is especially burdensome to CNS neurons. Current research has not produced treatment to prevent and halt progression of neurodegeneration. Hence, novel targeting strategies are desperately needed. Recent investigations in histone post-translational modifications (PTMs) reveal new mechanistic insight and highlight unexplored targets to ameliorate neurodegeneration. As various histone PTMs dictate and facilitate DSB repair, they represent an underexploited area in investigating DNA damage and incorrect repair aiding neurodegeneration. Here, we review the histone PTM alterations in several neurodegenerative diseases: Amyotrophic Lateral Sclerosis/Frontotemporal Dementia, Parkinson's Disease, Alzheimer's Diseases, Multiple Sclerosis, and Huntington's Disease. These findings emphasize that histone PTM alterations can enable an aberrant DNA damage response (DDR) leading to neurodegeneration. Further research into the connections between histone PTMs and DNA damage in decaying neurons will illuminate novel targets to dampen the aberrant DDR and promote neuronal survival.}, } @article {pmid41300833, year = {2025}, author = {Bai, R and Cheng, Z and Diao, Y}, title = {SLC30A3 as a Zinc Transporter-Related Biomarker and Potential Therapeutic Target in Alzheimer's Disease.}, journal = {Genes}, volume = {16}, number = {11}, pages = {}, pmid = {41300833}, issn = {2073-4425}, support = {2020NZ010008//the major and Special Projects of Fujian Province/ ; 2022C006R//High level Talent Innovation and Entrepreneurship Project of Quanzhou/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/drug therapy ; *Cation Transport Proteins/genetics/metabolism ; Biomarkers/metabolism ; *Zinc/metabolism ; Transcriptome ; Gene Regulatory Networks ; Gene Expression Profiling ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with unclear pathogenic mechanisms. Dysregulated zinc metabolism contributes to AD pathology. This study aimed to identify zinc metabolism-related hub genes to provide potential biomarkers and therapeutic targets for AD.

METHODS: We performed an integrative analysis of multiple transcriptomic datasets from AD patients and normal controls. Differentially expressed genes and weighted gene co-expression network analysis (WGCNA) were combined to identify hub genes. We then conducted Gene Set Enrichment Analysis (GSEA), immune cell infiltration analysis (CIBERSORT), and receiver operating characteristic (ROC) curve analysis to assess the hub gene's biological function, immune context, and diagnostic performance. Drug-gene interactions were predicted using the DrugBank database.

RESULTS: We identified a single key zinc transporter-related hub gene, SLC30A3, which was significantly downregulated in AD and demonstrated potential diagnostic value (AUC 0.70-0.80). Lower SLC30A3 expression was strongly associated with impaired synaptic plasticity (long-term potentiation, long-term depression, calcium signaling pathway, and axon guidance), mitochondrial dysfunction (the citrate cycle and oxidative phosphorylation), and pathways common to major neurodegenerative diseases (Parkinson's disease, AD, Huntington's disease, and amyotrophic lateral sclerosis). Furthermore, SLC30A3 expression correlated with specific immune infiltrates, particularly the microglia-related chemokine CX3CL1. Zinc chloride and zinc sulfate were identified as potential pharmacological modulators.

CONCLUSIONS: Our study systematically identifies SLC30A3 as a novel biomarker in AD, linking zinc dyshomeostasis to synaptic failure, metabolic impairment, and neuroimmune dysregulation. These findings offer a new basis for developing targeted diagnostic and therapeutic strategies for AD.}, } @article {pmid41302089, year = {2025}, author = {Anjum, F and Hulbah, MJ and Shamsi, A and Mohammad, T}, title = {Exploring TANK-Binding Kinase 1 in Amyotrophic Lateral Sclerosis: From Structural Mechanisms to Machine Learning-Guided Therapeutics.}, journal = {Life (Basel, Switzerland)}, volume = {15}, number = {11}, pages = {}, pmid = {41302089}, issn = {2075-1729}, support = {KSRG-2024-446//King Salman Center for Disability Research/ ; }, abstract = {TANK-binding kinase 1 (TBK1) has emerged as one of the most compelling genetic contributors to amyotrophic lateral sclerosis (ALS), with heterozygous loss-of-function and pathogenic missense variants identified in patients across the ALS-frontotemporal dementia (FTD) spectrum. TBK1 participates in various core cellular processes associated with motor neuron vulnerability, including autophagy, mitophagy, and innate immune regulation, indicating that TBK1 is likely a key determinant of ALS pathogenesis. Structurally, TBK1 exhibits a trimodular organization comprising a kinase domain, a ubiquitin-like domain, and a scaffold/dimerization domain. Multiple experimentally resolved conformations and inhibitor-bound complexes provide a foundation for structure-guided therapeutic design. Here, we synthesize current genetic and mechanistic evidence linking TBK1 dysfunction to ALS, emphasizing its dual roles in autophagy and neuroinflammation. We also summarize advances in structure-based and AI-assisted drug discovery approaches targeting TBK1. Finally, we outline key translational challenges, including isoform selectivity, biomarker validation, and central nervous system (CNS) delivery, highlighting TBK1 as a promising yet complex therapeutic target in ALS. By integrating computational modeling, machine learning frameworks, and experimental pharmacology, future research may accelerate the translation of TBK1 modulators into clinically effective therapies.}, } @article {pmid41302575, year = {2025}, author = {Batterman, S and Islam, MK and Goutman, S}, title = {Development of Life Course Exposure Estimates Using Geospatial Data and Residence History.}, journal = {International journal of environmental research and public health}, volume = {22}, number = {11}, pages = {}, pmid = {41302575}, issn = {1660-4601}, support = {1P30TW017885-03/NH/NIH HHS/United States ; 1R01NS127188-03/NH/NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; 1R01ES030049-03/NH/NIH HHS/United States ; 1K23ES027221-02/NH/NIH HHS/United States ; }, mesh = {Humans ; *Environmental Exposure/analysis ; Middle Aged ; Male ; *Amyotrophic Lateral Sclerosis/epidemiology ; Adult ; Female ; Particulate Matter/analysis ; *Air Pollutants/analysis ; Aged ; Cohort Studies ; Soot/analysis ; Spatial Analysis ; Vehicle Emissions/analysis ; Geographic Information Systems ; }, abstract = {Life course exposure estimates developed using geospatial datasets must address issues of individual mobility, missing and incorrect data, and incompatible scaling of the datasets. We propose methods to assess and resolve these issues by developing individual exposure histories for an adult cohort of patients with amyotrophic lateral sclerosis (ALS) and matched controls using residence history and PM2.5, black carbon, NO2, and traffic intensity estimates. The completeness of the residence histories was substantially improved by adding both date and age questions to the survey and by accounting for the preceding and following residence. Information for the past five residences fully captured a 20-year exposure window for 95% of the cohort. A novel spatial multiple imputation approach dealt with missing or incomplete address data and avoided biases associated with centroid approaches. These steps boosted the time history completion to 99% and the geocoding success to 92%. PM2.5 and NO2, but not black carbon, had moderately high agreement with observed data; however, the 1 km resolution of the pollution datasets did not capture fine scale spatial heterogeneity and compressed the range of exposures. This appears to be the first study to examine the mobility of an older cohort for long exposure windows and to utilize spatial imputation methods to estimate exposure. The recommended methods are broadly applicable and can improve the completeness, reliability, and accuracy of life course exposure estimates.}, } @article {pmid41302657, year = {2025}, author = {Singh, A and Zeig-Owens, R and Cannon, MF and Moline, T and Schwartz, T and Prezant, DJ}, title = {Amyotrophic Lateral Sclerosis (ALS)-Related Mortality Among World Trade Center-Exposed and Non-World Trade Center-Exposed Rescue and Recovery Workers.}, journal = {International journal of environmental research and public health}, volume = {22}, number = {11}, pages = {}, pmid = {41302657}, issn = {1660-4601}, support = {U01 OH011309/OH/NIOSH CDC HHS/United States ; U01 OH011934/OH/NIOSH CDC HHS/United States ; 200-2011-39383/OH/NIOSH CDC HHS/United States ; 200-2011-39378/OH/NIOSH CDC HHS/United States ; 200-2017-93426/OH/NIOSH CDC HHS/United States ; 200-2017-93326/OH/NIOSH CDC HHS/United States ; 75D301-22-P-15204/OH/NIOSH CDC HHS/United States ; 75D301-22-R-72142/OH/NIOSH CDC HHS/United States ; 75D301-22-R-72244/OH/NIOSH CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality ; Middle Aged ; Adult ; *September 11 Terrorist Attacks ; Male ; *Occupational Exposure/adverse effects ; Female ; Aged ; Young Adult ; Adolescent ; *Rescue Work/statistics & numerical data ; New York City/epidemiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare but fatal neurodegenerative disease. Some occupational exposures are associated with ALS. This study evaluated ALS mortality rates in World Trade Center (WTC)-exposed and non-WTC-exposed rescue/recovery workers. Fire department workers who were 18-70 years old on 11 September 2001 (9/11) were included in the study (N = 33,122). Follow-up began on the later of 9/11 or on their hire date, and ended at the earliest death date or 31 December 2023. Cause of death data were obtained from the National Death Index; ALS (specifically motor neuron disease)-related mortality was the primary outcome. Demographic data were obtained from the fire departments' databases. We estimated standardized mortality ratios (SMRs) and 95% CIs for ALS-related mortality in WTC-exposed and non-WTC-exposed workers using US population rates as a reference. Multivariable-adjusted Poisson regression models estimated relative rates (RRs) and 95% CIs for ALS-related mortality in the WTC-exposed vs. non-WTC-exposed groups. Between 9/11 and 31 December 2023, five WTC-exposed and sixteen non-WTC-exposed participants died of ALS. ALS mortality rates were lower in WTC-exposed than in non-WTC-exposed rescue/recovery workers (RR = 0.54, 95% CI = 0.49-0.60). ALS-related mortality was not elevated in WTC-exposed (SMR = 0.44, 95% CI = 0.14-1.03) or non-WTC-exposed rescue/recovery workers (SMR = 1.06, 95% CI = 0.60-1.72) compared with the US general population. This initial evaluation of ALS in WTC-exposed workers indicates that the risk of ALS death is not increased in this population.}, } @article {pmid41303337, year = {2025}, author = {Genin, EC and Lespinasse, F and Mauri-Crouzet, A and Dupuis, L and Paquis-Flucklinger, V}, title = {SLP2/PHB Aggregates in ALS Mouse Models and Patients: Implications Beyond CHCHD10-Associated Motor Neuron Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {22}, pages = {}, pmid = {41303337}, issn = {1422-0067}, support = {FRM: MND202004011475//Fondation pour la Recherche Médicale/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; Mice ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Prohibitins ; Male ; Female ; Spinal Cord/metabolism/pathology ; Protein Aggregates ; Mice, Transgenic ; Hippocampus/metabolism/pathology ; Aged ; Middle Aged ; *Membrane Proteins/metabolism/genetics ; Frontotemporal Dementia/metabolism/genetics/pathology ; *Repressor Proteins/metabolism/genetics ; RNA-Binding Protein FUS/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Mutation ; C9orf72 Protein/genetics ; *Protein Aggregation, Pathological/metabolism ; Mitochondrial Proteins ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron (MN) degeneration, frequently overlapping with frontotemporal dementia (FTD). Protein aggregation is a hallmark of these disorders, yet the role of aggregates in ALS pathogenesis remains unclear. Previously, stomatin-like protein 2 (SLP2) and prohibitin (PHB) aggregates were identified in a model of CHCHD10-related ALS (Chchd10[S59L/+] mice). This study raises the question of the presence and possible involvement of these aggregates in ALS beyond CHCHD10-associated motor neuron disease (MND). Using immunohistofluorescence, we analyzed SLP2/PHB expression in the spinal MNs and hippocampus of two ALS mouse models: Fus[ΔNLS] and Sod1[G86R]. Additionally, post-mortem spinal cord tissues from 27 ALS and ALS-FTD patients were analyzed. SLP2/PHB aggregates were identified in spinal MNs and the hippocampus of Fus[ΔNLS] mice but not in Sod1[G86R] mice. In ALS patients, SLP2/PHB aggregation was observed in four cases, including two with C9ORF72 mutations. Interestingly, aggregates were absent in SOD1-associated ALS patients. These findings suggest that SLP2/PHB aggregation is not specific to CHCHD10 variants but may contribute to the pathogenesis of ALS from different origins. The age-related accumulation of these aggregates highlights their potential role in disease progression and as therapeutic targets. Future studies should investigate their mechanistic contributions across different ALS subtypes.}, } @article {pmid41303502, year = {2025}, author = {Hassan, M and Shahzadi, S and Moustafa, AA and Kloczkowski, A}, title = {Neurodegeneration Through the Lens of Bioinformatics Approaches: Computational Mechanisms of Protein Misfolding.}, journal = {International journal of molecular sciences}, volume = {26}, number = {22}, pages = {}, pmid = {41303502}, issn = {1422-0067}, support = {1R01HG012117-04/NH/NIH HHS/United States ; }, mesh = {Humans ; *Computational Biology/methods ; *Neurodegenerative Diseases/metabolism ; *Protein Folding ; Animals ; Protein Aggregates ; Protein Aggregation, Pathological/metabolism ; }, abstract = {Protein and peptide aggregation has become a prominent focus in biomedical research due to its critical role in the development of neurodegenerative diseases (NDs) and its relevance to industrial applications. Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are closely associated with abnormal aggregation processes, highlighting the need for a deeper understanding of their molecular mechanisms. In recent years, a wide range of computational methods, bioinformatics tools, and curated databases have been developed to predict and analyze sequences and structures that are prone to aggregation. These in silico approaches offer valuable insights into the underlying principles of aggregation and contribute to the identification of potential therapeutic targets. This review provides a concise overview of the current bioinformatics resources and computational techniques available for studying protein and peptide aggregation, intending to guide future research efforts in the field of neurodegenerative disease modeling and drug discovery.}, } @article {pmid41303511, year = {2025}, author = {Gbadamosi, M and Romano, G and Simbula, M and Canarutto, G and Ottoboni, L and Corti, S and Feiguin, F}, title = {TDP-43 Regulates Rab4 Levels to Support Synaptic Vesicle Recycling and Neuromuscular Connectivity in Drosophila and Human ALS Models.}, journal = {International journal of molecular sciences}, volume = {26}, number = {22}, pages = {}, pmid = {41303511}, issn = {1422-0067}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Synaptic Vesicles/metabolism ; Humans ; *Neuromuscular Junction/metabolism ; Motor Neurons/metabolism ; *Drosophila Proteins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; *rab4 GTP-Binding Proteins/metabolism/genetics ; Microtubule-Associated Proteins/metabolism/genetics ; Drosophila melanogaster/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Drosophila ; }, abstract = {The pathological loss of nuclear TDP-43 is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to extensive alterations in RNA metabolism and a broad number of neuronal transcripts. However, the key effectors linking TDP-43 dysfunction to synaptic defects remain unclear. In this study, using Drosophila and human iPSC-derived motoneurons, we identify Rab4 as a direct and conserved target of TDP-43, whose expression is necessary and sufficient to recover synaptic vesicle recycling, neuromuscular junction growth, and locomotor function in TDP-43-deficient motoneurons. Moreover, Rab4 activity promotes the presynaptic recruitment of futsch/MAP1B, a microtubule-associated protein also regulated by TDP-43, which autonomously supports synaptic growth and vesicle turnover. Together, these findings define a TDP-43/Rab4/futsch/MAP1B regulatory axis that couples endosomal dynamics to cytoskeletal assembly. Furthermore, this functionally coherent module provides a mechanistic basis for understanding how synaptic vulnerability is amplified in disease and offers a framework to identify key compensatory targets capable of sustaining neuronal function in the absence of TDP-43.}, } @article {pmid41306156, year = {2025}, author = {Pereira de Oliveira, M and Lima Monteiro, F}, title = {When the Body Falls Silent: A Case Report of Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {17}, number = {10}, pages = {e95427}, pmid = {41306156}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both upper and lower motor neurons, resulting in muscle weakness, atrophy, and, ultimately, respiratory failure. We present the case of a 49-year-old man who sustained a right wrist injury in January 2023, for which he sought evaluation by his general practitioner (GP). Due to an unfavorable recovery, he was referred to the emergency department (ED) in September of the same year, where the diagnostic workup was initiated. Following a series of complementary diagnostic tests, a diagnosis of ALS was established at the end of September. Electromyography demonstrated widespread denervation with both acute and chronic neurogenic changes, while complementary diagnostic studies excluded alternative etiologies. The patient subsequently began follow-up with a multidisciplinary team encompassing the various domains of ALS management over the following 17 months. Riluzole therapy was initiated. He ultimately passed away in February 2025, having demonstrated remarkable resilience throughout the course of his illness. This case highlights the devastating impact of early-onset ALS and underscores the importance of maintaining clinical suspicion when evaluating adults presenting with progressive neuromuscular symptoms. The rapid disease progression and associated psychosocial burden emphasize the critical role of multidisciplinary management, early palliative integration, and strong primary care involvement in optimizing patient and family support.}, } @article {pmid41306819, year = {2025}, author = {Hsueh, SJ and Hsueh, HW and Chen, YF and Chen, TF and Tsai, LK and Chiang, MC and Hsieh, ST and Wu, WC and Chao, CC}, title = {Implications of perivascular spaces in amyotrophic lateral sclerosis: clinical significance and structural correlation.}, journal = {Brain communications}, volume = {7}, number = {6}, pages = {fcaf448}, pmid = {41306819}, issn = {2632-1297}, abstract = {Perivascular space (PVS) dysfunction may potentially contribute to the development and progression of amyotrophic lateral sclerosis (ALS). This study investigated the clinical relevance of PVS dysfunction in ALS. Two PVS parameters were quantified in patients with ALS: (i) the enlarged perivascular space (ePVS) score and (ii) the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. These parameters were analysed in relation to the clinical, structural and prognostic features of ALS. The study included 55 patients with ALS (33 men; mean age, 61.38 ± 10.95 years). The DTI-ALPS index was markedly reduced in the patients compared to age- and gender-matched controls, and there were no differences in ePVS scores between the two groups. The ePVS total score was positively correlated with the ALS progression, as measured by the monthly change in the revised ALS functional rating scale. The ePVS basal ganglia regional score was inversely correlated with muscle strength. Additionally, both the ePVS score and the DTI-ALPS index were associated with regional grey matter volumes of the superior frontal gyrus and middle frontal gyrus, and the DTI-ALPS index was associated with diffusion parameters of the corticostriatal and corticothalamic tracts. This study underscores the importance of PVS dysfunction in ALS according to the ePVS and a reduced DTI-ALPS index, which were respectively associated with disease progression, neurological deficits, including reduced muscle strength, and cortical and subcortical structural changes.}, } @article {pmid41306922, year = {2025}, author = {Bhuiyan, TR and Khanam, F and Basher, SR and Dash, P and Chowdhury, MI and Haque, S and Harun, NB and Akter, A and Karmakar, PC and Hakim, A and Amin, S and Kamruzzaman, M and Parvin, N and Ahmed, T and Butts, J and Pasetti, MF and Wahid, R and Sztein, MB and Maier, N and White, JA and Tomashek, KM and Bourgeois, AL and Baqar, S and Kotloff, KL and Qadri, F and Chen, WH}, title = {Safety and immunogenicity of a recombinant double-mutant heat-labile toxin derived from enterotoxigenic Escherichia coli in healthy Bangladeshi adults delivered by three different routes.}, journal = {Frontiers in bacteriology}, volume = {4}, number = {}, pages = {}, pmid = {41306922}, issn = {2813-6144}, support = {HHSN272200800013C/AI/NIAID NIH HHS/United States ; HHSN272200800057C/AI/NIAID NIH HHS/United States ; INV-008763/GATES/Gates Foundation/United States ; U19 AI181108/AI/NIAID NIH HHS/United States ; }, abstract = {INTRODUCTION: Enterotoxigenic Escherichia coli (ETEC) is a common cause of acute watery diarrhea in areas lacking access to clean water, sanitation, and hygiene. This Phase 1 trial measured the safety and immunogenicity of double-mutant heat-labile enterotoxin (dmLT) of ETEC in healthy adults in Bangladesh, where ETEC is endemic.

METHODS: Five cohorts of 15 participants each were enrolled and randomized 4:1 to receive vaccine dmLT or placebo (12 vaccine and 3 placebo recipients per cohort). The 3 oral or sublingual doses of 5 μg or 25 μg dmLT were administered 2 weeks apart; the 2 intradermal doses of 0.3 μg dmLT were administered 3 weeks apart. Safety was assessed by collecting solicited and unsolicited adverse events. The immune responses measured included dmLT-specific serum IgA and IgG, serum toxin neutralizing antibody, dmLT-specific IgA and IgG antibody secreting cells (ASC), and IgA and IgG antibodies in lymphocyte supernatant (ALS).

RESULTS: All doses of dmLT delivered by different routes were well tolerated; adverse events were few, mild, and transient. Serum, ALS, and ASC IgA and IgG responses, as well as LT neutralizing antibody responses, were greatest among recipients of 25 μg oral and 0.3 μg intradermal doses. In contrast, sublingual dosing induced modest responses; there was virtually no serum antibody response to 5 μg sublingual dose and only sporadic ALS and ASC responses with 5 μg and 25 μg doses.

DISCUSSION: In conclusion, dmLT was well tolerated, and immune responses were dependent on dmLT dose and route of administration. The encouraging tolerability and immunogenicity results further highlight dmLT's potential not only as a vaccine but also as an adjuvant as reported by others or as a candidate vaccine antigen.

CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, identifier NCT03548064.}, } @article {pmid41307139, year = {2025}, author = {Al Assaad, H and Messabih, K and Bendjaballah-Lalaoui, N and Boucheffa, Y and Thibault-Starzyk, F and Travert, A}, title = {High-temperature CO2 capture by Li4SiO4: IR spectroscopic evidence for the double shell model.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {27}, number = {48}, pages = {26119-26130}, doi = {10.1039/d5cp02957k}, pmid = {41307139}, issn = {1463-9084}, abstract = {This study investigates the mechanisms of CO2 capture by Li4SiO4 employing in situ Fourier transform infrared spectroscopy (FT-IR) combined with multivariate data analysis, with particular attention being paid to the influence of structural modifications derived from natural diatomite on the CO2 sorption performance of Li4SiO4. Three samples were examined: a reference Li4SiO4 material synthesized from pure SiO2 (SiO2-LS), a stoichiometric mixture using calcined diatomite (ND-LS) and an over-stoichiometric sample containing 10% calcined diatomite (10% ND-LS). FTIR analysis confirmed the formation of carbonate species during CO2 uptake. Chemometric analysis using principal component analysis (PCA) and multivariate curve resolution-alternating least squares (MCR-ALS) allowed identification of the successive formation of two distinct carbonate species (species 1 and species 2), supporting the double-shell carbonation model. In ND-derived samples, a distinct band at 1140 cm[-1], attributed to the symmetric stretching vibration (ν1) of a carbonate species associated with magnesium carbonates, was identified. The presence of surface MgCO3 associated with species 1 in ND-derived samples was found to enhance CO2 capture kinetics by facilitating carbonate layer formation through interfacial diffusion pathways. This study provides valuable insights into the carbonation mechanisms of Li4SiO4, demonstrating that calcined diatomite improves CO2 uptake efficiency and opening new perspectives for the optimization of lithium silicate-based CO2 sorbents through targeted compositional modifications.}, } @article {pmid41307543, year = {2026}, author = {Macpherson, CE and Wani, DK and Li, H and Rana, V and Blacutt, M and Bello-Haas, VD and Quinn, L}, title = {Physical Therapist Interventions for People With Amyotrophic Lateral Sclerosis Across Disease Stages: A Systematic Review of Efficacy.}, journal = {Physical therapy}, volume = {106}, number = {1}, pages = {}, doi = {10.1093/ptj/pzaf142}, pmid = {41307543}, issn = {1538-6724}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/therapy/physiopathology ; *Physical Therapy Modalities ; Exercise Therapy/methods ; Vital Capacity ; }, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease causing declines in muscular strength that affect respiratory function and functional independence. Although physical therapist interventions have been studied in ALS, their efficacy and evidence quality have not been systematically assessed across disease stages.

OBJECTIVE: The objective of this study was to examine the efficacy of physical therapist interventions on clinical outcomes across ALS disease stages.

DESIGN: This study was a systematic review using Joanna Briggs Institute methodology.

SETTING: Multiple settings were used.

PARTICIPANTS: The participants were adults (>18 years old) with ALS or motor neuron disease.

INTERVENTIONS: Physical therapist interventions within the professional scope of practice included therapeutic exercise, pulmonary training, manual therapy, and multimodal approaches.

OUTCOME MEASURES: Outcome measures included effect sizes (ESs) and 95% CIs calculated for forced vital capacity (FVC) and the Amyotrophic Lateral Sclerosis Rating Scale (ALSFRS) or the ALSFRS revised (ALSFRS-R).

RESULTS: Six databases were searched from inception to January 2025. Thirty-nine studies were included (25 experimental, 14 observational). Outcomes were heterogeneous, with 94 measures across studies: 23 included the ALSFRS or ALSFRS-R, and 16 included FVC. Most interventions targeted early-stage ALS (n = 27), limiting comparisons across stages. Multimodal training had moderate-quality evidence, with moderate effects on the ALSFRS-R (ES = 0.56 [95% CI = 0.09-1.03]), and low-quality evidence, with negligible effects on FVC (ES = -0.03 [95% CI = -1.47 to 1.41]). Pulmonary interventions had moderate-quality evidence, with small effects on FVC (ES = 0.40 [95% CI = -0.18 to 0.98]), and low-quality evidence, with negligible effects on the ALSFRS-R (ES = 0.04 [95% CI = -0.25 to 0.33]).

CONCLUSIONS: A range of physical therapist interventions for ALS were assessed, although most were early phase or low quality. Multimodal and pulmonary interventions showed modest benefits in the ALSFRS-R and FVC, respectively. However, variability in outcome measures and limited research beyond early-stage disease highlight the need for stage-specific trials using consistent functional outcomes.

RELEVANCE: This review highlights the breadth of studies of physical therapy in ALS and underscores the need for more rigorous, targeted research.}, } @article {pmid41307665, year = {2025}, author = {Montalesi, E and Caissutti, D and Moliterni, C and Ferrante, A and Pepponi, R and Garofalo, T and Sorice, M and Misasi, R and Candelise, N}, title = {Proteostasis network response to environmental chronic stress: linking survival to protein aggregation in a human neuroblastoma cellular model.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {82}, number = {1}, pages = {430}, pmid = {41307665}, issn = {1420-9071}, support = {I83C22002190005//Istituto Superiore di Sanità/ ; AR224190750776B1//Sapienza Università di Roma/ ; B89J22001910007//Fondazione Cassa di Risparmio di Pistoia e Pescia/ ; 2022APEBMY//Ministero dell'Università e della Ricerca/ ; 2022XL4TE9_003//Ministero dell'Università e della Ricerca/ ; P2022LZP9T//Ministero dell'Università e della Ricerca/ ; 20223RXEEC//Ministero dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Neuroblastoma/metabolism/pathology ; *Proteostasis ; Cell Line, Tumor ; *Stress, Physiological ; DNA-Binding Proteins/metabolism ; *Protein Aggregates ; Autophagy ; Cell Survival ; Proteasome Endopeptidase Complex/metabolism ; Phosphorylation ; *Protein Aggregation, Pathological/metabolism ; }, abstract = {Proteins tend to misfold upon stressful events that alter their homeostasis, potentially leading to protein aggregation. A tight regulation of synthesis, folding and degradation, defined as proteostasis network (PN), is required to ensure the functionality of the cell. PN is of utmost importance in post-mitotic cells such as neurons, where protein quality must be preserved for their entire lifetime. Most neurodegenerative disorders are associated with dysregulation of this network. Here, we describe the alteration in key components of the PN during chronic stress and link them with the increase in the amyloid burden and with the aggregation of the protein TDP-43, a major player in Amyotrophic Lateral Sclerosis and other neurodegenerative diseases. Neuroblastoma SH-SY5Y cells were treated with a panel of environmental stressors and analyzed after 24 h and 72 h. Treatments resulted in altered PN functionality, including proteasome impairment, halted protein synthesis, engulfed bulk and selective autophagy, in the absence of overt cell death. Thioflavin staining showed increased amyloid burden throughout treatments, associated with phosphorylated TDP-43 (pTDP-43). Biochemical analyses further revealed the cleavage and increased insolubility of pTDP-43. Our results suggest that TDP-43 is a central player during the integrated stress response to chr onic insults and that increased amyloid burden may reflect the global wellfare of a cellular system, pointing toward the alteration of the PN as the main drive for the onset of sporadic neurodegenerative disorders.}, } @article {pmid41308261, year = {2026}, author = {Shimano, K and Hattori, T and Yasuda, E and Hase, T and Kina, S and Miyake, T and Yokota, T}, title = {Explainable machine learning algorithm for classifying resting-state functional MRI in amyotrophic lateral sclerosis.}, journal = {Neural networks : the official journal of the International Neural Network Society}, volume = {196}, number = {}, pages = {108359}, doi = {10.1016/j.neunet.2025.108359}, pmid = {41308261}, issn = {1879-2782}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/classification ; *Magnetic Resonance Imaging/methods/classification ; *Machine Learning ; Middle Aged ; Male ; Female ; Neural Networks, Computer ; *Brain/diagnostic imaging/physiopathology ; *Algorithms ; Adult ; Aged ; Rest ; Brain Mapping/methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects multiple brain systems. Altered brain function can be observed through resting-state functional magnetic resonance imaging (rs-fMRI). While machine learning offers significant advantages in capturing complex signal patterns across numerous voxels, its decision-making process often lacks transparency. This study aimed to develop an explainable machine learning pipeline to classify patients with ALS and healthy control (HC) using rs-fMRI data.

METHODS: Thirty patients with ALS and 30 HCs were enrolled. The pipeline consisted of three key components: (1) preprocessing of rs-fMRI data using independent component analysis, followed by dual regression to reduce dimensionality and generate individual network maps; (2) training of a three-dimensional convolutional neural network (3D-CNN) to classify each individual image as either ALS or HC; and (3) application of saliency map and Grad-CAM++ to visualize the reasoning behind the model's classification.

RESULTS: The 3D-CNN achieved high classification accuracy using the sensorimotor network (SMN) map (78.3%) and the visual network (VN) map (83.3%). Simultaneously, saliency map and Grad-CAM++ highlighted brain regions that contributed to the classification, and some of which were consistent with regions showing intergroup differences in the dual regression analysis.

DISCUSSION: This study developed a novel explainable machine learning model capable of extracting features and classifying rs-fMRI data. Our results showed altered functional integrity in the SMN and VN in ALS. Our pipeline holds the potential to extract features of rs-fMRI data, enabling classification of neurological diseases with explainability.}, } @article {pmid41309196, year = {2025}, author = {Jamwal, RS and Sharma, B and Minerva, and Gupta, A and Misri, S and Shankaryan, R and Shah, R and Kumar, R}, title = {Protein misfolding and its dual role in neurodegeneration and cancer progression.}, journal = {Advances in protein chemistry and structural biology}, volume = {148}, number = {}, pages = {355-377}, doi = {10.1016/bs.apcsb.2025.10.001}, pmid = {41309196}, issn = {1876-1631}, mesh = {Humans ; *Neoplasms/metabolism/pathology ; *Protein Folding ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Disease Progression ; Unfolded Protein Response ; }, abstract = {Protein misfolding is a fundamental biological process with profound implications for human health and disease. Typically, proteins assume precise three-dimensional structures to perform their functions, a process safeguarded by the proteostasis network, which comprises molecular chaperones, the ubiquitin-proteasome system (UPS), and autophagy. However, genetic mutations, oxidative stress, and environmental insults can disrupt folding, leading to the accumulation of non-functional or toxic conformations. In neurodegenerative diseases such as Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral Sclerosis (ALS), chronic misfolding results in toxic protein aggregates like amyloid-β, tau, and α-synuclein. These disrupt synaptic function, induce oxidative and nitrosative stress, and trigger apoptosis, ultimately leading to progressive neuronal loss. Dysregulation of the unfolded protein response (UPR) and weakened proteostasis with aging exacerbate disease pathology. In contrast, cancer cells utilize protein misfolding to enhance their survival and progression. Misfolded oncoproteins, such as mutant p53, not only evade degradation but also acquire oncogenic properties. Tumor cells hijack the UPR and chaperone networks, upregulate heat shock proteins, and manipulate oxidative stress responses to withstand hypoxia, nutrient deprivation, and rapid proliferation. Cancer stem cells (CSCs) further adapt to proteotoxic stress, contributing to tumor heterogeneity, therapy resistance, and immune evasion. The dual role of protein misfolding, driving degeneration in neurons while supporting proliferation in tumors, underscores its centrality in disease biology. Future research should focus on identifying early biomarkers of proteostasis imbalance and exploiting shared molecular pathways for the development of novel therapeutic interventions.}, } @article {pmid41311585, year = {2025}, author = {Norton, MJ and Byrne, JP and Bedenik, T and Ryan, M and Brogan, C and Dwyer, D and Walsh, K and Ní Shé, É}, title = {Understanding the Mechanisms that Operate within CHIME: A Realist Review Protocol.}, journal = {HRB open research}, volume = {8}, number = {}, pages = {94}, pmid = {41311585}, issn = {2515-4826}, abstract = {BACKGROUND: Recovery originated from the civil rights movement of the 1960s/70s. However, no universally accepted definition of recovery had been constructed until 1993 when William A. Anthony suggested that recovery involved living one's best life even with mental health difficulties. In 2011, Leamy et al. created CHIME [ Connectiveness, Hope, Identity, Meaning and purpose and Empowerment]. A concept that represents the key characteristics of recovery. It derived from a literature review into recovery from psychosis. Since 2011, the literature has examined these concepts individually and collectively to understand what they are in reality. However, few studies have investigated the internal mechanisms that causes a person to move from unwellness to recovery via CHIME. As such this proposed realist review will explore how and why the mechanisms within CHIME operate in individuals recovering from mental health challenges.

METHODS: This review forms work package one of a PhD study into CHIME and mental health recovery in Ireland. It complies with relevant guidelines relating to realist reviews including Pawson et al's. updated methodology, which consists of six phases: 1) setting up the review advisory panel and constructing initial programme theories; 2) searching for evidence; 3) selecting and appraising evidence; 4) extracting data; 5) analysing and synthesising data; and 6) ethics and dissemination.

This proposed review will address a gap in the literature on the mechanism involved in recovery from mental health challenges. Unlike other review types, a realist review is theory orientated, allowing one to answer this review question by exploring how, why, and through what circumstances individuals reach recovery through CHIME. This review will inform future work packages of this PhD study. The proposed review will be written up and submitted to a peer-reviewed journal. Dissemination outside academia will be considered.

REGISTRATION ID: CRD420251038961.}, } @article {pmid41311831, year = {2025}, author = {Guan, S and Wang, S and Shi, Y and Leng, Y and Ming, Y and Hou, Z and Yu, Y and Wang, Z and Liu, J}, title = {Comparative safety analysis of Riluzole, Edaravone and Tofersen in ALS management: insights from FAERS database.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1687698}, pmid = {41311831}, issn = {1663-9812}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. Riluzole, Edaravone, and Tofersen, three promising treatments, have distinct profiles that merit comparative analysis to guide clinical decision-making.

METHODS: This study utilizes a pharmacovigilance analysis of adverse events reported in the FDA Adverse Event Reporting System database from Q1 2004 to Q2 2024. Employing disproportionality, we assessed and compared the AE signals associated with Riluzole, Edaravone, and Tofersen to elucidate their safety profiles in ALS treatment. Finally, applying the Random Walk with Restart (RWR) algorithm to the protein-protein interaction (PPI) network for selecting drug target genes that have a strong correlation genes associated with severe adverse reactions. Finally, their interactions with the target were assessed through molecular docking and transcriptome analysis.

RESULTS: The analysis included 2106 AE reports for Riluzole, 2466 AE reports for Edaravone, and 136 for Tofersen. Highlights the higher incidence of adverse reactions associated with Riluzole, including abdominal discomfort, hypoaesthesia oral, and hepatic enzyme increased, as well as a significant correlation between Edaravone and falls, gait disturbance, and aphasia. Tofersen exhibits different adverse reactions compared to Riluzole and Edaravone, such as headaches, csf red blood cell count positive. Comparative analysis revealed that the three drugs shared a serious adverse reaction, which is thrombosis. RWR analysis identified seven targets related to thrombosis caused by the three drugs, including F10 and MMP9. Subsequently, molecular docking and transcriptome analysis indicate a favorable binding interaction between the drug candidate and the F10 molecule.

CONCLUSION: This comprehensive evaluation underscores the importance of understanding the distinct AE profiles of Riluzole, Edaravone, and Tofersen in clinical practice, providing valuable insights for personalized ALS management. Future research with rigorous prospective designs is recommended to validate these findings and explore the mechanisms underlying the reported adverse events.}, } @article {pmid41311968, year = {2025}, author = {Ogura, T and Matsuura, U and Machida, M and Nagai, K and Kajimoto, S and Tahara, S and Nakabayashi, T}, title = {RNA-Mediated Inhibition Mechanism of Liquid-Liquid Phase Separation and Subsequent Aggregation Revealed by Raman Microscopy.}, journal = {JACS Au}, volume = {5}, number = {11}, pages = {5749-5757}, pmid = {41311968}, issn = {2691-3704}, abstract = {Liquid-liquid phase separation (LLPS) is a phenomenon where homogeneous solutions of biomacromolecules separate into two liquid phases and generate liquid droplets enriched in specific biomolecules. LLPS of neurodegeneration-related proteins, including fused in sarcoma (FUS), promotes their aggregation, causing fatal diseases such as amyotrophic lateral sclerosis (ALS). Recent studies showed that RNAs regulate LLPS of these proteins and inhibit their aggregation, which may play an important role in preventing the disease onset; however, the underlying molecular mechanisms remain elusive. It is also unknown whether endogenous RNAs regulate LLPS and subsequent aggregation in cells. In this study, we investigated features of RNAs that enable their entrance into FUS droplets and inhibition of FUS aggregation via droplets and clarified the underlying mechanisms using Raman microscopy. We found that RNA length is one of the primary factors governing both the aggregation-inhibition effect and the localization of RNAs in the droplets in buffer solutions. Short (<50-nt) RNAs were concentrated inside the droplets and inhibited the aggregation. Our quantification method using Raman microscopy revealed that the short RNAs are enriched in FUS droplets by binding to FUS proteins through electrostatic interactions. On the other hand, long (>1000-nt) RNAs were not concentrated and dissolved the droplets. Raman imaging of living cells revealed that intracellular FUS droplets are enriched with endogenous RNAs at levels comparable to in vitro droplets and exhibit high fluidity, confirming that endogenous RNAs play a crucial role in suppressing droplet-to-aggregate transition of FUS in cells. These findings indicate that short RNAs stabilize FUS droplets through heterotypic RNA-FUS interactions that compete with homotypic FUS-FUS direct contacts responsible for aggregation, whereas binding of long RNAs enhances FUS solubility and promotes droplet dissolution. Our study highlights the protective role of RNAs against pathogenic aggregation of neurodegeneration-related proteins via droplets.}, } @article {pmid41312566, year = {2026}, author = {Kwinta, R and Morawiec, N and Bączyk, J and Kubicka-Bączyk, K and Adamczyk-Sowa, M}, title = {Aging immunity - the role of T and B cells in neurological disorders among older adults.}, journal = {Neurologia i neurochirurgia polska}, volume = {60}, number = {1}, pages = {15-25}, doi = {10.5603/pjnns.106498}, pmid = {41312566}, issn = {0028-3843}, mesh = {Humans ; *Aging/immunology ; *B-Lymphocytes/immunology ; Aged ; *T-Lymphocytes/immunology ; *Immunosenescence/immunology ; *Nervous System Diseases/immunology ; Alzheimer Disease/immunology ; Adaptive Immunity ; Parkinson Disease/immunology ; }, abstract = {INTRODUCTION: Immunosenescence is a natural process of immune system aging, which leads to significant changes in the functioning of both innate and adaptive immunity. Alterations in T and B lymphocytes can significantly impact the progression of neurological diseases including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

STATE OF THE ART: Immunosenescence affects T and B cell subsets, reducing their proliferative capacity and altering cytokine profiles. In MS, these changes promote disease progression and diminish responses to immunomodulatory therapies. In AD and PD, dysfunctional T and B cells contribute to sustained neuroinflammation, exacerbating neurodegeneration. ALS is similarly associated with altered adaptive immunity.

CLINICAL IMPLICATIONS: Recognizing how immunosenescent T and B cells contribute to disease in older adults is crucial for refining treatment strategies. These age-related immune changes may explain varied responses to therapies and highlight the need for novel approaches targeting the aged immune system in neurodegenerative diseases.

FUTURE DIRECTIONS: Future research should focus on identifying the mechanisms by which immunosenescent lymphocytes modulate neuroinflammation and neurodegeneration in aging populations. Novel biomarkers and immunomodulatory therapies tailored to older adults could significantly improve outcomes in patients with neurological diseases.}, } @article {pmid41313264, year = {2026}, author = {Chancel, A and Fort, P and Maciel, RM and Duval, B and Malcey, J and Bellini, S and Schmidt, MH and Luppi, PH}, title = {Comparative distribution of the hypothalamic neurons activated during wakefulness and paradoxical (REM) sleep using male TRAP2-red mice: contribution of orexin, MCH, Lhx6, and a new marker Meis2.}, journal = {Sleep}, volume = {49}, number = {4}, pages = {}, doi = {10.1093/sleep/zsaf368}, pmid = {41313264}, issn = {1550-9109}, mesh = {Animals ; Male ; Orexins/metabolism ; *Neurons/physiology/metabolism ; Mice ; *Hypothalamus/physiology/cytology/metabolism ; *Hypothalamic Hormones/metabolism/physiology ; *Melanins/metabolism/physiology ; *Wakefulness/physiology ; *Pituitary Hormones/metabolism/physiology ; *Sleep, REM/physiology ; *Transcription Factors/metabolism/physiology ; *Nerve Tissue Proteins/metabolism/physiology ; *Homeodomain Proteins/metabolism/physiology ; LIM-Homeodomain Proteins/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; Mice, Transgenic ; Neuropeptides/physiology ; }, abstract = {STUDY OBJECTIVES: Paradoxical sleep (PS) is a state involving numerous hypothalamic neuronal subpopulations, many remaining neurochemically uncharacterized. Our goal was to compare hypothalamic neurons active during wakefulness or PS rebound (PSR) and explore their potential overlap, with a focus on melanin-concentrating hormone (MCH), Orexin (Orx), Lhx6, and a new contingent of Meis2-expressing neurons.

METHODS: In the same male TRAP2-red mouse, neurons activated during wakefulness (4 h) and PSR (2 h) express TdTomato and c-Fos, respectively. Double-labeling and triple immunofluorescence with neurochemical markers were performed to characterize and quantify cell populations in hypothalamic structures.

RESULTS: Twelve hypothalamic structures showed distinct activation patterns. The anterior hypothalamic area (AHA), zona incerta (ZI), and tuberal nucleus contained more activated neurons during PSR than wakefulness, whereas the paraventricular hypothalamic, supraoptic, parasubthalamic nuclei, and retrochiasmatic area were predominantly activated during wakefulness. MCH and Lhx6 neurons were mainly recruited during PSR, whereas Orx neurons were more activated during wakefulness. The ventral subpopulation of MCH neurons showed higher activation during PSR than the dorsal subpopulation. Additionally, ~30 per cent of the c-Fos+ neurons in ZI and ~20 per cent in LHA expressed Meis2. Overall, ~20 per cent of all hypothalamic neurons activated during PSR are now neurochemically identified.

CONCLUSIONS: Our study identifies new neuronal populations activated during PSR in AHA, ZI, and tuberal nucleus. We further provide evidence that Meis2 is expressed in novel populations of neurons activated during PSR. In summary, our results using male TRAP2-red mice characterize the cell populations activated during wakefulness and PSR, opening experimental paths for determining their function regarding vigilance states. Statement of Significance Wakefulness and paradoxical sleep are very similar at the electroencephalographic level. It remains relevant to determine the potential overlap of the neurons active during each vigilance state. We here took advantage of the powerful transgenic male TRAP2-red mice to directly compare in the same animal the brain cell activation during both states, with a focus on the hypothalamus. A deeper knowledge of each individual subpopulation of hypothalamic neurons within complex brain circuits underlying the sleep-waking cycle will help the understanding and validation of treatments of sleep disorders, at least those directly linked to demonstrated hypothalamic dysfunction such as narcolepsy (Orx neurons), amyotrophic lateral sclerosis (MCH and Orx signaling) or neurodegenerative diseases (Parkinson's and Alzheimer diseases).}, } @article {pmid41313410, year = {2025}, author = {Goel, F and Singh, P and Rai, SN and Yadav, DK}, title = {Nrf2/Keap1 Signaling Axis in the Brain: Master Regulator of Oxidative Stress in Neurodegenerative and Psychiatric Disorders.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {197}, pmid = {41313410}, issn = {1559-1182}, mesh = {Humans ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Signal Transduction/physiology ; *Oxidative Stress/physiology ; *Mental Disorders/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; }, abstract = {Oxidative stress is a crucial factor in the development of CNS disorders, including neurodegenerative and psychiatric conditions. The Nrf2/Keap1 signaling axis plays a central role in defending against oxidative damage by regulating antioxidant and cytoprotective gene expression. Beyond its antioxidant function, Nrf2 influences neurogenesis, synaptic plasticity, mitochondrial bioenergetics, and glial neuronal interactions, all of which are vital for maintaining neural integrity and cognitive performance. Dysregulation of this pathway through altered dimerization, post-translational modifications, or impaired regulation contributes to the pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, leading to protein aggregation, mitochondrial dysfunction, and neuroinflammation. Emerging evidence also implicates aberrant Nrf2 activity in psychiatric disorders such as depression, schizophrenia, and bipolar disorder, where redox imbalance and neuroimmune activation disrupt neural function. This review summarizes the molecular structure and regulation of the Nrf2/Keap1 pathway, including basal and stress-induced activation, post-translational modifications, and cross-talk with PI3K/Akt, MAPK, and NF-κB signaling. We highlight cell-type-specific roles of Nrf2 in neurons, astrocytes, and microglia, and the gene expression networks that drive CNS antioxidant and detoxification responses. Recent therapeutic strategies include natural and synthetic Nrf2 activators, gene therapy approaches, and nanotechnology-based delivery systems. While the translational potential of Nrf2-targeted interventions is considerable, challenges remain, including risks of overactivation and oncogenicity, lack of reliable biomarkers, and barriers related to blood-brain barrier permeability, dose, timing, and bioavailability. By integrating advances in neuroscience, pharmacology, and molecular medicine, this review emphasizes the promise of Nrf2 as a unifying therapeutic target across diverse CNS pathologies. Future directions include precision modulation through epigenetic regulation and circRNAs, as well as personalized pharmacotherapy. The Nrf2/Keap1 axis represents a multidisciplinary platform for developing multimodal interventions to preserve brain health in neurodegenerative and psychiatric disorders.}, } @article {pmid41313609, year = {2026}, author = {Maciel, ACMG and da Silva, AAM and Medeiros da Fonseca, JD and Vieira, RGDS and da Silva, LS and Lima, TBWE and Pondofe, KM and Otto-Yáñez, M and Torres-Castro, R and Vera-Uribe, R and Vilaró, J and Dourado Junior, MET and Resqueti, VR and Fregonezi, GAF}, title = {Effects of Body Position on Respiratory Pressure and Muscle Activity in Amyotrophic Lateral Sclerosis and Healthy Subjects.}, journal = {Respiratory care}, volume = {71}, number = {3}, pages = {307-314}, doi = {10.1177/19433654251389828}, pmid = {41313609}, issn = {1943-3654}, support = {/NGO/US Non-government Organization/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Case-Control Studies ; *Respiratory Muscles/physiopathology ; Female ; Middle Aged ; Electromyography ; Aged ; *Posture/physiology ; *Muscle Strength/physiology ; Spirometry ; Maximal Respiratory Pressures ; Supine Position/physiology ; Adult ; Healthy Volunteers ; Sitting Position ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal heterogeneous neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons and spinal cord. Measurement of respiratory muscle strength has been shown to be an important assessment in the decision-making process and can be assessed by maximum inspiratory (PImax) and expiratory pressures (PEmax), sniff nasal inspiratory (SNIP) and expiratory (SNEP) pressures. Body position appears to have a significant effect on respiratory muscle strength. The aim of this study was to observe the difference in peak values of SNIP and SNEP of the respiratory muscles measured in 2 different positions (seated and supine with 45° elevation) in subjects with ALS and a group of matched healthy subjects.

METHODS: This is a case-control study of subjects with ALS and healthy subjects. Spirometry and surface electromyography (EMG) of the sternocleidomastoid, scalene, rectus abdominis, and external oblique muscles were assessed during PImax and PEmax maneuvers in the seated position, and SNIP and SNEP in the seated and supine positions at 45° elevation (randomized).

RESULTS: SNEP values in the 45° elevation were lower than in the sitting position in ALS (70.3 ± 26.7 vs 57.3 ± 22.8 cm H2O, P = .041). SNIP and SNEP were lower in ALS in the 45° elevation compared with healthy subjects (69.1 ± 27.2 vs 95.5 ± 23.5 cm H2O; 57.3 ± 22.5 vs 92.7 ± 26.4 cm H2O, P = .041). In subjects with ALS, baseline electromyographic activity of the sternocleidomastoid muscle at rest was higher than in healthy subjects in both positions (P = .041). No significant differences in electrical activity were found for other variables and measurements.

CONCLUSIONS: In ALS, nasal pressure may be affected by reduced diaphragm and abdominal muscle effectiveness in the supine position. The sternocleidomastoid muscle showed increased electrical activity in the supine position with 45° elevation compared with controls, which may indicate muscle weakness.}, } @article {pmid41314187, year = {2025}, author = {Taher, Y and Ibrahim, S and Ahmed, D}, title = {BENIGN FASCICULATION SYNDROME AMONG HEALTH CARE WORKERS, A SINGLE CENTER STUDY.}, journal = {Georgian medical news}, volume = {}, number = {366}, pages = {64-68}, pmid = {41314187}, issn = {1512-0112}, mesh = {Humans ; Male ; *Health Personnel/psychology ; Female ; Cross-Sectional Studies ; Middle Aged ; Adult ; *Fasciculation/epidemiology/physiopathology/diagnosis/psychology ; *Anxiety/epidemiology/physiopathology ; *Depression/epidemiology/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology/epidemiology ; Prevalence ; Syndrome ; Electromyography ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Benign fasciculation syndrome (BFS) is a neurological disease manifested as persistent muscle twitching with the absence of a serious underlying pathology. Unlike the fasciculations that characterizes the most serious condition like amyotrophic lateral sclerosis (ALS), the BFS is not associated with weakness or muscle atrophy. Although the exact underlying mechanism of BFS is not well understood, it seems that anxiety, depression and the fear from having ALS play an important role especially among health care workers.

AIM: To detect the frequency and characteristics of BFS among a group of health care workers and to verify its possible correlation with the anxiety, depression and fear of having MND.

PATIENTS AND METHOD: In this comparative cross-sectional study, BFS was diagnosed in health care workers as well as the comparative group reflecting general population based on the clinical characteristics of fasciculation and by having normal neurological examination and normal nerve conduction study (NCS) and electromyograph (EMG). Anxiety and depression will be assessed according to generalized anxiety disorder 7 score (GAD-7) and patients health questionnaire 9 (PHQ-9).

RESULT: Our study revealed a significantly higher prevalence of Benign Fasciculation Syndrome (BFS) among healthcare workers (13.9%) compared to the general population (3.0%). This difference was statistically significant (p=0.002), indicating that healthcare workers face over five times the odds of developing BFS. Among affected healthcare workers, the most frequently reported clinical features accompanying fasciculations were perceived motor weakness (33.3%), sensory symptoms (26.7%), and tremor (26.7%). The average duration of symptoms was just over three years. A striking finding was the strong association between BFS and psychological comorbidities. Within the BFS group, 60% of individuals suffered from anxiety, with over half of these cases classified as severe. Similarly, 33.3% of BFS patients were diagnosed with depression. Statistical analysis confirmed that healthcare workers with anxiety or depression had a five-fold increased risk of having BFS compared to their non-affected colleagues (p=0.003 and p=0.016, respectively).

CONCLUSIONS: In conclusion, this study identifies healthcare workers as a population at significantly increased risk for Benign Fasciculation Syndrome (BFS). The condition is strongly associated with and likely precipitated by high rates of severe anxiety and depression within this cohort. These findings underscore the critical importance of integrating psychological screening and mental health support into the diagnostic and therapeutic management of BFS for healthcare professionals.}, } @article {pmid41314255, year = {2026}, author = {Odonchimed, S and Imamura, K and Inoue, H}, title = {Neurodegenerative disease and autophagy in iPSC-based models.}, journal = {Neuroscience research}, volume = {222}, number = {}, pages = {104991}, doi = {10.1016/j.neures.2025.104991}, pmid = {41314255}, issn = {1872-8111}, mesh = {Humans ; *Autophagy/physiology ; *Induced Pluripotent Stem Cells/physiology ; *Neurodegenerative Diseases/pathology/physiopathology/metabolism ; Animals ; }, abstract = {Neurodegenerative diseases are characterized by the gradual deterioration of specific neuronal populations, ultimately resulting in motor, cognitive, or behavioral impairments. Despite the worldwide increase in disease incidence, effective therapies remain unavailable. A common pathological hallmark of neurodegenerative diseases is the accumulation of misfolded protein aggregates. Accordingly, numerous studies and therapeutic strategies have focused on targeting these toxic aggregates and protein quality control via autophagy, a vital cellular recycling mechanism. Autophagy dysregulation has been implicated in the pathogenesis of several neurodegenerative diseases. Induced pluripotent stem cell (iPSC) technology has emerged as a powerful platform for modeling neurodegenerative diseases, and iPSC-based models provide human-relevant systems for studying autophagic dysfunction in vitro. In this review, we discuss the key findings of recent studies investigating autophagy in iPSC-based models of neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and other diseases.}, } @article {pmid41314744, year = {2025}, author = {Gunasekaran, B and Arifin, AH and Yu, WH and Hanafi, S and Rao, KDK and Salvamani, S}, title = {Precision medicine in neurodegenerative diseases: From research to clinical practice.}, journal = {Progress in brain research}, volume = {297}, number = {}, pages = {1-52}, doi = {10.1016/bs.pbr.2025.08.006}, pmid = {41314744}, issn = {1875-7855}, mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/therapy/genetics/diagnosis ; Biomarkers ; }, abstract = {The chapter outlines how precision medicine is reshaping the way neurodegenerative diseases (NDs) which includes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are understood, diagnosed, and treated. It discusses the limitations of current therapies, which mainly address symptoms without altering disease progression. Genetic and molecular factors that influence disease development are described, including distinctions between familial and sporadic forms. The chapter also covers the roles of epigenetic changes, gene expression, protein dysfunction, mitochondrial DNA, and non-coding RNAs in NDs. Biomarkers in blood and cerebrospinal fluid, along with imaging techniques and digital tools, are presented as key elements in early diagnosis and disease monitoring. Patient stratification based on clinical features, molecular profiles, and biomarkers helps guide treatment decisions and improve outcomes. The chapter reviews ongoing developments in genotype-based drug design, gene therapy, pharmacogenomics, and personalized lifestyle strategies. Clinical case studies show how these approaches are being used in practice. The chapter also discusses challenges in applying precision medicine, such as trial design, data integration, unequal access, and regulatory hurdles. Finally, it highlights the future tools like single-cell transcriptomics, digital twins, and global research collaborations that aim to bring precision approaches into everyday care.}, } @article {pmid41314745, year = {2025}, author = {Fatima, S and Tiwari, S and Siddiqi, B and Quadri, SN and Abdin, MZ}, title = {Biomarkers: From early detection to treatment personalization.}, journal = {Progress in brain research}, volume = {297}, number = {}, pages = {131-153}, doi = {10.1016/bs.pbr.2025.08.008}, pmid = {41314745}, issn = {1875-7855}, mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/therapy/metabolism ; *Precision Medicine/methods ; Early Diagnosis ; }, abstract = {Neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), present increasing issues associated with the unavoidable aging of the world's population. These challenges are further highlighted by the socioeconomic consequences of these diseases. The identification and use of biomarkers for prompt diagnosis, careful observation, and efficient treatment approaches is essential to overcoming these obstacles. The primary methods for diagnosing neurodegenerative illnesses are invasive procedures like lumbar punctures to measure CSF fluid or functional brain imaging methods. Biomarkers for underlying proteinopathy in blood serum and cerebral fluid have been the focus of recent biological research, particularly in vivo. With their ability to provide novel pathways for early detection, illness progression tracking, and individualized treatment plans, biomarkers have become essential instruments in precision medicine. The classification of biomarkers including fluid, digital imaging, and molecular biomarkers is examined in this chapter, with an emphasis on their function in neurodegenerative diseases. In neurodegenerative illnesses and the aging brain, tau, amyloid-β, α-synuclein, and TDP-43 are commonly seen to be deposited together rather than separately. These may be disregarded, and it might be challenging to determine their clinicopathological significance. An overview of illness pathophysiology, diagnostic implications, and the most recent molecular and ultrastructural categories for neurodegenerative disorders are given in this chapter. Addressing these issues through interdisciplinary research and technological advancements will be crucial for the future of biomarker-driven precision medicine. This chapter provides an in-depth overview of the evolving landscape of biomarkers and their transformative impact on the early detection and personalized treatment of neurodegenerative diseases.}, } @article {pmid41314746, year = {2025}, author = {Ceballos, MWG and Sy, FFA and Akbar, A and Taofiq, A}, title = {Multi-omics integration in disease research.}, journal = {Progress in brain research}, volume = {297}, number = {}, pages = {155-189}, doi = {10.1016/bs.pbr.2025.08.012}, pmid = {41314746}, issn = {1875-7855}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; *Proteomics/methods ; *Genomics/methods ; *Metabolomics/methods ; Animals ; Multiomics ; }, abstract = {Neurodegenerative diseases, marked by complex molecular mechanisms and diverse clinical features, challenge conventional research approaches. This chapter emphasizes the value of multi-omics integration in understanding the biology of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Genomic studies reveal risk variants such as APOE ε4 in Alzheimer's and rare mutations in familial forms. Transcriptomics highlights gene expression changes, including synaptic dysfunction in early Parkinson's and alternative splicing errors in TARDBP-related ALS. Proteomics identifies key protein aggregates like amyloid beta and alpha-synuclein, along with modifications such as hyperphosphorylated tau that correlate with cognitive decline. Metabolomics uncovers metabolic alterations, including mitochondrial dysfunction in Parkinson's and lipid peroxidation in ALS, which contribute to disease progression. By combining these layers with high-throughput tools like single-cell sequencing, spatial transcriptomics, and mass spectrometry, researchers can reconstruct molecular networks linking genetic risk, gene regulation, protein dysfunction, and metabolic imbalance. This approach enables patient stratification into molecular subtypes, such as neuroinflammatory clusters defined by microglial gene signatures and cytokine expression. Biomarkers from blood and cerebrospinal fluid allow for minimally invasive disease monitoring. Despite challenges such as data heterogeneity and limited standardization, multi-omics approaches support biomarker discovery and therapeutic development. Integrating these datasets with neuroimaging and digital tools enhances diagnostic precision and guides targeted interventions, such as antisense therapies for SOD1-linked ALS. Multi-omics integration is thus a critical foundation for advancing personalized strategies in neurodegenerative disease research.}, } @article {pmid41314748, year = {2025}, author = {Quadri, SN and Tiwari, S and Siddiqi, B and Fatima, S and Khan, MA and Abdin, MZ}, title = {Advanced neuroimaging in precision neurology: Tools, trends, and translational impact.}, journal = {Progress in brain research}, volume = {297}, number = {}, pages = {221-246}, doi = {10.1016/bs.pbr.2025.08.005}, pmid = {41314748}, issn = {1875-7855}, mesh = {Humans ; *Neuroimaging/methods/trends ; *Neurodegenerative Diseases/diagnostic imaging ; *Precision Medicine/methods/trends ; Translational Research, Biomedical ; *Neurology/methods/trends ; Artificial Intelligence ; Machine Learning ; }, abstract = {Advances in neuroimaging are revolutionizing the landscape of precision neurology by enabling high-resolution, multimodal visualization of brain structure, function, and pathology. As traditional, symptom-based frameworks fall short in capturing the biological complexity of neurodegenerative diseases, imaging modalities such as structural MRI, diffusion tensor imaging, functional MRI, PET, and hybrid PET/MRI have emerged as essential tools for early diagnosis, patient stratification, and therapeutic monitoring. These technologies not only reveal hallmark features like hippocampal atrophy and disrupted neural networks but also uncover molecular signatures such as amyloid and tau deposition, synaptic density, and neuroinflammation. Integration with artificial intelligence (AI) and machine learning (ML) further enhances diagnostic precision by decoding subtle imaging patterns, facilitating subtype classification, and predicting disease progression. Despite transformative progress, disparities in access and implementation remain a critical challenge, particularly in low- and middle-income countries. This chapter provides a comprehensive overview of neuroimaging modalities, their diagnostic and prognostic relevance across major neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, ALS, and frontotemporal dementia and the evolving role of hybrid platforms and AI integration in shaping the future of individualized neurological care.}, } @article {pmid41315422, year = {2025}, author = {Wang, S and Yao, T}, title = {Multi-omics framework integrating genetics microbiome and immunity for understanding motor neuron degeneration pathogenesis.}, journal = {NPJ biofilms and microbiomes}, volume = {11}, number = {1}, pages = {236}, pmid = {41315422}, issn = {2055-5008}, support = {2020B22//Doctoral Fund of The First Affiliated Hospital of Harbin Medical University/ ; 2022-KYYWF-0301//Innovative Scientific Research Funding Project of Harbin Medical University/ ; PL2024H140//Natural Science Foundation of Heilongjiang Province/ ; ZL2024H001//The Key Project of the Joint Fund of the Natural Science Foundation of Heilongjiang Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/microbiology/immunology ; *Gastrointestinal Microbiome/genetics ; Mendelian Randomization Analysis ; Biomarkers ; Gene Expression Profiling ; Multiomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) remains a devastating neurodegenerative disorder with poorly understood pathogenesis. We conducted Mendelian randomization (MR) analyses integrating cardiovascular factors, gut microbiota (GM) composition, and immune cell phenotypes with transcriptomic profiling to establish causal relationships with ALS susceptibility. MR revealed causal associations between elevated low-density lipoprotein cholesterol, apolipoprotein B, systolic blood pressure, and increased ALS risk. GM analysis identified protective Alistipes species effects and detrimental Bacteroides associations. Multiple immune cell subsets demonstrated significant disease associations, particularly CD3 + T cell populations and CD62L+ monocytes. Colocalization studies identified 53 genes with shared genetic architecture, enabling differential expression analysis across datasets. Predictive modeling developed a five-gene biomarker panel achieving 96% training accuracy and 93% external validation. Quantitative PCR confirmed differential expression patterns for biomarkers in patient cohorts. This multi-omics investigation establishes ALS as a complex disorder with actionable cardiovascular and microbiome therapeutic targets, providing applications for risk stratification and prevention.}, } @article {pmid41315851, year = {2025}, author = {Xu, H and Li, B and Chen, Y and Lin, Y and Zhang, A and Wu, L}, title = {N-palmitoyl glycine differentially modulates TRPM4 and TRPC5 and is causally linked to Brugada syndrome.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {1854}, pmid = {41315851}, issn = {2399-3642}, support = {81930105//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82370312//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; *TRPM Cation Channels/metabolism/genetics ; *TRPC Cation Channels/metabolism/genetics ; *Brugada Syndrome/genetics/metabolism ; Rabbits ; Humans ; Myocytes, Cardiac/metabolism/drug effects ; Male ; *Glycine/analogs & derivatives/metabolism/pharmacology ; }, abstract = {Brugada syndrome (BrS) is an inherited cardiac arrhythmic disorder associated with an increased risk of malignant ventricular arrhythmia and sudden death. Mendelian randomisation implicated N-palmitoyl glycine (PalGly) in BrS risk and identified BrS-associated proteins (DCC, CR1, CTSB, NAAA, DEFB1, EPHA1, IGF1/IGFBP3/ALS, and LTA), for which molecular docking further predicted moderate binding affinities with PalGly. PalGly enhanced calcium sparks in ventricular cardiomyocytes without affecting Nav1.5 or Kv4.3/KChiP2 but activated TRPC5 (EC50 104 nM), as confirmed by patch-clamp. TRPM4, a channel mediating sodium influx at negative potentials and reported to link to BrS when mutated, was directly inhibited by PalGly (IC50 = 7 nM). Functionally, PalGly shortened APD in cardiomyocytes and QT in male rabbit hearts, whereas ML204 (TRPC5 inhibitor) further shortened APD in isolated cardiomyocytes. Transcriptomic and lipidomic analyses further indicated immune pathway suppression. Our study underscores the involvement of PalGly, TRPC5, and inflammation-related proteins in the pathophysiology of BrS.}, } @article {pmid41316718, year = {2026}, author = {Vasta, R and Matteoni, E and Pellegrino, G and Canosa, A and Manera, U and Palumbo, F and Grassano, M and Cabras, S and Maccabeo, A and D'Ovidio, F and Mora, G and Gallone, S and D'Angelo, E and Mazzini, L and De Marchi, F and Moglia, C and Chiò, A and Calvo, A}, title = {The Epidemiology of Primary Lateral Sclerosis: Results from a Population-Based Cohort.}, journal = {Annals of neurology}, volume = {99}, number = {3}, pages = {606-613}, pmid = {41316718}, issn = {1531-8249}, mesh = {Humans ; Male ; Female ; Middle Aged ; Aged ; Italy/epidemiology ; Registries ; Incidence ; *Motor Neuron Disease/epidemiology/diagnosis ; Cohort Studies ; Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Age of Onset ; Adult ; }, abstract = {OBJECTIVE: In this population-based study, we described the epidemiology of primary lateral sclerosis (PLS) in northern Italy and compared the clinical characteristics of patients with PLS to those with predominant upper motor neuron (PUMN) involvement and classic amyotrophic lateral sclerosis (ALS).

METHODS: Patients from the PARALS registry diagnosed with probable or definite PLS between 2007 and 2021 were included. Crude annual incidence rates were calculated, along with age- and sex-specific rates. A survival analysis was performed to identify prognostic factors at diagnosis. Covariates included sex, age at onset, site of onset, diagnostic delay, forced vital capacity (FVC), change in ALS Functional Rating Scale (ΔFRS), and change in body mass index (ΔBMI).

RESULTS: A total of 57 PLS patients (2.7%) were included, with a crude incidence rate of 0.084 per 100,000 person-years. Compared to PUMN and classic ALS, PLS patients were younger (median onset age 63.5 years, interquartile range [IQR] 54.9-70.4) and predominantly female (male-to-female ratio 0.58). Bulbar onset occurred in 11 cases (19.3%), all of whom later developed spinal symptoms. At censoring, 38 patients (66.7%) were still alive (median survival 8.3 years, IQR 5.7-12.3), corresponding to a point prevalence of 0.89 per 100,000. Survival was significantly associated with age at onset (hazard ratio [HR] 1.17, 95% confidence interval [CI]: 1.05-1.33, p = 0.001), male sex (HR 4.41, 95% CI: 1.24-15.6, p = 0.02), and FVC at diagnosis (HR 0.95, 95% CI: 0.93-0.98, p = 0.006).

INTERPRETATION: PLS was confirmed to be rarer than other ALS phenotypes. Patients had a higher age at onset than previously reported and a female predominance. Sex, age at onset, and respiratory function were key prognostic factors. ANN NEUROL 2026;99:606-613.}, } @article {pmid41316805, year = {2026}, author = {Taha, M and Huang, S and Wang, X and Subasi, A and Morren, JA}, title = {Electromyography Signal Classification With Artificial Intelligence for Detection of Neuromuscular Disorders Using a Large Clinically-Acquired Database.}, journal = {Muscle & nerve}, volume = {73}, number = {2}, pages = {319-328}, doi = {10.1002/mus.70087}, pmid = {41316805}, issn = {1097-4598}, support = {//Cleveland Clinic Foundation/ ; //Lerner Research Institute-Artificial Intelligence in Medicine (AIM) Internal Funding Program/ ; }, mesh = {Humans ; *Electromyography/methods ; Databases, Factual ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Artificial Intelligence ; Male ; Female ; Middle Aged ; *Neuromuscular Diseases/diagnosis/physiopathology ; Aged ; Adult ; Neural Networks, Computer ; Signal Processing, Computer-Assisted ; Muscle, Skeletal/physiopathology ; Algorithms ; }, abstract = {INTRODUCTION/AIMS: Artificial intelligence (AI) has shown potential in analyzing electromyography (EMG) signals, but clinical applicability remains limited by studies based on small, curated datasets, and variable accuracy. This study evaluated AI performance in classifying needle electromyography (EMG) signals as muscle activity versus background/noise/artifact, and then in distinguishing three clinical categories: amyotrophic lateral sclerosis (ALS), myopathy, and non-disease controls.

METHODS: Data from the Cleveland Clinic Foundation EMG Database (CCFDB), a large clinically acquired EMG dataset was utilized for this study. A two-step classification approach was used: a convolutional neural network (CNN) to separate muscle activity from background/noise/artifact, followed by a random forest algorithm and CNNs for clinical category classification. Feature extraction techniques included Short-Time Fourier Transform (STFT), Discrete Wavelet Transform (DWT), Continuous Wavelet Transform (CWT), and Wavelet Packet Decomposition (WPD).

RESULTS: EMG data from 608 participants (266 ALS, 89 myopathy, 253 non-disease controls), totaling 11,456 muscle recordings, and 15,613 segments of muscle activity were included. The muscle activity detection model achieved 85.4% accuracy. For clinical category classification, CWT with a two-layer CNN performed best on the CCFDB (62% accuracy). Deeper CNN architectures did not consistently improve performance. On the publicly available curated EMGlab dataset, the best accuracy using the same AI models was higher (91%).

DISCUSSION: AI can assist in EMG analysis, but the performance gap between curated and clinically-acquired datasets underscores the need for robust models capable of handling signal variability and complexity in authentic clinical contexts. Future efforts should focus on clinically-oriented AI development to improve translational applicability.}, } @article {pmid41316902, year = {2026}, author = {Jang, GE and Lee, I and Andrews, JA and Cheung, YKK and Redzepagic, M and Mitsumoto, H}, title = {Startle Reflex in Primary Lateral Sclerosis (PLS): A Comparison With Amyotrophic Lateral Sclerosis (ALS).}, journal = {Muscle & nerve}, volume = {73}, number = {2}, pages = {304-308}, doi = {10.1002/mus.70071}, pmid = {41316902}, issn = {1097-4598}, support = {//Spastic Paraplegia Foundation/ ; //ALS Association/ ; //Mitsubishi Tanabe Pharma Corporation/ ; //MDA Wings Over Wall Street/ ; //David Marren and the Family/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/epidemiology ; Female ; Male ; Middle Aged ; Aged ; *Reflex, Startle/physiology ; Cross-Sectional Studies ; *Motor Neuron Disease/physiopathology/diagnosis/epidemiology ; Adult ; Acoustic Stimulation ; }, abstract = {INTRODUCTION/AIMS: There is a lack of information about startle reflex (SR) in primary lateral sclerosis (PLS). This study examined the presence and prevalence of SR in PLS and compared findings with amyotrophic lateral sclerosis (ALS).

METHODS: 46 PLS and 54 ALS participants were assessed through structured interviews in this cross-sectional study. Fisher's exact test was used to compare reported SR prevalence. Multivariable linear regression was utilized to study associations between disease group and SR frequency in response to sudden stimuli.

RESULTS: SR differed markedly between the two groups, with a higher prevalence in PLS (93.5%) than ALS (20.4%; p < 0.001). Among ALS patients, SR was present in all upper motor neuron (UMN)-predominant cases, which accounted for 54.5% of the SR-positive ALS group, but only 10.4% of probable/definite ALS cases. In SR-positive patients, response frequency to sudden stimuli exceeded 60% in both ALS and PLS, most often triggered by auditory stimuli. Younger age, shorter disease duration, and PLS diagnosis were associated with more frequent SR.

DISCUSSION: SR is significantly more common in PLS than in ALS. Notably, UMN-predominant ALS, although limited in number, showed a higher prevalence of SR (6 out of 6, 100%), indicating that predominant UMN involvement may be a key determinant of SR across both conditions. These hypothesis-generating findings suggest that SR may serve as a novel clinical marker in PLS and UMN-predominant ALS, warranting further validation through prospective studies.}, } @article {pmid41319328, year = {2025}, author = {Michelutti, M and Huppertz, HJ and Anderl-Straub, S and Volkmann, H and Urso, D and Tafuri, B and Nigro, S and Manganotti, P and Rosenbohm, A and Ludolph, AC and Otto, M and Logroscino, G and Müller, HP and Kassubek, J}, title = {MRI-DTI Biomarkers Along the Continuum of Behavioral Variant Frontotemporal Dementia.}, journal = {European journal of neurology}, volume = {32}, number = {12}, pages = {e70438}, pmid = {41319328}, issn = {1468-1331}, mesh = {Humans ; *Frontotemporal Dementia/pathology/diagnostic imaging ; *Diffusion Tensor Imaging/methods ; Male ; Female ; Middle Aged ; Aged ; *White Matter/pathology/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging ; *Gray Matter/pathology/diagnostic imaging ; Magnetic Resonance Imaging/methods ; *Brain/pathology/diagnostic imaging ; Atrophy/pathology ; Biomarkers ; Longitudinal Studies ; }, abstract = {BACKGROUND: We investigated whether diffusion tensor imaging (DTI) and atlas-based volumetry (ABV) could track specific patterns of brain white matter (WM) microstructure and gray matter (GM) volumes in behavioral variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis with frontotemporal dementia (ALS-FTD).

METHODS: MRI datasets from 65 bvFTD (including 19 with longitudinal MRI), 18ALS-FTD, and 39 controls were analyzed. White matter fractional anisotropy (FA) differences were assessed using unbiased Whole Brain-based Spatial Statistics (WBSS) and a hypothesis-driven complementary approach consisting of Tract-Wise FA Statistics (TFAS) in Tracts of Interest (TOIs) and ABV in Structures of Interest (SOIs). FA maps were correlated with disease severity (FTLD-CDR sum of boxes). A random forest algorithm classified participants employing TOI and SOI data.

RESULTS: At baseline, both bvFTD and ALS-FTD exhibited WM changes in several tracts including the uncinate fasciculi, tracts originating in the corpus callosum, and the inferior and superior longitudinal fasciculi. Atrophy was most pronounced in the frontal lobes and caudate nuclei. Longitudinally, bvFTD demonstrated an antero-posterior spread of WM degeneration, particularly along the corpus callosum and inferior longitudinal fasciculus, with relatively modest cortical atrophy progression. Random forest analysis identified the most discriminative TOIs and SOIs including the uncinate fasciculus and the amygdala.

CONCLUSIONS: Our findings demonstrate a similar pattern of structural and microstructural changes in bvFTD and ALS-FTD, with a specific involvement of the corticospinal tract for ALS-FTD, and support the utility of combined DTI and ABV in tracking disease progression across the FTLD spectrum.}, } @article {pmid41319477, year = {2026}, author = {Benussi, A and Vucic, S}, title = {Emergent technologies and applications of TMS and TMS-EEG in clinical neurophysiology for early and differential diagnosis: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {182}, number = {}, pages = {2111459}, doi = {10.1016/j.clinph.2025.2111459}, pmid = {41319477}, issn = {1872-8952}, mesh = {Humans ; *Transcranial Magnetic Stimulation/methods/trends ; *Electroencephalography/methods/trends ; Diagnosis, Differential ; *Nervous System Diseases/physiopathology/diagnosis ; Early Diagnosis ; *Neurophysiology/methods ; }, abstract = {This chapter examines how emerging neurophysiological technologies are transforming the early and differential diagnosis of neurological disorders. While imaging and fluid biomarkers have greatly advanced the field, they remain limited by cost, invasiveness, and their inability to directly capture dynamic brain activity. Neurophysiological techniques, particularly transcranial magnetic stimulation (TMS) and TMS combined with EEG, offer a unique, non-invasive means of probing cortical excitability, connectivity, and plasticity with millisecond precision. Recent technological and analytical breakthroughs are moving these approaches from research laboratories into clinical practice. By detecting subtle network dysfunctions that precede structural degeneration, they open the possibility of identifying disease in its prodromal or even presymptomatic stages, when interventions may be most effective. This chapter outlines the principles of advanced TMS paradigms and TMS-EEG and explores their application across a range of conditions, including amyotrophic lateral sclerosis, dementias, and movement disorders. It also highlights how integrating neurophysiological measures with blood-based biomarkers and computational tools, such as machine learning, can enhance diagnostic accuracy and guide individualized treatment strategies. Together, these innovations establish neurophysiology as a cornerstone of precision neurology, linking mechanistic insights to clinical decision-making and enabling earlier diagnosis, improved patient stratification, and more targeted therapeutic interventions.}, } @article {pmid41320876, year = {2025}, author = {Tang, YB and Zhang, J and Liu, Q}, title = {tRNA-derived small noncoding RNAs: Roles in brain aging and neurodegenerative disorders.}, journal = {Zoological research}, volume = {46}, number = {6}, pages = {1575-1587}, pmid = {41320876}, issn = {2095-8137}, mesh = {*Aging/physiology ; *Neurodegenerative Diseases/genetics/metabolism ; Animals ; *Brain/physiology/metabolism ; *RNA, Transfer/metabolism/genetics ; *RNA, Small Untranslated/metabolism/genetics ; Humans ; }, abstract = {Transfer ribonucleic acid-derived small ribonucleic acids (tsRNAs) are an emerging class of regulatory noncoding RNAs produced through the precise cleavage of mature or precursor tRNAs (pre-tRNAs). Once considered degradation byproducts, tsRNAs are now recognized as key modulators of gene expression, epigenetic regulation, and cellular stress responses. In recent years, growing evidence has implicated tsRNAs in the aging process of the brain and in the pathogenesis of age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). These small RNAs are involved in modulating synaptic function, neuronal survival, and neuroinflammation, and their expression profiles are dynamically altered in response to aging and disease-associated stressors. This review summarizes the biogenesis, classification, and molecular and cellular mechanisms of tsRNAs, with an emphasis on their subcellular locations and associated biological functions. We further explore their roles in brain aging and age-related neurodegenerative diseases and the emerging potential of tsRNAs as biomarkers and therapeutic targets for age-related neurological disorders while highlighting current challenges and future directions in this rapidly advancing field.}, } @article {pmid41322345, year = {2025}, author = {Senghor, HVF and Rubio, RD and Marco, C and Salazar-Villacorta, A and Padró-Miquel, A and Beltran, S and Matalonga, L and Márquez, F and Sy, HA and Sy, M and Povedano, M and Diop, AG and Ndiaye, M and Rodríguez Cruz, PM}, title = {SYNE1 Deficiency Manifesting Primarily With Motor Neuron Disease.}, journal = {Neurology. Genetics}, volume = {11}, number = {6}, pages = {e200306}, pmid = {41322345}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: SYNE1 deficiency is an autosomal recessive disorder with a broad phenotypic spectrum, most commonly presenting as adult-onset cerebellar ataxia with or without motor neuron dysfunction. We aimed to expand this spectrum by describing the clinical and genetic findings in 2 unrelated families with early-onset motor neuron disease and virtually no cerebellar signs over time.

METHODS: We performed detailed clinical, neurophysiologic, and genetic studies of 2 unrelated families with juvenile amyotrophic lateral sclerosis (ALS) and biallelic variants in SYNE1.

RESULTS: The phenotypes of both families showed onset of symptoms in childhood or adolescence, with signs of upper and lower motor neuron dysfunction in multiple territories suggestive of juvenile ALS. Patients developed progressive muscle weakness, eventually leading to respiratory distress and bulbar signs. Whole-exome sequencing identified SYNE1 biallelic truncating variants in both families: a homozygous nonsense variant, c.23131C>T (p.Gln7711*), in Family 1, and a novel homozygous splice-site variant, c.17851-1G>A, in Family 2. Notably, mild or no cerebellar manifestations were observed during the follow-up.

DISCUSSION: This report highlights a novel phenotype of SYNE1 deficiency characterized by early-onset motor neuron disease and virtually no cerebellar manifestations, broadening the phenotypic spectrum of this complex neurodegenerative disease. These findings support investigating SYNE1 variants in juvenile ALS and including SYNE1 in motor neuron disease gene panels.}, } @article {pmid41322353, year = {2025}, author = {Sanghai, N and Barzegar Behrooz, A and Latifi-Navid, H and Fahanik Babaei, J and Tranmer, GK}, title = {Phosphoproteomics-guided tau biomarker discovery in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD).}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1714196}, pmid = {41322353}, issn = {1662-4548}, } @article {pmid41322641, year = {2025}, author = {Carvalho, JHS and Faria, BS and Freitas, RC and Brazaca, LC and Janegitz, BC}, title = {Paper-Based Electrochemical Device Modified with Palladium: Sensor for the Detection of Serotonin and an Immunosensor for the Detection of SOD1.}, journal = {ACS omega}, volume = {10}, number = {46}, pages = {55887-55897}, pmid = {41322641}, issn = {2470-1343}, abstract = {The early and accurate detection of superoxide dismutase 1 (SOD1) and other biomarkers is crucial for the diagnosis and monitoring of neurodegenerative diseases such as amyotrophic lateral sclerosis. This study reports the development of a low-cost paper-based electrochemical sensor for the detection of serotonin (5-HT) and an immunosensor for the detection of SOD1, the potential biomarkers associated with these diseases. The sensor was fabricated using a conductive ink composed of carbon nanotubes and glass varnish onto an office paper substrate, with a palladium electrochemically deposited on the working electrode. To improve the device's stability and water resistance, the paper surface was treated with beeswax, enhancing its hydrophobicity. Cyclic voltammetry was used to observe the electrochemical behavior, with differential pulse voltammetry applied to 5-HT. An analytical calibration curve was generated, with a limit of detection of 0.35 μmol/L for 5-HT, demonstrating a linear range of 7.00-100 μmol/L in PBS. The Pd-modified electrode enabled efficient immobilization of antibodies, facilitating the selective detection of SOD1 via antigen-antibody interactions. Electrochemical impedance spectroscopy was employed for label-free SOD1 quantification, yielding a linear response in the range of 1.0-100 nmol·L[-1] and a limit of detection of 0.72 nmol·L[-1]. The proposed electrochemical immunosensor demonstrates high sensitivity, selectivity, and affordability, making it a promising tool for early stage screening of neurodegenerative disease biomarkers in real-world clinical samples.}, } @article {pmid41323448, year = {2025}, author = {Tang, H and Jiang, P and Chen, J}, title = {Research Landscapes and Gaps in Neuropsychiatric Assessment for Neurodegenerative Diseases: A Bibliometric Study on Huntington's Disease, Amyotrophic Lateral Sclerosis, and Multiple System Atrophy.}, journal = {Dementia and geriatric cognitive disorders extra}, volume = {15}, number = {1}, pages = {174-191}, pmid = {41323448}, issn = {1664-5464}, abstract = {INTRODUCTION: The aim of the study was to provide a comprehensive overview of the current application of tools used for assessing neuropsychiatric symptoms (NPSs) in patients with Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple system atrophy (MSA) through bibliometric analysis.

METHODS: Publications published between 2014 and 2023 were searched using the Web of Science Core Collection database (WoSCC). Only articles and reviews published in the English language were included. CiteSpace was used to analyze the countries, keyword patterns, and reference co-citations. A detailed full-text analysis was further conducted across all studies to assess the usage of NPS assessment tools.

RESULTS: Our analysis included 530 publications demonstrating consistent annual growth, reflecting rising global interest in NPSs within neurodegenerative and neuroinflammatory diseases. However, these studies reveal research deficiency in current assessment methodologies that demands more attention. Research output remains predominantly concentrated in developed nations with aging populations, particularly the USA, which leads in both publication volume and quality. The primary focus of current research involves evaluating the validity of existing assessment tools, while emerging investigations explore next-generation assessment tools designed to enhance diagnostic precision and enable personalized treatment strategies. Despite these advances, widespread clinical adoption remains limited, and further validation studies are required to establish their reliability across diverse populations and disease stages.

CONCLUSION: This study highlights the growing importance of NPSs in neurodegenerative diseases, particularly in HD, ALS, and MSA. We identify hotspots and deficiencies in the research field of validating NPS assessment tools, integrating NPSs into the diagnostic framework and elucidating neurobiological mechanisms. These findings will contribute to enhanced diagnostic and therapeutic approaches for neurodegenerative diseases.}, } @article {pmid41323626, year = {2025}, author = {Pérez-Fuentes, MDC and Molero Jurado, MDM and Romanos-Rodríguez, A and Barragán Martín, AB and Gómez-Gómez, FJ and Aguado-Campos, J}, title = {Simulation-based training in emotional intelligence and self-esteem: enhancing effectiveness and wellbeing in healthcare.}, journal = {Frontiers in public health}, volume = {13}, number = {}, pages = {1667192}, pmid = {41323626}, issn = {2296-2565}, mesh = {Humans ; *Emotional Intelligence ; *Self Concept ; Female ; Male ; Spain ; Adult ; *Simulation Training/methods ; Middle Aged ; *Health Personnel/education/psychology ; Primary Health Care ; Physicians/psychology ; }, abstract = {INTRODUCTION: The study focuses on the training of health professionals, traditionally based on technical skills and specialized knowledge. However, the importance of integrating emotional intelligence and self-esteem has gained recognition for its impact on the quality of patient care and professional wellbeing. This study examines how targeted interventions in these areas can improve wellbeing and professional effectiveness in primary care settings.

METHOD: A multicenter study was conducted with a pre-experimental design, assessing participants before and after the intervention, with no control group. Participants were 106 physicians and nurses in primary care centers in Andalusia, Spain. The intervention consisted of an Advanced Life Support (ALS) training program implemented in a blended learning format that combined online theoretical instruction with in-person practical sessions. The course integrated theoretical modules, hands-on workshops, and simulation-based exercises aligned with international resuscitation guidelines. The Brief Inventory of Emotional Intelligence and the Rosenberg Self-Esteem Scale were used. Data analysis was performed using nonparametric tests and the Wilcoxon test to assess pre- and post-intervention variations.

RESULTS: Correlations between self-esteem and several dimensions of emotional intelligence showed significant post-intervention increases. The intrapersonal and interpersonal factors of emotional intelligence showed significant improvements in their mean scores. However, no significant changes in stress management, mood, or self-esteem were observed in the total sample.

CONCLUSION: The study highlights the efficacy of incorporating emotional intelligence and self-esteem training in the training of health professionals, demonstrating improvements in stress management and adaptability. The variations in the effects of the intervention suggest the need to adapt future interventions to the specific characteristics of each profession. Integrating these programs into health education could significantly enhance the quality of patient care and the wellbeing of health professionals.}, } @article {pmid41323796, year = {2025}, author = {Kang, M and Lin, WH and Li, Y and Xu, F and Zhou, X and Si, C and Dai, J and He, J and Schacht, I and Gan, Z and Huang, V and Li, LC}, title = {SCAD: A modular platform for efficient delivery of duplex RNA to the CNS and beyond.}, journal = {Molecular therapy. Nucleic acids}, volume = {36}, number = {4}, pages = {102757}, pmid = {41323796}, issn = {2162-2531}, abstract = {Oligonucleotide therapeutics-including antisense oligonucleotides and duplex RNAs such as small interfering RNAs, small activating RNAs, and microRNAs-hold immense potential for treating both genetic and acquired diseases by modulating gene expression in a target-specific manner. However, effective delivery to extrahepatic tissues, particularly the central nervous system, remains a significant challenge. While N-Acetylgalactosamine conjugation has enabled liver-specific delivery of oligonucleotides leading to several approved siRNA drugs for hepatic indications, there remains a significant unmet need for effective treatment options in the CNS space. We have developed the smart chemistry-aided delivery platform that enables duplex RNA delivery by conjugating to an accessory oligonucleotide, which facilitates protein binding and promotes cellular uptake. Through extensive screening, we identified an optimal SCAD architecture that demonstrates enhanced cell-free protein binding and in vitro activity. In rodent models, local administration of SCAD-siRNA conjugates resulted in broad biodistribution throughout the CNS and sustained mRNA knockdown for over 5 months, with a favorable safety profile. The SCAD platform also exhibited efficient delivery to other extrahepatic tissues, including the eye, lung, and joint. The modular design of SCAD can be easily adapted to any duplex RNA, making it a powerful tool for advancing oligonucleotide therapeutics.}, } @article {pmid41326746, year = {2025}, author = {Stærmose, TS and Blicher, JU and Dalal, SS}, title = {Movement Related Beta-Band Modulation with OPM-MEG: A Pilot Study.}, journal = {Brain topography}, volume = {39}, number = {1}, pages = {3}, pmid = {41326746}, issn = {1573-6792}, mesh = {Humans ; *Magnetoencephalography/methods/instrumentation ; Pilot Projects ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; *Beta Rhythm/physiology ; Movement/physiology ; Middle Aged ; Female ; Adult ; Aged ; *Brain/physiopathology/physiology ; }, abstract = {Optically pumped magnetometers (OPMs) represent a significant advancement in magnetoencephalography (MEG), offering high sensitivity without cryogenic cooling and enabling flexible sensor placement. In this pilot study, we evaluated whether a small, zero-contact 16-channel OPM array can capture movement-related beta-band modulation (event-related desynchronization/synchronization; ERD/ERS) in healthy participants and explored feasibility in a single patient with amyotrophic lateral sclerosis (ALS). MEG responses to visually cued active and passive finger movements were recorded in a magnetically shielded room with the OPM array and separately with 306-channel superconducting quantum interference device (SQUID). Time-frequency analyses focused on beta-band activity across baseline, ERD, and ERS periods. In healthy participants, both OPM and SQUID successfully captured movement-related beta oscillations, with no significant differences between active and passive conditions or between measurement systems, based on non-parametric tests. In the ALS patient, movement-related responses were attenuated and more affected by artifacts in the OPM data compared with SQUID, limiting interpretability. Although movement artifacts were noted, the OPM system provided group-level results in healthy controls comparable to SQUID-based MEG, demonstrating its viability and potential for rapid, flexible deployment. These findings indicate that a compact zero-contact OPM array can reliably measure movement-related cortical beta activity and may offer a cost-effective alternative to cryogenic MEG systems. In ALS, however, the present results should be interpreted strictly as a feasibility demonstration, and larger patient cohorts will be required to establish reliability and clinical utility.}, } @article {pmid41327179, year = {2025}, author = {Eshak, D and Arumugam, M}, title = {Nanomaterials: an overview of current trends and future prospects in neurological disorder treatment.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {1366}, pmid = {41327179}, issn = {1479-5876}, mesh = {Humans ; *Nervous System Diseases/therapy/drug therapy ; *Nanostructures/therapeutic use/chemistry ; Animals ; Blood-Brain Barrier ; }, abstract = {The World Health Organization (WHO) has identified neurological disorders (NDs) as one of the major health concerns worldwide, resulting in high mortality rates. NDs are conditions affecting the central and peripheral nervous systems, including the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, neuromuscular junctions, and muscles. These neurological diseases include Alzheimer's disease, Parkinson's disease, glioma/brain cancer, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuroinfections, ischemic stroke, trauma, hypoxia/anoxia, and depression. Unfortunately, these disorders remain difficult to treat due to the limited ability of conventional drugs to cross the blood-brain barrier (BBB) and achieve significant pharmacological effects in the brain. There is an urgent need to develop methods that can enhance drug efficacy and bypass the BBB. The application of various nanomaterials represents a promising approach to address these neurological disorders. Drugs incorporated with nanomaterials help improve therapeutic outcomes, reduce toxicity, provide better stability, enable targeted delivery, and enhance drug loading capacity. Numerous types and morphologies of inorganic and organic nanomaterials are increasingly employed for treating NDs, including quantum dots, dendrimers, metal nanoparticles, polymeric nanoparticles, liposomes, carbon nanotubes, metal oxide nanoparticles, and micelles. Their exceptional properties such as sensitivity, selectivity, and potential to bypass the BBB make them suitable for both diagnosis and treatment of NDs. In this review article, we briefly summarize the etiology and pathophysiology of various NDs along with current literature highlighting the use of nanomaterials for treating neurological disorders.}, } @article {pmid41327675, year = {2025}, author = {Kiristioglu, MO and Akova, B and Sogutlu Sari, E and Baykara, M}, title = {Anterior segment optical coherence tomography in corneal diseases: A bibliometric analysis and visualization research of global research trends (1994-2024).}, journal = {Medicine}, volume = {104}, number = {48}, pages = {e45679}, pmid = {41327675}, issn = {1536-5964}, mesh = {*Tomography, Optical Coherence/methods/trends ; *Bibliometrics ; Humans ; *Corneal Diseases/diagnostic imaging ; *Biomedical Research/trends ; *Anterior Eye Segment/diagnostic imaging ; }, abstract = {PURPOSE: This study provides a bibliometric analysis of global research on anterior segment optical coherence tomography (AS-OCT) in corneal diseases, mapping key research trajectories, collaborations, and emerging trends.

METHODS: A systematic search in the Web of Science Core Collection on January 1, 2025, retrieved 3634 records (1994-2024). After excluding non-English publications, non-ophthalmology studies, and non-corneal research, 2079 publications were analyzed using VOSviewer and CiteSpace for citation networks, coauthorship trends, and keyword co-occurrence.

RESULTS: AS-OCT research has grown significantly (Mann-Kendall τ = 0.929, P < .001). The United States led in publications (639 papers, 19,594 citations), followed by China (333 papers, 4502 citations). The University of California was the most productive institution. The first AS-OCT study, published in the Archives of Ophthalmology (1994) by Izatt JA et al, marked the field's inception. The most cited article was Huang et al's 1991 Science paper on optical coherence tomography. Recent trends highlight the integration of artificial intelligence, deep learning, and optical coherence elastography in AS-OCT applications. The top 3 contributing journals were Cornea, Journal of Refractive Surgery, and Journal of Cataract and Refractive Surgery. Coauthorship analysis identified Jodhbir S. Mehta and David Huang as central figures in AS-OCT research collaborations.

CONCLUSION: AS-OCT research has expanded significantly, enhancing diagnostics, surgical planning, and disease monitoring. Artificial intelligence-driven analytics and optical coherence elastography are promising future directions. This bibliometric analysis guides advancing AS-OCT research and clinical applications.}, } @article {pmid41327964, year = {2025}, author = {He, QF and Lin, YH and Zheng, ZL and Zeng, MH and Lin, X and Liu, XY and Kang-Yang, and Zhang, QI and Lin, MT and Wang, N and Wang, ZQ and Lin, F}, title = {Comprehensive Profiling of Annexins in Neuromuscular Disorders Reveals a Unique Signature in Dysferlinopathy.}, journal = {European journal of neurology}, volume = {32}, number = {12}, pages = {e70442}, pmid = {41327964}, issn = {1468-1331}, support = {2023J01620//Natural Science Fundation of Fujian Province/ ; 2024Y9196//Joint Funds for the Innovation of Science and Technology, Fujian Province/ ; }, mesh = {Humans ; *Muscular Dystrophies, Limb-Girdle/metabolism/pathology ; Male ; *Annexins/metabolism ; Female ; Adult ; Middle Aged ; Muscle, Skeletal/pathology/metabolism ; *Neuromuscular Diseases/metabolism/pathology ; Aged ; Young Adult ; Dysferlin ; }, abstract = {BACKGROUND: Annexins are a family of calcium-dependent membrane-binding proteins implicated in membrane repair and inflammation, yet their immunoreactivity patterns in neuromuscular disorders remain poorly characterized. This study systematically examined the immunoreactivity profiles of annexins A1, A2, A4, A5, A6, A7, and A11 across various muscular dystrophies, including muscular dystrophies, inflammatory myopathies, lipid storage myopathy (LSM), and amyotrophic lateral sclerosis (ALS).

METHODS: Muscle biopsies from patients with dysferlinopathy, Duchenne/Becker muscular dystrophy (DMD/BMD), myotonic dystrophy type 1 (DM1), oculopharyngeal muscular dystrophy (OPMD), facioscapulohumeral muscular dystrophy (FSHD), LSM, inflammatory myopathies, and ALS, along with controls, were analyzed. Immunofluorescence and immunoblot assays were used to assess annexin localization and abundance, and quantitative immunoreactivity levels were statistically compared with controls.

RESULTS: Dysferlinopathy showed a distinct upregulation of multiple annexins (A1, A2, A4, A5, A6, and A7). These annexins were primarily localized to the extracellular matrix, with additional cytoplasmic accumulation in atrophied fibers. Annexin A6 was strongly associated with the sarcolemma, while annexin A7 was diffusely distributed. In contrast, other myopathies such as OPMD and FSHD exhibited reduced or unchanged annexin immunoreactivity. Inflammatory myopathies partially mirrored the dysferlinopathy pattern, though annexin A2 levels were lower. ALS samples displayed minimal immunoreactivity, restricted to focal cytoplasmic annexin A1 and sparse sarcolemmal annexin A6.

CONCLUSIONS: These findings reveal a unique annexin signature in dysferlinopathy, suggesting a potential involvement in membrane repair and inflammatory modulation. The differential expression across disorders highlights the diverse roles of annexins in muscle pathophysiology and supports their utility as diagnostic biomarkers and therapeutic targets.}, } @article {pmid41328354, year = {2026}, author = {Huang, Q and Wang, S and Liu, Z and Rao, L and Cheng, K and Mao, X}, title = {Engineering exosomes for targeted neurodegenerative therapy: innovations in biogenesis, drug loading, and clinical translation.}, journal = {Theranostics}, volume = {16}, number = {1}, pages = {545-579}, pmid = {41328354}, issn = {1838-7640}, mesh = {Humans ; *Exosomes/metabolism ; *Neurodegenerative Diseases/drug therapy/therapy ; Animals ; *Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism ; Bioengineering/methods ; Translational Research, Biomedical ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS), are characterized by progressive neuronal dysfunction and limited therapeutic options, largely due to the restrictive nature of the blood-brain barrier (BBB). Exosomes, naturally occurring extracellular vesicles (EVs), have gained attention as innovative drug delivery vehicles owing to their intrinsic ability to cross the BBB, minimal immunogenicity, high biocompatibility, and capability to carry diverse therapeutic cargos such as proteins, nucleic acids, and small molecules. Furthermore, exosomes can be bioengineered to enhance drug-loading efficiency and targeting specificity, positioning them as a versatile and effective platform for treating NDDs. In this review, we summarize recent advances in exosome biogenesis, secretion, and engineering, with an emphasis on innovative strategies for exosome isolation, drug loading, and surface modification. We further explore their roles in modulating neuroinflammation, promoting neural regeneration, and enabling precise therapeutic delivery. Critical challenges associated with large-scale production, quality control, and regulatory compliance under Good Manufacturing Practices (GMP) are also discussed. Collectively, these developments underscore the transformative potential of engineered exosomes in advancing precision therapies for neurodegenerative disorders and offer strategic insights into their clinical translation.}, } @article {pmid41328555, year = {2026}, author = {Maier, A and Koc, Y and Steinfurth, L and Kettemann, D and Norden, J and Riitano, A and Schmitt, P and Kolzarek, F and Subramanian, S and Münch, C and Spittel, S and Meyer, T}, title = {Agreement Between the Harmonized and the Self-Explanatory Versions of the Revised ALS Functional Rating Scale in a Clinical Setting.}, journal = {Muscle & nerve}, volume = {73}, number = {2}, pages = {250-259}, pmid = {41328555}, issn = {1097-4598}, support = {//Boris Canessa ALS Stiftung/ ; H4017703513237604//Martin Herrenknecht Fonds for ALS Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Female ; Male ; Middle Aged ; Aged ; Prospective Studies ; *Severity of Illness Index ; Adult ; Reproducibility of Results ; }, abstract = {INTRODUCTION/AIMS: The harmonized version of the ALS Functional Rating Scale - Revised (ALSFRS-R) is typically administered according to standard operating procedures (SOPs) to ensure procedural consistency. In contrast, obtaining the self-explanatory (SE) version of the ALSFRS-R does not include the use of SOPs. The aim of this study was to examine the level of agreement between the harmonized and the SE version of the ALSFRS-R in a cohort of ALS patients.

METHODS: In a prospective study, the harmonized ALSFRS-R was assessed in 107 ALS patients. In parallel, all patients independently completed the ALSFRS-R-SE, either on a printed form (n = 36) or remotely via the ALS App (n = 71). Agreement between methods was investigated using Spearman's correlation, Lin's concordance correlation coefficient (CCC), Deming regression, Bland-Altman plots and item-level statistics including Kendall's tau-b and the Stuart-Maxwell test.

RESULTS: Total scores from ALSFRS-R and ALSFRS-R-SE showed high correlation (ρ = 0.91-0.95) and concordance (CCC > 0.9). Deming regression (intercept≈0; slope≈1) and Bland-Altman analysis (95% of values within limits of agreement [LoA]) revealed no systematic bias. Item-level agreement was high (76.6% on average), with some variability in items such as handwriting, walking, and dyspnea. ALS progression rates were consistent (differences ≤ 0.02). ALSFRS-R-SE remained robust across remote digital and paper-based assessments.

DISCUSSION: The strong agreement between the harmonized and self-explanatory versions of the ALSFRS-R supports their interchangeable use. The SE format may facilitate remote digital assessment and reduce complexity of ALSFRS-R assessment in research and clinical practice. Further studies are warranted to validate the ALSFRS-R-SE across larger cohorts, multiple languages, and diverse rater groups.}, } @article {pmid41328916, year = {2025}, author = {Ahsan, A and Kar, O and Akter, K and Ta, HDK and Shen, CJ and Datta, K and Chatterjee, B and Huang, CC and Majumder, P}, title = {Regulatory Functions of TDP-43 and FMRP in Non-Neuronal Diseases: Are Co-Targeted mRNAs the Keys?.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {39}, number = {23}, pages = {e71292}, doi = {10.1096/fj.202502281R}, pmid = {41328916}, issn = {1530-6860}, support = {110-2320-B-038-090-MY3//National Science and Technology Council (NSTC)/ ; }, mesh = {Humans ; *Fragile X Messenger Ribonucleoprotein 1/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *RNA, Messenger/genetics/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Fragile X Syndrome/genetics/metabolism ; }, abstract = {RNA binding proteins (RBPs) act as the central nodal point in shaping the cellular transcriptome through their involvement in various aspects of RNA metabolism including stability, splicing, polyadenylation, modifications, translation and transport. Dysregulation in the function of various RBPs can be associated with different human pathophysiological conditions. Owing to their ability to regulate various RNA metabolism-associated processes, the same RBPs can functionally be involved in human pathologies with distinct underlying pathophysiological mechanisms. Two such important RBPs, namely TDP-43 and FMRP, have long been implicated respectively, in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) etc. and in neurodevelopmental diseases like fragile-X syndrome (FXS). However, numerous recent reports indicate that these ubiquitously expressed proteins can regulate important cellular functions and signaling cascades, misregulation which results in different disease phenotypes. In this review, the association of TDP-43 and FMRP with different non-neuronal disease mechanisms has been discussed. Furthermore, to anticipate yet-to-be-explored non-neuronal disease mechanisms involving mismanagement in co-regulation of spatial and temporal transport/translation processes of TDP-43 and FMRP targeted RNAs, as observed in neuronal diseases for example, autism, RNA target databases of these two proteins are compared followed by GO and KEGG analysis. The lists of RNAs co-targeted by TDP-43 and FMRP are presumably involved in different non-neuronal diseases and disease-associated mechanistic pathways and will open up new phases of research to establish new disease mechanism(s). Different disease mechanisms and their interconnections expectantly will also lead to the discovery of new drug targets.}, } @article {pmid41329282, year = {2025}, author = {Grigoryev, PN and Zefirov, AL and Mukhamedzyanov, RD and Salafutdinov, II and Islamov, RR and Mukhamedyarov, MA}, title = {Synaptic Vesicle Exocytosis and Endocytosis in Motor Nerve Endings of Transgenic Mice Modeling Amyotrophic Lateral Sclerosis upon Antioxidant Treatment and Gene-Cell Therapy.}, journal = {Doklady biological sciences : proceedings of the Academy of Sciences of the USSR, Biological sciences sections}, volume = {525}, number = {1}, pages = {354-358}, pmid = {41329282}, issn = {1608-3105}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/metabolism/genetics/pathology ; *Exocytosis/drug effects ; *Endocytosis/drug effects ; Mice, Transgenic ; *Motor Neurons/metabolism/drug effects ; Mice ; *Synaptic Vesicles/metabolism/drug effects ; *Antioxidants/pharmacology ; Disease Models, Animal ; *Genetic Therapy ; Humans ; }, abstract = {Exocytosis and endocytosis of synaptic vesicles were studied in experiments with motor nerve endings of diaphragm neuromuscular preparations isolated from transgenic mice with a model of amyotrophic lateral sclerosis (ALS); treatment simulated antioxidant (edaravone) and gene-cell (umbilical cord blood mononuclear cells (UCB-MNCs) producing VEGF, GDNF, and NCAM) therapies. None of the treatments was found to significantly change the FM 1-43 fluorescent dye loading due to synaptic vesicle endocytosis. Gene-cell therapy increased the rate of dye unloading due to synaptic vesicle exocytosis, while antioxidant therapy did not change the FM 1-43 unloading rate. Based on the findings, gene-cell therapy was assumed to facilitate synaptic vesicle transport to release sites upon high-frequency stimulation in motor nerve endings of transgenic mice.}, } @article {pmid41329328, year = {2026}, author = {Robinson, AE and Knack, SKS and Driver, BE and Prekker, ME and Perlmutter, MC and Bunting, AJ and Simpson, NS and Braude, DA and Crowe, RP and Puskarich, MA}, title = {Trends in Prehospital First-Attempt Use of Supraglottic Airways in Non-Cardiac Arrest Patients: A Descriptive Study.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/10903127.2025.2593579}, pmid = {41329328}, issn = {1545-0066}, abstract = {OBJECTIVES: This study aims to characterize the national prehospital trends in primary supraglottic airway use in non-cardiac arrest patients with various methods, including rapid sequence airway (RSA), defined as administration of a sedative and paralytic to facilitate supraglottic airway (SGA) placement. We compared this SGA-first practice to other methods of prehospital airway management.

METHODS: This was a retrospective analysis of a national emergency medical services (EMS) database containing 9-1-1 calls over a five-year period. Only ALS-level calls were included. We compared the incidence of SGA- and tracheal-intubation-first attempts by paramedics. We excluded interfacility transfers, patients in or near cardiac arrest, and surgical airways before intubation.

RESULTS: There were 355,511 encounters with endotracheal tube (ETT) or SGA placement, of which 316,392 patients were excluded, most commonly for cardiac arrest and peri-cardiac arrest, leaving 36,058 (92%) managed with tracheal intubation first and 3,061 (8%) managed with a SGA first. Trauma was the primary reason for encounter for approximately 28% of both groups. SGA-first approaches increased over the five-year period from 3.5% to 8.7% of invasive airway attempts. The type of SGA changed substantially over the study period, with use of the iGel increasing (42% to 82%), and the King LTSD decreasing (50% to 14%). Neuromuscular blocking agents were used in 74% of encounters.

CONCLUSIONS: Among prehospital patients not in cardiac arrest, supraglottic airway devices comprise 8% of initial advanced airway management, with increasing use over time. Placement is usually facilitated by use of a sedative and neuromuscular blocking agent.}, } @article {pmid41330444, year = {2026}, author = {Rosso, F and Magdalena, R and Torazza, C and Bacchetti, F and Milanese, M and Poletti, A and Bonanno, G and Cristofani, R and Bonifacino, T}, title = {Non-cell autonomous autophagy in amyotrophic lateral sclerosis: A new promising target?.}, journal = {Neurobiology of disease}, volume = {218}, number = {}, pages = {107203}, pmid = {41330444}, issn = {1095-953X}, support = {R21 AR080407/AR/NIAMS NIH HHS/United States ; //National Recovery and Resilience Plan/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Autophagy/physiology ; Humans ; Animals ; Microglia/metabolism ; Astrocytes/metabolism/pathology ; Motor Neurons/pathology/metabolism ; Neuroglia/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative non-cell-autonomous disease with no cure, thus research is intensely focused on identifying pharmacological targets. Several studies aimed to clarify the pathogenic mechanisms and involvement in various cell types. A crucial factor in ALS is autophagy, which plays a key role in degrading intracellular protein aggregates. The connection between ALS and autophagy is reinforced by the fact that several genes mutated in ALS are linked to fundamental aspects of autophagy. The blockage of the autophagic flux was observed in ALS motor neurons, where it occurs earlier than in glia. However, the inconsistent effects of autophagy modulators in preclinical and clinical studies indicate the need for a deeper understanding of the role of autophagy in other cell types, such as astrocytes, microglia, and oligodendrocytes. Astrocytes and microglia are significantly impacted by autophagy dysregulation, contributing to neurodegeneration in both mouse and human-derived models. Autophagy is overactivated early in the disease, even before symptoms appear. This overactivation is influenced by the timing and specific tissue involved. It can alter cells' immunophenotype, favouring proinflammatory responses and affecting the cellular environment and autophagy in the surrounding cells. In contrast, oligodendrocytes show mild autophagic alterations. Additionally, sex hormones may affect proper autophagy function and ALS progression. The lack of information on how sex influences autophagy in glia highlights the need for more nuanced investigation into this mechanism. Future research should focus on these aspects, paving the way for personalised pharmacological approaches that consider the roles of cell types, time of intervention, and sex.}, } @article {pmid41331940, year = {2025}, author = {Hogan, AL and Kane, M and Chiu, P and Richter, G and Maurel, C and Wu, S and Scherer, NM and Don, EK and Lee, A and Blair, IP and Chung, RS and Morsch, M}, title = {Human TDP-43 overexpression in zebrafish motor neurons triggers MND-like phenotypes through gain-of-function mechanism.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {41331940}, issn = {2051-5960}, support = {Ideas Grant 2029547//National Health and Medical Research Council/ ; 20200003//The ALS Foundation, Netherlands/ ; DIS-202403-01218//FightMND/ ; R21 DA056320/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Zebrafish ; *DNA-Binding Proteins/genetics/metabolism ; *Motor Neurons/metabolism/pathology/drug effects ; Animals, Genetically Modified ; Humans ; Disease Models, Animal ; Phenotype ; Zebrafish Proteins/genetics/metabolism ; *Motor Neuron Disease/pathology/genetics/metabolism/drug therapy ; Riluzole/pharmacology ; Mutation ; Neuromuscular Junction/pathology ; }, abstract = {Dysregulation of the TAR DNA-binding protein 43 (TDP-43), including intraneuronal cytoplasmic mislocalisation and aggregation is a feature of multiple neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD), limbic-predominant age-related TDP-43 encephalopathy (LATE) and alzheimer’s disease (AD). Unravelling the causes and functional consequences of TDP-43 dysregulation is paramount to understanding disease mechanisms as well as identifying effective therapeutic targets. Here we present a comprehensive in vivo characterisation of three stable transgenic zebrafish models that express human TDP-43 variants in motor neurons. We demonstrate that overexpression of predominantly nuclear wildtype TDP-43, cytoplasm-targeted TDP-43, and an ALS-linked variant (G294V) each induce toxic gain-of-function effects, leading to impaired motor function, motor neuron loss, and muscle atrophy. Importantly, these models reveal distinct phenotypes, with the ALS-linked mutant exhibiting axonal transport deficits and neuromuscular junction disruption, while cytoplasmic mislocalised TDP-43 heightened susceptibility to oxidative stress. Two FDA-approved drugs used to treat ALS, edaravone and riluzole, were examined in these models and revealed that edaravone, but not riluzole, was effective in rescuing motor deficits associated with cytoplasmic TDP-43 expression and, to a lesser extent, ALS-linked mutant TDP-43. Collectively, these findings reveal distinct pathological consequences of TDP-43 dysregulation, providing neuron-centric mechanistic insights, and establish the humanised TDP-43 zebrafish as an efficient system for preclinical therapeutic testing.}, } @article {pmid41332529, year = {2025}, author = {Sun, X and Hudson, HR and Orr, TC and Koutarapu, S and Rosenbloom, A and Ingalls, M and Braubach, O and Keene, CD and Beechem, JM and Orr, ME}, title = {Spatial Multi-Omics Workflow and Analytical Guidelines for Alzheimer's Neuropathology.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41332529}, issn = {2692-8205}, support = {R56 NS131387/NS/NINDS NIH HHS/United States ; R25 AG073119/AG/NIA NIH HHS/United States ; R21 AG087907/AG/NIA NIH HHS/United States ; U54 AG079754/AG/NIA NIH HHS/United States ; R01 AG079224/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; R01 AG085182/AG/NIA NIH HHS/United States ; R01 AG068293/AG/NIA NIH HHS/United States ; I01 BX005717/BX/BLRD VA/United States ; }, abstract = {Spatial biology technologies enable high-dimensional profiling within intact tissues, revealing how molecular and cellular organization drives function and disease. As these platforms gain broader adoption, standardized analytical frameworks are needed to ensure data quality and reproducibility. Here, we present an end-to-end pipeline for the GeoMx Digital Spatial Profiler that simultaneously generates whole-transcriptome and 637-protein measurements from user-defined regions within the same tissue sections. The workflow integrates morphology-guided region selection, quality control, normalization, and multi-modal data interpretation. Applied to formalin-fixed cortical tissues from Alzheimer's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, and controls, the framework resolves spatially distinct molecular domains. Transcript and protein signals diverge across amyloid plaque cores and surrounding glial-rich regions, with RNA-protein concordance varying by disease condition, while single-neuron profiling with and without pathogenic tau deposition illustrates protein assay sensitivity. This dataset provides a rigorously validated resource for spatial multi-omic analyses and establishes broadly applicable guidelines for reliable, reproducible profiling of complex tissues.}, } @article {pmid41332610, year = {2025}, author = {Brown, AL and Zanovello, M and Mikheenko, A and Dattilo, D and Pellegrini, F and Bryce-Smith, S and Mattedi, F and Mehta, PR and Vargas, JNS and , and Humphrey, J and Keuss, MJ and Fratta, P}, title = {Sensitivity to TDP-43 loss and degradation resistance determine cryptic exon biomarker potential.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41332610}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, abstract = {Cryptic splicing caused by TDP-43 proteinopathy is a hallmark of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, which cryptic splicing events (CEs) are the most sensitive to TDP-43 depletion, where CEs localise within cells, and how specific CEs are in human tissues is poorly defined. Analyses of in vitro TDP-43 knockdowns and postmortem RNA-seq datasets revealed that a small subset out of thousands of CEs are specific markers for TDP-43 proteinopathy in vivo. Nonsense-mediated decay (NMD) masked a portion of CEs, influencing their subcellular localization and detectability in tissue. Dose-dependent TDP-43 depletion identified "early-responsive" CEs, which possess stronger splice sites and denser, more canonical TDP 43 binding motifs. Finally, we developed a composite cryptic burden score that effectively captured TDP-43 pathology across heterogeneous tissues and correlated with regional vulnerability and genetic background. Our work identifies robust biomarkers and offers new insights into TDP-43-mediated splicing dysregulation in neurodegeneration.}, } @article {pmid41332773, year = {2025}, author = {Chlebowski, AC and Yang, Y and Siddique, NA and Siddique, T and Spencer, PS and Steele, JC and Kisby, GE}, title = {Development of Patient-Derived Neuroprogenitor Cells (hNPCs), Neurons and Astrocytes to Explore the Etiology of Guam Parkinsonism-Dementia Complex (PDC).}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41332773}, issn = {2692-8205}, support = {R41 ES026225/ES/NIEHS NIH HHS/United States ; }, abstract = {Parkinsonism-Dementia Complex (PDC) is one phenotype of a disappearing neurodegenerative disease (Guam ALS-PDC) that shows clinical and neuropathological relationships with amyotrophic lateral sclerosis (ALS), atypical parkinsonism and Alzheimer's disease. ALS-PDC has been linked with exposure to environmental factors (notably cycad plant neurotoxins), but evidence from human and animal studies is inconclusive. Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful in vitro system to explore the underlying cause of PDC. iPSC lines were derived from lymphocytes of a PDC-affected Guamanian Chamorro female patient and an age- and gender-matched healthy Chamorro resident of PDC-unaffected Saipan using non-integrating episomal plasmids. iPSCs derived from both patients expressed pluripotency markers (Oct4, SSEA-4, TRA-1-60, Sox2) prior to the generation of neuroprogenitor cells (hNPCs), neurons and astrocytes. An embryoid body protocol was used to derive hNPCs from both iPSC lines while a differentiation media was used to generate neurons from hNPCs. hNPCs derived from both iPSC patients' lines displayed established neuroprogenitor markers (nestin, Sox2), while the differentiated hNPCs exhibited both neuronal (beta-tubulin III, Map2, doublecortin) and synaptic (synaptophysin, PSD-95) markers. Expression of these protein markers in hNPCs and neurons by dot blotting was also observed for both lines. Astrocyte progenitor cells and mature astrocytes with appropriate markers were also developed from the hNPCs of both lines using commercial kits. Development of these patient-derived iPSCs provides a human model for evaluating the role of environmental (e.g., cycad toxins) and genetic factors in ALS-PDC and possibly other related neurodegenerative diseases.}, } @article {pmid41332782, year = {2025}, author = {Sidibe, DK and Smith, EM and Spivey, ML and Vogel, MC and Maday, S}, title = {Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.11.17.688722}, pmid = {41332782}, issn = {2692-8205}, abstract = {Sequestosome 1/p62 (hereafter referred to as p62) is a multifunctional protein that orchestrates various cellular stress response pathways including autophagy, proteasome-mediated degradation, antioxidant defense, nutrient sensing, and inflammatory signaling. Mutations in distinct functional domains of p62 are linked with the neurodegenerative disease amyotrophic lateral sclerosis (ALS), underscoring its importance in neural cells. Neurons and astrocytes perform distinct roles in brain physiology and thus encounter a unique landscape of cellular stress. However, how p62 is regulated in these cell types in response to various stress modalities remains largely unexplored. Several functions for p62 depend on engagement with ubiquitinated substrates. Thus, we investigated how the regulation of p62-ubiquitin conjugates differs between neurons and astrocytes exposed to two stress modalities: lysosomal membrane damage and metabolic stress. Lysosomal damage triggered ubiquitin-dependent assembly of p62 puncta in both neurons and astrocytes. In contrast, nutrient deprivation elicited different responses between neurons and astrocytes. Neurons formed p62-ubiquitin structures more prominently and displayed a greater dependence on ubiquitin for p62 clustering. Together, these findings reveal cell-type-specific and stress-specific regulation of p62-ubiquitin conjugates, indicating that neurons and astrocytes can deploy distinct quality control strategies.}, } @article {pmid41333389, year = {2025}, author = {Kabra, K and Dressman, D and Talcoff, R and Yidenk, M and Rifai, OM and Hoover, BN and Shneider, NA and Elyaman, W and Area-Gomez, E and Bradshaw, EM}, title = {Loss of Nuclear TDP-43 Impairs Lipid Metabolism in Microglia-Like Cells.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41333389}, issn = {2693-5015}, support = {R01 AG076018/AG/NIA NIH HHS/United States ; R21 AG073882/AG/NIA NIH HHS/United States ; RF1 AG058852/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive motor neuron loss, with TDP-43 pathology present in over 90% of cases. While neuroinflammation is a recognized hallmark, the role of microglia in ALS pathogenesis remains incompletely understood. Here, we demonstrate that TDP-43 regulates microglial function via triglyceride metabolism. Using shRNA-mediated TARDBP knockdown in human monocyte-derived microglia-like cells (MDMi), we observed suppressed cholesterol biosynthesis, upregulated fatty acid uptake, lipid droplet accumulation, enhanced phagocytic activity, and increased IL-1β production. Inhibiting diacylglycerol acyltransferase (DGAT) enzymes reduced lipid droplet formation, phagocytosis, and IL-1β, directly linking the triglyceride pathway to microglial activation. Patient-derived MDMi from both sporadic and TARDBP-mutant ALS cases showed overlapping as well as distinct alterations, some of which were reversed by DGAT inhibition. Our findings identify dysregulated triglyceride metabolism as a novel pathway through which TDP-43 mediates microglial dysfunction, highlighting a potential therapeutic target for ALS.}, } @article {pmid41334667, year = {2026}, author = {Kalita, M and Jędrzejowska, M and Potulska-Chromik, A and Aragon-Gawińska, K and Franaszczyk, M and Stokłosa, T and Lipowska, M and Kostera-Pruszczyk, A}, title = {SIGMAR1 gene-related neuromuscular disorders - what do we know?.}, journal = {Neurologia i neurochirurgia polska}, volume = {60}, number = {1}, pages = {92-99}, doi = {10.5603/pjnns.106304}, pmid = {41334667}, issn = {0028-3843}, mesh = {Humans ; Sigma-1 Receptor ; *Receptors, sigma/genetics ; Child ; Male ; *Hereditary Sensory and Motor Neuropathy/genetics/diagnosis ; Mutation ; }, abstract = {INTRODUCTION: Distal hereditary motor neuropathies (dHMNs) are a clinically and genetically diverse group of rare neuromuscular disorders characterized by progressive distal muscle weakness and atrophy, often with early onset and sparing of sensory function. One subtype, Jerash-type dHMN (dHMNJ), is caused by biallelic mutations in the SIGMAR1 gene and presents with pyramidal signs in addition to distal weakness.

MATERIAL AND METHODS: A literature review was conducted by searches of the MEDLINE and PubMed databases using selected terms. Relevant original articles, case reports, case series, and reviews were selected as data sources.

DISCUSSION: SIGMAR1-related disorders (SIGMAR1-RD) encompass a broad clinical spectrum including dHMN and juvenile amyotrophic lateral sclerosis (ALS) phenotypes. The Sigma-1 receptor plays a key role in cellular stress responses, ER-mitochondria interaction, and neuronal survival. Clinical presentation often includes distal muscle weakness and atrophy with pyramidal signs.

We present a 12-year-old boy with distal muscle weakness, foot drop, and pyramidal signs. Genetic testing identified a homozygous c.247T > C (p.Phe83Leu) SIGMAR1 variant, previously classified as a variant of uncertain significance (VUS).

CONCLUSION: This article supports the pathogenicity of the c.247T > C (p.Phe83Leu) SIGMAR1 variant and underlines the need for broader genetic testing in hereditary motor neuropathies.}, } @article {pmid41334676, year = {2026}, author = {Nakajima, M and Naruse, H and Riku, Y and Ueda, K and Matsukawa, T and Mitsui, J and Nakamura, Y and Ishida, S and Yamada, T and Moro, N and Kotsuki, N and Nagai, K and Tokushige, SI and Uchibori, A and Oishi, C and Yabata, H and Urushitani, M and Iwasaki, Y and Ishiura, H and Toda, T and Tsuji, S and Ichikawa, Y}, title = {Novel in-frame duplication variant of SOD1 in a Japanese family with familial amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {352-362}, doi = {10.1080/21678421.2025.2593302}, pmid = {41334676}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Superoxide Dismutase-1/genetics ; Female ; Male ; Middle Aged ; Pedigree ; Adult ; Japan ; Aged ; Mutation/genetics ; *Gene Duplication/genetics ; Spinal Cord/pathology ; East Asian People ; }, abstract = {OBJECTIVES: To analyze the cases of a family with a novel in-frame duplication variant (NM_000454.5:c.357_357 + 2dup, p.Val120dup) of SOD1 and a structural model of the mutated SOD1 protein.

METHODS: The clinical profiles of three patients in the family were analyzed, including the neuropathological findings of the proband's mother. Genetic analyses were conducted for three patients. cDNA and in silico structural analyses were performed to evaluate the effects of duplication variants on the structure of SOD1.

RESULTS: The clinical features of the patients included predominant involvement of the lower motor neurons, asymmetric onset of motor symptoms in the lower limbs, and a relatively rapid progression of muscular weakness and respiratory insufficiency. Neuropathological findings revealed severe loss of spinal cord motor neurons, and immunohistochemistry using an anti-misfolded SOD1 antibody revealed aggregates in the spinal cord. Genetic analyses revealed a c.357_357 + 2dup at the exon 4-intron 4 boundary of SOD1 in three patients. cDNA analysis of the proband suggested the presence of a valine (p.Val120dup) duplication in the heterozygous state, and the SOD1 transcript level showed no significant differences from those of healthy controls. In silico structural analyses predicted that p.Val120dup could affect the structure of the β-barrels and copper ion binding site of SOD1, suggesting an abnormal conformation of SOD1 that is predicted to interfere with the binding of copper ions.

CONCLUSION: We identified a novel in-frame duplication variant in the C-terminus of β7 of SOD1. This genotype-structure-phenotype study of SOD1 provides valuable insights into disease-causing mechanisms.}, } @article {pmid41335671, year = {2025}, author = {Petrikic, D and Dos Santos, RFF and Sipoli, GV and Santos, KMM and Nogueira Neto, GN and Nohama, P}, title = {Robotic Arm: Assistive Technology for Independent Feeding.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-5}, doi = {10.1109/EMBC58623.2025.11253161}, pmid = {41335671}, issn = {2694-0604}, mesh = {*Robotics/instrumentation ; Humans ; *Self-Help Devices ; Equipment Design ; }, abstract = {Disabilities, such as those caused by spinal cord injury, stroke, cerebral palsy, amyotrophic lateral sclerosis and amputations, can impair upper limb function and limit eating autonomy, requiring third-party assistance. Thus, assistive technologies have emerged as viable alternatives for promoting greater independence and social inclusion. This article presents the development of an educational robotic arm with 5 degrees of freedom for use as a meal-assist robot. A 3D printer was used for the utensils and wood for the base. To receive user commands, a voice recognition module was implemented to identify the five programmed commands. To verify the effectiveness of the proposed method, several tests were conducted, including a water transfer test and execution time measurement. The assistive device successfully transported more than 75% of the water and completed each feeding cycle in 21 s, demonstrating its effectiveness in aiding the feeding process.}, } @article {pmid41335863, year = {2025}, author = {Li, M and Yao, Y and Dong, B and Wang, K and Yu, H and Xu, M and Ming, D}, title = {A Novel Approach to Improve SSVEP-BCI Performance Through Neurofeedback Training.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-6}, doi = {10.1109/EMBC58623.2025.11254803}, pmid = {41335863}, issn = {2694-0604}, mesh = {Humans ; *Brain-Computer Interfaces ; *Neurofeedback/methods ; *Evoked Potentials, Visual/physiology ; Male ; Adult ; Electroencephalography ; Female ; }, abstract = {Brain-Computer interface (BCI), which translates neural activities into commands for external devices, holds significant promise for clinical rehabilitation and assisted movement for individuals with motor disabilities. Among various BCI paradigms, the steady-state visual evoked potential (SSVEP) based BCI garnered considerable attention due to its relatively stable and high-speed communication capabilities. However, a notable portion of the population, referred to as BCI illiteracy, struggles to effectively control BCI systems due to their inability to generate or modulate the neural patterns required for interaction. To address this issue, we proposed a user-centered approach using neurofeedback training (NFT) to improve individual's performance on SSVEP-BCI. As a result, after a five-day training period, significant improvements in SSVEP-BCI performance were only observed in the training group rather than the control group without training. Notably, some subjects initially determined as BCI-illiterate also gained effective control of the BCI system after training. Further analysis revealed that the improvement of SSVEP-BCI performance had a close link with increased power and inter-trial phase coherence of the SSVEP response, indicating that NFT successfully strengthened the user's task-related neural responses. These findings highlight the potential of NFT as a user-centered intervention to improve BCI control performance, offering a promising pathway to address BCI illiteracy and promote the broader application of BCI systems.Clinical Relevance- This study proposes an effective approach to enhancing the controllability of SSVEP-BCI systems, addressing the critical issue of individual control limitations. The developed method demonstrates significant clinical potential for promoting SSVEP-BCI applications, particularly in facilitating communication and device control for patients with severe motor impairments, such as amyotrophic lateral sclerosis (ALS) and locked-in syndrome (LIS).}, } @article {pmid41336280, year = {2025}, author = {Hong, J and Rao, P and Wang, W and Chen, S and Najafizadeh, L}, title = {ChatBCI-4-ALS: A High-Performance, LLM-Driven, Intent-Based BCI Communication System for Individuals with ALS.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-6}, doi = {10.1109/EMBC58623.2025.11253329}, pmid = {41336280}, issn = {2694-0604}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; *Brain-Computer Interfaces ; Algorithms ; *Communication Devices for People with Disabilities ; Electroencephalography ; Event-Related Potentials, P300 ; Language ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that leads to significant motor and speech impairments, increasing the need for alternative means of communication to support quality of life. P300 speller brain computer interfaces (BCIs) have shown promise in facilitating non-muscular communication by detecting P300 event-related potentials (ERPs) in response to visual stimuli. However, these systems are generally slow and can not fully address the communication needs of ALS patients, specially, when the primary goal is to convey intent with minimal cognitive load. In this paper, we present ChatBCI-4-ALS, the first intent-based BCI communication system designed for individuals with ALS. ChatBCI-4-ALS leverages large language models (LLMs) and employs a dynamic flash algorithm to enhance typing speed, and enable efficient communication of the user's intent beyond exact lexical matches. Additionally, we introduce new semantic-based quantitative performance metrics to evaluate the effectiveness of intent-based communication. Results from online experiments suggest that ChatBCI-4-ALS achieves record-breaking average spelling speed of 23.87 char/min (with the best case scenario of 42.16 char/min), and a best information transfer rate (ITR) of 128.85 bits/min, marking an advancement in P300 BCI-based communication systems.}, } @article {pmid41336457, year = {2025}, author = {Khan, JS and Mohammadi, M and Ammitzboll, AL and Hagen, EM and Blicher, J and Obal, I and Cardoso, ASS and Kirtas, O and Kaseler, RL and Rasmussen, J and Struijk, LNSA}, title = {Wrist Range of Motion Variability for Adaptive Exoskeleton Design: A Study on users with and without SCI or ALS.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-6}, doi = {10.1109/EMBC58623.2025.11251763}, pmid = {41336457}, issn = {2694-0604}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Exoskeleton Device ; *Range of Motion, Articular ; *Spinal Cord Injuries/physiopathology/rehabilitation ; Male ; Middle Aged ; *Wrist/physiopathology ; Female ; Equipment Design ; Adult ; }, abstract = {Wrist exoskeletons hold promise for assisting individuals with motor impairments such as spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS). However, existing designs often lack adjustability and adaptability to the individual wrist range of motion (ROM), which is crucial for safety and usability. This study presents a literature review of the wrist abduction/adduction ROM measurements in individuals without motor disability and individuals with motor impairments and highlights on the measurement details and findings. This study also investigates wrist abduction/adduction ROM in three user groups: fifteen individuals without any motor disability, two individuals with ALS, and five with SCI. The experimental procedure included the completion of three trials, where ROM was measured and analyzed to determine intergroup variability. Individuals without motor disability exhibited the largest ROM range, while SCI users had reduced adduction. Our findings highlight the need for user-specific ROM considerations in exoskeleton design to optimize functionality and prevent discomfort or injury. This study contributes to the development of adjustable and user-centered wrist exoskeletons, addressing safety and usability gaps in the current state of the art.Clinical Relevance- The observed ROM differences between users with and without disabilities underscore the importance of tailoring exoskeletons to specific user needs, emphasizing the role of variability as a critical factor in rehabilitation.}, } @article {pmid41336481, year = {2025}, author = {Sid'El Moctar, SM and Nasrallah, C and Rida, I and Boudaoud, S}, title = {iEMG-Based Diagnosis of ALS and Myopathy using 1D-CNN.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-5}, doi = {10.1109/EMBC58623.2025.11251693}, pmid = {41336481}, issn = {2694-0604}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; *Electromyography/methods ; *Neural Networks, Computer ; *Muscular Diseases/diagnosis/physiopathology ; Algorithms ; Signal Processing, Computer-Assisted ; Sensitivity and Specificity ; *Diagnosis, Computer-Assisted/methods ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) and myopathy are debilitating neuromuscular disorders that require accurate and timely diagnosis for effective management. Traditional electromyography (EMG)-based diagnostic methods rely on manual interpretation, which is time-consuming and prone to variability. This study proposes an approach that directly classifies EMG signals using a one-dimensional convolutional neural network (1D-CNN) without feature extraction, addressing the limitations of existing methods that depend on handcrafted features and focus primarily on binary classification. The proposed model is evaluated on a publicly available EMG dataset, achieving an overall accuracy of 99.27%, with macro and weighted precision, recall, and F1-scores exceeding 99% across ALS, myopathy, and healthy subjects. Unlike previous approaches that require extensive preprocessing, our method maintains high classification performance while reducing computational complexity, offering a clinically relevant multiclass classification framework. Although our method achieves high classification performance, it also maintains a strong balance between sensitivity and specificity, ensuring reliable and accurate neuromuscular disorder diagnosis, making it a practical tool for clinical applications. Future research will focus on improving model generalizability, expanding dataset diversity, and integrating real-time deployment for enhanced diagnostic utility.}, } @article {pmid41336792, year = {2025}, author = {Santos Cardoso, AS and Kaseler, RL and Ammitzboll, AL and Hagen, EM and Blicher, J and Obal, I and Kirtas, O and Khan, JS and Mohammadi, M and Jochumsen, M and Andreasen Struijk, LNS}, title = {Mastering Tongue-Computer Interfaces: A Pilot Study on How Users Improve With Practice.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-6}, doi = {10.1109/EMBC58623.2025.11251588}, pmid = {41336792}, issn = {2694-0604}, mesh = {Humans ; *Tongue/physiology ; Male ; Pilot Projects ; Adult ; *User-Computer Interface ; Middle Aged ; Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation ; Spinal Cord Injuries/physiopathology/rehabilitation ; Female ; }, abstract = {Tongue-operated input devices allow people with motor disabilities to interact with technology and their environment. Many such devices use barbell piercings to track the position of the tongue. Recent developments in tongue-computer interfacing have led to the proposal of a frame-integrated tracer that is not attached to the user's tongue. This study sought to investigate how an individuals ability to use their tongue to manipulate an integrated tracer evolves through use. Five people without motor disabilities and seven people with motor disabilities used a non-invasive inductive tongue-computer interface over six and three sessions, respectively. Among the individuals with motor disabilities were five people with spinal cord injury (SCI) and two men with amyotrophic lateral sclerosis (ALS). Their performance was evaluated at the start of each session using an intraoral target selection task. The participants with no motor disabilities showed a 26% improvement in median target selection time and a 15% improvement in median success rate. The median success rate for subjects with SCI improved by 40%, but the median target selection time stayed constant. Meanwhile, one participant with ALS increased his speed, while the other saw no substantial improvement. Furthermore, compared to the participants without disabilities, the participants with motor disabilities had a higher tendency to select the wrong target. Our findings provide further evidence that repeated use of a tongue-operated input device increases intraoral target selection speed and accuracy. Participants with motor disabilities may require longer dwell times to avoid unintentionally selecting targets when they move the activation unit.}, } @article {pmid41336973, year = {2025}, author = {Buczak, MK and Brignone, J and Cole, KM and Caden Hamrick, W and Bromberg, MB and Zhang, H and George, JA}, title = {Predicting Motor Intent from Residual Neck Muscle Activity in Individuals with Neck Weakness from ALS.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-6}, pmid = {41336973}, issn = {2694-0604}, support = {DP5 OD029571/OD/NIH HHS/United States ; R21 EB035378/EB/NIBIB NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Neck Muscles/physiopathology ; Electromyography ; Male ; Middle Aged ; *Muscle Weakness/physiopathology ; Female ; }, abstract = {The long-term goal of this work is to restore dexterous and intuitive head-neck motion to patients with Amyotrophic Lateral Sclerosis (ALS). ALS is an idiopathic disease characterized by progressive paralysis. Some patients experience neck weakness such that their heads permanently drop to their chests, causing pain and extreme difficulty eating, navigating, and socializing. We previously developed the Utah Neck Exoskeleton, a powered neck brace that supports the head and uses electric motors to move the head in a large range of motion, counteracting head drop. However, the exoskeleton has been controlled either with a joystick or gaze tracking, both of which are difficult to use for parts of the ALS population. Here, we show that the residual neck muscles of ALS patients with neck weakness can be used to determine intended neck position and motion. Electromyographic (EMG) signals were recorded from the neck muscles of two individuals with ALS, low clinical functional scores, and self-reported neck weakness. EMG was then mapped to either steady-state head position or the direction of head motion using convolutional neural networks. Despite the patients having neck weakness and limited range of motion, EMG signals were sufficient to accurately classify both steady-state head position and the direction of head motion (97.1% and 83.12% median accuracy, respectively). As such, this work demonstrates that EMG may serve as a dexterous and intuitive control modality for real-time head-neck movement, and in conjunction with the Utah Neck Exoskeleton, may ultimately improve quality of life for individuals with head drop.Clinical RelevanceResidual neck muscle activity in ALS patients can be recorded via surface EMG and potentially used to reliably predict intended head position and motion.}, } @article {pmid41337107, year = {2025}, author = {Mallol-Ragolta, A and Gonzalez-Machorro, M and von Heynitz, R and Scherzer, K and Cordts, I and Schuller, B}, title = {Detection of Amyotrophic Lateral Sclerosis with Computer Audition: An Impact Analysis of Different Speech Tasks.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-5}, doi = {10.1109/EMBC58623.2025.11254090}, pmid = {41337107}, issn = {2694-0604}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; *Speech ; }, abstract = {We investigate the performance difference between training generic and task-based systems for the automatic detection of patients with Amyotrophic Lateral Sclerosis (ALS) from speech. We exploit the paralinguistic information embedded in their speech while producing the sustained vowel /a:/, repeating the syllables /da/-/da/ and /da/-/ba/ - separately -, reading a text passage, and describing a picture. While the former system consists of a single model, the latter is composed of five task-dedicated models, each one in charge of processing the speech samples corresponding to each task. We also analyse the performance of each task-dedicated model individually. We conduct our experiments on the novel, German-speaking AIMnd dataset. The obtained results - assessed in terms of the Unweighted Average Recall (UAR) - indicate that the task-based systems outperform the generic ones in two out of the four scenarios explored. The generic system only outperforms the task-based system in one scenario. In terms of the task-dedicated models, the SVClinear-based classifier exploiting the extended Geneva Minimalistic Acoustic Parameter Set (eGeMAPS) extracted from the sustained vowel /a:/ production task yields the best performance on the Test set with a UAR of 92%.}, } @article {pmid41337593, year = {2025}, author = {Ji, W and Zhang, Y and Zhang, L and Liu, Q and Niu, S and Feng, Y and Chen, F and Liu, X and Li, X}, title = {VAPB is a negative regulator of STING-mediated innate immune signaling.}, journal = {Science advances}, volume = {11}, number = {49}, pages = {eaea3996}, pmid = {41337593}, issn = {2375-2548}, mesh = {*Membrane Proteins/metabolism/genetics ; *Immunity, Innate ; *Signal Transduction ; Animals ; Humans ; Mice ; *Vesicular Transport Proteins/genetics/metabolism ; Herpesvirus 1, Human/immunology ; Amyotrophic Lateral Sclerosis/genetics ; Interferon Type I/metabolism/genetics ; HEK293 Cells ; Herpes Simplex/immunology/virology/genetics ; Protein Serine-Threonine Kinases/metabolism ; STING Protein ; }, abstract = {Stimulator of IFN genes (STING) is an endoplasmic reticulum (ER) signaling receptor involved in the type I interferon response to pathogen- or self-derived cytosolic double-stranded DNA. Excessive activation of STING is associated with many diseases, but the regulatory mechanism of STING activation remains to be further elucidated. Here, we identify VAPB as a negative regulator of STING-mediated innate immune response. VAPB deficiency increases the expression of type I interferons under resting conditions or upon stimulation. Mechanistically, VAPB associates and translocates with STING, thereby regulating STING translocation, oligomerization, and recruitment of TBK1. In vivo, deficiency of VAPB enhances the expression of type I interferons and prevents lethality following HSV-1 infection. Furthermore, VAPB P56S, a pathogenic mutation causing amyotrophic lateral sclerosis (ALS), can promote STING-mediated innate immune response under resting conditions, which might contribute to further understanding of the relationship between cGAS-STING pathway and ALS. Our study identifies VAPB as a critical regulating factor in cGAS-STING-mediated innate immune responses.}, } @article {pmid41339165, year = {2026}, author = {Wang, Y and Zhang, Q}, title = {Insights and considerations on predicting cognitive and behavioral disturbances in MND with pure motor onset.}, journal = {Journal of the neurological sciences}, volume = {480}, number = {}, pages = {125673}, doi = {10.1016/j.jns.2025.125673}, pmid = {41339165}, issn = {1878-5883}, mesh = {Humans ; *Motor Neuron Disease/complications/psychology/diagnosis ; *Cognition Disorders/etiology/diagnosis ; *Mental Disorders/etiology/diagnosis ; Disease Progression ; Longitudinal Studies ; }, abstract = {This commentary discusses the study by Bicaj et al., which examines baseline predictors of cognitive and behavioral disturbances (C/BI) in motor neuron diseases (MNDs) with pure motor onset. The study's longitudinal design and use of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) provide valuable insights into extramotor progression in MNDs. While the study offers important findings, including potential predictors such as age at onset and specific ECAS scores, it is limited by sample size and potential biases. Suggestions for future research include larger multicenter studies, incorporating biomarkers, and addressing confounding factors to refine risk stratification and clinical management of MND.}, } @article {pmid41339846, year = {2025}, author = {Moriyoshi, H and Akagi, A and Riku, Y and Sone, J and Miyahara, H and Yoshida, M and Katsuno, M and Iwasaki, Y}, title = {Contribution of comorbid pathologies to amyotrophic lateral sclerosis with cognitive or behavioral abnormalities.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {19}, pmid = {41339846}, issn = {1471-2377}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/epidemiology/complications/psychology ; Male ; Female ; Aged ; Comorbidity ; Aged, 80 and over ; Middle Aged ; *Cognition Disorders/epidemiology/pathology ; DNA-Binding Proteins/metabolism ; *Mental Disorders/epidemiology/pathology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) often presents with cognitive or behavioral abnormalities. The cortical involvement of TAR DNA-binding protein-43 (TDP-43) pathology is considered a major cause of these abnormalities. However, the contribution of underlying comorbid pathologies remains unclear.

METHODS: We investigated the clinicopathological characteristics of 29 autopsy cases of ALS with cognitive or behavioral abnormalities and evaluated the association between clinical symptoms and comorbid pathologies such as Alzheimer's disease (AD), argyrophilic grain disease (AGD), dementia with Lewy bodies (DLB), and primary age-related tauopathy (PART), as well as the presence of cortical TDP-43 pathology.

RESULTS: Of the 29 patients, 17 exhibited comorbid pathologies (AD, AGD, or PART), which may contribute to cognitive or behavioral abnormalities. None of the cases met the pathological criteria for DLB. The group with comorbid pathologies was significantly older, but clinical symptoms did not differ between the groups. Behavioral abnormalities and memory impairment were frequently observed in both groups. All six subjects without cortical TDP-43 pathology had comorbid pathologies, which had a notable effect on cognitive or behavioral abnormalities. Hippocampal sclerosis and memory impairment were observed in ALS cases without comorbid pathologies.

CONCLUSION: A high frequency of comorbid pathologies is observed in elderly patients with ALS presenting with cognitive or behavioral abnormalities. There are cases of ALS in which comorbid pathologies such as AD, AGD, and PART may contribute to cognitive or behavioral abnormalities, even in the absence of cortical TDP-43 pathology. Hippocampal sclerosis of ALS may contribute to memory impairment independently of comorbid pathologies.}, } @article {pmid41341060, year = {2025}, author = {Shan, J and Taghavi, A and Caine, EA and Sekioka, R and Rajchin, V and Burke, JM and Watkins, JM and Childs-Disney, JL and Disney, MD}, title = {A Live-Cell NanoBRET Assay to Monitor RNA-Protein Interactions and Their Inhibition by Small Molecules.}, journal = {ACS central science}, volume = {11}, number = {11}, pages = {2154-2171}, pmid = {41341060}, issn = {2374-7943}, abstract = {RNA-protein interactions are critical for cellular processes, including translation, pre-mRNA splicing, post-transcriptional modifications, and RNA stability. Their dysregulation is implicated in diseases such as myotonic dystrophy type 1 (DM1) and amyotrophic lateral sclerosis (ALS). To investigate RNA-protein interactions, here is described a live-cell NanoBioluminescence Resonance Energy Transfer (NanoBRET) assay to study the interaction between expanded r-(CUG) repeats [r-(CUG)[exp]] and muscleblind-like 1 (MBNL1), central to DM1 pathogenesis. This r-(CUG)[exp] sequesters MBNL1, a regulator of alternative pre-mRNA splicing, in nuclear foci causing splicing dysregulation. In the NanoBRET assay, r-(CUG)[exp] acts as a scaffold to bring into proximity a BRET pair, MBNL1-NanoLuciferase (NanoLuc) and MBNL1-HaloTag, enabling a quantitative readout of RNA-protein interactions. Following assay optimization, an RNA-focused small molecule library was screened, identifying ten compounds with shared chemotypes that disrupt the r-(CUG)[exp]-MBNL1 complex. Nuclear magnetic resonance (NMR) studies revealed these inhibitors bind to the 1 × 1 UU internal loops formed when r-(CUG)[exp] folds. Five of these molecules rescued two cellular hallmarks of DM1 in patient-derived myotubes, alternative pre-mRNA splicing defects and formation of nuclear r-(CUG)/MBNL1-positive foci. These results demonstrate that the NanoBRET assay is a powerful tool to study RNA-protein interactions in live cells and to identify small molecules that alleviate RNA-mediated cellular pathology.}, } @article {pmid41341242, year = {2024}, author = {Gutman, B and Shmilovitch, AH and Aran, D and Shelly, S}, title = {Twenty-Five Years of AI in Neurology: The Journey of Predictive Medicine and Biological Breakthroughs.}, journal = {JMIR neurotechnology}, volume = {3}, number = {}, pages = {e59556}, pmid = {41341242}, issn = {2817-092X}, abstract = {Neurological disorders are the leading cause of physical and cognitive disability across the globe, currently affecting up to 15% of the world population, with the burden of chronic neurodegenerative diseases having doubled over the last 2 decades. Two decades ago, neurologists relying solely on clinical signs and basic imaging faced challenges in diagnosis and treatment. Today, the integration of artificial intelligence (AI) and bioinformatic methods is changing this landscape. This paper explores this transformative journey, emphasizing the critical role of AI in neurology, aiming to integrate a multitude of methods and thereby enhance the field of neurology. Over the past 25 years, integrating biomedical data science into medicine, particularly neurology, has fundamentally transformed how we understand, diagnose, and treat neurological diseases. Advances in genomics sequencing, the introduction of new imaging methods, the discovery of novel molecular biomarkers for nervous system function, a comprehensive understanding of immunology and neuroimmunology shaping disease subtypes, and the advent of advanced electrophysiological recording methods, alongside the digitalization of medical records and the rise of AI, all led to an unparalleled surge in data within neurology. In addition, telemedicine and web-based interactive health platforms, accelerated by the COVID-19 pandemic, have become integral to neurology practice. The real-world impact of these advancements is evident, with AI-driven analysis of imaging and genetic data leading to earlier and more accurate diagnoses of conditions such as multiple sclerosis, Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease, and more. Neuroinformatics is the key component connecting all these advances. By harnessing the power of IT and computational methods to efficiently organize, analyze, and interpret vast datasets, we can extract meaningful insights from complex neurological data, contributing to a deeper understanding of the intricate workings of the brain. In this paper, we describe the large-scale datasets that have emerged in neurology over the last 25 years and showcase the major advancements made by integrating these datasets with advanced neuroinformatic approaches for the diagnosis and treatment of neurological disorders. We further discuss challenges in integrating AI into neurology, including ethical considerations in data use, the need for further personalization of treatment, and embracing new emerging technologies like quantum computing. These developments are shaping a future where neurological care is more precise, accessible, and tailored to individual patient needs. We believe further advancements in AI will bridge traditional medical disciplines and cutting-edge technology, navigating the complexities of neurological data and steering medicine toward a future of more precise, accessible, and patient-centric health care.}, } @article {pmid41341425, year = {2025}, author = {Rubaiat, R and Templeton, JM and Schneider, SL and De Silva, U and Madanian, S and Poellabauer, C}, title = {Exploring Speech Biosignatures for Traumatic Brain Injury and Neurodegeneration: Pilot Machine Learning Study.}, journal = {JMIR neurotechnology}, volume = {4}, number = {}, pages = {e64624}, pmid = {41341425}, issn = {2817-092X}, abstract = {BACKGROUND: Speech features are increasingly linked to neurodegenerative and mental health conditions, offering the potential for early detection and differentiation between disorders. As interest in speech analysis grows, distinguishing between conditions becomes critical for reliable diagnosis and assessment.

OBJECTIVE: This pilot study explores speech biosignatures in two distinct neurodegenerative conditions: (1) mild traumatic brain injuries (eg, concussions) and (2) Parkinson disease (PD) as the neurodegenerative condition.

METHODS: The study included speech samples from 235 participants (97 concussed and 94 age-matched healthy controls, 29 PD and 15 healthy controls) for the PaTaKa test and 239 participants (91 concussed and 104 healthy controls, 29 PD and 15 healthy controls) for the Sustained Vowel (/ah/) test. Age-matched healthy controls were used. Young age-matched controls were used for concussion and respective age-matched controls for neurodegenerative participants (15 healthy samples for both tests). Data augmentation with noise was applied to balance small datasets for neurodegenerative and healthy controls. Machine learning models (support vector machine, decision tree, random forest, and Extreme Gradient Boosting) were employed using 37 temporal and spectral speech features. A 5-fold stratified cross-validation was used to evaluate classification performance.

RESULTS: For the PaTaKa test, classifiers performed well, achieving F 1-scores above 0.9 for concussed versus healthy and concussed versus neurodegenerative classifications across all models. Initial tests using the original dataset for neurodegenerative versus healthy classification yielded very poor results, with F 1-scores below 0.2 and accuracy under 30% (eg, below 12 out of 44 correctly classified samples) across all models. This underscored the need for data augmentation, which significantly improved performance to 60%-70% (eg, 26-31 out of 44 samples) accuracy. In contrast, the Sustained Vowel test showed mixed results; F 1-scores remained high (more than 0.85 across all models) for concussed versus neurodegenerative classifications but were significantly lower for concussed versus healthy (0.59-0.62) and neurodegenerative versus healthy (0.33-0.77), depending on the model.

CONCLUSIONS: This study highlights the potential of speech features as biomarkers for neurodegenerative conditions. The PaTaKa test exhibited strong discriminative ability, especially for concussed versus neurodegenerative and concussed versus healthy tasks, whereas challenges remain for neurodegenerative versus healthy classification. These findings emphasize the need for further exploration of speech-based tools for differential diagnosis and early identification in neurodegenerative health.}, } @article {pmid41341510, year = {2025}, author = {Yang, J and Yang, F and Chen, G and Liu, M and Yuan, S and Zhang, TE}, title = {Receptor-mediated mitophagy: a new target of neurodegenerative diseases.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1665315}, pmid = {41341510}, issn = {1664-2295}, abstract = {Neurodegenerative diseases are a category of neurological conditions with high prevalence that pose major treatment challenges. Common pathologies involve protein accumulation and mitochondrial damage. Mitophagy maintains cellular homeostasis by removing defective mitochondria, which are associated with the pathogenesis of neurodegenerative diseases. Although the ubiquitin-dependent mitophagy mediated by the PINK1-Parkin pathway has been extensively studied, growing evidence indicates that receptor-mediated mitophagy plays a crucial compensatory role in neurons, particularly when the PINK1-Parkin pathway is impaired. This review focuses on the emerging field of receptor-mediated mitophagy, systematically elaborating its role as a key homeostatic mechanism operating independently of the canonical PINK1/Parkin pathway. It provides a focused analysis of the specific functions and activation mechanisms of key receptors-including BNIP3, NIX, FUNDC1, and AMBRA1-in models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, this review explores the clinical potential of targeting these specific receptors for precise intervention, aiming to provide a new theoretical foundation and direction for developing therapeutic strategies against neurodegenerative diseases.}, } @article {pmid41341655, year = {2025}, author = {Almalki, S and Salama, M and Taylor, MJ and Ahmed, Z and Tuxworth, RI}, title = {C9orf72-related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1671906}, pmid = {41341655}, issn = {1662-5099}, abstract = {The G4C2 repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While healthy individuals have fewer than 30 repeats, affected patients may carry hundreds to thousands. This expansion accounts for approximately 40% of familial ALS and 25% of familial FTD cases, and between 5 and 10% cases of sporadic ALS and FTD. Three overlapping pathological mechanisms have been proposed for the C9orf72 expansion: loss of function due to protein deficiency, gain of function through RNA foci, and the production of toxic dipeptide repeat proteins (DPRs) via repeat-associated non-ATG (RAN) translation. This systematic review investigates the role of DNA damage in C9orf72-related ALS-FTD. Analysis of twelve peer-reviewed studies showed that C9orf72 repeat expansions and DPRs compromise genome stability across four experimental models: human cell lines, induced pluripotent stem cell-derived neurons, rodent neurons, and postmortem tissue. We identified four mechanisms underlying DNA damage accumulation: disruption of the ATM pathway, impairment of DNA repair efficiency, formation of R-loops, and mitochondrial dysfunction with oxidative stress. In addition, several consequences of DNA damage were identified, including misrepair-mediated repeat expansion and activation of STING pathway. These findings highlight the key role of DNA damage in C9orf72-related pathology. Consistent with this, targeting DNA damage response factors extended lifespan and improved motor function in mouse models. This review highlights the contribution of DNA damage to C9orf72 pathology and suggest new therapeutic avenues, including personalized approaches based on genetic background.}, } @article {pmid41341745, year = {2025}, author = {Finsterer, J}, title = {Are Insulin and Metformin Really Protective on Amyotrophic Lateral Sclerosis by Blocking the Astrocytic Cx43 Channel?.}, journal = {Chronic diseases and translational medicine}, volume = {11}, number = {4}, pages = {318-319}, pmid = {41341745}, issn = {2589-0514}, } @article {pmid41342556, year = {2025}, author = {Braspenning, SE and Ohnezeit, D and DeGulis, OA and Wilson, AC and Mohr, IJ}, title = {TDP-43 promotes efficient HSV-1 replication in human DRG-derived neurons.}, journal = {Journal of virology}, volume = {99}, number = {12}, pages = {e0091525}, pmid = {41342556}, issn = {1098-5514}, support = {R01 AI176335/AI/NIAID NIH HHS/United States ; R01-AI176335, R01-AI170583/NH/NIH HHS/United States ; 452022210//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; R01 AI170583/AI/NIAID NIH HHS/United States ; 554758329//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Herpesvirus 1, Human/physiology ; *Virus Replication ; *Neurons/virology/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Fibroblasts/virology/metabolism ; Cell Line ; *Herpes Simplex/virology/metabolism ; Epithelial Cells/virology/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a versatile nuclear RNA-binding protein that performs important functions in RNA localization, processing, and stability. In the neurodegenerative disease amyotrophic lateral sclerosis (ALS) TDP-43 forms toxic, insoluble cytoplasmic aggregates that ultimately lead to neuronal loss. Although TDP-43 is expressed in every cell type, its function and subcellular localization are particularly important for neuronal homeostasis. However, it is unknown if TDP-43 has a role during herpesvirus infection. Herpes simplex virus type-1 (HSV-1), a ubiquitous neurotropic pathogen, is considered a contributing factor to neurodegenerative disorders. In this study, we tested the requirement for TDP-43 during HSV-1 infection in neuronal and non-neuronal cells. HSV-1 infection of epithelial cells and primary fibroblasts did not change overall TDP-43 abundance, nor did TDP-43 depletion detectably alter HSV-1 productive replication in a multicycle growth experiment. By contrast, when TDP-43 was depleted in neuronally-derived, differentiated HD10.6 cells, HSV-1 infectious virus production was significantly reduced in both single- and multicycle growth experiments. Notably, TDP-43 depletion restricts viral lytic gene expression at the immediate-early phase. Through nanopore direct RNA-sequencing, we uncovered enhanced intron retention in two essential viral genes-ICP0 and UL15-upon TDP-43 depletion. Thus, while depletion of TDP-43 does not detectably affect HSV-1 reproduction in epithelial cells and fibroblasts, TDP-43 is required for efficient replication in HD10.6 cells through modifying the abundance and splicing of viral mRNAs.IMPORTANCEHerpes simplex virus type-1 is a widespread neurotropic pathogen that can cause life-threatening infections of the brain and is increasingly linked to neurodegenerative disease. However, due to the lack of scalable in vitro human neuronal models or small animal models that recapitulate disease, little is known about virus-host interactions in neurons specifically. Using human epithelial cells, primary fibroblasts and a human neuron-derived cell line, we uncovered a cell type specific TDP-43 requirement for efficient HSV-1 virus replication. TDP-43 is a critical neuronal disease factor gene, and we showed it promotes HSV-1 gene expression and splicing of viral mRNAs in neuron-derived cells. This raises the possibility that targeting of TDP-43 could reveal a new antiviral strategy for severe HSV-1 infections. This work further provides valuable insights into the possible etiology of neurodegenerative disease and highlights the importance of studying virus-host interactions in relevant cell types.}, } @article {pmid41343582, year = {2025}, author = {Saunders, N and Magnussen, C and Kang, H and Blais, M and Bhinder, H and Pfeffer, G and Genuis, SK and Bouvier, L and Anand, T and Abou-Haidar, R and Abrahao, A and Boivin, MN and Bowser, R and Bubela, T and Chiappini, J and Das, S and Dhanoa, A and Dupré, N and Evans, A and Ferry, N and Frater, Y and Genge, A and Graham, SJ and Greiner, R and Medina, YI and Johnston, WS and Jones, KE and Karamchandani, J and Kriz, J and Luth, W and Matte, G and Rogaeva, E and Robertson, J and Seres, P and Tam, F and Taylor, D and Tremblay-Desbiens, C and Velde, CV and Yunusova, Y and Zinman, L and Kalra, S}, title = {Comprehensive analysis platform to understand, remedy, and eliminate amyotrophic lateral sclerosis (CAPTURE ALS): Study protocol for a Canadian multicenter, multimodal, longitudinal observational study.}, journal = {PloS one}, volume = {20}, number = {12}, pages = {e0332430}, pmid = {41343582}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/pathology ; Humans ; Canada/epidemiology ; Longitudinal Studies ; Prospective Studies ; Biological Specimen Banks ; Female ; Male ; Biomarkers ; }, abstract = {BACKGROUND: The marked heterogeneity of Amyotrophic Lateral Sclerosis (ALS) combined with a lack of biomarkers are key contributing factors to the lack of disease-modifying treatments. The Comprehensive Analysis Platform to Understand Remedy and Eliminate ALS (CAPTURE ALS) is a Canadian platform designed to create the most comprehensive picture of people living with ALS with the objective of facilitating ALS research initiatives worldwide.

OBJECTIVES: The main aims of CAPTURE ALS include: (1) to characterize ALS and healthy controls with biosamples and data in order to provide the most comprehensive picture of individuals living with ALS to date; (2) to create a de-identified database and biosample repository linked to detailed clinical information; and (3) to develop and implement an inclusive and transparent participant engagement strategy to be active throughout all stages of CAPTURE ALS.

METHODS/RESULTS: CAPTURE ALS is a prospective, multicenter, observational, longitudinal study. People living with ALS, or a related disease and healthy controls undergo a harmonized protocol including the collection of detailed clinical information, neurological and cognitive examination, speech recording, advanced magnetic resonance imaging, and biosampling. Data and samples are stored in a biobank operating under an open science governance framework. An inclusive and transparent participant engagement strategy was designed and implemented throughout all stages of CAPTURE ALS. Four sites are operating in the consortium with a fifth being onboarded. The target enrollment is 120 affected participants and 50 controls, with the first participant visit having occurred in March 2022. Recruitment is ongoing.

DISCUSSION: CAPTURE ALS is a scalable clinical research platform that connects scientists and patients to facilitate efficient translational research. The unique and deeply phenotyped data and biosamples are a global resource towards the development of biomarkers and understanding ALS biology. This study is registered at clinicaltrials.gov (NCT: NCT05204017).}, } @article {pmid41345007, year = {2026}, author = {Marimbun, M and Nengsih, N and Saidah, S}, title = {The invisible twitch: How fasciculations in ALS often go unnoticed by patients.}, journal = {Journal of the neurological sciences}, volume = {480}, number = {}, pages = {125676}, doi = {10.1016/j.jns.2025.125676}, pmid = {41345007}, issn = {1878-5883}, } @article {pmid41345047, year = {2026}, author = {Bahbah, EI}, title = {Tetramethylpyrazine nitrone: a multifaceted neuroprotective agent in neurodegenerative disorders.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {3}, pages = {325-339}, pmid = {41345047}, issn = {1758-2032}, mesh = {Humans ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Pyrazines/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Animals ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) share key pathological features, including oxidative stress, mitochondrial dysfunction, and impaired protein homeostasis, yet remain without effective disease-modifying therapies. Tetramethylpyrazine nitrone (TBN), a synthetic derivative of tetramethylpyrazine bearing a free radical-scavenging nitrone moiety, has emerged as a promising multi-target neuroprotective agent. This review synthesizes preclinical and clinical data supporting TBN's therapeutic potential in AD, PD, and ALS. In AD models, TBN reduces amyloid-β accumulation and tau hyperphosphorylation, enhances autophagic clearance, preserves synaptic integrity, and improves cognitive performance. In PD models, TBN confers dopaminergic neuroprotection, restores motor function, and promotes α-synuclein degradation, effects mediated largely through activation of the PGC-1α/Nrf2 pathway and augmentation of the ubiquitin-proteasome system (UPS). In ALS models, TBN mitigates motor neuron loss, improves motor performance, and extends survival, likely via the PGC-1α/Nrf2/HO-1 axis and enhanced autophagic activity. Phase I studies have established TBN's favorable oral and intravenous pharmacokinetics, effective blood - brain barrier penetration, and overall safety and tolerability in healthy volunteers. Owing to its multi-pathway mechanism, principally engaging antioxidant/mitochondrial pathways and proteostasis (autophagy/UPS), TBN represents a compelling candidate for continued clinical development, either as monotherapy or in combination with disease-specific interventions.}, } @article {pmid41345183, year = {2025}, author = {Kamiyama, D and Kamiyama, R and Nishida, Y and Sego, A and Vining, GB and Bui, KC and Fitch, M and Do, HGT and Avraham, O and Chihara, T}, title = {The Vap33 signaling axis precisely coordinates the timing of motoneuron dendritogenesis in neural map development.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {10893}, pmid = {41345183}, issn = {2041-1723}, support = {P40 OD018537/OD/NIH HHS/United States ; R01 NS107558/NS/NINDS NIH HHS/United States ; NS107558//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *Motor Neurons/metabolism/cytology ; *Drosophila Proteins/metabolism/genetics ; Signal Transduction ; cdc42 GTP-Binding Protein/metabolism ; Drosophila melanogaster/metabolism ; *Dendrites/metabolism ; *Neurogenesis/physiology ; Humans ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Cell Membrane/metabolism ; GTP-Binding Proteins ; }, abstract = {In Drosophila motoneurons, spatiotemporal dendritic patterns are established in the ventral nerve cord. While many guidance cues have been identified, the mechanisms of temporal regulation remain unknown. Previously, we identified the actin modulator Cdc42 GTPase as a key factor in this process. In this report, we further identify the upstream factors that activate Cdc42. Using single-cell genetics, FRET-based imaging, and biochemical techniques, we demonstrate that the guanine nucleotide exchange factor Vav is anchored to the plasma membrane via the Eph receptor tyrosine kinase, enabling Cdc42 activation. VAMP-associated protein 33 (Vap33), a potential Eph ligand supplied non-cell-autonomously, may induce Eph autophosphorylation, initiating downstream signaling. Traditionally known as an ER-resident protein, Vap33 is secreted extracellularly at the onset of Cdc42 activation, acting as a temporal cue. In humans, VAPB-the ortholog of Vap33-is similarly secreted in the spinal cord, and its dysregulation leads to amyotrophic lateral sclerosis type 8 (ALS8). Our findings may help inform future studies on how VAPB signaling contributes to motor circuit formation in both physiological and disease contexts.}, } @article {pmid41345272, year = {2025}, author = {Duhayyim, MA}, title = {An efficient dimensionality reduction framework using metaheuristic optimization with deep learning models for amyotrophic lateral sclerosis disease progression prediction.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {1165}, pmid = {41345272}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/pathology/physiopathology ; Humans ; *Deep Learning ; Disease Progression ; Algorithms ; Dimensionality Reduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disastrous neuro-degenerative infection which affects motor neuron inhabitants of the spinal cord, brainstem, and cerebral cortex, resulting in progressive disorder and demise from respiratory difficulty. ALS is considerably assorted disorder comprising symptoms such as muscle weakness, difficulty in swallowing, speaking, breathing, and changes in mental and emotional health. Hence, this disease requires more beneficial medication and also, successful treatment is affected by heterogeneous disease development, resulting in issues with patient stratification. Recently, many researches have been published by using deep learning (DL) and machine learning (ML) methods and, more commonly, artificial intelligence (AI). This paper presents a Dimensionality Reduction Framework Using Metaheuristic Optimization with Deep Learning Models for the Amyotrophic Lateral Sclerosis Disease Progression Prediction (DRMODL-ALSDP) method. The aim is to provide an effectual model for the progression prediction of ALS disease using advanced techniques. Initially, the data pre-processing stage applies min-mx normalization to transform raw data into a suitable format. Furthermore, SMOTE is employed to address class imbalance by upsampling the minority classes in disease progression stages. Furthermore, the binary swordfish movement optimization algorithm (BSMOA) technique is used for feature selection. Moreover, the hybrid of a temporal convolutional network and long short-term memory with attention mechanism (TCN-LSTM-AM) technique is employed for the classification process. Finally, the marine predator's algorithm (MPA) technique optimally fine-tunes the hyperparameter values and improves classification performance. A widespread simulation is performed to verify the performance of the DRMODL-ALSDP model. The comparison study of the DRMODL-ALSDP model accentuated the superior accuracy output of 98.17% over existing methods.}, } @article {pmid41345490, year = {2025}, author = {Ji, C and Li, P and Ma, S and Li, J and Zhou, J and Zhu, J and Dong, D and Yang, T and Yang, P}, title = {Correlation analysis of serum neurofilament light chain and glial fibrillary acidic protein levels with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {506}, pmid = {41345490}, issn = {2045-2322}, support = {2021BEG03032//Key Research and Development Program of Ningxia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; *Neurofilament Proteins/blood ; *Glial Fibrillary Acidic Protein/blood ; Male ; Female ; Middle Aged ; Biomarkers/blood ; Aged ; Case-Control Studies ; Adult ; Disease Progression ; }, abstract = {Neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) are considered to be a promising biomarker for the diagnosis of amyotrophic lateral sclerosis (ALS) and assessment of disease progression. To investigate the correlation between serum neurofilament light chain protein (NFL) and glial fibrillary acidic protein (GFAP) levels and amyotrophic lateral sclerosis (ALS). Serum NFL and GFAP levels were measured in 12 ALS patients and 12 healthy controls (HC) using the Single-molecule array (Simoa) technique. Serum NFL and GFAP levels in ALS patients were 81.49 ± 47.06 pg/mL and 104.42 ± 37.31 pg/mL, respectively, significantly higher than those in healthy controls (9.21 ± 3.05 pg/mL and 57.71 ± 11.64 pg/mL; P < 0.001). Serum NFL and GFAP levels in ALS patients were correlated with the duration of the disease as respectively (r = 0.746, P = 0.005; r = 0.668, P = 0.018). In this study, we investigated the diagnostic value of serum NFL and GFAP levels in the ALS population and their clinical significance using the Simoa technique. The results showed that serum NFL and GFAP levels may be potential biomarkers for ALS diagnosis, and is positively correlated with disease progression. However, its diagnostic specificity awaits further studies that include disease controls.}, } @article {pmid41345582, year = {2025}, author = {Ebrahimian, A and Moradi, A and Athari, SZ and Farajdokht, F}, title = {Restless legs syndrome as a comorbidity in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {23}, pmid = {41345582}, issn = {1471-2377}, support = {74962//Student Research Committee, Tabriz University of Medical Sciences/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Restless Legs Syndrome/epidemiology ; Comorbidity ; Prevalence ; }, abstract = {BACKGROUND: Restless Legs Syndrome (RLS), characterized by an urge to move the legs, is linked to neurodegenerative diseases. Emerging evidence suggests a higher RLS prevalence in Amyotrophic Lateral Sclerosis (ALS), impacting quality of life. However, there is lack of comprehensive review addressing its prevalence and associated risk factors. This meta-analysis estimates RLS prevalence in ALS patients compared to healthy controls.

METHODS: We searched PubMed, Embase, Web of Science, and Scopus for studies assessing RLS in ALS patients versus controls, adhering to PRISMA guidelines. Two reviewers independently extracted data and assessed bias using Joanna Briggs Institute (JBI) checklist. Meta-analysis used Comprehensive Meta-Analysis software with a random-effects model due to heterogeneity. The certainty of evidence was appraised using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework.

RESULTS: Out of 291 studies, eight studies (792 ALS, 716 controls) were included. The pooled RLS prevalence in ALS was 17% (95% CI: 14.0%-21.1%; I²: 56.5%; p-value < 0.001). The fixed effect meta-analysis of four studies indicated that the difference of RLS prevalence was statically significant between patients with ALS and healthy controls (OR: 5.65; CI: 2.86-11.13; P-value < 0.001; I²: 28.7.).

CONCLUSION: RLS is significantly more prevalent in ALS patients, potentially worsening sleep and quality of life, mental health, and social well-being. Therefore, it is essential to draw clinicians' attention to RLS in ALS patients due to its potential impact on overall health.}, } @article {pmid41347668, year = {2025}, author = {Yuen, HK and Szynkiewicz, SH and Richardson, K and Benge, M and Lowman, JD and Spraberry, SB and Jiang, N and Kazamel, M}, title = {Effects of a Coach-Guided Online Yogic Breathing Program on Quality of Life in People With Amyotrophic Lateral Sclerosis: A Mixed-Methods Pilot RCT.}, journal = {The American journal of hospice & palliative care}, volume = {}, number = {}, pages = {10499091251403506}, doi = {10.1177/10499091251403506}, pmid = {41347668}, issn = {1938-2715}, abstract = {ObjectivesThis study aims to evaluate the feasibility and acceptability of an online coach-guided yogic breathing exercise (YBE) program on improving quality of life (QoL) in persons with amyotrophic lateral sclerosis (PwALS).MethodsA waitlist pilot randomized controlled trial with a post-program individual qualitative interview was employed. Thirteen adults with ALS participated in the YBE program, with 7 in the YBE group and 6 in the waitlist group. The program consisted of twelve 30-min online YBE sessions in which each participant received one-on-one coaching from a certified yoga therapist over six consecutive weeks. ALS Specific Quality of Life-Revised (ALSSQOL-R) was the outcome measure.ResultsAll but 2 participants in the YBE training group completed the 12 sessions, with an overall attendance rate of >97%. Compared to the waitlist group using the Mann-Whitney U test, the YBE group showed significant improvement in the change scores of the physical symptoms and intimacy domains of the ALSQOL-R at post-test. No significant differences in the change scores between the YBE and waitlist groups in the total score and other domains of the ALSQOL-R were observed. Thematic analysis of participants' interview about their experiences with the program revealed two themes: sense of control over breathing and emotional regulation through relaxation.ConclusionDespite the small sample size, the high attendance rate and positive feedback indicate that the YBE program is feasible and acceptable to PwALS. The YBE program demonstrated significant QoL benefits for PwALS. Participants reported enhanced control over their breathing and better emotional regulation.}, } @article {pmid41347776, year = {2026}, author = {Mora, T and Roche, D and Andrés Benito, P and Caravaca Puchades, A and Povedano, M}, title = {Integrating administrative health data and machine learning to predict ALS onset.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {671-677}, doi = {10.1080/21678421.2025.2596691}, pmid = {41347776}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; *Machine Learning ; Female ; Predictive Learning Models ; Aged ; Random Forest ; Male ; Boosting Machine Learning Algorithms ; Classification Algorithms ; Prediction Algorithms ; Spain/epidemiology ; Logistic Models ; }, abstract = {BACKGROUND: This study aims to develop a Machine Learning (ML) model to predict the initial diagnosis of Amyotrophic Lateral Sclerosis (ALS).

METHODS: To predict ALS, a stacked model combining four ML algorithms-logistic Regression, Decision Tree, Random Forest, and Extreme Gradient Boosting-was implemented. The analysis utilized healthcare administrative data from Catalonia, encompassing 2,924,590 elderly individuals from 2014 to 2021, which were linked to socioeconomic factors and medication records.

RESULTS: The stacked model successfully predicted first-time ALS diagnoses, achieving an AUC of 0.86, with an accuracy of 0.86, specificity of 0.88, and sensitivity of 0.84. The most influential predictors included immunization encounters, South American origin, general medical and special examinations, hypertensive heart disease, and counseling. Other relevant features were sciatica, heart failure, liver metastases, healthcare use patterns, and chronic conditions such as hypertension, kidney disease, and hypercholesterolemia. These features reflect early clinical symptoms and healthcare usage patterns relevant to ALS detection.

CONCLUSIONS: Machine Learning models, particularly stacked approaches, show promising results in predicting ALS diagnoses using administrative health data. Continued research is necessary to improve detection strategies and support their integration into healthcare systems.}, } @article {pmid41348294, year = {2025}, author = {Luu, S and McGuiness, OA and Menadue, C and Piper, AJ and Wong, KK and Yee, BJ and Gray, EL}, title = {Early assessment in bulbar-onset amyotrophic lateral sclerosis detects similar rates of nocturnal desaturation and orthopnoea compared to non-bulbar-onset disease.}, journal = {Sleep & breathing = Schlaf & Atmung}, volume = {30}, number = {1}, pages = {3}, pmid = {41348294}, issn = {1522-1709}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/classification/therapy/physiopathology ; Male ; Female ; Middle Aged ; *Oximetry ; Aged ; Retrospective Studies ; Early Diagnosis ; *Oxygen Saturation/physiology ; Polysomnography ; Noninvasive Ventilation ; }, abstract = {BACKGROUND: Pulmonary function measures are commonly used to determine timing of non-invasive ventilation (NIV) initiation in amyotrophic lateral sclerosis (ALS). However, these tests may be difficult to perform and unreliable in those with bulbar disease. We evaluated the rates of orthopnoea and nocturnal desaturation detected using nocturnal pulse oximetry (NPO), two key criteria for NIV initiation, separately in people with bulbar-onset and non-bulbar-onset ALS.

METHODS: We conducted a retrospective analysis of 93 individuals with ALS undergoing three consecutive nights of NPO screening. Demographics, diurnal respiratory function measures and NPO data were compared. Nocturnal desaturation was defined as > 2% of total sleep time with oxygen saturation < 90%.

RESULTS: Twenty-nine people had bulbar-onset ALS and 64 had non-bulbar-onset ALS. The prevalence of orthopnoea and the proportion with nocturnal desaturation were similar between bulbar-onset and non-bulbar-onset groups (24% vs. 20% and 76% vs. 67%, respectively). People with bulbar-onset ALS were older and underwent initial oximetry earlier in their disease trajectory following ALS-symptom onset than those with non-bulbar-onset ALS (67 ± 10.5 vs. 61 ± 11.9 years old, p = 0.02 and 17.5 (11.00-24.75) vs. 31.0 (18.00-63.50) months, p = 0.005, respectively).

CONCLUSION: People with bulbar-onset ALS were assessed with NPO sooner, but nocturnal desaturation was detected at similar rates to those with non-bulbar-onset ALS. Absence of orthopnoea and preserved lung function were poor indicators of nocturnal desaturation in both groups. Given the difficulties performing respiratory function tests in people with bulbar disease, early and regular NPO assessment in bulbar-onset ALS is warranted, even without symptoms.}, } @article {pmid41349278, year = {2026}, author = {García-Parra, B and Guiu, JM and Povedano, M and Modamio, P}, title = {Real-world evidence supporting orphan drugs approvals for rare neuromuscular disorders in the European Union and the United States: Review of public assessment reports (2015-2025).}, journal = {Current opinion in pharmacology}, volume = {86}, number = {}, pages = {102586}, doi = {10.1016/j.coph.2025.102586}, pmid = {41349278}, issn = {1471-4973}, mesh = {Humans ; United States ; *Orphan Drug Production/legislation & jurisprudence ; *Drug Approval ; *Neuromuscular Diseases/drug therapy ; European Union ; United States Food and Drug Administration ; *Rare Diseases/drug therapy ; }, abstract = {Real-world data (RWD) and real-world evidence (RWE) are becoming essential complements to conventional clinical trials for drug assessment, particularly for rare neuromuscular disorders where small patient populations heighten outcome uncertainty. Robust RWE could reduce that uncertainty and inform regulatory decisions on orphan drugs (ODs). To review how the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have incorporated RWE into OD approvals for neuromuscular diseases from January 2015 to January 2025. We reviewed all publicly available EMA European Public Assessment Reports and FDA review packages for ODs targeting neuromuscular indications. Each document was screened for mention of RWD sources and by the regulatory weight assigned to the resulting RWE. We identified 14 OD approvals by the EMA and 13 by the FDA, with greater use of RWE by the FDA. Indications comprised spinal muscular atrophy (3/3 EMA/FDA), amyotrophic lateral sclerosis (1/3), amyloid neuropathies (2/2), Friedreich ataxia (1/1), Lambert-Eaton syndrome (1/1), myasthenia gravis (2/2), myotonic disorders (1/0), and Duchenne muscular dystrophy (2/1). Among 18 evaluable dossiers, clinical outcome assessments (COA) were reported as follows: patient-reported outcomes - 39.1%, clinician-reported outcomes - 34.7%, observer-reported outcomes - 13.1 %, and performance outcomes - 13.1%. Only tofersen incorporated all COA types. The use of RWE for the evaluation of ODs is increasing for both the FDA and the EMA, more so for the former than for the latter. Harmonized methodological standards and transparent reporting frameworks are urgently needed to generate quality evidence that benefits stakeholders.}, } @article {pmid41349534, year = {2026}, author = {Franklin, HD and Crerar, H and Parnandi, N and Lattke, M and Majewski, S and Clarke, BE and Pallikonda, H and Howell, M and Boulton, SJ and Patani, R}, title = {Hypoxic stress is an early pathogenic event in human VCP-mutant ALS astrocytes.}, journal = {Stem cell reports}, volume = {21}, number = {1}, pages = {102723}, pmid = {41349534}, issn = {2213-6711}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Astrocytes/metabolism/pathology ; *Valosin Containing Protein/genetics/metabolism ; Induced Pluripotent Stem Cells/metabolism/cytology ; *Mutation ; Cell Hypoxia/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics ; Mitochondria/metabolism ; *Stress, Physiological ; Signal Transduction ; Motor Neurons/metabolism/pathology ; *Hypoxia ; }, abstract = {Astrocytes are essential regulators of neuronal health, and their dysfunction contributes to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Using human induced pluripotent stem cell (iPSC)-derived astrocytes carrying ALS-associated VCP mutations, we uncover cell-autonomous activation of the hypoxia response under basal conditions. VCP-mutant astrocytes exhibit increased nuclear hypoxia-inducible factor (HIF)-1ɑ, mitochondrial depolarization, and lipid droplet accumulation. Mimicking hypoxia in control astrocytes by HIF-1ɑ stabilization with dimethyloxalylglycine recapitulates these phenotypes. Transcriptomic and CUT&RUN profiling reveal direct HIF-1ɑ binding to canonical hypoxia-responsive genes in VCP-mutant astrocytes and a transcriptional signature of metabolic reprogramming and mitochondrial dysfunction under normoxia. Furthermore, conditioned medium from hypoxia-exposed astrocytes fails to rescue RNA-binding protein mislocalization in motor neurons, unlike medium from healthy counterparts. Together, these findings demonstrate that aberrant HIF-1ɑ activation drives astrocytic dysfunction and compromises neuronal support, identifying hypoxic stress as an early and functionally consequential event in VCP-mutant ALS, with therapeutic implications for targeting HIF-1ɑ signaling.}, } @article {pmid41349953, year = {2026}, author = {Trubshaw, M and Kohl, O and Gohil, C and van Es, MWJ and Quinn, AJ and Yoganathan, K and Edmond, E and Proudfoot, M and Zokaei, N and Raymont, V and Pitt, J and Thayanandan, T and Thompson, AG and Talbot, K and Hu, MT and Perquin, MN and Kocagoncu, E and Rowe, JB and Woolrich, MW and Nobre, AC and Turner, MR}, title = {Divergence of cortical neurophysiology across different neurodegenerative disorders compared to healthy ageing.}, journal = {Progress in neurobiology}, volume = {257}, number = {}, pages = {102865}, pmid = {41349953}, issn = {1873-5118}, mesh = {Humans ; Magnetoencephalography ; Aged ; Male ; Female ; *Amyotrophic Lateral Sclerosis/physiopathology ; Middle Aged ; *Alzheimer Disease/physiopathology ; *Healthy Aging/physiology ; *Parkinson Disease/physiopathology ; *Cerebral Cortex/physiopathology ; Aged, 80 and over ; *Neurodegenerative Diseases/physiopathology ; *Aging/physiology ; }, abstract = {Neurodegenerative diseases involve disruption of healthy brain network communication occurring before the emergence of symptoms. Magnetoencephalography (MEG) is sensitive to the magnetic fields generated by cortical neuronal activity, and is the most spatio-temporally accurate method of directly assessing neuronal activity non-invasively. We used MEG to directly compare three neurodegenerative disorders with a large healthy cohort to characterise patterns of activity deviating from healthy ageing. Task-free MEG recordings were acquired from patients with Alzheimer's disease (AD, n = 29), Parkinson's disease (PD, n = 25), amyotrophic lateral sclerosis (ALS, n = 33) and healthy controls (HC, n = 191). Healthy ageing trajectories for metrics including spectral power (local neuronal recruitment), connectivity (long-range communication), 1/f exponent (power spectrum slope, which may reflect inhibition), and oscillatory speed were extracted. These metrics were compared pairwise between HC and patient groups, controlling for age and sex. The modelled trajectories of healthy ageing included increasing beta power and oscillatory speed, with reduced power spectrum slope. PD, AD, and ALS groups all showed reductions in beta power and slowing of oscillatory activity compared to matched HC. In AD, older patients showed lower beta power compared with younger patients. Compared with matched HC, the power spectrum slope was uniquely reduced in ALS, in contrast to the increase seen in PD and AD. Gamma connectivity increased in AD and ALS. MEG has unique potential as a source of biomarkers that might be used to detect deviation from healthy ageing if applied at an earlier presymptomatic stage of neurodegeneration than current tools permit. It might also provide outcome measures for prevention trials.}, } @article {pmid41350059, year = {2026}, author = {Sarker, SC and Chen, J and Wang, C and He, S and Yu, H and Li, X and Cui, H}, title = {ALS target-site mutations and overexpression synergistically enhance mesosulfuron resistance in Lolium perenne.}, journal = {Pesticide biochemistry and physiology}, volume = {216}, number = {Pt 2}, pages = {106802}, doi = {10.1016/j.pestbp.2025.106802}, pmid = {41350059}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Lolium/genetics/drug effects/enzymology ; *Herbicide Resistance/genetics ; *Sulfonylurea Compounds/pharmacology ; Mutation ; *Herbicides/pharmacology ; *Plant Proteins/genetics/metabolism ; }, abstract = {The invasive weed Lolium perenne (perennial ryegrass) poses a considerable threat to winter wheat crops in China and is hardly controlled by acetolactate synthase (ALS) inhibitors after years of application. In this study, four L. perenne populations from different locations in Henan were collected to evaluate the mechanisms of target site resistance to mesosulfuron-methyl. The resistant index (RI) of these four populations ranged from 122.73 to 149.26 compared to the susceptible population. ALS gene sequencing revealed three specific target site mutations: Pro-197-Thr, Asp-376-Glu, and Trp-574-Leu. Among these, Trp-574-Leu has not been previously reported in L. perenne. Three simultaneous double mutations were found in the same individual: Pro-197-Thr and Asp-376-Glu (Group I); Pro-197-Thr and Trp-574-Leu (Group II); and Asp-376-Glu and Trp-574-Leu (Group III). The gene expression levels of the double mutant groups were significantly higher than those of the susceptible plants. The I50 values obtained from the ALS enzyme assays showed that all three double mutant groups demonstrated a 136.75 to 149-fold increase compared to the enzyme activity of susceptible plants. Molecular docking analysis of mutant ALS proteins with mesosulfuron-methyl indicated that the mutant proteins had a reduced binding affinity to the herbicide. This reduced affinity was due to the disruption of hydrogen bonds and other key interactions, which contributed to increased herbicide resistance. Double target site mutations in a single ALS gene are a crucial mechanism for conferring high levels of mesosulfuron-methyl resistance in L. perenne.}, } @article {pmid41350075, year = {2026}, author = {Wu, G and Chen, Y and Yao, Y and Huang, W and Wu, K}, title = {Integrating network toxicology and molecular docking to uncover mechanisms of novel herbicide-induced neurodegeneration.}, journal = {Pesticide biochemistry and physiology}, volume = {216}, number = {Pt 2}, pages = {106821}, doi = {10.1016/j.pestbp.2025.106821}, pmid = {41350075}, issn = {1095-9939}, mesh = {*Herbicides/toxicity/chemistry ; *Molecular Docking Simulation ; Humans ; *Neurodegenerative Diseases/chemically induced/metabolism ; Protein Interaction Maps ; }, abstract = {Rising global reliance on novel herbicides has outpaced understanding of their potential neurotoxicity. This study employs an integrative network-toxicology pipeline to clarify how five widely used compounds, including mesotrione, topramezone, flufenazopyr, glufosinate-ammonium and beflubutamid-M, may contribute to Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis pathogenesis. We first predicted toxic liabilities in eMolTox, SwissADME and ProTox, then harvested 310 human targets via PubChem, ChEMBL, STITCH and Swiss Target Prediction. Intersection with 3668-3429 disease genes (GeneCards/ OMIM) revealed 91-176 shared targets per disorder. PPI networks constructed in STRING and refined with Cytoscape (MCODE, cytoHubba) and novel NodeIdentifyR algorithm converged on eleven high-impact hub genes: EGFR, GSK3B, SRC, AKT1, MAPT, CASP3, MMP9, MTOR, PTK2, BCL2L1 and MAPK8. GO and KEGG enrichment analyses highlighted apoptosis, PI3K-Akt and MAPK signaling dysregulation. Single-cell and bulk transcriptomic atlases confirmed aberrant expression of these hubs in patient brains; Molecular docking demonstrated low-nanomolar affinities of all herbicides for multiple hub proteins, with mesotrione and topramezone displaying the broadest binding spectra and SRC emerging as a common high-affinity site. Molecular dynamics simulations supported stable binding in a representative herbicide-protein complex. Additionally, in vivo and in vitro experiments using Glufosinate-ammonium exposure corroborated the computational findings, underscoring the robustness of our approach. Together, these results establish a systems-level framework linking environmental herbicide exposure to neurodegeneration and nominate tractable targets for surveillance and therapeutic intervention.}, } @article {pmid41350201, year = {2026}, author = {Hokkoku, K and Inoue, M and Yamada, S and Namba, H and Matsukura, K and Mukai, T and Chiba, T and Hatanaka, Y and Kobayashi, S and Sonoo, M}, title = {Reply to the letter by Marimbun et al. on fasciculation awareness in ALS.}, journal = {Journal of the neurological sciences}, volume = {480}, number = {}, pages = {125677}, doi = {10.1016/j.jns.2025.125677}, pmid = {41350201}, issn = {1878-5883}, } @article {pmid41350409, year = {2025}, author = {Cheng, S and Zhong, C and Zhu, H and Mu, K and Jiang, H and Zhong, P and Ma, Z and Liu, X and Wang, Z and Liu, R and Ding, Y}, title = {Structural mechanisms and insights on multiple nanobodies binding diverse SOD1 epitopes.}, journal = {Communications biology}, volume = {9}, number = {1}, pages = {30}, pmid = {41350409}, issn = {2399-3642}, mesh = {*Superoxide Dismutase-1/chemistry/metabolism/immunology/genetics ; *Single-Domain Antibodies/chemistry/metabolism/immunology ; Humans ; *Epitopes/chemistry/immunology/metabolism ; Protein Binding ; Amyotrophic Lateral Sclerosis ; Models, Molecular ; Crystallography, X-Ray ; Protein Conformation ; }, abstract = {Copper/zinc superoxide dismutase (SOD1) is a crucial metalloenzyme that mitigates oxidative stress by scavenging superoxide anion radicals. Mutations and aggregation of SOD1 are closely linked to the pathogenesis of amyotrophic lateral sclerosis (ALS). Targeting pathogenic SOD1 with nanobodies presents a promising therapeutic approach. We report the first high-resolution crystal structures of SOD1 in complex with three distinct nanobodies (Nb1, Nb2, and Nb3) and their multimeric assemblies (1:2 and 1:3 stoichiometries), revealing distinct binding epitopes primarily mediated by their complementarity determining regions (CDRs) through hydrogen bonds, salt bridges, and hydrophobic interactions. Structural and biophysical analyses using isothermal titration calorimetry (ITC) and fluorescence-detection size-exclusion chromatography (FSEC) demonstrated that all three nanobodies bind SOD1 simultaneously with nanomolar affinities (KD values ranging from 23.2 nM to 529 nM). Notably, engineered multimeric tandem nanobodies (Nb1-Nb2-Nb3) achieved higher affinity (KD = 4.39 nM) compared to single nanobodies, as validated by ITC. Characterization via dynamic light scattering (DLS) further revealed colloidal stability of SOD1-nanobody complexes. These results provide the first atomic-resolution insights into multi-nanobody targeting of SOD1 without steric interference, establishing a foundation for developing high-affinity tools to detect and manipulate SOD1 in ALS and related neurodegenerative diseases.}, } @article {pmid41350806, year = {2025}, author = {Nakamura, R and Tohnai, G and Atsuta, N and Matsuda, Y and Morimoto, S and Ito, D and Katsuno, M and Izumi, Y and Morita, M and Iwata, I and Yabe, I and Nakazato, T and Hattori, N and Hirayama, T and Kano, O and Tamura, A and Suzuki, N and Aoki, M and Shibuya, K and Kuwabara, S and Oda, M and Hashimoto, R and Aiba, I and Ishihara, T and Onodera, O and Yamashita, T and Ishiura, H and Bokuda, K and Shimizu, T and Ikeda, Y and Hasegawa, K and Tanaka, F and Yokota, T and Kanai, K and Noto, YI and Kaji, R and Watanabe, H and Konishi, T and Hasegawa, M and Fukaya, H and Niwa, JI and Doyu, M and Okada, Y and Nakamura, S and Ozawa, F and Okano, H and Nakatochi, M and Sobue, G and , }, title = {A genome-wide association study identifies the GPM6A locus associated with age at onset in ALS.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {1720}, pmid = {41350806}, issn = {2399-3642}, support = {23FC0201//Ministry of Health, Labour and Welfare (Ministry of Health, Labour and Welfare, Japan)/ ; JP23ek0109492, JP23ak0101111, JP23ak0101124, JP24wm0425009//Japan Agency for Medical Research and Development (AMED)/ ; JP24ak0101216, JP24ak0101222, JP25wn0625519, JP25ak0101216, JP25ak0101222, JP25ek0109617//Japan Agency for Medical Research and Development (AMED)/ ; JP23ek0109538//Japan Agency for Medical Research and Development (AMED)/ ; JP23bm1123046, JP23kk0305024, JP23bm1423002//Japan Agency for Medical Research and Development (AMED)/ ; JP24bm1423003//Japan Agency for Medical Research and Development (AMED)/ ; JP23bm1123046, JP23kk0305024, JP23bm1423002//Japan Agency for Medical Research and Development (AMED)/ ; JP19km0405216//Japan Agency for Medical Research and Development (AMED)/ ; 19K07973//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K07359//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K07509//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 19K06523//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K07359//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 19K07973//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K07509//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K06835//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K07359//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K07509//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 25K10781//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 21H05278//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 19K06523//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K06975//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22H02988//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K06975//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K24249//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 21H05278//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 16H06277//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22H04923//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22H03350//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *Genome-Wide Association Study ; Age of Onset ; Female ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Aged ; Genetic Predisposition to Disease ; Adult ; *GPI-Linked Proteins/genetics ; Japan ; }, abstract = {Amyotrophic lateral sclerosis (ALS) exhibits considerable clinical variability, such as differences in age at onset (AAO). Multiple factors, including genetic factors, may underlie this variability; however, the specific determinants remain unclear. To identify genes affecting AAO, we have conducted a genome-wide association study in Japanese patients with ALS (discovery cohort: n = 1808; replication cohort: n = 207). Here, we show that the minor A allele of rs113161727 at the ADAM29-GPM6A locus is associated with a younger AAO in the discovery cohort (effect, -4.27 years; p = 4.60 × 10[-8]); this finding has been confirmed in the replication cohort (p = 0.0068) and meta-analysis (p = 1.08 × 10[-9]). Among 65 ALS patients with a SOD1 mutation, the AAO has been found to be 10.2 years younger in those with the A allele than in those without it (p = 0.002). This variant correlates with GPM6A upregulation in iPSC-derived motor neurons, suggesting GPM6A as a candidate AAO modifier. Overall, our study highlights the impact of genetic modifiers on ALS heterogeneity and provides a potential target for delaying disease onset.}, } @article {pmid41351663, year = {2025}, author = {Amirian, R and Merati, A and Babamohamadi, M and Mirahmadi, Y and Esfahani, ML and Rahmani, S and Izadi, Z and Rezazadeh, D}, title = {Navigating the Autophagy Maze: ATG and Their Impact on Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {260}, pmid = {41351663}, issn = {1559-1182}, mesh = {*Autophagy/genetics/physiology ; Humans ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Animals ; *Autophagy-Related Proteins/metabolism/genetics ; Signal Transduction ; }, abstract = {Autophagy, a tightly regulated process essential for maintaining cellular homeostasis, plays a critical role in the pathogenesis and progression of neurodegenerative diseases (NDs). These disorders-marked by diverse mechanisms and clinical heterogeneity-pose significant challenges in developing effective therapies. Central to the autophagic machinery are autophagy-related genes (ATGs), whose functions and variants are increasingly recognized as pivotal in modulating disease-specific pathways. This review explores the intricate roles of ATGs in NDs, emphasizing the need for a comprehensive understanding of molecular signaling networks, protein-protein interactions, and regulatory checkpoints that may serve as therapeutic targets. We highlight recent advancements in disease modeling, autophagy assays, and biomarker identification that facilitate the translation of ATG-related discoveries into clinical practice. Furthermore, we underscore the importance of interdisciplinary collaboration across academia, industry, clinical medicine, and regulatory bodies to harness the therapeutic potential of autophagy. This article aims to serve as a detailed roadmap for understanding the role of ATGs in NDs and to illuminate promising avenues for future research and therapeutic development.}, } @article {pmid41352634, year = {2026}, author = {Geleta, LA and Doyle, C and Garton, FC and Fowler, M and Carr, JM and Akkari, PA and McRae, AF and Rogers, ML and Madakkatel, I and Benyamin, B}, title = {The roles of human endogenous retrovirus in neurodegenerative diseases: A systematic review.}, journal = {Brain, behavior, and immunity}, volume = {132}, number = {}, pages = {106201}, doi = {10.1016/j.bbi.2025.106201}, pmid = {41352634}, issn = {1090-2139}, mesh = {Humans ; *Endogenous Retroviruses/genetics/physiology ; *Neurodegenerative Diseases/virology/genetics ; Alzheimer Disease/virology ; Amyotrophic Lateral Sclerosis/virology ; Parkinson Disease/virology ; Frontotemporal Dementia/virology ; }, abstract = {BACKGROUND: Human endogenous retroviruses (HERVs) constitute ∼8 % of the human genome, far exceeding the 2 % occupied by protein-coding genes. Although most HERV sequences are inactive, some HERV elements can be reactivated under certain conditions and may contribute to neurodegenerative diseases (NDDs). However, the findings vary across different HERV families, disease models, and detection methods. Here, we systematically review and synthesize the available evidence on the role of HERVs in human NDDs and reconcile inconsistencies in the literature.

METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library, PsycINFO, Scopus, Web of Science, CINAHL, and Emcare to identify relevant studies. Two independent reviewers screened studies, assessed quality, and extracted data. Qualitative synthesis was conducted for all included NDDs, specifically Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson's disease (PD), and due to data availability, meta-analysis was used to assess the impact of HERVs antibodies on ALS only.

RESULTS: Twenty-six studies (N ranges: 6-485) met the inclusion criteria, with majority focusing on HERV-K and ALS. Across studies, the association between HERV expression and NDDs was inconsistent, particularly for ALS, PD, and FTD, whereas investigations in AD showed a more consistent upregulation of specific HERVs. Studies relying on polymerase chain reaction (PCR) (typically smaller) showed inconsistent associations (21 studies), while RNA sequencing studies reported consistent associations (9 studies). A preliminary meta-analysis revealed a fivefold increase [OR: 5.83; 95 % CI: 4.14, 8.18] in ALS risk among participants with positive HERV antibodies.

CONCLUSIONS: The inconsistencies in HERV involvement across NDDs highlight the need for further studies employing standardized methodologies. RNAseq findings on the association of HERVs expression and NDDs support the need for large-scale RNA sequencing studies (rather than small, PCR studies) and careful tissue selection to clarify HERVs' role in NDDs. The association of HERV-K antibodies with ALS risk and prognosis suggests a significant role in disease, which could help detect biomarkers and used as a target for treatment.}, } @article {pmid41352688, year = {2026}, author = {Chikuchi, R and Kato, Y and Tomatsu, A and Nishisaki, S and Kawakami, Y and Yoshimura, T and Li, J and Iguchi, Y and Onodera, K and Hashimoto, R and Aiba, I and Nakamura, R and Tohnai, G and Atsuta, N and Sobue, G and Okada, Y and Katsuno, M and Yokoi, S}, title = {The TDP-43[I383V] heterozygous mutation results in increased TDP-43 expression and altered neuronal activity in ALS patient-derived iPSC motor neurons.}, journal = {Neuroscience research}, volume = {222}, number = {}, pages = {105003}, doi = {10.1016/j.neures.2025.105003}, pmid = {41352688}, issn = {1872-8111}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Motor Neurons/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Humans ; *DNA-Binding Proteins/genetics/metabolism ; Animals ; Mutation/genetics ; Rats ; Heterozygote ; Coculture Techniques ; Cells, Cultured ; }, abstract = {TAR-binding protein 43 (TDP-43) is a pathogenic RNA-binding protein associated with amyotrophic lateral sclerosis (ALS). To elucidate the pathogenesis of ALS, we generated induced pluripotent stem cells (iPSCs) from lymphoblastoid cell line (LCL) cells of an ALS patient with the TDP-43[I383V] heterozygous mutation. Furthermore, we generated isogenic wild-type iPSCs from wild-type LCL cells using scarless genome editing with CRISPR/Cas9. A modified iPSC-derived motor neuron culture method utilizing BrainPhys neuronal medium and rat astrocyte co-culture effectively promoted and maintained neuronal activity. Under these conditions, the TDP-43[I383V] heterozygous mutation resulted in increased TDP-43 protein expression through prolonged stabilization. Moreover, mutant iPSC-derived motor neurons showed increased numbers of pre-synapses and altered neuronal activity. These results suggest that the modified motor neuron culture method can help elucidate abnormalities in TDP-43 expression, synapse formation, and neuronal activity caused by the heterozygous TDP-43[I383V] mutation. The model developed in this study has the potential to facilitate the analysis of the early pathological phenotype of ALS.}, } @article {pmid41352714, year = {2026}, author = {Maas, D and Spindler, A and Zappi, I and Shapiro, J and Lo Sicco, KI}, title = {Response to Vaz de Faria et al's ''Forehead atrophy in frontal fibrosing alopecia: An ultrasonographic and histopathological study of 10 patients".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {4}, pages = {e265-e266}, doi = {10.1016/j.jaad.2025.10.159}, pmid = {41352714}, issn = {1097-6787}, } @article {pmid41352717, year = {2026}, author = {Doche, I and Vaz de Faria, JR}, title = {Response to Maas et al, "Response to Vaz de Faria et al's "Forehead atrophy in frontal fibrosing alopecia: An ultrasonographic and histopathological study of 10 patients"".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {4}, pages = {e267}, doi = {10.1016/j.jaad.2025.12.015}, pmid = {41352717}, issn = {1097-6787}, } @article {pmid41352930, year = {2026}, author = {Queral-Beltran, A and Lacorte, S and Tauler, R}, title = {GC-orbitrap-HRMS with ROIMCR and MSident targeted and non-targeted analysis of persistent organic pollutants in fish-based certified reference materials.}, journal = {Analytica chimica acta}, volume = {1383}, number = {}, pages = {344892}, doi = {10.1016/j.aca.2025.344892}, pmid = {41352930}, issn = {1873-4324}, mesh = {Animals ; *Gas Chromatography-Mass Spectrometry/standards/methods ; *Fishes ; *Persistent Organic Pollutants ; Reference Standards ; }, abstract = {The use of fish-based reference materials allows the validation of analytical methods used for the monitoring of persistent organic pollutants (POPs) in environmental samples. Thus, the aim of this work has been to apply and validate the Regions of Interest Multivariate Curve Resolution (ROIMCR) procedure, in a first instance, to quantify POPs using two fish-based certified reference materials (CRM) provided by the Institute of Reference Materials (IRMM); and also to identify, with the MSident program, the presence of more POPs in the same samples. Samples were extracted and analyzed by gas chromatography coupled to an Orbitrap mass spectrometer (GC-HRMS). A targeted analysis was performed to quantify the four certified POPs: hexachlorobenzene (HCBz) and hexachlorobutadiene (HCBu) in ERM®-CE100 and pentachlorobenzene (PeCB) and α, β, γ, and δ-hexachlorocyclohexane (HCH) in ERM®-CE103. Quantitative estimations obtained with ROIMCR method were compared with those obtained using the instrument vendor's Xcalibur software. Two tailed t-tests were performed and good agreement was observed between the two approaches and with the certified values. A non-targeted analysis approach was then performed to characterize other unknown POPs present in the samples. Data processed with the ROIMCR method in the non-targeted acquisition mode was complemented with the MSident chemical identification procedure, which allowed the annotation of several polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), phthalates, and polychlorinated biphenyls (PCBs). The presence of some of these compounds was confirmed with the analysis of validation standard mixture samples containing 43 POPs. The ROIMCR methodology herein proposed allows, in a first instance, the quantitative analysis of multiple unknown contaminants present in the analyzed fish-based certified samples by using GC-HRMS data and also, combined with the MSident program, enables a qualitative analysis which could provide a comprehensive assessment of POP pollution patterns in fish or other environmental samples.}, } @article {pmid41354105, year = {2026}, author = {Mendes Araújo, L and Chianca, T and Persaud, C and Hartung, P and Soares, Y and Almirón, G and João, R}, title = {Respiratory strength training for patients with amyotrophic lateral sclerosis: A meta-analysis of randomized controlled trials.}, journal = {Respiratory medicine}, volume = {251}, number = {}, pages = {108560}, doi = {10.1016/j.rmed.2025.108560}, pmid = {41354105}, issn = {1532-3064}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation/therapy ; Randomized Controlled Trials as Topic ; *Breathing Exercises/methods ; Male ; Middle Aged ; Respiratory Muscles/physiopathology ; *Resistance Training/methods ; Female ; Treatment Outcome ; Aged ; Maximal Respiratory Pressures ; }, abstract = {INTRODUCTION: Respiratory strength training (RST) has been considered as a possible add-on treatment for amyotrophic lateral sclerosis (ALS). However, the benefits of RST are still controversial. We performed a meta-analysis of randomized controlled trials (RCTs) on the efficacy of RST in patients with ALS.

METHODS: PubMed, Embase and Cochrane Central were searched for RCTs comparing the use of RST with sham therapy or minimal device load in patients with ALS. The main outcomes were maximal expiratory pressure (MEP), maximal inspiratory pressure (MIP) and the ALS functioning rating scale (ALSFRS-R) score. Statistical analysis was performed using R software and heterogeneity was assessed with I[2] statistics.

RESULTS: Four RCTs were included with a total of 138 patients. RST was used to treat 69 (50 %) patients. The mean age was 60.2 ± 10.4 years, with 82 (62.3 %) male patients. Follow-up ranged from 2 to 8 months. Subgroup analysis of expiratory muscle training protocols showed a statistically significant improvement in MEP (MD 20.22 cmH2O; 95 % CI 2.66-37.77; p = 0.04). In overall analyses, there was no difference between groups regarding MEP (MD 9.40 cmH2O; 95 % CI -11.57-30.37; p = 0.25), MIP (MD 3.26 cmH2O; 95 % CI -9.23-15.75; p = 0.38), FVC (MD 4.05 %predicted; 95 % CI -0.91-9.01; p = 0.08) and ALSFRS-R score (MD 0.01 points; 95 % CI -0.29-0.32; p = 0.85).

CONCLUSION: In this meta-analysis of RCTs including patients with ALS, expiratory muscle training was associated with increased MEP compared with sham or minimal load. However, no statistically significant associations were found for overall RST in MIP, FVC, MEP, and ALSFRS-R.}, } @article {pmid41354564, year = {2026}, author = {Mouhi, S and Pio, T and Andersen, J}, title = {Revisiting oligodendrocytes in amyotrophic lateral sclerosis using human multicellular stem cell models.}, journal = {Trends in cell biology}, volume = {36}, number = {9}, pages = {778-793}, pmid = {41354564}, issn = {1879-3088}, support = {F31 NS135955/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Oligodendroglia/pathology/metabolism ; Animals ; *Models, Biological ; *Stem Cells ; Cell Lineage ; Cell Differentiation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration, muscle wasting, and eventual paralysis. The clinical and genetic complexity along with rapid disease progression has hindered efforts to model the disease and develop effective treatments. Rodent models and human tissue studies point to dysfunction in oligodendrocyte lineage cells early in disease, although the underlying mechanisms remain unclear. Advances in stem cell research have introduced novel platforms to investigate cells in the oligodendrocyte lineage and their interactions with neurons and other glial cells in complex human genetic backgrounds. This Review summarizes the literature implicating oligodendrocyte lineage cells in ALS and discusses both the potential and limitations of in vitro-derived cultures to shed light on their vulnerabilities and cellular interactions.}, } @article {pmid41354852, year = {2025}, author = {Oraha, J and Wagner, R and Bergh, S and Lee, NJ and Kirik, D and Petersén, Å}, title = {Differential effects of overexpression of mutant huntingtin and TDP-43 in agouti-related protein neurons in the arcuate nucleus of the hypothalamus in mice.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {253}, pmid = {41354852}, issn = {2051-5960}, mesh = {Animals ; *DNA-Binding Proteins/genetics/metabolism ; *Neurons/metabolism/pathology ; *Agouti-Related Protein/metabolism/genetics ; Male ; *Arcuate Nucleus of Hypothalamus/metabolism/pathology ; Female ; Mice ; Mice, Transgenic ; *Nerve Tissue Proteins/genetics/metabolism ; Huntingtin Protein ; Humans ; Mutation/genetics ; *Nuclear Proteins/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {The spectrum of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) and Huntington disease (HD) are fatal neurodegenerative disorders with no major disease-modifying therapies. Recent work has shown that the hallmark pathological proteins TAR DNA binding protein of 43 kDa (TDP-43) in FTD/ALS and mutant huntingtin (mHTT) in HD may be interlinked. Furthermore, these disorders share early features of altered metabolism and psychiatric symptoms that have been suggested to arise from pathology in the hypothalamus, an important brain region involved in the regulation of metabolism and emotions. Agouti-related protein (AgRP)-expressing neurons localised exclusively to the arcuate nucleus (ARC) of the hypothalamus are key modulators of body weight regulation and food seeking behaviour, and they have recently been implicated in anxiety- and anhedonic-like processes. The aim of this study was to investigate the effects of overexpression of TDP-43 or mHTT in AgRP-expressing neurons on metabolic, behavioral and neuropathological features in mice. Flex-switch adeno associated viral vectors expressing human wild-type TDP-43, mHTT or green fluorescent protein to serve as a control, were injected into male and female AgRP-Cre mice to target the ARC using stereotactic surgery. We demonstrate targeted overexpression of transgenes including formation of mHTT inclusions in the ARC of the hypothalamus. Overexpression of mHTT led to a significant reduction in AgRP fibres in the hypothalamus 21 weeks post-injection, as well as higher food consumption in female mice. Overexpression of TDP-43 did not lead to the development of any metabolic or behavioral phenotypes in the mice. Our data suggest that AgRP neurons in the ARC are protected from the toxic effects resulting from overexpression of TDP-43 whereas they display some sensitivity to mHTT overexpression resulting in mHTT inclusion formation, reduction in AgRP fibers and sex-specific effects on food consumption. Taken together, other hypothalamic neuronal populations may be more important for the development of non-motor features resulting from overexpression of TDP-43 and mHTT in the hypothalamus.}, } @article {pmid41354869, year = {2025}, author = {Tahedl, M and Kleinerova, J and McKenna, MC and Siah, WF and Hardiman, O and Hengeveld, JC and Doherty, MA and McLaughlin, RL and Tan, EL and Hutchinson, S and Bede, P}, title = {Putative mitochondrial components of frontotemporal lobar degeneration: topological correlations between mitochondrial density and atrophy in FTLD/FTD phenotypes.}, journal = {Journal of neurology}, volume = {273}, number = {1}, pages = {11}, pmid = {41354869}, issn = {1432-1459}, support = {(HRB EIA-2017-019/HRBI_/Health Research Board/Ireland ; JPND-Cofund-2-2019-1/HRBI_/Health Research Board/Ireland ; SFI SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {Humans ; Male ; Female ; Atrophy/pathology ; *Frontotemporal Lobar Degeneration/pathology/diagnostic imaging/metabolism/genetics ; Middle Aged ; Aged ; *Mitochondria/pathology/metabolism ; *Frontotemporal Dementia/pathology/diagnostic imaging ; Phenotype ; Magnetic Resonance Imaging ; *Brain/pathology/diagnostic imaging ; Prospective Studies ; }, abstract = {BACKGROUND: Frontotemporal lobar degeneration encompasses a spectrum of clinically, radiologically, and molecularly heterogeneous conditions. Clinical phenotypes are defined based on predominant neuropsychological manifestations and the selective involvement of specific brain regions determines the core symptoms, disability profiles, and care needs. While the unique anatomical patterns of cortical and subcortical degeneration along the FTLD/FTD spectrum are well recognised, the molecular basis of this selective vulnerability remains unclear.

METHODS: A large prospective neuroimaging study has been undertaken to explore topological associations between phenotype-specific atrophy patterns and physiological mitochondrial density along the FTLD/FTD spectrum. Patients with behavioural variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), semantic variant primary progressive aphasia (svPPA), C9orf72-positive ALS-FTD, C9orf72-negative ALS-FTD, and a cohort of healthy controls (HC) were included. FTD phenotypes were first contrasted to healthy controls and the resulting voxelwise maps were correlated to physiological mitochondrial density maps.

RESULTS: We have identified voxelwise associations between atrophic change and physiological mitochondrial density. The resulting correlation coefficients over the entire GM mask revealed weak topological associations with r = 0.217 in C9NEG ALS-FTD, r = 0.251 in C9POS ALS-FTD, r = 0.213 in bvFTD, r = 0.182 in nfvPPA, and r = 0.292 in svPPA at p FWE < 0.001. Our region-of-interest analyses revealed moderate-to-strong regional associations between mitochondrial density and focal degenerative change with r values above 0.65 in multiple brain regions in all five FTD subgroups. Brain regions exhibiting the most significant associations between volume loss and mitochondrial density in each FTD subgroup are the very regions that define the core clinical manifestations of the given phenotype.

DISCUSSION: Cortical and subcortical brain regions with high physiological mitochondrial density are particularly vulnerable to neurodegenerative change in FTD. While these anatomical associations do not indicate direct causation, mitochondrial metabolism may represent an important component in the cascade of focal degeneration.}, } @article {pmid41355735, year = {2025}, author = {Pal, P and Carrer, M and Weiss, L and Jaime, OG and Cheng, C and Shmara, A and Boock, V and Bosch, D and Youssef, M and Fazeli, Y and Afetian, M and Grossman, TR and Hicks, MR and Jafar-Nejad, P and Kimonis, V}, title = {Antisense oligonucleotides targeting valosin-containing protein ameliorate muscle pathology and molecular defects in cell and mouse models of multisystem proteinopathy.}, journal = {Clinical and translational medicine}, volume = {15}, number = {12}, pages = {e70530}, pmid = {41355735}, issn = {2001-1326}, support = {UM1 TR004927/TR/NCATS NIH HHS/United States ; //Cure VCP Disease Inc. Ionis Pharmaceuticals, Inc./ ; 1297770//Muscular Dystrophy Association/ ; }, mesh = {Animals ; *Valosin Containing Protein/genetics/metabolism/antagonists & inhibitors ; Mice ; *Oligonucleotides, Antisense/pharmacology/therapeutic use ; Disease Models, Animal ; Humans ; Muscle, Skeletal/pathology ; Muscular Dystrophies, Limb-Girdle/genetics ; Frontotemporal Dementia/genetics ; Myositis, Inclusion Body ; Osteitis Deformans/genetics ; }, abstract = {BACKGROUND: Valosin-containing protein (VCP) related disease, also known as multisystem proteinopathy 1 (MSP1), is an autosomal dominant disease caused by gain-of-function pathogenic variants of the VCP gene. The disease presents with variable combinations of inclusion body myopathy, early-onset Paget's disease of bone, frontotemporal dementia and may also overlap with familial amyotrophic lateral sclerosis. There is currently no treatment for this progressive disease associated with early demise resulting from proximal limb girdle and respiratory muscle weakness. We hypothesise that regulating VCP hyperactivity to normal levels can reduce the disease pathology.

MAIN TOPICS COVERED: In this study, we assessed the effect of antisense oligonucleotides (ASOs) specifically targeting the human VCP gene in the patient (R155H) iPSC-derived skeletal muscle progenitor cells (SMPCs). ASOs were well tolerated up to a concentration of 5 µM and significantly reduced VCP protein expression in the SMPCs by 48% (95% CI [39-56]). We also treated the transgenic mouse model of VCP disease with the overexpressed humanised VCP severe A232E pathogenic gene variant (VCP A232E mice) with weekly subcutaneous ASO injections starting from 6 months of age for 3 months. In the skeletal muscle of transgenic mice, ASOs resulted in 30% (95% CI [27-32]) knockdown of VCP protein compared with control ASO. The ASO-mediated reduction of VCP expression in muscle tissue was associated with improvement in autophagy flux and reduction in TAR DNA binding protein 43 (TDP-43) expression, hallmarks of VCP related MSP1. In addition, ASO-treated VCP A232E mice showed improvements in functional tests of muscle strength, such as rotarod and inverted screen test compared with mice treated with control ASO.

CONCLUSIONS: These results suggest that targeting VCP could be beneficial in preventing the progression of the VCP myopathy and hold promise for the treatment of patients with VCP related MSP1.

KEY POINTS: VCP multisystem proteinopathy 1 is caused by gain-of-function pathogenic variants of the VCP gene. VCP targeting ASOs were well tolerated and significantly reduced VCP, TAR DNA binding protein 43 (TDP 43), and autophagy protein expression in the (R155H) iPSC-derived skeletal muscle progenitor cells (SMPCs). The ASOs reduced VCP, TDP-43, and autophagy flux expression, and improved functional tests of muscle strength in the humanized VCP A232E mice.}, } @article {pmid41356579, year = {2025}, author = {Seyam, MK and Shaik, RA and Miraj, M and Alzahrani, NS and Shaik, AR and Ajmera, P and Kalra, S and Miraj, SA and Shawky, GM and Nurani, KM and A, P}, title = {Effect of mobile phone applications on medication adherence among patients with coronary artery diseases: A scoping review.}, journal = {World journal of cardiology}, volume = {17}, number = {11}, pages = {114140}, pmid = {41356579}, issn = {1949-8462}, abstract = {Patients with cardiovascular disease rely on medication to achieve favorable long-term clinical results. Poor adherence has been linked to a relative increase in mortality of 50%-80% as well as higher health care costs. This scoping review thus aimed to explore the evidence of the effects of mobile health care apps on medication adherence in patients with cardiovascular diseases. A comprehensive data search and extraction was done in line with the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist. A total of 10 studies were included for the review. The mean pooled improvement in adherence was found to be 18% and the most effective tool was the digital therapeutics app discussed in Li et al's study. Smartphones and apps enhance coronary artery disease management by promoting medication compliance. Challenges include data security and smartphone usage among the elderly. Tailored apps or voice assistants offer potential solutions.}, } @article {pmid41356587, year = {2025}, author = {Liu, HR and Weng, JL}, title = {Interpreting fractional flow reserve-guided percutaneous coronary intervention vs coronary artery bypass grafting outcomes.}, journal = {World journal of cardiology}, volume = {17}, number = {11}, pages = {113225}, pmid = {41356587}, issn = {1949-8462}, abstract = {Kataveni et al's meta-analysis offers an important contemporary synthesis of randomized evidence comparing fractional flow reserve-guided percutaneous coronary intervention and coronary artery bypass grafting (CABG) in multivessel coronary artery disease (CAD). The pooled analysis found no significant difference in all-cause mortality or stroke, yet CABG was superior in reducing myocardial infarction, major adverse cardiac events, and repeat revascularization. These results confirm CABG's durability even in the era of physiological lesion assessment and second-generation drug-eluting stents. From a traditional Chinese medicine (TCM) perspective, multivessel CAD corresponds to syndromes such as "heart vessel obstruction" and "Qi and blood stagnation", in which local blockage is compounded by systemic imbalance. While revascularization addresses the structural impediment to blood flow, TCM approaches, including herbal medicine, acupuncture, and lifestyle therapy, aim to improve microcirculation, reduce inflammation, and support recovery, potentially mitigating recurrent ischemic events. This commentary argues that future research should integrate optimal revascularization strategies with rigorously evaluated TCM interventions to address both the anatomical and systemic dimensions of CAD and improve long-term patient outcomes.}, } @article {pmid41359166, year = {2026}, author = {Gondim, FAA and Fernandes, JMA and Dutra Junior, AM and Thomas, FP}, title = {Four families with slowly progressive ALS due to p.Val120Leu SOD1 variant in Northeast Brazil.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {393-397}, doi = {10.1080/21678421.2025.2597943}, pmid = {41359166}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *Superoxide Dismutase-1/genetics ; Male ; Female ; Brazil/epidemiology ; Middle Aged ; Adult ; Disease Progression ; Pedigree ; *Mutation/genetics ; Aged ; }, abstract = {Objective: SOD1 mutations are the second most prevalent variants in amyotrophic lateral sclerosis (ALS). Epidemiological data about SOD1 mutations are scarce in Brazil. Here, we report the clinical and genetic findings of four Brazilian families with p.Val120Leu SOD1 variant. Methods: This study is part of an epidemiological study of the prevalence of ALS conducted in the State of Ceará, Brazil. We reviewed the medical records of families with p.Val120Leu (c.358G > C, exon 5) SOD1 variant seen at the Walter Cantídio University Hospital, Federal University of Ceará, Brazil. Results: We identified 15 patients from 4 families with p.Val120Leu SOD1 variant among 251 ALS patients. Of these, six were personally examined and had ALS confirmed and five had confirmatory genetic testing (four homozygous and one heterozygous). C9orf72 testing was normal in the heterozygous patient. In two families, three older heterozygous patients (genetically tested) had no signs or symptoms of ALS. The mean age of symptom onset was 46.7 ± 13.4 years. Features of ALS in the four families were very similar, with prolonged disease duration and upper and lower motor neuron involvement, fulfilling the Revised El Escorial, Awaji, and Gold Coast diagnostic criteria. All examined living patients had limb onset and a few bulbar symptoms. Conclusion: p.Val120Leu SOD1 variant leads to slowly progressive ALS with incomplete penetrance. Our findings are similar to a previous report of ALS due to p.Asp90Ala SOD1 variant.}, } @article {pmid41359202, year = {2025}, author = {Guerra-Hernández, J and Mauro-Gutiérrez, F and Rodríguez-Puerta, F and Pascual, A}, title = {Scaling and sampling dependencies of forest canopy height mapping towards jurisdictional biomass reporting using airborne LiDAR and small-area estimation.}, journal = {Carbon balance and management}, volume = {21}, number = {1}, pages = {12}, pmid = {41359202}, issn = {1750-0680}, support = {2023.15225.TENURE.008//Fundação para a Ciência e a Tecnologia/ ; PID2022-140104OA-I00//Spanish Ministry of Science and Innovation/ ; }, abstract = {Consolidated airborne laser scanning (ALS) programs, satellite imagery and spaceborne structural measurements have enabled major advances in canopy height mapping that translate towards the forest carbon biomass arena. However, we must carefully evaluate the cost of using fine-grained canopy height products to predict biomass under calibration models scoped at the scale of inventory plots. In this study, we estimated biomass using field plots and ALS metrics before predicting biomass over a jurisdiction of ~ 15,500 km[2] in Spain using 10 m, 25 m, 44 m, and 100 m as prediction scales. We altered the scale of ALS-based biomass predictors in 10 sub-jurisdictions intensively surveyed by the Spanish National Forest Inventory (NFI) before estimating mean and total biomass using three options: (i) traditional NFI design-based (DB) estimation, (ii) a model-based (MB) approach using scale-varying canopy height metrics from ALS and NFI plots, and (iii) an small-area estimation (SAE) implemntation designed for sub-jurisdictional domains. Higher uncertainties - relative standard errors (SE) - were found for DB, particularly at sub-jurisdictional and stratum levels. We observed a consistent increase in uncertainty for MB estimation from the finest 10 m scale up to 100 m. In MB estimation, the maximum relative bias reached 11% for 10-m predictions compared to the baseline estimate at the NFI sampling native resolution. The bias associated with the prediction scale ranged from + 5% (25 m) to -8% (100 m). The mean biomass estimates for SAE generally ranged between DB and MB but at lower uncertainty to the former, especially as the NFI sampling becomes scarcer and not enough for solid inference of biomass mean. The SEA statistics helped to disentangle biomass comparisons between ALS-based inference and the traditional NFI estimation that do not incorporate remote sensing data.}, } @article {pmid41359433, year = {2026}, author = {Zulhairy-Liong, NA and Edgar, S and Ellis, M and Zhu, D and Lai, K and Capelle, DP and Sabirin, S and Pek, EW and Nair, P and Ang, CM and Kennerson, ML and Shahrizaila, N and Ahmad-Annuar, A}, title = {Novel and rare variants in amyotrophic lateral sclerosis genes identified in Malaysian patients.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {328-337}, doi = {10.1080/21678421.2025.2582832}, pmid = {41359433}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Malaysia/epidemiology ; Male ; Female ; Middle Aged ; RNA-Binding Protein FUS/genetics ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; DNA-Binding Proteins/genetics ; Ataxin-2/genetics ; Aged ; Adult ; Asian People/genetics ; Mutation/genetics ; Genetic Predisposition to Disease/genetics ; }, abstract = {There is limited information on the genetic architecture of amyotrophic lateral sclerosis (ALS) in Southeast Asian populations. To address this knowledge gap, we performed 1) SOD1 (exon 1-4), FUS (exon 13-15), TARDBP (exon 6) and ATXN2 repeat expansion screening in 201 multi-ethnic Malaysian (Malay, Chinese, Indian and others) ALS patients, 2) C9orf72 repeat expansion testing in 179 subset patients, and 3) a panel of 61 ALS-associated genes screening in 112 subset cases using either whole genome (n = 21) or exome (n = 91) sequencing datasets. Among the patients, the observed mutational frequencies in key ALS genes were: SOD1 3.0% (6/201), C9orf72 2.2% (4/179), ATXN2 2.0% (4/201), FUS 1.5% (3/201), and TARDBP 1.5% (3/201). Of the 112 cases that underwent WGS/WES, 6.3% (7/112) comprised of pathogenic and likely pathogenic variants in FIG4 (p.Lys657Serfs*2), FUS (p.Arg485Profs*32), TARDBP (p.Ile383del), NEK1 (p.Ile633Asnfs*28), GRN (c.599-1G > C), CYP27A1 (p.Met1Thr) and SPAST (p.Glu449Gly). Additionally, 42.9% (48/112) had at least one variant of uncertain significance (VUS) in 34 genes. Notably, in the 24 genes classified as 'definitive' by the ClinGen ALS Spectrum Disorders Gene Curation Expert Panel, five patients (4.5%, 5/112) harbored more than one likely pathogenic variant and/or VUS. However, burden analysis revealed no significant differences in clinical characteristics between patients with varying numbers of variants. Our findings highlight the utility of next-generation sequencing in elucidating the genetic basis of ALS in Malaysian and Southeast Asian ethnic groups, including the identification of several novel variants of clinical interest as well as increasing diagnostic yield up to 47.7%.}, } @article {pmid41360752, year = {2026}, author = {Ma, JY and Wang, X and Cai, Y and Wang, G and Lu, M and Feng, K and Zhao, Y and Wu, X and Zhang, X and Wu, H and Yu, W and Ma, M and Ge, Z and Zhang, Y}, title = {Anionic Liposomes as Optimal Membrane Fusion Carriers Enabling in Situ Multiplexed Detection of Extracellular Vesicle MicroRNAs.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {10}, pages = {e19758}, pmid = {41360752}, issn = {2198-3844}, support = {2022YFA1205802//National Key Research and Development Program of China/ ; 2022YFC2406504//National Key Research and Development Program of China/ ; 82572399//National Natural Science Foundation of China/ ; 82302370//National Natural Science Foundation of China/ ; BF2024062//Frontier Technologies R&D Program of Jiangsu/ ; BK20230836//Natural Science Foundation of Jiangsu Province/ ; KYCX24_0471//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; CXJH_SEU 25140//SEU Innovation Capability Enhancement Plan for Doctoral Students/ ; }, mesh = {*Extracellular Vesicles/genetics/metabolism ; Humans ; *Liposomes/chemistry ; *MicroRNAs/analysis/genetics ; Liquid Biopsy/methods ; *Membrane Fusion ; Anions/chemistry ; Biomarkers, Tumor ; }, abstract = {Extracellular vesicle (EV) microRNAs (miRNAs) are promising liquid biopsy biomarkers for non-invasive diagnosis, monitoring, and therapeutic evaluation of cancer. However, sensitive EV miRNA detection is hindered by complex pre-analytical processing. Here, the authors present an anionic liposome (AL) assisted membrane fusion strategy enabling one-step multiplexed quantification of EV miRNAs directly from plasma without EV isolation or RNA extraction, termed EValarm (Anionic Liposome Assisted miRNAs Monitoring for Extracellular Vesicles). Liposomes encapsulating probes are prepared using a microfluidic chip, achieving catalytic signal amplification after target recognition of miRNA. Systematic lipid screening identified ALs as optimal carriers, exhibiting minimal background and superior sensitivity compared to cationic and neutral liposomes. The AL-based assay delivered accuracy comparable to quantitative PCR with a streamlined workflow. Applied to 106 clinical samples from lymphoma patients and healthy controls, integration with artificial intelligence achieved high accuracy (AUC > 0.99). In summary, this study demonstrates a platform enabling direct and sensitive plasma EV miRNA detection, offering strong potential for clinical translation in cancer liquid biopsy.}, } @article {pmid41361196, year = {2025}, author = {Zhao, R and Bai, Y and Zhang, S and Zhu, J and Liu, H and Ni, G}, title = {An open dataset of multidimensional signals based on different speech patterns in pragmatic Mandarin.}, journal = {Scientific data}, volume = {12}, number = {1}, pages = {1934}, pmid = {41361196}, issn = {2052-4463}, mesh = {Humans ; *Speech ; Electroencephalography ; *Language ; Brain-Computer Interfaces ; Electromyography ; China ; Brain/physiology ; }, abstract = {Speech is essential for human communication, but millions of people lose the ability to speak due to conditions such as amyotrophic lateral sclerosis (ALS) or stroke. Assistive technologies like brain-computer interfaces (BCIs), can convert brain signals into speech. However, these technologies still face challenges in decoding accuracy. This issue is especially challenging for tonal languages like Mandarin Chinese. Furthermore, most existing speech datasets are based on Indo-European languages, which hinders our understanding of how tonal information is encoded in the brain. To address this, we introduce a comprehensive open dataset, which includes multimodal signals from 30 subjects using Mandarin Chinese across overt, silent, and imagined speech modes, covering electroencephalogram (EEG), surface electromyogram (sEMG), and speech recordings. This dataset lays a valuable groundwork for exploring the neural encoding of tonal languages, investigating tone-related brain dynamics, and improving assistive communication strategies. It supports cross-linguistic speech processing research and contributes to data-driven neural speech decoding technology innovations.}, } @article {pmid41361897, year = {2026}, author = {Rosenfeld, J and Abrahams, S and McHutchinson, C and Ajroud-Driss, S and Weber, M and Paganoni, S and Mitsumoto, H and Genge, A and Grosskreutz, J and Van Den Berg, L and Andrews, J and Kiernan, MC}, title = {Utility of patient subgrouping in ALS clinical trials: a World Federation of Neurology white paper.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {493-500}, doi = {10.1080/21678421.2025.2593308}, pmid = {41361897}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/classification/diagnosis ; *Clinical Trials as Topic/methods ; *Neurology/standards ; *Societies, Medical/standards ; }, abstract = {The heterogeneity among the amyotrophic lateral sclerosis (ALS)/MND patient population is well recognized but not well understood. Such heterogeneity may represent a significant confound in our current and prior clinical trials as certain subgroups of patients might have a selective response (or resistance) to a novel therapeutic. The basis on which to segregate the patient population is, however, unclear. The ALS/MND Committee of the World Federation of Neurology (WFN) convened a symposium to discuss various strategies that might be considered for separating (stratifying) the population to further study. The results of that conference are presented here as a white paper, reflecting current understanding of several of the various criteria that could be implemented to divide the patient population as presented and discussed at that meeting. Consideration of grouping patients based on phenotype, cognitive involvement, imaging, or electrophysiology is presented here.}, } @article {pmid41362129, year = {2026}, author = {Ma, T and Zhu, H and Zhu, J and Zhao, J and Zhao, X}, title = {Evaluation of Pathogenicity, Host Resistance, Biological Properties, and Chemical Control of Xanthomonas fragariae Strain JD1 Causing Angular Leaf Spot on Strawberry.}, journal = {Plant disease}, volume = {110}, number = {7}, pages = {2702-2710}, doi = {10.1094/PDIS-10-25-2070-RE}, pmid = {41362129}, issn = {0191-2917}, mesh = {*Fragaria/microbiology/immunology ; *Plant Diseases/microbiology/immunology ; *Xanthomonas/pathogenicity/drug effects/genetics/physiology ; Plant Leaves/microbiology/immunology ; Phylogeny ; RNA, Ribosomal, 16S/genetics ; *Disease Resistance ; Virulence ; China ; }, abstract = {Angular leaf spot (ALS), caused by the quarantine pathogen Xanthomonas fragariae, is a major bacterial disease threatening global strawberry production. In China, its continued spread across multiple regions poses a significant and persistent epidemiological threat to the strawberry industry. Recently, ALS has emerged as a great threat to the strawberry industry in Jiande, Zhejiang Province (located at 29°N, 119°E). This study reports the first isolation and characterization of X. fragariae strain JD1 from symptomatic strawberry leaves in Jiande, Zhejiang Province. The identification of strain JD1 was confirmed through species-specific PCR, analysis of colony characteristics, and phylogenetic clustering based on 16S rRNA and HrpB gene sequences. Pathogenicity assays revealed strain JD1 resulted in water-soaked lesions progressing to necrotic patches on leaves, along with systemic colonization of crown tissues showing water-soaked, reddish-brown lesions without cavity formation. Additionally, resistance evaluation across six strawberry cultivars revealed that 'Yue Xiu' was the most susceptible, followed closely by 'Jiande Hong', 'Hong Yu', 'Li Fen', and 'Hong Yan', while 'Fen Yu' exhibited the highest resistance. Biological characterization showed that strain JD1 grows optimally at 25°C and pH 7.0, with significant inhibition observed at 35°C and under acidic (pH 4) or alkaline (pH 9) conditions. In bactericide screening, tetramycin and benziothiazolinone were identified as highly effective against X. fragariae strain JD1, followed by sintracin acetate aqueous with minor efficacy, whereas kasugamycin and quinoline copper showed limited or no efficacy. Collectively, these findings not only emphasize the threat posed by X. fragariae strain JD1 to strawberry production but also provide critical insights that inform integrated management strategies, including the use of resistant cultivars, environmental controls, and targeted bactericides, for controlling ALS.}, } @article {pmid41364388, year = {2026}, author = {Levine, AA and Rucker, JA and Cockerham, A and Cartner, J and Chambers, JD}, title = {U.S. health plan coverage of Neuromuscular Disease Therapies: An assessment of policy availability and restrictions.}, journal = {Journal of neuromuscular diseases}, volume = {13}, number = {3}, pages = {436-444}, pmid = {41364388}, issn = {2214-3602}, mesh = {Humans ; United States ; *Neuromuscular Diseases/therapy/economics ; *Insurance Coverage/statistics & numerical data ; *Health Policy ; *Medicaid/statistics & numerical data ; *Insurance, Health/statistics & numerical data ; }, abstract = {BACKGROUND: Health plan policies managing neuromuscular disease (NMD) therapies may impose burdensome requirements on patients and providers. While prior research has explored payer restrictions for rare NMD treatments, limited evidence exists on policies specifically governing therapy initiation and reauthorization.

OBJECTIVES: To examine initial and reauthorization coverage policies for therapies targeting five NMDs-Duchenne muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, generalized myasthenia gravis, and Lambert-Eaton myasthenic syndrome-across all U.S. state Medicaid programs and leading commercial health plans.

METHODS: We constructed a database of coverage decisions issued by 50 states and DC Medicaid programs and 35 major commercial insurers, including both fee-for-service and managed care organizations. We analyzed (1) policy availability and coverage frequency, (2) initial coverage requirements (e.g., subgroup restrictions, step therapy, prescriber type), (3) reauthorization criteria, and (4) approval durations.

RESULTS: Of 1204 potential decisions, 908 (75%) had publicly available policies. Of these, 558 (46%) included reauthorization criteria. Among covered therapies, 96% imposed restrictions beyond FDA label indications. Requirements varied by payer type, NMD, and therapy. Average approval durations were 6 months for initial coverage and 10 months for reauthorization.

CONCLUSIONS: Many plans lacked publicly accessible policies, and most covered therapies were subject to restrictive requirements. These barriers-such as step therapy, narrow prescriber criteria, and short approval periods-may delay treatment and disrupt care continuity. Findings underscore the need for greater transparency and reform in prior authorization and pharmacy benefit design to support timely access to NMD therapies.}, } @article {pmid41364409, year = {2026}, author = {Matur, Z and Deveci, Ş and Erdal, Y}, title = {Correlations of cerebrospinal fluid neurofilament light chain levels with clinical and electromyography findings in amyotrophic lateral sclerosis.}, journal = {Irish journal of medical science}, volume = {195}, number = {2}, pages = {975-983}, pmid = {41364409}, issn = {1863-4362}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/physiopathology/diagnosis ; Male ; *Neurofilament Proteins/cerebrospinal fluid ; Female ; Middle Aged ; Retrospective Studies ; Electromyography ; Aged ; Adult ; Biomarkers/cerebrospinal fluid ; Case-Control Studies ; }, abstract = {BACKGROUND: This study aimed to examine correlations between cerebrospinal fluid neurofilament light chain (CSF NfL) levels, and clinical and electrophysiological findings in amyotrophic lateral sclerosis (ALS). Compare CSF NfL and total protein levels between ALS and other central nervous system (CNS) neurodegenerative disorders.

METHODS: This retrospective study analyzed 46 ALS patients (Gold Coast criteria) and 33 non-ALS neurodegenerative controls. We documented time from symptom onset to diagnosis, revised ALS Functional Rating Scale (ALSFRS-R) scores at CSF sampling, initial involvement regions (bulbar/cervical/lumbosacral), and extent of lower motor neuron (LMN) involvement.

RESULTS: ALS patients had significantly higher CSF NfL levels than non-ALS controls (4221 ± 2585 vs. 3004 ± 2788 pg/mL, p = 0.025). In the ALS group, CSF NfL levels showed significant inverse correlation with ALSFRS-R scores (r = -0.332, p = 0.024), and patients demonstrating involvement in all four-region on needle electromyography exhibited the highest CSF NfL levels. Among the ALS cohort 18 patients (39%) had died by the last follow-up, and patients who died during the study exhibited significantly higher baseline CSF NfL levels (median: 5115 pg/mL) compared to surviving patients (median: 3276 pg/mL; p = 0.007).

CONCLUSIONS: Our study demonstrated that CSF NFL levels were significantly elevated in ALS compared to other neurodegenerative disorders. Higher CSF NFL concentrations correlated with more rapid functional decline, more extensive LMN degeneration, and poorer survival outcomes.}, } @article {pmid41365127, year = {2026}, author = {Kulappu Arachchige, SN and Abeykoon, AMH and Stevenson, MA and Kanci Condello, A and Shil, PK and Tulman, ER and Szczepanek, SM and Silbart, LK and Underwood, GJ and Noormohammadi, AH and Geary, SJ and Wawegama, NK and Browning, GF}, title = {Assessment of tracheal mucosal thicknesses is a preferable method for evaluation of the immunogenicity of Mycoplasma gallisepticum vaccines in poultry.}, journal = {Vaccine}, volume = {72}, number = {}, pages = {128063}, doi = {10.1016/j.vaccine.2025.128063}, pmid = {41365127}, issn = {1873-2518}, mesh = {Animals ; *Mycoplasma gallisepticum/immunology ; *Bacterial Vaccines/immunology/administration & dosage ; *Poultry Diseases/prevention & control/immunology/microbiology ; *Mycoplasma Infections/prevention & control/veterinary/immunology ; *Trachea/pathology/immunology ; Chickens ; Vaccines, Attenuated/immunology/administration & dosage ; *Mucous Membrane/pathology ; *Immunogenicity, Vaccine ; Vaccine Efficacy ; Poultry ; Vaccination ; Air Sacs/pathology ; }, abstract = {Live-attenuated vaccines are commonly used to control chronic respiratory disease (CRD) caused by Mycoplasma gallisepticum in poultry. A previous review found that measures of tracheal lesions are better indicators of the validity of a vaccine efficacy test than air sac lesions. Here we extend those observations by comparing the raw tracheal mucosal thickness (TMT) and gross air sac lesion score (ALS) data from published vaccine efficacy studies to provide insights into standardising methods for evaluation of M. gallisepticum vaccine efficacy by identifying the most discriminative and reproducible parameter to demonstrate the efficacy of vaccines and the validity of immunogenicity tests. Our analyses revealed that a higher proportion of trials detected a ≥ 80 % effectiveness of challenge based on TMT, with a significantly lower number of biological replicates, than ALS. Furthermore, a significantly higher proportion of vaccinated-and-challenged groups had a proportion protected of ≥80 %, a reduction in lesions of ≥30 % and a mitigated fraction of ≥0.80, with a significantly lower number of biological replicates, compared to the positive-control group when analyses were based on TMT rather than ALSs. These findings indicate that TMT is a more discriminative and reproducible parameter to assess the efficacy of a vaccine and the validity of an efficacy test, and hence that this should be the primary outcome variable used to evaluate M. gallisepticum vaccine efficacy studies. Furthermore, the ability of TMT to discriminate these groups with fewer biological replicates enhances animal welfare by reducing the number of animals needed for efficacy studies.}, } @article {pmid41366746, year = {2025}, author = {Huang, J and Liu, Y and Li, M and He, R and Tang, Z and Lei, Y and Zha, Y and Wei, J}, title = {Safety and efficacy of botulinum toxin injection for sialorrhea in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {496}, pmid = {41366746}, issn = {1471-2377}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; *Sialorrhea/drug therapy/etiology ; *Botulinum Toxins/therapeutic use/adverse effects/administration & dosage ; Treatment Outcome ; *Neuromuscular Agents/therapeutic use/administration & dosage/adverse effects ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, with 80% of ALS patients experiencing bulbar weakness at some stage of the disease. ALS patients with bulbar weakness often suffer from troublesome sialorrhea. Botulinum toxin injection, as a neuromuscular blocker, has been widely used in the treatment of sialorrhea. This paper evaluates the safety and efficacy of botulinum toxin injections for the treatment of sialorrhea in ALS patients through a systematic review and meta-analysis. METHODS: A systematic review and meta-analysis was conducted by searching eight databases, including PubMed, EMBASE, and CNKI, up to April 13, 2025. Eligible randomized controlled trials and quasi-experimental studies were analyzed using Review Manager 5.4 and Stata software. RESULTS: Thirteen studies (2 RCTs, 11 quasi-experimental studies) with 130 ALS patients were included. Botulinum toxin significantly reduced sialorrhea and improved quality of life (Z = 10.98, p < 0.00001; RD = 0.82, 95% CI: 0.67–0.97). The treatment effect was independent of toxin type (p = 0.48), injection site (p = 0.17), and ultrasound guidance use (p = 0.44). CONCLUSION: Botulinum toxin appears to be a safe and effective option for managing sialorrhea in ALS patients, regardless of injection technique. However, given that most included studies were observational, further validation through high-quality RCTs is warranted. TRIAL REGISTRATION: This meta-analysis has been registered with Prospero, and the registration number is CRD420251029441. The registration period is April 9, 2025.}, } @article {pmid41366786, year = {2025}, author = {Saracino, D and Cipriano, L and Houot, M and Querin, G and Rinaldi, D and Rametti-Lacroux, A and Wallon, D and Gerardin, E and Couratier, P and Boncoeur, MP and Lebouvier, T and , and Colliot, O and Pradat, PF and Migliaccio, R and Le Ber, I}, title = {Quantifying multimodal longitudinal brain changes in presymptomatic C9orf72 disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70902}, pmid = {41366786}, issn = {1552-5279}, support = {PRTS2015-2019PREV-DEMALS//ANR/DGOS - Assistance Publique-Hôpitaux de Paris (Dr Le Ber)/ ; ANR-10-IAIHU-06//Agence Nationale de la Recherche (Dr Le Ber)/ ; 2019-JPW2-0005-01STRATALS//JPND/ANR (Dr Pradat and Dr Le Ber)/ ; ANR-23-IACL-0008, PRAIRIE-PSAI//Agence Nationale de la Recherche as part of the "France 2030" program/ ; ANR-19-P3IA-0001, projectPRAIRIE3IAInstitute//Agence Nationale de la Recherche as part of the "Investissements d'avenir" program/ ; 101136607, projectCLARA//European Union's HORIZON EUROPE Framework Programme/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/pathology ; *Brain/pathology/diagnostic imaging ; *C9orf72 Protein/genetics ; Disease Progression ; *Frontotemporal Dementia/genetics/diagnostic imaging/pathology ; *Gray Matter/pathology/diagnostic imaging ; Longitudinal Studies ; Magnetic Resonance Imaging ; *White Matter/pathology/diagnostic imaging ; }, abstract = {INTRODUCTION: The presymptomatic phase of frontotemporal dementia and amyotrophic lateral sclerosis associated with C9orf72 repeat expansion features widespread structural brain changes. We aimed at fulfilling the unmet need of quantitative magnetic resonance imaging (MRI)-derived measures suitable for disease tracking.

METHODS: We compared the profile of longitudinal gray (GM) and white matter (WM) changes in 66 presymptomatic carriers and 52 controls over 3-year follow-up and appraised their annualized rate of change (ARC).

RESULTS: Both putamen (p < 0.01) and left insula (p = 0.005) volumes declined the most in carriers over 40, with an ARC up to four-fold higher than in controls. Increases in mean diffusivity occurred first in the left uncinate fasciculus, followed by thalamo-cortical bundles (p < 0.05), associated with higher neurofilament levels.

DISCUSSION: Our study highlighted the GM and WM structures showing the greatest longitudinal decline during the preclinical stage, whose ARC may serve as an MRI-derived biomarker for longitudinal surveillance and therapeutic outcome.

CLINICAL TRIAL REGISTRATION: NCT02590276 and NCT05358431.

HIGHLIGHTS: We studied longitudinal multimodal MRI changes in presymptomatic C9orf72 disease. Carriers displayed faster atrophy in putamen, insula and cerebellar regions. Mean diffusivity increased mainly in uncinate and thalamo-cortical tracts. These differences were even more significant in older (> 40) participants. We proposed targeted annualized rate of change as a quantitative biomarker.}, } @article {pmid41366852, year = {2025}, author = {Barahona-López, C and Plans-Beriso, E and Diez-Echave, P and Hernández, O and de Larrea, NF and Craciun, O and García-Ovejero, E and Petrova, D and Fernández-Martínez, NF and Arruabarrena-Blanco, E and Babb-de-Villiers, C and Turner, H and Jimenez, RC and Erady, C and Wilson, H and Fernández-Navarro, P and García-Esquinas, EG and Kuhn, I and Sánchez, P and Rodríguez-Artalejo, F and Sánchez, MJ and Moreno, V and Blackburn, L and Pollán, M and Kroese, M and Perez-Gomez, B}, title = {Personalized prevention of neurodegenerative diseases: scoping review and evidence gap map.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70980}, pmid = {41366852}, issn = {1552-5279}, support = {001/WHO_/World Health Organization/International ; 10040946//UKRI/ ; 101057721//Horizon Europe / H2020 Health/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/prevention & control/genetics ; Biomarkers ; *Precision Medicine/methods ; Evidence Gaps ; }, abstract = {Neurodegenerative diseases represent a major public health challenge due to their high prevalence and poor prognosis. Identifying biomarkers to stratify individuals by their risk of developing these diseases may help to define new personalized prevention interventions. The objective of this study was to conduct a scoping review of biomarkers for primary and secondary personalized prevention of neurodegenerative diseases. The search targeted biomarkers in adults or high-risk subpopulations in clinical or public health settings for Alzheimer's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Ultimately, 286 papers were included in the review and the interactive gap map. There is a strong focus on Alzheimer's disease, and most papers included -omics-based biomarkers and/or used artificial intelligence. Genetics/genomics are at the forefront of current scientific research, although there is a notable gap in studying gene-environment interactions, and studies in clinical settings are still scarce. HIGHLIGHTS: Research indicates a strong focus on Alzheimer´s disease and limited research in other diseases. Genetics and genomics are at the forefront of current scientific research. We found biomarkers for predicting progression in mild cognitive decline. There is a notable gap in studying gene-environment interactions. Studies investigating biomarkers in a clinical context are still scarce.}, } @article {pmid41367793, year = {2025}, author = {Yu, L and Yang, Z and Ming, Z and Zeng, S}, title = {Evaluation of ascending aorta and radial artery elasticity in patients with type 2 diabetes mellitus via velocity vector imaging.}, journal = {Quantitative imaging in medicine and surgery}, volume = {15}, number = {12}, pages = {12044-12054}, pmid = {41367793}, issn = {2223-4292}, abstract = {BACKGROUND: A decrease in arterial elasticity may contribute to accelerated atherosclerosis, the sequelae of which are the most common causes of death in type 2 diabetes mellitus (T2DM) patients. The aim of this study was to assess ascending aorta (AA) and radial artery (RA) elasticity in T2DM patients via velocity vector imaging (VVI).

METHODS: We enrolled 50 patients with T2DM and 52 age- and sex-matched nondiabetic individuals as controls. All the participants underwent echocardiography and RA ultrasound examinations. AA elasticity parameters, i.e., ascending aortic mean longitudinal strain (ALS), ascending aortic global circumferential strain (ACS), ascending aortic fractional area change (FAC), and RA elasticity parameters, i.e., radial arterial mean longitudinal strain (RLS) and radial arterial global circumferential strain (RCS), were evaluated with VVI. The differences in arterial elasticity parameters between diabetic and non-diabetic patients were evaluated by a paired t-test. Spearman correlation coefficients were calculated to demonstrate the relationship between arterial elasticity parameters and clinical risk factors and cardiovascular biometrics in T2DM patients.

RESULTS: We found that the T2DM group presented significantly lower ALS, ACS, FAC, RLS and RCS values than the control group did (all P<0.05). There were significant associations between all arterial elasticity parameters and glycosylated hemoglobin (HbA1c) and diabetes duration (ALS and HbA1c: r=-0.36, ALS and diabetes duration: r=-0.52, ACS and HbA1c: r=-0.32, ACS and diabetes duration: r=-0.38, FAC and HbA1c: r=-0.36, FAC and diabetes duration: r=-0.32, RLS and HbA1c: r=-0.39, RLS and diabetes duration: r=-0.46, RCS and HbA1c: r=-0.31, RCS and diabetes duration: r=-0.39, respectively; P<0.01). Additionally, the ALS was significantly negatively correlated with fasting plasma glucose (FPG) (r=-0.30, P<0.05).

CONCLUSIONS: The elasticity of the AA and RA in T2DM patients was impaired. Decreased arterial elasticity was associated with poor blood glucose control and a longer duration of diabetes. Further studies are needed to assess the clinical value of VVI findings for predicting future cardiac events.}, } @article {pmid41368443, year = {2025}, author = {Shamsi, A and Alrouji, M and AlOmeir, O and Tasqeruddin, S and Dinislam, K and Zuberi, A}, title = {Correction: CRISPR-Cas9: bridging the gap between aging mechanisms and therapeutic advances in neurodegenerative disorders.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1739705}, doi = {10.3389/fncel.2025.1739705}, pmid = {41368443}, issn = {1662-5102}, abstract = {[This corrects the article DOI: 10.3389/fncel.2025.1681891.].}, } @article {pmid41369024, year = {2026}, author = {Correa-Arrieta, C and Castellar-Leones, S and Ruiz-Ospina, E and Diaz-Ruiz, J and Sanchez-Peñarete, D and Rodriguez-Cruz, W and Bravo-Espejo, J and Uriza-Prias, DM and Ortiz-Corredor, F}, title = {Amyotrophic lateral sclerosis in Colombia: a population-based study of incidence and socioeconomic determinants.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {412-421}, doi = {10.1080/21678421.2025.2597944}, pmid = {41369024}, issn = {2167-9223}, mesh = {Humans ; Colombia/epidemiology ; Male ; Female ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/economics ; Middle Aged ; Incidence ; Cross-Sectional Studies ; Socioeconomic Factors ; Aged ; Adult ; Aged, 80 and over ; Young Adult ; }, abstract = {Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with variable global incidence. In Latin America, limited population-level data hinder accurate burden estimation and public health planning. This study estimated ALS incidence in Colombia from 1984 to 2024, analyzing regional distribution patterns and the demographic and socioeconomic profiles of affected individuals. Methods: This cross-sectional, population-based study analyzed 2185 clinically confirmed ALS cases reported to the Colombian National Institute of Health. Diagnoses were established using El Escorial or Gold Coast criteria. Annual and cumulative incidence rates were estimated using national population data. Demographic, geographic, and socioeconomic variables were classified under international standards, and all statistical analyses were performed using Python (version 3.12). Results: A total of 2185 ALS cases diagnosed between 1984 and 2024 were included. For the most recent decade (2015-2024), the national cumulative incidence was 41.46 per million inhabitants, with a steady increase in annual incidence. Bogotá and Caldas showed the highest cumulative incidence, whereas Chocó and Casanare reported the lowest. The mean age at diagnosis was 59.9 years, with a slight male predominance (male-to-female ratio 1.11:1). Socioeconomic disparities were evident: 18.0% of patients had no formal education, and over 40% were economically inactive at diagnosis. Conclusions: ALS incidence in Colombia is lower than that reported in high-income regions, but shows pronounced geographic and socioeconomic heterogeneity. These findings underscore the need to strengthen diagnostic capacity, improve equitable access to neurology services, and advance research on environmental and genetic determinants of ALS in Latin America.}, } @article {pmid41370023, year = {2026}, author = {Ding, W and Guo, J and Lu, Y and Li, X}, title = {Nocturnal hypoxemia mediates age-related sleep fragmentation in amyotrophic lateral sclerosis: a polysomnographic case-control study.}, journal = {Acta neurologica Belgica}, volume = {126}, number = {1}, pages = {251-258}, pmid = {41370023}, issn = {2240-2993}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Female ; Middle Aged ; Polysomnography ; *Hypoxia/physiopathology/etiology ; Aged ; Case-Control Studies ; *Sleep Deprivation/physiopathology/etiology ; *Aging/physiology ; Adult ; }, abstract = {OBJECTIVE: To evaluate sleep architecture disruptions in amyotrophic lateral sclerosis (ALS) using polysomnography (PSG) and identify clinical/demographic correlates for targeted interventions.

METHODS: Forty definite/probable ALS patients (revised El Escorial criteria) without primary sleep disorders and 40 age/sex/BMI-matched controls underwent full polysomnography (PSG). Sleep parameters (total sleep time [TST], sleep efficiency [SE], wake after sleep onset [WASO], N1-N3, rapid eye movement [REM] sleep), respiratory indices (AHI, minimum peripheral oxygen saturation (min SpO₂), SpO₂ range/coefficient of variation [CV]), and clinical metrics (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R], Hospital Anxiety and Depression Scale [HADS]) were compared. Multivariate regression identified independent sleep predictors, and mediation analysis quantified min SpO₂'s role in age-sleep fragmentation relationships.

RESULTS: ALS patients showed significantly reduced TST (371.54 ± 67.62 vs. 495.13 ± 45.69 min, p = 0.004), SE (69.95 ± 13.79 vs. 85.10 ± 7.03%, p = 0.009), N2 sleep (127.33 ± 56.75 vs. 204.28 ± 67.16 min, p = 0.013), N3 sleep (61.70 ± 33.67 vs. 91.90 ± 44.06 min, p = 0.021), and REM sleep (66.09 ± 35.85 vs. 84.66 ± 37.65 min, p = 0.012) alongside elevated WASO (131.70 ± 78.82 vs. 64.26 ± 44.18 min, p = 0.015). Nocturnal oxygenation was impaired (min SpO₂: 89.3 ± 3.1% vs. 93.7 ± 2.4%, p < 0.001; SpO₂ CV: 3.7 ± 1.5% vs. 1.8 ± 0.9%, p < 0.001), though AHI and REM AHI were comparable (AHI: p = 0.087; REM AHI: p = 0.134). Age (β = -0.28, p = 0.02) and min SpO₂ (β = 0.31, p = 0.01) independently predicted TST. Mediation analysis confirmed min SpO₂ partially explains age-related TST reduction (indirect effect: -0.14, 95% CI: -0.28 to - 0.03; accounting for 43.8% of the total effect).

CONCLUSION: Our data confirm profound sleep architecture disruption and nocturnal hypoxemia in ALS independent of primary sleep disorders. Critically, we establish min SpO₂ as a partial mediator of age-related sleep fragmentation, suggesting that early management of hypoxemia may improve sleep quality. Larger prospective studies validating these mechanisms and their impact on disease progression are warranted.}, } @article {pmid41371952, year = {2026}, author = {Dalton, C and Mojsilovic-Petrovic, J and Safren, N and Snoznik, C and Gebis, KK and Wang, YZ and Sutter, AB and Lamitina, T and Savas, JN and Kalb, RG}, title = {Ubiquitin Proteasome System Components, RAD23A and USP13, Modulate TDP-43 Solubility and Neuronal Toxicity.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {46}, number = {4}, pages = {}, pmid = {41371952}, issn = {1529-2401}, support = {S10 OD032464/OD/NIH HHS/United States ; R01 NS122908/NS/NINDS NIH HHS/United States ; R21 NS087077/NS/NINDS NIH HHS/United States ; R01 NS124802/NS/NINDS NIH HHS/United States ; R35 NS122257/NS/NINDS NIH HHS/United States ; R01 NS052255/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; HEK293 Cells ; *DNA-Binding Proteins/metabolism/genetics/toxicity/chemistry ; Rats ; *Neurons/metabolism ; *Proteasome Endopeptidase Complex/metabolism ; Solubility ; *DNA Repair Enzymes/metabolism/genetics ; Caenorhabditis elegans ; }, abstract = {At autopsy, >95% of ALS cases display a redistribution of the essential RNA binding protein TDP-43 from the nucleus into cytoplasmic aggregates. The mislocalization and aggregation of TDP-43 is believed to be a key pathological driver in ALS. Due to its vital role in basic cellular mechanisms, direct depletion of TDP-43 is unlikely to lead to a promising therapy. Therefore, we have explored the utility of identifying genes that modify its mislocalization or aggregation. We have previously shown that loss of rad-23 improves locomotor deficits in TDP-43 Caenorhabditis elegans models of disease and increases the degradation rate of TDP-43 in cellular models. To understand the mechanism through which these protective effects occur, we generated an inducible mutant TDP-43 HEK293 cell line. We find that knockdown of RAD23A reduces insoluble TDP-43 levels in this model and primary rat cortical neurons expressing human TDP-43[A315T] Utilizing a discovery-based proteomics approach, we then explored how loss of RAD23A remodels the proteome. Through this proteomic screen, we identified USP13, a deubiquitinase, as a new potent modifier of TDP-43 induced aggregation and cytotoxicity. We find that knockdown of USP13 reduces the abundance of sarkosyl insoluble mTDP-43 in both our HEK293 model and primary rat neurons, reduces cell death in primary rat motor neurons, and improves locomotor deficits in C. elegans ALS models.}, } @article {pmid41372737, year = {2025}, author = {Shah, A and Doshi, G}, title = {Stress and neurodegeneration: mechanistic insights and therapeutic opportunities for preserving brain resilience.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {41372737}, issn = {2240-2993}, abstract = {Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis are strongly influenced by persistent stress, which accelerates both their onset and progression. This review explores the intricate interplay between chronic stressors, oxidative and metabolic imbalances, protein misfolding, inflammatory responses, and psychosocial adversity, and their cumulative impact on the aging brain’s capacity for homeostasis. The loss of cellular resilience due to prolonged stress leads to maladaptive outcomes, including mitochondrial dysfunction, sustained neuroinflammation, breakdown in proteostasis, and disruption of hypothalamic-pituitary-adrenal axis signaling, all of which amplify neuronal vulnerability. The detailed molecular pathways that underlie these phenomena, the article identifies key mediators such as Reactive Oxygen species, mitochondrial regulators, heat shock proteins, and proinflammatory cytokines that drive neurodegeneration. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar up to 2025. Eligible publications included original research articles, clinical studies, and systematic reviews focusing on stress-related molecular pathways, oxidative metabolism, proteostasis, neuroinflammation, and therapeutic interventions in aging and neurodegenerative diseases. A qualitative synthesis of these studies was performed to identify key mechanisms, biomarkers, and emerging treatment strategies relevant to stress-induced neurodegeneration. Further, the review evaluates both established and emerging interventions aimed at mitigating these stress-driven processes. Lifestyle modifications such as aerobic exercise, calorie restriction, and cognitive behavioural therapies complement pharmacological agents like antioxidants, chaperone modulators, and anti-inflammatory drugs to enhance brain resilience and delay disease onset. Recent advances in the field, including integrated multi-omics profiling, biomarker discovery, and medicine approaches, promise to refine our ability to satisfy patients and deliver targeted therapies based on individual stress profiles. Additionally, the article discusses the neuroimmune-gut axis and the potential for interventions targeting microbiome-related inflammation. Early detection of stress-related biomarkers and personalized strategies holds considerable promise for improving clinical outcomes, enabling earlier diagnosis, and fostering tailored therapies that preserve cognitive function and independence in aging populations.}, } @article {pmid41373461, year = {2025}, author = {Butcher, EL and Arthur, S}, title = {Emerging Roles of Bile Acids in Neuroinflammation.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373461}, issn = {1422-0067}, mesh = {Humans ; *Bile Acids and Salts/metabolism ; *Neuroinflammatory Diseases/metabolism/pathology ; Animals ; Gastrointestinal Microbiome ; Signal Transduction ; Biomarkers/metabolism ; Blood-Brain Barrier/metabolism ; Inflammation/metabolism ; Central Nervous System/metabolism ; }, abstract = {Bile acids, once considered mere digestive detergents, have emerged as multifaceted signaling molecules with systemic influence extending far beyond the gastrointestinal tract. Recent discoveries reveal their capacity to modulate immune responses, cross the blood-brain barrier, and interact with central nervous system (CNS) cells through their receptors. Neuroinflammation, a key driver of neurodegenerative and neuroimmune disorders, is increasingly linked to bile acid signaling pathways that regulate glial activation, cytokine production, and neuronal survival. This review compiles the current evidence connecting bile acids to CNS inflammation, highlighting mechanistic insights, disease-specific alterations, and the gut-microbiome-bile acid-brain axis. It also explores the therapeutic potential of bile acid derivatives and receptor modulators, as well as their emerging role as biomarkers in conditions such as Alzheimer's disease, multiple sclerosis, and hepatic encephalopathy. Despite promising advances, critical gaps remain, including the need for bile receptor mapping in human CNS cells, standardized CNS bile acid profiling, and longitudinal metabolomic studies. Bridging these gaps may unlock new strategies for targeting neuroinflammation through bile acid-immune crosstalk.}, } @article {pmid41373533, year = {2025}, author = {Apolloni, S and Tortoriello, S and Milani, M and Rossi, S}, title = {Extracellular Matrix Remodeling in Motor Neuron Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373533}, issn = {1422-0067}, support = {GR-2021-12375436//Ministero della Salute/ ; PNRR project "Rome Technopole - Innovation Ecosystem"//European Union/ ; }, mesh = {Humans ; *Extracellular Matrix/metabolism/pathology ; *Motor Neuron Disease/metabolism/pathology ; Animals ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Motor Neurons/metabolism/pathology ; }, abstract = {The extracellular matrix (ECM) constitutes a dynamic scaffold composed of both cellular and non-cellular elements that not only ensure tissue integrity but also regulate signaling events crucial for development and homeostasis. While its dysregulation has long been investigated in cancer, fibrosis, and autoimmunity, increasing evidence implicates ECM remodeling in neurodegenerative diseases, including motor neuron diseases (MNDs). Amyotrophic lateral sclerosis and spinal muscular atrophy, the most studied MNDs, both exhibit profound ECM alterations that influence synaptic connectivity, glial reactivity, and neuroinflammation. This review outlines recent data on ECM dynamics in MNDs, highlighting shared and disease-specific mechanisms, their potential as biomarkers, and therapeutic opportunities targeting the ECM environment to preserve neuronal function and slow disease progression.}, } @article {pmid41373580, year = {2025}, author = {Salvany, S and Hernández, S and Casanovas, A and Gras, S and Piedrafita, L and Bosch-Queralt, M and Schwab, MH and Calderó, J and Esquerda, JE and Tarabal, O}, title = {Chronic Overexpression of Neuronal NRG1-III in Mice Causes Long-Term Detrimental Changes in Lower Motor Neurons, Neuromuscular Synapses and Motor Behaviour.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373580}, issn = {1422-0067}, support = {PID2021-122785OB-I00//Ministerio de Ciencia e Innovación/ ; 202005-30//Marató de TV3 Foundation/ ; }, mesh = {Animals ; *Motor Neurons/metabolism/pathology ; *Neuromuscular Junction/metabolism/pathology ; *Neuregulin-1/genetics/metabolism ; Mice ; Mice, Transgenic ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Motor Activity ; Disease Models, Animal ; Spinal Cord/metabolism/pathology ; Calcium/metabolism ; }, abstract = {Neuregulins (NRGs) are ligands of tyrosine kinase receptors from the ErbB family and play multiple developmental roles. NRG1-ErbB signaling regulates myelination and has been associated with amyotrophic lateral sclerosis (ALS) pathology. Given the potential therapeutic relevance of this pathway for motor neuron (MN) diseases, we employed a transgenic (TG) mouse with persistent neuronal overexpression of neuregulin type III (NRG1-III) to investigate its impact on the neuromuscular system. We performed an analysis of phenotypic changes in this TG model, including motor behavior, neuropathological evaluation by immunocytochemistry and ultrastructural examination of the spinal cord, peripheral nerves, and neuromuscular junctions (NMJs). Calcium dynamics in cultured MNs were also examined. We found that cholinergic C-boutons on TG MNs, where NRG1-III typically accumulates, exhibited upregulation of C-bouton-associated proteins and expansion of the subsynaptic cistern (SSC)-associated endoplasmic reticulum. Calcium imaging revealed altered homeostasis in TG MNs, accompanied by the upregulation of molecules linked to axonal plasticity. At NMJs, regressive changes involving autophagic dysregulation were observed. These alterations were accompanied by increased motor activity in behavioral tests. Overall, our findings indicate that persistently elevated NRG1-III signaling compromises MN connectivity and long-term health, a factor to consider when developing therapeutic strategies for neurodegenerative diseases such as ALS.}, } @article {pmid41373649, year = {2025}, author = {Mukhija, S and Hering, L and Schreiner, SJ and Lehner, F and Loosli, J and Togni, C and Otto, F and Ziegler, M and Weiss, T and Jung, HH and Briel, N}, title = {Multimodal Biomarker Characterization of the ALS/FTD Spectrum: A Real-World Clinical Dataset Analysis.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373649}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/cerebrospinal fluid/blood/metabolism ; *Biomarkers/blood/cerebrospinal fluid ; *Frontotemporal Dementia/diagnosis/blood/cerebrospinal fluid/metabolism ; Male ; Female ; tau Proteins/cerebrospinal fluid/blood ; Middle Aged ; Aged ; Cross-Sectional Studies ; Retrospective Studies ; Neuroimaging ; }, abstract = {Diagnosis and prognosis of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) spectrum remain largely dependent on clinical assessments due to a lack of established fluid biomarkers. While neurofilaments and the cerebrospinal fluid (CSF) phosphorylated-tau/total-tau ratio (pTau:tTau) have been studied, their limitations, including their lack of clinical implementation and low specificity, necessitate multimodal approaches. This study aimed to characterize the biological features of the ALS/FTD spectrum through integration of clinically available parameters. We conducted a retrospective, single-center, cross-sectional study analyzing routinely collected clinical, neuroimaging, CSF, and serum data from 229 samples, including 45 from patients with ALS, 26 from patients with FTD, 158 from patients with other neurodegenerative diseases, and 29 from cognitively healthy controls. We implemented propensity score-weighted comparisons, an F1 score-based optimal cut-point determination for the pTau:tTau ratio, and a regularized XGBoost-based multimodal feature modeling approach. The biomarker and model performance was evaluated by the area under the precision-recall curve (AUC-PR). Feature importance analysis identified characteristic indicators of the ALS/FTD spectrum. Consistent with the prior literature, the pTau:tTau ratio was significantly reduced in ALS/FTD, but the classification performance was modest (AUC-PR 0.32). A multimodal model integrating clinical, biofluid, and neuroimaging features achieved a notably better performance (AUC-PR 0.75). Feature importance analysis revealed an ALS/FTD signature beyond the pTau:tTau ratio characterized by higher global cognition, younger age, an altered Aβ42/pTau ratio, and immunoglobulin changes (CSF IgG:IgA, serum IgG). Integration of clinical routine data centered on tau, amyloid, and immunological pathophysiology as well as temporal disease dynamics provide a contextualized biological characterization of the ALS/FTD spectrum. This approach offers a foundation for hypothesis generation regarding ALS/FTD pathophysiology and biomarker-supported diagnosis.}, } @article {pmid41373784, year = {2025}, author = {Basavarajappa, BS and Subbanna, S}, title = {From Synaptic Plasticity to Neurotoxicity: Endocannabinoid Influence on Addiction and Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373784}, issn = {1422-0067}, mesh = {Humans ; *Endocannabinoids/metabolism ; *Neuronal Plasticity ; Animals ; *Neurodegenerative Diseases/metabolism ; *Substance-Related Disorders/metabolism ; Receptors, Cannabinoid/metabolism ; }, abstract = {The endocannabinoid system (eCBS) is a versatile neuromodulatory network that orchestrates synaptic plasticity, reward processing, and neuronal homeostasis. Increasing evidence implicates eCBS dysregulation in both addiction and neurodegenerative (ND) disorders, suggesting overlapping molecular and cellular mechanisms underlying these conditions. This review synthesizes recent advances in understanding how eCBS components-cannabinoid receptors (CB1 and CB2), endogenous ligands (anandamide and 2-arachidonoylglycerol), and their metabolic enzymes-modulate dopaminergic and glutamatergic signaling within reward and reinforcement circuits. Chronic exposure to drugs of abuse, including alcohol, opioids, cocaine, and methamphetamine, perturbs eCBS homeostasis, promoting oxidative stress, neuroinflammation, excitotoxicity, mitochondrial dysfunction, and protein aggregation-pathological features common to Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. These overlapping mechanisms disrupt neuronal integrity and contribute to progressive neurotoxicity, highlighting shared pathogenic pathways between addiction and neurodegeneration. Despite these advances, critical gaps remain in delineating how substance-induced eCBS alterations precipitate neurodegenerative cascades. Addressing these gaps will be essential for harnessing the eCBS as a therapeutic target to mitigate addiction-driven neurotoxicity and age-related cognitive decline.}, } @article {pmid41375620, year = {2025}, author = {Krysiak, D and Ćwiertnia, M and Wójcik, M and Babik, P and Suchanek, Ł and Jaskiewicz, F and Trojak-Piętka, J and Szlagor, M and Pollok-Waksmańska, W and Kawecki, M and Ilczak, T}, title = {Analysis of Medical Response Team Interventions and the Impact of Certified Training on the Treatment of Patients with Hypoglycaemia-A Simulation Study.}, journal = {Journal of clinical medicine}, volume = {14}, number = {23}, pages = {}, pmid = {41375620}, issn = {2077-0383}, abstract = {Background/objectives: The effectiveness of emergency medical procedures administered to a patient in a life-threatening condition depends, to a large degree, on the knowledge and skills of medical response team personnel. Their competencies can be developed through participation in training and then verified during emergency medicine championships. Methods: The research was conducted on the basis of one of the tasks carried out during the '16th International Winter Championships in Emergency Medicine'. The task was completed by 28 Polish emergency response teams from ambulance stations across the country. The teams carried out a simulated scenario related to procedures with a patient with hypoglycaemia. The teams' interventions were assessed in accordance with European Resuscitation Council (ERC) guidelines by judges selected from among academic lecturers and ERC instructors. Results: The research showed that 86% of the teams obtained the maximum number of points for adhering to safety procedures. Further, 61% of the teams obtained the maximum of 6 points for the initial assessment, with the average number of points obtained by the teams being 5.54. The average number of points for the physical examination was 21.04, with only one team obtaining the maximum result of 26 points. Additionally, 57% of the teams obtained the maximum number of 6 points for the medical consultation, with the average obtained by the teams being 5.43. The teams obtained, on average, 8.18 points for the correct treatment of hypoglycaemia, with 68% of the teams obtaining the maximum of 9 points. The research demonstrated a positive correlation between the quality of patient examination and the collection of medical data, and the effectiveness of hypoglycaemia treatment. It was also shown that if the team leader had completed an ALS course, they obtained higher scores for the treatment of hypoglycaemia, although this finding is specific to this scenario. Conclusions: The teams demonstrated generally high performance in a simulated hypoglycaemia scenario. More complete assessment and history-taking were associated with higher treatment scores. Correct treatment was achieved in 79% of ALS-led teams versus 44% of non-ALS teams, although this observation is specific to this simulation and should not be generalised.}, } @article {pmid41375893, year = {2025}, author = {Gratzer, A and Gdynia, N and Sasse, N and Beese, R and Winterholler, C and Bauer, Y and Schröter, C and Gdynia, HJ}, title = {Rehabilitation in Amyotrophic Lateral Sclerosis: Recommendations for Clinical Practice and Further Research.}, journal = {Journal of clinical medicine}, volume = {14}, number = {23}, pages = {}, pmid = {41375893}, issn = {2077-0383}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition characterized by the degeneration of upper and lower motor neurons. This degeneration leads to a gradual muscle weakness, dysarthria, dysphagia, respiratory insufficiency, and, in some patients, alterations in cognitive and behavioral performance. Regardless of advancements made in pharmacological and gene-targeted interventions, a definitive curative treatment remains elusive. Consequently, rehabilitation plays a pivotal role in preserving autonomy, participation, and overall quality of life. This review outlines the current evidence and clinical approaches related to multidisciplinary rehabilitation in ALS. It covers physical and occupational therapy, respiratory, speech and language, psychological, and palliative care domains. Evidence supports moderate tailored exercise programs, early respiratory therapy, and structured management of mobility deficits, spasticity, pain, dysphagia, and communication impairments as key elements of symptomatic treatment. Psychological and social support, which includes the involvement of caregivers and relatives, enhances emotional well-being and coping resilience. Even with progressive development of gene-targeted and disease-modifying therapies, rehabilitation will stay relevant for maintaining long-term motor function. This review highlights the need for standardized, evidence-based rehabilitation protocols and intensified neurorehabilitation research to strengthen clinical outcomes and quality of life as key therapeutic goals in ALS management.}, } @article {pmid41375912, year = {2025}, author = {Sancho, J and Ferrer, S and Signes-Costa, J}, title = {Noninvasive Ventilation Effectiveness in Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical medicine}, volume = {14}, number = {23}, pages = {}, pmid = {41375912}, issn = {2077-0383}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons; respiratory problems are the leading cause of death and hospital admissions and are secondary to progressive weakness of the respiratory muscles and upper airway. Noninvasive ventilation (NIV) can increase survival, alleviate symptoms, reduce hospital admissions, and improve the quality of life of these patients. The key factor in respiratory management of patients with ALS is achieving effective NIV; ineffective NIV has a negative impact on survival, with a reduction of up to 50% compared to patients with an effective technique. The most common cause of ineffective NIV is air leaks; other causes include upper airway obstruction events, residual hypoventilation, hyperventilation, and upper airway obstruction secondary to an oronasal mask. Regular monitoring of the effectiveness of NIV is essential given its impact on survival; the key tools that detect the main problems are the presence of hypoventilation symptoms, arterial blood gases, nocturnal oximetry and capnography, and built-in ventilator software. Different measures have been proposed to address the ineffectiveness of NIV, such as fitting the mask to reduce air leaks, increasing ventilatory support for residual hypoventilation, decreasing ventilatory support for hyperventilation, or a trial with a nasal mask to address oronasal interface effects. In the case of obstruction, the most common measure is to increase positive expiratory pressure during NIV. These measures enable NIV to be effective in 58% of cases, achieving a survival rate similar to that of patients who have effective NIV from the outset.}, } @article {pmid41376117, year = {2025}, author = {Ali, YY and Fares, NV and Ayad, MF and Abbas, MM}, title = {Toward Practical and Sensitive Fluorescence Analysis: Factorial Design-Optimized o-Phthalaldehyde Derivatization for Synchronous Spectrofluorimetric Determination of Modafinil in Plasma and Dosage Form.}, journal = {Luminescence : the journal of biological and chemical luminescence}, volume = {40}, number = {12}, pages = {e70383}, doi = {10.1002/bio.70383}, pmid = {41376117}, issn = {1522-7243}, mesh = {*o-Phthalaldehyde/chemistry ; *Modafinil/blood/analysis ; Spectrometry, Fluorescence/methods ; Humans ; Limit of Detection ; Tablets ; Molecular Structure ; Fluorescence ; }, abstract = {The current research discusses a simple, sensitive, and practical spectrofluorimetric method for Modafinil (MDF) analysis. MDF can improve the fatigue symptoms associated with amyotrophic lateral sclerosis. MDF's aliphatic primary amide moiety can undergo base-catalyzed condensation with o-phthalaldehyde to give a highly fluorescent isoindoline derivative measured at 445 nm using synchronous spectrofluorimetry with Δλ of 110 nm. Different factors were studied using a two-level factorial design to reach the optimum conditions for the analysis. The method validation was carried out following the International Conference on Harmonization guidelines. The calibration curve was established to illustrate how relative fluorescence intensity varies with MDF concentration, and linearity was attained over the range of 10-7000 ng mL[-1], with an average recovery of 100.51% ± 0.91%. The limit of detection (LOD) was determined to be 3.21 ng mL[-1] while the quantitation limit (LOQ) was found to be 9.74 ng mL[-1]. The developed method demonstrated its effectiveness in determining MDF in tablets and spiked human plasma with recoveries of 100.43% ± 0.16 and 96.07% ± 1.55, respectively. MoGAPI, AGREE, and BAGI assessments yielded scores of 72, 0.62, and 70, respectively. The results show that the method is user-friendly and can be used in routine applications.}, } @article {pmid41376376, year = {2025}, author = {Shi, Y and Zhao, T and Peng, L and Wang, P and Huang, X and Xu, F and Tan, Y and Peng, S and Xiong, T and Bai, Y and Liu, X and Wei, C and Zhang, W and Ding, H}, title = {Investigating the shared genetic architecture between post-traumatic stress disorder and neurodegenerative diseases: a large-scale genomewide cross-trait analysis.}, journal = {International journal of surgery (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1097/JS9.0000000000004347}, pmid = {41376376}, issn = {1743-9159}, abstract = {BACKGROUND: Post-traumatic stress disorder (PTSD), the most prevalent psychopathological consequence following traumatic events, profoundly impacts human life amidst global societal pressures. Emerging twin and family studies suggest that individuals with stress-related disorders face an elevated risk of neurodegenerative diseases, yet the genetic underpinnings of this association remain poorly understood.

METHODS: Here, we present a comprehensive framework elucidating this genetic basis. Using bivariate causal mixture models (MiXeR), we quantified polygenic overlap between PTSD (N = 1,280,933) and four neurodegenerative phenotypes (N = 115,803- 487,511), leveraging summary statistics from the largest PTSD genome-wide association study to date. Conditional/conjunction false discovery rate (FDR) analysis identified shared genomic loci.

RESULTS: MiXeR revealed considerable genetic variant sharing between neurodegenerative diseases and PTSD. Subsequent conjunction FDR analysis pinpointed 15 distinct shared loci. ρ-HESS local genetic correlation analysis identified seven significant local genetic correlations, with Chr6: 61,880,512-63,552,888 emerging as the most significant shared locus between PTSD and Alzheimer's disease. Cross-trait analyses using MTAG and CPASSOC identified 174 PTSD risk loci associated with at least one psychiatric disorder. Protein-coding genes mapped to known and novel shared loci exhibited specific spatial developmental trajectories. Through a framework incorporating five fundamental TWAS algorithm models, we identified 27 novel susceptibility genes that passed rigorous screening. Polygenic risk score (PRS) stratification in the UK Biobank cohort revealed dose-dependent relationships between PRS and risks of Alzheimer's disease, multiple sclerosis, and Parkinson's disease, with limited support for ALS and PTSD.

CONCLUSIONS: These findings illuminate the shared genetic architecture between PTSD and neurodegenerative phenotypes, advancing our understanding of their neurobiological interconnections. And enhance statistical power for detecting shared loci, thereby refining the characterization of common genetic mechanisms underlying PTSD and neurodegenerative pathologies.}, } @article {pmid41377283, year = {2025}, author = {Imtiaz, E and Mahato, RK and Soomro, S and Jadoon, M and Intikhab, S}, title = {Nanomedicine-enhanced delivery of CRISPR-Cas13 for RNA editing in C9orf72-associated ALS.}, journal = {Annals of medicine and surgery (2012)}, volume = {87}, number = {12}, pages = {9167-9168}, pmid = {41377283}, issn = {2049-0801}, } @article {pmid41377708, year = {2025}, author = {Khalid, YA and Saad, MB and Nasreddin, ME}, title = {Assessing junior doctors' knowledge and attitude on advanced life support in Egypt: a cross-sectional study.}, journal = {African journal of emergency medicine : Revue africaine de la medecine d'urgence}, volume = {15}, number = {4}, pages = {100927}, pmid = {41377708}, issn = {2211-4203}, abstract = {INTRODUCTION: Cardiovascular diseases are a leading cause of mortality worldwide, with cardiac arrest survival heavily dependent on timely and effective resuscitation efforts. Junior doctors often serve as first responders in hospitals, yet their advanced life support (ALS) knowledge and training adequacy remain underinvestigated in Egypt. This study assessed the knowledge and attitudes of junior doctors in Egypt regarding basic life support (BLS) and ALS, identified knowledge gaps, and suggests improvements in resuscitation training programs.

METHODS: A cross-sectional survey was conducted among 184 junior doctors, including house officers, general practitioners, and residents, across multiple healthcare centres in Egypt. Data was collected via an online questionnaire based on European Resuscitation Council guidelines, evaluating demographic factors, BLS/ALS knowledge, and attitudes toward cardiac arrest management. Statistical analysis explored associations between knowledge scores and participant characteristics.

RESULTS: Participants demonstrated inadequate knowledge with mean BLS and ALS scores of 59 % and 61.8 %, respectively. Significant deficiencies were noted in pediatric resuscitation, cardiac arrest diagnosis, IV access, and capnography interpretation. Residents and those attending ALS workshops scored significantly higher (p < 0.05), while prior clinical exposure did not correlate with higher knowledge scores. Most participants (91.3%) expressed a need for further ALS training.

DISCUSSION: Junior doctors in Egypt show deficient ALS knowledge with critical gaps that may impact patient outcomes. Structured ALS training and curriculum reforms are urgently needed to enhance emergency preparedness and improve cardiac arrest survival.}, } @article {pmid41378777, year = {2026}, author = {González-Velasco, Ó and Parlato, R and Yilmaz, R and Decker, L and Menge, S and Freischmidt, A and Yang, X and Tulasi, N and Brenner, D and Andersen, PM and Forsberg, KME and Schlachetzki, JCM and Brors, B and Voith von Voithenberg, L and Weishaupt, JH}, title = {Somatic gene mutations in the motor cortex of patients with sporadic amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {3}, pages = {778-784}, pmid = {41378777}, issn = {1460-2156}, support = {AIH23//AI Health Innovation Cluster/ ; YI 209/1-1, AOBJ 680080//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Motor Cortex/metabolism/pathology ; *Mutation/genetics ; Female ; Male ; Middle Aged ; Aged ; *RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of cortical and spinal motor neurons. Mendelian germline mutations often cause familial ALS (fALS) but only approximately 10% of sporadic ALS cases (sALS). We leveraged DNA and single-cell RNA sequencing data from autopsy tissue to explore the presence of somatic mosaic variants in sALS cases. Deep targeted panel sequencing of known ALS disease genes in motor cortex tissue revealed an enrichment of low allele frequency variants in sALS, but not in fALS with an identified monogenic cause. In silico analysis predicted increased pathogenicity of mosaic mutations in various known ALS mutational hot-spots. In particular, we identified the somatic FUS variant p.E516X, located in an established hotspot for germline ALS mutations, which leads to nucleo-cytoplasmic mislocalization and aggregation typical for ALS FUS pathology. Additionally, we performed somatic variant calling on single-cell RNA-sequencing data from sALS tissue and revealed a specific accumulation of somatic variants in excitatory neurons, reinforcing a neuron-autonomous disease initiation. Collectively, this study indicates that somatic mutations within the motor cortex, especially in excitatory neurons, may contribute to sALS development.}, } @article {pmid41379273, year = {2025}, author = {Zhang, R and Gao, B and Li, R and Zhou, R}, title = {Meta-analysis of the effects of dance- and movement-based kinesthetic games on cognitive function in older adults with cognitive impairment (CI) under different intervention periods.}, journal = {Aging clinical and experimental research}, volume = {37}, number = {1}, pages = {343}, pmid = {41379273}, issn = {1720-8319}, support = {24YJC890031//he Ministry of Education 's Youth Fund Project for Humanities and Social Sciences/ ; 22PJC094//Shanghai Pujiang Program/ ; }, mesh = {Humans ; *Cognitive Dysfunction/therapy/psychology ; Aged ; *Cognition/physiology ; *Video Games ; *Dancing ; *Dance Therapy/methods ; Male ; Randomized Controlled Trials as Topic ; *Exercise Therapy/methods ; Female ; }, abstract = {OBJECTIVE: To evaluate the effects of different types and durations of exergame interventions on cognition in elderly individuals with cognitive impairment (CI) through a meta-analysis.

METHODS: A computerized search was conducted in databases including Cochrane Library, PubMed, Web of Science, Embase, and CNKI from database inception to September 2025. Quality assessment and data extraction were performed on the included studies. Results measures included the MoCA , MMSE, etc. The study designs were randomized controlled trials or qua-si-experimental studies. The Cochrane Handbook's risk of bias tool was used for quality assessment, and Rev Man 5.0 software was employed to conduct meta-analyses on the ef-fects of dance-based and movement-based exergames on cognitive function in elderly CI patients.

RESULTS: A total of 13 studies involving 433 CI patients were included. Analysis of the 13 studies showed that dance-based exergaming was significantly superior to exercise-based exergaming in cognitive ability (SMD = 0.73, P < 0.01); interventions lasting ≥8 weeks were more effective than those lasting <8 weeks (SMD = 1.01, P = 0.02).

CONCLUSION: Dance-based exergames significantly improve cognition in elderly individu-als with CI, with better effects observed in long-term interventions. However, more high-quality studies are needed to verify these findings and to supplement analyses on ex-ercise dose effects.}, } @article {pmid41379346, year = {2026}, author = {Canosa, A and Callegaro, S and Manera, U and Vasta, R and Cabras, S and Di Pede, F and De Mattei, F and Palumbo, F and Iazzolino, B and Dei Giudici, A and Matteoni, E and Zocco, G and Minerva, E and Maccabeo, A and Pellegrino, G and Pascariu, D and Grassano, M and Piombino, P and Testa, M and Polverari, G and Fuda, G and Merulla, I and Casale, F and Gallone, S and Moglia, C and Calvo, A and Pagani, M and Chiò, A}, title = {Brain metabolic connectivity in ALS due to C9ORF72 hexanucleotide expansion: a [[18]F]FDG-PET study.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {53}, number = {4}, pages = {2786-2798}, pmid = {41379346}, issn = {1619-7089}, mesh = {Humans ; *C9orf72 Protein/genetics ; *Fluorodeoxyglucose F18 ; Male ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/metabolism ; Female ; Middle Aged ; *Positron-Emission Tomography ; *Brain/metabolism/diagnostic imaging ; Aged ; *DNA Repeat Expansion ; Adult ; }, abstract = {PURPOSE: Our aim was to investigate brain metabolic connectivity, as assessed via [[18]F]FDG-PET, in ALS patients carrying the C9ORF72 expansion (C9-ALS).

METHODS: We compared brain metabolism of C9-ALS and patients without mutations of the main ALS-related genes (ctrl-ALS) through the two-sample t-test model of SPM12. Metabolic clusters showing a significant difference between the two groups were used as seed regions for an interregional correlation analysis (IRCA) in each group to evaluate metabolic connectivity.

RESULTS: As compared to ctrl-ALS, C9-ALS showed a relative hypometabolism in bilateral thalamus and left precentral and postcentral gyri, and a relative hypermetabolism in bilateral cerebellum and brainstem. In the IRCA, a positive correlation was found between the thalamic seed region and the cingulate cortex, including its anterior part. This correlation was broader in C9-ALS than in Ctrl-ALS. A negative correlation between the thalamic seed region and the sensorimotor cortex was only found in C9-ALS. In the IRCA, based on the cerebellar/brainstem cluster, positive correlations with the seed region substantially represented autocorrelation in both groups. Negative correlation, which mainly included frontal cortices, was more extensive in C9-ALS than in Ctrl-ALS.

CONCLUSION: In the comparison with ctrl-ALS, C9-ALS showed a relatively lower metabolism in the thalami and a relatively higher metabolism in the brainstem and the cerebellum. As compared to ctrl-ALS, C9-ALS showed a predominant involvement of the salience network, which is related to cognitive and behavioural control. The cerebellum might be recruited to cope with cognitive impairment to a greater extent in C9-ALS than in ctrl-ALS.}, } @article {pmid41379813, year = {2026}, author = {Dashnaw, CM and Gonzalez, M and Abdolvahabi, A and Bassett, PT and Lato, TJ and Balamurali, R and Guberman-Pfeffer, MJ and Shaw, BF}, title = {Heteroaggregation of Wild-Type and ALS Mutant SOD1.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {1}, pages = {90-108}, doi = {10.1021/acschemneuro.5c00632}, pmid = {41379813}, issn = {1948-7193}, support = {R01 EY036371/EY/NEI NIH HHS/United States ; R25 GM146265/GM/NIGMS NIH HHS/United States ; }, mesh = {*Superoxide Dismutase-1/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Mutation/genetics ; *Superoxide Dismutase/genetics/metabolism ; *Protein Aggregates ; }, abstract = {The presence of wild-type (WT) Cu, Zn superoxide dismutase-1 (SOD1) can increase the toxicity of mutant SOD1 proteins linked to amyotrophic lateral sclerosis (ALS). The mechanism of synergy is unclear but might involve interactions between WT and mutant SOD1 in native or non-native states. One unanswered question is will the diverse rates of mutant SOD1 homofibrillization converge in the presence of WT SOD1? To answer this question, we assessed the coaggregation of mutant and WT SOD1 in vitro, including (i) how WT SOD1 affected the formation rate and stability of mutant fibrils and (ii) the proximity of WT and mutant SOD1 in heterofibrils. For most mutations studied, the presence of WT SOD1 slowed nucleation and propagation of mutant fibrils while increasing fibril thermostability. The D90A SOD1 protein was one exception: WT SOD1 had a nearly negligible effect on its rate of nucleation. The cross-seeding of soluble mutant SOD1 with WT fibrils (and of soluble WT SOD1 with mutant fibrils) suggests that both proteins can occupy the same fibril. Mass spectrometry of heterofibrils treated with an NHS-ester cross-linker (∼8 Å) suggested that WT and E100G mutant SOD1 are colocalized in heterofibrils, possibly stacked in an alternating configuration.}, } @article {pmid41380476, year = {2026}, author = {Gu, Y and Chen, Y and Tang, X and Guo, J and Hu, J and Yang, W and Li, J and Chen, X and Fan, D and Chen, GB and He, J and Ren, Y and Dong, Y and Sato, C and Chen, Y and Zinman, L and Rogaeva, E and Zhang, M}, title = {Multi-omics analyses identify potential epigenetic loci associated with survival in amyotrophic lateral sclerosis across diverse populations.}, journal = {EBioMedicine}, volume = {123}, number = {}, pages = {106071}, pmid = {41380476}, issn = {2352-3964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/mortality ; DNA Methylation ; *Epigenesis, Genetic ; Polymorphism, Single Nucleotide ; Male ; Female ; Middle Aged ; CpG Islands ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; *Genetic Loci ; Aged ; Genotype ; Epigenomics/methods ; Whole Genome Sequencing ; Multiomics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with highly diverse survival time. However, genetic and epigenetic factors influencing ALS survival across diverse populations remain unclear.

METHODS: We performed whole-genome sequencing (WGS) and DNA methylome array in blood DNA of patients with ALS. For survival analysis, we used Cox proportional hazards model for genetic variants, DNA methylation (DNAm) of CpG sites or CpG-SNPs in Chinese and Canadian cohorts, followed by meta-analysis. We performed pathway enrichment analysis for candidate genes inferred from DNAm events associated with survival. In paired genome and methylome data, we analysed the effect of the candidate CpG-SNP genotypes on DNAm status.

FINDINGS: Genome-wide cross-population meta-analysis of common variants in 511 patients with ALS showed a suggestive association of CAV1/CAV2 rs117002347 genotypes with survival. Epigenome-wide cross-population meta-analysis in 459 patients revealed that ALS survival was significantly linked to DNAm of 88 CpGs on 40 genes, and highlighted the AMPK and cytoskeleton pathways. Epigenome-wide cross-population meta-analysis of CpG-SNPs in 459 patients identified 8 loci on 4 genes, including BAG6 (cg27014438/rs28732154), which was further validated in another 204 patients with ALS. Moreover, analysis of paired genome/epigenome data (n = 454) indicated that BAG6 rs28732154 genotypes may modulate cg27014438 methylation, which is also a cis-eQTM of BAG6 expression in blood.

INTERPRETATION: Our study identified BAG6 cg27014438 methylation as a potential epigenetic modifier of ALS survival. BAG6 cg27014438 methylation is modulated by rs28732154 genotypes, and linked to BAG6 expression. Our findings extended our understanding of epigenetic modifiers in ALS survival.

FUNDING: This work was supported by the National Natural Science Foundation of China (82071430, 82371878) (MZ), Shanghai Municipal Natural Science Foundation General Program (22ZR1466400) (MZ), the Fundamental Research Funds for the Central Universities (MZ), the G. Harry Sheppard Memorial Research Fund, and Canadian Consortium on Neurodegeneration in Aging (ER).}, } @article {pmid41380670, year = {2025}, author = {Fujioka, Y and Ishigaki, S}, title = {Decoding ALS from the tail end of RNA.}, journal = {Cell genomics}, volume = {5}, number = {12}, pages = {101102}, pmid = {41380670}, issn = {2666-979X}, mesh = {Cell Nucleus ; Single-Cell Analysis ; *Gene Expression Profiling ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Lobar Degeneration/genetics/pathology ; *RNA, Small Nuclear/analysis ; *Brain/pathology ; Neurons/metabolism/pathology ; Sequence Analysis, RNA ; }, abstract = {In this issue of Cell Genomics, McKeever et al.[1] generate a single-nucleus transcriptomic atlas of ALS/FTLD brain and reveal widespread alternative polyadenylation changes. Their findings highlight 3' end RNA processing as a central integrator of stress responses, cell-type specificity, and disease susceptibility, offering new mechanistic insight and potential therapeutic directions.}, } @article {pmid41381004, year = {2026}, author = {Maas, D and Spindler, A and Zappi, I and Shapiro, J and Lo Sicco, KI}, title = {Response to Olsen et al's "Summation and recommendations for the safe and effective use of topical and oral minoxidil".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {4}, pages = {e287-e288}, doi = {10.1016/j.jaad.2025.09.118}, pmid = {41381004}, issn = {1097-6787}, } @article {pmid41381656, year = {2025}, author = {Riley, S and Nguyen, V and Bhattacharjee, R and Ng, PQ and Ritchie, T and Kamath, KS and Fisk, I and Gecz, J and Kumar, R and Searle, IR}, title = {TMT-based quantitative proteomic assessment of Vicia sativa induced neurotoxicity by β-cyano-L-alanine and γ-glutamyl-β-cyano-L-alanine in SH-SY5Y cells.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {510}, pmid = {41381656}, issn = {2045-2322}, support = {LP200200957//Australian Research Council/ ; UA720//South Australian Grains and Industry Trust/ ; BB/V018108/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Humans ; *Proteomics/methods ; Cell Line, Tumor ; Tandem Mass Spectrometry ; *Proteome ; *Dipeptides/toxicity ; Apoptosis/drug effects ; Oxidative Stress/drug effects ; *Alanine/analogs & derivatives/toxicity ; }, abstract = {β-cyano-L-alanine (BCA) and γ-glutamyl-β-cyano-L-alanine (GBCA) are the primary antinutritional compounds in Vicia sativa, a high-protein, drought-tolerant legume. While their neurotoxicity in monogastric animals has been reported, the molecular basis remains largely unknown. In this study, we optimised a rapid in vitro assay using retinoic acid-differentiated SH-SY5Y human neuroblastoma cells to assess BCA and GBCA toxicity, and then applied Tandem mass tags (TMT)-mass spectrometry (MS)-based quantitative proteomics to identify dysregulated proteins. BCA treatment dysregulated the proteins involved in DNA damage, translation, and oxidative stress, many of which are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease, as well as various cancers. In contrast, GBCA impacted the proteins linked to mitosis, cell cycle regulation, and apoptosis pathways. Interestingly, the absence of overlapping dysregulated proteins between BCA- and GBCA-treated cells suggested that the two toxins likely induce neurotoxicity via distinct mechanisms. These findings offer new insights into the molecular and cellular alterations caused by V. sativa toxins and their implications for animal feed safety.}, } @article {pmid41381924, year = {2025}, author = {Soares, ÁM and de Paula Cruz, ECO and da Silva, LG and de Sousa, YG and Távora, DGF and de Albuquerque, LAF}, title = {Anatomical references for the transopercular approach to the insula: a 1.5 Tesla magnetic resonance study.}, journal = {Neurosurgical review}, volume = {49}, number = {1}, pages = {63}, pmid = {41381924}, issn = {1437-2320}, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; Female ; Male ; Adult ; Middle Aged ; *Insular Cortex/anatomy & histology/surgery ; *Cerebral Cortex/anatomy & histology/surgery ; Young Adult ; Aged ; Adolescent ; Brain Mapping/methods ; }, abstract = {OBJECTIVE: This study aimed to establish the topographic relation of the limiting sulci of the insula with structures on the brain surface, in addition to determining a new anatomical point to objectively identify the Berger-Sanai quadrants.

METHODS: 1.5 Tesla MRI was used to analyze 100 insulas and their relation to the brain surface. The projection of the anterior (ALS), superior (SLS), and inferior (ILS) limiting sulci of the insula onto the brain surface was determined, together with the relations between these sulci and the anterior Sylvian point (ASP), the inferior frontal sulcus (IFS), and the superior temporal sulcus (STS). The central point of the Berger-Sanai quadrants was identified based on the inferior Rolandic point (IRP). The projection of this central point onto the insula and the brain surface were also identified.

RESULTS: The following measurements were calculated: the mean anteroposterior distance between the ASP and ALS, 3.2 mm ± 0.7 mm; the mean craniocaudal distance from the ASP to the SLS, 10.5 mm ± 1.8 mm; the mean craniocaudal distance between the IFS and SLS, 15.5 mm ± 2.5 mm; the mean craniocaudal distance from the end of the IFS to the SLS, 13.5 mm ± 2.9 mm; the mean craniocaudal distance between the STS and ILS, 4.0 mm ± 1.9 mm; the mean craniocaudal distance from the end of the STS to the ILS, 6.1 mm ± 2.4 mm; and the mean laterolateral distance from the STS to the ILS, 22.7 mm ± 3.5 mm. The central point of the Berger Sanai quadrants was determined to be over the Sylvian fissure, at a mean distance of 7.3 mm ± 1.2 mm anterior to the IRP. This point projected over the precentral gyrus in 79% of cases and the posterior short gyrus of the insula in 68%.

CONCLUSIONS: The data obtained in this study demonstrate a close topographic relationship between easily identifiable structures on the brain surface (ASP, IFS and STS) and the limiting sulci of the insula. We propose a simple, novel way to find the central point of the Berger Sanai quadrants based on their relation with the IRP. The findings determined here can assist neurosurgeons in locating the insula, especially in transopercular approaches.}, } @article {pmid41383013, year = {2026}, author = {Hor, JH and Ow, JR and Ng, W and Ramasamy, B and Tabaglio, T and Lim, KNH and Bin Muzakar, MI and Lim, VJW and Gurrampati, RR and Rajarethinam, R and Ngo, ST and Ramadass, V and Ling, SC and Lakshmanan, M and Wee, KB and Ng, SY}, title = {BLOC1S1 depletion via splice-switching oligonucleotides improves mitochondrial respiration and rescues ALS phenotypes.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {34}, number = {3}, pages = {1672-1683}, pmid = {41383013}, issn = {1525-0024}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy/pathology ; Animals ; *Mitochondria/metabolism/genetics ; Humans ; Mice ; Disease Models, Animal ; Motor Neurons/metabolism ; Phenotype ; *Oligonucleotides, Antisense/genetics ; Cell Respiration ; Induced Pluripotent Stem Cells/metabolism ; *RNA Splicing ; *Oligonucleotides/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and debilitating neurodegenerative disease, yet the mechanisms underlying disease onset and progression remain poorly understood, particularly in sporadic ALS. Emerging evidence suggests that mitochondrial dysfunction and metabolic dysregulation are central to ALS pathophysiology. A key feature of ALS motor neurons (MNs) is hyper-acetylation of mitochondrial proteins, which disrupt mitochondrial respiration and energy homeostasis. In this study, we identify BLOC1S1 (also known as GCN5L1) as a novel regulator of mitochondrial acetylation in ALS. We demonstrate that BLOC1S1 is significantly upregulated in ALS patient-derived MNs, postmortem motor cortices, and spinal cords of ALS mouse models. Functional studies in induced pluripotent stem cell-derived MNs reveal that BLOC1S1 depletion rescues key disease phenotypes. Therefore, we develop an efficacious splice-switching antisense oligonucleotide that induces nonsense-mediated decay of BLOC1S1 transcripts as a potential therapeutic candidate. Besides mitigating ALS-relevant cellular deficits in MN cultures from diverse genetic backgrounds, it was validated to extend disease-free and overall survival that is associated with improved rotarod performance in an ALS mouse model. These findings establish BLOC1S1 as a critical modifier of disease progression in ALS and highlight its potential as a novel therapeutic target.}, } @article {pmid41384353, year = {2025}, author = {Yu, H and Zhang, X and Liu, Z and Zhang, L}, title = {Explaining Isoform Selectivity of c-Jun N-Terminal Kinase 3 (JNK3) Inhibitors through Its Development and Structural Insights.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {24}, pages = {25665-25688}, doi = {10.1021/acs.jmedchem.5c01488}, pmid = {41384353}, issn = {1520-4804}, mesh = {*Mitogen-Activated Protein Kinase 10/antagonists & inhibitors/metabolism/chemistry ; Humans ; *Protein Kinase Inhibitors/chemistry/pharmacology ; Structure-Activity Relationship ; Animals ; Models, Molecular ; Protein Isoforms/metabolism/antagonists & inhibitors ; }, abstract = {c-Jun N-terminal kinase 3 (JNK3), a member of the mitogen-activated protein kinase (MAPK) family, is selectively enriched in the brain. It plays a significant role in the pathogenesis of neurodegenerative disorders, glaucoma, amyotrophic lateral sclerosis, and cancer, which makes it a promising drug target. However, the advancement of JNK3 inhibitors has been challenged by limited isoform selectivity. This article explains the pathway regulated by JNK3 and the unique functions of JNK3. A detailed structural analysis of JNK3 complexes with ligands is presented to uncover the molecular basis of binding interactions. The inhibitors are systematically classified according to their chemical scaffolds, and the reason for their isoform selectivity was discussed, providing a structural rationale for the evolution of JNK3 inhibitor design. The perspective concludes with an exploration of the challenges in the discovery of selective JNK3 inhibitors and proposes innovative strategies to surmount these obstacles.}, } @article {pmid41385026, year = {2025}, author = {Kara, NS and Ozisik, O and Baudot, A and Slachtova, L}, title = {Investigating the Potential Roles of Environmental Exposures on the Pathology of Amyotrophic Lateral Sclerosis by Overlap Analysis.}, journal = {Neurotoxicity research}, volume = {43}, number = {6}, pages = {51}, pmid = {41385026}, issn = {1476-3524}, support = {AMX-19-IET-007//Initiative d'Excellence d'Aix-Marseille Université/ ; PRIMUS UK 21/MED/012//Univerzita Karlova v Praze/ ; OP JAK MSCA//Ministerstvo Školství, Mládeže a Tělovýchovy/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *Environmental Exposure/adverse effects ; Vehicle Emissions/toxicity ; Pesticides/toxicity ; Toluene/toxicity ; Smoking/adverse effects ; Computational Biology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease causing motor neuron loss. 90-95% of ALS cases are sporadic, and the interplay of genetic predispositions and environmental exposures is essential in ALS pathology. Several neurotoxic exposures, such as smoking, pesticides, and organic solvents, have been implicated as affecting the risk of ALS. However, it is unclear how these exposures impact specific cellular mechanisms and influence ALS risk. We investigated the potential mechanisms of toxicity of diesel exhaust, toluene, pesticides, and smoking on ALS pathology through a bioinformatics approach. We retrieved the gene sets targeted by these environmental exposures, and the gene sets involved in ALS-associated biological processes. We performed overlap analysis to assess the statistical significance of the overlap between the gene sets associated with environmental exposures and those linked to ALS. Response to oxidative stress, synaptic signaling, lipid metabolic process, cellular oxidant detoxification, and regulation of gliogenesis significantly overlapped with the gene sets targeted by each of the four environmental exposures. Contrarily, chaperone-mediated autophagy, DNA repair, and regulation of action potential, significantly overlapped only with the gene sets targeted by diesel exhaust, pesticides, and toluene, respectively. Finally, transport across the blood-brain barrier, vesicle-mediated transport, actin filament-based transport, autophagy, transport to the Golgi and subsequent modification of proteins, metabolism of lipids, regulation of neurotransmitter receptor levels, and axon guidance significantly overlapped only with the gene set targeted by tobacco smoke pollution. This study aims to investigate the molecular relationships between neurotoxic exposures and ALS by overlap analysis, providing a framework that can be applied to investigate other exposure-disease interactions.}, } @article {pmid41385186, year = {2025}, author = {Mitsiadou, D and Xirodimas, DP and Polanowska, J}, title = {NEDD8, stress granules, and amyotrophic lateral sclerosis: unveiling the therapeutic potential of the NEDP1 protease.}, journal = {Essays in biochemistry}, volume = {69}, number = {5}, pages = {}, pmid = {41385186}, issn = {1744-1358}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; Animals ; *Stress Granules/metabolism ; *NEDD8 Protein/metabolism ; }, abstract = {Protein quality control (PQC) systems are crucial for maintaining cellular proteostasis, particularly under stress that promotes misfolded protein accumulation. A central component of this response is the assembly of stress granules (SGs), cytoplasmic condensates of RNA and proteins that temporarily stall translation. Aberrant SG dynamics, often linked to mutations in SG proteins, contribute to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), where persistent protein aggregates are hallmarks. This review examines the emerging role of the ubiquitin-like modifier NEDD8 and its deconjugating enzyme NEDP1 in regulating SG homeostasis. Recent studies identify NEDP1 as a critical factor controlling SG clearance. Inhibition of NEDP1 enhances SG turnover, prevents pathological solidification, and promotes the disassembly of toxic aggregates through hyper-NEDDylation of PARP1, a DNA repair enzyme that also governs SG dynamics. Unlike broad-spectrum PARP1 inhibitors, which can impair DNA repair and cause cytotoxicity, NEDP1 inhibition offers a stress-specific approach that preserves normal cellular functions. Encouragingly, NEDP1 inhibition effectively causes aggregate elimination in ALS patient-derived fibroblasts and restores motility in Caenorhabditis elegans disease models. Altogether, these findings highlight NEDP1 as a key regulator of SG regulation and a promising therapeutic target for ALS and related neurodegenerative disorders.}, } @article {pmid41386298, year = {2026}, author = {Ealy, A and Serapiglia, AM and Panicker, N}, title = {Sterile innate immune mechanisms in neurodegenerative diseases.}, journal = {The Journal of biological chemistry}, volume = {302}, number = {2}, pages = {111039}, pmid = {41386298}, issn = {1083-351X}, support = {R00 AG066862/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Immunity, Innate ; *Neurodegenerative Diseases/immunology/pathology ; Animals ; Amyotrophic Lateral Sclerosis/immunology/pathology ; Parkinson Disease/immunology/pathology ; Alzheimer Disease/immunology/pathology ; Signal Transduction ; Multiple Sclerosis/immunology/pathology ; }, abstract = {Neurodegenerative diseases are characterized by the dysfunction and death of susceptible neuronal populations. Increasing evidence has demonstrated that sustained neuroinflammation and activation of innate immune complexes underlie neurodegeneration, worsening disease progression and outcomes. Sterile inflammation (which occurs in the absence of infection) can be triggered by neurodegenerative disease-associated misfolded proteins. These studies highlight the need to decipher the complexities of innate immune signaling mechanisms and their contribution to neuropathology. In this review, we focus on major neurodegenerative diseases that have a well-documented neuroinflammatory component: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and frontotemporal dementia. In the context of these diseases, we discuss recent advances in innate-immune mechanisms that have been demonstrated to partake in disease progression and neurodegeneration. These include evolutionarily conserved innate-immune signaling complexes whose uncontrolled activation amplifies neurodegeneration, damaging lipid droplets that accumulate within myeloid cells and prevent their ability to clear toxic protein aggregates, as well as genome-wide studies-implicated genes/proteins. The individual and/or concerted actions of these pathways could be leveraged to rationally target the pathogenesis or progression of neurodegenerative diseases.}, } @article {pmid41386880, year = {2025}, author = {Eshak, D and Arumugam, M}, title = {Integrative analysis of transcriptomics and drug-target networks identifies SMN1 as a novel biomarker and therapeutic target for amyotrophic lateral sclerosis.}, journal = {Journal, genetic engineering & biotechnology}, volume = {23}, number = {4}, pages = {100615}, pmid = {41386880}, issn = {2090-5920}, abstract = {Amyotrophic lateral sclerosis (ALS) is a prevalent and debilitating neurodegenerative disorder characterized by the selective degeneration of motor neurons. This study aims to unravel the molecular mechanisms underlying ALS through an integrated analysis of drug-target networks and gene expression data. Gene expression datasets related to ALS, including GSE115130 and GSE76220, were retrieved from the GEO database and systematically analyzed. Differential gene expression (DEG) analysis identified key upregulated and downregulated genes, while weighted gene co-expression network analysis (WGCNA) uncovered gene modules associated with ALS pathology. DEG analysis revealed genetic insights into ALS by pinpointing genes potentially involved in disease development and progression. WGCNA provided a systems-level understanding of ALS mechanisms, identifying highly correlated gene clusters and their relationship with clinical ALS characteristics. In the GSE115130 dataset, 6,105 genes were upregulated and 6,069 were downregulated. Conversely, the GSE76220 dataset showed 4,850 upregulated genes and 7,691 downregulated genes. Using the STRING database, a protein-protein interaction (PPI) network was constructed to investigate the functional relationships among ALS-associated genes. The findings highlighted the significant role of the survival motor neuron 1 (SMN1) gene in ALS, particularly in sporadic cases. Additionally, drug-target network mapping identified potential therapeutic targets and candidate drugs, offering valuable insights into the molecular mechanisms of ALS and possible interventions. This integrative approach underscored SMN1 as a novel diagnostic biomarker and potential therapeutic target for ALS, emphasizing its critical role in disease pathogenesis. These findings pave the way for further mechanistic studies and clinical validation, aiming to enhance therapeutic strategies for ALS.}, } @article {pmid41386904, year = {2025}, author = {eBioMedicine, }, title = {The accelerating pace of amyotrophic lateral sclerosis research.}, journal = {EBioMedicine}, volume = {122}, number = {}, pages = {106079}, doi = {10.1016/j.ebiom.2025.106079}, pmid = {41386904}, issn = {2352-3964}, } @article {pmid41386992, year = {2026}, author = {Myers, AK and Sakheim, M and Rivell, C and Fengler, C and Festa, LK and Guerra, KM and Jarrahy, L and Shin, R and Case, M and Chapman, C and Basel, L and Springer, S and Kern, N and Gidicsin, J and Cho, G and Kim, S and Tighiouart, M and Golden, JA}, title = {Anxiety-Associated Behaviors Following Ablation of Miro1 from Cortical Excitatory Neurons.}, journal = {eNeuro}, volume = {13}, number = {1}, pages = {}, pmid = {41386992}, issn = {2373-2822}, support = {R01 NS100007/NS/NINDS NIH HHS/United States ; R56 NS100007/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *rho GTP-Binding Proteins/genetics/metabolism/deficiency ; *Anxiety/metabolism/genetics/pathology ; Mice ; *Neurons/metabolism ; Male ; *Mitochondrial Proteins/genetics/metabolism ; *Cerebral Cortex/metabolism/pathology ; Mitochondria/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Behavior, Animal/physiology ; Female ; Disease Models, Animal ; }, abstract = {Autism spectrum disorder, schizophrenia, and bipolar disorder are neuropsychiatric conditions that manifest early in life with a wide range of phenotypes, including repetitive behavior, agitation, and anxiety (American Psychological Association, 2013). While the etiology of these disorders is incompletely understood, recent data implicate a role for mitochondrial dysfunction (Norkett et al., 2017; Khaliulin et al., 2025). Mitochondria translocate to intracellular compartments to support energetics and free-radical buffering; failure to achieve this localization results in cellular dysfunction (Picard et al., 2016). Mitochondrial Rho-GTPase 1 (Miro1) resides on the outer mitochondrial membrane and facilitates microtubule-mediated mitochondrial motility (Fransson et al., 2003). The loss of MIRO1 is reported to contribute to the onset/progression of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease (Kay et al., 2018). We have hypothesized that MIRO1 also has a role in nervous system development (Lin-Hendel et al., 2016). To test this, we ablated Miro1 from cortical excitatory progenitors by crossing floxed Miro1 mice with Emx1-Cre mice and studied mice of both sex. We found that mitochondrial mislocalization in migrating excitatory neurons was associated with reduced brain weight, decreased cortical volume, and subtle cortical disorganization. Adult Miro1 conditional mutants exhibit agitative-like behaviors, including decreased nesting and abnormal home cage activity. The mice exhibited anxiety-like behavior and avoided confined spaces, features that have been linked to several human behavioral disorders. Our data link MIRO1 function with mitochondrial dynamics in the pathogenesis of several neuropsychiatric disorders and implicate intracellular mitochondrial dynamics to several anxiety-like behaviors.}, } @article {pmid41387380, year = {2026}, author = {Savasan-Sogut, M and Campos-Melo, D and Strong, MJ}, title = {3'UTR variants of ALS-linked RNAs modify subcellular and cellular phenotypes.}, journal = {The FEBS journal}, volume = {293}, number = {8}, pages = {2500-2513}, pmid = {41387380}, issn = {1742-4658}, support = {SOP-160442//CIHR/Canada ; SOP-160442//CIHR/Canada ; }, mesh = {*3' Untranslated Regions/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Genetic Variation ; *Spinal Cord/metabolism ; *Polyadenylation ; Phenotype ; Pseudopodia/pathology ; Sequestosome-1 Protein ; Superoxide Dismutase-1 ; Neurofilament Proteins ; }, abstract = {While most human genes express mRNA 3'untranslated region (3'UTR) variants of different lengths, their impact on cell physiology and disease remains largely unknown. Here, we studied 3'UTR length heterogeneity in amyotrophic lateral sclerosis (ALS) and determined that three ALS-linked transcripts exhibit lengthening of their 3'UTRs in patient samples. We investigated phenotypical effects in a neuronal cell line expressing these 3'UTRs and observed that expression of these unique 3'UTRs induces morphological changes at different levels. Among the most expressed 3'UTR variants in ALS, NEFH 3'UTR-Long induces the formation of nuclear RNA clusters, and Superoxide Dismutase 1 3'UTR-Long diminishes filopodia in the plasma membrane. Sequestosome 1 3'UTR-Long did not show major changes in nuclear RNA clusters or filopodia. Our findings provide the first evidence that 3'UTRs can modulate cellular phenotype independent of the coding region, further expanding the impact of alterations in mRNA biogenesis in ALS.}, } @article {pmid41388206, year = {2025}, author = {Schmitt, P and Schumann, P and Koerbs, A and Lin, HJ and Grehl, T and Weyen, U and Petri, S and Rödiger, A and Steinbach, R and Großkreutz, J and Bernsen, S and Weydt, P and Wolf, J and Günther, R and Baum, P and Metelmann, M and Weishaupt, JH and Streubel, B and Kasper, DC and Koc, Y and Kettemann, D and Norden, J and Walter, B and Münch, C and Spittel, S and Maier, A and Körtvélyessy, P and Meyer, T}, title = {Motor phenotypes and neurofilament light chain in genetic amyotrophic lateral sclerosis-results from a multicenter screening program.}, journal = {Journal of neurology}, volume = {273}, number = {1}, pages = {22}, pmid = {41388206}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/physiopathology/diagnosis ; *Neurofilament Proteins/blood ; Male ; Female ; Middle Aged ; C9orf72 Protein/genetics ; Phenotype ; Aged ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; Adult ; Disease Progression ; Cohort Studies ; DNA-Binding Proteins/genetics ; }, abstract = {OBJECTIVE: In genetic amyotrophic lateral sclerosis (ALS), the clinical phenotypes, disease progression and neurofilament light chain (NfL) levels are incompletely characterized.

METHODS: In a total cohort of 1988 ALS patients, a subcohort of genetic ALS linked to C9orf72 (n = 137), SOD1 (n = 54), TARDBP (n = 27), and FUS (n = 19) was investigated. The phenotypes of onset region, propagation and motor neuron involvement were analyzed according to the OPM classification. Serum NfL (sNfL) was measured and related to ALS progression (ALSPR, monthly change of ALS Functional Rating Scale-Revised). To quantify NfL elevation relative to ALSPR, the logNfL(index), the log-transformed ratio of sNfL to ALSPR was calculated.

RESULTS: C9orf72-associated ALS showed frequent bulbar onset (n = 42.6%), higher ALSPR (0.95, SD 0.84), highest NfL (116.3, SD 72.7 pg/mL) and logNfL(index) (5.02, SD 0.88). SOD1-ALS had mostly limb onset (n = 96.1%), slower ALSPR (0.57, SD 0.60), high NfL (76.1, SD 61.4 pg/mL) and a comparably high logNfL(index) (4.94, SD 1.03). FUS-ALS exhibited mostly limb onset (82.4%), lower motor neuron dysfunction (70.6%), a wide range of faster (22.2%) to slower ALSPR (55.6%), lower NfL (66.2, SD 32.9) and logNfL(4.65, SD 0.9). TARDBP-ALS displayed the lowest ALSPR (0.53, SD 0.52), the lowest NfL (43.3, SD 31.8 pg/mL) and the lowest logNfL(index) (4.40, SD 0.7).

CONCLUSION: In C9orf72-ALS, the phenotype and NfL profile are close to typical ALS. The finding of distinct phenotypes and NfL patterns in SOD1-, FUS- and TARDBP-associated ALS underscores the relevance of genetic ALS for prognostic counseling, clinical trial design, treatment expectations and unraveling of pathogenic mechanisms in ALS.}, } @article {pmid41389101, year = {2025}, author = {Li, Y and Zhou, Y and Yu, L and Bi, Y and Yi, L and Li, C and Liu, Y}, title = {Myeloid Irf5 Deficiency Enhances the Therapeutic Efficacy of IMD-0354 in a TDP-25-Induced Neurodegeneration Model.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {290}, pmid = {41389101}, issn = {1559-1182}, support = {H2024206009//the Hebei Natural Science Foundation/ ; 81901290//the National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Interferon Regulatory Factors/deficiency/metabolism ; *DNA-Binding Proteins/toxicity/metabolism ; Macrophages/metabolism/drug effects ; Mice, Knockout ; Mice ; Disease Models, Animal ; Mice, Inbred C57BL ; Apoptosis/drug effects ; Motor Neurons/metabolism/drug effects/pathology ; Mitochondria/metabolism/drug effects ; Cell Line ; Amyotrophic Lateral Sclerosis/drug therapy ; Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Nerve Degeneration/drug therapy/pathology/metabolism ; *Myeloid Cells/metabolism/drug effects ; }, abstract = {Neuroinflammation is recognized as a key contributor to the pathogenesis and progression of amyotrophic lateral sclerosis (ALS), with dysregulated innate immune activation implicated in exacerbating neuronal injury. However, the molecular mechanisms by which macrophages contribute to neurodegeneration in motor neurons harboring TAR DNA-binding protein 43 (TDP-43) mutations are not fully understood. M1 macrophages were generated from the bone marrow of Irf5 knockout or wild-type mice and co-cultured with the NSC34 motor neuron-like cell line overexpressing the C-terminal fragment of TDP-43 (TDP-25) using a Transwell system. Mitochondrial alterations, and apoptosis were evaluated through Western blotting, flow cytometry, and transmission electron microscopy. IMD-0354 mitigated mitochondrial dysfunction and apoptosis induced by TDP-25 exposure. This neuroprotective effect was attenuated in the presence of pro-inflammatory macrophages. Notably, the absence of Irf5 expression in macrophages amplified the protective efficacy of IMD-0354. Irf5 expression in macrophages may modulate the therapeutic efficacy of IMD-0354 in the context of TDP-43-associated proteinopathy, indicating a potential target for enhancing treatment strategies in ALS-related neurodegeneration through inhibiting inflammation.}, } @article {pmid41389317, year = {2026}, author = {Argo, A and Puntarello, M and Malta, G and Tarantino, M and Midiri, M and Pellerito, S and Albano, GD and Zerbo, S}, title = {Verification of the persistence of sperm traces under different chain-of-custody conditions. Care pathway and justice for victims of sexual violence and abuse.}, journal = {Forensic science, medicine, and pathology}, volume = {22}, number = {2}, pages = {533-540}, pmid = {41389317}, issn = {1556-2891}, mesh = {Humans ; Male ; *Spermatozoa/chemistry ; *Specimen Handling/methods ; *Sex Offenses ; DNA Fingerprinting ; Sperm Proteins ; Chromatography, Affinity ; *Semen ; Crime Victims ; Seminal Proteins/analysis ; }, abstract = {The primary aim of this study was to verify the persistence of seminal traces under varying chain-of-custody conditions, along with determining how different contamination factors, time intervals between collection, and storage methods influence the detectability of semen in the context of sexual assault cases. This study combined laboratory and field analyses to simulate real-case scenarios. Three forensic detection tools-Sperm Tracker Lab, Sperm Tracker Spray, and RSID™ tests-were evaluated on multiple substrates (skin, hair, nylon, cotton, and car interiors) and under various contamination conditions, including the presence of blood, dust, soil, and bodily fluids. Detection techniques included contact-pressure methods (Sperm Tracker Lab), application on uneven surfaces (Sperm Tracker Spray), fluorescence-based searches with ALS (alternative light sources), and immunochromatographic testing (RSID™ kits) for sperm-specific proteins. Positive findings were confirmed via microscopic examination and DNA analysis. All the samples were labelled and stored following strict chain-of-custody protocols. Sperm Tracker Spray demonstrated consistent effectiveness, successfully detecting minimal volumes (1-2 µL) across a wide range of materials. Conversely, ALS showed reduced sensitivity, especially in the presence of diluted or minimal traces and on textured or dark fabrics. RSID™ kits provided reliable confirmation of the presence of semen, even when environmental or biological contamination was present. Accurate and thorough documentation of the chain of custody proved essential for preserving sample authenticity and reducing the risk of error. The findings underscore the importance of a multidisciplinary forensic approach combining specialized reagents, confirmatory immunochromatographic testing, and rigorous adherence to chain-of-custody procedures. This integrated strategy enhances the reliability of seminal trace detection in investigations of sexual assault. Moreover, verifying trace persistence under diverse conditions contributes significantly to the evidentiary value of forensic samples in judicial contexts.}, } @article {pmid41389796, year = {2026}, author = {Alessandrini, F and Wright, M and Kurosaki, T and Perloff, OS and Ngo, M and Kofler, JK and Donnelly, CJ and Maquat, LE and Kiskinis, E}, title = {TDP-43 dysfunction compromises UPF1-dependent mRNA metabolism in ALS.}, journal = {Neuron}, volume = {114}, number = {4}, pages = {640-660.e10}, pmid = {41389796}, issn = {1097-4199}, support = {R01 NS134166/NS/NINDS NIH HHS/United States ; R21 NS131713/NS/NINDS NIH HHS/United States ; R35 GM149268/GM/NIGMS NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; R01 GM059614/GM/NIGMS NIH HHS/United States ; R01 NS104219/NS/NINDS NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; R21 GM147719/GM/NIGMS NIH HHS/United States ; R01 AG086270/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *RNA, Messenger/metabolism ; *Trans-Activators/metabolism/genetics ; *Motor Neurons/metabolism ; *RNA Helicases/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Phosphorylation ; 3' Untranslated Regions ; Animals ; }, abstract = {Up-frameshift protein 1 (UPF1)-mediated mRNA decay maintains transcriptome integrity and cellular homeostasis. However, its role in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by TAR DNA-binding protein 43 (TDP-43) pathology and disrupted mRNA metabolism in motor neurons (MNs), remains unresolved. Here, we integrated RNA sequencing (RNA-seq) after UPF1 knockdown with RNA immunoprecipitation (RIP)-seq of phosphorylated UPF1 to delineate direct UPF1 targets in induced pluripotent stem cell (iPSC)-derived MNs. These transcripts are enriched for autophagy and structurally characterized by GC-rich, long 3' untranslated regions (3' UTRs). UPF1 activity, measured by this transcript signature, is diminished in TDP-43-depleted and ALS patient MNs. Mechanistically, TDP-43 depletion impairs UPF1 phosphorylation; the two proteins interact in an RNA-dependent manner and co-aggregate in pathological inclusions in ALS tissue. Transcriptomic analyses reveal convergent regulation of alternative polyadenylation and 3' UTR length by UPF1 and TDP-43, processes disrupted in ALS models and patient neurons. Our study defines the mRNA surveillance network of UPF1 in MNs and uncovers a link between RNA decay, TDP-43 dysfunction, and ALS neurodegeneration.}, } @article {pmid41389988, year = {2026}, author = {Gomez-Almeria, M and Martinez-Gonzalez, L and Matos, AT and Rodriguez-Cueto, C and Vaz, AR and Martín-Baquero, R and Pérez de la Lastra, C and Infantes, R and Fernández-Ruiz, J and Palomo, V and Gil, C and Brites, D and Martinez, A and de Lago, E}, title = {Assessment of the therapeutic effect of IGS2.7, a CK1δ protein kinase inhibitor, in combination with riluzole for the treatment of ALS-associated TDP-43 proteinopathy.}, journal = {Neuropharmacology}, volume = {285}, number = {}, pages = {110804}, doi = {10.1016/j.neuropharm.2025.110804}, pmid = {41389988}, issn = {1873-7064}, mesh = {*Riluzole/administration & dosage/pharmacology/therapeutic use ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; Mice ; *Neuroprotective Agents/pharmacology/administration & dosage ; Drug Therapy, Combination ; *Casein Kinase Idelta/antagonists & inhibitors/metabolism ; *TDP-43 Proteinopathies/drug therapy ; *Protein Kinase Inhibitors/pharmacology/administration & dosage/therapeutic use ; Mice, Transgenic ; Male ; Dose-Response Relationship, Drug ; DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease for which no effective treatments currently exist. The FDA and EMA have approved only riluzole, a drug that modestly extends patient survival by 3-18 months. In our research, we have identified a novel CK1δ inhibitor, IGS2.7, which modulates TDP-43 proteinopathy, the main ALS pathological hallmark, in both patient-derived cellular models and TgTDP-43 mice. To assess the potential of IGS2.7 as a therapeutic candidate and considering riluzole remains the standard care for ALS patients, we evaluated its effects in combination with riluzole. Our results demonstrate that co-administration of IGS2.7 and riluzole at effective doses does not cause adverse effects. However, no additional therapeutic benefit was observed beyond that of IGS2.7 monotherapy, suggesting that IGS2.7 may be viable as either a stand-alone treatment or as an adjunct to riluzole. Notably, when suboptimal doses of both drugs were administered, a combined effect was observed. This suggests that, once IGS2.7 reaches clinical testing, its use together with lower doses of riluzole may enhance therapeutic efficacy while potentially minimizing side effects. Additional in vivo pre-clinical studies will be required to further evaluate this possibility, although only clinical trials will ultimately determine its clinical relevance.}, } @article {pmid41391687, year = {2026}, author = {Donison, N and Hintermayer, MA and Palik, J and Fisher, J and Volkening, K and Strong, MJ}, title = {MAPK family members differentially regulate pThr175 tau-mediated pathogenicity.}, journal = {Neurobiology of disease}, volume = {218}, number = {}, pages = {107223}, doi = {10.1016/j.nbd.2025.107223}, pmid = {41391687}, issn = {1095-953X}, support = {//National Hockey League Players Association/ ; }, mesh = {Animals ; *tau Proteins/metabolism ; Phosphorylation ; Male ; *Brain Injuries, Traumatic/metabolism/pathology ; Humans ; Rats ; Mice ; Rats, Sprague-Dawley ; *Tauopathies/metabolism/pathology ; Mice, Inbred C57BL ; Threonine/metabolism ; Mitogen-Activated Protein Kinase 8/metabolism ; }, abstract = {The phosphorylation of tau is a critical determinant of both its physiological function and the induction of pathological misfolding and aggregation. We have previously provided evidence that tau phosphorylation at Thr175 results in the exposure of the N-terminal phosphatase-activating domain (PAD) leading to the subsequent phosphorylation of Thr231, and formation of tau oligomers. A number of tauopathies, including chronic traumatic encephalopathy (CTE), amyotrophic lateral sclerosis with cognitive impairment (ALSci), and experimental traumatic brain injury (TBI) have been proposed to be associated with this cascade of events. However, the cellular mechanism by which Thr175 tau is phosphorylated remains unclear. In this study we identified ERK2, JNK1, and p38 as candidate kinases through molecular and histological analyses in a rodent model of TBI, where increased kinase activity and protein interaction were associated with pThr175 tau. We confirmed that both ERK2 and JNK1 are capable of phosphorylating Thr175 tau in vitro, but only ERK2-mediated phosphorylation of Thr175 tau induced the pathological cascade characterized by PAD exposure and the generation of oligomeric, truncated and neurofibrillary tau. Thr175 phosphorylation was also associated with an altered interaction between tau and the molecular chaperone protein DnaJC7, which regulates tau misfolding. Additionally, we observed that pThr175 and pThr231 tau were increased by oxidative stress, which was associated with the activation of the MAPK signaling pathways. These findings further clarify the mechanisms leading to Thr175 tau phosphorylation and its role in pathological tau formation by identifying ERK1 and JNK2 as important cellular mediators.}, } @article {pmid41392158, year = {2025}, author = {Le Friec, J and Mourier, H and Couly, S and Cubedo, N and Dubois, K and Meunier, J and Delprat, B and De Zordo-Banliat, A and Ayad, T and Virieux, D and Su, TP and Lasbleiz, C and Maurice, T and Liévens, JC}, title = {Positive modulation of sigma-1 receptor: a new weapon to mitigate disease progression in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {68}, pmid = {41392158}, issn = {2047-9158}, support = {grant 23667//AFM-Téléthon/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics/pathology ; *Receptors, sigma/metabolism/agonists ; Sigma-1 Receptor ; Zebrafish ; Disease Progression ; Mice ; Humans ; Mice, Transgenic ; Motor Neurons/drug effects/metabolism ; Disease Models, Animal ; C9orf72 Protein/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterised by degeneration of motor neurons, leading to muscle weakness and progressive paralysis. Currently, no treatment is available to halt or reverse the progression of the disease. Oxidative stress, mitochondrial dysfunction, accumulation of unfolded proteins and inflammation are interconnected key actors involved in ALS. A potent therapeutic strategy would be to find molecules that break this vicious circle leading to neuronal dysfunction and death. Targeting sigma-1 receptor (S1R) could meet this objective, as this chaperone protein modulates many cell survival mechanisms. So far, the impact of S1R activation in ALS has been studied using specific agonists and mostly on the SOD1 mutation that represents only 2% of patients. In the present study, the impact of two different S1R activators, the reference agonist PRE-084 and the positive modulator OZP002, was compared on two key ALS genes: TDP43 and C9orf72.

METHODS: The dissociation of S1R from Binding immunoglobulin Protein (BiP) was determined using ELISA. OZP002 toxicity was compared to PRE-084 on zebrafish larvae with increasing concentrations. The efficacy of OZP002 and PRE-084 was evaluated on the locomotor escape response of zebrafish expressing mutant TDP43 or one C9orf72 toxic dipeptide. Their effects on NRF2 target gene expression were studied by qPCR. The beneficial effect was further examined on the locomotor performances of TDP43[A315T] mice using rotarod and beam walking tests. We also performed analysis on motor neuron loss and glial reactivity.

RESULTS: OZP002 is a positive modulator of S1R, that increases the dissociation of the S1R-BiP complex induced by orthosteric agonists. S1R activation by both OZP002 and PRE-084 restored the locomotor response of ALS zebrafish expressing either TDP43 or one C9orf72 toxic dipeptide. The neuroprotection was due at least in part to the NRF2 cascade stimulation but not with a direct interaction. More importantly, OZP002 and PRE-084 prevented locomotor defects and degeneration of spinal motor neurons in TDP43[A315T] transgenic mice. Astroglial and microglial reactivities were also reduced by both activators.

CONCLUSIONS: We here emphasize the therapeutic value of S1R activation in mitigating ALS pathology. Additionally, we show that the positive modulators pave the way for the development of new S1R-activating compounds for ALS treatment.}, } @article {pmid41392526, year = {2026}, author = {Maitland, S and Birkbeck, M and Schofield, I and Best, L and Scott, J and Blamire, A and Whittaker, RG}, title = {MRI of Neurogenic Human Motor Units Following Poliomyelitis.}, journal = {Muscle & nerve}, volume = {73}, number = {3}, pages = {403-411}, pmid = {41392526}, issn = {1097-4598}, support = {//NIHR Newcastle Biomedical Research Centre/ ; }, mesh = {Humans ; Female ; Male ; *Poliomyelitis/diagnostic imaging/complications/physiopathology/pathology ; Middle Aged ; *Magnetic Resonance Imaging/methods ; *Motor Neurons/physiology/pathology ; Electromyography ; Aged ; Retrospective Studies ; *Muscle, Skeletal/diagnostic imaging/physiopathology/innervation ; Adult ; Electric Stimulation ; }, abstract = {INTRODUCTION/AIMS: Surviving motor units in neurogenic diseases demonstrate collateral reinnervation. Scanning electromyography (EMG) reveals normal motor unit corridor length, but with "silent regions," suggesting that reinnervation does not result in increased motor unit size but may increase motor unit complexity. Motor unit magnetic resonance imaging (MUMRI) pairs MR imaging with electrical nerve stimulation to visualize individual motor units. This study aimed to assess the motor unit dimensions and complexity in patients with previous poliomyelitis compared to healthy controls.

METHODS: Patients with a history of polio were recruited from the British Polio Fellowship, compared to a retrospective cohort of healthy controls. They underwent medical history and examination of lower limb power, fatigue assessment (fatigue severity score, FSS), and a 3 T MUMRI scan of the less-affected lower limb. The cross-sectional area, maximum, and minimum Feret diameter of the motor unit territories in tibialis anterior were calculated. Motor unit complexity was computed using the Hausdorff box-counting method.

RESULTS: Of 12 polio survivors, n = 8 (6 female) were suitable for analysis and were compared to 19 controls. The mean motor unit maximum Feret diameter was 10.3 ± 3.1 mm compared to 8.4 ± 5.2 mm in controls (p = 0.34). The mean shape complexity was 0.59 ± 0.12 compared to 0.45 ± 0.2 in controls (p = 0.03).

DISCUSSION: Polio survivors demonstrate motor units with normal dimensions but increased shape complexity, indicating nonuniform collateral reinnervation largely limited to existing territories. The size and shape of motor units could help in understanding the physiological processes behind reinnervation, both in polio and other neurogenic diseases such as amyotrophic lateral sclerosis.}, } @article {pmid41392874, year = {2026}, author = {Jung, HJ and Cheong, EN and So, J and Kang, HW and Choi, Y and Lee, EJ and Kim, H and Lim, YM}, title = {ALS With and Without Upper Motor Neuron Signs: A Comparative Study Supporting the Gold Coast Criteria.}, journal = {Annals of clinical and translational neurology}, volume = {13}, number = {5}, pages = {984-993}, pmid = {41392874}, issn = {2328-9503}, support = {2023IP0108//Asan Institute for Life Sciences, Asan Medical Center/ ; RS-2023-00211443//Ministry of Science and ICT, South Korea/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/pathology/blood ; Male ; Female ; Middle Aged ; Aged ; Disease Progression ; *Evoked Potentials, Motor/physiology ; Biomarkers/blood ; Adult ; Magnetic Resonance Imaging ; White Matter/pathology/diagnostic imaging ; }, abstract = {OBJECTIVE: The Gold Coast criteria permit diagnosis of amyotrophic lateral sclerosis (ALS) even without upper motor neuron (UMN) signs. However, whether ALS patients with UMN signs (ALSwUMN) and those without (ALSwoUMN) share similar characteristics and prognoses remains unclear. This study compared clinical features, disease progression, electrophysiological findings, biomarker profiles, imaging parameters, and survival between these groups.

METHODS: ALS patients diagnosed according to the Gold Coast criteria were classified into ALSwUMN (n = 51) and ALSwoUMN (n = 20) groups. We evaluated clinical data, motor evoked potentials (MEP), and serum biomarkers, including cardiac Troponin T, neurofilament light chain, glial fibrillary acidic protein, and brain-derived neurotrophic factor. Imaging parameters, including cortical thickness and white matter volume, were also evaluated. Survival was analyzed using the Kaplan-Meier method.

RESULTS: The groups showed broadly similar clinical features, disease progression, and biomarker profiles. Abnormal MEPs were more frequent in ALSwUMN (94.0%) than in ALSwoUMN (63.2%, p = 0.017). Both groups demonstrated cortical thinning in the precentral and entorhinal regions compared to healthy controls. ALSwUMN exhibited thinning in the lateral orbitofrontal, insular, and temporal pole regions, while ALSwoUMN showed thinning in the pars opercularis. White matter volume was reduced in both groups in the thalamus, cerebellum, and amygdala, with additional brainstem atrophy in ALSwUMN. No significant survival difference was observed.

INTERPRETATION: Despite minor distinctions in electrophysiological and imaging findings, ALSwoUMN had overall comparable clinical profiles and outcomes to ALSwUMN. These findings support recognizing ALSwoUMN within the ALS spectrum under the Gold Coast criteria.}, } @article {pmid41393069, year = {2025}, author = {Yan, K and Deng, J and Yong, Y and Bi, F}, title = {Proteomic Identification of ALDOA as a Pathogenic TDP-43 Interaction Partner in ALS.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {15}, number = {}, pages = {123-132}, pmid = {41393069}, issn = {1179-9900}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons, and its pathogenesis has not been fully elucidated. TAR DNA-binding protein 43 (TDP-43), as one of the key pathogenic genes in ALS, participates in the disease process through interactions with various proteins. This study aims to investigate the interaction mechanism between TDP-43 and aldolase A (ALDOA) in ALS.

METHODS: HEK293T cell models transfected with wild-type and mutant TDP-43 (TDP-43[M337V]) plasmids were constructed. The interaction between TDP-43 and ALDOA was analyzed through proteomic screening of specific peptides and co-immunoprecipitation, and the co-localization of the two in cells was detected by immunofluorescence. Changes in ALDOA expression levels after intervention with mutant TDP-43 were detected by Western blot and quantitative real-time PCR.

RESULTS: Proteomic analysis identified ALDOA as a potential interacting protein of TDP-43. Protein-protein interaction (PPI) analysis, co-immunoprecipitation, and immunofluorescence experiments further confirmed that both wild-type and mutant TDP-43 interact with ALDOA. Western blot and quantitative real-time PCR results showed that, compared with the wild-type TDP-43 group, the ALDOA expression was significantly increased in the TDP-43[M337V] mutant group.

CONCLUSION: TDP-43 interacts with ALDOA in ALS, and the TDP-43[M337V] mutation significantly promotes ALDOA expression, suggesting that ALDOA may be involved in the pathogenesis of TDP-43-mediated ALS. These findings provide new insights into the pathogenesis of ALS and highlight a potential therapeutic target.}, } @article {pmid41393525, year = {2025}, author = {Guedes, A and de Camargo, OP and Matos, EP and Carreiro, MC and Rios, FF and Guimarães, AHS and Meyer, KA and de Lima, NFL and Barreto, BG and de Mattos, ESR and Antunes, CR and Barreto, ESR}, title = {EVALUATION OF A DECADE OF ONCOLOGICAL-ORTHOPEDIC PROCEDURES IN BRAZIL (2015-2024) AND THE IMPACT OF COVID-19.}, journal = {Acta ortopedica brasileira}, volume = {33}, number = {spe3}, pages = {e297250}, pmid = {41393525}, issn = {1413-7852}, abstract = {OBJECTIVE: To evaluate the regional distribution of hospital admission authorizations (AIH), total and average hospitalization cost (AHC), average length of stay, number of deaths and mortality rate related to oncological-orthopedic procedures funded by the Unified Health System (SUS) between 2015 and 2024, with an emphasis on the impact of the COVID-19 pandemic.

METHODS: Ecological study with time series based on data obtained from the SUS Hospital Information System, analyzed by Brazilian regions in the pre-pandemic, pandemic and post-pandemic periods. Regional differences were calculated using ANOVA or Kruskal-Wallis. The impact of the pandemic was analyzed using T-tests and ARIMA with intervention. Statistical analysis was performed in R.

RESULTS: 9,120 AIHs were recorded, mostly in the Southeast (4,375) and South (2,252) regions. Multiple regional variations were found for all the variables evaluated. Only the AHC was impacted - there was an increase in costs per procedure; The other variables maintained the trend after the beginning of the pandemic.

CONCLUSIONS: Despite the increase in the AHC, we did not observe significant variation in the number of AIH, ALS, and MR when analyzing the pre-pandemic and pandemic periods, suggesting that there was no direct impact on the performance of the analyzed procedure. Level of Evidence III; Retrospective f comparative study e.}, } @article {pmid41394620, year = {2025}, author = {Vivek, R and Kume, T and Roschdi, S and Record, MT and Hoskins, AA and Butcher, SE}, title = {TDP-43 controls RNA structure through high affinity lattice interactions.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394620}, issn = {2692-8205}, support = {R35 GM118131/GM/NIGMS NIH HHS/United States ; R35 GM136261/GM/NIGMS NIH HHS/United States ; S10 RR013790/RR/NCRR NIH HHS/United States ; }, abstract = {TDP-43 is an RNA binding protein implicated in neurodegenerative disease. TDP-43 binds to GU dinucleotide repeats, which are highly abundant sequences in human RNA. Here we show TDP-43 has one of the highest affinities and specificities measured for an RNA binding protein. Binding prevents formation of the pUG fold, an intramolecular quadruplex, and conversely pUG fold formation prevents TDP-43 binding. A rapid on-rate allows TDP-43 to capture single stranded RNA prior to folding. The protein recognizes the RNA as a 1D lattice, in which overlapping binding sites produce efficient initial binding events that interfere with subsequent interactions. This effect is partially overcome by RNA facilitated protein-protein interactions, which serve to increase the on-rate of a second TDP-43 molecule. In conjunction with all atom models, these data reveal how TDP-43 recognizes RNA repeat sequences and identify an interplay between RNA folding and protein recognition that may be relevant to human disease.}, } @article {pmid41394638, year = {2025}, author = {Sutter, AB and Buksh, BF and Mojsilovic-Petrovic, J and Dalton, C and Till, NA and Morgan, DC and MacMillan, DWC and Kalb, RG}, title = {The molecular mechanism of uptake and cell-to-cell transmission of arginine-containing dipeptide repeat proteins.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394638}, issn = {2692-8205}, support = {R01 NS122908/NS/NINDS NIH HHS/United States ; R01 NS124802/NS/NINDS NIH HHS/United States ; R35 GM134897/GM/NIGMS NIH HHS/United States ; }, abstract = {Micro-satellite repeat expansion of the 5' GGGGCC 3' sequence in the C9orf72 gene is the most common monogenic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) translated from the mutant allele can be detected in postmortem brains of afflicted individuals. The arginine containing peptides, poly-PR and poly-GR, are particularly noxious to cells. Both have been shown to undergo cell-cell transmission, but the underlying mechanisms are not understood. We found rapid internalization and nucleolar localization of bath-applied hemagglutinin (HA) tagged poly-PR with twenty repeats (HA-PR20) in cell lines and neurons. Small molecule and RNAi approaches implicated a temperature-dependent, fluid phase endocytosis mechanism in HA-PR20 uptake. We sought to identify DPR-related cell surface uptake factors using a high-resolution proximity labeling technique developed in the MacMillan group, termed μMap. DPR-iridium conjugates identified candidate cell-surface proteins which were interrogated in an RNAi screen. Focusing on our strongest candidate, chondroitin sulfate proteoglycan 4 (CSPG4), we showed that cellular uptake of HA-PR20 is blocked by inhibition of glycosaminoglycan chain synthesis (using drugs or RNAi) and knockdown or ablation of CSPG4 (using RNAi or CRISPR editing). Reduction of CSPG4 protected PR20-induced neuronal toxicity. We used a dual reporter system to interrogate in vitro neuron-to-neuron transmission of PR50 and found that PR50 synthesized by one neuron readily spread to neighboring neurons. Transmission was significantly reduced when CSPG4 was knocked down. These results suggest CSPG4 is an important factor in poly-PR internalization and transmission and therefore may be a therapeutic target to slow DPR transmission and disease progression.}, } @article {pmid41394659, year = {2025}, author = {Tendulkar, S and Wu, T and Strickland, A and Hackett, AR and Sato-Yamada, Y and Mao, X and Sasaki, Y and Milbrandt, J and Bloom, AJ and DiAntonio, A}, title = {Dysregulated lactate metabolism synergizes with ALS genetic risk factors to accelerate motor decline.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394659}, issn = {2692-8205}, support = {R37 NS065053/NS/NINDS NIH HHS/United States ; R01 NS087632/NS/NINDS NIH HHS/United States ; RF1 AG013730/AG/NIA NIH HHS/United States ; R01 NS119812/NS/NINDS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; }, abstract = {Neurons rely on glial 'lactate shuttling' for metabolic support, which declines with aging and in neurodegenerative disease. Full disruption of lactate shuttling in peripheral nerves causes progressive axon degeneration, but we were interested to understand how partial disruption, a scenario more relevant to aging and disease, contributes to neurodegeneration risk. Pyruvate and lactate are interconverted by lactate dehydrogenases (LDHA and LDHB) in both lactate producing and consuming cells. We therefore began by investigating Ldhb knockout mice (loss of LDHA, the dominant LDH in liver and muscle, caused embryonic lethality), and discovered that they develop progressive neuromuscular junction atrophy and functional decline without axon degeneration. Because even Ldhb [+/-] heterozygosity significantly affects motor behavior, we also wondered about a potential link to congenital disease and pursued this by identifying rare loss-of-function LDHB variants among ALS patients. Next, to better understand how LDHB loss leads to motor decline, we selectively deleted it in defined cell types. SC-specific deletion caused robust motor defects, whereas motor neuron-specific deletion has little effect. Reasoning that neuronal LDHB deficiency could model age-associated decline in lactate metabolism, we asked whether it would interact with ALS genetic risk. Indeed, motor-neuron LDHB deficiency synergizes with relatively mild ALS risk variants- TDP43 [Q331K] and Sod1 [D83G] knock-in alleles-to produce early motor neuropathy, indicating that LDHB loss enhances disease risk. These findings establish lactate metabolism as a modifier of motor system vulnerability and highlight it as a therapeutic target in peripheral as well as central neurodegeneration.}, } @article {pmid41394670, year = {2025}, author = {O'Connor, JT and Loo, HQ and Guo, C and Pickles, S and Sundali, S and Jawahar, VM and Dickson, DW and Bloom, AJ and Petrucelli, L and Gitler, AD and Milbrandt, J and DiAntonio, A}, title = {TDP-43 suppression of ATP8A2 cryptic splicing implicates phosphatidylserine-driven neuroinflammation in ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394670}, issn = {2692-8205}, support = {R01 NS133348/NS/NINDS NIH HHS/United States ; R01 NS087632/NS/NINDS NIH HHS/United States ; R01 NS065053/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R35 NS137447/NS/NINDS NIH HHS/United States ; F32 AG086044/AG/NIA NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; R01 NS132330/NS/NINDS NIH HHS/United States ; R35 NS137159/NS/NINDS NIH HHS/United States ; }, abstract = {Inappropriate externalization of phosphatidylserine (PS) is a candidate mechanism of pathogenic neuroinflammation, a critical driver of neurodegenerative disease. ATP8A2, a flippase that maintains PS on the plasma membrane inner leaflet, is mutated in both Wabbler-lethal mice and patients with the ataxia syndrome CAMRQ4. Here, we identify ATP8A2 as a target of TDP-43 cryptic exon suppression, and demonstrate that ATP8A2 loss leads to immune-mediated neurodegeneration. ATP8A2 splicing is significantly dysregulated following TDP-43 depletion in human neurons and in brains of patients with Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). In mice, Atp8a2 loss increases PS exposure and promotes neuroinflammation. Depletion of peripheral macrophages rescues motor axon degeneration and doubles Atp8a2 knockout mouse lifespan, while depletion of both peripheral macrophages and central microglia quadruples lifespan and improves coordination. Hence, ATP8A2 is a pathologically relevant TDP-43 target and inhibition of phagocytic immune cell attack against neurons is a potential treatment for patients with CAMRQ4 and ALS-FTD.}, } @article {pmid41394711, year = {2025}, author = {Mehta, PR and Solomon, T and Pickles, S and Harley, P and Barioglio, M and Schweingruber, C and Marrero-Gagliardi, A and Gao, Y and Mattedi, F and Barattucci, S and Lin, LT and Ryadnov, E and Zanovello, M and Cammack, AJ and Isaacs, AM and Burrone, J and Shaw, CE and Keuss, MJ and Petrucelli, L and Fratta, P and Ruepp, MD}, title = {U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394711}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, abstract = {TDP-43 nuclear depletion in amyotrophic lateral sclerosis (ALS) causes de-repression of cryptic exons (CEs) in multiple transcripts, including UNC13A and STMN2, disrupting synaptic transmission and neurite outgrowth. We developed a therapeutic U7 snRNA (tU7) approach that suppresses TDP-43-dependent mis-splicing, restores target gene expression, rescues neuronal functions in human iPSC-derived neurons, and shows target engagement in vivo, positioning tU7-mediated splicing correction as a promising therapeutic strategy for ALS.}, } @article {pmid41394713, year = {2025}, author = {Ross, D and Lewis, O and McLean, O and Bhanot, S and Donahue, S and Baker, R and Dias, R and Eagerton, D and Mohanty, V and Mohanty, BK}, title = {Thermally activated irreversible homogenization of G-quadruplexes in an ALS/FTD-associated gene.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394713}, issn = {2692-8205}, abstract = {A significant proportion of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases exhibit a substantial copy number expansion of the hexanucleotide GGGGCC/GGCCCC sequence in the C9ORF72 gene. The GGGGCC sequence forms a non-canonical DNA structure called a G-quadruplex (G4) which has been associated with the disease states and with nucleic acid condensate formation. G4s can fold into various topologies, which can differentially impact fidelity of DNA synthesis. However, how G4 conformational heterogeneity and its regulation impact hexanucleotide repeat expansion is unclear, and important clues may lie in the thermodynamic properties of different G4 topologies. Here, we use temperature-swept CD spectroscopy to observe configurational homogenization of an initially heterogeneous population of G4s over a small range of temperatures, demonstrating thermally activated behavior. We further show that this reaction is irreversible, since subsequent temperature sweeps do not show CD shifts from non-parallel to parallel G4 topologies. Finally, we provide an analytical theory based on a two-state thermodynamic model which is compatible with experimental evidence, and we discuss alternate mechanisms for the homogenization transition. These findings suggest that kinetic regulation of non-canonical DNA structures may play a role in cellular homeostasis or disease pathogenesis.}, } @article {pmid41395145, year = {2025}, author = {Yi, X and Zhou, W and Cheng, C and Chen, X}, title = {Remimazolam-remifentanil general anaesthesia without muscle relaxants for percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: A retrospective analysis.}, journal = {Indian journal of anaesthesia}, volume = {69}, number = {12}, pages = {1413-1416}, pmid = {41395145}, issn = {0019-5049}, } @article {pmid41395267, year = {2025}, author = {Roy, T and Al-Chalabi, A and Iacoangeli, A and Al Khleifat, A}, title = {Biomarkers in ALS trials: from discovery to clinical utility.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1636303}, pmid = {41395267}, issn = {1662-4548}, abstract = {INTRODUCTION: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disorder characterized by motor neuron degeneration, leading to muscle weakness, paralysis, and eventual respiratory failure. Despite advances in understanding its pathology, effective therapies remain limited, underscoring the need for reliable biomarkers to aid early diagnosis, monitor disease progression, and optimize clinical trials. This systematic review explores the role of biomarkers in ALS, focusing on their application in clinical trials to accelerate therapeutic development and enhance patient care.

METHODS: A comprehensive search of PubMed, EMBASE, MedLine, and Google Scholar identified 93 studies investigating various biomarkers, including neurofilament light chain (NFL), inflammatory markers, genetic markers like SOD1 and C9orf72, and imaging modalities.

RESULTS: NFL emerged as a robust biomarker, strongly correlating with disease progression and therapeutic response, and was frequently used in trials like RESCUE-ALS and CENTAUR. Genetic biomarkers, such as C9orf72 and SOD1 mutations, provided insights into ALS mechanisms and informed targeted therapeutic approaches. Emerging biomarkers, such as retroviral elements, show potential but require further validation. Included studies span key trials such as Lighthouse-II, MIROCALS, and MND-SMART.

DISCUSSION: This systematic review evaluates which biomarkers are currently validated for monitoring disease progression and therapeutic response in ALS clinical trials, including protein, genetic, inflammatory, metabolic, and imaging markers. It also highlights the critical role of biomarkers in advancing MND clinical trials by enabling adaptive trial designs, patient stratification, and the use of surrogate endpoints, thereby reducing trial duration and improving efficiency. The review also highlights the translational gap between biomarker discovery and clinical application, emphasizing their potential to optimize trial design and patient stratification. While biomarkers like NFL have transformed trial methodologies, challenges such as disease specificity and inter-patient heterogeneity persist. Future efforts should focus on multimodal biomarker approaches to achieve comprehensive disease assessment and advance personalized therapeutic strategies, ultimately improving outcomes for patients with MND.}, } @article {pmid41395499, year = {2025}, author = {Li, L and Yang, W and Hong, Y and He, Q and Lu, X and Wang, H and Tao, P and Shu, C and Chen, M and Bao, G and Jiang, L}, title = {Identification of Nanoplastics by Probing the Viscous Nanoenvironment.}, journal = {Small science}, volume = {5}, number = {12}, pages = {e202500430}, pmid = {41395499}, issn = {2688-4046}, abstract = {With the growing prevalence of global microplastic and nanoplastic pollution, the accumulation of nanoplastics in the human body has increased, heightening the risk of noncommunicable diseases including cancer, cardiovascular disease, and amyotrophic lateral sclerosis. However, the development of fluorescent probes for detecting nanoplastics remains challenging due to the lack of reactive sites on nanoplastics for conventional design of responsive probes. In this work, a novel strategy for the sensitive detection of nanoplastics by probing the viscous nanoenvironment surrounding them is presented. This study synthesizes a cationic fluorescent probe, Purification by silica gel column chromatography (CH2Cl2/MeOH) provided (E)-2-(2-(4-(dimethylamino)nanphthalen-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium (named HCY due to its structural similarity to hemicyanine dyes) as a tawny solid (HCY), via a simple one-step reaction. HCY demonstrates high sensitivity to nanoplastics, achieving an 8.5-fold fluorescence enhancement in the presence of carboxylated polystyrene nanoplastics, with a detection limit of 0.153 μg mL[-1]. Moreover, HCY exhibits excellent biocompatibility, enabling the monitoring of nanoplastics level in living cells and visualization of nanoplastics distribution in zebrafish. This work offers a new design strategy for responsive fluorescent probes and provides a promising avenue for detecting environmental pollutants.}, } @article {pmid41396180, year = {2026}, author = {Xu, X and Zhou, Q and Zhang, X and Li, T and Niu, L and Xu, G and Chen, S and Shao, Y and Le, W}, title = {Untargeted metabolomics based on LC-MS and GC-MS reveal metabolic reprogramming and putative biomarkers in amyotrophic lateral sclerosis.}, journal = {Chinese medical journal}, volume = {139}, number = {4}, pages = {610-619}, pmid = {41396180}, issn = {2542-5641}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; *Metabolomics/methods ; *Biomarkers/metabolism/blood ; Male ; Female ; Middle Aged ; *Gas Chromatography-Mass Spectrometry/methods ; Chromatography, Liquid/methods ; Adult ; Aged ; ROC Curve ; Metabolic Reprogramming ; Liquid Chromatography-Mass Spectrometry ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unknown etiology. The absence of reliable biochemical and imaging markers often delays diagnosis and limits treatment effectiveness. As metabolic reprogramming is increasingly recognized as a hallmark of ALS, a comprehensive untargeted metabolomics analysis was employed to identify critical metabolic perturbations in ALS and explore novel candidate biomarkers with potential utility in clinical diagnosis.

METHODS: Plasma from two independent cohorts comprising 399 participants (170 ALS patients, 200 healthy controls, and 29 ALS-unrelated neurological disease controls) was included. Cohort 1 was recruited from Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital (April 2020-September 2022), and cohort 2 from Sichuan Academy of Sciences-Sichuan Provincial Hospital, Ruijin Hospital, Shanghai Jiaotong University Affiliated Sixth People's Hospital, and The First Affiliated Hospital of Dalian Medical University (October 2022-February 2023). Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approaches were used to identify metabolic alterations and potential diagnostic biomarkers for ALS. Complementary multivariable and univariable statistical approaches were applied to characterize disease-specific metabolic reprogramming in ALS. In addition, the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of differential metabolites, and binary logistic regression analysis was used to construct a multivariate biomarker model.

RESULTS: Metabolic changes of ALS were mainly observed in amino acids, fatty acyls , and purines. Inosine and hypoxanthine were found to be the most significantly and critically dysregulated metabolites in ALS. Aminoacyl-transfer ribonucleic acid (tRNA) biosynthesis and amino acid metabolism were regarded as the most significantly perturbed pathways. Across both cohorts, 26 metabolites were consistently changed. Notably, a biomarker panel comprising hypoxanthine, inosine, and trigonelline was constructed using binary logistic regression, achieving excellent diagnostic performance in distinguishing ALS from controls, with an area under the ROC curve of 0.982 in cohort 1 (sensitivity 0.970, specificity 0.940) and 0.934 in cohort 2 (sensitivity 0.942, specificity 0.791).

CONCLUSION: The disturbed pathways and biomarker candidates identified in this study may provide novel insights into ALS pathogenesis and improve diagnostic strategies.}, } @article {pmid41396654, year = {2026}, author = {Šakotić, RJ and Crişan, I}, title = {Laying the Groundwork for Clinical Neuropsychology in Romania: Beliefs and Practices of Psychologists Regarding Validity Testing in Clinical Assessment.}, journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists}, volume = {41}, number = {3}, pages = {}, doi = {10.1093/arclin/acaf116}, pmid = {41396654}, issn = {1873-5843}, mesh = {Humans ; Romania ; Male ; Female ; Adult ; Surveys and Questionnaires ; *Neuropsychology/standards/methods ; Reproducibility of Results ; Middle Aged ; *Neuropsychological Tests/standards ; *Attitude of Health Personnel ; Psychologists ; }, abstract = {OBJECTIVE: The present study aimed to explore and document Romanian psychologists' practices and beliefs regarding validity testing in clinical assessment, given the lack of neuropsychology as a practice field in this country.

METHOD: We developed a questionnaire addressing several key aspects, including demographic and professional information, and beliefs and practices related to validity testing in clinical assessment. The questionnaire was distributed to all practitioners licensed in clinical psychology registered on the official website of the Romanian College of Psychologists (RCP). The final sample consisted of 344 practitioners, 312 of whom had been active in assessments during the previous year.

RESULTS: Our findings revealed several cultural particularities, including the preference of 49.4% of the sample for employing the Tree Drawing Test (Koch, K. (1954). Der Baumtest - Der Baumzeichenversuch als psychodiagnostisches Hilfsmittel. Hans Huber. Romanian translation by Mocanu, S. (2002). Testul Arborelui - Diagnosticul psihologic cu ajutorul testului arborelui. Profex. Bucuresti) - a projective drawing technique - as a validity test. Only 16.7% of practitioners reported using empirically supported validity tests in clinical evaluations, and several performance validity tests were reported by 2-12.5% of the sample. Additionally, the prevalence of malingering was estimated to be 5%-20% and most respondents associated it with personality disorders.

CONCLUSIONS: The results indicate a need to bridge the gap between science and practice by adopting evidence-based approaches within the Romanian assessment culture. Our survey offers novel empirical insights into the current state of validity assessment in Romania, thereby contributing foundational knowledge that may support the legitimization and further development of neuropsychology within the national context.}, } @article {pmid41396714, year = {2026}, author = {Haenssler, AE and Okada, J and Eshghi, M and Clark, A and Iyer, A and Richburg, BD and Cavanaugh, R and Onnela, JP and Burke, KM and Berry, JD and Green, JR and Connaghan, KP}, title = {What can vowel acoustics reveal about the communicative participation of people living with ALS?.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {632-640}, pmid = {41396714}, issn = {2167-9223}, support = {K23 DC019179/DC/NIDCD NIH HHS/United States ; R42 DC019877/DC/NIDCD NIH HHS/United States ; R01 DC021446/DC/NIDCD NIH HHS/United States ; R15 DC018944/DC/NIDCD NIH HHS/United States ; K24 DC016312/DC/NIDCD NIH HHS/United States ; R01 DC017291/DC/NIDCD NIH HHS/United States ; F32 DC020896/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Female ; Male ; Middle Aged ; Aged ; *Speech Acoustics ; *Speech Intelligibility/physiology ; Speech Production Measurement ; Adult ; *Phonetics ; }, abstract = {Objective: Bulbar dysfunction often diminishes the accuracy and speed of the tongue, lip, and jaw movements necessary for speech production. Vowel acoustic features derived from speech recordings can serve as sensitive markers of articulatory accuracy and movement timing. We examined whether degraded speech caused by amyotrophic lateral sclerosis (ALS), assessed through vowel acoustic features, was associated with communicative participation restrictions. As a secondary aim, we assessed the association of two global speech characteristics, rate and intelligibility, with vowel features and communicative participation. Materials & Methods: Thirty-three people with ALS (plwALS) recorded a reading passage and completed surveys using a smartphone application. Speaking rate and acoustic vowel features (duration, vowel articulation index [VAI]) were extracted from the recordings. Three speech-language pathologists rated speech intelligibility. Communicative participation was assessed using the Communicative Participation Item Bank (CPIB) short form. Bivariate correlation, partial correlation, and regression analyses were used to evaluate the associations between vowel features, intelligibility, speaking rate, and CPIB scores. Results: Significant bivariate correlations, ranging from rs = -0.39 to rs = 0.64, were found between speech variables and CPIB scores. A combined regression model including VAI, vowel duration, and sex explained 52% of the variance in CPIB scores. Including speaking rate or intelligibility in the partial correlation analysis attenuated the associations between vowel acoustics and CPIB. Conclusions: Vowel features and global dysarthria characteristics are linked to communicative participation in ALS. Clinical practices designed to target vowel production, speaking rate, and intelligibility may help to maintain daily communication in ALS.}, } @article {pmid41397557, year = {2026}, author = {Esposto, J and Stock, NL and Huber, RJ and Martic, S}, title = {Differential binding of copper and zinc to a TDP-43 RNA recognition motif decapeptide and disulfide formation at residues C173/5 revealed by ESI-MS/MS.}, journal = {Analytical biochemistry}, volume = {710}, number = {}, pages = {116031}, doi = {10.1016/j.ab.2025.116031}, pmid = {41397557}, issn = {1096-0309}, mesh = {*Copper/metabolism/chemistry ; *Zinc/metabolism/chemistry ; *DNA-Binding Proteins/chemistry/metabolism ; Spectrometry, Mass, Electrospray Ionization/methods ; *Disulfides/chemistry/metabolism ; Tandem Mass Spectrometry ; Humans ; Binding Sites ; *RNA Recognition Motif ; Protein Binding ; }, abstract = {Copper (Cu) and zinc (Zn) metal ions play important roles in the proper functioning and localization of neurological proteins, such as transactive response DNA-binding protein 43 (TDP-43), which is linked to amyotrophic lateral sclerosis (ALS). Previous experimental and computational studies have identified putative Zn-binding regions within the RNA recognition motif 1 (RRM1) of TDP-43. However, Cu-binding interactions have been less explored despite their redox activity in regulating thiol (C173/175) conversion to disulfide within the RRM1 domain, influencing protein structure and function. Herein, the structural characterization and fragmentation pattern analysis of a TDP-43 decapeptide (166-HMIDGRWCDC-175), within RRM1, coordinated to Cu(II) and Zn(II) ions using electrospray ionization tandem mass spectrometry (ESI-MS/MS) was conducted under non-denaturing conditions. Higher-energy collision dissociation (HCD) fragmentation analysis identified that Cu(II) prefers His/Met residues, while Zn(II) was weakly coordinated to various binding sites in the peptide, specifically His, Met, Glu, Cys, Trp and Asp residues. Computational modeling using a metal ion binding server (MIB2) confirmed the binding sites and coordination sphere of metal-peptide complexes. No significant coordination to C173 and C175 was observed with Cu or Zn, as identified by using a double Cys mutant peptide. A complete thiol-to-disulfide conversion was observed in the presence of Cu(II)/(I) only, which was confirmed by the comparison of a preformed intramolecular disulfide peptide. Overall, unique differential coordination environments were observed for each metal ion with the peptide. The study provides new insights into metal ion interactions with TDP-43 RRM1 peptide, leading to a greater understanding of metal homeostasis in TDP-43 protein biochemistry and neurodegeneration.}, } @article {pmid41397872, year = {2026}, author = {Tam, SB and Waldeck, NJ and Wright, M and Mojsilovic-Petrovic, J and Baker, EM and Kiskinis, E and Bass, J and Kalb, RG}, title = {A role for the cholinergic neuron circadian clock in RNA metabolism and mediating neurodegeneration.}, journal = {Life science alliance}, volume = {9}, number = {3}, pages = {}, pmid = {41397872}, issn = {2575-1077}, support = {P30 CA060553/CA/NCI NIH HHS/United States ; R01 NS122908/NS/NINDS NIH HHS/United States ; R01 NS124802/NS/NINDS NIH HHS/United States ; T32 HL007909/HL/NHLBI NIH HHS/United States ; }, mesh = {*Circadian Clocks/genetics/physiology ; Animals ; Humans ; Mice ; *Cholinergic Neurons/metabolism/physiology ; *RNA/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Transcriptome/genetics ; Neurodegenerative Diseases/genetics/metabolism ; ARNTL Transcription Factors/genetics/metabolism ; Alternative Splicing/genetics ; RNA-Binding Proteins/metabolism/genetics ; Circadian Rhythm/genetics ; Male ; Gene Regulatory Networks ; Gene Expression Regulation ; Spinal Cord/metabolism ; }, abstract = {Circadian clocks are encoded by a transcription-translation feedback loop that aligns physiological processes with the solar cycle. Previous work linking the circadian clock to the regulation of RNA-binding proteins (RBPs) provides a foundation for the vital examination of their mechanistic connections in the context of amyotrophic lateral sclerosis (ALS)-a fatal neurodegenerative disease commonly marked by disrupted RBP function. Here, we reveal that the spinal cord cholinergic neuron rhythmic transcriptome is enriched for genes associated with ALS and other neurodegenerative diseases. We show that there is time-of-day-dependent expression of ALS-linked RBP transcripts and rhythmic alternative splicing of genes involved in microtubule cytoskeleton organization, intracellular trafficking, and synaptic function. Through in silico analysis of RNA sequencing data from sporadic ALS patients, we find that gene expression profiles altered in disease correspond with rhythmic gene networks. Finally, we report that clock disruption through cholinergic neuron-specific deletion of clock activator BMAL1 increases neurodegeneration and drives time-of-day-dependent alternative splicing of RNA processing genes. Our results establish a role for the cholinergic neuron circadian clock in RNA metabolism and mediating neurodegeneration.}, } @article {pmid41398098, year = {2026}, author = {Pieper, AA and Paul, BD}, title = {Hydrogen Sulfide Signaling in Neurodegenerative Movement Disorders.}, journal = {Handbook of experimental pharmacology}, volume = {292}, number = {}, pages = {65-93}, pmid = {41398098}, issn = {0171-2004}, support = {R01 AG071512/AG/NIA NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; P50 DA044123/DA/NIDA NIH HHS/United States ; I01 BX005976/BX/BLRD VA/United States ; R21 AG073684/AG/NIA NIH HHS/United States ; }, mesh = {*Hydrogen Sulfide/metabolism ; Humans ; *Signal Transduction ; Animals ; *Neurodegenerative Diseases/metabolism/physiopathology/drug therapy ; Brain/metabolism/physiopathology ; *Movement Disorders/metabolism ; Gasotransmitters/metabolism ; }, abstract = {Hydrogen sulfide (H2S) is a gaseous signaling molecule, also known as a gasotransmitter, present in nearly all mammalian organs. It plays crucial roles in regulating various physiological processes in both the brain and peripheral systems. The body maintains tight control over H2S levels, as both excessive and deficient levels can disrupt normal physiological functions and lead to disease. H2S has a significant impact on cognitive and motor functions, which are often compromised in neurodegenerative disorders. It modulates signaling and metabolism primarily by post-translationally modifying reactive cysteine residues on proteins through sulfhydration, also known as persulfidation. This chapter reviews the signaling mechanisms regulated by H2S in neurodegenerative diseases that significantly affect motor function, specifically focusing on Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), and Leigh syndrome (LS), as well as other mitochondrial disorders. While PD, HD, and SCA are linked to decreased levels of H2S, elevated levels of H2S are associated with ALS, DS, and LS. We also explore potential therapeutic applications of modulating H2S levels in the brain.}, } @article {pmid41398118, year = {2025}, author = {Dunlop, RA and Cox, PA and Mehta, P and Stommel, EW and Banack, SA}, title = {miRNA Biomarkers Diagnose Amyotrophic Lateral Sclerosis in Circulating Blood.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {298}, pmid = {41398118}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/blood/diagnosis/genetics ; Humans ; Biomarkers/blood ; Female ; Middle Aged ; Male ; *MicroRNAs/blood/genetics ; Aged ; Adult ; Area Under Curve ; Sensitivity and Specificity ; }, abstract = {A rapid, accurate diagnostic test for amyotrophic lateral sclerosis (ALS) would reduce diagnostic delays and improve patient outcomes. We extracted eight circulating miRNAs from 788 blood plasma samples and analyzed them using qPCR for ALS diagnostic accuracy. The biomarker parameters were established previously using 449 individual blood samples and applied prospectively to an independent cohort for validation of a predictive model. The primary outcome was ALS classification accuracy as measured by diagnostic sensitivity, specificity, positive and negative predictive values (PPV, NPV), and area under the curve (AUC). The secondary outcome was comparative fold-regulation values determined prior to data collection. The diagnostic test had an AUC of 0.98 (95% CI 0.97-0.99), with 97% sensitivity (95% CI 96-98), 93% specificity (95% CI 90-96), 93% PPV (95% CI 91-96), and 97% NPV (95% CI 96-98). The fold-regulation values exceeded or were equal to prior calculated values. Streamlined methods resulted in higher diagnostic accuracy, cut both assay time and cost, reduced technical barriers, and enhances the feasibility for widespread clinical adoption. The high accuracy of this diagnostic biomarker suggests that continued evaluation is warranted.}, } @article {pmid41398473, year = {2026}, author = {Moffatt, C and Arora, A and Vaeth, KF and Guzman, BB and Bhardwaj, G and Hoelscher, A and Gifford, LB and Russ, HA and Dominguez, D and Taliaferro, JM}, title = {TDP-43 directly inhibits mRNA accumulation in neurites through modulation of mRNA stability.}, journal = {The EMBO journal}, volume = {45}, number = {3}, pages = {692-721}, pmid = {41398473}, issn = {1460-2075}, support = {F31GM155957//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; F31GM151819//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35 GM133385/GM/NIGMS NIH HHS/United States ; R01 NS122911/NS/NINDS NIH HHS/United States ; R35GM133385//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35 GM142864/GM/NIGMS NIH HHS/United States ; R01NS122911//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; T32GM136444//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; F31 GM151819/GM/NIGMS NIH HHS/United States ; T32 GM136444/GM/NIGMS NIH HHS/United States ; F31 GM155957/GM/NIGMS NIH HHS/United States ; R35GM142864//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {Animals ; *RNA, Messenger/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Humans ; Mice ; *RNA Stability ; *Neurites/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Motor Neurons/metabolism ; Ganglia, Spinal/metabolism ; }, abstract = {The subcellular localization of many mRNAs to neuronal projections allows neurons to efficiently and rapidly react to spatially restricted external cues. However, for most of these RNAs, the mechanisms that govern their localization are unknown. Here, using subcellular fractionation and single-molecule RNA FISH, we found that loss of TDP-43 results in increased accumulation of hundreds of mRNAs in neurites. Using high-throughput functional assays in cells and high-throughput binding assays in vitro, we subsequently identified specific regions within these mRNAs that mediate their TDP-43-dependent localization and interaction with TDP-43. We found that the same regions also mediated TDP-43-dependent mRNA instability, suggesting a mechanism by which TDP-43 regulates mRNA localization. ALS-associated mutations in TDP-43 resulted in similar mRNA mislocalization phenotypes as did TDP-43 loss in mouse dorsal root ganglia and human iPS-derived motor neurons. These findings establish TDP-43 as a direct negative regulator of mRNA abundance in neurites and suggest that mislocalization of specific transcripts may occur in ALS patients.}, } @article {pmid41398973, year = {2025}, author = {Veh, A and Ewald, M and da Cruz Neris Geßner, V and Giridhar, NJ and Hutchings, AJ and Stigloher, C and Binotti, B and Heinze, KG and Lüningschrör, P}, title = {Age-dependent removal of Atg9-containing vesicle accumulations in motoneuron disease models by physical exercise.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {69}, pmid = {41398973}, issn = {2047-9158}, support = {DFG LU 2347/3-1//Deutsche Forschungsgemeinschaft/ ; 218894163//Deutsche Forschungsgemeinschaft/ ; F-N-439//Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg/ ; Z-12 to KGH//Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg/ ; }, mesh = {Animals ; *Physical Conditioning, Animal/physiology ; Mice ; Disease Models, Animal ; *Synaptic Vesicles/metabolism/pathology ; *Motor Neuron Disease/metabolism/pathology ; Autophagy/physiology ; *Autophagy-Related Proteins/metabolism ; Motor Neurons/metabolism ; Neuromuscular Junction/metabolism/pathology ; Mice, Knockout ; Mice, Transgenic ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Atg9-containing vesicles are enriched in synapses and undergo cycles of exo- and endocytosis similarly to synaptic vesicles, thereby linking presynaptic autophagy to neuronal activity. Dysfunction of presynaptic autophagy is a pathophysiological mechanism in motoneuron disease (MND), which leads to impaired synaptic integrity and function. Here, we asked whether boosting neuronal activity by physical exercise modulates the cellular and motor phenotypes of Plekhg5-deficient mice, an MND model with defective presynaptic autophagy.

METHODS: To characterize the vesicle accumulations in Plekhg5-deficient mice, we performed immunohistochemical staining, electron microscopy, and super-resolution imaging. Following voluntary running wheel exercise, we quantified the histopathological changes within the spinal cord and at neuromuscular junctions using an unbiased machine-learning approach. Additionally, we analyzed the motor performance of the animals by measuring their grip strength. To assess changes in the autophagic flux upon physical exercise in vivo, we utilized mRFP-GFP-LC3 expressing mice. The presence of Atg9-containing vesicle clusters in SOD1[G93A] was analyzed to examine the relevance of this pathological feature in a second MND model.

RESULTS: We found marked accumulations of Atg9-containing vesicles at presynaptic sites of Plekhg5-deficient mice, which could be cleared by four weeks of voluntary running wheel exercise in young but surprisingly not in aged Plekhg5-deficient mice. However, physical exercise in aged mice led to synaptic vesicle sorting into the Atg9-containing vesicle accumulations without their removal. In line with these findings, short-term voluntary exercise triggered motoneuron autophagy in young but not old mice. Pointing to a broader role of Atg9-containing vesicles in the pathophysiology of MND, we also found Atg9-containing vesicle accumulations in SOD1[G93A] mice, a well-established ALS model. Strikingly, physical exercise in presymptomatic SOD1[G93A] mice resulted in a reduction of the vesicle accumulations.

CONCLUSIONS: Our data highlight the essential role of Atg9 in presynaptic autophagy and suggest that boosting autophagy by physical exercise provides a tool to maintain presynaptic function at the early but not late stages of Plekhg5-associated MND and possibly amyotrophic lateral sclerosis.}, } @article {pmid41399249, year = {2025}, author = {Dellarole, IL and Aprea, V and Catania, M and Battipaglia, C and Romeo, A and Villa, C and Burato, A and Celauro, L and Bella, ED and Riva, N and Salvi, E and Rossi, G and Fede, GD and Legname, G and De Houwer, JFH and Alberici, A and Borroni, B and Seelaar, H and van Swieten, JC and Moda, F and Caroppo, P}, title = {Detection of TDP-43 seeds in CSF of presymptomatic and symptomatic genetic FTD/ALS.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70989}, pmid = {41399249}, issn = {1552-5279}, support = {PNRR-MCNT2-2023-12377336//Ministero della Salute/ ; 2021-650-104//JPND/ ; }, mesh = {Humans ; *DNA-Binding Proteins/cerebrospinal fluid/genetics ; *Frontotemporal Dementia/genetics/cerebrospinal fluid/diagnosis ; Male ; Female ; Middle Aged ; C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/diagnosis ; Progranulins/genetics ; Mutation/genetics ; Aged ; tau Proteins/genetics/cerebrospinal fluid ; Adult ; Biomarkers/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid/genetics ; }, abstract = {INTRODUCTION: Seed amplification assays (SAAs) have shown promising results in detecting misfolded transactive response (TAR) DNA-binding protein 43 (TDP-43) in cerebrospinal fluid (CSF) of genetic frontotemporal dementia (FTD). To date, the use of SAA has yet to be evaluated in presymptomatic individuals.

METHODS: Thirty patients carrying GRN or C9orf72 mutations, 2 microtubule-associated protein tau (MAPT) carriers, 14 presymptomatic subjects, and 27 controls underwent CSF collection. We used SAA for detecting misfolded TDP-43 (TDP-43_SAA) and single molecule array (SIMOA) technology for neurofilament light chain (NfL) dosage.

RESULTS: TDP-43 seeding activity was detected in 67% of TDP-43-linked symptomatic patients, with a specificity of 93%. Almost half of presymptomatic subjects tested positive, mostly GRN carriers. Interestingly, among TDP-43_SAA positive presymptomatic individuals, two GRN carriers underwent phenoconversion.

DISCUSSION: TDP-43_SAA can also detect misfolded TDP-43 in the CSF of presymptomatic individuals. A possible link exists between positive TDP-43_SAA and conversion to the symptomatic phase.

HIGHLIGHTS: Seed amplification assay of transactive response (TAR) DNA-binding protein 43 (TDP-43_SAA) can detect misfolded TDP-43 in the cerebrospinal fluid (CSF) of patients with genetic frontotemporal dementia (FTD), linked to GRN and C9orf72 mutations. TDP-43_SAA can detect misfolded TDP-43 also in the CSF of presymptomatic individuals. In both groups, most TDP-43_SAA positive cases were carriers of GRN mutation. Two GRN carriers that resulted TDP-43_SAA positive converted to the symptomatic phase of the disease.}, } @article {pmid41399314, year = {2026}, author = {Chung, WKV and Chan, KP and Hsu, DY and Ma, YKS and Chan, LYE and Ng, SH and Chow, SLE and Hong, YF and Chan, YHJ and Ma, YK and Lee, S and Lui, WCJ and Cheng, HWB}, title = {A 10-year service evaluation of a multidisciplinary neuro-palliative care model in motor neuron disease: Impact on palliative care service delivery & advance care planning.}, journal = {Palliative medicine}, volume = {40}, number = {2}, pages = {253-264}, doi = {10.1177/02692163251396020}, pmid = {41399314}, issn = {1477-030X}, mesh = {Humans ; *Motor Neuron Disease/therapy/nursing ; *Palliative Care/organization & administration/methods ; Male ; Female ; Retrospective Studies ; Hong Kong ; Middle Aged ; Aged ; *Advance Care Planning/organization & administration ; *Patient Care Team/organization & administration ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND: Multidisciplinary neuro-palliative care has been increasingly recommended for the management of patients with motor neuron disease. While international guidelines have highlighted the importance of early palliative care referral, the best model of practice has not been well-defined.

AIM: The objective of this study is to evaluate the outcomes of a structured multidisciplinary neuro-palliative care model developed in regional hospitals in Hong Kong.

DESIGN: A 10-year retrospective chart review.

SETTING/PARTICIPANTS: Adult motor neuron disease patients under care of three regional hospitals in Hong Kong. Data of patients under the care of multidisciplinary neuro-palliative care taskforce and those who were not were analyzed.

RESULTS: There were 140 motor neuron disease patients included in study. Patients in multidisciplinary neuro-palliative care group received more healthcare intervention and palliative care services, including occupational therapist (92.86% vs 78.57%, p = 0.021), dietician (67.35% vs 42.86%, p = 0.007) and speech therapist (96.94% vs 76.19%, p = 0.000) services, community support by non-governmental organizations (74.49% vs 19.05%, p = 0.000) and formal bereavement support (78.26% vs 17.07%, p = 0.000). Significantly more patients in multidisciplinary neuro-palliative care group had completed Advance Medical Directives (46.94% vs 4.76%, p = 0.000). Patients under multidisciplinary care had longer survival compared to those who were not (HR 0.539, 95% CI 0.372-0.782, p = 0.001). This remains significant after adjusting for factors affecting survival in multivariate analysis.

CONCLUSIONS: Multidisciplinary neuro-palliative care demonstrated benefits in motor neuron disease patients in terms of better care coordination and service delivery, higher rate of Advance Medical Directive completion, with possible better survival observed. Future prospective studies are warranted to assess the impact on patient-centered outcomes.}, } @article {pmid41399419, year = {2025}, author = {Chen, HW}, title = {Axial Spinal Traction as a Potential Modulator of Cerebrospinal and Glymphatic Circulation in Neurodegenerative Diseases: A Technical Report and Biomechanical Hypothesis.}, journal = {Cureus}, volume = {17}, number = {12}, pages = {e99153}, pmid = {41399419}, issn = {2168-8184}, abstract = {Impairment of glymphatic function contributes to the accumulation of metabolic and proteinaceous waste products implicated in neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and certain spinocerebellar ataxias. Pelvis-stabilized axial spinal traction (PSAST) is a biomechanical technique designed to produce brief, controlled cranio-caudal elongation of the vertebral column and spinal dural sac, potentially generating transient pressure gradients capable of influencing cerebrospinal fluid (CSF) dynamics and glymphatic circulation. The technique has been applied in the author's musculoskeletal practice for more than eight years without observed persistent or treatment-related adverse effects, although such practice-based experience does not constitute a formal safety evaluation. Improved sleep quality has been the most consistently reported patient-perceived response to PSAST, a clinically notable observation given the dependence of glymphatic function on consolidated slow-wave sleep. These practice-based observations provide preliminary, hypothesis-generating support for exploring whether controlled axial elongation may modulate cerebrospinal and glymphatic physiology. To the best of the author's knowledge, this report presents the first peer-reviewed technical description of a reproducible, whole-axis axial spinal traction procedure with defined force parameters intended to examine potential modulation of CSF and glymphatic circulation. The report outlines the PSAST protocol and its biomechanical rationale and safety considerations and proposes its potential relevance as a noninvasive, investigational approach for conditions associated with impaired glymphatic function.}, } @article {pmid41399686, year = {2026}, author = {Riyapan, S and Chokvanich, W and Chakorn, T and Somboonkul, B and Chantanakomes, J and Phinyo, N and Konwitthayasin, P and Buangam, K and Saengsung, P}, title = {Implementation of high-performance CPR by basic life support (BLS) personnel: a pilot study in Thailand.}, journal = {Resuscitation plus}, volume = {27}, number = {}, pages = {101164}, pmid = {41399686}, issn = {2666-5204}, abstract = {BACKGROUND: High-performance cardiopulmonary resuscitation (HP-CPR) is a structured, pit-crew-style resuscitation model that has been shown to improve performance in advanced life support (ALS) systems. However, its applicability in volunteer-based basic life support (BLS) settings remains uncertain. This study aimed to describe the implementation of HP-CPR training for BLS personnel in Bangkok, Thailand, and to evaluate its impact on BLS performance using video-based process indicators, as well as to report patient- and system-level characteristics before and after the intervention.

METHODS: We conducted a single-centre, before-and-after study of adults with non-traumatic out-of-hospital cardiac arrest (OHCA) managed by the Siriraj EMS Centre between July 2022 and January 2025. HP-CPR training for BLS personnel was delivered over a fivemonth period. The primary outcome was BLS performance, assessed through predefined process indicators using video review. Secondary outcomes included system-level characteristics and clinical outcomes.

RESULTS: Of 423 patients screened, 214 met the inclusion criteria (110 pre-intervention; 104 post-intervention). Video recordings were available for 39 cases. Post-training, significant improvements were observed in two performance indicators: "counting during CPR" (0.0 % vs. 66.7 %, p < 0.01) and the "hover technique" (0.0 % vs. 62.5 %, p < 0.01). Other indicators, including uninterrupted CPR, assisted ventilation, AED use, and data handover, improved but did not reach statistical significance. Secondary outcomes-including AED use, CPR initiation by BLS, prehospital return of spontaneous circulation (ROSC), and survival outcomes-showed no significant differences between phases.

CONCLUSION: Following HP-CPR training, improvements were observed in selected BLS process indicators. However, further research is needed with larger sample sizes to assess the long-term impact of HP-CPR training in volunteer-based EMS systems.}, } @article {pmid41399798, year = {2025}, author = {Ghosh, S and Debnath, I and Bhunia, S and Nandi, S and Ashique, S and Nayak, A and Mallick, S and Basak, S}, title = {Decoding natural products for neuroprotection: Pathway networks and structural insights for drug development.}, journal = {Chinese herbal medicines}, volume = {17}, number = {4}, pages = {643-672}, pmid = {41399798}, issn = {2589-3610}, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, are progressive disorders marked by neuronal dysfunction and death, driven by pathological mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, apoptosis, and protein misfolding. Despite scientific advances, current treatments remain largely palliative, underscoring the need for multitargeted therapeutic strategies. This narrative review synthesizes preclinical and clinical evidence to explore the neuroprotective potential of natural products, with a focus on their ability to modulate key molecular pathways implicated in NDs. A comprehensive literature search across Scopus, ScienceDirect, PubMed, MDPI, and Web of Science identified relevant studies. Bioactive compounds such as curcumin, resveratrol, ginsenosides, quercetin, and marine-derived molecules like fucoxanthin and phlorotannin demonstrated antioxidant, anti-inflammatory, anti-amyloidogenic, and mitochondrial-protective effects by modulating pathways including PI3K/Akt, NF-κB, and Nrf2/ARE, thereby mitigating neuronal damage and promoting cell survival. Natural products from diverse sources, including honey, ginseng, marine macroalgae, and cyanobacteria, exhibited broad-spectrum neuroprotective properties, with advances in nano-formulations improving bioavailability and brain penetration. Furthermore, emerging approaches such as gene-drug interaction studies and scaffold-based drug design offer promising avenues for enhancing clinical translation. While natural products provide a holistic, multitargeted approach to combat NDs, challenges related to bioavailability and therapeutic translation persist, necessitating future research that integrates advanced drug delivery systems, precision medicine, and synthetic modifications to develop innovative and effective treatment paradigms.}, } @article {pmid41400569, year = {2026}, author = {Vacchiano, V and Cherici, A and Criante, MS and Mengoli, E and Fonti, C and Bonan, L and de Pasqua, S and Donadio, V and Giannoccaro, MP and Rizzo, G and Quarta, CC and Marzocchi, E and Taggi, F and Liguori, R and , }, title = {Cognitive and behavioral impairment may influence shared care planning and treatment decisions in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {622-631}, doi = {10.1080/21678421.2025.2597937}, pmid = {41400569}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/complications ; Female ; Male ; Middle Aged ; Aged ; *Cognitive Dysfunction/psychology/etiology/therapy ; Neuropsychological Tests ; *Decision Making, Shared ; Decision Making ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons, often accompanied by cognitive and/or behavioral impairments. Shared Care Planning (SCP) involves a collaborative decision-making process, playing a key role in aligning medical treatments with patient values. This study aimed to investigate potential associations between neuropsychological impairment and treatment decisions in ALS patients. Methods: We included 118 ALS patients who had completed at least the cognitive section of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). As part of routine clinical practice, patients were invited to participate in Shared Care Planning (SCP) discussions regarding key medical interventions, namely noninvasive ventilation (NIV), artificial nutrition via PEG/RIG, and tracheostomy. Results: SCP discussions were initiated with 78% of patients. NIV was accepted by 96% of patients, PEG/RIG by 63.9% and tracheostomy by 17.8%. Patients who accepted PEG/RIG were more frequently female (p = 0.047) and had significantly lower adjusted scores on the total ECAS (p = 0.027), ALS-specific domains (p = 0.020), verbal fluency (p = 0.012), and semantic fluency (p = 0.042), compared to those who refused PEG/RIG. Acceptance of tracheostomy was more common among younger patients (p < 0.001) and those with cognitive or behavioral impairments (p = 0.014). Binary logistic regression analysis, using tracheostomy acceptance as the dependent variable and age, sex, and Strong's diagnostic categories as independent variables, revealed a significant association with age (p = 0.002) and with certain Strong's categories, particularly ALS with combined cognitive and behavioral impairment (ALS-CBI) (p = 0.031). Conclusions: Cognitive and behavioral impairment appeared to increase the likelihood of consenting to invasive treatments in ALS patients.}, } @article {pmid41400574, year = {2025}, author = {Huang, S and Li, A and Ling, Y and Yang, X and Wang, J and Yuan, J and Qin, D and Yao, X}, title = {Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2025.1224}, pmid = {41400574}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord, for which no cure currently exists. Previous studies have shown that abnormal mitochondrial homeostasis and defective mitophagy occur in neurodegenerative diseases, including ALS. Here, we provide evidence that PINK1-Parkin-dependent mitophagy is impaired in multiple ALS mouse models, including the SOD1[G93A], TDP43[A315T], and rNLS8 strains, leading to the accumulation of damaged mitochondria in affected motor neurons. These findings suggest that mitophagy may be a druggable target for ALS treatment. A classical mitophagy agonist, urolithin A (UA) was used in this study. UA-induced mitophagy antagonizes ALS pathologies in the ALS SOD1[G93A] transgenic C. elegans model in a pink-1 (PTEN-induced kinase 1)- and pdr-1 (Parkinson's disease-related 1)-dependent manner. Furthermore, pharmacological activation of mitophagy by UA improves locomotor behavior, delays motor neuron degeneration and reduces neuroinflammation in ALS SOD1[G93A] transgenic mice. In conclusion, our results establish impaired mitophagy as a hallmark of ALS motor neuron degeneration and demonstrate that its pharmacological activation offers a neuroprotective strategy with therapeutic potential.}, } @article {pmid41401197, year = {2026}, author = {Yang, L and Liu, T and Li, HG and Wang, G and Deng, S}, title = {Functional divergence of ALMTs mediates organic acid transport and callose synthesis for aluminum tolerance in rose myrtle.}, journal = {Plant physiology}, volume = {200}, number = {1}, pages = {}, doi = {10.1093/plphys/kiaf655}, pmid = {41401197}, issn = {1532-2548}, support = {32500264//National Science Foundation of China/ ; 2020-KJCX011//Guangdong Forestry Science and Technology Innovation/ ; 2023B1212060046//Guangdong Science and Technology Plan Project/ ; }, mesh = {*Aluminum/toxicity ; *Glucans/biosynthesis/metabolism ; *Plant Proteins/metabolism/genetics ; Gene Expression Regulation, Plant/drug effects ; *Organic Anion Transporters/metabolism/genetics ; Biological Transport ; Arabidopsis/genetics/metabolism ; Malates/metabolism ; Adaptation, Physiological ; Plant Roots/drug effects/metabolism ; Plants, Genetically Modified ; }, abstract = {Ionic aluminum (Al) forms in acidic soils and inhibits plant growth, even at low concentrations. Rose myrtle (Rhodomyrtus tomentosa), a shrub native to tropical and subtropical regions, thrives in acidic-Al soils. Here, we found that mild concentrations of Al promote rose myrtle growth. Transcriptomic disturbances induced by low or high Al stress were predominantly nonoverlapping in the species. Mild Al stress (0.1 mM Al3+) enhanced rose myrtle root elongation through the upregulation of xyloglucan metabolism, nutrient uptake and utilization, and auxin transport. In contrast, high Al stress (1 mM Al3+) activated detoxification pathways, including the secretion of organic acid and glutathione metabolism. Members of the aluminum-activated malate transporter (ALMT) family, particularly the conserved RtALMT11 and variable RtALMT18, play a pivotal role in Al tolerance. Heterologous expression of RtALMT11 and RtALMT18 complemented the Al-sensitive phenotype of almt1-KO Arabidopsis (Arabidopsis thaliana). High Al3+ induced the expression of RtALMT11, mediating the synthesis of callose, which may serve as a physical barrier to mitigate Al penetration and facilitate vacuolar Al sequestration. RtALMT18 pre-emptively regulated internal defense in the stele independently of aluminum load, while also functioning as a proton/malate transporter. Beyond enhancing Al tolerance, RtALMT18 promoted the growth of transgenic Arabidopsis and poplar (Populus alba × Populus glandulosa, "84K"). The functional divergence within the ALMT family reveals distinct roles in promoting the growth of rose myrtle under low Al conditions and during the high-Al detoxification process. These findings uncover Al's dual role as both a growth promoter and stress inducer, offering insights for developing Al-tolerant crops and rehabilitating acidic soils.}, } @article {pmid41401652, year = {2026}, author = {Braverman, A and Frenkel, A and Schwarzfuchs, D and Jaffe, E and Bitan, Y}, title = {Verbal and visual information exchange in EMS-to-ED patient handovers: An observational and attitudinal study.}, journal = {International emergency nursing}, volume = {84}, number = {}, pages = {101735}, doi = {10.1016/j.ienj.2025.101735}, pmid = {41401652}, issn = {1878-013X}, mesh = {Humans ; *Patient Handoff/standards/statistics & numerical data ; Male ; Female ; Israel ; Adult ; Emergency Service, Hospital/organization & administration/statistics & numerical data ; *Emergency Medical Services/methods/standards/statistics & numerical data ; Middle Aged ; Surveys and Questionnaires ; *Attitude of Health Personnel ; Communication ; }, abstract = {BACKGROUND: Although effective information exchange during emergency medical services (EMS)-to-emergency department (ED) patient handovers is critical for care continuity and patient safety, handover communication patterns and information gaps remain poorly characterized.

OBJECTIVE: To characterize verbal and visual information exchange patterns in EMS-to-ED handovers while comparing EMS and ED staff perceptions of handover quality.

METHODS: This was a dual-methods study conducted at a tertiary medical center in Israel (June-November 2024) in which 83 EMS-to-ED handovers [35 advanced life support (ALS), 48 basic life support (BLS)] were directly observed. We documented information elements, duration, and communication patterns via a structured checklist. In addition, an electronic survey (Qualtrics) of 103 participants (62 EMS, 41 ED staff) was used to assess perceptions with 6-point Likert scales. Statistical analyses utilized Mann-Whitney U tests, effect sizes (Cohen's d), and 95 % confidence intervals (CIs).

RESULTS: The handovers were dominated by verbal communication (97.6 %, 95 % CI: 91.6-99.3 %) of brief duration [ALS: Median = 40 s, interquartile range (IQR) 35-45; BLS: Median = 25 s, IQR 25-35]. Significant information gaps included: pre-hospital treatment details, which were absent in 36.1 % of the handovers (95 % CI: 26.6-46.9 %), allergy details in 55.4 %, and demographic details in 61.4 %. The ALS teams provided more complete information than did BLS teams (treatment: 94 % vs. 46 %, p < 0.001; allergies: 60 % vs. 33 %, p = 0.02). EMS documentation was available in only 7.2 % of handovers (95 % CI: 3.4-14.9 %). Patient background documents were valued more by ED staff than by EMS personnel (Median = 4.84 vs. 3.44, p < 0.001, d = 0.98), and they reported higher confidence in using received information (Median = 4.12 vs. 3.15, p < 0.001, d = 0.78).

CONCLUSIONS: Because EMS-to-ED handovers rely almost exclusively on brief verbal communication, they are vulnerable to information loss. Critical safety-relevant information (allergies, medications) is frequently omitted, with BLS teams showing greater gaps than ALS teams. Structured handover protocols may improve information completeness and continuity of care by incorporating digital tools to complement verbal communication.}, } @article {pmid41402228, year = {2026}, author = {Vovard, B and Faure-de Baets, J and Codron, P and Allain, P and Cassereau, J}, title = {Assessment of social cognition impairments in patients with amyotrophic lateral sclerosis: How can it be improved? A systematic review.}, journal = {Revue neurologique}, volume = {182}, number = {1-2}, pages = {10-25}, doi = {10.1016/j.neurol.2025.11.003}, pmid = {41402228}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/diagnosis ; *Social Cognition ; Theory of Mind/physiology ; Neuropsychological Tests/standards ; Empathy/physiology ; *Cognitive Dysfunction/diagnosis/psychology/etiology ; Emotions/physiology ; }, abstract = {OBJECTIVES: The aim of this review was to evaluate the current evidence on which part of social cognition is impaired in amyotrophic lateral sclerosis (ALS) patients among emotion recognition, affective empathy and Theory of Mind (ToM) and to suggest improvements in social cognition testing protocols.

METHODS: A systematic review was conducted according to PRISMA guidelines. We included controlled cross-sectional or longitudinal studies published in English before September 1, 2024, that assessed social cognition in non-demented ALS patients. Searches were performed in Medline, Embase, Web of Science, and PsycINFO using specific MeSH terms. Studies using social cognition tests as a primary or secondary outcome were included.

RESULTS: Thirty-four studies were analyzed. Impairments in emotion recognition - especially for negative emotions - were frequently reported, even in cognitively preserved ALS patients. Results for cognitive ToM were mixed and may be confounded by executive dysfunction or test limitations. In contrast, affective ToM deficits were more consistently identified. However, no included study directly assessed affective empathy. Tests used in the reviewed studies were often overly specific and lacked ecological validity, which may explain inconsistent results across domains and weak correlations with imaging or executive function.

CONCLUSION: Social cognition is increasingly recognized as a key non-motor domain affected in ALS. However, current assessment tools may lack the sensitivity and ecological validity needed to capture real-life deficits. The implementation of dynamic, multimodal assessments such as real-life social interaction tests or tests like the Movie Assessment for Social Cognition (MASC) could improve detection and guide clinical interventions but remain to be validated for ALS patients.}, } @article {pmid41403093, year = {2026}, author = {Ghaderi, S and Mohammadi, S and Kalra, S}, title = {Hippocampal Subfield Integrity and Age-Driven Neural Correlates of Appetite Loss in Amyotrophic Lateral Sclerosis.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {63}, number = {4}, pages = {1067-1078}, doi = {10.1002/jmri.70206}, pmid = {41403093}, issn = {1522-2586}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/complications ; Female ; Middle Aged ; Cross-Sectional Studies ; *Magnetic Resonance Imaging ; *Hippocampus/diagnostic imaging/physiopathology/pathology ; Aged ; Appetite ; Age Factors ; }, abstract = {BACKGROUND: Appetite loss is a non-motor symptom in amyotrophic lateral sclerosis (ALS) linked to poorer prognosis. While the hippocampus regulates "meal memory", a key cognitive modulator of eating behavior, its structural role in ALS-related appetite loss is unknown.

PURPOSE: To determine if hippocampal subfield integrity influences appetite dysregulation in ALS and to evaluate the strength of neuroanatomical versus demographic factors.

STUDY TYPE: Cross-sectional secondary analysis.

POPULATION: Thirty-two patients with ALS (mean age: 58.97 ± 8.91 years; 24 males) and 22 non-neurodegenerative controls (NNDc) (mean age: 53.86 ± 9.98 years; 16 males).

FIELD STRENGTH/SEQUENCE: 3T; 3D T1-weighted magnetization-prepared rapid gradient-echo (MP2RAGE) and 3D T2-weighted turbo spin-echo (T2-SPACE) sequences.

ASSESSMENT: Appetite was measured using the Council on Nutrition Appetite Questionnaire (CNAQ). Hippocampal subfield volumes (CA1, CA2/3, CA4/DG, stratum radiatum/lacunosum/moleculare [SRLM], subiculum) and asymmetry indices were segmented from T1w and T2w images using the HIPS automated pipeline.

STATISTICAL TESTS: Analysis of Covariance (ANCOVA) (adjusting for age, sex, body mass index (BMI), total intracranial volume (TIV), and subfield volumes/asymmetry) and hierarchical multiple regression analyses were used. Significance was set at p < 0.05.

RESULTS: Patients with ALS (adjusted mean: 29.51 ± 0.53) had significantly lower adjusted CNAQ scores compared to controls (adjusted mean: 31.98 ± 0.66; mean difference: -2.47, partial η [2] = 0.195). In the ANCOVA model, left SRLM volume was the only significant neuroanatomical covariate (F [1, 30] = 6.45, partial η [2] = 0.177). However, hierarchical regression revealed that age was the only consistent independent predictor of CNAQ scores (B = -0.158), explaining the largest variance (ΔR [2] = 0.165). Hippocampal volumes and asymmetry did not remain significant predictors after adjusting for age (left SRLM: p = 0.853; SRLM asymmetry: p = 0.868).

DATA CONCLUSION: Appetite loss is a non-motor symptom in ALS. While associated with lower left SRLM volume at the group level, appetite decline is more robustly and independently associated with advancing age.

EVIDENCE LEVEL: 3.

TECHNICAL EFFICACY: 3.}, } @article {pmid41404604, year = {2025}, author = {Bilal Jilani, S and Ashok, N and Bomble, YJ and Guss, AM and Olson, DG}, title = {Engineering Clostridium thermocellum for production of 2,3-butanediol from cellulose.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41404604}, issn = {2692-8205}, support = {P20 GM113132/GM/NIGMS NIH HHS/United States ; }, abstract = {Clostridium thermocellum is a promising host for consolidated bioprocessing due to its ability to directly ferment cellulose into fuels and chemicals. However, natural product formation in this organism is limited. Here, we report engineering C. thermocellum for the production of 2,3-butanediol (23BD), a valuable industrial chemical. We functionally expressed a thermophilic 23BD pathway in this organism resulting in a 23BD titer of 19.7 mM from cellulose, representing a metabolic yield of 24%. We used a cell-free systems biology approach to identify limiting steps in the 23BD pathway, revealing that exogenous 23BD dehydrogenase (BDH) activity was essential for production, while native acetolactate synthase (ALS) and acetolactate decarboxylase (ALDC) activities were present but limiting in the parent strain. This approach also revealed redox balance limitations. We demonstrated that this improved understanding of redox balance limitations could be used to increase 23BD titer in vivo, showing that adding acetate could be used to increase 23BD yield. This work establishes a foundation for developing C. thermocellum into a robust platform for 23BD production directly from cellulose and highlights the utility of cell-free systems for guiding metabolic engineering in non-model organisms.}, } @article {pmid41404692, year = {2025}, author = {Żur-Wyrozumska, K}, title = {A case of an ALS patient with an SQSTM1 mutation - implications for the p62/NF-κB/Nrf2/autophagy pathways in the selection of individualised therapeutic strategies: a preliminary report.}, journal = {Folia medica Cracoviensia}, volume = {65}, number = {3}, pages = {173-183}, doi = {10.24425/fmc.2025.156692}, pmid = {41404692}, issn = {2957-0557}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Sequestosome-1 Protein/genetics ; Middle Aged ; Female ; NF-E2-Related Factor 2/genetics/metabolism ; Autophagy/genetics ; NF-kappa B/genetics ; Mutation ; Signal Transduction ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) represents a heterogeneous group of neurodegenerative disorders sharing a common ALS phenotype but arising from diverse genetic and molecular mechanisms. Among the genes implicated in ALS, SQSTM1, encoding the multifunctional protein p62, plays a pivotal role in maintaining neuronal homeostasis through the regulation of autophagy and the crosstalk between NF-κB and Nrf2 pathways. Disruption of these mechanisms contributes to oxidative stress, neuroinflammation, and protein aggregation in motor neurons.

MATERIAL AND METHODS: A comprehensive genetic analysis, including next-generation sequencing (NGS), whole-exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA), was performed in a patient clinically diagnosed with ALS. Literature data regarding the role of SQSTM1, NF-κB/Nrf2 signaling, and autophagy modulation in ALS pathogenesis were reviewed to contextualize the findings.

CASE PRESENTATION: We describe a 49-year-old woman with a 12-month history of progressive - bulbar-onset ALS. Genetic testing revealed a heterozygous SQSTM1 c.1175C>T (p.Pro392Leu) variant inherited from her father, classified as likely pathogenic. The patient received dimethyl fumarate (Nrf2 activator), celecoxib (NF-κB inhibitor), and rapamycin (mTOR pathway modulator) as part of an individualized treatment strategy.

DISCUSSION: Mutations in SQSTM1 contribute to ALS pathogenesis through dysregulation of autophagy, impaired protein clearance, and excessive neuroinflammation mediated by NF-κB activation. The interplay between NF-κB and Nrf2 signaling pathways suggests that targeted therapeutic modulation may attenuate neurodegeneration. The patient's case illustrates the clinical and molecular heterogeneity of ALS and supports the concept of pathway-specific, precision medicine approaches.

CONCLUSIONS: This case highlights the relevance of SQSTM1-related pathogenic mechanisms within the heterogeneous ALS spectrum and underscores the importance of advanced genetic testing for identifying candidates for personalized therapy.}, } @article {pmid41405451, year = {2025}, author = {Liampas, I and Kimiskidis, VK and Zouvelou, V and Veltsista, D and Moscholouri, A and Triantafyllou, E and Daponte, A and Xirou, S and Sterpi, AE and Salakou, S and Poulidou, V and Arnaoutoglou, M and Tsouris, Z and Ralli, S and Dardiotis, E and Papagiannopoulos, S and Zampetakis, A and Zaganas, Ι and Mitsias, P and Giannakis, A and Konitsiotis, S and Kefalas, F and Alexiou, E and Stoiloudis, P and Parissis, D and Kiamelidis, S and Terzoudi, A and Tsivgoulis, G and Rentzos, M and Chroni, E}, title = {Greek Registry for Amyotrophic Lateral Sclerosis (ALS-GR): An Observational Cohort of Individuals With ALS Across 11 Specialized Centers in Greece.}, journal = {European journal of neurology}, volume = {32}, number = {12}, pages = {e70403}, pmid = {41405451}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/physiopathology/drug therapy/therapy ; Greece/epidemiology ; *Registries ; Male ; Middle Aged ; Female ; Aged ; Cohort Studies ; Disease Progression ; Adult ; Riluzole/therapeutic use ; }, abstract = {BACKGROUND: Epidemiological studies on amyotrophic lateral sclerosis (ALS) in Greece are scarce and outdated.

METHODS: We performed an observational cohort study in 11 specialized centres across Greece. Adult individuals with ALS diagnosed based on the Gold Coast criteria were recruited. Data were collected on socio-demographics, somatometrics, comorbidities, early life exposures, disease-related parameters, riluzole intake, motor and non-motor symptoms, as well as functional progression. Follow-up evaluations were scheduled on approximately 6-9-12-18-24 months. Our aim was to identify shortcomings in the monitoring of patients with ALS in specialized centers, delineate the course of the disease, and capture factors related to the earlier occurrence of ALS and potential diagnostic delays.

RESULTS: A total of 229 ALS patients were included in the present registry. The average age of diagnosis was 63.7 years, with an average 12.8-month interval between symptom onset and diagnosis. The presence of bulbar symptoms at onset was associated with shorter diagnostic delays. Systematic physical exercise was strongly linked to the earlier onset of symptoms. Disease progression was slower during the prediagnostic stage, more precipitous over the first year following diagnosis, and milder thereafter (~1-point monthly decline in ALSFRS-R on average, post-diagnosis). The majority of associated motor and non-motor symptoms accumulated over time. The overwhelming majority of patients were prescribed the liquid form of riluzole, which exhibited an excellent tolerability profile. Greek islands are probably the most underprivileged in terms of specialized monitoring of ALS cases.

CONCLUSIONS: The present observational cohort study mapped key aspects and shortcomings of ALS management in Greece.}, } @article {pmid41406304, year = {2026}, author = {Geva, M and Goldberg, YP and Leitner, ML and Cruz-Herranz, A and Hand, R and Chen, K and Gershoni Emek, N and Tan, AM and Paganoni, S and Berry, JD and Macklin, EA and Shefner, JM and Cudkowicz, ME and Hayden, MR}, title = {Pridopidine treatment in ALS: subgroup analyses from the HEALEY ALS Platform trial.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {432-444}, doi = {10.1080/21678421.2025.2597935}, pmid = {41406304}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/diagnosis ; Male ; Female ; Double-Blind Method ; Middle Aged ; *Piperidines/therapeutic use ; Aged ; Treatment Outcome ; Adult ; Receptors, sigma/agonists ; Disease Progression ; Sigma-1 Receptor ; }, abstract = {Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Pridopidine, a selective sigma-1 receptor agonist, was evaluated in Regimen D of the HEALEY ALS Platform Trial. Although the primary endpoint (ALS Functional Rating Scale-Revised (ALSFRS-R) total score accounting for survival at 24 weeks) was not met, a predefined subgroup analysis suggested slowed disease progression in ALS patients with definite and early disease (<18 months from onset). This report presents an exploratory analysis that further investigates pridopidine in rapidly progressing participants with definite/probable ALS and early-disease, where treatment effects may be more pronounced. Methods: The randomized, double-blind, placebo-controlled phase 2 trial assigned participants to pridopidine 45 mg bid or placebo, and placebo patients were shared across four trial regimens. The primary outcome was ALSFRS-R total score, with secondary outcomes assessing respiratory, bulbar, and speech functions. Results: Of 163 participants randomized to Regimen D, 72 met subgroup criteria (pridopidine: n = 37; shared placebo: n = 35). At week 24, pridopidine slowed ALSFRS-R total score decline (32%; Δ2.90, p = 0.03) and slowed decline of ALSFRS-R respiratory function (62%; Δ1.20, p = 0.03) and dyspnea (88%; Δ0.85, p = 0.005). ALSFRS-R-Bulbar function stabilized, with articulation and speaking rate declines reduced by 93% (Δ0.43, p = 0.0007) and 70% (Δ0.43, p = 0.002), respectively. Pridopidine was well-tolerated, with a safety profile comparable to placebo. All p values are nominal. Conclusion: Post hoc subgroup analysis suggests therapeutic benefits of pridopidine in patients that had definite/probable ALS and with early-disease progression, supporting further evaluation in a Phase 3 trial.}, } @article {pmid41406788, year = {2026}, author = {Vijayakumar, S and Schwaighofer, A and de Juan, A and Rocha de Oliveira, R and Mach-Aigner, A and Lendl, B and Ramer, G}, title = {Fusion of incomplete QCL-IR and ECD datasets using MCR-ALS to extend the viable concentration range for studying protein denaturation.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {349}, number = {}, pages = {127340}, doi = {10.1016/j.saa.2025.127340}, pmid = {41406788}, issn = {1873-3557}, mesh = {*Protein Denaturation ; *Circular Dichroism/methods ; Spectrophotometry, Infrared/methods ; *Lasers, Semiconductor ; *Proteins/chemistry ; }, abstract = {While several techniques exist to study the secondary structure of proteins, mid-IR and electronic circular dichroism spectroscopy are complementary techniques that stand out for liquid measurements due to their non-destructive nature, broad applicability and ease of use. CD spectroscopy however is only used to measure low protein concentrations and suffers from signal interferences from common buffers. With advances in laser-technology, the achievable pathlengths used in IR-spectroscopy have increased with the use of external cavity quantum cascade lasers (EC-QCL) as light sources. This has not only enabled protein denaturation to be studied without aggregates clogging the measurement cell, as was the case with shorter pathlengths, but also expanded the concentration range that can be measured with the technique. Yet, the concentration range where both IR and CD measurements can be made has only a small overlap. In this study, the IR and CD spectra obtained during the thermal denaturation of α-chymotrpysin (α-CT) in the overlapping concentration range of the two spectroscopy techniques, between 10mgmL[-1] to 40mgmL[-1], are used to extract more information about the denaturation process of the protein and its concentration dependence. To this end, the protein denaturation spectra from both methods between 20°C to 80°C are fused and analyzed using multivariate curve resolution-alternating least squares (MCR-ALS), a bilinear unmixing technique that provides thermal profiles and pure fingerprints of the protein conformations involved in the denaturation process. However, in these measurements, a large and information-dense part of the CD spectra found at the lowest UV wavelengths cannot be used due to the saturated signal linked to high protein concentration levels. A modified version of MCR-ALS is hence introduced to overcome this issue, which allows all available information to be used without sacrificing the quality of the fit. The prowess of the adapted MCR-ALS technique as a tool for data fusion was demonstrated by not only providing a better fit than the individual models (CD and IR spectra analyzed separately), but also by aiding in squeezing out information about a third protein conformation that forms during the denaturation of α-CT.}, } @article {pmid41407165, year = {2026}, author = {Ghosh, N and Ghosh, J and Ghosh, S and Sinha, K and Sil, PC}, title = {Nutraceutical interventions for neuroprotection: a comprehensive review.}, journal = {Biochemical pharmacology}, volume = {245}, number = {}, pages = {117637}, doi = {10.1016/j.bcp.2025.117637}, pmid = {41407165}, issn = {1873-2968}, mesh = {Humans ; *Dietary Supplements ; Animals ; *Neuroprotective Agents/administration & dosage ; *Gastrointestinal Microbiome/drug effects/physiology ; *Neuroprotection/drug effects/physiology ; *Neurodegenerative Diseases/metabolism/prevention & control ; Probiotics/administration & dosage ; }, abstract = {Nutraceuticals, bioactive compounds derived from food sources, are emerging as promising agents for neuroprotection, particularly through their modulation of gut health. Unlike conventional single-molecule therapeutics that often target isolated pathways, nutraceuticals offer a multi-targeted approach by influencing the gut-brain axis, a bidirectional communication network linking the gut microbiota and the central nervous system. Key nutraceuticals such as probiotics, prebiotics, polyphenols, omega-3 fatty acids, and vitamins have been shown to beneficially alter microbiota composition, reduce intestinal inflammation, and strengthen gut barrier integrity. These changes can significantly influence brain function by modulating neurotransmitter activity and systemic immune responses. This review compares the holistic action of nutraceuticals with the more focused effects of single-molecules, particularly in the context of neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's Disease and Motor Neuron Diseases like amyotrophic lateral sclerosis. It discusses how nutraceuticals may mitigate key pathological features of these conditions-including neuroinflammation, oxidative stress, and mitochondrial dysfunction, through gut-mediated pathways. Despite their potential, challenges remain regarding the standardization of formulations, bioavailability, dosage optimization, and long-term safety. Further clinical research is needed to validate the efficacy of nutraceuticals as complementary or alternative strategies to traditional neuroprotective agents.}, } @article {pmid41409685, year = {2025}, author = {Ran, X and Wuu, J and Qin, ZS and Cooper-Knock, J and Granit, V and Grignon, AL and Li, Y and Lin, E and Fernandez, MC and Colato, D and Carberry, N and Lill, CM and Piazza, P and Malaspina, A and Benatar, M}, title = {Predicting Phenoconversion to Clinically Manifest ALS: Results of a Large-Scale Proteomic Study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41409685}, support = {R01 NS105479/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, abstract = {The study of pre-symptomatic amyotrophic lateral sclerosis (ALS) and the design of disease prevention trials are greatly hampered by our inability to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease, and when. In this longitudinal Olink Explore high-throughput proteomic study, 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls were included. We identified 81 proteins whose concentrations changed prior to phenoconversion; characterized the longitudinal trajectory of these proteins; and identified a core panel of 19 proteins that, collectively, predicted phenoconversion over the 0.5- to 5-year time horizons (areas under curve 0.80-0.89) and yielded estimates of time-to-phenoconversion with a mean absolute error of 1.6 years. These findings were replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (e.g. NEFL, EDA2R, CA3) and that a multi-protein panel outperformed NEFL alone in estimating time-to-phenoconversion. This work sheds light on the biology of pre-symptomatic ALS. Moreover, our identification of a panel of novel susceptibility/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention.}, } @article {pmid41411011, year = {2026}, author = {Lawley, KS and Kang, TW and Rech, RR and Karmakar, M and Carroll, R and Perez Gomez, AA and Amstalden, K and Jones-Hall, Y and Threadgill, DW and Welsh, CJ and Young, CR and Brinkmeyer-Langford, C}, title = {The association between virus-induced spinal cord pathology and the genetic background of the host.}, journal = {Journal of neuropathology and experimental neurology}, volume = {85}, number = {4}, pages = {331-340}, pmid = {41411011}, issn = {1554-6578}, support = {P30 ES029067/ES/NIEHS NIH HHS/United States ; //National Institute for Neurological Disorders and Stroke (NINDS)/ ; 2P30 ES029067//National Institute for Environmental Health Sciences (NIEHS)/ ; DGE 1746932//National Science Foundation Graduate Research/ ; R01 NS103934/NS/NINDS NIH HHS/United States ; //National Institute for Neurological Disorders and Stroke/ ; R01 NS103934/NH/NIH HHS/United States ; 2P30 ES029067//National Institute for Environmental Health Sciences/ ; DGE 1746932//National Science Foundation/ ; }, mesh = {Animals ; *Theilovirus/pathogenicity/genetics ; Mice ; *Spinal Cord/pathology/virology ; *Cardiovirus Infections/pathology/genetics ; Female ; Disease Models, Animal ; Male ; }, abstract = {Theiler's murine encephalomyelitis virus (TMEV) infection in mice has been used to study diverse neurological diseases, including multiple sclerosis and epilepsy. In this investigation, 5 strains of collaborative cross (CC) mice were infected with TMEV and examined clinically and histologically at days 4, 14, and 90 post-infection (dpi). All CC strains tested exhibited lumbar spinal cord and/or ventral peripheral nerve lesions by 14 dpi; CC027, CC023, and CC078 strains exhibited lesions at 4 dpi. At 90 dpi, lesions were remnants of the inflammatory responses associated with earlier infection; there was skeletal muscle atrophy in the CC023 strain. Increased microglial/macrophage reactivity was observed in all strains at 4 and 14 dpi, but not at 90 dpi. TMEV mRNA expression was greatest in the CC023 and CC078 strains at the acute timepoints; TMEV was completely cleared in all mice at 90 dpi. The neuropathological and clinical profiles in CC023 mice, mainly at 14 dpi, share some clinical and histologic features with those in amyotrophic lateral sclerosis patients. This work demonstrates how viral infection might interact with the genetic background of a susceptible individual to contribute to the onset, clinical presentation and persistence of lesions despite viral clearance.}, } @article {pmid41411702, year = {2026}, author = {Lebkuecher, AL and Coslett, HB and Buxbaum, LJ}, title = {The cognitive neuropsychology of action semantics: A review.}, journal = {Cortex; a journal devoted to the study of the nervous system and behavior}, volume = {194}, number = {}, pages = {159-190}, doi = {10.1016/j.cortex.2025.11.008}, pmid = {41411702}, issn = {1973-8102}, mesh = {Humans ; *Semantics ; *Cognition/physiology ; *Brain/physiology/physiopathology ; Neuropsychology ; }, abstract = {The conceptual knowledge that mediates our ability to use familiar objects, understand viewed actions, and engage in communication about actions is often termed "action semantics". The underlying format, cognitive organization, and neural substrates of these representations are matters of active scientific investigation. This review synthesizes the large and diverse literature on action semantics in individuals with neurological disorders characterized by prominent motor deficits (e.g., Parkinson's disease and Amyotrophic lateral sclerosis), as well as those for whom motor deficits are often less prominent (e.g., Alzheimer's disease, Frontotemporal Dementia, stroke). Research in these two groups of disorders is strikingly "siloed" and offers many contradictory findings with respect to whether action semantic representations are abstract (i.e., "disembodied") or grounded in sensory and motor features that reflect the way knowledge was acquired. Findings across these populations also disagree as to whether action semantic representations are organized somatotopically or with a semantic feature-based architecture, and mediated by anterior motor-related or relatively posterior sensory-related brain regions. Many of these disparate findings can be reconciled with consideration of a multidimensional, multimodal representational architecture mediated by a distributed left-lateralized network of brain regions. We provide suggestions for specific methodological approaches for research with neurological populations that may further our understanding of the format, organization, and neural substrates of action semantics.}, } @article {pmid41412960, year = {2026}, author = {Goutman, SA and Stouffer, DG and Jang, DG and Park, J and Murdock, BJ and Auchus, RJ}, title = {Sex Hormones Associate With Amyotrophic Lateral Sclerosis Risk and Survival.}, journal = {Annals of clinical and translational neurology}, volume = {13}, number = {3}, pages = {612-617}, pmid = {41412960}, issn = {2328-9503}, support = {R01TS000339/ACL/ACL HHS/United States ; AL200064//U.S. Department of Defense/ ; //Eric and Linda Novak/ ; //James and Margaret Hiller/ ; //Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund/ ; //Stanford Morris ALS Research Fund/ ; K23ES027221/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; R01NS120926/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; //University of Michigan/ ; R01TS000339/ACL/ACL HHS/United States ; K23ES027221/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; R01NS120926/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality ; Female ; Male ; Middle Aged ; Aged ; *Gonadal Steroid Hormones/blood ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) risk differs by sex and age, implicating sex hormones as potential modifiers. This study examined plasma levels of biologically active sex hormones and their association with ALS odds and survival in cases (females n = 131, males n = 189) and controls (females n = 138, males n = 150) from the University of Michigan Pranger ALS Clinic. Higher 11-ketotestosterone levels were associated with increased ALS odds. In females, higher estrone, androstenedione, and 11-hydroxyandrostenedione were associated with increased ALS odds, while elevated estrone and estradiol predicted shorter survival. These findings highlight the potential significance of sex hormones in ALS.}, } @article {pmid41414999, year = {2025}, author = {Kamadi, EN and Shah, J and Hooker, J and Jenkins, TM and Sokhi, DS}, title = {Clinical phenotypes of motor neurone disease in a Kenyan hospital-based population.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1662690}, pmid = {41414999}, issn = {1664-2295}, abstract = {BACKGROUND: Motor neurone disease (MND) presentation is globally heterogenous and data on the clinical phenotype in Sub-Saharan Africa (SSA) is scarce. We sought to address this by describing the profile of MND patients in a Kenyan hospital-based population.

METHODS: The medical charts of all adult MND patients assessed in the facility between January 2010 and December 2023 were retrospectively reviewed. The biographical data and clinical features of these patients were captured from their electronic and manual health records and statistical analysis performed.

RESULTS: In total, 160 patients had their data analyzed. The male to female ratio was 1.76:1. The median age at presentation was 55.0 (IQR: 45.0-68.0) years with a median diagnosis delay of 4.0 (IQR: 2.0-8.5) months. The site of first symptom onset was the lower limbs in 34.4% and the bulbar region in 33.1% [95% CI (26.4-42.5%)]. Notably, 59% of the patients were not tested for HIV and amongst those tested, 13.9% were HIV positive on ART. Majority (56.2%) of the patients were on Riluzole.

CONCLUSION: This Kenyan case series of MND patients demonstrated a higher rate of bulbar onset disease [33.1, 95% CI (26.4-42.5%), p = 0.018] in comparison to what has been demonstrated in other African studies. A finding that supports geographic variation in MND presentation and that emphasizes the need for region specific genetic studies.}, } @article {pmid41417044, year = {2026}, author = {Rott, N and Reinsch, L and Dirks, B and Böttiger, BW}, title = {[The new European Resuscitation Council (ERC) guidelines 2025-Overview of the most important changes; the first 3-5 min are decisive].}, journal = {Die Anaesthesiologie}, volume = {75}, number = {1}, pages = {44-50}, pmid = {41417044}, issn = {2731-6866}, mesh = {Adult ; Humans ; Advanced Cardiac Life Support/standards ; *Cardiopulmonary Resuscitation/standards/methods ; Epinephrine/administration & dosage ; Europe ; Heart Arrest/therapy ; *Practice Guidelines as Topic ; *Resuscitation/standards/methods ; Time Factors ; }, abstract = {In October 2025 the new resuscitation guidelines of the European Resuscitation Council (ERC) were published. In the chapter on advanced life support (ALS) for adults the update emphasizes topics such as efficient ventilation with adequate chest compressions, early defibrillation, identification and treatment of reversible causes as rapidly as possible and the administration of epinephrine in cases of non-defibrillatable cardiac arrest. The aim of the guidelines is to sustainably improve survival rates after cardiac arrest through structured and evidence-based care systems.}, } @article {pmid41417753, year = {2026}, author = {Lam, P and Zygmunt, DA and Bennett, M and Ashbrook, A and Hefty, J and Martin, PT}, title = {Gne deletion in adult mice can cause thrombocytopenia, anemia, myopathy, bleeding, and death.}, journal = {Journal of neuromuscular diseases}, volume = {13}, number = {3}, pages = {474-492}, pmid = {41417753}, issn = {2214-3602}, support = {P50 HD117373/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Thrombocytopenia/genetics ; *Anemia/genetics ; *Hemorrhage/genetics ; *Multienzyme Complexes/genetics ; Gene Deletion ; Disease Models, Animal ; Muscle, Skeletal/pathology/metabolism ; *Muscular Diseases/genetics ; Mice, Transgenic ; }, abstract = {The GNE gene encodes the UDP-GlcNAc-2-epimerase/ManNAc kinase, a bifunctional enzyme required for the synthesis of sialic acid. The mouse Gne gene is essential for embryonic development, but humans with recessive partial loss of function GNE mutations can develop infantile thrombocytopenia, juvenile amyotrophic lateral sclerosis, or adult-onset myopathy (GNE myopathy). We have created inducible Gne[lox/lox] gene deletion mice to study how loss of Gne in adult mice relates to these disease states. Systemic Gne gene deletion in tamoxifen-treated Rosa-CreER[T2]/Rosa-CreER[T2]Gne[lox/lox] mice caused uniform fatality within 30 days of gene deletion with spontaneous bleeding, thrombocytopenia, and anemia. Skeletal myofiber-specific Gne deletion in tamoxifen-treated HSA-CreER[T2/+]Gne[lox/lox] mice had no bleeding and no muscle pathology at 60 or 270 days post-treatment. Intramuscular injection of AAV.MCK.GFP-Cre in Gne[lox/lox] mice also showed little to no evidence of muscle pathology, while AAV.CMV.GFP-Cre caused extensive muscle damage, reduced muscle force, and changed expression of markers for muscle regeneration, muscle cell senescence, muscle denervation, and muscle atrophy. These data demonstrate that Gne is an essential gene in adult mice that can mimic aspects of human hematologic and muscle diseases caused by GNE mutations, but suggests induction of muscle disease requires loss of gene GNE expression in cell types beyond skeletal myofibers.}, } @article {pmid41419037, year = {2026}, author = {Henriksson, S and Bäckström, M and Westberg, H and Hagberg, J}, title = {PCDD/Fs in food products produced near a contaminated former sawmill - concentrations, congener profiles and risk assessment.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {390}, number = {}, pages = {127529}, doi = {10.1016/j.envpol.2025.127529}, pmid = {41419037}, issn = {1873-6424}, mesh = {Polychlorinated Dibenzodioxins/analysis ; *Food Contamination/analysis/statistics & numerical data ; Risk Assessment ; Sweden ; Animals ; *Benzofurans/analysis ; Dibenzofurans, Polychlorinated ; Cattle ; Sheep ; Humans ; Environmental Monitoring ; *Environmental Pollutants/analysis ; Dietary Exposure/statistics & numerical data ; Milk/chemistry ; Soil Pollutants/analysis ; }, abstract = {Hillringsberg, a former sawmill site in Sweden, is severely contaminated with polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). This study collected site-specific data to assess the human health risks associated with locally produced food. To evaluate potential exposure, samples of salmon, perch, cow's milk, cattle, and sheep were collected near the site and analyzed for PCDD/Fs. The findings reveal that the most frequently detected congeners in the food samples corresponded with the most abundant congeners in the soil, underscoring the impact of contaminated sites on PCDD/F concentrations in locally produced food. Particularly concerning is the level of PCDD/Fs in sheep meat, which was found to be 11 times higher than the Tolerable Weekly Intake (TWI) for adults and 26 times higher for children. Comparing food samples from the sawmill site to those from the National Swedish Control Programme revealed that all food samples from Hillringsberg exhibited some level of contamination, even though the concentrations of PCDD/Fs remained below the European Maximum Limits (MLs) and Action Limits (ALs). The concentrations and patterns of contaminants in nearly all samples, particularly those from sheep, cattle and perch, were influenced by local contamination from the historical use of pentachlorophenol (PCP) at the old sawmill site. PCA showed that sheep and soil samples from the storage area exhibited strong covariance. Perch and sediment samples from the sawmill pond were also grouped together. These findings highlight the necessity of evaluating food production activities near contaminated sites during the initial stages of site-specific risk assessments. Ensuring food safety in these areas is crucial, and if necessary, relocating grazing lands, fish farms, and similar operations can help mitigate health risks associated with contaminated food.}, } @article {pmid41419286, year = {2025}, author = {Phillips, G and Sharma, D and O'Reilly, G and Romero, L and Cameron, P}, title = {Developing emergency care systems in low-income and middle-income countries: a scoping review to examine the role of leadership and governance.}, journal = {BMJ open}, volume = {15}, number = {12}, pages = {e102624}, pmid = {41419286}, issn = {2044-6055}, mesh = {Humans ; *Developing Countries ; *Leadership ; *Emergency Medical Services/organization & administration ; }, abstract = {BACKGROUND: More knowledge and resources are required to strengthen 'leadership and governance' (L+G) as a central building block to further develop emergency care (EC) systems in low-income and middle-income countries (LMICs).

OBJECTIVES: This scoping review aimed to examine and map the impact of individual, collective or institutional L+G on the development of EC systems (prehospital and facility-based) in LMICs.

ELIGIBILITY CRITERIA: English language publications from January 2005 to April 2024 that linked any L+G action with the development and capacity of everyday EC in LMICs, specifically excluding disaster responses.

SOURCES OF EVIDENCE: Medline (Ovid), Embase (Ovid), CINAHL, Web of Science (Clarivate), Central (Cochrane Central Register of Controlled Trials), Global Health (Ovid) and select grey literature.

CHARTING METHODS: Data from all eligible papers were jointly extracted using a piloted tool developed from the literature and WHO's EC Systems Framework. L+G descriptors included level (from clinical to national) and components (informed by Siddiqi et al's LMIC health system 'good governance' framework and a synthesis of EC policy documents). Impact of L+G on EC systems and key lessons were extracted from each publication.

RESULTS: From an initial 9713 items, 129 papers were included for final analysis and divided by EC component: prehospital (n=35), facility-based (n=53) and 'whole of EC system' (n=41). Qualitative and descriptive papers were most common, and 72 out of a possible 131 LMICs were represented. Findings were heterogeneous across all building blocks of EC systems and for different components of leadership and/or governance. Cross-cutting L+G themes were identified that demonstrated consistent impact across all EC systems development: government recognition, vision and human rights framing; coalition-building for effective partnerships and trained, empowered EC clinicians demonstrating emotionally intelligent, transformational leadership.

CONCLUSIONS: Applying new models such as Theories of Change and Social Network Analysis concepts may assist to illuminate how effective L+G is attained, what are the essential components and how these influence EC systems for better patient-centred outcomes. Further understanding the role of L+G for EC systems has utility for future EC clinician leadership training and policy-maker awareness, to strengthen resilience of overall health systems against likely future shocks.}, } @article {pmid41419800, year = {2025}, author = {Sun, Y and Zhong, Q and Chu, X and Wan, D and Peng, Y}, title = {Total intravenous anesthesia without neuromuscular blockers for ureteral lithotripsy in an ALS patient with orthopnea: a case report.}, journal = {BMC anesthesiology}, volume = {26}, number = {1}, pages = {52}, pmid = {41419800}, issn = {1471-2253}, mesh = {Humans ; Middle Aged ; *Anesthesia, Intravenous/methods ; *Lithotripsy/methods ; *Amyotrophic Lateral Sclerosis/complications ; Male ; *Ureteral Calculi/complications/surgery ; Propofol/administration & dosage ; Remifentanil ; Anesthetics, Intravenous/administration & dosage ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) rarely need urological surgery. This case report describes the successful use of total intravenous anesthesia (TIVA) with propofol and remifentanil combined with laryngeal mask airway (LMA) ventilation in a 55-year-old ALS patient with severe orthopnea who underwent ureteral lithotripsy. Given the progressive respiratory muscle weakness and inability to tolerate supine positioning, a tailored anesthetic approach is imperative. By avoiding neuromuscular blockers and minimizing opioid doses, we aimed to reduce postoperative respiratory depression. The procedure was completed uneventfully, with stable hemodynamics and rapid postoperative recovery. This case underscores the importance of individualized anesthetic strategies in neuromuscular disorders to optimize safety and outcomes.}, } @article {pmid41419928, year = {2025}, author = {An, J and Hendricks, N and Wheeler, J and Hincks, J and Benitez, JAR and Snyder, JM and Kraemer, BC and Liachko, NF and Elkon, KB}, title = {Neuronal TDP-43 pathology drives astrocytic interferon response in a mouse model of ALS.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {29}, pmid = {41419928}, issn = {1742-2094}, support = {R01 AG066729/AG/NIA NIH HHS/United States ; IK6 BX006467/BX/BLRD VA/United States ; RF1AG055474/NH/NIH HHS/United States ; I01 BX004044/BX/BLRD VA/United States ; R01AG066729/NH/NIH HHS/United States ; I01BX004044//The United States Department of Veterans Affairs/ ; RF1 AG055474/AG/NIA NIH HHS/United States ; P30 DK017047/DK/NIDDK NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; IK6BX006467//The United States Department of Veterans Affairs/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Astrocytes/metabolism/pathology ; Disease Models, Animal ; *DNA-Binding Proteins/genetics/metabolism ; Mice, Transgenic ; *Neurons/pathology/metabolism ; Humans ; *Interferon Type I/metabolism ; Mice, Inbred C57BL ; }, abstract = {Neuroinflammation is implicated in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Amongst potential innate immune mediators of disease, Type I interferon (IFN-I) could play an important role due to its ability to inhibit protein synthesis and affect neuronal synapses and metabolism. These effects could be cell intrinsic or non-cell autonomous mediated by glia or immune cells. We examined IFN-I in rNLS8 mice that have been engineered to express doxycycline suppressible human Transactive response DNA binding protein 43 kDa (hTDP-43) with a defective nuclear localization signal (hTDP-43ΔNLS) regulated by the neurofilament heavy chain (NEFH) promoter. Following induction of hTDP-43ΔNLS in rNLS8 mice, we observed upregulation of IFN-I stimulated genes (ISG) and, specifically, activation of the DNA sensor, cyclic GMP-AMP synthase (cGAS), as determined by mass spectrometry identification of the cyclic dinucleotide, cGAMP, in whole brain. To determine the cellular source of IFN-I, we performed single nucleus RNA sequencing of whole brain. We observed that ISG were most highly upregulated in astrocytes suggesting that astrocytes themselves were largely responsible for IFN-I production and / or response in rNLS8 mice. This observation was confirmed by immunohistochemical and immunofluorescence staining of IFN-I stimulated proteins in astrocytes in the cerebrum, especially in the hippocampus. These results point to a pivotal role of astrocytes in responding to cell damage at a relatively early phase of disease which prior studies have shown is partially reversible.}, } @article {pmid41420107, year = {2026}, author = {Campos-Ribeiro, MA and Donnarumma, E and Nolte, H and Cobine, P and Vimont, E and Milenkovic, D and Hernandez-Camacho, JD and Langa-Vives, F and Kornobis, E and Pénard, E and Yde, S and Langer, T and Paquis-Flucklinger, V and Wai, T}, title = {Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.}, journal = {EMBO molecular medicine}, volume = {18}, number = {2}, pages = {542-574}, pmid = {41420107}, issn = {1757-4684}, support = {ANR-21-CE14 0052-02//Agence Nationale de la Recherche (ANR)/ ; ANR-23-CE13-0043-01//Agence Nationale de la Recherche (ANR)/ ; ANR-10-INSB-04-01//Agence Nationale de la Recherche (ANR)/ ; ANR-10-LABX-62-IBEID//Agence Nationale de la Recherche (ANR)/ ; INNOV 164-2022//Institut Pasteur (Pasteur Institute)/ ; }, mesh = {Animals ; Oxidation-Reduction ; *Mitochondrial Proteins/genetics/metabolism ; Mice ; *Signal Transduction ; *Mitochondria/metabolism ; *Cytochromes c/metabolism ; Humans ; Disease Models, Animal ; Mutation ; Gene Knock-In Techniques ; Mitochondrial Diseases/genetics/pathology ; }, abstract = {Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause mitochondrial disease. Knock-in mice modeling the human CHCHD10[S59L] variant associated with ALS-FTD develop a mitochondrial cardiomyopathy driven by CHCHD10 aggregation and activation of the mitochondrial integrated stress response (mtISR). We show that cardiac dysfunction is associated with dual defects originating at the onset of disease: (1) bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using protease-inactive Oma1[E324Q/E324Q] knock-in mice, we show that blunting mtISR in Chchd10[S55L/+] mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment. Proteomic profiling of insoluble mitochondrial proteins in Chchd10[S55L/+] mice reveals widespread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria is rescued by the addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Thus, mutant CHCHD10 insolubility compromises metabolic resilience by impairing bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.}, } @article {pmid41420832, year = {2026}, author = {Wang, X and Wei, M and Qiao, Y}, title = {Modulation of Liquid-to-Solid Phase Transition in Coacervates for Neurodegenerative Disease Treatments.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {27}, number = {2}, pages = {e202500795}, doi = {10.1002/cbic.202500795}, pmid = {41420832}, issn = {1439-7633}, support = {2023YFC2507000//National Key R&D Program of China/ ; 22272183//National Natural Science Foundation of China/ ; T2425001//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Phase Transition ; Animals ; }, abstract = {Coacervates formed through liquid-liquid phase separation represent a fundamental model for protocell and serve as a membraneless organelle in living cells, modulating various biological processes. During aging or under stress, protein misfolding and oligomerization trigger aberrant liquid-to-solid phase transition (LSPT), a process driven by multivalent interactions. These phase transitions disrupt cellular equilibrium, leading to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The regulatory strategies is summarize to enhance molecular interactions in coacervate LSPT into three categories, including physical stimulation, molecular modulation, and sequence regulation. This review aims to establish a conceptual framework for modulating coacervate LSPT and further explores potential clinical treatments for neurodegenerative diseases.}, } @article {pmid41420983, year = {2026}, author = {Garcia-Delgado, AB and Bega, S and Campos-Cuerva, R and Martín-Banderas, L and Paradas, C and Fernandez-Muñoz, B}, title = {Generation of the human iPSC line ESi148-A from a patient with sporadic amyotrophic lateral sclerosis.}, journal = {Stem cell research}, volume = {90}, number = {}, pages = {103889}, doi = {10.1016/j.scr.2025.103889}, pmid = {41420983}, issn = {1876-7753}, mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism/cytology/pathology ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Cell Line ; Leukocytes, Mononuclear/metabolism/cytology ; Male ; }, abstract = {Nearly 90% of patients with amyotrophic lateral sclerosis (ALS) do not carry mutations in genes previously associated with the disease and are classified as sporadic cases with no identified genetic cause. In this study, peripheral blood mononuclear cells from a patient with sporadic ALS were reprogrammed to generate the human induced pluripotent stem cell (iPSC) line ESi148-A. The line was thoroughly characterized for pluripotency and genomic stability. These cells provide a valuable resource for generating 3D biomodels, such as cortical or spinal cord organoids, to investigate disease mechanisms and develop novel therapeutic approaches for sporadic ALS.}, } @article {pmid41422050, year = {2025}, author = {Valletta, M and Briel, N and Yuksekel, I and Barboure, M and Coward, A and De Houwer, JFH and Fawad, A and González-Mayoral, A and Iaccarino, G and Martínez-Dubarbie, F and Moukaled, S and Andreasson, U and Gobom, J and Brinkmalm, A and Tijms, B and Zetterberg, H and Blennow, K and Suárez-Calvet, M and Schöll, M and Paterson, RW and Montoliu-Gaya, L and Sogorb-Esteve, A}, title = {Fluid biomarkers for neurodegenerative diseases: a comprehensive update.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {12}, pmid = {41422050}, issn = {1758-9193}, mesh = {Humans ; *Neurodegenerative Diseases/blood/cerebrospinal fluid/diagnosis ; *Biomarkers/blood/cerebrospinal fluid ; Animals ; }, abstract = {Fluid biomarkers are revolutionizing the diagnosis and management of neurodegenerative diseases by enabling earlier diagnosis and disease monitoring. In particular, blood-based biomarkers have emerged as a minimally invasive and scalable alternative to cerebrospinal fluid analysis. Recent advances in blood-based tau biomarkers have shown high diagnostic accuracy for Alzheimer’s disease (AD). Other neurodegenerative diseases—such as synucleinopathies, frontotemporal lobar degeneration, limbic-predominant age-related TDP-43 encephalopathy (LATE), and amyotrophic lateral sclerosis—pose substantial challenges due to their heterogeneous clinical presentations and the current absence of robust biomarkers for hallmark pathologies. Nonetheless, promising candidate markers are emerging for improved disease characterization and staging. Technological innovations, including single-molecule arrays (Simoa), advanced mass spectrometry workflows and nucleic acid linked immune-sandwich assay (NULISA) have markedly enhanced the sensitivity and precision of biomarker quantification from low-concentration biological matrices. More recently, the development of fully automated platforms shows great promise for routine measurement of blood-based biomarkers in clinical settings. Despite this progress key challenges remain, including the need for improved assay reproducibility, standardization, and the optimization of clinical workflows. In this review, we provide a comprehensive update on recent progress in fluid biomarker research across AD and major neurodegenerative diseases, highlight technological advances in detection methods, and discuss current challenges and opportunities for clinical translation.}, } @article {pmid41422089, year = {2025}, author = {Jun, YW and Lee, S and Almeida, S and Freude, KK and Ichida, JK and Gao, FB}, title = {The Ku80-p53-SIRT1 axis in DNA damage response contributes to sporadic and familial ALS and FTD.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {1007}, pmid = {41422089}, issn = {2041-1723}, support = {NA/ALZ/Alzheimer's Association/United States ; R01NS101986//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R37 NS057553/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; NRF-2019R1A6A3A03034014//National Research Foundation of Korea (NRF)/ ; R37NS057553//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Sirtuin 1/metabolism/genetics ; *Tumor Suppressor Protein p53/metabolism/genetics ; Animals ; *DNA Damage ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism ; *Ku Autoantigen/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Neurons/metabolism/pathology ; Mutation ; Acetylation ; Disease Models, Animal ; Male ; Phosphorylation ; Female ; Drosophila ; }, abstract = {Although TDP-43 pathology is found in most sporadic and familial ALS and FTD cases, other shared pathogenic mechanisms remain largely unknown. Here we show that SIRT1 levels are decreased and acetylated p53 levels are increased in iPSC-derived neurons from sALS patients and with the FTD3-causing CHMP2B mutation. Ectopic expression of SIRT1 in these patient neurons rescues neurodegeneration and reduces acetylated p53 levels. DNA damage is elevated in both sALS and FTD3 neurons, leading to increased phosphorylation of p53 at Serine 15 and elevated levels of Ku80. Knockdown of either p53 or Ku80 rescues neurodegeneration and increases SIRT1 levels in these neurons. Moreover, ectopic expression of SIRT1 or genetic knockdown of either p53 or Ku80 suppresses retinal neurodegeneration caused by FTD3-associated mutant CHMP2B protein in an in vivo Drosophila model. These findings identify a dysregulated SIRT1-p53 feedback loop as a common pathogenic mechanism and promising therapeutic target in both sporadic and familial ALS/FTD.}, } @article {pmid41423553, year = {2026}, author = {Tang, C and Foucher, J and Öijerstedt, L and Ombelet, F and Ingre, C and Van Damme, P and Van Laere, K and De Vocht, J and Koole, M}, title = {Support vector machine classification of [18]F-FDG PET scans across subtypes of amyotrophic lateral sclerosis.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {53}, number = {5}, pages = {3437-3447}, pmid = {41423553}, issn = {1619-7089}, support = {12AQF24N//FWO/ ; fundamental clinical investigatorship//KU Leuven/ ; Een Hart voor ALS//KU Leuven/ ; Laeversfonds voor ALS Onderzoek//KU Leuven/ ; E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders//E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders/ ; ALS Liga België//ALS Liga België/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/classification/genetics ; *Fluorodeoxyglucose F18 ; *Support Vector Machine ; Male ; Female ; Middle Aged ; Adult ; Aged ; *Positron Emission Tomography Computed Tomography ; *Positron-Emission Tomography ; }, abstract = {PURPOSE: While [18]F-FDG PET imaging has demonstrated diagnostic value in people with Amyotrophic Lateral Sclerosis (PwALS) and group-level differences were identified between different disease subtypes (e.g., genetic and clinical variants), refining and validating a machine-learning-based subject-level diagnostic algorithm may improve the general applicability and reliability of [18]F-FDG PET as a diagnostic tool in ALS. In this study, we employed support vector machines (SVM) to further explore the diagnostic potential of [18]F-FDG PET in ALS, alongside its ability to classify between different genetic subtypes or clinical phenotypes.

METHODS: [18]F-FDG PET data of 36 healthy volunteers (HV), 25 people with ALS-mimicking diseases (Mimics), and 167 PwALS, grouped by genetic status (e.g., sporadic (sALS) or carrying a C9orf72 hexanucleotide repeat expansion (ALS[C9orf72RE]) and onset (bulbar or spinal) type, acquired with Biograph 'TruePoint' PET/CT scanner, were included in the study (Dataset 1). A second dataset of 183 PwALS and 31 Mimics acquired with Biograph 'HiRez' scanner was included as an independent cross-validation set (Dataset 2). PET images were spatially normalised to MNI space to fit linear SVMs with cross-validation. Only age-matched groups were considered to eliminate age-related effects.

RESULTS: For Dataset 1, the linear SVM resulted in an average accuracy of 0.86 for the classification of ALS vs. HV, 0.53 for ALS vs. Mimics, 0.83 for ALS[C9orf72RE] vs. sALS, and 0.58 for bulbar vs. spinal onset. These findings were corroborated with Dataset2, with an accuracy of up to 0.76 for ALS[C9orf72RE] vs. sALS, and 0.59 for bulbar vs. spinal.

CONCLUSION: [18]F-FDG brain PET imaging, combined with SVM and age-matching, can distinguish between ALS[C9orf72RE] and sALS with good accuracy, but lacks sufficient discriminative power to differentiate between ALS and Mimics and between different sites of onset.}, } @article {pmid41423699, year = {2025}, author = {Luan, W and San Gil, R and Madrid San Martin, L and Cao, MC and Vassallu, F and Venturato, J and West, PK and Brown-Wright, H and Bademosi, AT and Chye, YJ and Wu, HY and Harutyunyan, A and Robinson, KJ and Chang, MS and Blizzard, CA and Scotter, EL and Igaz, LM and Walker, AK}, title = {Synaptic changes contribute to persistent extra-motor behaviour deficits in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {26}, pmid = {41423699}, issn = {2051-5960}, support = {IG2422//Motor Neurone Disease Australia/ ; Discovery grant//FightMND/ ; Bill Guest Mid-Career Research Fellowship//FightMND/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism/psychology/physiopathology ; DNA-Binding Proteins/genetics/metabolism ; Mice, Transgenic ; Humans ; *Synapses/pathology/metabolism ; Disease Models, Animal ; Mice ; Male ; Frontotemporal Dementia/pathology ; }, abstract = {Extra-motor symptoms are increasingly recognised in amyotrophic lateral sclerosis (ALS), encompassing cognitive, social, and behavioural deficits. TAR DNA binding protein 43 (TDP-43) pathology is the central disease marker of almost all cases of ALS and approximately half of frontotemporal dementia (FTD). However, the mechanisms linking TDP-43 pathology with extra-motor symptoms in TDP-43-associated neurodegenerative diseases remain unresolved. In this study, we used the rNLS8 mouse model, which expresses human TDP-43 with an ablated nuclear localisation sequence (hTDP-43∆NLS) in a doxycycline-regulatable manner causing progressive motor decline reminiscent of ALS, to delineate molecular changes associated with disease-relevant phenotypes. We found that in addition to previously reported dramatic motor decline, rNLS8 mice also develop extra-motor phenotypes consistent with FTD, including disinhibition-like and anxiety-like behaviours, and social interaction impairments. These changes began in the earliest disease stages and remained readily detectable even when rNLS8 mice became severely motor impaired. Notably, extra-motor deficits persisted in rNLS8 mice that had recovered motor function upon hTDP-43∆NLS transgene suppression. This correlates with widespread mis-splicing of RNA in rNLS8 cortex at disease onset with n = 814 genes showing differential exon usage, a molecular phenotype of TDP-43 loss of function. Mis-splicing persists in the rNLS8 cortex in recovery and may represent lasting impacts of cytoplasmic TDP-43 expression. Further, proteomics analysis of the cortex of rNLS8 mice revealed depletion of synaptic proteins, particularly those involved in glutamatergic signalling pathways, which also persisted following hTDP-43∆NLS transgene suppression. Similar changes to the glutamatergic pathway were detected in transcriptomic and proteomic datasets from human ALS and FTD post-mortem cortex. Our findings suggest that targeting glutamatergic synaptic components may be an avenue to correct extra-motor deficits associated with TDP-43 pathology.}, } @article {pmid41426430, year = {2025}, author = {van Vugt, JJFA and Zwamborn, RAJ and Dolzhenko, E and Eberle, MA and Weisburd, B and Bekema, E and Kooyman, M and Wang, BN and , and Kamsteeg, EJ and Losekoot, M and Baas, F and Novy, C and Høyer, H and van Eijk, RPA and van Es, MA and van Rheenen, W and Al-Chalabi, A and van den Berg, LH and Veldink, JH}, title = {The role of disease-associated short tandem repeats in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {6}, pages = {fcaf482}, pmid = {41426430}, issn = {2632-1297}, abstract = {Short tandem repeats (STRs) are recognized contributors to various neurodegenerative disorders, with evidence supporting genetic pleiotropy among these STRs. Multiple STRs have been associated with amyotrophic lateral sclerosis (ALS), although the strength of evidence supporting each association varies. To establish the role of disease-associated repeat expansions as pleiotropic risk factors in ALS susceptibility and progression, we genotyped a panel of 39 STRs, known to cause neurological diseases, within Project MinE in 6519 patients and 2412 controls, utilizing 100 and 150 bp short-read sequencing technology. Pathogenic allele frequencies were compared to those in a control cohort comprising 4930 Genome Aggregation Database (gnomAD) genomes. Repeat sizes and motif changes were detected using ExpansionHunter and ExpansionHunter Denovo. We developed a model to predict genotyping failures in STRs and established a best-practice protocol for assessing the accuracy of STR genotyping in short-read sequencing data. Following our genotyping assessment, 11 out of the 39 STRs exhibited insufficient genotyping accuracy, warranting caution in studying these STRs using these tools in combination with short-read sequencing. Furthermore, the observed differences in STR genotyping accuracy across studies applying different sequencing technologies and genotyping tools in control cohorts highlight the importance of a carefully designed experimental setup when interpreting potential disease-associated STR findings. Pathogenic C9orf72 and premutated ATXN2 expansions were confirmed to be significantly associated with ALS susceptibility. Additionally, pathogenic C9orf72 expansions were significantly associated with reduced mean ALS survival by 11.5 months and an earlier mean age at onset by 2.4 years. Premutation expansions in ATXN1 showed a nominally significant association with ALS susceptibility, while pathogenic expansions in NIPA1 displayed a nominally significant association with ALS survival. Previously reported ALS-associated pleiotropy in HTT and STMN2 could not be confirmed. Motif changes were identified in BEAN1, RFC1, ATXN8, C9orf72, DAB1, FXN and SAMD12; however, none of the motif changes were linked to ALS. Re-evaluation of clinical data from patients with ALS and a repeat expansion typically associated with another disease revealed that 7% of these patients' diagnoses had to be reclassified to the disease associated with the repeat expansion (e.g. Kennedy's disease or spinocerebellar ataxia). This underscores the value of broad STR screening in neurodegenerative cases. Pathogenic and premutation STRs were also found in controls in unexpected high frequencies, suggesting reduced penetrance or underdiagnosis, and highlighting the need for caution when interpreting genetic associations with disease without a proper control cohort.}, } @article {pmid41427267, year = {2025}, author = {Finney, CA and An, L and Winchester, LM and Vogel, J and Wilkins, HM and Burns, JM and Swerdlow, RH and Slawson, C and Rothstein, JD and , and Lutz, MW and Saloner, R and Shvetcov, A}, title = {Mapping the circulating proteome across neurodegeneration: A harmonized, consortium-scale framework for uncovering molecular pathophysiology.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41427267}, issn = {2692-8205}, support = {RF1 AG064227/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; K23 AG090757/AG/NIA NIH HHS/United States ; R21 TR003589/TR/NCATS NIH HHS/United States ; }, abstract = {Large-scale plasma proteomics offers unprecedented opportunities to investigate the systemic biology of neurodegeneration, yet technical heterogeneity, site-specific artifacts, and clinical confounding remain major barriers to reproducible discovery. Leveraging data from 13,733 individuals with Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), Parkinson's disease dementia (PDD), amyotrophic lateral sclerosis (ALS), and non-impaired controls in the Global Neurodegeneration Proteomics Consortium (GNPC), we present a scalable and generalizable analytical framework for harmonizing and interpreting consortium-scale proteomic datasets. Using a high-dimensional perturbation framework, we systematically benchmark five commonly used batch correction methods across a range of realistic confounding structures, including site-disease imbalance, nonlinear effects, and heteroskedasticity. Empirical Bayes modelling via limma consistently emerged as the most robust method, optimally balancing removal of site-related technical variance with retention of disease-relevant biological signal. On this harmonized foundation, we resolve neurodegenerative disease plasma signatures, including a shared immune-metabolic axis in AD and PD, neuromuscular disruption in ALS, and proteostatic imbalance in PD. Tissue and cell-type enrichment highlight widespread immune-endocrine involvement in AD and hematopoietic activation in PD. Demographically matched analyses nominate distinct, candidate biomarkers across diseases, including lipid, redox, and complement factors in AD, lysosomal and cytoskeletal proteins in PD, and muscle-derived markers in ALS. This study establishes a scalable analytical framework for integrating real-world proteomic data and provides a disease-resolved catalogue of circulating signatures to inform biomarker development and targeted intervention across neurodegenerative diseases.}, } @article {pmid41428120, year = {2025}, author = {Freri, F and Spinelli, EG and Canu, E and Basaia, S and Castelnovo, V and Müller, HP and Kassubek, J and Ludolph, AC and Krishnamurthy, SS and Roselli, F and Filippi, M and Agosta, F}, title = {Uncovering hypothalamic network disruption in ALS.}, journal = {Journal of neurology}, volume = {273}, number = {1}, pages = {37}, pmid = {41428120}, issn = {1432-1459}, support = {EU Joint Programme - Neurodegenerative Disease Research (JPND) - HiCALS project//European Commission/ ; Next Generation EU/National Recovery//European Union/ ; Resilience Plan//European Union/ ; Investment PE8-Project Age-It. Project code: PE00000015; CUP master: D43C22003100007//European Union/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; Female ; Male ; Middle Aged ; *Hypothalamus/diagnostic imaging/physiopathology/pathology ; Magnetic Resonance Imaging ; Aged ; Adult ; *White Matter/diagnostic imaging/pathology ; *Nerve Net/diagnostic imaging/physiopathology ; Disease Progression ; *Connectome ; }, abstract = {BACKGROUND: Structural MRI studies have shown hypothalamic atrophy and altered white matter (WM) connectivity in amyotrophic lateral sclerosis (ALS), as a possible substrate of hypermetabolism in this condition. However, hypothalamic functional connectivity and its association with clinical features in ALS remain unclear. This study explored hypothalamic resting-state functional connectivity (RS-FC) in ALS patients compared to controls and its relationship with disease severity defined by the ALS Functional Rating Scale (ALSFRS-r), body mass index (BMI), disease duration, progression rate, survival, hypothalamic volume, and WM integrity.

METHODS: Seventy-one ALS patients and 39 healthy controls underwent structural and RS functional MRI. The bilateral hypothalamus was segmented, and a seed-based RS-FC analysis was performed. Group differences in hypothalamic RS-FC and their correlations with ALSFRS-r scores, BMI, disease duration, progression rate, survival, hypothalamic volume, and WM integrity were assessed. Tract-based spatial statistics was performed to estimate the correlation between WM damage in ALS and hypothalamic RS-FC.

RESULTS: ALS patients showed increased hypothalamic RS-FC with caudate nuclei compared to controls. Additionally, greater disease severity correlated with increased hypothalamic RS-FC with the caudate nuclei and orbitofrontal cortex. Hypothalamic RS-FC mean values also associated with FA in the genu of corpus callosum and forceps minor and disease progression rate. No significant correlations were observed with other clinical features.

CONCLUSIONS: These findings support hypothalamic alterations in ALS. Early detection of hypothalamic changes could be useful in prognostic stratification and evaluating intervention effects.}, } @article {pmid41428212, year = {2026}, author = {Grønbæk-Thygesen, M and Kampmeyer, C and Eschger, P and Tatham, MH and Arts, M and Hofmann, K and Lindorff-Larsen, K and Boomsma, W and Hartmann-Petersen, R}, title = {The Importance of UBQLN2 Ubiquitylation for Its Turnover and Localization.}, journal = {Biochemistry}, volume = {65}, number = {1}, pages = {52-63}, doi = {10.1021/acs.biochem.5c00619}, pmid = {41428212}, issn = {1520-4995}, mesh = {Humans ; *Ubiquitination ; Autophagy-Related Proteins ; Adaptor Proteins, Signal Transducing/metabolism ; *Cell Cycle Proteins/metabolism/genetics/chemistry ; Proteasome Endopeptidase Complex/metabolism ; Lysine/metabolism ; Proteolysis ; Protein Domains ; *Ubiquitins/metabolism ; HEK293 Cells ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Ubiquitin/metabolism ; }, abstract = {UBQLN2 is a member of the UBL-UBA domain protein family that functions as extrinsic substrate receptors for the 26S proteasome. UBQLN2 has been shown to undergo phase separation in vitro. In cells, UBQLN2 forms condensates that may be of importance for tuning protein degradation via the ubiquitin-proteasome system and potentially of relevance for UBQLN2-linked amyotrophic lateral sclerosis (ALS). Here we show that UBQLN2 is ubiquitylated on lysine residues in the N-terminal UBL domain. The C-terminal region of UBQLN2 is lysine-depleted, and we show that introducing lysine residues in this region leads to its E6AP-dependent degradation. The UBL domain critically stabilizes UBQLN2 and protects it from proteasomal degradation. Fusion of ubiquitin to the UBQLN2 N-terminus stabilizes UBQLN2 and increases its propensity for locating in puncta, indicating that ubiquitylation of the UBQLN2 UBL domain regulates abundance and localization.}, } @article {pmid41428348, year = {2026}, author = {Elman, L and Wymer, J and Lomen-Hoerth, C}, title = {Tofersen, SOD1, and the Treatability of Amyotrophic Lateral Sclerosis.}, journal = {JAMA neurology}, volume = {83}, number = {2}, pages = {103-104}, doi = {10.1001/jamaneurol.2025.4927}, pmid = {41428348}, issn = {2168-6157}, } @article {pmid41428860, year = {2026}, author = {Curtis, SE and Tatlock, S and O'Hara, L and Seçinti, E and Mehdiyoun, NF and Ayala-Nunes, L and Flynn, J and Fernelius, K and Hodson, N and Delbecque, L}, title = {Patient experience and clinical outcome assessment validity in amyotrophic lateral sclerosis: a targeted literature review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {285-300}, doi = {10.1080/21678421.2025.2604233}, pmid = {41428860}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/diagnosis ; *Quality of Life/psychology ; *Outcome Assessment, Health Care/methods ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To identify relevant concepts of measurement for people with amyotrophic lateral sclerosis (ALS) and to evaluate the face and content validity of clinical outcome assessments (COAs) that can be used to measure treatment benefits in ALS clinical trials.

METHODS: A targeted literature review was conducted to explore patient experience (stage 1) and COAs used in ALS research (stage 2). Abstracts were screened against predefined eligibility criteria; full-text articles were reviewed for eligible abstracts and relevant data were extracted. Face and content validity of the identified COAs were assessed.

RESULTS: Stage 1 searches identified 3,527 abstracts, of which 12 full-text articles, two summary reports, and one conference poster were included in this review. Twenty-five symptoms and 35 health-related quality of life (HRQoL) impacts were identified. Frequently reported symptoms included breathing and speech difficulties and muscle/limb weakness, each associated with a diverse range of impacts, including those related to emotional wellbeing, physical function, social and leisure activities, and activities of daily living. Stage 2 searches identified 119 COAs, of which 28 were reviewed. Many had acceptable face (13/28) and content validity (15/28), but 13 had not involved patients during development; only 10 were clearly worded and seven were lengthy, increasing patient burden risk.

CONCLUSIONS: This review identified wide-ranging symptoms and HRQoL impacts experienced by people with ALS, but detailed qualitative evidence is sparse. Multiple COAs were identified as potential measures in ALS clinical trials.}, } @article {pmid41428861, year = {2026}, author = {Soliman, R and Swelam, MS and Fahmy, N and Rashed, HR}, title = {Translation and validation of the Arabic version of the amyotrophic lateral sclerosis assessment questionnaire (ALSAQ40-AR).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {592-601}, doi = {10.1080/21678421.2025.2603311}, pmid = {41428861}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis ; Female ; Male ; Surveys and Questionnaires/standards ; Reproducibility of Results ; Middle Aged ; *Quality of Life/psychology ; Prospective Studies ; Adult ; Aged ; Egypt ; Translations ; Psychometrics ; }, abstract = {AIM: To validate Arabic version of the ALSAQ-40, (ALSAQ40-AR) and assess the QOL in a cohort of Egyptian patients with ALS.

METHODS: This is a prospective study. One hundred consecutive ALS patients were included from the Neuromuscular Unit, Ain Shams University Hospital, in the period from February 2022 to June 2024. Functional and cognitive assessments were done using the Arabic version of ALSFRS-R and ECAS-EG questionnaires, respectively. Disease stage was identified via Kings Clinical Staging. QOL was evaluated using the Arabic WHOQOL-BREF and an Arabic version of ALSAQ-40.

RESULTS: ALSAQ40-AR showed high internal consistency using Cronbach's alpha of >0.9, Inter-rater reliability was tested, values for all variables were compared, and no statistically significant differences were found (ICC = .997). Both WHOQOL-BREF and ALSAQ40-AR domains demonstrated significant correlation with each other and with ALSFRS-R (p-value < 0.0001), denoting construct validity. Moreover, ALSAQ40-AR domains correlated significantly with time since disease onset, and showed significant increase across disease stages (p-value < 0.0001). Ceiling and floor effects were analyzed in both QOL scales, but only WHOQOL-BREF showed ceiling and floor effects.

CONCLUSION: ALSAQ40-AR and the WHOQOL-BREF were reliable and valid tools to evaluate QOL in patients with ALS; we suggest that the validated ALSAQ40-AR is more suited for ALS patients because it is a disease specific questionnaire that showed higher internal consistency with no floor or ceiling effects. QOL in ALS was correlated with time since disease onset, disease stage, functional, and cognitive disabilities.}, } @article {pmid41428942, year = {2025}, author = {Sannes, A and Rognli, EW and Hanssen-Bauer, K and Torp, NC and Storfossen, SK and Høstaker, MN and Aalberg, M}, title = {Barriers to and Facilitators of Implementation of Internet-Delivered Therapist-Guided Therapy in Child and Adolescent Mental Health Services: Systematic Review and Bayesian Meta-Analysis.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e83543}, pmid = {41428942}, issn = {1438-8871}, mesh = {Adolescent ; Child ; Humans ; *Adolescent Health Services ; Bayes Theorem ; *Child Health Services ; *Internet ; *Mental Health Services ; *Psychotherapy/methods ; }, abstract = {BACKGROUND: Internet-delivered therapist-guided therapy (e-therapy) represents a promising approach for enhancing accessibility, treatment fidelity, and scalability within child and adolescent mental health services (CAMHS).

OBJECTIVE: This systematic review aimed to (1) identify and synthesize determinants of implementation, specifically barriers to and facilitators of e-therapy in CAMHS structured according to the Consolidated Framework of Implementation Research (CFIR); and (2) provide pooled benchmark estimates of key implementation outcomes for fidelity, cost-effectiveness, and acceptability.

METHODS: A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-compliant systematic review was performed across PsycINFO, MEDLINE, Web of Science, CINAHL, Embase, Cochrane, and ProQuest Dissertations & Thesis on June 6, 2025-to identify peer-reviewed studies assessing implementation outcomes or determinants of e-therapy in the context of outpatient CAMHS (ages 8-18 years). Barriers and facilitators were synthesized qualitatively with thematic analysis applying CFIR. A parallel quantitative synthesis of Proctor et al's taxonomy of implementation outcomes was performed using Bayesian multilevel random-effects meta-analyses to estimate pooled effect sizes and 95% credible intervals (CIs). By combining quantitative benchmarks of implementation success with qualitative insights into contextual determinants, the review provides an integrated understanding of what drives effective e-therapy implementation in CAMHS. Study quality was assessed using the CASP (Critical Appraisal Skills Programme) checklist, Cochrane Risk of Bias tool, and Risk Of Bias In Non-randomized Studies-of Interventions tool. Small study effects were evaluated using funnel plots, sensitivity analyses, and the Egger test.

RESULTS: From 50,026 screened reports, 50 studies published between 2007 and 2025 were included: 18 randomized controlled trials, 17 cohort, and 15 qualitative or mixed methods studies. Most studies originated from Western Europe (n=34), Northern America (n=11), and Oceania (n=5), targeting anxiety (n=24) and depression (n=9), through cognitive behavioral therapy-based programs (n=47), with parallel parent content (n=31). Therapist guidance was primarily asynchronous (n=43). Among the 39 studies reporting determinants, common barriers and facilitators were identified across intervention, organization, therapist, and patient domains, structured via CFIR. Pooled implementation outcomes showed modest dropout rates (~20%, CI 14%-27%), high module completion (~68%, CI 60%-75%), low therapist time (24 min per wk per patient, 95% CI 19-28), and high patient satisfaction (24/32 on Client Satisfaction Questionnaire-8, 95% CI 22-27; and 76% satisfaction rate, 95% CI 62%-87%), suggesting e-therapy is resource efficient and acceptable if implemented successfully.

CONCLUSIONS: This review provided the first integrated synthesis of pooled benchmarks for implementation outcomes of e-therapy in CAMHS and modifiable determinants to inform future service planning and scale-up. These findings highlighted service-level enablers, such as leadership anchoring, targeted use, technical stability, structured patient flow, and therapist training, that organizations could prioritize to strengthen sustainable e-therapy implementation in CAMHS.}, } @article {pmid41428955, year = {2026}, author = {Jih, KY and Tsai, YS and Fang, SY and Hsu, FC and Sytwu, HP and Liao, YC and Tsai, PC and Lee, YC}, title = {SOD1 mutations in Taiwanese ALS patients: Clinical characteristics, frequency, and a p.T138R founder effect.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {338-347}, doi = {10.1080/21678421.2025.2604236}, pmid = {41428955}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/diagnosis ; *Superoxide Dismutase-1/genetics ; Taiwan/epidemiology ; Female ; Male ; Middle Aged ; *Mutation/genetics ; Adult ; *Founder Effect ; Aged ; Polymorphism, Single Nucleotide/genetics ; Cohort Studies ; }, abstract = {OBJECTIVE: Mutations in SOD1 are a well-established genetic cause of amyotrophic lateral sclerosis (ALS), exerting toxic gain-of-function effects that promote protein misfolding and aggregation in motor neurons and glial cells. The emergence of SOD1-targeted antisense oligonucleotide therapy underscores the clinical importance of precise genetic diagnosis. This study aimed to determine the frequency, clinical characteristics, and potential founder effect of SOD1 mutations in a large Taiwanese ALS cohort, and to evaluate their aggregation propensity in vitro.

METHODS: All coding exons of SOD1 were analyzed by Sanger sequencing in 650 unrelated Taiwanese patients with ALS. Haplotype analysis using single nucleotide polymorphism markers flanking SOD1 was conducted to assess a potential founder effect. Protein cross-linking assays were performed to assess the aggregation propensity of 11 SOD1 variants.

RESULTS: Seventeen pathogenic SOD1 variants were identified in 26 probands and 12 affected relatives. Mean age at onset was 48.9 ± 14.9 years, and 8% had bulbar-onset ALS. The most frequent variant was p.T138R (8 probands), followed by p.G11A (3 probands). The other 15 variants each occurred in a single family. A shared ancestral haplotype was observed among p.T138R carriers. Cross-linking experiments demonstrated oligomer formation in all tested mutant SOD1 proteins compared to the wild-type protein, supporting their pathogenicity.

CONCLUSIONS: SOD1 mutations account for approximately 4% of ALS cases in Taiwan, are associated with earlier onset and predominantly spinal-onset ALS, and include a p.T138R founder variant. These findings highlight the importance of genetic screening in ALS, particularly in guiding eligibility for emerging targeted therapies.}, } @article {pmid41429156, year = {2025}, author = {Gomes, MDM and Freitas, MRG}, title = {Jean-Martin Charcot at 200: revolutionizing neurology through a multidisciplinary lens.}, journal = {Arquivos de neuro-psiquiatria}, volume = {83}, number = {11}, pages = {1-5}, pmid = {41429156}, issn = {1678-4227}, mesh = {History, 19th Century ; *Neurology/history ; Humans ; }, abstract = {As we near the bicentenary of his birth, Jean-Martin Charcot (1825-1893) is remembered not only as the founder of modern neurology but also as a uomo universale. His multidisciplinary approach transcended 19[th]-century medicine, establishing neurology as a distinct discipline while integrating art, psychology, and philosophy into his study of the nervous system. His work laid foundations for neurodegenerative diseases (amyotrophic lateral sclerosis [ALS], Parkinson's disease, multiple sclerosis [MS]), functional neurological disorders (FNDs), and psychoanalysis, foreshadowing neuroplasticity and the mind-body connection. His innovative teaching at Salpêtrière-merging anatomy with artistic documentation-revolutionized medical education, inspiring figures from Freud to modern neuroscientists. Two centuries later, Charcot's legacy endures not just in eponyms but in his unifying vision of brain, mind, and art - a timeless model for interdisciplinary medicine. The present paper explores his impact on neurodegenerative research, functional disorders, medical pedagogy, and the humanities.}, } @article {pmid41430073, year = {2025}, author = {Fava, VM and Perico, J and Orlova, M and Dallmann-Sauer, M and Xu, YZ and Thuc, NV and Thai, VH and Belone, AF and Latini, ACP and Schurr, E}, title = {Bridging pleiotropic mechanisms in leprosy type-1 reactions and neurodegenerative diseases.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {45036}, pmid = {41430073}, issn = {2045-2322}, support = {FP 22/9//Leprosy Research Initiative/ ; }, mesh = {Humans ; *Leprosy/genetics/complications/pathology ; *Parkinson Disease/genetics ; *Neurodegenerative Diseases/genetics ; Male ; Genetic Predisposition to Disease ; Female ; Protein Kinases/genetics ; Middle Aged ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Ubiquitin-Protein Ligases/genetics ; *Genetic Pleiotropy ; PTEN-Induced Putative Kinase ; }, abstract = {Leprosy is an infectious disease of the skin and peripheral nervous system. Sudden episodes of hyperinflammation, known as Type 1 Reactions (T1R), are a main contributor to permanent nerve damage in leprosy. The genetic component associated with the neuro-inflammatory phenotype of T1R displays pleiotropic effects with Parkinson's disease (PD). In this study, we explored the genetic overlap between PD and T1R and expanded the evaluation of pleiotropic effects between T1R and other neurodegenerative disorders. We replicated the association of PD-linked rare variants in PRKN with T1R in Vietnamese leprosy patients. Analysis of 24 PD associated-genes revealed compound effects between rare protein-altering variants and T1R in the interacting genes PRKN/PINK1 (P = 2.7[-05]; OR = 4.0) and a combination of rare/low frequency variants in the LRRK2/GAK pair (P = 6.7[-05]; OR = 0.54). These findings validated a genetic overlap between T1R and PD with two distinct axes, one of shared risk via PRKN/PINK1 and a second of antagonistic pleiotropic via LRRK2/GAK. When testing an additional 94 genes associated with neurodegenerative diseases we identified variants in the amyotrophic lateral sclerosis disease-linked gene TBK1 associated with T1R (P = 0.004; OR = 12.9). Our results highlight shared biological processes between leprosy and neurodegenerative diseases, which may indicate candidate drugs for repurposing to improve T1R management.}, } @article {pmid41430470, year = {2026}, author = {Piol, D and Khalil, B and Robberechts, T and Killian, T and Georgopoulou, M and Partel, G and Wouters, D and Hecker, N and Tziortzouda, P and Verresen, Y and Corthout, N and Kint, S and Vandereyken, K and Van Damme, P and Voet, T and Davie, K and Poovathingal, S and Van Den Bosch, L and Aerts, S and Sifrim, A and Da Cruz, S}, title = {Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.}, journal = {Nature neuroscience}, volume = {29}, number = {1}, pages = {53-66}, pmid = {41430470}, issn = {1546-1726}, support = {962700//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; 1060285//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *RNA-Binding Protein FUS/genetics/metabolism ; Eukaryotic Translation Initiation Factor 5A ; *Axons/metabolism ; *Peptide Initiation Factors/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Mice ; Motor Neurons/metabolism ; *Protein Biosynthesis/physiology ; Drosophila ; Mutation/genetics ; Mice, Transgenic ; }, abstract = {Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined. Here we applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping. Among transcripts found in mature axons, the most enriched biological process is protein translation, and localization of translation machinery was confirmed using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery. In particular, eukaryotic initiation factor 5a (Eif5a), a translation factor involved in elongation and termination, is found to be locally impaired in mutant FUS axons with reduced levels of its active hypusinated form. Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis. Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development.}, } @article {pmid41431371, year = {2025}, author = {Dobbertin, T and Schirmer, L}, title = {Spatially Resolved Profiling of Compartmentalized Muscle and Brain Inflammation.}, journal = {European journal of immunology}, volume = {55}, number = {12}, pages = {e70119}, pmid = {41431371}, issn = {1521-4141}, support = {P1180016//Gemeinnützige Hertie-Stiftung/ ; GRK2727(InCheck)//Deutsche Forschungsgemeinschaft/ ; FOR2690(SCHI1330/7-2)//Deutsche Forschungsgemeinschaft/ ; SPP2395(SCHI1330/10-1)//Deutsche Forschungsgemeinschaft/ ; FOR5705(SCHI1330/13-1)//Deutsche Forschungsgemeinschaft/ ; SCHI1330/2-1//Deutsche Forschungsgemeinschaft/ ; SCHI1330/4-1//Deutsche Forschungsgemeinschaft/ ; SCHI1330/11-1//Deutsche Forschungsgemeinschaft/ ; 950584//H2020 European Research Council/ ; }, mesh = {Humans ; Animals ; *Muscle, Skeletal/immunology/pathology/metabolism ; Proteomics/methods ; *Brain/immunology/pathology ; Inflammation/immunology ; *Neuroinflammatory Diseases/immunology ; *Encephalitis/immunology ; Transcriptome ; }, abstract = {Spatial omics technologies enable high-resolution mapping of transcriptomic, proteomic, and metabolic profiles within intact tissues, revealing how immune, stromal, and parenchymal cells interact in situ during inflammation. Chronic inflammation in skeletal muscle and the central nervous system is spatially organized within defined niches that shape disease progression and therapeutic response. In skeletal muscle, spatial analyses have uncovered fiber-type-specific vulnerability, regenerative trajectories, and immune-stromal crosstalk in disorders such as Duchenne muscular dystrophy and inclusion body myositis. In the central nervous system, these approaches have revealed compartmentalized neuroinflammation in multiple sclerosis, innate immune activation in amyotrophic lateral sclerosis, and immune evasion in glioma. Integration with single-cell gene expression enables inference of cell-cell communication networks and identification of spatial gradients of immune activation and tissue remodeling. Despite major advances, clinical translation remains limited by small cohorts, methodological variability, and insufficient functional validation. As spatial profiling becomes more accessible, standardized, and scalable, it promises to stratify inflammatory disease states, identify tissue-resident immune programs, and guide mechanism-based therapies. Hence, spatial omics provide an unprecedented opportunity to resolve the cellular architecture of inflammation, revealing not only where immune activity occurs, but how it is orchestrated within complex tissue microenvironments.}, } @article {pmid41431415, year = {2026}, author = {Cho, W and Lee, SY and Yoo, SH and Cho, B and Kim, KH and Hwang, IY}, title = {Home Healthcare Needs and Characteristics of Patients with Serious Illnesses Who Use Hospital-Affiliated Home-Based Medical Care in Korea.}, journal = {Yonsei medical journal}, volume = {67}, number = {1}, pages = {62-70}, pmid = {41431415}, issn = {1976-2437}, support = {RS-2021-KH120239//Patient-Centered Clinical Research Coordinating Center/Korea ; }, mesh = {Humans ; Male ; Female ; Republic of Korea ; Aged ; Retrospective Studies ; Middle Aged ; Aged, 80 and over ; Emergency Service, Hospital/statistics & numerical data ; *Home Care Services/statistics & numerical data ; *Health Services Needs and Demand ; *Home Care Services, Hospital-Based/statistics & numerical data ; Neoplasms/therapy ; }, abstract = {PURPOSE: The number of homebound adults with serious illnesses is increasing. This study aimed to examine the healthcare needs and characteristics of patients who use a hospital-affiliated physician-led home-based medical care (HBMC) program and identify factors associated with emergency department (ED) visits in Korea.

MATERIALS AND METHODS: This retrospective observational study included patients who used a HBMC program at a tertiary hospital between 2020 and 2023. Patient characteristics and home healthcare needs were analyzed by disease category: cancer, advanced neurologic disease, and others. Multivariable logistic regression analysis was used to identify factors associated with ED visits within 30 days of a physician's home visit.

RESULTS: A total of 600 patients were registered and received home visits; 58.5% had cancer and 29.7% had advanced neurologic diseases, e.g., amyotrophic lateral sclerosis. The median age was 72 years [interquartile range (IQR), 62.8-81.0], and 87.0% were dependent in daily activities. The median number of medications per patient was 6 (IQR, 3-10); 66.3% took ≥5 medications and 25.7% took ≥10 (excessive polypharmacy). Physicians provided not only physical examinations (100%) and symptom assessment (90.8%), but also home environment evaluation (86.7%), medical device management (62.0%), advanced care planning (40.7%), and acute health issue management (32.5%). Within 30 days, 19.2% of patients visited the ED. Excessive polypharmacy and cancer diagnosis were associated with increased ED visits.

CONCLUSION: Most patients who used the hospital-affiliated HBMC program had cancer, advanced neurologic disease, and polypharmacy. Targeted HBMC programs are needed for patients with serious illnesses living at home.}, } @article {pmid41432316, year = {2026}, author = {Genge, A and Rothstein, J and De Silva, S and Zinman, L and Chum, M and Chiò, A and Sobue, G and Aoki, M and Yoshino, H and Doyu, M and Selness, D and Todorovic, V and Hirai, M and Sasson, N and Takahashi, F and Cecić, M and Wamil, A and Apple, S}, title = {Phase 3b Extension Study MT-1186-A04 to Evaluate the Continued Efficacy and Safety of Edaravone Oral Suspension for Up to an Additional 48 Weeks in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {73}, number = {4}, pages = {534-543}, pmid = {41432316}, issn = {1097-4598}, support = {//Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/administration & dosage/therapeutic use ; Male ; Middle Aged ; Double-Blind Method ; Female ; Aged ; Treatment Outcome ; Administration, Oral ; *Free Radical Scavengers/administration & dosage/therapeutic use/adverse effects ; Adult ; Suspensions ; *Antipyrine/analogs & derivatives/administration & dosage/therapeutic use ; }, abstract = {INTRODUCTION/AIMS: An On/Off dosing regimen of intravenous (IV) edaravone and edaravone oral suspension is currently approved in the US for treatment of amyotrophic lateral sclerosis (ALS). Placebo-controlled clinical trials showed that IV edaravone slows physical functional decline. Study MT-1186-A04 continued to examine the efficacy and safety of investigational once daily and approved on/off dosing of edaravone oral suspension in patients with ALS.

METHODS: Study MT-1186-A04 (NCT05151471) was a phase 3b, multicenter, randomized, double-blind, parallel group extension study for up to an additional 48 weeks following 48-week Study MT-1186-A02 that randomized patients to investigational once daily or approved 105-mg on/off dosing of edaravone oral suspension. Patients who met Study MT-1186-A04 eligibility criteria, including Study MT-1186-A02 completion, continued in the same treatment regimen as Study MT-1186-A02. The primary efficacy endpoint for MT-1186-A04 was time from randomization in Study MT-1186-A02 to a ≥ 12-point decrease in ALS Functional Rating Scale-Revised (ALSFRS-R) or death, whichever happened first.

RESULTS: Over 96 weeks, including Study MT-1186-A02, daily dosing did not show a statistically significant difference vs. approved on/off dosing for the primary endpoint (p = 0.78). Edaravone oral suspension was well tolerated, and no new safety concerns were identified in either group.

DISCUSSION: Similar to Study MT-1186-A02, once daily edaravone oral suspension in extension Study MT-1186-A04 did not show superiority in terms of the primary efficacy endpoint, but had equivalent efficacy, safety, and tolerability, compared with the approved On/Off regimen. The results reinforce the appropriateness of the approved dosing regimen.}, } @article {pmid41436842, year = {2025}, author = {Mao, H and Matsubara, T and Tanaka, N and Peled, N and Farzaneh, H and Melania Lon, D and Suzuki, N and Richardson, RM and Cole, AJ and Fang, X and Stufflebeam, SM}, title = {Transcriptomic decoding of regional cortical vulnerability to drug-resistant epilepsy using 7T MRI.}, journal = {Communications biology}, volume = {9}, number = {1}, pages = {121}, pmid = {41436842}, issn = {2399-3642}, support = {P41 EB015896/EB/NIBIB NIH HHS/United States ; P41 EB030006/EB/NIBIB NIH HHS/United States ; S10 OD023637/OD/NIH HHS/United States ; U54 MH091657/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; Female ; Male ; *Drug Resistant Epilepsy/genetics/diagnostic imaging/physiopathology ; Adult ; *Transcriptome ; *Cerebral Cortex/diagnostic imaging/physiopathology/metabolism ; Young Adult ; Case-Control Studies ; Adolescent ; Gene Expression Profiling ; Middle Aged ; }, abstract = {The mechanism by which genetic risk leads to cortical vulnerability in drug-resistant epilepsy (DRE) remains unclear. This study used 7T structural and resting-state functional MRI to investigate cortical neural activity alterations in 105 DRE patients and 105 healthy controls (HCs), and to explore related genetic mechanisms. Vertex-wise analyses of mean amplitude of low-frequency fluctuation (mALFF) and regional homogeneity (ReHo) revealed that DRE patients primarily exhibited decreased mALFF and increased ReHo in the Cingulo-Opercular Network. Using the Allen Human Brain Atlas, we conducted spatial transcriptomic analysis via partial least squares (PLS) and gene enrichment analysis to identify gene categories associated with these functional changes. The results showed that cortical alterations were related to epilepsy-general genes (e.g., TMEM74, KCNN2, RBFOX1) and brain-relevant genes. Genes positively correlated with mALFF alterations enriched in mitochondrial inner membrane, matrix, and carboxylic acid metabolism; negatively in chromatin remodeling, binding, and postsynapse. Genes positively correlated with ReHo alterations enriched in nucleic acid-related catalytic activity, ribonucleoprotein granule, and centrosome; negatively in amyotrophic lateral sclerosis, mitochondrial membrane, and pyrophosphatase activity. These findings link spatial brain activity abnormalities in DRE to specific genetic signatures and biological pathways, suggesting new mechanistic insights and potential therapeutic targets for this difficult-to-treat condition.}, } @article {pmid41437053, year = {2025}, author = {Su, WM and Duan, QQ and He, SY and Liu, RY and Wen, XJ and Zhang, N and Chen, T and Cao, B and Chen, YP}, title = {Loss of Y chromosome and its implications in male amyotrophic lateral sclerosis: insights from the UK Biobank.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {48}, pmid = {41437053}, issn = {1741-7015}, support = {no. 82371422 and no. 81971188//the National Natural Science Fund of China/ ; no. 2022YFC2703101//the National Key Research and Development Program of China/ ; no. 2023HXFH032//the 1·3·5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/mortality ; Male ; United Kingdom/epidemiology ; Middle Aged ; *Chromosomes, Human, Y/genetics ; Biological Specimen Banks ; Aged ; Adult ; Prognosis ; UK Biobank ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) shows a male predominance, yet the underlying mechanism remains unclear. Although the loss of Y chromosome (LOY) in peripheral blood - a male-specific genetic alteration - has been implicated in certain neurodegenerative disorders (NDDs), its association with ALS in men remains unexplored and has not been explored.

METHODS: We focused on men in the UK Biobank to investigate whether LOY influences the risk and prognosis of ALS. Initially, the LOY level for each male participant was determined using sequencing data. Subsequently, Cox proportional hazards (Cox PH) model analysis was used to assess LOY-associated risk of ALS; thirdly, piecewise linear regression, Kaplan-Meier, and Cox PH analysis assessed LOY's associations with ALS age at onset (AAO) and survival. Fourthly, multiple analytical methods were implemented to explore the relationship between LOY and ALS indicators, including plasma GFAP (glial fibrillary acidic protein) and NfL (neurofilament light chain). Finally, sensitivity analysis was carried out.

RESULTS: Our final cohort consisted of 158,953 male participants, with a mean follow-up of 11.7 years. Among them, 297 individuals developed ALS. After adjusted multiple confounding factors, including C9orf72 hexanucleotide repeat expansion (HRE), male participants with LOY exhibited an elevated risk of developing ALS (HR [95% CI]: 1.619 [1.059-2.475], p = 0.026). LOY carrier may be more likely to be associated with a later AAO and shorter survival; however, this association did not reach statistical significance in multivariate models. Additionally, our findings revealed that LOY was significantly associated with elevated plasma NfL levels (p = 0.004). Moreover, the median Log2 R ratios of Y chromosome (mLRRY value) exhibited a modest inverse correlation with plasma GFAP levels (Pearson's r = - 0.059). Nevertheless, LOY did not exert an influence on the longitudinal trends of NfL and GFAP and was not clearly associated with C9orf72 HRE status.

CONCLUSIONS: Our results indicate that LOY makes a potential contribution to the risk of ALS and the elevation of plasma NfL levels. While LOY's impact on ALS AAO and survival requires further validation, these findings identify it as a promising sex‑specific therapeutic target and support its potential for stratifying male ALS patients toward personalized treatments.}, } @article {pmid41437896, year = {2026}, author = {Lona-Durazo, F and Byrne, RP and Pilon, MO and Greicius, MD and Dubé, MP and Belloy, ME and McLaughlin, RL and Gagliano Taliun, SA}, title = {Sex-aware causal inference assessment of the immune system in complex neurodegenerative diseases.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {8}, pages = {2716-2730}, pmid = {41437896}, issn = {1460-2156}, support = {//Alzheimer Society of Canada/ ; AD6192920/CAPMC/CIHR/Canada ; P30 AG066515/AG/NIA NIH HHS/United States ; 21/RC/10294_P2//Research Ireland/ ; McLaughlin/Apr21/879-791//MND association/ ; //FRQS/ ; 189919/CAPMC/CIHR/Canada ; //Fonds de Recherche du Québec/ ; Byrne/Oct22/979-799//MND association/ ; //Canada Research Chairs Program/ ; PJT191687/CAPMC/CIHR/Canada ; PJT183817/CAPMC/CIHR/Canada ; P30AG066515/NH/NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *Neurodegenerative Diseases/immunology/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Sex Characteristics ; Alzheimer Disease/immunology/genetics ; *Parkinson Disease/immunology/genetics ; *Immune System ; Amyotrophic Lateral Sclerosis/immunology/genetics ; Genetic Predisposition to Disease ; }, abstract = {Sex differences, in terms of prevalence, symptoms and disease progression, are established in the aetiology of complex neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease, but the underlying biology driving these differences remains poorly understood. There is emerging evidence from genetic and functional analyses affirming the role of the immune system in such diseases, but a thorough assessment of sex differences in the link between the immune system and neurodegenerative diseases remains lacking. Here, we applied a robust causal inference approach, two-sample Mendelian randomization, to evaluate the causal effect of immune-related protein levels on three neurodegenerative diseases with large-scale sex-stratified genome-wide association data available: amyotrophic lateral sclerosis (females = 10 895 cases, 57 062 controls; males = 15 547 cases, 50 145 controls); Parkinson's disease (females = 7947 cases, 90 662 controls; males = 13 020 cases, 89 660 controls); and Alzheimer's disease (females = 18 822 cases, 281 415 controls; males = 17 293 cases, 213 339 controls). As exposures, we focused on 932 immune system-related proteins with significant protein cis-quantitative trait loci (false discovery rate cut-off < 0.01) from a large sex-combined plasma protein dataset (n = 33 477), for which corresponding genes were included in the Immunology Database and Analysis Portal gene list. We tested for a causal relationship between genetically predicted levels of each of these proteins and each neurodegenerative disease in sex-stratified and sex-combined data, followed by colocalization and estimation of sex-differential effects. We additionally performed exploratory analyses using sex-combined CSF protein cis-quantitative trait loci (n = 971) as exposures. We observed evidence for a sex-differential causal relationship between FCGR2A and Parkinson's disease and between CD2AP, MAMDC2, PCDH17 or CSF3 and Alzheimer's disease. We validated significant results using two independent protein cis-quantitative trait loci datasets for those plasma proteins available. After performing sensitivity analyses, we validated the potential causal relationships of OMG on Parkinson's disease and of GRN, SERPINF2 and TREM2 on Alzheimer's disease. Mendelian randomization with CSF protein cis-quantitative trait loci showed a potential causal effect of ADGRE2, GPNMB and COLEC11 on Parkinson's disease and of CD33 on Alzheimer's disease, without evidence of sex-differential effects. Finally, we substantiated our findings of protein-disease pairs using triangulation, specifically reporting independent supporting evidence from the literature and drug-related databases. Overall, our results point to potential causal effects of genetically predicted levels of immune system-related plasma and CSF proteins in Alzheimer's disease and Parkinson's disease, some of which may be considered as potential candidates for drug development.}, } @article {pmid41437944, year = {2026}, author = {Tannemann, N and Tsarenko, O and Herbstreit, F and Gestmann, M and Brenner, T and Szalai, C}, title = {Enhancing theoretical BLS knowledge with virtual reality: a randomized controlled trial in medical students.}, journal = {Resuscitation plus}, volume = {27}, number = {}, pages = {101169}, pmid = {41437944}, issn = {2666-5204}, abstract = {BACKGROUND: High-quality cardiopulmonary resuscitation (CPR) training, including both technical and non-technical skills, is essential for medical students. Virtual reality (VR) offers immersive learning environments that may enhance traditional teaching methods. This study investigates the impact of a single VR session prior to an Advanced Life Support (ALS) course on knowledge and performance of basic life support skills among medical students.

METHODS: In this single blind randomized controlled trial, 126 fourth-year medical students with prior Basic Life Support (BLS) training were assigned to either an intervention group (n = 66) with an additional 3-part immersive VR session covering BLS theory and practice or a control group (n = 60) receiving standard preparation. All participants underwent a seminar based on advanced life support principles as dictated by the European Resuscitation Council (ERC) and International Liaison Committee on Resuscitation (ILCOR) guidelines. Theoretical knowledge was assessed via multiple-choice questionnaires at three time points (baseline, post-course, 12 weeks later). Practical skills were evaluated through an Objective Structured Clinical Examination (OSCE). Data were analyzed using Wilcoxon tests, repeated-measures ANOVA, and linear mixed models. Student evaluations were used to gauge subjective satisfaction with the scenario during teaching.

RESULTS: No significant differences were observed between groups at baseline. The intervention group demonstrated significantly greater gains in knowledge at both post-course (p < 0.01) and follow-up (p = 0.04). However, no significant differences were found in OSCE performance. The VR group's improvement over time was significantly higher, suggesting a positive effect of VR on knowledge retention. Students were satisfied with the addition of a VR scenario in the teaching format.

CONCLUSION: A single VR session prior to ALS training enhanced theoretical knowledge but did not significantly affect practical performance. Students were open to integration of the technology into training, so that VR may serve as a valuable adjunct in CPR education. Further research is needed to evaluate its long-term impact and the optimal integration method into curricula.}, } @article {pmid41438236, year = {2025}, author = {Li, T and Gao, Y and Zhou, J and Chen, Y and Zhang, S and Gong, X and Liu, Y}, title = {Advancements in the application of brain-computer interfaces based on different paradigms in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1658315}, pmid = {41438236}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurological condition that leads to the gradual loss of movement and communicative abilities, significantly diminishing the quality of life for affected individuals. Recent advancements in neuroscience and engineering have propelled the swift evolution of brain-computer interfaces (BCIs), which are now extensively utilised in medical rehabilitation, military applications, assistive technologies, and various other domains. As a communication medium facilitating direct interaction between the brain and the external world independent of the peripheral nervous system, BCI provides ALS patients with an innovative method for communication and control, offering unparalleled prospects for improving their quality of life. Recent collaborative endeavours among several specialists have markedly enhanced the precision and velocity of diverse BCI paradigms, signifying a breakthrough in BCI applications for ALS. Nonetheless, obstacles and constraints remain. This study methodically extracted pertinent literature from the Web of Science and PubMed databases in accordance with PRISMA guidelines. Following stringent inclusion and exclusion criteria, 23 studies were identified. This data allows us to summarise the application results and current limitations of several BCI paradigms in motor control and communication, while delineating prospects in multimodal fusion and adaptive calibration. This review presents evidence-based references for the effective translation and application of BCI technology in ALS rehabilitation.}, } @article {pmid41438688, year = {2026}, author = {Su, T and Li, Z and Yang, Y and Dai, Y and Li, Y and Zhao, H}, title = {In vitro 3D models of neuron-astrocyte interactions.}, journal = {Biochemistry and biophysics reports}, volume = {45}, number = {}, pages = {102400}, pmid = {41438688}, issn = {2405-5808}, abstract = {The pathological processes of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis) also include relationships between neuron and glia cells. Conventional two-dimensional (2D) cell cultures have limitations to mimic the microenvironment of cells inside living organisms because of flaws in intercellular relationships investigated using 2D cell cultures. Recent advances have introduced three-dimensional (3D) cell cultures that have the capability to create 3D cellular architecture to mimic advanced platforms for scientific inquiries into neurodegenerative diseases, simulating microenvironments inside living organisms.This review provides a brief overview of the development of in vitro 3D cell culture models of astrocytes and attempts to highlight the role of astrocytes in crucial pathophysiologic events occurring in 3D cultures. Studies have shown the use of in vitro 3D cultures to better represent the dual functions of astrocytes in neurodegenerative disorders. Looking ahead to the future, novel advances in microfluidics and multi-omics analysis promise to further improve 3D cultures and push forward new insights into neurological dysfunction to spark innovative advances for treatment strategies.}, } @article {pmid41439884, year = {2025}, author = {Di Gregorio, R}, title = {A Novel Single-Loop Mechanism for Neck Rehabilitation.}, journal = {Biomimetics (Basel, Switzerland)}, volume = {10}, number = {12}, pages = {}, pmid = {41439884}, issn = {2313-7673}, support = {FAR 2023//University of Ferrara/ ; }, abstract = {Trauma, amyotrophic lateral sclerosis (ALS), and head and neck cancer (HNC), which cause neck pain, are only some of the possible issues requiring suitable therapy for alleviating or even healing the neck dysfunctions they cause. Static and dynamic neck braces are commonly employed in therapies for neck recovery and in the necessary measurements to quantify neck impairment or to set up a suitable therapy. Serial and parallel mechanisms, among others, have been proposed for neck braces. Here, a novel single-loop spherical mechanism is proposed for a possible neck brace. Its kinematics and mobility analyses are presented with reference to their specific applications in a neck brace. Then, dimensional synthesis with a set of neck brace's kinematic requirements is addressed to compute the geometric constants that guarantee an orientation workspace similar to that of the human neck. The presented analyses and syntheses show that the new proposal is effective and can alleviate some concerns about already-proposed mechanisms for neck braces.}, } @article {pmid41440030, year = {2025}, author = {Su, J and Alaiz Noya, J and Lingappa, AF and Solas, D and Tong, J and Daughrity, L and Castanedes-Casey, M and Kurti, A and Dickson, DW and Lingappa, VR and Petrucelli, L and Zhang, Y}, title = {Preclinical Evaluation of the Assembly Modulator PAV-615 in a Mouse Model of C9orf72-Associated ALS/FTD.}, journal = {Cells}, volume = {14}, number = {24}, pages = {}, pmid = {41440030}, issn = {2073-4409}, support = {ADSF-24-1284327-C//Alzheimer's Disease Strategic Fund grant/ ; NA//Robert Packard Center for ALS Research at Johns Hopkins/ ; NA//Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program/ ; NA//BrightFocus Foundation/ ; NA//Target ALS Foundation/ ; U19 AG063911/AG/NIA NIH HHS/United States ; NA//Cure Alzheimer's Fund/ ; NA//Kissick Family Foundation/ ; U54NS123743, R35 NS137447, P01NS084974, R01NS132330 and R01NS117461//National Institutes of Health/National Institute of Neurological Disorders and Stroke/ ; P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; NA//Association for Frontotemporal Degeneration Biomarkers Initiative/ ; R01 NS117461/NS/NINDS NIH HHS/United States ; R01 AG089380/AG/NIA NIH HHS/United States ; R01 NS132330/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; 5P30AG0062677, ALLFTD U19AG063911, R01AG089380 and R01AG085307//National Institutes of Health/National Institute on Aging/ ; R01 AG085307/AG/NIA NIH HHS/United States ; R35 NS137447/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism ; Disease Models, Animal ; *Frontotemporal Dementia/drug therapy/genetics/pathology/metabolism ; Mice ; Humans ; Male ; Mice, Transgenic ; Drug Evaluation, Preclinical ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that share clinical and pathological features, as well as genetic causes. A G4C2 repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of ALS and FTD, collectively referred to as c9ALS/FTD. Assembly modulation is a new therapeutic approach which appears to target allosteric sites on aberrant forms of multi-protein complexes and restore them to the healthy state. Recent findings demonstrate that tetrahydroisoquinolone (THIQ)-based protein assembly modulators can ameliorate ALS/FTD-associated phenotypes in cellular and animal models. In the present study, we investigated the effects of PAV-615, a novel and advanced THIQ-based modulator, in a c9ALS/FTD mouse model expressing 149 G4C2 repeat expansions (referred to as 149R mouse model). Specifically, PAV-615 was administered to 5-month-old 149R mice via intraperitoneal injection for one month. Motor function was evaluated using the hang wire test, while anxiety-like behavior and hyperactivity were assessed using the open-field test. Pathological markers, including dipeptide repeat (DPR) proteins, phosphorylated TAR DNA-binding protein 43 (pTDP-43) and ataxin 2-positive stress granules, were quantified by Meso Scale Discovery and immunohistochemistry assays. Compared with vehicle-treated controls, PAV-615 significantly improved motor performance and modestly reduced anxiety-like behavior and hyperactivity in 149R mice. Moreover, PAV-615 treatment significantly decreased cortical DPR, pTDP-43 and ataxin 2-positive stress granule burdens. These results support assembly modulation as a promising therapeutic approach treatment of ALS/FTD.}, } @article {pmid41440090, year = {2025}, author = {Martucci, G and Bonilauri, SC and Canalini, A and Baraldi, M and Costantini, L and Mora, F and Vacondio, P}, title = {Integrating Neurology, Palliative Care and Emergency Services in ALS: A Community-Integrated Neuropalliative Pathway in Modena, Italy.}, journal = {Brain sciences}, volume = {15}, number = {12}, pages = {}, pmid = {41440090}, issn = {2076-3425}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes severe motor, respiratory and communication impairment and imposes a high psychosocial burden on patients and families. Recent evidence shows that integrated neuropalliative care-early collaboration between neurology and palliative services with community support-improves quality of life and reduces avoidable hospitalisations. Yet there are few descriptions of how such integration is operationalised.

OBJECTIVE: This study examines a Community-Integrated Neuropalliative Pathway (CINP) implemented in the province of Modena (Emilia-Romagna, Italy), analysing how neurology, palliative care and emergency services collaborate to provide continuous, person-centred care for people with ALS.

METHODS: A single, holistic case study was conducted following Yin's analytical approach. Data sources included ten semi-structured interviews with neurologists, palliative physicians, nurses, home-care professionals and emergency clinicians; ethnographic observations in the ALS outpatient clinic; relevant organisational documents (the regional Clinical Pathway on ALS); and aggregated quantitative data from the palliative care registry (January 2023-December 2024). Thematic analysis with investigator triangulation was used to explore care integration, advance care planning and emergency coordination. Quantitative data were summarised descriptively.

RESULTS: Three interrelated themes were identified: (1) Progressive and flexible integration between neurology and palliative care. Neurologists remained longitudinal reference points while palliative teams were activated in response to evolving needs and became more relevant with the progression of the disease. Regular multidisciplinary meetings and shared discharge planning facilitated coordination. (2) The shared culture of advance care planning. Professionals framed advance care planning (ACP) as a relational, iterative process anchored in therapeutic relationships. Shared care plans, once completed, triggered an electronic Emergency Warning ("warning 118") procedure that notified the emergency service of patient preferences. (3) The integration of palliative and emergency services. The warning system enabled emergency clinicians to respect care plans and avoid aggressive interventions during crises. Quantitative data on 47 ALS patients followed by territorial palliative services showed that 16 had an active Emergency Warning flag; among these, most died at home or in a hospice rather than in hospital.

CONCLUSIONS: The Modena CINP exemplifies how a public health system can operationalise early neuropalliative integration and connect hospital, community and emergency services. The qualitative findings illustrate the cultural and organisational shifts required for continuous care, while the quantitative data show that the system is correctly used and that patients with the Emergency Warning activation died mostly at home or in a hospice. Lessons from this analytical case study can inform the development of similar pathways in other regions, although further research is needed to assess outcomes in larger populations and such models need to be adapted to local contexts.}, } @article {pmid41441345, year = {2025}, author = {Endo, K and Kubota, K and Karino, K and Sato, R and Miura, S and Ueda, Y and Iwashita, Y}, title = {Setting the Next Vital Sign Observation Interval as a Learning Objective in Simulation-Based Nursing Education: A Prospective Exploratory Observational Study.}, journal = {Nursing reports (Pavia, Italy)}, volume = {15}, number = {12}, pages = {}, pmid = {41441345}, issn = {2039-4403}, abstract = {Background/Objectives: Abnormal vital signs often precede in-hospital clinical deterioration, but little is known about how nurses decide when to recheck vital signs. We examined how nurse characteristics relate to the next vital sign observation interval after detecting abnormal values and how this decision could be used as a learning objective in simulation-based education. Methods: In this prospective exploratory observational study at a university hospital in Japan, twenty-seven nurses used a full-body patient simulator across three scenarios: normal, low-urgency, and moderate-risk (moderately abnormal vital signs according to National Early Warning Score 2 [NEWS2] risk bands). After each assessment, participants specified in hours the interval they considered appropriate for the next vital sign observation. Nurse characteristics included years of clinical experience, advanced life support (ALS) training, and prior experiences recognizing or responding to deterioration. Mann-Whitney U tests and multiple regression were used to explore univariate and adjusted associations. Results: In the low-urgency scenario, ALS training was associated with shorter intervals (median 1 h vs. 3 h; p = 0.04). In the moderate-risk scenario, univariate analyses showed shorter intervals among nurses with greater experience and among those with ALS training (both p < 0.01). In adjusted models for the moderate-risk scenario, years of experience and prior experiences of recognizing and responding to deterioration were independently associated with shorter intervals (all p < 0.05), whereas ALS training was not. Conclusions: The decision to shorten observation intervals appears to reflect experiential aspects of clinical judgment. Integrating "setting the next observation interval" as an explicit learning objective in simulation may help strengthen nurses' clinical judgment for early recognition of deterioration. As an exploratory, single-center study with a small sample and fixed scenario order, these findings should be interpreted cautiously and used to guide larger confirmatory studies and curricular design. This study was not registered.}, } @article {pmid41446138, year = {2025}, author = {Ozguney, B and Puterbaugh, RZ and Viswanathan, R and Shenoy, J and Mohanty, P and Mittal, J and Fawzi, NL}, title = {Site-specific methionine oxidation alters structure and phase separation of TDP-43 C-terminal domain.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41446138}, issn = {2692-8205}, support = {R01 NS116176/NS/NINDS NIH HHS/United States ; }, abstract = {TAR DNA binding protein 43 (TDP-43), a key protein linked to ALS pathology, undergoes phase separation and forms functional assemblies via condensation within cells. The conserved region (CR) within its C-terminal domain (CTD) mediates self-assembly through helix-helix interactions, while the flanking intrinsically disordered regions (IDRs) contribute to phase separation through transient interactions involving aromatic and hydrophobic residues. The CTD contains ten methionine residues distributed equally between these regions, making it particularly susceptible to oxidative modifications. While methionine oxidation is known to impair phase separation, neither the precise mechanism nor the specific contribution of methionines in the CR compared to the IDRs has been determined. Here, we combine NMR spectroscopy and all-atom molecular dynamics (MD) simulations to reveal if and how methionine oxidation in each region differentially affects CTD structure and phase separation. We demonstrate that all methionine residues are vulnerable to oxidation, leading to distinct regional effects: oxidation of CR methionines disrupts helical structure and directly impairs intermolecular helical association, while oxidation of IDR methionines disrupts long-range contacts. Hence, oxidation of methionines in both regions contributes to impaired phase separation, albeit through different mechanisms. These findings establish methionines as critical redox-sensitive modulators of TDP-43 phase behavior and provide molecular insights into how oxidative stress may contribute to TDP-43 dysregulation in neurodegenerative diseases.}, } @article {pmid41449086, year = {2025}, author = {Jankowiak, T and Cholewiński, M and Kryściak, K and Krok, E and Grycz, K and Bączyk, M}, title = {Increase in Ia Afferent Synaptic Excitation of SOD1 G93A Mouse Motoneurons by 2-Week Anodal Trans-Spinal Direct Current Stimulation Does Not Ameliorate the Cellular Burden of the Disease.}, journal = {The European journal of neuroscience}, volume = {62}, number = {12}, pages = {e70375}, pmid = {41449086}, issn = {1460-9568}, support = {2017/26/D/NZ7/00728//National Science Center/ ; 2019/35/B/NZ4/02058//National Science Center/ ; }, mesh = {Animals ; *Motor Neurons/physiology ; Male ; *Amyotrophic Lateral Sclerosis/physiopathology/therapy/genetics/pathology ; Mice ; Mice, Transgenic ; *Superoxide Dismutase/genetics ; *Excitatory Postsynaptic Potentials/physiology ; Superoxide Dismutase-1 ; Receptors, AMPA/metabolism ; *Synapses/physiology ; Spinal Cord/physiopathology ; Electric Stimulation ; }, abstract = {An imbalance between cells' intrinsic excitability and synaptic excitation levels underlies the spinal motoneuron (MN) pathophysiology in Amyotrophic Lateral Sclerosis. Recently, a transient restoration of the deficient Ia synaptic excitation of spinal MNs in the presymptomatic SOD1 G93A mice was achieved by applying a single trans-spinal direct current stimulation (tsDCS) session. Here we investigate whether two-week repeated tsDCS applied to presymptomatic SOD1 G93A animals can permanently alter spinal MN synaptic excitation levels and in this way affect intracellular metabolic pathways and cellular burden of the disease. Anodal, cathodal, or sham polarization of 100 μA was applied to P30-P35 SOD1 G93A male mice, and passive membrane properties and Ia excitatory post-synaptic potential (EPSP) characteristics were investigated by intracellular recordings of spinal MNs in vivo. A second cohort of animals was used to test the impact of our intervention on Ia synapse morphology, intracellular metabolic pathways activity, and disease markers. Anodal tsDCS evoked a strong increase in maximal Ia EPSPs amplitudes, coupled with a significant upregulation of GluR4 subunits of AMPA receptors at the Ia synapse. The cathodal polarization failed to induce any alteration to Ia synapse morphology, but increased the input resistance of MNs. However, changes in MN electrophysiological profile and Ia synapse morphology did not translate into alterations of intracellular molecular pathways activity and did not decrease the cellular burden of the disease. Our results indicate a strong polarity-dependent plasticity of spinal MNs in SOD1 G93A mice in response to tsDCS, which however does not alleviate disease burden.}, } @article {pmid41450148, year = {2026}, author = {Li, A and Cao, SQ and Fang, EF and Su, H}, title = {Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.}, journal = {Autophagy}, volume = {22}, number = {3}, pages = {637-639}, pmid = {41450148}, issn = {1554-8635}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism ; *Mitophagy/drug effects ; Animals ; *Motor Neurons/drug effects/pathology/metabolism ; Humans ; Mitochondria/metabolism/drug effects ; Caenorhabditis elegans ; Mice ; *Nerve Degeneration/pathology/drug therapy ; Protein Kinases/metabolism ; Disease Models, Animal ; }, abstract = {Mitochondrial dysfunction is widely recognized as a key driver of aging and neurodegenerative diseases, with mitophagy acting as an essential cellular mechanism for the selective clearance of damaged mitochondria. While pharmacological activation of mitophagy has been reported to exert beneficial effects across multiple neurodegenerative diseases, its functional relevance in amyotrophic lateral sclerosis (ALS) remains poorly characterized. Our recent study published in EMBO Molecular Medicine demonstrates that PINK1-PRKN-dependent mitophagy is markedly impaired in ALS motor neurons. Through high-content drug screening, we identified a potent mitophagy agonist isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba that stabilizes the PINK1-TOMM complex on the outer mitochondrial membrane, enhances PINK1-PRKN-dependent mitophagy, and ameliorates motor neuron degeneration in ALS-like Caenorhabditis elegans, mouse models, and induced pluripotent stem cell-derived motor neurons. Consequently, ISO is able to alleviate ALS-associated phenotypes. In this commentary, we contextualize these findings broadly to discuss whether pharmacologically induced mitophagy can act as an effective therapeutic strategy, distinct from current clinical approaches, for the development of ALS-targeted treatments.}, } @article {pmid41450325, year = {2026}, author = {Gamez, J and Carmona, F and Syriani, EE and Morales-Fuciños, M and Gamez, A}, title = {Early Dropped Head Syndrome Is More Prevalent in C9orf72 and FUS/TLS ALS.}, journal = {Muscle & nerve}, volume = {73}, number = {4}, pages = {551-558}, doi = {10.1002/mus.70126}, pmid = {41450325}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications/epidemiology ; *C9orf72 Protein/genetics ; Male ; Female ; *RNA-Binding Protein FUS/genetics ; Middle Aged ; Aged ; Adult ; Prevalence ; Cohort Studies ; *Muscle Weakness/genetics/epidemiology ; Dropped Head Syndrome ; }, abstract = {INTRODUCTION/AIMS: Dropped head syndrome (DHS) is common in advanced stages of amyotrophic lateral sclerosis (ALS), but infrequently reported among the early symptoms. We explored the frequency of DHS in a genetic ALS cohort harboring pathogenic variants to determine whether DHS is a prognostic factor for survival, particularly when appearing at an early stage.

METHODS: We collected the following variables to investigate a phenotype/genotype correlation: pathogenic variant (PV), sex, age at clinical ALS onset, time between ALS onset and DHS onset, and between DHS onset and death. DHS appearing within 12 months of clinical onset was classified as early DHS (EDHS); otherwise, as late DHS (LDHS).

RESULTS: We observed DHS in 62 of 93 patients with genetic ALS, with a median of 26.5 months between ALS clinical onset and identification of DHS. DHS was present in 72.1% of the 43 patients with C9orf72 expansions, 52.9% of the 34 with SOD1 , 100% of the 10 with FUS/TLS, and 50% of the 6 with other ALS gene PVs. EDHS appeared in 16 patients. Ten EDHS patients were C9orf72, and six were FUS/TLS . DHS was a significant factor for survival in the age-adjusted Cox regression model. The hazard ratio was 11.63 times higher for patients with DHS, with age as a concomitant variable.

DISCUSSION: Our results suggest that DHS is more prevalent in patients with C9orf72 and FUS/TLS than in those with SOD1 and other ALS-linked genes, and a risk factor for short survival, especially when appearing within 12 months of ALS onset.}, } @article {pmid41453576, year = {2026}, author = {Viteri, JA and Kerr, NR and Brennan, CD and Paradkar, P and Suleiman, LA and Wendt, CD and Xu, C and An, H and Wang, M and Nishimune, H and Santin, JM and Arnold, WD}, title = {Reduced cortico-muscular output is associated with intrinsic hypoexcitability and reduced persistent inward currents in motor cortex neurons of TDP-43[Q331K] ALS mice.}, journal = {Neurobiology of disease}, volume = {218}, number = {}, pages = {107247}, doi = {10.1016/j.nbd.2025.107247}, pmid = {41453576}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics ; *Motor Cortex/physiopathology/metabolism ; Mice ; *DNA-Binding Proteins/genetics ; Mice, Transgenic ; *Motor Neurons/physiology ; Evoked Potentials, Motor/physiology ; Male ; Disease Models, Animal ; *Muscle, Skeletal/physiopathology ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by spinal and cortical motor neuron loss and progressive neuromuscular decline. When ALS pathology involves the primary motor cortex (PMC), cortical excitability is often disrupted, yet how these alterations map onto motor deficits during symptomatic ALS remains unclear. To investigate this, we examined the neuromuscular function, cortico-muscular output, and neuronal excitability of symptomatic 4-month-old TDP-43[Q331K] mice. TDP-43 mice exhibited reduced neuromuscular excitability and impaired strength compared to WT mice. Cranial motor evoked potentials were significantly reduced in TDP-43 mice, indicating decreased cortical output to muscle. Compared to WT mice, whole-cell patch-clamp recordings from TDP-43 PMC layer V pyramidal neurons revealed intrinsic hypoexcitability, diminished persistent inward currents (PICs), and decreased excitatory synaptic activity. Corroborating PIC findings, immunohistochemical analysis showed that PMC layer V neurons exhibited reduced signal intensity of the PIC-associated proteins Nav1.6 and 5-HT2C. Bulk RNA-seq of the cortex showed distinct transcriptional profiles in TDP-43 mice, with enrichment analysis indicating altered pathways relating to ion transport, synaptic signaling, and neuronal excitability. These results suggest that cortex-wide transcriptional changes may reflect broader and additional molecular mechanisms underlying cortical hypoexcitability in ALS. Together, our results demonstrate that symptomatic TDP-43[Q331K] mice exhibit a reduction in cortico-muscular output and PMC neuron excitability, accompanied by reduced PICs and PIC-associated proteins within these neurons. These findings identify cortical hypoexcitability as a defining feature of the TDP-43[Q331k] ALS mouse model and establish multi-level associations between cortical cellular-level dysfunction and impaired motor systems output.}, } @article {pmid41454086, year = {2025}, author = {Mi, X and Shan, K and Ye, X and Cheng, R}, title = {AAD-2004 through clearing H2O2 reduces astrocyte proliferation and promotes neural regeneration after spinal cord injury.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {3371}, pmid = {41454086}, issn = {2045-2322}, support = {ZKKY2023003//Zhejiang Medical Association/ ; 2024KY658//Scientific Research Program of Zhejiang Medical Technology/ ; }, mesh = {*Spinal Cord Injuries/drug therapy/metabolism/pathology/physiopathology ; Animals ; *Hydrogen Peroxide/metabolism ; *Astrocytes/drug effects/metabolism ; *Nerve Regeneration/drug effects ; Cell Proliferation/drug effects ; Mice ; *Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Disease Models, Animal ; Cells, Cultured ; }, abstract = {To assess the effect of AAD-2004 on spinal cord injury (SCI) and to explore its mechanism, we employed an in vitro model using OGD/R-challenged astrocytes to investigate the effects of AAD-2004 against cell death (terminal deoxynucleotidyl transferase dUTP nick-end labeling, tunel), oxidative stress (H2O2 level), and the expression of the key neuroprotective factor MAP2.AAD-2004[2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] is a hydrogen peroxide(H2O2) scavenger primarily used for the treatment of amyotrophic lateral sclerosis and Alzheimer disease that has demonstrated certain neuroprotective properties. In parallel, modified allen's method was adopted, further exploring the potential molecular mechanism in vivo. Based on these conditions, histological and behavioral analysis were performed by Nissl staining, basso mouse scale and footprint analysis. The level of molecules associated with glial scar formation, nerve regeneration, axonal regeneration and H2O2 level were analyzed using western blot, immunofluorescence staining and H2O2 kit. AAD-2004 significantly improved the movement function after SCI and inhibited the proliferation of astrocytes, thus preventing the formation of glial scar by inhibiting of H2O2. At the same time, AAD-2004 promoted nerve regeneration, and the effect was due to neuronal regeneration and axonal regeneration pathways. The expression levels of GFAP and vimentin were significantly downregulated in AAD-2004-treated, and the expression level of Ki67 and PH3 were downregulated. The mean fluorescence intensity of neuronal regeneration (Neun[+]and MAP2[+]) and axonal regeneration-related (NF[+] and GAP43[+]) were significantly upregulated after AAD-2004 treatment. Scavenging H2O2 level is a viable therapeutic strategy, and that AAD-2004 is prospective, and that scavenging H2O2 facilitated nerve regeneration and inhibited glial scar formation for SCI.}, } @article {pmid41454587, year = {2026}, author = {Coulton, JB and He, Y and Budelier, MM and Barthélemy, N and Ireland, MD and Hu, M and Graham, D and Ferguson, T and Berry, JD and Bateman, RJ and Miller, TM and Ly, CV}, title = {Neurofilament Proteoforms in Amyotrophic Lateral Sclerosis Are Different in Cerebrospinal Fluid and Blood.}, journal = {Annals of neurology}, volume = {99}, number = {4}, pages = {857-862}, pmid = {41454587}, issn = {1531-8249}, support = {R01 NS138499/NS/NINDS NIH HHS/United States ; T32 NS121881/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Male ; Biomarkers/blood/cerebrospinal fluid ; Female ; Middle Aged ; Aged ; Protein Isoforms/cerebrospinal fluid/blood ; Adult ; }, abstract = {We used targeted immunopurification-mass spectrometry (IP-MS) to characterize human neurofilament light chain (NfL) proteoforms across various compartments to assess their alterations in amyotrophic lateral sclerosis (ALS). NfL is truncated in cerebrospinal fluid (CSF) and blood in patients with sporadic ALS (sALS) and these proteoforms differ between compartments. Mid-domain species were elevated in CSF whereas plasma NfL proteoforms were mostly comprised of the tail subdomain region. Our results suggest NfL isoforms are proteolyzed and differentially distributed between ALS biofluid compartments and that analyzing by these specific regions or in ratios between regions can provide improvements in biomarker utility. These insights enhance the understanding of NfL and its potential for disease monitoring and therapeutic targeting in ALS. ANN NEUROL 2026;99:857-862.}, } @article {pmid41454699, year = {2026}, author = {Feng, B and Xiang, W and Shan, T and Chen, X and Zheng, S and Shen, S and Wang, C}, title = {Low-Temperature Aluminum-Zinc Hydrogen-Aided Battery.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {65}, number = {7}, pages = {e24485}, doi = {10.1002/anie.202524485}, pmid = {41454699}, issn = {1521-3773}, abstract = {The need for reliable power sources in cold environments drives the development of efficient low-temperature batteries. While zinc-air batteries (ZABs) are promising due to low cost, high safety, and environmental compatibility, their performance at low temperatures is limited by sluggish kinetics. Here, we report an aluminum-zinc hydrogen-aided battery (AZ-HAB) that overcomes this limitation through a synergistic redesign of both electrodes. At the cathode, the kinetically favorable hydrogen oxidation reaction (HOR) replaces the oxygen evolution reaction (OER), reducing the charging potential and enhancing high-rate performance at low temperatures. The anode uses a composite structure (Al@Zn) with Zn pre-deposited on Al, leveraging Al's high activity and low deposition overpotential. This design reduces the full-cell resistance to one-third that of bare Zn, promotes uniform Zn deposition, and lowers polarization by 200 mV at 150 mA cm[-] [2]. The synergistic effect of both electrodes accelerates reaction kinetics, enabling an 11-fold longer cycle life than conventional ZABs at -20 °C. This work presents a viable strategy for high-performance energy storage and electric vehicles in extremely cold environments.}, } @article {pmid41454905, year = {2026}, author = {Gómez-Tortosa, E and Agüero-Rabes, P and Roa-Escobar, J and Sainz, MJ and Viñas, J and Téllez, R and Martínez-Ulloa, P and Pérez-Pérez, J}, title = {MAPT p.V363I mutation in a patient with presenile dementia and late amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {481-484}, doi = {10.1080/21678421.2025.2604238}, pmid = {41454905}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications ; Female ; *tau Proteins/genetics ; *Mutation/genetics ; Middle Aged ; Aged ; }, abstract = {There are limited reports of motor neuron disease associated with MAPT mutations. We present a woman, carrier of the pathogenic MAPT V363I mutation, who developed a presenile dementia and, after 7 years, amyotrophic lateral sclerosis affecting both bulbar and spinal segments. This mutation has been reported in ten previous cases with various cognitive phenotypes and corticobasal syndrome, but not motor neuron disease. We also review the handful of MAPT mutations associated with motor neuron disease.}, } @article {pmid41455134, year = {2026}, author = {Du, O and Wu, YJ and Li, MY and Du, JR}, title = {The role of HMGB1 in central nervous system (CNS) diseases: mechanisms and therapeutic perspectives.}, journal = {Cytokine}, volume = {198}, number = {}, pages = {157099}, doi = {10.1016/j.cyto.2025.157099}, pmid = {41455134}, issn = {1096-0023}, mesh = {Humans ; *HMGB1 Protein/metabolism ; *Central Nervous System Diseases/metabolism/therapy/pathology ; Animals ; Biomarkers/metabolism ; }, abstract = {Central nervous system (CNS) diseases represent a major global health burden and are among the leading causes of disability and mortality worldwide. The pathological mechanisms underlying CNS disorders are complex and multifactorial, involving processes such as neuroinflammation, oxidative stress, neuronal damage, and synaptic dysfunction. High-mobility group box 1 (HMGB1), a member of the high-mobility group box (HMGB) protein family, is predominantly localized in the nucleus under physiological conditions, where it contributes to DNA repair, transcriptional regulation, and other cellular functions. However, in various CNS pathologies-including stroke, traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), glioblastoma (GBM), epilepsy, depression, multiple sclerosis (MS), and schizophrenia-HMGB1 is released or secreted into the extracellular space. There, it plays a key role in regulating neuroinflammation, cell death, cell migration, and tissue damage and repair, thereby contributing to disease pathogenesis and progression. HMGB1 not only functions as a critical regulator in the progression of CNS diseases but also serves as a biomarker for predicting poor clinical outcomes. Moreover, a growing body of evidence indicates that therapeutic strategies targeting HMGB1 can significantly alleviate pathological damage in various CNS disorders, highlighting its potential as a promising therapeutic target. This review comprehensively summarizes the structure, post-translational modifications, release mechanisms, and receptor systems of HMGB1, along with its roles and mechanisms in CNS diseases. It also discusses the potential of HMGB1 as a biomarker and examines emerging HMGB1-targeted therapeutic strategies, aiming to provide a theoretical foundation for the treatment and drug development of CNS disorders.}, } @article {pmid41455589, year = {2026}, author = {Ruiz-Ortiz, M and Esteban-Pérez, J and Gómez-Grande, A and Martínez-Albero, E and Benito-León, J}, title = {Motor band sign in [18]F-FDG PET/CT studies: a biomarker of degenerative upper motor neuron disease? A study of three cases and literature review.}, journal = {Neurologia}, volume = {41}, number = {2}, pages = {501931}, doi = {10.1016/j.nrleng.2025.501931}, pmid = {41455589}, issn = {2173-5808}, mesh = {Humans ; *Positron Emission Tomography Computed Tomography ; Fluorodeoxyglucose F18 ; *Motor Neuron Disease/diagnostic imaging ; Male ; Middle Aged ; Female ; Aged ; Biomarkers ; Amyotrophic Lateral Sclerosis/diagnostic imaging ; Radiopharmaceuticals ; }, abstract = {INTRODUCTION: Motor neuron diseases (MND) encompass conditions like amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), marked by progressive degeneration of upper and/or lower motor neurons. The identification of specific biomarkers is crucial to reduce diagnostic delays.

METHODS: This study presents three clinical cases evaluated at the Hospital Universitario 12 de Octubre, where the motor band sign on brain 18 F-FDG PET/CT aided the diagnosis of MND. The studies were conducted using a SIEMENS Biograph True Point 6, with a review of relevant literature.

RESULTS: In all three patients, PET/CT revealed hypometabolism in the prerolandic region, indicative of the motor band sign, contributing to the diagnosis of PLS or ALS.

DISCUSSION: The motor band sign on 18F-FDG PET/CT emerges as a potential marker of upper motor neuron involvement, though the heterogeneity of MNDs and variability across studies call for further research to establish its specificity and sensitivity.

CONCLUSION: The motor band sign on 18F-FDG PET/CT is a promising biomarker for MNDs, although further studies are required to confirm its diagnostic validity.}, } @article {pmid41456082, year = {2026}, author = {Erro, ME and Zelaya, MV and Eraña, H and de Gordoa, JSR and García-Amigot, F and Simonovska-Serra, A and Caballero, MC and Ferrer, I and Gelpi, E and Jericó, I and Castilla, J}, title = {Variably Protease-Sensitive Prionopathy: Two New Cases With Motor Neuron-Dementia Syndrome.}, journal = {Annals of clinical and translational neurology}, volume = {13}, number = {4}, pages = {827-833}, pmid = {41456082}, issn = {2328-9503}, support = {19-2021//Health Department of Navarre Government/ ; //European Regional Development Fund/ ; //Federal Ministry Labour, Social Affairs, Health, Care and Consumer Protection/ ; PID2021-122201OB-C21//Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación/ ; PID2024-160022OB-I00//Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación/ ; CEX2021-001136-S//Severo Ochoa Excellence accreditation/ ; }, mesh = {Humans ; *Frontotemporal Dementia/pathology/genetics ; Male ; *Prion Diseases/pathology/genetics/complications ; Middle Aged ; Female ; Aged ; *Motor Neuron Disease/pathology/genetics ; Prion Proteins/genetics/metabolism ; Amyotrophic Lateral Sclerosis ; }, abstract = {We describe two patients with variably protease-sensitive prionopathy (VPSPr) who developed progressive upper motor neuron symptoms, insomnia, behavioral and cognitive decline, compatible with primary lateral sclerosis associated with frontotemporal dementia (FTD). Neuropathology revealed a spongiform encephalopathy with frontotemporal and pronounced thalamic involvement, associated with fine synaptic abnormal prion protein conformer (PrP[Sc]) deposits, microplaques, and intraneuronal aggregates. Western blot analysis revealed a characteristic VPSPr proteolytic profile, lacking the diglycosylated band. Both patients were methionine homozygous at PRNP codon 129 and carried no pathogenic mutations. These cases illustrate that VPSPr can present with a prominent motor neuron syndrome and FTD features.}, } @article {pmid41456636, year = {2026}, author = {Kopalli, SR and Vadia, N and Varma, P and Mishra, S and Joshi, N and Bansal, P and Al-Hasnaawei, S and Chauhan, AS and Jain, H and Nathiya, D and Devi, A and Jayasingh Chellammal, HS and Gupta, P and Wal, P and Koppula, S}, title = {Neurodevelopmental origins of neurodegeneration: a lifespan perspective on brain vulnerability.}, journal = {Brain research}, volume = {1873}, number = {}, pages = {150134}, doi = {10.1016/j.brainres.2025.150134}, pmid = {41456636}, issn = {1872-6240}, mesh = {Humans ; *Brain/growth & development ; *Neurodegenerative Diseases/etiology/genetics ; Pregnancy ; Prenatal Exposure Delayed Effects ; Animals ; Female ; *Neurodevelopmental Disorders ; Gastrointestinal Microbiome ; Longevity/physiology ; }, abstract = {Neurodegenerative disorders-including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis-are increasingly understood to have origins in early neurodevelopmental disturbances. This review examines how genetic, epigenetic, and environmental factors impact brain development during critical periods, predisposing individuals to neurodegeneration later in life. Prenatal and early-life exposures such as maternal stress, malnutrition, infection, and environmental toxins can alter key developmental processes, leading to long-term vulnerability. Mechanistic pathways linking early-life disruptions to neurodegenerative outcomes include persistent mitochondrial dysfunction, chronic neuroinflammation, increased oxidative stress, and aberrant synaptic pruning, all of which contribute to progressive neuronal damage and dysfunction. The gut-brain axis is also discussed as a key intermediary, where early microbiota dysbiosis alters neuroimmune signaling and inflammatory responses, modulating susceptibility to age-related neurological disorders. In this context, the review highlights emerging molecular and imaging biomarkers capable of detecting subtle neurodevelopmental deviations that may precede clinical symptoms by decades. The paper emphasizes the need for early-life interventions, including maternal nutritional optimization, management of prenatal stress, and microbiome-targeted strategies, as potential tools to reduce long-term neurological risk. Furthermore, it proposes the integration of precision medicine approaches aimed at individualized risk assessment and therapeutic targeting of developmental pathways. Adopting a lifespan perspective, this review argues for a paradigm shift from reactive to preventive strategies in neurology. Understanding the developmental roots of neurodegeneration opens new avenues for research and intervention, enabling resilience and reducing disease burden through early diagnostics and tailored therapeutics across the lifespan.}, } @article {pmid41458376, year = {2025}, author = {Qian, G and Ding, L and Tan, C and Wang, L and Long, C}, title = {Mucosal immune response modulated by secreted and membrane-bound hydrolases of Candida albicans in vulvovaginal candidiasis.}, journal = {Frontiers in fungal biology}, volume = {6}, number = {}, pages = {1692795}, pmid = {41458376}, issn = {2673-6128}, abstract = {Vulvovaginal candidiasis (VVC) affects the physical and mental health of millions of women worldwide. The leading cause of VVC, Candida albicans, can induce a strong mucosal inflammatory reaction during the VVC infection, where secreted and membrane-bound adhesion and hydrolases seem to be the key virulent factors to promote the mucosal antifungal immunity and immunopathology. Several hydrolases, such as Saps, Als, candidalysin, lipases, and phospholipases, have been identified in vaginal secretions isolated from VVC patients; however, the immune impacts of some hydrolases have not been well documented. In this review, we focus on the literature that addresses the immunopathogenic roles of the Als adhesin family or proteinase, such as Sap and candidalysin, in VVC. Our goal is to expand our knowledge of VVC pathogenesis in order to provide new strategies for VVC treatment.}, } @article {pmid41459056, year = {2025}, author = {Auclair-Ouellet, N and Kassem, O and Bronner, S and Oula, ML and Binda, S}, title = {Leveraging microbiome-based interventions to improve the management of neurodegenerative diseases: evidence for effects along the microbiota-gut-brain axis.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1699884}, pmid = {41459056}, issn = {2296-861X}, abstract = {The microbiota-gut-brain axis (MGBA) has recently emerged as a useful model for the understanding of the onset and progression of neurodegenerative diseases (NDDs). Microbiome-based interventions using biotic supplements (probiotics, prebiotics, synbiotics, postbiotics) can modulate the MGBA and constitute relevant solutions to help reduce the risk of neurological changes associated with NDDs and manage symptoms. This narrative review provides a summary of the functioning of the MGBA and of its interactions with disease processes involved in the onset and progression of NDDs. Microbiome-based interventions and their mechanisms of action are reviewed, and important considerations for the design of interventions are discussed. Next, preclinical and clinical studies on the potential of microbiome-based interventions in Alzheimer's disease (AD), Parkinson's disease (PD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) are reviewed. Evidence related to biomarkers of pathology (e.g., beta-amyloid or alpha-synuclein protein depositions), neuroinflammation, and metabolic activity is summarized, along with emerging evidence for the improvement of clinical symptoms and disease trajectories. Overall, preclinical studies show that microbiome-based supplements have significant positive effects on mechanisms and pathways involved in the pathophysiology of NDDs. Clinical studies show that these interventions provide important benefits both in terms of biomarkers and clinical symptoms. However, evidence is limited in some key clinical areas, such as mental wellbeing in AD and cognition in PD, and for the management of clinical symptoms in ALS and HD overall. Gaps in knowledge and open questions as well as perspectives for future research are discussed.}, } @article {pmid41460923, year = {2025}, author = {Korada, S and Tam, OH and Greco, HC and Hammell, MG and Dubnau, J and Sher, RB}, title = {LINE-1 retrotransposition in a mouse TDP-43 model of neurodegeneration marks motor cortex neurons for cell-intrinsic and cell non-autonomous programmed cell death.}, journal = {PLoS genetics}, volume = {21}, number = {12}, pages = {e1012007}, pmid = {41460923}, issn = {1553-7404}, support = {R01 AG076493/AG/NIA NIH HHS/United States ; R01 AG078788/AG/NIA NIH HHS/United States ; R01 AG079898/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *DNA-Binding Proteins/genetics/metabolism ; *Long Interspersed Nucleotide Elements/genetics ; *Motor Cortex/pathology/metabolism ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Dementia/genetics/pathology ; Humans ; Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Retroelements/genetics ; Endogenous Retroviruses/genetics ; Mice, Transgenic ; Neuroglia/metabolism/pathology ; }, abstract = {A key pathological feature of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) is the loss of nuclear localization and accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43). TDP-43 is a nucleic acid-binding protein involved in transcriptional repression, mRNA splicing, and the regulation of retrotransposable elements (RTEs) and endogenous retroviruses (ERVs). RTEs/ERVs are mobile virus-like genetic elements that constitute about 45% of our genome and encode the capacity to replicate through an RNA intermediate and insert cDNA copies at de novo chromosomal locations. A causal role of RTEs/ERVs has been demonstrated in Drosophila in mediating both intracellular toxicity of TDP-43 and the intercellular spread of toxicity from glia to neurons. RTEs/ERVs are inappropriately expressed in postmortem tissues from ALS, FTD, and Alzheimer's Disease (AD) patients, but the role of RTEs/ERVs has not yet been examined in a vertebrate model of TDP-43 pathology. We utilized established transgenic mouse models that overexpress moderate levels of human wild-type TDP-43 or a mutant version with a specific ALS-causal Q331K amino acid substitution, together with a LINE-1-EGFP retrotransposon indicator line. We found that TDP-43 animals exhibit broad expression of RTEs/ERVs with LINE-1 retrotransposition in glia and neurons in the motor cortex. Expression begins with onset of neurological phenotypes, earlier in hTDP-43-Q331K animals and later in hTDP-43-WT. The LINE-1-EGFP retrotransposition reporter transiently labels spatially clustered groups of neurons and glia at the time of onset of motor symptoms, while EGFP-labeled neurons undergo cell death and are therefore lost over time. Unlabeled cells also die as a function of distance from the clusters of LINE-1-EGFP labeled neurons and glial cells. Together, these findings support the hypothesis that TDP-43 pathology triggers RTE/ERV expression in the motor cortex, that such expression marks cells for programmed cell death, with cell non-autonomous effects on nearby neurons and glial cells.}, } @article {pmid41461417, year = {2026}, author = {Palma-Bautista, C and Rojano-Delgado, AM and Rey, MD and Gherekhloo, J and Domínguez-Valenzuela, JA and Jorrín-Novo, JV and Plaza, G and Osuna, MD and De Prado, R}, title = {Understanding cross- and multiple-herbicide resistance in Setaria adhaerens from olive orchards with two decades of multiple herbicides use.}, journal = {Pesticide biochemistry and physiology}, volume = {217}, number = {}, pages = {106883}, doi = {10.1016/j.pestbp.2025.106883}, pmid = {41461417}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology ; *Herbicide Resistance ; *Olea ; Glutathione Transferase/metabolism ; Glycine/analogs & derivatives/pharmacology ; Cytochrome P-450 Enzyme System/metabolism ; }, abstract = {Two populations of Setaria adhaerens (resistant [R] and susceptible [S]) have been identified in Spanish olive orchards. The R population shows multiple resistance to chlorotoluron (PSII inhibitor), diclofop-methyl (ACCase inhibitor), tribenuron-methyl (ALS inhibitor), glyphosate (EPSPS inhibitor), and oxyfluorfen (PPO inhibitor), along with potential natural tolerance to diflufenican (PDS inhibitor). This study evaluated herbicide efficacy at field rates, enzyme activity (ALS, ACCase, EPSPS, PPO, PSII), and the role of cytochrome P450 and glutathione-S-transferases using malathion and NBD-Cl, respectively. The S population was fully controlled by all herbicides except diflufenican, which showed only ∼45 % control in both populations, indicating possible innate tolerance. In the R population, chlorotoluron, diclofop-methyl, tribenuron-methyl, and glyphosate had no effect on enzyme activity, suggesting non-target site resistance (NTSR). In contrast, oxyfluorfen inhibited PPO activity only in the S population, indicating target-site resistance (TSR). NBD-Cl showed no activity, ruling out glutathione-S-transferases-mediated metabolism. However, malathion restored over 50 % sensitivity to chlorotoluron, diclofop-methyl, and tribenuron-methyl in the R population, suggesting enhanced metabolism likely mediated by cytochrome P450 monooxygenases. Metabolic profiling further confirmed enhanced herbicide detoxification in the R population as a key resistance mechanism. These findings highlight the complexity of resistance in S. adhaerens and underline the urgent need to incorporate metabolic resistance monitoring into weed management programs. Future studies will focus on unraveling the molecular basis of these resistance mechanisms.}, } @article {pmid41461594, year = {2026}, author = {Lee, WT and Varghese, P and Gaunt, A}, title = {Post-Operative C-Reactive Protein as a Predictor of Anastomotic Leak Following Robotic Colorectal Surgery.}, journal = {World journal of surgery}, volume = {50}, number = {2}, pages = {424-431}, doi = {10.1002/wjs.70217}, pmid = {41461594}, issn = {1432-2323}, mesh = {Humans ; Male ; *C-Reactive Protein/analysis/metabolism ; *Anastomotic Leak/diagnosis/blood/etiology ; Female ; Aged ; Retrospective Studies ; Middle Aged ; *Robotic Surgical Procedures/adverse effects ; Predictive Value of Tests ; Biomarkers/blood ; *Colectomy/methods/adverse effects ; Postoperative Period ; Anastomosis, Surgical ; Colorectal Neoplasms/surgery ; }, abstract = {AIM: Postoperative C-reactive protein (CRP) levels are good predictors of anastomotic leak (AL) following colorectal surgery, with postoperative day-3 CRP thresholds ranging between 162 and 195 mg/L in open and laparoscopic resections. This study aims to determine a cut-off CRP value that predicts ALs following robotic colorectal surgery and identifies patients suitable for safe early discharge.

METHODS: A single-center retrospective analysis of patients who underwent an elective robotic colorectal resection, with primary anastomosis, between February 2017 and December 2024, was conducted. Primary outcome measure was clinically and radiologically confirmed AL (graded). Data were analyzed using IBM SPSS v30.0.0.

RESULTS: Seven hundred eighty-four elective robotic colorectal resections with anastomosis were performed. Median age was 69 years (IQR 60-77), 448 male, 336 female, and BMI 27.5 (IQR 24.4-31.1), indication for surgery was cancer in 681 (86.9%) patients. 51 (6.5%) patients had an AL, of which 12/51 (23.5%) had a grade ≥ 3 leak. A POD-3 CRP level of 136.0 mg/L (73% sensitivity, 79% specificity, and AUC 0.788) and POD-4 CRP level of 94.4 mg/L (84% sensitivity, 62% specificity, and AUC 0.806) were predictive of AL. At POD-5, a cut-off CRP of 243 mg/L (88% sensitivity, 73% specificity, and AUC 0.818) was predictive of ALs requiring re-operation and/or escalation to level 2-3 care. Male sex, colo-rectal anastomoses, and resections performed before 2020 were associated with higher AL rates.

CONCLUSION: Postoperative CRP levels have high predictive value in early detection and exclusion of AL, facilitating early patient discharge under the enhanced recovery after surgery (ERAS) pathways. CRP thresholds in robotic colorectal resections are lower than previously reported thresholds in open and laparoscopic surgery.}, } @article {pmid41462890, year = {2025}, author = {Fajkić, A and Belančić, A and Lam, YW and Rački, V and Pilipović, K and Janković, T and Mežnarić, S and Mršić-Pelčić, J and Vitezić, D}, title = {Novel Translational Concept: Axon-to-Muscle Exosomal Signaling as an Emerging Therapeutic Target in Spinal Muscular Atrophy.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41462890}, issn = {2227-9059}, abstract = {Spinal muscular atrophy (SMA) has transitioned from a uniformly fatal disease to a treatable condition, yet incomplete neuromuscular recovery underscores the limits of current SMN-restorative therapies. Emerging data implicate disrupted axon-to-muscle exosomal signaling as an important, overlooked driver of residual dysfunction. Exosomes, nanovesicles mediating bidirectional neuronal-muscular communication, carry synaptic organizers, trophic factors, and microRNAs essential for neuromuscular junction integrity. SMN deficiency alters exosomal biogenesis and cargo, leading to loss of agrin-MuSK signaling, impaired β-actin transport, and muscle atrophy. Comparative insights from amyotrophic lateral sclerosis and muscular dystrophy reveal that stem-cell-derived or engineered exosomes restore synaptic stability, enhance regeneration, and cross biological barriers safely. Thus, we speculate herein on a translational model integrating exosome-based therapies with existing genetic interventions to achieve durable, systems-level recovery in SMA. Exosomal profiling may further yield minimally invasive biomarkers for disease monitoring and treatment optimization, establishing vesicle-mediated communication as a novel therapeutic axis in neuromuscular medicine.}, } @article {pmid41462986, year = {2025}, author = {Vauti, F and Eilers, L and Kroll, A and Köster, RW}, title = {Genomic Organization, Evolutionary Conservation and Expression of Ataxin-2 and Ataxin-2-like Genes Underscore the Suitability of Zebrafish as a Model Organism for SCA2 and Related Diseases.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41462986}, issn = {2227-9059}, support = {11-76251- 2714/2024 (ZN4545)//This project was supported by the BrightBrain initiative, which is funded by zu-kunft.niedersachsen, the joint science funding program of the Lower Saxony Ministry of Science and Culture and the Volkswagen Foundation/ ; }, abstract = {Background/Objectives: The Ataxin-2 protein (ATXN2) plays an essential role in RNA metabolism and many cellular processes. Dysregulation or mutation of the Ataxin-2 gene (ATXN2) can lead to neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). Despite numerous efforts in this field in other animal models, little is known about Atxn2 in zebrafish. In this study, we aim to investigate the potential suitability of zebrafish as a model for Atxn2-related diseases by performing basic analyses on Atxn2. Methods: We performed a bioinformatic protein analysis of Atxn2 from zebrafish and its paralog Atxn2l in relation to human and other vertebrate homologues. Based on a structural analysis of the atxn2 and atxn2l genes, the expression of the predicted transcripts was detected by RT-PCR and the spatiotemporal expression pattern was determined by whole-mount in situ hybridization. Results: We found similarities between the protein sequences of Atxn2 and Atxn2l in zebrafish and their functional domains with those of orthologs in humans and other vertebrates. The predicted transcripts of atxn2 and atxn2l were experimentally verified and their spatiotemporal expression patterns were determined during zebrafish development. Splicing variants were detected for both genes, suggesting a different role for the isoforms in different tissues. Conclusions: These findings provide new insights into the atxn2 and atxn2l genes, suggesting the zebrafish as a suitable animal model for functional studies and research on disease modeling of SCA2 and ALS.}, } @article {pmid41463070, year = {2025}, author = {Goyal, NA and Andrews, JA and Oskarsson, BE and Wiedau, MH and Kasarskis, EJ and Forrest, BD and Zhang, R and Bracci, PM and Davis, MW and Azhir, A and McGrath, MS}, title = {Quantitative Measures of Time to Loss of 15% Vital Capacity and Survival Extension in Slowly Progressive Amyotrophic Lateral Sclerosis (ALS) Patients Treated with the Immune Regulator NP001 Suggests an Immunopathogenic Subset of ALS.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41463070}, issn = {2227-9059}, support = {Neuvivo - NP001//Ari Azhir/ ; }, abstract = {Background/Objectives: Overall survival in patients with amyotrophic lateral sclerosis (ALS) is linked to the rate of predicted respiratory vital capacity (PVC) loss. The objective of this study was to test whether changes in quantitative PVC measures over time linked to survival would define an immunopathogenic subset of ALS responsive to NP001, a regulator of innate immunity. Methods: In a retrospective study, data from intent-to-treat (ITT) population of two phase 2 trials of NP001 were evaluated for over time changes in PVC, time-to-event (TTE) loss of 15% PVC and PVC change from baseline, as linked to survival outcomes in patients treated with NP001 vs placebo. Results: Treatment with NP001 was associated with a significantly lower risk compared to placebo in the loss of 15% PVC over six months (p = 0.01; HR = 0.60, 95% CI: 0.39, 0.90). Data from the two trials were subsequently divided by a disease progression rate (DPR) value of 0.50 units of ALSFRS-R score lost per month for analysis of slow vs. rapid disease. In ALS patients with slowly progressive disease (DPR < 0.50), TTE PVC changes from baseline were slowed (p < 0.0005) and overall survival extended significantly (18.5 months) in NP001-treated vs. placebo groups. The rapidly progressive ALS patients (DPR ≥ 0.50) treated with NP001 showed no significant difference in PVC change or survival from the placebo group. Conclusions: These hypothesis-generating observations suggest that inflammation might play a significant role in the loss of respiratory function in a major subset of ALS patients.}, } @article {pmid41463293, year = {2025}, author = {Xie, V and Franco, MC and Martin, LJ}, title = {Human Mutant Dynactin Subunit 1 Causes Profound Motor Neuron Disease Consistent with Possible Mechanisms Involving Axonopathy, Mitochondriopathy, Protein Nitration, and T-Cell-Mediated Cytolysis.}, journal = {Biomolecules}, volume = {15}, number = {12}, pages = {}, pmid = {41463293}, issn = {2218-273X}, support = {R01 NS102479/NS/NINDS NIH HHS/United States ; 1R01NS107417-04A1/NH/NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Anterior Horn Cells/metabolism/pathology ; *Axons/pathology ; *Dynactin Complex/genetics ; Mice, Transgenic ; *Mitochondrial Diseases/genetics ; *Motor Neuron Disease/genetics ; *Motor Neurons/metabolism/pathology ; Mutation ; *Protein Processing, Post-Translational/genetics ; Quinazolinones/pharmacology ; Spinal Cord Diseases ; T-Lymphocytes/immunology ; *Tyrosine/metabolism/analogs & derivatives ; Mitochondrial Dynamics/drug effects ; Male ; Female ; }, abstract = {Mutations in the gene encoding the p150 subunit of the dynactin complex (DCTN1) are linked to amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Perry syndrome. These neurodegenerative diseases can cause muscle weakness and atrophy, parkinsonian-like symptoms, and paralysis. To examine the evolution of neuropathology caused by a mutation in DCTN1 and cellular mechanisms of disease for therapeutic discovery, we characterized mice expressing either human wildtype or mutant (G59S) DCTN1. Neuron-specific expression of mutant, but not wildtype, DCTN1 caused fatal age-related paralytic disease and motor neuron (MN) degeneration in the spinal cord with axonopathy and chromatolysis without apoptotic morphology. MNs became positive for cleaved caspase-3, cleaved caspase-8, and nitrated Hsp90. Mitochondria accumulated and appeared fragmented and dysmorphic and then were lost. This pathology was accompanied by invasion of CD95- and CD8-positive mononuclear T cells into the ventral horn and accumulation of TNFα and IL9. Administration of the mitochondrial division inhibitor-1 (Mdivi-1) protected MNs and extended the lifespan of G59S-DCTN1 mice. A mitochondrial permeability transition pore inhibitor also extended lifespan. Thus, mutant DCTN1 causes degeneration of MNs associated with axonopathy, mitochondriopathy, nitrative stress, and caspase activation. It appears as retrograde neurodegeneration and inflammatory T-cell-like cytolysis. Mitochondria are possible therapeutic targets in DCTN1-linked neurodegenerative disorders.}, } @article {pmid41463333, year = {2025}, author = {Tendero-Lopez, D and Dominguez, M and Aguilar-Aragon, M}, title = {Modelling Neural Disorders with the D. melanogaster Larval Peripheral and Adult Dopaminergic Systems.}, journal = {Biomolecules}, volume = {15}, number = {12}, pages = {}, pmid = {41463333}, issn = {2218-273X}, mesh = {Animals ; *Drosophila melanogaster/metabolism ; Larva/metabolism ; *Disease Models, Animal ; Humans ; *Dopamine/metabolism ; *Dopaminergic Neurons/metabolism/pathology ; *Nervous System Diseases/metabolism ; Parkinson Disease/metabolism ; }, abstract = {The increasing prevalence of neurological disorders highlights the need for disease animal models to elucidate the underlying biomolecular and cellular mechanisms of disease and to facilitate studies aimed at developing effective treatments. The fruit fly Drosophila melanogaster, at both larval and adult stages, can serve as an effective model for different human-relevant neurological diseases. Larvae are particularly suited for studying peripheral nervous system disorders, such as Charcot-Marie-Tooth and amyotrophic lateral sclerosis, while adults enable investigations of higher-order cognitive functions and age-related conditions, including Parkinson's disease and depression-like behaviours. Combining larval and adult models offers a complementary framework to dissect the biomolecular pathways of neurological disorders and accelerate preclinical research.}, } @article {pmid41464612, year = {2025}, author = {Klumb, S and Haley, L and Hathaway, C and Irby, J and Cheng, J and Rumley, J}, title = {Degenerative Cervical Myelopathy Diagnosis and Its Differentiation from Neurological Mimics, MS and ALS: A Literature Review.}, journal = {Journal of clinical medicine}, volume = {14}, number = {24}, pages = {}, pmid = {41464612}, issn = {2077-0383}, abstract = {Multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and degenerative cervical myelopathy (DCM) share features that may confound diagnosis. DCM is caused by degenerative changes in the cervical spine leading to spinal cord compression and injury, resulting in significant disability. Misdiagnosis of DCM for a similar neurological condition can lead to further spinal cord damage from delayed surgical treatment. Here we review the diagnostic criteria, clinical signs and symptoms, and imaging typical for DCM, and two of its clinical mimics, MS and ALS. Shared motor symptoms of all three conditions can make diagnosis difficult, especially early in disease course. Noteworthy differences include neck and shoulder pain in DCM, visual disturbances in MS, and bulbar symptoms and the absence of sensory deficits in ALS. In DCM and MS, MRI is used to support the diagnosis, with specific findings on MRI that differentiate DCM versus MS. In ALS, MRI is used to rule out differential diagnoses. Applying the diagnostic criteria for MS and ALS, as well as understanding the typical presentation and MRI findings of DCM, is crucial. Through discussion of these conditions, this review aims to help limit misdiagnosis rates, allowing for early management, which can improve long-term patient outcomes.}, } @article {pmid41464650, year = {2025}, author = {Sonaglioni, A and Nicolosi, GL and Lombardo, M and Baravelli, M and Muti, P}, title = {Comparative Meta-Analysis of Left Ventricular Mechanics in Takotsubo Syndrome and Anterior STEMI Due to Left Anterior Descending Artery Occlusion.}, journal = {Journal of clinical medicine}, volume = {14}, number = {24}, pages = {}, pmid = {41464650}, issn = {2077-0383}, support = {N/A//Ministero della Salute/ ; }, abstract = {Background: Takotsubo syndrome (TTS) often mimics anterior ST-elevation myocardial infarction (STEMI) caused by left anterior descending (LAD) occlusion, yet the two entities differ fundamentally in pathophysiology and mechanical behavior. Two-dimensional speckle-tracking echocardiography (2D-STE) enables detailed assessment of left ventricular (LV) deformation beyond conventional ejection fraction (LVEF). This meta-analysis compared global and regional LV strain patterns in TTS versus LAD-related anterior STEMI during the acute phase. Methods: A systematic search of PubMed, Embase, and Scopus through October 2025 identified observational case-control studies directly comparing TTS and angiographically confirmed anterior STEMI, with LV mechanics assessed by 2D-STE. Random-effects models were used to pool standardized mean differences (SMDs) for LVEF; global longitudinal strain (GLS); apical, mid-ventricular, and basal longitudinal strain (ALS, MLS, BLS); and global radial strain (GRS). Heterogeneity (I[2]), publication bias (funnel plots, Egger's test), meta-regression, and leave-one-out sensitivity analyses were performed. Results: Six studies comprising 221 TTS and 290 anterior STEMI patients met the inclusion criteria. TTS patients were older, predominantly female, and had fewer metabolic risk factors, while LV size was comparable. LVEF was significantly lower in TTS (SMD -1.149; 95% CI -2.20 to -0.10; p = 0.032), with stable findings across sensitivity analyses and no evidence of publication bias. GLS, ALS, MLS, and BLS showed only a non-significant trend toward greater impairment in TTS, and these comparisons were limited by marked inter-study heterogeneity. In contrast, GRS was significantly and consistently more reduced in TTS (SMD -1.284; 95% CI -1.59 to -0.98; p < 0.001), indicating more profound global radial dysfunction. Meta-regression showed no significant influence of demographic factors or vendor-specific software on LVEF or GLS differences. Conclusions: Compared with LAD-related anterior STEMI, TTS is associated with more severely depressed LVEF and markedly impaired radial strain, while longitudinal strain differences remain inconclusive and suggest only a potential trend toward greater dysfunction, reflecting the limited and heterogeneous evidence. These findings are consistent with diffuse, stress-induced myocardial stunning in TTS and suggest that 2D-STE may aid differentiation between stress cardiomyopathy and ischemic infarction in the acute setting, although longitudinal strain parameters should be interpreted cautiously and regarded as hypothesis-generating.}, } @article {pmid41465278, year = {2025}, author = {Marzetti, E and Di Lorenzo, R and Calvani, R and Coelho-Júnior, HJ and Landi, F and Pesce, V and Picca, A}, title = {Linking Cell Architecture to Mitochondrial Signaling in Neurodegeneration: The Role of Intermediate Filaments.}, journal = {International journal of molecular sciences}, volume = {26}, number = {24}, pages = {}, pmid = {41465278}, issn = {1422-0067}, support = {D1.2024//Università Cattolica del Sacro Cuore/ ; D1.2025//Università Cattolica del Sacro Cuore/ ; Ricerca Corrente 2025//Italian Ministry of Health/ ; DM 1557 11.10.2022//European Commission/ ; 2022YNENP3//Italian Ministry of University and Research/ ; }, mesh = {Humans ; *Mitochondria/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Intermediate Filaments/metabolism/pathology ; *Signal Transduction ; Neurons/metabolism/pathology ; }, abstract = {Mitochondrial dysfunction is a pivotal contributor to neurodegeneration. Neurons heavily rely on mitochondrial oxidative metabolism and therefore need highly efficient quality control mechanisms, including proteostasis, mitochondrial biogenesis, fusion-fission dynamics, and mitophagy, to sustain bioenergetics and synaptic function. With aging, deterioration of mitochondrial quality control pathways leads to impaired oxidative phosphorylation, excessive reactive oxygen species generation, calcium imbalance, and defective clearance of damaged organelles, ultimately compromising neuronal viability. Pathological protein aggregates, such as α-synuclein in Parkinson's disease, β-amyloid and tau in Alzheimer's disease, and misfolded superoxide dismutase 1 and transactive response DNA-binding protein 43 in amyotrophic lateral sclerosis, further aggravate mitochondrial stress, establishing self-perpetuating cycles of neurotoxicity. Such mitochondrial defects underscore mitochondria as a convergent pathogenic hub and a promising therapeutic target for neuroprotection. Intermediate filaments (IFs), traditionally viewed as passive structural elements, have recently gained attention for their roles in cytoplasmic organization, mitochondrial positioning, and energy regulation. Emerging evidence indicates that IF-mitochondria interactions critically influence organelle morphology and function in neurons. This review highlights the multifaceted involvement of mitochondrial dysfunction and IF dynamics in neurodegeneration, emphasizing their potential as targets for novel therapeutic strategies.}, } @article {pmid41465496, year = {2025}, author = {López-Royo, T and Gascón, E and Moreno-Martínez, L and Macías-Redondo, S and Zaragoza, P and Manzano, R and Osta, R}, title = {Region-Specific Expression Patterns of lncRNAs in the Central Nervous System: Cross-Species Comparison and Functional Insights.}, journal = {International journal of molecular sciences}, volume = {26}, number = {24}, pages = {}, pmid = {41465496}, issn = {1422-0067}, support = {PI21/00372//Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER) "Una manera de hacer Europa" from the European Union/ ; CB18/05/0037//CIBERNED/ ; A19_23R//Consolidated Groups from Gobierno de Aragón/ ; PRTR-C17.I1//The Spanish Ministry of Science and Innovation with funds from the European Union NextGenerationEU, from the Recovery, Transformation and Resilience Plan/ ; FPU19/05625//Ministerio de Universidades from Gobierno de España/ ; PT20/00109//Instituto de Salud Carlos III/ ; }, mesh = {*RNA, Long Noncoding/genetics/metabolism ; Animals ; Humans ; Male ; Female ; Mice ; *Central Nervous System/metabolism ; Spinal Cord/metabolism ; Species Specificity ; Brain/metabolism ; Gene Expression Profiling ; Organ Specificity ; }, abstract = {Increasing evidence demonstrates that long noncoding RNAs (lncRNAs) are crucial for brain evolution and proper development and function of the central nervous system (CNS), exhibiting specific time-, spatial-, and sex-biassed expression patterns. This study investigated whether region-specific spatial expression patterns of brain-relevant lncRNAs are conserved between the mouse and human CNS. Demonstrating such cross-species conservation informs the translational value of mouse models for lncRNA biology. To test this, the expression of 14 lncRNAs was studied in the adult CNS of mice and humans across three different regions (spinal cord, brainstem, and frontal cortex), and age effects were assessed in mice. The results demonstrated conserved expression patterns between the two species, with region-specific changes. The frontal cortex exhibited high expression of Meg3, Miat, and Pvt1 lncRNAs, while the spinal cord showed high levels of Hotair and Gas5. Additionally, Malat1 displayed lower levels in females compared to males in the spinal cord compared to other regions. Finally, through GO functional enrichment analysis and literature review, this study emphasizes the role of lncRNAs in CNS physiology and disease, suggesting their involvement in neurological processes and conditions such as cortical development, neuronal synapsis, schizophrenia, Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Overall, this research highlights the importance of further investigating the role of lncRNAs in brain function and their potential as key players in neurological disorders, opening the door to explaining the high region- and sex-specific effects of these disorders.}, } @article {pmid41465514, year = {2025}, author = {Riku, Y and Brion, JP and Ando, K and Uchihara, T and Iwasaki, Y}, title = {The Determinant of Tau Spreading in Alzheimer's Disease: Dependent on Senile Plaque, Neural Circuits, or Spatial Proximity?.}, journal = {International journal of molecular sciences}, volume = {26}, number = {24}, pages = {}, pmid = {41465514}, issn = {1422-0067}, support = {JPMH23FC1008//MHLW Research on rare and intractable diseases Program/ ; 23K06935, 25K22597, and 25K10781//JSPS-KAKENHI/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *tau Proteins/metabolism ; *Plaque, Amyloid/metabolism/pathology ; Animals ; Neurofibrillary Tangles/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Brain/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is neuropathologically characterized by tau-immunopositive neurofibrillary tangles (NFTs) and amyloid-β (Aβ)-immunopositive senile plaques. According to the widely accepted amyloid cascade hypothesis, Aβ pathology represents the upstream event in AD pathophysiology and induces tau aggregation. However, numerous studies have suggested that tau aggregates correlate more closely with neuronal loss and regional brain atrophy than with Aβ depositions. Tau aggregation in AD demonstrates a hierarchical spreading pattern beginning in the transentorhinal cortex, but the mechanisms underlying this spreading manner of lesions remain to be elucidated. This review aims to address current controversies regarding tau pathology in AD from the perspectives of both the 'amyloid cascade' and 'tauopathy' hypotheses. From the 'amyloid cascade' viewpoint, Aβ deposition prominently involves distal axon and axon terminals, and in some regions, there are anatomical correspondences between axonal Aβ pathology and cytoplasmic tau aggregations (e.g., a close relationship between senile plaques in the molecular layer of the hippocampal dentate gyrus and NFTs in the transentorhinal cortex). Nevertheless, this model cannot explain the whole body of hierarchical spreading of tau aggregation because notable spaciotemporal discrepancies also exist in many regions. From the 'tauopathy' perspective, the distribution of tau aggregates in AD involves key nodes within the memory circuits. Also, experimental studies have suggested that patient-derived tau exhibits seeding and neuron-to-neuron propagation properties. Interestingly, tau aggregation in AD appears to spread laterally in a proximity-dependent, cortico-cortical fashion rather than along long-range memory circuits. This contrasts with the system-selective, poly-nodal degenerations seen in four-repeat tauopathies, amyotrophic lateral sclerosis, or spinocerebellar degenerations. Moreover, the proportions of three-repeat and four-repeat isoforms shift during the maturation of NFTs in AD. Overall, spreading patterns of tau-pathology in AD cannot be fully explained by Aβ pathology and also differ from the system degeneration seen in other tauopathies.}, } @article {pmid41466038, year = {2025}, author = {Cauchi, RJ and Tosolini, AP}, title = {ALS: a field in motion.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {44791}, pmid = {41466038}, issn = {2045-2322}, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder driven by complex interactions among genetic, environmental, developmental, and resilience-related factors. The studies in this Scientific Reports’ Collection highlight major advances across diverse domains that collectively broaden our understanding of ALS pathogenesis. Genetic insights emphasise the need for functional validation, as shown by the non-pathogenic behaviour of the KIF5A P986L variant in Drosophila. Neuroimaging findings reveal hypothalamic atrophy in primary lateral sclerosis, underscoring widespread extra-motor involvement. Epidemiological analyses propose that early-life exposures may form the initial steps in a multistage pathway to ALS, while geographic correlations between ALS and multiple sclerosis suggest shared environmental determinants. Experimental model innovations demonstrate selective muscle preservation in SOD1-G93A mice and introduce electrical impedance myography as a sensitive detection method in zebrafish. Mechanistic work shows that stress influences ALS through PI3K/Akt and focal adhesion pathways, linking environment to cellular vulnerability. Finally, cognitive and brain reserve emerge as important modifiers of disease expression and progression. Together, these studies illustrate ALS as a multisystem, lifespan-spanning disorder shaped by both vulnerability and resilience. Their integration offers a forward-looking framework for advancing biomarker discovery, mechanistic research, and therapeutic development in ALS.}, } @article {pmid41466416, year = {2026}, author = {Howard, I and Simmons, Z}, title = {Does the ACT Have ImpACT for ALS?.}, journal = {Muscle & nerve}, volume = {73}, number = {3}, pages = {377-379}, doi = {10.1002/mus.70117}, pmid = {41466416}, issn = {1097-4598}, } @article {pmid41466523, year = {2026}, author = {Watabe, K}, title = {Praja1 E3 ubiquitin ligase and the role it plays in neurodegeneration.}, journal = {The FEBS journal}, volume = {293}, number = {8}, pages = {2208-2211}, doi = {10.1111/febs.70383}, pmid = {41466523}, issn = {1742-4658}, mesh = {Humans ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Neurodegenerative Diseases/genetics/pathology/enzymology/metabolism ; tau Proteins/metabolism/genetics ; Animals ; Ubiquitination ; alpha-Synuclein/metabolism/genetics ; }, abstract = {Protein aggregation and transmission are hallmarks of neurodegenerative diseases. Praja1 E3 ubiquitin ligase has been shown to suppress the aggregation of causative proteins in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Parkinson's disease, Huntington's disease, and spinocerebellar degeneration, which include transactivation response DNA-binding protein of 43 kDa, fused in sarcoma, superoxide dismutase 1, α-synuclein, huntingtin, and ataxin-3. Aoki et al. demonstrated that Praja1 ubiquitinates and degrades tau, a key molecule in tauopathies such as Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and corticobasal syndrome, furthering our understanding of the role of Praja1 in neurodegenerative diseases and potential therapeutic approaches.}, } @article {pmid41467385, year = {2026}, author = {Zhou, Z and Zhao, Y and Fan, X and Zhang, J and Niu, R and Ma, Y and Xie, F and Tang, P and Mei, X and Zhang, L and Deng, J}, title = {CD11c + microglia: From basic research to clinical application.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {4538-4549}, pmid = {41467385}, issn = {1673-5374}, abstract = {CD11c + microglia are a functionally specialized subpopulation of microglia that play a crucial role in the pathophysiological processes of various central nervous system diseases. This review synthesizes compelling evidence that CD11c + microglia exhibit unique transcriptomic and phagocytic characteristics. These characteristics distinguish them from homeostatic microglia and support their specialized functions. During development, CD11c + microglia are crucial for the maturation of oligodendrocytes and the integrity of white matter, particularly in regions such as the corpus callosum and cerebellum. In preclinical models of neurodegenerative diseases (such as Alzheimer's disease and amyotrophic lateral sclerosis) and central nervous system injuries (such as stroke and spinal cord injury), they are consistently associated with neuroprotective phenotypes. CD11c + microglia exhibit enhanced phagocytic capacity near amyloid plaques and damaged neurons, helping to clear pathological protein aggregates and cell debris, thereby reducing neurotoxicity and promoting a repair environment. The current consensus is that specific microenvironmental cues, particularly hazard signaling molecules damage-associated molecular patterns and cytokines (such as interferon-γ), are the main drivers of the differentiation and activation of CD11c + microglia. Among these, the TREM2-APOE signaling axis is a key and widely accepted regulatory pathway for their survival, proliferation, and functional status. The plasticity of CD11c + microglia is regulated by multiple signaling pathways, including CSF1R, SIRPα-CD47, interferon-γ, and the complement cascade. Emerging therapeutic strategies aim to regulate their activities through gene targeting, metabolic intervention, and immune regulation using TREM2 agonists, CSF1R inhibitors, or nanopharmacological methods. However, challenges remain in defining specific CD11c + biomarkers, understanding environment-dependent functions, and achieving targeted delivery. Future prospects depend on clearly addressing individual developmental issues, deciphering the molecular switches that control phenotypic plasticity, and developing highly specific therapeutic strategies to leverage their beneficial functions, thereby paving the way for new intervention methods for neurological diseases.}, } @article {pmid41467421, year = {2026}, author = {Huerta, TJ and Urbina-Muñoz, V and Urra-Alvarez, V and Villablanca, C and Gomez-Perez, LS and Saavedra, B and Contreras, T and Vidal, RL}, title = {Cell-based immunotherapy for neurodegenerative disease: A promising avenue.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {4623-4632}, pmid = {41467421}, issn = {1673-5374}, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease are characterized by progressive neuronal loss and chronic neuroinflammation, with current treatments remaining largely symptomatic. This review explores the potential of cell-based immunotherapy as a disease-modifying strategy. Advances in stem cell biology and immune engineering have facilitated the development of therapies using mesenchymal stem cells, chimeric antigen receptor T cells, macrophages, regulatory T cells, modified macrophages, and monoclonal antibodies. These approaches aim to regulate immune mechanisms implicated in neurodegeneration, such as microglial activation, systemic inflammation, and immune checkpoint dysregulation. Notably, macrophage-mediated delivery systems, such as genetically modified cells expressing neurotrophic factors or antioxidant enzymes, have demonstrated neuroprotective effects. Likewise, emerging data support T-cell modulation and monoclonal antibody development as therapeutic targets in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease. We highlight current preclinical findings, underlying mechanisms, and translational challenges, emphasizing that immunomodulatory cell therapies represent a promising avenue for precision medicine in neurodegenerative diseases.}, } @article {pmid41467429, year = {2026}, author = {Liang, X and Qin, R and Qin, Q and Xu, W and Xu, H and Lai, X and Shao, L and Li, C and Xie, M and Xiong, X and Tang, Q and Chen, L}, title = {Therapeutic potential of astrocyte transdifferentiated neurons.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {4854-4864}, pmid = {41467429}, issn = {1673-5374}, abstract = {The permanent functional deficits resulting from the inability of adult mammalian central nervous system neurons to regenerate after injury present a significant clinical challenge. While traditional stem cell transplantation strategies continue to encounter ethical concerns and the risk of immune rejection, this impasse has shifted regenerative medicine research toward targeting endogenous astrocytes. Due to their intrinsic plasticity, widespread distribution throughout the central nervous system, and affinity for neurodevelopmental lineage, astrocytes are a unique target for in situ neuronal regeneration. This review systematically elucidates the core regulatory network governing astrocyte transdifferentiation, identifying 10 key signaling pathways, such as Wnt signaling pathway, that form a cascade regulatory system. Directed overexpression of transcription factors such as NeuroD1, Ascl1, or Neurog2 can directly initiate neuronal phenotypic conversion. Meanwhile, small molecule compounds such as valproic acid combined with CHIR99021 activate endogenous neurogenic programs by inhibiting the bone morphogenetic protein signaling axis. Notably, polypyrimidine tract binding protein 1 (PTB) gene silencing significantly enhances transdifferentiation efficiency by suppressing the microRNA 124/re1 silencing transcription factor (miR-124/REST) feedback loop. From a translational perspective, a multidimensional evaluation system based on morphological, molecular marker, and electrophysiological properties has demonstrated considerable therapeutic potential. In stroke models, NeuroD1-mediated transdifferentiation replenished approximately 30% of lost cortical neurons and improved motor coordination, evidenced by enhanced performance in food pellet retrieval, grid walking, and cylinder tests compared with controls. In spinal cord injury studies, SOX2-induced glutamatergic neurons moderately reduced glial scar density by about 25%, permitting regenerating axons to pass through while preserving the supportive structure of scar. In neurodegenerative contexts, PTB inhibition yielded functionally mature dopaminergic neurons and reconstructed nigrostriatal pathways in Parkinson's disease models. In Alzheimer's disease models, adeno-associated virus-delivered NeuroD1 induced whole-brain neural circuit remodeling, generating 500,000 new neurons widely distributed across the cortex and hippocampus, accompanied by improved cognitive performance. Current technical limitations include off-target effects of adeno-associated virus vectors, which cause nonspecific gene expression and require rigorous validation via Cre-loxP lineage tracing. Transdifferentiation efficiency is also highly influenced by regional microenvironments: gray matter astrocytes show higher conversion rates than those in white matter, and oxidative stress increases apoptosis among newly generated neurons. Clinical translation is further constrained by the safety of delivery systems and the aging tissue microenvironment, where transforming growth factor beta 1 is often elevated. Ferroptosis inhibitors have been shown to nearly double the survival rate of transdifferentiated cells, offering a novel strategy to mitigate oxidative damage. Based on current evidence, astrocyte transdifferentiation enables neural functional recovery across multiple disease models through endogenous repair mechanisms. Future advances should focus on optogenetically inducible vectors for spatiotemporal precision, non-viral delivery systems to mitigate vector-related risks, and integration of long-term safety validation in non-human primates with single-cell multi-omics technologies to facilitate the clinical translation of personalized regenerative therapies.}, } @article {pmid41467438, year = {2026}, author = {Zhao, J and Wang, J and Guo, X}, title = {Organoids: Key advances, optimization, and technological iterations in their application to neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {4734-4744}, pmid = {41467438}, issn = {1673-5374}, abstract = {Organoid technology, as an innovative approach, has shown great potential in disease modeling, target screening, and the development of treatment strategies. However, traditional organoids still have three major limitations in research: the absence of specific cell types, the lack of blood-brain barrier structure, and insufficient reproducibility of experimental results. In recent years, researchers have gradually overcome these limitations by introducing innovative techniques such as advanced culture methods, microfluidic systems, bioprinting, organoid transplantation, and assembloid construction. This progress has facilitated the widespread application of organoids in the study of neurodegenerative diseases. This paper aims to systematically review the technological innovations of organoids in the study of neurodegenerative diseases. By summarizing classical organoid construction strategies and their limitations, it emphasizes the value of organoids in comprehensive applications within neurodegenerative disease research. In this review, we focus on five specific neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Research in these diseases demonstrates that organoids improve experimental accessibility and reduce development cycles in disease modeling, target discovery, and therapeutic strategy formation. Using customized equipment and gene editing techniques, these organoids can be tailored to specific needs, providing pathophysiologically relevant disease models and enhancing our understanding of neurodegenerative diseases. Although organoid technology has demonstrated significant advantages in disease research, its potential for treating neurodegenerative diseases has not yet been fully explored, which may become an important direction for future research.}, } @article {pmid41467439, year = {2026}, author = {Dong, T and Zhang, T and Wang, H and Zhang, J and Abdullah, R and Sun, B and Peng, G}, title = {Microbiota-gut-brain axis and bile acids-driven neuromodulation.}, journal = {Neural regeneration research}, volume = {21}, number = {9}, pages = {4122-4134}, pmid = {41467439}, issn = {1673-5374}, abstract = {Bile acids emerge as multifunctional signaling molecules with dual hepatic and microbial origins, acting through farnesoid X receptor and Takeda G protein-coupled receptor 5 to influence inflammation and metabolism. Their dysregulation is consistently observed across various neurodegenerative diseases. The microbiota-gut-brain axis is a pivotal conduit for bile acids-driven neuromodulation, while sex-specific bile acid profiles and signaling pathways introduce critical biological heterogeneity. Emerging translational evidence indicates the promise of bile acids as biomarkers and therapeutic targets, yet highlights the critical hurdles that need to be addressed to realize precision interventions. Our core findings are: (1) Bile acids are far more than mere metabolic byproducts. They orchestrate core pathological processes such as neuroinflammation and energy metabolism. Their functions, whether neuroprotective or neurotoxic, are highly context-dependent, varying with cell type and disease-specific pathological backgrounds, thus exhibiting a potent "double-edged sword" effect. (2) The "microbiota-bile acids-brain axis" serves as a crucial bridge linking peripheral metabolic dysregulation to central nervous system pathology. (3) Sexual dimorphism emerges as a fundamental biological variable essential for understanding the heterogeneity in bile acid profiles and disease susceptibility. The primary contribution of this work is the proposal of an integrated "microbiota-bile acids-sex" framework that systematically describes the key scientific challenge of the context-dependent, dual roles of bile acids. Ultimately, this review champions a paradigm shift from a traditional brain-centric view to a systemic, metabolic perspective, establishing the bile acid system as a promising target for future precision therapeutic interventions.}, } @article {pmid41467440, year = {2026}, author = {Akbergenov, R and Wolfer, DP and Gillingham, D and Shcherbakov, D}, title = {Error-prone translation as a driver of proteostasis collapse and neurodegeneration.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {4594-4602}, pmid = {41467440}, issn = {1673-5374}, abstract = {Error-prone translation, resulting in inaccuracies in protein synthesis, is increasingly recognized as a critical contributor to proteostasis disruption and the pathogenesis of age-related neurological disorders. In recent years, numerous studies have elucidated that stochastic errors during mRNA translation may act as a molecular "tipping point" initiating pathogenic protein misfolding. A detailed analysis of how translation errors lead to protein misfolding, aggregation, and subsequent neurotoxicity will facilitate the identification of promising therapeutic targets for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This article explores the contribution of mistranslation to proteostasis decline, focusing on the unique vulnerabilities of neuronal cells. We review the sources of translation errors, effects of ribosomal ambiguity and error-restrictive mutations, role of proteostatic mechanisms (such as molecular chaperones, ubiquitin-proteasome system, and unfolded protein response), and provide a unified perspective that links age-related translational infidelity to neurodegeneration. By synthesizing the most recent data obtained with genetically modified cellular and animal model studies, we highlight how age-associated decline in translational fidelity exacerbates proteostasis failure and propose potential therapeutic interventions targeting translation accuracy to mitigate neurodegeneration.}, } @article {pmid41467443, year = {2026}, author = {Yang, Y and Chen, M and Ding, L and Liu, J and Luo, J and Yan, R and Ning, J and Xie, S and Li, X and Ren, Z and Zhou, R and Chen, Z}, title = {Mitochondria-associated endoplasmic reticulum membranes and calcium ion exchange: A novel direction for aging and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {4745-4757}, pmid = {41467443}, issn = {1673-5374}, abstract = {Mitochondria-associated endoplasmic reticulum membranes serve as crucial signaling hubs mediating communication between the endoplasmic reticulum and mitochondria, and play a central role in calcium ion exchange. This dynamic interface regulates key cellular processes including bioenergetic metabolism, apoptosis, autophagy, and stress responses. Dysregulation of calcium transport associated with mitochondria-associated endoplasmic reticulum membranes can disrupt intracellular homeostasis, leading to mitochondrial dysfunction, oxidative stress, and neuronal death, which are hallmarks of aging and neurodegenerative diseases. This review systematically examines the functions of protein complexes within mitochondria-associated endoplasmic reticulum membranes and the pathogenic mechanisms of calcium signaling regulated by these membranes in neurodegenerative disorders. It places particular emphasis on structural alterations in calcium ion transport machinery as a common mechanism underlying various neurodegenerative diseases. In Alzheimer's disease, mitochondria-associated endoplasmic reticulum membranes exhibit a hyperactive state, promoting the generation of amyloid-β and enhancing calcium ion flux from the endoplasmic reticulum to the mitochondria. In contrast, in Parkinson's disease and amyotrophic lateral sclerosis, the activity of mitochondria-associated endoplasmic reticulum membranes is reduced, leading to a decline in mitochondrial calcium ion buffering capacity and exacerbating excitotoxicity. Proteins residing in mitochondria-associated endoplasmic reticulum membranes are disrupted across various neurodegenerative diseases, resulting in abnormal communication between the endoplasmic reticulum and mitochondria. Recent studies indicate that mitochondria-associated endoplasmic reticulum membranes play a bidirectional role in disease progression, and compensatory mechanisms often exacerbate the pathological process. Therapeutic strategies aimed at preserving the integrity of mitochondria-associated endoplasmic reticulum membranes hold promise for alleviating neurodegenerative damage. Therefore, calcium ion exchange mediated by mitochondria-associated endoplasmic reticulum membranes plays a key role in aging and neurodegenerative diseases, making it a highly promising therapeutic target.}, } @article {pmid41467445, year = {2026}, author = {Dikwella, N and Lingor, P and Tzeplaeff, L}, title = {Seeing amyotrophic lateral sclerosis in a multi-omic perspective.}, journal = {Neural regeneration research}, volume = {21}, number = {8}, pages = {3567-3568}, pmid = {41467445}, issn = {1673-5374}, } @article {pmid41468379, year = {2025}, author = {Spencer, BE and Irwin, DJ and Van Deerlin, VM and Suh, E and Lee, EB and Elman, L and Quinn, CC and Amado, D and Baer, M and Grossman, M and Wolk, DA and McMillan, CT}, title = {Polygenic associations with clinical and neuropathological trait heterogeneity across TDP-43 proteinopathies.}, journal = {PloS one}, volume = {20}, number = {12}, pages = {e0338398}, pmid = {41468379}, issn = {1932-6203}, support = {RF1 NS145263/NS/NINDS NIH HHS/United States ; F32 AG079618/AG/NIA NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; R01 NS109260/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Multifactorial Inheritance ; *TDP-43 Proteinopathies/genetics/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Male ; Female ; *DNA-Binding Proteins/genetics ; Aged ; Phenotype ; Middle Aged ; Genetic Predisposition to Disease ; }, abstract = {TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 (FTLD-TDP), and limbic-predominant age-related TDP-43 encephalopathy, encompass a spectrum of clinical and neuropathological traits. Despite mounting evidence for shared genetic risk across TDP-43 proteinopathies, the modifiers of individual-level traits are unknown. We aimed to identify polygenic contributions to trait heterogeneity across TDP-43 proteinopathies. We used weighted correlation analysis of GWAS summary statistics for ALS, FTLD-TDP, and hippocampal sclerosis of aging (HS-Aging) to identify data-driven clusters of highly correlated single nucleotide polymorphisms (SNPs). We performed gene ontology enrichment analysis for each identified cluster. We derived cluster-specific polygenic scores and evaluated their association with clinical and neuropathological traits in an independently evaluated sample of individuals who met neuropathological and/or genetic criteria for FTLD-TDP or ALS (n = 260). We identified 5 distinct data-driven clusters, including 3 GWAS phenotype-specific clusters (FTLD-TDP, ALS, HS-Aging) and 2 clusters representing the overlap between a pair of GWAS phenotypes (ALS-FTLD and FTLD-HS). Pathway analysis revealed biologically meaningful associations including distinct GWAS phenotype-specific processes within clusters. Cluster-specific ALS and FTLD-TDP polygenic risk each associated with individual-level clinical traits, even within the context of autosomal dominant mutation carriers, where higher ALS polygenic risk associated with neuromuscular impairment and higher FTLD-TDP polygenic risk associated with cognitive-behavioral impairment. Moreover, higher FTLD-TDP polygenic risk associated with higher TDP-43 burden within characteristic FTLD-TDP brain regions. We suggest that there are polygenic modifiers of clinical and neuropathological traits across TDP-43 proteinopathies that may contribute to individual-level differences, including likelihood for developing FTLD or ALS.}, } @article {pmid41468784, year = {2026}, author = {Palanivel, V and Salkar, A and Shenoy, A and Eva, TA and Perera, R and Chitranshi, N and Gupta, V and You, Y and Mirzaei, M and Graham, SL and Gupta, V and Basavarajappa, D}, title = {Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies.}, journal = {Neuropeptides}, volume = {115}, number = {}, pages = {102583}, doi = {10.1016/j.npep.2025.102583}, pmid = {41468784}, issn = {1532-2785}, mesh = {Humans ; *Neuropeptide Y/metabolism ; *Neurodegenerative Diseases/metabolism ; Animals ; Signal Transduction/physiology ; Oxidative Stress/physiology ; Receptors, Neuropeptide Y/metabolism ; }, abstract = {Neuropeptide Y (NPY), a widely distributed and highly conserved neuropeptide, plays a central role in the regulation of diverse physiological processes, including stress responses, energy homeostasis, vascular tone, and immune modulation, via activation of its receptor subtypes. Beyond its physiological roles, the dysregulation of NPY expression has been documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Machado-Joseph disease, and retinal disorders such as diabetic retinopathy and glaucoma. These alterations in NPY levels and receptor activity highlight its potential not only as a biomarker for disease progression but also as a promising therapeutic target. Previous evidence revealed that NPY exerts neuroprotection by alleviating excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while concurrently facilitating neurogenesis, synaptic plasticity, and cellular resilience. NPY activates receptor-mediated intracellular signaling cascades like PI3K/Akt, MAPK/ERK, and p38K, that control cellular survival, proteostasis, and inflammation and thereby influence disease trajectories. Understanding NPY operation with these mechanisms can unveil new avenues for targeted therapy. Current insights into the complex roles of NPY in neurodegeneration are discussed in this review, and their implications in diagnostic and treatment strategies are addressed.}, } @article {pmid41471389, year = {2025}, author = {Gershoni Emek, N and Tan, AM and Geva, M and Fekete, A and Abate, C and Hayden, MR}, title = {Pridopidine, a Potent and Selective Therapeutic Sigma-1 Receptor (S1R) Agonist for Treating Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {12}, pages = {}, pmid = {41471389}, issn = {1424-8247}, abstract = {Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). The S1R is a ubiquitous chaperone protein enriched in the central nervous system and regulates multiple pathways critical for neuronal cell function and survival, including cellular stress responses, mitochondrial function, calcium signaling, protein folding, and autophagy. S1R has a crucial role in the ER mitochondria-associated membrane (MAM), whose dysfunction is implicated in several neurodegenerative diseases. By activating the S1R, pridopidine corrects multiple cellular pathways necessary to the cell's ability to respond to stress, which are disrupted in neurodegenerative diseases. Pridopidine restores MAM integrity; rescues Ca[2+] homeostasis and autophagy; mitigates ER stress, mitochondrial dysfunction, and oxidative damage; and enhances brain-derived neurotrophic factor (BDNF) axonal transport and secretion, synaptic plasticity, and dendritic spine density. Pridopidine demonstrates neuroprotective effects in in vivo models of neurodegenerative diseases (NDDs). Importantly, pridopidine demonstrates the biphasic dose response characteristic of S1R agonists. In clinical trials in HD and ALS, pridopidine has shown benefits across multiple endpoints. Pridopidine's mechanism of action, modulating core cellular survival pathways, positions it as a promising candidate for disease modification for different nervous system disorders. Its broad therapeutic potential includes neurodevelopmental disorders, and rare diseases including Wolfram syndrome, Rett syndrome, and Vanishing White Matter Disease. Here, we review the experimental data demonstrating pridopidine's S1R-mediated neuroprotective effects. These findings underscore the therapeutic relevance of S1R activation and support further investigation of pridopidine for the treatment of different neurodegenerative diseases including ALS and HD.}, } @article {pmid41472414, year = {2026}, author = {Wu, J and Tao, Z and Cao, J and Hu, W and Jiang, M and Li, Y and Cao, H and Liao, M and Zhao, N}, title = {Cytochrome P450 and glutathione S-transferase may confer bensulfuron-methyl resistance in Cyperus iria.}, journal = {Pest management science}, volume = {82}, number = {4}, pages = {3708-3716}, doi = {10.1002/ps.70492}, pmid = {41472414}, issn = {1526-4998}, support = {2021YFD1700100//National Key Research and Development Program of China/ ; X202510364082//College Students' Innovation Training Project in Anhui Agricultural University/ ; }, mesh = {*Herbicide Resistance/genetics ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; *Herbicides/pharmacology ; *Sulfonylurea Compounds/pharmacology ; *Cyperus/drug effects/genetics/enzymology/metabolism ; *Glutathione Transferase/metabolism/genetics ; *Plant Proteins/metabolism/genetics/chemistry ; Acetolactate Synthase/genetics ; }, abstract = {BACKGROUND: Rice flatsedge (Cyperus iria L.) is one of the most troublesome weeds infesting rice fields across China. Bensulfuron-methyl, an acetolactate synthase (ALS)-inhibiting herbicide, has been widely used for the control of Cyperaceae weeds in rice production. However, long-term and extensive use of this herbicide has resulted in the evolution of resistant C. iria populations. In this study, a suspected bensulfuron-methyl-resistant (R) population collected from a rice field that survived field-recommended applications was investigated to elucidate its resistance level and underlying mechanism.

RESULTS: Compared with a susceptible (S) population, the R population exhibited a high level of resistance to bensulfuron-methyl [resistance index (RI) = 12.88] and cross-resistance to metazosulfuron (RI = 11.66), bispyribac-sodium (RI = 9.10) and penoxsulam (RI = 6.35). No mutations were detected in the ALS gene, and ALS expression levels did not differ significantly between the R and S plants. Pretreatment with the cytochrome P450 inhibitor malathion and the glutathione S-transferase inhibitor 4-chloro-7-nitrobenzoxadiazole effectively reversed bensulfuron-methyl resistance in R plants. Liquid chromatography tandem mass spectrometry analysis showed that the R plants metabolized bensulfuron-methyl significantly faster than the S plants. RNA sequenccing analysis revealed remarkable upregulation of CYP97A3 and GSTF1 in the R population, while molecular docking indicated strong binding affinities between both enzymes and bensulfuron-methyl at their active sites.

CONCLUSION: These results reveal that enhanced expression of CYP97A3 and GSTF1 may contribute to bensulfuron-methyl resistance in C. iria, highlighting the role of metabolic detoxification in the evolution of non-target-site resistance in this species. © 2025 Society of Chemical Industry.}, } @article {pmid41474642, year = {2026}, author = {Luo, H and Yang, Y and Cao, X and Deng, C and Chen, H}, title = {Unveiling the Genetic Association Between Hemoglobin Concentration and Amyotrophic Lateral Sclerosis.}, journal = {Brain and behavior}, volume = {16}, number = {1}, pages = {e71152}, pmid = {41474642}, issn = {2162-3279}, support = {82171422//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/blood ; *Hemoglobins/genetics/metabolism ; Genome-Wide Association Study ; Motor Neurons/metabolism ; Mendelian Randomization Analysis ; Induced Pluripotent Stem Cells/metabolism ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Although previous studies have suggested an association between hemoglobin (Hb) concentration and amyotrophic lateral sclerosis (ALS), the precise cause-and-effect relationship between them is still unclear. This study aims to investigate the causal correlation between Hb concentration and ALS, and explore the potential genes related to their association.

METHODS: We extracted summary statistical data of Hb concentration and ALS from genome-wide association studies (GWAS), performed Mendelian randomization (MR) analyses, and conducted RNA sequencing of motor neurons different from ALS patient-derived induced pluripotent stem cells (iPSCs), followed by an intersection analysis between differentially expressed genes (DEGs) in ALS motor neurons and selected instrumental variables (IVs) associated with Hb concentration.

RESULTS: As a result, Hb concentration had a negative causal relationship with the risk of ALS, established through IVW (OR = 0.854; 95% CI: 0.767-0.951; p = 0.00418) of the univariable MR analysis. A multivariable MR further confirmed that this causal link remained robust, even when accounting for confounders including systolic blood pressure, total cholesterol levels, body mass index, LDL cholesterol, diastolic blood pressure, and smoking. Importantly, genetically predicted ALS did not show a causal connection to Hb concentration. Additionally, RNA sequencing analysis and qRT-PCR results revealed that transcripts for BACH1 and FLVCR1 were upregulated, while those for TRIM58 were downregulated in SOD1[D90A] ALS motor neurons, compared to the control. In motor neurons differentiated from a sporadic ALS patient-derived iPSCs, qRT-PCR showed increased transcript levels of BACH1, and decreased transcript levels of FLVCR1 and TRIM58. These three genes were intersected with harmonized SNPs between Hb concentration and ALS.

CONCLUSION: Our study concludes that genetically predicted Hb concentration exhibited an independent inverse causal association with the risk of developing ALS, with potential involvement of genes such as BACH1, FLVCR1, and TRIM58.}, } @article {pmid41475066, year = {2026}, author = {Kaji, R and Nishi, Y and Ishida, T and Takase, T and Ueda, T and Maeda, T and Izumi, Y and , }, title = {Clinical safety of ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis: Open-label extension of a phase 2/3 randomized controlled study.}, journal = {Journal of the neurological sciences}, volume = {480}, number = {}, pages = {125701}, doi = {10.1016/j.jns.2025.125701}, pmid = {41475066}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; *Vitamin B 12/analogs & derivatives/adverse effects/administration & dosage/therapeutic use ; Female ; Middle Aged ; Aged ; Double-Blind Method ; Treatment Outcome ; Injections, Intramuscular ; Adult ; Dose-Response Relationship, Drug ; }, abstract = {OBJECTIVE: To develop combined therapies for amyotrophic lateral sclerosis (ALS), we investigated the long-term safety of ultra-high-dose methylcobalamin (50-mg intramuscular, twice weekly) in patients with advanced ALS.

METHODS: As an open-label extension of a multicenter, randomized, double-blind, placebo-controlled phase 2/3 study, patients were enrolled and administered methylcobalamin 50 mg intramuscularly twice weekly for up to 52 weeks.

RESULTS: In total, 144 patients (mean age, 62.1 years; 61.1 % male) were included, and the overall disease duration was 53.2 ± 17.9 months, with 85.4 % of patients having an ALS severity stage ≥3. The incidence of adverse events was 94.4 %, and adverse drug reactions occurred in 3.5 % of patients, which included proteinuria (2.1 %) and single cases of supraventricular arrhythmia, increased blood urea, and hypertension (0.7 % each). None led to discontinuation or death. The survival rate at 52 weeks was 85.7 %, and as shown for the following patient subgroups: by ALS severity (stage 1-2, 100 %; 3, 85.3 %; 4, 82.8 %; 5, 82.0 %) and by presence of tracheostomy (with, 88.8 %; without, 84.1 %). The median change in the ALS functional rating scale total score from baseline to 52 weeks was -1.0.

CONCLUSION: There were no particular safety issues as reported in the phase 2/3 study and no clear deterioration in survival rate or physical function when ultra-high-dose methylcobalamin was administered intramuscularly in patients with advanced ALS. This regimen could be a candidate for initial therapy with further add-on to overcome ALS in the future.}, } @article {pmid41475349, year = {2026}, author = {Dubey, SK and Chaubey, D and Ikenaga, C and Lin, WW and Bellen, HJ and Lloyd, TE}, title = {Aberrant nuclear pore complex degradation contributes to neurodegeneration in VCP disease.}, journal = {Neuron}, volume = {114}, number = {5}, pages = {850-867.e8}, pmid = {41475349}, issn = {1097-4199}, support = {R01 AG068043/AG/NIA NIH HHS/United States ; R01 AR076390/AR/NIAMS NIH HHS/United States ; R01 NS094239/NS/NINDS NIH HHS/United States ; }, mesh = {*Valosin Containing Protein/genetics/metabolism ; Animals ; Humans ; *Nuclear Pore/metabolism/genetics ; Drosophila Proteins/metabolism/genetics ; Drosophila ; *Nuclear Pore Complex Proteins/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Mutation ; Active Transport, Cell Nucleus ; Nuclear Proteins/metabolism ; Intracellular Signaling Peptides and Proteins ; }, abstract = {Defective nucleocytoplasmic transport (NCT) has emerged as a contributing factor in the pathogenesis of neurodegenerative diseases and aging. Valosin-containing protein (VCP) is an AAA+ATPase required for disassembly of protein complexes, and mutations in VCP cause neurodegenerative and neuromuscular diseases. We find that VCP is required for quality control of nuclear pore complexes (NPCs) by extracting selected nucleoporins from NPCs for proteasome-mediated degradation. Pathogenic VCP variants cause a reduction in nucleoporins in Drosophila, induced pluripotent stem cell (iPSC)-derived motor neurons, and muscle biopsies from patients, indicating a dominant gain-of-function mechanism. Mechanistically, disease-associated mutations in VCP result in increased recruitment to NPCs through interactions with Ufd1-Npl4, leading to the removal of a subset of nucleoporins from NPCs and disrupting NCT. These findings show that the VCP-Ufd1-Npl4 pathway regulates NPC quality control and that disease-associated variants aberrantly activate the VCP-Ufd1-Npl4 complex to degrade NPCs and disrupt NCT.}, } @article {pmid41475669, year = {2026}, author = {Mirzalieva, O and Reed, RE and Haas, AL and Juncker, MA and Logarbo, P and Klein, JM and Worthylake, D and Desai, SD}, title = {ISG15 dysregulates endoplasmic reticulum-mitochondrial contacts and calcium homeostasis in Ataxia telangiectasia.}, journal = {Cellular signalling}, volume = {139}, number = {}, pages = {112347}, doi = {10.1016/j.cellsig.2025.112347}, pmid = {41475669}, issn = {1873-3913}, mesh = {*Mitochondria/metabolism ; *Endoplasmic Reticulum/metabolism ; Humans ; *Calcium/metabolism ; Homeostasis ; *Cytokines/metabolism/genetics ; *Ubiquitins/metabolism/genetics ; Fibroblasts/metabolism ; GTP Phosphohydrolases/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Mitochondrial Proteins/metabolism ; }, abstract = {Dysregulation of endoplasmic reticulum and mitochondrial (ER:Mit) contacts and mitochondrial calcium (mitCa[2+]) homeostasis are found in several neurodegenerative disorders, including Ataxia Telangiectasia (A-T). However, the cellular basis of these defects remains unclear. Previously, we demonstrated that the aberrantly elevated Interferon-Stimulated Gene 15 (ISG15) pathway inhibits protein polyubiquitylation, its dependent protein turnover, and mitophagy pathways in A-T. Literature indicates that silencing of mitochondrial ubiquitin ligase 1 (MUL1) stabilizes mitofusin2 (MFN2) and attenuates mitCa[2+] uptake from ER to Mit (mitCa[2+]influx) in primary neurons. We have replicated these findings in apparently healthy fibroblasts. We hypothesized that elevated ISG15 may inhibit ubiquitin-dependent MUL1-mediated degradation of MFN2 and dysregulate ER:Mit contacts and mitCa[2+] homeostasis in A-T fibroblasts. Concurrently, MFN2 is stabilized in A-T, MUL1-silenced A-T, MUL1/ISG15-silenced A-T vs ISG15-silenced A-T fibroblasts. Moreover, the number of ER:Mit contacts is increased in A-T vs ISG15-silenced A-T fibroblasts. Notably, mitCa[2+]efflux is significantly attenuated in A-T vs ISG15-silenced A-T fibroblasts in which mitCa[2+]efflux is restored to levels comparable to those observed in normal fibroblasts. The mitCa[2+]efflux remains attenuated in MUL1 and MUL1/ISG15-silenced A-T fibroblasts. We conclude that ISG15 impairs MUL1/MFN2-mediated regulation of ER:Mit contacts and attenuates mitCa[2+]efflux, which may, in turn, cause Ca[2+] overload-mediated mitochondrial damage in A-T. These findings suggest that ISG15 silencers may correct mitochondrial abnormalities and improve mitochondrial health in A-T patients and in those with other neurodegenerative disorders in which ISG15 is elevated, such as ALS.}, } @article {pmid41476266, year = {2026}, author = {Cai, F and Xu, D and Yang, D and Huang, F and Song, X and Jiang, Q and Wan, S and Zhao, Y and Zhou, J}, title = {Multidimensional predictors of fatigue in amyotrophic lateral sclerosis: a cross-sectional study in China.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {3294}, pmid = {41476266}, issn = {2045-2322}, support = {Grant No. ZY2025Q006//Hubei Provincial Administration of Traditional Chinese Medicine/ ; Grant No. 82575246//National Natural Science Foundation of China/ ; GZY-KJS-2025-008 and Joint Fund, 2023AFD128//Science and Technology Special Project of State Administration of Traditional Chinese Medicine and Hubei Provincial Natural Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/psychology ; Cross-Sectional Studies ; *Fatigue/etiology/epidemiology/physiopathology/diagnosis ; China/epidemiology ; Female ; Male ; Middle Aged ; Quality of Life ; Sleep Quality ; Depression ; Aged ; Medicine, Chinese Traditional ; }, abstract = {This study aims to identify key predictors of fatigue in patients with amyotrophic lateral sclerosis (ALS) and examine the interaction of physiological, psychological, and social factors to inform management strategies. A descriptive cross-sectional study. Between June 2023 and June 2024, a cohort of 239 patients diagnosed with ALS enrolled at the Integrated Traditional Chinese and Western Medicine Center, Hubei Provincial Hospital of Traditional Chinese Medicine. The participants were evaluated using validated instruments that assessed motor function, depressive symptoms, sleep quality, and social determinants. Stepwise multiple regression analysis was conducted to identify independent predictors of fatigue. The ALS Functional Rating Scale-Revised (ALSFRS-R), depression (PHQ-9), sleep quality (PSQI), and residential status were significant predictors of fatigue, accounting for 28.6% of the variance (R2= 0.286). The use of traditional Chinese medicine was associated with a reduction in fatigue, whereas muscle strength exhibited an inverse correlation with the severity of fatigue. Fatigue in ALS is influenced by multiple factors, extending beyond motor decline to include psychological well-being, sleep quality, and the social environment. These findings highlight the need for multidisciplinary, personalized strategies that integrate both biomedical and supportive care approaches to enhance the quality of life for ALS patients.}, } @article {pmid41476442, year = {2025}, author = {Kato, N and Hashida, G and Sahara, W}, title = {Short-Term Effects of Exercise Therapy on Muscle Characteristics in Patients With Mild-to-Moderate Amyotrophic Lateral Sclerosis: A Preliminary Case Series Study.}, journal = {Cureus}, volume = {17}, number = {12}, pages = {e100383}, pmid = {41476442}, issn = {2168-8184}, abstract = {BACKGROUND: Exercise therapy is recommended for patients with amyotrophic lateral sclerosis (ALS), but its effects on muscle mass and intramuscular conditions remain unclear. In recent years, ultrasonography has enabled the simple and non-invasive estimation of muscle mass and intramuscular conditions. This study aimed to investigate the short-term effects of exercise therapy on muscle characteristics in patients with mild-to-moderate ALS using ultrasonography.

METHODS:  Ambulatory patients with ALS and an ALS Functional Rating Scale-Revised (ALSFRS-R) score of ≥30 underwent moderate-intensity exercise therapy for 3-4 weeks. Primary outcome measures included muscle strength (handgrip strength (HGS) and ankle dorsiflexion strength (ADFS)), muscle thickness (MT), echo intensity (EI), and the ratio of muscle strength to muscle thickness for both the forearm muscles and the tibialis anterior muscle. The Bayesian Wilcoxon signed-rank test was used to compare outcomes before and after the intervention.

RESULTS:  Six consecutive patients with ALS (median age: 75.5 years; three males (50%) and three females (50%); four with bulbar onset (66.7%) and two with upper limb onset (33.3%)) were included. Following the intervention, the muscle thickness of the forearm muscles and the tibialis anterior muscle decreased. However, qualitative muscle characteristics were partially maintained or improved: the echo intensity of the forearm muscles was maintained, and the ratio of ankle dorsiflexion strength to muscle thickness of the tibialis anterior muscle showed a large increase.

CONCLUSION:  In patients with mild-to-moderate ALS, exercise therapy resulted in short-term qualitative changes in muscle, while a concurrent reduction in muscle mass may have attenuated these effects. The benefits of exercise therapy may have been counteracted by muscle mass loss, suggesting the need for future studies to investigate the combined effects of exercise and nutritional therapy on muscle characteristics and activities of daily living (ADL).}, } @article {pmid41477139, year = {2025}, author = {Syamal, M}, title = {Treatment of Neurogenic Voice Disorders.}, journal = {World journal of otorhinolaryngology - head and neck surgery}, volume = {11}, number = {4}, pages = {541-547}, pmid = {41477139}, issn = {2589-1081}, abstract = {This overview serves as a foundational resource for clinicians caring for neurologically complex patients presenting with voice complaints. Neurogenic voice disorders are diverse in their clinical presentations and therapeutic approaches. A thorough medical history, including family history, detailed laryngeal examination, voice assessments, and neuroimaging, are imperative, as well as a multidisciplinary, collaborative approach with neurologists, speech language pathologists, and patient caregivers. Disorders such as amyotrophic lateral sclerosis (ALS), cerebrovascular accidents (strokes), Huntington's disease, myasthenia gravis (MG), Parkinson's disease (PD), and voice tremor should be understood by otolaryngologists. Each condition presents unique challenges and requires tailored treatment strategies ranging from supportive therapies and pharmacological interventions to surgery. Voice management techniques, including the use of botulinum toxin for hyperkinetic disorders and deep brain stimulation for refractory cases, are highlighted as promising interventions.}, } @article {pmid41478512, year = {2026}, author = {Strohmer, B and Grosh, K and Montañana-Rosell, R and Mora, S and Ausborn, J and Allodi, I}, title = {Spinal circuit mechanisms constrain therapeutic windows for ALS intervention: A computational modeling study.}, journal = {Neurobiology of disease}, volume = {219}, number = {}, pages = {107253}, pmid = {41478512}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/therapy/pathology ; *Motor Neurons/physiology ; Animals ; *Spinal Cord/physiopathology ; Computer Simulation ; Interneurons/physiology ; Mice ; Humans ; *Models, Neurological ; *Nerve Net/physiopathology ; Disease Models, Animal ; *Neural Networks, Computer ; Mice, Transgenic ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive breakdown of neural circuits which leads to motoneuron death. Earlier work from our lab showed that dysregulation of inhibitory V1 interneurons precedes the degeneration of excitatory V2a interneurons and motoneurons and that stabilizing V1-motoneuron connections improved motor function and saved motoneurons in the SOD1[G93A] ALS mouse model. However, the optimal timing for this intervention remains unclear. To address this, we developed a spiking neural network model of spinal locomotor circuits to simulate healthy and ALS-like conditions. By modeling changes in network connectivity and synaptic dynamics, we predict that V1 dysregulation induces an imbalance in motoneuron output which results in flexor-biased activity, leading to the disruption of flexor-extensor coordination, and potentially contributing to selective vulnerability of flexor motoneurons. Stabilizing V1 synapses preserved motor output even after motoneuron loss, suggesting that therapeutic benefit is possible into symptomatic stages. However, model predictions also highlighted that after sustained synaptic loss and the development of slower synaptic dynamics within the network, synaptic stabilization leads to maladaptive extensor-biased activity, suggesting that excitatory/inhibitory balance impacts treatment effectiveness. Finally, the model indicated that V1 stabilization could lead to rescue of the V2a excitatory interneurons, a finding that we were able to confirm experimentally in the SOD1[G93A] ALS mouse model. By exploring different scenarios of synaptic loss and cell dysregulation during synaptic stabilization, our models provide a framework for predicting candidate time windows for spinal circuit interventions, which may guide future preclinical investigations.}, } @article {pmid41479097, year = {2026}, author = {Stamatelopoulos, D and Papakonstantinou, E and Bacopoulou, F and Vlachakis, D}, title = {Polyphenols from Olive Oil: A Promising Therapeutic Approach for Neurodegenerative Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {1490}, number = {}, pages = {343-349}, pmid = {41479097}, issn = {0065-2598}, mesh = {*Olive Oil/chemistry/therapeutic use ; Humans ; *Polyphenols/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Neuroprotective Agents/therapeutic use ; Animals ; Oxidative Stress/drug effects ; Antioxidants/therapeutic use ; Diet, Mediterranean ; Anti-Inflammatory Agents/therapeutic use ; }, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, ALS, and Huntington's disease pose a growing global health challenge due to their prevalence in aging populations and their devastating impact on cognitive and motor functions. Current treatments focus on symptom management, with no options available to reverse neuronal damage. Emerging evidence highlights the potential role of extra virgin olive oil (EVOO) polyphenols in neuroprotection, particularly in the context of the Mediterranean diet, which is associated with lower rates of neurodegenerative disorders. EVOO's rich polyphenolic compounds, including hydroxytyrosol, oleuropein, tyrosol, and oleocanthal, exhibit potent antioxidant, anti-inflammatory, and neuroprotective properties. These bioactive molecules have shown potential in modulating disease-specific pathways, such as reducing oxidative stress, inhibiting abnormal protein aggregation, and regulating neuroinflammation. This paper explores the therapeutic potential of olive oil polyphenols for neurodegenerative diseases, detailing their mechanisms of action across different conditions. Our findings suggest that incorporating EVOO into dietary and medical interventions could serve as a promising strategy for mitigating neurodegenerative disease progression and enhancing cognitive health.}, } @article {pmid41479703, year = {2025}, author = {Wan, P and Zhou, SQ and Ke, QH}, title = {Very early recurrence after pancreatic cancer resection: Unmasking the "biological R2" enigma and rethinking prognostic paradigms.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {12}, pages = {114403}, pmid = {41479703}, issn = {1948-9366}, abstract = {Pancreatic ductal adenocarcinoma (PDAC), a "silent killer" with elusive early symptoms and poor prognosis, sees nearly half of patients experience recurrence within a year post-curative-intent surgery. Very early recurrence (VER), defined as recurrence within 12 weeks postoperatively and first termed "biological R2 resection" by Belfiori et al, remains a clinical puzzle. Martlı et al's recent retrospective cohort study offers crucial insights into this understudied issue, identifies predictive factors that challenge long-held beliefs, and calls for a rethink of risk stratification and postoperative management for PDAC patients. Martlı et al studied 303 PDAC patients at a high-volume center from 2019 to 2024, with VER affecting 9.24% (28 patients) of the cohort. The study's strength lies in combining traditional statistical analyses and machine learning (random forest modeling) to capture nonlinear relationships between clinicopathological factors and VER risk. Key findings include: (1) Poorly differentiated (G3) tumors are the strongest VER predictor (OR = 2.43, P < 0.001; random forest importance score = 0.35), with 92.85% of VER patients having G3 tumors (vs 45.81% of non-VER patients); (2) Contrary to prior studies, pancreatic head tumors (89.28% of VER patients vs 83.66% of non-VER patients, P = 0.031) were linked to VER; (3) Elevated red cell distribution width is a weaker predictor (random forest importance score = 0.20, P = 0.03 for group difference, P = 0.079 in multivariate analysis); and (4) VER correlates with significantly higher 6-month mortality (32.44% vs 14.77% in non-VER patients, P = 0.032).}, } @article {pmid41479723, year = {2025}, author = {Jing, C and Liu, K}, title = {Taming colonic anastomotic leakage: Wisdom from the ancient Chinese legend of Yu the Great.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {12}, pages = {113423}, pmid = {41479723}, issn = {1948-9366}, abstract = {Colonic anastomotic leakage (AL) remains the most severe complication of colorectal surgery, significantly increasing morbidity, mortality, and healthcare burdens. The ideal solution - complete AL prevention without a defunctioning stoma - has long eluded surgeons and patients. Hu et al proposed total enteric flow diversion using a modified ileostomy tube with an inflatable balloon, demonstrating its efficacy in completely preventing AL in porcine models. This innovation echoes the ancient legend of Yu the Great, a Chinese hero renowned for taming the Yellow River's catastrophic floods. Unlike his father, who failed by merely building embankments to block water, Yu succeeded by dredging channels to redirect floods seaward. This paradigm of "diversion over obstruction" applies equally to AL prevention. Beyond Hu et al's balloon technique, alternatives like the C-seal, the SafeHeal Colovac+ anastomosis protection device and Tong et al's biodegradable stent-based diverting techniques show promise in clinical trials. Key challenges remain: Diversion efficiency, device migration risks, and patient tolerance. We must accelerate such like breakthroughs in non-stoma diversion strategies to transform AL management.}, } @article {pmid41479929, year = {2025}, author = {Bagrodia, A and Vaithiyam, V and Laguduva Mohan, S}, title = {Large colorectal lesions: Expanding the boundaries of endoscopic management.}, journal = {World journal of gastrointestinal endoscopy}, volume = {17}, number = {12}, pages = {115008}, pmid = {41479929}, issn = {1948-5190}, abstract = {Large colorectal lesions (≥ 3 cm) present a significant therapeutic challenge due to their potential for malignancy and the technical difficulties they encounter. Endoscopic resection techniques, including endoscopic mucosal resection, endoscopic submucosal dissection, and endoscopic full-thickness resection, have revolutionized the management of these lesions by offering organ-preserving alternatives to surgery with favorable outcomes. We read with great interest and commended Zhu et al for their valuable study on the endoscopic treatment of large colorectal lesions. Zhu et al's study provides crucial real-world evidence regarding the safety and effectiveness of advanced endoscopic resection techniques in this challenging patient group. These findings support the possibility of achieving high rates of complete resection with acceptable adverse event profiles, reinforcing the role of endoscopic mucosal resection and submucosal dissection in routine practice. This editorial also offers a comprehensive review of the current literature, discusses its clinical implications, explores future directions, and compares endoscopic resection methods with surgical options. Zhu et al's study findings not only validate the efficacy of advanced endoscopic resection but also signify a paradigm shift from surgical to organ-preserving strategies in colorectal oncology, a transformation that requires deliberate system-wide training and capacity building.}, } @article {pmid41480190, year = {2025}, author = {Ganzetti, M and Valsasina, P and Barkhof, F and Rocca, MA and Filippi, M and Prados, F and Craveiro, L}, title = {SynSpine: an automated workflow for the generation of longitudinal spinal cord synthetic MRI data.}, journal = {Frontiers in neuroinformatics}, volume = {19}, number = {}, pages = {1649440}, pmid = {41480190}, issn = {1662-5196}, abstract = {BACKGROUND: Spinal cord atrophy is a key biomarker for tracking disease progression in neurological disorders, including multiple sclerosis, amyotrophic lateral sclerosis, and spinal cord injury. Recent MRI advancements have improved atrophy detection, particularly in the cervical region, facilitating longitudinal studies. However, validating atrophy quantification algorithms remains challenging due to limited ground truth data.

OBJECTIVE: This study introduces SynSpine, a workflow for generating synthetic spinal cord MRI data (i.e., digital phantoms) with controlled levels of artificial atrophy. These phantoms support the development and preliminary validation of spinal cord imaging pipelines designed to measure degeneration over time.

METHODS: The workflow consists of two phases: (1) generating synthetic MR images by isolating, extracting and scaling the spinal cord, simulating atrophy on the PAM50 template; (2) performing non-rigid registration to align the synthetic images with the subject's native space, ensuring accurate anatomical correspondence. A proof-of-concept application utilizing the Active Surface and Reg methods implemented in Jim demonstrated its effectiveness in detecting atrophy across various levels of simulated atrophy and noise.

RESULTS: SynSpine successfully generates synthetic spinal cord images with varying atrophy levels. Non-rigid registration did not significantly affect atrophy measurements. Atrophy estimation errors, estimated using Active Surface and Reg methods, varied with both simulated atrophy magnitude and noise level, exhibiting region-dependent differences. Increased noise led to higher measurement errors.

CONCLUSION: This work presents a novel and modular framework for simulating spinal cord atrophy data using digital phantoms, offering a controlled setting for testing spinal cord analysis pipelines. As the simulated atrophy may over-simplify in vivo conditions, future research will focus on enhancing the realism of the synthetic dataset by simulating additional pathologies, thus improving its application for evaluating spinal cord atrophy in clinical and research contexts.}, } @article {pmid41480315, year = {2025}, author = {Wang, CL and Zeng, M and Luo, Y}, title = {Unmasking the high-risk phenotype in autoimmune gastritis: A pathologist's roadmap for the clinician.}, journal = {World journal of gastroenterology}, volume = {31}, number = {48}, pages = {115244}, pmid = {41480315}, issn = {2219-2840}, mesh = {Humans ; *Stomach Neoplasms/pathology/diagnosis/immunology ; *Autoimmune Diseases/pathology/immunology/diagnosis ; *Gastritis/pathology/immunology/diagnosis ; Biopsy ; *Neuroendocrine Tumors/pathology/immunology/diagnosis ; Phenotype ; Risk Factors ; *Precancerous Conditions/pathology/immunology/diagnosis ; *Gastric Mucosa/pathology/immunology ; Risk Assessment ; Pathologists ; Ki-67 Antigen/analysis ; Prognosis ; Disease Progression ; }, abstract = {Li et al's recent work on the risk factors for autoimmune gastritis provides clinical context for the vast majority of gastric neuroendocrine tumors (G-NETs). However, a deeper understanding of the underlying pathology is needed for precise clinical management. Our letter details the predictable stepwise progression of type 1 G-NETs from autoimmune-driven corporal atrophy and hypergastrinemia to a clear microscopic sequence of enterochromaffin-like cell precursor lesions, including linear hyperplasia, micronodular hyperplasia, and dysplasia. We highlight the definitive diagnostic thresholds that separate these precursors from overt neoplasia: The 0.5 mm size rule and the presence of submucosal invasion. We advocate for a "prognostic biopsy protocol" in which pathologists actively report these precursor lesions and use Ki-67 to grade G-NETs, providing a quantitative risk assessment. This pathology-centric approach transforms surveillance, allowing clinicians to act on objective microscopic milestones rather than waiting for macroscopically visible tumors.}, } @article {pmid41480396, year = {2025}, author = {Arafat, A and Soliman, SMA and Farghaly, TA and Ebrahim, NAA}, title = {Exercise with induced pluripotent stem cells enhances Wnt1-Lmx1a signaling and dopaminergic neurogenesis to alleviate Parkinsonian symptoms.}, journal = {World journal of stem cells}, volume = {17}, number = {12}, pages = {113924}, pmid = {41480396}, issn = {1948-0210}, abstract = {This article focused on the recent contribution by Jiang et al, who demonstrated that voluntary exercise can significantly potentiate the effects of induced pluripotent stem cell transplantation in a Parkinson's disease (PD) model through activation of the Wnt1-Lmx1a signaling cascade. Jiang et al's findings highlight the role of exercise as a molecular modulator of neurogenesis and support the development of integrated strategies combining physical activity, stem cell transplantation, and biomaterials to improve outcomes in PD. We highlight exercise as a molecular modulator that fosters a neurogenic milieu, recommend examining additional developmental signals (sonic hedgehog, fibroblast growth factor 8, bone morphogenetic protein), and suggest biomaterial-based strategies to support graft survival and integration. We also stress the need to optimize exercise regimens in relation to transplantation, framing these insights within a translational strategy for advancing regenerative therapies in PD.}, } @article {pmid41480618, year = {2025}, author = {Hu, G and Gogzheyan, C and Panja, S and Sil, S and Gendelman, HE}, title = {Extracellular vesicle-based therapies for neurodegenerative diseases.}, journal = {NeuroImmune pharmacology and therapeutics}, volume = {4}, number = {4}, pages = {377-390}, pmid = {41480618}, issn = {2750-6665}, support = {R01 MH121402/MH/NIMH NIH HHS/United States ; R01 NS034239/NS/NINDS NIH HHS/United States ; }, abstract = {Extracellular vesicles (EVs) are mediators of neurodegeneration and emerging therapeutic tools for central nervous system disorders. On the one hand, they help spread beta amyloid, tau, α-synuclein, TDP-43, and mutant SOD1, contributing to the signs and symptoms of Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, and Huntington's Diseases. By activating glial cells, they promote chronic neuroinflammation through carrying cytokines, inflammasomes, and chemokines. On the other hand, EVs' ability to transport neuroregulatory products and cross the blood-brain barrier makes them ideal vehicles for drug delivery. Their function can be surface-modified to deliver targeted therapies, including anti-inflammatory and neuroprotective regulatory RNAs, proteins, and lipids, as well as factors that help maintain neural homeostasis. Notably, we suggest that colostrum-derived EVs, enriched with growth factors and immune-regulatory microRNAs, offer a natural, scalable, and biocompatible source for neuroprotective treatment. Although EVs can act as "Janus-faced" entities - serving both as disease initiators and versatile therapeutic vehicles - controlling their activity can enable immune-based therapeutics for neurodegenerative diseases.}, } @article {pmid41480876, year = {2026}, author = {Majumdar, T and Das, PK and Bisoi, A and Jana, B and Singh, PC}, title = {Three-State Unfolding of Telomeric G-Quadruplexes through Conformational Switching in Crowded Cell-like Conditions.}, journal = {Biochemistry}, volume = {65}, number = {2}, pages = {195-206}, doi = {10.1021/acs.biochem.5c00486}, pmid = {41480876}, issn = {1520-4995}, mesh = {*G-Quadruplexes ; *Telomere/chemistry ; Humans ; Circular Dichroism ; Nucleic Acid Conformation ; Potassium Chloride/chemistry ; Hydrophobic and Hydrophilic Interactions ; Molecular Dynamics Simulation ; }, abstract = {The unfolding of telomeric G-quadruplexes (G4s) is a key step in telomere elongation and regulation. Within cells, the highly crowded intracellular milieu significantly influences the structural stability and dynamics of G4s; however, the molecular mechanism governing their unfolding under such conditions remains poorly understood. In this study, we have investigated the thermal unfolding of various human telomeric G4 sequences in KCl, both in the absence and presence of molecular crowders, using temperature-dependent circular dichroism (CD) spectroscopy combined with singular value decomposition, multivariate curve resolution alternating least-squares (MCR-ALS), and well-tempered metadynamics simulations. In KCl alone, telomeric G4s exhibit a two-state unfolding mechanism, where the hybrid-type topology directly converts into the unfolded random-coil state. In contrast, under crowded conditions, particularly in the presence of hydrophobic crowders, the unfolding follows a three-state pathway involving a distinct intermediate. The hybrid structure initially transitions to a parallel-type topology at elevated temperatures before fully unfolding. This stabilization of the parallel topology arises from preferential interactions between hydrophobic crowders and the exposed loop nucleobases of the parallel G4 form. On the other hand, hydrophilic crowders exert minimal influence on the unfolding pathway, which remains similar to that observed in KCl solution. Overall, these findings provide molecular-level insights into the unfolding process of telomeric G4 DNA in crowded cell-like environments and may be useful in understanding the complex telomere elongation process.}, } @article {pmid41481411, year = {2026}, author = {Ortholand, J and Gensollen, N and Durrleman, S and Du Montcel, ST}, title = {Joint model with latent disease age: Overcoming the need for reference time.}, journal = {Statistical methods in medical research}, volume = {35}, number = {2}, pages = {225-239}, doi = {10.1177/09622802251399917}, pmid = {41481411}, issn = {1477-0334}, mesh = {Humans ; *Models, Statistical ; Disease Progression ; Amyotrophic Lateral Sclerosis/physiopathology ; Longitudinal Studies ; Age Factors ; Time Factors ; Survival Analysis ; Female ; Male ; }, abstract = {Heterogeneity of the progression of neurodegenerative diseases is one of the main challenges faced in developing therapies. Thanks to the increasing number of clinical databases, progression models have allowed a better understanding of this heterogeneity. Joint models have proven their effectiveness by combining longitudinal and survival data. Nevertheless, they require a reference time, which is ill-defined for neurodegenerative diseases, where biological underlying processes start before the first symptoms. In this work, we propose a joint non-linear mixed-effect model with a latent disease age, to overcome this need for a precise reference time. We used a longitudinal model with a latent disease age as a longitudinal sub-model. We associated it with a survival sub-model that estimates a Weibull distribution from the latent disease age. We validated our model on simulated data and benchmarked it with a state-of-the-art joint model on data from patients with Amyotrophic Lateral Sclerosis (ALS). Finally, we showed how the model could be used to describe ALS heterogeneity. Our model got significantly better results than the state-of-the-art joint model for absolute bias on ALS functional rating scale revised score (4.21(SD 4.41) versus 4.24(SD 4.14)(p-value=1.4×10-17)), and mean-cumulative-AUC for right-censored events on death (0.67(0.07) versus 0.61(0.09)(p-value=1.7×10-03)). To conclude, we propose a new model better suited in the context of unreliable reference time.}, } @article {pmid41481500, year = {2026}, author = {Leon, AM and Sucasaca, A and Choque-Quispe, BM and Medina, WT}, title = {Physical and nutritional properties of meat analogues obtained by high-moisture extrusion with the inclusion of high Andean algae flours: Llaska (Cladophora crispata) and Cushuro (Nostoc sphaericum).}, journal = {Food science and technology international = Ciencia y tecnologia de los alimentos internacional}, volume = {}, number = {}, pages = {10820132251409012}, doi = {10.1177/10820132251409012}, pmid = {41481500}, issn = {1532-1738}, abstract = {Environmental impact of the meat industry and the adverse effects of excessive meat consumption, has prompted the search for sustainable and healthy protein alternatives. This study assessed the physical and textural properties and nutritional profile of two meat analogues processed by high-moisture extrusion, including Llaska (Cladophora crispata) (AL) and Cushuro (Nostoc sphaericum) (AC) flours. Color was evaluated by digital image analysis; textural profile analysis (TPA) was determined by compression tests. The nutritional profile was determined by proximate analysis, spectrophotometric, and chromatographic techniques. AL and AC were green and dark brown, respectively. The luminosity and hue of AC are similar to chicken meat. TPA shows that ALs had a greater degree of hardness and texturization than ACs. AL and AC, processed at a temperature of 135 °C and moisture level of 75% and 65%, respectively, exhibited textures comparable to that of chicken meat. Nutritionally, ACs showed higher antioxidant capacity (∼15,382 μMol Trolox/100 g), ∼30 times higher than chicken meat. Amino acid profiles indicate that both samples provide essential amino acids comparable to chicken meat, which are indispensable in a healthy diet. Consequently, these algae have potential to enrich the nutritional profile of meat analogues as a possible healthy and sustainable alternative to conventional meats.}, } @article {pmid41481541, year = {2026}, author = {Lehto, A and Zapf, A and Hermann, A and Machts, J and Vielhaber, S and Koppenbrink, J and Edbauer, D and Kasper, E and Prudlo, J}, title = {Homozygosity for the C allele at UNC13A rs12608932 seems to compromise cognition in ALS independently of the cognitive domains.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {348-351}, doi = {10.1080/21678421.2025.2608238}, pmid = {41481541}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/complications/psychology ; *Polymorphism, Single Nucleotide/genetics ; Aged ; *Nerve Tissue Proteins/genetics ; *Homozygote ; Retrospective Studies ; Alleles ; *Cognitive Dysfunction/genetics/etiology ; Cognition/physiology ; Adult ; Neuropsychological Tests ; Cohort Studies ; Genetic Predisposition to Disease ; Germany ; }, abstract = {The common single nucleotide polymorphism (SNP) rs12608932 located at a cryptic splice in the UNC13A gene has been reported to modify the clinical phenotype of ALS, but it is unclear whether homozygosity for the C-allele at UNC13A rs12608932 modifies specific domains of cognition in ALS. We analyzed retrospective data from a German cohort and found that the proportion of cognitively or behaviorally impaired patients was higher in the high-risk group of homozygous C-allele carriers. Patients with C/C alleles had lower scores than controls on verbal fluency, executive functioning, and delayed memory recall, but did not differ significantly from other ALS genotypes. Furthermore, informant ratings suggested higher disinhibition in the C/C carriers. These findings indicate that the C/C risk variant of UNC13A rs12608932 may contribute to general cognitive vulnerability rather than domain-specific deficit.}, } @article {pmid41482475, year = {2026}, author = {Bernsen, S and Weydt, P}, title = {Hereditary transthyretin amyloidosis with hand weakness and bulbar involvement.}, journal = {Practical neurology}, volume = {26}, number = {5}, pages = {506-509}, doi = {10.1136/pn-2025-004950}, pmid = {41482475}, issn = {1474-7766}, mesh = {Humans ; Male ; Aged ; *Amyloid Neuropathies, Familial/complications/genetics/diagnosis ; *Muscle Weakness/etiology ; *Hand/physiopathology ; Mutation/genetics ; }, abstract = {A 76-year-old man developed progressive motor weakness, bulbar symptoms and hand muscle atrophy, initially suspected to be due to motor neurone disease. Unexpected findings on cardiological evaluation identified amyloidosis, and genetic testing confirmed the TTR p.Val50Met mutation, indicating late-onset hereditary transthyretin amyloidosis with a mixed neuropathic and cardiac phenotype. The diagnosis was delayed and complicated by minimal sensory symptoms and the atypical presentation.}, } @article {pmid41483413, year = {2026}, author = {Khan, T and Mahboob, H and Zehra, M and Saqib, HW and Ahmad, M}, title = {Super excitability at 7 ms: a superior prognostic biomarker beyond CMAP in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {1}, pages = {71}, pmid = {41483413}, issn = {1590-3478}, } @article {pmid41484784, year = {2026}, author = {Katzenschlager, S and Kaltschmidt, N and Dietrich, M and Fiedler-Kalenka, M and Klemm, S and Kofler, O and Mohr, S and Eisner, C and Neuhaus, C and Simon, C and Weigand, MA and Weilbacher, F and Popp, E}, title = {Prehospital transesophageal echocardiography versus conventional advanced life support in out-of-hospital cardiac arrest (PHTEE-OHCA) - a randomized controlled pilot study.}, journal = {Critical care (London, England)}, volume = {30}, number = {1}, pages = {45}, pmid = {41484784}, issn = {1466-609X}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy ; Male ; Female ; Pilot Projects ; Middle Aged ; Aged ; *Echocardiography, Transesophageal/methods/standards/statistics & numerical data ; Emergency Medical Services/methods/standards/statistics & numerical data ; *Advanced Cardiac Life Support/methods/standards/statistics & numerical data ; Cardiopulmonary Resuscitation/methods ; }, abstract = {BACKGROUND: Transesophageal echocardiography during out-of-hospital cardiac arrest can be performed during ongoing chest compressions and may improve resuscitation quality, but its prehospital use has not been systematically evaluated. To assess the feasibility, diagnostic yield, and impact of prehospital TEE on resuscitation metrics and advanced life support (ALS) interventions during OHCA.

METHODS: We conducted a randomized controlled trial in a physician-staffed two-tiered emergency medical service (EMS). Adults with ongoing non-traumatic OHCA were randomized 1:1 to standard ALS or ALS plus TEE. The primary endpoints were hands-off time and chest compression fraction (CCF) from EMS arrival to return of spontaneous circulation (ROSC) or resuscitation termination. Secondary endpoints included ROSC at hospital admission, survival to hospital discharge, neurological status at hospital discharge, and TEE findings. Analyses followed the intention-to-treat principle.

RESULTS: Of 249 screened patients, 35 were randomized and 32 analyzed (TEE n = 15; control n = 17). Median hands-off time was 4 s in both groups. Mean CCF was higher in the TEE group (96.2%) than the control group (91.6%), with a mean difference of 4.6% (95% confidence interval 2.5-6.7; p < 0.001). Sustained ROSC occurred in 40% (TEE) versus 71% (control; p = 0.083). The control group had an eCPR rate of 41%, compared to 20% in the TEE group. Using TEE, an incorrect area of maximal compression or inadequate depth was identified in 23% and 14%, respectively.

CONCLUSION: Prehospital TEE during OHCA was feasible without negatively interfering with CPR metrics, and provided clinically relevant diagnostic information and procedural guidance, warranting further evaluation in larger trials.

TRIAL REGISTRATION: German Clinical Trials Register DRKS00028695 registered on 28 April 2022.}, } @article {pmid41485061, year = {2026}, author = {Waldherr, SM and Eck, RJ and Hincks, JC and Currey, HN and Goldberg, M and McMillan, PJ and Saxton, AD and Hulsey-Vincent, HJ and Latimer, CS and Kraemer, BC and Liachko, NF}, title = {Calcineurin depletion coincides with phosphorylated TDP-43 deposition in a mouse model of ALS/FTLD-TDP.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {33}, pmid = {41485061}, issn = {2051-5960}, support = {F99AG088436/NH/NIH HHS/United States ; R01 AG066729/AG/NIA NIH HHS/United States ; IK6 BX006467/BX/BLRD VA/United States ; F99 AG088436/AG/NIA NIH HHS/United States ; I01 BX005762/BX/BLRD VA/United States ; IK6BX006467//U.S. Department of Veterans Affairs/ ; P30 AG066509/AG/NIA NIH HHS/United States ; R01AG066729/NH/NIH HHS/United States ; I01BX005762//U.S. Department of Veterans Affairs/ ; R01SN0064131/NH/NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; }, mesh = {Animals ; Female ; Male ; Mice ; *Brain/metabolism ; Caenorhabditis elegans ; *Calcineurin/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Phosphorylation ; *TDP-43 Proteinopathies/metabolism ; Primary Cell Culture ; Mice, Inbred C57BL ; DNA-Binding Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) exhibit predominantly cytoplasmic phosphorylated inclusions of the protein TDP-43 as the major neuropathological lesion. Phosphorylated TDP-43 can modify protein aggregation and promote neuronal dysfunction and neurodegeneration in models of ALS and FTLD-TDP. The phosphatase calcineurin has previously been shown to directly dephosphorylate TDP-43 in vitro and prevent accumulation of phosphorylated TDP-43 in vivo in C. elegans. However, it is unknown whether dysregulation of calcineurin contributes to increased TDP-43 phosphorylation and neurodegeneration in the mammalian brain. Here we show in an inducible mouse model of ALS/FTLD-TDP driven by expression and cytoplasmic mislocalization of human TDP-43 (rNLS8 mice), calcineurin protein decreases dramatically in the brain. This depletion coincides with increased levels of the TDP-43 kinase CDC7 and accumulation of phosphorylated TDP-43, and precedes frank neurodegeneration. Using brain-wide single nucleus RNA sequencing (snRNAseq) in symptomatic rNLS8 mice, we find cell-type selective reduced expression of catalytic and regulatory subunits of calcineurin predominantly in GABAergic and glutamatergic neurons. In mouse primary neuron culture and C. elegans models of ALS/FTLD-TDP, we demonstrate activation or overexpression of calcineurin protects against accumulation of phosphorylated TDP-43, neurotoxicity, and neurodegeneration. Taken together, our data suggests calcineurin dysregulation may be a major contributor to loss of brain resilience mechanisms against phosphorylated TDP-43. Restoring calcineurin activity may present a new target for intervening in TDP-43 proteinopathies, including ALS and FTLD-TDP.}, } @article {pmid41485128, year = {2026}, author = {Mordes, DA and Smeyers, J}, title = {TBK1 orchestrates autophagy and endo-lysosomal pathways in human neurons.}, journal = {Autophagy}, volume = {22}, number = {3}, pages = {632-634}, pmid = {41485128}, issn = {1554-8635}, support = {R01 AG089849/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Protein Serine-Threonine Kinases/metabolism/genetics ; *Autophagy/physiology ; *Lysosomes/metabolism ; *Endosomes/metabolism ; *Neurons/metabolism ; Phosphorylation ; rab GTP-Binding Proteins/metabolism ; rab7 GTP-Binding Proteins ; Sequestosome-1 Protein/metabolism ; Signal Transduction ; }, abstract = {Haploinsufficiency of TBK1 causes familial ALS and frontotemporal dementia (FTD), yet the mechanisms by which TBK1 loss leads to neurodegeneration remain unclear. Using deep proteomics and phospho-proteomics, we demonstrate that TBK1 regulates select macroautophagy/autophagy factors, targeting cargo receptors and autophagy initiation factors, and also sustains the phosphorylation of the late endosomal marker RAB7A in stem cells and stem cell-derived excitatory neurons. We further uncovered novel TBK1-dependent phosphorylation sites in the key autophagy protein SQSTM1/p62. Loss of TBK1 function results in a cell-autonomous neurodegenerative phenotype characterized by impaired neurite outgrowth and lysosomal dysfunction.}, } @article {pmid41486180, year = {2026}, author = {Tarutani, A and Nonaka, T and Ohtani, R and Imai, K and Ito, Y and Tsuji, H and Mochizuki, A and Tamaoka, A and Arai, T and Robinson, AC and Mann, DMA and Kosaka, T and Takahashi, H and Kakita, A and Yoshida, M and Hasegawa, M}, title = {Co-aggregation of annexin A11 and TDP-43 in FTLD/MND with primary lateral sclerosis phenotype.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {34}, pmid = {41486180}, issn = {2051-5960}, support = {JP24wm0625120//Japan Agency for Medical Research and Development/ ; JP21wm0425019//Japan Agency for Medical Research and Development/ ; JP24dk0207074h0001//Japan Agency for Medical Research and Development/ ; JP20K16482//Japan Society for the Promotion of Science/ ; JP25K21773//Japan Society for the Promotion of Science/ ; JP24H00624//Japan Society for the Promotion of Science/ ; JPMJCR18H3//Japan Science and Technology Agency/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; Male ; Female ; Aged ; Middle Aged ; *Annexins/metabolism ; *Motor Neuron Disease/pathology/metabolism ; *Frontotemporal Lobar Degeneration/pathology/metabolism ; Phenotype ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Brain/pathology/metabolism ; }, abstract = {TDP-43 proteinopathies, such as frontotemporal degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), are classified into five neuropathological subtypes, Types A to E, according to the morphology of TDP-43 inclusions. Recent cryo-electron microscopy analysis of FTLD-TDP cases demonstrated that TDP-43 filaments composing the inclusions are structurally different depending on the subtype, and remarkably, co-assembled heteromeric filaments of TDP-43 and annexin A11 (ANXA11) were identified in Type C. Therefore, the involvement of ANXA11 in TDP-43 proteinopathy should be further examined. Here, we pathologically and biochemically analyzed four cases of primary lateral sclerosis-phenotype FTLD/motor neuron disease (MND) with TDP-43 pathology (PLS-TDP), and found that ANXA11 co-localizes with FTLD-TDP Type A pathology in PLS-TDP. Immunoblot analysis of the PLS-TDP cases revealed that the banding patterns of C-terminal and chymotrypsin-resistant fragments of TDP-43 are distinct from those of FTLD-TDP Types A, B and C. In addition, the N-terminal fragments of ANXA11 appear to be different from those of FTLD-TDP Type C. Filaments extracted from PLS-TDP cases were TDP-43- and ANXA11-immunopositive, suggesting the presence of TDP-ANXA11 heteromeric filaments. These results suggest that co-aggregation of ANXA11 and TDP-43 may serve as a neuropathological and biochemical indicator distinguishing PLS from ALS in FTLD/MND.}, } @article {pmid41486306, year = {2026}, author = {Zhuang, SP and Huang, HW and Zeng, JY and Shi, JY and Lin, HY and Chen, S and Wu, Y and Huang, NX and Zou, ZY and Chen, HJ}, title = {Superficial white matter microstructural impairments correlate with functional alterations and disease severity in early-stage amyotrophic lateral sclerosis.}, journal = {La Radiologia medica}, volume = {131}, number = {4}, pages = {680-692}, pmid = {41486306}, issn = {1826-6983}, support = {Nos. 2023CXA009//Fujian Provincial Health Technology Project/ ; Nos. 2024QNA011//Fujian Provincial Health Technology Project/ ; No.2024J01625//Fujian Provincial Natural Science Foundation of China/ ; Nos. 2024Y9253//Fujian Province Joint Funds for the Innovation of Science and Technology/ ; Nos. 2024Y9256//Fujian Province Joint Funds for the Innovation of Science and Technology/ ; No. S202410392033//College Student Innovation Training Program of Fujian Medical University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; Male ; Female ; *White Matter/diagnostic imaging/pathology/physiopathology ; Middle Aged ; Severity of Illness Index ; Aged ; *Magnetic Resonance Imaging/methods ; Case-Control Studies ; Adult ; }, abstract = {PURPOSE: White matter (WM) damage is a key pathophysiological process in amyotrophic lateral sclerosis (ALS). However, alterations in superficial WM (SWM) have not been systematically explored. This study aimed to assess SWM microstructural changes in early-stage ALS and their associations with cortical functional alterations and disease severity.

METHODS: Forty-two early-stage ALS patients and 48 healthy controls were included. Disease severity was evaluated using the revised ALS Functional Rating Scale (ALSFRS-R). The SWM was identified by sampling voxels along the cortical surface, maintaining a fixed distance (2 mm) from the gray matter/WM interface and removing deep white matter regions. SWM microstructural impairments were evaluated via neurite orientation dispersion and density imaging. Functional disturbances in the cortical regions corresponding to impaired SWM were measured by assessing regional homogeneity (ReHo) that reflects local synchronization of neuronal activity.

RESULTS: Patients showed a decreased neurite density index (NDI) in specific SWM regions, primarily including the bilateral precentral gyrus, supplementary motor area, paracentral lobule, and postcentral gyrus (family-wise error-corrected P < 0.05). Additionally, significant ReHo reductions were observed in cortical regions corresponding to compromised SWM. Both SWM NDI and cortical ReHo values significantly correlated with the ALSFRS-R score. Cortical ReHo alterations mediated the relationship between the SWM NDI value and the ALSFRS-R score (mediation effect = 0.103). SWM NDI assessments effectively identified ALS (area under the curve = 0.725-0.926).

CONCLUSION: Our findings highlight the SWM disruption as a crucial neurobiological substrate involved in early-stage ALS neuropathological mechanisms.}, } @article {pmid41486410, year = {2026}, author = {Wang, F and Zhang, KY and Zhu, LJ and Li, WJ and Wu, Y and Gao, X and Ma, XR and Yin, XH and Wu, JB and Ye, XK and Dong, ZJ and Wang, DX and Zhou, Z and Wang, SD and Han, L and Jiang, ZN and Zhao, JW}, title = {Microglial HVCN1 Deficiency Improves Movement and Survival of SOD1[G93A] ALS Mice by Enhancing Microglial Migration and Neuroprotection.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {13}, pages = {e12149}, pmid = {41486410}, issn = {2198-3844}, support = {STI2030-MajorProjects2021ZD0201705//National Key R&D Program of China/ ; NSFC82371576//National Natural Science Foundation of China/ ; BZZ19J005//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Microglia/metabolism ; Mice ; Disease Models, Animal ; *Neuroprotection/physiology/genetics ; Motor Neurons/metabolism ; *Cell Movement/genetics ; Humans ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease characterized by progressive loss of motor neurons. Current clinically available drugs targeting neurons show minor survival extension and no motor improvement in ALS patients. This shifts the focus of ALS research toward non-neuronal cells, particularly microglia, a critical driver of ALS pathogenesis. Highly druggable ion channels are key regulators of microglia function. Here, Hydrogen voltage gated channel 1 (HVCN1) was screened out as the most highly expressed ion channel in microglia, and was upregulated in microglia of SOD1[G93A] mice and patients. Deletion of HVCN1 in microglia increased motor neuron survival, rescued the innervated neuromuscular junctions in the muscle, reduced glial activation and decreased the level of both misfolded protein and myelin debris in the ALS mice. Importantly, these pathological improvements were translated into significant motor improvement and survival extension in the ALS mice, exhibiting better effects than the current clinical drugs. HVCN1 deletion enhanced microglia migration and their homeostatic state with elevated neurotrophic functions. Mechanistically, HVCN1 ablation promoted microglial migration via suppressing Akt signaling. Our results identify HVCN1 as a novel promising therapeutic target for ALS, opening a new avenue to further develop specific inhibitors for HVCN1 to alleviates ALS.}, } @article {pmid41488323, year = {2025}, author = {Lotlikar, MS and Zellmer, JC and Bhattacharyya, R}, title = {Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1733659}, pmid = {41488323}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.}, } @article {pmid41488805, year = {2026}, author = {Klassen, P and Alexudis, C and Klose, V and de San José, NG and Huss, A and Bachhuber, F and Soylu, Ö and Fazeli, B and Erhart, D and Laible, M and Anderl-Straub, S and Jesse, S and Otto, M and Ludolph, AC and Tumani, H and Halbgebauer, S}, title = {Increased transmembrane protein 119 (TMEM119) levels in the cerebrospinal fluid of patients with mild cognitive impairment due to Alzheimer's disease suggest early microglial involvement.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {18}, number = {1}, pages = {e70240}, pmid = {41488805}, issn = {2352-8729}, abstract = {INTRODUCTION: We aimed to evaluate the potential of the microglial marker transmembrane protein 119 (TMEM119) in the cerebrospinal fluid (CSF) as a (differential) diagnostic biomarker for neurodegenerative diseases.

METHODS: Following assay validation, we used enzyme-linked immunosorbent assay to measure CSF TMEM119 in 174 patients from six diagnostic groups: Alzheimer's disease (AD, n = 35), amyotrophic lateral sclerosis (ALS, n = 33), cerebral microangiopathy (CM, n = 25), frontotemporal lobar degeneration (FTLD, n = 28), Lewy body diseases (n = 21), and non-neurodegenerative controls (n = 33).

RESULTS: CSF TMEM119 levels were elevated in the AD group compared to the control (p = 0.004), CM (p = 0.005), and FTLD (p = 0.023) groups. Levels were higher in both mild cognitive impairment (MCI-AD) and dementia (ADD) subgroups when compared to controls. For the discrimination of AD from controls, the area under the curve (AUC) was 0.78.

DISCUSSION: Our results indicate that CSF TMEM119 may have potential as a biomarker representing microglial involvement in early and later stages of AD.

HIGHLIGHTS: Elevated levels of TMEM119 were observed in the CSF of patients with AD.Increased CSF TMEM119 was seen in MCI-AD patients compared to controls.Elevated levels in MCI-AD underscore early microglial involvement in AD.In the AD group, an association was found between CSF TMEM119 and CSF total tau.CSF TMEM119 may provide valuable information on neuroinflammation.}, } @article {pmid41489058, year = {2026}, author = {Pilotto, F and Toth, TD and Bond, S and Schmitz, A and Diab, R and Tenlep, SYN and Mooney, B and Erni, S and Schobesberger, M and Scheidegger, O and Peitsch, C and Saxena, S}, title = {Engineered GM1 Intersects Between Mitochondrial and Synaptic Pathways to Ameliorate ALS Pathology.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {20}, pages = {e14128}, pmid = {41489058}, issn = {2198-3844}, support = {31ER30_179595//E-Rare/ ; //InnoMedica Schweiz AG/ ; //Swiss Foundation for Research on Muscle Diseases/ ; //Spinal Cord Injury/Disease Research Program (SCIDRP), University of Missouri/ ; 725825/ERC_/European Research Council/International ; 179436/SNSF_/Swiss National Science Foundation/Switzerland ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; Animals ; Mice ; *Mitochondria/metabolism/drug effects ; Humans ; Motor Neurons/metabolism/drug effects ; *G(M1) Ganglioside/pharmacology ; Disease Models, Animal ; Endoplasmic Reticulum Stress/drug effects ; C9orf72 Protein/genetics ; *Synapses/metabolism/drug effects ; Induced Pluripotent Stem Cells/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal condition marked by the degeneration of motor neurons. ALS has been linked to numerous genes with diverse biological roles, reflecting a highly intricate and multifaceted disease process. This diversity poses significant challenges in developing universally effective and bioavailable treatments. Advancing therapeutic strategies require uncovering molecular pathways that are major drivers of ALS. We conducted proteomic analyses of human iPSC-derived motor neurons carrying C9ORF72 mutations, alongside spinal ventral horns from mice with pathogenic C9orf72-mutations. This cross-species approach revealed disruptions in synaptic vesicle release, endoplasmic reticulum (ER) and mitochondrial stress responses as conserved ALS pathogenic mechanisms. Disease progression was associated with accumulation of cytotoxic protein aggregates and oxidative stress. We analyzed the potential of GM1, an established neuroprotective molecule, to reverse these pathogenic features. To enhance the pharmacokinetics of GM1, we developed Talineuren (TLN), a nanoliposome-based formulation of the active pharmaceutical ingredient GM1 ganglioside that improves its bioavailability. GM1 stabilized mitochondrial Ca[2][+] handling, improved energy metabolism, and alleviated ER stress, preventing protein aggregation and restoring cellular proteostasis and counteracted behavioral deficits in C9orf72 and SOD1-G93A mouse models. Together, these findings underscore the central, convergent role for cellular disruptions in ALS and position TLN as a promising therapeutic candidate.}, } @article {pmid41490046, year = {2026}, author = {Maheswari Jawahar, V and Zeng, Y and Armour, EM and Yue, M and Citrano, K and Lovchykova, A and Reeves, MM and Rawlinson, B and DeTure, M and Dunmore, JA and Song, Y and Ball, SK and Wszolek, ZK and Graff-Radford, NR and Boeve, BF and Knopman, DS and Day, GS and Small, SA and Dickson, DW and Ward, ME and Gendron, TF and Zhang, Y and Prudencio, M and Gitler, AD and Petrucelli, L}, title = {TDP-43-mediated alternative polyadenylation is associated with a reduction in VPS35 and VPS29 expression in frontotemporal dementia.}, journal = {PLoS biology}, volume = {24}, number = {1}, pages = {e3003573}, pmid = {41490046}, issn = {1545-7885}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R01 NS120992/NS/NINDS NIH HHS/United States ; R35 NS137159/NS/NINDS NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; R01 NS117461/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Polyadenylation/genetics ; Female ; *Vesicular Transport Proteins/genetics/metabolism ; Male ; Aged ; 3' Untranslated Regions/genetics ; Middle Aged ; Aged, 80 and over ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) dysfunction is a hallmark of several neurodegenerative diseases, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer's disease. Although cryptic exon inclusion is a well-characterized consequence of TDP-43 loss of function, emerging evidence reveals broader roles in RNA metabolism, notably in the regulation of alternative polyadenylation (APA) of disease-relevant transcripts. In the present study, we examined 3' untranslated region lengthening events in the brains of individuals with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), focusing on the functional impact of APA dysregulation. To investigate whether TDP-43-mediated APA events occur in the postmortem brain, we measured the 3' untranslated region length of the retromer component vacuolar protein sorting 35 (VPS35) and the ETS transcription factor (ELK1) in the frontal cortex of a large cohort of FTLD-TDP patients and of healthy controls, and evaluated if these APA events are associated with FTLD-TDP clinical characteristic, markers of TDP-43 pathology [e.g., hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA], or the expression of VPS35 and VPS29 proteins, the latter being essential to the retromer complex. We identified robust 3' untranslated region lengthening of VPS35 and ELK1 in FTLD-TDP, which strongly associated with markers of TDP-43 pathology, and ELK1 APA also associated with an earlier age of disease onset. Functionally, VPS35 APA was associated with reduced VPS35 and VPS29 protein expression, and lower VPS35 levels were associated with increased hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA. Together, these data implicate APA dysregulation as a critical downstream consequence of TDP-43 dysfunction and suggest that TDP-43 loss may contribute to retromer impairment through APA-mediated repression of retromer subunits.}, } @article {pmid41490238, year = {2026}, author = {Ni, S and Chen, K and Wang, H and Chen, S and Qiu, Y and Wang, T and Mo, F and Wang, S and Li, B and Bai, Y and Zhao, J and Zhai, X and Li, Z}, title = {A new paradigm of bidirectional regulation of the gut-spinal cord axis.}, journal = {Neural regeneration research}, volume = {21}, number = {9}, pages = {4100-4111}, pmid = {41490238}, issn = {1673-5374}, abstract = {The bidirectional interactions of spinal cord injury, multiple sclerosis, and amyotrophic lateral sclerosis with the gut operate through a distinct gut-spinal cord axis, rather than being fully explained by the conventional gut-brain axis. The spinal cord, with its unique anatomical and physiological features, serves as a central hub of communication. The gut and spinal cord communicate through various pathways, including the immune system and the autonomic and enteric nervous systems. This review summarizes existing clinical and basic research on the relationship between gut homeostasis and spinal cord diseases. First, we present findings from epidemiological studies showing that patients with spinal cord disorders often exhibit altered gut function, which may be influenced by antibiotic exposure and environmental factors. Second, we review the key physiological and anatomical structures of the gut-spinal cord axis, including the intestinal barrier, gut microbiota, and enteric nervous system, all of which are involved in maintaining gut health, as well as sensory neurons, motor neurons, and interneurons in spinal nerve regulation. Third, we describe the roles of the three axes (microbial, immune, and neural) in bidirectional regulation and their pathological mechanisms. Moreover, vicious cycles involving these axes can exacerbate spinal cord disorders. Fourth, we outline potential biomarkers in the gut-spinal cord axis, such as uridine, hypoxanthine, and 5-methoxytryptophan. Fifth, we propose several treatment strategies with potential clinical applications, including fecal microbiota transplantation and the use of probiotics and prebiotics. Finally, this review emphasizes the gut-spinal cord axis as a promising therapeutic target, highlighting the need for multi-omics integration, longitudinal cohort studies, and individualized interventions to resolve existing debates. Overall, the recognition of the gut-spinal cord axis provides a conceptual shift that extends beyond the gut-brain framework.}, } @article {pmid41491573, year = {2026}, author = {Kuramitsu, Y and Itou, J and Munakata, Y and Okazaki, K}, title = {Transverse incisions improve scar outcomes in anterolateral supine approach total hip arthroplasty: a patient observer scar assessment scale-based study.}, journal = {Arthroplasty (London, England)}, volume = {8}, number = {1}, pages = {2}, pmid = {41491573}, issn = {2524-7948}, abstract = {BACKGROUND: This study compared transverse and longitudinal skin incisions in anterolateral supine (ALS) total hip arthroplasty (THA), focusing on cosmetic and sensory outcomes using the Patient Observer Scar Assessment Scale (POSAS).

METHODS: A retrospective analysis was conducted on 132 hips that underwent primary ALS THA performed by a single surgeon between 2019 and 2024. Longitudinal incisions were used until December 2022, and transverse incisions aligned with relaxed skin tension lines were used thereafter. POSAS 3.0 was used to evaluate scar quality across satisfaction, appearance, and sensory domains.

RESULTS: Baseline characteristics were similar between groups, except for follow-up duration and incision length. No significant differences were found in POSAS scores. However, regression analysis revealed that transverse incision significantly improved satisfaction (P = 0.04) and appearance (P < 0.05). Sensory scores were significantly affected by follow-up duration (P < 0.001).

CONCLUSION: Transverse incisions in ALS THA may enhance cosmetic satisfaction without compromising sensory outcomes. These findings support the potential role of personalized incision planning for improving patient-reported outcomes following THA. Video Abstract.}, } @article {pmid41492782, year = {2026}, author = {Dallaire, JS and Bachand, MP and Shaul, J and Lareau-Trudel, E}, title = {Mortality and Complications of Percutaneous Gastrostomy in Amyotrophic Lateral Sclerosis Patients.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-8}, doi = {10.1017/cjn.2025.10510}, pmid = {41492782}, issn = {0317-1671}, abstract = {BACKGROUND: Installation of a percutaneous gastrostomy tube is often needed for patients with amyotrophic lateral sclerosis (ALS) who develop severe dysphagia. However, there is uncertainty regarding the optimal timing for this procedure, especially with regard to the decline in respiratory function. Several guidelines suggest that gastrostomy should be placed before the forced vital capacity (FVC) drops below 50%, since the procedural risks are heightened. However, multiple studies argue that this procedure could be safe in patients with an FVC of less than 50%.

METHODS: In this retrospective study, we reviewed the medical records of all patients with ALS who had a gastrostomy at our center between 2010 and 2023. Our primary objective was to identify the 30-day mortality rate and the incidence of complications after this procedure. Also, we investigated whether predictive factors of adverse outcomes could be identified, particularly to evaluate if there was an association with pulmonary function.

RESULTS: We included 54 patients. The 30-day mortality rate was 9.3%, and the incidence of major complications was 16.7%. There was no statistical difference in complications between percutaneous endoscopic and radiologically inserted gastrostomy procedures. Predictive factors for complications were pre-existing pulmonary disease, pre-procedural CO2 levels and, although not statistically significant, diabetes. There was no association between FVC and the occurrence of adverse outcomes, although only 70% of patients had a measure of pulmonary function.

CONCLUSION: In our study, there was no correlation between FVC and the occurrence of adverse events from the gastrostomy procedure. This suggests that the traditional cutoff of 50% FVC level should be re-examined and explored further in future studies.}, } @article {pmid41493066, year = {2026}, author = {De Vocht, J and Costello, E and McHutchison, C and Radakovic, R and Foucher, J and McMackin, R and Peelo, C and van den Berg, L and Hardiman, O and Van Damme, P and Pender, N and Abrahams, S and Lulé, D and , }, title = {Prioritizing neuropsychological research and care in Amyotrophic Lateral Sclerosis (ALS): building an international neuropsychological framework for ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {711-714}, doi = {10.1080/21678421.2025.2610290}, pmid = {41493066}, issn = {2167-9223}, } @article {pmid41493706, year = {2026}, author = {Hashemi, M and Shafiei Asheghabadi, P and Moassesfar, M and Mashhadikhan, S and Nasirzade, S and Vasheghani Farahani, A and Mehdizadeh, S and Minaei, S and Rahmani, M and Jamshidian, F and Farahani, N and Reiter, RJ and Taheriazam, A and Hasani Sadi, F and Hushmandi, K and Alimohammadi, M and Rahimzadeh, P and Entezari, M}, title = {MicroRNAs and Long Non-Coding RNAs Affect the Mechanisms Involved in Age-Related Neurodegeneration in a Manner Depending on RNA-Binding Proteins.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {343}, pmid = {41493706}, issn = {1559-1182}, mesh = {Humans ; *RNA, Long Noncoding/metabolism/genetics ; *MicroRNAs/genetics/metabolism ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; *Aging/genetics/pathology/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are marked by progressive neuronal loss and aberrant protein aggregation, presenting substantial global healthcare challenges. Recent research has illuminated the pivotal roles of RNA-binding proteins (RBPs) and non-coding RNAs (ncRNAs), notably microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in the molecular pathogenesis of age-related neurodegeneration. RBPs orchestrate RNA metabolism and engage extensively with miRNAs and lncRNAs to modulate gene expression at the post-transcriptional level. Dysregulation of these interactions precipitates pathological phenomena such as protein misfolding, stress granule formation, and disrupted RNA processing, thereby exacerbating neuronal dysfunction and death. Specific miRNAs have been implicated in regulating key neurodegenerative biomarkers, including tau and amyloid-β in AD, motor neuron maintenance in ALS, and survival pathways in HD. Elucidating the intricate interplay between RBPs and ncRNAs holds significant promise for the development of therapeutic strategies aimed at ameliorating RNA-mediated mechanisms in neurodegenerative disorders.}, } @article {pmid41493797, year = {2026}, author = {Esteve, D and Bresque, M and Okhuevbie, D and Ramachandran, S and Pehar, M and Vargas, MR}, title = {Lactate Dehydrogenase Inhibition Reverts the Fatty Acid-Induced Neurotoxic Phenotype of Astrocytes.}, journal = {Glia}, volume = {74}, number = {3}, pages = {e70136}, pmid = {41493797}, issn = {1098-1136}, support = {R01 NS089640/NS/NINDS NIH HHS/United States ; R01 NS122973/NS/NINDS NIH HHS/United States ; R01NS089640/NS/NINDS NIH HHS/United States ; R01NS122973/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Astrocytes/drug effects/metabolism/pathology/enzymology ; Humans ; *Fatty Acids/toxicity ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; *L-Lactate Dehydrogenase/antagonists & inhibitors/metabolism/genetics ; Mice, Transgenic ; Mice ; Cells, Cultured ; Motor Neurons/drug effects/metabolism/pathology ; Coculture Techniques ; Phenotype ; Spinal Cord/pathology ; Mice, Inbred C57BL ; Disease Models, Animal ; Lipid Metabolism/drug effects ; Lipid Droplets/metabolism/drug effects ; Male ; }, abstract = {Astrocytes are central to lipid metabolism in the central nervous system. Due to their morphological and functional characteristics, astrocytes can uptake fatty acids (FAs) from the bloodstream and extracellular space and store them in lipid droplets (LD). LD are dynamic organelles, whose accumulation in astrocytes has been shown to occur upon exposure to various stress stimuli. Different hypotheses proposed to explain motor neuron degeneration in amyotrophic lateral sclerosis (ALS) implicate mitochondrial dysfunction and oxidative stress. Mitochondrial dysfunction in astrocytes is associated with elevation of cytoplasmic lipids and lipid-binding proteins. We observed increased LD in the spinal cord of symptomatic ALS mice, as well as in human transdifferentiated astrocytes obtained from ALS patients. Using a co-culture model, we examined the effect of FA overload and its impact on astrocyte-motor neuron interaction. LD accumulation was tightly coupled with an NF-κB-driven proinflammatory response in nontransgenic astrocytes, correlating with motor neuron toxicity. These results provide additional evidence to the notion that altered energy balance may contribute to neuronal death in ALS. Furthermore, pharmacological inhibition of lactate dehydrogenase (LDH) reversed LD accumulation in mouse and human astrocytes expressing ALS-linked mutations. Genetic ablation of LDHA similarly reduced LD accumulation in response to FA treatment. Collectively, our data underscore the role of lipid metabolism in astrocyte-neuron interactions in ALS models and suggest that LD accumulation, rather than serving solely as a protective mechanism, reflects a metabolic stress state linked to a detrimental phenotypic transformation in astrocytes.}, } @article {pmid41495602, year = {2026}, author = {Vahsen, BF and Pasterkamp, RJ}, title = {Microglia in C9orf72-associated amyotrophic lateral sclerosis: More or less active?.}, journal = {Neural regeneration research}, volume = {21}, number = {9}, pages = {4253-4254}, pmid = {41495602}, issn = {1673-5374}, } @article {pmid41495620, year = {2026}, author = {Li, Y and Feng, Y and Liu, X and Yuan, R and Chen, S and Wang, J and Pan, C and Li, G and Tang, Z}, title = {Functional near-infrared spectroscopy: Systematic mapping of abnormal brain function features in neurological disorders.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {4506-4522}, pmid = {41495620}, issn = {1673-5374}, abstract = {Functional near-infrared spectroscopy quantifies cerebral hemodynamic signals by capturing oxygenation-dependent changes in hemoglobin in a noninvasive, portable, and ecologically valid manner, providing a unique insight into neurovascular coupling. However, functional imaging biomarkers with high ecological validity for neurological disorders such as stroke, Parkinson's disease, dementia, amyotrophic lateral sclerosis, epilepsy, spinal cord injury, and traumatic brain injury are lacking, limiting the mechanistic understanding, treatment evaluations, and individualized interventions. The aim of this review is to systematically summarize evidence from the past decade on the use of functional near-infrared spectroscopy under the aforementioned conditions, synthesize its value for revealing neural mechanisms and assessing therapeutic responses, and identify current technical bottlenecks and future directions for advancement. Collectively, the findings demonstrate that functional near-infrared spectroscopy possesses substantial and far-reaching potential for uncovering the neural mechanisms underlying disease and for evaluating treatment-induced changes in brain function. Equipped with wearable probes, functional near-infrared spectroscopy can continuously and noninvasively monitor brain activity in naturalistic environments for extended periods, thereby overcoming the limitations of conventional imaging modalities that can only acquire data under restricted settings. This capability can furnish unprecedented objective neuroimaging evidence for neuroregenerative therapy research. Moreover, the portability of functional near-infrared spectroscopy allows it to be integrated into neurofeedback training systems: hemoglobin signals can be fed back to participants within milliseconds, enabling targeted, individualized, closed-loop modulation of brain function and considerably expanding the scope of hemodynamics-based neurofeedback. When combined with other brain function assays (such as electroencephalography) and intervention techniques (such as transcranial magnetic stimulation and transcranial direct current stimulation), functional near-infrared spectroscopy also supplies high-temporal-resolution hemodynamic information, laying a critical foundation for the construction of high-precision noninvasive brain-computer interfaces, real-time cognitive-state decoding, and adaptive neuromodulation. Admittedly, almost all existing functional near-infrared spectroscopy studies are still observational and have small sample sizes, short follow-ups, and insufficient controls-shortcomings that together produce low-grade evidence. Therefore, there is still a significant gap before clinical translation can be achieved. Technically, the limited penetration depth of functional near-infrared spectroscopy restricts sampling to the superficial cortex, leaving deep nuclei largely unreachable. In addition, no consensus exists across devices regarding optode layout, light-source choice, motion-artifact correction, or analytical pipelines, creating pronounced heterogeneity that undermines reproducibility. With artificial intelligence and big data analytics advancing rapidly, functional near-infrared spectroscopy embedded within multimodal fusion frameworks is now poised to systematically map aberrant brain function signatures of neurological disorders, identify pathological regions suitable for targeted intervention, and provide real-time assessments of functional changes produced by neuroregenerative therapies.}, } @article {pmid41496108, year = {2026}, author = {Wang, YW and Zhang, Y and Hu, X and Li, X and Han, L and Wang, DX and Ding, T}, title = {Recurarization after sugammadex reversal in a patient with amyotrophic lateral sclerosis: Case report.}, journal = {Medicine}, volume = {105}, number = {1}, pages = {e46928}, pmid = {41496108}, issn = {1536-5964}, mesh = {Humans ; *Sugammadex ; Female ; *Amyotrophic Lateral Sclerosis/complications ; Rocuronium ; Aged ; *Neuromuscular Nondepolarizing Agents/adverse effects ; *gamma-Cyclodextrins ; Gastrostomy/methods ; Androstanols/adverse effects ; Respiratory Insufficiency/etiology ; Neuromuscular Blockade/adverse effects ; *Delayed Emergence from Anesthesia ; }, abstract = {RATIONALE: Amyotrophic lateral sclerosis (ALS) confers heightened and unpredictable sensitivity to nondepolarizing neuromuscular blocking agents and a high risk of postoperative respiratory failure. Although sugammadex reliably reverses rocuronium, recurarization may occur and is likely under-recognized in ALS. We report 2 ALS patients undergoing percutaneous endoscopic gastrostomy, one of whom developed delayed recurarization after apparent reversal.

PATIENT CONCERNS: Both women (67 and 68 years) presented with progressive dysphagia requiring percutaneous endoscopic gastrostomy. Case 1 had dyspnea, dysarthria, and long-standing noninvasive positive-pressure ventilation; Case 2 had bulbar signs without preoperative ventilatory support. The key perioperative concern in both cases was ventilatory failure from residual neuromuscular block.

DIAGNOSES: ALS had been established clinically. In Case 2, recurarization was diagnosed shortly after extubation when acute hypercapnic respiratory failure and clinical weakness followed an earlier recovery to a train-of-four (TOF) ratio of 92%.

INTERVENTIONS: Intravenous anesthesia with propofol and remifentanil was used. Case 1 received rocuronium 10 mg (0.2 mg/kg) and was reversed with sugammadex 90 mg (2 mg/kg) at TOF count 0, achieving a TOF ratio of 98% within 3 minutes before extubation and postoperative noninvasive ventilation. Case 2 received rocuronium 30 mg (0.6 mg/kg) and sugammadex 200 mg (3.8 mg/kg) at TOF count 1, recovered to a TOF ratio of 92% at 4 minutes, but developed respiratory failure 3 minutes after extubation; mask ventilation and neostigmine 2 mg with atropine 0.25 mg were given.

OUTCOMES: Case 1 recovered uneventfully and was discharged on postoperative day (POD) 6. Case 2 required intensive care unit admission, re-intubation on POD 1, and re-extubation on POD 3; she was discharged on POD 23 without new neurologic deficits.

LESSONS: In ALS, recurarization can occur despite seemingly adequate sugammadex reversal. When rocuronium is used, sugammadex is recommended for reversal, with vigilant quantitative neuromuscular monitoring and extended post-extubation observation to detect delayed weakness.}, } @article {pmid41496184, year = {2026}, author = {Portaro, S and Latella, D and Manuli, A and Calderone, A and Calabrò, RS}, title = {Bridging the gap in sexuality and neuromuscular disorders: a scoping review of an overlooked but crucial topic.}, journal = {Sexual medicine reviews}, volume = {14}, number = {1}, pages = {}, doi = {10.1093/sxmrev/qeaf076}, pmid = {41496184}, issn = {2050-0521}, support = {//Current Research Funds 2024-2025/ ; //Ministry of Health, Italy/ ; }, mesh = {Humans ; *Neuromuscular Diseases/psychology ; *Quality of Life/psychology ; *Sexuality/psychology ; *Sexual Dysfunction, Physiological/psychology ; Social Stigma ; *Sexual Health ; }, abstract = {INTRODUCTION: Neuromuscular disorders (NMDs) comprise a group of conditions affecting the muscles and/or the nerves controlling them, resulting in progressive muscle weakness. Beyond the physical limitations, NMDs can significantly impact quality of life (QoL), including sexuality. Sexuality, as defined by the World Health Organization, encompasses physical, psychological, and social dimensions. However, research exploring the multifaceted impact of NMDs on sexual well-being remains limited, despite the potential influence of physical impairments, psychological distress, and social stigma.

OBJECTIVES: This scoping review aims to synthesize the existing literature on sexuality in individuals with NMDs, identifying the interplay of physical, psychological, and social factors affecting sexual QoL, highlighting research gaps, and informing future research and clinical practice.

METHODS: A scoping review was conducted using PubMed, Web of Science, Cochrane Library, Embase, and Scopus databases (up to May 15, 2025) to identify studies examining sexuality in individuals with NMDs. Studies addressing physical, psychological, and social factors influencing sexual health in NMD patients were included. Data were extracted using a standardized form and synthesized narratively. The review was registered on Open OSF (DOI https://doi.org/10.17605/OSF.IO/RP9U2).

RESULTS: Fourteen studies with various conditions such as Duchenne muscular dystrophy, amyotrophic lateral sclerosis (ALS), myotonic dystrophy type 1, myasthenia gravis, and Charcot-Marie-Tooth disease were included, from interviews to surveys. One key theme that emerged was the extent to which personal narratives reveal the emotional weight of stigma, the struggle with body image, and how intimacy is peripheral in medical institutions. In surveys, many said their sexual activity had declined, particularly among people with progressive diseases like ALS and myotonic dystrophy. Many of these studies also pointed to how sexual health was directly associated with QoL, a good reminder that it's an important aspect of well-being that we need to pay more attention to in care and support.

CONCLUSION: This scoping review highlights a significant gap in research regarding sexuality in individuals with NMDs. The limited number of studies identified underscores the need for further research to understand the complex interplay of physical, psychosocial, and social factors affecting sexual well-being in this population.}, } @article {pmid41497595, year = {2025}, author = {Zhong, W and Scialò, C and Gatta, B and Häfliger, M and Leu, N and Lurati, F and Peter, M and Ramesh, N and Roschitzki, B and Jagannath, S and Manglunia, R and de Cecco, E and Lim, SM and Wilkins, OG and Aguzzi, A and Ward, M and Fratta, P and Petrucelli, L and Lagier-Tourenne, C and Polymenidou, M}, title = {Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41497595}, issn = {2692-8205}, support = {RM1 NS133601/NS/NINDS NIH HHS/United States ; }, abstract = {Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) shows striking clinical and neuropathological heterogeneity, yet a systematic analysis of subtype-specific features and inter-patient variability was missing. We treated human neurons and neuron-like cells with 30 postmortem brain samples and quantified neoaggregate formation, loss of function and changes in the TDP-43 interactome to define determinants of seeding outcomes. Potent FTLD-TDP-A seeds drove a progressive collapse of physiological TDP-43 interactions accompanied by functional loss. Beyond the burden of pathological TDP-43, we identified the fibrillar core of the lysosomal protein TMEM106B as a critical pro-seeding factor. Transient lysosomal injury markedly enhanced neoaggregation and loss of function, likely by promoting fibril interactions with native TDP-43. Our work establishes a mechanistic link between TMEM106B and TDP-43 aggregation, identifies lysosomal escape as a key driver of pathology and introduces the strongest model yet for seeded TDP-43 aggregation and loss of function, to enable discovery of disease modifiers.}, } @article {pmid41498289, year = {2025}, author = {Ram, J and Glickman, MH}, title = {The many faces of p97/Cdc48 in mitochondrial homeostasis.}, journal = {Essays in biochemistry}, volume = {69}, number = {5}, pages = {}, pmid = {41498289}, issn = {1744-1358}, mesh = {*Valosin Containing Protein/metabolism/genetics ; Humans ; *Mitochondria/metabolism ; *Homeostasis ; Animals ; *Adenosine Triphosphatases/metabolism/genetics ; Mitochondrial Proteins/metabolism ; Mitochondria Associated Membranes ; Nuclear Proteins ; }, abstract = {Through its various roles in protein quality control, membrane dynamics, and cellular survival pathways, the AAA+ ATPase p97/valosin-containing protein emerges as a significant regulator of mitochondrial homeosta sis. This review comprehensively examines the multifaceted functions of p97 in mitochondrial biology, spanning from mitochondria-associated degradation to newly discovered functions in organellar cross-talk and disease pathogenesis. Underlying its cellular importance, p97 mutations are found in amyotrophic lateral sclerosis and frontotemporal dementia. To elucidate its mechanistic contribution to these processes, we provide a detailed table (Table 1) listing all known mitochondrial Cdc48/p97 substrates and associ ated proteins, categorized by their respective pathways. Recruitment to most of these substrates occurs by specialized adaptors, including Doa1/phospholipase A-2-activating protein, UBXD8, and UBXN1. p97 orchestrates the extraction and proteasomal degradation of outer mitochondrial membrane proteins, which are essential for maintaining mitochondrial integrity. For example, by controlling the turnover of fusion factors MFN1/2 and fission machinery, p97 regulates mitochondrial dynamics. p97 also governs apoptotic signaling through the regulated degradation of anti-apoptotic factors, such as myeloid cell leukemia-1 and VDAC, thereby modulating mitochondrial permeability. In mitophagy, p97 enables the clearance of damaged organelles by extracting ubiquitinated substrates and recruiting autophagy machinery. Beyond proteolysis, p97 facilitates recycling of endoplasmic reticulum-mitochondria contact sites through regulation of UBXD8-dependent lipid metabolism. Recent discoveries have revealed p97's involvement in pathogen host interactions and circular RNA-mediated regulation, thereby expanding our understanding of its cellular functions. The emerging picture positions p97 as an integrative hub co-ordinating mitochondrial protein homeostasis, organellar dynamics, and cell fate decisions, with therapeutic potential for metabolic and neurodegenerative disorders.}, } @article {pmid41498343, year = {2026}, author = {Spencer, C and Connon, CC and Seashols-Williams, SJ}, title = {Semen extraction efficiency and recovery before and after washing from reusable period underwear.}, journal = {Journal of forensic sciences}, volume = {71}, number = {2}, pages = {962-969}, doi = {10.1111/1556-4029.70255}, pmid = {41498343}, issn = {1556-4029}, mesh = {Humans ; DNA Fingerprinting ; *Semen/cytology ; Acid Phosphatase/analysis ; Microsatellite Repeats ; Male ; *DNA/isolation & purification ; *Laundering ; *Specimen Handling/methods ; Female ; Spermatozoa ; }, abstract = {When sexual assault evidence kits do not yield biological evidence demonstrating sexual contact, clothing such as undergarments is evaluated for the presence of semen. Menstrual underwear is a new type of undergarment and feminine product encountered as evidence in sexual assaults. They are composed of absorbent and leak-proof layers and can be washed and re-worn multiple times. The objective of this work was to determine a best practice for semen and DNA recovery from reusable menstrual underwear. Simulated postcoital samples were deposited on three different brands of menstrual underwear, and alternate light source evaluation failed for two of the three brands tested, though acid phosphatase testing was positive for all three brands tested. Testing of individual layers versus cuttings of a portion of the stain found that a full-depth cutting results in optimal biological sample recovery. Mock postcoital deposits were then washed once or twice and subjected to serological and DNA workflows, with varying results in acid phosphatase and P30 testing after washing once or twice between brands. However, sperm recovery was successful in all samples, and complete short tandem repeat (STR) profiles were obtained from both sperm and nonsperm fractions from all samples, regardless of washing status. With these findings, while sperm recovery has the highest likelihood of success with a full-thickness cutting, forensic scientists should be cautious in depending on ALS for stain location. Additionally, biological materials remain in these brands of menstrual underwear after washing, and therefore, biological material from previous sexual contact could remain and be detectable.}, } @article {pmid41498389, year = {2026}, author = {Wang, XC and Yang, C and Lv, H and Zhang, XJ and Zhou, WT and Lu, P and Yu, Y and Fu, H and She, Y}, title = {A GC-MS Data Analysis Platform for Untargeted Metabolomics with Enhanced Coeluting Peak Resolution.}, journal = {Analytical chemistry}, volume = {98}, number = {2}, pages = {1416-1426}, doi = {10.1021/acs.analchem.5c05471}, pmid = {41498389}, issn = {1520-6882}, mesh = {*Gas Chromatography-Mass Spectrometry/methods ; *Metabolomics/methods ; Algorithms ; Data Analysis ; Data Analytics ; Least-Squares Analysis ; }, abstract = {Gas chromatography-mass spectrometry (GC-MS) remains challenged by the accurate resolution of coeluting peaks and the correction of retention time shift in large-scale batch analysis. Here, we introduce AntDAS-CPR, an integrated data analysis platform tailored for untargeted GC-MS-based metabolomics. The platform incorporates modules for total ion chromatogram (TIC) peak resolution, retention time shift correction, component registration, chemometric analysis, and compound identification. In this work, the TIC peak resolution module was specifically optimized through the development of a dynamic elimination multivariate curve resolution-alternating least-squares (DEMCR-ALS) algorithm, which employs multiple initialization strategies to enhance the resolution of coeluting peaks and reduce dependence on initial estimates inherent in conventional methods. The performance of AntDAS-CPR was comprehensively evaluated using standard mixtures and complex food matrix data sets. It was compared with state-of-the-art GC-MS data analysis tools, including AMDIS, ADAP-GC, MS-DIAL, and eRah. Comparative results demonstrated that AntDAS-CPR consistently outperforms existing methods in both targeted and untargeted analysis. The platform is freely accessible at http://www.pmdb.org.cn/antdascpr.}, } @article {pmid41498587, year = {2026}, author = {Maskell, KG and Cook, AL and King, AE and Dickson, TC and Blizzard, CA}, title = {Modeling amyotrophic lateral sclerosis (ALS) in vitro: from mechanistic studies to translatable drug discovery.}, journal = {Lab on a chip}, volume = {26}, number = {5}, pages = {1108-1122}, doi = {10.1039/d5lc00577a}, pmid = {41498587}, issn = {1473-0189}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Humans ; *Drug Discovery ; Animals ; *Models, Biological ; }, abstract = {Amyotrophic lateral sclerosis is a rapidly progressing, fatal neurodegenerative disease that causes selective degeneration of the corticomotor system. Currently, ALS remains incurable, and the available treatment options offer little in the way of extending life or improving quality of life. This is due, at least in part, to a lack of representative disease models. In vitro modeling offers rapid, experimentally accessible platforms for mechanistic discovery research and drug screening, but modeling the complexity of ALS - a multicellular, multisystem disease - in a dish, is not without its challenges. Here, we review the current landscape of in vitro pre-clinical ALS research, with emphasis on the development of compartmentalised culture and the promise this holds for translatable modeling of ALS.}, } @article {pmid41498748, year = {2026}, author = {Byrd, A and Marmorale, LJ and Marcinowski, S and Dykstra, MM and Addison, V and Barmada, SJ and Buchan, JR}, title = {Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism.}, journal = {The Journal of cell biology}, volume = {225}, number = {2}, pages = {}, pmid = {41498748}, issn = {1540-8140}, support = {R01NS113943/NH/NIH HHS/United States ; T32 GM136536/GM/NIGMS NIH HHS/United States ; F31NS134123-01/NH/NIH HHS/United States ; R01 GM114564/GM/NIGMS NIH HHS/United States ; R01GM114564/NH/NIH HHS/United States ; DGE-1746060//National Science Foundation/ ; P30 AG072931/AG/NIA NIH HHS/United States ; F31NS141379/NH/NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; T32GM136536/NH/NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; P330AG072931//Michigan Alzheimer's Disease Research Center/ ; F31 NS141379/NS/NINDS NIH HHS/United States ; F31 NS134123/NS/NINDS NIH HHS/United States ; R56NS128110/NH/NIH HHS/United States ; R37 NS113943/NS/NINDS NIH HHS/United States ; //University of Arizona/ ; R01NS097542/NH/NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; }, mesh = {*Endosomal Sorting Complexes Required for Transport/metabolism/genetics ; Humans ; *Nedd4 Ubiquitin Protein Ligases/metabolism/genetics ; *Lysosomes/metabolism ; *DNA-Binding Proteins/metabolism/genetics/toxicity ; Ubiquitination ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *Ubiquitin-Protein Ligase Complexes/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Ubiquitin-Protein Ligases/metabolism/genetics ; Animals ; *Endosomes/metabolism ; Multivesicular Bodies/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; HEK293 Cells ; }, abstract = {A pathological hallmark in >97% of amyotrophic lateral sclerosis (ALS) cases is the cytoplasmic mislocalization and aggregation of TDP-43, a nuclear RNA-binding protein, in motor neurons. Driving clearance of cytoplasmic TDP-43 reduces toxicity in ALS models, though how TDP-43 clearance is regulated remains controversial. We conducted an unbiased yeast screen using high-throughput dot blotting to identify genes that affect TDP-43 levels. We identified ESCRT complex genes, which induce membrane invagination (particularly at multivesicular bodies; MVBs) and genes linked to K63 ubiquitination (particularly cofactors of the E3 ubiquitin ligase Rsp5; NEDD4 in humans), as drivers of TDP-43 endolysosomal clearance. TDP-43 colocalized and bound Rsp5/NEDD4 and ESCRT proteins, and perturbations to either increased TDP-43 aggregation, stability, and toxicity. NEDD4 also ubiquitinates TDP-43. Lastly, TDP-43 accumulation induces giant MVB-like vesicles, within which TDP-43 accumulates in a NEDD4-dependent manner. Our studies shed light on endolysosomal-mediated cytoplasmic protein clearance, a poorly understood proteostasis mechanism, which may help identify novel ALS therapeutic strategies.}, } @article {pmid41499987, year = {2026}, author = {Poulidou, V and Tseriotis, VS and Bombaci, A and Vucic, S and Pavey, N and Papagiannopoulos, S and Kimiskidis, VK and Arnaoutoglou, M}, title = {The split elbow sign in amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {56}, number = {2}, pages = {103134}, doi = {10.1016/j.neucli.2025.103134}, pmid = {41499987}, issn = {1769-7131}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Elbow/physiopathology ; *Muscle, Skeletal/physiopathology ; *Muscle Weakness/physiopathology/diagnosis ; Muscle Strength ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) patients can exhibit split phenomena, with preferential weakness of specific muscle groups. The aim of this review is to investigate the split elbow (SE) phenomenon (different weakness/wasting pattern between biceps and triceps) as a potential clinical and neurophysiological feature in ALS.

METHODS: Our study was reported according to the PRISMA statement and registered in PROSPERO (CRD42024528359). MEDLINE, SCOPUS, Web of Science, and grey literature sources were searched using the terms "split elbow" and "amyotrophic lateral sclerosis" up to April 2025. English-written peer-reviewed, randomized, non-randomized, observational, diagnostic accuracy, and case-control studies were included. Study quality was assessed using Joanna Briggs Institute critical appraisal tool. Regarding muscle strength, we pooled the standardized mean difference of normalized Medical Research Council (MRC) scores using random effects. We used a bivariate random-effects model to evaluate SE index (SEICMAP, compound muscle action potential of biceps/triceps) in distinguishing ALS from controls.

RESULTS: Seven studies with 1941 ALS patients (61.8 % male) met inclusion criteria. Pooled standardized mean difference (triceps - biceps MRC scores) was -0.17 [95 % CI, -1.03 to 0.69], p = 0.63, indicating no significant difference in muscle strength between elbow flexion and extension. Between-study heterogeneity was high (I[2] = 97.1 % [95.5 %; 98.2 %], p < 0.0001). The SEICMAP demonstrated only moderate accuracy in distinguishing ALS from controls (pooled sensitivity, specificity, and AUC of 0.789 [0.655-0.880], 0.580 [0.487-0.668], and 0.661, respectively).

CONCLUSIONS: Current evidence does not support a consistent SE pattern in ALS. Methodological variability and small sample sizes limit the generalizability of available findings, indicating that the SE is unlikely to provide meaningful diagnostic utility in routine clinical practice.}, } @article {pmid41500819, year = {2026}, author = {Zorotovich, J and Andrews, C}, title = {Multidisciplinary care for amyotrophic lateral sclerosis in rural Appalachia: Tales from the Clinic Coordinator.}, journal = {Palliative & supportive care}, volume = {24}, number = {}, pages = {e29}, pmid = {41500819}, issn = {1478-9523}, } @article {pmid41500873, year = {2026}, author = {Pérez-Bonilla, M and Borrego, PD and Mora-Ortiz, M and Fernández-Baillo, R and Mayordomo-Riera, FJ and López, EG}, title = {Voice-Based Prediction of Survival in Amyotrophic Lateral Sclerosis (ALS) Patients Using Biomechanical Acoustic Markers.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2025.12.014}, pmid = {41500873}, issn = {1873-4588}, abstract = {OBJECTIVE: To evaluate whether voice-derived acoustic and biomechanical features can serve as non-invasive biomarkers for mortality-risk prediction and survival stratification in patients with amyotrophic lateral sclerosis (ALS).

METHODS: We conducted a retrospective study including 50 ALS patients evaluated in a phoniatrics consultation with available sustained vowel recordings, demographic data, and functional assessments. Nested logistic regression models were developed to predict clinical outcomes, progressively incorporating demographic variables, functional indices (Grade, Roughness, Breathiness, Asthenia, Strain, and Barthel), acoustic features (fundamental frequency, jitter, shimmer, harmonics-to-noise ratio), and biomechanical voice parameters (Pr1-Pr22). Model performance was assessed using receiver operating characteristic curves and area under the curve (AUC) comparisons via DeLong tests. Stepwise Akaike Information Criterion (StepAIC) was applied to optimize the final model. A Cox proportional hazards model was used to evaluate the association between voice parameters and survival time.

RESULTS: The final StepAIC model, which included a subset of biomechanical features, achieved excellent predictive performance (AUC = 0.903, 95% confidence interval: 0.816-0.989), significantly outperforming baseline and acoustic-only models. Bootstrapping confirmed the model's robustness and generalizability. Cox regression analysis showed that the derived risk scores stratified patients into tertiles with significantly different survival probabilities (log-rank P < 0.0001; hazard ratio for high vs. low-risk group = 11.2).

CONCLUSION: Biomechanical voice features are strong predictors of mortality in ALS and outperform traditional clinical and acoustic indices. These findings support the integration of voice analysis into ALS monitoring protocols as a non-invasive, cost-effective, and scalable prognostic tool.}, } @article {pmid41502663, year = {2025}, author = {Ma, Y and Tian, H and Xiao, W and Ma, Y and Su, H and Zhu, L and Jiang, Y and Ge, L and Li, Y and Yuan, M and Liu, X}, title = {Machine Learning Approaches for Optimizing Drug Combinations in Neurodegenerative Diseases: A Brief Review.}, journal = {ACS omega}, volume = {10}, number = {48}, pages = {57950-57973}, pmid = {41502663}, issn = {2470-1343}, abstract = {As the global population ages, the prevalence of neurodegenerative diseases (NDDs)(?)including Alzheimer's disease, Parkinson's disease, Huntington's disease, Multisystem Atrophy (multiple system atrophy), and amyotrophic lateral sclerosis(?)continues to rise, largely driven by environmental, metabolic, and lifestyle risk factors. Advances in computational technologies, particularly machine learning (ML) and deep learning, are reshaping research in this field. This review summarizes the major features of these diseases and emphasizes the role of ML in drug discovery, virtual screening, drug repurposing, and drug combination optimization. Representative approaches include support vector machines for classification, convolutional neural networks|convolutional neural network for imaging analysis, recurrent neural networks for temporal biomedical data, and transformers for multimodal integration. These methods highlight the potential of computational strategies to improve therapeutic development. In addition, the review underscores the substantial incidence rates and socioeconomic burden of these conditions, which have made them focal points for algorithmic innovation. With research evolving rapidly, the development of AI-driven approaches is expected to enable more effective, targeted interventions and improve patient outcomes. This Perspective provides a concise overview of current progress and identifies promising future directions in the fight against NDDs.}, } @article {pmid41503832, year = {2026}, author = {Tuli, S and Patel, P and Shethji, A and Gau, D}, title = {Mitochondria and the Actin Cytoskeleton in Neurodegeneration.}, journal = {Cytoskeleton (Hoboken, N.J.)}, volume = {83}, number = {4}, pages = {200-210}, pmid = {41503832}, issn = {1949-3592}, support = {R00 CA267180/CA/NCI NIH HHS/United States ; TL1 TR001858/NH/NIH HHS/United States ; CA267180/NH/NIH HHS/United States ; }, mesh = {Humans ; *Mitochondria/metabolism/pathology ; Animals ; *Actin Cytoskeleton/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Mitochondrial Dynamics ; }, abstract = {Mitochondrial dysfunction and cytoskeletal disorganization are widely recognized hallmarks of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although these disorders differ in clinical presentation and etiology, accumulating evidence points to a shared cellular vulnerability at the intersection of mitochondrial dynamics and actin cytoskeletal regulation. In this review, we examine the emerging role of actin-mitochondria crosstalk as a convergent mechanism in neurodegeneration. We discuss how disruptions in actin filament remodeling, mitochondrial fission and fusion, organelle transport, and mitophagy contribute to neuronal dysfunction and loss across these diseases. Particular attention is given to disease-specific pathways, including cofilin-actin rod formation in AD, α-synuclein-driven actin disruption in PD, mutant huntingtin's effects on mitochondrial fragmentation in HD, and profilin-1-associated mitochondrial defects in ALS. By synthesizing findings from diverse models, we highlight how perturbations in the cytoskeleton-mitochondria interface may act as an upstream trigger and amplifier of neurodegenerative cascades. We also outline key knowledge gaps and propose future directions for research, with an emphasis on targeting actin-mitochondrial interactions as a potential therapeutic strategy across multiple neurodegenerative conditions.}, } @article {pmid41504056, year = {2025}, author = {Lymperopoulos, A and M'Sadoques, AJ and Stoicovy, RA and Altsman, VL}, title = {Why Is Epinephrine Preferred for Cardiac Arrest? The Answer May Lie in β2-Adrenergic Receptor Activation.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {30}, number = {12}, pages = {47927}, doi = {10.31083/FBL47927}, pmid = {41504056}, issn = {2768-6698}, support = {R01 #HL155718-01//National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) grant/ ; #333609-2025//American Foundation for Pharmaceutical Education (AFPE) Gateway to Research Scholarship/ ; }, mesh = {*Epinephrine/therapeutic use/pharmacology ; Humans ; *Heart Arrest/drug therapy ; *Receptors, Adrenergic, beta-2/metabolism ; *Vasoconstrictor Agents/therapeutic use/pharmacology ; Cardiopulmonary Resuscitation/methods ; Animals ; }, abstract = {Epinephrine (Epi, adrenaline) is routinely used during cardiopulmonary resuscitation (CPR) for cardiac arrest and is a first line treatment according to the international advanced life support (ALS) guidelines, which recommend 1 mg Epi be administered every 3-5 minutes during CPR. However, specific pharmacological factors that may distinguish Epi from other vasopressor agents used during CPR are unclear. This opinion article argues that one such factor, perhaps even the most important, is the activation of the β2-adrenergic receptor (AR) subtype, which only Epi, among all vasopressor hormones, can induce. β2AR activation equips Epi with more robust capabilities for pulse generation in the pacemaker cells (sinoatrial node) for the heart and of restoring contractile function in ischemic/hypoxic cardiomyocytes via sodium/potassium pump activation, compared to all other vasopressor hormones, including the closely related catecholamine norepinephrine (NE, noradrenaline). These additional actions of Epi via the β2AR, which are probably not shared by NE or other vasopressor agents, may make it particularly useful in situations where simple blood pressure elevation is insufficient, such as cardiac arrest.}, } @article {pmid41504098, year = {2026}, author = {Aazmi, O and Aswale, AR and Chugh, J}, title = {H[+] Ions and ATP Reshape the Conformational Landscape of an RNA Recognition Motif and Regulate Its Fibrillation.}, journal = {Journal of the American Chemical Society}, volume = {148}, number = {2}, pages = {2295-2306}, doi = {10.1021/jacs.5c15374}, pmid = {41504098}, issn = {1520-5126}, mesh = {*Adenosine Triphosphate/chemistry/metabolism ; Hydrogen-Ion Concentration ; *RNA-Binding Protein FUS/chemistry/metabolism ; *RNA Recognition Motif ; Protein Conformation ; Humans ; Nuclear Magnetic Resonance, Biomolecular ; Ions/chemistry ; *RNA/chemistry ; }, abstract = {Proteins exist as dynamic ensembles, with their native states comprising interconverting conformational substates critical to their physiological functions and participation in disease states. Fused in sarcoma (FUS), an RNA-binding protein implicated in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), contains an RNA recognition motif (RRM) known to form fibrillar aggregates. Here, we investigate the conformational plasticity of FUS-RRM in its native state using advanced NMR techniques, particularly [15]N chemical exchange saturation transfer and heteronuclear adiabatic relaxation dispersion experiments, to capture slow and fast microsecond (μs) time scale dynamics. We further examine the influence of environmental factors such as pH and ATP on the conformational plasticity and the aggregation behavior of FUS-RRM. Our findings show that both ATP and pH perturb the fast and slow μs time scale dynamics of FUS-RRM and thus the aggregation behavior. Specifically, a contrasting effect of ATP on slow and fast μs-ms dynamics at pH 6.4 and 4.6, along with the corresponding changes in aggregation behavior, suggests a complex relationship among ATP, pH, and protein aggregation kinetics. The study suggests that these environmental perturbations behave as kinetic regulators of FUS-RRM's propensity for aggregation.}, } @article {pmid41504202, year = {2025}, author = {Wu, JY and Ye, S and Yin, TL and Zhang, S and Zheng, DF and Fu, JY and Ma, GW and Fan, DS}, title = {Amyotrophic Lateral Sclerosis With Concurrent LHON-associated m.14484T>C Mutation: A Case Report and Literature Review.}, journal = {Revista de neurologia}, volume = {80}, number = {11}, pages = {44110}, pmid = {41504202}, issn = {1576-6578}, support = {81873784//National Natural Sciences Foundation of China/ ; 82071426//National Natural Sciences Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; }, mesh = {Adult ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Mutation ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that mostly presents as sporadic cases. Currently, no mitochondrial-related gene mutations have been identified as the cause of ALS. Mitochondrial gene mutations cause rare hereditary diseases, and the symptoms of pure muscle weakness and muscle atrophy are rarely observed.

CASE REPORT: We report the case of a young patient clinically diagnosed with ALS concurrently associated with a pathogenic mutation in the mitochondrially encoded nicotinamide adenine dinucleotide: ubiquinone oxidoreductase core subunit 6 (MT-ND6) gene. However, the pathogenic relationship between the MT-ND6 gene and ALS has not been confirmed.

CONCLUSION: We provide a case report and a literature review aimed at increasing the understanding of the connection between the two. It is essential to consider the potential modifying role of mitochondrial pathogenic genes in ALS.}, } @article {pmid41504722, year = {2026}, author = {Bąkowska-Żywicka, K}, title = {[Erratum for: Genetic and Molecular Pathomechanisms of Amyotrophic Lateral Sclerosis and Therapeutic Perspectives – Current State of Knowledge, K. Kalkowski Postepy Biochem. 71(3):252-259].}, journal = {Postepy biochemii}, volume = {71}, number = {4}, pages = {435-436}, doi = {10.18388/pb.2025_643}, pmid = {41504722}, issn = {0032-5422}, } @article {pmid41504787, year = {2026}, author = {de Barros, JAMM and Vasconcelos, AFB and Gomes, ALCB and de Sousa, LMG and Meira, AT}, title = {"Bright Tongue" and "Wine Glass" signs in amyotrophic lateral sclerosis.}, journal = {Neuroradiology}, volume = {68}, number = {3}, pages = {701-703}, pmid = {41504787}, issn = {1432-1920}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Adult ; Diagnosis, Differential ; *Magnetic Resonance Imaging/methods ; Diffusion Magnetic Resonance Imaging ; }, abstract = {A 43-year-old male patient presented with monoparesis in his left leg, which had persisted for one year, then progressed to spastic dysarthria, tetraparesis, wide-based gait, muscle atrophy, weakness, fasciculations, and signs of pyramidal signs in all limbs. Brain MRI findings revealed hyperintensities on T2/FLAIR and diffusion-weighted imaging (DWI) along the corticospinal tracts, extending from the corona radiata and internal capsules to the brainstem, the "bright tongue sign" and the "wine glass sign,". This case highlights the classic findings in amyotrophic lateral sclerosis, which was confirmed by electroneuromyography.}, } @article {pmid41504939, year = {2026}, author = {Evola, V and Parmar, MS}, title = {Targeting neuroinflammation in neurodegenerative disorders: the emerging potential of semaglutide.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {75}, number = {1}, pages = {13}, pmid = {41504939}, issn = {1420-908X}, mesh = {Humans ; Semaglutide ; *Glucagon-Like Peptides/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroinflammatory Diseases/drug therapy ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {BACKGROUND: Chronic neuroinflammation is increasingly recognized not as a secondary effect but as a primary driver of neurodegenerative disease progression. In conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD), and Lewy body dementia (LBD), dysregulated glial activity, marked by sustained microglial and astrocytic activation, initiates a cascade of cytokine release, oxidative stress, and impaired neuronal support. This review synthesizes recent advances in understanding these shared inflammatory processes, emphasizing how glia-centric pathology shapes disease-specific trajectories and therapeutic responses.

FINDINGS: Within this framework, we evaluate the therapeutic potential of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) with emerging neuroprotective properties. Preclinical studies suggest that semaglutide can suppress pro-inflammatory signaling, mitigate oxidative injury, and enhance key anti-inflammatory and neuroprotective pathways that restore trophic support and cellular resilience. We also examine real-world evidence and emerging human clinical trial data, which recently demonstrated that semaglutide rapidly modulates AD pathology by significantly reducing cerebrospinal fluid (CSF) levels of p-tau, t-tau, and neurogranin, and promoting a less inflammatory CD8[+]T-cell signature. In addition to reduction in neuroinflammation marker, YKL-40. While subsequent large-scale Phase 3 trials in early AD did not meet primary cognitive endpoints (CDR-SB) despite favorable biomarker modulation.

CONCLUSION: Positioning semaglutide as a therapeutic option targeting neuroinflammation-mediated neuropathology, this review underscores its potential for repurposing as a disease-modifying therapy across diverse neurodegenerative disorders and highlights the urgent need for targeted trials in MS, ALS, FTD, HD, and LBD-conditions that remain without effective immunomodulatory treatments despite clear inflammatory origins. However, while direct CSF measurements confirm limited but measurable BBB penetration, the clinical translation of its effects remains a key challenge.}, } @article {pmid41505016, year = {2026}, author = {Bronovitsky, E and Chaprov, K and Khizeva, A and Ivanova, T and Pravdivceva, E and Bobkov, T and Morozova, O and Krayushkina, A and Nebogatikov, V and Ninkina, N and Ustyugov, A}, title = {Retrospective Study of the Physiological and Molecular Features of the S-FUS (1-359) Mouse Transgenic Model with an ALS-like Phenotype: Lifespan, Body Weight Dynamics, Movement Disorders, and Dysregulation of the Dopaminergic System.}, journal = {Journal of molecular neuroscience : MN}, volume = {76}, number = {1}, pages = {8}, pmid = {41505016}, issn = {1559-1166}, support = {FFSG-2024-0020//Ministry of Science and Higher Education of the Russian Federation/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology/physiopathology ; Mice, Transgenic ; Mice ; *Dopamine/metabolism ; Male ; *RNA-Binding Protein FUS/genetics/metabolism ; *Disease Models, Animal ; Female ; *Longevity ; *Body Weight ; Spinal Cord/metabolism ; Oxidative Stress ; Caspase 3/metabolism/genetics ; Phenotype ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to disability and death. Genetic animal models, like transgenic mice, are critical for studying disease mechanisms and developing therapies. Model validity, experimental standardization, and predictability are key to successful research. This retrospective study analyzed physiological parameters of the S-FUS (1-359) transgenic mouse model over 10 years, focusing on lifespan, body weight dynamics, symptomatic stages, and molecular changes. Hemizygous mice had a mean lifespan of 137.8 days (males) and 125.1 days (females), longer than homozygous counterparts. The symptomatic stage, marked by motor deficits, began at ~ 123 days and lasted 10-15 days. Body weight loss correlated with disease progression, reaching 28.93% of baseline at death. Molecular analysis revealed regional FUS expression differences (midbrain > spinal cord), alongside proinflammatory cytokine activation (Il6, Tnf alpha) and oxidative stress. Dopaminergic dysregulation was evident, with striatal dopamine/metabolite levels rising 40-60%, linked to Maob downregulation and impaired GABAergic inhibition. Midbrain-selective caspase-3 suppression suggested a shift from apoptosis to necroptosis, while spinal cord astrogliosis indicated compensatory mechanisms. Heterogeneity in lifespan, symptom onset timing, and disease duration was observed, underscoring the need for rigorous experimental design, particularly for therapies aiming to delay symptoms or extend survival. Dopamine oxidation emerged as a novel neurotoxicity contributor, highlighting potential therapeutic targets: modulating dopaminergic signaling and reducing oxidative stress.}, } @article {pmid41506565, year = {2026}, author = {Liang, HY and Huang, PH}, title = {Concerns regarding the causal inference and statistical methods in Laine et al's study on obstetric anal sphincter injuries.}, journal = {American journal of obstetrics and gynecology}, volume = {234}, number = {6}, pages = {e232}, doi = {10.1016/j.ajog.2026.01.001}, pmid = {41506565}, issn = {1097-6868}, } @article {pmid41508039, year = {2026}, author = {Kim, SH and So, JH and Kim, YH and Kim, HS and Park, NY and Kim, JB and Jo, DS and Yeom, E and Lee, JA and Bae, JE and Cho, DH}, title = {Proteasome inhibition by VR23 enhances autophagic clearance of FUS[P525L]-mediated persistent stress granule in SH-SY5Y cells.}, journal = {Molecular brain}, volume = {19}, number = {1}, pages = {10}, pmid = {41508039}, issn = {1756-6606}, support = {RS-2024-00463344//Ministry of Education/ ; P0025489//Ministry of Trade, Industry and Energy/ ; }, mesh = {*Autophagy/drug effects ; Humans ; *Proteasome Inhibitors/pharmacology ; *Stress Granules/metabolism/drug effects ; Cell Line, Tumor ; *Proteasome Endopeptidase Complex/metabolism ; Poly-ADP-Ribose Binding Proteins/metabolism ; RNA Recognition Motif Proteins/metabolism ; RNA Helicases/metabolism ; Macrolides/pharmacology ; Lysosomes/metabolism/drug effects ; DNA Helicases ; }, abstract = {Autophagy is a conserved catabolic pathway that preserves cellular homeostasis through lysosomal degradation. Beyond its general role in proteostasis, selective autophagy mediates the clearance of selective cellular targets such as persistent stress granules (SGs), in a process termed granulophagy. SGs are dynamic cytoplasmic assemblies that normally disassemble after stress relief; however, their aberrant persistence has arisen as a pathological feature of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). However, the molecular regulation of granulophagy remains incompletely understood. Here, we established a tandem fluorescent SG reporter system with mCherry-pHluorin-FUS[P525L], enabling live-cell visualization of granulophagic flux. Using this system, we screened a chemical library and identified VR23, a proteasome inhibitor, as a potent inducer of granulophagy. VR23 promoted SG clearance through autophagic mechanisms, as evidenced by enhanced LC3 colocalization, lysosome-dependent degradation, and Bafilomycin A1-sensitive flux. Notably, disruption of SG assembly via G3BP1 inhibition abolished VR23-induced clearance, confirming its SG selectivity. These findings suggest a link between proteasome inhibition and granulophagy, highlighting VR23 as a valuable tool compound to dissect the mechanisms of SG turnover, and provide a platform for discovering modulators of pathological SG clearance in protein aggregation.}, } @article {pmid41509200, year = {2025}, author = {Mahendran, TS and Bremer, A and Gui, X and Singh, A and Basalla, JL and Chittori, S and Marzahn, MR and Das, T and Mittag, T and Banerjee, PR}, title = {Viscoelasticity and interface properties of multi-component condensates govern protein sequestration and suppression of amyloid formation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41509200}, issn = {2692-8205}, support = {R01 NS121114/NS/NINDS NIH HHS/United States ; R35 GM138186/GM/NIGMS NIH HHS/United States ; }, abstract = {Stress granules (SGs) are multi-component protein-RNA condensates widely viewed as crucibles for fibril formation in neurodegenerative diseases such as amyotrophic lateral sclerosis. Here, we test this model by examining whether SG-mimics promote or suppress amyloid formation. Using multi-component programmable peptide-nucleic acid condensates, we show that condensates delay amyloid assembly by sequestering soluble proteins, and that fibrils grow in the dilute phase. Systematic tuning of condensate material properties reveals two key modulating mechanisms: the density of fibril-forming proteins at condensate interfaces dictates the lag phase of fibril assembly, and condensate viscoelasticity regulates protein efflux-driven fibril growth. These principles extend to SG-mimic condensates formed by G3BP1 and RNA, suggesting that SGs may function as potent suppressors rather than crucibles of pathological amyloid assembly.}, } @article {pmid41509469, year = {2025}, author = {Park, J and Stepanova, A and Dash, J and Southwell, N and Zhao, D and Konrad, C and Tyagi, P and Kwan, JY and Shneider, NA and Mentis, GZ and Manfredi, G and Kawamata, H}, title = {A mouse model of CHCHD10 p.R15L familial ALS presents mild, age-related motor neuron degeneration without protein instability or mitochondrial dysfunction.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.29.696888}, pmid = {41509469}, issn = {2692-8205}, support = {R35 NS122209/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in the mitochondrial protein CHCHD10 (D10) cause a spectrum of hereditary neurodegenerative disorders. Among these, the p.R15L variant is linked to a slowly progressive, late-onset familial form of amyotrophic lateral sclerosis (ALS) with unclear pathogenic mechanisms. To better understand this, we investigated a knock-in (KI) mouse model carrying the p.R15L mutation in the endogenous protein. Unlike previously described mutant D10 KI models, p.R15L KI mice exhibited normal D10 protein levels, with no evidence of large protein aggregates. Mitochondrial respiration and hydrogen peroxide emission in mitochondria isolated from muscle and brain were unaltered. Similarly, fibroblasts from human p.R15L carriers exhibited normal D10 levels and unchanged oxidative phosphorylation function. Histochemical analyses of p.R15L KI muscle revealed mild increases in mitochondrial enzymatic activity in a subset of muscle fibers and muscle transcriptomics showed elevated expression of PGC-1α, suggesting enhanced mitochondrial biogenesis. p.R15L KI mice developed subtle, late-onset phenotypes, including reduced body weight and motor activity and increased anxiety-like behavior. Importantly, in aged mice electrophysiological studies demonstrated decreased amplitude of the compound muscle action potential, commensurate with a moderate loss of spinal cord motor neurons and elevated serum neurofilament light levels, indicative of neurodegeneration. Together, these results indicate that the p.R15L mutation produces a mild, late-onset motor neuron phenotype in mice, partially recapitulating the human disease, without mitochondrial functional or morphological alterations. The findings indicate that p.R15L D10 selectively impairs mouse motor neurons through a gain-of-function mechanism, providing a genetically accurate yet mild in vivo model of familial ALS.}, } @article {pmid41509476, year = {2025}, author = {Saez-Calveras, N and Verheijen, BM and Morgan, N and Hill, E and Taylor, S and Oyanagi, K and Kakita, A and Song, Y and Joachimiak, LA and Vaquer-Alicea, J and Diamond, MI and Lu, Y}, title = {Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) features CTE-like tau seeds in brain and spinal cord.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.22.696002}, pmid = {41509476}, issn = {2692-8205}, abstract = {UNLABELLED: Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a fatal neurodegenerative disorder that was once hyperendemic in the island of Guam (Mariana Islands, US) and a few other Pacific locales. Despite extensive investigations into its origins, the etiology of ALS/PDC remains unclear. ALS/PDC is, at the neuropathology level, characterized by tau-dominant multiple proteinopathy in brain and spinal cord. It was recently reported that Guam ALS/PDC brain extracts exhibit tau seeding activity in fluorescence resonance energy transfer (FRET)-based biosensor cells. To build upon those findings and explore the nature of tau seeds in ALS/PDC in more detail, we used an alanine mutational scanning (Ala scan) approach to determine the seeding profile of tau in nervous tissues of Guam ALS/PDC cases. First, we confirmed the detection of tau seeding activity in ALS/PDC brain samples in tau biosensor cells. Notably, we could also detect potent tau seeding activity in spinal cord. Subsequent Ala scan assays demonstrated that ALS/PDC tau displays an aggregate incorporation pattern that resembles that of chronic traumatic encephalopathy (CTE)-type tau. This result is consistent with recent electron cryo-microscopy studies of tau, which revealed that ALS/PDC tau filaments are predominantly of the CTE-type. The structural characteristics and seeding behavior of ALS/PDC tau, as well as the regional distribution of tau pathology at post-mortem, suggest that ALS/PDC is a CTE-like tauopathy.

SIGNIFICANCE STATEMENT: Neurodegenerative tauopathies are characterized by proteinaceous deposits containing microtubule-associated tau in nervous tissue. Emerging evidence suggests that disease-associated tau proteins adopt abnormal, self-propagating conformations characteristic of prions. Here, we employed alanine mutational scanning (Ala scan) to determine the nature of prion-like tau seeds in ALS/PDC, a mysterious disorder that occurred formerly in high incidence in certain regions in the western Pacific. We show that the Ala scan incorporation profile of ALS/PDC tau is similar to that of abnormal tau proteins in chronic traumatic encephalopathy (CTE). The findings lend support to the idea that ALS/PDC can be classified structurally as a CTE-like tauopathy. This work may have important implications for our understanding of ALS/PDC as well as common neurological disorders beyond the Pacific.}, } @article {pmid41510219, year = {2025}, author = {Moll, S and Tannemann, N and Gestmann, M and Brenner, T and Herbstreit, F and Szalai, C}, title = {Redesigning Advanced Life Support teaching and assessment using a constructive alignment approach.}, journal = {MedEdPublish (2016)}, volume = {15}, number = {}, pages = {48}, pmid = {41510219}, issn = {2312-7996}, abstract = {Advanced Life Support (ALS) is a crucial component of medical training. Previously, a single-person OSCE-Station (Objective Structured Clinical Exam) was used to assess these skills, focusing primarily on the team leader role and emphasizing theoretical knowledge. However, students demonstrated deficiencies in key algorithm-compliant practical skills, such as cardiac massage, mask ventilation and defibrillator use, and struggled to integrate into a team-based resuscitation approach. To address this, a constructive alignment approach was used to revise the course and offer a guideline-appropriate, three-person resuscitation model. Learning outcomes and assessment targets were aligned with the course activities to increase student engagement and increase desired skill attainment. In the summer semester 2023, students and lecturers were briefed on the new structure of the course and assessment, specific skills were highlighted, and a model video was provided. The OSCE format was adjusted to assess both practical and non-technical skills. In the new setup, each student was randomly assigned one of three roles and assessed using role-specific checklists with defined criteria, focusing on non-technical and practical abilities. Course activity included training and practice in the three-person resuscitation approach. A team OSCE (tOSCE) approach for assessment was used, with one student for each role being examined. Results indicated both subjective and objective markers of satisfaction in course activities and tOSCE results. A team-based OSCE station proves effective for teaching combined practical and non-technical competencies.}, } @article {pmid41510529, year = {2026}, author = {Reedy, MB and Abdul Azeem, M and Subramaniam, T and Salamat, S and Rowley, H and Beinlich, B}, title = {Neuroinvasive West Nile Virus Presenting as Subacute Progressive Quadriparesis and Intractable Pain: A Case Report.}, journal = {Case reports in neurological medicine}, volume = {2026}, number = {}, pages = {5565739}, pmid = {41510529}, issn = {2090-6668}, abstract = {West Nile virus (WNV) is the most common mosquito-borne infection in North America; while most cases are asymptomatic, fewer than 1% develop neuroinvasive disease with significant morbidity and mortality. We report a 57-year-old man from rural Wisconsin who presented with a 10-week history of progressive asymmetric quadriparesis and severe intractable pain, preceded by fatigue, shoulder pain, and paresthesias. Neurologic examination demonstrated mild encephalopathy, bulbar involvement, and mixed upper and lower motor neuron signs. MRI showed patchy thoracic cord T2 hyperintensities and diffuse lumbar ventral root enhancement. Electrodiagnostic studies revealed diffuse active denervation and reduced compound muscle action potentials, initially raising concern for amyotrophic lateral sclerosis. Elevated WNV IgM and IgG titers in serum and cerebrospinal fluid confirmed neuroinvasive WNV infection. Despite treatment with corticosteroids and intravenous immunoglobulin, the patient deteriorated and was transitioned to hospice care. Autopsy demonstrated T-cell-mediated meningoencephalitis with widespread lymphocytic inflammation involving motor neurons, spinal cord, ventral rootlets, and peripheral nerves, consistent with diffuse axonopathy. This case underscores that neuroinvasive WNV may closely mimic motor neuron disease and emphasizes the importance of serologic testing for accurate diagnosis. Management remains supportive, and outcomes can be severe due to extensive central and peripheral nervous system involvement.}, } @article {pmid41510716, year = {2026}, author = {Bano, A and Khan, AA and Kushwaha, SP and Aleena, and Zaidi, SMH and Misbahul Hasan, S and Fatima, A}, title = {Indole Scaffolds in Neurological Therapeutics: Synthesis, Structure- Activity Relationships and Drug-Receptor Interactions.}, journal = {Mini reviews in medicinal chemistry}, volume = {26}, number = {13}, pages = {1046-1069}, pmid = {41510716}, issn = {1875-5607}, mesh = {Humans ; *Indoles/chemistry/chemical synthesis/pharmacology/therapeutic use ; Structure-Activity Relationship ; *Nervous System Diseases/drug therapy ; Animals ; *Neuroprotective Agents/chemical synthesis/chemistry/pharmacology/therapeutic use ; Molecular Structure ; }, abstract = {INTRODUCTION: Indole is a privileged heterocyclic scaffold that plays a crucial role in medicinal chemistry due to its strong ability to bind to various biological receptors and interact with diverse molecular targets. Indole exhibits both biological and chemical significance. Its structural versatility allows for precise chemical modifications, making it an essential framework in drug discovery. This review discusses the structure-activity relationships, synthesis, and interactions of indole derivatives, particularly in relation to targets within the central nervous system.

METHODS: A detailed literature survey was conducted using databases such as Google Scholar, Elsevier, PubMed, ACS, PubChem, ScienceDirect, and RSC to understand the structural modifications of indole derivatives and their therapeutic potential. Both research and review articles related to indole- based compounds were thoroughly studied to prepare this review article.

RESULTS: There are over 40 FDA-approved drugs containing an indole nucleus used to treat various diseases, underscoring its potential in neurotherapeutics. This review highlights innovative synthetic strategies, including green chemistry approaches, that improve the drug-likeness and bioavailability of indole derivatives. Indole continues to be an indispensable scaffold in the development of novel therapeutics aimed at addressing the growing burden of neurological disorders.

DISCUSSION: This review aims to provide a comprehensive analysis of the therapeutic potential of indole-based compounds for the treatment of neurological disorders. However, challenges like blood-brain barrier permeability and long-term safety must be addressed for clinical success. Nonetheless, this review will help in designing and developing newer indole-based molecules in the discovery of neurological drug development.

CONCLUSION: Due to its broad spectrum of biological activities and favorable pharmacokinetic properties, indole is an impressive scaffold for the treatment of various neurological disorders. Indole demonstrates remarkable therapeutic potential against a range of central nervous system-related conditions, including Alzheimer's disease, epilepsy, migraine, stroke, Parkinson's disease, prion disease, amyotrophic lateral sclerosis, and Huntington's disease.}, } @article {pmid41510728, year = {2026}, author = {González-Jiménez, KA and Herrera-Mayorga, EV and Paredes Sánchez, FA and Niño-García, N and Torres-Castillo, JA and Martínez-Padrón, HY and Sánchez-Sánchez, M}, title = {New Drug Therapies Against Targeting Neurodegenerative Diseases: A Comprehensive Review.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249397580251117044621}, pmid = {41510728}, issn = {1875-6166}, abstract = {Neurodegenerative diseases encompass well-characterized behavioral, cognitive, and movement disorders that affect older people, impacting all facets of daily life. In Alzheimer's disease, specific antibodies targeting the β-amyloid protein (aducanumab, lecanemab, and others) are gaining special interest due to the approval of the first particular drugs against this disease. In Parkinson's disease, most drugs were approved several decades ago; however, new Phase II clinical trials point to monoclonal antibodies as a promising approach, and the report of alkaloids also suggests various therapeutic targets against this disease. Pick's disease has a low prevalence; currently, no drugs are approved by government agencies. However, thanks to molecular tools, it has been possible to elucidate therapeutic targets implicated in the appearance of the disease. α-synuclein is the main therapeutic target in Lewy body disease; most of the reported molecules are in clinical Phases I and II. Additionally, drug repositioning may emerge as a viable option in the search for effective treatments against this disease. In amyotrophic lateral sclerosis, the appearance of newly approved drugs such as tofersen and edaravone, and some others in clinical Phase II (bosutinib), opens a new era in the understanding and treatment of this condition. Altered emotions and progressive damage in some brain regions characterize schizophrenia and vascular dementia. Combinations of tricyclic drugs are a trend that aims to increase the cognitive performance of patients with schizophrenia. In vascular dementia, numerous in vivo trials with molecules of different natures (flavonoids and lactones) have yielded positive results, delaying the progression of the disease. This review examines recent reports on molecules evaluated in vivo and in vitro models of the primary neurodegenerative diseases.}, } @article {pmid41511321, year = {2025}, author = {Borgheai, SB and Achorn, BE and Zisk, AH and Hosni, SM and Richter, KEG and Menniti, FS and Shahriari, Y}, title = {A Comprehensive Overview of Neurophysiological Correlates of Cognitive Impairment in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {15}, number = {1}, pages = {}, pmid = {41511321}, issn = {2073-4409}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; NSF-2006012//U.S. National Science Foundation/ ; P20GM103430//Institutional Development Award (IDeA) Network for Biomedical Research Excellence/ ; NSF-1913492//U.S. National Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/genetics ; *Cognitive Dysfunction/physiopathology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to the gradual loss of motor control, typically resulting in paralysis and death within 3 to 5 years of diagnosis. ALS shares neuropathological and genetic associations with fronto-temporal dementia (FTD), a neurodegenerative condition primarily impacting cognitive functions. These two conditions are increasingly viewed as manifestations of a single molecular disease process that affects distinct brain systems, impacting motor neuronal pathways in ALS and fronto-cortical functions in FTD. However, this simple dichotomy belies the complexity of these conditions. In particular, patients with primary motor ALS can also experience significant cognitive deficits. Investigating the pathobiological and neurophysiological underpinnings of these impairments is essential for a comprehensive understanding of ALS and may open avenues for targeted therapies to alleviate these debilitating symptoms. Moreover, the biophysical correlates of cognitive deficits in ALS may serve as sensitive biomarkers for evaluating potential therapeutics. In this narrative review, we begin with an overview of the clinical features and genetics of ALS, followed by a review of the associated cognitive deficits that are adjunctive to motor decline. We then highlight neuroimaging studies from our laboratory and the broader literature, using EEG and other modalities that are beginning to uncover systems-level brain disruptions potentially underlying cognitive impairment in motor-dominant ALS.}, } @article {pmid41511493, year = {2026}, author = {Yu, J and Zhang, J and Jiang, Y and Ma, C and Wang, W and Zhang, K and Tian, R and Chen, H and Han, H and Sun, H and Peng, C and Zhang, H and Xu, X}, title = {Identification of a novel nonsense variant in ARR3 in a family with early-onset high myopia.}, journal = {Genes & genomics}, volume = {48}, number = {3}, pages = {409-418}, pmid = {41511493}, issn = {2092-9293}, support = {81873677//Natural Science Foundation of China/ ; }, mesh = {Animals ; Female ; Humans ; Male ; Mice ; *Codon, Nonsense/genetics ; *Myopia/genetics/pathology ; Orphan Nuclear Receptors/genetics/metabolism ; Paternal Inheritance ; Pedigree ; Rod Opsins/genetics/metabolism ; Child, Preschool ; }, abstract = {BACKGROUNDS: Early-onset high myopia (EoHM) is a severe refractive error that can result in significant vision loss. A known genetic cause involves mutations in the X-linked Arrestin-3 (ARR3) gene, which typically presents with a female-limited inheritance pattern, in which asymptomatic fathers transmit the variant to their affected daughters. OBJECTIVE: This study aims to present a unique case of EoHM characterized by paternal transmission of a novel ARR3 variant and to explore potential underlying molecular mechanisms through an exploratory bioinformatic analysis. METHODS: We collected the clinical phenotypes for the family and sequenced the blood using NGS and Sanger sequencing. Bioinformatic analysis of the GSE5338 dataset revealed a potential interaction network involving ARR3, NR2E3 (a photoreceptor development regulator), and OPN1MW (a cone opsin gene). RESULTS: The proband exhibited severe EoHM with stretched axial lengths (ALs) (24.09 and 24.43 mm) and pronounced myopic astigmatism. The asymptomatic father passed on a new nonsense variation in the ARR3 gene, c.7A > T (p.K3Ter). Exploratory bioinformatic analysis of a murine retinal dataset hinted at a possible regulatory relationship, wherein overexpression of the photoreceptor transcription factor Nr2e3 might be linked to the downregulation of Arr3 and the cone opsin gene Opn1mw. CONCLUSIONS: This study reports a novel ARR3 mutation within a family affected by EoHM, expanding the known mutational spectrum of this disease and offering vital insights for genetic counseling. Furthermore, our bioinformatic analysis has generated a hypothesis that NR2E3-mediated downregulation of both ARR3 and OPN1MW may contribute to the disease phenotype, a link that warrants future investigation in human models.}, } @article {pmid41511639, year = {2026}, author = {Keerthipriya, MS and Kotambail, A and Deekshitha, M and Mahima, R and Ramyashree, MB and Rao, BM and Biswas, P and Baskar, D and Balaji, P and Mehta, M and Gray, O and Wasik, KA and Emde, AK and Polavarapu, K and Preethish-Kumar, V and Reddy, P and Thomas, PT and Nashi, S and Arunachal, G and Vengalil, S and Nalini, A}, title = {Clinical trajectories and genetic profiles of SOD1-related amyotrophic lateral sclerosis: insights from a single-center cohort in India.}, journal = {Journal of neurology}, volume = {273}, number = {1}, pages = {72}, pmid = {41511639}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/epidemiology ; *Superoxide Dismutase-1/genetics ; India/epidemiology ; Male ; Female ; Middle Aged ; Adult ; Cohort Studies ; Mutation ; Exome Sequencing ; Retrospective Studies ; Age of Onset ; Young Adult ; Aged ; }, abstract = {Mutations in the superoxide dismutase 1 (SOD1) gene are a predominant, genetic cause of amyotrophic lateral sclerosis (ALS). Given the marked variability in SOD1 variant prevalence and clinical manifestations across global populations, this study aimed to characterize the genetic and clinical profile of SOD1-associated ALS (SOD1-ALS) in a large cohort of Indian patients. Whole-exome sequencing (WES) was performed for the retrospective cohort, along with comprehensive bioinformatic analyses and interpretation of genetic variants. Data were analyzed using descriptive statistics and Kaplan-Meier survival analysis to assess clinical and survival outcomes. Among 765 individuals who underwent WES, 37 probands (4.8%) from 33 families were identified with SOD1-ALS, representing a substantial 24.2% of familial ALS (fALS) cases. Patients showed a male preponderance (1.64:1) with a mean age at onset of 41.9 ± 13.1 years. Analysis revealed 23 distinct pathogenic/likely pathogenic SOD1 variants, including four novel variants. Remarkably, a high frequency of homozygous variants (6 patients) were observed in the cohort, which were associated with earlier disease onset. Most patients presented with a lower limb onset (67.6%) and a lower motor neuron phenotype. Survival was noted to be prolonged in carriers of H47R, V88M, and I152N variants, while those with juvenile onset showed reduced survival. In conclusion, this study provides the first comprehensive characterization of SOD1-ALS in the Indian population, revealing a distinct genetic profile with a unique spectrum of SOD1 variants and a higher prevalence of homozygous cases. These detailed genotype-phenotype correlations contribute significantly to the genetic etiology of ALS.}, } @article {pmid41511908, year = {2026}, author = {Tsujisawa, Y and Takahashi-Iwata, I and Yabe, I and Mukaino, M and Shibamoto, I}, title = {Utility of Simple Speech Measures in Amyotrophic Lateral Sclerosis Assessment: Focus on Alternating Motion Rate as a Screening Tool.}, journal = {Folia phoniatrica et logopaedica : official organ of the International Association of Logopedics and Phoniatrics (IALP)}, volume = {}, number = {}, pages = {1-16}, doi = {10.1159/000550424}, pmid = {41511908}, issn = {1421-9972}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive degeneration of motor neurons. Early detection of bulbar symptoms is crucial for timely diagnosis and intervention; however, variability in symptom progression complicates clinical assessment.

METHODS: This retrospective observational study aimed to classify patients with ALS into three groups - spinal onset, spinal onset with bulbar involvement, and bulbar onset - and to identify speech evaluation metrics that effectively differentiate these groups. Data from 68 patients with ALS were retrospectively analyzed. Speech samples were collected and evaluated for alternating motion rate (AMR), maximum phonation time (MPT), nasality, maximum tongue pressure (MTP), speech rate, and speech intelligibility. Group comparisons and receiver operating characteristic (ROC) curve analyses were conducted to assess discriminatory ability.

RESULTS: AMR significantly differed among the three groups, with the spinal-onset group demonstrating the highest rates and the bulbar-onset group showing the lowest rates. ROC analysis indicated that AMR exhibited excellent discriminatory power, particularly in distinguishing spinal-from bulbar-onset ALS. Significant differences were also observed in MTP, nasality, speech rate, and speech intelligibility, although some metrics were less effective in differentiating the intermediate group. No significant group differences were found in MPT.

CONCLUSION: These findings suggest that the AMR is a sensitive and easily administered measure for detecting bulbar symptoms and distinguishing ALS subtypes. The intermediate characteristics observed in the spinal-onset with bulbar involvement group support this classification as a distinct clinical phenotype. Combining AMR with secondary measures such as MTP, nasality, speech rate, and speech intelligibility may enhance early detection of bulbar symptoms and improve clinical decision-making.}, } @article {pmid41512036, year = {2026}, author = {Zhu, B and Liu, Z and Van, R and Wang, H and Kuang, S and Jia, Y and Leon, EC and Yang, F and Zhang, J and Yang, J and Hong, H and Lobo, F and Yu, A and Wang, J and Tanzi, RE and Zhang, C and Mao, X and Shao, Y and Ran, C}, title = {Highly sensitive chemiluminescence imaging of misfolded proteins in neurodegenerative models.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {2}, pages = {e2513311123}, pmid = {41512036}, issn = {1091-6490}, support = {R01 AG083759/AG/NIA NIH HHS/United States ; R01AG085562//HHS | NIH (NIH)/ ; R21 AG059134/AG/NIA NIH HHS/United States ; R01AG055413//HHS | NIH (NIH)/ ; R21 AG080222/AG/NIA NIH HHS/United States ; R01AG083759//HHS | NIH (NIH)/ ; S10 OD028609/OD/NIH HHS/United States ; CSTB2024NSCQ-MSX0365//CSTC | Natural Science Foundation of Chongqing Municipality ()/ ; S10OD028609//HHS | NIH (NIH)/ ; R21AG059134//HHS | NIH (NIH)/ ; 2025MSXM061//CQMHC | Science-Health Joint Medical Scientific Research Project of Chongqing ()/ ; R21 AG078749/AG/NIA NIH HHS/United States ; R21AG078749//HHS | NIH (NIH)/ ; R01 AG055413/AG/NIA NIH HHS/United States ; R01 AG085562/AG/NIA NIH HHS/United States ; R56 AG059814/AG/NIA NIH HHS/United States ; R56AG059814//HHS | NIH (NIH)/ ; }, mesh = {Animals ; *Protein Folding ; Humans ; *Luminescent Measurements/methods ; alpha-Synuclein/metabolism/chemistry ; *Neurodegenerative Diseases/metabolism ; Mice ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism/chemistry ; Alzheimer Disease/metabolism ; Parkinson Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Protein misfolding in the brain is a key pathological hallmark of neurodegenerative diseases. Optical imaging of misfolded proteins in disease models is essential for elucidating etiology and early diagnosis. However, developing specific optical imaging probes for each misfolded protein is time-consuming and challenging, leaving many pathological targets without effective detection tools, especially for in vivo imaging. Here, we present a dual-mode chemiluminescence strategy that enables both generic and specific detection of misfolded proteins using a single probe platform. In the generic mode, we demonstrate that ADLumin-1, a chemiluminescent probe, enables highly sensitive detection of diverse misfolded proteins in vitro, achieving up to 128-fold higher signal enhancement than Thioflavin T, and allows noninvasive imaging in mice models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. In the specific mode, ADLumin-1 combined with protein misfolding cyclic amplification allows femtomolar-level detection of α-synuclein in cerebrospinal fluid, while integration with a bio-orthogonal chemiluminescence resonance energy transfer technique enables in vivo discrimination of α-synuclein from Aβ. This dual-mode, modular approach offers a practical solution to the current probe limitations, with potential preclinical and clinical applications in neurodegenerative disorders.}, } @article {pmid41512823, year = {2026}, author = {Guo, L and Mann, JR and Mauna, JC and Copley, KE and Wang, H and Rubien, JD and Bergmann, CA and Carey, JL and Merjane, J and Ngo, M and Xu, J and Odeh, HM and Lin, J and Lee, BL and Ganser, L and Robinson, E and Kim, KM and Murthy, AC and Paul, T and Portz, B and Gleixner, AM and Diaz, Z and Smirnov, A and Padilla, G and Lavorando, E and Espy, C and Shang, Y and Huang, EJ and Chesi, A and Fawzi, NL and Myong, S and Donnelly, CJ and Shorter, J}, title = {Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains.}, journal = {Molecular cell}, volume = {86}, number = {1}, pages = {114-134.e10}, pmid = {41512823}, issn = {1097-4164}, support = {R01 NS122908/NS/NINDS NIH HHS/United States ; R21 NS133676/NS/NINDS NIH HHS/United States ; R01 NS121143/NS/NINDS NIH HHS/United States ; T32 GM132039/GM/NIGMS NIH HHS/United States ; T32 NS086749/NS/NINDS NIH HHS/United States ; F31 NS129101/NS/NINDS NIH HHS/United States ; R01 NS105756/NS/NINDS NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; R21 AG064940/AG/NIA NIH HHS/United States ; UL1 TR001878/TR/NCATS NIH HHS/United States ; T32 GM007601/GM/NIGMS NIH HHS/United States ; RF1 NS121143/NS/NINDS NIH HHS/United States ; R01 GM147677/GM/NIGMS NIH HHS/United States ; RF1 AG090910/AG/NIA NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; R01 NS116176/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *RNA-Binding Protein FUS/genetics/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism/chemistry ; Animals ; *Prions/genetics/metabolism/chemistry ; Motor Neurons/metabolism/pathology/drug effects ; *RNA/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Oligonucleotides/genetics/metabolism/pharmacology ; Phase Transition ; Protein Domains ; RNA-Binding Proteins/metabolism/genetics ; Protein Aggregates ; }, abstract = {RNA-binding proteins (RBPs) with prion-like domains (PrLDs), such as FUS and TDP-43, condense into functional liquids, which can transform into pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs that prevent FUS fibrillization by promoting liquid phases and distinct short RNAs that prevent and reverse FUS condensation and fibrillization. These activities require interactions with multiple RNA-binding domains of FUS and are encoded by RNA sequence, length, and structure. We define a short RNA that dissolves cytoplasmic FUS aggregates, restores nuclear FUS, and mitigates FUS toxicity in optogenetic models and ALS patient-derived motor neurons. Another short RNA dissolves cytoplasmic TDP-43 aggregates, restores nuclear TDP-43, and mitigates TDP-43 toxicity. Since short RNAs can be effectively delivered to the human brain, these oligonucleotides could have utility for ALS/FTD and related disorders.}, } @article {pmid41512846, year = {2026}, author = {Zou, C and Li, P and Li, B and Sparwasser, T and Yuan, J}, title = {Next steps in regulatory T cells: Biology and clinical application.}, journal = {Cell}, volume = {189}, number = {1}, pages = {6-22}, doi = {10.1016/j.cell.2025.11.035}, pmid = {41512846}, issn = {1097-4172}, mesh = {*T-Lymphocytes, Regulatory/immunology ; Humans ; Animals ; Interleukin-2/therapeutic use ; Immune Tolerance ; Graft vs Host Disease/immunology ; Amyotrophic Lateral Sclerosis/immunology/therapy ; Forkhead Transcription Factors/metabolism ; }, abstract = {Recent advances in regulatory T cell (Treg) biology and clinical application of Treg-based treatments show promise as a new generation of transforming therapeutics for immune-related disorders, positioning Tregs as a "living drug" to rebuild immune tolerance and repair damaged tissues simultaneously. This perspective summarizes the key knowledge on Treg biology and highlights the recent important discoveries in the development of clinical applications based on Treg biology, from low-dose interleukin-2 therapy showing promising results in trials for ALS and adoptive Treg transfer demonstrating efficacy in preventing GVHD to early pilot studies of CAR Tregs. Drawing on these advances, we provide perspectives on key research priorities and translational challenges and set forth a roadmap that integrates basic and clinical insights into developing next-generation therapies focusing on precision tolerance strategies.}, } @article {pmid41513843, year = {2026}, author = {Keritam, O and Kleinveld, VE and Klotz, S and Caliskan, H and Mayerhofer, M and Sener, M and Jäger, F and Weng, R and Bormann, D and Pugna, I and Gebert, J and Fedak, I and Renner, A and Antoniewicz, L and Rath, J and Zulehner, G and Krenn, M and Zimprich, F and Löscher, WN and Cetin, H}, title = {Demographic, clinical and genetic characteristics of patients with amyotrophic lateral sclerosis from two specialised centres in Austria.}, journal = {Journal of neurology}, volume = {273}, number = {1}, pages = {74}, pmid = {41513843}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/physiopathology/diagnosis ; Austria/epidemiology ; Female ; Male ; Middle Aged ; Retrospective Studies ; Aged ; Adult ; Registries ; C9orf72 Protein/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness and ultimately death from respiratory failure. Heterogeneity in disease trajectories and outcomes among patients with ALS (pwALS) is influenced by healthcare access, rehabilitation, and palliative care, but real-world data on demographic and clinical characteristics remain scarce in many countries, including Austria.

OBJECTIVES: To characterise the demographic, clinical, and genetic landscape of pwALS in Austria.

METHODS: In this retrospective cohort study, we included pwALS diagnosed according to the Gold Coast criteria and treated at two large tertiary referral centres. Demographic, clinical, and genetic data were extracted from the local ALS registries, and survival was determined via linkage with Statistik Austria, censored in December 2023.

RESULTS: A total of 341 patients with motor neuron disease were included (44.9% female), of whom 5% were diagnosed with primary lateral sclerosis and 2.9% with progressive muscular atrophy. Among pwALS (n = 314), spinal onset was most common (67.2%), followed by bulbar onset (29.6%) and respiratory onset (2.5%). Median survival from symptom onset was 36.0 months (IQR 20.0-74.0), with age at onset (HR 1.04, 95% CI 1.02-1.05; p < 0.0001), diagnostic delay (HR 0.97, 95% CI 0.96-0.98; p < 0.0001), and PEG tube placement (HR 0.72, 95% CI 0.50-1.00; p = 0.0478) as the only independent predictors of survival. (Likely) pathogenic variants were identified in 5.5% of patients, including two in SOD1 and one each in C9orf72, OPTN, TARDBP, and FUS.

CONCLUSIONS: This study provides the first comprehensive description of the demographic, clinical, and genetic characteristics of pwALS in Austria, offering valuable real-world insight into disease presentation and genetic diversity.}, } @article {pmid41513898, year = {2026}, author = {Roos, AK and Forsberg, S and Stenvall, E and Andersen, PM and Zetterström, P and Nordin, A and Forsberg, KME}, title = {Heterogeneous phenotype and cardiovascular comorbidities in Swedish patients with spinobulbar muscular atrophy.}, journal = {Journal of neurology}, volume = {273}, number = {1}, pages = {75}, pmid = {41513898}, issn = {1432-1459}, support = {FO 2022-0309//Hjärnfonden/ ; FO2023-0088//Hjärnfonden/ ; 2012-3167//Vetenskapsrådet/ ; 2017-03100//Vetenskapsrådet/ ; . JLL-980693//Region Jämtland Härjedalen/ ; 2012.0091//Knut och Alice Wallenbergs Stiftelse/ ; 2014.0305//Knut och Alice Wallenbergs Stiftelse/ ; 2020.0232//Knut och Alice Wallenbergs Stiftelse/ ; F2021-0044//Neuroförbundet/ ; 2023.10//Ulla-Carin Lindquists stiftelse för ALS-forskning/ ; 2023.16//Ulla-Carin Lindquists stiftelse för ALS-forskning/ ; RV-993493//Västerbotten Läns Landsting/ ; RV-996140//Västerbotten Läns Landsting/ ; RV-939329//Västerbotten Läns Landsting/ ; RV56103-7002829//Västerbotten Läns Landsting/ ; RV-1014212//Västerbotten Läns Landsting/ ; RV-996234//Västerbotten Läns Landsting/ ; RV-941598//Västerbotten Läns Landsting/ ; }, mesh = {Humans ; Male ; Middle Aged ; Sweden/epidemiology ; Female ; *Cardiovascular Diseases/epidemiology/blood/physiopathology ; Phenotype ; Aged ; Receptors, Androgen/genetics ; Comorbidity ; Adult ; Cohort Studies ; Bulbo-Spinal Atrophy, X-Linked/epidemiology ; Neurofilament Proteins/blood ; *Diabetes Mellitus/epidemiology ; }, abstract = {BACKGROUND: Spinobulbar muscular atrophy (SBMA) is an X-linked neuromuscular disorder characterized by adult-onset progressive muscle atrophy, flaccid paresis, and bulbar palsy. In addition, increasing evidence indicates that SBMA is a multisystem disorder with prominent non-motor symptoms, such as sensory neuropathy, androgen insensitivity, and glucose intolerance. This study aimed to further characterize the clinical manifestations and biomarker profile in a large Swedish SBMA cohort.

METHODS: 49 genetically confirmed SBMA patients were identified from a motor neuron disease database at Umeå University Hospital, Sweden. CAG repeat length in the androgen receptor (AR) gene was assessed by RP-PCR. Blood samples were analyzed for cardiovascular and muscle biomarkers. Clinical data were collected from medical records and interviews, with autopsy findings reviewed in two cases.

RESULTS: The mean CAG repeat length was 43.1, with a mean age at motor symptom onset of 58.6 years. Notably, 19% of patients initially presented with sensory symptoms. High prevalence of hypertonia (70%), diabetes mellitus (39%), and cardiac disease (38%) was observed. Elevated troponin levels were common, and pNfL (neurofilament light chain in plasma) was elevated in seven patients, likely reflecting combined cerebrovascular and cardiovascular comorbidity. Importantly, two of these seven patients exhibited rapid disease progression, and a concomitant diagnosis of ALS was confirmed histopathologically.

DISCUSSION: This cohort was characterized by a relatively low number of AR gene CAG repeats and a late onset of motor symptoms. Sensory symptoms frequently occurred before motor decline. Cardiovascular disease and diabetes were common comorbidities and, in some cases, preceded neurological symptoms. These findings underscore the need for improved clinical awareness of the heterogeneous presentation of SBMA and support routine cardiovascular monitoring to reduce diagnostic delays and prevent early mortality.}, } @article {pmid41515048, year = {2025}, author = {Ramírez-May, AG and Rivera-Cruz, MDC and Mendoza-López, MR and Acosta-Pech, RG and Trujillo-Narcía, A and Bautista-Muñoz, C}, title = {The Use of Rhizospheric Microorganisms of Crotalaria for the Determination of Toxicity and Phytoremediation to Certain Petroleum Compounds.}, journal = {Plants (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {41515048}, issn = {2223-7747}, abstract = {Microbial toxicity tests in the rhizosphere play an important role in the risk assessment and phytoremediation of chemical compounds in the environment. Tests for the inhibition of nodule number (NN), Rhizobia in the rhizosphere (RhR), Rhizobium in nodules (RhN) and arbuscular mycorrhizal fungi (AMFs) are important to evaluate the toxicity as well as the removal of total petroleum hydrocarbons (TPHs), 15 linear alkanes (LAs), and total linear alkanes (TLAs). The inhibition and removal was evaluated at 60 (vegetative stage, VS) and 154 days (reproductive stage, RS) of the life cycle of Crotalaria incana and Crotalaria pallida in soil with four doses of CRO (3, 15, 30, and 45 g/kg) plus a control (16 treatments). Results indicated that RhN and five structures of the AMFs present an index of toxicity (IT < 1), and the microbiological variable is inhibited by the CRO. RhR exhibits a hormesis index (IT > 1) that is stimulated by the CRO in the VS and RS for C. incana and C. pallida. The highest removal of TPHs (77%) was in the rhizosphere of C. incana in the RS with 45 g/kg of CRO. C. pallida removed the greatest amount of TLA (91%). There was a positive correlation between the RhR and the removal of TPHs, TLA, and LAs (higher molecular weight). It could be argued that symbiotic microorganisms are significant for use in toxicity testing, and the rhizosphere of C. incana and C. pallida can be used for the phytoremediation of HTPs and ALs in loamy-clay soil contaminated with CRO.}, } @article {pmid41516158, year = {2025}, author = {Lee, BC and Wang, CC and Chen, SP and Tsai, HJ}, title = {Multilevel Screening Platform Utilizing Cellular and Zebrafish Models to Identify Short Peptides with High Improvement of Motor Neuron Growth.}, journal = {International journal of molecular sciences}, volume = {27}, number = {1}, pages = {}, pmid = {41516158}, issn = {1422-0067}, support = {NSTC-114-2313-B-030-001//National Science and Technology Council, Taiwan/ ; 9991F02-1120232 and A0113210//Fu Jen Catholic University, Taiwan/ ; CPL-202508003//Collaborative Research Project between Fu Jen Catholic University Hospital and Fu Jen Catholic University, Taiwan/ ; }, mesh = {Animals ; Zebrafish ; *Motor Neurons/drug effects/metabolism/cytology ; *Peptides/pharmacology ; Disease Models, Animal ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; Neuronal Outgrowth/drug effects ; Humans ; }, abstract = {Zebrafish is emerging as a model animal for phenotype-based drug screening. Drugs screened from the zebrafish platform have advanced into clinical trials, underscoring their translational potential. Amyotrophic lateral sclerosis is a progressive motor neurons (MN) degenerative disease with few approved drugs. Previously, supplementation with exogenous recombinant phosphoglycerate kinase 1 (Pgk1) was found to improve MN growth through its interaction with receptor Eno2. To bypass the high complexity and cost of full-length Pgk1 production, a short segment within Pgk1 (M08) was predicted as the key motif interacting with Eno2, and a zebrafish phenotypic screening platform was established to find the most neurotrophic compound(s) among M08 and its mutants. We first found that M08-injected zebrafish embryos significantly increased branched caudal primary MNs (CaPMNs). However, compared to M08 (59.20 ± 1.80%), M039, among 17 mutants further screened, showed even more improvement of branched CaPMNs, up to 74.54 ± 3.73%. Next, when we administered the M039 peptide to C9ORF72-knockdown ALS-like zebrafish embryos, it improved axonal growth and swimming ability. Then, we employed a cellular model as a secondary screen, and M039 exhibited improved neurite outgrowth of MN (NOMN) and reduced p-Cofilin in NSC34 neural cells grown in ALS-like condition. Therefore, by using a zebrafish MN phenotype as a primary screening platform, we identified a mutated short peptide M039 having the most pronounced positive effect on improving neurite growth among all 17 mutants in comparison to parental M08, demonstrating the feasibility of zebrafish screening as a cost-effective strategy for finding promising neuroprotective short peptides that serve as neurotherapeutic potentials.}, } @article {pmid41517507, year = {2025}, author = {Koska, V and Teufel, S and Aytulun, A and Weise, M and Ringelstein, M and Guthoff, R and Meuth, SG and Albrecht, P}, title = {Evolution of Retinal Morphology Changes in Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical medicine}, volume = {15}, number = {1}, pages = {}, pmid = {41517507}, issn = {2077-0383}, abstract = {Background/Objectives: To compare changes in the thickness of retinal layers between patients with amyotrophic lateral sclerosis (ALS) and healthy controls using optical coherence tomography. Amyotrophic lateral sclerosis is a degenerative disease of the upper and lower motoneurons with a rapidly progressive course, but non-motor symptoms such as decreased ocular motility and reduced visual acuity have also been reported. Specific biomarkers or surrogate parameters assessing neurodegeneration in ALS are of interest. Methods: In a retrospective, longitudinal study using optic coherence tomography of the retinal layers, we compared changes in the thickness of the layers between patients with ALS and healthy controls. Correlations to clinical scores, such as the modified ranking scale, were analyzed. Results: In our cohort of patients with early ALS (disease duration 5.15 ± 21.4 months at baseline), we neither observed differences in retinal layer thickness at baseline nor did the thickness changes in any retinal layer differ in comparison to healthy controls at baseline. Moreover, we observed no significant thickness changes over the course of the observational period in our patients with ALS. However, a correlation analysis revealed a negative association of the thickness change rates in the complex of ganglion cell and inner plexiform layer and the inner nuclear layer with a higher modified Rankin scale at follow-up. Conclusions: This study adds to the notion that OCT may not be a suitable tool to monitor atrophy and disease progression in ALS. However, further longitudinal studies with longer follow-up times and larger cohorts are warranted.}, } @article {pmid41517538, year = {2025}, author = {Dziadkowiak, E and Marschollek, K and Kwaśniak-Nowakowska, A and Zimny, A and Rałowska-Gmoch, W and Boroń, M and Koszewicz, M}, title = {Establishing Diagnostic and Differential Diagnostic Criteria for Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical medicine}, volume = {15}, number = {1}, pages = {}, pmid = {41517538}, issn = {2077-0383}, abstract = {Motor neuron disease (MND) represents a broad and heterogeneous group of disorders involving the upper or lower motor neurons, represented mainly by amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA) and progressive bulbar palsy (PBP). Primary motor neuronopathies are characterized by progressive degenerative loss of anterior horn cell motoneurons (lower motor neurons) or loss of giant pyramidal Betz cells (upper motor neurons). Rare atypical variants of MND-ALS include flail arm syndrome (FA), flail leg syndrome (FL), facial-onset sensory and motor neuronopathy (FOSMN), finger extension weakness and downbeat nystagmus motor neuron disease (FEWDON-MND) and long-standing and juvenile MND-ALS. In this article, we present a review of diagnostic criteria and the differential diagnosis for MND, focusing on ALS.}, } @article {pmid41517697, year = {2026}, author = {Wang, Z and Yao, L and Tu, M}, title = {Evaluating the causal connections between sleep duration and disease prevalence: A comprehensive systematic review and meta-analysis of Mendelian randomization studies.}, journal = {Medicine}, volume = {105}, number = {2}, pages = {e45225}, pmid = {41517697}, issn = {1536-5964}, mesh = {Humans ; Mendelian Randomization Analysis ; *Sleep/genetics/physiology ; Prevalence ; Genetic Predisposition to Disease ; Sleep Duration ; }, abstract = {BACKGROUND: The causal link between sleep duration and diverse health conditions remains unconfirmed. This meta-analysis aimed to clarify these relationships by synthesizing Mendelian randomization (MR) study evidence.

METHODS: PubMed was systematically searched up to February 15, 2024, for MR studies exploring genetic predispositions to sleep duration/insomnia (short/long/overall sleep duration, insomnia) and associations with circulatory, digestive, neurodegenerative, metabolic diseases, and cancers. Eligible effect estimates were meta-analyzed.

RESULTS: Fifty-one MR studies were included. Genetic variations in sleep traits were strongly linked to elevated risk of 12 cardiovascular diseases, obesity-related metrics (Type 2 diabetes, fasting glucose/insulin, HbA1c), neurological disorders (Alzheimer, amyotrophic lateral sclerosis, Parkinson disease), mental health conditions (attention-deficit/hyperactivity disorder, autism, bipolar disorder, major depressive disorder, schizophrenia), inflammatory bowel disease, and lung cancer.

CONCLUSION: Genetic evidence confirms causal associations between sleep characteristics and multiple diseases, emphasizing sleep's key role in health promotion and supporting personalized sleep management to reduce disease risk.}, } @article {pmid41517814, year = {2026}, author = {Jacob, SM and Son, B and Bagheri, S and Lee, S and Leckie, J and Chohan, B and Belway, C and Mascarenhas, J and Mobach, T and Korngut, LW and Sharkey, KA and Park, J and Nguyen, MD and Kim, SH and Pfeffer, G}, title = {The Oral Microbiome in Amyotrophic Lateral Sclerosis Shows Differentially Abundant Organisms in Limb Versus Bulbar Onset Disease: A Binational Study.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {22}, number = {1}, pages = {66-75}, pmid = {41517814}, issn = {1738-6586}, support = {//ALS Canada Discovery Grant/Canada ; //Barry Barrett Foundation/Canada ; /CAPMC/CIHR/Canada ; //International Development Research Council/Canada ; //Rose Family Foundation/Canada ; //Fondation Brain Canada/Canada ; /MOHW/Ministry of Health and Welfare/Korea ; RS-2024-00348451/MSIT/Ministry of Science and ICT, South Korea/Korea ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons leading to progressive disability and death. Approximately 10% of cases are caused by single-gene disorders with the remaining 90% of cases presumed to be caused by a combination of environmental and genetic factors. The microbiome (the ensemble of microorganisms that colonize body surfaces and organs) was recently identified for its importance in the pathogenesis of ALS.

METHODS: In this study, we recruited 100 participants from two ethnically and geographically distinct sites (71 from Calgary, Canada, and 29 from Seoul, Republic of Korea) which included 59 ALS participants and 41 controls. All participants provided saliva samples for oral microbial analysis using 16S rRNA sequencing. Basic demographic information was collected from all participants, and ALS participants provided additional clinical information including site of disease onset, disease duration, and ALS Functional Rating Scale - Revised score.

RESULTS: Significant differences in beta diversity of the oral microbiomes were seen between limb- and bulbar-onset ALS participants. Two bacterial genera were differentially abundant between these groups, Bifidobacteriaceae Bifidobacterium was enriched in bulbar-onset cases, while Pasteurellaceae Haemophilus was enriched in limb-onset cases. No significant differences were found between ALS participants and controls, but there were significant differences when comparing participants from different sites of recruitment. Amongst household pairs (n=35 pairs), ALS participants differed from control participants at the Seoul site.

CONCLUSIONS: Despite the cohort and household effects, our study identified differentially abundant organisms that may be important to the phenotypic variability of ALS and should be considered for future study. Our study provides novel insights into design for future multi-site microbiome research in ALS.}, } @article {pmid41517820, year = {2026}, author = {Choi, SJ and Park, H and Sung, JJ}, title = {First Korean Case of C9orf72-Related Amyotrophic Lateral Sclerosis With Progressive Supranuclear Palsy-Like Features.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {22}, number = {1}, pages = {125-127}, pmid = {41517820}, issn = {1738-6586}, } @article {pmid41517981, year = {2026}, author = {Xu, X and Xu, J and Zhao, B and Guo, B and Wei, S and Li, B and Qi, Z and Chen, S and Wang, G and Liu, X}, title = {Target-site mutations and non-target-site detoxification confer ALS-inhibitor resistance in Bromus japonicus populations in China.}, journal = {Pest management science}, volume = {82}, number = {4}, pages = {3874-3883}, doi = {10.1002/ps.70510}, pmid = {41517981}, issn = {1526-4998}, support = {//the HAAFS Science and Technology Innovation Special Project (2022KJCXZX-LYS-13)/ ; //the Basic Research Funds of Hebei Academy of Agriculture and Forestry Sciences (2024060203)/ ; //the HAAFS Youth Innovation Fund Project (2023LYS03)/ ; }, mesh = {*Herbicide Resistance/genetics ; *Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Herbicides/pharmacology ; China ; Mutation ; *Plant Proteins/genetics/metabolism/antagonists & inhibitors ; }, abstract = {BACKGROUND: The emergence of herbicide-resistant Japanese brome (Bromus japonicus) populations has been increasingly documented throughout China. Two such populations, DZ-R and XL-R, exhibit resistance to acetolactate synthase (ALS)-inhibiting herbicides, yet their resistance level and mechanism remain undetermined. This study sought to: (i) quantify resistance levels to flucarbazone-sodium, mesosulfuron-methyl, and pyroxsulam; (ii) screen for ALS mutations conferring target-site resistance (TSR); and (iii) characterize non-target-site resistance (NTSR) mechanisms using a multi-omics approach.

RESULTS: Whole-plant bioassay results indicated that the resistance indices of DZ-R and XL-R populations were 111.3 and 90.5 to flucarbazone-sodium, 36 and 206.4 to mesosulfuron-methyl, and 109.8 and 429.5 to pyroxsulam. The TSR mechanism was mediated by distinct ALS gene mutations: a Pro197-Ser substitution in DZ-R and a Pro197-Thr substitution in XL-R. Integrated transcriptomic, metabolomics and malathion-inhibited bioassay analyses revealed the NTSR mechanism, identifying two ABCB4, ABCG48, ABCB11 genes, two unnamed ABC, POD 35, POD P7-like, GST1, GSTU17, 2 GSTU6, IN2-1-like isoform X3 genes, three unnamed GST, GT 73C6-like, ZWY2020_001091, cis-zeatin O-GT, CYP74A15, noroxomaritidine synthase 2-like, indole-2-monooxygenase-like genes and four unnamed CYP450 genes as candidate genes. These genes participated in ATP-binding cassette transporters, phenylpropanoid biosynthesis, glutathione metabolism and zeatin biosynthesis metabolic pathways that synergistically mediate herbicide detoxification. Notably, two putative flucarbazone-sodium degradation pathways were deduced in the resistant populations.

CONCLUSION: Collectively, these findings demonstrated that both TSR and NTSR mechanisms contributed to herbicide resistance in the DZ-R and XL-R populations. Future research should prioritize functional validation of the identified candidate genes to elucidate their specific roles in herbicide metabolism. © 2026 Society of Chemical Industry.}, } @article {pmid41518572, year = {2026}, author = {Zhang, Z and Zhang, M and Cao, Z and Zhao, H and Li, X and Luo, P}, title = {Fibrillarin: bridging ribosome biogenesis and apoptosis in cellular stress and disease.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {31}, number = {1}, pages = {11}, pmid = {41518572}, issn = {1573-675X}, support = {82171363//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Apoptosis/genetics ; *Ribosomes/metabolism/genetics ; *Stress, Physiological ; *Chromosomal Proteins, Non-Histone/metabolism/genetics ; Tumor Suppressor Protein p53/metabolism/genetics ; Animals ; *Neoplasms/genetics/metabolism/pathology ; Cell Nucleolus/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; }, abstract = {Nucleolar stress has emerged as a critical regulatory mechanism linking ribosome biogenesis defects to apoptotic cell death in various pathological conditions. Fibrillarin (FBL), the catalytic component of box C/D small nucleolar ribonucleoproteins, participates in multiple forms of programmed cell death through both p53-dependent and p53-independent pathways across diverse disease contexts including cancer and neurodegeneration. In malignancies including breast cancer, colorectal cancer, and hepatocellular carcinoma, FBL overexpression promotes apoptosis resistance, whereas in Alzheimer's disease and ALS/FTD, FBL dysfunction contributes to pathological neuronal death. Dysregulation of FBL can lead to excessive apoptosis or apoptosis resistance depending on cellular context and disease state. Various cellular stressors trigger aberrant FBL function, disrupting rRNA processing and ribosome assembly, which then activates nucleolar stress responses that culminate in cell death through ribosomal protein-MDM2-p53 axis activation or selective translational control of survival factors in a context-dependent manner. Therefore, targeting FBL-mediated apoptotic pathways is considered an important avenue for the treatment of various cancers and neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of FBL-regulated apoptosis in disease pathogenesis and provide a systematic overview of current therapeutic strategies targeting nucleolar stress pathways, including RNA polymerase I inhibitors and precision medicine approaches based on p53 status, which may provide important therapeutic targets that merit further investigation.}, } @article {pmid41518628, year = {2026}, author = {Chevet, ML and Garnier, M and Fadel, M and Scherer, C and Cassereau, J and Levaillant, M and Codron, P}, title = {Epidemiology of Amyotrophic Lateral Sclerosis in the Pays de la Loire, France: A 20-Year Study from a Centralized Diagnostic Center.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-8}, pmid = {41518628}, issn = {1423-0208}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal motor neurons disease with multifactorial etiology. The epidemiology of ALS in France is mainly documented through the Limousin regional registry (FRALim). We aimed to determine the incidence and clinical characteristics of ALS cases over a 20-year period in another French region, the Pays de la Loire, served by a single centralized diagnostic center.

METHODS: All patients diagnosed with ALS at the Angers University Hospital reference center between 2003 and 2023 were retrospectively included. Demographic and clinical data were extracted from medical records, and incidence rates were calculated using annual population estimates from the National Institute of Statistics and Economic Studies. Spatial analyses were performed to identify over-incidence areas and potential environmental or occupational determinants.

RESULTS: A total of 1,316 patients were diagnosed with ALS during the study period, corresponding to a crude incidence rate of 1.88 cases per 100,000 person-years (95% CI: 1.78-1.98), with no significant variation over time. The standardized incidence rate was 1.73 (95% CI: 1.63-1.83). The mean age at symptom onset was 63.6 ± 11.2 years, 58.7% of patients were male. The mean disease duration was 3.7 ± 3.5 years. ALS onset was spinal in 70.3%, bulbar in 27.9%, and respiratory in 1.7% of cases. Familial or genetic forms accounted for 6% of patients. Four geographical over-incidence areas were identified, with no correlation found with pesticide use, air pollution, or other environmental indicators. One occupational cluster was observed among farmers in a specific commune, prompting a dedicated investigation.

CONCLUSION: This 20-year retrospective study provides the first epidemiological data on ALS in western France. The incidence and clinical features are consistent with national and European data. The identification of spatial and occupational clusters underlines the importance of continued regional surveillance and of prospective, registry-based studies to clarify environmental and occupational risk factors for ALS.}, } @article {pmid41518742, year = {2026}, author = {Milella, G and Carlone, S and Luisi, F and Velucci, V and Defazio, G}, title = {Facial-onset SOD1 amyotrophic lateral sclerosis: A case report and systematic review.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {145}, number = {}, pages = {111856}, doi = {10.1016/j.jocn.2026.111856}, pmid = {41518742}, issn = {1532-2653}, mesh = {Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/complications ; *Facial Paralysis/genetics/etiology ; *Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Facial-onset weakness is an exceptionally rare presentation of SOD1-associated amyotrophic lateral sclerosis (ALS), and its natural history, anatomical spread, and prognostic implications remain unclear.

METHODS: We report a woman carrying a heterozygous SOD1 A5T variant who presented with isolated, rapidly progressive bilateral facial palsy, and we performed a PRISMA-compliant systematic review of MEDLINE, Scopus, and Web of Science to identify genetically confirmed SOD1-positive ALS with facial-onset weakness. Case-level demographic, genetic, clinical, neurophysiological, and outcome data were extracted and synthesised descriptively.

RESULTS: Eleven patients were included (7 men, 4 women; mean age at onset 52.3 years). Seven SOD1 variants were represented, predominantly associated with short survival (e.g. A5V, C7G, A5T). Facial weakness was initially confined to the lower face in 5/11 patients, while 6/11 had combined upper and lower facial involvement. Disease spread followed a stereotyped pattern: early contralateral facial recruitment (mean 3.6 months), rapid bulbar involvement (4.2 months), and later extension to the upper limbs (9.2 months), frequently with side-concordance between facial and arm involvement. Lower motor neuron (LMN) signs predominated in the early phases of the disease. Survival was short (median 16 months), lower than reported for unselected SOD1-ALS cohorts with the same genotypes. Three patients received tofersen, with heterogeneous outcomes.

CONCLUSIONS: Facial-onset SOD1 ALS defines a distinctive phenotype characterised by LMN-predominant facial palsy in early phases, near-neighbour spread, and an aggressive course exceeding genotype-based expectations. Prompt recognition and genetic testing in progressive facial palsy unresponsive to immunotherapy are essential to ensure access to gene-targeted treatments.}, } @article {pmid41520601, year = {2026}, author = {Squintani, G and Muzio, MD and Rasera, A and Paio, F and Borin, GU and Humaidan, K and Orlando, D and Refatti, N and Romito, S and Tinazzi, M and Bonetti, B and Ermani, M}, title = {Sensory and motor cortical hyperexcitability in patients with amyotrophic lateral sclerosis: are they related? a prospective pilot study.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {183}, number = {}, pages = {2111485}, doi = {10.1016/j.clinph.2025.2111485}, pmid = {41520601}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Female ; Male ; Middle Aged ; *Motor Cortex/physiopathology ; Pilot Projects ; *Evoked Potentials, Motor/physiology ; *Evoked Potentials, Somatosensory/physiology ; Aged ; Transcranial Magnetic Stimulation/methods ; *Somatosensory Cortex/physiopathology ; Prospective Studies ; Adult ; }, abstract = {OBJECTIVE: Our study evaluates sensory and motor cortical hyperexcitability as diagnostic biomarkers in ALS patients and investigates their relationship, identifying distinct or interconnected pathophysiological mechanisms in different sub-groups.

METHODS: We examined 26 ALS patients and 18 healthy controls. Motor cortex excitability was assessed using transcranial magnetic stimulation to measure the motor evoked potential (MEP) suppression ratio. Somatosensory cortex excitability was evaluated through upper-limb somatosensory evoked potentials (SEPs) with conventional and paired-pulse techniques. Statistical analyses included parametric/non-parametric tests, correlation analyses, and χ[2] tests. ROC analysis was used to assess diagnostic performance. Significance threshold was p < 0.05.

RESULTS: ALS patients showed a significantly reduced MEP suppression ratio (p < 0.001) with excellent discriminative power (100 % accuracy). SEP suppression ratio was significantly lower in ALS (p < 0.001), with sensitivity 76.3 %, specificity 91.7 %, and accuracy 84 %. In patients with giant SEPs, a strong inverse correlation was observed between MEP and SEP suppression ratios (r =  - 0.70, p < 0.001).

CONCLUSIONS: MEP and SEP suppression ratio are robust biomarkers of motor cortical dysfunction in ALS patients with a highlighting cortical heterogeneity between sub-groups, suggesting cortical interconnection.

SIGNIFICANCE: Alongside confirming motor and sensory cortical hyperexcitability as ALS hallmarks, this study reveals subgroup-specific patterns suggesting a compensatory interplay between sensory and motor cortex.}, } @article {pmid41520654, year = {2026}, author = {Mehdiyoun, NF and Wright, J and Robinson, RL and Brandt, AU and Hoyt, M and Guo, J and Ball, N and Iqbal, H and Ringland, C and Milligan, G and Curtis, SE}, title = {Evaluating ALSFRS-R as an indicator of disease milestones and functional independence: An observational study of US neurologists and their patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {481}, number = {}, pages = {125732}, doi = {10.1016/j.jns.2026.125732}, pmid = {41520654}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Activities of Daily Living ; *Neurologists ; *Disease Progression ; Cross-Sectional Studies ; Female ; Middle Aged ; Male ; United States ; Aged ; *Severity of Illness Index ; }, abstract = {BACKGROUND: The Revised Amyotrophic Lateral Sclerosis (ALS) Functional Rating Scale (ALSFRS-R) is a clinician-reported outcome measure monitoring disease progression in people living with ALS (pALS). This study examined the relationship of ALSFRS-R scores with disease progression and independence levels for activities of daily living (ADLs) among pALS.

METHODS: Real-world data, including the ALSFRS-R, were drawn from a cross-sectional survey of US neurologists treating pALS (Adelphi ALS Disease Specific Programme™), conducted between July 2020 and March 2021. ALSFRS-R scores were modeled against 11 pre-defined disease milestones. The relationship between ALSFRS-R scores and levels of independence in 24 ADLs was examined using ordered logistic regression.

RESULTS: Fifty-nine neurologists provided data for 379 pALS (mean age: 59.5 years; mean disease duration: 16.1 months). Estimated mean ALSFRS-R total score decreased (worsened) from 46.1 at first consultation regarding ALS symptoms to 25.1 upon receipt of a feeding tube. In general, pALS were likely to be completely dependent in most ADLs when their ALSFRS-R total scores were ≤ 25. A 1-point decrease in ALSFRS-R total score was associated with increased risks of losing independence across all ADLs. For each ADL, a 1-point decrease in domain score was associated with varying risks of losing independence across different domains.

CONCLUSIONS: There is a correlation between ALSFRS-R scores and levels of independence in ADLs among pALS, facilitating score interpretation for monitoring disease and function status. Yet, the relevance of the ALSFRS-R total score diminishes in advanced stages of ALS, indicating a need for additional measures to provide comprehensive evaluation.}, } @article {pmid41521074, year = {2026}, author = {Ham, HJ and Lee, JA}, title = {Stress granules as a central hub linking organelle stress, aging, and neurodegeneration.}, journal = {BMB reports}, volume = {59}, number = {2}, pages = {85-100}, pmid = {41521074}, issn = {1976-670X}, mesh = {Humans ; *Aging/metabolism/physiology ; *Stress Granules/metabolism/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Organelles/metabolism ; Autophagy ; Neurons/metabolism ; }, abstract = {Stress granules (SGs) are dynamic cytoplasmic assemblies composed of RNAs and proteins that form in response to cellular stress, serving to halt translation and protect cellular integrity. In neurons, SGs mediate adaptive, pro-survival responses to acute stress; however, their dysregulation has been increasingly associated with both aging and neurodegenerative diseases. Aging neurons frequently exhibit changes in SG dynamics-with an increased propensity to form SGs while displaying reduced efficiency in their clearance-resulting in persistent granules that can facilitate the accumulation of pathological protein aggregates (e.g., TDP-43 or tau). Aberrant SG formation and defective clearance mechanisms are implicated in the pathogenesis of key neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). Recent findings have shown that SGs interface with organelles such as lysosomes, mitochondria, and the endoplasmic reticulum, utilizing autophagic and other protein quality-control mechanisms for clearance. As these clearance pathways progressively decline with age, SGs can transition from promoting cellular adaptation to contributing to cellular dysfunction. In this mini-review, we examine how aging influences SG biology, detail the role of SGs in neurodegenerative diseases, and discuss emerging mechanistic insights and therapeutic strategies aimed at modulating SG dynamics in the context of brain aging. [BMB Reports 2026; 59(2): 85-100].}, } @article {pmid41521076, year = {2025}, author = {Lee, SP and Choi, J and Park, JH and Lee, KN and Lee, HL and Sung, W}, title = {Predictors of Percutaneous Endoscopic Gastrostomy-Related Complications in Amyotrophic Lateral Sclerosis: A 19-Year Retrospective Study From a Tertiary Center.}, journal = {Journal of digestive diseases}, volume = {26}, number = {11-12}, pages = {492-508}, doi = {10.1111/1751-2980.70025}, pmid = {41521076}, issn = {1751-2980}, mesh = {Humans ; *Gastrostomy/adverse effects/methods ; *Amyotrophic Lateral Sclerosis/complications ; Retrospective Studies ; Male ; Female ; Risk Factors ; Tertiary Care Centers ; Middle Aged ; Aged ; *Deglutition Disorders/etiology/surgery ; *Postoperative Complications/etiology/epidemiology ; Ileus/complications ; Pneumoperitoneum/etiology ; Enteral Nutrition/methods/adverse effects ; Adult ; *Gastroscopy/adverse effects ; }, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that inevitably leads to swallowing difficulties as the disease progresses. Percutaneous endoscopic gastrostomy (PEG) is recommended for optimal supportive management of dysphagia among these patients. We aimed to investigate PEG-related complications and risk factors in patients with ALS.

METHODS: Medical records of the ALS patients who underwent PEG from March 2006 to February 2025 in a single tertiary care center were retrospectively reviewed. PEG-related complications and risk factors were assessed through chart review, endoscopic reports and images, radiological findings, and follow-up data.

RESULTS: Altogether 501 ALS patients (262 men) underwent PEG, of whom 60 developed early complications and 82 developed late complications, including 11 patients who developed both. Pneumoperitoneum was more common in underweight patients (p = 0.004), and wound infection was more common in patients with pre-PEG ileus (p = 0.044). Multivariate analysis revealed that low albumin level, long procedure time, and ileus were significantly associated with early complications. Obesity and ileus were independent risk factors for buried bumper syndrome. Those with an internal bolster at the upper body of the stomach and with an external bolster in the midline of the abdomen were at significant risk of inadvertent PEG removal.

CONCLUSIONS: Albumin and body mass index extremes are predictors of complications, and care is needed when PEG is performed on patients with pre-PEG ileus. To reduce such risks, the PEG tube should not be inserted into the upper body of the stomach or the midline of the abdomen.}, } @article {pmid41523190, year = {2026}, author = {Jiang, Y and Fu, Y and Song, X and Wang, X and Li, J and Cheng, L and Chen, Y and Zhang, Y and Wang, J and Yi, X and Palaniyappan, L}, title = {Microstructure and gene expression influence gyrification in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {1}, pages = {fcaf491}, pmid = {41523190}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. Beyond well-established grey and white matter pathology, alterations in cortical gyrification have recently been observed, yet their clinical relevance and molecular underpinnings remain to be understood. Here, we investigated this premise by examining its microstructural and transcriptional basis in 60 patients with amyotrophic lateral sclerosis (median age = 55, range = 25-72 years) and 60 matched controls (median age = 56, range = 27-72 years) using structural and diffusion MRI. Patients exhibited a significant reduction in local gyrification index within bilateral precentral and postcentral gyri, left middle frontal gyrus and left superior parietal lobule. This was accompanied by reduced fractional anisotropy in the white matter tracts, primarily involving the corticospinal tract and corpus callosum. Higher local gyrification index and fractional anisotropy values were associated with better motor function as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, and local gyrification index also showed positive associations with global cognitive status. A mediation analysis indicated that fractional anisotropy partially accounted for the relationship between local gyrification index and functional disability, suggesting that disrupted white matter pathways contribute to the clinical impact of gyrification changes. To explore underlying mechanisms, we integrated neuroimaging findings with transcriptomic data from the Allen Human Brain Atlas. Regions of reduced local gyrification index showed spatial convergence with cortical expression of amyotrophic lateral sclerosis-related genes such as TARDBP and C9orf72, enriched for biological processes related to protein aggregation, axon guidance and synaptic signalling. Together, these findings suggest that cortical gyrification abnormalities in amyotrophic lateral sclerosis are closely linked to white matter degeneration, functional impairment and genetic vulnerability, thereby offering an integrative window into the multiscale pathology of amyotrophic lateral sclerosis.}, } @article {pmid41524979, year = {2026}, author = {Sun, Y and Huang, C and Pan, Y and Zhang, H and He, X}, title = {Muscle Fibrosis in Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Diagnostic Advances, and Therapeutic Strategies.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {357}, pmid = {41524979}, issn = {1559-1182}, support = {2021KY727//Health Commission of Zhejiang Province, Medical and health project/ ; A20210510//Hangzhou Municipal Health Commission, Medical and health science project/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy/pathology/diagnosis/metabolism/complications ; Fibrosis ; *Muscle, Skeletal/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder primarily characterized by the degeneration of motor neurons. However, the pathological process of ALS extends beyond the central nervous system, with dynamic changes in skeletal muscle playing a crucial role in the progression of the disease. Recent research has shown that muscle fibrosis, marked by the abnormal accumulation of extracellular matrix (ECM), leads to reduced muscle elasticity, compromised contractile function, and impaired regeneration of neuromuscular junctions (NMJs). This condition represents not only the final stage of muscle atrophy in ALS but also a significant factor accelerating disease progression through "neuromuscular interactions." We conducted a systematic review of the molecular mechanisms of muscle fibrosis in ALS. This included examining the dysregulation of transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF/CCN2), and the Wnt/β-catenin signaling pathways. We also considered key cellular contributors, such as fibro-adipogenic precursor cells and macrophages. The review also covers the use of non-invasive imaging techniques, such as MRI and muscle ultrasound, for early detection and monitoring. We also evaluate potential therapeutic approaches, ranging from anti-fibrotic drugs and gene therapy to physical interventions. In summary, muscle fibrosis is a promising therapeutic target that could complement strategies focused on motor neurons, ultimately improving functional outcomes in patients with amyotrophic lateral sclerosis.}, } @article {pmid41525811, year = {2026}, author = {Pradhan, LK and Das, SK}, title = {Zebrafish neural regeneration: mechanistic insights into human nervous system repair.}, journal = {Neuroscience}, volume = {596}, number = {}, pages = {1-15}, doi = {10.1016/j.neuroscience.2026.01.009}, pmid = {41525811}, issn = {1873-7544}, mesh = {Animals ; *Zebrafish/physiology ; *Nerve Regeneration/physiology ; Humans ; Neurodegenerative Diseases/physiopathology ; Disease Models, Animal ; }, abstract = {The zebrafish (Danio rerio) is a powerful vertebrate model for studying neurodegenerative diseases and regenerative medicine due to its genetic similarity to humans and its unique ability to regenerate the central nervous system (CNS). This review synthesizes key findings on zebrafish neural regeneration across the retina, spinal cord, and brain, emphasizing translational relevance. Zebrafish effectively model disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, stroke, epilepsy, autism spectrum disorders, and CNS injuries. Unlike mammals, they restore damaged axons and recover function through a permissive extracellular matrix, transient inflammation, and glial plasticity. In the retina, Müller glia reprograms after injury to generate progenitors that replace lost neurons, regulated by Wnt/β-catenin, Shh, EGF, Hippo/YAP, and ROCK signaling. In the spinal cord, ependymo-radial glia forms a laminin- and fibronectin-rich "glial bridge," guided by FGF and CTGF signaling, supporting axon regrowth. In the brain, GFAP- and Olig2-positive radial glia drive neurogenesis within ventricular niches, integrating new neurons while maintaining circuit integrity. Regeneration involves transient Notch suppression, context-specific Wnt and FGF activation, and immune modulation without fibrosis. Advances in single-cell RNA sequencing, CRISPR-Cas9, lineage tracing, and multi-omics have identified injury-induced progenitor states, regulators (ascl1a, lin28, sox2, stat3), and epigenetic programs enabling regeneration. Emerging research on bioelectric signaling, microbiota-brain interactions, and lipid mediators further expands systemic understanding. Overall, zebrafish provide a unified model for decoding vertebrate CNS regeneration and guiding therapeutic strategies to restore neural repair in humans.}, } @article {pmid41525886, year = {2026}, author = {Zimyanin, V and Dash, BP and Simolka, T and Glaß, H and Pal, A and Haidle, F and Zarnack, K and Verma, R and Khatri, V and Deppmann, C and Zunder, E and Müller-McNicoll, M and Redemann, S and Hermann, A}, title = {Compartment-specific transcriptome of motor neurons reveals impaired extracellular matrix signaling and activated cell cycle kinases in FUS-ALS.}, journal = {Neurobiology of disease}, volume = {219}, number = {}, pages = {107268}, pmid = {41525886}, issn = {1095-953X}, support = {R01 GM144668/GM/NIGMS NIH HHS/United States ; }, mesh = {*Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *RNA-Binding Protein FUS/genetics/metabolism ; *Extracellular Matrix/metabolism ; *Transcriptome ; Humans ; *Cell Cycle Proteins/metabolism/genetics ; *Protein Serine-Threonine Kinases/metabolism/genetics ; Signal Transduction/physiology ; Polo-Like Kinase 1 ; *Proto-Oncogene Proteins/metabolism/genetics ; Axons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Mutation ; Animals ; }, abstract = {Mutations in FUSED IN SARCOMA (FUS) cause juvenile-onset amyotrophic lateral sclerosis (ALS). Early pathogenesis of FUS-ALS involves impaired transcription and splicing, DNA damage response, and axonal degeneration. However, the molecular pathophysiology and the link between somatic and axonal phenotypes are still poorly understood. We evaluated whether compartment-specific transcriptome differences could distinguish and drive early axonal degeneration. We used iPSC-derived motor neurons (MNs) coupled with microfluidic approaches to generate RNA-sequencing profiles from axonal and somatodendritic compartments. We demonstrate that the axonal transcriptome is unique and distinct, with RNA metabolism, extracellular secretion, and matrix disassembly pathways particularly enriched in distal axonal compartments. FUS mutation leads to changes in distinct pathways that were clustered in only a few distinct protein-protein interaction (PPI) networks. Somatodendritic changes upon FUS mutation include WNT signaling, mitochondrial, extracellular matrix (ECM)-, and synapse-related functions. In contrast, analysis of the axonal transcriptome in mutant MNs centers on the PLK1 pathway, mitochondrial gene expression, and regulation of inflammation. Comparison to CLIP-seq data revealed a significant enrichment for PLK1 and DNA replication pathways in axons. PLK1 upregulation did not activate cell-cycle re-entry but contributed to mutant MNs survival, and its inhibition increased neuronal cell death. We propose that upregulation of PLK1 represents an early event in the pathogenesis of ALS and could act in response to DNA damage, mitochondrial damage, and immune response activation in the affected cells. Additionally, downregulation of ECM pathways in the somatodendritic compartment and axons could explain strongly compromised dynamics of axonal outgrowth. Overall, we provide a novel valuable resource of the potential targets and affected processes changed in the specific compartments of FUS-ALS motor neurons.}, } @article {pmid41525888, year = {2026}, author = {Tessitore, S and Torazza, C and Bonifacino, T and Bacchetti, F and Roselli, F and Raiteri, L and Milanese, M and Bonanno, G}, title = {Focus on the excitatory and inhibitory neurotransmission imbalance in amyotrophic lateral sclerosis: a harmful disease player or a potential therapeutic opportunity?.}, journal = {Neurobiology of disease}, volume = {219}, number = {}, pages = {107272}, doi = {10.1016/j.nbd.2026.107272}, pmid = {41525888}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/metabolism ; Humans ; Animals ; *Synaptic Transmission/physiology ; Glutamic Acid/metabolism ; *Neural Inhibition/physiology ; gamma-Aminobutyric Acid/metabolism ; Motor Neurons/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. Evidence indicates that ALS is a "multifactorial" and "multicellular" disease; however, the causes of ALS remain elusive, as the mechanisms underlying the disease have not yet been completely clarified. One major proposed mechanism, first described in 1990, is the glutamate excitotoxicity theory. This theory suggests that excessive glutamatergic neurotransmission, combined with impaired glutamate clearance, significantly contributes to motor neuron degeneration. Aberrant glutamate neurotransmission may lead to precocious motor neuron hyperexcitability in the brain cortex and spinal cord, which can be later followed by hypoexcitability phases. Accumulating evidence suggests that impairment in inhibitory neurotransmission is relevant for excitation/inhibition imbalance, leading to excitotoxicity, a critical feature of ALS. Gamma-aminobutyric acid (GABA) and glycine are the primary inhibitory neurotransmitters that modulate neuronal excitability, including that of motor neurons. In ALS, dysfunction of inhibitory processes and loss of cortical and spinal inhibitory interneurons are observed. Renshaw cells, which mediate recurrent inhibition in the spinal cord, seem particularly vulnerable. The interactions among neurotransmitters, including glutamate, GABA, and glycine, play pivotal roles in regulating the excitation/inhibition balance. Auto- or hetero-receptor-mediated interactions are crucial, but auto- or hetero-transporter-mediated neurotransmission control, as well as other molecular mechanisms that regulate neuronal interplay, are also relevant, as they can be altered in pathological conditions such as ALS. To facilitate the search for new effective therapies for ALS, attention toward the impairment of inhibitory neurotransmission is essential to determine the role of excitation/inhibition imbalance on excitotoxicity. Different pharmacological agents are being used to treat other pathologies in which the excitation/inhibition ratio is impaired. Among these, we highlighted the potential of novel glycine and GABA receptor ligands and transporter inhibitors, as stand-alone interventions or in combination with other treatments. The present review aims to elucidate the complex interplay between excitatory and inhibitory neurotransmission in ALS, exploring the potential to target this imbalance for therapeutic purposes.}, } @article {pmid41527739, year = {2026}, author = {Le, J and Hu, X and Jiang, Y and Wang, Q and Ma, Q and Cui, W}, title = {Insights into phosphoproteomic studies and prospects of phosphoproteins as biomarkers for brain disorders.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {1}, pages = {5-25}, doi = {10.1177/13872877251411546}, pmid = {41527739}, issn = {1875-8908}, mesh = {Humans ; *Phosphoproteins/metabolism ; *Proteomics/methods ; Biomarkers/metabolism ; *Brain Diseases/metabolism/diagnosis ; Animals ; Phosphorylation ; }, abstract = {The dysregulation of phosphorylation networks plays a critical role in the pathogenesis of a wide spectrum of brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic stroke, drug abuse, major depressive disorder, and schizophrenia. Notably, phosphorylated isoforms of microtubule-associated protein tau and neurofilament heavy polypeptide are already utilized in clinical diagnostics, highlighting the promise of protein phosphorylation signatures as biomarkers for prediction, diagnosis, prognosis, and treatment monitoring. Recent advances in deep phosphoproteomic technologies now facilitate the comprehensive mapping of phosphorylation alterations across diverse biological samples and disease stages. This review summarizes current phosphoproteomic studies aimed at identifying biomarkers for brain disorders and elaborates on the promising application of phosphorylated proteins in this context.}, } @article {pmid41530082, year = {2026}, author = {Cooper, P and Lu, M and Chan, M and Wilman, A and Kalra, S and Ghavanini, AA}, title = {Exploring the Value of Brain T2* Weighted and FLAIR Imaging for Diagnosing Amyotrophic Lateral Sclerosis.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-6}, doi = {10.1017/cjn.2026.10527}, pmid = {41530082}, issn = {0317-1671}, abstract = {OBJECTIVES: Early diagnosis of amyotrophic lateral sclerosis (ALS) is essential for treatment initiation and symptom management, yet it remains challenging due to nonspecific symptoms and the lack of reliable diagnostic biomarkers. Although conventional MRI sequences such as T2* weighted and fluid-attenuated inversion recovery (FLAIR) have shown potential in identifying upper motor neuron abnormalities, their diagnostic utility in ALS is not well established. This study aimed to evaluate the sensitivity and specificity of brain T2* weighted and FLAIR MRI sequences in diagnosing ALS using prospectively collected data and to assess associations with disease severity.

METHODS: Data were analyzed from 20 patients with ALS and 20 healthy controls enrolled at the Edmonton site of the Canadian ALS Neuroimaging Consortium 1 (CALSNIC-1) study. Single-slice 2D axial susceptibility-weighted echo planar imaging (SWEPI) and FLAIR images were independently rated by a blinded neurologist and radiologist for signs of corticospinal tract and motor cortex abnormalities. Sensitivity and specificity were calculated, and linear regression was used to examine associations with ALS Functional Rating Scale-Revised (ALSFRS-R) scores.

RESULTS: T2* weighted and FLAIR MRI sequences showed high specificity (0.95 and 0.85, respectively) but low sensitivity (both 0.25) for ALS diagnosis. No significant correlation was found between imaging abnormalities and ALSFRS-R scores. Inter-rater reliability was poor (κ = 0.25 for SWEPI; κ = 0.14 for FLAIR).

CONCLUSION: While T2* weighted and FLAIR MRI sequences may have some specificity for ALS, our study suggests they are not sufficiently sensitive to be used as reliable diagnostic tools for ALS.}, } @article {pmid41530593, year = {2026}, author = {Muneer, MA and Tariq, I and Zulfiqar, E and Saaki, SS and Gupta, I and Bokhari, SMNA and Verma, A and Mehta, R and Sah, R and Ahmed, SI}, title = {Efficacy and safety of dextromethorphan/quinidine in treating pseudobulbar affect in neurological disorders: A systematic review and dose-classified network meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {1}, pages = {159}, pmid = {41530593}, issn = {1590-3478}, mesh = {Humans ; *Dextromethorphan/administration & dosage/adverse effects/pharmacology/therapeutic use ; Drug Combinations ; *Nervous System Diseases/drug therapy/complications ; *Pseudobulbar Palsy/drug therapy ; *Quinidine/administration & dosage/adverse effects/pharmacology/therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Pseudobulbar affect (PBA) is a disabling neuropsychiatric condition characterized by sudden, involuntary episodes of crying or laughing incongruent with mood. It occurs in several neurological disorders, including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, and traumatic brain injury (TBI). Dextromethorphan/quinidine (DM/Q) is the only Food and Drug Administration (FDA)-approved therapy for PBA, but optimal dosing and safety profiles remain uncertain.

OBJECTIVE: To evaluate the efficacy and safety of different DM/Q dosing regimens for treating PBA through a systematic review and network meta-analysis.

METHODS: A comprehensive search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted through March 2025. Randomized controlled trials reporting outcomes on the Center for Neurologic Study-Lability Scale (CNS-LS), Visual Analog Scale-Quality of Life (VAS-QOL), Visual Analog Scale-Quality of Recovery (VAS-QOR), and adverse events were included. Analyses were performed using R (netmeta package), and bias was assessed with the Cochrane RoB 2.0 tool.

RESULTS: Five randomized controlled trials comprising 605 participants were analyzed. DM/Q 20/10 mg and 30/10 mg significantly improved CNS-LS scores (mean difference [MD] - 2.52 and - 2.45, respectively), while DM/Q 30/30 mg produced greater gains in VAS-QOL (MD 17.20) and VAS-QOR (MD 14.90). Dizziness was the only statistically significant, dose-related adverse event.

CONCLUSION: DM/Q combination therapy provides effective symptom control for PBA, with favorable tolerability. Both 20/10 mg and 30/10 mg doses improve emotional lability, while 30/30 mg yields additional quality-of-life benefits. Further studies should assess long-term safety and disorder-specific dosing optimization.}, } @article {pmid41531269, year = {2026}, author = {Elmaleh, B and Faust, O and Rosenzweig, R}, title = {The ALS-associated E425K mutation uncouples DNAJC7 from the Hsp70 chaperone cycle.}, journal = {The FEBS journal}, volume = {293}, number = {12}, pages = {3485-3501}, pmid = {41531269}, issn = {1742-4658}, support = {1093/22//Israel Science Foundation/ ; //Minerva Foundation/ ; ERC-CoG-2024 101169856//H2020 European Research Council/ ; }, mesh = {*HSP70 Heat-Shock Proteins/metabolism/genetics/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *HSP40 Heat-Shock Proteins/genetics/metabolism/chemistry ; Protein Binding ; *Mutation ; Molecular Chaperones/genetics/metabolism/chemistry ; Models, Molecular ; Protein Domains ; Binding Sites ; Heat-Shock Proteins ; }, abstract = {DNAJC7, a member of the J-domain protein (JDP/Hsp40) family, plays a key role in protein homeostasis by regulating Hsp70 activity and preventing protein aggregation. Mutations in DNAJC7 have been linked to amyotrophic lateral sclerosis (ALS); yet, the molecular mechanisms by which these variants impair chaperone function remain poorly understood. DNAJC7 is a conserved chaperone featuring both a canonical J-domain, essential for Hsp70 activation, and three TPR domains, which serve as protein-protein binding interfaces. Here, we investigate the structural and functional consequences of the ALS-associated E425K mutation located within the conserved J-domain. Using NMR spectroscopy, we show that although the E425K mutation does not alter the structure of the protein, it significantly disrupts the conserved J-domain-Hsp70 interaction. We further identify a second Hsp70-binding interface within the TPR domains, which interacts with the C-terminal EEVD motif of Hsp70. This TPR-EEVD interaction is preserved in the E425K mutant but cannot compensate for the loss of J-domain binding or restore DNAJC7-dependent Hsp70 activation. Functionally, we show that the TPR domains of DNAJC7 directly bind TDP-43 and prevent its aggregation and that this holdase activity is retained in the E425K mutant. However, the mutant fails to support client transfer to Hsp70 and the subsequent Hsp70-mediated substrate refolding. Together, these findings demonstrate that DNAJC7 requires coordinated action of both J-domain and TPRs to regulate Hsp70 function and that disruption of J-domain-mediated activation uncouples DNAJC7 from the Hsp70 cycle, providing a mechanistic basis for its dysfunction in ALS.}, } @article {pmid41531792, year = {2026}, author = {Yang, X and Huang, S and Wang, Y and Yuan, J and Yao, X}, title = {Identification of Comprehensive Landscape of Peripheral Immunity and Chemokine-Related Genes in Amyotrophic Lateral Sclerosis.}, journal = {ImmunoTargets and therapy}, volume = {15}, number = {}, pages = {566733}, pmid = {41531792}, issn = {2253-1556}, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Progressive loss of motor neuron function and disruption of the blood-brain barrier are key features of ALS. Under the influence of chemokines, peripheral immune cells migrate into the central nervous system, thereby affecting the neuronal microenvironment. The aim of this study is to classify ALS based on the immune characteristics of peripheral blood in patients with the disease, and to construct prognostic models.

PATIENTS AND METHODS: A total of 397 ALS patients and 645 healthy controls (GSE112676 and GSE112680) were included. ALS chemotactic subtypes were constructed based on differentially expressed genes of chemokine and chemokine receptors (CCRs). The Cibersort algorithm was used to investigate the abundance of immune cells in peripheral blood. Univariate Cox regression analysis was performed to screen for CCRs genes, clinical characteristics, and immune cells associated with prognosis. Prognostic models were constructed based on these variables. Finally, external validation was conducted using samples from ALS patients diagnosed at the First Affiliated Hospital of Sun Yat-sen University.

RESULTS: There were significant differences in the abundance of peripheral immune cells between ALS patients and healthy controls. 17 CCRs genes were identified as differentially expressed. CCL23, CCR8, CXCR4, site of onset, age of onset, and "CD4 naive T cells" were demonstrated to be significantly correlated with survival time. Two chemotactic subtypes were established. Eight prognostic models could distinguish between high-risk and low-risk ALS patients. At year five, the areas under the receiver operating characteristic curves for the PlsRcox, Coxboost, and Xgboost algorithms were 0.747, 0.733, and 0.728, respectively. External test sets successfully validated these results.

CONCLUSION: ALS patients exhibit peripheral immune abnormalities. Peripheral immune status could be used to distinguish ALS subtypes and construct prognostic models. Understanding peripheral immune changes in ALS patients may inform potential immunotherapies.}, } @article {pmid41531877, year = {2025}, author = {Finsterer, J}, title = {There is currently no evidence that long-COVID-19 leads to neurodegenerative diseases such as SDAT, amyotrophic lateral sclerosis, or Parkinson's disease.}, journal = {Brain circulation}, volume = {11}, number = {4}, pages = {354-355}, pmid = {41531877}, issn = {2455-4626}, } @article {pmid41532955, year = {2026}, author = {Bernal-Vicente, BN and Ponce, I and Ríos-Castro, E and Moreno-Castilla, P and Tovar-Y-Romo, LB}, title = {Unveiling the Proteomic Landscape of Extracellular Vesicles: Implications for Neurodegeneration and Neuroprotection.}, journal = {Journal of neurochemistry}, volume = {170}, number = {1}, pages = {e70350}, pmid = {41532955}, issn = {1471-4159}, support = {IN214723//Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Proteomics/methods ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Neuroprotection/physiology ; Biomarkers/metabolism ; }, abstract = {Extracellular vesicles (EVs) are instrumental mediators of intercellular communication and molecular exchange in neurodegenerative and neurovascular diseases. This review integrates recent advances in EV proteomics to elucidate their roles in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and ischemic stroke. Across these conditions, EVs carry disease-relevant proteins that reflect and influence key pathological processes such as synaptic dysfunction, neuroinflammation, blood-brain barrier (BBB) disruption, and cell death. Proteomic profiling of brain- and biofluid-derived EVs has uncovered specific biomarkers and signaling pathways, ranging from tau and α-synuclein in AD and PD to mutant SOD1 in ALS and complement activation in stroke and TBI. Moreover, cell-type-specific EVs (e.g., from neurons, astrocytes, microglia, and stem cells) have been shown to exert either protective or deleterious effects, modulating apoptosis, axonal regeneration, and immune responses. Recent evidence highlights the translational potential of EVs as non-invasive biomarkers and therapeutic vectors across multiple disorders. By mapping shared and divergent proteomic signatures in EVs, we review the mechanistic relevance and clinical utility of EVs in neurodegeneration and CNS injury.}, } @article {pmid41533211, year = {2026}, author = {Shu, X and Zeng, J and Zhang, K}, title = {TREM2-mediated Crosstalk in ALS: Microglial Fate Transition, Protein Aggregate Clearance, and Peripheral Nerve Repair.}, journal = {Neuroscience bulletin}, volume = {42}, number = {9}, pages = {2173-2178}, pmid = {41533211}, issn = {1995-8218}, } @article {pmid41534442, year = {2026}, author = {Nomura, E and Morihara, R and Osakada, Y and Yunoki, T and Takemoto, M and Yamashita, T and Ishiura, H}, title = {The utility of Gold Coast criteria for amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {481}, number = {}, pages = {125733}, doi = {10.1016/j.jns.2026.125733}, pmid = {41534442}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Female ; Retrospective Studies ; Male ; Sensitivity and Specificity ; Middle Aged ; Aged ; Early Diagnosis ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease. Current diagnostic criteria, including the revised El Escorial (rEE) and Awaji (AW) criteria, have limitations in sensitivity. The Gold Coast (GC) criteria were proposed to simplify diagnosis and improve early detection, but their real-world performance remains unclear.

METHODS: We retrospectively analyzed 260 patients suspected of ALS who were admitted to our department between 2013 and 2022. The GC, AW, and rEE criteria were applied to data from initial hospitalization. Final diagnoses were based on follow-up data, and sensitivity/specificity were compared using McNemar's test.

RESULTS: The GC criteria showed equivalent sensitivity (91.6 %), but higher specificity (75.9 %) compared to all combined AW and rEE categories. GC sensitivity was significantly higher than that of AW/rEE definite/probable categories. False negatives of GC criteria were often due to insufficient LMN signs, particularly in bulbar-onset cases. Subgroup analysis showed consistent trends.

CONCLUSION: The GC criteria demonstrated high sensitivity and moderate specificity, supporting their clinical utility in early ALS diagnosis. However, variability in clinical presentation and retrospective limitations suggest the need for further prospective validation.}, } @article {pmid41534661, year = {2026}, author = {Costa, I and Barbosa, DJ and Remião, F and Sousa, ME and Silva, R}, title = {A dive into the untapped potential of marine compounds in counteracting neurodegeneration.}, journal = {Pharmacology & therapeutics}, volume = {279}, number = {}, pages = {108982}, doi = {10.1016/j.pharmthera.2026.108982}, pmid = {41534661}, issn = {1879-016X}, mesh = {Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/physiopathology ; *Neuroprotective Agents/therapeutic use/pharmacology/isolation & purification ; *Aquatic Organisms ; *Biological Products/therapeutic use/pharmacology/isolation & purification ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by the progressive breakdown and eventual loss of synapses and neurons, primarily driven by the accumulation of pathologically altered proteins within the brain and spinal cord. These diseases have complex and multifactorial etiologies, involving a broad spectrum of pathophysiological mechanisms, many of which remain incompletely understood. Nonetheless, several key pathways are consistently implicated across these conditions, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis. Given their rising prevalence and the persistent lack of effective disease-modifying therapies, the development of novel therapeutic strategies capable of targeting multiple pathophysiological processes is of critical importance for delaying or halting disease progression. In this context, marine natural compounds have emerged as promising candidates for counteracting neurodegeneration, owing to their ability to modulate key pathophysiological hallmarks of distinct neurodegenerative diseases. Derived from a wide range of marine organisms - including algae, sponges, fungi, and cyanobacteria - these bioactive molecules possess unique chemical structures and exhibit a broad spectrum of neuroprotective effects. Many have demonstrated potent antioxidant, anti-apoptotic, and mitochondrial-stabilizing activities in preclinical models. This review highlights recent advances in the discovery and characterization of marine-derived compounds with therapeutic potential in neurodegenerative diseases, contextualizing their pathologic mechanisms.}, } @article {pmid41534682, year = {2026}, author = {Sangari, S and Lackmy-Vallée, A and Peyre, I and Pradat, PF and Marchand-Pauvert, V}, title = {Afferent-driven modulation of spinal interneuron circuits across disease stages in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {219}, number = {}, pages = {107270}, doi = {10.1016/j.nbd.2026.107270}, pmid = {41534682}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Interneurons/physiology ; Female ; *Spinal Cord/physiopathology ; Male ; Motor Neurons/physiology ; Middle Aged ; *Afferent Pathways/physiopathology ; Aged ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progressively disrupts voluntary motor command through combined cortical and spinal motor neuron degeneration. However, how spinal circuits reorganize during the disease remains poorly understood, particularly in humans. This study examined the function of excitatory and inhibitory spinal interneuron circuits that control upper and lower limb movements, using non-invasive electrophysiological techniques targeting specific afferent-motoneuron pathways at cervical and lumbar levels. These segments are clinically relevant, as spinal-onset forms constitute the predominant clinical presentation of ALS. We compared patients with ALS at different stages of functional impairment to healthy individuals. Spinal circuits predominantly driven by muscle spindle afferents (group Ia and II) showed, at the group level, a marked reduction in inhibition together with enhanced propriospinal excitation. In contrast, pathways mediated by tendon afferents (group Ib) and cutaneous inputs appeared preserved in unstratified analyses. However, when accounting for disease stage, inhibitory dysfunction emerged as an early feature, whereas excitation increased progressively with functional impairment, and modulations also became detectable in Ib- and cutaneous-driven responses. These findings reveal an afferent- and stage-dependent hierarchy of spinal dysfunction, following a reproducible sequence from early disinhibition to maladaptive excitation. This dynamic pattern mirrors the organization observed in preclinical spinal models and aligns with cortical pathophysiology, where widespread loss of inhibition precedes selective increases in excitation. Together, these results refine the mechanistic understanding of motor network disorganization in ALS and identify inhibitory interneurons as potential therapeutic targets to stabilize spinal network function.}, } @article {pmid41535729, year = {2026}, author = {Tong, SC and Zhang, J and Diao, CJ and Zhao, L and Lu, ZY}, title = {Tuning the Liquid-Liquid Phase Separation of FUS by Phosphorylation: A Role of Domain-Specific Compensation.}, journal = {The journal of physical chemistry. B}, volume = {130}, number = {4}, pages = {1437-1446}, doi = {10.1021/acs.jpcb.5c07950}, pmid = {41535729}, issn = {1520-5207}, mesh = {Phosphorylation ; *RNA-Binding Protein FUS/chemistry/metabolism ; Phase Separation ; Molecular Dynamics Simulation ; Protein Domains ; Humans ; Biomolecular Condensates/chemistry ; }, abstract = {Biomolecular condensates, a type of subcellular or membraneless organelle, form through liquid-liquid phase separation (LLPS) driven by multivalent interactions. As an RNA-binding protein, FUS participates in biological processes by forming dynamic liquid condensates via LLPS, with its abnormal fibrous aggregation associated with neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Experiments show that phosphorylation inhibits LLPS of the FUS low-complexity domain (LCD) under low salt conditions, whereas for full-length FUS, phosphorylation does not block initial LLPS but inhibits the conversion of liquid droplets to toxic aggregates. The molecular mechanism underlying the difference between the two remains unknown. In this molecular dynamics simulation study, we examined condensate structural characteristics and compared wild-type (WT) versus phosphorylated condensates, revealing the molecular details of how full-length FUS avoids LLPS impairment through synergistic compensatory regulation among various domains. As for the FUS-LCD system, the extent to which their LLPS is reduced by phosphorylation is associated with the number of phosphorylation sites. Moreover, we have developed a model for analyzing the viscoelasticity of the condensates, which revealed that altered interaction patterns impact condensate viscoelasticity. This study characterizes the postphosphorylation architecture of FUS condensates and elucidates the molecular mechanisms by which phosphorylation regulates condensate formation and properties.}, } @article {pmid41535829, year = {2026}, author = {Fang, C and Jin, J and Shi, W and Xu, X and Li, H and Duan, Q and Yu, X and Wu, S and Lu, T and Hu, F and Qin, X and Huang, J and Sun, D and Zhang, M and He, S and Dang, J and He, Q and Zhang, Q and Gan, S}, title = {Accelerated brain aging in amyotrophic lateral sclerosis and its prognostic associations: a cohort study.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {86}, pmid = {41535829}, issn = {1741-7015}, support = {2020SF-098//Key Research and Development Projects of Shaanxi Province/ ; 32400880//National Natural Science Foundation of China/ ; 32400926//National Natural Science Foundation of China/ ; 2022JQ-964//Natural Science Basic Research Program of Shaanxi Province/ ; 2408085MC081//Anhui Provincial Natural Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/physiopathology/mortality ; Female ; *Brain/diagnostic imaging/pathology ; Male ; Prognosis ; *Aging/pathology ; Magnetic Resonance Imaging ; Aged ; Cohort Studies ; Middle Aged ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, appearing to be associated with accelerated brain aging. Although increased brain age has been associated with mortality risk in older adults, it remains unclear how the brain aging process is accelerated in ALS and how this acceleration relates to patient prognosis.

METHODS: One hundred seventy sporadic ALS patients and 84 age- and sex-matched HCs were recruited and underwent neuropsychological tests and T1-weighted magnetic resonance imaging (MRI) scans. A brain-age prediction model was developed using a 3D-Conformer deep learning framework trained on 4310 healthy T1-weighted MRI data from public datasets. Brain age was predicted in HCs and ALS patients, and then the predicted-age difference (PAD = brain age-chronological age) was calculated. In the ALS cohort, the neuroanatomical association of PAD was examined, and cell-specific gene expression of PAD-related volume loss was analyzed using transcriptomic data from the Allen Human Brain Atlas. Associations between PAD, neuropsychological performance, clinical characteristics, and survival outcomes were further evaluated in ALS patients.

RESULTS: The brain aging process was accelerated in ALS by an average PAD of 1.77 years, which was predominantly associated with a widespread loss of gray matter volume. Cell-specific gene expression analyses showed microglia, inhibitory neurons, endothelial cells, and pericytes as significant contributors to the accelerated brain aging in ALS, with endothelial cells and pericytes being essential for constructing the blood-brain barrier (BBB) and microglia being involved in neuroinflammation. The acceleration in brain aging was more prominent in older patients and was associated with cognitive impairments. Notably, older brain age at initial diagnosis was an independent risk factor for death (hazard ratio, 1.026; 95% CI [1.008, 1.045]) and was associated with shorter survival and more rapid disease progression.

CONCLUSIONS: Accelerated brain aging is common in ALS; this could be hypothesized to be associated with the interplay between BBB breakdown and neuroinflammation, leading to gray matter degeneration. Furthermore, older brain age at initial diagnosis is associated with worse clinical outcomes. These findings suggest that therapeutic strategies targeting neuroinflammation and BBB integrity may help attenuate accelerated brain aging and improve prognosis.}, } @article {pmid41536515, year = {2026}, author = {Voldřich, R and Svoboda, N and Kachlířová, Z and Bartáková, L and Charvát, F and Netuka, D}, title = {Urodynamic outcomes and prognostic determinants following endovascular treatment of spinal dural arteriovenous fistulas.}, journal = {Brain & spine}, volume = {6}, number = {}, pages = {105913}, pmid = {41536515}, issn = {2772-5294}, abstract = {INTRODUCTION: The prognosis of untreated spinal dural arteriovenous fistulas (SDAVFs) is unfavorable. Current outcome scales used to assess the effect of surgery or endovascular treatment (EVT) rely largely on patient-reported symptoms and may underestimate actual impairment. Moreover, prognostic factors remain debated and conclusions in the literature are inconsistent.

RESEARCH QUESTION: The aim was to quantify urological outcomes after SDAVF embolization using specialized urodynamic testing, compare these objective findings with subjective outcomes derived from traditional scales, and identify prognostic factors associated with unfavorable clinical results.

METHODS: In this single-center retrospective study, all patients underwent EVT as first-line therapy. Clinical status was assessed using Aminoff-Logue scale (ALS), compared with preoperative data, and correlated with angiographic findings. Urodynamic testing was performed to objectively evaluate bladder function.

RESULTS: Twent-four patients met the inclusion criteria. Urodynamic testing was performed in 14 (58 %) patients. The most frequent abnormal finding was bladder hyposensitivity (79 %), followed by pathological post-void residual volume (64 %) and elevated bladder capacity (50 %). Six (43 %) patients reported no subjective urological symptoms (ALS = 0); urodynamic testing revealed two or more pathological parameters in all of them. EVT failure and subsequent surgery predicted gait deterioration (p = 0.011) as well as detrusor overactivity (p = 0.001). Symptom duration over one year (p = 0.038) and fistula location above the T9 level (p = 0.021) were negative prognostic factors for bladder function.

CONCLUSION: The results suggest a potential underestimation of urological impairment when relying on subjective scales and highlight the need for standardized urodynamic testing. They also emphasize the importance of early treatment of SDAVF.}, } @article {pmid41536906, year = {2025}, author = {Yang, X and Zheng, J and Wang, X and Cai, H and Yu, J}, title = {Pathogenic mechanisms of amyotrophic lateral sclerosis-linked VAPB P56S mutation in the degeneration of corticospinal motor neurons.}, journal = {Ageing and neurodegenerative diseases}, volume = {5}, number = {3}, pages = {}, pmid = {41536906}, issn = {2769-5301}, support = {Z01 AG000959/ImNIH/Intramural NIH HHS/United States ; ZIA AG000946/ImNIH/Intramural NIH HHS/United States ; }, abstract = {AIM: The endoplasmic reticulum (ER)-localized vesicle-associated membrane protein-associated protein B (VAPB) is implicated in many cellular processes, such as ER-organelle tethering, calcium homeostasis, and unfolded protein response. The P56S missense mutation in VAPB has been associated with familial forms of motor neuron diseases such as typical amyotrophic lateral sclerosis (ALS), atypical ALS, and spinal muscular atrophy. However, it has not been determined how the VAPB P56S mutation induces the degeneration of corticospinal motor neurons (CSMNs) in ALS.

METHODS: Using homozygous knock-in (KI) mice expressing P56S VAPB, we investigated the mutation's pathogenic impacts and underlying mechanisms on the survival and function of CSMNs. We performed a wide variety of assays to examine the behavioral, histological, cellular, and molecular abnormalities of KI mice.

RESULTS: Compared with wild-type controls, KI mice showed the downregulated protein level of mutant VAPB, proteinase K-resistant cytoplasmic inclusions of mutant VAPB in CSMNs, abnormal hyperactivity, impaired motor coordination, neuronal loss of CSMNs, and axonal degeneration of pyramidal and corticospinal tracts. Mechanistic studies revealed that the VAPB P56S mutation rendered the mutant protein destabilized and inclusion-prone in cortical neurons, and the proteasomal degradation played a critical role in modulating mutant VAPB's protein level and inclusion formation. In addition, the VAPB P56S mutation disrupted ER-mitochondria contacts, impaired VAPB-PTPIP51 interaction and IP3R-VDAC interaction, elevated cytosolic Ca[2+], activated CaMKII, and increased CRMP2 phosphorylation. Moreover, the VAPB P56S mutation activated the IRE1-XBP1/p38 mitogen-activated protein kinase (MAPK)/ c-Jun N-terminal kinase (JNK) pathway, increased tau hyperphosphorylation, and upregulated p53 expression and phosphorylation.

CONCLUSION: These findings demonstrate the progressive degeneration of CSMNs induced by VAPB P56S mutation and indicate the involvement of the Ca[2+]-CaMKII-CRMP2 and IRE1-p38 MAPK/JNK-tau/p53 pathways in the pathogenic process.}, } @article {pmid41538404, year = {2026}, author = {Zhao, Y and Liu, Y and Yuan, B and Yu, W and Li, T and Zhang, J and Ye, F and Fu, Y}, title = {Pharmacophore Reorganization-Based Design, Synthesis, and Safener Activity of Novel Isoxazole-Piperazinone Derivatives.}, journal = {Journal of agricultural and food chemistry}, volume = {74}, number = {3}, pages = {2737-2748}, doi = {10.1021/acs.jafc.5c15324}, pmid = {41538404}, issn = {1520-5118}, mesh = {*Herbicides/chemistry/pharmacology/chemical synthesis ; *Isoxazoles/chemistry/pharmacology ; Acetolactate Synthase/antagonists & inhibitors/chemistry/metabolism ; Pharmacophore ; Oryza/drug effects/growth & development/enzymology ; Structure-Activity Relationship ; Drug Design ; Plant Weeds/drug effects/enzymology/growth & development ; *Piperazines/chemistry/pharmacology ; Molecular Structure ; Plant Proteins/antagonists & inhibitors/chemistry/metabolism ; Enzyme Inhibitors/chemistry/pharmacology/chemical synthesis ; Molecular Docking Simulation ; }, abstract = {Bensulfuron, an acetolactate synthase (ALS)-inhibiting herbicide, is widely used in rice cultivation for the effective control of sedge and broadleaf weeds. However, japonica varieties are highly sensitive to this herbicide and can develop phytotoxicity when it is improperly applied. Herbicide safeners enhance crop tolerance to herbicides without reducing their weed control efficacy, offering a significant strategy for the safe use of herbicides. To alleviate bensulfuron-induced phytotoxicity in rice, a series of novel isoxazole-piperazinone derivatives were designed through pharmacophore recombination. The structures of the target compounds were confirmed by infrared spectroscopy, [1]H and [13]C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. The spatial configuration of compound II-1 was further determined by single-crystal X-ray diffraction. Bioactivity assays demonstrated that most target compounds effectively reduced bensulfuron-induced phytotoxicity in rice. Evaluation of key physiological parameters, including plant growth indices, ALS enzyme activity, and detoxification enzyme activity, revealed that compounds II-10 and II-40 exhibited superior safener activity compared to isoxadifen-ethyl. Molecular structure analysis and absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions indicated that compound II-10 possesses good pharmacokinetic properties comparable to those of isoxadifen-ethyl. Molecular docking analysis revealed that compound II-10 exerts its protective effect by competitively binding to the ALS active site with bensulfuron. Furthermore, ecological risk predictions suggested that compound II-10 poses low or negligible toxicity risks to nontarget organisms such as mammals, birds, and algae. Overall, these results highlight compound II-10 as a promising structure for the development of novel herbicide safeners.}, } @article {pmid41538578, year = {2026}, author = {Khan, M and Saeed, U and Piracha, ZZ and Ozsahin, I and Shao-Chun, C}, title = {Innovative public-health strategies for neurodegenerative disease: leveraging diversified ultraviolet irradiation as a next-generation therapy.}, journal = {Brazilian journal of biology = Revista brasleira de biologia}, volume = {85}, number = {}, pages = {e297765}, doi = {10.1590/1519-6984.297765}, pmid = {41538578}, issn = {1678-4375}, mesh = {Humans ; *Neurodegenerative Diseases/radiotherapy/therapy ; *Ultraviolet Therapy/methods ; Oxidative Stress/radiation effects ; Animals ; *Ultraviolet Rays ; Public Health ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis are escalating worldwide, straining healthcare systems and leaving patients with therapies that are largely palliative. Emerging evidence positions diversified ultraviolet (UV) irradiation as a groundbreaking, non-invasive strategy to counter these disorders. Beyond its traditional use in sterilization, specific UV spectra, UV-B (280-320 nm), UV-C (200-280 nm), and far-UV (207-222 nm), are now recognized for modulating oxidative stress, restoring mitochondrial function, correcting apoptotic dysregulation, and enhancing DNA repair. Innovative approaches such as riboflavin-mediated phototherapy and photobiomodulation (PBM) show the capacity to disaggregate toxic protein aggregates like β-amyloid and α-synuclein, boost antioxidant defenses, stimulate neurotrophic factors, and quell neuroinflammation. Preclinical models and early clinical trials reveal preserved cognition, enhanced neurogenesis, and reduced disease biomarkers, suggesting real translational promise. From a public-health perspective, UV-based interventions offer a cost-effective, scalable option for aging populations and resource-limited settings, especially when integrated with community-level health technologies and remote delivery platforms. Continued investigation of optimal dosing, long-term safety, and mechanistic pathways will be pivotal to unlock the full therapeutic and population-wide impact of this novel modality.}, } @article {pmid41540870, year = {2026}, author = {Ghika, N and Accolla, E and Girardin, F and Theaudin, M}, title = {[Pharmacotherapy of neuromuscular diseases : what's new in 2025].}, journal = {Revue medicale suisse}, volume = {22}, number = {945}, pages = {66-70}, doi = {10.53738/REVMED.2026.22.945.48049}, pmid = {41540870}, issn = {1660-9379}, mesh = {Humans ; *Neuromuscular Diseases/drug therapy/physiopathology ; Amyotrophic Lateral Sclerosis/drug therapy ; Oxidative Stress/drug effects ; Friedreich Ataxia/drug therapy/physiopathology ; }, abstract = {Two new drugs have recently become available for treating neuromuscular diseases: omaveloxolone and tofersen. Omaveloxone, which is available in Switzerland, mitigates mitochondrial oxidative stress and has been shown to slow the clinical progression of Friedreich's ataxia. Tofersen is an antisense oligonucleotide that induces posttranscriptional silencing of the SOD1 (superoxide dismutase 1) gene, which is involved in familial forms of amyotrophic lateral sclerosis. Although its efficacy has so far only been indirectly demonstrated through its ability to reduce serum neurofilament levels, it is available on a compassionate use basis in Switzerland.}, } @article {pmid41542389, year = {2026}, author = {Bolger, I and Shaw, R and Tam, OH and Roque, CG and Jackson, CA and O'Neill, K and , and Smith, C and Phatnani, H and Natarajan, K and Hammell, MG}, title = {TDP-43 dysfunction leads to the accumulation of cryptic transposable element-derived exons, crypTEs, in iPSC derived neurons and ALS/FTD patient tissues.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41542389}, issn = {2692-8205}, support = {P30 CA016087/CA/NCI NIH HHS/United States ; R01 NS118570/NS/NINDS NIH HHS/United States ; }, abstract = {TDP-43 is an RNA and DNA binding protein that plays major roles in regulating RNA processing. In particular, TDP-43 dysfunction leads to the accumulation of cryptic splice isoforms that result from improperly spliced mRNAs. In addition to its role in regulating splicing, TDP-43 is also known to regulate the expression of transposable elements (TEs). TEs are mobile genetic elements which comprise a significant proportion of the human genome, but are normally silenced in healthy somatic cells. TEs are interspersed throughout the genome, both in gene-depleted regions and within gene introns and gene regulatory sequences. We used optimized long-read RNA sequencing assays to generate catalogs of mis-spliced and mis-expressed genes and TEs in human neurons depleted for TDP-43. In addition to known TDP-43 driven cryptic isoforms, we identified hundreds of TDP-43 dependent spliced RNAs that form cryptic gene-TE fusion events as a result of mis-splicing of TE sequences into gene transcripts. Among these TDP-43 dependent cryptic gene-TE transcripts (crypTEs), we found: TEs that provide alternate gene promoters/5'UTRs, TEs that act as cassette exons inside host gene mRNAs, as well as TEs that provide alternate transcript 3' ends. These cryptic gene-TE fusions are predicted to induce aberrant expression of ALS relevant genes, nonsense mediated decay (NMD) products, as well as novel peptides from gene-TE fusions within the gene coding sequence. Using coupled long-read RNA (Iso-seq) and single-nucleus (snRNA-seq) profiles from postmortem ALS tissues, we further verified that many of these crypTE transcripts are enriched in frontal cortex samples from ALS donors with cognitive involvement (ALSci) and associated with altered expression of those genes in deep layer cortical excitatory neurons. In short, TDP-43 dependent crypTEs greatly expand the catalogs of TDP-43 dependent cryptic splice isoforms and represent a novel mechanism by which TE dysregulation impacts ALS.}, } @article {pmid41542616, year = {2026}, author = {Cheng, T and Tripathi, S and Guo, Y and Vedula, P and Li, R and Potanin, M and Soley, N and Yan, AY and Vatsaraj, I and Harris, C and Greenstein, JL and Taylor, CO and Coyne, AN and Rothstein, JD}, title = {Identification of molecular and clinical ALS subgroups based on TDP-43 loss of function molecular markers from population-based patient-derived iPS motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41542616}, issn = {2692-8205}, support = {R01 NS122236/NS/NINDS NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a uniformly fatal neurodegenerative disease characterized by progressive cortical and spinal motor neuron loss, with most patients surviving only 2-5 years post-diagnosis. While approximately 10% of cases are familial (fALS), the remaining 90% are sporadic (sALS) with unknown genetic drivers. Importantly, clinical presentations are heterogeneous in both sporadic and familial ALS, underscoring the complexity of the disease. A pathological hallmark of ALS is the mislocalization of RNA-binding protein TDP-43 from the nucleus to the cytoplasm. This mislocalization produces both loss of function consequences, such as widespread RNA processing and splicing defects, as well as potential toxic gain of function effects associated with cytoplasmic aggregation.

RESULTS: In this study, we used RT-PCR data from induced pluripotent stem cell-derived motor neurons derived from 180 sALS and C9orf72 fALS patients from the Answer ALS collection to identify biological subgroups based on TDP-43 loss-of-function signatures. Spectral embedding revealed four distinct molecular clusters, including one subgroup genetically similar to controls and another with the most dysregulated mRNA expression, suggesting differing disease severity. Linear mixed models were then used to assess the longitudinal trajectory of over 90 clinical measures, and the between-cluster interaction effects were evaluated.

CONCLUSIONS: 36 clinical outcomes showed significant differences across clusters, supporting the presence of biologically and clinically distinct ALS subtypes based on the TDP-43 associated pathogenic cascade. These findings demonstrate a critical role of RNA profiling in uncovering biologically meaningful subtypes of ALS, potentially allowing for more precise prognostic tools and the development of future personalized therapeutic approaches.}, } @article {pmid41543999, year = {2026}, author = {Robinson, GA and Phillips, MR and Horne, K and Ceslis, A and McCombe, PA and Henderson, RD}, title = {Assessment of language and executive functions in ALS: the brief executive Language screen.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {641-651}, doi = {10.1080/21678421.2025.2607398}, pmid = {41543999}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology/diagnosis ; *Executive Function/physiology ; Female ; Male ; Middle Aged ; Neuropsychological Tests ; Aged ; *Language ; *Language Disorders/etiology/diagnosis ; *Cognition Disorders/etiology/diagnosis ; Language Tests ; }, abstract = {Objective: Language and executive functioning are two domains commonly impacted in ALS and should be assessed sensitively and briefly. This paper investigates the utility of the Brief Executive Language Screen (BELS) in ALS. Methods: ALS patients (N = 27) were compared to age, education, and pre-morbid intelligence-matched healthy controls (N = 91) at the group level using ANCOVA and t-tests. A case series was also conducted to explore individual and subgroup performance on the BELS and Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Results: Groups were largely matched on neuropsychology baseline measures. The ALS group performed significantly worse on BELS Propositional Language and Executive Function subtests, and on overall BELS scores. Group results suggest setting a goal can increase phonemic fluency and spontaneous speech output, after controlling for motor speed. The case series revealed almost half of patients (across all subgroups) were impaired on the BELS, compared to 15% impaired on the ECAS (patients on the more severe end of the ALS-FTD spectrum). Conclusions: The BELS rapidly assesses language and executive functions, and provides valuable information for management of cognitive difficulties (i.e., goal setting), which can help improve or maintain conversational speech. The BELS may help to identify subtle impairments that may otherwise go undetected.}, } @article {pmid41545051, year = {2026}, author = {Trad, G and Lenglet, T and Ledoux, I and Querin, G and Blancho, S and Marchand-Pauvert, V and Hogrel, JY and Pradat, PF}, title = {Safety and efficacy of the Atalante exoskeleton in the rehabilitation of French patients with amyotrophic lateral sclerosis: a prospective, monocentric, open, uncontrolled, interventional protocol, EXALS.}, journal = {BMJ open}, volume = {16}, number = {1}, pages = {e109620}, pmid = {41545051}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology ; Prospective Studies ; *Exoskeleton Device ; France ; Quality of Life ; Female ; Male ; Middle Aged ; Walking ; Gait ; *Exercise Therapy/methods/instrumentation ; Aged ; Muscle Strength ; Adult ; Postural Balance ; *Gait Disorders, Neurologic/rehabilitation/etiology ; Treatment Outcome ; }, abstract = {INTRODUCTION: Robotic rehabilitation on locomotion is a new approach in amyotrophic lateral sclerosis (ALS) and previous studies showed its feasibility. In this study, we aim to evaluate safety, patient's experience and efficacy of a gait training programme with the Atalante exoskeleton, compared with usual care, on walking ability, functional capacity and other symptoms associated with ALS.

METHODS AND ANALYSIS: EXALS is a monocentric, prospective, interventional, open trial. 20 slowly progressing patients with gait deficits will be recruited. The study is conducted in three phases, each lasting 6 weeks, following the ABA procedure. Phase B represents the intervention phase, during which patients practise their gait training at a rhythm of three sessions/week, as an add-on to usual care. In the two phases A, patients receive usual care with no additional treatment. An evaluation is planned before, in the middle and at the end of each phase. The primary outcome of the study is safety and tolerability of the Atalante exoskeleton. Secondary outcomes include: participants' subjective impact and experience, attitude and motivation, efficacy and interactivity of the exoskeleton, walking ability, functional capacity, spasticity, balance, postural stability, lower limb muscle strength, quality of life, pain, fatigue, anxiety and depression. Statistical analyses will include descriptive methods for all variables and adverse events. Quantitative outcomes are analysed using repeated-measures ANOVA (analysis of variance) across the seven visits, with post hoc tests applied when appropriate. Nominal outcomes are evaluated using Cochran's Q test with McNemar pairwise comparisons when significant. Associations between variables are examined using Spearman correlation coefficients. Missing data will be replaced using linear interpolation, and sensitivity analyses will be planned. Qualitative interview data are analysed using thematic analysis.

ETHICS AND DISSEMINATION: This study was approved by the French ethics committee CPP Nord-Ouest I (no. 23.02378.000201). Participant data are anonymised and securely stored in the laboratory's database, accessible only to the research team. Results will be disseminated through peer-reviewed journals and conferences.NCT06199284.}, } @article {pmid41545942, year = {2026}, author = {Sun, W and Luan, H and Li, S and Wang, P and Gong, J and Xu, C and Han, X and Wen, B and Lv, S and Wei, C}, title = {Circulating adipokines level and the risk of neurodegenerative diseases: a two‑sample mendelian randomization study and proteomic analysis.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {90}, pmid = {41545942}, issn = {1471-2377}, support = {2017YFC1310103//the National Key Research and Development Program of China/ ; 2021ZD0201802//the STI2030-Major Projects/ ; }, mesh = {Mendelian Randomization Analysis ; Humans ; Proteomics ; *Adipokines/blood/genetics ; *Neurodegenerative Diseases/genetics/blood ; Genome-Wide Association Study ; Adiponectin/blood/genetics ; Leptin/blood ; Chemokine CCL2/blood ; Resistin/blood ; }, abstract = {BACKGROUND: Observational studies have suggested associations between circulating adipokines and neurodegenerative diseases, but the causal nature of these relationships remains unclear. This study evaluated the causal effects of adipokines on neurodegenerative diseases using Mendelian randomization (MR) and validated key findings through proteomic analysis. METHODS: Two-sample MR was performed using genome-wide association study (GWAS) summary statistics for adiponectin (N = 39,883), leptin (N = 57,232), resistin (N = 21,758), and monocyte chemoattractant protein-1 (MCP-1; N = 21,758). Outcomes included Alzheimer’s disease (AD; N = 63,926), Parkinson’s disease (PD; N = 482,730), and amyotrophic lateral sclerosis (ALS; N = 36,052). The inverse-variance weighted (IVW) method was applied for primary causal estimates, with sensitivity analyses assessing pleiotropy and heterogeneity. Significant MR findings were further examined in a proteomic cohort. RESULTS: Higher genetically predicted adiponectin levels were significantly associated with a reduced risk of AD (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.65–0.96, p = 0.019). This association remained robust across multiple sensitivity analyses, with no evidence of horizontal pleiotropy or heterogeneity. By contrast, no causal relationships were identified for leptin, resistin, or MCP-1 with the risk of AD, PD, or ALS. Complementing the genetic findings, proteomic analysis further revealed that plasma adiponectin levels were downregulated in mild cognitive impairment patients who experienced cognitive deterioration compared with those showing cognitive improvement. CONCLUSION: The findings provide genetic evidence supporting a potential protective role of adiponectin in AD, with the proteomic results offering complementary, directionally consistent support. Adiponectin may represent a potential biomarker and therapeutic target for AD.}, } @article {pmid41546073, year = {2026}, author = {Dewan, MF and Rayani, AM and Hannan, J}, title = {Improving nursing students' clinical experience with genetics: the influence of prior knowledge and leadership support through the Donabedian Model.}, journal = {BMC nursing}, volume = {25}, number = {1}, pages = {}, pmid = {41546073}, issn = {1472-6955}, abstract = {BACKGROUND: As advancements in genetics and genomics continue to evolve, nursing students need to be equipped with prior knowledge and academic leadership support (ALS) to interpret genetic information, educate patients, and participate in clinical decision-making. ALS is actions or behaviors by leaders to support, guide, and empower their students. The incorporation of genetics/genomics into the nursing curriculum has been recognized on a global scale. AIM: To evaluate the impact of nursing students’ prior knowledge of genetics/Genomics and genomics and academic leadership support on their clinical experience. METHOD AND DESIGN: A cross-sectional study was conducted among nursing students at xxxxx University College of Nursing, Saudi Arabia, between December 2024 and February 2025 (IRB# KSU-HE-24-1055). A total of 169 participants completed an online survey. RESULTS: Most participants were in their fourth year, internship year, or enrolled in postgraduate programs (BSN = 118; Master’s = 46; PhD = 3). The average age was 26.6 years (SD = 5.8), and more participants were female (58.5%) than male (41.5%). Male participants reported receiving higher levels of leadership support than their female counterparts did. ALS on clinical experience (p < 0.01); and prior knowledge (p < 0.008); R2 = 0.440 with large effect size = 0.78. CONCLUSIONS: Integrating genetics and genomics education into the nursing curriculum is needed to meet today’s healthcare standards. Academic nursing leaders in educational settings play a key role in advancing nursing students’ curriculum thereby increasing their knowledge and preparedness for clinical practice. IMPLICATION FOR PROFESSION AND/OR PATIENT CARE: Educational settings that integrate nursing genetics and genomics courses into curricula and provide leadership support to students will improve their clinical experience and enhance patients’ care. IMPACT: What problem did the study address? ALS is a key driver of improving students’ clinical experience. What were the main findings? Male nursing students reported higher levels of leadership support than female nursing students highlighting the need for strategies that support equity and prevent disparities in educational settings on the basis of gender. Who will benefit? Nurse educators and nurse leaders could utilize these findings to improve educational environments. Nurses with up-to-date knowledge will benefit their patients’ outcomes by being better informed. REPORTING METHOD: We adhered to the STROBE guidelines for cross-sectional research.}, } @article {pmid41546756, year = {2026}, author = {White, MA and Crowley, L and Massenzio, F and Li, X and Niblock, M and Milani, S and Coleman, MP and Barmada, SJ and Sreedharan, J}, title = {Inhibiting Glycogen Synthase Kinase 3 Suppresses TDP-43-Mediated Neurotoxicity in a Caspase-Dependent Manner.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {370}, pmid = {41546756}, issn = {1559-1182}, support = {P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R37 NS113943/NS/NINDS NIH HHS/United States ; }, mesh = {*Glycogen Synthase Kinase 3/antagonists & inhibitors/metabolism ; Animals ; *DNA-Binding Proteins/toxicity/metabolism ; Humans ; *Caspases/metabolism ; Neurons/drug effects/metabolism/pathology ; Phosphorylation/drug effects ; Mice ; Motor Neurons/drug effects/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases characterised by TAR DNA-binding protein 43 kDa (TDP-43) pathology. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration in Drosophila. Here, we investigated the potential of GSK3 inhibition to ameliorate TDP-43-mediated toxicity in mammalian neurons. We show that TDP-43 activates GSK3 and promotes caspase-dependent cleavage of TDP-43, generating C-terminal fragments. We determine the functional importance of the N-terminal Asp89 caspase cleavage site in regulating TDP-43 proteostasis in both wild-type and ALS-linked TDP-43 variants and show that GSK3 inhibition selectively reduces truncated TDP-43 species, lowers nuclear TDP-43 levels, and improves neuronal survival. Neuroprotective effects were conserved in primary rodent cortical neurons, primary mouse motor neurons, and human iPSC-derived cortical neurons, highlighting the potentially broad therapeutic potential of GSK3 inhibition. We also find that the GSK3 inhibitor CHIR99021 reduces GSK3 RNA and protein expression and increases GSK3 phosphorylation, indicating novel mechanisms by which it acts to inhibit GSK3 activity. Unexpectedly, an N-terminally truncated variant (TDP-43[N-Del]), originally designed as a negative transfection control, exerted modest toxicity, potentially through retained susceptibility to caspase cleavage. Together, our findings uncover a caspase-mediated mechanism linking GSK3 activity to TDP-43 turnover, localisation, and neurotoxicity, and position GSK3 inhibition as a promising strategy to mitigate TDP-43-driven neurodegeneration in ALS-FTD.}, } @article {pmid41546910, year = {2026}, author = {Elyasi, L and Wężyk, M}, title = {Exosome-derived microRNAs from stem cells from human exfoliated deciduous teeth (SHED): Emerging therapeutics for neurodegenerative disorders.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {195}, number = {}, pages = {119001}, doi = {10.1016/j.biopha.2026.119001}, pmid = {41546910}, issn = {1950-6007}, mesh = {Humans ; *Exosomes/metabolism/genetics ; *Neurodegenerative Diseases/therapy/genetics/metabolism ; *Tooth, Deciduous/cytology/metabolism ; *MicroRNAs/genetics/metabolism ; Animals ; *Stem Cells/metabolism ; *Stem Cell Transplantation/methods ; Tooth Exfoliation ; }, abstract = {Neurodegenerative diseases (NDDs) cause progressive damage of brain structures, resulting in a loss of function and, eventually, the patient's death. Current therapeutic strategies are limited to late stages of the disease, culminating in palliative care, while tackling the underlying causes of neurodegeneration could halt or at least slow down the disease at an early stage. In this vein, stem cell transplantation therapies are emerging as a promising alternative, as such as cells can penetrate the central nervous system, engraft, differentiate, and secrete neurotrophic, neuro-regenerative, and neuroprotective factors. Stem cells derived from human exfoliated deciduous teeth (SHED) have demonstrated significant regenerative potential in various biological systems and pathological conditions, showing high proliferative capacity and multipotency to differentiate into neuronal cells both in vivo and in vitro, apparently functioning through exosome-derived microRNAs (exos-miRs). Here, we summarize recent reports on specific miRs from SHED's exosomes, which exert diverse regulatory functions counteracting oxidative stress, and provide immunomodulatory and neurotrophic benefits contributing to the treatment of neurodegeneration in NDDs. We discuss clinical and preclinical evidence supporting the potential of SHED cells in the treatment of NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, focal cerebral ischemia, and peripheral nerve damage. We also highlight that the use of SHED in NDDs treatment remains largely underexplored, opening a wide field for further research. We suggest deeper studies on the role of SHED-exos-miRs in NDDs, including their proneurotrophic activity, reduction of genotoxic neuronal stress, and disruption of proinflammatory signaling pathways.}, } @article {pmid41547243, year = {2026}, author = {Dorothy Wong, ZY and Kang, X and Shi, Y and Fan, R and Zhang, C and Min, D and Sun, N and Ma, Y and Tang, ML}, title = {Autophagy-tethering compounds (ATTECs) as an emerging and potentially transformative drug discovery approach.}, journal = {European journal of medicinal chemistry}, volume = {305}, number = {}, pages = {118585}, doi = {10.1016/j.ejmech.2026.118585}, pmid = {41547243}, issn = {1768-3254}, mesh = {Humans ; *Autophagy/drug effects ; *Drug Discovery ; Proteolysis/drug effects ; Proteolysis Targeting Chimera ; Lysosomes/metabolism/drug effects ; Animals ; Molecular Structure ; }, abstract = {Targeted protein degradation (TPD) strategies leveraging the ubiquitin-proteasome system (UPS), such as proteolysis-targeting chimeras (PROTACs), have gained wide recognition. While the UPS predominantly degrades short-lived soluble proteins, the lysosome-mediated system (LMS) excels at processing larger substrates, including protein aggregates, organelles, and macromolecular complexes. Recently, autophagy-tethering compounds (ATTECs) have emerged as a promising strategy for targeted degradation, harnessing the autophagy-lysosome system (ALS) to enable proximity-induced degradation. These heterobifunctional molecules, composed of LC3-binding warheads and TOI (target of interest) ligands linked together, provide therapeutic potential against disease-causing targets. This review outlines the therapeutic applications of ATTECs in human diseases, highlights recent progress in their development, and explores future opportunities for expanding this emerging class of degradation technologies through ALS from medicinal chemistry perspective.}, } @article {pmid41547996, year = {2026}, author = {Iacono, D and Murphy, EK and Perl, DP and Day, RM}, title = {γ-Radiation induces region-specific subcellular alterations of amyotrophic lateral sclerosis and frontotemporal dementia markers in swine brain.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {5627}, pmid = {41547996}, issn = {2045-2322}, support = {312516-1.00-66721//DoW/USU Brain Tissue Repository and Neuropathology Research Program/ ; DM178018//US Defense Medical Research and Development Program/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Brain/radiation effects/metabolism/pathology ; Swine ; Male ; *Gamma Rays/adverse effects ; Biomarkers/metabolism ; *Frontotemporal Dementia/metabolism/pathology/etiology ; Swine, Miniature ; }, abstract = {Low-dose radiation (LDR) effects on the brain have been poorly investigated. Studies have also questioned whether radiation increases ALS risk. We assessed the expression levels of a series of proteins associated with ALS and ALS-FTD in the brains of swine exposed to low-dose radiation to explore this notion. Male Gottingen minipigs were exposed to a single total-body γ-radiation (1.79 Gy). After 28 days, brains from 9 RAD to 6 SH animals were collected. Using neuroanatomically based dissection and Western Blotting, we compared levels of ALS/ALS-FTD markers (SOD1, FUS/TLS, C9orf72, STMN2, ubiquitin, TDP43 (N and C terminal), and pTDP43) in RAD vs. SH animals in frontal cortex (FCtx), striatum (Str), hippocampus (Hip), thalamus/hypothalamus (Thal/Hyp), and cerebellum (Cere). Cytosolic FUS/TLS decreased in the Thal/Hyp and remained unchanged in all other regions; nuclear levels increased in the FCtx and decreased in the Hip of RAD vs. SH. Cytosolic C9orf72 remained unchanged across all brain regions; nuclear levels decreased in the Hip of RAD vs. SH. Cytosolic STMN2 remained unchanged in all brain regions and decreased in the nuclear fraction of the Hip of RAD vs. SH. Cytosolic and nuclear ubiquitin remained unchanged across brain regions, except for an increase in the FCtx. TDP-43 (N and C terminal) levels remained unchanged in cytosolic and nuclear fractions across all brain regions; finally, cytosolic pTDP43 (S403/404) increased in the FCtx, Str and Thal/Hyp of RAD vs. SH. LDR-induced ALS/ALS-FTD-marker changes differ across brain regions and subcellular compartments. These changes are not necessarily associated with increased activation or potentiation of the main molecular processes associated with ALS pathogenesis; surprisingly, they may produce beneficial effects.}, } @article {pmid41548000, year = {2026}, author = {Potla, KM and Cheerlin Mishma, JN and Vankayalapati, S and Suchetan, PA and Sebastian, R and Gayatri, B and Tawfeek, AM and Alam, M and Islam, MS}, title = {Comprehensive analysis of florasulam: crystal structure, reactivity, sensitivity, and bioactivity using structural, spectroscopic, and computational approaches.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {3416}, pmid = {41548000}, issn = {2045-2322}, mesh = {*Sulfonamides/chemistry/pharmacology ; Crystallography, X-Ray ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; *Herbicides/chemistry/pharmacology ; Acetolactate Synthase/chemistry/metabolism/antagonists & inhibitors ; *Pyrimidines/chemistry/pharmacology ; Molecular Structure ; }, abstract = {The title compound, N-(2,6-difluorophenyl)-8-fluoro-5-methoxy-[1,2,4]triazolo[1,5-c]pyrimidine-2-sulfonamide (Florasulam), a triazolopyrimidine sulfonanilide herbicide, was investigated using experimental and computational techniques. Single-crystal X-ray diffraction revealed a V-shaped geometry stabilized by intramolecular C–F···π interactions and a unique 1D ribbon packing formed through N–H···N, C–H···O, and S = O···π interactions. Hirshfeld surface and energy framework analyses confirmed the nature and strength of intermolecular forces. DFT and TD-DFT calculations provided insights into optimized geometry, vibrational frequencies, and electronic transitions consistent with experimental spectra. The HOMO–LUMO gap indicated high chemical stability, while MEP analysis highlighted reactive sites. Autoxidation susceptibility was assessed through bond dissociation energies. Molecular docking against ALS (Acetolactate Synthase) proteins demonstrated strong binding affinity, supported by molecular dynamics simulations confirming protein–ligand complex stability. This integrative study highlights Florasulam’s potential in herbicide design.}, } @article {pmid41548719, year = {2026}, author = {Li, X and Wan, R and Zhao, Y and Wu, Y and Chen, X and Li, Q and Luo, C}, title = {Decoding synaptic imbalance in neurodegenerative diseases: From pathological analysis to targeted intervention.}, journal = {Ageing research reviews}, volume = {115}, number = {}, pages = {103028}, doi = {10.1016/j.arr.2026.103028}, pmid = {41548719}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism/physiopathology ; *Synapses/pathology/metabolism ; Animals ; *Aging/pathology/metabolism ; Oxidative Stress ; Neuronal Plasticity/physiology ; *Synaptic Transmission/physiology ; }, abstract = {Synapses serve as the central functional components mediating information transmission, integration, and storage within the central nervous system (CNS). Their functionality depends on the synergistic interplay of the presynaptic membrane, synaptic cleft, and postsynaptic membrane-three structures that collectively sustain neurotransmitter secretion, postsynaptic signaling, and synaptic plasticity. Of note, synaptic impairment represents an early, shared pathological hallmark across aging and age-related neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). This damage emerges prior to the demise of neuronal cell bodies and the manifestation of clinical symptoms, with its location and severity directly shaping disease phenotypes. Importantly, such synaptic dysfunction is closely linked to the pathological proteins specific to each disorder. This review comprehensively synthesizes current research advances regarding synaptic impairment in age-related neurodegenerative diseases. It elaborates on the location-specific pathological features of synaptic damage in AD, PD, HD, and ALS, with particular emphasis on their associations with disease-related pathological markers. Additionally, the work unpacks five core mechanisms driving synaptic dysfunction: the toxic effects of pathological proteins, dysregulated synaptic protein homeostasis, excitotoxicity coupled with disrupted calcium balance, oxidative stress and inflammatory responses, and deficiencies in neurotrophic factors. Ultimately, it summarizes potential biomarkers and targeted intervention strategies, aiming to provide a systematic reference for mechanistic investigations, early diagnosis, and clinical management of neurodegenerative diseases.}, } @article {pmid41548740, year = {2026}, author = {Qaisar, R}, title = {Fiber-type-specific architecture and pathophysiology of the neuromuscular junction.}, journal = {Neuroscience}, volume = {597}, number = {}, pages = {13-26}, doi = {10.1016/j.neuroscience.2026.01.015}, pmid = {41548740}, issn = {1873-7544}, mesh = {*Neuromuscular Junction/physiopathology/pathology/physiology ; Animals ; Humans ; *Muscle Fibers, Slow-Twitch/physiology/pathology ; *Muscle Fibers, Fast-Twitch/physiology/pathology ; *Neuromuscular Junction Diseases/physiopathology/pathology ; }, abstract = {The neuromuscular junction (NMJ) is a specialized synapse essential for translating neuronal signals into muscle contraction. This review examines the complex structural, functional, and molecular differences in NMJs that innervate fast- and slow-twitch skeletal muscle fibers. Fast-twitch fibers, optimized for rapid and powerful contractions, possess elaborate NMJs with deep folds, high neurotransmitter turnover, and greater vulnerability to synaptic fatigue and degeneration. In contrast, slow-twitch fiber NMJs exhibit simpler but more stable architectures that support sustained, fatigue-resistant activity. These differences are not fixed but subject to activity-dependent plasticity and pathological remodeling. Chronic stimulation, injury, and aging influence NMJ morphology, with fast-twitch junctions more prone to degeneration in conditions such as ALS, myasthenia gravis, and diabetic neuropathy. Slow-twitch NMJs often resist early deterioration due to superior trophic support, metabolic stability, and more robust expression of synaptic organizers, such as agrin and PGC-1α. Several key signaling pathways, including agrin-MuSK-LRP4, Wnt/β-catenin, and neuregulin/ErbB, govern NMJ maintenance with fiber-type-specific nuances. These insights underscore the importance of tailoring therapeutic strategies to the muscle fiber phenotype. Gene therapies, neuromuscular electrical stimulation, and biomaterial scaffolds are emerging as promising modalities for preserving or restoring NMJ integrity, especially in fast-twitch fibers at higher risk of degeneration. Understanding fiber-type-specific NMJ biology enhances our understanding of motor control, muscle aging, and neuromuscular disease progression, and it opens pathways for precision therapeutics that target vulnerable synapses with structural and functional specificity. This review introduces a novel perspective by emphasizing fiber-type-specific NMJ differences and their implications for targeted therapies.}, } @article {pmid41549027, year = {2026}, author = {Shenouda, M and Shenouda, S and Kartono, B and Eid, S and Cheng, C and Robertson, J}, title = {Small molecule JRMS modulating importin-β1 chaperone activity as a therapeutic strategy reducing TDP-43 pathology.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {1}, pages = {e00834}, pmid = {41549027}, issn = {1878-7479}, mesh = {Animals ; Humans ; *beta Karyopherins/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *Molecular Chaperones/metabolism ; Mice ; Neurons/drug effects/metabolism ; *TDP-43 Proteinopathies/metabolism/drug therapy/pathology ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Neuronal cytoplasmic aggregation and nuclear depletion of the TAR DNA-binding protein 43 (TDP-43) is the most characteristic pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing toxicity through cytoplasmic gain and nuclear loss of function mechanisms. In addition to its canonical role in nuclear cytoplasmic transport (NCT), the nuclear import receptor, importin-β1 (KPNB1) also acts as a molecular chaperone capable of preventing and reversing aberrant protein aggregation. Previous studies have demonstrated that increased expression of KPNB1 solubilizes TDP-43 aggregates and restores its nuclear localization. Here, we identify JRMS, a small molecule that enhances the chaperone activity of KPNB1 by increasing its cytoplasmic availability. JRMS treatment reduced cytoplasmic aggregation and promoted nuclear localization of full-length and pathological truncated TDP-43 variants across multiple experimental systems, including cell lines, primary neurons, iPSC-derived cortical neurons, organotypic brain slices and in vivo model. The effects of JRMS were KPNB1 dependent and occurred without inducing cytotoxicity or perturbing basal NCT. These findings identify JRMS as a promising therapeutic strategy for targeting TDP-43 pathology in ALS/FTD and other related TDP-43 proteinopathies.}, } @article {pmid41551521, year = {2026}, author = {Xu, S and Lu, GR}, title = {Potential of lysine succinylation as a therapeutic target for gallstone formation: An insightful strategy.}, journal = {World journal of gastroenterology}, volume = {32}, number = {1}, pages = {114865}, pmid = {41551521}, issn = {2219-2840}, mesh = {Animals ; Humans ; Mice ; AMP-Activated Protein Kinases/metabolism ; Disease Models, Animal ; Gallbladder/pathology/cytology ; *Gallstones/pathology/metabolism/prevention & control/etiology/drug therapy ; *Lysine/metabolism ; Protein Processing, Post-Translational/drug effects ; Signal Transduction/drug effects ; Succinic Acid/metabolism ; }, abstract = {Cholelithiasis has a complex pathogenesis, necessitating better therapeutic and preventive strategies. We recently read with interest Wang et al's study on lysine acetyltransferase 2A (KAT2A)-mediated adenosine monophosphate-activated protein kinase (AMPK) succinylation in cholelithiasis. Using mouse models and gallbladder mucosal epithelial cells, they found that KAT2A inhibits gallstones through AMPK K170 succinylation, thereby activating the AMPK/silent information regulator 1 pathway to reduce inflammation and pyroptosis. This study is the first to connect lysine succinylation with cholelithiasis, offering new insights and identifying succinylation as a potential therapeutic target. Future research should confirm these findings using patient samples, investigate other post-translational modifications, and use structural biology to clarify succinylation-induced conformational changes, thereby bridging basic research to clinical applications.}, } @article {pmid41551727, year = {2026}, author = {Singh, S and Singh, P and Varada, MP and Vijaivasudev, MJ and Kumar, R and Malik, I}, title = {eVGeMdb: a manually curated database for experimentally validated genetic modifiers of neurodegenerative disorders.}, journal = {NAR molecular medicine}, volume = {3}, number = {1}, pages = {ugaf044}, pmid = {41551727}, issn = {2976-856X}, abstract = {Genetic modifiers are genes that, while not directly causing disease, can alter the onset, progression, severity, or specific phenotypes of a disease by interacting with the primary disease-causing genes. Despite their importance, knowledge of these modifiers remains fragmented across different experimental models of neurodegenerative disorders (NDs). To address this lacuna, we developed eVGeMdb (https://project.iith.ac.in/cgntlab/eVGeMdb/), a manually curated, comprehensive database of experimentally validated genetic modifiers of major NDs, including Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Spinocerebellar ataxias, Fragile X-associated Tremor/Ataxia Syndrome, and other general PolyQ disorders. eVGeMdb integrates modifiers from commonly used diverse experimental model systems, including Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, cellular models (human, mice, Drosophila cells), and mouse. The database currently incorporates over 17000 entries, each annotated with experimental context, gene-specific functional information, relevant human orthologs, and links to protein-protein interaction networks and enriched pathways. The resource enables cross-disease and model-specific comparisons, allowing the identification of both universal and disease-specific modifiers. By consolidating dispersed genetic modifier information into a single, accessible platform, eVGeMdb provides a comprehensive tool for researchers in the field to explore modifier effects, prioritize experimental validations, formulate novel hypotheses, and investigate pathophysiological mechanisms underlying neurodegenerative disorders.}, } @article {pmid41552526, year = {2026}, author = {Turcatel, GA and Moura, S}, title = {Glutamate Receptor Agonists as Triggers of Neurotoxicity: Decoding Pathways of Five Neurotoxins and Potential Therapeutic Targets.}, journal = {ACS omega}, volume = {11}, number = {1}, pages = {70-81}, pmid = {41552526}, issn = {2470-1343}, abstract = {l-Glutamate (l-Glu) is one of the primary excitatory neurotransmitters in the nervous system, functioning through both ionotropic and metabotropic receptors. The release of l-Glu into the synaptic cleft, its interaction with receptors, and its reuptake are meticulously regulated by excitatory amino acid transporters. The structural similarity of various compounds to l-glutamate is crucial to their ability to interact with NMDA, AMPA, and kainate receptors. These interactions can significantly influence neural communication and function. Overstimulation of these receptors, which operate as ion channels, results in an increased level of calcium ion influx, a phenomenon known as excitotoxicity, which is often linked to neurodegeneration. Many neurodegenerative conditions are linked to both acute and chronic exposures to neurotoxins, whether they originate within the body (endogenous) or from external sources (exogenous). These neurotoxins often function as l-glutamate receptor agonists, potentially contributing to the progression of these diseases. This perspective focuses on key neurotoxins, including β-N-methylamino-l-alanine (l-BMAA), quinolinic acid (QUIN), domoic acid, β-N-oxalyl-l-α,β-diaminopropionic acid (β-ODAP), homocysteine (Hcy), and l-homocysteate, all of which exhibit complementary mechanisms of action. We will explore their structural characteristics and mechanisms through which they induce neurotoxicity. Understanding the neurotoxic mechanisms of these compounds is essential for elucidating the pathology of neurodegenerative diseases, such as amyotrophic lateral sclerosis, neurolathyrism, and amnesic shellfish poisoning. This review summarizes the findings of 64 studies to clarify these relationships involving classic events associated with neurodegeneration such as mitochondrial damage, oxidative stress, and activation of proapoptotic pathways. In summary, the distinctive properties of these neurotoxins provide valuable insights that could help in the development of future therapeutic drugs aimed at treating and alleviating the effects of neurodegenerative diseases. Understanding how these neurotoxins interact with neuronal pathways can guide researchers in designing more effective interventions.}, } @article {pmid41552817, year = {2025}, author = {Chen, Y and Xiao, W and Qian, C and Huang, L and Lv, J and Wang, Z and Luo, Y}, title = {System Xc-pathway as a potential regulatory target in neurological disorders.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1701320}, pmid = {41552817}, issn = {1663-9812}, abstract = {The System Xc-pathway is composed of the 12-transmembrane transporter protein SLC7A11 (xCT) and the single-channel transmembrane protein SLC3A2 (CD98hc). We detail the pathway's characteristics and distribution within the central nervous system, as well as its canonical role in maintaining glutathione synthesis and inhibiting ferroptosis, and its emerging non-canonical functions in metabolic coupling and neuroimmunity. A core theme is the pathway's context-dependent and often paradoxical role across major neurological disorders, including ischemic stroke, Alzheimer's disease, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. Critically, we analyze how pathological activation of N-methyl-D-aspartate receptors (NMDARs) can dysregulate System Xc-through mechanisms involving calcium overload, reactive oxygen species, and specific signaling axes (e.g., Nrf2, PP2A/AMPK/HMGB1), thereby exacerbating excitotoxicity and oxidative damage. Conversely, System Xc-dysfunction can further fuel NMDAR-mediated injury, creating vicious pathogenic cycles. This analysis reveals that System Xc-is not a unitary target but a dynamic node within a complex network. Consequently, effective therapeutic strategies must move beyond broad inhibition and instead aim for nuanced, cell-type-specific, and disease-stage-precise modulation. This approach will selectively correct the dysfunction of System Xc-while preserving its essential physiological roles. It presents both a significant challenge and a promising frontier for future neuroprotective drug development.}, } @article {pmid41553037, year = {2026}, author = {Shahid, N and Azhar, L and Hussain, I and Khan, MS}, title = {Emerging Alzheimer's therapies: clinical efficacy versus economic feasibility.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {5}, pages = {519-521}, pmid = {41553037}, issn = {1758-2032}, } @article {pmid41553108, year = {2026}, author = {Rudnicki, SA and Giacomelli, E and Herder, K and Ingre, C and Kupfer, S and Malik, FI and Meng, L and Paganoni, S and Schellenberg, K and Scirocco, E and Simkins, T and Wei, J and Shefner, JM and , }, title = {The Use of Durable Medical Equipment in COURAGE-ALS, a Phase 3, Multicentre, Randomized Clinical Trial for ALS.}, journal = {Muscle & nerve}, volume = {73}, number = {4}, pages = {608-614}, doi = {10.1002/mus.70150}, pmid = {41553108}, issn = {1097-4598}, support = {//Cytokinetics, Incorporated/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Double-Blind Method ; Female ; Male ; Aged ; Middle Aged ; *Durable Medical Equipment/statistics & numerical data ; *Noninvasive Ventilation/instrumentation ; *Wheelchairs ; Treatment Outcome ; }, abstract = {INTRODUCTION/AIMS: Durable medical equipment (DME)-wheelchairs, non-invasive ventilation, gastrostomy tubes, and communication devices-provides vital support for individuals with amyotrophic lateral sclerosis (ALS). Here, we describe DME use in COURAGE-ALS evaluating reldesemtiv's efficacy and safety in ALS, to evaluate if DME use can be considered an endpoint of interest in ALS trials.

METHODS: COURAGE-ALS, a multicentre, double-blind, randomized, placebo-controlled clinical trial was conducted at 83 sites in the United States, Canada, Europe, and Australia. Participants were randomized 2:1 to receive reldesemtiv or placebo for 24 weeks, followed by 24 weeks of active drug treatment. Exploratory outcomes included reasons for prescribing, extent of use, DME types, and regional differences.

RESULTS: Among 482 participants, 166 (34.4%) were using at least one DME item at baseline. Among 276 participants completing study visits through Week 24, 130 (47.1%) initiated use of a total of 188 new DME items post-baseline through 24 weeks. Manual wheelchairs were most used at baseline (89 items) and initiated (47 items) during the trial. Both baseline DME use and initiating a new item were associated with lower ALS Functional Rating Scale-Revised scores and worse quality of life. The trial was terminated early due to futility. Treatment assignment did not impact DME use. Regional disparities were noted.

DISCUSSION: This study shows that DME is commonly prescribed to ALS trial participants. Further understanding of geographic differences in DME access and their impact on clinical outcomes is warranted prior to including DME use as an endpoint in ALS trials.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: (NCT04944784).}, } @article {pmid41553204, year = {2026}, author = {Sánchez-Lloria, P and Barcala-Furelos, R and Otero-Agra, M and Aranda-García, S and Martínez-Isasi, S and Muñoz-Barús, I and Rodríguez-Núñez, A and Iglesias-Vázquez, JA}, title = {[Intentional drowning as a method of self-inflicted injury and suicide: a 21-year analysis of Galicia].}, journal = {Revista espanola de salud publica}, volume = {100}, number = {}, pages = {}, pmid = {41553204}, issn = {2173-9110}, mesh = {Humans ; Retrospective Studies ; Female ; Spain/epidemiology ; *Drowning/epidemiology ; Adolescent ; Male ; Child, Preschool ; *Self-Injurious Behavior/epidemiology ; Child ; Adult ; Middle Aged ; Aged, 80 and over ; Young Adult ; Infant ; *Suicide/statistics & numerical data ; Aged ; Longitudinal Studies ; Time Factors ; Suicide, Attempted/statistics & numerical data ; }, abstract = {OBJECTIVE: Drowning and suicide are interconnected complex phenomena and represent significant Public Health issues. The aim of this paper was to identify and describe the characteristics and factors associated with intentional drownings in Galicia (Spain), analyzing a retrospective cohort of twenty-one years.

METHODS: A descriptive, retrospective, and longitudinal study (2001-2021) was conducted analyzing a cohort of patients aged 0 to 100 years who were treated by Basic and Advanced Life Support (BLS/ALS) units of the FPUS 061 and by hospitals within the Galician Health Service (SERGAS). Records coded with a diagnosis of drowning or near-drowning were included and were recoded as fatal or non-fatal drowning according to international recommendations. Additionally, records containing the terms suicide, self-harm, or suicide attempt in prehospital or hospital documentation were also included.

RESULTS: Ninety-nine cases were documented, representing 9% of all drownings in Galicia and 14% of individuals aged over sixty five who drowned. Eighty-two percent of the victims were residents of the municipality where the incident occurred, and 60% were women. Ninety-nine percent had a prior diagnosis of mental health disorder. Individuals over sixty five accounted for 53% of the cases, with a mortality rate of 50%. The presence of witnesses was associated with lower mortality.

CONCLUSIONS: There is a relationship between intentional drownings and mental health disorders. In these events, the presence of witnesses is a protective factor, while advanced age is a risk factor for mortality. Intentional drowning is a complex and understudied health issue, so prevention and Public Health strategies should be implemented to reduce these preventable deaths.}, } @article {pmid41553546, year = {2026}, author = {Dey, A and Baumeister, TR and Evans, KC and Koppelmans, V and Luk, C and McLaren, DG and Parnianpour, P and Seres, P and , and Kalra, S}, title = {Data-driven disease subgrouping in ALS: a multicenter cerebral functional connectivity study.}, journal = {Journal of neurology}, volume = {273}, number = {2}, pages = {87}, pmid = {41553546}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/classification/drug therapy ; Male ; Female ; Middle Aged ; Magnetic Resonance Imaging ; Aged ; Disease Progression ; Adult ; }, abstract = {BACKGROUND: In a clinically-heterogeneous disease such as ALS, it is crucial to identify early disease changes that impair real-world functioning. The lack of consensus across clinical approaches, coupled with the subjectiveness of their evaluation, impedes our understanding of disease processes underlying early and advanced disease. This study presents neuroimaging as a potential supplementary approach that provides objectivity to the identification and evaluation of disease stage-specific ALS subgroups.

METHODS: Cerebral functional connectivity and its association with clinical function was evaluated in 174 ALS patients and 165 healthy controls enrolled in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants were subgrouped using two approaches: (1) a data-driven hierarchical clustering of cerebral activation and 2) contemporary clinical criteria. The data-driven approach utilized data from resting-state functional magnetic resonance imaging. The clinical approach utilized three clinical subgrouping methods - two derived from trial enrollment criteria for the drugs Riluzole and Edaravone, and the third on the median disease progression rate of the patient sample.

RESULTS: Each subgrouping approach identified two patient subgroups with different symptom durations, disease progression rates, and cognitive/motor/lung functions - albeit with differences across approaches. The data-driven approach identified greater spatial extents of cerebral connectivity alterations compared to the clinical approaches.

CONCLUSION: Observations of clinical and cerebral connectivity differences were specific to the stratification approach. Given the ability of the data-driven approach to identify alterations in both clinical and cerebral function corresponding to disease stage, this approach presents a potential biomarker for patient stratification, clinical trial enrichment, disease and therapeutic monitoring.}, } @article {pmid41553588, year = {2026}, author = {Bjørklund, G and Butnariu, M and Caunii, A and Peana, M}, title = {Metallothioneins in Neurodegenerative Diseases: Metal Homeostasis, Autoimmunity, and Therapeutic Potential.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {373}, pmid = {41553588}, issn = {1559-1182}, mesh = {Humans ; *Metallothionein/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/immunology ; *Homeostasis/physiology ; Animals ; *Metals/metabolism ; *Autoimmunity/physiology ; Oxidative Stress ; }, abstract = {Neurodegenerative diseases, including multiple sclerosis, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and are frequently linked to metal dysregulation, oxidative stress, and immune dysfunction. Metallothioneins (MTs), a family of cysteine-rich, metal-binding proteins, are critical in maintaining metal homeostasis, mitigating oxidative damage, and modulating immune responses, functions highly relevant in these pathologies. MTs regulate essential metals like copper and iron by preventing their participation in harmful redox reactions and control zinc availability for enzymatic and signaling processes. They also detoxify neurotoxic metal(oid)s such as cadmium, mercury, lead, and arsenic, thereby reducing their adverse neurological and immunological effects. In autoimmune neurodegeneration, MTs modulate pro- and anti-inflammatory cytokines (e.g., IL-6, TNF-α, IL-10) and influence immune cell activity, particularly microglia and T cells, which are central to neuroinflammation and autoimmunity. Through these mechanisms, MTs play a dual role in sustaining immune homeostasis and counteracting oxidative stress. Their capacity to integrate metal regulation with immune modulation positions them as promising therapeutic targets, with preclinical and some clinical evidence supporting strategies to enhance MT expression or develop MT-mimetic agents to address both metal dysregulation and immune imbalance. Additionally, MTs show emerging utility as biomarkers, as alterations in MT isoform expression and metal-bound complexes in biofluids have been associated with disease onset, progression, and therapeutic response in specific neurodegenerative conditions. This article reviews the multifaceted roles of MTs in neurodegenerative diseases, emphasizing their function in metal and immune regulation and their emerging potential as therapeutic targets and clinical biomarkers.}, } @article {pmid41554495, year = {2026}, author = {Phillips, EM and Edwards, JG and Aiello, L and Gilliam, CA and Seltz, LB and Spencer, DJ and Rassbach, CE}, title = {The Effect of Mistreatment From Patients and Families on Pediatric Resident Professional Identity Formation.}, journal = {Academic pediatrics}, volume = {26}, number = {3}, pages = {103221}, doi = {10.1016/j.acap.2026.103221}, pmid = {41554495}, issn = {1876-2867}, mesh = {Humans ; *Internship and Residency ; Female ; Male ; *Social Identification ; *Pediatrics/education ; Qualitative Research ; *Physician-Patient Relations ; Burnout, Professional/psychology ; *Pediatricians/psychology ; Psychological Safety ; Adult ; Attitude of Health Personnel ; Patient-Centered Care ; *Professional-Family Relations ; }, abstract = {OBJECTIVE: Mistreatment by patients and families is linked to adverse patient outcomes and physician burnout, and particularly affects women and underrepresented in medicine (UIM) physicians. We sought to explore how this source of mistreatment affects trainee professional identity formation (PIF), a key process in the development of altruistic physicians.

METHODS: We conducted this multi-institutional qualitative study between May and October 2023 with semistructured interviews of pediatric residents. We used the constant comparative method consistent with modified grounded theory to analyze data through a lens of Cruess et al's model of PIF in medicine.

RESULTS: We interviewed 32 pediatric residents and identified 4 primary themes, which we used to develop a conceptual model. 1) Residents identify patient- and family-centered care as core to their professional identity, while acknowledging their vulnerability to mistreatment from patients and families. 2) Mistreatment threatens resident PIF through fractured patient-provider relationships, negative impacts on patient care, and decreased psychological safety of the learning environment. 3) Mistreatment that is frequent, unaddressed, and centered around personal traits is particularly damaging to PIF. 4) Residents employ various strategies to mitigate the negative impacts of mistreatment and ultimately deepen their professional identity.

CONCLUSIONS: Mistreatment from patients and families negatively affects pediatric residents' well-being, learning, and professional identity, with particular impacts on women and UIM residents. Our study informs ways that institutions can best structure support to navigate mistreatment while optimizing trainee learning and PIF, along with patient care.}, } @article {pmid41555948, year = {2026}, author = {Deniz, R and Çiftçi, B}, title = {Emphasizing the biopsychosocial dimension in post-traumatic orthopedic recovery.}, journal = {World journal of psychiatry}, volume = {16}, number = {1}, pages = {115015}, pmid = {41555948}, issn = {2220-3206}, abstract = {Chronic pain and disability following acute orthopedic trauma are not only physical concerns but also deeply intertwined with psychological well-being. The recent retrospective cohort study by Yang et al, published, provides compelling evidence of significant associations between depression, anxiety, and postoperative recovery. These findings align with an expanding body of literature that confirms the need for orthopedic rehabilitation to adopt a biopsychosocial perspective. This letter contextualizes Yang et al's study within current evidence, highlighting the roles of sleep disturbance, catastrophizing, stress, neurobiological mechanisms, and coping strategies in shaping recovery. It further emphasizes the importance of integrating nursing-led and multidisciplinary interventions to address both physical and psychological domains, ultimately promoting holistic recovery.}, } @article {pmid41556284, year = {2026}, author = {Cao, W and Yu, L and Wang, Z and Deng, B and Fan, D}, title = {Neutrophil-Secreted Enzymes and ALS Risk: Exploring a Potential Mechanistic Link.}, journal = {Annals of neurology}, volume = {99}, number = {3}, pages = {591-605}, doi = {10.1002/ana.78161}, pmid = {41556284}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/enzymology/epidemiology/blood ; Female ; *Neutrophils/enzymology/metabolism ; Male ; Aged ; Middle Aged ; Peroxidase/metabolism ; Neurofilament Proteins/metabolism/blood ; }, abstract = {OBJECTIVE: Peripheral immunity plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We previously showed that elevated neutrophil counts are associated with increased risk of ALS occurrence and faster disease progression, potentially through axonal damage. However, the mechanisms linking neutrophils to ALS occurrence remain unclear. Neutrophil-secreted enzymes, key markers of neutrophil activity, may mediate these effects. We therefore investigated the role of neutrophil-secreted enzymes in ALS occurrence.

METHODS: Six neutrophil-secreted enzymes were selected from the UK Biobank-Proteomics Platform. Cox proportional hazards regression was used to examine associations between these enzymes and ALS occurrence. Multiple sensitivity analyses were conducted to ensure robustness. Stratified analyses evaluated potential effect modifications by age, sex, and body mass index (BMI). To investigate whether neutrophil-secreted enzymes contribute to ALS occurrence via a "dying-back" mechanism, mediation analysis was performed to assess the indirect effect of neurofilament light chain (NfL) levels in this relationship.

RESULTS: Individuals who later developed ALS showed significantly higher levels of neutrophil-secreted enzymes prior to disease onset, suggesting that neutrophil activation occurs before ALS occurrence. Elevated enzyme levels were associated with an increased risk ALS occurrence. Furthermore, we observed a linear positive correlation between enzyme levels and NfL concentrations. Mediation analysis indicated that the effects of MPO and S100A12 on ALS onset were partially mediated through axonal injury.

INTERPRETATION: Elevated neutrophil-secreted enzymes are associated with an increased risk of ALS occurrence. This finding provides mechanistic insight into neutrophil involvement in ALS and identifies these enzymes as potential therapeutic targets. ANN NEUROL 2026;99:591-605.}, } @article {pmid41556400, year = {2026}, author = {Howard, I and Lyerly, M and Reimer, R and Patwa, H and Darling, L}, title = {Symptom Burden and Care Satisfaction in US Military Veterans With ALS: Results of a National Survey.}, journal = {Muscle & nerve}, volume = {73}, number = {4}, pages = {623-629}, doi = {10.1002/mus.70147}, pmid = {41556400}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology/psychology/diagnosis ; *Veterans/psychology ; United States/epidemiology ; *Patient Satisfaction ; Middle Aged ; Male ; Female ; Symptom Burden ; Surveys and Questionnaires ; Aged ; United States Department of Veterans Affairs ; Adult ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) affects military veterans at a higher rate than the general civilian population. The aim of the present study is to assess symptom burden and satisfaction with care among persons with ALS care enrolled in the US Veterans Health Administration (VA).

METHODS: A custom online survey was created with questions about symptom prevalence and management as well as care satisfaction. A survey link was sent by email to all veterans with an ICD-10 diagnosis of ALS in the VA for whom an email address was available in the electronic health record.

RESULTS: Responses were received from 413 individuals (16% response rate). Respondents reported high care satisfaction and higher prevalence of treatment of symptoms compared to prior surveys of persons with ALS in the United States. Self-reported outcomes, including treatment, education, and satisfaction, were better for Veterans receiving care exclusively within the VA compared to those receiving care at both VA and non-VA facilities or receiving care exclusively at non-VA facilities. Areas for further improvement identified in the survey include education on genetic testing and research and management of non-motor symptoms.

DISCUSSION: This survey indicates that, overall, veterans with ALS receive comprehensive symptom-based care within the nationalized VA care system and report high levels of satisfaction. Furthermore, this study provides baseline data and findings that may be used for quality improvement efforts across a large healthcare system and may serve as a model for similar efforts in other health systems.}, } @article {pmid41557054, year = {2026}, author = {Shi, Y and Wang, H and Chen, J and Ren, J and Sun, X and Qu, M and Zhao, T and Han, C and Yuan, J and Meng, F and Lu, L}, title = {α-Synuclein Deletion Leads to Hyposmia: due to Defective Autophagy Induced by Abnormal PI3K/mTOR Signaling Pathway in Olfactory Bulb.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {378}, pmid = {41557054}, issn = {1559-1182}, mesh = {Animals ; *alpha-Synuclein/deficiency/metabolism ; *Autophagy ; *TOR Serine-Threonine Kinases/metabolism ; *Signal Transduction ; *Olfactory Bulb/metabolism/pathology ; *Phosphatidylinositol 3-Kinases/metabolism ; Mice, Knockout ; *Gene Deletion ; Apoptosis ; Proto-Oncogene Proteins c-akt/metabolism ; }, abstract = {α-Synuclein has been the center of focus in understanding synucleinopathies such as Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, dementia with Lewy bodies, for decades. Most researches focus on its pathology. However, its physiological function remains elusive, especially in olfactory system, one of the original sites to find α-synuclein accumulation in Parkinson's disease. In the present study, α-synuclein knockout (KO) mice were employed to study its physiological function. KO mice exhibited olfaction impairment with cell apoptosis in olfactory bulb. To identify molecules underlying olfactory dysfunction, we employed proteomics based on isobaric tags for relative and absolute quantification (iTRAQ). 188 differentially expressed proteins were identified between KO mice and its littermate control of wildtype mice. Bioinformatic analysis highlighted Phosphatidyl-inositol-3-kinase (PI3K) pathway. Hence, we examined its activation and found that both PI3K and its downstream, protein kinase B(AKT) is hyperactivated with α-synuclein deficiency. Mammalian target of Rapamycin (mTOR), a switch of autophagy, was activated followed by uncoordinated 51-like kinase 1, the autophagy initiator, inhibition. The specific substrate of autophagy, P62 was accumulated, indicating that autophagy was blocked. This blockade of autophagy led to Caspase 8 mediated apoptosis characterized by an increased ratio of B-cell lymphoma-2 (BCL-2)-associated X protein (BAX) to BCL-2 (BAX/BCL-2), reduced mitochondrial complex I activity, and decreased mitochondrial membrane potential. To summarize, α-synuclein played roles in maintaining the normal structure and function of olfactory system. α-Synuclein deletion induced Caspase 8 mediated apoptosis due to the defective autophagy by PI3K/mTOR hyperactivation.}, } @article {pmid41557441, year = {2026}, author = {Wu, J and Pyko, A and Chourpiliadis, C and Hu, Y and Hou, C and Brauner, S and Piehl, F and Ljungman, P and Ingre, C and Fang, F}, title = {Long-Term Exposure to Air Pollution and Risk and Prognosis of Motor Neuron Disease.}, journal = {JAMA neurology}, volume = {83}, number = {3}, pages = {213-222}, pmid = {41557441}, issn = {2168-6157}, support = {R01 TS000348/TS/ATSDR CDC HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Air Pollution/adverse effects ; Case-Control Studies ; Disease Progression ; *Environmental Exposure/adverse effects ; *Motor Neuron Disease/epidemiology/diagnosis/etiology ; Particulate Matter/adverse effects ; Prognosis ; Registries ; Risk Factors ; Sweden/epidemiology ; }, abstract = {IMPORTANCE: Air pollution exposure has been associated with an increased risk of neurodegenerative diseases; however, evidence is limited for motor neuron disease (MND), especially regarding disease progression.

OBJECTIVE: To determine whether long-term exposure to air pollution is associated with the risk and prognosis of MND.

This population-based, nested case-control study used Swedish health register data of incident MND cases diagnosed between 2015 and 2023 with up to 8 years of follow-up. Participants included patients with MND, 5 age- and sex-matched population controls without MND per patient with MND, and full siblings of the patients with MND. Data were analyzed between November 6, 2024, and November 4, 2025.

EXPOSURES: Mean yearly concentrations of particulate matters of 2.5 µm or less, 10 µm or less, or 2.5 to 10 µm in diameter (PM2.5, PM10, PM2.5-10) and nitrogen dioxide (NO2) were assessed at the residential address using a spatiotemporal model to approximate accumulated air pollution exposure.

MAIN OUTCOME AND MEASURES: Association between air pollution and risk of MND was assessed by comparing cases to both population and sibling controls. Flexible parametric survival models estimated the association between air pollution exposure and the risk of mortality (or use of invasive ventilation) after MND diagnosis (case-only analyses). Based on the rate of decline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score and its subscores after diagnosis, patients were classified into fast (upper 25th percentile) or slow (lower 75th percentile) progression. Logistic regression was used to assess air pollution exposure and the risk of fast progression.

RESULTS: The study included 1463 patients with MND, 7310 population controls, and 1768 sibling controls. The mean (SD) age for all patients with MND was 67.3 (11.7) years, and 814 (55.6) were male. In the population comparison, long-term air pollution was associated with an increased risk of MND; per IQR increase in the 10-year average level, the odds ratio was 1.21 (95% CI, 1.09-1.34) for PM2.5, 1.30 (95% CI, 1.19-1.42) for PM2.5-10, 1.29 (95% CI, 1.18-1.42) for PM10, and 1.20 (95% CI, 1.12-1.29) for NO2. A higher level of PM10 or NO2 was associated with a higher hazard of mortality, whereas a higher level of all PMs was associated with faster functional decline, particularly motor and respiratory functions, after MND diagnosis.

CONCLUSIONS AND RELEVANCE: The findings of this case-control study suggest that air pollution, even at relatively low levels typical of Sweden, may contribute both to the risk of developing MND and disease prognosis after MND diagnosis.}, } @article {pmid41557593, year = {2026}, author = {Meyer, T and Maier, A and Grehl, T and Weyen, U and Rödiger, A and Smesny, U and Steinbach, R and Grosskreutz, J and Göricke, B and Bernsen, S and Weydt, P and Fabian, R and Petri, S and Lumi, R and Bjelica, B and Boentert, M and Lingor, P and Kettemann, D and Norden, J and Walter, B and Riitano, A and Schumann, P and Münch, C and Spittel, S}, title = {Minimum important slowing of disease progression as determined by the ALS functional rating scale - a survey of patient expectations toward disease-modifying drugs in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {457-468}, doi = {10.1080/21678421.2026.2615117}, pmid = {41557593}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/psychology/diagnosis ; *Disease Progression ; Female ; Male ; Middle Aged ; Aged ; Surveys and Questionnaires ; Severity of Illness Index ; Adult ; }, abstract = {Objective: To define the minimum important slowing (MIS) of ALS progression that patients would expect from disease-modifying drug treatment in ALS. Methods: In a survey of ALS patients, the MIS in ALS progression (change in the ALS Functional Rating Scale-Revised, ALSFRS-R) was assessed by asking: "At what point of slowing of ALS, as determined by the ALSFRS-R, do you consider a drug to be important?" Data were collected during clinic visits or remotely via the ALS App. Participants were differentiated in the prognostic groups of slower (<0.5), intermediate (≥0.5 and ≤1.0), or faster (>1.0) ALS progression (ALSPR; ALSFRS-R/month). Results: Of 522 participants (ALS App, n = 397; clinic, n = 125), 395 (75.7%) completed the survey, while 127 (24.3%) selected the option "cannot estimate". The distribution of MIS was as follows: modest slowing of ALS progression (5% and 10% slowing, n = 146 patients, 36.9%), moderate slowing (20%, 30%, and 40% slowing, n = 135, 34.2%), and major slowing (≥50% slowing, n = 114, 28.9%). Median MIS was 20% (IQR 10-50%). Patients with faster ALSPR more frequently assessed a major slowing as the MIS (n = 18, 36.0%) compared to those with slower ALSPR (n = 54, 25.2%). Conclusion: A considerable number of participants viewed a modest slowing in ALS progression as the MIS, followed closely by preferences for moderate and major slowing. Expectations varied according to patients' individual ALS progression. These insights may inform the design of future clinical trials in ALS. Study limitations include potential selection and response biases, as well as the predominantly remote digital assessment.}, } @article {pmid41558795, year = {2026}, author = {Yi, W and Xu, Z and Feng, D and Guan, L and Tang, J and Zou, Y}, title = {Computational Exploration of the Molecular Mechanism of Epigallocatechin Gallate against TDP-43 Aggregation.}, journal = {Journal of chemical information and modeling}, volume = {66}, number = {3}, pages = {1826-1839}, doi = {10.1021/acs.jcim.5c02616}, pmid = {41558795}, issn = {1549-960X}, mesh = {*Catechin/analogs & derivatives/pharmacology/chemistry/metabolism ; *Molecular Dynamics Simulation ; *DNA-Binding Proteins/chemistry/metabolism ; *Protein Aggregates/drug effects ; Humans ; Protein Binding ; }, abstract = {Cytoplasmic accumulation of the transactive response deoxyribonucleic acid (DNA)-binding protein of 43 kDa (TDP-43) aggregates represents the primary pathological hallmark of TDP-43 proteinopathies including amyotrophic lateral sclerosis (ALS) and chronic traumatic encephalopathy (CTE). Inhibiting TDP-43 aggregation or disrupting its preformed fibrils might be promising strategies to prevent or delay the development of TDP-43 proteinopathies. Recently, the green tea polyphenol, epigallocatechin gallate (EGCG), was observed to prevent the formation of TDP-43 oligomeric species and fibrillar aggregates. Nevertheless, the atomic-level mechanism of this inhibition has been incompletely characterized. In this study, we performed a multitude of replica exchange with solute tempering 2 (REST2) and all-atom molecular dynamics (MD) simulations of 46.8 μs in total on TDP-43 models with and without EGCG. The REST2 simulation results revealed that EGCG impedes the β-sheet structure formation and interferes the interchain interaction of TDP-43304-348 dimer. Subsequent analyses show that EGCG could alter the distribution of free energy landscape and hinder the residue-residue interaction of the dimer. The binding analyses confirmed that EGCG preferentially bound to M307, F313, F316, W334, M339, Q344, and Q346 residues, and hydrophobic, polar, and π-π stacking interactions dominate the binding of EGCG on the dimer. Additional conventional molecular dynamics (MD) simulations demonstrated that the protofibrillar tetramer is the minimal stable TDP-43304-348 protofibril. Taking the tetramer as a protofibril model, we found that EGCG could reduce the structural stability and disrupt the β-sheet structure of TDP-43304-348 protofibril, thus possessing a destabilization effect on its higher-order structure. This investigation unveils the atomic-level mechanism by which EGCG against TDP-43 aggregation, which may provide potential fundamental knowledge of therapeutic strategies for TDP-43 proteinopathies.}, } @article {pmid41559796, year = {2026}, author = {Jun, YW and Hass, EP and Lee, S and Fazzio, TG and Gao, FB}, title = {Mislocalization of FTD3-associated mutant CHMP2B to the nucleus of human neurons due to loss of a nuclear export signal.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {45}, pmid = {41559796}, issn = {2051-5960}, support = {R01 HD072122/HD/NICHD NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Neurons/metabolism/pathology ; *Nuclear Export Signals/genetics ; *Cell Nucleus/metabolism ; Exportin 1 Protein ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Nerve Tissue Proteins/genetics/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Mutation/genetics ; Karyopherins/metabolism ; Active Transport, Cell Nucleus ; Receptors, Cytoplasmic and Nuclear/metabolism ; Cytoplasm/metabolism ; Cells, Cultured ; Cerebral Cortex ; Endosomal Sorting Complexes Required for Transport ; }, abstract = {Frontotemporal dementia linked to chromosome 3 (FTD3) is caused by a splice site point mutation in CHMP2B, resulting in the production of mutant proteins CHMP2B[In5] and CHMP2B[Δ10]. Here, we found that wildtype CHMP2B (CHMP2B[WT]) is mostly present in the cytoplasm, but CHMP2B[In5] is mislocalized to the nucleus of human induced pluripotent stem cell (iPSC)-derived cortical neurons. To understand the underlying mechanism, we identified a previously unreported nuclear export signal (NES) in the C-terminus of CHMP2B. Functional assays, including CRM1 inhibition and site-directed mutagenesis of key hydrophobic residues, demonstrated that this NES motif is both necessary and sufficient for nuclear export of CHMP2B[WT] and ALS-associated CHMP2B[Q206H], and its loss in CHMP2B[In5] is responsible for the observed nuclear mislocalization. CHMP2B[Δ10] remains in the cytoplasm due to the presence of an artificial NES in the C-terminus. These results reveal the presence of an NES in CHMP2B and highlight the need to dissect the gain-of-toxic nuclear functions of CHMP2B[In5] in FTD3 pathogenesis.}, } @article {pmid41560764, year = {2026}, author = {Ge, Y and Zhu, J and Ren, Y and Wu, X and Zhou, B and Wu, Y and Ge, Y}, title = {Trans-Generational Morphological Trait Plasticity in Parthenogenetic Offspring of Two Brachionus dorcas Morphotypes Induced by Asplanchna Kairomones.}, journal = {Ecology and evolution}, volume = {16}, number = {1}, pages = {e72956}, pmid = {41560764}, issn = {2045-7758}, abstract = {We compared trans-generational (F0-F12) morphological trait plasticity induced by Asplanchna kairomones between two Brachionus dorcas morphotypes (long-posterior spines, LS; short-posterior spines, SS) along with life-table parameters of the non-induced morphotypes. Under control conditions, SS rotifers tended to show higher fertility and smaller body size than LS rotifers. Low kairomone concentrations (50 and 200 ind./L) tended to increase body size in SS offspring, while exposure to 50, 200, and 800 ind./L kairomones induced spine elongation in both morphotypes, with posterolateral spine (PS) length increasing with kairomone concentration. Compared to the F0 generation, offspring of both morphotypes in unexposed controls showed generational fluctuations in body size; LS offspring exhibited shortening or no change in anteromedian spine (AMS) and anterolateral spine (ALS) lengths, while SS offspring showed elongation or no change in these spine lengths and PS length. Across all kairomone treatments, significant elongation of AMS and ALS in LS offspring was typically observed only in later generations, whereas SS offspring exhibited significant elongation from F1 through F12; LS offspring showed significant PS elongation from F2 through F12, with maximum lengths in the later generations (F5-F12), while SS offspring showed significant PS elongation from F1 through F12, peaking in early generations (F2-F4). Notably, the multi-generational mean PS length in SS offspring remained significantly shorter than that in LS offspring under each kairomone treatment. Overall, SS offspring appeared to employ a synergistic defense combining increased body size and spine elongation favoring a "rapid and moderate response," whereas LS offspring exhibited a "slow and extreme defense" strategy. These divergent strategies may result from evolutionary trade-offs involving resource allocation, environmental predictability, and genetic constraints.}, } @article {pmid41561436, year = {2025}, author = {Ishaq, SM and Russell, AP}, title = {Potential role of stress granules and myogranules in amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1686230}, pmid = {41561436}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper and lower motor neurones, leading to muscle wasting, paralysis and respiratory failure. Pathological cytoplasmic aggregation of the RNA-binding protein transactive response DNA-binding protein 43 (TDP-43) protein occurs in neural tissues in ~97% of all ALS cases, and is also observed in skeletal muscle. Cytoplasmic aggregation of TDP-43 is believed to contribute to ALS pathogenesis; however, its precise mechanistic role/s continues to elude the field. This mini review explores the potential role and regulation of two TDP-43-associated RNA-protein assemblies, stress granules (SGs) and myogranules (MGs). We review the current understanding of SG and MG formation and their potential role in ALS-related neurodegeneration and muscle pathology. We also highlight limitations and strengths and suggest future directions for research.}, } @article {pmid41561437, year = {2025}, author = {Kim, SH and Boos, CE and Scalf, M and Wilkemeyer, AK and Smith, LM and Tibbetts, RS}, title = {Interactome screening implicates BAG6 as a suppressor of UBQLN2 misfolding in ALS/FTD.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1720347}, pmid = {41561437}, issn = {1662-5099}, support = {R01 CA180765/CA/NCI NIH HHS/United States ; R35 GM126914/GM/NIGMS NIH HHS/United States ; RF1 AG069483/AG/NIA NIH HHS/United States ; T32 HG002760/HG/NHGRI NIH HHS/United States ; }, abstract = {Ubiquilin-2 (UBQLN2) is a ubiquitin (Ub)-binding shuttle protein that is mutated in X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS/FTD-linked mutations in UBQLN2 disrupt its conformation, increasing its tendency to form cytoplasmic aggregates that may disrupt cellular regulation through loss-of-function (LOF) and gain-of-function (GOF) effects. Here, we performed quantitative mass spectrometry (MS)-based interactome analysis of wild-type (UBQLN2[WT]) and ALS-mutant UBQLN2 (UBQLN2[ALS]) proteins using inducible pluripotent stem cells (iPSCs) and induced motor neurons (iMNs). Proteins showing enhanced association with UBQLN2[ALS] proteins included PEG10, a known degradation target of UBQLN2, and BAG6, a chaperone involved in the triage of mislocalized proteins (MLPs). BAG6 knockdown inhibited the solubility recovery of both UBQLN2[WT] and UBQLN2[ALS] proteins following heat stress (HS), suggesting it functions as a UBQLN2 holdase. In addition, knockdown of BAG6 or knockout of UBQLN2 led to PEG10 accumulation, implicating both in PEG10 turnover; however, neither BAG6 nor UBQLN2 was required for PEG10 degradation in response to HS. A highly aggregation-prone UBQLN2[4XALS] mutant harboring four different ALS-associated mutations showed increased PEG10 binding and modestly delayed PEG10 turnover while PEG10 degradation was not significantly different between UBQLN2[WT] and iPSCs expressing a UBQLN2[P497H] clinical mutant. The combined findings implicate BAG6 as a UBQLN2 holdase and identify a suite of proteins whose altered binding may contribute to pathologic changes in UBQLN2-associated ALS/FTD.}, } @article {pmid41561680, year = {2026}, author = {Lizio, A and Lops, J and Farè, M and Pezzera, S and Piras, R and Sideri, R and Tornabene, D and Lunetta, C and Diamanti, L and Sansone, VA and Cerri, F}, title = {Development and validation of predictive models for 6-month gastrostomy timing in amyotrophic lateral sclerosis.}, journal = {BMJ neurology open}, volume = {8}, number = {1}, pages = {e001336}, pmid = {41561680}, issn = {2632-6140}, abstract = {BACKGROUND: Dysphagia is common in amyotrophic lateral sclerosis (ALS), contributing to malnutrition and accelerated disease progression. Although early nutritional intervention is recommended, the optimal timing for percutaneous endoscopic gastrostomy (PEG) placement remains uncertain. This study aimed to develop and validate simple prediction models, accessible via an online calculator, to identify ALS patients likely to require PEG within 6 months.

METHODS: We conducted a retrospective cohort study including ALS patients followed at three Italian reference centres between February 2018 and October 2023. Predictors of PEG placement within 6 months were identified using univariate and multivariable binary logistic regression models. Prediction models were developed following Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines and underwent both internal and external validation.

RESULTS: In the development cohort (n=263; median age 63.8 years), 138 patients (52.5%) underwent PEG within 6 months. Three models were developed: the Anamnestic Prediction Model, based on age, onset site and non-invasive ventilation (NIV), showed fair predictive performance. The Anamnestic and Functional Prediction Model, incorporating age, bulbar subscore of Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-r) and forced vital capacity (%), demonstrated strong predictive performance (Brier score: 0.1230), excellent discrimination (concordance index (c-index) 0.91) and good calibration (Hosmer-Lemeshow p=0.59). The Anamnestic and Nutritional Prediction Model, including age, onset site, NIV, body mass index and weight loss, showed good predictive performance (Brier score: 0.1719), discrimination (c-index 0.81) and calibration (Hosmer-Lemeshow p=0.48). These findings were confirmed in an external validation cohort of 116 ALS patients.

CONCLUSIONS: The prediction models provide accurate, easily implementable tools to predict PEG need within 6 months, enabling timely nutritional interventions that may improve outcomes and care quality in ALS.}, } @article {pmid41562832, year = {2026}, author = {Aranda-Abreu, GE and Rojas-Durán, F and Hernández-Aguilar, ME and Herrera-Covarrubias, D and Tlapa-Monge, LR and Mestizo-Gutiérrez, SL}, title = {The Molecular Architecture of Neurodegeneration: An Integrative Overview of Convergent Mechanisms.}, journal = {NeuroSci}, volume = {7}, number = {1}, pages = {}, pmid = {41562832}, issn = {2673-4087}, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's disease represent a major challenge in neuroscience due to their complex, multifactorial nature and the absence of curative treatments. These disorders share common molecular mechanisms, including oxidative stress, mitochondrial dysfunction, proteostasis collapse, calcium dyshomeostasis, chronic neuroinflammation, and the prion-like propagation of misfolded proteins. Together, these processes trigger a cascade of cellular damage that culminates in synaptic dysfunction and programmed neuronal death. This review integrates current evidence on the sequential stages of neurodegeneration, emphasizing the convergence of oxidative, inflammatory, and proteotoxic pathways that drive neuronal vulnerability. Moreover, it explores emerging therapeutic strategies aimed at restoring cellular homeostasis, such as Nrf2 activation, modulation of the unfolded protein response (UPR), enhancement of autophagy, immunotherapy against pathological proteins, and gene therapy approaches. The dynamic interplay among mitochondria, endoplasmic reticulum, and glial cells is highlighted as a central element in disease progression. Understanding these interconnected mechanisms provides a foundation for developing multi-targeted interventions capable of halting or delaying neuronal loss and improving clinical outcomes in neurodegenerative disorders. This work provides an integrative and introductory overview of the convergent mechanisms underlying neurodegeneration rather than an exhaustive mechanistic analysis.}, } @article {pmid41562880, year = {2026}, author = {Fiorella, ML and Ballini, L and Lavermicocca, V and Ragno, MS and Restivo, DA and Marchese-Ragona, R}, title = {Dysphagia and Dysarthria in Neurodegenerative Diseases: A Multisystem Network Approach to Assessment and Management.}, journal = {Audiology research}, volume = {16}, number = {1}, pages = {}, pmid = {41562880}, issn = {2039-4330}, abstract = {Dysphagia and dysarthria are common, co-occurring manifestations in neurodegenerative diseases, resulting from damage to distributed neural networks involving cortical, subcortical, cerebellar, and brainstem regions. These disorders profoundly affect patient health and quality of life through complex sensorimotor impairments. Objective: The aims was to provide a comprehensive, evidence-based review of the neuroanatomical substrates, pathophysiology, diagnostic approaches, and management strategies for dysphagia and dysarthria in neurodegenerative diseases with emphasis on their multisystem nature and integrated treatment approaches. Methods: A narrative literature review was conducted using PubMed, Scopus, and Web of Science databases (2000-2024), focusing on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Search terms included "dysphagia", "dysarthria", "neurodegenerative diseases", "neural networks", "swallowing control" and "speech production." Studies on neuroanatomy, pathophysiology, diagnostic tools, and therapeutic interventions were included. Results: Contemporary neuroscience demonstrates that swallowing and speech control involve extensive neural networks beyond the brainstem, including bilateral sensorimotor cortex, insula, cingulate gyrus, basal ganglia, and cerebellum. Disease-specific patterns reflect multisystem involvement: PD affects basal ganglia and multiple brainstem nuclei; ALS involves cortical and brainstem motor neurons; MSA causes widespread autonomic and motor degeneration; PSP produces tau-related damage across multiple brain regions. Diagnostic approaches combining fiberoptic endoscopic evaluation, videofluoroscopy, acoustic analysis, and neuroimaging enable precise characterization. Management requires multidisciplinary Integrated teams implementing coordinated speech-swallowing therapy, pharmacological interventions, and assistive technologies. Conclusions: Dysphagia and dysarthria in neurodegenerative diseases result from multifocal brain damage affecting distributed neural networks. Understanding this multisystem pathophysiology enables more effective integrated assessment and treatment approaches, enhancing patient outcomes and quality of life.}, } @article {pmid41563042, year = {2026}, author = {Bergh, S and Simonsson, O and Petersén, Å}, title = {Analyses of the Effects of Wild-Type TDP-43 Overexpression in Oxytocin Neurons in Mice.}, journal = {Neuropathology and applied neurobiology}, volume = {52}, number = {1}, pages = {e70059}, pmid = {41563042}, issn = {1365-2990}, support = {2022/01092//Swedish Research Council/ ; //Brain Foundation/ ; //Region Skåne/ ; 2019.0467//Knut and Alice Wallenberg Foundation/ ; }, mesh = {Animals ; *Neurons/metabolism ; *Oxytocin/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Paraventricular Hypothalamic Nucleus/metabolism ; Mice, Transgenic ; }, abstract = {Selective TDP-43 overexpression in oxytocin neurons in the paraventricular nucleus of the hypothalamus causes a decrease in oxytocin-immunopositive cells compared to uninjected mice. AAV-mediated TDP-43 overexpression in oxytocin neurons does not appear to be a major driver of behavioural and metabolic phenotypes in mice.}, } @article {pmid41563518, year = {2026}, author = {Boomsma, A and Doyle, C and Sai, N and Rogers, ML and Lee, SH and Benyamin, B}, title = {The differences in sex ratio between sporadic and familial amyotrophic lateral sclerosis: a systematic review.}, journal = {Journal of neurology}, volume = {273}, number = {2}, pages = {92}, pmid = {41563518}, issn = {1432-1459}, support = {Research Training Program//Australian Government/ ; DIS-202303-00932//FightMND/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; *Sex Ratio ; Male ; Female ; *Sex Characteristics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is more prevalent in males than in females. However, it is unclear whether the difference in sex ratio is observed similarly in sporadic compared to familial ALS. Here, we conducted a systematic review to investigate the differences in sex ratio between familial and sporadic ALS. Following the meta-analysis of observational studies in epidemiology (MOOSE) guidelines, this study searched Ovid MEDLINE, Embase, Emcare, SCOPUS and Cochrane databases. We used a random-effects meta-analysis to estimate sex ratios in a total of 9269 ALS patients (4135 female, 5134 male) across 20 included studies. We confirmed that ALS is more prevalent in males than in females (sex ratio: 1.25 (95%CI 1.14-1.37). However, when we stratified the analyses, the sex ratio was only different in sporadic ALS. Male-to-female ratios were 1.29 (95% CI 1.16-1.42) for sporadic ALS and 1.05 (95% CI 0.93-1.18) for familial ALS. A further analysis showed a pooled risk ratio of 1.07 (95% CI 1.00-1.15), indicating a 7% higher likelihood of males being diagnosed with sporadic rather than familial ALS. These findings highlight the importance of considering sex-specific factors in ALS research and clinical practice.}, } @article {pmid41564501, year = {2026}, author = {Han, L and Zang, S and Li, W and Yue, H and Zhou, X and Chen, J and Geng, M and Duan, W and Xie, Z and Zhan, Z}, title = {Discovery of the thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors.}, journal = {Bioorganic & medicinal chemistry}, volume = {135}, number = {}, pages = {118571}, doi = {10.1016/j.bmc.2026.118571}, pmid = {41564501}, issn = {1464-3391}, mesh = {Humans ; STING Protein ; Animals ; *Membrane Proteins/antagonists & inhibitors/metabolism ; Mice ; Structure-Activity Relationship ; Molecular Structure ; cGAS-STING Signaling Pathway ; *Drug Discovery ; *Thiazoles/pharmacology/chemistry/chemical synthesis ; Dose-Response Relationship, Drug ; Signal Transduction/drug effects ; }, abstract = {The adaptor molecule STING is embedded in the endoplasmic reticulum (ER) membrane. In innate immunity, STING is a critical cascade in regulating the cytoplasmic DNA-recognizing signaling. Aberrant STING signaling facilitates the host body to secrete an intolerable level of inflammatory cytokines as well as interferons, causing interferonopathies including STING-associated infantile vasculopathy, familial chilblain lupus, and amyotrophic lateral sclerosis. Suppressing the disordered STING signaling has demonstrated to ameliorate the inflammatory impairments of interferonopathy diseases. In this article, we provide the discovery of thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors. Through the structure-activity relationship (SAR) exploration, we identified compound 11 h as an oral-available STING inhibitor possessing cellular mouse- or human-STING inhibiting IC50 of 8.8 or 11.5 nM. Compound 11 h markedly hindered the cellular STING cascade in both murine- and human-derived cells. Furthermore, 11 h achieved robust in vivo activity opposing MAS-2-caused systemic inflammatory damage and cisplatin-caused renal inflammation and injury. Proposed binding model of 11 h-STING indicates that 11 h engages the transmembrane area of STING.}, } @article {pmid41564770, year = {2026}, author = {Lee, H and Jo, Y and Jung, M and Lee, JH and Kim, TH and Lee, J and Kim, DJ and Rahmati, M and Smith, L and Pizzol, D and Son, Y and Park, J and Ahn, SH and Yon, DK and Choi, DW and Kang, J}, title = {Heavy metal exposure and all health outcomes: An umbrella review of meta-analyses.}, journal = {Journal of hazardous materials}, volume = {503}, number = {}, pages = {141141}, doi = {10.1016/j.jhazmat.2026.141141}, pmid = {41564770}, issn = {1873-3336}, mesh = {Humans ; *Environmental Exposure/adverse effects ; Meta-Analysis as Topic ; *Metals, Heavy/toxicity ; }, abstract = {We aimed to systematically evaluate the strength and credibility of evidence linking exposure to five major heavy metals, including arsenic, cadmium, lead, mercury, and chromium, with health outcomes (PROSPERO, CRD420251169899). Literature searches of PubMed/Embase, CINAHL, and Google Scholar up to April 20, 2025, identified meta-analyses of observational studies assessing these associations. Effect sizes were recalculated using random-effects models and expressed as equivalent odds ratios (eOR) with 95 % confidence intervals (CIs). The methodological quality of the included reviews was assessed using the AMSTAR2, and the credibility of associations was graded according to predefined criteria: Class I (convincing), Class II (highly suggestive), Class III (suggestive), Class IV (weak), and non-significant (NS). A total of 35 meta-analyses encompassing 103 health outcomes were included. Arsenic exposure was associated with melanoma (eOR 1.50 [95 % CI, 1.0-2.24], CE=IV), digestive cancers (1.23 [1.07-1.41], CE=III), gestational diabetes mellitus (1.47 [1.11-1.95], CE=III), hypertension (1.15 [1.06-1.24], CE=III), and preterm birth (1.12 [1.04-1.21], CE=III). Lead exposure showed significant associations with autistic disorder in children (12.70 [3.93-41.10], CE=IV), hearing loss (7.55 [6.69-8.53], CE=III), age-related eye disease (9.80 [1.72-55.85], CE=IV), and amyotrophic lateral sclerosis (1.46 [1.16-1.83], CE=III). Mercury exposure was linked to increased risk in membranous nephropathy (5.75 [1.54-21.44], CE=IV) and thyroid cancer (1.90 [1.55-2.33], CE=IV). Cadmium exposure was associated with renal cancer (1.47 [1.26-1.71], CE=II), cardiovascular disease (1.33 [1.05-1.69], CE=IV), stroke (1.36 [1.10-1.68], CE=III), diabetes mellitus (1.27 [1.07-1.52], CE=III), fracture risk (1.30 [1.13-1.49], CE=III), and age-related eye disease (113.26 [16.86-760.68], CE=III). Chromium exposure was associated with stomach cancer (1.28 [1.16-1.41], CE=I), supporting convincing evidence. Overall, exposures to these metals were consistently associated with diverse diseases across organ systems and life stages, suggesting proactive implications against heavy metal exposures.}, } @article {pmid41565003, year = {2026}, author = {Baek, Y and Lee, H and Park, ES and Park, M and Wee, Y and Kim, H and Roh, SH and Ha, NC}, title = {Structural Comparison of the Human G93A Mutant SOD1 to the Wild-type SOD1 Filaments.}, journal = {Journal of molecular biology}, volume = {438}, number = {6}, pages = {169642}, doi = {10.1016/j.jmb.2026.169642}, pmid = {41565003}, issn = {1089-8638}, mesh = {Humans ; *Superoxide Dismutase-1/genetics/chemistry/metabolism/ultrastructure ; Amyotrophic Lateral Sclerosis/genetics ; Mutation ; Cryoelectron Microscopy ; Animals ; Models, Molecular ; Mice ; Superoxide Dismutase ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by Cu, Zn-superoxide dismutase (SOD1) misfolding and aggregation, particularly in familial cases. The G93A mutation in SOD1, strongly associated with familial ALS, is widely studied in transgenic mouse models of the disease. In this study, we investigated the filament structure of the G93A mutant SOD1 using cryo-electron microscopy. The resulting fibrils consisted of a single protofilament with a left-handed helical twist, closely resembling those formed by wild-type (WT) SOD1 under identical conditions. Self- and cross-seeding experiments promoted filament formation in both WT and G93A mutant SOD1, compared to the no-seed condition. Notably, the G93A mutant exhibited significantly higher susceptibility to proteolysis in its native state than WT SOD1. Mass spectrometry analysis suggested that the structurally disordered electrostatic loop acts as a key common intermediate structure in filament formation for both WT and G93A mutant SOD1. These findings suggest that shared filament formation pathways underlie the aggregation of both WT and G93A mutant SOD1, providing new insights into the molecular mechanisms contributing to ALS pathogenesis.}, } @article {pmid41565302, year = {2026}, author = {Warita, H and Urushitani, M and Atsuta, N and Izumi, Y and Kano, O and Shimizu, T and Nakayama, Y and Narita, Y and Nodera, H and Fujita, T and Mizoguchi, K and Morita, M and Aoki, M}, title = {Addendum to the 2023 clinical practice guidelines for amyotrophic lateral sclerosis in Japan: approval and integration of novel disease-modifying therapies.}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {66}, number = {2}, pages = {67-73}, doi = {10.5692/clinicalneurol.cn-002198}, pmid = {41565302}, issn = {1882-0654}, mesh = {Humans ; Administration, Oral ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; Consensus ; *Drug Approval ; Drug Therapy, Combination ; Edaravone/administration & dosage ; Genetic Therapy ; Japan ; Oligonucleotides, Antisense/administration & dosage ; *Practice Guidelines as Topic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an intractable motor neuron disease characterized by progressive degeneration of motor neurons with varying degrees of frontotemporal lobe dysfunction. This English summary of the addendum to the Japanese clinical practice guidelines for ALS outlines major recent advances in pharmacological therapy in Japan. Following the development of the 2023 guidelines, three additional medications-oral edaravone, high-dose intramuscular mecobalamin, and tofersen-have been introduced. Oral edaravone, with its ease of administration, demonstrates pharmacokinetics comparable to the intravenous formulation. High-dose mecobalamin reduces functional decline when initiated early in the disease course. Tofersen, an antisense oligonucleotide, is the first gene-targeted therapy approved in Japan for patients with copper/zinc superoxide dismutase gene-related ALS, highlighting the importance of genetic testing and counseling in all ALS cases. This addendum provides updated expert consensus recommendations for the use, dosing, and monitoring of these therapies, while emphasizing the need for thorough communication about the ethical and psychological dimensions of genetic testing. It also addresses practical considerations for combination therapy, noting that up to three or four anti-ALS agents are now available in Japan. The long-term safety and efficacy of these therapies, as well as their potential synergistic or additive effects, remain to be clarified through real-world data and prospective registries. The objectives of this addendum are twofold: to present these advances and recommendations in English to foster international collaboration, and to inform the global ALS community about the latest therapeutic strategies in Japan. In addition, ongoing efforts to harmonize clinical evaluation standards and promote international clinical trials are highlighted, with the goal of improving patient outcomes and advancing ALS research worldwide.}, } @article {pmid41565509, year = {2026}, author = {Lee, NC and Lin, CH and Chien, YH and Hwu, WL}, title = {Genetic testing for adult-onset neurodegenerative diseases: A clinical perspective.}, journal = {Journal of the Formosan Medical Association = Taiwan yi zhi}, volume = {125 Suppl 1}, number = {}, pages = {S99-S104}, doi = {10.1016/j.jfma.2026.01.021}, pmid = {41565509}, issn = {0929-6646}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/diagnosis ; *Genetic Testing/methods ; High-Throughput Nucleotide Sequencing ; DNA Copy Number Variations ; Age of Onset ; Parkinson Disease/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Adult ; Alzheimer Disease/genetics/diagnosis ; Genetic Risk Score ; }, abstract = {Adult-onset neurodegenerative diseases (AOND), such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, severely affect patients' quality of life. Pathogenic single-nucleotide variations (SNVs) and small insertions and deletions (indels) can disrupt genes involving ANOD, and expansion of short tandem repeats such as trinucleotide repeats is an important etiology of hereditary ataxia. Variations in more than one gene combined to create polygenic risk scores (PRS) for multifactorial types of AOND. Recently, genome structural variations (SVs) like copy number variations (CNVs) and expansion of long repeats are increasingly identified as the etiologies of AOND. Tools for molecular diagnosis of AOND have evolved from Sanger sequencing to next-generation sequencing (NGS) such as short-read whole-exome sequencing (WES) and whole-genome sequencing (WGS), and long-read sequencing is especially helpful in solving SVs and expansions of long repeats. Patients might have affected and/or at-risk family members at the time of diagnosis, so genetic counseling for risk handling and birth planning need to be conducted with caution. This review will help readers to better understand the genetic testing for AOND.}, } @article {pmid41567979, year = {2025}, author = {Hamdalla, RH and Bhaskar, VB and Tian, C}, title = {Brain-derived extracellular vesicles potentially mediate crosstalk with peripheral organs in neurodegenerative diseases.}, journal = {Frontiers in cell and developmental biology}, volume = {13}, number = {}, pages = {1710150}, pmid = {41567979}, issn = {2296-634X}, support = {R01 HL153176/HL/NHLBI NIH HHS/United States ; }, abstract = {Brain-Derived Extracellular vesicles (BDEVs) are emerging mediators of intra- and interorgan communication in neurodegenerative diseases (NDs) such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). A growing body of evidence suggests that BDEVs play an important role in modulating intercellular communication within the central nervous system in the pathogenesis of many NDs. By transporting non-coding RNAs (e.g., miRNAs) and important pathological proteins, BDEVs also influence peripheral organs and contribute to the progression of disease in the central nervous system (CNS). This review extends the understanding of NDs beyond solely brain dysfunction and gives a novel framework for the progression of these diseases, uniquely emphasizing the currently underexplored mechanisms by which BDEV-mediated communication exacerbates or potentially initiates peripheral dysfunction or complications. It maps and clarifies the specific and potential mechanisms by which CNS-originating EV activity proliferates systemic dysfunction, presenting new opportunities and areas for therapeutic and diagnostic treatments for NDs. These findings are contextualized across multiple NDs, including Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and Multiple Sclerosis (MS), by incorporating data on dysregulated BDEV miRNAs and toxic proteins to map the pathway of BDEV-mediated disease spread.}, } @article {pmid41569095, year = {2026}, author = {Charbonnel, T and Richard, E and Dupuis, A and Palla, M and Vourc'h, P and Corcia, P and Al Ojaimi, Y and Blasco, H}, title = {The preclinical discovery and development of edaravone for the treatment of amyotrophic lateral sclerosis: what lessons have we learnt?.}, journal = {Expert opinion on drug discovery}, volume = {21}, number = {2}, pages = {147-160}, doi = {10.1080/17460441.2026.2619067}, pmid = {41569095}, issn = {1746-045X}, mesh = {*Edaravone/pharmacology/administration & dosage ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; Drug Discovery/methods ; Neuroprotective Agents/pharmacology/administration & dosage ; Drug Development/methods ; Mice, Transgenic ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/administration & dosage ; Oxidative Stress/drug effects ; Mice ; Blood-Brain Barrier/metabolism ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with limited therapeutic options. Among the few approved drugs, edaravone, a free radical scavenger developed originally for ischemic stroke, has attracted particular attention for its ability to counteract oxidative stress, a key driver of neurodegeneration. Its amphipathic structure and ability to cross the blood-brain barrier support its potential neuroprotective action.

AREAS COVERED: The authors discuss preclinical studies demonstrating edaravone's ability to reduce oxidative damage, preserve mitochondrial function, and modulate neuroinflammatory responses in ALS cellular and animal models. They discuss variations in dosage, timing, and disease models that produced heterogeneous results. In transgenic mice, edaravone may delay symptom onset and modestly extend survival, but these effects are inconsistent and often limited to early disease stages.

EXPERT OPINION: Clinically, edaravone provides modest benefits in a subset of patients, reflecting the translational gap between preclinical efficacy and clinical relevance. This case highlights broader challenges in ALS drug discovery, including limited model predictivity, methodological variability, and lack of patient stratification. The edaravone experience highlights key lessons for future neuroprotective approaches: the importance of standardized preclinical design, integration of human-based models, early pharmacokinetic validation, and biomarker-driven trials to advance precision neuroprotection in ALS.}, } @article {pmid41569660, year = {2026}, author = {Özkan, B and Ramge, JM and Wiesner, D and Scekic-Zahirovic, J and Antonucci, S and Nungeß, S and Gebauer, D and Ignatius, A and Weishaupt, JH and Haffner-Luntzer, M and Roselli, F}, title = {Reduced osteogenic factors and early osteoblast senescence in SOD1(G93A) ALS mouse model.}, journal = {JCI insight}, volume = {11}, number = {5}, pages = {}, pmid = {41569660}, issn = {2379-3708}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Osteoblasts/metabolism/pathology ; Mice ; Disease Models, Animal ; *Superoxide Dismutase-1/genetics/metabolism ; *Cellular Senescence/genetics ; *Osteogenesis/genetics ; Mice, Transgenic ; Humans ; X-Ray Microtomography ; Female ; Male ; Cell Differentiation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease. Emerging evidence suggests manifestations beyond the neuromuscular system. Bone alterations are part of the ALS clinical picture; it remains unclear whether they are secondary to muscle denervation or due to an autonomous process. We investigated skeletal involvement in the SOD1(G93A) mouse model at presymptomatic (P45) and symptomatic (P110) stages through biomechanical and transcriptomic approaches. Three-point bending revealed significant reductions in femoral rigidity and maximum bending force in SOD1 mutants at P45, indicating early structural deficits. Micro-CT analysis demonstrated reduced trabecular bone mineral density and thickness at P45, with progressive trabecular loss and cortical thinning by P110. Histological examination revealed marked osteoblast loss at P45, suggesting impaired bone formation as the primary early mechanism. Transcriptomics of bulk bone and cultured osteoblasts from P45 mice identified dysregulation of bone differentiation, including downregulation of osteoblast differentiation genes and upregulation of negative regulators of ossification and increased cell senescence signatures. Unfolded protein response was upregulated in SOD1 osteoblasts. Immunohistochemistry confirmed the senescence phenotype with increased p16Ink4a level in SOD1 osteoblasts. These findings suggest that bone deterioration precedes overt motor symptoms and is linked to osteoblast premature senescence.}, } @article {pmid41569987, year = {2026}, author = {Wang, WR and Liu, GD and Ren, DX and Liu, XY}, title = {Allostatic load in thyroid cancer is higher than that of other cancers: A secondary analysis using NHANES.}, journal = {PloS one}, volume = {21}, number = {1}, pages = {e0341063}, pmid = {41569987}, issn = {1932-6203}, mesh = {Humans ; *Thyroid Neoplasms/physiopathology/pathology ; Female ; Male ; Cross-Sectional Studies ; Middle Aged ; *Allostasis/physiology ; Nutrition Surveys ; Adult ; ROC Curve ; Aged ; Secondary Data Analysis ; }, abstract = {BACKGROUND: To compare the levels of allostatic load score (ALS) between thyroid cancer patients and patients with other types of cancer and explore whether ALS mediates the association between thyroid cancer and alterations in physiological function.

METHODS: This cross-sectional study conducted a secondary analysis of 181 cancer patients using NHANES data from 2007 to 2020, including 91 individuals with thyroid cancer. Generalized linear regression, logistic regression, and sensitivity analysis were used to analyze the association between thyroid cancer and ALS in three different models. Receiver operating characteristic (ROC) curve analysis and feature importance analysis were utilized to assess the clinical predictive value of thyroid cancer. We also conducted a series of mediation analyses to examine the mediating role of ALS.

RESULTS: The ALS in thyroid cancer patients was higher than that in other cancer types (P < 0.05). Thyroid cancer was significantly associated with ALS even after adjusting for demographic variables (β = 0.770, 95%CI: 0.315-1.480; OR=2.255, 95%CI: 1.111-4.575). This association remained robust to missing data (all P < 0.05) and was not confounded by drinking, diabetes, or thyroid disease (all P > 0.05). Although thyroid cancer had limited predictive value on ALS, it exerted strong explanatory power. The mediation analysis conducted with imputed data and adjusted for confounding variables revealed that ALS fully mediated the effect of thyroid cancer on red cell distribution width (RDW) (IE: β = 0.103, P = 0.008; DE: β = 0.389, P = 0.056), with a mediation proportion of 20.93%.

CONCLUSION: Our findings revealed that thyroid cancer condition were associated with elevated AL. AL mediated the relationship between thyroid cancer and RDW.}, } @article {pmid41570741, year = {2026}, author = {Genin, EC and Paquis-Flucklinger, V}, title = {ALS-related proteinopathies: From TDP-43 to mitochondrial proteinopathies.}, journal = {Current opinion in neurobiology}, volume = {97}, number = {}, pages = {103163}, doi = {10.1016/j.conb.2025.103163}, pmid = {41570741}, issn = {1873-6882}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Animals ; *Mitochondria/metabolism/pathology ; *Mitochondrial Proteins/metabolism ; *TDP-43 Proteinopathies/metabolism/pathology ; Superoxide Dismutase-1/metabolism ; RNA-Binding Protein FUS/metabolism ; *Mitochondrial Diseases/metabolism ; DNA-Binding Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons. ALS often overlaps clinically and pathologically with frontotemporal dementia (FTD), the second most common form of dementia. Like many neurodegenerative disorders, both ALS and FTD share a crucial pathological hallmark, the aggregation of misfolded proteins into insoluble inclusions in degenerating neurons. This process is referred to as proteinopathy. This review focuses on the proteinopathies associated with ALS, including aggregates of TDP-43, SOD1, FUS, and CHCHD10, which disrupt critical cellular processes such as RNA metabolism, mitochondrial function, and protein homeostasis. The review highlights to the identification of new types of mitochondrial and cytosolic aggregates linked to CHCHD10-related ALS. Although the precise pathological mechanisms remain to be fully elucidated, strategies aimed at restoring proteostasis and reducing protein aggregation may be promising therapeutic approaches for treating ALS, as they directly target fundamental pathogenic mechanisms.}, } @article {pmid41571168, year = {2026}, author = {Malvandi, AM and Gerosa, L and Maroni, P and Orlando, ME and Mohammadipour, A and Lombardi, G}, title = {miRNA-206 in muscle and central nervous system crosstalk during exercise: A double-edged sword with therapeutic potential.}, journal = {Neuroscience and biobehavioral reviews}, volume = {183}, number = {}, pages = {106569}, doi = {10.1016/j.neubiorev.2026.106569}, pmid = {41571168}, issn = {1873-7528}, mesh = {*MicroRNAs/metabolism ; Humans ; Animals ; *Muscle, Skeletal/metabolism ; *Exercise/physiology ; *Central Nervous System/metabolism ; *Brain/metabolism ; }, abstract = {Physical activity triggers complex molecular responses in skeletal muscle, with increasing evidence showing systemic signaling roles for muscle-derived microRNAs (myomiRs). Among these, miR-206 has attracted attention for its dual function: promoting muscle regeneration but potentially harming the central nervous system (CNS). This review examines how miR-206 expression is regulated during exercise and its effects on muscle biology-such as fiber-type specification, mitochondrial changes, and neuromuscular junction (NMJ) repair. It also explores the paradoxical effects of high miR-206 levels in the CNS, where it targets brain-derived neurotrophic factor (BDNF), reducing neuroplasticity and increasing vulnerability to neuropsychiatric and neurodegenerative diseases. The review highlights disease-specific aspects, showing miR-206 as harmful in Alzheimer's, stroke, and depression, but potentially protective in amyotrophic lateral sclerosis (ALS). We discuss its potential as a biomarker and therapeutic target, stressing tissue-specific regulation approaches. Overall, miR-206 plays a key role in muscle-brain communication, with important implications for exercise, aging, and CNS disorders.}, } @article {pmid41571758, year = {2026}, author = {Lacour, A and Vassallu, F and Romussi, S and Rayes, D and Igaz, LM}, title = {Cytoplasmic TDP-43 leads to early behavioral impairments without neurodegeneration in a serotonergic neuron-specific C. elegans model.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {6068}, pmid = {41571758}, issn = {2045-2322}, support = {PICT 2019-0480 (To DR)//Agencia Nacional de Promoción de la Ciencia y la Tecnología ANPCYT Argentina/ ; P40 OD010440/OD/NIH HHS/United States ; PIP No. 11220200101606CO (To DR)//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PGI: 24/B291 (To DR)//Universidad Nacional del Sur/ ; PICT 2019-1585 (To LMI)//Agencia Nacional de Promoción de la Ciencia y la Tecnología ANPCYT Argentina/ ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Serotonergic Neurons/metabolism/pathology ; Disease Models, Animal ; *Cytoplasm/metabolism ; Caenorhabditis elegans Proteins/metabolism/genetics ; Humans ; *Behavior, Animal ; Serotonin/metabolism ; Animals, Genetically Modified ; TDP-43 Proteinopathies/metabolism/genetics ; Fluoxetine/pharmacology ; }, abstract = {TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are marked by the pathological cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43), leading to progressive neuronal dysfunction and degeneration. To investigate the early functional consequences of TDP-43 mislocalization, we generated Caenorhabditis elegans models expressing either wild-type human TDP-43 or a variant with a mutated nuclear localization signal (ΔNLS), specifically in serotonergic neurons. These neurons were chosen because in C. elegans they regulate well-characterized behaviors, providing a straightforward readout of neuronal function. We found that expression of either TDP-43 variant impaired serotonin-dependent behaviors-including pharyngeal pumping, egg-laying, and locomotion slowing upon food encounter-with the cytoplasmic ΔNLS form causing more severe deficits. These behavioral impairments are evident even while the serotonergic neurons remain apparently normal in structure, suggesting that neuronal dysfunction precedes overt neurodegeneration. Moreover, the serotonergic HSN neurons that control egg-laying were also partially responsive to the selective serotonin reuptake inhibitor fluoxetine, suggesting that neurotransmitter release remains functional to some extent. Altogether, our findings demonstrate that TDP-43 expression causes neuronal dysfunction leading to behavioral deficits, even in the absence of detectable structural pathology and that its mislocalization to the cytoplasm results in more severe behavioral impairments. This C. elegans model provides a genetically tractable system to dissect early mechanisms of TDP-43-mediated neuronal dysfunction and to identify therapeutic strategies targeting predegenerative stages of ALS/FTD.}, } @article {pmid41571890, year = {2026}, author = {Lee, J and Lee, GR and Lee, HI and Kwon, M and Kim, T and Lee, JR and Lee, SY and Jeong, W}, title = {Rgnef regulates bone mass through the activation of RhoA and Rac1.}, journal = {Experimental & molecular medicine}, volume = {58}, number = {1}, pages = {243-253}, pmid = {41571890}, issn = {2092-6413}, support = {RS-2024-00357657//National Research Foundation of Korea (NRF)/ ; RS-2023-00217798//National Research Foundation of Korea (NRF)/ ; 2019R1A6C1010020//Korea Basic Science Institute (KBSI)/ ; RP-Grant 2022//Ewha Womans University (Ewha)/ ; }, mesh = {Animals ; *rac1 GTP-Binding Protein/metabolism ; *rhoA GTP-Binding Protein/metabolism ; Mice ; Osteoclasts/metabolism/cytology ; Osteogenesis ; Osteoblasts/metabolism/cytology ; NF-kappa B/metabolism ; *Guanine Nucleotide Exchange Factors/metabolism/genetics ; *Bone and Bones/metabolism ; Female ; Cell Differentiation ; Bone Resorption/metabolism ; Signal Transduction ; Mice, Knockout ; Mice, Transgenic ; Rho Guanine Nucleotide Exchange Factors/metabolism/genetics ; Neuropeptides ; }, abstract = {Rho guanine nucleotide exchange factor (Rgnef/p190RhoGEF), a RhoA-specific guanine nucleotide exchange factor, has been implicated in cancer and amyotrophic lateral sclerosis, but little is known about its role in bone. Here we investigate the roles of Rgnef in bone metabolism using Rgnef-deficient and overexpressing mice. Compared with littermate wildtype mice, Rgnef-deficient mice had increased bone mass owing to lower osteolysis and higher osteogenesis, and Rgnef-overexpressing transgenic mice had the opposite bone phenotype. Rgnef deficiency inhibited osteoclast formation and resorptive function and promoted osteoblast differentiation and mineralization, whereas Rgnef overexpression had the reverse effect. Mechanistically, Rgnef promotes osteoclastogenesis by enhancing the activity of nuclear factor kappa B (NF-κB), mitogen-activated protein kinases and AKT through the activation of RhoA and Rac1 and attenuates osteoblastogenesis through the RhoA/Rac1-mediated NF-κB activation. Moreover, Rgnef-deficient mice were protected from bone loss caused by lipopolysaccharide-induced inflammation or ovariectomy. Thus, Rgnef is a crucial regulator of bone metabolism and could serve as a potential new target for treating bone diseases.}, } @article {pmid41572285, year = {2026}, author = {Straczkiewicz, M and Burke, KM and Calcagno, N and Premasiri, A and Carney, KT and Vieira, FG and Onnela, JP and Berry, JD}, title = {Short prescribed exercises can quantify upper limb functioning in neurodegenerative disease.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {23}, number = {1}, pages = {28}, pmid = {41572285}, issn = {1743-0003}, mesh = {Humans ; *Upper Extremity/physiopathology ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology ; Female ; Accelerometry ; Longitudinal Studies ; Male ; *Exercise Therapy/methods ; Middle Aged ; Aged ; Digital Health ; Wearable Electronic Devices ; }, abstract = {BACKGROUND: Digital health technologies (DHTs) can quantify movements in daily routines but rely heavily on participant adherence over prolonged wear times.

METHODS: We analyzed accelerometry data from wrist-worn devices during short at-home episodes of prescribed exercises performed by 329 individuals living with amyotrophic lateral sclerosis (ALS) in a longitudinal study. We developed an automated and interpretable signal processing method to estimate four metrics describing exercise repetitions, i.e., their count, duration, intensity, and similarity. We examined their associations with time elapsed from enrollment and ALS Functional Rating Scale-Revised (ALSFRS-R) using linear mixed effect models. We also compared them with previously validated free-living metrics that require substantial sensor wear-time. Finally, we studied how many repetitions are sufficient to determine participants' upper limb functioning.

RESULTS: Three out of four exercise metrics (all but count) demonstrated significant association with ALSFRS-R outcomes. The duration of exercise repetitions increased, while intensity and similarity of movement decreased over time (all p-value < 0.001), indicating longer but less vigorous and less consistent upper limb movements over time. Exercise intensity was determined as the most robust exercise-based predictor of changes in upper limb function, and it was comparable to free-living metrics, which required at 21 h of sensor wear time (R-squared 0.899 vs. 0.860, respectively). Sensitivity analysis indicated that as few as five exercise repetitions were sufficient to yield statistically significant associations with ALSFRS-R.

CONCLUSIONS: These results suggest that prescribed exercise can effectively quantify upper limb function and track longitudinal decline comparably to free-living observation. The proposed method may serve as an alternative that decreases participation burden, increases study adherence, and extends diagnostic accessibility.}, } @article {pmid41572495, year = {2026}, author = {Zaman, A and Drake, SS and Fournier, AE}, title = {Extracellular Vesicle-Derived microRNAs as Fluid Biomarkers in Neurodegenerative Diseases: A Systematic Review.}, journal = {Journal of neurochemistry}, volume = {170}, number = {1}, pages = {e70323}, pmid = {41572495}, issn = {1471-4159}, support = {//MS Canada/ ; /CAPMC/CIHR/Canada ; //Fonds de Recherche du Québec - Santé/ ; //Myelin Repair Foundation/ ; //Fonds de recherche du Québec/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/genetics/cerebrospinal fluid/blood/metabolism ; *Extracellular Vesicles/metabolism/genetics ; *MicroRNAs/cerebrospinal fluid/metabolism/blood ; Biomarkers/cerebrospinal fluid/blood/metabolism ; Animals ; }, abstract = {Given the absence of curative treatments for neurodegenerative diseases, early detection and therapeutic intervention are critical to slowing disease progression. Extracellular vesicles (EVs) have emerged as promising biomarkers for neurodegeneration, owing to their accessibility in bodily fluids and dynamic molecular cargo, including microRNAs (miRNAs). The last decade has seen accumulating evidence for miRNA dysregulation in circulating EVs from people with neurodegenerative diseases; however, assessing reproducibility between studies remains challenging, largely due to clinical and methodological heterogeneity. In this systematic review, we comprehensively searched the MEDLINE database for studies investigating miRNA expression in biofluids from people with neurodegenerative diseases. We extracted miRNA expression data from 185 peer-reviewed publications, published until June of 2025, reporting altered miRNA levels in fluid-derived EVs from people with neurodegenerative diseases. We consolidated results between studies to identify the most frequently dysregulated miRNAs across diseases, with a focus on Alzheimer's disease, Parkinson's disease, mild cognitive impairment, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia, stroke, traumatic brain injury, and schizophrenia. Evaluating tissue specificity of frequently dysregulated miRNAs revealed enrichment of select miRNAs in the nervous system relative to blood and immune compartments. Summarizing miRNA regulation across biofluids emphasized consistencies between cerebrospinal fluid and plasma, but not serum. We highlight circulating miRNAs that may be reflective of neuropathology, including miR-143-3p, miR-127-3p, miR-9-5p, miR-15a-5p, and miR-125b-5p. Finally, we provide a repository of miRNA expression data from over 30 neurodegenerative conditions which can be exploited to further investigate miRNA regulation in diseases of interest.}, } @article {pmid41572578, year = {2026}, author = {She, JW and Lin, LA and Aerathupalathu Janardhanan, J and Wang, IC and Hsu, FC and Tseng, HS and Hsiao, YS and Yu, HH}, title = {Precision Channel Engineering of Nanotube-Embedded Organic Electrochemical Transistors for Ultrasensitive Neurofilament Light Chain Detection.}, journal = {ACS applied bio materials}, volume = {9}, number = {4}, pages = {2271-2281}, pmid = {41572578}, issn = {2576-6422}, mesh = {*Neurofilament Proteins/analysis ; *Electrochemical Techniques/instrumentation ; *Nanotubes/chemistry ; *Transistors, Electronic ; *Biosensing Techniques ; *Biocompatible Materials/chemistry/chemical synthesis ; Materials Testing ; Humans ; Particle Size ; }, abstract = {The quantitative monitoring of neurofilament light chain (Nf-L) is critical for the early diagnosis and prognosis of neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), yet achieving femtomolar sensitivity in a portable, label-free format remains a formidable challenge. Here, we report a high-performance organic electrochemical transistor (OECT) immunosensor engineered via the precise template-free electropolymerization of a dual-functional poly(EDOT-COOH-co-EDOT-EG3) copolymer. By systematically modulating the polymerization kinetics, we elucidated a decisive structure-function relationship governing biosensing efficacy: while microstructured channels formed at longer deposition times exhibited superior intrinsic transconductance due to maximized volumetric capacitance, the optimized nanotubular architecture provided the ideal balance of open porosity and accessible surface area. This specific nanotopography facilitated a significantly higher density of covalent antibody immobilization compared to its microstructured counterpart, thereby dominating the signal transduction mechanism through enhanced dielectric barrier formation upon antigen binding. Capitalizing on this morphology-governed sensitivity, the platform achieved a theoretical limit of detection (LOD) of 0.062 fg/mL (3σ criterion) and a rigorous LOD of 32.77 fg/mL (Hubaux-Vos method) across a broad dynamic range, along with exceptional selectivity and operational stability over 500 cycles. These findings underscore the critical role of precision channel engineering in bioelectronics, establishing a robust, lithography-free pathway for next-generation point-of-care diagnostics targeting diseases.}, } @article {pmid41572777, year = {2026}, author = {Liu, X and Lv, Z and Xu, G and Chen, Y and Liu, H and Xu, P}, title = {Investigating the Multiple Regulatory Mechanisms and Therapeutic Targets of PHLDA1 in Neurological Diseases.}, journal = {Current neuropharmacology}, volume = {24}, number = {8}, pages = {1206-1223}, pmid = {41572777}, issn = {1875-6190}, mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Transcription Factors/metabolism ; Signal Transduction/physiology ; }, abstract = {PHLDA1 (pleckstrin homology-like domain family A member 1) is a pleiotropic regulatory protein that affects key biological processes such as apoptosis, pyroptosis, immune inflammation, autophagy, metabolism, and oxidative stress. PHLDA1 plays a significant role in the pathological mechanisms of neurological diseases. This article systematically reviews the molecular characteristics of PHLDA1 and its core role in cerebrovascular diseases such as cerebral ischemia/ reperfusion injury, cerebral hemorrhage, subarachnoid hemorrhage, epilepsy, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Studies have shown that PHLDA1 promotes disease progression by regulating signalling pathways such as the NF-κB, MAPK, NLRP3 inflammasome, PPARγ, and Nrf2 pathways, thereby exacerbating neuroinflammation, mitochondrial dysfunction, endoplasmic reticulum stress, and pyroptosis in neurons. Its expression is regulated by the dynamic balance of miRNAs (such as miR-194 and miR-101), transcription factors (Egr1 and BHLHE40), and heat shock proteins (HSPs/HSF1). In addition, PHLDA1 has become a potential target for intervention in neurodegenerative and ischemic injuries by inhibiting FundC1-mediated mitochondrial autophagy, regulating microglial polarization, and activating TRAF6-dependent neuroinflammation. This article not only clarifies the pathogenic mechanism of PHLDA1 but also summarizes the relevant intervention strategies targeting PHLDA1, hoping to provide a corresponding theoretical basis and reference for the development of precision therapies for neurological diseases.}, } @article {pmid41573891, year = {2025}, author = {Gomberg, TA and Elmsaouri, S and Kopalle, HM and Baughn, MW and Beccari, MS and McAlonis-Downes, M and Artates, JW and Pant, D and Mak, H and Smargon, AA and Sander, TC and Garcia, E and Lee, DP and Cleveland, DW and Yeo, GW}, title = {Dual-targeting snRNA gene therapy rescues STMN2 and UNC13A splicing in TDP-43 proteinopathies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.01.691001}, pmid = {41573891}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by the selective deterioration of motor neurons in the central nervous system (CNS). A key driver of this pathogenesis is nuclear loss of ALS-associated protein TDP-43, leading to mis-splicing of TDP-43 targets including important neuronal genes STMN2 and UNC13A . Here, we have developed a gene therapy strategy for ALS and related TDP-43 proteinopathies, to correct mis-splicing of both STMN2 and UNC13A cryptic exons using small nuclear RNAs (snRNAs) encoded from a single vector. We identified promoter sequence elements to increase therapeutic snRNA expression by 10-fold, then further optimized the expression cassette with combinatorial snRNA targeting to rescue multiple cryptic splicing targets. The engineered snRNAs restored normal pre-mRNA processing of both STMN2 and UNC13A transcripts despite TDP-43 loss of function, rescuing stathmin-2 protein levels in iPSC derived motor neurons, restoring their axonal regeneration capacity to wild-type levels. In addition, adeno-associated virus (AAV) delivery of the snRNAs to the murine central nervous system in the constitutive cryptic splicing model Stmn2 [HumΔGU] fully restored cortical Stmn2 pre-mRNA processing, highlighting the utility of snRNAs as a therapeutic modality in vivo . Together, this study demonstrates that snRNAs are a promising and versatile therapeutic strategy for the simultaneous correction of multiple aberrant transcripts affected by cryptic splicing in TDP-43 proteinopathies.}, } @article {pmid41574092, year = {2026}, author = {Khurana, S and Gourie-Devi, M and Vats, Y and Verma, S and Ganguly, NK and Chugh, P and Sharma, A and Khanna, L and Dhawan, U and Taneja, V}, title = {Clinical and genetic determinants of survival in amyotrophic lateral sclerosis patients from North India.}, journal = {Brain communications}, volume = {8}, number = {1}, pages = {fcag003}, pmid = {41574092}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration, with significant clinical and genetic variability. While the role of genetic factors is well-established in ALS pathogenesis, their impact on survival outcomes remains poorly understood, particularly in the Indian population. We performed whole-exome sequencing in 159 ALS patients from North India (familial = 2, sporadic = 157). Clinical parameters, including age at onset, site of onset, sex, family history and survival, were recorded. Males exhibited shorter survival than females, but did not achieve statistical significance (median: 48 versus 60 years, P = 0.05). Bulbar-onset patients developed ALS at a significantly older age (mean: 59.7 versus 54 years, P = 0.007) and experienced poorer survival outcomes than spinal-onset patients (median: 48 versus 60 months, P = 0.03). A small subset of ALS patients (6.3%, n = 10) had very long survival duration of more than 10 years. We identified 102 genetic variants in 92 ALS patients, of which 45 variants were novel. According to American College of Medical Genetics and Genomics guidelines, 13.5% of total variants were pathogenic, 19.8% were likely pathogenic, and 66.7% were variants of uncertain significance. The presence of genetic variations was significantly associated with delayed onset (mean: 53.4 versus 57.1 years, P = 0.049) and diminished life expectancy (median: 48 versus 60 months, P = 0.029). Variations in more than one gene were detected in 16.7% of the patients, supporting the theory of oligogenic basis for ALS. After adjusting for age at onset, increased risk of mortality was associated with males [hazard ratio = 1.740, 95% confidence interval (CI) = 1.105-2.740] and rare genetic variations (hazard ratio = 1.533, 95% CI = 1.001-2.350). Furthermore, bulbar onset (hazard ratio = 1.75, 95% CI = 1.11-2.75) was found to be a negative prognostic factor for survival. Our study provides valuable insights into the genetic complexity and its impact on clinical outcomes in ALS patients of North Indian origin.}, } @article {pmid41575675, year = {2026}, author = {Kopalli, SR and Wankhede, N and Rahangdale, SR and Sammeta, S and Aglawe, M and Koppula, S and Taksande, B and Upaganlawar, A and Umekar, M and Kale, M}, title = {Age-driven dysbiosis: gut microbiota in the pathogenesis and treatment of aging disorders.}, journal = {Biogerontology}, volume = {27}, number = {1}, pages = {42}, pmid = {41575675}, issn = {1573-6768}, mesh = {Humans ; *Dysbiosis/microbiology/therapy ; *Aging/physiology ; *Gastrointestinal Microbiome/physiology ; Probiotics/therapeutic use ; Animals ; *Nervous System Diseases/microbiology/therapy ; Fecal Microbiota Transplantation ; }, abstract = {Aging, a complex physiological and molecular process, has undergone significant changes, of which gut microbiome composition has surfaced as an important key in the maintenance of neurological health. Recent studies have revealed the significant impact of age-related gut dysbiosis in the induction of neuroinflammation, metabolic syndrome, disruptions in gut-brain axis, and age-related neurological decline. Although significant studies have revealed the impact of the microbiome-gut-brain axis in individual neurological diseases, an aging-focused holistic synthesis has not yet been adequately developed. This review provides a critical assessment of the involvement of age-related dysbiosis of gut microbiota in the development and progression of neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cognitive aging of the elderly, and to focus on age-related microbial patterns and mechanisms of dysbiosis related to neurological aging, including inflammation and immune system dysregulation, metabolic changes, oxidative stress, barrier dysfunction, and gut-brain communication through enteroendocrine, enteric neural, and vagal mechanisms, and to emphasize disease-specific and common microbial patterns of dysbiosis and beneficial and harmful microbial roles in aging diseases. This review assesses some of the latest promising therapies aimed at the microbiota, such as probiotics, prebiotics, dietary therapies, fecal microbiota transplantation, as well as pharmacological therapies, and critically discusses their limitations in terms of interindividual variability and their generalisation and applicability. Focusing on mechanistic, comparative, and translation aspects, this review offers a comprehensive approach to neurological aging due to gut microbiota and identifies gaps for future precision microbiome-based interventions.}, } @article {pmid41577086, year = {2026}, author = {Mercadante, S and Petronaci, A and Casuccio, A}, title = {Clinical Changes in Patients With Amyotrophic Lateral Sclerosis Admitted to a Home Care Program.}, journal = {Journal of pain and symptom management}, volume = {71}, number = {4}, pages = {560-566}, doi = {10.1016/j.jpainsymman.2025.12.026}, pmid = {41577086}, issn = {1873-6513}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/psychology ; *Home Care Services ; *Palliative Care/methods ; Female ; Male ; Aged ; Middle Aged ; Italy ; Advance Care Planning ; Longitudinal Studies ; Symptom Burden ; }, abstract = {BACKGROUND: There is a lack of information in the literature about patients with amyotrophic lateral sclerosis (ALS) followed at home.

AIM: To characterize ALS patient demographics, longitudinal symptom trajectories, cognition, healthcare utilization, and advance care planning of an Italian home-based palliative care program cohort.

METHODS: New patients with ALS who required home palliative care were recruited for a period of one year and followed up for six months. Demographics, Karnofsky, ALS subtype, date of diagnosis, awareness, as well as ECAS (Edinburgh Cognitive and Behavioral ALS Screen) were recorded, as well as the date of diagnosis and initiation of home palliative care were collected. The use of noninvasive ventilation (NIV), mechanical ventilation by tracheostomy, gastrostomy, nasogastric tube, parenteral nutrition, were recorded at admission and during home care assistance. The existence of advance directives and shared advance care planning (ACP) was also collected. The ALS Functional Rating Scale-Revised (ALS-FRS-R) and symptom burden was measured by Edmonton Symptom Assessment System (ESAS) were measured at two-month intervals for six months.

RESULTS: Data from 34 consecutive patients with ALS admitted to palliative home care were analyzed over the period considered. While Karnofsky level significantly decreased, ECAS did not show significant changes. The need for vital supports, particularly NIV, increased over time. Only one patient provided an ACP decision at admission, and none provided a living will. The involvement of a legal administrator facilitated the use of ACP significantly over the six months. Seven patients died at home during the first six months of home palliative care, and one patient was lost to follow-up, because they were transferred to another region. No patient was admitted to hospice in the first six months of home palliative care.

CONCLUSION: In patients with ALS admitted to home palliative care Karnofsky level, total ESAS and ALS-FRS-R score slowly but significantly decreased over six months. Only six patients died within this period. The use of NIV increased over time. No patient required hospital or hospice admission. ACP and living wills were minimal, although ACP rate increased during the study period. The program enabled patients to remain in their homes, reducing the need for hospital care.}, } @article {pmid41577334, year = {2026}, author = {Berner, KJ and Mese, PO and Bowblis, JR and Applebaum, R}, title = {The Prevalence and Impact of Vaccination Programs: Differences Between Nursing Homes and Assisted Living Communities.}, journal = {Journal of the American Medical Directors Association}, volume = {27}, number = {3}, pages = {106107}, doi = {10.1016/j.jamda.2025.106107}, pmid = {41577334}, issn = {1538-9375}, mesh = {Humans ; *Nursing Homes/statistics & numerical data ; *Assisted Living Facilities/statistics & numerical data ; *Immunization Programs/statistics & numerical data ; Ohio ; Prevalence ; COVID-19/prevention & control/epidemiology ; Female ; Hospitalization/statistics & numerical data ; }, abstract = {OBJECTIVES: To compare the prevalence of vaccination programs between nursing homes (NHs) and assisted living communities (ALs) and examine how these programs relate to perceived hospitalization risk and temporary admission suspensions due to outbreaks.

DESIGN: Descriptive analysis of facility-level survey data from the 2023 Ohio Biennial Survey of Long-Term Care Facilities, which has a >90% response rate.

SETTING AND PARTICIPANTS: All licensed NHs and ALs in Ohio were surveyed and answered questions related to vaccination programs (n = 736; n = 623).

METHODS: Three measures were analyzed: presence of a vaccination program for 7 vaccine-preventable illnesses [influenza; COVID-19; respiratory syncytial virus (RSV); pneumococcal; hepatitis B; shingles; and tetanus, diphtheria, and pertussis (Tdap)], perceived risk of transferring residents to the hospital for these illnesses, and temporary suspension of admissions due to outbreaks. All measures were binary and sample averages were calculated separately for NHs and ALs. Facility characteristics associated with COVID-19-related admission suspensions were compared.

RESULTS: NHs had a higher prevalence of vaccination programs for all 7 vaccine-preventable illnesses compared with ALs. The largest differences were observed for RSV, pneumococcal, hepatitis B, shingles, and Tdap. ALs reported higher perceived risk of transferring residents to the hospital for all illnesses, whereas NHs reported the highest perceived risk for respiratory illnesses. Temporary admission suspensions due to outbreaks were uncommon; when reported, they were primarily associated with COVID-19. Facilities with COVID-19-related suspensions were more likely to be smaller and not-for-profit/government owned. NHs with outbreaks were more often located in rural areas, and ALs with outbreaks were more often located in urban areas.

CONCLUSIONS AND IMPLICATIONS: Significant disparities exist in vaccination program implementation between NHs and ALs. Expanding vaccination programs in ALs may reduce hospitalization risk and strengthen outbreak prevention. Targeted policy efforts, improved education, and resource allocation are needed to ensure equitable access to comprehensive vaccination programs across long-term care settings.}, } @article {pmid41578918, year = {2026}, author = {Silva, ST and de Queiroz Aquino, LM and Aires, DN and de Souza, AA and de Macedo, JVB and da Silva Teixeira, S and de Melo, LP and de Macedo Borges, LRD and Lindquist, ARR and de Medeiros Valentim, RA and Ribeiro, T}, title = {Pain and fatigue in amyotrophic lateral sclerosis: a multiple methods study.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {5}, pages = {555-564}, pmid = {41578918}, issn = {1758-2032}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/epidemiology ; *Fatigue/etiology/therapy/epidemiology ; Cross-Sectional Studies ; *Pain/etiology/epidemiology ; Brazil ; Female ; Male ; Middle Aged ; Retrospective Studies ; Prospective Studies ; Physical Therapy Modalities ; Aged ; Adult ; Pain Management ; }, abstract = {INTRODUCTION: Pain and fatigue are frequent symptoms in individuals with Amyotrophic Lateral Sclerosis (ALS) and the literature is controversial regarding the effectiveness of physiotherapy practices for managing these symptoms.

OBJECTIVE: To analyze the profile of pain and fatigue symptoms in a Brazilian sample with ALS and identify physiotherapy practices.

METHODS: A multimethods study composed of prospective cross-sectional design and systematic retrospective design. Data on pain and fatigue were collected and literature searches were conducted and risk of bias (PEDRro scale) and evidence quality (SIGN system) were evaluated.

RESULTS: The sample (72 individuals) had a mean score of 4.31 (pain) and 37.2 (fatigue), indicating moderate levels of symptoms. The systematic review identified various physiotherapy practices for treating pain and fatigue.

CONCLUSION: Prospective analysis of pain and fatigue profiles in individuals with ALS in Brazil revealed moderate levels of both symptoms. The systematic retrospective analysis indicated uncertainty regarding the effect of physiotherapy.}, } @article {pmid41579294, year = {2026}, author = {Foffani, G and Urso, D and Hiller, J and Piccininni, M and Marin, B and Logroscino, G}, title = {The multistep pathogenic hypothesis of amyotrophic lateral sclerosis is incompatible with the epidemiological data.}, journal = {European journal of epidemiology}, volume = {41}, number = {1}, pages = {1-13}, pmid = {41579294}, issn = {1573-7284}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/etiology ; Female ; Incidence ; Bayes Theorem ; Male ; Middle Aged ; Aged ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease whose incidence increases with age. According to the gene-time-environment hypothesis, ALS onset occurs through the interaction between genes and environmental exposures during ageing, which may involve a continuous accumulation process. Alternatively, the multistep pathogenic hypothesis, based on the Armitage-Doll multistep model from cancer research, posits that a discrete number of specific sequential "hits" are necessary to trigger ALS. Here we analyzed three large population-based epidemiological datasets of ALS to formally test whether the ALS age-incidence curve is better described by a power law, as predicted by the Armitage-Doll model, or by an exponential function, which is generally associated to continuous accumulation of damage and is incompatible with the Armitage-Doll model. We obtained moderate-to-extreme Bayesian evidence in favor of the exponential function compared to the power law. Cancer data were instead better aligned, as expected, with the power law. These results suggest that the multistep pathogenesis hypothesis based on the Armitage-Doll model cannot be extended from cancer to ALS, because it is incompatible with the epidemiological data. This calls for a re-consideration of the current understanding of ALS pathogenesis. Our work also warns against extending the Armitage-Doll multistep model from cancer to other aging-related diseases solely based on age-incidence curves.}, } @article {pmid41579663, year = {2026}, author = {Casabona, E and Cusato, J and Clari, M and Albanesi, B and Cattaneo, D and Giulio, PD and Dimonte, V}, title = {Association between anticholinergic burden scales and recurrent falls in independently living older adults: a cross-sectional study.}, journal = {Geriatric nursing (New York, N.Y.)}, volume = {69}, number = {}, pages = {103853}, doi = {10.1016/j.gerinurse.2026.103853}, pmid = {41579663}, issn = {1528-3984}, mesh = {Humans ; *Accidental Falls/statistics & numerical data/prevention & control ; Cross-Sectional Studies ; *Cholinergic Antagonists/adverse effects/therapeutic use ; Female ; Aged ; Male ; *Independent Living ; Aged, 80 and over ; Recurrence ; }, abstract = {This study examined the association between medications with anticholinergic (ACh) activity and the risk of falls in community-dwelling older adults enrolled in a home monitoring service. A cross-sectional design was applied, and logistic regression analyses were adjusted for age, sex, comorbidities, and functional status. The sample included 84 participants who had experienced at least one fall, of whom 72.6% were single fallers and 27.4% recurrent fallers (≥2 falls in 12-months of observation). Participants were divided into two groups: those taking medications (n = 55) and those not on medication (n = 29). A total of 126 falls were reported, with no significant difference in the number of falls between the two groups. The prevalence of ACh burden, assessed using ten different scales, ranged from 5.4% to 30.9% among fallers. Within the medication group, no significant differences were observed in the presence of ACh burden (≥1) between single and recurrent fallers. However, recurrent fallers in this group (n = 15) had higher scores on some scales compared with single fallers. Despite this, the discriminative ability of the ACh burden scales for identifying recurrent fallers were limited, with several, particularly the ALS and CrAS scales, failing to reach acceptable thresholds. After adjustment, the AAS scale suggested that older adults were over nine times more likely to experience recurrent falls compared with a single fall (OR=9.24; 95% CI 1.02-77.49; p = 0.004). Overall, these findings highlight the limited clinical utility of current ACh burden scales in supporting medication review as part of fall prevention strategies for older adults.}, } @article {pmid41579806, year = {2026}, author = {Sarwar, S and Mehmood, T and Iqbal, M}, title = {Advanced spectral modeling for bacterial strains: A MARS-PLS2 approach with Lasso regularization and baseline optimization.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {351}, number = {}, pages = {127506}, doi = {10.1016/j.saa.2026.127506}, pmid = {41579806}, issn = {1873-3557}, mesh = {Least-Squares Analysis ; *Bacteria/chemistry/classification ; Spectroscopy, Fourier Transform Infrared ; Spectrophotometry, Infrared/methods ; Algorithms ; }, abstract = {The natural characteristics of the infrared spectroscopic data are that it tends to distort the baseline, there is high-dimensionality and non-linear correlation that hinder reliable prediction of biochemical properties. To overcome these obstacles, this study introduces an integrated MARS-PLS2-Lasso framework that incorporates the effective baseline correction, non-linear regression, latent variable extraction, and sparse variable selection to promote the chemometric modeling accuracy and interpretability. Out of four baseline correction methods, viz. Asymmetric Least Squares (ALS), AirPLS, Polynomial fitting, and Wavelet baseline correction, the Wavelet method (sym8, Level 5) was found to be the most successful, in that it was able to represent local spectral variation with low-frequency noise. This technique achieved high predictive accuracy with RMSE = 0.2846-0.6857, MAE = 0.2371-0.5445 and MSE = 0.0810-0.4705 specifying both high model fit and minimal residual error across bacterial spectra. The Wavelet-corrected spectra revealed six key functional regions that contributed most significantly to bacterial differentiation: 720cm[-1] to 750cm[-1] (C-Cl stretching, CH bending), 1000cm[-1] to 1300cm[-1] (C-O stretching, esters, carboxylic acids), 1500cm[-1] to 1650cm[-1] (CC stretching), 1687cm[-1] to 1793cm[-1] (CO stretching, conjugated carbonyls), 2771cm[-1] to 3143cm[-1] (CH stretching, alkanes, alkenes), 3290cm[-1] to 3595cm[-1] (O-H and NH stretching). Vibrational domains of interest are biochemical components of lipids, proteins, amides and polysaccharides that determine the structural integrity and metabolic activity of bacteria. The proposed MARS-PLS2-Lasso model leverages Multivariate Adaptive Regression Splines (MARS) to capture nonlinear relationships through adaptive basis functions, while Partial Least Squares (PLS2) extracts latent components that maximize covariance between spectral predictors and multiple bacterial responses. Lasso regularization adds sparsity to the model and reduces the complexity of the model, as well as penalizes less interesting basis functions, which overfit the model. Such a combination is used to provide a reasonable approximation of the parameter even in high-dimensional spectral data. In general, MARS-PLS2-Lasso provides a sound, interpretable, and chemically consistent way of high dimensional infrared spectral modeling. It is highly predictive, less noisy and has a more adequate manner of interpreting spectral-biochemical interactions, and thus, a bright way of bacteria modeling, spectral diagnostics and further use in bio-analytical spectroscopy.}, } @article {pmid41579929, year = {2026}, author = {Murakami, K and Sudou, N and Kurata, A and Kawaguchi-Niida, M}, title = {An ALS-associated mutant SOD1 protein can be eliminated in microglia culture by selective autophagy.}, journal = {Neuroscience}, volume = {598}, number = {}, pages = {47-58}, doi = {10.1016/j.neuroscience.2026.01.017}, pmid = {41579929}, issn = {1873-7544}, mesh = {Animals ; *Microglia/metabolism/pathology ; *Autophagy/physiology ; Superoxide Dismutase-1/metabolism ; *Superoxide Dismutase/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Mutation ; Spinal Cord/pathology/metabolism ; Mice, Transgenic ; Mice ; Cell Line ; Humans ; Cells, Cultured ; }, abstract = {The acquired toxicity of the familial amyotrophic lateral sclerosis (ALS)-associated mutant Zn-superoxide dismutase 1 (SOD1) protein has been implicated in motoneuron death, and cytosolic aggregates or inclusions have been observed in the cytoplasm of motoneurons, astrocytes, and neuronal axons but not in that of microglia. This study elucidates the mechanisms by which mutant SOD1 does not aggregate in and is cleared by microglia. We generated pcDNA3-Venus-tagged SOD1 constructs: wild-type SOD1 and mutant SOD1 were used as controls, and the A4V, D90A, and G93A SOD1 mutants were used as disease-related constructs; these plasmids were introduced into the Ra2 microglia line for subsequent evaluation. In spinal cords collected from postsymptomatic G93A mice, very little aggregation of the mutant SOD1 protein was detected in microglia, consistent with previous reports. Our new findings, which were based on immunohistochemical, Western blot, and enzyme immunoassay analyses, revealed that the protein expression of mutant SOD1 in microglia is significantly lower than that of wild-type SOD1. Furthermore, we observed the recovery of mutant SOD1 protein levels in autophagy suppression experiments and its colocalization with WDFY3, a selective autophagy-related protein. These in vitro results demonstrate that only the mutant SOD1 protein (i.e., not wild-type SOD1) is degraded by selective autophagy. Furthermore, we found that both wild-type and mutant SOD1 are secreted directly from microglia. These findings provide an opportunity to elucidate the precise mechanism through which microglia manage mutant SOD1 proteins during the pathological process of ALS and are likely to lead to improvements in ALS treatment strategies.}, } @article {pmid41581145, year = {2026}, author = {McCourt, B and Lemr, K and Chakrabarti, S and Woidke, E and Ramaiah, S and Singh, V and Sangwan, N and Brown, JM and Cominelli, F and Rodriguez-Palacios, A and Burberry, A}, title = {C9orf72 in myeloid cells prevents an inflammatory response to microbial glycogen.}, journal = {Cell reports}, volume = {45}, number = {2}, pages = {116906}, pmid = {41581145}, issn = {2211-1247}, support = {R01 AG085316/AG/NIA NIH HHS/United States ; P30 DK097948/DK/NIDDK NIH HHS/United States ; R00 AG057808/AG/NIA NIH HHS/United States ; K99 AG057808/AG/NIA NIH HHS/United States ; R03 AG080175/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Glycogen/metabolism ; Humans ; Amyotrophic Lateral Sclerosis/microbiology/metabolism/pathology/genetics ; *Inflammation/pathology/metabolism ; *C9orf72 Protein/metabolism/genetics ; Mice ; *Myeloid Cells/metabolism ; Brain/metabolism ; Male ; Gastrointestinal Microbiome ; }, abstract = {Gut dysbiosis and neural inflammation occur in patients with amyotrophic lateral sclerosis (ALS), including those with a causal mutation in chromosome 9 open reading frame 72 (C9ORF72). How gut commensals interact with common ALS genotypes to impart risk of neural degeneration remains unclear. Here, we identify 10 phylogenetically diverse bacterial strains that promote cytokine release in a C9orf72-dependent manner. Metatranscriptomics implicated the glycogen biosynthesis pathway as a driver of inflammation. Colonization of germ-free C9orf72-deficient mice with Parabacteroides merdae that produced inflammatory glycogen enhanced monocytosis, blood-brain barrier breakdown, and T cell infiltration into the central nervous system. Enzymatic digestion of glycogen in the gut promoted survival of C9orf72-deficient mice and dampened microglial reactivity in the brain. A survey of human fecal samples demonstrated that inflammatory forms of glycogen were present in gut contents from 15/22 patients with ALS, 1/1 patient with C9ORF72 frontotemporal dementia (FTD), and 4/12 healthy controls. Together, the results of this work identify bacterial glycogen as a modifiable mediator of immune homeostasis in the gut and brain.}, } @article {pmid41581503, year = {2026}, author = {Hung, ST and Linares, GR and Chang, WH and Eoh, Y and Krishnan, G and Mendonca, S and Hong, S and Shi, Y and Santana, M and Kueth, C and Macklin-Isquierdo, S and Perry, S and Duhaime, S and Maios, C and Chang, J and Perez, J and Couto, A and Lai, J and Li, Y and Alworth, SV and Hendricks, E and Wang, Y and Zlokovic, BV and Dickman, DK and Parker, JA and Zarnescu, DC and Gao, FB and Ichida, JK}, title = {PIKFYVE inhibition mitigates disease in models of diverse forms of ALS.}, journal = {Cell}, volume = {189}, number = {3}, pages = {987-992}, doi = {10.1016/j.cell.2026.01.004}, pmid = {41581503}, issn = {1097-4172}, support = {R01 NS091546/NS/NINDS NIH HHS/United States ; }, } @article {pmid41581940, year = {2026}, author = {Behera, P and Rangappa, N and Chandrashekar, M and Mishra, A and Chinnathambi, S and Mishra, M}, title = {The multifaceted role of antimicrobial peptides in neurodegeneration: Insights from Drosophila and beyond.}, journal = {Advances in protein chemistry and structural biology}, volume = {149}, number = {}, pages = {419-444}, doi = {10.1016/bs.apcsb.2025.08.003}, pmid = {41581940}, issn = {1876-1631}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/immunology/pathology/metabolism ; *Antimicrobial Peptides/immunology/metabolism ; Drosophila ; *Antimicrobial Cationic Peptides/immunology ; }, abstract = {Antimicrobial peptides (AMPs) are tiny proteins essential for innate immunity in various taxa, including mammals and insects. They provide defence against a wide range of pathogens, including bacteria, viruses, fungi, and parasites. Apart from their antimicrobial properties, new studies have revealed the roles of AMPs in brain ageing, neurodegeneration, and neuroinflammation. With an emphasis on their dysregulation in glial and neuronal tissues and their role in neuroinflammation, mitochondrial dysfunction, and neuronal loss, we reviewed the new function of AMPs beyond their antimicrobial activity. Findings from Drosophila models of Huntington's disease, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Ataxia-telangiectasia show that immune pathways, like Toll and immune deficiency, drive persistent or ectopic AMP expression, which is similar to the inflammatory processes seen in human neurodegenerative diseases. Furthermore, the dual function of AMPs as mediators of sterile inflammation and protective immunological agents reveals a universal paradox. The translational relevance of these findings is further supported by comparisons with human AMPs, such as LL-37 and β-defensins. LL-37 and β-defensins levels were found to be increased in the cerebrospinal fluid of patients suffering from meningitis. LL-37 is released from neurons and activates glial cells, boosting the production of inflammatory cytokines and decreasing neuronal survival. This chapter redefines AMPs as not only sentinels of microbial defence but also as important participants in preserving or disturbing brain homeostasis by establishing them as a link between immunity and neurobiology.}, } @article {pmid41582437, year = {2026}, author = {Chen, X and Cao, Z and Liang, X and Zhao, T and Wang, Y}, title = {TRIM9 and TRIM26 Interact with UBQLN2[P497H] to Modulate Its Proteasomal Degradation.}, journal = {ACS chemical biology}, volume = {21}, number = {2}, pages = {230-234}, pmid = {41582437}, issn = {1554-8937}, support = {R35 ES031707/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Ubiquitin-Protein Ligases/metabolism ; *Proteasome Endopeptidase Complex/metabolism ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Tripartite Motif Proteins/metabolism ; *Cell Cycle Proteins/metabolism/genetics ; Proteolysis ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; HEK293 Cells ; Mutation ; Protein Binding ; Autophagy-Related Proteins ; Nerve Tissue Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. ALS-linked mutations in UBQLN2 promote protein aggregation and disrupt proteostasis, yet the mutation-specific protein interactomes and their functional relevance remain poorly defined. We employed APEX2 proximity labeling, together with affinity enrichment of biotinylated peptides and LC-MS/MS analysis, to profile the interactomes of wild-type UBQLN2 and two ALS-linked variants, UBQLN2[P497H] and UBQLN2[P497S]. We identified 785 unique biotinylated proteins, many of which exhibit augmented enrichment in the proximity proteomes of the two mutants over wild-type UBQLN2. Notably, the E3 ubiquitin ligases TRIM9 and TRIM26 were selectively enriched in the proximity proteome of UBQLN2[P497H], which we validated by coimmunoprecipitation followed by Western blot analysis. Fractionation analysis revealed coaccumulation of TRIM9 and TRIM26 with UBQLN2[P497H] in the insoluble fraction, consistent with its heightened aggregation propensity. Treatment of UBQLN2[P497H]-expressing cells with a proteasomal inhibitor led to elevated accumulation of a C-terminal UBQLN2 fragment that is absent in cells expressing wild-type UBQLN2 or its P497S mutant. Individual knockdown of TRIM9 and TRIM26 significantly increased the abundance of the fragment, establishing UBQLN2[P497H] as a substrate for TRIM9- and TRIM26-mediated ubiquitinylation and subsequent proteasomal degradation. These findings nominate TRIM9 and TRIM26 as specific interactors of UBQLN2[P497H] and as regulators of a previously underexplored C-terminal UBQLN2 fragment, suggesting that impaired clearance of this species may contribute to ALS pathogenesis.}, } @article {pmid41582654, year = {2026}, author = {Long, C and Horty, LG}, title = {Synthesis of Florasulam Stable Isotopes to Enable Identification of Degradants by Mass Spectrometry for Re-registration Studies.}, journal = {Journal of labelled compounds & radiopharmaceuticals}, volume = {69}, number = {2}, pages = {e70005}, doi = {10.1002/jlcr.70005}, pmid = {41582654}, issn = {1099-1344}, mesh = {*Food Safety ; *Herbicides/analysis/chemical synthesis/chemistry ; Isotope Labeling ; Europe ; *Weed Control/legislation & jurisprudence/methods ; *Pyrimidines/analysis/chemical synthesis/chemistry ; *Sulfonamides/analysis/chemical synthesis/chemistry ; Mass Spectrometry ; Chemistry Techniques, Synthetic ; Edible Grain/chemistry ; }, abstract = {Florasulam is a triazolopyrimidine herbicide that controls broadleaf and grass weeds in cereal crops and turf. It acts as an acetolactase synthase (ALS) inhibitor, blocking the synthesis of essential amino acids required for plant growth. Due to its potency, florasulam is effective at very low application rates making it cost-effective with reduced environmental off-target effects. As is common practice, florasulam has been subject to periodic reviews by regulatory agencies during re-registration requirements since its introduction into the market in 1998. The goal of these reviews is to ensure that the herbicide carries out its intended use without creating adverse side effects to humans and the environment. Since scientific methods are continually evolving and being developed, global regulatory agencies can require additional studies to address data gaps for pesticide renewals. During this re-registration process for florasulam, new environmental fate studies were conducted to meet new European Food Safety Authority (EFSA) guidelines. Consequently, florasulam-[triazole([13]C,[15]N2)] and florasulam-[phenyl([13]C6)] stable isotopes were synthesized to support the re-registration process.}, } @article {pmid41583004, year = {2025}, author = {Hu, Z and Wan, JJ and Yan, QQ and Fan, Y and Liu, J}, title = {Exploring rare coding variants in UK biobank: preliminary associations with motor neuron disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1735522}, pmid = {41583004}, issn = {1663-4365}, abstract = {INTRODUCTION: Previous studies have illuminated a significant genetic component in motor neuron disease (MND) pathogenesis, with several causative genes identified. However, a substantial proportion of MND cases remain genetically unexplained, particularly regarding the comprehensive contribution of rare, high-impact variants across the exome.

METHODS: Leveraging whole-exome sequencing data from nearly half a million UK Biobank participants, we systematically investigated the association between high-confidence protein-truncating variants (HC PTVs) and MND risk in a Caucasian subset. Our large-scale gene-based association analysis utilized REGENIE software and LOFTEE-defined HC PTVs.

RESULTS: We identified significant preliminary associations between HC PTVs in 14 genes and an increased risk of MND. Notably, while NEK1 has been previously implicated in ALS, the remaining 13 genes (BLVRB, KLHL32, RIMS2, DYDC2, DCBLD1, ANXA4, COMP, TRIM42, ANO4, NFX1, CFAP206, CKAP2L, and ANGPTL4) show preliminary associations as novel candidate loci for the disease. Functional enrichment analyses further indicated that these genes are significantly involved in critical biological pathways, including collagen-containing extracellular matrix organization and ciliary function. Furthermore, tissue specificity analysis highlighted a strong enrichment of these genes' expression in brain regions, with the hypothalamus showing the highest specificity.

DISCUSSION: These findings suggest a potential expansion of the known genetic landscape of MND, and highlight novel biological pathways implicated in its pathogenesis. This study underscores the power of large-scale population genetics in uncovering critical disease mechanisms and offers new avenues for mechanistic research and therapeutic development for MND, pending independent validation.}, } @article {pmid41583923, year = {2026}, author = {Gonzalez, M and Lato, TJ and Alonzo, EA and Park, S and Green, MT and Soto-Rodriguez, N and Shaw, BF}, title = {Does sod1 encode a molecular clock? Mutations that mimic asparagine deamidation inhibit heterodimerization with ALS-mutant SOD1.}, journal = {RSC chemical biology}, volume = {7}, number = {3}, pages = {473-484}, pmid = {41583923}, issn = {2633-0679}, support = {R01 EY036371/EY/NEI NIH HHS/United States ; }, abstract = {The self-exchange of subunits by protein homodimers is a common protein-protein interaction in vivo. In heterozygous genetic disorders involving homodimeric gene products, both mutant and WT proteins can exchange subunits (heterodimerize). This form of heterodimerization can be analytically challenging to study. In this paper, we used capillary electrophoresis to investigate how deamidation of multiple asparagine residues (to aspartate) in homodimeric Cu, Zn superoxide dismutase-1 (SOD1) affected the rate and free energy of heterodimerization between WT and mutant SOD1 that cause amyotrophic lateral sclerosis (ALS). To model asparagine deamidation, Asn to Asp substitutions were introduced at five Asn residues predicted to undergo the most rapid deamidation in SOD1 (N26D, N131D, N139D, N65D, N19D). This model of penta-deamidated SOD1 did not heterodimerize with WT SOD1 or E100K SOD1 (linked to ALS). In contrast, the quad-variant N26D/N131D/N139D/N19D SOD1 did heterodimerize. These results suggest that the WT SOD1 protein has an intrinsic "timer" or "molecular clock" (as spontaneous Asn deamidation has been described) that effectively stops its heterodimerization after the SOD1 protein has existed in solution for ∼3 months.}, } @article {pmid41583971, year = {2018}, author = {Lawson, V and Robbins, NM}, title = {The Potential Misdiagnosis of Multifocal Motor Neuropathy as Amyotrophic Lateral Sclerosis-A Case Series.}, journal = {US neurology}, volume = {14}, number = {2}, pages = {102-107}, pmid = {41583971}, issn = {1758-4000}, support = {K23 NS042713/NS/NINDS NIH HHS/United States ; }, abstract = {Multifocal motor neuropathy (MMN) is a rare neuropathy that is often treatable with immunomodulatory therapy if diagnosed early. However, accurate diagnosis is difficult due to a significant overlap of symptoms with other neurological conditions, such as amyotrophic lateral sclerosis (ALS). Evidence of immunoglobulin M (IgM) anti-ganglioside GM1 antibodies and electrodiagnostic findings of conduction block are useful diagnostic criteria for MMN but are not universal findings. This review explores the differential diagnosis of MMN and ALS and discusses three cases of MMN initially diagnosed as ALS, in which the correct diagnosis allowed effective treatment. These cases highlight the need for greater awareness of MMN among physicians.}, } @article {pmid41585268, year = {2025}, author = {Srivastav, J and Sharma, S}, title = {Viral and non-viral cellular therapies for neurodegeneration.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1718669}, pmid = {41585268}, issn = {2296-858X}, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive loss of neurons and still lack curative treatment options. In this review, we describe current and developing therapeutic strategies that include viral vector-based gene delivery, antisense oligonucleotide (ASO) and RNA interference methods, stem cell transplantation, and genome editing technologies. Adeno-associated viruses (AAVs) and lentiviruses have been used for gene delivery in preclinical and clinical studies, while ASOs are under development to reduce expression of pathogenic proteins such as tau, α-synuclein, and mutant huntingtin. Cellular therapies, including mesenchymal stem cell (MSC)-based paracrine support and transplantation of neurons derived from induced pluripotent stem cells (iPSCs), are being evaluated, particularly in PD and AD. We also discuss important gene targets such as APOE4, GBA1, SCNA, and MAPT, and how treatment strategies may differ between monogenic and polygenic forms of these disorders. Lastly, we highlight recent efforts focused on genes like TREM2, PINK1, and progranulin, and examine their role in the future development of gene- and cell-based interventions.}, } @article {pmid41585784, year = {2026}, author = {Jilani, SB and Ashok, N and Bomble, YJ and Guss, AM and Olson, DG}, title = {Engineering Clostridium thermocellum for production of 2,3-butanediol from cellulose.}, journal = {Metabolic engineering communications}, volume = {22}, number = {}, pages = {e00269}, pmid = {41585784}, issn = {2214-0301}, support = {P20 GM113132/GM/NIGMS NIH HHS/United States ; }, abstract = {Clostridium thermocellum is a promising host for consolidated bioprocessing due to its ability to directly ferment cellulose into fuels and chemicals. However, natural product formation in this organism is limited. Here, we report engineering C. thermocellum for the production of 2,3-butanediol (23BD), a valuable industrial chemical. We functionally expressed a thermophilic 23BD pathway in this organism resulting in a 23BD titer of 19.7 mM from cellulose, representing a metabolic yield of 24%. We used a cell-free systems biology approach to identify limiting steps in the 23BD pathway, revealing that exogenous 23BD dehydrogenase (BDH) activity was essential for production, while native acetolactate synthase (ALS) and acetolactate decarboxylase (ALDC) activities were present but limiting in the parent strain. This approach also revealed redox balance limitations. We demonstrated that this improved understanding of redox balance limitations could be used to increase 23BD titer in vivo, showing that adding acetate could be used to increase 23BD yield. This work establishes a foundation for developing C. thermocellum into a robust platform for 23BD production directly from cellulose and highlights the utility of cell-free systems for guiding metabolic engineering in non-model organisms.}, } @article {pmid41586107, year = {2025}, author = {Berthiaume, AA and Kleist, KN and Reda, SM and Setti, SE and Wu, W and Johnston, JL and Taylor, RW and Stein, LR and Church, KJ}, title = {ATH-1105 mitigates multiple pathologies in ALS models both alone and in combination with riluzole.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1582765}, pmid = {41586107}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration, muscle atrophy, and paralysis. The complexity of ALS pathology, driven by factors such as TDP-43 pathology, excitotoxicity, and neuroinflammation, has hindered therapeutic development. While riluzole (an anti-excitotoxic agent) is the current standard treatment, additional therapeutics are needed to address the broad spectrum of ALS-related pathology. ATH-1105, a small-molecule positive modulator of hepatocyte growth factor (HGF) signaling, has shown promise in preclinical models of ALS. Given the multifactorial nature of ALS and the growing recognition that combination approaches may represent the best treatment options, we investigated the therapeutic potential of ATH-1105 in a TDP-43-driven mouse model of ALS, by comparing and combining it with the known efficacious treatment of riluzole. Additionally, we characterize the mechanism by which ATH-1105 induces neuroprotective effects, emphasizing its effects on TDP-43 pathology.

METHODS: In vivo, the impact of daily oral treatment with ATH-1105, alone and in combination with riluzole, was evaluated in Prp-TDP43[A315T] hemizygous transgenic ALS mice. In vitro, the impact of ATH-1105 on TDP-43-related pathology was assessed in rat primary spinal motor neurons subjected to glutamate toxicity. To demonstrate target engagement, the neuroprotective effects of ATH-1105 were assessed via siRNA-mediated knockdown of MET (HGF receptor).

RESULTS: In vivo, ATH-1105 significantly improved neuromuscular function and reduced body weight loss, neurodegeneration, inflammation, and TDP-43 phosphorylation. The combination of ATH-1105 with riluzole led to greater therapeutic effects than either treatment alone. In vitro, the neuroprotective effects of ATH-1105 were shown to be associated with MET activation in motor neurons, which was confirmed via siRNA-mediated knockdown of MET. In motor neurons subjected to glutamate toxicity, ATH-1105 reduced extranuclear and phosphorylated TDP-43, and increased GSK3β phosphorylation (inactivation), a kinase involved in TDP-43 pathology. Additionally, ATH-1105 reduced the abnormal increase in autophagic proteins following glutamate toxicity.

DISCUSSION: Our study underscores the therapeutic potential of ATH-1105 in treating ALS, both as a standalone treatment and in combination with riluzole. ATH-1105 demonstrates neuroprotective effects that slow neuromuscular deterioration in a relevant mouse model, aligning with the need to counteract the neurodegeneration central to ALS.}, } @article {pmid41586560, year = {2026}, author = {Muñoz-Rugeles, L and Alvarez-Idaboy, JR and Espinosa Rincón, N and Mejía-Ospino, E}, title = {Chemical repair of oxidized aromatic amino acids by monohydroxylated 2-pyridones.}, journal = {The Journal of chemical physics}, volume = {164}, number = {4}, pages = {}, doi = {10.1063/5.0307155}, pmid = {41586560}, issn = {1089-7690}, mesh = {Oxidation-Reduction ; *Pyridones/chemistry ; *Amino Acids, Aromatic/chemistry ; Tyrosine/chemistry ; Kinetics ; Density Functional Theory ; *Antioxidants/chemistry ; }, abstract = {The oxidative modification of tryptophan and tyrosine residues in proteins has been strongly associated with the onset and progression of neurodegenerative disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis. Consequently, the identification of small molecules capable of repairing these oxidized residues is of considerable medicinal interest. In this study, the antioxidant activity of four hydroxy-2-pyridones against tyrosyl and tryptophanyl radicals was investigated in silico using density functional theory, with the aim of elucidating their structure-activity relationships at the molecular level. Thermochemical analyses were conducted to evaluate the most favorable repair pathways, focusing on formal hydrogen transfer (FHT) and single electron transfer (SET) processes. For exergonic reactions, kinetic parameters were determined within the quantum mechanics-based overall free radical scavenging activity (QM-ORSA) protocol, providing predictive data on radical-scavenging efficiency. The results indicate that three of the tested pyridones can repair the tyrosyl radical and that two of them react at rates comparable with the dityrosine formation, thereby competing with this deleterious pathway. In contrast, all four pyridones are able to reduce the tryptophanyl radical, although the calculated kinetics suggest that they may not efficiently suppress the Trp-Trp cross-linking in small peptides. Mechanistic analysis further revealed that FHT proceeds through proton-coupled electron transfer for tyrosyl radical repair, whereas tryptophanyl radical repair involves a proton-electron sequential transfer mechanism. These findings establish hydroxy-2-pyridones as promising scaffolds for the rational design of neuroprotective antioxidants and provide molecular insights that may guide the development of new therapeutic agents targeting oxidative stress.}, } @article {pmid41586932, year = {2026}, author = {Ma, H and Liu, M and Yang, J and Li, J and He, A and Li, M and Guan, W and Shi, J and Teng, J}, title = {Lipid Metabolic Mediators Bridge Ischemic Heart Disease and Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {396}, pmid = {41586932}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; *Lipid Metabolism/genetics/physiology ; *Myocardial Ischemia/metabolism/genetics ; Mendelian Randomization Analysis ; MicroRNAs/metabolism/genetics ; Sphingomyelins/blood ; }, abstract = {While epidemiological studies have linked cardiovascular disease (CVD) and amyotrophic lateral sclerosis (ALS), the causal pathways remain unclear. This study aims to clarify the causal relationship between CVD and ALS, with a focus on lipid metabolism as a potential mediator. We conducted a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between CVD and ALS. Furthermore, we utilized mediation MR, summary-data-based MR analysis (SMR), the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) pathway analysis, miRNA interaction prediction analysis, and protein-protein interaction (PPI) studies to validate the mediating effect of lipid metabolism on the risk of CVD and ALS onset, as well as to predict potential signaling pathways and mechanisms. The MR analysis revealed a significant association between CVD, particularly IHD, and an increased risk of ALS. Mediation analysis indicated that the level of sphingomyelin (d34:0) in serum may mediate the effect of IHD on ALS, along with the identification of seven additional types of plasma metabolites. Furthermore, KEGG and GO analyses highlighted lipid metabolism pathways, including "cholesterol metabolism" and the "phospholipid metabolic process." Additionally, miRNA interaction prediction analysis identified MFGE8 as a potential therapeutic target. Our study identifies IHD as a vascular risk factor for ALS, driven by lipid metabolic dysregulation. The identification of sphingomyelin (d34:0) and MFGE8 as key mediators in lipid metabolic dysregulation offers potential preventive and therapeutic strategies for CVD patients at elevated risk of ALS.}, } @article {pmid41587040, year = {2026}, author = {Tanaka, H and Black, LE and Forrest, SL and Danics, K and Sadia, N and Khodadadi, M and Tator, C and Smith, DH and Tartaglia, MC and Stewart, W and Kovacs, GG}, title = {Spinal Cord Tau and Protein Copathologies Associated With Chronic Traumatic Encephalopathy.}, journal = {JAMA neurology}, volume = {83}, number = {3}, pages = {231-241}, pmid = {41587040}, issn = {2168-6157}, support = {RF1 NS138030/NS/NINDS NIH HHS/United States ; U01 NS137500/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *tau Proteins/metabolism ; Male ; Female ; *Chronic Traumatic Encephalopathy/pathology/metabolism ; Case-Control Studies ; Aged ; *Spinal Cord/pathology/metabolism ; Middle Aged ; Retrospective Studies ; alpha-Synuclein/metabolism ; DNA-Binding Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; Autopsy ; Brain/pathology/metabolism ; }, abstract = {IMPORTANCE: Exposure to repetitive head impacts (RHI) is associated with increased risk of a range of neurodegenerative diseases, including Alzheimer disease and amyotrophic lateral sclerosis. However, while the protein pathologies in the brains of individuals with the RHI-associated pathology of chronic traumatic encephalopathy (CTE) are well described, the spinal cord pathology in at-risk individuals remains poorly understood.

OBJECTIVE: To evaluate spinal cord pathologies associated with RHI exposure or CTE neuropathologic change (CTE-NC) in the brain.

This case-control study of a retrospective autopsy series (June 2019 to August 2025) was performed among autopsied individuals who served as RHI-exposed cases or controls in a multicenter brain bank collaboration. Data analysis was performed from January 2024 to November 2025.

EXPOSURES: RHI history and CTE-NC presence.

MAIN OUTCOMES AND MEASURES: Informant-reported clinical history as well as symptoms and immunohistochemistry for phosphorylated tau (p-tau), phosphorylated TAR DNA-binding protein 43 (p-TDP-43), α-synuclein, and amyloid-β (Aβ), as well as amyloid precursor protein and human leukocyte antigen DR.

RESULTS: Of 70 autopsied individuals (62 male, 8 female; mean [SD] age, 64.40 [13.94] years), 20 showed CTE-NC in the brain. All cases with CTE-NC exhibited spinal cord p-tau deposits, especially in cases aged 65 years or older with prior RHI (n = 14), often showing extensive spinal tau pathology as both neuronal (all 14 cases) and astrocytic (12 of 14 cases [86%]) p-tau deposits. Spinal p-tau pathology was associated with microglial activation and motor symptoms. Notably, among the individuals with CTE-NC and prior RHI who were aged 65 years or older, additional spinal protein pathologies were present, comprising p-TDP-43 inclusions (9 of 14 cases [64%]), Aβ deposits (13 of 14 cases [93%]), and α-synuclein deposits (7 of 14 cases [50%]), with all 4 of these pathologies present in 4 individuals (29%). In total, across all 20 CTE-NC cases, p-TDP-43 inclusions were confined to the spinal cord in 5 of the 10 individuals with spinal p-TDP-43 pathology. In contrast, among 50 individuals without CTE-NC, typically sparse p-tau deposits were seen in only 27 (54%). Among the 23 confirmed cases with a history of RHI, 16 (70%) exhibited CTE-NC, while 7 (30%) did not. Spinal tau pathology was more severe in those with CTE-NC; however, astrocytic tau pathology was also present in the group without CTE-NC, unlike in controls without RHI or CTE.

CONCLUSIONS AND RELEVANCE: This case-control study provides autopsy evidence of a high prevalence of complex spinal pathology in individuals with CTE-NC, supporting the concept of trauma-related encephalomyelopathy. The frequent co-occurrence of p-TDP-43, Aβ, and α-synuclein pathologies in individuals aged 65 years or older with CTE-NC suggests that cumulative trauma might contribute to widespread misfolded protein aggregation.}, } @article {pmid41588209, year = {2026}, author = {Hou, M and Xie, X and Hu, J and Rominger, A and Shi, K and Xiao, L and Tang, Y and Hu, S}, title = {Systemic brain-body metabolic coupling patterns in amyotrophic lateral sclerosis: a whole-body [[18]F] fluorodeoxyglucose PET/CT study across clinical phenotypes.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {53}, number = {6}, pages = {3936-3950}, pmid = {41588209}, issn = {1619-7089}, support = {81801740//National Natural Science Foundation of China/ ; 82272045//National Natural Science Foundation of China/ ; 2023LNJJ16//Clinical Research Foundation of the National Clinical Research Center for Geriatric Diseases(XIANGYA)/ ; 2022M723561//China Postdoctoral Science Foundation/ ; 2024JJ2094//Science Fund for Distinguished Young Scholars of Hunan Province/ ; grant number:Z2023004//National Key Clinical Specialty Scientific Research Project/ ; 2021RC4056//Science and Technology Innovation Program of Hunan Province/ ; CEIEC-2022-ZM02-0219//Key Program of Ministry of Industry and Information Technology of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; *Fluorodeoxyglucose F18 ; *Positron Emission Tomography Computed Tomography ; *Whole Body Imaging ; Male ; Phenotype ; Female ; *Brain/metabolism/diagnostic imaging ; Middle Aged ; Aged ; Radiopharmaceuticals ; Case-Control Studies ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both central and peripheral systems. Its marked heterogeneity and variable prognosis suggest pathophysiology beyond motor neuron degeneration. This study aimed to map brain–body metabolic networks using whole-body [18F]FDG PET/CT, characterize systemic remodeling, and to identify clinically meaningful brain-organ coupling axes and peripheral prognostic markers (lung, small intestine, cervical cord, intrinsic spinal muscles), providing imaging candidates for phenotype-informed stratification and hypothesis generation for future multimodal studies. METHODS: We enrolled 121 ALS patients and 83 controls who underwent whole-body [18F]FDG PET/CT. Standardized uptake value ratios (SUVr), mean Standardized uptake value (SUVmean), and maximum Standardized uptake value (SUVmax) were extracted from brain regions and 11 peripheral organs. Interregional metabolic correlation networks were constructed, and subgroup analyses were performed according to King's stage, progression rate, site of onset, genetic mutations, and non-motor symptoms (NMS). Associations between metabolic alterations and survival were examined using longitudinal follow-up. RESULTS: Compared to controls, ALS patients exhibited hypometabolism in the frontal lobe and motor cortex, but hypermetabolism in the posterior cingulate and parahippocampal regions. Peripheral alterations included increased metabolism in the liver, spleen, thoracic spinal cord, and spinal muscles, as well as reduced metabolism in the lungs. Brain–body network analysis revealed that advanced King's stages were associated with strengthened brain–heart metabolic coupling. Rapid progression subtypes exhibited enhanced brain-spinal cord coupling and concomitant hypometabolism in the small intestine and thoracic spinal cord. Bulbar-onset ALS demonstrated increased cardiac metabolism but reduced brain–heart coupling. Patients with genetic mutations or NMS exhibited disrupted brain–body co-variation. In unadjusted analyses, survival analysis demonstrated that lung and intestinal hypometabolism and hypermetabolism in the intrinsic spinal muscles and cervical spinal cord were significantly associated with poor prognosis; after Benjamini–Hochberg false discovery rate correction, only intrinsic spinal muscle SUVr remained significant. CONCLUSION: ALS is a systemic disorder characterized by widespread remodeling of brain–body metabolic networks. Whole-body [18F]FDG PET/CT enables the detection of multi-organ metabolic abnormalities and uncovers inter-system coupling mechanisms, offering biomarkers for stratification, prognosis prediction, and individualized management.}, } @article {pmid41588556, year = {2026}, author = {Wei, Z and Wang, R}, title = {Vanadium Nitride Decorated Graphene With Abundant Active Sites as Chemical Anchor of Polysulfides and Redox Catalysts in Aluminum Sulfur Batteries for Enhanced Performance.}, journal = {ChemSusChem}, volume = {19}, number = {2}, pages = {e202501845}, pmid = {41588556}, issn = {1864-564X}, abstract = {Aluminum-sulfur (Al-S) batteries are garnering significant interest as candidates for affordable energy storage systems due to their high theoretical capacity of 1672 mAh g[-1] and the cost-effectiveness of naturally abundant aluminum and sulfur. Nevertheless, challenges such as poor cyclic reversibility and limited practical capacity have resulted in only a few reversibly operating Al-S cells to date. In this study, we introduce an improved Al-S battery configuration by incorporating a novel VN@graphene catalyst into the sulfur cathode in Al-S battery applications. Comprehensive electrochemical tests and ex situ characterizations reveal that, during discharge, the catalyst effectively suppresses the polysulfide shuttle effect through strong adsorption, whereas during charging, it enhances sulfide redox kinetics. Consequently, the modified Al-S cell delivers an initial capacity of approximately 1354 mAh g[-1], maintaining around 507 mAh g[-1] after 200 cycles.}, } @article {pmid41588889, year = {2026}, author = {Thakur, A and Chowdhury, KR and Kumar, A and Sharma, VV and Bhatia, R}, title = {Targeting Non-coding RNAs in Neurodegeneration: Advances in Therapeutic RNA Modalities and Next-Gen Delivery Technologies.}, journal = {Current Alzheimer research}, volume = {23}, number = {4}, pages = {245-269}, pmid = {41588889}, issn = {1875-5828}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/genetics ; *RNA, Untranslated/therapeutic use/genetics ; Animals ; MicroRNAs ; *Genetic Therapy/methods ; Drug Delivery Systems ; }, abstract = {Non-coding RNA (ncRNA)-based therapies represent an emerging and transformative approach in the treatment of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)/Motor Neuron Disease (MND). This review explored the potential for targeting microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, reinforced by promising results from clinical trials demonstrating their capacity to modulate disease pathways. The incorporation of cutting-edge computational methodologies, including RNA structure prediction and gene regulatory network analysis, has been at the forefront in enhancing the efficacy of ncRNA-based treatments. Moreover, chemical methods have improved RNA molecules' stability, accuracy, and directed delivery, enhancing their therapeutic effects. Moreover, cutting-edge RNA editing technologies like Clustered Regularly Interspaced Short Palindromic Repeats/CRISPRassociated protein 13 (CRISPR/Cas13) are advancing our ability to directly manipulate ncRNA expression, offering a powerful avenue for addressing the molecular origins of neurodegeneration. Despite these advances, challenges persist, particularly in ensuring the specificity, delivery efficiency, and long-term efficacy of these treatments. Nanotechnology provides innovative solutions to these obstacles, facilitating more efficient and precise RNA delivery, especially to neuronal tissue. In conclusion, ncRNA-based therapies, while still in nascent stages, represent a hopeful frontier in the fight against NDs. With ongoing research and technological advancements, these therapies could not only halt disease progression but also redefine the future of ND treatment, offering new avenues for patients' care and clinical success.}, } @article {pmid41589677, year = {2026}, author = {Ozkan, A and Padmanabhan, HK and Shipman, SL and Azim, E and Kumar, P and Sadegh, C and Basak, AN and Macklis, JD}, title = {Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {41589677}, issn = {2050-084X}, support = {R01 NS049553/NS/NINDS NIH HHS/United States ; NS045523/NS/NINDS NIH HHS/United States ; R01 NS045523/NS/NINDS NIH HHS/United States ; DP1 NS106665/NS/NINDS NIH HHS/United States ; NS049553/NS/NINDS NIH HHS/United States ; Regeneration Project Fellowship//McKnight Brain Research Institute/ ; }, mesh = {Animals ; Mice ; *Cell Differentiation ; *Neurons/physiology ; *SOXD Transcription Factors/metabolism/genetics ; *Proteoglycans/metabolism ; Chondroitin Sulfate Proteoglycan 4 ; *Cerebral Cortex/cytology ; *Pyramidal Tracts/cytology/physiology ; Nerve Tissue Proteins/metabolism/genetics ; *Neural Stem Cells/physiology/metabolism ; Neurogenesis ; Basic Helix-Loop-Helix Proteins ; }, abstract = {Corticospinal neurons (CSN) centrally degenerate in amyotrophic lateral sclerosis (ALS), along with spinal motor neurons, and loss of voluntary motor function in spinal cord injury (SCI) results from damage to CSN axons. For functional regeneration of specifically affected neuronal circuitry in vivo, or for optimally informative disease modeling and/or therapeutic screening in vitro, it is important to reproduce the type or subtype of neurons involved. No such appropriate in vitro models exist with which to investigate CSN selective vulnerability and degeneration in ALS, or to investigate routes to regeneration of CSN circuitry for ALS or SCI, critically limiting the relevance of much research. Here, we identify that the HMG-domain transcription factor Sox6 is expressed by a subset of NG2+ endogenous cortical progenitors in postnatal and adult cortex, and that Sox6 suppresses a latent neurogenic program by repressing proneural Neurog2 expression by progenitors. We FACS-purify these progenitors from postnatal mouse cortex and establish a culture system to investigate their potential for directed differentiation into CSN. We then employ a multi-component construct with complementary and differentiation-sharpening transcriptional controls (activating Neurog2, Fezf2, while antagonizing Olig2 with VP16:Olig2). We generate corticospinal-like neurons from SOX6+/NG2+ cortical progenitors and find that these neurons differentiate with remarkable fidelity compared with corticospinal neurons in vivo. They possess appropriate morphological, molecular, transcriptomic, and electrophysiological characteristics, without characteristics of the alternate intracortical or other neuronal subtypes. We identify that these critical specifics of differentiation are not reproduced by commonly employed Neurog2-driven differentiation. Neurons induced by Neurog2 instead exhibit aberrant multi-axon morphology and express molecular hallmarks of alternate cortical projection subtypes, often in mixed form. Together, this developmentally-based directed differentiation from cortical progenitors sets a precedent and foundation for in vitro mechanistic and therapeutic disease modeling, and toward regenerative neuronal repopulation and circuit repair.}, } @article {pmid41589772, year = {2026}, author = {Zhu, J and Wen, T and Gao, N and Wu, B and Ma, M and Sun, X and Liu, F and Lin, P and Liu, S}, title = {Elevated Serum SIRT2 Is Associated With Rapid Progression and Cognitive Impairment in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {73}, number = {5}, pages = {781-787}, doi = {10.1002/mus.70162}, pmid = {41589772}, issn = {1097-4598}, support = {2020M672067//the China postdoctoral science foundation/ ; NSFC82001354//National Natural Science Foundation of China/ ; 2025CXPT133//Key R&D Program of Shandong Province, China/ ; Z-2017-24-2509//Yantu Neuroscience Specialized Research Fund Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/complications/psychology ; *Sirtuin 2/blood ; Female ; Male ; Disease Progression ; Middle Aged ; Cross-Sectional Studies ; Aged ; Biomarkers/blood ; *Cognitive Dysfunction/blood/etiology ; Cohort Studies ; Enzyme-Linked Immunosorbent Assay ; Adult ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) lacks reliable biomarkers to predict disease trajectories or guide therapeutic strategies. Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase implicated in cytoskeletal destabilization and neuroinflammatory pathways in preclinical ALS models, represents a promising yet unvalidated biomarker candidate. We aimed to translate preclinical findings by validating SIRT2's role in ALS.

METHODS: A cross-sectional cohort study was conducted, comparing serum SIRT2 levels, measured via enzyme-linked immunosorbent assay (ELISA), between 182 ALS patients and 65 healthy controls. Clinical progression rates were derived from the ALS Functional Rating Scale-Revised (ALSFRS-R), and cognitive function was assessed using the Mini-Mental State Examination (MMSE) and Edinburgh Cognitive and Behavioral ALS Screen (ECAS).

RESULTS: SIRT2 levels were significantly elevated in ALS patients versus controls, though diagnostic accuracy was modest (AUC = 0.620). Furthermore, SIRT2 levels showed a weak but significant positive correlation with disease progression rate (r = 0.182, p = 0.014) and inverse correlations with cognitive scores on both MMSE (r = -0.250, p = 0.032) and ECAS (r = -0.286, p = 0.031). Notably, SIRT2 demonstrated a limited but detectable ability to stratify patients into fast- and slow-progressing subgroups (AUC = 0.635).

DISCUSSION: These findings provide preliminary clinical evidence linking elevated serum SIRT2 to disease progression and cognitive impairment in ALS, thereby supporting its role in disease heterogeneity. This work lends clinical support to preclinical insights, suggesting SIRT2 may aid in prognosis prediction and may represent a potential therapeutic target, necessitating further studies.}, } @article {pmid41591303, year = {2026}, author = {Zhang, Y and Liu, Y and Yao, Z and Lai, H and Chen, X and Wang, Z and Bao, Y and Li, T and Zhou, X and Chen, X and Yang, P}, title = {Alphaviral Capsid Proteins Inhibit Stress Granule Assembly via Competitive RNA Binding With G3BP1.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {20}, pages = {e17009}, pmid = {41591303}, issn = {2198-3844}, support = {2025YFC3409700//National Key Research and Development Project of China/ ; 2025JCXK02//Interdisciplinary Research Project of Hangzhou Normal University/ ; 2025M772812//China Postdoctoral Science Foundation/ ; 32470733//National Natural Science Foundation of China/ ; 32170696//National Natural Science Foundation of China/ ; WU2022A002//Center of Synthetic Biology and Integrated Bioengineering of Westlake University/ ; }, mesh = {*RNA Recognition Motif Proteins/metabolism/genetics ; *Stress Granules/metabolism ; *Poly-ADP-Ribose Binding Proteins/metabolism/genetics ; *Semliki forest virus/metabolism/genetics ; *RNA Helicases/metabolism ; *Capsid Proteins/metabolism/genetics ; *DNA Helicases/metabolism/genetics ; Humans ; Alphavirus/metabolism ; Virus Replication ; Animals ; }, abstract = {Viral infection is one of the conditions that induce stress granule (SG) formation, a cellular defense mechanism that exerts antiviral effects. To counteract this host response, viruses have evolved a broad spectrum of strategies to inhibit SG formation. However, the molecular mechanisms underlying SG inhibition remain poorly understood. The nucleocapsid proteins play a critical role in virus replication and host interaction. Here, using Semliki Forest Virus (SFV) as a model, we uncover the function of the alphavirus nucleocapsid in SG inhibition. This inhibitory function depends on oligomerization mediated by an N-terminal α-helix and with a positively charged intrinsically disordered region (IDR). We show that SFV capsid directly competes with G3BP1 for RNA binding, thereby disrupting G3BP1-RNA liquid-liquid phase separation (LLPS) in vitro and SG assembly in cells. This mechanism is conserved across the alphavirus family but is not shared by the nucleocapsid of SARS-CoV-2 or other endemic viruses examined. Notably, expression of a peptide from SFV capsid is sufficient to inhibit SG formation induced by Amyotrophic Lateral Sclerosis (ALS)-associated mutations, suggesting potential therapeutic applications. Our findings reveal mechanistic insight into SG modulation by the viral capsid protein and provide a possible bioengineering tool for probing SG dynamics in health and disease.}, } @article {pmid41592170, year = {2026}, author = {Allen, MD and Diab, V and Lezaic, N and Binet, M and Gentil, BJ and Blanchard, O and Genge, A and Massie, R}, title = {The genetics of autosomal recessive ALS: a review of the common forms and their phenotypes.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {246-255}, doi = {10.1080/21678421.2026.2615110}, pmid = {41592170}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Phenotype ; Cell Cycle Proteins/genetics ; *Genes, Recessive/genetics ; Membrane Transport Proteins/genetics ; Mutation/genetics ; Superoxide Dismutase-1/genetics ; Transcription Factor TFIIIA/genetics ; Proteins ; Guanine Nucleotide Exchange Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive degeneration of upper and lower motor neurons. Most forms of ALS associated with a suspected causal variant are inherited in an autosomal dominant manner. However, there is an important subset of autosomal recessive (AR) variants, often associated with early-onset or atypical clinical features. Advances in genetic sequencing have led to increased recognition of AR ALS. In this review, we focus on four key confirmed AR ALS-associated genes, which appear to be most common-ALS2, SPG11, OPTN, and the D90A variant of SOD1-reviewing their pathophysiology and unique clinical manifestations. We also highlight very rare AR mutations implicated in ALS, including SYNE1, ATP13A2, and FUS, and some associated with overlap syndromes or debated pathogenicity including SIGMAR1, ERLIN1, and ERLIN2. These genes are involved in an array of processes including axonal transport, endosomal trafficking, oxidative stress response, and autophagy, suggesting distinct mechanisms of motor neuron degeneration. Some forms of AR ALS more frequently present with juvenile onset and slower progression, but other genes are associated with broader phenotypic spectra. This includes overlap with hereditary spastic paraplegia (HSP) and hereditary ataxias. Understanding these AR forms of ALS may enhance diagnostic precision, improve prognostication, and may pave the way for targeted gene therapies. This review underscores the emerging significance of AR inheritance in ALS and calls for deeper investigation into its molecular and clinical dimensions.}, } @article {pmid41592787, year = {2026}, author = {Mammone, RM and Willis, E and Ruivo, P and Finesso, GE and Cox, A and Assenmacher, CA and Radaelli, E and Piersigilli, A and Miranda, IC}, title = {Pathology associated with human CAR T cell administration in NOD.Cg-Prkdc[scid]Il2rg[tm1Wjl]/SzJ (NSG) mice: A retrospective analysis.}, journal = {Veterinary pathology}, volume = {63}, number = {3}, pages = {462-477}, pmid = {41592787}, issn = {1544-2217}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Mice, Inbred NOD ; Retrospective Studies ; Mice ; Humans ; *Receptors, Chimeric Antigen/immunology ; Graft vs Host Disease/pathology ; *Immunotherapy, Adoptive/adverse effects/veterinary ; Female ; *T-Lymphocytes/immunology ; Mice, SCID ; Disease Models, Animal ; }, abstract = {Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for neoplasia and autoimmune diseases. Immunocompromised mice are a common model to test the efficacy and safety of CAR T cells of human origin. Preclinical toxicity associated with human CAR T-cell products encompasses a spectrum of morphologic changes, with currently limited documentation in the scientific literature. The purpose of this retrospective study was to characterize the histopathologic features associated with human CAR T-cell administration in immunodeficient NOD.Cg-Prkdc[scid] Il2rg[tm1Wjl]/SzJ (NSG) mice (n = 392) submitted to 3 different academic institutions in the United States between 2017 and 2024. Lesions were categorized into xenogeneic graft-versus-host disease (xGvHD) (n = 287), aberrant proliferation of human T cells (n = 188), vascular pathologies (n = 66), on-target/off-tumor (OTOT) toxicity (n = 44), immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) in mice previously humanized with human CD34+ hematopoietic stem cells (HSCs) (n = 21), and acute lysis syndrome (ALS) (n = 5). This study provides veterinary pathologists with descriptive guidance on the pathology associated with human CAR T-cell therapy in immunodeficient mice. Additional molecular data and detailed information related to each construct are necessary to further investigate the translatability of such liabilities to the clinical setting.}, } @article {pmid41593242, year = {2026}, author = {Hobson, R and Levy, SHS and Singal, CMS and Flaherty, D and Xiao, H and Ciener, B and Reddy, H and Zabinyakov, N and Kim, CY and Teich, AF and Shneider, NA and Bradshaw, EM and Elyaman, W}, title = {Clonal CD8[+] T cells populate the leptomeninges and coordinate with immune cells in human degenerative brain diseases.}, journal = {Nature immunology}, volume = {27}, number = {2}, pages = {323-335}, pmid = {41593242}, issn = {1529-2916}, support = {PF-IMP-870699//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; P30 AG066462/AG/NIA NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; RF1 NS142171/NS/NINDS NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; P30 CA013696/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *CD8-Positive T-Lymphocytes/immunology/metabolism ; *Meninges/immunology/pathology ; Brain/immunology/pathology ; Microglia/immunology/metabolism ; *Alzheimer Disease/immunology/pathology ; Female ; Receptors, Antigen, T-Cell/genetics ; *Neurodegenerative Diseases/immunology ; *Parkinson Disease/immunology ; Aged ; *Amyotrophic Lateral Sclerosis/immunology ; Male ; Memory T Cells/immunology ; Animals ; }, abstract = {Meningeal immune cells monitor the central nervous system (CNS) and influence neuroinflammation in mice, but the human leptomeningeal immune landscape and the changes that occur in this immunological niche in neurodegeneration remain underexplored. Here we performed single-cell RNA and T cell receptor (TCR) sequencing of 99,625 high-quality immune cells from 57 leptomeninges and brain samples from donors with Alzheimer's disease (AD), amyotrophic lateral sclerosis and Parkinson's disease and found that although the leptomeninges are home to highly clonally expanded CD8 tissue-resident memory (TRM) T cells, the maximal level of clonal expansion was decreased in AD in comparison to non-neurodegenerative controls. Intra-patient paired tissue analysis further revealed that brain and leptomeningeal TCR repertoires share significant similarities, but tissue-specific clones emerge in AD. Finally, in AD, the degree of CD8 TRM clonal expansion was positively correlated with microglial TGFB2, suggesting that brain and leptomeningeal immune cells coordinate their activities in AD. In addition to identifying key inflammatory dynamics in the human degenerating CNS, this study establishes a foundational resource for future studies that could inform treatment for AD and other neuroinflammatory diseases.}, } @article {pmid41593859, year = {2026}, author = {Pathak, K and Kumari, T and Aggarwal, L and Singh, V}, title = {Preventive dietary and lifestyle strategies for neurodegenerative diseases: a comprehensive review.}, journal = {Nutritional neuroscience}, volume = {29}, number = {8}, pages = {984-1009}, doi = {10.1080/1028415X.2026.2615456}, pmid = {41593859}, issn = {1476-8305}, mesh = {Humans ; *Neurodegenerative Diseases/prevention & control ; *Life Style ; Exercise ; Animals ; Intermittent Fasting ; Oxidative Stress ; Caloric Restriction ; *Diet ; Feeding Behavior ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis, are rising sharply across the globe. These incurable and progressive conditions lead to severe cognitive and motor impairments, diminish the quality of life, and place a substantial burden on healthcare systems. In response to this growing challenge, the present review offers an integrative and forward-thinking perspective focused on modifiable daily habits that have the potential to preserve brain health and reduce the risk of neurodegeneration. Mounting evidence reveals that everyday lifestyle choices, including food habits, physical activity, sleep, and stress, profoundly shape long-term cognitive outcomes. Neuroprotective diets such as the Mediterranean and ketogenic diets reduce oxidative stress, enhance mitochondrial efficiency, and promote neurogenesis, whereas the Western diet accelerates cognitive decline. Intermittent fasting and caloric restriction trigger autophagy and ketone production, offering metabolic resilience. Functional foods such as berries, walnuts, and leafy greens combat inflammation and oxidative damage. Physical activity and resistance training boost synaptic plasticity and neurotransmitter balance. In addition, high-quality sleep and effective stress control help preserve neuronal integrity and lower neuroinflammatory markers. By integrating insights from neuroscience, nutrition, and behavioral medicine, this review highlights how multiple modifiable factors, when adopted consistently, can work in synergy to preserve cognitive health, delay disease onset, and reduce progression.}, } @article {pmid41594611, year = {2026}, author = {Dong, C and Lv, D and Dong, Y and Zhang, Z and Li, Q and Chen, Z}, title = {Advances in Cardiolipin Analysis: Applications in Central Nervous System Disorders and Nutrition Interventions.}, journal = {Biomolecules}, volume = {16}, number = {1}, pages = {}, pmid = {41594611}, issn = {2218-273X}, support = {2022CXPT037//the Key R&D Program of Shandong Province, China/ ; 5501290015//the Advanced Researcher Fund of Jiangsu University/ ; 202510299087//National Training Program of Innovation and Entrepreneurship for Undergraduates/ ; }, mesh = {Humans ; *Cardiolipins/metabolism/analysis ; *Central Nervous System Diseases/metabolism/diet therapy ; Animals ; Mitochondria/metabolism ; }, abstract = {Cardiolipin (CL), a unique dimeric phospholipid predominantly enriched in the inner mitochondrial membrane, is a crucial determinant of mitochondrial structure and function. Its content, fatty acyl composition, and oxidation state are associated with mitochondrial bioenergetics, dynamics, and cellular signaling. Disruptions in CL metabolism are increasingly implicated in the pathogenesis of various central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and traumatic brain injury. This narrative review summarizes recent advances in the analytical techniques employed for CL analysis. The principles and applications of mass spectrometry-based platforms, nuclear magnetic resonance, Fourier-transform infrared spectroscopy, atomic force microscopy-infrared spectroscopy, and fluorescent probes were discussed, with an emphasis on their strengths in revealing the structure, composition, dynamics, and spatial distribution of CL. Furthermore, the evidence of CL abnormalities in various CNS disorders was assessed, often showing decreased CL levels, loss of polyunsaturated species, and increased oxidation associated with mitochondrial dysfunction and neuronal apoptosis. Furthermore, the nutritional interventions for CL modulation were discussed, such as polyunsaturated fatty acids, polyphenols, carotenoids, retinoids, alkaloids, and triterpenoids, which summarize their potential health-beneficial effects in remodeling the CL acyl chain, preventing oxidation, and regulating mitochondrial homeostasis. Overall, this review provided insight into integrating CL analysis and dietary modulation in understanding CL-related pathologies in CNS disorders.}, } @article {pmid41594924, year = {2026}, author = {Bao, Y and Miao, G and He, N and Bao, X and Shi, Z and Hu, C and Liu, X and Wang, B and Sun, C}, title = {Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.}, journal = {Biology}, volume = {15}, number = {2}, pages = {}, pmid = {41594924}, issn = {2079-7737}, abstract = {Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer's disease, Parkinson's disease, and Huntington's disease-the major protagonists of NDs-while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials.}, } @article {pmid41595662, year = {2026}, author = {Stoian, II and Nistor, D and Levai, MC and Popa, DI and Popescu, R}, title = {Directional Modulation of the Integrated Stress Response in Neurodegeneration: A Systematic Review of eIF2B Activators, PERK-Pathway Agents, and ISR Prolongers.}, journal = {Biomedicines}, volume = {14}, number = {1}, pages = {}, pmid = {41595662}, issn = {2227-9059}, abstract = {Background and Objectives: The integrated stress response (ISR) is a convergent node in neurodegeneration. We systematically mapped open-access mammalian in vivo evidence for synthetic ISR modulators, comparing efficacy signals, biomarker engagement, and safety across mechanisms and disease classes. Methods: Following PRISMA 2020, we searched PubMed (MEDLINE), Embase, and Scopus from inception to 22 September 2025. Inclusion required mammalian neurodegeneration models; synthetic ISR modulators (eIF2B activators, PERK inhibitors or activators, GADD34-PP1 ISR prolongers); prespecified outcomes; and full open access. Extracted data included model, dose and route, outcomes, translational biomarkers (ATF4, phosphorylated eIF2α), and safety. Results: Twelve studies met the criteria across tauopathies and Alzheimer's disease (n = 5), prion disease (n = 1), amyotrophic lateral sclerosis and Huntington's disease (n = 3), hereditary neuropathies (n = 2), demyelination (n = 1), and aging (n = 1). Among interpretable in vivo entries, 10 of 11 reported benefit in at least one domain. By class, eIF2B activation with ISRIB was positive in three of four studies, with one null Alzheimer's hAPP-J20 study; PERK inhibition was positive in all three studies; ISR prolongation with Sephin1 or IFB-088 was positive in both studies; and PERK activation was positive in both studies. Typical regimens included ISRIB 0.1-2.5 mg per kg given intraperitoneally (often two to three doses) with reduced ATF4 and phosphorylated eIF2α; oral GSK2606414 50 mg per kg twice daily for six to seven weeks, achieving brain-level exposures; continuous MK-28 delivery at approximately 1 mg per kg; and oral IFB-088 or Sephin1 given over several weeks. Safety was mechanism-linked: systemic PERK inhibition produced pancreatic and other exocrine toxicities at higher exposures, whereas ISRIB and ISR-prolonging agents were generally well-tolerated in the included reports. Conclusions: Directional ISR control yields consistent, context-dependent improvements in behavior, structure, or survival, with biomarker evidence of target engagement. Mechanism matching (down-tuning versus prolonging the ISR) and exposure-driven safety management are central for translation.}, } @article {pmid41596063, year = {2025}, author = {Herbert, A}, title = {G-Quadruplexes Abet Neuronal Burnout in ALS and FTD.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {41596063}, issn = {2076-3921}, abstract = {Expansion of d(GGGGC)n repeat in the C9ORF72 gene is causal for Amyotrophic Lateral Sclerosis (ALS) and Frontal Temporal Dementia (FTD). Proposed mechanisms include Repeat-Associated Non-AUG translation or the formation of G-quadruplexes (GQ) that disrupt translation, induce protein aggregation, sequester RNA processing factors, or alter RNA editing. Here, I show, using AlphaFold V3 (AF3) modeling, that the TAR DNA-binding protein (TDP-43) docks to a complex of GQ and hemin. TDP-43 methionines lie over hemin and likely squelch the generation of superoxide by the porphyrin-bound Fe. These TDP-43 methionines are frequently altered in ALS patients. Tau protein, a variant of which causes ALS, also binds to GQ and heme and positions methionines to detoxify peroxides. Full-length Tau, which is often considered prone to aggregation and a prion-like disease agent, can bind to an array composed of multiple GQs as a fully folded protein. In ALS and FTD, loss-of-function variants cause an uncompensated surplus of superoxide, which sparks neuronal cell death. In Alzheimer's Disease (AD) patients, GQ and heme complexes bound by β-amyloid 42 (Aβ4) are also likely to generate superoxides. Collectively, these neuropathologies have proven difficult to treat. The current synthesis provides a framework for designing future therapeutics.}, } @article {pmid41596266, year = {2026}, author = {Ryu, IS and Ha, DI and Jung, YJ and Lee, HJ and Kim, I and Lim, YN and Min, HS and Kim, SH and Yoon, I and Cho, HJ and Ryu, JH}, title = {Modulation of the miR-485-3p/PGC-1α Pathway by ASO-Loaded Nanoparticles Attenuates ALS Pathogenesis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {2}, pages = {}, pmid = {41596266}, issn = {1422-0067}, support = {RS-2023-00283779//Ministry of SMEs and Startups/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/drug therapy ; *MicroRNAs/genetics/metabolism ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Nanoparticles/chemistry ; Mice ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Spinal Cord/metabolism/pathology ; Humans ; *Oligonucleotides, Antisense/administration & dosage/pharmacology ; Disease Models, Animal ; Signal Transduction/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration with limited treatment options. In this study, we investigated the pathological role of microRNA-485-3p (miR-485-3p) in ALS, particularly its regulation of PGC-1α, a transcriptional coactivator essential for mitochondrial function and neuroprotection. We also evaluated the therapeutic potential of BMD-001S, a nanoparticle-based formulation encapsulating an antisense oligonucleotide targeting miR-485-3p. Our results demonstrated that miR-485-3p expression was significantly elevated in both SOD1[G93A]-expressing HMC3 microglial cells and in the spinal cords of SOD1[G93A] transgenic mice at late disease stages, implicating its contribution to ALS pathogenesis. Intravenous administration of BMD-001S effectively reduced miR-485-3p levels and restored PGC-1α mRNA and PGC-1α protein expression in the spinal cord. These molecular changes were associated with notable therapeutic outcomes, including reduced SOD1 protein aggregation, decreased neuroinflammation, and lower neurofilament light chain concentrations in cerebrospinal fluid. Moreover, BMD-001S treatment was associated with improvements in electrophysiological parameters and preservation of neuromuscular junction integrity during the observation period in SOD1[G93A] transgenic mice. Taken together, these findings suggest that miR-485-3p/PGC-1α pathway is a promising therapeutic target in ALS and support the potential of BMD-001S as a novel treatment strategy for the disease.}, } @article {pmid41596533, year = {2026}, author = {Bogus, K and Marchesi, N and Campagnoli, LIM and Pascale, A and Pałasz, A}, title = {Glial Cells as Key Mediators in the Pathophysiology of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {27}, number = {2}, pages = {}, pmid = {41596533}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism/physiopathology/etiology ; *Neuroglia/metabolism/pathology ; Animals ; Microglia/metabolism/pathology ; Amyotrophic Lateral Sclerosis ; }, abstract = {Neurodegenerative disorders are characterized by progressive neuronal loss and dysfunction, yet increasing evidence indicates that glial cells are central mediators of both disease initiation and progression. Astrocytes, microglia, and oligodendrocyte lineage cells modulate neuronal survival by regulating neuroinflammation, metabolic support, synaptic maintenance, and proteostasis. However, dysregulated glial responses, including chronic microglial activation, impaired phagocytosis, altered cytokine production, and mitochondrial dysfunction, contribute to persistent inflammation and structural degeneration observed across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and multiple sclerosis. Recent advances in single-cell and spatial omics have revealed extensive glial heterogeneity and dynamic shifts between neuroprotective and neurotoxic phenotypes, emphasizing the context-dependent nature of glial activity. This review summarizes current knowledge regarding the multifaceted involvement of glial cells in neurodegenerative disorders.}, } @article {pmid41598508, year = {2026}, author = {Torikai, T and Ohara, H and Takeuchi, J and Yokoi, T and Itoh, Y and Koto, T and Shiraishi, A and Inoue, M}, title = {Surgical Outcomes and Differences in Values of Ocular Parameters Following Vitrectomy for Macular Hole over a 10-Year Period.}, journal = {Journal of clinical medicine}, volume = {15}, number = {2}, pages = {}, pmid = {41598508}, issn = {2077-0383}, abstract = {Background/Objectives: We aimed to compare the surgical outcomes of macular hole (MH) cases and evaluate how the axial length (AL) affected the outcomes. Methods: Six hundred and sixty-three eyes with MHs that underwent vitrectomy over the past 10 years were reviewed. The changes in AL were compared to those of 1948 eyes with idiopathic epiretinal membranes (ERMs) operated on during the same period. The MH cases for the 5 years from 2014 to 2018 were designated as the MH2014 group, and those from 2019 to 2023 as the MH2019 group. The ERM cases were divided similarly into the ERM2014 and ERM2019 groups. The clinical characteristics of the cases and surgical outcomes were compared. Results: The MH diameter, closure rate, and baseline and postoperative visual acuity were not significantly different. The use of the inverted internal limiting membrane flap technique was significantly higher in the MH2019 group (58%) than in the MH2014 group (24%, p < 0.001). The mean AL was significantly longer in the MH2019 group (25.2 ± 2.4 mm) than in the MH2014 group (24.6 ± 2.1 mm, p = 0.004). The incidence of myopic MHs with AL ≥ 26 mm and AL ≥ 30 mm was higher in the MH2019 group (30.9%, p = 0.008, 6.4%, p = 0.017, respectively). There was a significant trend for longer ALs over 10 years in the MH group (p = 0.002), but not in the ERM group. Conclusions: The increased AL and the rising proportion of eyes with myopic MHs indicate that the patient profile of eyes with MHs has changed over the past decade.}, } @article {pmid41599185, year = {2026}, author = {Benech, H and Flament, V and Lhotellier, C and Roucairol, C and Joudinaud, T}, title = {New Insights into Drug Development via the Nose-to-Brain Pathway: Exemplification Through Dodecyl Creatine Ester for Neuronal Disorders.}, journal = {Pharmaceutics}, volume = {18}, number = {1}, pages = {}, pmid = {41599185}, issn = {1999-4923}, abstract = {Brain disorders remain a major global health challenge, highlighting the urgent need for innovative therapeutic strategies and efficient drug-delivery approaches. Among alternative routes, intranasal administration has garnered significant interest over recent decades, not only for its systemic delivery but also for its unique ability to bypass the bloodstream and the blood-brain barrier via the Nose-to-Brain (NtB) pathway. While numerous reviews have explored the opportunities and challenges of this route, industrial considerations-critical for successful clinical implementation and commercial development-remain insufficiently addressed. This review provides a comprehensive and critical assessment of the NtB pathway from a drug development and chemistry, manufacturing, and controls perspective, addressing key constraints in pre-clinical-clinical extrapolation, formulation design, device selection, dose feasibility, chronic safety, and regulatory requirements. We also discuss recent advances in neuronal targeting mechanisms, also with a focus on the role of trigeminal nerves. Dodecyl creatine ester (DCE), a highly unstable in plasma creatine prodrug developed by Ceres Brain Therapeutics, is presented as an illustrative case study. Delivered as a nasal spray, DCE enables direct neuronal delivery, exemplifying the potential of the NtB pathway for disorders characterized by neuronal energy deficiency, including creatine transporter deficiency and mitochondrial dysfunction. Overall, the NtB pathway-or, more precisely, the "Nose-to-Neurons" pathway-offers distinct advantages for unstable molecules and metabolic supplementation, particularly in neuron-centric diseases. Its successful implementation will depend on rational molecule design, optimized nasal formulations, appropriate devices, and early integration of industrial constraints to ensure feasibility, scalability, and safety for long-term treatment.}, } @article {pmid41599225, year = {2026}, author = {Bernatoniene, J and Kopustinskiene, DM and Casale, R and Medoro, A and Davinelli, S and Saso, L and Petrikonis, K}, title = {Nrf2 Modulation by Natural Compounds in Aging, Neurodegeneration, and Neuropathic Pain.}, journal = {Pharmaceutics}, volume = {18}, number = {1}, pages = {}, pmid = {41599225}, issn = {1999-4923}, support = {S-A-UEI-23-7//Research Council of Lithuania (LMTLT)/ ; }, abstract = {This review summarizes the role of nuclear factor erythroid 2-related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders-including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis-evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management.}, } @article {pmid41599368, year = {2026}, author = {Niziński, P and Szalast, K and Makuch-Kocka, A and Paruch-Nosek, K and Ciechanowska, M and Plech, T}, title = {Experimental Models and Translational Strategies in Neuroprotective Drug Development with Emphasis on Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {2}, pages = {}, pmid = {41599368}, issn = {1420-3049}, support = {2022/47/O/NZ7/00155//National Science Centre/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; *Drug Development/methods ; *Translational Research, Biomedical ; Neurons/drug effects/metabolism ; Blood-Brain Barrier/metabolism ; Disease Models, Animal ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs (2002-2012) estimated ~99.6% attrition, while PD programs (1999-2019) achieved an overall success rate of ~14.9%. In vitro platforms are assessed, ranging from immortalized neuronal lines and primary cultures to human-induced pluripotent stem cell (iPSC)-derived neurons/glia, neuron-glia co-cultures (including neuroinflammation paradigms), 3D spheroids, organoids, and blood-brain barrier (BBB)-on-chip systems. Complementary in vivo toxin, pharmacological, and genetic models are discussed for systems-level validation and central nervous system (CNS) exposure realism. The therapeutic synthesis focuses on AD, covering symptomatic drugs, anti-amyloid immunotherapies, tau-directed approaches, and repurposed drug classes that target metabolism, neuroinflammation, and network dysfunction. This review links experimental models to translational decision-making, focusing primarily on AD and providing a brief comparative context from other NDDs. It also covers emerging targeted protein degradation (PROTACs). Key priorities include neuroimmune/neurovascular human models, biomarker-anchored adaptive trials, mechanism-guided combination DMTs, and CNS PK/PD-driven development for brain-directed degraders.}, } @article {pmid41599691, year = {2026}, author = {Zhao, X and Zheng, Y and Cai, X and Yao, Y and Qin, D}, title = {The Expanding Role of Non-Coding RNAs in Neurodegenerative Diseases: From Biomarkers to Therapeutic Targets.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {1}, pages = {}, pmid = {41599691}, issn = {1424-8247}, support = {Y202248634//Zhejiang Provincial Department of Education Project/ ; Y202454271//Zhejiang Provincial Department of Education Project/ ; }, abstract = {Non-coding RNAs have emerged as central regulators of gene expression in neurodegenerative diseases, offering new opportunities for diagnosis and therapy. This review synthesizes current knowledge on microRNAs, long non-coding RNAs, and circular RNAs in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, emphasizing their roles in synaptic function, proteostasis, mitochondrial biology, and neuroinflammation. We evaluate evidence supporting non-coding RNAs as circulating and tissue-based biomarkers for early detection, disease monitoring, and patient stratification, and we compare analytical platforms and biofluid sources. Mechanistic insights reveal how non-coding RNAs modulate pathogenic protein aggregation, neuronal excitability, immune cell crosstalk, and blood-brain barrier integrity. Translational efforts toward RNA-targeted interventions are reviewed, including antisense oligonucleotides, small interfering RNAs, miRNA mimics and inhibitors, circular RNA decoys, and extracellular vesicle-mediated delivery systems. We discuss pharmacological modulation, delivery challenges, safety concerns, and strategies to enhance specificity and CNS penetration. Finally, we outline emerging computational and multi-omics approaches to prioritize therapeutic targets and propose a roadmap for advancing non-coding RNA research from preclinical models to clinical trials. Addressing biological heterogeneity and delivery barriers will be pivotal to realizing the diagnostic and therapeutic promise of the non-coding transcriptome in neurodegenerative disease. Collaboration across disciplines and rigorous clinical validation are urgently needed.}, } @article {pmid41601535, year = {2025}, author = {Zhu, Y and Zhang, G and Liu, H and Yin, T and Zhang, J and Yang, Y and Bai, L and Liu, X and Fan, D and Ye, S}, title = {Depression mediates motor dysfunction's effect on sleep quality in ALS: a mediation analysis study.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1643367}, pmid = {41601535}, issn = {1662-4548}, abstract = {INTRODUCTION: Poor sleep quality affects 50-63% of Amyotrophic lateral sclerosis (ALS) patients, exacerbating disease burden and reducing quality of life. This study aimed to investigate the relationships among disease severity, depressive symptoms, and sleep quality in ALS, with a focus on the mediating effects of depression.

METHODS: Our study enrolled 408 ALS patients. Disease severity was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R), sleep quality via the Pittsburgh Sleep Quality Index (PSQI), and psychological status using the Hamilton Depression (HAMD) and Anxiety (HAMA) scales. Statistical analyses included Spearman correlations, multivariate regression, and mediation analysis (Hayes' PROCESS macro).

RESULTS: Poor sleep quality (PSQI > 5) was observed in 54.4% of patients. Multivariate analysis found ALSFRS-R (β = -0.135, p = 0.042) and HAMD (β = 0.270, p < 0.001) correlated with sleep quality. Initial mediation analysis using the full ALSFRS-R and PSQI scales was not significant. Aimed to further explore the correlation, we derived specific subscales ALSFRS-R' (motor/respiratory components) and PSQI' (sleep efficiency/ daytime dysfunction), which more correlated with each other. Mediation analysis of these subscales revealed that depressive symptoms accounted for 36.3% of the indirect effect between ALSFRS-R' and PSQI'.

DISCUSSION: Our cross-sectional exploratory study suggests that depression may partly mediate the relationship between motor dysfunction and poor sleep quality in patients with ALS. Although our mediation analysis suggested a potential association, further longitudinal cohort studies are needed to confirm these findings. The potential mediating role of depression underscores the need for an integrated clinical management approach addressing not only motor symptoms but psychological well-being as well.}, } @article {pmid41601590, year = {2025}, author = {Garbuzova-Davis, S and Manora, L and Borlongan, CV}, title = {Apolipoprotein A1 reduces blood-spinal cord barrier leakage, improves astrocytic coverage, and enhances motor neuron survival to restore the neurovascular unit in ALS mice.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1684694}, pmid = {41601590}, issn = {1663-4365}, support = {R21 NS132576/NS/NINDS NIH HHS/United States ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive, age-related motor neuron degenerative disease with multiple causal factors. Dyslipidemia has been identified as an important pathological element. Impaired lipid protein metabolism manifests in ALS patients and in an ALS mouse model. Apolipoprotein components are the primary regulators of plasma lipid metabolism. Apolipoprotein A1 (ApoA1), a high-density lipoprotein, acts as an antioxidant and reduces inflammation, preventing blood vessel injury. However, the effects of ApoA1 upon the ALS-damaged endothelium in the CNS are unknown. The objective of the study was to determine the effect(s) of injecting ApoA1 into G93A SOD1 mice at the early symptomatic stage.

METHODS: A single dose of ApoA1 or media was systemically administered into 13-week-old G93A SOD1 male and female mice. Body weight and tests of motor function were evaluated weekly for 4 weeks post-injection. Permeability of spinal cord capillaries was determined by Evans blue (EB) fluorescent dye injected into mice at 17 weeks of age. Immunohistochemical analyses determined the statuses of glial cells and ApoA1 distributions in ALS mice cervical/lumbar spinal cords. Motor neurons in cervical/lumbar spinal cord ventral horns of ApoA1-treated and media-injected ALS mice were stained with cresyl violet for histological analyses.

RESULTS: ApoA1 injected into G93A SOD1 mice at the early symptomatic stage significantly benefited both male and female animals by (1) delaying behavioral disease progression; (2) reducing EB capillary leakage into spinal cord parenchyma; (3) lessening astrogliosis and microgliosis; (4) protein incorporation into capillary endothelium and motor neurons; and (5) improving survival of motor neurons in the spinal cord.

CONCLUSION: Our novel data showed that systemically administered ApoA1 benefited ALS mice of both sexes, likely by beneficial effects on damaged microvessels, possibly engendering restoration of neurovascular unit integrity. Moreover, an anti-inflammatory ApoA1 effect was demonstrated by the reduction of glial cell activation, potentially mitigating vascular injury. The results of our preclinical study suggest that ApoA1 may be a potential protein-mediated therapeutic for restoring vascular function. Our novel strategy may lead to future clinical trials, furthering our goal of effectively treating ALS patients.}, } @article {pmid41601624, year = {2025}, author = {Yang, J and Song, X and Yan, S and Li, Q and Yang, W}, title = {The gut microbiota influences neurodegenerative diseases through the gut-brain axis: molecular mechanisms and effects on immune function.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1739329}, pmid = {41601624}, issn = {1664-3224}, mesh = {Humans ; *Neurodegenerative Diseases/immunology/microbiology/therapy/etiology/metabolism ; Animals ; *Gastrointestinal Microbiome/immunology ; *Brain/immunology/metabolism ; Fecal Microbiota Transplantation ; *Brain-Gut Axis/immunology ; Probiotics/therapeutic use ; Prebiotics ; }, abstract = {The pathogenesis of neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is complex and multifactorial. Recent studies indicate that the microbiota-gut-brain axis (MGBA) plays a crucial role in the development and progression of NDDs. The MGBA concept reveals a complex bidirectional regulatory network between the gut microbiota and the central nervous system (CNS), linking them through immune, neural, endocrine, and metabolic pathways. This review summarizes the components of the MGBA, communication pathways between gut microbiota and the brain, and mechanisms by which gut microbiota influence the onset and progression of NDDs. Finally, preclinical therapeutic approaches for NDDs are discussed, evaluating preclinical trial data for probiotics, prebiotics, and fecal microbiota transplantation.}, } @article {pmid41601803, year = {2025}, author = {An, X and Hou, D and Miao, MY and Zhou, YM and Qi, S and Zhang, L and Li, H and Zhou, JX}, title = {Noninvasive monitoring of inspiratory effort in mechanical ventilation: a dual-database bibliometric analysis from 1990 to 2025.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1747437}, pmid = {41601803}, issn = {2296-858X}, abstract = {INTRODUCTION: This study conducts a bibliometric analysis to map the intellectual structure, evolution, and emerging trends in research on airway pressure-based indexes for monitoring inspiratory effort.

METHODS: Systematic searches of the Web of Science Core Collection (WOSCC) and Pubmed were performed for publications dated between 1990 and 2025. Bibliometric parameters, including publication trends, country and affiliation contributions, author influence, journal distribution, keyword co-occurrence, and reference co-citation networks, were analyzed using Bibliometrix and CiteSpace.

RESULTS: The analysis included 291 publications from WOSCC. The annual publication output showed a near U-shaped trend, with an initial decline after the 1990s, followed by a strong resurgence after 2011. Italy was the most productive country, followed by the USA and France. The Institut National de la Sante et de la Recherche Medicale emerged as the leading institution. The journal Chest published the most articles, while the American Journal of Respiratory and Critical Care Medicine had the highest total citations. Laurent Brochard was identified as the most prolific and influential author. Keyword analysis highlighted "occlusion pressure" and "mechanical ventilation" as core themes. Reference co-citation clustering revealed major research domains, including "acute respiratory distress syndrome," "self-inflicted lung injury," and "nasal high flow." Burst detection analysis indicated that "respiratory drive," "lung injury," and "critically ill patients" are emerging research frontiers. Complementary analysis of 242 PubMed clinical studies confirmed these trends and highlighted growing clinical focus on "fluid responsiveness" and "amyotrophic lateral sclerosis."

CONCLUSION: Research on airway pressure-based indices has evolved from physiological studies into a crucial clinical tool for respiratory monitoring. The field exhibits strong international collaboration and emphasizes core areas, including acute respiratory failure and lung-protective ventilation. Analysis of clinical study data confirms these trends and highlights emerging applications in the assessment of fluid responsiveness and neuromuscular disorders. These findings support the ongoing development of personalized ventilation strategies based on monitoring respiratory effort.}, } @article {pmid41602910, year = {2026}, author = {Li, Q and Zhang, G and Zheng, H and Zhao, T and Zhang, H and Zhang, Y and Luo, H and Xu, Y}, title = {ABCA1 acts as a protective modulator in amyotrophic lateral sclerosis.}, journal = {iScience}, volume = {29}, number = {1}, pages = {114320}, pmid = {41602910}, issn = {2589-0042}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease lacking reliable biomarkers and effective therapeutic targets. We performed an integrative multiscale analysis combining global epidemiology, whole-blood transcriptomics, machine learning, and Mendelian randomization (MR). We developed a nine-gene diagnostic signature (AUC = 0.75 in external validation) and identified ATP-binding cassette transporter A1 (ABCA1) as a central feature. MR analyses supported a protective causal relationship between increased ABCA1 expression and reduced ALS risk (OR = 0.93, p = 0.02). We validated this at the protein level, finding serum ABCA1 significantly elevated in an in-house ALS cohort (p = 0.006) and correlated with metabolic parameters (BMI and LDL). Spatiotemporal profiling confirmed ABCA1 upregulation in ALS patient blood and spinal cords, and progressive upregulation in ALS model mice. Collectively, we validated a diagnostic signature and identified ABCA1 as a protective, compensatory biomarker in ALS, emphasizing the link between metabolic adaptation and neurodegeneration.}, } @article {pmid41602992, year = {2025}, author = {Czyżewski, Ł and Petrzak-Nocuń, K and Strząska-Kliś, Z and Wyzgał, J and Religioni, U and Augustynowicz, A and Świtalski, J and Dudziński, Ł and Silczuk, A}, title = {Illness acceptance and quality of life in amyotrophic lateral sclerosis: the role of health and environmental factors.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1721044}, pmid = {41602992}, issn = {1664-2295}, abstract = {PURPOSE: To determine the extent to which illness acceptance accounts for variability in health-related quality of life (HRQoL) among adults with amyotrophic lateral sclerosis (ALS) attending a hospital-based outpatient clinic, after controlling for sociodemographic and health variables.

MATERIALS AND METHODS: We conducted a single-center, cross-sectional study in a hospital outpatient clinic. Adults with ALS completed the World Health Organization Quality of Life-BREF (WHOQOL-BREF) and the Acceptance of Illness Scale (AIS), plus a sociodemographic and health questionnaire.

RESULTS: Forty-five patients were analyzed (mean age 52 ± 14 years; 58% women). WHOQOL-BREF domain means were: physical 46.9 ± 14.1, psychological 51.2 ± 16.9, social 53.0 ± 24.6, environment 58.4 ± 18.4. Mean AIS was 20.4 ± 8.1. AIS correlated positively with all domains (r = 0.40-0.52, all p ≤ 0.006). In age- and sex-adjusted models, AIS independently predicted higher scores: physical β = 0.96 (p = 0.003), psychological β = 0.94 (p = 0.013), social β = 1.47 (p = 0.003), environment β = 1.10 (p = 0.025). Percutaneous endoscopic gastrostomy (PEG) was associated with lower physical and environment scores than oral feeding. Respiratory status differentiated physical and psychological scores. Better living conditions related to higher psychological and environment scores. Time from first symptoms to diagnosis correlated with AIS (ρ = 0.37, p = 0.014).

CONCLUSION: Illness acceptance is a robust, independent correlate of HRQoL across domains in ALS. Care should pair symptom control with brief acceptance-focused, educational, and family communication interventions, and address environmental needs. Decisions on PEG and non-invasive ventilation (NIV) should include routine dietetic, psychological, and speech-language input. Longitudinal studies should test AIS as a mediator of somatic and environmental interventions on HRQoL.}, } @article {pmid41603250, year = {2026}, author = {Naumann, M and Wierschin, TM and Kretschmer, S and Dash, BP and Held, A and Salzinger, A and Peikert, K and Karlek, A and Glaß, H and Großmann, D and Günther, R and Petri, S and Rödiger, A and Brenner, D and Pan-Montojo, F and Aronica, E and Kipp, M and Zimyanin, V and Sterneckert, J and Grehl, T and Seebacher, ND and Böckers, TM and Catanese, A and Wainger, BJ and Oeckl, P and Lee-Kirsch, MA and Hermann, A}, title = {RIG-I Mediated Neuron-Specific IFN Type 1 Signaling in FUS-ALS Induces Neurodegeneration and Offers New Biomarker-Driven Individualized Treatment Options for (FUS-)ALS.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {18}, pages = {e17135}, pmid = {41603250}, issn = {2198-3844}, support = {CRC237 369799452/B21//German Research Foundation (DFG)/ ; CRC237 369799452/A11//German Research Foundation (DFG)/ ; CRC369 501752319/C06//German Research Foundation (DFG)/ ; 01GM2206C (GAIN)//German Federal Ministry of Education and Research (BMBF)/ ; 01GL2405H (DZKJ)//German Federal Ministry of Education and Research (BMBF)/ ; na//Stichting ALS Nederland/ ; na//Hermann und Lilly Schilling-Stiftung für Medizinische Forschung/ ; //Clinician Scientist program of the Medical Faculty of the University of Rostock (RAS)/ ; //Stichting ALS Nederland/ ; //Hermann und Lilly Schilling-Stiftung für Medizinische Forschung/ ; }, mesh = {Humans ; *Receptors, Immunologic/metabolism ; Signal Transduction/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Biomarkers/metabolism ; *DEAD Box Protein 58/metabolism/genetics ; *Motor Neurons/metabolism ; *Interferon Type I/metabolism/genetics ; cGAS-STING Signaling Pathway ; Immunity, Innate/genetics ; }, abstract = {Recent research demonstrated activation of the innate immune system in ALS models. This pathway can be activated by cGAS-STING sensing of cytosolic DNA that accumulates as a result of chronic DNA damage and defective mitochondria, both of which was identified as pathology in FUS-ALS. Therefore, we analyzed innate immune pathways in FUS-ALS, which revealed upregulation of interferon-stimulated genes (ISGs) and activation of the TBK1-IRF3 pathway in FUS[mut] iPSC-derived spinal motor neurons (sMNs). Accumulation of cytosolic dsRNA and its sensor RIG-I, but not MDA5, was found to be significantly upregulated in FUS[mut] sMNs, which was abolished upon siRNA-mediated knockdown of RIG-I. RIG-I was highly expressed in FUS-ALS post-mortem α-MNs. IFN treatment of FUS[wt] sMNs phenocopied the axonal degeneration of FUS[mut] sMNs. Mitochondrial transcription, a known source of dsRNA, was found to be upregulated in compartmental axonal RNAseq analysis and its inhibition reduced ISGs in FUS-ALS sMNs. The JAK-STAT inhibitor ruxolitinib alleviated the upregulated ISG expression and reversed the axonal degeneration of sMNs. Finally, we analyzed ISG expression in peripheral blood from 18 FUS-ALS patients, eight of whom had a significantly elevated interferon signature. RIG-I-mediated innate immune activation in sMNs may be an interesting novel individualized biomarker-driven therapeutic target in (FUS-) ALS. A one-sentence summary of your paper: RIG-I-mediated innate immune activation is found in FUS-ALS spinal motor neurons caused by cytosolic dsRNA accumulation due to mitochondrial transcriptional activation and is amenable to JAK-STAT inhibition and might thus be an interesting novel individualized biomarker-driven therapeutic approach in (FUS-) ALS.}, } @article {pmid41604235, year = {2026}, author = {Al-Ameer, HJ and Basheer, NM and H, M and Shankhyan, A and Panigrahi, R and Arora, V and Azizjanov, K and Eshchanov, E and Ataullaev, Z}, title = {Neuroimmune Cross-Talk and Multilevel Cascades in Fentanyl Toxicity: Interplay of Hypoxic Stress, Glial Activation, and Synaptic Dysregulation in Systems-Level Neurodegeneration.}, journal = {Journal of applied toxicology : JAT}, volume = {46}, number = {5}, pages = {1404-1416}, doi = {10.1002/jat.70069}, pmid = {41604235}, issn = {1099-1263}, mesh = {Humans ; Animals ; *Neuroglia/drug effects/metabolism ; *Neurodegenerative Diseases/chemically induced/immunology ; *Fentanyl/toxicity ; *Synapses/drug effects ; *Analgesics, Opioid/toxicity ; *Neuroimmunomodulation/drug effects ; *Hypoxia ; }, abstract = {Fentanyl, an ultra-potent synthetic opioid, has traditionally been characterized by its acute toxic effects, particularly respiratory depression. However, accumulating research indicates that its neurobiological influence extends far beyond its short pharmacological window, intersecting with several core mechanisms implicated in major neurodegenerative disorders. This review integrates multiscale evidence to propose a unified conceptual framework in which fentanyl may function not only as an acute neurotoxin but also as a putative accelerator of long-term neurodegenerative vulnerability. Drawing from molecular signaling, cellular stress pathways, glial-neuronal cross-talk, neurovascular regulation, synaptic architecture, and large-scale neural networks, we highlight fentanyl's capacity to trigger a convergent cascade encompassing hypoxic-metabolic reprogramming, mitochondrial fragmentation, TLR4-NF-κB-driven inflammation, NLRP3 inflammasome activation, complement-mediated synaptic pruning, astrocytic EAAT2 downregulation, and blood-brain barrier compromise. These alterations propagate through recursive cross-talk loops that progressively diminish neuronal resilience, destabilize oscillatory coherence, and weaken circuit-level adaptability. Importantly, mechanistic overlaps with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis suggest that fentanyl exposure may be mechanistically associated with processes capable of accelerating disease onset, exacerbating progression, or unmasking latent vulnerabilities, particularly in genetically or metabolically predisposed individuals. By reframing fentanyl as a systems-level destabilizer capable of imprinting persistent neurobiological changes, this model underscores the need for comprehensive biomarker development, longitudinal risk assessment, and targeted neuroprotective interventions. The integrative framework presented herein offers a foundation for predicting the long-term neurological consequences of fentanyl exposure and calls for urgent reconsideration of its role in population-level neurodegenerative risk.}, } @article {pmid41604971, year = {2026}, author = {Ahamad, S and Akshinthala, P and Fazal, F and Sah, GK and Khan, MH and Upadhyay, A and Bhat, SA and Hussain, MK}, title = {Small-molecule-based activation of Wnt/β-catenin signaling: An underexplored yet promising strategy for neuroprotection.}, journal = {Bioorganic chemistry}, volume = {170}, number = {}, pages = {109540}, doi = {10.1016/j.bioorg.2026.109540}, pmid = {41604971}, issn = {1090-2120}, mesh = {Humans ; *Small Molecule Libraries/pharmacology/chemistry ; *Neuroprotective Agents/pharmacology/chemistry ; *Wnt Signaling Pathway/drug effects ; Animals ; *beta Catenin/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Molecular Structure ; }, abstract = {The Wnt/β-catenin pathway regulates key processes such as neurogenesis, synaptic plasticity, and neuroinflammation, each disrupted in neurodegenerative disorders like AD, PD, ALS, and stroke. Small molecules have shown potential to restore this signaling axis and confer neuroprotection. While these molecules modulate Wnt activity, none has achieved FDA approval, primarily due to poor brain permeability, off-target effects, and insufficient biomarker-based validation. Moreover, current strategies remain disproportionately focused on GSK-3β, with other viable targets, such as DKK1, NOTUM, SFRP-1, sclerostin, and Dvl-CXXC5 or Axin-β-catenin interactions, largely underexplored. Natural products, particularly flavonoids and diterpenoids, offer valuable scaffolds; however, their SAR remain poorly characterized, and promising synthetic leads often lack further development. This review highlights recent pharmacological advances, emerging molecular targets, and key translational barriers. Future success will depend on optimizing pharmacokinetics, improving brain-targeted delivery, and integrating biomarker-driven strategies into clinical trial design.}, } @article {pmid41605460, year = {2026}, author = {Martínez-Alesón, P and Benito-Casado, C and Fernández-Martos, CM and Polanco Mora, MJ}, title = {Pleiotrophin/Midkine Pathway Is Dysregulated in a TDP-43[A315T] Mouse Model of Amyotrophic Lateral Sclerosis (ALS).}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {46}, number = {1}, pages = {e70044}, pmid = {41605460}, issn = {1440-1789}, support = {FUSPBS-PPC03/2018//University San Pablo CEU-Santander precompetitive grants/ ; SBPLY/17/180501/000303//Junta de Comunidades de Castilla-la Mancha/ ; PIPF-2023/SAL-GL-29613//Consejería de Educación, Ciencia y Universidades Comunidad de Madrid/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Midkine/metabolism ; *Cytokines/metabolism ; *Carrier Proteins/metabolism ; Mice ; Disease Models, Animal ; Signal Transduction/physiology ; Mice, Transgenic ; Spinal Cord/metabolism/pathology ; DNA-Binding Proteins/genetics ; Humans ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterized by progressive degeneration of both upper and lower motor neurons, along with skeletal muscles innervated by them. The identification of key molecules involved in disease pathology remains crucial for ALS, as no curative treatment is currently available. Pleiotrophin (PTN) and midkine (MK) are closely related, heparin-binding cytokines with overlapping effects. These molecules have been shown to be neuroprotective by modulating neuroinflammation, supporting neuronal survival, growth, and differentiation, and enhancing synaptic strength and plasticity. Despite their reported neuroprotective properties, the involvement of PTN and MK signaling in ALS has not been previously investigated. In this study, we characterized the expression of the PTN/MK pathway in the lumbar spinal cords (SCs) of TDP-43[A315T] mice across different disease stages. We report a significant upregulation of Ptn, Mdk, and its receptor protein tyrosine phosphatase zeta (Ptprz1) mRNA levels at end-stage of disease in the lumbar SC of TDP-43[A315T] mice compared with age-matched wild-type littermates. Protein levels of PTN and MK were also upregulated at end-stage of disease. By immunofluorescence analysis, we also observed an upregulation of the immunostaining of both cytokines in neurons, astrocytes, microglia, and pericytes-like structures at end-stage of disease in the SC of TDP-43[A315T] mice. These findings open a new avenue to further study the potential role of the PTN/MK signaling axis in the pathogenesis of ALS. Trial Registration: Animal Ethics Committee of the Hospital Nacional de Parapléjicos in Toledo (Spain): Approval No. 26/OH 2018.}, } @article {pmid41605610, year = {2026}, author = {Oreskovic, E and Petzold, A and Petropoulos, IN and Hau, S}, title = {Corneal confocal microscopy as a paraclinical test in neurodegenerative disease: a scoping review.}, journal = {The British journal of ophthalmology}, volume = {110}, number = {9}, pages = {971-980}, doi = {10.1136/bjo-2025-328181}, pmid = {41605610}, issn = {1468-2079}, mesh = {Humans ; Microscopy, Confocal/methods ; *Neurodegenerative Diseases/diagnosis/diagnostic imaging ; *Cornea/innervation/diagnostic imaging ; *Nerve Fibers/pathology ; *Corneal Diseases/diagnosis ; }, abstract = {Corneal confocal microscopy (CCM) is a non-invasive imaging technique that enables quantification of the corneal sub-basal nerve plexus and has emerged as a potential surrogate biomarker for peripheral neurodegeneration. This scoping review evaluated current evidence on the use of CCM in assessing corneal nerve fibre changes across neurodegenerative diseases (NDDs) and explored its potential as a paraclinical diagnostic and monitoring tool. A comprehensive search of PubMed and Scopus was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines to identify studies reporting quantitative CCM metrics, including corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fibre length (CNFL). Both cross-sectional and longitudinal studies of patients with NDDs were included, and findings were narratively synthesised. 50 studies were included: Parkinson's disease (n=13), multiple sclerosis (n=11), cerebrovascular accidents (n=7), post-COVID-19 neuropathy (n=5), amyotrophic lateral sclerosis (n=4), chronic inflammatory demyelinating polyneuropathy (n=4), Alzheimer's disease (n=3), Fabry disease (n=2) and neurofibromatosis type 1 (n=1). CNFL and CNFD were consistently reduced in Parkinson's disease, multiple sclerosis, cerebrovascular accidents, amyotrophic lateral sclerosis, chronic inflammatory demyelinating polyneuropathy and post-COVID-19 neuropathy, whereas CNBD results were inconsistent. The strongest evidence supported the role of CCM in Parkinson's disease and multiple sclerosis. CNFL and CNFD emerged as the most reliable CCM-derived metrics across NDDs, supporting their potential as objective biomarkers for neurodegeneration. While findings support the potential of CCM as a paraclinical diagnostic tool, methodological heterogeneity in image acquisition, analysis software and study design limited comparability. Standardised imaging and analysis protocols are needed to enable broader clinical application and validation across NDDs.}, } @article {pmid41606859, year = {2025}, author = {Dehbasteh, M and Naderi Tehrani, N and Parastar, H}, title = {Multivariate curve resolution followed by partial least squares-discriminant analysis combined with Vis-NIR hyperspectral imaging for rice authentication.}, journal = {Food research international (Ottawa, Ont.)}, volume = {221}, number = {Pt 1}, pages = {117266}, doi = {10.1016/j.foodres.2025.117266}, pmid = {41606859}, issn = {1873-7145}, mesh = {*Oryza/chemistry/classification ; Least-Squares Analysis ; Discriminant Analysis ; *Hyperspectral Imaging/methods ; Spectroscopy, Near-Infrared/methods ; Multivariate Analysis ; *Food Contamination/analysis ; Iran ; Reproducibility of Results ; }, abstract = {Rice serves as a staple food for nearly half the global population, especially in Asia, where it is a major agricultural commodity. Nonetheless, deceptive practices, like blending premium and inferior rice varieties and selling them at inflated prices, present a considerable challenge to the industry. This study aims to authenticate rice samples using visible-short wavelength hyperspectral imaging (Vis-SWNIR HSI). To achieve this goal, 163 intact rice samples were sourced from three northern provinces of Iran (Gilan, Mazandaran and Golestan), including four different varieties (Hashemi, Shiroodi, Fajr and Neda). Samples were scanned by HSI device to record their cubic data. The HSI data of different samples were used in a column-wise augmented data matrix with pixels of different samples as rows and wavelengths as columns. The pure spatial (distribution maps) and spectral profiles of desired components were extracted using multivariate curve resolution-alternating least squares (MCR-ALS). As low-quality rice samples are considered adulterants for high-quality samples, the obtained data were used to differentiate samples by their origin as well as in adultertation detection. To the best of our knowledge, the MCR-ALS algorithm has not been used for rice authentication before using their intact forms. Further chemometric analyses, including principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA), were applied to the spectral-resolved profiles of samples. This enables us to discriminate three different origins and four varieties of rice samples, as well as for adulteration detection, providing classification accuracies of 94.4 %, 82.75 % and 100 % in the prediction sets, respectively. Such an outcome indicates the practical feasibility of imaging methods for rapid, cost-effective and non-invasive food authentication purposes.}, } @article {pmid41607656, year = {2025}, author = {Ha, LL and Mitra, S and Ho, DT and Fillingham, B and Berry, JD and Swoboda, KJ and Alves, CRR}, title = {Circulating Tau Profiles in Pediatric and Adult Patients with Spinal Muscular Atrophy.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41607656}, support = {K01 NS134784/NS/NINDS NIH HHS/United States ; R01 HD054599/HD/NICHD NIH HHS/United States ; R21 NS108015/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: To determine alterations in circulating Tau and phosphorylated Tau (pTau) profiles in pediatric and adult patients with spinal muscular atrophy (SMA).

METHODS: Circulating total Tau, pTau-181, pTau-217, pTau-262, and pTau-396 concentrations were measured across three cohorts: 1) adults including healthy controls, SMA patients, and ALS patients; 2) pediatric SMA patients and age-matched controls; and 3) pediatric SMA patients treated with onasemnogene abeparvovec.

RESULTS: Distinct alterations in circulating Tau species were detected in adult SMA and ALS. Among all measurements, pTau-262 emerged as the only species specifically elevated in adult SMA, while total Tau levels were comparable between adult SMA and controls but significantly increased in ALS. Tau alterations were not consistently observed in pediatric SMA, although a small subset showed elevated levels, underscoring the value of individualized biomarker monitoring upon diagnosis. In gene-therapy-treated infants, Tau levels increased transiently several weeks after onasemnogene abeparvovec injection, paralleling previously described neurofilament kinetics and suggesting acute, treatment-associated neuronal stress.

CONCLUSIONS: Circulating Tau, particularly pTau-262, may serve as a disease-relevant biomarker in adult SMA, while pediatric profiles appear more heterogeneous. Transient Tau elevations after gene therapy may reflect acute neuronal vulnerability and warrant further investigation.}, } @article {pmid41607759, year = {2026}, author = {Kirkik, D and Ozadenc, HM and Kalkanli Tas, S}, title = {Machine learning approaches to early detection of delayed wound healing following gastric cancer surgery.}, journal = {World journal of gastrointestinal oncology}, volume = {18}, number = {1}, pages = {114499}, pmid = {41607759}, issn = {1948-5204}, abstract = {Delayed wound healing following radical gastrectomy remains an important yet underappreciated complication that prolongs hospitalization, increases costs, and undermines patient recovery. In An et al's recent study, the authors present a machine learning-based risk prediction approach using routinely available clinical and laboratory parameters. Among the evaluated algorithms, a decision tree model demonstrated excellent discrimination, achieving an area under the curve of 0.951 in the validation set and notably identifying all true cases of delayed wound healing at the Youden index threshold. The inclusion of variables such as drainage duration, preoperative white blood cell and neutrophil counts, alongside age and sex, highlights the pragmatic appeal of the model for early postoperative monitoring. Nevertheless, several aspects warrant critical reflection, including the reliance on a postoperative variable (drainage duration), internal validation only, and certain reporting inconsistencies. This letter underscores both the promise and the limitations of adopting interpretable machine learning models in perioperative care. We advocate for transparent reporting, external validation, and careful consideration of clinically actionable timepoints before integration into practice. Ultimately, this work represents a valuable step toward precision risk stratification in gastric cancer surgery, and sets the stage for multicenter, prospective evaluations.}, } @article {pmid41609580, year = {2026}, author = {Purvinsh, Y and Matveyenka, M and Kurouski, D}, title = {Elucidation of Molecular Mechanisms of Lipid-Altered Cytotoxicity of TDP-43 Fibrils.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {4}, pages = {823-832}, pmid = {41609580}, issn = {1948-7193}, support = {R35 GM142869/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *DNA-Binding Proteins/metabolism/chemistry/toxicity ; Rats ; Humans ; *Amyloid/metabolism ; Phosphatidylserines/metabolism ; Cardiolipins/metabolism ; *Lipid Bilayers/metabolism ; Endosomes/metabolism ; }, abstract = {Progressive aggregation of TAR DNA-binding protein 43 (TDP-43) is a hallmark of numerous neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, and limbic predominant age-related TDP-43 encephalopathy (LATE). This highly conserved nuclear RNA/DNA-binding protein is involved in the regulation of RNA processing. The C-terminal domain (CTD) of TDP-43 plays a key role in protein solubility, cellular localization, and protein-protein interactions. CTD is rich in glycine, glutamine, and asparagine, which facilitate TDP-43 aggregation into amyloid oligomers and fibrils observed in the brain. In this study, we examine the role of lipid bilayers in the aggregation properties of the CTD of TDP-43. We found that lipid bilayers composed of anionic phosphatidylserine and cardiolipin accelerated TDP-43 aggregation. Although lipids did not alter the secondary structure, they altered the cytotoxicity that TDP-43 fibrils exerted to rat dopaminergic cells. Using molecular methods, we showed that TDP-43 fibrils damage cell endosomes. This causes aggregate leakage into the cytosol, where TDP-43 fibrils impair cell autophagy, simultaneously triggering a severe unfolded protein response in the endoplasmic reticulum. Our results indicate that TDP-43 aggregation may be linked to pathological changes in the lipid profiles of neurons.}, } @article {pmid41610283, year = {2026}, author = {Hayes, JM and Fornagiel, M and Kipust, A and Peters, GA and Goldberg, SA and Cash, RE}, title = {Statewide Emergency Medical Services Protocols for Field-Initiated Blood Resuscitation.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/10903127.2026.2623431}, pmid = {41610283}, issn = {1545-0066}, abstract = {OBJECTIVES: Prehospital blood transfusion by emergency medical services (EMS) is associated with improved outcomes in trauma patients, but little is known about the statewide protocols that influence the availability and use of prehospital blood. This study aimed to describe statewide EMS protocols regarding field-initiated prehospital blood and blood product transfusion across the U.S.

METHODS: This was a cross-sectional analysis of publicly available statewide EMS protocols pertaining to field-initiated blood or blood product use during ground transport by advanced life support (ALS) clinicians. We excluded protocols specific to critical care or interfacility transport. We used a standardized data collection tool to compare clinical indications, blood product type, and considerations for pediatrics and biologically female patients who may bear children in the future. Descriptive statistics were used to describe the protocols.

RESULTS: We identified 31 states and the District of Columbia with publicly available statewide EMS protocols. Thirteen (42%) of these protocols allowed for field-initiated prehospital blood transfusion. There was variability regarding recommendations for transfusion indications and the details of administration in the protocols. All protocols allowed for transfusion in traumatic emergencies, and nine (69%) allowed for transfusion in medical emergencies. Three (23%) protocols specifically recommended low titer group O whole blood, and three (23%) protocols allowed transfusion during cardiac arrest. Nine (69%) protocols allowed for transfusion in pediatric patients. Only four (31%) protocols included special considerations for transfusing blood to biologically female patients.

CONCLUSIONS: While most statewide EMS protocols in the US did not include field-initiated blood transfusion, the protocols that do exist vary widely. With the increasing implementation of prehospital blood programs, these findings suggest an opportunity to provide more robust evidence-based guidelines for prehospital blood transfusion to improve patient care and outcomes.}, } @article {pmid41610293, year = {2026}, author = {Gauld, N and Cleland, J and Buchanan, S and Hikaka, J and Frampton, C and Buetow, S}, title = {Riluzole use and reasons for non-use in people with amyotrophic lateral sclerosis in Aotearoa New Zealand.}, journal = {The New Zealand medical journal}, volume = {139}, number = {1628}, pages = {50-57}, doi = {10.26635/6965.7238}, pmid = {41610293}, issn = {1175-8716}, support = {//This research was funded by a Health Research Council Research Activation Grant, a Motor Neurone Disease New Zealand grant and some voluntary time by the authors./ ; }, mesh = {Humans ; *Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; New Zealand ; Female ; Male ; Middle Aged ; *Neuroprotective Agents/therapeutic use ; Aged ; Surveys and Questionnaires ; Adult ; }, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS), the most common form of motor neurone disease (MND), is a neurodegenerative condition with typically short life expectancy. Riluzole, the only survival prolonging medication funded in Aotearoa New Zealand, has high uptake in other developed countries.

AIMS: To quantify riluzole use in New Zealand, identify factors associated with its use and explore reasons for non-use.

METHODS: In 2025, people in New Zealand diagnosed with MND were invited to self-complete questionnaires. Data were collected via Qualtrics, exported to Excel and analysed using descriptive and inferential statistics. Respondents with progressive muscular atrophy or primary lateral sclerosis diagnoses were excluded from this analysis.

RESULTS: Of 115 respondents, 55 (48%) were currently taking riluzole, 14 (12%) had taken it previously and 42 (36%) had never taken it. Common reasons for non-use included riluzole not being offered and concerns about lack of effectiveness and/or side effects. Uptake was lower with bulbar onset than limb onset (p<0.05).

CONCLUSIONS: People with ALS in New Zealand have low uptake of riluzole, despite its survival benefits. Prescribers and people with ALS need up-to-date information about riluzole's benefit-risk profile to increase uptake and confidence in prescription and use. Liquid riluzole is needed in New Zealand to aid uptake.}, } @article {pmid41611003, year = {2026}, author = {Flose, BR and Silva, KCN and Juliano, MA and Trevisani, VFM and França, CN and Corral, MA and Nali, LHDS and Shio, MT}, title = {Antibody response against HERV-K polymerase and envelope by patients with multiple sclerosis.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {584}, number = {}, pages = {120870}, doi = {10.1016/j.cca.2026.120870}, pmid = {41611003}, issn = {1873-3492}, mesh = {Humans ; *Endogenous Retroviruses/immunology/enzymology ; *Multiple Sclerosis/immunology/blood/virology ; Enzyme-Linked Immunosorbent Assay ; *Viral Envelope Proteins/immunology ; Female ; Male ; Adult ; *Antibodies, Viral/immunology/blood ; Middle Aged ; *Antibody Formation ; Gene Products, env/immunology ; }, abstract = {INTRODUCTION: Human Endogenous Retroviruses (HERVs) are viruses that have infected germ cells of our ancestors millions of years ago and compose 8% of human genome. The expression of HERVs is associated with neurological disorders such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). The humoral immune response against peptides from the envelope proteins, but not to polymerase, of HERV-K has been previously described. The aim of this study is to evaluate anti-HERV- K polymerase (pol) humoral response in patients with MS.

METHODS: GenBank platform were used to select peptides with similarity above 50%, comparing HERV sequences (K or W) with the protein Myelin Oligodendrocyte Glycoprotein (MOG). The synthesized peptides were used in the ELISA test for anti-HERV-K (pol - polymerase) and W (env - envelope) antibodies in serum of patients with MS (31) and healthy population (54) with no history of autoimmune diseases.

RESULTS: One peptide (pep) related to HERV-W env and 8 peptides of HERV-K env or pol were selected and synthesized. Validation of the indirect ELISA with sera from MS patients showed that there was immunoreactivity for all peptides compared to healthy population (p < 0.0001). HERV-K env peptide 5 (WSGNQTLETRD) and 7 (ECVANSAVIL) showed the highest values of sensitivity and specificity, as well as diagnostic accuracy with 95.16% and 96.77%, respectively. HERV-K pol peptides 6 (LGIPTYAM), 8 (VTHVPSFR) and 9 (STVKTFTYLD) have demonstrated high values of accuracy 82.26, 80.65 and 82.26, respectively. These cutoff values were used to calculate the ELISA index - EI. The MS samples had a higher EI compared to the healthy population for almost all peptides of HERV-K pol (p < 0.001).

CONCLUSION: The present work showed a humoral response related to HERV-K pol and env, as well as HERV-W env, by patients with MS. All diagnostic parameters are appreciable, which makes it possible to use this tool to better understand the mechanisms related to viral immunology in patients.}, } @article {pmid41611549, year = {2026}, author = {Santurtún, A and Medín, P and Riancho, JA and Santiago-Setién, M and Ortiz, F and López de Munain, A and Almendra, R and Riancho, J}, title = {Corrigendum to "Temporo-spatial analysis of amyotrophic lateral sclerosis in Spain: Altitude and land use as new determinants of the disease" [Sci. Total Environ., 957 (2024), 177796].}, journal = {The Science of the total environment}, volume = {1015}, number = {}, pages = {181474}, doi = {10.1016/j.scitotenv.2026.181474}, pmid = {41611549}, issn = {1879-1026}, } @article {pmid41612406, year = {2026}, author = {Bigi, A and Chiti, F}, title = {Understanding liquid-liquid phase separation through TDP-43: fundamental principles, subcellular compartmentalisation, and role of solid inclusion formation.}, journal = {Genome biology}, volume = {27}, number = {1}, pages = {}, pmid = {41612406}, issn = {1474-760X}, support = {#NEXTGENERATIONEU (NGEU) - National Recovery and Resilience Plan (NRRP), Investment PE8─Project Age-It: "Ageing Well in an Ageing Society" (D.R. 1557 11.10.2022).//Ministero dell'Università e della Ricerca/ ; Fondi di Ateneo RICATEN 2024 and RICATEN 2025//Università degli Studi di Firenze/ ; Fondi di Ateneo RICATEN 2023, RICATEN 2024 and RICATEN 2025//Università degli Studi di Firenze/ ; }, mesh = {Phase Separation ; *DNA-Binding Proteins/metabolism/chemistry ; Humans ; *Inclusion Bodies/metabolism ; Animals ; Cell Compartmentation ; Amyotrophic Lateral Sclerosis/metabolism ; Neurodegenerative Diseases/metabolism ; }, abstract = {Phase separation is an important process in biology associated with formation of membraneless organelles but possibly related to the emergence of solid inclusions. TDP-43 is a largely studied paradigmatic case, as it forms neuronal cytoplasmic inclusions in neurodegenerative diseases and is an essential component of many membraneless organelles. Here, we review the physicochemical fundamentals of liquid-liquid phase separation (LLPS) of TDP-43 and its fragments in vitro, showing that full-length TDP-43 requires RNA or chaperones to form stable liquid droplets. We describe TDP-43-containing membraneless organelles and the debate on whether these assemblies represent reservoirs for pathological solid inclusion formation.}, } @article {pmid41612503, year = {2026}, author = {Takahashi, K and Kato, C and Ueda, K and Nakamura, S and Ozawa, F and Moritoki, N and Shibata, S and Takahashi, S and Morimoto, S and Okano, H}, title = {Diagnostic potential of cryptic exon-derived peptides in serum extracellular vesicles for sporadic amyotrophic lateral sclerosis.}, journal = {Inflammation and regeneration}, volume = {46}, number = {1}, pages = {}, pmid = {41612503}, issn = {1880-9693}, support = {JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP25H00007//Japan Society for the Promotion of Science/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP25ek0109811//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; JP25wm0625519//Japan Agency for Medical Research and Development/ ; 2024A04//Japan Intractable Diseases（Nanbyo）Research Foundation/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration and loss of upper and lower motor neurons, with approximately 90% of cases being sporadic (sporadic ALS, SALS). A reliable diagnostic biomarker remains an unmet clinical need in SALS, with misdiagnosis and diagnostic delay hindering early management. The mislocalization of the RNA-binding protein TDP-43 (encoded by TARDBP), a pathological hallmark of SALS, could lead to aberrant splicing that produces transcripts with cryptic exons and, consequently, cryptic peptides. This study proposes cryptic peptides in serum extracellular vesicles as a novel candidate diagnostic biomarker of SALS. We included 10 healthy controls and 20 patients with SALS and quantified cryptic peptides predicted from cryptic exon sequences using mass spectrometry-based proteomics. Cryptic peptides from four proteins (RANBP1, IGLON5, ACTN1, ALPK2) were detected in participants, with the IGLON5 cryptic peptide detected significantly more frequently in SALS than in HC (adjusted P = 0.044). The number of detected cryptic peptides classified SALS and healthy controls with acceptable performance (area under the curve = 0.82). In conclusion, cryptic peptides could have diagnostic performance for SALS, warranting further validation.}, } @article {pmid41613186, year = {2025}, author = {An, W and Jin, Z and Li, Y}, title = {Dual role of exosomes in neurodegenerative diseases: a molecular bridge between neuroinflammation and transmission of pathological proteins.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1708655}, pmid = {41613186}, issn = {1664-2295}, abstract = {Neurodegenerative diseases (NDDs) are complex disorders characterized by the progressive loss of neuronal function. Their pathological mechanisms involve multiple levels, including neuroinflammation, abnormal protein aggregation, and disrupted cell signaling. Diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), multiple sclerosis (MS), and prion diseases not only severely impact patients' quality of life but also pose significant challenges for medical research due to their complex pathogenesis and the lack of effective treatments. In recent years, extracellular vesicles (EVs), particularly exosomes, have garnered increasing attention for their critical role in cell-to-cell communication. Exosomes are membrane-enclosed nanovesicles approximately 30-150 nm in diameter that can carry proteins, lipids, nucleic acids, and other bioactive molecules, influencing recipient cells through paracrine or distant signaling. This review aims to summarize the roles of exosomes as mediators of neuroinflammation and as vehicles for intercellular transmission of pathogenic proteins in neurodegenerative diseases.}, } @article {pmid41613245, year = {2026}, author = {Aronsen, J}, title = {You have ALS: a nurse's revolt against despair.}, journal = {Journal of research in nursing : JRN}, volume = {}, number = {}, pages = {17449871251407834}, doi = {10.1177/17449871251407834}, pmid = {41613245}, issn = {1744-988X}, } @article {pmid41613680, year = {2025}, author = {Yamazaki, J and Hideyama, T and Teramoto, S and Kato, H and Aizawa, H and Kwak, S and Terashi, H}, title = {Age-Related Changes in Matrix Metalloproteinase-9 Expression in Spinal Motor Neurons of Normal Mice.}, journal = {Cureus}, volume = {17}, number = {12}, pages = {e100305}, pmid = {41613680}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving the degeneration of upper motor neurons (UMNs) and lower motor neurons (LMNs). Although the cause of motor neuron (MN) degeneration in patients with ALS remains unknown, certain MN types (such as oculomotor neurons) and MNs within the Onuf (Onuf-Mannen) nucleus are preserved until the terminal stage. We previously generated mice with a selective knockout of adenosine deaminase acting on RNA 2 (ADAR2) in cholinergic neurons (ADAR2[flox/flox] /vesicular acetylcholine transporter (VAChT)-Cre.Fast; AR2). AR2 mice exhibit slow progressive loss of LMNs accompanied by TAR DNA-binding protein 43 (TDP-43) pathology against a background of insufficient editing at the GluA2 glutamine/arginine (Q/R) site due to ADAR2 deficiency. This model confirmed that insufficient editing at the GluA2 Q/R site, due to reduced ADAR2 activity, contributes to the pathogenesis of ALS. Furthermore, in AR2 mice, more frequent death of fast-fatigable motor neurons (FF MNs) was observed owing to differences in vulnerability under ADAR2-deficient conditions. Similar changes were observed during normal aging in the control mice. These findings suggest that investigating the characteristics of FF MNs may be useful for analyzing neuronal death in ALS. Recently, matrix metalloproteinase-9 (MMP-9), a marker of FF MNs, was reported to induce neurodegeneration. However, the distribution of MMP-9 in normal spinal MNs and its age-related changes remain unclear. Therefore, we investigated the MMP-9 expression patterns in normal mice at six and 12 months of age. In the present study, the number of MNs in the anterior horn (AH) decreased with age, as did the number of MMP-9-positive MNs. Furthermore, as aging has been shown to induce the abnormal localization of TDP-43 in MMP-9-positive MNs, these MNs were considered vulnerable to degeneration. These findings suggest that MMP-9 not only functions as a marker for FF MNs but may also act as a potentially useful marker for MNs prone to degeneration with TDP-43 pathology, or for early degeneration in both physiological aging and age-related diseases, including ALS. Future investigations of MMP-9 expression in patients with ALS and in ALS mouse models are considered useful for elucidating ALS pathogenesis.}, } @article {pmid41614057, year = {2025}, author = {Subramani, NK and Venugopal, S and Rajan, AP}, title = {An integrated subtractive genomics and immunoinformatic approach for designing a multi-epitope peptide vaccine against methicillin-resistant Staphylococcus aureus.}, journal = {Frontiers in bioinformatics}, volume = {5}, number = {}, pages = {1745495}, pmid = {41614057}, issn = {2673-7647}, abstract = {INTRODUCTION: MRSA is a multi-drug-resistant bacteria responsible for severe infections that has become a major health concern. Due to constraints of traditional methods, there is a need for developing a new approach to prevent the MRSA-related infections by targeting key pathogens.

METHODS: Initially, the subtractive genomics was applied to the MRSA proteome to identify non-homologous, essential, and virulence targets using comparative BLAST-based screening. Further, immunoinformatic tools were employed for B- and T-cell epitope prediction and vaccine construction with appropriate adjuvants and linkers, followed by immune simulation and molecular docking with immune receptors.

RESULTS: Comparative metabolic pathway analysis identified 294 MRSA pathway proteins, with acetolactate synthase (ALS) as a non-homologous, essential, and virulent protein that is involved in the branched amino acid biosynthesis pathway. The constructed ALS vaccine consists of 3 B-cell and 19 T-cell epitopes exhibited stable immunological features with 97.55% global population coverage. Molecular docking revealed that ALS exhibited a superior binding affinity with the TLR4 receptor (-1,438.7 kcal/mol) than the TLR2 receptor (-1,103.5 kcal/mol), which was further confirmed by high structural stability and compactness analysis. Immune simulations also exhibited elevated IgM, IgG subtypes, and cytokine productions, suggesting a robust humoral and cellular immunity.

DISCUSSION: Identified ALS highlights its biological relevance in MRSA survival. The stability predictions with TLR4 suggested effective activation of innate immunity that may enhance antigen presentation and downstream adaptive immunity. The validation of the ALS vaccine's safety and immunogenicity further requires comprehensive in vitro and in vivo examinations.

CONCLUSION: Thus, ALS is recognized as a promising MRSA vaccine candidate and has the potential to activate immune responses effectively.}, } @article {pmid41614607, year = {2026}, author = {Combe, P and Subecz, C and Le Goff, G and Plamont, MA and Bohl, D and Gueroui, Z}, title = {Concentration-dependent cytoplasmic phase separation of TDP-43 drives aggregation and proteinopathy.}, journal = {The FEBS journal}, volume = {293}, number = {14}, pages = {4167-4184}, pmid = {41614607}, issn = {1742-4658}, support = {MND202003011470//Fondation pour la Recherche Médicale/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics/chemistry ; Humans ; Phase Separation ; *Cytoplasm/metabolism ; *Protein Aggregation, Pathological/metabolism/genetics/pathology ; Cell Nucleus/metabolism ; Protein Aggregates ; Oxidative Stress ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *Frontotemporal Lobar Degeneration/pathology/genetics/metabolism ; Animals ; Stress Granules/metabolism ; }, abstract = {TDP-43 mislocalization and aggregation are common features of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the mechanisms underlying the transition of nuclear TDP-43 to cytoplasmic aggregates, and their contribution to disease pathogenesis, remain poorly understood. To address this gap, we present a methodology to chemically control the assembly and disassembly of cytoplasmic TDP-43 condensates. By fusing TDP-43 to a phase separation-prone protein scaffold, we can induce the formation of cytoplasmic TDP-43 condensates or, conversely, promote nuclear localization upon addition of a disassembly molecule. TDP-43 accumulates into various assemblies, ranging from submicrometric puncta to larger aggregate-like structures that display hallmarks of proteinopathy in a concentration-dependent manner. Furthermore, oxidative stress drives the maturation of TDP-43 assemblies from puncta into aggregates through interactions with stress granule components. Finally, we show that cytoplasmic TDP-43 aggregates deplete nuclear endogenous TDP-43 and induce cytotoxicity. Collectively, these findings highlight the local cytoplasmic concentration of TDP-43 and stress exposure as key determinants in the onset of TDP-43 proteinopathy, providing a relevant model to study pathological TDP-43 aggregation.}, } @article {pmid41615807, year = {2026}, author = {Azizzadeh, M and Pirker-Kees, A and Wouters, EFM and Janssen, DJA and Spaetgens, B and Breyer-Kohansal, R and Breyer, MK}, title = {Association of allostatic load with frailty trajectories and the mediating role of depressive symptoms.}, journal = {The Journal of frailty & aging}, volume = {15}, number = {2}, pages = {100132}, pmid = {41615807}, issn = {2260-1341}, mesh = {Humans ; *Allostasis/physiology ; Aged ; *Frailty/psychology/physiopathology/epidemiology/diagnosis ; *Depression/epidemiology/physiopathology/psychology ; Female ; *Frail Elderly/psychology/statistics & numerical data ; Male ; Aged, 80 and over ; Middle Aged ; Adult ; Risk Factors ; Geriatric Assessment/methods ; }, abstract = {BACKGROUND: Frailty is a dynamic, age-related condition marked by progressive loss of resilience. Its risk factors include socioeconomic status and physiological stress burden, such as allostatic load score (ALS), remain unclear. This study aims to examine the role of depression in the association between ALS and frailty trajectories.

METHODS: We analyzed data from 5885 LEAD cohort participants aged 25-82 years at baseline and from 3564 participants with follow-up data. Frailty status (robust, pre-frail, frail) was defined using the Fried phenotype, and transitions between visits were assessed. ALS was calculated from 14 parameters spanning cardiovascular, metabolic, and body composition measures. Associations of ALS with frailty status at baseline and with frailty transitions at follow-up were examined, and depressive symptoms were tested as a mediator.

RESULTS: At baseline, 62.3% of participants were robust, 36.2% pre-frail, and 1.5% frail. Between visits, 16.3% transitioned to a worse frailty stage, while 17.7% improved. Higher ALS was linked to increased odds of being pre-frail/frail at baseline (OR 1.11; 95% CI: 1.08-1.15), and to a higher risk of transitioning from robust to pre-frail/frail (RRR 1.06; 95% CI: 1.02-1.09). Depressive symptoms mediated 35% (95% CI: 25-47%) of the cross-sectional and 17% (95% CI: 6.6-43%) of the longitudinal association between ALS and frailty.

CONCLUSIONS: Socioeconomic factors influenced frailty onset but not its progression, whereas depressive symptoms mediated approximately 17% of the effect of ALS on frailty development over time. These findings highlight the importance of exploring the effect of interventions for depression on frailty progression.}, } @article {pmid41616079, year = {2026}, author = {Steenkjaer, CH and Storgaard, JH and Levison, L and Blicher, JU}, title = {A national survey of pseudobulbar affect and symptomatic treatment in Amyotrophic Lateral Sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {565-571}, doi = {10.1080/21678421.2026.2620448}, pmid = {41616079}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications/diagnosis ; Female ; Cross-Sectional Studies ; *Pseudobulbar Affect/epidemiology/diagnosis/etiology/drug therapy/therapy ; Male ; Middle Aged ; Aged ; Denmark/epidemiology ; Prevalence ; Antidepressive Agents/therapeutic use ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: We aimed to determine diagnostic prevalence and symptom burden of pseudobulbar affect (PBA) in patients with Amyotrophic Lateral Sclerosis (ALS) in Denmark and differences in ongoing symptomatic treatment.

METHODS: In this national cross-sectional survey study, participants with ALS completed an online survey regarding PBA and PBA symptoms, which were quantified through the Center for Neurologic Study Lability Scale (CNS-LS). A CNS-LS score ≥ 13 served as a threshold indicative of PBA.

RESULTS: 157 participants with ALS were recruited. 12.1% were diagnosed with PBA and were more likely to receive antidepressant medication compared to those not diagnosed with PBA (47.4% compared to 15.2%, p = 0.002). 30.6% scored ≥13 in the CNS-LS; however, the proportion of participants treated with antidepressants was similar compared to those scoring below the ≥13 threshold (25% compared to 16.5%, p = 0.27). Of those not diagnosed with PBA, 23.2% scored ≥13 in the CNS-LS. This PBA symptomatic, but undiagnosed group was less likely to receive symptomatic treatment compared to patients with diagnosed PBA (12.5% compared to 47.4%, p = 0.009). No differences were seen in CNS-LS score between these groups.

CONCLUSIONS: The proportion of diagnosed PBA among the study population was low compared to previous studies; however, the proportion of patients with symptoms of possible PBA was markedly higher. Patients with known PBA were more likely to receive recommended symptomatic treatment compared to patients not diagnosed with PBA, despite symptoms indicative of PBA. These findings highlight the potential underrecognition of PBA in ALS and concurrent absence of symptomatic treatment.}, } @article {pmid41616251, year = {2026}, author = {Sang, Y and Ren, J and Aballay, A}, title = {A gut-activated NHR-86-CYP pathway mediates the neuroprotective effects of Enterococcus faecium probiotics in a nematode model of amyotrophic lateral sclerosis.}, journal = {PLoS biology}, volume = {24}, number = {1}, pages = {e3003627}, pmid = {41616251}, issn = {1545-7885}, support = {P40 OD010440/OD/NIH HHS/United States ; R01 AI117911/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Probiotics/pharmacology ; Caenorhabditis elegans/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Enterococcus faecium/metabolism ; Oxidative Stress/drug effects ; Disease Models, Animal ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; *Neuroprotective Agents/pharmacology ; Reactive Oxygen Species/metabolism ; Motor Neurons/metabolism ; Signal Transduction ; Animals, Genetically Modified ; }, abstract = {Neurodegenerative diseases are often associated with oxidative stress, and while probiotics may influence neuronal health, the underlying mechanisms remain poorly understood. Using the sod-1 A4VM amyotrophic lateral sclerosis (ALS) model in Caenorhabditis elegans, we investigated the protective effects of the probiotic Enterococcus faecium against oxidative stress-induced neurodegeneration. Animals fed E. faecium showed reduced motor neuron degeneration under oxidative stress compared to those maintained on a standard Escherichia coli diet. Transcriptome analysis revealed a significant enrichment of oxidoreductase genes, including cytochrome P450 (cyp) genes. RNAi-mediated knockdown of cyp genes impaired E. faecium-mediated neuroprotection, and this loss correlated with increased reactive oxygen species (ROS) levels. We identified the conserved nuclear hormone receptor NHR-86 as a key regulator of cyp gene expression and neuroprotection. Loss of nhr-86 abolished the probiotic's protective benefits, while transgenic expression of nhr-86 restored cyp induction and neuronal resilience. Importantly, intestinal expression of NHR-86 was sufficient to restore CYP induction and neuronal resilience, whereas neuronal knockdown had no effect, indicating that gut NHR-86 activity is essential for this protective pathway. These findings reveal a previously uncharacterized NHR-CYP regulatory axis activated by an intestinal probiotic, highlighting a mechanistic link between microbial signals and host neuroprotection.}, } @article {pmid41617608, year = {2026}, author = {Tankéré, P and Bernard, E and Herquelot, E and Denis, H and Sfeir, L and Saint-Raymond, C and Mallaret, M and Lavergne, F and Baillieul, S and Peter-Derex, L and Tamisier, R and Pépin, JL}, title = {Health trajectories of patients with amyotrophic lateral sclerosis before and after initiation of non-invasive ventilation: a French nationwide database analysis.}, journal = {Thorax}, volume = {81}, number = {10}, pages = {999-1007}, doi = {10.1136/thorax-2025-223974}, pmid = {41617608}, issn = {1468-3296}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/mortality/complications ; *Noninvasive Ventilation/methods ; France/epidemiology ; Female ; Male ; Aged ; Databases, Factual ; Middle Aged ; *Respiratory Insufficiency/therapy/etiology ; }, abstract = {BACKGROUND: Management of amyotrophic lateral sclerosis (ALS) is complicated by heterogeneous presentation and unpredictable disease course. This study described disease trajectories before and after initiation of non-invasive ventilation (NIV) therapy in individuals with ALS, examined the relationship between NIV initiation timing and survival and analysed health trajectory clusters.

METHODS: Data were extracted from the French national health insurance reimbursement system database for individuals with ≥1 reimbursement for NIV from January 2015 to December 2019, and ≥1 ALS disease code. Health trajectory clusters were determined using time sequence analysis through K-clustering.

RESULTS: We analysed data from 3443 individuals with ALS (58% male, median age 67 years). The median (IQR) time from ALS diagnosis to NIV initiation was 10.8 (4.5-22.2) months and death occurred 21.5 (12.8-33.9) months after diagnosis. Tracheostomy/gastrostomy was performed in 3.9%/33.4% of patients, respectively. Unsupervised machine learning clustering identified four distinct patient groups. NIV initiation was late in two Clusters (A and B); these individuals were younger, had fewer comorbidities and more physiotherapy sessions before/after NIV. Survival after NIV initiation was longer in Clusters B and C; these individuals had lower rates of depression/anxiety, more prescription of mechanical in/exsufflation therapy and fewer home and emergency hospitalisations. Cluster B was unique, showing late NIV initiation and long post-NIV survival. This cluster was more likely to have spinal onset, a higher rate of obstructive sleep apnoea and fewer comorbidities.

CONCLUSIONS: There was marked heterogeneity between patients with ALS and their care trajectories. Our data do not support a universal benefit for early initiation of NIV therapy.}, } @article {pmid41618346, year = {2026}, author = {Öijerstedt, L and Mravinacová, S and Olofsson, J and Azizi, L and Bergström, S and Yazdani, S and De Vita, N and Aksoylu, IS and Foucher, J and Juto, A and Kläppe, U and Nilsson, P and Månberg, A and Ingre, C}, title = {Ratios of CSF proteins reflect cognitive function in ALS.}, journal = {Alzheimer's research & therapy}, volume = {18}, number = {1}, pages = {}, pmid = {41618346}, issn = {1758-9193}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/complications ; Female ; Biomarkers/cerebrospinal fluid ; Male ; Aged ; Middle Aged ; *Cognition Disorders/etiology/cerebrospinal fluid ; *Cerebrospinal Fluid Proteins/cerebrospinal fluid ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Cognitive impairment is a recognised feature of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Despite advances in understanding cognitive impairment in ALS, no fluid biomarkers reliably predict these changes. Prior research in Alzheimer disease (AD) has demonstrated that CSF protein ratios enhance biomarker accuracy by mitigating inter-individual variability, improving diagnostic precision. In AD, ratios involving synaptic markers have shown stronger associations with cognitive outcomes than single proteins, motivating evaluation of a similar ratio-based approach in ALS. METHODS: Building on findings from the AD field, we analysed 47 CSF proteins, suggested to be associated to neurodegeneration, in 66 patients with ALS and explored protein ratios to evaluate their utility in detecting cognitive impairment, hypothesising shared mechanisms between neurodegenerative diseases. Elastic net regression identified the most predictive protein pairs associated with cognitive impairment, assessed with the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). RESULTS: Elastic net identified seven single proteins (NEFM, NPTX2, GAP43, IGFBP4, IGFBP7, SPP1, CDH8) and eight protein pairs associated with ECAS total score. Ratios were generally more informative than individual proteins, with PTPRN2/GAP43 showing the strongest association with ECAS scores, indicating an enhanced ability to capture cognitive changes. Several of the proteins in the most predictive pairs have previously been implicated to associate to cognitive impairment in AD. CONCLUSION: Our findings indicate that protein ratios outperform single-protein analyses in detecting associations with cognitive impairment, aligning with advancements in AD research. By extending the concept of CSF protein ratios from AD to ALS, this study highlights shared pathological mechanisms and suggests that similar proteins are linked to cognitive dysfunction in both diseases.}, } @article {pmid41618385, year = {2026}, author = {Koyama, T and Tsumura, H and Okita, R and Yamazaki, K and Hasegawa, A and Imamura, K and Kato, T and Iwata, H and Kojima, R and Inoue, H and Matsumoto, S and Okuno, Y}, title = {Chemical genomics language model toward reliable and explainable compound-protein interaction exploration.}, journal = {Journal of cheminformatics}, volume = {18}, number = {1}, pages = {29}, pmid = {41618385}, issn = {1758-2946}, support = {JP24KJ1510//Japan Society for the Promotion of Science/ ; 22K06112//Japan Society for the Promotion of Science/ ; JP24H01771//Grant-in-Aid for Transformative Research Areas (A) "Latent Chemical Space"/ ; JP22bm0804034//Japan Agency for Medical Research and Development/ ; }, abstract = {Accurate prediction of compound-protein interactions (CPIs) is crucial for chemical biology and drug discovery. Despite recent advancements, existing deep learning (DL)-based CPI models often struggle to simultaneously achieve high generalization performance, quantify prediction confidence, and ensure explainability. Here, we propose ChemGLaM, a chemical genomics language model designed to address these three crucial challenges, thereby enabling reliable and explainable CPI predictions. ChemGLaM integrates independently pre-trained chemical and protein language models through an interaction block with a cross-attention mechanism, achieving near state-of-the-art performance in predicting novel CPIs at a low computational cost. Incorporating uncertainty estimation and attention visualization enables ChemGLaM to enhance the success rate of virtual screening and to provide molecular insights into CPIs. To demonstrate the practical impact of ChemGLaM, we constructed a publicly available database containing large-scale CPI predictions for every possible pairing between all 20,434 human proteins and all 11,455 drugs and validated its practical applicability in a case study on amyotrophic lateral sclerosis. ChemGLaM marks an important step forward in addressing the challenges of AI-driven CPI exploration and drug discovery.Scientific ContributionThis study established a unified CPI prediction framework that simultaneously achieves high generalization performance, confidence quantification, and explainability. We leveraged this framework to create a community resource by constructing a comprehensive CPI database and demonstrated its practical utility by successfully prioritizing hit compounds and deconvoluting their targets in a phenotypic screening for amyotrophic lateral sclerosis.}, } @article {pmid41618386, year = {2026}, author = {Omranikhoo, H and Rezaee, M and Verdizadeh, A and Goudarzi, Z and Jafari, M and Gholami, A and Poursadeghfard, M and Keshavarz, K}, title = {Cost-utility analysis of Edaravone compared to Riluzole in patients with amyotrophic lateral sclerosis (ALS) in Iran.}, journal = {Cost effectiveness and resource allocation : C/E}, volume = {24}, number = {1}, pages = {}, pmid = {41618386}, issn = {1478-7547}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating disease that damages motor neurons. Currently, two drugs, Riluzole and Edaravone, have been shown to slow the progression of this condition. This study aimed to evaluate the cost-utility of Edaravone compared to Riluzole in ALS patients.

METHODS: This is an economic evaluation and cost-utility analysis from Iran’s health system perspective using a 10-year and 20-year Markov model. Cost data were collected from medical records and expert interviews, while clinical outcomes and transition probabilities were obtained from a clinical trial study. The robustness of the findings was tested through both deterministic and probabilistic sensitivity analysis. Data was analyzed using Excel 2019 and TreeAge Pro 2020 software.

RESULTS: The findings of this study indicated that the cost of treatment and QALYs obtained from Edaravone (58,077 PPP$ and 1.66) compared to Riluzole (53,216 PPP$ and 1.37) were estimated to be higher in Iran. The calculated ICUR was equal to 16,704 PPP$ which is considered to be a cost-effective option in terms of the cost-effectiveness threshold to treat the patients with ALS. Furthermore, a one-way sensitivity analysis showed that the model is most affected by the cost discount rate and the price of Edaravone. Edaravone was identified as the best treatment strategy in 66% of simulations, making it the preferred option across different willingness to pay scenarios.

CONCLUSION: The findings of the study indicated that the Edaravone may be a more cost-effective and affordable option compared to the Riluzole. Consequently, the availability of this drug in the country is likely to improve the quality of life and increase the survival rates of patients.}, } @article {pmid41618645, year = {2026}, author = {Verhoeff, MC and van Selms, MKA and Lobbezoo, F}, title = {A Personal Exploration of Oral Health in Amyotrophic Lateral Sclerosis (ALS) Through the Eyes of a Multifaceted Authority.}, journal = {Journal of oral rehabilitation}, volume = {53}, number = {5}, pages = {1059-1064}, pmid = {41618645}, issn = {1365-2842}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Oral Health ; *Oral Hygiene ; Male ; Female ; }, abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that impairs motor function, including oral musculature, complicating oral hygiene and care. Despite its impact, oral health in ALS patients remains under-addressed. This personal scoping review explores oral health in ALS through the dual lens of Dr. Maurits K.A. van Selms-a dental researcher and ALS patient-highlighting care, research, and education priorities.

METHODS: Semi-structured interviews were conducted via email with Dr. van Selms, using a topic guide adapted from a prior personal scoping review. The interview covered personal experiences and professional insights into oral health care, research, and education in ALS. Responses were analysed and synthesised into thematic agendas.

RESULTS: Dr. van Selms emphasised the neglect of oral hygiene in ALS care. He advocated for patient-informed, tailored guidelines based on functional capacity, interdisciplinary collaboration, and improved accessibility to dental services. In research, he called for ethically sensitive, patient-centered studies that reduce the burden of oral care. Educationally, he stressed the need for inclusive training across disciplines and stakeholder levels, promoting self-advocacy and awareness. Instructional materials, such as videos, were recommended to support caregivers and patients.

CONCLUSION: This personal scoping review underscores the importance of integrating oral health into ALS management. Dr. van Selms' unique perspective reveals gaps in care delivery, research ethics, and education, advocating for interdisciplinary collaboration and proactive guideline development. His insights offer a roadmap for improving oral health outcomes and quality of life in ALS and similar neurodegenerative conditions.}, } @article {pmid41619021, year = {2026}, author = {Dressler, D and Frevert, J and Johnson, EA and Fink, K and Pellett, S and Pandey, S and Walter, U and Tacik, P and Kanovsky, P and Shahidi, GA and Brüggemann, N and Rosales, RL and Relja, M and Jin, L and Rodriguez, JAS and Pan, L and Francisco, GE and Shang, H and Bai, X and Adib Saberi, F}, title = {Iatrogenic botulism: a risk for botulinum toxin's medical use?.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {133}, number = {6}, pages = {949-957}, pmid = {41619021}, issn = {1435-1463}, mesh = {Humans ; *Botulism/chemically induced/etiology ; *Iatrogenic Disease ; *Botulinum Toxins/adverse effects/therapeutic use ; *Neuromuscular Agents/adverse effects ; }, abstract = {Botulinum toxin (BT) is infamous for its extreme toxicity. If it enters the bloodstream, it can cause botulism presenting with a typical pattern of motor and autonomic dysfunction. An international expert panel organised by IAB-Interdisciplinary Working Group for Movement Disorders explored iatrogenic botulism after BT's medical use (IB), reached conclusions and formulated recommendations. When injected into its target tissue, BT binds to gangliosides on cholinergic nerve terminals before it is internalised permanently. Small amounts of BT, however, are circulating within the bloodstream. When BT type B is applied, IB-B occurs frequently, typically affecting the autonomic nervous system. When BT type A is applied, IB-A only occurs in special circumstances, even when high doses are used. We identified 236 patients with IB-A in the literature. All IB-A was mild or moderate and fully reversible. In 212 patients, it occurred with unapproved BT use. In 116 of them, unapproved BT preparations were used, in 81, unapproved indications were treated and in 15, underlying neuromuscular impairment including myasthenia gravis, Lambert-Eaton myasthenic syndrome, amyotrophic lateral sclerosis and spinal muscle atrophy were contraindications for BT use. In 24 patients, IB-A occurred in approved BT use. Their evaluation was frequently incomplete, so that causes for IB-A often remain unclear. They may include presence of differential diagnosis, subclinical neuromuscular impairment and interference with additional diseases. When IB is suspected, proper evaluation is necessary to verify it and to identify its causes. Off-label use is common in BT therapy. However, it should be performed with caution, especially in children and when high doses are applied. High BT doses should not be applied to low volumes of target tissues, in order not to exceed the BT binding capacity.}, } @article {pmid41619170, year = {2026}, author = {Steffke, C and Brenner, D and Catanese, A}, title = {Reply to "Extending the Interpretation of Biomarker Dynamics in SOD1-ALS Proteomics".}, journal = {Annals of neurology}, volume = {99}, number = {2}, pages = {546-547}, pmid = {41619170}, issn = {1531-8249}, } @article {pmid41619791, year = {2026}, author = {Yazdani, S and Seitz, C and Andersson, J and Ingre, C and Fang, F and Lovik, A}, title = {Methodological considerations in the analysis of survival data in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {445-456}, doi = {10.1080/21678421.2026.2615111}, pmid = {41619791}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/mortality/diagnosis ; Humans ; Survival Analysis ; }, abstract = {Survival outcomes are commonly analyzed in studies with data from patients with progressive, neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Given the fast progression of ALS, survival analyses are, however, often difficult to perform and interpret. In this methodological article we demonstrate on real-world data how the choices we make in the study design, data collection, and analysis could influence the results. The factors we consider in this study are length of follow-up, sample size, timing of sample collection, and choice of covariables adjusted for in the models. We further discuss the importance of each of these contributing factors and about how to avoid mistakes in interpreting and reporting survival data in ALS and other rare, progressive diseases.}, } @article {pmid41620396, year = {2026}, author = {Carroll, E and Scaber, J and Pasniceanu, IS and Dafinca, R and Gordon, D and Candalija, A and Talbot, K}, title = {Mutant TDP-43 drives impairments in axonal transport and glycolysis in a mouse stem-cell-derived motor neuron model of amyotrophic lateral sclerosis (ALS).}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {193}, pmid = {41620396}, issn = {2041-4889}, mesh = {Animals ; *Motor Neurons/metabolism/pathology ; *Glycolysis ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *DNA-Binding Proteins/genetics/metabolism ; *Axonal Transport ; Mice ; Humans ; Mutation/genetics ; Disease Models, Animal ; Cell Survival ; *Mouse Embryonic Stem Cells/metabolism ; }, abstract = {TDP-43 dysfunction is thought to be central to ALS pathogenesis. Studying mutations in the gene which encodes TDP-43, TARDBP, provides a valuable opportunity to gain insight into how TDP-43 dysfunction alters cellular homoeostasis. Our group has previously developed a TDP-43[M337V] mouse embryonic stem cell-derived motor neuron (mESC-MN) model, which expresses a single copy of the human TARDBP gene expressing the pathogenic M337V mutation at low levels. Here, we perform extensive phenotypic characterisation of this model, and show that TDP-43[M337V] leads to reduced MN viability, impaired axonal transport and reduced basal glycolysis compared to TDP-43[WT] controls. Altered neuronal viability and function occurs in the absence of TDP-43 mislocalisation or aggregation, suggesting 'proteinopathy' is downstream of these ALS-relevant phenotypes. These findings provide further support for a link between TDP-43 dyshomeostasis, cellular bioenergetics and axonal transport and suggest these pathways warrant further investigation as targets for therapeutic intervention.}, } @article {pmid41621017, year = {2026}, author = {Aynaashe, A and Kursula, P}, title = {Genetic commonalities between rare subtypes of ALS and CMT: insights into molecular mechanisms of neurodegeneration.}, journal = {Amino acids}, volume = {58}, number = {1}, pages = {8}, pmid = {41621017}, issn = {1438-2199}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Charcot-Marie-Tooth Disease/genetics/metabolism/pathology ; Axonal Transport/genetics ; Mutation ; Superoxide Dismutase-1/genetics/metabolism ; Valosin Containing Protein/genetics/metabolism ; Mitochondria/metabolism/genetics/pathology ; Kinesins/genetics/metabolism ; Dynactin Complex/genetics/metabolism ; Flavoproteins/genetics/metabolism ; DNA Helicases ; Multifunctional Enzymes ; Phosphoric Monoester Hydrolases ; RNA Helicases ; Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth disease (CMT) are two distinct neurodegenerative disorders. While ALS is characterised by rapidly progressive motor neuron degeneration, leading to severe complications and death, CMT as a peripheral neuropathy is less severe, and patients have a longer life span, although with a compromised quality of life. Despite their clinical differences, current knowledge suggests that familial ALS (fALS) and CMT may share common genetic and molecular mechanisms. We aimed to identify shared genes mutations and molecular pathways between fALS and CMT through a literature and database search. Thirteen genes were identified, involved in distinct cellular processes: axonal transport (DYNC1H1, KIF5A, SPG11, DCTN1), protein homeostasis (NEFH, VCP, SOD1), RNA metabolism (GARS, SETX), cellular stress response (HSPB1, FIG4), and mitochondrial function (MFN2, CHCHD10). While these linkages to the two diseases are rare for each gene, understanding possible mechanistic commonalities at the molecular level can initiate new research directions, help in identifying additional common genes between neurodegenerative disorders, and improve diagnostics.}, } @article {pmid41621673, year = {2026}, author = {Dev, A and Mehta, H and Vinay, K}, title = {Response to Gao et al's "Can we navigate the pitfalls of tofacitinib RCTs in vitiligo? Addressing long-term safety and generalizability for enhanced clinical translation".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {1}, pages = {e53-e54}, doi = {10.1016/j.jaad.2026.01.059}, pmid = {41621673}, issn = {1097-6787}, } @article {pmid41621861, year = {2026}, author = {Loan, A and D'Mello, R and Li, Y and Nurkan, T and Minic, Z and Wang, J and Man Chan, H}, title = {Prenatal low-dose MeHg exposure leads to proteomic and transcriptomic alterations consistent with neurodegenerative disease in the cerebellum of C57BL/6 mice.}, journal = {The Journal of toxicological sciences}, volume = {51}, number = {2}, pages = {89-100}, doi = {10.2131/jts.51.89}, pmid = {41621861}, issn = {1880-3989}, mesh = {Animals ; *Cerebellum/metabolism/drug effects ; Female ; *Methylmercury Compounds/toxicity/administration & dosage ; Mice, Inbred C57BL ; Pregnancy ; *Proteomics ; *Transcriptome/drug effects ; *Prenatal Exposure Delayed Effects/genetics/chemically induced ; *Neurodegenerative Diseases/genetics/chemically induced/metabolism ; Oxidative Stress/drug effects ; Developmental Origins of Health and Disease ; Reactive Oxygen Species/metabolism ; *Proteome ; *Maternal Exposure/adverse effects ; }, abstract = {Methylmercury (MeHg) is a global pollutant that readily crosses the blood-brain barrier and placenta, posing significant risks to fetal neurodevelopment. While the cerebellum is a recognized target of MeHg toxicity in adults, the effect of fetal exposure remains poorly defined. In this study, we investigated the neurotoxic effects of low-dose MeHg exposure (0.2 ppm via drinking water) on the cerebellums of prenatal C57BL/6 mice using integrated transcriptomic and proteomic analyses. Cerebellar tissues collected from postnatal day 90-120 (P90-120) mice (n = 3/group) were processed for RNA sequencing and proteomics analysis. Differentially expressed genes (DEGs) and proteins (DEPs) revealed significant changes (n = 4/group) in multiple pathways associated with neurodegeneration, including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Overlapping transcriptomic and proteomic findings identified potential underlying mechanisms such as chemical carcinogenesis driven by reactive oxygen species and retrograde endocannabinoid signaling, underscoring the central role of oxidative stress in MeHg-induced neurotoxicity. Collectively, these results indicate that prenatal MeHg exposure induces persistent molecular alterations consistent with neurodegenerative processes and synaptic dysfunction, despite the absence of overt behavioral changes at the time of sacrifice. The long-term consequences for delayed symptom onset and the potential contribution of these changes to the etiology of neurodevelopmental disorders warrant further investigation.}, } @article {pmid41622338, year = {2026}, author = {Salehcheh, M and Nikravesh, M and Aghebat-Bekheir, S and Matin, M}, title = {Manganese concentrations in biological matrices and amyotrophic lateral sclerosis (ALS): a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {2}, pages = {216}, pmid = {41622338}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; Hair ; *Manganese/metabolism/blood ; }, abstract = {BACKGROUND: Manganese (Mn) is an essential but neurotoxic trace element implicated in neurodegenerative disorders. Its association with amyotrophic lateral sclerosis (ALS) remains uncertain. We conducted a systematic review and meta-analysis to evaluate whether Mn concentrations differ between ALS patients and healthy controls.

METHODS: We systematically searched PubMed, EMBASE, Web of Science, and Scopus for observational studies comparing Mn concentrations between ALS patients and healthy controls. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Heterogeneity was assessed with the I² statistic, and publication bias was evaluated by Egger's test.

RESULTS: Twelve studies (446 ALS cases, 652 controls) measuring Mn in blood, serum, cerebrospinal fluid (CSF), hair, urine, toenail, plasma, or tissue were included. The pooled SMD was 0.05 (95% CI: - 0.20 to 0.30; p = 0.68; I² = 71.7%), indicating no significant difference in Mn concentrations. Subgroup analyses by biological matrix and analytical method showed no consistent pattern; meta-regression identified analytical method as a significant source of heterogeneity.

CONCLUSION: No publication bias was detected (Egger's p = 0.53). Peripheral Mn concentrations do not differ significantly between ALS patients and controls. Future research should employ longitudinal and CNS-targeted approaches, incorporating occupational exposure assessment and standardized analytical protocols.}, } @article {pmid41622459, year = {2026}, author = {Diaz, G and Hetz, C}, title = {Protein disulfide isomerases in amyotrophic lateral sclerosis: Endoplasmic reticulum proteostasis and neuromuscular function.}, journal = {Neural regeneration research}, volume = {21}, number = {11}, pages = {5226-5227}, doi = {10.4103/NRR.NRR-D-25-01874}, pmid = {41622459}, issn = {1673-5374}, } @article {pmid41622476, year = {2026}, author = {Liu, J and Zhou, L and Deng, Y and Xu, R}, title = {Amyotrophic lateral sclerosis: Neural repair strategies based on multi-target synchronous interventions.}, journal = {Neural regeneration research}, volume = {21}, number = {11}, pages = {5181-5195}, doi = {10.4103/NRR.NRR-D-25-00221}, pmid = {41622476}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease that targets motor neurons in the cerebral cortex, medulla oblongata, and spinal cord. This review focuses on the current concepts in the aetiopathogenesis and diagnosis of amyotrophic lateral sclerosis, aiming to explore potential neural repair strategies (curative and/or progression-retarding therapeutics). Recent studies have highlighted that the complex pathogenesis of amyotrophic lateral sclerosis is related to its multifactorial aetiology, including proteostasis disruption, impaired RNA metabolism and DNA repair, cytoskeletal and axonal transport defects, excitotoxicity, neuroinflammation, mitochondrial dysfunction, oligodendrocyte dysfunction, nucleocytoplasmic transport deficits, lipid dyshomeostasis, and autophagy. Several approved drugs are currently used to treat patients with amyotrophic lateral sclerosis; however, their curative efficacy is limited. Thus, the search for effective therapeutic strategies for amyotrophic lateral sclerosis requires a comprehensive understanding of its pathogenesis. Current evidence indicates that a single drug cannot provide a satisfactory therapeutic effect. Additionally, multiple pathophysiological processes and related targets are involved in the pathogenesis of amyotrophic lateral sclerosis. Therefore, research on multi-target synchronous interventions may be the path forward for discovering and developing potential neural repair strategies.}, } @article {pmid41623487, year = {2026}, author = {Lian, L and Robinson, H and Daniels, N and Prieto, GA and Poplawski, GHD and Lopez-Gonzalez, R}, title = {Aberrant CDK4/6-driven cell-cycle reentry drives neuronal loss and defines a therapeutic target in C9orf72 ALS/FTD.}, journal = {iScience}, volume = {29}, number = {2}, pages = {114596}, pmid = {41623487}, issn = {2589-0042}, abstract = {The C9orf72 hexanucleotide repeat expansion (G4C2) is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet targeted therapies remain unavailable. Here, we show that induced pluripotent stem cell (iPSC)-derived post-mitotic neurons from C9orf72 carriers exhibit age-dependent cell-cycle reentry, increased S-phase entry, and elevated cyclin and CDK expression. Mechanistically, arginine-containing dipeptide repeat proteins (poly-GR and poly-PR) translated from G4C2 repeats drive this aberrant activation through stimulation of the CDK4/6 pathway, whereas poly-GP and C9orf72 loss-of-function show no effect. Importantly, the FDA-approved CDK4/6 inhibitor palbociclib normalizes cell-cycle progression, reduces S-phase entry, decreases motor neuron death, and restores synaptic proteins PSD95 and synapsin-1. Single-nucleus RNA sequencing from C9orf72 patient cortex reveals cell-cycle activation within excitatory neuron subclusters and alterations in DNA repair and cell-cycle regulation pathways, supporting our in vitro findings. These findings establish cell-cycle dysregulation as a central pathogenic mechanism in C9orf72 ALS/FTD and highlight CDK4/6 signaling as a promising therapeutic target.}, } @article {pmid41623730, year = {2026}, author = {Surtees, JE and Lambert, CV}, title = {Maintenance of competence in rarely performed clinical skills by advanced life support providers in Gauteng, South Africa: A mixed-methods study.}, journal = {African journal of emergency medicine : Revue africaine de la medecine d'urgence}, volume = {16}, number = {1}, pages = {100932}, pmid = {41623730}, issn = {2211-4203}, abstract = {INTRODUCTION: Advanced Life Support (ALS) providers are highly trained emergency care professionals with a broad range of clinical skills. Confidence and competence to perform a clinical skill or intervention has been linked to frequency of application. Differences in training, caseloads, and the context in which ALS providers operate can influence how often they get to perform different skills. Although the Health Professions Council of South Africa (HPCSA) mandates Continuing Professional Development (CPD), there is no requirement for ALS providers to demonstrate maintenance of procedural competence. In this study we investigated approaches to the maintenance of competency in rarely performed clinical skills among a sample of Gauteng-based ALS providers.

METHODS: An exploratory, descriptive mixed-methods design was employed. A quantitative survey of 41 ALS providers assessed frequency of performance and self-reported confidence across 55 clinical skills was performed in March 2023. This was followed by two focus group discussions to explore in greater depth participant's experiences with regard to maintenance of clinical skills.

RESULTS: More than half of the 55 skills we assessed were reported to be "rarely" performed. Confidence to perform a particular skill generally mirrored the frequency with which the skill was performed. Focus group participants identified valuable strategies for maintaining skills that included clinical rotations across diverse work environments, peer discussions, instructional videos, and CPD-accredited courses that included a practical component. Limitations were identified in the current CPD system with regard to maintenance of clinical skills.

CONCLUSION: Skill decay and a reduction in confidence among ALS providers can be linked to infrequent performance of certain clinical skills and interventions. A more purposeful coordinated strategy involving education and training providers, employers and practitioners is required to better support the maintenance of clinical skills that are infrequently performed.}, } @article {pmid41624110, year = {2026}, author = {Debernard, S and Gassias, E and Aguilar, P and Maria, A and Fuentes, A and Couzi, P and Bozzolan, F and Durand, N and Force, E}, title = {Involvement of Taiman in juvenile hormone signaling controlling sexual maturation in a male moth.}, journal = {Current research in insect science}, volume = {9}, number = {}, pages = {100122}, pmid = {41624110}, issn = {2666-5158}, abstract = {In insects, juvenile hormone (JH) is essential for orchestrating reproductive events. For example, in the male moth Agrotis ipsilon, the behavioral response to female sex pheromone is linked to neuronal sensitivity in the primary olfactory centers (antennal lobes, ALs), and the maturation of accessory sex glands (ASGs) are known to be age- and JH-dependent. The molecular basis of this regulatory action of JH is not fully deciphered, and we show here that the heterodimerizing partner of Methoprene-tolerant called Taiman (Tai) is essential for the sexual maturation of male A. ipsilon. Tai expression in ALs and ASGs is elevated from the third day of adult life and is responsible for the acquisition of behavioral responsiveness to the sex pheromone and ASG maturation. Tai-deficient old males exhibited altered sexual behavior and delayed ASG maturation. Moreover, the expression levels of Tai and Krüppel homolog 1 (Kr-h1), an early JH-induced transcription factor, were reduced in ALs and ASGs of JH-deprived and Tai-deficient old males, respectively. Exogenous JH injection into young males resulted in precocious sexual maturation and this JH induction was suppressed by Tai silencing. Our results demonstrate that Tai is an actor of the JH signaling pathway that operates in ALs and ASGs to promote pheromone information processing and consequently the display of sexual behavior in synchrony with ASG maturation, ultimately optimizing male reproductive success. Thus, this study provides additional insights into the molecular mechanisms underlying hormonal regulation of sexual maturation in insects.}, } @article {pmid41625181, year = {2026}, author = {Zhen, J and Liu, Q and Xue, X and Hao, F and Zhang, S and Liu, N and Li, Z and Chen, J and Cheng, J}, title = {The Application Value of Nursing Interventions Based on the Chronic Illness Trajectory Framework in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology research international}, volume = {2026}, number = {}, pages = {1280057}, pmid = {41625181}, issn = {2090-1852}, abstract = {This prospective study evaluated the impact of nursing interventions based on the Chronic Illness Trajectory Framework (CITF) on anxiety, depression, mental toughness, sleep quality, and ALSFRS-R scores in amyotrophic lateral sclerosis (ALS) patients to enhance care strategies. Eighty ALS patients were enrolled from the Department of Neurology at the First Hospital of Shanxi Medical University between February 2023 and March 2024. Participants were randomly assigned to an intervention group (CITF-based nursing interventions) or a control group (standard care). Over an 8-week period, the intervention group demonstrated significantly lower anxiety and depression scores, higher mental toughness, and improved sleep quality compared to the control group (p < 0.05). Additionally, the intervention group achieved higher ALSFRS-R scores (31.63 ± 3.54 vs. 29.58 ± 3.38) (p < 0.05). These findings indicate that CITF-based nursing interventions effectively reduce negative emotional states, enhance mental resilience, improve sleep quality, and boost overall quality of life in ALS patients. Based on this study, nurses can integrate CITF-based interventions into standard ALS care to enhance patients' emotional well-being and functional outcomes. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2500108691.}, } @article {pmid41625544, year = {2025}, author = {Douglas, H and Di Vincenzo, M and Dossa, RFJ and Nunziante, L and Sujit, S and Arulkumaran, K}, title = {Levels of shared autonomy in brain-robot interfaces: enabling multi-robot multi-human collaboration for activities of daily living.}, journal = {Frontiers in human neuroscience}, volume = {19}, number = {}, pages = {1718713}, pmid = {41625544}, issn = {1662-5161}, abstract = {Individuals with ALS and other severe motor impairments often rely on caregivers for daily tasks, which limits their independence and sense of control. Brain-robot interfaces (BRIs) have the potential to restore autonomy, but many existing systems are task-specific and highly automated, which reduces the users' sense of empowerment and limits opportunities to exercise autonomy. In particular, shared autonomy approaches hold promise for overcoming current BRI limitations, by balancing user control with increased robot capabilities. In this work, we introduce a collaborative BRI that integrates non-invasive EEG, EMG, and eye tracking to enable multi-user, multi-robot interaction in a shared kitchen environment with mobile manipulators. Our system modulates assistance through three levels of autonomy-Assisted Teleoperation, Shared Autonomy, and Full Automation-allowing users to retain meaningful control over task execution while reducing effort for routine operations. We conducted a controlled user study comparing autonomy conditions, evaluating performance, workload, ease of use, and agency. Our results show that, while Full Automation was generally preferred by users due to lower workload and higher usability, Shared Autonomy provided higher reliability and preserved user agency, especially in the presence of noisy EEG decoding. Although there was significant individual variability in EEG decoding performance, our post-hoc analysis revealed the potential benefits of customizing pipelines for each user. Finally, we note that our findings are specific to the multi-modal configuration tested and should not be interpreted as a universal claim about the superiority of any autonomy level, and, furthermore, our user study was limited by the use of healthy adults rather than target population (e.g., individuals with ALS), gender imbalance, and a relatively small sample size, which may affect generalizability. Project website: https://coopopen.github.io/.}, } @article {pmid41626035, year = {2025}, author = {Jackson, MC and Azarraga, RB and Fraix, MP and Agrawal, DK}, title = {Stage-Based Communication Rehabilitation in Amyotrophic Lateral Sclerosis (ALS): A Review of Strategies for Enhancing Quality of Life.}, journal = {Archives of internal medicine research}, volume = {8}, number = {4}, pages = {359-371}, pmid = {41626035}, issn = {2688-5654}, support = {R25 AI179582/AI/NIAID NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable progressive degenerative neuromuscular disease. One way ALS affects patients is through dysarthria significantly impacting a patient's quality of life by affecting their ability to communicate. This makes maintaining relationships, identity and autonomy difficult, all of which affect psychological wellbeing - a determinant of the quality of life. Dysarthria makes communication difficult, and because the regions affected by ALS first are different for each patient, creating strategies for rehabilitating communication can be challenging. In this review we explore the different communication rehabilitation options available and organize them based on if they are usable based on the onset of intelligibility and locked in state. Interventions before the onset of intelligibility in the early stage are proactive measures such as voice banking and education which empower patient autonomy and a sense of control. Interventions between onset of intelligibility and the locked-in state in the middle stage are alternative and augmentative communication strategies varied in accessibility and usability in patients based on their preferences and functional ability. Late-stage interventions which work after a patient with ALS has entered a locked-in state, are the most technologically advanced alternative and augmentative communication devices and rehabilitate function inaccessible by other methods in this disease stage. While assessing patient values and recommending interventions which meet patient needs is most important in rehabilitation of communication in patient with ALS, using a stage-based approach to evaluate and recommend the treatment of dysarthria and communication rehabilitation will optimize quality of life throughout the progression of disease.}, } @article {pmid41626491, year = {2026}, author = {Akimoto, Y and Miyamae, Y and Shigemori, H}, title = {Effects of Cyanidin Derivatives for the Aggregation of Cu/Zn Superoxide Dismutase 1.}, journal = {ACS omega}, volume = {11}, number = {3}, pages = {3849-3865}, pmid = {41626491}, issn = {2470-1343}, abstract = {Cu/Zn superoxide dismutase 1 (SOD1), whose aggregation is considered cytotoxic, is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Therefore, inhibiting SOD1 aggregation may represent a promising strategy for the treatment and prevention of this disease. We first screened seven polyphenols using an optimized thioflavin T (Th-T) assay and found that cyanidin exhibited the strongest inhibitory activity among the seven polyphenols. We then compared cyanidin with its derivatives(?)delphinidin, petunidin, malvidin, and cyanidin-3-glucoside (C3G). In this study, we concluded that delphinidin had the strongest antifibrillation activity among the five cyanidin derivatives. Turbidity, transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), circular dichroism (CD) spectroscopy, and Fourier transform infrared (FT-IR) spectroscopy indicated that the inhibitory activity was influenced by the number of phenolic hydroxyl groups on the B-ring of the cyanidin derivatives. Based on the LDH assay, delphinidin was the most effective compound in preventing the formation of cytotoxic SOD1 aggregates in the cells. Furthermore, we found that the compounds also interfered with the SOD1 cross-linking. Finally, we transfected GFP-SOD1A4 V into Neuro2a cells and observed that the compounds' inhibitory activity on intracellular aggregation was limited.}, } @article {pmid41628199, year = {2026}, author = {Hasan, MM and Mostaid, MS and Bepari, AK and Reza, HM and Hossain, M}, title = {Discovery of a novel Keap1 inhibitor for neurodegeneration through virtual screening and molecular dynamics simulations.}, journal = {PloS one}, volume = {21}, number = {2}, pages = {e0341965}, pmid = {41628199}, issn = {1932-6203}, mesh = {*Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors/metabolism/chemistry ; *Molecular Dynamics Simulation ; Humans ; NF-E2-Related Factor 2/metabolism/chemistry ; Molecular Docking Simulation ; Animals ; Protein Binding ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/chemistry/pharmacokinetics ; Drug Discovery ; }, abstract = {Oxidative stress is a key feature of Alzheimer's disease (AD) and other neurodegenerative disorders. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway controls redox balance, and disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has become a promising therapeutic approach. Marine natural products (MNPs), because of their structural diversity and bioactivity, are an underexplored source of potential neuroprotective compounds. This study aimed to identify novel marine-derived inhibitors of the Keap1-Nrf2 interaction using a comprehensive in silico pipeline. A total of 14,492 compounds from an open-access MNP database were virtually screened against the Keap1 Kelch domain through molecular docking. The top 1,329 candidates exhibited strong binding affinities, with several reaching scores comparable to the co-crystallized reference ligand L5F. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling was employed to assess pharmacokinetic properties, brain penetration, and safety, leading to the identification of compound 145398-61-4 as the most promising hit. Molecular dynamics (MD) simulations verified the structural stability of the Keap1-145398-61-4 complex, while binding free energy calculations indicated energetically favorable interactions. Additional validation using principal component analysis (PCA) and highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy analysis further confirmed the stability of this interaction. Overall, our in silico study identified compound 145398-61-4 as a novel Keap1-Nrf2 inhibitor, highlighting its potential as a lead candidate for developing treatments for Alzheimer's disease and other neurodegenerative disorders, such as amyotrophic lateral sclerosis and multiple sclerosis.}, } @article {pmid41628987, year = {2026}, author = {Xue, X and Cui, H and Hu, S and Ma, H and Wei, S and Huang, H and Li, X and Huang, Z}, title = {Both target-site and non-target-site resistance mechanisms confer mesosulfuron-methyl resistance in Silene conoidea L.}, journal = {Pesticide biochemistry and physiology}, volume = {218}, number = {}, pages = {106905}, doi = {10.1016/j.pestbp.2025.106905}, pmid = {41628987}, issn = {1095-9939}, mesh = {*Herbicide Resistance/genetics ; *Sulfonylurea Compounds/pharmacology ; Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Herbicides/pharmacology ; Plant Proteins/genetics/metabolism ; Molecular Docking Simulation ; Mutation ; }, abstract = {Silene conoidea L., a common weed in wheat fields, is mainly controlled by acetolactate synthase (ALS)-inhibiting herbicides such as mesosulfuron-methyl. In this study, we investigated a mesosulfuron-methyl resistant population to elucidate the resistance mechanisms. The resistant (R) population displayed a high level of resistance to mesosulfuron-methyl, with the resistance index (RI) of 18.87. It also exhibited cross-resistance to halosulfuron-methyl, florasulam, flumetsulam, and flucarbazone‑sodium. In vitro ALS enzyme activity in the R population was 22.85-fold higher than in the susceptible (S) population. A W574L mutation (leucine replaced tryptophan) was identified in the ALS gene of the R population. Through molecular docking, this substitution of amino acid weakened the π-π stacking interaction between mesosulfuron-methyl molecule and the non-mutated ALS enzyme. The R population also showed significantly higher ALS expression than the S population, while the ALS gene copy number did not differ between the two populations. Pretreatment with malathion (cytochrome P450 inhibitor) and NBD-Cl (glutathione S-transferases inhibitor) reduced mesosulfuron-methyl resistance by 43.92 % and 29.20 %, respectively. Indicating that CYP450s and GSTs are involved in resistance. Transcriptome and qPCR analyses identified significant upregulation of three ABC transporter genes, three CYP450 genes, and one GST gene in the R population. Meanwhile, KEGG pathway analysis indicated that the photosynthetic pathways were significantly affected after mesosulfuron-methyl treatment. This is the first report of mesosulfuron-methyl resistance in S. conoidea, involves both target site resistance and non-target site resistance mechanisms.}, } @article {pmid41629112, year = {2026}, author = {Kuzmanova, BR and Kuzmanova, MR and Elgizouli, M and Tatrai, B and Möller, JC}, title = {Novel KIF5A variant in a patient with early-onset levodopa-responsive Parkinson's syndrome.}, journal = {BMJ case reports}, volume = {19}, number = {2}, pages = {}, doi = {10.1136/bcr-2025-267762}, pmid = {41629112}, issn = {1757-790X}, mesh = {Humans ; Male ; *Kinesins/genetics ; *Levodopa/therapeutic use ; Adult ; Mutation ; *Parkinson Disease/genetics/drug therapy ; Antiparkinson Agents/therapeutic use ; *Parkinsonian Disorders/genetics/drug therapy ; }, abstract = {We present the case of a male in his mid-30s with a progressive complex neurological phenotype primarily characterised by levodopa-responsive parkinsonism with motor fluctuations as well as gait ataxia, peripheral neuropathy and finally also spastic paraplegia. Genetic analysis identified a novel heterozygous variant in the KIF5A gene: c.937G>A (p.Glu313Lys). This variant is genetically classified as likely pathogenic. Other pathogenic mutations in the KIF5A gene are associated with hereditary spastic paraplegia type 10, Charcot-Marie-Tooth disease type 2 and amyotrophic lateral sclerosis. We discuss the clinical, genetic and prognostic implications of this finding.}, } @article {pmid41629214, year = {2026}, author = {Malard, F}, title = {Transcript-Level Modulation of O-GlcNAc Transferase for Aging-Related Neurodegenerative Diseases.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {27}, number = {2}, pages = {e202500774}, pmid = {41629214}, issn = {1439-7633}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics/enzymology ; *N-Acetylglucosaminyltransferases/genetics/metabolism/antagonists & inhibitors ; *Aging/metabolism/genetics ; Animals ; RNA, Messenger/metabolism/genetics ; RNA Splicing ; }, abstract = {The O-GlcNAc Transferase (OGT) is responsible for the addition of β-O-linked N-acetyl-D-glucosamine (O-GlcNAc) to serine and threonine residues, thereby regulating more than 8000 human proteins through O-GlcNAcylation. In the brain, reduced O-GlcNAc levels, which can arise from insufficient OGT activity, have been increasingly linked to aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. While current strategies focus on restoring O-GlcNAc levels via O-GlcNAcase (OGA) inhibition, recent discoveries highlight transcript-level regulation of OGT as a direct and promising therapeutic target. This concept article explores the role of intron detention and decoy exon-mediated splicing repression in limiting OGT pre-mRNA maturation and proposes the use of antisense oligonucleotides or selective splicing factor degraders to promote productive splicing and nuclear export of OGT mRNA. By enhancing OGT expression independently of O-GlcNAc feedback, these approaches aim to restore proteostasis and improve resilience to neurodegeneration, offering a novel therapeutic approach for aging-related neurodegenerative diseases.}, } @article {pmid41630787, year = {2026}, author = {Mukai, T and Kanbayashi, T and Kobayashi, M and Okano, MP and Tachiyama, K and Miyaji, Y and Hatanaka, Y and Kobayashi, S and Sonoo, M}, title = {Discrimination of spontaneous activity in needle EMG based on the quantitative assessment of the discharge rhythm using "Random Index".}, journal = {Clinical neurophysiology practice}, volume = {11}, number = {}, pages = {65-71}, pmid = {41630787}, issn = {2467-981X}, abstract = {OBJECTIVE: Discrimination between EMG activity such as fibrillation potentials/positive sharp waves (Fib/PSW), end plate spikes (EPS), fasciculation potentials (FP), and contaminating voluntary motor unit potentials (MUP) is mandatory for EMG diagnosis. Discharge rhythm is the key for discrimination. We devised a new parameter, Random Index (RI), which quantifies the rhythm and takes a value from 0 to 1, smaller for regular trains of discharges. This study evaluated the utility of RI as well as modified versions of the regularity indices proposed in past reports.

METHODS: EMG records of patients with amyotrophic lateral sclerosis were retrospectively reviewed. EPS were collected also from a healthy volunteer. The EMG activity was classified by an expert. RI and other regularity indices as well as the median instantaneous firing rate (IFRm) were calculated.

RESULTS: Analyzed sequences were 73 Fib/PSW, 27 EPS, 24 FP, and 36 MUP. The four types were clearly separated over the 2-dimensional plots of regularity indices vs. IFRm. Especially, Fib/PSW and EPS were far separated in these plots. RI achieved significantly better discrimination between Fib/PSW and MUP than other indices.

CONCLUSION: RI is a robust tool for discriminating EMG activity.

SIGNIFICANCE: RI and other regularity indices would be useful for educational purpose.}, } @article {pmid41630926, year = {2026}, author = {Saucier, J and Al-Qadi, M and Allain, EP and Robichaud, PP and Chamard-Witkowski, L and Alvarez, M and Dion-Côté, AM and Richard, L and Crapoulet, N and Ben Amor, M}, title = {Expanding the Genetic Landscape of ATXN2 Variants: Insights From a Biallelic Trinucleotide Repeat Expansion in an Acadian Family.}, journal = {Neurology. Genetics}, volume = {12}, number = {1}, pages = {e200345}, pmid = {41630926}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Spinocerebellar ataxias are a diverse group of autosomal dominant cerebellar ataxias. SCA2 is a complex ataxia with various extracerebellar symptoms, including parkinsonism, dystonia, hyporeflexia, and cognitive impairment. ATXN2 is a modulator of neurologic disease: Expansions of at least 37 CAG (glutamine) repeats are pathogenic for SCA2, while expansions in the intermediate range (30-32) convey risk for the development of neurodegenerative disorders including Parkinson disease and amyotrophic lateral sclerosis. Homozygous variants are exceedingly rare. This study describes a novel ATXN2 presentation identified in an Acadian family from New Brunswick, Canada: a CAG repeat expansion within the fully penetrant range of SCA2, asymptomatic in the heterozygous state and resulting in a neurodegenerative disorder in homozygous patients.

METHODS: Three individuals, 2 siblings and their cousin, were investigated for a neurodegenerative disorder with overlapping phenotypes. The affected individuals and their 5 immediate family members underwent whole-genome sequencing analyzed by ExpansionHunter, repeat-primed PCR and Sanger sequencing.

RESULTS: Sequencing revealed a homozygous 39/39 CAG repeat expansion with 4 CAA interruptions in ATXN2 across all 3 affected individuals. After experiencing childhood intellectual or learning difficulties, the patients developed a pyramidal syndrome with spastic gait and a major neurocognitive disorder characterized by prominent frontal signs during their late twenties. Within a decade, all patients completely lost their autonomy. Shared phenotypic features included ataxia, spasticity, aphasia, dysphagia, myoclonus, atypical parkinsonism, incontinence, diffuse cortical atrophy with frontal predominance, and cerebellar atrophy. The same 39 CAG repeat allele with 4 CAA interruptions was identified in heterozygous state in 4 asymptomatic parents (age 65+) and 1 sibling in their thirties. Three carriers consented to further investigation with a neurologic examination, neuropsychological assessment, and cerebral MRI. Clinical and radiologic signs of disease were absent, despite the carriers' ages and their heterozygous expansion in the fully penetrant range of SCA2.

DISCUSSION: This study describes a novel ATXN2 expansion within the classic pathogenic range for SCA2 that manifests as an early-onset neurodegenerative disorder in the homozygous state, while being asymptomatic into late adulthood in the heterozygous state.}, } @article {pmid41631638, year = {2026}, author = {Allen, S and Howard, J and McDermott, CJ and Boardman, F and McNeill, A}, title = {Limited data capture on reproductive medicine use in amyotrophic lateral sclerosis: implications for monitoring access.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {608-610}, doi = {10.1080/21678421.2026.2618124}, pmid = {41631638}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Genetic Testing/statistics & numerical data ; *Genetic Counseling ; *Reproductive Medicine/statistics & numerical data ; United Kingdom ; Huntington Disease/genetics ; Female ; *Health Services Accessibility ; }, abstract = {There is very limited evidence around the use of reproductive genetic testing in individuals with amyotrophic lateral sclerosis (ALS)-linked gene variants. This study aimed to identify the use of reproductive genetic testing in these individuals to understand patterns of (under)utilization and to identify barriers to equitable access. Freedom of information requests were sent in January 2025 to the 22 regional clinical genetics centers across the UK around reproductive services for individuals with, or at risk for, ALS and Huntington's disease. Limited data were available with only six trusts answering in full. The data that our study yielded raises significant concerns and inconsistencies regarding clinical recording and reporting of reproductive genetic counseling and testing. The absence of standardized retrievable data limits the ability to assess utilization and may point toward a systemic issue in data capture of reproductive genetic services for individuals at risk of ALS, and by extension, those affected by other genetic conditions.}, } @article {pmid41633359, year = {2026}, author = {Xie, X and Liu, J and Liang, W and Zhang, Y and Gong, X and Yuan, S and Qi, C and Huang, M and Shi, L and Hou, M and Zhang, M and Liu, W and Sun, W and Wu, Y and Li, C and Cao, Z and Jing, H and Qian, L and Liu, J and Yuan, S and Wang, Q and Shen, Y and Liu, Z and Li, Y and Pan, H and Zhu, B and Shan, B and He, K and Wang, W and Zou, C and Li, Y and Chou, JJ and Yuan, J}, title = {Repression of RIPK1 kinase by INPP5D inhibits expression of diverse proinflammatory mediators and late-onset Alzheimer's disease risk factors.}, journal = {Immunity}, volume = {59}, number = {2}, pages = {419-437.e11}, doi = {10.1016/j.immuni.2026.01.014}, pmid = {41633359}, issn = {1097-4180}, mesh = {*Alzheimer Disease/metabolism/genetics ; Animals ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/genetics ; Microglia/metabolism ; Humans ; Mice ; *Inflammation Mediators/metabolism ; Risk Factors ; DNA-Binding Proteins/metabolism ; Signal Transduction ; Mice, Knockout ; Mice, Inbred C57BL ; Genome-Wide Association Study ; }, abstract = {Genome-wide association studies strongly implicate neuroinflammation in late-onset Alzheimer's disease (LOAD). Genetic risk loci for LOAD are enriched for genes expressed in microglia, but the relationship among microglial LOAD risk genes has been unclear. We found that the N-terminal SH2 domain of INPP5D, an important LOAD risk gene, directly interacted with the cell death regulator RIPK1 at p-Y383 to suppress RIPK1 kinase activation. Microglial INPP5D deficiency cell-autonomously promoted RIPK1-mediated transcriptional induction of diverse LOAD risk genes, proinflammatory cytokines, complements, and ROS mediators, as well as proinflammatory signaling mediators such as Toll-like receptors (TLRs), MyD88, Nlrp3, gasdermin D, and Zbp1. RIPK1-regulated microglial transcriptomic signatures were found in microglial subtypes implicated in human Alzheimer's disease (AD) pathogenesis. Furthermore, microglial INPP5D deficiency promoted aging-dependent RIPK1-mediated development of neuronal TDP-43 pathology, neuronal loss, and motor dysfunction in a non-cell-autonomous manner. Our data suggest that INPP5D functions as an intracellular rheostat in regulating RIPK1-mediated neuroinflammation for promoting aging-related neurodegenerative diseases, including LOAD and AD-amyotrophic lateral sclerosis comorbidity.}, } @article {pmid41633603, year = {2026}, author = {Tian, X and Song, Z and Huang, Y and Yao, W}, title = {[Analysis of early complications and risk factors in patients with amyotrophic lateral sclerosis after percutaneous endoscopic gastrostomy].}, journal = {Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences}, volume = {58}, number = {1}, pages = {190-195}, pmid = {41633603}, issn = {1671-167X}, mesh = {Humans ; *Gastrostomy/adverse effects/methods ; Middle Aged ; *Amyotrophic Lateral Sclerosis/surgery ; Male ; Female ; Retrospective Studies ; Risk Factors ; *Postoperative Complications/etiology/epidemiology ; Aged ; *Enteral Nutrition/adverse effects/methods ; *Gastroscopy/adverse effects ; Adult ; Logistic Models ; }, abstract = {OBJECTIVE: To explore risk factors of early complications (≤14 days) and the clinical characteristics in patients with amyotrophic lateral sclerosis (ALS) after percutaneous endoscopic gastrostomy (PEG).

METHODS: Patients diagnosed with ALS who underwent first PEG insertion between January 2011 and December 2020 were eligible. Medical records were retrospectively reviewed to determine clinical characteristics and outcomes (≤14 days) of patients who underwent the pull type PEG. Grouping was performed based on the presence and severity of complications, and SPSS 27.0 statistical software was used for data analysis. Finally, Logistic regression model was applied for multivariate factor analysis of risk factors related to complications.

RESULTS: In the study, 192 cases of PEG were all successfully completed, with 97 (51%) males, mean age of ALS onset disease (55±11) years and 93 (48%) bulbar onset symptoms included. Complications occurred in 40 (21%) cases after PEG within 14 days, all of which had fever, including 16 cases without clear infection focus, 18 cases of respiratory tract infections, and 6 cases of fistula site infections. In the study, 13 (7%) cases had major complications, including 11 cases of respiratory tract infection and 2 cases of stoma infection. Two cases of respiratory tract infection died due to respiratory failure, and the remaining 11 cases recovered after upgraded antibiotic. No complications, such as tube dislodgement, benign pneumoperitoneum, hemorrhage or buried bumper syndrome occurred. The operation time and postoperative hospital stay were longer in the complication group than in the non-complication group [(16±5) min vs. (13±5) min, P < 0.001; 6 (5, 9) d vs. 5 (3, 7) d, P=0.009]. Compared with the mild complication group, the creatinine and triglyceride in the major complication group were significantly lower [(46.5±16.2) μmol/L vs.(66.8±16.4) μmol/L, P＜0.001; (1.1±0.5) mmol/L vs.(1.6±0.7) mmol/L, P=0.038], and the operation time was significantly longer [(20±5) min vs. (15±5) min, P=0.002]. Further, Logistic regression model analysis revealed that the operation time was also independent associated with complications (OR=1.132, 95%CI: 1.051-1.220, P=0.001).

CONCLUSION: PEG was a reliable method for ALS patients to put nutrition tube. Postoperative fever was the most common complications. Long surgical duration was an independent risk factor for the occurrence of complications (≤14 d).}, } @article {pmid41634873, year = {2026}, author = {Garrigos, D and Martinez-Morga, M and Pombero, A and García-Lopez, R and Pastor, D and Riquelme, D and Blanquer, M and Iniesta, F and Valdor, R and Geijo-Barrientos, E and Hargus, G and Moraleda, JM and Martínez, S}, title = {Chaperone mediated autophagy is deficient in spinal motoneurons of ALS patients with TDP-43 proteinopathy.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {41634873}, issn = {2051-5960}, support = {Grant Numbers SEV-2017-0723//Spanish State Research Agency, through the "Severo Ochoa" Programme for Centres of Excellence in R&D/ ; SAF2017-83702-R and PID2020-11817RB-I00//Spanish Ministerio de Ciencia e Innovación/ ; Grant Number 2018/041//Generalitat Valenciana (program Prometeo II)/ ; RD21/0017/0017; RD21/0017/0001//Instituto de Salud Carlos III (ISCIII) through the RICORS Project TERAV/ ; Ramon y Cajal (RYC) 2019-027520-I//Ministerio de Ciencia e Innovación/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Motor Neurons/pathology/metabolism ; *Spinal Cord/pathology/metabolism ; *Chaperone-Mediated Autophagy/physiology ; Female ; Lysosomal-Associated Membrane Protein 2/metabolism ; Male ; Middle Aged ; Aged ; DNA-Binding Proteins/metabolism ; Microtubule-Associated Proteins/metabolism ; Adult ; *TDP-43 Proteinopathies/pathology/metabolism ; *Autophagy/physiology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons (MNs), ultimately resulting in paralysis and respiratory failure within 3 to 5 years of onset. Fewer than 10% of ALS cases are familial (fALS), while the vast majority are sporadic (sALS) with an unknown etiology. A pathological hallmark of ALS is the accumulation of misfolded TDP-43 protein aggregates within MNs. Although TDP-43 is known to be degraded via chaperone-mediated autophagy (CMA), the status of CMA activity in sALS has not been previously explored. To investigate this, we analyzed CMA in human spinal cord tissue by assessing the expression of LAMP2A, a key lysosomal receptor and marker of CMA activity. In control samples, spinal cord MNs exhibited robust LAMP2A expression. In contrast, MNs from sALS patients showed a marked reduction in LAMP2A levels, coinciding with the presence of TDP-43 pathology. Notably, analysis of LC3, a marker of macroautophagy, revealed no significant differences in expression between control and sALS MNs. Interestingly, MNs within the Onuf’s nucleus, a population known to be resistant to degeneration in ALS, retained normal LAMP2A expression and did not exhibit TDP-43 aggregation in sALS cases. These findings demonstrated that CMA is essential for the clearance of TDP-43 in spinal cord MNs and that its dysfunction may contribute to the pathogenesis of sALS. Furthermore, the high dependence of spinal cord MNs on CMA activity may underlie their selective vulnerability to degeneration when CMA is impaired, and highlight CMA enhancement as a promising therapeutic strategy to restore proteostasis and prevent MN degeneration in ALS.}, } @article {pmid41635116, year = {2026}, author = {Wang, Y and Lipton, SA}, title = {Aberrant Protein S-Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases.}, journal = {Journal of neurochemistry}, volume = {170}, number = {2}, pages = {e70365}, pmid = {41635116}, issn = {1471-4159}, support = {R56 AG065372/AG/NIA NIH HHS/United States ; R01 AG078756/AG/NIA NIH HHS/United States ; R01 AG056259/AG/NIA NIH HHS/United States ; DP1 DA041722/DA/NIDA NIH HHS/United States ; /NH/NIH HHS/United States ; U01 AG088679/AG/NIA NIH HHS/United States ; R35 AG071734/AG/NIA NIH HHS/United States ; ReMIND-L DISC4 16292//California Institute for Regenerative Medicine/ ; R01 DA048882/DA/NIDA NIH HHS/United States ; RF1 AG057409/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; *Mutation/genetics ; *Protein Processing, Post-Translational/physiology/genetics ; Animals ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease/Lewy body dementia (PD/LBD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are driven by complex interactions of genetic and environmental factors. While genome wide association studies (GWAS) have uncovered a number of risk gene variants (e.g., APOE, SNCA [encoding α-synuclein], and protein disulfide isomerase [PDI]), these genetic factors alone cannot fully explain disease onset or progression. Emerging evidence suggests that post-translational modifications of proteins, particularly S-nitrosylation (SNO), act as a critical link between environmental stress and neurodegenerative pathology. Here, we review data showing that while physiological protein SNO regulates diverse neuronal processes, aberrant SNO, occurring very commonly in the diseased brain, can disrupt protein function in ways that mimic the deleterious effects of rare genetic mutations. We advance the concept of "mutational mimicry," whereby aberrant SNO of key neuronal or glial proteins reproduces the functional consequences of known specific genetic mutations, ultimately converging on common pathways of synaptic dysfunction emanating from mitochondrial and metabolic impairment, proteostasis, neuroinflammation, and so on. Supporting this framework, proteomic analyses show significant overlap between abnormally S-nitrosylated proteins in diseased brains and known genetic risk factors in AD and PD/LBD as well as in ALS. By linking redox biology to human genetics, this review highlights how environmental factors can phenocopy or enhance genetic susceptibilities. Understanding this convergence not only provides novel insight into disease mechanisms but also suggests new therapeutic targets to intervene in these convergent pathways with the goal of halting neurodegenerative processes.}, } @article {pmid41635251, year = {2026}, author = {Li, X and Ding, W and Lu, Y and Sun, M and Xu, E}, title = {Nocturnal Hypoxia and Sleep-Disordered Breathing as Potential Early Biomarkers of Respiratory Progression in Mild ALS.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-6}, doi = {10.1017/cjn.2026.10557}, pmid = {41635251}, issn = {0317-1671}, abstract = {BACKGROUND: Early detection of respiratory decline is crucial in amyotrophic lateral sclerosis (ALS). We tested if nocturnal polysomnography (PSG) predicts dyspnea onset in mild ALS patients with preserved daytime function.

METHODS: In this study, 41 mild ALS patients (ALS Functional Rating Scale-Revised [ALSFRS-R] ≥ 37, sitting forced vital capacity [FVC] ≥80% predicted, no dyspnea) and 41 matched controls underwent baseline assessment, including ALSFRS-R scoring, pulmonary function tests, and overnight PSG. ALS patients were followed for 12 months. Baseline apnea-hypopnea index (AHI) and oxygen saturation (mean SpO2, minimum SpO2) were analyzed as continuous predictors and using exploratory thresholds (AHI ≥ 5 events/h, min SpO2 ≤ 88%, mean SpO2 ≤ 95%) for dyspnea onset (Dyspnea-ALS-15 [DALS-15] > 0).

RESULTS: Compared to controls, ALS patients had significantly higher AHI (p = 0.004) and lower minimum SpO2 (p = 0.018). The ALSFRS-R orthopnea subscore showed a significant positive correlation with mean and minimum SpO2 (P < 0.05). Cox regression identified baseline AHI (HR 1.08 per event/h; 95% CI 1.01-1.15, p = 0.028) and minimum SpO2 (HR 0.94 per %; 95% CI 0.88-0.99, p = 0.033) as independent predictors of dyspnea onset within 12 months. Thresholds AHI ≥ 5 (HR 2.28, p = 0.031) and min SpO2 ≤ 88% (HR 2.42, p = 0.027) also predicted increased risk. Patients meeting ≥1 threshold (n = 25/37) showed trends toward greater FVC and ALSFRS-R decline.

CONCLUSIONS: In patients with mild ALS and normal daytime function, specific nocturnal PSG parameters (AHI, minimum SpO2) predicted the risk of dyspnea within 12 months. This longitudinal study provides novel evidence that PSG could identify early respiratory vulnerability in the incipient stage, earlier than conventional FVC-based monitoring, supporting its potential utility in refining early intervention strategies. Validation in larger cohorts is warranted.}, } @article {pmid41637622, year = {2026}, author = {Du, C and Li, Y and Wu, R and Shen, Y and Yang, J and Xiao, X and Zhou, Y}, title = {Aberrant Splicing Signatures Underpin Oligodendrocyte Damage in ALS and Neuron Loss in FTD.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {17}, pages = {e14886}, pmid = {41637622}, issn = {2198-3844}, support = {2023YFC2307802//National Key R&D Program of China/ ; 2042022dx0003//Fundamental Research Funds for the Central Universities/ ; 2025AFA051//Hubei Provincial Natural Science Foundation of China/ ; 2023AFB182//Hubei Provincial Natural Science Foundation of China/ ; 2023KFZZ007//Open Project of Hubei Key Laboratory/ ; 32525018//National Natural Science Foundation of China/ ; 82341023//National Natural Science Foundation of China/ ; 324B2009//National Natural Science Foundation of China/ ; 82401650//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Dementia/genetics/pathology ; *Oligodendroglia/pathology/metabolism ; *Neurons/pathology/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Female ; *RNA Splicing/genetics ; Biomarkers ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two severe diseases sharing similar genetic, pathological, and clinical features, including TDP-43 pathology. However, differences in molecular changes between ALS and FTD remain elusive. Here, integrating large sets of bulk and single-nucleus RNA-seq from ALS/FTD patients revealed expression and splicing changes indicating more severe oligodendrocyte damage in ALS than FTD, and more significant neuron loss in FTD. Specifically, we identified 31 oligodendrocyte-specific and 507 neuron-specific aberrant splicing junctions as potential biomarkers with robust classification performance, and experimentally validated a novel target in patient tissues. Moreover, we found that abnormally spliced transcripts produced de novo peptides in patients' cerebrospinal fluids. Importantly, we further identified the targets of TDP-43 in glial cells and decoded the differential RNA-binding protein (RBP) contexts of TDP-43-regulated aberrant splicing. These findings uncover that ALS and FTD patients have distinct dysfunctional cell populations harboring specific aberrant splicing signatures, suggesting varying cellular impacts and providing potential biomarkers and insights into molecular mechanisms underlying ALS/FTD.}, } @article {pmid41638255, year = {2026}, author = {Yeh, CH and Chen, SC}, title = {Comments on Huang et al's "Proteomic profiling reveals distinct inflammatory and neurogenic endotypes in rosacea".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {6}, pages = {e423-e424}, doi = {10.1016/j.jaad.2025.12.114}, pmid = {41638255}, issn = {1097-6787}, } @article {pmid41638429, year = {2026}, author = {Madsen, M and Rønne, ME and Petersen, AB and Tandrup, T and Pilgaard, B and Holck, J and Aachmann, FL and Wilkens, C and Klau, LJ and Svensson, B}, title = {Dissecting a two-domain alginate lyase of family PL6 reveals a mechanistic basis for substrate specificity and enzyme activity.}, journal = {The Journal of biological chemistry}, volume = {302}, number = {3}, pages = {111227}, pmid = {41638429}, issn = {1083-351X}, mesh = {Substrate Specificity ; *Polysaccharide-Lyases/metabolism/chemistry/genetics ; Protein Domains ; *Bacteroides/enzymology ; }, abstract = {Alginate lyases (ALs) cleave 4-O-glycosidic linkages in alginate, composed of mannuronate (M) and guluronate (G) residues via β-elimination with preference for either one or several M-M, M-G, G-M, G-G linkages. ALs in polysaccharide lyase family 6 (PL6) present different specificities and modes of action and contain either one or two parallel β-helix domains. About half of almost 600 PL6 sequences are of the two-domain type, all located in the phyla Pseudomonadota and Bacteroidota. Here, functional roles are described for the N- and C-terminal domains (NTD and CTD) using BoPL6, a two-domain AL from the human gut bacterium Bacteroides ovatus CP926, which is specific for G in subsite +1. The NTD contains the catalytic site, but BoPL6-NTD markedly preferred the model substrate polyMG and cleaved M-G bonds in endo-mode, whereas the NTD + CTD mixture, similarly to BoPL6, acted with highest activity on model substrate polyG in exo-mode, verified by time-resolved [1]H-NMR. The CTD was not catalytically active but bound polyguluronate and, when mixed with BoPL6-NTD, promoted activity on polyG, yielding products of DP 1‒3, similarly to BoPL6. This defines a crucial role of the CTD in shaping the active site in BoPL6, as validated by substrate docking. The BoPL6 E634A mutant in the conserved CTD DEST loop, interacting with the active site in two-domain PL6 enzymes, was inactive, while the corresponding CTD mutant mixed with the NTD did not form the WT structure and had highly reduced activity on polyG but acted on polyMG in endo-mode with improved rate and conversion.}, } @article {pmid41638908, year = {2026}, author = {Villarroel-Campos, D and Vargas, JNS and Wallace, M and Sun, K and Sleigh, JN and Fratta, P and Schiavo, G}, title = {TBK1 activity regulates the directionality of axonal transport of signalling endosomes.}, journal = {Life science alliance}, volume = {9}, number = {4}, pages = {}, pmid = {41638908}, issn = {2575-1077}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/S006990/1/MRC_/Medical Research Council/United Kingdom ; MR/Y010949/1/MRC_/Medical Research Council/United Kingdom ; 107116/Z/15/Z//Wellcome Trust Senior Investigator Awards/ ; 223022/Z/21/Z//Wellcome Trust Senior Investigator Awards/ ; }, mesh = {*Axonal Transport/physiology ; *Protein Serine-Threonine Kinases/metabolism/genetics ; *Endosomes/metabolism ; Animals ; Humans ; Signal Transduction ; rab GTP-Binding Proteins/metabolism/genetics ; Phosphorylation ; rab7 GTP-Binding Proteins ; Motor Neurons/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Axons/metabolism ; Protein Transport ; Neurons/metabolism ; Mice ; }, abstract = {The polarised and complex morphology of neurons poses massive challenges for efficient cargo delivery between the axon and soma, a process termed axonal transport. We have previously shown that the retrograde axonal transport of pro-survival, neurotrophic signalling endosomes relies on Rab7 in motor neurons, and that their trafficking is impaired in the early stages of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we report the effect of Rab7 phosphorylation on the transport of these signalling endosomes. We show that the ALS-linked kinase TBK1 phosphorylates Rab7 at S72 in neurons, altering its binding to cytoplasmic dynein adaptors. Accordingly, both TBK1 knockdown and the expression of a loss-of-function Rab7 mutant (S72E) induce aberrant bidirectional movement of signalling endosomes without modifying neuronal polarity or endosomal sorting. This alteration is specific for signalling endosomes, as axonal transport of lysosomes and mitochondria remains unaffected. We have therefore discovered a new TBK1 function that ensures the unidirectional transport of signalling endosomes, suggesting that reduced TBK1 activity determines retrograde transport dysfunctions and long-range signalling impairments.}, } @article {pmid41639245, year = {2026}, author = {Fernandes, AR and Owen, AP and Faroqi, AH and Lee, J and Sachdeva, GS and Morderer, D and Hoffmann, C and Madden, B and Zhang, S and Ren, Y and Boschen, SL and Pandey, A and Rossoll, W and McLean, PJ}, title = {A split biotin ligase approach reveals proteins associated with oligomeric alpha-synuclein during aggregation.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41639245}, issn = {2045-2322}, support = {A2021615S//BrightFocus Foundation/ ; U54 NS110435/NS/NINDS NIH HHS/United States ; U01 CA271410/CA/NCI NIH HHS/United States ; 024079//Michael J. Fox Foundation for Parkinson's Research/ ; 24A10//Florida Department of Health Ed and Ethel Moore AD Research Program/ ; APDA#11-08//Mayo Clinic American Parkinson's Disease Association Center for Advanced Research/ ; R21 AG085314/AG/NIA NIH HHS/United States ; R01 AG077771/AG/NIA NIH HHS/United States ; U01CA271410/BC/NCI NIH HHS/United States ; RF1AG076122/GF/NIH HHS/United States ; R01 AG068581/AG/NIA NIH HHS/United States ; 23A04//Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Grant/ ; R01 AG076122/AG/NIA NIH HHS/United States ; }, mesh = {*alpha-Synuclein/metabolism/chemistry/genetics ; Humans ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates ; *Carbon-Nitrogen Ligases/metabolism/genetics ; Recombinant Fusion Proteins/metabolism ; Proteomics/methods ; Biotin/metabolism ; Phosphorylation ; Protein Binding ; }, abstract = {Lewy pathology can form over decades in patients with Lewy body diseases, but the causal cellular mechanisms associated with this process remain unclear. This project aims to discover proteins that associate with monomeric and/or oligomeric alpha-synuclein during early stages of the aggregation process. To mimic aggregation processes, cells expressing a synuclein-biotin ligase fusion protein were treated with human recombinant pre-formed fibrils and subjected to BioSITe and mass spectrometry. Using a novel split biotin ligase fused to alpha-synuclein facilitated the identification of proteins specifically associated with multimeric alpha-synuclein. A total of 581 proteins were differentiated into potential interactors of monomeric versus multimeric alpha-synuclein in physiological versus aggregated conditions. The data reveal potentially relevant phosphorylation mechanisms, connections to insulin processing, and a potential interaction with ALS/FTD-associated FUS. Interestingly, we propose that loss of specific interactions may contribute to pathology in patients with sporadic onset of Lewy body diseases. Future studies will validate both true interaction of highlighted proteins with alpha-synuclein, and the impact of such proteins on alpha-synuclein aggregation.}, } @article {pmid41639347, year = {2026}, author = {Tosi, M and Favero, F and Zuccalà, M and Visha, E and Caushi, F and Barizzone, N and Pomella, N and Follia, L and Corrado, L and Corà, D and Martignetti, L and Leone, M and D'Alfonso, S}, title = {A multi-omics study on monozygotic twins discordant for amyotrophic lateral sclerosis and literature review underline a potential role for innate immunity and epigenetic dysregulation in disease mechanisms.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {3}, pages = {230}, pmid = {41639347}, issn = {1590-3478}, support = {DIG-ALS//AriSLA/ ; PRIN project GENIALS//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/immunology ; *Twins, Monozygotic/genetics ; Multiomics ; *Epigenesis, Genetic ; *Immunity, Innate/genetics ; Female ; Male ; DNA Methylation ; Middle Aged ; Aged ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration. Although genetic contributions to both familial and sporadic ALS (sALS) cases are well established, a substantial portion of ALS heritability remains unexplained, suggesting the involvement of other genetic and epigenetic factors. METHODS: To address this gap, we have devised a comprehensive multi-omics approach in a pair of Italian monozygotic twins discordant for ALS, performing DNA methylation, transcriptomic, and whole exome sequencing (WES). We then conducted a structured literature research on ALS-discordant monozygotic twins (n = 45) and on case-control sALS (~ 7000 patients and ~ 3000 controls), investigated for at least one of the omics approaches. RESULTS: Our exploratory analysis reveals distinct transcriptomic and epigenetic profiles underlying the discordant disease phenotypes in genetically identical individuals, particularly implicating immune system functions and brain development pathways. Notably, a comprehensive comparison of our results with existing literature underlined the involvement of pathways related to NK cell activation, chemokine production, and signal transduction, suggesting potential shared disease associated mechanisms across ALS cases. CONCLUSIONS: This hypothesis-generating study, although limited by the sample size, demonstrates the utility of multi-omics approaches in uncovering broader pathological insights into ALS, speculating on the possible contribution of innate immunity and epigenetic dysregulation in disease processes. This work provides a foundation for future research aimed at identifying disease-associated processes and biomarkers.}, } @article {pmid41639687, year = {2026}, author = {Zhang, N and Su, WM and Chen, T and Zhang, Q and Cao, B and Wang, Y and Chen, YP}, title = {From pathogenesis to therapy: the emerging role of regulatory T cells in amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {50}, pmid = {41639687}, issn = {1742-2094}, support = {82371422//National Natural Science Fund of China/ ; 2022YFC2703101//National Key Research and Development Program of China/ ; 2023HXFH032//1·3·5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/therapy/pathology ; *T-Lymphocytes, Regulatory/immunology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord, with a pathogenesis that remains incompletely understood. Increasing evidence in recent years has highlighted the pivotal role of neuroinflammation in ALS, in which regulatory T cells (Tregs) emerge as key modulators of the neuroimmune response. This review systematically summarizes recent advances in understanding Treg biology in ALS, including their dynamic alterations across different disease stages and their potential immunoregulatory mechanisms, while also highlighting ongoing clinical trials and emerging cellular therapeutic strategies targeting Tregs. Current evidence suggests that Tregs not only participate in the immunopathology of ALS but also represent a promising target for therapeutic intervention. Nevertheless, there are still significant challenges, including incomplete mechanistic insights, limited clinical validation and obstacles to the implementation of Treg-based therapies. Overall, Treg research in ALS provides valuable directions for elucidating disease mechanisms and developing novel immune-based interventions.}, } @article {pmid41639826, year = {2026}, author = {Shoji, H and Ishikawa, Y and Watanabe, J and Takahashi, S and Sawakami, K and Segawa, H and Ohashi, M}, title = {Differential diagnosis of degenerative cervical myelopathy considered in patients spine surgeons referred to neurologists: a retrospective cohort study.}, journal = {BMC musculoskeletal disorders}, volume = {27}, number = {1}, pages = {}, pmid = {41639826}, issn = {1471-2474}, mesh = {Humans ; Retrospective Studies ; Female ; Diagnosis, Differential ; Aged ; Middle Aged ; Male ; *Neurologists ; *Cervical Vertebrae/surgery ; *Spinal Cord Diseases/diagnosis ; *Referral and Consultation ; *Spinal Cord Compression/diagnosis/etiology ; Spondylosis ; }, abstract = {BACKGROUND: When patients suspected of degenerative cervical myelopathy present with atypical neurological findings, the spine surgeons generally referred the patients to neurologists preoperatively to distinguish it from non-compressive neurological diseases. This study aimed to elucidate the diseases that should be differentiated from degenerative cervical myelopathy and the differentiation points. METHODS: We conducted a retrospective cohort study, and extracted consecutive patients who were suspected of degenerative cervical myelopathy with spinal cord compression and consulted a spine surgeon but were referred to a neurologist from 2011 to 2021 because of atypical findings. The main reason for consultation with a neurologist and the definitive diagnosis were investigated. RESULTS: Sixty-eight patients were included (60 men and 8 women; median age [interquartile range], 72 [63–76]). The main reasons for consultation with a neurologist were lack of sensory disturbance in 43 patients, lack of upper extremity symptoms and/or atypical gait impairment in 13, and symptoms in the unilateral upper and lower extremities in 3, and others. Definitive diagnoses were degenerative cervical myelopathy in 40 patients, non-compressive neurological diseases in 26, and others in 2. Non-compressive neurological diseases included parkinsonian syndromes in 9 patients, amyotrophic lateral sclerosis in 3, cerebrovascular disease in 3, and others. Regarding paresis of upper extremity in patients with lack of sensory disturbance, bilateral extensive type and no abnormality in upper extremity were related to non-compressive neurological diseases. In patients with lack of upper extremity symptoms and/or atypical gait impairment, 8 of 10 patients with non-spastic gait were diagnosed with non-compressive neurological diseases, and 5 of them with parkinsonian syndromes. CONCLUSIONS: Non-compressive neurological disease should be considered in patients with a lack of sensory disturbance who present with bilateral extensive paresis or no neurological abnormality in the upper extremity. Parkinsonian syndromes should be considered as differential diagnosis for patients presenting with non-spastic abnormal gait.}, } @article {pmid41640102, year = {2026}, author = {Ross, D and Lewis, O and McLean, O and Bhanot, S and Donahue, S and Baker, R and Dias, R and Eagerton, D and Mohanty, V and Mohanty, BK}, title = {Thermally activated history-dependent homogenization of G-quadruplexes in an ALS/FTD-associated gene.}, journal = {Biophysical journal}, volume = {125}, number = {6}, pages = {1445-1455}, pmid = {41640102}, issn = {1542-0086}, support = {T32 GM144273/GM/NIGMS NIH HHS/United States ; }, mesh = {*G-Quadruplexes ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; *C9orf72 Protein/genetics ; Circular Dichroism ; Mutation ; Thermodynamics ; Humans ; }, abstract = {A significant proportion of familial amyotrophic lateral sclerosis and frontotemporal dementia cases exhibit a substantial copy number expansion of the hexanucleotide GGGGCC/GGCCCC sequence in the C9ORF72 gene. The GGGGCC sequence forms a noncanonical DNA structure called a G-quadruplex (G4), which has been associated with the disease states and with nucleic acid condensate formation. G4s can fold into various topologies, which can differentially impact fidelity of DNA synthesis. However, how G4 conformational heterogeneity and its regulation impact hexanucleotide repeat expansion is unclear, and important clues may lie in the thermodynamic properties of different G4 topologies. Here, we use temperature-swept CD spectroscopy to observe configurational homogenization of an initially heterogeneous population of G4s over a small range of temperatures, demonstrating thermally activated behavior. The G4s adopt the parallel configuration after the temperature sweep, and subsequent temperature sweeps show little to no reversal back to nonparallel topologies, suggesting the homogenization is history-dependent. Finally, we provide an analytical theory based on a two-state thermodynamic model which is compatible with experimental evidence, and we discuss alternate mechanisms for the homogenization transition. These findings suggest that kinetic regulation of noncanonical DNA structures may play a role in cellular homeostasis or disease pathogenesis.}, } @article {pmid41640104, year = {2026}, author = {Karros, M and DiFulco, M and Nogid, A}, title = {Tofersen: A Novel Option for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {The Annals of pharmacotherapy}, volume = {60}, number = {8}, pages = {795-804}, doi = {10.1177/10600280251408862}, pmid = {41640104}, issn = {1542-6270}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Superoxide Dismutase-1/genetics/cerebrospinal fluid ; *Oligonucleotides, Antisense/administration & dosage/therapeutic use/adverse effects ; Animals ; }, abstract = {OBJECTIVE: This review summarizes current evidence on the efficacy and safety of tofersen (Qalsody) in treating amyotrophic lateral sclerosis (ALS).

DATA SOURCES: PubMed, MEDLINE, Google Scholar, and ClinicalTrials.gov were searched using the keywords: Qalsody, BIIB067, antisense oligonucleotides, SOD1, and amyotrophic lateral sclerosis. Articles published from inception to November 2025 were included.

English-language studies assessing the pharmacokinetics, pharmacology, efficacy, and safety of tofersen were included. Prescribing information and real-world evidence were also reviewed.

DATA SYNTHESIS: Tofersen is an intrathecally administered antisense oligonucleotide targeting superoxide dismutase 1 (SOD1) mRNA. Early trials demonstrate dose-dependent reductions in cerebrospinal fluid (CSF) SOD1 protein levels of -33% and slower ALS Functional Rating Scale (ALSFRS-R) decline compared to placebo (-1.19 vs -5.63 points). In Phase 3 trials, tofersen reduced CSF SOD1 by 29% and plasma neurofilament light chain (NfL) by 60%, while biomarkers increased in the placebo group. There was no significant difference in ALSFRS-R decline between tofersen and placebo (-6.98 vs -8.14; P = 0.97). Real-world data show favorable patient-related outcomes and improvement in ALSFRS-R. Adverse effects are primarily lumbar puncture related with serious neurologic events documented in 7% of tofersen recipients.Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs:As the first Food and Drug Administration (FDA)-approved gene-directed therapy for SOD1 ALS, tofersen directly targets the underlying genetic cause. Barriers include the need for genetic confirmation and intrathecal administration.

CONCLUSION: Tofersen provides a promising targeted treatment option for pathogenic SOD1 ALS. Ongoing studies will clarify its long-term clinical impact.}, } @article {pmid41640493, year = {2025}, author = {Li, SC}, title = {Evolving target: A 16-year progressive framework for shifting the rubric of scientific publishing toward transparency, artificial intelligence, and the Economic Impact Factor for impact that matters.}, journal = {World journal of stem cells}, volume = {17}, number = {12}, pages = {111748}, pmid = {41640493}, issn = {1948-0210}, abstract = {Reflecting on 16 years of continuous evolution at the World Journal of Stem Cells, this editorial offers a forward-looking vision for redefining the framework of scientific publishing. With the emergence of artificial intelligence, open science, and the growing need for translational value, we propose shifting from traditional citation-based assessments toward an impact and progress framework, anchored by the Economic Impact Factor. The World Journal of Stem Cells experience, grounded in metrics and milestones, supports this evolution: Among the more than 1200 published articles since inception, our top 10 cited works have collectively accrued over 2475 citations, led by Kyurkchiev et al (398 citations) and Casteilla et al (392 citations). Emerging scholars such as Ann De Becker and Nipha Chaicharoenaudomrung have shaped the next generation of research, as seen in our top 10 junior authors table. Clinically, World Journal of Stem Cells has supported critical translational work, such as Tsang et al's mesenchymal stem cell stroke trial (27 citations), illustrating real-world impact. Thematic breadth remains a cornerstone, with 22 focus areas including artificial intelligence-integrated programming, spatial single-cell biology, CRISPR-based gene editing, and bench-to-bedside translation. As Nature and other leading publishers move toward transparent peer review, World Journal of Stem Cells embraces editorial co-creation, recognizing peer reviewers and editors as contributors with "10000-foot eagle views" by publishing peer-review reports side-by-side with the related manuscripts since its inception. Together, these shifts signify a call to recalibrate what we value in science - not just what is cited, but what truly counts.}, } @article {pmid41640615, year = {2026}, author = {Wang, G and Pan, SJ}, title = {Integrative acupoint stimulation within enhanced recovery after endoscopic procedures: Harnessing the neuroimmune axis for enhanced gastrointestinal recovery.}, journal = {World journal of gastroenterology}, volume = {32}, number = {3}, pages = {114048}, pmid = {41640615}, issn = {2219-2840}, mesh = {Humans ; *Acupuncture Points ; *Enhanced Recovery After Surgery ; *Gastrointestinal Tract/surgery/innervation ; Hypothalamo-Hypophyseal System/immunology ; *Neuroimmunomodulation/physiology ; *Perioperative Care/methods ; Pituitary-Adrenal System ; *Postoperative Complications/prevention & control ; Randomized Controlled Trials as Topic ; Recovery of Function ; *Transcutaneous Electric Nerve Stimulation/methods ; Treatment Outcome ; }, abstract = {Enhanced recovery after surgery (ERAS) programs have transformed perioperative care, yet delayed gastrointestinal function and excessive neuroendocrine stress remain major obstacles to optimal recovery. Hong et al's randomized controlled trial embedded acupoint-based neuromodulation - meridian-timed acupoint application combined with transcutaneous electrical acupoint stimulation - within an ERAS framework and demonstrated accelerated gastrointestinal recovery accompanied by endocrine attenuation. This article offers a structured critical appraisal of the trial, emphasizing methodological rigor, mechanistic plausibility, and alignment with ERAS core principles of stress mitigation, functional restoration, and patient experience. The observed reductions in norepinephrine, cortisol, and aldosterone suggest modulation of the hypothalamic-pituitary-adrenal axis as a key mediator of benefit. Future research priorities include multicenter, sham-controlled validation; integration of autonomic and inflammatory biomarkers (heart rate variability, interleukin-6, tumor necrosis factor-α, C-reactive protein); and pragmatic evaluation of cost-effectiveness and acceptability. Positioning acupoint stimulation within precision-integrative perioperative care could advance ERAS from a recovery protocol to a system of host-response modulation. Integrative acupoint neuromodulation thus represents a biologically coherent, low-risk, and scalable strategy for enhancing resilience, accelerating gastrointestinal recovery, and improving surgical outcomes worldwide.}, } @article {pmid41640951, year = {2026}, author = {Cui, X and Yin, BQ and Chen, L}, title = {Remote telerehabilitation for frailty management in liver transplant candidates: A feasible yet underutilized strategy.}, journal = {World journal of hepatology}, volume = {18}, number = {1}, pages = {114880}, pmid = {41640951}, issn = {1948-5182}, abstract = {This letter reviews Loschi et al's study evaluating structured telerehabilitation for frail cirrhotic liver transplant candidates, which fills a critical pre-transplant care gap. The video-based program, using low-cost tools and asynchronous sessions, improved liver frailty index reduction and function in adherent patients (29.8%) although a high attrition rate (70%) highlighted engagement challenges. Limitations include a small, non-randomized sample, mixed frailty subgroups, and unexplored long-term effects. Future directions emphasize hybrid models, patient-centered barrier analysis, and policy-driven frailty screening. This work advances digital health for cirrhosis; however, larger trials are needed to optimize outcomes.}, } @article {pmid41641215, year = {2026}, author = {Zhang, Y and Wang, JJ and Xing, HY and Yan, J}, title = {Neurofeedback for autism spectrum disorder: Current evidence, challenges, and future directions.}, journal = {World journal of psychiatry}, volume = {16}, number = {2}, pages = {114358}, pmid = {41641215}, issn = {2220-3206}, abstract = {Neurofeedback therapy (NFT) has emerged as a promising noninvasive intervention for autism spectrum disorder (ASD), targeting core symptoms such as social communication deficits and emotional dysregulation. This editorial synthesizes findings from recent studies, including Wang et al's retrospective analysis (2025), which reported improvements in Social Responsiveness Scale and Aberrant Behavior Checklist scores following NFT combined with conventional therapy. Mechanistically, NFT may modulate prefrontal gamma-band activity, enhances neuroplasticity in social brain networks (e.g., default mode network, a brain network involved in social cognition), and optimizes cognitive processing via event-related potential changes (e.g., shortened P300 latency). Emerging trends include hybrid approaches (e.g., NFT with repetitive transcranial magnetic stimulation and artificial intelligence-driven protocols). However, challenges persist in protocol standardization, long-term efficacy validation, and biomarker identification. Future research must prioritize large-scale randomized trials, neuromarker discovery, and individualized protocols to establish NFT as a viable component of precision psychiatry for ASD.}, } @article {pmid41641779, year = {2026}, author = {Varderidou-Minasian, S and Jakobs, CE and Pasteuning-Vuhman, S and Gal, L and Timmers, A and Altelaar, M and Lorenowicz, MJ and Pasterkamp, RJ}, title = {Mesenchymal stem cell-derived extracellular vesicle treatment of induced pluripotent stem cell-derived motor neurons with different amyotrophic lateral sclerosis genetic backgrounds.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {5035-5043}, pmid = {41641779}, issn = {1673-5374}, abstract = {Motor neurons derived from induced human pluripotent stem cells offer a powerful model to study motor neuron diseases, such as amyotrophic lateral sclerosis. While widely used, our knowledge of the proteomic changes in these models is rather rudimentary. In this study, we conducted a comparative proteomic analysis of induced pluripotent stem cell–derived motor neurons carrying amyotrophic lateral sclerosis–associated mutations in C9ORF72, TARDBP, or FUS. This revealed both mutation-specific and shared proteomic signatures, unveiling common and divergent disease mechanisms. Using these new insights, we then evaluated the therapeutic potential of mesenchymal stem cell–derived extracellular vesicles. These experiments showed a functional effect of mesenchymal stem cell–derived extracellular vesicles in amyotrophic lateral sclerosis-FUS motor neurons in vitro and their ability to reverse proteomic changes more generally in motor neurons with different amyotrophic lateral sclerosis genetic backgrounds. These findings highlight key molecular pathways involved in amyotrophic lateral sclerosis at the protein level and support the potential of mesenchymal stem cell–derived extracellular vesicles as a versatile therapeutic approach.}, } @article {pmid41641857, year = {2026}, author = {Marcinkowska, K and Wrzesińska-Krupa, B and Obrępalska-Stęplowska, A}, title = {Insights Into Sequences of Viral and Bacterial Origin in the Metatranscriptome of Centaurea cyanus L. Susceptible and Resistant to Acetolactate Synthase (ALS)-Inhibiting Herbicides.}, journal = {Environmental microbiology reports}, volume = {18}, number = {1}, pages = {e70287}, pmid = {41641857}, issn = {1758-2229}, support = {2020/04/X/NZ9/01767//National Science Centre/ ; }, mesh = {*Herbicides/pharmacology ; *Acetolactate Synthase/antagonists & inhibitors ; *Bacteria/genetics/classification/isolation & purification ; *Herbicide Resistance/genetics ; Plant Weeds/virology/microbiology/drug effects ; Arylsulfonates/pharmacology ; Transcriptome ; Plant Viruses/genetics/classification/isolation & purification ; Centaurea ; }, abstract = {Cornflower (Centaurea cyanus L.) is a widespread weed in cereal crops and is commonly controlled with sulfonylurea herbicides. In Poland, populations of cornflower resistant to acetolactate synthase inhibiting herbicides, such as tribenuron-methyl, have been increasingly reported. Both target-site and non-target-site resistance mechanisms may contribute to this phenomenon. Plant-associated microorganisms are known to play essential roles in alleviating abiotic stress. Moreover, weeds are considered reservoirs of plant pathogenic viruses. Since bacteria and viruses associated with cornflower have not been analysed to date, data mining was undertaken to identify viral and bacterial sequences in metatranscriptome datasets obtained from plant biotypes that are both susceptible and highly resistant to tribenuron-methyl. Using MEGAN6 and Kraken2, taxonomic classification revealed the presence of sequences of two double-stranded RNA viruses belonging to the family Partitiviridae, which have not been described before. For bacterial sequences, 19 genera were identified, including Bacillus, Mesorhizobium and Acinetobacter, some of which are associated with plant growth promotion or xenobiotic degradation. Although the presence of partitiviruses was unrelated to herbicide resistance status, some bacterial genera (e.g., Rothia) were more abundant in resistant than in susceptible plants. These results suggest that those bacterial genera present in weeds may be involved in counteracting ALS-inhibiting herbicides.}, } @article {pmid41642424, year = {2026}, author = {Sun, Y and Huang, C and Pan, Y and Zhang, H and He, X}, title = {Correction: Muscle Fibrosis in Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Diagnostic Advances, and Therapeutic Strategies.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {418}, doi = {10.1007/s12035-026-05721-2}, pmid = {41642424}, issn = {1559-1182}, } @article {pmid41642483, year = {2026}, author = {Alhajeri, MM and Abukhaled, Y and Alkhanjari, RR and Bassiouni, W and Al-Ali, H and Baig, A and Sembaij, SH and Al Muhairi, FA and Dimassi, Z and Hamdan, H and Abd-Elrahman, KS}, title = {Neuroglial Function and Hormonal Modulation in Neurodegenerative Diseases: The Influence of Sex Hormones.}, journal = {Cellular and molecular neurobiology}, volume = {46}, number = {1}, pages = {43}, pmid = {41642483}, issn = {1573-6830}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Neuroglia/metabolism/pathology ; *Gonadal Steroid Hormones/metabolism ; }, abstract = {Astrocytes, microglia, and oligodendrocytes, key neuroglial cell types, are essential for central nervous system (CNS) homeostasis, immune regulation, and neuronal support. In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), glial dysfunction contributes to pathogenesis via chronic inflammation, synaptic disruption, oxidative stress, and impaired myelination. Growing evidence highlights the regulatory influence of sex hormones on glial function. These hormones modulate inflammatory tone, synaptic remodeling, and remyelination, potentially contributing to sex-based differences in disease incidence, progression, and treatment response. This review synthesizes current understanding of glial involvement in neurodegeneration and examines how gonadal hormones interact with astrocytes, microglia, and oligodendrocytes. By integrating glial biology with neuroendocrinology, we propose that hormone-glia interactions represent promising, personalized targets for sex-informed therapies in CNS disorders.}, } @article {pmid41642988, year = {2026}, author = {Wells, TL and Galani, M and Popoli, R and Zagoraiou, L and Akay, T}, title = {Compensatory scaling of modulatory neural populations in response to motor challenges.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {6}, pages = {e2519741123}, pmid = {41642988}, issn = {1091-6490}, mesh = {Animals ; Mice ; *Motor Neurons/physiology/metabolism ; *Interneurons/physiology/metabolism ; Serotonin/metabolism ; Muscle, Skeletal/physiology ; Spinal Cord/physiology ; Brain Stem/physiology/metabolism ; Locomotion/physiology ; Cholinergic Neurons/physiology/metabolism ; Male ; Acetylcholine/metabolism ; Electromyography ; }, abstract = {Precise and adaptable movements are achieved by well-regulated muscle contractions, which are mainly governed by the excitability of motor neurons. Several neuromodulatory systems originating in the motor cortex, brainstem, and spinal cord regulate motor neuron excitability via the release of neurotransmitters such as acetylcholine and serotonin. However, these systems can have seemingly similar effects on motor neuron output, raising questions about interaction during movement. To address this, we investigated two modulatory systems in mice: the cholinergic V0c interneurons in the spinal cord and the serotonergic system in the brainstem. Electromyographic and behavioral recordings revealed that, when compared to control mice, mice whose V0c interneuron cholinergic output was genetically inactivated failed to display speed-dependent modulation of the gastrocnemius muscle, and exhibited lower amplitude bursting in the gastrocnemius muscle during swimming. c-Fos expression in this population during locomotion also indicated that they are active in a speed-dependent manner. Relative to control mice, those mice whose V0c interneurons had their cholinergic output inactivated showed upregulated activity in motor-related serotonergic populations while trotting at higher speeds but not while walking at lower speeds, indicating that serotonin plays a compensatory role in the absence of functional V0c interneurons. Last, we observed a progressive recruitment of these two populations in mice with amyotrophic lateral sclerosis, and the recruitment of serotonergic neurons is hastened in those mice whose V0c interneurons had their cholinergic output inactivated. These findings highlight that modulatory systems scale their activity to match motor demand across various circumstances.}, } @article {pmid41643021, year = {2026}, author = {Jiang, X and Schaeffer, L and Patni, D and Russo, T and Lee, CZ and Aguilar, C and Marques, C and Jansen-West, K and Hruska-Plochan, M and Ray-Soni, A and Lim, SM and Held, A and Yue, M and Castellanos Otero, P and Aryal, S and Beaussant, HDAM and Basu, H and Takakuwa, H and Daughrity, LM and Ramesh, N and Da Costa, P and A A Quadros, AR and Nolan, M and Reyes, CJF and Wheeler, H and Moran, LC and Griesman, G and Wymann, B and Trombetta, BA and Lopez-De-Silanes, ES and Canori, M and Krishnan, G and Vieira Souza Da Silva, Y and Eriani, G and Albers, MW and Arnold, SE and Song, Y and Jain, A and Chiu, IM and Zhang, YJ and Gao, FB and Wainger, BJ and Polymenidou, M and Petrucelli, L and Martin, F and Lagier-Tourenne, C}, title = {Blocking RAN translation without altering repeat RNAs rescues C9ORF72-related ALS and FTD phenotypes.}, journal = {Science (New York, N.Y.)}, volume = {391}, number = {6785}, pages = {eadv2600}, pmid = {41643021}, issn = {1095-9203}, support = {R01 AG058063/AG/NIA NIH HHS/United States ; RF1 NS127407/NS/NINDS NIH HHS/United States ; R01 AG078377/AG/NIA NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; RM1 NS133601/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; R01 NS057553/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy ; *C9orf72 Protein/genetics ; Codon ; Dipeptides/genetics ; Disease Models, Animal ; *DNA Repeat Expansion ; DNA-Binding Proteins/metabolism ; *Frontotemporal Dementia/genetics/pathology/therapy ; Induced Pluripotent Stem Cells ; Motor Neurons/pathology ; Mutation ; Phenotype ; *Protein Biosynthesis ; *ran GTP-Binding Protein/genetics ; *RNA/genetics/metabolism ; HEK293 Cells ; Male ; Female ; Mice, Inbred C57BL ; }, abstract = {GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Toxicity is thought to result from the accumulation of either repeat RNAs and/or dipeptide repeat proteins (DPRs) translated from repeat-containing transcripts through repeat-associated non-AUG (RAN) translation. To disentangle RNA from DPR toxicity, we mutated a CUG codon predominantly used to initiate DPR translation from all three reading frames. This mutation disrupted DPR synthesis while preserving the expression of repeat-containing RNAs. Despite the accumulation of RNA foci, behavioral deficits and pathological abnormalities, including p-TDP-43 inclusions, STING activation, motor neuron loss, neuroinflammation, and increased plasma neurofilament concentration, were alleviated in C9ORF72 mice. Base editing of the CUG codon also improved molecular phenotypes and survival in patient induced pluripotent stem cell-derived neurons, which highlights the potential of therapeutically targeting DPR production rather than repeat RNAs.}, } @article {pmid41643078, year = {2026}, author = {Fernandez, R and Sívori, M}, title = {[Clinical scale of ventilatory failure risk in patients with amyotrophic lateral sclerosis].}, journal = {Medicina}, volume = {86}, number = {1}, pages = {60-72}, pmid = {41643078}, issn = {1669-9106}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/mortality/physiopathology ; Retrospective Studies ; Female ; *Respiratory Insufficiency/etiology/mortality ; *Hypercapnia/etiology/diagnosis ; Male ; Middle Aged ; Risk Factors ; Prognosis ; Aged ; Risk Assessment ; Respiration, Artificial ; Sensitivity and Specificity ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes atrophy and paralysis of skeletal muscles, including respiratory muscles. The development of ventilatory failure determines the prognosis. The primary outcome was to determine which common clinical variables can be predictors of daytime hypercapnia and develop a risk model of ventilatory failure. Secondary outcome was to determinate the survival rate of high-risk patients with and without hypercapnia.

MATERIALS AND METHODS: Retrospective study. Patients with ALS without mechanical ventilation were selected and followed from June 2015 to May 2024. They underwent arterial blood carbon dioxide measurement and classified into two groups: hypercapnic (pCO2 ≥45 mmHg) and normocapnic (pCO2 <45 mmHg). Different predictive models for hypercapnia were constructed.

RESULTS: An association between orthopnea (p=0.0001), dyspnea (p=0.02) and FVC <50% (p=0.04) was found. The predictive model constructed with the following variables: orthopnea, dyspnea and ALSFRS-R score ≤21, presented a good performance on the detection hypercapnia risk. A score > 23 points had a sensitivity of 80.6% and a specificity of 72.8% for detecting patients at high risk of hypercapnia. Normocapnic patients at high risk who start mechanical ventilation before developing hypercapnia improve their survival rate by 6 months (p=0.17).

DISCUSSION: The risk score includes easily obtained clinical variables and is effective in detecting patients at risk for hypercapnia. Initiating mechanical ventilation in at-risk patients who have not yet developed hypercapnia has a clinically significant impact on survival.}, } @article {pmid41643564, year = {2026}, author = {Ma, Z and Zheng, J and Wang, H and Chen, C and Yue, J and Duan, X and Jiang, H}, title = {A Novel Classification of Esophageal Anastomotic Leaks and Its Impact on Healing Time After Esophagogastrostomy.}, journal = {Cancer research and treatment}, volume = {}, number = {}, pages = {}, doi = {10.4143/crt.2025.1029}, pmid = {41643564}, issn = {2005-9256}, abstract = {PURPOSE: Anastomotic leakage (AL) is a severe complication after esophagogastrostomy, yet the classifications of AL and their associated healing times are poorly understood.

MATERIALS AND METHODS: This study retrospectively analyzed 117 cases of AL among 2,728 patients who underwent esophagectomy with circular stapled esophagogastric anastomosis at Tianjin Medical University Cancer Institute and Hospital from January 1, 2019, to March 31, 2024. AL cases were categorized into four types based on the direction of leakage (anterior, right, posterior, and left). The differences in healing times among these four types were analyzed using the log-rank test. A multivariable Cox model was used to identify factors associated with healing time.

RESULTS: The incidence of AL was 4.3% (117/2728), with a median occurrence time of 9 days (Interquartile Range[IQR]: 5) and a median healing time of 56 days (IQR:64). Single cervical ALs accounted for 17.5%, with significantly shorter healing times compared to intrathoracic leaks (33 days vs. 61 days, p=0.018). Right-sided leaks were the most common (49.6%), while left-sided leaks healed faster than right- and posterior-sided leaks (42 days vs. 63 days vs. 70 days, p<0.05). Body Mass Index (BMI), diabetes, and neoadjuvant therapy did not influence healing time. In 117 AL patients, the occurrence of tracheoesophageal fistula (p=0.004) and the placement of trans-fistula reverse drainage tubes (p=0.002) were associated with healing time.

CONCLUSION: These findings provide valuable insights for clinicians to better understand the mechanisms of AL development and predict the healing times.}, } @article {pmid41643607, year = {2026}, author = {Cásedas, G and Rojas-Márquez, H and Ventura, L and Moliner, C and Maggi, F and Rubio-Castellanos, A and López, V}, title = {Involvement of Keap1/Nrf2 and the antioxidant defence in cytoprotective effects induced by cannabis polyphenols in SH-SY5Y neuronal cells.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {196}, number = {}, pages = {119048}, doi = {10.1016/j.biopha.2026.119048}, pmid = {41643607}, issn = {1950-6007}, mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Polyphenols/pharmacology/isolation & purification ; *Antioxidants/pharmacology/metabolism ; *Neurons/drug effects/metabolism/pathology ; Cell Line, Tumor ; Oxidative Stress/drug effects ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *Cannabis/chemistry ; *Cytoprotection/drug effects ; Neuroprotective Agents/pharmacology ; Molecular Docking Simulation ; Signal Transduction/drug effects ; *Plant Extracts/pharmacology ; Hydrogen Peroxide ; }, abstract = {Oxidative stress (OS) is widely recognized as a central promoter to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). Cannabis sativa L. synthesizes a complex array of bioactive compounds that extends well beyond the well-known cannabinoids to include a diverse suite of polyphenols, terpenes, fatty acids, tocopherols, and proteins. The non-cannabinoid polyphenolic fraction is composed primarily of flavonoids, stilbenoids, lignans, and lignanamides, which contribute substantially to the plant's antioxidant, anti-inflammatory, and neuroprotective properties. This study investigates the redox-modulating and cytoprotective properties of a polyphenolic fraction derived from Cannabis sativa L. in SH-SY5Y neuroblastoma cells. Neurons were treated with various concentrations of the aqueous polyphenolic cannabis extract and exposed to oxidative stress using hydrogen peroxide (100 µM). Protein and gene expression related to redox signalling were analyzed via Western blot and qPCR, and molecular docking studies were performed in silico. Furthermore, antioxidant enzymes activity was measured by spectrophotometry. Results revealed that the phenolic fraction significantly activated the Keap1/Nrf2 pathway, increased expression of PRDX1 and PRDX3, and enhanced endogenous antioxidant defences. Simultaneously, it reduced endoplasmic reticulum stress-induced apoptosis (via Bax/Bcl-2 modulation) and attenuated inflammatory markers, including NO, NF-κB2, IL-6, and IL-8. In silico docking studies identified Leu583 as a key residue in Nrf2-ligand interactions. These findings suggest that Cannabis sativa L. polyphenols are key bioactive compounds modulating redox homeostasis and inflammation, and offering neuroprotective benefits with potential relevance in diseases involving mitochondrial dysfunction and oxidative damage.}, } @article {pmid41643661, year = {2026}, author = {Liu, H and Liu, M and Liu, Y and Gui, G and Paul, T and Lu, YN and Huang, Z and Wang, H and Xiao, Y and Zheng, Z and Periz, G and Shi, Y and Ichida, JK and Myong, S and Ji, H and Wang, J}, title = {C9orf72 hexanucleotide repeat RNA drives transcriptional dysregulation through genome-wide DNA:RNA hybrid G-quadruplexes.}, journal = {Neuron}, volume = {114}, number = {6}, pages = {1045-1065.e13}, pmid = {41643661}, issn = {1097-4199}, support = {R01 HG009518/HG/NHGRI NIH HHS/United States ; R01 NS128494/NS/NINDS NIH HHS/United States ; R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; }, mesh = {*G-Quadruplexes ; Humans ; *RNA/genetics ; *C9orf72 Protein/genetics ; *DNA Repeat Expansion/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; *DNA/genetics ; *Transcription, Genetic ; Frontotemporal Dementia/genetics ; Gene Expression Regulation/genetics ; Motor Neurons/metabolism ; Animals ; }, abstract = {A hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. While repeat RNAs are implicated in disease pathogenesis, their mechanisms of action remain incompletely understood. Here, we show that GGGGCC repeat RNA engages chromatin genome-wide preferentially at promoter regions in patient cells. This interaction obstructs RNA polymerase II and transcription factors with GC-rich motifs, leading to broad transcriptional repression. Biochemical assays, single-molecule imaging, and native bisulfite sequencing analyses demonstrate that GGGGCC repeat RNA intrinsically forms DNA:RNA hybrid G-quadruplexes (HQs) with cognate DNA, providing a structural basis for transcriptional interference. Stabilization of these G-quadruplex structures exacerbates neuronal vulnerability to metabolic stress in patient-derived motor neurons and cortical organoids, whereas restoring key gene dysregulation improves resistance. These findings uncover a previously unrecognized trans-acting mechanism whereby repetitive RNAs form hybrid structures with genomic DNA, disrupt gene regulation, and contribute to neurodegeneration.}, } @article {pmid41645155, year = {2026}, author = {McDonald, DW and Chugh, N and Sava, R and Duennwald, ML}, title = {FUS and TDP-43 aggregation are uncoupled from toxicity in ageing yeast models.}, journal = {BMC biology}, volume = {24}, number = {1}, pages = {}, pmid = {41645155}, issn = {1741-7007}, support = {RGPIN-2024-05867//Natural Sciences and Engineering Research Council of Canada/ ; }, mesh = {*RNA-Binding Protein FUS/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Saccharomyces cerevisiae/genetics/physiology/metabolism ; *Protein Aggregates ; *Aging ; Humans ; Saccharomyces cerevisiae Proteins/metabolism ; }, abstract = {BACKGROUND: Protein aggregation is indicative of the loss of proteostasis associated with neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Proteins like Fused in sarcoma (FUS) and Tar DNA-binding protein 43 (TDP-43) accumulate and aggregate in the cytosol of neurons in ALS/FTD. Yet, it remains unclear how ageing affects FUS and TDP-43 aggregation, and how these aggregates in turn influence neurodegeneration in ALS/FTD. In addition, mistranslation can reduce longevity, challenge proteostasis, and modulate protein aggregation. To investigate how ageing and mistranslation modulate FUS and TDP-43 aggregation and toxicity, we enlist tractable and reliable yeast models.

RESULTS: Using optimized low-expression FUS and TDP-43 yeast models, we demonstrate that chronological ageing antagonizes proteostasis, the steady state levels and solubility of molecular chaperones, and aggregation of FUS and TDP-43. In addition, mistranslation caused by tRNA variants further antagonize FUS and TDP-43 aggregation and synergize to exacerbate FUS and TDP-43 cytotoxicity.

CONCLUSIONS: Our work provides new insights into factors that uncouple FUS and TDP-43 aggregation from toxicity and support a rather protective role for FUS and TDP-43 aggregates in promoting longevity.}, } @article {pmid41646005, year = {2026}, author = {Peng, J and Fan, T and Wang, J and Deng, Y and Xu, R}, title = {Current potential biomarkers for Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis: review of literature.}, journal = {Dialogues in clinical neuroscience}, volume = {28}, number = {1}, pages = {17-39}, pmid = {41646005}, issn = {1958-5969}, mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood/metabolism ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism/cerebrospinal fluid ; *Parkinson Disease/diagnosis/metabolism ; *Alzheimer Disease/diagnosis/metabolism/cerebrospinal fluid ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are several common neurodegenerative diseases (NDs). At present, is the lack of effective diagnosis, progression, prognosis and therapeutic biomarkers. it is a urgent demand to search the relevant confident biomarkers.

AREA COVERED: This review systematically analysed the potential biomarkers of blood, cerebrospinal fluid, neuroimaing and emerging non-invasive indicators, and synthesises current evidences on the biomarkers of AD, PD and ALS about diagnosis, progression, prognosis and therapeutic, especially diagnosis biomarkers.

EXPERT COMMENTARY: In this review, we focus on discussing relevant diagnosis, progression, prognosis and therapeutic biomarkers for AD, PD and ALS in recent years, and prospecting the possible future directions of relevant biomarkers.}, } @article {pmid41646275, year = {2025}, author = {Naddaf, R and Shmilovich, H and Carasso, S and Keshet-David, R and Herren, R and Gefen, T and Goshen-Lago, T and Zwang, Y and Livyatan, I and Shental, N and Haberfeld, O and Straussman, R and Markar, SR and Nilsson, M and Kashtan, H and Ben-Aharon, I and Geva-Zatorsky, N}, title = {Esophageal microbiome correlates with post-esophagectomy anastomotic leak in cancer patients.}, journal = {ESMO gastrointestinal oncology}, volume = {8}, number = {}, pages = {100172}, pmid = {41646275}, issn = {2949-8198}, abstract = {BACKGROUND: Despite continuous improvement in long-term survival after esophagectomy, potential serious post-operative complications, such as anastomotic leaks (ALs), still occur. Several risk factors for ALs have been proposed, including environmental factors. Our main objective was to examine the correlation of esophageal tumor microbiome composition and functional profile with ALs. Additionally, we analyzed the microbiome of esophageal tumors and their potential correlation with clinical features of the patients.

MATERIALS AND METHODS: Surgical specimens of esophageal tumors and adjacent normal tissues were collected from consecutive patients who underwent an esophagectomy. Formalin-fixed paraffin-embedded (FFPE) tissue samples were processed using 16S ribosomal DNA multiple fragments amplicon sequencing to characterize bacterial microbiome composition. The tumor and normal tissue microbiome and bacterial functional profile were analyzed based on the clinical outcome of ALs.

RESULTS: Out of 60 patients who met the inclusion criteria, 52 (86.7%) patients had both normal adjacent tissue (NAT) and tumor (T) FFPE samples included with sufficient bacterial DNA extracted for analysis. A total of 28% of participants had esophageal ALs. Proportion tests [P < 0.05, false discovery rate (FDR) < 0.25] revealed operational taxonomic units (OTUs) significantly present in T samples as opposed to NAT samples, as well as significantly present OTUs in patients with AL as opposed to patients without AL complication.

CONCLUSIONS: In this study, we provide a profile of the understudied esophageal microbiome and its connection to ALs. Our results can provide potential clues on how to avoid ALs by considering a patient's personal microbiome when providing perioperative care.}, } @article {pmid41646374, year = {2026}, author = {Cropper, H and Mir, F and Liu, J and Srivastava, V and Ramizuddin, M and Kopecky, K and Mocanu, E and Dachet, F and Jiang, QL and Soni, M and Valyi-Nagy, T and Mnatsakanova, D and Abrams, C and Song, F and Loeb, J}, title = {Axonal dying back of upper motor neurons in human ALS.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41646374}, issn = {2693-5015}, support = {T32 AG057468/AG/NIA NIH HHS/United States ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) present with arm, leg, or bulbar weakness with or without spasticity. While genetics plays a clear role in a subset of cases, it cannot explain why symptoms start focally or how upper (UMN) and lower motor neuron (LMN) systems are linked. Here, we examined the clinicopathological relationships between UMN and LMN disease in ten ALS patients. Detailed clinical assessments were obtained and tissues from the motor cortex, brainstem, and spinal cord were collected via a rapid autopsy protocol. Tissues were stained for UMN/LMN, myelin, axons, microglia, and pTDP43. Total RNA-sequencing was performed in the medulla, cervical, and lumbar spinal cords from each patient to identify pathways enriched at sites of disease onset. None of the patients had symptoms of frontotemporal dementia (FTD), but all had focal sites of clinical onset and spasticity, indicating both UMN and LMN involvement. Postmortem examination showed LMN degeneration and microglial activation were highest at sites of disease onset. In contrast, UMN degeneration of the corticospinal tract (CST) was present equally at all levels of the spinal cord up through the medulla, regardless of the site of disease onset. Surprisingly, there was no evidence of UMN degeneration of cortical motor neurons or their projecting axons above the brainstem. Similarly, while extensive pTDP43 aggregates were seen in degenerating LMNs, no pTDP43 aggregates were seen in UMN cell bodies or their axons. Mechanistically, RNA-sequencing implicated inflammatory pathways, especially at sites of disease onset. Our findings suggest that many ALS patients without FTD have a dying back of UMN axons, independent of the site of disease onset, which stops in the brainstem with preservation of cortical motor neurons and their proximal axons. Our findings suggest that UMN axonal degeneration can be directly triggered by LMN degeneration and inflammation.}, } @article {pmid41647790, year = {2025}, author = {Raymond, J and Larson, T and Nair, T and Kaufman, J and Horton, DK and Weisskopf, M and Mohidul, S and Mehta, P}, title = {Age-period-cohort effect on motor neuron disease mortality in the United States, 2001-2020.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1751690}, pmid = {41647790}, issn = {1664-2295}, abstract = {INTRODUCTION: Motor neuron diseases (MND) are progressively fatal diseases causing loss of motor neurons throughout the body. Recent studies have suggested an increase in prevalence and mortality of amyotrophic lateral sclerosis (ALS), the most common adult-onset MND. It is unclear whether the increase is because of earlier diagnosis or potentially new exposures. Age-period-cohort (APC) analysis can help identify contributors to temporal disease trends by differentiating impacts of biological aging, historical time period, and birth cohort. The aim of this study is to evaluate APC effects on MND mortality in the United States from 2001 to 2020.

METHODS: We analyzed deaths by MND for the period 2001-2020 in subjects aged 40-84 years. We used APC modeling to compute net drift, local drift, longitudinal age curve, rate ratios (RR), and confidence intervals (CI) for each period and cohort. Analysis used the APC Web Tool provided by the United States' National Cancer Institute.

RESULTS: Over the 20-year period, there were 119,890 MND deaths. Men consistently had higher mortality compared to women. Analysis yielded noteworthy birth cohort effects for men. For men, the cohort RR decreased from 1919 to 1953 and peaked again between 1959 and 1963. Men born after 1973 had a reduced RR = 0.77 (95% CI = 0.63-0.94). Women born after 1973 had a cohort RR = 1.00 (95% CI = 0.75-1.34).

CONCLUSION: APC analysis revealed potentially impactful age, period, and cohort effects in U.S. MND mortality between 2001 and 2020, with higher mortality among men and evidence of sex-specific cohort patterns. Cohort effects suggest potential generational differences in risk. Further investigation is needed to disentangle ascertainment effects from true etiologic influences.}, } @article {pmid41649614, year = {2026}, author = {Mukherjee, R and Mehan, S and Choudhary, D and Rana, R and Das Gupta, G and Samant, R and Tongra, M}, title = {Sulforaphane-Mediated Multitarget Therapeutic Effects in Methylmercury-Induced ALS-Like Pathology: Comparative Analysis and Multifaceted Approach to Neuroprotection and Systemic Recovery.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {422}, pmid = {41649614}, issn = {1559-1182}, mesh = {Animals ; Sulfoxides/pharmacology/therapeutic use ; *Isothiocyanates/pharmacology/therapeutic use ; Female ; Methylmercury Compounds/toxicity ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/chemically induced/physiopathology ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Recovery of Function/drug effects ; *Neuroprotection/drug effects ; Oxidative Stress/drug effects ; Rats, Sprague-Dawley ; Rats ; Antioxidants/metabolism ; Signal Transduction/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by motor neuron loss driven by oxidative stress, neuroinflammation, and dysregulated survival signaling. The objective of this study was to evaluate the neuroprotective efficacy and safety of sulforaphane (SUFP) in a methylmercury (MMHg[+])-induced preclinical rat model of ALS, with comparison to omaveloxolone (OVX) and dimethyl fumarate (DIMT). SUFP treatment, particularly at 4 mg/kg, significantly restored antioxidant defense mechanisms through upregulation of Nrf2, HO-1, and SIRT1 while suppressing pro-inflammatory cytokines (IL-1β, TNF-α), apoptotic markers (Bax, caspase-3), and stress-related signaling pathways including p75NTR, PI3K/Akt, and MAPKs. These molecular effects translated into meaningful functional recovery, as evidenced by improvements in grip strength, locomotor performance, spatial memory, and depressive-like behavior. Histopathological evaluation demonstrated attenuation of demyelination and preservation of neuronal architecture in cortical, hippocampal, and cerebellar regions. Beyond central neuroprotection, SUFP exerted systemic benefits by normalizing hepatic enzymes, improving skeletal muscle integrity, restoring redox balance, stabilizing neurofilament and myelin-associated proteins, and correcting hematological alterations. Comparative analysis revealed that SUFP conferred superior neuroprotection with a favorable safety profile relative to OVX and, although slightly less efficacious than DIMT, exhibited reduced systemic toxicity. Molecular docking further supported SUFP's interaction with Nrf2-Keap1 targets, reinforcing its antioxidant and anti-inflammatory mechanisms. Collectively, these findings identify SUFP as a multifaceted and well-tolerated therapeutic candidate for ALS, supporting its further translational and clinical evaluation.}, } @article {pmid41649950, year = {2026}, author = {Komori, S and Ito, D and Hashizume, A and Yamada, S and Kishimoto, Y and Kawase, T and Kondo, A and Suzuki, M and Hatanaka, M and Oba, C and Katsuno, M}, title = {Characteristics of muscle cramps as a prodromal symptom of sporadic amyotrophic lateral sclerosis.}, journal = {Journal of neuromuscular diseases}, volume = {13}, number = {5}, pages = {1065-1075}, pmid = {41649950}, issn = {2214-3602}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; *Muscle Cramp/physiopathology/etiology ; Female ; *Prodromal Symptoms ; Male ; Middle Aged ; Aged ; Disease Progression ; Adult ; }, abstract = {BACKGROUND: Prodromal symptoms of sporadic amyotrophic lateral sclerosis (SALS) including muscle cramps were reported; however, their detailed characteristics have not been sufficiently studied.

OBJECTIVES: To clarify the detailed profiles of prodromal symptoms in SALS.

METHODS: Patients with SALS (n = 47) and healthy controls (n = 25) were enrolled. A questionnaire-based survey was conducted to investigate symptoms before and after disease onset, including sensory, autonomic, sleep, cognitive disturbances, and frequent muscle cramps. Frequent muscle cramps were defined as those occurring at least twice per month in the lower limbs, or at least once per month in the upper limbs or trunk. We evaluated the relationship between surveyed symptoms and clinical characteristics.

RESULTS: Prodromal frequent muscle cramps were observed in 29.8% of SALS patients, most frequently in the lower limbs. With disease progression, the sites with cramps increased, and the frequency of cramps during awakening also increased. The SALS patients with prodromal cramps had greater lean mass than those without (p = 0.023). Multivariate analysis showed that the presence of cramps after disease onset was associated with a slower longitudinal decline in the ALSFRS-R score (p = 0.048). Upper limb-onset SALS patients experienced cramps more frequently before onset than bulbar-onset patients did (p = 0.033).

CONCLUSIONS: Frequent muscle cramps often precede muscle weakness during the prodromal phase of limb-onset SALS. The frequency of cramps increased with disease progression. Prodromal cramps were associated with lean mass, whereas cramps after disease onset were associated with a slower rate of disease progression.}, } @article {pmid41651252, year = {2026}, author = {Hnath, B and Ekambaram, S and Dokholyan, NV}, title = {Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers.}, journal = {Neurobiology of disease}, volume = {220}, number = {}, pages = {107309}, pmid = {41651252}, issn = {1095-953X}, support = {R35 GM134864/GM/NIGMS NIH HHS/United States ; }, mesh = {*Superoxide Dismutase-1/metabolism/genetics ; *Extracellular Vesicles/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Animals ; Mutation ; *Motor Neurons/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in paralysis and death within three to five years. Mutations in over forty different proteins have been linked to ALS, raising debate over whether ALS is a single disease or multiple disorders with similar symptoms. Mutations in Cu,Zn superoxide dismutase 1 (SOD1) are found in only 2-3% of ALS cases, yet misfolded SOD1 appears in both sporadic (sALS) and familial (fALS) patients. Furthermore, mutations in TDP-43 or FUS increase levels of misfolded SOD1 on extracellular vesicles (EVs). Small EVs isolated from ALS patient samples have been shown to cause death of wild-type motor neurons and myotubes, supporting the theory that EVs play a role in spreading disease. We hypothesize that the previously identified toxic trimeric SOD1 spreads via EVs in ALS and influences the distribution of other ALS-related proteins, suggesting a common mechanism. To test this, we isolate EVs from motor neuron-like cells expressing mutations that stabilize trimers. We then perform a sandwich enzyme-linked immunosorbent assay (ELISA) using a CD9 capture antibody to measure whether misfolded SOD1 and 17 other ALS-related proteins increase or decrease on EVs with trimer stabilization. We identify which EV release pathway is affected by trimeric SOD1 using endocytosis and exocytosis inhibitors and analyze altered protein interaction pathways through co-immunoprecipitation and mass spectrometry proteomics. Our results show that VAPB, VCP, and Stathmin-2 increase on EVs when trimers are stabilized. The common pathway linking these ALS-associated proteins and SOD1 appears to involve multiple mechanisms, including the Caveolae endocytosis pathway, pointing to a novel hybrid EV release pathway in ALS. Overall, our findings show that trimeric SOD1 influences EV cargo and spread in ALS.}, } @article {pmid41651385, year = {2026}, author = {Raina, GS and Mehan, S and Das Gupta, G}, title = {Neuroprotection via IGF-1 neuronal signaling activation by melatonin and edaravone synergy in methylmercury-induced ALS-like neurotoxicity: Comprehensive analysis of brain regions, spinal cord, CSF, and blood plasma.}, journal = {Neurotoxicology}, volume = {113}, number = {}, pages = {103398}, doi = {10.1016/j.neuro.2026.103398}, pmid = {41651385}, issn = {1872-9711}, mesh = {Animals ; *Methylmercury Compounds/toxicity ; Rats ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Melatonin/pharmacology/administration & dosage ; *Brain/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/chemically induced/metabolism/drug therapy ; Signal Transduction/drug effects ; *Edaravone/pharmacology/administration & dosage ; *Insulin-Like Growth Factor I/metabolism ; Spinal Cord/drug effects/metabolism/pathology ; Male ; Drug Synergism ; Oxidative Stress/drug effects ; Neurons/drug effects/metabolism ; Rats, Sprague-Dawley ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration, oxidative stress, neuroinflammation, and neurotransmitter imbalances. This study explored the neuroprotective potential of melatonin (MLT), alone and in combination with edaravone (EDR), in a methylmercury (MEME)-induced ALS rat model. MEME exposure effectively replicated ALS pathology, causing behavioral deficits, oxidative stress, neuroinflammation, apoptosis, and widespread structural damage in critical brain regions and the spinal cord. MLT administration at 5 mg/kg (MLT5) and 10 mg/kg (MLT10) significantly mitigated MEME-induced neurotoxicity in a dose-dependent manner. MLT improved motor function, reduced depressive-like behavior, and restored body weight. Biochemically, MLT enhanced antioxidant defenses, including superoxide dismutase (SOD) and catalase (CAT), reduced pro-inflammatory cytokines, interleukin-1 beta (IL-1β), increased anti-inflammatory cytokines, interleukin-10 (IL-10), and restored neurotransmitter balance like dopamine and Gamma-Aminobutyric Acid (GABA). Mechanistically, MLT activated the IGF-1 signaling pathway, promoting neuronal survival and reducing apoptosis (Caspase-3 expression). Histopathological analyses confirmed that MLT preserved neuronal and glial integrity, reduced demyelination, and restored myelin basic protein (MBP) levels in brain and cerebrospinal fluid. The combination of MLT and EDR exhibited synergistic neuroprotective effects, surpassing the efficacy of individual treatments in reducing oxidative stress, inflammation, and neuronal damage. Behavioral and biochemical improvements were paralleled by systemic recovery, as evidenced by normalized hematological parameters and reduced methylmercury accumulation in brain tissues. These findings underscore MLT, particularly in combination with EDR, as a potent therapeutic agent for ALS, offering multi-targeted neuroprotection. Future studies should explore its translational potential in clinical settings for the treatment of neurodegenerative diseases.}, } @article {pmid41652348, year = {2026}, author = {Johansen, H and Nakken, O and Holmøy, T and Fredheim, OMS}, title = {Disease trajectories and end of life care in a Norwegian ALS cohort.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {}, pmid = {41652348}, issn = {1471-2377}, mesh = {Humans ; *Terminal Care/methods/statistics & numerical data ; Norway/epidemiology ; Retrospective Studies ; *Amyotrophic Lateral Sclerosis/therapy/mortality ; *Palliative Care ; Female ; Male ; Aged ; Middle Aged ; Cohort Studies ; Aged, 80 and over ; }, abstract = {OBJECTIVE: This retrospective cohort study aims to provide comprehensive data on the disease trajectory and end-of-life care in patients dying from ALS.

METHODS: The study presents detailed information on a cohort dying from ALS in the area served by Akershus University Hospital from 2011 to 2022. Data was obtained from the patient medical records.

RESULTS: 118 patients were included. 65 patients (55%) were referred to the Department of Palliative medicine for specialist palliative care, with a median duration from referral to death of two months and one third of patients not being able to communicate verbally at the time of referral. The most common life-sustaining treatment was non-invasive ventilation and percutaneous endoscopic gastrostomy, whereas most prevalent limitation of life-sustaining treatment was withholding of tracheostomy with invasive ventilation. Hospital was the most common place of death with 54 (46%) of all deaths. For in-hospital-deaths, the most common place of death was the palliative care ward, with 21 patients (39%), but a substantial proportion (17%) died at intensive or intermediate care units. Overall, 37% of in-hospital deaths had been admitted to either intensive or intermediate care units during their last week of life, which may suggest these patients deteriorated rapidly without having documented advanced care planning and therefore received resource demanding and futile treatment during the last week of life.

CONCLUSION: Many patients lived in their own homes until admitted to their last hospital stay in life. However, these last hospital stays were frequently characterized by insufficient advanced care planning, leading to futile overtreatment.

TRIAL REGISTRATION: Retrospectively registered.}, } @article {pmid41652471, year = {2026}, author = {Scekic-Zahirovic, J and Antonucci, S and Wiesner, D and Ebner, C and El Hajj, H and Aousji, O and Halablab, K and Fan, Y and Zelaya, A and Yartas, G and Baskar, K and Çakmak, EA and Bayer, D and Sung, HK and Dupuis, L and Park, J and Roselli, F}, title = {Large-scale mapping of the MCH network in ALS mice reveals the vulnerability of dopaminergic and GABAergic neurons in zona incerta.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {41652471}, issn = {2051-5960}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Melanins/metabolism ; *Zona Incerta/pathology/metabolism ; *GABAergic Neurons/pathology/metabolism ; *Hypothalamic Hormones/metabolism ; Mice, Transgenic ; *Pituitary Hormones/metabolism ; *Dopaminergic Neurons/pathology/metabolism ; Mice ; Disease Models, Animal ; Superoxide Dismutase-1/genetics ; Male ; Humans ; Neural Pathways/pathology ; }, abstract = {Weight loss and hypermetabolism are early and prognostically significant features of amyotrophic lateral sclerosis (ALS) and are associated with hypothalamic atrophy and degeneration of melanin-concentrating hormone (MCH) neurons that regulate energy balance. To investigate whether MCH vulnerability arises from upstream network dysfunction, we performed whole-brain retrograde rabies tracing in SOD1G93A mice. We identified an early, selective loss of monosynaptic inputs from the zona incerta (ZI), a dopaminergic (DA)/gamma-aminobutyric acid (GABA)ergic nucleus that preceded MCH neuron degeneration. Neurochemical profiling confirmed the DA/GABAergic identity of these ZI input neurons, and ZI/DAergic neurons later degenerated. ALS-related pathology emerged early in the ZI, paralleling pathology in the motor cortex, while anterograde mapping revealed that motor cortical projections preferentially targeted the ZI, linking vulnerable motor and metabolic networks. Loss of ZI/DAergic neurons was observed in conjunction with weight loss in non-SOD1 ALS models. These findings identify the ZI as an early-affected node within hypothalamic networks and suggest that disruption of DA/GABAergic inputs to MCH neurons is associated with subsequent MCH and DA neuronal vulnerability, degeneration and metabolic imbalance in ALS.}, } @article {pmid41653003, year = {2026}, author = {Brooks, BR and Shefner, J and Apple, S}, title = {Study 19 (MCI186-19) Post Hoc Analyses.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S19-S22}, pmid = {41653003}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/therapeutic use ; Treatment Outcome ; Disease Progression ; Female ; Male ; *Free Radical Scavengers/therapeutic use ; }, abstract = {While randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy of therapies in amyotrophic lateral sclerosis (ALS), post hoc analyses can provide critical insights into clinical effectiveness, treatment durability, and subpopulation responses. Several post hoc analyses of Study MCI186-19 (Study 19), the pivotal phase 3 RCT that supported the United States Food and Drug Administration approval of intravenous edaravone, have been performed to explore the broader clinical impact of this therapy. These analyses assessed the long-term treatment efficacy, changes in individual ALS Functional Rating Scale-Revised item scores, survival and additional milestone events, and the impact of edaravone in patient subgroups defined by disease progression trajectories using latent class analysis. Collectively, these findings reinforce the long-term clinical benefit of edaravone and demonstrate that edaravone may offer benefits across a spectrum of ALS disease trajectories, beyond those defined in the original study criteria. These studies help address questions not captured in the original RCT and may inform future trial design and treatment decisions.}, } @article {pmid41653004, year = {2026}, author = {Brooks, BR and Berry, JD and Ciepielewska, M}, title = {Survival of Intravenous Edaravone-Treated Patients With ALS: Evidence From Administrative Claims Analyses.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S23-S25}, pmid = {41653004}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Edaravone/administration & dosage/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/mortality ; Female ; Retrospective Studies ; Male ; Aged ; Middle Aged ; *Free Radical Scavengers/administration & dosage/therapeutic use ; Administration, Intravenous ; United States/epidemiology ; Treatment Outcome ; }, abstract = {Randomized controlled trials remain the cornerstone of evidence generation in amyotrophic lateral sclerosis (ALS), yet their inherent challenges, including disease rarity, heterogeneity, and limited validated biomarkers, highlight the need for complementary clinical evidence. This exploratory, retrospective study assessed overall survival in patients with ALS treated with intravenous (IV) edaravone using data from a large United States administrative claims database of patients enrolled from August 2017 to March 2020. Patients receiving IV edaravone (n = 318) were propensity score matched 1:1 with controls not treated with IV edaravone (n = 318), adjusting for 11 covariates. Median overall survival was 29.5 versus 23.5 months for the edaravone-treated group compared to controls, with a 27% reduced risk of death observed in the treated cohort (p = 0.005). These findings, together with existing data from the pivotal phase 3 Study MCI186-19 of IV edaravone, contribute to the growing body of literature suggesting a dual benefit of edaravone on both function and survival in ALS, offering critical insights for clinicians, patients, and payers navigating ALS treatment decisions.}, } @article {pmid41653005, year = {2026}, author = {Genge, A and Apple, S}, title = {Safety of Intravenous Edaravone in Clinical Practice.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S13-S15}, pmid = {41653005}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; Edaravone ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Antipyrine/analogs & derivatives/adverse effects/administration & dosage/therapeutic use ; *Free Radical Scavengers/adverse effects/administration & dosage ; Administration, Intravenous ; Female ; Pharmacovigilance ; Male ; Middle Aged ; Aged ; }, abstract = {This article summarizes the post-marketing pharmacovigilance safety data of intravenous (IV) edaravone during the 1- and 3-year periods following its launch for amyotrophic lateral sclerosis (ALS) in the United States. The most frequently reported adverse events (AEs) and serious AEs (SAEs) included those consistent with ALS disease progression, such as fatigue and muscular weakness, and were not qualitatively different from those reported in previous ALS trials. There were AEs and SAEs associated with IV administration, such as administration site reactions, and five non-fatal anaphylaxis SAEs were reported. No new safety signals were identified, and IV edaravone continues to demonstrate a favorable safety profile. These insights are especially useful as treatment transitions to edaravone oral suspension, which avoids IV-related complications. These findings underscore the importance of ongoing clinical safety assessments in informing ALS treatment decisions.}, } @article {pmid41653006, year = {2026}, author = {Gwathmey, KG and Apple, S}, title = {Introduction to the Supplement.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S3-S6}, pmid = {41653006}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/therapeutic use ; Neuroprotective Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with marked phenotypic and clinical heterogeneity. Three active pharmaceutical agents are currently approved by the United States Food and Drug Administration (FDA) for ALS: riluzole, edaravone (including intravenous [IV] and oral suspension formulations), and tofersen. Study MCI186-19 (Study 19) was a pivotal, phase 3 randomized controlled trial that demonstrated a significant reduction in physical functional decline vs. placebo in Japanese patients with ALS and contributed to FDA approval of IV edaravone in 2017. Edaravone oral suspension was FDA-approved in May 2022 following the results of Study MT-1186-A01, which showed it was well tolerated with a safety profile consistent with IV edaravone. Following Study 19, the clinical benefit of edaravone has remained an active area of investigation. This supplement presents data from clinical trials, post hoc analyses, and clinical studies that expand understanding of the use of edaravone in broader ALS populations. Topics include safety in clinical practice, generalizability of efficacy, clinical treatment outcomes, and health economics and outcomes research studies. Together, these findings aim to inform clinicians, researchers, and stakeholders regarding the evolving evidence base for edaravone in the management of ALS.}, } @article {pmid41653008, year = {2026}, author = {Brooks, BR and Ennist, DL and Beaulieu, D and Apple, S}, title = {Generalizability of Edaravone Efficacy.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S16-S18}, pmid = {41653008}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Edaravone/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Female ; Male ; Treatment Outcome ; *Free Radical Scavengers/therapeutic use ; Middle Aged ; Aged ; Disease Progression ; Vital Capacity/drug effects ; Retrospective Studies ; }, abstract = {The pivotal phase 3 trial MCI186-19 (Study 19) demonstrated the efficacy of intravenous edaravone in slowing functional decline in patients with amyotrophic lateral sclerosis (ALS), leading to United States Food and Drug Administration approval. Study 19 utilized a targeted enrollment enrichment strategy based on post hoc analyses from earlier trials, selecting patients with higher baseline function, more rapid disease progression, and better respiratory status. To evaluate the generalizability of Study 19 results, subsequent post hoc analyses assessed the efficacy of edaravone in broader ALS populations. One machine learning-based analysis retrospectively applied a validated model to Study 16 data, stratifying patients by predicted risk of respiratory decline. This detectable effect cluster analysis suggested that up to 70% of Study 16 participants may have benefited from edaravone. A second analysis investigated edaravone efficacy in patients from Study 19 with forced vital capacity (FVC) < 80% predicted (%p) at the start of treatment, since FVC ≥ 80%p was one of the Study 19 inclusion criteria. Both high- and low-FVC subgroups demonstrated reduced ALS functional rating scale-revised decline at 48 weeks when treated continuously with edaravone. These findings support the potential benefit of edaravone in a wider range of patients with ALS than those enrolled in Study 19, providing important insights into how clinical trial enrichment strategies may influence perceived efficacy, and underscoring the need for future prospective studies in more diverse ALS populations.}, } @article {pmid41653010, year = {2026}, author = {Abrahao, A and Zinman, L and Apple, S}, title = {Current and Ongoing Clinical Studies.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S26-S28}, pmid = {41653010}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/therapeutic use ; *Clinical Trials as Topic ; *Free Radical Scavengers/therapeutic use/administration & dosage ; *Antipyrine/analogs & derivatives/therapeutic use/administration & dosage ; }, abstract = {This article provides a comprehensive overview of current and ongoing studies evaluating intravenous (IV) edaravone and edaravone oral suspension in the treatment of amyotrophic lateral sclerosis (ALS). In addition to data from clinical practice and post hoc analyses, multiple observational and interventional studies are underway to better understand the efficacy, safety, and biological impact of edaravone in clinical settings. Key studies include SUNRISE Japan, a long-term postmarketing surveillance study of IV edaravone in Japanese patients with ALS; the ALS/Motor Neuron Disease Natural History Study, a longitudinal registry designed to inform clinical trial design and track ALS progression; and the REFINE-ALS study, which is actively collecting biomarker data to elucidate the pathophysiologic mechanisms influenced by edaravone. For edaravone oral suspension, United States Food and Drug Administration approval was supported by Study MT-1186-A01, a phase 3 trial assessing safety and tolerability over 48 weeks, with extension Study MT-1186-A03. Study MT-1186-A02, conducted as an FDA postmarketing commitment, and its extension, Study MT-1186-A04, evaluated whether investigational once daily dosing showed superior efficacy vs. the approved on/off dosing regimen. Collectively, these studies contribute to a growing body of evidence supporting the use of edaravone as a therapeutic option for ALS. They also underscore the importance of continued data collection from both clinical trials and clinical settings to inform optimal treatment strategies and combination therapy approaches as more agents become available in an evolving ALS treatment landscape.}, } @article {pmid41653014, year = {2026}, author = {Abrahao, A and Ciepielewska, M and Zinman, L}, title = {Value of Clinical Evidence and Health Economics and Outcomes Research (HEOR) Studies.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S7-S12}, pmid = {41653014}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Outcome Assessment, Health Care ; Amyotrophic Lateral Sclerosis/economics/therapy ; Randomized Controlled Trials as Topic ; *Evidence-Based Medicine ; *Economics, Medical ; }, abstract = {Randomized controlled trials (RCTs) remain the gold standard for establishing the efficacy and safety of new treatments. However, clinical evidence derived from the systematic analysis of real-world data generated through routine clinical practice can complement RCT data by offering insights into treatment performance in broader, more heterogeneous patient populations and clinical care settings. The integration of high-quality clinical evidence into health economics and outcomes research (HEOR) is increasingly important, as it supports healthcare decision-making across multiple stakeholders, including regulatory agencies, payers, clinicians, and patients. Multiple study designs, such as pragmatic trials, hybrid RCTs, external control arms, and observational studies, can provide valuable clinical evidence beyond the controlled trial setting. These data can enhance understanding of comparative effectiveness, patient-reported outcomes, treatment safety, and healthcare utilization and costs. The field of amyotrophic lateral sclerosis offers a compelling example of how clinical evidence derived from global registries and clinical studies has advanced understanding of disease epidemiology, treatment patterns, and the effectiveness of therapies, including riluzole and edaravone. Consequently, this review and the associated supplementary articles are meant to serve as a primer to inform clinicians of the potential contribution of clinical evidence to HEOR studies.}, } @article {pmid41653524, year = {2026}, author = {Kim, SH and Roh, YS}, title = {Effects of a theory-based advanced life support booster training program on competency retention in nursing students: A randomized controlled trial.}, journal = {Nurse education in practice}, volume = {92}, number = {}, pages = {104754}, doi = {10.1016/j.nepr.2026.104754}, pmid = {41653524}, issn = {1873-5223}, mesh = {Humans ; *Students, Nursing/psychology ; *Clinical Competence/standards ; Female ; *Retention, Psychology ; Male ; Education, Nursing, Baccalaureate ; Educational Measurement ; Adult ; }, abstract = {AIM: This study evaluated the effectiveness of a theory-based advanced life support (ALS) booster training program on six-month retention of knowledge, skills performance and teamwork.

BACKGROUND: Retention of ALS competencies is vital for nursing students, yet skills and knowledge often decline within months of initial training.

DESIGN: A randomized controlled trial was conducted.

METHODS: A convenience sample of 65 fourth-year nursing students were randomly assigned to an experimental group (n = 33) receiving a two-hour booster session based on mastery learning and deliberate practice theories or to a control group (n = 32). ALS knowledge, skills and teamwork were measured at baseline and six months post-training. Data were analyzed using non-parametric tests and generalized estimating equation.

RESULTS: Both groups experienced declines over time. However, the experimental group showed significantly better retention in skills performance (p < .001) and teamwork (p = .025). Knowledge retention was higher but not statistically significant (p = .116).

CONCLUSIONS: A brief, theory-based booster session effectively improved long-term retention of ALS skills and teamwork, supporting its integration into nursing education.}, } @article {pmid41653702, year = {2026}, author = {Sebastianelli, L and Versace, V and Ferrazzoli, D and Ortelli, P and Trinka, E and Sellner, J and Nardone, R}, title = {Neurophysiology in the mirror: A tri-layer model of mirror movements informed by TMS evidence.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {184}, number = {}, pages = {2111692}, doi = {10.1016/j.clinph.2026.2111692}, pmid = {41653702}, issn = {1872-8952}, mesh = {Humans ; *Transcranial Magnetic Stimulation/methods ; *Movement Disorders/physiopathology ; *Motor Cortex/physiology/physiopathology ; Functional Laterality/physiology ; *Evoked Potentials, Motor/physiology ; Movement/physiology ; Pyramidal Tracts/physiology/physiopathology ; }, abstract = {OBJECTIVE: Mirror movements are involuntary, task-coupled contractions in contralateral homologous muscles during unilateral movement. While often described as a developmental remnant or rare clinical sign, mirror movements offer insight into the physiological mechanisms that underlie motor lateralization and interhemispheric balance. This review aimed to synthesize the available neurophysiological evidence-primarily from transcranial magnetic stimulation (TMS)-and propose a structured, mechanism-based framework for interpreting mirror movements across neurological conditions.

METHODS: A structured narrative review was conducted of studies published between 1966 and November 2025 using TMS in individuals with congenital, developmental, or acquired mirror movements. Studies using neuroimaging or peripheral electrophysiology were included selectively to support anatomical or functional interpretation of TMS findings. Data were organized into three mechanistic layers based on prevailing neurophysiological signatures rather than etiology alone.

RESULTS: Three non-mutually exclusive mechanisms were identified: (I) persistent fast-conducting ipsilateral corticospinal projections, primarily in congenital mirror movement syndromes and early brain injury; (II) deficient transcallosal inhibition, observed in conditions affecting interhemispheric balance such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and callosal agenesis; and (III) bilateral overactivation of premotor and supplementary motor areas, especially under conditions of impaired motor program selection or increased task demands.

CONCLUSIONS: Mirror movements can be interpreted within a tri-layer model reflecting distinct disruptions in corticospinal connectivity, interhemispheric inhibition, and supraspinal motor control.

SIGNIFICANCE: This framework provides an integrative model for interpreting neurophysiological findings in mirror movements, offering insight into hierarchical motor control without implying specific diagnostic or therapeutic applications.}, } @article {pmid41654003, year = {2026}, author = {Sia, T and Sheehy, TP and Morgan, P and Wools, CA and Zhao, Y and Gibbs, R and Mathieson, S and Smith, AA}, title = {Trajectory of Mobility Function Decline for People With Motor Neuron Disease.}, journal = {Archives of physical medicine and rehabilitation}, volume = {107}, number = {6}, pages = {1291-1297}, doi = {10.1016/j.apmr.2026.01.028}, pmid = {41654003}, issn = {1532-821X}, mesh = {Humans ; *Motor Neuron Disease/physiopathology/complications ; Female ; Male ; Retrospective Studies ; Middle Aged ; Aged ; *Mobility Limitation ; Longitudinal Studies ; Disease Progression ; Muscle Weakness/physiopathology/etiology ; Wheelchairs/statistics & numerical data ; Adult ; }, abstract = {OBJECTIVES: The primary aim of this study was to explore factors that may influence the rate of mobility function decline. A secondary aim was to identify the impact of neck weakness on mobility decline in people living with motor neuron disease (MND).

DESIGN: Retrospective, longitudinal observational study design.

SETTING: This study was conducted at a Statewide Progressive Neurological Disease Service (SPNDS) in inpatients, outpatients, and community-based services. The SPNDS clinic treats adults with MND from both metropolitan and rural settings.

PARTICIPANTS: Adults with MND attending the SPNDS were recruited to participate in the study.

INTERVENTIONS: Not applicable.

MAIN OUTCOME MEASURES: Categorical data relating to mobility function (walking endurance, gait aid used, and level of assistance required) were recorded. Neck weakness was measured as present or absent based on the participant's subjective report and/or objective observation of head position when upright.

RESULTS: Results from the 358 participants recruited showed that the median time to loss of independent gait was 30.5 months (range, 4-239; interquartile range [IQR], 26), full-time wheelchair use was 34 months (IQR, 35; range, 5-238), and median time to becoming housebound was 28 months from MND symptom onset (IQR, 24.5; range, 5-219 mo). A total of 141 (39.4%) participants had neck weakness. The presence of neck weakness resulted in earlier loss of independent gait and quicker to become housebound. There was no significant difference in time to full-time wheelchair use between participants with or without neck weakness.

CONCLUSIONS: There was an effect of both phenotype and neck weakness on the trajectory of mobility function decline in people with MND. Overall, people with amyotrophic lateral sclerosis phenotype (bulbar, cervical, or lumbar onset) experienced a more rapid rate of decline in mobility function than those with flail limb and primary lateral sclerosis phenotypes. In addition, those demonstrating neck weakness were quicker to decline in mobility than those without neck weakness.}, } @article {pmid41654110, year = {2026}, author = {Shen, Y and Shen, S and Luo, ZG}, title = {Gene-targeted versus broad-spectrum therapies in ALS: comparative lessons and strategic outlook.}, journal = {Journal of genetics and genomics = Yi chuan xue bao}, volume = {53}, number = {7}, pages = {1159-1179}, doi = {10.1016/j.jgg.2026.01.012}, pmid = {41654110}, issn = {1673-8527}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; *Genetic Therapy/methods ; Precision Medicine ; *Gene Targeting/methods ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentless and fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and ultimately, respiratory failure. Despite a growing understanding of its complex pathophysiology, therapeutic options remain limited. This review critically analyzes recent clinical advances by comparing two divergent strategies, including precision gene-targeted therapies for monogenic ALS subtypes and broad-spectrum agents for the wider sporadic population. While gene therapies like tofersen demonstrate clear molecular target engagement, their translation to robust clinical benefit remains a challenge. In contrast, broad-spectrum agents have faced consistent late-stage failures, often due to the disease's underlying diversity, which undermines a one-size-fits-all approach. We argue that this heterogeneity, coupled with a lack of predictive biomarkers and the difficulty of late-stage intervention, represents the core barrier to progress. The future of ALS therapeutics therefore depends on a strategic pivot toward personalized medicine. This requires prospectively stratifying patients, developing rational combination therapies, and intervening earlier in the disease course, ultimately treating ALS as a syndrome of distinct molecular diseases rather than a single entity.}, } @article {pmid41655130, year = {2026}, author = {Xiang, Q and Liu, Y and Wang, J}, title = {Golgi fragmentation driven by the USP11-ITCH axis triggers autolysosomal failure in neurodegeneration.}, journal = {Autophagy}, volume = {22}, number = {5}, pages = {1132-1133}, pmid = {41655130}, issn = {1554-8635}, mesh = {Animals ; *Lysosomes/metabolism ; *Golgi Apparatus/metabolism/pathology ; Humans ; *Ubiquitin-Protein Ligases/metabolism ; Autophagy ; *Neurodegenerative Diseases/metabolism/pathology ; *Thiolester Hydrolases/metabolism ; Neurons/metabolism ; Proteotoxic Stress ; Repressor Proteins ; }, abstract = {Golgi fragmentation is a prominent early hallmark of neurodegenerative diseases such as Alzheimer disease (AD) and amyotrophic lateral sclerosis (ALS), yet the shared molecular mechanisms underlying this phenomenon remain poorly understood. Here we identify the E3 ubiquitin ligase ITCH as a central regulator of Golgi integrity and proteostasis. Elevated ITCH disrupts both cis- and trans-Golgi networks, dislocates lysosomal hydrolase sorting factors, and impairs maturation of hydrolases. The ensuing lysosomal dysfunction leads to autophagosome accumulation and defective clearance of accumulated cytoplasmic toxic proteins like TARDBP/TDP-43. Genetic and pharmacological inhibition of ITCH restores autolysosomal degradation and protects neurons in both mammalian and Drosophila models. Aberrant buildup of the deubiquitinase USP11 drives ITCH accumulation, intensifying neuronal proteotoxic stress in individuals with AD and ALS. These findings reveal a mechanistic pathway connecting Golgi disorganization, autolysosomal impairment, and proteotoxic stress in neurodegeneration.}, } @article {pmid41656808, year = {2025}, author = {Yu, C and Zeng, W and Meekrathok, P and Bu, Y and Wang, J and Qiu, J}, title = {[Heterogeneity in the regulation of cellular stress responses by FUS gene mutations associated with amyotrophic lateral sclerosis].}, journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences}, volume = {50}, number = {10}, pages = {1755-1770}, pmid = {41656808}, issn = {1672-7347}, support = {2019RS1010//the Project of Department of Science and Technology of Hunan Province/ ; }, mesh = {*RNA-Binding Protein FUS/genetics/chemistry/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Mutation ; Nuclear Localization Signals/genetics ; *Stress, Physiological/genetics ; }, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective death of motor neurons, exhibiting marked clinical heterogeneity and lacking effective treatment. The etiology and pathogenic mechanisms remain incompletely understood. The FUS (fused in sarcoma) gene is one of the key causative genes in ALS. Pathogenic mutations in the encoded protein are predominantly clustered in the C-terminal nuclear localization signal (NLS) region, and distinct NLS mutation sites show considerable differences in pathogenic potency, clinical phenotypes, and molecular mechanisms. This study focuses on 2 representative pathogenic NLS mutations of FUS (FUS[R514S] and FUS[P525L]) to investigate their differential regulation of cellular stress responses and explore the underlying mechanisms.

METHODS: Multiple sequence alignment of FUS protein homologs from 12 species was performed using an online tool from the National Center for Biotechnology Information (NCBI) to determine the evolutionary conservation of residues R514 and P525. The three-dimensional (3D) structure of the nuclear transport receptor-FUS complex [Protein Data Bank (PDB) ID: 5YVG] was analyzed and visualized using PyMOL. Structure of FUS mutants were generated using the mutation wizard tool in PyMOL by selecting the target conformational isomer and executing the mutation workflow. Tet-on inducible expression cell models for FUS wild-type (WT) and mutant FUS (FUS[R514SS] and FUS[P525L]) were established in human embryonic kidney 293T (HEK293T) cells. Protein expression levels and subcellular localization of FUS were assessed by Western blotting and immunofluorescence assay, respectively. FUS aggregation states were compared between WT and mutant FUS using a digitonin-based permeabilization and extraction assay, followed by sodium dodecylsulfate-polyacrylamide gel electrophoresis-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting analysis. Blue native PAGE (BN-PAGE) was used to evaluate the stability of FUS-containing complexes. Mitochondrial membrane potential and reactive oxygen species (ROS) levels were measured by flow cytometry. Stress granule (SG) formation was induced using sodium arsenite, and the effects of WT and mutant FUS on SG dynamics were analyzed by immunofluorescence assay. Protein expression changes of mitochondrial function-related proteins [translocase of outer membrane 20 kD subunit (Tom20) and voltage-dependent anion channel 1 (VDAC1)] and key molecules of the integrated stress response (ISR) pathway [phosphorylated-eukaryotic initiation factor 2 alpha (p-eIF2α) and activating transcription factor 4 (ATF4)] were examined by Western blotting.

RESULTS: Sequence alignment revealed that R514 and P525 are highly conserved across FUS homologs from 12 species. Structural analysis indicated that the FUS[R514S] and FUS[P525L] mutations disrupt hydrogen bonding or hydrophobic interactions between FUS and importin-β2, weakening the stability of these interactions. Western blotting confirmed the successful establishment of inducible WT and mutant FUS expression cell models, and exogenous FUS expression slightly suppressed endogenous FUS protein levels. Immunofluorescence assay demonstrated that WT FUS is predominantly localized in the nucleus, whereas both FUS[R514S] and FUS[P525L] mutants mislocalize to the cytoplasm with a punctate, granular distribution. Compared with WT FUS, neither mutant significantly affected mitochondrial membrane potential, ROS levels, or the homeostasis of mitochondrial function-related proteins (all P>0.05). Upon sodium arsenite exposure, mutant FUS formed SGs more rapidly, generated SGs with larger diameters, and displayed distinct intracellular distribution and aggregation patterns relative to WT (P>0.05). After drug withdrawal, WT and mutant FUS showed no significant difference in their effects on SG disassembly (P<0.05). Under basal conditions, FUS[R514S] exhibited significantly higher eIF2α phosphorylation levels than WT, and ATF4 protein levels also showed an increasing trend (P<0.05). No statistically significant difference was observed between FUS[P525L] and WT FUS in these measures (P>0.05). Sodium arsenite treatment increased eIF2α phosphorylation across all groups, eliminating inter-mutant differences.

CONCLUSIONS: Distinct pathogenic NLS mutations of FUS differentially regulate cellular stress responses through different mechanisms, contributing to ALS initiation and progression. Among these, FUS[P525L] promotes the formation of larger stress granules, whereas FUS[R514S] more readily activates the cellular ISR.}, } @article {pmid41657419, year = {2026}, author = {Wang, Z and Huang, J and Yun, D}, title = {Current and emerging therapeutic strategies for amyotrophic lateral sclerosis: from pharmacological approaches to gene and stem cell therapies.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1729302}, pmid = {41657419}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that involves upper and lower motor neurons, severely impairing patients' quality of life. The complex interaction of genetic and environmental factors in ALS pathophysiology complicates therapeutic development. Currently available disease-modifying pharmacological therapies for ALS offer limited efficacy, only slowing disease progression to a modest degree. The recent market withdrawal of a previously approved therapy (AMX0035) further underscores the challenges in this field. Biological targets for ALS and related neurodegenerative diseases offer a unique avenue for therapeutic intervention. With the advancement of genetic engineering technology, innovative therapies such as Stem cell therapy and gene therapy are also discussed, offering a promising horizon for ALS treatment. In addition, the management of ALS symptoms plays a key role in improving the daily lives of people with the disease. In this review, we summarize various strategies for treating ALS, providing an overview of the disease.}, } @article {pmid41658391, year = {2026}, author = {Kanj, G and Malaeb, D and Sakr, F and Dabbous, M and Obeid, S and Hallit, S and Fekih-Romdhane, F}, title = {Psychometric properties of an Arabic translation of the short form of the affective lability scale in a sample of Lebanese adults.}, journal = {Frontiers in psychology}, volume = {17}, number = {}, pages = {1642617}, pmid = {41658391}, issn = {1664-1078}, abstract = {BACKGROUND: The present study aimed to investigate the psychometric properties of an Arabic version of the Affective Lability Scale in its short form (ALS-18) within an Arabic-speaking sample. Particularly, the concurrent validity, sex invariance and factorial structure were examined.

METHODS: The total sample of this cross-sectional study consisted of 748 adults, with a mean age of 34.48 ± 13.25 years, 66.5% females. After completing the forward-backward translation for cultural and linguistic adaptation, concurrent validity was assessed through correlations with related constructs, Confirmatory Factor Analysis was conducted to examine the factorial structure, and internal reliability as well as measurement invariance across sex were tested, the latter being through multigroup analyses.

RESULTS: The fit of the scale's original three-factor model was suggested through confirmatory factor analyses. Full measurement invariance at the configural, metric, and scalar levels was attained. The scale also yielded concurrent validity, with results indicating associations with increased levels of depression, anxiety and stress, and lower levels of self-esteem. The study's findings further denoted good internal consistency of the Arabic ALS-18 with values of McDonald's ω and Cronbach's α greater than 0.70.

CONCLUSION: Results revealed that the Arabic ALS-18 is a reliable and valid self-report measure that could be utilized among an Arabic-speaking population to assess affective lability. The availability of the Arabic version of the ALS-18 is deemed to increase its use for research and provide a foundation for future clinical validation studies, globally benefiting Arabic-speaking individuals.}, } @article {pmid41658940, year = {2026}, author = {Farinazzo, G and Giagnorio, E and Marcuzzo, M and Cattaneo, M and Malacarne, C and Cavalcante, P and Bonanno, S and Maderna, E and Pensato, V and Gellera, C and Marucci, G and Mazzetti, S and Salvi, E and Lauria, G and Marcuzzo, S}, title = {MicroRNA profiling in post-mortem spinal cord of C9ORF72-related ALS patients reveals molecular pathways involved in motor neuron degeneration.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1741065}, pmid = {41658940}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder causing progressive motor neuron death in cortex, brainstem and spinal cord. The most common genetic cause is the G4C2 hexanucleotide repeat expansion in the non-coding region of exon 1 of C9ORF72, accounting for ~40% of familial and ~7% of sporadic ALS. RNA dysregulation is increasingly recognized as a key contributor to ALS pathogenesis. This study aimed to identify specific microRNAs (miRNAs) involved in motor neuron degeneration in C9ORF72-ALS.

METHODS: We profiled 754 miRNAs in human post-mortem spinal cord tissue from C9ORF72-ALS patients and healthy donors. Laser capture microdissection isolated ventral horn regions, and in silico target prediction identified potential genes and pathways regulated by differentially expressed miRNAs. Target genes were validated by Real time PCR.

RESULTS: Two subsets of miRNAs were exclusively expressed in ventral horn regions: miR-200b-3p and miR-346 in C9ORF72-ALS patients, and miR-30d-5p, miR-106b-5p and miR-135a-5p in healthy donors. Target prediction and molecular analysis identified putative genes and pathways linked to cell death, inflammation, protein metabolism, DNA modification, excitotoxicity, autophagy and vesicles trafficking.

DISCUSSION: This study identifies specific miRNAs and their target genes as key molecules in motor neuron degeneration in C9ORF72-ALS. Restoring their expression could represent a therapeutic approach for ALS.}, } @article {pmid41659424, year = {2026}, author = {Chen, R and Stockwell, I and Pierce, JC and Peak-Chew, SY and Huang, M and Newell, K and Ghetti, B and Cousin, MA and Greger, IH and Ryskeldi-Falcon, B}, title = {Pathological TDP-43 filaments accumulate at synapses and cause synaptic dysfunction.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41659424}, issn = {2692-8205}, support = {R01 NS110437/NS/NINDS NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; RF1 AG071177/AG/NIA NIH HHS/United States ; R01 AG080001/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; R01 NS137469/NS/NINDS NIH HHS/United States ; }, abstract = {The assembly of TAR DNA-binding protein 43 (TDP-43) into amyloid filaments within neurons is a hallmark of multiple neurodegenerative diseases, including motor neuron diseases (MND), frontotemporal dementias (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). These diseases result from the deterioration and loss of neurons, with synaptic dysfunction and neuronal hyperexcitability being prominent early events. Pathogenic mutations in the TDP-43 gene, TARDBP, that promote filament formation have established a causal role for TDP-43 assembly in neurodegenerative diseases. However, the molecular mechanisms underlying filament accumulation and their contribution to neurodegeneration are poorly understood. TDP-43 filaments can propagate between neurons in a prion-like manner, which may underlie the progressive spread and accumulation of TDP-43 pathology in disease. Here, we studied early stages of TDP-43 filament accumulation following internalisation of patient-derived TDP-43 filaments by mouse and human cortical neurons. Using proximity labelling, we identified molecular environments and putative interactions of TDP-43 filaments. We found that TDP-43 filaments accumulated at synapses, particularly in proximity to the presynaptic active zone, which we confirmed in FTD patient brain sections. Electron cryo-tomography (cryo-ET) directly visualised abundant TDP-43 filaments spanning the presynaptic cytoplasm in situ, which contacted synaptic vesicles and the plasma membrane. Functional measurements revealed that the accumulation of TDP-43 filaments led to presynaptic dysfunction and subsequent neuronal hyperexcitability. These findings suggest that synapses are a major early site of TDP-43 filament accumulation, relevant to their propagation, and directly link TDP-43 filament gain of function to synaptic dysfunction.}, } @article {pmid41659894, year = {2026}, author = {Boucher Grenon, J and Doyon, C and Laliberté, T and Campeau-Lecours, A}, title = {Design of a low-cost mechanical 3D-Printed hand orthosis for grasping assistance in activities of daily living.}, journal = {Journal of rehabilitation and assistive technologies engineering}, volume = {13}, number = {}, pages = {20556683261422642}, pmid = {41659894}, issn = {2055-6683}, abstract = {The ability to grasp objects has a significant impact on the independence of individuals following a stroke, a spinal cord injury, or for those who are living with amyotrophic lateral sclerosis. In most cases, physical rehabilitation is not sufficient to regain the hand function necessary for day-to-day life. Hand orthoses capable of providing grasping assistance in activities of daily living are therefore crucial to a more independent lifestyle. However, most available options struggle to offer an acceptable balance between cost, size, weight and functionality, resulting in limited use in practice. This article presents a low-cost, 3D-printed hand orthosis that relies solely on mechanical elements to aid in finger flexion. An underactuated, flexible design for the fingers with nylon strips as spring blades was used to achieve a design that costs only 27% of the price of comparable commercially available options, as well as being very lightweight and easily customizable. It was also demonstrated that rigid thumb supports allowed the orthosis to be used in the majority of daily grasping tasks. Finally, the use of the proposed mechanism was shown to be able to provide up to 4 N of flexion assistance to the finger when using a medium wrap grip.}, } @article {pmid41660682, year = {2026}, author = {Li, J and Zhu, D and Yang, W and Guan, T and Yang, L and Gong, W and Liu, X and You, J and Feng, J and Chen, X}, title = {Lifestyle-Associated Metabolic Signature Predicts the Risk of Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {73}, number = {5}, pages = {822-831}, doi = {10.1002/mus.70166}, pmid = {41660682}, issn = {1097-4598}, support = {24Y12800900//Shanghai Science and Technology Commission 2024 Science and Technology Innovation Action Plan Medical Innovation research field project/ ; 82371431//National Natural Science Foundation project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/epidemiology/diagnosis ; Female ; *Life Style ; Hand Strength/physiology ; Middle Aged ; Male ; Aged ; Risk Factors ; Metabolomics ; United Kingdom/epidemiology ; Body Mass Index ; }, abstract = {INTRODUCTION/AIMS: Although the association between certain lifestyle factors and the risk of amyotrophic lateral sclerosis (ALS) has been recognized, the potential mechanism underlying it remains unexplored. This study aimed to identify the metabolic signature indicative of lifestyle factors related to ALS, to examine its association with ALS risk, and to evaluate the mediating effects of muscle strength underlying these associations.

METHODS: This study used UK Biobank data, including ALS diagnoses, potential ALS-related factors, metabolomics, and hand grip strength. A total protective factor score was calculated from lifestyle data. Multivariable Cox regression analyzed associations between the score, its components, and ALS risk. ALS-related metabolic signatures were identified via elastic net regression. ALS risk across signature levels was compared by log-rank tests. Mediation analysis assessed the role of baseline hand grip strength.

RESULTS: 248,222 participants were included in this study. Among lifestyle factors, the total protective factor score, no military service, and higher body mass index were significantly associated with reduced ALS risk. The metabolic signature derived from 163 metabolites indicative of potential ALS-associated protective factors was identified and found to be associated with lower ALS risk. Baseline hand grip strength of both hands was also associated with reduced ALS risk. Mediation analysis revealed that right-hand grip strength significantly mediated the associations between the total protective factor score, the metabolic signature, and ALS risk.

DISCUSSION: Our study highlights the potential of the metabolic signature as a biomarker for early disease identification and underscores the importance of lifestyle-based prevention strategies.}, } @article {pmid41661021, year = {2026}, author = {Pervushina, EV and Kutlubaev, MA and Kuznetsova, DR and Karimova, GI and Kachemaeva, OV and Mkhitaryan, EA}, title = {[Combination of amyotrophic lateral sclerosis with Alzheimer's disease].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {126}, number = {1}, pages = {132-136}, doi = {10.17116/jnevro2026126011132}, pmid = {41661021}, issn = {1997-7298}, mesh = {Humans ; *Alzheimer Disease/complications/diagnosis ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; }, abstract = {The combination of amyotrophic lateral sclerosis (ALS) with Alzheimer's disease is rare. Currently, it is unclear whether such comorbidity is an accidental coincidence or a manifestation of a specific pathological process. A case of simultaneous occurrence of classic symptoms of the bulbar form of ALS and Alzheimer's disease is presented. The possible mechanisms of the combination of two diseases are analyzed.}, } @article {pmid41661136, year = {2026}, author = {Liu, X and Wang, J and Zhan, J and Wang, Q and Lin, X and Li, H and Li, H}, title = {Dual-Field Amplification via Nanotip-Engineered Catalysts for Efficient Spin-State and Ion Regulation in Aluminum-Sulfur Batteries.}, journal = {ACS nano}, volume = {20}, number = {7}, pages = {5591-5601}, doi = {10.1021/acsnano.5c16319}, pmid = {41661136}, issn = {1936-086X}, abstract = {Modulating the electronic structure of catalysts through external magnetic fields is a promising strategy for enhancing electrocatalytic activity, which has been successfully demonstrated in the oxygen evolution reaction (OER), zinc-air batteries and lithium-sulfur batteries. However, conventional magnetic regulation approaches typically focus solely on spin-state modulation, neglecting the ion transport limitations in practical systems. Additionally, existing permanent magnets and ferromagnetic additives generate magnetic fields with limited intensity and nonuniform directionality, restricting their effectiveness. Herein, we propose a tip-enhanced magnetic-electric dual-field strategy by rationally designing ferromagnetic NiCo2O4 catalysts with nanotip architectures to address long-standing kinetic bottlenecks in aluminum-sulfur (Al-S) batteries. Finite element analysis demonstrates that the high-curvature tips significantly amplify local electric and magnetic fields by approximately 4.2- and 2.6-fold, respectively, under an external field. Moreover, the induced spin-state transition of Ni[3+] to high-spin (HS) states enhances d-p orbital hybridization with polysulfide intermediates, effectively lowering reaction barriers. This dual enhancement synergistically promotes ion transport via magnetohydrodynamic (MHD) effects, leading to substantially reduced voltage hysteresis and markedly improved electrochemical performance, delivering a high reversible capacity of 513 mAh g[-1] after 700 cycles in Al-S batteries. By integrating geometric field amplification with spin-state modulation, this work presents a highly efficient and scalable strategy for approach to designing high-performance catalysts for advanced Al-S batteries.}, } @article {pmid41661214, year = {2026}, author = {Miller, TM and Cudkowicz, ME and Shaw, PJ and Genge, A and Sobue, G and Bucelli, RC and Chiò, A and Van Damme, P and Ludolph, AC and Glass, JD and Andrews, JA and Babu, S and Benatar, M and McDermott, CJ and Salachas, F and Bruneteau, G and Al-Chalabi, A and Amorin, M and Nestorov, I and Graham, D and Lin, L and Sun, P and McNeill, M and Malek, S and Inra, J and Garafalo, S and Fradette, S and , }, title = {Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis.}, journal = {JAMA neurology}, volume = {83}, number = {2}, pages = {115-125}, pmid = {41661214}, issn = {2168-6157}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Double-Blind Method ; *Oligonucleotides/therapeutic use/administration & dosage ; *Oligonucleotides, Antisense/therapeutic use ; *Superoxide Dismutase-1/genetics ; Treatment Outcome ; }, abstract = {IMPORTANCE: Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are attributable to a pathogenic variant in the superoxide dismutase 1 (SOD1) gene. Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene.

OBJECTIVE: To evaluate the long-term effects of tofersen in adults with SOD1-ALS.

The phase 3, randomized, double-blind, placebo-controlled VALOR trial (A Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tofersen in SOD1-ALS; conducted from March 2019 to July 2021) evaluated tofersen use over 28 weeks in adults (18 years and older) with weaknesses attributable to ALS and a confirmed SOD1 pathogenic variant at 32 sites in 10 countries; participants could then enroll in an open-label extension (OLE; completed August 2024).

INTERVENTION AND EXPOSURE: Adults with SOD1-ALS were randomly assigned 2:1 to receive tofersen (100 mg) or placebo over a 24-week period in the VALOR study. All participants in the OLE were treated with tofersen.

MAIN OUTCOMES AND MEASURES: Integrated analysis of VALOR and the OLE study aimed to compare early start vs placebo/delayed start (approximately 6 months later) treatment with tofersen. Key efficacy end points included measures of axonal injury and neurodegeneration (neurofilament), function and strength, quality of life, and survival.

RESULTS: VALOR enrolled 108 participants with 42 unique SOD1 pathogenic variants (mean [SD] age: placebo/delayed-start group 51.2 [11.6] [n = 36]; early-start group: 48.1 [12.6] [n = 72]) with 19 (53%) and 43 (60%) of participants being male in the placebo/delayed- and early-start groups, respectively. Overall, 95/108 participants (88%) enrolled in the OLE, and 46 participants completed the OLE (early-start group, 34 [47%]; placebo/delayed-start group, 12 [33%]). At OLE completion, participants could have accumulated 3.5 years or more (range, 192-276 weeks) of follow-up from the start of VALOR. Over 148 weeks, earlier initiation of tofersen (compared to later initiation) was associated with numerically less decline in measures of clinical function (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, -9.9 vs -13.5 points), respiratory function (slow vital capacity, -13.8% vs -18.1%), muscle strength (handheld dynamometry megascore, -0.38 vs -0.43 points), and quality of life (Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 score, 17.0 vs 22.5 points; EuroQol 5 Dimension, 5 Level Questionnaire score, -0.1 vs -0.2 points). Tofersen prolonged survival relative to the expected natural history of SOD1-ALS. Most adverse events were consistent with ALS progression or known procedural adverse effects. All serious neurological adverse events were reversible; few led to tofersen discontinuation.

CONCLUSIONS AND RELEVANCE: Final data from VALOR and the OLE demonstrated the benefit of tofersen in SOD1-ALS and provide clear rationale for its use in this population.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: VALOR NCT02623699; OLE NCT03070119.}, } @article {pmid41663779, year = {2026}, author = {Roy, KK and Kumari, R and Upadhyay, AK and Mohanty, S}, title = {Tailoring treatments: pharmacogenomics in the management of neurodegenerative diseases.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {41663779}, issn = {2240-2993}, abstract = {Neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis are growing more common worldwide, yet treatment is still poor. Conventional therapies can have unforeseen side effects, produce poor medication reactions, and take longer to work. This persistent treatment gap highlights the need for novel approaches to these disorders' complex distinctions. Pharmacogenomics, which examines how genetic differences affect drug response, is a promising new subject and an urgent solution. Pharmacogenomics tailors medicine selection and administration to each patient's genetic profile, addressing the main causes of poor treatment response and preventable side effects. This research has enabled precision medicine that can improve neurodegenerative disease therapy and reduce harm. In this in-depth research, we examine neurodegenerative disease management issues, pharmacogenomics breakthroughs, and how incorporating genetics to clinical practice can improve outcomes. We examine the latest evidence that genetics affect drug breakdown, efficacy, and toxicity. We also discuss the challenges and opportunities of applying this knowledge. Pharmacogenomic approaches must be widely applied to make medicines for these awful disorders safer, more effective, and really suited to patient needs, according to our compilation.}, } @article {pmid41664997, year = {2026}, author = {Leykam, L and Forsberg, KME and Andersen, PM and Brännström, T and Weiner, S and Rönnholm, J and Blennow, K and Zetterberg, H and Marklund, SL and Gobom, J and Zetterström, P}, title = {N-Truncated Superoxide Dismutase-1 in Cerebrospinal Fluid Is Folded and Active.}, journal = {Journal of neurochemistry}, volume = {170}, number = {2}, pages = {e70382}, pmid = {41664997}, issn = {1471-4159}, support = {101053962//European Union's Horizon Europe research and innovation programme/ ; //Fort Knox Charity Foundation/ ; //Olsson och Olsson Foundation/ ; 2012-3167//Vetenskapsrådet/ ; 2017-00915//Vetenskapsrådet/ ; 2017-03100//Vetenskapsrådet/ ; 2019-02397//Vetenskapsrådet/ ; 2022-00732//Vetenskapsrådet/ ; 2022-01018//Vetenskapsrådet/ ; 2023-00356//Vetenskapsrådet/ ; 2012.0091//Knut och Alice Wallenbergs Stiftelse/ ; 2014.0305//Knut och Alice Wallenbergs Stiftelse/ ; 2020.0232//Knut och Alice Wallenbergs Stiftelse/ ; 2012-0262//Swedish Brain Foundation/ ; 2012-0305//Swedish Brain Foundation/ ; 2013-0279//Swedish Brain Foundation/ ; 2016-0303//Swedish Brain Foundation/ ; 2020-0353//Swedish Brain Foundation/ ; 2022-0270//Swedish Brain Foundation/ ; 2024-0048//Swedish Brain Foundation/ ; ALZ2022-0006//Swedish Brain Foundation/ ; //Västerbotten Läns Landsting/ ; //King Gustaf V:s and Queen Victoria's Freemason's Foundation/ ; //Ulla-Carin Lindquists stiftelse för ALS-forskning/ ; 2.1.12-1605-14//Neuroförbundet Association/ ; 2.1.6-452-20//Neuroförbundet Association/ ; 223-1881-13//Neuroförbundet Association/ ; 223-2808-12//Neuroförbundet Association/ ; //European Partnership on Metrology/ ; //Cure Alzheimer's Fund/ ; //Stiftelsen för Gamla Tjänarinnor/ ; //National Institute for Health and Care Research/ ; //University College London/ ; //UK Dementia Research Institute/ ; }, mesh = {*Superoxide Dismutase-1/cerebrospinal fluid/genetics/chemistry/metabolism ; Humans ; Animals ; Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/enzymology ; *Protein Folding ; Mice ; }, abstract = {Mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) are a well-established cause of amyotrophic lateral sclerosis (ALS). The mutations promote SOD1 misfolding, resulting in protein aggregation and motor neuron degeneration. SOD1 is normally a structurally stable enzyme, and the mechanisms underlying SOD1 misfolding remain poorly understood. Approximately one third of SOD1 in cerebrospinal fluid (CSF) exhibits an N-terminal truncation, the biological significance of which remains unclear. This is remarkable given the dramatic effects ALS-linked C-terminal truncations have on the enzyme. In this study, we identified the truncation site and investigated its impact on SOD1 stability and enzymatic activity. Edman degradation revealed the cleavage site between Asn-26 and Gly-27, generating a 26-residue peptide that was confirmed by mass spectrometry. We analyzed postmortem tissues from different parts of the central nervous system (CNS), including the choroid plexus, and found only trace amounts of N-terminally truncated SOD1. Biochemical characterization of the SOD1 in CSF was done by size exclusion chromatography, ion exchange chromatography, and mass spectrometry. Our findings demonstrate that SOD1 in CSF retains full enzymatic activity, that the N-terminally truncated variant is mainly present in heterodimers with native SOD1 subunits, and that the dimer remains folded and active, with both fragments of the truncated SOD1 fixed after proteolysis. Truncated SOD1 was absent in human plasma. In mice, only transgenically expressed human SOD1 underwent truncation in CSF, whereas endogenous murine SOD1 remained intact. Lastly, the N-terminal truncation does not induce misfolding, unlike the destabilizing effects observed with C-terminal truncations. The location where the truncation takes place and the underlying mechanism could not be identified. Whether the N-truncated SOD1 variant contributes to ALS pathogenesis remains to be determined.}, } @article {pmid41665027, year = {2026}, author = {Huang, S and Bei, Y and Zhang, Q and Nan, H and Li, J}, title = {Behavioral Variant Frontotemporal Dementia With C9orf72 Intermediate Repeat Expansion : A case report.}, journal = {Alzheimer disease and associated disorders}, volume = {40}, number = {1}, pages = {62-64}, doi = {10.1097/WAD.0000000000000718}, pmid = {41665027}, issn = {1546-4156}, mesh = {Humans ; Male ; Brain/pathology/diagnostic imaging ; *C9orf72 Protein/genetics ; *DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics/pathology ; }, abstract = {Hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene has been identified as the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). While large pathogenic expansions can reach hundreds to thousands of repeats, the lower limit for the number of pathogenic repeats remains controversial. Pathogenic threshold ranges from 30 to >60 repeats. Here, we report a rare case of behavioral variant frontotemporal dementia (bvFTD) associated with a C9orf72 repeat expansion of 49 units, a size that falls within the intermediate-length range. The patient presented with progressive neuropsychiatric decline, which progressed to include emotional blunting and memory impairment. Neuroimaging demonstrated bilateral temporal and hippocampal atrophy, with a reduction in glucose metabolism observed in the left fronto-parieto-temporal cortex and thalamus. This study may provide crucial clinical evidence for the ongoing debate on the pathogenicity of intermediate-length alleles in C9orf72 .}, } @article {pmid41665049, year = {2026}, author = {Grassano, M and Palumbo, F and Mora, G and Gallone, S and De Marco, G and Merulla, I and Paolantonio, C and Maccabeo, A and Canosa, A and Manera, U and Vasta, R and Iazzolino, B and Testa, M and Fuda, G and Salamone, P and Marchese, G and Casale, F and Moglia, C and Calvo, A and Borghero, G and Chiò, A}, title = {Sex-Specific Genetic Architecture of ALS: Evidence of a Female Protective Effect?.}, journal = {Annals of neurology}, volume = {99}, number = {6}, pages = {1536-1544}, pmid = {41665049}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Female ; Male ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Middle Aged ; Genetic Predisposition to Disease/genetics ; DNA-Binding Proteins/genetics ; *Sex Characteristics ; Aged ; Italy/epidemiology ; Cohort Studies ; Whole Genome Sequencing ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) shows sex differences in incidence and age of onset, yet the underlying biological mechanisms remain poorly understood.

METHODS: We investigated sex-specific genetic architecture in an Italian ALS cohort with whole-genome sequencing (1,333 ALS cases, 755 controls). We performed a sex-stratified burden analysis of rare variants in ALS-associated genes and compared the proportions of male and female ALS patients carrying pathogenic or rare damaging variants. Key findings were replicated in the AnswerALS cohort (n = 723). Gene-specific sex ratios and familial history for C9ORF72, SOD1, and TARDBP were examined in an expanded dataset of 2,301 Italian ALS patients.

RESULTS: Sex-stratified burden testing revealed that rare variants in ALS genes were enriched in female cases versus controls (odds ratio [OR] 5.47, 95% confidence interval [CI] 1.60-34.29) but not in male cases. Female ALS patients more frequently carried rare damaging variants compared to males (23.2% vs 18.3%; OR 1.38, 95% CI 1.05-1.81), a finding that was replicated in the AnswerALS cohort (18.9% vs 12.4%; OR 1.58, 95% CI 1.10-2.26). Gene-level analyses of TARDBP carriers revealed a male predominance (2.1:1), yet a higher rate of familial history among females (40.4% vs 24.5%; OR 2.13, 95% CI 1.03-4.39).

INTERPRETATION: Females with ALS exhibited a higher overall burden of rare damaging variants, suggesting sex-related differences in genetic liability. Gene-level analyses indicate that the influence of sex varies across ALS genes, particularly TARDBP. These findings help explain epidemiological patterns and have implications for the identification of sex-linked protective mechanisms. ANN NEUROL 2026;99:1536-1544.}, } @article {pmid41665181, year = {2026}, author = {Chiò, A and Calvo, A}, title = {Before Symptoms Begin: Immune Activation in Preclinical ALS.}, journal = {Annals of neurology}, volume = {99}, number = {3}, pages = {588-590}, pmid = {41665181}, issn = {1531-8249}, } @article {pmid41665706, year = {2026}, author = {Giacomini, PS and Voss, P and Devonshire, V and Schneider, R and Macaron, G and Hussein, S and Blanchette, F and de Villers-Sidani, É}, title = {Eye tracking as a digital biomarker in neurodegenerative diseases.}, journal = {Journal of neurology}, volume = {273}, number = {2}, pages = {133}, pmid = {41665706}, issn = {1432-1459}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/physiopathology ; Biomarkers ; *Eye-Tracking Technology ; }, abstract = {Oculomotor abnormalities are a common finding in neurodegenerative diseases due to degeneration of neural pathways and brain regions involved in controlling eye movements. Pathological changes to the dorsolateral prefrontal cortex, basal ganglia, superior colliculus and cerebellum produce subtle changes in eye-movement metrics that may not be detected by clinical examination. The present review addresses the potential use of eye-movement biomarkers in neurodegenerative conditions such as multiple sclerosis, Parkinson's disease, Alzheimer's disease and other dementias, and amyotrophic lateral sclerosis. Eye-movement metrics such as saccades, anti-saccades, fixation and smooth pursuit are prognostic of disease progression, can differentiate pathologic subtypes as an aid to diagnosis, and enable clinicians to evaluate early worsening of motor and cognitive function. The cost of medical technologies limits their optimal use and accessibility in clinical practice. The shortage of subspecialist neurologists further limits access to care. New eye-tracking technologies incorporated into widely-accessible digital devices such as smart phones and tablets now permit detailed assessments with minimal equipment requirements, providing an important non-invasive and potentially cost-effective method for patient evaluation in routine clinical practice and as an aid to treatment decision-making. Digital biomarkers can be readily employed by healthcare professionals such as family physicians, nurses and pharmacists to bridge the care gaps, potentially providing them with powerful tools that can be broadly adopted to improve the delivery of care to patients with neurodegenerative conditions.}, } @article {pmid41665722, year = {2026}, author = {Peter, AS and Kandasamy, I and Ranjith, S and Jeyarajan, S and Chidambaram, P and Kumarasamy, A}, title = {Recombinant AMPs (Epinecidin-1 and its Variants): A New Hope against Invasive Fungal Infections against Candida spp. and Aspergillus flavus.}, journal = {Current microbiology}, volume = {83}, number = {4}, pages = {168}, pmid = {41665722}, issn = {1432-0991}, support = {311/RUSA(2.0)/2018//RUSA 2.0 Biological Sciences/ ; 01706/P6/2021//Tamil Nadu State Council for Higher Education/ ; IIRPSG-2024-01-01898, dt.11.02.2025//ICMR/ ; }, mesh = {*Aspergillus flavus/drug effects/growth & development ; *Antifungal Agents/pharmacology/chemistry ; Microbial Sensitivity Tests ; *Candida/drug effects/growth & development ; Biofilms/drug effects/growth & development ; *Antimicrobial Peptides/pharmacology/genetics/chemistry ; *Antimicrobial Cationic Peptides/pharmacology/genetics ; Recombinant Proteins/pharmacology/genetics/chemistry ; Molecular Docking Simulation ; Candidiasis/microbiology ; Hyphae/drug effects/growth & development ; Fish Proteins ; }, abstract = {To enhance stability and antimicrobial efficacy of antimicrobial peptide (AMP) epinecidin-1, we previously engineered three variants - GK-epi-1, Variant-1 and Variant-2-by substituting alanine and histidine residues with lysine. Our current study focuses on the antifungal capabilities of Epinecidin-1 and its variants against the clinical isolates of Candida spp. (Candida albicans, C. tropicalis, C. krusei & C. glabrata) and Aspergillus flavus. Computational docking studies are evidenced, the peptides had strong affinity against all fungal receptor examined which indicates their efficacy to interact with the Candida cell membrane receptors (Exo-B-(1,3)-Glucanase, Secreted aspartic proteinase (SAP) 1 & N-terminal domain adhesin: Als 9 - 2). Minimum Inhibitory Concentration (MIC), Minimum Fungicidal Concentration (MFC) and antibiofilm assays revealed its potent antifungal activity, particularly in disrupting biofilm formation. Effects of peptides on hyphal growth inhibition activity and Scanning Electron Microscopy (SEM) confirmed that the mechanism of action involves pore formation, hyphal disruption and induction of reactive oxygen species in Candida cell membrane. The antifungal spectrum was extended to A. flavus, a known ocular pathogen, where combination therapy using sub-inhibitory concentrations of Epinecidin-1 and its variant peptides with Amphotericin B and Miconazole showed enhanced synergistic effects, reducing required dosages for effective pathogen control.}, } @article {pmid41666062, year = {2026}, author = {Jin, J and Wang, H and Daly, I and Zhao, X and Li, S and Cichocki, A}, title = {A Fully Unsupervised Online Classification Algorithm for Event-Related Potential based Brain-Computer Interfaces.}, journal = {IEEE transactions on bio-medical engineering}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TBME.2026.3663323}, pmid = {41666062}, issn = {1558-2531}, abstract = {OBJECTIVE: Brain-computer interfaces (BCIs) based on event-related potentials (ERPs) are among the most accurate and reliable BCIs. However, current mainstream classification algorithms struggle to eliminate the need for calibration and rely on expensive labeled data, limiting the practical usability of ERP based BCIs. The development of fully unsupervised algorithms is essential for the advancement of practical applications of BCI systems.

METHODS: In this study, we propose a novel unsupervised classification method called sliding-window distribution distance maximization (sDDM). This algorithm utilizes sliding windows to highlight important temporal features and transforms the metric of inter-class differences from absolute distances to relative distribution distances in Mahalanobis space, while incorporating information on target event similarity from the BCI paradigm. Additionally, our proposed spatial dimensionality reduction strategy ensures smaller spatial dimensions and more prominent spatial features.

RESULTS: We compare our proposed method to other state of-the-art unsupervised classification methods and evaluate it offline on our self-collected dataset, a public dataset recorded during the use of a P300 Speller by patients with ALS, and the BCI Competition III Dataset II. Our results demonstrate that our proposed method achieves the best spelling accuracy across all datasets, surpassing other unsupervised algorithms. We further explore its improvement effectiveness through ablation experiments.

CONCLUSION: Our proposed method enhances the performance of unsupervised classification in ERP-based BCIs.}, } @article {pmid41666800, year = {2026}, author = {Maidi, AZM and Suram, RP and Deniz, Y and An, SL and Hong, Y}, title = {Heart rate variability as a non-invasive biomarker of autonomic dysfunction in amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Autonomic neuroscience : basic & clinical}, volume = {264}, number = {}, pages = {103393}, doi = {10.1016/j.autneu.2026.103393}, pmid = {41666800}, issn = {1872-7484}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; *Heart Rate/physiology ; *Autonomic Nervous System Diseases/physiopathology/diagnosis/etiology ; Biomarkers ; *Autonomic Nervous System/physiopathology ; }, abstract = {OBJECTIVE: This study assessed heart rate variability (HRV) alterations in amyotrophic lateral sclerosis (ALS) patients compared to healthy control groups using both frequency-domain and time-domain HRV parameters.

METHODS: A systematic review and meta-analysis were conducted using studies retrieved from PubMed, Embase, Web of Science, and Cochrane Library databases up to November 13, 2024. Fourteen studies were included in the qualitative synthesis and eight in the quantitative analysis.

RESULTS: ALS patients exhibited significantly reduced Low Frequency (LF) and High Frequency (HF) HRV parameters compared to healthy controls (p < 0.001 and p = 0.02, respectively). Time-domain parameters also showed significant reductions: RMSSD (p < 0.001), SDNN (p < 0.001), and pNN50% (p = 0.01). Despite an overall decrease in HRV, the LF/HF ratio did not show a statistically significant difference (p = 0.12).

CONCLUSION: Patients with ALS demonstrate autonomic dysfunction, evidenced by significant reductions in key time-domain (RMSSD, SDNN, pNN50%) and frequency-domain (LF, HF) parameters, suggesting impaired parasympathetic modulation. HRV may serve as a valuable, non-invasive biomarker for the early detection and management of cardiorespiratory complications in ALS.}, } @article {pmid41667820, year = {2026}, author = {Vicencio, E and Gomez, L and Beltran, S and Hernandez, F and Rodriguez, L and Bravo, C and Jofré, T and Gálvez, F and Labrador, L and Rojas-Rivera, D and Cortés, BI and Cortez, C and Manque, P and Woehlbier, U}, title = {FAM120A - a protein inserted in the ALS disease network.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41667820}, issn = {2045-2322}, support = {11240328//Agencia Nacional de Investigación y Desarrollo/ ; 1230823//Agencia Nacional de Investigación y Desarrollo/ ; 1150743//Agencia Nacional de Investigación y Desarrollo/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; Spinal Cord/metabolism/pathology ; Motor Neurons/metabolism/pathology ; Mice ; Humans ; Superoxide Dismutase-1/genetics/metabolism ; Disease Models, Animal ; Mice, Transgenic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disabling and fatal neurological disease, which is characterized by the loss of motor neuron function in the brain and spinal cord. Due to genetic complexity, ALS disease is not well understood. By applying a bioinformatic approach, referred to as convergent analysis, we identified the poorly characterized protein FAM120A as a new candidate gene related to RNA metabolism, a process known to be affected during ALS disease. We studied Fam120A in the context of ALS in vivo and in vitro using an ALS mouse model and a cellular model. We found that Fam120A mRNA levels were decreased in the pre-symptomatic stage in the spinal cord of SOD1G93A mice, while Fam120A protein levels were decreased at the symptomatic stage. Fam120A was expressed mainly in neurons in the spinal cord. Overexpression of FAM120A in a motor neuron cell culture model decreased the levels of SOD1G93A aggregates. In summary, our results warrant further studies of FAM120A in the context of ALS, since it appears to be involved in disease progression and might have a role in proteostasis maintenance.}, } @article {pmid41668129, year = {2026}, author = {Garnier, M and Gouju, J and Rousseau, A and Zidane-Marinnes, M and Scherer, C and Cassereau, J and Letournel, F and Codron, P}, title = {Exploratory assessment of phosphorylated TDP-43 immunoreactivity in minor salivary glands of patients with ALS.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {41668129}, issn = {2051-5960}, } @article {pmid41668214, year = {2026}, author = {Cao, MC and Swanson, MEV and Basak, I and McDonald, K and Arnold, FJ and Stockford, CM and Guo, G and Curtis, MA and Faull, RLM and Hughes, SM and Spada, AR and Dragunow, M and Scotter, EL}, title = {Lost in translation: absence of KIAA1324/ELAPOR1 protein in pathological TDP-43-affected neurons in ALS/FTD.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {41668214}, issn = {2051-5960}, support = {T32 AG000096/NH/NIH HHS/United States ; R35 NS122140/NH/NIH HHS/United States ; 865871//Muscular Dystrophy Association/ ; 23-CSDA-618//American Academy of Neurology/ ; PG12747//Robert Packard Center for ALS Research, Johns Hopkins University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Neurons/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Frontotemporal Dementia/pathology/metabolism/genetics ; Female ; Male ; *Brain/metabolism/pathology ; Aged ; Middle Aged ; RNA, Messenger/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Aged, 80 and over ; Cell Line, Tumor ; Proteins ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a movement disorder lacking effective diagnostics and therapeutics, largely due to its clinical and etiological heterogeneity. The unifying hallmark of TDP-43 pathology is found in approximately 97% of ALS patients, and 50% of frontotemporal dementia (FTD) patients. Indeed, TDP-43 has a central role in ALS/FTD disease mechanisms. An mRNA target of TDP-43 loss of function, KIAA1324/ELAPOR1, is consistently upregulated in various RNA-sequencing datasets from systems with TDP-43 depletion.

METHODS: This study sought to investigate the TDP-43 target gene, KIAA1324, in the context of human brain tissue. We performed immunohistochemistry and image analysis on 10 ALS and 10 control brains to quantify the protein levels of KIAA1324 in TDP-43 pathology-affected cells. We then used immunocytochemistry of iPSC-derived neurons and mass spectroscopy of SH-SY5Y cells to investigate the relationship between KIAA1324 mRNA and the function of its cognate protein KIAA1324.

RESULTS: KIAA1324 expression was enriched in neurons in the human brain. While KIAA1324 mRNA increased in iPSC-derived neurons with TDP-43 depleted from the nucleus in vitro, in human post-mortem brain neurons, KIAA1324 protein was significantly decreased (p < 0.05) in cells with pathological TDP-43 (nuclear-cleared TDP-43 and cytoplasmic, phosphorylated TDP-43). This may be due to the alternative polyadenylation of KIAA1324 detected with TDP-43 depletion from iPSC-derived neurons, hypothesised to affect translation efficiency. Mass spectrometry of SH-SY5Y cells revealed that overexpression of KIAA1324 protein affects a network of mitochondrial proteins.

CONCLUSIONS: The clear inverse relationship between KIAA1324 mRNA levels and TDP-43 function, and the near complete absence of KIAA1324 protein from neurons with pathological TDP-43 in post-mortem brain tissue, suggests KIAA3142 function is impaired in TDP-43 proteinopathies. Therefore, in addition to there being various disease mechanisms implicated in ALS, and TDP-43 being a challenging disease target to restore, KIAA1324 emerges as another of the many targets downstream of TDP-43 that may need to be addressed to demonstrate a therapeutic effect in ALS/FTD.}, } @article {pmid41669804, year = {2026}, author = {Nadeem, H}, title = {Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Have Distinct Prediagnostic Blood Biochemical Profiles.}, journal = {Annals of neurology}, volume = {99}, number = {3}, pages = {827}, doi = {10.1002/ana.78173}, pmid = {41669804}, issn = {1531-8249}, } @article {pmid41670738, year = {2026}, author = {Thorarinsson, BL and Sveinsson, OA and Hilmarsson, A and Sigurthorsdottir, TB and Andersen, PM}, title = {Treating SOD1-ALS with tofersen results in nonprogressive chronic ALS-a case series from Iceland.}, journal = {Journal of neurology}, volume = {273}, number = {2}, pages = {140}, pmid = {41670738}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/cerebrospinal fluid ; *Superoxide Dismutase-1/genetics ; Female ; Male ; Middle Aged ; Iceland ; Neurofilament Proteins/cerebrospinal fluid ; Aged ; Mutation ; *Oligonucleotides, Antisense/therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. We describe four patients with hereditary ALS caused by the p.Gly94Ser SOD1 mutation who were treated monthly with the intrathecal antisense oligonucleotide tofersen in a clinical setting at Landspitali University Hospital of Iceland. After initiating treatment 15-26 months ago, no significant clinical deterioration was observed, and three patients showed signs of clinical improvement, with some recovery of motor function. All four patients currently present with chronic nonprogressive ALS, a phenotype not previously observed or documented. Concomitantly, the concentration of neurofilament light chain (Nf-L) in the cerebrospinal fluid decreased to the normal range. This clinical benefit and decrease in Nf-L levels were detected regardless of the patient's initial ALSFRS-R score. No serious adverse events were observed. Notably, we observed a clinically meaningful effect in two patients who had been ill for several years before treatment was instituted, raising questions about who should receive treatment and the biology of paresis and motor neuron cell loss in patients with ALS. Although only a minority of ALS patients carry a SOD1 mutation, the advent of this new precision medicine has profound implications for ALS management.}, } @article {pmid41671402, year = {2026}, author = {Shi, M and Ge, W and Li, C and Liu, B and Deng, X and Liu, C and Zheng, M and Zhang, P and Li, L and Guo, Y and Han, Y and Yang, Y and Yu, YV and Jin, YN}, title = {Versatile CRISPR-Cas Tools for Gene Regulation in Zebrafish via an Enhanced Q Binary System.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {23}, pages = {e11485}, pmid = {41671402}, issn = {2198-3844}, support = {32070832//National Natural Science Foundation of China/ ; 32150610476//National Natural Science Foundation of China/ ; 2042022dx0003//Fundamental Research Funds for the Central Universities/ ; }, mesh = {Animals ; *Zebrafish/genetics ; *CRISPR-Cas Systems/genetics ; Animals, Genetically Modified/genetics ; *Gene Expression Regulation/genetics ; Zebrafish Proteins/genetics ; DNA-Binding Proteins/genetics ; Gene Knockdown Techniques/methods ; *Gene Editing/methods ; }, abstract = {CRISPR-Cas systems revolutionize gene regulation across diverse organisms, including zebrafish. However, most zebrafish studies still rely on transient delivery of CRISPR components, with limited use of transgenic models, primarily restricted to Cas9-mediated knockouts. This limitation arises from challenges in achieving sustained, tissue-specific, and efficient expression of transgenic CRISPR effectors. To address these challenges, we introduce CRISPR-Q, a transgenic system that combines the QFvpr/QUAS binary expression platform with CRISPR-Cas technologies. CRISPR-Q overcomes the drawbacks of transient mRNA or protein delivery and circumvents the toxicity and transgene silencing issues associated with other binary systems, such as Gal4/UAS. The system enables robust and spatiotemporal expression of CasRx or dCas9vpr, allowing precise transcript knockdown (CRISPR-QKD) or gene activation (CRISPR-Qa). Using CRISPR-QKD, we achieve effective knockdown of smn1 and simultaneous knockdown of tardbp and tardbpl, modeling spinal muscular atrophy and amyotrophic lateral sclerosis, respectively. CRISPR-Qa activates endogenous lin28a and sox9b, demonstrating its functional versatility. We further validate CRISPR-Q's tissue-specific applicability in heart-specific transgenic zebrafish. Together, CRISPR-Q represents a robust and versatile platform for studying gene function and modeling human diseases in zebrafish, with broad potential for adaptation in other model organisms.}, } @article {pmid41672113, year = {2026}, author = {Prova, NS and Elsayyid, MW and Tanis, JE}, title = {Superoxide dismutase impacts extracellular vesicle shedding and uptake.}, journal = {Free radical biology & medicine}, volume = {247}, number = {}, pages = {540-550}, pmid = {41672113}, issn = {1873-4596}, support = {P20 GM103446/GM/NIGMS NIH HHS/United States ; R01 GM135433/GM/NIGMS NIH HHS/United States ; S10 OD030321/OD/NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics/metabolism ; *Extracellular Vesicles/metabolism/genetics ; Reactive Oxygen Species/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Superoxide Dismutase/genetics/metabolism ; Cilia/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Caenorhabditis elegans Proteins/genetics/metabolism ; Humans ; Mutation ; Neuroglia/metabolism ; Sensory Receptor Cells/metabolism ; }, abstract = {Extracellular vesicles (EVs), which transfer bioactive macromolecules between cells, play a critical role in the pathogenesis of multiple neurodegenerative diseases. Focus has centered on how altered EV contents propagate disease and on the potential for EVs as diagnostic biomarkers, while the effects of pathogenic factors on EV release are poorly understood. Using a functional endogenous reporter, we showed that the key antioxidant enzyme superoxide dismutase 1 (SOD-1) is expressed in C. elegans EV-releasing neurons, localizes to the cytoplasm, and reduces levels of reactive oxygen species (ROS). We then defined how sod-1 mutations affect EV shedding from sensory neuron primary cilia into the environment, ciliary enrichment of proteins packaged into EVs, and glial uptake of EVs in vivo, by imaging C. elegans expressing fluorescent protein-tagged EV cargoes. Deletion of SOD-1, as well as the SOD-1(G85R) amyotrophic lateral sclerosis (ALS) pathogenic variant, increased EV shedding from the cilium distal tip, and this was associated with greater abundance of EV cargo in this ciliary compartment. In contrast, loss of SOD-1 reduced the glial uptake of a different EV subpopulation that is shed from the ciliary base, without affecting release into the environment. These results demonstrate that SOD-1 has a subtype-specific effect on the release of EVs with distinct signaling potentials. Intriguingly, we discovered that exposure to paraquat, which increases mitochondrial ROS, reduced the shedding of both distal tip and ciliary base-derived EVs. These opposing effects of the sod-1 mutations and paraquat treatment on EV release suggest that ROS in distinct subcellular compartments may differentially impact ciliary EV shedding.}, } @article {pmid41672134, year = {2026}, author = {Maneu, V and García, AG}, title = {P2X7 receptors as targets for neuroprotection.}, journal = {Neuropharmacology}, volume = {289}, number = {}, pages = {110877}, doi = {10.1016/j.neuropharm.2026.110877}, pmid = {41672134}, issn = {1873-7064}, mesh = {Humans ; *Receptors, Purinergic P2X7/metabolism ; Animals ; *Purinergic P2X Receptor Antagonists/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuroinflammatory Diseases/metabolism/drug therapy ; *Neuroprotection/drug effects/physiology ; }, abstract = {In this review we explore the potential of P2X7 receptor blockers to elicit neuroprotection. This conjecture is based on a reasonably well-established role of this receptor in activating glial cells to maintain a chronic low-level neuroinflammatory state in the brain of patients suffering some neurodegenerative diseases (NDDs). In this context we briefly discuss evidence supporting the role of P2X7 receptors (P2X7) in the pathogenesis of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. From a pathogenic point of view these diseases have specific features but all share a low level neuroinflammatory state with microglia activation and enhanced P2X7 expression. Next, we comment on available P2X7 blockers with central nervous system (CNS) target engagement. Then, we deal with the proof-of-concept concerning the potential of some blockers to mitigate the neuroinflammatory state in preclinical models of the target diseases above mentioned. We follow with a discussion of the scarce number of clinical trials done with some P2X7 blockers in inflammatory diseases. Finally, we discuss the current discrepancy between promising preclinical data and the limited number of clinical trials exploring P2X7 antagonists in NDDs. We provide some clues that may boost clinical trials with single P2X7 blockers but particularly, with their association with other medicines currently being used or that are intended to be prescribed in the treatment of NDDs.}, } @article {pmid41672538, year = {2026}, author = {Zarrouk, S and Finsterer, J}, title = {SCA3 Can Manifest Phenotypically with ALS-like Characteristics.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {}, number = {}, pages = {}, doi = {10.2169/internalmedicine.6851-25}, pmid = {41672538}, issn = {1349-7235}, } @article {pmid41672542, year = {2026}, author = {Takubo, M and Matsumoto, Y and Sasaki, C and Ikeda, K and Sugeno, N and Warita, H and Aoki, M}, title = {Response to the Letter by Dr. Zarrouk et al.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {}, number = {}, pages = {}, doi = {10.2169/internalmedicine.6957-25}, pmid = {41672542}, issn = {1349-7235}, } @article {pmid41673022, year = {2026}, author = {Ali, M and Biswas, A and Iglseder, A and Kumar, V and Kumar, S and Gupta, S and Hollaus, M and Pfeifer, N and Lohani, B}, title = {Terrestrial and Airborne Laser Scanning Dataset of Trees in the Shivalik Range, India with Field Measurements and Leaf-Wood Classifications.}, journal = {Scientific data}, volume = {13}, number = {1}, pages = {}, pmid = {41673022}, issn = {2052-4463}, support = {DST/CE/2024140//Department of Science and Technology, Ministry of Science and Technology (DST)/ ; }, abstract = {Annotated datasets are essential for training and evaluating machine learning models in forest ecology. This dataset provides high-resolution, annotated LiDAR point clouds of 674 individual trees from 12 forest plots in the Shivalik Range of northern Haryana, India, representing 24 species. Data were acquired using Terrestrial Laser Scanning (TLS) and Airborne Laser Scanning (ALS), include field-measured attributes such as species identity and Diameter at Breast Height (DBH), and terrestrial and aerial RGB imagery. TLS point clouds were georeferenced and co-registered with centimetre-level accuracy, enabling precise integration with ALS data. The dataset includes segmented individual trees and wood-leaf classifications, suitable for applications such as tree morphology analysis, biomass estimation, and species classification. To support benchmarking, outputs from established classification algorithms (LeWoS, TLSeparation, CANUPO, and Random Forest) are included. As one of the first open-access LiDAR datasets from Indian tropical forests, it provides critical reference data for developing and validating forest structure models. It can also aid biomass mapping efforts in support of large-scale missions such as NASA-ISRO's NISAR and ESA's BIOMASS.}, } @article {pmid41673769, year = {2026}, author = {Sharma, S and Vandenakker, A and Cortés-Pérez, C and Milne, S and Douville, RN}, title = {Implications of virus-induced stress granules in tauopathies.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {4}, pmid = {41673769}, issn = {2047-9158}, support = {#2401-3152//St. Boniface Hospital Foundation/ ; RGPIN-2016-05761//Natural Sciences and Engineering Research Council of Canada/ ; }, mesh = {Humans ; *Tauopathies/virology/metabolism/pathology ; *Stress Granules/virology/metabolism/pathology ; *tau Proteins/metabolism ; Animals ; *Virus Diseases/metabolism/complications ; }, abstract = {Tauopathies are characterized by aberrant tau structure and function, which is associated with neurodegenerative dementias, such as Alzheimer's disease, Pick's disease, and frontotemporal dementia, as well as the motor neuron disease amyotrophic lateral sclerosis. Consistent association of these neurodegenerative conditions with viruses suggests an interplay between viral activity and the development of tauopathy. In this review, we explore how tau dysregulation may facilitate viral activity, and conversely, how viruses may drive tauopathy. We further discuss how stress granules (SGs) are a likely hub for the interactions between tau and viral components, leading to tau deregulation. Within the network of SG proteins analyzed, 15 proteins were identified to be both tau interactors and implicated in viral processes, having dual functionality. These SG proteins are further discussed in terms of their relationship with tauopathy, viral replication, and neurodegeneration. Concrete examples of synergistic and competing effects between tau and viruses are highlighted, revealing both pathological and protective mechanisms. This dichotomy underscores a complexity that is both disease- and virus-specific, within the context of SG biology and tau pathology. While the viral involvement in tauopathies could be considered detrimental, it may provide insights into antiviral therapeutics to target the accumulation and misfolding of tau in these neurodegenerative diseases.}, } @article {pmid41673790, year = {2026}, author = {Zheng, W and Xu, L and Cai, J and Hou, J and Chen, L and Zhang, N and Zhan, S and Fan, D and He, J}, title = {Comprehensive clinical and genetic architecture of familial amyotrophic lateral sclerosis in China: A 15-year cohort study with 302 families.}, journal = {Neural regeneration research}, volume = {21}, number = {6}, pages = {2573-2579}, pmid = {41673790}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202606000-00072/figure1/v/2026-02-11T151048Z/r/image-tiff The growing recognition of the role of genetics in the development of amyotrophic lateral sclerosis is evident. However, there has yet to be a comprehensive analysis of the clinical characteristics and genetics of familial amyotrophic lateral sclerosis in an Asian population. This study aimed to provide an in-depth analysis of the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinic-based cohort of patients from the Chinese mainland. Enrollment of 302 amyotrophic lateral sclerosis families from 28 provinces was undertaken from January 2008 to September 2023. A group-based trajectory model for disease progression based on amyotrophic lateral sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores was validated using bootstrap internal validation in patients with familial amyotrophic lateral sclerosis, as well as patients with sporadic amyotrophic lateral sclerosis (matched at a 1:4 ratio, with replacement). DNA samples from 244 index patients were screened for variants in the pathogenic genes SOD1, FUS, TDP43, and C9ORF72, of which 146 were also subjected to genome-wide next-generation sequencing. Gene-level burden analysis was used to evaluate the distribution of rare variants in the cohort. We found that rapid dynamic disease progression was associated with an older age at onset, shorter diagnostic delay, lower body mass index, bulbar onset, and ≥ 1 affected first-degree relative. Certain attributes, such as age at onset and time from onset to diagnosis, had comparable impacts on the clinical progression trajectories of both familial amyotrophic lateral sclerosis and sporadic amyotrophic lateral sclerosis. Harboring pathogenic/likely pathogenic variants in amyotrophic lateral sclerosis-causative genes reduced the age of onset of familial amyotrophic lateral sclerosis. Among the patients with familial amyotrophic lateral sclerosis, 17.8% possessed ≥ 2 pathogenic/likely pathogenic variants. Sequencing kernel association test analysis showed that the SOD1 rare variant burden (P = 1.3e-15) was associated with a significant risk of familial amyotrophic lateral sclerosis. Our findings conclusively confirmed the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinical cohort from China, contributing to a deeper understanding of genotype-phenotype relationships in familial amyotrophic lateral sclerosis. This comprehensive evaluation of specific clinical characteristics, clinical prognosis, and genetic variants of amyotrophic lateral sclerosis based on detailed clinical and genetic information may lead to the development of genotype-specific treatment approaches.}, } @article {pmid41674118, year = {2026}, author = {Sun, S and Xin, J and Zhang, Y and Yang, B and Su, D and Ni, R and Ma, Q and Li, N and Ma, G and Peng, Q and Chen, S and Prehn, JHM and Tam, KY and Wang, H and Ying, Z}, title = {p62/SQSTM1 Condensation Modulates Mitochondrial Clustering to Participate in Mitochondrial Quality Control.}, journal = {Aging cell}, volume = {25}, number = {2}, pages = {e70402}, pmid = {41674118}, issn = {1474-9726}, support = {32471048//National Natural Science Foundation of China/ ; 32371018//National Natural Science Foundation of China/ ; 82022022//National Natural Science Foundation of China/ ; 82071274//National Natural Science Foundation of China/ ; BM2013003//Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases/ ; 23KJA310005//Natural Science Foundation of Jiangsu Provincial Higher Education Institutions/ ; YXY2301006//Interdisciplinary Basic Frontier Innovation Program of Suzhou Medical College of Soochow University/ ; //Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases/ ; //Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD)/ ; 0062/2021/A//Science and Technology Development Fund/ ; MYRG2022-00171-FHS//the University of Macau/ ; }, mesh = {*Mitochondria/metabolism ; Humans ; *Sequestosome-1 Protein/metabolism/genetics ; Mitophagy ; PTEN-Induced Putative Kinase ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; }, abstract = {Mitochondrial quality control is tightly associated with aging-related neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Previous studies reported that ALS/FTD-associated protein p62 drives "mitochondrial clustering" (perinuclear clustering of fragmented and swollen mitochondria) during PINK1/Parkin-mediated mitophagy, but the underlying molecular mechanism, especially the precise role of p62 in mitochondrial clustering during mitophagy and the potential relationship between the mitochondrial quality control mediated by p62 and disease pathogenesis of ALS/FTD, remains unclear. Here, using cell biology in combination with an optogenetic tool, we show that the phase separation (condensation) of p62 mediates the clustering of damaged mitochondria to form "grape-like" clusters during PINK1/Parkin-mediated mitophagy, which is tightly associated with aging-related neurodegenerative diseases. In addition, our data suggest this mitochondrial clustering process is an arrest mechanism driven by p62 condensation (beyond the function of other autophagy receptors in mitophagy), which acts as a "brake" to reduce the surface area of dysfunctional mitochondria within cytoplasm for minimizing mitochondrial turnover in cells. Moreover, ALS/FTD-related pathological mutations perturb p62 condensation, thereby inhibiting mitochondrial clustering and destroying the "brake" machinery of mitochondrial quality control. Together, our data highlight how p62 condensation modulates organelle quality control in cell biology, and the important role of p62 condensation in both physiology and pathology.}, } @article {pmid41674618, year = {2026}, author = {Xu, H and Petrozziello, T and Boudi, A and Shibata, S and Huntress, SS and Shahryari, A and Zhao, X and Kesavan, M and Granucci, EJ and Castillo Torres, AL and Monsanto, RZB and Lemanski, J and Jana, B and De Esch, CEF and Cudkowicz, ME and Berry, JD and , and Brand, H and Talkowski, ME and Mouro Pinto, R and Gao, D and Sadri-Vakili, G}, title = {Transcriptomic profiling uncovers mis-splicing and gene fusions in amyotrophic lateral sclerosis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.02.05.26345503}, pmid = {41674618}, support = {R01 NS126420/NS/NINDS NIH HHS/United States ; }, abstract = {Advances in transcriptomics have transformed our understanding of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, revealing disrupted gene expression profiles and highlighting the multi-system biology of ALS. Despite major advances, transcriptomic studies have only begun to capture the complexity and the molecular hierarchy of transcriptomic alterations in ALS. To resolve and characterize the transcriptome in ALS, we performed a comprehensive reanalysis of bulk RNA sequencing from the New York Genome Center ALS Consortium cohort across five post-mortem tissues including motor and frontal cortex, cervical and lumbar spinal cord, and cerebellum. By deploying dual analytical pipelines - one reference-based to model canonical events and one de novo to detect transcript structural novelties - we disentangled the quantitative and qualitative architectures of ALS. Our reference-based analysis revealed that ALS transcriptome is defined primarily by splicing failure rather than changes in gene expression. Aberrant splicing events, particularly intron retention, outnumbered differentially expressed genes by an order of magnitude. This widespread loss of fidelity disproportionately affected RNA-binding proteins, suggesting a collapse in their autoregulatory feedback loops. Deconvolution of these signals identified distinct cellular vulnerabilities: transcriptional disruptions were enriched in glial cells in sporadic cases but in neuronal cells in C9ORF72-positive cases. Furthermore, we observed sex-specific dysregulation, with male patients exhibiting greater disruption in guanosine triphosphatase signaling and ciliary organization pathways. In parallel, our de novo analysis uncovered a significant burden of disease-specific gene fusions that were absent in controls. Whole-genome sequencing of the same individuals, together with a larger reference population confirmed that disease-specific fusions do not arise from genomic structural variants, indicating a transcriptional rather than genomic origin. Investigation into the mechanism of these RNA-based fusions revealed a critical deviation in splice site definition: while canonical splice junctions exhibit a high density of binding motifs for polyA-binding or 3'-cleaveage proteins approximately 50 base pairs upstream of the splice donor site (left junction), ALS-specific fusion junctions displayed a dramatic depletion of these motifs in the same region. Functionally, the presence of these sparse disease-specific fusions was strongly correlated with severe splicing outliers in genes governing guanosine triphosphatase activity, converging with the tissue- and male-specific defects identified in our reference-based analysis. Altogether, our results delineated a transcriptome characterized by aberrant splicing with tissue-and sex-specific changes and identified structural-variant-independent RNA fusions as candidate disease modifiers that may amplify pathology. This integrated view provides a mechanistic scaffold for splicing-centered and RNA-structural therapeutic strategies for ALS.}, } @article {pmid41674784, year = {2025}, author = {Yashooa, RK and Nabi, AQ and Smail, SW and Azeez, SS and Nooh, WA and Mustafa, SA and Al-Farha, AA and Capitanio, N and Shekha, MS}, title = {CRISPR-Cas technologies in neurodegenerative disorders: mechanistic insights, therapeutic potential, and translational challenges.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1737468}, pmid = {41674784}, issn = {1664-2295}, abstract = {CRISPR-Cas genome-editing technologies have emerged as powerful tools for precise DNA and RNA modulation, offering promising therapeutic strategies for neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This review critically evaluates current CRISPR/Cas applications in neurodegeneration, with emphasis on mechanistic insights, therapeutic outcomes, and translational feasibility. Preclinical and early translational studies demonstrate that CRISPR-Cas platforms can correct pathogenic mutations, suppress toxic gene expression, and restore neuronal function. Advanced modalities, including base and prime editing, CRISPRi/a, and RNA-targeting Cas systems, improve precision and reduce genomic damage, which is particularly advantageous in post-mitotic neurons. Emerging CRISPR-based diagnostics (e.g., SHERLOCK and DETECTR), AI-assisted sgRNA design, and machine-learning approaches for predicting off-target effects further enhance the safety, stratification, and monitoring of CRISPR therapeutics. In parallel, patient-derived brain organoids and assembloids provide scalable human-relevant platforms for mechanistic studies and preclinical validation. Despite this progress, major challenges remain, including efficient delivery across the blood-brain barrier, immune responses, long-term safety, and ethical and regulatory considerations. Overall, CRISPR-Cas technologies hold strong potential as disease-modifying interventions for neurodegenerative disorders, provided that advances in delivery systems, artificial intelligence integration, and regulatory oversight continue to evolve toward clinical translation.}, } @article {pmid41674816, year = {2026}, author = {Jiang, S and Chen, F and Ma, H and Wu, S and Tang, X and Pan, X and Li, Q and Tao, A and Xu, J and Qi, J and Fang, P and Chen, J and Zhang, L}, title = {Cloning and functional verification of endogenous U6 promoters for developing an efficient CRISPR/Cas9-mediated genome editing system in kenaf (Hibiscus cannabinus L.).}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41674816}, issn = {2693-5015}, abstract = {The U6 promoter plays a pivotal role in the CRISPR/Cas9 system by driving the transcription of single guide RNA (sgRNA), which directs Cas9 to achieve precise genome editing. Endogenous U6 promoters typically exhibit superior transcriptional activation efficiency compared to exogenous counterparts, thereby enhancing the efficacy of genome editing. However, the endogenous U6 promoter in kenaf (Hibiscus cannabinus L.) remains uncharacterized. In this study, we conducted a homologous search of the kenaf genome using the Arabidopsis U6 (AtU6-26) RNA sequence as a reference, identifying two candidate promoters, HcU6-1 and HcU6-14. Promoter fragments were amplified from the genomic DNA of kenaf cultivar 'Fuhong 952' and subsequently cloned into a GUS fusion expression vector. Histochemical staining revealed transcriptional activity for both promoters, with HcU6-14 demonstrating significantly stronger activity. To evaluate editing efficiency, we constructed a CRISPR/Cas9 vector containing HcALS sgRNA, driven by either the kenaf U6-14P promoter or the cotton U6-9P (GbU6-9P) promoter. Kenaf hairy roots were regenerated via Agrobacterium rhizogenes K599-mediated transformation. Sequencing analysis of ALS gene fragments from these hairy roots confirmed successful targeted editing when using the kenaf U6-14P promoter, whereas no base mutations were detected with the cotton U6 promoter. These findings highlight the superior editing efficiency of the kenaf U6 promoter and provide a critical foundation for advancing functional genomics research in kenaf.}, } @article {pmid41675725, year = {2026}, author = {Patel, T and Henna, F and Sharif, I and Javed, I and Mustafa, F and Sharif, H and Nasir, F and Javaid, M and Usman, SF and Hanani, C and Anand, N}, title = {A narrative review on the therapeutic potential of stem cells in neurodegenerative diseases: advances, insights, and challenges.}, journal = {Annals of medicine and surgery (2012)}, volume = {88}, number = {2}, pages = {1441-1453}, pmid = {41675725}, issn = {2049-0801}, abstract = {BACKGROUND: Neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) are set apart by progressive neuronal loss and concomitant functional decline. Traditional therapies are equipped with only symptomatic relief, devoid of neurorestorative properties. Stem-cell-based therapies have the potential to revolutionize neurological care by replenishing lost cells, mitigating inflammation, and fostering a neuroprotective environment.

OBJECTIVES: This narrative review aims to appraise the treatment potential of various stem cell types in managing NDs, highlighting their functional pathways, delivery methods, and current experimental validation.

METHODS: A comprehensive literature search was carried out based on data retrieved from PubMed, The Cochrane Library, and ClinicalTrials.gov. Thirty-one studies that fulfill PICO criteria and only English-language publications are incorporated in this review. No part of the study design, data collection, analysis, or interpretation was conducted using artificial intelligence.

RESULTS: Stem cells, including embryonic stem cells, mesenchymal stem cells (MSCs), induced pluripotent stem cells, and neural stem cells, possess distinctive regenerative properties. MSC-derived exosomes can traverse the blood-brain barrier and improve nerve cell longevity. Administration routes such as intravenous, intranasal, and direct brain transplantation are being studied. Neurodegenerative conditions such as PD, AD, HD, and ALS have been widely studied for therapeutic benefits.

CONCLUSION: Regardless of their potential, stem cell therapies raise health risks, including neoplastic growth and immunological incompatibility, alongside bioethical issues. Developments in genetic modification, nanotechnology, and preconditioning strategies are being analyzed to optimize outcomes. Long-term research, harmonization of protocols, and extended patient follow-up are essential for the safe and effective development of medical applications.}, } @article {pmid41677019, year = {2026}, author = {Bjørnstadjordet, M and Kvernmo, HB and Bråthen, G and Simpson, MR and Sando, SB and Hagen, K and Devik, K and Wergeland, T}, title = {Four decades of ALS care: a retrospective study of epidemiology, clinical course and changes in management.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {422-431}, doi = {10.1080/21678421.2026.2627903}, pmid = {41677019}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy/diagnosis ; Female ; Retrospective Studies ; Male ; Aged ; Norway/epidemiology ; Middle Aged ; Riluzole/therapeutic use ; Aged, 80 and over ; Noninvasive Ventilation ; *Disease Management ; Incidence ; Disease Progression ; }, abstract = {BACKGROUND: Several interventions have been introduced for amyotrophic lateral sclerosis (ALS) in recent decades, and population-level studies investigating their use and impact are needed. This study describes the epidemiology, disease trajectory, and changes in clinical management of ALS in a county of Norway over a 38-year period.

METHODS: We conducted a retrospective chart review of all ALS cases diagnosed between 1986 and 2024 in Trøndelag county, Norway. Data were extracted from medical records using a standardized electronic case report form. Patients were stratified by time of diagnosis into four groups.

RESULTS: A total of 429 patients were included (56% male). Median age at symptom onset was 68 years. The age-standardized incidence of ALS was 3.32 per 100,000 person-years (95%CI 2.90-3.74) and increased over time (p = 0.002). Bulbar onset occurred in 38% of cases. Median diagnostic delay was 13 months (95%CI 12-14), without significant improvement over time. Median survival was 28 months (95%CI 26-31) from symptom onset, shorter among bulbar-onset patients. Use of riluzole, percutaneous endoscopic gastrostomy, and noninvasive ventilation (NIV) increased over the study period, whereas median survival remained stable. Emergency initiation of ventilation occurred in 25% (NIV n = 41/167) and 89% (invasive ventilation n = 16/18) of cases in which these treatment modalities were used.

CONCLUSION: This comprehensive regional study reveals a rising incidence of ALS in Trøndelag, with increased adoption of supportive interventions over time.}, } @article {pmid41677584, year = {2026}, author = {Minuti, A and Silvestro, S and Muscarà, C and Scuruchi, M and D'Angiolini, S}, title = {PCB 153 Modulates Genes Involved in Proteasome and Neurodegeneration-Related Pathways in Differentiated SH-SY5Y Cells: A Transcriptomic Study.}, journal = {Cells}, volume = {15}, number = {3}, pages = {}, pmid = {41677584}, issn = {2073-4409}, support = {RRC-2025-23686388//Ministero della Salute/ ; }, mesh = {Humans ; *Polychlorinated Biphenyls/toxicity/pharmacology ; *Proteasome Endopeptidase Complex/metabolism/genetics/drug effects ; *Cell Differentiation/drug effects/genetics ; Cell Line, Tumor ; *Transcriptome/drug effects/genetics ; *Neurodegenerative Diseases/genetics ; Cell Survival/drug effects ; Neurons/drug effects/metabolism ; Gene Expression Profiling ; Signal Transduction/drug effects/genetics ; Tretinoin/pharmacology ; }, abstract = {Polychlorinated biphenyls (PCBs) are persistent environmental contaminants associated with neurotoxicity and increased risk of neurodegenerative diseases. PCB 153, a highly abundant non-coplanar congener, bioaccumulates in human tissues and impairs homeostasis. This study investigated the transcriptomic effects of PCB 153 (2,2',4,4',5,5'-Hexachlorobiphenyl) in retinoic acid (RA)-differentiated SH-SY5Y neuronal cells to identify early, sub-cytotoxic molecular alterations. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay after 24 h exposure to increasing PCB 153 concentrations. RNA-Seq was performed on cells treated with 5 μM PCB 153, the highest non-cytotoxic dose. Sequencing reads were quality-filtered, aligned to the human genome, and analyzed with DESeq2. Functional enrichment was conducted using Gene Ontologies and KEGG pathways. Western blot analyses were performed to assess protein level changes in selected targets. RNA-Seq identified 1882 significantly altered genes (q-value < 0.05). Gene Ontology analysis revealed strong enrichment of proteasome-related terms, with most proteasomal subunits displaying coordinated upregulation. KEGG analysis further showed significant enrichment of Alzheimer's (AD), Parkinson's (PD), amyotrophic lateral sclerosis (ALS), and other neurodegenerative disease pathways. These findings indicate that PCB 153 triggers a pronounced proteostatic response in neuron-like cells, suggesting early disruption of protein homeostasis that may contribute to mechanisms associated with neurodegeneration.}, } @article {pmid41677614, year = {2026}, author = {Salamotas, I and Stavropoulou De Lorenzo, S and Stachtiari, A and Taxiarchis, A and Tsolaki, M and Michailidou, I and Preza, E}, title = {From Dish to Trial: Building Translational Models of ALS.}, journal = {Cells}, volume = {15}, number = {3}, pages = {}, pmid = {41677614}, issn = {2073-4409}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/pathology ; Humans ; Induced Pluripotent Stem Cells/metabolism/pathology ; *Translational Research, Biomedical ; Animals ; *Models, Biological ; Clinical Trials as Topic ; Motor Neurons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, marked by progressive degeneration of upper and lower motor neurons. Clinically, genetically, and pathologically heterogeneous, ALS poses a major challenge for disease modeling and therapeutic translation. Over the past two decades, induced pluripotent stem cells (iPSCs) have reshaped our understanding of ALS pathogenesis and emerged as a promising translational platform for therapy development. ALS modeling has further expanded with the advent of three-dimensional systems, including ALS-on-chip platforms and organoid models, which better capture cell-cell interactions and tissue-level phenotypes. Despite these advances, effective disease-modifying therapies remain elusive. Recent clinical trial setbacks highlight the need for improved trial design alongside robust, translational iPSC models that can better predict therapeutic response. Nonetheless, the outlook is promising as large iPSC patient cohorts, quantitative phenotyping combined with genetically informed patient stratification, and reverse translational research are beginning to close the gap between in vitro discovery and clinical testing. In this review, we summarize the major advances in iPSC technology and highlight key iPSC-based studies of sporadic ALS. We further discuss emerging examples of iPSC-informed therapeutic strategies and outline the challenges associated with translating iPSC-derived mechanistic insights and pharmacological findings into successful clinical therapies.}, } @article {pmid41678108, year = {2026}, author = {Umesh, SB and Sadanandan, B and Marabanahalli Yogendraiah, K and Vijayalakshmi, V}, title = {The Impact of Zinc on Cellular Dynamics, Brain Function, and its Therapeutic Potential in Neuronal Regeneration.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {436}, pmid = {41678108}, issn = {1559-1182}, mesh = {Humans ; Animals ; *Zinc/pharmacology/therapeutic use/metabolism ; *Brain/drug effects/physiology ; *Nerve Regeneration/drug effects/physiology ; *Neurons/drug effects/metabolism ; Neurogenesis/drug effects ; }, abstract = {Zinc is a vital trace element that plays a central role in maintaining brain function, regulating cellular dynamics, and promoting neuronal repair. As the second most abundant transition metal in the central nervous system, zinc is essential for neurotransmission, synaptic plasticity, and neurogenesis, processes that underlie higher cognitive functions such as learning and memory. Its homeostasis is tightly controlled, as dysregulation contributes to the onset and progression of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. At the cellular level, zinc serves as a critical regulator of proliferation, differentiation, and survival, influencing the behavior of neural and mesenchymal stem cells. Through modulation of signaling pathways such as PI3K/Akt and MAPK, zinc governs cell growth, maturation, and neuroprotection. Physiological levels support axonal sprouting, neurite extension, and synaptic connectivity, whereas excessive release under pathological conditions exacerbates oxidative stress and excitotoxicity. Emerging evidence highlights zinc's therapeutic role in neuronal regeneration. Controlled supplementation enhances neurogenesis, reduces apoptosis, restores synaptic activity, and improves memory outcomes in experimental models of neural injury. Zinc-enriched biomaterials and scaffolds are also being developed for neural tissue engineering, where the incorporation of zinc enhances neurite outgrowth, cell adhesion, and network repair. Beyond neuroregeneration, zinc-based nanomaterials are gaining biomedical significance. Zinc oxide nanoparticles (ZnO NPs) exhibit potent anticancer activity against human cancer cell lines by inducing reactive oxygen species generation, DNA damage, and apoptosis. Additionally, other zinc nanoparticles, including zinc sulfide and zinc-doped biomaterials, show potential in tissue repair, wound healing, and drug delivery applications. Collectively, these findings underscore zinc's multifaceted role in neural function, regenerative biology, and nanomedicine. Advancing our understanding of zinc-mediated mechanisms may enable the development of novel zinc-targeted therapeutic strategies for treating neurodegenerative diseases and promoting functional recovery after brain injury.}, } @article {pmid41678358, year = {2026}, author = {Johari, M and Folland, C and Saito, Y and Oud, MM and Parmar, JM and Töpf, A and Kurbatov, S and Ampleeva, M and Zakharova, EY and Chekmareva, IA and Shirokova, KS and Atiakshin, D and van Beek, R and Gardeitchik, T and Kamsteeg, EJ and Medici, E and Donker Kaat, L and Nemoto, J and Komaki, H and Okabe, T and Kimoto, Y and Tokito, T and Nakanowatari, M and Oya, Y and Bruels, CC and Stafki, SA and Estrella, EA and Littel, HR and Kunkel, LM and Kang, PB and Osei-Owusu, I and Pais, L and O'Leary, M and Austin-Tse, C and O'Donnell-Luria, A and Mangilog, B and Genetti, CA and Valivullah, ZM and Radio, FC and D'Amico, A and Ciolfi, A and Tartaglia, M and Perrin, A and Van Goethem, C and Sole, G and Martin-Négrier, ML and Cossée, M and Milic Rasic, V and Kovacevic, G and Kosac, A and Moreno, CAM and Gontijo Camelo, C and Zanoteli, E and Habib, C and Fahey, MC and Beggs, AH and Poulsen, NS and Vissing, J and Straub, V and Savarese, M and Tasca, G and Voermans, NC and Laing, NG and Udd, B and Nishino, I and Ravenscroft, G}, title = {Missense variants in TUBA4A cause myo-tubulinopathies.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, pmid = {41678358}, issn = {1460-2156}, support = {P50 HD105351/HD/NICHD NIH HHS/United States ; R01 HG009141/HG/NHGRI NIH HHS/United States ; U01 HG011755/HG/NHGRI NIH HHS/United States ; UM1 HG008900/HG/NHGRI NIH HHS/United States ; }, abstract = {Tubulinopathies encompass a spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked de novo or dominantly inherited TUBA4A missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, spastic ataxia, and recently, an isolated congenital myopathy, the full phenotypic and genotypic spectrum of TUBA4A-related disorders remains incompletely characterised. In this multi-centre study, we identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Remarkably, individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease. In the remaining two families, we observed probands with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation. The coexistence of neuromuscular and neurodegenerative features with protein aggregation defines a multisystem proteinopathy. These two families thus establish the first association between TUBA4A and multisystem proteinopathy. Our cohort exhibited diverse genotypes and inheritance patterns: four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. We observed a range of disease onset, from congenital to late adulthood. Creatine kinase levels were variable, ranging from normal to highly elevated. Cardiac function remained preserved across the cohort. Muscle biopsies showed heterogenous myopathic changes, including myofibre size variation, nemaline bodies, core-like regions, and internal nuclei. Immunohistochemical analysis revealed protein accumulations positive for TDP-43 (n=2), p62 (n=5), and TUBA4A (n=6). Complementary in silico and in vitro investigations suggested that the identified TUBA4A variants cause significant protein abnormalities and may differentially impact microtubule dynamics. Correlation analyses integrating clinical severity, variant location, and mechanistic readouts further demonstrated that domain specificity within TUBA4A influences both the pattern of muscle involvement and the extent of microtubule disruption. Our findings establish myo-tubulinopathies as distinct clinical entities, encompassing both primary myopathies and multisystem proteinopathies with muscle involvement. This study broadens the phenotypic and genotypic spectrum of TUBA4A-related disorders beyond autosomal dominant or de novo mechanisms and neurodegenerative presentations. These results underscore the importance of considering TUBA4A variants in the differential diagnosis of axial myopathies and multisystem proteinopathies, regardless of central nervous system (CNS) involvement.}, } @article {pmid41678537, year = {2026}, author = {Helal, MM and Almosilhy, NA and Abo-Elnour, DE and Jaffal, RSY and Allam, EG and Almosilhy, MA and Batarseh, SF and Meshref, M}, title = {Targeting metabolic dysfunction in amyotrophic lateral sclerosis: therapeutic potential of GLP-1 receptor agonists.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {513-539}, doi = {10.1080/21678421.2026.2627901}, pmid = {41678537}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Glucagon-Like Peptide-1 Receptor Agonists ; Animals ; Glucagon-Like Peptide-1 Receptor/metabolism ; *Metabolic Diseases/drug therapy/metabolism ; Hypoglycemic Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss and profound systemic metabolic dysfunction, including hypermetabolism, weight loss, insulin resistance, and altered glucose and lipid homeostasis. Increasing recognition of these metabolic abnormalities has driven interest in repurposing antidiabetic therapies, particularly glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs), for ALS. Beyond their established metabolic actions, GLP-1RAs exert pleiotropic effects relevant to neurodegeneration, including modulation of neuroinflammation, mitochondrial function, oxidative stress, excitotoxicity, and cell-survival signaling, with selected agents demonstrating central nervous system penetration. This narrative review summarizes current knowledge on metabolic impairment in ALS and critically evaluates the mechanistic rationale, preclinical evidence, and emerging clinical data supporting or opposing the use of GLP-1-based therapies in this disease. Preclinical studies suggest that GLP-1 signaling can provide neuroprotective and neurotrophic effects in ALS models, although findings are heterogeneous and highly dependent on compound selection, delivery strategy, and experimental design. In contrast, available clinical evidence is limited and does not demonstrate therapeutic benefit in ALS, while raising important safety concerns, particularly related to weight loss, lean mass reduction, and altered glucose regulation, factors associated with a worse prognosis in ALS. Collectively, current data indicate that although GLP-1-based therapies may have compelling biological plausibility and beneficial effects in other neurodegenerative disorders (NDGs), their role in ALS remains uncertain and potentially harmful. Well-designed, ALS-specific clinical studies are required to clarify safety, efficacy, and patient selection before GLP-1RAs can be considered for therapeutic use in this vulnerable population.}, } @article {pmid41679263, year = {2026}, author = {Martínez-Hernáez, Á and Insunza, A and Vidal, F}, title = {"Those eyes that look at you:" somatic modes of care in professional encounters with amyotrophic lateral sclerosis patients.}, journal = {Social science & medicine (1982)}, volume = {395}, number = {}, pages = {119065}, doi = {10.1016/j.socscimed.2026.119065}, pmid = {41679263}, issn = {1873-5347}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/therapy ; Qualitative Research ; *Professional-Patient Relations ; Spain ; Female ; Male ; *Caregivers/psychology ; Communication ; }, abstract = {In the advanced stages of amyotrophic lateral sclerosis (ALS), individuals experience a gradual and irreversible loss of speech and voluntary movement, while cognitive and emotional capacities often remain largely preserved. ALS frequently culminates in the locked-in state (LIS), where subjectivity endures despite an almost complete breakdown of expressive capacity. This article examines how professional caregivers sustain relational engagement and recognition under such conditions. The analysis draws on eleven qualitative interviews with social workers, psychologists, occupational therapists, nurses, and a neurologist working in Catalonia (Spain) in long-term home-based and community care for people with ALS. A hermeneutic phenomenological approach was used to explore how professionals perceive, interpret, and respond to patients whose expressive capacities have largely disappeared. Findings show that communication does not cease but is reconfigured into embodied forms such as gaze, muscle tone, breathing patterns, tears, and silence. Caregivers describe these signs as requiring perceptual attunement and temporal continuity. Building on Thomas Csordas's idea of somatic modes of attention, we conceptualize "somatic modes of care" as the embodied, affective, and ethical practices through which relation and subjectivity are sustained when language fails, a dimension inherent to all care, but rendered especially visible and indispensable in ALS and LIS. For professionals, personhood emerges as a fragile relational achievement upheld through recognition, memory, and sustained presence. Somatic modes of care thus offer an analytic lens for understanding how subjectivity is maintained under radical communicative constraints, with implications for clinical practice and for broader debates on care, embodiment, and relational ethics.}, } @article {pmid41681063, year = {2026}, author = {Kim, MS and Nam, Y and Kim, KT}, title = {Ultrasonographic Measurements of Tongue Thickness and Swallowing Dysfunction in Amyotrophic Lateral Sclerosis: A Feasibility Study.}, journal = {Annals of rehabilitation medicine}, volume = {50}, number = {1}, pages = {71-79}, pmid = {41681063}, issn = {2234-0645}, abstract = {OBJECTIVE: To explore whether ultrasonographic measurements of tongue thickness are associated with swallowing function and related clinical domains in patients with amyotrophic lateral sclerosis (ALS), this feasibility study was conducted. Few studies have examined the usefulness of ultrasonographic tongue thickness measurement in patients with ALS, but its association with physiological measures remains unclear.

METHODS: Ten patients with ALS underwent tongue thickness measurement using ultrasonography. Clinical assessments including the Korean version of the ALS Functional Rating Scale-Revised (K-ALSFRS-R), Functional Oral Intake Scale (FOIS), Eating Assessment Tool-10 (EAT-10), Dysphagia Handicap Index, Korean version of the Swallowing Quality of Life Questionnaire, Mini Nutritional Assessment-Short Form (MNA-SF), handgrip strength, and bioelectrical impedance analysis for skeletal muscle index (SMI) were performed. Swallowing physiology was evaluated using the Modified Barium Swallow Impairment Profile (MBSImP), Penetration-Aspiration Scale. Simple and partial Pearson's correlation analyses as well as univariate regression were performed with adjustments for age, sex, and body mass index (BMI).

RESULTS: Tongue thickness showed significant associations with multiple functional and systemic measures in the unadjusted analyses, including FOIS, EAT-10, MNA-SF, BMI, SMI, K-ALSFRS-R. After adjustment, the most consistent associations were observed with the MBSImP oral, pharyngeal, and combined phase scores.

CONCLUSION: Tongue ultrasonography may serve as a radiation-free method to preliminarily assess bulbar involvement in ALS. Tongue thickness was most specifically associated with dysphagia outcomes, particularly MBSImP. Given the feasibility design and small sample size, larger longitudinal studies are warranted to confirm its clinical utility in monitoring the progression of dysphagia in patients with ALS.}, } @article {pmid41683467, year = {2026}, author = {Czaj, PV and Szewczyk-Golec, K and Nuszkiewicz, J and Woźniak, A}, title = {Gut Dysbiosis and Microbiota-Derived Metabolites in Neurodegenerative Diseases: Molecular and Biochemical Mechanisms Along the Gut-Brain Axis.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {3}, pages = {}, pmid = {41683467}, issn = {1420-3049}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/microbiology/etiology ; *Gastrointestinal Microbiome ; *Dysbiosis/metabolism/microbiology ; Animals ; *Brain/metabolism ; Oxidative Stress ; *Brain-Gut Axis ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) share key molecular features, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and progressive neuronal loss. Increasing evidence indicates that gut dysbiosis and alterations in microbiota-derived metabolites are involved in these processes through multiple pathways along the gut-brain axis. However, while broad compositional changes are well-documented, a critical knowledge gap remains regarding the specific biochemical signal transduction pathways translating dysbiosis into pathology. This narrative review addresses this gap by synthesizing current human and experimental studies addressing gut microbiota alterations in AD, PD, and ALS, with particular emphasis on the biochemical and molecular mechanisms mediated by gut-derived metabolites. Dysbiosis in neurodegenerative diseases is frequently associated with reduced abundance of short-chain fatty acid (SCFA)-producing bacteria and altered metabolism of SCFAs, bile acids, tryptophan-derived indoles, trimethylamine-N-oxide (TMAO), and lipopolysaccharides (LPS). These microbial metabolites have been shown to modulate intestinal and blood-brain barrier integrity, influence Toll-like receptor- and G protein-coupled receptor-dependent signaling, regulate microglial activation, and affect molecular pathways related to protein aggregation in experimental models. In addition, emerging evidence highlights the involvement of oxidative and nitrosative stress, immune-metabolic crosstalk, and altered xenobiotic metabolism in microbiota-host interactions during neurodegeneration. By integrating microbiological, metabolic, and molecular perspectives, this review underscores the important and emerging role of microbiota-derived molecules in neurodegenerative disorders and outlines key chemical and metabolic pathways that may represent targets for future mechanistic studies and therapeutic strategies.}, } @article {pmid41683564, year = {2026}, author = {Jamerlan, A and Hulme, J}, title = {From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {3}, pages = {}, pmid = {41683564}, issn = {1422-0067}, support = {RS-2025-02292973//Ministry of Oceans and Fisheries/ ; RS-2021-NR060117//Ministry of Education/ ; }, mesh = {Humans ; *Proteostasis ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Protein Folding ; Kinetics ; Proteotoxic Stress ; Autophagy ; Frontotemporal Dementia/metabolism/genetics/pathology ; Proteasome Endopeptidase Complex/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases that, despite the availability of symptomatic and modestly beneficial treatments, still lack therapies capable of halting disease progression. A histopathological hallmark of both diseases is the cytoplasmic deposition of TDP-43 in neurons, which is attributed to both intrinsic (e.g., mutations, aberrant cleavage) and extrinsic factors (e.g., prolonged oxidative stress, impaired clearance pathways). Mutations and certain PTMs (e.g., cysteine oxidation) destabilize RNA binding, promoting monomer misfolding and increasing its half-life. Disruptions to core ubiquitin-proteasome system (UPS) subunits impede efficient processing, contributing to the clearance failure of misfolded TDP-43 monomers. The accumulation of monomers drives phase separation within stress granules, creating nucleation hotspots that eventually bypass the thermodynamic barrier, resulting in exponential growth. This rapid growth then culminates in the failure of the autophagy-lysosome pathway (ALP) to contain the aggregation, resulting in a self-sustaining feed-forward loop. Here, we organize these factors into a conceptual kinetic cascade that links TDP-43 misfolding, phase separation, and clearance failure. Therapeutic strategies must therefore move beyond simple clearance and focus on targeting these kinetic inflection points (e.g., oligomer seeding, PTM modulation).}, } @article {pmid41683920, year = {2026}, author = {Auburger, GWJ and Key, J and Gispert, S and Lastres-Becker, I and Almaguer-Mederos, LE and Bassa, C and Auburger, A and Auburger, G and Arsovic, A and Deller, T and Sen, NE}, title = {Bioinformatic Analyses of the Ataxin-2 Family Since Algae Emphasize Its Small Isoforms, Large Chimerisms, and the Importance of Human Exon 1B as Target of Therapies to Prevent Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {27}, number = {3}, pages = {}, pmid = {41683920}, issn = {1422-0067}, support = {AU96/21-1//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Animals ; Humans ; Amino Acid Sequence ; *Ataxin-2/genetics/metabolism/chemistry ; *Computational Biology/methods ; *Evolution, Molecular ; *Exons ; Invertebrates/chemistry/genetics/metabolism ; *Neurodegenerative Diseases/genetics ; Peptides/genetics ; Phylogeny ; Plants/chemistry/genetics/metabolism ; Protein Isoforms/genetics/metabolism ; }, abstract = {Polyglutamine expansion in Ataxin-2 (ATXN2) is responsible for rare, dominantly inherited Spinocerebellar Ataxia type 2 (SCA2). Together with its paralog Ataxin-2-like (ATXN2L), both proteins have received much interest, since the deletion of their yeast and fly orthologs alleviates TDP-43-triggered neurotoxicity in Amyotrophic Lateral Sclerosis models. Their typical structure across evolution combines LSm with LSm-Associated Domains and a PAM2 motif. To understand the physiological regulation and functions of Ataxin-2 homologs, the phylogenesis of sequences was analyzed. Human ATXN2 harbors multiple alternative start codons, e.g., from an intrinsically disordered sequence (IDR) present since armadillo, or from the polyQ sequence that arose since amphibians, or from the LSm domain since primitive eukaryotes. Multiple smaller isoforms also exist across the C-terminus. Therapeutic knockdown of polyQ expansions in human ATXN2 should selectively target exon 1B. PolyQ repeats developed repeatedly, usually framed and often interrupted by (poly)Pro, originally near PAM2. The LSmAD sequence appeared in algae as the characteristic Ataxin-2 feature with strong conservation. Frequently, Ataxin-2 has added domains, likely due to transcriptional readthrough of neighbor genes during cell stress. These chimerisms show enrichment of rRNA processing; nutrient store mobilization; membrane strengthening via lipid, protein, and glycosylated components; and cell protrusions. Thus, any mutation of Ataxin-2 has complex effects, also affecting membrane resilience.}, } @article {pmid41684011, year = {2026}, author = {Chico, L and Schirinzi, E and Balestrini, L and Polzella, M and Siciliano, G}, title = {Nrf2-Activating Natural Compounds in Neurodegenerative Diseases: Targeting Oxidative Stress and Protein Aggregation.}, journal = {International journal of molecular sciences}, volume = {27}, number = {3}, pages = {}, pmid = {41684011}, issn = {1422-0067}, mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Oxidative Stress/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; *Biological Products/pharmacology/therapeutic use ; *Protein Aggregates/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; *Protein Aggregation, Pathological/drug therapy/metabolism ; Signal Transduction/drug effects ; Antioxidants/pharmacology/therapeutic use ; Proteotoxic Stress ; }, abstract = {Neurodegenerative diseases (NDs) are among the leading causes of disability and mortality worldwide and are characterized by multifactorial pathogenesis involving interconnected mechanisms, such as oxidative stress, protein misfolding and aggregation, neuroinflammation, and mitochondrial dysfunction. Dysregulation of transcription factors, governing cellular defense responses, particularly nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant and proteostatic pathways, plays a critical role in neurodegenerative processes. Currently, available pharmacological treatments for NDs are largely symptomatic, as no disease-modifying therapies exist. Natural bioactive compounds have emerged as promising multi-target agents, demonstrating antioxidant, anti-aggregative, and anti-apoptotic properties, frequently mediated through activation of the Nrf2 signaling pathways. These compounds may represent valuable supportive strategies alongside conventional drug treatments, potentially contributing to the modulation of multiple pathogenic mechanisms. This review summarizes key oxidative stress- and protein aggregation-driven mechanisms underlying Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. It further examines the neuroprotective potential of plant-, fungi-, and marine-derived natural compounds, with particular emphasis on Nrf2 activation. Beyond redox regulation, the broader role of Nrf2 in maintaining proteostasis is discussed. Overall, the review highlights Nrf2-inducing nutraceuticals as promising complementary, multi-target approaches for neuroprotection in NDs.}, } @article {pmid41684905, year = {2026}, author = {Goutman, SA and Guo, K and Park, J and Jang, DG and Teener, SJ and Webber-Davis, IF and Famie, JP and Piecuch, CE and Hur, J and Murdock, BJ}, title = {Natural Killer Cell Dysregulation During ALS Disease Progression: A Gene Expression Analysis.}, journal = {Neurology open access}, volume = {2}, number = {1}, pages = {}, pmid = {41684905}, issn = {2998-7601}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative motor neuron disease with a pathophysiology that features dysregulated natural killer (NK) cells that are capable of damaging neurons. Although NK cells are associated with ALS progression and survival, their specific characteristics and how these characteristics change over the course of disease is unknown. The current study examines NK cell gene expression during ALS with the goal of identifying dysregulated genes and pathways in NK cells over the course of disease in order to identify potential new therapeutic targets.

METHODS: ALS participants with an El Escorial ALS diagnosis were recruited from the University of Michigan Pranger ALS Clinic, and control participants were recruited via internet-based notifications. Blood was collected from participants and NK cells were isolated from participants with ALS at two timepoints (baseline and longitudinal) and age- and sex-matched healthy controls at one timepoint. RNA was extracted from the NK cells and quantified using a transcript-counting technology for 578 immune-related genes. Differential gene expression analysis was used to identify individual genes that were dysregulated in ALS at baseline and longitudinally, While GO and KEGG pathway analyses were performed to identify dysregulated pathways at both timepoints.

RESULTS: NK cells from participants with ALS (n=36, median age 62.6 years (54.5-69.4), 50% female) showed a 2-fold or greater reduced expression of four pro-inflammatory genes at baseline relative to control participants (N=35, median age 64.3 years (55.2-71.8), 51% female) including IFNG, FCGR1A/B, and FAS; in ALS participants over 130 genes showed a 2-fold change in expression. Dysregulated genes and pathways at the later timepoint were related to cell polarization, activation, signaling, and cell-cell adhesion. In particular, genes associated with classical Type 1 inflammation decreased while Type 2 genes increased.

DISCUSSION: NK cells grow more dysregulated with ALS progression, shifting from a classical Type 1 phenotype to a Type 2 phenotype, though a larger study will be needed to confirm these initial findings. The findings also suggest NK cells contribute to early, but not late, ALS progression. Targeting specific NK cell pathways during early ALS may be a viable therapeutic strategy.}, } @article {pmid41684936, year = {2026}, author = {Cotto, BA and Zhang, L and Fait, B and Peralta, C and Kilic, E and Molina, H and Heintz, N and Schmidt, EF}, title = {Divergent mitochondrial and metabolic adaptations shape selective vulnerability in ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.01.30.702552}, pmid = {41684936}, issn = {2692-8205}, abstract = {Neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) exhibit striking cell-type selectivity, yet the basis for this vulnerability remains elusive. Here, we uncover that even closely related neurons can harbor distinct mitochondrial properties that shape their response to disease. Using TOM-Tag, a circuit-based AAV-based strategy for cell type-specific mitochondrial immunopurification from projection neurons, we performed integrative proteomic, metabolomic, transcriptomic, and functional analyses of mitochondria from ALS-vulnerable corticospinal projection neurons (CSPNs) and resilient corticothalamic projection neurons (CTPNs) in vivo. We discovered that CSPNs and CTPNs exhibit divergent mitochondrial profiles at baseline, despite sharing cortical layer and developmental origin. CTPNs were primed for antioxidant buffering and fatty acid metabolism, whereas CSPNs were enriched for oxidative phosphorylation components. In ALS, CTPNs employed mitochondrial flexibility and redox defense, whereas CSPNs exhibited respiratory failure and metabolic stress. These findings reveal that intrinsic mitochondrial programs vary even between similar neurons, and that this hidden layer of diversity may critically shape susceptibility to neurodegeneration. By enabling high-resolution access to mitochondria in defined neuronal circuits, TOM-Tag offers a powerful new lens for dissecting disease mechanisms and identifying cell-specific therapeutic targets.}, } @article {pmid41685589, year = {2026}, author = {de Jesus, H and Alves, I and Lopes, D and Simão, S and Leitão, AC and Pronto-Laborinho, AC and Conceição, V and Oliveira Santos, M and de Carvalho, M}, title = {Cognitive Dysfunction Is Associated With an Underestimation of Respiratory Function in ALS.}, journal = {Muscle & nerve}, volume = {73}, number = {5}, pages = {882-886}, pmid = {41685589}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/psychology ; Female ; Male ; Retrospective Studies ; Aged ; Middle Aged ; Vital Capacity/physiology ; *Cognitive Dysfunction/physiopathology ; Phrenic Nerve/physiopathology ; }, abstract = {INTRODUCTION/AIMS: The association between low forced vital capacity (FVC) and cognitive impairment in ALS is ambiguous; it could be due to respiratory dysfunction and/or poor effort from cognitive deficits. We used the objective, non-volitional phrenic nerve motor response amplitude (PAmp) to clarify how cognitive status affects the relationship between diaphragmatic strength and FVC.

METHODS: This retrospective study included 73 patients with ALS followed in our clinic. FVC and PAmp were measured, and cognitive status was assessed with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Regression models tested for associations between FVC and distinct ECAS domains and whether these domains influenced the PAmp-FVC relationship.

RESULTS: PAmp (β = 0.58, p = 0.001) and its interaction with an abnormal ECAS's Executive score (β = -0.20, p < 0.045) were significant predictors of FVC. The latter indicated that patients with abnormal executive function had lower FVC than cognitively normal patients at similar PAmp values. Moreover, in patients with abnormal executive function, a reduction in PAmp was associated with a shallower decline in FVC. Severe bulbar dysfunction was also negatively associated with FVC (β = -0.22, p = 0.024).

DISCUSSION: FVC may underestimate respiratory capacity in cognitively impaired patients; therefore, we recommend non-volitional measures when evaluating ALS patients with executive dysfunction.}, } @article {pmid41685660, year = {2026}, author = {Pérez-Fuentes, MDC and Molero Jurado, MDM and Romanos-Rodríguez, A and Martos Martínez, Á and Gómez-Gómez, FJ and Aguado-Campos, J}, title = {Self-efficacy and Communication in Health Personnel After Simulation Training in Cardiopulmonary Resuscitation: A Quasi-experimental Study.}, journal = {Inquiry : a journal of medical care organization, provision and financing}, volume = {63}, number = {}, pages = {469580251411471}, pmid = {41685660}, issn = {1945-7243}, mesh = {Humans ; *Self Efficacy ; Male ; Adult ; Female ; *Cardiopulmonary Resuscitation/education ; *Communication ; Middle Aged ; *Health Personnel/education/psychology ; *Simulation Training ; Spain ; Surveys and Questionnaires ; Aged ; Clinical Competence ; Young Adult ; }, abstract = {This study aimed to evaluate the impact of a simulation-based Advanced Life Support (ALS) training programme on the self-efficacy and communication of health personnel. The research focussed on whether such training could enhance both technical and non-technical skills, particularly in managing cardiopulmonary resuscitation (CPR) situations. A quasi-experimental pre- and post-intervention study was conducted in primary care centres across Andalusia, Spain. A total of 106 health personnel (doctors and nurses), aged 21 to 65 years, participated in the study. Participants completed questionnaires measuring self-efficacy and communication styles before and after a 27-hour blended ALS training programme, which incorporated high-fidelity simulation exercises. Communication was assessed across several dimensions, including expressiveness, preciseness, impression manipulativeness, and emotionality. Post-intervention analysis revealed significant changes in communication styles. Specifically, doctors exhibited a reduction in "impression manipulativeness," while nurses showed an increase in "expressiveness." Although self-efficacy scores improved slightly after the training, the changes were not statistically significant. Correlational analyses indicated that higher self-efficacy was positively associated with "expressiveness" and "preciseness," and negatively associated with "emotionality." In conclusion, simulation-based ALS training led to improved communication among health personnel, with distinct patterns emerging between doctors and nurses. While the simulation training did not significantly increase self-efficacy, the trends observed suggest potential benefits. These findings support the inclusion of simulation in continuing professional development programmes to strengthen non-technical skills essential for effective CPR performance.}, } @article {pmid41686235, year = {2026}, author = {}, title = {Intime Mitbewohner - Das Mikrobiom als unterschätzter Faktor in Klinik und Praxis.}, journal = {Wiener klinische Wochenschrift}, volume = {138}, number = {3-4}, pages = {127}, doi = {10.1007/s00508-026-02714-y}, pmid = {41686235}, issn = {1613-7671}, } @article {pmid41686369, year = {2026}, author = {Qaisar, R}, title = {Extracellular vesicles at the neuromuscular junction: messengers of synaptic health and disease.}, journal = {Cell and tissue research}, volume = {403}, number = {2}, pages = {20}, pmid = {41686369}, issn = {1432-0878}, mesh = {*Extracellular Vesicles/chemistry/metabolism ; *Neuromuscular Junction/metabolism/pathology ; Homeostasis ; Motor Neurons/chemistry/cytology ; *Neurodegenerative Diseases/pathology/therapy ; Humans ; Animals ; }, abstract = {Extracellular vesicles (EVs) have emerged as pivotal modulators of neuromuscular junction (NMJ) biology, reshaping our understanding of synaptic communication, maintenance, and degeneration. This review consolidates current insights into the roles of EVs derived from motor neurons, muscle fibers, and Schwann cells in regulating NMJ integrity. In healthy states, EVs deliver trophic factors, structural proteins, and regulatory RNAs that promote the clustering of acetylcholine receptors, presynaptic stability, and axonal growth. Motor neuron EVs carry Wnt7a, synaptophysin, and PGC-1α, while muscle-derived EVs deliver miR-206, agrin, and caveolin-3. Schwann cell EVs contribute neurotrophic support via NRG1 and GDNF. In contrast, diseased or aged NMJs exhibit EV cargo dysregulation, marked by the presence of misfolded proteins (e.g., SOD1, TDP-43), pro-inflammatory cytokines, and reduced regenerative miRNAs. These changes contribute to synaptic dismantling, neuroinflammation, and impaired repair in conditions such as ALS, SMA, MG, and sarcopenia. The review highlights the bidirectional nature of EV signalling and its dynamic regulation by neuronal activity and stress. Emerging therapeutic strategies include engineering EVs to deliver protective cargo, targeting them to NMJ components, and designing biomaterial-based depots for sustained release. Furthermore, EV signatures in blood and muscle hold promise as non-invasive biomarkers for early detection of NMJ decline in ALS, SMA, MG, and sarcopenia. Despite promising preclinical data, challenges remain in EV characterization, targeting specificity, and clinical translation. This review underscores a paradigm shift: EVs are not passive byproducts but active messengers of neuromuscular health and disease, with realistic applications in diagnostics, regenerative therapy, and personalized medicine.}, } @article {pmid41687010, year = {2026}, author = {Torrella, P and Martínez, M and Riera, J and Argudo, E}, title = {A Homemade Low-Cost Agar-Agar Extracorporeal Membrane Oxygenation Cannulation Model for Extracorporeal Resuscitation Simulation.}, journal = {ASAIO journal (American Society for Artificial Internal Organs : 1992)}, volume = {72}, number = {7}, pages = {e140-e143}, doi = {10.1097/MAT.0000000000002664}, pmid = {41687010}, issn = {1538-943X}, mesh = {*Extracorporeal Membrane Oxygenation/methods/education/instrumentation ; Humans ; *Agar ; Manikins ; *Catheterization/methods ; *Cardiopulmonary Resuscitation/education ; *Simulation Training/methods ; }, abstract = {Extracorporeal cardiopulmonary resuscitation (ECPR) using venoarterial extracorporeal membrane oxygenation (VA ECMO) is a life-saving intervention for selected patients in refractory cardiac arrest. Given the procedure's technical complexity and time-critical nature, simulation-based training has become essential to ensure both technical proficiency and effective team coordination. However, current commercial simulators are often prohibitively expensive and lack the capacity to integrate ECMO cannulation into standard advanced life support (ALS) scenarios, limiting their real-world applicability and dissemination. To address this gap, we developed a low-cost, customizable phantom using agar-agar, basic household materials, and repurposed medical components. Our model enables ultrasound-guided vascular access, cannula insertion, and initiation of extracorporeal blood flow. It can be easily embedded within ALS mannequins, allowing seamless integration into high-fidelity ECPR simulations. The phantom realistically reproduces key procedural steps and supports training under the high-stress, time-sensitive conditions typical of ECPR. Its adaptability allows use in both technical workshops and in situ simulations involving multidisciplinary teams. This accessible, eco-friendly solution provides a practical alternative to commercial models, promoting broader implementation of ECPR training programs. It represents a step forward in bridging the gap between theoretical knowledge and hands-on practice in critical care education.}, } @article {pmid40594383, year = {2025}, author = {Bernardi, S and Vitolo, S and Gabellini, C and Marchese, M and Ferraro, E}, title = {Trimetazidine stimulates intracellular Ca[2+] transients and zebrafish locomotor activity in spinal neurons.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {22854}, pmid = {40594383}, issn = {2045-2322}, support = {GSA23C003//Telethon Foundation/ ; AFM 23771//AFM-TELETHON/ ; P2022LSW98//PRIN 2022 PNRR/ ; }, mesh = {Animals ; Zebrafish/physiology ; *Calcium/metabolism ; Animals, Genetically Modified ; *Motor Neurons/drug effects/metabolism ; *Locomotion/drug effects ; *Trimetazidine/pharmacology ; *Spinal Cord/drug effects/cytology/metabolism ; *Calcium Signaling/drug effects ; }, abstract = {The metabolic modulator trimetazidine (TMZ) is an antianginal recently found to improve skeletal muscle performance in mice models of sarcopenia and of amyotrophic lateral sclerosis (ALS). The mechanism underlying the effect of TMZ on locomotor activity has been proposed to rely on its ability to enhance metabolic efficiency with a consequent improvement of myogenesis and of neuromuscular junction (NMJ) and muscle function. However, although promising and therefore under clinical trials, the mechanism of action of TMZ has not been clearly disclosed; here we hypothesized that it might involve the modulation of neuronal Ca[2+] flows. We studied the effect of TMZ on Ca[2+] dynamics in vivo, by using the transgenic zebrafish line Tg(neurod1:GCaMP6f) in which the neuronal expression of the Ca[2+] indicator GCaMP allows to visualize Ca[2+] dynamics in neurons of zebrafish larvae. By this elegant tool, we demonstrated, for the first time, that TMZ promotes an increase of intracellular Ca[2+] transients in zebrafish spinal neurons likely enhancing motor neuron firing, which correlates with enhanced motor performance induced by this drug. Even though elevated intracellular Ca[2+] levels have often been associated to neurotoxicity, it is unclear if the neuronal excitability features in some neuro-muscular disorders are compensatory or pathological. Therefore, this newly reported effect of TMZ which transiently and selectively enhances spinal neuron firing deserves to be further detailed and taken into account when the possible repurposing of this drug is proposed for the treatment of neuro-muscular disorders.}, } @article {pmid40595276, year = {2025}, author = {Sancho-Cantus, D and Sanchis, ES and Casani-Cubel, J and Privado, J and Escriba, J and Carriquí-Suárez, AB and Benlloch, M and Cerón, JJ and Rubio, CP and Cubero-Plazas, L and de la Rubia Ortí, JE}, title = {Prediction of antioxidant capacity, age, and sex on sleep impairment in patients with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {21145}, pmid = {40595276}, issn = {2045-2322}, support = {2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; 2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; 2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; 2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; 2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; 2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; 2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Age Factors ; *Amyotrophic Lateral Sclerosis/complications/metabolism ; *Antioxidants/metabolism ; Cross-Sectional Studies ; Oxidative Stress ; Quality of Life ; Sex Factors ; *Sleep Wake Disorders/etiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by high levels of inflammation and oxidative stress, predominantly affecting males, particularly those between the ages of 50 and 65 years. It is characterised by progressive loss of motor neurones, leading to both motor and non-motor symptoms, such as sleep impairment, diagnosed in most patients, which adversely affects their quality of life. Therefore, this study aimed to determine the predictive role of antioxidant capacity, psychological distress, age, and sex on sleep impairment in an adult population of patients with ALS. A descriptive, quantitative, cross-sectional study was conducted using a sample of 74 patients diagnosed with bulbar or spinal ALS. To assess sleep disturbances in these patients, the Pittsburgh sleep quality index (PSQI), epworth sleepiness scale (ESS), and Insomnia severity index were used. Additionally, plasma antioxidant capacity was analysed using the total antioxidant capacity (TEAC), Cupric Ion reducing antioxidant capacity (CUPRAC), and ferric reducing power (FRAP). Anxiety and depression measures were used to measure psychological distress. Men exhibited a higher antioxidant status (lower oxidative stress) than women, and higher antioxidant capacity was associated with fewer sleep impairments (β = -0.43). Psychological distress may increase sleep impairment (β = -0.26). Furthermore, older individuals experienced less sleep impairment (β = -0.27), while sex had minimal influence on sleep deterioration, although it appears that men had fewer disturbances (β = -0.12). Having a higher antioxidant status, lower psychological distress, being male, and being older seem to act as predictors of reduced sleep impairment in ALS. Specifically, these four predictors account for 32% of sleep deterioration.Clínical trial registration: The present descriptive, quantitative, cross-sectional study was part of a clinical trial involving ALS patients, registered under the number NCT04654689 (https://clinicaltrials.gov/study/NCT04654689#wrapper).}, } @article {pmid40596818, year = {2025}, author = {Moreno-García, L and Moreno-Martínez, L and de la Torre, M and Macías-Redondo, S and García-Redondo, A and Osta, R and Toivonen, JM and Calvo, AC}, title = {Circular RNA expression in ALS is progressively deregulated and tissue-dependent.}, journal = {BMC genomics}, volume = {26}, number = {1}, pages = {576}, pmid = {40596818}, issn = {1471-2164}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *RNA, Circular/genetics/metabolism ; Animals ; Humans ; Mice ; Male ; Female ; Spinal Cord/metabolism ; Disease Models, Animal ; Muscle, Skeletal/metabolism ; Mice, Transgenic ; Superoxide Dismutase-1/genetics ; Organ Specificity ; *Gene Expression Regulation ; }, abstract = {BACKGROUND: There is increasing evidence on the role of circular RNAs (circRNAs) in neuronal and muscular processes. Accordingly, their dysregulation is associated with neurodegenerative diseases and myopathies. We investigated circRNA expression in the central nervous system (CNS) and skeletal muscle, the two main tissues affected in amyotrophic lateral sclerosis (ALS).

RESULTS: Based on circRNA sequencing analysis in spinal cord from ALS mice (SOD1G93A) followed by a literature search, 30 circRNAs potentially involved in ALS were tested. All selected circRNAs were downregulated in the SOD1G93A spinal cord, whereas only half of these were quantifiable and were generally upregulated in quadriceps muscle of SOD1G93A mice. Such tissue-dependent expression pattern was observed in both sexes and circRNA abundance in the spinal cord was higher than in the muscle, both in wild type and in SOD1G93A mice. Finally, we assessed the 18 circRNAs with the largest expression differences and the highest degree of interspecies conservation in brain samples from sporadic ALS (sALS) patients and healthy controls. Similar to the mouse model, circRNA levels tended to decrease in the CNS of sALS patients.

CONCLUSIONS: Expression of circRNAs may be systematically altered in the two tissues most affected by ALS in a progressive and opposed manner. Although more detailed studies are warranted, circRNAs are potentially related to ALS etiopathogenesis and could possibly serve as future biomarkers, therapeutic targets, or customized therapeutic tools to modulate the pathology.}, } @article {pmid40597943, year = {2025}, author = {Duan, Q and Li, C and Wei, C and Wang, Q and Wang, B and Sun, L and He, Y and Qin, J and Huang, X}, title = {Botulinum toxin type A for amyotrophic lateral sclerosis lower limb spasm: two case reports.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {263}, pmid = {40597943}, issn = {1471-2377}, support = {No.2024AFD137//the Natural Science Foundation of Hubei Province (Joint Fund Program)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; Male ; *Botulinum Toxins, Type A/therapeutic use/administration & dosage ; Middle Aged ; *Neuromuscular Agents/therapeutic use/administration & dosage ; *Lower Extremity/physiopathology ; *Muscle Spasticity/drug therapy/etiology ; *Spasm/drug therapy/etiology ; }, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) often experience spasticity, which can severely affect their ability to perform basic activities like standing and walking, potentially diminishing their already compromised quality of life. Botulinum toxin type A (BTX-A) is a first-line drug for spastic management. However, there are limited reports on its effectiveness in reducing muscle tone among ALS patients, with scarcely any related research conducted in China. We conducted the clinical observation and follow-up study through the relevant ethical post (ChiCTR2200061794). Clinical registration was on July 2, 2022. All participants provided written informed consent.

CASE PRESENTATION: We report two cases of middle-aged male patients, both diagnosed with ALS, who presented with symptoms such as limb stiffness and walking limitation due to increased muscle tone in the lower limbs. Based on the spasticity of the patient's lower limbs, the corresponding target muscles were selected for BTX-A treatment under ultrasound guidance, and the patients were evaluated on relevant functional scales before injection (baseline, T0) and at three follow-up visits (T1: 2 weeks, T2: 4 weeks, T3: 8 weeks).

CONCLUSION: Appropriate BTX-A injected into the target muscles could effectively depress the spasticity of ALS patients without apparent side effects.}, } @article {pmid40599765, year = {2025}, author = {Wei, X and Qin, W}, title = {Exploring causal links between brain functional networks and neurodegenerative disease risk using Mendelian randomization.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251348844}, pmid = {40599765}, issn = {2542-4823}, abstract = {BACKGROUND: Resting-state functional magnetic resonance imaging (rsfMRI) is pivotal for mapping alterations in brain functional networks associated with neurodegenerative diseases, particularly Alzheimer's disease (AD). However, the causal mechanisms linking such network dysfunction to disease pathogenesis remain unresolved.

OBJECTIVE: This study aimed to elucidate bidirectional causal relationships between 191 resting-state fMRI phenotypes (derived from 34,691 individuals) and six neurodegenerative diseases, specifically AD, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis (MS), dementia with Lewy bodies (DLB), and Parkinson's disease (PD), using disease-specific GWAS data from European-ancestry cohorts.

METHODS: Bidirectional two-sample Mendelian randomization (MR) was performed using rsfMRI phenotypes from Zhao et al. (2022) and GWAS summary statistics (AD: ieu-b-5067/ebi-a-GCST90027158, ALS: ebi-a-GCST90027164, FTD: ieu-b-43, MS: ieu-b-18, DLB: ebi-a-GCST90001390, PD: ieu-b-7). Instrumental variables were filtered for significance (p < 5 × 10^-8), with sensitivity analyses (MR-PRESSO, Cochran's Q, MR-Egger) to ensure robustness.

RESULTS: Forward MR identified 26 rsfMRI phenotypes causally linked to neurodegenerative diseases. AD risk was associated with reduced cerebellum-subcortical connectivity (OR = 0.957, p = 0.004), while heightened cerebellar activity increased DLB risk (OR = 2.58, p = 0.0063). Reverse MR revealed 64 disease-to-network effects: AD altered default mode network connectivity (OR = 0.965, p = 0.034), and PD disrupted salience-central executive network interactions (OR = 0.950, p = 0.00011).

CONCLUSIONS: This study establishes robust bidirectional causal pathways between brain functional networks and neurodegenerative diseases, with AD showing unique vulnerability in cerebellar-subcortical and default mode circuits. These findings highlight network-specific therapeutic targets for AD and related disorders.}, } @article {pmid40600271, year = {2025}, author = {Narayanan, A and Seaberg, BL and Buxton, A and Vernino, A and Williams, VE and Matarazzo, A and Kekre, J and Subramanian, B and Wang, W and Rutkowski, JM and Hook, M and McCreedy, DA and Muthuchamy, M and Rimer, M}, title = {Lymphatic dysfunction correlates with inflammation in a mouse model of amyotrophic lateral sclerosis.}, journal = {Disease models & mechanisms}, volume = {18}, number = {7}, pages = {}, pmid = {40600271}, issn = {1754-8411}, support = {W81XWH2210678//Congressionally Directed Medical Research Programs/ ; W81XWH2210678//U.S. Department of Defense/ ; //Texas A and M University/ ; 25POST1378441//American Heart Association/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology/complications ; Disease Models, Animal ; *Inflammation/pathology/physiopathology/complications ; *Lymphatic Vessels/physiopathology/pathology ; Spinal Cord/pathology/physiopathology ; Muscle, Skeletal/pathology/physiopathology ; Mice ; Mice, Transgenic ; Superoxide Dismutase-1/metabolism ; Mice, Inbred C57BL ; *Lymphatic System/physiopathology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, ultimately fatal neurodegenerative disease, without effective modifying treatments. It affects both lower and upper motor neurons, causing skeletal muscle denervation and paralysis. Regardless of the mechanisms that initiate and drive ALS, chronic neuroinflammation and systemic immune system activation play key roles in disease progression. The lymphatic system is a network of vessels and organs essential for immune surveillance, tissue fluid balance and lipid absorption, critical for the resolution and progression of inflammation in the periphery. Its recent rediscovery in the central nervous system raises the possibility of it playing similar roles in neurological and neurodegenerative diseases featuring prominent neuroinflammation, such as ALS. We hypothesized that the structure and function of lymphatics are compromised in the most widely used murine model of ALS, the SOD1-G93A mouse. We found that these mice exhibit lymph transport dysfunction, diminished intrinsic lymphatic vessel tonic and phasic contractions, and an association between inflammation and lymphatic marker upregulation, despite absence of major structural changes in lymphatic network coverage in key affected tissues in the disease, skeletal muscle and spinal cord.}, } @article {pmid40600544, year = {2026}, author = {El Elhaj, A and Onger, ME}, title = {Exploring Neurodegenerative Diseases: Bridging the Gap between in vitro and in vivo Models.}, journal = {Current pharmaceutical design}, volume = {32}, number = {6}, pages = {407-414}, pmid = {40600544}, issn = {1873-4286}, mesh = {*Neurodegenerative Diseases/drug therapy/physiopathology/pathology ; Humans ; Animals ; *Disease Models, Animal ; }, abstract = {Neurological disorders are brain conditions characterized by the loss of nerve cells, leading to a decline in function. Standard examples include dementia, tremors, involuntary movements, muscle weakness, and autoimmune attacks. The most common form of dementia is Alzheimer's, affecting over 5 million elderly individuals, while tremors, stiffness, and slow movement are caused by Parkinson's. Involuntary movements and emotional problems are caused by Huntington's, while muscle weakness and eventual demise are caused by Amyotrophic lateral sclerosis. Vision problems, fatigue, and difficulty walking are caused by Multiple sclerosis (MS), an autoimmune disease that attacks the myelin sheath. In vitro models provide cost and complexity reduction, environmental control, and high-throughput. Researchers employ both cell-based (in vitro) and animal- based (in vivo) models to investigate neurodegenerative illnesses and endeavor to formulate novel treatments for diverse conditions. In vitro models provide cost and complexity reduction, environment control, and high-throughput screening of potential therapeutic agents compared to in vivo models. Nevertheless, they possess constraints, including the absence of intricate interactions that transpire in the entire organism and the inability to reproduce the disease progression completely.}, } @article {pmid40601808, year = {2025}, author = {Huang, J and Wang, B}, title = {Nanoscale Insights into the Formation Reaction Mechanism of Si-Al Oligomers in Alkali-Activated Materials.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {41}, number = {27}, pages = {17415-17425}, doi = {10.1021/acs.langmuir.4c05076}, pmid = {40601808}, issn = {1520-5827}, abstract = {Alkali-activated materials (AAM) have garnered significant attention as environmentally friendly alternatives to cement due to their potential to mitigate greenhouse gas emissions and facilitate the effective utilization of industrial waste streams. Silicon-aluminum (Si-Al) monomers serve as the cornerstone units within the nanocomposite structure of AAMs, playing a pivotal role in the polycondensation reactions (PR) that govern their formation. Despite extensive research on the PR processes within AAM, the nanoscale reaction mechanisms remain elusive. In this study, MD simulations based on the ReaxFF were employed to delve into the structural evolution and reaction mechanisms of PR processes at the nanoscale. Analyses employing radial distribution functions, bond lengths, and bond angles demonstrated the robustness of the models developed in this investigation. The simulations revealed that when three Si-Al nanomolecular monomers, namely [SiO2(OH)2][2-], [SiO(OH)3][-], and [Al(OH)4][-], undergo pairwise PR, distinct reaction pathways emerge, leading to the formation of various Si-Al oligomers that collectively constitute the framework of the AAM gel. During the assembly of Si-Al oligomers, we aim to shed light on the crucial role played by Al monomers in driving the reaction forward and the subsequent polymerization of Si-Al oligomers. This disparity underscores Al's pivotal function in the PR mechanism, illuminating its indispensable role in governing the molecular architecture and kinetics of these complexes.}, } @article {pmid40602529, year = {2025}, author = {Lai, IC and Wei, JC}, title = {Comment on Mendoza et al's "Association between use of antihypertensives and treatment of actinic keratoses: A TriNetX population-based study".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {4}, pages = {e157-e158}, doi = {10.1016/j.jaad.2025.03.105}, pmid = {40602529}, issn = {1097-6787}, } @article {pmid40602557, year = {2025}, author = {Rodriguez-Romano, A and Gonzalez-Valdivieso, J and Moreno-Martinez, L and Vázquez Costa, JF and Osta, R and Rico, P}, title = {Injectable borax-loaded alginate hydrogels reduce muscle atrophy, modulate inflammation, and promote neuroprotection in the SOD1[G93A] mouse model of ALS through mechanisms involving IGF-Akt-mTOR signaling.}, journal = {International journal of biological macromolecules}, volume = {319}, number = {Pt 4}, pages = {145645}, doi = {10.1016/j.ijbiomac.2025.145645}, pmid = {40602557}, issn = {1879-0003}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; *Hydrogels/chemistry ; Mice ; *Muscular Atrophy/drug therapy/pathology/metabolism ; Disease Models, Animal ; *Alginates/chemistry ; Signal Transduction/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Superoxide Dismutase-1/genetics ; Inflammation/drug therapy/pathology ; Motor Neurons/drug effects/metabolism ; *Neuroprotection/drug effects ; Neuroprotective Agents/pharmacology ; Mice, Transgenic ; Muscle, Skeletal/drug effects/pathology/metabolism ; Borates ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a prevalent condition characterized by motor neuron loss and skeletal muscle paralysis. Despite being associated to mutations in over 40 genes, its etiology remains elusive without a cure or effective treatment. ALS, historically considered a motor neuron disease, is defined today as a multisystem disorder involving non-neuronal cell types, including early muscle pathology independent of motor neuron degeneration (dying back hypothesis), thus skeletal muscle actively contributes to disease pathology, making it a viable therapeutic target for ALS. Our previous research has shown that boron transporter NaBC1 (encoded by the SLC4A11 gene), after activation co-localizes with integrins and growth factor receptors synergistically enhancing muscle repair. Here we investigate the effects of injectable alginate-based hydrogels for controlled local borax release in Amyotrophic Lateral Sclerosis muscle. Treated mice showed improved motor function, prolonged survival, and activation of essential muscle metabolic pathways, leading to enhanced muscle repair and reduced atrophy and inflammation. Interestingly, local muscle repair activation provided retrograde neuroprotection by preserving motor neurons and reducing neuro-inflammation. This study highlights the role of muscle tissue in ALS pathology, supporting its targeting with NaBC1-based therapies for muscle regeneration.}, } @article {pmid40602832, year = {2025}, author = {Abgueguen, E and Tortarolo, M and Rouviere, L and Marcuzzo, S and Camporeale, L and Henriques, A and Pasetto, L and Culley, GR and Bonetto, V and Marian, A and Lejeune, BL and Visbecq, A and Lauria, G and Kabashi, E and Callizot, N and Bendotti, C and Miniou, PY}, title = {Sephin1 reduces TDP-43 cytoplasmic mislocalization and improves motor neuron survival in ALS models.}, journal = {Life science alliance}, volume = {8}, number = {9}, pages = {}, pmid = {40602832}, issn = {2575-1077}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; *Motor Neurons/drug effects/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; Mice ; Zebrafish ; Humans ; Unfolded Protein Response/drug effects ; Mice, Transgenic ; Cell Survival/drug effects ; Endoplasmic Reticulum Stress/drug effects ; Cytoplasm/metabolism ; Mitochondria/metabolism/drug effects ; Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; Oxidative Stress/drug effects ; Spinal Cord/metabolism ; }, abstract = {A pathological hallmark of ALS is the abnormal accumulation of misfolded proteins (e.g., TDP-43) and enlarged endoplasmic reticulum (ER), indicating ER stress. To resolve this stress, cells initiate the Unfolded Protein Response (UPR). However, unresolved stress leads to apoptosis. In ALS, UPR activation fails to resolve proteostasis impairment. UPR activation modulators, among them Sephin1, reduce protein aggregates and improve motor neuron survival in ALS models. We demonstrate that following glutamate intoxication, Sephin1 increases motor neuron survival by reducing mitochondria ROS production and extranuclear TDP-43. Sephin1 reduces abnormal splicing because of TDP-43 nuclear loss of function following oxidative stress. In SOD1[G93A] mice, Sephin1 treatment decreases TDP-43 in triton-insoluble fraction, improving motor neuron survival in spinal cord. Sephin1 improves motor neurons survival, motor function and survival of mutated TDP-43 transgenic zebrafish. Sephin1 improves motor neuron survival in ALS models by reducing TDP-43 cytoplasmic mislocalization and its toxicity. These findings open new therapeutic opportunities for Sephin1 in neurodegenerative pathologies with TDP-43 proteinopathy, including ALS.}, } @article {pmid40603049, year = {2025}, author = {Tsuiji, H}, title = {[Elucidation of the Molecular Mechanism Underlying Aberrant Formation of RNA Granules in Neurons of ALS Patients and Its Regulation].}, journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan}, volume = {145}, number = {7}, pages = {583-588}, doi = {10.1248/yakushi.24-00209-1}, pmid = {40603049}, issn = {1347-5231}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/therapy/etiology ; Humans ; RNA-Binding Protein FUS/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; C9orf72 Protein/genetics ; *RNA/metabolism/genetics ; *Motor Neurons/metabolism ; Animals ; RNA Splicing/genetics ; RNA-Binding Proteins/metabolism ; *Cytoplasmic Granules/metabolism ; Dipeptides/metabolism ; Protein Biosynthesis/genetics ; Spliceosomes/metabolism ; DNA Repeat Expansion/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by progressive muscle atrophy throughout the body. In nearly all ALS patients, abnormal accumulation of the RNA-binding protein TDP-43 is observed in degenerating motor neurons. We have found that RNA-binding proteins such as TDP-43 and FUS are concentrated in GEM bodies, where they contribute to the integrity of the spliceosome machinery involved in pre-RNA splicing. Additionally, the most common cause of ALS, repeat expansion in the C9orf72 gene, triggers abnormal repeat-associated non-AUG (RAN) translation, leading to the accumulation of neurotoxic dipeptide repeat (DPR) proteins. We have identified that these DPR proteins may inhibit GEM body formation and contribute to ALS pathology. Furthermore, therapeutic approaches to suppress RAN translation using dCas13 technology are under development, offering promising new strategies to address abnormalities in RNA metabolism in ALS.}, } @article {pmid40603051, year = {2025}, author = {Ito, L and Galipon, J}, title = {[Development of RNA Hydrogels as a Potential System for Intracellular Biomimicry: A Method for the In Vitro Synthesis of ALS/FTD-related (G4C2)n RNA with over 100 Repeats].}, journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan}, volume = {145}, number = {7}, pages = {601-607}, doi = {10.1248/yakushi.24-00209-3}, pmid = {40603051}, issn = {1347-5231}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; *RNA/chemical synthesis/genetics/chemistry ; Humans ; *Hydrogels ; G-Quadruplexes ; C9orf72 Protein/genetics ; DNA-Directed RNA Polymerases ; *Repetitive Sequences, Nucleic Acid/genetics ; Viral Proteins ; *Biomimetics/methods ; RNA-Binding Proteins/metabolism ; *Frontotemporal Dementia/genetics ; }, abstract = {In the motor neurons of amyotrophic lateral sclerosis (ALS) patients, excessive (G4C2)n repeats in the intronic region of the C9orf72 gene are transcribed to RNA, forming G-quadruplexes that sequester RNA-binding proteins, leading to gelation within the cytoplasm as one of the many mechanisms leading to pathogenesis. While ALS patients frequently harbor over 700 repeats, this kind of 100% GC-rich region is very difficult to clone, and past studies report the necessity to add additional sequences in the middle to clone more than a few dozen repeats. The goal of this study was the in vitro production of the longest repetitive RNA to date consisting solely of (G4C2)n repeats. T4 DNA ligase was used to connect (G4C2)10 stretches of DNA with 3nt overhangs. Then, using a heat-resistant T7 RNA polymerase, the RNA obtained contained transcripts over 100 repeats. Artificial biomimetic RNA gels generated by scaling up this synthesis method are expected to contribute to elucidating the molecular mechanisms of repetitive sequence-related pathogenesis, as well as screening for drugs that can disrupt the gel structure.}, } @article {pmid40605360, year = {2025}, author = {De Wel, B and Mobach, T and Pfeffer, G and Jewett, G}, title = {Tofersen Treatment Normalizes Neurofilament Levels in Autosomal Recessive SOD1 Amyotrophic Lateral Sclerosis.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-2}, doi = {10.1017/cjn.2025.10350}, pmid = {40605360}, issn = {0317-1671}, } @article {pmid40605510, year = {2025}, author = {Yeh, TS and Rotem, RS and Weisskopf, MG}, title = {Type 2 diabetes mellitus, antidiabetics, and the risk of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {775-783}, pmid = {40605510}, issn = {2167-9223}, support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; R21 NS099910/NS/NINDS NIH HHS/United States ; }, mesh = {Israel/epidemiology ; *Diabetes Mellitus, Type 2/drug therapy/epidemiology ; Case-Control Studies ; *Amyotrophic Lateral Sclerosis/epidemiology ; Risk Factors ; Protective Factors ; *Hypoglycemic Agents/therapeutic use ; Insulin/therapeutic use ; Humans ; Male ; Female ; Middle Aged ; Aged ; Follow-Up Studies ; Time Factors ; }, abstract = {Background: Research on the link between Type 2 Diabetes mellitus (T2DM) and amyotrophic lateral sclerosis (ALS) has produced mixed results. The potential role of antidiabetic medications in ALS etiology is also unclear. To contribute to these discussions, we aimed to examine the connections between T2DM, antidiabetic medications, and ALS using data from a large Israeli health fund. Methods: A total of 504 ALS cases diagnosed in 2002-2018 and 42,873 matched controls were considered in this population-based nested case-control study. T2DM was ascertained using diagnosis codes, laboratory test results, and medication use history, employing a 3-year lag from initial ALS diagnosis date to minimize chances for reverse causation. Multivariable-adjusted odds ratios (OR) were estimated for the association between T2DM, antidiabetic medications, and ALS. Results: T2DM overall was not linked with ALS (multivariable-adjusted odds ratio (OR) = 0.94, 95% confidence interval (CI): 0.72-1.23). However, T2DM with a history of insulin use showed a protective association with ALS (OR = 0.29; 95% CI = 0.09-0.92) compared to the non-T2DM group. A similar trend of protective associations with ALS was observed for T2DM with history of use of other antidiabetic medications, but none were statistically significant, and all associations were further attenuated after adjusting for insulin use. Conclusions: We observe a potential protective effect of T2DM-linked insulin use on risk of ALS. Although caution is necessary due to the limited number of ALS cases with insulin exposure, the observed protective association may suggest a biological pathway worth exploring for future therapeutic development.}, } @article {pmid40605998, year = {2025}, author = {Qin, H and Hussain, L and Liu, Z and Yan, X and Awwad, FA and Butt, FM and Salaria, UA and Ismail, EAA}, title = {Optimizing deep learning models to combat amyotrophic lateral sclerosis (ALS) disease progression.}, journal = {Digital health}, volume = {11}, number = {}, pages = {20552076251349719}, pmid = {40605998}, issn = {2055-2076}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, poses a significant challenge for targeted treatment development. Accurate prediction of its progression is crucial for this endeavor.

METHODS: This study investigated deep learning methods for ALS progression prediction using the publicly available PRO-ACT dataset. Initially, machine learning models (XGBoost, LightGBM) and a deep learning sequential model were evaluated with default parameters, using R-squared (R2) and Root Mean Squared Error (RMSE) as performance metrics.

RESULTS: Notably, the deep learning model demonstrated superior predictive performance with default settings (RMSE: 4.565, R2: 0.716), followed by XGBoost (RMSE: 4.625, R2: 0.709) and LightGBM (RMSE: 4.596, R2: 0.716). Subsequently, hyperparameter optimization significantly enhanced the deep learning model's performance, achieving the highest prediction accuracy (RMSE: 4.511, R2: 0.718). Slight improvements were also observed for XGBoost (RMSE: 4.532, R2: 0.715) and LightGBM (RMSE: 4.551, R2: 0.716). Furthermore, the optimized XGBoost model demonstrated exceptional classification performance in distinguishing between bulbar and limb onset ALS, with a sensitivity of 100%, specificity of 97.44%, accuracy of 97.96%, F1-score of 95.96%, Matthews Correlation Coefficient (MCC) of 94.12%, and an Area Under the Curve (AUC) of 0.9550. Feature importance analysis with optimized XGBoost identified ZBTB2P1 as the most influential feature, followed by RNF181, with WASH9P being the least influential among the top eight.

CONCLUSIONS: These findings convincingly demonstrate the potential of optimized XGBoost and deep learning for ALS progression prediction and classification, particularly with optimized parameters. This approach offers significant potential for early risk stratification, personalized treatment planning, enhanced prognostic communication, diagnostic support, streamlined disease monitoring, and improved clinical decision-making, ultimately contributing to better patient outcomes and potentially reducing ALS-related mortality.}, } @article {pmid40606671, year = {2025}, author = {Zhan, X and Xuan, T and Chen, X and He, J and Ren, Y and Meng, Y and Chen, G and Li, H}, title = {Case Report: A case of ALS type 6 associated with a FUS gene variant and right limb muscle weakness and atrophy as the initial symptom.}, journal = {Frontiers in genetics}, volume = {16}, number = {}, pages = {1578249}, pmid = {40606671}, issn = {1664-8021}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons. This degeneration results in increasing muscle weakness, ultimately culminating in respiratory failure and death. Mutations in the fused in sarcoma (FUS) gene have been identified as a significant cause of ALS. Here, we present the case of a 40-year-old woman who exhibited right limb muscle weakness and atrophy as her initial symptom. Whole genome sequencing revealed a mutation in the FUS gene, specifically c.1450_1456delinsCCC (p.Tyr484Profs*44), leading to a diagnosis of ALS type 6 (ALS6). The c.1450_1456delinsCCC (p.Tyr484Profs*44) mutation is a frameshift mutation resulting from a non-triplet base deletion in the coding region of the FUS gene. This mutation is novel and has not been previously reported in China or internationally. Furthermore, the onset of muscle weakness and atrophy exclusively in the ipsilateral limb is very rare among ALS patients, and we have found no related reports. This case report aims to enhance medical professionals' understanding of the complexities associated with ALS caused by FUS gene mutations and the onset of ALS symptoms, thereby facilitating more accurate clinical diagnosis and treatment.}, } @article {pmid40607043, year = {2025}, author = {Doeleman, LC and de Jong, JFF and van Eeden, VGM and Schober, P and Hollmann, MW and van Schuppen, H}, title = {Airway management by ambulance nurses during out-of-hospital cardiac arrest.}, journal = {Resuscitation plus}, volume = {25}, number = {}, pages = {100999}, pmid = {40607043}, issn = {2666-5204}, abstract = {BACKGROUND: Adequate airway management in out-of-hospital cardiac arrest (OHCA) is crucial for ventilation and oxygenation. Advanced airway management with a supraglottic airway device (SAD) or endotracheal tube (ETT) follows bag-valve-mask (BVM) ventilation, with emergency front-of-neck access as a rescue-option. EMS protocols on airway management in OHCA have changed over the years and during the COVID-pandemic. This study assessed subsequent changes in airway management and the success of different strategies.

METHODS: An observational study was conducted with data from ARREST, 2019-2023. All consecutive adult OHCA patients who had resuscitation attempted by EMS were included. Patients were excluded if helicopter emergency medical services were involved. Changes in devices used intra-arrest and their first-pass success were analyzed.

RESULTS: The proportion of cases with an SAD attempt increased, and with an ETT decreased. The definitive airway device used was an SAD in 59% (95% CI: 57-60%), an ETT in 21% (95% CI: 19-22%), and BVM in 14% (95% CI: 13-15%). First pass success for ETT increased from 53% to 68%. Average SAD first pass success was 93%.

CONCLUSION: During cardiopulmonary resuscitation (CPR) by ambulance nurses, the use of SADs increased, and that of ETTs decreased. Although ETT first pass success improved, it was lower than the guideline-recommended standard for performing intubations prehospitally. First pass success for SAD was high. This adds support for current Dutch ambulance guidelines recommending an SAD for primary choice of advanced airway by EMS during CPR. However, improvement of intubation techniques and skills remain a necessity for selected OHCA patients.}, } @article {pmid40607624, year = {2026}, author = {Holdom, CJ and Williamson, JL and O'Reilly, G and Henderson, RD and Neville, S and Ngo, ST and Dick, TJM and Steyn, FJ}, title = {Lower-limb biomechanics in motor neuron disease: a joint-level perspective of gait disruption.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {44-54}, doi = {10.1080/21678421.2025.2523945}, pmid = {40607624}, issn = {2167-9223}, mesh = {Humans ; Biomechanical Phenomena/physiology ; Male ; Female ; *Motor Neuron Disease/physiopathology/complications ; Middle Aged ; *Lower Extremity/physiopathology ; Aged ; *Gait Disorders, Neurologic/etiology/physiopathology ; Range of Motion, Articular/physiology ; *Gait/physiology ; Ankle Joint/physiopathology ; }, abstract = {Background: Motor neuron disease (MND) profoundly impacts mobility, yet gait-specific dysfunctions due to MND remain poorly understood. Methods: We characterized lower-limb gait alterations in people living with MND (plwMND) using advanced biomechanical tools. Nine plwMND and nine non-neurodegenerative disease controls walked on an instrumented treadmill at self-selected speeds. Ground reaction forces and joint motions were measured to model lower-limb kinetics, kinematics, and energetics. Results: PlwMND had reduced forward propulsive (p < 0.001) and braking (p = 0.002) ground reaction forces. Ankle range of motion was 10.0 ± 3.1° lower (p = 0.035) with peak positive ankle moment and power 33% and 72% lower, respectively (both: p < 0.001), in plwMND compared to controls. Conclusions: These lower-limb impairments highlight the ankle as an early and critical locus of dysfunction, with distal weakness driving compensatory proximal strategies, increasing walking inefficiency and fatigue. Integrating biomechanical and clinical data offers new insights into gait disruption in MND, supporting the development of targeted, personalized interventions to maintain independent mobility.}, } @article {pmid40607881, year = {2025}, author = {Song, X and Wang, X and Hu, F and Liu, P and Liu, Z and Yi, J and Xu, R and Cao, W and Zhang, Y and Wang, J and Grecucci, A and Yi, X and Chen, BT}, title = {Association of Reduced Brain Metabolism With Motor Function and Survival in Amyotrophic Lateral Sclerosis Patients With Neurofilament Heavy (NEFH) Gene Mutation.}, journal = {European journal of neurology}, volume = {32}, number = {7}, pages = {e70261}, pmid = {40607881}, issn = {1468-1331}, support = {2021YFA0805202//National Key Research and Development Program of China/ ; 2020XJ88//Scientific research project of Xiangnan University/ ; 2024ZZTS0954//Fundamental Research Funds for Central Universities of the Central South University/ ; 2023JJ50382//Natural Science Foundation of Hunan Province/ ; D202303077714//Scientific research project of Hunan Provincial Health Commission/ ; //"The 14th Five-Year Plan" Application Characteristic Discipline of Hunan Province/ ; //the Aid Program for Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province, China/ ; 2021ZD0201803//Science and Technology Innovation 2030/ ; 82171431//Program of the National Natural Science Foundation of China/ ; 82371445//Program of the National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/mortality/diagnostic imaging ; Female ; Male ; Middle Aged ; *Neurofilament Proteins/genetics ; Mutation ; *Brain/metabolism/diagnostic imaging ; Aged ; Prospective Studies ; Adult ; Positron Emission Tomography Computed Tomography ; Fluorodeoxyglucose F18 ; Glucose/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that impairs both upper and lower motor neurons. Mutations in the neurofilament heavy (NEFH) gene are associated with a higher risk for ALS. This study aimed to evaluate the brain metabolism in patients with ALS and NEFH gene mutations (NEFH-ALS) and assess its correlation with emotional and cognitive changes.

METHODS: This prospective study enrolled 119 patients with ALS and 128 age- and gender-matched health controls. Study assessments included demographic data collection, questionnaires for motor function, cognition, and depression, and brain F-18 FDG PET/CT (18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT)) scan. Correlation between brain metabolism and clinical questionnaire scores was performed. Chain-mediation model analysis for the NEFH-ALS group was conducted. Cox regression and Kaplan-Meier survival analysis were also performed.

RESULTS: There were 26 NEFH-ALS patients. Patients with NEFH-ALS showed brain glucose hypometabolism in the cortex-striatum/limbic system-brainstem circuit when compared with healthy controls (p < 0.05). Decreased brain glucose metabolism was correlated with impairments of motor function (r = 0.477, p = 0.014, FDR corrected p = 0.014), cognitive scores (r = 0.549, p = 0.004, FDR corrected p = 0.009), and depression (r = -0.523, p = 0.009, FDR corrected p = 0.009). This study showed that brain glucose hypometabolism could lead to impairment of motor function, which was mediated by cognition and depression. Survival analysis showed that brain glucose metabolism was an independent prognostic factor for patients with ALS.

CONCLUSIONS: Reduced brain glucose metabolism in the cortex-striatum/limbic system-brainstem circuit may potentially serve as an independent prognostic factor for patients with ALS and NEFH mutation.}, } @article {pmid40607987, year = {2025}, author = {Collins, M and Kwapiszeski, H and An, J and Garcia, D and Peller, D and Ladha, S and Bowser, R and Bakkar, N}, title = {Transthyretin abnormalities in amyotrophic lateral sclerosis: High molecular weight species in cerebrospinal fluid and stromal deposits in choroid plexus.}, journal = {Journal of neuropathology and experimental neurology}, volume = {84}, number = {11}, pages = {1022-1035}, pmid = {40607987}, issn = {1554-6578}, support = {R01 NS061867/GF/NIH HHS/United States ; F31 NS080614/NH/NIH HHS/United States ; R01 NS061867/NS/NINDS NIH HHS/United States ; //Barrow Neurological Foundation/ ; //Achievement Rewards for College Scientists Foundation, Inc. Pittsburgh Chapter/ ; F31 NS080614/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/pathology/metabolism ; *Prealbumin/cerebrospinal fluid/metabolism/genetics ; *Choroid Plexus/metabolism/pathology ; Female ; Male ; Middle Aged ; Aged ; Molecular Weight ; Adult ; Aged, 80 and over ; }, abstract = {Transthyretin (TTR) is a plasma and cerebrospinal fluid (CSF) protein involved in transporting thyroid hormone and retinol, with additional roles in the central nervous system (CNS). The tetrameric structure of TTR is essential for its functions and tetramer dissociation and aggregation into pathological amyloid fibrils is implicated in multiple diseases. Altered levels of TTR have previously been described in amyotrophic lateral sclerosis (ALS) in both CSF and CNS tissue. However, whether altered TTR levels in ALS reflect TTR pathology in CSF or in the choroid plexus (CP) cells that synthesize CNS TTR is unknown. Here, we comprehensively assayed native and aggregated TTR in ALS patient CSF and postmortem ALS CP. Using a nondenaturing native polyacrylamide gel electrophoresis-based assay, we identified high molecular weight TTR aggregates in the CSF of ALS patients. We also observed increased levels of TTR RNA and protein in ALS CP, as well as TTR granule deposits in CP stroma of ALS but not control cases. Taken together, our results reveal new forms of TTR dysfunction in ALS and uncover TTR-related morphological abnormalities in the CP in ALS patients.}, } @article {pmid40608121, year = {2025}, author = {Ruzi, Z and Zha, W and Yuan, HY and Liu, J}, title = {RNA G-quadruplexes: emerging regulators of gene expression and therapeutic targets.}, journal = {Functional & integrative genomics}, volume = {25}, number = {1}, pages = {143}, pmid = {40608121}, issn = {1438-7948}, support = {22262002//National Natural Science Foundation of China/ ; }, mesh = {*G-Quadruplexes ; Humans ; *Gene Expression Regulation ; *RNA/chemistry/genetics/metabolism ; Animals ; Neoplasms/genetics ; SARS-CoV-2 ; Neurodegenerative Diseases/genetics ; Alternative Splicing ; }, abstract = {RNA G-quadruplexes (rG4s) are non-canonical, four-stranded secondary structures formed by guanine-rich RNA sequences. These dynamic elements have garnered significant attention for their critical roles in regulating gene expression, including translation, alternative splicing, mRNA localization, and stability. This review synthesizes recent progress in understanding the structural determinants and formation dynamics of rG4s, highlighting the contributions of sequence motifs, ionic conditions, and RNA-binding proteins to their stability and function. Functional studies reveal that rG4s modulate key oncogenic transcripts (e.g., MYC, BCL2), contribute to splicing regulation, and influence intracellular RNA trafficking. In pathological contexts, rG4s have been implicated in the molecular etiology of cancers, neurodegenerative diseases such as amyotrophic lateral sclerosis and Fragile X syndrome, and viral replication mechanisms in pathogens including HIV and SARS-CoV-2. Advances in high-throughput techniques, such as G4-seq, rG4-seq, and live-cell imaging, have facilitated the global identification and characterization of rG4s in physiological and disease settings. Moreover, the therapeutic targeting of rG4s using small molecules holds promise for selective gene regulation and biomarker development. Comparative analyses across in vitro, in vivo, and clinical studies underscore the cell-type-specific and context-dependent roles of rG4s, especially in mediating stress responses and apoptosis. Despite methodological limitations and challenges in achieving targeted delivery, rG4s represent a compelling frontier for precision medicine. This review outlines current insights and future directions toward harnessing rG4 biology for therapeutic innovation.}, } @article {pmid40608189, year = {2025}, author = {Sharma, VK}, title = {Dysbiosis and Neurodegeneration in ALS: Unraveling the Gut-Brain Axis.}, journal = {Neuromolecular medicine}, volume = {27}, number = {1}, pages = {50}, pmid = {40608189}, issn = {1559-1174}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/microbiology/therapy ; *Dysbiosis/complications/physiopathology/therapy ; *Gastrointestinal Microbiome/physiology ; Animals ; *Brain-Gut Axis/physiology ; *Brain/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disorder marked by the progressive degeneration of motor neurons in the brain and spinal cord. Despite decades of research, ALS remains incurable, diagnostically elusive, and is accompanied by rapid clinical decline, morbidity, and mortality. Its pathophysiology involves a complex interplay of genetic mutations (SOD1, C9/f72), environmental triggers, oxidative stress, neuroinflammation, and the accumulation of misfolded proteins, such as TDP-43 and SOD1. These factors disrupt cellular homeostasis aggravates excitotoxicity and neuronal death. Existing treatments, such as riluzole (a glutamate release modulator) and edaravone (a free radical scavenger), offer limited benefits, modestly prolonging survival or slowing functional decline without halting progression. Investigational approaches include antisense oligonucleotides targeting mutant SOD1 or C9orf72 genes, stem cell-based motor neuron replacement, and biomarker discovery to enable earlier diagnosis and progression monitoring. ALS patients frequently exhibit gastrointestinal (GI) symptoms, including dysphagia, sialorrhea, constipation, delayed gastric emptying, and pancreatic/parotid deficiencies. These observations underscore a close association between GI dysfunction and ALS pathogenesis. Also, recent studies implicate the gut-brain-microbiota axis in disease evolution, with microbial metabolites influencing neuroimmune interactions, synaptic plasticity, myelination, and skeletal muscle function. These studies indicate that dysbiosis-an imbalance in gut microbiota-may have a crucial role in ALS progression by impairing intestinal barrier integrity, promoting endotoxemia, and driving systemic inflammation. Conversely, ALS progression itself worsens dysbiosis, creating a vicious cycle of neuroinflammation and neurodegeneration. Preclinical and clinical evidence suggests that interventions targeting gut microbiota-such as prebiotics, probiotics, antibiotics, or phage therapy-could alleviate symptoms and slow disease progression and specific probiotic strains have also shown promise in reducing oxidative stress and inflammation in animal models. These findings highlight the urgent need to elucidate the functional role of gut microbiota in ALS to unlock novel diagnostic and therapeutic avenues. This review synthesizes current knowledge on the pathophysiology of ALS, with a focus on the emerging role of the gut-brain-microbiota axis. It highlights how dysbiosis influences diverse disease markers and neurodegenerative mechanisms, offering insights into potential therapeutic strategies and identifying key research gaps and future directions.}, } @article {pmid40609398, year = {2025}, author = {Yazdanian, T and Azimi, P and Babu, S}, title = {Cervical spinal cord MRI in ALS individuals: a systematic review and meta-analysis.}, journal = {NeuroImage. Clinical}, volume = {47}, number = {}, pages = {103832}, pmid = {40609398}, issn = {2213-1582}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Cervical Cord/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; Diffusion Tensor Imaging ; }, abstract = {BACKGROUND: Disease tracking and prognostication of amyotrophic lateral sclerosis (ALS) can be quite challenging in people living with ALS, due to the complexity of central nervous system disease biology. This systematic review and meta-analysis aim to summarize cervical spinal cord quantitative MRI (qMRI) biomarker changes in individuals with ALS.

METHODS: PubMed, Scopus, Cochrane Library, and Web of Science databases were searched up to August 2023. The terms used were "ALS", "cervical spinal cord", "MRI"," diffusion tensor imaging (DTI)", " fractional anisotropy (FA)", " mean diffusivity (MD) "," magnetization transfer ratio (MTR)", " cross-sectional area (CSA)", " radial diffusivity (RD) ", and " atrophy ". The Newcastle-Ottawa scale (NOS) was used to assess study quality. We calculated the pooled: 1) Standardized mean difference (SMD) and 95% CIs for comparative assessment of qMRI parameters in ALS individuals and the healthy population. 2) Estimate the mean of qMRI parameters for normative values in two groups by CMA software. Heterogeneity and publication bias were determined by the I-squared statistic and funnel plots.

RESULTS: Thirty studies, with 1817 participants (35.9 % female) were included in this review, and 29 had a NOS ≥ 5 which indicates high-quality of data overall. The SMD analysis showed (a) significant decrease in CSA along the whole length of cervical cord (C1-C7) (p value < 0.0001), with a preferential thinning of the cervical enlargement region (C4-C6 region) (p value < 0.0001) (b) significant decrease in FA (p value < 0.0001), particularly FA left lateral corticospinal tract (p value < 0.0001) and (c) a significant increase in MD (p value < 0.0001) in ALS individuals compared to controls. The pooled analysis reveals that the mean (SD) values for ALS individuals versus controls for (a) CSA (in mm[2]) were C1 [73.4 (0.75), 78.5 (0.67), 6.9 % difference]; C2 [70.6 (3.1), 71.5 (3.5), 1.2 % difference]; C3 [69.8(1.5), 74.9 (1.9), 7.3 % difference]; C4 [71.9 (1.8), 77.6 (2.8), 7.9 % difference]; C5 [71.8 (2.5), 79.5 (3.3), 10.7 % difference]; C6 [66.8 (2.7), 73.7 (3.7), 10.3 % difference]; C7 [56.7 (F2.2), 62.1 (2.5), 9.5 % difference]; (b) FA [0.54 (0.03), 0.56 (0.03)]; (c) MD[1.11 (0.18), 0.88(0)]; and (d) FA LLCST [ 0.65 (0.04), 0.77 (0.04)], respectively. The mean (SD) value of the MTR and RD for ALS individuals was 40.3 (2.3), and 0.70 (0.0).

CONCLUSIONS: qMRI metrics of spinal cord show discriminatory potential between ALS and healthy controls. The selective atrophy of the cervical enlargement (C4-C6) is replicable across multiple studies as seen in this metanalysis and hence is a potential imaging marker for quantifying and tracking lower motor neuron degeneration in ALS.}, } @article {pmid40609634, year = {2025}, author = {Lukianenko, N and Kang, DM and Bekci, A and Kim, YK and Lim, S}, title = {Nucleocytoplasmic HDAC Inhibition Drives Acetylation-dependent TDP-43 Mislocalization and Disulfide-linked Oligomerization.}, journal = {Journal of molecular biology}, volume = {437}, number = {19}, pages = {169318}, doi = {10.1016/j.jmb.2025.169318}, pmid = {40609634}, issn = {1089-8638}, mesh = {Humans ; Acetylation/drug effects ; *Histone Deacetylase Inhibitors/pharmacology ; *Disulfides/metabolism ; *DNA-Binding Proteins/metabolism/chemistry ; *Histone Deacetylases/metabolism ; *Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Protein Multimerization/drug effects ; HEK293 Cells ; }, abstract = {TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), are characterized by aberrant cytoplasmic mislocalization and aggregation of TDP-43. Here, we established a live-cell TDP43-BiFC model to visualize TDP-43 oligomerization in real time and screened diverse cellular stressors. Histone deacetylase (HDAC) inhibition emerged as the most potent trigger of TDP-43 oligomerization. In particular, selective inhibition of the shuttling HDAC4/5 with LMK-235 induced an early and robust formation of cytoplasmic TDP-43 oligomers, comparable to or even exceeding the effect of the pan-HDAC inhibitor apicidin. In contrast, nuclear-restricted HDAC1/3 inhibition by MS-275 prolonged TDP-43 retention in the nucleus with minimal cytoplasmic mislocalization or oligomerization, underscoring distinct roles for nuclear versus nucleocytoplasmic HDACs. Inhibition of cytoplasmic HDAC6 (tubastatin A) had no significant effect. Notably, both shuttling and pan-HDAC inhibition increased TDP-43 acetylation and promoted the accumulation of stable, disulfide-linked TDP-43 oligomers. These findings identify lysine acetylation as a key regulator of disulfide bond-dependent TDP-43 oligomerization and suggest that targeting nucleocytoplasmic HDACs could be a novel therapeutic strategy in TDP-43 proteinopathies.}, } @article {pmid40610071, year = {2025}, author = {Selvaraj, C and Vijayalakshmi, P and Desai, D and Manoharan, J}, title = {Proteostasis imbalance: Unraveling protein aggregation in neurodegenerative diseases and emerging therapeutic strategies.}, journal = {Advances in protein chemistry and structural biology}, volume = {146}, number = {}, pages = {1-34}, doi = {10.1016/bs.apcsb.2024.11.008}, pmid = {40610071}, issn = {1876-1631}, mesh = {Humans ; *Proteostasis ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Autophagy ; *Protein Aggregation, Pathological/metabolism/therapy/pathology ; *Protein Aggregates ; }, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are defined by the accumulation of misfolded and aggregated proteins, which impair cellular function and result in progressive neuronal death. This chapter examines the critical function of proteostasis-cellular protein homeostasis-in sustaining neuronal health and its disruption as a key factor in disease progression. Proteostasis is upheld by a complex array of mechanisms, which encompass molecular chaperones, the ubiquitin-proteasome system, autophagy-lysosomal pathways, and mitochondrial quality control. Impairment of these systems leads to protein misfolding and aggregation, resulting in toxic cellular environments that promote neurodegeneration. Novel therapeutic approaches focus on restoring proteostasis through the enhancement of cellular protein folding, degradation, and clearance mechanisms. This encompasses small molecule chaperones, gene therapy, RNA-based treatments, immunotherapy, autophagy inducers, and stem cell-based approaches, each addressing distinct components of the proteostasis network to mitigate or prevent disease progression. While these therapies show potential, challenges persist, such as possible side effects, selective targeting, and the efficacy of blood-brain barrier penetration. Personalized medicine and combination therapies customized to specific disease profiles are increasingly recognized for their potential to improve efficacy and safety. This chapter consolidates recent developments in therapies aimed at proteostasis, addresses the challenges encountered in clinical applications, and outlines potential future directions for transformative treatments. Ongoing research indicates that proteostasis modulation may significantly alter the course of neurodegenerative disease treatment, potentially enhancing patient outcomes and quality of life.}, } @article {pmid40610146, year = {2025}, author = {Olivieri, AC}, title = {Hazards of using multivariate curve resolution for processing first-order spectral data. A rotational ambiguity analysis.}, journal = {Analytica chimica acta}, volume = {1367}, number = {}, pages = {344304}, doi = {10.1016/j.aca.2025.344304}, pmid = {40610146}, issn = {1873-4324}, abstract = {BACKGROUND: A growing number of reports are discussing the use of multivariate curve resolution - alternating least-squares (MCR-ALS) to process matrices built with first-order data, e.g., spectra. Although the results are promising, almost no complementary analysis of the impact of rotational ambiguity on the obtained solutions has been reported.

RESULTS: Several experimental data sets involving spectra (near infrared, UV-visible absorption, fluorescence emission) were processed with MCR-ALS, and then analyzed with channel-wise N-BANDS regarding the presence of rotational ambiguity. In cases of low spectral overlapping, almost unique profiles were found in the retrieved analyte concentration profiles. In cases of high spectral overlapping, however, substantial ambiguity was estimated in the analyte concentration profiles, making the analytical results less reliable. This is even more pronounced when uncalibrated components occur in the test samples. Channel-wise N-BANDS calculations agreed with the results from randomly initialized MCR-ALS models.

SIGNIFICANCE: Researchers using MCR-ALS in multivariate calibration protocols based on first-order data should always accompany the decomposition results with a rotational ambiguity analysis. This would provide insight into the reliability of the retrieved profiles, the estimation of the analyte concentrations and the qualitative interpretation of the spectra.}, } @article {pmid40610342, year = {2025}, author = {Trubshaw, M and Yoganathan, K and Gohil, C and Stagg, CJ and Nobre, AC and Talbot, K and Woolrich, M and Thompson, AG and Turner, MR}, title = {Gamma activation spread reflects disease activity in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {177}, number = {}, pages = {2110823}, pmid = {40610342}, issn = {1872-8952}, support = {203139/WT_/Wellcome Trust/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; NIHR203316/DH_/Department of Health/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; Magnetoencephalography/methods ; Aged ; *Gamma Rhythm/physiology ; Hand Strength/physiology ; Adult ; *Motor Cortex/physiopathology ; Disease Progression ; }, abstract = {OBJECTIVE: A non-invasive measure of cerebral motor system dysfunction would be valuable as a biomarker in amyotrophic lateral sclerosis (ALS). Task-based magnetoencephalography (tMEG) measures the magnetic fields generated by cortical neuronal oscillatory activity during task performance. Gamma activations are periods of high-power and high-frequency cortical oscillations integral to motor control.

METHODS: tMEG was undertaken during 60 bilateral isometric hand grip exercises in ALS (n = 42) and compared with healthy controls (HC, n = 33). Gamma activation spread (GAS) was estimated by calculating the number of activated regions during each 100 ms time-bin and compared statistically between groups. Gamma activation patterns were visualised by plotting each participant's brain activity separately as a 2-dimensional video.

RESULTS: There was no difference in grip strength between groups. GAS was greatly increased in the ALS group compared to HC (p < 0.001) and correlated positively with rate of ALSFRS-R progression (t = 1.35, p = 0.023) and a fine motor sub-score (t = -1.18, p = 0.047).

CONCLUSIONS: ALS was associated with a marked increase in regional spread of gamma frequency activation, greater in those with higher disease progression rates.

SIGNIFICANCE: The regional spread of gamma activity may reflect disease activity in ALS, with potential application as an experimental medicine readout.}, } @article {pmid40611592, year = {2025}, author = {DuVal, MG and Noga, T and Beecher, G}, title = {Long-Term Tofersen and CSF Macrophage Inclusions in Superoxide Dismutase 1 Amyotrophic Lateral Sclerosis.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-3}, doi = {10.1017/cjn.2025.10351}, pmid = {40611592}, issn = {0317-1671}, } @article {pmid40612293, year = {2025}, author = {Bayleyegn Derso, T and Mengistu, BA and Demessie, Y and Fenta, MD and Getnet, K}, title = {Neural stem cells in adult neurogenesis and their therapeutic applications in neurodegenerative disorders: a concise review.}, journal = {Frontiers in molecular medicine}, volume = {5}, number = {}, pages = {1569717}, pmid = {40612293}, issn = {2674-0095}, abstract = {The idea of using stem cell therapy to treat neurodegenerative diseases has undergone significant change over the years and has made significant progress recently. Neurotrophins, growth factors, and transcription factors regulate neural stem cell proliferation and differentiation. Disruption of these regulatory mechanisms, including negative feedback, can contribute to neurodegenerative diseases. Contemporary research highlights a growing global concern regarding diverse neurodegenerative disorders affecting both humans and animals. These conditions arise from neuronal cell death, axonal regeneration failure, and impairment of neuronal structure. Current pharmacological treatments primarily offer symptomatic relief without altering disease progression. Consequently, researchers are investigating innovative therapeutic strategies, with neural stem cell therapy emerging as a promising avenue. Adult neural stem cells, embryonic neural stem cells, and induced pluripotent stem cells represent potential cell sources, although challenges such as ethical considerations and technical limitations remain. The therapeutic application of neural stem cells holds significant promise for addressing neurodegenerative diseases, including Alzheimer's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, and multiple sclerosis. Neural stem cell therapy aims to replenish lost neurons and promote neural regeneration in these conditions. While clinical trials have demonstrated some success in improving cognitive and motor functions in individuals with neurodegenerative impairments, challenges such as immunological rejection, the identification of compatible cell sources, ethical concerns, treatment efficacy, and potential side effects necessitate thorough investigation before widespread clinical implementation. Despite these challenges, neural stem cell-based therapy offers substantial potential for revolutionizing the treatment of neurodegenerative diseases and central nervous system injuries. This paper, therefore, explores adult neurogenesis and the therapeutic potential of neural stem cells within the dynamic field of neurodegenerative disorders.}, } @article {pmid40612333, year = {2025}, author = {Rossip, MG and Hastings, J and Burwinkel, H and Lavrova, E and Steinbrenner, R and Bensaid, N and Cooke, DL and Pantanelli, SM}, title = {Relative Behavior of Modern Intraocular Lens Power Calculation Formulas Across a Realistic Range of Biometry Values.}, journal = {Clinical ophthalmology (Auckland, N.Z.)}, volume = {19}, number = {}, pages = {2037-2045}, pmid = {40612333}, issn = {1177-5467}, abstract = {PURPOSE: To investigate the relative performance of modern intraocular lens (IOL) power calculation formulas over a wide range of biometric parameters.

PATIENTS AND METHODS: Through the concept of emmetropization there exists a mean keratometry, anterior chamber depth, lens thickness, and white-to-white for a given axial length (AL). Using a database of biometric values from 2721 surgery naïve eyes, these relationships were modeled and used to create an artificial dataset of 170 eyes with an anatomically realistic distribution of biometric parameters. Biometric values for each artificial eye were entered into the ESCRS IOL power calculation website. The emmetropic IOL power was calculated for Barrett Universal II, Cooke K6, Kane, PEARL-DGS, HofferQST, EVO v2.0, and Hill-RBF v3.0. Separately, emmetropic IOL powers were calculated for the Zeiss AI formula. The disparity between the formulas was evaluated to determine the ALs at which they diverged.

RESULTS: For eyes with ALs between 22.5 and 28.1 mm, emmetropic IOL powers and spherical equivalent predictions differed by less than 0.25 D. Outside this range, spherical equivalent predictions differed by 0.25 D or more. At ALs < 19.5 mm the difference in emmetropic IOL power across the formulas exceeded 1.0 D.

CONCLUSION: This work helped to identify an implementation error in Pearl-DGS, which was corrected in collaboration with the formula's author. Cataract surgeons should consider that formula choice still has a clinically meaningful impact on refractive outcomes in eyes with axial lengths of <22.5 mm and >28.1 mm. We estimate that this may represent more than 10% of the population.}, } @article {pmid40613809, year = {2025}, author = {Veenstra, J and Ozog, D and Ghosh, S}, title = {Response to Yang et al's "A Disproportionality Analysis on Benzoyl Peroxide and Its Risk of Malignancy Using the FDA Adverse Event Reporting System".}, journal = {The Journal of investigative dermatology}, volume = {145}, number = {12}, pages = {3199-3201}, doi = {10.1016/j.jid.2025.05.025}, pmid = {40613809}, issn = {1523-1747}, } @article {pmid40613930, year = {2026}, author = {Qi, Y and Xu, J and Wang, Y and Gao, Y and Sun, Z and Deng, Z and Shao, Y and Li, P and Nieland, JDV}, title = {Changes of Sonic Hedgehog mediated FAK/ERK pathway proteins in amyotrophic lateral sclerosis model mice.}, journal = {Psychopharmacology}, volume = {243}, number = {1}, pages = {145-156}, pmid = {40613930}, issn = {1432-2072}, support = {202303021221206//Shanxi Provincial Key Research and Development Project/ ; 2024-148//Shanxi Provincial Education Department/ ; 2024ZYY2B050//Health Commission of Shanxi Province/ ; }, mesh = {Animals ; *Hedgehog Proteins/metabolism/agonists ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Spinal Cord/metabolism/pathology ; *Focal Adhesion Kinase 1/metabolism ; *Extracellular Signal-Regulated MAP Kinases/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Muscle, Skeletal/metabolism/pathology ; Humans ; Signal Transduction ; Male ; Motor Neurons/metabolism ; *MAP Kinase Signaling System/physiology ; }, abstract = {Sonic Hedgehog (SHH) has been shown to be cytoprotective against oxidative stress in a cellular model of amyotrophic lateral sclerosis, and it may support the proliferation and differentiation of endogenous stem cells along the motor neuron lineage and stimulate motor neuron growth and axon formation. However, there is less validation of the role of SHH in a mouse model of amyotrophic lateral sclerosis(ALS). In hSOD1G93A transgenic mice, we found that the expression of SHH, FAK, ERK, p-FAK, and p-ERK was progressively decreased in the spinal cord tissue of hSOD1 mice over time from Western Blot and immunohistochemistry. And compared to the hSOD1 control group, the SHH, FAK, ERK, p-FAK, p-ERK protein levels increased by stimulating SHH with an agonist, while SHH, FAK, p-FAK protein decreased significantly by inhibiting SHH. And the HE staining results of mouse gastrocnemius muscle showed that the agonist group had an increased muscle morphology and more muscle fibers, while the inhibitor group had an atrophied muscle morphology and fewer muscle fibers, than the hSOD1 control group. This confirmed the upstream-downstream relationship among SHH, FAK, and ERK in the spinal cord tissues of hSOD1 mice. Western blot analysis of ERK and p-ERK and immunohistochemical staining revealed declining ERK protein expression in hSOD1 mice, which progressively decreased over time. PUR increased ERK expression, whereas CYC had no significant effect on its reduction. So PUR can activate SHH protein and enhance the function of FAK/ERK. SHH is suggested to play a protective role in the muscle tissue of hSOD1 mice through the FAK/ERK pathway.}, } @article {pmid40614474, year = {2025}, author = {Montenegro, MF and Morales, JMN and Morán Vieyra, FE and Borsarelli, CD}, title = {Eco-friendly synthesis of a silver nanohybrid with carbon dots derived from Quebracho Colorado leaves and its application in the colorimetric detection of Al[3].}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {343}, number = {}, pages = {126628}, doi = {10.1016/j.saa.2025.126628}, pmid = {40614474}, issn = {1873-3557}, abstract = {The Schinopsis lorentzii tree leaves were utilized for the first time in the production of carbon dots (CDs) with a diameter of 6 nm through hydrothermal carbonization at 200 °C. The heating of AgNO3 aqueous solutions up to 70 °C in the presence of CDs results in the formation of silver nanohybrids (AgNP@CDs), with a zeta potential of -48 mV, a diameter of 33 nm, and a surface plasmon resonance (SPR) absorption band centered at 440 nm. Among the various cations examined, only the incorporation of Al[3+] in the AgNP@CDs solution induced a color shift from yellow to brown, leading to the formation of colloidal aggregates with an approximate diameter of 550 nm. The formation of AgNP@CDs nanohybrids and aggregates in the absence and presence of Al[3+], respectively, was modeled by combining UV-vis absorption spectra with multivariate curve resolution-alternating least squares (MCR-ALS) analysis. For the AgNP@CDs, a sequential nucleation-aggregation mechanism was observed, with a global activation energy of 28 kJ/mol. In the presence of Al[3+], a four-species sequential mechanism describes the progressive formation of larger aggregates, with dose-response curves that are characteristic of highly cooperative binding equilibriums with an average global binding constant of 7 × 10[4] M[-1]. The analytical performance of the AgNP@CDs resulted in a sensitivity of 0.03 μM, a linear range between 10 and 20 μM, and a limit of detection of 3.5 μM. These parameters are consistent with those previously reported for the colorimetric determination of Al[3+] using AgNPs capped with different molecules.}, } @article {pmid40614501, year = {2025}, author = {Yu, H and Wang, C and Phuntsho, S and He, T and Naidu, G and Han, DS and Shon, HK}, title = {Highly selective lithium recovery from seawater desalination brine using Li2TiO3 membrane-coated capacitive deionization.}, journal = {Water research}, volume = {285}, number = {}, pages = {124113}, doi = {10.1016/j.watres.2025.124113}, pmid = {40614501}, issn = {1879-2448}, mesh = {*Lithium/isolation & purification/chemistry ; *Seawater/chemistry ; *Titanium/chemistry ; *Water Purification/methods ; *Membranes, Artificial ; Electrodes ; Salts/chemistry ; Adsorption ; }, abstract = {Selective lithium (Li) recovery from seawater-based resources is challenged by low Li concentrations and the presence of competing ions such as Na[+], K[+], Mg[2+], and Ca[2+]. This study presents an innovative approach by integrating capacitive deionization (CDI) with a titanium-based lithium-ion sieve (LIS) membrane-coated cathode and an anion exchange membrane (AEM)-coated anode for enhanced Li recovery from seawater desalination brine (SWDB). The cathode was fabricated using Li2TiO3 (LTO) adsorbent through rolling pressing and dip coating methods. Characterization confirmed the successful fabrication of the LTO membrane-coated electrode. The performance of the LTO-AEM-CDI system was evaluated using simulated SWDB through an adsorption-rinsing-desorption operational mode. The results indicated that the rinsing stage plays a crucial role in significantly enhancing Li selectivity. A 10-cycle stability test demonstrated the system's reliability, maintaining the active Li selectivity (ALS) consistently above 100 across all cycles. This research highlights the potential of combining LIS, membrane technologies, and CDI for effective Li extraction from seawater-based resources.}, } @article {pmid40614636, year = {2025}, author = {Hirayama, T and Nagasawa, J and Shibukawa, M and Morioka, H and Yokoyama, T and Tsuda, H and Bokuda, K and Ogino, M and Takao, H and Morita, M and Takahashi, Y and Nakamura, R and Atsuta, N and Urushitani, M and Yamanaka, K and Izumi, Y and Kano, O}, title = {Survey research on the awareness and usage of accessibility features of information and communication technology devices among patients with amyotrophic lateral sclerosis.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {139}, number = {}, pages = {111434}, doi = {10.1016/j.jocn.2025.111434}, pmid = {40614636}, issn = {1532-2653}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Middle Aged ; Male ; Female ; Aged ; Surveys and Questionnaires ; Caregivers/psychology ; *Communication Devices for People with Disabilities ; *Awareness ; Adult ; *Information Technology ; }, abstract = {We aimed to explore perceptions of digital technology and the usage of information and communication technology (ICT) devices among patients with amyotrophic lateral sclerosis (ALS) and their caregivers. In October 2023, we held a nationwide webinar titled "ALS Café" and distributed a self-report questionnaire to patients with ALS and caregivers, including family members, which covered topics such as awareness, usage of accessibility features, and current support for the use of ICT devices. Thirty-one patients with ALS and 24 of their caregivers responded (average age: 57.1 ± 10.1). The ALS Functional Rating Scale-Revised (ALSFRS-R) score was 26.6 ± 14.1. Overall, 69.6 % of respondents were aware of accessibility features, 71.4 % of those under 70, and 50.0 % of those over 70. Frequently used features included browsing assistance (32.1 %), voice operation (30.4 %), mouse or touch pen operation (26.8 %), synthesized voice reading (23.2 %), gaze input operation (19.6 %), and switch operation (14.3 %). Self-help assistance for ICT devices was used by 65.8 % of respondents with an ALSFRS-R score ≥ 20 and 11.8 % with an ALSFRS-R score < 20. Regarding government services, 85 % of respondents were unaware of ICT support centers for persons with disabilities. This study revealed the awareness and usage of accessibility features of ICT devices among patients with ALS and their caregivers. Raising awareness of accessibility features among older adults and improving support systems for those with mild symptoms are necessary.}, } @article {pmid40614949, year = {2025}, author = {Sarkar, SK and Gubert, C and Hannan, AJ}, title = {The microbiota-inflammasome-brain axis as a pathogenic mediator of neurodegenerative disorders.}, journal = {Neuroscience and biobehavioral reviews}, volume = {176}, number = {}, pages = {106276}, doi = {10.1016/j.neubiorev.2025.106276}, pmid = {40614949}, issn = {1873-7528}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/immunology/microbiology ; *Inflammasomes/metabolism/immunology ; *Gastrointestinal Microbiome/physiology ; Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Brain/metabolism/immunology ; *Receptors, Purinergic P2X7/metabolism ; }, abstract = {In various neurodegenerative disorders, inflammation and associated inflammasome activation play an important role. The most prevalent and extensively researched inflammasomes are NLRP3 inflammasomes, which are triggered by pathogens or danger signals mediating inflammatory reaction. Extracellular ATP also activates NLRP3 by stimulating the purinergic receptor P2X7 (P2X7R). Central and peripheral cells, including those in the gut, have been shown to have activated inflammasomes during pathological changes co-occurring with inflammation in various neurodegenerative disorders. Gut injury or dysfunction is increasingly recognised as one of the peripheral pathogenic characteristics of many neurodegenerative disorders, and has been found to associate with changes in gut microbes. In this article, we review data from preclinical and clinical studies regarding the involvement of the NLRP3 inflammasome and the purinergic receptor P2X7R in the pathophysiology of major CNS disorders involving neurodegeneration, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), and the most common form of motor neuron disease, amyotrophic lateral sclerosis (ALS). We also scrutinise the relationship of the NLRP3 inflammasome to intestinal microbiota alterations in these diseases. Both the NLRP3 inflammasome and P2X7R have been shown to play important roles in the pathogenesis and progression of these neurodegenerative diseases. However, most studies have focused on central nervous system (CNS) pathology, particularly within the brain, with comparatively less attention given to their contribution to gut pathology. Additionally, changes in the microbial ecosystems of the intestine have also been implicated in these disorders. However, the association between gut microbiota alterations and inflammasome activity in the pathology of these neurodegenerative disorders remains poorly understood. Therefore, further investigation is urgently needed to explore the microbiota-inflammasome-brain axis in these neurodegenerative conditions, in order to better understand their contribution to disease pathogenesis and progression, and identify novel therapeutic targets and new approaches to prevention and treatment.}, } @article {pmid40615926, year = {2025}, author = {Chen, C and Zhu, S and Zheng, Z and Ding, X and Shi, W and Xia, T and Gu, X}, title = {A Genome-wide study on the genetic and causal effects of smoking in neurodegeneration.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {743}, pmid = {40615926}, issn = {1479-5876}, support = {82171193//Natural Science Foundation for Young Scientists of Shanxi Province/ ; ZDXK202232//Jiangsu Provincial Medical Key Discipline/ ; }, mesh = {Humans ; *Genome-Wide Association Study ; *Smoking/adverse effects/genetics ; *Genetic Predisposition to Disease ; *Neurodegenerative Diseases/genetics ; Mendelian Randomization Analysis ; Parkinson Disease/genetics ; Risk Factors ; Alzheimer Disease/genetics ; Causality ; Linkage Disequilibrium/genetics ; Polymorphism, Single Nucleotide/genetics ; }, abstract = {BACKGROUND: Smoking represents the largest preventable risk factor for human health, yet previous studies have failed to establish conclusive evidence regarding the causal relationship between smoking and neurodegenerative diseases. This study employs genetic correlation and Mendelian randomization analyses to investigate the potential association between smoking and neurodegenerative disorders.

METHODS: This study analyzed summary data from genome-wide association studies (GWAS) on smoking and neurodegenerative diseases. Genetic correlations were evaluated using linkage disequilibrium score regression (LDSC), and causal relationships were assessed through multiple Mendelian randomization methods including inverse-variance weighted (IVW), MR-Egger regression, weighted median (WME), weighted mode (WM), and simple mode (SM). sensitivity analyses were performed to examine heterogeneity, horizontal pleiotropy, and conduct leave-one-out analysis.

RESULTS: whether an individual had ever smoked regularly (SmkInit) is positively correlated with an increased risk of Alzheimer's disease (AD) (rg = 0.134, P = 2.74 × 10⁻⁸) and negatively correlated with the risk of Parkinson's disease (PD) (rg = - 0.100, P = 1.8 × 10⁻[4]). cigarettes per day (CigDay) are associated with a higher risk of AD (rg = 0.162, P = 4.26 × 10⁻⁵). Smoking cessation (SmkCes) is linked to an elevated risk of AD (rg = 0.1466, P = 1.5 × 10⁻[4]), whereas age of initiation of regular smoking (AgeSmk) is negatively correlated with AD risk (rg = - 0.181, P = 8.63 × 10⁻⁶) but positively correlated with PD risk (rg = 0.170, P = 2.0 × 10⁻[4]). Results suggest that both SmkInit and CigDay significantly increase AD risk (OR = 1.030, P = 1.74 × 10⁻⁴; OR = 1.022, P = 5.04 × 10⁻⁴), while SmkCes is associated with a reduced risk of PD (OR = 0.638, P = 1.91 × 10⁻⁶) and amyotrophic lateral sclerosis (ALS) (OR = 0.830, P = 5.29 × 10⁻⁶).

CONCLUSION: This study identified significant genetic associations between smoking behaviors and neurodegenerative diseases. CigDay and SmkInit increased AD risk, while SmkCes was linked to reduced risks of PD and ALS.}, } @article {pmid40616030, year = {2025}, author = {Kikkawa, Y and McIntosh, L and Mavin, TJ and Barlow, M and O'Brien, L and Hodge, S and Janssens, S}, title = {Developing a learning tool for advanced life support and resuscitation: Performance Reflection Model for Resuscitation (PRM-Resus).}, journal = {BMC medical education}, volume = {25}, number = {1}, pages = {1001}, pmid = {40616030}, issn = {1472-6920}, support = {AQIRF100-2020-CV//Advance Queensland/ ; 2615//Betty McGrath Mater Research/ ; }, mesh = {Humans ; *Clinical Competence ; *Simulation Training/methods ; *Resuscitation/education ; *Advanced Cardiac Life Support/education ; Models, Educational ; Video Recording ; }, abstract = {BACKGROUND: Acquiring proficiency in advanced life support (ALS) can pose challenges for novice learners. Simulation-based training (SBT) is widely used to address this, offering learners opportunities to practise and receive feedback during debriefing. However, existing performance tools often lack the clarity, behavioural specificity, and educational scaffolding required to support deep reflective learning. This study aimed to develop and evaluate the Performance Reflection Model for Resuscitation (PRM-Resus) and to integrate it with the ALS Team Model and structured video exemplars as a comprehensive learning package to enhance ALS training.

METHODS: The study involved four phases. Phase 1 created the ALS Team Model to clarify individual roles. Phase 2 focused on co-designing PRM-Resus, using team expertise and the Team Model to create behaviourally anchored performance descriptors. In Phase 3, video scenarios were produced to represent ALS team performance at varying proficiency levels. Phase 4 evaluated the PRM-Resus through expert think-aloud studies. Qualitative content analysis was used alongside Cronbach's alpha to assess internal consistency and its use for SBT.

RESULTS: The PRM-Resus comprises four domains-clinical skills, clinical knowledge, team management, and leadership-each defined by behavioural descriptors across three performance levels. The participating experts endorsed the tool's clarity, structure, and educational value for novice learners. Internal consistency was high (α > 0.95). When used alongside the ALS Team Model and video exemplars, PRM-Resus facilitated deeper performance analysis, which had potential for enhancing post-simulation reflection and supporting faculty development.

CONCLUSIONS: This study presents a novel, interdisciplinary framework that integrates PRM-Resus, the ALS Team Model, and video exemplars to support reflective learning in ALS simulation. Together, these tools help novice learners build a concrete understanding of effective team performance and enable educators to deliver more structured feedback. Further research should explore its impact on learner development and potential translation into improved clinical outcomes.}, } @article {pmid40616089, year = {2025}, author = {Al Kamaly, O and Al-Khateeb, LA and Halim, MK and Katamesh, NS and Magdy, G and Abbas, AEF}, title = {D-optimal candexch algorithm-enhanced machine learning UV-spectrophotometry for five-analyte determination in novel anti-glaucoma formulations and ocular fluids: four-color sustainability framework with NQS assessment and UN-SDG integration.}, journal = {BMC chemistry}, volume = {19}, number = {1}, pages = {198}, pmid = {40616089}, issn = {2661-801X}, support = {PNURSP2025R917//Princess Nourah Bint Abdulrahman University/ ; }, abstract = {The novel anti-glaucoma ophthalmic preparation containing latanoprost, netarsudil, and benzalkonium chloride has posed a significant challenge due to its complexity and the lack of environmentally sustainable quantification methods, with only a single published method available for its quantification that lacks environmental consideration. This study aims to address this crucial gap by presenting a novel and sustainable approach using machine learning-enhanced UV-spectrophotometric chemometric models for the concurrent quantification of latanoprost, netarsudil, benzalkonium chloride, and two related compounds in ophthalmic preparations and aqueous humour. A strategic multi-level, multi-factor experimental design creates a 25-mixture calibration set for four models (PLS, GA-PLS, PCR, and MCR-ALS). The key novelty was using the D-optimal design generated by MATLAB's candexch algorithm to construct a robust validation set, overcoming random data splitting limitations in machine learning chemometric methods and ensuring unbiased evaluation across concentrations. The optimized MCR-ALS model outperforms in predictive ability, with recovery percentages of 98-102%, low root mean square errors of calibration and prediction, favorable bias-corrected mean square error of prediction, relative root mean square error within acceptable limits, and adequate limits of detection for pharmaceutical analysis. The Greenness Index Spider Charts and the Green Solvents Selection Tool were applied to replace hazardous solvents. A total of seven advanced evaluation tools were employed to assess the method's greenness, blueness, violetness, and whiteness, highlighting its eco-friendly profile, practical relevance, and innovation potential. Additionally, the method's environmental and societal benefits were further validated using the Need, Quality, Sustainability (NQS) index. Overall, this machine learning-based framework contributes meaningfully to ten United Nations Sustainable Development Goals (UN-SDGs), underscoring its value for future-oriented pharmaceutical research.}, } @article {pmid40617623, year = {2025}, author = {Faure-de Baets, J and Besnard, J and Cassereau, J and Emmelin, E and Allain, P}, title = {Assessment of social cognition in patients with amyotrophic lateral sclerosis: protocol for a cross-sectional comparative study at Angers University Hospita.}, journal = {BMJ open}, volume = {15}, number = {7}, pages = {e097543}, pmid = {40617623}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Cross-Sectional Studies ; *Social Cognition ; Neuropsychological Tests ; Male ; Female ; Case-Control Studies ; Research Design ; Middle Aged ; Cognition ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder primarily affecting motor neurons. In addition to motor impairments, ALS frequently involves cognitive and behavioural disturbances, including deficits in social cognition, which can impact interpersonal interactions and decision-making. Despite increasing recognition of these impairments, existing assessment tools often rely on static stimuli, limiting their ecological validity.

METHODS AND ANALYSIS: This cross-sectional, single-centre study aims to assess social cognition abilities in patients with ALS compared with healthy controls using a combination of dynamic and static neuropsychological tools. The primary outcome measure will be performance on the Movie for the Assessment of Social Cognition, an ecologically valid test evaluating theory of mind. Secondary outcomes will include emotion recognition (static and dynamic tasks: Ekman Faces and French Emotion Evaluation Test), mood assessments (Hospital Anxiety and Depression Scale) and clinical variables such as disease severity (ALS Functional Rating Scale-Revised), cognitive function (Edinburgh Cognitive and Behavioural Screen, Mini-Mental State Examination) and disease staging (King's ALS Clinical Staging System). A total of 74 participants (37 patients with ALS and 37 matched healthy controls) will be recruited. Group differences will be analysed using analysis of variance, while regression models will explore associations between social cognitive deficits and clinical markers of ALS progression.

ETHICS AND DISSEMINATION: This study has been approved by the French Ethics Committee (CPP) Ouest I under reference 2020-A01213-36. Data collection and processing comply with French and European data protection regulations (GDPR, Loi Informatique et Libertés). Findings will be disseminated through peer-reviewed journals and scientific conferences and will contribute to improving neuropsychological assessment methods for ALS.

TRIAL REGISTRATION NUMBER: NCT04406675.}, } @article {pmid40618254, year = {2026}, author = {Singh, A and Subramanian, M and Singh, A}, title = {MicroRNAs in the pathogenesis of neurodegenerative disorders: Potential as therapeutic targets.}, journal = {Neural regeneration research}, volume = {21}, number = {7}, pages = {2772-2778}, pmid = {40618254}, issn = {1673-5374}, support = {R01 EY032959/EY/NEI NIH HHS/United States ; }, abstract = {Neurodegenerative diseases (neurodegenerative disorders) are marked by the progressive degeneration of the structure and function of the central nervous system. They may result in the deterioration of cognitive, motor, and functional abilities. Diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis represent some of the most prominent examples of neurodegenerative disorders. Despite scientific advancement in understanding disease pathology and prognosis, the therapeutic strategies available for management remain limited. In recent years, microRNAs, small non-coding RNA molecules, have emerged as key players in the pathogenesis of neurodegenerative disorders. Therefore, understanding how these microRNAs affect disease pathology and pathway signaling is essential, and may open microRNAs as new avenues for potential therapeutic intervention. This review explores the role of microRNAs in various neurodegenerative diseases, discuss how microRNAs affect signaling pathways, and examine the potential of microRNAs as therapeutic targets.}, } @article {pmid40618260, year = {2026}, author = {Zhang, J and Ma, W and Liu, R and Li, X and Yuan, Z and Cheng, J}, title = {Neuromodulatory role and therapeutic potential of N 6 -methyladenosine RNA methylation in neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {21}, number = {6}, pages = {2191-2204}, pmid = {40618260}, issn = {1673-5374}, abstract = {N 6 -methyladenosine RNA methylation, an essential post-transcriptional modification, dynamically regulates RNA metabolism and plays a crucial role in neuronal function. Growing evidence suggests that dysregulated N 6 -methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. However, the precise mechanisms by which N 6 -methyladenosine modification influences these conditions remain unclear. This review summarizes the role of m 6 A modification and its associated regulators in neurodegeneration, focusing on their involvement in key pathological processes. In Alzheimer's disease, m 6 A modification contributes to synaptic dysfunction, mitochondrial damage, and neuronal apoptosis. Evidence from APP/PS1, 5xFAD, tau transgenic, and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer's disease progression through neuroinflammation, circular RNAs dysregulation, and autophagy-related mechanisms. In Parkinson's disease, altered N 6 -methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs. In multiple sclerosis and amyotrophic lateral sclerosis, N 6 -methyladenosine affects immune activation, myelin repair, and the regulation of disease-associated genes such as TDP-43 . Beyond N 6 -methyladenosine, other RNA methylation modifications-such as m 1 A, m 5 C, m 7 G, uracil, and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function, RNA metabolism, and neuronal stress responses. Additionally, N 6 -methyladenosine exhibits cell type-specific functions: in microglia, it regulates inflammatory activation and phagocytic function; in astrocytes, it modulates metabolic homeostasis and glutamate-associated neurotoxicity; in neurons, it affects synaptic function and neurodegeneration-related gene expression; and in adult neural stem cells, it controls differentiation, neurogenesis, and cognitive plasticity. Recently, several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N 6 -methyladenosine modification, providing new opportunities for disease intervention, with the targeting of N[6]-methyladenosine-related pathways emerging as a promising therapeutic strategy. However, challenges persist in optimizing the specificity and delivery of these therapeutic approaches.}, } @article {pmid40618341, year = {2025}, author = {Asghari Jafari, E and Arabi, M and Bereimipour, A}, title = {Integrated genomic and molecular insights into astrocyte- and oligodendrocyte-derived amyotrophic lateral sclerosis: focus on miRNAs and extracellular vesicles.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {71}, number = {6}, pages = {1-8}, doi = {10.14715/cmb/2025.71.6.1}, pmid = {40618341}, issn = {1165-158X}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *MicroRNAs/genetics/metabolism ; Humans ; *Astrocytes/metabolism/pathology ; *Oligodendroglia/metabolism/pathology ; *Extracellular Vesicles/metabolism/genetics ; Computational Biology/methods ; *Genomics/methods ; Signal Transduction ; }, abstract = {Motor neurons in the brain and spinal cord begin to die off in Amyotrophic lateral sclerosis (ALS), a disease that can be fatal. Molecular pathways in neurological disease, especially ALS, remain a challenge in the medical sciences. In this disease, a disorder in both astrocytes and oligodendrocytes can cause the disease to progress. This study aimed to investigate the molecular mechanisms and find key elements between these two cells in ALS with a bioinformatics perspective. In this study, using integrated and continuous bioinformatics analytics by various tools and databases, we investigated genes, protein products, and miRNAs between astrocytes and oligodendrocytes. The obtained data were involved in the Cellular senescence, actin cytoskeleton, and cell cycle signaling pathways. Then, after careful evaluation of the information, TP53, MDM2, KRAS, PTPRC, and GSK proteins were candidates, which are regulated by hsa-miR-564, hsa-miR-496-5p, hsa-miR-324-5p, hsa-miR-296-5p, and hsa-miR-4258-3p miRNAs. Finally, the four genes had a more robust and better relationship in this study between astrocyte and oligodendrocyte-derived ALS.}, } @article {pmid40618376, year = {2025}, author = {Scirocco, E and Allen, MD and Giacomelli, E and Ajroud-Driss, S and Andrews, J and Banack, S and Bede, P and Benatar, M and Cheung, K and Corcia, P and de Carvalho, M and Elman, L and Fink, JK and Genge, A and Hardiman, O and Harms, M and Heitzman, D and Jang, G and Kano, O and Kiernan, MC and Lee, I and Ludolph, A and Mehta, P and Ozdinler, H and Rezania, K and Schito, P and Sherman, AV and Silani, V and Sorenson, E and Turner, MR and Van Den Berg, L and Mitsumoto, H and Paganoni, S}, title = {Toward therapeutic trials in primary lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {623-630}, doi = {10.1080/21678421.2025.2527123}, pmid = {40618376}, issn = {2167-9223}, mesh = {Humans ; *Clinical Trials as Topic/methods ; *Motor Neuron Disease/drug therapy/therapy/diagnosis ; }, abstract = {Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder primarily affecting the upper motor neurons. People living with PLS experience progressive physical and communication disability, which typically evolves slowly over several years. In contrast to amyotrophic lateral sclerosis (ALS), life expectancy is anticipated to be normal. Disease-modifying medications are not available and PLS drug development has been challenging. This review considers recent advances and ongoing initiatives aimed at promoting clinical trial readiness for PLS. Ongoing clinical research efforts include patient registries and biorepositories, natural history studies, outcome measure validation, and biomarker development. These international collaborative efforts are essential for developing the first therapeutic trials for people living with PLS.}, } @article {pmid40618857, year = {2025}, author = {Balbi, M and Torazza, C and Altosole, T and Ravera, S and Farinini, E and Tessitore, S and Bacchetti, F and Rosso, F and Musante, I and Alfei, S and Cerminara, M and Puliti, A and Filaci, G and Fenoglio, D and Leardi, R and Fedele, E and Bonanno, G and Milanese, M and Bonifacino, T}, title = {The complex phenotype and function of spinal cord microglia during ALS progression and the impact of metabotropic glutamate receptor type 5 down-regulation in SOD1[G93A] mice.}, journal = {Neurobiology of disease}, volume = {213}, number = {}, pages = {107017}, doi = {10.1016/j.nbd.2025.107017}, pmid = {40618857}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Microglia/metabolism/pathology ; *Spinal Cord/metabolism/pathology ; *Receptor, Metabotropic Glutamate 5/metabolism/genetics ; Mice, Transgenic ; Mice ; Disease Progression ; Superoxide Dismutase-1/genetics/metabolism ; Phenotype ; Down-Regulation ; Disease Models, Animal ; Mice, Inbred C57BL ; }, abstract = {Over the last few decades, scientists' attention has shifted from neuronal to non-neuronal cells to explain the mechanisms at the basis of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). ALS is a multifactorial and multicellular disease in which microglia have a central role, during disease progression. We previously demonstrated that metabotropic glutamate receptor 5 (mGluR5) is dysfunctional in the spinal cord of the SOD1[G93A] ALS mice, and its in-vivo genetic or pharmacological dampening ameliorates disease outcome and astrocyte and microglia reactivity. Here, we studied the expression of typical phenotype-related markers during the disease progression in spinal cord microglia cells acutely isolated from early asymptomatic and late symptomatic SOD1[G93A] ALS mice. Moreover, we investigated whether reducing mGluR5 affected the microglia phenotype and function. In contrast to what we previously observed in astrocytes, mGluR5 expression decreased during disease progression in microglia acutely isolated from adult SOD1[G93A] mice. In-vivo genetic mGluR5 downregulation did not affect microglia phenotype-relevant markers, which evidenced a unique expression distribution. Conversely, mGluR5 reduction ameliorated redox balance and bioenergetics of adult microglia. Microglia cultured from the spinal cord of SOD1[G93A] pups showed that in-vitro mGluR5 pharmacological manipulation by the negative allosteric modulator CTEP partially modified their bioenergetic and oxidative status. Overall, our results suggest that mGluR5 manipulation ameliorates microglia phenotype and function in ALS by both direct and indirect mechanisms. Consequently, we hypothesised that the improvement of microglia reactive status by in-vivo mGluR5 downregulation or CTEP pharmacological modulation is supported by ameliorated bioenergetic metabolism, and the indirect astrocyte's phenotype change that promotes an improvement of the surrounding environment.}, } @article {pmid40619651, year = {2025}, author = {Chauhan, S and Maan, P and Panghal, A}, title = {TDP-43 Proteinopathies in ALS and FTLD: Mechanistic Insights and Therapeutic Approaches.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273374466250617085832}, pmid = {40619651}, issn = {1996-3181}, abstract = {TAR DNA-binding protein 43 (TDP-43) is a vital RNA/DNA-binding protein involved in RNA metabolism, playing a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Approximately 97% of sporadic ALS (sALS), familial ALS (fALS) and FTLD cases are associated with pathological inclusions of hyperphosphorylated and ubiquitinated TDP-43 and genetic mutations in TAR DNA binding protein (TARDBP). Besides TARDBP, mutations in other genes such as C9ORF72, SOD1, FUS, and NEK1 are also linked to other fALS cases. Cytoplasmic mislocalization, aberrant post-translational modifications, and amyloid- like aggregation characterize TDP-43 pathology. These pathological changes impair essential cellular processes, including gene expression, mRNA stability, and RNA metabolism. Mechanisms of TDP-43-induced toxicity include disruption of endocytosis, mitochondrial dysfunction, and progressive cellular damage. Additionally, liquid-liquid phase separation (LLPS) and prion-like propagation are emerging as central features of its pathological spread. This review summarizes advances in understanding TDP-43's physiological functions and pathological mechanisms in ALS and FTLD. It highlights key processes underlying TDP-43 toxicity, such as aggregation, selective neuronal vulnerability, and regional susceptibility. Finally, this review summarizes evolving therapeutic strategies aimed at mitigating TDP-43-related toxicity through disaggregation, targeting mislocalization, and addressing upstream dysfunctions and challenges faced in the development of effective therapies for ALS and FTLD.}, } @article {pmid40619836, year = {2026}, author = {Feng, Y and Wang, X and Chen, C and Wang, D and Hou, C and Wang, Y and Hu, H and Chen, P and Qin, L and Wan, Q and Yao, X and He, ML}, title = {Carbon Quantum Dots Assisted Virus Tracking: From Skin to Brain.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {38}, number = {6}, pages = {e2508464}, pmid = {40619836}, issn = {1521-4095}, support = {11104020//RGC General Research Fund of Hong Kong Special Administrative Region/ ; C1018-23G//Collaborative Research Fund/ ; 7005874//Strategic funds/ ; 7020032//Strategic funds/ ; 9680149//Strategic funds/ ; //City University of Hong Kong/ ; JCYJ20240813153107010//Shenzhen Basic Research Program/ ; 9229501-14-YX//IDM Project/ ; 2025A1515011479//Basic and Applied Basic Research Foundation of Guangdong Province/ ; }, mesh = {*Quantum Dots/chemistry ; Animals ; Humans ; *Skin/virology/metabolism ; *Carbon/chemistry ; *Herpesvirus 1, Human/physiology ; *Brain/virology/metabolism ; Mice ; }, abstract = {Incurable infection by herpes simplex virus 1 (HSV-1) can cause severe encephalitis and neurodegenerative diseases, e.g., Alzheimer's disease (AD) and amyotrophic lateral sclerosis. How HSV-1 reaches the brain from the initial infection site remains inconclusive. Here, an innovative approach combining carbon quantum dots (CQDs) with dissolving microneedles (dMN) for real-time tracking of HSV-1 from skin to brain is presented. Upon application, CQDs-HSV-1 is released from the dMN through the swelling of interstitial fluid (ISF) in skin and subsequently monitored by living imaging. Remarkably, it is observed that HSV-1 preferentially infects peripheral skin nerves, almost all viruses directly enter to brain via the spinal cord within 10-30 min, while few viruses enter the brain through the bloodstream via tail vein injection at the same time. Spinal cord injury (SCI) significantly delays the HSV-1 transport from skin to brain but has no effect on the virus's travel from blood to brain. In a microfluid system, HSV-1 shows preferential neurite infection, then transports to the cell body of differentiated SH-SY5Y cells, highlighting the viral traffic process in neurons. The integration of CQDs-virus labelling technology and dMN delivery model presents a promising tool for investigating the in vivo transport routes of neurotropic viruses with initial skin infections.}, } @article {pmid40619865, year = {2025}, author = {Vogel, E}, title = {Value-Scapes of Death: Livestock Veterinarians and the Regulation of Farm Animal Life in the Netherlands.}, journal = {Medical anthropology}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/01459740.2025.2527089}, pmid = {40619865}, issn = {1545-5882}, abstract = {This article examines the crucial role of veterinarians in making animal death valuable, enabling productive life, and managing uncontrolled dying. Based on ethnographic fieldwork on dairy farms in the Netherlands, and considering veterinarians as gatekeepers of the food chain, health practitioners, and governance actors, I articulate the "value-scapes" of food production that shape which animals die, when, and how, and whether death is desirable, a waste, or a warning. Veterinization here narrates how veterinary expertise is shaped by diverse societal concerns like food security, public health, animal welfare, and ecological sustainability, and knotted into shifting and multifaceted formations of Dutch-European animality.}, } @article {pmid40620684, year = {2025}, author = {Chen, P and Wang, F and Ling, B and Zhu, Y and Lin, H and Huang, J and Wang, X}, title = {Mesenchymal Stem Cell-Derived Extracellular Vesicles: Emerging Therapies for Neurodegenerative Diseases.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {8547-8565}, pmid = {40620684}, issn = {1178-2013}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Mesenchymal Stem Cells/cytology ; *Extracellular Vesicles/metabolism/transplantation ; Biomarkers/metabolism ; *Mesenchymal Stem Cell Transplantation/methods ; }, abstract = {Neurodegenerative diseases are a group of chronic diseases characterized by a gradual loss of neurons that worsens over time and dysfunction. These diseases are extremely harmful, not only affecting the physical health of the patients, but also having a serious impact on their quality of life. They mainly include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), etc. Their pathogenesis is complex, and it is difficult for the existing treatments to effectively slow down the progression of the disease. In recent years, Mesenchymal Stem Cells (MSCs) have received widespread attention for their anti-inflammatory, immunomodulatory and neuroprotective properties. In this context, MSC-derived Extracellular Vesicles (MSC-EVs) have demonstrated unique therapeutic potential as a cell-free therapeutic strategy. MSC-EVs are rich in bioactive substances such as proteins, lipids, mRNAs and miRNAs, which can pass through the blood-brain barrier and be targeted to the diseased area to regulate neuronal survival, synaptic plasticity and neuroinflammatory responses. In addition, compared with stem cell therapy, MSC-EVs have the advantages of low immunogenicity, easy storage and transportation, and avoiding ethical controversies. However, their clinical application still faces challenges: standardized isolation and purification techniques have not been unified, vesicle loading efficiency and targeting need to be further optimized, and long-term safety needs to be systematically evaluated. This review focuses on the role of MSC-EVs in the development of neurological diseases and explores their possible dual roles, both favorable and unfavorable, in the context of neurological diseases. In addition, this review provides a review of current studies on EVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases and provides a comprehensive review of the prospects and challenges of MSC-EVs in clinical applications.}, } @article {pmid40620778, year = {2025}, author = {Pavlenko, TA and Chesnokova, NB and Beznos, OV and Shikareva, NN and Nodel, MR and Shevtsova, KV and Panina, UV and Shteinberg, DA and Kukharskaya, OA and Sukhanova, IS and Pukaeva, NE and Kukharsky, MS and Ovchinnikov, RK}, title = {Superoxide dismutase activity in tear fluid and blood of patients and mouse model of amyotrophic lateral sclerosis: a pilot study.}, journal = {PeerJ}, volume = {13}, number = {}, pages = {e19623}, pmid = {40620778}, issn = {2167-8359}, mesh = {*Amyotrophic Lateral Sclerosis/enzymology/blood ; Animals ; Humans ; Pilot Projects ; *Tears/enzymology ; Mice ; Disease Models, Animal ; Male ; Middle Aged ; Mice, Transgenic ; Female ; Superoxide Dismutase-1/blood/metabolism ; *Superoxide Dismutase/blood/metabolism ; Aged ; Adult ; RNA-Binding Protein FUS/genetics/metabolism ; Biomarkers/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive degeneration of motor neurons and skeletal muscle atrophy. The heterogeneity of clinical symptoms and the lack of reliable biomarkers hamper diagnostics of ALS. The dysfunction of superoxide dismutase 1 (SOD1) protein is considered one of the molecular mechanisms underlying ALS pathology. We measured total SOD activity in the tear fluid and blood serum of ALS patients, healthy volunteers, and in the ALS mouse model, harboring the human truncated form of fused in sarcoma (FUS) protein-FUS (1-359). The average SOD activity in tear fluid did not differ between ALS patients and the control group. However, an increased proportion of patients with low SOD activity in tear fluid was observed compared to the control group. In contrast, SOD activity in blood serum was higher in the ALS group. Transgenic FUS (1-359) mice showed decreased SOD activity in tear fluid at both presymptomatic and symptomatic stages of ALS. SOD activity in blood serum did not differ between transgenic and control animals. These findings suggest that changes in SOD activity in the tear fluid of ALS patients and transgenic FUS (1-359) mice reflect local metabolic disturbances in the eyes associated with ALS.}, } @article {pmid40621104, year = {2025}, author = {Rosene, MJ and Benitez, BA}, title = {Cysteine string protein α and a link between rare and common neurodegenerative dementias.}, journal = {NPJ dementia}, volume = {1}, number = {1}, pages = {15}, pmid = {40621104}, issn = {3005-1940}, support = {R01 NS118146/NS/NINDS NIH HHS/United States ; R21 NS127211/NS/NINDS NIH HHS/United States ; }, abstract = {The maintenance of protein homeostasis and overall protein quality control dysfunction are associated with dementia. Cysteine string protein α (CSPα) is an endolysosomal cochaperone that facilitates the fusion of secretory and synaptic vesicles to the cell membrane. CSPα interacts with multiple proteins related to the proteostasis network and exocytic pathways and is often dysfunctional in synaptopathies. Since the initial discovery of CSPα 30 years ago, subsequent research has demonstrated a protective role of CSPα, especially in synaptic maintenance. However, the discovery of heterozygous CSPα mutations in 2011 causing adult-onset neuronal ceroid lipofuscinosis (ANCL) shifted the back-then prevalent dogma of unique synaptic function to include an endolysosomal role for CSPα. Recently, CSPα has been involved in the exocytosis of aggregate-prone proteins through either the misfolding-associated protein secretion (MAPS) or unconventional secretory pathways linking the molecular mechanism of rare and common neurodegenerative diseases. Here, we propose a novel molecular and pathophysiological model of CSPα-associated dementia, outline the increasing evidence of a broader role of CSPα in neurodegeneration, propose the role of CSPα in the synaptic secretion of neurodegenerative-associated proteins, and discuss the modulation of CSPα as a molecular target for common dementias.}, } @article {pmid40621236, year = {2025}, author = {Rani, D and Chandan, SK and Devi, E}, title = {Motor Unit Number Estimation for Evaluating Disease Progression and Comparison With Functional Rating Scale Scores in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {17}, number = {6}, pages = {e85348}, pmid = {40621236}, issn = {2168-8184}, abstract = {Introduction Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease characterized by degeneration of motor neurons in the brain, brainstem, and spinal cord. While the ALS Functional Rating Scale-Revised (ALSFRS-R) is commonly used to assess functional decline, its limitations highlight the need for more objective biomarkers. Motor unit number estimation (MUNE) is an electrophysiological technique that may provide a more sensitive measure of disease progression. This study aims to evaluate the utility of MUNE as a biomarker in ALS and compare its performance with ALSFRS-R. Methods This was a prospective, single-center, observational study conducted over 18 months. A total of 31 patients with definite or probable ALS, diagnosed per the Revised El Escorial Criteria, were enrolled. MUNE and ALSFRS-R assessments were performed at baseline and after six months. MUNE was calculated using the multi-point incremental method in the upper extremity. Data were analyzed using paired t-tests and Pearson's correlation coefficients. Subgroup analyses by age, sex, and symptom onset site were also conducted. Results Both MUNE and ALSFRS-R scores declined significantly over six months. The mean MUNE decreased from 16.36 ± 5.22 to 13.37 ± 4.96 (p < 0.0001), while the ALSFRS-R score declined from 42.06 ± 3.24 to 36.72 ± 4.89 (p < 0.0001). The mean rate of decline was significantly greater for MUNE (23.6 ± 15.31) than for ALSFRS-R (13.91 ± 8.18; p = 0.001). No significant associations were observed between MUNE and patient age, sex, or site of symptom onset. Correlation between MUNE and ALSFRS-R was weak at both time points. Conclusions MUNE demonstrated a significantly greater rate of decline than ALSFRS-R, suggesting higher sensitivity to motor neuron loss over time. These findings support using MUNE as a reliable and objective biomarker for monitoring disease progression in ALS. Incorporating MUNE into clinical practice and research may improve prognostication, enable earlier therapeutic intervention, and enhance patient stratification in clinical trials. Further large-scale studies are needed to validate its routine use.}, } @article {pmid40621427, year = {2025}, author = {Gunduz, A and Akıncı, T and Kargın, OA and Tutuncu, M and Arslan, S and Uzun, N}, title = {Correlation analysis between excitability in the somatosensory cortex and structural changes in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {10}, number = {}, pages = {202-208}, pmid = {40621427}, issn = {2467-981X}, abstract = {OBJECTIVE: We aimed to investigate the excitability of the somatosensory cortex and its relationship to structural changes in motor and sensory pathways, and motor excitability in amyotrophic lateral sclerosis (ALS).

PATIENTS AND METHOD: We included all consecutive individuals with ALS, fulfilling the "definite" or "probable" ALS criteria. We recorded surround inhibition (SI) and recovery function (RC) of somatosensory evoked potentials (SEPs), resting motor threshold, and cortical silent period (cSP), and performed volumetric analysis and diffusion tensor imaging (DTI).

RESULTS: We included 15 patients with ALS and 12 healthy individuals of similar age and sex. At the group level, the mean SEP-RC% at ISI 5 ms was higher in the ALS group than in healthy participants (all SEP-RC% at 5 ms p < 0.001). SEP-SI was lost in one-third of individuals with ALS. A negative correlation was found between the duration of the cSP and SEP-RC%, whereas no correlations were observed between SEP parameters and radiological volumetric analysis of the corticospinal tract, medial lemniscus, or cortical thickness of the precentral and postcentral gyri.

CONCLUSION: Somatosensory hyperexcitability is present in ALS, and SI is lost in a subset of patients with ALS.

SIGNIFICANCE: Somatosensory hyperexcitability correlates well with cSP but not with structural changes.}, } @article {pmid40621723, year = {2026}, author = {Anani, T and Pradat-Peyre, JF and Delbot, F and Desnuelle, C and Rolland, AS and Devos, D and , and Pradat, PF}, title = {Feature selection using metaheuristics to predict annual amyotrophic lateral sclerosis progression.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {62-77}, doi = {10.1080/21678421.2025.2522399}, pmid = {40621723}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Disease Progression ; Male ; Female ; Middle Aged ; *Machine Learning ; Aged ; Cohort Studies ; Predictive Value of Tests ; Prognosis ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease with no curative treatment and affecting motor neurons, leads to motor weakness, atrophy, spasticity and difficulties with speech, swallowing, and breathing. Accurately predicting disease progression and survival is crucial for optimizing patient care, intervention planning, and informed decision-making.

METHODS: Data were gathered from the PRO-ACT database (4659 patients), clinical trial data from ExonHit Therapeutics (384 patients) and the PULSE multicenter cohort aimed at identifying predictive factors of disease progression (198 patients). Machine learning (ML) techniques including logistic/linear regression (LR), K-nearest neighbors, decision tree, random forest, and light gradient boosting machine (LGBM) were applied to forecast ALS progression using ALS Functional Rating Scale (ALSFRS) scores and patient survival over one year. Models were validated using 10-fold cross-validation, while Kaplan-Meier estimates were employed to cluster patients according to their profiles. To enhance the predictive accuracy of our models, we performed feature selection using ANOVA and differential evolution (DE).

RESULTS: LR with DE achieved a balanced accuracy of 76.05% on validation (ranging from 68.6% to 79.8% per fold) and 76.33% on test data, with an AUC of 0.84. With Kaplan-Meier's estimates, we identified five distinct patient clusters (C-index = 0.8; log-rank test p value ≤0.0001). Additionally, LGBM predictions for ALSFRS progression at 3 months yielded an RMSE of 3.14 and an adjusted R[2] of 0.764.

CONCLUSION: This study showcases the potential of ML models to provide significant predictive insights in ALS, enhancing the understanding of disease dynamics and supporting patient care.}, } @article {pmid40622676, year = {2025}, author = {Wei, Y and Li, D and Yang, R and Liu, Y and Luo, X and Zhao, W and Yang, H and Chen, Z and Shen, C and Wang, Y and Huang, Z}, title = {TIA1-mediated stress granules promote neurodegeneration by sequestering HSP70 mRNA in C9orf72 mice.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {12}, pages = {4482-4494}, doi = {10.1093/brain/awaf248}, pmid = {40622676}, issn = {1460-2156}, mesh = {Animals ; *T-Cell Intracellular Antigen-1/metabolism/genetics ; *HSP70 Heat-Shock Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Mice ; *Stress Granules/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; Humans ; Mice, Knockout ; RNA, Messenger/metabolism ; Male ; Motor Neurons/metabolism/pathology ; Motor Cortex/metabolism/pathology ; Disease Models, Animal ; Female ; Nerve Degeneration/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease with progressive loss of motor neurons in the central nervous system. Recent studies have reported that there are mutations at the T-cell antigen-1 (TIA1) domain site in some ALS patients. TIA1 is a key component of stress granules (SGs), but its role and mechanism in ALS pathogenesis remain unclear. In this study, we found that TIA1 was upregulated in the motor cortex of post-mortem ALS patients as well as in the motor cortex neurons of C9orf72-poly-Gly-Ala (GA) mice (ALS mice). TIA1 knockout in the CNS [TIA1Nestin-conditional knockout (CKO) mice] alleviated motor neuron loss, neuroinflammation and motor dysfunction in C9orf72-poly-GA mice. Mechanistically, RNA sequencing combined with the C9orf72-ALS/frontotemporal dementia patient single nucleus RNA-sequencing database revealed that mRNA of heat shock protein 70 (HSP70) family member genes such as HSPa1b were upregulated in the motor cortex of TIA1Nestin-CKO ALS mice. We further found that TIA1-mediated SG formation was increased during ALS pathogenesis, leading to HSP70 mRNA being sequestered into SGs. This reduced HSP70 expression, impairing the degradation of poly-GA aggregates by the UBQLN2-HSP70 pathway and exacerbating C9orf72-ALS progression. Taken together, these findings highlight a previously unrecognized role of TIA1-mediated SGs in promoting ALS pathogenesis by sequestering HSP70 mRNA, suggesting potential therapeutic targets for ALS treatment.}, } @article {pmid40622763, year = {2025}, author = {Tra, NT and Kiryu-Seo, S and Kida, H and Wakatsuki, K and Tashiro, Y and Tsutsumi, M and Ataka, M and Iguchi, Y and Nemoto, T and Takahashi, R and Katsuno, M and Kiyama, H}, title = {Absence of the axon initial segment in sensory neuron enhances resistance to amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {11}, pages = {4030-4044}, pmid = {40622763}, issn = {1460-2156}, support = {21K19310//Japan Society for the Promotion of Science/ ; 23H04229//Japan Society for the Promotion of Science/ ; 24K02350//Japan Society for the Promotion of Science/ ; 23K24695//Japan Society for the Promotion of Science/ ; //JSPS/ ; 21K19310//KAKENHI/ ; 23H04229//KAKENHI/ ; 24K02350//KAKENHI/ ; 23K24695//KAKENHI/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; Mice ; Ganglia, Spinal/pathology/metabolism ; *Sensory Receptor Cells/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Activating Transcription Factor 3/metabolism/genetics ; Disease Models, Animal ; *Axon Initial Segment/pathology ; *Axons/pathology ; Mice, Transgenic ; Proteasome Endopeptidase Complex/metabolism/genetics ; Mitochondria/metabolism/pathology ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Proteasome dysfunction in ALS is considered to cause the accumulation of protein aggregates, which leads to motor neuron degeneration; however, the resilience of motor neurons to ALS pathology might be impaired long before the appearance of protein aggregates. Intriguingly, sensory dorsal root ganglion (DRG) neurons are not susceptible to ALS pathology despite their processes coexisting with axons of motor neurons in the same spinal nerves. Both DRG neurons and motor neurons in ALS model mice express activating transcription factor 3 (ATF3), a well-known marker of nerve injury and disease progression, suggesting that both types of neurons respond to ALS pathology. However, it remains unknown why only DRG neurons are resilient to ALS pathological damage. To address this issue, we used a nerve injury model in combination with unique injury-induced genetically engineered mice, in which genetic control with an Atf3 regulatory element enables proteasome ablation and mitochondrial visualization specifically in damaged neurons. Using the strategy, we found that DRG neurons are resistant to damage in proteasome-deficient conditions, whereas spinal motor neurons degenerate in the same conditions. This might be because DRG neurons lack the typical axon initial segment (AIS), which normally exists in mature neurons and acts as a gate for the selective transport of cargo to axons. The absence of a typical AIS in DRG neurons facilitated increased entry of mitochondria into the axon upon injury, with or without proteasome function. In contrast, damaged motor neurons lacking the proteasome failed to disassemble the AIS, which prevented increased mitochondrial influx into axons and led to energy depletion and degeneration. In the absence of the AIS, DRG neurons in the ALS mouse model are able to deliver sufficient mitochondria into the axon to prevent pathological damage. However, impaired proteasome function in ALS motor neurons results in retention of the AIS gate and failure of mitochondrial transport to axons. This is a possible reason why DRG neurons have greater resilience to ALS pathological damage compared with spinal motor neurons. Collectively, this study opens new directions for the understanding of neurodegenerative diseases at early stages of disturbed protein homeostasis.}, } @article {pmid40624208, year = {2025}, author = {Tavares, M and Lúcio, MJ and Borges, J and Carriço, F and Guimarães, MJ and Drummond, M}, title = {The impact of obstructive sleep apnea and the prognostic role of level III polysomnography at the onset of amyotrophic lateral sclerosis.}, journal = {Sleep & breathing = Schlaf & Atmung}, volume = {29}, number = {4}, pages = {235}, pmid = {40624208}, issn = {1522-1709}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/physiopathology/mortality ; *Polysomnography ; *Sleep Apnea, Obstructive/diagnosis/physiopathology/therapy ; Male ; Female ; Middle Aged ; Prognosis ; Cross-Sectional Studies ; Aged ; Noninvasive Ventilation ; Adult ; }, abstract = {PURPOSE: Sleep disturbances are considered an early manifestation of Amyotrophic lateral sclerosis (ALS). However, sleep-disordered breathing (SDB) in ALS remains underexplored. The primary outcome of this study is to describe the clinical, functional and polygraphic characteristics of ALS patients with baseline SDB and to compare those with and without obstructive sleep apnea (OSA) in level III polysomnography (PSG) at diagnosis. Secondary outcomes included identification of baseline factors predictive of non-invasive ventilation (NIV) initiation/death during follow-up and assessing the role of level III PSG performed at the initial clinical evaluation in ALS prognosis regarding timing to NIV initiation and death.

METHODS: A cross-sectional study was conducted on 74 patients between September 2023 and September 2024. For the primary outcome, only patients that exhibited baseline SDB were included (45 patients). The population (45) was divided into 2 groups: Group 1 (n = 26; obstructive apnea/hypopnea index ≥ 5) and Group 2 (n = 19; obstructive apnea/hypopnea index < 5). For the secondary outcomes, all 74 patients were included regardless of sleep events.

RESULTS: Patients with OSA had a higher baseline body mass index (p = 0.03) and lower nocturnal average oxygen saturation (p = 0.03). A lower forced vital capacity (p < 0.001) and higher transcutaneous carbon dioxide (p = 0.005) at baseline were predictive of timing to NIV initiation.

CONCLUSIONS: Our study highlights the importance of performing respiratory functional testing and transcutaneous carbon dioxide assessment in ALS prognosis, regarding timing to NIV initiation. Although level III PSG is vital in the diagnosis and treatment of SDB, further studies are needed to clarify its role at disease onset and identify additional potentially predictors of timing to NIV initiation/death in ALS patients.}, } @article {pmid40624572, year = {2025}, author = {Pham, TK and Verber, N and Turner, MR and Malaspina, A and Collins, MO and Mead, RJ and Shaw, PJ}, title = {Glutathione oxidation in cerebrospinal fluid as a biomarker of oxidative stress in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {36}, pmid = {40624572}, issn = {2047-9158}, support = {MRC/S004920/1/MRF_/MRF_/United Kingdom ; NIHR203321//NIHR Sheffield Biomedical Research Centre/ ; }, } @article {pmid40625110, year = {2025}, author = {Luo, Y and Xiong, S and Ehdaie, A and Sun, H and Yang, G and Luo, D and Li, J and Wang, X and Zhang, Z and Cai, L and Liu, H and Shehata, M}, title = {Predictive Parameters for Impending Steam Pops During High-Power Short-Duration Ablation for Atrial Fibrillation.}, journal = {Pacing and clinical electrophysiology : PACE}, volume = {48}, number = {8}, pages = {836-842}, doi = {10.1111/pace.70003}, pmid = {40625110}, issn = {1540-8159}, support = {20240216//Liu Hanxiong Famous Doctor Studio of Chengdu/ ; 2024NSFSC1709//the Natural Science Foundation of Sichuan Province/ ; CSY-YN-01-2023-041//Scientific Research Project of The Third People's Hospital of Chengdu/ ; }, mesh = {Humans ; *Atrial Fibrillation/surgery ; Male ; Female ; Retrospective Studies ; *Catheter Ablation/adverse effects/methods ; Middle Aged ; *Steam ; Aged ; }, abstract = {BACKGROUND: High-power short-duration (HPSD) radiofrequency ablation (RFA) for atrial fibrillation (AF) treatment carries the risk of steam pops (SPs) due to rapid tissue heating. However, methods to predict impending SP during HPSD-RFA remain undefined.

OBJECTIVE: This study aims to establish a quantitative criterion for predicting SPs during HPSD-RFA.

METHODS: Retrospective analysis was performed on 489 patients undergoing HPSD-RFA for AF, focusing on corresponding RFA parameters in those who experienced SPs.

RESULTS: Among 1943 ablation lesions (ALs) delivered in 18 patients with SPs, 24 ALs had SP occurrence. Tip temperature, RFA duration, and ablation index were not significantly different between SP ALs and non-SP ALs. The mean contact force was significantly higher in SP ALs (12 g vs. 9, p < 0.001). All SPs adhered to the following criteria: impedance drop ≥8Ω during the first 4 s of RFA, impedance variability <5Ω within the first 4 s of RFA (24/24 vs. 79/247, p < 0.001), no events in the posterior wall of the left atrium, impedance drop ≥12Ω within 4-12 s. By halting delivery of RFA early with this finding in approximately five ALs per patient, the risk of SP complications could be significantly mitigated.

CONCLUSION: Monitoring impedance trends in the initial 4 s of HPSD-RFA can effectively predict impending SP occurrences. Automated algorithms should be developed to halt RFA delivery in this setting.}, } @article {pmid40625857, year = {2025}, author = {Khorrami, F and Gupta, N and Zhou, X and Liang, Y and Yucel, YH}, title = {A Novel Retinal Nerve Fiber Layer Biomarker of Amyotrophic Lateral Sclerosis (ALS) Identified Using Longitudinal in vivo Ocular Imaging.}, journal = {Eye and brain}, volume = {17}, number = {}, pages = {69-79}, pmid = {40625857}, issn = {1179-2744}, abstract = {PURPOSE: Like motor neurons, retinal ganglion cells (RGCs) have long axons and high metabolic demands, making them vulnerable to disruption of axonal transport. Unlike motor neurons, the RGC axons are accessible to high-resolution non-invasive optical imaging in their intraocular portion. A non-invasive in vivo retinal imaging biomarker can be valuable for amyotrophic lateral sclerosis (ALS) diagnosis and monitoring. We aim to assess the presence of inner retinal pathology in a mouse model of ALS and its possible progression with age.

METHODS: Transgenic SOD1G93A mice (n=8, 4M/4F) and age-matched controls (n=8, 4M/4F) underwent in vivo retinal imaging with confocal scanning laser ophthalmoscopy (cSLO) coupled with optical coherence tomography (OCT) at 20 weeks of age. Another group of SOD1G93A mice (n=20, 6M/14F) and age-matched controls (n=20, 6M/14F) underwent longitudinal in vivo retinal imaging with the same device. Each retinal imaging session included infrared reflectance (IR) and blue reflectance (BR) cSLO coupled with OCT. Hyperreflective puncta located in the retinal nerve fiber layer (RNFL) were counted in a blinded fashion in ALS and control mice. The number of puncta at 20 weeks of age in ALS mice was compared with controls using Wilcoxon test. The rates of increase of puncta number were analyzed using a Generalized Linear Mixed-Effect Model (GLMM) for genotype, time, and sex.

RESULTS: IR-cSLO coupled with OCT revealed hyperreflective puncta located in the RNFL of ALS mice. IR-cSLO fundus imaging at the age of 20 weeks showed ALS mice had significantly higher number of puncta compared to controls (2.1±2.3 vs 0.5±0.8; (mean±SD), respectively, p=0.036). GLMM analysis showed both ALS mutation and age were significantly associated with the rate of increase of puncta number (p=0.000232 and p=0.000366, respectively). In addition, female ALS mice had a steeper increase of puncta compared to male ALS mice (0.21±0.04 log number puncta/week vs 0.16±0.04, respectively; p=0.037).

CONCLUSION: Our findings demonstrate distinct inner retinal nerve fiber layer pathology, detected using cSLO coupled with OCT, which worsens over time. These findings support the potential of retinal imaging as a translationally relevant, non-invasive biomarker for ALS diagnosis or disease monitoring in humans.}, } @article {pmid40626296, year = {2025}, author = {Li, D and Wang, P and Zhang, M and Zhang, X and Yao, H and Liu, X}, title = {Advances in examination methods for adolescent idiopathic scoliosis.}, journal = {Pediatric discovery}, volume = {3}, number = {1}, pages = {e2518}, pmid = {40626296}, issn = {2835-5598}, abstract = {The purpose of this article is to provide an overview of techniques for evaluating patients with adolescent idiopathic scoliosis (AIS). It encompasses the history, clinical examinations, and diagnostic imaging methods for AIS. These methods include digital radiological examination, EOS® imaging, nuclear medicine, ultrasound, body surface topography techniques such as the Moiré pattern technique, raster stereophotography, and DIERS formetric 4D as well as computed tomography and magnetic resonance imaging (MRI). Traditionally, full-spine standing X-rays have been the standard for diagnosing AIS. High-quality clinical assessments may continue as a reference for assessing other spinal deformities. However, the new diagnostic imaging methods aim to reduce radiation exposure while maintaining image quality and practicality. Emerging technologies demonstrate strong reliability and effectiveness in diagnostic imaging of AlS. These techniques may be beneficial for diagnosing and monitoring AIS and its progression without requiring high levels of radiation exposure. The article is a search and summary of the PubMed electronic database to understand the current and future status of AIS imaging technology, which can not only help to introduce other researchers to the field but also serve as a valuable source for healthcare professionals to study existing methods, develop new ones, or select evaluation strategies.}, } @article {pmid40626770, year = {2025}, author = {Devrim, İ and Ergun, D and Kaçar, P and Çelebi, MY and Özer, A and Koyun, E and Koç, Y and Yıldız, ÖD and Akgül, E and Ayhan, FY and Bayram, N}, title = {The Comparison of Flushing With Prefilled Saline Syringes Versus Manually Prepared Saline Syringes on Colonization of Peripheral Intravenous Catheters in Children.}, journal = {Journal of infusion nursing : the official publication of the Infusion Nurses Society}, volume = {48}, number = {4}, pages = {247-252}, pmid = {40626770}, issn = {1539-0667}, mesh = {Humans ; *Syringes ; Child ; *Saline Solution/administration & dosage ; *Catheterization, Peripheral/adverse effects ; Turkey ; *Catheter-Related Infections/prevention & control ; *Catheters, Indwelling/microbiology ; Infusions, Intravenous ; Child, Preschool ; }, abstract = {We appreciate the study performed and described by Devrim et al, who practice at Dr. Behçet Uz Children's Diseases and Surgery Training and Research Hospital in Izmir, Turkey. This study aimed to compare the colonization rates of short-term PIVC tips between patients' catheters flushed with manually prepared saline syringes and single-use prefilled saline syringes. The practice of manually preparing saline syringes for use in flushing intravenous catheters is uncommon in many health care organizations. While many health care organizations have permanently exchanged manual flush syringe preparation for prefilled single-use saline syringes, we are respectful of professionals and organizations who serve in areas where practice is different. As noted, we appreciate Devrim et al's study and described findings. The conclusion of this study affirms and further substantiates the INS Infusion Therapy Standards of Practice described in Standard 38. Flushing and Locking. Practice Recommendation - A. Use single-dose systems (eg, single-dose vials and syringes or prefilled labeled syringes) for all VAD flushing and locking. Additional recommendations are listed in A.2. and A.3. Use commercially manufactured prefilled flush syringes (when available) to reduce the risk of catheter-associated bloodstream infection (CABSI) and device failure, save time for syringe preparation, and aid optimal flushing technique and objectives. 3. Do not use IV solution containers (eg, bags or bottles) as a source for obtaining flush solutions (see Standard 56, Compounding and Preparation of Parenteral Solutions and Medications).}, } @article {pmid40627876, year = {2025}, author = {Zeinab, EM and Lynn, K and Mohammad, M and Houssein, HA}, title = {Meckel's diverticulum in patient with early-onset ALS: A case report.}, journal = {International journal of surgery case reports}, volume = {133}, number = {}, pages = {111585}, pmid = {40627876}, issn = {2210-2612}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease primarily affecting the neuromuscular system. Gastrointestinal manifestations are typically functional in nature, while mechanical obstructions are rarely reported. Meckel's diverticulum (MD), a congenital gastrointestinal anomaly, is often asymptomatic but can cause obstruction in rare adult cases.

CASE REPORT: We present the case of a 30-year-old male with early-onset ALS who presented with signs of intestinal obstruction, including severe abdominal pain, vomiting, and obstipation. Imaging revealed a closed-loop small bowel obstruction. Emergency laparotomy identified a torsed Meckel's diverticulum as the underlying cause. Surgical resection was performed, and the postoperative course was managed with tracheostomy and PEG placement due to progressive ALS-related respiratory and swallowing impairment. The patient was successfully stabilized and discharged with ongoing multidisciplinary support. The patient was discharged three weeks later in a stable condition and remains alive under multidisciplinary follow-up.

DISCUSSION: This case highlights the diagnostic challenge of distinguishing mechanical from functional gastrointestinal symptoms in patients with advanced ALS. While neurodegenerative progression often explains GI complaints in ALS, this case emphasizes the need to consider alternative etiologies, including surgical emergencies like MD-related obstruction.

CONCLUSION: Mechanical small bowel obstruction due to Meckel's diverticulum in ALS is exceedingly rare. Timely diagnosis and intervention, supported by multidisciplinary perioperative care, are critical for favorable outcomes in this high-risk population. Despite significant ALS-related comorbidities, the patient's outcome was favorable with stable discharge and ongoing respiratory and nutritional support.}, } @article {pmid40629037, year = {2025}, author = {Wood, H}, title = {Brain-computer interface restores naturalistic speech to a man with ALS.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {8}, pages = {409}, pmid = {40629037}, issn = {1759-4766}, } @article {pmid40629298, year = {2025}, author = {Douglas, A and McPhee, M and Fisher, F and Cheng, C and Henders, A and Ziser, L and Stout, JC and Kiernan, MC and Osborne, R and Mathers, S}, title = {Using cluster analysis to identify the health literacy strengths and challenges of people living with motor neurone disease in Australia.}, journal = {BMC health services research}, volume = {25}, number = {1}, pages = {942}, pmid = {40629298}, issn = {1472-6963}, mesh = {Humans ; *Health Literacy/statistics & numerical data ; Female ; Male ; Cluster Analysis ; *Motor Neuron Disease/psychology ; Middle Aged ; Australia ; Aged ; Surveys and Questionnaires ; Adult ; Caregivers/psychology ; Aged, 80 and over ; }, abstract = {BACKGROUND: There is growing appreciation of the role health literacy plays in population health and health care design. Health literacy encompasses an individual's capacity to manage their health and the responsiveness of the health system. Our aim was to identify the health literacy strengths and challenges in an Australian cohort living with motor neurone disease (MND), including both people living with the disease and their carers.

METHODS: This study used the Health Literacy Questionnaire and eHealth Literacy Questionnaire for health literacy assessment. Using a secure online platform, an anonymous survey was disseminated which included demographic data and clinical measurements. Descriptive statistical analysis and cluster analysis were employed to describe the sample and to identify different health literacy patterns in subgroups of people living with MND and their carers.

RESULTS: A total of 227 people participated (171 people living with MND and 56 carers). Cluster analysis generated fifteen cluster profiles for the cohort living with MND and seven cluster profiles for carers. The variability and potential significance of patterns of health literacy strengths and challenges within the MND community are described. There was extensive diversity within the sampled population, with a mix of sociodemographic backgrounds across each cluster profile.

CONCLUSIONS: The health literacy cluster profiles created from this study provide insight into the full spectrum of where the challenges and strengths exist for individuals and subgroups of people managing this fatal disease. The results from this study pave the way for generating system wide interventions that address health literacy diversity, to create more enabling health care environments for all those affected by MND.}, } @article {pmid40629407, year = {2025}, author = {Choi, Y and Chung, WS}, title = {Glial phagocytosis for synapse and toxic proteins in neurodegenerative diseases.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {81}, pmid = {40629407}, issn = {1750-1326}, support = {2020M3E5D9079912//Ministry of Science and ICT, South Korea/ ; 2021R1A2C3005704//Ministry of Science and ICT, South Korea/ ; 2022M3E5E8081188//Ministry of Science and ICT, South Korea/ ; IBS-R025-A1//Institute for Basic Science/ ; }, mesh = {Humans ; *Neuroglia/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Phagocytosis/physiology ; *Synapses/metabolism/pathology ; Animals ; }, abstract = {Glia, as resident immune and supportive cells of the central nervous system, play a critical role in maintaining brain homeostasis. One of their key homeostatic functions is phagocytic capacity in pruning synapses and removing cellular debris/protein aggregates, a process vital for synaptic plasticity and brain maintenance. However, these phagocytic functions are often dysregulated with aging and in neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. This review aims to examine the phagocytic roles of glia under both physiological and pathological conditions, with a special focus on their interactions with misfolded protein aggregates, including amyloid beta, tau, alpha synuclein, prion, huntingtin, and TAR DNA-binding protein 43. We also explore the fate of ingested molecules after being phagocytosed by glia-whether they are degraded, accumulate intracellularly, or are transferred between cells-and their implications for disease progression. Finally, we review current therapeutic strategies and the potential approaches for modulating glial phagocytosis to mitigate several NDs. We believe that understanding the exact mechanisms of glial phagocytosis and clearance will serve as key elements in developing future treatments for NDs.}, } @article {pmid40629595, year = {2025}, author = {Liu, G and Liu, N and Xu, Y and Su, F}, title = {Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: A bibliometric analysis.}, journal = {Medicine}, volume = {104}, number = {27}, pages = {e43180}, pmid = {40629595}, issn = {1536-5964}, support = {202134068//Jinan City 2021 Science and Technology Innovation Development Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Lobar Degeneration/genetics ; *Bibliometrics ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics ; Mutation ; }, abstract = {OBJECTIVE: This study analyzes the research hotspots and future directions of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis.

METHODS: Relevant literature was searched using the Web of Science database and analyzed using econometric tools such as CiteSpace and VOSviewer.

RESULTS: A total of 145 articles were included in this study, involving 317 research institutions in 31 countries and regions. Acta Neuropathologica is a prominent journal in terms of issuance and influence, and countries such as the United States and Japan, as well as institutions such as the University of Pennsylvania, occupy an important position in the research. The keywords cover various aspects such as disease characteristics and gene mutations; highly-cited literature focuses on TDP-43 protein and C9orf72 gene mutations. Research hotspots include TDP-43 protein disease-driven pathomechanisms, RNA-related studies, clinical manifestations of the disease and genetic studies, etc. In recent years, research focus has shifted to RNA, C9orf72 gene and so on.

CONCLUSION: To our knowledge, this study is the first econometric evaluation of the FTLD-ALS literature, and although there are limitations such as relying on the number of documents and citation relationships, and a single source of data, it provides a valuable reference for research in this field and helps to promote subsequent research.}, } @article {pmid40629698, year = {2025}, author = {Murdock, BJ and Park, J and Jang, DG and Zhao, B and Teener, SJ and Webber-Davis, IF and Zhao, L and Feldman, EL and Goutman, SA}, title = {In Vitro Modeling of Natural Killer Cell Cytotoxicity to Inform Personalized ALS Therapeutics.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {10}, pages = {2036-2044}, pmid = {40629698}, issn = {2328-9503}, support = {R01NS127188/NH/NIH HHS/United States ; //Peter R. Clark Fund for ALS Research/ ; R01NS120926/NH/NIH HHS/United States ; //Coleman Discovery Fund/ ; 20-IIA-431//ALS Association/ ; //Scott L. Pranger/ ; R01TS000339/ACL/ACL HHS/United States ; R01 TS000339/TS/ATSDR CDC HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; //Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund/ ; //Sinai Medical Staff Foundation/ ; AL200064//U.S. Department of Defense/ ; //Hiller and Novak Families/ ; //NeuroNetwork for Emerging Therapies at the University of Michigan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/drug therapy ; *Killer Cells, Natural/drug effects/immunology ; Female ; Male ; *Piperidines/pharmacology ; Middle Aged ; Aged ; *Pyrimidines/pharmacology ; Precision Medicine/methods ; Adult ; *Cytotoxicity, Immunologic/drug effects ; *Protein Kinase Inhibitors/pharmacology ; }, abstract = {OBJECTIVE: Natural killer (NK) cells might contribute to motor neuron death in amyotrophic lateral sclerosis (ALS) through direct cytotoxicity, a process that could be inhibited with the FDA-approved JAK/STAT pathway inhibitor, tofacitinib. This study aimed to verify that tofacitinib can suppress NK cell cytotoxicity, investigate if immune cell profiles can predict responsiveness to tofacitinib, and assess the role of NK cell cytotoxicity in ALS progression.

METHODS: Primary NK cells were isolated from peripheral blood samples of ALS participants and healthy controls. NK cells were then co-cultured with target cancer cells, with or without tofacitinib, to assess their cytotoxic activity. Flow cytometry was used to generate immune profiles for each participant, based on 154 immune markers, to explore correlations with NK cell cytotoxicity and response to tofacitinib. The potential association between NK cell cytotoxicity and disease severity, as measured by the revised ALS Functional Rating Scale, was also assessed. All analyses were stratified by age and sex.

RESULTS: Tofacitinib effectively reduced the cytotoxicity of primary NK cells isolated from the blood of ALS participants (n = 80) and healthy controls (n = 71), with immune cell profiles correlating with the response to tofacitinib. However, NK cell cytotoxicity was lower in ALS participants compared to healthy controls and showed no association with ALS progression.

INTERPRETATION: These findings confirm that tofacitinib suppresses NK cell cytotoxicity, and that immune profiling may help identify treatment responder groups. However, further research is needed to fully understand the role and timing of NK cell activity in ALS pathogenesis.}, } @article {pmid40629851, year = {2025}, author = {Lawless, MJ and Chan, N and Patel, K and Wang, M and Colter, DC}, title = {Qualification of a electrochemiluminescence assay for the detection of human urinary neurotrophin receptor p75.}, journal = {Bioanalysis}, volume = {17}, number = {12}, pages = {807-815}, pmid = {40629851}, issn = {1757-6199}, mesh = {Humans ; *Luminescent Measurements/methods ; *Electrochemical Techniques/methods ; Biomarkers/urine ; Limit of Detection ; *Urinalysis/methods ; }, abstract = {The extracellular domain of the neurotrophin receptor p75 has been shown to be a prominent biomarker for both disease diagnosis and progression for amyotrophic lateral sclerosis. This urinary analyte may serve as a valuable fluid biomarker which greatly increases the ease of sample collection in both healthy volunteers and patients. In this paper, the method development and validation for an electrochemiluminescence assay is described. This assay completely uses commercially available reagents and can be performed using common lab equipment found in most bioanalytical labs. This method shows good accuracy and precision, high sensitivity as well as good parallelism illustrating the ability of the method to detect and report on urinary concentrations of neurotrophin receptor p75. The assay can quantitate as low as 78 pg/mL of neurotrophin receptor p75 and > 98% of healthy urine samples tested fell within the dynamic range of the assay.}, } @article {pmid40630909, year = {2025}, author = {Peller, J and Trevisan, MA and Bujia, G and Aguirre, F and Shalom, DE and Taitz, A and Henze, S and Bastola, S and Osik, J and Shewcraft, RA and Jiang, P and Schwartz, J and Heiman-Patterson, T and Sherman, ME and Wipperman, MF and Levy, O and Shou, G and Sillay, KA and Ostrow, LW and Fraenkel, E and Berry, JD and Navar Bingham, I and Roitberg, EG}, title = {Reliable monitoring of respiratory function with home spirometry in people living with amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1588992}, pmid = {40630909}, issn = {1664-2295}, abstract = {INTRODUCTION: Monitoring respiratory function is essential for assessing the progression of Amyotrophic Lateral Sclerosis (ALS) and planning interventions. Remote pulmonary function testing offers a promising alternative to in-clinic visits by reducing participant burden and enabling more frequent and accessible measurements.

METHODS: To evaluate the feasibility and reliability of home-based spirometry in ALS, we built on the Radcliff Study, a fully remote, longitudinal, exploratory study conducted at home by 67 people with ALS (pALS). After an initial training period, participants managed their coaching autonomously, performing spirometry independently or requesting assistance from trained personnel.

RESULTS: We demonstrate that combining flexible coaching with a predefined automatic quality control protocol yields consistent and reliable spirometry results for tracking respiratory function over time. This approach reveals that home-measured Slow Vital Capacity (SVC) and Forced Vital Capacity (FVC) evolve similarly and follow a linear trajectory throughout the study period (7.7 ± 4.0 months), in both slow and fast progressor subpopulations.

DISCUSSION: The observed linearity in respiratory trajectories supports the potential for early and accurate estimation of progression, reinforcing the feasibility of less frequent monitoring without compromising assessment precision and reducing the burden on both pALS and the healthcare system. Furthermore, our results align with reported in-clinic pulmonary tests, validating remote monitoring as a means to promote more equitable and accessible clinical trial designs.}, } @article {pmid40631187, year = {2025}, author = {Scheutzow, AN and Thanthirige, S and Siffer, G and Sorkin, AD and Wohlever, ML}, title = {E3 ligase recruitment by UBQLN2 protects substrates from proteasomal degradation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40631187}, issn = {2692-8205}, support = {S10 OD021619/OD/NIH HHS/United States ; }, abstract = {Ubiquilins are a family of proteins critical to cellular proteostasis that are also linked to several neurodegenerative diseases, with specific mutations in UBQLN2 causing dominant, X-linked ALS. Despite an initial characterization as proteasomal shuttle factors, Ubiquilins have paradoxically been reported to stabilize numerous substrates. The basis of this triage decision remains enigmatic. Many other fundamental aspects of Ubiquilin function are unclear at the mechanistic level, such as the physiological significance of Ubiquilin phase separation, the unique role of each Ubiquilin paralog, and the mechanistic defects of ALS mutants. To address these questions, we utilized a library of triple knockout (TKO) rescue cell lines with physiological expression of single Ubiquilin paralogs or disease mutants in an isogenic background. Our findings reveal that UBQLN2 has a unique ability to protect substrates from degradation and that substrate stabilization correlates with the recruitment of multiple E3 ligases, including SCF[bxo7]. We propose that E3 ligase recruitment promotes UBQLN2 phase separation, which protects substrates from proteasomal degradation. Consistent with this model, we demonstrate that ALS mutants, which were previously shown to have altered phase separation properties, also show a defect in substrate stabilization. Finally, we show that substrate stabilization appears to be a general feature of proteins that interact with the UBQLN2 Sti1 domains as amyloid precursor protein (APP) is also protected from proteasomal degradation by the formation of biomolecular condensates. This proposal unifies many existing observations in the field and presents a new paradigm for understanding Ubiquilin function in neurodegenerative disease.}, } @article {pmid40631777, year = {2025}, author = {LaBarge, B and Lorenz, FJ and Gniady, JP}, title = {Association of Laryngeal Dystonia With Common Neurologic Disorders.}, journal = {The Laryngoscope}, volume = {135}, number = {11}, pages = {4259-4262}, pmid = {40631777}, issn = {1531-4995}, support = {UL1 TR002014/TR/NCATS NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Middle Aged ; Aged ; *Dystonia/epidemiology/complications ; *Laryngeal Diseases/epidemiology/complications ; *Nervous System Diseases/epidemiology/complications ; Prevalence ; Adult ; Case-Control Studies ; }, abstract = {OBJECTIVE: Laryngeal dystonia is a heterogenous disorder consisting of involuntary spasms of laryngeal muscles. There are multiple forms including adductor, abductor, and mixed phenotypes. The disorder is thought to be multifactorial, with various reported associations with family history of dystonia or movement disorders. The relationship between laryngeal dystonia and various neurologic disorders is not well defined in the literature.

METHODS: We utilized the TriNetX de-identified electronic medical record database system spanning 2010-2023 to assess the prevalence of laryngeal dystonia with common neurologic disorders, compared to an age-sex matched control population. We included patients with the laryngeal spasm J38.5 ICD-10 code and 64617 CPT code, in order to categorize laryngeal dystonia patients undergoing chemodenervation.

RESULTS: The patient cohort consisted of approximately 4000 patients. 75% were female, 71% were white, and the mean age was 61 years. The laryngeal dystonia population had an elevated relative risk of Parkinson's disease (RR = 2.7, 1.8-3.9, 95% CI). In contrast, the relative risk of Alzheimer's disease was decreased in the laryngeal dystonia population (RR = 0.28, 0.16-0.48, 95% CI). There were no differences between the laryngeal dystonia and control populations for multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, migraine, muscular dystrophy, or cerebral palsy.

CONCLUSION: Laryngeal dystonia patients have a significantly greater association with Parkinson's disease and less association with Alzheimer's disease compared to the control population. There were no meaningful associations with the remainder of the neurologic conditions included in the study.}, } @article {pmid40632556, year = {2025}, author = {Shaked, R and Katz, M and Cohen-Dvashi, H and Diskin, R}, title = {The prefusion structure of the HERV-K (HML-2) Env spike complex.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {28}, pages = {e2505505122}, pmid = {40632556}, issn = {1091-6490}, support = {209/20//Israel Science Foundation (ISF)/ ; }, mesh = {*Endogenous Retroviruses/chemistry/metabolism/genetics ; Cryoelectron Microscopy ; Humans ; Models, Molecular ; *Gene Products, env/chemistry/metabolism ; }, abstract = {The human endogenous retrovirus K (HERV-K) is a retrovirus that got assimilated into the human genome in ancient times and has been inherited in our germline ever since. It enters cells using a class-I spike protein (Env) that mediates receptor recognition and membrane fusion. On top of having a biological role during development, HERV-K is activated in amyotrophic lateral sclerosis, various cancers, and other pathological conditions. Antibodies that target the HERV-K spike complex have therapeutic value, flagging the spike as a novel drug target. Here, we use cryo-EM to determine the trimeric structure of the HERV-K spike. The spike presents a distinct structure, which substantially differs from other class-I fusogens. Nevertheless, some general architectural features suggest a common origin with other retroviruses. The ability to structurally characterize the HERV-K spike may facilitate the development of antibody-based therapies.}, } @article {pmid40632651, year = {2025}, author = {Dos Santos, M and Bezprozvannaya, S and McAnally, JR and Cai, C and Liu, N and Olson, EN}, title = {A mechanistic basis of fast myofiber vulnerability to neuromuscular diseases.}, journal = {Cell reports}, volume = {44}, number = {7}, pages = {115959}, pmid = {40632651}, issn = {2211-1247}, support = {P50 HD087351/HD/NICHD NIH HHS/United States ; R01 AR071980/AR/NIAMS NIH HHS/United States ; R01 HL130253/HL/NHLBI NIH HHS/United States ; R01 NS055028/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Muscle Fibers, Fast-Twitch/metabolism/pathology ; *Neuromuscular Diseases/pathology/metabolism/genetics ; Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; Muscular Atrophy/pathology/genetics/metabolism ; Muscle, Skeletal/metabolism/pathology ; Male ; Mice, Inbred C57BL ; Muscle Fibers, Skeletal/metabolism ; }, abstract = {Neuromuscular diseases such as amyotrophic lateral sclerosis and sarcopenia cause muscle atrophy, which preferentially affects fast-twitch glycolytic myofibers. The mechanisms underlying the susceptibility of fast myofibers to disease remain unclear. To investigate this, we analyzed the transcriptional profiles of myonuclei from denervated muscle fibers. We found that the fast muscle gene program and the transcription factor Maf were repressed upon denervation. Overexpression of Maf in mice prevented loss of muscle mass caused by denervation by repressing atrophic genes and restoring fast gene expression. Similar repression of fast genes and Maf was observed in muscles from mice and humans with amyotrophic lateral sclerosis. Notably, Maf overexpression in human skeletal muscle cells in vitro prevented muscle atrophy and activated the expression of fast muscle genes. Our findings highlight a key role for Maf in maintaining muscle mass and could offer a promising therapeutic strategy to preserve muscle function during disease, aging, and injury.}, } @article {pmid40633079, year = {2025}, author = {Al-Akeedi, JM and Khudiar, HH and Al Muhtaser, STM and Al-Fahham, AA}, title = {Genotypes of Candida albicans and its cooperative interaction with Streptococci isolated from throat infections.}, journal = {Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego}, volume = {53}, number = {3}, pages = {378-383}, doi = {10.36740/Merkur202503112}, pmid = {40633079}, issn = {1426-9686}, mesh = {*Candida albicans/genetics/isolation & purification/physiology ; Humans ; Genotype ; Biofilms/growth & development ; *Streptococcus/isolation & purification/genetics/physiology ; *Streptococcal Infections/microbiology ; *Pharyngitis/microbiology ; }, abstract = {OBJECTIVE: Aim: This study was aimed to detect and determine genotypes of Candida albicans and its cooperative interaction with streptococci isolated from throat infections.

PATIENTS AND METHODS: Materials and Methods: This survey was carried out during November 2023 and March 2024 to collect a total of 80 throat swab samples from patients in in Al-Sadr Medical City in Najaf during. Candida was isolated from culturing throat swab samples on Sabouraud agar, and Blood agar. Each isolate (Candida & Streptococci) enhanced in monoculture using enrichment media; Potato Dextrose broth. Molecular assay included detecting three of biofilm forming genes; Als1, Als2, Als3.

RESULTS: Results: Twelve out of fifteen Candida isolates showed increase in number after mixing with Streptococci and incubation. In contrast, three isolates showed no change or decrease after mixing in co-culture media. Five Candida isolates (out of 15 isolates) were positive in gel electrophoresis to three biofilm genes classified as first genotype (CALSG1). Four Candida isolates were negative in gel electrophoresis to three biofilm genes, classified as second genotype (CALSG2). Other Candida isolates were positive to one or two of three biofilm genes, classified with genotypes (CALSG3, CALSG4, CALSG5 and CALSG6).

CONCLUSION: Conclusions: Candida albicans has biofilm formation genes (Als), which attract other organisms, like streptococci resulting in synergistic interaction. Despite the presence of some Als genes, it's not necessary to found strong biofilm results as Als genes may not be translated to form biofilm.}, } @article {pmid40633900, year = {2025}, author = {Singh, N and Mishra, D and Gomes, J}, title = {Deleterious Sequestosome 1 mutations G262R and P438L in amyotrophic lateral sclerosis cause autophagy and oxidative stress imbalance.}, journal = {Neuroscience}, volume = {581}, number = {}, pages = {233-246}, doi = {10.1016/j.neuroscience.2025.07.011}, pmid = {40633900}, issn = {1873-7544}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Sequestosome-1 Protein/genetics/metabolism ; *Autophagy/genetics ; *Oxidative Stress/genetics ; Cell Line, Tumor ; DNA-Binding Proteins/metabolism ; Signal Transduction ; Mutation ; NF-E2-Related Factor 2/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease (NDD) prevalent across the world. It is known that mutations in ALS associated genes can cause imbalances between cellular processes such as apoptosis, necroptosis, autophagy and proteasomal degradation that remove dysfunctional and aggregating proteins. Two rare missense variants namely G262R (G > A) and P438L (C > T) in Sequestosome 1 (SQSTM1), were identified by our group in a cohort of Indian ALS patients. SQSTM1 codes for p62, which is an autophagy adaptor protein involved in several signaling pathways. In this study, we investigated how these SQSTM1 mutations affect autophagy and the oxidative stress response pathway in SH-SY5Y cells through quantitative RT-PCR, immunoblotting and confocal microscopy. In addition, we examined how changes in the downstream signaling pathways alters nuclear-cytoplasmic localization of TDP-43 protein, a marker protein usually found in cytoplasmic inclusions in ALS patient tissues. We observed up-regulation of autophagy marker proteins LC3-II and ubiquitin, and down-regulation of oxidative stress marker protein Nrf2. Along with LC3-II, p-OPTN and ATG5, proteins that are also associated with autophagy were up-regulated. We also observed an increase in cytoplasmic localization of TDP-43 protein in cells expressing these p62 mutant proteins. Overall, our study provides evidence that the G262R (G > A) and P438L (C > T) mutations are deleterious through mechanisms that increase cytoplasmic localization of TDP-43, and adversely affect the autophagy and oxidative stress response pathway.}, } @article {pmid40635530, year = {2025}, author = {Manicardi, A and Mora, G and Araujo, ALS and Gaines, TA and Lozano-Juste, J and Torra, J}, title = {Analysis of multiple-herbicide resistant Amaranthus palmeri populations from Spain points to an introduction of the eccDNA from America.}, journal = {Pest management science}, volume = {81}, number = {10}, pages = {6807-6819}, pmid = {40635530}, issn = {1526-4998}, support = {PRTR-C17.I1//European Union NextGenerationEU, AGROALNEXT, GVA/ ; 801586//H2020 Marie Skłodowska-Curie Actions/ ; PID2020-113229RB-C42//Spanish State Research Agency and the European Regional Development Fund, EU (ERDF)/ ; PID2021-128826OAI00//Spanish MCIN/AEI/ ; RYC2020-029097-I//Spanish MCIN/AEI/ ; RYC2018-023866-I//Spanish MCIN/AEI/ ; CISEJI/2022/26//Generalitat Valenciana, Plan GenT/ ; RED2022-134285-T(PalmerNET)//Spanish Ministry of Science and Innovation/ ; }, mesh = {*Amaranthus/genetics/drug effects ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Spain ; Acetolactate Synthase/genetics/antagonists & inhibitors ; Glyphosate ; Glycine/analogs & derivatives/pharmacology ; 3-Phosphoshikimate 1-Carboxyvinyltransferase/antagonists & inhibitors/genetics ; Plant Weeds/genetics/drug effects ; Plant Proteins/genetics/metabolism ; Introduced Species ; }, abstract = {BACKGROUND: The herbicide-resistant invasive weed species Amaranthus palmeri threatens agricultural production and native plant ecology in Spain, as well as in other European countries. Understanding whether herbicide resistance alleles evolve in situ or are introduced via gene flow remains unclear. To address this, we characterized multiple resistance to acetolactate synthase (ALS)-- and 5-enolpyruvylshikimate-3phosphate synthase (EPSPS)-inhibiting herbicides in two Spanish A. palmeri populations at the plant level. Additionally, we analyzed the extra-chromosomal circular DNA (eccDNA) to determine whether glyphosate resistance resulted from local selection pressure or was introduced by gene flow.

RESULTS: Both populations exhibit individuals that survived both herbicide MoA, with multiple resistance mechanisms to ALS- and EPSPS-inhibiting herbicides. Eight different ALS allele mutations were identified in resistant plants, including Pro-197-Ile, reported only in one species previously. Glyphosate resistance in the two populations is to the result of gene duplication mediated by eccDNA. Spanish and North American eccDNAs showed complete identity, with no single nucleotide polymorphisms (SNPs) found between the partial analyzed sequences of noncoding regions.

CONCLUSION: We confirm for the first time in Europe resistance to ALS and EPSPS inhibitors at both the population and individual levels in two Spanish A. palmeri populations. The absence of SNPs in the eccDNA from Spanish populations compared to the reference American sequence and the presence of target-site mutations in the ALS gene occurred without selective pressure from ALS herbicides, suggests that the origin of resistance traits may have evolved elsewhere and been introduced from the place of origin to Spain. However, it is important to note that the limited number of populations studied and the partial sequencing of eccDNA do not provide definitive confirmation of the exact origins of resistance mechanisms. This work raises concerns about the arrival of this and potentially other new herbicide-resistant A. palmeri populations in Europe posing challenges for management. © 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid40637865, year = {2025}, author = {Coleman, A and Touzé, A and Farag, M and Pengo, M and Murphy, MJ and Hassan, Y and Thackeray, O and Fayer, K and Field, S and Nakajima, M and Broom, EL and Hobbs, NZ and Huxford, B and Donkor, N and Camboe, E and Dey, KC and Zirra, A and Ahmed, A and Gameiro Costa, AR and Sorrell, H and Zampedri, L and Lombardi, V and Wade, C and Mangion, S and Fneich, B and Heslegrave, A and Zetterberg, H and Scahill, R and Noyce, A and Malaspina, A and Chataway, J and Tabrizi, SJ and Byrne, LM}, title = {Evaluating finger-prick blood collection for remote quantification of neurofilament light in neurological diseases.}, journal = {Journal of neurology}, volume = {272}, number = {8}, pages = {501}, pmid = {40637865}, issn = {1432-1459}, support = {MR/W026686/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Neurofilament Proteins/blood ; Male ; Female ; Middle Aged ; Biomarkers/blood ; Adult ; Aged ; *Blood Specimen Collection/methods/standards ; *Nervous System Diseases/blood/diagnosis ; Cohort Studies ; Parkinson Disease/blood ; Amyotrophic Lateral Sclerosis/blood ; Huntington Disease/blood/diagnosis ; Multiple Sclerosis/blood ; }, abstract = {Promising blood-based biomarkers of neuropathology have emerged with potential for therapeutic development and disease monitoring. However, these tools will require specialist tertiary services for integration into clinical management. Remote sampling for biomarker assessment could reduce burden of in-person clinical visits for such tests as well as increasing the sampling frequency and patient geographical outreach. Here, we evaluated a finger-prick blood collection approach for remote quantification of neurofilament light (NfL), a candidate blood-based biomarker evident in various neurological disorders, and other exploratory markers of neuronal injury and neuroinflammation (GFAP, tau). Matched samples from venepuncture and finger-prick were collected and processed into plasma and/or serum to directly compare analyte levels from a multi-disease discovery cohort (n = 54 healthy controls; n = 57 Huntington's disease (HD); n = 34 multiple sclerosis; n = 7 amyotrophic lateral sclerosis; n = 11 Parkinson's disease), and a HD confirmatory cohort (n = 57 healthy controls; n = 64 HD). Two delayed processing conditions were compared, three- and seven-day delay, simulating ambient shipment. Capillary NfL and GFAP concentrations were equivalent to those in venous serum and plasma in the multi-disease discovery cohort and HD confirmatory cohort. Only NfL remained stable after a seven-day processing delay in both venous and capillary serum samples. Using NfL concentrations from capillary blood, we replicated previously published disease group differences measured in venous blood. This data supports our finger-prick approach for remote collection and quantification of NfL. With the widespread applications for NfL across the spectrum of neurological disorders, this has the potential to transform disease monitoring, prognosis, and therapeutic development within clinical practice and research.}, } @article {pmid40639550, year = {2025}, author = {Mondal, M and Chouksey, A and Gurjar, V and Tiwari, R and Srivasatava, RK and Mishra, PK}, title = {Micro(nano)plastics in the brain: Epigenetic perturbations in progression to neurodegenerative diseases.}, journal = {Neurotoxicology and teratology}, volume = {110}, number = {}, pages = {107521}, doi = {10.1016/j.ntt.2025.107521}, pmid = {40639550}, issn = {1872-9738}, mesh = {Humans ; *Neurodegenerative Diseases/chemically induced/genetics ; *Epigenesis, Genetic/drug effects ; Animals ; *Brain/drug effects/metabolism ; Mitochondria/drug effects ; DNA Methylation/drug effects ; Disease Progression ; }, abstract = {As global plastic production escalates, micro(nano)plastics (MNPs) have become pressing ecological and biomedical concerns. These pollutants are increasingly implicated in the pathogenesis of neurodegenerative diseases. Due to their nanoscale size and surface reactivity, MNPs can cross the blood-brain barrier, accumulating in neural tissues. Once internalized, they disrupt neuronal homeostasis by inducing oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, key processes in neurodegenerative progression. Mitochondria, central to neuronal energy and redox regulation, are particularly vulnerable, leading to impaired ATP production, elevated ROS, and pro-apoptotic signaling. Recent studies reveal that MNPs also induce epigenetic changes, including aberrant DNA methylation, histone modifications, and dysregulation of non-coding RNAs. These alterations can result in synaptic instability, persistent transcriptional reprogramming, and heightened susceptibility to diseases like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. The mitochondrial epigenome is a vital target of MNP-induced disruption, offering potential biomarkers like methylated mtDNA and microRNAs for early diagnosis and prognosis. Understanding the molecular mechanisms behind these epigenetic alterations is essential for developing practical diagnostic tools and therapies. This review provides a comprehensive overview of MNP-induced neurodegeneration, focusing on mitochondrial and epigenetic disruptions. Moreover, it explores emerging biosensing technologies for detecting MNP-induced epigenetic alterations, highlighting the urgent need for further investigation to fully understand the neurotoxic potential of MNPs and develop preventive and therapeutic strategies for mitigating their effects on brain health.}, } @article {pmid40640025, year = {2026}, author = {Kim, S and Yang, M and Ku, B and Cha, E and Seo, W and Son, I and Kang, H and Kim, D and Song, B and Yang, CS and Kim, S}, title = {Corrigendum to "Efficacy of mecasin for treatment of amyotrophic lateral sclerosis: A phase IIa multicenter randomized double-blinded placebo-controlled trial" [J. Ethnopharmacol. 320 (2023) 116670].}, journal = {Journal of ethnopharmacology}, volume = {356}, number = {}, pages = {120239}, doi = {10.1016/j.jep.2025.120239}, pmid = {40640025}, issn = {1872-7573}, } @article {pmid40640528, year = {2025}, author = {McGuigan, A and Blair, HA}, title = {Tofersen: A Review in Amyotrophic Lateral Sclerosis Associated with SOD1 Mutations.}, journal = {CNS drugs}, volume = {39}, number = {9}, pages = {903-912}, pmid = {40640528}, issn = {1179-1934}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Superoxide Dismutase-1/genetics ; Mutation ; *Oligonucleotides/therapeutic use/adverse effects/pharmacology ; *Oligonucleotides, Antisense/therapeutic use/adverse effects ; }, abstract = {Tofersen (QALSODY[®]) is the first drug approved for the treatment of amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (SOD1) mutations. Tofersen is an antisense oligonucleotide that induces SOD1 mRNA degradation. In the 28-week, placebo-controlled, multinational, phase III VALOR trial, intrathecally administered tofersen reduced plasma concentrations of neurofilament proteins (biomarker for neuro-axonal injury) and total SOD1 protein in cerebrospinal fluid in patients with SOD1 mutation-associated ALS. These reductions were sustained in a long-term, open-label extension study. The decline in functional outcomes was not significantly reduced with tofersen treatment compared with placebo in the 28-week phase III trial, although in the longer-term open-label study, early tofersen initiation was associated with slowed functional decline versus delayed tofersen initiation. Tofersen had an acceptable tolerability profile in clinical trials with a favourable benefit-to-risk balance. In summary, tofersen is a new disease-modifying therapy for patients with ALS attributed to an SOD1 mutation, offering reductions in levels of a biomarker associated with neurodegeneration and disease progression, with an acceptable tolerability profile.}, } @article {pmid40640855, year = {2025}, author = {Soliman, SS and Talib, NFA and Elghobashy, MR and Rahman, MAA}, title = {Sustainable analysis of COVID-19 Co-packaged paxlovid: exploring advanced sampling techniques and multivariate processing tools.}, journal = {BMC chemistry}, volume = {19}, number = {1}, pages = {206}, pmid = {40640855}, issn = {2661-801X}, abstract = {The drawbacks of random sampling not only hinder the development of more reliable and efficient methods but also weaken their accuracy, predictive abilities, and validity across several domains. During the current study, a pioneering statistical technique namely, Latin Hypercube Sampling (LHS) was integrated with different multivariate chemometric models namely; Partial Least Squares (PLS), Genetic Algorithm‑Partial Least Squares (GA-PLS), Artificial Neural Networks (ANN), and Multivariate Curve Resolution‑Alternating Least Squares (MCR-ALS). This integration aimed to achieve full data coverage and thereby enhance the predictive powers of these models. Being of clinical significance, Paxlovid[®], a newly co-packaged antiCOVID-19 drug containing ritonavir (RNV)-boosted nirmatrelvir (NMV), was utilized as a study subject to demonstrate the powerful potentials of LHS in enhancing models' robustness and predictive accuracy. The LHS technique was able to provide well-interpreted and informative samples by capturing essential variabilities across the input space without any increase in sample numbers. It was compared and outperformed the random sampling Monte Carlo technique. A comprehensive comparison between the developed models was held where the RMSEP was relatively reduced by 14.1%, 8.9%, 53.1%, and 34.6% for RNV and NMV, respectively using the ANN and MCR-ALS models. Various preprocessing techniques were employed to improve signal quality for PLS construction, yielding superior results (RMSEC of 0.19 for both RNV and NMV) compared to the original, unprocessed spectral data (RMSEC of 0.21 for both RNV and NMV). The Principal Component Analysis score plot was constructed, confirming the consistency of the dataset and the absence of systematic errors, enhancing confidence in the models' robustness. A new hybrid variable selection strategy (GA-ICOMP-PLS) was developed to enhance the robustness and parsimony of the GA-PLS model. Prediction error values of 0.15 and 0.14 were successfully achieved for RNV and NMV, respectively, indicating strong predictive power and generalization. Consistent with sustainability and eco-friendly goals, the current study pioneers the usage of green-blue-white alternatives to conventional analytical methods. A comprehensive assessment was conducted using the "Sample Preparation Metric of Sustainability", the "Analytical Greenness metric for Sample Preparation" and the "Analytical Greenness metric" alongside two solvent sustainability evaluation tools. These evaluations yielded promising results, with green quadrant classification and high scores of 5.89, 0.67, and 0.82 for each metric, respectively, as well as satisfactory t- and F-test values. Moreover, the models achieved outstanding results on the RGB12 metric and Blueness Applicability Grade Index, scoring 96.8% and 82.5, respectively, highlighting their broad applicability, high efficiency, and alignment with eco-friendly analytical practices.}, } @article {pmid40640892, year = {2025}, author = {Noh, MY and Kwon, HS and Kwon, MS and Nahm, M and Jin, HK and Bae, JS and Kim, SH}, title = {Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {82}, pmid = {40640892}, issn = {1750-1326}, support = {RS-2024-00348451//Korea Dementia Research Center/ ; }, mesh = {Humans ; *Microglia/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; *Biomarkers/metabolism ; Animals ; }, abstract = {Recent advances in our understanding of non-cell-autonomous mechanisms in neurodegenerative diseases (NDDs) have highlighted microglial dysfunction as a core driver of disease progression. Conditions such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and frontotemporal dementia (FTD) share features of impaired microglial phagocytosis, chronic neuroinflammation, and metabolic dysregulation. These insights have prompted new therapeutic strategies targeting microglial function and emphasized the need for reliable biomarkers to monitor disease progression and treatment response. Well-established therapeutic targets, such as triggering receptor expressed on myeloid cells 2 (TREM2), progranulin (PGRN), and sortilin (SORT1), along with emerging candidates including LILRB4, P2Y6R, TAM receptors, and neuroinflammation-related markers, are discussed alongside novel blood, cerebrospinal fluid (CSF), and imaging biomarkers. Despite notable progress, many of these biomarkers remain restricted to preclinical studies and face translational challenges due to species-specific differences, lack of standardization, and clinical heterogeneity. Emerging technologies-including single-cell omics, spatial transcriptomics, and artificial intelligence (AI)-driven integration of multimodal data-offer new opportunities to align biomarker profiles with evolving disease states and improve patient stratification. Building on the model of companion diagnostics (CDx) in oncology, integrating multimodal biomarker strategies holds promise for guiding personalized interventions, improving clinical outcomes, and deepening our mechanistic understanding of microglial contributions across the neurodegenerative spectrum.}, } @article {pmid40640916, year = {2025}, author = {Lemarchant, S and Engelhardt, B and Cicchetti, F and Bix, GJ and Janus, A and Godfrin, Y and Blasco, H and Campbell, M and de Rus Jacquet, A}, title = {Restoring brain barriers: an innovative approach for treating neurological disorders.}, journal = {Fluids and barriers of the CNS}, volume = {22}, number = {1}, pages = {72}, pmid = {40640916}, issn = {2045-8118}, mesh = {Humans ; *Blood-Brain Barrier/drug effects/physiopathology/pathology/metabolism ; *Nervous System Diseases/drug therapy/therapy/pathology ; Animals ; }, abstract = {The complex etiology of neurological disorders is a major challenge to the identification of therapeutic candidates. Tackling brain vascular dysfunction is gaining attention from the scientific community, neurologists and pharmaceutical companies, as a novel disease-modifying strategy. Here, we provide evidence that at least 41% of neurological diseases and related conditions/injuries display a co-pathology of blood-brain and blood-spinal cord barrier alterations and dysfunctions, and we discuss why this figure may represent only a fraction of a larger phenomenon. We further provide clinical evidence that barrier status may contribute to pathological and functional outcomes in patients. Finally, we discuss drug candidates under development to repair brain barriers.}, } @article {pmid40640965, year = {2025}, author = {Wright, K and Warren, F and Bucci, S and Dunn, BD and Jones, S and O'Mahen, H and Taylor, RS and Medina-Lara, A}, title = {A study protocol for a randomized controlled feasibility trial of behavioural therapy for interepisode bipolar symptoms (STABILISE).}, journal = {Pilot and feasibility studies}, volume = {11}, number = {1}, pages = {97}, pmid = {40640965}, issn = {2055-5784}, support = {NIHR302220//National Institute for Health and Care Research/ ; }, abstract = {BACKGROUND: In between episodes of (hypo) mania and major depression, people with bipolar disorder can experience ongoing low mood or mood instability, and these may also be present as part of cyclothymic disorder. This is a phase II evaluation of an adapted form of behavioural therapy (STABILISE) for inter-episode bipolar symptoms. The study aims to establish the feasibility and acceptability of the therapy and research procedures, including an economic component, to inform a future definitive trial.

METHODS: Patients will be randomised 1:1 to either Treatment as Usual (control arm) or Treatment as Usual plus STABILISE intervention (intervention arm). Follow up points will be at 14, 30 and 52 weeks post eligibility confirmation, with 30 weeks as the primary end point. We aim to recruit 60 individuals meeting diagnostic criteria for a Bipolar Spectrum Disorder, and reporting ongoing bipolar symptoms (low mood or mood instability) outside of a manic or severe depressive episode. Feasibility and acceptability will be examined through recruitment and retention rates, completion rates for the candidate primary outcome measures (PHQ9, ALS-SF, QoL.BD and BRQ) and feedback from participants on their experience of study participation and therapy. Proceeding to a definitive trial will be indicated if the following criteria are met: (i) trial participation is deemed, or can be made, sufficiently safe; (ii) recruitment rate indicates that larger-scale recruitment would be feasible (recruitment rate of at least two participants per month within at least one site, with mitigation plan if overall target sample size not met); (iii) for candidate primary outcome measure follow up data is available at 30 weeks from at least 75% of participants, or from between 55 and 74% with clear plan for improvement.

DISCUSSION: This study is a randomised, controlled feasibility trial that builds on an initial case series of the STABILISE approach. The findings will be used to establish whether a future, definitive trial is feasible and to refine the research procedures and therapy protocol.

TRIAL REGISTRATION: ISRCTN18207465. Registered 13th March 2024, https://www.isrctn.com/ISRCTN18207465 .}, } @article {pmid40641139, year = {2025}, author = {Sun, Y and Wei, K and Liao, X and Wang, J and Gao, L and Pang, B}, title = {Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review).}, journal = {International journal of molecular medicine}, volume = {56}, number = {3}, pages = {}, pmid = {40641139}, issn = {1791-244X}, mesh = {*Microglia/metabolism/pathology ; Humans ; *Lipid Metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and neuroinflammation, with microglial dysfunction emerging as a central driver of pathogenesis. Microglia, the central nervous system‑resident immune cells, exhibit dual pro‑inflammatory and anti‑inflammatory phenotypes, dynamically regulated by lipid metabolic reprogramming. Chronic activation of M1 microglia exacerbates neuronal damage, while M2 microglia promote tissue repair via phagocytic clearance and neurotrophic factor secretion. Lipid dysregulation‑marked by ceramide accumulation, cholesterol esterification defects and oxidized lipid‑driven neuroinflammation‑critically modulates microglial polarization. Mechanistic studies reveal that mitochondrial dysfunction, lysosomal stress and ferroptosis intersect with lipid metabolic pathways to amplify neurotoxicity. Therapeutic strategies targeting lipid homeostasis, such as TREM2 agonism, demonstrate efficacy in preclinical models by restoring microglial function and mitigating pathology. This review synthesizes emerging evidence linking microglial lipid metabolism to NDD progression, highlighting novel biomarkers and therapeutic avenues to disrupt the lipid‑neuroinflammation axis in neurodegeneration.}, } @article {pmid40641248, year = {2025}, author = {Yang, K and Liu, Y and Deng, W and Gong, Z and Huang, L and Li, Z and Zhang, M}, title = {Astrocytes Contribute to Motor Neuron Degeneration in ALS via the TRAIL-DR5 Signaling Pathway.}, journal = {Journal of neurochemistry}, volume = {169}, number = {7}, pages = {e70146}, pmid = {40641248}, issn = {1471-4159}, support = {2024AOXIANG05//Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital/ ; 82271478//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Motor Neurons/pathology/metabolism ; Mice ; *TNF-Related Apoptosis-Inducing Ligand/metabolism ; *Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism ; *Signal Transduction/physiology ; *Astrocytes/metabolism/pathology ; *Nerve Degeneration/pathology/metabolism ; Mice, Transgenic ; Humans ; Superoxide Dismutase-1 ; Disease Models, Animal ; Superoxide Dismutase/genetics ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons. The mechanisms underlying the selective degeneration of motor neurons in ALS remain poorly understood, underscoring the need for further investigation into the factors driving this process. In this study, we utilized ALS mouse models and an in vitro NSC34 motor neuron cell line expressing the SOD1[G93A] mutation to identify a novel pathogenic mechanism wherein astrocyte-secreted Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to Death Receptor 5 (DR5)on motor neurons, leading to caspase-8 activation and subsequent neuronal death. Blocking DR5 with neutralizing antibodies significantly attenuated TRAIL-induced motor neuron death. These findings provide the first evidence that TRAIL may serve as a potential therapeutic target in ALS, offering new insights into the mechanisms of motor neuron degeneration in this disease.}, } @article {pmid40642215, year = {2025}, author = {Ahmed, Z and Samaddar, S and Hassieb, M and Sadek, R and Morozova, V and Begum, S}, title = {Multi-path direct current spinal stimulation extended survival in the SOD1-G93A model of amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1594169}, pmid = {40642215}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons in the spinal cord and brain. We have developed a novel non-invasive approach, MultiPath-DCS, which utilizes direct current stimulation at multiple sites along the neural axis to provide simultaneous spinal and peripheral stimulation targeted at the affected limbs. MultiPath-DCS modulates the excitability of spinal cord neurons. This effect is significant for ALS, as motor neuron hyperexcitability is a fundamental characteristic of the disease.

METHODS: This study used a transgenic mouse model of ALS (SOD1-G93A). Anodal-MultiPath-DCS was applied with six electrodes: three on the spine (centered on T13 and with an anodal polarity), two on the sciatic nerves (one on each nerve), and one on the abdomen. Mice were divided into two groups (stimulated vs. unstimulated or sham-stimulated). The stimulated animals received stimulation for one hour a day, three times a week, for three weeks. Survival was calculated from the onset of the disease and birth until the animal's endpoint. We also performed various electrophysiological and molecular experiments to uncover the mechanism of action.

RESULTS: We demonstrated molecular changes induced by anodal MultiPath-DCS, including (a) reduced expression of mutant SOD1 protein, (b) decreased expression of elevated NKCC1, (c) reduced phosphorylated tau, (d) increased expression of HSP70, and (e) increased expression of LC3B. Additionally, we found that treatment with Anodal-MultiPath-DCS (anode on the spinal column) reduces long-term neuronal spinal excitability, slows the progression of muscle weakness, and extends the lifespan of stimulated mice. The mean survival time in the control group was 12.4 days. In comparison, the mean survival time in the stimulated group was 21.6 days using a therapeutic stimulation paradigm, representing a 74% increase in survival from disease onset. Spinal motor neuron survival showed a 54% increase in stimulated compared to non-stimulated groups.

DISCUSSION: Combined, this data provides evidence that Anodal-MultiPath-DCS reduces hyperexcitability and enhances the clearance of misfolded proteins by modulating autophagy and proteolytic systems. By decreasing spinal excitability and clearing toxic proteins from motor neurons, Anodal-MultiPath-DCS promotes survival and could serve as a disease-modifying intervention for ALS.}, } @article {pmid40642867, year = {2025}, author = {Pang, C and Cao, W and Xie, J and Li, Y and Zhu, L and Yu, H and Fan, D and Deng, B}, title = {Prediagnosis Insights Into Amyotrophic Lateral Sclerosis: Clinical Symptoms and Medication Use.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {16}, number = {4}, pages = {e70003}, pmid = {40642867}, issn = {2190-6009}, support = {81901273//National Natural Science Foundation of China/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/epidemiology/mortality ; Female ; Male ; Aged ; Middle Aged ; Incidence ; United Kingdom/epidemiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) has a prolonged latency period, though its preclinical characteristics remain poorly understood. This study uses UK Biobank data to explore and compare ALS's pre-diagnostic features, including symptoms and medication use, aiming to provide insights into the disease's underlying mechanisms.

METHODS: Clinical symptoms and medications were identified from self-reports, hospital records, and death registry data. Propensity score matching was used to match ALS with Alzheimer's disease (AD) and Parkinson's disease (PD), ensuring balance in socioeconomic factors to compare symptoms 0-5 years before diagnosis. Cox regression analysis was applied to assess the associations between medication use and the risk of incident ALS and mortality after ALS diagnosis.

RESULTS: A total of 753 ALS cases were observed in 502 417 participants, with an incidence rate of 10.58 per 100 000 person-years. In the ALS cohort, the male-to-female ratio was 2.9, with a median age at onset of 64.61 years (Interquartile range (IQR): 56.80-71.31) and a median survival time post-diagnosis of 9.08 months (IQR: 3.18-18.98), while females (log-rank p = 0.038) and individuals with earlier (< 64.61 years) disease onset (log-rank p < 0.001) had longer survival periods. In the 5 years prior to diagnosis, ALS showed a higher incidence of falls compared to ad (11.3% vs. 3.2%, p < 0.001), but a lower incidence than PD (10.7% vs. 28.3%, p < 0.001). Additionally, ALS had a lower incidence of depression (4.6% vs. 25.6%, p < 0.001), anxiety (3.5% vs. 18.1%, p < 0.001), sleep disorders (1.4% vs. 7.2%, p < 0.001), hypotension (3.4% vs. 30.5%, p < 0.001), constipation (0.3% vs. 4.9%, p < 0.001), and urinary dysfunction (2.2% vs. 8.7%, p < 0.001) compared with PD. The use of calcium channel blockers may be a risk factor for incident ALS (adjusted HR 1.61, 95% CI: 1.22-2.12, p < 0.001).

CONCLUSIONS: Pre-diagnostic presentations of falls are more frequent in ALS than in AD, but less frequent than in PD. However, ALS exhibits fewer psychiatric symptoms and autonomic dysfunction compared with PD. The use of calcium channel blockers may be associated with an increased risk of developing ALS in the future.}, } @article {pmid40643147, year = {2026}, author = {Vélez-Gómez, B and Cabrera-Serrano, M and Paradas, C}, title = {Utilization of patient-reported outcome measures in amyotrophic lateral sclerosis management: a cross-sectional study of Spanish neurologists.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {35-43}, doi = {10.1080/21678421.2025.2523940}, pmid = {40643147}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology/diagnosis ; Cross-Sectional Studies ; *Patient Reported Outcome Measures ; *Neurologists/psychology ; Spain/epidemiology ; Male ; Female ; Middle Aged ; Surveys and Questionnaires ; Quality of Life ; Attitude of Health Personnel ; Adult ; *Disease Management ; }, abstract = {Objective: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that significantly impacts quality of life. Patient-Reported Outcome Measures (PROMs) offer a patient-centered approach by capturing self-reported assessments of symptoms and well-being. Despite their recognized value, PROM integration into ALS management remains inconsistent. This study evaluates the attitudes, practices, and barriers experienced by Spanish neurologists regarding PROM use in ALS care. Methods: A cross-sectional survey was distributed to Spanish neurologists specializing in neuromuscular disorders. The questionnaire assessed familiarity with and use of PROMs, as well as perceived benefits and barriers to their implementation. Statistical analysis included descriptive statistics, group comparisons, and exploratory factor analysis (EFA) to identify underlying factors influencing PROM use. Results: Among 60 neurologists surveyed, 93.3% were familiar with PROMs, yet only 18.3% used them routinely. PROM use did not vary significantly with years of experience, type of clinical setting, exclusive dedication to neuromuscular disorders, or the percentage of time spent on patient care. The only variable approaching significance was the number of ALS patients managed daily, with higher patient volumes associated with more frequent PROM use. Over 70% of non-users cited limited consultation time as a barrier; however, factor analysis indicated that time constraints were not a substantial limitation. PROMs were valued for supporting clinical decision-making, monitoring disease progression, and improving patient engagement. Conclusions: While PROMs are widely recognized for their potential in ALS care, barriers hinder their use. Targeted training, simplified tools, and culturally adapted PROMs are needed to facilitate broader adoption and improve outcomes.}, } @article {pmid40643479, year = {2025}, author = {Sgromo, C and Tosi, M and Olgasi, C and De Marchi, F and Favero, F and Venturin, G and Piola, B and Cucci, A and Corrado, L and Mazzini, L and D'Alfonso, S and Follenzi, A}, title = {Identification of Transcriptomic Differences in Induced Pluripotent Stem Cells and Neural Progenitors from Amyotrophic Lateral Sclerosis Patients Carrying Different Mutations: A Pilot Study.}, journal = {Cells}, volume = {14}, number = {13}, pages = {}, pmid = {40643479}, issn = {2073-4409}, support = {N. 68155.//The study was supported by the AGING Project for Department of Excellence at the Department of Translational Medicine (DIMET), Università del Piemonte Orientale, Novara, Italy and DIG-ALS, AriSLA Foundation. AF was supported by CSP - Compagnia San Paolo T/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Induced Pluripotent Stem Cells/metabolism/pathology ; Pilot Projects ; Kruppel-Like Factor 4 ; *Mutation/genetics ; *Transcriptome/genetics ; *Neural Stem Cells/metabolism/pathology ; Female ; Middle Aged ; Male ; Cell Differentiation ; C9orf72 Protein/genetics ; Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons with a phenotypic and genetic heterogeneity and elusive molecular mechanisms. With the present pilot study, we investigated different genetic mutations (C9orf72, TARDBP, and KIF5A) associated with ALS by generating induced pluripotent stem cells (iPSCs) from peripheral blood of ALS patients and healthy donors. iPSCs showed the typical morphology, expressed stem cell markers both at RNA (OCT4, SOX2, KLF4, and c-Myc) and protein (Oct4, Sox2, SSEA3, and Tra1-60) levels. Moreover, embryoid bodies expressing the three germ-layer markers and neurospheres expressing neural progenitor markers were generated. Importantly, the transcriptomic profiles of iPSCs and neurospheres were analyzed to highlight the differences between ALS patients and healthy controls. Interestingly, the differentially expressed genes (DEGs) shared across all ALS iPSCs are linked to extracellular matrix, highlighting its importance in ALS progression. In contrast, ALS neurospheres displayed widespread deficits in neuronal pathways, although these DEGs were varied among patients, reflecting the disease's heterogeneity. Overall, we generated iPSC lines from ALS patients with diverse genetic backgrounds offering a tool for unravelling the intricate molecular landscape of ALS, paving the way for identifying key pathways implicated in pathogenesis and the disease's phenotypic variability.}, } @article {pmid40643880, year = {2025}, author = {Wang, P and Shang, H and Li, C}, title = {Association of creatinine level with neurodegenerative disorders: a prospective cohort study and Mendelian randomization analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {10}, pages = {5123-5132}, pmid = {40643880}, issn = {1590-3478}, support = {24NSFSC0358//Sichuan Science and Technology Program/ ; }, mesh = {Humans ; Mendelian Randomization Analysis ; *Creatinine/blood/urine ; Male ; Female ; *Neurodegenerative Diseases/blood/genetics/urine/epidemiology ; Middle Aged ; Prospective Studies ; Genome-Wide Association Study ; Aged ; *Amyotrophic Lateral Sclerosis/blood/genetics/epidemiology/urine ; Cohort Studies ; United Kingdom/epidemiology ; Biomarkers/blood ; }, abstract = {BACKGROUND: Multiple evidence has suggested interaction between neurodegenerative disorders (NDDs) and creatinine, a metabolite derived from the high-energy product creatine. However, findings across studies have shown inconsistency, and the effect direction remains controversial. Here, we aimed to explore the link between creatinine and the risk of NDDs.

METHODS: Utilizing data from the UK Biobank, we investigated the association between baseline serum and urine creatinine and the risk of common NDDs using Cox proportional hazards regression analysis. Furthermore, we performed genetic correlation and Mendelian randomization analyses based on summary statistics from genome-wide association studies.

RESULTS: A higher level of serum creatinine at baseline was associated with a lower risk of incident amyotrophic lateral sclerosis (ALS) (beta=-0.013, SE = 0.004, P = 1.88E-03). From the genetic perspective, a significant and negative genetic correlation was identified between serum creatinine and ALS risk (genetic correlation: -0.17, P = 0.017). Mendelian randomization analysis corroborated the primary finding, indicating that serum creatinine was associated with a reduced risk of ALS (OR: 0.92, 95% CI: 0.86-0.98, P = 0.01). Moreover, a higher level of baseline serum creatinine was associated with a reduced risk of incident Alzheimer's disease (beta=-4.89E-03, SE = 2.24E-03, P = 0.03), though the effect size was small.

CONCLUSIONS: These findings enhance our understanding of creatinine's role in the risk of NDDS, suggest the potential of targeting creatinine as a biomarker of ALS, and hold implications for designing therapeutic interventions in clinical trials.}, } @article {pmid40644388, year = {2026}, author = {Holanda Braga, CAO and Diniz, DS}, title = {Characterizing changes in functioning in Brazilian patients with ALS using a comprehensive ICF core set.}, journal = {Disability and rehabilitation}, volume = {48}, number = {1}, pages = {179-186}, doi = {10.1080/09638288.2025.2532124}, pmid = {40644388}, issn = {1464-5165}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation ; Male ; Female ; Brazil ; Middle Aged ; *International Classification of Functioning, Disability and Health ; *Disability Evaluation ; Aged ; Longitudinal Studies ; Activities of Daily Living ; *Persons with Disabilities/rehabilitation ; }, abstract = {PURPOSE: To longitudinally describe the impact of amyotrophic lateral sclerosis (ALS) using a core set based on the International Classification of Functioning, Disability and Health (ICF).

PATIENTS AND METHODS: Between May 2021 and August 2022, 42 Brazilian patients with ALS (21 men/21 women, mean age 59.92 years, 23.8% with bulbar-onset ALS and 76.2% with spinal-onset ALS) were included. Patients diagnosed at least 6 months previously were assessed using 42 ICF categories at baseline and every six months thereafter for 16 months. The Friedman test was used to compare three time points, followed by Wilcoxon post hoc analyses. The Bonferroni method was applied. P-values ≤0.05 were considered significant. Overall and subgroup (bulbar-onset/spinal-onset ALS) analyses were performed.

RESULTS: Significant changes were found in 24/42 ICF categories. The most affected Body Functions included respiratory muscle functions (b445), power of muscles of one limb (b7301), muscle power (b730) and gait pattern (b770). Early disabilities involved pain sensation (b280) and respiratory functions. Limitations in Activities and Participation included transferring oneself (d420), hand and arm use (d445), dressing (d540), washing oneself (d510) and speaking (d330).

CONCLUSION: This ICF core set may help determine key facilitators and barriers to functioning and disability in ALS, guiding rehabilitation efforts.}, } @article {pmid40644419, year = {2025}, author = {Bertran-Recasens, B and Vidal-Notari, S and Hernández Guillamet, G and López Seguí, F and Vidal-Alaball, J and Jiménez-Balado, J and Rubio, MA}, title = {Epidemiology of amyotrophic lateral sclerosis: a population-based analysis, 2015-2020.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {784-793}, doi = {10.1080/21678421.2025.2527887}, pmid = {40644419}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/mortality ; Female ; Male ; Aged ; Spain/epidemiology ; Middle Aged ; Incidence ; Prevalence ; Aged, 80 and over ; Comorbidity ; Cohort Studies ; Adult ; Follow-Up Studies ; }, abstract = {Background: Epidemiological data on amyotrophic lateral sclerosis (ALS) in Spain have primarily been derived from small cohort studies, with limited information on survival and comorbidities. This study presents a 10-year follow-up of a large, well-phenotyped community-dwelling ALS cohort in Catalonia, Spain. Methods: This observational study utilized data from the Information System for the Development of Research in Primary Care (SIDIAP), which includes health records for 6,301,095 individuals from 2015 to 2020. We assessed ALS incidence, prevalence, comorbidities, territorial distribution, mortality, and survival times. Results: From 2015 to 2020, 1173 ALS cases were identified, with a median age at diagnosis of 68 years, and 50.4% of cases were female. Incidence and prevalence were estimated at 2.39 per 100,000 person-years and 7.98 cases per 100,000 persons. Dementia was present in 6.8% of cases before ALS diagnosis, while depression and/or anxiety affected 45.7%. Median survival from diagnosis was 2.19 years. Multivariate analysis identified older age at diagnosis (HR: 1.04, 95% CI: 1.04-1.05, p value < 0.001), alcohol abuse (HR: 1.56, 95% CI: 1.04-2.56, p value = 0.017), history of stroke (HR: 1.47, 95% CI: 1.07-2.04, p = 0.006), and dementia (HR: 1.57, 95% CI: 1.18-2.12, p value = 0.001) as independent predictors of mortality. Conclusions: ALS incidence and prevalence in Catalonia are higher than previously estimated for Spain and align closely with rates observed in other Western countries. Older age at diagnosis, alcohol abuse, stroke history, and dementia were all significantly associated with reduced survival. These findings underscore important risk factors affecting prognosis, offering valuable insights into ALS progression.}, } @article {pmid40646945, year = {2025}, author = {Davì, F and Iaconis, A and Cordaro, M and Di Paola, R and Fusco, R}, title = {Nutraceutical Strategies for Targeting Mitochondrial Dysfunction in Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {14}, number = {13}, pages = {}, pmid = {40646945}, issn = {2304-8158}, abstract = {In neurons, mitochondria generate energy through ATP production, thereby sustaining the high energy demands of the central nervous system (CNS). Mitochondrial dysfunction within the CNS was implicated in the pathogenesis and progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, often involving altered mitochondrial dynamics like fragmentation and functional impairment. Accordingly, mitochondrial targeting represents an alternative therapeutic strategy for the treatment of these disorders. Current standard drug treatments present limitations due to adverse effects associated with their chronic use. Therefore, in recent years, nutraceuticals, natural compounds exhibiting diverse biological activities, have garnered significant attention for their potential to treat these diseases. It has been shown that these compounds represent safe and easily available sources for the development of innovative therapeutics, and by modulating mitochondrial function, nutraceuticals offer a promising approach to address neurodegenerative pathologies. We referred to approximately 200 articles published between 2020 and 2025, identified through a focused search across PubMed, Google Scholar, and Scopus using keywords such as "nutraceutical," "mitochondrial dysfunction," and "neurodegenerative diseases. The purpose of this review is to examine how mitochondrial dysfunction contributes to the genesis and progression of neurodegenerative diseases. Also, we discuss recent advances in mitochondrial targeting using nutraceuticals, focusing on their mechanisms of action related to mitochondrial biogenesis, fusion, fission, bioenergetics, oxidative stress, calcium homeostasis, membrane potential, and mitochondrial DNA stability.}, } @article {pmid40648447, year = {2025}, author = {Lovrinčević, M and Papa, I and Janeš, D and Hodak, L and Pentek, T and Đuka, A}, title = {New Possibilities of Field Data Survey in Forest Road Design.}, journal = {Sensors (Basel, Switzerland)}, volume = {25}, number = {13}, pages = {}, pmid = {40648447}, issn = {1424-8220}, support = {HRZZ-UIP-2019-04-7766//Croatian Science Foundation/ ; }, abstract = {Field data, as the basis for planning and designing forest roads, must have high spatial accuracy. Classical (using a theodolite and a level) and modern (based on total stations and GNSSs) surveying methods are used in current field data survey for forest road design. This study analyzed the spatial accuracy of classical and modern surveying methods, the accuracy of spatial data recorded using a UAV equipped with an RGB camera at different flight altitudes, and the accuracy of lidar data of the Republic of Croatia. This study was conducted on a forest area where salvage logging was carried out, which enabled the use of a GNSS receiver in RTK mode as a reference method. The highest RMSE values of the spatial coordinates were recorded for measurements obtained with the classical surveying method (0.89 m) and a total station (0.33 m). The flight altitude of the UAV did not significantly affect the spatial error of the collected data, which ranged between 0.07 and 0.09 m. The cross-terrain slope, as one of the factors that significantly affect the amount of earthworks, did not differ statistically significantly between the methods. The ALS error was strongly influenced by the cross-terrain slope. The authors conclude that the new survey methods (SfM and lidar data) provide high-accuracy data but also draw attention to challenges in their use, such as vegetation and biomass on the ground.}, } @article {pmid40649859, year = {2025}, author = {Tomczak, J and Kapsa, A and Boczek, T}, title = {Adenylyl Cyclases as Therapeutic Targets in Neuroregeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40649859}, issn = {1422-0067}, support = {2020/39/D/NZ4/01250//National Science Center/ ; }, mesh = {Humans ; *Adenylyl Cyclases/metabolism ; Animals ; *Nerve Regeneration/drug effects ; Signal Transduction/drug effects ; Cyclic AMP/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuronal Plasticity ; }, abstract = {Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling-a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac), and cAMP-response element-binding protein (CREB). Among the various AC isoforms, calcium-sensitive AC1, AC8, and AC5, as well as bicarbonate-responsive soluble AC (sAC), have emerged as crucial mediators of neuroplasticity and axon regeneration. These isoforms coordinate diverse cellular responses-including gene transcription, cytoskeletal remodeling, and neurotransmitter release-to metabolic, synaptic, and injury-related signals. Dysregulation of AC activity has been implicated in the pathophysiology of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, as well as in chronic pain syndromes. Pharmacological modulation of cAMP levels through AC activation, phosphodiesterase (PDE) inhibition, or pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor signaling has shown therapeutic promise in preclinical models by enhancing neurogenesis, remyelination, and synaptic repair. Conversely, targeted inhibition of specific AC isoforms, particularly AC1, has demonstrated efficacy in reducing maladaptive plasticity and neuropathic pain. This review highlights the diverse roles of ACs in neuronal function and injury response and discusses emerging strategies for their therapeutic targeting.}, } @article {pmid40649921, year = {2025}, author = {Neumann, S and Heumann, R}, title = {Is the Voltage-Dependent Anion Channel a Major Player in Neurodegenerative Diseases?.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40649921}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Voltage-Dependent Anion Channels/metabolism/genetics ; Animals ; Mitochondria/metabolism ; }, abstract = {The family of voltage-dependent anion channels (VDACs) comprises three isoforms (VDAC-1, VDAC-2, VDAC-3). VDACs have been extensively described as localised in the outer mitochondrial membrane where they are involved in the exchange of ions, metabolites, and ATP/ADP between mitochondria and cytosol. The VDAC interacts with disease-specific proteins and thus regulates the mitochondrial function and controls the cellular energy resources, explaining its involvement in cell death and apoptosis. In addition, VDAC-1 and -2 can also be found at other cellular locations such as in the sarcoplasmic reticulum, in the endoplasmic reticulum, as well as in the plasma membrane. Through single-channel pore regulation, oligomerisation, or changed expression levels the VDAC is involved in different neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and others. Here, we critically summarise current discussions about the VDAC as a common key player for these diseases. We suggest that the VDAC acts as a transmembrane multifunctional regulatory protein which might serve as a pharmacological target for the development of novel drugs against neurodegenerative diseases such as the application of recombinant antibody technology.}, } @article {pmid40649976, year = {2025}, author = {Jiménez-García, AM and Tortorella, ME and Nishimura, AL and Arias, N}, title = {The Differential Effects of Genetic Mutations in ALS and FTD Genes on Behavioural and Cognitive Changes: A Systematic Review and Meta-Analysis.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40649976}, issn = {1422-0067}, support = {PID2023-151715OB-IOO//Ministry of Science and Innovation/ ; PLEC2022-009464//European Union NextGeneration EU/PRTR/ ; CPP2022-009646//European Union NextGeneration EU/PRTR/ ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics/psychology ; *Amyotrophic Lateral Sclerosis/genetics/psychology ; *Mutation ; *Cognition ; tau Proteins/genetics ; C9orf72 Protein/genetics ; Progranulins/genetics ; Superoxide Dismutase-1/genetics ; Endosomal Sorting Complexes Required for Transport/genetics ; RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are linked by shared genetic mutations and overlapping clinical features, forming a clinical spectrum. This systematic review and meta-analysis analysed 97 studies, including 3212 patients with key ALS/FTD gene mutations, to identify gene-specific behavioural profiles. Chromosome 9 open reading frame 72 (C9orf72) mutations were strongly associated with psychotic symptoms and aggression, while superoxide dismutase 1 (SOD1) mutations had minimal cognitive effects. Progranulin (PGRN) mutations correlated with apathy and hallucinations, microtubule-associated protein tau (MAPT) mutations with disinhibition, and charged multivesicular body protein 2B (CHMP2B) with social impairments. Fused in sarcoma (FUS) mutations caused early sleep disturbances, TANK-binding kinase 1 (TBK1) led to disinhibition, and presenilin 1 and 2 (PSEN1/2) was linked to severe aggression. Prodromal cognitive changes in PGRN, MAPT, and CHMP2B mutations suggested early disease onset. Despite overlapping symptoms and clinical heterogeneity, understanding gene-specific patterns could inform tailored care strategies to enhance the quality of life for ALS and FTD patients. This study calls for refined guidelines integrating genetic behavioural profiles to improve patient and family support.}, } @article {pmid40650046, year = {2025}, author = {Cattaneo, M and Giagnorio, E and Lauria, G and Marcuzzo, S}, title = {Therapeutic Approaches for C9ORF72-Related ALS: Current Strategies and Future Horizons.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40650046}, issn = {1422-0067}, support = {//Italian Ministry of Health (RRC)/ ; T4-AN-09 prog. ZRPOS2//CALabria HUB per Ricerca Innovativa ed Avanzata- CALHUB.RIA "Creazione di Hub delle Sci-enze della Vita"/ ; prog. ZRA124//AriSLA foundation, "Bulb-Omics"/ ; PNRR-MCNT2-2023-12377336//the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS,/ ; }, mesh = {Humans ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/pathology ; Animals ; DNA Repeat Expansion ; Gene Editing ; Genetic Therapy/methods ; Mutation ; Oligonucleotides, Antisense/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. One of its major genetic causes is C9ORF72, where mutations lead to hexanucleotide repeat expansions in the C9ORF72 gene. These expansions drive disease progression through mechanisms, including the formation of toxic RNAs and the accumulation of damaged proteins such as dipeptide repeats (DPRs). This review highlights these pathogenic mechanisms, focusing on RNA foci formation and the accumulation of toxic DPRs, which contribute to neuronal damage. It also discusses promising targeted therapies, including small molecules and biological drugs, designed to counteract these specific molecular events. Small molecules such as G-quadruplex stabilizers, proteasome and autophagy modulators, and RNase-targeting chimeras show potential in reducing RNA foci and DPR accumulation. Furthermore, targeting enzymes involved in repeat-associated non-AUG (RAN) translation and nucleocytoplasmic transport, which are crucial for disease pathogenesis, opens new therapeutic avenues. Even some anti-viral drugs show encouraging results in preclinical studies. Biological drugs, such as antisense oligonucleotides and gene-editing technologies like CRISPR-Cas, were explored for their potential to specifically target C9ORF72 mutations and modify the disease's molecular foundations. While preclinical and early clinical data show promise, challenges remain in optimizing delivery methods, ensuring long-term safety, and improving efficacy. This review concludes by emphasizing the importance of continued research and the potential for these therapies to alter the disease trajectory and improve patient outcomes.}, } @article {pmid40650266, year = {2025}, author = {Bashar, MA and Dash, N and Mitra, S and Dash, R}, title = {Disclosing Pathogenic Variant Effects on the Structural Dynamics of the VAPB MSP Domain Causing Familial ALS.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40650266}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Molecular Dynamics Simulation ; *Vesicular Transport Proteins/genetics/chemistry/metabolism ; Protein Domains ; Mutation ; Protein Structure, Secondary ; Protein Binding ; }, abstract = {Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB) serves as a tethering factor that interacts with various proteins and recruits these proteins to the ER surface, exerting multiple functions, such as organelle membrane tethering, lipid transfer between organelles, regulation of calcium homeostasis, autophagy, and the unfolded protein response (UPR). Its interaction is often mediated by its MSP (major sperm) domain, which binds with FFAT (two phenylalanines in an acidic tract)-motif-containing proteins. However, pathogenic variations, such as P56S, P56H, and T46I, in the VAPB MSP domain lead to the familial form of amyotrophic lateral sclerosis (ALS8). Still, the underlying pathophysiology of ALS8 due to pathogenic variations in the VAPB MSP domain remains elusive. In this study, we conducted molecular dynamics (MD) simulations to understand the pathogenic-variant-derived changes in the structural dynamics of the VAPB MSP domain. We found that pathogenic variants altered the fluctuations and conformational dynamics of the VAPB protein. Analyzing the organizations of the secondary structure revealed that pathogenic variants changed the composition of secondary structure elements, especially increasing the proportion of α-helix while reducing β-sheet formation, which might affect the organelle tethering and other functions of VAPB, as well as VAPB homodimer and heterodimer formation. Taken together, these findings can be further investigated through in vivo and/or in vitro studies to not only clarify the pathophysiology of ALS8 resulting from VAPB MSP domain pathogenic variants but also develop novel therapeutics for the disease that restore the native structural organizations as well as fluctuations and motions.}, } @article {pmid40651187, year = {2025}, author = {Chang, J and Teo, AH and Shaw, TB and Dupuis, L and Ngo, ST and Steyn, FJ}, title = {Deciphering hypothalamic pathology in ALS: insights into non-motor symptoms and disease progression.}, journal = {EBioMedicine}, volume = {118}, number = {}, pages = {105845}, pmid = {40651187}, issn = {2352-3964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/etiology/physiopathology/diagnosis ; *Hypothalamus/pathology/metabolism/diagnostic imaging/physiopathology ; Disease Progression ; Animals ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with highly heterogeneous clinical presentations. Among the non-motor features increasingly recognised as clinically relevant is the dysregulation of energy balance, with weight loss-particularly due to fat mass loss-emerging as a significant modifier of disease risk, progression, and survival. In this context, the hypothalamus-a key regulator of homeostatic and metabolic processes-has gained attention for its potential role in ALS pathophysiology. This Review synthesises emerging evidence of hypothalamic involvement in ALS, including neuronal loss, proteinopathy, and volume loss observed through histological and neuroimaging studies. We critically examine current imaging approaches and their technical limitations and explore neuroendocrine dysfunction across the hypothalamic-pituitary axes. Collectively, these findings suggest that hypothalamic dysfunction may contribute to clinically relevant metabolic, sleep, behavioural, and cognitive changes in ALS, adding to our understanding of ALS as a multisystem disease. Continued investigation of the hypothalamus may reveal novel biomarkers, inform risk stratification, and identify therapeutic opportunities to address disease heterogeneity and improve clinical outcomes.}, } @article {pmid40651326, year = {2025}, author = {Yang, S and Ma, Y and Fu, H and Wang, C and Zhang, Y}, title = {Association between allostatic load and trouble sleeping in U.S. adults.}, journal = {Journal of psychosomatic research}, volume = {196}, number = {}, pages = {112206}, doi = {10.1016/j.jpsychores.2025.112206}, pmid = {40651326}, issn = {1879-1360}, mesh = {Humans ; *Allostasis/physiology ; Female ; Male ; Cross-Sectional Studies ; Middle Aged ; United States/epidemiology ; Adult ; Nutrition Surveys ; *Sleep Wake Disorders/epidemiology/physiopathology ; Aged ; }, abstract = {OBJECTIVE: This study examined the association between allostatic load and trouble sleeping and assessed whether this relationship varies based on allostatic load score (ALS) criteria.

METHODS: This cross-sectional survey utilized nationally representative data from the National Health and Nutrition Examination Survey (NHANES). ALS was derived using empirical and clinical criteria based on eight biomarkers reflecting cardiovascular, metabolic, and immune function. Weighted multivariate logistic regression was employed to analyze the association between ALS and trouble sleeping, with subgroup analyses conducted to assess gender-specific differences.

RESULTS: Of 5331 participants included in this study, 1485 (29 %) reported trouble sleeping. In multivariate-adjusted logistic regression, higher ALS was associated with increased odds of trouble sleeping (empirical ALS: OR 1.13 [95 % CI 1.07-1.18]; clinical ALS: OR 1.08 [95 % CI 1.04-1.13]). Subgroup analyses confirmed the consistency of this association across genders.

CONCLUSION: This study provides robust evidence of a significant association between ALS and trouble sleeping, supported by observed OR of 1.13 (empirical) and 1.08 (clinical). The consistency of findings across both empirical and clinical ALS underscores the potential role of physiological dysregulation in sleep health, highlighting the need for integrated approaches to stress and sleep management.}, } @article {pmid40651399, year = {2025}, author = {Ma, Y and Wu, S and Liu, H and Ren, C and Xie, Y and Deng, G and Yao, S and Wang, X and Qin, C}, title = {Sodium lignosulfonate alkylates based-biosurfactants for efficient remediation of oily sludge.}, journal = {Journal of environmental management}, volume = {391}, number = {}, pages = {126553}, doi = {10.1016/j.jenvman.2025.126553}, pmid = {40651399}, issn = {1095-8630}, mesh = {*Sewage/chemistry ; *Surface-Active Agents/chemistry ; *Lignin/analogs & derivatives/chemistry ; Spectroscopy, Fourier Transform Infrared ; Biosurfactants ; }, abstract = {An alkylated sodium lignosulphonate (ALS) was prepared for highly efficient thermal washing treatment of oily sludge. The ALS was characterized for their chemical structure and surface activity. Furthermore, ALS was used as a thermal cleaning agent to treat oily sludge under different conditions to obtain an optimal thermal washing process. Finally, the oily sludge before and after thermal washing were characterized to explore its structural and compositional changes. Results obtained from the Fourier Transform Infrared spectroscopy (FT-IR) and Two-dimensional Heteronuclear Single Quantum Coherence(2D-HSQC) confirmed the successful grafting of fatty acid chains(C12) onto the LS molecules. ALS was an ideal surfactant with suitable HLB value and excellent surface tension reduction, foaming and emulsification properties. The optimum thermal washing process for oily sludge was: thermal washing temperature 30 °C, ALS concentration 1.5 g/L.}, } @article {pmid40652712, year = {2025}, author = {Brüge, A and Ponimaskin, E and Labus, J}, title = {Targeting the serotonergic system in the treatment of neurodegenerative diseases-emerging therapies and unmet challenges.}, journal = {Pharmacological reviews}, volume = {77}, number = {5}, pages = {100071}, pmid = {40652712}, issn = {1521-0081}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Serotonin/metabolism ; Receptors, Serotonin/metabolism ; *Serotonin Agents/therapeutic use/pharmacology ; Molecular Targeted Therapy ; }, abstract = {More than 65 million people worldwide experience neurodegenerative diseases, such as Alzheimer disease, frontotemporal dementia, Parkinson disease, and amyotrophic lateral sclerosis. As the risk of developing these diseases increases with age, increasing life expectancy will further accelerate their prevalence. Despite major advances in the understanding of the molecular mechanisms of neurodegeneration, no curative therapy is available to date. Neurodegenerative diseases are known to be associated with alterations in serotonergic neurotransmission, which might critically contribute to the pathogenesis of these diseases. Therefore, targeting the serotonergic system appears to be a promising therapeutic approach. In this review, we provide a comprehensive overview of pathological changes in serotonergic neurotransmission in different neurodegenerative diseases and discuss novel treatment strategies based on targeted modulation of the serotonergic system. We primarily focus on the therapeutic approaches modulating serotonin homeostasis, its biosynthesis, and the modulation of defined serotonin receptors. SIGNIFICANCE STATEMENT: A common feature of multiple neurodegenerative diseases is dysregulation of the serotonergic system at the cellular, molecular, and genetic levels that strongly contributes to specific pathological phenotypes. Targeting these alterations represents a suitable therapeutic strategy to combat disease-relevant pathomechanisms, slow down disease progression, and overcome pathological consequences.}, } @article {pmid40653411, year = {2025}, author = {Wei, Y and Zhang, Y and Yu, D}, title = {Low-dose IL-2 reinvigorates the immunoguardians of neurodegenerative diseases.}, journal = {Trends in immunology}, volume = {46}, number = {9}, pages = {608-610}, doi = {10.1016/j.it.2025.07.004}, pmid = {40653411}, issn = {1471-4981}, mesh = {Humans ; *Interleukin-2/therapeutic use/administration & dosage ; *Immunotherapy/methods ; *Neurodegenerative Diseases/immunology/therapy ; Animals ; *Amyotrophic Lateral Sclerosis/immunology/therapy ; Immune Tolerance ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease caused by motor neuron loss. In a recent Phase 2b trial, Bensimon and colleagues report that the addition of low-dose interleukin 2 (LD-IL-2) immunotherapy to standard of care (SOC) shows promise in enhancing immune tolerance and improving survival in individuals with slower disease progression.}, } @article {pmid40653468, year = {2025}, author = {Liu, Z and Sun, L and Gao, N and Li, W and Pang, L}, title = {Reciprocal regulation of GPNMB/HIF-1α for Inhibition of neuronal ferroptosis in delayed encephalopathy after acute carbon monoxide poisoning.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {154}, pmid = {40653468}, issn = {2051-5960}, support = {JJKH20231233KJ//Jilin Provincial Education Department/ ; Z2023LJL001//Tianhua Health Foundation of Jilin Province/ ; 82372211//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Ferroptosis/physiology/drug effects ; Rats ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; *Carbon Monoxide Poisoning/metabolism/complications ; Male ; Rats, Sprague-Dawley ; *Neurons/metabolism/pathology ; *Membrane Glycoproteins/metabolism ; PC12 Cells ; *Brain Diseases/metabolism/etiology/pathology ; Oxidative Stress/physiology/drug effects ; }, abstract = {Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is the most common complication after acute carbon monoxide (CO) poisoning. However, the pathogenesis of DEACMP remains ambiguous. The neuroprotective role of GPNMB has been observed in amyotrophic lateral sclerosis and Parkinson's disease. GPNMB was elevated in the brain tissues of DEACMP rats, while its function in DEACMP remains unclear. In this study, a CO poisoning rat model and oxygen-glucose deprivation (OGD)-treated PC-12 cells were established as an in vivo and in vitro DEACMP model, respectively. The ferroptosis inhibitor Ferrostatin-1 (Fer-1) ameliorated cognitive impairment, inflammation and oxidative stress of rats with DEACMP as assessed by Morris Water Maze test, ELISA assay and commercial kits of oxidative markers. Immunofluorescence, qRT-PCR or western blot showed that GPNMB was elevated in CA1 hippocampal tissues of CO-poisoned rats. Additionally, TUNEL staining, ELISA assay and western blot revealed that GPNMB rescued OGD-induced cell apoptosis, inflammation and ferroptosis in PC-12 cells. Mechanistical study showed that STAT3 was a transcriptional activator of GPNMB as detected by luciferase and ChIP assays, and co-immunoprecipitation and immunofluorescence staining revealed that GPNMB stabilized HIF-1α by direct binding. Functionally, GPNMB protected against OGD-induced impairments via inducing HIF-1α. Furthermore, GPNMB attenuated cognitive impairment, oxidative stress and neuronal ferroptosis of rats with DEACMP. In conclusion, GPNMB/HIF-1α exhibited neuroprotective effects via suppressing ferroptosis in DEACMP.}, } @article {pmid40653481, year = {2025}, author = {Marabita, M and Marchioretti, C and Aravamudhan, A and Zito, S and Falconieri, A and Zuccaro, E and Andreotti, R and Gambarotto, L and Metti, S and Tonellato, M and Adami, V and Park, KH and Gunthorpe, MJ and Large, CH and Marasco, A and Vianello, S and Rosati, J and Belluzzi, E and Pozzuoli, A and Biz, C and Ruggieri, P and Basso, M and Poletti, A and Alvaro, G and Sorarù, G and Bonaldo, P and Rossetto, O and Pilati, N and Pennuto, M}, title = {Kv3 channel agonist ameliorates the phenotype of a mouse model of amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {153}, pmid = {40653481}, issn = {2051-5960}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism/genetics ; *Shaw Potassium Channels/agonists/metabolism/genetics ; Disease Models, Animal ; Humans ; Mice, Transgenic ; Mice ; Phenotype ; Muscle, Skeletal/metabolism/drug effects/pathology ; Male ; Mice, Inbred C57BL ; Female ; Superoxide Dismutase-1/genetics ; }, abstract = {Voltage-gated potassium channels, Kv3.1, Kv3.2, Kv3.3, and Kv3.4, facilitate rapid repolarization and shape action potentials, which are crucial to maintaining high-frequency firing. Little is known about the expression and function of Kv3 channels in skeletal muscle. We show that these channels are expressed in type IIa/IIx fibers, and their transcript levels progressively increase from postnatal age to adulthood in physiological context. In mature myofibers, the Kv3.1 and Kv3.4 channels are enriched in the muscle triads. The expression of the Kv3 channel is lost upon acute motor unit damage, in mouse models of amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), and the skeletal muscle of patients with sporadic ALS. Early treatment of ALS and SBMA mice with AUT00201, a positive allosteric modulator of Kv3 channels, improved the phenotype of ALS mice specifically, suggesting that positive modulation of Kv3 channels is a novel therapeutic option for patients with ALS.}, } @article {pmid40653816, year = {2025}, author = {Bozovic, I and Licina, E and Bjelica, B and Milicevic, O and Palibrk, A and Basta, I and Peric, S and Pavlovic, A and Stevic, Z and Mijajlovic, M}, title = {Transcranial Brain Parenchyma Sonographic Findings in Familial and Sporadic Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {32}, number = {7}, pages = {e70272}, pmid = {40653816}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics/pathology ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; Aged ; *Ultrasonography, Doppler, Transcranial/methods ; Adult ; *Brain/diagnostic imaging ; *Substantia Nigra/diagnostic imaging ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. Transcranial sonography (TCS) is a valuable tool for assessing deep brain structures. This study aimed to analyze TCS findings in both sporadic (sALS) and familial ALS (fALS) patients and compare them to healthy controls (HC).

METHODS: This cross-sectional study included 278 patients with sALS and 31 patients with genetically confirmed fALS, and 93 age- and gender- matched HC. TCS was used to assess substantia nigra (SN) and brainstem raphe (BR) echogenicity and third ventricle diameter (TVD). Functional disability was evaluated using the ALS Functional Rating Scale-Revised.

RESULTS: BR hypoechogenicity was more frequent in fALS (41.9%) and sALS (37.4%) patients, compared to HC (10.8%) (p < 0.001). Right SN hyperechogenicity was observed in 28.1% of sALS, 16.1% of fALS, and 8.6% of HC (p = 0.004). Left SN hyperechogenicity was found in 33.5% of sALS, 29.0% of fALS, and 4.3% of HC (p = 0.004). SN hyperechogenicity findings on either side were highest in sALS (48.4%) compared to fALS (31.0%) and HC (13.3%) (p < 0.001), with a borderline difference between fALS and sALS (p = 0.08). BR hypoechogenicity and SN hyperechogenicity were more common in male patients. Increased TVD correlated with older age, later disease onset, bulbar onset, and lower MMSE scores.

CONCLUSIONS: TCS is an easily applicable and sensitive diagnostic tool that offers novel insights into several brainstem structures and identify significant differences in their echogenicity between ALS patients and healthy controls, while pointing out similar but not identical patterns of echogenicity in both ALS forms.}, } @article {pmid40654715, year = {2025}, author = {van Zuiden, W and Meimoun, TD and Bar, C and Siany, A and Moshe, L and Yacovzada, N and Weizman, E and Neumann, M and Buchman, AS and Wang, Y and Bennett, DA and Glass, JD and Trautwig, AN and Seyfried, NT and Cooper-Knock, J and Hornstein, E}, title = {TDP-43 toxic gain of function links ALS, FTD and Alzheimer's Disease through splicing dysregulation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40654715}, issn = {2692-8205}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, abstract = {Loss of nuclear TDP-43 splicing activity is a common feature across neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but its relevance to Alzheimer's disease (AD) remains unclear. Here, we show that TDP-43 pathology in AD is broadly associated with splicing abnormalities, including aberrant splicing of amyloid precursor protein (APP). TDP-43 drives the formation of elongated APP isoforms, disrupting alternative splicing across ALS, FTLD-TDP and AD, providing a compelling mechanism for a long-standing observation of APP isoform dysregulation. We further establish a mechanistic link between TDP-43, APP splicing, and Aβ pathology. Surprisingly, the disruption to alternative APP splicing is mediated by a toxic gain of cytoplasmic TDP-43 function, rather than loss of its nuclear role. Using proximity proteomics and base editing in human iPSC-derived neurons, we show that TDP-43 pathology causes cytoplasmic co-sequestration of splicing regulators SCAF11, SRSF5, and TIAL1. Knockdown of these regulators also results in APP mis-splicing and increased Aβ burden, without affecting other TDP-43 targets such as STMN2 or UNC13A. Together, our findings suggest that TDP-43-mediated splicing dysfunction upstream of APP contributes to the pathogenesis of seemingly disparate neurodegenerative diseases, uniting AD and ALS/FTLD-TDP through a shared molecular mechanism.}, } @article {pmid40654957, year = {2025}, author = {Sheth, U and Harrison, R and Ferber, K and Rosenbaugh, EG and Bevis, A and Khillan, R and Benatar, M and Bjorklund, NL and Di Daniel, E and Harris, GA and Kahn, OI and Liu, Y and Zetterberg, H and Mitic, LL and Graham, D and Gendron, TF}, title = {Measuring neurofilament light in human plasma and cerebrospinal fluid: a comparison of five analytical immunoassays.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40654957}, issn = {2692-8205}, support = {U01 NS107027/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVES: Neurofilament light (NfL) is an established biofluid marker of neuroaxonal injury for neurological diseases. Several high-throughput and sensitive immunoassays have been developed to quantify NfL in blood and cerebrospinal fluid (CSF), facilitating the use of NfL as a biomarker in research and clinical practice. However, because of the lack of rigorous comparisons of assays, it has been difficult to determine whether data are comparable and whether assay performance differs. Here, we compared the performance of five NfL immunoassays.

METHODS: To assess the five NfL immunoassays (Fujirebio, ProteinSimple, Quanterix, Roche and Siemens), we used pooled plasma or pooled CSF, as well as unique samples from 20 healthy controls and 20 individuals with El Escorial defined probable or definite amyotrophic lateral sclerosis (ALS), to evaluate precision, parallelism and/or bias. We also examined correlations between plasma and CSF NfL concentrations within and across assays and evaluated their ability to differentiate healthy controls from individuals with ALS.

RESULTS: Four of the five assays demonstrated exemplary performance based on our analyses of precision and parallelism. Across the five assays, NfL concentrations were lower in plasma than in CSF, although they displayed a high degree of correlation. We noted bias across assays; plasma NfL concentrations were lowest for the Roche assay and highest for the ProteinSimple assay. In addition, all assays reliably distinguished healthy controls from individuals with ALS using plasma or CSF NfL.

CONCLUSIONS: Four NfL assays demonstrated similar analytic performance. Alongside performance, other factors such as costs, accessibility, useability, footprint, and intended use, should be considered.}, } @article {pmid40654973, year = {2025}, author = {Sangwan, S and Rieder, HE and Moore, D and Khanlou, N and Novitch, B and Geisberg, M and Eisenberg, DS}, title = {A structure-guided antibody detects SOD1 oligomers in diverse ALS genotypes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40654973}, issn = {2692-8205}, support = {R01 AG029430/AG/NIA NIH HHS/United States ; }, abstract = {Antibodies offer versatility as diagnostic and therapeutic tools to target specific protein epitopes. However, the transient nature of intermediate protein conformations, such as that of amyloid oligomers, poses a challenge for antibody development. We use a structure-guided approach to generate a monoclonal antibody against oligomers of Superoxide Dismutase 1 (SOD1). Mutations in SOD1 are linked to a subset of familial Amyotrophic Lateral Sclerosis (fALS), a fatal neurodegenerative disease. Based on the corkscrew-like features of non-native SOD1 oligomers previously determined, we generate an antibody specific to SOD1 oligomers. We show that the antibody, CSAb detects SOD1 oligomers, not fibrils or native SOD1, and alleviates the cytotoxic effects of SOD1 oligomers in a cell culture model of primary motor neurons. Immunohistochemical analyses of human ALS subjects show CSAb reactivity in both neuronal and non-neuronal cells. Finally, we provide evidence that CSAb reactive SOD1 oligomers are present in non-SOD1 linked fALS and sporadic ALS subjects. Together, our study provides a new probe against SOD1 oligomers and suggests that cytotoxic SOD1 oligomers are prevalent in diverse ALS genotypes.}, } @article {pmid40654997, year = {2025}, author = {Barbieri, EM and Linsenmeier, M and Whiteman, KR and Cheng, Y and Braganza, S and Copley, KE and Miranda-Castrodad, P and Lewis, B and Villafañe, K and Amado, DA and Davidson, BL and Shorter, J}, title = {Scouring the human Hsp70 network uncovers diverse chaperone safeguards buffering TDP-43 toxicity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40654997}, issn = {2692-8205}, support = {K99 AG075242/AG/NIA NIH HHS/United States ; T32 GM132039/GM/NIGMS NIH HHS/United States ; F31 NS129101/NS/NINDS NIH HHS/United States ; K08 NS114106/NS/NINDS NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; F32 NS108598/NS/NINDS NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; }, abstract = {Cytoplasmic aggregation and concomitant dysfunction of the prion-like, RNA-binding protein TDP-43 underpin several fatal neurodegenerative diseases, including amyotrophic lateral sclerosis. To elucidate endogenous defenses, we systematically scoured the entire human Hsp70 network for buffers of TDP-43 toxicity. We identify 30 J-domain proteins (2 DNAJAs, 10 DNAJBs, 18 DNAJCs), 6 Hsp70s, and 5 nucleotide-exchange factors that mitigate TDP-43 toxicity. Specific chaperones reduce TDP-43 aggregate burden and detoxify diverse synthetic or disease-linked TDP-43 variants. Sequence-activity mapping unveiled unexpected, modular mechanisms of chaperone-mediated protection. Typically, DNAJBs collaborate with Hsp70 to suppress TDP-43 toxicity, whereas DNAJCs act independently. In human cells, specific chaperones increase TDP-43 solubility and enhance viability under proteotoxic stress. Strikingly, spliceosome-associated DNAJC8 and DNAJC17 retain TDP-43 in the nucleus and promote liquid-phase behavior. Thus, we disambiguate a diverse chaperone arsenal embedded in the human proteostasis network that counters TDP-43 toxicity and illuminate mechanistic gateways for therapeutic intervention in TDP-43 proteinopathies.}, } @article {pmid40655294, year = {2025}, author = {Rinofner-Kreidl, S}, title = {Ist das Gegebene noch zu retten? Über Chancen und Gefahren einer Politisierung der Phänomenologie.}, journal = {Husserl studies}, volume = {41}, number = {2}, pages = {267-302}, doi = {10.1007/s10743-025-09363-5}, pmid = {40655294}, issn = {0167-9848}, abstract = {Dieser Essay zielt darauf, eine Mehrdeutigkeit der Rede von "Politisierung" herauszuarbeiten, die sowohl für die Selbstkritik phänomenologischen Denkens als auch für die Kritik der Phänomenologie als eines öffentlichen Diskurses von Bedeutung ist. Die fraglichen Unterschiede betreffen das Verständnis dessen, was infolge einer Politisierung des Denkens anders konzipiert, kontextualisiert oder interpretiert wird, ob eine Politisierung intrinsisch oder extrinsisch motiviert und begründet ist und wie Art und Reichweite der daran geknüpften Ansprüche argumentiert werden können. Zwei Optionen werden erörtert: (1) eine interne Politisierung, die als phänomenologisch-methodischer Umgang mit Gegebenem und als kollektiv praktizierter Evidenzstil charakterisiert wird; (2) eine externe Politisierung, die sich als standort- und kontextabhängige weltanschauliche Idee und Praxis darstellt. Letztere versteht sich als eine politische Forderung und Erwartung, die eine thematisch einseitige bzw. verengte und / oder unreflektierte, unkritische, womöglich vorurteils- und ressentimentgeleitete phänomenologische Untersuchung korrigiert. Es wird argumentiert, dass interne Politisierung auf einer Metaebene stattfindet, auf der über Natur und Selbstbegrenzung der phänomenologischen Analyse nachgedacht wird. In konkreten Phänomenanalysen schlägt sich interne Politisierung lediglich indirekt, über deren methodische und theoretische Rahmung, nieder. Interne Politisierung ist mit autonomer Vernunftausübung verträglich. Dies gilt nicht für jede Form externer Politisierung, die als direkter Eingriff auf der gegenständlichen Ebene, im Zuge der Interpretation konkreter Phänomene, erfolgt. Zu klären ist: Wie können zulässige und eventuell unabdingbare Formen von Politisierung von unzulässigen unterschieden werden? Unter welchen Bedingungen unterliegt die Politisierung des Denkens einem Selbstwiderlegungseinwand?}, } @article {pmid40655414, year = {2025}, author = {Thiry, L and Sirois, J and Durcan, TM and Stifani, S}, title = {Derivation and Culture of Enriched Phrenic-Like Motor Neurons From Human iPSCs.}, journal = {Bio-protocol}, volume = {15}, number = {13}, pages = {e5363}, pmid = {40655414}, issn = {2331-8325}, abstract = {The fatal motor neuron (MN) disease amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of the phrenic MNs (phMNs) controlling the activity of the diaphragm, leading to death by respiratory failure. Human experimental models to study phMNs are lacking, hindering the understanding of the mechanisms of phMN degeneration in ALS. Here, we describe a protocol to derive phrenic-like MNs from human induced pluripotent stem cells (hiPSC-phMNs) within 30 days. During spinal cord development, phMNs emerge from specific MN progenitors located in the dorsalmost MN progenitor (pMN) domain at cervical levels, under the control of a ventral-to-dorsal gradient of Sonic hedgehog (SHH) signaling and a rostro-caudal gradient of retinoic acid (RA). The method presented here uses optimized concentrations of RA and the SHH agonist purmorphamine, followed by fluorescence-activated cell sorting (FACS) of the resulting MN progenitor cells (MNPCs) based on a cell-surface protein (IGDCC3) enriched in hiPSC-phMNs. The resulting cultures are highly enriched in MNs expressing typical phMN markers. This protocol enables the generation of hiPSC-phMNs and is highly reproducible using several hiPSC lines, offering a disease-relevant system to study mechanisms of respiratory MN dysfunction. While the protocol has been validated in the context of ALS research, it can be adopted to study human phrenic MNs in other research fields where these neurons are of interest. Key features • This protocol generates enriched hiPSC-derived phrenic motor neuron cultures. • The protocol can be used to develop models to study human respiratory motor neuron disease. • The protocol allows the generation of phrenic motor neuron preparations with potential for motor neuron replacement strategies. • The protocol requires experience in hiPSC culturing and FACS-based cell sorting for a successful outcome.}, } @article {pmid40655970, year = {2023}, author = {Vardheim, EG and Toft, A and Nielsen, JE and Hasselbalch, SG and Simonsen, AH}, title = {Cerebrospinal fluid ubiquitin as a biomarker for neurodegenerative diseases: A systematic review.}, journal = {Neuroscience applied}, volume = {2}, number = {}, pages = {102438}, pmid = {40655970}, issn = {2772-4085}, abstract = {Ubiquitin plays a vital role in neuronal proteostasis, as a major but often overlooked component of neurotoxic protein aggregates across neurodegenerative diseases. Although neuropathological changes can be present for years before clinical onset, early and accurate diagnosis remains an immense challenge in this disease category. The level of ubiquitin in cerebrospinal fluid (CSF) has been assessed as a biomarker for several disease entities. This systematic review compares current findings and evaluates the potential of CSF ubiquitin as a fluid biomarker. A systematic literature search identified studies comparing CSF ubiquitin levels between a control group and patients with one of the following diseases: Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), Lewy body dementia (DLB), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). All included studies were reviewed systematically by two independent authors. 171 studies were identified. A total of 17 studies met the eligibility criteria and were included. Nine out of 13 studies found a significant increase of CSF ubiquitin in AD patients compared with control groups. Correlations between CSF ubiquitin and other established biomarkers were demonstrated in seven studies. A single study was included for both HD and DLB respectively, each showing significantly higher CSF ubiquitin in patients compared to controls. In patients with PD, FTD or ALS, CSF ubiquitin levels were generally equal to those of the control groups, with two studies showing significantly decreased concentrations in a PD and an FTD cohort. Presently, the available body of research is insufficient to assess whether CSF ubiquitin could contribute to the clinical setting, alongside established markers of neurodegeneration. The correlation of elevated CSF ubiquitin with AD is well-founded, whilst validation of reduced or unchanged levels in the other neurodegenerative diseases will determine the usefulness of the biomarker in clinical practice.}, } @article {pmid40657896, year = {2025}, author = {Dogra, SR and Bhonsle, J and Sharma, A}, title = {MicroRNA Dysregulation in Neurodegeneration: Role, Biomarker Potential and Therapeutics.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-12}, doi = {10.1017/cjn.2025.10361}, pmid = {40657896}, issn = {0317-1671}, abstract = {Neurodegenerative diseases (NDDs) are a group of complex disorders marked by pathophysiological mechanisms involving protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation. Irrespective of extensive research advances, NDDs have become a serious global concern and persist as a major therapeutic challenge. In recent years, microRNAs (miRNAs), a class of small non-coding RNAs, have established a pivotal role in combating NDDs. The altered expression of miRNAs is reported to be associated with the progression of various NDDs. This review aims to discuss miRNA biogenesis; dysregulation in NDDs, specifically Alzheimer's disease, Parkinson's disease (PD) and amyotrophic lateral sclerosis; their potential as biomarkers; and promising therapeutic targets. Additionally, there are various emerging technologies discussed that are advanced approaches to enhance miRNA-based diagnostics and therapeutics.}, } @article {pmid40658257, year = {2025}, author = {Fasano, A and Vacchiano, V and Bonan, L and McMackin, R and Nasseroleslami, B and Hardiman, O and Liguori, R}, title = {Neurophysiological biomarkers of networks impairment in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {8}, pages = {507}, pmid = {40658257}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Biomarkers ; Transcranial Magnetic Stimulation ; *Nerve Net/physiopathology ; Electroencephalography ; Electromyography ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease involving motor system as well as cognitive domains. There is an urgent need for objective biomarkers that can subcategorize subjects into homogeneous groups based on disease pathobiology.In this review, we discuss novel neurophysiological techniques that provide detailed, multiscale and multidimensional insights into ALS networks impairment, spanning from the micro-columnar architecture of the motor cortex to motor and cognitive networks. Specifically, Transcranial Magnetic Stimulation (TMS) paradigms can be used to evaluate the status of excitatory and inhibitory networks within the layers of the motor cortex. Abnormalities in functional connectivity between the two motor areas, as well as within the frontal-temporal and frontal parietal networks, can be characterized using novel source-localization analysis of high-density electroencephalography (EEG). TMS and EEG techniques provide data that correlate with both motor and cognitive impairment. Furthermore, cortico-muscular coherence analysis can be used to assess functional dysregulation within the entire motor system, and novel surface electromyography (EMG) techniques, such as motor unit number estimation, motor unit number index, and nerve excitability testing studies provide useful insights into axonal loss and membrane ion channel dysfunctions in lower motor neurons.The integrated analysis of these biomarkers provides valuable insights into the clinical and biologic heterogeneity of the disease, aiding the intelligent design of next generation precision-based therapeutics.}, } @article {pmid40659018, year = {2025}, author = {Yang, EJ}, title = {Combined Herbal Medicine (<italic>Achyranthes bidentata</italic>, <italic>Gastrodia elata</italic>, and <italic>Chaenomeles sinensis</italic>) Increases Anti-Inflammatory and Anti-Oxidative Effects in a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Pharmacology}, volume = {}, number = {}, pages = {1-14}, doi = {10.1159/000547388}, pmid = {40659018}, issn = {1423-0313}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the loss of motor neurons, finally leading to death by respiratory failure. However, no effective drug is available for treating patients with ALS owing to the complex pathological mechanisms. Herbal medicines are globally known for the effects of their multiple bioactive components and lack of adverse effects. This study investigated the effects of a combined herbal medicine formulation containing Achyranthes bidentata Blume, Gastrodia elata Blume, and Chaenomeles sinensis Koehne extracts on motor function and to analyze the underlying biological mechanisms in the gastrocnemius and tibia anterior muscles and spinal cord of hSOD1G93A mice.

METHODS: Rotarod and footprint analyses were performed to examine motor function. The biological mechanisms were examined using Western blot and immunohistochemistry analyses of the muscles and spinal cord in hSOD1G93A mice.

RESULTS: Herbal medicine treatment improved motor function in hSOD1G93A mice by reducing the expression of inflammation-related proteins (glial fibrillary acidic protein and CD11b) and oxidative stress-related proteins (heme oxygenase 1 and ferritin) in the gastrocnemius and tibia anterior muscles and spinal cord. It also regulated autophagy in the muscles and spinal cord of hSOD1G93A mice.

CONCLUSION: Collectively, these findings suggest that the herbal medicine formulation reported herein may facilitate management of diseases with complex pathological mechanisms, such as ALS, or those with unclear pathological mechanisms.}, } @article {pmid40659544, year = {2025}, author = {Stenvall, E and Grönlund, KÅ and Rohan, Z and Zetterström, P and Nordin, A and Forsberg, K}, title = {Pathology of three ALS patients with FUS variants, including one likely benign Q23L variant lacking FUS inclusions.}, journal = {Human molecular genetics}, volume = {34}, number = {18}, pages = {1553-1562}, pmid = {40659544}, issn = {1460-2083}, support = {FO2023-0088//Swedish Brain Foundation/ ; FO2024-0232//Swedish Brain Foundation/ ; //Börje Salming ALS Foundation/ ; 2023.10//Ulla-Carin Lindquist Foundation/ ; 2023.16//Ulla-Carin Lindquist Foundation/ ; //Neuroförbundet Association/ ; RV-1005785//Västerbotten County Council/ ; RV-1013622//Västerbotten County Council/ ; RV-993493//Västerbotten County Council/ ; RV-996234//Västerbotten County Council/ ; RV-1014212//Västerbotten County Council/ ; RV-996140//Västerbotten County Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Inclusion Bodies/pathology/metabolism/genetics ; Motor Neurons/pathology/metabolism ; Mutation ; Nuclear Localization Signals/genetics ; *RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Fused in sarcoma (FUS) is an RNA-binding protein implicated in juvenile amyotrophic lateral sclerosis (ALS). Mutations in the FUS gene, particularly those affecting the nuclear localization signal (NLS), impair nuclear import and lead to cytoplasmic accumulation of FUS inclusions in motor neurons. However, the pathological and clinical significance of FUS variants outside the NLS remains less understood. Here, we describe clinical and histopathological findings from three ALS patients carrying FUS variants: two with NLS-region variants (R495X and P525L), and one with a variant in the N-terminal region outside the NLS (Q23L). The patients carrying NLS variants presented with aggressive, juvenile-onset spinal and bulbar ALS, characterized primarily by lower motor neuron involvement and rapid disease progression. In contrast, the Q23L patient exhibited a slowly progressive disease course, with predominantly upper motor neuron signs. Neuropathological analysis revealed cytoplasmic FUS inclusions in motor neurons of patients with NLS variants, consistent with typical FUS pathology. In contrast, the Q23L patient lacked FUS inclusions and instead displayed pTDP-43 pathology in the hippocampus, neocortex (including the motor cortex), nucleus olivaris, lentiform nucleus, striatum, and some lower motor neurons. Taken together, these results suggest that Q23L is most likely a benign variant. As antisense oligonucleotides (ASOs) targeting FUS are currently being explored in clinical trials, further neuropathological investigations are needed to determine whether ASO-mediated FUS silencing would be effective for patients carrying FUS variants outside the NLS region.}, } @article {pmid40659932, year = {2025}, author = {Castelnovo, V and Canu, E and Basaia, S and Spinelli, EG and Freri, F and Schito, P and Russo, T and Falzone, Y and Verde, F and Torre, S and Poletti, B and Tremolizzo, L and Appollonio, I and Ticozzi, N and Silani, V and Filippi, M and Agosta, F}, title = {Brain functional connectivity changes in amyotrophic lateral sclerosis with apathy and depression.}, journal = {Journal of neurology}, volume = {272}, number = {8}, pages = {509}, pmid = {40659932}, issn = {1432-1459}, support = {StG-2016_714388_NeuroTRACK//H2020 European Research Council/ ; Investment PE8 - Project Age-It: "Ageing Well in an Ageing Society"//Ministero dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/complications/psychology ; *Apathy/physiology ; Male ; Female ; Middle Aged ; *Depression/diagnostic imaging/physiopathology/etiology ; Aged ; *Brain/physiopathology/diagnostic imaging ; Magnetic Resonance Imaging ; Connectome ; Neural Pathways/physiopathology/diagnostic imaging ; }, abstract = {BACKGROUND: Apathy and depression are the most prevalent neuropsychiatric symptoms in amyotrophic lateral sclerosis (ALS). Although insufficiently investigated, their distinction holds important clinical relevance for accurate diagnosis of ALS with behavioural impairment and for patients' prognosis and management. In the present study, we aimed to assess both apathy and depressive symptoms in patients with ALS and whether they have similar or different functional neural correlates.

METHODS: Using graph analysis and connectomics, global and lobar nodal properties and regional functional brain connectivity were assessed in ALS patients without apathy/depression (ALSn, n = 42), with apathy without depression (ALSa, n = 14), with depressive symptoms without apathy (ALSd, n = 20), and with apathy and depressive symptoms (ALSad, n = 6), and 46 healthy controls. Correlations between brain functional properties, apathy and depressive symptoms were performed in all patients.

RESULTS: Depressive symptoms were related with reduced path length within bilateral basal ganglia (BG) network, and apathy was related with increased path length, decreased nodal strength and local efficiency within left BG network. ALSa patients showed altered functional nodal properties within BG network compared to ALSn and ALSd. Compared to healthy controls and all non-apathetic patients (ALSn and ALSd), all apathetic patients (ALSa and ALSad) exhibited altered functional nodal properties within parietal, occipital and frontal networks. Non-apathetic patients, compared to apathetic patients, showed relatively preserved functional nodal properties in the BG network.

CONCLUSIONS: Our findings indicate differences in brain functional neural organization associated with apathy and depression, underscoring the importance of distinguishing these symptoms in ALS and highlighting the need for targeted interventions.}, } @article {pmid40660191, year = {2025}, author = {Schmidt, R and Slotina, E and Meissner, F and Metelmann, M and Ilse, B and Vogt, V and Freytag, A}, title = {Palliative care pathways in Amyotrophic Lateral Sclerosis (ALS): a sequence analysis of health claims data.}, journal = {BMC palliative care}, volume = {24}, number = {1}, pages = {200}, pmid = {40660191}, issn = {1472-684X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; *Palliative Care/methods/statistics & numerical data/standards ; Male ; Female ; Cross-Sectional Studies ; Retrospective Studies ; Germany ; Aged ; Middle Aged ; Adult ; Insurance Claim Review/statistics & numerical data ; Aged, 80 and over ; *Critical Pathways/statistics & numerical data/standards ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disease requiring palliative care. Despite the availability of palliative care services, utilization patterns among people with ALS (pALS) remain poorly understood. This study aimed to analyze palliative care utilization (i.e., primary palliative care (PPC), specialized palliative homecare (SPHC), inpatient palliative care, hospice services) in the last year of life among pALS, to identify distinct care pathways using sequence analysis, and examine their association with end-of-life care quality.

METHODS: A retrospective cross-sectional study using German health claims data (2016 - 2019). Sequence analysis with Temporal Needleman-Wunsch alignment and clustering identified pathway clusters based on type, order, and timing of palliative care services. The study included 1,295 pALS who died between 2016 and 2019 and were insured with a large German health insurance provider. Inclusion required an ALS diagnosis without concurrent cancer.

RESULTS: Of 1,295 pALS, 695 (53.7%) received palliative care. Sequence analysis identified nine distinct care pathway clusters. Quality indicators varied highly across clusters. Pathways involving SPHC, either alone, with PPC, and/or with hospice care, showed fewer emergency visits, hospital stays, and in-hospital deaths, suggesting higher end-of-life care quality.

CONCLUSIONS: Palliative care utilization varies substantially in type, order, and timing. Findings suggest that end-of-life care quality depends not only on the provision of palliative care but also on when and on how different services are combined. Future research should examine the role of interdisciplinary collaboration in palliative care pathways and explore preferences and clinical characteristics of pALS to better understand factors influencing end-of-life care quality.}, } @article {pmid40660446, year = {2026}, author = {Singh, D}, title = {Mitochondrial Dysfunction in Neurodegenerative Disorders: Role of Prototype Targeted Drug Delivery Solutions.}, journal = {Current drug safety}, volume = {21}, number = {2}, pages = {94-107}, doi = {10.2174/0115748863375490250626163609}, pmid = {40660446}, issn = {2212-3911}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/physiopathology/metabolism ; *Mitochondria/drug effects/metabolism/pathology ; Animals ; *Drug Delivery Systems/methods ; Nanoparticles ; *Mitochondrial Diseases/drug therapy ; }, abstract = {Mitochondrial dysfunction plays a central role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Targeted drug delivery to mitochondria represents a promising therapeutic strategy to mitigate neuronal degeneration and preserve mitochondrial function in these devastating conditions. This review provides a comprehensive overview of recent advances in targeted drug delivery solutions for mitochondrial dysfunction in neurodegenerative disorders. The mechanisms underlying mitochondrial dysfunction in AD, PD, HD, and ALS are explored, highlighting the specific challenges and opportunities for therapeutic intervention. Emerging drug delivery technologies are discussed, including mitochondriaresponsive systems, nanoparticles, peptides, and viral vectors, designed to deliver therapeutic agents directly to mitochondria along with suitable case studies. Furthermore, preclinical and clinical studies evaluating the efficacy and safety of mitochondria-targeted therapeutics are reviewed, and future directions and challenges in the field are outlined. By elucidating the intersection of mitochondrial biology and drug delivery, this review aims to inspire further research and innovation toward effective treatments for neurodegenerative diseases.}, } @article {pmid40661236, year = {2025}, author = {López-Royo, T and Moreno-Martínez, L and Rada, G and Macías-Redondo, S and Calvo, AC and García-Redondo, A and Manzano, R and Osta, R}, title = {LncRNA levels in the central nervous system as novel potential players and biomarkers in amyotrophic lateral sclerosis.}, journal = {Non-coding RNA research}, volume = {14}, number = {}, pages = {145-155}, pmid = {40661236}, issn = {2468-0540}, abstract = {Research in amyotrophic lateral sclerosis (ALS) faces major burdens, including the urgent need for sensitive and specific biomarkers, the identification of novel and effective therapeutic targets and a deeper understanding of the mechanisms driving the disease. In this line, long non-coding RNAs (lncRNAs) have emerged as promising candidates due to their regulatory role in a variety of important biological processes such as RNA metabolism, neuroinflammation, apoptosis or proteostasis. This study aims to elucidate the expression profile of 14 lncRNAs in both the SOD1[G93A] mouse model and ALS patients. Different stages of the disease (presymptomatic, symptomatic and terminal) and 3 regions of the central nervous system (CNS) differentially affected by ALS (spinal cord, brainstem and frontal cortex) were included in the experimental design. In SOD1[G93A] mice, all 14 lncRNAs exhibited differential expression patterns influenced by sex, age, and region, except for Malat1, Neat1, and H19, which displayed consistent expression patterns (Malat1 was decreased, while Neat1 and H19 were increased). These patterns were most prominent in the spinal cord, where lncRNAs were overall down-regulated. In contrast, in the brainstem and frontal cortex, lncRNAs were predominantly up-regulated. Notably, Gas5 expression levels in frontal cortex and spinal cord at the terminal stage correlated with the onset and progression of motor coordination and strength decline. Additionally, three lncRNAs (Gas5, Neat1 and Myoparr) were found to significantly correlate with survival. In human ALS samples, increased levels of NEAT1 and SNHG16 were observed in the brainstem, and of MEG3 and H19 in the frontal cortex, whereas MALAT1 levels were decreased in frontal cortex. In conclusion, this work supports lncRNAs as promising candidates as novel players and potential biomarkers in ALS and highlights SOD1[G93A] mice as a good model to study lncRNAs in the CNS in the context of this disease.}, } @article {pmid40661315, year = {2025}, author = {Anjum, F and Bakhuraysah, M and Alsharif, A and Mohammad, T and Shamsi, A and Hassan, MI}, title = {Emerging biomarkers in amyotrophic lateral sclerosis: from pathogenesis to clinical applications.}, journal = {Frontiers in molecular biosciences}, volume = {12}, number = {}, pages = {1608853}, pmid = {40661315}, issn = {2296-889X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition marked by the gradual loss of motor neurons in the brain and spinal cord. As the most common adult-onset motor neuron disease, ALS manifests through gradually worsening muscle weakness that ultimately progresses to complete paralysis. The disease presents in both sporadic and familial forms. Diagnosis is often delayed until substantial and irreversible motor neuron damage has already occurred. Clinical outcomes in ALS have only been defined through large-scale clinical trials with lengthy follow-up periods due to the disease's inherent heterogeneity and the absence of disease-specific biomarkers. Current biomarker detection methods, such as invasive cerebrospinal fluid (CSF) analysis or advanced imaging, are impractical for routine use, particularly in late-stage ALS. Several blood-based biomarkers have shown promise, including neurofilament levels, cryptic RNA-derived peptides, and immune-mediated changes, which may enable non-invasive monitoring. Nevertheless, the development of these methods is hindered by technical challenges, such as blood matrix interference and low analyte abundance. Among the emerging biomarkers, neurofilament light chain (NfL) appears to be the most promising, as its concentrations change in line with disease progression and distinguish clinically relevant groups. NfL facilitates patient stratification based on clinical progression rates (e.g., rapid vs slow progressors), while cryptic exon-derived peptides, such as UNC13A-derived peptides, enable genetic stratification by identifying molecular subtypes linked to TDP-43 pathology (e.g., C9orf72 vs sporadic ALS). These biomarkers hold promise to optimize clinical trial design through enriched cohort selection and accelerating therapeutic translation by monitoring target engagement. In this review, we have summarized recent developments in ALS biomarker studies, focusing on neurofilaments in each biofluid, transcriptomic signatures, and neuroinflammatory biomarkers, emphasizing technical challenges surrounding reproducibility in measurement. Finally, we discussed the potential integration of these biomarkers into clinical practice to advance drug development through precision medicine, thereby enabling shorter and more targeted clinical trials.}, } @article {pmid40661327, year = {2025}, author = {Kawakami, Y and Iguchi, Y and Li, J and Amakusa, Y and Yoshimura, T and Chikuchi, R and Yokoi, S and Iida, M and Riku, Y and Iwasaki, Y and Hirose, T and Nakagawa, S and Katsuno, M}, title = {Downregulation of NEAT1 due to loss of TDP-43 function exacerbates motor neuron degeneration in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {4}, pages = {fcaf261}, pmid = {40661327}, issn = {2632-1297}, abstract = {TAR DNA-binding protein 43 (TDP-43) is of particular interest in the pathogenesis of amyotrophic lateral sclerosis (ALS). It has been speculated that loss of nuclear TDP-43 and its cytoplasmic aggregation contributes to neurodegeneration. Although considerable attention has been paid to RNA metabolism in TDP-43 function, TDP-43 is also known to act as a transcription factor. This study found that the expression of Nuclear-enriched abundant transcript 1 (NEAT1), a long-non-coding RNA, was substantially downregulated in motor neurons with nuclear TDP-43 loss, but upregulated in those with preserved nuclear TDP-43, in the postmortem spinal cords of patients with sporadic ALS. TDP-43 depletion induced Neat1 downregulation in Neuro2a cells, primary cortical neurons, and mouse spinal motor neurons. Furthermore, TDP-43 was found to positively regulate NEAT1 at the transcriptional level. Finally, Neat1 knockout exacerbates neurodegeneration of hSOD1[G93A] mice accompanied by increased misfolded superoxide dismutase 1 (SOD1) aggregations. Transcriptome analysis revealed that Neat1 knockout reduced protein folding-related genes, such as heat shock protein family A member 1A (Hspa1a), in the spinal cords of hSOD1[G93A] mice. Our results indicated that the loss of TDP-43 function enhances ALS neurodegeneration by losing the protective effect of NEAT1.}, } @article {pmid40661462, year = {2025}, author = {Ye, Y and Zhang, Z and Xiao, Y and Zhu, C and Wright, N and Asbury, J and Huang, Y and Wang, W and Gomez-Isaza, L and Troncoso, JC and He, C and Sun, S}, title = {DCPS modulates TDP-43 mediated neurodegeneration through P-body regulation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.06.13.659508}, pmid = {40661462}, issn = {2692-8205}, support = {P30 AG066507/AG/NIA NIH HHS/United States ; }, abstract = {The proteinopathy of the RNA-binding protein TDP-43, characterized by nuclear clearance and cytoplasmic inclusion, is a hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). Through CRISPR interference (CRISPRi) screening in human neurons, we identified the decapping enzyme scavenger (DCPS) as a novel genetic modifier of TDP-43 loss-of-function (LOF)-mediated neurotoxicity. Our findings reveal that TDP-43 LOF leads to aberrant mRNA degradation, via disrupting the properties and function of processing bodies (P-bodies). TDP-43 interacts with P-body component proteins, potentially influencing their dynamic equilibrium and assembly into ribonucleoprotein (RNP) granules. Reducing DCPS restores P-body integrity and RNA turnover, ultimately improving neuronal survival. Overall, this study highlights a novel role of TDP-43 in RNA processing through P-body regulation and identifies DCPS as a potential therapeutic target for TDP-43 proteinopathy-related neurodegenerative diseases.}, } @article {pmid40661641, year = {2025}, author = {Foord, C and Prjibelski, AD and Hu, W and Michielsen, L and Vandelli, A and Narykov, O and Evans, B and Hsu, J and Belchikov, N and Jarroux, J and He, Y and Ross, ME and Hajirasouliha, I and Tartaglia, GG and Korkin, D and Tomescu, AI and Tilgner, HU}, title = {A spatial long-read approach at near-single-cell resolution reveals developmental regulation of splicing and polyadenylation sites in distinct cortical layers and cell types.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40661641}, issn = {2692-8205}, support = {R01 GM135247/GM/NIGMS NIH HHS/United States ; R35 GM152101/GM/NIGMS NIH HHS/United States ; U01 DA053625/DA/NIDA NIH HHS/United States ; R01 HD111089/HD/NICHD NIH HHS/United States ; T32 DA039080/DA/NIDA NIH HHS/United States ; T32 GM132083/GM/NIGMS NIH HHS/United States ; RF1 MH121267/MH/NIMH NIH HHS/United States ; R35 GM138152/GM/NIGMS NIH HHS/United States ; R01 LM014017/LM/NLM NIH HHS/United States ; }, abstract = {Genome-wide single-cell and spatial long-read approaches have gained traction, but mostly lack single-cell resolution - and yield limited read lengths. Here, we introduce spatial ISOform sequencing (Spl-ISO-Seq), which reveals exons and polyadenylation sites from long reads with near-single-cell resolution. Spl-ISO-Seq selects long cDNAs and doubles to triples read lengths compared to standard preparations. Adding a highly specific software tool (Spl-ISOquant) and comparing human post-mortem pre-puberty samples of the visual cortex (8-11 years) to post-puberty samples (16-19 years), we find that cortical layers harbor stronger splicing and poly(A)-site regulation than the adjacent white matter, with enrichment of multiple protein-domain types. For oligodendrocytes however, developmental splicing changes are stronger in white matter. Among cortical layers, layer 4 has the most developmental changes in alternative-exon inclusion in excitatory neurons and in poly(A) sites. We also find many repeat elements, especially ERV1 long terminal repeats downstream of developmentally-regulated layer 4 exons. Overall, alternative splicing changes are linked to synapses - specifically at the post-synapse. Age-linked splicing changes in layers 1-3 and 4 are associated with autism spectrum disorder but not with schizophrenia, amyotrophic lateral sclerosis and Alzheimer's disease. These results root developmental splicing changes during puberty and the resulting protein changes in specific layers and cell types. More generally, our new technologies enable new observations for any complex tissue.}, } @article {pmid40661843, year = {2025}, author = {Malmström, N and Öhlén, J and Nilsson, S and Nygren, I and Andersen, PM and Jakobsson Larsson, B and Ozanne, A}, title = {Transformed Parenthood in the Face of ALS: A Profound Struggle for Both Ill Parents and Co-parents.}, journal = {Global qualitative nursing research}, volume = {12}, number = {}, pages = {23333936251348143}, pmid = {40661843}, issn = {2333-3936}, abstract = {When a parent is diagnosed with a progressive, fatal neurodegenerative disease, such as amyotrophic lateral sclerosis (ALS), it can have major effects on the family's health. Parenthood itself may also be affected, potentially fueling an urgent need for support from healthcare. Research focusing on this group of parents is nevertheless limited. The aim of this study was to illuminate the meaning of parenthood when a parent has ALS, from the perspective of ill parents and co-parents. An interpretive qualitative study was conducted, using data gathered from interviewing 26 parents (13 ill parents and 13 co-parents) with children living at home in Sweden. Applying a phenomenological hermeneutical analysis, structural analyses depicted the burdensome, complex impact that ALS can have on parenthood, redefining its meaning while forcing parents to face the difficult challenges it brings. The interpreted whole revealed how navigating this transformed parenthood meant a profound struggle, as the parents strived to balance their own emotional pain from grief and worry with remaining stable and supportive for their children. To promote the health of families affected by ALS, more proactive, tailored support is needed within ALS nursing, along with early integration of a palliative approach and attention to the parental perspective.}, } @article {pmid40663766, year = {2025}, author = {Matthews, AM and Whiteley, AM}, title = {UBQLN2 in neurodegenerative disease: mechanistic insights and emerging therapeutic potential.}, journal = {Biochemical Society transactions}, volume = {53}, number = {4}, pages = {823-833}, pmid = {40663766}, issn = {1470-8752}, support = {R01 NS131660/NS/NINDS NIH HHS/United States ; T32 GM142607/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Autophagy-Related Proteins/genetics/metabolism ; *Adaptor Proteins, Signal Transducing/genetics/metabolism ; *Neurodegenerative Diseases/metabolism/genetics/therapy ; Animals ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Autophagy ; Mutation ; Mitochondria/metabolism ; Frontotemporal Dementia/genetics/metabolism ; *Cell Cycle Proteins/genetics/metabolism ; }, abstract = {Ubiquilins (UBQLNs) regulate cellular protein turnover by shuttling proteins, or 'clients', to the proteasome or autophagy pathways for degradation. Of the five different UBQLN genes in humans, UBQLN2 is the most highly expressed in the nervous system and muscle tissue and has been linked to multiple neurodegenerative diseases. In particular, point mutations of UBQLN2 cause an X-linked, dominant form of amyotrophic lateral sclerosis (ALS), ALS with frontotemporal dementia (ALS/FTD), or FTD. Failed protein degradation is a hallmark of many neurodegenerative diseases, including ALS and FTD; however, it is not clear exactly how ALS/FTD-associated UBQLN2 mutations contribute to pathogenesis. Recent studies have revealed the complexity of UBQLN2 biology and allow deeper understanding as to how UBQLN2 dysfunction may contribute to neurodegenerative disease. UBQLN2 is necessary for mitochondrial protein degradation and for regulating mitochondrial turnover, both of which are essential for motor neurons and have been implicated in the pathogenesis of ALS. Stress granule (SG) formation and regulation are also affected by UBQLN2 mutations, and their dysregulation may contribute to the toxic protein aggregation and SG changes observed in neurodegenerative disease. Finally, there are compelling links connecting UBQLN2 dysfunction with changes to downstream neuronal morphology, function, and behavior. This review will detail the emerging consensus on how UBQLN2 protects against neurodegenerative disease and will provide insights into potential therapeutic approaches.}, } @article {pmid40664112, year = {2025}, author = {Sahoo, BR and Bardwell, JC}, title = {Protein and RNA chaperones.}, journal = {Molecular aspects of medicine}, volume = {104}, number = {}, pages = {101384}, doi = {10.1016/j.mam.2025.101384}, pmid = {40664112}, issn = {1872-9452}, mesh = {Humans ; *Molecular Chaperones/metabolism/chemistry ; *RNA/metabolism/chemistry ; G-Quadruplexes ; Animals ; Protein Folding ; Protein Aggregates ; *RNA-Binding Proteins/metabolism/chemistry ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Cells preserve macromolecular homeostasis by utilizing molecular chaperones that prevent aggregation or promote correct folding of protein and RNA. Here we discuss non-traditional proteinaceous chaperones like RNA-binding chaperones that work by modulating RNA structure, preventing aberrant interactions, and regulating intracellular granule dynamics. We also discuss the chaperone functions of other macromolecules such as nucleic acids, and in particular G-quadruplexes, which are very effective at preventing protein aggregation and accelerating protein folding. These chaperones are particularly important in G-quadruplex linked amyloid aggregation and repeat-expansion diseases such as Parkinson's disease and amyotrophic lateral sclerosis, where RNA aggregation and misfolded protein accumulation co-occur. By comparing protein and non-protein chaperone systems, we highlight the principles that underlie chaperone action across molecular classes.}, } @article {pmid40664152, year = {2025}, author = {Keivan Behjou, N and Seyedalipour, B and Hosseini Faradonbeh, SM and Hosseinkhani, S and Chaeichi, MJ}, title = {Exploring the role of ethylammonium bromide as an ionic liquid in amyloid aggregation modulation for ALS-linked hSOD1 E49K mutant.}, journal = {Bioorganic chemistry}, volume = {163}, number = {}, pages = {108740}, doi = {10.1016/j.bioorg.2025.108740}, pmid = {40664152}, issn = {1090-2120}, mesh = {Humans ; *Amyloid/metabolism/antagonists & inhibitors ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy ; Dose-Response Relationship, Drug ; *Ionic Liquids/chemistry/pharmacology ; Molecular Dynamics Simulation ; Molecular Structure ; Mutation ; Protein Aggregates/drug effects ; *Quaternary Ammonium Compounds/chemistry/pharmacology ; Structure-Activity Relationship ; *Superoxide Dismutase-1/genetics/metabolism/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt ; }, abstract = {Ionic liquids (ILs) offer a diverse and tunable approach to inhibiting amyloid protein formation, providing new strategies to develop anti-amyloidogenic agents for amyloid-based diseases, as explored in protein-IL research. This study explores the formation of amyloid aggregates of the E49K mutant under amyloidogenic conditions and evaluates the inhibitory potential of ethylammonium bromide (EABr) as an anti-amyloidogenic agent relevant to ALS pathology. The effect of EABr was studied using molecular dynamics simulations, FTIR spectroscopy, ANS fluorescence, ThT fluorescence, and TEM imaging. EABr promotes the formation of compact structures by reducing the exposure of contagious hydrophobic pockets in the E49K mutant aggregates, as monitored by ANS fluorescence. EABr binds with moderate affinity to the E49K mutant forms, inhibiting fibrillation by stabilizing aggregation-prone regions, as shown in fluorescence quenching. The decrease in ThT fluorescence intensity and the inhibition of fibril formation in a concentration-dependent manner highlight the interaction of EABr with the E49K mutant throughout the incubation period. TEM images during the saturation phase provide compelling evidence that EABr inhibits the formation of amyloid fibrils in the E49K mutant, thus supporting ThT analysis results. These findings demonstrate that EABr can inhibit amyloid formation of the E49K SOD1 mutant in vitro, supporting its potential as a lead compound for further pharmacological studies.}, } @article {pmid40664547, year = {2026}, author = {Müllhaupt, G and Hechelhammer, L and Graf, N and Mordasini, L and Schmid, HP and Engeler, DS and Abt, D}, title = {Reply to Francesco Montorsi, Edoardo Pozzi, Marco Bianchi, et al's Letter to the Editor re: Gautier Müllhaupt, Lukas Hechelhammer, Nicole Graf, et al. Prostatic Artery Embolisation Versus Transurethral Resection of the Prostate for Benign Prostatic Obstruction: 5-year Outcomes of a Randomised, Open-label, Noninferiority Trial. Eur Urol Focus 2024;10:788-95.}, journal = {European urology focus}, volume = {12}, number = {2}, pages = {304}, doi = {10.1016/j.euf.2025.06.017}, pmid = {40664547}, issn = {2405-4569}, } @article {pmid40665048, year = {2025}, author = {Imam, F and Saloner, R and Vogel, JW and Krish, V and Abdel-Azim, G and Ali, M and An, L and Anastasi, F and Bennett, D and Pichet Binette, A and Boxer, AL and Bringmann, M and Burns, JM and Cruchaga, C and Dage, JL and Farinas, A and Ferrucci, L and Finney, CA and Frasier, M and Hansson, O and Hohman, TJ and Johnson, ECB and Kivimaki, M and Korologou-Linden, R and Ruiz Laza, A and Levey, AI and Liepelt-Scarfone, I and Lu, L and Mattsson-Carlgren, N and Middleton, LT and Nho, K and Oh, HS and Petersen, RC and Reiman, EM and Robinson, O and Rothstein, JD and Saykin, AJ and Shvetcov, A and Slawson, C and Smets, B and Suárez-Calvet, M and Tijms, BM and Timmers, M and Vieira, F and Vilor-Tejedor, N and Visser, PJ and Walker, KA and Winchester, LM and Wyss-Coray, T and Yang, C and Bose, N and Lovestone, S and , }, title = {The Global Neurodegeneration Proteomics Consortium: biomarker and drug target discovery for common neurodegenerative diseases and aging.}, journal = {Nature medicine}, volume = {31}, number = {8}, pages = {2556-2566}, pmid = {40665048}, issn = {1546-170X}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; U01 AG079847/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; R01 AG057911/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; T32 MH135853/MH/NIMH NIH HHS/United States ; RF1 AG057471/AG/NIA NIH HHS/United States ; R01 AG061800/AG/NIA NIH HHS/United States ; R01 AG057339/AG/NIA NIH HHS/United States ; R01 AG069453/AG/NIA NIH HHS/United States ; U01 AG058922/AG/NIA NIH HHS/United States ; R01 AG044546/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; RF1 AG053303/AG/NIA NIH HHS/United States ; R01 TS000341/TS/ATSDR CDC HHS/United States ; T32 MH020016/MH/NIMH NIH HHS/United States ; R01 AG053960/AG/NIA NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; RF1 AG058501/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; RF1 AG062553/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; U01 AG045390/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; U54 NS092089/NS/NINDS NIH HHS/United States ; R01 AG064227/AG/NIA NIH HHS/United States ; RF1 AG057470/AG/NIA NIH HHS/United States ; R01 AG083740/AG/NIA NIH HHS/United States ; R01 AG056477/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Proteomics/methods ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Drug Discovery ; *Aging/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Parkinson Disease/metabolism ; Alzheimer Disease/metabolism ; Frontotemporal Dementia/metabolism ; }, abstract = {More than 57 million people globally suffer from neurodegenerative diseases, a figure expected to double every 20 years. Despite this growing burden, there are currently no cures, and treatment options remain limited due to disease heterogeneity, prolonged preclinical and prodromal phases, poor understanding of disease mechanisms, and diagnostic challenges. Identifying novel biomarkers is crucial for improving early detection, prognosis, staging and subtyping of these conditions. High-dimensional molecular studies in biofluids ('omics') offer promise for scalable biomarker discovery, but challenges in assembling large, diverse datasets hinder progress. To address this, the Global Neurodegeneration Proteomics Consortium (GNPC)-a public-private partnership-established one of the world's largest harmonized proteomic datasets. It includes approximately 250 million unique protein measurements from multiple platforms from more than 35,000 biofluid samples (plasma, serum and cerebrospinal fluid) contributed by 23 partners, alongside associated clinical data spanning Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This dataset is accessible to GNPC members via the Alzheimer's Disease Data Initiative's AD Workbench, a secure cloud-based environment, and will be available to the wider research community on 15 July 2025. Here we present summary analyses of the plasma proteome revealing disease-specific differential protein abundance and transdiagnostic proteomic signatures of clinical severity. Furthermore, we describe a robust plasma proteomic signature of APOE ε4 carriership, reproducible across AD, PD, FTD and ALS, as well as distinct patterns of organ aging across these conditions. This work demonstrates the power of international collaboration, data sharing and open science to accelerate discovery in neurodegeneration research.}, } @article {pmid40665049, year = {2025}, author = {Shvetcov, A and Johnson, ECB and Winchester, LM and Walker, KA and Wilkins, HM and Thompson, TG and Rothstein, JD and Krish, V and Imam, FB and , and Burns, JM and Swerdlow, RH and Slawson, C and Finney, CA}, title = {APOE ε4 carriers share immune-related proteomic changes across neurodegenerative diseases.}, journal = {Nature medicine}, volume = {31}, number = {8}, pages = {2590-2601}, pmid = {40665049}, issn = {1546-170X}, support = {R21TR003589//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01AG064227//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 AG053960/AG/NIA NIH HHS/United States ; R01 AG089497/AG/NIA NIH HHS/United States ; P50AG025688//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U01 AG061357/AG/NIA NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; 23AARG-1023/ALZ/Alzheimer's Association/United States ; MRF2040081//Department of Health | National Health and Medical Research Council (NHMRC)/ ; R21 TR003589/TR/NCATS NIH HHS/United States ; R01AG089497//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R35NS132179//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 AG057339/AG/NIA NIH HHS/United States ; RF1 AG057471/AG/NIA NIH HHS/United States ; R01 AG061800/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; R01 AG057911/AG/NIA NIH HHS/United States ; U19AG068054//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P30 AG072973/AG/NIA NIH HHS/United States ; P30AG072973//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01AG07816//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U01 AG046161/AG/NIA NIH HHS/United States ; K08AG08604//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 AG064227/AG/NIA NIH HHS/United States ; RF1 AG057470/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Apolipoprotein E4/genetics/immunology ; *Neurodegenerative Diseases/genetics/immunology/metabolism ; Proteomics/methods ; Parkinson Disease/genetics/immunology ; Alzheimer Disease/genetics/immunology ; Male ; Female ; Amyotrophic Lateral Sclerosis/genetics/immunology ; Aged ; Frontotemporal Dementia/genetics/immunology ; Heterozygote ; *Proteome/genetics ; Middle Aged ; alpha-Synuclein ; tau Proteins ; }, abstract = {The APOE ε4 genetic variant is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and is increasingly being implicated in other neurodegenerative diseases. Using the Global Neurodegeneration Proteomics Consortium SomaScan dataset covering 1,346 cerebrospinal fluid (CSF) and 9,924 plasma samples, we used machine learning-based proteome profiling to identify an APOE ε4 proteomic signature shared across individuals with AD, frontotemporal dementia (FTD), Parkinson's disease dementia (PDD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and nonimpaired controls. This signature was enriched in pro-inflammatory immune and infection pathways as well as immune cells, including monocytes, T cells and natural killer cells. Analysis of the dorsolateral prefrontal cortex proteome for 262 donors from the Accelerating Medicines Partnership for AD UPenn Proteomics Study revealed a consistent APOE ε4 phenotype, independent of neurodegenerative pathology, including amyloid-β tau and gliosis for all diseases, as well as TDP-43 in ALS and FTD cases, and α-synuclein in PD and PDD cases. While systemic proteomic changes were consistent across APOE ε4 carriers, their relationship with clinical and lifestyle factors, such as hypertension and smoking, varied by disease. These findings suggest APOE ε4 confers a systemic biological vulnerability that is necessary but not sufficient for neurodegeneration, emphasizing the need to consider gene-environment interactions. Overall, our study reveals a conserved APOE ε4-associated pro-inflammatory immune signature persistent across the brain, CSF and plasma irrespective of neurodegenerative disease, highlighting a fundamental, disease-independent biological vulnerability to neurodegeneration. This work reframes APOE ε4 as a pleiotropic immune modulator rather than an AD-specific risk gene, providing a foundation for precision biomarker development and early intervention strategies across neurodegenerative diseases.}, } @article {pmid40665686, year = {2025}, author = {Lee, B and Cho, ST and Kim, R and Chung, KW and Kwon, TJ and Kim, UK and Kim, YR and Choi, BO and Park, JS}, title = {DCTN1-associated neurological disorder with symptoms similar to spinal bulbar muscular atrophy.}, journal = {Journal of neuromuscular diseases}, volume = {12}, number = {6}, pages = {804-813}, pmid = {40665686}, issn = {2214-3602}, mesh = {Humans ; Male ; *Dynactin Complex/genetics ; Pedigree ; Middle Aged ; Female ; Adult ; Mutation, Missense ; Republic of Korea ; Phenotype ; }, abstract = {BackgroundDynactin 1 (DCTN1) mutations are associated with diverse neurological disorders, including distal hereditary motor neuropathy, Perry syndrome, and amyotrophic lateral sclerosis. This study focused on a family with symptoms resembling spinal and bulbar muscular atrophy, showing severe vocal cord paralysis, to understand DCTN1-related neurological disorders in Koreans.MethodClinical examinations revealed variable phenotypes, such as proximal limb weakness, chronic hypercapnia, and gynecomastia, alongside vocal cord paralysis. Whole-exome sequencing identified a missense mutation, c.1175G > A, in DCTN1. Three more Korean families with the same mutation were analyzed to explore a potential founder effect. Microsatellite analysis indicated a shared haplotype, suggesting a common genetic origin.ResultThis study identified a missense mutation, c.1175G > A, in DCTN1 in the initial family with features resembling spinal and bulbar muscular atrophy. The mutation was also present in three other Korean families, indicating a potential founder effect. Microsatellite analysis confirmed a shared haplotype among these families. Meanwhile, the patients also manifested additional clinical features such as peripheral neuropathy and gynecomastia.ConclusionThis study highlights clinical heterogeneity in Korean patients with DCTN1-associated neurological disorders and identifies a potential founder mutation, c.1175G > A, expanding the clinical spectrum of DCTN1 mutations with clinical features of spinal bulbar muscular atrophy. Understanding such genetic and clinical diversity is crucial for accurate diagnoses and management, with implications for future research and therapeutic strategies.}, } @article {pmid40666341, year = {2025}, author = {Petrozziello, T and Mizerak, E and Krishnamoorthy, A and Donahue, RA and Castillo Torres, AL and Monsanto, RZB and Hammerschlag, BL and Fillingham, B and Kivisäkk, P and Timmons, J and Fox, K and Arnold, SE and Cohen, J and Klee, J and Paganoni, S and Cudkowicz, ME and Chibnik, LB and Berry, JD and Sadri-Vakili, G}, title = {Plasma tau and phosphorylated tau at T181 are altered in amyotrophic lateral sclerosis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.06.26.25330363}, pmid = {40666341}, support = {P30 AG062421/AG/NIA NIH HHS/United States ; }, abstract = {There is an unmet need for reliable biomarkers for amyotrophic lateral sclerosis (ALS). Recent studies have demonstrated that the levels of the microtubule-associated protein tau, are altered in plasma and cerebrospinal fluid (CSF) from people with ALS. Our previous findings demonstrated that while the ratio between tau and phosphorylated tau at T181 (pTau-T181) is decreased, increases in CSF tau correlated with faster disease progression in people with ALS. Here, we measured tau and pTau-T181 in plasma samples from participants with ALS and healthy controls (HC) using two methods (Quanterix Simoa and Meso Scale Discovery, MSD). Using both assays, there was an increase in pTau-T181 levels and in the pTau-T181:tau ratio in ALS compared to HC andlarger increases in pTau-T181 and pTau-T181:tau ratio at baseline correlated with faster ALS progression. Plasma total tau levels were increased in ALS compared to HC on the MSD assay and decreased on Quanterix Simoa assay. Collectively, our results suggest that plasma pTau-T181 levels are increased in ALS. Future studies should aim to clarify its role as a diagnostic or prognostic biomarker for ALS.}, } @article {pmid40666348, year = {2025}, author = {Johari, M and Folland, C and Saito, Y and Oud, MM and Parmar, JM and Töpf, A and Kurbatov, S and Ampleeva, M and Zakharova, EY and Chekmareva, IA and Shirokova, KS and Atiakshin, D and Gardeitchik, T and Kamsteeg, EJ and Medici, E and Kaat, LD and Bruels, CC and Stafki, SA and Estrella, EA and Littel, HR and Kunkel, LM and Kang, PB and Osei-Owusu, I and Pais, L and O'Leary, M and Austin-Tse, C and O'Donnell-Luria, A and Mangilog, B and Radio, FC and D'Amico, A and Ciolfi, A and Tartaglia, M and Perrin, A and Van Goethem, C and Sole, G and Martin-Négrier, ML and Cossée, M and Genetti, CA and Valivullah, ZM and Milic, V and Kovacevic, G and Kosac, A and Moreno, CAM and Camelo, CG and Zanoteli, E and Fahey, MC and Beggs, AH and Vissing, J and Straub, V and Savarese, M and Tasca, G and Voermans, N and Laing, NG and Udd, B and Nishino, I and Ravenscroft, G}, title = {Missense variants in TUBA4A cause myo-tubulinopathies.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40666348}, support = {P50 HD105351/HD/NICHD NIH HHS/United States ; R01 HG009141/HG/NHGRI NIH HHS/United States ; U01 HG011755/HG/NHGRI NIH HHS/United States ; UM1 HG008900/HG/NHGRI NIH HHS/United States ; }, abstract = {Tubulinopathies encompass a wide spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked de novo or dominantly inherited TUBA4A missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, hereditary spastic ataxia, and more recently, an isolated report of congenital myopathy, the full phenotypic and genotypic spectrum of TUBA4A-related disorders remains incompletely characterised. In this multi-centre study, we identified 13 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Remarkably, affected individuals in 17 families presented with a primary axial myopathy without any identified CNS involvement or history of such disease. In the remaining two families, we observed probands with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness, establishing the first documented association between TUBA4A variants and multisystem proteinopathy. Our cohort exhibited diverse genotypes and associated inheritance patterns: four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had homozygous TUBA4A variants, where the biallelic genotype was found to be associated with the disease, and the heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous TUBA4A variants were classified as "isolated-sporadic cases" where parental samples were unavailable. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. We observed a range of disease onset, from congenital to late adulthood. Creatine kinase levels were also variable, ranging from normal to highly elevated. Cardiac function remained preserved across the cohort. Muscle biopsies revealed a range of pathologies, including myofibre size variation, myofibre atrophy, nemaline bodies, core-like regions, internal nuclei, and endomysial fibrosis. Immunohistochemical staining showed evidence of proteinopathy, with autophagic features and TUBA4A accumulation in patient myofibres. Complementary in silico and in vitro investigations suggested that the identified TUBA4A substitutions cause significant protein abnormalities and may differentially impact microtubule dynamics. Our findings establish myo-tubulinopathies as distinct clinical entities, encompassing both primary myopathies and multisystem proteinopathies with muscle involvement. This study broadens the phenotypic and genotypic spectrum of TUBA4A-related disorders beyond autosomal dominant or de novo mechanisms and neurodegenerative presentations. These results underscore the importance of considering TUBA4A variants in the differential diagnosis of axial myopathies and multisystem proteinopathies, regardless of central nervous system (CNS) involvement.}, } @article {pmid40667039, year = {2025}, author = {Sinha, IR and Ye, Y and Li, Y and Sandal, PS and Wong, PC and Sun, S and Ling, JP}, title = {Inhibition of nonsense-mediated decay in TDP-43 deficient neurons reveals novel cryptic exons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40667039}, issn = {2692-8205}, support = {RF1 NS129878/NS/NINDS NIH HHS/United States ; R01 NS127925/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; U01 FD008129/FD/FDA HHS/United States ; R01 AG078948/AG/NIA NIH HHS/United States ; RF1 NS095969/NS/NINDS NIH HHS/United States ; }, abstract = {TAR DNA-binding protein 43 kDa (TDP-43) is an essential splicing repressor whose loss of function underlies the pathophysiology of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Nuclear clearance of TDP-43 disrupts its function and leads to the inclusion of aberrant cryptic exons. These cryptic exons frequently introduce premature termination codons resulting in the degradation of affected transcripts through nonsense-mediated mRNA decay (NMD). Conventional RNA sequencing approaches thus may fail to detect cryptic exons that are efficiently degraded by NMD, precluding identification of potential therapeutic targets. We generated a comprehensive set of neuronal targets of TDP-43 in human iPSC-derived i[3]Neurons (i[3]N) by combining TDP-43 knockdown with inhibition of multiple factors essential for NMD, revealing novel cryptic targets. We then restored expression of selected NMD targets in TDP-43 deficient i[3]Ns and determined which genes improved neuronal viability. Our findings highlight the role of NMD in masking cryptic splicing events and identify novel potential therapeutic targets for TDP-43-related neurodegenerative disorders.}, } @article {pmid40667053, year = {2025}, author = {Chizari, S and Zanovello, M and Kong, S and Saigal, V and Brown, AL and Turchetti, V and Zampedri, L and Skorupinska, I and Minicuci, GM and Paron, F and Tonin, P and Marchetto, G and Li, Z and Colón-Mercado, JM and Dattilo, D and Barattucci, S and Gatt, A and Qi, A and Hanna, M and Ward, M and Petrucelli, L and Romano, M and Vattemi, G and Buratti, E and Malapsina, A and Merve, A and Machado, PM and Soraru, G and Fratta, P and Jiang, N}, title = {TDP-43 pathology induces CD8[+] T cell activation through cryptic epitope recognition.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40667053}, issn = {2692-8205}, support = {S10 OD026986/OD/NIH HHS/United States ; T32 AI055428/AI/NIAID NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, abstract = {Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features of amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), two degenerative diseases of the CNS and muscle. The loss of TDP-43 nuclear function results in the aberrant inclusion of cryptic exons in mRNA transcripts, leading to the expression of de novo proteins. Clonally expanded and highly differentiated CD8[+] T cells have been observed in individuals with TDP-43 proteinopathies and therapeutics modulating the T cell response have recently been found to extend survival. However, the target antigens mediating T cell activation have remained elusive. Here, we investigate whether the de novo proteins induced by aberrant cryptic splicing due to TDP-43 nuclear loss can act as neo-antigens. We detect the HDGFL2 cryptic peptide and multiple other TDP-43 cryptic exons in IBM skeletal muscle, where their presence correlates with enrichment of T cells and class I antigen presentation pathways. Furthermore, we identify epitopes deriving from HDGFL2 and IGLON5 cryptic peptides which are recognized by clonally expanded and functionally differentiated populations of CD8[+] T cells in ALS and IBM Patients. Finally, we demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to the cryptic peptide derived epitopes (cryptic epitopes) and are able to kill TDP-43 deficient astrocytes. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology.}, } @article {pmid40667180, year = {2025}, author = {Tam, SB and Waldeck, NJ and Wright, M and Mojsilovic-Petrovic, J and Baker, EM and Kiskinis, E and Bass, J and Kalb, RG}, title = {A role for the spinal cord cholinergic neuron circadian clock in RNA metabolism and mediating ALS disease phenotypes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.05.06.652480}, pmid = {40667180}, issn = {2692-8205}, abstract = {Circadian clocks are encoded by a transcription-translation feedback loop that aligns physiological processes with the solar cycle. Previous work linking the circadian clock to the regulation of RNA-binding proteins (RBPs) and alternative splicing provides a foundation for the vital examination of their mechanistic connections in the context of amyotrophic lateral sclerosis (ALS)-a fatal neurodegenerative disease commonly marked by disrupted RBP function. Here, we reveal that the spinal cord cholinergic neuron rhythmic transcriptome is enriched for genes associated with ALS and other neurodegenerative diseases. We show that there is time-of-day-dependent expression of ALS-linked RBP transcripts and rhythmic alternative splicing of genes involved in fundamental neuronal processes, such as microtubule cytoskeleton organization, intracellular trafficking, and synaptic function. We demonstrate clock-dependent expression of ALS-linked RBP Ataxin 2 in this neuronal subtype. Further, through in silico analysis of RNA sequencing data from sporadic ALS patients, we find that gene expression profiles altered in disease correspond with rhythmic gene networks. Finally, we report that clock disruption through cholinergic neuron-specific deletion of clock activator BMAL1 (i) increases lumbar spinal cord motor neuron loss and sciatic nerve axon degeneration and (ii) drives time-of-day-dependent alternative splicing of genes associated with RNA metabolism, including genes encoding ALS-linked RBPs (e.g., Matr3 , Srsf7 , and Ythdf2). Our results establish a role for the cholinergic neuron circadian clock in RNA metabolism and mediating neurodegeneration.}, } @article {pmid40667260, year = {2025}, author = {Ghayal, NB and Crook, RJ and Jain, A and Sachdeva, G and Roemer, SF and Sekiya, H and DeTure, MA and Baker, M and Coster, W and Oskarsson, BE and Josephs, KA and Rademakers, R and van Blitterswijk, M and Dickson, DW}, title = {Expanding the spectrum of annexin A11 proteinopathy in frontotemporal lobar degeneration and motor neuron disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.06.26.661831}, pmid = {40667260}, issn = {2692-8205}, abstract = {Aggregation of TAR DNA-binding protein 43 (TDP-43) is strongly associated with frontotemporal lobar degeneration (FTLD-TDP), motor neuron disease (MND-TDP), and overlap disorders like FTLD-MND. Three major forms of motor neuron disease are recognized and include primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), and progressive muscular atrophy (PMA). Annexin A11 (ANXA11) is understood to aggregate in amyotrophic lateral sclerosis (ALS-TDP) associated with pathogenic variants in ANXA11 , as well as in FTLD-TDP type C. Given these observations and recent reports of ANXA11 variants in patients with semantic variant frontotemporal dementia (svFTD) and FTD-MND presentations, we sought to characterize ANXA11 proteinopathy in an autopsy cohort of 379 cases with FTLD-TDP, as well as FTLD-MND and MND-TDP cases subclassified neuropathologically into PLS, ALS, and PMA. All FTLD-TDP type C cases had ANXA11 proteinopathy. However, ANXA11 proteinopathy was present in over 40% of FTLD-MND and in 38 out of 40 FTLD-PLS cases (95%), of which 80% had TDP type B or an unclassifiable TDP-43 proteinopathy and 15% had TDP type C. Genetic analyses excluded pathogenic ANXA11 variants in all ANXA11-positive cases. We thus demonstrated novel forms of ANXA11 proteinopathy strongly associated with FTLD-PLS, but not with TDP type C or pathogenic ANXA11 variants. Given the emerging relationship of ANXA11 in TDP-43 proteinopathies, we propose that TDP-43 and ANXA11 proteinopathy (TAP) comprises the molecular pathology of cases with abundant inclusions that are co-immunoreactive for both proteins and we subclassify three types of TAP based on distinct clinical and neuropathologic features.}, } @article {pmid40668826, year = {2025}, author = {Komarova, K and Gelfand, NA and Remacle, F and Levine, RD and Chakraborty, S and Jackson, TL and Kostko, O and Thiemens, MH}, title = {Photoselective isotope fractionation dynamics of N2 with cosmo and atmospheric chemistry perspectives.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {29}, pages = {e2511172122}, pmid = {40668826}, issn = {1091-6490}, support = {2019722//BSF-NSF/ ; T0205.20//FNRS | Fonds pour la Formation à la Recherche/ ; DE-AC02-05CH11231//DOE office of Science/ ; 2009959//NSF-BSF/ ; }, abstract = {Stable isotope ratio measurements provide valuable insights into a broad range of natural processes, from planetary atmospheres and climate to interstellar chemistry. Nitrogen, which has two stable isotopes, exhibits varying isotope ratios across the solar system. To model these observations, the isotope fraction as a function of energy is essential. At the Advanced Light Source (ALS), we measured the photodissociation of molecular nitrogen (N2) with vacuum UV photons where a single photon is sufficiently energetic to dissociate the strong bond. The nitrogen atoms produced are scavenged with H2 to form ammonia, whose isotopic makeup is determined. Blending the experiments with dynamical computations that include the shielding of light, we examine the isotopic composition and electronic atomic states produced. The measured photodissociation of N2 at a natural isotopic composition with a frequency broad light beam exceptionally strongly favors the formation of the heavier nitrogen isotope, [15]N. Computations concur and suggest that the maximum in the quantum yield reflects significant variations in the specific electronic quantum states of the product N atoms that have quite different reactivities. Our quantum computations show that at similar energies, photodissociation of [14]N[14]N and [15]N[14]N can lead to different product channels. The computed dynamics include extensive state-selective spin-orbit and nonadiabatic couplings affecting the light absorption and dissociation pathways that proceed via the triplet manifold of states. Our results are relevant for future exploration missions, both in situ and sample-return and for other molecules such as O2 and CO.}, } @article {pmid40669270, year = {2025}, author = {Martinelli, I and Simonini, C and Zucchi, E and Gianferrari, G and Bedin, R and Ghezzi, A and Mandrioli, J}, title = {Predictors from systemic and neuro-inflammation in amyotrophic lateral sclerosis: A monocentric experience.}, journal = {Journal of neuroimmunology}, volume = {406}, number = {}, pages = {578683}, doi = {10.1016/j.jneuroim.2025.578683}, pmid = {40669270}, issn = {1872-8421}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/immunology ; Female ; Male ; Middle Aged ; Retrospective Studies ; Aged ; Biomarkers/blood ; *Neuroinflammatory Diseases/blood/diagnosis ; Adult ; Prognosis ; alpha 1-Antitrypsin/blood ; Inflammation/blood ; Chitinase-3-Like Protein 1/blood ; Cohort Studies ; Membrane Glycoproteins ; Receptors, Immunologic ; }, abstract = {While the role of systemic and neuroinflammatory players is actually consolidated in amyotrophic lateral sclerosis (ALS) pathogenesis, a representative and reliable panel of inflammatory prognostic biomarkers is still lacking. This retrospective study on 182 ALS patients from the Modena ALS Center, investigates biomarkers of axonal injury (neurofilaments) and microglial and astrocytic activation (SerpinA1, TREM2, CHI3L1, OPN and S100B, respectively). In a subpopulation of patients, we examined blood count-derived parameters, including the Systemic-Immune-Inflammation index (SII), Systemic Inflammation Response Index (SIRI) and Aggregate Systemic Inflammation Index (AISI). All variables were analyzed for association with clinical features in the entire cohort and then in sex- and age-based subgroups. SerpinA1CSF was significantly lower in females [4.43 μg/ml (IQR 2.76-6.3) vs 5.61 μg/ml (IQR 3.39-9.16),p = 0.032], while SII indexes was oppositely distributed [higher in females, 540.67 (IQR 363.05-807.24) vs 384.89 (IQR 307.5-578.52),p = 0.015]. In univariate survival analysis, without overcoming neurofilaments, SIRI (HR 1.43, 95 %CI 1.03-1.966,p = 0.03), AISI (HR 1.002, 95 %CI 1.001-1.003, p = 0.002) and SII (HR 1.001, 95 %CI 1.0003-1.001,p = 0.003) impact negatively on survival, with AISI retaining its power at multivariate analysis (HR 1.002, 95 %CI 1.0004-1.001,p = 0.012). SerpinA1CSF levels influenced survival only for females (HR 1.042, 95 %CI 1.0065-1.078,p = 0.02), in a similar manner of SIRI (HR 1.483, 95 %CI 1.082-2.0334,p = 0.014) and SII (HR 1.00099, 95 %CI 1.0008-1.003,p = 0.001). Our data revealed the influence of sex on survival by SerpinA1CSF, CHI3L1CSF and systemic biomarkers in females. However, both neurofilaments and CHI3L1CSF outperform the other neuroinflammatory biomarkers at predicting rate of disease progression, so the prognostic meaning of these measure alone remains unconclusive, requiring larger collaborative studies.}, } @article {pmid40669676, year = {2025}, author = {Su, X and Tan, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Feng, H}, title = {DAPK1 induces motor neuron apoptosis in hSOD1[G93A]-linked amyotrophic lateral sclerosis via regulating the Xiap/JNK pathway.}, journal = {Molecular and cellular neurosciences}, volume = {134}, number = {}, pages = {104029}, doi = {10.1016/j.mcn.2025.104029}, pmid = {40669676}, issn = {1095-9327}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Apoptosis ; *Death-Associated Protein Kinases/metabolism/genetics ; *Motor Neurons/metabolism ; *X-Linked Inhibitor of Apoptosis Protein/metabolism ; Animals ; Superoxide Dismutase-1/genetics/metabolism ; *MAP Kinase Signaling System ; MicroRNAs/metabolism/genetics ; Male ; Female ; Mice ; Middle Aged ; }, abstract = {Death-associated protein kinase 1 (DAPK1) is critically involved in regulating cell death in various neurodegenerative disorders. However, the role of DAPK1 in the pathogenesis of amyotrophic lateral sclerosis (ALS) remains unclear. Here, we found that the expression of DAPK1 significantly increased in ALS, showing a negative correlation with miR-501-3p. Upregulating DAPK1 led to an increase in motor neuron apoptosis by inhibiting Xiap. Conversely, silencing of DAPK1 protected motor neurons against hSOD1[G93A]-induced apoptosis by activating Xiap. Furthermore, we demonstrate that the neuroprotective impact of DAPK1-knockdown was inhibited by Embelin, an inhibitor of Xiap. These results suggest that modulating the DAPK1/Xiap signaling cascade protects motor neurons from apoptosis, indicating its potential as a therapeutic target in ALS. Significantly, these findings offer new directions for treatment options for ALS patients.}, } @article {pmid40670663, year = {2025}, author = {Tanaka, Y and Sunamura, N and Kajitani, R and Ikeguchi, M and Kunimoto, R}, title = {Long-read RNA sequencing unveils a novel cryptic exon in MNAT1 along with its full-length transcript structure in TDP-43 proteinopathy.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {1056}, pmid = {40670663}, issn = {2399-3642}, mesh = {Humans ; *Exons ; Amyotrophic Lateral Sclerosis/genetics ; *TDP-43 Proteinopathies/genetics ; *DNA-Binding Proteins/genetics/metabolism ; RNA Splicing ; Sequence Analysis, RNA ; Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; }, abstract = {Understanding the role of transcript isoforms is essential for elucidating disease mechanisms. TDP-43 regulates RNA splicing, and its dysfunction in neurons is a hallmark of some neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). While an association between TDP-43-dependent cryptic exons and disease pathogenesis has been suggested, an approach to investigate how cryptic exons disrupt transcript isoforms has yet to be established. In this study, we developed IsoRefiner, a novel method for identifying full-length transcript structures using long-read RNA-seq. Leveraging this method, we performed long-read RNA-seq, guided by prior short-read RNA-seq, to comprehensively determine the full-length structures of aberrant transcripts due to TDP-43 dysregulation in human iPSC-derived motor neurons. We identified a novel TDP-43-dependent cryptic exon in the MNAT1 gene, along with its full-length transcript structure. Furthermore, we confirmed the presence of the MNAT1 cryptic exon in patients with ALS and FTD. Our findings deepen understanding of TDP-43 proteinopathy and advance splicing research.}, } @article {pmid40671688, year = {2025}, author = {Masegosa, VM and Fritz, E and Corvalan, D and Rojas, F and Garcés, P and Navarro, X and Bloms-Funke, P and van Zundert, B and Herrando-Grabulosa, M}, title = {Novel Dual Mechanism GRT-X Agonist Acting on Kv7 Potassium Channel/Translocator Protein Receptor Prevents Motoneuron Degeneration Following Exposure to Mouse and Human Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Astrocyte-Conditioned Media.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {15}, pages = {2887-2900}, pmid = {40671688}, issn = {1948-7193}, mesh = {Animals ; *Astrocytes/metabolism/drug effects ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Motor Neurons/drug effects/metabolism/pathology ; *Frontotemporal Dementia/metabolism/pathology ; Mice ; Rats ; Culture Media, Conditioned/pharmacology ; *Neuroprotective Agents/pharmacology ; *Receptors, GABA/metabolism ; Cells, Cultured ; Mice, Transgenic ; Spinal Cord/drug effects/metabolism ; Nerve Degeneration/metabolism ; Superoxide Dismutase-1/genetics ; *KCNQ2 Potassium Channel/agonists/metabolism ; Rats, Sprague-Dawley ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) form a continuous spectrum of aggressive neurodegenerative diseases affecting primarily motoneurons (MNs) and cortical frontotemporal neurons. Noncell autonomous mechanisms contribute to ALS/FTD, wherein astrocytes release toxic factor(s) detrimental to MNs. Because of the multifactorial nature of ALS, single-pathway-focused therapies have limited effectiveness in improving ALS. Therefore, novel combinatorial therapies are currently being pursued. Here, we evaluated whether the simultaneous activation of two complementary targets, the voltage-gated potassium channels 7.2/3 (Kv7.2/3) and the mitochondrial translocator protein (TSPO), by a novel synthesized compound (GRT-X) is an effective neuroprotective treatment in ALS in vitro models. We exposed primary rat ventral spinal cord neuronal cultures and rat spinal cord organotypic cultures to astrocyte-conditioned medium derived from primary mouse ALS astrocytes expressing mutant human SOD1 (SOD1[G93A]-ACM) or from human-induced pluripotent stem cell (iPSC)-derived astrocytes carrying an ALS-causing mutation in SOD1 (SOD1[D90A]-ACM) or an ALS/FTD-causing mutation in TDP-43 (TDP43[A90 V]-ACM). We report that the diverse human and mouse ALS/FTD-ACMs compromise the MN viability. Remarkably, GRT-X led to consistent protection of MNs. Moreover, ALS/FTD-ACM increases oxidative stress levels, which are prevented with GRT-X treatment. Together, we show that the complementary activation of TSPO and Kv7.2/3 may offer a novel therapeutic strategy for ALS/FTD due to its capacity to protect MNs from noncell-autonomous toxicity induced by diseased astrocytes.}, } @article {pmid40671798, year = {2025}, author = {Akan, T and Gelir, F and Aishwarya, R and Bhuiyan, MS and Bhuiyan, MAN}, title = {AFTG-Net: A Deep Attention-based Fusion Framework of Topological and Gradient Features for Pathological Image Analysis.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40671798}, issn = {2693-5015}, support = {P20 GM121307/GM/NIGMS NIH HHS/United States ; }, abstract = {Skeletal muscle pathology is observed by structural disruptions in sarcomeres, increased central nuclei, and changes in myofiber cross-sectional area. In order to classify amyotrophic lateral sclerosis (ALS), diabetes, and healthy controls, pathologists examine the changes in myofiber size using Wheat Germ Agglutinin (WGA) stained histopathological images of various skeletal muscles (quadriceps, gastrocnemius, tibialis anterior, extensor digitorum longus, and soleus). Histological image analysis of skeletal muscle pathology is laborious and subject to inter- and intra-user variability, which can affect diagnosis accuracy and consistency. Conventional techniques like ImageJ-based tools are time-consuming and produce varying outcomes due to their manual cell counting, segmentation, and thresholding. This study introduces AFTG-Net, an attention-based machine learning framework that classifies skeletal muscle histopathological images using complementary geometric and topological descriptors. The model uses globally structural information from Topological Data Analysis (TDA) based on persistent homology and local edge and texture patterns from the Histogram of Oriented Gradients. We suggest a cross-weighted fusion approach that uses cosine similarity to adaptively balance the contributions of these heterogeneous features in order to improve their discriminative power. This integration enables the model to effectively distinguish pathological changes associated with amyotrophic lateral sclerosis (ALS) and Type I diabetes from healthy muscle tissue. We conducted comprehensive comparisons with various state-of-the-art and baseline methods, such as traditional feature-based and deep learning models. We assessed all models by analyzing WGA-stained skeletal muscle images from wild-type and disease models (G93A*SOD1 for ALS and Akita for type 1 diabetes). AFTG-Net outperformed all other models by achieving 92% classification accuracy in distinguishing healthy and diseased muscle fibers. By reducing human intervention, subjectivity, and analysis time, AFTG-Net improves scalability and diagnostic consistency, making it a valuable tool for both biomedical research and clinical practice.}, } @article {pmid40672150, year = {2025}, author = {Akiyama, T and Zeng, Y and Guo, C and Gautier, O and Koepke, L and Bombosch, J and Sianto, O and Ross, JP and Hoang, PT and Zhao, LY and Spencer, C and Monje, M and Day, JW and Gitler, AD}, title = {KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40672150}, issn = {2692-8205}, support = {R35 NS137159/NS/NINDS NIH HHS/United States ; R25 NS065741/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; T32 AG047126/AG/NIA NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; }, abstract = {Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to decreased SMN levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. Here, we demonstrate that SMN deficiency results in downregulation of KIF5A in human neurons and in a mouse model of SMA. We provide evidence that reduced SMN levels impair axon regeneration, which is rescued by KIF5A overexpression and that the RNA-binding protein SMN functions to stabilize KIF5A mRNA. These findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as a new SMN target. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.}, } @article {pmid40672153, year = {2025}, author = {Sang, X and Jiao, H and Meng, Q and Fang, X and Sundaram, KS and Zhou, J and Xu, Y and Alvarado, AIW and Nuryyev, RL and Ourenik, J and Ourednik, V and Huang, IS and Liu, X and Mei, Y and Qian, T and Ciechanover, A and Pizzo, DP and Lane, MA and Zholudeva, LV and An, J and Snyder, EY and Hu, H and Huang, Z}, title = {The cryo-EM-delineated mechanism underlying mimicry of CXCR4 agonism enables widespread stem cell neuroprotection in a mouse model of ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40672153}, issn = {2692-8205}, support = {R01 GM057761/GM/NIGMS NIH HHS/United States ; }, abstract = {G-protein coupled receptors (GPCRs) are transmembrane proteins that mediate a range of signaling functions and, therefore, offer targets for a number of therapeutic interventions. Chemokine receptor CXCR4, a GPCR, plays versatile roles in normal and abnormal physiological processes. Synthetic CXCR4 antagonists have been extensively studied and approved for the clinical treatment of cancer and other diseases. We recently elucidated the structural mechanisms underlying CXCR4 antagonism using cryogenic electron microscopy (cryo-EM). CXCR4 agonism by synthetic molecules is an unanticipated therapeutic intervention we recently unveiled. The structural mechanisms underlying those actions remain poorly understood yet could help elucidate a new class of drugs. Here we demonstrate a synthetic dual-moiety strategy that combines simplified agonistic and antagonistic moieties taken from natural agonistic and antagonistic chemokines, respectively, to design de novo peptide mimics of biological function of natural CXCR4 agonist SDF-1α. Two peptides so generated, SDV1a and SDVX1 were shown to mimic the action of SDF-1α in activating CXCR4 signaling pathways and cell migration. The structural mechanism of these peptides in the mimicry of CXCR4 agonism was illustrated by cryo-EM structures of CXCR4 bound and activated by the peptides in the presence of G protein, revealing common interactions with the receptor by these peptides in comparison with SDF-1α that explain their close mimicry and conformational changes leading to CXCR4 signal activation. The therapeutic benefit of one of these peptides, SDV1a, was demonstrated in the SOD1[G93A] mouse model of the spinal motor neuron degenerative disease, amyotrophic lateral sclerosis (ALS) wherein the success of neuroprotective actions of transplanted human neural stem cells (hNSCs) is directly correlated with the expanse of diseased neuroaxis traversed by the donor cells; SDV1a enabled broader neuroprotective coverage while also permitting a much less invasive route of cell administration for extending life. Taken together, these results provide insights into the structural determinants of therapeutic CXCR4 agonism which may allow the design of adjunctive drugs that improve cell-based treatments of central nervous system (CNS) diseases.}, } @article {pmid40672164, year = {2025}, author = {Braspenning, SE and Ohnezeit, D and DeGulis, OA and Wilson, AC and Mohr, IJ}, title = {TDP-43 promotes efficient HSV-1 replication in human DRG-derived neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.07.08.662712}, pmid = {40672164}, issn = {2692-8205}, support = {R01 AI170583/AI/NIAID NIH HHS/United States ; R01 AI176335/AI/NIAID NIH HHS/United States ; }, abstract = {UNLABELLED: TAR DNA-binding protein 43 (TDP-43) is a versatile nuclear RNA-binding protein that performs important functions in RNA localization, processing and stability. In the neurodegenerative disease amyotrophic lateral sclerosis (ALS) TDP-43 forms toxic, insoluble cytoplasmic aggregates that ultimately lead to neuronal loss. Although TDP-43 is expressed in every cell type, its function and subcellular localization are particularly important for neuronal homeostasis. However, it is unknown if TDP-43 has a role during herpesvirus infection. Herpes simplex virus type-1 (HSV-1), a ubiquitous neurotropic pathogen, is considered a contributing factor to neurodegenerative disorders. In this study, we tested the requirement for TDP-43 during HSV-1 infection in neuronal and non-neuronal cells. HSV-1 infection of epithelial cells and primary fibroblasts did not change overall TDP-43 abundance, nor did TDP-43 depletion detectably alter HSV-1 replication in a multicycle growth experiment. By contrast, when TDP-43 was depleted in neuronally derived, matured HD10.6 cells, HSV-1 infectious virus production was significantly reduced in both single- and multicycle growth experiments. Notably, TDP-43 depletion restricts viral lytic gene expression at the immediate-early phase. Through nanopore direct RNA-sequencing we uncovered enhanced intron retention in two essential viral genes upon TDP-43 depletion. Thus, while depletion of TDP-43 does not affect replication in epithelial cells and fibroblasts, TDP-43 is required for efficient replication in HD10.6 cells through modifying the abundance and splicing of viral mRNAs.

IMPORTANCE: Herpes simplex virus type-1 is a widespread neurotropic pathogen that can cause life-threatening infections of the brain and is increasingly linked to neurodegenerative disease. However, due to the lack of scalable in vitro human neuronal models or small animal models that recapitulate disease, little is known about virus-host interactions in neurons specifically. Using human epithelial cells, primary fibroblasts and a human neuron-derived cell line, we uncovered a cell type specific TDP-43 requirement for efficient HSV-1 virus replication. TDP-43 is a critical neuronal disease gene, and we showed it promotes virus gene expression and splicing of viral mRNAs in neuron-derived cells. This work provides valuable insights into the possible etiology of neurodegenerative disease and highlights the importance of studying virus-host interactions in relevant model systems.}, } @article {pmid40672281, year = {2025}, author = {Hogan, AL and Kane, M and Chiu, P and Richter, G and Maurel, C and Wu, S and Scherer, NM and Don, EK and Lee, A and Blair, I and Chung, R and Morsch, M}, title = {Human TDP-43 overexpression in zebrafish motor neurons triggers MND-like phenotypes through gain-of-function mechanism.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.07.06.663393}, pmid = {40672281}, issn = {2692-8205}, abstract = {Dysregulation of the TAR DNA-binding protein 43 (TDP-43), including intraneuronal cytoplasmic mislocalisation and aggregation is a feature of multiple neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD), limbic-predominant age-related TDP-43 encephalopathy (LATE) and alzheimers disease (AD). Unravelling the causes and functional consequences of TDP-43 dysregulation is paramount to understanding disease mechanisms as well as identifying effective therapeutic targets. Here we present a comprehensive in vivo characterisation of three stable transgenic zebrafish models that express human TDP-43 variants in motor neurons. We demonstrate that overexpression of predominantly nuclear wildtype TDP-43, cytoplasm-targeted TDP-43, and an ALS-linked variant (G294V) each induce toxic gain-of-function effects, leading to impaired motor function, motor neuron loss, and muscle atrophy. Importantly, these models reveal distinct phenotypes, with the ALS-linked mutant exhibiting axonal transport deficits and neuromuscular junction disruption, while cytoplasmic mislocalised TDP-43 heightened susceptibility to oxidative stress. Two FDA-approved drugs used to treat ALS, edaravone and riluzole, were examined in these models and revealed that edaravone, but not riluzole, was effective in rescuing motor deficits associated with cytoplasmic TDP-43 expression and, to a lesser extent, mutant TDP-43 [G294V] . Collectively, these findings reveal distinct pathological consequences of TDP-43 dysregulation, providing neuron-centric mechanistic insights, and establish the humanised TDP-43 zebrafish as an efficient system for preclinical therapeutic testing.}, } @article {pmid40672339, year = {2025}, author = {Zeng, Y and Sianto, O and Lovchykova, A and Liu, C and Akiyama, T and Petrucelli, L and Gitler, AD}, title = {Nonsense-mediated decay masks cryptic splicing events caused by TDP-43 loss.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40672339}, issn = {2692-8205}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; R35 NS137159/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; T32 AG047126/AG/NIA NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; }, abstract = {In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is lost from the nucleus, leading to cryptic exon inclusion events in dozens of neuronal genes. Here, we show that many cryptic splicing events have been missed by standard RNA-sequencing analyses because they are substrates for nonsense-mediated decay. By inhibiting nonsense-mediated decay in neurons we unmask hundreds of novel cryptic splicing events caused by TDP-43 depletion, providing a new picture to TDP-43 loss of function in neurons.}, } @article {pmid40673636, year = {2025}, author = {An, D and Wu, Y and Han, J and Fang, P and Bu, Y and Ji, G and Deng, J and Song, X}, title = {m6A Methylation-Induced Autophagy Impairment by TFEB Regulation in SOD1-G93A ALS Cell Model.}, journal = {American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics}, volume = {198}, number = {8}, pages = {221-229}, doi = {10.1002/ajmg.b.33048}, pmid = {40673636}, issn = {1552-485X}, support = {H2021206223//Natural Science Foundation of Hebei Province/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/metabolism ; Humans ; Methylation ; *Autophagy/genetics ; Methyltransferases/genetics/metabolism ; Mitophagy/genetics ; Mitochondria/metabolism/genetics ; Animals ; RNA, Messenger/genetics/metabolism ; }, abstract = {We investigate the role of m6A RNA methylation in regulating transcription factor EB (TFEB) and its contribution to mitochondrial autophagy (mitophagy) dysfunction in amyotrophic lateral sclerosis (ALS). ALS cell models were used to analyse mitophagy markers and TFEB expression under METTL3 and TFEB modulation, using RT-qPCR, Western blot, MeRIP, RIP, and immunofluorescence. Elevated m6A methylation and reduced TFEB expression were observed in hSOD1-G93A models. METTL3 overexpression suppressed TFEB expression, leading to impaired mitophagy, while METTL3 knockdown alleviated these effects. MeRIP assays confirmed increased m6A modifications on TFEB mRNA, and RIP assays demonstrated direct interaction between METTL3 and TFEB mRNA. Notably, TFEB overexpression rescued mitophagy dysfunction, whereas TFEB knockdown exacerbated the impairment. METTL3-mediated m6A methylation inhibits mitophagy by downregulating TFEB expression, revealing the m6A-TFEB pathway as a promising therapeutic target for ALS.}, } @article {pmid40673749, year = {2025}, author = {Rong, P and Liston, E}, title = {An Explanatory Model of Speech Communication Centered on Multiscale Rhythmic Modulation: Implications for Motor Speech Assessment and Intervention for Individuals With Amyotrophic Lateral Sclerosis.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {68}, number = {7S}, pages = {3678-3702}, doi = {10.1044/2025_JSLHR-24-00286}, pmid = {40673749}, issn = {1558-9102}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Male ; Female ; Middle Aged ; Aged ; *Speech/physiology ; Speech Production Measurement/methods ; Cues ; Adult ; Phonetics ; *Speech Disorders/etiology/physiopathology ; Speech Acoustics ; Biomechanical Phenomena ; Periodicity ; }, abstract = {PURPOSE: This study proposed an explanatory model of speech communication centered on multiscale rhythmic modulation to inform motor speech assessment and management. To these ends, a fit-for-purpose, automated measurement tool was used to evaluate and/or cross-validate (a) the previously reported effect of a neuromotor disorder-amyotrophic lateral sclerosis (ALS)-and (b) the effects of two cueing strategies, commonly used in managing motor speech disorders, on rhythmic modulation of speech.

METHOD: A secondary analysis was carried out on the X-ray Microbeam database. The analyzed data included the articulatory-kinematic and acoustic recordings of a phonetically loaded sentence produced by 19 individuals with ALS and 23 neurologically healthy controls in one habitual style and two nonhabitual styles as elicited by the slow and clear speech cues, respectively. The measurement tool quantified the modulation patterns of four articulators as well as four critical-band and one wide-band envelopes at three linguistically relevant timescales (delta, theta, beta/gamma) to assess rhythm control at the prosodic, syllabic, and subsyllabic levels. To address the research aims, the disease and speaking style effects on all modulation metrics were evaluated.

RESULTS: For Aim 1, speakers with ALS showed reduced modulation depth of multiple articulators and critical-band envelopes at all timescales. For Aim 2, the slow speech cue elicited changes in articulatory modulation at multiple timescales, globally enhancing the control of all and especially syllabic and subsyllabic rhythms in speakers with ALS. Clear speech primarily elicited changes in articulatory modulation at the theta timescale, generating a more restricted effect on syllabic rhythm.

CONCLUSIONS: The findings generally aligned with our prior research, supporting the robust utility of the measurement tool for assessing rhythmic disturbances of speakers with ALS. Moreover, this tool showed promise for delineating cueing-elicited changes in rhythmic modulation of speech, which has potential implications in tailoring and evaluating the outcomes of behavioral intervention.}, } @article {pmid40673755, year = {2025}, author = {Banerjee, A and Sanyal, D and Chattopadhyay, K}, title = {Investigating the Stability, Flexibility, and Phase Separation Properties of H46R and H80R Disease Mutants of SOD1: Insights into ALS Pathogenesis.}, journal = {Biochemistry}, volume = {64}, number = {15}, pages = {3358-3371}, doi = {10.1021/acs.biochem.5c00289}, pmid = {40673755}, issn = {1520-4995}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/enzymology/pathology/metabolism ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; Humans ; Mutation ; Enzyme Stability ; Protein Stability ; Protein Structure, Secondary ; Protein Folding ; Molecular Dynamics Simulation ; Phase Separation ; }, abstract = {Human Cu, Zn superoxide dismutase (SOD1) is the primary enzyme in the cellular antioxidant defense system. Mutations in SOD1 are associated with amyotrophic lateral sclerosis (ALS), where protein misfolding and aggregation contribute to the disease pathology. Recently, SOD1 mutants have been shown to undergo phase separation, forming protein-rich droplets that can serve as precursors to the fibrillar aggregates, the pathological hallmarks of ALS. Protein phase separation is a critical process for membraneless organelle formation and the regulation of cellular activities, and its disruption is associated with neurodegeneration. In this study, we investigated two ALS-associated SOD1 mutants, H46R and H80R, and compared them to the wild-type (WT) and Apo forms to elucidate the relationship between phase separation and SOD1's biophysical properties. Using computational studies, chemical denaturation, in vitro condensate formation assays, and analyzing their dynamic behavior, we explored how these mutants influence protein phase separation propensity. Our findings demonstrate that altered secondary structures, stability, and inherent disorder in these mutants directly impact their phase separation behaviors. This study provides new insights into the role of phase separation in ALS pathogenesis and its potential as a therapeutic target.}, } @article {pmid40673945, year = {2026}, author = {Shan, D and Sun, X and Tang, Y and Zhao, Y and Yan, C and Liu, F}, title = {FUS protein nuclear loss in skin biopsy: A window into the pathology and diagnosis of fused in sarcoma-associated amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {85}, number = {2}, pages = {203-205}, doi = {10.1093/jnen/nlaf077}, pmid = {40673945}, issn = {1554-6578}, support = {ZR2023MH180//Natural Science Foundation of Shandong Province/ ; 20201125//Qilu Young Scholar Program of Shandong University/ ; }, } @article {pmid40673975, year = {2025}, author = {Giorgi, A and Heckman, CJ and Perreault, MC}, title = {Spinally projecting serotonergic neurons in motor network modulation.}, journal = {Journal of neurophysiology}, volume = {134}, number = {5}, pages = {1619-1628}, doi = {10.1152/jn.00139.2025}, pmid = {40673975}, issn = {1522-1598}, support = {20153//National Science Foundation (NSF)/ ; }, mesh = {*Serotonergic Neurons/physiology ; Animals ; Humans ; *Spinal Cord/physiology/cytology ; *Motor Neurons/physiology ; *Brain Stem/physiology/cytology ; Serotonin/metabolism ; }, abstract = {Spinally projecting serotonergic (5-HTsp) neurons represent a heterogeneous population of brainstem neurons whose relevance to the control of movement has largely been inferred. Numerous studies across multiple species have suggested that 5-HTsp neurons exert a widespread influence on spinal sensorimotor networks, operating at multiple levels (primary afferents, interneurons, and motoneurons) through various serotonin receptor subtypes. However, despite the anatomical and neurochemical complexity of the 5-HTsp system, supporting evidence has been mostly derived from indirect approaches [e.g., exogenous application of serotonin (5-HT) and agonists/antagonists of 5-HT receptors]. Direct demonstrations of specific anatomical and functional connectivity have been limited, occasionally yielding discrepant results. Consequently, as the primary provider of serotonin to the spinal cord, the exact contributions of 5-HTsp neurons remain to be fully elucidated. For this mini-review, we sifted through the literature of the last six decades, starting after the characterization of brainstem raphe nuclei and monoaminergic systems, to provide a clearer picture of the anatomy and influences of different 5-HTsp neuron populations on sensorimotor circuits and motor behaviors. We focused on studies reporting direct manipulation of brainstem 5-HTsp neurons, excluding those targeting 5-HT neurotransmission by exogenous application of 5-HT. This emphasis aims to highlight the urgency of resolving how 5-HTsp neuron subpopulations differentiate anatomically and functionally so they can be integrated as dedicated components in current models of supraspinal control of movement and motor diseases such as Parkinson's and amyotrophic lateral sclerosis. Along the way, we point out gaps in knowledge that may be filled using newly available research tools.}, } @article {pmid40675338, year = {2025}, author = {Shtilbans, A}, title = {Combination Supplement Therapy: A New Frontier in Treatment of Neurodegenerative Diseases.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tjnut.2025.07.004}, pmid = {40675338}, issn = {1541-6100}, abstract = {This review highlights the importance and potential beneficial effects of dietary supplements, including taurine, tauroursodeoxycholic acid (TUDCA), curcumin, coenzyme Q10, creatine, and N-acetylcysteine, in the management of neurodegenerative diseases. Studies in preclinical models have consistently shown significant potential of these supplements in mitigating neurodegenerative pathology. Through a range of mechanisms targeting different molecular pathways, these supplements demonstrate therapeutic outcomes in preclinical models of conditions such as Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, and Huntington disease. This review discusses published data on each of these supplements in the context of neurodegenerative diseases. It also discusses a combination therapy concept and proposes a strategy to formulate an optimal blend of these supplements. This combination approach will target key processes, including mitochondrial dysfunction, protein misfolding, neuroinflammation, and oxidative stress responsible for neurodegenerative conditions. Additionally, this review examines various models used for both the initial screening and subsequent assessment of candidate supplement combinations.}, } @article {pmid40675818, year = {2025}, author = {Mei, I and Nichterwitz, S and Leboeuf, M and Nijssen, J and Lenoel, I and Repsilber, D and Lobsiger, CS and Hedlund, E}, title = {Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations.}, journal = {Genome research}, volume = {35}, number = {9}, pages = {1975-1991}, pmid = {40675818}, issn = {1549-5469}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Animals ; *Motor Neurons/metabolism/pathology ; *Superoxide Dismutase-1/genetics ; Mice ; *Mutation ; Humans ; Transcriptome ; Disease Models, Animal ; Mice, Transgenic ; Gene Expression Regulation ; *Transcription, Genetic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons (MNs) that innervate skeletal muscles. However, certain MN groups including ocular MNs, are relatively resilient. To reveal key drivers of resilience versus vulnerability in ALS, we investigate the transcriptional dynamics of four distinct MN populations in SOD1G93A ALS mice using LCM-seq and single-molecule fluorescent in situ hybridization. We find that resilient ocular MNs regulate few genes in response to disease. Instead, they exhibit high baseline gene expression of neuroprotective factors, including En1, Pvalb, Cd63, and Gal, some of which vulnerable MNs upregulate during disease. Vulnerable MN groups upregulate both detrimental and regenerative responses to ALS and share pathway activation, indicating that breakdown occurs through similar mechanisms across vulnerable neurons, albeit with distinct timing. Meta-analysis across four rodent mutant Sod1 MN transcriptome data sets identify a shared vulnerability code of 39 genes, including Atf4, Nupr1, Ddit3, and Penk, involved in apoptosis, as well as a proregenerative and antiapoptotic signature consisting of Atf3, Vgf, Ina, Sprr1a, Fgf21, Gap43, Adcyap1, and Mt1 Machine learning using genes upregulated in SOD1G93A spinal MN predicts disease in human stem cell-derived SOD1E100G MNs and shows that dysregulation of VGF, INA, and PENK is a strong disease predictor across species and SOD1 mutations. Our study reveals MN population-specific gene expression and temporal disease-induced regulation that together provide a basis to explain ALS selective vulnerability and resilience and that can be used to predict disease.}, } @article {pmid40678914, year = {2025}, author = {Calma, AD and Pavey, N and Silva, CS and Tsuji, Y and Van den Bos, MAJ and Farrar, MA and Menon, P and Vucic, S}, title = {Clinical Utility of Far-Field Potentials in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {72}, number = {4}, pages = {616-624}, pmid = {40678914}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; Aged ; *Ulnar Nerve/physiopathology ; Adult ; *Action Potentials/physiology ; Electromyography ; Muscle, Skeletal/physiopathology ; ROC Curve ; Neural Conduction/physiology ; }, abstract = {INTRODUCTION/AIMS: Far field potentials (FFP) have been proposed as a reliable neurophysiological prognostic biomarker in amyotrophic lateral sclerosis (ALS). This study evaluates the diagnostic utility of ulnar nerve FFP in ALS.

METHODS: Comprehensive peripheral neurophysiological assessments were conducted in 62 ALS and 43 ALS-mimicking disorder participants. The ulnar nerve was stimulated at the wrist, recording motor responses over the abductor digit minimi (ADM) muscle. Conventional compound muscle action potentials (CMAP), FFP, and near field potential amplitudes were recorded, alongside the split-hand index, neurophysiological index, motor unit number estimation (MScanFit-MUNE), and motor unit index (MUNIX). Diagnostic utility was evaluated using receiver operating characteristic (ROC) analysis.

RESULTS: In ALS, FFP amplitude was significantly lower (5.07 ± 0.36 mV) compared to ALS mimics (8.25 ± 0.40 mV, p < 0.001). FFP amplitude exhibited a moderate-to-strong correlation with neurophysiological biomarkers, including CMAP amplitude (ρ = 0.77, p < 0.001), split-hand index (ρ = 0.53, p < 0.001), neurophysiological index (ρ = 0.52, p < 0.001), MUNIX (ρ = 0.69, p < 0.001), and MScanFit-MUNE (ρ = 0.66, p < 0.001). Weak-to-moderate correlations were also observed with clinical measures of disease progression, including upper limb muscle strength, ALS functional rating score-revised (ALSFRS-R) and the rate of decline in the ALSFRS-R fine motor subscore. ROC analysis demonstrated that FFP amplitude reliably distinguished ALS from mimicking disorders (AUC = 0.80, 95% CI: 0.71-0.89), with consistent diagnostic accuracy across ALS phenotypes.

DISCUSSION: The diagnostic capability of FFP amplitude was comparable to established neurophysiological biomarkers utilized in ALS. It is a promising prognostic and diagnostic biomarker for ALS. Its simplicity and reproducibility complement traditional neurophysiological measures, offering potential for clinical application in ALS diagnosis and monitoring.}, } @article {pmid40679526, year = {2025}, author = {Khairullin, AE and Efimova, DV and Teplov, AY and Khabibrakhmanov, AN and Nagiev, KK and Grishin, SN and Ziganshin, AU and Mukhamedyarov, MA}, title = {Impairment of P2 Receptor-Mediated Modulation of Skeletal Muscle Contractions in Transgenic Mice with Modeled Amyotrophic Lateral Sclerosis.}, journal = {Bulletin of experimental biology and medicine}, volume = {179}, number = {1}, pages = {20-23}, pmid = {40679526}, issn = {1573-8221}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/metabolism/genetics ; Mice, Transgenic ; Mice ; *Muscle Contraction/drug effects/physiology ; *Muscle, Skeletal/drug effects/metabolism/physiopathology ; Disease Models, Animal ; Adenosine Triphosphate/pharmacology ; *Receptors, Purinergic P2/metabolism/genetics ; RNA-Binding Protein FUS/genetics/metabolism ; Diaphragm/drug effects/physiopathology/metabolism ; Male ; }, abstract = {We studied the effects of ATP on skeletal muscle contractility in FUS-transgenic mice with amyotrophic lateral sclerosis (ALS) model. Mechanomyography showed that ATP application did not increase the amplitude of electrically induced contractions of the diaphragm muscle, m. extensor digitorum longus, and soleus muscle in FUS-transgenic mice unlike wild-type mice. Application of a non-selective P2 receptor antagonist suramine and application of ATP against the background of suramine did not change the amplitude of contractions of the studied skeletal muscles in FUS-transgenic mice. Thus, FUS model of ALS is based on the impairment of purinergic regulation of skeletal muscle contractile activity, which can play a role in the pathogenesis of ALS.}, } @article {pmid40680585, year = {2025}, author = {Osoba, HO}, title = {Commentary on 'Retinal Alterations Induced by Amyotrophic Lateral Scerosis: an Analysis Using Optical Coherence Tomography': Drawing Out the Ramifications.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {140}, number = {}, pages = {111514}, doi = {10.1016/j.jocn.2025.111514}, pmid = {40680585}, issn = {1532-2653}, } @article {pmid40680640, year = {2025}, author = {Vucic, S}, title = {Gamma activation in amyotrophic lateral sclerosis: Support for the interneuronal dysfunction theory.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {177}, number = {}, pages = {2110827}, doi = {10.1016/j.clinph.2025.2110827}, pmid = {40680640}, issn = {1872-8952}, } @article {pmid40681220, year = {2025}, author = {Abd El-Aziz, MK and Wadan, AS and Albahttiti, ATI and Moradikor, N}, title = {Emotional stress and cardiovascular health: Impacts on neurodegenerative disease progression.}, journal = {Progress in brain research}, volume = {294}, number = {}, pages = {101-133}, doi = {10.1016/bs.pbr.2025.04.004}, pmid = {40681220}, issn = {1875-7855}, mesh = {Humans ; *Stress, Psychological/physiopathology/complications/metabolism ; *Neurodegenerative Diseases/physiopathology/metabolism ; *Cardiovascular Diseases/physiopathology/metabolism ; Disease Progression ; Hypothalamo-Hypophyseal System/physiopathology/metabolism ; Pituitary-Adrenal System/physiopathology/metabolism ; }, abstract = {Stress is an inevitable part of people's lives and is considered to have a severe impact on health, especially in the case of cardiovascular diseases and neurodegenerative diseases. This chapter aims to reveal the links between emotional stress, cardiovascular health, and neurodegenerative disease progression. Chronic stress is therefore recognized as a significant cause of cardiovascular diseases mainly because of the effects it has on the hypothalamic-pituitary-adrenal (HPA) axis and the (SNS) sympathetic which neurodegenerative nervous are diseases system such (as ALS) through inflammation of Alzheimer's mechanisms and disease, vascular such as Parkinson's functions. The mechanisms of work also establish the crosstalk between CVD and NDD, demonstrating that they share genetic, molecular, and systemic associations. It is essential to know these pathways to design interventions that will help prevent or lessen the effects of stress on health and thus enhance patient care.}, } @article {pmid40681694, year = {2025}, author = {Muqaku, B and Dorst, J and Wiesenfarth, M and Otto, M and Ludolph, AC and Oeckl, P}, title = {Peptidomic analysis of CSF reveals new biomarker candidates for amyotrophic lateral sclerosis.}, journal = {EMBO molecular medicine}, volume = {17}, number = {8}, pages = {1926-1949}, pmid = {40681694}, issn = {1757-4684}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/cerebrospinal fluid/pathology ; *Biomarkers/cerebrospinal fluid ; Female ; Male ; Middle Aged ; Aged ; *Peptides/cerebrospinal fluid ; Cohort Studies ; Mass Spectrometry ; Proteomics/methods ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, and novel biomarkers are needed. We applied mass-spectrometry-based peptidomic analysis in cerebrospinal fluid (CSF) samples of ALS and non-neurodegenerative control patients (Con) from a discovery (n = 48) and validation (n = 109) cohort for biomarker discovery. Systematic selection revealed a panel of eight novel peptide biomarker candidates for ALS (out of 33,605) derived from seven proteins. In the validation cohort, NFL, MAP1B, MYL1, and APOC1 peptides were upregulated, and peptides from CADM3, SCG1, and PENK were downregulated in ALS compared to Con. The peptides (except NFL) were not changed in other neurodegenerative diseases, including Alzheimer´s disease, frontotemporal dementia and Parkinson´s disease. Combination of all peptides in a logistic regression model led to an area under the curve value of 98% for the discrimination of ALS from controls. Data of the NFL peptide strongly correlated with an established NFL immunoassay (Ella, r = 0.97). The peptide biomarker candidates are derived from proteins with different function, and their determination with our method provides the opportunity for simultaneous investigation of key processes in ALS.}, } @article {pmid40682648, year = {2025}, author = {Belosludtseva, NV and Mikheeva, IB and Starinets, VS and Dubinin, MV and Belosludtsev, KN}, title = {Age-Dependent Changes in Mitochondrial Regulatory Mechanisms in the Spinal Cord of SOD1-G93A-Transgenic Mice with the Phenotype of Amyotrophic Lateral Sclerosis.}, journal = {Bulletin of experimental biology and medicine}, volume = {179}, number = {1}, pages = {34-40}, pmid = {40682648}, issn = {1573-8221}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice, Transgenic ; *Mitochondria/metabolism/genetics/ultrastructure/pathology ; Mice ; *Spinal Cord/metabolism/pathology/ultrastructure ; *Superoxide Dismutase-1/genetics/metabolism ; Motor Neurons/metabolism/pathology/ultrastructure ; Ubiquitin-Protein Ligases/genetics/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; Protein Kinases/genetics/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; GTP Phosphohydrolases/genetics/metabolism ; Dynamins/genetics/metabolism ; Phenotype ; Mitochondrial Dynamics/genetics ; Mitochondrial Proteins/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Humans ; Male ; Mitophagy ; NF-E2-Related Factor 2 ; PTEN-Induced Putative Kinase ; }, abstract = {Age-dependent changes in the expression level of genes encoding proteins responsible for mitochondrial homeostasis were studied in relation to ultrastructural abnormalities in the mitochondria of motor neurons in the anterior horns of the spinal cord in a transgenic model of amyotrophic lateral sclerosis (SOD1-G93A mice). The expression of the Drp1, Mfn2, Ppargc1a, and Nefl genes was reduced, and the expression of the Nfe2l2, Pink1, and Parkin genes was enhanced in mice with the genotype of the familial form of the disease at the age of 22 weeks corresponding to the symptomatic stage in comparison with wild-type mice (C57BL6 × SJL) and non-transgenic littermates (SOD1-G93A(Tg-)) of the same age. Comparative analysis of spinal cord tissue samples from 8 and 12 weeks-old animals revealed no significant differences in the expression levels of genes encoding proteins responsible for mitochondrial dynamics, biogenesis, and mitophagy. Electron microscopic examination showed pronounced structural alterations in mitochondria in the soma of lower motor neurons of SOD1-G93A(Tg+) mice at the symptomatic stage, which manifested in the appearance of "ring-like" mitochondrial structures, matrix swelling, destruction of membranes in the cristae, and increased number of autophagolysosomes. The role of mitochondrial homeostasis disorders in the progression of amyotrophic lateral sclerosis is discussed.}, } @article {pmid40682794, year = {2025}, author = {Sheikh Saleh, D and Mraer, L and Fatima, H and Gubari, H and Alsayed, MA and Hassan, FE}, title = {Decoding the Dialogue: Immunity and central nervous system interactions in neurodegenerative diseases.}, journal = {The Egyptian journal of immunology}, volume = {32}, number = {3}, pages = {20-31}, doi = {10.55133/eji.320303}, pmid = {40682794}, issn = {1110-4902}, mesh = {Humans ; *Neurodegenerative Diseases/immunology ; *Central Nervous System/immunology ; Animals ; Immunity, Innate ; *Neuroimmunomodulation ; Microglia/immunology ; Astrocytes/immunology ; Blood-Brain Barrier/immunology ; }, abstract = {This review article aims to discuss neuroimmune interactions by emphasizing the role of central and peripheral immunities in central nervous system (CNS) protection and function, as well as how abnormalities in this relationship may be implicated in the genesis of neurodegenerative diseases (NDDs). Immune elements that play roles within the CNS both during stable and infectious states are described. Innate CNS immunity is explored as a distinct entity comprised of the brain blood barrier, CNS parenchyma, and resident immune cells-microglia and astrocytes, whose roles in antigen recognition and clearance and neuromodulation are further enumerated. Due to the inability of the CNS to independently initiate an adaptive immune response, the necessary recruitment and regulation of elements from the peripheral immune system (PIS) are described in a process that, in chief, utilizes resident antigen-presenting cells to prime naïve T-cells, which later enter the CNS through areas of access to the cerebrospinal fluid. The previous modes of interaction especially enable microglia, astrocytes, and T-cells to play part in neurodevelopment and plasticity, and the proposed mechanisms by which they participate in synaptic pruning, neurogenesis, and memory are examined. In addition to its protective role, the PIS has also been shown to play a regulatory role in the CNS, where it drives responses that optimize immune function, such as fever and sickness behavior. Due to the high level of involvement of the immune system within the CNS, dysregulations of the immune system are thought to be implicated in numerous NDD pathogeneses, where neuroinflammation both causes and is caused by immune reactions. Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are particularly discussed.}, } @article {pmid40682810, year = {2025}, author = {Gao, J and Douglas, AGL and Chalitsios, CV and Scaber, J and Talbot, K and Turner, MR and Thompson, AG}, title = {Neurodegenerative disease in C9orf72 repeat expansion carriers: population risk and effect of UNC13A.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {11}, pages = {3865-3871}, pmid = {40682810}, issn = {1460-2156}, support = {MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; Thompson/Jan20/952-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; Thompson/Apr23/896-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; //My Name'5 Doddie Foundation/ ; }, mesh = {Humans ; C9orf72 Protein/genetics ; Middle Aged ; Female ; Male ; *DNA Repeat Expansion/genetics ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Aged ; *Frontotemporal Dementia/genetics/epidemiology ; Heterozygote ; *Neurodegenerative Diseases/genetics/epidemiology ; *Nerve Tissue Proteins/genetics ; Incidence ; *Proteins/genetics ; Aged, 80 and over ; Genotype ; Genetic Predisposition to Disease ; Cohort Studies ; }, abstract = {The C9orf72 hexanucleotide repeat expansion (HRE) is the most common monogenetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neurodegenerative disease incidence in C9orf72 HRE carriers has been studied using cohorts from disease-affected families or by extrapolating from population disease incidence, potentially introducing bias. Age-specific cumulative incidence of ALS and dementia was estimated using Kaplan-Meier and competing risk models in C9orf72 HRE carriers compared to matched controls in UK Biobank. Risk modification by UNC13A genotype was examined. Of 490 331 individuals with valid genetic data, 701 had >100 repeats in C9orf72 [median age 55 (interquartile range 48-62), follow-up 13.4 years (12.3-14.1)]. The cumulative incidence of ALS or dementia was 66% (95% confidence interval 57%-73%) by age 80 in C9orf72 HRE carriers versus 5.8% (4.5%-7.0%) in controls, or 58% (50%-64%) versus 5.1% (4.1%-6.4%), accounting for the competing risk of other-cause mortality. Forty-one per cent of dementia incidence accrued between age 75-80. C-allele homozygosity at rs12608932 in UNC13A increased ALS or dementia risk in C9orf72 HRE carriers [hazard ratio 1.81 (1.18-2.78)]. C9orf72 HRE disease was incompletely penetrant in this population-based cohort, with risk modified by UNC13A genotype. This has implications for counselling at-risk individuals and modelling expected phenoconversion for prevention trials.}, } @article {pmid40683276, year = {2025}, author = {Harkness, JR and McDermott, JH and Marsden, S and Jamieson, P and Metcalfe, KA and Khan, N and Macken, WL and Pitceathly, RDS and Record, CJ and Maroofian, R and Kleopa, K and Christodoulou, K and Sabir, A and Islam, L and Santra, S and Durmusalioglu, EA and Atik, T and Isik, E and Cogulu, O and Urquhart, JE and Beaman, GM and Demain, LA and Jackson, A and Blakes, AJM and Byers, HJ and Bennett, H and Lin, WH and Adamson, A and Patel, S and Yue, WW and Taylor, RW and Reunert, J and Marquardt, T and Buchert, R and Haack, T and Losch, H and Ryba, L and Lassuthova, P and Valkovičová, R and Haberlová, J and Lauerová, B and Trúsiková, E and Polavarapu, K and Kilicarslan, OA and Lochmüller, H and Zamani, M and Chamanrou, N and Shariati, G and Sadeghian, S and Azizimalamiri, R and Maddirevula, S and AlMuhaizea, M and Alkuraya, FS and Horvath, R and Gungor, S and Manzur, A and Munot, P and Matthews, R and Banka, S and Reilly, MM and Bennett, D and O'Keefe, RT and Newman, WG}, title = {Acute-onset axonal neuropathy following infection in children with biallelic RCC1 variants: a case series.}, journal = {The Lancet. Neurology}, volume = {24}, number = {8}, pages = {667-680}, doi = {10.1016/S1474-4422(25)00198-X}, pmid = {40683276}, issn = {1474-4465}, mesh = {Adolescent ; Animals ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; *Cell Cycle Proteins/genetics ; *Infections/complications ; *Peripheral Nervous System Diseases/etiology ; Drosophila ; Nuclear Proteins ; Guanine Nucleotide Exchange Factors ; }, abstract = {BACKGROUND: The reasons why some individuals have severe neuropathy following an infection are not known. Through the agnostic screening of children with acute axonal neuropathy after an infection, we identified several families with biallelic variants in RCC1. We aimed to describe the clinical phenotype of these patients, and the molecular and cellular pathology associated with the genetic variants identified in these families.

METHODS: For this case series, we identified children affected by a severe, acute-onset axonal neuropathy following infection through an international research consortium of paediatric neurologists and clinical geneticists from nine countries (Canada, Cyprus, Czechia, Germany, Iran, Saudi Arabia, Slovakia, Türkiye, and the UK). Clinical assessments included nerve conduction studies and neuroimaging. We did exome or genome sequencing in DNA samples from all patients. We characterised the proteins encoded by the genetic variants by use of thermal stability and enzymatic assays, using recombinantly expressed proteins. We assessed cellular protein transport under heat or oxidative stress by use of immunofluorescence in primary fibroblasts, obtained from patients. We generated a humanised Drosophila knock-in model to assess the effects of stress on the in vivo function of RCC1.

FINDINGS: Between Nov 2, 2011, and July 10, 2024, we identified 24 individuals from 12 families who had severe, acute-onset axonal neuropathy following infection (13 female and 11 male patients, with a mean age at diagnosis of 1 year 10 months [SD 2·27]). Eight biallelic missense variants in RCC1 were identified in affected individuals with autosomal recessive inheritance. Patients had variable phenotypes, ranging from rapidly progressive fatal axonal neuropathy to mild motor neuropathy with impaired walking. Neurological presentation was often secondary to an infection, resulting in initial misdiagnoses of Guillain-Barré syndrome in several patients. 15 children had disease recurrence. The disease was fatal in 15 patients. The RCC1 variants in these patients code for proteins that alter GDP-to-GTP exchange activity and have reduced thermal stability in vitro. In primary fibroblasts, heat shock or oxidative stress revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model of the disease revealed a fatal intolerance to oxidative stress.

INTERPRETATION: We describe an autosomal recessive, acute-onset paediatric axonal neuropathy, seemingly triggered by infection, that affects individuals with biallelic RCC1 variants. In these children, the disease can mimic Guillain-Barré syndrome. The pathological mechanisms underlying this novel axonal neuropathy might overlap with those of amyotrophic lateral sclerosis. Cellular studies indicate that RCC1 variants affect nucleocytoplasmic transport, which is crucial for healthy axonal function. Future studies should be directed at pre-symptomatic treatment by exploring ways to maintain nucleocytoplasmic transport.

FUNDING: National Institute for Health and Care Research, LifeArc, and Wellcome Trust.}, } @article {pmid40683546, year = {2025}, author = {Mehboodi, M and Namdari, MP and Abdollahi, Z and Mobarezi, Z and Kiani, M and Chamani, F and Khanbabaie, H and Rabiei, S and Maleki, MH and Sanati, H and Shahedin, GJ and Isaei, E}, title = {The relationship between increased levels of microbiota-derived lipopolysaccharide in obesity and the pathophysiology of neurodegenerative diseases.}, journal = {Microbial pathogenesis}, volume = {207}, number = {}, pages = {107905}, doi = {10.1016/j.micpath.2025.107905}, pmid = {40683546}, issn = {1096-1208}, mesh = {Humans ; *Lipopolysaccharides/metabolism ; *Obesity/microbiology/complications ; *Neurodegenerative Diseases/physiopathology/microbiology/etiology ; *Gastrointestinal Microbiome/physiology ; Animals ; Inflammation ; Blood-Brain Barrier ; Oxidative Stress ; }, abstract = {Lipopolysaccharide (LPS), a potent pro-inflammatory endotoxin derived from the outer membrane of Gram-negative bacteria, has been identified as a crucial link between obesity-related systemic inflammation and the onset of neurodegenerative diseases. Modifications in gut microbiota associated with obesity disrupt the integrity of the intestinal barrier, resulting in increased permeability and heightened levels of circulating LPS a phenomenon known as metabolic endotoxemia. The elevated presence of LPS promotes persistent low-grade inflammation and oxidative stress, both of which are critical contributors to neurodegeneration. This review aims to explore the biological pathways through which LPS influences the development and advancement of neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). The role of LPS in exacerbating neuroinflammation through the activation of microglia and the impairment of the blood-brain barrier (BBB) is thoroughly examined. Moreover, the review delves into the interrelated effects of obesity-related systemic inflammation, insulin resistance, and mitochondrial dysfunction in enhancing LPS-driven neurodegenerative mechanisms. Special emphasis is placed on the common pathological characteristics present in these disorders, such as protein misfolding, neuronal apoptosis, and disrupted synaptic function, which may be exacerbated by LPS-related processes. By clarifying the relationships between obesity, LPS, and neurodegenerative diseases, this review underscores potential therapeutic approaches aimed at modulating gut microbiota, improving intestinal barrier function, and mitigating systemic inflammation to prevent or decelerate the progression of these debilitating disorders.}, } @article {pmid40683959, year = {2025}, author = {Khera, P and Kumar, A and Kapila, R}, title = {Decision tree for severity assessment of neurodegenerative diseases using possibility approach and gait dynamics.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {26247}, pmid = {40683959}, issn = {2045-2322}, mesh = {Humans ; Severity of Illness Index ; Male ; *Neurodegenerative Diseases/diagnosis/physiopathology ; Female ; *Decision Trees ; *Gait/physiology ; Middle Aged ; Aged ; Parkinson Disease/physiopathology/diagnosis ; Huntington Disease/physiopathology/diagnosis ; Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Adult ; *Gait Analysis/methods ; }, abstract = {Accurate and timely diagnosis of neurodegenerative disease (NDD) severity is crucial for clinical needs. Existing assessment methods for grading disease severity are mostly dependent on movement disorder specialist opinion resulting in subjectivity and inherent limitations. Gait instrumentation, on the other hand, can be used as a reliable tool to record various contrasting primary gait features. However, these features are agonized by individual's physical dimensions causing data dispersion. This study proposes normalized feature set, and a decision tree (DT) based model to evaluate NDD severity. The study investigates the use of raw sensor signals from foot resistive switches (FSR) to determine high-level gait features for detection of disease severity in patients suffering from neurodegenerative disorders. The methodology includes three-step DT-based approach. First, NDD patients were classified from healthy controls (HC). Disorders were categorized into Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Finally, disease severity was determined on clinical scale. Experimental results were established using 11,084 gait pattern recordings from NDD patients and HC. The proposed framework achieved a high coefficient of determination (R[2] ≈ 0.90) and low error rates with stratified 10-fold cross-validation. Comparatively, it outperformed conventional DT models. Statistical validation via the Wilcoxon signed-rank test confirmed the significance of the finding. The proposed computer aided gait analysis framework demonstrated high accuracy and reliability in diagnosing NDD severity. The accuracy and reliability of proposed framework for disease severity diagnosis is crucial for dose management and to determine the disease progress rate in NDD patients.}, } @article {pmid40684739, year = {2025}, author = {Rudell, EC and Cutti, L and Turra, GM and Angonese, PS and Tasca, VF and Dos Santos, OD and Patterson, E and Merotto, A}, title = {Variability and spatial distribution of ALS-inhibitor resistance mechanisms in Brazilian Echinochloa crus-galli.}, journal = {Plant physiology and biochemistry : PPB}, volume = {228}, number = {}, pages = {110237}, doi = {10.1016/j.plaphy.2025.110237}, pmid = {40684739}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Echinochloa/genetics/drug effects/enzymology ; *Herbicide Resistance/genetics ; Brazil ; Mutation ; Polymorphism, Single Nucleotide ; *Herbicides/pharmacology ; *Plant Proteins/genetics/antagonists & inhibitors/metabolism ; }, abstract = {Barnyardgrass (Echinochloa crus-galli (L.) P. Beauv.) is a hexaploid weed, commonly found in rice fields. The field-level frequencies of the herbicide resistance mechanisms present in barnyardgrass remain unknown. This study developed and compared molecular marker assays for detecting mutations in the ALS genes, analyzing their frequency and spatial distribution in Southern Brazil rice fields. The ALS gene of 52 accessions was sequenced to identify mutations associated with resistance. Single Nucleotide-Amplified Polymorphism (SNAP) and PCR Allele Competitive Extension (PACE®) markers were developed for detecting ALS mutations: A122T, A205N, W574L, and S653N. A total of 233 accessions that survived imidazolinone application were collected. A greenhouse assay identified 195 and 84 accessions resistant to imazapyr + imazapic and penoxsulam, respectively. Molecular assays detected 188 resistant accessions, with W574L, S653N, A122T, and A205N mutations present in 43 %, 29 %, 17 %, and 5 % of resistant samples, respectively. 6 % of accessions carried mutations in two positions, while six resistant accessions lacked any mutation. Efficiency of SNAP and PACE methods was 90 % and 82 %, respectively. Discrepancies between methods were resolved using Nanopore sequencing. The detection threshold was one resistant per 25 susceptible DNA samples and one per 10 using leaf discs in SNAP. All mutations were distributed geographically, with the frequency of W574L increasing from 40 % in 2017/2018 to 47 % in the 2022/2023 season. ALS resistance was detected in 80 % of the accessions. Epidemiological studies, like this, that track resistance mechanisms, including the occurrence, distribution, and variability of mutations, are crucial for improving weed control recommendations.}, } @article {pmid40684811, year = {2025}, author = {Debernard, S and Aguilar, P and Maria, A and Fuentes, A and Couzi, P and Bozzolan, F and Gassias, E and Force, E}, title = {Endocrine responses in the pheromone induction of male sexual maturation in an insect.}, journal = {Insect biochemistry and molecular biology}, volume = {183}, number = {}, pages = {104365}, doi = {10.1016/j.ibmb.2025.104365}, pmid = {40684811}, issn = {1879-0240}, mesh = {Animals ; Male ; *Sex Attractants/metabolism/pharmacology ; *Sexual Maturation ; Juvenile Hormones/metabolism ; *Moths/growth & development/physiology/metabolism/genetics ; Female ; Insect Proteins/metabolism/genetics ; }, abstract = {In animals, sexual maturation is marked by the development of reproductive behaviors in synchronism with the acquisition of fertility, and this timing is influenced by chemosensory experiences. In naïve and immature individuals, exposure to sex pheromones may accelerate sexual development, and mechanisms underlying this pheromone induction are not fully identified. Using the moth Agrotis ipsilon, we showed that pre-exposure of immature males to female sex pheromones led to early increases in the performance of sex pheromone-triggered oriented flight as well as in the maturation of accessory sex glands (ASGs) producing seminal proteins. Conjointly, biosynthesis and circulating amounts of juvenile hormone (JH) raised with an upregulation of the expression of JH receptor, Methoprene-tolerant 1 (Met1) and the JH-inducible transcription factor, Krüppel homolog 1 (Kr-h1) in ASGs and the primary olfactory centers, the antennal lobes (ALs). In the sex pheromone pre-exposed immature males, the loss of function of Met1 or Kr-h1 caused a reduction in the induction of the sex pheromone behavioral responsiveness and the ASG secretory activity. Taken together, our results showed that the accelerated effects of sex pheromone pre-exposure on male sexual maturation are mediated by increased JH biosynthesis. This ultimately leads to early induction of JH signaling in ASGs for seminal protein production and in ALs for the central processing of pheromone information, which causes the display of sexual behavior in male A. ipsilon. Finally, this study expands our understanding of endocrine mechanisms by which animals can modulate their fitness according to past olfactory experiences.}, } @article {pmid40684954, year = {2025}, author = {Zheng, B and Du, S and Wei, M and Xia, W and Jiang, Y and Zhou, J and Zhang, J}, title = {Association of allostatic load and dietary inflammatory index with depressive symptoms among U.S. adults: NHANES 2007-2018.}, journal = {Journal of affective disorders}, volume = {391}, number = {}, pages = {119955}, doi = {10.1016/j.jad.2025.119955}, pmid = {40684954}, issn = {1573-2517}, mesh = {Humans ; *Allostasis/physiology ; Male ; Female ; Nutrition Surveys ; Middle Aged ; Adult ; *Inflammation/epidemiology ; *Depression/epidemiology/etiology ; United States/epidemiology ; *Diet/adverse effects/statistics & numerical data ; *Stress, Psychological/epidemiology ; Biomarkers ; Cross-Sectional Studies ; Aged ; }, abstract = {BACKGROUND: Both chronic stress and pro-inflammatory diets have been independently linked to depressive symptoms (DSs). However, their joint effects are uncertain.

METHODS: This study included 20,446 U.S. adults from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. Chronic stress was quantified using allostatic load score (ALS) derived from eight biomarkers. Dietary inflammatory potential was quantified using Dietary Inflammation Index (DII) calculated from two 24-h dietary recalls. DSs were assessed using the Patient Health Questionnaire-9 (PHQ-9). Weighted logistic regression, restricted cubic splines (RCS), mediation, and population attributable fraction (PAF) analyses were conducted.

RESULTS: Both ALS (adjusted odds ratio [aOR] = 1.23, 95 % confidence interval [CI]: 1.16-1.29) and DII (aOR = 1.21, 95%CI:1.15-1.26) independently and synergistically increased DSs risk, showing significant linear trends (both P-overall<0.001) with no evidence of nonlinearity. The highest-risk group (highest ALS quartile + pro-inflammatory diet) exhibited a 3.94-fold increased risk (aOR = 4.94, 95 % CI: 2.73-8.94) compared to the reference group. DII partially mediated the ALS-DSs association (mediation proportion: 4.27 %, 95 % CI: 2.96 %-6.00 %). Eliminating high ALS and pro-inflammatory diets could prevent 40.4 % (95 % CI: 31.7-49.2 %) of depression cases.

LIMITATIONS: The cross-sectional design limits causal inference, and residual confounding may exist due to unmeasured factors.

CONCLUSIONS: This study highlights the independent, synergistic, and mediated effects of ALS and DII on DSs. Integrated interventions addressing both stress and diet may help mitigate depression burden in U.S. adult.}, } @article {pmid40685330, year = {2025}, author = {Far, BF and Akbari, M and Habibi, MA and Katavand, M and Nasseri, S}, title = {CRISPR Technology in Disease Management: An Updated Review of Clinical Translation and Therapeutic Potential.}, journal = {Cell proliferation}, volume = {58}, number = {11}, pages = {e70099}, pmid = {40685330}, issn = {1365-2184}, mesh = {Humans ; Animals ; *CRISPR-Cas Systems ; *Translational Research, Biomedical ; Gene Editing ; Genetic Engineering/methods ; Genetic Variation ; COVID-19/therapy ; SARS-CoV-2 ; Immunotherapy ; }, abstract = {CRISPR-Cas9 technology has rapidly advanced as a transformative genome-editing platform, facilitating precise genetic modifications and expanding therapeutic opportunities across various diseases. This review explores recent developments and clinical translations of CRISPR applications in oncology, genetic and neurological disorders, infectious diseases, immunotherapy, diagnostics, and epigenome editing. CRISPR has notably progressed in oncology, where it enables the identification of novel cancer drivers, elucidation of resistance mechanisms, and improvement of immunotherapies through engineered T cells, including PD-1 knockout CAR-T cells. Clinical trials employing CRISPR-edited cells are demonstrating promising results in hematologic malignancies and solid tumours. In genetic disorders, such as hemoglobinopathies and muscular dystrophies, CRISPR-Cas9 alongside advanced editors like base and prime editors show significant potential for correcting pathogenic mutations. This potential was affirmed with the FDA's first approval of a CRISPR-based therapy, Casgevy, for sickle cell disease in 2023. Neurological disorders, including Alzheimer's, ALS, and Huntington's disease, are increasingly targeted by CRISPR approaches for disease modelling and potential therapeutic intervention. In infectious diseases, CRISPR-based diagnostics such as SHERLOCK and DETECTR provide rapid, sensitive nucleic acid detection, particularly valuable in pathogen outbreaks like SARS-CoV-2. Therapeutically, CRISPR systems target viral and bacterial genomes, offering novel treatment modalities. Additionally, CRISPR-mediated epigenome editing enables precise regulation of gene expression, expanding therapeutic possibilities. Despite these advances, significant challenges remain, including off-target effects, delivery methodologies, immune responses, and long-term genomic safety concerns. Future improvements in editor precision, innovative delivery platforms, and enhanced safety assessments will be essential to fully integrate CRISPR-based interventions into standard clinical practice, significantly advancing personalised medicine.}, } @article {pmid40685584, year = {2026}, author = {Young, CA and Chaouch, A and Mcdermott, CJ and Al-Chalabi, A and Chhetri, SK and Waters, N and Buccleuch, R and Mills, RJ and Tennant, A and , }, title = {Patient reported outcome measures require scale metrification and quantified precision: evidence from the assessment of breathlessness in people with ALS/MND.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {55-61}, doi = {10.1080/21678421.2025.2533870}, pmid = {40685584}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Dyspnea/diagnosis/etiology ; *Patient Reported Outcome Measures ; Male ; Female ; Middle Aged ; Aged ; Reproducibility of Results ; }, abstract = {Introduction: Precision (how closely repeated measures match) and responsiveness (ability to detect change over time) are critical properties of patient reported outcome measures (PROMs). Smallest Detectable Difference (SDD) is a useful statistic regarding precision; Minimal Detectable Change (MDC) and Minimal Important Change (MIC) assess responsiveness. Methods: We examined measurement properties of Numeric Rating Scale for Breathlessness, ALSFRS-R respiratory subscale and Dyspnea-12, contributed by participants in the Trajectories of Outcome in Neurological Conditions-ALS study. Rasch analysis converts ordinal scale data to interval equivalents. Results: Data from 1120 people with ALS showed ALSFRS-R Respiratory is only valid as ordinal data. The NRS Breathlessness requires computation from a wider NRS set for Rasch analysis; its SDD is 3.2, MDC 2.59, MIC 2.39, with score range of 0-10. The Dyspnea-12 has SDD 7.0, MDC 6.14, MIC 4.5, with score range of 0-36. The %MDC, indicating smallest change detectable above measurement error as % of scale range, is superior for the Dyspnea-12 (17.1%) compared to the NRS Breathlessness (25.9%). Another advantage of Dyspnea-12 is transformation of raw ordinal to interval equivalent data using published conversion tables. Both NRS and Dyspnea-12 have disadvantages of MIC < MDC. Conclusions: Accurate measurement underpins optimal clinical decision making and high-quality research. Informed choice of PROMs reduces risk of misinterpreting clinical and research data. Patients want PROMs which they feel give an accurate account of their progression when participating in research and communicating with their clinical team. The Dyspnea-12 is preferrable for clinical and research use based on its psychometric properties.}, } @article {pmid40687373, year = {2025}, author = {Hollensen, AK and Sørensen, MH and Thomsen, SV and Thomsen, HS and Damgaard, CK}, title = {Using circular RNAs to target toxic RNA-binding proteins in amyotrophic lateral sclerosis.}, journal = {Molecular therapy. Methods & clinical development}, volume = {33}, number = {3}, pages = {101525}, pmid = {40687373}, issn = {2329-0501}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration and is in many cases associated with mutations in genes encoding RNA-binding proteins (RBPs), including fused in sarcoma (FUS) and heterogeneous nuclear ribonuclearprotein A1 (hnRNPA1). These mutations often cause cytoplasmic mislocalization and aggregation of these typically nuclear proteins. Current treatment options for ALS are limited, highlighting the need for new therapeutic strategies. Here, we demonstrate an approach using circular RNAs (circRNAs) to target disease-associated RBPs for degradation. We designed circRNAs containing binding sites for both the target RBPs (FUS or hnRNPA1) and ring finger and CCCH-type domains 2 (RC3H2), an RNA-binding E3 ubiquitin ligase. Through RNA immunoprecipitations and protein analyses, we show that these circRNAs can form ternary complexes with their target RBPs and RC3H2. Importantly, we observed significant reductions in steady-state protein levels of ALS-associated FUS-P525L (20%) and hnRNPA1-P288S (30%) mutants when treated with their respective targeting circRNAs. These findings provide proof of concept for using circRNAs as scaffolds to promote the degradation of disease-associated RBPs, establishing a foundation for developing advanced RNA-based therapeutic strategies for ALS and potentially other RBP-related diseases.}, } @article {pmid40688669, year = {2025}, author = {Zhu, RK and Shi, J and Zhou, HJ and Ge, L and Yin, WH and Zeng, H and Wang, XW}, title = {Biological applications of graphene-based nanomaterials in neurodegenerative diseases.}, journal = {Materials today. Bio}, volume = {33}, number = {}, pages = {102064}, pmid = {40688669}, issn = {2590-0064}, abstract = {Neurodegenerative diseases (NDDs) have become a major challenge in global public health due to neurotoxicity caused by progressive neuronal degeneration and abnormal protein aggregation, which has attracted widespread attention. Graphene-based nanomaterials provide innovative solutions for the early diagnosis and precise treatment of NDDs by virtue of their ultra-high conductivity, large specific surface area and multifunctional properties. In this paper, we systematically discuss the key applications of these materials in the diagnosis and treatment of NDDs, and deeply analyze the technological breakthroughs and clinical translation challenges. The core of this paper is to illustrate that graphene-based nanomaterials are expected to reshape the paradigm of NDDs diagnosis and treatment through cross-scale technological innovations, promoting the synergistic development of early diagnosis, personalized treatment and real-time monitoring, and providing a transformative strategy for overcoming NDDs.}, } @article {pmid40689333, year = {2025}, author = {Tian, M and Xin, C and Huo, J and Liu, Q and Dong, H and Bai, L and Wang, Y and Li, R and Liu, Y}, title = {Unlocking amyotrophic lateral sclerosis: the role of adiponectin in inflammation and disease progression.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1605822}, pmid = {40689333}, issn = {1664-2295}, abstract = {INTRODUCTION: In amyotrophic lateral sclerosis (ALS), immune cells become activated, resulting in a persistent pro-inflammatory milieu and contributing to the development of ALS. Adiponectin produces anti-inflammatory effects via its adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2). Currently, there has been limited research conducted on the correlation between adiponectin and inflammation in ALS.

METHODS: This cross-sectional study recruited a cohort of 82 ALS patients and 25 controls. Adiponectin and inflammatory mediators in plasma were measured using enzyme-linked immunosorbent assay (ELISA). Furthermore, flow cytometry, immunocytochemistry, and ELISA were employed to examine the levels of AdipoR1, AdipoR2, and inflammatory markers in monocytes and macrophages obtained from ALS patients. The effects of Adiponectin receptor agonists (AdipoRon) on AdipoR expression, inflammatory responses, and macrophages polarization were investigated.

RESULTS: Plasma adiponectin level in ALS patients was markedly lower than controls. This decrease was found to be positively associated with IL-1β, IL-2, IL-6, IL-8, and TNF-α, while negatively correlated with IL-4 and IL-10. Furthermore, there was a positive correlation between plasma adiponectin level and ALS Functional Rating Scale-Revised (ALSFRS-R), and a negative correlation with the disease progression rate (δFS). Mediation research demonstrated that IL-2, or TNF-α, or IL-10 acted as a mediator between adiponectin and δFS. AdipoR1 and AdipoR2 showed a notable increase in expression in peripheral blood monocytes and activated macrophages obtained from ALS patients, concomitant with elevated level of IL-1β. AdipoRon treatment resulted in a decrease in the expression of AdipoR1. Simultaneously, AdipoRon decreased the levels of IL-1β and MHC-II, while boosting the levels of IL-10 and CD206. This regulation enabled the transformation of macrophages from the M1 to the M2 phenotype, therefore aiding in the protection of neurons.

CONCLUSION: Our findings demonstrated a notable association between adiponectin level and inflammation in the peripheral regions of ALS patients. These results may offer new understanding into the control of inflammation and propose a possible treatment approach for ALS.}, } @article {pmid40689409, year = {2025}, author = {El Haj, M and Hallit, S and Boutoleau-Bretonnière, C}, title = {Pupil response as a window into cognitive processing in amyotrophic lateral sclerosis.}, journal = {eNeurologicalSci}, volume = {40}, number = {}, pages = {100575}, pmid = {40689409}, issn = {2405-6502}, abstract = {PURPOSE: This preliminary study aimed to investigate whether the pupil size reflects cognitive load in patients with amyotrophic lateral sclerosis (ALS).

METHODS: Pupil activity was monitored in three patients with ALS and a group of healthy control participants (n = 16) while performing three tasks: a forward span task, a backward span task, and a control task involving counting aloud. These tasks were designed to impose increasing cognitive demands, with the backward span task being the most challenging.

RESULTS: Analysis revealed no significant difference in pupil size between patients with ALS and controls for the forward or backward spans or the control condition. Both groups demonstrated a consistent pattern of increased pupil size during the backward span task compared to the forward span task, and during the forward span task compared to the control condition.

CONCLUSION: These findings suggest that pupil dilation reflects task-related cognitive load similarly in ALS patients and healthy controls. This supports the use of pupillometry as a non-invasive and sensitive marker of cognitive processing in ALS.}, } @article {pmid40689424, year = {2025}, author = {Poletti, B and Aiello, EN and Curti, B and Torre, S and De Luca, G and D'Ambrosio, C and Gendarini, C and Cocuzza, A and Colombo, E and Maranzano, A and Verde, F and Morelli, C and Messina, S and Doretti, A and Monti, A and Silani, V and Ticozzi, N}, title = {Unraveling the contribution of executive functions to language impairment in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {739-747}, doi = {10.1080/21678421.2025.2529409}, pmid = {40689424}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology ; Male ; Female ; *Executive Function/physiology ; Middle Aged ; Aged ; Neuropsychological Tests ; *Language Disorders/etiology/psychology/diagnosis ; Adult ; }, abstract = {Objectives: This study aims to unravel the association between language deficits and executive functions in non-demented amyotrophic lateral sclerosis (ALS) patients by means of 1) assessing the executive determinants of language impairment (LI) and 2) simultaneously testing the effects of both executive and language performances on phonemic verbal fluency (PVF) deficits. Methods: N = 299 non-demented ALS patients underwent the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), being also assessed for behavioral/psychiatric and motor-functional features. Two sets of logistic models were run: the first, regressing an impaired vs. unimpaired performance on each ECAS-Language (ECAS-L) tasks based on each task of the ECAS-Executive Functioning (ECAS-EF); the second, regressing an impaired vs. unimpaired performance on each ECAS-Fluency tasks based on both ECAS-L and ECAS-EF tasks. Within these models, demographic, motor-functional, and psychiatric/behavioral measures were covaried for. Results: Defective Naming and Comprehension performances were predicted by lower scores on the Sentence Completion task (p ≤ 0.002), whilst defective Spelling performances by lower Alternation scores (p < 0.001). Defective performances on Verbal fluency - S and Verbal fluency - C tasks were predicted by lower Backward Digit Span and Sentence Completion scores, respectively (p ≤ 0.008). Discussion: In ALS patients, inhibitory and set-shifting abilities majorly contribute to LI, whilst PVF deficits are mostly linked to dysexecutive features.}, } @article {pmid40689468, year = {2025}, author = {Costello, E and De Vocht, J and Beswick, E and Mac Domhnaill, É and Peelo, C and Foucher, J and Mayberry, EJ and Chiwera, T and Hiemstra, F and Caravaca Puchades, A and Iazzolino, B and Palumbo, F and Alves, I and Kasper, E and Galvin, M and Heverin, M and Ingre, C and Mcdermott, CJ and Shaw, P and Al-Chalabi, A and Van Den Berg, LH and Povedano Panadés, M and Chiò, A and Carvalho, M and Bencheikh, S and Corcia, P and Mouzouri, M and Hermann, A and Abrahams, S and Pender, N and Van Damme, P and Hardiman, O}, title = {Neuropsychological assessment practices in PRECISION-ALS: challenges and opportunities for harmonization.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {748-757}, doi = {10.1080/21678421.2025.2527877}, pmid = {40689468}, issn = {2167-9223}, mesh = {Humans ; *Neuropsychological Tests/standards ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis/complications ; Male ; Longitudinal Studies ; Female ; *Cognitive Dysfunction/diagnosis/etiology ; }, abstract = {OBJECTIVE: To gather comprehensive insights regarding current neuropsychological assessment practices in PRECISION-ALS, a pan-European research and industry consortium, to propose areas which can be harmonized and facilitate more robust cross-country comparisons.

METHODS: Representatives from PRECISION-ALS sites were surveyed with a semi-structured interview, gathering information on how people with ALS are assessed for cognitive/behavioral change, including how they are initially screened, classified as impaired/unimpaired, and followed up longitudinally. Assessment practices across PRECISION-ALS sites were summarized using descriptive analysis.

RESULTS: Ten of the eleven PRECISION-ALS sites perform cognitive and/or behavioral screening at least once during the course of the disease, using the Edinburgh Cognitive and Behavioral ALS Screen, either for clinical or research purposes. All centers categorize impairment, but differ how it is defined, with some using local norms, and others using other countries' norms. Most sites account for age and education, but differ in how these factors are considered. Longitudinal protocols vary in terms of the number of assessments, time intervals, and use of alternative versions. Behavioral screening is more consistently implemented, with the ECAS caregiver interview as the standard tool, however there is a lack of clarity in how this data is applied. Many sites supplement cognitive and behavioral screening with additional measures of mood and/or neuropsychiatric symptoms.

CONCLUSIONS: These findings illustrate areas of commonality and divergence in neuropsychological screening practices. Site-specific variations are likely to confound research involving cross-country data-sharing. PRECISION-ALS, in generating prospective population-based datasets, will provide agreed harmonized protocols for neuropsychological assessment across participating sites.}, } @article {pmid40690048, year = {2025}, author = {Palumbo, F and Iazzolino, B and Moglia, C and Manera, U and Matteoni, E and Cabras, S and Brunetti, M and Gallone, S and Callegaro, S and Vasta, R and Mora, G and De Marchi, F and Corrado, L and D'Alfonso, S and Mazzini, L and Canosa, A and Grassano, M and Calvo, A and Chiò, A}, title = {Exploring the phenotypic fingerprints of ANXA11 variants in ALS: a population-based study in an European cohort.}, journal = {Journal of neurology}, volume = {272}, number = {8}, pages = {524}, pmid = {40690048}, issn = {1432-1459}, support = {RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; 20228N7573//Ministero dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; 101017598//H2020 Health/ ; 101137074//HORIZON EUROPE Framework Programme/ ; DIG-ALS//ARISLA/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/complications/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Annexins/genetics ; Cohort Studies ; *Cognitive Dysfunction/genetics/epidemiology/etiology ; Phenotype ; Italy/epidemiology ; Adult ; C9orf72 Protein/genetics ; Registries ; }, abstract = {BACKGROUND: Annexin A11 (ANXA11) has emerged as a significant gene associated with amyotrophic lateral sclerosis (ALS) and cognitive impairments. This study aimed to evaluate the prevalence and clinical and cognitive features of pathogenic variants in ANXA11 in an Italian ALS cohort.

METHODS: Data were collected from the Piemonte and Valle d'Aosta Register for ALS between 2009 and 2020. Only patients who underwent whole genome sequencing (WGS) were included. Clinical and cognitive assessments were compared among patients with ANXA11-ALS, wild-type ALS (WT-ALS), and C9ORF72-ALS.

RESULTS: Among 1,486 ALS patients, 18 (1.4%) were found to carry ANXA11 variants, four of which were classified as benign or likely benign. Three patients (16.7%) also had co-occurring variants in ERBB4 (erb-b2 receptor tyrosine kinase 4), EPHA4 (ephrin type-A receptor 4), or C9ORF72 (chromosome 9 open reading frame 72). Patients with ANXA11-ALS had significantly lower education levels (6.2 vs. 8.9 years), higher BMI at diagnosis (26.7 vs. 24.5), and a higher prevalence of cognitive impairment (100% vs. 47%) compared to WT-ALS. Cognitive testing revealed more severe deficits in executive function, attention, psychomotor speed, non-verbal intelligence, and cognitive flexibility, though no behavioral differences were observed. Compared to C9ORF72-ALS, ANXA11-ALS patients were older at diagnosis (66.6 vs. 60.3 years), had lower education levels (6.2 vs. 9.0 years), and higher rates of cognitive impairment (100% vs. 68.7%).

DISCUSSION: Pathogenic ANXA11 variants are relatively common in ALS and are strongly associated with cognitive impairment. Including ANXA11 in routine genetic screening may enhance diagnostic precision and therapeutic strategies for ALS patients.}, } @article {pmid40690785, year = {2025}, author = {Gates, KE and Mefferd, AS and Stipancic, KL}, title = {Exploring Methodological Decisions for Calculating the Minimally Detectable Change in Dysarthria: Reliability, Statistics, and Standard Error of Measurement.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {68}, number = {8}, pages = {3771-3788}, pmid = {40690785}, issn = {1558-9102}, support = {R01 DC019648/DC/NIDCD NIH HHS/United States ; R03 DC015075/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Dysarthria/etiology/physiopathology/rehabilitation/diagnosis ; Reproducibility of Results ; *Speech Intelligibility ; Male ; Female ; Middle Aged ; Adult ; Aged ; Parkinson Disease/complications ; Amyotrophic Lateral Sclerosis/complications ; Multiple Sclerosis/complications ; Speech Production Measurement ; Huntington Disease/complications ; }, abstract = {PURPOSE: The minimally detectable change (MDC), widely used in rehabilitation sciences to interpret changes in outcome measures, is calculated using a reliability method, reliability statistic, and standard error of measurement (SEM). This study examined how different methodological choices affect MDC thresholds of speech intelligibility in speakers with dysarthria. The goals of this study were to compare MDCs calculated using (a) three different reliability methods, (b) two different reliability statistics, and (c) three different SEM calculations.

METHOD: Recordings of the Speech Intelligibility Test from 200 speakers including speakers with amyotrophic lateral sclerosis (n = 16), Huntington's disease (n = 44), multiple sclerosis (n = 60), and Parkinson's disease (n = 40), along with healthy controls (n = 40), were drawn from two databases. Thirty inexperienced listeners completed two sessions, providing orthographic transcriptions of 20 speakers. MDCs of intelligibility were calculated using (a) three reliability methods (i.e., test-retest, split-half, and intrarater), (b) two reliability statistics (i.e., Pearson r and intraclass correlation coefficients [ICCs]), and (c) three different formulas for calculating the SEM. Kruskal-Wallis tests were used to assess the effects of reliability methods, statistics, and SEM calculations.

RESULTS: Significant differences were found between the MDCs when using split-half and test-retest reliability, when using Pearson r and ICC, and when using two of the three SEM calculations.

CONCLUSIONS: Results demonstrate that methodological decisions can impact MDCs of speech intelligibility in speakers with dysarthria, highlighting the need for specific, detailed reporting of methodology used to calculate MDCs in future work. Findings can provide methodological guidance for future studies and contextualize existing research on intelligibility changes.}, } @article {pmid40691077, year = {2026}, author = {Dinh, TTH and Imura, C and Shiokawa, M and Ayabe, S and Yoshiki, A and Inoue, H and Amano, T}, title = {A partial deletion of the Tardbp 3'UTR affects TDP-43 regulation and leads to motor dysfunction in mice.}, journal = {Experimental animals}, volume = {75}, number = {1}, pages = {40-49}, pmid = {40691077}, issn = {1881-7122}, mesh = {Animals ; *DNA-Binding Proteins/genetics/metabolism ; *3' Untranslated Regions/genetics ; Motor Neurons/pathology/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Mice ; Spinal Cord/metabolism ; Disease Models, Animal ; *Gene Deletion ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that causes the selective loss of motor neurons. A histopathological hallmark of ALS is the cytoplasmic aggregation of TDP-43, a ubiquitously expressed RNA-binding protein involved in transcription and splicing regulation. To prevent abnormal accumulation, TDP-43 controls its expression levels through an autoregulatory feedback loop. While most ALS studies have focused on pathogenic variants that impair the protein function of TDP-43, the mechanisms underlying endogenous TDP-43 dysregulation mediated by non-coding elements, including the 3' untranslated region (3'UTR), remain incompletely understood. In this study, we generated a mouse model carrying a targeted deletion of the Tardbp 3'UTR that encompasses the TDP-binding region, polyadenylation signals, and alternative intronic sequences. Our findings demonstrate that the Tardbp 3'UTR is essential for normal mouse development. Loss of this region led to decreased Tardbp mRNA expression and embryonic lethality after gastrulation. Young heterozygous mice were phenotypically normal with no overt disruption in TDP-43 autoregulation. However, aged heterozygous mice displayed mild locomotor dysfunction accompanied by a modest increase in spinal cord TDP-43 protein levels and a reduction in motor neuron numbers. These findings indicate that regulatory elements within the Tardbp 3'UTR play a pivotal role in normal development and contribute to TDP-43 pathology relevant to ALS.}, } @article {pmid40691976, year = {2025}, author = {Pandey, P and Das, R and Yadav, H and Mukherjee, A and Mutsuddi, M}, title = {RNA helicase maheshvara interacts with TDP-43 and exacerbates neurodegeneration in Drosophila model of amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {214}, number = {}, pages = {107036}, doi = {10.1016/j.nbd.2025.107036}, pmid = {40691976}, issn = {1095-953X}, support = {//Institute of Eminence/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; *Drosophila Proteins/metabolism/genetics ; Drosophila ; Animals, Genetically Modified ; *DEAD-box RNA Helicases/metabolism/genetics ; *Nerve Degeneration/pathology/metabolism/genetics ; }, abstract = {Drosophila maheshvara (mahe) encodes a conserved DEAD box RNA helicase that regulates various important signaling pathways like Notch and JAK/STAT, pathways that have been functionally implicated in neuronal development. In order to identify novel modulators of mahe as well as to unravel its role in neurodegenerative disorders, a genetic modifier screen using Drosophila models of neurodegenerative disorders was carried out. From this screen, we identified mahe to be a potent modifier of TDP-43 mediated proteinopathy in Drosophila model of Amyotrophic Lateral Sclerosis (ALS). We demonstrate that Mahe genetically interacts and associates with cytosolic hyperphosphorylated toxic aggregates of TDP-43 leading to enhanced TDP-43 mediated neurodegenerative phenotype. Increased autophagy, cytoskeletal disruption, and FMRP-mediated translational repression of neuronal target Futsch were observed, potentially contributing to neuronal dysfunction. The current study indicates a strong interaction of mahe and TDP-43 (TARDBP) resulting in augmentation of TDP-43 mediated neurodegenerative phenotypes which parallels ALS clinical pathology.}, } @article {pmid40692425, year = {2025}, author = {Yang, Z and Wu, Y and Gao, J and Hu, S and Wang, J and Jing, R}, title = {Comparison of the Peripapillary Structure-Vessel Density Relationship Before and After Axial Length Magnification Correction Using Different Methods.}, journal = {Clinical & experimental ophthalmology}, volume = {53}, number = {8}, pages = {908-917}, doi = {10.1111/ceo.14585}, pmid = {40692425}, issn = {1442-9071}, support = {2023HXKT033//Horizontal Project/ ; 2024HXKT054//Horizontal Project/ ; (QN)202302//The Youth fund of The Second Affiliated Hospital of Xi'an Jiaotong University/ ; }, mesh = {*Axial Length, Eye/diagnostic imaging/physiopathology ; *Myopia/diagnosis/pathology/physiopathology ; Tomography, Optical Coherence/methods ; Nerve Fibers/pathology ; *Optic Disk/diagnostic imaging/pathology ; *Retinal Vessels/diagnostic imaging/pathology ; Choroid/diagnostic imaging/pathology ; Case-Control Studies ; Humans ; Male ; Female ; Young Adult ; Adult ; Computed Tomography Angiography/methods ; }, abstract = {BACKGROUND: To evaluate changes in OCTA-derived structural and vascular parameters before and after axial length (AL) magnification correction using two different formulas, and to explore their correlations with vessel density (VD).

METHODS: This study included 45 high myopic eyes and 45 age- and gender-matched controls. Both 6 × 6 mm[2] optic nerve head imaging and biological measurement were performed using OCTA. Magnification correction was performed using both the Bennett formula and the device's built-in algorithm. Parameters analysed included retinal nerve fibre layer (RNFL) thickness, superficial vascular complex (SVC) VD, deep vascular complex (DVC) VD, and choroidal VD.

RESULTS: In long AL eyes, uncorrected values underestimated RNFL thickness and SVC VD but overestimated DVC VD and choroidal VD; discrepancies increased with AL. The opposite pattern was observed in shorter eyes. After correction, all vascular parameters except DVC VD showed significant changes in the high myopia group, while non-high myopic eyes showed no significant differences. The two correction methods showed strong agreement across all layers. RNFL thickness correlated strongly with SVC VD, and choroidal thickness (CT) with choroidal VD, both before and after correction. Post-correction, AL was no longer associated with RNFL thickness or SVC VD, while its correlation with CT and choroidal VD persisted. Mediation analysis showed AL fully mediated the CT-choroidal VD relationship, with a stronger effect post-correction.

CONCLUSIONS: Magnification correction is crucial in high myopic eyes. Both formulas showed high consistency. Correction eliminated AL's confounding effects on RNFL and SVC VD, while emphasising its mediating role between CT and choroidal VD.}, } @article {pmid40693147, year = {2025}, author = {Mageto, LM and Aboge, GO and Mekuria, ZH and Gathura, P and Juma, J and Mugo, M and Kebenei, CK and Imoli, D and Ongadi, BA and Kering, K and Mbae, CK and Kariuki, S}, title = {Genomic characterization of Vibrio cholerae isolated from clinical and environmental sources during the 2022-2023 cholera outbreak in Kenya.}, journal = {Frontiers in microbiology}, volume = {16}, number = {}, pages = {1603736}, pmid = {40693147}, issn = {1664-302X}, support = {D43 TW011519/TW/FIC NIH HHS/United States ; }, abstract = {BACKGROUND: Cholera remains a public health challenge in Kenya. To better understand its dynamics, we analyzed Vibrio cholerae genomes from clinical and environmental samples collected during the 2022-2023 outbreak. These strains were compared with historical genomes from Kenya, Uganda, Tanzania, and Haiti to inform strategies for cholera prevention, control, and elimination in Kenya.

METHODS: Clinical (stool) and environmental (wastewater, drinking water, and household effluent) samples were collected from Nairobi county. Samples were analyzed for V. cholerae using culture and real time PCR. The environmental (n = 17) and clinical (n = 70) isolates were then subjected to phenotypic antimicrobial susceptibility testing using the Kirby-Bauer disk diffusion method. Whole genome sequencing was employed to characterize the genome, detect antimicrobial resistance genes, virulence factors, and mobile genetic elements. Phylogenetic analysis was performed to assess the genetic relationship and diversity of isolates from 2022 to 2023 outbreak, comparing them with isolates from historical outbreaks.

RESULTS: Clinical isolates carried key virulence genes (ctxA, ctxB7, zot, and hlyA) and were 100% resistant to multiple antibiotics, including ampicillin, cefotaxime, ceftriaxone, and cefpodoxime, but remained susceptible to gentamicin and chloramphenicol. In contrast, environmental isolates lacked ctxB gene but harbored toxR, als, and hlyA, showing variable antibiotic resistance (59% to ampicillin, 41% to trimethoprim-sulfamethoxazole, and 47% to nalidixic acid). All clinical isolates from 2022 to 2023 outbreak harbored IncA/C2 plasmids and several antimicrobial resistance genes including bla PER-7. Phylogenetic analysis revealed high genetic diversity in environmental strains, clustering outside the 7th pandemic El Tor lineage, while clinical isolates were highly clonal. Genomes from 2022 to 2023 outbreak were closely related to Kenyan cholera outbreak genomes from 2016 (15 single nucleotide polymorphisms, T13 lineage).

CONCLUSION: The 2022-2023 outbreak likely resulted from re-emergence of previously circulating strains rather than a new introduction. While the role of environmental reservoirs as a source of human infection remains unclear in our study, environmental isolates possess virulent and antimicrobial resistance genes that may spread via horizontal gene transfer. This highlights the need for continuous genomic surveillance to monitor V. cholerae evolution, track transmission patterns, and mitigate the spread of antimicrobial resistance.}, } @article {pmid40694206, year = {2025}, author = {Mahto, K and Kuwar, OK and Maloo, A and Kalia, N}, title = {Therapeutic potential of luteolin in neurodegenerative disorders: targeting Nrf2, NFĸB, MAPK, and JAK-STAT pathways to combat neuroinflammation and apoptosis.}, journal = {Inflammopharmacology}, volume = {33}, number = {9}, pages = {5011-5021}, pmid = {40694206}, issn = {1568-5608}, mesh = {*Luteolin/pharmacology/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Apoptosis/drug effects ; Signal Transduction/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism ; NF-E2-Related Factor 2/metabolism ; Neuroprotective Agents/pharmacology ; STAT Transcription Factors/metabolism ; Janus Kinases/metabolism ; NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's disease, Multiple sclerosis and Amyotrophic Lateral Sclerosis, are characterized by progressive neuronal loss, oxidative stress, chronic neuroinflammation, mitochondrial dysfunction, and apoptosis. The Nrf2/ARE, IĸB/NFĸB, MAPK/AP-1, and JAK-STAT signaling pathways play a pivotal role in these pathological processes, making them promising therapeutic targets. Luteolin, a naturally occurring flavonoid, has demonstrated potent antioxidant, anti-inflammatory, and neuroprotective properties by modulating these interconnected pathways. Activation of Nrf2/ARE signaling by luteolin enhances cellular antioxidant defences, while its inhibition of NFĸB, MAPK/AP-1, and JAK-STAT pathways suppresses neuroinflammation and apoptotic signalling, thereby mitigating neuronal damage. Emerging evidences suggest that luteolin effectively reduces neurotoxic effects by regulating inflammatory cytokine production, stabilizing mitochondrial function, and maintaining redox homeostasis. Its ability to interfere with crosstalk between these signaling pathways highlights its potential as a multi-targeted neuroprotective agent. Preclinical studies have provided strong evidence supporting luteolin's role in mitigating neurodegeneration, suggesting its applicability in neurodegenerative disease management. These findings underscore the therapeutic potential of luteolin in neurodegenerative diseases by targeting multiple pathological mechanisms. However, further investigations are needed to fully elucidate its molecular mechanisms and optimize its therapeutic benefits.}, } @article {pmid40694827, year = {2025}, author = {Berry, J and Raymond, J and Larson, T and Horton, DK and Han, M and Nair, T and Al-Chalabi, A and Mehta, P}, title = {Amyotrophic Lateral Sclerosis as a Multistep Process in the United States: A Population-Based Study.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {9}, pages = {1858-1864}, pmid = {40694827}, issn = {2328-9503}, support = {/CC/CDC HHS/United States ; /CC/CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Female ; Male ; United States/epidemiology ; Middle Aged ; *Registries/statistics & numerical data ; Aged ; Incidence ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease that typically results in death within 3-5 years from symptom onset. However, little is known about the environmental exposures, clinical aspects, or social determinants of health factors that may be associated with the disease. Multistep modeling has been previously applied to cancer research, demonstrating a linear relationship between logs of incidence and age. This method may help to understand the mechanisms involved in the development of ALS in the United States (e.g., environmental exposures, genetic mutations). We aim to assess whether ALS is a multistep process among patients enrolled in the largest ALS registry in the world-the United States' National ALS Registry.

METHODS: Incident ALS cases, defined as confirmed and likely, cases between 2012 and 2019 were obtained from the National ALS Registry. Age-standardized incidence was calculated for all cases and by sex. The log incidence of ALS was regressed against the log of age (years) at case determination, on average, for each year and by sex.

FINDINGS: Between 2012 and 2019, there was a mean of 5253 incident ALS cases (confirmed or likely) per year. We identified a linear relationship between the log of the average incidence and log age overall (r[2] = 0.99), for men (r[2] = 0.99), and for women (r[2] = 0.98). The incidence slope estimates were 4.8 (95% CI: 4.4-5.1) overall, 4.7 (95% CI: 4.4-5.1) for men, and 5.0 (95% CI: 4.5-5.5) for women.

INTERPRETATION: The linear relationships observed overall, for men, and for women are consistent with a multi-step process. The slope estimates, on average, are approximately 5.0, which suggests that the development of ALS is a six-step process. Further investigation of these steps can elucidate potential risk factors and treatments for ALS.}, } @article {pmid40696471, year = {2025}, author = {Lin, CF and Chen, YH and Yeh, CC and Hsu, SPC and Fu, YS}, title = {Xenotransplantation of Human Umbilical Mesenchymal Stromal Cells Derived from Wharton's Jelly Mitigates Mouse Amyotrophic Lateral Sclerosis.}, journal = {Stem cell research & therapy}, volume = {16}, number = {1}, pages = {395}, pmid = {40696471}, issn = {1757-6512}, support = {V114C-203//Taipei Veterans General Hospital/ ; 113-2314-B-075-061//National Science and Technology Council in Taiwan/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/pathology ; Animals ; Humans ; *Mesenchymal Stem Cells/cytology/metabolism ; *Mesenchymal Stem Cell Transplantation ; Mice ; Mice, Transgenic ; Superoxide Dismutase-1 ; *Wharton Jelly/cytology ; Spinal Cord/pathology ; Transplantation, Heterologous ; Superoxide Dismutase/genetics/metabolism ; Umbilical Cord/cytology ; Motor Neurons/pathology ; Disease Models, Animal ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive degeneration of motor neurons in the cerebral cortex, brainstem, and spinal cord, eventually leading to paralysis, respiratory failure, and death. Currently, no effective treatment exists for ALS.

METHODS: This study examined the therapeutic potential of human umbilical cord mesenchymal stromal cells (HUMSCs) by transplanting 2 × 10⁶ HUMSCs into the spinal canal of transgenic mice expressing mutant human superoxide dismutase 1 (SOD1) at 8 weeks of age.

RESULTS: Survival analysis showed that the SOD1 group lived up to 171 days, while the SOD1 + HUMSCs group survived up to 199 days, extending lifespan by 17 days on average. Motor function tests, including rotarod performance, grip strength, open field activity, and balance beam tests, demonstrated that while the SOD1 group experienced progressive decline, the SOD1 + HUMSCs group showed improvement. Electrophysiological assessments at 20 weeks of age revealed weak muscle action potential in the SOD1 group, whereas the SOD1 + HUMSCs group exhibited noticeable improvements. Histological analysis indicated significant spinal cord atrophy in the SOD1 group, while HUMSCs transplantation mitigated this degeneration. Moreover, HUMSCs reduced blood-spinal cord barrier leakage and T lymphocyte infiltration, alleviating inflammation. The number and size of activated microglia and astrocytes increased in the SOD1 group but were reduced with HUMSCs treatment. Additionally, HUMSCs preserved more motor neurons in the anterior horns.

CONCLUSION: Collectively, transplantation of HUMSCs effectively reduced inflammatory reaction in spinal cord, decreased loss of neurons, ameliorated disease deterioration, and extended life span, suggesting that it could serve as a new direction of ALS treatment to improve patients' quality of life or behavioral function.}, } @article {pmid40697273, year = {2025}, author = {Gomes-Duarte, A and Pascoal, S and Haselberg, R and Sogorb-Gonzalez, M and van Deventer, S}, title = {Targeting oxidized phosphatidylcholines in SOD1-associated ALS: therapeutic potential of PC-OxPL-VecTab[®].}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1620181}, pmid = {40697273}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration. Mutations in the superoxide dismutase 1 (SOD1) gene account for a significant fraction of familial ALS (fALS) cases. Oxidative stress and oxidized phosphatidylcholines (PC-OxPL) contribute to neuroinflammation and neuronal damage, and to motor neuron degeneration in ALS. We previously demonstrated the therapeutic efficacy of an AAV-delivered anti-PC-OxPL single-chain variable fragment (PC-OxPL-VecTab[®]) in neutralizing PC-OxPL toxicity in the periphery and central nervous system (CNS), but the therapeutic potential of PC-OxPL-VecTab[®] has not been investigated in the context of fALS and SOD1-associated ALS. We report that PC-OxPL accumulation contributes to the pathological phenotypes associated with SOD1[G93A] iPSC-derived motor neurons and the corresponding mouse model. The current findings further demonstrate that PC-OxPL-VecTab[®] is efficacious in neutralizing the downstream effects of SOD1-associated PC-OxPL accumulation, such as altered gene expression and axonal health in SOD1 motor neurons, as well as a pathological lipid profile in the SOD1[G93A] mouse model. Collectively, the present study underscores the significance of PC-OxPL dysfunction in the context of SOD1 genotypes and sheds light on the potential of PC-OxPL-VecTab® for therapeutically targeting ALS.}, } @article {pmid40698100, year = {2025}, author = {Singh, D and Singhal, S and Kanaujiya, V and Ranjan, A and Mani, VE and Paliwal, VK and Jain, V and Aishwarya, A and Agarwal, R}, title = {Ganglion Cell Layer Thickness as a Biomarker for Amyotrophic Lateral Sclerosis Functional Outcome: An OCT study.}, journal = {Romanian journal of ophthalmology}, volume = {69}, number = {2}, pages = {200-207}, pmid = {40698100}, issn = {2501-2533}, mesh = {Humans ; *Tomography, Optical Coherence/methods ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; *Retinal Ganglion Cells/pathology ; *Visual Acuity/physiology ; *Nerve Fibers/pathology ; Adult ; *Optic Disk/pathology ; Aged ; Intraocular Pressure/physiology ; Biomarkers ; }, abstract = {AIM: This study aims to evaluate various optical coherence tomography (OCT) parameters in patients diagnosed with amyotrophic lateral sclerosis (ALS).

METHODS: Assessment of BCVA was done using Snellen charts, and subjective refraction was done to achieve a BCVA for distance and near. Measurement of intraocular pressure (IOP) was done with Goldman applanation tonometry. Stereoscopic fundus examination was performed using a 90D lens to assess the status of the optic nerve and retina, ruling out any ocular pathology. The patients were then subjected to OCT scanning to measure optic nerve head and macular parameters. Optical coherence tomography was performed using CIRRUS™ HD OCT (500-21822) (version 8.0.0.518) (Carl Zeiss Meditec, Dublin, CA, USA). The analyzed area was centered manually, and the absence of segmentation errors was confirmed for each scan.

RESULTS: RE Avg RNFL and LE Avg RNFL showed weak correlations with ALSFRS, indicated by Pearson Correlation coefficients of 0.073 and -0.026, respectively. The p-values (0.637 and 0.86) suggested that these correlations were not statistically significant. RE Avg GCL and LE Avg GCL, on the other hand, exhibited moderate positive correlations with ALSFRS scores, with correlation coefficients of 0.337 (RE) and 0.389 (LE). These correlations were statistically significant, as indicated by p-values of 0.021 and 0.006, respectively, suggesting a substantial association between GCL thickness and ALS functional outcomes.

DISCUSSION: All patients in our study were clinically diagnosed cases of ALS, as per the El Escorial criteria. Age group-wise analysis showed statistically significant thinning overall as well as quadrant-wise RNFL parameters in patients less than 50 years compared to age-matched controls, indicating that the pathological process occurring in larger motor neurons in ALS might also be happening in smaller sensory neurons of the retina, causing thinning, which was not due to age-related process. Although GCIPL thinning was occurring in our cases, though statistically not significant compared to control, the significant positive correlation observed between GCIPL and ALS functional outcome and between RNFL and GCIPL measurements highlighted the fact that though the axonal degeneration in retinal neurons might not be translating to the same extent in ganglion cells in ALS, the subtle thinning of GCIPL correlated strongly with functional disability in patients with ALS, implying better functional scores with higher values of GCIPL parameters.

CONCLUSION: In summary, GCL measurements in both eyes showed a notable relationship with ALSFRS, whereas RNFL did not appear to correlate significantly.}, } @article {pmid40699658, year = {2025}, author = {Brezic, N and Gligorevic, S and Sic, A and Knezevic, NN}, title = {Protein Misfolding and Aggregation as a Mechanistic Link Between Chronic Pain and Neurodegenerative Diseases.}, journal = {Current issues in molecular biology}, volume = {47}, number = {4}, pages = {}, pmid = {40699658}, issn = {1467-3045}, abstract = {Chronic pain, defined by persistent pain beyond normal healing time, is a pervasive and debilitating condition affecting up to 30-50% of adults globally. In parallel, neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss and cognitive or motor decline, often underpinned by pathological protein misfolding and aggregation. Emerging evidence suggests a potential mechanistic link between chronic pain and NDs, with persistent pain contributing to neuroinflammatory states and protein homeostasis disturbances that mirror processes in neurodegeneration. This review explores the hypothesis that protein misfolding and aggregation serve as a mechanistic bridge between chronic pain and neurodegeneration. We systematically examine molecular pathways of protein misfolding, proteostasis dysfunction in chronic pain, and shared neuroimmune mechanisms, highlighting prion-like propagation of misfolded proteins, chronic neuroinflammation, and oxidative stress as common denominators. We further discuss evidence from experimental models and clinical studies linking chronic pain to accelerated neurodegenerative pathology-including tau accumulation, amyloid dysregulation, and microglial activation-and consider how these insights open avenues for novel therapeutics. Targeting protein aggregation, enhancing chaperone function, modulating the unfolded protein response (UPR), and attenuating glial activation are explored as potential strategies to mitigate chronic pain and possibly slow neurodegeneration. Understanding this intersection not only elucidates chronic pain's role in cognitive decline but also suggests that interventions addressing proteostasis and inflammation could yield dual benefits in pain management and neurodegenerative disease modification.}, } @article {pmid40699743, year = {2025}, author = {Wang, S and Pan, L and Sun, C and Ma, C and Pan, H}, title = {Balancing Microglial Density and Activation in Central Nervous System Development and Disease.}, journal = {Current issues in molecular biology}, volume = {47}, number = {5}, pages = {}, pmid = {40699743}, issn = {1467-3045}, support = {32260194 to S.Wang, and 82071245 and 82360238 to H.Pan//National Natural Science Foundation of China/ ; 20224BAB206038 to S.Wang, 20224BAB206042 to C.Sun, and 20202ACB215003 and 20232ACB205008 to H.Pan//Natural Science Foundation of Jiangxi Province/ ; }, abstract = {Microglia, the resident immune cells of the central nervous system, play multifaceted roles in both health and disease. During development, they regulate neurogenesis and refine neural circuits through synaptic pruning. In adulthood, microglia maintain homeostasis and dynamically respond to pathological insults, where they contribute to responding to neuroinflammatory challenges. This review summarizes microglial contributions to neurodevelopment and also outlines their function across various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, highlighting both protective and detrimental effects. Finally, recent advances in microglial-targeted therapies and lifestyle-based interventions are highlighted, underscoring the translational potential of modulating microglial states. Elucidating the dual roles of microglia in development and disease could guide the design of therapeutic strategies aimed at enhancing neuroprotection while minimizing neurotoxicity.}, } @article {pmid40699841, year = {2025}, author = {Long, X and Wang, Y and Meng, H}, title = {Dicer Is Involved in Cytotoxicity and Motor Impairment Induced by TBPH Deficiency.}, journal = {Current issues in molecular biology}, volume = {47}, number = {6}, pages = {}, pmid = {40699841}, issn = {1467-3045}, support = {82171414//National Natural Science Foundation of China/ ; 2022SS02//Suzhou Science and Technology Plan Projec/ ; }, abstract = {TDP-43 is an RNA-binding protein linked to amyotrophic lateral sclerosis (ALS), possibly associated with a role in miRNA biogenesis, which is still not fully understood. Herein we investigated the impact of the Drosophila homolog of TDP-43, TBPH, on genes related to miRNA biogenesis. A TBPH knockout significantly reduced mRNA transcription and protein levels of DCR-1 and DCR-2, whereas an overexpression of DCR-1 and DCR-2 in a TBPH knockdown background exacerbated compound eye damage, with variations in severity that were sex-dependent. Neuronal TBPH RNAi consistently shortened lifespan, with males and females exhibiting distinct survival profiles. DCR-1 and DCR-2 knockdown worsened the locomotor defects induced by TBPH deficiency, thus reinforcing the functional link between TBPH and DCR. In TBPH-deficient flies, the pharmacological activation of Dicer promoted reverse locomotion behavior, with a preference for backward movement. Overall, we show that TBPH is a key regulator of DCR protein expression, highlighting its conserved role in miRNA dysregulation associated with motor function and cytotoxicity in ALS-like pathology in Drosophila models.}, } @article {pmid40699852, year = {2025}, author = {Takahashi, A and Miyagishi, H and Tsuruta, K and Nango, H and Hirose, D and Aono, Y and Tanigawa, M and Nishimura, K and Saito, M and Kawato, T and Saigusa, T and Kosuge, Y}, title = {Miyako Bidens pilosa Extract Ameliorates Allodynia and Suppresses Spinal Microglial Activation in Mice with Partial Sciatic Nerve Ligation.}, journal = {Current issues in molecular biology}, volume = {47}, number = {6}, pages = {}, pmid = {40699852}, issn = {1467-3045}, support = {2024-2025//Tsuchiya Cultural Foundation/ ; #22Dokusen11//a Nihon University Research Grant/ ; 2024//a grant to encourage and promote research projects at the School of Pharmacy, Nihon University/ ; 24K14758//Japan Society for the Promotion of Science/ ; }, abstract = {Neuropathic pain, characterized by chronic allodynia, remains difficult to manage with current pharmacotherapies. Microglial activation plays a pivotal role in the development and maintenance of neuropathic pain and represents a promising therapeutic target. We previously demonstrated that Miyako Bidens pilosa extract powder (MBP), derived from Miyako Island, Okinawa, suppresses glial activation in a mouse model of amyotrophic lateral sclerosis. In this study, we investigated the analgesic potential of MBP in a mouse model of neuropathic pain. Neuropathic pain was induced in male ICR mice by partial sciatic nerve ligation (PSNL). Mice were orally administered MBP (2 g/kg) or vehicle daily. Mechanical allodynia was assessed using von Frey filaments. On postoperative day 7, MBP-treated mice exhibited significantly reduced allodynia compared to vehicle-treated mice. MBP also attenuated thermal hyperalgesia on postoperative day 7. Lumbar spinal cords (L5) were subjected to immunohistochemical analysis for ionized calcium-binding adaptor molecule 1 (Iba1), a microglial marker. MBP significantly decreased the number of Iba1-positive microglia in the ipsilateral dorsal horn. These results suggest that MBP alleviates neuropathic pain, at least in part, by suppressing microglial activation in the spinal cord. MBP may represent a novel plant-derived therapeutic candidate for treating neuropathic pain.}, } @article {pmid40700130, year = {2025}, author = {Swindell, WR}, title = {Meta-Analysis of Gene Expression in Bulk-Processed Post-Mortem Spinal Cord from ALS Patients and Normal Controls.}, journal = {NeuroSci}, volume = {6}, number = {3}, pages = {}, pmid = {40700130}, issn = {2673-4087}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron failure and poor prognosis. This study performed a meta-analysis of gene expression datasets that compared bulk-processed post-mortem spinal cord from ALS and control (CTL) patients. The analysis included 569 samples (454 ALS, 115 CTL) from 348 individuals (262 ALS, 86 CTL). Patterns of differential expression bias, related to mRNA abundance, gene length and GC content, were discernable from individual studies but attenuated by meta-analysis. A total of 213 differentially expressed genes (DEGs) were identified (144 ALS-increased, 69 ALS-decreased). ALS-increased DEGs were most highly expressed by microglia and associated with MHC class II, immune response and leukocyte activation. ALS-decreased DEGs were abundantly expressed by mature oligodendrocytes (e.g., the MOL5 phenotype) and associated with myelin production, plasma membrane and sterol metabolism. Comparison to spatial transcriptomics data showed that DEGs were prominently expressed in white matter, with increased DEG expression strongest in the ventral/lateral white matter. These results highlight white matter as the spinal cord region most strongly associated with the shifts in mRNA abundance observed in bulk-processed tissues. These shifts can be explained by attrition of mature oligodendrocytes and an ALS-emergent microglia phenotype that is partly shared among neurodegenerative conditions.}, } @article {pmid40700505, year = {2025}, author = {Huang, WP and Kumar, V and Yap, K and An, H and John, SJ and Hodgson, RE and Avila, AS and Day, E and Ellis, BCS and Chung, TH and Lord, J and Müller-McNicoll, M and Makeyev, EV and Shelkovnikova, TA}, title = {M6A-dependent RNA condensation underlies FUS autoregulation and can be harnessed for ALS therapy development.}, journal = {Science advances}, volume = {11}, number = {30}, pages = {eadx1357}, pmid = {40700505}, issn = {2375-2548}, mesh = {*RNA-Binding Protein FUS/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Humans ; RNA Splicing ; *Adenosine/analogs & derivatives/metabolism ; Introns ; Mutation ; Methylation ; RNA, Messenger/genetics/metabolism ; *RNA/metabolism/genetics ; RNA Splicing Factors ; Nerve Tissue Proteins ; }, abstract = {Mutations in the FUS gene cause aggressive amyotrophic lateral sclerosis (ALS-FUS). Beyond mRNA, FUS generates partially processed transcripts retaining introns 6 and 7. We demonstrate that these FUSint6&7-RNA molecules form nuclear condensates, scaffolded by the highly structured intron 7 and associated with nuclear speckles. Using hybridization-proximity labeling proteomics, we show that the FUSint6&7-RNA condensates are enriched for splicing factors and the N6-methyladenosine (m6A) reader YTHDC1. These ribonucleoprotein structures facilitate posttranscriptional FUS splicing and depend on m6A/YTHDC1 for integrity. In cells expressing mutant FUS, FUSint6&7-RNAs become hypermethylated, which in turn stimulates their condensation and splicing. We further show that FUS protein is repelled by m6A. Thus, ALS-FUS mutations may cause abnormal activation of FUS posttranscriptional splicing through altered RNA methylation. Notably, ectopic expression of FUS intron 7 sequences dissolves endogenous FUSint6&7-RNA condensates, down-regulating FUS mRNA and protein. Our findings reveal a condensation-dependent mechanism regulating FUS splicing, with possible therapeutic implications for ALS.}, } @article {pmid40701662, year = {2026}, author = {Toomey, J and Lewis, J and Hannikainen, IR and Earp, BD}, title = {A qualitative study of true self judgments, epistemic access, and medical decision-making.}, journal = {Journal of medical ethics}, volume = {52}, number = {7}, pages = {453-458}, doi = {10.1136/jme-2025-110957}, pmid = {40701662}, issn = {1473-4257}, mesh = {Humans ; *Judgment ; Female ; Qualitative Research ; *Decision Making ; Male ; Adult ; *Self Concept ; *Clinical Decision-Making ; Middle Aged ; }, abstract = {BACKGROUND: Toomey et al (2024) found that US participants were more likely to follow a medical treatment preference-expressed after substantial cognitive decline-of a third person rather than their own future self. This correlated with a greater tendency to see the third person as still their true self. We hypothesised that the greater epistemic access one has to one's own true self as opposed to others might drive this difference.

METHODS: A codebook designed to capture different kinds of evidence and reasoning was developed, and participants' explanations for their treatment decisions in Toomey et al's study were coded and qualitatively analysed.

RESULTS: In first-person cases, participants were more likely to explain their treatment decision with reference to perceived direct access to their own true self. In contrast, in third-person cases, participants more often relied on proxies or heuristics, such as the presumption that an expressed preference is an authentic one or that preferences expressed with greater cognition tend to better reflect the true self.

CONCLUSIONS: These findings support the hypothesis that differential epistemic access to the true self in first- and third-person cases may drive different medical treatment decisions. Participants may be trying to follow the patient's 'true' or 'authentic' preference in all cases, but relying on different kinds of evidence in so doing.}, } @article {pmid40702249, year = {2025}, author = {Sulthana, N and Mittal, P and Goyal, A and Ballal, S and Maharana, L and Rana, AJ and Khan, Y and Goyal, K and Mishra, R and Ali, H and Gupta, G and Hussain, MS}, title = {Targeting ASK1 signaling in neurodegeneration: molecular insights and therapeutic promise.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {30}, number = {9-10}, pages = {2019-2041}, pmid = {40702249}, issn = {1573-675X}, mesh = {Humans ; *MAP Kinase Kinase Kinase 5/metabolism/genetics/antagonists & inhibitors ; *Neurodegenerative Diseases/genetics/metabolism/drug therapy/pathology ; *Signal Transduction ; Animals ; Apoptosis ; Endoplasmic Reticulum Stress ; Oxidative Stress ; }, abstract = {Apoptosis signal-regulating kinase 1 (ASK1), a redox-sensitive member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, is a master regulator of neuronal apoptosis as well as neuroinflammation in neurodegenerative disorders (NDs). Under oxidative and endoplasmic reticulum stress conditions, ASK1 sets off a series of pathways, ultimately leading to impairment of cellular functions and the cell's demise. The comprehensive review focuses on the diverse contributions of ASK1 to neurodegeneration driven by Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Human and animal evidence links dysregulated ASK1 signaling is related to amyloid deposition, tau hyperphosphorylation, neuroinflammation, abnormal protein folding, and subsequent neurodegeneration. ASK1 plays a role in tau hyperphosphorylation and amyloid-beta-induced neurotoxicity in AD. ASK1-mediated apoptosis of dopaminergic neurons caused by oxidative stress and aggregation of α-synuclein contributes to PD. Furthermore, ASK1 activation is associated with motor neuron degeneration in ALS related to endoplasmic reticulum stress caused by mutant SOD1. Moreover, the pathogenesis of HD involves the activation of ASK1 by the cellular stress caused by mutant huntingtin protein. ASK1 signaling potentiates inflammatory signals in MS because it is involved in demyelination and neuronal injury. Nonetheless, obstacles persist such as developing brain-targeted therapies, reducing adverse systemic effects, and defining disease-stage-specific functions of ASK1. This review aims to comprehensively examine the role of ASK1 signaling in major NDs, discuss its upstream and downstream regulatory mechanisms, and evaluate the current and emerging therapeutic strategies targeting ASK1.}, } @article {pmid40702789, year = {2025}, author = {Zota, I and Calogeropoulou, T and Chanoumidou, K and Charalampopoulos, I and Gravanis, A}, title = {Synthetic microneurotrophins: Neurotrophin receptors for therapeutics of neurodegenerative diseases.}, journal = {British journal of pharmacology}, volume = {182}, number = {19}, pages = {4466-4489}, doi = {10.1111/bph.70143}, pmid = {40702789}, issn = {1476-5381}, support = {Dinnesmin//FP7 Health/ ; //European Regional Development Fund of the European Union and Greek/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Dehydroepiandrosterone/analogs & derivatives/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Receptors, Nerve Growth Factor/metabolism ; Nerve Growth Factors ; Blood-Brain Barrier/metabolism ; }, abstract = {Neurodegenerative disorders are characterised by the chronic progressive degeneration of specific neuronal subtypes, neuroinflammation, myelin damage and synaptic loss. Despite their growing incidence, advancements in effective treatments remain limited, because of lack of knowledge for the aetiology of the diverse pathophysiology to design systematic therapies. Several studies highlight the role of neurotrophic factors (NTFs) as potential neuroprotective, regenerative therapies for these disorders. Although NTFs hold protective and regenerative potential for chronic neuroinflammatory and neurodegenerative conditions, major hurdles impair their clinical use, such as optimising the dosage of NTFs, minimising the invasiveness of delivery methods, overcoming blood-brain-barrier (BBB) impermeability and managing side effects. In the last two decades our group have synthesised and screened a large chemical library of steroidal analogues of dehydroepiandrosterone (DHEA), an endogenous steroid hormone, for their ability to mimic neurotrophin neuroprotective and neurogenic actions. Interestingly, DHEA was shown to interact with all neurotrophin receptors, acting most probably as an ancestral neurotrophin early in evolution. However, its chronic pharmacological use is questioned by its action as a major precursor of steroidogenesis. This review highlights the findings of numerous preclinical studies on these synthetic, non-toxic, BBB permeable DHEA derivatives, named microneurotrophins (MNTs), deprived of endocrine actions, activators of specific neurotrophin receptors. The multimodal actions of MNTs against neuronal death and activation of microglia, in addition to their beneficial effects in synaptogenesis and neurogenesis, place them as interesting lead molecules in the armamentarium of therapeutics for neurodegeneration.}, } @article {pmid40703193, year = {2025}, author = {Govaarts, R and Scheijbeler, EP and Beeldman, E and Fraschini, M and Griffa, A and Engels, MMA and van der Kooi, AJ and Pijnenburg, YAL and de Visser, M and Stam, CJ and Raaphorst, J and Hillebrand, A}, title = {Longitudinal changes in MEG-based brain network topology of ALS patients with cognitive/behavioral impairment-An exploratory study.}, journal = {Network neuroscience (Cambridge, Mass.)}, volume = {9}, number = {3}, pages = {824-841}, pmid = {40703193}, issn = {2472-1751}, abstract = {Amyotrophic lateral sclerosis (ALS) with only motor impairment (ALS-pure motor) and the behavioral variant of frontotemporal dementia (bvFTD) are hypothesized to represent extreme ends of a disease spectrum, which encompasses ALS with cognitive/behavioral impairment (ALSci/bi). In this longitudinal magnetoencephalography (MEG) study, we investigated changes in brain network topology of ALSci/bi over time as compared with ALS-pure motor and bvFTD patients. Resting-state MEG was recorded in ALS-pure motor (n = 9), ALSci/bi (n = 16), and bvFTD (n = 16) at baseline and 5-month follow-up, projected to source space. The corrected version of the amplitude envelope correlation was applied to compute frequency-band-specific functional connectivity between brain regions, from which the backbone of the functional networks was constructed using the minimum spanning tree (MST) approach. Reference MSTs were computed based on the functional connectivity matrices for ALS-pure motor and bvFTD, against which the networks of ALSci/bi were compared. We showed that, at baseline, networks in the theta band of ALSci/bi patients were more similar to ALS-pure motor than bvFTD. At follow-up, ALSci/bi patients' beta-band network similarity had moved away from ALS-pure motor and resembled bvFTD. In conclusion, our findings suggest that brain networks of ALSci/bi patients move along the ALS-bvFTD spectrum over time, from ALS-pure motor to bvFTD-like topology.}, } @article {pmid40703981, year = {2025}, author = {Yang, C and Feng, T and Hu, F}, title = {Progranulin deficiency does not exacerbate TDP-43 pathology in TDP-43 transgenic mouse models.}, journal = {NPJ dementia}, volume = {1}, number = {1}, pages = {16}, pmid = {40703981}, issn = {3005-1940}, support = {R01 NS095954/NS/NINDS NIH HHS/United States ; R21 AG078741/AG/NIA NIH HHS/United States ; }, abstract = {The progranulin (PGRN) protein is tightly linked with TDP-43 proteinopathy in neurodegenerative diseases. However, how PGRN regulates TDP-43 proteinopathy remains unclear. In this study, we investigated the effect of PGRN loss on TDP-43 pathology in the TDP-43[Q331K] knock-in mice expressing an ALS-linked TDP-43 mutation at the endogenous level, and in the transgenic mice overexpressing human TDP-43 in neurons. We found that PGRN deficiency leads to mild glial activation and behavioral deficits in TDP-43[Q331K] mice without inducing typical TDP-43 pathology. RNA-seq analysis reveals upregulation of immune pathways and downregulation of myelination-related pathways in PGRN-deficient TDP-43[Q331K] mice. In addition, we observed myelination defects in human TDP-43 transgenic mice, but PGRN loss does not exacerbate TDP-43 pathology, myelination defects, and motor deficits in this mouse strain. Our studies demonstrated that PGRN deficiency exacerbates behavioral deficits and glial pathology caused by TDP-43 Q331K mutation but has minimal effect on TDP-43 pathology in mouse models.}, } @article {pmid40704616, year = {2026}, author = {Young, CA and Chaouch, A and Mcdermott, CJ and Al-Chalabi, A and Chhetri, SK and Bidder, C and Ellis, C and Annadale, J and Mills, RJ and Tennant, A and , }, title = {Fatigue in amyotrophic lateral sclerosis/motor neuron disease: prevalence, influences and trajectories.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {78-89}, doi = {10.1080/21678421.2025.2533881}, pmid = {40704616}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; Male ; Female ; *Fatigue/epidemiology/etiology/diagnosis ; Middle Aged ; Aged ; *Amyotrophic Lateral Sclerosis/epidemiology/complications ; Prevalence ; Adult ; Aged, 80 and over ; Young Adult ; Cohort Studies ; }, abstract = {Objective: In a large cohort of people with amyotrophic lateral sclerosis/motor neuron disease (pwALS), we examined the age-sex prevalence of fatigue, its relationship to other symptoms and functioning, and trajectories over time. Methods: Data from the Trajectories of Outcome in Neurological Conditions study were analyzed by Rasch analysis, structural equation and group-based trajectory models. Results: Fatigue was reported by 97.8% on Neurological Fatigue Index-MND (NFI-MND) and 96.4% on Numeric Rating Scale Fatigue among 1058 pwALS: mean age 65 (range 20-90); mean duration 23 months (range 0-301); 60.7% male; onset 26.5% Bulbar, 71.5% Limb and 2.0% Respiratory. Mean (metric) level on NFI-MND was 12.8 (SD 5.3; range 0-24). Cut-points on the NFI-MND of 10 and 15 divided fatigue into mild (27.3%); moderate (36.1%) and severe (36.2%). Structural equation modeling showed that function, cognition, spasticity, dyspnea and pain have descending order of effect. Over average 11.6 months follow-up, 60.5% had stable fatigue, 23.8% increased fatigue level, while 15.8% showed declining fatigue. Trajectory analysis showed three groups, low, average and high fatigue. Those with low trajectories had less spasticity, worry, cognitive problems, as well as better functioning, longer duration and were less likely to be male. High fatigue trajectory was associated with worse spasticity, cognition and anxiety. Conclusions: Fatigue is extremely common among pwALS, thus more work is required on fatigue management. In addition to treating fatigue itself, the current study shows that targeting cognition, spasticity, dyspnea and pain might be fruitful.}, } @article {pmid40704719, year = {2026}, author = {Rafiei, F and Jadidi, K and Nejat, F and Khabazkhoob, M and Nabovati, P}, title = {Ophthalmic Quality of Life and Its Association With Visual Function, Accommodative and Binocular Vision Performance in Keratoconus Patients: A Study Using Rasch Analysis‏.}, journal = {Cornea}, volume = {45}, number = {7}, pages = {851-859}, doi = {10.1097/ICO.0000000000003935}, pmid = {40704719}, issn = {1536-4798}, mesh = {Humans ; *Quality of Life/psychology ; *Keratoconus/physiopathology/psychology ; Male ; Adult ; Female ; *Visual Acuity/physiology ; *Vision, Binocular/physiology ; *Accommodation, Ocular/physiology ; Surveys and Questionnaires ; Young Adult ; Psychometrics ; Adolescent ; Contrast Sensitivity/physiology ; }, abstract = {PURPOSE: To investigate the relationship between ophthalmic quality of life with visual function and accommodative/binocular vision performance in patients with keratoconus (KCN), using the Keratoconus Outcomes Research Questionnaire (KORQ).

METHODS: Seventy patients with KCN were recruited in this study (average age: 27.04 ± 5.60). A Persian adaptation of the KORQ was developed, and its psychometric properties were evaluated through Rasch analysis. The associations between study variables and the KORQ subscales, activity limitations (AL-S) and symptoms (S-S), were evaluated through linear regression models.

RESULTS: The Persian KORQ demonstrated good psychometric properties after removing items 5 and 8 from the AL-S and items 4 and 5 from the S-S. The analysis showed a statistically significant direct association between the AL-S score and age (β: 0.280, P < 0.05). In addition, there was a statistically significant direct relationship between the AL-S score with best-corrected visual acuity in the better eye (β: 0.279, P = 0.048), binocular contrast sensitivity (β: 0.319, P = 0.033), and steep keratometry in the better eye (β: 0.409, p-0.007). The near negative fusional vergence parameters-blur (β: -0.460, P = 0.012), break (β: -0.403, P = 0.027), and recovery (β: -0.391, P = 0.033)-showed a statistically significant inverse association with the S-S score.

CONCLUSIONS: The Persian KORQ is a reliable tool for assessing ophthalmic quality of life in Persian-speaking patients with KCN. The KCN-related AL-S are primarily influenced by age, basic visual functions, and the severity of KCN in the better eye. Deficits in certain binocular vision metrics, particularly a diminished near negative fusional vergence amplitude, may contribute to the symptoms reported by patients with KCN.}, } @article {pmid40704991, year = {2025}, author = {Ganssauge, J and Hawkins, S and Namboori, SC and Leung, SK and Mill, J and Bhinge, A}, title = {Rapid and inducible mislocalization of endogenous TDP43 in a novel human model of amyotrophic lateral sclerosis.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {40704991}, issn = {2050-084X}, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism/pathology ; Cytoplasm/metabolism ; Cell Nucleus/metabolism ; Protein Transport ; }, abstract = {Transactive response DNA binding protein 43 kDa (TDP43) proteinopathy, characterized by the mislocalization and aggregation of TDP43, is a hallmark of several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). In this study, we describe the development of a new model of TDP43 proteinopathy using human induced pluripotent stem cell (iPSC)-derived neurons. Utilizing a genome engineering approach, we induced the mislocalization of endogenous TDP43 from the nucleus to the cytoplasm without mutating the TDP43 gene or using chemical stressors. Our model successfully recapitulates key early and late pathological features of TDP43 proteinopathy, including neuronal loss, reduced neurite complexity, and cytoplasmic accumulation and aggregation of TDP43. Concurrently, the loss of nuclear TDP43 leads to splicing defects, while its cytoplasmic gain adversely affects microRNA expression. Strikingly, our observations suggest that TDP43 is capable of sustaining its own mislocalization, thereby perpetuating and further aggravating the proteinopathy. This innovative model provides a valuable tool for the in-depth investigation of the consequences of TDP43 proteinopathy. It offers a clinically relevant platform that will accelerate the identification of potential therapeutic targets for the treatment of TDP43-associated neurodegenerative diseases, including sporadic ALS.}, } @article {pmid40705135, year = {2025}, author = {Jung, HJ and Jeong, WS and Kang, HW and Kang, M and Lee, EJ and Lim, YM and Park, JS and Kim, H}, title = {Serum GFAP predicts survival in advanced ALS: a prospective multicenter study.}, journal = {Journal of neurology}, volume = {272}, number = {8}, pages = {532}, pmid = {40705135}, issn = {1432-1459}, support = {RS-2023-00211443//Ministry of Science and ICT, Republic of Korea/ ; 2023IP0108//Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea/ ; 25-BR-04-01//KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT, Republic of Korea/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality/diagnosis ; *Glial Fibrillary Acidic Protein/blood ; Male ; Female ; Middle Aged ; *Neurofilament Proteins/blood ; Aged ; *Brain-Derived Neurotrophic Factor/blood ; Biomarkers/blood ; Prospective Studies ; Disease Progression ; Adult ; Prognosis ; ROC Curve ; }, abstract = {BACKGROUND: Neurofilament light chain (NfL) is a well-established biomarker of axonal damage in amyotrophic lateral sclerosis (ALS), but its limited disease specificity warrants the identification of complementary markers. This study aimed to evaluate the prognostic value of serum glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor (BDNF) as adjunctive biomarkers to NfL in ALS.

METHODS: Serum NfL, GFAP, and BDNF levels were measured using ultrasensitive single-molecule array (SIMOA) assays in two independent ALS cohorts from Asan Medical Center (n = 65) and Kyungpook National University Chilgok Hospital (n = 53), along with 15 healthy controls. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. Associations with clinical severity, disease progression rate, and survival were evaluated using correlation analyses, Kaplan-Meier survival estimates, and Cox proportional hazards models.

RESULTS: Serum NfL, GFAP, and BDNF levels were significantly elevated in ALS versus controls, with area under the curve (AUC) values of 0.969, 0.613, and 0.875, for NfL, GFAP, and BDNF, respectively. NfL and GFAP levels increased with advancing King's stage (NfL: τ = 0.226, p = 0.011; GFAP: τ = 0.160, p = 0.023), though only NfL correlated with disease progression rate (r = 0.309, p = 0.001). Notably, elevated GFAP was independently associated with poorer survival in advanced ALS (King's stage 3-4), with a hazard ratio of 6.907 (95% CI: 1.978-24.119, p = 0.002).

CONCLUSIONS: While NfL remains a robust marker of ALS progression, GFAP may serve as an independent prognostic marker in late-stage disease. Combining these markers may enhance prognostic accuracy and support personalized ALS care.

Neurofilament light chain (NfL) is a widely accepted biomarker for axonal damage in ALS and correlates with disease progression. However, its lack of disease specificity limits its standalone prognostic value, necessitating the discovery of complementary biomarkers to improve prognostic accuracy.

WHAT THIS STUDY ADDS: This study demonstrates that while NfL remains a strong indicator of ALS progression, glial fibrillary acidic protein (GFAP) serves as an independent prognostic marker, particularly in advanced stages of the disease. Furthermore, it shows that serum BDNF levels are also elevated in ALS patients.

Combining NfL and GFAP as a biomarker panel could significantly enhance prognostic accuracy and facilitate more personalized treatment strategies for ALS patients, especially in later disease stages. This could guide clinical trial design and improve patient stratification for therapeutic interventions.}, } @article {pmid40706449, year = {2025}, author = {Sluyts, Y and Van Schil, K and Deconinck, T and Oedit, R and Baets, J and De Ridder, W}, title = {TBK1-associated motor neuron disease with concomitant vacuolar myopathy: a case resembling a multisystem proteinopathy.}, journal = {Neuromuscular disorders : NMD}, volume = {53}, number = {}, pages = {105445}, doi = {10.1016/j.nmd.2025.105445}, pmid = {40706449}, issn = {1873-2364}, mesh = {Humans ; Aged ; *Protein Serine-Threonine Kinases/genetics ; *Muscular Diseases/genetics/complications/pathology/physiopathology/diagnosis ; Male ; *Amyotrophic Lateral Sclerosis/genetics/complications/pathology ; *Motor Neuron Disease/genetics/complications/pathology ; *Lysosomal Storage Diseases/genetics/complications/pathology/physiopathology ; Muscle, Skeletal/pathology ; Mutation ; Phenotype ; }, abstract = {We present a 75-year-old patient with an amyotrophic lateral sclerosis (ALS)-myopathy overlap phenotype and a pathogenic variant in TBK1. The ALS-myopathy overlap phenotype was extensively documented clinically, with mixed myopathic and neurogenic findings on needle EMG, muscle MRI and muscle biopsies, with presence of rimmed vacuoles immunoreactive for P62 in particular. A concomitant presentation of motor neuron disease (MND) and myopathy is most notably associated with a very rare, inherited group of diseases, known as multisystem proteinopathies (MSPs). An increasing number of genes have already been linked to an MSP phenotype, of which VCP-related MSP is the most frequent. In this report we expand the spectrum of clinical presentations of TBK1-associated disease and describe pathophysiological similarities between TBK1- and VCP-related disease.}, } @article {pmid40706681, year = {2025}, author = {Murat de Montai, Q and Perray, L and Mathian, A and Dorgham, K and Gorochov, G and Charre, C and Chasset, F}, title = {Invited Reply to Chen et al's ''Response to Quitterie Murat de Montai et al, 'Interferon-α biological activity is associated with disease activity and risk of flare in cutaneous lupus erythematosus: A monocentric study of 184 patients'".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {6}, pages = {e207-e209}, doi = {10.1016/j.jaad.2025.07.041}, pmid = {40706681}, issn = {1097-6787}, } @article {pmid40706981, year = {2025}, author = {Saenz-Martinez, E and Collia, M and Rodriguez-Garraus, A and Gil, AG and Lopez de Cerain, A and Azqueta, A}, title = {Evaluation of potassium bromate as a positive control in the in vivo Fpg-modified comet assay for the detection of oxidised bases.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {205}, number = {}, pages = {115663}, doi = {10.1016/j.fct.2025.115663}, pmid = {40706981}, issn = {1873-6351}, mesh = {Animals ; *Bromates/toxicity ; *Comet Assay/methods ; *DNA Damage/drug effects ; Rats, Wistar ; Rats ; Male ; *DNA-Formamidopyrimidine Glycosylase/metabolism ; Oxidation-Reduction ; Liver/drug effects ; }, abstract = {The in vivo comet assay is validated for genotoxicity testing and included in ICH, ECHA, and EFSA strategies. However, OECD test guideline (TG) 489 In vivo Mammalian Alkaline Comet Assay covers only the standard version, detecting DNA strand breaks (SB) and alkali-labile sites (ALS), limiting mechanistic insights. Inclusion of the enzyme formamidopyrimidine DNA glycosylase (Fpg) allows detection of oxidised bases; 52 studies using enzymes to reveal DNA lesions undetectable with the standard comet assay were identified (Collins et al., 2020). Despite its frequent use, fewer than one-third of studies employing enzymes include positive controls, which would aid standardization and OECD TG 489 integration. The present study evaluates potassium bromate (KBrO3) as a potential positive control for the Fpg-modified comet assay. Wistar rats were dosed twice by oral gavage with different doses of KBrO3 following OECD TG 489 principles, with DNA damage assessed in liver, duodenum, kidney, brain, and whole blood. Ethyl methanesulfonate (EMS) was used as a positive control for the standard version. The inclusion of Fpg digestion enhances assay sensitivity and specificity, and DNA oxidation damage induced by KBrO3 is detected in kidney, liver, and duodenum within 3 h, indicating that it may be a good positive control.}, } @article {pmid40707187, year = {2025}, author = {Kikuchi, R and Ishihara, K and Shiota, J and Kawamura, M and Yoshida, M}, title = {[An autopsy case of spinal bulbar muscular atrophy concomitant with multiple system atrophy pathology].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {65}, number = {8}, pages = {588-594}, doi = {10.5692/clinicalneurol.cn-002087}, pmid = {40707187}, issn = {1882-0654}, mesh = {Aged ; Humans ; Male ; Autopsy ; *Multiple System Atrophy/pathology/complications ; }, abstract = {We describe an autopsy case of spinal bulbar muscular atrophy (SBMA) concomitant with multiple system atrophy (MSA). A Japanese male patient developed gait disturbance in his twenties. His brother and niece also presented with similar clinical symptoms. His condition gradually worsened, and he became immobile at the age of 50 years. Genetic analysis revealed the expansion of CAG repeats of the SBMA gene. At 63 years of age, cerebellar ataxia symptoms emerged. Magnetic resonance images of the head showed a "hot cross bun sign" at the pontine basis and bilateral atrophy of the middle cerebellar peduncles and cerebellar hemispheres, suggesting MSA. He died of pneumonia at the age of 65 years, with a clinical illness of approximately 40 years. The neuropathological diagnosis was consistent with both SBMA and MSA. Neurons of the spinal anterior horn and brainstem motor nuclei were diminished. 1C2 (polyglutamine) immunoreactive intranuclear and intracytoplasmic inclusions were observed in the neurons in the substantia nigra, brainstem tegmentum, pontine nuclei, spinal anterior horn cells and Onuf's nucleus. These findings were suggestive of SBMA. Meanwhile, neurons of the inferior olivary nuclei, pontine nuclei, and Purkinje cells were nearly completely lost. The cerebellar white matter, pontine basis, and middle cerebellar peduncles showed a prominent loss of fibers. α-synuclein positive glial cytoplasmic inclusions were observed in widespread areas. These findings were suggestive of MSA. To the best of our knowledge, another case of SBMA accompanying MSA, similar to the present case, have been reported to date. Moreover, several cases of pathologically proven amyotrophic lateral sclerosis and MSA have been reported. The development of molecular biological techniques and accumulation of pathologically diagnosed patients may reveal common pathological mechanisms in SBMA and MSA.}, } @article {pmid40707625, year = {2025}, author = {Watanabe, Y and Suzuki, N and Nakagawa, T and Hosogane, M and Akiyama, T and Kageyama, N and Funayama, Y and Warita, H and Morimoto, S and Okano, H and Aoki, M and Nakayama, K}, title = {ALS-associated RNA-binding proteins promote UNC13A transcription through REST downregulation.}, journal = {The EMBO journal}, volume = {44}, number = {17}, pages = {4745-4771}, pmid = {40707625}, issn = {1460-2075}, support = {22K15702//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 21K07411//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23H02821//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 21H02458//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 24K02300//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP21H05278//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP22K15736//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP23bm1123046//Japan Agency for Medical Research and Development (AMED)/ ; JP23kk0305024//Japan Agency for Medical Research and Development (AMED)/ ; JP21wm0425009//Japan Agency for Medical Research and Development (AMED)/ ; JP23bm1423002//Japan Agency for Medical Research and Development (AMED)/ ; JP24ek0109631//Japan Agency for Medical Research and Development (AMED)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *RNA-Binding Proteins/metabolism/genetics ; *Repressor Proteins/genetics/metabolism ; *Nerve Tissue Proteins/genetics/metabolism ; Down-Regulation ; *RNA-Binding Protein FUS/metabolism/genetics ; Motor Neurons/metabolism/pathology ; Heterogeneous Nuclear Ribonucleoprotein A1/metabolism/genetics ; DNA-Binding Proteins/metabolism/genetics ; *Transcription, Genetic ; HEK293 Cells ; Nuclear Matrix-Associated Proteins ; RE1-Silencing Transcription Factor ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective loss of motor neurons. Although multiple pathophysiological mechanisms have been identified, no comprehensive understanding of these heterogeneous processes has been achieved. The ALS-associated RNA-binding protein (RBP) TDP-43 has previously been shown to stabilize UNC13A mRNA by preventing cryptic exon inclusion. Here, we show that the ALS-associated RBPs MATR3, FUS, and hnRNPA1 regulate UNC13A expression by targeting the transcriptional repressor REST. These RBPs bind to and downregulate REST mRNA to promote UNC13A transcription. Loss of any of these RBPs in cultured cells or in iPSC-derived motor neurons carrying the ALS-causing FUS P525L mutation leads to REST overexpression, and the same is observed in motor neurons of individuals with familial or sporadic ALS. The functional convergence of four RBPs on the regulation of UNC13A expression underscores the important role of this process for synaptic integrity, and its association with ALS pathogenesis could be relevant for the development of new therapeutic agents.}, } @article {pmid40707812, year = {2025}, author = {Akbari Lakeh, M and Bootsma, S and van Nellestijn, R and Tinnevelt, GH and Jansen, JJ}, title = {An end-to-end data analysis framework for real-time detection and source identification of pollution events via e-nose networks.}, journal = {Analytical and bioanalytical chemistry}, volume = {417}, number = {25}, pages = {5771-5783}, pmid = {40707812}, issn = {1618-2650}, support = {TKITOETKI2020_EBI//TKI E&I/ ; }, abstract = {Ambient air pollution contributes to an estimated 4.2 million premature deaths worldwide each year, underscoring the imperative for advanced air quality management tools. In heavily industrialized regions, diffuse fugitive leaks and concentrated stack emissions threaten public health and ecosystems, making real-time monitoring and accurate source apportionment indispensable. To address these challenges, we introduce an end-to-end data analysis framework that employs a distributed network of low-cost electronic noses (e-noses) to deliver spatially and temporally resolved emission monitoring. The real-time, high-resolution outputs of e-noses are deconvoluted into discrete emission events using a chemometric pipeline including principal component analysis (PCA), hierarchical cluster analysis (HCA), and multivariate curve resolution-alternating least squares (MCR-ALS). Each event is then characterized within a 5W attribution schema, which identifies what anomaly was detected, when, and where it occurred, why it arose, and who is responsible for mitigation, thereby creating a searchable database of pollution incidents. By combining real-time, low-cost sensing with robust multivariate analysis and stakeholder-centered reporting, this framework enables transparent emission accountability. In turn, it supports rapid mitigation responses and strengthens regulatory compliance in complex industrial regions.}, } @article {pmid40708508, year = {2026}, author = {Rana, A and Malviya, R and Rajput, S and Sridhar, SB and Wadhwa, T}, title = {Trends in Nanoparticle-based Strategies for the Management of Neuroinflammation.}, journal = {CNS & neurological disorders drug targets}, volume = {25}, number = {1}, pages = {39-55}, pmid = {40708508}, issn = {1996-3181}, mesh = {Humans ; *Neuroinflammatory Diseases/drug therapy ; Animals ; *Nanoparticles/therapeutic use ; *Drug Delivery Systems/methods ; *Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/drug effects ; Microglia/drug effects ; }, abstract = {Neuroinflammation, characterised by an overactive immune system in the brain and spinal cord, has now been tied to several neurodegenerative diseases. Here, immune cells invade into the brain, activating astrocytes and microglia. Neuroinflammation is a common symptom of many neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This inflammatory reaction occurs within the central nervous system (CNS). Neurological dysfunction results from the inflammatory response, which arises in reaction to any kind of brain injury. Regulating neuroinflammation can be useful for controlling brain disorders associated with neuroinflammation. Several targeted drug delivery systems attempt to treat neuroinflammation caused by neurodegenerative illnesses or brain tumours by targeting the microglia and other immune cells in the central nervous system. Therefore, biodegradable and biocompatible NPs (nanoparticles) could be developed as a treatment for neurodegenerative diseases caused by neuroinflammation or as a less invasive means of transporting other drugs across the blood-brain barrier. Numerous applications of gold nanoparticles (AuNPs) in the treatment of neurological diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are studied in this article. To prevent neuroinflammation and microglia over-activation, some NPs have recently been found to be effective anti-inflammatory medication carriers that cross the blood-brain barrier.}, } @article {pmid40709087, year = {2025}, author = {Wang, G and Zhou, X and Pang, X and Ma, K and Li, L and Song, Y and Hou, D and Wang, X}, title = {Pharmacological effects, molecular mechanisms and strategies to improve bioavailability of curcumin in the treatment of neurodegenerative diseases.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1625821}, pmid = {40709087}, issn = {1663-9812}, abstract = {With the global population aging, the incidence of neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, has been progressively increasing. However, effective therapeutic strategies and clinical drugs for these disorders remain scarce. Curcumin, a natural polyphenolic compound primarily derived from the herbaceous plant Curcuma longa L., has been proposed as a promising candidate for ND treatment based on the excellent antioxidant, anti-inflammatory and neuroprotective properties. Its pharmacological activities encompass scavenging reactive oxygen species, mitigating toxic protein aggregation and cytotoxicity, repairing mitochondrial dysfunction, and inhibiting excessive neuronal apoptosis. Compared with synthetic drugs, curcumin demonstrates a more favorable safety profile with fewer side effects. Nevertheless, its clinical application is substantially hindered by poor bioavailability, which stems from low aqueous solubility, inefficient intestinal absorption, and rapid metabolism and systemic elimination. Conventional administration methods often fail to achieve effective concentrations in vivo. Further clinical trials are also required to validate the therapeutic efficacy and potential adverse effects in human subjects. This article systematically reviews the pathogenesis of NDs and the knowledge on curcumin including pharmacological effects, neuroprotective mechanisms, functions across specific NDs and advanced strategies to enhance the bioavailability, with the aim of promoting the development and clinical translation of curcumin-based therapeutics for NDs.}, } @article {pmid40709254, year = {2025}, author = {Dokholyan, N and Hnath, B and Dokholyan, R and Simmons, Z}, title = {Trimeric superoxide dismutase 1 antibody as a universal biomarker for ALS.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40709254}, issn = {2693-5015}, support = {R35 GM134864/GM/NIGMS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to the loss of motor neurons, resulting in paralysis and death. Currently, there are no specific biomarkers available for diagnosing ALS. As a result, diagnosis currently relies on excluding other conditions, which forces patients to endure months or even years of uncertainty. The absence of a specific, reliable diagnostic tool has hindered both early intervention and therapeutic progress. Here we develop a novel synthetic antibody that can detect a toxic form of a known protein linked to ALS. This trimeric assembly of superoxide dismutase 1 (SOD1) is a soluble, structurally distinct oligomer that is highly toxic in cell models. The antibody selectively binds this trimer and differentiates individuals with the disease from healthy people and from those with other neurodegenerative diseases (Alzheimer's and Parkinson's disease). This breakthrough provides the first disease-specific diagnostic tool for this condition and reveals a shared pathological signature across patients, even in cases without genetic mutations. After decades without a specific diagnostic tool, this antibody signifies a long-awaited breakthrough, finally offering clinicians and researchers a reliable window into ALS pathology.}, } @article {pmid40709577, year = {2025}, author = {Dukic, S and van Veenhuijzen, K and Westeneng, HJ and McMackin, R and van Eijk, RPA and Sleutjes, BTHM and Nasseroleslami, B and Hardiman, O and van den Berg, LH}, title = {Altered EEG Response of the Parietal Network in Asymptomatic C9orf72 Carriers.}, journal = {Human brain mapping}, volume = {46}, number = {11}, pages = {e70275}, pmid = {40709577}, issn = {1097-0193}, support = {AV2022-0004//Stichting ALS Nederland/ ; AV2022-0005//Stichting ALS Nederland/ ; 23-PPG-674-1//The ALS Association/ALS Finding A Cure/ ; }, mesh = {Humans ; Male ; Female ; *C9orf72 Protein/genetics ; Electroencephalography ; Middle Aged ; Adult ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics ; *Parietal Lobe/physiopathology ; Aged ; Heterozygote ; *Nerve Net/physiopathology ; Reaction Time/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron degeneration. Around 10% of cases have a genetic basis, with the C9orf72 hexanucleotide repeat expansion being the most common cause in individuals of European ancestry. Detecting early alterations in at-risk individuals could aid in identifying biomarkers for timely diagnosis and intervention. In this study, we investigated electrophysiological changes in asymptomatic C9orf72 mutation carriers using EEG, focusing on cognitive and motor networks, as these individuals are at risk of developing impairments in both domains. This study included 87 asymptomatic family members (AFM) of patients with familial C9orf72 ALS, comprising 37 individuals carrying the pathological repeat expansion (C9+) and 50 without it (C9-). High-density EEG was recorded during the sustained attention to response task (SART), which is a Go/NoGo paradigm that engages the frontoparietal and motor networks. Task performance was recorded and six behavioral measures were extracted: NoGo accuracy, Go accuracy, total accuracy, anticipation error, average response time, and response time variability. Analyses were conducted on EEG data in both sensor- and source-space, using stimulus- and response-locked data. The stimulus-locked Go and NoGo data were analysed within two time windows: 180-350 ms (N2) and 300-600 ms (P3), while response-locked Go data were analysed within a -100 to 100 ms time window. Linear mixed models were used to quantify differences between groups, incorporating familial pedigree to control for between-subject dependencies. While the two groups did not significantly differ in any SART performance measures, EEG analyses revealed differences. During the stimulus-locked N2, significant differences were observed in sensor-space, primarily in central electrodes during both NoGo and Go conditions, with C9+ AFM exhibiting an increased negative potential. Source analysis confirmed these findings and localized the increased activity in the bilateral precuneus and superior parietal regions. Further analysis of the response-locked data supported the involvement of the same posterior regions. No significant relationships were found between these EEG observations and SART performance. These findings provide the first evidence of EEG changes in AFM carrying the C9orf72 repeat expansion. The observed functional changes in the parietal regions may reflect genotype-related effects on the motor control network, potentially contributing to early pathophysiology. In contrast, clinical assessments and task performance did not differ between groups, suggesting that our EEG findings may hold promise as biomarkers for monitoring the risk of conversion to symptomatic disease and warrant further exploration to assess their predictive value for future symptom onset.}, } @article {pmid40710301, year = {2025}, author = {Pasqualucci, E and Angeletti, D and Rosso, P and Fico, E and Zoccali, F and Tirassa, P and De Virgilio, A and de Vincentiis, M and Severini, C}, title = {Management of Dysarthria in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {14}, number = {14}, pages = {}, pmid = {40710301}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/physiopathology ; *Dysarthria/therapy/diagnosis/etiology/physiopathology/complications ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) stands as the leading neurodegenerative disorder affecting the motor system. One of the hallmarks of ALS, especially its bulbar form, is dysarthria, which significantly impairs the quality of life of ALS patients. This review provides a comprehensive overview of the current knowledge on the clinical manifestations, diagnostic differentiation, underlying mechanisms, diagnostic tools, and therapeutic strategies for the treatment of dysarthria in ALS. We update on the most promising digital speech biomarkers of ALS that are critical for early and differential diagnosis. Advances in artificial intelligence and digital speech processing have transformed the analysis of speech patterns, and offer the opportunity to start therapy early to improve vocal function, as speech rate appears to decline significantly before the diagnosis of ALS is confirmed. In addition, we discuss the impact of interventions that can improve vocal function and quality of life for patients, such as compensatory speech techniques, surgical options, improving lung function and respiratory muscle strength, and percutaneous dilated tracheostomy, possibly with adjunctive therapies to treat respiratory insufficiency, and finally assistive devices for alternative communication.}, } @article {pmid40710591, year = {2025}, author = {Sadler, GL and Lewis, KN and Narayana, VK and De Souza, DP and Mason, J and McLean, C and Gonsalvez, DG and Turner, BJ and Barton, SK}, title = {Correction: Sadler et al. Lipid Metabolism Is Dysregulated in the Motor Cortex White Matter in Amyotrophic Lateral Sclerosis. Metabolites 2022, 12, 554.}, journal = {Metabolites}, volume = {15}, number = {7}, pages = {}, pmid = {40710591}, issn = {2218-1989}, abstract = {In the original publication [...].}, } @article {pmid40712406, year = {2025}, author = {Sunter, K and Binay, A and Turhan, MA and Koc, MA and Akyol, C and Karahan, ZC and Gecim, IE}, title = {Effect of Preoperative Bowel Preparation and Diet on Anastomotic Healing and the Colon Microbiota: An Experimental Model.}, journal = {The Journal of surgical research}, volume = {313}, number = {}, pages = {516-525}, doi = {10.1016/j.jss.2025.06.061}, pmid = {40712406}, issn = {1095-8673}, mesh = {Animals ; Female ; Rats, Wistar ; *Preoperative Care/methods ; Matrix Metalloproteinase 9/metabolism ; *Gastrointestinal Microbiome/physiology ; Rats ; *Anastomotic Leak/prevention & control/microbiology/etiology ; *Colon/microbiology/surgery ; Anti-Bacterial Agents/administration & dosage ; Enterococcus faecalis/isolation & purification ; Anastomosis, Surgical/adverse effects ; Cathartics/administration & dosage ; Wound Healing ; Collagenases/metabolism ; Disease Models, Animal ; }, abstract = {INTRODUCTION: Intestinal microbiota members, particularly Enterococcus faecalis, play significant roles in the pathogenesis of anastomotic leaks (ALs), with key mechanisms involving collagenase production and matrix metalloproteinase-9 (MMP-9) activation. Diet strongly affects microbiota composition, with Western diets (WDs) promoting dysbiosis, which may exacerbate AL. The effects of mechanical bowel preparation (MBP) and oral antibiotics on AL remain unclear. This experimental study explored the impact of preoperative diet and MBP on AL, focusing on the intestinal microbiota.

METHODS: Sixty-four female Wistar albino rats were fed a WD or standard diet (SD) for 3 weeks before surgery. The rats were subsequently divided into subgroups according to MBP or oral antibiotic administration. Enterococcus colonies were analyzed throughout the procedure, and their correlation with AL was evaluated by assessing collagenase activity and MMP-9 tissue concentrations.

RESULTS: Enterococcus colony collagenase activity was significantly greater in the WD group than in the SD group (P = 0.024). Moreover, anastomotic burst pressures were nonsignificantly lower in the WD group. Finally, MMP-9 levels and collagenase activity were significantly lower in the groups that received either diet with oral antibiotics and MBP than in other subgroups (P = 0.045 and P = 0.007, respectively).

CONCLUSIONS: An SD, especially combined with MBP and oral antibiotics, plays a critical role in reducing the risk of AL by modulating collagenase activity in E faecalis and MMP-9 tissue concentrations in rats. Thus, dietary interventions may improve surgical outcomes; however, further clinical studies are necessary to validate these results in human populations.}, } @article {pmid40712472, year = {2025}, author = {Yousef, AM and Cantor-Cutiva, LC and Hunter, EJ}, title = {Mapping 74 years in acoustic analysis of voice disorders: A bibliometric review and future research directions.}, journal = {Journal of communication disorders}, volume = {117}, number = {}, pages = {106555}, pmid = {40712472}, issn = {1873-7994}, support = {R01 DC012315/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Bibliometrics ; *Voice Disorders/diagnosis/physiopathology ; *Speech Acoustics ; Speech Production Measurement ; }, abstract = {PURPOSE: This paper conducts a bibliometric analysis to identify and examine the strengths, gaps, and trends in research on acoustic voice assessment for voice disorders.

METHODS: A bibliometric analysis was performed on journal articles about voice disorders and acoustic voice assessment in English, Spanish, and Portuguese using seven indexed databases. The analyzed bibliometric parameters included publication year, authors, institutions, countries, journals, subject areas, and keywords. VOSviewer software was used for keyword co-occurrence analysis and authorships network analysis. The initial search yielded 6532 publications, with 1253 relevant papers after screening (1951-2024).

RESULTS: Publications in acoustic voice assessment had 74 years of exponential growth (25 % published after 2021). The publishing journals covered 80 categories and subjects. Artificial Intelligence, though recent, was among the top journal subjects. Health conditions like dementia, Alzheimer's, Amyotrophic lateral sclerosis, and depression were underassessed compared to Parkinson's. The literature focused on four separate themes: physiology of voice-affecting conditions; speech acoustics for evaluating dysphonia; speech production measurements for treating voice disorders; machine learning integration for voice disorder assessment.

CONCLUSIONS: Taking a wide view of acoustic voice assessment demonstrated research strengths and gaps-highlighting where it is used and not used-and the co-occurrence of various voice assessment topics. These insights reveal future opportunities to implement acoustic voice assessment.}, } @article {pmid40713843, year = {2025}, author = {Burg, T and Van Den Bosch, L}, title = {Glycerophospholipids in ALS: insights into disease mechanisms and clinical implication.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {85}, pmid = {40713843}, issn = {1750-1326}, support = {#00099187//Fondation Thierry Latran/ ; ABMM//ABMM/ ; ALS Liga België (A cure for ALS)//ALS Liga België (A cure for ALS)/ ; 12AIK24N//FWO/ ; G0C1620N//FWO/ ; G088523N//FWO/ ; G026924N//FWO/ ; C14/22/132//Onderzoeksraad, KU Leuven/ ; IDN/22/ 012//Onderzoeksraad, KU Leuven/ ; Muscular Dystrophy Association//Muscular Dystrophy Association/ ; Target ALS//Target ALS/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Glycerophospholipids/metabolism ; Animals ; Lipid Metabolism/physiology ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting the adult motor system, with no effective treatments available. Despite extensive research efforts, the exact pathological cascade leading to progressive motor neuron degeneration remains elusive. Recent evidence highlights significant modifications in lipid metabolism during ALS progression, even before the onset of motor symptoms. Glycerophospholipids, the primary components of cellular membranes, are frequently altered in ALS patients and models. These lipids not only play a structural role in membranes, but also contribute to cellular metabolism, signaling pathways, and cell type-specific processes such as neuronal transmission and muscle contraction. In this review, we discuss glycerophospholipid physiological functions in the motor system and review recent studies demonstrating their alterations and the possible underlying pathological mechanisms in ALS. Furthermore, we discuss challenges emerging from studying lipid alterations in neurodegeneration and evaluate the therapeutic potential of glycerophospholipids.}, } @article {pmid40715064, year = {2025}, author = {Sinha, IR and Sandal, PS and Spence, H and Burns, GD and Mallika, AP and Abbasinejad, F and Irwin, KE and Cruz, ALF and Wang, V and Marx, SR and Rodríguez, JL and Langmead, B and Gregory, JM and Wong, PC and Ling, JP}, title = {Large-scale RNA-Seq mining reveals ciclopirox olamine induces TDP-43 cryptic exons.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {6878}, pmid = {40715064}, issn = {2041-1723}, support = {UH3NS115608//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; F31 NS135935/NS/NINDS NIH HHS/United States ; R33NS115161//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; OAC1920103//National Science Foundation (NSF)/ ; 1U01FD008129//U.S. Department of Health & Human Services | U.S. Food and Drug Administration (U.S. Food & Drug Administration)/ ; R01 NS127186/NS/NINDS NIH HHS/United States ; R33 NS115161/NS/NINDS NIH HHS/United States ; R01NS095969//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 NS095969/NS/NINDS NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; R01NS127186//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; T32 CA153952/CA/NCI NIH HHS/United States ; U01 FD008129/FD/FDA HHS/United States ; UH3 NS115608/NS/NINDS NIH HHS/United States ; DGE2139757//National Science Foundation (NSF)/ ; }, mesh = {Humans ; Animals ; Mice ; *Exons/genetics/drug effects ; *Ciclopirox/pharmacology ; *DNA-Binding Proteins/genetics/metabolism ; RNA-Seq ; Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Nuclear clearance and cytoplasmic aggregation of TDP-43, initially identified in ALS-FTD, are hallmark pathological features observed across a spectrum of neurodegenerative diseases. We previously found that TDP-43 loss-of-function leads to transcriptome-wide inclusion of deleterious cryptic exons, a signature detected in presymptomatic biofluids and postmortem ALS-FTD brain tissue, but the upstream mechanisms that lead to TDP-43 dysregulation remain unclear. Here, we developed a web-based resource (SnapMine) to determine the levels of TDP-43 cryptic exon inclusion across hundreds of thousands of publicly available RNA sequencing datasets. We established cryptic exon inclusion levels across a variety of human cells and tissues to provide ground truth references for future studies on TDP-43 dysregulation. We then explored studies that were entirely unrelated to TDP-43 or neurodegeneration and found that ciclopirox olamine (CPX), an FDA-approved antifungal, can trigger the inclusion of TDP-43-associated cryptic exons in a variety of mouse and human primary cells. CPX induction of cryptic exons arises from heavy metal toxicity and oxidative stress, suggesting that similar vulnerabilities could play a role in neurodegeneration. Our work demonstrates how diverse datasets can be linked through common biological features and underscores how public archives of sequencing data remain a vastly underutilized resource with tremendous potential for uncovering novel insights into complex biological mechanisms and diseases.}, } @article {pmid40716079, year = {2025}, author = {Finsterer, J}, title = {Comment on 'Quantification of Skeletal Muscle at the First Lumbar Level for Prognosis in Amyotrophic Lateral Sclerosis' by Cao et al.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {16}, number = {4}, pages = {e70038}, pmid = {40716079}, issn = {2190-6009}, } @article {pmid40716120, year = {2025}, author = {Arora, T and Thorgersen, JK and Jones, KE and Allen, SM and Schulze, DG and Dunker, Ø and Tankisi, H and Nilsen, KB}, title = {Test-retest measurement properties of the MScanFit method for motor unit number estimation in individuals with Amyotrophic Lateral Sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {178}, number = {}, pages = {2110940}, doi = {10.1016/j.clinph.2025.2110940}, pmid = {40716120}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; Aged ; *Motor Neurons/physiology ; Reproducibility of Results ; Adult ; *Muscle, Skeletal/physiopathology ; *Electromyography/methods/standards ; *Recruitment, Neurophysiological/physiology ; }, abstract = {OBJECTIVE: MScanFit is one of the Motor Unit Number Estimation (MUNE) methods considered as a potential biomarker for Amyotrophic Lateral Sclerosis (ALS) diagnosis and clinical trials. We investigated the test-retest measurement properties of MScanFit across multiple muscles in individuals with ALS.

METHODS: We recorded MUNE from Abductor Pollicis Brevis (APB), Abductor Digiti Minimi (ADM), and Tibialis Anterior (TA) muscles in seventeen adults with ALS separated by 1-2 weeks. Intraclass correlation and concordance correlation coefficients provided reliability estimates. Overall agreement was evaluated using pairedt-tests or the Wilcoxon signed-rank test and an estimation statistical approach. The standard error of measurement and the smallest detectable change provided the extent of agreement.

RESULTS: The reliability coefficients ranged from 0.66 to 0.91. The measurement error was high (standard error of measurement > 10 %). The smallest detectable change was high (24-61 units) at an individual level, although smaller (∼10 units) at a group level (N = 10-30) CONCLUSION: MScanFit has moderate-to-excellent reliability and can reliably detect smaller changes at a group level, but is limited in reliably detecting smaller changes at an individual level.

SIGNIFICANCE: The MScanFit MUNE can potentially serve as a group-level biomarker in ALS clinical trials.}, } @article {pmid40717725, year = {2025}, author = {Wen, T and Zhu, J and Sun, S and Chen, Y and Gao, N and Ma, M and Chen, X and Liu, S and Lin, P and Deng, Y}, title = {Thalamic nuclei volumes are related to disease stage in patients with amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1616239}, pmid = {40717725}, issn = {1662-4548}, abstract = {OBJECTIVE: To explore atrophy patterns in thalamic nuclei at different phases of amyotrophic lateral sclerosis (ALS) and determine any correlations between thalamic nucleus volume and either cognitive impairments or motor disabilities.

METHODS: We used the King's clinical staging system for ALS to divide 76 consecutive patients with ALS by disease stage. We investigated patterns of thalamic atrophy in the patients and in 94 healthy controls (HCs). Cognitive functions were evaluated with the Mini-Mental State Examination (MMSE), Frontal Assessment Battery, Boston Naming Test, and Auditory Verbal Learning Test.

RESULTS: Considering all ALS patients, no significant differences were observed in the volume of any thalamic nuclei between the ALS group and HCs. Thalamic nucleus volumes remained normal in ALS patients at King's Stage 2 and Stage 3. However, atrophy was detected in the bilateral anteroventral nucleus, bilateral pulvinar-limitans, bilateral mediodorsal-paratenial-reuniens, bilateral motor hub, bilateral sensory hub, and bilateral intralaminar nucleus in patients who had reached King's Stage 3. In these patients, the volume of the bilateral motor nuclei was associated with the revised ALS Functional Rating Scale scores, and that of the right pulvinar-limitans independently correlated with MMSE scores.

CONCLUSION: Our study provides a comprehensive profile of thalamic atrophy in ALS patients. The thalamic atrophy patterns in these patients extremely differs at different King's Stages, and we suggest that these alterations might result largely from sequential, regional patterns of TDP-43 pathology in ALS. Furthermore, thalamic atrophy might play important roles in motor disability and global cognitive impairments observed in patients with ALS.}, } @article {pmid40717814, year = {2025}, author = {Righes, G and Semenzato, L and Koutsikos, K and Zanato, V and Pinton, P and Giorgi, C and Patergnani, S}, title = {The role of autophagy in the pathogenesis and treatment of multiple sclerosis.}, journal = {Autophagy reports}, volume = {4}, number = {1}, pages = {2529196}, pmid = {40717814}, issn = {2769-4127}, abstract = {Autophagy is a crucial cellular process responsible for the degradation and recycling of damaged or unnecessary components, maintaining cellular homeostasis and protecting against stress. Dysregulation of autophagy has been implicated in a variety of neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Various types of autophagy exist, each with distinct mechanisms, such as macroautophagy, mitophagy, lipophagy, and chaperone-mediated autophagy. These processes are essential for the removal of toxic substrates like protein aggregates and dysfunctional mitochondria, which are vital for neuronal health. In neurodegenerative diseases, the impairment of these clearance mechanisms leads to the accumulation of harmful substances, which accelerate disease progression. Modulating autophagy has emerged as a promising therapeutic strategy, with ongoing studies investigating molecules that can either stimulate or regulate this process. However, despite its potential, significant challenges remain in translating preclinical findings into clinically effective treatments. In this review, we will explore the different types of autophagy, their roles in neurodegenerative diseases, and the therapeutic potential associated with modulating these processes.}, } @article {pmid40717876, year = {2025}, author = {Castillo-Bustamante, M and Anderson, C and Gutierrez, VA}, title = {The Use of Posturography in Vestibular Evaluation of Neurodegenerative Disorders: Diagnostic and Rehabilitative Impacts.}, journal = {Cureus}, volume = {17}, number = {7}, pages = {e88752}, pmid = {40717876}, issn = {2168-8184}, abstract = {Neurodegenerative disorders, such as Parkinson's disease, multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis, frequently present with vestibular dysfunction and balance disturbances, significantly impacting patients' quality of life and increasing the risk of falls. Vestibular impairments in these conditions can manifest as dizziness, unsteadiness, and difficulty maintaining postural control, further complicating the motor and cognitive deficits typical of these diseases. As a result, the assessment and management of balance dysfunction in neurodegenerative disorders have become crucial components of care. Posturography, an objective method for evaluating postural stability and balance control, has emerged as a valuable tool in the vestibular evaluation of patients with neurodegenerative conditions. By providing precise, quantitative measurements of balance deficits, posturography allows for a detailed analysis of postural control mechanisms that may be compromised due to vestibular involvement. This technique not only aids in diagnosing vestibular dysfunction but also plays a key role in developing targeted rehabilitation strategies. When integrated into vestibular rehabilitation (VR) programs, posturography can guide individualized therapy aimed at mitigating fall risk, improving functional mobility, and enhancing patients' overall quality of life. VR exercises, tailored to address specific balance deficits identified through posturographic analysis, can be particularly beneficial in promoting compensatory mechanisms and optimizing patients' functional abilities. This review highlights the significance of posturography as both a diagnostic and therapeutic tool in managing vestibular impairments associated with neurodegenerative diseases, offering the potential for improved outcomes through more personalized and effective rehabilitation interventions.}, } @article {pmid40717894, year = {2025}, author = {Yu, M and Ma, H and Lai, X and Wu, J and Shen, M and Yan, J}, title = {Stem cell extracellular vesicles: a new dawn for anti-inflammatory treatment of neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1592578}, pmid = {40717894}, issn = {1663-4365}, abstract = {Mesenchymal stem cell-derived extracellular vesicles, as carriers for intercellular communication, are rich in bioactive substances such as proteins and nucleic acids, and show unique potential in the treatment of neurodegenerative diseases. Their vesicular structure, with a diameter of 30-150 nm, can penetrate the blood-brain barrier and modulate the activity of microglia and astrocytes by delivering functional molecules. This process inhibits the release of pro-inflammatory factors and enhances the expression of anti-inflammatory mediators, thereby alleviating neuroinflammation in the pathological process of neurodegenerative diseases. As natural drug carriers, extracellular vesicles can improve the targeted delivery efficiency of therapeutic molecules. However, their specific anti-inflammatory mechanisms remain not fully understood and require further exploration. This article discusses the anti-inflammatory effects in the context of neurodegenerative diseases and provides a summary and outlook on the anti-inflammatory actions associated with extracellular vesicles from past research.}, } @article {pmid40720711, year = {2025}, author = {Hardiman, O}, title = {When Does Amyotrophic Lateral Sclerosis Begin, and How Can We Tell?.}, journal = {Neurology}, volume = {105}, number = {4}, pages = {e214058}, doi = {10.1212/WNL.0000000000214058}, pmid = {40720711}, issn = {1526-632X}, } @article {pmid40720712, year = {2025}, author = {Benatar, M and Cai, X and McDermott, MP and Granit, V and Grignon, AL and Colato, D and Fernandez, MC and Li, Y and McBane, K and Mesa, L and Stanislaw, C and Andersen, PM and Carberry, N and Wuu, J}, title = {Proposed Research Criteria for Mild Motor Impairment as a Prodromal Syndrome in Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {105}, number = {4}, pages = {e213917}, pmid = {40720712}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/physiopathology ; Female ; *Prodromal Symptoms ; Male ; Middle Aged ; Adult ; Longitudinal Studies ; Disease Progression ; Cohort Studies ; Aged ; }, abstract = {BACKGROUND AND OBJECTIVES: The presymptomatic stage of amyotrophic lateral sclerosis (ALS) is typically assumed to be clinically silent. Our previous work, however, has revealed evidence of a prodromal stage, termed mild motor impairment (MMI). In this study, we propose operational criteria for MMI, describe its frequency in a genetically diverse cohort, and examine the association between MMI and time to ALS phenoconversion.

METHODS: Pre-Symptomatic Familial ALS (Pre-fALS) study, initiated in 2007, is a longitudinal natural history and biomarker study of unaffected carriers of any ALS-associated pathogenic variant. Proposed research criteria for MMI were developed based on clinical review of case histories of ALS phenoconverters in the Pre-fALS study. These criteria were then systematically applied to the remaining Pre-fALS cohort. Among phenoconverters and presymptomatic carriers, cumulative probabilities of phenoconversion were estimated for those with and without MMI at baseline. Cox proportional hazard models evaluated associations between risk factors (MMI, age, genotype) and time from baseline to ALS phenoconversion.

RESULTS: The study cohort includes 49 controls (mean age 38.9, 61% female), 153 presymptomatic carriers (mean age 43.1, 61% female), and 31 ALS phenoconverters (mean age 54.4, 58% female). Seven criteria for MMI are proposed, each reflecting a different pattern of upper/lower motor neuron signs, without corresponding weakness, in 1 or more of 4 topographic regions. MMI, defined as meeting ≥1 of these criteria, was observed at 1 or more study visits in 17 of 31 phenoconverters (55%) before clinically manifest ALS, 66 of 153 presymptomatic carriers (43%) who had not yet phenoconverted, and 7 of 49 controls (14%). Among all mutation carriers, the 25th percentile (95% CI) of time to phenoconversion was, respectively, 3.7 (1.6-4.7) and 14.1 (8.9-∞) years for those with and without MMI at baseline, with a hazard ratio of 5.1 (95% CI 2.2-12.2, p < 0.0001). Moreover, the hazard rate of phenoconversion was 1.7 times higher for every 10-year increase in age and varied by genotype.

DISCUSSION: MMI is a recognizable syndrome. Although nonspecific, it identifies presymptomatic carriers at elevated risk of ALS phenoconversion. Combining MMI with emerging biomarkers of underlying pathology may help differentiate those who are prodromal from those who are not prodromal for ALS. Characterization and study of MMI, including replication in other studies, may empower early therapeutic intervention and ALS prevention efforts.}, } @article {pmid40720999, year = {2025}, author = {Zheng, W and Luo, J and Yang, Y and Guo, X and Song, F and Li, F and Xiao, F}, title = {Neural dynamics impairments in amyotrophic lateral sclerosis patients and their associations with clinical characteristics: An observational cohort study.}, journal = {Brain research bulletin}, volume = {229}, number = {}, pages = {111482}, doi = {10.1016/j.brainresbull.2025.111482}, pmid = {40720999}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Middle Aged ; Female ; Electroencephalography/methods ; Aged ; Cohort Studies ; *Brain/physiopathology ; Nonlinear Dynamics ; Adult ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the central nervous system. It remains unclear whether pathological changes in ALS can lead to abnormalities in neural dynamics and how these abnormalities relate to key clinical characteristics of ALS.

METHODS: Nonlinear neural dynamics analyses of electroencephalography (EEG) sensorimotor channels were conducted using recurrence quantification analysis (RQA), permutation Lempel-Ziv complexity (PLZC), shannon entropy (ShannonE) and permutation entropy (PermEn). Whole-brain spatiotemporal topological dynamics were assessed using microstate analysis.

RESULTS: The study shows that the nonlinear neural dynamics across all frequency bands in the sensorimotor channels of ALS patients are impaired (reduction in Shannon Entropy of Diagonal Line Length Distribution [ENTR]). Frequency-specific nonlinear neural dynamics indicate increased nonlinear neural dynamics in high-frequency bands (with increases in PLZC in beta2 (20-25 Hz)). Nonlinear neural dynamics in low-frequency bands decreases (with decreases in ShannonE in theta (4-7 Hz)) and is negatively correlated with disease duration. ENTR across all frequency bands and ShannonE in the theta band of the sensorimotor channels are potential protective factors for ALS. Furthermore, sensorimotor channel analysis shows a close relationship with whole-brain spatiotemporal topological neural dynamics. Duration A is positively correlated with RR, DET and ENTR, while Occurrence B is negatively correlated with it.

CONCLUSIONS: The study demonstrates widespread abnormalities in the neural dynamics of ALS, which are closely related to clinical characteristics of ALS. There is also a close relationship between the neural dynamics of sensorimotor channels and whole-brain spatiotemporal topological dynamics in ALS patients.}, } @article {pmid40721761, year = {2025}, author = {Xu, H and Zheng, Y and Lu, X and Liu, L and Wan, R and Zhang, S and Li, G and Le, R and Liang, Y}, title = {Accuracy of 7 intraocular lens power calculation formulas in primary angle-closure glaucoma eyes, according to axial length and anterior chamber depth.}, journal = {BMC ophthalmology}, volume = {25}, number = {1}, pages = {431}, pmid = {40721761}, issn = {1471-2415}, support = {(Project Number: MS25H120013)//Zhejiang Provincial Natural Science Foundation Exploration Project./ ; (Project Number: MS25H120013)//Zhejiang Provincial Natural Science Foundation Exploration Project./ ; (Project Number: MS25H120013)//Zhejiang Provincial Natural Science Foundation Exploration Project./ ; (Project Number: MS25H120013)//Zhejiang Provincial Natural Science Foundation Exploration Project./ ; (Project Number: 2025KY1021)//Zhejiang Provincial Medical and Health Project./ ; (Project Number: 2025KY1021)//Zhejiang Provincial Medical and Health Project./ ; (Project Number: 2025KY1021)//Zhejiang Provincial Medical and Health Project./ ; (Project Number: 2025KY1021)//Zhejiang Provincial Medical and Health Project./ ; (Project Number: 2025ZL404)//Zhejiang Province Traditional Chinese Medicine Science and Technology Plan Project/ ; (Project Number: 2025ZL404)//Zhejiang Province Traditional Chinese Medicine Science and Technology Plan Project/ ; (Project Number: 2025ZL404)//Zhejiang Province Traditional Chinese Medicine Science and Technology Plan Project/ ; (Project Number: 2025ZL404)//Zhejiang Province Traditional Chinese Medicine Science and Technology Plan Project/ ; }, mesh = {Humans ; *Glaucoma, Angle-Closure/surgery/physiopathology ; Retrospective Studies ; Female ; *Anterior Chamber/pathology ; Male ; *Lenses, Intraocular ; *Axial Length, Eye/pathology ; Aged ; Middle Aged ; Biometry/methods ; Refraction, Ocular/physiology ; *Optics and Photonics ; Lens Implantation, Intraocular ; Intraocular Pressure/physiology ; Phacoemulsification ; Visual Acuity ; Aged, 80 and over ; Reproducibility of Results ; }, abstract = {PURPOSE: To assess the impact of Axial Length (AL) and anterior chamber depth (ACD) on the performance of the Kane, EVO 2.0, Barrett Universal II (BU II), SRK/T, Haigis, Holladay 2 and Hoffer Q formulas when calculating intraocular lens power in primary angle-closure glaucoma (PACG) patients.

SETTING: Eye hospital, Wen Zhou Medical University, Zhejiang, China.

DESIGN: Retrospective, consecutive case series.

METHODS: Patients who underwent cataract surgery diagnosed with PACG or not were included. The main outcome measures comprised mean prediction error (ME), mean absolute refractive error (MAE), median absolute refractive error (MedAE). Additionally, the proportions of eyes with postoperative refractive errors within ± 0.25 diopter (D), ± 0.50 D, ± 0.75 D, and ± 1.00 D were calculated. Subgroup analyses were conducted based on AL and ACD.

RESULTS: A total of 116 eyes were included, with 66 in the PACG group and 50 in the control group. The PACG group showed significantly larger MAEs compared to the control group. In PACG eyes, the BUII formula tends to cause negative residual refractive errors, while the Kane, EVO, and Holladay 2 formulas often lead to positive ones (P < 0.01). Notably, the SRK/T and Haigis formulas demonstrated better predictability for ME (P < 0.01). PACG patients with an AL under 22 mm or an ACD under 2.5 mm have lower IOL power calculation predictability (P < 0.05). Subgroup analysis shows that PACG eyes with both AL under 22 mm and ACD under 2.5 mm have the lowest predictability and are most prone to significant prediction errors (P < 0.05). A negative correlation was found between postoperative prediction error and AL.

CONCLUSIONS: PACG eyes showed lower prediction accuracy, especially in short ALs and shallow ACD cases. SRK/T and Haigis formulas had better ME predictability. The study stresses optimizing IOL power calculation formulas for PACG eyes, considering AL and ACD effects.}, } @article {pmid40722288, year = {2025}, author = {Dhakal, D and Chen, C and Zhang, B and Li, G}, title = {Health-Related Quality of Life, Psychological Health, and Patient-Reported Outcomes of Amyotrophic Lateral Sclerosis Patients in China.}, journal = {Brain sciences}, volume = {15}, number = {7}, pages = {}, pmid = {40722288}, issn = {2076-3425}, abstract = {Objectives: This study explored the health-related quality of life (HRQoL), psychological health, and patient-reported outcomes (PROs) of patients with amyotrophic lateral sclerosis (ALS) in China, providing insights for enhancing clinical care. Methods: A cross-sectional study was conducted among Chinese ALS patients between February and May 2024. Demographics, clinical characteristics, and PROs were assessed. HRQoL and psychological health were evaluated via the 5-item amyotrophic lateral sclerosis assessment questionnaire (ALSAQ-5) and the 4-item patient health questionnaire (PHQ-4), respectively. Spearman's rank correlation, multiple linear regression, and the Kruskal-Wallis H test were used to analyze associations between clinical factors, HRQoL, and psychological health. Results: A total of 237 participants aged 46-65 years (63.3%) were included. The mean ALSAQ-5 score was 64.86±19.34, indicating an impaired HRQoL, whereas the mean PHQ-4 score (5.82 ± 4.10,) suggested varied degree of anxiety and depression. Age, disease duration, ALS severity, fatigue, stress, and pain severity, and respiratory support were significantly associated with HRQoL (p < 0.05). Age, stress severity, and pain severity were significant predictors of psychological distress (p < 0.01). Patients reported diagnostic delay, profound lifestyle changes (96.4%), fear of paralysis (84.8%), and death (49.8%). Most patients (80.6%) expressed a strong desire to stop ALS progression, prioritizing treatments that improve breathing, muscle weakness, swallowing, and mobility issues. Conclusions: ALS profoundly impacts patients' HRQoL and psychological health. Integrating PROs into clinical care strategies is crucial for improving patient outcomes and guiding treatment priorities.}, } @article {pmid40722307, year = {2025}, author = {Ghaderi, S and Mohammadi, S and Fatehi, F}, title = {Magnetic Resonance Neuroimaging in Amyotrophic Lateral Sclerosis: A Comprehensive Umbrella Review of 18 Studies.}, journal = {Brain sciences}, volume = {15}, number = {7}, pages = {}, pmid = {40722307}, issn = {2076-3425}, abstract = {Background/Objectives: Despite extensive research, the underlying causes of amyotrophic lateral sclerosis (ALS) remain unclear. This umbrella review aims to synthesize a vast body of evidence from advanced magnetic resonance imaging (MRI) studies of ALS, encompassing a wide range of neuroimaging techniques and patient cohorts. Methods: Following the PRISMA guidelines, we conducted an extensive search of four databases (PubMed, Scopus, Web of Science, and Embase) for articles published until 3 December 2024. Data extraction and quality assessment were independently performed using the AMSTAR2 tool. Results: This review included 18 studies that incorporated data from over 29,000 ALS patients. Structural MRI consistently showed gray matter atrophy in the motor and extra-motor regions, with significant white matter (WM) atrophy in the corticospinal tract and corpus callosum. Magnetic resonance spectroscopy revealed metabolic disruptions, including reduced N-acetylaspartate and elevated choline levels. Functional MRI studies have demonstrated altered brain activation patterns and functional connectivity, reflecting compensatory mechanisms and neurodegeneration. fMRI also demonstrated disrupted motor network connectivity and alterations in the default mode network. Diffusion MRI highlighted microstructural changes, particularly reduced fractional anisotropy in the WM tracts. Susceptibility-weighted imaging and quantitative susceptibility mapping revealed iron accumulation in the motor cortex and non-motor regions. Perfusion MRI indicated hypoperfusion in regions associated with cognitive impairment. Conclusions: Multiparametric MRI consistently highlights widespread structural, functional, and metabolic changes in ALS, reflecting neurodegeneration and compensatory mechanisms.}, } @article {pmid40722336, year = {2025}, author = {Balz, LT and Uttner, I and Weishaupt, J and Ludolph, AC and Taranu, D and Vardakas, I and Jung, S and Fangerau, T and Erhart, DK and Senel, M and Tumani, H and Lulé, DE}, title = {Quality of Life in Multiple Sclerosis Compared to Amyotrophic Lateral Sclerosis: Fatigue and Fast Disease Progression Interferes with the Ability to Psychosocially Adjust.}, journal = {Brain sciences}, volume = {15}, number = {7}, pages = {}, pmid = {40722336}, issn = {2076-3425}, abstract = {Background/Objectives: Multiple sclerosis (MS) is a complex neurological disease that is associated with a broad spectrum of physical and psychological symptoms. Psychosocial adjustment (PSA) refers to the ability to cope with these challenges, which influence quality of life (QoL) and depressiveness in ways not yet fully understood. This study explores the relationship of PSA and disease-specific symptoms in MS, including fatigue, a prominent MS symptom. Additionally, PSA was compared to Amyotrophic Lateral Sclerosis (ALS) to disentangle the impact of disease trajectory on PSA. Methods: We interviewed 77 MS patients using patient-reported outcome measures on QoL and depression and compared them to 30 ALS patients. Confirmatory factor analysis and regression analysis were used to identify PSA indicators and predictors in MS, while t-tests assessed PSA differences across diseases. Results: Key PSA indicators in MS included physical (PQoL), mental (MQoL), and subjective (SQoL) quality of life, as well as depressiveness, with cognitive and motor fatigue emerging as significant predictors. MS patients had higher PQoL and SQoL and lower levels of depression compared to ALS patients, while both groups were comparable with regard to MQoL. Conclusions: PSA in MS is supported by high QoL and low depression levels, with fatigue being a significant predictor. Despite different disease trajectories, patients with MS and ALS showed comparable MQoL, indicating that both diseases similarly impact mental QoL, reflecting a partial overlap in psychosocial adjustment. Overall, psychosocial adjustment was more favorable in MS, likely due to its slower disease progression compared to ALS.}, } @article {pmid40724820, year = {2025}, author = {Tomaszewska-Zaremba, D and Gajewska, A and Misztal, T}, title = {Anti-Inflammatory Effects of Cannabinoids in Therapy of Neurodegenerative Disorders and Inflammatory Diseases of the CNS.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40724820}, issn = {1422-0067}, mesh = {Humans ; *Cannabinoids/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Animals ; *Inflammation/drug therapy ; Central Nervous System/drug effects ; *Central Nervous System Diseases/drug therapy ; }, abstract = {Many neurodegenerative diseases are associated with immune system disorders, while neurodegenerative processes often occur in inflammatory conditions of the Central Nervous System (CNS). Cannabinoids exhibit significant therapeutic potential due to their dual ability to modulate both neural and immune functions. These compounds have a broad spectrum of action, allowing them to target multiple pathological mechanisms underlying neurodegenerative and inflammatory CNS diseases. The present review outlines the therapeutic potential of cannabinoids, with a focus on their anti-inflammatory properties, in the treatment of neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, as well as inflammatory CNS disorders like multiple sclerosis and HIV-associated dementia.}, } @article {pmid40725035, year = {2025}, author = {Bordoni, M and Scarian, E and Viola, C and Dragoni, F and Di Gerlando, R and Rizzo, B and Diamanti, L and Gagliardi, S and Pansarasa, O}, title = {Impact of SOD1 Transcript Variants on Amyotrophic Lateral Sclerosis Severity.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40725035}, issn = {1422-0067}, support = {Ricerca Corrente 2022-2024//Italian Ministry of Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Middle Aged ; Male ; Female ; Aged ; Severity of Illness Index ; Disease Progression ; Leukocytes, Mononuclear/metabolism ; Cell Line, Tumor ; RNA, Messenger/genetics/metabolism ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that affects motor neurons of people, leading to death. This pathology can be caused by mutations in different genes, including superoxide dismutase 1 (SOD1). Previous studies have pointed out the presence of two transcripts of SOD1, a short one and a long one. The aim of this study was the investigation of these two transcripts both in the SH-SY5Y cell line and in patients' peripheral blood mononuclear cells. We found that the shortest SOD1 transcript is upregulated under stress conditions in both the cellular model and the patients' cells. Moreover, we found a potential correlation between the short SOD1 transcript and the severity of the pathology, which also correlates with the age of patients. No correlation was found between SOD1 transcripts and the progression of the disease. These data suggest a toxic effect of short SOD1 transcripts in ALS patients, by affecting the severity of the pathology making it a possible biomarker for this disease. Interestingly, our data suggest that a short SOD1 transcript does not influence and drive disease progression. The finding of a biomarker will have suitable implications as indicators of disease severity and from the perspective of drug development.}, } @article {pmid40725270, year = {2025}, author = {Tahri, A and Niccolai, E and Amedei, A}, title = {Neurosteroids, Microbiota, and Neuroinflammation: Mechanistic Insights and Therapeutic Perspectives.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40725270}, issn = {1422-0067}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Neuroinflammatory Diseases/metabolism/microbiology/therapy ; Animals ; *Neurosteroids/metabolism ; *Neurodegenerative Diseases/metabolism/microbiology ; Brain/metabolism ; Inflammation ; }, abstract = {The gut-brain axis (GBA) represents a complex bidirectional communication network that links the gut microbiota (GM) and the central nervous system (CNS). Recent research has revealed that neurosteroids (NSs) play crucial roles in modulating neuroinflammatory responses and promoting neuroprotection. Meanwhile, GM alterations have been associated with various neuroinflammatory and neurodegenerative conditions, such as multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. This review aims to provide a comprehensive overview of the intricate interactions between NS, GM, and neuroinflammation. We discuss how NS and metabolites can influence neuroinflammatory pathways through immune, metabolic, and neuronal mechanisms. Additionally, we explore how GM modulation can impact neurosteroidogenesis, highlighting potential therapeutic strategies that include probiotics, neuroactive metabolites, and targeted interventions. Understanding these interactions may pave the way for innovative treatment approaches for neuroinflammatory and neurodegenerative diseases, promoting a more integrated view of brain health and disease management.}, } @article {pmid40725930, year = {2025}, author = {He, Y and Ming, W and Tan, Y and Wang, Y and Wang, M and Li, H and Jiao, Z and Hou, Y}, title = {The effectiveness of cognitive behavioral therapy in patients with motor neuron disease: A systematic review.}, journal = {Medicine}, volume = {104}, number = {30}, pages = {e43597}, pmid = {40725930}, issn = {1536-5964}, mesh = {Humans ; *Cognitive Behavioral Therapy/methods ; *Motor Neuron Disease/psychology/therapy ; Quality of Life ; Caregivers/psychology ; Anxiety/therapy/etiology ; Depression/therapy/etiology ; Treatment Outcome ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a neurodegenerative disorder that causes progressive loss of motor function. With limited disease-modifying drug therapies, cognitive behavioral therapy (CBT) has emerged as a key nonpharmacological intervention. This systematic review evaluated CBT's therapeutic potential across clinical domains to inform psychosocial care of patients with MND.

METHODS: Comprehensive searches were performed in PubMed, Web of Science, Cochrane Library, and Embase, from inception until February 2025. Two researchers independently screened the literature, extracted data, assessed study quality, and resolved disagreements via consensus or third-party consultation.

RESULTS: Five studies involving 561 patients were included. Compared with conventional care, CBT significantly improves patients' quality of life and psychological flexibility. However, the effects on caregiver burden and physical health were not statistically significant. CBT modalities included acceptance and commitment therapy, dialectical behavior therapy, rational-emotive behavior therapy, mindfulness cognitive therapy, and metacognitive training. Traditional CBT demonstrated superior efficacy in reducing anxiety and depression compared to acceptance and commitment therapy.

CONCLUSION: CBT effectively enhances psychological flexibility and quality of life and reduces anxiety and depression in patients with MND. The standardization of outcome measures requires improvement. High-quality randomized controlled trials are needed to further assess CBT's impact of CBT on caregiver burden and patients' physical health.}, } @article {pmid40726139, year = {2025}, author = {Jin, X and Wang, X and Zheng, D and Yuan, P and Li, J and Qiu, T and Zhang, H and Chen, Y and Zhang, J and Wu, F and Liu, Q and Grecucci, A and Zhang, Y and Wang, J and Yi, X and Palaniyappan, L and Braden, BB}, title = {Disrupted Glucose Metabolism Covariance Network in Amyotrophic Lateral Sclerosis.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {7}, pages = {e70537}, pmid = {40726139}, issn = {1755-5949}, support = {U22A20377//National Natural Science Foundation of China/ ; 2024PT5109//The Scientific Research Program of FuRong Laboratory/ ; 2022LNJJ09//Project Program of National Clinical Research Center for Geriatric Disorders/ ; 2024ZZTS0954//Fundamental Research Funds for the Central Universities of Central South University/ ; CB-C2022//Fonds de Recherche du Québec - Santé/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; Female ; Male ; Middle Aged ; Aged ; *Glucose/metabolism ; Positron-Emission Tomography ; Fluorodeoxyglucose F18 ; *Nerve Net/metabolism/diagnostic imaging ; Disease Progression ; Adult ; *Brain/metabolism/diagnostic imaging ; }, abstract = {AIMS: This study aimed to characterize the topological changes in glucose metabolism covariance networks in amyotrophic lateral sclerosis (ALS).

METHODS: We assessed the interregional coordination of [18]F-FDG-PET data to examine topological alterations in individualized glucose metabolism covariance networks in 127 ALS patients compared to 128 healthy controls (HC).

RESULTS: Compared to HC, ALS patients showed reduced small-worldness (lower normalized clustering coefficient, higher normalized characteristic path length) and decreased global and local efficiency, suggesting impaired global integration and local segregation. These network metrics correlated with disease progression and motor function. Regionally, altered degree centrality affected motor and default mode networks, and related to GABAa and mGluR5 receptor expression. Transcriptomic associations further linked these changes to immune function, synaptic signaling, and protein regulation. Bidirectional shifts in connectivity strength were observed, with both increased connectivity and disease progression independently predicting reduced survival.

CONCLUSION: Our findings may provide valuable biomarkers for monitoring the progression of ALS and suggest potential mechanistic pathways for the development of innovative therapeutic strategies for this disorder.}, } @article {pmid40726565, year = {2025}, author = {Dukic, S and Govaarts, R and Hillebrand, A and de Visser, M and Seeck, M and McMackin, R}, title = {Novel approaches to EEG and MEG in motor neurone disease: IFCN Handbook Chapter.}, journal = {Clinical neurophysiology practice}, volume = {10}, number = {}, pages = {301-315}, pmid = {40726565}, issn = {2467-981X}, abstract = {Motor neurone diseases (MNDs) are increasingly being acknowledged as network disorders, with cortical dysfunction and degeneration extending beyond the motor cortex. Measures of this broader cortical pathophysiology are providing promising candidates in the search for diagnostic and prognostic biomarkers of the MNDs. Electroencephalography (EEG) and magnetoencephalography (MEG) offer a direct view of neural network activity by detecting changes in electromagnetic fields of the brain. Measurements based on EEG/MEG have often been overlooked in the search for MND biomarkers, largely due to their limited spatial resolution and the perceived challenges associated with noise in these signals. However, with recent developments in sensor technology and source reconstruction algorithms, alongside substantial improvement in pipelines that address noise, EEG/MEG-based measures can now be readily employed for spatiotemporally-precise, economical and non-invasive characterisation of cortical network pathophysiology in MNDs. Here, we provide an overview of how EEG/MEG signals have been employed to quantify neural network function in MND. We outline the advantages and limitations of these measurements, discuss the most clinically promising EEG/MEG studies of MNDs to date, and highlight future directions warranted to harness the full potential of these technologies for understanding and assessing MNDs.}, } @article {pmid40726766, year = {2025}, author = {Bingham, IN and Norel, R and Roitberg, EG and Peller, J and Trevisan, MA and Agurto, C and Merler, M and Shalom, DE and Aguirre, F and Embon, I and Taitz, A and Harris, D and Wright, A and Seaver, K and Sullivan, S and Green, JR and Ostrow, LW and Fraenkel, E and Berry, JD}, title = {Listener effort measures clinically meaningful change of dysarthria in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {4}, pages = {fcaf232}, pmid = {40726766}, issn = {2632-1297}, support = {K24 DC016312/DC/NIDCD NIH HHS/United States ; R42 DC019877/DC/NIDCD NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disease that can cause progressive bulbar dysfunction and dysarthria, resulting in reduced quality of life. Quantitative motor speech analysis can identify features of dysarthria that worsen with ALS progression but are not, inherently, clinically meaningful. Listener effort (LE) is a clinician-rated feature describing how much effort the listener needs to exert to understand the dysarthric speaker. This study investigated whether LE could act as a clinically meaningful measure of ALS dysarthria that could be used as an outcome measure in clinical trials. The Everything ALS Speech Study obtained longitudinal clinical information and speech recordings from 292 participants. In a subset of 125 participants, we measured speaking rate and three speech-language pathologists (SLPs) with expertise in ALS rated LE. We also built and tested a LE prediction algorithm to predict the SLPs' rating of LE. In addition, all speech recordings and associated clinical data are now being made available to ALS researchers via the Everything ALS portal. LE intra- and inter-rater reliability was very high (ICC 0.94-0.95). LE correlated with other measures of dysarthria at baseline and changed over time in participants with ALS (slope 0.77 pts/month, SE = 0.15, P < 0.001) but not controls (slope 0.005 pts/month, SE = 0.02, P = 0.807). The slope of LE progression was faster in people with bulbar onset than non-bulbar onset ALS (1.66 points/month versus 0.42 pts/month; P < 0.001) but was similar in all participants who had bulbar dysfunction at baseline, regardless of ALS site of onset (1.52 pts/month for bulbar onset versus 0.98 pts/month for non-bulbar onset with current bulbar involvement; P = 0.36). The LE prediction model predicted the true LE, with an average R [2] of 0.83 ± 0.07. Dysarthria is associated with decreased quality of life in people with ALS. Quantitative measures of dysarthria in ALS could be useful as ALS clinical trial outcome measures, providing insight into the progression of bulbar symptoms. Speaking rate quantifies progression but is variable across speaking stimuli, emotional states and contextual factors. LE is more inherently clinically meaningful, can be measured reliably by SLPs, changes quantitatively over time and is highly reproducible, thus may be useful as a clinical outcome assessment for ALS clinical trials. Furthermore, a LE prediction model is effective at predicting LE scores and should be validated on an external dataset.}, } @article {pmid40727259, year = {2025}, author = {Sun, W and Zhu, A and Chang, H and Xia, J and Gao, J and Zhang, Z and Chi, F and Zhu, Y and Bao, X}, title = {Causal associations and shared genetic etiology between neurodegenerative diseases and constipation.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251362469}, pmid = {40727259}, issn = {2542-4823}, abstract = {BACKGROUND: There is increasing evidence suggesting a correlation between neurodegenerative diseases (NDDs) and constipation; however, their genetic relationship and causal mechanisms remain inadequately elucidated.

OBJECTIVE: We aim to investigate the causal link and shared genetic basis between NDDs and constipation.

METHODS: We obtained summary statistics from large-scale genome-wide association studies, encompassing five NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), as well as constipation. The primary analysis employed five Mendelian randomization methods to evaluate causal effects, while linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) were utilized to investigate genetic correlations. Additionally, significant pleiotropic SNPs were identified using pleiotropic analysis under the composite null hypothesis (PLACO) and functional mapping and annotation (FUMA). Finally, enrichment analysis was conducted to explore the biological pathways associated with the identified pleiotropic genes.

RESULTS: MR analysis revealed a significant causal relationship between AD and an enhanced risk of constipation was demonstrated (OR = 1.043, 95% CI: 1.015-1.073, p = 0.003), while no causality was found between PD, MS, ALS, LBD, and the risk of constipation (p > 0.05). LDSC and HDL analysis revealed a significant positive genetic correlation between AD and constipation. Using PLACO combined with FUMA, we identified 30 overlapping pleiotropic loci, with pathway enrichment analysis revealing important biological pathways related to Aβ metabolism and processing, tau protein process, and the complement and coagulation cascades.

CONCLUSIONS: Our study indicates that AD is a contributing factor to constipation and uncovers the complex genetic mechanisms linking AD and constipation, which holds significant implications for diagnosis and treatment of both conditions.}, } @article {pmid40727601, year = {2025}, author = {Termkijwanich, P and Sanguanwit, P and Yuksen, C and Trakulsrichai, S and Sricharoen, P}, title = {Different Resuscitation Termination Criteria for Out of Hospital Cardiac Arrest; A Prognostic Accuracy Study.}, journal = {Archives of academic emergency medicine}, volume = {13}, number = {1}, pages = {e59}, pmid = {40727601}, issn = {2645-4904}, abstract = {INTRODUCTION: Termination of resuscitation (TOR) rules in out of hospital cardiac arrest (OHCA) varies across different healthcare settings and populations. This study aimed to externally validate ten TOR rules for predicting death before hospital admission among OHCA patients.

METHODS: A retrospective prognostic accuracy study analyzed 379 non-trauma OHCA patients (≥18 years) in Bangkok who were either treated by the emergency medical services (EMS) of Ramathibodi Hospital or transported to Ramathibodi's emergency department by another EMS provider (January 2010 - March 2023). The predictive performance of ten TOR rules (AHA-BLS, AHA-ALS, Korean Cardiac Arrest Research Consortium (KoCARC) rules I, II, and III, Goto's rule, Shihabashi's rule, the New Model I, Helsinki's, and Petrie's rule) in predicting death before hospital admission as well as false positive rates (FPRs) of rules at various resuscitation times were calculated and reported with 95% confidence interval (CI).

RESULTS: Among 379 OHCA patients, 308 (81.27%) died before hospital admission and 71 (18.73%) survived to discharge. The New model I demonstrated the most conservative predictive performance with sensitivity of 96.7% (95% CI: 93.0-98.8), NPV of 91.5% (95% CI: 82.5-96.8), and area under the curve (AUC) of 0.74 (95% CI: 0.70-0.79). The KoCARC III showed FPR of 2.8%. Based on the initial presenting criteria, the FPR varied at different resuscitation time points, with increasing FPR over 30 minutes. Among all rules, Helsinki's and AHA-BLS showed the highest FPRs (1.14 - 21.13 and 1.14 - 23.94, respectively) while the KoCARC TOR rules III demonstrated the most conservative consistency in maintaining a low FPR (0-2.82%) throughout time.

CONCLUSION: The KoCARC III demonstrated relatively high safety for TOR decisions in Bangkok's OHCA population, with the lowest FPR, and high sensitivity and NPV. TOR rules showed higher FPRs compared to previous studies. These findings should be interpreted with caution due to the retrospective design, potential selection bias, and EMS protocol changes over the 10-year study period.}, } @article {pmid40728364, year = {2025}, author = {Wang, M and Guo, X and Zhang, H and Zhang, N and Yin, T and Gao, Y and Kang, J and Hu, Y and Fan, D and Ye, S}, title = {Educational adjustments for the Chinese version of the Edinburgh Cognitive and Behavioral Screen (ECAS): establishing normative data.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {702-708}, doi = {10.1080/21678421.2025.2539904}, pmid = {40728364}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; Middle Aged ; China/epidemiology ; *Educational Status ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/psychology ; Aged ; Adult ; *Neuropsychological Tests/standards ; Reference Values ; Mental Status and Dementia Tests ; Young Adult ; Cognition/physiology ; }, abstract = {BACKGROUND: The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a cognitive screening tool designed for patients with amyotrophic lateral sclerosis (ALS). It has been translated into various languages and used globally. This study aimed to establish normative data for the Chinese version of the ECAS to better serve the Mandarin population.

METHODS: We enrolled 358 healthy individuals from different regions of China, all of whom completed the ECAS, and 340 also completed the Mini-Mental State Examination (MMSE). The participants were categorized into six age groups and five education groups.

RESULTS: ECAS scores were found to be related to education level (p < 0.001). After Bonferroni correction for multiple comparisons, we determined that there were no significant differences in total ECAS scores between the junior middle school and senior middle school groups, leading to their combination into a single middle school group. We established cutoff values for the ECAS on the basis of education group. After adjusting for age, sex, and education level, a significant correlation was found between MMSE scores and total ECAS scores (p < 0.001), indicating a high level of consistency in the cognitive assessment.

CONCLUSION: We have established norms for the ECAS on the basis of education level, and the ECAS is highly consistent with the MMSE in the assessment of cognition. These norms will be instrumental in future clinical and follow-up work for Mandarin ALS patients.}, } @article {pmid40728732, year = {2025}, author = {Tuddenham, JF and Fujita, M and Lee, E and Nimmagadda, N and Khairallah, A and Harbison, C and Flowers, XE and Coronas-Samano, G and Maniatis, S and Daly, A and Schneider, JA and Teich, AF and Vonsattel, JPG and Sims, PA and Elyaman, W and Bradshaw, EM and Ostrow, LW and Phatnani, H and Shneider, NA and Bennett, DA and De Jager, PL and Przedborski, S and Menon, V and Olah, M}, title = {Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord.}, journal = {Acta neuropathologica}, volume = {150}, number = {1}, pages = {10}, pmid = {40728732}, issn = {1432-0533}, support = {NS107442//National Institute of Health, USA/ ; R01 NS107442/NS/NINDS NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; CS-02018-191971//Chan-Zuckerberg Neurodegeneration Challenge Network/ ; NS117583//National Institute of Health, USA/ ; S10 OD020056/OD/NIH HHS/United States ; P30 CA013696/CA/NCI NIH HHS/United States ; RF1 AG057473/AG/NIA NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; AG057473//National Institute of Health, USA/ ; R25 MH129256/MH/NIMH NIH HHS/United States ; R01 NS117583/NS/NINDS NIH HHS/United States ; RF1 AG057473/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/pathology/genetics/metabolism ; Humans ; *Spinal Cord/immunology/metabolism/pathology ; *Microglia/metabolism/immunology ; *Transcriptome ; Single-Cell Analysis ; *Brain/immunology/metabolism/pathology ; Female ; Male ; Middle Aged ; Aged ; }, abstract = {Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in the ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.}, } @article {pmid40730020, year = {2025}, author = {Martins, AP and Mattos, AHB and Pupe, CCB and Martinez, ARM and Nucci, A and França, MC}, title = {The novel missense variant D40V causes a young adult presentation of ANXA11-related myopathy.}, journal = {Neuromuscular disorders : NMD}, volume = {53}, number = {}, pages = {105443}, doi = {10.1016/j.nmd.2025.105443}, pmid = {40730020}, issn = {1873-2364}, mesh = {Humans ; Female ; Adult ; *Mutation, Missense ; *Annexins/genetics ; *Muscular Diseases/genetics/physiopathology ; Phenotype ; }, abstract = {Pathogenic variants in the ANXA11 gene, which encodes the calcium-dependent phospholipid ligand protein Annexin A11, have been recently associated with amyotrophic lateral sclerosis, frontotemporal dementia and/or muscle disease. ANXA11-related myopathy is characterized by slowly progressive adult-onset limb-girdle weakness combined with axial and facial muscle involvement. Here we expand the spectrum of ANXA11-related myopathy with the description of a 38-year-old Brazilian woman with prominent distal and bulbar manifestations combined with dropped head caused by the novel p.D40V ANXA11 variant. This report widens both the genotypic and phenotypic spectrum of ANXA11-related myopathy. It also points to the pathophysiological relevance of amino acid changes at the highly conserved 40th Annexin A11 residue.}, } @article {pmid40730054, year = {2025}, author = {Zhao, J and Bai, J and Wang, H and Zhang, Y and Zhang, J and Zhu, Y and Pang, X and Chen, Z and Ling, L and Cheng, H and Li, M and Huang, X}, title = {Diagnostic value of EMG of sternocleidomastoid and trapezius in assessing bulbar lower motor neuron involvement in amyotrophic lateral sclerosis patients.}, journal = {Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology}, volume = {84}, number = {}, pages = {103040}, doi = {10.1016/j.jelekin.2025.103040}, pmid = {40730054}, issn = {1873-5711}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; *Electromyography/methods ; Middle Aged ; Female ; *Superficial Back Muscles/physiopathology ; Aged ; *Motor Neurons/physiology ; *Neck Muscles/physiopathology ; Adult ; Reproducibility of Results ; Sensitivity and Specificity ; }, abstract = {The diagnostic value of needle electromyography (EMG) of sternocleidomastoid (SCM) and trapezius (TRA) in assessing bulbar lower motor neuron involvement (LMN) remained controversial. 203 sporadic amyotrophic lateral sclerosis (ALS) patients were enrolled to assess the correlation between EMG abnormalities in SCM and TRA and bulbar LMN involvement. Additionally, difference analysis and diagnostic consistency analysis of EMG abnormalities in GEN (genioglossus), SCM, and TRA were compared. Finally, separate effects of EMG abnormalities in GEN, SCM, and TRA on diagnostic gradings were examined according to the Awaji-Shima criteria. 22 (18.2 %) and 65 (53.7 %) patients without bulbar LMN involvement showed EMG abnormalities in SCM and TRA. In contrast, 19 (23.2 %) and 11 (13.4 %) patients with bulbar LMN involvement showed normal EMG results in SCM and TRA. Multivariate logistic regression analyses showed that both EMG abnormalities in SCM and TRA were correlated with bulbar LMN involvement (P < 0.001). SCM showed electrophysiological characteristics similar to GEN when compared to TRA. However, TRA (67.0 %) showed significantly higher rates of EMG abnormalities than SCM (41.9 %) and GEN (40.4 %) in the whole study population. Reclassified diagnostic gradings showed no significant difference when evaluating EMG abnormalities in individual muscles to indicate bulbar LMN involvement (P = 0.072). EMG abnormalities in SCM and TRA could not fully represent bulbar LMN involvement but were correlated with it. It's advisable to prioritise TRA as a better option when a patient cannot tolerate an EMG examination in the GEN. To enhance the diagnostic evaluation, an EMG examination of GEN could be served as the last choice.}, } @article {pmid40730291, year = {2025}, author = {Magdalena, R and Ferrada, L and Ramírez, E and Smith-Ghigliotto, JF and Salazar, K and Nualart, F}, title = {Dehydroascorbic acid impairs neurite growth through RIPK1-associated caspase activation.}, journal = {Free radical biology & medicine}, volume = {239}, number = {}, pages = {406-416}, doi = {10.1016/j.freeradbiomed.2025.07.036}, pmid = {40730291}, issn = {1873-4596}, mesh = {*Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/genetics ; *Neurites/drug effects/metabolism/pathology ; Animals ; *Dehydroascorbic Acid/pharmacology ; Enzyme Activation/drug effects ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Imidazoles/pharmacology ; Indoles/pharmacology ; *Caspases/metabolism ; Mice ; Amino Acid Chloromethyl Ketones/pharmacology ; Ascorbic Acid ; Antioxidants/pharmacology ; Humans ; }, abstract = {Axonal and neurite loss is a common event in neurodegenerative diseases, such as Alzheimer's disease or amyotrophic lateral sclerosis, which are enhanced by oxidative damage and reactive oxygen species (ROS) production. In the central nervous system, vitamin C can be found as ascorbic acid (AA), its reduced form, or dehydroascorbic acid (DHA), its oxidized form. Vitamin C mainly acts as an antioxidant agent, and homeostasis in the brain is maintained through its recycling between neurons and astrocytes. However, DHA accumulation under pathophysiological conditions has been associated with changes in neuronal metabolism and necroptotic cell death through RIPK1 activation. Furthermore, recent studies show that DHA accumulation induces significant neurite loss; however, it is unknown whether this effect is associated with RIPK1 activation. Here, we show that DHA treatment on neurospheres (NE) in vitro induces significant neurite shortening and reduced branching, effects associated with early RIPK1 activation and inhibited through Necrostatin-1s and zVAD-FMK treatment, suggesting the activation of apoptotic mechanisms. Finally, we propose DHA, the oxidized form of vitamin C, impairs neurite growth through ripk1-associated caspase activation.}, } @article {pmid40731193, year = {2025}, author = {Turkbey, B and Schoots, IG and Haider, MA}, title = {Reply to Masatomo Kaneko, Vasileios Magoulianitis, Vinay Duddalwar, et al's Letter to the Editor re: Baris Turkbey, Henkjan Huisman, Andriy Fedorov, et al. Requirements for AI Development and Reporting for MRI Prostate Cancer Detection in Biopsy-naive Men: PI-RADS Steering Committee, Version 1.0. Radiology 2025;315:e240140.}, journal = {European urology}, volume = {88}, number = {5}, pages = {e102}, doi = {10.1016/j.eururo.2025.07.005}, pmid = {40731193}, issn = {1873-7560}, } @article {pmid40732891, year = {2025}, author = {Hein, ZM and Arbain, MFF and Kumar, S and Mehat, MZ and Hamid, HA and Che Ramli, MD and Che Mohd Nassir, CMN}, title = {Intermittent Fasting as a Neuroprotective Strategy: Gut-Brain Axis Modulation and Metabolic Reprogramming in Neurodegenerative Disorders.}, journal = {Nutrients}, volume = {17}, number = {14}, pages = {}, pmid = {40732891}, issn = {2072-6643}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy ; *Fasting/physiology ; Gastrointestinal Microbiome/physiology ; Animals ; *Brain/metabolism ; *Brain-Gut Axis/physiology ; *Neuroprotection ; Energy Metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Metabolic Reprogramming ; Intermittent Fasting ; }, abstract = {Intermittent fasting (IF) is emerging as a heterogeneous neurometabolic intervention with the possibility of changing the course of neurodegenerative diseases. Through the modulation of the gut-brain axis (GBA), cellular bioenergetics (or metabolic) reprogramming, and involvement in preserved stress adaptation pathways, IF influences a range of physiological mechanisms, including mitobiogenesis, autophagy, circadian rhythm alignment, and neuroinflammation. This review critically synthesises current preclinical and early clinical evidence illustrating IF's capability to supplement synaptic plasticity and integrity, reduce toxic proteins (proteotoxic) burden, and rehabilitate glial and immune homeostasis across models of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The key players behind these effects are bioactive metabolites such as short-chain fatty acids (SCFA) and β-hydroxybutyrate (BHB), and molecular mediators such as brain-derived neurotrophic factor (BDNF). We feature the therapeutic pertinence of IF-induced changes in gut microbiota composition, immune response, and mitochondrial dynamics, and we discuss emerging approaches for merging IF into precision medicine frameworks. Crucial challenges include individual variability, protocol optimisation, safety in cognitively vulnerable populations, and the need for biomarker-guided, ethically grounded clinical trials. Finally, we propose IF as a scalable and flexible intervention that, when personalised and integrated with other modalities, may reframe neurodegeneration from a model of irreversible decline to one of modifiable resilience.}, } @article {pmid40733876, year = {2025}, author = {Wang, Q and Liu, Y and Zou, G and Liang, Z and Liu, H and Yang, BR and Qin, Z}, title = {Modeling light propagation for under-display sensing in a smartphone.}, journal = {Optics express}, volume = {33}, number = {15}, pages = {30847-30858}, doi = {10.1364/OE.565761}, pmid = {40733876}, issn = {1094-4087}, abstract = {Under-display sensing (UDS) is essential to achieve bezel-less smartphones (infinity display). However, light penetrating or reflected by the display panel is distorted, deteriorating UDS signals. Therefore, light propagation should be accurately modeled to analyze and optimize UDS. This study proposes a universal model that recognizes the light propagation mode using the Fresnel number. Under-display ambient light sensors (ALS), under-display cameras (UDC), and proximity sensors are identified to work in the geometric optics, Fraunhofer diffraction, and Fresnel diffraction regimes, respectively. A commercial smartphone is adopted to demonstrate the model's effectiveness and provide domain knowledge. First, regarding the angular response attenuation in under-display ALS, the geometric obstruction by the pixel layout is simulated after acquiring the display panel's microphotograph. Measured data agrees with the simulation with an error smaller than 10 degrees in the viewing angle's full width at half maximum. Next, the UDC is simulated using Fraunhofer diffraction to provide full-color pictures containing blurring caused by the pixel layout's diffraction, showing high similarity with photographs. Finally, Fresnel diffraction dominates the under-display proximity sensor, which utilizes a weakly collimated infrared beam. An approximate solution of the signal on the detector is a scaled Fraunhofer diffraction pattern whose magnification is determined by the sensor configuration. The source-detector orientation influences the background noise (the signal level when no user is present), which is simulated and compared with experimental data, providing an optimal orientation of 45 degrees. The gap between the sensor and the display panel is also investigated through simulation and experiment, demonstrating that Fresnel diffraction is more effective than geometric optics or Fraunhofer diffraction. The proposed model with solid experimental verification on a commercial smartphone can help rationally design UDS and provide insight into the light propagation problem in smartphones.}, } @article {pmid40735390, year = {2025}, author = {Liu, Y and Chen, G and Li, M and Li, M and Xie, D and Luo, Z}, title = {Development of long-acting riluzole transdermal patch against amyotrophic lateral sclerosis: Mechanistic insights into polyglyceryl-3 dioleate-enhanced drug release and skin permeation.}, journal = {International journal of pharmaceutics: X}, volume = {10}, number = {}, pages = {100363}, pmid = {40735390}, issn = {2590-1567}, abstract = {Patients with amyotrophic lateral sclerosis (ALS) often experience difficulty swallowing, making oral administration unsuitable for effective treatment. A transdermal drug delivery system (TDDS) offers a long-acting, non-invasive alternative for ALS therapy. In this study, a riluzole transdermal patch capable of sustained release over 72 h was developed. In vitro skin permeation and pharmacokinetic experiments were conducted to evaluate the impact of various factors-including drug loading, type and concentration of chemical penetration enhancers (CPEs), and type of pressure-sensitive adhesive-on riluzole absorption through the skin. The optimized patch formulation contained 17 % (w/w) riluzole and 10 % (w/w) polyglyceryl-3 dioleate (PGD), with an adhesive layer thickness of 111 μm. The final prescription penetration rate of riluzole was found to be 2.96 μg/(h·cm[2]). Optimized formulation displayed enhanced stability and prolonged pharmacokinetic performance (C max = 74.34 ± 13.62 ng/mL, MRT0-t = 34.91 ± 11.31 h). No significant skin irritation was observed. The role of PGD in the in vitro release and in vivo transdermal absorption of riluzole was thoroughly investigated. The results revealed that PGD not only reduced the interaction between riluzole and the pressure-sensitive adhesive, enhancing drug release but also increased the fluidity of skin lipids, leading to improved transdermal absorption. This study provides a comprehensive molecular-level understanding of PGD's effect on riluzole permeation, offering valuable insights for the rational selection of CPEs in the development of riluzole TDDS.}, } @article {pmid40735897, year = {2025}, author = {Leonardo, C and Bjorling, A and Chadwick, KA}, title = {Factors Associated With Type 1 Thyroplasty Revision: Insights From the TriNetX Database.}, journal = {The Laryngoscope}, volume = {135}, number = {12}, pages = {4774-4780}, doi = {10.1002/lary.32478}, pmid = {40735897}, issn = {1531-4995}, mesh = {Humans ; Male ; *Reoperation/statistics & numerical data ; Female ; Retrospective Studies ; *Laryngoplasty/methods/statistics & numerical data ; Middle Aged ; Databases, Factual ; Aged ; Risk Factors ; *Vocal Cord Paralysis/surgery ; Adult ; }, abstract = {OBJECTIVES: Type 1 thyroplasty (T1T), or medialization laryngoplasty (ML), is a laryngeal framework surgery that corrects glottic insufficiency. Prior studies report revision rates of T1T from 5% to 40%, but factors influencing the need for revision have not been studied in detail. The objectives of this study were to determine the revision rate of T1T and identify patient factors associated with revision.

METHODS: Retrospective cohort study. Patients undergoing T1T (CPT 31591) were identified in TriNetX, a global collaborative network with data from over 128 million patients. The revision rate was determined by the percentage of patients undergoing a second T1T at least 30 days after the initial procedure. Patient factors (demographics, surgical history, and comorbidities) were compared between groups.

RESULTS: A total of 4029 patients underwent T1T; 323 (8.02%) patients underwent revision T1T. Patients undergoing revision were slightly older at initial surgery compared to those not requiring revision (63.5 vs. 61.2 years, p = 0.02), and more likely to be of White or American Native race. Comorbidities associated with revision include pulmonary diseases, neurological conditions, and mental health disorders. A history of thyroidectomy or tracheostomy was also associated with revision. Gender, geographic region, tobacco use, emphysema, Parkinson's disease, and amyotrophic lateral sclerosis were not associated with the need for revision T1T.

CONCLUSION: This is the first comprehensive analysis of factors associated with revision T1T using the TriNetX database. Certain demographic and patient factors may influence the likelihood of requiring revision T1T, potentially impacting patient selection and providing a basis for individualized preoperative patient counseling.

LEVEL OF EVIDENCE: Level III.}, } @article {pmid40735987, year = {2025}, author = {Ergin, AD}, title = {Nanotechnological Approaches for Mitochondrial Targeting in Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {25}, number = {28}, pages = {3251-3266}, pmid = {40735987}, issn = {1873-4294}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Mitochondria/drug effects/metabolism ; *Nanotechnology ; *Drug Delivery Systems ; Animals ; Nanoparticles/chemistry ; *Neuroprotective Agents/chemistry/pharmacology ; }, abstract = {OBJECTIVES: Mitochondria are dynamic organelles essential for energy metabolism and cellular homeostasis, playing critical roles in ATP production, calcium regulation, redox balance, and apoptosis. However, mitochondrial dysfunction is a central factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. Given the essential role of mitochondria in neuronal survival, targeted therapeutic strategies that restore mitochondrial function have gained significant attention. This review explores the latest advances in mitochondrial-targeted therapies and their potential applications in neurodegenerative diseases.

METHODS: A comprehensive literature review was conducted on mitochondrial-targeted therapeutic strategies, with a focus on nanotechnology-based drug delivery systems. The analysis includes various nanoparticle-based approaches, such as liposomes, DQAsomes, and polymeric nanoparticles, which have demonstrated high biocompatibility, controlled drug release, and enhanced mitochondrial targeting efficiency. Additionally, mitochondria-penetrating peptides and delocalized lipophilic cations (DLCs) are discussed for their role in improving drug localization within mitochondria and overcoming biological barriers, including the blood-brain barrier (BBB).

RESULTS: Recent research shows the potential of mitochondrial-targeted antioxidants, peptides, and biocompatible nanocarriers in arranging mitochondrial dysfunction and protecting neurons from oxidative damage. Various nanoparticle-based drug delivery systems have demonstrated the ability to selectively target mitochondria, improving drug bioavailability, therapeutic efficacy, and neuroprotective outcomes in neurodegenerative diseases.

CONCLUSION: Mitochondria-targeted therapies provide promising avenues for disease-modifying treatments aimed at preserving neuronal integrity and delaying disease progression. The unique properties of nanoparticles, such as their ability to enhance drug stability, facilitate controlled release, and achieve precise mitochondrial localization, make them valuable tools for neurodegenerative disease therapy. Future research should focus on optimizing delivery systems, validating clinical applicability, and exploring interdisciplinary approaches to accelerate translation into effective treatments.}, } @article {pmid40736059, year = {2026}, author = {Zhao, Q and Zhao, Z and Zhao, G and Xue, L and Chen, L and Zhou, G and Liang, J and Qin, M and Hu, M}, title = {Effect of Defocus Incorporated Multiple Segments (Fog Vision +0.50 D) Combined With 0.01% Atropine on the Preclinical and Early Stages of Myopia in Children.}, journal = {Journal of pediatric ophthalmology and strabismus}, volume = {63}, number = {1}, pages = {11-22}, doi = {10.3928/01913913-20250530-04}, pmid = {40736059}, issn = {1938-2405}, mesh = {Humans ; *Atropine/administration & dosage ; Female ; *Myopia/therapy/physiopathology/diagnosis ; Male ; Child ; *Refraction, Ocular/physiology ; Retrospective Studies ; *Mydriatics/administration & dosage ; Follow-Up Studies ; Axial Length, Eye ; Treatment Outcome ; *Eyeglasses ; Ophthalmic Solutions ; Child, Preschool ; Visual Acuity/physiology ; Disease Progression ; Adolescent ; }, abstract = {PURPOSE: To retrospectively analyze the efficacy of multi-zone positive optical defocus lenses (DIMS) + fog vision + 0.01% atropine for the treatment of children with preclinical and early stages of myopia.

METHODS: The axial length (AL) and refraction were analyzed at baseline and after 12 months of follow-up in 192 eyes treated with combined therapy. The success of treatment was defined as an annual AL growth rate within the physiological growth range and myopia progression of -0.50 diopters (D)/year or greater. Subgroup analysis was performed to investigate the percentage of treatment success in the overall population compared to the subgroups based on baseline AL and age.

RESULTS: Overall, the success rates were 87% and 93% for AL control and myopia control, respectively. Compared to before combined therapy, there was an increase in AL after treatment (boys: P < .001; girls: P < .001). The change in spherical equivalent (SE) was consistent with the change in AL, with both boys and girls showing an increase in SE after treatment, with a statistically significant difference in girls (boys: P = .059; girls: P = .001). There was no statistically significant difference in the percentage of treatment success in either boys or girls based on baseline AL and age subgroups compared to the overall population.

CONCLUSIONS: The treatment regimen of DIMS + fog vision + 0.01% atropine demonstrated significant control effects on myopia in preclinical and early stages of myopia in children across different genders, baseline ALs, and ages. Timely intervention is recommended once a tendency toward myopia is observed in children.}, } @article {pmid40736930, year = {2025}, author = {Chen, X and Zhuang, J and Chen, Z and Liu, S and Xu, Y and Chen, C and Yi, J and Yu, F and Xie, B and He, F}, title = {The relationship between allostatic load levels and time to deterioration of health-related quality of life in non-small cell lung cancer patients.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, pmid = {40736930}, issn = {1932-2267}, support = {grant number 2023J01093//Fujian Provincial Natural Science Foundation Project/ ; }, abstract = {BACKGROUND AND PURPOSE: Allostatic load (AL) significantly impacts patient outcomes. This study aimed to explore the association between AL levels and time to deterioration (TTD) of health-related quality of life (HRQoL) in non-small cell lung cancer (NSCLC) patients.

METHODS: A prospective study (May 2017-September 2022) included 362 NSCLC patients from The First Affiliated Hospital of Fujian Medical University. HRQoL was assessed using EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires, and AL-related biomarkers were collected. Univariate and multivariate Cox regression analyses evaluated the impact of AL on HRQoL TTD.

RESULTS: TTD events were most common in global health status (QL), physical functioning (PF), and dyspnea (LC-DY). Lower AL levels delayed TTD in emotional functioning (EF) (HR = 2.041, 95% CI: 1.404-2.969, P < 0.001), cognitive functioning (CF) (HR = 1.613, 95% CI: 1.082-2.403, P = 0.019), insomnia (SL) (HR = 1.553, 95% CI: 1.064-2.266, P = 0.022), constipation (CO) (HR = 2.114, 95% CI: 1.179-3.791, P = 0.012), and hemoptysis (LC-HA) (HR = 2.316, 95% CI: 1.037-5.172, P = 0.041). Multivariate analysis confirmed these findings, except for insomnia, which lost significance.

CONCLUSIONS: Lower AL levels delayed TTD in EF, CF, CO, and LC-HA, highlighting AL's role in preserving HRQoL in NSCLC patients.

HRQoL is critical for cancer survivors. This study underscores the importance of AL to improve HRQoL outcomes in NSCLC patients.}, } @article {pmid40737092, year = {2025}, author = {Dargan, R and Mikheenko, A and Johnson, NL and Packer, BE and Li, Z and Craig, EJ and Como, CN and Sarbanes, SL and Bereda, C and Hao, Y and Mehta, PR and Keuss, M and Nalls, MA and Qi, YA and Weller, CA and Fratta, P and Ryan, VH}, title = {Altered mRNA transport and local translation in i3Neurons with RNA-binding protein knockdown.}, journal = {Nucleic acids research}, volume = {53}, number = {14}, pages = {}, pmid = {40737092}, issn = {1362-4962}, support = {/AG/NIA NIH HHS/United States ; Fi2GM142475/GM/NIGMS NIH HHS/United States ; ZIAAG000547/HH/HHS/United States ; /NH/NIH HHS/United States ; ZIAAG000534/HH/HHS/United States ; /NS/NINDS NIH HHS/United States ; Fi2GM146657/GM/NIGMS NIH HHS/United States ; ZIA AG000534/ImNIH/Intramural NIH HHS/United States ; ZIA AG000547/ImNIH/Intramural NIH HHS/United States ; //Center for Alzheimer's and Related Dementias/ ; }, mesh = {*RNA, Messenger/metabolism/genetics ; *Protein Biosynthesis ; Humans ; *RNA-Binding Proteins/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *RNA Transport ; Gene Knockdown Techniques ; Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; Induced Pluripotent Stem Cells/metabolism/cytology ; *Neurons/metabolism ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism ; Neurites/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Transcriptome ; Frontotemporal Dementia/genetics/metabolism ; }, abstract = {Neurons rely on messenger RNA (mRNA) transport and local translation to facilitate rapid protein synthesis in processes far from the cell body. These processes allow precise spatial and temporal control of translation and are mediated by RNA-binding proteins (RBPs), including those associated with neurodegenerative diseases. Here, we use proteomics, transcriptomics, and microscopy to investigate the impact of RBP depletion on mRNA transport and local translation in induced pluripotent stem cell-derived neurons. We find thousands of transcripts enriched in neurites and that many of these transcripts are locally translated, possibly due to the shorter length of transcripts in neurites. Loss of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS)-associated RBPs TDP-43 and hnRNPA1 induce distinct alterations in the neuritic proteome and transcriptome. TDP-43 knockdown (KD) leads to slightly increased neuritic mRNA and translation, while hnRNPA1 loss has more moderate effects on local mRNA profiles, possibly due to compensation by hnRNPA3. These results highlight the crucial role of FTD/ALS-associated RBPs in mRNA transport and local translation in neurons and the importance of these processes in neuron health and disease.}, } @article {pmid40737511, year = {2025}, author = {Turner, MR}, title = {Inverting the logic in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {11}, pages = {3783-3786}, pmid = {40737511}, issn = {1460-2156}, abstract = {Turner highlights survivorship bias in the study of neurodegenerative disorders such as ALS, suggesting that meaningful progress may require a fundamental shift in focus from the affected to the resilient, and from what is seen to what is not. Neurodegeneration should be viewed as a loss of tolerance as much as a gain of toxicity.}, } @article {pmid40738791, year = {2025}, author = {Roy, A and Dawson, VL and Dawson, TM}, title = {From metabolism to mind: The expanding role of the GLP-1 receptor in neurotherapeutics.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {22}, number = {5}, pages = {e00712}, pmid = {40738791}, issn = {1878-7479}, mesh = {Humans ; Animals ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Glucagon-Like Peptide-1 Receptor/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy/metabolism ; *Brain/drug effects/metabolism ; }, abstract = {GLP-1 receptor agonists (GLP-1RAs), initially approved for diabetes and obesity, are now under investigation for neuroprotective effects in a range of neurological disorders. These agents, whose receptors are widely expressed in brain regions involved in cognition and metabolism, modulate neurotransmitter release and promote neurogenesis. While preclinical studies consistently demonstrate benefits in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), clinical trial outcomes have been variable, largely owing to heterogeneity in study populations and trial design. Newer agents, such as NLY01 and tirzepatide, are under development to enhance central nervous system penetration and efficacy. Although GLP-1RAs are generally safe in metabolic conditions, their use in neurological diseases requires careful monitoring and patient selection. Future directions include developing reliable biomarkers, implementing precision medicine strategies, and exploring the use of combination therapies to maximize therapeutic potential.}, } @article {pmid40739673, year = {2025}, author = {Zheng, X and Yuan, W and Li, L and Ma, H and Zhu, M and Li, X and Feng, X}, title = {Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) to tackle central nervous system diseases: role as a promising approach.}, journal = {European journal of medical research}, volume = {30}, number = {1}, pages = {690}, pmid = {40739673}, issn = {2047-783X}, mesh = {Humans ; *Proprotein Convertase 9/metabolism/genetics ; *PCSK9 Inhibitors/therapeutic use ; *Central Nervous System Diseases/drug therapy/metabolism ; Animals ; }, abstract = {Atherosclerosis-associated disease (ASD) represents a complex pathological condition, characterized by the formation of atherosclerotic plaques within the arterial walls, encompassing cholesterol depositions, which is primarily attributed to elevated levels of low-density lipoprotein-cholesterol (LDL-C). A log-linear association between the absolute magnitude of LDL-C exposure and ASD risk has been widely studied. High levels of LDL-C have been acknowledged as the predominant culprit. The previous research findings have demonstrated that PCSK9 inhibitors (PCSK9i) can remarkably diminish the risk of ASD. The current research has primarily focused on the relevance of PCSK9 to the cardiovascular system and lipid metabolism; however, an increasing body of evidence shows that PCSK9 is pivotal in pathogenic processes in other organ systems. Yet, PCSK9's impact on the brain is complex and not fully clarified, although several recent studies emphasize a putative role of its impact on various neurodegenerative disorders. Among neurological disorders, not only stroke but neurogenesis, neural cell differentiation, central LDL receptor metabolism, neural cell apoptosis, neuroinflammation, alcohol use disorder (AUD), amyotrophic lateral sclerosis(ALS), and Alzheimer's Disease (AD) are related to PCSK9. PCSK9 expression in brain is low but greatly upregulated in neurological disorders. Therefore, PCSK9 is a promising pathway for the treatment of central nervous diseases. This review comprehensively describes evidence from the previous research on the effects of PCSK9i on the central nervous system, with a focus on the clinical potential of PCSK9i. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop treatments for the neurological diseases based on PCSK9i.}, } @article {pmid40740086, year = {2025}, author = {Ghazali, L and Hamid, SSA and Mohamad, H and Aziz, A}, title = {Clinical review of laryngomalacia in a tertiary hospital.}, journal = {The Medical journal of Malaysia}, volume = {80}, number = {4}, pages = {443-447}, pmid = {40740086}, issn = {0300-5283}, mesh = {Humans ; *Laryngomalacia/diagnosis/epidemiology/therapy/classification ; Male ; Female ; Retrospective Studies ; Tertiary Care Centers ; Infant ; Severity of Illness Index ; Infant, Newborn ; }, abstract = {INTRODUCTION: Laryngomalacia is the most common cause of stridor in infants, with severity ranging from mild to severe forms. Accurate classifications of severity is essential for guiding management and improving outcomes.

MATERIAL AND METHODS: We conducted a retrospective study of paediatric patients under two years of age diagnosed with laryngomalacia at a tertiary referral centre between January 2010 and December 2020. Data collected included demographic details, clinical presentation, comorbidities, endoscopic findings, treatment, and follow-up duration. Severity was classified using a symptoms-based scoring system by Shah et al, while laryngomalacia types were determined according to Olney et al's endoscopic classification. Association between severity, endoscopic findings, comorbidities and treatment choice were analysed using logistic regression.

RESULTS: A total of 148 patients were included (59.49% male). Mild, moderate, and severe laryngomalacia were observed in 45.27%, 35.14%, and 19.59% of patients, respectively. Type 3 laryngomalacia, identified via endoscopy, was significantly associated with severe disease (p<0.001). Comorbidities, particularly gastroesophageal reflux disease, cardiac, pulmonary, syndromic, neurological conditions and synchronous airway lesions, were significantly linked to higher severity (p<0.05). A strong association was found between severity and treatment: moderate cases had 89.6 times, and severe cases 133.3 times, the odds of receiving surgical intervention compared to mild cases (p<0.001).

CONCLUSION: Mild laryngomalacia was most prevalent, but severity increased with specific comorbidities and endoscopic findings. Objective symptom scoring and endoscopic classification are valuable for assessing severity and guiding appropriate management in laryngomalacia.}, } @article {pmid40740123, year = {2026}, author = {Giacomelli, E and Scirocco, E and Higgins, M and Pilja, A and Paganoni, S and Ho, D}, title = {Research access barriers in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {207-214}, doi = {10.1080/21678421.2025.2539900}, pmid = {40740123}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/epidemiology ; Humans ; *Biomedical Research ; *Health Services Accessibility ; }, abstract = {As the general population ages, amyotrophic lateral sclerosis (ALS) incidence and prevalence are expected to rise, and the barriers that limit participation in ALS clinical research studies may increase. In this report, we highlight key challenges and available resources for accessing clinical research. We emphasize the importance of education and engagement among individuals with ALS and their families, clinicians, and researchers. Addressing accessibility and fostering trust in ALS research participation is essential to advance treatments for this devastating disease. We propose practical strategies to overcome participation barriers, including decentralized trial models, remote participation options, and expanded outreach through patient navigators, advisory committees, and digital tools. Strengthening partnerships among individuals with ALS, caregivers, researchers, ALS organizations, regulators, and industry, will help align research efforts with community needs and accelerate therapeutic development.}, } @article {pmid40740433, year = {2025}, author = {Shahim, P and AlQahtani, A and Kokkinis, AD and Kazmi, N and Ezuma-Ngwu, M and Misra, J and Harmison, G and Benoit, N and Jones, M and Howe, E and Schindler, AB and Joe, GO and Grunseich, C}, title = {CSF and blood neuronal injury biomarkers in spinal bulbar muscular atrophy and amyotrophic lateral sclerosis 4.}, journal = {Brain communications}, volume = {7}, number = {4}, pages = {fcaf275}, pmid = {40740433}, issn = {2632-1297}, abstract = {Spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis 4 (ALS4) are two forms of motor neuron disease characterized by clinically slow disease progression. Based on the current limited human studies, the contribution of central nervous neurodegeneration to these diseases and the rate of clinical progression is unclear. Neuronal proteins glial fibrillary acidic protein (GFAP), neurofilament light (NfL) chain, or Total-tau measured in either cerebrospinal fluid or blood could serve as sensitive markers of neurodegeneration. We studied 56 adult participants (32 SBMA, 7 ALS4, and 17 controls) who were enrolled at the National Institutes of Health, of whom 22 (10 SBMA, 7 ALS4, and 5 controls) underwent paired CSF and serum sampling, and of whom 6 participants were assessed longitudinally up to 24 months from initial visit. An additional 7 controls completed CSF sampling only. CSF GFAP, NfL chain, and Total-tau correlated with corresponding levels in serum (r = 0.74, r = 0.47, and r = 0.70, respectively). CSF GFAP was increased in patients with SBMA (median, 8840 pg/mL, interquartile range (IQR) 5780-10489) as compared to controls (median, 5315 pg/mL, IQR 1822-6657; P = 0.029) but not compared with ALS4 (median, 5015 pg/mL, IQR 3172-9803; P = 0.31). Patients with SBMA had increased concentrations of CSF NfL chain (median, 719 pg/mL, IQR 483-773) as compared to ALS4 (median, 307 pg/mL, IQR 187-629; P = 0.034) or controls (median, 395 pg/mL, IQR 307-497; P = 0.024). In contrast, serum concentrations of either biomarker did not differ significantly between SBMA, ALS4, or controls. Higher CSF GFAP and NfL chain levels were associated with lower SBMA Functional Rating Scale scores (r = -0.49 and r = -0.42, respectively). Over the course of 24 months, the average change in SBMA Functional Rating Scale was -0.83 points, while the changes in CSF GFAP and NfL chain were progressive (increased 1.4-fold and 1.3-fold, respectively). Our data suggest that SBMA patients have increased concentrations of CSF GFAP and NfL chain as compared to ALS4 and controls, and higher levels of these biomarkers are associated with disease severity. Importantly, these results indicate that SBMA is associated with progressive neurodegeneration and that either CSF GFAP or NfL chain may be useful for patient stratification and monitoring treatment effects in clinical trials.}, } @article {pmid40740556, year = {2025}, author = {Mirenayat, MS and Fakharian, A and Valizadeh, M and Abedi, M and Sadeghi, S and Zahiri, R and Haghi Ashtiani, B and Masaebi, F and Zamani, B}, title = {Evaluation of Inspiratory Muscle Training Effect Compared With Diaphragmatic Breathing in Respiratory Parameters in Amyotrophic Lateral Sclerosis Patients: A Randomized Controlled Trial.}, journal = {Medical journal of the Islamic Republic of Iran}, volume = {39}, number = {}, pages = {37}, pmid = {40740556}, issn = {1016-1430}, abstract = {BACKGROUND: Many patients with amyotrophic lateral sclerosis (ALS) experience respiratory failure. The use of respiratory muscle training exercises can improve the respiratory function of these patients. This study aimed to evaluate the effect of inspiratory muscle training (IMT) on respiratory muscle function in ALS patients.

METHODS: In the current randomized controlled clinical trial study, 22 patients were randomly divided into intervention (n = 11) and control groups (n = 11). In the control group, patients used only chest-opening training and diaphragm exercises. Patients in the intervention group used IMT in addition to controlled exercises (chest opening training and diaphragm exercises). Respiratory function by spirometry and monitoring of maximum inspiratory and expiratory pressure, functional capacity with a 6-minute walk test, and arterial blood gases were also assessed by ABG analysis at baseline and after 8 weeks. A comparative analysis of variables was performed with a student t-test, considering type 1 error (α = 0.05) using SPSS 27 software.

RESULTS: The indexes included maximal inspiratory pressure (PImax) (P = 0.000) and maximal expiratory pressures PEmax (P = 0.002). The strength of breathing muscles index (S-index) (P = 0.002) had a significant increase before and after rehabilitation in both groups (P ˂ 0.05). In intergroup analysis, the only factor with a significant increase was PImax (P = 0.019).

CONCLUSION: The use of IMT, along with chest opening training and diaphragm exercises, can cause a relative improvement of the respiratory muscles' function indexes, especially PImax in ALS patients. More clinical trials are required.}, } @article {pmid40740926, year = {2025}, author = {Ding, Y and Xing, YX and Sun, NZ}, title = {Managements of bile leakage after liver transplantation: Commentary on recent findings.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {7}, pages = {108148}, pmid = {40740926}, issn = {1948-9366}, abstract = {Bile leakage remains a formidable challenge in post-liver transplantation management, posing significant risks to patient outcomes and graft survival. This editorial provides a critical appraisal of the recent clinical study by Gu et al, which compared the efficacy of stent placement vs endoscopic nasobiliary drainage (ENBD) for treating post-transplant bile leaks. By retrospectively analyzing data from their institutional cohort of liver transplant recipients with bile leaks, the authors evaluated the therapeutic success rates and clinical outcomes between the stent and ENBD groups, with a focused discussion on the relative advantages of each approach. Gu et al demonstrated that both stent placement and ENBD were effective in managing post-transplant bile leaks, with comparable therapeutic outcomes. However, the study also recognized its limitations, such as the lack of an assessment of the impact of bile leak severity on outcome and the absence of long-term follow-up data. The editorial further highlights the pressing need for advancing research on long-term complications post-liver transplantation and underscores the pivotal role of clinical stratification and physician expertise in guiding therapeutic decisions. In summary, Gu et al's study enhances our understanding of mitigating post-transplant complications like bile leaks and offers evidence-based insights to refine clinical protocols. This commentary aims to contextualize current research trends and future directions in the field, advocating for sustained innovation and evidence-driven practice.}, } @article {pmid40741286, year = {2024}, author = {Garand, KLF and Malek, AM and Ambrocio, KR}, title = {Linking Oropharyngeal Swallowing Physiology and Functional Clinical Predictors in Amyotrophic Lateral Sclerosis.}, journal = {Perspectives of the ASHA special interest groups}, volume = {9}, number = {1}, pages = {282-291}, pmid = {40741286}, issn = {2381-4764}, support = {IK1 RX001628/RX/RRD VA/United States ; K24 DC012801/DC/NIDCD NIH HHS/United States ; TL1 TR000061/TR/NCATS NIH HHS/United States ; }, abstract = {PURPOSE: We aimed to quantify oropharyngeal swallowing physiology in amyotrophic lateral sclerosis (ALS) and examine relationships between swallowing impairments and ratings of pulmonary function (forced vital capacity percent predicted, FVC % pre) and functional status (ALS Functional Rating Scale-Revised, ALSFRS-R).

METHOD: A retrospective analysis of swallowing-related data of persons with ALS (PALS) was completed. Their Modified Barium Swallow Impairment Profile component, Oral Total (OT), and Pharyngeal Total (PT) scores were compared with data from age- (±1 year) and sex-matched healthy controls retrieved from an archival normative data set using Mann-Whitney U tests. Relationships between PALS' OT and PT scores, FVC % pre, and ALSFRS-R were examined using Pearson product-moment correlations and multiple linear regression modeling.

RESULTS: Twenty-one PALS (12 women), with a mean age of 62.2 ± 9.9 years, were included in the analyses. Compared to healthy controls, PALS exhibited significantly worse function across 13 (76%) physiological swallowing components (all p < .05). OT and PT scores significantly differed between PALS and healthy controls (each p < .001), with higher scores (worse impairment) observed in the former. When adjusting for age and sex, FVC % pre was a significant predictor of OT score (p = .045). An inverse relationship was found with ALSFRS-R and OT score (p = .052). FVC % pre (p = .061) and ALSFRS-R (p = .54) did not significantly predict PT score.

CONCLUSIONS: PALS demonstrated swallowing impairments across oropharyngeal domains and the esophageal component. In our PALS cohort, FVC % pre was a useful clinical indicator of oral swallowing impairment.}, } @article {pmid40741338, year = {2025}, author = {Marek, A and Brož, B and Kriegelstein, M and Nováková, G and Hojcsková, J and Blechová, M and Žáková, L and Jiráček, J and Maletínská, L}, title = {Late-stage labeling of diverse peptides and proteins with iodine-125.}, journal = {Journal of pharmaceutical analysis}, volume = {15}, number = {7}, pages = {101198}, pmid = {40741338}, issn = {2214-0883}, abstract = {The preparation of specifically iodine-125 ([125]I)-labeled peptides of high purity and specific activity represents a key tool for the detailed characterization of their binding properties in interaction with their binding partners. Early synthetic methods for the incorporation of iodine faced challenges such as harsh reaction conditions, the use of strong oxidants and low reproducibility. Herein, we review well-established radiolabeling strategies available to incorporate radionuclide into a protein of interest, and our long-term experience with a mild, simple and generally applicable technique of [125]I late-stage-labeling of biomolecules using the Pierce iodination reagent for the direct solid-phase oxidation of radioactive iodide. General recommendations, tips, and details of optimized chromatographic conditions to isolate pure, specifically [125]I-mono-labeled biomolecules are illustrated on a diverse series of (poly)peptides, ranging up to 7.6 kDa and 67 amino acids (aa). These series include peptides that contain at least one tyrosine or histidine residue, along with those featuring disulfide crosslinking or lipophilic derivatization. This mild and straightforward late-stage-labeling technique is easily applicable to longer and more sensitive proteins, as demonstrated in the cases of the insulin-like growth factor binding protein-3 (IGF-BP-3) (29 kDa and 264 aa) and the acid-labile subunit (ALS) (93 kDa and 578 aa).}, } @article {pmid40744389, year = {2025}, author = {Nelson, VK and Begum, MY and Suryadevara, PR and Madhuri Kallam, SD and Panda, SP and Bodapati, A and Sanga, V and Bishoyi, AK and Ballal, S and Monsi, M and Walia, C and Prasad, GVS and Abomughaid, MM and Shukla, S and Chauhan, P and Jha, NK}, title = {Natural bioactive compounds as modulators of autophagy: A herbal approach to the management of neurodegenerative diseases.}, journal = {European journal of pharmacology}, volume = {1005}, number = {}, pages = {178003}, doi = {10.1016/j.ejphar.2025.178003}, pmid = {40744389}, issn = {1879-0712}, mesh = {Humans ; *Autophagy/drug effects ; *Neurodegenerative Diseases/drug therapy/pathology/metabolism ; Animals ; *Biological Products/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Polyglutamine (polyQ), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) disease are a significant health concern that affects millions of people every year worldwide. The main pathological hallmark of various NDs is the formation of misfolded protein aggregation and accumulation of inclusion bodies. These protein aggregates are mainly responsible for producing toxic effects and initiating neuronal cell death, ultimately promoting various NDs. On the other hand, the patients suffering from these kinds of diseases live in impaired conditions, imposing a substantial financial burden on the family. However, the current treatment strategies can only offer temporary relief from the disease symptoms and can't reverse the disease completely. Hence, there is an urgent need for specific and novel drug treatment that can significantly eradicate NDs. Ubiquitin proteasome system (UPS) and autophagy are the two essential intracellular defensive mechanisms that are involved in clearing the protein aggregates, pathogens, and damaged organelles from the cytoplasm and maintaining protein homeostasis. Nevertheless, UPS is inefficient in removing some kinds of organelles and aggregating-prone proteins, specifically in neuronal and glial cells. Under this kind of circumstance, the autophagy mechanism plays a vital role in eliminating the accumulated protein aggregates and other toxic elements from the cytoplasm of the neuronal cells that initiate oxidative stress. However, in NDs, the autophagy function is impaired, and the protein aggregates can't be eliminated effectively. Hence, forced up-regulation of autophagy function by applying various external agents could be a potential therapeutic strategy to control NDs like AD, PD, HD, and ALS. In this review, we focused on different kinds of plant-derived compounds that induce autophagy. We also discussed the role of these plant-derived autophagy modulators in various NDs. In this way, the current review will be a standalone reference to the researchers working in this area.}, } @article {pmid40744561, year = {2025}, author = {Mora, G and Gil-Monreal, M and Osuna, MD and Vijayarajan, VBA and Montull, JM and Llenes, JM and Recasens, J and Cirujeda, A and Marí, AI and Torra, J}, title = {First case of triple resistance to EPSPS, ALS, and synthetic auxin herbicides in Bassia scoparia (L.) Voss in Europe.}, journal = {Pesticide biochemistry and physiology}, volume = {213}, number = {}, pages = {106529}, doi = {10.1016/j.pestbp.2025.106529}, pmid = {40744561}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology ; *Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Herbicide Resistance/genetics ; *3-Phosphoshikimate 1-Carboxyvinyltransferase/antagonists & inhibitors/genetics/metabolism ; *Bassia scoparia/drug effects/genetics/enzymology ; *Indoleacetic Acids/pharmacology ; Plant Proteins/genetics/metabolism ; }, abstract = {Bassia scoparia (L.) Voss has evolved resistance to five herbicide modes of action (MoAs) worldwide, including multiple resistance to up to four MoAs. Seeds were collected from a putatively resistant B. scoparia population (GUI-R) that survived successive herbicide applications of synthetic auxins, acetolactate synthase (ALS), and 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) inhibitors in a no-till winter cereal field in Catalonia, Spain, in 2022, to assess resistance levels and mechanisms. Dose-response assays confirmed that GUI-R was 2-, 340-, 42.7-, and 60-fold more resistant to glyphosate, thifensulfuron, MCPA, and 2,4-D, respectively, based on plant weight, and 3.2-, 123-, 57.9-, and 32-fold more resistant based on plant survival. GUI-R showed cross-resistance to imazamox (46 % survival), but not to dicamba or fluroxypyr (100 % mortality), at the label rate. Preliminary studies using malathion pre-treatment, a cytochrome P450 inhibitor, reversed 2,4-D resistance in GUI-R at the label rate, resulting in a 97 % reduction in biomass. Molecular studies revealed that GUI-R has 4.9 additional copies of the EPSPS:ALS gene, with no known mutations and less shikimate accumulation than the susceptible population. ALS gene sequencing identified the Pro197Ser, Pro197Leu, and Trp574Leu mutations, along with a combined Pro197Ser + Trp574Leu mutation. In conclusion, EPSPS gene amplification and ALS mutations confer target-site resistance to glyphosate, thifensulfuron and imazamox in GUI-R. Resistance to 2,4-D and MCPA is probably driven by P450-mediated non-target-site resistance and further research is necessary to confirm mechanisms. This biotype represents the first case of glyphosate resistance in Europe for the species, as well as the first triple resistance.}, } @article {pmid40744595, year = {2025}, author = {Li, J and Zhang, Y and Li, L and Wei, S and Huang, Z and Chen, L and Huang, H}, title = {Expression of Echinochloa oryzoides CYP71A1 and GSTU23 catalyzes the metabolism of thiobencarb, thereby conferring resistance.}, journal = {Pesticide biochemistry and physiology}, volume = {213}, number = {}, pages = {106555}, doi = {10.1016/j.pestbp.2025.106555}, pmid = {40744595}, issn = {1095-9939}, mesh = {*Echinochloa/drug effects/genetics/metabolism/enzymology ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology/metabolism ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; *Thiocarbamates/metabolism/pharmacology ; *Plant Proteins/genetics/metabolism ; *Glutathione Transferase/metabolism/genetics ; }, abstract = {Echinochloa oryzoides (Ard.) Fritsch. is a notorious and prevalent weed in paddy fields. Thiobencarb (TB), a thiocarbamate herbicide, is widely applied in paddy fields for the control of pre-emergence weeds. However, owing to the prolonged and large-scale usage of TB, certain Echinochloa oryzoides populations have evolved resistance to it. In this study, a population of Echinochloa oryzoides from a paddy field was suspected of being resistant to the TB herbicide. Notably, this population also displayed multiple resistance and cross-resistance to Acetolactate synthase (ALS), Acetyl-CoA carboxylase (ACCase), and hormone-based herbicides. The resistance to TB was partially reversed by 50.8 % and 44.7 % upon treatment with a glutathione S-transferase (GST) inhibitor (NBD-Cl) and a cytochrome P450 inhibitor (malathion), respectively. This confirmed that metabolic resistance was the predominant mechanism underlying the observed resistance. RNA-seq analysis uncovered the overexpression of CYP71A1 and GSTU23 in the resistant (R) population. This study is the first to screen and validate metabolic enzymes capable of effectively metabolizing TB in an Echinochloa oryzoides. Functional verification was conducted using a yeast in vitro expression system, which confirmed the metabolic capabilities of both CYP71A1 and GSTU23 genes towards TB. Collectively, these findings demonstrate that the overexpression of CYP71A1 and GSTU23 in the R population endows Echinochloa oryzoides with the evolutionary capacity to develop resistance to thiobencarb. This study has shed light on the resistance mechanisms of Echinochloa oryzoides to TB, thereby enhancing our understanding of its herbicide tolerance. Moreover, these results highlight the necessity for targeted strategies to control resistant populations, ultimately contributing to more effective and sustainable herbicide resistance management in agriculture.}, } @article {pmid40744617, year = {2025}, author = {Kaspary, TE and Cutti, L and Turra, GM and Angonese, PS and Dos Santos, OD and Merotto, A}, title = {Conyza bonariensis resistance to glyphosate and ALS inhibitors involves target and non-target site resistance.}, journal = {Pesticide biochemistry and physiology}, volume = {213}, number = {}, pages = {106501}, doi = {10.1016/j.pestbp.2025.106501}, pmid = {40744617}, issn = {1095-9939}, mesh = {Glyphosate ; *Herbicide Resistance/genetics ; *Glycine/analogs & derivatives/pharmacology ; *Herbicides/pharmacology ; *Acetolactate Synthase/antagonists & inhibitors/genetics/metabolism ; *Conyza/drug effects/genetics ; Mutation ; Plant Proteins/genetics/antagonists & inhibitors/metabolism ; }, abstract = {Herbicide resistance in Conyza bonariensis (hairy fleabane) poses a significant challenge to agricultural systems worldwide. The genetic variability and prolific seed production of this species contribute significantly to its adaptative potential and fast spread in the agricultural fields. This study aimed to investigate the mechanisms underlying multiple herbicide resistance to glyphosate and ALS inhibitors in C. bonariensis biotypes from Southern Brazil. Resistance factors exceeded 100 times for chlorimuron-ethyl and 49 times for glyphosate. DNA Sequencing revealed the target-site mutations Pro106Thr in the EPSPS gene conferring glyphosate resistance, and Pro197Arg and Trp574Leu in the ALS gene contributing to chlorimuron-ethyl resistance. Additionally, the resistance factor decreased at least 80 % for resistant biotypes after application of chlorimuron-ethyl following treatment with the P450 inhibitor malathion, which might indicate enhanced metabolism mediated by cytochrome P450 enzymes. Copy number variation and overexpression of ALS and EPSPS genes were not related to resistance. Biotype II carries the Pro197Arg mutation and exhibited cross-resistance to imazethapyr, diclosulam, bispyribac‑sodium, and flucarbazone‑sodium. Biotypes carrying the Trp574Leu mutation were resistant to imazethapyr, diclosulam and flucarbazone‑sodium but demonstrated varying resistance patterns to bispyribac‑sodium, highlighting the complexity of resistance mechanisms. These findings underscore the importance of understanding both target and non-target-site resistance mechanisms to develop effective management strategies, including herbicide rotation and molecular diagnostics, to mitigate the spread of herbicide-resistant C. bonariensis in agricultural systems.}, } @article {pmid40745959, year = {2026}, author = {Dogra, S and Kouznetsova, VL and Tsigelny, IF}, title = {Repurposing FDA-approved drugs for treatment of amyotrophic lateral sclerosis using machine learning.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {198-206}, doi = {10.1080/21678421.2025.2536027}, pmid = {40745959}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Machine Learning ; *Drug Repositioning/methods ; United States Food and Drug Administration ; United States ; Drug Approval ; Molecular Docking Simulation ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by loss of motor neurons. Current medications are largely ineffective, associated with side effects, and hindered by a lack of agreement over treatment pathways. The time-intensive process and high costs further limit the development of therapeutics. Therefore, this research aimed to identify FDA-approved drugs that inhibit three proteins (Casein kinase 1, Protein tyrosine kinase 2, Ephrin type-A receptor 4) associated with ALS.

METHODS: A machine learning (ML) model was trained for each protein to identify an inputted compound as an active inhibitor of that protein. The FDA-approved drugs were then screened through these models, and 18 drugs were identified as likely inhibitors for all three proteins. The results were validated through protein-ligand docking of each drug to its respective protein(s).

RESULTS: Risperidone was the most active drug, with an average ML score of 1 and binding affinity of -8.9. The ML scores and binding affinities had a strong correlation, indicating reliability.

CONCLUSION: This research predicted multiple drugs that can simultaneously target many proteins involved in ALS, creating more effective treatment options at a lower cost. This procedure can be applied to efficiently discover drugs for other diseases in the future.}, } @article {pmid40746518, year = {2025}, author = {Liu, QZ and Zeng, L and Sun, NZ}, title = {Radiomics for preoperative pancreatic ductal adenocarcinoma risk stratification: Cross-population validation, multidimensional integration, challenges, and future directions.}, journal = {World journal of radiology}, volume = {17}, number = {7}, pages = {110048}, pmid = {40746518}, issn = {1949-8470}, abstract = {This editorial critically evaluated Liu et al's recent retrospective analysis of 283 Chinese patients with resectable pancreatic ductal adenocarcinoma (PDAC) that validated a preoperative computed tomography-based risk scoring system originally developed in South Korea. The scoring system incorporated five parameters: (1) Tumor size; (2) Portal venous phase density; (3) Necrosis; (4) Peripancreatic infiltration; and (5) Suspected metastatic lymph nodes. While demonstrating satisfactory recurrence prediction capability without requiring complex technologies, thereby supporting clinical utility in Chinese populations, the study exhibited notable limitations. Most analyzed patients lacked neoadjuvant chemotherapy exposure, resulting in underrepresentation of low-risk subgroups. Additionally, the short follow-up duration potentially compromised long-term prognostic assessment. Contemporary advances in radiomics coupled with machine learning have enhanced multimodal data integration for PDAC management. However, clinical implementation continues to confront challenges including variability in imaging parameters, incomplete understanding of molecular underpinnings, and confounding treatment effects. Future investigations should prioritize developing multidimensional predictive frameworks that synergize radiographic, molecular, and clinical data. Prospective multicenter validation and artificial intelligence-powered real-time risk stratification systems represent essential steps to overcome current barriers in precision medicine translation, ultimately advancing personalized therapeutic strategies for PDAC.}, } @article {pmid40746624, year = {2025}, author = {Kashyap, PV and Singh, D and Nair, A and Jaiswal, A and Pandey, V}, title = {Effect of Edaravone Therapy on Amyotrophic Lateral Sclerosis Functional Rating Score (ALS-FRS) in Patients of Amyotrophic Lateral Sclerosis (ALS) in Central India: A Retrospective Open Label Study.}, journal = {Annals of neurosciences}, volume = {}, number = {}, pages = {09727531251357377}, pmid = {40746624}, issn = {0972-7531}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons and is characterised by a diverse range of clinical manifestations. With the understanding of its pathophysiology, many treatments have emerged in last two decades. This study aims to evaluate the impact of intravenous Edaravone on Amyotrophy Lateral Sclerosis Functional Rating Scale (ALS-FRS) scores and patient survival outcomes of Amyotrophic Lateral Sclerosis patients in Central India.

METHODS: This retrospective study was conducted over a span of 2.5 years and included patients diagnosed with definitive or probable ALS, as per the revised El Escorial criteria. The effects of intravenous (IV) Edaravone on ALS-FRS-R scores were compared between two groups: the intervention group (patients who received IV Edaravone) and the non-intervention group (patients who did not receive IV Edaravone). Data collected included demographic details and ALS-FRS-R scores that were recorded at baseline after each treatment cycle, for a total six cycles. These scores were compared with those of the control group at the corresponding time points. Survival outcomes were also evaluated between the two groups and side effect profile of the drug was also noted.

RESULTS: Data of ALS patients (definitive and probable) were screened, and 62 patients were enrolled, of which 12 were excluded, thus there were 25 ALS patients in the intervention group and 25 patients in the non-intervention group. The two groups were matched for demographic parameters and the ALS-FRS scores were noted at the baseline at each cycle till 6 cycles and compared. It was inferred that the scores were not significant statistically (p > .001) among the two groups, nor did the survival rates vary significantly.

CONCLUSION: Intravenous Edaravone therapy had no beneficial effect on the ALS-FRS score in the intervention group when compared to the non-intervention group, nor did the survival rates improve. Keywords: Amyotrophic lateral sclerosis, Edaravone Therapy, ALS FRS Score.}, } @article {pmid40746751, year = {2025}, author = {Sabetta, E and Rallmann, K and Bergquist, J and Taba, P and Pfaff, AL and Poudel, BH and Ferrari, D and Locatelli, M and Kõks, S}, title = {Comprehensive identification of pathogenic tandem repeat expansions in sporadic amyotrophic lateral sclerosis: advantages of long-read vs. short-read sequencing.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {250}, number = {}, pages = {10593}, pmid = {40746751}, issn = {1535-3699}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; *DNA Repeat Expansion/genetics ; Aged ; Adult ; *Sequence Analysis, DNA/methods ; High-Throughput Nucleotide Sequencing/methods ; Whole Genome Sequencing/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder presenting progressive weakness of the bulbar and extremity muscles, leading to a wide-ranging clinical phenotype. More than 30 genes have been associated to genetically inherited ALS yet, approximately 85%-90% of ALS cases are sporadic. Short tandem repeats expansions, have recently been found in clinically diagnosed ALS patients and are currently investigated as potential genetic biomarkers. In this paper we compare the investigation of pathological tandem repeat expansions on a group of ALS patients by comparing the standard short-read sequencing (SRS) technique with a long-read-sequencing (LRS) method which has recently become more accessible. Blood samples from 47 sporadic ALS cases were subjected to SRS by Illumina Whole Genome Sequencing. The genome-wide tandem repeat expansions were genotyped using GangSTR, while wANNOVAR was used for variant annotation. Uncertain cases were further explored using LRS. SRS identified pathological expansions in HTT, ATXN2, and CACNA1A genes in one patient, which were not confirmed with LRS. The latter identified large tandem repeat expansions in the C9orf72 gene of one patient that were missed by SRS. Our findings suggest that LRS should be preferred to SRS for accurate identification of pathological tandem repeat expansions.}, } @article {pmid40747225, year = {2025}, author = {Li, J and Wang, W}, title = {Challenges of Klebsiella pneumoniae infections post-liver transplantation: Insights and future directions.}, journal = {World journal of hepatology}, volume = {17}, number = {7}, pages = {107213}, pmid = {40747225}, issn = {1948-5182}, abstract = {Klebsiella pneumoniae infections (KPIs), particularly carbapenem-resistant Klebsiella pneumoniae (CRKP), pose significant challenges in liver transplantation (LT) recipients, with high morbidity and mortality. Guo et al's study highlights risk factors, such as elevated day-one alanine aminotransferase levels and prolonged catheterization, and identifies polymyxin B and ceftazidime/avibactam as effective treatments. However, limitations like the absence of pre-transplant colonization data and host-pathogen interaction insights highlight the need for enhanced strategies. Future directions should include routine CRKP colonization surveillance, immune and genomic profiling, and the development of novel therapeutics. By integrating these approaches, we can improve the prevention, diagnosis, and treatment of KPIs in LT patients.}, } @article {pmid40747386, year = {2025}, author = {Arnold, WD and Castoro, R and Saxena, S}, title = {Innovations In Physical Medicine and Rehabilitation: Advances in the Diagnosis, Treatment, and Care of Amyotrophic Lateral Sclerosis.}, journal = {Missouri medicine}, volume = {122}, number = {3}, pages = {199-205}, pmid = {40747386}, issn = {0026-6620}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy/rehabilitation ; *Physical and Rehabilitation Medicine/trends/methods ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that causes loss of upper and lower motor neurons, leading to muscle weakness and ultimately death. This review highlights recent advancements in Neuromuscular Medicine and Physical Medicine and Rehabilitation (PM&R), emphasizing innovations in the diagnosis, treatment, and care delivery for ALS. The field of PM&R emphasizes a multidisciplinary, patient-centered approach, incorporating advanced diagnostic tools, therapeutic strategies, adaptive equipment, and telerehabilitation to optimize function. Neuromuscular PM&R physicians play a key role in managing symptoms and maximizing functional independence. Current disease-modifying therapies include riluzole and edaravone which provide only modest benefits, but emerging gene therapies like tofersen for SOD1-related ALS offer promise for targeted treatment for genetic forms of ALS. Future advancements in regenerative therapies, biotechnologies, and digital health integration hold the potential to improve care and enhance the quality of life and functional independence of individuals living with ALS.}, } @article {pmid40747856, year = {2025}, author = {Guilfoyle, J and Fan, Y and SÁnchez-SoliÑo, O and Boiser, J and Vinikoor-Imler, L}, title = {Symptoms prior to diagnosis among a diverse patient population with amyotrophic lateral sclerosis In the USA.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {664-672}, doi = {10.1080/21678421.2025.2538599}, pmid = {40747856}, issn = {2167-9223}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/ethnology/physiopathology ; Black or African American/statistics & numerical data ; Cohort Studies ; Ethnicity ; Retrospective Studies ; United States/epidemiology ; White/statistics & numerical data ; Asian/statistics & numerical data ; Hispanic or Latino/statistics & numerical data ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) symptom onset is gradual and may include muscle weakness, dysarthria, dysphagia, and respiratory difficulties among others. The objective of this study is to describe sex and racial/ethnic variation in limb and bulbar symptom diagnoses before ALS diagnosis in the USA.

METHODS: This retrospective cohort study was conducted using Optum's de-identified Market Clarity Data with a patient identification period between January 2015 and December 2019. Cases were identified using ICD-9/10 codes and were required to have ≥3 years of continuous enrollment or EHR activity prior to diagnosis. Descriptive statistics of symptom frequency and onset were stratified by sex and race.

RESULTS: This study identified 7121 individuals with ALS, 3303 female (46%) and 3818 male (54%). Most identified as Non-Hispanic White (67.5%), followed by African American (6.6%), Hispanic (3.6%), and Asian (0.9%), with 21.4% missing race/ethnicity. In the 3 years before ALS diagnosis, 42.9% of subjects were diagnosed with ≥1 bulbar symptom, 74.5% with ≥1 limb symptom, and 34.6% with both. Females more likely to be diagnosed than males: any bulbar 47.1% versus 39.3%, (p < 0.0001), any limb 76.0% versus 73.2%, (p = 0.007), both 38.1% versus 31.6%, (p < 0.0001). Variation by race/ethnicity was observed for limb symptoms (p < 0.0001) and both bulbar and limb symptoms (p = 0.008), but not bulbar symptoms alone (p = 0.07). Symptom onset to ALS was longer for females and varied by race/ethnicity.

CONCLUSION: Females were more likely to present with bulbar and limb symptoms prior to ALS diagnosis and African American patients were more likely to present with limb symptoms than other race/ethnicities.}, } @article {pmid40750607, year = {2025}, author = {Nógrádi, B and Molnár, K and Kristóf, R and Horváth, O and Huang, YT and Ridgway, Z and Elicegui, A and Fuertes-Alvarez, S and Alonso-Martin, S and Szebeni, GJ and Gémes, N and Ramadan, A and Smith, HL and Krizbai, IA and Patai, R and Siklós, L and Klivényi, P and Chaytow, H and Gillingwater, TH}, title = {The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {7053}, pmid = {40750607}, issn = {2041-1723}, support = {2021/MNDS/RP/8430GILL//MND Scotland (Motor Neuron Disease Scotland)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/pathology/metabolism/genetics ; *Receptors, CCR2/metabolism/genetics/immunology ; Animals ; *Chemokine CCL2/metabolism/immunology/genetics ; Humans ; Male ; *Neuromuscular Junction/pathology/metabolism/immunology ; Mice ; Muscle, Skeletal/pathology/metabolism/innervation/immunology ; Disease Models, Animal ; Macrophages/immunology/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Female ; Mice, Transgenic ; Leukocytes/immunology/metabolism ; }, abstract = {Systemic immune changes have been implicated in amyotrophic lateral sclerosis (ALS), but precise mechanisms and cellular targets remain unknown. Neuromuscular junction (NMJ) denervation is another major pathophysiological event in ALS, but it remains unclear whether immune system dysregulation contributes to this process. Here, we report leukocyte and macrophage infiltration in ALS patient-derived skeletal muscle biopsies. Immune cell infiltration was replicated across the hTDP-43, TDP-43[A315T] (male only) and TDP-43[M337V] mouse models, occurring from pre-symptomatic stages and targeted to NMJ-enriched muscle regions. Proteomic analysis implicated the CCL2-CCR2 axis as a driving factor. CCL2[+] cells were enriched around NMJs in hTDP-43 mice, and in ALS patient skeletal muscle. Local treatment with CCL2-neutralising antibodies or normal IgG antibodies in hTDP-43 mice reduced leukocyte infiltration and ameliorated NMJ denervation. These results demonstrate that the CCL2-CCR2 axis drives immune cell infiltration targeting NMJs in ALS, identifying a potential avenue for therapeutic intervention to prevent NMJ denervation.}, } @article {pmid40750781, year = {2025}, author = {Arnold, J and Pathak, P and Jin, Y and Pont-Esteban, D and McCann, CM and Lehmacher, C and Bonadonna, JP and Lewko, T and Burke, KM and Cavanagh, S and Blaney, L and Rishe, K and Cole, T and Paganoni, S and Lin, D and Walsh, CJ}, title = {Personalized ML-based wearable robot control improves impaired arm function.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {7091}, pmid = {40750781}, issn = {2041-1723}, mesh = {Humans ; *Robotics/instrumentation/methods ; *Wearable Electronic Devices ; *Arm/physiopathology/physiology ; Male ; Biomechanical Phenomena ; Female ; Stroke Rehabilitation/instrumentation/methods ; Middle Aged ; Movement/physiology ; Adult ; Shoulder/physiopathology ; Aged ; Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation ; Stroke/physiopathology ; Range of Motion, Articular ; }, abstract = {Portable wearable robots offer promise for assisting people with upper limb disabilities. However, movement variability between individuals and trade-offs between supportiveness and transparency complicate robot control during real-world tasks. We address these challenges by first developing a personalized ML intention detection model to decode user's motion intention from IMU and compression sensors. Second, we leverage a physics-based hysteresis model to enhance control transparency and adapt it for practical use in real-world tasks. Third, we combine and integrate these two models into a real-time controller to modulate the assistance level based on the user's intention and kinematic state. Fourth, we evaluate the effectiveness of our control strategy in improving arm function in a multi-day evaluation. For 5 individuals post-stroke and 4 living with ALS wearing a soft shoulder robot, we demonstrate that the controller identifies shoulder movement with 94.2% accuracy from minimal change in the shoulder angles (elevation: 3.4°, depression: 1.7°) and reduces arm-lowering force by 31.9% compared to a baseline controller. Furthermore, the robot improves movement quality by increasing their shoulder elevation/depression (17.5°), elbow (10.6°) and wrist flexion/extension (7.6°) ROMs; reducing trunk compensation (up to 25.4%); and improving hand-path efficiency (up to 53.8%).}, } @article {pmid40751342, year = {2025}, author = {Corcia, P and Erazo, D and Amador, MDM and Beltran, S and Bernard, E and Blasco, H and Boutoleau-Bretonniere, C and Bruneteau, G and Camdessanche, JP and Camu, W and Cassereau, J and Choumert, A and Codron, P and Cintas, P and De La Cruz, E and Danel, V and Desnuelle, C and Eyraud, N and Esselin, F and Fauret, AL and Lefilliatre, M and Fleury, MC and Genestet, S and Grapperon, AM and Guy, N and Jacquin-Piques, A and Beauvais, K and Lautrette, G and Le Masson, G and Mathis, S and Piegay, AS and Pittion-Vouyovitch, S and Sauleau, P and Soriani, MH and Vershueren, A and Mouzat, K and Guissart, C and Couratier, P and Vourc'h, P}, title = {Prevalence of SOD1 and C9orf72 Variants Among French ALS Population: The GENIALS Study.}, journal = {European journal of neurology}, volume = {32}, number = {8}, pages = {e70302}, pmid = {40751342}, issn = {1468-1331}, support = {//Biogen/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; C9orf72 Protein ; Superoxide Dismutase-1/genetics ; France/epidemiology ; Female ; Male ; Middle Aged ; Aged ; Adult ; *Proteins/genetics ; Prevalence ; *Superoxide Dismutase/genetics ; Age of Onset ; Genetic Variation ; }, abstract = {RATIONALE: Amyotrophic Lateral Sclerosis (ALS) is a fatal motoneuron disease in which genetics plays a central role for both familial and sporadic ALS cases. Systematic genetic analysis for all ALS patients is recommended at the time of diagnosis, leading to an early proposal of specific genetic therapy. Currently, C9orf72 is considered the most frequently mutated gene in ALS. Patients with a SOD1 pathogenic or probably pathogenic variants (ACMG classification) are eligible for SOD1 antisense oligonucleotide therapy.

OBJECTIVE: To determine the frequency of SOD1 variants and C9orf72 G4C2 repeats in a French ALS population and to describe genotype-phenotype relationships.

MATERIAL AND METHODS: One thousand incident ALS patients were enrolled from 22 ALS centers in France and followed up for 12 months. Epidemiological, familial history, neurological data, and genetic status were collected.

MAIN RESULTS: C9orf72 G4C2 repeats and SOD1 variants were observed in 7.6% and 1.6%, respectively. Fifty percent of SOD1 patients and 51% of C9orf72 patients had sporadic ALS. Fifteen different SOD1 variants were identified within the five exons and one intron. C9orf72 patients had a significantly younger age at onset and a trend toward a faster progression compared to non-expanded C9orf72 patients. Moreover, among the non-SOD1 non-C9orf72 population, patients with at least one C9orf72 copy with two G4C2 repeats had a shorter disease duration.

CONCLUSION: This study confirms SOD1 variants low frequency in the French population and highlights the more rapid disease progression observed in patients carrying C9orf72 expansions. These findings underscore the importance of systematic genetic screening at diagnosis.}, } @article {pmid40751692, year = {2026}, author = {Trudel, P and Quesnel-Olivo, MH and Blais, M and Ramanathan, U and Dupré, N}, title = {ALS patients and PAD: description and comparison of patients from a neuromuscular clinic in Canada.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {118-124}, doi = {10.1080/21678421.2025.2539894}, pmid = {40751692}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy/epidemiology/psychology ; Male ; Female ; Aged ; Retrospective Studies ; Middle Aged ; Canada/epidemiology ; *Suicide, Assisted/statistics & numerical data/psychology ; Adult ; Palliative Care ; Aged, 80 and over ; }, abstract = {OBJECTIVES: In Canada, patients with ALS (PALS) who meet specific criteria can request Medical Assistance in Dying (MAiD), also known as Physician-Assisted Death (PAD). However, little is known about the characteristics of those patients. This study describes PALS who died of MAiD and compares them with patients who died from natural disease complications.

METHODS: A retrospective study of 209 consecutive PALS' electronic medical records was performed. Patients selected had follow-up at the CHU de Québec-Université Laval and died between January 2014 and April 2023. Sociodemographic and disease evolution data were collected. Fisher's exact test and Kolmogorov-Smirnov tests were used.

RESULTS: The analysis included 174 patients. MAiD PALS (N = 64) were mainly males (54.7%), of median age 67 years, in a relationship (68.7%), and parents of adult children (71.9%). Both cohorts had similar past medical histories of depressive disorders (15%, p > 0.999). MAiD PALS elected to use percutaneous endoscopic gastrostomy (PEG) feeding in 18.7% of cases compared to 28.2% of PALS who died of complications of ALS (p = 0.203). Palliative care teams were significantly more likely to be involved with PALS elected to request MAiD (86.6%, p = 0.023).

DISCUSSION: PALS who request MAiD share similar demographic and clinical characteristics with those who died from natural disease progression in our cohort. Trends toward differences were observed, namely, in the rate of disease progression, with PALS who requested MAiD more likely to be fast progressors than their counterparts, and in PEG feeding use with ALS MAiD patients less likely to request it. Palliative care involvement was more prevalent with MAiD PALS.}, } @article {pmid40752076, year = {2025}, author = {Mamangam, S and Brimson, JM}, title = {Rhodamine-B induces amyotrophic lateral sclerosis symptoms like -behaviours in zebrafish.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {287}, number = {}, pages = {107515}, doi = {10.1016/j.aquatox.2025.107515}, pmid = {40752076}, issn = {1879-1514}, mesh = {Animals ; *Zebrafish/physiology ; *Water Pollutants, Chemical/toxicity ; Male ; *Behavior, Animal/drug effects ; Brain/drug effects/metabolism/pathology ; *Rhodamines/toxicity ; *Amyotrophic Lateral Sclerosis/chemically induced ; Oxidative Stress/drug effects ; }, abstract = {Rhodamine B (RhB), often misused as a food adulterant, accumulates in the brain, causing oxidative stress and neurodegeneration. However, its detrimental effects on molecular mechanisms still require further investigation. The zebrafish is a model organism for studying neurodegeneration and neuropathology. We aimed to investigate the impacts of RhB on neuro-molecular and behaviours in Adult male zebrafish. Zebrafish were exposed to varying RhB concentrations of 0.25, 0.5, 1.0 μM and Rotenone (RoT) of 0.5 μM for 21 days. Behavioural assessments, including the mirror test, shoal preference test, T-maze and Y-maze tests, and novel tank test, were conducted to evaluate the impact of RhB on zebrafish behaviour. Furthermore, biochemical, neurochemical, and histopathological changes in the zebrafish brains were analysed. The neuronal behaviour patterns, such as reduced anxiety-like behaviour, time spent near or interacting with the mirror image, and cognitive dysfunction, were significantly affected by RhB in a time-dose-dependent manner when compared to those of control zebrafish. The glutathione reductase, catalase, lipid peroxidation, and reactive oxygen species levels were significantly increased, and acetylcholinesterase, glutathione peroxidase, superoxide dismutase, butyrylcholinesterase, serotonin, dopamine, and monoamine oxidase A and B were significantly reduced when exposed to RhB, when compared to those of control zebrafish. The C9orf72, btg2, fus, cfos, vgf, drd1b, npas4a, egr1, pax6a, vgf, ubb, atxn2, ier2a, tradbpa, tuba812 and grin1a mRNA levels were significantly upregulated. At the same time, sod1, bdnf, gabra1, and gabra2a were significantly down-regulated in the brain of RhB-exposed zebrafish compared to the control fish. These results suggested that RhB exposure can induce neurodegeneration in zebrafish mimicking Amyotrophic Lateral Sclerosis (ALS).}, } @article {pmid40753073, year = {2025}, author = {Lv, G and Sayles, NM and Huang, Y and Mancinelli, C and McAvoy, K and Shneider, NA and Manfredi, G and Kawamata, H and Eliezer, D}, title = {Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {7121}, pmid = {40753073}, issn = {2041-1723}, support = {R01NS139141//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; S10OD026974//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 NS139141/NS/NINDS NIH HHS/United States ; F31AG077836//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R35 NS122209/NS/NINDS NIH HHS/United States ; S10OD016320//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; RF1AG066493//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; S10OD028556//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01 AG066493/AG/NIA NIH HHS/United States ; R35NS122209//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 961871-02//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; P30CA016087//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; S10RR027699//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; F31HL154651//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; SF349247//Simons Foundation/ ; U01NS134684//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Amyloid/metabolism/ultrastructure/chemistry/genetics ; *Mitochondrial Proteins/genetics/metabolism/chemistry/ultrastructure ; *DNA-Binding Proteins/genetics/metabolism/chemistry ; Cryoelectron Microscopy ; *Transcription Factors/genetics/metabolism/chemistry/ultrastructure ; Mutation ; *Neurodegenerative Diseases/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Frontotemporal Dementia/genetics/metabolism ; Models, Molecular ; Parkinson Disease/genetics/metabolism ; }, abstract = {Mitochondrial proteins CHCHD10 and CHCHD2 are mutated in rare cases of heritable FTD, ALS and PD and aggregate in tissues affected by these diseases. Here, we show that both proteins form amyloid fibrils and report cryo-EM structures of fibrils formed from their disordered N-terminal domains. The ordered cores of these fibrils are comprised of a region highly conserved between the two proteins, and a subset of the CHCHD10 and CHCHD2 fibril structures share structural similarities and appear compatible with sequence variations in this region. In contrast, disease-associated mutations p.S59L in CHCHD10 and p.T61I in CHCHD2, situated within the ordered cores of these fibrils, cannot be accommodated by the wildtype structures and promote different protofilament folds and fibril structures. These results link CHCHD10 and CHCHD2 amyloid fibrils to neurodegeneration and further suggest that fibril formation by the WT proteins could also be involved in disease etiology.}, } @article {pmid40753166, year = {2025}, author = {Rothstein, JD and Keeley, O and Warlick, C and Miller, TM and Ly, CV and Glass, JD and Coyne, AN}, title = {Sporadic ALS induced pluripotent stem cell derived neurons reveal hallmarks of TDP-43 loss of function.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {7092}, pmid = {40753166}, issn = {2041-1723}, support = {R01 NS122236/NS/NINDS NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; NS132836//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Neurons/metabolism/pathology ; C9orf72 Protein/genetics/metabolism ; Nuclear Pore/metabolism/pathology ; Male ; Nuclear Pore Complex Proteins/metabolism/genetics ; Female ; Brain/metabolism/pathology ; Frontotemporal Dementia/genetics/metabolism/pathology ; Middle Aged ; }, abstract = {Nuclear loss and cytoplasmic buildup of the RNA-binding protein TDP-43 is a hallmark of ALS and related disorders. While studies using artificial TDP-43 depletion in neurons have revealed changes in gene expression and splicing, their relevance to actual patients remained unclear. Induced pluripotent stem cell (iPSC)-derived neurons (iPSNs) from 180 individuals, including controls, C9orf72 ALS/FTD, and sporadic ALS (sALS) patients were used to generate and analyze ~32,500 qRT-PCR data points across 20 genes which identified variable, time-dependent signatures of TDP-43 loss of function in individual lines. Notably, the same changes were also seen in postmortem brain tissue from the same patients, confirming that iPSNs accurately model disease. Inducing damage to the nuclear pore complex, specifically by reducing the nucleoporin POM121 in healthy iPSNs, was enough to replicate the molecular changes associated with ALS/FTD TDP-43 dysfunction. This directly links nuclear pore integrity to TDP-43-related pathology. Encouragingly, repairing nuclear pore injury in sALS iPSNs restored normal gene processing disrupted by TDP-43 loss. This study (1) provides a valuable population-scale resource for studying TDP-43 dysfunction in ALS, (2) confirms that patient-derived iPSNs closely reflect disease processes seen in the brain, and (3) demonstrates that targeting nuclear pore injury may offer a promising therapeutic strategy in ALS.}, } @article {pmid40754251, year = {2025}, author = {Sepulveda, M and MartinezTraub, F and Ojeda, P and Mella, J and Ojeda, J and Pinto, C and Diaz, R and Rozas, P and Sepulveda, C and Kerr, B and Morales, V and Saaranen, M and Ruddock, L and Medinas, DB and Henriquez, JP and Hetz, C}, title = {Expression of amyotrophic lateral sclerosis associated protein disulfide isomerase A3 D217N variant recapitulates early morphological alterations at the neuromuscular junction.}, journal = {Neurobiology of disease}, volume = {214}, number = {}, pages = {107045}, doi = {10.1016/j.nbd.2025.107045}, pmid = {40754251}, issn = {1095-953X}, support = {//US Army Medical Research Acquisition Activity/ ; //U.S. Air Force Office of Scientific Research/ ; //FONDAP program/ ; //Swiss Consolidation Grant -The Leading House for the Latin American Region/ ; //São Paulo Research Foundation/ ; //Muscular Dystrophy Association/ ; //ALS Association/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Neuromuscular Junction/pathology/metabolism ; *Protein Disulfide-Isomerases/genetics/metabolism ; Mice, Transgenic ; Mice ; Humans ; Disease Models, Animal ; Motor Neurons/pathology/metabolism ; Mutation ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by neuromuscular connectivity decline followed by motoneuron loss. Altered proteostasis is suggested as a transversal pathogenic mechanism, notably involving dysfunction at the level of the endoplasmic reticulum (ER). Protein disulfide isomerases (PDIs) are key enzymes that catalyze protein folding and disulfide bond formation in the ER. Importantly, PDIs function is disrupted in ALS. We previously identified mutations in the gene encoding PDIA3 (also known as Grp58 or ERp57) as risk factors for ALS, which were associated with altered neuromuscular junction (NMJ) organization when expressed in zebrafish, a phenotype recapitulated in PDIA3-null mice. Here, we generated a transgenic mouse line overexpressing the ALS-linked PDIA3 variant D217N and performed a comprehensive characterization of ALS-like features. The transgenic line exhibited moderate overexpression of mutant PDIA3[D217N], which led to morphological alterations at the NMJ resembling those observed in ALS models and patients, along with abnormal distribution of oxidative and glycolytic muscle fibers. However, mutant PDIA3[D217N] expression did not result in motor impairment, coordination deficits, or motoneuron loss. At the molecular level, we observed reduced expression of SV2 in the spinal cord, an important synaptic protein involved in NMJ function. Our findings further support the involvement of PDIA3 dysfunction as a risk factor in the emergence of early features of ALS.}, } @article {pmid40754996, year = {2025}, author = {Stam, R}, title = {Low frequency magnetic field exposure and neurodegenerative disease: systematic review of animal studies.}, journal = {Electromagnetic biology and medicine}, volume = {44}, number = {4}, pages = {566-580}, doi = {10.1080/15368378.2025.2540435}, pmid = {40754996}, issn = {1536-8386}, mesh = {Animals ; *Magnetic Fields/adverse effects ; *Neurodegenerative Diseases/etiology/pathology/therapy ; Humans ; Disease Models, Animal ; }, abstract = {Epidemiological studies have found an association between occupational exposure to low frequency magnetic fields and the occurrence of motor neuron disease and Alzheimer's disease. No association has been found for Parkinson's disease and the evidence for multiple sclerosis is insufficient. Animal models studying the effects of low frequency magnetic fields on neurodegenerative disease induction or progression could provide more evidence on causation and the underlying mechanisms. A systematic search and review was conducted of peer-reviewed research articles involving animal experiments on the effects of low frequency magnetic field exposure on behavioural and neuroanatomical outcomes relevant for neurodegenerative diseases in humans. Firstly, experimental studies in naive animals do not support a causal relationship between exposure to low frequency magnetic fields and the induction of neuropathology relevant for Alzheimer's disease, but the number of studies relevant for motor neuron disease, multiple sclerosis and Parkinson's disease is too limited to draw conclusions. Secondly, experimental studies in existing animal models for neurodegenerative disease support a therapeutic (beneficial) effect of low frequency magnetic field treatment on behavioural and neuroanatomical abnormalities relevant for dementia (including Alzheimer's disease), multiple sclerosis and Parkinson's disease and no effect on disease progression in models relevant for motor neuron disease.}, } @article {pmid40755012, year = {2025}, author = {Chen, S and Xu, C and Liu, C and Li, J and Ke, S and Lu, Y and Huang, Y and Chen, J and Lin, F and Huang, H and Zou, Z}, title = {Immune checkpoint changes correlate with the progression and prognosis of amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {57}, number = {1}, pages = {2540023}, pmid = {40755012}, issn = {1365-2060}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/blood/diagnosis ; Male ; Female ; Middle Aged ; Prognosis ; Disease Progression ; CD4-Positive T-Lymphocytes/immunology/metabolism ; Aged ; Biomarkers/blood ; *Programmed Cell Death 1 Receptor/blood/immunology ; Neurofilament Proteins/blood ; Adult ; Case-Control Studies ; Flow Cytometry ; *Immune Checkpoint Proteins/blood ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) urgently requires robust biomarkers for early diagnosis and prognostic stratification. This study aims to investigate the diagnostic and prognostic potential of membrane-bound and soluble immune checkpoint molecules in ALS pathogenesis.

METHODS: In the present study at Fujian Medical Union Hospital, 72 participants (46 ALS and 26 healthy controls [HC]) underwent flow cytometry analysis of PD-1 expression in CD4[+] T cells and its subsets. A second cohort (n = 93, 44 ALS, 30 HC and 19 ALS mimics [Mimics]) was evaluated using Luminex technology for 14 serum immune checkpoint molecules. A single-molecule array was used to screen the neurofilament light chain (NFL) in serum.

RESULTS: Flow cytometry revealed elevated PD1 expression in CD4[+] T cells, particularly in Th9 and Th17 subsets (p < 0.05). ALS patients exhibiting a greater percentage of PD-1 in CD4[+] T cells showed accelerated functional decline. Serum analyses identified four elevated soluble checkpoints in ALS versus both HCs and Mimics (sPD-1/sBTLA/sCTLA-4/sCD27, p < 0.05), with sCD28/TIM-3 showing higher in ALS than in Mimics, and sGITR/sCD137/sIDO/sCD80/sLAG3/sPD-L2 elevating in ALS compared to HCs. Soluble TIM-3 correlated inversely with ALSFRS-R, while sPD-L1 demonstrated dual associations: negative with ALSFRS-R and positive with NFL (all p < 0.05).

CONCLUSIONS: Our research demonstrated a considerable increase in membrane-bound and soluble PD-1 in ALS patients, correlating with disease progression and worse prognosis. Furthermore, we explored 13 other immune checkpoint molecules. Collectively, these molecules may be implicated in peripheral immune mechanisms underlying ALS pathogenesis. While baseline PD-1 levels show some association with prognosis, their elevation potentially indicates an unfavorable course.}, } @article {pmid40757018, year = {2025}, author = {Kato, N and Suzuki, R and Kaneko, H and Horimoto, Y}, title = {Effects of telerehabilitation on physical function and activities of daily living in patients with amyotrophic lateral sclerosis: a scoping review.}, journal = {Journal of physical therapy science}, volume = {37}, number = {8}, pages = {427-434}, pmid = {40757018}, issn = {0915-5287}, abstract = {[Purpose] This study aimed to clarify the effects of telerehabilitation on physical function and activities of daily living in patients with amyotrophic lateral sclerosis through a literature review. [Participants and Methods] We conducted a scoping review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews reporting guidelines. The PubMed, Scopus, Web of Science, and ProQuest databases were searched. Study design, type of interventions, telerehabilitation methods, adherence, effectiveness, adverse events, and patient satisfaction were extracted from the selected literature. [Results] Four case-series and one case-control study were identified. The interventions included respiratory muscle training (two studies), aerobic exercise, stretching, and comprehensive physical therapy (one study each). Various modalities were used, including videoconferencing, on-demand instructional videos, and real-time monitoring of vital signs using wearable devices. No serious adverse events were reported in any study. The dropout rate was 0-21%, and the compliance rate was 90%, indicating high adherence. Improvements in respiratory function and ADL were observed following respiratory rehabilitation. Patient satisfaction with telerehabilitation was high. [Conclusion] Telerehabilitation may improve adherence, respiratory function, and activities of daily living in patients with amyotrophic lateral sclerosis. However, its effects on other aspects of physical function remain unclear. Further high-quality studies are needed to establish evidence-based practices.}, } @article {pmid40757593, year = {2024}, author = {Orsini, M and Pinto, WBVR and Sgobbi, P and Oliveira, ASB}, title = {PRKAG2 Variant, Motor Neuron Disease, and Parkinsonism: Fortuitous Association or a Potentially Underestimated Pathophysiological Mechanism?.}, journal = {Muscles (Basel, Switzerland)}, volume = {3}, number = {3}, pages = {235-241}, pmid = {40757593}, issn = {2813-0413}, abstract = {A 72-year-old Brazilian woman presented with a 4-year history of rest tremors of the hands, followed by slowness of movement, and a diagnosis of idiopathic Parkinson's disease. She was started on dopamine agonists with significant improvement. After three years, she complained about slowly progressive dysphagia, dysphonia, quadriparesis, and cramps and fasciculations. A neurological examination disclosed distal-dominant quadriparesis, dysarthria, atrophy and fasciculation of the tongue, global brisk tendon reflexes, fasciculations, bilateral ankle clonus, and moderate spasticity of the lower limbs. She had also palpitations, dyspnea, and one episode of paroxysmal atrial fibrillation. Electrocardiography revealed a short PR interval, a widened QRS complex, and the delta wave, suggestive of Wolff-Parkinson-White syndrome. Brain and spine MR imaging, a cerebrospinal fluid analysis, and general serum lab exams were unremarkable. Needle electromyography disclosed chronic denervation involving cervical, thoracic, lumbosacral, and bulbar levels associated with acute denervation, including positive sharp waves, fasciculations, and fibrillation potentials. This patient fulfilled the diagnostic criteria for amyotrophic lateral sclerosis associated with parkinsonism. A broad next-generation sequencing-based panel disclosed the presence of the novel heterozygous variant c.1247C > T (p.Pro416Leu) in the PRKAG2 gene (NM_016203.4). Clinicians must be aware of the possibility of PRKAG2 variants in complex clinical scenarios associating cardiac arrhythmia, preexcitation syndromes, hypertrophic cardiomyopathy, motor neuron disease, and parkinsonism.}, } @article {pmid40758256, year = {2025}, author = {Sharma, A and Nb, K}, title = {Dose-dependent effects of Arimoclomol in ALS: insights from a network meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {11}, pages = {6073-6074}, pmid = {40758256}, issn = {1590-3478}, } @article {pmid40758370, year = {2025}, author = {Lam, K and Cenzer, I and Ankuda, CK and Levy, CR and Smith, AK and Covinsky, KE and Kotwal, AA}, title = {Social Participation Among Older Adults Before and After Long-Term Care Facility Entry.}, journal = {JAMA internal medicine}, volume = {185}, number = {10}, pages = {1257-1265}, pmid = {40758370}, issn = {2168-6114}, support = {K24 AG068312/AG/NIA NIH HHS/United States ; K23 AG065438/AG/NIA NIH HHS/United States ; R03 AG074038/AG/NIA NIH HHS/United States ; P01 AG066605/AG/NIA NIH HHS/United States ; K76 AG064427/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Social Participation/psychology ; Female ; Male ; Aged ; *Long-Term Care ; Aged, 80 and over ; Longitudinal Studies ; United States ; *Nursing Homes/statistics & numerical data ; *Assisted Living Facilities ; Medicare ; Quality of Life ; }, abstract = {IMPORTANCE: Social participation is essential throughout life and is associated with decreased mortality and increased quality of life. It is unknown whether long-term care facility (LTCF) entry disrupts or facilitates it.

OBJECTIVES: To determine longitudinal trends in social participation before and after entry into nursing homes (NHs) and assisted living facilities (ALs) and to explore factors associated with participation.

This nationally representative longitudinal cohort study using prospectively collected annual data from the US National Health and Aging Trends Study from 2011 to 2019 included community-dwelling Medicare beneficiaries entering LTCFs. Interviews conducted 4 years before and 2 years after NH or AL entry (index date) were included. Data analysis was performed from September 16, 2022, to May 25, 2025.

MAIN OUTCOMES AND MEASURES: Two categories of social participation comprising 5 activities were assessed: socialization (visiting with friends or family and going out for enjoyment) and community participation (attending religious services, participating in clubs or other organized activities, and volunteering). Participation over time was modeled using linear splines before, upon, and after LTCF entry. Modified Poisson regressions were used to explore associations with maintaining and starting activities, adjusted for age, sex, race and ethnicity, and proxy response were used.

RESULTS: The total sample included 606 LTCF entrants (weighted mean [SD] age 85 [7.4] years, 404 female [66% weighted]), of whom 104 individuals were Black (7%), 23 Hispanic (4%), 464 White (86%); and 15 of any other race and ethnicity (3%). Before entry, social participation decreased in all activities (-4.7 to -2.0% annually). Of the total, 275 (44%) entered a NH and 331 (56%) entered an AL facility. Upon entry, going out for enjoyment decreased (-14.1%), but club participation and religious attendance increased (15.6% and 12.6%, respectively). Before LTCF entry, social participation decreased in all activities (-4.7 to -2.0% annually). After entry, going out for enjoyment decreased (-14.1%), but club participation and religious attendance (12.6%) increased (15.6% and 12.6%, respectively). In exploratory analyses, women were more likely to maintain visits (adjust risk ratio [aRR], 1.3; 95% CI, 1.1-1.5) and start attending religious services (aRR, 1.6; 95% CI, 1.0-2.8). NH residents were less likely to go out for enjoyment (aRR, 0.6; 95% CI, 0.5-0.8 for maintaining; aRR, 0.6; 95% CI, 0.4-1.0 for starting) and keep attending religious services (aRR, 0.7; 95% CI, 0.6-0.9). Black, Hispanic, and residents of other race or ethnicity were much less likely to start going out for enjoyment (aRR, 0.3; 95% CI, 0.1-0.8).

CONCLUSIONS AND RELEVANCE: This cohort study found that LTCF entry generally promoted community participation and reduced socialization. Benefits may be less likely among men, NH entrants, and residents of racial and ethnic minority groups.}, } @article {pmid40758885, year = {2025}, author = {Miller, SL and Green, KM and Crone, B and Switzenberg, JA and Tank, EMH and Krans, A and Jansen-West, K and Wieland, CM and Ji, EW and Petrucelli, L and Barmada, SJ and Boyle, AP and Todd, PK}, title = {Cryptic intronic transcriptional initiation generates efficient endogenous mRNA templates for C9orf72-associated RAN translation.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {32}, pages = {e2507334122}, pmid = {40758885}, issn = {1091-6490}, support = {BLRD BX004842//U.S. Department of Veterans Affairs (VA)/ ; F31NS100302//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS097542 P01NS08497 and R35NS097273//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 GM144484/GM/NIGMS NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; R01NS113943 and 1R56NS128110//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21HG011493 and R01GM144484//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; R01NS099280//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21 HG011493/HG/NHGRI NIH HHS/United States ; F31 NS100302/NS/NINDS NIH HHS/United States ; F31127371//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Animals ; *Introns/genetics ; Humans ; *RNA, Messenger/genetics/metabolism ; Mice ; *Protein Biosynthesis ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Frontotemporal Dementia/genetics/metabolism ; DNA Repeat Expansion ; *ran GTP-Binding Protein/genetics/metabolism ; Transcription, Genetic ; }, abstract = {Intronic GGGGCC hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite its intronic location, this repeat avidly supports synthesis of pathogenic dipeptide repeat (DPR) proteins via repeat-associated non-AUG (RAN) translation. However, the template RNA species that undergoes RAN translation endogenously remains unclear. Using long-read based 5' RNA ligase-mediated rapid amplification of cDNA ends (5' Repeat-RLM-RACE), we identified C9orf72 transcripts initiating within intron 1 in a C9BAC mouse model, patient-derived iNeurons, and iNeuron-derived polysomes. These cryptic m[7]G-capped mRNAs are at least partially polyadenylated and are more abundant than transcripts derived from intron retention or circular intron lariats. In RAN translation reporter assays, intronic template transcripts-even those with short (32 nucleotide) leaders-exhibited robust expression compared to exon-intron and repeat-containing lariat reporters. To assess endogenous repeat-containing lariat RNA contributions to RAN translation, we enhanced endogenous lariat stability by knocking down the lariat debranching enzyme Dbr1. However, this modulation did not impact DPR production in patient-derived iNeurons. These findings identify cryptic, linear, m[7]G-capped intron-initiating C9orf72 mRNAs as an endogenous template for RAN translation and DPR production, with implications for disease pathogenesis and therapeutic development.}, } @article {pmid40758998, year = {2025}, author = {Jin, Y and Ganguly, P and Shea, JE and Buratto, SK and Bowers, MT}, title = {Aggregation of TDP-43307-319: A Dual Pathway to Forming Cylindrins and Fibrils and a Contribution to the Etiology of Amyotrophic Lateral Sclerosis.}, journal = {The journal of physical chemistry. B}, volume = {129}, number = {32}, pages = {8099-8114}, doi = {10.1021/acs.jpcb.5c02640}, pmid = {40758998}, issn = {1520-5207}, mesh = {*Amyotrophic Lateral Sclerosis/etiology/metabolism/genetics ; *DNA-Binding Proteins/chemistry/genetics/metabolism ; Molecular Dynamics Simulation ; Humans ; Microscopy, Atomic Force ; Protein Aggregates ; Mutation ; Mass Spectrometry ; }, abstract = {The pathological aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is a hallmark of amyotrophic lateral sclerosis, and mutations within its low-complexity domain are known to influence its aggregation propensity and toxicity. Previous studies from our group and others have shown that TDP-43307-319 located at the C-terminus of TDP-43 is toxic and can form higher-order oligomers and fibrils. Of particular interest are the hexamers, which adopt a cylindrin structure that has been strongly correlated to neurotoxicity. In this study, we used a combination of ion mobility spectroscopy-mass spectrometry (IMS-MS), atomic force microscopy (AFM), and molecular dynamics simulations to probe the oligomer distribution resulting from the earliest times (the first 5 to 15 min) of incubation at varying concentrations for three different TDP-43307-319 mutations: wild-type (WT), A315T, and G314V. In this way, it was possible to trace the oligomer distributions at the initial stages of aggregation while avoiding the complication from aggregation-induced sedimentation over long periods. We found that both WT and A315T rapidly form stable hexamers and higher-order oligomers at low concentrations. As the concentration is increased, the IMS-MS oligomer distribution changes to favor small oligomers over the hexamers and higher-order oligomers for both WT and A315T. AFM shows that this shift in oligomer distribution is due to the formation of fibrils that are seeded by trimers and tetramers. This complex concentration dependence is attributed to two different kinetic paths: one at low concentration that favors the formation of hexamers/cylindrins and one at high concentration that favors fibril formation. Furthermore, the G314V mutation is nontoxic and does not show evidence of the two kinetic paths as hexamers are not formed at any concentration whereas fibril formation is observed at all concentrations.}, } @article {pmid40759286, year = {2025}, author = {Gunner, G and Basu, H and Lu, Y and Bergstresser, M and Sun, L and Neel, D and Choi, SY and Chiu, IM}, title = {Gasdermin D is activated but does not drive neurodegeneration in SOD1[G93A] model of ALS: Implications for targeting pyroptosis.}, journal = {Neurobiology of disease}, volume = {214}, number = {}, pages = {107048}, pmid = {40759286}, issn = {1095-953X}, support = {F32 AG084174/AG/NIA NIH HHS/United States ; R01 DK127257/DK/NIDDK NIH HHS/United States ; T32 AG000222/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Pyroptosis/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Mice ; *Phosphate-Binding Proteins/metabolism/genetics ; Mice, Inbred C57BL ; Disease Models, Animal ; Male ; Mice, Transgenic ; Superoxide Dismutase-1/genetics ; *Intracellular Signaling Peptides and Proteins/metabolism ; Female ; Spinal Cord/metabolism/pathology ; Nerve Degeneration/metabolism/pathology ; Microglia/metabolism/pathology ; Motor Neurons/metabolism/pathology ; Gasdermins ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, microgliosis, and neuroinflammation. While pyroptosis, an inflammatory form of programmed cell death, has been implicated in ALS, the specific role of Gasdermin D (GSDMD) - the primary executioner of pyroptosis - remains unexplored. In this study, we examined the function of GSDMD in the well-established SOD1[G93A] mouse model of ALS. Our results showed robust GSDMD activation in the spinal cords of SOD1[G93A] animals with elevated expression in Iba1+ microglia. To explore its role in disease progression, we bred C57Bl/6 J.SOD1[G93A] mice onto a C57Bl/6NJ.GSDMD-deficient background. In comparing SOD1[G93A]; Gsdmd+/+ and SOD1[G93A]; Gsdmd-/- mice, we found that Gsdmd loss did not affect disease onset, weight loss, or grip strength decline in either male or female animals. Notably, GSDMD deficiency resulted in a modest but statistically significant increase in mortality in SOD1[G93A] mice. Moreover, GSDMD absence had minimal impact on astrogliosis, microgliosis and motor neuron loss. These findings show that while GSDMD is activated in the ALS mouse model, its loss does not mitigate key ALS behavioral phenotypes, gliosis or motor neuron loss. This study provides insights into the potential therapeutic relevance of targeting pyroptosis and inflammatory pathways in ALS.}, } @article {pmid40760014, year = {2025}, author = {Farahani, A and Hansen, JY and Bazinet, V and Shafiei, G and Collins, DL and Dadar, M and Kalra, S and Dagher, A and Misic, B}, title = {Network spreading and local biological vulnerability in amyotrophic lateral sclerosis.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {1153}, pmid = {40760014}, issn = {2399-3642}, support = {RGPIN-2017-04265//Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology)/ ; PJT-180439//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; CRC-2022-00169//Canada Research Chairs (Chaires de recherche du Canada)/ ; MJFF-021133//Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/metabolism/physiopathology/genetics ; Humans ; Female ; Atrophy ; Male ; Middle Aged ; *Motor Cortex/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; Neuroimaging ; Aged ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that predominantly targets the motor system. Spread of pathology is thought to be driven by both local vulnerability and network architecture. Namely, molecular and cellular features may confer vulnerability to specific neuronal populations, while synaptic contacts may also increase exposure to pathology in connected neuronal populations. However, these principles are typically studied in isolation and it remains unknown how local vulnerability and network spreading interact to shape cortical atrophy. Here, we investigate how network structure and local biological features shape the spatial patterning of atrophy in ALS. We analyze the Canadian ALS Neuroimaging Consortium (CALSNIC) dataset and estimate cortical atrophy using deformation based morphometry (DBM). The course of atrophy closely aligns with structural connectivity. Atrophy is also more likely to occur in regions that share similar metabolic profiles. Disease epicenters are located in motor cortex. Epicenter probability maps show transcriptomic enrichment for biological processes involved in mitochondrial function as well as support cells, including endothelial cells and pericytes. Finally, individual differences in epicenter location correspond to individual differences in clinical and cognitive symptoms and differentiate patient subtypes.}, } @article {pmid40760594, year = {2025}, author = {Zhang, Q and Zhou, X and Yang, G and Zhang, L}, title = {Atopic dermatitis in amyotrophic lateral sclerosis successfully treated by dupilumab: A case report.}, journal = {Medicine}, volume = {104}, number = {31}, pages = {e43737}, pmid = {40760594}, issn = {1536-5964}, mesh = {Humans ; Male ; Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage ; *Amyotrophic Lateral Sclerosis/complications ; *Dermatitis, Atopic/drug therapy/complications ; Pruritus/drug therapy/etiology ; }, abstract = {RATIONALE: Atopic dermatitis (AD) is a common skin disorder characterized by symmetric erythematous papules in flexural areas, with pruritus of varying intensity persisting throughout its course. Amyotrophic lateral sclerosis (ALS) is a neurological disease with progressive loss of muscle function, and its treatment remains a challenge worldwide. When patients suffer from both conditions, the skin issues are often overlooked by both physicians and family members. However, the pruritus becomes unbearable for the patients, particularly as they experience a progressive loss of the ability to scratch autonomously.

PATIENT CONCERNS: An elderly 75-year-old male patient with comorbid ALS and AD, suffering from prolonged pruritus, had lost faith in all topical and oral medications.

DIAGNOSIS: AD and ALS.

INTERVENTIONS: The patient received subcutaneous dupilumab with an initial 600 mg dose followed by 300 mg every 2 weeks, and was monitored for 12 weeks during follow-up.

OUTCOMES: The patient exhibited gradual reduction in pruritus severity and skin lesions throughout the treatment course. No adverse reactions other than mild conjunctivitis were reported.

LESSONS: This case demonstrates the successful application of dupilumab in an AD patient with comorbid ALS. It not only provides a clinically instructive case reference for dupilumab therapy in AD, but also underscores that pruritus in ALS patients warrants greater clinical attention.}, } @article {pmid40760788, year = {2025}, author = {Ke, S and Yan, J and Li, B and Feng, X}, title = {Causal Association Between Immune Cell Traits and Risk of Multiple Malignant and Nonmalignant CNS Diseases: A Mendelian Randomization and Single-Cell Transcriptomic Analysis.}, journal = {Brain and behavior}, volume = {15}, number = {8}, pages = {e70632}, pmid = {40760788}, issn = {2162-3279}, mesh = {Humans ; Mendelian Randomization Analysis ; Single-Cell Analysis ; Quantitative Trait Loci/genetics ; Glioblastoma/genetics/immunology ; *Central Nervous System Diseases/genetics/immunology ; Transcriptome ; Gene Expression Profiling ; Brain Neoplasms/genetics/immunology ; }, abstract = {BACKGROUND: The influence of immune cell traits (ICTs) on the onset of multiple brain diseases has been previously investigated; however, it is limited by the sample size or colocalization evidence. Besides, the impact remains inconclusive.

METHODS: We performed a Mendelian randomization (MR) study to elucidate the causal correlation between significant ICTs and diverse brain disorders and explored the biomarkers linked to glioblastoma (GBM), a form of solid tumor, by integrating expression quantitative trait locus (eQTL) and single-cell RNA sequencing (scRNA-seq) analyses. The nonnegative matrix factorization (NMF) method was utilized to reclassify malignant cells into distinct cell states. Related functional analyses at the scRNA-seq level were also performed.

RESULTS: We examined 731 ICTs across 13 brain disorders; impacts from these ICTs varied a lot across different brain diseases. Such ICTs mainly involved T/natural killer (NK) cell activation, B cell differentiation, and myeloid cell suppression or activation. Pleiotropy or heterogeneity in current results has been checked and excluded via sensitivity analyses. Specifically, colocalization analyses demonstrated protective roles of distinct ICTs in T/B/NK cell panels for amyotrophic lateral sclerosis (ALS) and GBM, while myeloid and human leukocyte antigen (HLA)-associated traits were associated with increased risk of Alzheimer's disease (AD), and then two memory cell traits were linked to the increased risk of major depressive disease (MDD). By NMF, we identified six distinct cell states within GBM cells. Furthermore, we established an eight-marker glioblastoma risk signature (GBRS) using scRNA-seq and eQTL data, with higher GBRS scores observed in the NFkB cluster and EGFR cluster, indicating their highlighted aggression among malignant cells. Epigallocatechin gallate could be an effective treatment candidate targeting the EGFR cluster via markers of SQLE and VCP.

CONCLUSION: Our findings identified causal effects of distinct ICTs on both malignant and nonmalignant brain diseases and underscored the pivotal role of neuroinflammation in their etiology. With combined evidence from eQTL and scRNA-seq, GBM could be better characterized and managed.}, } @article {pmid40760897, year = {2025}, author = {Kicherova, OA and Doyan, YI and Kicherova, KP and Reichert, LI and Root, VA}, title = {[Sporadic form of Guam disease (ALS-parkinsonism-dementia complex)].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {125}, number = {7}, pages = {135-141}, doi = {10.17116/jnevro2025125071135}, pmid = {40760897}, issn = {1997-7298}, mesh = {Humans ; Male ; Diagnosis, Differential ; *Frontotemporal Dementia/diagnosis ; Middle Aged ; Aged ; *Parkinsonian Disorders/diagnosis ; Female ; *Dementia/diagnosis ; }, abstract = {Guam disease (ALS-parkinsonism-dementia complex) is a rare endemic condition of progressive generalized degeneration of CNS neurons. Despite the apparent association of the disease with the Pacific region, sporadic cases of Guam disease have been described in other countries of the world, where the term "ALS with frontotemporal dementia" is used to refer to it. The authors cite their own clinical case of the disease, as well as discuss aspects of the clinical presentation, etiology, pathogenesis, diagnosis, and differential diagnosis of similar conditions.}, } @article {pmid40762148, year = {2025}, author = {Mascias Cadavid, J and Mena Bravo, A and Barkhaus, P and Barnes, B and Benatar, M and Breevoort, S and Brown, A and Carter, GT and Crayle, J and Foucher, J and Heiman-Patterson, T and Hobson, E and Jackson, C and Jhooty, S and Mallon, E and Mcdermott, C and Pattee, G and Pierce, K and Pioro, E and Ratner, D and Rivner, M and Tito, E and Wicks, P and Bedlack, R}, title = {ALSUntangled #80: ISRIB (Integrated stress response InhiBitor).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {821-824}, doi = {10.1080/21678421.2025.2542919}, pmid = {40762148}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; Animals ; Stress Granules/drug effects/metabolism ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we assess ISRIB, a molecule that attenuates the integrated stress response (ISR). The ISR is an intracellular signaling network through which cells normally respond to stress, but in ALS it appears to be overactive, leading to the formation of "stress granules" which some but not all investigators believe can triggerapoptotic cell death. ISRIB can attenuate the formation of these stress granules while still allowing parts of protein synthesis to continue. Pre-clinical data demonstrate that ISRIB is beneficial in cell models of ALS. A small number of patients taking ISRIB in Spain report symptomatic improvements with little or no side effects, though we have not been able to independently verify these benefits. There are no clinical trials evaluating ISRIB in any condition and questions about its solubility and bioavailability have arisen. Currently, we do not have enough evidence to endorse the use of ISRIB for treating ALS. We support further research in disease models and clinical trials to study pharmacokinetics, safety and efficacy.}, } @article {pmid40762423, year = {2025}, author = {Mietzner, G and Lümkemann, L and Schreiber, F and Brüggemann, J and Benramadan, A and Al-Dubai, M and Sciarra, A and Knoll, C and Kuehn, E and Speck, O and Schreiber, S and Mattern, H}, title = {Assessing Arterial Patterns in the Motor Cortex With 7 Tesla Magnetic Resonance Imaging and Vessel Distance Mapping.}, journal = {Human brain mapping}, volume = {46}, number = {11}, pages = {e70311}, pmid = {40762423}, issn = {1097-0193}, support = {362321501//Deutsche Forschungsgemeinschaft/ ; 425899996//Deutsche Forschungsgemeinschaft/ ; 446268581//Deutsche Forschungsgemeinschaft/ ; 501214112//Deutsche Forschungsgemeinschaft/ ; BB-DARS//Deutsche Alzheimer Gesellschaft/ ; MD-DARS//Deutsche Alzheimer Gesellschaft/ ; }, mesh = {Humans ; *Motor Cortex/blood supply/diagnostic imaging/anatomy & histology ; Male ; *Magnetic Resonance Imaging/methods ; Female ; Adult ; Young Adult ; *Cerebral Arteries/diagnostic imaging/anatomy & histology ; Image Processing, Computer-Assisted ; Middle Aged ; }, abstract = {Leveraging high-resolution 7 T magnetic resonance imaging (MRI) and vessel distance mapping (VDM), the arterial supply patterns and dominances of the motor cortex, which could previously only be studied postmortem, were assessed in vivo and fully noninvasively. Beyond vessel patterns and dominances, the potential relation between the vascularization and the motor cortex thickness was studied. Twenty-one healthy participants underwent 7 T MRI scans to map arterial supply and motor cortex at 0.45 mm isotropic resolution. The motor cortex vasculature was segmented manually with vessel-specific labels. VDM was utilized to estimate the vessel-specific supply regions and, subsequently, assess vessel patterns and dominances. Statistical tests were applied to test if the vasculature impacts mean motor cortical thickness estimates. Vessel patterns, that is the presence of supplying vessels, were classified as three-, four-, and five-vessel patterns with a prevalence of 26.3%, 50.0%, and 23.7%, respectively. Vessel dominance, that is the ratio of supply volumes, of the ACA branches showed dominance of the pericallosal artery, callosomarginal artery, and equal contribution, in 34.2%, 34.2%, and 31.6% of the cases, respectively. For the MCA groups, the prevalence of precentral group dominance, central group dominances, and equal contribution was 13.2%, 34.2%, and 52.6%, respectively. Although the central and precentral groups were found in all hemispheres, the postcentral group was found in 28.9% of hemispheres with highly variable supply contribution. Statistical tests returned no significance for the effect of vessel patterns and dominances on the mean motor cortex thickness. With 7 T MRI and VDM, the motor cortex vascularization can be assessed fully noninvasively and longitudinally while providing overall good concordance with previous post mortem studies. Our comprehensive analysis of arterial motor cortex vascularization showed considerable variability between hemispheres, rendering the usage of pattern-specific atlases and analysis more suitable than single normative representations. The successful translation from post mortem to in vivo enables the study of vascular reserve in disorders affecting the motor cortex, such as ALS, and can be translated to other brain regions and neurodegenerative diseases in the future.}, } @article {pmid40763713, year = {2026}, author = {Linna, N and Tervonen, LA and Aaltonen, M and Portaankorva, AM and Krüger, J}, title = {Epidemiology of Amyotrophic Lateral Sclerosis in Western and Northern Finland.}, journal = {Neuroepidemiology}, volume = {60}, number = {4}, pages = {643-652}, doi = {10.1159/000547562}, pmid = {40763713}, issn = {1423-0208}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Finland/epidemiology ; Female ; Retrospective Studies ; Male ; Incidence ; Prevalence ; Aged ; Middle Aged ; Adult ; Aged, 80 and over ; C9orf72 Protein/genetics ; Registries ; Frontotemporal Dementia/epidemiology ; }, abstract = {INTRODUCTION: The aims of this study were to define the incidence and prevalence of amyotrophic lateral sclerosis (ALS) in two north-western regions in Finland and to assess clinical ALS phenotypes in these areas.

METHODS: We conducted a retrospective epidemiologic study by using hospital discharge registers in the regions of Central Ostrobothnia (population 68,158 in 2019) and Northern Ostrobothnia (population 412,830). All patients diagnosed with ALS during 2010-2019 and living in either region were included in the incidence study. The prevalence day was December 31, 2019. All ALS diagnoses were retrospectively re-evaluated and the clinical phenotype data reviewed and reassessed.

RESULTS: In total, 214 ALS patients were identified. The age-adjusted 10-year incidence of ALS was 5.4/100,000 person-years in Central Ostrobothnia and 4.6/100,000 person-years in Northern Ostrobothnia. The age-adjusted prevalence rates were 13.1 and 14.6/100,000, respectively. The mean survival after the diagnosis was 16.8 months. Frontotemporal dementia (FTD) was identified in 15% of all patients. ALS-FTD was relatively more common among patients with bulbar- or respiratory-onset ALS (25%) than among those with limb-onset ALS (8%). Approximately 13% of the ALS patients had a positive family history for ALS. Genetic testing had been performed in 53% of all cases and the most tested mutations were C9orf72 hexanucleotide repeat expansion (32%) and D90A-SOD1 (40%). C9orf72 repeat expansion was detected in 8% and a D90A-SOD1 mutation in 6% of all cases, that is, 26% and 14% of all tested cases, respectively.

CONCLUSION: The incidence and prevalence rates of ALS in Finland are among the highest in the world. ALS-FTD seems to be more common among patients with bulbar- or respiratory-onset ALS than among those with spinal-onset disease. Cognitive evaluation of ALS patients and offering a possibility to genetic testing should be systematic in clinical practice.}, } @article {pmid40764041, year = {2025}, author = {Nguyen, M and Orengo, JP and Grouls, A}, title = {Letter: Advance Care Planning Documentation Changes Among Neurologists in an Amyotrophic Lateral Sclerosis Clinic with Addition of Specialist Palliative Care.}, journal = {Journal of palliative medicine}, volume = {28}, number = {11}, pages = {1427-1428}, doi = {10.1177/10966218251365262}, pmid = {40764041}, issn = {1557-7740}, } @article {pmid40764342, year = {2025}, author = {Lépine, S and Maussion, G and Schneider, A and Nauleau-Javaudin, A and Castellanos-Montiel, MJ and Ambriz, GJ and Spiegelman, D and Abdian, N and Franco-Flores, AK and Haghi, G and Gursu, L and Fiorini, MR and Dilliott, AA and Farhan, SMK and Chaineau, M and Durcan, TM}, title = {Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme inhibitor MLN4924.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {28555}, pmid = {40764342}, issn = {2045-2322}, mesh = {*Pyrimidines/pharmacology ; Humans ; *Motor Neurons/metabolism/drug effects ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; *Cyclopentanes/pharmacology ; *Transcriptome ; *NEDD8 Protein/metabolism/antagonists & inhibitors ; Gene Knock-In Techniques ; Gene Expression Profiling ; Mutation ; Induced Pluripotent Stem Cells/metabolism ; }, abstract = {A growing body of knowledge implicates perturbed RNA homeostasis in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that currently has no cure and few available treatments. Dysregulation of the multifunctional RNA-binding protein TDP-43 is increasingly regarded as a convergent feature of this disease, evidenced at the neuropathological level by the detection of TDP-43 pathology in most patient tissues, and at the genetic level by the identification of disease-associated mutations in its coding gene TARDBP. To characterize the transcriptional landscape induced by TARDBP mutations, we performed whole-transcriptome profiling of motor neurons (MNs) differentiated from two knock-in iPSC lines expressing the ALS-linked TDP-43 variants p.A382T or p.G348C. Our results show that the TARDBP mutations significantly altered the expression profiles of mRNAs and microRNAs of the 14q32 cluster in MNs. Using mutation-induced gene signatures and the Connectivity Map database, we identified compounds predicted to restore gene expression toward wild-type levels. Among top-scoring compounds selected for further investigation, the NEDD8-activating enzyme inhibitor MLN4924 effectively improved cell viability and neuronal activity, highlighting a possible role for protein post-translational modification via NEDDylation in the pathobiology of TDP-43 in ALS.}, } @article {pmid40764463, year = {2025}, author = {Landry, C and Costanzo, JP and Mitne-Neto, M and Zatz, M and Schaffer, AE and Hatzoglou, M and Muotri, AR and Miranda, HC}, title = {Convergent activation of the integrated stress response and ER-mitochondria uncoupling in VAPB-associated ALS.}, journal = {EMBO molecular medicine}, volume = {17}, number = {9}, pages = {2299-2331}, pmid = {40764463}, issn = {1757-4684}, support = {R01 DK060596/DK/NIDDK NIH HHS/United States ; K01 NS116119/NS/NINDS NIH HHS/United States ; DK060596/GF/NIH HHS/United States ; R01 NS123524/NS/NINDS NIH HHS/United States ; R37 DK060596/DK/NIDDK NIH HHS/United States ; R01NS123524/GF/NIH HHS/United States ; K01NS116119//NIH NINDS/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *Mitochondria/metabolism/pathology ; *Endoplasmic Reticulum Stress ; *Vesicular Transport Proteins/genetics/metabolism ; Induced Pluripotent Stem Cells/metabolism ; *Endoplasmic Reticulum/metabolism ; Motor Neurons/metabolism/pathology ; Activating Transcription Factor 4/metabolism ; Membrane Potential, Mitochondrial ; }, abstract = {Vesicle-associated membrane protein-associated protein-B (VAPB) is an endoplasmic reticulum (ER) membrane-bound protein. The P56S mutation in VAPB causes a dominant, familial form of amyotrophic lateral sclerosis (ALS). However, the mechanism by which this mutation leads to motor neuron (MN) degeneration remains unclear. Utilizing inducible pluripotent stem cell (iPSC)-derived MNs expressing either wild-type (WT) or P56S VAPB, we demonstrate that the mutant protein reduces neuronal firing and disrupts ER-mitochondria-associated membranes (ER MAMs), with a time-dependent decline in mitochondrial membrane potential (MMP), hallmarks of MN pathology. These findings were validated in patient-derived iPSC-MNs. Additionally, VAPB P56S MNs show increased susceptibility to ER stress, elevated expression of the Integrated Stress Response (ISR) regulator ATF4 under stress, and reduced global protein synthesis. Notably, pharmacological ISR inhibition using ISRIB rescued ALS-associated phenotypes in both VAPB P56S and patient-derived iPSC-MNs. We present the first evidence that the VAPB P56S mutation activates ISR signaling via mitochondrial dysfunction in human MNs. These findings support ISR modulation as a strategy for ALS intervention and highlight the need for patient stratification in clinical trials.}, } @article {pmid40764817, year = {2025}, author = {Hu, Y and Chourpiliadis, C and Ingre, C and Ahlqvist, VH and Sun, J and Song, H and Pawitan, Y and Piehl, F and Fang, F}, title = {Hospital-treated infections and the risk and prognosis of amyotrophic lateral sclerosis: A population-based study.}, journal = {Journal of internal medicine}, volume = {298}, number = {4}, pages = {349-360}, pmid = {40764817}, issn = {1365-2796}, support = {R01TS000348/ACL/ACL HHS/United States ; 1R01NS131433-01//National Institute for Aging and the National Institute of Neurological Disorders and Stroke/ ; R01 TS000348/TS/ATSDR CDC HHS/United States ; R01 NS131433/NS/NINDS NIH HHS/United States ; MegaALS 802091//European Research Council Starting Grant/ ; 2023-02428//Swedish Research Council/ ; R01 TS000324/TS/ATSDR CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/epidemiology/etiology/diagnosis ; Male ; Female ; Prognosis ; Middle Aged ; Case-Control Studies ; Aged ; Risk Factors ; Sweden/epidemiology ; Registries ; *Infections/complications/therapy/epidemiology ; Disease Progression ; }, abstract = {BACKGROUND: Infection has been suspected as a risk factor for amyotrophic lateral sclerosis (ALS). However, previous research has focused on specific pathogens and rarely examined the influence of infection on disease progression.

OBJECTIVES: To assess whether hospital-treated infections correlate with the risk and prognosis of ALS.

METHODS: Using data from the Swedish Motor Neuron Disease Quality Registry, we conducted three nested case-control studies, including 1159 individuals diagnosed with ALS during 2015-2023 and 5795 age- and sex-matched population controls, 1558 full-sibling controls, and 680 spouse controls, respectively. We used conditional logistic regression to estimate the association of hospital-treated infections with subsequent risk of ALS and Cox model to assess the association of pre- or post-diagnostic infections with mortality after an ALS diagnosis.

RESULTS: Hospital-treated infections before diagnosis were associated with an increased risk of ALS in the population comparison (odds ratio [OR] 1.31; 95% confidence interval [CI] 1.15-1.49). A similar association was noted after excluding infections within 3-, 5-, or 10-years preceding ALS diagnosis and was confirmed in sibling and spouse comparisons, although results were not always statistically significant. Patients with a hospital-treated infection before diagnosis were more likely to present with bulbar symptoms, poorer functional status, and higher prevalence of anxiety and depressive symptoms at diagnosis than others. Pre-diagnostic infections were not associated with mortality, whereas post-diagnostic infections were associated with increased mortality (hazard ratio [HR] 1.89; 95%CI 1.59-2.24) among ALS patients.

CONCLUSION: Hospital-treated infections are associated with an increased risk of ALS and may modify its clinical presentation at diagnosis. Post-diagnostic infections are associated with poor survival in ALS.}, } @article {pmid40766128, year = {2025}, author = {Homann, J and Smith, AG and Morgan, S and Frick, EA and Liu, F and Viallon, V and Maurya, R and Korologou-Linden, R and Dobricic, V and Ohlei, O and Deecke, L and Hajizadah, F and Zhao, Y and Artaud, F and Smith-Byrne, K and Kolijn, PM and Huerta, JM and Winter, N and Guevara, M and Jimenez-Zabala, A and Sánchez, MJ and Trobajo-Sanmartín, C and Cabrera-Castro, N and Vinagre, A and Petrova, D and Sieri, S and Key, TJ and Wareham, N and Kaaks, R and Travis, RC and Hahn, T and Baker, S and Kelly, SM and Vermeulen, R and Peters, S and Masala, G and Sacerdote, C and Finkel, N and , and Elbaz, A and Hess, M and Katzke, V and Bertram, L and Gudnason, V and Robinson, O and Chen, H and Middleton, L and Winchester, LM and Tzoulaki, I and Gudmundsdottir, V and Walker, KA and Ferrari, P and Riboli, E and Gunter, MJ and Lill, CM}, title = {Large-scale plasma proteomics uncovers preclinical molecular signatures of Parkinson's disease and overlap with other neurodegenerative disorders.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40766128}, support = {U01 HL096812/HL/NHLBI NIH HHS/United States ; N01 AG012100/AG/NIA NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; U01 HL096917/HL/NHLBI NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; U01 HL096902/HL/NHLBI NIH HHS/United States ; R01 AG065596/AG/NIA NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; U01 HL096814/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; U01 HL096899/HL/NHLBI NIH HHS/United States ; 75N92022D00001/HL/NHLBI NIH HHS/United States ; }, abstract = {Parkinson's disease (PD) remains incurable, with a long preclinical phase currently undetectable by existing methods. In the largest proteomic study in neurodegenerative diseases to date, we analyzed blood samples from ~74,000 individuals across discovery and validation cohorts. In the EPIC4PD discovery case-cohort, large-scale profiling of 7,285 proteins (SomaScan-7K) in 4,538 initially unaffected participants (574 incident cases) identified 17 proteins that predict PD up to 28 years before diagnosis. Additional proteins revealed sex-specific effects and time-dependent effect trajectories, capturing disease progression before symptom onset. Replication in three prospective cohorts (n=64,856; 1,034 incident cases) confirmed at least 12 key pre-diagnostic biomarkers with strong evidence, including TPPP2, HPGDS, ALPL, MFAP5, OGFR, ACAD8, TCL1A, GPC4, GSTA3, LCN2, KRAS, and GJA1. Preclinical biomarkers showed 86% concordant effect directions in independent prevalent PD cases (n=2,592; p=1.6×10[-19]). Furthermore, in the longitudinal Tracking PD cohort (n=794), HPGDS and MFAP5 also predicted cognitive decline. Notably, several of the identified PD biomarkers overlapped with those for incident Alzheimer's disease and amyotrophic lateral sclerosis, indicating shared molecular signatures. A machine learning-derived protein score improved PD risk prediction in external validation. This extensive proteomics effort identified novel, actionable biomarkers opening new avenues for early PD risk stratification and precision medicine.}, } @article {pmid40766389, year = {2025}, author = {Ferreon, JC and Choi, KJ and Quan, MD and Tsoi, PS and Ferreon, CC and Coskun, U and Liao, SJ and Ferreon, ACM}, title = {Modulation of biomolecular aggregate morphology and condensate infectivity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.07.30.667758}, pmid = {40766389}, issn = {2692-8205}, abstract = {Neurodegenerative diseases are characterized by pathological aggregates exhibiting distinct morphologies, such as neurofibrillary tangles and dense circular Lewy body-like structures in Alzheimer's disease, and round hyaline gel-like inclusions and skein-like filaments in amyotrophic lateral sclerosis. However, the mechanisms driving the formation of these diverse morphological structures remain poorly understood. Employing advanced microscopy, including fluorescence lifetime imaging, we investigated condensate aging and aggregation mechanisms of the prion-like domain of hnRNPA1 (A1PrD), a ribonucleoprotein implicated in both disorders. Using a simplified system across various salt and RNA conditions, we demonstrate that homotypic and heterotypic interactions between A1PrD and RNA significantly influence aggregate morphology and amyloid fibril formation, yielding diverse structures including thin fibrils, solid gels, and filamentous starburst aggregates. By tracking aggregate morphogenesis, we observed shifts in fluorescence lifetimes that reflect differences in condensate microenvironments, highlighting distinct homotypic and heterotypic interaction dynamics. Our findings indicate that amyloid fibril formation can initiate within fluid condensates or at the interfaces of solid gels. Moreover, early amyloid-rich fluid starbursts demonstrated the capability to fuse with or recruit younger amyloid-poor droplets, exemplifying prion-like infectivity and accelerating fibril formation. Collectively, our study provides evidence that the interplay between solution composition and the kinetic balance of liquid-liquid phase separation, gelation, and fibrillation contributes to the diverse pathological aggregate morphologies observed in neurodegenerative diseases.}, } @article {pmid40766632, year = {2025}, author = {Lacour, A and Vassallu, F and Rayes, D and Igaz, LM}, title = {Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40766632}, issn = {2692-8205}, support = {P40 OD010440/OD/NIH HHS/United States ; }, abstract = {TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are marked by the pathological cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43), leading to progressive neuronal dysfunction and degeneration. To investigate the early functional consequences of TDP-43 mislocalization, we generated Caenorhabditis elegans models expressing either wild-type human TDP-43 or a variant with a mutated nuclear localization signal (ΔNLS), specifically in serotonergic neurons. These neurons were chosen because i) serotonin deficits are a feature of ALS/FTD and ii) in C. elegans, they regulate well-characterized behaviors, providing a straightforward readout of neuronal function. We found that expression of either TDP-43 variant impaired serotonin-dependent behaviors-including pharyngeal pumping, egg-laying, and locomotion slowing upon food encounter-with the cytoplasmic ΔNLS form causing more severe deficits. Serotonergic neurons remained i) morphologically intact, indicating that neuronal dysfunction precedes overt neurodegeneration; and ii) partially responsive to the selective serotonin reuptake inhibitor fluoxetine, suggesting that neurotransmitter release is still partially functional. Altogether, our findings demonstrate that cytoplasmic TDP-43 disrupts neuronal signaling and behavior early in disease progression. This C. elegans model provides a genetically tractable system to dissect early mechanisms of TDP-43-mediated dysfunction and to identify therapeutic strategies targeting predegenerative stages of ALS/FTD.}, } @article {pmid40767546, year = {2025}, author = {Dupuis, L and Robertson, J}, title = {Is amyotrophic lateral sclerosis less severe in mice than in humans?.}, journal = {Current opinion in neurology}, volume = {38}, number = {5}, pages = {581-587}, pmid = {40767546}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/physiopathology/pathology ; Animals ; Humans ; *Disease Models, Animal ; Mice ; Gene Knock-In Techniques ; Mice, Transgenic ; }, abstract = {PURPOSE OF REVIEW: We review here novel knock-in models of amyotrophic lateral sclerosis (ALS).

RECENT FINDINGS: Knock-in mouse models of various familial forms of ALS generally display a mild motor phenotype, with limited progression, that do not recapitulate the full-blown clinical picture of ALS.

SUMMARY: ALS is a devastating neurodegenerative disease in humans. Typically manifesting in the fifth or sixth decade of life, ALS leads to progressive motor dysfunction and death, usually within 2-5 years from symptom onset. A subset of ALS cases are dominantly inherited. Over the last 30 years, multiple mouse models of ALS have been generated, and recent advances in mouse genome editing techniques have enabled the generation of mouse strains carrying orthologous mutations in endogenous genes that mirror those causing familial forms of ALS. Intriguingly, many of these knock-in mouse models develop much milder phenotypes than patients with ALS carrying the same mutations. A full-blown ALS clinical phenotype seems to be only elicited upon overexpression of mutant genes beyond the endogenous levels. Here, we review these novel models and argue that these models could represent how ALS manifests in the mouse species. We also evaluate how these models could be used for characterizing mechanisms and preclinical drug evaluation.}, } @article {pmid40767591, year = {2026}, author = {Garrou, F and De Marchi, F and Corrado, L and Sacchetti, GM and D'alfonso, S and Morbelli, SD and Perani, D and Mazzini, L and Tondo, G}, title = {Challenging the boundaries: c9orf72 mutation presenting as Alzheimer's disease.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {215-218}, doi = {10.1080/21678421.2025.2541761}, pmid = {40767591}, issn = {2167-9223}, mesh = {Humans ; *C9orf72 Protein/genetics ; Male ; *Alzheimer Disease/genetics/diagnosis/diagnostic imaging ; Middle Aged ; *Mutation/genetics ; *Proteins/genetics ; Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Positron-Emission Tomography ; DNA Repeat Expansion/genetics ; }, abstract = {C9orf72 hexanucleotide repeat expansion is a major cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), while its link with Alzheimer's disease (AD) is still unclear. We describe the case of a 53-year-old man with progressive memory and language deficits, mood disturbances, and a positive family history for ALS-FTD. Cerebrospinal fluid showed amyloid positivity, confirmed by amyloid-PET, with normal tau levels; [[18]F]FDG-PET revealed an AD-like temporoparietal hypometabolism. Genetic testing detected a pathogenic C9orf72 expansion, also present in his mother. This case suggests phenotypic heterogeneity of C9orf72-related disorders and a possible interplay with amyloid pathology.}, } @article {pmid40767769, year = {2025}, author = {Petre, AM and Thieschafer, JS and Palsuledesai, C and Cornille, K and Chang, A and Li, L and Distefano, MD}, title = {In Vivo Metabolic Labeling with an Isoprenoid Probe Reveals APOE Allele-Specific Differences in the Prenylome.}, journal = {ACS chemical biology}, volume = {20}, number = {8}, pages = {1951-1961}, pmid = {40767769}, issn = {1554-8937}, support = {R01 AG077772/AG/NIA NIH HHS/United States ; RF1 AG077772/AG/NIA NIH HHS/United States ; RF1 AG056976/AG/NIA NIH HHS/United States ; R35 GM141853/GM/NIGMS NIH HHS/United States ; R01 AG081426/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Alleles ; *Apolipoprotein E3/genetics/metabolism ; *Apolipoprotein E4/genetics/metabolism ; *Apolipoproteins E/genetics/metabolism ; Mice, Transgenic ; Neuropathology ; *Protein Prenylation ; *Terpenes/metabolism/chemistry ; Alzheimer Disease/pathology ; }, abstract = {Prenylation is a ubiquitous process in eukaryotes consisting of the irreversible post-translational modification of proteins through the attachment of a lipophilic isoprenoid moiety to a cysteine residue near their C-terminus. Due to the important functional roles of prenylated proteins, their participation and/or dysregulation has been linked to numerous diseases, including ALS, progeria, cancer, and Alzheimer's disease (AD). In humans, the APOE4 variant is the greatest known genetic risk factor for late-onset sporadic AD with carriers of two E4 alleles having up to 15 times the risk of developing AD. To begin to unravel the potential relationship between protein prenylation, AD, and APOE variants, it is necessary to study whether different APOE genotypes affect protein prenylation systemically. In the work described here, a methodology for metabolic labeling of prenylated proteins in living mice was first developed. It was then applied to humanized mouse strains that carry human APOE3 or APOE4 alleles. Prenylomic profiling revealed that a number of prenylated proteins were present at higher levels in animals harboring the APOE4 gene compared with those with the APOE3 allele, especially in the liver─a major APOE-producing organ. Importantly, some of these proteins have links to AD neuropathology.}, } @article {pmid40771035, year = {2026}, author = {Hattori, N and Mukai, Y and Nishikawa, N and Hasegawa, K and Tomiyama, M and Kimura, Y and Tsuboi, Y and Takahashi, R and Nakamura, R and Izumi, Y and Watanabe, H and Seki, M and Sekiguchi, K and Tateishi, S and Matsushita, Y and Nakamura, Y}, title = {Efficacy and Safety of IncobotulinumtoxinA for Treatment of Sialorrhea: A Multicenter, Phase 3 Study in Japan.}, journal = {Movement disorders clinical practice}, volume = {13}, number = {1}, pages = {120-130}, pmid = {40771035}, issn = {2330-1619}, support = {//Teijin Pharma/ ; }, mesh = {Humans ; *Sialorrhea/drug therapy/etiology ; *Botulinum Toxins, Type A/adverse effects/therapeutic use/pharmacology/administration & dosage ; Male ; Female ; Middle Aged ; Japan ; Aged ; *Neuromuscular Agents/adverse effects/therapeutic use ; Adult ; Treatment Outcome ; }, abstract = {BACKGROUND: Sialorrhea, caused by various neurological diseases, impairs patient health and quality of life. After the results of a randomized controlled trial, incobotulinumtoxinA was approved for the treatment of chronic sialorrhea in the United States and Europe; however, no pharmacotherapy has been approved in Japan.

OBJECTIVE: The aim was to evaluate the efficacy and safety of incobotulinumtoxinA treatment for chronic sialorrhea in a single-arm phase 3 study in Japan.

METHODS: Patients with chronic sialorrhea caused by neurological diseases (Parkinson's disease, atypical parkinsonism, and stroke, group A) and broader diseases (eg, muscular dystrophy and amyotrophic lateral sclerosis, group B) were enrolled. IncobotulinumtoxinA 100 U was injected into the salivary glands once every 16 weeks for 48 weeks. A primary endpoint was assessed in group A, whereas secondary endpoints and safety were assessed in both groups.

RESULTS: From November 2021 to August 2023, 92 patients (58 and 34 in groups A and B, respectively) received incobotulinumtoxinA at 28 institutions. The primary endpoint, the least square mean (standard error) of change in unstimulated salivary flow rate from baseline to 4 weeks, was -0.08 (0.009, 95% confidence interval [CI]: -0.10, -0.06) g/min, achieving the prespecified efficacy criteria (upper limit of the 95% CI <-0.04). The secondary endpoints were consistent across efficacy measures, indicating that reduced salivary secretion and improved drooling symptoms persisted for 48 weeks. The most common adverse events were dry mouth and dysphagia.

CONCLUSIONS: The first study in Japan confirmed the efficacy of incobotulinumtoxinA treatment for chronic sialorrhea with good patient tolerability and no new safety concerns.}, } @article {pmid40771731, year = {2025}, author = {Shi, DD and Tian, J and Ding, J}, title = {Adenosine deaminase in pleural effusion: Bridging diagnosis and the pathophysiology of inflammation.}, journal = {World journal of clinical cases}, volume = {13}, number = {22}, pages = {106925}, pmid = {40771731}, issn = {2307-8960}, abstract = {This editorial underscores the importance of Maranhão et al's study, which investigates pleural adenosine deaminase (P-ADA) as a biomarker for inflammatory pleural effusions. Despite advances in imaging, distinguishing between inflammatory and non-inflammatory causes of pleural effusion remains a diagnostic challenge. The authors conducted a rigorous retrospective cohort analysis of 157 patients (124 with inflammatory exudates and 33 with non-inflammatory transudates), establishing a robust cutoff value of P-ADA ≥ 9.00 U/L for diagnosing inflammatory diseases using receiver operating characteristic curve analysis and internal statistical calibration. This is the first study to define a standardized P-ADA threshold in a Brazilian cohort, addressing previous inconsistencies in cutoff values. Furthermore, the authors delved into the pathophysiological mechanisms underlying elevated P-ADA, linking it to purinergic signaling pathways and immune cell activation, particularly emphasizing the role of ADA2 isoforms in macrophages and lymphocytes. Their findings support P-ADA as a non-invasive, cost-effective biomarker for early diagnosis, treatment stratification, and minimizing the need for invasive procedures such as thoracentesis. This has particular relevance in resource-limited settings, where streamlined diagnostics can reduce healthcare costs and improve patient outcomes. Future studies must prioritize global validation, explore the integration of adenosine deaminase with additional biomarkers (e.g., interleukin 6, C-reactive protein), and support the development of point-of-care technologies.}, } @article {pmid40772263, year = {2025}, author = {Atwal, MS and Nimac, J and Čerček, U and Goesch, SR and Goesch, HR and Tziortzouda, P and Ercolani, T and Zatorska, A and Pasha, T and Carre, I and Mitchell, J and Troakes, C and Tummers, B and Župunski, V and Rogelj, B and Hortobágyi, T and Hirth, F}, title = {Accumulation of TDP-43 causes karyopherin-α4 pathology that characterises amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1558227}, pmid = {40772263}, issn = {1662-4548}, abstract = {Cytoplasmic mislocalisation and nuclear depletion of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis (ALS), including mutations in the C9ORF72 gene that characterise the most common genetic form of ALS (C9ALS). Studies in human cells and animal models have associated cytoplasmic mislocalisation of TDP-43 with abnormalities in nuclear transport receptors, referred to as karyopherins, that mediate the nucleocytoplasmic shuttling of TDP-43. Yet the relationship between karyopherin abnormalities and TDP-43 pathology are unclear. Here we report karyopherin-α4 (KPNA4) pathology in the spinal cord of TDP-43-positive sporadic ALS and C9ALS patients. Structural analyses revealed the selective interaction between KPNA subtypes, especially KPNA4, with the nuclear localisation signal (NLS) of TDP-43. Targeted cytoplasmic mislocalisation and nuclear depletion of TDP-43 caused KPNA4 pathology in human cells. Similar phenotypes were observed in Drosophila whereby cytoplasmic accumulation of the TDP-43 homolog, TBPH, caused the nuclear decrease and cytosolic mislocalisation of the KPNA4 homolog, Importin-α3 (Impα3). In contrast, induced accumulation of Impα3 was not sufficient to cause TBPH mislocalisation. Instead, targeted gain of Impα3 in the presence of accumulating cytosolic TBPH, restored Impα3 localisation and partially rescued nuclear TBPH. These results demonstrate that cytoplasmic accumulation of TDP-43 causes karyopherin pathology that characterises ALS spinal cord. Together with earlier reports, our findings establish KPNA4 abnormalities as a molecular signature of TDP-43 proteinopathies and identify it as a potential therapeutic target to sustain nuclear TDP-43 essential for cellular homeostasis affected in ALS and frontotemporal dementia.}, } @article {pmid40772638, year = {2025}, author = {Menge, S and Decker, L and Freischmidt, A}, title = {Genetics of ALS - genes and modifier.}, journal = {Current opinion in neurology}, volume = {38}, number = {5}, pages = {568-573}, pmid = {40772638}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genetic Predisposition to Disease/genetics ; Mitochondria/genetics ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a complex genetic disorder, and the pace of discoveries is very rapid. This review aims at briefly summarizing our current knowledge, and at discussing the progress of the last two years.

RECENT FINDINGS: Common variation in numerous genes and variants in some nuclear-encoded mitochondrial genes were linked to an increased or modified risk of ALS, respectively. Mitochondrial function, i.e. specific mitochondrial haplotypes and loss-of-function variants in mitochondria-related genes, was identified as potent modifier of ALS survival, but not risk. Pioneering analyses of copy number variations in ALS-related genes revealed an increased load in ALS, but causality is unclear. A rare hyperactive variant of ER stress associated transcription factor CREB3 was linked to both substantially decreased ALS risk and slower disease progression. Furthermore, variants in IGFBP7 were linked to rare "ALS reversals", but existence of such phenotypes is controversial.

SUMMARY: Common variation increasing ALS risk contributes to our understanding of sporadic ALS, and novel structural variants have the potential to at least partly explain the missing heritability in ALS. Identification of mitochondrial function and ER stress signaling as potent disease modifiers provide valuable starting points for therapeutic approaches beyond targeting single causative genes.}, } @article {pmid40772655, year = {2025}, author = {He, J and Fan, D}, title = {Amyotrophic lateral sclerosis in Mainland China: clinical translational challenges and opportunities.}, journal = {Current opinion in neurology}, volume = {38}, number = {5}, pages = {596-605}, pmid = {40772655}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy/diagnosis ; China/epidemiology ; *Translational Research, Biomedical ; Biomarkers ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) imposes a growing medical and socioeconomic burden in China. This review synthesizes recent advances in understanding ALS epidemiology, biomarker discovery, therapeutic innovations, and policy frameworks in China. It highlights the urgency of addressing challenges, including fragmented healthcare resources, translational medicine gaps, and regional inequities, while emphasizing China's unique contributions to global ALS research.

RECENT FINDINGS: Chinese ALS cohorts exhibit distinct epidemiological profiles, including a younger mean age of onset and prolonged median survival. Policy initiatives, such as ALS inclusion in rare disease registries and insurance reforms, aim to reduce financial burdens of patients. Multimodal biomarker exploration has advanced integrated diagnostic models combining neurofilament light chain (NfL) and clinical data platforms. Neuroimaging and electrophysiological studies reveal glymphatic dysfunction, white matter degeneration, and neuromuscular junction abnormalities, with novel links to hepatic metabolism. Genomic analyses identify population-specific variants. Therapeutic innovations in China include not only biopharmaceuticals, but also integrative traditional Chinese medicine (TCM) approaches.

SUMMARY: China's ALS landscape is transitioning towards precision medicine through biomarker-guided diagnostics and multidisciplinary care models. Key priorities include establishing a national ALS registry, standardizing biomarker validation, and expanding clinical trials to bridge translational medicine gaps.}, } @article {pmid40772881, year = {2025}, author = {Zheng, Y and Li, M and Chen, X and Zheng, Z and Chen, Z and Tian, R and Zhao, YG}, title = {SOD1 is delivered to lysosomes via autophagy to maintain lysosomal function and integrity.}, journal = {The Journal of cell biology}, volume = {224}, number = {10}, pages = {}, doi = {10.1083/jcb.202501007}, pmid = {40772881}, issn = {1540-8140}, support = {32222021//National Natural Science Foundation of China/ ; 32170753//National Natural Science Foundation of China/ ; 2021YFA1300800//National Key Research and Development Program/ ; 2021 ZT09Y104//Guangdong Innovative and Entrepreneurial Research Team Program/ ; KQTD20210811090115021//Shenzhen Talent Program/ ; ZDSYS20220402111000001//Shenzhen Science and Technology Innovation Program/ ; GZNL2024A01008//R&D Program of Guangzhou Laboratory/ ; 2021QN02Y378//Guangdong Program/ ; //SUSTech Distinguished Young Scientist Team Program/ ; }, mesh = {*Lysosomes/metabolism/enzymology ; *Autophagy ; *Superoxide Dismutase-1/metabolism/genetics ; Humans ; Reactive Oxygen Species/metabolism ; Amyotrophic Lateral Sclerosis/genetics/pathology/enzymology ; Animals ; HEK293 Cells ; Autophagy-Related Protein 8 Family/metabolism/genetics ; Mice ; }, abstract = {The gene encoding superoxide dismutase 1 (SOD1) is often mutated in familial amyotrophic lateral sclerosis (ALS), affecting motor neurons. Compared with ALS-associated mutant SOD1, the function of WT SOD1 is less explored. We demonstrate that during starvation, WT and mutant SOD1 are transported into lysosomes. Genome-wide CRISPR interference (CRISPRi) screening identified autophagy-related proteins and the autophagic receptor TP53INP1 as key mediators. TP53INP1 binds ATG8 family proteins, preferentially LC3C, and directly interacts with SOD1. Within lysosomes, SOD1 retains its enzymatic activity. Starvation induces elevated levels of lysosomal reactive oxygen species (ROS), which are further increased by knocking down SOD1 or TP53INP1. Lysosomal degradation activities and membrane integrity are also compromised in the absence of SOD1 or TP53INP1. We reveal a novel function of SOD1 in maintaining lysosomal activity and integrity, and a previously unrecognized role of autophagy in delivering cytosolic enzymes into lysosomes for catalytic purposes, rather than for degradation.}, } @article {pmid40772974, year = {2025}, author = {Anjum, F and Bakhuraysah, MM and Hulbah, MJ and Alsharif, A and Mohammad, T and Hassan, MI}, title = {Aggregation-Prone Pathogenic SOD1 Variants in Amyotrophic Lateral Sclerosis: Insights from Computational Genomics and Evolutionary Conservation.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {3}, pages = {99}, pmid = {40772974}, issn = {1559-1166}, support = {KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; Humans ; *Mutation, Missense ; Evolution, Molecular ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and a median survival of 3-5 years post-diagnosis. While the etiology of ALS remains elusive, mutations in SOD1, encoding the Cu/Zn superoxide dismutase enzyme, are strongly associated with familial ALS (fALS). These mutations promote a toxic gain-of-function, primarily through SOD1 misfolding and aggregation. We systematically assessed 244 SOD1 missense mutations using a multi-tiered computational framework encompassing structural, functional, and pathogenic predictors. Sequence-based predictors (SIFT, PolyPhen-2, FATHMM) and structure-guided tools (mCSM, PremPS, DynaMut2) identified 79 destabilizing mutations, 64 of which were classified as pathogenic by phenotype predictors (PhD-SNP, SNPs&GO, MutPred2). Twelve mutations resided in evolutionarily conserved regions, with eight (D84N, G73C, H72Y, P67A, P67R, P67S, R144G, S60I) exhibiting pronounced aggregation propensity via SODA analysis. Notably, H72Y disrupts a zinc-binding residue critical for structural integrity and catalysis. Protein-protein interaction networks linked SOD1 to ALS-associated pathways, highlighting its involvement in oxidative stress and protein homeostasis. Our integrative approach highlights the power of computational genomics in unraveling mutation-driven SOD1 dysfunction, offering mechanistic insights into ALS pathogenesis and guiding therapeutic strategies focused on aggregation-prone variants.}, } @article {pmid40773352, year = {2025}, author = {Setsu, S and Morimoto, S and Nakamura, S and Ozawa, F and Okano, H}, title = {Protocol for the induction of human spinal motor neurons from human induced pluripotent stem cells for studying amyotrophic lateral sclerosis.}, journal = {STAR protocols}, volume = {6}, number = {3}, pages = {104016}, pmid = {40773352}, issn = {2666-1667}, mesh = {Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Motor Neurons/cytology/metabolism ; Cell Differentiation ; *Spinal Cord/cytology ; *Cell Culture Techniques/methods ; }, abstract = {Here, we present a protocol for inducing spinal lower motor neurons (LMNs) from human induced pluripotent stem cells (iPSCs). We describe steps for preparation of a chemically induced transitional state (CTraS), transduction with Sendai virus, and LMN differentiation and maintenance. We then detail procedures for live imaging for single-cell-based survival analysis and neurite length of LMNs using BioStation and immunocytochemistry for induction efficiency check. This protocol is optimized for amyotrophic lateral sclerosis (ALS) research and large-scale screening. For complete details on the use and execution of this protocol, please refer to Setsu et al.[1].}, } @article {pmid40774708, year = {2025}, author = {Brown, KR and Quinton, ML and Tidmarsh, G and Cumming, J}, title = {Athletes' access to, attitudes towards and experiences of help-seeking for mental health: a scoping review.}, journal = {BMJ open}, volume = {15}, number = {8}, pages = {e097492}, pmid = {40774708}, issn = {2044-6055}, mesh = {Humans ; *Athletes/psychology ; *Patient Acceptance of Health Care/psychology ; *Mental Health ; *Mental Disorders/therapy/psychology ; *Help-Seeking Behavior ; *Mental Health Services ; *Health Services Accessibility ; }, abstract = {OBJECTIVES: Athletes have been found to experience a similar prevalence of mental health issues to non-athletes. However, they are subjected to a greater array of barriers to help-seeking for mental health, including sport-specific factors. This scoping review synthesised the literature on athletes' access to, attitudes towards and experiences of help-seeking for mental health from formal (mental health professionals such as psychiatrists) and semiformal sources (those who are not mental health professionals but are a service provider such as a coach).

DESIGN: The Joanna Briggs Institute framework and recommendations were used alongside the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Protocols checklist for scoping reviews. This scoping review was predominantly informed by Arksey and O'Malley's framework for scoping reviews, supplemented by Levac et al's additional recommendations. Rickwood and colleagues' help-seeking frameworks informed the research question, inclusion/exclusion criteria and analysis.

DATA SOURCES: The search terms and synonyms of "athlete" AND "mental health" AND "help-seeking" were searched in PsychINFO, Embase, MEDLINE, APA PsychArticles Full Text, Web of Science Core Collection, Scopus, Sport Discus, CINAHL and Proquest (Education Database, Health & Medical Collection, Nursing & Allied Health database, Psychology Database, Public Health Database, Education Collection, and Medicine & Education). These searches were conducted at three time points between April 2022 and 2024.

ELIGIBILITY CRITERIA: The inclusion and exclusion criteria were initially predetermined and specified in the protocol paper published in BMJ Open. Primary research articles, interventions and systematic reviews that referred to semiformal and formal sources of support were included.

DATA EXTRACTION AND SYNTHESIS: The lead reviewer (KRB) screened all titles and abstracts, and full texts, and extracted data from all included studies. A second reviewer was involved in screening and extracting 20%-30% of studies at each stage. Findings were synthesised descriptively (eg, study population, data collection method and location of studies) and by content (eg, access, attitudes and experiences, sources of support, use of theory and the validity of quantitative measures used).

RESULTS: After screening 4954 titles and abstracts and 275 full texts in Covidence, 104 papers were included in the review. This comprised of 87 primary research articles, 13 interventions and 4 systematic reviews. Most of the primary articles and interventions were published in the USA (50%). 49.4% of the primary articles used quantitative methods, 34.5% used qualitative methods and 16.1% used mixed methods. Attitudes towards mental health help-seeking were investigated in 78.8% of the included studies, experiences of help-seeking in 53.8% and access to sources of support in 31.7% of studies. Of the primary articles and interventions, formal sources were investigated in 55% of studies, semiformal sources in 2% and both in 26% of studies.

CONCLUSIONS: This scoping review of 104 papers showed the benefit of using help-seeking frameworks to shape and analyse a review. Analysing the results using these frameworks provided a novel contribution to the literature, showing where the athlete help-seeking literature base is currently focused and identified gaps for further research. For example, there is a need for further research on athletes in less developed nations, more qualitative and mixed methods studies, and further research on athletes' access to mental health support and their interactions with semiformal sources. The results have applied implications in public health and sport by highlighting the different factors that impact athlete help-seeking, and therefore areas where they require support.}, } @article {pmid40775105, year = {2025}, author = {Pasternack, N and Paulsen, O and Nath, A}, title = {Machine learning predicts distinct biotypes of amyotrophic lateral sclerosis.}, journal = {European journal of human genetics : EJHG}, volume = {33}, number = {10}, pages = {1290-1299}, pmid = {40775105}, issn = {1476-5438}, support = {NS003130//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {*Machine Learning ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Transcription, Genetic ; Multigene Family ; Gene Expression Regulation ; Humans ; Male ; Female ; Middle Aged ; Aged ; Transcriptome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is universally fatal and has no cure. Heterogeneity of clinical presentation, disease onset, and proposed pathological mechanisms are key reasons why developing impactful therapies for ALS has been challenging. Here we analyzed data from two postmortem cohorts: one with bulk transcriptomes from 297 ALS patients and a separate cohort of single cell transcriptomes from 23 ALS patients. Using unsupervised machine learning, we found three groups of ALS patients characterized by synaptic dysfunction (34%), neuronal regeneration (47%), and neuronal degeneration (19%). Each of these ALS subtypes had unique patterns of transcriptional dysregulation that could represent novel therapeutic targets. We then developed a supervised machine learning model that was about 80% accurate at predicting ALS subtype based on patient demographic and clinical data. Together, we established three biologically distinct subtypes of ALS that can be predicted by clinical and demographic data.}, } @article {pmid40775435, year = {2025}, author = {Xu, W and Guo, Z and Guan, Y and Lv, S and Gao, X and Luo, W and Cheng, T and Shao, Z and Tao, B and Wang, T and Qiu, Z}, title = {Machine learning-based proteomics profiling of ALS identifies downregulation of RPS29 that maintains protein homeostasis and STMN2 level.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {1177}, pmid = {40775435}, issn = {2399-3642}, support = {82473207//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32271000//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; *Proteomics/methods ; *Machine Learning ; Down-Regulation ; *Ribosomal Proteins/metabolism/genetics ; Motor Neurons/metabolism ; *Proteostasis ; Animals ; Biomarkers/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The molecular understanding of ALS is hampered by the lack of experimental models recapitulating disease heterogeneity and analytical framework integrating multi-omics datasets. Here, we developed a pipeline integrating machine learning and consensus clustering to analyze a large-scale dataset of patient-derived motor neuron models from Answer ALS. Compared to the transcriptome, proteomic profiling closely correlates with ALS pathology, which is interrogated to identify 110 proteomics-based biomarkers (Proteomics Markers for ALS 110, PMA110). Functional enrichment highlights dysregulation of ALS pathways, including protein translation and neuronal function. By integrating ALS subtype-specific proteins with patient postmortem proteomics, we found that RPS29 was consistently downregulated in ALS models and patient motor neurons. RPS29 is required for neuronal viability by maintaining ribosome profiling and accurate translation, and suppressing pathological translation. RPS29 downregulation suppresses translation of STMN2, an essential protein for motor neurons, in iPSC-derived motor neurons. Taken together, this study provides a robust framework for ALS proteomics, identifies RPS29 as a quality controller of protein translation, and presents a translational mechanism for STMN2 maintenance in ALS.}, } @article {pmid40775651, year = {2025}, author = {Li, MJ and Li, Q and Zhao, MM and Kim, H and Feng, RQ and Guo, MN and Heng, JP and Yang, JK and Liu, C}, title = {Spectrum and epidemiology of rare diseases in a Chinese natural population of 14.31 million residents, 2012-2023.}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {410}, pmid = {40775651}, issn = {1750-1172}, support = {82341076//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Rare Diseases/epidemiology ; Female ; Male ; China/epidemiology ; Child ; Adolescent ; Adult ; Middle Aged ; Child, Preschool ; Young Adult ; Aged ; Infant ; Incidence ; Registries ; Infant, Newborn ; East Asian People ; }, abstract = {BACKGROUND: Rare diseases, though individually uncommon, collectively affect a significant portion of the population. However, their epidemiology in China remains underexplored. A population-based rare disease registry comprising 14.31 million individuals was conducted between 2012 and 2023 by the Beijing Municipal Health Big Data and Policy Research Center. Rare disease cases were identified via ICD-10 codes mapped to China's national rare disease lists (2018 and 2023) and international databases. Age-standardized incidence rates (ASIR) were calculated per 100,000 person-years with 95% confidence intervals.

RESULTS: Our analysis identified 12,371 rare disease cases, with the overall ASIR increasing from 6.109 in 2012 to 7.394 in 2023. Rare neurologic diseases accounted for 52.12% of cases, followed by systemic and rheumatologic diseases (16.89%) and rare neoplastic diseases (9.99%). The most frequently diagnosed rare diseases included generalized myasthenia gravis, ANCA-associated vasculitis, and malignant melanoma. Significant sex-based differences were observed, with female patients more affected by systemic and rheumatologic conditions, while male patients showed a higher incidence of respiratory disorders. Pediatric patients predominantly presented with inborn errors of metabolism and rare immune diseases. Comparisons with global data revealed notable disparities, such as a higher prevalence of Wilson's disease and a lower incidence of amyotrophic lateral sclerosis (ALS) in China.

CONCLUSIONS: This study represents the first large-scale, population-based analysis of rare diseases in China, revealing distinct epidemiological patterns. These findings underscore the critical need for healthcare policies that address the unique challenges posed by rare diseases in China.}, } @article {pmid40776416, year = {2025}, author = {Thiry, L and Pulimood, NS and Tang, YM and Stifani, S}, title = {Dysregulated Expression of Inflammasome and Extracellular Matrix Genes in C9orf72-ALS/FTD Microglia.}, journal = {ASN neuro}, volume = {17}, number = {1}, pages = {2542998}, pmid = {40776416}, issn = {1759-0914}, mesh = {*Microglia/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *Inflammasomes/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Induced Pluripotent Stem Cells ; *Extracellular Matrix/genetics/metabolism ; DNA Repeat Expansion/genetics ; Cells, Cultured ; }, abstract = {Hexanucleotide repeat expansion (HRE) in the non-coding region of the gene C9orf72 is the most prevalent mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 HRE contributes to neuron degeneration in ALS/FTD through both cell-autonomous mechanisms and non-cell autonomous disease processes involving glial cells such as microglia. The molecular mechanisms underlying the contribution of C9orf72-HRE microglia to neuron death in ALS/FTD remain to be fully elucidated. In this study, we generated microglia from human C9orf72-HRE and isogenic iPSCs using three different microglia derivation methods. RNA sequencing analysis reveals a cell-autonomous dysregulation of extracellular matrix (ECM) genes and genes involved in pathways underlying inflammasome activation in C9orf72-HRE microglia. In agreement with elevated expression of inflammasome components, conditioned media from C9orf72-HRE microglia enhance the death of C9orf72-HRE motor neurons implicating microglia-secreted molecules in non-cell autonomous mechanisms of C9orf72 HRE pathology. These findings suggest that aberrant activation of inflammasome-mediated mechanisms in C9orf72-HRE microglia results in a pro-inflammatory phenotype that contributes to non-cell autonomous mechanisms of motor neuron degeneration in ALS/FTD.}, } @article {pmid40776984, year = {2025}, author = {Wen, D and Li, Q and Li, Y and Yan, W and Wang, Y and Liu, Y}, title = {OPTN deficiency through CRISPR/Cas9 downregulates autophagy and mitophagy in a SOD1-G93A-expressing transgenic cell line.}, journal = {IBRO neuroscience reports}, volume = {19}, number = {}, pages = {307-316}, pmid = {40776984}, issn = {2667-2421}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the loss of upper and lower motor neurons (MNs) and is the most common adult paralysis neurodegenerative disease. Dysregulated autophagy, which has been reported in the pathogenesis of familial ALS, has been found in superoxide dismutase 1 (SOD1) transgenic mice and cell lines. Optineurin (OPTN) is a signal regulator that coordinates many crucial cellular processes, including autophagy, mitophagy and aggrephagy. Recent studies have shown that OPTN gene mutations are correlated with ALS, glaucoma and Paget's disease of the bone. Indeed, defects in autophagosome-lysosome fusion have been reported in patients with ALS-associated OPTN mutations. However, the exact function of OPTN in the pathology of ALS remains unknown. To determine the function of OPTN, we generated OPTN-knockdown cell lines from SOD1-G93A-expressing NSC34 cells with the clustered regularly interspaced short palindromic repeats/associated system 9 (CRISPR/Cas9) approach. In our research, we observed that the loss of OPTN resulted in the impairment of autophagy and mitophagy pathways. Moreover, the mitochondrial transmembrane potential was depolarized by LV-sgRNA-OPTN. On the basis of observations of live cells, the production of reactive oxygen species (ROS) was increased, the autophagic flux decreased, and the autophagic flux merged with that of mitochondria according to confocal live-cell imaging. A decreased LC3-II and an increased p62 levels indicated that autophagy pathway activation was decreased. The protein levels of VDAC1 and TBK1 decreased after OPTN knockdown, suggesting that mitophagy was blocked. Our results suggest that OPTN plays a pivotal role in regulating autophagy and mitophagy.}, } @article {pmid40777082, year = {2025}, author = {Otomo, A and Nishijima, K and Murakami, Y and Ishikawa, M and Yudahira, H and Shimakura, K and Okano, H and Aoki, M and Kimura, H and Hadano, S}, title = {Investigation of early axonal phenotypes in an iPSC-derived ALS cellular model using a microfluidic device.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1590732}, pmid = {40777082}, issn = {1662-5102}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of upper and lower motor neurons. Mutations in the FUS/TLS gene have been reported as the second most common mutation in Japanese patients with familial ALS. In recent years, lower motor neurons (LMNs) differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients have been widely used to analyze the mechanisms of neuronal cell death and degeneration.

METHODS: In this study, we developed a microfluidic device designed to observe axonal growth, morphology, and trafficking at high resolution in neurons derived from induced pluripotent stem cells (iPSCs) and tested whether our microfluidic device effectively evaluates neurodegenerative phenotypes. We used iPSCs carrying homozygous FUS/TLS mutations (FUS_H517D) to induce LMNs by expressing NEUROG2, ISL1, and LHX3 under the control of the tetracycline regulation system.

RESULTS AND DISCUSSIONS: After seven days of in vitro differentiation (DIV7), we confirmed that over 95% of iPSCs differentiated into HB9-positive LMNs. Notably, the cell viability of FUS_H517D LMNs was comparable to that of LMNs differentiated from iPSCs without the FUS/TLS mutation at DIV7. However, by DIV14 and DIV21, the viability of FUS_H517D LMNs was notably lower than that of control LMNs, indicating degeneration of FUS_H517D LMNs after differentiation. Using our microfluidic device, we assessed axonal phenotypes in FUS_H517D LMNs. Under oxidative stress conditions, we observed that the axonal length of FUS_H517D LMNs was significantly shorter than that of control cells as early as DIV7, with this axonal growth restriction becoming more pronounced by DIV11. This suggests that axonal growth restriction is an early detectable phenotype in degenerating neurons. Additionally, we examined mitochondrial trafficking within axons in our device, which is often disrupted in degenerative neurons. Our results showed a significant increase in the number of motile mitochondria in FUS_H517D LMNs, with retrograde transport accounting for a large portion of trafficking. Our microfluidic device-based culture and evaluation system using FUS_H517D LMNs offers a valuable ALS cellular model focused on early axonal phenotypes. This approach contributes to the study of molecular mechanisms underlying axonal degeneration in ALS.}, } @article {pmid40777853, year = {2025}, author = {Zhao, Q and Zhang, B and Chen, X and Fu, P and Yang, Y and Wang, Q}, title = {Global, regional, and national burden of motor neuron disease in adults aged 65 years and older from 1990 to 2021 and forecast to 2040.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1641887}, pmid = {40777853}, issn = {1664-2295}, abstract = {AIM: Given the significant social burden of motor neuron disease (MND) among elderly patients (aged ≥ 65 years) and the lack of detailed research on its epidemiological characteristics, this study aims to elucidate the temporal trends and distributional characteristics of MND in the elderly from 1990 to 2021, as well as to forecast its future burden.

METHODS: The age-standardized rates (ASR) and absolute numbers of MND-related incident, prevalent, death, and disability-adjusted life years (DALYs) among older patients (aged ≥ 65 years) globally were derived from the Global Burden of Disease (GBD) study from 1990 to 2021. The data were derived by gender, age group and geographic region. An estimated annual percentage change (EAPC) was estimated to represent temporal trends, and a Bayesian Age-Period-Cohort model was used to forecast the future burden of elderly MND.

RESULTS: In 2021, the global ASRs of incidence, prevalence, mortality, and DALYs for elderly MND were 3.63 (95% uncertainty intervals [UI], 2.95-4.36), 11.45 (95% UI, 8.69-14.88), 3.28(95% UI, 2.90-3.61), and 59.92 (95% UI, 53.94-65.53), respectively. Elderly patients those were from high socio-demographic index (SDI) region, as well as males, exhibited the highest burden. From 1990 to 2021, the global ASRs of elderly MND increased, with EAPCs of 0.43 (95% confidence interval [CI], 0.38-0.49), 0.58 (95% CI, 0.48-0.68), 0.90 (95%CI, 0.75-1.06), and 0.84 (95% CI, 0.71-0.96), respectively. Positive correlations were found between sociodemographic index and the burden of elderly MND. Health inequalities were evident across 204 countries and regions, with the inequality slope index raised from 23.46 (95% CI: 18.52-28.40) in 1990 to 80.70 (95% CI: 65.07-96.32) in 2021. Compared to the figures observed in 2021, our forecasts indicate a continued rise in the burden of elderly MND up to 2040, with the projected ASIR expected to reach 3.15 (95% UI, 2.28-4.01) and the ASMR anticipated to be 3.32 (95% UI, 2.11-4.55).

CONCLUSION: The burden of MND among elderly patients is substantial, particularly in high SDI region and among males. From 1990 to 2021, the global burden of elderly MND has exhibited an increasing trend. The burden of elderly MND varies significantly across the world, necessitating more targeted screening strategies and preventive measures to address the issue of elderly MND.}, } @article {pmid40777887, year = {2025}, author = {Ek, JE and Wittig, J and Rogers, J and Soar, J and , }, title = {A survey of Advanced Life Support practices in countries implementing the European Resuscitation Council guidelines.}, journal = {Resuscitation plus}, volume = {25}, number = {}, pages = {101032}, pmid = {40777887}, issn = {2666-5204}, abstract = {OBJECTIVE: The 2025 European Resuscitation Council (ERC) Advanced Life Support (ALS) Guidelines writing group aims to produce inclusive guidelines enabling implementation by National Resuscitation Councils (NRC) based on local resources and practices. We aimed to describe ALS practices across NRCs to further inform the 2025 ERC ALS Guidelines.

METHODS: A cross-sectional survey was conducted to assess clinical practices for defibrillation, drugs and airway management during ALS in out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) amongst countries represented by an NRC. NRCs were invited to suggest practices for consideration in the 2025 ERC ALS Guidelines.

RESULTS: Among 31 NRCs, 30 (96.8 %) provided data. Defibrillation pads were used for OHCA in 21 (70 %) and for IHCA in 15 (50 %) of countries, while paddles were reported by 3 (10 %) and 6 (20 %) for OHCA and IHCA, respectively. Most NRCs reported not using a pre-charging strategy (23 [76.7 %] OHCA; 26 [86.7 %] IHCA). Amiodarone was the primary antiarrhythmic (26 [89.7 %], OHCA; 28 [93.3 %], IHCA), and adrenaline was the primary vasopressor (27 [90 %], OHCA; 29 [96.7 %], IHCA). Airway management practices varied, 12 (41.4 %) reported supraglottic airway devices as the primary choice for OHCA and 1 (3.3 %) for IHCA, while 22 (73.3 %) reported tracheal tubes for IHCA and only 9 (31 %) for OHCA. Open-ended responses emphasised the importance of guidance in low-resource settings.

CONCLUSION: Current ALS practices vary across countries, and between OHCA and IHCA settings with a need to consider low-resource settings. Understanding these practices has implications for guideline development and research planning.}, } @article {pmid40778304, year = {2025}, author = {Zhang, K and Wen, M and Nan, X and Zhao, S and Li, H and Ai, Y and Zhu, H}, title = {NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategies.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1604378}, pmid = {40778304}, issn = {1663-4365}, abstract = {NMDA receptors (NMDARs) are widely distributed throughout the central nervous system (CNS) and play pivotal roles in normal physiological processes such as synaptic plasticity, learning, and memory. Substantial evidence indicates that NMDAR dysfunction, particularly excessive calcium influx, critically contributes to the pathogenesis of major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Dysregulated glutamatergic signaling synergizes with pathological protein aggregation (e.g., Aβ, α-synuclein, mutant huntingtin) to drive neuronal loss. We systematically delineate NMDAR-related mechanisms underlying neurodegeneration, highlighting spatial-specific roles (e.g., synaptic NMDAR-mediated neuroprotection versus extrasynaptic NMDAR-mediated excitotoxicity) and crosstalk with mitochondrial dysfunction and oxidative stress. We critically evaluate current therapeutic strategies targeting NMDARs, including subunit-selective modulators, downstream effector modulation, and glutamate transporter modulation designed to restore NMDAR homeostasis. Consequently, NMDARs and their modulators represent promising therapeutic targets for these refractory conditions. This review comprehensively summarizes current research on the involvement of NMDARs and the glutamatergic system in neurodegenerative diseases. Furthermore, we discuss the clinical application of NMDAR-targeting agents and explore emerging therapeutic strategies focused on modulating NMDAR-related pathways. This article aims to provide a reference for elucidating the molecular mechanisms underlying these neurodegenerative disorders and to highlight potential avenues for future drug development.}, } @article {pmid40778857, year = {2025}, author = {Hasegawa-Ogawa, M and Onda-Ohto, A and Nakajo, T and Funabashi, A and Ohya, A and Yazaki, R and Okano, HJ}, title = {Dominant-negative isoform of TDP-43 is regulated by ALS-linked RNA-binding proteins.}, journal = {The Journal of cell biology}, volume = {224}, number = {10}, pages = {}, pmid = {40778857}, issn = {1540-8140}, support = {JP16H07218//Japan Society for the Promotion of Science/ ; JP17K09766//Japan Society for the Promotion of Science/ ; JP17K14967//Japan Society for the Promotion of Science/ ; JP20K15904//Japan Society for the Promotion of Science/ ; JP21K07302//Japan Society for the Promotion of Science/ ; JP23K06812//Japan Society for the Promotion of Science/ ; //Uehara Memorial Foundation/ ; //Jikei University Graduate Research Fund/ ; //Jikei University School of Medicine/ ; }, mesh = {*DNA-Binding Proteins/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; *RNA-Binding Protein FUS/metabolism/genetics ; Protein Isoforms/genetics/metabolism ; Heterogeneous-Nuclear Ribonucleoprotein K/metabolism/genetics ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism/genetics ; Heterogeneous Nuclear Ribonucleoprotein A1 ; HEK293 Cells ; Alternative Splicing ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; }, abstract = {TDP-43, an RNA-binding protein (RBP) encoded by the TARDBP gene, is crucial for understanding the pathogenesis of neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Dysregulated TDP-43 causes motor neuron loss, highlighting the need for proper expression levels. Here, we identify a dominant-negative isoform among the multiple TARDBP splicing variants and validate its endogenous expression using a developed antibody against its translated product. Furthermore, we revealed that ALS-associated RBPs regulate its expression: hnRNP K promotes its splicing and expression, while hnRNP A1 and FUS suppress these processes through distinct mechanisms. hnRNP A1 inhibits hnRNP K-mediated splicing, and FUS represses the dominant-negative isoform through both its translational inhibition and hnRNP K suppression. Notably, ALS-mutant FUS weakens this regulatory mechanism, leading to impaired repression of hnRNP K and the dominant-negative isoform. Our findings suggest a regulatory network involving ALS-linked RBPs that govern TDP-43 isoform expression and provide new insights into how disruptions in this network contribute to ALS pathogenesis.}, } @article {pmid40779173, year = {2025}, author = {Gil Chong, P and Mazon, M and Cerdá-Alberich, L and Beser Robles, M and Carot, JM and Vázquez-Costa, JF and Martí-Bonmatí, L}, title = {Machine learning diagnostic model for amyotrophic lateral sclerosis analysis using MRI-derived features.}, journal = {Neuroradiology}, volume = {67}, number = {10}, pages = {2803-2812}, pmid = {40779173}, issn = {1432-1920}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Machine Learning ; *Magnetic Resonance Imaging/methods ; Male ; Female ; Middle Aged ; *Image Interpretation, Computer-Assisted/methods ; Aged ; Algorithms ; Adult ; }, abstract = {PURPOSE: Amyotrophic Lateral Sclerosis is a devastating motor neuron disease characterized by its diagnostic difficulty. Currently, no reliable biomarkers exist in the diagnosis process. In this scenario, our purpose is the application of machine learning algorithms to imaging MRI-derived variables for the development of diagnostic models that facilitate and shorten the process.

METHODS: A dataset of 211 patients (114 ALS, 45 mimic, 22 genetic carriers and 30 control) with MRI-derived features of volumetry, cortical thickness and local iron (via T2* mapping, and visual assessment of susceptibility imaging). A binary classification task approach has been taken to classify patients with and without ALS. A sequential modeling methodology, understood from an iterative improvement perspective, has been followed, analyzing each group's performance separately to adequately improve modelling. Feature filtering techniques, dimensionality reduction techniques (PCA, kernel PCA), oversampling techniques (SMOTE, ADASYN) and classification techniques (logistic regression, LASSO, Ridge, ElasticNet, Support Vector Classifier, K-neighbors, random forest) were included. Three subsets of available data have been used for each proposed architecture: a subset containing automatic retrieval MRI-derived data, a subset containing the variables from the visual analysis of the susceptibility imaging and a subset containing all features.

RESULTS: The best results have been attained with all the available data through a voting classifier composed of five different classifiers: accuracy = 0.896, AUC = 0.929, sensitivity = 0.886, specificity = 0.929.

CONCLUSION: These results confirm the potential of ML techniques applied to imaging variables of volumetry, cortical thickness, and local iron for the development of diagnostic model as a clinical tool for decision-making support.}, } @article {pmid40779613, year = {2026}, author = {Chaouch, A and Crook, A and Douglas, AGL and McDermott, CJ and Al-Chalabi, A and McNeill, A and Bedford, J and Howard, J and MacLeod, R}, title = {The use of genetic testing in amyotrophic lateral sclerosis (ALS): a practical approach.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {28-34}, doi = {10.1080/21678421.2025.2539895}, pmid = {40779613}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Genetic Testing/methods ; Genetic Counseling ; Genetic Predisposition to Disease/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disease thought to be precipitated by genetic, environment and lifestyle factors. In the UK, whole genome sequencing has become available to all people living with ALS, regardless of their family history or age of onset of disease. However, there is currently no formal guidance on how to deliver genetic counseling and testing in busy mainstream clinics. This article offers practical suggestions to clinicians who may wish or need to discuss genomic testing. As more clinical trials and targeted gene therapies develop, it is likely that conversations will evolve, reflecting the dynamic nature of this important and complex field.}, } @article {pmid40780661, year = {2025}, author = {Goleva, E and Berdyshev, E and Kreimer, S and Leung, DYM}, title = {Response to Chang et al's "Abrocitinib versus dupilumab: Impact on skin barrier function and proteomics in atopic dermatitis".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {6}, pages = {e217-e219}, doi = {10.1016/j.jaad.2025.05.1462}, pmid = {40780661}, issn = {1097-6787}, } @article {pmid40781905, year = {2025}, author = {Steffke, C and Baskar, K and Bachhuber, F and Wiesenfarth, M and Dorst, J and Schuster, J and Schöberl, F and Reilich, P and Regensburger, M and German, A and Günther, R and Vidovic, M and Petri, S and Meyer, T and Hagenacker, T and Grosskreutz, J and Weyen, U and Weydt, P and Haarmeier, T and Lingor, P and Wolf, J and Hermann, A and Prudlo, J and Günther, K and Knehr, A and Elmas, Z and Uzelac, Z and Witzel, S and Ruf, WP and Freischmidt, A and Ho, R and Ludolph, AC and Weishaupt, JH and Tumani, H and Oeckl, P and Brenner, D and Catanese, A}, title = {Targeted Proteomics upon Treatment with Tofersen Identifies Novel Response Markers for Superoxide Dismutase 1-Linked Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {98}, number = {6}, pages = {1318-1334}, pmid = {40781905}, issn = {1531-8249}, support = {SFB 1506//Deutsche Forschungsgemeinschaft/ ; Ca2/1//Deutsche Gesellschaft für Muskelkranke/ ; AlamarNeurologyGrant//Alamar Biosciences/ ; Exzellenzstipendium2022_EKES.18//Else Kröner-Fresenius-Stiftung/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid/genetics/blood ; Male ; Female ; Middle Aged ; *Proteomics/methods ; *Superoxide Dismutase-1/genetics ; Biomarkers/cerebrospinal fluid/blood ; Aged ; Adult ; Neurofilament Proteins/cerebrospinal fluid ; Longitudinal Studies ; }, abstract = {OBJECTIVE: Tofersen is the first effective and approved therapy for superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS [SOD1-ALS]). Following treatment with tofersen, neurofilament levels in patients' cerebrospinal fluid (CSF) and serum seem to respond earlier than clinical parameters. This evidence prompted us to hypothesize that this novel treatment could provide an opportunity to identify additional biomarkers responsive to therapy in SOD1-ALS.

METHODS: We investigated a panel of 120 neural, glial, and inflammatory markers in CSF and serum samples longitudinally collected from a total of 28 SOD1-ALS patients at baseline, and after 3, 6 and 12 months of treatment with tofersen, followed by validation with conventional methodology.

RESULTS: We identified a set of proteins, including neurofilament light chain, neurofilament heavy chain, amyloid-beta 1-40 and amyloid-beta 1-42, neuropeptide Y (NPY), and ubiquitin C-terminal hydrolase L1 (UCHL1), whose CSF levels both differed between SOD1-ALS and the control group, and were responsive to tofersen at 3 and 6 months after treatment initiation. Another group of markers, including the neuropentraxin (NPTX) family members NPTX1, NPTX2 and NPTXR, did not separate untreated SOD1-ALS from controls, but was responsive to tofersen. At 12 months on tofersen the levels of neurofilament light chain, neurofilament heavy chain, NPTX1, NPTX2, and NPTXR remained reduced compared with baseline, and correlated with the clinical response to tofersen. Consistent with increasing CSF pleocytosis and intrathecal immunoglobulin production, inflammatory markers were significantly increased after 12 months of treatment.

INTERPRETATION: Our results highlight a complex, time-dependent differential response of CSF biomarkers to tofersen treatment, and may pave the way for developing a panel of responsive proteins to make biomarker endpoints more robust in clinical trials for SOD1-ALS and beyond. ANN NEUROL 2025;98:1318-1334.}, } @article {pmid40782358, year = {2026}, author = {St Clair-Sullivan, N and Brighton, LJ and Jha, P and Bone, AE and Sudirman, NA and Maddocks, M and Bayly, J}, title = {Assistive technologies for people with advanced disease and in palliative care: a scoping review.}, journal = {Disability and rehabilitation. Assistive technology}, volume = {21}, number = {1}, pages = {32-48}, doi = {10.1080/17483107.2025.2536175}, pmid = {40782358}, issn = {1748-3115}, mesh = {Humans ; *Self-Help Devices ; *Palliative Care ; Quality of Life ; *Persons with Disabilities/rehabilitation ; Dementia/rehabilitation ; Neoplasms ; Parkinson Disease/rehabilitation ; }, abstract = {Population ageing, multi-morbidity and associated disability is shifting global demand for health and care services. Innovative solutions are required to meet the evolving needs of people with advanced disease, support independent functioning and quality of life. This scoping review aimed to map and examine evidence on the role of assistive technology in adults with advanced disease and those receiving palliative care. A systematic search of Medline, Embase, PsychINFO and Cinahl, was conducted from inception to 31[st] July 2024 for studies investigating use of assistive technologies in people with advanced disease or receiving palliative care. Titles and abstracts were independently screened before full texts retrieved for eligibility review, data extraction, synthesis and descriptive analysis. 23/811 screened papers met eligibility criteria. Participants included ALS/MND (n13/23); palliative care (n4/23); cancer (n2/23); dementia (n2/23); Parkinson's (n1/23) and frailty (n1/23). Studies evaluated assistive technologies supporting ten functional domains; most frequently to support communication and information management (n13/23), least frequently orthoses and prosthesis, and domestic activities and participation in domestic life (n1/23). Outcomes of assistive technology use related to functioning, quality of life, dignity in end-of-life care and health service use. Implications for individual users, device design and delivery are discussed. This review highlights potential benefits of assistive technologies and gaps in research on their use for adults with advanced disease or receiving palliative care. Empirical evidence is limited and focuses on communication enhancing high-tech devices. Future research should explore assistive technology's impact over time on health outcomes, alongside strategies to integrate provision in care.}, } @article {pmid40783116, year = {2025}, author = {Chang, JW and Wang, F}, title = {Response to Goleva et al, "Response to Chang et al's 'Abrocitinib versus dupilumab: Impact on skin barrier function and proteomics in atopic dermatitis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {6}, pages = {e221-e223}, doi = {10.1016/j.jaad.2025.07.063}, pmid = {40783116}, issn = {1097-6787}, } @article {pmid40783546, year = {2025}, author = {Du, M and Akerman, SC and Fare, CM and Ruan, L and Vidensky, S and Mamedova, L and Koo, K and Lee, J and Rothstein, JD}, title = {Divergent and convergent TMEM106B pathology in murine models of neurodegeneration and human disease.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {169}, pmid = {40783546}, issn = {2051-5960}, support = {R35 NS132179/NS/NINDS NIH HHS/United States ; R35NS132179/NH/NIH HHS/United States ; HT94252310136//U.S. Department of Defense/ ; }, mesh = {Animals ; Humans ; *Membrane Proteins/metabolism/genetics ; Disease Models, Animal ; *Nerve Tissue Proteins/metabolism/genetics ; Mice ; *Frontotemporal Dementia/pathology/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Brain/pathology/metabolism ; Mice, Transgenic ; *Neurodegenerative Diseases/pathology/metabolism ; *Tauopathies/pathology/metabolism ; Male ; Female ; }, abstract = {TMEM106B is a lysosome/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of the endogenous TMEM106B protein in murine models of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy using an extensively validated TMEM106B antibody. We found profound correlations between the endogenous TMEM106B protein with known TDP-43 and tau pathology in murine models of C9-ALS/FTD and tauopathy, respectively. By using an antibody previously shown to recognize the pathologic TMEM106B C-terminal fragments, we then performed a similar analysis on postmortem brain tissues from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). Convergent evidence from both murine models and human patients links TMEM106B to TDP-43 nuclear clearance at the cellular level in C9-ALS. By characterizing endogenous TMEM106B in mice and human postmortem tissue, our work reveals essential considerations that must be taken when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.}, } @article {pmid40783639, year = {2025}, author = {Lin, CY and Nelson, A and Lee, W and Feng, Z and Lee, YS}, title = {Characterization of lower urinary tract dysfunction in a mouse model of amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {29190}, pmid = {40783639}, issn = {2045-2322}, support = {2022-040//Cleveland Clinic Technology Development Investment Project and Ohio Third Frontier Technology Validation and Start-up Fund/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/genetics ; Disease Models, Animal ; Mice ; Female ; Male ; Mice, Transgenic ; Superoxide Dismutase-1/genetics ; Electromyography ; Urodynamics ; Urethra/physiopathology ; *Lower Urinary Tract Symptoms/physiopathology/etiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by a progressive loss of motor function due to degeneration of motor neurons. In addition to motor-related symptoms, increasing evidence from clinical studies indicate lower urinary tract (LUT) dysfunctions (urge incontinence) are found in patients with ALS, which causes a significant negative impact on quality of life. However, it remains unclear whether LUT dysfunction can be validated in preclinical ALS models. Here, we attempt to answer this question by using comprehensive urodynamic testing with electromyogram of external urethral sphincter (EUS) activity in both female and male SOD1-G93A ALS mice at both 9 weeks of age (pre-onset stage) and 16 weeks of age (early symptomatic stage). Our results demonstrate that the detrusor muscle is hyperactive, voiding volume is decreased, and the EUS relaxation period is shorter in female and male SOD1-G93A ALS mice at both 9 weeks and 16 weeks of age, compared to age-matched wild-type animals. The symptoms of urge incontinence found in the current study are similar to the clinical findings, indicating that SOD1-G93A ALS mice can be used as a preclinical model to develop therapeutics for ALS patients with LUT dysfunction.}, } @article {pmid40784541, year = {2025}, author = {Haidar, M and Viden, A and Daniel, C and Cuic, B and Wang, T and Rosier, M and Tomas, D and Mills, SA and Govier-Cole, A and Djouma, E and Perera, ND and Luikinga, S and Rytova, V and Barton, SK and Gonsalvez, DG and Palmer, LM and McLean, C and Kiernan, MC and Vucic, S and Turner, BJ}, title = {Cortical hyperexcitability drives dying forward amyotrophic lateral sclerosis symptoms and pathology in mice.}, journal = {Progress in neurobiology}, volume = {252}, number = {}, pages = {102809}, doi = {10.1016/j.pneurobio.2025.102809}, pmid = {40784541}, issn = {1873-5118}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology ; *Motor Neurons/pathology/physiology ; Mice ; Spinal Cord/pathology ; Disease Models, Animal ; Mice, Transgenic ; Neuromuscular Junction/pathology ; *Cerebral Cortex/physiopathology/pathology ; DNA-Binding Proteins/metabolism ; *Cortical Excitability/physiology ; Male ; Mice, Inbred C57BL ; }, abstract = {Degeneration of both upper motor neurons in the brain and lower motor neurons in the spinal cord defines amyotrophic lateral sclerosis (ALS), but how they are linked in ALS pathophysiology is unclear. Here, we uncover a cortical origin of neurodegeneration in ALS mediated by upper motor neuron hyperexcitability. Chronic hyperexcitability of upper motor neurons induced by excitatory chemogenetics in healthy adult mice induced progressive motor deficits, weakness and core pathological hallmarks of ALS, including upper motor neurons loss, synaptic pathology, corticospinal tract degeneration and reactive gliosis. Importantly, upper motor neuron hyperexcitability and loss were sufficient to drive degeneration of lower motor neurons and their distal axons and neuromuscular junctions, associated with astrocyte and microglial activation in spinal cord. Cortical hyperexcitability also triggered cytoplasmic TAR DNA binding protein 43 (TDP-43) aggregation in upper motor neurons and lower motor neurons, placing hyperexcitability upstream of TDP-43 proteinopathy in ALS. These findings establish a cortical origin of ALS mediated by upper motor neurons, consistent with an anterograde mechanism of neurodegeneration throughout the central and peripheral nervous systems.}, } @article {pmid40784657, year = {2025}, author = {Babcock, KJ and Abdolmohammadi, B and McKee, AC}, title = {Recent Advances in Chronic Traumatic Encephalopathy.}, journal = {The American journal of pathology}, volume = {195}, number = {11}, pages = {2048-2058}, pmid = {40784657}, issn = {1525-2191}, support = {P30 AG072978/AG/NIA NIH HHS/United States ; R01 AG062348/AG/NIA NIH HHS/United States ; R01 NS119651/NS/NINDS NIH HHS/United States ; U54 NS115266/NS/NINDS NIH HHS/United States ; }, abstract = {Exposure to repeated head impacts (RHIs), such as those experienced in contact sports or military service, can lead to the development of chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy. CTE cannot be diagnosed during life, only by post-mortem neuropathologic examination. The pathognomonic lesion of CTE consists of a perivascular accumulation of hyperphosphorylated tau as neurofibrillary tangles and dotlike neurites, preferentially at the depths of cortical sulci. The biomechanics of RHI involve acceleration, deceleration, and rotational forces that distort brain tissue and strain fragile structures, such as blood vessels and axons, especially in the crevices of the brain, where these forces are localized. CTE is unique from other tauopathies in its molecular structure, pattern, and regional distribution of tau. Studies in American football, rugby, and ice hockey players demonstrate a dose-response relationship between years of exposure to sport and increased CTE risk and severity. The clinical symptoms associated with CTE are classified as traumatic encephalopathy syndrome. Exposure to RHI also increases the deposition of other pathologic proteins, including β-amyloid, α-synuclein, and transactive response DNA-binding protein (TDP-43), raising the risk for other neurodegenerations, such as Alzheimer disease, Lewy body disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis.}, } @article {pmid40785560, year = {2025}, author = {Glas, G}, title = {[De psychiater als activist].}, journal = {Tijdschrift voor psychiatrie}, volume = {67}, number = {6}, pages = {319-320}, pmid = {40785560}, issn = {0303-7339}, } @article {pmid40785665, year = {2025}, author = {Plaitano, EG and Pate, BL and Ryan, KM}, title = {Teaching Emergency Medical Technicians about Advanced Life Support Interventions: Pilot Study of an Online Continuing Education Course.}, journal = {Disaster medicine and public health preparedness}, volume = {19}, number = {}, pages = {e233}, pmid = {40785665}, issn = {1938-744X}, support = {F31 DA062393/DA/NIDA NIH HHS/United States ; }, mesh = {Humans ; Pilot Projects ; *Emergency Medical Technicians/education ; Surveys and Questionnaires ; *Education, Continuing/methods/standards ; *Education, Distance/methods ; Male ; Female ; *Teaching/standards/statistics & numerical data ; Adult ; Educational Measurement/methods ; Clinical Competence/standards ; }, abstract = {OBJECTIVES: Emergency Medical Technician (EMT) scope of practice guidelines in the US suggest that EMTs should assist paramedics with advanced skills during patient care. However, learning to assist with these skills is not an EMT national education requirement. This study examined the feasibility and impact of a short, online pilot continuing education course in providing EMTs with the confidence and basic knowledge to assist with advanced interventions.

METHODS: The pilot cohort included licensed EMTs (n=10) self-enrolled in a continuing education class listed on the institution's EMS continuing education website and advertised on social media. Optional, anonymous questionnaires and multiple-choice exams were administered to students pre/post-course. Statistical analysis included paired nonparametric tests.

RESULTS: Total scores were 43% higher on the post-exam (88/100, 95% CI [76, 100]) compared to the pre-exam (45/100, 95% CI [37, 53]) (P<0.05). Self-reported comfort was higher on the post-evaluation for needle thoracostomy (95% increase), advanced airways (25% increase), EKGs (19% increase), intravenous access (14% increase), and communication (22% increase).

CONCLUSIONS: Results suggest that short, online continuing education courses on BLS-ALS interface for EMTs might be efficacious in improving both comfort and knowledge of selected advanced interventions often used by paramedics, although larger future studies are needed.}, } @article {pmid40787400, year = {2025}, author = {Hwang, D and Park, SA and Kim, JH and Lee, SY and Lee, J and Kim, HS and Kim, KA and Lee, SH and Oh, TJ and Lee, J and An, S}, title = {Gold Nanoparticle-mRNA Conjugates Encapsulated in Lipid Nanoparticles for Coordinated Codelivery of Multiple mRNAs.}, journal = {ACS omega}, volume = {10}, number = {30}, pages = {32998-33007}, pmid = {40787400}, issn = {2470-1343}, abstract = {Gold nanoparticles (AuNPs) can be engineered to be utilized as carriers via anchoring multiple nucleic acids, including mRNAs, in specific ratios. However, the negative charge of mRNA-AuNP conjugates presents significant challenges for efficient cellular uptake and subsequent expression. To overcome this limitation, we developed a delivery system that combines mRNA-AuNP conjugation with lipid nanoparticles (LNPs) to enhance intracellular delivery. In our approach, AuNPs were functionalized with a thiolated antisense leader sequence (ALS), oligonucleotides complementary to the 5'-end leader sequence of the 5'-untranslated region (UTR) of the mRNA. This functionalization resulted in the formation of mRNA-ALS-AuNP conjugates, which were then encapsulated within LNPs. When we compared the ALS-AuNP@LNP constructs to ALS-AuNPs alone, ALS-AuNP@LNP demonstrated superior delivery and expression of enhanced green fluorescence protein (EGFP) mRNA across multiple cell lines, as evidenced by robust green fluorescence. Furthermore, this system enables the precise codelivery of multiple mRNAs in defined ratios, as demonstrated by the successful codelivery of EGFP and mCherry mRNAs. These findings highlight the potential of the mRNA-ALS-AuNP@LNP platform as an effective and versatile tool for advancing mRNA-based therapeutics and vaccine development.}, } @article {pmid40787733, year = {2025}, author = {Raaphorst, J and Gullick, NJ and Shokraneh, F and Brassington, R and Min, M and Ali, SS and Gordon, PA}, title = {Non-targeted immunosuppressive and immunomodulatory therapies for idiopathic inflammatory myopathies.}, journal = {The Cochrane database of systematic reviews}, volume = {8}, number = {8}, pages = {CD015855}, pmid = {40787733}, issn = {1469-493X}, mesh = {Humans ; *Myositis/drug therapy ; *Immunosuppressive Agents/therapeutic use/adverse effects ; Randomized Controlled Trials as Topic ; Dermatomyositis/drug therapy ; *Immunomodulating Agents/therapeutic use/adverse effects ; Bias ; Child ; Adult ; Polymyositis/drug therapy ; }, abstract = {BACKGROUND: Idiopathic inflammatory myopathies (IIM) are autoimmune-mediated inflammatory disorders of skeletal muscles with non-muscle involvement in some people, which carry significant morbidity and mortality. Treatment of IIM represents an area of unmet need. This review is an update of a review previously published in 2012, as new and promising data on non-targeted treatments have emerged.

OBJECTIVES: To assess the effects (benefits and harms) of non-targeted immunosuppressant and immunomodulatory treatments for IIM: dermatomyositis (DM, including juvenile dermatomyositis, jDM), immune-mediated necrotising myopathy (IMNM), anti-synthetase syndrome (ASS), overlap-myositis (OM) and polymyositis (PM). We also included cancer-related myositis and amyopathic dermatomyositis.

SEARCH METHODS: On 3 February 2023, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, Embase, MEDLINE, ClinicalTrials.gov and WHO ICTRP. We intended to check references and citations, and contact experts to identify additional studies, but lacked the resources.

SELECTION CRITERIA: We included all randomised controlled trials (RCTs) or quasi-RCTs involving participants (adults and children) with IIM according to defined criteria. We included non-targeted immunosuppressants and immunomodulatory treatments alone or in combination, compared with a placebo, no treatment or another non-targeted immunosuppressant or immunomodulatory treatment. Our two primary outcomes were improvement of function or disability and improvement of muscle strength compared with baseline. By preference, we used the Health Assessment Questionnaire Disability Index (HAQ-DI) for disability and the Manual Muscle Test-8 (MMT8) score (adults or children) for muscle strength. Other outcomes were achievement of definitions of improvement (DOI) (the International Myositis Assessment and Clinical Studies (IMACS) Group or the more recent total improvement scores (TIS); for children, we reported achievement of improvement defined by the Paediatric Rheumatology International Trials Organisation (PRINTO)), cumulative corticosteroid dose, change in skin disease activity, serious adverse event and withdrawals for lack of benefit or adverse events.

DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess the risk of bias, we used the domain-based Cochrane risk of bias tool (RoB 1). We used fixed-effect models and, when needed, random-effects models for meta-analysis. We created summary of findings tables for any comparison for which data were available but prioritised comparisons of the following with placebo, no treatment or standard care: immunoglobulin, azathioprine and methotrexate. We included other comparisons as additional tables. We assessed the certainty of evidence using the GRADE approach.

MAIN RESULTS: We identified 16 studies (789 participants). The risk of bias in all but one study was high or unclear. Intravenous immunoglobulin (IVIg), compared to placebo, probably improves disability and muscle strength in participants with refractory IIM (standardised mean difference (SMD) 0.86, 95% confidence interval (CI) 0.51 to 1.21 (disability) and 0.78, 95% CI 0.43 to 1.13 (muscle strength); 3 RCTs, 136 participants; both moderate-certainty evidence). IVIg has a higher response rate based on American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria than placebo (risk ratio (RR) 1.80, 95% CI 1.26 to 2.56; 1 RCT, 95 participants; moderate-certainty evidence). IVIg, compared to placebo, improves skin symptoms (Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) total activity score 0 to 100; higher worse) in people with refractory DM (mean difference (MD) -8.20, 95% CI -11.91 to -4.49; 1 RCT, 95 participants; moderate-certainty evidence). There may be more serious adverse events with IVIg than with placebo (RR 1.91, 95% CI 0.50 to 7.30; 2 RCTs, 144 participants; very low-certainty evidence), but little or no difference between IVIg and placebo in withdrawals for either lack of benefit or adverse events (RR 1.02, 95% CI 0.24 to 4.33; 3 RCTs, 154 participants; very low-certainty evidence). For azathioprine versus placebo, one study showed little or no effect of azathioprine on improvement in muscle strength, but the evidence was very uncertain (RR 1.33, 95% CI 0.43 to 4.13; 1 RCT; 16 participants; very low-certainty evidence). The evidence was also very uncertain for cumulative steroid dose (MD 12.06 mg/kg, 95% CI -6.09 to 30.21; 1 RCT, 16 participants; very low-certainty evidence). This early study did not assess IMACS DOI or CDASI or measure function or disability. Serious adverse events and withdrawals for either lack of benefit or adverse events were not systematically reported. For methotrexate, there may be little or no improvement in adults with DM or PM in function (Amyotrophic Lateral Sclerosis Functional Rating Scale 0 to 40, higher better) (MD 1.24, 95% CI -1.60 to 4.08; 1 RCT, 27 participants; very low-certainty evidence), muscle strength (MMT scale 0 to 80, higher better) (MD -5.68, 95% CI -12.94 to 1.58; 1 RCT, 27 participants; very low-certainty evidence), achievement of IMACS DOI (RR 1.01, 95% CI 0.74 to 1.39; 1 RCT, 27 participants; very low-certainty evidence). Cumulative steroid dose was measured, but the data could not be analysed, and change in CDASI was not measured. In children with new-onset jDM on a background therapy of prednisone, a higher proportion may achieve minimal improvement according to the PRINTO criteria with methotrexate than with placebo (RR 1.40, 95% CI 1.01 to 1.96; 1 RCT, 93 participants; low-certainty evidence). Serious adverse events may occur slightly more frequently with methotrexate (RR 1.48, 95% CI 0.54 to 4.07; 2 RCTs, 124 participants; low-certainty evidence). There may be fewer withdrawals for lack of benefit or adverse events with methotrexate (RR 0.62, 95% CI 0.37 to 1.05; 3 RCTs, 151 participants; low-certainty evidence).

AUTHORS' CONCLUSIONS: Our review shows improvement in disability, muscle strength and skin symptoms following IVIg in people with refractory DM (for PM, these data are not reliable; other subtypes have not been investigated in RCTs). The improvements related to IVIg in DM may be clinically meaningful, but the absence of established minimal clinically important differences (MCIDs) for both disability and muscle strength in IIM does not facilitate interpretation. For the other agents, the small number of trials of immunosuppressive and immunomodulatory therapies is inadequate to decide whether these agents are beneficial in IIM (excluding IBM). Our review shows room for improvement in the conduct and reporting of clinical trials in IIM, as well as the need to further investigate MCIDs for important outcome measures in IIM.}, } @article {pmid40788112, year = {2025}, author = {Guha, A and Si, Y and Smith, R and Singh, BK and Zogu, B and Yadav, A and Smith, KA and Kazamel, M and Jiang, N and Ho, R and Thalacker-Mercer, A and Andrabi, SA and Da Silva Pereira, JDT and Salgado, JS and Agrawal, M and Velic, EH and King, PH}, title = {The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity.}, journal = {Aging}, volume = {17}, number = {8}, pages = {2033-2062}, pmid = {40788112}, issn = {1945-4589}, support = {R21 NS111275/NS/NINDS NIH HHS/United States ; R01 NS092651/NS/NINDS NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; I01 BX006231/BX/BLRD VA/United States ; T32 NS095775/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Fibroblast Growth Factors/metabolism/genetics/blood ; Animals ; Mice ; *Oxidative Stress ; Male ; Female ; *Muscle, Skeletal/metabolism/pathology ; Middle Aged ; Spinal Cord/metabolism/pathology ; Mice, Transgenic ; Aged ; Klotho Proteins ; Superoxide Dismutase-1/genetics/metabolism ; Myokines ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1[G93A] mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, β-Klotho, with higher levels detected in ALS muscle biopsies and lower levels in post-mortem muscle compared to controls. Plasma FGF21 levels were increased in ALS patients and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In cellulo, FGF21 was induced in differentiating muscle cells and ectopic treatment with FGF21 enhanced muscle differentiation. Ectopic FGF21 mitigated oxidative stress-induced loss of viability in iPSC-derived ALS motor neurons and muscle cells expressing SOD1[G93A]. In summary, FGF21 is a novel biomarker in ALS which exerts trophic effects in the neuromuscular system.}, } @article {pmid40788946, year = {2025}, author = {Donjon, A and Boumendil, C}, title = {Using LEXY and LINuS Optogenetics Tools and Automated Image Analysis to Quantify Nucleocytoplasmic Transport Dynamics in Live Cells.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {221}, pages = {}, doi = {10.3791/68585}, pmid = {40788946}, issn = {1940-087X}, mesh = {*Optogenetics/methods ; *Active Transport, Cell Nucleus ; *Optical Imaging/methods ; Fluorescent Dyes ; Cell Culture Techniques ; }, abstract = {Nucleocytoplasmic transport (NCT) is essential for maintaining cellular homeostasis, and its disruption is involved in various diseases, including neurodegenerative disorders and amyotrophic lateral sclerosis. This underscores the need to develop tools to monitor and quantify NCT. Amongst these tools, the fast and reversible optogenetics probes, LEXY (light-inducible nuclear export system) and LINuS (light-inducible nuclear localization signal), allow the measurement of NCT dynamics in live cells. The original publications describe manual segmentation and quantification of the fluorescent probe signal in the nucleus and cytosol upon transfection of LEXY and LINuS constructs in live-cell imaging. However, both transfection and manual segmentation limit the number of cells that can be analyzed and are subject to imprecision due to potential user-dependent errors. While the high speed and reversibility provided by optogenetics should, in principle, allow for high sensitivity in detecting changes in NCT dynamics, it depends on the acquisition parameters and analysis of a sufficient number of cells. We have therefore established lentiviral vectors expressing LEXY and LINuS to create stable cell lines, tested live imaging markers and control conditions, and implemented a semi-automated image analysis pipeline that allows for the analysis of hundreds of cells. This analysis method uses the open-access software FIJI, is accessible to beginners in bioinformatics, and does not require advanced computer setups. Here we provide a step-by-step protocol to set up LEXY as an example of these optogenetic tools to monitor nuclear export, from preparation of the samples to live-cell imaging acquisition and automated analysis, while demonstrating how to adapt the protocol for other conditions, controls, or models in any lab. All plasmids and cell lines used in this protocol will be made available to the scientific community, therefore further increasing the accessibility of the method.}, } @article {pmid40789150, year = {2025}, author = {Roy, D and Dashora, C and Patel, AB}, title = {Excitatory and Inhibitory Activity Is Differentially Affected in SOD1[G37R] Mouse Model of ALS: A [1]H-[[13]C]-NMR Analysis.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {16}, pages = {3162-3173}, doi = {10.1021/acschemneuro.5c00208}, pmid = {40789150}, issn = {1948-7193}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology/physiopathology ; Male ; Disease Models, Animal ; Mice, Transgenic ; Mice ; *Superoxide Dismutase-1/genetics/metabolism ; *Spinal Cord/metabolism ; *Cerebral Cortex/metabolism ; Magnetic Resonance Spectroscopy ; Astrocytes/metabolism ; Carbon Isotopes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder marked by the selective degeneration of motor neurons in the central nervous system. In this study, neuronal and astroglial metabolic activities were evaluated in the cerebral cortex and spinal cord of an 18 month-old male SOD1[G37R] mouse model of ALS using [1]H-[[13]C]-nuclear magnetic resonance spectroscopy in tissue extracts in conjunction with an infusion of [1,6-[13]C2]glucose or [2-[13]C]acetate, respectively. The cerebral metabolic fluxes were obtained by fitting a three-compartment metabolic model to the [13]C turnover of amino acids from [13]C-glucose. The SOD1[G37R] mice exhibited decreased forelimb strength and hindlimb function compared to age-matched controls. The spinal cord of SOD1[G37R] mice exhibited a reduction in aspartate, glutamate, N-acetylaspartate, and N-acetylaspartylglutamate levels and an increase in myo-inositol, glutamine, and taurine levels. The increased acetate oxidation rate suggests heightened inflammatory conditions in the cerebral cortex and spinal cord of SOD1[G37R] mice. The glutamatergic and GABAergic TCA cycle and neurotransmitter cycle fluxes were reduced in the spinal cord of SOD1[G37R] mice. In contrast, glutamatergic fluxes were increased in the cerebral cortex. These data suggest heightened excitatory activity in the cerebral cortex and differential degeneration of excitatory and inhibitory neurons in the spinal cord in advanced conditions of ALS.}, } @article {pmid40790269, year = {2025}, author = {Yang, S and Wijegunawardana, D and Sheth, U and Veire, AM and Salgado, JMS and Arab, T and Agrawal, M and Zhou, J and Pereira, JD and Gendron, TF and Guo, JU}, title = {Aberrant splicing exonizes C9orf72 repeat expansion in ALS/FTD.}, journal = {Nature neuroscience}, volume = {28}, number = {10}, pages = {2034-2043}, pmid = {40790269}, issn = {1546-1726}, support = {R35 GM152208/GM/NIGMS NIH HHS/United States ; T32 NS041228/NS/NINDS NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; DP2 GM132930/GM/NIGMS NIH HHS/United States ; S10 OD030363/OD/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; *C9orf72 Protein/genetics ; *Exons/genetics ; *DNA Repeat Expansion/genetics ; Serine-Arginine Splicing Factors/genetics ; RNA Splicing/genetics ; Alternative Splicing/genetics ; Fibroblasts/metabolism ; Neurons/metabolism ; }, abstract = {A nucleotide repeat expansion (NRE) (GGGGCC)n within the first annotated intron of the C9orf72 (C9) gene is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While previous studies have shown that C9 NRE produces several toxic dipeptide repeat (DPR) proteins, the mechanism by which an intronic RNA segment can access the cytoplasmic translation machinery remains unclear. By selectively capturing and sequencing NRE-containing RNAs (NRE-capture-seq) from patient-derived fibroblasts and neurons, we found that, in contrast to previous models, C9 NRE is retained as part of an extended exon 1 due to the usage of various downstream alternative 5' splice sites. These aberrant splice isoforms accumulate in C9-ALS/FTD brains, and their production is promoted by serine/arginine-rich splicing factor 1 (SRSF1). Antisense oligonucleotides targeting either SRSF1 or the aberrant C9 splice isoforms reduced the levels of DPR. Together, our findings revealed a crucial role of aberrant splicing in the biogenesis of NRE-containing RNAs and demonstrated potential therapeutic strategies to target these pathogenic transcripts.}, } @article {pmid40791023, year = {2025}, author = {}, title = {Correction to "Innovative Synchronous Spectrofluorometric Method for Assessing a Novel Drug Combination in Amyotrophic Lateral Sclerosis: In Vivo Human Application With Greenness and Sustainability Evaluation".}, journal = {Luminescence : the journal of biological and chemical luminescence}, volume = {40}, number = {8}, pages = {e70286}, doi = {10.1002/bio.70286}, pmid = {40791023}, issn = {1522-7243}, } @article {pmid40791706, year = {2025}, author = {Spencer, BE and Irwin, DJ and Van Deerlin, VM and Suh, E and Lee, EB and Elman, L and Quinn, CC and Amado, D and Baer, M and Grossman, M and Wolk, DA and McMillan, CT}, title = {Polygenic associations with clinical and neuropathological trait heterogeneity across TDP-43 proteinopathies.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.10.05.23296613}, pmid = {40791706}, abstract = {OBJECTIVE: TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 (FTLD-TDP), and limbic-predominant age-related TDP-43 encephalopathy, encompass a spectrum of clinical and neuropathological traits. Despite mounting evidence for shared genetic risk across TDP-43 proteinopathies, the modifiers of individual-level traits are unknown. We aimed to identify polygenic contributions to trait heterogeneity across TDP-43 proteinopathies.

METHODS: We used weighted correlation analysis of GWAS summary statistics for ALS, FTLD-TDP, and hippocampal sclerosis of aging (HS-Aging) to identify data-driven clusters of highly correlated single nucleotide polymorphisms (SNPs). We performed gene ontology enrichment analysis for each identified cluster. We derived cluster-specific polygenic scores and evaluated their association with clinical and neuropathological traits in an independently evaluated sample of individuals who met neuropathological and/or genetic criteria for FTLD-TDP or ALS (n=260).

RESULTS: We identified 5 distinct data-driven clusters, including 3 GWAS phenotype-specific clusters (FTLD-TDP, ALS, HS-Aging) and 2 clusters representing the overlap between a pair of GWAS phenotypes (ALS-FTLD and FTLD-HS). Pathway analysis revealed biologically meaningful associations including distinct GWAS phenotype-specific processes within clusters. Cluster-specific ALS and FTLD-TDP polygenic risk each associated with individual-level clinical traits, even within the context of autosomal dominant mutation carriers, where higher ALS polygenic risk associated with neuromuscular impairment and higher FTLD-TDP polygenic risk associated with cognitive-behavioral impairment. Moreover, higher FTLD-TDP polygenic risk associated with higher TDP-43 burden within characteristic FTLD-TDP brain regions.

INTERPRETATION: We suggest that there are polygenic modifiers of clinical and neuropathological traits across TDP-43 proteinopathies that may contribute to individual-level differences, including likelihood for developing FTLD or ALS.}, } @article {pmid40792523, year = {2025}, author = {Duan, QQ and Su, WM and Gu, XJ and Long, J and Jiang, Z and Yin, KF and Cai, WC and Cao, B and Chi, LY and Gao, X and Li, JR and Chen, YP}, title = {Genetically Predict Diet-derived Antioxidants and Risk of Neurodegenerative Diseases Among Individuals of European Descent: A Mendelian Randomization Study.}, journal = {Brain and behavior}, volume = {15}, number = {8}, pages = {e70766}, pmid = {40792523}, issn = {2162-3279}, support = {2022NSFSC0749//The National Natural Science Fund of Sichuan/ ; 2022YFC2703101//National Key Research and Development Program of China/ ; 2023YFS0269//The Science and Technology Bureau Fund of Sichuan Province/ ; }, mesh = {Female ; Humans ; Male ; Amyotrophic Lateral Sclerosis/genetics ; *Antioxidants/metabolism ; Diet ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics ; Parkinson Disease/genetics ; Polymorphism, Single Nucleotide ; *White People/genetics ; }, abstract = {BACKGROUND: The incidence of neurodegenerative disorders (NDDs) is increasing, and currently, there are no curative treatments available for these conditions. The potential benefits of supplementation with diet-derived antioxidants and their metabolites for NDDs remain a subject of debate. In this study, we employed a two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between elevated circulating antioxidant levels and the risk of NDDs.

METHODS: We used single-nucleotide polymorphisms (SNPs) related to diet-derived antioxidants and p < 1E-05 as instrumental variables (IVs). The NDDs we studied included Parkinson's disease (PD) (33,674 cases and 449,056 controls), Alzeimers disease (AD) (111,326 cases and 677,663 controls), amyotrophic lateral sclerosis (ALS) (27,205 cases and 110,881 controls), and frontotemporal dementia (FTD) (3526 cases and 9402 controls) from GWASs conducted in the European descent. Two-sample MR was performed together with a series of sensitivity analyses. The main statistical analyses were conducted using the package "TwoSampleMR (V.0.5.6)" in R (V.4.2.0).

RESULTS: Genetically predicted levels of α-tocopherol and carotene were found to be associated with a reduced risk of ALS, with odds ratios (OR) of 0.45 (95% confidence interval [CI]: 0.31, 0.66; p = 3.97 × 10^-5) and 0.82 (95% CI: 0.68, 0.99; p = 0.0427), respectively. Similarly, vitamin E (OR 0.70; [95% CI 0.50, 0.98]; p  = 0.0358) and ascorbate (OR 0.85; [95% CI: 0.73, 0.98]; p = 0.0216) demonstrated a protective effect against PD. Furthermore, elevated levels of retinol were associated with a reduced incidence of FTD, with an OR of 0.92 (95% CI: 0.86, 0.99; p = 0.0196), although they were also linked to an increased risk of ALS (OR 1.02 [95% CI 1.01, 1.04], p = 0.0017) and PD (OR 1.06 [95% CI 1.02, 1.09], p = 0.0121). No significant causal association was observed between circulating antioxidants and AD.

CONCLUSION: This MR study indicated a potential protective effect of α-tocopherol and carotene on ALS, vitamin E and ascorbate on PD, and retinol on FTD, while also identifying retinol as a risk factor for ALS and PD. These findings could contribute to the exploration of dietary therapies for NDDs. Further research is necessary to substantiate the potential associations between diet-derived antioxidants or their metabolites and the risk of NDDs in individuals.}, } @article {pmid40794238, year = {2026}, author = {Jellinger, KA}, title = {Comorbid pathologies and their impact on progressive supranuclear palsy: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {133}, number = {5}, pages = {831-841}, pmid = {40794238}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Supranuclear Palsy, Progressive/epidemiology/pathology ; Comorbidity ; }, abstract = {Progressive supranuclear palsy, a four-repeat tauopathy, is clinically characterized by early postural instability and falls, vertical supranuclear palsy, levodopa poorly-responsive parkinsonism, pseudobulbar palsy, and cognitive impairment. It is morphologically featured by accumulation of hyperphosphorylated tau protein in neurons and glia predominantly in the basal ganglia, brainstem tegmentum and frontal cortex, associated with degeneration of the extrapyramidal system and cortical atrophy. Isolated PSP neuropathology is uncommon, with nearly 70% showing co-neuropathologies including Alzheimer-type, Lewy body, TDP-43 pathologies, argyrophilic grains, and other tauopathies and neurodegenerative disorders (Parkinson disease, amyotrophic lateral sclerosis). The most common comorbid conditions are hypertension, cardiovascular and cerebrovascular diseases, diabetes mellitus, polyneuropathies, muscular and urological disorders. Due the increased prevalence of comorbidities and their eminent impact on the progress and outcome of the disease, clinical trials should account for them in their design and selection. However, currently little is known about co-pathologies in these patients. In view of the eminent burden of comorbidities and resulting therapeutic consequences, the frequency of the different co-pathologies in PSP and their clinical impact will be discussed. It should provide insight into their pathogenic backgrounds as a basis for adequate treatment procedures to improve the quality of life of patients with this fatal disease.}, } @article {pmid40794569, year = {2025}, author = {Benatar, M and Staffaroni, AM and Wuu, J and McDermott, MP and Quintana, M and Swidler, J and Andersen, G and Huey, ED and Turner, MR and Macklin, EA and Berry, JD and McMillan, CT and Gendron, T and Onyike, C and Rosen, H and Heuer, HW and Grignon, AL and Dave, KD and Balas, C and Gleixner, A and Satlin, A and Dunn, B and Dacks, P and Boxer, AL}, title = {Design considerations for C9orf72 disease prevention trials.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {11}, pages = {3844-3855}, pmid = {40794569}, issn = {1460-2156}, support = {//Association for Frontotemporal Degeneration/ ; //ALS Association/ ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/prevention & control ; *Frontotemporal Dementia/genetics/prevention & control ; *Clinical Trials as Topic/methods ; DNA Repeat Expansion/genetics ; Research Design ; }, abstract = {The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for ∼10% of all amyotrophic lateral sclerosis and 10%-15% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease. Strategies for the design of disease prevention trials among clinically unaffected C9orf72 carriers have begun to emerge separately in the amyotrophic lateral sclerosis and frontotemporal dementia fields. However, recognition of the need to define neurodegenerative diseases based on biology underscores the need to consider all potential clinical manifestations of a C9orf72 repeat expansion together, rather than the traditional siloed approach of focusing on only amyotrophic lateral sclerosis or only frontotemporal dementia. Indeed, emerging clinical and biological markers that might be used to quantify pre-symptomatic disease progression and to predict the short-term risk of phenoconversion to clinically manifest disease are shared across the phenotypic spectrum. Given the anticipated progress in the development of therapeutic strategies to target the C9orf72 repeat expansion, and the enthusiasm for prevention trials among the unaffected C9orf72 repeat expansion carrier population, now is the time to begin work on the design of disease prevention trials. To this end, The Association for Frontotemporal Degeneration and The ALS Association supported a multi-stakeholder workshop (in Washington D.C., June 2024) to unify efforts to design a prevention trial for the population at elevated genetic risk for the phenotypic spectrum of C9orf72 disease. Here we describe recommendations emanating from this workshop for the selection of outcome measures, delineation of eligibility criteria, optimal use of biomarkers and digital health technologies, potential analytic frameworks and relevant regulatory considerations related to C9orf72 disease prevention trials. We also emphasize the importance of the amyotrophic lateral sclerosis and frontotemporal dementia communities working together in partnership with the C9orf72 repeat expansion carrier community, the regulatory authorities and the broader drug development community.}, } @article {pmid40795306, year = {2026}, author = {Guo, J and Zou, Q and Xu, J and Lei, J and Yin, X and Li, B and Fu, J and Mi, J and Wang, Y and Huang, H and Zhang, CY and Chen, X}, title = {In vivo self-assembled SOD1-siRNAs mitigate muscle atrophy and denervation in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {3}, pages = {785-800}, pmid = {40795306}, issn = {1460-2156}, support = {//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy/complications ; *Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Mice ; *RNA, Small Interfering/administration & dosage/genetics ; *Muscular Atrophy/genetics/therapy/etiology/pathology ; Humans ; Disease Models, Animal ; Extracellular Vesicles/metabolism ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the death of both upper and lower motor neurons. Approximately 20% of familial ALS cases are associated with mutations in the superoxide dismutase type 1 (SOD1) gene. Developing a specific strategy to characteristically silence the pathogenic SOD1 gene remains a crucial goal amidst significant challenges. In this study, we developed a synthetic biology strategy to reprogramme the liver as a tissue chassis for the in vivo self-assembly of small extracellular vesicles (sEVs)-encapsulated SOD1-siRNA, aiming to target spinal neurons and silence mutant SOD1 specifically in Tg(SOD1G93A) transgenic mice. We designed a cytomegalovirus (CMV) promoter-directed synthetic construct to encode a SOD1-siRNA along with a neuron-targeting rabies virus glycoprotein (RVG) tagged on the sEV surface. Theoretically, upon liver uptake, this construct reprogrammes liver cells to generate and self-assemble SOD1-siRNAs into RVG-tagged sEVs. Subsequently, the sEV-encapsulated SOD1-siRNAs are transported via the endogenous sEV circulation and guided by the RVG tag to the spinal neurons. Experimental results illustrated that intravenous administration of this synthetic construct effectively facilitated in vivo self-assembly of SOD1-siRNAs into circulating sEVs. The functional delivery of SOD1-siRNAs to the spinal cord and cerebral cortex was confirmed through in vivo tracking of sEVs and sEV-encapsulated siRNAs. Treatment of Tg(SOD1G93A) transgenic mice with this construct significantly reduced mutant SOD1 protein levels in the spinal cord and cerebral cortex. Consequently, the characteristic symptoms of ALS, including decreased body weight, shortened lifespan, compromised motor function, muscle atrophy, neuroinflammation, motor neuron loss and neuromuscular junction degeneration, were substantially ameliorated by the synthetic construct. Furthermore, an AAV-based strategy was devised for the enduring self-assembly of sEV-encapsulated SOD1-siRNA, whereby a single injection led to substantial and sustained inhibition of mutant SOD1 and significant symptom amelioration in transgenic mice. Overall, this study established an effective and convenient therapeutic approach for mitigating muscle atrophy and denervation in animal model, presenting a promising solution for future ALS treatment.}, } @article {pmid40795649, year = {2025}, author = {Rabbani, MG and Alif, SM and Zhou, Z and Ryan, J and Karim, MN}, title = {Association between higher serum uric acid levels and cognitive function: a systematic review and meta-analysis.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {80}, number = {10}, pages = {}, pmid = {40795649}, issn = {1758-535X}, mesh = {Humans ; *Uric Acid/blood ; *Cognition/physiology ; Male ; Female ; Cross-Sectional Studies ; Biomarkers/blood ; }, abstract = {BACKGROUND: Serum uric acid (SUA) levels may be associated with cognitive function, but findings have been inconsistent, potentially varying by cognitive domain and sex. We aimed to determine the association of SUA and different domains of cognitive function.

METHODS: Five electronic databases were searched to identify relevant peer-reviewed articles. Studies investigating the association between SUA levels and cognitive function were included. Standardized mean difference (SMD) was calculated, and separate meta-analyses were conducted for each of the domains. Risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale. Between-study heterogeneity was investigated through subgroup analysis and a meta-regression model using study-level covariates.

RESULTS: Ten prospective cohort and 16 cross-sectional studies were eligible for inclusion, but only a subset of these studies was included in each meta-analysis. Pooled estimates from cross-sectional studies showed that higher SUA levels were significantly associated with better global cognition (n = 6, SMD = 2.27, 95% CI, 1.18-3.35), and learning and memory (n = 4, SMD = 1.49, 95% CI, 1.12-1.87). Sensitivity analysis, excluding the study conducted on amyotrophic lateral sclerosis patients, resulted in better performance estimates for executive function (n = 4, SMD = 0.51, 95% CI, 0.47-0.55) and language (n = 2, SMD = 0.75, 95% CI, 0.71-0.79). The pooled result from 2 prospective cohort studies found a positive relationship between SUA levels and attention (SMD = 0.22, 95% CI, 0.07-0.36). Serum uric acid levels were associated with executive function and learning and memory in males, and with language in females.

CONCLUSIONS: Higher SUA levels were associated with better global cognitive performance executive function, learning and memory, attention and language. These findings highlight low SUA levels as a potentially useful biomarker for cognitive decline.}, } @article {pmid40796055, year = {2025}, author = {Tedeschi, V and Ciancio, R and Magliocca, G and Esposito, E and Piccirillo, S and Rubino, V and Preziuso, A and Spadoni, T and Muraglia, ND and Ruggiero, G and Pannaccione, A and Secondo, A}, title = {Lysosomal TPC2 channel as a new target of chlorpromazine and clomipramine to induce protective autophagy in L-BMAA-induced neurodegeneration.}, journal = {Biochemical pharmacology}, volume = {242}, number = {Pt 2}, pages = {117219}, doi = {10.1016/j.bcp.2025.117219}, pmid = {40796055}, issn = {1873-2968}, mesh = {*Autophagy/drug effects/physiology ; Animals ; *Lysosomes/metabolism/drug effects ; *Clomipramine/pharmacology ; Mice ; *Chlorpromazine/pharmacology ; *Calcium Channels/metabolism ; Humans ; Neuroprotective Agents/pharmacology ; Motor Neurons/drug effects/metabolism ; }, abstract = {Several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) are characterized by toxic aggregates accumulation due to autophagy blockade, prompting researchers to identify new autophagy-activating drugs. Here we tested, in an in vitro ALS/PDC model, the neuroprotective effects of the antipsychotic Chlorpromazine (CPZ) and the antidepressant Clomipramine (CMI), chosen by drug repurposing approach for their ability to stimulate TPC2 lysosomal channel. Patch-clamp electrophysiology on enlarged lysosomes in NSC-34 motor neurons showed that CPZ and CMI induced large inwardly-rectifying currents, that were inhibited by TPC2 synthetic blocker trans-Ned-19. The same currents were evoked by TPC2 endogenous agonist NAADP and its mimetic agent TPC2-A1-N, and inhibited by trans-Ned-19 and siRNAs against TPC2 (siTPC2). CPZ and CMI elicited a significant [Ca[2+]]i increase that rapidly induced nuclear translocation of TFEB (transcription factor EB), the master regulator of autophagy. Accordingly, TPC2 stimulation by both the drugs boosted autophagy, as revealed by the activation of autophagy initiators ULK and AMPK α and modification of LC3-II/p62(SQSTM1) ratio. Furthermore, by normalizing autophagy markers, CPZ and CMI counteracted the detrimental effects induced by L-BMAA, a neurotoxin mimicking ALS/PDC. Notably, siTPC2 partially reverted CMI- and CPZ-induced neuroprotection as well as that produced by NAADP. At mitochondrial level, these drugs prevented ATP reduction and ROS overproduction in motor neurons exposed to L-BMAA for 24 h. For a longer L-BMAA exposure, CPZ and CMI counteracted LDH, cytochrome C and SMAC/DIABLO release, thus preventing cell demise. These findings suggest that TPC2 activation by drug repurposing could provide novel therapeutic options for ALS via autophagy regulation.}, } @article {pmid40796666, year = {2025}, author = {Lowry, ER and Patel, T and Costa, JA and Chang, E and Tariq, S and Melikyan, H and Davis, I and Aziz, S and Ntermentzaki, G and Lotti, F and Wichterle, H}, title = {Embryonic motor neuron programming factors reactivate immature gene expression and suppress ALS pathologies in postnatal motor neurons.}, journal = {Nature neuroscience}, volume = {28}, number = {10}, pages = {2044-2053}, pmid = {40796666}, issn = {1546-1726}, support = {R01 NS109217/NS/NINDS NIH HHS/United States ; R01NS109217//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS116141//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS140764/NS/NINDS NIH HHS/United States ; K99 NS121136/NS/NINDS NIH HHS/United States ; R01NS140764//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; K99NS121136//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS116141/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *Motor Neurons/metabolism/pathology/physiology ; Mice ; *Transcription Factors/genetics/metabolism ; *LIM-Homeodomain Proteins/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *Gene Expression Regulation, Developmental/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Animals, Newborn ; Humans ; Spinal Cord ; }, abstract = {Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resilience of young motor neurons could be restored by reexpression of the embryonic motor neuron selector transcription factors ISL1 and LHX3. We found that viral reexpression of ISL1 and LHX3 selectively in postnatal motor neurons reactivates aspects of their youthful gene expression program and alleviates key disease-relevant phenotypes in the SOD1[G93A] mouse model of ALS. Our results suggest that redeployment of lineage-specific neuronal selector transcription factors can be an effective strategy to attenuate age-dependent phenotypes in neurodegenerative disease.}, } @article {pmid40797499, year = {2025}, author = {Wang, X and Cui, H and Xu, Z}, title = {Reevaluating the diagnosis of right coronary artery absence: A thoughtful analysis of a case report.}, journal = {Medicine}, volume = {104}, number = {32}, pages = {e43620}, pmid = {40797499}, issn = {1536-5964}, mesh = {Humans ; Male ; Middle Aged ; *Coronary Vessel Anomalies/diagnostic imaging/diagnosis ; Coronary Angiography/methods ; Computed Tomography Angiography/methods ; Percutaneous Coronary Intervention/methods ; Chest Pain/etiology ; *Coronary Vessels/diagnostic imaging ; }, abstract = {RATIONALE: This reevaluation challenges the diagnostic certainty of coronary angiography (CAG) and computed tomography angiography (CTA) in confirming right coronary artery (RCA) agenesis, as presented in Seok Oh et al's case. It underscores the critical need for multimodal imaging to avoid misdiagnosis of rare coronary anomalies.

PATIENT CONCERNS: A 57-year-old male presented with severe chest pain lasting several hours, accompanied by hemodynamic instability and ST-segment elevation consistent with myocardial infarction.

DIAGNOSES: CAG revealed total occlusion of the left circumflex artery (LCX) and suggested that the RCA territory was supplied by a superdominant LCX. Coronary CTA later indicated the absence of the RCA, though diagnostic uncertainties remained.

INTERVENTIONS: Emergent percutaneous coronary intervention was performed to address the LCX occlusion, resulting in clinical stabilization.

OUTCOMES: Reanalysis of published CAG images revealed no definitive evidence of LCX extending to RCA territory. CTA suggested the "RCA-supplying branch" was likely a coronary vein, implying possible misinterpretation of a left-dominant system with anomalous small RCA.

LESSONS: This case highlights the challenges of diagnosing rare coronary anomalies and emphasizes the importance of multi-modal imaging for accurate evaluation and decision-making.}, } @article {pmid40798859, year = {2025}, author = {Vijaya Bhaskar, AV and Vijayakumar, I and Torra, J and Runge, F and Hennessy, M and Forristal, PD}, title = {Insights into ALS-inhibiting herbicide resistance in Poa annua in an arable cropping system.}, journal = {Pest management science}, volume = {81}, number = {12}, pages = {8128-8136}, pmid = {40798859}, issn = {1526-4998}, support = {//Department of Agriculture, Food and the Marine, Ireland/ ; }, mesh = {*Herbicide Resistance/genetics ; *Acetolactate Synthase/antagonists & inhibitors/genetics ; *Herbicides/pharmacology ; *Plant Proteins/genetics/antagonists & inhibitors/metabolism ; *Plant Weeds/drug effects/genetics/enzymology ; Mutation ; }, abstract = {BACKGROUND: Dependence on a single herbicide type to control a broad-spectrum of weeds has resulted in cases of resistance to acetolactate synthase (ALS) inhibitors in weeds normally considered lower priority such as Poa annua, being recorded in winter wheat fields in Ireland. This study characterizes resistance to ALS-inhibiting sulfonylureas (SU), sulfonylamino-carbonyl-triazolinones (SCT) and triazolopyrimidine (TP) herbicides in five resistance-suspect populations (POAAN-R1 to POAAN-R5).

RESULTS: Variability in cross-resistance levels were noted in the POAAN-R populations, correlating with target-site mutations and specific amino acid substitutions. Mutations Pro-197-Thr in POAAN-R1, Pro-197-Thr + Trp-574-Leu in POAAN-R4, and Trp-574-Leu in POAAN-R5 confer high levels of resistance to SU, SU + SCT and TP herbicides (GR50 resistance index, RI >10). In POAAN-R2, Pro-197-Gln confers high resistance to SU and SU + SCT (RI >10) and low resistance to TP (RI = 3.2). POAAN-R3 with Pro-197-Thr + Pro-197-Gln, confers moderate resistance to SU and SU + SCT (RI >5) and high resistance to TP (RI >10). All sequenced plants had homozygous mutations that evolved independently in ALS1 (Pro-197-Gln) or ALS2 (Pro-197-Thr or Trp-574-Leu) isoforms. Among the alternative non-residual herbicides evaluated, clethodim and glyphosate effectively controlled P. annua populations.

CONCLUSION: Pro-197-Thr and/or Pro-197-Gln, as well as the combination of Pro-197-Thr + Trp-574-Leu were identified for the first time in P. annua in this study. As cultural/non-chemical management of P. annua is challenging, the primary control in cereal crops will likely be the use of non-ALS herbicide modes of action, including the application of pre-emergence or autumn residual-type herbicides. © 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid40799366, year = {2025}, author = {Gao, B and Wang, L and Gong, J and Zhu, Z and Liu, Q and Yuan, H and Wang, H}, title = {The interplay between physical exercise and autophagy signaling in brain health, neurodegenerative diseases and aging.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1579208}, pmid = {40799366}, issn = {1663-4365}, abstract = {Brain health is increasingly recognized as a critical component of overall wellbeing, particularly concerning neurodegenerative diseases, which are characterized by the progressive degeneration of the nervous system. Conditions such as Alzheimer's disease (AD) and Parkinson's disease, together with less common disorders, resembling Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), significantly impact cognitive and physical health, affecting over 50 million individuals worldwide. This review explores the multifaceted relationship between brain health and neurodegeneration, emphasizing the roles of biological, environmental, and lifestyle factors. Notably, physical activity has been identified as a potent intervention that enhances neuroplasticity and metabolic resilience while mitigating the effects of neurodegeneration. Research indicates that exercise activates autophagy, which is crucial for clearing neurotoxic aggregates like amyloid-beta and α-synuclein, thereby promoting neuronal health. Additionally, exercise stimulates the production of neurotrophic factors such as BDNF and GDNF, which are essential for neuronal survival and function. Despite the promising findings regarding exercise as a preventive and therapeutic strategy for neurodegenerative diseases, further investigation into the underlying mechanisms is necessary to optimize these interventions. This review aims to elucidate the complex interactions between exercise, autophagy, and brain health to provide insights into effective strategies for combating neurodegeneration.}, } @article {pmid40801430, year = {2025}, author = {Foster-Powell, A and Rostami-Hodjegan, A and Meno-Tetang, G and Mager, DE and Ogungbenro, K}, title = {Mathematical Modeling of Neuroinflammation in Neurodegenerative Diseases.}, journal = {CPT: pharmacometrics & systems pharmacology}, volume = {14}, number = {12}, pages = {1908-1922}, pmid = {40801430}, issn = {2163-8306}, support = {BB/W509930/1//Biotechnology and Biosciences Research Council (BBSRC) Industrial CASE studentship in collaboration with AstraZeneca (AZ), UK/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology/physiopathology ; Animals ; *Models, Biological ; *Inflammation ; *Models, Theoretical ; *Neuroinflammatory Diseases ; }, abstract = {Age-related neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD) are an increasing public health concern. Whereas the pathology of these diseases is complex, chronic central inflammation, or neuroinflammation, is commonly observed across many neurodegenerative diseases. Despite a huge wealth of resources and promising preclinical testing, effective disease-modifying therapies do not exist. This failure is owing to a combination of poor biological understanding of this response, unsuitable animal models, and poor scaling from pathway up to clinical levels. In order to address these challenges, systems-level mathematical models may be utilized. Here, we provide a background on neuroinflammation and summarize available mathematical models of this response. Models described by ordinary, partial, and delay differential equations, and Boolean logic are introduced and discussed. The results as discussed in this review suggest logic-based modeling as a formalism capable of managing the challenges associated with the modeling of CNS diseases.}, } @article {pmid40801981, year = {2025}, author = {Goleij, P and Amini, A and Sanaye, PM and Heidari, MM and Tabari, MAK and Aschner, M and Larsen, DS and Khan, H and Daglia, M}, title = {The IL-12 family cytokines in neurodegenerative diseases: dual roles in neurotoxicity and neuroprotection.}, journal = {Inflammopharmacology}, volume = {33}, number = {9}, pages = {5235-5256}, pmid = {40801981}, issn = {1568-5608}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy/immunology ; Animals ; *Interleukin-12/metabolism ; *Neuroprotection/physiology/drug effects ; Neuroprotective Agents/pharmacology ; *Cytokines/metabolism ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss and chronic neuroinflammation. Increasing evidence highlights the interleukin-12 (IL-12) cytokine family-including IL-12, IL-23, IL-27, and IL-35-as central regulators of immune responses in the central nervous system (CNS). IL-12 and IL-23 predominantly promote pro-inflammatory pathways by driving Th1/Th17 activity, microglial activation, and neurotoxicity, whereas IL-27 and IL-35 exert anti-inflammatory and neuroprotective effects through IL-10 induction and expansion of regulatory immune subsets. This review synthesizes disease-specific expression patterns and experimental findings, underscoring the dual pathogenic and protective roles of these cytokines. Therapeutic strategies targeting IL-12 family signaling have shown promise in preclinical and clinical contexts. In AD, blockade of IL-12/IL-23 reduced amyloid burden and improved cognition, while agents such as tadalafil and bergapten enhanced IL-27-mediated neuroprotection via PI3K/Akt, Wnt/β-catenin, and cGMP/PKG pathways. In MS, approaches including p40 blockade (ustekinumab, ABT-874), interferon-β therapy, hematopoietic stem cell transplantation, and B-cell depletion (ocrelizumab) variably suppressed IL-12/IL-23 and augmented IL-27/IL-35, influencing relapse rates and progression. Natural compounds such as curcumin, berberine, and vitamin D further highlight metabolic and dietary opportunities for cytokine modulation. In PD, combinatorial regimens combining herbal formulations with anti-inflammatory agents dampened IL-12-driven macrophage activation and supported dopaminergic neuron survival. Taken together, IL-12 family cytokines emerge as both biomarkers and therapeutic targets in NDs. However, context-dependent activity, blood-brain barrier constraints, and incomplete understanding-particularly of IL-35-pose translational challenges warranting further investigation.}, } @article {pmid40802071, year = {2025}, author = {Yamashita, T and Yokota, O and Ousaka, D and Sun, H and Haraguchi, T and Ota-Elliott, RS and Matsuoka, C and Kawano, T and Nakashima-Yasuda, H and Fukui, Y and Nakano, Y and Morihara, R and Hasegawa, M and Hosono, Y and Terada, S and Takaki, M and Ishiura, H}, title = {Biallelic variants in DNAJC7 cause familial amyotrophic lateral sclerosis with the TDP-43 pathology.}, journal = {Acta neuropathologica}, volume = {150}, number = {1}, pages = {19}, pmid = {40802071}, issn = {1432-0533}, support = {JP23K08543//Japan Society for the Promotion of Science/ ; JP23K10450//Japan Society for the Promotion of Science/ ; JP23K27514//Japan Society for the Promotion of Science/ ; JP24wm0425019//Japan Agency for Medical Research and Development/ ; JP23ek0109673//Japan Agency for Medical Research and Development/ ; }, mesh = {Adult ; Aged ; Animals ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Brain/pathology/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *HSP40 Heat-Shock Proteins/genetics ; Motor Neurons/pathology/metabolism ; Pedigree ; Zebrafish ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. ALS pathology primarily involves the failure of protein quality control mechanisms, leading to the accumulation of misfolded proteins, particularly TAR DNA-binding protein 43 (TDP-43). TDP-43 aggregation is a central pathological feature of ALS. Maintaining protein homeostasis is critical and facilitated by heat shock proteins (HSPs), particularly the HSP40 family, which includes co-chaperones such as DNAJC7. Here, we report a family with three siblings affected by ALS who carry a homozygous c.518dupC frameshift variant in DNAJC7, a member of the HSP40 family. All three patients exhibited progressive muscle weakness, limb atrophy, bulbar palsy, and respiratory failure. Pathological examination revealed degeneration of both upper and lower motor neurons, with phosphorylated TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortices. Immunoblot analysis were consistent with a type B pattern of phosphorylated TDP-43 in the precentral gyrus. Immunohistochemistry and RNA sequencing analyses demonstrated a substantial reduction in DNAJC7 expression at both the protein and RNA levels in affected brain regions. In a TDP-43 cell model, DNAJC7 knockdown impaired the disassembly of TDP-43 following arsenite-induced stress, whereas DNAJC7 overexpression suppressed the assembly and promoted the disassembly of arsenite-induced TDP-43 condensates. Furthermore, in a zebrafish ALS model, dnajc7 knockdown resulted in increased TDP-43 aggregation in motor neurons and reduced survival. To the best of our knowledge, this study provides the first evidence linking biallelic loss-of-function variants in DNAJC7 to familial ALS with TDP-43 pathology.}, } @article {pmid40802439, year = {2025}, author = {Sousa, ES and Silva, LACD and Paiva, RM and Soares, KD and Azevedo, IC and Santos, VEP}, title = {Transitional Care for Patients with Amyotrophic Lateral Sclerosis to the Home: A Scoping Review.}, journal = {Revista brasileira de enfermagem}, volume = {78}, number = {3}, pages = {e20240297}, pmid = {40802439}, issn = {1984-0446}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Transitional Care/standards/trends ; *Home Care Services/trends/standards ; }, abstract = {OBJECTIVES: to map the care required for the transition of patients with Amyotrophic Lateral Sclerosis to the home environment.

METHODS: a scoping review was conducted following the JBI guidelines. The search for publications on the topic was carried out in databases such as PubMed and Web of Science between February and May 2023. Full-text studies that addressed the research objective were included. Letters to the editor, editorials, and opinion articles were excluded.

RESULTS: the final sample consisted of seven articles. Regarding care, the studies highlighted assistance with basic life needs, care planning, protocol development, the use of telehealth, and communication between healthcare services.

CONCLUSIONS: the care required for the transition of individuals with Amyotrophic Lateral Sclerosis to the home environment ranges from assistance with basic human needs to the coordination with other healthcare services. Altogether, these actions contribute to a safe and effective transitional process.}, } @article {pmid40806146, year = {2025}, author = {Coutinho, KMD and Rabelo, H and Fernandes, F and Coutinho, KD and Valentim, RAM and Dias, AP and Valentim, JLRDS and Batista, NADN and Romão, MH and Cunha, PSD and Cunha-Oliveira, A and Henriques, S and de Melo, LP and Vale, SHL and Leite-Lais, L and de Lima, KC}, title = {Effectiveness of a Learning Pathway on Food and Nutrition in Amyotrophic Lateral Sclerosis.}, journal = {Nutrients}, volume = {17}, number = {15}, pages = {}, pmid = {40806146}, issn = {2072-6643}, support = {TED 132/2018//Ministério da Saúde/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Female ; Male ; Middle Aged ; *Health Education/methods ; Adult ; Longitudinal Studies ; Brazil ; Caregivers/education ; Aged ; Health Personnel/education ; *Patient Education as Topic/methods ; Nutritional Status ; Education, Distance ; Health Knowledge, Attitudes, Practice ; Malnutrition/prevention & control ; Learning ; }, abstract = {Background/Objectives: Health education plays a vital role in training health professionals and caregivers, supporting both prevention and the promotion of self-care. In this context, technology serves as a valuable ally by enabling continuous and flexible learning. Among the various domains of health education, nutrition stands out as a key element in the management of Amyotrophic Lateral Sclerosis (ALS), helping to prevent malnutrition and enhance patient well-being. Accordingly, this study aimed to evaluate the effectiveness of the teaching and learning processes within a learning pathway focused on food and nutrition in the context of ALS. Methods: This study adopted a longitudinal, quantitative design. The learning pathway, titled "Food and Nutrition in ALS," consisted of four self-paced and self-instructional Massive Open Online Courses (MOOCs), offered through the Virtual Learning Environment of the Brazilian Health System (AVASUS). Participants included health professionals, caregivers, and patients from all five regions of Brazil. Participants had the autonomy to complete the courses in any order, with no prerequisites for enrollment. Results: Out of 14,263 participants enrolled nationwide, 182 were included in this study after signing the Informed Consent Form. Of these, 142 (78%) completed at least one course and participated in the educational intervention. A significant increase in knowledge was observed, with mean pre-test scores rising from 7.3 (SD = 1.8) to 9.6 (SD = 0.9) on the post-test across all courses (p < 0.001). Conclusions: The self-instructional, technology-mediated continuing education model proved effective in improving participants' knowledge about nutrition in ALS. Future studies should explore knowledge retention, behavior change, and the impact of such interventions on clinical outcomes, especially in multidisciplinary care settings.}, } @article {pmid40806220, year = {2025}, author = {Blaudin de Thé, FX and Klemann, CJHM and De Witte, W and Widomska, J and Delagrange, P and Mannoury La Cour, C and Fouesnard, M and Elouej, S and Mayl, K and Lévy, N and Krupp, J and Jeggo, R and Moingeon, P and Poelmans, G}, title = {Identifying Therapeutic Targets for Amyotrophic Lateral Sclerosis Through Modeling of Multi-Omics Data.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806220}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Humans ; Molecular Targeted Therapy ; Proteomics/methods ; *Genomics/methods ; Drug Discovery ; Computational Biology/methods ; Multiomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons, leading to loss of muscle control, and, ultimately, respiratory failure and death. Despite some advances in recent years, the underlying genetic and molecular mechanisms of ALS remain largely elusive. In this respect, a better understanding of these mechanisms is needed to identify new and biologically relevant therapeutic targets that could be developed into treatments that are truly disease-modifying, in that they address the underlying causes rather than the symptoms of ALS. In this study, we used two approaches to model multi-omics data in order to map and elucidate the genetic and molecular mechanisms involved in ALS, i.e., the molecular landscape building approach and the Patrimony platform. These two methods are complementary because they rely upon different omics data sets, analytic methods, and scoring systems to identify and rank therapeutic target candidates. The orthogonal combination of the two modeling approaches led to significant convergences, as well as some complementarity, both for validating existing therapeutic targets and identifying novel targets. As for validating existing targets, we found that, out of 217 different targets that have been or are being investigated for drug development, 10 have high scores in both the landscape and Patrimony models, suggesting that they are highly relevant for ALS. Moreover, through both models, we identified or corroborated novel putative drug targets for ALS. A notable example of such a target is MATR3, a protein that has strong genetic, molecular, and functional links with ALS pathology. In conclusion, by using two distinct and highly complementary disease modeling approaches, this study enhances our understanding of ALS pathogenesis and provides a framework for prioritizing new therapeutic targets. Moreover, our findings underscore the potential of leveraging multi-omics analyses to improve target discovery and accelerate the development of effective treatments for ALS, and potentially other related complex human diseases.}, } @article {pmid40806339, year = {2025}, author = {Sonkodi, B}, title = {The Microbiota-Gut-Brain Axis in Light of the Brain Axes and Dysbiosis Where Piezo2 Is the Critical Initiating Player.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806339}, issn = {1422-0067}, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism ; *Brain/metabolism ; Circadian Rhythm ; *Dysbiosis/metabolism/microbiology ; *Gastrointestinal Microbiome/physiology ; Hippocampus/metabolism ; *Ion Channels/metabolism ; }, abstract = {The current opinion paper puts into perspective how altered microbiota transplanted from Alzheimer's patients initiates the impairment of the microbiota-gut-brain axis of a healthy recipient, leading to impaired cognition primarily arising from the hippocampus, dysfunctional adult hippocampal neurogenesis, dysregulated systemic inflammation, long-term spatial memory impairment, or chronic pain with hippocampal involvement. This altered microbiota may induce acquired Piezo2 channelopathy on enterochromaffin cells, which, in turn, impairs the ultrafast long-range proton-based oscillatory synchronization to the hippocampus. Therefore, an intact microbiota-gut-brain axis could be responsible for the synchronization of ultradian and circadian rhythms, with the assistance of rhythmic bacteria within microbiota, to circadian regulation, and hippocampal learning and memory formation. Hippocampal ultradian clock encoding is proposed to be through a Piezo2-initiated proton-signaled manner via VGLUT3 allosteric transmission at a distance. Furthermore, this paper posits that these unaccounted-for ultrafast proton-based long-range oscillatory synchronizing ultradian axes may exist not only within the brain but also between the periphery and the brain in an analogous way, like in the case of this depicted microbiota-gut-brain axis. Accordingly, the irreversible Piezo2 channelopathy-induced loss of the Piezo2-initiated ultradian prefrontal-hippocampal axis leads to Alzheimer's disease pathophysiology onset. Moreover, the same irreversible microdamage-induced loss of the Piezo2-initiated ultradian muscle spindle-hippocampal and cerebellum-hippocampal axes may lead to amyotrophic lateral sclerosis and Parkinson's disease initiation, respectively.}, } @article {pmid40806377, year = {2025}, author = {Ghosh, M and Bayat, AH and Pearse, DD}, title = {Small Extracellular Vesicles in Neurodegenerative Disease: Emerging Roles in Pathogenesis, Biomarker Discovery, and Therapy.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806377}, issn = {1422-0067}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/therapy/metabolism/diagnosis/pathology/etiology ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's, Parkinson's, ALS, and Huntington's pose a growing global challenge due to their complex pathobiology and aging demographics. Once considered as cellular debris, small extracellular vesicles (sEVs) are now recognized as active mediators of intercellular signaling in NDD progression. These nanovesicles (~30-150 nm), capable of crossing the blood-brain barrier, carry pathological proteins, RNAs, and lipids, facilitating the spread of toxic species like Aβ, tau, TDP-43, and α-synuclein. sEVs are increasingly recognized as valuable diagnostic tools, outperforming traditional CSF biomarkers in early detection and disease monitoring. On the therapeutic front, engineered sEVs offer a promising platform for CNS-targeted delivery of siRNAs, CRISPR tools, and neuroprotective agents, demonstrating efficacy in preclinical models. However, translational hurdles persist, including standardization, scalability, and regulatory alignment. Promising solutions are emerging, such as CRISPR-based barcoding, which enables high-resolution tracking of vesicle biodistribution; AI-guided analytics to enhance quality control; and coordinated regulatory efforts by the FDA, EMA, and ISEV aimed at unifying identity and purity criteria under forthcoming Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines. This review critically examines the mechanistic roles, diagnostic potential, and therapeutic applications of sEVs in NDDs, and outlines key strategies for clinical translation.}, } @article {pmid40806469, year = {2025}, author = {Wang, J and Shen, Y and Liao, P and Yang, B and Jiang, R}, title = {Roles of Ion Channels in Oligodendrocyte Precursor Cells: From Physiology to Pathology.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806469}, issn = {1422-0067}, support = {82401445//National Natural Science Foundation of China/ ; 82271249//National Natural Science Foundation of China/ ; 2024M752251//China Postdoctoral Science Foundation/ ; 2024NSFSC1636//Sichuan Science and Technology Program/ ; 2024HXBH013//Post doctor Research Fund of West China Hospital of Sichuan University/ ; ZYYC23002//1-3-5 Project for Disciplines of Excellence of West China Hospital of Sichuan University/ ; GZC20241141//Postdoctoral Fellowship Program of CPSF/ ; }, mesh = {Humans ; *Ion Channels/metabolism ; Animals ; *Oligodendrocyte Precursor Cells/metabolism/pathology ; Oligodendroglia/metabolism ; Cell Differentiation ; }, abstract = {Oligodendrocyte precursor cells (OPCs) are a distinct and dynamic glial population that retain proliferative and migratory capacities throughout life. While traditionally recognized for differentiating into oligodendrocytes (OLs) and generating myelin to support rapid nerve conduction, OPCs are now increasingly appreciated for their diverse and non-canonical roles in the central nervous system (CNS), including direct interactions with neurons. A notable feature of OPCs is their expression of diverse ion channels that orchestrate essential cellular functions, including proliferation, migration, and differentiation. Given their widespread distribution across the CNS, OPCs are increasingly recognized as active contributors to the development and progression of various neurological disorders. This review aims to present a detailed summary of the physiological and pathological functions of ion channels in OPCs, emphasizing their contribution to CNS dysfunction. We further highlight recent advances suggesting that ion channels in OPCs may serve as promising therapeutic targets across a broad range of disorders, including, but not limited to, multiple sclerosis (MS), spinal cord injury, amyotrophic lateral sclerosis (ALS), psychiatric disorders, Alzheimer's disease (AD), and neuropathic pain (NP). Finally, we discuss emerging therapeutic strategies targeting OPC ion channel function, offering insights into potential future directions in the treatment of CNS diseases.}, } @article {pmid40806541, year = {2025}, author = {Bedja-Iacona, L and Forget, A and Boisseau, C and Marouillat, S and Chudinova, A and Veyrat-Durebex, C and Guissart, C and Lumbroso, S and Raoul, C and Andres, CR and Blasco, H and Couratier, P and Corcia, P and Verschueren, A and Mouzat, K and Vourc'h, P}, title = {Improving ALS Molecular Diagnosis Through Functional Assays: Reassessment of a SOD1 Variant of Uncertain Significance.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806541}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Superoxide Dismutase-1/genetics/metabolism ; Animals ; Humans ; Zebrafish ; Genetic Testing/methods ; Mutation ; Male ; }, abstract = {Genetic testing in amyotrophic lateral sclerosis (ALS) often reveals variants of uncertain significance (VUS), which are frequently omitted from diagnostic reports or reported with limited clinical interpretation. To address this gap, we developed a rapid functional assessment pipeline in collaboration with FILSLAN, the French ALS care network, combining in vitro and in vivo neurogenetic assays. We illustrate this approach through the reclassification of the SOD1 p.Val120Leu variant, identified in an ALS patient, as pathogenic. Functional studies demonstrated that this variant leads to cytoplasmic aggregation, reduced neurite outgrowth, and abnormal motor behavior in zebrafish. These results support the systematic use of functional assays to clarify the pathogenicity of uncertain variants, thereby improving diagnostic accuracy, preventing misdiagnosis, and enabling timely therapeutic interventions in ALS.}, } @article {pmid40806624, year = {2025}, author = {Șerban, M and Toader, C and Covache-Busuioc, RA}, title = {The Redox Revolution in Brain Medicine: Targeting Oxidative Stress with AI, Multi-Omics and Mitochondrial Therapies for the Precision Eradication of Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806624}, issn = {1422-0067}, mesh = {Humans ; *Oxidative Stress/drug effects ; *Mitochondria/metabolism/drug effects ; *Neurodegenerative Diseases/metabolism/therapy/drug therapy ; *Artificial Intelligence ; Oxidation-Reduction ; Antioxidants/therapeutic use/pharmacology ; Biomarkers/metabolism ; *Precision Medicine/methods ; Animals ; Reactive Oxygen Species/metabolism ; Brain/metabolism ; Multiomics ; }, abstract = {Oxidative stress is a defining and pervasive driver of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). As a molecular accelerant, reactive oxygen species (ROS) and reactive nitrogen species (RNS) compromise mitochondrial function, amplify lipid peroxidation, induce protein misfolding, and promote chronic neuroinflammation, creating a positive feedback loop of neuronal damage and cognitive decline. Despite its centrality in promoting disease progression, attempts to neutralize oxidative stress with monotherapeutic antioxidants have largely failed owing to the multifactorial redox imbalance affecting each patient and their corresponding variation. We are now at the threshold of precision redox medicine, driven by advances in syndromic multi-omics integration, Artificial Intelligence biomarker identification, and the precision of patient-specific therapeutic interventions. This paper will aim to reveal a mechanistically deep assessment of oxidative stress and its contribution to diseases of neurodegeneration, with an emphasis on oxidatively modified proteins (e.g., carbonylated tau, nitrated α-synuclein), lipid peroxidation biomarkers (F2-isoprostanes, 4-HNE), and DNA damage (8-OHdG) as significant biomarkers of disease progression. We will critically examine the majority of clinical trial studies investigating mitochondria-targeted antioxidants (e.g., MitoQ, SS-31), Nrf2 activators (e.g., dimethyl fumarate, sulforaphane), and epigenetic reprogramming schemes aiming to re-establish antioxidant defenses and repair redox damage at the molecular level of biology. Emerging solutions that involve nanoparticles (e.g., antioxidant delivery systems) and CRISPR (e.g., correction of mutations in SOD1 and GPx1) have the potential to transform therapeutic approaches to treatment for these diseases by cutting the time required to realize meaningful impacts and meaningful treatment. This paper will argue that with the connection between molecular biology and progress in clinical hyperbole, dynamic multi-targeted interventions will define the treatment of neurodegenerative diseases in the transition from disease amelioration to disease modification or perhaps reversal. With these innovations at our doorstep, the future offers remarkable possibilities in translating network-based biomarker discovery, AI-powered patient stratification, and adaptive combination therapies into individualized/long-lasting neuroprotection. The question is no longer if we will neutralize oxidative stress; it is how likely we will achieve success in the new frontier of neurodegenerative disease therapies.}, } @article {pmid40806770, year = {2025}, author = {Sharbafshaaer, M and Pepe, R and Notariale, R and Canale, F and Tessitore, A and Tedeschi, G and Trojsi, F}, title = {Neuroaxonal Degeneration as a Converging Mechanism in Motor Neuron Diseases (MNDs): Molecular Insights into RNA Dysregulation and Emerging Therapeutic Targets.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806770}, issn = {1422-0067}, support = {PERMEALS PNRR-MAD-2022-12375731//Italian Ministry of Health/ ; }, mesh = {Humans ; *Motor Neuron Disease/genetics/metabolism/pathology/therapy ; Animals ; *RNA/genetics/metabolism ; *Axons/pathology/metabolism ; *Nerve Degeneration/genetics/pathology ; Molecular Targeted Therapy ; }, abstract = {Motor Neuron Diseases (MNDs) such as Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), Hereditary Spastic Paraplegia (HSP), Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1), Multisystem Proteinopathy (MSP), Spinal and Bulbar Muscular Atrophy (SBMA), and ALS associated to Frontotemporal Dementia (ALS-FTD), have traditionally been studied as distinct entities, each one with unique genetic and clinical characteristics. However, emerging research reveals that these seemingly disparate conditions converge on shared molecular mechanisms that drive progressive neuroaxonal degeneration. This narrative review addresses a critical gap in the field by synthesizing the most recent findings into a comprehensive, cross-disease mechanisms framework. By integrating insights into RNA dysregulation, protein misfolding, mitochondrial dysfunction, DNA damage, kinase signaling, axonal transport failure, and immune activation, we highlight how these converging pathways create a common pathogenic landscape across MNDs. Importantly, this perspective not only reframes MNDs as interconnected neurodegenerative models but also identifies shared therapeutic targets and emerging strategies, including antisense oligonucleotides, autophagy modulators, kinase inhibitors, and immunotherapies that transcend individual disease boundaries. The diagnostic and prognostic potential of Neurofilament Light Chain (NfL) biomarkers is also emphasized. By shifting focus from gene-specific to mechanism-based approaches, this paper offers a much-needed roadmap for advancing both research and clinical management in MNDs, paving the way for cross-disease therapeutic innovations.}, } @article {pmid40807333, year = {2025}, author = {Godela, A and Rogacz, D and Pawłowska, B and Biczak, R}, title = {Natural Neuroinflammatory Modulators: Therapeutic Potential of Fungi-Derived Compounds in Selected Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {15}, pages = {}, pmid = {40807333}, issn = {1420-3049}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Fungi/chemistry ; *Biological Products/therapeutic use/pharmacology/chemistry ; Animals ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis remain incurable. Current therapeutic strategies primarily focus on slowing disease progression, alleviating symptoms, and improving patients' quality of life, including the management of comorbid conditions. Over the past few decades, the incidence of diagnosed neurodegenerative disorders has risen significantly. As the number of affected individuals continues to grow, so does the urgent need for effective treatments that can halt or mitigate the progression of these diseases. Among the most promising therapeutic resources are bioactive compounds derived from fungi. The high quality of proteins, polysaccharides, unsaturated fatty acids, triterpenoids, sterols, and secondary metabolites found in fungi have attracted growing interest from researchers across multiple disciplines. One intensively studied direction involves the use of naturally occurring fungi-derived nutraceuticals in the treatment of various diseases, including neurodegenerative conditions. This article provides an overview of recent findings on fungal compounds-such as phenolic compounds, carbohydrates, peptides and proteins, and lipids-that may have potential applications in the treatment of neurodegenerative diseases and the alleviation of their symptoms.}, } @article {pmid40807722, year = {2025}, author = {Lee, S and Lee, S}, title = {Text Typing Using Blink-to-Alphabet Tree for Patients with Neuro-Locomotor Disabilities.}, journal = {Sensors (Basel, Switzerland)}, volume = {25}, number = {15}, pages = {}, pmid = {40807722}, issn = {1424-8220}, support = {IITP-2025-RS-2024-00436765//the Korea government(MSIT)/ ; 2025//KOREATECH/ ; }, mesh = {Humans ; *Blinking/physiology ; *Amyotrophic Lateral Sclerosis/physiopathology ; Algorithms ; Eye-Tracking Technology ; }, abstract = {Lou Gehrig's disease, also known as ALS, is a progressive neurodegenerative condition that weakens muscles and can lead to paralysis as it progresses. For patients with severe paralysis, eye-tracking devices such as eye mouse enable communication. However, the equipment is expensive, and the calibration process is very difficult and frustrating for patients to use. To alleviate this problem, we propose a simple and efficient method to type texts intuitively with graphical guidance on the screen. Specifically, the method detects patients' eye blinks in video frames to navigate through three sequential steps, narrowing down the choices from 9 letters, to 3 letters, and finally to a single letter (from a 26-letter alphabet). In this way, a patient is able to rapidly type a letter of the alphabet by blinking a minimum of three times and a maximum of nine times. The proposed method integrates an API of large language model (LLM) to further accelerate text input and correct sentences in terms of typographical errors, spacing, and upper/lower case. Experiments on ten participants demonstrate that the proposed method significantly outperforms three state-of-the-art methods in both typing speed and typing accuracy, without requiring any calibration process.}, } @article {pmid40808389, year = {2026}, author = {Petrovic, D and Perçin, G and Vilchez, D}, title = {Shuttle and stabilize: H1.2-FUS complex in amyotrophic lateral sclerosis pathogenesis.}, journal = {Neural regeneration research}, volume = {21}, number = {8}, pages = {3531-3532}, pmid = {40808389}, issn = {1673-5374}, } @article {pmid40808411, year = {2026}, author = {Cheng, Y and Zhao, Y and Chen, C and Zhang, F}, title = {Metallothionein and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {21}, number = {8}, pages = {3449-3461}, pmid = {40808411}, issn = {1673-5374}, abstract = {Neurodegenerative diseases, which mainly include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Wilson's disease, and Huntington's disease, are a group of disorders characterized by loss of neurons in the brain and spinal cord. However, the underlying pathogenetic mechanisms of these disorders remain unclear. The metal ion hypothesis is considered a possible cause of a variety of neurodegenerative diseases. This hypothesis posits that the homeostatic imbalance of metal ions leads to oxidative stress, neuroinflammation, excessive aggregation of pathological proteins, and other serious consequences in neurons. The powerful endogenous metal ion chelator metallothionein plays an important role in regulating metal ion homeostasis to alleviate neurodegenerative diseases. This article provides an overview of the pathogenesis of neurodegenerative diseases in relation to metal ions such as copper, iron, and zinc and the contribution of metallothionein to the regulation of metal ion homeostasis. The review focuses on the role of metal ions in the course of neurodegenerative diseases and the molecular mechanisms through which endogenous metallothionein ameliorates metal ion overload to alleviate neurodegenerative diseases. A thorough understanding of these molecular mechanisms can provide a theoretical foundation for the development of new therapeutic strategies, with the aim of more effectively treating these devastating diseases in the future.}, } @article {pmid40808423, year = {2026}, author = {Xia, K and Huang, N and Wang, Y and Zhang, G and Tang, L and Zhang, L and Yao, M and Liu, Z and Huang, T and Fan, D}, title = {Shared genetic link and causal inference between blood lipids, lipid-lowering drugs and amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {21}, number = {8}, pages = {3824-3830}, pmid = {40808423}, issn = {1673-5374}, abstract = {Growing evidence suggests that abnormal lipid metabolism occurs in amyotrophic lateral sclerosis, even in the presymptomatic stage, implying an etiologic link. However, the genetic mechanism underlying altered lipid levels in amyotrophic lateral sclerosis remains elusive. Therefore, in this study, we performed genetic correlation analysis, a cross-trait meta-analysis, tissue-specific enrichment analysis, and bidirectional two-sample Mendelian randomization analysis of European population to explore whether there is a genetic and causal relationship between lipids and amyotrophic lateral sclerosis. The effect of lipid-lowering drugs on amyotrophic lateral sclerosis was also evaluated using a drug target Mendelian randomization approach. The results showed a positive genetic correlation between amyotrophic lateral sclerosis and both high-density lipoprotein cholesterol and apolipoprotein A1 and identified 71 independent shared loci between amyotrophic lateral sclerosis and high-density lipoprotein cholesterol, as well as 55 independent shared loci between amyotrophic lateral sclerosis and apolipoprotein A1. These shared loci were enriched in the lipid metabolic pathway and the alcohol metabolic pathway. Further Mendelian randomization analysis targeting lipid-lowering drugs showed that single nucleotide polymorphisms within the ACLY and PCSK9 genes had a protective effect against amyotrophic lateral sclerosis risk by decreasing low-density lipoprotein cholesterol. The combination of ACLY and PCSK9 inhibitors has a greater protective effect on amyotrophic lateral sclerosis risk than that of PCSK9 inhibitors alone. In summary, there is a common genetic structure between lipids and amyotrophic lateral sclerosis. Mendelian randomization analysis supports an association between elevated blood lipids and the risk of developing amyotrophic lateral sclerosis, and the use of ACLY or PCSK9 inhibitors may improve disease prognosis.}, } @article {pmid40808456, year = {2025}, author = {Frau, F and Bosia, M and Bischetti, L and Cappelli, G and Carotenuto, A and Diamanti, L and Montemurro, S and Agostoni, G and Bechi, M and D'Imperio, D and Lago, S and Noccetti, S and Simi, N and Ceroni, M and Iodice, R and Signorini, M and Arcara, G and Bambini, V}, title = {Ten years of using the APACS test: a multistudy cross-diagnostic analysis of pragmatic profiles and their relationship with Theory of Mind.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {380}, number = {1932}, pages = {20230495}, pmid = {40808456}, issn = {1471-2970}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Theory of Mind ; *Social Communication Disorder ; }, abstract = {Pragmatic impairments are largely documented, yet rarely considered in clinical practice, also owing to a poor characterization of pragmatic profiles across conditions, as well as some overlap with theory of mind (ToM) in the conceptualization of pragmatics. Here, we present the outcome of a 10-year programme that started with creating a novel test, the Assessment of Pragmatic Abilities and Cognitive Substrates (APACS)-which we evolved by its application alongside ToM assessment in seven clinical groups (i.e. amyotrophic lateral sclerosis, multiple sclerosis, right-hemisphere stroke, Parkinson's disease, traumatic brain injury, schizophrenia and dyslexia). The multistudy cross-diagnostic analysis of 454 participants revealed that receptive pragmatic skills were impaired in all clinical groups compared with controls, with schizophrenia showing the most severely impaired profile, whereas expressive pragmatic skills were impaired in four neurological conditions (i.e. Parkinson's disease, amyotrophic lateral sclerosis, right-hemisphere stroke and traumatic brain injury). The association with ToM was limited to receptive pragmatics and was moderate in the whole sample. Overall, pragmatic impairment emerged as a diffuse feature of neurological and psychiatric illnesses, which contributes to defining complex socio-communicative phenotypes but cannot be equated to a social cognition deficit and should hence be the target of specific assessment and intervention.This article is part of the theme issue 'At the heart of human communication: new views on the complex relationship between pragmatics and Theory of Mind'.}, } @article {pmid40808471, year = {2025}, author = {Zhang, L and Cai, L and Lin, H and Wu, W and Zhu, Y and Cai, J and Hu, C and Lin, X and Sun, H and Wei, X}, title = {Two Birds With One Stone: The Protective Role of the Antidiabetic Drug Sodium-Glucose Cotransporter-2 Inhibitor in Neurodegenerative Diseases.}, journal = {The European journal of neuroscience}, volume = {62}, number = {3}, pages = {e70221}, doi = {10.1111/ejn.70221}, pmid = {40808471}, issn = {1460-9568}, support = {2021J01397//Natural Science Foundation of Fujian, China/ ; 2022GGA010//Fujian Provincial Health Technology Project/ ; 2023Y9347//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; 2023Y9298//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; 2023Y9343//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; }, mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; *Neurodegenerative Diseases/genetics/drug therapy ; Polymorphism, Single Nucleotide ; Sodium-Glucose Transporter 2/genetics ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Hypoglycemic Agents/therapeutic use/pharmacology ; Mendelian Randomization Analysis ; Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Parkinson Disease/genetics ; Genome-Wide Association Study ; Protein Interaction Maps ; }, abstract = {The neuroprotective role of sodium-glucose cotransporter-2 inhibitor (SGLT2i) has attracted considerable interest. The purpose of this study was to investigate the role of SGLT2i in several common neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Utilizing drug-target Mendelian randomization (MR) and colocalization, we used single nucleotide polymorphisms (SNPs) proximal to the SLC5A2 gene to analyze the influence of SGLT2i on AD, PD, ALS, and MS. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. Phenome-wide association study (PheWAS) was used to probe the relationship of SGLT2i with other characteristics. Protein-protein interaction (PPI) networks were used to explore how SLC5A2 affects other proteins, and enrichment analysis was used to explore possible biological processes. The MR analysis showed that SGLT2i was negatively associated with AD (OR = 0.77, p = 0.01), PD (OR = 0.52, p = 0.04), ALS (OR = 0.60, p = 0.01), and MS (OR = 0.33, p = 0.027), indicating that SGLT2i could reduce the risk of AD by 23%, PD by 48%, ALS by 40%, and MS by 67%. The colocalization supported this conclusion. The PheWAS showed that SGLT2i was associated with body mass index and systolic blood pressure. SGLT2i is biologically closely related to the development of NDs. This study suggested that SGLT2i was able to reduce the risk of NDs. SGLT2i may perform this process through many mechanisms. This study provides a new perspective on the treatment of NDs; clinical trials and relevant experiments are necessary to further validate the neuroprotective effects of SGLT2i.}, } @article {pmid40808712, year = {2025}, author = {Farrokhi, Z and Zakavi, SA and Sarafraz, A and Valifard, M and Yousefzadeh, S and Mashhadi Tafreshi, Z and Anbiyaee, O and Rostami, N and Asadi Anar, M and Deravi, N}, title = {Acoustic signatures of bulbar ALS: Predictive modeling with sustained vowels and LightGBM.}, journal = {eNeurologicalSci}, volume = {40}, number = {}, pages = {100579}, pmid = {40808712}, issn = {2405-6502}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a degenerative neurologic disease with no definitive biomarkers for early detection. This paper discusses the use of acoustic analysis of sustained vowel phonations (SVP) and machine learning in ALS detection.

METHODS: An SVP corpus of 128 (64 /a/ and 64 /i/) from 31 patients with ALS and 33 healthy controls (HC) was employed. 131 acoustic features, including jitter, shimmer, Mel-Frequency Cepstral Coefficients (MFCCs), and Pathological Vibrato Index (PVI), were extracted. A LightGBM (Light Gradient Boosting Machine)-based model was built and optimized using 5-fold cross-validation to separate ALS cases. Model performance and feature importance were evaluated.

RESULTS: The model performed well with high predictability, yielding an RMSLE of 0.162 and most predictions closely correlating with actual diagnoses. The top features obtained were S55_i, CCI(2), and dCCa(12), which were consistently at the top of the ranking list, indicating their role in ALS detection. The PVI was determined to be a significant biomarker with high values having high correlations with ALS diagnoses. But the multimodal nature of the predictive values indicated some flaws in generalization.

CONCLUSION: This paper demonstrates the applicability of acoustic analysis and machine learning for early ALS detection. The proposed method provides an affordable, low-cost, and non-invasive way for ALS diagnosis with potential for application in telemedicine and clinical settings. Future research must expand datasets and integrate additional diagnostic modalities to improve the model's robustness and clinical translation.}, } @article {pmid40810164, year = {2025}, author = {Alo, B and Lamers, C}, title = {Crossing Barriers: Advancements in Macromolecular Therapeutics for Neurodegenerative Diseases and Strategies to Overcome the Blood-Brain Barrier.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {8}, pages = {2353-2383}, pmid = {40810164}, issn = {2575-9108}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, present considerable challenges for our societies and health systems due to their progressive nature, the demographic shift toward older populations, and limited treatment options. Recent advances in macromolecular therapeutics, including antibodies, peptides, and proteins, offer novel therapeutic modalities for a broad range of diseases. Their high potency and specificity hold promise for disease-modifying therapies to combat neurodegenerative diseases. However, the blood-brain barrier poses a significant challenge for the effective delivery of these large molecules to the central nervous system. This review discusses the physiological role of the blood-brain barrier and its influence on restricting the exposure of macromolecules in the brain. Furthermore, emerging strategies for enhancing blood-brain barrier permeability to macromolecules are highlighted. This review summarizes modifications designed to utilize receptor-mediated uptake, adsorptive-mediated transcytosis, carrier-mediated transport, and nanoparticle-based delivery systems to overcome the blood-brain barrier. Additionally, we emphasize the importance of testing macromolecular therapeutics for their blood-brain barrier permeability and review the methods for such in vitro and in vivo testing. Finally, we shed light on therapeutics in preclinical and clinical development for neurodegenerative diseases and their challenges.}, } @article {pmid40812017, year = {2025}, author = {Chahal, S and Debnath, A and Kumari, R and Ridhal, P and Sahoo, RK and Biswal, BK and Mishra, A and Siwach, P}, title = {Antihypertensive potential of diosgenin: A comparative pharmacoinformatics study.}, journal = {Computers in biology and medicine}, volume = {196}, number = {Pt C}, pages = {110911}, doi = {10.1016/j.compbiomed.2025.110911}, pmid = {40812017}, issn = {1879-0534}, mesh = {Humans ; *Diosgenin/chemistry/pharmacology ; *Molecular Docking Simulation ; *Antihypertensive Agents/chemistry/pharmacology ; Molecular Dynamics Simulation ; *Receptor, Angiotensin, Type 1/chemistry/metabolism ; }, abstract = {The angiotensin II type 1 receptor (AT1R) is an important target protein involved in the regulation of hypertension, a major public health concern affecting 1.28 billion individuals globally. The existing drugs have serious side-effects on medium to long term use, and therefore, search for safer and more effective drug molecules is highly needed. This study explores the antihypertensive potential of thirty-six natural terpenoids targeting the AT1R, with Allisartan isoproxil (active form, LCA) used as a positive control. After initial screening based on the Lipinski rule of five and in silico ADMET profiling, twenty-five terpenoids were selected for molecular docking studies. Diosgenin and Neoandrographolide emerged as lead compounds with superior binding affinities compared to std. drug, LCA. Diosgenin's favorable non-toxic profile (class 6) and significant molecular interactions with critical amino acids in AT1R make it a strong candidate for further validation through MD studies. Molecular dynamics simulations at a microsecond revealed protein stability by reducing fluctuations, a compact and more stable contact exhibited by Diosgenin. Furthermore, MM-PBSA analysis showed a stronger binding affinity and thermodynamic stability of Diosgenin compared to LCA. Diosgenin exhibited no cytotoxicity in HaCaT normal keratinocyte cells at concentrations up to 22 μM (24 h) and 20 μM (48 h), as determined by in vitro validation, indicating its safety for further therapeutic evaluation. Additionally, PPI network and hub genes analysis identified potential molecular targets for Diosgenin, including SRC, ABL1, IGF1R, and JAK2, suggesting possible mechanistic role. Diosgenin is a promising natural therapeutic candidate for hypertension treatment, which could regulate vascular function, smooth muscle cell activity, and endothelial function via various mechanisms by influencing IGF1R, JAK2, KIT, MDM2, MET, and IL2 demonstrated through KEGG pathway analysis.}, } @article {pmid40812811, year = {2025}, author = {Dougherty, M and Bartels, SM and Smith, JG and Zeliadt, SB and Hyde, J and Kim, B}, title = {The use of cost analysis in examinations of health coaching interventions: a scoping review protocol.}, journal = {BMJ open}, volume = {15}, number = {8}, pages = {e104082}, pmid = {40812811}, issn = {2044-6055}, mesh = {Scoping Reviews as Topic ; Humans ; *Mentoring/economics/methods ; Research Design ; *Health Promotion/economics/methods ; Costs and Cost Analysis ; Cost-Benefit Analysis ; *Health Care Costs ; }, abstract = {INTRODUCTION: Health coaching is the process of working with a trained coach, peer, or healthcare professional towards self-determined health and wellness goals. Health coaching is being increasingly adopted in multiple healthcare settings and has been shown to improve overall health outcomes and long-term maintenance of chronic conditions in multiple countries and healthcare settings. Research surrounding the costs of implementing health coaching and its effects on healthcare costs, particularly long-term costs, has been limited. Although analysis of healthcare costs has become an important priority in recent years, the available literature looking at the cost impacts of health coaching is small and inconclusive, finding mixed results with a variety of methodologies. This scoping review aims to identify gaps in the literature and help set a research agenda regarding the costs of health coaching implementation and its impacts.

METHODS AND ANALYSIS: The scoping review will be structured according to Levac et al's enhancement to Arksey and O'Malley's framework for conducting scoping reviews. PubMed, Embase, and the Health and Medicine Collection will be searched for peer-reviewed research that includes health and wellness coaching and some measurement of cost. Details about the type of study, cost analysis, methodology and results from the included articles will be extracted and summarised. Full-text publications, excluding editorials and opinion pieces, included in this scoping review will be published in 2017 or later, will be written in English, will align with the definition of health coaching as described by the National Board for Health and Wellness Coaching, and will include cost measurement. This review will include publications not captured in the previous integrative literature review looking at the cost-effectiveness of health coaching.

ETHICS AND DISSEMINATION: Findings will be disseminated through a peer-reviewed publication and through presentations to both health system and community-based entities currently using or considering adopting health coaching. Ethics approval is not a requirement for this review as no human research participants will be involved. All data will be obtained from publicly available literature, with no primary data generated.}, } @article {pmid40812817, year = {2025}, author = {Visser, M and de Mul, M and Ahaus, K and Weggelaar-Jansen, AM}, title = {Navigating value complexity in care pathway development: a qualitative case study.}, journal = {BMJ open}, volume = {15}, number = {8}, pages = {e098157}, pmid = {40812817}, issn = {2044-6055}, mesh = {Humans ; Qualitative Research ; Netherlands ; Retrospective Studies ; *Critical Pathways/standards ; Patient Care Team ; Decision Making ; Leadership ; }, abstract = {OBJECTIVES: Care pathways (CPs) are widely used to standardise and improve healthcare delivery. However, CP development is often shaped by value (or normative) complexity. This study empirically explores how value complexity unfolds in a CP development programme.

DESIGN: A qualitative single-case study was conducted as part of a 2-year action research programme. The study followed a 'research-follow-action' strategy, in which action and learning occurred during the programme phase, followed by retrospective analysis using Greenhalgh et al's 'rules of thumb' as a reflective lens.

SETTING: A Dutch specialised rehabilitation hospital (13 sites, 800 employees approximately, ~16 000 patients annually). In three CP development cycles, 11 multidisciplinary teams were guided in CP development in a quality collaborative approach.

PARTICIPANTS: 26 respondents participated in 44 reflective conversations; 19 respondents completed reflective questionnaires and 169 participatory observation reports were included. Participants were purposively sampled and included representatives from the leadership triad (rehabilitation physicians, managers and healthcare professionals) and members of senior management involved in CP development.

RESULTS: Two overarching themes were identified: goal (mis)alignment and prolonged decision-making processes negatively impacted motivation and impeded CP development. Goal alignment between stakeholders was hindered by shifting organisational priorities, creating tensions between improving care quality and ensuring financial viability. Decision-making was challenged by role uncertainty and the complexities of multidisciplinary collaboration in CP development teams. Reflective dialogues, small-scale experimentation and financial modelling supported teams in navigating these tensions to varying degrees.

CONCLUSIONS: This study illustrates how value complexity unfolds in CP development and underscores the importance of ongoing stakeholder management, reflectivity, formative evaluation and dialogue. Greenhalgh et al's rules of thumb provided interpretive value in exploring these complexities but require a solid theoretical understanding and an awareness of the rules' interrelationships. A complexity-informed approach integrating ongoing reflection and adaptability can enrich CP development methodologies, enabling healthcare professionals and action researchers to engage constructively with value complexity in complex change processes. Further research is needed to develop and implement practical strategies for enhancing stakeholder engagement and decision-making in diverse healthcare settings.}, } @article {pmid40813983, year = {2025}, author = {Wang, YT and Li, Q and Liu, JC and Chen, C and Ding, HX and Zha, X and Zhang, K}, title = {Cystatin F-a key player in central nervous system disease.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {203}, pmid = {40813983}, issn = {1742-2094}, support = {81901005//National Natural Science Foundation of China/ ; 81571046//National Natural Science Foundation of China/ ; 2022-MS-203//Natural Science Foundation of Liaoning Province/ ; JYTMS20230122//Basic Scientific Research Project of the Education Department of Liaoning Province/ ; LJKZ0755//Educational Department of Liaoning province/ ; 2023JH2/20200116//Department of Science & Technology of Liaoning province/ ; }, mesh = {Humans ; *Central Nervous System Diseases/metabolism ; Animals ; *Cystatins/metabolism ; Biomarkers, Tumor ; }, abstract = {Cystatin F is an endogenous cysteine protease inhibitor that belongs to the type II cystatin family. It has several unique characteristic structures that determine some of its specific functions. Cystatin F is expressed predominantly in peripheral immune cells and in the microglia of the central nervous system (CNS). Under physiological conditions, the expression of cystatin F in the CNS is minimal. However, emerging evidence suggests that it is significantly upregulated in several CNS diseases. Intriguingly, the role of cystatin F differs across disease contexts-serving a neuroprotective function while promoting pathological progression. Moreover, its function may shift across different pathological stages within the same disorder, reflecting a multifaceted pathophysiology. Cystatin F primarily acts by modulating neuroinflammation, clearing debris, and orchestrating immune responses via its selective expression in disease-associated microglia. As a vital player in CNS diseases, various intervention strategies targeting cystatin F have been proposed, including receptor-interacting protein kinase 1 pathway inhibition, miRNA targeting, mRNA stabilization, necroptosis inhibition, transcriptional regulation and upstream pathway modulation. Several approaches have yielded encouraging results in preclinical models, underscoring the therapeutic potential of modulating cystatin F activity. This review provides a comprehensive overview of the structural features, biological functions, and diverse roles of cystatin F in CNS diseases, including Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, stroke, Aicardi-Goutières syndrome, prion disease, and glioblastoma. Recent advances in therapeutic interventions focusing on cystatin F have been critically assessed, and key challenges related to clinical translation are outlined, offering new perspectives on therapeutic directions.}, } @article {pmid40815260, year = {2025}, author = {Jensen, KS}, title = {N-terminal acetylation of superoxide dismutase 1 accelerates amyloid formation without general destabilization of the apo state.}, journal = {Protein science : a publication of the Protein Society}, volume = {34}, number = {9}, pages = {e70267}, pmid = {40815260}, issn = {1469-896X}, support = {202004888//Vetenskapsrådet/ ; 20230966//Crafoordska Stiftelsen/ ; //Royal Physiographic Society of Lund/ ; 4002-00258//Natur og Univers, Det Frie Forskningsråd/ ; //Per-Eric and Ulla Schyberg's Foundation/ ; M23-0143//Åke Wiberg's Foundation/ ; }, mesh = {*Superoxide Dismutase-1/chemistry/metabolism/genetics ; Acetylation ; Humans ; *Amyloid/chemistry/metabolism ; Protein Processing, Post-Translational ; Protein Stability ; Amyotrophic Lateral Sclerosis/metabolism ; Protein Folding ; }, abstract = {Co- and post-translational modifications can significantly impact the structure, dynamics, and function of proteins. In this study, we investigate how N-terminal acetylation affects misfolding and self-assembly of the enzyme superoxide dismutase 1 (SOD1), implicated in amyotrophic lateral sclerosis (ALS). Studies of protein inclusions in patient samples and animal models have shown that wild-type SOD1 can form amyloid fibrils even when no mutations are found in the sod1 gene. This has identified SOD1 amyloid formation as a possible common denominator of ALS and may suggest that co- and post-translational modifications, like N-terminal acetylation found in human SOD1, can be a factor in disease development. In this work, the impact of N-terminal acetylation of SOD1 on stability and aggregation is characterized. Results show that the structure and thermal stability of the apo state are unaffected by the modification while the amyloid formation rate is significantly enhanced. This is caused by a shortening of the nucleation phase together with an increase of fibril elongation by more than 10-fold upon N-terminal acetylation of SOD1. Collectively, the findings demonstrate how regulation by co- and post-translational modifications can influence protein misfolding and self-assembly.}, } @article {pmid40817956, year = {2025}, author = {Mannan, A and Sharma, A and Singh, TG}, title = {Boosting Brain Clean-Up: Can Targeting UPS Genes Offer Neuroprotection?.}, journal = {Molecular neurobiology}, volume = {62}, number = {12}, pages = {16512-16556}, pmid = {40817956}, issn = {1559-1182}, mesh = {Humans ; *Neuroprotection/genetics ; Animals ; *Brain/metabolism/pathology ; *Ubiquitin/metabolism/genetics ; *Proteasome Endopeptidase Complex/genetics/metabolism ; Neurodegenerative Diseases/genetics/metabolism ; *Gene Targeting/methods ; }, abstract = {The ubiquitin-proteasome system (UPS) plays a critical role in protein homeostasis within eukaryotic cells. This review article examines the UPS's role in neuronal morphology and neurodegeneration through systematic analysis of current research. In neurodegenerative disorders (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), UPS dysfunction contributes significantly to pathogenesis through accumulation of ubiquitinated misfolded proteins, disruption of cellular proteostasis, impaired substrate ubiquitination, and proteasomal deterioration. The UPS maintains normal central nervous system (CNS) function by regulating protein degradation. When this system fails, cellular proteostasis becomes compromised, accelerating neurodegeneration. Recent research has identified potential interventions for UPS activation through genetic modification and synthetic compounds. This review assesses how specific UPS components could serve as pharmacological targets for treating NDDs. By modulating UPS-mediated genes and pathways, novel therapeutic strategies may emerge for conditions including AD, PD, HD), and ALS. Current evidence suggests the UPS represents a promising therapeutic target for addressing the fundamental protein homeostasis disruptions underlying these devastating neurological conditions. Targeting this system could potentially slow disease progression by restoring proper protein degradation mechanisms and preventing toxic protein accumulation characteristic of NDDs.}, } @article {pmid40818509, year = {2025}, author = {Wang, Y and Lin, J and Qu, Y and Ding, Y and Ye, Z and Zhu, Z and Chen, W and Chen, Z and Sun, H and Hu, F and Chen, C and Fang, L and Li, R and Zhang, B and Wang, N and Fu, Y and Chen, W and Zhang, Q}, title = {Biomarker profile of a Chinese ALS cohort: A comprehensive clinical-biomarkers-imaging analysis.}, journal = {Neurobiology of disease}, volume = {214}, number = {}, pages = {107059}, doi = {10.1016/j.nbd.2025.107059}, pmid = {40818509}, issn = {1095-953X}, support = {//National Natural Science Foundation of China/ ; //Major Scientific Research Program for Young and Middle-aged Health Professionals of Fujian Province/ ; //Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnostic imaging/genetics ; Male ; Female ; Middle Aged ; Biomarkers/blood ; Aged ; Retrospective Studies ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; Neurofilament Proteins/blood ; Glial Fibrillary Acidic Protein/blood ; China ; Adult ; Cohort Studies ; Alzheimer Disease/blood ; Glymphatic System/diagnostic imaging ; Choroid Plexus/pathology/diagnostic imaging ; East Asian People ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal central nervous system neurodegenerative disease, but the relationships among genetic mutations, plasma biomarkers, glymphatic system and clinical variables remain unclear.

METHODS: This study retrospectively collected data from April 2015 to November 2024 from the Department of Neurology of First Affiliated Hospital, Fujian Medical University, China. ALS patients (including genetic ALS (gALS) and sporadic ALS (sALS)), Alzheimer's disease (AD) patients, and healthy controls (HC) were included. Plasma glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau 181 (p-tau181), amyloid-beta 42 (Aβ42) and amyloid-beta 40 (Aβ40) concentrations were measured using ultrasensitive single molecule array (Simoa). All ALS individuals underwent genetic screening. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used to assess motor function. The choroid plexus volume (CPV) and enlarged perivascular spaces (EPVS) were used to assess glymphatic function.

RESULTS: Firstly, we found that plasma levels of NfL (p < 0.001) and p-tau181 (p < 0.001) were significantly higher in ALS than in HC. Compared with sALS, gALS had a significantly higher plasma ptau181 (p < 0.05), Aβ42/40 ratio (p < 0.001). Secondly, gALS had more severe glymphatic dysfunction than sALS (p < 0.05), plasma GFAP (ρ = 0.57, p < 0.05) and p-tau181 (ρ = 0.58, p < 0.05) in gALS showed significant correlations with CPV. Thirdly, plasma GFAP was significantly associated with motor function (ρ = -0.35, p < 0.01) and its progression rate (ρ = 0.24, p < 0.05) in gALS.

CONCLUSIONS: The gALS exhibit a more severe and complex biomarker profile than sALS, in which plasma GFAP showed a significant correlation in disease progression.}, } @article {pmid40819256, year = {2025}, author = {Nagel, DA and Charlton, P and Azar, R and Koenig, L and Burns, K and Kean, T}, title = {RADAR-ES: A Methodological Framework for Conducting Environmental Scans in Health Services Delivery Research.}, journal = {Journal of primary care & community health}, volume = {16}, number = {}, pages = {21501319251363783}, pmid = {40819256}, issn = {2150-1327}, mesh = {Humans ; *Health Services Research/organization & administration ; *Research Design ; }, abstract = {AIM: To propose a methodological framework for conceptualizing, planning, and implementing an environmental scan (ES) in health services delivery research (HSDR).

BACKGROUND: An ES is a methodological approach employed to examine a range of practices, policies, issues, programs, technologies, trends, and opportunities from a variety of data sources to inform program or policy development. Despite the wide use of ESs in health care to inform decision-making, a lack of methodological guidance exists to support researchers in planning and conducting an ES in HSDR.

METHODS: Adapting McMeekin et al's process for developing methodological frameworks, we identified literature that described approaches to planning and conducting ESs in addition to exemplar articles that featured ESs in HSDR. We integrated original research findings and synthesized data from all sources to generate an evidence-informed methodological framework.

RESULTS: We developed RADAR-ES that consists of 5 phases and is informed by 4 guiding principles: (1) Recognizing the Issue; (2) Assessing Factors for ES; (3) Developing an ES Protocol; (4) Acquiring and Analyzing the Data; and (5) Reporting the Results.

CONCLUSION: RADAR-ES will provide comprehensive guidance for researchers and health services stakeholders who plan and conduct ESs in HSDR.}, } @article {pmid40819305, year = {2026}, author = {Guarnaccia, M and La Cognata, V and Gentile, G and Morello, G and Cavallaro, S}, title = {Unraveling the missing heritability of amyotrophic lateral sclerosis: Should we focus more on copy number variations?.}, journal = {Neural regeneration research}, volume = {21}, number = {5}, pages = {1997-1998}, pmid = {40819305}, issn = {1673-5374}, } @article {pmid40819564, year = {2025}, author = {Ramírez-Núñez, O and Rico-Ríos, S and Torres, P and Ayala, V and Fernàndez-Bernal, A and Ceron-Codorniu, M and Andrés-Benito, P and Vinyals, A and Maqsood, S and Ferrer, I and Pamplona, R and Portero-Otin, M}, title = {Nuclear pore complex dysfunction drives TDP-43 pathology in ALS.}, journal = {Redox biology}, volume = {86}, number = {}, pages = {103824}, pmid = {40819564}, issn = {2213-2317}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; Mice ; *Nuclear Pore/metabolism/pathology/genetics ; *Nuclear Pore Complex Proteins/metabolism/genetics ; Disease Models, Animal ; Oxidative Stress ; Oxidation-Reduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and pathological aggregation of TDP-43. While protein misfolding and impaired autophagy are established features, accumulating evidence highlights the nuclear pore complex (NPC)as a vulnerable, redox-sensitive hub in ALS pathogenesis. Here, we show that selective loss of NPC components, particularly the scaffold proteins NUP107 and NUP93, and FG-repeat-containing components-is a consistent finding across ALS postmortem spinal cord, SOD1^G93A and TDP-43 mutant mouse models, and human cell systems.CRISPR-mediated depletion of NUP107 in human cells triggers hallmark features of ALS pathology, including cytoplasmic TDP-43 mislocalization, increased phosphorylation, and autophagy dysfunction. Conversely, TDP-43 knockdown perturbs NPC composition, suggesting a reciprocal regulatory loop. Crucially, we demonstrate that oxidative stress exacerbated NPC subunit mislocalization and enhanced TDP-43 aggregation. Using oxime blotting and DNPH assays, we show that FG-repeat subunits of NPC were direct targets of redox-driven carbonylation, indicating that oxidative modifications compromise NPC integrity thuspotentially affecting nucleocytoplasmic transport. Our findings established NPC dysfunction as a redox-sensitive driver of TDP-43 pathology in ALS and highlight nucleocytoplasmic transport as a promising therapeutic axis. The susceptibility of long-lived NPC proteins to oxidative damage provides a mechanistic link between redox stress, proteostasis collapse, and neurodegeneration.}, } @article {pmid40821619, year = {2023}, author = {Kao, TH and Perry, BJ}, title = {The Current State and Future Directions of Swallowing Care in Amyotrophic Lateral Sclerosis.}, journal = {Current physical medicine and rehabilitation reports}, volume = {11}, number = {2}, pages = {199-211}, pmid = {40821619}, issn = {2167-4833}, support = {K23 NS123369/NS/NINDS NIH HHS/United States ; L30 NS123988/NS/NINDS NIH HHS/United States ; }, abstract = {PURPOSE OF REVIEW: Difficulty swallowing (dysphagia) is of great concern to patients with ALS as its complications can increase mortality and reduce the quality of life. This review aims to provide an overview of the recent developments and the current state of assessment, treatment, and management of dysphagia in ALS.

RECENT FINDINGS: The optimal timing of assessment, treatment, and management of dysphagia may be early in the ALS disease process, even before the dysphagia occurs. There is wide heterogeneity in SLP practice patterns for the management of dysphagia.

SUMMARY: Dysphagia is common and debilitating; however, for various reasons, there is no clear consensus on how best to manage dysphagia in this population. Future work centered around predicting swallowing decline and improving interventions aimed at prolonging swallowing function in the early stages of the disease process may promote improved dysphagia care.}, } @article {pmid40821656, year = {2025}, author = {Sanghai, N and Tranmer, GK}, title = {Use of Proteomics to Explore Biomarkers of Amyotrophic Lateral Sclerosis (ALS): Proof of Principle from Humanized SOD1 Mouse to Human ALS.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {8}, pages = {2415-2430}, pmid = {40821656}, issn = {2575-9108}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare motor neurodegenerative disease affecting multiple cellular proteins during the progression of the disease. ALS was first discovered by Charcot in 1869, and since then, scientists have been unable to identify a singular cause of the disease. Further, there are no effective treatments available to cure ALS. The benchmark discovery of humanized preclinical SOD1 mouse models, which recapitulates the clinical and pathological phenotypes of human ALS, gives hope to medicinal chemists and neuroscientists around the globe that a suitable drug-like molecule can be discovered and translated into human beings as a means to slow down the progression of the disease. However, little success has been achieved until now in terms of finding an effective treatment for heterogenic and incurable ALS. One area marked for improvement is the use of semiquantitative, antibody-based targeted Western blotting (WB) experiments, which lack the power to analyze multiple cellular events within the entire dysregulated proteomic system. With the inconsistency of WB experiments, unexpected cellular pathways go undiscovered, and hence, loss of translation with no target engagement is seen from preclinical to human clinical ALS. Recent advancements in discovery-based quantitative proteomics have many advantages over WB. These innovative techniques could help solve the inherent problem in WB and their inability to discover multiple altered proteins with the added capability of longitudinal analysis in preclinical SOD1 models, further validating the findings in human ALS. Herein, we applied a holistic approach to summarize various reports on the use of proteomics in ALS from the published literature, and importantly, we found that using a discovery-based proteomics approach in SOD1 preclinical ALS models has revealed a more diverse and global picture of pathological proteins that affect multiple pathways during different stages of disease progression. Furthermore, we found that the proteomic profiling of the humanized SOD1 mouse model provided a proof of principle for translating the diverse pathological biomarker proteins identified in clinical human ALS cases. Moreover, we believe that advancements in the proteomics approach toward ALS biomarkers could bridge the gap between preclinical and clinical studies, enabling scientists worldwide to discover novel biomarkers and treatments that modify the progression of ALS.}, } @article {pmid40821767, year = {2025}, author = {Zhao, S and Fu, D and Lin, Y and Sun, X and Wang, X and Wu, X and Zhang, X}, title = {The role of the microbiome on immune homeostasis of the host nervous system.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1609960}, pmid = {40821767}, issn = {1664-3224}, mesh = {Humans ; *Gastrointestinal Microbiome/immunology ; *Homeostasis/immunology ; Animals ; *Central Nervous System/immunology ; Nervous System Diseases/immunology/microbiology ; }, abstract = {The gut microbiota is often termed the "second genome" of the human body. It has been shown to be one of the most significant environmental factors (non-genetic) influencing the onset, progression, and prognosis of various neurological and psychiatric disorders through its interactions with the host immune, nervous, and endocrine systems. Changes in the function and composition of the gut microbiota are strongly associated with amyotrophic lateral sclerosis, autism spectrum disorder, depression, Parkinson's disease, and Alzheimer's disease. This review summarizes the research regarding the associations and regulatory mechanisms between the gut microbiota and the central nervous system in order to explore the role of the gut microbiota in maintaining neural homeostasis.}, } @article {pmid40822158, year = {2025}, author = {Cao, G and Shi, X and Wang, X and Yang, L and Wang, P and Yuan, Y and Tan, H}, title = {Combined Single-Bundle Anterior Cruciate Ligament and Anterolateral Structure Reconstruction Through a Modified Single Femoral Tunnel.}, journal = {Arthroscopy techniques}, volume = {14}, number = {7}, pages = {103614}, pmid = {40822158}, issn = {2212-6287}, abstract = {Anterior cruciate ligament (ACL) injuries are among the most common sports injuries, and ACL reconstruction is an important treatment method. Residual rotational stability following isolated ACL reconstruction is the main reason for graft rupture and unsatisfactory results. Many researchers have shown that combined ACL and anterolateral structure (ALS) reconstruction could decrease rotational instability and graft rupture rate, as well as improve satisfaction. Various methods have been described to reconstruct the ACL and ALS jointly. However, previous methods still have disadvantages, such as undesirable tunnel convergence, complex maneuver, and insufficient graft filling in the tibial tunnel. Therefore, we present our technique for reconstruction of the ACL and ALS through a modified single femoral tunnel. We have obtained promising clinical outcomes with this technique.}, } @article {pmid40822241, year = {2025}, author = {Tan, X and Gao, N}, title = {The emerging role of cellular senescence in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1599492}, pmid = {40822241}, issn = {1662-4548}, abstract = {Cellular senescence is a state of permanent cell cycle arrest and is considered a key contributor to aging and age-related diseases, including amyotrophic lateral sclerosis (ALS). The physiological processes of aging lead to a variety of molecular and cellular phenotypes, and evidence of overlap between ALS and aging-related biomarkers suggests that cell type-specific senescence may be a critical factor in ALS. Senescent microglial cells, astrocytes, and neurons have been detected in ALS patients and animal models. However, while accumulating evidence suggests a potential link between cellular senescence and ALS, this connection remains not yet conclusively established. Importantly, how senescent cells may contribute to the neuropathophysiology of ALS remains largely unknown. Additionally, the growing popularity of anti-aging therapies has highlighted the potential of senescent cell clearance as a promising strategy for treating age-related diseases, including ALS. This review provides an overview of cellular senescence, discusses recent advances in understanding how senescence in different cell types influences ALS pathogenesis, and explores the potential role of anti-senescence therapies in ALS treatment.}, } @article {pmid40824324, year = {2025}, author = {Jagaraj, CJ and Mehta, P and Hunter, J and Atkin, JD}, title = {A Slower-Progressing TDP-43 rNLS8 Mouse Model for ALS: Implications for Preclinical and Mechanistic Studies.}, journal = {Neuromolecular medicine}, volume = {27}, number = {1}, pages = {59}, pmid = {40824324}, issn = {1559-1174}, support = {51909/00//Fight MND Drug Development grant/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/drug therapy/physiopathology ; *DNA-Binding Proteins/genetics/physiology/biosynthesis ; *Disease Models, Animal ; Mice ; *Doxycycline/therapeutic use/administration & dosage/pharmacology ; Mice, Transgenic ; Humans ; Disease Progression ; Hand Strength ; Motor Neurons/pathology ; Male ; Rotarod Performance Test ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by motor neuron degeneration, muscle weakness, paralysis, and eventual death, with TAR DNA-binding protein 43 (TDP-43) pathology observed in almost all cases. Mouse models based on TDP-43 are thus essential for studying ALS and developing therapeutic approaches. The TDP-43 rNLS8 mouse model expresses a human TDP-43 transgene with a mutated nuclear localization sequence (hTDP-43 ΔNLS), but this is normally suppressed by the presence of doxycycline (Dox). Disease is initiated by removal of Dox, which replicates key ALS features, including TDP-43 pathology, neuromuscular junction denervation, motor neuron loss, and reduced survival. However, this model has a rapid disease progression which limits its use for extended preclinical studies and investigation of early disease mechanisms. To overcome these limitations, we explored whether maintaining low Dox concentrations in the diet (10-20 mg/kg) could slow disease progression. Our findings demonstrate that this approach significantly reduced hTDP-43 ΔNLS expression (up to 4.8-fold), which delayed disease onset by four weeks. Disease progression, assessed by rotarod performance, grip strength, and neurological scores, was extended from six to 15 weeks, with a threefold increase in survival. Despite slower progression, at the end stage, mice displayed similar levels of neuroinflammation, motor neuron loss, as Dox off mice. These findings highlight slower-progressing TDP-43 rNLS8 mice as a robust model for preclinical and early disease mechanism studies.}, } @article {pmid40824591, year = {2025}, author = {Kong, M and Yu, W and Guo, J and Wang, Z and Fan, D}, title = {Two-step Mendelian randomization reveals a lipid-driven protective effect of type 2 diabetes on ALS.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {10}, pages = {5133-5144}, pmid = {40824591}, issn = {1590-3478}, support = {81873784//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; BYSYZD2021004//key Program of Peking University Third Hospital/ ; }, mesh = {Mendelian Randomization Analysis ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Protective Factors ; *Diabetes Mellitus, Type 2/genetics/metabolism ; *Lipid Metabolism/genetics ; Fatty Acids/metabolism ; Glucose/metabolism ; Humans ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with few therapeutic options. Observational data suggest that type 2 diabetes mellitus (T2DM) might protect against ALS, yet the mechanisms are unclear. Clarifying whether glucose or lipid metabolism underpins this protective effect could guide targeted interventions.

OBJECTIVE: This study aims to investigate if T2DM reduces ALS risk through glycemic or lipid pathways using a two-step Mendelian Randomization (MR) approach.

METHODS: Summary-level genetic data were sourced from FinnGen (n = 440,735), MAGIC (n = 200,622), UK Biobank (n = 115,078), and Project MinE (n = 138,086). Two-sample MR assessed T2DM's causal effect on ALS, followed by multivariable MR adjusting for glycemic traits to identify metabolic pathways. A two-step MR analyzed significant blood metabolites contributing to the T2DM-ALS relationship. Sensitivity analyses confirmed the robustness of these findings.

RESULTS: T2DM exhibited a protective causal association with ALS (inverse variance weighting OR = 0.956, 95% CI 0.916-0.997, p = 0.037). Glycemic traits did not mediate this protection; instead, lipid metabolism played a role. Specifically, a 1 SD reduction in LDL diameter was linked to a 16.7% decrease in ALS risk, accounting for 24.4% of T2DM's protective effect. Similarly, a 1 SD decrease in total esterified cholesterol (TEC) reduced ALS risk by about 13.2%, contributing to 13.3% of T2DM's overall protective impact. No evidence of horizontal pleiotropy was observed.

CONCLUSION: T2DM's protective influence on ALS primarily involves lipid rather than glucose pathways, highlighting TEC and LDL particle diameter as crucial mediators. Targeting lipid metabolism may offer new therapeutic strategies to reduce ALS risk or progression, potentially leading to focused nutritional interventions and biomarker development.}, } @article {pmid40824693, year = {2025}, author = {Voronov, D and Park, S and Huang, L and Islegen-Wojdyla, A and Gullikson, E and Padmore, H and Wang, T and Idir, M}, title = {Fabrication and characterization of a full-size ultra-precise lamellar grating for the Cosmic beamline at ALS-U.}, journal = {Journal of synchrotron radiation}, volume = {32}, number = {Pt 5}, pages = {1194-1200}, pmid = {40824693}, issn = {1600-5775}, support = {DE-AC02-05CH11231//US Department of Energy, Office of Science/ ; DE-SC0012704//US Department of Energy, Office of Science/ ; BNL LDRD 17-016//US Department of Energy, Office of Science/ ; FWP-PS032//US Department of Energy, Office of Science/ ; }, abstract = {We have developed a new process for the production of ultra-precise variable line spacing (VLS) lamellar diffraction gratings through nanofabrication. The process enables the fabrication of full-size X-ray gratings with sub-nanometre accuracy in groove depth, an optimal land-to-groove ratio, and uniform groove depth across the entire grating area. We also established a method for evaluating VLS groove density variation using stitched Fizeau interferometry. The measurements confirmed the exceptionally high accuracy of the VLS groove density in the fabricated gratings, which is well within the specification tolerances while the residual groove density errors are vanishingly small. The gold-coated grating demonstrated near-theoretical diffraction efficiency across the energy range of 100-1200 eV.}, } @article {pmid40824756, year = {2026}, author = {García-Casanova, PH and Gascón-Giménez, F and Castillo-Villalba, J and Benatar, M and Vázquez-Costa, JF}, title = {Neurofilament light chain dynamics in the pre-symptomatic phase of amyotrophic lateral sclerosis: a case report.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {219-223}, doi = {10.1080/21678421.2025.2542918}, pmid = {40824756}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; Female ; Adult ; *Neurofilament Proteins/blood ; Disease Progression ; *Prodromal Symptoms ; Biomarkers/blood ; }, abstract = {This case report aims to describe the presymptomatic and prodromal phases of the disease in a sporadic patient with amyotrophic lateral sclerosis (ALS). A 41-year-old woman presented with acute hypesthesia due to transverse myelitis, with normal serum NfL levels. After six months, an increase in serum NfL, without clinical correlate, was found. One year after the myelitis, while serum NfL continued to increase, she experienced mild motor symptoms in the right hand, without definite signs of ALS. Disease progression over the following months finally lead to an ALS diagnosis, just as the NfL reached its peak. The emergence of both mild motor impairment as a prodromal stage of disease, and the sustained increase in NfL presymptomatically in a patient with sporadic ALS, highlights the expected similarities between genetic and non-genetic forms of disease. This case suggests the utility of NfL as a risk/susceptibility biomarker for predicting phenoconversion also in sporadic ALS patients.}, } @article {pmid40825663, year = {2025}, author = {Zhang, L and Pang, XW and Zhang, LY and Zhu, LF and Li, WN and Chu, YH and Zhou, LQ and Tian, DS and Qin, C and Chen, L}, title = {Gut Microbiota and White Matter Integrity: A Two-Sample Mendelian Randomization Analysis.}, journal = {eNeuro}, volume = {12}, number = {9}, pages = {}, pmid = {40825663}, issn = {2373-2822}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology/genetics ; Mendelian Randomization Analysis ; *White Matter/diagnostic imaging/pathology ; Male ; Female ; }, abstract = {The causal relationship between gut microbiota (GM) and white matter injury and communication remains unclear. We aimed to scrutinize the plausible causal impact of GM on white matter hyperintensities (WMHs), white matter microstructure, white matter connectivity, and multiple neurological diseases via Mendelian randomization study. We identified four WMH-related bacterial taxa, including class Melainabacteria, order Gastranaerophilales, family Alcaligenaceae, and genus Ruminiclostridium 6 In addition, three bacterial taxa were discovered that have consistent effect on multiple aspects of white matter microstructure. Furthermore, we found 12 strong associations between genetic liability in GM and white matter connectivity. Among these bacterial taxa, the family Clostridiaceae 1 demonstrated a protective effect against ischemic stroke (IS). The genus Barnesiella showed protective effect on IS and small vessel stroke while posed a risk effect on neuromyelitis optica spectrum disorder (NMOSD), as well as on aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). The order Desulfovibrionales and family Desulfovibrionaceae showed protective effect against cardioembolic stroke, and the genus Ruminococcus gnavus group showed a protective effect on amyotrophic lateral sclerosis. In terms of the mapped genes of statistically significant bacterial taxa, genes such as CPNE1, PIGU, MED22, SURF6, DOCK10, and COPS3 exhibited a significant causal correlation with the corresponding white matter connectivity. This study demonstrated a genetically predicted causal relationship between GM and WMH, white matter microstructure, white matter connectivity, and multiple neurological diseases, based on GWAS data from mixed-sex cohorts without sex-stratified summary statistics. These findings highlight the potential role of GM in influencing brain structural integrity.}, } @article {pmid40825784, year = {2025}, author = {Flores, BN and Yu, SB and Cohen, IV and Fanok, MH and Luan, W and Maciuca, RD and Sun, LD and Tsai, RM and Vissers, M and Smits, L and Bunte, TM and Bakardjiev, A and Balasundar, S and Calvert, MEK and Chin, MY and Dobbins, SK and Dowdle, WE and Fang, M and Heuberger, JAAC and Ha, CL and Huang, F and Miyamoto, T and Osipov, M and Madrid San Martin, L and Saund, K and Tatarakis, D and Vu, AQ and Xiong, C and Yeo, GW and Groeneveld, GJ and van den Berg, LH and Dhuria, S and Estrada, AA and Jennings, D and Sandmann, T and Ho, C and Scearce-Levie, K and Yulyaningsih, E and Walker, AK and Di Paolo, G and Kane, LA and Troyer, MD and Lewcock, JW}, title = {Investigational eIF2B activator DNL343 modulates the integrated stress response in preclinical models of TDP-43 pathology and individuals with ALS in a randomized clinical trial.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {7690}, pmid = {40825784}, issn = {2041-1723}, support = {R01 HG004659/HG/NHGRI NIH HHS/United States ; U24 HG009889/HG/NHGRI NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Humans ; Animals ; Mice ; Disease Models, Animal ; Double-Blind Method ; Female ; Male ; *DNA-Binding Proteins/metabolism/genetics ; Middle Aged ; Spinal Cord/metabolism/pathology/drug effects ; Adult ; Aged ; Brain/metabolism/pathology/drug effects ; Leukocytes, Mononuclear/metabolism/drug effects ; Acetamides ; Cyclohexylamines ; }, abstract = {Neuronal TDP-43 aggregates are a hallmark ALS pathology. The integrated stress response (ISR) occurs downstream of TDP-43 pathology and may promote neurodegeneration. Here we demonstrate that a CNS penetrant small molecule eIF2B activator inhibits the ISR in cellular models of ALS and the brain of an inducible mouse model of TDP-43 pathology, where it transiently slowed progression of locomotor deficits and neurodegeneration. ISR activation was observed in ALS patient spinal cord and CSF. The investigational drug DNL343 was advanced into Phase 1 and Phase 1b randomized, double-blind, placebo-controlled trials in healthy and ALS participants, respectively (NCT04268784/NCT05006352); the primary objective in both studies was to investigate the safety and tolerability DNL343. DNL343 demonstrated a half-life supporting once-daily dosing and showed extensive CSF distribution. DNL343 was generally well tolerated and reduced ISR biomarkers in peripheral blood mononuclear cells and CSF of ALS participants. Therefore, DNL343 is a useful investigational drug to explore the effects of ISR inhibition in ALS models and individuals with neurological diseases.}, } @article {pmid40826370, year = {2025}, author = {Feneberg, E and Thompson, AG and Charles, PD and Vendrell, I and Kessler, BM and Fischer, R and Ansorge, O and Gray, E and Talbot, K and Turner, MR}, title = {TDP-43 pathology is associated with divergent protein profiles in ALS brain and spinal cord.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {175}, pmid = {40826370}, issn = {2051-5960}, support = {ARUK AVR01961//Alzheimer's Research UK small grant/ ; Clinical Post Doctoral Fellowship//Guarantors of Brain/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; *Spinal Cord/metabolism/pathology ; Female ; Male ; Aged ; Middle Aged ; *Brain/pathology/metabolism ; Inclusion Bodies/pathology/metabolism ; Proteomics ; Alzheimer Disease/pathology/metabolism ; Cerebral Cortex/pathology/metabolism ; Aged, 80 and over ; Parkinson Disease/pathology/metabolism ; }, abstract = {Neuronal and glial cytoplasmic inclusions positive for TAR DNA-binding protein 43 (TDP-43) are the defining pathological hallmark of 97% of amyotrophic lateral sclerosis (ALS) and 50% of frontotemporal dementia (FTD). The ALS-FTD clinicopathological spectrum variably involves cortical and spinal anterior horn cell pathology. The broader protein composition of these inclusions is of major importance to understanding pathogenesis, clinical heterogeneity and biomarker development. This study examined the proteome associated with TDP-43 inclusions in ALS, using mass spectrometry-based proteomic analysis of spinal cord and cerebral cortex from donors with phosphoTDP-43 positive ALS (n = 16), alpha-synuclein positive Parkinson's disease (PD, n = 8), phosphotau and beta-amyloid positive Alzheimer's disease (AD, n = 8) and age matched non-neurological controls (n = 8), comparing ALS with non-ALS conditions, spinal cord with cerebral cortex samples, and detergent-soluble with -insoluble fractions. Increased abundance of TDP-43 in the detergent-insoluble fraction of ALS cortex and spinal cord tissue confirmed disease-specific protein enrichment by serial fractionation. The most striking alterations between ALS and other conditions were found in the detergent-insoluble fraction of spinal cord, with predominant enrichment of endosomal and extracellular vesicle pathways. In the cortex mitochondrial membrane/envelope and ion transmembrane transport pathways were enriched in the detergent-insoluble fraction. RNA/DNA metabolic processes (in spinal cord) versus mitochondrial and synaptic protein pathways (in cortex) were upregulated in the detergent-soluble fraction of ALS cases and downregulated in the insoluble protein fraction. Whilst motor cortex and spinal cord may not optimally reflect disease-specific pathways in AD, in PD a significant enrichment of alpha-synuclein in the detergent-insoluble fraction of spinal cord was found. Among proteins concordantly elevated in the detergent-insoluble fractions of spinal cord and cortex, there was greater representation of proteins encoded by ALS-associated genes, specifically Cu/Zn superoxide dismutase 1, valosin containing protein and TDP-43 (odds ratio 16.34, p = 0.002). No significant increase in TDP-43 interacting proteins was observed in either detergent-soluble or -insoluble fractions. Together, this study shows a divergence in the composition of proteins associated with TDP-43 positive detergent-insoluble inclusions between spinal cord and cerebral cortex. A common upregulation of proteins encoded by ALS-causing genes implicates their role in the pathogenesis of the ALS-FTD spectrum of diseases beyond TDP-43. Data are available via ProteomeXchange with identifier PXD067060.}, } @article {pmid40826812, year = {2025}, author = {Asano, H and Kawaguchi, T and Kato, C and Morimoto, S and Yano, M and Minaguchi, M and Yasuda, D and Fukushima, K and Okano, H}, title = {Ropinirole Functions Through a Dopamine Receptor D2-Independent Mechanism to Ameliorate Amyotrophic Lateral Sclerosis Phenotypes in TARDBP-Mutant iPSC-Derived Motor Neurons.}, journal = {Journal of neurochemistry}, volume = {169}, number = {8}, pages = {e70183}, pmid = {40826812}, issn = {1471-4159}, support = {JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP20H00485//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Induced Pluripotent Stem Cells/drug effects/metabolism ; *Motor Neurons/drug effects/metabolism ; *Receptors, Dopamine D2/genetics/agonists/metabolism ; Humans ; *Indoles/pharmacology/therapeutic use ; Animals ; *Dopamine Agonists/pharmacology ; *DNA-Binding Proteins/genetics ; Phenotype ; Mice ; Mutation ; Reactive Oxygen Species/metabolism ; Cells, Cultured ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron (MN) degeneration. Ropinirole hydrochloride (ROPI), a dopamine receptor D2 (DRD2) agonist, was identified through phenotypic screening of MNs derived from patient-derived induced pluripotent stem cells (iPSCs) as a disease model and has emerged as a promising candidate drug for ALS treatment. The ROPALS trial, a phase I/IIa trial in patients with ALS, suggested the safety and efficacy of ROPI, albeit in a small sample size. Interestingly, a DRD2 antagonist and modulator only partially mitigated the suppressive effect of ROPI on the ALS phenotype, and the detailed mechanism of ROPI activity remains unclear. Therefore, in this study, we investigated whether the therapeutic effects of ROPI in ALS are dependent on DRD2. For this purpose, we generated DRD2-deficient iPSCs and showed that ROPI effectively reduced neuronal cell death, reactive oxygen species (ROS) production, and neuronal hyperexcitation, independently of DRD2. Further analyses revealed that ROPI corrected aberrant RNA splicing and restored the mRNA expression of mitochondrial proteins in a DRD2-independent manner. Our findings suggest that ROPI not only functions as a canonical DRD2 agonist but also has pleiotropic DRD2-independent effects, offering a novel avenue for treatment strategies that target multiple pathways involved in ALS pathology.}, } @article {pmid40827427, year = {2025}, author = {Mehta, AK and Kojimoto, G and O'Riordan, DL and Leavell, YL and Maiser, S and Grouls, A and Smith, AK and Pantilat, SZ and Kluger, BM and Bischoff, KE}, title = {Patients' and Caregivers' Perceptions of Specialty Palliative Care for Amyotrophic Lateral Sclerosis: A Multicenter Evaluation.}, journal = {Muscle & nerve}, volume = {72}, number = {5}, pages = {1081-1090}, doi = {10.1002/mus.70006}, pmid = {40827427}, issn = {1097-4598}, support = {A142921//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Female ; *Caregivers/psychology ; *Palliative Care/psychology/methods ; Male ; Middle Aged ; Aged ; *Patient Satisfaction ; Adult ; Surveys and Questionnaires ; Quality of Life ; *Perception ; }, abstract = {INTRODUCTION/AIMS: Specialty palliative care (SPC) aims to optimize quality of life for people with life-limiting illnesses. Previous studies support benefits of SPC for people with amyotrophic lateral sclerosis (pALS) and their caregivers; however, few studies have compared patient and caregiver experiences with ALS care and SPC.

METHODS: An online survey assessing satisfaction with care was distributed to pALS and caregivers who had received SPC. Those who completed the survey were also invited to participate in a semi-structured interview.

RESULTS: Thirty-four people (10 pALS, 25 caregivers) from 26 ALS clinics in 20 states completed the survey. Sixteen also provided a qualitative interview. Respondents were most commonly satisfied with their ALS team's ability to answer questions (81%), counsel them regarding ALS medications (78%), and manage motor symptoms (77%). Respondents were least commonly satisfied with their ALS team's ability to manage mood (50%), address spiritual/existential concerns (48%), and help them find in-home care providers (38%). SPC was initiated an average of 14.6 months after ALS diagnosis. Respondents were most commonly satisfied with their SPC team's responsiveness to time-sensitive needs between scheduled visits (82%) and management of mood (80%) and non-pain physical symptoms (73%). Respondents were least commonly satisfied with their SPC team's ability to help with equipment needs (52%), make decisions about procedures (50%), and find in-home caregivers (46%). Interviews highlighted the emotional support and care coordination that SPC teams provide.

DISCUSSION: pALS and caregivers identified distinct and complementary strengths of ALS and SPC teams, suggesting that collaboration between teams may provide the most comprehensive care.}, } @article {pmid40828747, year = {2026}, author = {Vijayaraghavan, A and Nair, SS and Poyuran, R and Sukumaran, S and Sundaram, S}, title = {Neuroimmunological Crossroads: A Rare Co-occurrence of Myasthenia Gravis and IgLON-related Amyotrophic Lateral Sclerosis.}, journal = {Neurology India}, volume = {74}, number = {1}, pages = {148-150}, doi = {10.4103/neurol-india.Neurol-India-D-25-00148}, pmid = {40828747}, issn = {1998-4022}, } @article {pmid40829685, year = {2025}, author = {Wang, Y and Zhou, Y and Tian, H and Li, Q and Chen, Y and Wang, L and Yin, Z and Zhou, J and Liang, F}, title = {NF-κB signalling pathway in neurodegenerative diseases: Acupuncture as a potential therapeutic approach.}, journal = {Brain research}, volume = {1865}, number = {}, pages = {149893}, doi = {10.1016/j.brainres.2025.149893}, pmid = {40829685}, issn = {1872-6240}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/metabolism ; *Acupuncture Therapy/methods ; *Signal Transduction/physiology ; Animals ; *NF-kappa B/metabolism ; }, abstract = {The NF-κB signaling pathway plays a crucial role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, particularly through its role in the regulation neuroinflammation, oxidative stress, protein misfolding, and apoptosis. Emerging evidence suggests that acupuncture modulates the NF-κB pathway, thus offering therapeutic potential by mitigating neuroinflammation, reducing oxidative stress, and protecting mitochondrial function. Specifically, acupuncture inhibits NF-κB activation, downregulates pro-inflammatory mediators like TNF-α and IL-6, and mitigates neurotoxicity and apoptosis. These effects are substantiated in animal models of Alzheimer's and Parkinson's diseases, with preliminary evidence in amyotrophic lateral sclerosis models. However, current studies largely rely on preclinical models with limited acupoint selection, short observation periods, and a lack of standardized protocols, posing challenges for translation to clinical settings. Future research should prioritize well-designed clinical trials, expand acupoint combinations, and explore synergistic effects with conventional therapies, aiming to maximize acupuncture's therapeutic efficacy in neurodegenerative diseases.}, } @article {pmid40829878, year = {2025}, author = {Malaspina, A}, title = {Moving past NfL? Multibiomarker models for ALS prognosis and stratification.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {12}, pages = {1129}, doi = {10.1136/jnnp-2025-336814}, pmid = {40829878}, issn = {1468-330X}, } @article {pmid40829936, year = {2025}, author = {Dey, S and Quintanilla, C and Bitlis, D and Gautam, M and Ozdinler, PH and Martina, M}, title = {Cell Type-Specific Alterations in Excitability and Inhibition of Upper Motor Neurons in AlsinKO Mice, a Model of Juvenile Onset ALS.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {45}, number = {39}, pages = {}, pmid = {40829936}, issn = {1529-2401}, support = {R01 NS112292/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics/pathology ; Mice ; Disease Models, Animal ; Female ; Male ; Mice, Transgenic ; *Motor Neurons/physiology ; *Neural Inhibition/physiology/genetics ; *Motor Cortex/physiopathology/pathology ; Green Fluorescent Proteins/genetics ; }, abstract = {In amyotrophic lateral sclerosis (ALS) motor cortex, hyperexcitability is detected in both familial and sporadic cases, suggesting its centrality in the ALS phenotype; the underlying mechanisms, however, remain largely obscure. Here we utilize male and female UCHL1-eGFP (UeGFP) mice, in which the corticospinal neurons of the motor cortex are labeled with green fluorescent protein, to investigate the intrinsic excitability and synaptic inhibitory inputs on distinct neuron populations in WT-UeGFP and presymptomatic AlsinKO-UeGFP mice, which lack Alsin function and are a well-characterized mouse model for juvenile cases of ALS. We show that in the motor cortex of AlsinKO-UeGFP mice, eGFP-positive layer 5 pyramidal neurons, which represent upper motor neurons, show a decrease in intrinsic excitability compared with WT, whereas the electrophysiological properties of eGFP-negative cells, which identify callosal projection neurons, are unaffected. This alteration in intrinsic excitability, however, is counterbalanced by a decrease in the frequency of spontaneous inhibitory currents due to a cell-specific reduction in the number of inhibitory synaptic contacts on upper motor neurons. Thus, the overall excitability of upper motor neurons only displays negligible changes despite large alterations in intrinsic excitability and inhibitory synaptic input, which may explain why mice do not exhibit a prominent motor phenotype. The presence of this homeostatic interaction between intrinsic excitability and synaptic inhibition raises the question of which of the two changes is primary, and which is secondary, and shows that decreased function of motor cortex interneurons is an early event in ALS with Alsin mutations.}, } @article {pmid40830488, year = {2025}, author = {Schippers, A and Vansteensel, MJ and Freudenburg, ZV and Luo, S and Crone, NE and Ramsey, NF}, title = {Don't put words in my mouth: speech perception can falsely activate a brain-computer interface.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {22}, number = {1}, pages = {181}, pmid = {40830488}, issn = {1743-0003}, support = {101070939//HORIZON EUROPE European Innovation Council/ ; UH3 NS114439/NS/NINDS NIH HHS/United States ; UGT7685//Stichting voor de Technische Wetenschappen/ ; ERC-Advanced 'iConnect' project, grant ADV 320708/ERC_/European Research Council/International ; UH3NS114439/NS/NINDS NIH HHS/United States ; U01DC016686/DC/NIDCD NIH HHS/United States ; PPS-2021-02//Dutch Brain Foundation/ ; U01 DC016686/DC/NIDCD NIH HHS/United States ; SGW-406-18-GO-086//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; }, mesh = {Humans ; *Brain-Computer Interfaces ; *Speech Perception/physiology ; Male ; Adult ; Electrocorticography ; Female ; Speech/physiology ; *Sensorimotor Cortex/physiology ; Support Vector Machine ; }, abstract = {BACKGROUND: Recent studies have demonstrated that speech can be decoded from brain activity which in turn can be used for brain-computer interface (BCI)-based communication. It is however also known that the area often used as a signal source for speech decoding BCIs, the sensorimotor cortex (SMC), is also engaged when people perceive speech, thus making speech perception a potential source of false positive activation of the BCI. The current study investigated if and how speech perception may interfere with reliable speech BCI control.

METHODS: We recorded high-density electrocorticography (HD-ECoG) data from five subjects while they performed a speech perception and a speech production task. We first evaluated whether speech perception and production activated the SMC. Second, we trained a support-vector machine (SVM) on the speech production data (including rest). To test the occurrence of false positives, this decoder was then tested on speech perception data where every perception segment that was classified as a produced syllable rather than rest was considered a false positive. Finally, we investigated whether perceived speech could be distinguished from produced speech and rest.

RESULTS: Our results show that both the perception and production of speech activate the SMC. In addition, we found that decoders that are highly reliable at detecting self-produced syllables from brain signals may generate false positive BCI activations during the perception of speech and that it is possible to distinguish perceived speech from produced speech and rest, with high accuracy.

CONCLUSIONS: We conclude that speech perception can interfere with reliable BCI control, and that efforts to limit the occurrence of false positives during daily-life BCI use should be implemented in BCI design to increase the likelihood of successful adoptation by end users.}, } @article {pmid40830661, year = {2025}, author = {Chia, R and Moaddel, R and Kwan, JY and Rasheed, M and Ruffo, P and Landeck, N and Reho, P and Vasta, R and Calvo, A and Moglia, C and Canosa, A and Manera, U and Snyder, A and Saez-Atienzar, S and Grassano, M and Brunetti, M and Casale, F and Ray, A and Arvind, K and Comertpay, B and Zhu, M and Gibbs, JR and , and Alba, C and Dawson, TM and Rosenthal, LS and Hall, AJ and Pantelyat, AY and Narendra, DP and Ehrlich, DJ and Walker, KA and Kosa, P and Bielekova, B and Egan, JM and Candia, J and Tanaka, T and Ferrucci, L and Dalgard, CL and Scholz, SW and Chiò, A and Traynor, BJ}, title = {A plasma proteomics-based candidate biomarker panel predictive of amyotrophic lateral sclerosis.}, journal = {Nature medicine}, volume = {31}, number = {10}, pages = {3440-3450}, pmid = {40830661}, issn = {1546-170X}, support = {P30 AG066507/AG/NIA NIH HHS/United States ; 1ZIAAG000933//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; ZIA NS003154/ImNIH/Intramural NIH HHS/United States ; ZIA AI001242/ImNIH/Intramural NIH HHS/United States ; ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; *Biomarkers/blood ; *Proteomics/methods ; Male ; Female ; Middle Aged ; Aged ; Cross-Sectional Studies ; *Blood Proteins/metabolism ; Machine Learning ; Adult ; Case-Control Studies ; }, abstract = {Identifying a reliable biomarker for amyotrophic lateral sclerosis (ALS) is crucial for clinical practice. Here, in this cross-sectional study, we used the Olink Explore 3072 platform to investigate plasma proteomics as a biomarker tool for this neurodegenerative condition. Thirty-three proteins were differentially abundant in the plasma of patients with ALS (n = 183) versus controls (n = 309). We replicated our findings in an independent cohort (n = 48 patients with ALS and n = 75 controls). We then applied machine learning to create a model that diagnosed ALS with high accuracy (area under the curve, 98.3%). By analyzing plasma samples from individuals before ALS symptoms emerged, we estimated the age of clinical onset and showed that the disease process-impacting skeletal muscle, nerves and energy metabolism-occurs years before symptoms appear. Our research suggests that plasma proteins can be a biomarker for this fatal disease and offers molecular insights into its prodromal phase.}, } @article {pmid40830689, year = {2026}, author = {Rusecka, JM and Kierdaszuk, B and Stępniak, I and Rydzanicz, M and Stawiński, P and Gambin, T and Loska, D and Kacprzak, MM and Kaliszewska, M and Piekutowska-Abramczuk, D and Kamińska, AM and Pronicka, E and Bartnik, E and Kostera-Pruszczyk, A and Płoski, R and Sobczyńska-Tomaszewska, A and Tońska, K}, title = {Ataxia and oculomotor apraxia caused by a large-scale deletion in the senataxin gene.}, journal = {Journal of applied genetics}, volume = {67}, number = {3}, pages = {757-767}, pmid = {40830689}, issn = {2190-3883}, support = {2014/15/B/NZ5/00434//Narodowe Centrum Nauki/ ; 2012/05/B/NZ2/01627//Narodowe Centrum Nauki/ ; 2013/09/N/NZ5/00836//Narodowe Centrum Nauki/ ; IP2015 019874//Ministerstwo Edukacji i Nauki/ ; VENTURES/2011-8/3//Fundacja na rzecz Nauki Polskiej/ ; }, mesh = {Humans ; *RNA Helicases/genetics ; *DNA Helicases/genetics ; *Multifunctional Enzymes/genetics ; Female ; Male ; *Sequence Deletion ; Adult ; *Apraxias/genetics/congenital ; DNA Copy Number Variations ; *Ataxia/genetics ; Cogan Syndrome ; }, abstract = {Senataxin, an RNA/DNA helicase, is a key protein providing genome stability and one of the best characterized R-loop-binding factors playing an important role in transcription and DNA repair processes. Pathogenic SETX gene variants cause autosomal recessive spinocerebellar ataxia with axonal neuropathy (AOA2, MIM #606002) and autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4, MIM #602433), rare neurodegenerative disorders characterized by juvenile onset of progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy, combined upper and lower motor neuron symptoms, and increased serum alpha-fetoprotein (AFP; specific for AOA2). We report two cases of adult patients presenting with cerebellar syndrome, scanned speech, and exercise intolerance which started in the second/third decade of life and were followed by muscle weakness and impaired gait coordination. Whole exome sequencing (WES) was performed to analyze single nucleotide and copy number variants. A decreased coverage of a genomic region of around 16 kb on chromosome 9 (chr9:132,295,852-132,311,876), suggesting a deletion encompassing 5 exons of the SETX gene (exons 11-15, NM_015046.7) was observed. This homozygous SETX (9q34.13) deletion leads to a frame shift and consequently truncation of the helicase domain in the protein. Loss-of-function variants in the SETX gene are known to be pathogenic. Statistical analysis of NGS data from the Polish population identified a few heterozygous carriers, suggesting its region-specific origin.}, } @article {pmid40830802, year = {2025}, author = {Tzeplaeff, L and Galhoz, A and Meijs, C and Caldi Gomes, L and Kovac, A and Menzel, A and Değirmenci, H and Alaamel, A and Kaya, HC and Çelik, AG and Dinçer, S and Korucuk, M and Karaüzüm, SB and Bayraktar, E and Çiftçi, V and Bilge, U and Koç, F and Demleitner, AF and Buchberger, A and von Heynitz, R and Gmeiner, V and Knellwolf, C and Mouzouri, M and Wuu, J and Başak, AN and Andersen, PM and Kohlmayer, F and Ashton, NJ and Kuban, W and Lenz, C and Rogers, ML and Zilka, N and Corcia, P and Lerner, Y and Weber, M and Turcanova Koprusakova, M and Uysal, H and Benatar, M and Menden, MP and Lingor, P}, title = {Identification of a presymptomatic and early disease signature for amyotrophic lateral sclerosis (ALS): protocol of the premodiALS study.}, journal = {Neurological research and practice}, volume = {7}, number = {1}, pages = {56}, pmid = {40830802}, issn = {2524-3489}, support = {SyNergy - ID 390857198//Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology/ ; 01ED2204A//Bundesministerium für Bildung und Forschung/ ; No. 950293 - COMBAT-RES//European Union's Horizon 2020 Research and Innovation Programme/ ; 3-18370//Ministry of Health of Israel/ ; ANR-21-JPW2-0007-03//Agence Nationale de la Recherche/ ; 01ED2204B//Bundesministerium für Bildung und Forschung/ ; 01ED2204B//Karlsruhe School of Elementary Particle and Astroparticle Physics: Science and Technology, Karlsruhe Institute of Technology/ ; 32ND30_206536//Swiss National Science Foundation (SNSF)/ ; 2021/03/Y/NZ7/00111//Polish National Science Center (NCN)/ ; R01 NS105479/NS/NINDS NIH HHS/United States ; EXC 2145//Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology/ ; 112N004//Scientific and Technological Research Council of Turkey (TÜBİTAK)/ ; 05-CIG-Rogers 2022//FightMND/ ; R01NS105479//U.S. National Institutes of Health/ ; }, abstract = {INTRODUCTION: The median time to diagnosis of amyotrophic lateral sclerosis (ALS) is approximately 12 months after the onset of first symptoms. This diagnostic delay is primarily due to the nonspecific nature of early symptoms and the clinical challenges in differentiating ALS from its mimics. Therefore, the discovery of reliable biomarkers for the early and accurate diagnosis of ALS represents a critical medical need.

METHODS: A total of 330 participants will be recruited across six international study sites. The cohort will include (1) pre-symptomatic gene mutation carriers, (2) symptomatic individuals up to 12 months after symptom onset with either ALS, ALS mimics, or a pure motor syndrome with yet unclear assignment, and (3) healthy controls. Participants will engage in a one-year longitudinal study, consisting of an initial evaluation at baseline visit and a follow-up visit 12 months later. Assessments will include an environmental and medical history questionnaire, neurological examinations, olfactory testing, cognitive/behavioral evaluations, and the collection of biological samples (serum, plasma, urine, tear fluid, and cerebrospinal fluid). Proteomic, metabolomic, and lipidomic analyses will be performed using mass spectrometry and targeted immunoassays, with all samples processed under standardized protocols. The resulting multimodal dataset will be systematically integrated in an effort to uncover a presymptomatic and early ALS signature. Perspective The premodiALS study aim to identify a clinico-molecular signature characteristic of presymptomatic and early ALS. These findings may have relevance to early diagnosis and future clinical practice for ALS disease.}, } @article {pmid40831763, year = {2025}, author = {B S, P and Talwar, P}, title = {Influence of palmitoylation in axonal transport mechanisms in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1613379}, pmid = {40831763}, issn = {1662-5102}, abstract = {Progressive functional loss and death of neurons are characteristics of neurodegenerative diseases such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). These diseases are often linked with disruptions in axonal transport and synaptic functions. Accumulation of misfolded proteins is observed as a commonly shared pathology for these diseases, where aberrant accumulation of amyloid beta (Aβ), tau, α-synuclein (α-syn) and TAR DNA-binding protein 43 (TDP-43), are found in AD, PD and ALS, respectively. These accumulations are observed to be involved in disrupting axonal transport and compromising neuronal survival. Axonal transport is an essential process where proper functioning of the transport mechanism is important for maintaining neuronal hemostasis by transporting of proteins, organelles and neurotransmitter complexes. This review explores the role of palmitoylation in regulating neuronal axonal transport and their impact on other neuronal functions along with neurodegeneration mechanisms. Palmitoylation is a reversible lipid modification, which is widely studied second to phosphorylation. Enzymes like palmitoyl acyltransferases and acyl-protein thioesterases are responsible for attachment and detachment of palmitic acid causing palmitoylation and depalmitoylation of neuronal proteins. In axonal transport, palmitoylation influences the localization and functioning of the proteins, which connectively plays a role in synaptic stability by interacting with synaptic scaffolding proteins and neurotransmission receptors.}, } @article {pmid40832231, year = {2025}, author = {Jude, JJ and Haro, S and Levi-Aharoni, H and Hashimoto, H and Acosta, AJ and Card, NS and Wairagkar, M and Brandman, DM and Stavisky, SD and Williams, ZM and Cash, SS and Simeral, JD and Hochberg, LR and Rubin, DB}, title = {Decoding intended speech with an intracortical brain-computer interface in a person with longstanding anarthria and locked-in syndrome.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.08.12.668516}, pmid = {40832231}, issn = {2692-8205}, abstract = {Intracortical brain-computer interfaces (iBCIs) for decoding intended speech have provided individuals with ALS and severe dysarthria an intuitive method for high-throughput communication. These advances have been demonstrated in individuals who are still able to vocalize and move speech articulators. Here, we decoded intended speech from an individual with longstanding anarthria, locked-in syndrome, and ventilator dependence due to advanced symptoms of ALS. We found that phonemes, words, and higher-order language units could be decoded well above chance. While sentence decoding accuracy was below that of demonstrations in participants with dysarthria, we are able to attain an extensive characterization of the neural signals underlying speech in a person with locked-in syndrome and through our results identify several directions for future improvement. These include closed-loop speech imagery training and decoding linguistic (rather than phonemic) units from neural signals in middle precentral gyrus. Overall, these results demonstrate that speech decoding from motor cortex may be feasible in people with anarthria and ventilator dependence. For individuals with longstanding anarthria, a purely phoneme-based decoding approach may lack the accuracy necessary to support independent use as a primary means of communication; however, additional linguistic information embedded within neural signals may provide a route to augment the performance of speech decoders.}, } @article {pmid40832276, year = {2025}, author = {Ramani, B and Ehsani, K and Kampmann, M}, title = {The Hsp40 co-chaperone DNAJC7 modifies polyglutamine but not polyglycine aggregation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40832276}, issn = {2692-8205}, support = {K08 NS133300/NS/NINDS NIH HHS/United States ; R25 NS070680/NS/NINDS NIH HHS/United States ; }, abstract = {Polyglutamine (polyQ) diseases, including Huntington's disease and several spinocerebellar ataxias, are caused by abnormally expanded CAG nucleotide repeats, which encode aggregation-prone polyQ tracts. Substantial prior evidence supports a pathogenic role for polyQ protein misfolding and aggregation, with molecular chaperones showing promise in suppressing disease phenotypes in cellular and animal models. In this study, we developed a FRET-based reporter system that models polyQ aggregation in human cells and used it to perform a high-throughput CRISPR interference screen targeting all known molecular chaperones. This screen identified as a strong suppressor of polyQ aggregation the Hsp40 co-chaperone DNAJC7, which has previously been shown to modify aggregation of other disease proteins (tau and TDP-43) and has mutations causative for amyotrophic lateral sclerosis. We validated this phenotype and further established a physical interaction between DNAJC7 and polyQ-expanded protein. In contrast, DNAJC7 did not modify aggregation of polyglycine (polyG) in a FRET-based model of neuronal intranuclear inclusion disease. In addition to establishing new inducible, scalable cellular models for polyQ and polyG aggregation, this work expands the role of DNAJC7 in regulating folding of disease-associated proteins.}, } @article {pmid40832293, year = {2025}, author = {Inami, S and Jenny, BP and Akpoghiran, O and Gallagher, SI and Strich, AK and Tonoki, A and Trotti, D and Haeusler, AR and Koh, K}, title = {Increased neuronal activity restores circadian function in Drosophila models of C9orf72-ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40832293}, issn = {2692-8205}, support = {R21 NS135762/NS/NINDS NIH HHS/United States ; RF1 NS114128/NS/NINDS NIH HHS/United States ; }, abstract = {Circadian rhythm disruptions are common across neurodegenerative diseases, but their link to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. The C9orf72 hexanucleotide repeat expansion is the most prevalent genetic cause of ALS/FTD. Here, we used Drosophila models expressing toxic arginine-rich dipeptides (PR or GR) or GGGGCC hexanucleotide repeats to investigate circadian deficits in C9orf72-ALS/FTD. We found that circadian rhythmicity and period length were disrupted in a repeat number-, dosage-, and age-dependent manner. Additionally, we observed lower levels of the neuropeptide PDF, a key regulator of free-running circadian rhythms, as well as decreased projection complexity and reduced neuronal activity in PDF-expressing neurons. Importantly, increases in neuronal activity significantly restored circadian function under select conditions. These results implicate reduced neuronal activity in C9orf72-ALS/FTD circadian deficits, underscoring the importance of precisely tuned, circuit- and stage-specific interventions.}, } @article {pmid40832332, year = {2025}, author = {Garrett, TL and Wintermute, L and Armitage, M and Ward, S and Halim, IA and Mousa, MH and Gerber, K and Elbasiouny, SM}, title = {Circular continuum of alpha motoneuron types.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.08.12.669858}, pmid = {40832332}, issn = {2692-8205}, support = {R01 NS091836/NS/NINDS NIH HHS/United States ; R01 NS131816/NS/NINDS NIH HHS/United States ; }, abstract = {UNLABELLED: Alpha-motoneurons (α-MNs) are traditionally classified into slow (S), fast fatigue-resistant (FR), and fast-fatigable (FF), which exist along a continuum of properties between slow and fast, enabling the generation of graded force and seamless movement. Using combinations of markers, we developed novel immunohistochemistry protocols that enabled co-labeling of six major and transitional α-MN types throughout the mouse lumbar spinal cord with unprecedented detail. Intriguingly, our protocols labeled for the first time: α-MNs of the fast fatigue intermediate (FI) type; a previously undescribed transitional α-MN subtype (FR/FI); and a novel subtype of α-MNs exhibiting hybrid characteristics of both S and FF types - termed S/FF - which resist ALS degeneration. Electrophysiological recordings confirmed FR/FI and S/FF subtypes, both exhibiting mixed traits. The discovery of S/FF subtype reveals that α-MNs exist along a circular continuum between slow and fast types, challenging the traditional linear model and reshaping our understanding of their role in motor control.

NEW & NOTEWORTHY: This study introduces a novel immunohistochemistry protocol to co-label six distinct types of adult spinal cord motor neurons. This technical innovation led to a conceptual paradigm shift, revealing a circular continuum of motor neuron subtypes rather than a linear one. This new framework provides unprecedented precision for studying their varying susceptibility to degeneration in diseases like ALS, with broad implications for understanding motor control in health and disease.}, } @article {pmid40832740, year = {2025}, author = {Lang, C}, title = {Sleep alterations in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {38}, number = {5}, pages = {606-613}, pmid = {40832740}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Sleep Wake Disorders/etiology/physiopathology ; }, abstract = {PURPOSE OF REVIEW: This review summarizes recent evidence on sleep disturbances in amyotrophic lateral sclerosis (ALS), emphasizing their role as intrinsic features of the disease process rather than consequence of motor decline.

RECENT FINDINGS: Emerging data suggest that sleep disturbances such as sleep fragmentation, rapid eye movement sleep (REM) and non rapid eye movement sleep (NREM) alterations and circadian changes often precede classic motor symptoms. Structural and functional hypothalamic changes have been observed in early ALS, suggesting a direct role in sleep-wake dysregulation. In addition, impaired glymphatic clearance during sleep may contribute to neurodegeneration by impairing the removal of protein waste. Polysomnographic studies and cohort data support the presence of prodromal sleep abnormalities in both symptomatic patients and gene mutation carriers. Noninvasive ventilation has shown benefits not only in respiratory management but also in improving sleep quality and overall prognosis.

SUMMARY: Sleep alterations in ALS are increasingly recognized as early indicators and potential modulators of disease progression. The hypothalamus and the glymphatic system emerge as key contributors to these disturbances, highlighting sleep as a therapeutic target. Understanding the role of sleep in ALS pathophysiology may aid in earlier diagnosis and novel intervention strategies aimed at modifying disease course.}, } @article {pmid40832743, year = {2025}, author = {Verde, F}, title = {Neurochemical biomarkers of amyotrophic lateral sclerosis: recent developments.}, journal = {Current opinion in neurology}, volume = {38}, number = {5}, pages = {614-619}, doi = {10.1097/WCO.0000000000001411}, pmid = {40832743}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism/cerebrospinal fluid/blood ; *Biomarkers/blood/cerebrospinal fluid/metabolism ; *Neurofilament Proteins/cerebrospinal fluid/blood/metabolism ; DNA-Binding Proteins/blood ; tau Proteins/blood ; }, abstract = {REVIEW PURPOSE: To provide an overview of the recent developments in the field of neurochemical biomarkers of amyotrophic lateral sclerosis (ALS).

RECENT FINDINGS: Neurofilaments, especially NFL, have been confirmed to be good biomarkers for ALS. NFL may be diagnostically useful but its main role is as prognostic and pharmacodynamic biomarker. Inflammatory biomarkers, especially the chitinases, might also serve as pharmacodynamic biomarkers in treatment trials targeting neuroinflammation. GFAP could reflect cognitive-behavioural impairment. CSF dipeptides are diagnostic biomarkers for ALS caused by the C9ORF72 exanucleotide repeat expansion and may be used to confirm target engagement by experimental drugs. Levels of TDP-43 (virtually the ideal biomarker for ALS) in CSF and plasma have not been demonstrated to be consistently altered in ALS. However, promising advancements have been achieved in seed amplification assays for the protein, in its quantification in plasma extracellular vesicles, and in the measurement of CSF levels of a protein reflecting splicing dysfunction of TDP-43. Finally, blood phosphorylated tau has emerged as an ALS biomarker linked to lower motor neuron (or muscle) pathology.

SUMMARY: NFL is still the best neurochemical biomarker for ALS. However, substantial advances have been recently made, especially regarding detection of TDP-43 and blood phosphorylated tau.}, } @article {pmid40832750, year = {2025}, author = {Erdi-Krausz, G and Shaw, PJ}, title = {Antisense oligonucleotide therapy in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {38}, number = {5}, pages = {574-580}, doi = {10.1097/WCO.0000000000001413}, pmid = {40832750}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/drug therapy ; Humans ; *Oligonucleotides, Antisense/therapeutic use ; Animals ; C9orf72 Protein ; Superoxide Dismutase-1 ; *Genetic Therapy/methods ; Superoxide Dismutase/genetics ; DNA-Binding Proteins/genetics ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with few treatment options available. The approval of tofersen, an antisense oligonucleotide, for SOD1 -ALS by the FDA and EMA may herald a new era of treatment in these patients.

RECENT FINDINGS: So far, trials against the most common genetic form of ALS, C9orf72 , have been unsuccessful, but new preclinical data may show a promising new direction to take. Clinical trials targeting other, more rare genetic mutations associated with familial ALS are currently underway. Other research assessing the use of ASOs to target aberrant splicing associated with sporadic forms of ALS has also produced promising results in preclinical models, using patient-derived induced cellular models and animal models. These therapies are focussed largely on alleviating and reversing TDP-43 pathology, opening up the possibility of not only arresting disease progression, but reversing neurodegeneration.

SUMMARY: ASO therapies have made some promising steps towards treating familial ALS, particularly SOD1 . Ongoing early clinical/preclinical phase research is underway to utilise this technology in other genetic mutations linked with ALS, as well as in sporadic cases.}, } @article {pmid40833646, year = {2025}, author = {Das, B and Baruah, SMB and Roy, S and Bhattacharyya, DK}, title = {An effective framework to study signal transmission due to non-homogeneous extracellular space in neuron.}, journal = {Journal of biological physics}, volume = {51}, number = {1}, pages = {24}, pmid = {40833646}, issn = {1573-0689}, mesh = {*Extracellular Space/metabolism ; *Neurons/cytology/metabolism/physiology ; Neural Conduction ; *Models, Neurological ; Humans ; }, abstract = {Nerve conduction velocity studies are essential to understanding neurological disorders like ALS, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, carpal tunnel syndrome, sciatic nerve disorders, and multiple sclerosis, which are marked by slowed signal conduction. Various ions in the extracellular space (ECS) and the nerve fiber regulate signal propagation, making it crucial to analyze ECS's impact on signal transmission. This study examines how a non-homogeneous extracellular space affects nerve conduction velocity using a modified cable model that incorporates ECS parameters such as its diameter and resistance. The results suggest that a non-homogeneous extracellular space significantly impacts the conduction velocity of propagating signals, leading to variations in the conduction velocity, signal delays, phase shifts, and resonance. The model has been thoroughly examined using various combinations of electrophysiological parameters of the ECS and nerve fibers to simulate a wide range of biological conditions, and the simulated results have been consistent and align with the existing findings.}, } @article {pmid40835551, year = {2025}, author = {Rajsic, S and Treml, B and Breitkopf, R and Lederer, W}, title = {Ethical Considerations for Patients Requiring Extracorporeal Cardiopulmonary Resuscitation.}, journal = {Journal of cardiothoracic and vascular anesthesia}, volume = {39}, number = {12}, pages = {3541-3550}, doi = {10.1053/j.jvca.2025.07.032}, pmid = {40835551}, issn = {1532-8422}, mesh = {Humans ; *Extracorporeal Membrane Oxygenation/ethics/methods ; *Cardiopulmonary Resuscitation/ethics/methods ; *Heart Arrest/therapy ; }, abstract = {Immediate recognition of cardiac arrest and the initiation of cardiopulmonary resuscitation (CPR) can significantly improve survival chances. The use of extracorporeal membrane oxygenation during CPR (eCPR) could further enhance survival rates. Current evidence supports the implementation of eCPR as a part of the Advanced Life Support protocol, which may positively affect survival and long-term neurological outcomes and provide additional time for diagnosing and treating the underlying cause of cardiac arrest. Based on the patient's potential for recovery and neurological outcome, multidisciplinary teams can pursue weaning of the patient from mechanical support or withdrawal of care in the case of an unfavorable outcome. These decisions should align with the patient's values, prognosis, and ethical guidelines. A healthcare system that actively promotes eCPR as a standardized part of every Advanced Life Support protocol may face challenges, such as an increased number of patients requiring constant care in long-term care facilities. This could potentially lead to a reduced quality of life and create burdens on patients, families, the healthcare system, and society. Furthermore, in cases of potential organ donation, the principles of beneficence and autonomy may place healthcare providers in significant ethical dilemmas. Given the potential for eCPR to become a standard of care for eligible patients, this work focuses on the ethical and social implications, as well as the impact on the healthcare system.}, } @article {pmid40836724, year = {2025}, author = {Gupta, S and Tomar, S and Soni, R and Anadure, R and Somashekhar, M and Singhal, A}, title = {Efficacy and Safety of Edaravone in Amyotrophic Lateral Sclerosis: It is Safe but Does Not Stop Progression.}, journal = {The Journal of the Association of Physicians of India}, volume = {73}, number = {7}, pages = {68-71}, doi = {10.59556/japi.73.1044}, pmid = {40836724}, issn = {0004-5772}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/therapeutic use/adverse effects/administration & dosage ; Middle Aged ; Male ; Female ; Prospective Studies ; Disease Progression ; Riluzole/therapeutic use/administration & dosage ; Aged ; Adult ; India ; *Free Radical Scavengers/therapeutic use/adverse effects/administration & dosage ; Treatment Outcome ; Neuroprotective Agents/therapeutic use/administration & dosage ; }, abstract = {BACKGROUND: Edaravone is recommended for amyotrophic lateral sclerosis (ALS) based on a study showing an effect on a defined subset of patients.

AIM: To document the effect of edaravone in a cohort of ALS patients from India to find out if, after starting edaravone, there is a plateau period or significant slowing from baseline to compare results with existing literature.

METHODS: This was a single-center, prospective observational study with no control arm (due to ethical reasons). ALS patients >18 years of age, not requiring respiratory support or tube feeding, were included. All patients were given edaravone infusion in addition to standard of care and oral riluzole 50 mg twice daily. This consisted of giving the drug in monthly cycles over 6 months. The first cycle consisted of daily infusion of the drug for 14 days followed by a drug-free interval for the remaining part of the month. From cycle 2 to cycle 6, the patients received the drug for the first 10 days of the month followed by a drug-free interval for the remaining part of the month. The primary outcome was a significant change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score from baseline at 6 months. Secondary outcomes were monthly change in ALSFRS-R scores when compared with the previous month and baseline, change in the first 3 months compared to the change in the next 3 months, adverse drug effects, and number of deaths. The study was registered with the Indian Council of Medical Research Clinical Trial Registry of India with the trial number CTRI/2019/11/021838. Paired t-test was used for statistical analysis.

RESULTS: Thirty patients received the drug along with riluzole. Twenty-three patients completed all six monthly infusions. Two died (3 months), two developed adverse reactions (3 months) and did not want further infusions (one had breathing difficulty and the other had hypotension during infusion). Two withdrew consent due to perceived poor effectiveness of the drug. The mean ALSFRS-R at baseline was 35.17 [standard deviation (SD) 8.01; range 20-46]. The primary outcome showed a significant decline in the mean last available ALSFRS-R score 6 months by -4.9 (SD 1.21) (p < 0.01). For the secondary outcome measure, mean monthly ALSFRS-R score was calculated before each infusion after excluding dropouts. There was a significant monthly decline in ALSFRS-R score: -0.93 (SD 0.58), -1.0 (-0.52), -0.90 (SD 0.71), -0.87 (SD 0.61), -0.82 (SD 0.57), -0.95 (SD 0.63), respectively (p < 0.001). There was also a progressive monthly decline when compared to baseline. The rate of decline in the first 3 months was the same as in the remaining 3 months: -2.5 (SD 0.73) vs -2.6 (SD 0.98) (p = 0.3).

CONCLUSION: Edaravone infusion does not stop or significantly slow progression of disease from baseline but is safe.}, } @article {pmid40837837, year = {2025}, author = {Zhao, S and Chen, R and An, Y and Zhang, Y and Ma, C and Gao, Y and Lu, Y and Yang, F and Bai, X and Zhang, J}, title = {Correction: Optineurin overexpression ameliorates neurodegeneration through regulating neuroinflammation and mitochondrial quality in a murine model of amyotrophic lateral sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1670545}, doi = {10.3389/fnagi.2025.1670545}, pmid = {40837837}, issn = {1663-4365}, abstract = {[This corrects the article DOI: 10.3389/fnagi.2025.1522073.].}, } @article {pmid40837865, year = {2025}, author = {Khan, H and Riaz, H and Ahmed, A and Kiyani, MM and Jawad, SM and Ud Din Shah, SS and Abualait, T and Al-Hussain, F and Li, HT and Bashir, S}, title = {CRISPR/Cas9 a genomic engineering technology for treatment in ALS mouse models.}, journal = {Regenerative therapy}, volume = {30}, number = {}, pages = {575-583}, pmid = {40837865}, issn = {2352-3204}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by the death of motor neurons in the spinal cord and brain regions, leading to a reduced survival rate in patients. Nearly 20 gene mutations are associated with ALS, with SOD1, FUS, TARDBP, and C9orf72 mutations being more common. Ninety percent of ALS cases are related to sporadic ALS, while the remaining 10 % are associated with familial ALS. CRISPR/Cas9, a genome engineering technology known as clustered regularly interspaced short palindromic repeats/CRISPR-associated system 9, has the potential for gene editing and for studying the underlying mechanisms of ALS in mouse models. This technique enables neuroscientists to reverse mutations found in ALS mouse models, providing new hope for understanding the complexities of ALS. Additionally, this tool can create mutations to probe the functional changes of genetic diseases. Using CRISPR/Cas9 with an in vivo delivery method involving adeno-associated vectors, it is possible to silence mutations in the SOD1-linked ALS mouse model. Some limitations related to CRISPR/Cas9 have been discussed in previous studies and need to be addressed before clinical trials can proceed. In this review-based study, we summarise the latest research on CRISPR/Cas9 genome editing for ALS in mouse models and discuss its limitations and future prospects as well.}, } @article {pmid40838580, year = {2025}, author = {Tse, NY and Caga, J and Ahmed, RM and Mazumder, S and Nguyen, C and Huynh, W and Karjalainen, A and Timmins, HC and Ramsey, E and Talbot, DL and Halliday, GM and Kiernan, MC and Devenney, EM}, title = {Behavioral subtypes impact prognosis and survival in amyotrophic lateral sclerosis: a clustering-based approach.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {729-738}, doi = {10.1080/21678421.2025.2522402}, pmid = {40838580}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/psychology/diagnosis/complications ; Male ; Female ; Middle Aged ; Prognosis ; Cluster Analysis ; Cross-Sectional Studies ; Aged ; *Apathy/physiology ; Adult ; Cohort Studies ; }, abstract = {BACKGROUND: Behavioral impairments are well established in amyotrophic lateral sclerosis (ALS). A refined understanding of the contribution of delineated patterns of behavioral impairments to prognosis is vitally important.

METHODS: Leveraging data-driven two-step cluster analysis, we first stratified a large cross-sectional cohort of 170 ALS patients into distinct phenotypic subtypes based on their baseline behavioral profiles, as determined by the well-validated and informant-rated Motor Neuron Disease Behavioral Instrument (MiND-B). Mixed-effects model and multivariate Cox regression analyses were performed to compare rate of functional decline as measured by the revised ALS functional rating scale (ALSFRS-R) over follow-up assessments in 121 participants, as well as survival duration (n = 130), between the behavioral subtypes. Results: Clustering analysis yielded three behavioral phenotypes characterized by 1) intact behavioral functioning (n = 125), 2) apathy alone (n = 20), and 3) concurrent disinhibition and stereotypical behavior (n = 25). Apathy was associated with both significantly shorter survival (p = .003) and most rapid functional decline across follow-up assessments (both p <.001). Importantly, this pervasive effect was not observed in other behavioral cluster groups.

CONCLUSIONS: Extending previous cross-sectional work, current findings offer delineation of the trajectory of clinical outcomes associated with classic behavioral phenotypes of ALS. Converging with past evidence of unique disease and progression profile in ALS patients with apathy, our work provides strong support for behavioral change and in particular apathy as a reliable indicator of poor prognosis across cross-sectional and longitudinal markers of clinical outcomes.}, } @article {pmid40838713, year = {2026}, author = {Noor, SM and Reddy, DH and Srikanth, Y and Viswanadh, MK and Dumala, N and Chakravarthy, G and Nalluri, BN and Naryanarao, A and Duguluri, S and Yadagiri, G and Prasanna, VS and Sundaram, S and Gujjari, L and Ramakrishna, K}, title = {Morin hydrate: a comprehensive review on therapeutic potential in treating neurological diseases.}, journal = {Nutritional neuroscience}, volume = {29}, number = {1}, pages = {55-79}, doi = {10.1080/1028415X.2025.2544605}, pmid = {40838713}, issn = {1476-8305}, mesh = {*Flavonoids/therapeutic use/pharmacology ; Humans ; *Nervous System Diseases/drug therapy ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Flavones ; }, abstract = {Background: Morin hydrate is a polyphenolic flavonoid present in various vegetables, fruits, nuts, and sea products. It has been reported to offer multiple protective effects against a range of diseases, including cancer, cardiovascular, liver, neurological, metabolic, and renal disorders.Objective: This review highlights the molecular mechanisms and therapeutic potential of Morin in neurological diseases, including Parkinson's disease, Alzheimer's disease, traumatic brain injury, neuropathic pain, stroke, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, depression, anxiety, sleep, encephalopathy, schizophrenia, and psychosis, etc.Methods: The research and review articles were collected from the Pubmed, Scopus, Web of Science, and Google Scholar databases using 'Morin' and the above-mentioned neurological diseases as keywords.Results: The neuroprotective effects of Morin are primarily attributed to its ability to mitigate oxidative stress, inflammation, excitotoxicity, calcium dysregulation, mitochondrial dysfunction, neurotransmitter alterations, protein modifications, and enzymatic inhibition.Conclusion: Despite its promising pharmacological profile, the clinical adaptation of Morin for combating neurological diseases requires further validation through comprehensive preclinical and clinical investigations.}, } @article {pmid40838943, year = {2025}, author = {Hiraoka, T and Tamura, M and Moriguchi, Y and Kuji, R and Mino, T and Akiba, M and Takahashi, Y and Yoshino, K and Suzaki, A and Sugimoto, K and Oshika, T}, title = {Choroidal Thickness Distribution and Its Association With Axial Length and Spherical Equivalent in Schoolchildren Assessed by Wide-Field Swept-Source Optical Coherence Tomography.}, journal = {Translational vision science & technology}, volume = {14}, number = {8}, pages = {33}, pmid = {40838943}, issn = {2164-2591}, mesh = {Humans ; *Tomography, Optical Coherence/methods ; Child ; *Choroid/diagnostic imaging/anatomy & histology ; Adolescent ; Female ; Male ; Prospective Studies ; *Axial Length, Eye/diagnostic imaging ; Myopia ; }, abstract = {PURPOSE: The purpose of this study was to evaluate the distribution of choroidal thickness (ChT) in schoolchildren using wide-field swept-source optical coherence tomography (SS-OCT) and to investigate its association with axial length (AL) and spherical equivalent (SE).

METHODS: This prospective study included 176 eyes from 88 healthy Japanese schoolchildren aged 6 to 15 years (mean age = 9.9 ± 2.4 years). Wide-field SS-OCT was used to measure ChT across a 57 degrees × 57 degrees fundus area. After excluding poor-quality images, 169 eyes were included in the final analysis. The ChT distribution was evaluated by dividing the obtained images into a 3 × 3 grid comprising 9 sections. ChT measurements were performed automatically with custom-designed software. ChT values were compared among the nine regions, and correlations with AL and SE were assessed for each grid section. Additionally, the findings in schoolchildren were compared with historical data from adults.

RESULTS: Mean ChT values across the 9 regions ranged from 172 ± 29 µm in the nasal-inferior region to 307 ± 39 µm in the temporal region. The choroid was thicker in the temporal and macular regions and thinner around the optic disc and inferior regions. Significant negative correlations were found between ChT and AL across all regions (R = -0.50 to -0.23, P < 0.05), indicating that longer ALs were associated with thinner choroids. Similarly, significant positive correlations were observed between ChT and SE (R = 0.19 to 0.55, P < 0.05), demonstrating that higher degrees of myopia were associated with thinner choroids. Moreover, ChT in schoolchildren was generally thicker compared to that in adults.

CONCLUSIONS: This study provides a detailed analysis of ChT distribution in schoolchildren, revealing regional variability and a generally thicker choroid compared with adults. The significant correlations between ChT, AL, and SE across all regions suggest a potential role for ChT in ocular growth and myopia progression. These findings underscore the need for longitudinal studies to investigate causal relationships between ChT distribution and myopia development.

TRANSLATIONAL RELEVANCE: Wide-field choroidal mapping identifies early structural biomarkers for pediatric myopia progression and control.}, } @article {pmid40839108, year = {2025}, author = {Mukherjea, N and Khandelwal, A and Saluja, R and Kalra, N}, title = {The Role of the human microbiome in neurodegenerative diseases: A Perspective.}, journal = {Current genetics}, volume = {71}, number = {1}, pages = {17}, pmid = {40839108}, issn = {1432-0983}, mesh = {Humans ; *Neurodegenerative Diseases/microbiology ; *Microbiota ; Parkinson Disease/microbiology ; *Gastrointestinal Microbiome ; Alzheimer Disease/microbiology ; Inflammasomes ; Inflammation/microbiology ; }, abstract = {Advances in diagnostics, therapeutics, and large-scale clinical studies have significantly expanded our understanding how human health is shaped by the microorganisms that colonize the body since birth. This article explores the rapidly evolving field of human microbiome research, focusing upon how microbial communities influence neurological health and contribute to the development of neurodegenerative diseases (NDs). Multiple factors, including age, lifestyle, and immunological memory, are recognized as major determinants of an individual's microbiome composition, which in turn can influence the onset and the progression of disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These conditions have been linked to mechanisms including the aggregation of pathogenic proteins (e.g., amyloid-β and α-synuclein), inflammation driven by activation of the Toll-like receptor (TLR) signaling pathway, the NLRP3 inflammasome, as well as the modulatory effect of microbial metabolites such as short-chain fatty acids (SCFAs) and lipopolysaccharides (LPS). The article also highlights ongoing research and emerging strategies aimed at leveraging the human microbiome for better diagnosis, and management of NDs.}, } @article {pmid40839404, year = {2025}, author = {Li, Z and Jiang, J and Song, J and Bai, L and Pan, L}, title = {One Glutathione S-Transferase Gene, GSTU163, Was Involved in Mesosulfuron-methyl Resistance in Alopecurus japonicus.}, journal = {Journal of agricultural and food chemistry}, volume = {73}, number = {35}, pages = {21829-21841}, doi = {10.1021/acs.jafc.5c08615}, pmid = {40839404}, issn = {1520-5118}, mesh = {*Plant Proteins/genetics/metabolism ; *Glutathione Transferase/genetics/metabolism ; *Sulfonylurea Compounds/pharmacology ; *Herbicides/pharmacology ; *Herbicide Resistance ; *Poaceae/genetics/drug effects/enzymology ; Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; Gene Expression Regulation, Plant/drug effects ; }, abstract = {Alopecurus japonicus, an annual grass damaging wheat and canola fields in China, has evolved resistance to mesosulfuron-methyl, an acetolactate synthase (ALS)-inhibiting herbicide commonly used for its control. In this study, the resistant population (R) exhibited 22.93-fold resistance to mesosulfuron-methyl, and single-dose screening revealed cross-resistance to five other ALS-inhibiting herbicides. ALS gene sequencing revealed no known resistance mutations. Pretreatment with the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) increased the sensitivity of the R population to mesosulfuron-methyl. RNA-seq and quantitative real-time polymerase chain reaction (RT-qPCR) identified significant upregulation of one cytochrome P450 gene, two GST genes, and three glycosyltransferase genes, with AjGSTU163 showing the highest upregulation in the R population. Heterologous expression of AjGSTU163 in yeast significantly enhanced growth on mesosulfuron-methyl-containing media by mitigating ROS accumulation. Knockout of rice homologue OsGSTU163 slightly increased sensitivity to mesosulfuron-methyl in rice. This study first reported that GST contributes to mesosulfuron-methyl resistance in A. japonicus.}, } @article {pmid40840854, year = {2025}, author = {Fernàndez-Bernal, A and Mota, N and Pamplona, R and Area-Gómez, E and Portero-Otin, M}, title = {Mission cholesterol: Uncovering its hidden role in ALS neurodegeneration.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1871}, number = {8}, pages = {168021}, doi = {10.1016/j.bbadis.2025.168021}, pmid = {40840854}, issn = {1879-260X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Cholesterol/metabolism ; Animals ; Neurons/metabolism/pathology ; Endoplasmic Reticulum/metabolism/pathology ; Mitochondria/metabolism/pathology ; Astrocytes/metabolism/pathology ; }, abstract = {Cholesterol is a central determinant of membrane architecture, signaling, and cellular homeostasis in the central nervous system (CNS). While historically viewed as a structural component, emerging evidence highlights its dynamic regulatory role in neuronal function, particularly through its compartmentalized synthesis, trafficking, and turnover. This review examines the complex landscape of cholesterol metabolism in the CNS, emphasizing the cooperative roles of astrocytes and neurons, the partitioning of biosynthetic pathways, and the barriers that distinguish brain cholesterol pools from peripheral sources. We focus on mitochondria-associated endoplasmic reticulum membranes (MAMs) as key regulatory platforms for cholesterol sensing, esterification, and signaling, underscoring their emerging role in neurodegenerative diseases. Disruptions in MAM integrity, lipid raft composition, and transcriptional regulation of cholesterol-handling genes have been linked to pathologies such as amyotrophic lateral sclerosis (ALS), particularly through the actions of TDP-43. By consolidating recent findings from lipidomics, cell biology, and disease models, we propose that cholesterol dyshomeostasis constitutes a shared mechanistic axis across diverse neurodegenerative conditions. Understanding this axis offers novel insights into the metabolic vulnerability of neurons and highlights cholesterol metabolism as a promising target for therapeutic intervention.}, } @article {pmid40841001, year = {2025}, author = {Zheng, X and Jia, G and Zhao, Y and Yan, T}, title = {Involvement of four alga toxins in the risks of human neurodegenerative diseases: Toxicogenomic data mining and bioinformatics analysis.}, journal = {Journal of environmental sciences (China)}, volume = {158}, number = {}, pages = {151-164}, doi = {10.1016/j.jes.2025.02.036}, pmid = {40841001}, issn = {1001-0742}, mesh = {Humans ; *Neurodegenerative Diseases/chemically induced/epidemiology ; Computational Biology ; *Marine Toxins/toxicity ; Toxicogenetics ; Data Mining ; Amino Acids, Diamino/toxicity ; Okadaic Acid/toxicity ; Oxocins/toxicity ; Cyanobacteria Toxins ; Microcystins ; }, abstract = {Alga toxins have recently emerged as an environmental risk factor, especially to neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. However, the association between the alga toxins β-N-methylamino-L-alanine (BMAA), brevetoxin B, cyanoginosin LR, okadaic acid and neurodegenerative diseases remains inadequately investigated. Therefore, the aim of this study was to elucidate the potential associations. Four sets of differentially expressed genes related with BMAA, brevetoxin B, cyanoginosin LR and okadaic acid in Homo sapiens and genes linked to neurodegenerative disease development were respectively collected from the Comparative Toxicogenomic Database. Metascape analysis and cluster community analysis of four alga toxins highlighted protein-protein interaction enrichment and hub genes, while biological processes analysis showed that the dominant pathways involved in harmful effects triggered by four alga toxins were the apoptotic signaling pathway, regulation of amyloid protein formation, inflammatory response and endoplasmic reticulum stress. Genes related to the interactions between four alga toxins and neurodegenerative diseases were selected and analyzed, revealing that the relevant pathways and genes were those involved in apoptotic mitochondrial changes and neuroinflammatory response pathways. The adverse outcome pathway frameworks were constructed according to the analysis results for toxins and associated neurodegenerative diseases. These discoveries provide a new perspective for us to gain a deeper understanding of the neurotoxic effects of four alga toxins.}, } @article {pmid40841583, year = {2025}, author = {Watanabe, K and Ema, T and Shimizu, K and Yamada, K and Nakashima, M and Saitsu, H}, title = {A Japanese familial spastic paraplegia associated with a missense UBQLN2 variant.}, journal = {Journal of human genetics}, volume = {70}, number = {12}, pages = {645-648}, pmid = {40841583}, issn = {1435-232X}, support = {JP23K27566//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP25ek0109760//Japan Agency for Medical Research and Development (AMED)/ ; JP25ek0109674//Japan Agency for Medical Research and Development (AMED)/ ; JP25ek0109637//Japan Agency for Medical Research and Development (AMED)/ ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Adaptor Proteins, Signal Transducing/genetics ; Amyotrophic Lateral Sclerosis/genetics ; *Autophagy-Related Proteins/genetics ; *Cell Cycle Proteins/genetics ; Genetic Predisposition to Disease ; Japan ; *Mutation, Missense/genetics ; Pedigree ; *Spastic Paraplegia, Hereditary/genetics/pathology ; East Asian People/genetics ; }, abstract = {UBQLN2 is located on Xp11.21 and encodes the ubiquilin 2 protein involved in protein homeostasis. Heterozygous or hemizygous missense variants in UBQLN2 cause amyotrophic lateral sclerosis (ALS). In addition, rare cases of primary lateral sclerosis (PLS) and spastic paraplegia (SPG) associated with UBQLN2 variants have also been reported. Here, we report four male patients in a family with SPG carrying a hemizygous missense UBQLN2 variant (NM_013444.4:c.1442G>T, p.(Gly481Val)). These patients showed childhood-onset lower limb spasticity, progressing to gait disturbance. The mean onset age (11 years) was earlier than that of previous ALS (49.6 years), SPG (29 years) and PLS (25.5 years) cases, and their progression was slower than in ALS or PLS. Literature review reveals Pro506 missense variants are associated with various motor neuron disease phenotypes, with some SPG patients progressing to ALS. Therefore, we consider that careful follow-up is warranted for UBQLN2-related SPG patients.}, } @article {pmid40841608, year = {2025}, author = {Snow, M and Cameron, B and Pond, R and Trudell, R and Snyder, S and Torres-Hernandez, L and Deschamps, D and Tulimaiau, D and Hawkinson, K and Russell, M and Horan, D and Walters, J and Fox, JH and Arlian, B and Chariot, A and Nguyen, L and George, L}, title = {An Elongator mouse model of ALS spotlights TDP-43 in the motor neuron nucleolus.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {1259}, pmid = {40841608}, issn = {2399-3642}, support = {P20 GM103474/GM/NIGMS NIH HHS/United States ; R15 NS090384/NS/NINDS NIH HHS/United States ; P20GM103474//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R15NS090384//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Motor Neurons/metabolism/pathology ; *Cell Nucleolus/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; Mice ; Mice, Knockout ; Humans ; Spinal Cord/metabolism/pathology ; }, abstract = {Dysfunction of Elongator is associated with amyotrophic lateral sclerosis (ALS). Here, we describe mouse models in which either Elongator subunit 1(Elp1) or subunit 3 (Elp3) is selectively ablated in alpha motor neurons of the spinal cord. These mice exhibit a progressive loss of motor strength and motor neuron degeneration. To interrogate the molecular mechanisms that contribute to motor neuron cell death in these mice, we examine multiple disease pathways, including the expression of TDP-43 whose cytoplasmic aggregation is associated with the human disease. Although TDP-43 is a well-characterized nuclear protein functioning in RNA metabolism and gene transcription, here we document TDP-43's robust presence in the nucleolus of wild-type motor neurons and its clearance from both the nucleus and the nucleolus of motor neurons in Elp conditional knockout mice. Thus, this study directly links dysfunction of Elongator with nucleolar disruption and TDP-43 clearing, two hallmark cellular pathologies of ALS.}, } @article {pmid40843608, year = {2025}, author = {Marshall, A and Goul, R and Dodson, B and Sakidja, R and Peelaers, H and Seacat, S and Bray, K and Ewing, D and Walsh, M and Wu, JZ}, title = {Probing the Effects of the First Atomic Layer on the Dynamic Behavior of Sub-2 nm MgO/Al2O3 Memristors.}, journal = {ACS applied materials & interfaces}, volume = {17}, number = {35}, pages = {49930-49942}, doi = {10.1021/acsami.5c04654}, pmid = {40843608}, issn = {1944-8252}, abstract = {As electronic devices continue to scale down from the current sub-5 nm range, atomic-scale control of defects becomes increasingly crucial to suppressing their impact on the physical properties of the devices. Memristors present an excellent example of a nonlinear and dynamic device with high speed and endurance required for electronic applications ranging from neuromorphic computing to nonvolatile memories. Herein we investigate the impact of atomic defects in sub-2 nm thick MgO/Al2O3 atomic layer stack (ALS) memristors that use an M1 (switching layer)/M2 (oxygen vacancy reservoir layer) bilayer structure grown using in vacuo atomic layer deposition (iALD). Intriguingly, we revealed a direct correlation of the atomic defects in the M2 layer with the memristor dynamic behavior using combined analysis of in situ scanning tunneling spectroscopy (iSTS) on the M2 layer and ex situ characterization on the memristors. Specifically, incomplete coverage of the first ALD atomic layer of M2 on the electrode yields defects at the M2/electrode interface. Despite the monotonic increase of ALD coverage, by almost 3-fold from ∼30% to >90%, at completion of the M2 layer of ∼0.7 nm in thickness, the impact of the defects on the M2/electrode interface has been found to be detrimental to both memristor switching speed and endurance. Guided by atomistic simulation, we addressed the issue of interface defects via tuning of the Al surface hydroxylation to increase the first atomic layer ALD coverage to ∼75%, leading to improved memristor switching speed and endurance by several orders of magnitude. These findings shed light on the correlation between the atomic defects and the dynamic behavior of sub-2 nm memristors and the importance of minimizing the atomic defects in memristors for future electronic applications.}, } @article {pmid40843685, year = {2025}, author = {Epplen, ASC and Stahlke, S and Theiss, C and Matschke, V}, title = {Which One Would You Choose?-Investigation of Widely Used Housekeeping Genes and Proteins in the Spinal Cord of an Animal Model of Amyotrophic Lateral Sclerosis.}, journal = {NeuroSci}, volume = {6}, number = {3}, pages = {}, pmid = {40843685}, issn = {2673-4087}, abstract = {Amyotrophic lateral sclerosis (ALS) remains a progressive neurodegenerative disease, lacking effective causal therapies. The Wobbler mouse model harboring a spontaneous autosomal recessive mutation in the vacuolar protein sorting associated protein (Vps54), has emerged as a valuable model for investigating ALS pathophysiology and potential treatments. This model exhibits cellular and phenotypic parallels to human ALS, including protein aggregation, microglia and astrocyte activation, as well as characteristic disease progression at distinct stages. Exploring the underlying pathomechanisms and identifying therapeutic targets requires a comprehensive analysis of gene and protein expression. In this study, we examined the expression of three well-established housekeeping genes and proteins-calnexin, ß-actin, and ßIII-tubulin-in the cervical spinal cord of the Wobbler model. These candidates were selected based on their demonstrated stability across various systems like animal models or cell culture. Calnexin, an integral protein of the endoplasmic reticulum, ß-actin, a structural component of the cytoskeleton, and ß-tubulin III, a component of microtubules, were quantitatively assessed using quantitative reverse transcription-polymerase chain reaction (RT-PCR) for gene expression and Western blotting for protein expression. Our results revealed no significant differences in the expression of CANX, ACTB, and TUBB3 between spinal cords of wild-type and Wobbler mice at the symptomatic stage (p40) at both the gene and protein levels. These findings suggest that the pathophysiological alterations induced by the Wobbler mutation do not significantly affect the expression of these crucial housekeeping genes and proteins at p40. Overall, this study provides a basis for further investigations using the Wobbler mouse model, while highlighting the potential use of calnexin, ß-actin, and ßIII-tubulin as reliable reference genes and proteins in future research to aid in the discovery for effective therapeutic interventions.}, } @article {pmid40843943, year = {2026}, author = {Musson, LS and Baxter, SK and Norman, P and O'Brien, D and Elliott, M and Bianchi, S and Kaltsakas, G and Mcdermott, CJ and Hobson, EV and Stavroulakis, T}, title = {Perceptions of healthcare professionals on optimal delivery of noninvasive ventilation care to people living with motor neuron disease.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {125-132}, doi = {10.1080/21678421.2025.2539896}, pmid = {40843943}, issn = {2167-9223}, mesh = {Humans ; *Noninvasive Ventilation/methods ; *Motor Neuron Disease/therapy/complications/psychology ; *Health Personnel/psychology ; Focus Groups ; Female ; Male ; *Attitude of Health Personnel ; *Perception ; Qualitative Research ; Quality of Life ; }, abstract = {Background: Patients with motor neuron disease (MND) often do not experience the full survival and quality of life benefits of noninvasive ventilation (NIV). Successful delivery of NIV is challenging to multiple healthcare professionals involved in the respiratory care patient journey and considering their perspectives is crucial in order to understand how to deliver optimal care. Objective: To identify the factors that influence NIV delivery in MND from a healthcare professional perspective and understand how obstacles can be overcome to optimize care. Methods: Qualitative focus group discussions with healthcare professionals delivering respiratory care and support to MND patients in the UK and charity representatives. Results: Thirty healthcare professionals and three charity representatives participated in five focus groups. A range of factors that influence the delivery of NIV across the entire respiratory care pathway were identified. These were grouped under four main themes: multidisciplinary working; NIV service structure; professional further education and training; and good use of NIV and effective ventilation. Conclusions: There is a need for specific resources to support service delivery; frequent, funded, and structured training to support healthcare professionals to deliver good care; as well as ways to encourage optimal staff practice so patients get the best care.}, } @article {pmid40844737, year = {2025}, author = {Manini, A and Brusati, A and Grassano, M and Scacciatella, G and Peverelli, S and Spagliardi, J and Pensato, V and Doretti, A and Vasta, R and Manera, U and Canosa, A and Brunetti, M and Gentilini, D and Messina, S and Verde, F and Moglia, C and Morelli, C and Dalla Bella, E and Keagle, PJ and Landers, JE and Gellera, C and Lauria Pinter, G and Chiò, A and Ratti, A and Calvo, A and Silani, V and Ticozzi, N}, title = {Whole genome sequencing analysis in primary lateral sclerosis (PLS) patients reveals mutations in neurological diseases-causing genes.}, journal = {Journal of neurology}, volume = {272}, number = {9}, pages = {587}, pmid = {40844737}, issn = {1432-1459}, support = {RF-2021-12374238//Ministero della Salute/ ; RF-2018-12367768//Ministero della Salute/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; Aged ; *Motor Neuron Disease/genetics ; Adult ; *Mutation/genetics ; Whole Genome Sequencing ; }, abstract = {BACKGROUND: Primary Lateral Sclerosis (PLS) is a rare, adult-onset neurodegenerative disease that predominantly affects upper motor neurons. Despite being considered mostly sporadic, familial cases and rare genetic variants in genes associated with amyotrophic lateral sclerosis, hereditary spastic paraplegia and other neurological disorders have been reported in some PLS cases. Due to its rare prevalence among general population, large genetic studies of PLS are lacking.

METHODS: Fifty patients diagnosed with PLS based on consensus criteria were enrolled between 2013 and 2022 for comprehensive phenotypic and genotypic analysis using whole genome sequencing. We analyzed rare single nucleotide variants (SNVs), deemed pathogenic, likely pathogenic or of uncertain significance (VUS) based on the American College of Medical Genetics and Genomics criteria, and repeat expansions (REs) exceeding the pathogenic threshold, in 290 genes involved in neurological disorders.

RESULTS: We identified mutations in 7 patients (13.7%), specifically SNVs in CAPN1 (Spastic paraplegia 76), TBK1 (amyotrophic lateral sclerosis/frontotemporal dementia, ALS4/FTD), LITAF (Charcot-Marie-Tooth disease 1C), POLG (chronic progressive external ophthalmoplegia), APP (Alzheimer's disease) and OPTN (ALS12 ± FTD), and one RE in ATXN8OS (spinocerebellar ataxia 8). Additionally, two VUS were found in ANTXR2, a candidate gene for PLS recently identified via truncating variant collapsing analysis, but none of them was loss-of-function (one synonymous and one in-frame insertion).

CONCLUSIONS: Our study demonstrates a notable genetic intersection between PLS and various neurological disorders, including motor neuron diseases, neuropathies, mitochondrial disorders, ataxias, and dementias. These findings underscore the relevance of further investigation in larger cohorts to fully elucidate PLS genetic architecture and highlight the need to reconsider the role of genetic testing in its diagnostic criteria.}, } @article {pmid40844868, year = {2025}, author = {Ramgopal, S and Cash, RE and Martin-Gill, C}, title = {Agency-Level Factors Associated with EMS Volume for High-Impact Clinical Conditions and Patient Populations.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/10903127.2025.2550598}, pmid = {40844868}, issn = {1545-0066}, abstract = {BACKGROUND: Emergency medical services (EMS) agencies play a crucial role in delivering prehospital care, yet significant variability exists in EMS call volume and the conditions encountered. Variation in EMS call volume across agencies (i.e., high- vs. low-frequency) for specific patient populations and clinical presentations across EMS agencies can have substantial impact on implementation strategies for new guidelines and performance measures. We sought to evaluate agency-level factors associated with EMS volume of specific clinical presentations to inform the planning of targeted quality improvement efforts and resource allocation related to specific high-impact clinical categories.

METHODS: We conducted a retrospective analysis of the 2022 and 2023 National EMS Information System datasets, identifying EMS agencies that consistently reported patient encounters over a two-year period. We categorized encounters by key patient populations and clinical presentations, including cardiac arrest, trauma, stroke, pediatric cases, advanced airway management, and non-transport disposition. We used negative binomial regression to assess factors associated with EMS volumes.

RESULTS: We included 7,230 EMS agencies, with 55,705,469 encounters. The median number of encounters by EMS agency was 1,988 encounters averaged per year (IQR 706-5,584 encounters averaged per year). Cardiac arrest was more frequent in mixed/volunteer agencies and less common in for-profit, non-hospital, and tribal-based EMS services. Trauma volume was higher in advanced life support (ALS) and critical care agencies, the West (relative to Midwest), and mixed/volunteer agencies (relative to non-volunteer agencies). Stroke volume was linked to greater ALS/critical care agencies and mixed/volunteer agencies but was lower in urban areas. Pediatric encounters were more common in urban, mixed/volunteer agencies, and tribal services but less frequent in for-profit and hospital-based agencies. Airway interventions were associated with ALS/critical care agencies, but were less frequent in tribal agencies. Non-transport occurred more commonly in ALS agencies and tribal agencies.

CONCLUSIONS: Distinct patterns of agency-level characteristics appear to exist in relation to the volume of EMS responses for specific patient populations and clinical presentations. These findings can inform agency-specific strategic planning for guideline implementation, resource allocation, and quality improvement in prehospital care.}, } @article {pmid40845103, year = {2025}, author = {Neeves, J and Petrić Howe, M and Ziff, OJ and Callaghan, B and Jutzi, D and Pal, K and Roumeliotis, TI and Choudhary, J and Isaacs, AM and Rigo, F and Bennett, CF and Ruepp, MD and Patani, R}, title = {An alternative cytoplasmic SFPQ isoform with reduced phase separation potential is up-regulated in ALS.}, journal = {Science advances}, volume = {11}, number = {34}, pages = {eadt4814}, pmid = {40845103}, issn = {2375-2548}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Cytoplasm/metabolism ; Protein Isoforms/genetics/metabolism ; *Alternative Splicing ; *PTB-Associated Splicing Factor/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Cell Nucleus/metabolism ; *Up-Regulation ; Animals ; Phase Separation ; }, abstract = {Splicing factor proline- and glutamine-rich (SFPQ) is an RNA binding protein that broadly regulates RNA metabolism. Although its nuclear roles are well studied, evidence of SFPQ's cytoplasmic functionality is emerging. Altered expression and nuclear-to-cytoplasmic redistribution of SFPQ have been recognized in amyotrophic lateral sclerosis (ALS) pathology, yet the mechanistic bases for these phenomena remain undetermined. We identified altered SFPQ splicing in ALS, increasing the expression of an alternative mRNA isoform lacking a nuclear localization sequence, which we termed "altSFPQ." We find that altSFPQ mRNA contributes to SFPQ autoregulation and is highly unstable yet exhibits context-specific translation with cytoplasm-predominant localization. Notably, reduced canonical SFPQ coincides with increased altSFPQ transcript expression in familial and sporadic ALS models, providing a mechanistic basis for SFPQ nuclear-to-cytoplasmic redistribution in patients with ALS. Last, we observe that the altSFPQ protein has reduced phase separation potential and differential protein binding compared to its canonical counterpart, providing insight into its mechanistic relevance to physiology and ALS pathogenesis.}, } @article {pmid40846833, year = {2025}, author = {Won, W and Lee, EH and Gotina, L and Chun, H and Lee, JH and Bhalla, M and Park, U and Kim, D and Kim, TY and Choi, JW and Kim, Y and Park, SJ and Lim, J and Park, JH and Kim, HJ and Heo, JY and Chung, W and Oh, MJ and An, HJ and Lee, J and Oh, SJ and Ryu, H and Pae, AN and Park, KD and Lee, CJ}, title = {Hemoglobin as a pseudoperoxidase and drug target for oxidative stress-related diseases.}, journal = {Signal transduction and targeted therapy}, volume = {10}, number = {1}, pages = {270}, pmid = {40846833}, issn = {2059-3635}, support = {R01 NS109537/NS/NINDS NIH HHS/United States ; IBS-R001-D2//Institute for Basic Science (IBS)/ ; }, mesh = {*Oxidative Stress/drug effects/genetics ; Humans ; Hydrogen Peroxide/metabolism ; Animals ; *Hemoglobins/metabolism/genetics ; *Alzheimer Disease/drug therapy/genetics/pathology/metabolism ; Astrocytes/metabolism/drug effects/pathology ; Mice ; *Parkinson Disease/drug therapy/genetics/pathology/metabolism ; Dopaminergic Neurons/metabolism/pathology/drug effects ; }, abstract = {Hemoglobin (Hb) is well known for transporting oxygen in the blood, but its role in the brain remains poorly understood. Here, we identified Hb in the cytosol, mitochondria, and nuclei of hippocampal and substantia nigra astrocytes and dopaminergic neurons. As a pseudoperoxidase, Hb decomposes hydrogen peroxide (H2O2) and mitigates H2O2-induced oxidative damage. However, in Alzheimer's disease, Parkinson's disease, and aging, excessive H2O2 diminishes astrocytic Hb, perpetuating a vicious cycle of oxidative stress and neurodegeneration. To counter the harmful effects of aberrant H2O2 production in diseases, we developed KDS12025, a BBB-permeable small molecule that enhances Hb pseudoperoxidase activity 100-fold, even at a low level of Hb. KDS12025 and its analogs achieve this enhancement through its electron-donating amine group, possibly stabilizing the complex between Hb, H2O2, and KDS12025. KDS12025 reduces astrocytic H2O2, alleviates astrogliosis, normalizes Hb, and reverts to a virtuous cycle of redox balance, preventing neurodegeneration without altering the oxygen-transport function of Hb. Gene silencing of Hb abrogates the impact of KDS12025 in both culture and animal models, confirming the necessity of Hb for the effects of KDS12025. KDS12025 extends survival and improves motor function even in severe amyotrophic lateral sclerosis and aging. Furthermore, the enrichment of astrocytic Hb in the nucleolus highlights a novel antioxidative mechanism potentially protecting against nuclear oxidative damage. Our findings suggest that Hb is a new therapeutic target for neurodegenerative diseases, with KDS12025 emerging as a first-in-class approach that enhances Hb pseudoperoxidase activity to reduce H2O2. Increasing Hb pseudoperoxidase activity with KDS12025 mitigates oxidative stress and alleviates neurodegeneration in AD, PD, and ALS patients and increases the degree of aging, with broad applicability for numerous oxidative-stress-driven diseases.}, } @article {pmid40847737, year = {2025}, author = {Novikov, V and Timothy, LTC and Fan, J and Sadek, K and Cowan, MF and Onuska, KM and Duennwald, M and Prado, VF and Prado, MAM}, title = {A Longitudinal Study of Sex Differences in a TDP-43 Mouse Model Reveals STI1 Regulation of TDP-43 Proteinopathy and Motor Deficits.}, journal = {Journal of neurochemistry}, volume = {169}, number = {8}, pages = {e70204}, pmid = {40847737}, issn = {1471-4159}, support = {03592-2021 RGPIN//Natural Sciences and Engineering Research Council of Canada/ ; 06577-2018 RGPIN//Natural Sciences and Engineering Research Council of Canada/ ; //Canadian Institutes of Health Research CGS-D/ ; //ALS Society of Canada/ ; PJT 159781/CAPMC/CIHR/Canada ; PJT 162431/CAPMC/CIHR/Canada ; //Canadian Institutes of Health Research CGS-M/ ; }, mesh = {Longitudinal Studies ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/physiopathology ; Sex Factors ; *DNA-Binding Proteins/genetics/metabolism ; Protein Folding ; HSP90 Heat-Shock Proteins/genetics/metabolism ; Brain/metabolism/pathology ; Spinal Cord/metabolism/pathology ; Disease Models, Animal ; *Proteostasis/genetics ; Mice, Inbred C57BL ; Mice, Transgenic ; Male ; Female ; Humans ; *Heat-Shock Proteins/genetics/metabolism ; Motor Activity/genetics ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease influenced by a complex interplay of age, genetics, and sex. Most ALS cases are sporadic, and individuals with this disease show elevated levels of TDP-43 in their central nervous system and aggregated cytoplasmic inclusions containing TDP-43 in neurons. Misfolded and aggregated proteins like TDP-43 can be refolded or marked for degradation by molecular chaperones and their co-chaperone partners. In this study, we use a mouse model of ALS that mildly overexpresses human wild-type TDP-43 in neurons to explore how aging affects the onset of motor abnormalities and proteinopathy in male and female mice. We found that the age-dependent onset of motor symptoms is more pronounced in male mice, despite both sexes sharing similar TDP-43 pathology. Further, we found that reducing the activity of STI1, an Hsp90 co-chaperone, was associated with reduced mislocalized TDP-43 in the brain and spinal cord and partially rescued some motor deficits. By contrast, overexpressing STI1 seemed to be deleterious, exacerbating the levels of C-terminal TDP-43 fragments in the cytoplasm, worsening motor abnormalities and reducing lifespan. Our findings reveal that sex is a key biological factor in an ALS mouse model of TDP-43 overexpression and provide novel insights on the role of STI1 and proteostasis in mediating TDP-43 pathology.}, } @article {pmid40847753, year = {2025}, author = {Yang, M and Wang, Q and Yan, R and Wang, X and Gu, J}, title = {Dimer-Specific FokT-seq Reveals DNA-Binding Dimerization and Novel Genomic Targets of TDP-43.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {42}, pages = {e08902}, pmid = {40847753}, issn = {2198-3844}, support = {32171258//National Natural Science Foundation of China/ ; 82330041//National Natural Science Foundation of China/ ; 92049107//National Natural Science Foundation of China/ ; 2022-72-18//Department of Science and Technology of Hubei Province/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *DNA/metabolism/genetics ; Protein Multimerization ; Protein Binding ; Dimerization ; }, abstract = {In postmortem brain tissues of patients with sporadic amyotrophic lateral sclerosis (ALS), the dimerization ability of TAR DNA-binding protein 43 (TDP-43) is impaired, accompanied by an accumulation of insoluble TDP-43. Thus, the loss of TDP-43 dimerization may play a critical driving role in ALS pathogenesis, although its underlying mechanism remains unclear. In this study, the FokT (FokI-TDP-43) system is developed, which fuses TDP-43 protein with FokI nuclease. By restoring TDP-43 dimerization, this system reactivates FokI nuclease activity, enabling the cleavage of DNA targets bound by TDP-43. Additionally, the FokT-seq (FokT combined with genome-wide unbiased identification of DNA double-strand breaks enabled by sequencing, Guide-seq) method is established, allowing genome-wide detection of DNA sites bound by dimerized TDP-43. These findings reveal the essential role of TDP-43 dimerization in DNA binding, identify a series of related targets. Furthermore, this study offers a powerful tool for investigating dimerized transcription factors.}, } @article {pmid40848171, year = {2026}, author = {Xu, H and Shao, Y and Zhang, J and Ni, Y and Xu, G and Liu, C and Liang, Y and Le, W}, title = {HSF-1 Regulates Autophagy to Govern Motor Function and Facilitate Toxic Protein Clearance in a C. elegans Model of Amyotrophic Lateral Sclerosis.}, journal = {Neuroscience bulletin}, volume = {42}, number = {4}, pages = {744-764}, pmid = {40848171}, issn = {1995-8218}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Caenorhabditis elegans ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Autophagy/physiology ; Disease Models, Animal ; *Transcription Factors/metabolism/genetics ; Motor Neurons/metabolism/pathology ; Animals, Genetically Modified ; Signal Transduction ; Locomotion/physiology ; }, abstract = {Heat shock factor-1 (HSF-1) plays a crucial role in orchestrating stress responses across diverse organisms and disease conditions. Here, we investigate how the HSF-1 signaling pathway influences the degradation of toxic proteins and neuropathological changes in the Caenorhabditis elegans model of amyotrophic lateral sclerosis (ALS). We found that overexpressing HSF-1 improves locomotor ability and increases the survival rate of ALS C. elegans. Moreover, we observed a deceleration of motor neuron degeneration, demonstrating the protective effect of HSF-1 on neurodegenerative processes. Transcriptomic analysis revealed notable changes in genes associated with autophagy and neurodegeneration, underscoring HSF-1's critical involvement in ALS pathology. In addition, metabolomic profiling further highlighted the involvement of this pathway in metabolic reprogramming. Overall, our study underscores the critical role of the HSF-1 signaling pathway in improving survival rate, movement velocity, cellular integrity, and metabolic adaptation, providing new insights into the mechanisms underlying ALS and potential targets for therapeutic intervention.}, } @article {pmid40848497, year = {2026}, author = {Jiang, W and Su, Y and Guo, M and Wang, X and Liu, H and Liu, X and Zhang, Y}, title = {Detection of aging-induced vascular remodeling based on Raman imaging and deep learning.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {345}, number = {}, pages = {126832}, doi = {10.1016/j.saa.2025.126832}, pmid = {40848497}, issn = {1873-3557}, mesh = {*Spectrum Analysis, Raman/methods ; Animals ; *Deep Learning ; *Aging/pathology ; *Vascular Remodeling ; Mice ; Male ; Aorta/diagnostic imaging ; Mice, Inbred C57BL ; Muscle, Smooth, Vascular ; Collagen/metabolism ; }, abstract = {Vascular aging-related remodeling is a common pathological basis for many chronic diseases, so early detection of physical arterial aging is important for their prevention and control. Existing staining methods can only analyze a limited number of tissue components at a time and often suffer from inaccuracies caused by over- or under-staining. In this study, we performed high-quality Raman imaging to simultaneously analyze five components in mouse aortic sections: elastic fibers, types I and III collagen fibers, nuclei, and cytoplasm of vascular smooth muscle cells (VSMCs), detailing their content and distribution changes. Despite subtle differences in Raman spectra, young and aged aortic tissues were successfully distinguished using multivariate curve resolution-alternating least squares (MCR-ALS) analysis and deep learning, achieving an AUC of 0.986 (95 % CI: 0.979-0.992). Additionally, Raman imaging and metabolomics revealed metabolic changes in arterial aging related to collagen synthesis and post-modifications, offering new potential therapeutic targets. Thus we show that Raman imaging combined with advanced algorithms is potentially useful in detecting vascular-aging remodeling, as well as monitoring the aging process.}, } @article {pmid40848625, year = {2025}, author = {Gauden, AJ and Gu, B and Han, S and Telischak, NJ and Dodd, R and Do, HM and Marks, MP and Steinberg, GK}, title = {Multimodality treatment maximizing outcome in spinal dural arteriovenous fistulae.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {141}, number = {}, pages = {111571}, doi = {10.1016/j.jocn.2025.111571}, pmid = {40848625}, issn = {1532-2653}, mesh = {Humans ; *Central Nervous System Vascular Malformations/therapy/diagnostic imaging/surgery ; Male ; Female ; Middle Aged ; Retrospective Studies ; *Embolization, Therapeutic/methods ; Treatment Outcome ; Adult ; Aged ; Combined Modality Therapy/methods ; Microsurgery/methods ; Endovascular Procedures/methods ; Spinal Cord ; Young Adult ; *Neurosurgical Procedures/methods ; Adolescent ; }, abstract = {BACKGROUND: Spinal dural arteriovenous fistula (sDAVF) is a rare cause of myelopathy and progressive paraplegia. sDAVFs are the most frequent type of spinal vascular malformation and comprise 70 % of all vascular spinal malformations. Despite the availability and published efficacy of both microsurgical resection and endovascular embolization, the optimal treatment for sDAVFs remains to be determined. We aimed to assess the efficacy of a multimodal treatment approach to sDAVFs at our institution.

METHODS: A retrospective review of all sDAVFs treated between 1998 and 2021 at Stanford Hospital and Clinics was conducted. The medical records were inspected and data, including presenting symptoms, duration, angiographic features, and treatment modality, were extracted. Cure was defined as the absence of an arteriovenous fistulous connection on digital subtraction angiography and radiologic improvement on follow-up MRI. Functional outcomes were assessed at presentation and at last follow-up using the Aminoff-Logue Scale (ALS).

RESULTS: 47 patients underwent treatment of sDAVFs between August 1998 to May 2021. As an initial treatment, 32 patients underwent microsurgical excision, and 15 had endovascular embolization. Radiological cure was achieved in 84.4 % of patients during the first treatment and in 97.9 % of patients at the final treatment time point. At initial treatment, surgery cured the sDAVF in 84.4 % of patients, with endovascular embolization curing in 86.7 % of patients. When assessed as an additional treatment for failed prior treatment, surgery achieved cure in 80 % of patients and endovascular embolization in 100 % of patients. At all time points, high cure rates were observed, with success rates achieving 96.9 % and 100 % for surgery and endovascular embolization, respectively. A significant improvement in ALS Gait score was noted after treatment, with a mean reduction of 0.6 from baseline (p = 0.0003). A similar improvement trend was observed in the ALS Micturition score with a mean decrease of 0.3 points (p = 0.057).

CONCLUSIONS: Our study demonstrates high efficacy for cure and improved functional outcomes in both surgical and endovascular treatments, assuming good patient selection. This series also highlights the importance of a multimodality treatment approach in managing spinal dural arteriovenous fistulae. Further delineation is required to determine the radiological and patient factors that might recommend specific initial treatment modalities.}, } @article {pmid40848858, year = {2025}, author = {Chen, X and Ma, Y and Liu, H and Wang, Y}, title = {Multifunctional regulation and treatment of ubiquitin specific protease 10.}, journal = {Biochemical pharmacology}, volume = {242}, number = {Pt 1}, pages = {117251}, doi = {10.1016/j.bcp.2025.117251}, pmid = {40848858}, issn = {1873-2968}, mesh = {Humans ; *Ubiquitin Thiolesterase/metabolism/antagonists & inhibitors/chemistry/genetics ; Animals ; Neoplasms/drug therapy/metabolism/enzymology ; Neurodegenerative Diseases/drug therapy/enzymology/metabolism ; }, abstract = {USP10 is a critical deubiquitinating enzyme within the ubiquitin-specific protease family, playing multifaceted roles in cellular physiology and disease pathogenesis. Structurally composed of a G3BP1-interacting motif, a N-terminal domain (mediating most protein interactions), and a catalytic USP domain (residues 415-795, catalytic triad C424-H736-D751), USP10 regulates diverse cellular pathways by stabilizing key proteins through deubiquitination. It exhibits context-dependent functional duality, particularly in cancer: USP10 promotes tumorigenesis in various cancers (e.g., glioblastoma, esophageal, pancreatic, breast cancers) by stabilizing oncoproteins like CCND1, YAP1, HDAC7, and RUNX1, enhancing proliferation, metastasis, and immune evasion. Conversely, it suppresses tumors (e.g., NSCLC, CRC, thyroid cancer) by stabilizing tumor suppressors like p53, PTEN, and Axin1, inhibiting pathways such as Wnt/β-catenin. Beyond oncology, USP10 contributes to neurodegenerative diseases (neuroprotective in PD/ALS, neurotoxic in AD via Tau stabilization), viral immunity (inhibits SARS-CoV-2 infection), inflammatory responses, male reproduction, and metabolic/cardiovascular disorders. Its regulatory mechanisms include phosphorylation (e.g., by AMPK, AKT, ATM) controlling subcellular localization and activity, and ubiquitination via USP13. USP10's therapeutic significance drives inhibitor development (Spautin-1, D1, Wu-5, P22077, Parthenolide), though cross-reactivity within the USP family due to conserved catalytic domains remains a challenge. Novel strategies like PROTACs and engineered ubiquitin variants (UbVs) offer promise for future selective targeting of USP10 dysregulation in diverse diseases. A comprehensive understanding of its structure and context-specific functions is essential for exploiting its full therapeutic potential.}, } @article {pmid40849231, year = {2026}, author = {Fu, X and Gable, K and Gupta, SD and Zhang, K and Jia, B and Wang, W and Yang, X and Wang, L and Ge, L and Bönnemann, CG and Dunn, TM and Xiong, H}, title = {Characterization of novel and recurrent SPTLC2 variants in childhood-onset amyotrophic lateral sclerosis: Insights into sphingolipid dysregulation.}, journal = {Journal of neuromuscular diseases}, volume = {13}, number = {4}, pages = {655-664}, pmid = {40849231}, issn = {2214-3602}, mesh = {Child ; Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology ; Exome Sequencing ; Mutation ; *Serine C-Palmitoyltransferase/genetics ; *Sphingolipids/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder that progressively affects motor neurons. Gain-of-function mutations in serine palmitoyltransferase (SPT) genes, notably SPTLC1 and SPTLC2, have been linked to juvenile ALS. Here, we describe two childhood-onset ALS cases with distinct SPTLC2 mutations, providing new insights into sphingolipid dysregulation and its role in ALS pathogenesis.

MATERIAL AND METHODS: Two Chinese patients with early-onset ALS, both carrying SPTLC2 mutations, were recruited from Beijing Children's Hospital. We conducted whole-exome sequencing (WES) to identify genetic variants, followed by Sanger sequencing for validation. Sphingolipid profiles were analyzed using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Clinical evaluations included neurological assessments, brain MRI and electromyography. Additionally, mutant cell lines were established to assess the functional effects of the specific mutations.

RESULTS: Patient 1, a 6-year-old male, exhibited a novel heterozygous de-novo SPTLC2 variant (c.197T > G, p.T66R). Patient 2, a 7-year-old female, had a recurrent heterozygous de-novo SPTLC2 variant (c.778G > A, p.E260K). Both patients showed elevated levels of specific sphingolipids compared to controls, with distinct profiles between the SPTLC2-ALS and SPTLC1-hereditary sensory and autonomic neuropathy type 1 (HSAN1) cases. The novel p.T66R mutation was predicted to alter protein interactions within the SPT complex, potentially impairing sphingolipid homeostasis. Functional studies further revealed that the p.T66R variant reduces the inhibitory regulation of SPT by ORMDL proteins, leading to unrestrained SPT activity and excess sphingolipid production.

CONCLUSIONS: Our findings identify a novel SPTLC2 variant linked to childhood-onset ALS and reveal altered sphingolipid profiles associated with different genetic mutations. These results underscore the importance of sphingolipid metabolism in ALS and suggest potential avenues for targeted therapeutic interventions. Further research is needed to explore treatment options aimed at modulating sphingolipid levels and correcting genetic defects, as well as investigating potential biomarkers for early diagnosis.}, } @article {pmid40849485, year = {2025}, author = {Helal, MM and AbouShawareb, H and Abbas, OH and Haddad, R and Zain, Y and Osman, ASA and Hassan, AK}, title = {GLP-1 receptor agonists in Parkinson's disease: an updated comprehensive systematic review with meta-analysis.}, journal = {Diabetology & metabolic syndrome}, volume = {17}, number = {1}, pages = {352}, pmid = {40849485}, issn = {1758-5996}, abstract = {Previous studies have demonstrated an increased risk of developing Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM), as well as more severe and rapid motor and non-motor deterioration in diabetic PD patients compared to their non-diabetic counterparts. Additional research has suggested that diabetic subjects treated with glucagon-like peptide-1 (GLP-1) receptor agonists exhibit a reduced incidence of PD compared to those receiving other anti-diabetic medications. GLP-1 receptor agonists are FDA-approved therapies for T2DM, and recent studies have explored their potential as repurposed treatments for neurodegenerative diseases, including PD, AD, and ALS, as well as cerebrovascular disorders. This systematic review aims to assess the available literature on the efficacy and safety profiles of GLP-1 receptor agonists in PD management. A comprehensive search of PubMed, Scopus, CENTRAL, Web of Science, Embase, and ClinicalTrials.gov was conducted to identify relevant studies. The primary outcomes of this review include motor impairment in PD, as assessed by MDS-UPDRS Part III, as well as motor complications (Part IV) and motor experiences of daily living (Part II), and the incidence of gastrointestinal and systemic side effects. Meta-analysis showed that GLP-1 receptor agonists significantly improved motor function, as reflected by MDS-UPDRS Part III scores in the ON state (mean difference = - 2.88; p = 0.01; I[2] = 30%), although they were associated with a higher incidence of adverse events across all safety outcomes. Findings and conclusions of this review will contribute to a clearer understanding of the therapeutic potential of GLP-1 receptor agonists in PD, guiding future clinical research and treatment strategies.}, } @article {pmid40849781, year = {2025}, author = {Kurochkina, N and Rudrabhatla, P}, title = {Role of Calmodulin in Neurodegeneration and Neuroprotection.}, journal = {Mini reviews in medicinal chemistry}, volume = {25}, number = {13}, pages = {965-974}, pmid = {40849781}, issn = {1875-5607}, support = {1142025//School of Theoretical Modeling, Washington, DC, USA/ ; }, mesh = {*Calmodulin/metabolism/chemistry/antagonists & inhibitors ; Humans ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; Animals ; *Neuroprotection ; *Neuroprotective Agents/pharmacology/chemistry ; Calcium/metabolism ; }, abstract = {Intracellular calcium (Ca[2+]) levels are critical in maintaining cellular activities and are tightly regulated. Neuronal degeneration and regeneration rely on calcium-binding proteins. Calmodulin (CaM) is a calcium sensor and the primary regulator of receptors and ion channels that maintain calcium homeostasis. The calmodulin binding domains are present in proteins that serve as risk factors and biomarkers associated with Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and other neurodegenerative diseases, suggesting calmodulin ligands as emerging therapeutic targets for treatment. Inhibiting CaM to develop new therapies has drawbacks, as CaM is a ubiquitous molecule involved in many regulatory pathways. Recently, new strategies for disrupting CaM interactions with its targets have shown promising approaches to treatment. The structures of human CaM, its binding proteins, and inhibitors are well studied, with particular emphasis on the conservation of CaM amino acid sequences and the ability to bind protein fragments of high sequence variability, which exhibit common characteristics of amphipathic helices carrying basic amino acids. In this review, we discuss structural characteristics of CaM and its ligands in the context of transcriptional regulation. Specific binding of CaM to (1) basic region/helix-loop-helix/leucine zipper and (2) helix-turn-helix high mobility group box containing Sox families of transcription factors highlights common features of CaM binding sequences, which suggest their regulatory functions. We describe key proteins involved in neurodegeneration and transcription factors subject to calmodulin regulation that are candidates for the development of new approaches to treating neuronal diseases.}, } @article {pmid40851280, year = {2026}, author = {Tröger, J and Rouvalis, A and Dörr, F and Schwed, L and Linz, N and König, A and Machts, J and Vielhaber, S and Thies, T and Prudlo, J and Hermann, A and Kasper, E}, title = {Automatically measured speech intelligibility models bulbar-specific disease severity and progression in Amyotrophic Lateral Sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {101-109}, doi = {10.1080/21678421.2025.2549317}, pmid = {40851280}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/diagnosis ; Male ; Female ; Disease Progression ; Middle Aged ; *Speech Intelligibility/physiology ; Aged ; Cross-Sectional Studies ; Longitudinal Studies ; Severity of Illness Index ; Adult ; *Speech Disorders/etiology/diagnosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to widespread motor deterioration, including significant motor speech impairments. Speech intelligibility is a crucial component of communication affected in ALS, requiring objective, scalable assessment methods as an indicator of disease progression and treatment efficacy. Objective: This study investigates whether speech and bulbar function in ALS could be evaluated and monitored utilizing an automated digital measure of speech intelligibility derived from naturalistic picture descriptions. Methods: Speech recordings from 44 patients living with ALS (plwALS) and 49 matched healthy controls (HC) were analyzed and processed utilizing an automated speech analysis pipeline to extract an intelligibility score. These were part of a cross-sectional and longitudinal study involving two assessments. Results: The findings confirmed that speech intelligibility is significantly reduced in plwALS compared to HC. Those with bulbar-onset ALS have lower intelligibility than those with spinal-onset ALS, and the intelligibility of individuals with bulbar symptoms-regardless of the onset type-is lower than in plwALS without bulbar symptoms. Declining ALS-related speech scores correspond with worsening intelligibility in longitudinal assessments. Intelligibility correlates strongly with bulbar-specific clinical measures but not with global scores, highlighting its role in tracking bulbar progression. In some plwALS, we were able to demonstrate that automated speech analyses are more effective in detecting worsening in intelligibility earlier than standard clinical scoring. Conclusion: Our findings highlight that automated speech intelligibility assessments can be a valuable marker to improve clinical monitoring and facilitate earlier intervention in ALS as a supplement to standard assessments.}, } @article {pmid40851455, year = {2026}, author = {Ido, BJF and Dabilgou, AA and Doulgou, AS and Carama, EA and Ganame, MKL and Napon, C}, title = {Epidemiology, clinical features, and management of amyotrophic lateral sclerosis in the neurology department of the Bogodogo University Hospital in Ouagadougou, Burkina Faso.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {224-226}, doi = {10.1080/21678421.2025.2549323}, pmid = {40851455}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy/diagnosis ; Male ; Female ; Middle Aged ; Adult ; Retrospective Studies ; Hospitals, University ; Burkina Faso/epidemiology ; Aged ; Riluzole/therapeutic use ; *Disease Management ; Neurology ; Young Adult ; Follow-Up Studies ; }, abstract = {Objective: To describe the epidemiology, the clinical features, and the management of amyotrophic lateral sclerosis (ALS) in the neurology department of the Bogodogo University Hospital. Methods: This was a retrospective study including patients followed in the neurology department of the Bogodogo University Hospital between April 15, 2017 and December 31, 2024 for ALS. The socio-demographic, clinical and follow-up data of these patients were studied. Results: During our study period, 14 patients were followed for ALS, an average of 2 cases per year. The mean age of patients at symptom onset was 38.50 ± 14.23 years. The mean time to diagnosis was 19.71 ± 5.27 months. Four patients underwent no spinal cord magnetic resonance imaging (MRI). Riluzole was prescribed in 02 patients (14.29%). No patient benefited from noninvasive ventilation or gastrostomy. Six patients (42.85%) were discharged against medical advice. On December 31, 2024, there were 2 patients alive (14.29%), 5 patients who died (14.29%) and 7 patients (50%) who were lost to follow-up. Conclusion: Our cohort is characterized by a low hospital incidence, a young age of patients and difficulties in the care and follow-up of patients.}, } @article {pmid40851522, year = {2026}, author = {Morgan, KH and Havranek, K and Horn, C and Lee, ML and Thomas, S}, title = {You look at life through a different lens: a phenomenological study of living with amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {1}, pages = {13-23}, pmid = {40851522}, issn = {1758-2032}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; Adult ; Quality of Life/psychology ; }, abstract = {AIMS: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that progresses without periods of remission; few live more than five years beyond diagnosis. In this study we investigated the lived experiences of people diagnosed with ALS in the United States, in South Central Appalachia.

PATIENTS & METHODS: We selected the philosophical and methodological approach of existential phenomenology of Merleau-Ponty to identify what was most important or figural to participants, within the contexts of Body, Other People, World, and Time.

RESULTS: Through phenomenological interviews with 10 people living with ALS, six themes and 17 subthemes were identified covering the process of diagnosis, loss and devastation, support from others, assistive devices, a new purpose, and a change in perspective.

CONCLUSIONS: These themes offer insight into life with an ALS diagnosis so that this unique patient population may be better understood from a physical, medical, emotional, and spiritual standpoint.}, } @article {pmid40852180, year = {2025}, author = {Corcia, P and Stenson, K and Doutriaux, A and Hadjrabia, H and Boer, F and Issa, S and Marguet, S and Bernard, F and Nasanbat, E and Nowacki, G and de Pouvourville, G and Couratier, P}, title = {Epidemiology, disease evolution and economic burden of amyotrophic lateral sclerosis in France using the French national health data system.}, journal = {Brain communications}, volume = {7}, number = {4}, pages = {fcaf292}, pmid = {40852180}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a rare neurodegenerative disease that requires multidisciplinary care, resulting in extensive healthcare resource utilization. No study has explored the prevalence of amyotrophic lateral sclerosis or characterized associated healthcare resource utilization in France, despite its high burden on people living with amyotrophic lateral sclerosis, caregivers and the healthcare system. Herein, we conducted a France-wide retrospective study to describe the epidemiology, disease course and economic burden of amyotrophic lateral sclerosis. People living with amyotrophic lateral sclerosis were identified from the French population from 2012 to 2019 using the French national health data system. A milestone and symptom-based staging algorithm was developed to categorize the incident cohort into early, mid and late stages. Data were extracted on epidemiology, demographic and clinical characteristics and clinical treatments. Healthcare resource utilization and costs were analysed for amyotrophic lateral sclerosis cases and matched non-amyotrophic lateral sclerosis controls and at disease stages. Events of interests were identified, and a competing risk analysis was conducted. Comparative statistics were performed using paired t-test, ANOVA and χ[2] test. We identified 18 289 incident amyotrophic lateral sclerosis cases, 56.1% of whom were male. The average age at diagnosis was 68.4 (± 12.5) years. In 2019, the estimated incidence and prevalence were 3.5/100 000 person-years and 11.0/100 000 persons, respectively. All-cause hospitalizations were higher among people at mid stage (1.66 person-years) and late stage (2.82 person-years) than among people at early stage (1.46 person-years) and for the amyotrophic lateral sclerosis cases (1.98 person-years) than for the matched non-amyotrophic lateral sclerosis controls (0.45 person-years). Home hospitalization and rehabilitation admission were more prevalent among people in later stages. The rate of out-patient and ambulatory consultations to all specialties was 13.8 person-years for people at early and mid stages and 11.1 person-years for people at late stage and 13.0 and 8.7 person-years for the amyotrophic lateral sclerosis cases and the matched non-amyotrophic lateral sclerosis controls, respectively. Direct costs increased as the disease progressed and were also higher for the amyotrophic lateral sclerosis cases than for the matched non-amyotrophic lateral sclerosis controls. Amyotrophic lateral sclerosis imposes a significant health burden through incremental healthcare resource utilization across all stages that increases with disease progression. Out-patient and ambulatory resource consumption decreased as the disease progressed to a more severe form, accompanied by a corresponding increase in in-patient services. These findings shed light on the complex needs of people living with amyotrophic lateral sclerosis and the continued need for more efficacious treatments.}, } @article {pmid40852304, year = {2025}, author = {Yang, JE and Lee, JH and Boya, BR and Kim, YG and Byun, Y and Lee, J}, title = {Novel Pyrone-Based Biofilm Inhibitors against Azole-Resistant Candida albicans.}, journal = {ACS omega}, volume = {10}, number = {32}, pages = {36441-36454}, pmid = {40852304}, issn = {2470-1343}, abstract = {Candida albicans is an opportunistic fungus that is pathogenic in immunocompromised patients with life-threatening diseases such as HIV and cancer. C. albicans is the most common fungal species isolated from biofilms formed on implanted medical devices or on human tissue. Biofilm development of C. albicans is mainly driven by a transition from yeast to hyphal form involving core proteins such as HWP and ALS. We designed and synthesized novel α-pyrone-based analogues to investigate their potential in inhibiting biofilm formation and hyphal development of C. albicans . Among the synthesized compounds, three compounds (6f, 6j, and 6n) significantly inhibited C. albicans biofilm formation and reduced cell aggregation and hyphal formation in a dose-dependent manner. These compounds had minimal effects on planktonic cell growth while significantly reducing biofilm formation at 20-50 μg/mL, suggesting novel candidate compounds for managing drug-resistant strains of C. albicans . The three compounds may represent promising therapeutic options with potential synergistic effects when combined with existing antifungal agents.}, } @article {pmid40853517, year = {2025}, author = {Kokotis, P and Bakola, E and Schmelz, M and Rentzos, M and Papagiannopoupou, G and Tsivgoulis, G}, title = {Motor neuron axonal excitability changes in the clinical course of amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {11}, pages = {5847-5853}, pmid = {40853517}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology/diagnosis ; Female ; Male ; Middle Aged ; Aged ; *Motor Neurons/physiology ; *Axons/physiology ; Disease Progression ; ROC Curve ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by slowly progressive degeneration of upper motor neurons (UMNs) and lower motor neurons (LMNs). Although the pathogenesis of sporadic form of ALS has not been fully elucidated, the initial damage mostly leads to hyperexcitability of the central and peripheral motor neuron. The results of our study aimed to confirm the changes in the excitability of the peripheral motor axon and contribute to the emergence of these measurements as potential biomarkers for disease progression. A total of 56 ALS patients [24 women (43%), median age 62.5 (interquartile range: 53.75-70.25) years] were finally included in the study. Twenty-four healthy controls that were age- and sex-matched to the cases [12 women (50%), mean age 58.46 ± 8.84] were recruited. The first main finding of our study is the fact that abnormalities of the voltage gated K[+] ion channels were constantly present in ALS patients than in the controls. The multivariate analysis revealed that Superexcitability 7ms lower than - 21.06%, related to shorter survival. Additionally using receiver operating characteristic (ROC) curves, the c-statistic showed Superexcitability 7ms moderate predictive ability. The clinical significance of our results is that Superexcitability 7ms can be used as a biomarker not only for survival but also for disease progression.}, } @article {pmid40854024, year = {2025}, author = {Stiles, K and LaBarbera, V}, title = {Recognition and Treatment of Concurrent Amyotrophic Lateral Sclerosis and Myasthenia Gravis.}, journal = {Rhode Island medical journal (2013)}, volume = {108}, number = {9}, pages = {16-18}, pmid = {40854024}, issn = {2327-2228}, } @article {pmid40854500, year = {2025}, author = {Sheu, KL and Chen, CC and Chen, SC}, title = {Comments on Fakult et al's "Epidemiology of Merkel cell carcinoma in the United States".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {6}, pages = {e227-e228}, doi = {10.1016/j.jaad.2025.06.080}, pmid = {40854500}, issn = {1097-6787}, } @article {pmid40855203, year = {2025}, author = {Ferreira, J}, title = {Lymphatic system role in ALS.}, journal = {Lab animal}, volume = {54}, number = {9}, pages = {224}, doi = {10.1038/s41684-025-01610-8}, pmid = {40855203}, issn = {1548-4475}, } @article {pmid40855953, year = {2025}, author = {Logroscino, G and Giannoni-Luza, S and Urso, D and Hamdi, N}, title = {Heterogeneity of frequencies of motor neuron disease across ethnicities and geographical areas: focus on Arabic countries in the Mediterranean area.}, journal = {Current opinion in neurology}, volume = {38}, number = {5}, pages = {588-595}, pmid = {40855953}, issn = {1473-6551}, mesh = {Humans ; Mediterranean Region/epidemiology ; *Amyotrophic Lateral Sclerosis/epidemiology/ethnology/genetics ; Prevalence ; Incidence ; *Motor Neuron Disease/epidemiology/ethnology ; Registries ; Egypt/epidemiology ; Ethnicity ; }, abstract = {PURPOSE OF REVIEW: Although amyotrophic lateral sclerosis (ALS) epidemiology has been increasingly characterized in many regions, data from Arabic countries remain limited. This review aims to summarize the current knowledge on the burden of ALS in Arabic Mediterranean countries, with a particular focus on Egypt.

RECENT FINDINGS: ALS exhibits significant geographic and ethnic variability in terms of incidence, phenotype, and genetic background. Data from the Global Burden of Disease Study 2021 show that Egypt has one of the lowest age-standardized rates of ALS incidence, prevalence, and mortality in the Mediterranean basin. During the past three decades, Egypt has seen a notable decline in ALS-related Disability-Adjusted Life Years and deaths, in contrast to neighboring countries. A national registry has recently been initiated to enhance epidemiological surveillance in the country.

SUMMARY: ALS in Arabic Mediterranean countries presents a distinct epidemiological profile. These differences likely reflect a combination of genetic, demographic, and healthcare-related factors. Strengthening national registries and promoting regional collaborations will be crucial for gaining a deeper understanding of the determinants of ALS in these underrepresented populations.}, } @article {pmid40856010, year = {2025}, author = {Boyanova, S and Banks, G and Lipina, TV and Bains, RS and Forrest, H and Stewart, M and Carcolé, M and Milioto, C and Isaacs, AM and Wells, SE and Wiseman, FK}, title = {Multi-modal comparative phenotyping of knock-in mouse models of frontotemporal dementia/amyotrophic lateral sclerosis.}, journal = {Disease models & mechanisms}, volume = {18}, number = {8}, pages = {}, pmid = {40856010}, issn = {1754-8411}, support = {UKDRI-1014//UK Dementia Research Institute/ ; UKDRI-CIP0202//UK Dementia Research Institute/ ; UKDRI-1203//UK Dementia Research Institute/ ; ARUK-SRF2018A-001//Alzheimer's Research UK/ ; Isaacs/Apr20/876-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; A410-53658/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics/pathology ; *Frontotemporal Dementia/physiopathology/genetics/pathology ; Disease Models, Animal ; Phenotype ; *Gene Knock-In Techniques ; C9orf72 Protein ; Mice ; Behavior, Animal ; Aging/pathology ; DNA-Binding Proteins/genetics/metabolism ; Male ; Mice, Transgenic ; Memory, Short-Term ; Mice, Inbred C57BL ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive adult-onset neurodegenerative diseases with overlapping pathological and genetic origins. They are caused by multiple underlying mechanisms leading to a common collection of clinical features that occur in a spectrum. Here, we report side-by-side longitudinal behavioural, cognitive and sensory phenotyping of two mouse models of ALS/FTD, to determine which aspects of the disease they recapitulate. We used knock-in models, in which the endogenous mouse orthologues of the C9orf72 and TARDBP (encoding TDP-43) genes have been altered to model specific molecular aspects of ALS/FTD. We found that the C9orf72GR400/+ model exhibits age-related deficit in short-term memory and that parental genotype affects exploration activity in offspring. In the TardbpQ331K/Q331K model, we found age-related changes in weight, fat mass, locomotion and marble burying. In both models, we found no evidence of deficits in vision or olfactory habituation-dishabituation. These data provide new insight into genotype-phenotype relationships in these ALS/FTD mice, which can be used to inform model choice and experimental design in future research studies.}, } @article {pmid40856243, year = {2025}, author = {Seven, YB and Seven, ES and Kirbas Cilingir, E and Parikh, K and Aydin, M and Luca, EK and Nair, J and Leblanc, RM}, title = {Rapid mapping of spinal and supraspinal connectome via self-targeting glucose-based carbon dots.}, journal = {Nanoscale}, volume = {17}, number = {36}, pages = {20914-20923}, pmid = {40856243}, issn = {2040-3372}, support = {R21 NS119862/NS/NINDS NIH HHS/United States ; }, mesh = {*Carbon/chemistry ; Animals ; *Spinal Cord/metabolism/diagnostic imaging ; *Glucose/chemistry ; Blood-Brain Barrier/metabolism ; *Connectome ; *Quantum Dots/chemistry ; Mice ; Neurons/metabolism ; Brain/metabolism ; Spinal Cord Injuries/diagnostic imaging/metabolism ; Humans ; }, abstract = {The spinal cord is a highly dynamic network, playing significant roles in the vital functions of the brain. Disorders of the spinal cord, such as spinal cord injury and amyotrophic lateral sclerosis (ALS), are associated with neurodegeneration, often resulting in morbidity and mortality. The blood-brain barrier (BBB) poses a major challenge to imaging and therapeutic agents because less than 2% of small-molecule drugs and almost no large-molecule drugs can cross the BBB. Furthermore, spatial spectroscopy studies have shown highly heterogeneous BBB crossing with significant accumulation at the unintended brain regions. Thus, targeting systems that can cross the BBB at the spinal cord and precisely target specific cell types/populations are vitally needed. Carbon dots can be custom-designed to accumulate at the spinal cord; thus, they offer great potential as delivery platforms for imaging and therapeutic approaches. Since neurons are metabolically highly active and rely on glucose, we designed glucose-based carbon dots (GluCDs) with a diameter of ∼4 nm and glucose-like surface groups. We determined the CNS distribution of GluCDs on three scales: 1. brain regional distribution, 2. cellular tropism (e.g. neurons vs. glia), and 3. intracellular localization. We found that GluCDs (1) crossed the BBB at the spinal cord level, localized primarily to the spinal cord, and were quickly transported to higher centers in the brain, revealing supraspinal connectome within 4 hours after systemic delivery (minimally invasive and significantly faster than the available technologies); (2) almost exclusively localized to neurons without the need for a targeting ligand (neuronal self-targeting), and (3) were confined to late endosomal/lysosomal compartments in the neurons. Then, we verified our findings in a cervical spinal cord contusion injury model with GluCDs targeting the neurons at the injury epicenter. Therefore, GluCDs can be used as robust imaging agents to obtain rapid snapshots of the spinal/supraspinal network. GluCD nanoconjugates can open new avenues for targeted imaging of spinal cord injury. These findings can be extended to other spinal disorders such as ALS, spinal muscular atrophy, and spinal stroke.}, } @article {pmid40856865, year = {2025}, author = {Shandilya, C and Mani, S}, title = {Rho kinase isoforms in neurodegeneration: from cellular functions to therapeutic targets.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {846}, pmid = {40856865}, issn = {1573-4978}, mesh = {Humans ; *rho-Associated Kinases/metabolism/antagonists & inhibitors/genetics ; *Neurodegenerative Diseases/metabolism/drug therapy ; Mitochondria/metabolism ; Animals ; Mitophagy ; Neurons/metabolism ; Protein Isoforms/metabolism ; Signal Transduction ; Reactive Oxygen Species/metabolism ; Mitochondrial Dynamics ; Isoenzymes/metabolism ; Oxidative Stress ; }, abstract = {Mitochondria serve as an important cellular organelle for maintaining neurotransmission and synaptic plasticity in neuronal cells by playing a key role in ATP generation, maintaining calcium homeostasis, and regulating the levels of reactive oxygen species (ROS), etc. The regulation of the dynamic nature of mitochondria, including their fission, fusion, and removal of damaged mitochondria by mitophagy, is also very important for neuronal health. Abnormalities in mitochondrial processes, including but not limited to fission, fusion, and mitophagy, are known to be associated with numerous neurodegenerative diseases (NDDs), such as Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). In the recent past, the Rho kinase (ROCK) isoforms, particularly ROCK1 and ROCK2, have gained a lot of attention in NDDs, mainly for their role in regulating the dynamics of the mitochondria, mitophagy, and other cell signalling pathways. By adding phosphate groups to Drp1, ROCK1 is crucial in supporting excessive mitochondrial fission, causing the death of neuronal cells. On the other hand, ROCK2 inhibits Parkin-dependent mitophagy by inhibiting the PTEN protein, the activator of Parkin-dependent mitophagy. This impaired mitochondrial quality control via reduced mitophagic flux leads to oxidative stress and neuronal degeneration, the central pathological feature of NDDs. The inhibition of ROCK isoforms has shown great promise in neuroprotective effects, controlling the dynamics of mitochondria in neuronal cells, lowering inflammation, and improving motor and cognitive functions in preclinical models of different NDDs, indicating ROCK isoforms as an attractive therapeutic target in different NDDs. This review aims to highlight the therapeutic significance of targeting ROCK isoforms in different NDDs.}, } @article {pmid40857020, year = {2025}, author = {Krivickas, B and Scirocco, E and Giacomelli, E and Sharma, S and Benson, M and Keegan, M and Kulesa-Kelley, J and Chibnik, LB and Casagrande, G and Heyd, L and Chase, M and Drake, K and Mohapatra, S and Hagar, JL and Hasenoehrl, MG and Dagostino, D and Sherman, AV and Leite, A and Yu, H and Rosenthal, J and Miller, T and McCaffrey, A and Gwathmey, K and Locatelli, E and Bayat, E and Heitzman, D and Young, E and Goyal, NA and Whitesell, J and Felice, K and Ilieva, H and Swenson, A and Walk, D and Alameda, G and Foster, L and McIlduff, CE and Walsh, A and Zilliox, L and Ajroud-Driss, S and Bodkin, C and Katz, J and Ladha, S and Rivner, M and Rosow, L and Twydell, P and Wasiewski, W and Babu, S and Berry, JD and Paganoni, S}, title = {Multicenter Expanded Access Protocol for Research Through Access to Trehalose in People With Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {72}, number = {5}, pages = {1108-1116}, pmid = {40857020}, issn = {1097-4598}, support = {UF1 NS131791/NS/NINDS NIH HHS/United States ; UF1NS131791//Office of the Director of the National Institutes of Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Trehalose/therapeutic use ; Middle Aged ; Male ; Female ; Aged ; Disease Progression ; Adult ; Neurofilament Proteins/blood ; }, abstract = {INTRODUCTION/AIMS: Expanded access protocols (EAPs) allow individuals ineligible for clinical trials to receive investigational products. EAP data can be collected in parallel to randomized clinical trials (RCTs) and serve as a source of evidence in clinical practice. Here, we present the results of a National Institutes of Health (NIH)-funded EAP for amyotrophic lateral sclerosis (ALS).

METHODS: Participants received trehalose, a drug studied in a parallel RCT, for up to 24 weeks; clinical and biomarker data were collected throughout the study.

RESULTS: Seventy participants were enrolled at 20 study centers across the United States. Treatment with trehalose did not affect the levels of neurofilament light chain [estimated flat slope per month was -0.005, SE = 0.0078; 95% CI (-0.021, 0.011)] or disease progression [estimated least square mean change of the ALS Functional Rating Scale-Revised total score and slow vital capacity (percent predicted) from baseline to Week 24 were -5.6 (0.67); 95% CI (-7.0, -4.3) and -4.53 (4.308); 95% CI (-13.55, 4.48)], respectively. No unexpected treatment-related risks were identified. Serious adverse events were deemed not related to trehalose (20 occurrences in 13 [18.6%] participants with eight deaths).

DISCUSSION: This EAP establishes a framework for implementing multi-center EAPs that complement data collected from RCTs. Additional NIH-funded EAPs are currently underway. Data and additional serum samples collected in this study are available to the research community for further study.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT05597436.}, } @article {pmid40857153, year = {2025}, author = {Szewczyk, B and Zimyanin, V and Japtok, J and Held, A and Pal, A and Großmann, D and Glaß, H and Jürs, AV and Dash, BP and Bak, M and Naumann, M and Hartmann, C and Kuksenko, O and Günther, R and Kao, TT and Sameith, K and Dahl, A and Sterneckert, J and Aronica, E and Shneider, NA and Büttner, A and Catanese, A and Phatnani, H and Kipp, M and Wainger, BJ and Goswami, A and Hermann, A}, title = {Activation of polo-like kinase 1 correlates with selective motor neuron vulnerability in familial ALS.}, journal = {Cell reports}, volume = {44}, number = {9}, pages = {116113}, doi = {10.1016/j.celrep.2025.116113}, pmid = {40857153}, issn = {2211-1247}, mesh = {*Protein Serine-Threonine Kinases/metabolism/genetics ; Polo-Like Kinase 1 ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/enzymology ; *Motor Neurons/pathology/metabolism/enzymology ; *Cell Cycle Proteins/metabolism/genetics ; Humans ; *Proto-Oncogene Proteins/metabolism/genetics ; RNA-Binding Protein FUS/metabolism/genetics ; Animals ; DNA Damage ; Mice ; Mutation ; }, abstract = {Mutations in the Fused in Sarcoma (FUS) gene cause familial amyotrophic lateral sclerosis (ALS), characterized by selective degeneration of spinal motor neurons (sMNs) with relative sparing of cortical neurons (CNs). The mechanisms underlying this cell-type vulnerability remain unclear. Here, we compare CNs and sMNs derived from FUS-ALS models to assess differential responses to FUS mutations. We find that CNs are less affected than sMNs in DNA damage repair, axonal organelle trafficking, and stress granule dynamics. RNA sequencing (RNA-seq) reveals distinct transcriptomic signatures, with sMNs uniquely activating DNA damage responses involving cell cycle regulators, particularly polo-like kinase 1 (PLK1). PLK1 is highly expressed in sMNs but not CNs, correlating with greater nuclear FUS loss and splicing defects in sMNs. Cross-comparison with other familial ALS RNA-seq datasets highlights PLK1 upregulation as a shared molecular feature. These findings identify intrinsic differences between CNs and sMNs in FUS-ALS and suggest PLK1 as a potential driver of sMN vulnerability.}, } @article {pmid40857498, year = {2025}, author = {Zhao, B and Huggins, JE and Kang, J}, title = {Bayesian Inference on Brain-Computer Interfaces via GLASS.}, journal = {Journal of the American Statistical Association}, volume = {}, number = {}, pages = {}, pmid = {40857498}, issn = {0162-1459}, support = {R01 DA048993/DA/NIDA NIH HHS/United States ; R01 GM124061/GM/NIGMS NIH HHS/United States ; R01 MH105561/MH/NIMH NIH HHS/United States ; R21 HD054697/HD/NICHD NIH HHS/United States ; }, abstract = {Brain-computer interfaces (BCIs), particularly the P300 BCI, facilitate direct communication between the brain and computers. The fundamental statistical problem in P300 BCIs lies in classifying target and non-target stimuli based on electroencephalogram (EEG) signals. However, the low signal-to-noise ratio (SNR) and complex spatial/temporal correlations of EEG signals present challenges in modeling and computation, especially for individuals with severe physical disabilities-BCI's primary users. To address these challenges, we introduce a novel Gaussian Latent channel model with Sparse time-varying effects (GLASS) under a Bayesian framework. GLASS is built upon a constrained multinomial logistic regression particularly designed for the imbalanced target and non-target stimuli. The novel latent channel decomposition efficiently alleviates strong spatial correlations between EEG channels, while the soft-thresholded Gaussian process (STGP) prior ensures sparse and smooth time-varying effects. We demonstrate GLASS substantially improves BCI's performance in participants with amyotrophic lateral sclerosis (ALS) and identifies important EEG channels (PO8, Oz, PO7, and Pz) in parietal and occipital regions that align with existing literature. For broader accessibility, we develop an efficient gradient-based variational inference (GBVI) algorithm for posterior computation and provide a user-friendly Python module available at https://github.com/BangyaoZhao/GLASS.}, } @article {pmid40858193, year = {2025}, author = {Wu, Q and Liu, X and Zhang, T and Cui, S and Huang, B and Huang, C and Cao, Q and Xia, XG and Zhou, H}, title = {Astrocytes expressing mutant hnRNPA1 induce non-cell-autonomous motor neuron death.}, journal = {Brain research bulletin}, volume = {230}, number = {}, pages = {111522}, pmid = {40858193}, issn = {1873-2747}, support = {R01 NS089701/NS/NINDS NIH HHS/United States ; R01 NS095962/NS/NINDS NIH HHS/United States ; R01 NS110455/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Astrocytes/metabolism/pathology ; *Motor Neurons/pathology/metabolism ; Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism ; Rats, Transgenic ; Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Rats ; Cell Death/genetics/physiology ; Mutation ; Humans ; Disease Models, Animal ; Muscular Atrophy/pathology ; }, abstract = {Pathogenic mutation of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is causative to amyotrophic lateral sclerosis (ALS). Neuron death resulting from pathogenic hnRNPA1 may not require its presence across all pertinent cells types, including neurons, glia, and muscles. Rather, the exclusive presence of pathogenic hnRNPA1 in a specific cell type, such as astrocytes, may suffice to substantially alter cellular functions. Consequently, this alteration initiates abnormal interaction within intricate neuron-glia networks, culminating in non-cell-autonomous motor neuron death. To investigate the pivotal role of non-cell-autonomous neuron death in hnRNPA1-associated ALS, we developed transgenic rats overexpressing mutant hnRNPA1 in specifically astrocytes. The confined overexpression of pathogenic hnRNPA1 in astrocytes instigated a sequence of events resulting in motor neuron death and subsequent muscle atrophy. These findings underscore the critical, non-cell-autonomous contribution of astrocytes to hnRNPA1-induced neurodegeneration in ALS, and point toward astrocytic pathways as potential therapeutic targets.}, } @article {pmid40858416, year = {2025}, author = {Hao, R and He, C and Cheng, Y and Sang, S and Bai, Y}, title = {A plug-and-play data processing module for complex faults diagnosis.}, journal = {ISA transactions}, volume = {167}, number = {Pt A}, pages = {775-787}, doi = {10.1016/j.isatra.2025.07.061}, pmid = {40858416}, issn = {1879-2022}, abstract = {Intelligent fault diagnosis technology is a vital approach to detect and sustain contemporary equipment. Although it is widely utilized for equipment monitoring, the limited number of samples available in the industry and complex faults restrict its further development. This paper presents a plug-and-play data processing module to expand the number of samples and improve the internal relationship between them to improve the overall performance of the deep learning model. an Amplitude-phase composite data enhancement (APCUP) method for expanding training samples is designed in the module, which uses Discrete Fourier Transform to randomly fuse multiple fault types in proportion to generate new fault samples, achieving the goal of expanding the training dataset. Based on the interdependence of faults in real scenes, the module also designs an adjacent label smoothing (ALS) strategy to process the original label data, which smoothen the label over, prevents the excessive absolute classification and improves the robustness of the model. The efficacy and viability of the module have been demonstrated through comprehensive experimentation on the cutting-edge industrial robot arm platform and two public datasets. The incorporation of a data processing module has markedly enhanced the model's capacity to diagnose intricate faults. As the module processes the input, there is a significant increase in accuracy and a reduction in errors.}, } @article {pmid40858618, year = {2025}, author = {Lenoel, I and Ribon, M and Lorenc, F and Diebold, A and Philibert, CE and Robaldo, D and Badsi, M and Perronnet, J and Lameth, J and Berriat, F and Misawa, H and Coutelier, M and Cassel, R and Sarrazin, N and Jost-Mousseau, C and Bohl, D and Millecamps, S and Mallat, M and Brenner, D and Weishaupt, JH and Boillée, S and Lobsiger, CS}, title = {ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {7951}, pmid = {40858618}, issn = {2041-1723}, mesh = {Animals ; *Protein Serine-Threonine Kinases/genetics/deficiency/metabolism ; *Microglia/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mice ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Motor Neurons/metabolism/pathology ; Mice, Knockout ; Spinal Cord/pathology/metabolism ; Male ; Autophagy ; Disease Models, Animal ; Female ; Mice, Inbred C57BL ; Aging ; Brain/pathology/metabolism ; Humans ; }, abstract = {TANK-Binding Kinase 1 (TBK1) is involved in autophagy and immune signaling. Dominant loss-of-function mutations in TBK1 have been linked to Amyotrophic Lateral Sclerosis (ALS), Fronto-temporal dementia (FTD), and ALS/FTD. However, pathogenic mechanisms remain unclear, particularly the cell-type specific disease contributions of TBK1 mutations. Here, we show that deleting Tbk1 from mouse motor neurons does not induce transcriptional stress, despite lifelong signs of autophagy deregulations. Conversely, Tbk1 deletion in microglia alters their homeostasis and reactive responses. In both spinal cord and brain, Tbk1 deletion leads to a pro-inflammatory, primed microglial signature with features of ageing and neurodegeneration. While it does not induce or modify ALS-like motor neuron damage, microglial Tbk1 deletion is sufficient to cause early FTD-like social recognition deficits. This phenotype is linked to focal microglial activation and T cell infiltration in the substantia nigra pars reticulata and pallidum. Our results reveal that part of TBK1-linked FTD disease originates from microglial dysfunction.}, } @article {pmid40858858, year = {2025}, author = {Loo, YS and Yusoh, NA and Yap, K and Ng, CS}, title = {Programmable self-replicating JEV nanotherapeutics redefine RNA delivery in ALS.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {1282}, pmid = {40858858}, issn = {2399-3642}, support = {PM010CNI000148//International Brain Research Organization (IBRO)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; Animals ; *Encephalitis Virus, Japanese/genetics/physiology ; *Oligonucleotides, Antisense/administration & dosage/genetics ; *Genetic Therapy/methods ; MicroRNAs/genetics ; Virus Replication ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration, leading to paralysis and respiratory failure. Current therapies offer limited benefits, highlighting the need for novel therapeutic strategies. Antisense oligonucleotides (ASO) and CRISPR/Cas9 gene editing hold promise, but their effective delivery to the central nervous system (CNS) remains a significant challenge. Here, a potential approach involves utilizing engineered Japanese encephalitis virus (JEV) as a self-replicating nanocarrier for targeted ASO delivery to motor neurons. By leveraging JEV's natural neurotropism and "Trojan horse" mechanism of immune cell-mediated CNS entry, this strategy overcomes the blood-brain and blood-spinal cord barriers (BBB/BSCB). Incorporation of ASO sequences within the JEV genome facilitates co-packaging and sustained therapeutic delivery, while microRNA (miRNA)-mediated attenuation may enhance safety and CNS specificity. This theoretical framework offers a potential paradigm shift in CNS gene therapy for ALS and other neurodegenerative diseases by enabling efficient, targeted, and sustained ASO delivery. However, experimental validation remains critical to assess its safety and therapeutic efficacy.}, } @article {pmid40859014, year = {2025}, author = {Zhang, MY and Ma, Y and Wang, LQ and Xia, W and Li, XN and Zhao, K and Chen, J and Li, D and Zou, L and Wang, Z and Liu, C and Liang, Y}, title = {Distinct amyloid fibril structures formed by ALS-causing SOD1 mutants G93A and D101N.}, journal = {EMBO reports}, volume = {26}, number = {19}, pages = {4820-4846}, pmid = {40859014}, issn = {1469-3178}, support = {32271326//MOST | National Natural Science Foundation of China (NSFC)/ ; 32201040//MOST | National Natural Science Foundation of China (NSFC)/ ; 32071212//MOST | National Natural Science Foundation of China (NSFC)/ ; 22425704//MOST | National Natural Science Foundation of China (NSFC)/ ; 82188101//MOST | National Natural Science Foundation of China (NSFC)/ ; 12272276//MOST | National Natural Science Foundation of China (NSFC)/ ; 2024YFA1307301//MOST | National Key Research and Development Program of China (NKPs)/ ; 2023ZD0507202//National Science and Technology Major Project ()/ ; 2021TQ0252//China Postdoctoral Science Foundation (China Postdoctoral Foundation Project)/ ; 2021M700103//China Postdoctoral Science Foundation (China Postdoctoral Foundation Project)/ ; JCYJ20200109144418639//| Science and Technology Planning Project of Shenzen Municipality (Science and Technology Planning Project of Shenzhen of China)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; *Amyloid/chemistry/ultrastructure/metabolism/genetics ; Animals ; Mice ; Humans ; *Mutation ; Cryoelectron Microscopy ; Mice, Transgenic ; Models, Molecular ; Superoxide Dismutase ; }, abstract = {Two hundred eight genetic mutations in SOD1 have been linked to amyotrophic lateral sclerosis (ALS). Of these, the G93A and D101N variants maintain much of their physiological function, closely resembling that of wild-type SOD1, and the SOD1-G93A transgenic mouse is the most extensively used mouse line in the study of ALS. In this study, we report two cryo-EM structures of amyloid fibrils formed by G93A and D101N mutants of SOD1 protein. These mutations give rise to amyloid fibrils with distinct structures compared to native SOD1 fibrils. The fibril core displays a serpentine configuration featuring four β-strands, held together by two hydrophobic cavities and a salt bridge between Arg143 and Asp96 in the G93A fibril, and by a hydrophobic cavity and a salt bridge between Arg143 and Asp132 in the D101N fibril, demonstrating unique structural features for each mutant. Moreover, our results show that G93A fibrils are significantly more toxic than those formed by D101N, which do not show a marked increase in toxicity compared to wild-type SOD1 fibrils. This study sheds light on the structural mechanisms through which SOD1 mutants aggregate and induce cytotoxicity in ALS.}, } @article {pmid40859959, year = {2025}, author = {Mao, S and Qiao, R and Wang, Q and Shen, L and Li, D and Huo, X and Wang, J and Liu, K and Chen, W and Zhu, T and Zhang, B and Leng, S and Bai, Y}, title = {Activity and Heterogeneity of Astrocytes in Neurological Diseases: Molecular Mechanisms and Therapeutic Targets.}, journal = {MedComm}, volume = {6}, number = {9}, pages = {e70329}, pmid = {40859959}, issn = {2688-2663}, abstract = {Astrocytes, the most prevalent glial cells in the central nervous system (CNS), play crucial roles in maintaining CNS homeostasis and responding to various pathological stimuli. They play key roles in neural development, neurotransmission, neuroinflammation, metabolic support, and tissue repair. Recent advancements in single-cell sequencing have revealed the remarkable heterogeneity of astrocytes, with distinct subpopulations differentially contributing to disease progression in neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, intracerebral hemorrhage, and multiple sclerosis. In addition, they play an important role in various behavioral neuropsychiatric disorders. This review highlights the dual roles of astrocytes in disease progression, driven by their diverse molecular profiles and functions. It outlines the key molecular mechanisms underlying astrocyte heterogeneity and their impact on neuroinflammation, neuronal support, and ionic balance regulation. Additionally, the review discusses potential therapeutic strategies targeting astrocytes to modulate these processes, aiming to improve treatment outcomes in neurological diseases. By elucidating the specific roles of astrocyte subsets in disease, this review seeks to advance the development of precision medicine for astrocyte-related neurological disorders.}, } @article {pmid40860154, year = {2025}, author = {Li, D and Wei, Y and Yang, R and Luo, X and Liu, Y and Zhao, W and Yang, H and Wu, Y and Wang, Y and Huang, Z}, title = {An unrecognized mechanism of self-protection in degenerating neurons mediated by astrocytic YAP through Wnts/β-catenin/EAAT2 signaling in C9orf72-poly-GA mice.}, journal = {Theranostics}, volume = {15}, number = {16}, pages = {8176-8201}, pmid = {40860154}, issn = {1838-7640}, mesh = {Animals ; *Astrocytes/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; YAP-Signaling Proteins ; Mice ; Disease Models, Animal ; *C9orf72 Protein/genetics/metabolism ; Mice, Knockout ; *Excitatory Amino Acid Transporter 2/metabolism ; *Cell Cycle Proteins/metabolism ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; beta Catenin/metabolism ; Motor Neurons/metabolism/pathology ; *Wnt Signaling Pathway ; Neurons/metabolism ; Humans ; Signal Transduction ; }, abstract = {Rationale: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons in the central nervous system (CNS). Non-neuronal cells, particularly astrocytes, have been recognized as pivotal contributors to ALS onset and progression. However, the underlying mechanisms of interactions between astrocytes and motor neurons during ALS remain unclear. Recent studies have identified the neuronal Hippo kinase mammalian sterile 20-like kinase 1 (MST1) as a key regulator of neurodegeneration in ALS. Yes-associated protein (YAP), a major downstream effector of the Hippo pathway, is predominantly expressed in astrocytes. However, the role of astrocytic YAP in ALS and its underlying mechanisms remain unexplored. Methods: To evaluate the function of YAP in ALS, we established a C9orf72-poly-GA mouse model (ALS mice) via intracerebroventricular injection of AAV viruses. Furthermore, mice with conditional knockout (CKO) of YAP in astrocytes (YAP[GFAP]-CKO mice) were generated and then YAP[GFAP]-CKO ALS mice and their littermate controls (YAP[f/f] ALS mice) were used as experimental subjects. Behavioral tests, immunostaining, Nissl staining, quantitative real-time PCR (qPCR), and Western blotting were used to assess the effects of astrocytic YAP deletion in ALS progression. In addition, we investigated the role and mechanism of astrocytic YAP in the pathogenesis of ALS by integrating RNA sequencing (RNA-seq) from primary cultured astrocytes with single-nucleus transcriptomic (snRNA-seq) from C9orf72-ALS/FTD patients. Then, in vitro experiments including primary cultured astrocytes and neurons were used to further elucidate the potential molecular mechanism of astrocytic YAP in ALS. Finally, we evaluated the therapeutic effects of the excitatory amino acid transporter-2 (EAAT2) activator LDN-212320 and the Hippo kinase MST1/2 inhibitor XMU-MP-1 as candidate treatments for ALS. Results: We found that YAP was upregulated and activated specifically in astrocytes, but not in neurons or microglia, within the motor cortex of ALS mice. Conditional knockout of YAP in astrocytes exacerbated motor deficits, neuronal loss, pathological translocation of TDP-43, inflammatory infiltration, and reduced astrocytic proliferation in ALS mice. Mechanistically, Wnts secreted by degenerating neurons and astrocytes activated YAP/β-catenin signaling and further promoted the expression of EAAT2 in astrocytes, which prevented neuronal glutamate excitotoxicity, neuronal loss, and motor dysfunction in ALS mice. Interestingly, treatment with LDN-212320 promoted EAAT2 expression and partially restored motor deficits and neuronal loss in YAP[GFAP]-CKO ALS mice. Finally, activation of YAP by XMU-MP-1 upregulated β-catenin and EAAT2 expression, and partially alleviated motor deficits and neurodegeneration in ALS mice. Conclusions: These results identify an unrecognized mechanism of self-protection in degenerating neurons mediated by astrocytic YAP through Wnts/β-catenin/EAAT2 signaling to prevent glutamate excitotoxicity of neurons in ALS mice, and provide a novel drug target for ALS.}, } @article {pmid40861195, year = {2025}, author = {Chapman, LR and Shepheard, S and Verber, N and Turner, MR and Malaspina, A and Rogers, ML and Shaw, PJ}, title = {Urinary P75: a promising biomarker for amyotrophic lateral sclerosis.}, journal = {BMJ neurology open}, volume = {7}, number = {2}, pages = {e001088}, pmid = {40861195}, issn = {2632-6140}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease. The urinary neurotrophin receptor p75 extracellular domain (p75[ECD]) has previously been reported as a potential disease biomarker for diagnosis, severity assessment and monitoring therapeutic response.

METHODS: This study measured urinary p75[ECD] using an enzyme-linked immunoassay and normalised the results against urinary creatinine. Participants were recruited via A Multicentre Biomarker Resource Strategy in ALS (AMBroSIA) programme. Study participants included 97 ALS patients, 24 of whom were studied longitudinally, and 27 healthy controls. The study focused on urinary p75[ECD] and its potential association with different subtypes of ALS, change over time, disease progression, severity of symptoms and survival from symptom onset.

RESULTS: Confirming previous findings, urinary p75[ECD] levels were significantly higher in patients with ALS (median 6.78 ng/mg, 95% CI (5.12 to 9.23)) compared with controls (4.57 ng/mg, 95% CI (3.35 to 5.89)) at first study visit. There was a significant negative correlation between absolute change in the Revised ALS Functional Rating Scale score and p75[ECD] levels (Spearman's rho=-0.371, p≤0.0004, 95% CI (-0.543 to -0.169)), indicating that an increase in the severity of motor neuron injury correlated with an increase in p75[ECD] levels. There was a significant increase in p75[ECD] between first and second samples in the same participants, indicating an increase in the level of this biomarker longitudinally during the disease course (moderate effect size of -0.3).

CONCLUSIONS: Urinary p75[ECD] is a promising candidate as a biomarker, which increases with disease progression and has the potential to serve as a pharmacodynamic biomarker.}, } @article {pmid40862353, year = {2026}, author = {Harji, ZA and Rampal, CJ and Rodríguez, EC and Petel Légaré, V and Lissouba, A and Semmler, S and Liao, M and Ross, JP and Rouleau, GA and Vande Velde, C and Armstrong, GAB}, title = {TARDBP (TDP-43) Knock-in Zebrafish Display a Late-Onset Motor Phenotype and Loss of Large Spinal Cord Motor Neurons.}, journal = {Annals of neurology}, volume = {99}, number = {1}, pages = {178-197}, pmid = {40862353}, issn = {1531-8249}, support = {//CIHR/Canada ; //ALS Society of Canada/ ; //Weston Family Foundation/ ; //Fonds de Recherche du Québec/ ; //CIHR/Canada ; }, mesh = {Animals ; Zebrafish ; *Motor Neurons/pathology/metabolism ; *Spinal Cord/pathology/metabolism ; *Zebrafish Proteins/genetics/metabolism ; Phenotype ; *DNA-Binding Proteins/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Disease Models, Animal ; Gene Knock-In Techniques ; Animals, Genetically Modified ; }, abstract = {OBJECTIVE: Mutations in TARDBP (encoding TDP-43) are associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and include familial missense mutations where there are a lack of models and mechanisms examining how they are pathogenic.

METHODS: In this study, we developed 2 tardbp (Tdp-43) knock-in (KI) zebrafish mutant models encoding the analogous A382T and G348C variants and investigated their degenerative phenotypes.

RESULTS: We show that both models display reduced survival as well as an age-dependent motor phenotype that manifests at 1.5 years. Both variants in either the heterozygous or homozygous state did not impact protein expression levels of Tdp-43 in the central nervous system. However, homozygous G347C zebrafish displayed reduced expression levels of the tardbp transcript. We observed muscle cell atrophy starting at 1 year of age and loss of large spinal cord motor neurons in both KI models in older fish (2.35-3 years of age). We did not observe Tdp-43 aggregates. However, we did observe increased cytoplasmic Tdp-43 localization in spinal cord motor neurons in A379T zebrafish. At 1 year of age, whole spinal cord RNA-sequencing revealed an upregulation of neuroinflammatory transcripts in both models, as well as the selective downregulation of transcripts involved with synaptic function in G347C zebrafish, including syn2a, syn2b, syt2a, and stxbp1a.

INTERPRETATION: These novel models of common TDP-43 disease variants provide a unique opportunity to further our understanding of neurodegeneration in vivo and demonstrate that mutations in the same protein and domain can manifest with different phenotypes. ANN NEUROL 2026;99:178-197.}, } @article {pmid40863128, year = {2025}, author = {Pawłowska, M and Kruszka, J and Porzych, M and Garbarek, J and Nuszkiewicz, J}, title = {Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential.}, journal = {Metabolites}, volume = {15}, number = {8}, pages = {}, pmid = {40863128}, issn = {2218-1989}, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and share key pathological features such as oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Recent research has highlighted the potential of ketogenic metabolism, particularly the use of ketone bodies like β-hydroxybutyrate, as a therapeutic approach targeting these shared mechanisms. This review provides a comprehensive synthesis of current knowledge on the neuroprotective effects of ketogenic interventions, including both dietary strategies and exogenous ketone supplementation. We discuss how ketone bodies improve mitochondrial function, reduce reactive oxygen species, modulate inflammatory pathways, and influence neurotransmission and synaptic plasticity. Additionally, we examine experimental and clinical evidence supporting the application of ketogenic therapies in neurodegenerative diseases, highlighting disease-specific findings, benefits, and limitations. While preclinical data are robust and suggest meaningful therapeutic potential, clinical studies remain limited and heterogeneous, with challenges related to adherence, safety, and patient selection. The review also addresses the translational relevance of ketogenic strategies, considering their feasibility, combination with other therapies, and the need for personalized approaches based on genetic and metabolic profiles. By critically evaluating existing data, this article aims to clarify the mechanisms through which ketogenic metabolism may exert neuroprotective effects and to outline future directions for research and clinical application in the context of neurodegenerative disorders.}, } @article {pmid40864161, year = {2025}, author = {Zhu, Y and Cho, K and Lacin, H and Zhu, Y and DiPaola, JT and Wilson, BA and Patti, G and Skeath, JB}, title = {Loss of dihydroceramide desaturase drives neurodegeneration by disrupting endoplasmic reticulum and lipid droplet homeostasis in glial cells.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {40864161}, issn = {2050-084X}, support = {R01 NS036570/NS/NINDS NIH HHS/United States ; R01 NS122903/NS/NINDS NIH HHS/United States ; P30 DK056341/DK/NIDDK NIH HHS/United States ; NS036570/NS/NINDS NIH HHS/United States ; NS122903/NS/NINDS NIH HHS/United States ; ES2028365/ES/NIEHS NIH HHS/United States ; P30 DK020579/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Endoplasmic Reticulum/metabolism ; *Neuroglia/metabolism/pathology ; *Lipid Droplets/metabolism ; *Oxidoreductases/metabolism/genetics ; Homeostasis ; *Drosophila Proteins/metabolism/genetics ; Ceramides/metabolism ; *Drosophila melanogaster/genetics ; }, abstract = {Dihydroceramide desaturases convert dihydroceramides to ceramides, the precursors of all complex sphingolipids. Reduction of DEGS1 dihydroceramide desaturase function causes pediatric neurodegenerative disorder hypomyelinating leukodystrophy-18 (HLD-18). We discovered that infertile crescent (ifc), the Drosophila DEGS1 homolog, is expressed primarily in glial cells to promote CNS development by guarding against neurodegeneration. Loss of ifc causes massive dihydroceramide accumulation and severe morphological defects in cortex glia, including endoplasmic reticulum (ER) expansion, failure of neuronal ensheathment, and lipid droplet depletion. RNAi knockdown of the upstream ceramide synthase schlank in glia of ifc mutants rescues ER expansion, suggesting dihydroceramide accumulation in the ER drives this phenotype. RNAi knockdown of ifc in glia but not neurons drives neuronal cell death, suggesting that ifc function in glia promotes neuronal survival. Our work identifies glia as the primary site of disease progression in HLD-18 and may inform on juvenile forms of ALS, which also feature elevated dihydroceramide levels.}, } @article {pmid40864229, year = {2025}, author = {Xu, Y and Raban, MZ and Li, L and Nguyen, AD and Silva, SSM and Huang, G and Arnolda, G and Westbrook, JI and Wabe, N}, title = {Anticholinergic medication use and falls in Australian residential aged care: a retrospective multisite cohort study.}, journal = {Aging clinical and experimental research}, volume = {37}, number = {1}, pages = {257}, pmid = {40864229}, issn = {1720-8319}, support = {APP1170898//Australian National Health and Medical Research Council/ ; APP1170898//Australian National Health and Medical Research Council/ ; }, mesh = {Humans ; *Accidental Falls/statistics & numerical data/prevention & control ; *Cholinergic Antagonists/adverse effects/therapeutic use ; Female ; Male ; Aged ; Retrospective Studies ; Aged, 80 and over ; *Homes for the Aged/statistics & numerical data ; Australia ; New South Wales ; }, abstract = {BACKGROUND: Associations between anticholinergic load and falls remain understudied in residential aged care facilities (RACFs).

AIMS: To examine associations between anticholinergic load and falls in the first year after entry to an RACF.

METHODS: We aggregated routinely collected data from 27 RACFs in New South Wales, Australia. Anticholinergic load and falls were repeatedly measured for one year after residents first entered an RACF. Thirteen 28-day review periods were set. Associations between anticholinergic load in a review period and any falls in the next review period were examined, comprising 12 repeated measurements of associations. We included new residents aged ≥ 65 years, who entered an RACF between 1 July 2014 and 2 September 2021. Six scales were used: Anticholinergic Cognitive Burden (ACB), Anticholinergic Drug Scale (ADS), Anticholinergic Loading Scale (ALS), Anticholinergic Risk Scale (ARS), Chew's list, and Clinician-rated Anticholinergic Score (CrAS). We used mixed-effect logistic regression models, adjusting for potential confounders. Facility was used as a cluster variable.

RESULTS: For the 2300 residents (67.7% females), there were steady increases in mean anticholinergic load from the first to the 12th review period. Per one-point higher anticholinergic load was associated with an increased risk of falls, adjusted odds ratios: 1.08 (95% confidence interval[CI] 1.04, 1.12) using ACB, 1.11 (95%CI 1.06, 1.15) using ADS, 1.15 (95%CI 1.10, 1.21) using ALS, 1.10 (95%CI 1.04, 1.17) using ARS, 1.18 (95%CI 1.09, 1.27) using Chew's list, and 1.14 (95%CI 1.10, 1.19) using CrAS.

CONCLUSION: Anticholinergic scales may be useful to inform falls prevention programs for new RACF residents.}, } @article {pmid40864664, year = {2025}, author = {Popoli, R and Wells, TL and Akay, T}, title = {Unlocking new mechanisms for future ALS therapies: early interventions with cholinergic antagonists reduce neuromuscular decline.}, journal = {Journal of neurophysiology}, volume = {134}, number = {4}, pages = {1257-1272}, doi = {10.1152/jn.00306.2025}, pmid = {40864664}, issn = {1522-1598}, support = {2017//ALS Society of Canada (ALS Canada)/ ; 162357//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Mice ; Male ; Humans ; Female ; *Diamines/pharmacology/administration & dosage ; *Atropine/pharmacology/administration & dosage ; Disease Models, Animal ; *Cholinergic Antagonists/pharmacology ; Muscle, Skeletal/drug effects/innervation ; Mice, Transgenic ; Middle Aged ; Physical Conditioning, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by motor neuron loss, leading to muscle paralysis and death. C-boutons have been shown to be part of the compensatory mechanism behind delayed symptom onset, and are most active during vigorous exercises, like swimming. When mutant mice with silenced C-boutons perform this exercise, disease progression and behavioral performance drastically improve. Genetic manipulation of C-boutons in human patients remains limited, therefore, we sought to manipulate these synapses using cholinergic antagonists in the presence and absence of exercise in a mouse model of ALS. We demonstrate that atropine and methoctramine administration yield significant improvements in human endpoints, weight maintenance, treadmill performance, and grip strength. Most remarkably, muscle innervation was greatly enhanced at humane endpoints compared with controls, suggesting these drugs provide a protective effect against loss of motor control. We found that methoctramine provided greater benefits in the absence of exercise, hinting at the presence of novel cholinergic mechanisms that can be manipulated to preserve motor function. Moreover, we provide evidence that these results are independent of C-boutons, and that methoctramine does not appear to cross the blood-brain barrier (BBB). Our results reveal pharmacological mechanisms by which muscle denervation can be reduced, thereby decreasing the rate of disease progression. We have uncovered a promising avenue for improving ALS symptoms by pharmacologically manipulating cholinergic transmission. This mechanism presents as a possible therapy translatable to the clinical setting, which has the potential to prevent the loss of motor control in patients with ALS.NEW & NOTEWORTHY This study shows that blocking M2 receptors with methoctramine improves motor function and muscle innervation in an amyotrophic lateral sclerosis (ALS) mouse model, particularly in the absence of exercise. Further evaluation suggests that some of these beneficial effects are related to a peripheral mechanism. These findings highlight a potential new therapeutic approach for ALS that targets cholinergic signaling.}, } @article {pmid40864790, year = {2025}, author = {Du, Y and Fan, SS and Wu, H and He, J and He, Y and Meng, XY and Xu, X}, title = {Convergent and Divergent Mitochondrial Pathways as Causal Drivers and Therapeutic Targets in Neurological Disorders.}, journal = {Current issues in molecular biology}, volume = {47}, number = {8}, pages = {}, pmid = {40864790}, issn = {1467-3045}, support = {0801059201//the Research Fund for the Doctoral Program of Anhui Medical University/ ; 82303057//National Natural Science Foundation of China/ ; 2023AFB521//Natural Science Foundation of Hubei Province of China/ ; }, abstract = {Mitochondrial dysfunction is implicated across a spectrum of neurological diseases, yet its causal role and mechanistic specificity remain unclear. This study employed a multi-modal integrative analysis of mitochondrial gene expression in Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Parkinson's Disease (PD) to address these gaps. We combined machine learning for predictive modeling with genetic causal inference methods (Mendelian Randomization, colocalization, PheWAS), followed by drug enrichment analysis and molecular docking. Our machine learning models, particularly Support Vector Machine and Multi-layer Perceptron, effectively classified these conditions, with MS exhibiting the highest predictability (mean Accuracy: 0.758). Causal inference analyses identified specific gene-disease links; for instance, genetically predicted increased expression of PDK1 was causally associated with an elevated risk for both AD (OR = 1.041) and ALS (OR = 1.037), identifying pyruvate metabolism as a shared vulnerability. In contrast, genes like SLC25A38 emerged as highly predictive specifically for PD. We also observed evidence of potential brain-periphery interaction, such as a bidirectional causal relationship between red blood cell indices and MS risk. Finally, drug enrichment analysis highlighted Celecoxib, and subsequent molecular docking predicted a strong binding affinity to PDK1 (docking score S = -6.522 kcal/mol), generating hypotheses for potential metabolic modulation. Taken together, this study provides a computational hypothesis framework suggesting mitochondrial pathways and targets that warrant future biological validation. This study provides specific, genetically supported evidence for the causal role of mitochondrial pathways in neurological diseases and identifies tangible targets for future therapeutic development.}, } @article {pmid40865525, year = {2025}, author = {McEachin, ZT and Chung, M and Stratton, SA and Han, C and Kim, WJ and Sheth, U and Thomas, EV and Issenberg, E and Kamra, T and Merino, P and Levites, Y and Raj, N and Dammer, EB and Duong, DM and Ping, L and Shantaraman, A and Trautwig, AN and Gadhavi, J and Assefa, E and Gearing, M and Kelly, KM and Roemer, SF and DeTure, M and Asress, S and Kukar, T and Fournier, C and Dickson, DW and Petrucelli, L and Golde, TE and Oskarsson, B and Gendron, TF and Seyfried, NT and Glass, JD}, title = {Molecular impact of antisense oligonucleotide therapy in C9orf72-associated ALS.}, journal = {Cell}, volume = {188}, number = {23}, pages = {6424-6435.e17}, pmid = {40865525}, issn = {1097-4172}, support = {RF1 AG079318/AG/NIA NIH HHS/United States ; R01 NS105971/NS/NINDS NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 NS137434/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy/pathology/cerebrospinal fluid/metabolism ; Humans ; *C9orf72 Protein/genetics ; *Oligonucleotides, Antisense/therapeutic use ; Male ; Female ; Spinal Cord/metabolism/pathology ; Middle Aged ; Aged ; Biomarkers/cerebrospinal fluid ; DNA-Binding Proteins/metabolism ; Central Nervous System/metabolism ; }, abstract = {C9orf72-associated amyotrophic lateral sclerosis (c9ALS) is caused by an intronic G4C2 repeat expansion that leads to toxic RNA transcripts and dipeptide repeat proteins (DPRs). A clinical trial using the antisense oligonucleotide (ASO) BIIB078 to target these transcripts was discontinued after failing to provide clinical benefit. Here, we determine the extent of target engagement in the central nervous system (CNS) and elucidate pharmacodynamic cerebrospinal fluid (CSF) biomarkers following treatment. CSF from BIIB078-treated cases showed reduced DPRs and sustained increases in inflammatory biomarkers, including C-C motif chemokine ligand 26 (CCL26). BIIB078 was widely distributed in postmortem CNS tissue; however, DPRs and phosphorylated TDP-43 remained abundant. Proteomic signatures in c9ALS spinal cord were not altered with treatment, although a distinct increase in RNase T2 abundance that correlated with BIIB078 concentration was observed. Thus, despite widespread distribution, BIIB078 did not significantly impact key CNS pathologies, emphasizing the need to identify pharmacodynamic biomarkers that reflect disease-relevant neuropathological changes in response to ASO therapies.}, } @article {pmid40865585, year = {2025}, author = {Xu, C and Naudet, F and Kim, TT and Hengartner, MP and Horowitz, MA and Kirsch, I and Moncrieff, J and Pigott, E and Plöderl, M}, title = {Large responses to antidepressants or methodological artifacts? A secondary analysis of STAR∗D, a single-arm, open-label, nonindustry antidepressant trial.}, journal = {Journal of clinical epidemiology}, volume = {187}, number = {}, pages = {111943}, doi = {10.1016/j.jclinepi.2025.111943}, pmid = {40865585}, issn = {1878-5921}, mesh = {Humans ; *Antidepressive Agents/therapeutic use ; Male ; Female ; Middle Aged ; Adult ; Psychiatric Status Rating Scales ; Treatment Outcome ; *Depression/drug therapy ; Aged ; Artifacts ; *Major Depressive Disorder/drug therapy ; }, abstract = {OBJECTIVES: To replicate Stone et al's (2022) finding that the distribution of response in clinical antidepressant trials is trimodal with large, medium-effect, and small subgroups.

METHODS: To apply finite mixture modeling to pre-post Hamilton Depression Rating Scale (HDRS) differences (n = 2184) of STAR∗D study's level 1, a single-arm, open-label study. For a successful replication, the best fitting model had to be trimodal, with comparable components as in Stone et al. Secondary/sensitivity analyses repeated the analysis for different baseline levels of depression severity, imputed values, and patient-reported depression symptoms.

RESULTS: The best fitting models were either bimodal or trimodal but the trimodal solution did not meet criteria for replication. The bimodal model had 1 component with HDRS mean change of M = -13.0, SD = 6.7 and included 65.3% of patients, and another component with M = -1.8, SD = 5.1, 34.7%, respectively. For the trimodal model, the component with the largest change (M = -14.3, SD = 6.4) applied to 52% of patients, which differed substantially from the large effect component in Stone et al (M = -18.8, SD = 5.1), which applied to 7.2%. Secondary/sensitivity analyses arrived at similar conclusions, and for patient-reported depression symptoms the best fitting models were unimodal or bimodal.

CONCLUSION: This analysis failed to identify the trimodal distribution of response reported in Stone et al. In addition to being difficult to operationalize for regulatory purposes, results from mixture modeling are not sufficiently reliable to replace the more robust approach of comparing mean differences in depression rating scale scores between treatment arms.}, } @article {pmid40865732, year = {2025}, author = {Deighen, MR and Fakult, NJ and Mani, KA and Cullison, CR and Wang, M and Bordeaux, JS and Carroll, BT and Rothermel, LD and Zaorsky, NG}, title = {Response to Sheu et al, "Comments on Fakult et al's 'Epidemiology of Merkel cell carcinoma in the United States'".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {6}, pages = {e229-e230}, doi = {10.1016/j.jaad.2025.08.055}, pmid = {40865732}, issn = {1097-6787}, } @article {pmid40866479, year = {2025}, author = {Waheed, ZA and Colagar, AH and Seyedalipour, B and Baziyar, P}, title = {Uncovering the protein aggregation process through effect of G41D mutant SOD1 charge variation in ALS disease.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {31661}, pmid = {40866479}, issn = {2045-2322}, mesh = {*Superoxide Dismutase-1/genetics/chemistry/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Protein Aggregates ; *Mutation ; *Protein Aggregation, Pathological/genetics ; Amyloid/metabolism/chemistry ; }, abstract = {Neurodegenerative disorders are a group of hereditary and sporadic conditions that are characterized by progressive nervous system dysfunctions. Mutations in the gene encoding human superoxide dismutase 1 (hSOD1) were among the first to be proposed in line with the protein aggregation theory for ALS disease. This study aimed to characterize the (G41D) mutation/charge effects on the biochemical and biophysical properties of the SOD1 structure through computational and experimental methods. The computed average values of RMSD, RMSF, and Rg demonstrate that mutation results in a loss of conformational stability, increased flexibility, and greater compactness, all supporting the observed aggregation. The G41D mutant revealed distinct changes in β-sheet content compared to WT-SOD1 under amyloidogenic conditions, as confirmed by FTIR spectroscopy. Furthermore, the formation of amyloid/amorphous species was identified using ThT/ANS fluorescence and confirmed by TEM analysis. Mutations that alter the net negative charge of the SOD1 protein are crucial in misfolding and shortening the lag phase in SOD1 aggregation. Our results provide supporting evidence that these charge alterations, alongside amyloid-inducing agents at near-physiological pH, significantly contribute to the formation of amyloid-like species. Therefore, studying the G41D mutation may provide valuable insights into the mechanisms of fALS-associated aggregate formation, which holds promise for the development of highly effective inhibitors in reducing aggregates and therapeutic potential.}, } @article {pmid40866928, year = {2025}, author = {Tsang, VSK and Malaspina, A and Henson, SM}, title = {The metabolic intersection between immunosenescence and neuroinflammation in amyotrophic lateral sclerosis.}, journal = {Journal of inflammation (London, England)}, volume = {22}, number = {1}, pages = {36}, pmid = {40866928}, issn = {1476-9255}, support = {BBX009610/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons. Although it is traditionally viewed as a neuron-centric disease, neurodegeneration is increasingly linked to immunosenescence and age-related immune dysfunction, but the mechanisms connecting immune ageing to neurodegeneration remain poorly understood. In this review, we explore how metabolic reprogramming, especially the loss of metabolic plasticity in senescent immune cells, drives neuroinflammation in ALS. Senescent immune cells, including microglia and T cells, exhibit mitochondrial dysfunction, redox imbalance, impaired autophagy, and altered nutrient-sensing pathways that impair their homeostatic and reparative capacities. These cells adopt a metabolically demanding pro-inflammatory phenotype, sustaining an inflammatory secretome while promoting glial activation and neuronal damage. Finally, we discuss how targeting immunometabolic pathways may offer new therapeutic opportunities to restore immune balance, mitigate neuroinflammation, and potentially slow ALS progression. Understanding the metabolic basis of immune ageing is essential for developing effective, age-tailored interventions for ALS.}, } @article {pmid40868211, year = {2025}, author = {Flor, J and Silveira, AT and Martins, IA and Otero, LB and Silva, FM and Vizuete, AFK and Wink, MR and Rigatto, K}, title = {Biological Actions of Alamandine: A Scoping Review.}, journal = {Biomedicines}, volume = {13}, number = {8}, pages = {}, pmid = {40868211}, issn = {2227-9059}, abstract = {Objective: This scoping review aims to comprehensively map the existing literature on the mechanisms of action of Alamandine (ALA), a peptide within the renin-angiotensin system, and its effects across various physiological systems. Materials and Methods: Utilizing the Joanna Briggs Institute methodology, a thorough search of databases including PubMed, Embase, Scopus, and Web of Science was conducted up to 30 January 2025. The review focused on identifying studies that explore the biological and therapeutic roles of ALA in different contexts, incorporating in vivo, in vitro, and in silico research. Results: A total of 590 records were initially identified, with 25 meeting the eligibility criteria for inclusion in this review. China emerged as the leading contributor to the research in this area, with a significant focus on the cardiovascular system. The studies revealed that ALA exhibits a range of beneficial effects, including anti-inflammatory, vasodilatory, antifibrotic, and antiapoptotic actions. These effects are primarily mediated through the inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway and modulation of the nitric oxide pathway. The review also highlighted AL's potential in mitigating oxidative stress and its implications in treating cardiovascular diseases, fibrosis, and cancer. Conclusions: The findings suggest that ALA holds significant therapeutic potential, offering antihypertensive, anti-inflammatory, antifibrotic, and anticancer benefits without notable adverse effects, warranting further research to explore its full potential and mechanism of action.}, } @article {pmid40868276, year = {2025}, author = {Voicu, V and Toader, C and Șerban, M and Covache-Busuioc, RA and Ciurea, AV}, title = {Systemic Neurodegeneration and Brain Aging: Multi-Omics Disintegration, Proteostatic Collapse, and Network Failure Across the CNS.}, journal = {Biomedicines}, volume = {13}, number = {8}, pages = {}, pmid = {40868276}, issn = {2227-9059}, abstract = {Neurodegeneration is increasingly recognized not as a linear trajectory of protein accumulation, but as a multidimensional collapse of biological organization-spanning intracellular signaling, transcriptional identity, proteostatic integrity, organelle communication, and network-level computation. This review intends to synthesize emerging frameworks that reposition neurodegenerative diseases (ND) as progressive breakdowns of interpretive cellular logic, rather than mere terminal consequences of protein aggregation or synaptic attrition. The discussion aims to provide a detailed mapping of how critical signaling pathways-including PI3K-AKT-mTOR, MAPK, Wnt/β-catenin, and integrated stress response cascades-undergo spatial and temporal disintegration. Special attention is directed toward the roles of RNA-binding proteins (e.g., TDP-43, FUS, ELAVL2), m6A epitranscriptomic modifiers (METTL3, YTHDF1, IGF2BP1), and non-canonical post-translational modifications (SUMOylation, crotonylation) in disrupting translation fidelity, proteostasis, and subcellular targeting. At the organelle level, the review seeks to highlight how the failure of ribosome-associated quality control (RQC), autophagosome-lysosome fusion machinery (STX17, SNAP29), and mitochondrial import/export systems (TIM/TOM complexes) generates cumulative stress and impairs neuronal triage. These dysfunctions are compounded by mitochondrial protease overload (LONP1, CLPP), UPR maladaptation, and phase-transitioned stress granules that sequester nucleocytoplasmic transport proteins and ribosomal subunits, especially in ALS and FTD contexts. Synaptic disassembly is treated not only as a downstream event, but as an early tipping point, driven by impaired PSD scaffolding, aberrant endosomal recycling (Rab5, Rab11), complement-mediated pruning (C1q/C3-CR3 axis), and excitatory-inhibitory imbalance linked to parvalbumin interneuron decay. Using insights from single-cell and spatial transcriptomics, the review illustrates how regional vulnerability to proteostatic and metabolic stress converges with signaling noise to produce entropic attractor collapse within core networks such as the DMN, SN, and FPCN. By framing neurodegeneration as an active loss of cellular and network "meaning-making"-a collapse of coordinated signal interpretation, triage prioritization, and adaptive response-the review aims to support a more integrative conceptual model. In this context, therapeutic direction may shift from damage containment toward restoring high-dimensional neuronal agency, via strategies that include the following elements: reprogrammable proteome-targeting agents (e.g., PROTACs), engineered autophagy adaptors, CRISPR-based BDNF enhancers, mitochondrial gatekeeping stabilizers, and glial-exosome neuroengineering. This synthesis intends to offer a translational scaffold for viewing neurodegeneration as not only a disorder of accumulation but as a systems-level failure of cellular reasoning-a perspective that may inform future efforts in resilience-based intervention and precision neurorestoration.}, } @article {pmid40868609, year = {2025}, author = {Lisiecka, D and Dyson, N and Malpress, K and Smith, A and McNeice, E and Shack, P and Hutchinson, K}, title = {'Finally, in Hands I Can Trust': Perspectives on Trust in Motor Neurone Disease Care.}, journal = {Healthcare (Basel, Switzerland)}, volume = {13}, number = {16}, pages = {}, pmid = {40868609}, issn = {2227-9032}, abstract = {Integrated multidisciplinary care is recognised as essential for people living with motor neurone disease (PlwMND) and their families. The values underpinning integrated care, such as person-centredness, respect, empowerment, and co-production, are central to delivering meaningful and comprehensive support. Trust is an essential yet often overlooked element of effective person- and family-centred integrated care, particularly for PlwMND. While specialist multidisciplinary MND clinics represent the benchmark for evidence-based care, many PlwMND and their families depend significantly on local and community-based support services to maintain quality of life. Trust directly influences their engagement with these services and the continuity of care provided. Trust enables understanding of personal priorities and how they change as the disease progresses, ultimately allowing for person-centred care to happen. Trust is necessary to enable service co-production, which is a strong value of integrated care. Research highlights seven key domains of support essential to PlwMND and their carers: practical, social, informational, psychological, physical, emotional, and spiritual. Effective integrated care requires strong relationships built upon trust, shared decision-making, respect for individuality, and clear communication. Furthermore, due to the rapidly progressive nature of MND, care priorities and perceived symptom burdens may shift significantly over short periods, making flexible, temporally sensitive approaches critical. A dynamic, inclusive model of decision-making that fosters autonomy within and regular co-review of needs is recommended. This perspective paper examines how person- and family-centred integrated care is currently being delivered, what is working well, and how these practices can be further strengthened to enhance the care experiences of PlwMND, their families, and the health and social care providers involved. This paper builds on both theoretical knowledge and clinical experience to offer our perspective on the critical role of trust in co-producing integrated care for PlwMND. It brings together the voices of clinicians and researchers, alongside those with lived experience of MND. We propose a diagram of care that embeds the core values of integrated, person-centred care within the specific context of MND. Our aim is to enhance collaborative practices, strengthen cross-sector partnerships, and ultimately improve the care experiences for professionals, PlwMND, and their families.}, } @article {pmid40869205, year = {2025}, author = {Lewandowski, D and Konieczny, M and Różycka, A and Chrzanowski, K and Owecki, W and Kalinowski, J and Stepura, M and Jagodziński, P and Dorszewska, J}, title = {Cathepsins in Neurological Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {16}, pages = {}, pmid = {40869205}, issn = {1422-0067}, mesh = {Humans ; *Cathepsins/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; Lysosomes/metabolism ; Biomarkers/metabolism ; }, abstract = {Cathepsins, a family of lysosomal proteases, play critical roles in maintaining cellular homeostasis through protein degradation and modulation of immune responses. In the central nervous system (CNS), their functions extend beyond classical proteolysis, influencing neuroinflammation, synaptic remodeling, and neurodegeneration. Emerging evidence underscores the crucial role of microglial cathepsins in the pathophysiology of several neurological disorders. This review synthesizes current knowledge on the involvement of cathepsins in a spectrum of CNS diseases, including Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, Huntington's disease, and ischemic stroke. We highlight how specific cathepsins contribute to disease progression by modulating key pathological processes such as α-synuclein and amyloid-β clearance, tau degradation, lysosomal dysfunction, neuroinflammation, and demyelination. Notably, several cathepsins demonstrate both neuroprotective and pathogenic roles depending on disease context and expression levels. Additionally, the balance between cathepsins and their endogenous inhibitors, such as cystatins, emerges as a critical factor in CNS pathology. While cathepsins represent promising biomarkers and therapeutic targets, significant gaps remain in our understanding of their mechanistic roles across diseases. Future studies focusing on their regulation, substrate specificity, and interplay with genetic and epigenetic factors may yield novel strategies for early diagnosis and disease-modifying treatments in neurology.}, } @article {pmid40869392, year = {2025}, author = {Șerban, M and Toader, C and Covache-Busuioc, RA}, title = {Blueprint of Collapse: Precision Biomarkers, Molecular Cascades, and the Engineered Decline of Fast-Progressing ALS.}, journal = {International journal of molecular sciences}, volume = {26}, number = {16}, pages = {}, pmid = {40869392}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology/diagnosis ; Humans ; *Biomarkers/metabolism ; Disease Progression ; Animals ; Mitochondria/metabolism ; Precision Medicine ; Neurofilament Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is still a heterogeneous neurodegenerative disorder that can be identified clinically and biologically, without a strong set of biomarkers that can adequately measure its fast rate of progression and molecular heterogeneity. In this review, we intend to consolidate the most relevant and timely advances in ALS biomarker discovery, in order to begin to bring molecular, imaging, genetic, and digital areas together for potential integration into a precision medicine approach to ALS. Our goal is to begin to display how several biomarkers in development (e.g., neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), TDP-43 aggregates, mitochondrial stress markers, inflammatory markers, etc.) are changing our understanding of ALS and ALS dynamics. We will attempt to provide a framework for thinking about biomarkers in a systematic way where our candidates are not signals alone but part of a tethered pathophysiological cascade. We are particularly interested in the fast progressor phenotype, a devastating and under-characterized subset of ALS due to a rapid axonal degeneration, early respiratory failure, and very short life span. We will try to highlight the salient molecular features of this ALS subtype, including SOD1 A5V toxicity, C9orf72 repeats, FUS variants, mitochondrial collapse, and impaired autophagy mechanisms, and relate these features to measurable blood and CSF (biomarkers) and imaging platforms. We will elaborate on several interesting tools, for example, single-cell transcriptomics, CSF exosomal cargo analysis, MRI techniques, and wearable sensor outputs that are developing into high-resolution windows of disease progression and onset. Instead of providing a static catalog, we plan on providing a conceptual roadmap to integrate biomarker panels that will allow for earlier diagnosis, real-time disease monitoring, and adaptive therapeutic trial design. We hope this synthesis will make a meaningful contribution to the shift from observational neurology to proactive biologically informed clinical care in ALS. Although there are still considerable obstacles to overcome, the intersection of a precise molecular or genetic association approach, digital phenotyping, and systems-level understandings may ultimately redefine how we monitor, care for, and treat this challenging neurodegenerative disease.}, } @article {pmid40870005, year = {2025}, author = {Jeong, J and Kim, J and Kim, MS}, title = {Dual Nature of Mitochondrial Integrated Stress Response: Molecular Switches from Protection to Pathology.}, journal = {Genes}, volume = {16}, number = {8}, pages = {}, pmid = {40870005}, issn = {2073-4425}, mesh = {Humans ; *Mitochondria/metabolism/pathology/genetics ; *Stress, Physiological ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; }, abstract = {BACKGROUND: The mitochondrial integrated stress response (ISR) represents a fundamental cellular adaptation mechanism with dual protective and pathological roles. We critically analyzed current literature on ISR mechanisms, focusing on recent paradigm shifts including the 2020 discovery of the OMA1-DELE1-HRI axis, emerging controversies over context-dependent activation patterns, and the January 2025 clinical trial failures that have reshaped the therapeutic landscape.

METHODS: We reviewed recent literature (2020-2025) examining ISR mechanisms, clinical trials, and therapeutic developments through comprehensive database searches.

RESULTS: The field has evolved from simple linear pathway models to recognition of complex, context-dependent networks. Recent findings reveal that ISR activation mechanisms vary dramatically based on cellular metabolic state, with distinct pathways operating in proliferating versus differentiated cells. The "dark microglia" phenotype in neurodegeneration and DR5-mediated apoptotic switches exemplify pathological ISR manifestations, while adaptive responses include metabolic reprogramming and quality control enhancement.

CONCLUSIONS: The 2025 failures of DNL343 and ABBV-CLS-7262 in ALS trials underscore the need for precision medicine approaches that account for context-dependent ISR functions, temporal dynamics, and disease-specific mechanisms.}, } @article {pmid40870776, year = {2025}, author = {Semyalo, D and Joshi, R and Kim, Y and Omia, E and Alal, LB and Kim, MS and Baek, I and Cho, BK}, title = {Short-Wavelength Infrared Hyperspectral Imaging and Spectral Unmixing Techniques for Detection and Distribution of Pesticide Residues on Edible Perilla Leaves.}, journal = {Foods (Basel, Switzerland)}, volume = {14}, number = {16}, pages = {}, pmid = {40870776}, issn = {2304-8158}, support = {N/A//Chungnam National University/ ; }, abstract = {Pesticide residue analysis of agricultural produce is vital because of associated health concerns, highlighting the need for effective non-destructive techniques. This study introduces a method that combines short-wavelength infrared hyperspectral imaging with spectral unmixing to detect chlorfenapyr and azoxystrobin residues on perilla leaves. Sixty-six leaves were treated with pesticides at concentrations between 0 and 0.06%. The study utilized multicurve resolution-alternating least squares (MCR-ALS), a spectral unmixing method, to identify and visualize the distribution of pesticide residues. This technique achieved lack-of-fit values of 1.03% and 1.78%, with an explained variance of 99% for both pesticides. Furthermore, a quantitative model was developed that integrates insights from MCR-ALS with Gaussian process regression to estimate chlorfenapyr residue concentrations, resulting in a root mean square error of double cross-validation (RMSEV) of 0.0012% and a double cross-validation coefficient of determination (R[2]v) of 0.99. Compared to other chemometric approaches, such as partial least squares regression and support vector regression, the proposed integrated method decreased RMSEV by 67.57% and improved R[2]v by 2.06%. The combination of hyperspectral imaging with spectral unmixing offers advancements in the real-time monitoring of agricultural product safety, supporting the delivery of high-quality fresh vegetables to consumers.}, } @article {pmid40871062, year = {2025}, author = {Yang, HM}, title = {Overcoming the Blood-Brain Barrier: Advanced Strategies in Targeted Drug Delivery for Neurodegenerative Diseases.}, journal = {Pharmaceutics}, volume = {17}, number = {8}, pages = {}, pmid = {40871062}, issn = {1999-4923}, support = {03-2025-0200//Seoul National University Hospital/ ; }, abstract = {The increasing global health crisis of neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's disease is worsening because of a rapidly increasing aging population. Disease-modifying therapies continue to face development challenges due to the blood-brain barrier (BBB), which prevents more than 98% of small molecules and all biologics from entering the central nervous system. The therapeutic landscape for neurodegenerative diseases has recently undergone transformation through advances in targeted drug delivery that include ligand-decorated nanoparticles, bispecific antibody shuttles, focused ultrasound-mediated BBB modulation, intranasal exosomes, and mRNA lipid nanoparticles. This review provides an analysis of the molecular pathways that cause major neurodegenerative diseases, discusses the physiological and physicochemical barriers to drug delivery to the brain, and reviews the most recent drug targeting strategies including receptor-mediated transcytosis, cell-based "Trojan horse" approaches, gene-editing vectors, and spatiotemporally controlled physical methods. The review also critically evaluates the limitations such as immunogenicity, scalability, and clinical translation challenges, proposing potential solutions to enhance therapeutic efficacy. The recent clinical trials are assessed in detail, and current and future trends are discussed, including artificial intelligence (AI)-based carrier engineering, combination therapy, and precision neuro-nanomedicine. The successful translation of these innovations into effective treatments for patients with neurodegenerative diseases will require essential interdisciplinary collaboration between neuroscientists, pharmaceutics experts, clinicians, and regulators.}, } @article {pmid40872233, year = {2025}, author = {Garcia-Sherman, MC and Hamid, SA and Jackson, DN and Thomas, J and Lipke, PN}, title = {Functional Amyloids in Adhesion of Non-albicans Candida Species.}, journal = {Pathogens (Basel, Switzerland)}, volume = {14}, number = {8}, pages = {}, pmid = {40872233}, issn = {2076-0817}, support = {R01 GM098616/GM/NIGMS NIH HHS/United States ; 1R01GM098616-01/NH/NIH HHS/United States ; }, mesh = {Humans ; *Cell Adhesion ; *Candida/physiology/metabolism ; *Amyloid/metabolism ; Biofilms/growth & development ; Fungal Proteins/metabolism ; Candida albicans ; Candidiasis/microbiology ; Epithelial Cells/microbiology ; }, abstract = {Candida fungal species are the most common fungal opportunistic pathogens. Their ability to form antifungal resistant biofilms contributes to their increasing clinical frequency. These fungi express surface-anchored adhesins including members of the Als family. These adhesins mediate epithelial adhesion, aggregation, and biofilm formation. Many of the adhesins contain cross-β core sequences that form amyloid-like protein aggregates on the fungal surface. The aggregates mediate high-avidity bonding that contributes to biofilm establishment and persistence. Accordingly, autopsy sections from individuals with candidiasis and other mycoses have amyloids within abscesses. An amyloid-forming peptide containing a sequence from Candida albicans Als5 bound to C. albicans, C. tropicalis, and C. parapsilosis. C. albicans and C. tropicalis aggregated with beads coated with serum albumin, and the aggregates stained with the amyloid-binding dye thioflavin T. Additionally, an Als5-derived amyloid-inhibiting peptide blocked cell aggregation. The amyloid-inhibiting peptide also blocked C. albicans, C. tropicalis, and C. parapsilosis adhesion to monolayers of FaDu epithelial cells. These results show the involvement of amyloid-like interactions in pathogenesis in several Candida species.}, } @article {pmid40873038, year = {2026}, author = {Dulski, J and Boddapati, AK and Risi, B and Iruzubieta, P and Orlacchio, A and Fernández-Torrón, R and Castillo-Triviño, T and López de Munain, A and Vucic, S and Padovani, A and Kaat, LD and Barakat, TS and Petrucelli, L and Prudencio, M and Landers, JE and Weishaupt, JH and Prokop, A and Filosto, M and Wszolek, ZK and Pant, DC}, title = {Targeted plasma proteomics uncover proteins associated with KIF5A-linked SPG10 and ALS spectrum disorders.}, journal = {HGG advances}, volume = {7}, number = {1}, pages = {100498}, pmid = {40873038}, issn = {2666-2477}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics ; *Kinesins/genetics ; *Proteomics/methods ; Male ; Female ; Middle Aged ; *Spastic Paraplegia, Hereditary/blood/genetics ; Biomarkers/blood ; Adult ; *Proteome ; Aged ; }, abstract = {KIF5A (Kinesin family member 5A) is a motor protein that functions as a key component of the axonal transport machinery. Variants in KIF5A are linked to several neurodegenerative diseases, mainly spastic paraplegia type 10 (SPG10), Charcot-Marie-Tooth disease type 2 (CMT2), and amyotrophic lateral sclerosis (ALS). These diseases share motor neuron involvement but vary significantly in clinical presentation, severity, and progression. KIF5A variants are mainly categorized into N-terminal variants associated with SPG10/CMT2 and C-terminal variants linked to ALS. This study utilized a multiplex NULISA targeted platform to analyze plasma proteome from KIF5A-linked SPG10 and ALS individuals and compare them to healthy controls. Our results revealed distinct proteomic signatures, with significant alterations in proteins related to synaptic function and inflammation. Notably, neurofilament light polypeptide, a biomarker for neurodegenerative diseases, was elevated in KIF5A ALS but not in SPG10 individuals. Moreover, these findings can now be used to gain mechanistic understanding of axonopathies linking to N- versus C-terminal KIF5A variants affecting both central and peripheral nervous systems.}, } @article {pmid40874900, year = {2026}, author = {Shive, M and Hawryluk, E and Drucker, AM and Frazer-Green, L}, title = {Response to Chu et al's "Atopic dermatitis (eczema) guidelines: 2023 American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters GRADE- and Institute of Medicine-based recommendations".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {1}, pages = {196-199}, doi = {10.1016/j.jaad.2025.07.061}, pmid = {40874900}, issn = {1097-6787}, } @article {pmid40875372, year = {2025}, author = {Ghaffari, LT and Welebob, EA and Newton, SEB and Boehringer, AV and Cyliax, KL and Pasinelli, P and Trotti, D and Haeusler, AR}, title = {Neuronal activity-dependent gene dysregulation in C9orf72 i[3]Neuronal models of ALS/FTD pathogenesis.}, journal = {American journal of physiology. Cell physiology}, volume = {329}, number = {4}, pages = {C1085-C1100}, pmid = {40875372}, issn = {1522-1563}, support = {RF1 NS114128/NS/NINDS NIH HHS/United States ; R01NS109150//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; RF1NS114128//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NA//Aldrich Foundation/ ; R01 NS109150/NS/NINDS NIH HHS/United States ; R01 NS114128/NS/NINDS NIH HHS/United States ; NA//Farber Family Foundation/ ; R01NS114128//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism/pathology ; *Neurons/metabolism/pathology ; Transcriptome ; Animals ; DNA Repeat Expansion ; Gene Expression Regulation ; }, abstract = {The GGGGCC nucleotide repeat expansion (NRE) mutation in the C9ORF72 (C9) gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal activity plays an essential role in shaping biological processes within both healthy and neurodegenerative disease scenarios. Here, we show that at baseline conditions, C9-NRE-induced pluripotent stem cell-cortical neurons display aberrations in several pathways, including synaptic signaling and transcriptional machinery, potentially priming diseased neurons for an altered response to neuronal stimulation. Indeed, exposure to two pathophysiologically relevant stimulation modes, prolonged membrane depolarization or a blockade of K[+] channels, followed by RNA sequencing, induces a temporally divergent activity-dependent transcriptome of C9-NRE cortical neurons compared with healthy controls. This study provides new insights into how neuronal activity influences the ALS/FTD-associated transcriptome, offering a dataset that enables further exploration of pathways necessary for conferring neuronal resilience or degeneration.NEW & NOTEWORTHY A recent study using iPSC-derived cortical neurons reveals how neuronal activity drives gene dysregulation in C9ORF72-linked ALS/FTD. We uncover synaptic dysfunction, peroxisomal dysregulation, and NPAS4-linked transcriptional shifts, highlighting key disease-modifying pathways. Could these insights pave the way for new therapeutic targets? Explore our research and generate your own discoveries using our interactive dataset included in the link in the article.}, } @article {pmid40876427, year = {2025}, author = {Ibrahim, SI and Zaher, DM and Hersi, FA and Hamouda, AO and Al Hindawi, MA and Omar, HA}, title = {Repurposing edaravone in oncology: Bridging antioxidant defense and immune modulation.}, journal = {International immunopharmacology}, volume = {164}, number = {}, pages = {115413}, doi = {10.1016/j.intimp.2025.115413}, pmid = {40876427}, issn = {1878-1705}, mesh = {Humans ; *Edaravone/therapeutic use/pharmacology ; *Neoplasms/drug therapy/immunology ; Animals ; Drug Repositioning ; *Antioxidants/therapeutic use/pharmacology ; Tumor Microenvironment/drug effects ; *Antineoplastic Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; *Immunomodulating Agents/therapeutic use/pharmacology ; Immunomodulation/drug effects ; }, abstract = {Edaravone, a synthetic free radical scavenger originally approved for neurological disorders such as stroke and amyotrophic lateral sclerosis (ALS), is gaining attention for its emerging potential role in cancer. Beyond its well-established antioxidant properties, edaravone demonstrates significant anti-inflammatory and immunomodulatory activities, including the inhibition of key pathways such as NF-κB, JAK2/STAT3, and TLR4/IL-6, suggesting potential to modulate immune responses within the tumor microenvironment. This review discusses how edaravone disrupts oncogenic signaling, induces cell cycle arrest, and enhances apoptosis, particularly in cancer stem cells and therapy-resistant models. It also examines edaravone's dual role in combination therapies, where it may improve the cytotoxicity of chemotherapeutic and radiotherapeutic agents while simultaneously protecting normal tissues from treatment-induced toxicities. By linking mechanistic insights with therapeutic outcomes, this review highlights the rationale for repurposing edaravone as a potential adjuvant in cancer therapy. Although clinical data are currently limited, preliminary findings are encouraging and warrant further investigation into edaravone's potential use in cancer treatment regimens.}, } @article {pmid40877115, year = {2026}, author = {Hu, N and Ding, J and Tian, H and Shen, D and Yang, X and Niu, J and Liu, M and Cui, L}, title = {Impacts of oral supplementation of vitamin B12 and plasma levels of homocysteine on progression and survival in a Chinese ALS cohort.}, journal = {Neurological research}, volume = {48}, number = {7}, pages = {957-965}, doi = {10.1080/01616412.2025.2553147}, pmid = {40877115}, issn = {1743-1328}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Administration, Oral ; *Amyotrophic Lateral Sclerosis/blood/mortality/drug therapy/diet therapy ; China ; Cohort Studies ; Dietary Supplements ; Disease Progression ; Folic Acid/blood ; Follow-Up Studies ; *Homocysteine/blood ; *Vitamin B 12/blood/administration & dosage/therapeutic use ; East Asian People ; }, abstract = {OBJECTIVE: We investigate the impact of plasma levels of folate, vitamin B12 (VB12), homocysteine (HCY) and oral supplementation of folate and VB12 on amyotrophic lateral sclerosis (ALS) progression and survival.

METHODS: Patients with sporadic ALS were consecutively enrolled and regularly followed up. Oral supplementation of folate and VB12 was recommended to all involved patients. Tests of plasma levels of folate, VB12 and HCY were conducted before or after medication.

RESULTS: A total of 120 sporadic ALS patients with results of plasma folate, VB12 or HCY were finally included. Oral supplementation of VB12 significantly increased the plasma levels of folate (p < 0.01) and VB12 (p < 0.01), and lower HCY (p < 0.001). The progression rate of ALS patients in the first 3-6 months was negatively related to the plasma level of VB12 (p = 0.008). After taking VB supplements, the progression rate in the first 3-6 months was comparable to previous progression rate (p = 0.102) and significantly lower than that in the 9-12 month follow-up (p < 0.01). There was no significant difference in survival time between the two groups that took VB12 and those who did not take it neither between patients with high and low serum levels of folate, VB12 or HCY.

CONCLUSION: Oral intake of VB12 supplements may significantly increase plasma levels of folate and VB12 and decrease plasma levels of HCY in ALS patients. Oral supplementation of folate and VB12, and subsequent high levels of VB12 in serum, may lower the ALS progression at the early stages but show no significant impact on ALS survival time.}, } @article {pmid40878249, year = {2025}, author = {Silva, MM and Cunha, EM and Briois, V and Rochet, A}, title = {Unraveling hydride dynamics on cubic palladium nanoparticles.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {27}, number = {36}, pages = {19358-19364}, doi = {10.1039/d5cp02672e}, pmid = {40878249}, issn = {1463-9084}, abstract = {Palladium-based materials exhibit a high affinity for hydrogen molecules, enabling the effortless formation of a hydride phase. This property is widely exploited in several catalytic reactions and hydrogen storage materials. However, the effects of morphological parameters, support interactions, and formation kinetics remain incompletely understood. In this work, we applied in situ time-resolved X-ray absorption spectroscopy (XAS) to investigate the impact of nanoparticle sizes and support materials on the dynamic formation of palladium hydrides during thermal treatment under H2. A detailed analysis using multivariate curve resolution with alternating least squares (MCR-ALS) enabled the extraction of concentration profiles and the identification of pure species involved in the process, thereby revealing distinct kinetic behaviours across the samples. This study provides valuable insights into how particle size and support influence the kinetics of hydrogen absorption in palladium systems, which can significantly impact catalytic performance.}, } @article {pmid40878665, year = {2025}, author = {Abrahao, A and Da Silva, P and Ciepielewska, M and Zinman, L}, title = {Real-world safety and tolerability of intravenous edaravone in patients with amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {15}, number = {6}, pages = {305-312}, pmid = {40878665}, issn = {1758-2032}, mesh = {Humans ; *Edaravone/administration & dosage/adverse effects/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; *Free Radical Scavengers/administration & dosage/adverse effects ; }, abstract = {AIMS: This retrospective cohort study describes real-world safety and tolerability outcomes in United States-based edaravone-treated patients with ALS.

PATIENTS & METHODS: Amerita Specialty Infusion Services provided IV edaravone to patients with ALS treated with their first dose between 25 September 2017-30 September 2022. Mean ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) %-predicted measures were recorded within ± 100 days from care initiation to approximate baseline values.

RESULTS: Included patients (n = 243) received/were still receiving IV edaravone/edaravone oral suspension as of 30 September 2022. At initiation, 66.7% were male, mean age ± SD was 61.2 ± 11.2 years, and 61.3% were covered by government insurance. In patients with provider-recorded ALSFRS-R (n = 115) and FVC (n = 84) %-predicted measures within ± 100 days from care initiation, mean ± SD values were 35.1 ± 8.9 and 72.3% ± 21.7%, respectively. Mean ± SD therapy duration was 13.5 ± 11.4 months. Discontinuation reasons included death/hospice (n = 82), patient's choice (n = 38), doctor's choice (n = 31), insurance (n = 18), and other (n = 12). Reasons for IV edaravone discontinuation and IV edaravone administration access device were not associated.

CONCLUSIONS: Treatment discontinuation was primarily related to ALS disease progression/death, rather than safety or tolerability. This study representative of real-world patients with ALS suggests that edaravone showed consistent safety and tolerability profiles with previous studies.}, } @article {pmid40878817, year = {2025}, author = {Lester, DG and Talbot, K and Turner, MR and Thompson, AG and , }, title = {A Validated Model to Predict Severe Weight Loss in Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {9}, pages = {1907-1912}, pmid = {40878817}, issn = {2328-9503}, support = {Lester/2450/795/MNDA_/Motor Neurone Disease Association/United Kingdom ; Thompson/Jan20/952-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; MR/Y001095/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; *Weight Loss/physiology ; Female ; Male ; Middle Aged ; Aged ; Adult ; Severity of Illness Index ; }, abstract = {Severe weight loss in amyotrophic lateral sclerosis (ALS) is common, multifactorial, and associated with shortened survival. Using longitudinal weight data from over 6000 patients with ALS across three cohorts, we built an accelerated failure time model to predict the risk of future severe (≥ 10%) weight loss using five single-timepoint clinical predictors: symptom duration, revised ALS Functional Rating Scale, site of onset, forced vital capacity, and age. Model performance and generalisability were evaluated using internal-external cross-validation and random-effects meta-analysis. The overall concordance statistic was 0.71 (95% CI 0.63-0.79), and the calibration slope and intercept were 0.91 (0.69-1.13) and 0.05 (-0.11-0.21). This study highlights clinical factors most associated with severe weight loss in ALS and provides the basis for a stratification tool.}, } @article {pmid40878928, year = {2026}, author = {Chakraborty, A and Benassy, MN and Weil, D and Kundu, B}, title = {Optineurin Localization at the Centrosome, Spindle, and Midbody Implies Its Role in Cell Division.}, journal = {Cytoskeleton (Hoboken, N.J.)}, volume = {83}, number = {5}, pages = {250-258}, doi = {10.1002/cm.70015}, pmid = {40878928}, issn = {1949-3592}, mesh = {Humans ; *Centrosome/metabolism ; *Cell Cycle Proteins/metabolism ; HeLa Cells ; *Spindle Apparatus/metabolism ; Membrane Transport Proteins/metabolism ; *Cell Division/physiology ; *Transcription Factor TFIIIA/metabolism ; HEK293 Cells ; Mitosis ; }, abstract = {Optineurin (OPTN), a multifunctional cytosolic protein, is recognized as an autophagy adaptor. Its association with neurodegenerative diseases, like ALS, triggered extensive research. OPTN has been found in intracellular organelles, including the mitochondria, Golgi body, endosomes, microtubules, and the nucleus. The report of mitotic defects and delayed cell division in OPTN-depleted cells prompted us to explore OPTN's exact localization in the cell that could interfere with cell division assemblies. We used three distinct human cell lines, HeLa, HEK293, and SH-SY5Y, and probed them for OPTN localization using both centrosomal (Aurora A kinase, pericentrin, PCM1, Cep170, and γ-tubulin) and mitotic spindle markers (β-tubulin). Our immunofluorescence-based detection using wide-field fluorescence, confocal, and structured illumination microscopy (SIM) placed OPTN at the centrosome, which remained associated with the centriole after duplication and their migration during mitosis. OPTN was also observed at the junction of daughter cells during cytokinesis. Our finding reveals unmapped localizations of OPTN with key cytosolic assemblies that are directly involved in cell division.}, } @article {pmid40879079, year = {2025}, author = {Talbot, K and Thompson, AG}, title = {Unpacking the relationship between exercise and amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {10}, pages = {3431-3432}, doi = {10.1093/brain/awaf310}, pmid = {40879079}, issn = {1460-2156}, support = {/MRC_/Medical Research Council/United Kingdom ; //Lady Edith Wolfson Clinician Scientist Fellowship/ ; //NIHR Oxford Biomedical Research Centre/ ; //MND Association/ ; //LifeArc/ ; //My Name'5 Doddle Foundation/ ; //Alan Davidson Foundation/ ; //MND Scotland/ ; //Oxford/GSK Institute for Molecular and Computational Medicine/ ; }, } @article {pmid40879603, year = {2026}, author = {Karimi, S and Ghaheri, A and Madani, H and Beheshti Maal, A and Sadri, B and Khodadoust, E and Sharafi, F and Vosough, M and Nabavi, SM}, title = {Intravenous vs intrathecal transplantation of allogeneic GMP/GCP compliant Wharton's jelly mesenchymal stromal cells in ALS patients: a phase I study.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {1}, pages = {33-41}, pmid = {40879603}, issn = {1758-2032}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Mesenchymal Stem Cell Transplantation/methods ; Middle Aged ; Female ; Male ; Aged ; Adult ; Injections, Spinal ; Mesenchymal Stem Cells ; *Wharton Jelly/cytology ; Treatment Outcome ; Transplantation, Homologous/methods ; }, abstract = {INTRODUCTION: There are a few therapeutic approaches for Amyotrophic Lateral Sclerosis (ALS) which can only slow down or stop the disease progression for a limited period of time. Since it has been proven that Mesenchymal Stromal Cells (MSCs) produce neurotrophic factors and have some neuroprotective effects, stem cell therapy has been proposed as an alternative or add-on treatment for ALS patients.

METHOD & MATERIAL: In this open-label clinical trial, two-repeated dose of 60 million GMP compliant Wharton's Jelly-derived Mesenchymal Stromal Cells (WJ-MSCs) were transplanted intrathecally (#6 patients) or intravenously (#6 patients) twice with a 3-month interval.

RESULTS: No adverse events related to the intervention or injected cells were reported. While no significant improvement in the total revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) score or overall clinical efficacy was achieved, patients reported improvements in specific sub-items such as salivation, swallowing, and their speech. Additionally, reductions in muscle tremors and fasciculations, as well as increased muscle strength were observed.

CONCLUSION: In conclusion, using WJ-MSCs is safe and feasible in ALS patients, but the efficacy of these cells should be assessed in future studies with more patients, different routes of cell administration, and maybe with higher doses of the injected cells.}, } @article {pmid40881516, year = {2025}, author = {Swarnakar, R}, title = {Brain-Computer Interfaces in Rehabilitation: Implementation Models and Future Perspectives.}, journal = {Cureus}, volume = {17}, number = {7}, pages = {e88873}, pmid = {40881516}, issn = {2168-8184}, abstract = {Brain-computer interfaces (BCIs) represent an emerging advancement in rehabilitation, enabling direct communication between the brain and external devices to aid recovery in individuals with neurological impairments. BCIs can be classified into invasive, semi-invasive, non-invasive, or hybrid types. By interpreting neural signals and converting them into control commands, BCIs can bypass damaged pathways, offering therapeutic potential for conditions such as stroke, spinal cord injury, traumatic brain injury, and neurodegenerative diseases such as amyotrophic lateral sclerosis. BCIs' current applications, such as motor restoration via robotic exoskeletons and functional electrical stimulation, cognitive enhancement through neurofeedback and attention training, and communication tools for individuals with severe physical limitations, are largely being explored within research settings and are not yet part of routine clinical practice. Advances in EEG signal acquisition, machine learning, wearable and wireless systems, and integration with virtual reality are enhancing the clinical utility of BCIs by improving accuracy, adaptability, and usability. However, widespread clinical adoption faces challenges, including signal variability, training complexity, data privacy, and ethical and regulatory issues. Ethical challenges in BCI include issues related to the ownership and misuse of brain data, risks of neural interference, threats to autonomy and personal identity, as well as concerns around data privacy, user consent, emotional manipulation, and accountability in neural interventions. In this context, this editorial has also proposed one model (NEURO model checklist) for BCI implementation in rehabilitation. The future of BCIs in rehabilitation lies in developing personalized, closed-loop, and home-based systems, enabled by interdisciplinary collaboration among clinicians, engineers, neuroscientists, and policymakers. With continued research and ethical implementation, BCIs have the potential to transform neurorehabilitation and greatly enhance patient outcomes and quality of life.}, } @article {pmid40881531, year = {2025}, author = {Chase, RC and Cortes, P and Lamb, CJ and Francis, D and DeVault, KR and Pang, M}, title = {Factors That Predict Endoscopic Evaluation and Gastrostomy Placement in Patients With Neurologic Disorders and Dysphagia.}, journal = {Cureus}, volume = {17}, number = {7}, pages = {e88853}, pmid = {40881531}, issn = {2168-8184}, abstract = {BACKGROUND: Although patients with neurologic disorders commonly develop dysphagia, there remains little consensus on the role of initial esophagogastroduodenoscopy (EGD) or temporal guidance on gastrostomy placement. We aimed to characterize the predictors associated with EGD and gastrostomy recommendation at the initial gastroenterology consultation in patients with progressive neurologic disorders.

METHODS: This retrospective study spanned from December 31, 2010, to December 31, 2021, and included patients with both dysphagia and neurologic disorders. Multivariate logistic regression determined the predictors for EGD and gastrostomy recommendation after the initial visit.

RESULTS: Out of 273 patients, EGD was recommended for 163 (59.7%) at the initial evaluation. A diagnosis of amyotrophic lateral sclerosis (ALS) (odds ratio: 0.20; 95% confidence interval (CI): 0.07-0.52; P=0.001) and being referred by a neurologist (odds ratio: 0.37; 95% CI: 0.17-0.84; P<0.02) were the negative predictors of an initial EGD recommendation. Gastrostomy was recommended for 38 patients (13.9%) at the initial consultation. Dysphagia to both liquids and solids, body mass index, diagnosis of ALS, and clinical frailty scale scores were associated with gastrostomy (P≤0.01). A model of six variables had high predictive accuracy for EGD recommendation (area under the receiver operating characteristic curve: 0.7741).

CONCLUSIONS: This study proposes a predictive model for initial EGD recommendation. We suggest that when considered in conjunction with the predictive clinical features of ALS diagnosis and dysphagia to both solids and liquids, the clinical frailty scale and American Society of Anesthesiologists physical status classification system scores may help clinicians anticipate gastrostomy when applied to patients with any neurologic disorder.}, } @article {pmid40881744, year = {2025}, author = {Zeppieri, M}, title = {Advantages and future outlooks in the use of telemedicine in liver transplantation.}, journal = {World journal of transplantation}, volume = {15}, number = {3}, pages = {104825}, pmid = {40881744}, issn = {2220-3230}, abstract = {To maintain care during the coronavirus disease 2019 outbreak, telemedicine was implemented quickly. Jowell et al's pandemic study on telehealth integration and liver transplant evaluation is examined in this editorial. The study showed that telehealth did not affect clinical outcomes including time to evaluation, listing rates, or pre-transplant death. The study found that telehealth did not increase sociodemographic inequalities, suggesting a fair care framework. The editorial discusses how telemedicine in hepatology might help patients receive expert treatment while reducing logistical and financial burdens. Telehealth can democratize liver transplantation by delivering equivalent clinical results as in-person examinations. However, the editorial highlights technological barriers, difficulties in remotely assessing mental and physical health, and the need for specialized outreach to underserved communities. After the pandemic, telemedicine is essential to a more flexible, patient-centered healthcare system. The editorial encourages creativity and research to overcome challenges, improve hybrid care models, and ensure telehealth's egalitarian and successful potential. Pandemic insights can improve liver transplantation treatment and outcomes for diverse patient populations.}, } @article {pmid40881903, year = {2025}, author = {Shi, DD and Ding, J and Tian, J}, title = {Unraveling the enigma of salivary uric acid in periodontitis: Independent association, mechanistic insights, and future trajectories.}, journal = {World journal of clinical cases}, volume = {13}, number = {27}, pages = {108117}, pmid = {40881903}, issn = {2307-8960}, abstract = {This article explores the association between salivary uric acid (UA) and periodontitis, systematically analyzing its dual roles and research progress. Studies indicate that UA acts as a primary antioxidant in saliva under physiological conditions (accounting for 70%), protecting periodontal tissues by scavenging reactive oxygen species. However, when gum disease becomes severe, UA can switch roles and fuel inflammation, worsening tissue damage. Lorente et al's research found an independent inverse correlation between salivary UA levels and periodontitis severity (odds ratio = 6.14, P = 0.001), establishing 111 nmol/mL as a diagnostic threshold (area under the curve = 66%). Nevertheless, limitations include sample heterogeneity and failure to distinguish between gingivitis and periodontitis. Mechanistically, three hypotheses are proposed: The Antioxidant Depletion Hypothesis (UA oxidation consumption leading to feedback loops), the Microbial Metabolic Hijacking Hypothesis (pathogens utilizing UA as a carbon source to disrupt redox balance), and the Epithelial Barrier Dysfunction Hypothesis (UA deficiency causing downregulation of tight junction proteins). Future research should prioritize longitudinal cohorts to validate predictive value, integrate multi-omics to explore dysregulated signatures, and develop UA supplementation or targeted antioxidant therapies. This study provides novel insights into periodontitis diagnosis and mechanisms, advancing the application of salivary biomarkers in precision periodontics.}, } @article {pmid40883656, year = {2026}, author = {García-Parra, B and Guiu, JM and Povedano, M and Modamio, P}, title = {Geographic distribution of amyotrophic lateral sclerosis-related genes: a systematic review.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {4}, pages = {511-517}, pmid = {40883656}, issn = {1758-2032}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Genetic Predisposition to Disease ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease. There is no effective treatment, but disease-modifying therapies do exist. Objective. To identify the geographical distribution of ALS-related genes.

METHODS: A systematic review was conducted according to the PRISMA 2020 guidelines in PubMed and Web of Science. Inclusion criteria: patients with ALS, no age or gender restriction, English and Spanish languages, studies published until 31 July 2025.

RESULTS: Thirty-eight results were obtained, 32 were selected, 19 articles were assessed for eligibility, and 8 articles were included from databases. Three articles recommended by clinical experts were added, so 11 results were reviewed. This research showed that published articles on the geographic distribution of ALS-related genes are limited, particularly for underrepresented regions such as Africa.

CONCLUSION: The findings demonstrate the need for intensified international research to improve knowledge of the genetic epidemiology of ALS.}, } @article {pmid40884086, year = {2026}, author = {Khamkar, AS and Jha, S and Bakhla, AK and Chauhan, G}, title = {Large-scale genetic study identifies shared genetic regions between cerebrovascular and neurodegenerative diseases.}, journal = {International journal of stroke : official journal of the International Stroke Society}, volume = {21}, number = {4}, pages = {526-538}, doi = {10.1177/17474930251377513}, pmid = {40884086}, issn = {1747-4949}, mesh = {Humans ; *Cerebrovascular Disorders/genetics ; Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics ; Polymorphism, Single Nucleotide/genetics ; *Genetic Predisposition to Disease ; Linkage Disequilibrium ; Genetic Pleiotropy ; White People/genetics ; Asian People/genetics ; White ; }, abstract = {INTRODUCTION: Cerebrovascular diseases (CeVD) and neurodegenerative diseases (NDs) are two major neurological disorders, which are associated with increasing global morbidity and mortality. Population-based studies have indicated a complex link between CeVD and ND. However, the shared genetic etiology between these disease conditions remains less explored.

METHODS: We conducted genome-wide genetic correlation analysis and investigated the shared genetic architecture through pleiotropy analysis between ND and CeVD, like stroke and its subtypes, to understand shared genetic factors and biological mechanisms. Publicly available large-scale genome-wide association studies (GWAS) summary statistics data of cross-ancestry, European, and South Asian (SAS) ancestry were analyzed using methods implemented in the tools linkage disequilibrium score regression (LDSC), PLeiotropic Analysis under COmposite null hypothesis (PLACO), and Bayesian-based method of colocalization (COLOC).

RESULTS: We detected 116 shared genetic loci consisting of 770 lead pleiotropic single nucleotide polymorphisms (SNPs) (ND-CeVD P-range: 4.81×10[-8] to 4.57×10[-16]) and 40 shared causal genetic regions (ND-CeVD PP.H4-range: 0.70-0.9, posterior probability of H4 (PP.H4) ⩾ 0.7) between multiple CeVD and ND pairs. The genetic regions near ICA1L, HLA-DQA1, HLA-DRB1, MIR297, and PITX2 genes were identified as highly pleiotropic across multiple CeVD-ND pairs. We report ERGIC1 (5q35.1) for the first time as a shared causal genetic locus between Amyotrophic Lateral Sclerosis and small vessel stroke. The genetic risk score of stroke derived from the SAS population of the GIGASTROKE study was associated with ND (P-range = 2.23×10[-28] to 0.02), despite a small sample size compared to other ethnic groups, indicating high penetrance.

CONCLUSION: The shared genetic loci and pathway analysis in this study provide new genes and pathways shared between ND and CeVD, which may help in a better understanding of disease mechanisms in these neurological diseases.}, } @article {pmid40884436, year = {2025}, author = {Berry, JD and Bowser, R}, title = {Cardiac Troponin T in Tofersen-Treated SOD1 ALS Patients: Beginning to Resolve the Catch-22 of Identifying Treatment Responsive Biomarkers in ALS Drug Development.}, journal = {Muscle & nerve}, volume = {72}, number = {5}, pages = {1039-1041}, doi = {10.1002/mus.70017}, pmid = {40884436}, issn = {1097-4598}, } @article {pmid40884702, year = {2025}, author = {Hu, X and Wei, M and Zhang, H and Wang, M and Zhang, S and Li, B}, title = {Characteristics and influencing factors of pain in amyotrophic lateral sclerosis: a focus on symptom management.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {12}, pages = {6583-6593}, pmid = {40884702}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; Aged ; *Pain/etiology/psychology/epidemiology ; Self Efficacy ; Pain Measurement ; *Pain Management/methods ; Adult ; Social Support ; Fatigue/etiology ; Quality of Life ; }, abstract = {PURPOSE: To investigate the characteristics and influencing factors of pain symptoms in ALS patients, provide references for the formulation of pain coping measures in clinical practice.

MATERIALS AND METHODS: The research design was a cross-sectional study.ALS patients were investigated using scales such as the Brief Pain Inventory (BPI). Binary logistic regression equation and multiple linear regression equation were used to analyze the influencing factors of whether occur pain and pain degree in ALS patients.

RESULTS: 149 (74.1%) patients had pain symptoms, and 51 (25.4%) patients had pain as the first symptom. Patients with moderate to severe pain accounted for 60.4%. Fatigue, social support, self-efficacy, and poor sleep quality have been associated with whether occur pain in ALS patients. Personality traits, education, fatigue, social support, physical function, and self-efficacy were associated with pain levels in ALS patients.

CONCLUSIONS: Pain is an important indicator of functional decline, which can directly affect the rehabilitation outcome, reduce the quality of life of patients, and is crucial for predicting disease progression and optimizing end-of-life care, which should arouse the full attention of clinical medical personnel and scientific researchers. In the future, it is necessary to strengthen pain intervention in rehabilitation programs.}, } @article {pmid40884740, year = {2025}, author = {Kalasa Anil Kumar, AP and Subair, S and Basthikoppa Shivamurthy, P and Ummar, S and Rajeev, AC and Raju, R}, title = {Decoding ATXN2 Phosphocode: Structural Insights and Therapeutic Opportunities in Disease.}, journal = {The protein journal}, volume = {44}, number = {5}, pages = {483-500}, pmid = {40884740}, issn = {1875-8355}, mesh = {Humans ; *Ataxin-2/metabolism/chemistry/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology/drug therapy ; *Neoplasms/metabolism/genetics/drug therapy/pathology ; Phosphorylation ; Animals ; *Spinocerebellar Ataxias/metabolism/genetics/pathology ; Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; }, abstract = {Ataxin-2 (ATXN2), a key RNA-binding protein, regulates RNA metabolism, stress granule formation, and neuronal homeostasis, with dysregulated phosphorylation contributing to Spinocerebellar Ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), and cancer. This review integrates structural biology, phosphoproteomics, and interactome analyses to map six critical phosphosites (S772, T741, S624, S684, S784, S889) within ATXN2's intrinsically disordered regions. Modulated by kinases GSK3β and CDK13 and phosphatases like INPP5F, these sites orchestrate interactions with RNA-binding partners (e.g., ATXN2L, FXR2, STAU2) and co-regulated proteins (e.g., TP53BP1, NUP153), driving pathogenesis through disrupted autophagy, nucleocytoplasmic transport, and stress granule dynamics. We propose targeted therapies, including GSK3β inhibitors for ALS, antisense oligonucleotides for SCA2, and MTOR modulators for cancer, to restore ATXN2 function. By elucidating phosphocode of ATXN2, this work highlights novel avenues for precision medicine in neurodegenerative and oncogenic diseases.}, } @article {pmid40885336, year = {2025}, author = {Pavlović, MD}, title = {Response to Li et al's "Therapeutic efficacy of platelet-rich plasma combining with microneedling and topical minoxidil in refractory severe androgenic alopecia".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {6}, pages = {e231}, doi = {10.1016/j.jaad.2025.05.1463}, pmid = {40885336}, issn = {1097-6787}, } @article {pmid40885478, year = {2025}, author = {Hafiz, B and Aldahlawi, A and Ashqar, A and Hamzah, A and Alotaibi, Y and Bajunaid, K and Baeesa, S}, title = {Outcomes of Surgical versus Endovascular Treatment of Spinal Dural Arteriovenous Fistula: A Systematic Review and Meta-Analysis.}, journal = {World neurosurgery}, volume = {202}, number = {}, pages = {124420}, doi = {10.1016/j.wneu.2025.124420}, pmid = {40885478}, issn = {1878-8769}, mesh = {Humans ; *Central Nervous System Vascular Malformations/surgery ; *Endovascular Procedures/methods ; Treatment Outcome ; Embolization, Therapeutic/methods ; *Neurosurgical Procedures/methods ; *Microsurgery/methods ; }, abstract = {BACKGROUND: Spinal dural arteriovenous fistulas (SDAVFs) are the most prevalent type of spinal vascular malformation and can lead to progressive neurological impairments if left untreated. Endovascular embolization and microsurgical resection are treatment options, although the optimal treatment method remains a subject of debate. Our objective is to conduct a comprehensive systematic review and meta-analysis to compare the outcomes of endovascular and microsurgical treatments for SDAVFs.

METHODS: An exhaustive literature search was conducted in the PubMed, Embase, Scopus, and Web of Science databases, encompassing publications from 2014 to 2024. A total of 522 patients from 7 studies (417 surgical and 105 endovascular) met the inclusion criteria. Information on post-treatment complications, recurrence/failure rates, and functional improvement as assessed by the Aminoff-Logue Scale (ALS) or modified ALS was extracted. I[2] statistics were used to evaluate heterogeneity, and random-effects models were used to compute risk ratios and odds ratios.

RESULTS: Compared to endovascular intervention, surgical treatment was linked to significantly lower rates of recurrence or treatment failure (risk ratio: 0.19; 95% confidence interval: 0.09-0.39; P < 0.001), especially in long-term follow-up and thoracic-level studies. With greater ALS/modified ALS gains and a higher percentage of patients achieving full or partial recovery, functional improvement favored surgery. Although complication types varied, complication rates were similar across modalities (odds ratio: 0.84; 95% confidence interval: 0.48-1.49). Asymmetry in funnel plots indicated possible publication bias in favor of successful surgical outcomes.

CONCLUSIONS: For SDAVFs, surgical ligation provides better long-term results than endovascular embolization in terms of neurological recovery and recurrence prevention. Even though both procedures are usually safe, surgery is the recommended first-line course of action due to the higher failure and recurrence rates linked to embolization, especially in patients with operable anatomy and progressive symptoms.}, } @article {pmid40886845, year = {2026}, author = {Beraja, GE and Eber, AE and Yosipovitch, G}, title = {Response to Peng et al's "Efficacy and safety of 308-nanometer light-emitting diode phototherapy for prurigo nodularis: A randomized and self-controlled clinical trial".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {1}, pages = {e29-e30}, doi = {10.1016/j.jaad.2025.08.064}, pmid = {40886845}, issn = {1097-6787}, } @article {pmid40887101, year = {2025}, author = {Guillot, SJ and Luppi, PH and Dupuis, L and Bolborea, M}, title = {Sleep in neurodegenerative diseases: A focus on melatonin, melanin-concentrating hormone and orexin.}, journal = {Journal of neuroendocrinology}, volume = {37}, number = {11}, pages = {e70085}, pmid = {40887101}, issn = {1365-2826}, support = {ANR-16-CE16-0015//Agence Nationale de la Recherche/ ; ANR-16-CE92-0031//Agence Nationale de la Recherche/ ; ANR-19-CE17-0016//Agence Nationale de la Recherche/ ; ANR-20-CE17-0008//Agence Nationale de la Recherche/ ; ANR-24-CE37-4064//Agence Nationale de la Recherche/ ; //TargetALS/ ; //Fondation Thierry Latran/ ; //Association Francaise de Recherche sur la sclérose latérale amyotrophique/ ; //Radala Foundation for ALS Research/ ; //ARSLA/ ; //University of Starsbourg fundation/ ; //Fondation Bettencourt Schueller/ ; DEQ20180339179//Fondation pour la Recherche Médicale/ ; //Axa Research Funds/ ; }, mesh = {Humans ; *Melanins/metabolism/physiology ; *Orexins/metabolism ; *Neurodegenerative Diseases/physiopathology/metabolism ; *Melatonin/metabolism/physiology ; *Hypothalamic Hormones/metabolism/physiology ; *Pituitary Hormones/metabolism/physiology ; *Sleep/physiology ; Animals ; Circadian Rhythm/physiology ; }, abstract = {Sleep and circadian rest-activity rhythm alterations are recognised as inherent clinical features of various neurodegenerative diseases. Traditionally viewed as secondary manifestations of neurodegeneration, recent studies have revealed that disruptions in circadian rhythm and sleep-wake cycles can precede clinical symptoms and significantly contribute to the underlying pathophysiological progression. In this review, we summarise recent research on the impact of sleep and circadian rhythm alterations in ageing and major neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and frontotemporal dementia, highlighting the roles of melatonin, orexin, and melanin-concentrating hormone (MCH) systems as key regulators at the intersection of sleep and neurodegeneration. We argue that sleep and circadian alterations may serve as early biomarkers and therapeutic targets for these diseases.}, } @article {pmid40887165, year = {2025}, author = {Eising, J and Dissmeyer, N}, title = {Identification of arginylated N-termini with specific reagents.}, journal = {Methods in enzymology}, volume = {718}, number = {}, pages = {307-317}, doi = {10.1016/bs.mie.2025.06.024}, pmid = {40887165}, issn = {1557-7988}, mesh = {Humans ; *Protein Processing, Post-Translational ; *Arginine/metabolism/chemistry ; *Aminoacyltransferases/metabolism ; *Proteins/metabolism/chemistry ; Animals ; }, abstract = {N-terminal arginylation is a posttranslational modification of proteins that may determine their fate with respect to their stability and half-life and timing of their physiological and molecular function. Arginylated N-termini are in some documented cases N-degrons leading to degradation through the proteasome or autophagic-lysosomal system (ALS) regulating cellular homeostasis and global physiological alterations. Proteins that are targets of arginyl-transferases (Ates) capable of ligating arginine (Arg) residues to N-terminal amino groups and internal side chains show therefore high importance for manipulation in therapeutic and research contexts. Because of that, identifying those substrates is of high interest for all organisms from human to plant research. This chapter will shed some light onto methods for identification of arginylated N-termini with focus on specific antibodies targeting the N-terminally modified proteins.}, } @article {pmid40887399, year = {2025}, author = {Wang, Y and Lin, J and Qu, Y and Ding, Y and Ye, Z and Zhu, Z and Chen, W and Chen, Z and Sun, H and Hu, F and Chen, C and Fang, L and Li, R and Zhang, B and Wang, N and Fu, Y and Chen, W and Zhang, Q and , }, title = {Corrigendum to "Biomarker profile of a Chinese ALS cohort: A comprehensive clinical-biomarkers-imaging analysis".}, journal = {Neurobiology of disease}, volume = {215}, number = {}, pages = {107073}, doi = {10.1016/j.nbd.2025.107073}, pmid = {40887399}, issn = {1095-953X}, } @article {pmid40888144, year = {2025}, author = {Hullock, K and O'Cathain, A and Sampson, F and Woodward, J and Coates, E and Stavroulakis, T and White, SM and White, D and Norman, P and McDermott, C}, title = {Optimising Calorie Intake for People With Amyotrophic Lateral Sclerosis: A Process Evaluation of a Complex Behaviour Change Intervention.}, journal = {Health expectations : an international journal of public participation in health care and health policy}, volume = {28}, number = {5}, pages = {e70417}, pmid = {40888144}, issn = {1369-7625}, support = {//This project is funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-1016-20006) and supported by the NIHR Sheffield Biomedical Research Centre./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy/psychology ; Female ; Male ; *Energy Intake ; United Kingdom ; Middle Aged ; Aged ; Caregivers/psychology ; Process Assessment, Health Care ; Qualitative Research ; Adult ; }, abstract = {OBJECTIVE: To explore intervention fidelity and experiences of using a new intervention designed to optimise calorie intake in people with amyotrophic lateral sclerosis (ALS).

METHODS: A mixed-methods process evaluation was conducted alongside an ongoing randomised controlled trial across 15 ALS specialist centres in the United Kingdom. Data collection included 146 healthcare professional-completed fidelity checklists, audio recordings of 5 intervention sessions, and qualitative interviews with 32 healthcare professionals, patients and informal caregivers.

RESULTS: Intervention fidelity was high (88%: 1059/1204 items completed by healthcare professionals). Healthcare professionals, patients and informal caregivers within the sample recognised the intervention's value and engaged with it. Patients were motivated to use the intervention because they believed it could slow disease progression, and it gave them a sense of control. Despite challenges with the intervention, including patient concerns about weight gain and physical limitations in food preparation and consumption, patients in this sample remained committed to using the intervention. However, healthcare professionals suggested that these challenges may have negatively influenced trial recruitment and retention. Caregivers played a crucial role in supporting patients emotionally and physically, helping them to adhere to the intervention.

CONCLUSIONS: The intervention was feasible to implement and was delivered with fidelity. While patient engagement in this sample was strong, the intervention usability may be time-limited as physical function declines. Therefore, the intervention may be best suited for those with slower-progressing ALS who can manage the intervention and dietary changes. Moving forward, continued evaluation is needed to assess effectiveness and explore subgroup differences based on ALS type (slow vs. fast progressing).

PPIE CONTRIBUTION: PPI was integral to the process evaluation. PPI members reviewed key study documents, including the Participant Information Sheet and consent forms, leading to participant materials that were clear and easily understood. They also participated in developing the intervention.

TRIAL REGISTRATION: IRAS ID 275949, ISRCTN30588041.}, } @article {pmid40888599, year = {2026}, author = {Mearelli, M and Hirschberg, I and Weissleder, C and Giachino, C and Pérez, MJ and Dubroux, M and Provenzano, F and Rizzuti, M and Ottoboni, L and Sheth, U and Gendron, TF and Corti, S and Deleidi, M}, title = {C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal Crosstalk.}, journal = {Glia}, volume = {74}, number = {1}, pages = {e70080}, pmid = {40888599}, issn = {1098-1136}, support = {01GM1913//E-Rare3 INTEGRALS/ ; 490761034//Deutsche Forschungsgemeinschaft/ ; 01ED2005B//EU Joint Programme - Neurodegenerative Disease Research/ ; 101003329/ERC_/European Research Council/International ; }, mesh = {Humans ; *C9orf72 Protein/genetics/metabolism ; *Microglia/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Astrocytes/metabolism ; *DNA Repeat Expansion/genetics ; Cells, Cultured ; *Cell Communication/physiology ; Oxidative Stress ; }, abstract = {The C9orf72 hexanucleotide repeat expansion mutation is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but its cell type-specific effects on energy metabolism and immune pathways remain poorly understood. Using induced pluripotent stem cell (iPSC)-derived motor neurons, astrocytes, and microglia from C9orf72 patients and their isogenic controls, we investigated metabolic changes at the single-cell level under basal and inflammatory conditions. Our results showed that microglia are particularly susceptible to metabolic disturbances. While C9orf72 motor neurons exhibited impaired mitochondrial respiration and reduced ATP production, C9orf72 microglia presented pronounced increases in glycolytic activity and oxidative stress, accompanied by the upregulation of the expression of key metabolic enzymes. These metabolic changes in microglia were exacerbated by inflammatory stimuli. To investigate how these changes affect the broader cellular environment, we developed a human iPSC-derived triculture system comprising motor neurons, astrocytes, and microglia. This model revealed increased metabolic activity in all cell types and highlighted that microglia-driven metabolic reprogramming in astrocytes contributes to the vulnerability of motor neurons under inflammatory conditions. Our findings highlight the central role of microglia in driving metabolic dysregulation and intercellular crosstalk in ALS pathogenesis and suggest that targeting metabolic pathways in immune cells may provide new therapeutic avenues.}, } @article {pmid40888932, year = {2025}, author = {Platikanov, S and Palomas, A and Mata, MC and Tauler, R and Villar, J and Bragós, R and Bermejo, S and Jaumot, J and Lacorte, S}, title = {Coupling electrochemical and spectroscopic methods for river water dissolved organic matter characterization.}, journal = {Environmental monitoring and assessment}, volume = {197}, number = {9}, pages = {1071}, pmid = {40888932}, issn = {1573-2959}, support = {TED2021-131552B-C21 and TED2021-131552B-C22//Ministerio de Ciencia e Innovación (MCIN) y la Agencia Estatal de Investigación (AEI) and the European Union 'Next Generation EU/PRTR/ ; }, mesh = {*Rivers/chemistry ; *Environmental Monitoring/methods ; *Water Pollutants, Chemical/analysis ; Electrochemical Techniques ; Spectrometry, Fluorescence ; Spectrum Analysis ; *Humic Substances/analysis ; Dielectric Spectroscopy ; }, abstract = {Monitoring dissolved organic matter (DOM) in surface waters is essential for assessing ecosystem health and detecting pollution. However, conventional spectroscopic techniques often provide limited information about the electrochemical behavior of DOM. This study integrates electrochemical impedance spectroscopy (EIS) with classical methods such as UV-Vis absorption and fluorescence spectroscopies to improve DOM characterization in river water samples. In particular, this coupling provides additional insights into the electrochemical properties of DOM, which are not captured by conventional spectroscopic techniques. This study combined multiple data sources, including physicochemical parameters (e.g., water temperature, pH, conductivity), EIS spectral scores, fluorescence indices, and DOM fractions resolved by multivariate curve resolution-alternating least squares (MCR-ALS) applied to excitation-emission matrix (EEM) fluorescence data. The results from these different methods were then merged into a single dataset for a global principal component analysis (PCA), which allowed us to identify shared patterns and correlations across methods. The results revealed that low-altitude rivers showed the highest DOM content, followed by mid-altitude rivers, while high-altitude rivers presented the lowest. The PCA model indicated that low-frequency regions in the EIS spectra correlated with higher DOM content, whereas mid- to high-frequency regions were associated with lower DOM levels. These frequency-dependent patterns reflected differences in charge transfer and dielectric behavior of DOM in the river samples, which are not accessible through optical techniques. This highlights the potential of EIS as a complementary tool that provides electrochemical information on DOM composition for better water quality assessment.}, } @article {pmid40891024, year = {2026}, author = {Pan, Y and Spiteri, AG and Runwal, P and Sun, J and Hutchinson, DS and Kagawa, Y and Turner, BJ and Huang, C and Shah, AD and Schittenhelm, RB and Nicolazzo, JA}, title = {Increased ATP production and P-glycoprotein activity underlie the marked changes in blood-brain barrier transport of drugs in a mouse model of amyotrophic lateral sclerosis.}, journal = {British journal of pharmacology}, volume = {183}, number = {2}, pages = {280-295}, doi = {10.1111/bph.70147}, pmid = {40891024}, issn = {1476-5381}, support = {GNT2007912//National Health and Medical Research Council/ ; //FightMND/ ; 23AARF-1020292/ALZ/Alzheimer's Association/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *Blood-Brain Barrier/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *Adenosine Triphosphate/metabolism/biosynthesis ; Mice ; *ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Biological Transport ; Endothelial Cells/metabolism ; Male ; Humans ; Mice, Inbred C57BL ; Cells, Cultured ; Proteomics ; }, abstract = {BACKGROUND AND PURPOSE: Patients with amyotrophic lateral sclerosis (ALS) are prescribed many medications for symptomatic relief. However, how potential alterations to the blood-brain barrier (BBB) affect the brain exposure of drugs in ALS remains under-investigated.

EXPERIMENTAL APPROACH: We used high-dimensional proteomic analysis, cellular metabolism, and mitochondrial functional assays to characterise isolated brain microvascular endothelial cells (BMECs) from wildtype and SOD1[G93A] transgenic mice, a mouse model of familial ALS, at a late-symptomatic age (P115-120), together with a transcardiac brain perfusion technique to assess BBB function in situ.

KEY RESULTS: The BBB of the SOD1[G93A] transgenic (TG) mice was significantly altered, including a 1.3-fold decrease in apparent brain microvascular volume, and decreased BBB transport of [3]H-diazepam (1.4-fold) and [3]H-2-deoxy-D-glucose (1.2-fold). BMEC proteomic analysis revealed multiple changes in TG mice including altered transmembrane activity, metabolism, and mitochondrial function, as revealed by gene set enrichment analysis, alongside altered glucose transporter (Glut1) abundance. These proteomic findings supported the identified increase in mitochondrial basal/ATP-linked respiration, mitochondrial action potential, ATP production, and intracellular ATP levels in SOD1[G93A] mouse BMECs. The BBB transport of [3]H-digoxin, a specific ATP-binding cassette efflux P-glycoprotein (P-gp) substrate, was reduced by 11.0% in SOD1[G93A] mice. This was confirmed by a 46.7% reduction in BMEC uptake of [3]H-digoxin, an observation that was reversed by resolving the hypermetabolic state of SOD1[G93A] BMECs.

CONCLUSION AND IMPLICATIONS: These findings open possible therapeutic avenues that could be exploited to overcome P-gp-mediated CNS drug resistance in ALS.}, } @article {pmid40891053, year = {2025}, author = {Bilican, S and Nabawi, Y and Zhang, WH and Petrovic, D and Wehrmann, M and Muñoz-García, S and Koyuncu, S and Vilchez, D}, title = {C9orf72 ALS-causing mutations lead to mislocalization and aggregation of nucleoporin Nup107 into stress granules.}, journal = {FEBS letters}, volume = {599}, number = {21}, pages = {3047-3065}, pmid = {40891053}, issn = {1873-3468}, support = {CRC1678 (project B06 to D.V)//Deutsche Forschungsgemeinschaft/ ; Germany's Excellence Strategy-CECAD (EXC2030-39390661388)//Deutsche Forschungsgemeinschaft/ ; Largeinstrument grant (INST216/1329-1 FUGG to CECAD Proteomics Facility)//Deutsche Forschungsgemeinschaft/ ; Research Unit FOR5762 (project VI742/10-1 to D.V)//Deutsche Forschungsgemeinschaft/ ; 2021-EKSE.95 to D.V//Else Kröner-Fresenius-Stiftung/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Nuclear Pore Complex Proteins/metabolism/genetics ; Animals ; Humans ; Caenorhabditis elegans/genetics/metabolism ; *C9orf72 Protein/genetics/metabolism ; Caenorhabditis elegans Proteins/genetics/metabolism ; *Stress Granules/metabolism/genetics ; *Mutation ; RNA Recognition Motif Proteins/metabolism/genetics ; Motor Neurons/metabolism/pathology ; Poly-ADP-Ribose Binding Proteins/metabolism/genetics ; RNA Helicases/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Protein Aggregates ; DNA Helicases ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disorder caused by motor neuron degeneration. Hexanucleotide repeat expansions in the C9orf72 gene, the most common genetic cause of ALS (C9-ALS), drive toxicity through different mechanisms. These pathological changes include alterations in stress granules (SGs), ribonucleoprotein complexes formed under stress conditions. Here, we show that G3BP1, a core component of SGs, exhibits enhanced interaction with the nucleoporin Nup107 in motor neurons derived from patient iPSCs carrying C9orf72 mutations. Moreover, Nup107 colocalizes with SGs and aggregates in C9-ALS motor neurons. Notably, knockdown of npp-5, the Caenorhabditis elegans ortholog of Nup107, alleviates ALS-associated phenotypes in worm models, including reduced lifespan and impaired motility. Together, our findings provide insights into disease-related changes in C9-ALS pathogenesis.}, } @article {pmid40891271, year = {2026}, author = {Genuis, SK and Luth, W and Johnston, WS}, title = {Asymmetry and Alignment: Physician Perspective on Patient-Based Evidence for Improving Health Communication.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {53}, number = {5}, pages = {768-771}, doi = {10.1017/cjn.2025.10407}, pmid = {40891271}, issn = {0317-1671}, mesh = {Humans ; *Physician-Patient Relations ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; *Health Communication/methods ; *Physicians/psychology ; Female ; Male ; Patient-Centered Care ; Focus Groups ; *Attitude of Health Personnel ; *Communication ; }, abstract = {We investigated the response of experienced amyotrophic lateral sclerosis physicians to patient-based evidence pertaining to health communication. Fifteen expert amyotrophic lateral sclerosis (ALS) physicians participated in an in-person focus group. Focusing on clinical feasibility and first-hand experience, participants discussed recommendations from people with ALS and caregivers for improving communication. Data were qualitatively analyzed using conventional content analysis. Findings demonstrated shared and differing perspectives, and communication challenges. Findings suggest a difference in perspective centered on how to achieve the shared goal of patient-centered communication. We discuss asymmetry between healthcare professional perspectives and patient-based evidence, and opportunities for alignment that will advance effective health communication.}, } @article {pmid40891506, year = {2026}, author = {Pir, GJ and Buddenkotte, J and Alam, MA and Own, A and Eck, RJ and Kraemer, BC and Mandelkow, E and Steinhoff, M}, title = {TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.}, journal = {The FEBS journal}, volume = {293}, number = {2}, pages = {348-384}, pmid = {40891506}, issn = {1742-4658}, support = {//Katharina Hardt Foundation/ ; F99AG088436/NH/NIH HHS/United States ; F99 AG088436/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; //Cure Alzheimer's Fund/ ; 11S-0117 180326//Qatar National Research Fund/ ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics/metabolism ; *TDP-43 Proteinopathies/genetics/pathology/metabolism ; *DNA-Binding Proteins/genetics/metabolism/chemistry ; Disease Models, Animal ; Humans ; *Caenorhabditis elegans Proteins/genetics/metabolism ; *Neurodegenerative Diseases/genetics/pathology/metabolism ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Frontotemporal Dementia/genetics/pathology/metabolism ; }, abstract = {TDP-linked proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE), are characterised by pathogenic deposits containing transactive response DNA-binding protein 43 (TDP-43) in the brain and spinal cord of patients. These hallmark pathological features are associated with widespread neuronal dysfunction and progressive neurodegeneration. TDP-43's role as an essential RNA/DNA-binding protein in RNA metabolism and gene expression regulation is clear, but deciphering the intricate pathophysiological mechanisms underpinning TDP-43-mediated neurodegeneration is paramount for developing effective therapies and novel diagnostic tools for early detection before frank neuronal loss occurs. The nematode Caenorhabditis elegans, with highly conserved TDP-43 orthologue TDP-1, serves as a powerful genetic model to investigate the molecular underpinnings of TDP-43 proteinopathies. Here, we provide a brief overview of the structural and functional characteristics of TDP-43 and TDP-1, highlighting their conserved roles in RNA metabolism, stress responses, and neurodegeneration. We then delve into the pathobiology of TDP-43, drawing insights from C. elegans models expressing either monogenic TDP-43 variants or bigenic combinations with ALS-associated risk genes, and discuss how these models have advanced our understanding of the pathomechanisms of TDP-43 proteinopathies. By employing its simplicity and genetic manipulability, we discuss how these models have helped identify chemical and genetic suppressors of TDP-43-induced phenotypes, including small molecules like Pimozide and the probiotic Lacticaseibacillus rhamnosus HA-114, now in clinical trials. This review underscores the translational value of C. elegans in unraveling the biochemical pathways and interactions in TDP-43 proteinopathies that perturb cellular physiology, potentially facilitating mechanism-based therapy development.}, } @article {pmid40891814, year = {2026}, author = {Ekaterina Slotina, DM and Ditscheid, DRNB and Meissner, DPF and Wiese, A and Hezel, J and Marschall Dipl Oec, DMU and Wedding, APDMU and Freytag, PDRPMA}, title = {Quality of Palliative Care in Nursing Homes and Community Care in Deceased with Chronic Obstructive Pulmonary Disease (COPD), Dementia, Amyotrophic Lateral Sclerosis (ALS), and Cancer: A Retrospective Analysis of Claims Data (2016-2019).}, journal = {Journal of palliative care}, volume = {41}, number = {4}, pages = {377-384}, doi = {10.1177/08258597251353315}, pmid = {40891814}, issn = {2369-5293}, mesh = {Humans ; Female ; Male ; Retrospective Studies ; *Pulmonary Disease, Chronic Obstructive/nursing/therapy ; *Palliative Care/standards/statistics & numerical data ; Aged ; *Nursing Homes/statistics & numerical data/standards ; *Amyotrophic Lateral Sclerosis/nursing/therapy ; Aged, 80 and over ; *Quality of Health Care/statistics & numerical data/standards ; *Dementia/nursing/therapy ; *Neoplasms/nursing/therapy ; *Community Health Services/standards/statistics & numerical data ; Middle Aged ; }, abstract = {ObjectivePalliative care is more commonly provided to patients with cancer than to those with non-oncological conditions. Little is known about the prevalence of inappropriate care and whether differences exist depending on the underlying disease. This study investigates the care during the last month of life in patients with cancer and non-oncological conditions, such as amyotrophic lateral sclerosis (ALS), chronic obstructive pulmonary disease (COPD), and dementia, considering the care setting (nursing home vs. community care).MethodsWe conducted a population-based, retrospective analysis of deceased in 2016-2019 with COPD (n = 4,036), dementia (n = 40,853), or ALS (n = 608). Logistic regression analyses compared the care quality with that of the deceased with cancer (n = 58,315). Interaction analyses examined setting effects. Outcome measures included validated quality indicators: hospital and intensive care unit (ICU) stays, emergency service utilization, and place of death.ResultsDeceased with COPD, dementia, and ALS more frequently utilized emergency services compared to those with cancer (40.4%, 28.4%, 29.0% vs. 24.4%, respectively, p < .05) and were less likely to die in a hospital (excluding palliative care units; 38.2%, 15.3%, 25.7% vs. 40.3%, respectively, p < .05). Differences were observed in ICU (13.6%, 3.4%, 6.1% vs. 4.3%, respectively, p < .05) and hospital admissions (42.7% for COPD vs. 31.5% for oncological patients, p < .001). The same pattern was observed across all conditions: deceased in community care had higher rates in all quality indicators than those in nursing homes.ConclusionsThe results suggest differences in care quality depending on the underlying disease. Nononcological patients in community care are less frequently and less adequately cared for than oncological patients.}, } @article {pmid40894255, year = {2025}, author = {Hu, N and Chen, L and Hu, G and Ma, R}, title = {Advancements in extracellular vesicle therapy for neurodegenerative diseases.}, journal = {Exploration of neuroprotective therapy}, volume = {5}, number = {}, pages = {}, pmid = {40894255}, issn = {2769-6510}, support = {R01 DA043138/DA/NIDA NIH HHS/United States ; R01 MH112848/MH/NIMH NIH HHS/United States ; R21 DA042704/DA/NIDA NIH HHS/United States ; R21 DA046831/DA/NIDA NIH HHS/United States ; }, abstract = {Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation.}, } @article {pmid40894870, year = {2025}, author = {Manville, RW and Sidlow, R and Abbott, GW}, title = {Conifer metabolite pisiferic acid restores activity in human Kv1.2 potassium channels carrying pathogenic sequence variants.}, journal = {iScience}, volume = {28}, number = {9}, pages = {113283}, pmid = {40894870}, issn = {2589-0042}, support = {R01 NS107671/NS/NINDS NIH HHS/United States ; }, abstract = {Sequence variants in KCNA2, the gene encoding voltage-gated potassium channel Kv1.2, cause epilepsy, delayed cognitive development, and movement disorders. Drugs that directly correct mutant Kv1.2 function are lacking. Kv1.2 downregulation is also implicated in pain and amyotrophic lateral sclerosis (ALS). We recently found that the abietane diterpenoid pisiferic acid (PA) from conifer Chamaecyparis pisifera beneficially restores activity in pathogenic loss-of-function (LOF)-variant Kv1.1 channels. Here, using cellular electrophysiology, we classified 19 human Kv1.2 gene variants (pathogenic or of unknown significance) into LOF, gain of function (GOF), or mixed LOF/GOF. By hyperpolarizing their voltage dependence of activation, PA improved function in 13/13 LOF and 1/1 LOF/GOF pathogenic Kv1.2 variants tested, using cRNA ratios representative of autosomal dominant KCNA2 disorders. In silico docking, mutagenesis, and electrophysiology identified a PA binding site in the Kv1.2 voltage sensor. Given its in vitro efficacy and low preclinical toxicity, PA is a promising lead compound for Kv1.2 LOF disorders.}, } @article {pmid40895324, year = {2025}, author = {Tan, X and Liu, G and Li, X and Zhong, F and Su, Z and Wang, H}, title = {Amyotrophic Lateral Sclerosis and Risk of Common Cancer: Mendelian Randomization Interrogation of Causality and Mediation.}, journal = {Phenomics (Cham, Switzerland)}, volume = {5}, number = {3}, pages = {270-283}, pmid = {40895324}, issn = {2730-5848}, abstract = {UNLABELLED: Compared with the well-documented inverse comorbidity of common neurodegenerative diseases with some types of cancer, the association of amyotrophic lateral sclerosis (ALS) with cancer was obscure. This Mendelian randomization (MR) analysis was aimed to appraise the causal relationship of ALS with cancer. Leveraging summary statistics of genome-wide association study (GWAS) for ALS, overall-cancer and nine types of site-specific common solid cancer including colorectal cancer (CRC) in populations of European (discovery and replication) and East Asian ancestry, we investigated the causal association of ALS with cancer using inverse-variance weighted (IVW) method and complementary sensitivity analyses. We performed MR-based mediation analysis to assess possible role of serum lipid traits such as hyperlipidemia, one shared risk factor of ALS and CRC, in their causal association. We found that genetically-predicted ALS was not associated with overall-cancer and other tested types of cancer, but was causally associated with reduced risk of CRC [odds ratio (OR) 0.84; 95% confidence interval (95% CI) 0.74-0.96; p = 0.011, OR 0.32; 95% CI 0.15-0.69; p = 0.004, in datasets of European (discovery) and East Asian ancestry respectively]. We observed absences of directional pleiotropy (MR Egger, intercept = -0.02 and -0.02, p = 0.49 and 0.60), instrumental outlier (MR-PRESSO, p = 0.95 and 0.84) or heterogeneity (Cochran Q, p = 0.95 and 0.82). Null reverse causality of CRC with ALS was found in either datasets. However, we found no evidence of the inverse association of ALS with CRC in either the replication (OR 0.99; 95% CI 0.93-1.06) or the combined European datasets (OR 0.92; 95% CI 0.79-1.09). Mediation analysis in European datasets suggested that hyperlipidemia may affect the risk of CRC via ALS in an indirect manner, with the measured mediation effect of hyperlipidemia on CRC being -0.02 (95% CI -0.04 to -0.002, p = 0.03). Our two-sample MR study in trans-ethnic populations uncovered that genetically proxied ALS may be causally associated with reduced risk of CRC, providing new insight into the inverse comorbidity and etiological causality of neurodegenerative disease and cancer.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43657-024-00159-9.}, } @article {pmid40895800, year = {2025}, author = {D'Arrigo, C and Labbate, S and Galante, D}, title = {Boosting the Therapeutic Potential of Extracellular Vesicles Derived From Mesenchymal Stem Cells via Advanced Preconditioning for Neurodegenerative Disorders.}, journal = {Stem cells international}, volume = {2025}, number = {}, pages = {2616653}, pmid = {40895800}, issn = {1687-966X}, abstract = {Acute and chronic neurodegenerative conditions (NDs) are major causes of disability and mortality worldwide. Acute NDs encompass conditions such as stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). On the other hand, chronic NDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Currently, no definitive cure exists for these diseases, and available therapies focus primarily on slowing the progression of symptoms. Mesenchymal stem cells (MSCs), due to their multilineage differentiation capacity, immunomodulatory abilities, and regenerative properties, have gained attention in regenerative medicine. In recent years, extracellular vesicles (EVs) derived from MSCs have shown great promise as a cell-free therapeutic approach, eliminating the risks associated with direct MSCs use, such as tumorigenicity and poor cell survival after transplantation. EVs have emerged as powerful mediators of intercellular communication and tissue repair, exhibiting immunomodulatory, anti-inflammatory, and proregenerative properties. However, limitations such as low EVs yield and reduced efficacy due to MSCs replicative senescence restrict their therapeutic potential. Preconditioning strategies, including hypoxia, 3D cultures, and biochemical priming, have been explored in other fields to enhance EVs properties, yet their specific application to NDs remains under-reported. This review aims to address this gap by analyzing the preconditioning methods used to boost the therapeutic potential of MSCs-derived EVs for neurodegenerative diseases. These preconditioning strategies may enhance EVs yield, functional cargo, and targeted therapeutic efficacy for treating acute and chronic NDs.}, } @article {pmid40896593, year = {2025}, author = {Ueno, Y and Nakamura, Y and Hata, T}, title = {The potential role of microRNA-mediated motor neuron-muscle pathologic interactions in amyotrophic lateral sclerosis.}, journal = {Molecular therapy. Nucleic acids}, volume = {36}, number = {3}, pages = {102675}, pmid = {40896593}, issn = {2162-2531}, } @article {pmid40896928, year = {2025}, author = {Issa, NP and Aydin, S and Goicoechea, EB and Carberry, N and Garret, MA and Smith, S and Habib, AA and Soliven, B and Rezania, K}, title = {Intermuscular coherence from muscle pairs in the leg as a biomarker for amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {179}, number = {}, pages = {2110986}, pmid = {40896928}, issn = {1872-8952}, support = {R01 NS116262/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; *Muscle, Skeletal/physiopathology ; Middle Aged ; Female ; Electromyography/methods ; *Leg/physiopathology ; Aged ; Adult ; Biomarkers ; }, abstract = {OBJECTIVE: To evaluate the diagnostic potential of intermuscular coherence (IMC) measured from leg muscle pairs as an early-stage biomarker for amyotrophic lateral sclerosis (ALS).

METHODS: Surface electromyography (sEMG) was recorded in neurotypical subjects and patients with early-stage ALS from muscle pairs: gastrocnemius lateralis-gastrocnemius medialis (GLGM), tibialis anterior-extensor digitorum brevis (TAED), and vastus lateralis-vastus medialis (VLVM). IMC within the 20-40 Hz range (IMCβγ) and the imaginary component of coherency in the 20-40 Hz range (ICOHβγ) were calculated. Area under the receiver operating characteristic curves (AUC) was used to assess diagnostic performance.

RESULTS: IMCβγ was lower in ALS patients than neurotypical subjects for all three muscle pairs (p < 0.05 in all cases). Diagnostic performance (AUC) ranged from 0.69 to 0.78 and was highest for TAED. Reducing the effect of volume conduction by using ICOHβγ tended to improve the diagnostic ability (AUC range 0.76 to 0.84).

CONCLUSIONS: IMCβγ from leg muscles, particularly TAED, can help differentiate early-stage ALS patients from neurotypical individuals. ICOHβγ further improves diagnostic performance by reducing volume conduction artifacts.

SIGNIFICANCE: Leg muscle IMC measurements could aid in the early and accurate diagnosis of ALS.}, } @article {pmid40897843, year = {2025}, author = {Lai, Q and Zhang, X and Jiang, S and Krzyaniak, MD and Alayoglu, S and Agarwal, A and Liu, Y and Edenfield, WC and Kobayashi, T and Wang, Y and Dravid, V and Wasielewski, MR and Miller, JT and Kratish, Y and Marks, TJ}, title = {Stable single-site organonickel catalyst preferentially hydrogenolyses branched polyolefin C-C bonds.}, journal = {Nature chemistry}, volume = {17}, number = {10}, pages = {1488-1496}, pmid = {40897843}, issn = {1755-4349}, support = {DOE DE-SC0024448//U.S. Department of Energy (DOE)/ ; DE-FG02-99ER14999//U.S. Department of Energy (DOE)/ ; DE-SC0001329//U.S. Department of Energy (DOE)/ ; DE-SC0012704//U.S. Department of Energy (DOE)/ ; NSF ECCS-2025633//National Science Foundation (NSF)/ ; NNA04CC36G//NASA | Ames Research Center/ ; }, abstract = {Current methods of processing accumulated polyolefin waste typically require harsh conditions, precious metals or high metal loadings to achieve appreciable activities. Here we examined supported, single-site organonickel catalysts for polyolefin upcycling. Chemisorption of Ni(COD)2 (COD, 1,5-cyclooctadiene) onto Brønsted acidic sulfated alumina (AlS) yields a highly electrophilic Ni(I) precatalyst, AlS/Ni(COD)2, which is converted under H2 to the active AlS/Ni[II]H catalyst. This single-site system exhibits unique hydrogenolysis selectivity that favours cleaving branched polyolefin C-C linkages, enabling the hydrogenolytic separation of polyethylene and isotactic polypropylene (iPP) mixtures. Moreover, AlS/Ni[II]H remains highly selective and active for hydrogenolysis of iPP admixed with polyvinyl chloride, and the spent catalyst can be repeatedly regenerated by AlEt3 treatment. Experimental mechanistic analysis and density functional theory modelling reveal a turnover-limiting C-C scission pathway featuring β-alkyl transfer and strong olefin binding. These results highlight the potential of nickel-based systems for the selective upcycling of complex plastic waste streams.}, } @article {pmid40897992, year = {2025}, author = {Quigley, SE and Quigg, KH and Goutman, SA}, title = {Genetic and Mechanistic Insights Inform Amyotrophic Lateral Sclerosis Treatment and Symptomatic Management: Current and Emerging Therapeutics and Clinical Trial Design Considerations.}, journal = {CNS drugs}, volume = {39}, number = {10}, pages = {949-993}, pmid = {40897992}, issn = {1179-1934}, support = {R01NS127188/NH/NIH HHS/United States ; R01 TS000327/TS/ATSDR CDC HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01TS000327//Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry/ ; R01TS000344/ACL/ACL HHS/United States ; R01NS120926/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/physiopathology/drug therapy ; Animals ; Clinical Trials as Topic/methods ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both upper and lower motor neurons. ALS is classically characterized by painless progressive weakness, causing impaired function of limbs, speech, swallowing, and respiratory function. The disease is fatal within 2-4 years, often the result of respiratory failure. The pathologic hallmark for a majority of ALS cases is aberrant cytoplasmic accumulations of the nuclear protein TAR-DNA binding protein (TDP-43). A total of 10-15% of ALS can be attributed to a single gene mutation, known as genetic or "familial" ALS, while the remainder of cases are termed nongenetic or "sporadic" although heritability has been measured in up to 37% in this population. Complex interactions between genetics, environment, and physiologic susceptibility are thought to contribute to disease. Management is primarily supportive in nature, though there are several approved treatments worldwide. This review details the mechanisms and evidence of approved disease-modifying treatments, relevant measures to track disease burden and progression used in clinical trials, and approaches to pharmacologic management of common symptoms in ALS. As there is not currently a cure for ALS, research into the complex pathophysiologic and genetic alterations contributing to disease is of great interest. This review further discusses the current understanding of genetic etiologies and altered physiology leading to disease, such as neuroinflammation, integrated stress response, aberrant proteostasis and mitochondrial dysfunction, among others. The translation of preclinical discoveries into current investigational therapeutics, novel therapeutic categories such as antisense oligonucleotides and stem cell transplantation, as well as future horizons harnessing the power of artificial intelligence in drug development and clinical trials are discussed.}, } @article {pmid40898360, year = {2025}, author = {Scholl, LS and Demleitner, AF and Riedel, J and Adachi, S and Neuenroth, L and Meijs, C and Tzeplaeff, L and Caldi Gomes, L and Galhoz, A and Cordts, I and Lenz, C and Menden, M and Lingor, P}, title = {Identification and validation of a tear fluid-derived protein biomarker signature in patients with amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {187}, pmid = {40898360}, issn = {2051-5960}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnosis ; Male ; Female ; Middle Aged ; Biomarkers/metabolism ; Aged ; *Tears/metabolism ; Adult ; Machine Learning ; Cohort Studies ; Proteomics ; *Eye Proteins/metabolism ; }, abstract = {The diagnosis of Amyotrophic Lateral Sclerosis (ALS) remains challenging, particularly in early stages, where characteristic symptoms may be subtle and nonspecific. The development of disease-specific and clinically validated biomarkers is crucial to optimize diagnosis. Here, we explored tear fluid (TF) as a promising ALS biomarker source, given its accessibility, anatomical proximity to the brainstem as an important site of neurodegeneration, and proven discriminative power in other neurodegenerative diseases. Using a discovery approach, we profiled protein abundance in TF of ALS patients (n = 49) and controls (n = 54) via data-independent acquisition mass spectrometry. Biostatistical analysis and machine learning identified differential protein abundance and pathways in ALS, leading to a protein signature. These proteins were validated by Western blot in an independent cohort (ALS n = 51; controls n = 52), and their discriminatory performance was assessed in-silico employing machine learning. 876 proteins were consistently detected in TF, with 106 differentially abundant in ALS. A six-protein signature, including CRYM, PFKL, CAPZA2, ALDH16A1, SERPINC1, and HP, exhibited discriminatory potential. We replicated significant differences of SERPINC1 and HP levels between ALS and controls across the cohorts, and their combination yielded the best in-silico performance. Overall, this investigation of TF proteomics in ALS and controls revealed dysregulated proteins and pathways, highlighting inflammation as a key disease feature, strengthening the potential of TF as a source for biomarker discovery.}, } @article {pmid40898372, year = {2025}, author = {Augur, ZM and Fogo, GM and Arbery, MR and Stern, AM and Benoit, CR and Hsieh, YC and Young-Pearse, TL}, title = {Optineurin deficiency disrupts phosphorylated tau proteostasis and clusterin expression in human neurons.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {188}, pmid = {40898372}, issn = {2051-5960}, support = {F31AG082393-03//NIA Ruth L. Kirschstein Predoctoral Individual National Research Service Award/ ; F31 AG082393/AG/NIA NIH HHS/United States ; K00 AG079793/AG/NIA NIH HHS/United States ; K00AG079793//NIA Pathway to Independence Award/ ; R01 AG055909/AG/NIA NIH HHS/United States ; R01AG055909//NIH Grant/ ; }, mesh = {Humans ; *Neurons/metabolism/pathology ; *Membrane Transport Proteins/deficiency ; *Cell Cycle Proteins/deficiency ; *tau Proteins/metabolism ; *Alzheimer Disease/metabolism/pathology/genetics ; *Clusterin/metabolism ; Induced Pluripotent Stem Cells/metabolism ; *Proteostasis/physiology ; Phosphorylation ; *Transcription Factor TFIIIA/deficiency/genetics ; Female ; Autophagy ; Male ; Brain/metabolism/pathology ; Astrocytes/metabolism ; Aged ; }, abstract = {Optineurin (OPTN) is an autophagy adaptor protein involved in selective autophagy, including aggrephagy and mitophagy. Pathogenic mutations in OPTN have also been linked to amyotrophic lateral sclerosis, frontotemporal dementia, and glaucoma, supporting its role in the etiology of neurodegenerative diseases. Despite its established biological roles, knowledge about its potential contribution to Alzheimer's disease (AD) pathology and neuronal functioning is lacking. AD is characterized by the accumulation of extracellular amyloid-β plaques and intracellular phosphorylated tau (pTau) tangles, with dysfunction in the autophagy-lysosomal pathway exacerbating tau pathology and impairing proteostasis. To investigate the role of OPTN in neuronal proteostasis and AD, we utilized induced pluripotent stem cell-derived neuron (iN) and astrocyte (iA) models. Analyses revealed a significant negative correlation between OPTN and specific pTau epitopes in neurons, as well as a decrease in OPTN protein abundance in brain tissues of individuals with AD. Given these findings, we generated OPTN knockout (KO), heterozygous, and wildtype iNs and iAs using CRISPR/Cas9 editing of iPSCs in two genetic backgrounds. Loss of OPTN in iNs increased specific pTau proteoforms without substantially affecting autophagy processes or mitochondrial respiration. Despite no clear effect on mitochondrial function, several mitochondrial proteins, including OXCT1, were enriched in an unbiased analysis of the OPTN interactome in iNs, as well as proteins involved in intracellular trafficking. Proteomic analyses further identified intracellular clusterin, an AD risk gene, as significantly upregulated in OPTN KO iNs, suggesting OPTN may influence its intracellular processing. Our model system demonstrates modest roles for OPTN in certain neuronal biological processes and potential implications for AD pathogenesis. These findings also suggest that OPTN may exhibit functional redundancy with other autophagy adaptor proteins in human neurons, leading to relatively mild phenotypic changes with complete loss of OPTN.}, } @article {pmid40898454, year = {2025}, author = {Alharthi, S and Jafri, SA and Alzaedi, MA and Aljaed, NM and Eldoskey, MM and Abosabie, SAS and Oshi, M and Abosabie, SA and Kamal, NM}, title = {Multisystem inflammatory syndrome in children (MIS-C) presenting with valvulitis, myocarditis, and QTc prolongation: A case report from Saudi Arabia.}, journal = {Medicine}, volume = {104}, number = {35}, pages = {e43995}, pmid = {40898454}, issn = {1536-5964}, mesh = {Humans ; Female ; Child ; *COVID-19/complications/diagnosis/therapy ; *Myocarditis/etiology/diagnosis ; Saudi Arabia ; *Systemic Inflammatory Response Syndrome/diagnosis/complications/therapy ; *Long QT Syndrome/etiology/diagnosis ; Electrocardiography ; Diagnosis, Differential ; SARS-CoV-2 ; Echocardiography ; }, abstract = {RATIONALE: This case report highlights the complex clinical course and successful multidisciplinary management of a pediatric patient with multisystem inflammatory syndrome in children (MIS-C), who posed clinical dilemma at presentation. It underscores the ongoing clinical relevance of MIS-C as a post-Coronavirus disease 2019 sequelae and emphasizes the importance of maintaining a high index of suspicion for MIS-C in pediatric differential diagnoses, especially when symptoms overlap with other common conditions.

PATIENT CONCERNS: An 11-year-old previously healthy Saudi girl presented with gastrointestinal symptoms initially suggestive of acute appendicitis. Her condition rapidly deteriorated with signs of cardiovascular compromise.

DIAGNOSES: Surgical exploration confirmed a perforated appendix. Cardiac workup revealed elevated troponin levels, corrected QT interval prolongation (500 ms), ST-segment changes, and echocardiographic evidence of mitral and aortic regurgitation with reduced ejection fraction, leading to a diagnosis of MIS-C fulfilling both Centers for Disease Control and Prevention and World Health Organization criteria. Schwartz et al's criteria are widely accepted for diagnosing long QT syndrome, which guided our interpretation of the corrected QT interval prolongation observed in this case. According to the Centers for Disease Control and Prevention, MIS-C is defined by a constellation of symptoms occurring in individuals under 21 years with recent severe acute respiratory syndrome coronavirus 2 infection or exposure.

INTERVENTIONS: Management included intravenous immunoglobulin, corticosteroids, inotropes, diuretics, aspirin, and broad-spectrum antibiotics, coordinated by a multidisciplinary care team.

OUTCOMES: The patient experienced full cardiac recovery, confirmed through serial electrocardiogram and echocardiography over 1 year.

LESSONS: This case underscores the importance of recognizing MIS-C in children presenting with atypical symptoms such as abdominal pain. Timely diagnosis and early multidisciplinary intervention are essential to prevent serious cardiac complications.}, } @article {pmid40898457, year = {2025}, author = {Peng, S and Ouyang, J and Liu, Y and Wang, L and Liu, R}, title = {Causal effect of infectious mononucleosis on neurodegenerative diseases: A Mendelian randomization study.}, journal = {Medicine}, volume = {104}, number = {35}, pages = {e44145}, pmid = {40898457}, issn = {1536-5964}, support = {2019YFE0117100//the National key research and development program of China/ ; 82104603//the National Natural Science Foundation of China/ ; 82074174//the National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Infectious Mononucleosis/complications/genetics/epidemiology/virology ; Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/virology/etiology/epidemiology ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Alzheimer Disease/genetics ; Parkinson Disease/genetics ; Multiple Sclerosis/genetics ; }, abstract = {Neurodegenerative diseases (NDs) are common chronic diseases with unknown etiology, and the association between virus and its pathogenesis is not clear. The aim of this study is to explore the role of virus in the pathogenesis of NDs by analyzing the causal effect between infectious mononucleosis (IM) mainly caused by Epstein-Barr virus and NDs. Based on the summary statistics of a large-scale genome-wide association study, we analyzed the causal effects of IM and NDs by Mendelian randomization (MR) using genetic variants as instrumental variables, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. The reliability and stability of the MR analysis results were assessed by the MR-Egger intercept test, MR-PRESSO test, and heterogeneity test. Twenty-two single nucleotide polymorphisms that were significantly and strongly associated with IM were used as instrumental variables in the MR analysis. Inverse variance weighted as the main method of MR analysis shows that there were significant causal effects between IM and Alzheimer disease (OR: 1.037, 95% CI: 1.006-1.070) and Parkinson disease (OR: 0.964, 95% CI: 0.930-1.000), while IM was not significantly associated with amyotrophic lateral sclerosis (P = .269) and multiple sclerosis (P = .182). Sensitivity analyses showed that the results were robust. This study suggests that EB virus may contribute to the pathogenesis of NDs, and more research is needed to explore the specific mechanism of virus action on NDs.}, } @article {pmid40898684, year = {2026}, author = {Zhu, Y and Bai, J and Wang, H and Li, M and Yang, F and Pang, X and Du, R and Zhao, J and Huang, X and Cui, F}, title = {The difference between cystatin C- and creatinine-based estimated glomerular filtration rate and survival in amyotrophic lateral sclerosis: a population-based cohort study.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {2}, pages = {153-161}, pmid = {40898684}, issn = {1758-2032}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology/blood ; *Cystatin C/blood ; *Glomerular Filtration Rate/physiology ; Female ; Male ; Middle Aged ; *Creatinine/blood ; Aged ; Prognosis ; Cohort Studies ; Adult ; Biomarkers/blood ; }, abstract = {OBJECTIVES: We investigated the relationship between cystatin C- and creatinine-based estimated glomerular filtration rate (eGFRdiff) and amyotrophic lateral sclerosis (ALS) outcomes.

METHODS: We enrolled ALS patients diagnosed between January 2014 and December 2019. Experienced neurologists followed up the participants until January 2022. Absolute difference between eGFR (eGFRabdiff) and relative difference between eGFR (eGFRrediff) were obtained. Cox proportional hazard models were used to evaluate the relationship between eGFRdiff and ALS survival.

RESULTS: Negative eGFRabdiff were common in the patients (74.7%). For each SD increase of eGFRabdiff, the risk of poor prognosis for ALS patients decreased by 1.9% (HR, 0.981; 95% CI, 0.973-0.989). For each 10% increment in eGFRrediff, the risk of poor prognosis for ALS patients decreased by 17.7% (HR, 0.823; 95% CI, 754-0.898).

CONCLUSIONS: We found that large eGFRdiff was associated with poor prognosis in ALS. Monitoring eGFRdiff in ALS population facilitates prognostic stratification assessment and precise management.}, } @article {pmid40900744, year = {2025}, author = {Mani, S and Wasnik, S and Shandilya, C and Srivastava, V and Khan, S and Singh, KK}, title = {Pathogenic synergy: dysfunctional mitochondria and neuroinflammation in neurodegenerative diseases associated with aging.}, journal = {Frontiers in aging}, volume = {6}, number = {}, pages = {1615764}, pmid = {40900744}, issn = {2673-6217}, abstract = {The term "neurodegenerative diseases" (NDDs) refers to a range of aging-associated conditions, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Unique clinical symptoms and underlying pathological mechanisms distinguish each of these illnesses. Although these conditions vary, they share chronic neuroinflammation as a defining characteristic. Protein aggregation and mitochondrial dysfunction are believed to play a role in initiating the neuroinflammatory response and, subsequently, the development and course of these illnesses. Apart from providing energy to the cells, mitochondria are involved in the immunoinflammatory response associated with neurological disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and epilepsy. This involvement is attributed to controlling processes such as inflammasome activation and cell death. Under inflammatory conditions, the underlying regulatory mechanisms for these aging-associated disorders may include calcium homeostasis imbalance, mitochondrial oxidative stress, mitochondrial dynamics, and epigenetics. Various NDDs are linked to neuroinflammation and mitochondrial dysfunction. The linkages between these occurrences are becoming more apparent, but the etiology of these pathologic lesions is yet to be elucidated. This review examines the role of neuroinflammation and mitochondrial dysfunction in the growth and course of NDDs, emphasizing the possibility of identifying novel therapeutic targets to address aging-related neurodegenerative processes and retard the progression of these illnesses.}, } @article {pmid40901171, year = {2025}, author = {Budha, B and Chapagain, A and Adhikari, D and Bajracharya, S and Poudel, D and Budha, R and Adhikari, S and Gurmaita, RK}, title = {Acquired hemophilia a in a female with minimal change disease and hypothyroidism: a rare case report.}, journal = {Annals of medicine and surgery (2012)}, volume = {87}, number = {9}, pages = {6168-6172}, pmid = {40901171}, issn = {2049-0801}, abstract = {INTRODUCTION: Juvenile amyotrophic lateral sclerosis (J-ALS) is extremely rare neurodegenerative motor neuron disorder that begins in early childhood or adolescence, before the age of 25 years old. It is characterized by gradual disease progression with comparison to adult-onset ALS and is often linked to genetic mutations.

CASE PRESENTATION: A 16-years-old female presented with long history of generalized weakness since age of 10 years, followed by bilateral sensorineural hearing loss, bulbar symptoms, and limb spasticity. Neurological examination revealed upper motor neuron signs in upper limbs, lower motor neuron signs in lower limbs, and bulbar involvement. Nerve conduction test was normal however, MRI showed early degenerative changes, and diagnosed with J-ALS after careful evaluation. She was started on Riluzole. Despite ICU care and supportive interventions including PEG and tracheostomy, she succumbed to respiratory failure.

DISCUSSION: Rarity, atypical presentation, and finical constraints can delay diagnosis of J-ALS. However, early diagnosis after careful evaluation of clinical symptoms, medical history, electrophysiological and imaging studies followed by prompt treatment with Riluzole and supportive interventions can help prolong survival and improve quality of life.

CONCLUSION: J-ALS is a rare motor neuron disease which possess immense diagnostic challenges, can exhibit relentless progression over short period of time with time.}, } @article {pmid40901333, year = {2025}, author = {Agrawal, H and Gupta, N}, title = {Deep learning models for pathological classification and staging of oesophageal cancer.}, journal = {World journal of clinical oncology}, volume = {16}, number = {8}, pages = {109893}, pmid = {40901333}, issn = {2218-4333}, abstract = {This letter comments on Wei et al's study applying the Wave-Vision Transformer for oesophageal cancer classification. Highlighting its superior accuracy and efficiency, we discuss its potential clinical impact, limitations in dataset diversity, and the need for explainable artificial intelligence to enhance adoption in pathology and personalized treatment.}, } @article {pmid40901879, year = {2025}, author = {Sun, G and Li, X and Hu, J and Yang, T and Liu, C and Wang, Z and Li, D and Xu, W}, title = {De novo design of protein binders to stabilize monomeric TDP-43 and inhibit its pathological aggregation.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {36}, pages = {e2505320122}, pmid = {40901879}, issn = {1091-6490}, support = {2020YFA0909200//MOST | National Key Research and Development Program of China (NKPs)/ ; 32101181//MOST | National Natural Science Foundation of China (NSFC)/ ; 32494764//MOST | National Natural Science Foundation of China (NSFC)/ ; 92353302//MOST | National Natural Science Foundation of China (NSFC)/ ; 32170683//MOST | National Natural Science Foundation of China (NSFC)/ ; 82188101//MOST | National Natural Science Foundation of China (NSFC)/ ; 22425704//MOST | National Natural Science Foundation of China (NSFC)/ ; 22JC1410400//Science and Technology Commission of Shanghai Municipality (STCSM)/ ; JCYJ-SHFY-2022-005//Chinese Academy of Sciences, Shanghai Branch (ä¸ç§'院上海分院)/ ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry/genetics ; Humans ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates ; Protein Binding ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Amyloid/metabolism/chemistry ; Frontotemporal Lobar Degeneration/metabolism ; Protein Stability ; }, abstract = {Pathological aggregation of transactive response DNA binding protein of 43 kDa (TDP-43), primarily driven by its low-complexity domain, is closely associated with various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the therapeutic potential of preventing TDP-43 aggregation, no effective small molecule or biomacromolecule therapeutics have been successfully developed so far. Here, we introduce a protein design strategy that yields de novo designed proteins capable of stabilizing the key amyloidogenic region of TDP-43 in its native helical conformation with nanomolar binding affinity. The binding mechanism was further characterized by the NMR and mutagenesis study. More importantly, we demonstrated that our designed protein binders efficiently reduced TDP-43 amyloid aggregation both in vitro and in cells. Our work provides a strategy for designing protein stabilizer of the native conformation of pathological proteins for preventing its amyloid aggregation, shedding light on the development of potential therapeutic approaches for ALS, FTLD, and other protein aggregation-associated diseases.}, } @article {pmid40901987, year = {2025}, author = {Sun, Z and Li, C and Leitner, D and Wu, M and Zhang, J and Wisniewski, T and Ge, Y}, title = {Age-related Vascular Alterations in the Choroid Plexus: Novel Insights from Pathophysiology and Imaging Studies.}, journal = {Aging and disease}, volume = {17}, number = {5}, pages = {2304-2329}, pmid = {40901987}, issn = {2152-5250}, support = {F31 NS011004/NS/NINDS NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; U24 NS135568/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Choroid Plexus/blood supply/diagnostic imaging/pathology/physiopathology ; *Aging/pathology/physiology ; Magnetic Resonance Imaging ; Animals ; Blood-Brain Barrier ; }, abstract = {The choroid plexus (ChP), a highly vascularized brain structure responsible for cerebrospinal fluid (CSF) production, undergoes significant age-related changes that may contribute to neurodegenerative diseases involving disrupted immune regulation, fluid homeostasis and waste clearance. Compared to other brain regions, vascular research on the ChP remains limited despite its critical role as a central interface between the blood and CSF. This review focuses on age-related vascular and structural alterations in the ChP from both histopathological and neuroimaging perspectives, and explores their impact on CSF dynamics, immune regulation, and the integrity of the blood-CSF barrier (BCSFB). Rather than shrinking, the aging ChP often enlarges due to dystrophic changes, as shown in volumetric MRI studies. Histological studies reveal epithelial degeneration, basement membrane thickening, and stromal fibrosis in the normal aging process. In dementia such as Alzheimer's disease (AD), proteomic studies have identified upregulation of AD- and immune-related proteins, along with downregulation of proteins linked to CSF clearance and metabolic support. Emerging high-resolution contrast-enhanced MRI techniques now allow in vivo visualization of microvascular changes within the ChP, shedding light on its normal and abnormal aging processes. Understanding these alterations is critical, as they may influence the onset and progression of various neurological diseases such as AD, Parkinson's disease (PD), normal pressure hydrocephalus, and amyotrophic lateral sclerosis (ALS). The recent advancements and challenges described in this study underscore the need for deeper investigation into ChP aging to inform future diagnostic and therapeutic strategies of neurodegenerative diseases.}, } @article {pmid40902435, year = {2025}, author = {Midya, V and Bello, G and Andrew, AS and Re, DB and Stommel, EW and Arora, M}, title = {Dysregulation of hair-strand-based elemental biodynamics in amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {119}, number = {}, pages = {105907}, pmid = {40902435}, issn = {2352-3964}, support = {R35 ES030435/ES/NIEHS NIH HHS/United States ; U2C ES030859/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnosis/etiology ; Female ; Male ; *Hair/chemistry/metabolism ; Middle Aged ; Aged ; Case-Control Studies ; *Trace Elements ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare motor neurodegenerative disorder and is predominantly diagnosed in older adults. Altered levels of essential and toxic elements have been implicated in ALS pathophysiology; however, little is known about the longitudinal biodynamic patterns of these elements in patients with ALS.

METHODS: Using a single individual hair strand, we generated time series data of 400-800 time points approximately at 2 to 4 hourly resolution on 17 elemental intensities in ALS-positive cases and ALS-negative controls from a national collection and a regional centre in the US (on a total sample of 391, with 295 cases and 96 controls, with median age at hair collection over 60 years). The elements included were Li, Mg, P, S, Ca, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Sr, Sn, Ba, and Pb. We analysed the growth increments in single hair strands using laser ablation-inductively coupled plasma-mass spectrometry to create time-resolved signals of elemental exposure and intensity along the hair strand. Two complementary information-theoretic methods, cross-recurrence quantification analysis and transfer entropy-based network analysis, were employed to generate time-resolved features that quantify the synchronisation of multi-element biodynamics.

FINDINGS: Male ALS-positive cases had significantly lower synchronicity in Cu-Zn temporal biodynamics than ALS-negative controls (recurrence: log(β) = -1.64, p-value < 0.001, q-value = 0.03). Female ALS-positive cases had lower synchronicity in Cr-Ni temporal biodynamics than ALS-negative controls (recurrence: log(β) = -1.59, p-value < 0.001, q-value = 0.46). In both males and females, multiple centrality measures of Cu (that quantify the importance of Cu within a network of all elemental intensities) were significantly lower in ALS-positive cases than in ALS-negative controls [in males, closeness centrality of Cu: log(β) = -0.64, p-value = 0.002, q-value = 0.04; in females, eigenvector centrality of Cu: log(β) = -0.53, p-value = 0.02, q-value = 0.97].

INTERPRETATION: We demonstrate that ALS-positive cases have significantly higher odds of collapse in the synchronisation of elemental biodynamics and worse connectedness in copper-based networks compared to ALS-negative controls.

FUNDING: US National Institutes of Health (P30ES023515, R01ES026033, U2CES030859, U2CES026561, R35ES030435, UL1TR004419, 1OT2NS136938-01, 1R01ES034133-01) and CDC/ATSDR (R01TS000331, R01TS000324 and R01TS000285).}, } @article {pmid40903205, year = {2026}, author = {Ng, L and Sweeney, KD and Mercer, SW}, title = {Challenges in reducing the 10-item CARE Measure to a two-item version: comparison of patients' preferences with psychometric evaluation in a cross-sectional survey in Scotland.}, journal = {BJGP open}, volume = {10}, number = {1}, pages = {}, pmid = {40903205}, issn = {2398-3795}, abstract = {BACKGROUND: The Consultation and Relational Empathy (CARE) Measure is a widely used 10-item measure to assess patients' perceptions of physician empathy. Takahashi et al's (2022) recent study proposed a two-item version based on psychometric evaluation of survey responses, without considering patient preferences.

AIM: To apply Takahashi et al's psychometric method to UK data, and compare findings with patients' preferences on the two most important items.

DESIGN & SETTING: In 2022, a cross-sectional postal survey of 6291 Scottish adults was conducted.

METHOD: Using Takahashi et al's method, psychometric evaluation compared correlations between all possible two-item combinations with the original 10-item CARE Measure to identify the optimal two-item combination. Patients were also asked to select the two items they considered most important. Descriptive analysis examined the proportion of patients selecting each item, and level of agreement on the most popular two-item combination.

RESULTS: In total, 1053 (17%) of 6291 patients responded. Psychometric evaluation identified items 6 ('Showing care and compassion') and 8 ('Explaining things clearly') as the optimal two-item combination (Cronbach's alpha = 0.916, correlation = 0.953). This differed from patient preferences, with items 3 ('Really listening') and 8 receiving the highest proportion of votes (19% and 17%, respectively). Preferences also varied by age, deprivation level, and consultation complexity. The most popular two-item combination (items 3 and 8) was selected by 10% of responders, with 90% selecting other combinations.

CONCLUSION: The psychometrically optimal two-item combination did not align with patient preferences. Given variation in patient preferences and low agreement, reducing the CARE Measure to two-items may be inadvisable.}, } @article {pmid40903341, year = {2025}, author = {Vedula, P and Ishizuka, K and Hayashida, A and Sueo, K and Sawa, A}, title = {Stress-induced nuclear GAPDH: Scientific update and clinical application.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {22}, number = {6}, pages = {e00725}, pmid = {40903341}, issn = {1878-7479}, support = {P50 MH136297/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Animals ; *Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism ; *Cell Nucleus/metabolism ; *Stress, Physiological/physiology ; }, abstract = {Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is known as a moonlighting protein beyond its original glycolytic function. Stress-induced nuclear translocation of GAPDH has been reproducibly reported, which results in variety types of cellular responses, including cell death and dysfunction. Blocking this stress-induced cascade has been regarded as a target of drug discovery and development for human disease conditions, particularly for neurological and psychiatric diseases. There are promising small compounds that can block this cascade in cell and animal models. Nevertheless, the clinical trials for Parkinson's disease and amyotrophic lateral sclerosis with one of these compounds Omigapil were unsuccessful. Including these failure cases, this review article discussed the scientific frontline of GAPDH, particularly stress-induced nuclear GAPDH, and its potential for clinical applications.}, } @article {pmid40903652, year = {2025}, author = {Koyuncu, S and Dominguez-Canterla, Y and Alis, R and Salarzai, N and Petrovic, D and Flames, N and Vilchez, D}, title = {The aging factor EPS8 induces disease-related protein aggregation through RAC signaling hyperactivation.}, journal = {Nature aging}, volume = {5}, number = {9}, pages = {1750-1770}, pmid = {40903652}, issn = {2662-8465}, support = {VI742/4-2//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; EXC 2030-390661388//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 0.22.2.030MN//Fritz Thyssen Stiftung (Fritz Thyssen Foundation)/ ; CIAICO/2022/195//Generalitat Valenciana (Regional Government of Valencia)/ ; }, mesh = {Caenorhabditis elegans/genetics/metabolism ; Humans ; Animals ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Signal Transduction ; *Aging/genetics/metabolism ; Ubiquitination ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Protein Aggregation, Pathological/metabolism/genetics ; Huntington Disease/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; *rac GTP-Binding Proteins/metabolism ; *Protein Aggregates ; }, abstract = {Aging is a major risk factor for neurodegenerative diseases associated with protein aggregation, including Huntington's disease and amyotrophic lateral sclerosis (ALS). Although these diseases involve different aggregation-prone proteins, their common late onset suggests a link to converging changes resulting from aging. In this study, we found that age-associated hyperactivation of EPS8/RAC signaling in Caenorhabditis elegans promotes the pathological aggregation of Huntington's disease-related polyglutamine repeats and ALS-associated mutant FUS and TDP-43 variants. Conversely, knockdown of eps-8 or RAC orthologs prevents protein aggregation and subsequent deficits in neuronal function during aging. Similarly, inhibiting EPS8 signaling reduces protein aggregation and neurodegeneration in human cell models. We further identify the deubiquitinating enzyme USP4 as a regulator of EPS8 ubiquitination and degradation in both worms and human cells. Notably, reducing USP-4 upregulation during aging prevents EPS-8 accumulation, extends longevity and attenuates disease-related changes. Our findings suggest that targeting EPS8 and its regulatory mechanisms could provide therapeutic strategies for age-related diseases.}, } @article {pmid40903936, year = {2026}, author = {Shao, N and Zhang, X and Ge, Y and Tang, J and Gao, H and Si, W and Cai, B}, title = {O-GlcNAcylation: A molecular switch linking brain health to neurodegeneration.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {4715-4728}, pmid = {40903936}, issn = {1673-5374}, abstract = {Neurodegenerative disorders are typically caused by harmful protein accumulation and nerve cell damage. A post-translational modification called O-linked N-acetylglucosamine ylation acts as a critical regulator in these disorders by controlling protein behavior, cell signaling, and energy balance. This modification is dynamically balanced through the cooperative actions of O-linked N-acetylglucosamine transferase and O-GlcNAcase. In healthy brains, O-GlcNAcylation supports nerve cell function and survival, but its imbalance contributes to disease progression. Notably, the effects of O-GlcNAcylation differ across disorders. This review reveals how O-GlcNAcylation bridges molecular mechanisms to neurodegeneration, as well as the prospects of targeted O-linked N-acetylglucosamine acylation therapy for neurodegenerative diseases. In Alzheimer's disease, it blocks toxic changes in key proteins like tau and amyloid-beta. In Parkinson's disease, it reduces the clumping of alpha-synuclein, yet may disrupt dopamine production. In amyotrophic lateral sclerosis, it protects nerve fiber transport systems. Additionally, O-GlcNAcylation plays an indispensable part in other neurodegenerative conditions, including Huntington's disease, aging, Machado-Joseph disease, multiple sclerosis, and giant axonal neuropathy. New therapies targeting this mechanism include glucosamine supplements and O-GlcNAcase inhibitors, which show clinical promise but face translational challenges.}, } @article {pmid40903937, year = {2026}, author = {Martinez, P and van Zundert, B and Bustos, FJ}, title = {Reevaluating the role of skeletal muscle in amyotrophic lateral sclerosis pathogenesis: Insights from muscle-derived factors.}, journal = {Neural regeneration research}, volume = {21}, number = {7}, pages = {2944-2945}, pmid = {40903937}, issn = {1673-5374}, } @article {pmid40903950, year = {2026}, author = {Liu, Y and Tang, T and Cai, H and Liu, Z}, title = {Bidirectional communication between the gut microbiota and the central nervous system.}, journal = {Neural regeneration research}, volume = {21}, number = {8}, pages = {3411-3425}, pmid = {40903950}, issn = {1673-5374}, abstract = {In recent years, an increasing number of researchers have become interested in the bidirectional communication between the gut microbiota and the central nervous system. This communication occurs through the microbiota-gut-brain axis. As people age, the composition of the gut microbiota undergoes considerable changes, which are now known to play an important role in the development of many neurodegenerative diseases. This review aims to investigate the complex bidirectional signaling pathways between the gut and the brain. It summarizes the latest research findings on how the gut microbiota and its metabolites play critical roles in regulating inflammation, maintaining gut health, and influencing the development of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The review also analyzes the current clinical applications of gut microbiota-based treatments for neurological disorders, including fecal microbiota transplantation, probiotics, and prebiotics. Many studies show that the gut microbiota affects the brain in several ways. For example, it can produce substances such as short-chain fatty acids and activate inflammatory pathways. Studies involving animals and laboratory models have demonstrated that adjusting the gut microbiota can help improve behavior and reduce neurological problems. Recent metagenomic and metabolomics studies have shown that the microbiota plays a crucial role in maintaining the organism's health. Microorganisms primarily colonize the gut and are involved in host nutrient metabolism, maintaining the structural integrity of the intestine, preserving the intestinal mucosal barrier, and modulating the immune system. The gut microbiota communicates with the brain through a bidirectional microbiota-gut-brain axis. The composition of the gut flora changes considerably with age, and ecological dysregulation has been recognized as one of the twelve most recent hallmarks of aging. Recent studies have linked these changes to a variety of age-related neurological disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, and Huntington's disease. Specifically, the gut microbiota influences the brain through the production of key metabolites such as short-chain fatty acids and the activation of inflammatory and other relevant signaling pathways. In preclinical studies, targeted modulation of the gut microbiota, through methods such as fecal microbiota transplantation, probiotics, and prebiotics, has demonstrated potential in improving host behavioral outcomes. Therefore, gut microbiota-based treatments offer new hope for the treatment of nervous system diseases. However, due to the complexity of the gut microbiota and the potential adverse reactions associated with these therapies, researchers need to carefully assess their safety and efficacy before widespread clinical application.}, } @article {pmid40903956, year = {2026}, author = {Chen, Y and Yin, P and Chen, Q and Zhang, Y and Tang, Y and Jin, W and Yu, L}, title = {Neurodegenerative diseases and immune system: From pathogenic mechanism to therapy.}, journal = {Neural regeneration research}, volume = {21}, number = {8}, pages = {3387-3410}, pmid = {40903956}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are a class of disorders with the gradual loss of the central nervous system and peripheral nervous system. Neurodegenerative diseases manifest primarily as cognitive and behavioral disorders that adversely affect the lives of millions of people worldwide. Therefore, it is necessary to elucidate the mechanism of neurodegenerative diseases further and find effective new therapies. In recent years, increasing evidence has shown that the immune system plays a significant role in the pathophysiology of neurodegenerative diseases and regulates this process. The central and peripheral immune systems exert different roles in the disease progression. The development of neurodegenerative diseases is influenced by interactions between them. This review focuses on how the immune system, including microglia mediated nucleotide-binding oligomerization domain-like receptor protein 3 inflammation activation and T cell-mediated neuroinflammation, interactions with neurodegenerative diseases by modulating protein aggregation and blood-brain barrier permeability. Besides, we gave particular attention to glial cell-centered multicellular interactions and the inflammatory signaling pathway. Insight into the immune system's functions and cellular interactions is essential for progressing disease research. In addition, the functions and mechanisms of these immune cells also suggest new ideas and targets for treatment. Therefore, this review summarizes some of the existing treatment strategies for amyloid-beta, tau, neuroinflammation, α-synuclein, associated microbiota, immune modulation, and neural injury repair. In addition, this review summarizes and compares animal models of different common neurodegenerative diseases and clinical research progress. In view of the current research status, new research directions and suggestions are proposed.}, } @article {pmid40903965, year = {2026}, author = {Parikh, A and Cholavaram, A and Chitti Babu, AK and Deepankumar, K and Vijayan, M}, title = {Role of voltage-dependent anion channel 1 in neurodegeneration: Mechanisms, implications, and therapeutic potential.}, journal = {Neural regeneration research}, volume = {21}, number = {9}, pages = {4148-4156}, pmid = {40903965}, issn = {1673-5374}, abstract = {Voltage-dependent anion channel 1 is an integral outer membrane protein of the mitochondria that governs apoptosis, enables metabolite exchange, and influences mitochondrial activity. In neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease, oxidative stress, neuroinflammation, and mitochondrial dysfunction are frequent features. Voltage-dependent anion channel 1 is a key regulator of these processes. This review described the structure, membrane topology, and physiological function of voltage-dependent anion channel 1 in neurons and glial cells. We emphasize how it affects mitophagy, oxidative damage, and changes in mitochondrial permeability. Special attention is focused on how voltage-dependent anion channel 1 interacts with pathogenic proteins that damage mitochondrial integrity and cause neurotoxicity, including mutant huntingtin, phosphorylated tau, α-synuclein, amyloid-beta, and TAR DNA-binding protein 43. Furthermore, the paper examines the function of voltage-dependent anion channel 1 in astrocytic dysfunction and microglial activation, highlighting its impact on neuroinflammation. In a nutshell, we assess treatment strategies that target voltage-dependent anion channel 1, such as VBIT-4, a selective inhibitor of voltage-dependent anion channel 1 oligomerization, and newer methods, including structure-based drug design and CRISPR/Cas9 regulation. Improved knowledge of the hinter voltage-dependent anion channel 1 of the molecular mechanism may allow for new therapeutic approaches in neurodegenerative diseases.}, } @article {pmid40903966, year = {2026}, author = {Abbassi, Y and Fink, D and Cei, F and Niccolai, E and Amedei, A}, title = {TDP-43-immunity-microbiota axis in amyotrophic lateral sclerosis: A potential pathogenic mechanism.}, journal = {Neural regeneration research}, volume = {21}, number = {8}, pages = {3439-3448}, pmid = {40903966}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease marked by progressive motor neuron degeneration. Despite extensive research, effective treatments remain elusive, underscoring the need to explore the molecular mechanisms driving disease progression. The amyotrophic lateral sclerosis complexity is further compounded by its large heterogeneity, encompassing both genetic and sporadic forms, diverse phenotypic presentations, and highly variable progression rates. A key pathological feature of amyotrophic lateral sclerosis is the aggregation of TAR DNA-binding protein 43, which contributes to cellular toxicity, neuroinflammation, and neuronal dysfunction. This review explores the complex interplay between TAR DNA-binding protein 43 pathology, immunity dysregulation, and the gut-brain axis, with a focus on the role of microbiome-derived metabolites in amyotrophic lateral sclerosis. Neuroinflammation, mediated by both innate and adaptive immunity, plays a central role in disease pathogenesis, with TAR DNA-binding protein 43 influencing immune signaling and exacerbating neurotoxicity. Additionally, disruptions in gut microbiota composition and intestinal barrier integrity, frequently observed in amyotrophic lateral sclerosis patients, suggest a potential role for the gut-brain axis in modulating neurodegenerative processes. By integrating evidence from emerging studies, our aim is to clarify how TAR DNA-binding protein 43 aggregation contributes to neuroinflammation and immune dysfunction while exploring the gut microbiota role as both a modulator and potential biomarker of disease. Understanding these interactions could pave the way for novel therapeutic strategies, including microbiome-targeted interventions such as probiotics, dietary modifications, or immune-modulating therapies. Finally, unraveling the TAR DNA-binding protein 43-immune system-microbiome axis may offer new avenues for personalized treatments aimed at mitigating neuroinflammation, slowing amyotrophic lateral sclerosis progression, and improving patient outcomes and life quality.}, } @article {pmid40904199, year = {2025}, author = {Isik, S and Osman, S and Yeman-Kiyak, B and Shamshir, SRM and Sanchez, NME}, title = {Advances in Neurodegenerative Disease Therapy: Stem Cell Clinical Trials and Promise of Engineered Exosomes.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {9}, pages = {e70577}, pmid = {40904199}, issn = {1755-5949}, mesh = {Humans ; *Exosomes/transplantation/metabolism ; *Neurodegenerative Diseases/therapy ; Animals ; *Stem Cell Transplantation/methods/trends ; *Clinical Trials as Topic/methods ; }, abstract = {AIM: This review provides a systematic evaluation of 94 stem cell clinical trials to treat neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.

METHODS: Data were collected from using relevant search terms, focusing exclusively on stem cell therapy. Of the 8000+ participants in these trials, nearly 70% were enrolled in AD-related studies. Only three Phase 3 studies were conducted, and most trials were in the early phases (Phases 1 and 2). Mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, and embryonic stem cells are used the most to treat neurodegenerative diseases. This review also explores the emerging fields of preclinical and clinical investigations of stem cell-derived exosome-based therapies for neurodegenerative diseases.

RESULTS: Exosomes can cross the blood-brain barrier to deliver therapeutic molecules directly to the brain, offering a less invasive alternative to stem cell transplantation. Mesenchymal stem cell-derived exosomes, in particular, have demonstrated significant potential in preclinical models by reducing neuroinflammation, oxidative stress, and promoting neuronal regeneration. Additionally, recent advances in exosome engineering, including surface modifications, therapeutic agent loading, and transgenic modifications, have improved targeting, stability, blood-brain barrier delivery, and neural cell interactions, enabling targeted and effective treatment. Exosome-based therapies are in the preliminary phases of clinical investigation, with only three clinical trials.

CONCLUSION: Given the increasing interest in exosome therapy, clinical investigations are expected to increase. This growth will be driven by ongoing advancements in exosome technology, a deeper understanding of their therapeutic potential, and escalating demand for innovative treatment strategies for neurodegenerative diseases.}, } @article {pmid40904817, year = {2025}, author = {Kuo, T and Reynolds, T and Chen, L and Park, C and Rascati, K and Godley, P}, title = {Racial and ethnic disparities in ALS: a longitudinal electronic health records study.}, journal = {Therapeutic advances in neurological disorders}, volume = {18}, number = {}, pages = {17562864251365001}, pmid = {40904817}, issn = {1756-2856}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options and significant variability in care. Racial and ethnic disparities in ALS management and outcomes have been reported, but findings remain inconsistent.

OBJECTIVES: This study aimed to evaluate racial and ethnic disparities in ALS care, specifically differences in healthcare utilization, treatment patterns, and survival, within a large healthcare system.

DESIGN: This retrospective cohort study analyzed electronic health records from a large healthcare system in Texas for patients diagnosed with ALS between 2013 and 2023, examining racial and ethnic differences in treatment and outcomes.

METHODS: Patients were identified using International Classification of Diseases (ICD) codes. Baseline characteristics, including race/ethnicity and socioeconomic factors, were collected. Primary outcomes included the use of noninvasive ventilation (NIV), tracheostomy, gastrostomy, mobility aids, and ALS medications; secondary outcomes included time to diagnosis and survival. Racial and ethnic disparities were assessed using generalized linear regression and Cox proportional hazards models, adjusting for demographic and socioeconomic factors.

RESULTS: A total of 636 patients were included (74.5% Non-Hispanic White, 5.3% Non-Hispanic Black, 7.4% Hispanic, and 12.7% Other). Non-Hispanic Black patients had significantly higher tracheostomy rates than Non-Hispanic White patients (35.3% vs 8.7%; adjusted odds ratio (OR), 6.20; 95% confidence interval (CI), 2.43-15.84). Hispanic patients had lower odds of receiving riluzole (42.6% vs 61.8%; adjusted OR, 0.36; 95% CI, 0.18-0.71) and higher rates of emergency department visits (adjusted OR, 2.00; 95% CI, 1.09-3.65) and hospitalizations (adjusted OR, 2.57; 95% CI, 1.37-4.81). No significant racial or ethnic differences were observed in time to diagnosis or survival after adjustment.

CONCLUSION: Significant racial and ethnic disparities exist in ALS care, particularly in tracheostomy utilization, medication prescribing, and healthcare access. These findings underscore the need for targeted interventions to promote equitable ALS management, including provider education and improved healthcare accessibility.}, } @article {pmid40905501, year = {2026}, author = {Huang, Y and Wan, Y and Chen, J and Qin, M and Wang, J and Liang, H}, title = {Knowledge mapping of biomarkers in amyotrophic lateral sclerosis: a comprehensive bibliometric and visual analysis.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {2}, pages = {191-207}, pmid = {40905501}, issn = {1758-2032}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/metabolism/cerebrospinal fluid ; Humans ; *Biomarkers/cerebrospinal fluid ; *Bibliometrics ; Neurofilament Proteins ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease, and there is currently an urgent need to identify valuable biomarkers to accelerate diagnosis, optimize treatment and prognosis.

METHODS: To conduct a bibliometric analysis of publications related to "ALS biomarker" over the past 20 years, utilizing the subject search feature of the Web of Science Core Collection along with CiteSpace, VOSviewer, and Bibliometrix.

RESULTS: This review presents a 20-year bibliometric analysis of ALS biomarker research (2004-2024), analyzing 2535 publications showing rising trends. The United States led contributions, with Turner, Martin R as the most productive/cited author. Key research hotspots included cerebrospinal fluid, tdp-43, clinical trial, and neuroinflammation. Topics such as neurofilament light chain, machine learning, and exosomes could potentially represent the cutting edge of future research.

CONCLUSION: In summary, this study uses bibliometric analysis of ALS biomarker research to provide a forward-looking perspective on its future limitations and potential.}, } @article {pmid40905633, year = {2025}, author = {Verdés, S and Navarro, X and Bosch, A}, title = {Targeting Amyotrophic Lateral Sclerosis with Gene Therapy: From Silencing Genes to Enhancing Neuroprotection.}, journal = {Human gene therapy}, volume = {36}, number = {17-18}, pages = {1173-1198}, doi = {10.1177/10430342251372898}, pmid = {40905633}, issn = {1557-7422}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics/pathology ; *Genetic Therapy/methods ; *Gene Silencing ; *Neuroprotection/genetics ; Superoxide Dismutase-1/genetics ; Animals ; Oligonucleotides, Antisense/genetics/therapeutic use ; Genetic Vectors/genetics ; C9orf72 Protein/genetics ; Gene Editing ; RNA Interference ; }, abstract = {Gene therapy is emerging as a transformative approach for treating amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disease. While gene replacement has shown a groundbreaking success in spinal muscular atrophy, the complexity of ALS-due to frequent gain-of-function mutations and a heterogeneous etiology-presents significant challenges. Importantly, approximately 90% of ALS cases are sporadic, with unknown genetic mutation, further complicating patient stratification and therapeutic targeting. As a result, gene therapy strategies must often address multiple pathological mechanisms simultaneously. So far, current gene therapy strategies aim to either suppress toxic gene expression or promote neuroprotection, predominantly via viral-mediated delivery systems. This review will provide an overview of emerging preclinical and clinical gene therapy approaches for ALS, focusing on two main strategies: gene silencing and neuroprotection. Gene silencing techniques, including antisense oligonucleotides (ASOs), viral-mediated RNA interference, and gene editing, have demonstrated efficacy in reducing mutant gene expression, particularly in SOD1 and C9orf72 models, although clinical translation has so far yielded limited success. The recent Food and Drug Administration's approval of the ASO therapy Qalsody for SOD1-ALS underscores the clinical potential of these approaches. Neuroprotective strategies aim to enhance motor neuron survival through delivery of trophic factors, often targeting both central and peripheral tissues to harness retrograde transport mechanisms. We will discuss the advantages and limitations of various delivery vectors, targeting specificity, timing of intervention, and translational challenges, alongside current clinical trial data. This review aims to synthesize how these approaches may converge to address the multifaceted nature of ALS and guide the development of next-generation therapeutics.}, } @article {pmid40905723, year = {2025}, author = {Peng, C and Maiuri, T and Truant, R}, title = {Tipping the PARylation scale: Dysregulation of PAR signaling in Huntington and neurodegenerative diseases.}, journal = {Journal of Huntington's disease}, volume = {14}, number = {4}, pages = {293-303}, pmid = {40905723}, issn = {1879-6400}, mesh = {Humans ; *Huntington Disease/metabolism/genetics ; *Signal Transduction/physiology ; *Neurodegenerative Diseases/metabolism/genetics ; *Poly ADP Ribosylation/physiology ; Animals ; }, abstract = {Poly(ADP-ribosyl)ation (PARylation), a crucial post-translational modification, is catalyzed by ADP-ribosyltransferases (ARTs) and has significant implications in various cellular processes, including DNA damage response, cell signaling, and immune processes. Aberrant PAR signaling is implicated in numerous neurodegenerative diseases, including Alzheimer, Parkinson, amyotrophic lateral sclerosis, and cerebellar ataxia, where increased PAR levels and PARP1 activity are commonly observed. However, Huntington disease exhibits a unique characteristic: reduced PAR levels and impaired PARP1 activity even in prodromal phase. This finding challenges the prevailing understanding of PAR's role in neurodegeneration and suggests that dysregulation of PAR signaling, whether through overactivation or suppression, can lead to neuronal dysfunction. Herein, we discuss how this balance may impact neurodegenerative diseases, and possible connections between PAR signaling and emerging modifiers of disease onset identified by HD genome-wide association studies (GWAS).}, } @article {pmid40905788, year = {2026}, author = {Willemse, SW and Demaegd, KC and Van Eijk, RPA and Van Damme, P and Harrington, E and Harms, MB and Shneider, NA and Van Rheenen, W and Veldink, JH and Van Den Berg, LH and Van Es, MA}, title = {A VAPB (P56S) mutation in a Dutch patient with familial motor neuron disease: a case report.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {227-229}, doi = {10.1080/21678421.2025.2555218}, pmid = {40905788}, issn = {2167-9223}, mesh = {Humans ; *Motor Neuron Disease/genetics/diagnosis ; *Mutation/genetics ; Male ; Netherlands ; *Vesicular Transport Proteins/genetics ; Female ; Middle Aged ; Pedigree ; }, abstract = {The c.166C > T p.(Pro56Ser) or P56S mutation in the VAPB gene was initially identified as a cause of motor neuron disease in Brazil in a large extended pedigree comprising >1,500 individuals including more than 200 cases. This VAPB mutation gives rise to three phenotypes: late-onset spinal muscular atrophy, classical ALS with bulbar involvement, pyramidal signs and rapid disease progression, and atypical ALS with slow progression. Nearly all known cases originate from a single founder, with most cases outside of Brazil being related to this pedigree. However, there is one report of an independent German family with the same mutation on a different haplotype, indicating a second founder event. Here, we report the first Dutch patient with a P56S mutation in VAPB and motor neuron disease. Documenting rare genetic causes of MND and their natural history are of increasing importance in light of emerging gene-specific therapies.}, } @article {pmid40906007, year = {2025}, author = {Howard-Williams, EL and Ossman, P and Fuller, J}, title = {Respiratory-Onset Amyotrophic Lateral Sclerosis (ALS): A Rare Initial Presentation.}, journal = {Journal of general internal medicine}, volume = {40}, number = {16}, pages = {4059-4063}, pmid = {40906007}, issn = {1525-1497}, } @article {pmid40906043, year = {2025}, author = {García-Toledo, I and Godoy-Corchuelo, JM and Fernández-Beltrán, LC and Ali, Z and Guindo-Arroyo, A and Jiménez-Coca, I and Jiménez-Rodríguez, J and Javaloyes-García, K and Viñuela, M and Gómez-Pinedo, U and Saiz-Aúz, L and Rábano, A and Área-Gómez, E and Cunningham, TJ and Corrochano, S}, title = {TDP-43 dysregulation impairs cholesterol metabolism linked with myelination defects.}, journal = {Acta neuropathologica}, volume = {150}, number = {1}, pages = {23}, pmid = {40906043}, issn = {1432-0533}, support = {PIPF-2022/SAL-GL-24282//Consejería de educación, ciencia y universidades, Comunidad de Madrid/ ; PDI2020-1153-70RB-100//Ministerio de Ciencia e Innovación/ ; PID2023-147947OB-I00//Ministerio de Ciencia e Innovación/ ; CT58/21-CT59/21//Unversidad Complutense de Madrid/ ; }, mesh = {*Cholesterol/metabolism ; Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Myelin Sheath/metabolism/pathology ; Mice ; Humans ; *TDP-43 Proteinopathies/metabolism/pathology/genetics ; Male ; Brain/metabolism/pathology ; Mice, Transgenic ; Female ; Mice, Inbred C57BL ; Lipid Metabolism ; Frontal Lobe/metabolism/pathology ; Disease Models, Animal ; }, abstract = {TDP-43 is a nuclear protein encoded by the TARDBP gene, which forms pathological aggregates in various neurodegenerative diseases, collectively known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These diseases are characterized by multiple pathological mechanisms, with disruptions in lipid regulatory pathways emerging as a critical factor. However, the role of TDP-43 in the regulation of the brain lipid homeostasis and the potential connection of TDP-43 dysfunction to myelin alterations in TDP-43 proteionopathies remain poorly understood, despite the fact that lipids, particularly cholesterol, comprise nearly 70% of myelin. To investigate the causal relationship between TDP-43 dysfunction and disruptions in brain cholesterol homeostasis, we conducted multi-omics analyses (lipidomics, transcriptomics, and functional splicing) on the frontal cortex from the Tardbp[M323K/M323K] knock-in mouse model. Lipidomic analysis revealed alterations in lipid pathways related to membrane composition and lipid droplet accumulation, particularly affecting cholesterol-related species. We found higher lipid droplet accumulation in primary fibroblasts derived from these mice, as well as in the brain of the mutant mice. Similarly, the immunohistochemical detection of a lipid droplet marker was higher in the postmortem frontal cortex, gray matter, and white matter of FTLD-TDP patients compared to non-neurological controls. Transcriptomic analyses showed that TDP-43 pathology led to transcriptional dysregulation of genes essential for myelin production and maintenance. We identified impaired cholesterol metabolism, mainly through the downregulation of endogenous cholesterol synthesis, alongside upregulated cholesterol transport pathways, which we further replicated in FTLD-TDP patients transcriptomic datasets. Collectively, our findings suggest that TDP-43 dysfunction disrupts brain cholesterol homeostasis, potentially compromising myelin integrity.}, } @article {pmid40906916, year = {2025}, author = {Kakoty, V and Kang, JH and Lee, OH and Oh, DH and Ko, YT}, title = {Grueneberg Ganglion: An Unexplored Site for Intranasal Drug Delivery in Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {18}, pages = {3425-3437}, doi = {10.1021/acschemneuro.5c00376}, pmid = {40906916}, issn = {1948-7193}, mesh = {Animals ; Administration, Intranasal/methods ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Delivery Systems/methods ; Humans ; Mice ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {Neurological disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis pose significant challenges for treatment. Reasons for the difficulty in finding cures for these conditions include complications in early diagnosis, progressive and irreversible neuronal damage, and the presence of the blood-brain barrier (BBB), which hinders the delivery of drugs to the affected areas of the brain. Intranasal (INL) drug administration has increasingly gained popularity among researchers for targeting neurological conditions, because of its ability to bypass the BBB. However, chronic INL administration leads to nasal mucosa irritation. Additionally, rapid mucociliary clearance, a lack of targeted drug delivery, increased enzymatic degradation, and tight junctions that obstruct drug transport limit the clinical applicability of the INL route. To overcome these challenges, a unique region in the rodent nose, known as the Grueneberg Ganglion (GG), can be considered to be a novel site for INL drug administration. GG is a small structure housed under the snout cartilage of the nasal septum, approximately 1.5 mm from the nasal opening in mice. It is directly connected to the main olfactory bulb through axons. This Perspective aims to expand knowledge on why GG may be a viable option for INL delivery to combat neurological conditions. For better understanding, we have explained the INL administration in GG, using Alzheimer's Disease and INL insulin therapy as a role model for the current review.}, } @article {pmid40907612, year = {2025}, author = {Kumar, AP and Puthussery, DT}, title = {Regulation of PPAR-γ coactivator-1α and its implication in mitochondrial function and neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {112}, number = {}, pages = {102887}, doi = {10.1016/j.arr.2025.102887}, pmid = {40907612}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Mitochondria/metabolism ; Animals ; Gene Expression Regulation ; }, abstract = {Peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α, interacts with numerous transcription factors implicated in a wide spectrum of biological responses. It has been identified as a key player in the transcriptional regulation of many mitochondrial components. The activity of PGC1-α is regulated at multiple levels, such as gene expression, transcriptional, post-transcriptional, and post-translational modification. The purpose of this review is to highlight the data supporting PGC1-α-mediated regulation by transcriptional and post-translational modification. We summarize the mechanisms involved in PGC1-α regulation by phosphorylation (AMPK, p38 MAPK, Akt, and GSK3β), acetylation (GCN5, p300, and SRCC), and ubiquitination (E3-ubiquitin ligase). Moreover, the review focuses on the multidomain structure of PGC1-α, its expression in the brain, and the importance of PGC1-α-mediated mitochondrial functions. Mitochondrial dysfunction and impaired energy metabolism are key characteristics of neurodegenerative diseases like Alzheimer's, Huntington's, Parkinson's, amyotrophic lateral sclerosis, and multiple sclerosis. It is associated with reduced PGC1-α expression or activity, resulting in an imbalance in the maintenance of mitochondrial dynamics. In this backdrop, we additionally provide a comprehensive overview of the implication of PGC1-α in the pathogenesis of neurodegenerative disease. Overall, PGC1-α acts as a potential target for therapies to reduce mitochondrial dysfunction associated with neurodegenerative diseases and aid in neuroprotection.}, } @article {pmid40908143, year = {2025}, author = {Rodemer, W and Ra, I and Gujral, J and Jia, E and Juul, H and Zhang, B and Hoxha, K and Xing, B and Mehta, S and Farag, M and Rekulak, S and Porta, S and Jensen, FE and Talos, DM and Lee, VM}, title = {Network Dysfunction Precedes Neurodegeneration in a dox-Regulatable TDP-43 Mouse Model of ALS-FTD.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {45}, number = {41}, pages = {}, pmid = {40908143}, issn = {1529-2401}, support = {R37 NS115439/NS/NINDS NIH HHS/United States ; T32 AG000255/AG/NIA NIH HHS/United States ; R01 NS110688/NS/NINDS NIH HHS/United States ; R01 NS101156/NS/NINDS NIH HHS/United States ; R01 AG077692/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Mice ; *DNA-Binding Proteins/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics/pathology ; Male ; Disease Models, Animal ; Female ; Mice, Transgenic ; Humans ; Doxycycline ; Hippocampus/physiopathology/pathology ; *Nerve Net/physiopathology ; Electroencephalography ; *Nerve Degeneration/pathology/physiopathology ; }, abstract = {Neuronal hyperexcitability is a hallmark of amyotrophic lateral sclerosis (ALS), but its relationship with the TDP-43 aggregates that comprise the predominant pathology in over 90% of ALS cases remains unclear. Emerging evidence indicates that TDP-43 pathology induces neuronal hyperexcitability, which may contribute to excitotoxic neuronal death. To characterize TDP-43 mediated network excitability changes in a disease-relevant model, we performed in vivo continuous electroencephalography monitoring and ex vivo acute hippocampal slice electrophysiology in rNLS8 mice (males and females), which express human TDP-43 with a defective nuclear localization signal (hTDP-43ΔNLS). Surprisingly, we identified the presence of seizures in ∼64% of rNLS8 mice beginning ∼2.5 weeks after transgene induction (off-DOX). More broadly, we observed longitudinal changes in cortical EEG patterns and circuit hyperexcitability preceding neurodegeneration of vulnerable hippocampal subfields. Consistent with previous reports, we have observed broad dysregulation of AMPA subunit expression in mice expressing hTDP-43ΔNLS. These changes were most pronounced in the hippocampus, where we hypothesized they promote hyperexcitability and ultimately, excitotoxic cell death. Interestingly, hippocampal injection of AAV encoding inhibitory DREADDs (hM4Di) and daily activation with CNO ligand rescued anxiety deficits on the elevated zero maze but did not reduce neurodegeneration. Moreover, therapeutic doses of the antiseizure medications, valproic acid and levetiracetam, did not improve behavior or prevent neurodegeneration. These results highlight the complex relationship between TDP-43-mediated neuronal hyperexcitability and neurodegeneration. Although targeting hyperexcitability may ameliorate some behavioral deficits, our study suggests it may not be sufficient to halt or slow neurodegeneration in TDP-43-related proteinopathies.}, } @article {pmid40908144, year = {2025}, author = {Kim, SK and Gelfand, VI}, title = {PolyQ-Expansion of Ataxin-2 Disrupts Microtubule Stability and Impairs Axon Outgrowth.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {45}, number = {40}, pages = {}, pmid = {40908144}, issn = {1529-2401}, support = {R35 GM131752/GM/NIGMS NIH HHS/United States ; P40 OD018537/OD/NIH HHS/United States ; }, mesh = {Animals ; *Ataxin-2/genetics/metabolism ; *Microtubules/metabolism/genetics ; *Peptides/genetics/metabolism ; Humans ; *Neuronal Outgrowth/physiology/genetics ; Drosophila ; Female ; Animals, Genetically Modified ; Male ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster ; *Axons/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by mislocalization and aggregation of proteins in motor neurons. Ataxin-2 (ATXN2), an RNA-binding protein harboring 22-polyglutamine (polyQ) repeats, is a risk factor for ALS, when its polyQ repeats are expanded to 27-33 repeats. However, the physiological function of ATXN2 beyond its role in RNA regulation and how polyQ expansion in ATXN2 increases risk for ALS remain unclear. We previously demonstrated that Drosophila Atx2 functions as a regulator of microtubule (MT) dynamics in motor neurons. Here, we uncover the molecular mechanism underlying Atx2-mediated MT regulation and how polyQ expansion disrupts its function, using a mixed-sex population of Drosophila as a model system. Specifically, we show that Atx2 requires its RNA-binding Lsm domain to regulate MTs. Notably, the LSM domains of human ATXN2 rescue MT phenotype in Drosophila, demonstrating an evolutionarily conserved role of ATXN2 in MT regulation. Importantly, we find that polyQ-expanded ATXN2 forms cytoplasmic aggregates and leads to excessive MT destabilization. Additionally, polyQ expansion severely impairs axon outgrowth. Finally, we identify uncoordinated-76 (UNC-76/FEZ1) as a downstream effector of Atx2 in MT regulation and neuronal development.}, } @article {pmid40908696, year = {2025}, author = {Paul, S and Tiwari, P and Dubey, S}, title = {Precision Enzyme: Targeted Drug Discovery in Neurodegenerative Disorders.}, journal = {Protein and peptide letters}, volume = {32}, number = {8}, pages = {539-556}, pmid = {40908696}, issn = {1875-5305}, mesh = {Humans ; *Drug Discovery/methods ; *Neurodegenerative Diseases/drug therapy/enzymology ; Molecular Docking Simulation ; *Enzyme Inhibitors/chemistry/therapeutic use/pharmacology ; Animals ; }, abstract = {INTRODUCTION: Neurodegenerative disorders such as Alzheimer's, Parkinson's, and ALS are characterized by progressive neuronal dysfunction with limited therapeutic options. Recent advances in molecular biology and drug development have highlighted the therapeutic promise of precision enzyme targeting, offering novel strategies for disease modulation and symptom management.

METHODS: A comprehensive literature review spanning recent/current was conducted using PubMed, Scopus, and ScienceDirect. Studies focusing on enzyme-based targets, high-throughput screening, and molecular docking in neurodegeneration were included. Thematic synthesis was employed to categorize findings based on enzyme class, disease relevance, and therapeutic outcomes.

RESULTS: Key enzyme families such as kinases, proteases, and oxidoreductases were identified as pivotal modulators in disease progression. Emerging enzyme-targeted compounds demonstrated enhanced bioavailability, blood-brain barrier permeability, and disease-specific efficacy. Novel screening platforms and computational modeling enabled the precise selection of inhibitors, significantly improving the therapeutic index and reducing off-target effects.

DISCUSSION: Targeting enzymes implicated in neuroinflammation, oxidative stress, and protein misfolding has shown disease-modifying potential. Integrating precision drug discovery tools, such as AI-assisted modeling and enzyme kinetics, supports rational drug design. However, translational challenges persist due to variability in enzyme expression and disease heterogeneity.

CONCLUSION: Future research should focus on refining enzyme inhibitors and integrating biomarkers to facilitate personalized treatment strategies for neurodegenerative disorders. As the understanding of enzymatic roles in neurodegeneration deepens, precision enzyme-targeted drug discovery holds significant promise in transforming neurotherapeutic approaches.}, } @article {pmid40908710, year = {2025}, author = {Giove, E and Ferraro, PM and Lungu, M and Pasquinelli, L and Truffelli, R and Trinchero, C and Rebagliati, B and Caponnetto, C and Vignolo, M and Rao, F}, title = {Effects of Dog-Assisted Occupational Therapy on Upper Limb Functions in ALS and Other Neuromuscular Disorders: A Randomized Controlled Pilot Study.}, journal = {Muscle & nerve}, volume = {72}, number = {5}, pages = {1122-1129}, doi = {10.1002/mus.70012}, pmid = {40908710}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology/psychology ; Male ; Female ; Pilot Projects ; Middle Aged ; *Animal Assisted Therapy/methods ; *Upper Extremity/physiopathology ; Aged ; *Occupational Therapy/methods ; Animals ; Dogs ; Hand Strength/physiology ; *Neuromuscular Diseases/rehabilitation/physiopathology ; Treatment Outcome ; Adult ; }, abstract = {INTRODUCTION/AIMS: The beneficial effects of animal-assisted therapy (AAT) on balance, walking endurance, and mood symptoms in amyotrophic lateral sclerosis (ALS) have been previously demonstrated. In this study, we aimed at expanding upon these findings by further evaluating its effects on upper limb (UL) functions and mood symptoms both in ALS and other neuromuscular disorders (NMDs).

METHODS: Sixty-eight patients participated in a regular 2-week occupational therapy program once a day. For three days a week, in place of the traditional treatment, the AAT group (N = 34) performed a session in interaction with the therapy dog. Outcome measures included hand grip strength, manual dexterity, and mood symptoms. Differences between baseline and post-treatment values were assessed using the Wilcoxon Signed-Rank Test, and one-way analysis of covariance was used to examine between-group differences in post-treatment values, adjusting for baseline measurements.

RESULTS: Both groups improved in hand grip strength (p = 0.004-0.03), whereas mood symptoms improved exclusively in the AAT group (p = 0.0003-0.03). Post-treatment values were significantly better in the AAT group (p = 0.01-0.03). When ALS patients were analyzed separately, the improvement of hand grip strength and mood symptoms was observed only in the AAT group (p = 0.001-0.04), which accordingly showed better post-treatment values (p = 0.0007-0.05).

DISCUSSION: Our findings indicate that AAT has greater beneficial effects than traditional treatments on UL strength and mood symptoms. These findings have the potential to facilitate more effective rehabilitation strategies both in ALS and other NMDs.}, } @article {pmid40908789, year = {2026}, author = {Carletta, O and Perfetto, C and Rifai, OM and Manganelli, F and Waldron, FM and Maniatis, T and Gregory, JM and Gerbino, V}, title = {Genotype-specific interferon signatures in amyotrophic lateral sclerosis relate to disease severity.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {2}, pages = {489-501}, doi = {10.1093/brain/awaf324}, pmid = {40908789}, issn = {1460-2156}, support = {883-791//Motor Neuron Disease Association Biomedical/ ; //V.G. and T.M./ ; GR-2021-12375436//Italian Ministry of Health/ ; //AriSLA (motorTBK1)/ ; 2021/MNDS/RP/8440GREG//MND Scotland/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/immunology ; Humans ; Animals ; Female ; Male ; Mice ; Middle Aged ; Aged ; C9orf72 Protein/genetics ; Genotype ; *Interferon Type I/genetics/metabolism ; Superoxide Dismutase-1/genetics ; Severity of Illness Index ; Cohort Studies ; *Interferons/genetics ; Mice, Transgenic ; Adult ; Mutation ; }, abstract = {Innate immune signalling pathways are hyperactivated in the CNS of patients with amyotrophic lateral sclerosis (ALS), as well as in preclinical models with diverse causative backgrounds including TDP-43, SOD1 and C9orf72 mutations. This raises an important question of whether these pathways are key pathogenic features of the disease, and whether therapeutic amelioration could be beneficial. Here, we systematically profile type-I interferon (IFN)-stimulated gene (ISG) expression signatures using a non-biased approach in CNS tissue from a cohort of 36 individuals with ALS, including sporadic ALS (sALS; n = 18), genetic ALS caused by: (i) a C9orf72 hexanucleotide repeat expansion (C9-ALS; n = 11); and (ii) a SOD1 mutation (SOD1-ALS; n = 5), alongside age- and sex-matched individuals who died of a non-neurological cause (n = 12). Using this deeply phenotyped cohort we have implemented targeted transcriptomic analysis and immunohistochemistry to interrogate the nature and extent of the activation of the type-I IFN response in patients. We determined disease- and genotype-specific IFN signatures that correlate with clinical phenotype. Correlation analysis linked six ISGs with aggressive disease progression, as indicated by negative correlation with age at death in ALS patients. Notably, significant upregulation of ISGs was observed in C9-ALS patients, with higher ISG expression correlating with shorter disease duration. Noting that our genotype- and disease-specific signatures correlated with metrics of disease progression, we explored the therapeutic potential of targeting this pathway in a mouse model of ALS. Treatment with an IFN pathway inhibitor reduced IFN response markers, delayed disease progression, including motor decline, and extended survival in ALS mice. We conclude that upregulation of gene expression in the type-I IFN pathway represents a key pathological feature of ALS and that inhibiting this pathway may provide a promising therapeutic approach for treating ALS.}, } @article {pmid40909641, year = {2025}, author = {Dhawka, L and Evangelista, BA and Arooji, OK and Iannone, MA and Pellegrino, K and Traub, R and Li, X and Bedlack, R and Meeker, RB and Cohen, TJ and Stanley, N}, title = {Peripheral immune patterns enable robust cross-platform prediction of ALS onset and progression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909641}, issn = {2692-8205}, support = {F31 NS122242/NS/NINDS NIH HHS/United States ; P30 CA016086/CA/NCI NIH HHS/United States ; R21 AG084251/AG/NIA NIH HHS/United States ; R21 AI171745/AI/NIAID NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) progression rates vary dramatically between patients, yet the basis of this heterogeneity remains elusive, with no prognostic biomarkers existing to guide clinical decisions or stratify patients for therapeutic trials. Here, we identify a network of coordinated immune cell types, which exhibit differential disruption across progression groups. Using mass cytometry (CyTOF) to profile 2.2 million immune cells from 35 ALS patients stratified by progression rate and 9 healthy controls, we find that the extent of immune dysfunction cannot be reflected by examining differences in individual cell type frequencies. In contrast, analyses of correlation patterns between cell types revealed distinct immune organization patterns, where coordination complexity varied with disease progression. Across all progression groups, we observed striking immune reorganization in natural killer (NK) cells and a major shift from B cell/basophil coordination hubs in healthy controls to neutrophil/T cell-dominated patterns in ALS. Having established coordinated immune patterns, we developed machine learning models to further improve our ability to stratify between disease and non-disease cohorts, achieving superior performance compared to models using cell frequencies alone. Central and effector memory (CM/EM) CD4+ T cell interactions emerged as top discriminative features for disease status, while plasmacytoid dendritic cell (pDC) relationships, especially their ratio with regulatory T cells (T-regs), distinguished progression rates, supporting T-reg-based therapeutic approaches. These findings reframe ALS as a disease of immune coordination breakdown, pointing towards cell-type specific therapeutics and biomarkers that may extend beyond ALS to other neurodegenerative diseases characterized by immune dysfunction.}, } @article {pmid40909710, year = {2025}, author = {Gautier, O and Blum, JA and Nguyen, TP and Klemm, S and Yamakawa, M and Sinnott-Armstrong, N and Zeng, Y and Davis, CO and Bombosch, J and Nakayama, L and Guttenplan, KA and Chen, D and Kathira, A and Zhao, L and Rexach, JE and Greenleaf, WJ and Gitler, AD}, title = {An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909710}, issn = {2692-8205}, support = {R01 AG075802/AG/NIA NIH HHS/United States ; R01 NS128028/NS/NINDS NIH HHS/United States ; RF1 NS128800/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; S10 RR025518/RR/NCRR NIH HHS/United States ; RM1 HG010461/HG/NHGRI NIH HHS/United States ; R35 NS137159/NS/NINDS NIH HHS/United States ; }, abstract = {To uncover molecular determinants of motor neuron degeneration and selective vulnerability in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons from the SOD1-G93A ALS mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a novel cell state we named 'disease-associated motor neurons' (DAMNs). We identified transcription factor regulatory networks that govern how healthy cells transition into DAMNs as well as those linked to vulnerable and resistant motor neuron subtypes. Using spatial transcriptomics, we found reactive glia located near motor neurons early in disease, suggesting early signaling events between motor neurons and glia. Finally, we found that the human orthologs of genomic regions with differential accessibility in SOD1-G93A alpha motor neurons are enriched for single nucleotide polymorphisms associated with human ALS, providing evidence that the genetic underpinnings of motor neuron vulnerability are conserved.}, } @article {pmid40909834, year = {2025}, author = {Homann, J and Korologou-Linden, R and Viallon, V and Morgan, S and Dobricic, V and Deecke, L and Schessner, JP and Smith-Byrne, K and Birtles, D and Zhao, Y and Wuu, J and Artaud, F and Hajizadah, F and Huerta, JM and Ohlei, O and Lebedev, M and Kolijn, PM and Guevara, M and Jimenez-Zabala, A and Sánchez, MJ and Trobajo-Sanmartín, C and Colorado-Yohar, SM and Alonso-Martín, S and Petrova, D and Sieri, S and Berger, K and Peters, S and Wareham, N and Kaaks, R and Travis, RC and Vermeulen, RCH and , and Tzoulaki, I and Elbaz, A and Mann, M and Sacerdote, C and Masala, G and Katzke, V and Benatar, M and Bertram, L and Middleton, L and Riboli, E and Gunter, MJ and Ferrari, P and Robinson, O and Lill, CM}, title = {Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40909834}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form.

METHODS: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM).

FINDINGS: Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson's and Alzheimer's disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance.

INTERPRETATION: Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention.

FUNDING: Clinical Research in ALS and Related Disorders for Therapeutic Development (CreATe) Consortium, Cure Alzheimer's Fund, Michael J Fox Foundation, Interdisciplinary Centre for Clinical Research, University Münster.}, } @article {pmid40909873, year = {2025}, author = {Wang, X and Dong, B and Gan, Q and Li, J and Wu, P and Guan, Y and Wang, J}, title = {Unraveling the Vicious Cycle: Oxidative Stress and Neurotoxicity in Neurodegenerative Diseases.}, journal = {FASEB bioAdvances}, volume = {7}, number = {8}, pages = {e70041}, pmid = {40909873}, issn = {2573-9832}, abstract = {Oxidative stress is characterized by an imbalance between the production and elimination of free radicals, where the rate of free radical generation surpasses the rate of their removal. This imbalance can lead to tissue and organ damage, contributing to the pathogenesis of various diseases. The nervous system, due to its high oxygen consumption, is particularly susceptible to oxidative stress. Numerous neurotoxins can induce neurotoxicity through oxidative stress, thereby contributing to the onset of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Furthermore, neurotoxicity can exacerbate oxidative stress by disrupting mitochondrial metabolism and impairing the activity of antioxidant enzymes, thereby intensifying neurotoxic effects. This review examines the mechanisms underlying the interaction between oxidative stress and neurotoxicity and explores strategies to mitigate neurotoxicity by reducing oxidative stress, with the aim of informing future clinical approaches for the treatment of neurodegenerative diseases.}, } @article {pmid40910231, year = {2025}, author = {He, M and Zeng, S and Tang, Z and Qin, L and Yan, W and Wang, C and Zhang, H and Chen, Z and Long, Z}, title = {A Decade of Research on C9orf72 in Frontotemporal Dementia (2014-2024): A Bibliometric Analysis of Global Trends and Hotspots.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X388118250808030811}, pmid = {40910231}, issn = {1875-6190}, abstract = {INTRODUCTION: Frontotemporal dementia (FTD) is the third most frequent dementia and the leading dementia subtype in individuals under 65. The discovery of C9orf72 (chromosome 9 open reading frame 72) GGGGCC abnormal expansion is a major genetic cause of both FTD and amyotrophic lateral sclerosis (ALS), linking these diseases along a clinicopathological spectrum. This study aimed to depict the research landscape of C9orf72 in FTD over the past decade, track emerging research hotspots, and provide insights into under-researched areas.

METHOD: Based on the Web of Science database, a bibliometric analysis was conducted to explore publication trends, key contributors, funding sources, journal categories, co-authorship networks, and keyword co-occurrence, clustering, and bursts.

RESULTS: A total of 1,220 articles were identified, with sustained output of over 100 articles annually. The majority of contributions and funding support came from North America and Europe. Hot research themes included hexanucleotide repeats, nucleocytoplasmic transport, disease mechanisms, and therapeutic targets.

DISCUSSION: North America and Europe were highly productive, supported by higher regional prevalence, genetic burden, and robust funding. Ploy-GR in cerebrospinal fluid has emerged as a diagnostic biomarker. Pathogenic mechanisms remain complex, involving both gain- and loss-of-function effects. Metformin and antisense oligonucleotides were considered as potential therapeutics. Further research is needed in underrepresented populations and on the translational potential of emerging molecular targets.

CONCLUSION: This study offers a comprehensive overview of current trends and future directions over the past decade in C9orf72-related FTD research, allowing researchers-particularly those new to the area-to quickly understand the current landscape.}, } @article {pmid40910745, year = {2026}, author = {Simoni, D and Gotkine, M and Ben-Dov, IZ and Lerner, B}, title = {Identifying diagnostic markers in the health records of prediagnostic amyotrophic lateral sclerosis patients.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {90-100}, doi = {10.1080/21678421.2025.2539898}, pmid = {40910745}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/blood/epidemiology ; Male ; Female ; Middle Aged ; *Biomarkers/blood ; Retrospective Studies ; Aged ; Adult ; Case-Control Studies ; Longitudinal Studies ; Israel/epidemiology ; *Medical Records ; Early Diagnosis ; }, abstract = {Objective: Amyotrophic lateral sclerosis (ALS) has a poorly understood preclinical phase, particularly concerning diagnostic blood markers. Our objective was to determine whether distinct patterns in routinely collected clinical and laboratory markers exist during the preclinical phase and could be incorporated to facilitate early diagnosis. Methods: We conducted a longitudinal, retrospective, case-control study with health records of prediagnostic ALS patients (PDALS) from health maintenance organizations covering approximately 40% of the Israeli population. We included PDALS with at least 10 clinical visits and a minimal observation period of 36 months prior to the diagnosis date to measure differences between PDALS and controls and analyzed data from 1,810 adult individuals; 362 PDALS and 1,448 age- and sex-matched controls. Results: Significant differences were found in PDALS many months before the diagnosis date. These included biochemical parameters such as urea, creatinine, CK, calcium, iron, and liver enzymes, hematological values, and BMI. Some differences were detectable over 10 years prior to the diagnosis date. Conclusions: This study highlights the potential for early detection of ALS based on blood markers in the years preceding clinical diagnosis. These findings could significantly expedite diagnosis, identify individuals at risk for ALS, and uncover unrecognized disease mechanisms.}, } @article {pmid40911048, year = {2026}, author = {Massey, C and Hobson, E and McDermott, C and Griffiths, AW}, title = {Living with cough and secretion issues: the experiences of people with amyotrophic lateral sclerosis and their caregivers.}, journal = {Disability and rehabilitation}, volume = {48}, number = {5}, pages = {1353-1368}, doi = {10.1080/09638288.2025.2555973}, pmid = {40911048}, issn = {1464-5165}, abstract = {PURPOSE: To explore the experiences of people living with amyotrophic lateral sclerosis (ALS) and their caregivers managing cough and secretion problems.

METHODS: A qualitative study was completed with 15 individuals participating in 10 interviews; 10 people living with ALS and five informal caregivers. Interview methods were adapted to ensure inclusivity of participants who had physical, respiratory and communication impairments. Data was analysed inductively using reflexive thematic analysis.

RESULTS: Our analysis identified the challenges of living day to day with cough and secretion problems. Care coordination and the presence of informal caregivers were important in ensuring that cough and secretion interventions could be implemented successfully. Participants felt access to cough and secretion knowledge and skills specific to ALS was key to supporting care and supported them to acquire information which influenced decision-making around their care.

CONCLUSION: Cough and secretion care in ALS is multifaceted and multifactorial. Future development of clinical interventions in this area are needed to support the complex web of professionals, treatments and knowledge to optimise care.}, } @article {pmid40911406, year = {2026}, author = {Vieira, RGS and Lima, ÍNDF and Pondofe, KM and Maciel, ACMG and Dourado-Júnior, MET and Otto-Yáñez, M and Vilaró, J and Torres-Castro, R and Uribe, RV and da Fonsêca, JDM and Lo Mauro, A and Resqueti, VR and Aliverti, A and Fregonezi, GAF}, title = {Acute Effects of Mechanical Insufflation-Exsufflation on Cough Peak Flow, Chest Wall Volumes, and Breathing Pattern of Patients With Amyotrophic Lateral Sclerosis.}, journal = {Respiratory care}, volume = {71}, number = {1}, pages = {52-61}, doi = {10.1177/19433654251367414}, pmid = {40911406}, issn = {1943-3654}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Male ; Female ; *Insufflation/methods ; Middle Aged ; *Thoracic Wall/physiopathology ; *Cough/physiopathology/etiology ; Aged ; Plethysmography ; Adult ; Respiratory Muscles/physiopathology ; Peak Expiratory Flow Rate ; Respiration ; }, abstract = {BACKGROUND: Mechanical insufflation-exsufflation (MI-E) consists of increasing expiratory air flow, thereby promoting an increase in cough peak flow (CPF) and secretion clearance. Respiratory impairment, characterized by reduced lung volumes and ineffective cough, is the major cause of morbidity and mortality in patients with amyotrophic lateral sclerosis (ALS). This study aimed to assess the acute effects of MI-E on CPF and chest wall compartmental and operational volumes in patients with ALS.

METHODS: Ten ALS subjects (6 males) were studied by optoelectronic plethysmography (OEP) to assess the immediate effects of MI-E on CPF, chest wall volume variations and their distribution in the chest wall compartments, breathing pattern, and shortening velocity of the respiratory muscles before, during, and after the application of MI-E.

RESULTS: No differences were observed in the CPF analysis between time points (pre, MI-E, post). A significant increase in CPF (P = .01) was obtained immediately after the application of MI-E in subjects with spinal-onset ALS (n = 7). No significant differences in total and compartmental lung volumes and chest wall operational volumes were observed between pre MI-E (quiet breathing), during MI-E (after coughs 1, 2, and 3), and post MI-E time points.

CONCLUSIONS: The application of the MI-E technique may increase CPF in individuals with spinal ALS. However, no significant changes in total thoracic volumes, total and compartmental chest wall volumes, or changes in breathing patterns in the participants in our sample after the application of the technique were observed.}, } @article {pmid40911608, year = {2025}, author = {Li, Z and Qiao, Q and Han, Z and Liu, X and Wang, Y and Tang, H and Deng, L}, title = {Terrestrial laser scanning in forestry: Accuracy and efficiency in measuring individual tree parameters.}, journal = {PloS one}, volume = {20}, number = {9}, pages = {e0331126}, pmid = {40911608}, issn = {1932-6203}, mesh = {*Trees/anatomy & histology/growth & development ; *Forestry/methods ; Forests ; *Lasers ; Populus ; }, abstract = {With the growing global emphasis on forest resource monitoring, evaluating the accuracy of retrieving key individual tree parameters-such as tree position, tree height, and diameter at breast height (DBH)-using Terrestrial Laser Scanning (TLS) has become an important research focus. TLS has been widely applied in forest surveys due to its significant advantages in data acquisition efficiency and measurement precision. However, studies on the accuracy of extracting forest parameters from single-station, single-scan TLS data remain limited, underscoring the need for systematic evaluation and validation. This paper analyzes the accuracy and effectiveness of TLS in extracting structural parameters (tree height and DBH) and its position using Poplar and Styphnolobium as examples by using TLS, Airborne laser Scanning (ALS), and combining with field measurements. Results show that tree height estimates from single-scan TLS is limited in accuracy: the RMSE of 11.61 m in the Populus plot and 2.13 m in the Styphnolobium plot. Within a 50 m radius, single-scan TLS achieves a tree detection rate of 55.96-64.26% and a DBH RMSE of 1.60 cm (RRMSE: 9.03%). In addition, the point root mean square error of individual tree measurements remains at 0.11 m. These findings highlight the potential of TLS as an effective tool for forest inventory and provide a basis for evaluating the reliability of TLS-based plot measurements.}, } @article {pmid40912271, year = {2025}, author = {Heyne, S and Kuzmanova, A and Esser, P and Mehnert-Theuerkauf, A and Metelmann, M}, title = {[Psychosocial support needs and requirements for psychosocial care programs for caregivers of patients with ALS - A qualitative analysis from the "potentiALS" project].}, journal = {Psychotherapie, Psychosomatik, medizinische Psychologie}, volume = {75}, number = {11}, pages = {447-456}, doi = {10.1055/a-2679-1065}, pmid = {40912271}, issn = {1439-1058}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/nursing ; *Caregivers/psychology ; Male ; Female ; Middle Aged ; Aged ; *Social Support ; Qualitative Research ; Adult ; *Psychosocial Support Systems ; }, abstract = {ALS is a terminal illness that places significant burden on caregivers due to the intensive care demands. Little research exists on the specific design of psychological support programs for caregivers of ALS patients. This study aims to identify psychosocial needs of caregivers, specific therapeutic topics and structural requirements for tailored support programs.The study is based on a subset of qualitative data from a participatory mixed-methods observational study. Semi-structured, one-hour interviews were conducted with caregivers of ALS patients, either online or in person. The transcripts were analyzed using Mayring's qualitative content analysis.Four caregivers participated in the study. They reported a high need for psychological support, especially immediately following the diagnosis. Key themes included emotional relief through dialogue with psychologists, strategies for emotion regulation, and fostering self-care. Practical needs highlighted the importance of clear guidelines for caregiving organization, assistance with medical devices, and the development of supportive programs to help manage life and plan for the future during challenging circumstances. Participants emphasized that support programs should be flexible, easily accessible, and personalized. Individual sessions with the option of in-person or online formats were preferred. Caregivers highlighted the necessity of continuous support throughout the disease trajectory, particularly during critical phases.The results of our study highlight the psychosocial challenges faced by caregivers of ALS patients. The findings emphasize the need for comprehensive support systems that address both the emotional and practical needs of caregivers.}, } @article {pmid40912321, year = {2026}, author = {Durpoix, A and Blay, M and Moog, C and Rolling, J and Weiner, L and Lalanne, L and Weibel, S}, title = {Clarifying conceptualization of emotional dysregulation: Differences with emotional lability during 4-month DBT skills training - A naturalistic study.}, journal = {Journal of affective disorders}, volume = {392}, number = {}, pages = {120199}, doi = {10.1016/j.jad.2025.120199}, pmid = {40912321}, issn = {1573-2517}, mesh = {Humans ; Male ; Female ; Adult ; *Affective Symptoms/therapy/psychology ; *Emotional Regulation ; *Dialectical Behavior Therapy/methods ; Surveys and Questionnaires ; Treatment Outcome ; Middle Aged ; Bipolar Disorder/therapy/psychology ; }, abstract = {INTRODUCTION: Emotion dysregulation is common in many different psychiatric disorders and it can be effectively treated with the well-established Dialectical Behavioral Therapy (DBT). Despite its clinical relevance and increasing scientific interest, emotional dysregulation (ED) is sometimes conflated with emotional lability (EL). However, these constructs differ: ED involves top-down neurobiological processes, while EL involves bottom-up processes. As psychotherapy essentially influences top-down processes compared to pharmacotherapy, this study aimed to investigate whether ED is more sensitive to DBT than EL.

METHOD: Our naturalistic study involved the 39 participants (sex ratio = 9 m/30w, mean age = 33.23) who completed questionnaires assessing ED (DERS-36) and EL (ALS-18) before then after transdiagnostic DBT skills training (DBT-ST). The diagnoses of participants included BPD (64 %), BD (23 %), ADHD (23 %), addiction (17 %) or eating disorder (17 %). DBT was performed in a transdiagnostic group over 4 months.

RESULT: After DBT-ST, ED improved significantly with a medium effect size (d = 0.73), while EL showed no significant change (d = 0.13). The percentages of improvement on DERS were significantly higher than on ALS (p < 0.002, d = 0.50). The correlation between these both measures decreased during therapy from r = 0.37 to r = 0.32.

DISCUSSION: Our findings indicate that ED improved more than EL after DBT and that their correlation diminished during therapy. These results suggest that ED is a different process from EL and that ED is more sensitive to treatments like DBT Skills Training. To confirm these findings, further studies are needed ideally with larger sample size, long-term follow-up and a controlled design.}, } @article {pmid40912409, year = {2025}, author = {Bordoni, M and Scarian, E and Jacchetti, E and Viola, C and Diamanti, L and Dragoni, F and Di Gerlando, R and Rizzo, B and Raimondi, MT and Gagliardi, S and Pansarasa, O}, title = {HDAC6 and TDP-43 promote autophagy impairment in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {215}, number = {}, pages = {107079}, doi = {10.1016/j.nbd.2025.107079}, pmid = {40912409}, issn = {1095-953X}, mesh = {Humans ; *Histone Deacetylase 6/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Autophagy/physiology ; *DNA-Binding Proteins/metabolism/genetics ; Cell Line, Tumor ; Male ; Middle Aged ; RNA, Messenger/metabolism ; Female ; Leukocytes, Mononuclear/metabolism ; *Histone Deacetylases/metabolism/genetics ; Aged ; }, abstract = {TDP-43 is known to bind the mRNA of histone deacetylase 6 (HDAC6), influencing its RNA translation. Many studies suggest that HDAC6 participates in the regulation of autophagy, which we found impaired in sporadic amyotrophic lateral sclerosis (sALS) patients. Aim of this work is to evaluate the interaction between TDP-43 and HDAC6 mRNA and to evaluate the effect of the up- and down-regulation of HDAC6 on autophagy in SH-SY5Y cells. Protein level of HDAC6 and TDP-43 binding with HDAC6 mRNA by RNA immunoprecipitation were studied on sALS peripheral blood mononuclear cells (PBMCs). Initially, we observed increased level of HDAC6 protein and increased binding of its mRNA with TDP-43 in sALS PBMCs. We observed that TDP-43 transfection and aggregation in SH-SY5Y cells leads to overexpression of HDAC6. Our results indicate that the autophagy pathway is sensitive to both extremes of α-tubulin acetylation. Indeed, a marked reduction due to HDAC6 overexpression, as well as an excessive increase following HDAC6 downregulation, both result in autophagic dysfunction. This work supports the hypothesis that dysregulation of HDAC6 is a key factor in the disruption of the autophagy pathway previously detected in sALS PBMCs. Our work suggests for the first time that TDP-43 influences autophagy by binding and modulating HDAC6 mRNA. This new pathway suggests that in ALS the aggregation of TDP-43 leads to the overexpression of HDAC6 which impairs autophagy. Thus, our work suggest that in sALS HDAC6 should be tuned and these findings could be exploited in the future as possible therapeutic target.}, } @article {pmid40912729, year = {2025}, author = {LaBarbera, V and Dai, X and Sachs, G}, title = {Co-occurrence of ipsilateral partial Horner's syndrome in a patient with monomelic amyotrophy.}, journal = {BMJ case reports}, volume = {18}, number = {9}, pages = {}, doi = {10.1136/bcr-2025-265315}, pmid = {40912729}, issn = {1757-790X}, mesh = {Humans ; *Horner Syndrome/complications/diagnosis ; *Spinal Muscular Atrophies of Childhood/complications/diagnosis ; Male ; Female ; Diagnosis, Differential ; Middle Aged ; }, abstract = {Monomelic amyotrophy (MMA) is a lower motor neuron predominant disorder affecting an upper limb, which can mimic amyotrophic lateral sclerosis (ALS). It often presents with unilateral, distal upper limb weakness and atrophy, whose trajectory is one of an initial period of progression followed by a prolonged plateau, as opposed to the typically relentless progression as is seen in ALS. This case report describes a novel observation of a patient with MMA with an unexplained ipsilateral partial Horner's syndrome (miosis and ptosis). Horner's syndrome is known to result from sympathetic dysfunction from lesions from the hypothalamus to the cervical/upper thoracic spine and can be seen with brachial plexopathies, but has never been, to our knowledge, described in MMA. This finding is of interest because it may facilitate earlier diagnosis of MMA in isolated upper extremity, lower motor neuron-predominant syndromes, as Horner's syndrome is not known to complicate ALS.}, } @article {pmid40913365, year = {2025}, author = {Zhang, J and Kaiser, E and Marcelis, LFM and Vialet-Chabrand, S}, title = {DynG: a dynamic scaling factor for thermographic stomatal conductance estimation under changing environmental conditions.}, journal = {The New phytologist}, volume = {248}, number = {4}, pages = {2160-2173}, pmid = {40913365}, issn = {1469-8137}, support = {202006300044//China Scholarship Council/ ; 19652//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; }, mesh = {*Plant Stomata/physiology ; *Thermography/methods ; Temperature ; *Arabidopsis/physiology/genetics ; *Environment ; Plant Leaves/physiology ; Plant Transpiration/physiology ; }, abstract = {Thermal imaging is a key plant phenotyping and monitoring technique but faces major bottlenecks in accurately and efficiently inferring stomatal conductance (gsw) from leaf temperature. The conductance index (Ig) was previously proposed to estimate gsw from thermography by linking temperature differences between real and artificial leaves (ALs) based on the leaf energy balance. However, Ig is highly sensitive to environmental fluctuations, hampering interpretation and reducing reproducibility. We developed a simple and novel correction factor (named DynG) for Ig that accounts for environmental fluctuations when scaling Ig to gsw. This was achieved by capturing temperature variations in a set of ALs with a range of known constant pore conductances. This approach provided the Ig-conductance relationship, using ALs as a reference, to infer gsw of real leaves from their measured Ig. In fluctuating environments, gsw estimated using DynG showed greater accuracy and stability than gsw calculated from Ig alone, and was in good agreement with gsw determined using lysimetric and gas exchange methods. DynG's power was further showcased in distinguishing gsw of Arabidopsis genotypes differing in stomatal traits (Col-0, epf1epf2, and EPF2OE). We conclude that Ig corrected with DynG can reliably estimate gsw in fluctuating environments without complex modeling, opening new avenues for gsw phenotyping and monitoring.}, } @article {pmid40913874, year = {2025}, author = {Peethambaran, ST and Ashokan, A and Subhose, V}, title = {A case report on Ayurvedic management of progressive bulbar palsy-A rare amyotrophic lateral sclerosis phenotype.}, journal = {Journal of Ayurveda and integrative medicine}, volume = {16}, number = {5}, pages = {101176}, pmid = {40913874}, issn = {0975-9476}, abstract = {This case report is the description of a devastating illness, Progressive Bulbar Palsy (PBP) of a sixty-seven years old male patient. He presented with complaints of slurred speech, hearing impairment, generalised weakness of limbs, weakened grip to hold objects in hand, difficulty to walk with normal speed, frequent dizzy feeling while walking, severe fatigue, increased anger, heaviness of head, depression, anxiety, decreased memory and headache for 1 year. When he consulted conventional medicine, in Magnetic Resonance Imaging (MRI) of brain, only 'Partial empty sella' and age related mild cerebral atrophy was detected and the patient was diagnosed PBP clinically. They prescribed Riluzole 50 mg tablet twice a day and Fluoxetine 10mg capsules at night time for 3 months, but obtained no relief for symptoms and consulted this Out Patient Department (OPD). In Ayurvedic parlance, PBP resembles conditions like Kaphavruta vata. In this patient, Pittavritavata symptoms like bhrama (∼dizziness) was also present in increased severity. Diagnosis was done with the aid of Gold Coast diagnostic criteria. Internal and external medications with properties alleviating avarana (∼occlusion) of vata by kapha and pitta, shodhana (∼expelling the aggravated doshas and cleanses the body internally), rejuvenating (Rasayana) properties, for overall strengthening of nervous system and musculoskeletal system, enhancing balance and coordination, improving speech and memory were used. The assessment was done before and after the treatment by 'Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). The score before and after the treatment was 35 and 45 respectively out of 48. The treatment helped to increase the quality of life exceptionally as symptomatic relief was obtained. As it is a devastating disorder with poor prognosis and most probably will lead to death, it is advisable to repeat the treatments in regular intervals, depending on the recurrence of symptoms, if any.}, } @article {pmid40914405, year = {2025}, author = {Wang, J and Li, X and Yang, F and Guo, P and Ren, C and Duan, Z and Bi, M and Kong, Y and Zhang, Y and Lu, J}, title = {Exploration of endoplasmic reticulum stress-related gene markers in amyotrophic lateral sclerosis: a comprehensive analysis of bioinformatics and machine learning.}, journal = {Analytical biochemistry}, volume = {707}, number = {}, pages = {115969}, doi = {10.1016/j.ab.2025.115969}, pmid = {40914405}, issn = {1096-0309}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Machine Learning ; *Endoplasmic Reticulum Stress/genetics ; *Computational Biology/methods ; Gene Regulatory Networks ; Biomarkers/metabolism ; Molecular Docking Simulation ; }, abstract = {This study aimed to investigate potential biomarkers related to Endoplasmic reticulum (ER) stress in Amyotrophic lateral sclerosis (ALS) through a comprehensive bioinformatic approach. The gene expression profiles of ALS patients and healthy controls were downloaded from the Gene Expression Omnibus (GEO) database. ER stress-related genes were collected from the MSigDB databases and document literature. The "limma" R package was employed to detect the differentially expressed ER stress-related genes (DE-ERSGs). Three methods of machine learning were applied to select the hub DE-ERSGs. ROC curves were conducted to evaluate model performance. An external dataset was chosen to evaluate the diagnostic capability of hub genes. The CIBERSORT algorithm was used to evaluate the immune cell infiltration characteristics. Additionally, we constructed a systematic ceRNA regulatory network using Cytoscape software and predicted the possible drug candidates using the Enrichr platform. Molecular docking analysis was used to further validate the binding ability of the candidate drug molecules to the hub genes. Six hub DE-ERSGs (ABCA1, CKAP4, TOR1AIP1, MMP9, EDC4, and ALPP) were identified, and the related models performed well. These hub genes were concentrated in multiple pathways and related to various immune cells. Drugs such as nitroglycerin, diazepam, FENRETINIDE, and edaravone exhibited good binding affinity to the hub genes, indicating that they may be promising drugs for the management of ALS. This study revealed the essential role of ER stress in the pathogenesis of ALS from an integrative perspective, providing guidance for the development of new therapeutic targets and diagnostic strategies.}, } @article {pmid40914817, year = {2026}, author = {Alves, I and Aiello, EN and Lopes, D and Gromicho, M and Simão, S and Moreschi, A and De Luca, G and Curti, B and Silani, V and Ticozzi, N and Poletti, B and de Carvalho, M}, title = {Reliable change indices for the cognitive section of Portuguese version of the Edinburgh Cognitive and Behavioural ALS screen (ECAS).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {175-178}, doi = {10.1080/21678421.2025.2555216}, pmid = {40914817}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/diagnosis ; Male ; Female ; Middle Aged ; Aged ; Portugal ; *Neuropsychological Tests/standards ; Reproducibility of Results ; *Cognition Disorders/diagnosis/etiology ; *Cognition/physiology ; Adult ; }, abstract = {This study aimed to derive standardized regression-based (SRB) reliable change indices (RCIs) for the cognitive section of the Portuguese Edinburgh Cognitive and Behavioral ALS Screen (ECAS-C). Forty-nine MND patients undergoing the ECAS were followed-up (T1) at 7.2 ± 2 months (range = 5-12). RCIs were derived via an SRB approach by accounting for demographic, motor-functional and test-related variables. Practice effects were detected as to Total and Memory measures; all ECAS-C measures proved to be reliable at retest. Baseline ECAS-C measures predicted their follow-up performances. SRB RCIs herewith delivered will help assess MND patients' cognition over time, although they would benefit from further validation in independent cohorts.}, } @article {pmid40915735, year = {2025}, author = {Mazivila, SJ and Soares, JX and Santos, JLM}, title = {Multi-way calibration strategies involving excitation-emission data measurements from drug-modulated fluorescence in CdTe quantum dots and AgInS2 nanocrystals.}, journal = {Analytica chimica acta}, volume = {1373}, number = {}, pages = {344547}, doi = {10.1016/j.aca.2025.344547}, pmid = {40915735}, issn = {1873-4324}, abstract = {BACKGROUND: When using semiconductor quantum dots (QDs) for single-analyte sensing, recognition is commonly achieved through interactions with capping ligands attached to the QDs surface. These ligands form an organic layer that provides stability in solution and assures selectivity by binding the target analyte via surface functional groups. However, a common analytical challenge arises in the subsequent stage of the QD-based sensing scheme. Specifically, in a system combining CdTe and AgInS2 QDs, the CdTe QD core can effectively dock sodium-2-mercaptoethane sulfonate (MES) ligands, which act as recognition elements for amlodipine. In contrast, the AgInS2 QD core, may not properly anchor d-penicillamine (PCM) ligands, which bind selectively to olmesartan. This disparity in ligand-QDs affinity may lead to inconsistent excitation-emission fluorescence matrix (EEFM) signals. Such inconsistencies arise when the contribution of the four components present in the system 'CdTe QD-MES-amlodipine & AgInS2 QD-PCM-olmesartan' deviates from low-rank subspace estimated across different excitation/emission modes.

RESULTS: Upon analyzing a fixed-dosage form sample of amlodipine and olmesartan medoxomil, we demonstrate that the complexity of the mixture signal in EEFM measurements - whether from individual or combined single-analyte QD-based sensing scheme - can be experimentally assessed by determining the low-rank subspace of the analytical signals. Specifically, we evaluated whether the number of fluorescently responsive constituents across different excitation and emission modes matches the four components present in the system 'CdTe QD-MES-amlodipine & AgInS2 QD-PCM-olmesartan' - a prerequisite for the joint calibration of both analytes. If this condition is not met the analytes must be individually calibrated. Thus, a mixture of single-analyte QD-based sensing scheme, involving different concentrations of amlodipine and olmesartan medoxomil, was used to generate a set of EEFM measurements. A rank-two model was found optimal for emission wavelengths, while a rank-three model was calculated for excitation wavelengths. These results reveal an evident rank-deficient as at least four-components are present in the QD-sensing photoluminescence modulation process.

SIGNIFICANCE: The unfolded partial least-squares (U-PLS) model was successfully applied for the determination of amlodipine-net analyte signal (NAS) from binary CdTe QDs fluorescence modulation. In contrast, the olmesartan- NAS from ternary AgInS2 QDs fluorescence modulation did not allow a combined calibration. Consequently, the analytes must be individually calibrated based on their respective individual mixture signals using either PARAllel FACtor (PARAFAC) analysis or multivariate curve resolution - alternating least-squares (MCR-ALS) model according to the data structure.}, } @article {pmid40915850, year = {2025}, author = {Zhan, Y and Cao, Z and Qi, J and Luo, Y and Hu, L and Bai, L and Pan, L}, title = {Fenoxaprop-P-ethyl resistance in Alopecurus aequalis: Involvement of GSTF13 in addition to Ile-1781-Leu mutation.}, journal = {Pesticide biochemistry and physiology}, volume = {214}, number = {}, pages = {106614}, doi = {10.1016/j.pestbp.2025.106614}, pmid = {40915850}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology ; *Herbicide Resistance/genetics ; *Oxazoles/pharmacology ; *Propionates/pharmacology ; *Plant Proteins/genetics/metabolism ; *Poaceae/genetics/drug effects ; Mutation ; Acetyl-CoA Carboxylase/genetics/antagonists & inhibitors ; Acetolactate Synthase/genetics/antagonists & inhibitors ; *Glutathione Transferase/genetics/metabolism ; }, abstract = {Shortawn foxtail (Alopecurus aequalis Sobol.) is a challenging weed species to manage in wheat production systems globally. In prior research, we identified a field population of A. aequalis (Aa-R) that had developed resistance to the widely used acetolactate synthase (ALS)-inhibiting herbicide mesosulfuron-methyl. In this study, we found that the Aa-R population also exhibited significant resistance to the acetyl-CoA carboxylase (ACCase)-inhibiting herbicide fenoxaprop-P-ethyl and showed broad-spectrum resistance to other three ACCase-inhibiting herbicides, haloxyfop-P-methyl, clodinafop-propargyl, clethodim, and pinoxaden. Sequence analysis of the ACCase gene revealed the presence of a known resistance mutation (Ile-1781-Leu) in the Aa-R population. Pretreatment with the GST inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) decreased the resistance to fenoxaprop-P-ethyl in the Aa-R population. We amplified an upregulated GST gene in the Aa-R population, designated AaGSTF13. Transgenic rice calli and seedlings overexpressing AaGSTF13 exhibited resistance specifically to fenoxaprop-P-ethyl, and might enhance reactive oxygen species (ROS) scavenging capacity. Further transcriptome analyses suggested that the expressions of genes associated with ROS scavenging was upregulated in transgenic plants. Our results indicate that AaGSTF13 enhances detoxification metabolism and could potentially enhances ROS scavenging in transgenic rice, which might contribute to enhanced herbicide resistance. These findings suggest that AaGSTF13 represents a promising candidate gene for the genetic improvement of new rice varieties under herbicide stress conditions.}, } @article {pmid40916343, year = {2026}, author = {Wu, J and Guo, J and Wu, J and Song, J and Xu, J and Lin, Y and Huang, C and Shi, C and Li, J and Li, C and Chen, Y and Wang, W and Gao, J and Zhou, Q and Zhang, Y and Li, S and Li, XJ and Zhang, CY and Chen, X and Yan, S}, title = {In vivo self-assembled siRNAs ameliorate neurological pathology in TDP-43-associated neurodegenerative disease.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {3}, pages = {828-839}, doi = {10.1093/brain/awaf330}, pmid = {40916343}, issn = {1460-2156}, support = {2021YFA0805300//National Key Research and Development Program of China/ ; 82171244//National Natural Science Foundation of China/ ; 32470564//National Natural Science Foundation of China/ ; 81922026//National Natural Science Foundation of China/ ; 32170981//National Natural Science Foundation of China/ ; 82271902//National Natural Science Foundation of China/ ; 82394422//National Natural Science Foundation of China/ ; 82371874//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Mice ; *RNA, Small Interfering/administration & dosage/genetics/therapeutic use ; *DNA-Binding Proteins/genetics/metabolism ; Humans ; *Genetic Therapy/methods ; Disease Models, Animal ; *Neurodegenerative Diseases/pathology/genetics/therapy ; }, abstract = {Abnormal accumulation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Small interfering RNAs (siRNAs) targeting TDP-43 offer potential therapeutic strategies for these diseases. However, efficient and safe delivery of siRNAs to the CNS remains a challenge. Here, we present a synthetic biology-based approach that leverages endogenous small RNA processing machinery to self-assemble siRNA-encapsulating small extracellular vesicles and uses the natural circulatory system of the host to transport siRNAs. Specifically, we engineered liver cells to express and package TDP-43-targeting siRNAs into rabies virus glycoprotein-tagged small extracellular vesicles, which are released into the circulation and cross the blood-brain barrier to deliver siRNAs to the CNS. In a mouse model of TDP-43 pathology induced by stereotactic injection of mutant TDP-43 (M337V) virus, treatment with in vivo self-assembled TDP-43 siRNAs (IVSA-siR-TDP43) effectively reduced TDP-43 accumulation, leading to significant improvements in motor function and neuropathology. Additionally, an adeno-associated virus-based delivery system was used to produce IVSA-siR-TDP43, demonstrating sustained therapeutic effects in TDP-43-associated neurodegeneration. These findings highlight a novel, effective and minimally invasive gene therapy platform for addressing TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, offering a promising avenue for future clinical applications.}, } @article {pmid40916690, year = {2025}, author = {Sharma, S and Gupta, M and Sharma, S}, title = {Exploring Thiophene-Based Pharmacophores as Emerging Therapeutics for Neurodegenerative Disorders.}, journal = {Critical reviews in analytical chemistry}, volume = {}, number = {}, pages = {1-29}, doi = {10.1080/10408347.2025.2554239}, pmid = {40916690}, issn = {1547-6510}, abstract = {Neurodegenerative disorders (NDD) i.e., dementia of the Alzheimer's type, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a rising worldwide epidemic driven by aging populations and characterized by progressive neuronal impairment. In the face of symptomatic therapies, disease-modifying treatments are beyond reach, for many years, at least, owing to the multifactorial origin, including protein aggregation, oxidative stress, neuroinflammation, and neurotransmitter dysregulation. Here, we point out thiophene, a five-membered heterocyclic sulfur-containing scaffold, as an underinvestigated but highly versatile pharmacophore with great potential in therapeutics of NDD. Here, we provide a systematic review of thiophene derivatives identified between 2006 and 2024, highlighting that these compounds are capable of modulating the aggregation of amyloid-β, inhibiting acetylcholinesterase, alleviating oxidative stress, inhibiting the toxicity of α-synuclein, and restoring neurotransmitter homeostasis. Specific emphasis is placed on their structural malleability, blood-brain barrier penetrability, and multi-targeting, which collectively present advantages over traditional heterocyclic templates. Progress in the areas of structure-activity relationship (SAR)-motivated design, synthetic methods, molecular docking, and preclinical assessment is reviewed, leading to the establishment of lead thiophene scaffolds with micro or nanomolar-range activity. This review also provides future directions, such as the requirement of pharmacokinetic improvement, target verification, and translational research to bridge preclinical discoveries with clinical utility. This article collectively places thiophene derivatives as an innovative chemical platform for the design of next-generation drugs for neurodegenerative diseases.}, } @article {pmid40916891, year = {2025}, author = {Ludolph, A}, title = {Progress in ALS research 2025.}, journal = {Current opinion in neurology}, volume = {38}, number = {5}, pages = {566-567}, doi = {10.1097/WCO.0000000000001410}, pmid = {40916891}, issn = {1473-6551}, } @article {pmid40917547, year = {2025}, author = {Tai, XY and Toniolo, S and Llewellyn, DJ and van Duijn, CM and Husain, M and Manohar, SG}, title = {Detection of cognitive deficits years prior to clinical diagnosis across neurological conditions.}, journal = {Brain communications}, volume = {7}, number = {5}, pages = {fcaf307}, pmid = {40917547}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Understanding the cognitive trajectory of a neurological disease can provide important insight on underlying mechanisms and disease progression. Cognitive impairment is now well established as beginning many years before the diagnosis of Alzheimer's disease, but pre-diagnostic profiles are unclear for other neurological conditions that may be associated with cognitive impairment. We analysed data from the prospective UK Biobank cohort with study baseline assessment performed between 2006 and 2010 and participants followed until 2021. We examined data from 497 252 participants, aged between 38 and 72 years at baseline, with an imaging sub-sample of 42 468 participants. Using time-to-diagnosis and time-from-diagnosis data in relation to time of assessment, we compared a continuous measure of executive function and magnetic resonance imaging brain measures of total grey matter (GM) and hippocampal volume in individuals with ischaemic stroke, focal epilepsy, Parkinson's disease, multiple sclerosis, motor neurone disease (amyotrophic lateral sclerosis) and migraine. Of the 497 252 participants [226 206 (45.5%) men, mean (SD) age, 57.5(8.1) years], 12 755 had ischaemic stroke, 6758 had a diagnosis of focal epilepsy, 3315 had Parkinson's disease, 2315 had multiple sclerosis, 559 had motor neurone disease and 18 254 had migraine either at study baseline or diagnosed during the follow-up period. Apart from motor neurone disease, all conditions had lower pre-diagnosis executive function compared to controls (assessment performed median 7.4 years before diagnosis). At a group level, focal epilepsy and multiple sclerosis showed a gradual worsening in executive function up to 15 years prior to diagnosis, while ischaemic stroke was characterised by a modest decline for a few years followed by a substantial reduction at the time of diagnosis. By contrast, participants with migraine showed a mild reduction in pre-diagnosis cognition compared to controls which improved following clinical diagnosis. Pre-diagnosis MRI GM volume was lower than controls for stroke, Parkinson's disease and multiple sclerosis (scans performed median 1.7 years before diagnosis), while other conditions had lower volumes post-diagnosis. These cognitive trajectory models reveal disease-specific temporal patterns at a group level, including a long cognitive prodrome associated with focal epilepsy and multiple sclerosis. The findings may help to prioritise risk management of individual diseases and inform clinical decision-making.}, } @article {pmid40919318, year = {2025}, author = {Harrison, D and Billinton, A and Bock, MG and Clarke, NP and Digby, Z and Gabel, CA and Lindsay, N and Reader, V and Scanlon, J and Smolak, P and Thornton, P and Wescott, H and Watt, AP}, title = {Profile of NT-0527, a brain penetrant NLRP3 Inflammasome inhibitor suitable as an in vivo tool compound for neuroinflammatory disorders.}, journal = {RSC medicinal chemistry}, volume = {16}, number = {11}, pages = {5318-5332}, pmid = {40919318}, issn = {2632-8682}, abstract = {Inhibition of the NLRP3 inflammasome has emerged as a high potential treatment paradigm for the treatment of neuroinflammation, with demonstrated anti-neuroinflammatory effects in Parkinson's disease patients and a strong rationale in Alzheimer's disease and amyotrophic lateral sclerosis. To facilitate further progress in this field, brain penetrant NLRP3 inflammasome inhibitors as leads and tool compounds are required. We discovered a small molecule NLRP3 inflammasome inhibitor, NT-0527 (11), and extensively profiled this to reveal a highly potent, selective and brain penetrant compound. This was shown to be orally bioavailable, efficacious in an in vivo model of inflammation, and with good developability characteristics. However, NT-0527 exhibited CYP 2C19 time-dependent inhibition, which halted development, but this molecule could be employed as a valuable tool compound for the investigation of neuroinflammatory conditions where NLRP3 inflammasome activation is implicated.}, } @article {pmid40920272, year = {2025}, author = {Ku, JB and Pak, RJ and Ku, SS and Holland, RD and Kim, HS}, title = {Clinical Efficacy of Stem Cell Therapy in Neurotraumatic and Neurodegenerative Conditions: A Comparative Review.}, journal = {Tissue engineering and regenerative medicine}, volume = {22}, number = {8}, pages = {1051-1066}, pmid = {40920272}, issn = {2212-5469}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation ; *Spinal Cord Injuries/therapy ; Animals ; Amyotrophic Lateral Sclerosis/therapy ; *Cell- and Tissue-Based Therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Neurotraumatic conditions, such as spinal cord injury, brain injury, and neurodegenerative conditions, such as amyotrophic lateral sclerosis, pose a challenge to the field of rehabilitation for its complexity and nuances in management. For decades, the use of cell therapy in treatment of neurorehabilitation conditions have been explored to complement the current, mainstay treatment options; however, a consensus for standardization of the cell therapy and its efficacy has not been reached in the medical community. This study aims to provide a comparative review on the very topic of cell therapy use in neurorehabilitation conditions in an attempt to bridge the gap in knowledge.

METHODS: Studies were searched from the PubMed database published from 2014 to 2024 employing the terms including but not exclusive to "spinal cord injury," "brain injury," "amyotrophic lateral sclerosis," "regenerative medicine," "cell therapy," and "stem cell." Following the PRISMA 2020 statement, the studies were screened, included, and excluded. Thirty three studies were identified and selected for this review.

RESULTS: Countless researchers investigated the efficacy of various stem cell products for the treatment of numerous neurotraumatic conditions, such as spinal cord injury, traumatic brain injury, and neurodegenerative conditions such as amyotrophic lateral sclerosis. The recent decade of studies suggest that in neurotraumatic conditions, bone-marrow-derived and neural stem cells can be effective, and in neurodegenerative conditions, such as ALS, mesenchymal and neural stem cells can be efficacious.

CONCLUSION: Emerging data from the latest research is encouraging to the patients suffering from neurotraumatic and neurodegenerative conditions, which present themselves as a need for further studies with improved standardization in study design, including cell source specification, differentiation and culture method, and outcome measures to ensure a wide applicability.}, } @article {pmid40920400, year = {2025}, author = {Urso, D and Giannoni-Luza, S and Brayne, C and Ray, N and Logroscino, G}, title = {Incidence and Prevalence of Frontotemporal Dementia: A Systematic Review and Meta-Analysis.}, journal = {JAMA neurology}, volume = {82}, number = {11}, pages = {1144-1152}, pmid = {40920400}, issn = {2168-6157}, mesh = {Humans ; *Frontotemporal Dementia/epidemiology ; Incidence ; Prevalence ; }, abstract = {IMPORTANCE: Comprehensive incidence and prevalence rates of frontotemporal dementia are currently not available.

OBJECTIVE: To estimate the incidence and prevalence of frontotemporal dementia and its clinical variants in the overall population and age subgroups.

We systematically searched PubMed, EMBASE, and Scopus between January 1, 1990, and October 22, 2024, for population-based studies estimating the incidence and/or prevalence of FTD.

DATA EXTRACTION AND SYNTHESIS: Studies and data were screened and extracted independently by 2 investigators in accordance with PRISMA guidelines. Incident and prevalent cases together with the population at risk were pooled using random-effects meta-analysis. Differences in heterogeneity by FTD variants and populations at risk were estimated.

MAIN OUTCOMES AND MEASURES: Prevalent and incident cases as numerator were based on well-defined clinical criteria. Denominators were derived either from census population data or from author-defined populations at risk.

RESULTS: From 1854 screened articles, 32 eligible population-based studies were identified. Sixteen were on prevalence and 22 on incidence reporting FTD measures, including those with estimates for the whole population and for specific age subgroups. Pooled crude incidence for FTD was 2.28 (95% CI, 1.55-3.36) per 100 000 person-years and prevalence, 9.17 (95% CI, 3.59-23.42) per 100 000 people. The behavioral-variant FTD pooled crude incidence was 1.20 (95% CI, 0.67-2.16) per 100 000 person-years and prevalence, 9.74 (95% CI, 2.90-32.73) per 100 000 people. The primary progressive aphasia variant pooled crude incidence was 0.52 (95% CI, 0.35-0.79) per 100 000 person-years and prevalence, 3.67 (95% CI, 3.05-4.43). FTD incidence among individuals younger than 65 years was 1.84 (95% CI, 0.79-4.30) per 100 000 person-years and prevalence, 7.47 (95% CI, 4.13-13.49) per 100 000 people. The denominator based on census data showed less heterogeneity than the population at risk defined by the authors (I2: for incidence, 91.6% vs 97.6%, respectively, and for prevalence, 98.8% vs 99.2%, respectively).

CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, estimates indicate that FTD is comparable in frequency to dementia with Lewy bodies and occurs at higher rates than progressive supranuclear palsy, corticobasal syndrome, and amyotrophic lateral sclerosis. These results provide a foundation for future research and public health strategy, especially for underrepresented populations, to better comprehend the global burden of FTD. Our findings provide robust pooled estimates of the incidence and prevalence of FTD and its subtypes, offering a foundation for future research and public health planning.}, } @article {pmid40922457, year = {2025}, author = {Eroglu, E and Harmanci, N}, title = {Emerging Molecular Targets in Neurodegenerative Disorders: New Avenues for Therapeutic Intervention.}, journal = {Basic & clinical pharmacology & toxicology}, volume = {137}, number = {4}, pages = {e70107}, doi = {10.1111/bcpt.70107}, pmid = {40922457}, issn = {1742-7843}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/physiopathology/metabolism/genetics ; Animals ; *Molecular Targeted Therapy ; Autophagy/drug effects ; Drug Development ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and frontotemporal dementia represent a significant global health burden with limited therapeutic options. Current treatments are primarily symptomatic and fail to modify disease progression, emphasizing the urgent need for novel, mechanism-based interventions. Recent advances in molecular neuroscience have identified several non-classical pathogenic pathways, including neuroinflammation, mitochondrial dysfunction, impaired autophagy and proteostasis, synaptic degeneration and non-coding RNA dysregulation. In this focused review, we highlight emerging molecular targets such as TREM2, NLRP3, mTOR, TFEB, PINK1 and SIRT3, which offer promising avenues for therapeutic intervention. We also address challenges in target validation and translational drug development, while proposing future research directions that may facilitate the design of more effective treatments. A deeper understanding of these molecular mechanisms is essential for developing disease-modifying strategies to combat neurodegeneration.}, } @article {pmid40922888, year = {2025}, author = {Kademani, A and Avraam, C and Montenegro, D and Paloh, A and Somannagari, N and Gupta, A and Lafi, AW and Algaba, AE and Islam, R and Fahima, C and Siddiqui, HF}, title = {Exploring the Emerging Role of Stem Cell Therapy in Neurodegenerative Diseases and Spinal Cord Injury: A Narrative Review.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e89629}, pmid = {40922888}, issn = {2168-8184}, abstract = {Neurodegenerative diseases and spinal cord injuries (SCI) pose a significant burden on the healthcare system globally. Diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease precipitate cognitive, motor, and behavioral deficits. Parallelly, spinal cord injuries produce sensory and motor deficits, which are burdensome psychologically, socially, and economically. Current management strategies focus only on symptomatic relief, with no definitive cure. Stem cells have been explored for regenerative therapy. This review focuses on developments, limitations, and future potential of stem cell therapy. Stem cells affect the central nervous system via neuroprotective mechanisms, immunomodulatory effects, and mitigation of oxidative stress. The clinical implications of stem cell therapy in treating neurodegenerative diseases and SCI are debatable due to varied outcomes. Challenges related to sample size, long-term follow-up, and assessment of adverse effects should be mitigated in future research. Researchers are currently exploring optimal stem cell types along with various transplantation strategies. Biomaterials integrated with stem cells are a novel approach for treating neurodegenerative diseases and spinal cord injuries. Certain genetic modifications have shown improved results. Screening patients to ascertain better responses to therapy has proven to be a challenge. Other complications include graft vs. host reaction and degeneration of transplanted neurons due to pathogenesis and tumorigenesis. However, the majority of the potential stem cell therapeutic avenues are in the preclinical stage and are being tested on animal models. Guidelines pertaining to ethical concerns and regulatory frameworks need to be established to unfold the full potential of stem cell therapy in the clinical setting. Recent advances also show an increased need to formulate patient-specific approaches to treatment, ranging from stem cell selection to the technique of transplantation. Ongoing clinical trials can address the current challenges and leverage emerging technologies, leading to definitive treatments for neurodegenerative diseases and spinal cord injuries.}, } @article {pmid40923569, year = {2025}, author = {Stikvoort García, DJL and Goedee, HS and van den Berg, LH and Sleutjes, BTHM}, title = {Nerve Excitability in Asymptomatic Carriers and Amyotrophic Lateral Sclerosis Patients With C9orf72.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {12}, pages = {2470-2481}, pmid = {40923569}, issn = {2328-9503}, support = {//Stichting ALS Nederland/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; *C9orf72 Protein/genetics ; Male ; Female ; Middle Aged ; Adult ; Aged ; *Median Nerve/physiopathology ; Heterozygote ; Mutation ; }, abstract = {OBJECTIVE: We investigated the effects of C9orf72 mutation carriership on peripheral nerve excitability in asymptomatic individuals from families with a history of C9orf72 amyotrophic lateral sclerosis (ALS) and patients.

METHODS: We included 47 asymptomatic individuals from families with a history of C9orf72 ALS, of whom 23 were carriers (C9[+]) and 24 were noncarriers (C9[-]). In addition, 11 C9[+] and 110 C9[-] ALS patients and 50 healthy controls participated. Nerve excitability tests were conducted on the median nerve. We obtained standard excitability measurements as well as composites of these measurements that reflect various passive and active membrane properties. Data of C9[+] and C9[-] asymptomatic individuals were compared, followed by a kinship-adjusted comparison in asymptomatic individuals from the same families. We then compared C9[+] to C9[-] ALS patients.

RESULTS: In the subset of asymptomatic individuals from the same families, C9[+] individuals had lower values than C9[-] individuals on one of the composite excitability measurements (t = -2.15, p = 0.034), corresponding to a hypoexcitable profile consistent with smaller Na[+]-window currents. C9[+] ALS patients had a hyperexcitable profile with larger refractoriness at 2 ms and relative refractory periods than C9[-] ALS patients (t = 4.58, p < 0.001; t = 3.43, p = 0.002, respectively), which is in line with slower recovery of the Na[+]-channels from inactivation.

INTERPRETATION: Asymptomatic individuals and ALS patients carrying the C9orf72 mutation exhibit a unique electrophysiological phenotype, implicating altered Na[+]-channel characteristics compared to asymptomatic noncarriers and sporadic ALS patients. Monitoring hypoexcitable to hyperexcitable profile transitions in individuals carrying the C9orf72 mutation may be valuable as an early indicator of phenoconversion.}, } @article {pmid40923926, year = {2025}, author = {Arnold, L and Tomsitz, D and Buchillon, R and Leding, J and Senner, S and Frey, S and Janjic, N and French, LE and Heinzerling, L}, title = {Successful treatment of localized Merkel cell carcinoma with avelumab in a patient with amyotrophic lateral sclerosis.}, journal = {Immunotherapy}, volume = {17}, number = {12}, pages = {867-870}, pmid = {40923926}, issn = {1750-7448}, mesh = {Aged ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Antineoplastic Agents, Immunological/therapeutic use ; *Carcinoma, Merkel Cell/drug therapy/complications ; Immune Checkpoint Inhibitors/therapeutic use ; *Skin Neoplasms/drug therapy/complications ; Treatment Outcome ; }, abstract = {Currently, the first-line treatment of non-metastatic Merkel cell carcinoma (MCC) is complete resection. In case of unresectable or metastatic MCC, immune checkpoint inhibitor (ICI) therapy with avelumab (or in the US also pembrolizumab or retifanlimab) is indicated. We report on a patient with a primary, non-metastatic MCC on the left eyelid and amyotrophic lateral sclerosis (ALS). Due to ALS, the patient's communication was limited to eye movement and blinking. Complete resection or definitive radiotherapy of the tumor while preserving the function of the eye muscles was not possible. No prior data was available for patients with ALS under ICI therapy. In agreement with the patient and his family, a monotherapy with avelumab, a programmed death ligand 1 (PD-L1) inhibitor, was initiated. This led to a complete remission of the tumor with a progression-free survival of over 24 months and importantly no deterioration of the ALS.}, } @article {pmid40924345, year = {2025}, author = {Kutlubaev, MA and Pervushina, EV and Kiernan, MC}, title = {The nature of fatigue in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Acta neurologica Belgica}, volume = {125}, number = {6}, pages = {1535-1544}, pmid = {40924345}, issn = {2240-2993}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Fatigue/etiology/physiopathology ; Quality of Life ; }, abstract = {OBJECTIVES: Patients diagnosed with amyotrophic lateral sclerosis (ALS) typically describe symptoms of fatigue. Despite this frequency, the underlying mechanisms of fatigue are poorly understood, and are likely multifactorial. To help clarify mechanisms, the present systematic review was undertaken to determine the risk factors related to fatigue in ALS.

METHODS: A systematic review was conducted using PubMed and Google Scholar databases using key words. From a total of 40,014 articles, 18 articles were included in the final review, following PRISMA guidelines. Meta-regression and subgroup analyses were conducted to study the relationship between fatigue in ALS and different covariates.

RESULTS: Eighteen studies were included in the analysis. A number of factors were investigated, including age, sex, disease severity and duration, site of disease onset, neurophysiological parameters, and respiratory symptoms, depression and anxiety, sleep disorders, and pain. Combined analyses established that participants with ALS who reported fatigue had more severe disease, as confirmed by lower functional rating scores, than those who did not report fatigue. The remaining factors including depression, anxiety and pain, were not found to be related to the onset of fatigue in ALS. Overall, fatigue worsened quality of life in patients diagnosed with ALS.

DISCUSSION: Fatigue in ALS appears to be particularly associated with progressive neurological deficit and disability, linked to both central and peripheral neuromuscular mechanisms.}, } @article {pmid40925732, year = {2025}, author = {, }, title = {[Expert consensus on the diagnosis and treatment of sleep-disordered breathing related to neuromuscular diseases].}, journal = {Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases}, volume = {48}, number = {9}, pages = {815-830}, doi = {10.3760/cma.j.cn112147-20250614-00332}, pmid = {40925732}, issn = {1001-0939}, support = {82270107//National Natural Science Fundation of China/ ; }, mesh = {Humans ; *Neuromuscular Diseases/complications ; *Sleep Apnea Syndromes/diagnosis/therapy/etiology ; Noninvasive Ventilation ; Sleep Apnea, Obstructive/diagnosis/therapy ; China ; }, abstract = {Neuromuscular diseases are often accompanied by various types of sleep-related breathing disorders, which can exacerbate the underlying condition and are associated with a poor prognosis. Early identification is essential, and interventions such as non-invasive ventilation, oxygen therapy, and respiratory rehabilitation should be initiated promptly to mitigate disease progression and improve outcomes. Nevertheless, the rates of missed and misdiagnosed cases remain common in clinical practice. Currently, there are no standardized guidelines for the diagnosis and treatment of sleep-disordered breathing related to neuromuscular diseases in China. Therefore, based on the latest domestic and international research progress, and combined with domestic clinical diagnosis and treatment experience, the Sleep Disorder Group of Chinese Thoracic Society has brought together multidisciplinary experts to develop this expert consensus. This consensus provides a comprehensive overview of the epidemiology, clinical manifestations, diagnostic approaches, assessment strategies, and treatment of sleep-disordered breathing related to neuromuscular diseases. It formulates evidence-based recommendations to guide clinical practice, with the aim of providing standardized recommendations for their diagnosis and management.Statement 1: The neuromuscular disorders that are most frequently associated with sleep-disordered breathing include: myasthenia gravis (1A), amyotrophic lateral sclerosis (2B), post-polio syndrome (2B), myotonic dystrophy (2B), peripheral neuropathies (2C), and metabolic myopathies, among other neuromuscular conditions.Statement 2: Patients with neuromuscular disorders frequently develop multiple types of sleep-disordered breathing concurrently or sequentially, with obstructive sleep apnea (OSA) being the most prevalent manifestation. Distinct clinical manifestations of OSA are observed across different neuromuscular disease subtypes (1A).Statement 3: Neuromuscular disorders predispose to central sleep apnea (CSA), with clinical manifestations varying significantly across disease subtypes, stages of progression, and severity levels (1A).Recommendation 1: In patients with neuromuscular disorders exhibiting progressive hypercapnia or worsening hypoxemia, clinicians should investigate potential comorbid nocturnal alveolar hypoventilation and/or sleep-associated hypoxemia (1A).Recommendation 2: When sleep-disordered breathing is suspected, patients with neuromuscular disorders should be evaluated for symptoms of sleep-disordered breathing. Meanwhile, sleep monitoring, non-invasive CO2 monitoring, and related examinations should be actively performed according to the actual situation (1A). A polysomnography should be performed when there is a high clinical suspicion of sleep-disordered breathing but a negative result on a portable sleep monitor (1A).Recommendation 3: (1) Noninvasive positive pressure ventilation (NPPV) titration under polysomnography is the standard method to determine the effective treatment parameters for neuromuscular diseases with sleep-disordered breathing (1A). (2) Positive airway pressure titration in OSA patients with neuromuscular diseases should follow American Academy of Sleep Medicine (AASM) guidelines (1A). (3) For neuromuscular disorders with CSA or Cheyne-Stokes respiration, bi-level positive airway pressure (BPAP) with ST pattern is recommended (1A); When BPAP is not tolerated or accompanied by severe Cheyne-Stokes respiratory and heart failure in patients, adaptive support ventilation (ASV) should be used (2B). (4) Patients with neuromuscular disease and sleep-related alveolar hypoventilation should be treated with BPAP or variable assurance pressure support (VAPS) (1A). (5) BPAP with alternate frequency is preferred for neuromuscular disorders with "pseudo-central events" (1A).Recommendation 4: Oxygen therapy alone is not recommended for neuromuscular disease patients combined with sleep-disordered breathing (2D). Oxygen therapy with monitoring of CO2 level is recommended when non-invasive ventilation therapy cannot effectively correct hypoxemia (2C). Diaphragmatic pacing should not be routinely used in amyotrophic lateral sclerosis patients with respiratory failure (2B). Transvenous phrenic nerve stimulation is not currently applied to CSA caused by neuromuscular disorders (2D). Respiratory rehabilitation may improve respiratory muscle strength in a subset of patients with neuromuscular disorders (2B). Protiline can be used for REM-associated alveolar hypoventilation, and daytime sleepiness could be addressed with methylphenidate and modafinil (2C).Recommendation 5: Neuromuscular disease combined with sleep-disordered breathing is a chronic disease requiring patient-centered, individualized education and long-term follow-up management (1A).}, } @article {pmid40926822, year = {2025}, author = {Guo, W and Dong, L and Lu, Q and Xie, M and Yang, Y and Zhang, Y and Lu, X and Yu, Q}, title = {Association Between Cannabis Use and Neuropsychiatric Disorders: A Two-sample Mendelian Randomization Study.}, journal = {Alpha psychiatry}, volume = {26}, number = {4}, pages = {46108}, pmid = {40926822}, issn = {2757-8038}, abstract = {BACKGROUND: The progressive legalization and widespread use of cannabis has led to its use as a treatment for certain neuropsychiatric disorders. Traditional epidemiological studies suggest that cannabis use has an effect on some neurocognitive aspects. However, it is unclear whether cannabis use is causally related to common neuropsychiatric disorders. The present study was conducted to illustrate the causal relationships of genetically predicted cannabis use with common neuropsychiatric disorders.

METHODS: We used a two-sample Mendelian randomization method using genome-wide association study (GWAS) summary statistics obtained from publicly available databases on lifetime cannabis use and 10 neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), epilepsy, generalized epilepsy, focal epilepsy, migraine, migraine with aura, migraine without aura, schizophrenia (SCZ), anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), and Parkinson's disease (PD) were studied with a two-sample Mendelian randomization method for GWAS summary statistics. The inverse variance weighted (IVW) method was used as the main analysis model.

RESULTS: Our study suggests that lifetime cannabis use is associated with an increased risk of developing PD (odds ratio (OR) = 1.782; 95% CI 1.032-3.075; p = 0.038) and an increased risk of ADHD in female participants (OR = 1.650; 95% CI 1.051-2.590; p = 0.029).

CONCLUSIONS: Cannabis intake may cause adverse effects relating to certain neuropsychiatric disorders. Therefore, special attention should be paid to the side effects of addictive drugs during clinical treatment to avoid harmful effects on the brain and neurocognition.}, } @article {pmid40927826, year = {2025}, author = {Oh, YS and Jung, R and Yon, DK and Kim, MS and Shin, JH and Shin, JI and Song, TJ}, title = {The Burden of Motor Neuron Diseases in the United States, 1990-2021: A Systematic Analysis of the Global Burden of Disease Study 2021.}, journal = {Muscle & nerve}, volume = {72}, number = {5}, pages = {1130-1142}, pmid = {40927826}, issn = {1097-4598}, support = {//Ministry of Science and ICT, South Korea/ ; //Korea Health Industry Development Institute/ ; HI22C073600//Ministry of Health & Welfare, South Korea/ ; RS-2023-00262087//Ministry of Health & Welfare, South Korea/ ; //BK21 FOUR (Fostering Outstanding Universities for Research) funded by the Ministry of Education (MOE, Korea) and National Research Foundation of Korea (NRF-5199990614253, Education Research Center for 4IR-Based Health Care)./ ; //Bill and Melinda Gates Foundation/ ; //Australian National Health and Medical Research Council/ ; //Queensland Department of Health, Australia/ ; //Yonsei Fellowship/ ; IITP-2024-RS-2024-00438239//Institute for Information & Communications Technology Planning & Evaluation (IITP)/ ; TJS (RS-2022-II220621//Korean government (MSIT)/ ; //Korean Health Industry Development Institute (KHIDI)/ ; //Ministry of Education (MOE, Korea)/ ; NRF-5199990614253//National Research Foundation of Korea/ ; }, mesh = {Humans ; United States/epidemiology ; Male ; *Motor Neuron Disease/epidemiology/mortality ; Female ; *Global Burden of Disease/trends ; Middle Aged ; Aged ; Adult ; Disability-Adjusted Life Years ; Prevalence ; Incidence ; Young Adult ; Adolescent ; *Cost of Illness ; Aged, 80 and over ; Child ; Child, Preschool ; Infant ; Quality-Adjusted Life Years ; }, abstract = {INTRODUCTION/AIMS: There is a lack of up-to-date information on the burden of motor neuron diseases (MNDs) in the United States (US). This study aimed to estimate trends in the prevalence, incidence, mortality, and disability-adjusted life years (DALYs) for MNDs in the US from 1990 to 2021.

METHODS: We performed a secondary analysis of MNDs in the US using estimates of prevalence, incidence, and mortality obtained from analyses of the Global Burden of Disease 2021 dataset. These data were generated using DisMod-MR 2.1, a Bayesian meta-regression tool. Estimates were analyzed by age group, sex, region, and sociodemographic index (SDI).

RESULTS: In 2021, the age-standardized prevalence rate of MNDs in the US was 8.82 (95% uncertainty interval, 7.96-9.74) per 100,000, a 12.89% (3.10-23.66) increase from 1990 (7.82 per 100,000). Age-standardized MND-related DALY and mortality rates in 2021 were 41.36 (39.47-42.94) and 1.49 (1.38-1.56) per 100,000, respectively, increases of 4.14% (0.41%-7.68%) and 18.34% (13.86%-22.70%) compared to 1990. Geographic disparities were observed, with the West North Central reporting the highest DALY rates and the Middle Atlantic showing the lowest. The burden of MNDs was consistently greater in males across all metrics, with a male-to-female ratio of approximately 1.4:1. SDI was negatively correlated with age-standardized DALYs, years of life lost, and mortality rates.

DISCUSSION: The observed burden of MNDs in the US highlights the necessity for targeted public health interventions; equitable resource distribution; and further research into environmental, genetic, and sociodemographic factors that contribute to MNDs.}, } @article {pmid40928392, year = {2026}, author = {Silva, S and Aires, D and Souza, A and Macedo, J and Melo, L and Câmara, S and Valentim, R and Lindquist, AR and Samora, G and Ribeiro, T}, title = {What is the influence of fatigue, ALSFRS-R scores, cognitive status, and pain in individuals with Amyotrophic Lateral Sclerosis? A cross-sectional study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {469-476}, doi = {10.1080/21678421.2025.2557971}, pmid = {40928392}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/complications/psychology/epidemiology/diagnosis ; *Fatigue/etiology/epidemiology/diagnosis/psychology ; Cross-Sectional Studies ; Middle Aged ; Aged ; *Pain/etiology/epidemiology/diagnosis/psychology ; Adult ; Brazil/epidemiology ; *Cognition/physiology ; }, abstract = {Introduction: Fatigue remains a poorly understood symptom in individuals with ALS, and little is known about its associtation with other symptoms, including functional impairment, cognition, and pain. Objective: To identify the levels of fatigue, pain, ALSFRS-R, and cognition of a Brazilian group of individuals with ALS, in order to verify possible influences between these symptoms and fatigue. Methods: This is a cross-sectional study conducted with individuals with ALS who were recruited intentionally, using a non-probabilistic sampling method. After agreeing to participate, they were assessed using a standardized assessment form, and data regarding fatigue level, ALSFRS-R scores, cognition, and pain were collected. Data were analyzed by categorizing fatigue (with and without fatigue) and considering sociodemographic and clinical covariates, followed by comparisons, bivariate analyses, and multiple linear regression analyses. Results: Data were collected from 72 individuals with ALS. Inferential statistics indicated differences between fatigue categories concerning ALSFRS-R scores, cognition, and pain. After multiple linear regression analyses, an association between fatigue and the dependent variables was identified. Conclusion: Fatigue is associated with lower ALSFRS-R scores, poorer cognitive status, and higher levels of pain in a Brazilian cohort of ALS. Additionally, age, sex, education, and length of illness were identified as potential factors for fatigue occurrence, observed more frequently in females than in males with the condition.}, } @article {pmid40928424, year = {2025}, author = {Matsubara, T and Izumi, Y and Hatanaka, Y and Takahara, M and Kondo, A and Matsukura, K and Arakawa, A and Haga, T and Miyamoto, R and Naruse, H and Morino, H and Toda, T and Murayama, S and Saito, Y}, title = {A Novel Neuropathological Subtype of Amyotrophic Lateral Sclerosis Characterised by Prominent Astroglial TDP-43 Pathology.}, journal = {Neuropathology and applied neurobiology}, volume = {51}, number = {5}, pages = {e70036}, pmid = {40928424}, issn = {1365-2990}, support = {JP21wm0425019//AMED/ ; JP24tm0524002//AMED/ ; JP22H04923//JSPS KAKENHI/ ; JP22K15740//JSPS KAKENHI/ ; JP24K18698//JSPS KAKENHI/ ; JPMH23FC1008//MHLW Research on rare and intractable diseases Program/ ; //Kato Memorial Bioscience Foundation/ ; //Yukihiko Miyata Memorial Trust for ALS Research/ ; //Medical Research Grants of Takeda Science Foundation/ ; //Integrated Research Initiative for Living Well with Dementia (IRIDE) of the Tokyo Metropolitan Institute for Geriatrics and Gerontology/ ; }, abstract = {This study identified a novel amyotrophic lateral sclerosis subtype with prominent astroglial phosphorylated TDP‐43 inclusions and minimal neuronal inclusions. The patients shared a clinical phenotype of flail arm variant of ALS. These observations suggest a more critical role for astroglia than previously recognised.}, } @article {pmid40930472, year = {2025}, author = {Roger, AL and Huston, ML and Spaulding, M and Metz, CM and Froeb, R and Wu, R and Kehoe, S and Mitchell, GS and ElMallah, MK}, title = {Therapeutic acute intermittent hypoxia modestly improves breathing in Pompe disease.}, journal = {Respiratory physiology & neurobiology}, volume = {338}, number = {}, pages = {104489}, doi = {10.1016/j.resp.2025.104489}, pmid = {40930472}, issn = {1878-1519}, support = {K99 HL161420/HL/NHLBI NIH HHS/United States ; }, mesh = {*Glycogen Storage Disease Type II/therapy/complications/physiopathology ; Animals ; Mice ; Disease Models, Animal ; *Hypoxia ; alpha-Glucosidases/genetics/deficiency ; Male ; Diaphragm/physiopathology ; Motor Neurons/physiology ; Mice, Knockout ; *Respiration ; Mice, Inbred C57BL ; }, abstract = {Pompe disease is an autosomal recessive neuromuscular disorder characterized by a deficiency of acid α-glucosidase (GAA), an enzyme responsible for lysosomal glycogen degradation in all cells. Respiratory distress is a common symptom among patients with Pompe disease resulting from weakness of primary respiratory neuromuscular units of the diaphragm and genioglossus and the motor neurons which innervate them. The only FDA approved treatment is enzyme replacement therapy (ERT) of recombinant human GAA (rhGAA) which slows the decline of motor function and extends life expectancy. However, ERT does not cross the blood-brain barrier and thus, is unable to treat the critical pathology present in motor neurons hindering long-term efficacy. In the present study, we sought to explore an alternative treatment for Pompe patients to improve breathing by improving the function of motor neurons. Therapeutic acute intermittent hypoxia (tAIH) is a non-invasive therapeutic modality which has had success in improving respiratory and non-respiratory motor function in patients with spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Here, we treated adult Gaa[-/-] mice with a single, week-long tAIH protocol, followed by bi-weekly tAIH for 4 months. We report three critical findings: (1) both short and long-term tAIH therapy modestly improve breathing in Gaa[-/-] mice; (2) long-term tAIH-therapy in WT mice moderately elevates breathing responses; and (3) these trending improvements to respiration in Gaa[-/-] may be related to changes in chemoreflex activation, reduced kyphosis, and improved overlap of acetylcholine receptors and phrenic motor neuron axon terminals in the diaphragm muscle.}, } @article {pmid40930530, year = {2025}, author = {Geng, Y and Liu, C and Miao, H and Suen, MC and Xie, Y and Zhang, B and Han, W and Wu, C and Ren, H and Chen, X and Tai, HC and Wang, Z and Zhu, G and Cai, Q}, title = {Crystal structures of distinct parallel and antiparallel DNA G-quadruplexes reveal structural polymorphism in C9orf72 G4C2 repeats.}, journal = {Nucleic acids research}, volume = {53}, number = {17}, pages = {}, pmid = {40930530}, issn = {1362-4962}, support = {32301023//Natural Scientific Foundation of China/ ; 32071188//Natural Scientific Foundation of China/ ; 32471312//Natural Scientific Foundation of China/ ; 3502Z202373009//Natural Scientific Foundation of Xiamen/ ; 16101120//Hong Kong Special Administrative Region, China/ ; 161011121//Hong Kong Special Administrative Region, China/ ; AoE/M-403-16//Hong Kong Special Administrative Region, China/ ; AoE/M-401/20//Hong Kong Special Administrative Region, China/ ; //Hong Kong University of Science and Technology/ ; 3502Z20214001//Project of Xiamen Cell Therapy Research, China/ ; }, mesh = {*G-Quadruplexes ; *C9orf72 Protein/genetics/chemistry ; Humans ; Crystallography, X-Ray ; *DNA Repeat Expansion ; Models, Molecular ; Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics ; *DNA/chemistry/genetics ; Polymorphism, Genetic ; Nucleic Acid Conformation ; }, abstract = {The abnormal expansion of GGGGCC (G4C2) repeats in the noncoding region of the C9orf72 gene is a major genetic cause of two devastating neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These G4C2 repeats are known to form G-quadruplex (G4) structures, which are hypothesized to contribute to disease pathogenesis. Here, we demonstrated that four DNA G4C2 repeats can fold into two structurally distinct G4 conformations: a parallel and an antiparallel topology. The high-resolution crystal structure of the parallel G4 reveals an eight-layered dimeric assembly, formed by two identical monomeric units. Each unit contains four stacked G-tetrads connected by three propeller CC loops and is stabilized through 5'-to-5' π-π interactions and coordination with a central K+ ion. Notably, the 3'-ending cytosines form a C·C+·C·C+ quadruple base pair stacking onto the adjacent G-tetrad layer. In contrast, the antiparallel G4 adopts a four-layered monomeric structure with three edgewise loops, where the C6 and C18 bases engage in stacking interaction with neighboring G-tetrad via a K+ ion. These structurally distinct G-quadruplexes provide mechanistic insights into C9orf72-associated neurodegeneration and offer potential targets for the development of structure-based therapeutic strategies for ALS and FTD.}, } @article {pmid40930692, year = {2025}, author = {Wei, Y and Miao, H and Najafi, H and Kim, WJ}, title = {Precise measurement of motor neuron dysfunction in Drosophila ALS model via climbing assay and leg imaging.}, journal = {Methods in cell biology}, volume = {197}, number = {}, pages = {127-148}, doi = {10.1016/bs.mcb.2025.02.008}, pmid = {40930692}, issn = {0091-679X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Disease Models, Animal ; *Motor Neurons/pathology/metabolism ; *Drosophila melanogaster/physiology ; *Optical Imaging/methods ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder characterized by progressive degeneration of motor neurons, leading to muscle weakness, paralysis, and death. While there is a plethora of studies focusing on many aspects of ALS, the pathogenesis of this disease is not well understood, and effective treatments are scarce. Drosophila melanogaster is a powerful model organism for studying ALS due to its genetic tractability and its evolutionarily conserved cellular and molecular processes which are also shared between the fly and human. Here, we introduce two simple and cost-effective methodologies for assessing motor neuron dysfunction in Drosophila: (1) Fast Inexpensive Climbing Test (FICT), and (2) Economical Leg Fluorescence Imaging (ELFI). These methods are established based on using basic equipment and straightforward procedures, making them accessible and applicable in various research and educational settings. FICT provides a non-invasive and high-throughput measure of motor dysfunction, while ELFI allows for direct visualization of fluorescently labeled cells in the Drosophila leg, facilitating the study of cell-cell communications in vivo. Our approach emphasizes the importance of both neuronal and glial contributions to ALS pathogenesis, offering valuable insights for the development of novel therapeutic strategies. These methods democratize access to ALS research tools, promoting global scientific collaboration and advancing our understanding of this devastating disease.}, } @article {pmid40931262, year = {2026}, author = {Bonan, L and D'Angeli, D and Vacchiano, V and Postiglione, E and Incensi, A and Valentino, ML and Capellari, S and Donadio, V and Rizzo, G and Liguori, R}, title = {In-vivo evidence of synucleinopathy in parkinsonism due to VCP mutation.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {133}, number = {3}, pages = {433-438}, pmid = {40931262}, issn = {1435-1463}, mesh = {Humans ; *Valosin Containing Protein/genetics ; Male ; Aged ; *Parkinsonian Disorders/genetics/pathology ; *Mutation/genetics ; *alpha-Synuclein/metabolism ; *Synucleinopathies/genetics/pathology ; *Cell Cycle Proteins/genetics ; *Adenosine Triphosphatases/genetics ; }, abstract = {Multisystem proteinopathy 1 (MSP1) is a rare autosomal dominant disorder caused by mutations in the valosin-containing protein (VCP) gene typically presenting with inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Parkinsonism is a rare feature of MSP1, occurring in 3-4% of cases, with limited post-mortem evidence suggesting neuronal synucleinopathy. We report a case of VCP-related parkinsonism providing the first in vivo demonstration of phosphorylated alpha-synuclein deposition in skin biopsy, a highly sensitive and specific in vivo biomarker of synucleinopathy. A focused literature review on VCP-related parkinsonism is also presented to contextualize our findings. A 76-year-old man presented with akinetic-rigid parkinsonism, myopathy, pyramidal signs, and PDB. Genetic testing identified a pathogenic VCP mutation (c.277 C > T; p.R93C). Diagnostic workup included neuroimaging, electromyography, muscle biopsy, neuropsychological assessment, bone scintigraphy, and skin biopsy, which revealed abnormal intraneural phosphorylated α-synuclein deposits. Current evidence suggests that VCP mutations may promote alpha-synuclein aggregation in a subset of patients, leading to parkinsonism. This is the first in vivo demonstration of phosphorylated α-synuclein in a MSP1 patient, reinforcing the association between VCP mutations and synucleinopathy.}, } @article {pmid40931339, year = {2025}, author = {Epplen, ASC and Rothöft, M and Stahlke, S and Theiss, C and Matschke, V}, title = {Caffeine mitigates ROS accumulation and attenuates motor neuron degeneration in the wobbler mouse model of amyotrophic lateral sclerosis.}, journal = {Cell communication and signaling : CCS}, volume = {23}, number = {1}, pages = {394}, pmid = {40931339}, issn = {1478-811X}, mesh = {Animals ; *Caffeine/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism ; *Motor Neurons/drug effects/pathology/metabolism ; Disease Models, Animal ; *Reactive Oxygen Species/metabolism ; Mice ; Oxidative Stress/drug effects ; Male ; *Neuroprotective Agents/pharmacology ; *Nerve Degeneration/pathology/drug therapy ; NAD/metabolism ; Humans ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by oxidative stress and progressive motor neuron degeneration. This study evaluates the potential neuroprotective effects of caffeine in the Wobbler mouse, an established model of ALS.

METHODS: Wobbler mice received caffeine supplementation (60 mg/kg/day) via drinking water, and key parameters, including muscle strength, NAD metabolism, oxidative stress, and motor neuron morphology, were assessed at critical disease stages.

RESULTS: Caffeine delayed motor performance decline, as observed in grip strength tests during the early symptomatic phase. Histological analyses revealed that significantly fewer motor neurons were lost in caffeine-treated mice at p41, despite no changes in soma morphology. Biochemical assays demonstrated that caffeine significantly reduced ROS levels and restored NAD levels to wildtype-like values, although NMNAT2 protein expression remained unaffected. The data suggest that caffeine mitigates oxidative stress through alternative pathways, potentially involving enhanced mitochondrial function and antioxidative defenses.

CONCLUSIONS: These findings highlight the potential of caffeine as a protective agent for delaying motor neuron degeneration in ALS. Future studies should explore optimal dosing strategies, combinatorial treatment approaches, and the underlying molecular mechanisms, to enable translation of these findings to human ALS patients.}, } @article {pmid40931498, year = {2025}, author = {Alemán-Villa, KM and Armienta-Rojas, DA and Camberos-Barraza, J and Rábago-Monzón, ÁR and Camacho-Zamora, A and Osuna-Ramos, JF and Magaña-Gómez, JA and Guadrón-Llanos, AM and Calderón-Zamora, L and Norzagaray-Valenzuela, CD and Valdez-Flores, MA and Picos-Cárdenas, VJ and De la Herrán-Arita, AK}, title = {Neuroinflammation across the Spectrum of Neurodegenerative Diseases: Mechanisms and Therapeutic Frontiers.}, journal = {Neuroimmunomodulation}, volume = {32}, number = {1}, pages = {278-305}, doi = {10.1159/000548021}, pmid = {40931498}, issn = {1423-0216}, mesh = {Humans ; *Neurodegenerative Diseases/immunology/therapy ; *Neuroinflammatory Diseases/immunology/therapy ; Animals ; *Neuroimmunomodulation/physiology ; Immunity, Innate ; Adaptive Immunity ; }, abstract = {BACKGROUND: Neuroinflammation is a central and dynamic driver in the pathophysiology of multiple neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Rather than being a mere consequence of neuronal injury, inflammatory processes, mediated by microglia, astrocytes, peripheral immune cells, and a range of molecular mediators, actively influence disease onset, progression, and clinical manifestations.

SUMMARY: This review aims to synthesize current insights into the cellular and molecular mechanisms that orchestrate neuroinflammatory responses, emphasizing both convergent and disease-specific pathways. It examines the interaction between innate and adaptive immunity in shaping neuronal vulnerability, as well as the bidirectional communication between systemic and central immune systems. Special emphasis is placed on emerging therapeutic strategies, such as immunomodulatory drugs, glial-targeted interventions, and innovative delivery platforms. The discussion integrates findings from diverse disease models and disciplines to identify translational challenges and potential paths toward precision neuroimmunology.

KEY MESSAGES: The impact of neuroinflammation arises from a complex interaction of shared and disease-specific immune pathways, with both innate and adaptive mechanisms shaping neuronal vulnerability. The crosstalk between peripheral and central immune compartments further modulates disease course, underscoring the importance of understanding these interactions in therapeutic design. While emerging strategies targeting neuroinflammation, including immunomodulatory drugs, glial-focused interventions, and novel delivery platforms, hold considerable promise, their translation into clinical benefit requires overcoming challenges in specificity, safety, and delivery. Ultimately, integrating multidisciplinary insights into immune-brain communication will be critical to advancing precision medicine approaches for neurodegenerative disorders.}, } @article {pmid40931780, year = {2025}, author = {Sabirin, W and Abd Latif, SA and Ahmad, F and Zainuddin, SI and Lam, CL and Soo, CI and Sabirin, S and Chuah, KH and Shahrizaila, N and Capelle, DP}, title = {An evaluation of the ALSSQOL-SF in the Malaysian context through cognitive interviewing.}, journal = {Neurodegenerative disease management}, volume = {15}, number = {6}, pages = {297-304}, pmid = {40931780}, issn = {1758-2032}, mesh = {Humans ; Malaysia ; *Quality of Life/psychology ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/psychology ; Aged ; Adult ; }, abstract = {BACKGROUND: Quality of life is an important goal of care for people living with amyotrophic lateral sclerosis (ALS) and their carers. The ALS Specific Quality of Life instrument Short Form (ALSSQOL-SF) has been translated and validated in various cultural contexts, however its utility in the Malaysian cultural context has not yet been evaluated.

METHODS: The quality of life of 21 patients with ALS was evaluated using the ALSSOL-SF in either the English version or translated to the Malay language. A cognitive interview approach was utilized and the responses were transcribed and thematically analyzed.

RESULTS: Culture and language-related factors affecting the application of the ALSSQOL-SF were identified. Interpretations of intimacy and religiosity varied and sometimes differed significantly from the constructs underlying the ALSSQOL-SF domains.

CONCLUSION: The ALSSQOL-SF captured items from the physical domain better than those from the psycho-social and spiritual domains. Cognitive interviewing showed that patients mostly could not grasp the intended meaning of the items from the psycho-social and spiritual domains despite translation into the Malay language. There are limitations in adapting the ALSSQOL-SF for use in evaluation of QOL in Malaysian ALS patients. In the local setting a better understanding is needed about how aspects such as religion, intimacy and spiritual well-being are culturally reflected and expressed.}, } @article {pmid40931867, year = {2026}, author = {Pavey, N and Tieppo, A and Calma, AD and Hannaford, A and Grey, E and Orden, B and Ryder, J and Lee, E and Zablotska-Manos, I and Silsby, M and Menon, P and Vucic, S}, title = {Neck flexion weakness predicts respiratory dysfunction in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {256-262}, doi = {10.1080/21678421.2025.2557939}, pmid = {40931867}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Muscle Weakness/etiology/physiopathology/diagnosis ; Aged ; Respiratory Function Tests ; Adult ; *Respiration Disorders/etiology/diagnosis/physiopathology ; Prospective Studies ; Vital Capacity/physiology ; *Neck/physiopathology ; *Neck Muscles/physiopathology ; Spirometry ; }, abstract = {Objective: Neck flexion (NF) weakness is a frequently observed clinical feature in amyotrophic lateral sclerosis (ALS), particularly in advanced disease. The aim of the present study was to assess whether NF weakness could be a clinical biomarker for development of respiratory dysfunction. Methods: Sixty-two ALS patients were prospectively recruited at Brain and Nerve Research Center. Neck flexion strength was assessed by the Medical Research Council (MRC) score and handheld dynamometry (HHD). Respiratory function testing was assessed by spirometry, including forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). Site of disease onset, disease duration, and ALSFRS-R were recorded. Results: Neck flexion weakness (MRC ≤4) was evident in 27% of ALS patients. There was a significant reduction of FVC in ALS patients with weak NF (ALSNFweakness 70.0 ± 7.2%; ALSNFnormal 86.8 ± 2.4% predicted, p = 0.038). Additionally, reduction of HHD measurements was significantly correlated with FVC (R = 0.487, p < 0.001) and FEV1 (R = 0.465, p < 0.001), and was most prominent in bulbar onset ALS (FVC: R[2] = 0.673, p = 0.002). Of relevance, the presence of NF weakness (MRC ≤ 4) was a significant predictor of reduced FVC ≤50% predicted (Chi[2] = 7.68, p = 0.006), a threshold indicating need for ventilatory support. Conclusion: Neck flexion weakness, particularly when quantified by the MRC score and HHD, serves as a marker of respiratory dysfunction in ALS patients. This simple clinical assessment may herald the development of respiratory dysfunction and requirement for respiratory ventilatory support.}, } @article {pmid40932199, year = {2026}, author = {Spittel, S and Grehl, T and Weydt, P and Kettemann, D and Fabian, R and Rödiger, A and Smesny, U and Steinbach, R and Ilse, B and Weyen, U and Petri, S and Lumi, R and Bjelica, B and Lingor, P and Grosskreutz, J and Göricke, BM and Pfeilschifter, W and Schmeja, W and Dorst, J and Mensch, A and Siebert, J and Norden, J and Bernsen, S and Subramanian, SK and Hildebrandt, B and Walter, B and Münch, C and Maier, A and Meyer, T}, title = {Dextromethorphan/quinidine (DMQ) for reducing bulbar symptoms in amyotrophic lateral sclerosis - assessment of treatment experience in a multicenter study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {185-197}, doi = {10.1080/21678421.2025.2557932}, pmid = {40932199}, issn = {2167-9223}, mesh = {Humans ; *Dextromethorphan/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; Male ; Female ; Middle Aged ; *Quinidine/therapeutic use ; Aged ; Patient Reported Outcome Measures ; Drug Combinations ; Treatment Outcome ; Patient Satisfaction ; Adult ; }, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS), dextromethorphan/quinidine (DMQ) has been reported to reduce bulbar symptoms, including dysarthria and dysphagia. However, data on patients' perceptions of DMQ treatment are limited.

METHODS: Data on DMQ treatment were collected from 1065 ALS patients treated at 13 ALS centers between 10-2015 and 06-2025. Patient-reported outcome measures (PROM) of 179 participants were remotely assessed via the "ALS App". PROM included the self-explanatory version of the ALS Functional Rating Scale (ALSFRS-R-SE), the Net Promoter Score (NPS); and Treatment Satisfaction Questionnaire for Medication (TSQM-9).

RESULTS: Mean disease duration was 29.3 months (SD 38.1). ALS progression before treatment was 0.82 points/month (ALSFRS-R). Mean DMQ treatment duration was 8.4 months (SD 10.8), including 35.2% (n = 374) of shorter (<3 months), 35.3% (n = 375) of longer (3-9 months), and 29.5% (n = 313) of very long DMQ treatment (>9 months). Patients' recommendation (n = 178) was positive (NPS: +23) with higher scores after very long DMQ treatment (NPS +37) compared to longer (NPS +15) and shorter treatment (NPS +7.5), respectively. TSQM-9 scores (n = 163) demonstrated high satisfaction for effectiveness 60.0 (SD 25.9), convenience 73.8 (SD 18.2), and global satisfaction 63.4 (SD 29.8).

INTERPRETATION: The positive perception in PROM underscores the value of DMQ as an individualized treatment option for bulbar symptoms in ALS. However, shortage of clinical data, online assessment, and selection biases are among the limitations of this study that need to be addressed in further investigations.}, } @article {pmid40933233, year = {2025}, author = {Kang, K and Nunes, AS and Potter, IY and Mishra, RK and Geronimo, A and Adams, JL and Isroff, C and Wang, JE and Vaziri, A and Wills, AM and Pantelyat, A}, title = {Digital speech assessments and machine learning for differentiation of neurodegenerative diseases.}, journal = {Clinical parkinsonism & related disorders}, volume = {13}, number = {}, pages = {100389}, pmid = {40933233}, issn = {2590-1125}, support = {P30 AG066507/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Speech impairment is a prevalent symptom of neurological disorders, including Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), with mechanisms and severity varying across and within conditions. Scalable digital health tools and machine learning (ML) are essential for diagnosing and tracking neurodegenerative disease.

METHODS: A total of 92 individuals were included in this study (21 PSP, 21 PD, 18 HD, 15 ALS, and 16 healthy elderly controls (CTR)). The Rainbow Passage was collected on a digital device and analyzed to extract 12 speech features representing speech production. A set of Elastic Net ML models was trained on these speech features to differentiate between diagnostic classes. A specialized Support Vector Machine ML model was then developed to differentiate PSP from PD.

RESULTS: Elastic Net models achieved a balanced accuracy of 77% over 5 diagnostic classes (group-specific sensitivities of 76% for PSP, 67% for PD, 83% for HD, 73% for ALS, and 88% for CTR) and 83% over 4 diagnostic classes (group-specific sensitivities of 83% for PSP-PD, 83% for HD, 73% for ALS, and 94% for CTR). The PSP vs. PD classification model demonstrated a balanced accuracy of 85%, with sensitivity of 88% for PSP and 82% for PD. Key speech features differentiated clinical conditions, with Total Voiced Time being the strongest positive feature for combined PSP-PD. In HD, ALS, and CTR, Ratio Extra Words, Pauses per Second, and Intelligibility were the most strongly differentiating features, respectively. Articulatory Rate emerged as the most distinguishing feature between PD and PSP.

CONCLUSION: Our findings highlight the potential of digital health technology and ML in identifying and monitoring speech features in neurodegenerative diseases.}, } @article {pmid40933539, year = {2026}, author = {Aban, JL and Lucero-Prisno, DE and Ogaya, JB and Ong, CJN}, title = {Beyond Anaphylaxis: The Overlooked Forensic Complexity of COVID-19-Triggered Pseudoangioedema.}, journal = {Academic forensic pathology}, volume = {16}, number = {1}, pages = {18-19}, pmid = {40933539}, issn = {1925-3621}, abstract = {Gray et al's investigation into angioedema-anaphylaxis deaths amidst the COVID-19 pandemic raises important forensic implications, particularly concerning differential diagnostics in postmortem settings (1). However, a critical avenue requiring deeper contextualization is the immunopathological intersection between SARS-CoV-2-induced mast cell activation and bradykinin-mediated pathways (2).}, } @article {pmid40933646, year = {2025}, author = {Ferguson, R and Subramanian, V}, title = {Functional variants of CFAP410 affect the DNA damage response leading to motor neuron degeneration - Implications for ALS.}, journal = {iScience}, volume = {28}, number = {9}, pages = {113338}, pmid = {40933646}, issn = {2589-0042}, abstract = {Mutations in CFAP410, a basal body protein known to be required for the formation of primary cilia, have been identified as risk modifiers in amyotrophic lateral sclerosis (ALS), a devastating late onset neurodegenerative disorder with poor prognosis. CFAP410 is also implicated in the DNA damage response and interacts with Nek1, which has been shown to be mutated in ALS. Herein, we investigated the effect of knocking in an HA epitope tag and functional mutations into the endogenous Cfap410 gene by gene editing in mouse embryonic stem cells (mESCs). We show that primary cilia in these edited mESCs, as well as in the neural progenitors and neurons differentiated from them do not exhibit any significant difference in frequency. However, ESCs, neural progenitors, and neurons with knock-in Cfap410 variants are more susceptible to DNA damage and exhibit impaired interaction with Nek1. Our findings point to DNA damage as a convergent pathway leading to ALS.}, } @article {pmid40934454, year = {2025}, author = {Chen, Y and Sun, S and Bai, Z and Gao, N and Yu, W and Sun, X and Li, W and Zhao, Y and Yan, C and Lin, P and Liu, S}, title = {CSF Aβ, Tau, Axonal, Synaptic, Glial, Neural, and Inflammatory Biomarkers in Patients With Sporadic Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {105}, number = {7}, pages = {e213914}, doi = {10.1212/WNL.0000000000213914}, pmid = {40934454}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Male ; Female ; Middle Aged ; *tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; Adult ; Axons/pathology/metabolism ; Neuroglia/pathology ; Synapses/pathology ; Neurofilament Proteins/cerebrospinal fluid ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with multifactorial pathophysiologic mechanisms, yet reliable CSF biomarkers for the diagnosis of ALS are lacking. The aim of this study was to systematically identify CSF protein alterations in patients with sporadic ALS and to develop an effective CSF protein panel to aid in ALS diagnosis.

METHODS: This observational study was conducted at Qilu Hospital, Cheeloo College of Medicine, Shandong University. Using proximity extension assay, single-molecule array, and ELISA, approximately 200 proteins involved in different pathogenic events, including axonal damage, neuronal damage, glial responses, synaptic dysfunction, β-amyloid (Aβ) pathology, tau pathology, and neuroinflammation, were measured in the CSF. Moreover, Xtreme gradient boosting and logistic regression models were applied to develop a CSF protein panel to distinguish patients with sporadic ALS from disease controls (DCs), and the diagnostic performance was verified in an independent cohort.

RESULTS: A total of 180 participants were included, comprising 109 patients with sporadic ALS (mean age 56.7 ± 11.9 years, 58.7% male), 30 DCs (56.9 ± 12.6 years, 56.7% male), and 41 healthy controls (HCs, 57.1 ± 12.4 years, 63.4% male). Compared with HCs, patients with ALS had significantly elevated CSF levels of neurofilament light chain, chitinase proteins including chitotriosidase (CHIT1), and 55 other proteins, whereas CSF Aβ40, Aβ42, and GAP43 levels were significantly lower. Moreover, we identified a 3-protein CSF panel (CHIT1, N-CDase, and PDGF-R-alpha) that effectively distinguished patients with ALS from DCs, achieving an area under the curve of 0.927 (95% CI 0.883-0.971) in the original cohort and 0.912 (95% CI 0.841-0.985) in the replication cohort.

DISCUSSION: Using a combined approach, we comprehensively investigated CSF protein alterations in a cohort of newly diagnosed patients with ALS and provided further in vivo evidence supporting the presence of mixed copathologies in patients with ALS. Moreover, we developed a 3-protein CSF biomarker panel that effectively distinguished patients with ALS from DCs and validated its performance in an independent cohort. However, considering the relatively small cohort and lack of multiple comparison adjustments, further validation in larger, multicenter studies is warranted.}, } @article {pmid40934740, year = {2025}, author = {Omidbakhsh, S and Tankisi, H}, title = {Effect of reference electrode position on diagnostic accuracy of split hand index in ALS.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {55}, number = {5}, pages = {103101}, doi = {10.1016/j.neucli.2025.103101}, pmid = {40934740}, issn = {1769-7131}, } @article {pmid40935037, year = {2025}, author = {Wang, C and Liu, L and Liu, Y and Wei, Y and Wang, M and Huang, Y and Li, K and Lu, Q}, title = {Deep eutectic solvents-assisted alkali lignin modification for pyrolytic monophenols production.}, journal = {International journal of biological macromolecules}, volume = {328}, number = {Pt 1}, pages = {147584}, doi = {10.1016/j.ijbiomac.2025.147584}, pmid = {40935037}, issn = {1879-0003}, mesh = {*Lignin/chemistry ; *Deep Eutectic Solvents/chemistry ; *Phenols/chemistry/chemical synthesis ; *Alkalies/chemistry ; *Pyrolysis ; }, abstract = {The efficient valorization of alkali lignin (AL) remains a significant challenge due to the multiple impurities and complex structure of AL. Lignin modification through deep eutectic solvent (DES) and subsequent fast pyrolysis offers a promising alternative for AL valorization. Thus, this study comprehensively investigated the potential of DES-pretreated ALs (DESALs) for producing pyrolytic monophenols, with particular focus on the modification process of AL during DES pretreatment, the interaction of lignin-DES, and the techno-economic feasibility of the integrated technology. Notably, under optimal experimental conditions, the ChCl/ethylene glycol (CCEG) system demonstrated the greatest potential to enhance the yields of 4-vinyl syringol (4VS) and 4-propenyl syringol (4PS) to 12.09 wt%, achieving a selectivity of 40.60 %, without using a catalyst. Moreover, multiscale simulations were performed to illustrate the enhancement effect of DESs on the production of pyrolytic monophenols. The CCEG system exhibited the lowest |HOMO-LUMO| energy gap (161.80 kcal/mol) and the highest interaction energy (-56.56 kcal/mol). The chloride ions played an integral role in forming robust hydrogen bonds between CC and EG. Further investigation indicated that the adduct and acetal structures were synthesized, and their formation pathways were subsequently modeled. Finally, the CCEG system exhibited a negligible environmental impact and high economic feasibility.}, } @article {pmid40935268, year = {2025}, author = {Bonares, MJ and Shapiro, J and Vijayanathan, V and Abrahao, A and Zinman, L and Lau, C}, title = {Goal-Concordant Care in People With Amyotrophic Lateral Sclerosis Receiving Palliative Care.}, journal = {Journal of pain and symptom management}, volume = {70}, number = {6}, pages = {679-690}, doi = {10.1016/j.jpainsymman.2025.08.046}, pmid = {40935268}, issn = {1873-6513}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/mortality/psychology ; *Palliative Care/psychology ; Female ; Male ; Aged ; Retrospective Studies ; Middle Aged ; *Terminal Care ; *Patient Preference ; Aged, 80 and over ; Goals ; }, abstract = {CONTEXT: Although it is known where people with amyotrophic lateral sclerosis (ALS) are dying, less is known about whether they are dying where they want to.

OBJECTIVES: To determine the rate of dying in a preferred place and factors associated with doing so in people with ALS receiving clinic-based specialist palliative care.

METHODS: Retrospective cohort study of people with ALS receiving clinic-based specialist palliative care in Toronto, Canada between July 2022 and February 2024. Association between preferred and actual place of death was determined using a χ[2] test. Factors associated with dying in a preferred place were determined using a multivariable binary logistic regression analysis.

RESULTS: In 367 individuals, at time of consultation, median age was 67 years; 60.8% had a Palliative Performance Scale score between 50% and 60%, and 43.3% had noninvasive ventilation. Mortality rate up to February 2024 was 41.7%. About 85.4% stated a preference to die at home, 8.7% in hospital, and 5.9% in a hospice facility, whereas 54.9% died at home, 34% in hospital, and 11.1% in a hospice facility. Of those with known preferred and actual place of death, 70.1% died in a preferred place (χ[2] = 36.2; P < 0.001). Dying in a preferred place was associated with increasing age (odds ratio [OR] = 1.1; 95% confidence interval [CI] = 1.0-1.1) and having noninvasive ventilation (OR = 2.5; 95% CI = 1.0-6.2).

CONCLUSION: Younger age and not having noninvasive ventilation at the time of consultation may suggest a higher risk of goal-discordant end-of-life care and the need to engage in early future planning when these factors are identified.}, } @article {pmid40938039, year = {2025}, author = {Baroni, A and Moulton, C and Cristina, M and Sansone, L and Belli, M and Tasciotti, E}, title = {Nano- and Microplastics in the Brain: An Emerging Threat to Neural Health.}, journal = {Nanomaterials (Basel, Switzerland)}, volume = {15}, number = {17}, pages = {}, pmid = {40938039}, issn = {2079-4991}, support = {[Ricerca corrente]//Italian Ministry of Health/ ; }, abstract = {Nano- and microplastics (NMPs), with nanoplastics posing higher risks due to their smaller size and greater capacity for cellular and subcellular penetration, are being referred to as ubiquitous environmental neurotoxicants, due to their ability to pass through biological barriers, including the blood-brain barrier (BBB) and nasal olfactory epithelium, and to remain lodged in neural tissue. Upon uptake, such particles disturb neuronal homeostasis by multiple converging pathways, including oxidative stress, mitochondrial dysfunction, pathological protein aggregation, and chronic neuroinflammation, all closely involved with the molecular signatures of neurodegenerative disorders (Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis-ALS). In addition to their neurotoxicity, recent findings suggest that NMPs could disturb synaptic communication and neuroplasticity, thereby compromising the brain's capacity to recover from an injury, a trauma, or neurodegeneration, thus impacting the progression of the disease, our ability to treat it and eventually the efficacy of rehabilitation approaches. Despite these findings, our understanding remains hampered by analytical issues, the scarcity of standard detection methods, and a total lack of longitudinal studies in humans. This review combines multidisciplinary evidence on brain-plastic interactions and calls for accelerated advances in our ability to monitor bioaccumulation in humans, and to integrate neurotoxicology paradigms in the assessment of this underappreciated but growing threat to brain health.}, } @article {pmid40938412, year = {2026}, author = {Cantré, D and König, J and Makowsky, C and Dyrba, M and Prudlo, J}, title = {Midsagittal Midbrain Area and Midbrain-to-Pons-Ratio Cannot Distinguish Overlap Syndromes Between Amyotrophic Lateral Sclerosis and Progressive Supranuclear Palsy.}, journal = {Clinical neuroradiology}, volume = {36}, number = {1}, pages = {161-168}, pmid = {40938412}, issn = {1869-1447}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Supranuclear Palsy, Progressive/diagnostic imaging/pathology ; Diagnosis, Differential ; Male ; Female ; *Mesencephalon/diagnostic imaging/pathology ; Aged ; Middle Aged ; *Magnetic Resonance Imaging/methods ; *Pons/diagnostic imaging/pathology ; Sensitivity and Specificity ; }, abstract = {PURPOSE: When amyotrophic lateral sclerosis (ALS), a TDP-43 proteinopathy, and progressive supranuclear palsy (PSP), a tauopathy, are associated with frontotemporal dementia (ALS-FTD or PSP-FTD), clinical differentiation can be challenging. There are no established imaging biomarkers to differentiate ALS-FTD from PSP-FTD.

METHODS: We evaluated the midsagittal midbrain area (MBA) and the midbrain-to-pons-(MB/P)-ratios in T1 MPRAGE MRI of 36 PSP cases (n = 14 PSP-FTD), 77 ALS cases (n = 10 ALS-FTD), and 72 healthy controls (HC).

RESULTS: In ALS, both parameters were indistinguishable from HC. Patients with ALS-FTD had low MBA-values and MB/P-ratios not significantly different from cases of PSP. While ROC-analyses provided an excellent diagnostic accuracy of both parameters for differentiating PSP from HC (AUCMBA = 0.974) as well as PSP from ALS (AUCMBA = 0.982), midbrain morphometry provided poor diagnostic accuracy for distinguishing ALS-FTD from PSP-FTD (AUCMBA = 0,614).

CONCLUSION: The MBA and the MB/P-ratio are morphometric parameters that have proven reliable in atypical Parkinsonian syndromes. Both can distinguish between PSP and ALS in their typical clinical forms. However, they cannot differentiate between PSP-FTD and ALS-FTD.}, } @article {pmid40939256, year = {2025}, author = {Novo-Rigueiro, M and Crespo-De, A and Antelo-Pose, A and Novo-Veleiro, I}, title = {[Shoulder pain as a preceding symptom in amyotrophic lateral sclerosis: A retrospective descriptive and exploratory study].}, journal = {Rehabilitacion}, volume = {59}, number = {4}, pages = {100932}, doi = {10.1016/j.rh.2025.100932}, pmid = {40939256}, issn = {1578-3278}, } @article {pmid40940222, year = {2025}, author = {Poulin-Brière, A and Pozzi, S and Julien, JP}, title = {Antibody targeting TDP-43 mitigates pathogenic pathways induced by the cerebrospinal fluid of ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {22}, number = {6}, pages = {e00737}, pmid = {40940222}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/pathology/drug therapy/immunology/genetics ; Mice, Transgenic ; Humans ; Mice ; *DNA-Binding Proteins/immunology/genetics/metabolism ; *Antibodies, Monoclonal/administration & dosage/therapeutic use ; Male ; Disease Models, Animal ; Female ; Spinal Cord/pathology ; Motor Neurons/pathology/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the cytoplasmic mislocalization and accumulation of TAR DNA binding protein 43 (TDP-43). We reported previously the protective effects in a transgenic mouse model expressing ALS-linked mutant TDP-43[A315T] of a monoclonal antibody, called E6, binding specifically to the RNA Recognition Motif 1 (RRM1) domain of TDP-43. Here, we tested the effects of E6 antibody in an animal model of sporadic ALS based on the intracerebroventricular (i.c.v.) infusion during 14 days of cerebrospinal fluid (CSF) from sporadic ALS patients into transgenic mice expressing human TDP-43[WT]. Either intrathecal (i.t.) or i.c.v. injection of E6 antibody conferred protective effects in this model of disease. Thus, the CSF-inoculated E6 antibody reduced motor and cognitive impairments, mitigated TDP-43 proteinopathy and prevented neurofilament (Nf) disorganization in cortical and spinal neurons. Administration of E6 antibody reduced the loss of motor neurons in the spinal cord and the denervation of neuromuscular junctions. Moreover, E6 antibody promoted a switch toward features associated with a protective phenotype of microglial activation characterized by enhanced phagocytic function and reduced secretion of pro-inflammatory cytokines. The results suggest that an immunotherapy targeting the RRM1 domain of TDP-43 may confer protection against pathogenic pathways triggered by the CSF of ALS patients.}, } @article {pmid40940730, year = {2025}, author = {Graber, DJ and Cook, WJ and Sentman, ML and Murad-Mabaera, JM and Stommel, EW and Sentman, CL}, title = {Human CAR Tregs Targeting SOD1 and Expressing BDNF Reduce Inflammation and Delay Disease in G93A hSOD1-NSG Mice.}, journal = {Cells}, volume = {14}, number = {17}, pages = {}, pmid = {40940730}, issn = {2073-4409}, support = {P30 CA023108/CA/NCI NIH HHS/United States ; R44 NS132666/NS/NINDS NIH HHS/United States ; NS117895//NIH NINDS/ ; R21 NS102556/NS/NINDS NIH HHS/United States ; R21 NS117895/NS/NINDS NIH HHS/United States ; NS102556,//NIH NINDS/ ; NS132666//NIH NINDS/ ; }, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; Humans ; *Superoxide Dismutase-1/metabolism/genetics/immunology ; *T-Lymphocytes, Regulatory/immunology/metabolism ; Mice ; *Amyotrophic Lateral Sclerosis/immunology/pathology/genetics/therapy ; Mice, Transgenic ; *Inflammation/pathology ; *Receptors, Chimeric Antigen/metabolism/immunology ; Disease Models, Animal ; }, abstract = {Regulatory T cells (Tregs) have anti-inflammatory immunomodulatory activity and hold therapeutic potential for chronic neuroinflammatory neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). We are developing engineered human Tregs with enhanced disease-modifying activity for treating ALS. A combination of a disease-specific chimeric antigen receptor (CAR) recognizing misfolded human superoxide dismutase-1 (hSOD1) and constitutive expression of brain-derived neurotrophic factor (BDNF) was tested. The scFv region of CAR demonstrated binding to anterior horn tissues of ALS patients with and without familial ALS mutations in SOD1. Tregs transduced to express BDNF showed the ability to secrete BDNF and protect co-cultured neuronal cells from peroxidase toxicity. Co-expression of BDNF did not inhibit CAR Treg expansion, Treg markers, or CAR-mediated anti-inflammatory cytokine production. Human Tregs co-expressing CAR and BDNF were tested for activity in G93A hSOD1-NSG transgenic mice, which develop an early-onset and aggressive ALS-like disease and do not reject human cells. Human Tregs expressing CAR and BDNF delayed the onset of disease development, extended survival, and decreased spinal cord neuroinflammation. The engineered Tregs showed enhanced disease-modifying activity and hold promise as a therapy for ALS.}, } @article {pmid40940752, year = {2025}, author = {Lee, JH and Chang, W and Min, SS and Song, DY and Yoo, HI}, title = {Beyond Support Cells: Astrocytic Autophagy as a Central Regulator of CNS Homeostasis and Neurodegenerative Diseases.}, journal = {Cells}, volume = {14}, number = {17}, pages = {}, pmid = {40940752}, issn = {2073-4409}, support = {2023//Eulji University/ ; RS-2024-00438628//Korea Health Industry Development Institute/Republic of Korea ; }, mesh = {Humans ; *Autophagy ; *Neurodegenerative Diseases/pathology/metabolism ; *Astrocytes/metabolism/pathology ; *Homeostasis ; Animals ; *Central Nervous System/pathology/metabolism ; }, abstract = {Autophagy is a fundamental catabolic pathway critical for maintaining cellular homeostasis in the central nervous system (CNS). While neuronal autophagy has been extensively studied, growing evidence highlights the crucial roles of astrocytic autophagy in CNS physiology and pathology. Astrocytes regulate metabolic support, redox balance, and neuroinflammatory responses. These functions are closely linked to autophagic activity. The disruption of astrocytic autophagy contributes to synaptic dysfunction, chronic inflammation, myelin impairment, and blood-brain barrier instability. Dysregulation of astrocytic autophagy has been implicated in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This review summarizes the molecular mechanisms of autophagy in astrocytes and delineates its role in intercellular communication with neurons, microglia, oligodendrocytes, and endothelial cells. Furthermore, we will discuss current pharmacological approaches targeting astrocytic autophagy, with particular attention to repurposed agents such as rapamycin, lithium, and caloric restriction mimetics. Although promising in preclinical models, therapeutic translation is challenged by the complexity of autophagy's dual roles and cell-type specificity. A deeper understanding of astrocytic autophagy and its crosstalk with other CNS cell types may facilitate the development of targeted interventions for neurodegenerative diseases.}, } @article {pmid40940798, year = {2025}, author = {Li, L and Zheng, X and Ma, H and Zhu, M and Li, X and Sun, X and Feng, X}, title = {TREM2 in Neurodegenerative Diseases: Mechanisms and Therapeutic Potential.}, journal = {Cells}, volume = {14}, number = {17}, pages = {}, pmid = {40940798}, issn = {2073-4409}, mesh = {Humans ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Microglia/metabolism ; Phagocytosis ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), represent significant global health challenges, affecting millions and straining healthcare systems. These disorders involve progressive neuronal loss and cognitive decline, with incompletely elucidated underlying mechanisms. Chronic neuroinflammation is increasingly recognized as a critical contributor to disease progression. The brain's resident immune cells, microglia, are central to this inflammatory response. When overactivated, microglia and other immune cells, such as peripheral macrophages, can exacerbate inflammation and accelerate disease development. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily that demonstrates high expression on microglia in the central nervous system. TREM2 serves a vital role in regulating phagocytosis, synaptic pruning, and energy metabolism. This review examines the functions of TREM2 in neurodegenerative diseases and its potential as a therapeutic target, aiming to inform future treatment strategies.}, } @article {pmid40943143, year = {2025}, author = {Calcagnile, M and Alifano, P and Damiano, F and Pontieri, P and Del Giudice, L}, title = {A Perspective on the Role of Mitochondrial Biomolecular Condensates (mtBCs) in Neurodegenerative Diseases and Evolutionary Links to Bacterial BCs.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943143}, issn = {1422-0067}, support = {project 'NutrAge' (project nr. 7022)//CNR-DISBA/ ; FOE-2019 DBA.AD003.139//CNR/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism ; *Biomolecular Condensates/metabolism ; Animals ; Intrinsically Disordered Proteins/metabolism ; Mitochondrial Proteins/metabolism ; *Bacteria/metabolism ; }, abstract = {Biomolecular condensates (BCs), formed through liquid-liquid phase separation (LLPS), are membraneless compartments that dynamically regulate key cellular processes. Beyond their canonical roles in energy metabolism and apoptosis, Mitochondria harbor distinct BCs, including mitochondrial RNA granules (MRGs), nucleoids, and degradasomes, that coordinate RNA processing, genome maintenance, and protein homeostasis. These structures rely heavily on proteins with intrinsically disordered regions (IDRs), which facilitate the transient and multivalent interactions necessary for LLPS. In this review, we explore the composition and function of mitochondrial BCs and their emerging involvement in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Huntington's disease. We provide computational evidence identifying IDR-containing proteins within the mitochondrial proteome and demonstrate their enrichment in BC-related functions. Many of these proteins are also implicated in mitochondrial stress responses, apoptosis, and pathways associated with neurodegeneration. Moreover, the evolutionary conservation of phase-separating proteins from bacteria to mitochondria underscores the ancient origin of LLPS-mediated compartmentalization. Comparative analysis reveals functional parallels between mitochondrial and prokaryotic IDPs, supporting the use of bacterial models to study mitochondrial condensates. Overall, this review underscores the critical role of mitochondrial BCs in health and disease and highlights the potential of targeting LLPS mechanisms in the development of therapeutic strategies.}, } @article {pmid40943213, year = {2025}, author = {Liu, D and Yu, S and Ji, B and Peng, Q and Gao, J and Zhang, J and Guo, Y and Hu, M}, title = {Molecular Mechanisms of Herbicide Resistance in Rapeseed: Current Status and Future Prospects for Resistant Germplasm Development.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943213}, issn = {1422-0067}, support = {2023ZD0404203//Science and Technology Innovation 2030 Major Program/ ; 31901503//National Natural Science Foundation of China/ ; CARS-12//Agriculture Research System of China/ ; CX (23) 1001//Jiangsu Provincial Agricultural Science and Technology Independent Innovation Fund/ ; BE2021405//Jiangsu Province Key Research and Development Project/ ; }, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Brassica napus/genetics/drug effects ; Acetolactate Synthase/antagonists & inhibitors ; Plant Breeding/methods ; Plant Proteins/genetics ; Glycine/analogs & derivatives/pharmacology ; Gene Editing ; }, abstract = {Rapeseed (Brassica napus) is a globally important oilseed crop whose yield and quality are frequently limited by weed competition. In recent years, there have been significant advances in our understanding of herbicide-resistance mechanisms in rapeseed and in the development of herbicide-resistant rapeseed germplasm. Here, we summarize the molecular mechanisms of resistance to three herbicides: glyphosate, glufosinate, and acetolactate synthase (ALS) inhibitors. We discuss progress in the identification of new resistance genes and the development of herbicide-resistant rapeseed germplasm, from the initial identification of natural mutants to artificial mutagenesis screening, introduction of exogenous resistance genes, and gene editing. In addition, we describe how synthetic biology and directed protein evolution will contribute to precision-breeding efforts in the near future. This is the first review to systematically integrate non-target resistance mechanisms and the potential applications of multi-omics and AI technologies for breeding of herbicide-resistant rapeseed, together with strategies for managing the risks associated with gene flow, the evolution of herbicide-resistant weeds, and the occurrence of volunteer plants resulting from deployment of herbicide-resistant rapeseed. By synthesizing current knowledge and future trends, this review provides guidance for safe, effective, and innovative approaches to the sustainable development of herbicide-resistant rapeseed.}, } @article {pmid40943341, year = {2025}, author = {Yang, EJ}, title = {The Emerging Role of the Brain-Gut Axis in Amyotrophic Lateral Sclerosis: Pathogenesis, Mechanisms, and Therapeutic Perspectives.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943341}, issn = {1422-0067}, support = {(KIOM) KSN2224011//KIOM/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/microbiology/etiology/metabolism/pathology ; *Gastrointestinal Microbiome ; *Brain/metabolism ; Dysbiosis/microbiology/complications ; Animals ; *Brain-Gut Axis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Although genetic and environmental factors are established contributors, recent research has highlighted the critical role of the gut-brain axis (GBA) in ALS pathogenesis. The GBA is a bidirectional communication network involving neural, immune, and endocrine pathways that connect the gut microbiota with the central nervous system. Dysbiosis in ALS disrupts this axis, leading to increased intestinal permeability, neuroinflammation, and excitotoxicity. Notably, reductions in butyrate-producing bacteria, alterations in microbial metabolites, and enhanced NLRP3 inflammasome activation have been observed in patients with ALS. These changes may precede motor symptoms, suggesting a potential causative role. Interventions targeting the microbiome, such as dietary modulation, have shown promise in delaying disease onset and reducing inflammation. However, the clinical evidence remains limited. Given that gut dysbiosis may precede neurological symptoms, microbiota-targeted therapies offer a novel and potentially modifiable approach to ALS treatment. Understanding the role of GBA in ALS will open new avenues for early diagnosis and intervention. Further clinical trials are required to clarify the causal links and evaluate the efficacy of microbiome-based interventions. Understanding the brain-gut-microbiota axis in ALS could lead to new diagnostic biomarkers and therapeutic strategies.}, } @article {pmid40943639, year = {2025}, author = {Paniagua-Contreras, GL and Cano-Kobayashi, A and Fernández-Presas, AM and Ruíz-De la Cruz, M and Martínez-Gregorio, H and Vaca-Paniagua, F and Monroy-Pérez, E}, title = {Candida albicans Associated with Periodontal Disease Exhibits Different Clusters of Adhesion Gene and Protease Expression.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943639}, issn = {1422-0067}, mesh = {Humans ; *Candida albicans/genetics/isolation & purification/pathogenicity ; *Periodontal Diseases/microbiology ; *Fungal Proteins/genetics/metabolism ; Gene Expression Regulation, Fungal ; Male ; Adult ; Middle Aged ; Female ; Fibroblasts/microbiology ; }, abstract = {C. albicans has recently been described as a secondary colonizer associated with periodontal infections. This study aimed to determine the expression patterns of ALS and SAP family genes in C. albicans strains isolated from patients with periodontal disease (n = 268), and a control group of healthy individuals without any clinical signs of periodontal disease (n = 100) was included. C. albicans and the ALS and SAP genes were identified using polymerase chain reaction (PCR). An in vitro infection model was used with the strains using the human gingival fibroblast cell line. RNA was extracted using a QIAcube robotic workstation (Qiagen). A QuantiTect Reverse Transcription Kit (Qiagen) was used for first-strand cDNA synthesis. ALS and SAP gene expression in the strains was determined using real-time PCR. A total of 82.5% (n = 66) of the C. albicans strains were isolated from patients with moderate periodontitis, 10% (n = 8) from patients with chronic periodontitis, and 7.5% (n = 6) from patients with gingivitis. In the group of healthy individuals, C. albicans was identified in 9% (9/100). Overall, the most frequently expressed ALS genes in the strains from the three diagnoses were ALS1 (77/80), ALS3 (67/80), ALS4 (67/80), ALS6 (77/80), ALS7 (62/80), and ALS9 (73/80), while the most frequently expressed SAP genes were SAP1 (76/80), SAP6 (57/80), SAP9 (78/80), and SAP10 (77/80). The overall frequencies of expression of the ALS4, ALS9, SAP2, SAP3, SAP6, and SAP genes in the strains were statistically different across the three diagnoses. We identified different profiles of expression of the ALS and SAP genes in the strains of C. albicans that contribute directly to the degree of periodontal disease. Therefore, our findings may contribute to improving our knowledge of the molecular mechanisms of C. albicans in the pathogenesis of periodontal disease.}, } @article {pmid40943950, year = {2025}, author = {Pochhammer, J and Kiani, S and Hobbensiefken, H and Hobbensiefken, H and Reichert, B and Taivankhuu, T and Becker, T and Gundlach, JP}, title = {Lactate in Drainage Fluid to Predict Complications in Robotic Esophagectomies-A Pilot Study in a Matched Cohort.}, journal = {Journal of clinical medicine}, volume = {14}, number = {17}, pages = {}, pmid = {40943950}, issn = {2077-0383}, abstract = {Background/Objectives: Despite advances in minimally invasive procedures, anastomotic leakages (ALs) after esophageal resections mark the most feared complication. Its early detection can lead to quick interventional treatment with improved survival. Nonetheless, early detection remains challenging, and scores are imprecise and complex. Methods: In our study we analyzed mediastinal drainage fluid to find parameters suggesting AL even before it became clinically evident and correlated them to routine biomarkers. All patients with AL after robotically assisted esophageal resections were included and matched 1:1 with uneventful controls. Additionally, transhiatal distal esophageal resections operated during this period were included. Drainage fluid was collected on postoperative days (PODs) 1-4 with consecutive blood gas analysis. Test quality was determined by the area under the curve (AUC) of the receiver operating characteristic curve (ROC). Results: In total, 40 patients were included, with 17 developing AL. There were no significant differences in gender, age, BMI or oncological treatment. The 30-day morbidity rate was 65.0%. The study was restricted to events in the first 12 days. While lactate value in drainage fluid differed significantly from POD 3 onwards in the two groups, serum CRP remained without significant differences. We developed the LacCRP score (CRP/30 + lactate/2). The AUC on POD 3 was 0.96, with a sensitivity and specificity of 100% and 75%, respectively. An estimator of 1.08 was found in multivariate analysis: one-point increase in the LacCRP score increases AL probability by 8%. Conclusions: This study demonstrates that postoperative lactate determinations in drainage fluid can predict AL after esophageal resection, and its combination with serum CRP results in a reliable LacCRP score.}, } @article {pmid40944442, year = {2026}, author = {Brown, A and Stubberfield, C and Vieira, F and Bedlack, R}, title = {Examining IGFBP7 as a potential therapeutic target in people with ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {477-480}, doi = {10.1080/21678421.2025.2559441}, pmid = {40944442}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Insulin-Like Growth Factor Binding Proteins/genetics/metabolism ; Male ; Female ; Middle Aged ; Aged ; Spinal Cord/metabolism/pathology ; Motor Neurons/metabolism ; RNA, Messenger/metabolism ; Polymorphism, Single Nucleotide/genetics ; }, abstract = {A single nucleotide variant in an insulin-like growth factor (IGFBP7) promotor, which reduces IGFBP7 levels in brain, was previously associated with an ALS "reversal" phenotype. This raises the question of whether IGFBP7 might be a therapeutic target in ALS. Here, we use a combinatorial analysis to show that IGFBP7-Antisense (AS1) is associated with resistance to ALS. In ALS patients' blood, we demonstrate increased IGFPB7 protein relative to healthy controls. In ALS patients' spinal cords and iPS-derived motor neurons, we demonstrate increased IGFBP7 mRNA levels relative to healthy controls. These four new analyses support IGFBP7 as a possible therapeutic target in ALS.}, } @article {pmid40944932, year = {2026}, author = {Drouin, E and Hautecoeur, P and Kwiatkowski, A}, title = {Jean-Martin Charcot and the Clinical Foundations of Amyotrophic Lateral Sclerosis: A Historical Case Revisited.}, journal = {European neurology}, volume = {89}, number = {2}, pages = {97-101}, doi = {10.1159/000548249}, pmid = {40944932}, issn = {1421-9913}, mesh = {*Amyotrophic Lateral Sclerosis/history/pathology/diagnosis ; Humans ; History, 19th Century ; Middle Aged ; Male ; *Neurology/history ; }, abstract = {This article revisits an original case of bulbar-onset amyotrophic lateral sclerosis (ALS) recorded by Jean-Martin Charcot in 1877-78, highlighting his clinical methodology and its enduring significance. The case of Eugénie Florentine P., a 62-year-old patient at the Salpêtrière, illustrates Charcot's rigorous approach: precise observation of clinical signs, longitudinal documentation of disease progression, and anatomoclinical correlation confirmed by autopsy findings. Charcot identified the combined role of anterior horn and lateral column lesions, establishing ALS as a distinct nosological entity. While predecessors such as Aran, Cruveilhier, and Duchenne contributed key observations, Charcot synthesized clinical and pathological data to define the disease later known as "Charcot's disease." This historical perspective underscores the lasting value of bedside examination in an era dominated by neuroimaging and biomarkers. By comparing 19th-century clinical reasoning with current diagnostic and therapeutic challenges, the article demonstrates how Charcot's work continues to inform the modern multidisciplinary management of ALS.}, } @article {pmid40945542, year = {2025}, author = {Kollstrøm, AM and Grønlie, MB and Christiansen, N and Sandvig, A and Sandvig, I}, title = {Induced long-term potentiation improves synaptic stability and restores network function in ALS motor neurons.}, journal = {Neurobiology of disease}, volume = {216}, number = {}, pages = {107077}, doi = {10.1016/j.nbd.2025.107077}, pmid = {40945542}, issn = {1095-953X}, support = {//Olav Thon Foundation,/ ; //Alf Harborgs fund, ALS Norge, and the Central Norway Regional Health Authority/ ; //Norwegian University of Science and Technology/ ; //National Network of Advanced Proteomics Infrastructure/ ; //Norwegian University of Science and Technology/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology/metabolism ; *Motor Neurons/drug effects/physiology/pathology ; Humans ; *Synapses/drug effects/physiology ; *Long-Term Potentiation/physiology/drug effects ; Male ; Tetraethylammonium/pharmacology ; *Nerve Net/drug effects/physiopathology ; Female ; Potassium Channel Blockers/pharmacology ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing progressive dysfunction and degeneration of upper and lower motor neurons. An increasing body of evidence has identified synaptic alterations in patients and experimental models of ALS. Importantly, these have been associated with functional impairments in motor neuron networks, suggesting that synaptic impairments are early events in the disease cascade resulting in functional compensatory reconfigurations. The synapse may therefore represent a disease-modifying target to delay disease progression. In this study, we aimed to stabilize synapses and modify structural connectivity to restore network balance in ALS patient-derived motor neuron networks. To this end, we blocked the potassium channels using tetraethylammonium (TEA) which has been shown to induce chemical long-term potentiation (cLTP). The unperturbed ALS patient-derived motor neuron networks developed clear signs of subtle network dysfunction, including increased firing rate and bursting, and accompanying structural abnormalities. These features were partially restored by temporarily blocking the potassium channels. Specifically, the TEA-treated ALS networks were characterized by a reduction in aberrant branching and stabilization of dendritic spines, alongside a temporary reduction in firing rate and bursting. Furthermore, protein expression assays revealed restoration of dysregulated molecular pathways, including protein synthesis and metabolic pathways, and upregulation of pathways involved in synapse organization in the TEA-treated ALS networks. This is one of the first studies to integrate synaptic potentiation, proteomics, and functional network analysis of human ALS motor neurons. Collectively, these findings improve our understanding of the association between synaptic impairments and functional alterations in ALS, and demonstrate the therapeutic potential of targeting neuronal excitability and plasticity to promote network balance.}, } @article {pmid40946250, year = {2025}, author = {Zhu, J and Zhang, Y and Hu, S and He, X and Hong, X and Wei, W and Shu, S and Zhou, H and Yang, G and Zhang, H}, title = {Evaluating the predictive potential of Th1 (IFN-γ[+]CD4[+])/CD4[+] in rapidly progressive amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {9}, pages = {631}, pmid = {40946250}, issn = {1432-1459}, support = {2025HZZD09//The Construction Fund of Key Medical Disciplines of Hangzhou - Rare Disease (Motor Neuron Disease)/ ; 2025KY1187//Zhejiang Provincial Medical and Health Science and Technology Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/blood/immunology ; Male ; Female ; Middle Aged ; Disease Progression ; *Th1 Cells/immunology/metabolism ; Aged ; Machine Learning ; *CD4-Positive T-Lymphocytes/metabolism ; *Interferon-gamma/blood ; Adult ; }, abstract = {BACKGROUND: Th1 (IFN-γ[+]CD4[+])/CD4[+] cells exacerbate the release of pro-inflammatory cytokines, contributing to neuronal death. It is proposed that the peripheral immune system plays a pivotal role in the pathophysiology of amyotrophic lateral sclerosis (ALS). This study aims to develop an interpretable machine learning model based on blood Th1/CD4[+] cells to predict rapidly progressive ALS.

METHODS: We enrolled 564 patients with sporadic ALS who met the eligibility inclusion criteria for further analysis. Immune cells and cytokines were quantified using flow cytometric cell counting and a flow cytometry-based fluorescent bead capture assay. Multivariate Cox proportional hazards models and restricted cubic spline analyses were applied to estimate the correlation between Th1/CD4[+] cells and rapidly progressive ALS. The important variables identified through LASSO regression analysis were incorporated into the development of the machine learning model.

RESULTS: The multivariate Cox proportional hazards model revealed that, compared to the low Th1/CD4[+] group (Th1/CD4[+]  < 16.21), the high Th1/CD4[+] group (Th1/CD4[+]  ≥ 16.21) was positively associated with the rate of ALS progression (HR: 1.90, 95% CI: 1.34-2.70). Th1/CD4[+] is also associated with the decline in forced vital capacity (r = 0.11, P = 0.01). The machine learning model was built using Th1/CD4[+] in combination with the other 4 features. Xgboost performed best in the validation cohort, achieving an AUC of 0.804 and a G mean of 0.756.

CONCLUSIONS: Th1/CD4[+] (with an optimal cutoff value of 16.21) was established as an independent risk factor for rapid progression in ALS. The machine learning model incorporating Th1/CD4[+] demonstrated strong predictive performance.

TRIAL REGISTRATION: The prospective cohort study is registered with the Chinese Clinical Trial Registry (ID: ChiCTR2400079885) (http://www.chictr.org.cn/).}, } @article {pmid40947692, year = {2025}, author = {Manubolu, K and Peeriga, R}, title = {Revolutionizing Neurodegenerative Disease Management: The Synergy of AI and Pharmacy.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098375978250820220024}, pmid = {40947692}, issn = {1874-6128}, abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS), represent major healthcare challenges worldwide. Despite advances in diagnosis and treatment, these conditions remain incurable, and there is a need for more effective management strategies. The integration of artificial intelligence (AI) in healthcare has emerged as a promising solution, offering new approaches to diagnosis, personalized treatment, and patient care. This paper explores the potential of AI to revolutionize the management of neurodegenerative diseases, with a focus on its synergistic role in pharmacy. By leveraging AI in drug discovery, personalized treatment plans, and clinical decision-making, AI can enhance therapeutic outcomes and improve patient quality of life. The study reviews the current landscape of AI applications in neurodegenerative disease management, with a focus on pharmacy-related interventions. The review includes AI-driven approaches in genomics, biomarkers, drug repurposing, and clinical trials. It also examines AI's role in optimizing pharmaceutical care, improving medication adherence, and tailoring treatments based on individual genetic profiles. AI has demonstrated its capability to analyze vast datasets, from genetic information to clinical records, to identify novel drug targets and predict patient responses to specific therapies. The use of AI in precision medicine has enabled more accurate diagnosis and has facilitated the development of personalized treatments for neurodegenerative diseases. Additionally, AI tools are enhancing medication management by providing personalized therapy adjustments and improving adherence. AI offers transformative potential for the future of neurodegenerative disease management. Its integration into pharmacy practice promises more effective, individualized treatments, accelerating drug discovery, and optimizing patient care. As AI technologies continue to advance, their role in managing complex neurological disorders will become increasingly vital.}, } @article {pmid40949164, year = {2025}, author = {Roczkowsky, A and Rachubinski, RA and Hobman, TC and Power, C}, title = {Peroxisomes as emerging clinical targets in neuroinflammatory diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1642590}, pmid = {40949164}, issn = {1662-5099}, abstract = {Peroxisomes are membrane-bounded organelles that contribute to a range of physiological functions in eukaryotic cells. In the central nervous system (CNS), peroxisomes are implicated in several vital homeostatic functions including, but not limited to, reactive oxygen species signaling and homeostasis; generation of critical myelin sheath components (including ether phospholipids); biosynthesis of neuroprotective docosahexaenoic acid; breakdown of neurotoxic metabolites (such as very-long chain fatty acids); and, intriguingly, glial activation and response to inflammatory stimuli. Indeed, peroxisomes play a critical role in modulating inflammatory responses and are key regulators of the mitochondrial antiviral signaling (MAVS) protein-mediated response to infections. The importance of peroxisomes in CNS physiology is exemplified by the peroxisome biogenesis disorders (PBDs), a spectrum of inherited disorders of peroxisome assembly and/or abundance, that are characterized in part by neurological manifestations ranging from severe cerebral malformations to vision and hearing loss, depending on the individual disorder. Recently, peroxisome dysfunction has been implicated in neurological diseases associated with neuroinflammation including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson's disease while also contributing to the pathogenesis of neurotropic viruses including SARS-CoV-2, Human Pegivirus, HIV-1 and Zika virus. In the present review, we examine the diverse roles that peroxisomes serve in CNS health before reviewing more recent studies investigating peroxisome dysfunction in inflammatory brain disorders and also highlight potential peroxisomal targets for diagnostic biomarkers and therapeutic interventions.}, } @article {pmid40949365, year = {2025}, author = {Dai, JW and Xing, YX and Sun, NZ}, title = {Adjuvant chemotherapy for gallbladder cancer: Current evidence, controversies, and future directions.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {8}, pages = {108160}, pmid = {40949365}, issn = {1948-9366}, abstract = {Gallbladder cancer is an aggressive malignancy notorious for its poor prognosis and treatment challenges, even at early stages. In their recent work, Kim et al utilized data from the National Cancer Database to explore whether adding chemotherapy to surgical intervention could improve survival outcomes for patients diagnosed with stage II gallbladder cancer. The use of adjuvant chemotherapy following curative surgery in this patient population has been a long-standing source of debate. Historically, the lack of clear guidelines for managing stage II gallbladder cancer has resulted in inconsistent, sometimes contradictory findings from various studies regarding the effectiveness of postoperative chemotherapy. Consequently, many clinicians have relied on studies involving other biliary tract cancers to justify the routine use of prophylactic chemotherapy after surgery, aiming to minimize recurrence risk. Given the rarity, high mortality rate, and the small sample sizes typical in gallbladder cancer studies, Kim et al's contribution represents a significant and commendable effort to address these challenges. Kim et al designed a retrospective cohort study with well-defined inclusion criteria and clear treatment classifications. Notably, their findings suggested that in stage II gallbladder cancer, adjuvant chemotherapy did not yield a meaningful survival benefit over surgery alone. These results therefore casted doubt on the routine practice of administering chemotherapy to all patients postoperatively, prompted clinicians to reconsider their approach. Furthermore, this controversy directly influences clinical decisionmaking and guideline recommendations, as uncertainty regarding the benefit of adjuvant chemotherapy may lead to heterogeneous practices across different institutions and regions. This article critically assessed the research design, methodology, and clinical implications of the study by Kim et al. It also provided an in-depth exploration of the broader question regarding the appropriateness of adjuvant chemotherapy following surgery for stage II gallbladder cancer, highlighting the necessity of rigorous study designs to produce reliable evidence.}, } @article {pmid40949395, year = {2025}, author = {Han, S and Yu, LX and Zou, HP and Miao, YD and Lin, SX}, title = {Computed tomography-dominant surveillance strategies for colorectal cancer: Improving early detection of recurrence.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {8}, pages = {107340}, pmid = {40949395}, issn = {1948-9366}, abstract = {Colorectal cancer (CRC) is one of the most prevalent cancers globally, with a high recurrence rate following curative surgery, especially within the first 3 to 5 years. Post-surgical follow-up plays a vital role in detecting local and distant recurrences, significantly influencing survival rates. However, despite established guidelines recommending surveillance strategies, discrepancies persist regarding the optimal surveillance modality and patient adherence to follow protocols. Sala-Miquel et al's study emphasize the superiority of computed tomography in detecting metastasis and recurrence, while also shedding light on the critical role of adherence to surveillance protocols in improving patient outcomes. This editorial discusses the implications of these findings for clinical practice, providing a comprehensive overview of the current landscape of CRC surveillance and the path forward for improving patient outcomes.}, } @article {pmid40949612, year = {2025}, author = {Gao, L and Wang, J and Bi, Y}, title = {Nanotechnology for Neurodegenerative Diseases: Recent Progress in Brain-Targeted Delivery, Stimuli-Responsive Platforms, and Organelle-Specific Therapeutics.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {11015-11044}, pmid = {40949612}, issn = {1178-2013}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism/drug effects ; *Drug Delivery Systems/methods ; Nanomedicine/methods ; Nanoparticles/chemistry ; Organelles/drug effects/metabolism ; Liposomes/chemistry ; *Nanoparticle Drug Delivery System/chemistry ; Drug Carriers/chemistry ; }, abstract = {Neurodegenerative diseases-including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis-are characterized by progressive neuronal loss and complex pathological mechanisms such as protein aggregation, mitochondrial dysfunction, and neuroinflammation. Conventional therapies offer limited efficacy due to the blood-brain barrier (BBB) and lack of targeted delivery. Nanotechnology has emerged as a transformative strategy for precise brain-targeted treatment. This review summarizes recent advances in nanoparticle-based drug delivery systems, including polymeric nanoparticles, liposomes, inorganic nanomaterials, and biomimetic carriers, highlighting their design features, BBB-penetration mechanisms, and disease-specific applications. Emphasis is placed on stimuli-responsive nanocarriers that react to pH, reactive oxygen species, or enzyme activity, enabling site-specific drug release. Additionally, organelle-targeting strategies-particularly those directed at mitochondria and lysosomes-are explored for their role in subcellular precision therapy. The integration of diagnostic and therapeutic modalities in theranostic nanoplatforms is also discussed. By consolidating preclinical progress and emerging technologies, this review offers insights into the future of nanomedicine in treating neurodegenerative diseases and lays the groundwork for clinical translation.}, } @article {pmid40949727, year = {2025}, author = {Gu, Q and Shen, J and Chu, S and Huang, Q and Chen, A and Li, L and Li, R}, title = {Analysis of the resistance level and target site resistance mechanisms of Echinochloa crus-galli to penoxsulam from Hubei Province, China.}, journal = {PeerJ}, volume = {13}, number = {}, pages = {e19973}, pmid = {40949727}, issn = {2167-8359}, mesh = {*Echinochloa/drug effects/genetics/enzymology ; Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; China ; *Herbicide Resistance/genetics ; *Sulfonamides/pharmacology ; *Herbicides/pharmacology ; Mutation ; *Plant Weeds/drug effects/genetics ; Oryza/parasitology ; Plant Proteins/genetics/metabolism/antagonists & inhibitors ; Uridine/analogs & derivatives ; }, abstract = {Echinochloa crus-galli is a grass weed that infests rice fields and causes significant crop yield losses. In this study, we surveyed 15 resistant E. crus-galli populations collected from rice fields in Hubei Province, China, and investigated the resistance levels and target site resistance mechanisms to the acetolactate synthase (ALS) inhibitor penoxsulam. The results of whole-plant bioassay experiments revealed that 15 populations presented different levels of resistance to penoxsulam. The Trp-574-Leu mutation was detected in ten resistant populations, and the Pro-197-Leu mutation was detected in one resistant population. Additionally, the in vitro ALS activity in resistant populations (18-ETF, 18-WJJ, and 18-WMJ) was 51.28-, 5.51-, and 8.46-fold greater than that in the susceptible population. The ALS from these resistant populations requires a much higher penoxsulam concentration for activity inhibition. ALS gene expression in three resistant populations (18-ETF, 18-WJJ, and 18-WMJ) was 1.53-, 1.58-, and 1.41-fold greater than that in the susceptible population 18-NJ before penoxsulam treatment. Our results indicated that target-site mutation in ALS is at least partially responsible for barnyardgrass resistance to penoxsulam in Hubei Province.}, } @article {pmid40949955, year = {2025}, author = {Guo, C and Chen, K and Vatsavayai, SC and Akiyama, T and Zeng, Y and Liu, C and Sianto, O and Yang, E and Bombosch, J and Powell, R and Zhen, S and Mekhoubad, S and Morrie, RD and Miller, G and Green, EM and Petrucelli, L and Seeley, WW and Gitler, AD}, title = {Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40949955}, issn = {2692-8205}, support = {P50 AG023501/AG/NIA NIH HHS/United States ; R56 AG057195/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; R35 NS137159/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; }, abstract = {TDP-43 pathology is a defining pathological hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major feature of TDP-43 pathology is its nuclear depletion, leading to the aberrant inclusion of cryptic exons during RNA splicing. STMN2 and UNC13A have emerged as prominent TDP-43 splicing targets, but the broader impact of TDP-43-dependent cryptic splicing on neuronal function remains unclear. Here, we report new TDP-43 splicing targets critical for membrane excitability and synaptic function, including KALRN, RAP1GAP, SYT7 and KCNQ2. Using human stem cell-derived neurons, we show that TDP-43 reduction induces cryptic splicing and downregulation of these genes, resulting in impaired excitability and synaptic transmission. In postmortem brains from patients with FTD, these cryptic splicing events occur selectively in neurons with TDP-43 pathology. Importantly, suppressing individual cryptic splicing events using antisense oligonucleotides partially restores neuronal function, and combined targeting almost fully rescues the synaptic deficit caused by TDP-43 loss. Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD.}, } @article {pmid40950010, year = {2025}, author = {De La Cruz, PM and Lockett, A and Gomes, MT and Banerjee, S and Razee, A and Fisher, A and Cook, T and Lloyd, CD and Magaki, S and Umar, S and Oblak, AL and Machado, RF}, title = {Pulmonary Hypertension Promotes Neuroinflammation and Neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40950010}, issn = {2692-8205}, support = {R01 HL111656/HL/NHLBI NIH HHS/United States ; T32 HL091816/HL/NHLBI NIH HHS/United States ; R01 HL127342/HL/NHLBI NIH HHS/United States ; R01 HL161038/HL/NHLBI NIH HHS/United States ; R01 HL158108/HL/NHLBI NIH HHS/United States ; }, abstract = {INTRODUCTION: Pulmonary arterial hypertension (PAH) is associated with neurocognitive deficits and abnormal brain MRI. Little is known about the mechanisms underlying these clinical observations. TDP-43 is a proteinopathy associated with frontotemporal lobar degeneration (FTLD), Alzheimer's Disease, and Amyotrophic Lateral Sclerosis (ALS). In this study, we hypothesize PAH will result in gliosis, reduced neuronal density, and increased TDP-43 mislocalization.

METHODS: Sprague Dawley rats were randomly assigned to receive Vehicle (DMSO) Monocrotaline, or Sugen/Hypoxia to induce PH. Right heart catheterization was used to confirm PAH. Brain tissue was fixed and probed for microglia (Iba1), astrocytes (GFAP), neurons (NeuN), and TDP-43. Human PH vs control brain tissue was also probed for NeuN and TDP-43.

RESULTS AND CONCLUSIONS: We identify an increase in microglia and astrocyte density in the frontal cortex along with reduced neuronal density and neuronal TDP-43 mislocalization in rat models of PH. In addition, human PH frontal cortex demonstrated neuronal TDP-43 mislocalization. This is the first evidence of TDP-43 proteinopathy in PH.}, } @article {pmid40950480, year = {2025}, author = {Wolff, AW and Leha, A and Koch, JC and Demleitner, AF and Neuwirth, C and Friede, T and Weber, M and Lingor, P}, title = {Fasudil attenuates disease spreading in ALS - a post-hoc analysis of the ROCK-ALS trial.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40950480}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the spread of muscle weakness across body regions. The ROCK-ALS trial was a multicenter, randomized, double-blind, placebo-controlled phase 2 study assessing the safety, tolerability, and efficacy of the Rho kinase inhibitor fasudil as an add-on to riluzole in ALS patients. A key exploratory objective was to evaluate fasudil's effect on the spread of muscle weakness using the Motor Unit Number Index (MUNIX), a quantitative electrophysiological biomarker of lower motor neuron integrity. MUNIX was assessed in 10 muscles (5 on each body side) at baseline, day 26, day 90, and day 180. Correlations were assessed between baseline serum biomarkers-neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP)-and baseline clinical measures (ALSFRS-R, slow vital capacity, and MUNIX sum scores) as well as their monthly rates of change, to explore potential prognostic relationships. For the analysis of disease spreading, muscles were classified as newly affected based on MUNIX decline relative to contralateral values or prior measurements, using thresholds of ≥10%, ≥20%, or ≥30%. 118 participants were included in the intention-to-treat population, 78 had full MUNIX datasets at baseline and 67 had at least one follow-up. Baseline MUNIX sum scores correlated with subsequent ALSFRS-R decline, suggesting prognostic value. Additionally, at day 90, fasudil significantly reduced the number of newly affected muscles compared to placebo in a dose dependent manner over different thresholds. These findings support MUNIX as a sensitive biomarker for monitoring disease spreading and demonstrate that fasudil may attenuate the progression of lower motor neuron involvement in ALS.}, } @article {pmid40951286, year = {2025}, author = {Homann, J and Korologou-Linden, R and Viallon, V and Morgan, S and Dobricic, V and Deecke, L and Schessner, JP and Smith-Byrne, K and Birtles, D and Zhao, Y and Wuu, J and Artaud, F and Hajizadah, F and Huerta, JM and Ohlei, O and Lebedev, M and Kolijn, PM and Guevara, M and Jimenez-Zabala, A and Sánchez, MJ and Trobajo-Sanmartín, C and Colorado-Yohar, SM and Alonso-Martín, S and Petrova, D and Sieri, S and Berger, K and Peters, S and Wareham, N and Kaaks, R and Travis, RC and Vermeulen, RCH and , and Tzoulaki, I and Elbaz, A and Mann, M and Sacerdote, C and Masala, G and Katzke, V and Benatar, M and Bertram, L and Middleton, L and Riboli, E and Gunter, MJ and Ferrari, P and Robinson, O and Lill, CM}, title = {Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40951286}, issn = {2693-5015}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form.

METHODS: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM).

FINDINGS: Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson's and Alzheimer's disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance.

INTERPRETATION: Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention.

FUNDING: Clinical Research in ALS and Related Disorders for Therapeutic Development (CreATe) Consortium, Cure Alzheimer's Fund, Michael J Fox Foundation, Interdisciplinary Centre for Clinical Research, University Münster.}, } @article {pmid40951906, year = {2025}, author = {Telec, W and Al-Saad, S and Karbowski, L and Kłosiewicz, T and Baszko, A}, title = {Postshock Pacing in Cardiac Arrest: A Concise Review.}, journal = {Emergency medicine international}, volume = {2025}, number = {}, pages = {9067144}, pmid = {40951906}, issn = {2090-2840}, abstract = {Following an administered shock in cardiac arrest, the heart commonly experiences a short phase of inability to efficiently perfuse. Despite being a commonly used feature in the ICD population, postshock pacing (PSP) is yet to be adequately explored for its utility in this pulseless phase. Notably, an overwhelming proportion of available data for transcutaneous pacing in spontaneous cardiac arrest stem from the 1980s and 1990s and revolve largely around nonshockable, as opposed to shockable rhythms. The lack of large-scale clinical trials assessing the efficacy of transcutaneous PSP and the considerable advancements in technology and training facilities since the 1990s indicates a need for reevaluation of current understanding of PSP and its applicability in cardiac arrest. Shedding light into the possible implications of transcutaneous PSP in emergency setting cardiac arrest may not only reshape the current protocols of ALS but also carry the potential of improving survival rates. This concise review serves as a summary of the existing knowledge on the subject of PSP and reveals further possible directions for the development of this therapy.}, } @article {pmid40952044, year = {2026}, author = {Gao, Y and Brothwood, JL and Saini, H and O'Sullivan, GA and Bento, CF and McCarthy, JM and Wallis, NG and Di Daniel, E and Graham, B and Tams, DM}, title = {Altered Inflammatory Signature in a C9ORF72 -ALS iPSC-Derived Motor Neuron and Microglia Coculture Model.}, journal = {Glia}, volume = {74}, number = {1}, pages = {e70084}, pmid = {40952044}, issn = {1098-1136}, support = {/WT_/Wellcome Trust/United Kingdom ; //Astex Pharmaceuticals/ ; }, mesh = {*Microglia/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Motor Neurons/metabolism/pathology ; Humans ; Coculture Techniques ; Inflammation/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder involving multiple cell types in the central nervous system. The key pathological features of ALS include the degeneration of motor neurons and the initiation and propagation of neuroinflammation mediated by nonneuronal cell types such as microglia. Currently, the specific mechanisms underlying the involvement of microglia in neuroinflammation in ALS are unclear. Consequently, we generated several human-induced pluripotent stem cell (iPSC) derived motor neuron and microglia cocultures. We utilized ALS patient-derived iPSCs carrying a common genetic variant, the hexanucleotide repeat expansion (HRE) in C9ORF72, as well as C9ORF72 knockout (KO) iPSC lines. iPSC-derived motor neurons and microglia demonstrated expression of cell type-specific markers and were functional. Phenotypic assessments on motor neurons and microglia in mono- and cocultures identified dysfunction in the expression and secretion of inflammatory cytokines and chemokines in lipopolysaccharide (LPS)-stimulated C9ORF72 HRE and C9ORF72 KO microglia. Analysis of single-cell RNA sequencing data from microglia and motor neuron cocultures revealed cell type-specific transcriptomic changes. Specifically, we detected the removal of an LPS-responsive microglia subpopulation, correlating with a dampened inflammatory response in C9ORF72 HRE and C9ORF72 KO microglia. Overall, our results support the critical role of microglia-mediated neuroinflammation in ALS pathology, and our iPSC-derived models should prove a valuable platform for further mechanistic studies of ALS-associated pathways.}, } @article {pmid40952318, year = {2025}, author = {Guo, L and Xu, IQ and Nag, S and Xu, J and Chai, J and Simmons, Z and Ramasamy, S and Yeo, CJJ}, title = {Predicting Amyotrophic Lateral Sclerosis Mortality With Machine Learning in Diverse Patient Databases.}, journal = {Muscle & nerve}, volume = {72}, number = {4}, pages = {653-661}, pmid = {40952318}, issn = {1097-4598}, support = {C210112024//A*STAR Career Development Award (CDA)/ ; IRNMR21CPGJJ//National Neuroscience Institute (NNI) Pilot/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis ; *Machine Learning ; Male ; Databases, Factual ; Female ; Middle Aged ; Aged ; Prognosis ; Predictive Value of Tests ; Adult ; }, abstract = {INTRODUCTION: Predicting mortality in Amyotrophic Lateral Sclerosis (ALS) guides personalized care and clinical trial optimization. Existing statistical and machine learning models often rely on baseline or diagnosis visit data, assume fixed predictor-survival relationships, lack validation in non-Western populations, and depend on features like genetic tests and imaging not routinely available. This study developed ALS mortality prediction models that address these limitations.

METHODS: We trained Royston-Parmar and eXtreme Gradient Boosting models on the PRO-ACT database for 6- and 12-month mortality predictions. Each visit was labeled positive (for death) if death occurred within 6 or 12 months, negative if survival was confirmed beyond that, and excluded if follow-up was insufficient, assuming patients were alive up to their last recorded visit. Models were validated on independent datasets from the North American Celecoxib trial and a Singapore ALS clinic population. Feature importance and the impact of reducing predictors on performance were evaluated.

RESULTS: Models predicted mortality from any clinical visit with area under the curve (AUC) of 0.768-0.819, rising to 0.865 for 12-month prediction using 3-month windows. Albumin was the top predictor, reflecting nutritional and inflammatory status. Other key predictors included ALS Functional Rating Scale-Revised slope, limb onset, absolute basophil count, forced vital capacity, bicarbonate, body mass index, and respiratory rate. Models maintained robust performance on the independent datasets and after reducing inputs to seven key predictors.

DISCUSSION: These visit-agnostic models, validated across diverse populations, identify key prognostic features and demonstrate the potential of predictive modeling to enhance ALS care and trial design.}, } @article {pmid40952592, year = {2025}, author = {Chen, C and Wang, GQ and Li, DD and Zhang, F}, title = {Microbiota-gut-brain axis in neurodegenerative diseases: molecular mechanisms and therapeutic targets.}, journal = {Molecular biomedicine}, volume = {6}, number = {1}, pages = {64}, pmid = {40952592}, issn = {2662-8651}, support = {No. 82160690//National Natural Science Foundation of China/ ; No. ZK [2021]-014//Science and Technology Foundation of Guizhou Province/ ; No. 2020-39//Collaborative Innovation Center of Chinese Ministry of Education/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/therapy/microbiology/metabolism/etiology ; *Gastrointestinal Microbiome ; *Brain/metabolism ; Animals ; Dysbiosis ; Probiotics/therapeutic use ; *Brain-Gut Axis ; }, abstract = {The microbiota-gut-brain axis (MGBA) is an intricate bidirectional communication network that links intestinal microbiota with the central nervous system (CNS) through immune, neural, endocrine, and metabolic pathways. Emerging evidence suggests that dysregulation of the MGBA plays pivotal roles in the onset and progression of neurodegenerative diseases. This review outlines the key molecular mechanisms by which gut microbes modulate neuroinflammation, blood-brain barrier integrity, protein misfolding, and neuronal homeostasis. We discuss how microbial metabolites, such as short-chain fatty acids, tryptophan derivatives, and bile acids, interact with host to influence CNS functions. Disease-specific features are described across Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis, emphasizing the distinct and overlapping pathways through which gut dysbiosis may contribute to pathogenesis. We further explore the translational potential of microbiota-targeted therapies, including probiotics, fecal microbiota transplantation, dietary interventions, and small-molecule modulators. While preclinical results are promising, clinical trials reveal considerable variability, highlighting the need for personalized approaches and robust biomarkers. Challenges remain in deciphering causal relationships, accounting for inter-individual variability, and ensuring reproducibility in therapeutic outcomes. Future research should integrate multi-omics strategies, longitudinal human cohorts, and mechanistic models to clarify the role of the MGBA in neurodegeneration. Collectively, understanding the MGBA provides a transformative perspective on neurodegenerative disease mechanisms and offers innovative therapeutic avenues that bridge neurology, microbiology, and precision medicine.}, } @article {pmid40953163, year = {2025}, author = {Burrowes, KA and Marciante, AB and Mitchell, GS}, title = {Phrenic long-term facilitation following severe acute intermittent hypoxia is preserved in geriatric male rats.}, journal = {Journal of neurophysiology}, volume = {134}, number = {4}, pages = {1146-1152}, pmid = {40953163}, issn = {1522-1598}, support = {T32 HL134621/HL/NHLBI NIH HHS/United States ; R01 HL147554/HL/NHLBI NIH HHS/United States ; R01HL148030//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL147554//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL148030/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Male ; *Phrenic Nerve/physiopathology/physiology ; *Hypoxia/physiopathology ; Rats, Sprague-Dawley ; Rats ; *Aging/physiology ; *Long-Term Potentiation/physiology ; Adenosine/metabolism ; Serotonin/metabolism ; }, abstract = {Acute intermittent hypoxia (AIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). Although AIH comprised of moderate versus severe hypoxic episodes both elicit pLTF, they do so via completely distinct cellular mechanisms. In young adult male rats, moderate AIH (mAIH) elicits pLTF via a serotonin-driven, adenosine-constrained mechanism. In aged rats, mAIH-induced pLTF is diminished due to increased basal spinal adenosine levels that further constrain serotonin-driven pLTF. In contrast, in young male rats, severe AIH (sAIH) elicits pLTF via an adenosine-dominant, serotonin-constrained mechanism. Since basal spinal adenosine levels are elevated in aged male rats, we tested the hypothesis that adenosine-dependent, sAIH-induced pLTF is enhanced in aged versus young male rats. Young (∼3 mo) and aged (∼20 mo) male Sprague-Dawley rats were urethane-anesthetized, ventilated, vagotomized, paralyzed, and exposed to sAIH (3, 5-min episodes, arterial Po2 = 25-30 mmHg; 5-min intervals). Integrated phrenic nerve activity was measured before (baseline), during each hypoxic episode, and for 60 min post sAIH. Neither baseline phrenic burst amplitude, the short-term hypoxic phrenic response, nor pLTF (% change from baseline in phrenic burst amplitude) were different in aged versus young male rats (132 ± 19% vs. 99 ± 17%, respectively). Thus, although sAIH-induced pLTF is not significantly elevated in aged versus young male rats as predicted, the capacity for adenosine-driven plasticity is preserved, in contrast with serotonin-dependent, mAIH-induced pLTF.NEW & NOTEWORTHY We report new findings that advance our understanding of how cellular mechanisms underlying respiratory motor plasticity shift with age. Age-related shifts in the magnitude or mechanism driving plasticity have major clinical relevance as we work to translate AIH for therapeutic benefit in conditions such as chronic spinal cord injury or ALS, where subjects in ongoing clinical trials are often males of advanced age.}, } @article {pmid40955296, year = {2025}, author = {Tang, H and Yao, J and Wang, Z}, title = {Amyotrophic Lateral Sclerosis Masquerading as Multiple System Atrophy with Parkinsonism and Anxiety as Initial Manifestations.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {15}, number = {}, pages = {95-100}, pmid = {40955296}, issn = {1179-9900}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA) are both neurodegenerative disorders. While ALS may present with clinical features resembling Parkinsonism, there have been no definitive reports of ALS mimicking MSA, only cases of Primary lateral sclerosis (PLS) mimicking Parkinsonism.

METHODS: This article reports a case of ALS presenting with Parkinsonism and anxiety as the initial symptoms. Five years after the initial diagnosis of MSA, the patient developed signs of lower motor neuron involvement, including fasciculations and muscle atrophy, ultimately leading to a revised diagnosis of ALS. This study combines literature analysis to explore the reasons for misdiagnosis and identifies key differentiating features.

RESULTS: Specifically, muscle rigidity in ALS is characterized by a velocity-dependent increase in muscle tone caused by damage to the upper motor neurons. This symptom tends to be more pronounced in the lower limbs than in the upper limbs and is often accompanied by spastic gait. Objective examinations may reveal early atrophy of the frontal and temporal lobes of the cerebrum on head magnetic resonance (MR) imaging, whereas [18]F-FDG brain positron emission tomography (PET) may reveal reduced metabolism in the frontal and parietal lobes of the cerebrum with normal basal ganglial function, distinguishing ALS from basal ganglial metabolic decline in MSA.

DISCUSSION: To our knowledge, this is the first case of ALS misdiagnosed as MSA. Clinically, patients with parkinsonism who do not respond to dopaminergic drugs should be cautious about atypical ALS. Muscle rigidity manifesting as upper motor neuron damage, and MR and [18]F-FDG brain PET imaging can provide early differential diagnosis indicators.}, } @article {pmid40955309, year = {2025}, author = {Wang, L and Feng, L and Ning, B and Wang, Z and Dai, C and Li, M}, title = {Natural Products from Chinese Medicine Targeting NF-κB Signaling: Emerging Therapeutic Avenues for Neurodegenerative Diseases.}, journal = {Drug design, development and therapy}, volume = {19}, number = {}, pages = {8135-8159}, pmid = {40955309}, issn = {1177-8881}, mesh = {Humans ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Biological Products/pharmacology/chemistry ; *Medicine, Chinese Traditional ; Signal Transduction/drug effects ; Animals ; *Drugs, Chinese Herbal/pharmacology/chemistry ; }, abstract = {This review summarizes recent advances in leveraging natural products from Chinese medicine to modulate the nuclear factor kappa B (NF-κB) signaling pathway for the prevention and treatment of neurodegenerative diseases (NDDs), focusing specifically on Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). NF-κB proteins regulate cellular biological activity by binding to promoter regions in the nucleus and transcribing various protein-coding genes. Emerging evidence indicates that NF-κB plays a pivotal role in driving key hallmarks of NDD progression, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and dysregulation of the cell cycle. Natural products from Chinese medicine exert modulatory effects on NF-κB signaling through diverse pharmacological mechanisms, ultimately improving cognitive and motor impairments in preclinical NDDs models. The pleiotropic nature of natural products derived from traditional Chinese medicine (TCM)-which operate through subunit-specific modulation of NF-κB-underscores their potential as next-generation therapeutics. Investigating the intricate regulation of NF-κB by natural products from Chinese medicine will not only enrich our understanding of the pathogenesis of NDDs but also establish a theoretical foundation for the development of new therapeutic drugs for NDDs, providing innovative strategies for prevention and treatment.}, } @article {pmid40957031, year = {2023}, author = {Pressler, MP and Cooper, PS and Carter, W and Goldstein, RB and Mendelson, AM}, title = {Intrathecal Baclofen to Improve Functional Status in ALS: A Case Report.}, journal = {Pain medicine case reports}, volume = {7}, number = {4}, pages = {201-203}, pmid = {40957031}, issn = {2768-5152}, abstract = {BACKGROUND: Intrathecal pumps are well known to benefit patients with chronic pain as well as spasticity. Intrathecal baclofen (ITB) can offer doses 100-1000 times smaller with similar efficacy, compared to oral baclofen. Only 2 previous reports detailed improvement in functional status after patients with amyotrophic lateral sclerosis (ALS) received ITB.

CASE REPORT: Our patient presented with progressive bulbar palsy, further progressing to ALS. His lower extremity spasticity and tremors continued to progress over 3 years despite increased baclofen. At the time of implant, he expressed whole body tremors and spasticity to bilateral lower extremities, complicated by falls. Prior to the trial, the patient ambulated 50 feet. ITB was started at a rate of 100 mcg/day. After the implant, the patient's ambulation distance increased to 100 feet.

CONCLUSION: The patient and his wife reported resolution of his tremors and improvement in spasticity. This report details the functional improvement obtained from ITB in a patient with ALS.}, } @article {pmid40957416, year = {2025}, author = {Axakova, A and Ding, M and Cote, AG and Subramaniam, R and Senguttuvan, V and Zhang, H and Weile, J and Douville, SV and Gebbia, M and Al-Chalabi, A and Wahl, A and Reuter, J and Hurt, J and Mitchell, AA and Fradette, S and Andersen, PM and van Loggerenberg, W and Roth, FP}, title = {Landscapes of missense variant impact for human superoxide dismutase 1.}, journal = {American journal of human genetics}, volume = {112}, number = {10}, pages = {2295-2315}, pmid = {40957416}, issn = {1537-6605}, support = {RM1 HG010461/HG/NHGRI NIH HHS/United States ; UM1 HG011989/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; *Mutation, Missense/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Amino Acid Substitution ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease for which important subtypes are caused by variation in superoxide dismutase 1 (SOD1). Diagnosis based on SOD1 sequencing can not only be definitive but can also indicate specific therapies available for SOD1-associated ALS (SOD1-ALS). Unfortunately, SOD1-ALS diagnosis is limited by the fact that a substantial fraction (currently 26%) of ClinVar SOD1 missense variants are classified as "variants of uncertain significance" (VUSs). Although functional assays can provide strong evidence for clinical variant interpretation, SOD1 assay validation is challenging given the current incomplete and controversial understanding of SOD1-ALS disease mechanism. Using saturation mutagenesis and multiplexed cell-based assays, we measured the functional impact of over 2,000 SOD1 amino acid substitutions on both enzymatic function and protein abundance. The resulting "missense variant-effect maps" not only reflect prior biochemical knowledge of SOD1 but also provide sequence-structure-function insights. Importantly, our variant-abundance assay can discriminate pathogenic missense variation and provides new evidence for 41% of missense variants that had been previously reported as VUSs, offering the potential to identify additional people who would benefit from therapy approved for SOD1-ALS.}, } @article {pmid40957741, year = {2025}, author = {Soputro, NA and Kaouk, J}, title = {Reply to Fabrizio Di Maida, Carlo Andrea Bravi, Marcio Covas Moschovas, et al's Letter to the Editor re: Nicolas A. Soputro, Carter D. Mikesell, Salim K. Younis, et al. Propensity-matched Comparison of Single-port Transvesical Versus Standard Multiport Robotic Radical Prostatectomy. Eur Urol Oncol. In press. https://doi.org/10.1016/j.euo.2025.05.023.}, journal = {European urology oncology}, volume = {8}, number = {5}, pages = {1446}, doi = {10.1016/j.euo.2025.08.008}, pmid = {40957741}, issn = {2588-9311}, } @article {pmid40957956, year = {2025}, author = {Latif, MA and Kayess, O and Hasan, R}, title = {Gene pyramiding for enhancing resistance to blast and bacterial blight disease in rice through maker assisted selection.}, journal = {Biotechnology letters}, volume = {47}, number = {5}, pages = {106}, pmid = {40957956}, issn = {1573-6776}, mesh = {*Oryza/genetics/microbiology ; *Disease Resistance/genetics ; *Plant Diseases/microbiology/genetics ; *Plant Breeding/methods ; Xanthomonas ; Genes, Plant ; Magnaporthe ; }, abstract = {Diseases are a global threat to rice production. Among them, rice blast and bacterial blight (BB) are most significant. To enhance targeted disease resistance, the marker-assisted backcross breeding (MABB) approach was employed to pyramid two blast (Pi9 and Pb1) and three BB resistant (R) genes (Xa4, xa13, and Xa21) into a high-quality rice cultivar BRRI dhan100. The donor parents Pi9-US2 (Pi9), Pb1-US2 (Pb1), and IRBB58 (Xa4, xa13, and Xa21) contributed these five genes. We followed a triple-cross breeding strategy, followed by backcrossing, selfing, and foreground selection to produce BC3F5 progenies. Chi-square analysis of 420 BC3F2 individuals confirmed the inheritance patterns of blast and BB resistance were controlled by a simple Mendelian fashion. Finally, we selected 38 advanced lines (ALs), and among them, twelve lines possessed all 5 candidate R genes, while fifteen consisted of 4 genes in different combinations. The disease rating scale of these ALs varied from 0 to 3 for both blast and BB diseases, while BRRI dhan100 ranging from 7 to 9. The G23, G13, G5, G10, G15, and G29 ALs exhibited higher yields ranging from 7.22-7.34 ton ha[-1] compared to the check, BRRI dhan100. Marker-trait association analysis displayed molecular markers negatively associated with disease susceptibility. Therefore, gene introgression by MABB could effectively identify and functionally validate the candidate R genes with high accuracy to develop a resistant variety to multiple diseases in rice breeding programs.}, } @article {pmid40958089, year = {2025}, author = {Zhang, M and Lin, Y and Wei, H and Ju, Q and Gao, T and Zhang, Y and Shen, L and Sun, C}, title = {The membrane receptor CD44: roles in neurodegenerative diseases.}, journal = {Expert opinion on therapeutic targets}, volume = {29}, number = {10}, pages = {717-726}, doi = {10.1080/14728222.2025.2563243}, pmid = {40958089}, issn = {1744-7631}, mesh = {Humans ; *Hyaluronan Receptors/metabolism ; *Neurodegenerative Diseases/physiopathology/drug therapy ; Animals ; *Molecular Targeted Therapy ; Quality of Life ; Disease Progression ; Neuroinflammatory Diseases/physiopathology ; }, abstract = {INTRODUCTION: With the increasing prevalence of aging populations, the incidence of neurodegenerative diseases continues to rise, posing a serious threat to human health and quality of life. Owing to the highly complex pathogenesis of these disorders, the identification of effective therapeutic targets remains a major challenge. CD44, a cell surface glycoprotein, plays a central role in regulating cell proliferation, survival, adhesion, and migration. Emerging evidence further indicates that CD44 contributes to NF-κB activation, thereby amplifying inflammatory responses.

AREAS COVERED: Given its central role in neuroinflammation, CD44 has attracted increasing attention as a potential therapeutic target for neurodegenerative diseases. This review explores the involvement of CD44 in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), with particular emphasis on its contributions to neuroinflammatory processes, neuronal survival, and pathological protein aggregation.

EXPERT OPINION: Chronic low-grade neuroinflammation is a major driver of neurodegenerative diseases, including ALS, AD, and PD. Growing evidence implicates CD44 as a key contributor to disease pathogenesis, with several studies reporting significantly elevated CD44 expression in affected patients. These findings highlight the role of CD44 in disease progression and suggest that targeting CD44-mediated inflammation may offer a promising therapeutic strategy for neurodegenerative disorders.}, } @article {pmid40958367, year = {2025}, author = {Gao, M and Han, J and Zhu, Y and Wen, X and Feng, L and Zhou, T}, title = {Obesity Impacts Post-Myocardial Infarction Neovascularization by Downregulating AQP1 Expression via the TRPC5-NFATc3 Signaling Pathway.}, journal = {Comprehensive physiology}, volume = {15}, number = {5}, pages = {e70048}, doi = {10.1002/cph4.70048}, pmid = {40958367}, issn = {2040-4603}, support = {82470455//National Natural Science Foundation of China/ ; 82200463//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Myocardial Infarction/metabolism ; *TRPC Cation Channels/metabolism/genetics ; Mice ; *Obesity/metabolism/complications ; *Aquaporin 1/metabolism/genetics ; *NFATC Transcription Factors/metabolism/genetics ; Signal Transduction/physiology ; Down-Regulation ; Male ; Mice, Inbred C57BL ; Humans ; Neovascularization, Physiologic ; Endothelial Cells/metabolism ; }, abstract = {Obesity is associated with impaired angiogenesis and poor recovery following myocardial infarction (MI), yet the underlying molecular mechanisms remain poorly defined. The transient receptor potential cation channel subfamily C member 5 (TRPC5) is known to regulate angiogenesis, but its role in the context of obesity-related MI is unclear. Here, we show that TRPC5 expression is downregulated in obese mice hearts following MI, resulting in compromised angiogenic function. Riluzole, an FDA-approved drug for amyotrophic lateral sclerosis, activates TRPC5 and restores the migration, sprouting, and tube formation function of coronary artery endothelial cells isolated from diet-induced obese (DIO) MI mice. In obese mice, riluzole enhances post-MI neovascularization, reduces infarct size, and improves cardiac function. Notably, TRPC5-mediated angiogenesis requires aquaporin-1 (AQP1), whose expression is regulated by TRPC5 via the nuclear factor of activated T cells 3 (NFATc3) transcription factor. Silencing AQP1 abolishes the pro-angiogenic effects of TRPC5 activation, establishing AQP1 as a critical downstream effector. In conclusion, our data provide evidence that the TRPC5-NFATc3-AQP1 pathway is essential for post-MI angiogenesis in obesity and support riluzole as a promising therapeutic approach to enhance angiogenesis in obese individuals following MI.}, } @article {pmid40958536, year = {2025}, author = {Malik, P and Mian, P and Andrews, J and Rosebraugh, M and Ajroud-Driss, S}, title = {A Modeling Investigation of the CYP1A Drug Interactions of Riluzole.}, journal = {Clinical and translational science}, volume = {18}, number = {9}, pages = {e70358}, pmid = {40958536}, issn = {1752-8062}, mesh = {Humans ; Drug Interactions ; *Riluzole/pharmacokinetics/administration & dosage ; *Cytochrome P-450 CYP1A2/metabolism ; *Cytochrome P-450 CYP1A1/metabolism/antagonists & inhibitors ; *Models, Biological ; Fluvoxamine/pharmacokinetics/pharmacology ; Adult ; Cytochrome P-450 CYP1A2 Inhibitors/pharmacokinetics ; Male ; Female ; Middle Aged ; Young Adult ; }, abstract = {Cytochrome-P-450 (CYP)1A2 has been considered the major enzyme metabolizing riluzole since its approval. However, the inhibitor that was used in the original experiments, α-naphthoflavone, is also a potent inhibitor of CYP1A1. In this work, physiologically based pharmacokinetic (PBPK) modeling investigates the interplay between CYP1A1 and CYP1A2 and the relevance to drug-drug interactions. Following review of clinical and non-clinical data from literature, the relative contributions of CYP1A1, CYP1A2, and UGT1A8/9 to riluzole metabolism were assigned as 60%, 30%, and 10%, respectively. The model was calibrated on single-dose pharmacokinetic (PK) data from healthy subjects. The translational potential of the model was verified by predicting riluzole PK in people with amyotrophic lateral sclerosis, spinal muscular atrophy, advanced age, renal impairment, and hepatic impairment, and when administered with a high-fat meal. The relative contributions of CYP1A1 and CYP1A2 to metabolism were verified through prediction of an observed drug-drug interaction between riluzole and fluvoxamine-a strong CYP1A2 inhibitor and a weak CYP1A1 inhibitor-in children with obsessive-compulsive disorder. Overall, evidence suggests that CYP1A1 is a major enzyme metabolizing riluzole, and that CYP1A2 has similar or lower importance. Only clinically relevant inhibitors of both enzymes may pose a safety concern when administered with riluzole. Strong CYP1A1 inhibitors and strong CYP1A2 inhibitors may be used with caution if they do not significantly modulate the other enzyme. Concomitant use of CYP1A1 inducers may be reconsidered where possible. The enzymatic contributions to riluzole metabolism should be reconsidered after formal drug-drug interaction studies are completed.}, } @article {pmid40958756, year = {2026}, author = {Sheth, U and Harrison, R and Ferber, K and Rosenbaugh, EG and Bevis, A and Khillan, R and Benatar, M and Bjorklund, NL and Di Daniel, E and Harris, GA and Kahn, OI and Liu, Y and Zetterberg, H and Mitic, LL and Graham, D and Gendron, TF}, title = {Measuring neurofilament light in human plasma and cerebrospinal fluid: a comparison of five analytical immunoassays.}, journal = {Clinical chemistry and laboratory medicine}, volume = {64}, number = {2}, pages = {410-420}, pmid = {40958756}, issn = {1437-4331}, mesh = {Humans ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Immunoassay/methods ; Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/diagnosis ; Male ; Female ; Middle Aged ; Biomarkers/blood/cerebrospinal fluid ; Aged ; Adult ; }, abstract = {OBJECTIVES: Neurofilament light (NfL) is an established biofluid marker of neuroaxonal injury for neurological diseases. Several high-throughput and sensitive immunoassays have been developed to quantify NfL in blood and cerebrospinal fluid (CSF), facilitating the use of NfL as a biomarker in research and clinical practice. However, because of the lack of rigorous comparisons of assays, it has been difficult to determine whether data are comparable and whether assay performance differs. Here, we compared the performance of five NfL immunoassays.

METHODS: To assess the five NfL immunoassays (Fujirebio, ProteinSimple, Quanterix, Roche and Siemens), we used pooled plasma or pooled CSF, as well as unique samples from 20 healthy controls and 20 individuals with El Escorial defined probable or definite amyotrophic lateral sclerosis (ALS), to evaluate precision, parallelism and/or bias. We also examined correlations between plasma and CSF NfL concentrations within and across assays and evaluated their ability to differentiate healthy controls from individuals with ALS.

RESULTS: Four of the five assays demonstrated exemplary performance based on our analyses of precision and parallelism. Across the five assays, NfL concentrations were lower in plasma than in CSF, although they displayed a high degree of correlation. We noted bias across assays; plasma NfL concentrations were lowest for the Roche assay and highest for the ProteinSimple assay. In addition, all assays reliably distinguished healthy controls from individuals with ALS using plasma or CSF NfL.

CONCLUSIONS: Four NfL assays demonstrated similar analytic performance. Alongside performance, other factors such as costs, accessibility, usability, footprint, and intended use, should be considered.}, } @article {pmid40958782, year = {2025}, author = {Sun, LC and Li, WS and Chen, W and Zhao, DQ and Zhang, X and Li, CX and Ren, Z}, title = {Frontiers and Emerging Trends in Edaravone Research: A Bibliometric Analysis of Molecular Basis and Clinical Studies Using CiteSpace and VOSviewer.}, journal = {Journal of multidisciplinary healthcare}, volume = {18}, number = {}, pages = {5743-5758}, pmid = {40958782}, issn = {1178-2390}, abstract = {PURPOSE: Edaravone is a potent free-radical scavenger and antioxidant that has been widely investigated for its therapeutic potential in neurodegenerative diseases and oxidative stress-related conditions. Although previous studies have explored its molecular structure, pharmacological effects, and clinical applications, a comprehensive bibliometric analysis of its research trends and future directions remains lacking.

METHODS: This study employed bibliometric methods to analyze edaravone-related publications from 2000 to 2024, using the Web of Science Core Collection database. The analysis examined publication trends; contributions by countries, institutions, and authors; and keyword clustering. Data visualization tools, such as CiteSpace and VOSviewer, were utilized to identify research clusters and emerging trends in edaravone research.

RESULTS: The findings revealed a significant increase in edaravone-related publications, with China, Japan, and the United States as the leading contributors. Notable researchers, including Abe K and Yoshino H, have made substantial contributions to this field. Four major research clusters were identified: free radical scavenging, cerebral infarction, amyotrophic lateral sclerosis, and oxidative stress. Emerging trends suggest a growing interest in edaravone dexbornel for acute ischemic stroke treatment, as well as its potential applications in blood-brain barrier interactions and Alzheimer's disease.

CONCLUSION: This bibliometric analysis highlights the growing interest in edaravone and its potential clinical application, particularly in neuroprotection. While this study provides valuable insights into current research trends, future studies should incorporate a broader range of sources and languages to obtain a more comprehensive understanding of the impact and scope of edaravone.}, } @article {pmid40959204, year = {2025}, author = {Huang, C and Zheng, X and Wu, J and Li, J and Lin, Y and Chen, Y and Li, C and Song, X and Wang, W and Liu, Z and Wu, J and Gao, J and Tu, Z and Zhang, Z and Lai, L and Li, S and Li, XJ and Yan, S}, title = {A Novel Genetic TDP-43 Pig Model Mimics Multiple Key ALS-Like Features.}, journal = {MedComm}, volume = {6}, number = {9}, pages = {e70330}, pmid = {40959204}, issn = {2688-2663}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that lacks ideal models to comprehensively recapitulate its pathological features. TDP-43 pathology, a hallmark of neurodegenerative diseases, plays a critical role in disease progression. Given the anatomical and physiological similarities between pig and human brains, large animal models offer a unique advantage in more accurately simulating patient-specific disease characteristics. In this study, we rapidly established a TDP-43-induced neurodegenerative disease model in pigs through ear vein injection of the TDP-43[M337V] virus. Disease progression was systematically evaluated using behavioral assessments and pathological analyses. This porcine model produced extremely severe motor dysfunction accompanied by significant muscle atrophy and fibrosis. Additionally, characteristic TDP-43 pathological phenotypes were observed, including degeneration of spinal motor neurons and proliferation of glial cells in both the brain and spinal cord. Notably, TDP-43[M337V] induction led to a significant upregulation of TMEM106B, SOD1, and APOE4 levels. This TDP-43 porcine model recapitulates multiple key features of ALS and serves as a valuable complement to existing animal models, providing a robust platform for investigating TDP-43-related pathogenic mechanisms of TDP-43 and developing effective therapeutics.}, } @article {pmid40960157, year = {2025}, author = {Wang, J and Dai, L and Zhang, Z}, title = {Protein aggregation in neurodegenerative diseases.}, journal = {Chinese medical journal}, volume = {138}, number = {21}, pages = {2753-2768}, pmid = {40960157}, issn = {2542-5641}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; *Protein Aggregation, Pathological/metabolism ; DNA-Binding Proteins/metabolism ; Animals ; *Protein Aggregates/physiology ; }, abstract = {Neurodegenerative diseases constitute a group of chronic disorders characterized by the progressive loss of neurons. Major neurodegenerative conditions include Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Pathologically, these diseases are marked by the accumulation of aggregates formed by pathological proteins such as amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. These proteins assemble into amyloid fibrils that undergo prion-like propagation and dissemination, ultimately inducing neurodegeneration. Understanding the biology of these protein aggregates is fundamental to elucidating the pathophysiology of neurodegenerative disorders. In this review, we summarize the molecular mechanisms underlying the aggregation and transmission of pathological proteins, the processes through which these protein aggregates trigger neurodegeneration, and the interactions between different pathological proteins. We also provide an overview of the current diagnostic approaches and therapeutic strategies targeting pathological protein aggregates.}, } @article {pmid40960388, year = {2026}, author = {Jhilal, S and Marchesotti, S and Thirion, B and Soudrie, B and Giraud, AL and Mandonnet, E}, title = {Implantable Neural Speech Decoders: Recent Advances, Future Challenges.}, journal = {Neurorehabilitation and neural repair}, volume = {40}, number = {2}, pages = {157-172}, doi = {10.1177/15459683251369468}, pmid = {40960388}, issn = {1552-6844}, mesh = {Humans ; *Speech/physiology ; *Locked-In Syndrome/rehabilitation/physiopathology ; *Brain-Computer Interfaces ; }, abstract = {The social life of locked-in syndrome (LIS) patients is significantly impacted by their difficulties to communicate. Consequently, researchers have started to explore how to decode intended speech from neural signals directly recorded from the cortex. The first studies in the late 2000s reported modest decoding accuracies. However, thanks to fast advances in machine learning, the most recent studies have reached decoding accuracies high enough to be optimistic about the clinical benefit of neural speech decoders in the near future. We first discuss the selection criteria for implanting a neural speech decoder in LIS patients, emphasizing the advantages and disadvantages associated with conditions such as brainstem stroke and amyotrophic lateral sclerosis. We examine the key design considerations for neural speech decoders, demonstrating how successful implantation requires careful optimization of multiple interrelated factors including language representation, cortical recording areas, neural features, training paradigms, and decoding algorithms. We then discuss current approaches and provide arguments for potential improvements in decoder design and implementation. Finally, we explore the crucial question of who should learn to use the neural speech decoder-the patient, the machine, or both. In conclusion, while neural speech decoders present promising avenues for improving communication for LIS patients, interdisciplinary efforts spanning neurorehabilitation, neuroscience, neuroengineering, and ethics are imperative to design future clinical trials.}, } @article {pmid40960392, year = {2025}, author = {Scott, DD and Jena, L and Rajaram, A and Ang, J and Perez-Miller, S and Kumirov, V and Khanna, R and Khanna, M}, title = {Identifying interactions between TDP-43's N-terminal and RNA-binding domains.}, journal = {Protein science : a publication of the Protein Society}, volume = {34}, number = {10}, pages = {e70295}, pmid = {40960392}, issn = {1469-896X}, support = {ALSAL230220//DOD/ ; T32 GM008804/GM/NIGMS NIH HHS/United States ; R01 NS136684/NS/NINDS NIH HHS/United States ; GM008804/NH/NIH HHS/United States ; //University of Arizona/ ; 1R01NS136684-01/NH/NIH HHS/United States ; }, mesh = {*DNA-Binding Proteins/chemistry/metabolism/genetics ; Humans ; Protein Domains ; Nuclear Magnetic Resonance, Biomolecular ; *RNA/chemistry/metabolism ; Protein Binding ; Binding Sites ; *RNA-Binding Proteins/chemistry/metabolism ; }, abstract = {TAR DNA-binding Protein 43 kilodaltons (TDP-43) plays a crucial role in the pathophysiology and progression of amyotrophic lateral sclerosis, affecting familial and sporadic cases. TDP-43 is an intrinsically disordered multidomain protein that consists of an N-terminal domain (NTD1-102), two tandem RNA recognition motifs (RRM1102-177 and RRM2191-260), and an intrinsically disordered glycine-rich C-terminal261-414 domain. We previously identified a chemical probe that led to allosteric alterations between the RRM and NTD of TDP-43. We attributed these changes to potential interdomain interactions between the NTD and RRM segments. In this work, we compared the 2D [[1]H,[15]N] HSQC-NMR resonances of two constructs, TDP-43102-260 (RRM domain alone) against TDP-431-260 (NTD linked to RRM) and observed clustered shifts in the RNA-binding sites of both RRM domains. To investigate why these shifts appeared in the RRM domains in the absence of RNA, we hypothesized that the NTD domain could be stacking on the RRM domains. Thus, we modeled NTD-RRM interactions using protein-protein docking of TDP-43 subdomains that propose NTD stacking onto the RRM domains. Using Carr-Purcell-Meiboom-Gill NMR spectroscopy, we demonstrated evidence of an interaction between NTD1-102 and RRMs102-260. Finally, we investigated the impact of NTD on RNA binding using 2D [15]N-HSQC-NMR and microscale thermophoresis by titration of a short UG-rich RNA sequence and observed significant changes in RNA binding between TDP-43102-260 and TDP-431-260, further suggesting the NTD plays a role in TDP-43 RNA interactions.}, } @article {pmid40961613, year = {2025}, author = {Velasco Pereira, EA and Navarro-Cerrillo, RM}, title = {Post-fire regeneration dynamics of heterogeneous Mediterranean ecosystems using Landsat and ALS data.}, journal = {The Science of the total environment}, volume = {1001}, number = {}, pages = {180435}, doi = {10.1016/j.scitotenv.2025.180435}, pmid = {40961613}, issn = {1879-1026}, mesh = {*Environmental Monitoring/methods ; *Forests ; *Wildfires ; *Remote Sensing Technology ; *Ecosystem ; Mediterranean Region ; Pinus ; }, abstract = {Wildfires are major ecological disturbances that profoundly alter forest structure and function. However, the long-term structural recovery of Mediterranean ecosystems remains insufficiently understood, particularly across heterogeneous vegetation types. This study addresses this gap by developing and validating an integrated remote sensing methodology that combines multi-temporal Landsat imagery and low-density Airborne Laser Scanning (ALS) data to assess post-fire vegetation recovery over a 20-30-year period in Mediterranean forests dominated by Quercus ilex, Pinus halepensis, and shrubland. Random Forest models were used to relate ALS-derived structural attributes-vegetation height, canopy cover, and height diversity-to Landsat vegetation indexes and topographic predictors and applied Bayesian Additive Regression Trees (BART) to identify key drivers of regeneration. The ALS-Landsat models showed high predictive performance (R[2] = 0.68-0.94), with height diversity index (LHDI) achieving the highest accuracy across vegetation types. BART models explained up to 72 % of the variability in post fire structural metrics, identifying temperature, plant community, and succession stage as primary determinants of recovery. Results reveal distinct regeneration trajectories: shrublands exhibited rapid recovery in cover and height, while Pinus forests showed the slowest structural rebound, with many areas failing to regain pre-fire height after 30 years. These findings underscore the value of integrating ALS and Landsat data for monitoring postfire recovery of forest structural variables offering practical insights to guide post-fire restoration efforts.}, } @article {pmid40961705, year = {2025}, author = {Zhang, W and Munyaneza, V and Yi, B and Zhang, X and Zhang, P and Kant, S and Xu, F and Ding, G}, title = {Tolerance to aluminum toxicity in Brassica napus is mediated by regulating cell wall Al sequestration, antioxidant defense, and metabolic adaptation.}, journal = {Journal of hazardous materials}, volume = {498}, number = {}, pages = {139837}, doi = {10.1016/j.jhazmat.2025.139837}, pmid = {40961705}, issn = {1873-3336}, abstract = {Aluminum (Al) toxicity significantly limits crop growth in acidic soils. Here, we investigated the physiological responses of Al-tolerant (Al-T 806) and Al-sensitive (Al-S 482) Brassica napus cultivars under Al stress. The results revealed that Al-S 482 exhibited significant biomass reduction and root system damage under Al stress. Compared to Al-T 806, Al-S 482 accumulated higher levels of reactive oxygen species (ROS), including hydrogen peroxide (H2O2) and superoxide anions (O2[-]). Although both cultivars accumulated Al in their roots, Al-T 806 exhibited lower Al than Al-S 482. Notably, Al toxicity was primarily linked to Al accumulation in cell, with most Al tightly bound to Alkali-soluble pectin (ASP) and hemicellulose 1 (HC1). Al stress triggered significant increase in pectin synthesis and pectin methylesterase (PME) activity, particularly in the water-soluble pectin (WSP) fraction, increasing Al binding sites and promoting Al oxidation within cell walls. Additionally, increased organic acid production and shifts in tricarboxylic acid (TCA) cycle metabolites reduced energy demands, providing a key defense against Al toxicity. These findings offer insights into the physiological mechanisms underlying Al tolerance in B. napus, contributing to the development of Al-tolerant crop varieties.}, } @article {pmid40962156, year = {2025}, author = {Yipeng, X and Guiqian, W and Qiaochu, Z and Tengjie, H and Yan, Z and Hai, H and Jing, Z}, title = {Molecular mechanisms by which mitochondrial dysfunction drives neuromuscular junction degeneration in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {216}, number = {}, pages = {107103}, doi = {10.1016/j.nbd.2025.107103}, pmid = {40962156}, issn = {1095-953X}, support = {//Natural Science Foundation of Hubei Province/ ; //Natural Science Foundation of Hubei Province/ ; //2025–2026 Chinese Medicine Scientific Research Project of the Hubei Provincial Administration of Traditional Chinese Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Neuromuscular Junction/pathology/metabolism ; *Mitochondria/metabolism/pathology ; Animals ; Oxidative Stress/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive degeneration of motor neurons and early deterioration of neuromuscular junctions (NMJs). Increasing evidence indicates that mitochondrial dysfunction plays a pivotal role in driving NMJ degeneration in ALS.

OBJECTIVE: This review aims to comprehensively summarize the molecular mechanisms by which mitochondrial defects contribute to NMJ instability, with a particular focus on bioenergetics, calcium homeostasis, oxidative stress, and impaired mitochondrial biogenesis.

CONCLUSION: Mitochondrial dysfunction is a core driver of NMJ degeneration in ALS. Targeting mitochondrial biogenesis and metabolism-particularly through the PGC-1α pathway-represents a promising strategy to preserve NMJ integrity and slow disease progression.}, } @article {pmid40964304, year = {2025}, author = {Galloway, DA and Patterson, HL and Hoye, ML and Shen, T and Shabsovich, M and Schoch, KM and Ly, CV and Miller, TM}, title = {miR-146a is a Pleiotropic Regulator of Motor Neuron Degeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40964304}, issn = {2692-8205}, support = {F31 NS092340/NS/NINDS NIH HHS/United States ; R01 NS078398/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Here, we have profiled motor neuron microRNAs (miRNAs) during motor neuron degeneration in vivo to gain a better understanding of ALS pathophysiology. We demonstrate that one miRNA, miR-146a, is downregulated in diseased motor neurons despite upregulation in bulk tissue. Genetic deletion of miR-146a significantly extended survival in SOD1[G93A] mice with heterozygous animals demonstrating the largest benefit. A corresponding reduction in spinal cord gliosis but not motor neuron loss was observed. Finally, we observed that a proportion of miR-146a knockout animals develop spontaneous paralysis, motor neuron loss and chronic neuroinflammation with advanced age. Together these findings demonstrate that a single miRNA influences multiple aspects of motor neuron disease and highlights the complex role for neuroinflammation in ALS pathogenesis.}, } @article {pmid40964393, year = {2025}, author = {Streltsov, VA and Ganio, KE and Nuttall, SD and Hernandez, JA and Dennys, CN and Crouch, PJ and Estevez, AG and Franco, MC and Beckman, JS and Roberts, BR}, title = {The structure, redox chemistry and motor neuron toxicity of heterodimeric zinc-deficient SOD1-Implications for the toxic gain of function observed in ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40964393}, issn = {2692-8205}, support = {R01 AG070937/AG/NIA NIH HHS/United States ; R01 AG085587/AG/NIA NIH HHS/United States ; U01 AG061357/AG/NIA NIH HHS/United States ; }, abstract = {A subset of familial cases of amyotrophic lateral sclerosis (fALS) are caused by mutations to copper, zinc superoxide dismutase (Cu, Zn SOD1). There are over 200 mutations to SOD1 that have been associated with fALS and the majority of these mutations are dominantly inherited. Thus, individuals are heterozygous and express both wild-type SOD1 and the mutant form of the protein. Paradoxically, when rodent models are produced that mimic the co-expression of wild-type SOD1 with mutant fALS SOD1 the motor neuron disease accelerates. Previously, we have shown that the loss of zinc from an SOD1 kills cultured motor neurons due to a gained, redox activity catalyzed by the active-site copper. Furthermore, motor neuron toxicity of zinc-deficient SOD1 is enhanced by wild-type Cu, Zn SOD1. Because SOD1 exists as a non-covalent dimer, the enhanced toxicity might result from stabilization of the heterodimeric interface between zinc-deficient SOD1 and Cu, Zn-SOD1. However, experimentation with the heterodimer is difficult because SOD1 subunits exchange in minutes. To better characterize the role of dimer stabilization on the enhanced toxicity of fALS mutant SOD1 by wild type SOD1, we genetically tethered a zinc-deficient SOD1 subunit with a Cu, Zn SOD1 subunit with a 16-residue linker. The x-ray structure of the tethered heterodimer shows that zinc-deficient subunit adopts a wild-type-like conformation and is not misfolded. The heterodimer intermediate also produced peroxynitrite from nitric oxide, and the tethered SOD1 was strikingly toxic to primary cultures of motor neurons. This work supports the concept that zinc-deficient SOD1 is a likely toxic intermediate in ALS. Furthermore, the wild-type allele in human familial-SOD1 ALS patients may physically contribute to the dominant inheritance of SOD1 mutations through heterodimer formation.}, } @article {pmid40964461, year = {2025}, author = {Chen, HW}, title = {Sustained Bulbar and Respiratory Function in a Case Most Consistent With Bulbar-Onset Amyotrophic Lateral Sclerosis Following Axial Spinal Traction: A 21-Month Report.}, journal = {Cureus}, volume = {17}, number = {9}, pages = {e92341}, pmid = {40964461}, issn = {2168-8184}, abstract = {Bulbar-onset amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by early decline in speech, swallowing, and respiratory function, and is associated with a poor prognosis. We report the case of a woman whose treating neurologist determined, eight months after symptom onset, that her presentation was most consistent with bulbar-onset ALS. At 16 months, she began receiving intermittent pelvis-stabilized axial spinal traction (PSAST) as a supportive intervention. Remarkably, over the subsequent 21 months, she maintained oral intake and preserved respiratory function, an outcome atypical of the expected trajectory of bulbar-onset ALS. While this single case relies on provider reports for diagnostic confirmation, it raises the hypothesis that axial spinal traction may help sustain bulbar and respiratory function in ALS. Given the lack of effective treatment options, we present this case to raise awareness of a potential supportive approach that warrants further investigation.}, } @article {pmid40965373, year = {2025}, author = {Calcagno, N and Scirocco, E and Clampffer, E and Addy, G and Morgan, S and Parikh, N and Neel, DV and Scalia, J and Young, R and Locatelli, M and Mackie, DS and Berry, JD and Paganoni, S}, title = {Real-World Clinical Experience With Sodium Phenylbutyrate and Taurursodiol at a Single Amyotrophic Lateral Sclerosis Center in the United States.}, journal = {European journal of neurology}, volume = {32}, number = {9}, pages = {e70360}, pmid = {40965373}, issn = {1468-1331}, support = {//Amylyx Pharmaceuticals Inc/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; *Phenylbutyrates/therapeutic use/adverse effects ; Retrospective Studies ; Middle Aged ; Aged ; United States ; Adult ; }, abstract = {INTRODUCTION/AIMS: Sodium phenylbutyrate (PB) and taurursodiol (TURSO)-PB and TURSO-was approved as a treatment for amyotrophic lateral sclerosis (ALS) in the United States in 2022 based on the results of a phase 2 trial, but was voluntarily withdrawn from the market in 2024 after negative results from its phase 3 trial. The objective of our study was to describe the real-world clinical experience with PB and TURSO at one ALS clinic.

METHODS: This was a retrospective chart review of all ALS patients receiving a PB and TURSO prescription at the Massachusetts General Hospital ALS Clinic between October 1, 2022, and September 30, 2023. Data were extracted from patients' electronical medical records up to December 31, 2023.

RESULTS: A total of 441 ALS patients received a PB and TURSO prescription, with 329 (75%) initiating the medication. The average length of treatment was 285 days, and the rate of drug discontinuation during the study period was 41% (N=135). The most common reason for drug discontinuation was side effects (N=93, 69%), with the most common being gastrointestinal issues (N=69). No hospitalizations, deaths, or serious adverse events were considered related to treatment with PB and TURSO.

DISCUSSION: Experience in real-world clinical settings can help supplement trial data with information on the drug performance at various stages of disease progression. Adverse events impacted treatment persistence in routine clinical practice, underscoring the need for vigilant monitoring and tailored supportive interventions to optimize treatment adherence.}, } @article {pmid40966555, year = {2025}, author = {Weber, D}, title = {Amyotrophic Lateral Sclerosis.}, journal = {Radiologic technology}, volume = {96}, number = {6}, pages = {441-445}, pmid = {40966555}, issn = {1943-5657}, } @article {pmid40966720, year = {2026}, author = {Ljubikj, T and Mars, MZ and van der Geest, AT and Jakobs, CE and Bessler, N and Donega, V and van den Oetelaar, XPRM and de Wit, M and Pasterkamp, RJ}, title = {PU.1 restores microglial dysfunction caused by C9ORF72 repeat expansions in neural organoids.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {3}, pages = {801-817}, pmid = {40966720}, issn = {1460-2156}, support = {//Stichting ALS Nederland/ ; //MAXOMOD and INTEGRALS consortia/ ; //ERANet/ ; //ALS CURE project/ ; //Alzheimer Nederland/ ; //EU joint Program Neurodegenerative Diseases/ ; }, mesh = {*Microglia/metabolism/pathology ; *C9orf72 Protein/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Trans-Activators/metabolism/genetics ; *Proto-Oncogene Proteins/metabolism/genetics ; *Organoids/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Phagocytosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of upper and lower motor neurons and progressive muscle wasting. Accumulating evidence indicates a role for non-neuronal cells in ALS pathogenesis, but their exact role and mechanism-of-action remain incompletely understood. A hexanucleotide (GGGGCC) repeat expansion (HRE) in C9ORF72 is the most common genetic cause of ALS (C9-ALS) and a frequent cause of frontotemporal dementia (FTD). Several lines of experimental evidence support a role for the immune system and microglia in C9-ALS/FTD, and depending on experimental settings and species used, both reduced and increased microglial activity have been reported. To further study microglia in C9-ALS/FTD in the context of a complex, 3D disease environment, we developed cerebral organoids that innately develop microglia derived from induced pluripotent stem cells (iPSCs) of C9-ALS/FTD patients and controls. Here, we show reduced cellular complexity and transcriptional changes in C9 neural organoid-derived microglia (C9-oMGs), involving phagocytic, lysosomal and immune response pathways. The release of inflammatory cues from C9-ALS/FTD organoids is decreased and LAMP1 expression in C9-oMGs is reduced. Functional analysis using live imaging reveals impaired phagocytosis by C9-oMGs and reduced engulfment of the post-synaptic protein PSD-95 by C9-oMGs in organoids. Finally, our transcriptomics analysis identifies a PU.1 (encoded by SPI1) regulon as the most strongly downregulated transcription factor network in C9-oMGs. Viral overexpression of PU.1 rescues phagocytosis and gene expression defects in C9-microglia. Overall, our data demonstrate reduced microglial functions in a complex cellular disease environment and identify PU.1 as a potential target for restoring microglia changes in C9-ALS/FTD.}, } @article {pmid40966842, year = {2025}, author = {Sipilä, J and Jokela, M and Solje, E}, title = {Municipality-level incidence of clinically diagnosed amyotrophic lateral sclerosis, multiple sclerosis and Parkinson's disease.}, journal = {Journal of the neurological sciences}, volume = {478}, number = {}, pages = {123696}, doi = {10.1016/j.jns.2025.123696}, pmid = {40966842}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Male ; Incidence ; *Parkinson Disease/epidemiology/diagnosis ; Female ; *Multiple Sclerosis/epidemiology/diagnosis ; Middle Aged ; Aged ; Finland/epidemiology ; Registries ; Adult ; Cohort Studies ; Cities/epidemiology ; }, abstract = {BACKGROUND: The prevalences of Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Parkinson's Disease (PD) have been shown to covary which suggests that they may share common pathogenetic factors.

OBJECTIVE: Investigate the contemporaneous incidence patterns of ALS, MS, and PD on a municipal level in easternmost Finland.

METHODS: Previously published ALS (years 2010-2018) and MS (years 2012-2016) cohorts were leveraged and PD data (years 2010-2018) were obtained from the national drug reimbursement entitlement registry. Population data were collected from a governmental registry.

RESULTS: There were no municipalities with high incidences of all three disorders in both sexes. An ALS hotspot was observed in southeastern municipality of Tohmajärvi, driven by men. PD incidence was lowest in the central municipalities, around the urban area. Age-adjusted ALS and PD incidence was high and MS incidence low in Nurmes. Analyses of ALS and PD incidences using population aged >45 as reference showed an area of low PD incidence in the westernmost municipalities but no clear ALS incidence pattern. No municipality showed a high incidence of both disorders but the ones with the highest incidences are neighboring municipalities (Tohmajärvi and Kitee) in the southern part of the province. There was no correlation between ALS and PD incidence (p = 0.17).

CONCLUSIONS: Contemporaneous incidences of ALS, MS, and PD showed no correlations. These results suggest that epidemiological research for their common pathogenic factors needs to employ very long study periods and birth cohorts in large populations. Neuropathological and/or biomarker validation of cases should also be included whenever possible.}, } @article {pmid40967210, year = {2025}, author = {Wang, Y and van Dijk, C and Timpanaro, I and Hop, P and Kenna, B and Kooyman, M and Aronica, E and Pasterkamp, RJ and van den Berg, LH and Cooper-Knock, J and , and , and Veldink, JH and Kenna, K}, title = {SpliPath enhances disease gene discovery in case-control analyses of rare splice-altering genetic variants.}, journal = {Cell reports methods}, volume = {5}, number = {10}, pages = {101176}, pmid = {40967210}, issn = {2667-2375}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/genetics ; *RNA Splicing/genetics ; Case-Control Studies ; Quantitative Trait Loci/genetics ; *Genetic Variation/genetics ; Genetic Predisposition to Disease ; }, abstract = {We developed SpliPath as a generalizable framework to discover disease associations mediated by rare variants that induce experimentally supported mRNA splicing defects. Our approach integrates components of burden tests (BTs), traditional splicing quantitative trait locus (sQTL) analyses, and sequence-to-function AI models (SpliceAI and Pangolin). Central to the workings of SpliPath is our concept of collapsed rare variant splicing QTL (crsQTL). crsQTL groups rare variants that are predicted to alter splicing in the same way, specifically by linking them to shared splice junctions observed in independent (unpaired) RNA sequencing (RNA-seq) datasets. We demonstrate the utility of SpliPath through applications in amyotrophic lateral sclerosis (ALS). Through this, we showcase scenarios where SpliPath detects genetic associations that cannot be recovered by more simplistic combinations of BT and SpliceAI. We also nominate crsQTL for splice defects detected in large-scale analyses of ALS patient tissue.}, } @article {pmid40967225, year = {2025}, author = {McKeever, PM and Sababi, AM and Sharma, R and Xu, Z and Xiao, S and McGoldrick, P and Ketela, T and Sato, C and Moreno, D and Visanji, N and Kovacs, GG and Keith, J and Zinman, L and Rogaeva, E and Goodarzi, H and Bader, GD and Robertson, J}, title = {Single-nucleus transcriptome atlas of orbitofrontal cortex in ALS with a deep learning-based decoding of alternative polyadenylation mechanisms.}, journal = {Cell genomics}, volume = {5}, number = {12}, pages = {101007}, pmid = {40967225}, issn = {2666-979X}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *Polyadenylation/genetics ; *Deep Learning ; *Transcriptome/genetics ; *Prefrontal Cortex/metabolism/pathology ; Male ; C9orf72 Protein/genetics ; Female ; Frontotemporal Lobar Degeneration/genetics ; Middle Aged ; Aged ; Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are fatal neurodegenerative diseases sharing clinical and pathological features. Both involve complex neuron-glia interactions, but cell-type-specific alterations remain poorly defined. We performed single-nucleus RNA sequencing of the frontal cortex from C9orf72-related ALS (with and without FTLD) and sporadic ALS (sALS). Neurons showed prominent changes in mitochondrial function, protein homeostasis, and chromatin remodeling. Comparison with independent datasets from other cortical regions revealed consistent pathway alterations, including upregulation of STMN2 and NEFL across brain regions and subtypes. We further examined dysregulation of alternative polyadenylation (APA), an understudied post-transcriptional mechanism, uncovering cell-type-specific APA patterns. To investigate its regulation, we developed the alternative polyadenylation network (APA-Net), a multi-modal deep learning model integrating transcript sequences and RNA-binding protein (RBP) expression profiles to predict APA. This atlas advances our understanding of ALS/FTLD molecular pathology and provides a valuable resource for future mechanistic studies.}, } @article {pmid40967795, year = {2026}, author = {Machino, Y and Wakita, H and Niwa, A and Tomimoto, H and Shindo, A}, title = {Alterations of the Cytokines, Chemokines, and Growth Factors in the Cerebrospinal Fluid of Patients with Advanced-stage Amyotrophic Lateral Sclerosis.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {65}, number = {8}, pages = {1115-1119}, pmid = {40967795}, issn = {1349-7235}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Male ; Female ; Middle Aged ; Aged ; *Chemokines/cerebrospinal fluid ; *Cytokines/cerebrospinal fluid ; *Intercellular Signaling Peptides and Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Interleukin-15/cerebrospinal fluid ; Adult ; Interleukin-2/cerebrospinal fluid ; Interleukin-1beta/cerebrospinal fluid ; }, abstract = {Objective Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that mainly affects the motor neuron system and activates multiple molecular pathways including neuroinflammation. Changes in the levels of cytokines, chemokines, and growth factors in patients with advanced-stage ALS have not yet been reported. This study analyzed the levels of inflammatory cytokines, chemokines, and growth factors in the cerebrospinal fluid of ALS patients with an average ALS functional rating scale score revised (ALSFRS-R) of less than 10. Methods We analyzed the levels of 16 cytokines, 6 chemokines, and 5 growth factors in the CSF of patients with ALS. These levels were compared between patients with ALS and healthy controls. The relationship between ALSFRS-R and interleukin (IL)-1β, IL-2, and IL-15 levels was assessed. The discriminating ability of IL-1β, IL-2, and IL-15 was evaluated using a receiver operating characteristic curve analysis. Results The IL-1β, IL-2, and IL-15 levels in the CSF of patients with ALS were significantly higher than those in controls. IL-1β, IL-2, and IL-15 levels were negatively correlated with ALSFRS-R and demonstrated discriminatory ability between the ALS and control groups. Conclusion Our findings suggest that neuroinflammation may contribute to the pathomechanism of ALS, even in advanced stages, and that IL-1β, IL-2, and IL-15 may serve as potential immune parameters for advanced-stage ALS.}, } @article {pmid40968018, year = {2026}, author = {Parnianpour, P and Harrison, M and Benatar, M and Briemberg, H and Dionne, A and Dupré, N and Frayne, R and Genge, A and Graham, SJ and Korngut, L and Seres, P and Wilman, A and Zinman, L and Kalra, S and , }, title = {Progressive and Short-Interval Changes Observed in the Corticospinal Tract and Corpus Callosum of Patients with Amyotrophic Lateral Sclerosis: A Texture Analysis Study.}, journal = {AJNR. American journal of neuroradiology}, volume = {47}, number = {3}, pages = {714-722}, pmid = {40968018}, issn = {1936-959X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Pyramidal Tracts/pathology ; *Corpus Callosum/pathology ; Male ; Female ; Middle Aged ; Aged ; Disease Progression ; *Diffusion Tensor Imaging/methods ; *Image Interpretation, Computer-Assisted/methods ; Reproducibility of Results ; Sensitivity and Specificity ; Adult ; }, abstract = {BACKGROUND AND PURPOSE: Diffusion MRI measures indicative of white matter integrity have consistently been shown to be altered in the state of the corticospinal tract (CST) and corpus callosum (CC) of patients with amyotrophic lateral sclerosis (ALS). However, diffusion MRI acquisitions are not routinely collected as part of the standard medical imaging of patients with ALS. T1-weighted MRI scans are commonly available in the clinical assessment of most patients with ALS. While visual inspection of these scans reveals little about the cerebral pathology of ALS, analysis of their textural patterns has identified disease-related abnormalities in patients at various stages of the disease. The present study aimed to examine the spatial and temporal profile of CST and CC degeneration in patients with ALS using texture analysis of T1-weighted MRI scans obtained at baseline and at 4- and 8-month follow-ups.

MATERIALS AND METHODS: The study involved data from 64 patients with ALS and 83 healthy controls who participated in the multicenter Canadian ALS Neuroimaging Consortium (CALSNIC) project. The texture feature "autocorrelation" (autoc) was quantified along the superior-inferior course of the CST and along the anterior-posterior direction of the CC of participants.

RESULTS: Progressive textural changes were observed within the bilateral CST, particularly in the primary motor cortex region, posterior limb of the internal capsule, and the cerebral peduncle. As the disease progressed, significant textural changes developed in the middle and anterior parts of the CC. Autoc values in these regions correlated with the degree of upper motor neuron dysfunction on neurologic examination.

CONCLUSIONS: Progressive CST and CC degeneration was characterized in ALS using a novel imaging texture analysis approach, with changes observed over an interval of 4 months.}, } @article {pmid40968351, year = {2025}, author = {Jiang, Q and Wei, Q and Yang, T and Lin, J and Xiao, Y and Li, C and Zhang, L and Hou, Y and Ou, R and Wang, S and Liu, J and Liang, Y and Shang, H}, title = {Association between metabolic syndrome, its individual components and progression of amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {11}, pages = {5855-5862}, pmid = {40968351}, issn = {1590-3478}, support = {YCXJ-JZ-2022-007//Beijing E-town Coorperation & Development Foundation/ ; 2022ZDZX0023//Sichuan Science and Technology Program/ ; 82101485//National Natural Science Foundation of China/ ; 2023YFQ0098//Science and Technology Bureau Fund of Sichuan Province of China/ ; }, mesh = {*Metabolic Syndrome/blood/complications ; *Amyotrophic Lateral Sclerosis/blood/complications/mortality ; Prevalence ; Blood Glucose/metabolism ; Glycated Hemoglobin/metabolism ; Lipids/blood ; Logistic Models ; Kaplan-Meier Estimate ; Lower Extremity/pathology ; *Disease Progression ; Proportional Hazards Models ; Hypertension/blood/complications ; Glucose Intolerance/blood/complications ; Dyslipidemias/blood/complications ; Severity of Illness Index ; Humans ; Male ; Female ; Middle Aged ; Aged ; Retrospective Studies ; }, abstract = {BACKGROUND: Metabolic abnormalities play a pivotal role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Metabolic syndrome (MetS), a cluster of metabolic disorders, is highly prevalent among the elderly. However, the association between MetS and clinical characteristics, disease progression, and survival in ALS remains unclear.

METHODS: We included 529 ALS patients and collected demographic, clinical, and hematological data, including blood glucose, HbA1c, and lipid profiles. Patients were followed longitudinally. MetS was defined according to the criteria of the Chinese Diabetes Society. Multivariate logistic regression, Kaplan-Meier survival analysis, and Cox proportional hazards models were used to analyze.

RESULTS: Compared to ALS patients without MetS, those with MetS had higher proportion of lower limb onset (44.3% vs. 24.6%, P < 0.001), and a faster disease progression rate (0.60 vs. 0.55, P = 0.022). After adjusting for confounders, MetS and hypertension were significantly associated with fast disease progression (OR = 1.808, 95% CI: 1.048-3.120, P = 0.033; OR = 2.615, 95% CI: 1.358-5.035, P = 0.004), and remained significant after multiple correction. Interaction analysis revealed significant interactions between glucose intolerance and dyslipidemia (P = 0.038), and between glucose intolerance and BMI (P = 0.040), but lost significance after multiple correction. There was no significant difference in survival between ALS patients with and without MetS. After adjusting for confounders, there was no significant association between MetS and the risk of death.

CONCLUSION: MetS, particularly in the presence of hypertension, was associated with fast disease progression in ALS, though not with survival. These suggest metabolic dysfunction may influence ALS progression and warrant further investigation.}, } @article {pmid40968767, year = {2025}, author = {Prado, M and Adiao, KJ}, title = {Disease-Modifying Therapies in Amyotrophic Lateral Sclerosis: A Network Meta-Analysis of Randomized Clinical Trials.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-14}, doi = {10.1017/cjn.2025.10429}, pmid = {40968767}, issn = {0317-1671}, abstract = {BACKGROUND: Currently, there are no head-to-head studies to compare the efficacy of riluzole, edaravone, sodium phenylbutyrate and taurursodiol (SPT) and tofersen. This study aims to compare all possible interventions for amyotrophic lateral sclerosis (ALS) using network meta-analysis (NMA) methods.

METHODS: A conventional meta-analysis was done if at least two studies with the same intervention, control and outcomes were present. Since all studies included were randomized clinical trials, a NMA comparing five interventions was done, especially when similarity and consistency were assured. Both riluzole and edaravone had three clinical trials included, while SPT and tofersen each had one.

RESULTS: A total of 1601 ALS patients were included in this review, 1185 in the intervention group and 416 in the control group. Compared to placebo, ALS patients taking riluzole had 36% higher probability of surviving (OR: 1.36, I[2] = 4%, p = 0.03, FEML) while those in the edaravone group had 1.44 point lower ALSFRS-R score (SMD: 1.44, p = 0.19, I[2] = 98%, REML) at study end. Comparing all interventions in terms of mortality, all no interventions were significantly different to placebo. Moreover, compared to one another, no statistically significant differences were noted.

CONCLUSION: Despite the benefit of riluzole in terms of survival in conventional meta-analysis, non-significant findings and the lack of comparison of ALSFRS-R to placebo, edaravone, SPT and tofersen in NMA may preclude any strong recommendation for its use. Moreover, the difference in outcome measures limits important comparison between interventions, and while global consistency in NMA was satisfied, the heterogeneity of patient population limits the interpretability of our results.}, } @article {pmid40969213, year = {2025}, author = {Ciechanover, A and Livneh, I}, title = {Protein quality control systems in neurodegeneration - culprits, mitigators, and solutions?.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1604076}, pmid = {40969213}, issn = {1664-2295}, abstract = {A key hallmark of neurodegenerative diseases (NDDs) is the formation of neurotoxic protein aggregates, which are considered to reflect inadequate protein quality control (PQC). In agreement with this fundamental pathophysiologic characteristic, the two main cellular systems responsible for cellular protein removal - the ubiquitin-proteasome system (UPS) and autophagy - have been extensively studied in the context of NDD. The involvement of these proteolytic machineries was interpreted in different ways - some pointed them as dysfunctional systems that may underlie pathogenesis, while others suggested they fulfill protective roles which delay the clinical presentation of these diseases. Perhaps not surprisingly, the growing body of knowledge concerning the different types of NDD portrays a more complex picture, and no distinct generalization can be made regarding the contribution of either the neurotoxic protein substrate(s) or proteolytic system(s) to the development of NDD. For instance, in Parkinson's disease, the toxic aggregation of α-synuclein, Parkinson's canonical culprit protein, can stem from seemingly unrelated events. Among them, alterations in α-synuclein itself, a mutation in Parkin - an E3 ubiquitin ligase targeting proteins and organelles to proteasomal and lysosomal degradation, respectively, as well as a mutation in LRRK2 - a kinase postulated to be linked with α-synuclein through their common removal by chaperone-mediated autophagy. Also, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), the toxic aggregation of one protein - TDP-43 - can result from defects in other proteins, some of which are related to proteostasis, such as the shuttle protein Optineurin and the E3 ubiquitin ligase VCP. In contrast, ALS and FTLD demonstrate how common abnormalities leading to neurotoxic aggregate formation, may present clinically in profoundly different ways, from motor dysfunction to behavioral changes. In Alzheimer's Disease, the leading cause for dementia, rare cases were linked directly with PQC as they are caused by a mutation in one of the genes encoding ubiquitin itself, while the majority of cases were not directly linked to components of the two main proteolytic systems. All-in-all, the UPS and autophagy are heavily intertwined with NDD, either as part of the problem or as mitigating factors, and hopefully - as platforms for future therapeutics. In this review, we shall dissect NDDs from the perspective of protein turnover pathways, aiming to track both common and unique patterns of PQC failure in this group of diseases, which differ significantly from one another both in their clinical manifestations and affected anatomic regions, yet share the common trait of abnormal protein accumulation. We shall review some of the mechanistic understandings concerning protein aggregation in NDDs, describing the interactions of aggregated proteins with the UPS and autophagy, discuss recent controversies around the protein aggregates' hypothesis, and point to implications for developing therapeutic strategies.}, } @article {pmid40970514, year = {2025}, author = {Hartmann, C and Haß, C and Knobloch, M and Barrantes, I and Fumagalli, L and Premereur, J and Markert, F and Peters, M and Koromila, G and Hartmann, A and Jäger, K and Abel, J and Mancuso, R and Storch, A and Walter, M and Fuellen, G and Hermann, A}, title = {Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS.}, journal = {Aging cell}, volume = {24}, number = {11}, pages = {e70232}, pmid = {40970514}, issn = {1474-9726}, support = {DFG91b//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Microglia/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *RNA-Binding Protein FUS/metabolism ; *Cellular Senescence ; Active Transport, Cell Nucleus ; *Stress, Physiological ; Phagocytosis ; }, abstract = {Microglia, the brain's resident immune cells, are crucial for maintaining healthy brain homeostasis. However, as the brain ages, microglia can shift from a neuroprotective to a neurotoxic phenotype, contributing to chronic inflammation and promoting neurodegenerative processes. Despite the importance of understanding microglial aging, there are currently few human in vitro models to study these processes. To address this gap, we have developed a model in which human microglia undergo accelerated aging through inducible progerin expression. HMC3-Progerin cells display key age-related markers such as activation of the senescence-associated secretory phenotype (SASP) as well as an increase in DNA damage. These prematurely aged HMC3 cells show a reduced response to LPS activation, exhibit impairments in essential microglial functions including decreased migration and phagocytosis as well as transcriptomic alterations including a shift observed in aging and neurodegeneration. Additionally, we observed an impaired stress response and a defect in nucleocytoplasmic transport, especially affecting the amyotrophic lateral sclerosis (ALS) associated protein FUS. This suggests that microglia play a contributory role in driving neurodegenerative processes in the aging brain. Our microglia aging model offers a valuable tool for exploring how aged microglia affect brain function, enhancing our understanding of their role in brain aging.}, } @article {pmid40971138, year = {2025}, author = {Huang, X and Hou, G and Li, H and Zhu, Y and Yin, T and Zhang, N and Liu, H and Yang, Y and Bai, L and Ban, W and Zhang, J and Zhang, R and Fan, D and Ye, S}, title = {Impact of Brief Mindfulness Intervention on Emotions, Sleep and Quality of Life in Patients with Newly Diagnosed Amyotrophic Lateral Sclerosis: A Prospective Study.}, journal = {Neurology and therapy}, volume = {14}, number = {6}, pages = {2375-2386}, pmid = {40971138}, issn = {2193-8253}, support = {YJXJ-JZ-2021-0014//Beijing E-Town Cooperation & Development Foundation/ ; YCXJ-JZ-2022-007//Beijing E-Town Cooperation & Development Foundation/ ; BYSYZD2024007//PUTH Clinical Key Projects/ ; BYSYJC2024017//PUTH Fund for Interdisciplinary Research/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder causing significant suffering and mental health problems for patients. Many patients with ALS have a severe psychological reaction to the serious diagnosis when they are first diagnosed. This study aims to investigate the impact of a brief mindfulness intervention on emotions, sleep, and quality of life (QOL) in patients with ALS who have recently been diagnosed.

METHODS: This prospective intervention study enrolled patients who had been newly diagnosed with ALS. Participants received cognitive training and audio-led mindfulness exercises involving breathing awareness and body scan sessions for 10 days. The effectiveness of the intervention was evaluated by several scales.

RESULTS: Ninety-one patients (aged 54.15 [10.10] years, 52 male/39 female [57.10%/42.90%]) were finally enrolled in the analysis. The Chinese Version Perceived Stress Scale (CPSS) (t = 2.05, P = 0.04) and Epworth Sleepiness Scale (ESS) (Z = -2.03, P = 0.04) scores significantly decreased, and the 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ40) significantly increased (Z = -2.93, P < 0.01) following the brief mindfulness intervention. The Patient Health Questionnaire-9 (PHQ-9) (Z = -2.97, P < 0.01) and the 17-Item Hamilton Rating Scale for Depression (HAMD-17) (Z = -3.43, P < 0.01) were significantly reduced in patients with ALS diagnosed with depression. QOL was significantly improved in other patients with ALS (Z = -2.51, P = 0.01).

CONCLUSION: Our study indicated that a brief mindfulness intervention could be a potential way to reduce depression and improve daytime sleepiness, while also improving the QOL for newly diagnosed patients with ALS.}, } @article {pmid40971331, year = {2025}, author = {Mao, R and Zhao, S and Chen, J and Wang, L and Zheng, K and Li, B}, title = {Identification of novel biomarkers for cognitive function via an integrative analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {931-947}, doi = {10.1177/13872877251379853}, pmid = {40971331}, issn = {1875-8908}, mesh = {Animals ; Biomarkers/metabolism ; Mice ; *Alzheimer Disease/genetics/metabolism ; Humans ; *Cognition/physiology ; Disease Models, Animal ; Mice, Transgenic ; Male ; Amyloid beta-Peptides ; Genome-Wide Association Study ; Cell Line, Tumor ; Mice, Inbred C57BL ; Glutathione Peroxidase/metabolism/genetics ; Female ; Glutathione Peroxidase GPX1 ; }, abstract = {Cognitive dysfunction associated with various diseases and its biomarkers have been extensively studied. However, research focusing on biomarkers related to cognitive function remains limited. This study aims to identify potential biomarkers associated with cognitive function and validate them through in vitro and in vivo experiments to address the current research gaps. We employed GWAS, PWAS, and TWAS analyses, combined with Mendelian randomization and colocalization analysis, to identify potential cognitive function-related biomarkers from European cohorts. An Alzheimer's disease (AD) cell model was established in SH-SY5Y and BV2 cells using Aβ25-35 oligomers, and an APP/PS1 (AD mouse model) was purchased. The mRNA and protein expression levels of potential biomarkers were assessed in AD cells and mouse models using RT-qPCR and western blotting. Immunofluorescence was used to evaluate the fluorescence expression of these biomarkers in the AD cells, while immunohistochemistry was employed to assess staining intensity in the dorsolateral prefrontal cortex of AD model mice. Three potential biomarkers associated with cognitive function were identified: GPX1, CSE1L, and SULT1A1. KEGG enrichment analysis indicated that GPX1, CSE1L, and SULT1A1 are involved in various metabolic pathways, including those related to amyotrophic lateral sclerosis and Huntington's disease signaling. RT-qPCR and western blotting revealed low expression of GPX1 and CSE1L, and high expression of SULT1A1 in both AD cells and mouse models. These findings were further confirmed by immunofluorescence and immunohistochemistry, which demonstrated similar expression patterns in the AD cell and mouse models. GPX1, CSE1L, and SULT1A1 serve as biomarkers of cognitive function.}, } @article {pmid40971746, year = {2025}, author = {Kırbıyık, U and Astles, JR}, title = {Using Aggregated Proficiency Testing Results to Identify Systematic Error.}, journal = {The journal of applied laboratory medicine}, volume = {10}, number = {6}, pages = {1491-1503}, doi = {10.1093/jalm/jfaf126}, pmid = {40971746}, issn = {2576-9456}, mesh = {Humans ; *Laboratory Proficiency Testing/standards/statistics & numerical data/methods ; *Laboratories, Clinical/standards/statistics & numerical data ; *Clinical Laboratory Techniques/standards ; }, abstract = {BACKGROUND: Proficiency testing (PT) should identify systematic errors, which are likely to recur. The Clinical Laboratory Improvement Amendments of 1988 (CLIA) acceptance limits (ALs) include 3 standard deviations (3SD) and concentration limits. We investigated the ability of PT to detect systematic error, especially as affected by the different AL types.

METHODS: We removed any ungradable, duplicate, and irregular scores from CLIA laboratory PT data from 2008 to 2018. We calculated the overall miss rate, unsatisfactory event rate, i.e., score <80 (4 of 5 correct), and event rates for score 100 to 0. We used paired t-tests and the Wilcoxon signed-rank test to compare miss rates and unsatisfactory event rates between short- and long-term PT participants. We used the binomial distribution to estimate the expected event scores under the assumption that all misses were independent (random). We compared observed event scores with their expected values as a ratio.

RESULTS: Forty thousand five hundred ninety-six laboratories produced 15 140 128 event scores for 75 analytes. The distribution of event scores was skewed toward multiple event misses (score 0-60) compared to the predicted distribution. Miss rates and unsatisfactory rates were significantly higher for short-term laboratories. Plotting the log ratio of observed vs expected rates for event scores showed that the degree of systematic effect was substantial. The magnitude of the effect was less for 3SD ALs.

CONCLUSIONS: In an event, PT misses are often dependent. All ALs detected systematic error. Expressing systematic error using PT data could help to identify and remediate analytical issues.}, } @article {pmid40971894, year = {2026}, author = {Marcadet, L and Pelaez, MC and Desmeules, A and Serrano, J and Cheng, Z and Khademullah, CS and Parham, E and Kennedy, J and Troakes, C and Vance, C and Soliz, J and Durham, HD and Li, L and Dutchak, PA and Sephton, CF}, title = {Targeting lipid droplets in FUS-linked amyotrophic lateral sclerosis mitigates neuronal and astrocytic lipotoxicity.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {2}, pages = {472-488}, doi = {10.1093/brain/awaf328}, pmid = {40971894}, issn = {1460-2156}, support = {//Brain Canada Future Leader's Award/ ; 202309PJT-506236//Canadian Institute of Health Research/ ; RGPIN-2020-06376//Natural Sciences and Engineering Research Council of Canada/ ; DGECR-2020-00060//Natural Sciences and Engineering Research Council of Canada/ ; //ALS Canada-Brain Canada Discovery/ ; //ALS Canada-Brain Canada Hudson Translational Team/ ; //Mitacs/ ; //The London Neurodegenerative Diseases Brain Bank at King's College London/ ; //Brains for Dementia Research/ ; //Alzheimer's Research UK/ ; /ALZS_/Alzheimer's Society/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Astrocytes/metabolism/drug effects/pathology ; *RNA-Binding Protein FUS/genetics/metabolism ; Mice ; Humans ; *Lipid Droplets/metabolism/drug effects/pathology ; *Neurons/metabolism/drug effects/pathology ; Mice, Transgenic ; Spinal Cord/metabolism/pathology ; Female ; Male ; Disease Models, Animal ; Lipid Metabolism/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, muscle atrophy and systemic energy imbalance. Increasing evidence suggests a metabolic shift in ALS from glucose metabolism toward fatty acid utilization; however, the downstream consequences of this reprogramming on disease progression and neuropathology remain poorly defined. We investigated neurometabolic changes in ALS using in vitro and in vivo models of familial ALS expressing the human fused in sarcoma variant R521G (hFUSR521G), along with post-mortem spinal cord tissue from ALS-FUS cases. A combination of unbiased quantitative metabolomic profiling, immunolabelling, and biochemical and molecular approaches were employed. Mass spectrometry of cortical tissue from hFUSR521G mice and littermates revealed a significant increase in acylcarnitine moieties, key substrates used in mitochondrial β-oxidation and cellular energy production. Complementary cytohistological analyses in hFUSR521G mice demonstrated increased lipid droplets (LDs) and peroxidized lipids in both neurons and astrocytes, consistent with our post-mortem findings in spinal cords of individuals carrying FUS R495X or K510E mutations. Arimoclomol, previously shown to ameliorate behavioural phenotypes in this ALS mouse model, was found to enhance lipid metabolism and reduce lipotoxicity in hFUSR521G mice and in cultured neurons and astrocytes expressing FUS R521G. Mechanistically, arimoclomol enhanced LD-mitochondrial contacts and stimulated mitochondrial β-oxidation-dependent lipid catabolism under both basal and pro-inflammatory conditions. This effect was abrogated by etomoxir, an irreversible inhibitor of carnitine palmitoyltransferase I (CPT1), the rate-limiting enzyme of the carnitine shuttle, highlighting a CPT1-dependent mechanism for lipid mobilization. Together, these findings reveal a previously unrecognized role for mitochondrial lipid metabolism in ALS pathogenesis and identify a therapeutic pathway for mitigating the cytotoxic consequences of lipid and acylcarnitine accumulation in FUS-associated ALS.}, } @article {pmid40971912, year = {2026}, author = {Zhang, G and Ma, Y and Liu, Z and Jin, L and Zheng, D and Zhang, X and Jin, G}, title = {Intraocular lens power calculation formula accuracy in 1178 eyes with short axial length: systematic review and network meta-analysis.}, journal = {Journal of cataract and refractive surgery}, volume = {52}, number = {2}, pages = {202-207}, pmid = {40971912}, issn = {1873-4502}, mesh = {Humans ; *Axial Length, Eye/pathology ; *Biometry/methods ; *Lens Implantation, Intraocular ; *Lenses, Intraocular ; *Optics and Photonics ; *Refraction, Ocular/physiology ; }, abstract = {TOPIC: To systematically review the literature and conduct a comprehensive quantitative analysis to compare the accuracy of different intraocular lens (IOL) calculation formulas in eyes with short axial lengths (ALs).

CLINICAL RELEVANCE: The precision of the IOL formulas decreases when applied in eyes with short AL (AL <22 mm), and many new formulas for calculating IOL power have been proposed in the past few decades. However, the accuracy of these formulas has not been systematically compared when applied in eyes with short AL.

METHODS: This study systematically searched PubMed, Embase, Web of Science, and Cochrane Library databases to collect relevant research literature published between January 2003 and September 2023. Included were prospective or retrospective clinical studies involving cataract patients with short AL (AL <22 mm) and reporting the following outcomes: mean absolute error, median absolute error (MedAE), and percentage of eyes with a prediction error (PE) within ±0.25 diopters (D), ±0.50 D, and ±1.00 D. A network meta-analysis was performed using R software (v. 4.2.1).

RESULTS: 15 prospective or retrospective studies involving 1178 eyes and 12 calculation formulas were included in this study. The network meta-analysis showed that compared with the widely used Haigis formula, the Kane formula had a higher percentage of eyes with PE within the range of ±0.25 D, ±0.50 D, and ±1.00 D (all odds ratio >1, but P > .05). In addition, based on the surface under the cumulative ranking area (SUCRA), the Kane formula had the highest probability of predicting the PE of the eyes within the range of ±0.25 D, with its SUCRA value of 95.74%, followed by Haigis formula (94.79%) and Olsen Standalone formula (84.04%). The Kane and Olsen Standalone formulas had the lowest MedAE.

CONCLUSIONS: The Kane, Haigis, and Olsen Standalone formulas may perform better than other formulas in calculating the IOLs power in eyes with short AL. Nonetheless, significant uncertainty remains in this area. The accuracy of these formulas in patients with short AL needs to be verified by large multicenter registry studies.}, } @article {pmid40972344, year = {2025}, author = {Del Moro, L and Brunetta, E and Gershwin, ME and Selmi, C}, title = {Microglia and myeloperoxidase in neuroinflammatory and neurodegenerative diseases.}, journal = {Current opinion in immunology}, volume = {97}, number = {}, pages = {102660}, doi = {10.1016/j.coi.2025.102660}, pmid = {40972344}, issn = {1879-0372}, mesh = {Humans ; *Microglia/immunology/metabolism ; Animals ; *Neurodegenerative Diseases/immunology/metabolism/etiology/pathology ; *Peroxidase/metabolism ; *Neuroinflammatory Diseases/immunology/metabolism ; Blood-Brain Barrier/immunology/metabolism ; Oxidative Stress ; }, abstract = {The dogma of an impenetrable blood-brain barrier (BBB) has given way to the view that resident immune cells within the central nervous system respond to a variety of blood-borne soluble factors, particularly cytokines, and play an important functional role. In particular, microglia cells contribute to the regulation of neuroinflammation, with both protective and pathological roles. Specific microglia activation states variably influence the progression of neuroinflammatory and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Significant evidence indicates that gut microbiota-derived products regulate microglial function across the lifespan and influence the BBB. Myeloperoxidase (MPO) catalyzes the conversion of hydrogen peroxide and chloride ions into hypochlorous acid, a potent oxidant implicated in oxidative tissue damage and modulation of inflammatory signaling. Elevated MPO levels in the central nervous system have been correlated with human disease and the dysregulation of MPO activity in microglia is particularly detrimental, as it amplifies the oxidative stress, disrupts the BBB integrity, and potentiates the neuroinflammatory cascades through the activation of transcription factors like NF-κB. Targeting MPO activity through selective inhibitors or antioxidant strategies may attenuate microglial activation and reduce neuroinflammation, highlighting its potential as a therapeutic target, but the regulatory mechanisms governing MPO expression in microglia and its interplay with other inflammatory mediators remain poorly understood. New research efforts into the relationship between gut microbiota, microglia, MPO, and neuroinflammation are essential to unravel the complexities of neuropathology in a variety of conditions beyond neurodegenerative diseases.}, } @article {pmid40972658, year = {2025}, author = {Angrick, M and Luo, S and Rabbani, Q and Joshi, S and Candrea, DN and Milsap, GW and Gordon, CR and Rosenblatt, K and Clawson, L and Maragakis, N and Tenore, FV and Fifer, MS and Ramsey, NF and Crone, NE}, title = {Real-time detection of spoken speech from unlabeled ECoG signals: a pilot study with an ALS participant.}, journal = {Journal of neural engineering}, volume = {22}, number = {5}, pages = {}, pmid = {40972658}, issn = {1741-2552}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; }, mesh = {Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; *Brain-Computer Interfaces ; Computer Systems ; *Electrocorticography/methods ; Pilot Projects ; *Speech/physiology ; }, abstract = {Objective. Brain-computer interfaces hold significant promise for restoring communication in individuals with partial or complete loss of the ability to speak due to paralysis from amyotrophic lateral sclerosis (ALS), brainstem stroke, and other neurological disorders. Many of the approaches to speech decoding reported in the BCI literature have required time-aligned target representations to allow successful training-a major challenge when translating such approaches to people who have already lost their voice.Approach. In this pilot study, we made a first step toward scenarios in which no ground truth is available. We utilized a graph-based clustering approach to identify temporal segments of speech production from electrocorticographic (ECoG) signals alone. We then used the estimated speech segments to train a voice activity detection (VAD) model using only ECoG signals. We evaluated our approach using a leave-one-day-out cross-validation on open-loop recordings of a single dysarthric clinical trial participant living with ALS, and we compared the resulting performance to previous solutions trained with ground truth acoustic voice recordings.Main results. Our approach achieves a median timing error of around 530 ms with respect to the actual spoken speech. Embedded into a real-time BCI, our approach is capable of providing VAD results with a latency of only 10 ms.Significance. To the best of our knowledge, our results show for the first time that speech activity can be predicted purely from unlabeled ECoG signals, a crucial step toward individuals who cannot provide this information anymore due to their neurological condition, such as patients with locked-in syndrome.Clinical Trial Information. ClinicalTrials.gov, registration number NCT03567213.}, } @article {pmid40974174, year = {2026}, author = {Wang, C and Hong, L and Gong, W and Zhang, Q and Li, S and Zhao, J}, title = {Comparative Analysis of Volatile Constituents in Different Parts and Essential Oil of Pogostemon cablin Using GC-MS Combined with Chemometrics.}, journal = {Journal of AOAC International}, volume = {109}, number = {2}, pages = {261-272}, doi = {10.1093/jaoacint/qsaf090}, pmid = {40974174}, issn = {1944-7922}, support = {0005/2024/AKP//Science and Technology Development Fund, Macau SAR/ ; 2220004000117//Zhuhai Science and Technology Plan Project in the Social Development Field/ ; MYRG-GRG2024-00150-ICMS-UMDF//University of Macau/ ; CPG2025-00030-ICMS//University of Macau/ ; }, mesh = {*Oils, Volatile/analysis/chemistry ; Gas Chromatography-Mass Spectrometry/methods ; *Pogostemon/chemistry ; Plant Leaves/chemistry ; Plant Stems/chemistry ; *Volatile Organic Compounds/analysis ; Principal Component Analysis ; Chemometrics/methods ; Least-Squares Analysis ; Plant Components, Aerial/chemistry ; }, abstract = {BACKGROUND: Pogostemon cablin (P. cablin) is a valuable medicinal plant used in traditional medicine and the fragrance industry, but QC is challenging due to inconsistent stem-to-leaf ratios and frequent essential oil adulteration.

OBJECTIVE: This study compares volatile components in different parts (aerial parts, stems, and leaves) and essential oil of P. cablin to support QC (not less than 20% leaf) and its rational use.

METHODS: Volatile components in 21 batches of aerial parts, stems, and leaves, and 13 batches of essential oils, were analyzed using GC-MS. Multivariate curve resolution-alternating least-squares (MCR-ALS) was used for resolving co-eluted peaks, and chemical fingerprinting with chemometric techniques including hierarchical cluster analysis (HCA), principal component analysis (PCA), partial least-squares discriminant analysis (PLS-DA), and orthogonal partial least-squares discrimination analysis (OPLS-DA) were applied.

RESULTS: Volatile profiling identified 56, 47, 28, and 45 components in the aerial parts, leaves, stems, and essential oil of P. cablin, respectively. MCR-ALS resolved 10 major volatile compounds to create chemical fingerprints for each analytical sample type. Quantitative analysis showed higher patchouli alcohol in leaves (12.47 mg/g) compared to stems (2.05 mg/g), while stems had more pogostone (2.71 mg/g versus 1.40 mg/g in leaves). Aerial parts and essential oil showed significant compositional differences. Based on the results of qualitative and quantitative analysis, chemometric methods, including HCA, PCA, PLS-DA, and OPLS-DA, clearly differentiated the four types of P. cablin analytical samples.

CONCLUSION: Significant differences in volatile components across P. cablin parts and its essential oil support QC (not less than 20% leaf) and rational use.

HIGHLIGHTS: This study is the first to use MCR-ALS and other chemometrics for qualitative and quantitative analysis of P. cablin parts and essential oils, aiding QC.}, } @article {pmid40974909, year = {2025}, author = {Fazeli, B and Botzenhardt, S and Bachhuber, F and Klassen, P and Klose, V and Dorst, J and Wiesenfarth, M and Uzelac, Z and Jesse, S and Brenner, D and Anderl-Straub, S and Ludolph, AC and Otto, M and Weishaupt, J and Tumani, H and Halbgebauer, S}, title = {Comparative analysis of cerebrospinal fluid neurofilament medium, light and heavy chain in neurodegenerative diseases using an in-house assay for the detection of neurofilament medium chain.}, journal = {EBioMedicine}, volume = {120}, number = {}, pages = {105930}, pmid = {40974909}, issn = {2352-3964}, mesh = {Humans ; *Neurofilament Proteins/cerebrospinal fluid ; Male ; Female ; Biomarkers/cerebrospinal fluid ; *Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; Aged ; Middle Aged ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; ROC Curve ; Aged, 80 and over ; Frontotemporal Dementia/cerebrospinal fluid/diagnosis ; }, abstract = {BACKGROUND: Neurofilaments are key axonal proteins, with neurofilament light (NfL) and heavy (NfH) chain recognised as promising biomarkers for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, neurofilament medium chain (NfM) remained previously underexplored due to a lack of quantitative assays. In this study, we developed a sensitive immunoassay to measure NfM in cerebrospinal fluid (CSF) and analysed its levels in ALS, Alzheimer's disease (AD), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Correlations among neurofilaments and their diagnostic performance were also evaluated.

METHODS: In this study CSF levels of three neurofilament proteins were measured in 305 participants, including patients with ALS (n = 91), AD (n = 59), FTD (n = 38), LBD (n = 18), non-neurodegenerative controls (CTRL, n = 51), and 48 individuals initially evaluated for ALS but ultimately diagnosed with other conditions (CTRL.DD). NfM levels were quantified using a homemade sandwich ELISA, while NfL and NfH were measured using commercialised Ella cartridges.

FINDINGS: All three neurofilaments were significantly elevated in ALS compared to CTRL and CTRL.DD groups (p < 0.0001 for both), with NfM and NfL also increased in FTD (p < 0.0001 for both) and AD (NfM, p < 0.0001; NfL, p = 0.0001) compared to CTRL. NfH demonstrated the greatest distinction between ALS and FTD (p < 0.0001). Strong correlations were observed among neurofilament subunits, particularly between NfM and NfL (r = 0.93, 95% CI: 0.91-0.94, p < 0.0001). All neurofilaments effectively distinguished ALS from CTRL and CTRL.DD, with AUC values ranging from 0.92 to 0.99. NfM and NfL showed high accuracy in differentiating AD (NfM, AUC: 0.91; NfL, AUC: 0.89) and FTD (NfM, AUC: 0.91; NfL, AUC: 0.92) from CTRL, while NfH best separated ALS from FTD (AUC: 0.96).

INTERPRETATION: This study provides a quantitative comparison of NfM with NfL and NfH in a neurodegenerative cohort, highlighting its potential diagnostic value. Further research with larger cohorts, longitudinal studies, and investigations into neurofilament distribution in different compartments is needed to clarify the distinct roles of NfM, NfL, and NfH in the diagnosis and treatment of neurological diseases.

FUNDING: The present study was supported by the Else Kroener-Fresenius Foundation (2024-EKEA.126) and Chemische Fabrik Karl Bucher GmbH.}, } @article {pmid40975059, year = {2025}, author = {Sprunger, ML and Shinn, MK and Talir, SK and Lee, K and Pappu, RV and Jackrel, ME}, title = {Matrin-3 forms spherical and wormlike assemblies that are modulated by RNA binding and ALS/FTD-associated mutations.}, journal = {Molecular cell}, volume = {85}, number = {19}, pages = {3640-3660.e9}, pmid = {40975059}, issn = {1097-4164}, support = {R21 AG080393/AG/NIA NIH HHS/United States ; R35 GM128772/GM/NIGMS NIH HHS/United States ; R35 GM153303/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *RNA-Binding Proteins/genetics/metabolism/chemistry ; *Frontotemporal Dementia/genetics/metabolism ; *Mutation ; *RNA/metabolism/genetics/chemistry ; Protein Binding ; Nuclear Matrix-Associated Proteins ; }, abstract = {Matrin-3 (MATR3) is an RNA-binding protein (RBP) that is associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). MATR3 features two RNA recognition motifs, two zinc-finger motifs, and four intrinsically disordered regions. Here, we report that human MATR3 associates with itself to form nanoscale spherical assemblies at ultralow protein concentrations. Through concentration-dependent associations, the spheres, which are 20-30 nm in diameter, transition into wormlike assemblies. These observations are reminiscent of sphere-to-worm transitions and micellization of amphiphilic molecules. Using computations and experiments, we discovered that the pattern of inter-domain attractions and repulsions gives MATR3 an inverse bolaamphiphile-like architecture that explains the concentration-dependent assembly characteristics. RNA binding causes shortening of wormlike assemblies of MATR3, whereas ALS/FTD-associated mutations render MATR3 assemblies less responsive to modulation by RNA. Overall, our findings highlight the unique assemblies formed by MATR3 while also showing how RNA-dependent interactions and ALS/FTD-associated mutations modulate the assemblies.}, } @article {pmid40975067, year = {2025}, author = {Xie, M and Liang, Y and Miller, AS and Pallegar, PN and Umpierre, AD and Wang, N and Zhang, S and Nagaraj, NK and Fogarty, ZC and Ghayal, NB and Oskarsson, B and Zhao, S and Zheng, J and Shi, W and Akter, M and Qi, F and Nguyen, AT and Dickson, DW and Wu, LJ}, title = {Rod-shaped microglia interact with neuronal dendrites to attenuate cortical excitability during TDP-43-related neurodegeneration.}, journal = {Immunity}, volume = {58}, number = {12}, pages = {3113-3129.e8}, pmid = {40975067}, issn = {1097-4180}, support = {R01 AG082314/AG/NIA NIH HHS/United States ; R35 NS132326/NS/NINDS NIH HHS/United States ; RF1 AG082314/AG/NIA NIH HHS/United States ; U19 AG069701/AG/NIA NIH HHS/United States ; }, mesh = {*Microglia/immunology/pathology ; *Dendrites/immunology/pathology/physiology ; *Neurodegenerative Diseases/genetics/immunology/pathology/physiopathology ; *Cortical Excitability/genetics/immunology/physiology ; Cell Communication/immunology/physiology ; Intravital Microscopy ; Mice, Transgenic ; Stereotaxic Techniques ; Electrodes, Implanted ; Humans ; Middle Aged ; Aged ; Animals ; Mice ; Aged, 80 and over ; Male ; Female ; Case-Control Studies ; Disease Models, Animal ; *DNA-Binding Proteins/genetics ; Membrane Glycoproteins/deficiency/genetics ; Receptors, Immunologic/deficiency/genetics ; Neurons/immunology/pathology/physiology ; Gene Knockout Techniques ; Patch-Clamp Techniques ; Motor Cortex/pathology/physiopathology ; }, abstract = {Microglia, the principal immune cells of the central nervous system, have emerged as important players in sensing and regulating neuronal activity. While microglial activation is a hallmark in neurodegeneration, the specific role of microglia in disease-related cortical excitability remains unknown. Utilizing multichannel probe recordings and longitudinal in vivo calcium imaging, we observed neuronal hyperactivity at the initial stage of disease progression in a mouse model of TAR DNA-binding protein 43 (TDP-43) neurodegeneration (rNLS8, regulated nuclear localization sequence-deleted human TDP-43 transgenic mouse model). Spatial and single-cell RNA sequencing revealed a specific subpopulation of microglia, rod-shaped microglia, with a distinct morphology and direct response to cortical hyperactivity. Rod-shaped microglia predominantly interacted with neuronal dendrites and remodeled excitatory synaptic inputs to attenuate motor cortical hyperactivity. Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency led to a marked reduction of rod-shaped microglia accompanied by increased neuronal activity in rNLS8 mice. Together, our results suggest that rod-shaped microglia play a neuroprotective role by attenuating cortical hyperexcitability in TDP-43-related neurodegeneration.}, } @article {pmid40975292, year = {2025}, author = {Lewis, KN and Gonsalvez, DG and Turner, BJ and Barton, SK}, title = {Schwann cells as a therapeutic target for amyotrophic lateral sclerosis: A TDP-43 focussed review.}, journal = {Neurochemistry international}, volume = {190}, number = {}, pages = {106055}, doi = {10.1016/j.neuint.2025.106055}, pmid = {40975292}, issn = {1872-9754}, mesh = {Humans ; *Schwann Cells/metabolism/drug effects/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/therapy/pathology ; Animals ; *DNA-Binding Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable, lethal neurodegenerative disease and a proteinopathy with >97 % of cases characterised by pathological accumulation of TDP-43. TDP-43 is ubiquitously expressed and its pathological accumulation has now been identified in non-neuronal cells in both the central and peripheral nervous systems. Thus, the expansion to exploring other cells and their contribution to ALS pathogenesis may be the key to finding more effective treatments. Schwann cells are the myelinating cells of the peripheral nervous system, that encase neuronal axons to propagate action potentials, maintain neuronal health, and respond to neuronal activity in the extracellular environment. Despite Schwann cells being identified to exhibit aberrant TDP-43 proteinopathy in ALS patients, their role in disease remains elusive. Here, we review the potential contributions of Schwann cells to ALS as well as the prospective benefits of harnessing Schwann cells treat the disease.}, } @article {pmid40975951, year = {2025}, author = {von Quednow, E and Husain, N and Łajczak, P and Linha Secco, G and Koppanatham, A}, title = {Diagnostic accuracy of the Gold Coast Criteria for amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {179}, number = {}, pages = {2111005}, doi = {10.1016/j.clinph.2025.2111005}, pmid = {40975951}, issn = {1872-8952}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; Sensitivity and Specificity ; }, abstract = {OBJECTIVE: To compare the diagnostic accuracy of Gold Coast Criteria (GCC) with Revised El Escorial Criteria (rEEC) and Awaji Criteria (AC) in suspected amyotrophic lateral sclerosis (ALS).

METHODS: PubMed, EMBASE, Web of Science, Cochrane Library, and Google Scholar were searched through December 2024. Eligible studies assessed patients using GCC, rEEC, and/or AC, reporting or allowing calculation of sensitivity and specificity. Quality was evaluated using QUADAS-2 and STARD. "Probable+" included probable and definite classifications; "Possible+" encompassed possible to definite. Sensitivity analyses excluded the largest study with imputed data and included a sensitivity-only model. PRISMA-DTA compliant; PROSPERO CRD42025623678.

RESULTS: Nine studies (n = 9656), all from ALS referral centers, were included. GCC showed higher sensitivity (∼95 %) than rEEC and AC Probable+ (59 % and 54 %) and Possible+ (84 % and 85 %), but lower specificity (66 %) vs. rEEC (Probable+ 94 %, Possible+ 77 %) and AC (Probable+ 94 %, Possible+ 82 %). GCC achieved the highest AUC (0.95) and diagnostic odds ratio (36.1). Sensitivity-only analysis confirmed GCC performance (97 %).

CONCLUSIONS: GCC demonstrated superior sensitivity, potentially facilitating earlier recognition and trial inclusion. Their lower specificity requires caution, particularly in low-prevalence contexts. Applicability in unselected neurology populations remains uncertain.

SIGNIFICANCE: GCC may enable earlier ALS diagnosis and timely trial enrollment in referral centers.}, } @article {pmid40976462, year = {2025}, author = {Shi, M and Chu, F and Zhu, J}, title = {Stem cells therapy in neurodegenerative and neuroimmune diseases: Current status of treatments and future prospects.}, journal = {Pharmacological research}, volume = {221}, number = {}, pages = {107960}, doi = {10.1016/j.phrs.2025.107960}, pmid = {40976462}, issn = {1096-1186}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Animals ; *Stem Cell Transplantation/methods ; }, abstract = {Neurodegenerative and neuroimmune diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) share a common pathologic hallmark i.e. loss of neurons in the central nervous system (CNS), despite diverse pathological manifestations. These diseases present major challenges to global health due to incurable or extremely difficult to treat, imposing a heavy burden on society and families. Stem cell therapy, as a novel promising approach for treating various neurological diseases, harnesses the regenerative potential of stem cells to repair damaged neural tissues and circuits, and has become the only hope for patients to recover their health or delay the deterioration of disease symptoms. In recent years, researchers have successfully generated neurons from multiple types of stem cells, and good curative effects have been achieved in their animal models and in clinical trials. This comprehensive review elaborates on the relevant content of stem cell biology, focuses on conducting an in-depth analysis of the current application status of various stem cells in major neurodegenerative and neuroimmune diseases including MS, AD, PD and ALS, kindling the hope for the development of stem cell-based cell therapies in neurological diseases.}, } @article {pmid40977745, year = {2025}, author = {Wang, J and Li, Y and Xia, Y}, title = {C/EBPβ as a master regulator of inflammasome signaling in neurodegenerative diseases: mechanisms and therapeutic implications.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1656165}, pmid = {40977745}, issn = {1664-3224}, mesh = {Humans ; *Inflammasomes/metabolism/immunology ; *Neurodegenerative Diseases/metabolism/immunology/therapy/etiology ; Animals ; *Signal Transduction ; *CCAAT-Enhancer-Binding Protein-beta/metabolism/genetics ; }, abstract = {CCAAT/enhancer-binding protein beta (C/EBPβ), a key transcription factor, plays a central role in regulating inflammasome signaling in neurodegenerative diseases (NDs). This review synthesizes the mechanisms by which C/EBPβ modulates neuroinflammation and its potential as a therapeutic target. We conducted a comprehensive systematic review spanning January 1995 to June 2025, systematically querying Google Scholar and PubMed with the following keywords: neuroinflammation, inflammasome activation, C/EBPβ, therapeutic targeting, and neurodegenerative diseases. C/EBPβ exists in three isoforms-LAP1, LAP2, and LIP-each with distinct functions in inflammasome activation. In Alzheimer's disease (AD), C/EBPβ drives tau cleavage and Aβ pathology through the AEP axis and exacerbates neuroinflammation by upregulating APOE4. In Parkinson's disease (PD), C/EBPβ silencing reduces α-synuclein aggregation and dopaminergic neuron loss by suppressing the NLRP3 inflammasome. In Amyotrophic Lateral Sclerosis (ALS), C/EBPβ is hypothesized to contribute to TDP-43-associated inflammasome activation, though this requires further validation. In Multiple Sclerosis (MS), C/EBPβ may influence microglial activation and neuroinflammation, as shown in experimental autoimmune encephalomyelitis models. Modulators of the C/EBPβ-inflammasome axis include endogenous regulators like gut-derived metabolites and pharmacological interventions such as small-molecule inhibitors. Therapeutic strategies targeting C/EBPβ hold promise for mitigating neuroinflammation and neurodegeneration, though challenges remain in achieving isoform-specific targeting and blood-brain barrier penetration. Future directions include CRISPR-based editing and biomarker development for personalized therapies.}, } @article {pmid40977882, year = {2024}, author = {Yu, SF and Paulvannan, K and Solas, D and Lingappa, AF and Moreira, AR and Sahu, S and Michon, M and Macieik, A and Goldsmith, D and DeYarman, N and Mallesh, S and Prasad, MD and Maios, C and Ruan, K and Tomassy, GS and Jensen, E and McGuirk, E and Bader, V and Mueller-Schiffmann, A and Reed, JC and Lingappa, JR and Asundi, V and Hong, S and Jacobsen, S and Brandon, N and Ostrow, L and Lloyd, T and Parker, JA and Staats, KA and Ichida, J and Dodge, JC and Dey, D and Korth, C and Selvarajah, S and Lingappa, VR and Rosenfeld, J}, title = {Protein Assembly Modulation: A New Approach to Amyotrophic Lateral Sclerosis (ALS) Therapeutics.}, journal = {Journal of experimental neurology}, volume = {5}, number = {4}, pages = {210-230}, pmid = {40977882}, issn = {2692-2819}, support = {R01 AI048389/AI/NIAID NIH HHS/United States ; R01 NS037365/NS/NINDS NIH HHS/United States ; R21 AI101276/AI/NIAID NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating and progressive neurodegenerative disease with a complex, multifactorial pathophysiology, culminating in death of motor neurons. We introduce a new mechanism of ALS pathogenesis via study of a novel drug-like small molecule series that targets a subset of protein disulfide isomerase (PDI) within a previously largely unappreciated transient and energy-dependent multi-protein complex enriched for proteins of the ALS interactome. This drug, found by a novel phenotypic screen, has activity in cellular models for both familial and sporadic ALS, as well as in transgenic worms, flies, and mice bearing a diversity of human genes with ALS-associated mutations. The hit compound was initially identified as a modulator of human immunodeficiency virus (HIV) capsid assembly in cell-free protein synthesis and assembly (CFPSA) systems, with demonstrated antiviral activity against infectious HIV in cell culture. Its advancement for ALS-therapeutics, subsequent separation of activity against HIV and ALS into separate chemical subseries through structure-activity-relationship (SAR) optimization, and identification of the drug target by affinity chromatography as shown here, may provide insights into the molecular mechanisms governing pathophysiology of disordered homeostasis relevant to ALS.}, } @article {pmid40978405, year = {2025}, author = {Barasa, L and DeOrsey, L and O'Reilly, MD and Choudhary, S and Cahill, SE and Mathur, A and Rajoria, S and Green, RM and Allabaji, A and Nellikkalaya, S and Paul, S and Vidadala, SR and Kumar Sarkar, S and Patil, SN and Hale, J and Humphries, F and Fitzgerald, KA and Thompson, PR}, title = {Nitrofuran-Based STING Inhibitors.}, journal = {ACS omega}, volume = {10}, number = {36}, pages = {41693-41706}, pmid = {40978405}, issn = {2470-1343}, support = {T32 AI095213/AI/NIAID NIH HHS/United States ; T32 AI132152/AI/NIAID NIH HHS/United States ; }, abstract = {The cGAS-STING pathway plays a central role in the host response to foreign DNA. While cGAS-STING signaling is essential for antiviral immunity, aberrant STING activation is observed in amyotrophic lateral sclerosis (ALS), lupus, and autoinflammatory diseases such as Aicardi-Goutières syndrome (AGS) and STING associated vasculopathy with onset in infancy (SAVI). Thus, STING inhibitors are likely therapeutic agents. BB-Cl-amidine and LB244 are recently reported STING antagonists that work by blocking STING oligomerization. Herein, we describe the diverse strategies taken to optimize the potency of LB244. These efforts led to the development of UM-242 and UM-259. UM-242 and UM-259 both inhibit mouse and human STING-dependent signaling with efficacy similar to that of LB244. We further show that UM-242 and UM-259 maintain their potency against the most common human STING variant (R232) and inhibit STING signaling in primary human CD14+ monocytes. In summary, UM-242 and UM-259 represent additional novel scaffolds for the development of therapeutics to treat STING-dependent inflammatory diseases.}, } @article {pmid40978462, year = {2025}, author = {Anjum, F and Hawsawi, N and Almalki, AA and Shamsi, A and Hulbah, MJ and Bakhuraysah, M and Alsharif, A and Mohammad, T}, title = {Exploring bioactive phytochemicals as ULK1 activators for enhancing cytoprotective autophagy in amyotrophic lateral sclerosis.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1661744}, pmid = {40978462}, issn = {1663-9812}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that results in the degeneration of motor neurons and is typically linked to toxic aggregates of mutant superoxide dismutase 1 (SOD1) protein. As autophagy is critical for the removal of these toxic protein aggregates, stimulating autophagy has emerged as a promising therapeutic approach for ALS. Unc-51-like kinase 1 (ULK1) is a key regulator of autophagy and has been shown to have the potential to prevent ALS pathology when activated. However, synthetic ULK1 activators are frequently limited by toxicity and suboptimal pharmacokinetic profiles. This study aimed to identify natural ULK1 activators using a systematic virtual screening approach for potential ALS therapy.

MATERIALS AND METHODS: This study employed a comprehensive virtual screening approach to identify phytochemicals capable of activating ULK1. Natural compounds from the IMPPAT database were screened using molecular docking, followed by pan-assay interference compounds (PAINS) filtering, pharmacokinetic profiling, and density functional theory (DFT) analysis. Further, biological activity was predicted using the PASS tool, and candidate molecules were subjected to molecular dynamics (MD) simulations, essential dynamics, and binding free energy calculations via MM-PBSA.

RESULTS: The systematic screening in this study identified Candidine and Delavinone as high-affinity binders with reference to BL-918, proposing them as potential activators of ULK1. Both compounds demonstrated favorable drug-likeness, stable interactions with ULK1 in MD simulations, and promising ALS-relevant activity profiles. Essential dynamics and MM-PBSA further supported the binding stability and energetic favorability of these interactions.

CONCLUSION: Candidine and Delavinone emerge as promising phytochemical activators of ULK1 with potential therapeutic relevance for ALS. These findings warrant further experimental validation and preclinical studies to explore their efficacy in autophagy modulation and neuroprotection.}, } @article {pmid40979145, year = {2025}, author = {Galassi, L and Facchinetti, F}, title = {Towards comprehensive care in crush syndrome: Expanding the multidisciplinary framework.}, journal = {World journal of orthopedics}, volume = {16}, number = {9}, pages = {111218}, pmid = {40979145}, issn = {2218-5836}, abstract = {Crush syndrome demands an integrated multidisciplinary approach that spans acute surgical decisions and long-term functional recovery. In response to Khan et al's recent systematic review, we propose complementary perspectives that address two underrepresented dimensions: Vascular surgical decision-making and psychiatric rehabilitation. We emphasize the use of intraoperative technologies such as indocyanine green fluorescence angiography and compartment pressure monitoring to guide limb salvage strategies and reperfusion management. Additionally, we advocate for the systematic integration of mental health screening and trauma-informed psychiatric care to address the high prevalence of psychological distress in survivors. Embedding these domains into standardized protocols could enhance both short- and long-term outcomes, particularly in high-impact trauma and disaster settings.}, } @article {pmid40979210, year = {2025}, author = {Grimm, T and Otto-Sobotka, F and Steinker, D and Summ, O and Timmer, A and Groß, M}, title = {Patients and treatments in a neuropalliative outpatient clinic: an analysis of clinical routine data from five years of care.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1616153}, pmid = {40979210}, issn = {1664-2295}, abstract = {INTRODUCTION: The increasing prevalence of life-threatening neurological diseases raises the need for neuropalliative care. Setting up neurological palliative outpatient clinics is one way of addressing this need. This study aims to describe the patient clientele of a neurological palliative outpatient clinic and the spectrum of necessary treatments and interventions.

METHODS: In this longitudinal analysis, clinical routine data from a single centre were collected retrospectively from adult patients. The patient characteristics related to disease and treatment were evaluated descriptively. Factors influencing the need for ventilation were modelled in a logistic regression. The required treatment effort was modelled with a zero-inflated Beta regression. Results were reported as odds ratios with 95% confidence intervals (CIs).

RESULTS: Two hundred and thirty-two patients were included in the study. Ninety-one patients were women, 141 were men, and the mean age was 55.42 years. Neuropalliative patients represented diagnoses such as amyotrophic lateral sclerosis (ALS) (n = 81), ischemic stroke (n = 15), intracerebral haemorrhage (n = 15), Duchenne muscular dystrophy (n = 12), or craniocerebral trauma (n = 10). Palliative care counselling was the most common intervention for patients (n = 203), their close relatives (n = 177), and their nursing services (n = 75). Respiratory therapy (n = 188), speech and language therapy (n = 145), and physiotherapy (n = 143) were also frequently applied interventions. Sixty patients received botulinum toxin A treatment for hypersalivation, and 32 for spasticity. The odds of needing invasive ventilation increased by 3.7 (CI 1.7-7.8), and the need for mechanical insufflation-exsufflation increased by 2.2 (CI 1.1-4.3) in patients previously discharged from early neurological-neurosurgical rehabilitation. Prior intensive care treatment increased the odds of invasive ventilation by 5.1 (CI 2.2-11.5) and the use of mechanical insufflation-exsufflation by 2.3 (CI 1.1-4.8).

CONCLUSION: Neuropalliative outpatient clinics demand a wide range of diagnostic measures and interventions as well as a multidisciplinary approach. Further research is necessary to investigate the relation between diagnosis and treatment needs.

CLINICAL TRIAL REGISTRATION: https://drks.de/search/en/trial/DRKS00030778, identifier DRKS00030778.}, } @article {pmid40981102, year = {2025}, author = {Juranek, JK and Kordas, B and Podlasz, P and Bossowska, A and Banach, M}, title = {Current Evidence on the Involvement of RAGE-Diaph1 Signaling in the Pathology and Treatment of Neurodegenerative Diseases-An Overview.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {32}, number = {3}, pages = {}, pmid = {40981102}, issn = {1873-149X}, abstract = {Neurodegenerative diseases are a group of disorders characterized by the progressive deterioration of the structure and function of central nervous system neurons and include, among others, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's (PD), Alzheimer's (AD), and Huntington's (HD) diseases. And while all these diseases seem to have different genetic and environmental components, growing evidence shows that they share common underlying pathological features such as increased neuroinflammation and excessive oxidative stress. RAGE, the receptor for advanced glycation end-products, is a signal transduction receptor, and its activation triggers an increase in proinflammatory molecules, oxidative stressors, and cytokines. Diaph1, protein diaphanous homolog 1, is an actin modulator and an intracellular ligand of RAGE. Studies demonstrated that RAGE and Diaph1 act together, and their downstream signaling pathways play a role in neurodegeneration. Here, based on current evidence and our own research, we provide an overview of the RAGE-Diaph1 signaling and discuss the therapeutic potential of targeted therapy aimed at RAGE-Diaph1 signaling inhibition in the prevention and treatment of neurodegenerative diseases.}, } @article {pmid40981169, year = {2025}, author = {Motataianu, A and Barcutean, L and Ormenisan, I and Roman, M and Balasa, R and Bajko, Z and Dumitreasa, M}, title = {Clinical and Paraclinical Predictors of Survival in Amyotrophic Lateral Sclerosis: Results from a Three-Year Longitudinal Cohort Study.}, journal = {Medical sciences (Basel, Switzerland)}, volume = {13}, number = {3}, pages = {}, pmid = {40981169}, issn = {2076-3271}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; Longitudinal Studies ; Disease Progression ; Prognosis ; Aged ; Adult ; Prospective Studies ; Kaplan-Meier Estimate ; Proportional Hazards Models ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative disorder with highly variable progression and survival. Identifying early prognostic indicators is essential for patient stratification and management.

OBJECTIVES: To evaluate clinical, respiratory, and functional predictors of survival in a prospective cohort of ALS patients over a three-year period.

METHODS: A cohort of 44 ALS patients was followed from 2022 to 2025. Demographic and anthropometric characteristics, clinical data including ALS subtypes and phenotypes, site of onset, revised ALS functional rating scale (ALSFRS-R) and subscores, ALSFRS-R progression rate, time to diffusion and generalization, spirometric parameters, and progression patterns were assessed. Survival analysis was performed using Kaplan-Meier estimates and univariate and multivariate Cox proportional hazard regression analysis.

RESULTS: The overall median survival time was 53 months. Univariate Cox regression revealed that older age at onset, shorter diagnostic delay, lower respiratory function, lower vitamin D levels, and rapid vertical progression were associated with reduced survival. Bulbar-onset phenotype and rapid disease progression rate (ΔPR) were significant predictors of mortality. Specific ALSFRS-R subscores also showed prognostic relevance. A longer time to diffusion as well as a longer time to generalization were significantly associated with prolonged survival. Multivariate analysis confirmed the independent prognostic value of ΔPR, time to diagnosis, and ALSFRS-R swallowing and handwriting subscores.

CONCLUSIONS: This study supports the prognostic value of previously studied clinical and paraclinical markers in ALS and proposes novel predictors, ALSFRS-R handwriting, and time to diffusion, which require further validation in larger prospective cohorts.}, } @article {pmid40981475, year = {2025}, author = {Gosavi, R and Yap, R and Bell, S and Wilkins, S and Asghari-Jafarabadi, M and McMurrick, P}, title = {Anastomotic Leak Following Colon Cancer Resection: An Independent Predictor of Non-Oncologic Mortality and Morbidity.}, journal = {Journal of surgical oncology}, volume = {132}, number = {7}, pages = {1250-1256}, pmid = {40981475}, issn = {1096-9098}, mesh = {Humans ; Male ; Female ; *Colonic Neoplasms/surgery/mortality/pathology ; *Anastomotic Leak/mortality/etiology/epidemiology ; Retrospective Studies ; Aged ; Middle Aged ; *Adenocarcinoma/surgery/pathology/mortality ; Survival Rate ; Morbidity ; *Colectomy/adverse effects/mortality ; Aged, 80 and over ; Follow-Up Studies ; Anastomosis, Surgical/adverse effects ; Prognosis ; Risk Factors ; }, abstract = {BACKGROUND: Anastomotic leak (AL) is a serious complication following colon cancer resection, but its long-term impact on survival and recurrence remains uncertain.

OBJECTIVE: To evaluate the association between AL and postoperative outcomes, including overall survival (OS), replase-free survival (RFS), and cancer-specific survival (CSS), and to identify factors associated with increased risk of leak.

METHODS: This retrospective cohort study included 2217 patients with histologically confirmed Stage I-III colon adenocarcinoma who underwent curative-intent resection with primary anastomosis across three tertiary centres (2009-2025). Patients with benign pathology, carcinoma in situ (Stage 0), metastatic disease, or missing follow-up data were excluded. ALs were defined as clinically and/or radiologically confirmed disruptions occurring within 30 days postoperatively. No leaks were observed beyond this period. Outcomes were compared using Kaplan-Meier estimates and Cox regression models.

RESULTS: ALs, either clinical or radiological, occurred in 2.0% of patients (n = 44). Leaks were associated with significantly increased 30-day mortality (6.8% vs. 0.4%, p < 0.001), reoperation (86.4% vs. 3.4%, p < 0.001), and hospital stay (median 21 vs. 7 days, p < 0.001). In multivariable analysis, AL independently predicted 30-day mortality (AOR 13.6, 95% CI 9.9-18.6) and return to theatre (AOR 396.2, 95% CI 218.8-717.4). AL was associated with worse OS and DFS, but not CSS (p = 0.66).

CONCLUSIONS: AL is an independent predictor of postoperative morbidity and long-term nononcologic mortality in colon cancer patients. While OS and DFS were significantly reduced, CSS remained unaffected, a unique finding that challenges assumptions about leak-related oncologic progression. These results suggest that excess mortality stems from systemic complications and care disruption rather than cancer recurrence. Preventive strategies and early leak detection in high-risk patients are essential to improving outcomes.}, } @article {pmid40981770, year = {2025}, author = {Masrori, P and Tomé, SO and Dedeene, L and Remiche, G and Van Esch, H and Thal, DR and Van Damme, P}, title = {Tracing neuropathological signatures: TARDBP and C9orf72 double mutations in a Sicilian family.}, journal = {Human molecular genetics}, volume = {34}, number = {21}, pages = {1829-1835}, pmid = {40981770}, issn = {1460-2083}, support = {//Een Hart voor ALS", "Laeversfonds voor ALS Onderzoek" and "the Valéry Perrier Race against ALS/ ; IWT 135043//Vlaamse Impulsfinanciering voor Netwerken voor Dementie Onderzoek/ ; 1225725N//FWO/ ; A2022019F//BrightFocus Foundation/ ; C14-17-107//C1-internal funds from KU Leuven/ ; AARF-24-1300693/ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *DNA-Binding Proteins/genetics ; *Mutation ; Male ; Female ; Middle Aged ; DNA Repeat Expansion ; Pedigree ; Heterozygote ; *Proteins/genetics ; Aged ; }, abstract = {Co-occurrence of double heterozygosity in TARDBP and C9ORF72 is exceedingly rare in amyotrophic lateral sclerosis. While TARDBP mutations and C9ORF72 hexanucleotide repeat expansions have each been independently implicated in disease pathogenesis, their combined effect on disease progression and neuropathology remains unclear. We present the first study documenting a patient harboring both a TARDBP mutation and a C9ORF72 expansion, with comprehensive postmortem data available, to elucidate any additive or synergistic effects on disease course and pathological burden. Detailed clinical assessments tracked the patient's progression, and neuropathological examination was performed postmortem. The presence and extent of TDP-43 pathology and other hallmark features were evaluated and compared to known patterns in carriers of isolated C9ORF72 mutations. The patient's clinical trajectory and pathological findings did not show evidence of a more aggressive disease course or heightened pathological burden attributable to the additional TARDBP mutation. Instead, the disease manifested in a manner consistent with other C9ORF72 carriers, suggesting that double heterozygosity do not necessarily exacerbate ALS pathology.}, } @article {pmid40982298, year = {2025}, author = {Moojen, TB and Vlug, MS and Visser, E and Reijntjes, MA and Lange, JFM and Bislenghi, G and Carvello, M and Warusavitarne, J and Hompes, R and Stassen, LPS and Faiz, OD and Spinelli, A and D'Hoore, A and Bemelman, WA}, title = {Anastomotic leakage after ileoanal pouch surgery: risk factors and salvage rate.}, journal = {BJS open}, volume = {9}, number = {5}, pages = {}, pmid = {40982298}, issn = {2474-9842}, support = {974823//The Crohn's & Colitis Foundation/ ; }, mesh = {Humans ; *Anastomotic Leak/etiology/epidemiology/therapy/diagnosis ; Male ; Female ; Retrospective Studies ; *Proctocolectomy, Restorative/adverse effects ; Adult ; Risk Factors ; Middle Aged ; *Colonic Pouches/adverse effects ; *Salvage Therapy/statistics & numerical data ; *Colitis, Ulcerative/surgery ; Europe/epidemiology ; Anastomosis, Surgical/adverse effects ; }, abstract = {BACKGROUND: Chronic anastomotic leakage (AL) is the most common cause of pouch failure after restorative proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis. This study investigated factors associated with AL and successful salvage of leaking anastomoses after ileoanal pouch surgery.

METHOD: This multicentre retrospective cohort study included patients aged ≥ 18 years with ulcerative colitis or unclassified inflammatory bowel disease who underwent ileoanal pouch surgery between 2016 and 2021 in six European centres, with a > 12-month follow-up. The primary outcome was AL rate. Secondary outcomes included factors associated with AL occurrence, timing of AL diagnosis (early (< 21 days) versus late), AL management, AL salvage rate, and stoma-free survival.

RESULTS: Overall, 411 patients were included, of whom 13.6% (56) had a diagnosed AL. The rate of AL was significantly higher in low-volume (less than ten procedures annually) centres (28.0% versus 12.7%; P = 0.031). Of the 56 ALs, 44 were diagnosed as early leaks and 12 were diagnosed as late leaks. A three-stage approach was associated with late diagnosis and treatment. AL was managed using various techniques, including diverting ileostomy, antibiotics, and drainage. The overall AL salvage rate was 85.4%, but increased to 92% when diagnosed and treated early (compared with 60% when diagnosed and treated late; P = 0.010). Successful AL salvage was associated with long-term stoma-free status (P = 0.002). The median follow-up was 3.8 years (range 1.0-8.1 years). The long-term stoma-free rate was 95.5% in patients with AL diagnosed and treated early, but only 41.7% when diagnosed and treated late (P < 0.001).

CONCLUSION: Early diagnosis and treatment of AL diminishes the negative effect of AL after ileoanal pouch surgery. Proactive anastomotic assessment enable early diagnosis and management, especially in patients undergoing a three-stage approach.}, } @article {pmid40983097, year = {2026}, author = {Beyer, R and Höller, A and Schön, G}, title = {Risk of Falls and Fractures in People with Thalidomide Embryopathy.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {164}, number = {2}, pages = {143-150}, doi = {10.1055/a-2685-5018}, pmid = {40983097}, issn = {1864-6743}, mesh = {Humans ; *Accidental Falls/statistics & numerical data/prevention & control ; *Thalidomide/adverse effects ; Female ; Male ; *Fractures, Bone/epidemiology ; Middle Aged ; Risk Factors ; Adult ; *Abnormalities, Drug-Induced/epidemiology ; Comorbidity ; Germany/epidemiology ; Risk Assessment ; Young Adult ; Aged ; }, abstract = {Erfahrungen medizinischer Kompetenzzentren für Menschen mit Thalidomid-Embryopathie legen nahe, dass sturzbedingte Verletzungen vergleichsweise häufig vorkommen. Da Stürze im Alter Morbidität und Autonomieverluste begünstigen, wurden Sturz- und Frakturrisiken bei Thalidomid-Geschädigten untersucht.Onlinebefragung (Survey Monkey) zu funktionellen Einschränkungen sowie Sturzereignissen von Personen mit Thalidomid-Embryopathie (TE-Gruppe) und Nichtbetroffenen (Kontrollgruppe).206 Personen der TE-Gruppe und 183 der Kontrollgruppe wurden befragt. Einschränkungen des Hörens, des Gleichgewichtssinns, des Sehens, der Sensibilität und der Kraft waren in der TE-Gruppe signifikant häufiger als in der Kontrollgruppe. Personen der TE-Gruppe gaben signifikant häufiger Stürze und Verletzungen an als in der Kontrollgruppe.Menschen mit Thalidomid-Embryopathie haben im Vergleich zu Nichtbetroffenen häufiger Stürze mit schwerwiegenderen Verletzungen. Die Ergebnisse der vorliegenden Untersuchung verdeutlichen die Notwendigkeit einer individuellen Risikobewertung und präventiver Maßnahmen zur Sturzvermeidung in dieser Patientengruppe.}, } @article {pmid40983218, year = {2025}, author = {Teixeira-Pinheiro, LC and Gonçalves, RGJ and Furtado, M and Decotelli, AB and Vasques, JF and Maturano, M and Quintanilha Barbosa, RA and Marques da Costa, FV and Souza, LRQ and de Lima, MN and Maron-Gutierrez, T and Gomes, HR and Pizzochero, M and Domizi, P and Santiago, MF and Mendez-Otero, R and Gubert, F}, title = {Regional modulation of neurodegeneration and microglial activation by intravenous Wharton's jelly mesenchymal stromal cell therapy in a mouse model of amyotrophic lateral sclerosis.}, journal = {Neuroscience}, volume = {586}, number = {}, pages = {110-120}, doi = {10.1016/j.neuroscience.2025.09.029}, pmid = {40983218}, issn = {1873-7544}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/pathology ; *Mesenchymal Stem Cell Transplantation/methods ; *Microglia/pathology/metabolism/physiology ; Disease Models, Animal ; Female ; Motor Neurons/pathology ; Mice, Transgenic ; Mesenchymal Stem Cells ; Humans ; Mice ; *Wharton Jelly/cytology ; Spinal Cord/pathology ; *Nerve Degeneration/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition characterized by rapid degeneration of motoneurons (MNs), leading to progressive muscle atrophy and, ultimately, mortality within a few years of diagnosis. Although the precise mechanisms initiating MN degeneration are not fully understood, the involvement of non-neuronal cells, including microglia, in ALS pathophysiology is increasingly recognized. Mesenchymal stromal cell (MSC)-based therapies have emerged as a promising avenue for ALS treatment, yet clinical outcomes remain variable, underscoring the necessity for additional pre-clinical investigations. This study evaluated the therapeutic potential of human MSCs derived from Wharton's jelly (WJMSC) in the female SOD1[G93A] mouse model of ALS. Our results indicated that intravenous administration of WJMSC during the presymptomatic phase of the disease notably delayed the onset of motor deficits and extended the lifespan. This functional benefit was associated with the preservation of MNs in the cervical spinal cord. In the lumbar spinal cord, we did not observe MN neuroprotection, but we noted a temporary increase in microgliosis following WJMSC treatment. Our results supported the therapeutic benefits of human MSC in ALS, while also highlighting the differential responses of spinal-cord regions to the treatment during the disease progression. This study underscores the importance of targeting specific disease stages and regions for MSC therapy in ALS, paving the way for refined and potentially more effective therapeutic strategies.}, } @article {pmid40983232, year = {2026}, author = {Eceiza, MV and Gil-Monreal, M and Jimenez-Martinez, C and Estepa, L and Trebol-Aizpurua, E and Jugulam, M and Royuela, M and Zabalza, A}, title = {Glutathione metabolism and free amino acid profile in Amaranthus palmeri with non-target site-based resistance to sulfonylureas.}, journal = {Plant science : an international journal of experimental plant biology}, volume = {362}, number = {}, pages = {112781}, doi = {10.1016/j.plantsci.2025.112781}, pmid = {40983232}, issn = {1873-2259}, mesh = {*Amaranthus/metabolism/drug effects/genetics ; *Sulfonylurea Compounds/pharmacology ; *Glutathione/metabolism ; *Herbicides/pharmacology ; *Herbicide Resistance ; *Amino Acids/metabolism ; Glutathione Transferase/metabolism ; Plant Leaves/metabolism/drug effects ; Pyridines ; }, abstract = {Although the majority of Amaranthus palmeri populations resistant to ALS inhibitors are due to alterations in the enzyme (target-site resistance mechanism), there are some cases of resistance due to herbicide metabolization (which is a non-target site (NTS) mechanism). In this study, we investigated the physiology of a sensitive (S) population and a sulfonylurea-resistant population due to NTSR of A. palmeri (R). Both populations were grown hydroponically and treated with the ALS inhibitor nicosulfuron, alone or combined with NBD-Cl (GST inhibitor). Seven days later, free amino acid profile, glutathione (GSH) content and GST activity and expression were measured in the leaves. Only S population leaves showed the typical amino acid profile previously described after sulfonylureas; R population showed no change, suggesting that such physiological disruption is prevented as ALS activity is maintained through herbicide metabolism. In the S population, the herbicide-induced oxidative stress triggered an increase in GST activity and accumulation of glutathione-related compounds (GSH and its precursors). R population showed a higher basal GST activity than S population and GST activity was induced by the herbicide. Three Phy and three Tau GSTs were evaluated, but none were clearly linked to increased activity. Root length in agar plates was used as a marker of herbicide sensitivity in the presence or absence of NBD-Cl and malathion (P450s inhibitor). The results provide evidence that P450s are involved in NTSR in the population of A. palmeri of this study, as previously reported, and they suggest, for the first time in a dicot weed, the involvement of GSTs in sulfonylurea metabolism.}, } @article {pmid40983312, year = {2026}, author = {Silva, ECM and Helme, ZE and Silva, DRP and Morris, JL and Archbold, VSJ and Daly-Smith, A and Chalkley, A}, title = {Creating Active Schools: What Influences Continuous Implementation Following Adoption?.}, journal = {Journal of physical activity & health}, volume = {23}, number = {1}, pages = {51-62}, doi = {10.1123/jpah.2025-0075}, pmid = {40983312}, issn = {1543-5474}, mesh = {Humans ; *Exercise ; Focus Groups ; Qualitative Research ; *Health Promotion/organization & administration/methods ; *School Health Services/organization & administration ; *Schools/organization & administration ; Program Evaluation ; Child ; Female ; }, abstract = {BACKGROUND: Evidence on the long-term implementation and sustainability of whole-school physical activity programs remains limited. The Creating Active Schools (CAS) program incorporated the CAS Framework to support schools to focus on organizational and cultural change for physical activity. This study evaluates the medium-term implementation of CAS, after 2 academic years.

METHODS: A qualitative descriptive approach was employed. After 2 years of implementation, 35 participants from 30 Bradford schools, including school staff, CAS Champions, and Bradford CAS locality leads took part in semistructured focus groups. Thematic analysis followed a codebook method, combining inductive, data-driven insights with deductive themes based on McKay et al's implementation evaluation roadmap, and aligned to the Consolidated Framework Implementation Research.

RESULTS: The program increased the reach compared with the first year, with more staff buying into CAS and gaining confidence as advocates of physical activity. Schools shifted from creating new initiatives to embedding and sustaining previous efforts, and some schools required repeated doses to reinstate CAS as a priority where there had been high staff turnover or superficial initial buy-in. Core components of CAS that mitigated negative influences from the wider educational system, included peer-to-peer learning, and inter and intraknowledge exchange arising from the communities of practice. Collectively, these factors contributed to the combined agency within the school to implement CAS.

CONCLUSIONS: The medium-term implementation of whole-school physical activity programs is contingent on understanding the broader educational context and system influences. This study underscores the importance of communities of practice and supportive structures in sustaining school-based physical activity initiatives.}, } @article {pmid40983380, year = {2025}, author = {Schellenberg, KL and Caspar-Bell, G and Ellis, C and Johnston, W and King, A and King, M and Korngut, L and Kushneriuk, B and Lavoie, AJ and McGonigle, R and Newton, J and O'Connell, C and Shoesmith, C and Suchowersky, O and Warman-Chardon, J and Wunder, S and Pfeffer, G}, title = {Best practice recommendations for the clinical care of spinal bulbar muscular atrophy.}, journal = {CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne}, volume = {197}, number = {31}, pages = {E987-E999}, pmid = {40983380}, issn = {1488-2329}, mesh = {Humans ; Canada ; *Bulbo-Spinal Atrophy, X-Linked/therapy/diagnosis ; Male ; }, abstract = {BACKGROUND: Although rare in the general population, spinal bulbar muscular atrophy (SBMA) is an X-linked recessive neuromuscular condition that is highly prevalent in people identifying as First Nations and Métis in western Canada. The aim of this guideline is to improve and standardize care of SBMA, and to increase awareness of the condition.

METHODS: Our interdisciplinary working group conducted a needs assessment survey to aid in the development of guideline topic questions, followed by a literature search, evidence review, and external review by health practitioners and people with lived experience. We followed the ADAPTE framework to evaluate the only pre-existing SBMA guideline (2020 French national protocol) and the 2020 Canadian amyotrophic lateral sclerosis guideline for appropriateness of adaptation. Our process adhered to the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool; used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach; and followed the Guidelines International Network-McMaster Guideline Development Checklist. Indigenous community engagement was led by the Pewaseskwan Indigenous Research Group, who participated in the development of the guideline.

RECOMMENDATIONS: We developed 41 recommendations to address the continuum of care in SBMA, including diagnosis; multidisciplinary teams; management of limb and bulbar symptoms, respiratory and cardiac complications, and multisystem symptoms; female carriers; emotional supports; and considerations for Indigenous people. Spinal bulbar muscular atrophy is best managed by multidisciplinary teams that can address both its motor and nonmotor manifestations, including cardiac involvement, sensory symptoms, and metabolic dysfunction. Concerns for female carriers may include symptom management and genetic counselling. Providers should ensure culturally appropriate care for Indigenous people.

INTERPRETATION: In this guideline, we provide health care professionals with a culturally responsive standard of care for SBMA, and hope this will translate into improved quality of life for people affected by SBMA.}, } @article {pmid40983390, year = {2025}, author = {Breiner, A and Schellenberg, KL and Shoesmith, C}, title = {Integrating genetic testing into management of all patients with amyotrophic lateral sclerosis: a critical juncture.}, journal = {CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne}, volume = {197}, number = {31}, pages = {E1006-E1007}, pmid = {40983390}, issn = {1488-2329}, } @article {pmid40983577, year = {2025}, author = {Lee, LJ and Son, E and Butera, G and Park, J and Hussain, T and Wallen, GR}, title = {Caregiving stress and biological aging measured by epigenetic clocks: protocol for a scoping review.}, journal = {BMJ open}, volume = {15}, number = {9}, pages = {e095895}, pmid = {40983577}, issn = {2044-6055}, mesh = {Humans ; Scoping Reviews as Topic ; *Caregivers/psychology ; *Aging/genetics ; *Stress, Psychological/genetics ; *Epigenesis, Genetic ; DNA Methylation ; *Neoplasms ; Research Design ; }, abstract = {INTRODUCTION: Chronic caregiving stress accelerates biological aging, reflecting disease risk and mortality; however, the underlying mechanisms are poorly understood. Epigenetic clocks, which can be estimated from levels of DNA methylation in a subset of cytosine-phosphate-guanine loci in the genome, have been proposed as a promising biological age estimator. The objectives of this scoping review are to systematically scope the literature on the effects of stress on biological ageing measured by epigenetic clocks in family caregivers of patients diagnosed with cancer.

METHODS AND ANALYSIS: This review will be conducted following Joanna Briggs Institute methodology based on Arksey and O'Malley's and Levac et al's framework and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for scoping reviews. Studies will be included if (1) the studies focus on unpaid family caregivers of patients diagnosed with cancer; (2) caregivers are adults (≥18 years of age) and (3) the study measured epigenetic clocks. The search will encompass literature and peer-reviewed literature in PubMed/MEDLINE (National Library of Medicine), Embase (Elsevier), Cochrane CENTRAL (Wiley & Sons), Web of Science: Core Collection (Clarivate Analytics), CINAHL (EBSCOhost) and PsycInfo (American Psychological Association).

ETHICS AND DISSEMINATION: Since the scoping review methodology focuses on published literature, this study does not require ethical approval. We will publish our findings in a peer-reviewed journal and plan to disseminate our work in conferences and scientific meetings.

SCOPING REVIEW REGISTRATION: Open Science Framework (https://doi.org/10.17605/OSF.IO/KW7RT).}, } @article {pmid40983746, year = {2025}, author = {}, title = {Diagnosing ALS: a surprisingly arduous hike lasting 150 years.}, journal = {Nature medicine}, volume = {31}, number = {10}, pages = {3266-3267}, pmid = {40983746}, issn = {1546-170X}, } @article {pmid40983949, year = {2025}, author = {Cheng, S and Xiao, B and Luo, Z}, title = {Glycosylation in neuroinflammation: mechanisms, implications, and therapeutic strategies for neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {47}, pmid = {40983949}, issn = {2047-9158}, support = {2022YFC2503802//the National Key Research and Development Program of China/ ; z027001//The National Multidisciplinary Cooperative Diagnosis and Treatment Capacity Project for Major Diseases of Xiangya Hospital, Central South University/ ; 2021SK4001//the Innovative Construction Foundation of Hunan Province/ ; 2023JJ30924//the National Natural Science Foundation of Hunan province, China/ ; B202303076019//Scientific research project of Health Commission of Hunan Province/ ; }, mesh = {Humans ; Glycosylation ; *Neurodegenerative Diseases/metabolism/immunology/therapy ; Animals ; *Neuroinflammatory Diseases/metabolism ; Inflammation/metabolism ; Microglia/metabolism ; }, abstract = {Neuroinflammation is a key pathological mechanism underlying neurodegenerative diseases, and intricately interacts with protein glycosylation. Emerging evidence suggests that aberrant glycosylation disrupts immune homeostasis, activates microglia, and promotes the release of inflammatory mediators, thereby exacerbating neuroinflammatory responses. In addition, the inflammatory microenvironment can further dysregulate glycosylation patterns, creating a vicious cycle that amplifies disease pathology. Although the regulatory role of glycosylation in neuroinflammation associated with neurodegenerative diseases has been recognized, the precise molecular and cellular mechanisms remain incompletely understood. This review systematically examines the complex crosstalk between glycosylation and neuroinflammation, with a particular focus on the critical roles of glycosylation in key neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. We explore how glycosylation abnormalities contribute to disease pathogenesis through effects on immune recognition, protein aggregation, and cellular functions. Understanding the molecular underpinnings of these diseases may pave the way for the development of therapeutic strategies targeting glycosylation pathways, ultimately improving clinical outcomes for patients.}, } @article {pmid40985771, year = {2025}, author = {Provasek, VE and Bacolla, A and Rangaswamy, S and Kodavati, M and Mitra, J and Yusuf, IO and Malojirao, VH and Vasquez, V and Britz, GW and Li, GM and Xu, Z and Mitra, S and Garruto, RM and Tainer, JA and Hegde, ML}, title = {RNA/DNA-binding protein TDP43 regulates DNA mismatch repair genes with implications for genome stability.}, journal = {Nucleic acids research}, volume = {53}, number = {18}, pages = {}, pmid = {40985771}, issn = {1362-4962}, support = {R01 NS094535/NS/NINDS NIH HHS/United States ; R35 CA220430/NH/NIH HHS/United States ; //Texas Advanced Computing Center/ ; P01 CA092584/CA/NCI NIH HHS/United States ; R01NS094535/NH/NIH HHS/United States ; //Centennial Endowed Chair of Neurological Institute/ ; G-0010//Robert A. Welch Chemistry Chair/ ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; R35 CA220430/CA/NCI NIH HHS/United States ; //Sherman Foundation Parkinson's Disease Research Challenge Fund/ ; //University of Texas/ ; R03AG064266/NH/NIH HHS/United States ; //Houston Methodist Research Institute/ ; RP180813//Cancer Prevention and Research Institute of Texas/ ; RF1NS112719/NH/NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; CA092584/NH/NIH HHS/United States ; R01NS088645/NH/NIH HHS/United States ; }, mesh = {*DNA-Binding Proteins/genetics/metabolism ; Humans ; Animals ; *DNA Mismatch Repair/genetics ; Mice ; *Genomic Instability/genetics ; MutL Protein Homolog 1/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; MutS Homolog 3 Protein/genetics/metabolism ; MutS Homolog 2 Protein/genetics/metabolism ; Mismatch Repair Endonuclease PMS2/genetics/metabolism ; Neurons/metabolism ; DNA Breaks, Double-Stranded ; Gene Expression Regulation ; }, abstract = {TDP43 is an RNA/DNA-binding protein increasingly recognized for its role in neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to detrimental cytosolic aggregates and a reduction in nuclear functionality in neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expression. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include changes in MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find that aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and in post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.}, } @article {pmid40986355, year = {2025}, author = {Calvo, C and Swoboda, CO and Montecino-Morales, F and Nagar, S and Petrany, MJ and Sun, C and Bindu Durumutla, H and Quattrocelli, M and Millay, DP}, title = {The multimodal transcriptional response of denervated skeletal muscle involves regulation of Gramd1 genes impacting muscle size.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {39}, pages = {e2424246122}, pmid = {40986355}, issn = {1091-6490}, support = {R01 AG082697/AG/NIA NIH HHS/United States ; R01 AG078174/AG/NIA NIH HHS/United States ; R01AR068286//HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/ ; R01 HL166356/HL/NHLBI NIH HHS/United States ; R01 AR068286/AR/NIAMS NIH HHS/United States ; R03 DK130908/DK/NIDDK NIH HHS/United States ; R01AG082697//HHS | NIH | National Institute on Aging (NIA)/ ; }, mesh = {Animals ; Mice ; *Muscle, Skeletal/metabolism/innervation/pathology ; Neuromuscular Junction/metabolism ; Muscle Denervation ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Sciatic Nerve ; Autophagy ; Receptors, Cholinergic/metabolism ; Cholesterol/metabolism ; Gene Expression Regulation ; Muscle Fibers, Skeletal/metabolism ; Male ; Mice, Inbred C57BL ; Transcription, Genetic ; }, abstract = {The development and maintenance of the neuromuscular junction (NMJ) requires reciprocal signals between the nerve terminals and multinucleated skeletal muscle fibers (myofibers). This interaction drives highly specialized transcription in the subsynaptic or NMJ myonuclei within mature myofibers leading to clustering of acetylcholine receptors (AChRs). Here, we utilized single-nucleus RNA sequencing (snRNA-seq) to delineate the transcriptional response of myonuclei to denervation. Through snRNA-seq on skeletal muscle from two independent mouse models of denervation, sciatic nerve transection and amyotrophic lateral sclerosis, we identify a multimodal transcriptional response of NMJ-enriched genes and an alteration in cholesterol homeostasis in myofibers. Gramd1, a family of genes involved in nonvesicular cholesterol transport, are enriched at the NMJ in innervated muscle and upregulated in both models of denervation by the NMJ and extrasynaptic myonuclei. In vivo gain and loss of function studies indicate that Gramd1 genes regulate myofiber sizes. Mechanistically, we did not detect obvious changes in AChR clustering due to Gramd1 knockdown but revealed a role in autophagy after denervation. We uncovered a dynamic transcriptional response of myonuclei to denervation and highlight a critical role for Gramd1 to maintain myofiber sizes.}, } @article {pmid40986613, year = {2025}, author = {Savini, G and Hoffer, KJ and Nicolosi, D and Cooke, DL and Coutinho, CP and Grendele, A and Schiano-Lomoriello, D}, title = {Theoretical influence of segmented axial length on intraocular lens power calculation in short eyes.}, journal = {Journal of cataract and refractive surgery}, volume = {51}, number = {10}, pages = {839-844}, pmid = {40986613}, issn = {1873-4502}, mesh = {Humans ; *Axial Length, Eye/pathology ; *Lenses, Intraocular ; Retrospective Studies ; *Optics and Photonics ; *Biometry/methods ; Refraction, Ocular/physiology ; Male ; Female ; Aged ; Middle Aged ; Lens Implantation, Intraocular ; Phacoemulsification ; Visual Acuity/physiology ; }, abstract = {PURPOSE: To compare the segmented axial length (AL) provided by the Argos with the traditional AL provided by the IOLMaster 700 in short eyes and assess their impact on intraocular lens (IOL) power calculation.

SETTING: IRCCS Bietti Foundation, Rome, Italy.

DESIGN: Retrospective case series.

METHODS: Patients undergoing cataract or refractive surgery preoperative examinations were enrolled if their AL was <22.0 mm with the IOLMaster 700. The ALs given by the 2 biometers were compared. Using the formulas included in the ESCRS IOL calculator, the IOL power for a schematic eye was calculated with both AL measurements.

RESULTS: In 78 eyes, the traditional mean AL (21.22 ± 0.54 mm) was shorter than the segmented AL (21.29 ± 0.51 mm, P < .0001) with a proportional bias (r2 = 0.3312, P < .0001). The difference decreased with thicker lenses (r2 = 0.4941, P < .0001). Based on the IOL power calculated when the traditional AL was entered and the first negative refractive value was aimed at, the predicted refraction was more myopic with the Argos AL (P < .0001). The difference ranged from -0.18 ± 0.13 D (Cooke K6) to -0.24 ± 0.18 D (Barrett Universal II). The same IOL power would have been recommended by the ESCRS IOL calculator in only 40% to 50% of eyes, irrespective of formula used. The difference was minimized when the sum-of-segments option was used.

CONCLUSIONS: AL measurements provided by the Argos and IOLMaster 700 are not interchangeable for IOL power calculation in short eyes <22.0 mm.}, } @article {pmid40988103, year = {2026}, author = {Galaj, E and Inan, S and Bi, GH and Wiah, S and Adamson, G and Reitz, AB and Xi, ZX and Rawls, SM}, title = {Troriluzole attenuates opioid intake, reinforcing efficacy, seeking behaviours, physical dependence and antinociceptive tolerance in rats.}, journal = {British journal of pharmacology}, volume = {183}, number = {3}, pages = {505-519}, pmid = {40988103}, issn = {1476-5381}, support = {P30 DA013429/DA/NIDA NIH HHS/United States ; Z1ADA000633//Intramural Research Program/ ; 1R15DA057501/GF/NIH HHS/United States ; ZIA DA000633/ImNIH/Intramural NIH HHS/United States ; R01DA051205/GF/NIH HHS/United States ; P50 AA017823/AA/NIAAA NIH HHS/United States ; R01 DA051205/DA/NIDA NIH HHS/United States ; R15 DA057501/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Male ; Rats, Sprague-Dawley ; Drug Tolerance ; Rats ; *Analgesics, Opioid/administration & dosage ; Rats, Long-Evans ; *Opioid-Related Disorders/drug therapy ; Self Administration ; Oxycodone/administration & dosage ; *Drug-Seeking Behavior/drug effects ; Morphine/administration & dosage ; Behavior, Animal/drug effects ; Reinforcement, Psychology ; Riluzole/pharmacology ; }, abstract = {BACKGROUND AND PURPOSE: Riluzole, approved for amyotrophic lateral sclerosis (ALS), has a glutamate-modulating profile favourable for mitigating opioid addiction. It reduces neuronal glutamate release and enhances glutamate reuptake, offering advantages over agents that only increase glutamate reuptake. However, riluzole has pharmacokinetic liabilities that limit repurposing. To overcome these limitations, we designed and prepared the prodrug troriluzole (TRLZ), which retains the mechanistic profile of riluzole but with optimized metabolic and pharmacokinetic properties (e.g., higher oral bioavailability and less pharmacokinetic variability). As dysregulation of glutamate systems during opioid exposure contributes to adverse opioid effects, we tested the hypothesis that TRLZ would inhibit several opioid-derived adverse effects in rats.

EXPERIMENTAL APPROACH: In male Long-Evans and Sprague-Dawley rats, effects of TRLZ on oxycodone self-administration were investigated under fixed-ratio and progressive-ratio reinforcement schedules. Effects of TRLZ on food self-administration were also investigated. TRLZ effects on cue-induced reinstatement of oxycodone seeking, and on morphine-induced physical dependence, antinociceptive tolerance and respiratory depression were also investigated. TRLZ was administered intraperitoneally.

KEY RESULTS: TRLZ dose-dependently reduced oxycodone self-administration, reinforcing efficacy and cue-induced reinstatement of oxycodone seeking without affecting inactive lever responding. TRLZ, at high doses, also inhibited food self-administration. TRLZ reduced naloxone-precipitated withdrawal signs in morphine-dependent rats and antinociceptive tolerance during repeated morphine exposure. TRLZ also attenuated morphine-induced respiratory depression.

CONCLUSIONS AND IMPLICATIONS: TRLZ, already in clinical trials for cerebellar ataxia, also reduced opioid taking and seeking as well as opioid-derived adverse effects in rats, supporting further study in treating opioid use disorders and pain management.}, } @article {pmid40988456, year = {2025}, author = {Tian, J and Bai, D and He, S and Cao, Y and Liao, Y and Wang, J and Bai, L and Pan, L}, title = {Pro-197-his/ser mutation and the metabolic gene DsUGT84A1, synergistically confer resistance to tribenuron-methyl in Descurainia sophia.}, journal = {The Plant journal : for cell and molecular biology}, volume = {123}, number = {6}, pages = {e70487}, doi = {10.1111/tpj.70487}, pmid = {40988456}, issn = {1365-313X}, support = {2023YFD1401100//National Key Research and Development Program of China/ ; CARS-01//China Agriculture Research System/ ; CARS-16-E19//China Agriculture Research System/ ; 2022-31//Modern Agricultural Industrial Technology System of Hunan Province/ ; }, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Arylsulfonates/pharmacology/metabolism ; Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Plant Proteins/genetics/metabolism ; Mutation ; Cytochrome P-450 Enzyme System/genetics/metabolism ; *Plant Weeds/genetics/drug effects ; Plants, Genetically Modified ; Gene Expression Regulation, Plant ; }, abstract = {Descurainia sophia, an invasive weed in wheat fields of China, has developed notable resistance to the acetolactate synthase (ALS)-inhibiting herbicide tribenuron-methyl. In this study, a suspected resistant population (R) of D. sophia was investigated to assess its resistance level and elucidate the underlying mechanisms. Whole-plant bioassays revealed that the R population exhibited a 35.20-fold higher resistance index (RI) to tribenuron-methyl compared with a sensitive (S) population. Treatment with the cytochrome P450 inhibitor malathion partially reversed this resistance, indicating a metabolic component. Target-site resistance (TSR) analysis identified a mutation from proline (Pro) to histidine (His) or serine (Ser) at position 197 of the ALS gene in the R population. Additionally, high-performance liquid chromatography (HPLC) analysis indicated that enhanced tribenuron-methyl metabolism occurred in the R population compared with the S population. Three candidate P450 genes (CYP96A15, CYP81F1, CYP734A1), and one UDP-glycosyltransferase (UGT) gene (UGT84A1) were found to be upregulated in the R population, as verified by RNA sequencing and quantitative reverse transcription PCR (RT-qPCR). Candidate resistance genes were identified and expressed heterologously in Arabidopsis thaliana. Experimental data showed that compared with the green fluorescent protein (GFP) control group, the resistance of three transgenic Arabidopsis lines overexpressing the DsUGT84A1 gene to tribenuron-methyl was significantly increased. When all the plants in the GFP control group died, the fresh weight of these three transgenic lines remained above 20%. The above results fully confirm that the DsUGT84A1 gene demonstrates significant functions pertaining to resistance against tribenuron-methyl. However, the current data suggest that this novel metabolic gene (DsUGT84A1) may not confer cross-resistance among various ALS-inhibiting herbicides. In this respect, the TSR conferred by the Pro197His/Ser mutation may be responsible for cross-resistance. Additionally, antioxidant-related genes were upregulated in A. thaliana overexpressing DsUGT84A1, leading to a reduction in the toxicity level of reactive oxygen species (ROS). Notably, this study identifies and functionally characterizes the UGT gene DsUGT84A1 related to herbicide resistance in broadleaf weeds. This contributes to the understanding of herbicide resistance mechanisms, especially highlighting the role of UGT genes, and enhances the current understanding of resistance evolution in weeds.}, } @article {pmid40988501, year = {2025}, author = {Taule, T and Tysnes, OB and Aßmus, J and Morland, AS and Renså, MA and Revheim, T and Glesnes, S and Rekand, T}, title = {Early cognitive decline in amyotrophic lateral sclerosis and its relation to driving: an observational study.}, journal = {Journal of rehabilitation medicine}, volume = {57}, number = {}, pages = {jrm43483}, pmid = {40988501}, issn = {1651-2081}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Female ; *Automobile Driving/psychology ; Male ; Middle Aged ; *Cognitive Dysfunction/etiology ; Aged ; Adult ; Neuropsychological Tests ; Follow-Up Studies ; }, abstract = {OBJECTIVE: To determine whether early cognitive function in amyotrophic lateral sclerosis patients predicts future cognitive function and the decision to cease driving.

DESIGN: Observational study.

SUBJECTS: Patients with amyotrophic lateral sclerosis.

METHODS: Subjects underwent baseline assessments of cognitive function and driving ability within 4 months of diagnosis, with follow-up evaluation conducted 4 months thereafter. Two hypotheses were tested: (H1) cognitive status remains stable between baseline and follow-up, (H2) patients with baseline cognitive impairment cease driving earlier than those without cognitive changes. Data were analysed using t-tests and regression analysis, with visual inspection of the results.

RESULTS: Of 31 subjects tested at baseline, 5 were under 60 years old, 11 were female, 11 were cognitively impaired, and 61% were driving. Over the 4-month period, cognitive function of the subjects (n = 21) did not change significantly. There was no significant association between baseline cognitive function and follow-up driving status.

CONCLUSION: Early cognitive function assessment in amyotrophic lateral sclerosis predicts future cognitive function but not currently the decision to cease driving. Cognitive impairment occurs early in the disease, highlighting the importance of early evaluation and implementation of safety measures related to driving.}, } @article {pmid40988901, year = {2025}, author = {Miyashita, T and Tsushima, E and Ogihara, H}, title = {Factors Influencing the Loss of Ambulation in Patients With Amyotrophic Lateral Sclerosis: A Retrospective Cohort Study.}, journal = {Health science reports}, volume = {8}, number = {9}, pages = {e71282}, pmid = {40988901}, issn = {2398-8835}, abstract = {BACKGROUND AND AIMS: Loss of ambulation in patients with amyotrophic lateral sclerosis (ALS) reduces their social participation and quality of life. Moreover, loss of ambulation is one of the biggest obstacles for patients and their caretakers. However, prognostic factors for loss of ambulation in patients with ALS have not been clarified. This study aimed to investigate the time to loss of ambulation in Japanese patients with ALS and to identify factors associated with loss of ambulation.

METHODS: Overall, 62 patients with ALS were enrolled. Survey items included patient background, pre-existing medical conditions, and laboratory data. Cox proportional hazards regression analysis was performed with the time to loss of ambulation as the dependent variable and age at onset, sex, onset type, duration to diagnosis, ALS severity, diabetes mellitus (DM), and %forced vital capacity (%FVC) as independent variables.

RESULTS: The median time to loss of ambulation for all ALS patients was 16.5 (10.0-31.3) months. Cox regression analysis revealed a significant association between duration to diagnosis (HR: 0.94, 95% CI: 0.91-0.97, p < 0.001) and DM (HR: 3.30, 95% CI: 1.62-6.69, p < 0.001).

CONCLUSIONS: Time to diagnosis and history of diabetes are important factors associated with the time to loss of ambulation in patients with ALS.

TRIAL REGISTRATION: Retrospectively registered.}, } @article {pmid40989043, year = {2025}, author = {Marazziti, D and Carbone, MG and Arone, A and Gurrieri, R and Dell'Osso, L and Crowther, LF}, title = {Fueling the Cycle: Attachment, Cognition, and Emotion in Substance-Using Incarcerated Young Adults.}, journal = {Clinical neuropsychiatry}, volume = {22}, number = {4}, pages = {261-278}, pmid = {40989043}, issn = {2385-0787}, abstract = {OBJECTIVE: Youth violence, often linked to drug offenses, is a major concern in socially and politically unstable regions worldwide. Early attachment and stressors influence behavioral development, highlighting the importance of addressing underlying psychopathology. This study examined clinical, psychopathological, and cognitive profiles in incarcerated young adults with substance use issues, considering social, familial, and environmental factors.

METHOD: This cross-sectional study enrolled 40 male young adults (mean age 21.05 ± 1.15 years) with SUD, participating in a resocialization program in Medellin. Participants completed questionnaires assessing affective lability (ALS-SF), emotion dysregulation (DERS), executive functions (BRIEF-A), ADHD symptoms (ASRS), attachment styles (CA-MI-R), and stressful life events (SRRS). Data were analyzed using non-parametric tests, Spearman's rank correlations, and multiple linear regressions.

RESULTS: Multiple linear regression analyses revealed significant predictive relationships. The number of substances used was predicted by poorer emotional control (β = -0.440, p = .007), greater executive dysfunction (β = 0.060, p = .015), higher childhood trauma (β = -0.360, p = .006), and a higher CA-MI-R score (β = 2.316, p = .017). Childhood trauma reported was predicted by greater executive dysfunction (β = 0.536, p = .013), lower socioeconomic status (β = -0.119, p = .035), a greater number of substances used (β = -0.256, p = .006), benzodiazepine use (β = -0.299, p = .014), and poorer emotional control (β = -0.331, p = .016). Affective lability, emotion dysregulation, and executive dysfunction were significantly intertwined with ADHD traits.

CONCLUSIONS: This study provides evidence for the complex interplay of attachment, executive function, emotion regulation, and ADHD symptoms in incarcerated young adults with SUD. Executive dysfunction, impulsivity, emotional dysregulation, and attachment insecurity significantly contribute to substance use and childhood trauma, fueling a vicious cycle. Interventions addressing relational trauma, deficits, and broader factors are needed to disrupt this cycle, promote rehabilitation, and reduce recidivism.}, } @article {pmid40990022, year = {2025}, author = {Shimizu, T and Ohkuma, R and Homma, M and Nakayama, S and Sasaki, Y and Muto, S and Ieguchi, K and Watanabe, M and Taguchi, A and Takayanagi, D and Wada, Y and Horiike, A and Kubota, Y and Ariizumi, H and Shimokawa, M and Hirasawa, Y and Ishiguro, T and Suzuki, R and Iriguchi, N and Mura, E and Yoshimura, K and Tsuji, M and Kiuchi, Y and Suzuki, H and Yamochi, T}, title = {Tumor Akkermansia muciniphila predicts clinical response to immune checkpoint inhibitors in non-small-cell lung cancer patients with low PD-L1 expression.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1528594}, pmid = {40990022}, issn = {1664-3224}, mesh = {Humans ; *B7-H1 Antigen/metabolism/genetics ; *Carcinoma, Non-Small-Cell Lung/drug therapy/immunology/metabolism/mortality/pathology/microbiology ; *Immune Checkpoint Inhibitors/therapeutic use ; Male ; Female ; *Lung Neoplasms/drug therapy/immunology/microbiology/metabolism/pathology/mortality ; Middle Aged ; Aged ; Retrospective Studies ; Biomarkers, Tumor ; *Akkermansia ; Prognosis ; Treatment Outcome ; }, abstract = {INTRODUCTION: A prior retrospective analysis demonstrated that quantifying Programmed Cell Death Ligand 1 (PD-L1) expression using a phosphor-integrated dot (PID) score effectively predicted immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC) and other cancers. However, PD-L1 expression proved unreliable in some patients with low PD-L1 levels, highlighting the need for alternative biomarkers. A previous cohort study in NSCLC patients linked intestinal Akkermansia muciniphila (Akk) presence to improved ICI efficacy, particularly in low PD-L1 subgroups. Here, we evaluated tumor tissue Akk expression via immunohistochemical staining as a potential biomarker for ICI response in NSCLC.

METHODS: We retrospectively analyzed tumor tissues from 60 metastatic or recurrent NSCLC patients treated with ICIs. Immunohistochemical (IHC) staining was performed to assess Akk and PD-L1 expression, along with CD3 and CD68 in PD-L1-low samples. Transcriptomic profiling using RNA-sequencing was conducted on tumor samples to identify Akk-related gene expression patterns.

RESULTS: Tumor Akk expression showed no correlation with PD-L1 levels assessed via PID. Survival and multivariable Cox regression analyses revealed no association between Akk expression and progression-free survival (PFS) or overall survival (OS). In high PD-L1 patients, Akk status did not influence outcomes. However, among low PD-L1 patients, Akk-positive cases exhibited significantly worse PFS compared to Akk-negative cases (OS remained unchanged). Transcriptome analysis indicated that Akk positivity in low PD-L1 samples exhibited enrichment in oxidative phosphorylation and amyotrophic lateral sclerosis-related pathways and downregulation of spliceosome-associated pathways. No significant differences in tumor-infiltrating CD3+ T cells or CD68+ macrophages were observed between Akk-positive and Akk-negative tumors in the PD-L1-low group.

CONCLUSIONS: Tumor-associated Akk may serve as a negative predictive biomarker for ICI efficacy in NSCLC patients with low PD-L1 expression. Our findings suggest that tumor microbiota profiling, particularly targeting Akk, could refine patient stratification and therapeutic decision-making.}, } @article {pmid40990258, year = {2025}, author = {Baumeister, TR and Westeneng, HJ and van den Berg, L and , and Kalra, S and Iturria-Medina, Y}, title = {Multimodal Neuroimaging-Guided Stratification in Amyotrophic Lateral Sclerosis Reveals Three Disease Subtypes: A Multi-Cohort Analysis.}, journal = {Human brain mapping}, volume = {46}, number = {14}, pages = {e70341}, pmid = {40990258}, issn = {1097-0193}, support = {//Fondation Brain Canada/ ; //Shelly Mrkonjic ALS Research Fund/ ; //New Investigator start-up grant from McGill University's Healthy Brains for Healthy Lives Initiative (Canada First Research Excellence Fund)/ ; //ALS Society of Canada/ ; //CIHR/Canada ; //Canada Research Chairs/ ; //Fonds de Recherche du Québec - Santé/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/classification/pathology ; Male ; Female ; Middle Aged ; Disease Progression ; *Multimodal Imaging/methods ; *Gray Matter/diagnostic imaging/pathology ; *Neuroimaging/methods ; Aged ; *White Matter/diagnostic imaging/pathology ; Cohort Studies ; Adult ; Diffusion Magnetic Resonance Imaging ; Diffusion Tensor Imaging ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multisystem disease with marked pathophysiological and clinical heterogeneity, making individual and objective characterization of the degree of disease progression and disease-related subtrajectories challenging. Here, we use in vivo multimodal neuroimaging data and computational models to generate personalized indices of ALS progression and subtrajectory. We used structural and diffusion weighted imaging of 691 participants (58% ALS) from two independent ALS data sets (North American and Utrecht cohorts) to extract regional values of grey matter (DM) density and white matter (WM) microstructural integrity. Contrastive trajectory inference (cTI) allowed us to identify and separate latent, multivariate patterns in neuroimaging features highlighting ALS-associated pathological processes, which were used to generate subject-specific indices of disease progression and subtrajectory. Disease subtrajectories were based on distinct patterns of alterations in neuroimaging data considering subjects at different disease progression levels. The neuroimaging-based, personalized index of disease progression is indicative of clinical symptom severity (North American: p < 0.01 and Utrecht: p < 0.01) and displays alignment with the King's College staging system (p = 0.001 and p = 0.002). Three ALS subtrajectories were identified that displayed distinct alterations in the motor, limbic system, and widespread cortical and subcortical changes that also differed in clinical symptom manifestation. Our analysis has shown that neuroimaging data encodes subject-specific, disease-related patterns that can be leveraged to obtain an in vivo proxy of disease progression and putative disease subtype.}, } @article {pmid40991828, year = {2026}, author = {Deng, C and Zhang, J and Qiu, Y and He, H and Wang, J and Ma, M and Li, Y and Zeng, L and Luo, J and Ji, G}, title = {Antibacterial activity and mechanism of Myxin from Lysobacter antibioticus against Xanthomonas fragariae.}, journal = {Pest management science}, volume = {82}, number = {1}, pages = {661-674}, doi = {10.1002/ps.70233}, pmid = {40991828}, issn = {1526-4998}, support = {202301AS070080//Department of Science and Technology Basic Research Programs of Yunnan Province/ ; 202405AF140070//Yunnan Academician Expert Workstation/ ; }, mesh = {*Xanthomonas/drug effects/physiology ; *Anti-Bacterial Agents/pharmacology ; *Lysobacter/chemistry ; Fragaria/microbiology ; Plant Diseases/microbiology ; Microbial Sensitivity Tests ; Biofilms/drug effects ; }, abstract = {BACKGROUND: Xanthomonas fragariae (Xaf), the causative agent of angular leaf spot (ALS) in strawberries, poses a significant threat to the strawberry industry due to the current lack of effective biological control measures. Myxin, produced by Lysobacter antibioticus, exhibits good inhibitory activity against various pathogenic bacteria. However, the efficacy and mechanism of its antibacterial actions against X. fragariae remains poorly understood.

RESULTS: X. fragariae proliferation was almost completely suppressed by Myxin at 0.6 MIC (Minimum Inhibitory Concentration, MIC = 40 μg/mL). Biological characterization experiments found that Myxin can change the permeability of Xaf cell membrane, induce cell swelling, accumulate intracellular reactive oxygen species (ROS), hinder the synthesis of biofilm, Exopolysaccharide (EPS) and intracellular protein. Significant findings revealed a notable decrease in the expression of genes associated with ribosome metabolism, amino acid production, and energy metabolism, while genes related to oxidative stress were upregulated, and there was a change in the expression of genes involved in cell structure and exopolysaccharide biosynthesis.

CONCLUSION: This study reveals that the Myxin employs a multi-target antimicrobial strategy against X. fragariae. Our findings lay the groundwork for using Myxin and developing a disease management system for strawberry angular leaf spot. © 2025 Society of Chemical Industry.}, } @article {pmid40992079, year = {2025}, author = {Wu, HC and Huang, TW and Weng, EF and Lin, CY and Su, TP and Wu, HE and Wang, SM}, title = {Sigma-1 receptor counteracts non-cell-autonomous poly-PR-induced astrocytic oxidative stress in C9orf72 ALS.}, journal = {Redox biology}, volume = {87}, number = {}, pages = {103875}, pmid = {40992079}, issn = {2213-2317}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology/etiology ; *Oxidative Stress ; *Astrocytes/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; Animals ; Humans ; Mice ; *Receptors, sigma/metabolism/genetics ; Sigma-1 Receptor ; Disease Models, Animal ; NADPH Oxidase 4/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Hydrogen Peroxide/metabolism ; }, abstract = {C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by the accumulation of toxic dipeptide repeat proteins (DPRs) generated from G4C2 hexanucleotide repeat expansions. Among these, the arginine-rich poly-PR (proline-arginine) species is the most neurotoxic, eliciting glial activation and neuroinflammation via non-cell-autonomous mechanisms. Although growing evidence implicates glial cells, particularly astrocytes, in disease progression, the molecular pathways linking neuron-derived poly-PR to astrocyte-mediated oxidative stress remain poorly understood. We demonstrate that exogenous poly-PR induces robust NOX4 expression and hydrogen peroxide (H2O2) production in astrocytes through activation of the IKK/IκB/NF-κB p65 signaling pathway. Mechanistically, poly-PR promotes nuclear translocation of p65 and enhances its binding to the NOX4 promoter, thereby amplifying astrocytic oxidative stress. Overexpression of the Sigma-1 receptor (Sigma-1R), an endoplasmic reticulum-resident chaperone, significantly attenuates poly-PR-induced NOX4 transcription and reactive oxygen species (ROS) production by interacting with p65 and blocking its nuclear translocation, independently of upstream p65 phosphorylation. Notably, clemastine, a clinically approved Sigma-1R agonist, suppresses astrocytic NOX4 expression by disrupting p65 binding to the NOX4 promoter. In a mouse model of C9orf72 ALS, Sigma-1R deficiency exacerbates poly-PR-induced neurodegeneration, astrogliosis, and NOX4 upregulation, whereas Sigma-1R sufficiency confers neuroprotection and anti-inflammatory effects. This study identifies Sigma-1R as a critical modulator of non-cell-autonomous poly-PR toxicity and establishes its activation as a potent suppressor of astrocyte-derived oxidative stress. Our findings uncover a previously unrecognized glial mechanism driving C9orf72 ALS pathogenesis and support Sigma-1R activation, via clemastine, as a promising therapeutic strategy to mitigate neuroinflammation and disease progression.}, } @article {pmid40992439, year = {2025}, author = {Tien Vo, TT and Tsai, MH and Cheng, CY and Wang, YL and Lee, WJ and Lee, IT}, title = {The oral microbiome-redox-inflammation axis in neurodegeneration: mechanistic insights and therapeutic perspectives.}, journal = {Biochemical pharmacology}, volume = {242}, number = {Pt 3}, pages = {117362}, doi = {10.1016/j.bcp.2025.117362}, pmid = {40992439}, issn = {1873-2968}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/microbiology/therapy ; Oxidation-Reduction ; Animals ; *Microbiota/physiology ; *Mouth/microbiology/metabolism ; Dysbiosis/metabolism ; Oxidative Stress/physiology ; Inflammation/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {The oral microbiome is a highly diverse and metabolically active ecosystem that plays a pivotal role in maintaining oral and systemic homeostasis. Disruption of this balance, referred to as oral dysbiosis, has been increasingly implicated in the pathogenesis of neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Although the precise molecular mechanisms remain incompletely defined, accumulating evidence indicates that oxidative stress and redox signaling act as central mediators linking microbial imbalance to neuroinflammatory responses and progressive neuronal dysfunction. In this review, we critically synthesize interdisciplinary findings on the oral microbiome-brain axis, emphasizing redox-sensitive pathways that mediate communication between oral pathogens and the central nervous system. We discuss how reactive oxygen species (ROS), generated by microbial metabolites and pathogen-associated molecular patterns, activate various signaling cascades, thereby exacerbating neuroinflammation and glial activation. We further evaluate evidence that oral dysbiosis contributes to blood-brain barrier (BBB) disruption, peripheral immune priming, and chronic neuroimmune dysregulation. By integrating mechanistic, cellular, and clinical perspectives, we identify oxidative stress and redox signaling as critical biological bridges between oral dysbiosis and neurodegeneration. This framework highlights not only the translational potential of targeting redox pathways and the oral microbiome for preventive and therapeutic strategies but also the need for future research to clarify causal relationships and validate clinical applications.}, } @article {pmid40992657, year = {2025}, author = {Almaguer-Mederos, LE and Kandi, AR and Sen, NE and Canet-Pons, J and Berger, LM and Stokes, MP and Abell, K and Key, J and Gispert, S and Auburger, G}, title = {Spinal Cord Phosphoproteome of SCA2 Mouse Model Reveals Alteration of ATXN2-N-Term PRM-SH3-Actin Interactome and of Autophagy.}, journal = {Molecular & cellular proteomics : MCP}, volume = {24}, number = {11}, pages = {101072}, pmid = {40992657}, issn = {1535-9484}, mesh = {Animals ; *Autophagy ; *Ataxin-2/metabolism/genetics ; *Spinal Cord/metabolism/pathology ; Disease Models, Animal ; *Proteome/metabolism ; Mice ; Humans ; Phosphorylation ; *Spinocerebellar Ataxias/metabolism/pathology/genetics ; Peptides/metabolism ; Protein Interaction Maps ; }, abstract = {Toxic polyglutamine (polyQ) expansions in ataxin-2 (ATXN2) trigger neurodegenerative processes, causing spinocerebellar ataxia type 2, and enhancing TAR DNA-binding protein 43-dependent pathology in amyotrophic lateral sclerosis/frontotemporal dementia. Primary disease events can be compensated transiently, delaying disease manifestation. To define potential therapy targets, here we studied how cells modify phosphoprotein signals, using preferentially affected nervous tissue from end-stage Atxn2-CAG100-Knockin mice. The spinal cord phosphoproteome revealed massive hyperphosphorylations flanking the polyQ expansion in ATXN2 and for SQSTM1 and moderate hyperphosphorylations also for amyotrophic lateral sclerosis proteins, OPTN (optineurin), UBQLN2 (ubiquilin-2), TNIP1 (TNFAIP3 interacting protein 1), and TBK1-targeted TAX1BP1. Conversely, strong hypophosphorylations of WNK1 (protein kinase with no lysine 1), SPARCL1 (secreted protein acidic and cysteine rich-like 1), and PSMD9 (proteasome 19S regulator non-ATPase assembly chaperone P27) were found. Significant enrichments of SRC-homology domain type 3-containing proteins, autophagy/endocytosis factors, and actin modulators could be explained by N-terminal, polyQ-adjacent, proline-rich motifs in ATXN2, suggesting that spinocerebellar ataxia type 2 pathogenesis is highly similar to Huntington's disease, where neurotoxicity is mediated by abnormal polyQ-proline-rich motif-SRC-homology domain type 3 interactions. Validation of protein and mRNA levels was done in mouse spinal cord and embryonic fibroblasts or patient fibroblasts after bafilomycin or arsenite treatment, observing polyQ-dependent OPTN deficiency and SQSTM1 induction impairment. Overall, this phosphoproteome profile identified and quantified the main cellular efforts in adapting autophagy pathways to the aggregation propensity of the ATXN2-N-term.}, } @article {pmid40992838, year = {2025}, author = {Kim, HY and Bae, TH and Lee, SJ and Kim, SB and Kwon, YT and Ji, CH}, title = {Generation and characterization of engineered N-degrons of the N-degron pathway using the ubiquitin-reference technique.}, journal = {Methods in enzymology}, volume = {719}, number = {}, pages = {147-172}, doi = {10.1016/bs.mie.2025.06.005}, pmid = {40992838}, issn = {1557-7988}, mesh = {*Ubiquitin/metabolism/genetics/chemistry ; Proteolysis ; *Protein Engineering/methods ; Humans ; Proteasome Endopeptidase Complex/metabolism ; Recombinant Fusion Proteins/metabolism/genetics/chemistry ; Degrons ; }, abstract = {In the N-degron pathway, the degradation of proteins and other cellular constituents is governed by destabilizing N-terminal (Nt) amino acids of proteins. These degradation determinants, called N-degrons, modulate cellular degradative processes by binding to N-recognins that link their clients to the ubiquitin (Ub)-proteasome system (UPS) or the autophagy-lysosome system (ALS). Physiological N-degrons can be generated when the initiator methionine (Met, M) cotranslationally cleaved by Met amino peptidases (MetAPs), exposing the second residues to the Nt-position. Alternatively, endoproteolytic cleavages of folded proteins generate C-terminal (Ct) fragments exposing N-degrons. In either case, expressing physiological or engineered N-degron substrates is technically challenging, in part because the Nt-Met excision depends on specific second-position residues. To generate engineered N-degrons, the Ub fusion technique (UFT) employs a chimeric construct in which a Ub moiety is followed by X-substrate. Ub is cotranslationally cleaved off at Ct-Gly76 by deubiquitylases (DUBs). The resulting X-substrate can expose any of the principal amino acids listed in the genetic code possibly except for proline. Moreover, the half-lives of X-substrates can be precisely measured using the Ub reference technique (URT), in which M-reference-Ub-X-substrate is cleaved into M-reference-Ub and X-substrate. By comparing the ratio of two cleavage products, the decay of X-substrate can be quantitatively measured for various N-degrons. The URT critically contributed to identification and biochemical characterization of most N-recognins known in the Arg/N-degron pathway. Here, we describe detailed protocols for designing and using URT constructs to characterize substrate degradation, validate putative N-degrons, and assess their interactions with N-recognins in the Arg/N-degron pathway.}, } @article {pmid40992839, year = {2025}, author = {Lee, J and Lee, GE and Jung, CH and Lee, YJ and Kwon, YT}, title = {Characterization of the autophagic N-degron pathway and monitoring its chemical modulation for therapeutic development.}, journal = {Methods in enzymology}, volume = {719}, number = {}, pages = {173-210}, doi = {10.1016/bs.mie.2025.06.009}, pmid = {40992839}, issn = {1557-7988}, mesh = {*Autophagy/drug effects ; Humans ; *Sequestosome-1 Protein/metabolism ; Proteolysis/drug effects ; Lysosomes/metabolism ; Ubiquitin/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitination ; Animals ; Degrons ; }, abstract = {Cellular homeostasis relies on the regulated degradation of unnecessary or harmful biomaterials including proteins. The N-degron pathway plays a central role in quality control at the crossroad of the ubiquitin (Ub)-proteasome system (UPS) and the autophagy-lysosome system (ALS). In this pathway, single N-terminal (Nt) residues of substrate proteins act as degradation determinants, called N-degrons. In the UPS, N-degrons are recognized and bound by their cognate N-recognins such as a family of E3 Ub ligases carrying the UBR box to induce substrate ubiquitination for proteasomal degradation. Our earlier studies identified an autophagic version of the N-degron pathway that works cooperatively with the UPS. In this process, N-degrons bind the N-recognin p62/SQSTM1 and modulate its activity as an autophagy receptor, leading to lysosomal destruction of UPS-resistant cargoes. We also developed chemical mimetics of N-degrons that exert efficacy to accelerate the degradation of excessive or harmful biomaterials such as cellular wastes and subcellular organelles. Here, we describe biochemical assays to characterize p62 as an autophagic N-recognin. We also delve into methodologies to assess therapeutic efficacy of chemical N-degrons in the degradation of lipid droplets (LDs) through lipophagy and the clearance of invading bacteria through xenophagy. These protocols can be used to identify new ZZ-type N-recognins in mammals and other species as well as under various pathophysiological conditions in both the UPS and ALS.}, } @article {pmid40992840, year = {2025}, author = {Lee, JS and Lee, MJ and Kim, SB and Kwon, YT and Ji, CH}, title = {Characterization of the E3 ligase KCMF1 as a ZZ/N-recognin of the autophagic Arg/N-degron pathway.}, journal = {Methods in enzymology}, volume = {719}, number = {}, pages = {211-235}, doi = {10.1016/bs.mie.2025.06.010}, pmid = {40992840}, issn = {1557-7988}, mesh = {*Autophagy ; Humans ; *Arginine/metabolism ; Sequestosome-1 Protein/metabolism ; Proteolysis ; *Ubiquitin-Protein Ligases/metabolism/genetics/chemistry ; Ubiquitination ; Zinc Fingers ; HEK293 Cells ; Lysosomes/metabolism ; Degrons ; }, abstract = {In the Arg/N-degron pathway, Arg/N-degrons share the N-terminal (Nt) arginine (Nt-Arg) residue and hydrophobic amino acid residues that can be generated through Nt-arginylation by ATE1-encoded R-transferases (EC 2.3.2). In the ubiquitin-proteasome system (UPS), N-degrons are recognized by the UBR box of N-recognins that facilitate ubiquitination and proteasomal degradation. Arg/N-degrons also modulate the lysosomal degradation of proteins and other biomaterials via the autophagy-lysosome system (ALS). In this autophagic process, N-degrons function through their recognition by the ZZ-type zinc finger domain of the N-recognin p62/SQSTM1-1/Sequestosome-1. Recently, we identified the E3 ligase KCMF1 (potassium channel modulatory factor 1) as an autophagic N-recognin at the crossroads of the UPS and ALS. KCMF1 binds Nt-Arg and structurally related Nt-motifs through its ZZ domain, a structural equivalent to the ZZ domain of p62 as well as the UBR box of N-recognins. Under oxidative stress such as prolonged hypoxia where protein aggregates accumulate, the cysteine (Cys) residue at position 2 is Nt-exposed through the Nt-methionine (Nt-Met) excision and undergoes chemical oxidation into Cys sulfonic acid (CysO3) followed by Nt-arginylation. The resulting Arg-CysO3 N-degron binds KCMF1 to induce the assembly of lysine 63 (Lys63)-linked Ub chains, to which p62-type autophagic receptors bind via their Ub-associated (UBA) domain for autophagic degradation. Through this collaboration between the UPS and ALS, Arg-CysO3 N-degrons contribute the degradation of harmful protein species generated under cellular stresses. Here, we describe biochemical assays to characterize KCMF1 as an emerging N-recognin, including its interaction with synthetic N-degrons and its activity to undergo self-polymerization stimulated by N-degrons.}, } @article {pmid40993944, year = {2026}, author = {Nuovo, GJ and Crilly, C and Lietzke, A and Sawant, D}, title = {A Putative Role for the BCL2 Family of Proteins in the Pathophysiology of ALS.}, journal = {CNS & neurological disorders drug targets}, volume = {25}, number = {1}, pages = {67-76}, pmid = {40993944}, issn = {1996-3181}, support = {20160204//Alzheimer's Drug Discovery Foundation, New York, USA/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology/genetics ; Humans ; Animals ; *Proto-Oncogene Proteins c-bcl-2/metabolism ; Mice ; Female ; Male ; Aged ; Middle Aged ; DNA-Binding Proteins/metabolism/genetics ; Spinal Cord/metabolism/pathology ; Motor Neurons/metabolism/pathology ; Motor Cortex/metabolism/pathology ; Mice, Transgenic ; Disease Models, Animal ; }, abstract = {INTRODUCTION: Although motor neuron inclusions that contain hyperphosphorylated TDP- 43 protein (p-TDP-43) are considered an important clue in the pathophysiology of ALS, the main determinants of the neuronal dysfunction remain unknown.

METHODS: The spinal cords and motor cortex of 17 people (n=60 tissues) who died of ALS, with 10 controls were tested for p-TDP-43/neurofibrillary tangles (NFTs), biomarkers of neuroinflammation (GFAP, TMEM 119, miR-155, IL6, TNFα, IL1β, NF-κβ), neurodegeneration (NeuN, myelin basic protein) and BCL2 family proteins (BCL2, BCLW, BCLXL, and MCL1 each pro-survival as well as BIM, PUMA, NOXA, BAK, BAX each anti-survival) using in situ based methods including immunohistochemistry.

RESULTS: p-TDP-43 detection was strongly correlated with neuroinflammation and neurodegeneration in both humans and in a mouse model of ALS with the mutant human TDP-43 gene (B6.Cg- Tg(Prnp-TARDBP*A315T)95Balo/J). The expression of each BCL2 family protein was significantly increased compared to the controls and co-localized with p-TDP-43 in both human and mouse models.

DISCUSSION: To test whether altering BCL2 activity affects ALS pathophysiology, the FDAapproved drug venetoclax, which blocks BCL2, was started at age 3 mo IP in these mice and prevented clinical motor neuron dysfunction (n=5), whereas the untreated littermates (n=4) each died of end-stage paralysis at 5-7 mo. Blocking Bcl2 in the ALS mice reduced neurodegeneration 5-fold and neuroinflammation by 81%.

CONCLUSION: It is concluded that: 1) dysregulation of BCL2 family proteins is implicated in ALS, and 2) blocking Bcl2 alone in the mouse ALS model can markedly reduce the neurodegeneration.}, } @article {pmid40994605, year = {2025}, author = {Fu, CY and Zheng, Y and Zhai, CB and Huang, HB and Chen, X and Dong, YR and Hu, YB and Xu, W and Liu, J and Huang, Y and Sun, N and Chen, XY}, title = {Retinal vessel density alteration after FS-LASIK for myopia with different axial lengths.}, journal = {International journal of ophthalmology}, volume = {18}, number = {10}, pages = {1936-1943}, pmid = {40994605}, issn = {2222-3959}, abstract = {AIM: To compare the effects of different types of negative pressure suction on the macular and optic disc retinal vessel density (VD) in myopic patients with different axial lengths (ALs) undergoing femtosecond laser-assisted excimer laser in situ keratomileusis (FS-LASIK) by optical coherence tomography angiography (OCTA).

METHODS: A prospective, nonrandomized, controlled study. Participants underwent FS-LASIK surgery were divided into the short AL group (SAL, 22≤AL<26 mm) and the long AL group (LAL, 26≤AL<28 mm) according to the different ALs. Further, the two groups were divided into subgroups according to the corneal flap using VisuMax or WaveLight FS200 femtosecond laser (FS) platform. All patients underwent OCTA before the surgery and 1-day/1-week/1-month after the surgery. ANOVA statistically analyzed data with two-factor repeated measurement in SPSS.

RESULTS: Totally 108 participants (108 eyes, 18-35y) were divided into SAL group [22 patients (4 males and 18 females) were treated with VisuMax, and 24 (3 males and 21 females) were treated with WaveLight FS200] and LAL group [34 patients (4 males and 30 females) were treated with VisuMax, and 28 patients (6 males and 22 females) were treated with WaveLight FS200]. In the LAL group, there was no significant difference in macular superficial capillary plexuses vessel density (SCP-VD) in the fovea and perifovea region, but compared with the VisuMax subgroup, SCP-VD in the parafoveal region (t=2.647, P=0.010) and the whole area (t=2.030, P=0.047) in WaveLight FS200 subgroup decreased at one day after the operation and increased to a preoperative level at 1-week and 1-month after operation. There was no significant difference between SCP-VD in the two SAL subgroups, neither of deep capillary plexuses vessel density (DCP-VD) and optic nerve head vessel density (ONH-VD) in the SAL and LAL groups.

CONCLUSION: With the increase of AL and suction intensity, a transient decrease of SCP-VD in the macular region is observed at 1d postoperatively during FS-LASIK, and it increases to preoperative level at 1-week and 1-month postoperatively. However, the AL and suction intensity do not affect the macular DCP-VD and ONH-VD.}, } @article {pmid40995113, year = {2025}, author = {}, title = {69th Annual Meeting of the German Society of Neuropathology and Neuroanatomy (DGNN) - Meeting Abstracts: September 25-27, 2025 Frankfurt am Main, Germany.}, journal = {Free neuropathology}, volume = {6}, number = {}, pages = {17}, doi = {10.17879/freeneuropathology-2025-8974}, pmid = {40995113}, issn = {2699-4445}, abstract = {Sehr geehrte Damen und Herren, liebe Kolleginnen und Kollegen, im Namen der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie heiße ich Sie herzlich willkommen zur 69. Jahrestagung unserer Fachgesellschaft, die in diesem Jahr zudem das 75-jährige Jubiläum der DGNN feiert. Dieses besondere Jubiläum gibt uns Anlass, auf die Wurzeln und die beeindruckende Entwicklung unserer Fachgesellschaft zurückzublicken. Die Frankfurter Schule mit Persönlichkeiten wie Carl Weigert und Ludwig Edinger legte wesentliche Grundlagen für die Neurowissenschaften, deren Bedeutung bis heute kaum zu überschätzen ist. Ein entscheidender Schritt in der Geschichte unseres Faches war der Zusammenschluss der Neuropathologen in der "Arbeitsgemeinschaft morphologisch arbeitender Neurologen und Psychiater". Unterstützt durch den Pathologen Prof. Lauche und die Frankfurter Edinger-Stiftung fanden im Mai 1950 Vorgespräche statt, die schließlich am 7. Oktober 1950 zur Gründungsversammlung der "Vereinigung Deutscher Neuropathologen" führten. Diese Gründung legte den Grundstein für die heutige DGNN, die seit 75 Jahren als wissenschaftliche Plattform für Austausch und Fortschritt im Bereich der neuropathologischen Forschung dient. Besonders hervorheben möchte ich den hohen Stellenwert der Nachwuchsförderung in unserer Gesellschaft. Seit jeher ist es ein zentrales Anliegen der DGNN, junge Wissenschaftlerinnen und Wissenschaftler zu unterstützen, zu fördern und ihnen eine Plattform für ihre wissenschaftliche Entwicklung zu bieten. Nur durch die gezielte Förderung des wissenschaftlichen Nachwuchses können wir die Zukunft unseres Fachgebiets sichern und kontinuierlich neue Impulse für die Neuropathologie setzen. Der Kongress 2025 in Frankfurt am Main bietet uns erneut die Gelegenheit, in Vorträgen und Diskussionen die neuesten wissenschaftlichen Erkenntnisse zu erörtern sowie den kollegialen Austausch zu pflegen. Besonders freue ich mich auf das breite Spektrum an Themen und den angeregten Dialog, der unsere Fachgesellschaft lebendig hält. Mein Dank gilt allen Mitgliedern und Unterstützern, die die DGNN mit ihrem Engagement und ihrer Leidenschaft prägen und voranbringen. Ich wünsche uns allen einen erfolgreichen und inspirierenden Kongress sowie ein bedeutungsvolles Jubiläumsjahr. Mit herzlichen Grüßen Karl Heinz Plate Frankfurt am Main, im August 2025.}, } @article {pmid40997283, year = {2025}, author = {Grassano, M and Koumantakis, E and Palumbo, FF and Brunetti, M and De Marco, G and Merulla, I and Paolantonio, C and Iazzolino, B and Testa, M and Manera, U and Canosa, A and Vasta, R and Fuda, G and Salamone, P and Marchese, G and Casale, F and Gallone, S and Mora, G and Moglia, C and Calvo, A and Chiò, A}, title = {Genetic Variants Associated With Neurodegenerative Disorders in Patients With Amyotrophic Lateral Sclerosis and Phenotypic Variability.}, journal = {Neurology}, volume = {105}, number = {8}, pages = {e214180}, pmid = {40997283}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Female ; Male ; Aged ; Case-Control Studies ; Middle Aged ; Phenotype ; *Neurodegenerative Diseases/genetics ; *Genetic Variation/genetics ; *Genetic Predisposition to Disease/genetics ; }, abstract = {BACKGROUND AND OBJECTIVES: The genetic contribution to clinical heterogeneity in amyotrophic lateral sclerosis (ALS) remains poorly understood, particularly regarding the role of genes associated with other neurodegenerative disorders. This study aimed to determine whether rare variants in neurodegeneration-associated genes influence ALS risk and clinical phenotype.

METHODS: This case-control study included patients with ALS without pathogenic variants in major ALS genes from the population-based Piemonte and Valle d'Aosta Register for ALS and matched controls. High-impact rare variants (minor allele frequency <0.01% or novel) in 151 genes associated with neurodegenerative disorders were identified through whole-genome sequencing. Main outcomes included ALS risk, motor phenotype, cognitive status, and survival. Findings were replicated in the Project MinE dataset (6,596 ALS cases, 2,454 controls).

RESULTS: The study population consisted of 791 ALS patients (median age 67.9 years; 46.3% women) and 747 matched controls. One hundred twenty-seven ALS cases (16.1%) carried at least one rare variant in neurodegeneration-associated genes compared with 91 (12.2%) controls (odds ratio [OR] 1.37; 95% CI 1.04-1.80; p = 0.027). In particular, novel variants in Parkinson disease-associated genes (OR 3.62; 95% CI 1.33-9.80; p = 0.01) and hereditary neuropathy genes (OR 3.30; 95% CI 1.55-7.03; p = 0.002) conferred a 3-fold increased risk. These findings were independently replicated in the Project MinE dataset (OR 1.43; 95% CI 1.30-1.57; p < 0.001). Stratified analysis also confirmed the enrichment of rare variants in Parkinson disease and hereditary neuropathy-associated genes. Variant carriers were more likely to present with the flail arm phenotype (OR 2.05; 95% CI 1.05-3.98; p = 0.03) and showed increased risk of frontotemporal dementia (OR 1.85; 95% CI 1.04-3.21; p = 0.03) and shorter survival (hazard ratio 1.99; 95% CI 1.26-3.14; p = 0.003).

DISCUSSION: Rare variants in genes associated with other neurodegenerative disorders influence both ALS susceptibility and clinical features, highlighting genetic pleiotropy across neurodegenerative diseases. Our findings support a model in which ALS arises from a complex and heterogeneous genetic landscape involving multiple variants, often shared with other neurodegenerative conditions, that shape disease expression. Although these findings suggest potential future expansion of genetic screening beyond classical ALS genes, such variants should be interpreted cautiously in clinical practice pending further functional validation.}, } @article {pmid40997459, year = {2025}, author = {de Oliveira Pires, L and Wasicki, B and Abaei, A and Scekic-Zahirovic, J and Roselli, F and Fernandes, S and Bączyk, M}, title = {A computational model of tsDCS effects in SOD1 mice: from MRI-based design to validation.}, journal = {Computers in biology and medicine}, volume = {197}, number = {Pt B}, pages = {111082}, doi = {10.1016/j.compbiomed.2025.111082}, pmid = {40997459}, issn = {1879-0534}, mesh = {Animals ; Mice ; *Magnetic Resonance Imaging ; *Superoxide Dismutase-1/genetics/metabolism ; *Models, Neurological ; *Spinal Cord/diagnostic imaging/physiology ; Computer Simulation ; Mice, Inbred C57BL ; Mice, Transgenic ; Membrane Potentials/physiology ; }, abstract = {During trans-spinal direct current stimulation (tsDCS) the transmembrane potential of neurons is modified by an electric field (EF) induced due to externally applied direct current (DC). The resultant functional effects are being harnessed in the treatment of various neurological conditions; however, the fundamental mechanisms of action underlying tsDCS remain unclear. This ambiguity is largely attributed to the limited knowledge of the geometrical constraints of the EF in the polarized spinal regions. It is, then, essential to develop tools that enable researchers to plan tsDCS approaches in a controlled and systematic manner, ensuring the reproducibility of stimulation effects at spinal targets. With this paper, we aim to provide a comprehensive computational model of tsDCS intervention in mice to support further fundamental research in this area. Our model was constructed using high-resolution MRI scans of C57/B6 mice, which were segmented and reconstructed into a realistic mouse computational model. In vivo electrophysiological measurements of voltage gradients in SOD1 G93A mice were used to validate our model predictions in real-life scenarios. In both the modeling and in vivo studies, we employed a rostrocaudal arrangement of DC electrodes to replicate stimulation parameters that have proven effective for modulating murine spinal circuits. Both the computational and in vivo approaches yielded highly consistent results, with EF parameters primarily influenced by the distance between the target site and the tsDCS electrodes. We conclude that this developed model offers high accuracy in EF distribution and can significantly substantiate basic research in tsDCS.}, } @article {pmid40998074, year = {2025}, author = {Fischer, I}, title = {Considering Big tau as a novel and specific biomarker for spinal motor neuron pathology.}, journal = {Neurobiology of disease}, volume = {216}, number = {}, pages = {107118}, doi = {10.1016/j.nbd.2025.107118}, pmid = {40998074}, issn = {1095-953X}, support = {//William P. Snyder, III Chair Endowment/ ; }, mesh = {Humans ; *tau Proteins/metabolism ; Biomarkers/metabolism ; *Motor Neurons/pathology/metabolism ; Animals ; *Spinal Cord/pathology/metabolism ; *Motor Neuron Disease/metabolism/pathology/diagnosis ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; }, abstract = {Big tau is an isoform of tau that includes the large 4 A exon, resulting in an extended projection domain and an overall increase in apparent molecular weight from 40 to 65 kDa to 95-110 kDa. Its expression is highly restricted to the peripheral and autonomic nervous systems and select regions of the central nervous system. Although the precise function of Big tau remains unclear, we have proposed that the expanded projection domain of low molecular weight (LMW) tau by 250 amino acids of exon 4a and its structural properties may enhance axonal transport in long-projecting neurons and confer resistance to aggregation. Here, we propose a clinical perspective based on the properties of Big tau: the selective expression of Big tau in spinal motor neurons, but not in upper motor neurons or other spinal neuronal populations, is likely to make Big tau a specific biomarker for spinal motor neuron pathology. This expression pattern may be particularly valuable for tracking disease prognosis and progression in conditions such as amyotrophic lateral sclerosis (ALS) and related disorders, to identify when degeneration advances to lower motor neurons. Big tau could thus serve as a more specific biomarker to neurofilament or LMW tau proteins or can be used in combination with other biomarkers to enhance the specificity and sensitivity. This hypothesis can be readily tested using existing samples and assays applied to cerebrospinal fluid (CSF) and blood samples from patients. If validated through clinical studies, Big tau may provide clinicians with a new tool to better diagnose and monitor a variety of motor neuron degenerative disorders. To accelerate research in this area, I offer to share experimental data and an inventory of polyclonal antibodies specific to Big tau to the research community to enable further investigation of Big tau as a clinical biomarker.}, } @article {pmid40998540, year = {2025}, author = {Park, A and West, K and Darby, D and Brodtmann, A}, title = {Optineurin mutation-associated language variant frontotemporal dementia.}, journal = {BMJ case reports}, volume = {18}, number = {9}, pages = {}, doi = {10.1136/bcr-2025-266544}, pmid = {40998540}, issn = {1757-790X}, mesh = {Humans ; Female ; *Frontotemporal Dementia/genetics/diagnosis/diagnostic imaging ; Cell Cycle Proteins ; Middle Aged ; Membrane Transport Proteins ; *Transcription Factor TFIIIA/genetics ; Mutation ; Magnetic Resonance Imaging ; Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Positron-Emission Tomography ; }, abstract = {A right-handed woman in her early 50s presented with progressive language difficulties with visual and auditory hallucinations. Upper motor neuron signs were present without lower motor neuron signs, insufficient to make a diagnosis of amyotrophic lateral sclerosis (ALS). MRI showed bilateral superior temporal atrophy (right>left) and F-18 fluorodeoxyglucose-positron emmission tomography (FDG-PET) scan showed right temporal hypometabolism. Her clinical diagnosis was atypical or mixed language variant frontotemporal dementia (FTD) given the presence of agrammatism and phonemic intrusions. There was a family history of FTD and ALS. Genetic testing revealed a homozygous optineurin (OPTN) mutation. She experienced progressive auditory agnosias including musical agnosia and eventual mutism. A review of the literature reveals wide phenotypic variability of people with OPTN variants, emphasising the importance of genetic testing beyond that predicted by classical phenotypes.}, } @article {pmid40999448, year = {2025}, author = {Riaz, S and Steinsland, H and Boysen, A and Hanevik, K}, title = {Systemic IgG responses to glycosylated mucinase YghJ after experimental enterotoxigenic Escherichia coli infection.}, journal = {Gut pathogens}, volume = {17}, number = {1}, pages = {70}, pmid = {40999448}, issn = {1757-4749}, abstract = {BACKGROUND: The availability of a broadly protective vaccine against pathogenic Escherichia coli could help to reduce morbidity and mortality from severe gastrointestinal and systemic infections. E. coli vaccine development efforts often target protein virulence factors that natively are extensively glycosylated, but this glycosylation is absent from recombinantly produced vaccine antigens. Human IgA responses to the conserved virulence factor YghJ have recently been shown to frequently target glycosylated epitopes. Here we evaluated to what extent anti-YghJ IgG responses also target glycosylated epitopes, longevity of these responses, and to what extent the responses correlated with the IgA responses.

METHODS: Multiplex bead flow cytometric immunoassays were used to evaluate changes in anti-YghJ IgG levels and glycosylation specificity in serum and antibody in lymphocyte supernatant (ALS) collected from 21 volunteers experimentally infected with enterotoxigenic E. coli (ETEC) strain TW10722.

RESULTS: Following infection, most volunteers had substantially increased anti-YghJ IgG levels both in serum and ALS. The proportion of serum anti-YghJ IgG that specifically targeted glycosylated epitopes increased from 0.10 (Interquartile range [IQR]: 0.07, 0.21) before to 0.17 (IQR: 0.11, 0.38) 10 days after dose ingestion before returning to pre-infection levels after 28 days. The glycosylation-specific proportions correlated between IgG and IgA for both serum and ALS.

CONCLUSION: Our findings indicate that glycosylated epitopes are an important target for antibody immune responses and may play an important role in host immunity during the early phase of infection.}, } @article {pmid40999799, year = {2025}, author = {Murtada, R and Kim, C and Wang, XD and Yang, Y and Yu, Y}, title = {Chemoproteomic Profiling of Reactive Cysteines in Response to Oxidative Stress Induced by 6-Hydroxydopamine.}, journal = {Proteomics}, volume = {25}, number = {20}, pages = {47-55}, pmid = {40999799}, issn = {1615-9861}, support = {5T32CA265828-03/GF/NIH HHS/United States ; 1R01NS122533/GF/NIH HHS/United States ; R01 NS122533/NS/NINDS NIH HHS/United States ; T32 CA265828/CA/NCI NIH HHS/United States ; R01 NS137290/NS/NINDS NIH HHS/United States ; R01NS137290/GF/NIH HHS/United States ; }, mesh = {*Oxidopamine/pharmacology/toxicity ; *Oxidative Stress/drug effects ; Humans ; *Cysteine/metabolism/chemistry ; *Proteomics/methods ; *Proteome/metabolism/analysis ; Cell Line, Tumor ; Ubiquitin Thiolesterase/metabolism ; Oxidation-Reduction ; Neurons/metabolism/drug effects ; Iodoacetamide/chemistry ; }, abstract = {Although oxidative stress is a well-established driver of neurodegeneration, it remains poorly understood as to how the global cysteine (Cys) proteome is remodeled under oxidative stress conditions. Proteins with aberrantly modified cysteines in response to oxidative stress can induce and exacerbate neurodegeneration, contributing to disorders like Alzheimer's, Parkinson's, frontotemporal dementia, and amyotrophic lateral sclerosis. In this study, we induced oxidative stress in SH-SY5Y neuronal cells by subjecting them to the neurotoxin 6-hydroxydopamine (6-OHDA). To identify proteins with altered cysteine oxidation or PTM status, we used a desthiobiotin iodoacetamide (DBIA) probe, which selectively labels cysteines with unmodified and preserved thiols. Using these unbiased chemoproteomic strategies, we identified proteins with reduced Cys reactivity to DBIA in response to 6-OHDA-induced oxidative stress. Many of these proteins are critically involved in biological processes linked to cell stress responses (e.g., mitochondrial oxidative stress and apoptosis). Furthermore, we found that two key Cys on UCHL1 (a deubiquitinase critically involved in neurodegeneration) exhibited enhanced reactivity under oxidative stress conditions. Our study defines the remodeling of the Cys proteome under 6-OHDA-induced oxidative stress conditions. Furthermore, these findings suggest potential cysteine-mediated regulatory mechanisms in response to oxidative stress, providing a valuable resource for further exploration of cysteine modifications in the context of neurodegenerative signaling.}, } @article {pmid41000752, year = {2025}, author = {Koppisetti, RK and Barthélemy, NR and Horie, K and Ly, CV and Roberts, KF and Koutarapu, S and Melendez, J and Miller, TM and Sato, C and Ghoshal, N and Karch, CM and Bateman, RJ and Mukherjee, S}, title = {Distribution of big tau isoforms in the human central and peripheral nervous system.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41000752}, issn = {2692-8205}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; R01 NS110890/NS/NINDS NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; U54 NS123985/NS/NINDS NIH HHS/United States ; P41 GM103422/GM/NIGMS NIH HHS/United States ; RF1 NS110890/NS/NINDS NIH HHS/United States ; R56 NS110890/NS/NINDS NIH HHS/United States ; R01 NS095773/NS/NINDS NIH HHS/United States ; R01 NS138499/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: To characterize the distribution of "big tau," a longer tau isoform expressed in the peripheral nervous system (PNS) and select central nervous system (CNS) regions, and to examine its relationship with aging and neurodegeneration.

METHODS: We performed mass spectrometric sequencing of big tau sequence and mapped its distribution across the human nervous system. Postmortem samples included brains from Alzheimer's disease (AD), disease controls, and amyotrophic lateral sclerosis (ALS); spinal cord from young controls, disease controls and ALS; and peripheral nerves. Big and small tau levels were also quantified in the cerebrospinal fluid (CSF) from young normal controls, amyloid positive and amyloid negative participants.

RESULTS: Human 'big tau' results from the insertion of 355 amino acids in the tau protein, encoded by the exon 4a-long and not exon 4a-short. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms, expanding the known human tau repertoire. Total tau concentration is ~ 1000-fold higher in the brain than in PNS, where big tau rises sharply along a central-to-peripheral gradient, comprising ~ 50 % of total tau in peripheral nerves compared to only ~ 1 % in brain. CSF big tau levels remain unaltered with CSF Aβ abnormalities in AD, unlike the small tau isoform, which increases significantly with concomitant Aβ and cognitive abnormalities.

INTERPRETATION: Big tau exhibits a distinct distribution in the human nervous system, decoupled from the changes associated with brain-derived small tau in AD. These findings open opportunities for developing specific blood-based biomarkers to differentiate CNS versus PNS disorders.}, } @article {pmid41000837, year = {2025}, author = {Kabra, K and Dressman, D and Talcoff, R and Yidenk, M and Rifai, OM and Hoover, BN and Shneider, NA and Elyaman, W and Area-Gomez, E and Bradshaw, EM}, title = {Loss of Nuclear TDP-43 Impairs Lipid Metabolism in Microglia-Like Cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41000837}, issn = {2692-8205}, support = {R01 AG076018/AG/NIA NIH HHS/United States ; R21 AG073882/AG/NIA NIH HHS/United States ; RF1 AG058852/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive motor neuron loss, with TDP-43 pathology present in over 90% of cases. While neuroinflammation is a recognized hallmark, the role of microglia in ALS pathogenesis remains incompletely understood. Here, we demonstrate that TDP-43 regulates microglial function via triglyceride metabolism. Using shRNA-mediated TARDBP knockdown in human monocyte-derived microglia-like cells (MDMi), we observed suppressed cholesterol biosynthesis, upregulation of fatty acid metabolism genes, lipid droplet accumulation, enhanced phagocytic activity, and increased IL-1β production. Inhibiting diacylglycerol acyltransferase (DGAT) enzymes reduced lipid droplet formation, phagocytosis, and IL-1β, directly linking the triglyceride pathway to microglial activation. Patient-derived MDMi from both sporadic and TARDBP-mutant ALS cases showed overlapping as well as distinct alterations, some of which were reversed by DGAT inhibition. Our findings identify dysregulated triglyceride metabolism as a novel pathway through which TDP-43 mediates microglial dysfunction, highlighting a potential therapeutic target for ALS.}, } @article {pmid41000852, year = {2025}, author = {Salla, M and Obermayer, B and Cotta, M and Friebel, E and Campo-Garcia, J and Charalambous, G and Bueno, RJ and Lieu, D and Dabek, P and Helmuth, A and Tellides, G and Assi, R and Bankov, K and Lodrini, M and Deubzer, H and Beule, D and Chung, H and Radbruch, H and Capper, D and Heppner, F and Starossom, SC and Lareau, CA and Liu, I and Ludwig, LS}, title = {Cryo-mtscATAC-seq for single-cell mitochondrial DNA genotyping and clonal tracing in archived human tissues.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41000852}, issn = {2692-8205}, support = {K99 HG012579/HG/NHGRI NIH HHS/United States ; R00 HG012579/HG/NHGRI NIH HHS/United States ; R33 CA302491/CA/NCI NIH HHS/United States ; UM1 HG012076/HG/NHGRI NIH HHS/United States ; }, abstract = {High-throughput clonal tracing of primary human samples relies on naturally occurring barcodes, such as somatic mitochondrial DNA (mtDNA) mutations detected via single-cell ATAC-seq (mtscATAC-seq). Fresh-frozen clinical specimens preserve tissue architecture but compromise cell integrity, thereby precluding their use in multiomic approaches such as mitochondrial genotyping at single-cell resolution. Here, we introduce Cryo-mtscATAC-seq, a broadly applicable method for diverse pathophysiological contexts to isolate nuclei with their associated mitochondria ("CryoCells") from frozen samples for high-throughput clonal analysis. We applied Cryo-mtscATAC-seq to the neurodegenerated human brain, glioblastoma (GBM), pediatric neuroblastoma, and human aorta, and implemented mitobender, a computational tool to reduce ambient mtDNA in single-cell assays. Our approach revealed regional clonal gliogenesis and microglial expansions in amyotrophic lateral sclerosis (ALS), persistence of oligodendrocyte progenitor cell (OPC)-like clones in GBM recurrence, mtDNA depth heterogeneity after neuroblastoma chemotherapy, and oligoclonal proliferation of smooth muscle cells in human aorta. In conclusion, Cryo-mtscATAC-seq broadly extends mtDNA genotyping to archival frozen specimens across tissue types, opening new avenues for investigation of cell state-informed clonality in human health and disease.}, } @article {pmid41002383, year = {2025}, author = {Dash, BP and Hermann, A}, title = {Transcriptomic Alteration in FUS-ALS Points Towards Apoptosis-Rather than Ferroptosis-Related Cell Death Pathway.}, journal = {Cells}, volume = {14}, number = {18}, pages = {}, pmid = {41002383}, issn = {2073-4409}, support = {na//Schilling-Stirung/ ; na//University Rostock/ ; }, mesh = {*Ferroptosis/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Apoptosis/genetics ; *RNA-Binding Protein FUS/genetics/metabolism ; *Transcriptome/genetics ; Motor Neurons/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism ; Gene Expression Profiling ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal type of neurodegenerative disease marked by progressive and selective degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. However, the intricate molecular mechanisms underlying primary cell death pathways, including ferroptosis-related genes (FRGs) mediating MN dysfunction in ALS, remain elusive. Ferroptosis, a novel type of iron-dependent cell death with the accumulation of lipid peroxidation products, stands distinct from apoptotic-related stress and other cell death mechanisms. Although growing advances have highlighted the role of iron deposition, apoptosis and alteration of antioxidant systems in ALS pathogenesis, there is little data at the systems biology level. Therefore, we performed a comprehensive bioinformatic analysis of bulk RNA-sequencing (RNA-seq) data by systematically comparing the gene expression profiles from iPSC-derived MNs of ALS patients and healthy controls using our datasets as well as from the GEO database to reveal the role of ferroptosis-related gene alterations in ALS, especially in selective MN vulnerability of FUSED IN SARCOMA (FUS) mutations. In this study, we first identified differentially expressed genes (DEGs) between FUS mutant and healthy controls. Subsequently, the crossover genes between DEGs and FRGs were selected as differentially expressed ferroptosis-related genes (DEFRGs). Functional enrichment and protein-protein interaction (PPI) analysis of DEFRGs identified that DNA damage, stress response and extra cellular matrix (ECM) were the most significantly dysregulated functions/pathways in FUS-ALS causing mutations compared to healthy controls. While GSEA analysis showed enrichment of genes associated with apoptosis, the degree of ferroptosis and iron ion homeostasis/response to iron of FUS MNs was lower. Altogether, our findings may contribute to a better understanding of the relevant role of cell death pathways underlying selective vulnerability of MNs to neurodegeneration in FUS-ALS pathophysiology.}, } @article {pmid41002398, year = {2025}, author = {Zanini, G and Martinelli, I and Sinigaglia, G and Zucchi, E and Banchelli, F and Simonini, C and Gianferrari, G and Ghezzi, A and Mandrioli, J and Pinti, M}, title = {Circulating Serum Cell-Free Mitochondrial DNA in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {14}, number = {18}, pages = {}, pmid = {41002398}, issn = {2073-4409}, support = {CUP F93C24000310005//European Union-Next Generation EU, Mission 6, Component 2/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics ; Male ; Female ; *Cell-Free Nucleic Acids/blood ; *DNA, Mitochondrial/blood/genetics ; Middle Aged ; Case-Control Studies ; Biomarkers/blood ; Aged ; Adult ; }, abstract = {Mitochondrial dysfunction is a key pathological hallmark in amyotrophic lateral sclerosis (ALS), yet the role of circulating cell-free mitochondrial DNA (Cf-mtDNA) as a biomarker remains unclear. This study aimed to investigate serum Cf-mtDNA levels in ALS patients compared to healthy controls and explore its associations with disease biomarkers, clinical progression, and survival. We conducted a case-control study measuring Cf-mtDNA levels in serum samples from 54 ALS patients and 36 age- and sex-matched healthy controls using quantitative droplet digital PCR. Correlations between Cf-mtDNA levels and clinical features, neurofilament concentrations, inflammatory indices, and survival were assessed. The average Cf-mtDNA level in ALS patients was 2,426,315 copies/mL of serum (IQR: 865000-2475000), compared to 1,885,667 copies/mL of serum (IQR: 394250-2492500) in controls (p = 0.308). ROC analysis yielded an AUC of 0.595 (95% CI: 0.468-0.721), indicating very limited discriminant ability. Cf-mtDNA levels were inversely correlated with serum creatinine concentrations (r = -0.335, p = 0.018), but showed no significant associations with ALS phenotype, disease staging, neurofilaments, inflammatory indices, or survival. These findings suggest that, in a predominantly sporadic ALS cohort, serum Cf-mtDNA may not serve as a standalone diagnostic or prognostic biomarker, in contrast to previous reports. Methodological differences, cohort composition, and genetic heterogeneity may account for these discrepancies. Our results underscore the importance of further large-scale, longitudinal studies incorporating genetic stratification and multi-biomarker approaches to better elucidate the role of Cf-mtDNA in ALS pathophysiology.}, } @article {pmid41002422, year = {2025}, author = {Isik, FI and Galper, J and Pickford, R and Dzamko, N and Fu, Y and Kim, WS}, title = {Dysregulation of SELENOI Is Associated with TDP-43 Neuropathology in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {14}, number = {18}, pages = {}, pmid = {41002422}, issn = {2073-4409}, support = {R28 AA012725/AA/NIAAA NIH HHS/United States ; IM-202303-00957//FightMND/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; Middle Aged ; Male ; Female ; Aged ; Motor Neurons/metabolism/pathology ; Motor Cortex/metabolism/pathology ; Brain/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is characterized by progressive degeneration of motor neurons and accumulation of TAR DNA-binding protein 43 (TDP-43) in the brain. Increasing evidence indicates that aberration in lipid synthesis or regulation underlies neuronal dysfunction and degeneration. Phosphatidylethanolmine (PE) is an abundant phospholipid in the brain and is synthesized by the SELENOI gene. SELENOI is important in motor neuron development and function, as demonstrated in hereditary spastic paraplegia, a neurological disorder in which SELENOI is mutated. Despite this, virtually nothing was known about SELENOI in the context of ALS neuropathology. We therefore undertook a comprehensive assessment of PE in ALS brain tissues, using sophisticated liquid chromatography-mass spectrometry, and investigated how SELENOI regulates TDP-43 expression. PE levels were significantly decreased in the disease-affected motor cortex of ALS compared to controls and were inversely associated with disease duration. In contrast, PE levels were unaltered in the disease-unaffected cerebellum. Consistent with this, SELENOI expression was dysregulated only in the motor cortex of ALS. The correlation between SELENOI and TDP-43 was also lost in the motor cortex of ALS. A knockdown of SELENOI expression in neuronal cells caused an upregulation of TDP-43 expression. When put together, these results suggest that SELENOI dysregulation may contribute to TDP-43 pathology in ALS brain. Our study has provided new insights into an unrecognized pathway in ALS brain and revealed new targets for controlling TDP-43 pathology in ALS brain.}, } @article {pmid41002740, year = {2025}, author = {Bardhan, M and Anand, A and Javed, A and Chilo, MA and Khan, N and Garg, T and Surana, A and Huang, H and Samim, MM and Suresh, V and Khare, A and Menon, B and Kundu, T}, title = {Polymorphism of Melanocortin Receptor Genes-Association with Inflammatory Traits and Diseases.}, journal = {Diseases (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {41002740}, issn = {2079-9721}, abstract = {Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer's disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases.}, } @article {pmid41002898, year = {2025}, author = {Truong, TT and Singh, AA and Bang, NV and Vu, NMH and Na, S and Choi, J and Oh, J and Mondal, S}, title = {Mitochondria-Associated Membrane Dysfunction in Neurodegeneration and Its Effects on Lipid Metabolism, Calcium Signaling, and Cell Fate.}, journal = {Membranes}, volume = {15}, number = {9}, pages = {}, pmid = {41002898}, issn = {2077-0375}, support = {//This work was supported by a Research Grant of Pukyong National University (2023)/ ; }, abstract = {Mitochondria-associated membranes (MAMs) are essential for cellular homeostasis. MAMs are specialized contact sites located between the endoplasmic reticulum (ER) and mitochondria and control apoptotic pathways, lipid metabolism, autophagy initiation, and calcium signaling, processes critical to the survival and function of neurons. Although this area of membrane biology remains understudied, increasing evidence links MAM dysfunction to the etiology of major neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). MAMs consist of a network of protein complexes that mediate molecular exchange and ER-mitochondria tethering. MAMs regulate lipid flow in the brain, including phosphatidylserine and cholesterol; disruption of this process causes membrane instability and impaired synaptic function. Inositol 1,4,5-trisphosphate receptor-voltage-dependent anion channel 1 (IP3R-VDAC1) interactions at MAMs maintain calcium homeostasis, which is required for mitochondria to produce ATP; dysregulation promotes oxidative stress and neuronal death. An effective therapeutic approach for altering neurodegenerative processes is to restore the functional integrity of MAMs. Improving cell-to-cell interactions and modulating MAM-associated proteins may contribute to the restoration of calcium homeostasis and lipid metabolism, both of which are key for neuronal protection. MAMs significantly contribute to the progression of neurodegenerative diseases, making them promising targets for future therapeutic research. This review emphasizes the increasing importance of MAMs in the study of neurodegeneration and their potential as novel targets for membrane-based therapeutic interventions.}, } @article {pmid41003732, year = {2025}, author = {Yang, X and Jia, Z and Lian, X and Zhang, R and Li, B and Tian, D and Gao, X and Guo, S and Wang, B and Liu, H and Long, Y and Wang, L and Zhang, J and Xue, Q and Liang, Z and Han, Y and Feng, H and Huang, L and Wang, P and Shao, N and Shi, FD and Zhang, C}, title = {Ofatumumab treatment in patients with neuromyelitis optica spectrum disorder: a retrospective multicenter cohort study.}, journal = {Journal of neurology}, volume = {272}, number = {10}, pages = {655}, pmid = {41003732}, issn = {1432-1459}, support = {82301469//National Natural Science Foundation of China/ ; 82171777//National Natural Science Foundation of China/ ; 20JCJQJC00280//Natural Science Foundation of Tianjin Municipal Science and Technology Commission/ ; 24ZXGZSY00030//Tianjin Public Health Science and Technology Major Project/ ; TJSQNYXXR-D2-120//Tianjin Health Research Project/ ; TJWJ2024RC001//Tianjin Health Research Project/ ; 2024CZLJ003//Leading Talent of Changzhou "The 14th Five-Year Plan" High-Level Health Talents Training Project/ ; }, mesh = {Humans ; Female ; Male ; *Neuromyelitis Optica/drug therapy ; Retrospective Studies ; Adult ; Middle Aged ; *Antibodies, Monoclonal, Humanized ; Aquaporin 4/immunology ; Treatment Outcome ; Cohort Studies ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; Disability Evaluation ; }, abstract = {BACKGROUND: Ofatumumab is a fully human anti-CD20 monoclonal antibody that selectively and highly depletes B cells. However, limited data on ofatumumab treatment are available in patients with neuromyelitis optica spectrum disorders (NMOSD). In this study, we aimed to evaluate the efficacy and safety of subcutaneous ofatumumab in patients with NMOSD.

METHODS: We conducted a retrospective multicenter cohort study of patients with NMOSD who received ofatumumab treatment at 15 tertiary hospitals in China. The primary outcome was the annualized relapse rate (ARR). The secondary outcomes included disability measures (Expanded Disability Status Scale score, EDSS; the Aminoff-Logue Disability Scale, ALS), changes in aquaporin-4 IgG (AQP4-IgG) titers, and safety profiles during ofatumumab treatment.

RESULTS: A total of 112 patients (88% female, median age 44.0 years with interquartile range [IQR 29.5-57.5]) received ofatumumab treatment for a median of 1.7 years (IQR: 1.1-2.0). The median ARR decreased significantly from 2.0 (IQR 0.7-10.0) before ofatumumab to 0 (IQR 0.0-0.0; p < 0.001) after ofatumumab. Twenty-two patients (20%) experienced 25 relapses, with 20 (80%) occurring within the first year of initiating ofatumumab treatment and 19 (76%) classified as minor. The EDSS score from start to the last follow-up also improved significantly (median: pre-treatment 3.5, IQR 2.0-6.5, post-treatment: 2.0, IQR1.0-3.5, p < 0.001). Among 94 patients, 71 (76%) showed reduced AQP4-IgG titers at last follow-up. Injection-related reactions were reported in 13 (12%) of 112 patients. Twenty-four infections occurred in 20 patients (18%) during the ofatumumab treatment, with 92% (22/24) being grade 1 or 2 (CTCAE version 5.0). Only 2 patients (2%) experienced pneumonia requiring hospitalization and recovered after antibiotic treatment (grade 3). Hypogammaglobulinemia was recorded in 14% (13/95) of patients and was not associated with infection.

CONCLUSIONS: Subcutaneous ofatumumab treatment significantly reduces the relapse risk, limits worsening of disability, and reduces AQP4-IgG titers in NMOSD. Moreover, the safety profiles were generally acceptable. Further research is necessary to explore the sustained clinical response of ofatumumab in NMOSD.}, } @article {pmid41004063, year = {2025}, author = {Dellarole, IL and Lombardo, A and Ciullini, A and Cazzaniga, FA and Domina, R and Bacınoğlu, MB and Moda, F}, title = {Seed Amplification Assays as Powerful Tools for Detecting Peripheral Biomarkers in Prion-Like Diseases.}, journal = {Sub-cellular biochemistry}, volume = {112}, number = {}, pages = {293-320}, pmid = {41004063}, issn = {0306-0225}, mesh = {Humans ; *Biomarkers/metabolism/blood/cerebrospinal fluid ; *Prion Diseases/diagnosis/metabolism ; *Prions/metabolism ; *Nucleic Acid Amplification Techniques/methods ; Neurodegenerative Diseases/diagnosis ; }, abstract = {Seed amplification assays (SAAs) are highly sensitive and advanced techniques originally developed for the study and diagnosis of prion diseases. Thanks to their remarkably high sensitivity and specificity, SAAs are now widely employed in both research and clinical settings for prion detection, especially in peripheral tissues of patients with prion disorders. Many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, and amyotrophic lateral sclerosis, show prion-like mechanisms involving the misfolding and self-propagation of pathological proteins. As a result, SAAs are being adapted and refined for clinical use to improve the diagnosis of these conditions. This includes detecting traces of pathological proteins in cerebrospinal fluid as well as in minimally or noninvasively collected samples, such as blood, urine, skin, and olfactory mucosa. This chapter offers an overview of the role of SAAs in the clinical diagnosis of neurodegenerative diseases.}, } @article {pmid41004400, year = {2026}, author = {Hostetler, N and Zakutney, S and Pringle, CE and Zwicker, J and Breiner, A}, title = {Atypical features including acquired oculomotor apraxia in C9orf72-associated familial primary lateral sclerosis.}, journal = {Journal of neuromuscular diseases}, volume = {13}, number = {4}, pages = {808-816}, pmid = {41004400}, issn = {2214-3602}, mesh = {Humans ; Male ; Middle Aged ; *C9orf72 Protein/genetics ; *Apraxias/genetics/physiopathology/etiology ; Aged ; *Motor Neuron Disease/genetics/physiopathology ; Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Mutation ; Pedigree ; Frontotemporal Dementia/genetics/physiopathology ; Phenotype ; }, abstract = {BACKGROUND: The phenotypic variability of C9orf72-associated disease is broadening, including atypical and non-motor presentations. C9orf72-associated neurodegeneration has only rarely been associated with primary lateral sclerosis (PLS), and even more rarely with ocular motor apraxia.

OBJECTIVES: Describe a family with C9orf72 mutation presenting with frontotemporal dementia (FTD) and atypical PLS phenotypes and discuss the implications regarding 1) where PLS lies on the ALS-FTD spectrum, and 2) how C9orf72 mutations influence PLS clinically.

METHODS: Chart review.

RESULTS: A 52-year-old male experiencing 4 months of progressive right lower leg spasticity with a family history of FTD was referred to us. Within 15 months, he was anarthric and required a powered wheelchair. He developed acquired ocular motor apraxia, consistent with supranuclear ophthalmoplegia. He later developed laryngeal dystonia which led to his death. Ten years later, his 67-year-old brother presented with 8 months of progressive spastic dysarthria, hyperreflexia, right foot drop, and right facial weakness. Genetic testing revealed heterozygous C9orf72 hexanucleotide repeat expansion.

CONCLUSIONS: This family's presentation expands on sparse reports of C9orf72-associated PLS. The proband showcases a severity of ocular motor deficits not yet reported in PLS, extending ocular motor findings in MND. These deficits also provide clinical evidence of degeneration outside the motor cortex/spinal cord in PLS. The symptomatology (laryngeal dystonia, rapid progression) clinically overlaps with ALS/FTD, suggesting PLS may lie on the ALS-FTD spectrum. The severity and atypicality of this case also support suggestions that C9orf72 mutations amplify the spectrum/severity of disease observed in TDP-43 proteinopathies.}, } @article {pmid41004427, year = {2026}, author = {Fioretti, PV and Barbieri, A and Migazzi, A and Bressan, D and Grassano, M and Donini, L and Roccuzzo, M and Torrieri, MC and Conci, F and Ferracci, E and Invernizzi, S and Bowden, KM and Bacchetti, F and Cappelli, S and Peroni, D and Belli, R and Pancher, M and Mugoni, V and Scarduelli, G and Gianesello, M and Pasetto, L and Canarutto, G and Carra, S and Soldano, A and Bisio, A and Robbiati, S and Valentini, C and Nardella, C and Piazza, S and D'Agostino, VG and Quattrone, A and Sleiman, S and Whitfield, JR and Soucek, L and Vignoli, B and Viero, G and Tiberi, L and Zippo, A and Demichelis, F and Bonetto, V and Milanese, M and Buratti, E and Verde, F and Ticozzi, N and Calvo, A and Ratti, A and Shaw, PJ and Terenzio, M and Chiacchiera, F and Pennuto, M and Basso, M}, title = {MYC-driven gliosis impairs neuron-glia communication in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {5}, pages = {1604-1622}, pmid = {41004427}, issn = {1460-2156}, support = {752470//Horizon 2020/ ; GR-2016-02361552//Horizon 2020/ ; 20229HKCRT//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; //Fondazione CARITRO/ ; //European Regional Development Fund/ ; //UK Medical Research Council/ ; NIHR203321//NIHR Sheffield Biomedical Research Centre/ ; PNRR-MAD-2022-12375731//Ministero della Salute/ ; //International Center for Genetic Engineering and Biotechnology/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Animals ; Mice ; Humans ; *Neuroglia/metabolism/pathology ; *Gliosis/pathology/metabolism/genetics ; *Neurons/metabolism/pathology ; *Cell Communication/physiology ; Mice, Transgenic ; *Proto-Oncogene Proteins c-myc/metabolism/genetics ; DNA-Binding Proteins/genetics/metabolism ; Astrocytes/metabolism/pathology ; C9orf72 Protein/genetics/metabolism ; Disease Models, Animal ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Chronic activation of glial cells leads to the dysfunction and degeneration of motor and cortical neurons in amyotrophic lateral sclerosis and frontotemporal dementia with an unknown mechanism. To shed light on the molecular pathogenetic processes underlying the exordium and contribution of gliosis to disease onset and progression, we used cells, mice and patient-derived cells modelling TDP-43, SOD1 and C9ORF72-linked and sporadic ALS. Our data reveal a sequential disease progression, starting with enhanced glial reactivity and proliferation, and transitioning into inflammation with upregulation of pro-inflammatory genes. Using mouse genetics, we show that expression of mutant TDP-43 in astrocytes is necessary to cause gliosis and behavioural abnormalities. Mechanistically, we show that glial MYC gain-of-function drives neurodegeneration by promoting the release of astrocyte-derived extracellular vesicles that nonetheless fail to provide trophic support to surrounding neurons. Our research reveals a novel functional role for MYC in glia-to-neuron miscommunication in ALS.}, } @article {pmid41004918, year = {2025}, author = {Yanagawa, K and Ike, M and Aoyama, A and Yokoo, T and Terai, S and Hayashi, T and Onodera, O}, title = {Tongue shear wave elastography for bulbar dysfunction in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {179}, number = {}, pages = {2111367}, doi = {10.1016/j.clinph.2025.2111367}, pmid = {41004918}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/complications ; *Elasticity Imaging Techniques/methods ; Male ; Middle Aged ; *Tongue/diagnostic imaging/physiopathology ; Female ; Aged ; Prospective Studies ; Adult ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) often manifests with tongue involvement, leading to dysarthria and dysphagia. While current diagnostic methods are invasive or qualitative, the development of non-invasive quantitative assessments of tongue function is essential.

METHODS: A prospective study (March 2022 - March 2024) included 38 ALS patients (categorized by bulbar or spinal onset) and 12 controls. Clinical symptoms were evaluated using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). Tongue muscle elasticity was measured using shear wave elastography (LOGIQ® E9, 9 MHz).

RESULTS: Median shear modulus of the genioglossus (GG) muscle was significantly lower in bulbar-onset ALS (7.80 kPa, range 5.41-10.08) compared to spinal-onset ALS (12.48 kPa, range 8.50-21.42) and controls (14.16 kPa, range 11.37-20.21). The geniohyoid (GH) muscle showed similar patterns. Both muscles showed significantly reduced elasticity in bulbar-onset ALS compared to controls (p < 0.05). The GG muscle elasticity showed strong positive correlation with bulbar symptom severity on the ALSFRS-R.

CONCLUSIONS: Reduced tongue muscle elasticity in bulbar-onset ALS, along with its correlation with bulbar symptoms, suggests the potential utility of this technique for both diagnosis and prognosis.

SIGNATURE: These findings indicate that shear wave elastography is a promising noninvasive tool for the quantitative assessment of tongue dysfunction in ALS.}, } @article {pmid41005474, year = {2025}, author = {Li, Y and Liu, D and Li, S}, title = {IRE1/Xbp1 promotes the clearance of poly(GR) dipeptide repeats in amyotrophic lateral sclerosis.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {11}, pages = {110764}, pmid = {41005474}, issn = {1083-351X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Protein Serine-Threonine Kinases/metabolism/genetics ; Humans ; *X-Box Binding Protein 1/metabolism/genetics ; C9orf72 Protein/genetics/metabolism ; *Dipeptides/metabolism/genetics ; *Endoribonucleases/metabolism/genetics ; Mice ; Disease Models, Animal ; Signal Transduction ; Drosophila melanogaster ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders characterized by the expansion of GGGGCC (G4C2) repeats in the C9orf72 gene and progressive motor neuron degeneration. A key pathological hallmark of these diseases is the accumulation and cytoplasmic mislocalization of dipeptide repeat (DPR) proteins, particularly poly(GR), which are neurotoxic. Enhancing the clearance of poly(GR) represents a promising therapeutic strategy; however, the molecular mechanisms regulating poly(GR) turnover are not fully understood. Our previous work demonstrated that translationally stalled poly(GR) is targeted by the ribosome-associated quality control (RQC) pathway. In the present study, we identify the IRE1/Xbp1s signaling axis as an essential regulator of poly(GR) degradation. Ectopic expression of IRE1 or its downstream effector Xbp1s, as well as pharmacological activation of IRE1 using IXA4, significantly reduces poly(GR) protein levels in a Drosophila disease model, mammalian cell lines, fibroblasts derived from patients with C9orf72-ALS, and a C9orf72 transgenic mouse model. Mechanistically, RNA-sequencing analysis reveals that IRE1/Xbp1s signaling upregulates heat shock protein Hsp70Ba, which plays a critical role in maintaining poly(GR) proteostasis. Additionally, we show that the Rictor/AKT/VCP pathway contributes to the translational regulation and turnover of poly(GR). Importantly, activation of IRE1, either through ectopic expression or IXA4 treatment, mitigates motor neuron loss in the C9orf72 mouse model. Collectively, our findings highlight the IRE1/Xbp1s axis as a key modulator of poly(GR) clearance and suggest its therapeutic potential in ALS/FTD.}, } @article {pmid41005573, year = {2025}, author = {Marlow, TR and Bowden, KM and Collins, MO and Shaw, PJ}, title = {The potential role of misfolded wild-type SOD1 protein in sporadic amyotrophic lateral sclerosis (ALS): a review of the evidence.}, journal = {Neurobiology of disease}, volume = {216}, number = {}, pages = {107124}, doi = {10.1016/j.nbd.2025.107124}, pmid = {41005573}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Superoxide Dismutase-1/metabolism/genetics ; Protein Folding ; Animals ; Motor Neurons/metabolism/pathology ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterised by the selective loss of motor neurons in the motor cortex, brainstem and spinal cord. In 1993, the first ALS-linked gene mutations were identified in the Cu,Zn superoxide dismutase (SOD1) gene, which account for approximately 20 % of familial ALS cases. The mechanism of toxicity in this subset of patients is thought to arise from a gain-of-toxic function from the protein's propensity to misfold and aggregate into cytoplasmic inclusions. Immunohistochemical studies have shown that misfolded wildtype SOD1 (wtSOD1) is also detected in the motor neurons and glial cells of ALS patients without SOD1 mutations. It is proposed that disrupted, or aberrant, post-translational modifications cause wtSOD1 to adopt a toxic conformation similar to that of the mutant protein. Subsequent mechanistic studies have shown that this misfolded wtSOD1 can disrupt cellular function and lead to motor neuron death through pathways similar to those observed in mutant SOD1-ALS. Given the limited neuroprotective treatments currently available that can effectively slow or reverse disease progression, targeting a pathogenic mechanism that features in both familial and sporadic ALS cases represents a promising therapeutic approach for a broader patient population. This review examines the growing body of evidence that supports or challenges the role of misfolded wtSOD1 in the pathophysiology of sporadic ALS and explores the potential implications of this mechanism in disease progression. Understanding how misfolded wtSOD1 contributes to disease pathogenesis provides new opportunities for developing more widely available treatments for this devastating disease.}, } @article {pmid41005783, year = {2025}, author = {Ofosu, NN and Luth, W and Genuis, SK and Tymkow, K and Budiyanto, I and McGuckin, T and Campbell-Scherer, D and Johnston, WS}, title = {Challenges and opportunities for expediting ALS diagnosis in Alberta, Canada: a human-centred design approach.}, journal = {BMJ open}, volume = {15}, number = {9}, pages = {e104139}, pmid = {41005783}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Alberta ; Female ; Male ; Middle Aged ; Qualitative Research ; Referral and Consultation ; Aged ; *Delayed Diagnosis ; Interviews as Topic ; Adult ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal motor neuron disease. Diagnostic delay severely impairs patient access to ALS multidisciplinary clinics, available disease-modifying medications and therapies that may prolong survival.

OBJECTIVES: To investigate how patient and physician perspectives might be leveraged to promote timely ALS diagnosis, and how system-level barriers might be addressed to promote appropriate referral to ALS multidisciplinary care.

DESIGN AND SETTING: A qualitative study in Alberta, Canada, used human-centred design and interviews to map the diagnostic journeys of ALS patients and identify individual-level and system-level diagnostic barriers and opportunities.

PARTICIPANTS AND ANALYSIS: 30 semistructured interviews (10 patients; 20 physicians) were conducted. Data were inductively analysed with the aid of Miro board software. Patient and physician data were triangulated to identify key phases of the journey from symptom onset to confirmed ALS diagnosis and themes related to the diagnostic barriers and opportunities. Journey maps were created to visualise the diagnostic journey.

RESULTS: Patient journeys were comprised of five phases and commonly involved iterative cycles of referral and testing before an ALS diagnosis was confirmed. Four primary themes related to diagnostic barriers: difficulty recognising and responding effectively to early-stage ALS symptoms, absence of a single definitive diagnostic test, long wait times between referrals and clinical visits, and physician reluctance to pronounce an ALS diagnosis. Analysis indicated three approaches for improving diagnostic processes: increase ALS awareness; improve communication between referring physicians and physicians receiving referrals (consultants); and develop physician, diagnostic testing and multidisciplinary clinic referral forms that will guide symptom assessment and accurate referral.

CONCLUSIONS: Timely ALS diagnosis is challenging for patients navigating the frequently prolonged, circuitous diagnostic journey and physicians who struggle with referral pathways and the efficient diagnosis of this rare disease. Findings demonstrate the importance of increased ALS awareness and effective communication and response within referral pathways. Recommendations include strengthening the clinical approach of community-based physicians and supporting access and referral pathways. Current initiatives arising from this investigation seek to achieve meaningful change in timely referrals for progressive neurological diseases like ALS.}, } @article {pmid41005925, year = {2026}, author = {Marín-García, M and Gonzalez-Olmos, R and Gómez-Canela, C}, title = {Direct UV photolysis of cloperastine in aqueous solution: Kinetic model and degradation pathway.}, journal = {Journal of environmental sciences (China)}, volume = {159}, number = {}, pages = {670-682}, doi = {10.1016/j.jes.2025.03.025}, pmid = {41005925}, issn = {1001-0742}, mesh = {*Photolysis ; *Water Pollutants, Chemical/chemistry/radiation effects ; *Ultraviolet Rays ; Kinetics ; *Piperidines/chemistry/radiation effects ; Models, Chemical ; }, abstract = {The increasing production and release of synthetic organic chemicals, including pharmaceuticals, into our environment has allowed these substances to accumulate in our surface water systems. Current purification technologies have been unable to eliminate these pollutants, resulting in their ongoing release into aquatic ecosystems. This study focuses on cloperastine (CPS), a cough suppressant and antihistamine medication. The environmental impact of CPS usage has become a concern, mainly due to its increased detection during the COVID-19 pandemic. CPS has been found in wastewater treatment facilities, effluents from senior living residences, river waters, and sewage sludge. However, the photosensitivity of CPS and its photodegradation profile remain largely unknown. This study investigates the photodegradation process of CPS under simulated tertiary treatment conditions using UV photolysis, a method commonly applied in some wastewater treatment plants. Several transformation products were identified, evaluating their kinetic profiles using chemometric approaches (i.e., curve fitting and the hard-soft multivariate curve resolution-alternating least squares (HS-MCR-ALS) algorithm) and calculating the reaction quantum yield. As a result, three different transformation products have been detected and correctly identified. In addition, a comprehensive description of the kinetic pathway involved in the photodegradation process of the CPS drug has been provided, including observed kinetic rate constants.}, } @article {pmid41007432, year = {2025}, author = {Ramos-Velasco, B and Alcalde, J and Izquierdo, JM}, title = {Welander Distal Myopathy-Associated TIA1 E384K Mutation Disrupts Stress Granule Dynamics Under Distinct Stress Conditions.}, journal = {Biology}, volume = {14}, number = {9}, pages = {}, pmid = {41007432}, issn = {2079-7737}, support = {RTI2018-098517B-I00 and PID2021-126152OB-I00//Ministerio de Ciencia, Innovación y Universidades and Agencia Española de Investigación through FEDER funds (RTI2018-098517B-I00 and PID2021-126152OB-I00)/ ; }, abstract = {Cellular stress triggers the formation of diverse RNA-protein aggregates, which can be associated with physiological responses, pathological conditions, or even detrimental outcomes. Under stress-induced proteostasis disruption, these RNA-protein assemblies are known as stress granules (SGs). Targeting such condensates-while sparing functional RNAs and proteins-remains a major therapeutic challenge in protein aggregation disorders such as myopathies and neuropathies. In this study, we investigated the cellular response to various stress conditions in the context of the TIA1 E384K mutation, a founder variant implicated in both Welander distal myopathy (WDM) and amyotrophic lateral sclerosis (ALS). Cells were exposed to different stressors, including proteotoxic, proteostatic, chemotoxic, and osmotic insults, and the behavior of TIA1-related SGs was analyzed. Our findings reveal a distinct yet conserved pattern in the dynamics of TIA1-dependent SG formation and clearance, influenced by the specific type of stressor and modulated by eIF2α Ser35 phosphorylation. These results indicate that the WDM-associated TIA1 mutation leads to aberrant SG dynamics across different stress conditions. Collectively, these observations support the idea that TIA1 E384K-associated SG dysregulation plays a role in WDM and ALS pathogenesis and underscores the importance of multiple stress contexts in disease progression.}, } @article {pmid41007730, year = {2025}, author = {Schreiner, TG and Menéndez-González, M and Schreiner, OD and Ciobanu, RC}, title = {Intrathecal Therapies for Neurodegenerative Diseases: A Review of Current Approaches and the Urgent Need for Advanced Delivery Systems.}, journal = {Biomedicines}, volume = {13}, number = {9}, pages = {}, pmid = {41007730}, issn = {2227-9059}, abstract = {Neurodegenerative diseases (NDDs) pose an immense global health burden, and developing effective treatments is hindered by the blood-brain barrier (BBB). Intrathecal (IT) administration of therapeutics directly into the cerebrospinal fluid (CSF) bypasses the BBB, offering a promising avenue for antisense oligonucleotides (ASOs), gene therapies, antibodies, and stem cells for these disorders. This review synthesizes the current landscape of IT therapies for Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis based on the current literature and ClinicalTrials.gov. We highlight key trials and approaches, including the success of ASOs in spinal muscular atrophy and recent progress in other NDDs. However, the efficacy of these novel treatments is often constrained by the limitations of first-generation IT delivery systems, which struggle with uneven distribution, systemic leakage, and the demands of modern biologics. Drawing from recent analyses, we underscore the critical shortcomings of current devices and point out the innovations needed in shaping next-generation systems: subcutaneous access ports, CSF flow platforms, AI-driven adaptive dosing, nanoporous membranes, intrathecal pseudodelivery, and hydrogel scaffolds. We conclude by emphasizing the urgent need for these advanced IT drug delivery systems, alongside rigorous comparative assessments, cost-benefit analyses, and clear regulatory pathways to fully realize the potential of emerging CNS therapies and transform NDD management.}, } @article {pmid41008332, year = {2025}, author = {Bernetti, C and Cea, L and Buoso, A and Greco, F and Rossi, M and Pilato, F and Calandrelli, R and Di Gennaro, G and Di Lazzaro, V and Zobel, BB and Mallio, CA}, title = {A Comprehensive Overview of Subacute Combined Degeneration: MRI Diagnostic Challenges and Treatment Pathways.}, journal = {Brain sciences}, volume = {15}, number = {9}, pages = {}, pmid = {41008332}, issn = {2076-3425}, abstract = {Subacute combined degeneration (SCD) is a neurological disorder primarily caused by vitamin B12 deficiency. This condition leads to progressive demyelination and axonal damage, predominantly affecting the dorsal and lateral columns of the spinal cord. This review provides a comprehensive overview of SCD, detailing its complex etiology, pathophysiology, and clinical presentation. We highlight the critical role of magnetic resonance imaging (MRI) in the diagnostic process, discussing both the characteristic spinal cord findings and the more subtle intracranial abnormalities. Furthermore, we address the diagnostic challenges presented by conditions that mimic SCD in MRI, such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). We conclude by outlining current treatment pathways and identifying key areas for future research, including the use of advanced neuroimaging techniques and the potential for new therapeutic approaches. This updated synthesis aims to provide a clear framework for clinicians and researchers to better understand and manage SCD.}, } @article {pmid41008437, year = {2025}, author = {Packer, R and Rumbach, A and Farrell, A and Hutchinson, N and Verner-Wren, S and Henderson, R and McCombe, P}, title = {Living with Dysphagia and Dysarthria: A Qualitative Exploration of the Perspectives of People with Motor Neuron Disease and Their Caregivers.}, journal = {Healthcare (Basel, Switzerland)}, volume = {13}, number = {18}, pages = {}, pmid = {41008437}, issn = {2227-9032}, support = {Unknown//Health Practitioner Research Scheme Funding, Allied Health Professional Office of Queensland/ ; }, abstract = {Background/Objectives: Dysphagia and dysarthria are common and distressing symptoms of motor neuron disease (MND) progression. The medical complications of dysphagia and the influence of dysarthria on communication effectiveness have been documented. The aim of the current study was to describe the lived experience of dysphagia and dysarthria from the perspectives of both people with motor neuron disease (pwMND) and their caregivers. Methods: A qualitative descriptive study influenced by phenomenological principles was utilized in interviews with six pwMND and six caregivers. Results: Three themes were developed that captured participants' experiences of dysphagia and dysarthria: (1) "This is the way things are"; (2) Your whole life changes, but some things stay the same; (3) Juxtaposition to information and support. Conclusions: The findings advance our understanding of the lived experience of dysphagia and dysarthria in MND. Health professionals need to consider broader assessment practices across both mealtimes and communicative interactions and each individual's unique information and support needs when providing healthcare information.}, } @article {pmid41008523, year = {2025}, author = {Lin, H and Zhang, J and Hu, J and Ma, L and Lai, K and Zheng, C and Yang, Q and Zhang, L}, title = {Improvement of Soluble Expression, Stability, and Activity of Acetaldehyde Lyase by Elastin-like Polypeptides Fusion for Acetoin Production from Acetaldehyde.}, journal = {Biomolecules}, volume = {15}, number = {9}, pages = {}, pmid = {41008523}, issn = {2218-273X}, mesh = {*Acetaldehyde/metabolism ; *Elastin/chemistry/metabolism/genetics ; Escherichia coli/genetics/metabolism ; *Recombinant Fusion Proteins/genetics/metabolism/chemistry ; *Acetoin/metabolism ; Enzyme Stability ; *Peptides/chemistry/metabolism/genetics ; Kinetics ; Solubility ; Elastin-Like Polypeptides ; }, abstract = {To achieve the large-scale, low-cost preparation of acetaldehyde lyase (ALS), elastin-like polypeptides (ELPs) as non-chromatographic purification tags were employed to develop an ELP-ALS fusion protein in Escherichia coli. Induction expression results demonstrated that the ELPs tag efficiently improved the soluble expression of the ALS enzyme. Through two rounds of inverse transition cycling (ITC), highly pure ELP-ALS was obtained with an enzyme recovery rate of 85.77%, outperforming Ni[2+]-affinity chromatography (66.80%). The comparative analysis of enzymatic properties revealed that ELP fusion markedly improved the stability and substrate tolerance of the ALS enzyme. Kinetic parameter analysis under identical conditions showed that ELP-ALS possessed a Vmax of 15.25 U/mg and a kcat/Km of 73.05 s[-1]·M[-1], representing 1.86-fold and 2.97-fold improvements over His-ALS, respectively. Fed-batch reaction using ELP-ALS and acetaldehyde as biocatalyst and substrate, respectively, yielded 95.92 g/L acetoin with 49.32% increase compared to His-ALS (64.24 g/L). These results demonstrated the application potential of ELP-ALS as a promising biocatalyst for acetoin production from acetaldehyde due to its lower preparation cost, higher biocatalytic efficiency, better stability, and substrate tolerance.}, } @article {pmid41008528, year = {2025}, author = {Tian, Z and Jin, F and Geng, Z and Xu, Z and Shao, Q and Liu, G and Ji, X and Liu, J}, title = {Unraveling the Mystery of Hemoglobin in Hypoxia-Accelerated Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {15}, number = {9}, pages = {}, pmid = {41008528}, issn = {2218-273X}, support = {20230484436//the Beijing Nova Program/ ; CX23YQ01//the Chinese Institutes for Medical Research, Beijing/ ; 22JCZXJ00190//Beijing-Tianjin-Heibei Basic Research Cooperation Project/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Hemoglobins/metabolism ; *Hypoxia/metabolism/complications ; Animals ; Mitochondria/metabolism ; }, abstract = {Hypoxic stress is increasingly recognized as a convergent pathological factor in various age-related neurodegenerative diseases (NDDs), encompassing both acute events such as stroke and traumatic brain injury (TBI), and chronic disorders including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Recent studies have revealed that hemoglobin (Hb), beyond its classical oxygen-transport function, exhibits unexpected expression and functional relevance within the central nervous system. Notably, both cerebral and circulating Hb appear to be dysregulated under hypoxic and aging conditions, potentially influencing disease onset and progression of these diseases. However, Hb's impact on neurodegeneration appears to be context-dependent: in acute NDDs, it may exert neuroprotective effects by stabilizing mitochondrial and iron homeostasis, whereas in chronic NDDs, aberrant Hb accumulation may contribute to toxic protein aggregation and neuronal dysfunction. This review provides an integrative overview of the emerging roles of Hb in hypoxia-related NDDs, highlighting both shared and distinct mechanisms across acute and chronic conditions. We further discuss potential therapeutic implications of targeting Hb-related pathways in NDDs and identify key gaps for future investigation.}, } @article {pmid41008559, year = {2025}, author = {Steffan, D and Pezzini, C and Esposito, M and Franco-Romero, A}, title = {Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.}, journal = {Biomolecules}, volume = {15}, number = {9}, pages = {}, pmid = {41008559}, issn = {2218-273X}, mesh = {Humans ; *Mitochondria/metabolism/pathology/genetics ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; *Aging/metabolism/pathology ; *Central Nervous System/metabolism/pathology ; Animals ; DNA, Mitochondrial/genetics/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Mitophagy ; Mitochondrial Dynamics ; }, abstract = {Mitochondrial aging plays a central role in the functional decline of the central nervous system (CNS), with profound consequences for neurological health. As the brain is one of the most energy-demanding organs, neurons are particularly susceptible to mitochondrial dysfunction that arises with aging. Key features of mitochondrial aging include impaired mitochondrial dynamics, reduced mitophagy, increased production of reactive oxygen species (ROS), and accumulation of mitochondrial DNA (mtDNA) mutations. These alterations dramatically compromise neuronal bioenergetics, disrupt synaptic integrity, and promote oxidative stress and neuroinflammation, paving the path for the development of neurodegenerative diseases. This review also examines the complex mechanisms driving mitochondrial aging in the central nervous system (CNS), including the disruption of mitochondrial-organelle communication, and explores how mitochondrial dysfunction contributes to neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. By synthesizing current evidence and identifying key knowledge gaps, we emphasize the urgent need for targeted strategies to restore mitochondrial function, maintain cognitive health, and delay or prevent age-related neurodegeneration.}, } @article {pmid41009457, year = {2025}, author = {Scognamiglio, A and Corvino, A and Caliendo, G and Fiorino, F and Perissutti, E and Santagada, V and Severino, B}, title = {Druggability of Sodium Calcium Exchanger (NCX): Challenges and Recent Development.}, journal = {International journal of molecular sciences}, volume = {26}, number = {18}, pages = {}, pmid = {41009457}, issn = {1422-0067}, mesh = {*Sodium-Calcium Exchanger/metabolism/antagonists & inhibitors/chemistry ; Humans ; Animals ; Protein Isoforms/metabolism ; Calcium/metabolism ; }, abstract = {Na[+]/Ca[2+] exchangers (NCXs) are membrane transporters crucial for calcium homeostasis in excitable tissues, particularly in the central nervous system. Growing evidence indicates that NCX dysfunction contributes to calcium overload and neuronal damage in several neurological conditions. Thus, pharmacological modulation of NCX isoforms (NCX1, NCX2, and NCX3) has emerged as a potential therapeutic strategy for disorders such as stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD). However, the identification of selective modulators directed at specific NCX isoforms, or even different splice variants, remains challenging and limits their clinical validation. This Review aims to provide an updated overview of small-molecule NCX modulators, described over the last two decades. Chemical structures, mechanisms of action, and isoform specificity are discussed, along with the most commonly used biological assays for their functional evaluation.}, } @article {pmid41009467, year = {2025}, author = {Bowser, R and An, J and Schwartz, K and Sucholeiki, RL and Sucholeiki, I}, title = {ALS Patients Exhibit Altered Levels of Total and Active MMP-9 and Several Other Biomarkers in Serum and CSF Compared to Healthy Controls and Other Neurologic Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {18}, pages = {}, pmid = {41009467}, issn = {1422-0067}, support = {W81XWH-21-ALSRP-DTA//Department of Defense (DOD) Amyotrophic Lateral Sclerosis Research Program (ALSRP) Therapeutic Development Award (TDA)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid ; *Matrix Metalloproteinase 9/blood/cerebrospinal fluid ; *Biomarkers/blood/cerebrospinal fluid ; Male ; Female ; Middle Aged ; Aged ; Matrix Metalloproteinase 2/blood/cerebrospinal fluid ; Alzheimer Disease/blood/cerebrospinal fluid ; Case-Control Studies ; Cystatin C/blood/cerebrospinal fluid ; *Nervous System Diseases/blood/cerebrospinal fluid ; Adult ; Parkinson Disease/blood/cerebrospinal fluid ; Neurofilament Proteins/blood/cerebrospinal fluid ; Creatinine/blood/cerebrospinal fluid ; }, abstract = {Matrix metalloproteinases 2 and 9 (MMP-2, MMP-9) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, their protein levels and correlation with other biomarkers are not well understood. We measured total and active MMP-2/-9 and additional biomarkers (creatinine, neurofilament light, cystatin C, and alkaline phosphatase) in the serum of people with ALS (ALS, n = 30) and compared their levels with age-matched healthy controls (HC, n = 20) and other neurological diseases (diabetic nephropathy, Alzheimer's disease, Parkinson's disease; n = 8 each). We also measured MMP-2/-9 in a set of CSF samples from ALS (n = 30) and age-matched other neurological diseases (OND, n = 14). Lastly, we measured the competitive binding behavior of a dual MMP-2/MMP-9 inhibitor, AQU-118, against active MMP-9 in situ within the serum of ALS. We found significantly elevated levels of both total MMP-9 protein (two studies, 7.5 and 9.5-fold; both p < 0.0001) and active MMP-9 (2.5-fold; p < 0.0001) in ALS serum compared to HC. Serum NfL was significantly elevated (6-fold, p < 0.0001) and serum creatinine was significantly decreased (40%, p < 0.0001) in ALS compared to HC. There were significantly decreased levels of MMP-2 (two studies, 26 and 33%; p < 0.001 and p = 0.0001, respectively) in the serum of ALS as compared to HC. ALS also had significantly higher active MMP-9 in serum than patients with Alzheimer's disease and higher than Parkinson's disease or diabetic nephropathy. We confirmed that active MMP-9 in ALS is fully available for proteolytic activity in both serum and CSF and can be inhibited using an MMP-2/-9 inhibitor. Active MMP-9 is systemically elevated in ALS and therefore a therapeutic target for ALS drug development.}, } @article {pmid41009734, year = {2025}, author = {Genchi, G and Catalano, A and Carocci, A and Sinicropi, MS and Lauria, G}, title = {Copper, Cuproptosis, and Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {18}, pages = {}, pmid = {41009734}, issn = {1422-0067}, mesh = {*Copper/metabolism/toxicity ; Humans ; *Neurodegenerative Diseases/metabolism/etiology/pathology ; Animals ; Homeostasis ; }, abstract = {Copper is a vital micronutrient for animals and plants acting as a crucial cofactor in the synthesis of numerous metabolic enzymes and contributing to mitochondrial respiration, metabolism, oxido-reductive reactions, signal transmission, and oxidative and nitrosative damage. In the cells, copper may exist in the Cu[+] and Cu[++] oxidation states and the interconversion between these two states may occur via various redox reactions regulating cellular respiration, energy metabolism, and cell growth. The human body maintains a low level of copper, and copper deficiency or copper excess may adversely affect cellular functions; therefore, regulation of copper levels within a narrow range is important for maintaining metabolic homeostasis. Recent studies identified a new copper-dependent form of cell death called cuproptosis. Cuproptosis occurs due to copper binding to lipoylated enzymes (for instance, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase) in the tricarboxylic acid Krebs cycle. In recent years, extensive studies on copper homeostasis and copper-induced cell death in degenerative disorders, like Menkes, Wilson, Alzheimer, Parkinson's, Huntington's diseases, and Amyotrophic Lateral Sclerosis, have discussed the therapeutic potential of targeting cuproptosis. Copper contamination in the environment, which has increased in recent years due to the expansion of agricultural and industrial activities, is associated with a wide range of human health risks. Soil used for the cultivation of grapes has a long history of copper-based fungicide application (the Bordeaux mixture is rich in copper) resulting in copper accumulation at levels capable of causing toxicity in plants that co-inhabit the vineyards. Phytoremediation, which uses plants and biological solutions to remove toxic heavy metals and pesticides and other contaminants from soil and water, is an environmentally friendly and cost-effective technology used for the removal of copper. It requires plants to be tolerant of high levels of copper and capable of accumulating metal copper in plants' aerial organs and roots. This review aims at highlighting the importance of copper as an essential metal, as well as its involvement in cuproptosis and neurodegenerative diseases.}, } @article {pmid41009796, year = {2025}, author = {Awai, A and Johnson, EL and Leng, T and Patrickson, J and Zody, MC and Lillard, JW and On Behalf Of The Nygc Als Consortium, }, title = {Stratifying ALS Patients by Mode of Inheritance Reveals Transcriptomic Signatures Specific to sALS and fALS.}, journal = {International journal of molecular sciences}, volume = {26}, number = {18}, pages = {}, pmid = {41009796}, issn = {1422-0067}, support = {R25 GM058268/GM/NIGMS NIH HHS/United States ; R25GM058268.//NIH G-RISE/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Transcriptome/genetics ; Gene Expression Profiling ; Spinal Cord/metabolism/pathology ; Female ; Middle Aged ; Male ; Motor Cortex/metabolism ; Aged ; Gene Regulatory Networks ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease, marked by considerable clinical and molecular heterogeneity. While several genetic drivers have been linked to familial ALS (fALS), the biology of sporadic ALS (sALS)-which accounts for the majority of ALS cases-remains poorly defined. To address this gap, we analyzed 247 bulk mRNA-sequenced post-mortem tissue samples from the lumbar spinal cord and motor cortex and compared expression profiles between fALS, sALS, and controls. Variance-stabilized DEGs from DESeq2 analysis were used as inputs for weighted gene co-expression network analysis (WGCNA). Finally, gene ontology was used to identify transcriptomic signatures and biological pathways unique to sALS and fALS. In the spinal cord, sALS samples exhibited specific downregulation of mitochondrial complex I subunits (e.g., NDUFS8 and NDUFB7) and regulatory genes (e.g., AURKAIP1 and ATP5F1D), suggesting compromised metabolic resilience. In the motor cortex, a co-expression module associated with adaptive immune function and leukocyte infiltration was downregulated in sALS yet upregulated in fALS, indicating distinct inflammatory pathways between these two forms of ALS. Together, our findings highlight that while sALS and fALS are largely the same disease, they exhibit distinct transcriptomic signatures. By accounting for mode of inheritance in study designs-particularly sALS, which represents ~90% of ALS cases-researchers may reveal deeper insights into ALS pathology. This perspective could enable more targeted therapeutic strategies, ultimately improving outcomes for all ALS patients.}, } @article {pmid41011076, year = {2025}, author = {Della Toffola, J and Ricci, E and Quagliotto, M and Manganotti, P and Benussi, A}, title = {Non-Invasive Brain Stimulation for Amyotrophic Lateral Sclerosis: Current Evidence and Future Perspectives.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {61}, number = {9}, pages = {}, pmid = {41011076}, issn = {1648-9144}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology ; *Transcranial Magnetic Stimulation/methods/trends/standards ; *Transcranial Direct Current Stimulation/methods/trends/standards ; Brain/physiopathology ; }, abstract = {Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting the upper and lower motor neurons, with a bleak prognosis and few treatment options. Non-invasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), represent emerging approaches aimed at modulating cortical hyperexcitability, a relevant pathogenetic mechanism in ALS. Materials and Methods: A systematic review of the literature was conducted following the PRISMA guidelines, exploring the Scopus and PubMed databases from April to June 2025 with terms related to ALS and NIBS. A total of 18 relevant studies were selected from the initial 708 articles, analysing stimulation protocols, clinical and neurophysiological outcomes, and associated biomarkers; their validity was assessed using the revised Cochrane risk-of-bias (RoB2) tool. Results: The selected studies were extremely heterogeneous, with NIBS techniques, including magnetic (rTMS, cTBS, tSMS) and electrical (tDCS) stimulation, showing variable effects. Low-frequency protocols (1 Hz rTMS) and cTBS showed a slight slowing of clinical progression, while prolonged home stimulation with tDCS and tSMS showed more significant improvements in terms of efficacy, tolerability, and adherence. The main limitations concern the heterogeneity of patients and protocols and the lack of standardised biomarkers, which is why the analysis remained at a descriptive level. The use of telemonitoring and caregiver training are essential to ensure safety and accessibility. Conclusions: NIBS represents a promising therapeutic approach for ALS, but further multicentre, standardised studies with prolonged follow-up are needed. Future strategies should include customisation of stimulation, combination with other therapies, and extension of application to pre-symptomatic phases.}, } @article {pmid41011086, year = {2025}, author = {Moțățăianu, A and Andone, S and Maier, S and Chinezu, R and Roman, M and Dumitreasă, M and Bălașa, R and Ormenișan, I}, title = {Beyond Motor Decline in ALS: Patient-Centered Insights into Non-Motor Manifestations.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {61}, number = {9}, pages = {}, pmid = {41011086}, issn = {1648-9144}, support = {project number PN-III-P1-1.1-TE-2021-0960//Ministry of Research, Innovation, and Digitization, CNCS-UEFISCDI/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/psychology ; Male ; Female ; Middle Aged ; Aged ; Quality of Life/psychology ; Disease Progression ; Surveys and Questionnaires ; Sleep Wake Disorders/etiology ; Adult ; }, abstract = {Background and Objectives: Traditionally regarded as a purely motor disorder, amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. However, it is increasingly recognized as a condition with a broader clinical spectrum, encompassing a variety of non-motor symptoms (NMS) that significantly impact patients' quality of life and may influence disease progression and prognosis. Materials and Methods: The study included 44 patients diagnosed with probable or definite ALS and 35 healthy controls (HC). Functional neurological status, non-motor manifestations, and cognitive and affective domains were evaluated using the revised ALS Functional Rating Scale (ALSFRS-R), the Non-Motor Symptoms Questionnaire (NMSQuest), the Frontal Assessment Battery (FAB), and the Beck Depression Inventory (BDI), respectively. Results: A majority of ALS patients exhibited non-motor symptoms (NMS). Significant associations were identified between specific NMS domains and ALSFRS-R subdomains: sleep disturbances were associated with lower fine motor, respiratory, and total scores; digestive symptoms with lower bulbar, respiratory, and total scores; cardiovascular symptoms with lower total scores; urinary symptoms with higher bulbar subscores and a significantly slower progression rate (ΔPR); and sensory symptoms with higher gross motor subscores. BDI scores were negatively correlated with respiratory and bulbar functions, whereas FAB scores showed positive correlations with both bulbar and total ALSFRS-R scores. Conclusions: Non-motor symptoms are highly prevalent in this ALS cohort. These symptoms do not consistently correlate with greater motor impairment, as urinary and somatosensory involvement may occur independently of functional decline. Cognitive, affective, and behavioral alterations co-exist with motor symptoms and are associated with poorer overall functional performance.}, } @article {pmid41013664, year = {2025}, author = {Fortin-Bédard, N and Gbètoho Atigossou, OL and Flamand, VH and Bouffard, J and Routhier, F}, title = {The use of robotic arms for individuals with severe upper-limb disabilities.}, journal = {Neurological research and practice}, volume = {7}, number = {1}, pages = {69}, pmid = {41013664}, issn = {2524-3489}, abstract = {This letter to the editor aims to comment on the article « User expectations and experiences of an assistive robotic arm in amyotrophic lateral sclerosis: a multicenter observational study » recently published by Spittel et al. (Neurol Res Pract, 6(1), 42).}, } @article {pmid41013833, year = {2025}, author = {Spittel, S and Meyer, T and Weyen, U and Grehl, T and Weydt, P and Steinbach, R and Petri, S and Baum, P and Metelmann, M and Sperfeld, AD and Kettemann, D and Norden, J and Rödiger, A and Ilse, B and Grosskreutz, J and Hildebrandt, B and Walter, B and Münch, C and Maier, A}, title = {Response to Fortin-Bédard et al. "User expectations and experiences of an assistive robotic arm in amyotrophic lateral sclerosis: a multicenter observational study".}, journal = {Neurological research and practice}, volume = {7}, number = {1}, pages = {70}, doi = {10.1186/s42466-025-00405-z}, pmid = {41013833}, issn = {2524-3489}, } @article {pmid41016645, year = {2025}, author = {Thumbadoo, KM and Nementzik, LR and Swanson, MEV and Dieriks, BV and Dragunow, M and Faull, RLM and Curtis, MA and Blair, IP and Nicholson, GA and Williams, KL and Scotter, EL}, title = {A meta-analysis of genetic variant pathogenicity and sex differences in UBQLN2-linked amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Neurobiology of disease}, volume = {216}, number = {}, pages = {107127}, doi = {10.1016/j.nbd.2025.107127}, pmid = {41016645}, issn = {1095-953X}, support = {//Michael J Fox Foundation/ ; //Health Research Council Sir Charles Hercus Health Research Fellowship/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; *Autophagy-Related Proteins/genetics ; *Adaptor Proteins, Signal Transducing/genetics ; Male ; Female ; *Genetic Variation/genetics ; *Sex Characteristics ; *Cell Cycle Proteins/genetics ; *Ubiquitins/genetics ; }, abstract = {Ubiquilin 2, encoded by the X-linked UBQLN2 gene, is a ubiquitin-binding quality control protein. Pathogenic UBQLN2 genetic variants cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia (ALS/FTD), however, clinical phenotypes from these variants show striking inter- and intra-familial heterogeneity. Further, there are many UBQLN2 variants whose significance to disease is uncertain. Here, we examine the pathogenic potential of UBQLN2 variants reported in individuals with ALS/FTD and their non-symptomatic relatives. Meta-analysis from 27 published studies identified 186 affected individuals and 51 asymptomatic carriers, each harbouring one of 43 unique UBQLN2 coding variants. Features of identified variants, including evolutionary conservation, minor allele frequencies, localisation to protein domains, and in silico predictions of pathogenicity were compiled. Per biological sex, clinical features were compared between UBQLN2 variants segregated by pathogenicity. Pathogenic UBQLN2 variant carriers, most of whom are familial ALS cases, showed a sex-specific difference in age at onset wherein males developed disease on average 18.15 years prior to females (29.54 ± 11.9 versus 47.69 ± 13.4 years, p < 0.0001), with no change in disease duration (p = 0.2091). UBQLN2 variants of uncertain significance showed a bimodal distribution of onset age per sex suggesting a mixture of true benign and true pathogenic variants. In human brain tissue, two male UBQLN2 p.Thr487Ile (ALS-FTD and ALS) cases showed a greater burden of ubiquilin 2 aggregates than a related female case (ALS-FTD). These robust sex-specific differences in ALS/FTD presentation in carriers of pathogenic UBQLN2 variants may improve predictions of ALS/FTD risk in carriers, aiding in diagnosis and disease management.}, } @article {pmid41016762, year = {2025}, author = {Riku, Y and Kobayashi, R}, title = {[Pathomechanisms of frontotemporal lobar degeneration: from view of clinical neuropathology].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {65}, number = {10}, pages = {711-720}, doi = {10.5692/clinicalneurol.cn-002103}, pmid = {41016762}, issn = {1882-0654}, mesh = {Humans ; *Frontotemporal Lobar Degeneration/pathology/genetics/etiology ; tau Proteins/metabolism ; }, abstract = {Frontotemporal lobar degeneration (FTLD) encompasses frontotemporal dementia and related neurological disorders including motor neuron disease and movement disorders. During the 21th century, analyses of aggregative proteins suggested powerful hypotheses of gain-of-neurotoxicity or loss-of-function for aggregation-related proteins. However, recent translational researches in collaboration of basic studies and human pathology indicate that FTLD arises from more complex molecular mechanisms than dyshomeostasis of single molecules. Additionally, accumulation of clinicopathological evidences from various countries, genetic backgrounds or clinical specialties (e.g. neurology and psychiatry), suggests diverse phenotypes of FTLD, which are indicative of future paradigm-shift in the concept of FTLD. In this paper, we discuss FTLD pathomechanism on the basis of human pathology.}, } @article {pmid41017138, year = {2025}, author = {Kobayashi, H and Suzuki-Masuyama, H and Tanabe, H and Kato, H and Endoh-Yamagami, S}, title = {Neuronal Damage Induced by Gradual Oxidative Stress in iPSC-Derived Neurons: Implications for Ferroptosis Involvement and ALS Drug Evaluation.}, journal = {Journal of neurochemistry}, volume = {169}, number = {10}, pages = {e70246}, pmid = {41017138}, issn = {1471-4159}, support = {//internal funding from FUJIFILM Corporation/ ; }, mesh = {*Ferroptosis/drug effects/physiology ; *Oxidative Stress/drug effects/physiology ; *Induced Pluripotent Stem Cells/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Humans ; *Neurons/drug effects/pathology/metabolism ; Neuroprotective Agents/pharmacology ; Mice ; Edaravone/pharmacology ; Cells, Cultured ; *Motor Neurons/drug effects/metabolism/pathology ; }, abstract = {The molecular mechanisms underlying neurodegenerative diseases are not fully understood, but oxidative stress is known to play a central role in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). In this study, we developed a method to induce gradual oxidative stress in induced pluripotent stem cell (iPSC)-derived motor neurons and cortical excitatory neurons by omitting antioxidants in the media, aiming to create a platform for studying oxidative stress-dependent neuronal damage in neurodegenerative diseases. Neuroprotective effects in this platform were observed with edaravone, an approved ALS medicine, in iPSC-derived motor neurons, suggesting its potential for ALS drug evaluation. The oxidative stress-induced neuronal damage was accompanied by increased lipid peroxidation, and it was suppressed by ferroptosis inhibitors and an iron-specific chelator, suggesting that neurons died through ferroptosis. Furthermore, through a compound screen, a cholesterol biosynthesis inhibitor, AY 9944, was identified as being capable of inhibiting neuronal damage induced by oxidative stress. Additionally, neuroprotective activity was observed with 7-dehydrocholesterol, an immediate precursor of cholesterol, while the efficacy of AY 9944 was compromised by knockout of the EBP gene, which encodes an enzyme involved in cholesterol biosynthesis. These findings suggest the involvement of ferroptosis in the progression of neurodegenerative diseases and the inhibition of ferroptosis by modulating the cholesterol biosynthesis pathway, providing potential insights for drug development.}, } @article {pmid41017705, year = {2026}, author = {Wang, H and Wei, Y and Wang, J and Liu, J and Ou, S and Wang, J}, title = {Structure and function of voltage-gated sodium channel Nav1.6: Involvement in the pathological process of neural injury.}, journal = {Neural regeneration research}, volume = {21}, number = {8}, pages = {3352-3362}, pmid = {41017705}, issn = {1673-5374}, abstract = {The voltage-gated sodium channel Nav1.6, encoded by the sodium voltage-gated channel alpha subunit 8 gene, is a crucial regulator of neuronal excitability, with widespread expression throughout the central and peripheral nervous systems. Recent breakthroughs in structural biology, particularly the elucidation of the cryo-EM architecture of Nav1.6 at a resolution of 0.31 nm, have provided unprecedented insights into its molecular organization and functional modulation. As a key mediator of action potential initiation and propagation, Nav1.6 possesses unique biophysical properties, including persistent and resurgent sodium currents that critically influence neuronal firing patterns. This comprehensive review synthesizes current knowledge on the physiological functions and pathological roles of Nav1.6 in multiple neurological conditions. Key findings include the following: (1) Epilepsy studies reveal more than 250 sodium voltage-gated channel alpha subunit 8 mutations with distinct genotype-phenotype correlations, where gain-of-function variants lead to severe epileptic encephalopathies, while loss-of-function variants are associated with generalized epilepsy, highlighting the potential of Nav1.6-selective blockers such as XEN901 and GS967. (2) In Alzheimer's disease, Nav1.6 mediates amyloid-β oligomer-induced neuronal hyperexcitability through amyloid precursor protein-dependent membrane trafficking and regulates beta-secretase 1 expression via nuclear factor of activated T cells 1 signaling, suggesting novel disease-modifying strategies. (3) Parkinson's disease research has demonstrated that Nav1.6 upregulation in reactive astrocytes in the globus pallidus contributes to motor deficits through calcium-mediated abnormalities in neuronal synchronization. (4) Amyotrophic lateral sclerosis involves Nav1.6-dependent cortical hyperexcitability preceding motor neuron degeneration, with riluzole showing partial efficacy through sodium current modulation. (5) Multiple sclerosis pathophysiology features Nav1.6 redistribution in demyelinated axons, which drives calcium-dependent axonal injury via reverse Na + /Ca 2+ exchange. (6) Chronic pain mechanisms involve Nav1.6 overexpression in dorsal root ganglia neurons, regulated by the p38 mitogen-activated protein kinase and tumor necrosis factor-α signaling pathways. (7) Traumatic brain injury models show that exercise-induced cognitive improvement is correlated with the normalization of Nav1.6-mediated excitability. Therapeutic development has progressed from nonselective sodium channel blockers to precision approaches, including state-dependent pore blockers designed using structural insights; allosteric modulators targeting specific conformations; gene therapy strategies using clustered regularly interspaced short palindromic repeats and antisense oligonucleotides; and miRNA-based regulation of channel expression. Current challenges include achieving sufficient subtype selectivity, optimizing blood-brain barrier penetration, and developing clinically relevant biomarkers for patient stratification. Future directions emphasize the integration of advanced technologies-such as single-cell multiomics to map neuronal subtype-specific expression patterns, patient-derived organoids for personalized drug testing, and machine learning-assisted drug design-to accelerate translation. Large-scale collaborative efforts will be essential to validate therapeutic candidates and establish genotype-guided treatment protocols for Nav1.6-related disorders.}, } @article {pmid41017972, year = {2025}, author = {Feng, J and Hu, X and Liu, J and Wang, W and Chen, L and Pang, R and Zhang, A}, title = {Akkermansia muciniphila in neurological disorders: mechanisms and therapeutic potential via the gut-brain axis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1650807}, pmid = {41017972}, issn = {1662-4548}, abstract = {In recent years, the role of Akkermansia muciniphila (A. muciniphila) in neurological diseases has attracted increasing attention. As a probiotic, A. muciniphila is closely associated with host health, metabolism, and immunity, demonstrating therapeutic potential in various conditions such as obesity, atherosclerosis, inflammatory bowel disease, diabetes, and liver disorders. In the context of neurological diseases, A. muciniphila significantly influences the host brain through the microbiota-gut-brain axis (MGBA). This review summarizes the roles and mechanisms of A. muciniphila and its active components (e.g., the outer membrane protein Amuc_1100, extracellular vesicles AmEVs, and short-chain fatty acids SCFAs) in various neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), depression, cerebral palsy (CP), epilepsy (EP), autism spectrum disorder (ASD), and amyotrophic lateral sclerosis (ALS). It exerts protective effects by enhancing the intestinal barrier, regulating lipid metabolism, producing SCFAs, secreting neuroactive substances, and inhibiting neuroinflammation, thereby suggesting novel therapeutic avenues for neurological disorders. However, due to limited data from large-scale human clinical trials and the complexity of disease mechanisms and host-microbiota interactions, its clinical translation faces considerable challenges. Future efforts should focus on multicenter randomized controlled trials and in-depth mechanistic studies utilizing technologies such as metabolomics to facilitate evidence-based clinical application.}, } @article {pmid41018173, year = {2025}, author = {Tanaka, S and Kobayashi, M and Ikeguchi, R and Iwasaki, N}, title = {A Case of Amyotrophic Lateral Sclerosis With Coexisting Maturity-onset Diabetes of the Young Type 5.}, journal = {JCEM case reports}, volume = {3}, number = {11}, pages = {luaf219}, pmid = {41018173}, issn = {2755-1520}, abstract = {We report the case of a 60-year-old Japanese woman with genetically confirmed maturity-onset diabetes of the young type 5 [MODY5; HNF1B (hepatocyte nuclear factor 1B)-MODY] who developed amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder. MODY is a rare monogenic form of diabetes mellitus, typically associated with urogenital anomalies and pancreatic hypoplasia. At the age of 25, she was diagnosed with diabetes mellitus. The clinical findings, including bilateral renal cysts, agenesis of the pancreatic body and tail, and impaired insulin secretion without β-cell-specific autoimmune autoantibodies, suggested HNF1B-MODY. A 1.4-Mb hemiallelic deletion on chromosome 17q12 encompassing HNF1B was confirmed, and she was subsequently diagnosed with HNF1B-MODY. At age 59, she developed symptoms of a common cold, followed by dysarthria and limb weakness. The neurological examination revealed tongue fasciculations, spasticity, and hyperreflexia. Electromyography indicated widespread motor neuron degeneration, consistent with a diagnosis of definite ALS. Whole-exome sequencing revealed no known ALS-related pathogenic variants, and no ALS candidate genes were detected in the deleted region of 17q12. To our knowledge, this is the first reported case of concurrent ALS and HNF1B-MODY. While a direct genetic link is unclear, this co-occurrence may provide insights into the shared molecular pathways and warrants further investigation.}, } @article {pmid41018179, year = {2025}, author = {Liu, M and Niu, T and Zhang, X and Zhang, Z and Zhao, L and Li, J and Fu, S and Han, M and Li, R and Dong, H and Liu, Y}, title = {Development and validation of a predictive model for depression risk in patients with amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1639895}, pmid = {41018179}, issn = {1664-2295}, abstract = {INTRODUCTION: Depression is a severe neuropsychiatric manifestation in patients with amyotrophic lateral sclerosis (ALS), substantially impacting their quality of life and exacerbating caregiver burden, due to the need for different approaches in clinical care. However, a predictive model for the risk of depression in patients with ALS is lacking. This study aimed to develop and validate a predictive model using routinely accessible clinical and laboratory indicators to identify patients at high risk of depression.

METHODS: Patients with ALS who were hospitalized in the Department of Neurology at the Second Hospital of Hebei Medical University between March 2017 and December 2024 were included. Basic clinical data, laboratory test results, and relevant questionnaire scores were collected, and patients were divided into depressed and non-depressed groups. The least absolute shrinkage and selection operator regression and multivariate logistic regression analyses were applied for variable selection and model construction. Model performance was evaluated using the area under the receiver operating characteristic curve, calibration curves, decision curve analysis, and clinical impact curves, with internal validation performed via bootstrap resampling.

RESULTS: Depression was observed in 33.9% of patients. Significant predictors included educational level, sleep disorders, anxiety, Revised Amyotrophic Lateral Sclerosis Functional Rating Scale total scores, C-reactive protein levels, and the Systemic Inflammation Response Index. The final model demonstrated good predictive accuracy and clinical applicability. A depression risk scoring table was further developed based on the coefficients of the logistic regression.

CONCLUSION: The nomogram and the scoring table offer a reliable and practical approach for clinicians to identify patients with ALS who are at high risk for depression and enable early psychological intervention in clinical settings.}, } @article {pmid41018230, year = {2025}, author = {Qin, JY and Zhou, ZL and Zhou, YQ and Chen, Y and Yang, XY and Zhang, HQ and Xu, ZC}, title = {Double gene mutations of LRSAM1 and REEP1 and a new REEP1 mutation site found in a patient with amyotrophic lateral sclerosis with subjective paresthesia: A case report.}, journal = {Ibrain}, volume = {11}, number = {3}, pages = {393-399}, pmid = {41018230}, issn = {2769-2795}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. Although dyskinesia is the most prominent clinical manifestation of ALS, with an in-depth understanding of disease pathogenesis and clinical detection, more and more ALS patients are found to have nonmotor symptoms, such as sensory impairment. Genetic testing technology has developed rapidly in recent years. New genes have been proven to be involved in the pathogenesis of ALS. However, according to the existing research evidence, no literature has reported that patients with ALS have leucine-rich repeats and sterility α mutations in motif 1 (LRSAM1) and receptor expression accessory protein 1 (REEP1). The mutation sites of REEP1 gene have not been reported, and the simultaneous mutations of two genes have not been reported. In the largest human gene mutation frequency database gnomad, the mutation sites of two genes are currently defined as new heterozygous variants with unclear clinical significance. Therefore, this article reports the clinical data of this case to further deepen the clinicians' understanding of the disease, and may provide evidence for further study of the new genotype-phenotype of LRSAM1 and REEP1.}, } @article {pmid41018945, year = {2025}, author = {Vucic, S and Shahrizaila, N and Kano, O and Menon, P and Agustini, S and Kulkantrakorn, K and Atchayaram, N and Lee, YC and Prado, MB and Ng, KWP and Chai, J and Son, B and Talman, P and Nghia, HTT and Tuan, LTQ and Shibuya, K and Izumi, Y and Atsuta, N and Henderson, RD and Cui, L and Liu, M and Ohnmar, O and Rabani, R and Hong, YH and Sung, JJ and Fan, D and Raykar, V and Kuwabara, S and Kim, SH and Sobue, G and Kiernan, MC}, title = {Pan-Asian consortium for treatment and research in ALS (PACTALS) guidelines for management of amyotrophic lateral sclerosis.}, journal = {The Lancet regional health. Western Pacific}, volume = {62}, number = {}, pages = {101684}, pmid = {41018945}, issn = {2666-6065}, abstract = {The Pan-Asian Consortium for Treatment and Research in ALS (PACTALS) guidelines were developed for the management of amyotrophic lateral sclerosis (ALS) patients living in the Asia-Pacific countries, taking into consideration the ethnic, racial and economic diversity of the region. The majority of patients reside in low-income (limited-resource setting) and middle-income countries. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was utilised for development of the PACTALS management guidelines. Nine broad research questions, divided into sections, were addressed. Evidence was derived from existing Cochrane reviews, systematic reviews, meta-analysis, and randomized controlled trials (RCT) along with consensus when evidence was limited. Recommendations were provided for diagnostic pathways, use of disease modifying therapies, appropriateness of multidisciplinary care models, management of respiratory dysfunction, communication and nutrition, addressing symptoms that affect the quality of life, managing cognitive, behavioural and emotional symptoms as well as appropriate implementation of palliative care services and addressing end-of-life issues. The PACTALS guidelines provide a much-needed framework for the management of ALS patients living in the Asia-Pacific region. The management guidelines will be updated as the treatment landscape evolves and evidence of novel management approaches becomes available.}, } @article {pmid41019550, year = {2025}, author = {Chen, KQ and Cao, WJ and Liu, Z and Liu, RZ}, title = {Mini-review: Processed red meat intake and risk of neurodegenerative diseases.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1663647}, pmid = {41019550}, issn = {2296-861X}, abstract = {Neurodegenerative diseases (NDDs) are a group of disorders characterized by the progressive loss of neurons in specific areas of the central nervous system. In recent years, more and more research has focused on the influence of diet on NDDs. As a common food, processed red meat is widely consumed worldwide. Many studies have shown that processed red meat may increase the risk of cancer, diabetes and cardiovascular disease. Unfortunately, it is unclear whether processed red meat affects NDDs. Therefore, we reviewed the existing literature on the role of processed meats in NDDs. We concluded that intake of processed meat may have an adverse effect on NDDs.}, } @article {pmid41019660, year = {2025}, author = {Gómez Mendieta, MªA and Santiago Recuerda, A and Varela Cerdeira, M and Liebert Alvarez, B and Valdazo Alonso, M and Corpa Rodríguez, E}, title = {Non-Sedated Cannula Replacement in Home-Care Patients With Amyotrophic Lateral Sclerosis: Cost Reduction and Patient-Family Satisfaction Evaluation.}, journal = {Open respiratory archives}, volume = {7}, number = {4}, pages = {100480}, pmid = {41019660}, issn = {2659-6636}, abstract = {This study describes a home-based tracheostomy tube replacement protocol for individuals diagnosed with amyotrophic lateral sclerosis (ALS) requiring invasive mechanical ventilation. Implemented between May 2020 and July 2024, the protocol was offered to 16 eligible patients, with 14 opting for home-based care under the supervision of the Carlos III/La Paz Hospital. Procedures were conducted without sedation by a multidisciplinary team, with the aim of maintaining patient safety and continuity of care. A total of 120 home-based replacements were performed, most without major complications or the need for emergency hospitalization. In comparison to hospital-based procedures, the home protocol was associated with an estimated cost reduction of approximately €340 per case, potentially resulting in annual savings of €10,200. Patients reported high satisfaction, noting decreased caregiver burden and improved perceived quality of care. While limited by patient selection criteria, these preliminary findings suggest that home-based tracheostomy care may be a feasible, safe, and cost-effective alternative for long-term management in ALS.}, } @article {pmid41020397, year = {2026}, author = {Dergai, O and Wuu, J and Koziczak-Holbro, M and Malaspina, A and Granit, V and Hernandez, JP and Cooley, A and Sachdev, R and Yu, L and Bidinosti, M and Flotte, L and Nash, M and Jennings, LL and Berry, JD and Bruijn, LI and Brachat, S and Benatar, M}, title = {Skeletal Muscle Biomarkers of Amyotrophic Lateral Sclerosis: A Large-Scale, Multi-Cohort Proteomic Study.}, journal = {Annals of neurology}, volume = {99}, number = {2}, pages = {393-407}, pmid = {41020397}, issn = {1531-8249}, support = {U01 NS107027/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/metabolism/blood ; Biomarkers/cerebrospinal fluid/blood/metabolism ; *Proteomics/methods ; Male ; Female ; Middle Aged ; Aged ; Cohort Studies ; *Muscle, Skeletal/metabolism ; Adult ; Disease Progression ; }, abstract = {OBJECTIVE: Biomarkers with clear contexts of use are important tools for amyotrophic lateral sclerosis (ALS) therapy development. Understanding their longitudinal trajectory in the untreated state is key to their use as potential markers of pharmacodynamic response. To this end, we undertook a large-scale proteomic study in well-phenotyped cohorts to identify biomarker candidates of ALS disease state and disease progression.

METHODS: Clinical phenotypic data and biofluid samples, collected from patients with ALS and healthy controls through multiple longitudinal natural history studies, were used to identify biomarker candidates. Slow off-rate modified aptamer (SOMAmer)-based relatively quantitative measurement of ~7,000 proteins was performed in plasma and cerebrospinal fluid (CSF), with immunoassay validation of candidates of interest.

RESULTS: We identified 329 plasma proteins significantly differentially regulated between ALS and controls (adjusted p-value <0.05), with 25 showing >40% relative abundance. PDLIM3, TNNT2, and MYL11 had the greatest log-fold elevation, whereas ANTXR2 and ART3 had the greatest log-fold reduction. A similar set of plasma proteins was found to increase (eg, PDLIM3, TNNT2, and MYL11) or decrease (eg, ANTXR2, ART3, and MSTN) with disease progression. CSF proteins with the greatest log-fold elevation included NEFL, NEFH, CHIT1, CA3, MYL11, and GPNMB. These results were confirmed in an independent replication cohort. Moreover, tissue-specific signature enrichment suggests a significant contribution of muscle as a source of these biomarkers. Plasma KCNIP3 was elevated by ~60% in those on riluzole. Immunoassays provided orthogonal validation of plasma TNNT2 and CSF GPNMB.

INTERPRETATION: We identified an array of novel biomarkers with the potential to serve as response biomarkers to aid therapy development, as well as to shed light on the underlying biology of disease. ANN NEUROL 2026;99:393-407.}, } @article {pmid41021147, year = {2025}, author = {Xie, X and Wu, P and Wen, T and Jia, R and Zhang, R and Hu, F and Jin, J and Qin, X and Chen, QY}, title = {Iron and Ferritin Dyshomeostasis Intersect with Sex, Age, and Disease Severity in Amyotrophic Lateral Sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {4}, pages = {127}, pmid = {41021147}, issn = {1559-1166}, support = {82302973//National Natural Science Foundation of China/ ; YX6J010//Xi'an Jiaotong University "Young Talent Support Plan"/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood ; Male ; Female ; Middle Aged ; *Iron/blood ; *Ferritins/blood ; Aged ; Adult ; Homeostasis ; Sex Factors ; Age Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor neurons. Due to heterogeneity in both cause and clinical phenotype, accuracy of diagnosis and efficacy of treatment remain challenging. An evolving body of evidence point to the importance of the "gene-time-environment" hypothesis in ALS onset and progression. Despite extensive research, understanding of the complex environmental risk factors remains fragmented. In this study, we comprehensively analyzed the associations between trace elements, biochemical signatures, and modifiable risk factors among ALS patients stratified by age, sex, type of onset, disease severity, and progression. Specifically, we investigated blood concentrations of cadmium (Cd), lead (Pb), copper (Cu), zinc (Zn), calcium (Ca), magnesium (Mg), and iron (Fe) levels in 121 participants. Moreover, we examined the associations between trace metals, biochemical indicators including serum ferritin (SF), blood glucose, cholesterol (CHOL), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), cerebrospinal fluid (CSF) cell count, CSF total protein, as well as history of hypertension, hazardous chemical exposure, drinking, and smoking in ALS patients. Specifically, we report that high Fe levels were found in male and spinal-onset patients. Moreover, high serum ferritin was positively associated with age of onset, blood iron and glucose, as well as high disease severity. Results from this study highlight the complex characteristics of ALS and provide new insight for understanding the intricate relationship between disease phenotype, metal homeostasis, and modifiable risk factors.}, } @article {pmid41022136, year = {2025}, author = {Jutkowitz, E and Gadkari, G and Hsu, EC and Tunalilar, O and Smith, L and Hua, CL and Bunker, JN and Thomas, KS}, title = {Trends in Assisted Living and Memory Care Supply From 2019 to 2023.}, journal = {Journal of the American Medical Directors Association}, volume = {26}, number = {12}, pages = {105890}, doi = {10.1016/j.jamda.2025.105890}, pmid = {41022136}, issn = {1538-9375}, support = {R01 AG082308/AG/NIA NIH HHS/United States ; RF1 AG082308/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Assisted Living Facilities/supply & distribution/statistics & numerical data/trends ; United States ; Memory ; *Cognitive Dysfunction/therapy ; }, abstract = {OBJECTIVES: Describe geographic variation from 2019 to 2023 in assisted living (AL) and memory care supply, and its correlation with county-level characteristics.

DESIGN: Descriptive study of the supply of AL and memory care.

SETTING AND PARTICIPANTS: Licensed AL communities in the United States operating in 2019 and 2023.

METHODS: Data come from a national list of licensed ALs and the US Census Bureau's American Community Survey. The primary outcomes of interest were AL supply and memory care supply (beds per 1000 adults aged 65+ at the county level). We descriptively evaluated county characteristics by AL supply in 2019 and the change in AL supply from 2019 to 2023.

RESULTS: In 2023, counties with the highest AL and memory care supply were more likely to have greater wealth, higher educational attainment, and were urban. Between 2019 and 2023, 43% of counties had a decrease in AL supply, 35% of counties had no change in AL supply, and 22% of counties had an increase in AL supply. Counties with a decrease or no change in AL supply compared with increase in AL supply had a larger proportion of the population aged 65+ years, lower median household income, and were more rural. Between 2019 and 2023, 29% of counties had a decrease in memory care supply, 37% had no change in memory care supply, and 34% had an increase in memory care supply. Counties with unchanged or a decrease in memory care supply had lower educational attainment, more poverty, lower home values, and were more rural.

CONCLUSIONS AND IMPLICATIONS: We found low overall availability of AL and memory care supply and decreases in their supply in rural and socioeconomically disadvantaged counties. It is important to incentivize ALs, including memory care, to operate in underserved areas to ensure equitable access to these important long-term care settings.}, } @article {pmid41022144, year = {2025}, author = {Guo, W and Cai, S and Li, Y and McGarry, BE and Caprio, TV and Temkin-Greener, H}, title = {End-of-Life Outcomes and Staff Visits for Hospice Recipients Residing in Assisted Living.}, journal = {Journal of the American Medical Directors Association}, volume = {26}, number = {12}, pages = {105887}, doi = {10.1016/j.jamda.2025.105887}, pmid = {41022144}, issn = {1538-9375}, mesh = {Humans ; Retrospective Studies ; United States ; Male ; Female ; Aged ; *Assisted Living Facilities ; Medicare ; *Hospice Care ; Aged, 80 and over ; *Terminal Care ; }, abstract = {OBJECTIVES: To examine (1) whether hospice staff visits are associated with end-of-life (EOL) transitions, place of death (POD), and live discharges among assisted living (AL) residents, and (2) whether state AL regulations on staffing and medication administration influence these outcomes. We hypothesized that more frequent staff visits and specific regulatory provisions would be associated with improved EOL outcomes.

DESIGN: Retrospective cohort study using Medicare claims data from 2018-2019. Sensitivity analyses used logistic regression models to assess robustness.

SETTING AND PARTICIPANTS: National, population-based study of Medicare decedents residing in licensed AL communities across the United States. The main analytic sample included 42,466 AL residents who received hospice and died during enrollment. A separate sample of 61,851 was used to assess live discharges. Participants were identified by linking 9-digit ZIP codes of 10,452 licensed ALs to Medicare enrollment files. Individuals younger than 55 years, not enrolled in hospice, or enrolled in Medicare Advantage were excluded.

METHODS: Key exposures included the frequency of hospice staff visits (clinical vs nonclinical) and the presence of state AL regulations related to staffing and medication delegation. Outcomes included EOL transitions within the last 7 days of life, POD in AL vs other settings, and live discharges from hospice.

RESULTS: More frequent clinical staff visits were associated with lower rates of EOL transitions [-12 percentage points (pp)], reduced live discharges (-4 pp), and increased likelihood of dying in place (+4 pp; all P < .001). Nonclinical visits showed modest but consistent associations with improved outcomes. State regulations requiring on-site staffing and permitting medication delegation were associated with fewer transitions and higher rates of in-place death.

CONCLUSIONS AND IMPLICATIONS: Hospice staffing intensity, especially clinical visits, appears to be associated with EOL outcomes for AL residents. AL state regulations are also associated with hospice quality. These findings underscore the role of both organizational practices and regulatory policy in shaping hospice experiences in AL settings.}, } @article {pmid41022359, year = {2025}, author = {Liu, C and Lai, FF and Zhang, T and Mao, KJ and Wan, HT and He, Y}, title = {Roles and therapeutic potential of PARP-1 in neurodegenerative diseases.}, journal = {Biochemical pharmacology}, volume = {242}, number = {Pt 3}, pages = {117373}, doi = {10.1016/j.bcp.2025.117373}, pmid = {41022359}, issn = {1873-2968}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/enzymology/metabolism ; *Poly (ADP-Ribose) Polymerase-1/metabolism/antagonists & inhibitors ; Animals ; *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use/pharmacology ; DNA Damage/drug effects/physiology ; }, abstract = {Poly(ADP-ribose) polymerase 1 (PARP-1) was first discovered in the 1960 s, and over the past few decades, there has been growing evidence that PARP-1 plays a key role in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. With DNA damage detection and repair as its main function, PARP-1 is activated by regulation in the early stages of neurodegenerative diseases, quickly and effectively repairs mild DNA damage, and protects nerve cells from death. However, as the disease progresses, severe DNA damage causes PARP-1 to overactivate, resulting in neuronal cell death, including apoptosis, necrosis, and parthanatos, further exacerbating the disease progression. PARP-1 is also involved in the pathological process of neurodegenerative diseases, such as pathological protein aggregation, neuroinflammation, mitochondrial dysfunction, autophagy disorder, and damage to the blood-brain barrier. According to a large number of studies, PARP-1 inhibition has shown great therapeutic potential for neurodegenerative diseases, and the development of PARP-1 inhibitors has received increasing attention. Here, we review the role of PARP-1 in the process of neurodegenerative diseases and summarize the latest research progress and application of PARP-1 inhibitors in neurodegenerative diseases.}, } @article {pmid41022842, year = {2025}, author = {Sun, R and Zhuang, Y and Lin, Y and Hu, F}, title = {In situ secondary structure imaging of protein phase separation and aggregation by hyperspectral stimulated Raman scattering microscopy.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {8552}, pmid = {41022842}, issn = {2041-1723}, support = {22174085//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32350027//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {*Spectrum Analysis, Raman/methods ; Humans ; *Protein Aggregates ; Protein Structure, Secondary ; *Proteins/chemistry ; *Nonlinear Optical Microscopy/methods ; *Biomolecular Condensates/chemistry ; Phase Separation ; }, abstract = {Biomolecular condensates enable the coordination of cellular activities with high spatiotemporal selectivity. Many techniques have been developed to characterize protein condensate. However, direct visualization of protein structure in phase-separated condensate remains underexplored. Here we develop in situ quantitative imaging of secondary structure in protein condensates by stimulated Raman scattering (SRS) microscopy. Characteristic spectra of four secondary structures are obtained from protein amide I vibration analysis. Hyperspectral SRS imaging reveals significant enrichments and disordered to ordered structural changes during phase separation of ALS-related proteins. Time-lapse imaging of protein aging process directly visualizes heterogeneous β-sheet formation on the condensate surface. And secondary structures of mutant proteins are imaged to correlate amino acid sequence to phase separation property. Live-cell label-free imaging of protein structure is further demonstrated to exhibit pronounced heterogeneity in subcellular aggregates. Therefore, our technique provides crucial molecular-level information to investigate protein phase separation and its transition in pathological aggregation.}, } @article {pmid41022917, year = {2025}, author = {Chandramouli, P and Jayaseelan, R and Pandulu, G and Yaswanth, KK}, title = {Experimental and statistical investigation on uniaxial compressive performance of hybrid double skin tubular slender columns.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {33368}, pmid = {41022917}, issn = {2045-2322}, abstract = {Double-skin tubular columns have emerged as preferable in the construction sector because of their distinguished ease of benefits over traditional concrete columns. The uniaxial compression behaviour of the novel hybrid GFRP-concrete-steel double-skin tubular columns for different orientations is tested experimentally with various slenderness ratios. The experimental phase tested twenty-seven specimens by considering the three parameters such as fibre orientations (± 0°, 0°/90° and ± 45°), infill of the concrete (NSC, HSC and GPC) and void ratio (0.58, 0.6 and 0.68). The effect of these parameters was based on the ultimate load capacity, axial load-strain, and lateral deflection of DSTCs. The experimental tests revealed that as the column specimen's height increased, the confinement action became less effective. The test variables evaluated the effect of the slenderness ratio, the axial load-carrying capacity, ultimate axial strain, hoop strain, energy dissipation and ductility index. The fibre in 0/90° showed a higher energy dissipation and ductility index than the 0° and ± 45°. The load-carrying capacity of HSC infill revealed a 16% - 28% increase over the NSC and GPC. The axial strain showed a non-linear behaviour after 75% of the ultimate load. This study aims to develop a mathematical expression that predicts and optimises using a response surface methodology approach. The generated models were validated using Yu et al's model by introducing the slenderness ratio and proposed a new equation that closely agrees with the experimental results.}, } @article {pmid41024175, year = {2025}, author = {Bamber, R and Carlton, J and McDermott, C and Stavroulakis, T}, title = {Understanding health-related quality of life of informal carers in amyotrophic lateral sclerosis: a scoping review and conceptual framework.}, journal = {Health and quality of life outcomes}, volume = {23}, number = {1}, pages = {90}, pmid = {41024175}, issn = {1477-7525}, support = {NIHR301648//National Institute for Health and Care Research/ ; NIHR301648//National Institute for Health and Care Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/nursing ; *Quality of Life/psychology ; *Caregivers/psychology ; Patient Reported Outcome Measures ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive, life-limiting neurodegenerative disease. Informal carers provide extensive support, significantly impacting their health-related quality of life (HRQoL). Current HRQoL measurement using person-reported outcome measures (PROMs) in ALS carers lacks consistency and comprehensiveness, hindering robust assessment and synthesis. There is evident need for a comprehensive conceptual framework of HRQoL, to fully capture the multidimensional nature of caregiving in ALS. Such a framework is essential to inform research and clinical practice, ensuring relevant measurement and meaningful clinical discussions. This study aimed to develop this evidence-based framework.

METHODS: This study comprised two stages. Firstly, a scoping review was undertaken in March 2024 using Medline, Embase, and CINAHL to identify primary articles exploring HRQoL in ALS carers. Qualitative, mixed methods and quantitative articles using multi-item PROMs to assess HRQoL in informal ALS carers were included. Relevant themes and subthemes were extracted from articles and PROMs and mapped onto an existing conceptual framework for people with ALS (Quality of Life in ALS, QuALS), which covers physical, psychological, and social HRQoL domains in people with ALS. The Carer-QuALS framework was subsequently developed and refined using existing literature and consultation with ALS carers. PROMs within this review were then indexed against the finalised Carer-QuALS framework.

RESULTS: From 715 search results, 82 articles and 44 PROMs were eligible for inclusion. One new subtheme 'physical caring activities' emerged, while seven subthemes lacked support from the literature. In three structured consultation sessions, nine ALS carers, reviewed the draft Carer-QuALS framework (consisting of seven themes and 43 subthemes). Based on their input, one new subtheme 'privacy' was added, six subthemes were removed, and one was retained, despite lacking support from review literature. The final Carer-QuALS framework includes 37 subthemes: 8 physical, 6 social, and 23 psychological.

CONCLUSIONS: This review presents a comprehensive conceptual framework encompassing the multidimensional impact of ALS caregiving on the HRQoL of informal carers. The framework provides a resource that can be used by researchers, clinicians, and patient advocacy groups for multiple purposes (e.g., to support PROM selection to measure HRQoL, to guide future PROM development, and to facilitate discussions between informal carers and clinicians).}, } @article {pmid41024384, year = {2026}, author = {Gautam, M and Laith, A and Gunel, A and Yilmaz, M and Basak, N and Idrisoglu, H and Ozdinler, PH}, title = {Exosome Proteomics of SOD1[D90A] Mutation Suggest Early Disease Mechanisms, and FN1 as a Biomarker.}, journal = {Annals of clinical and translational neurology}, volume = {13}, number = {1}, pages = {131-143}, pmid = {41024384}, issn = {2328-9503}, support = {//A Long Swim/ ; //Les Turner ALS Foundation/ ; //The Queen B Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/metabolism/diagnosis ; *Exosomes/metabolism ; *Superoxide Dismutase-1/genetics ; Biomarkers/blood ; Proteomics ; Male ; Female ; *Fibronectins/blood/metabolism ; Mutation ; Middle Aged ; Disease Progression ; Adult ; }, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. Super oxide dismutase 1 (SOD1) gene mutations cause ALS, and the D90A mutation is associated with primarily upper motor neuron (UMN) loss.

OBJECTIVE: Our goal is to reveal the early cellular events in ALS pathology and identify potential pharmacokinetic biomarkers, using well-defined patient populations.

METHODS: Exosomes are isolated from serum either single or multiple time points from members of one family, who have SOD1[D90A] mutation, and their protein content is assessed by tandem mass-spec proteomics. Ingenuity Pathway analysis is used to highlight cellular events that are perturbed as the disease progressed. The linear regression analysis, using ALSFRS scores of patients and the protein content, helps identify potential pharmacokinetic biomarkers, which are confirmed with the ELISA assay.

RESULTS: Father, Son, and Daughter are at different disease stages and carry the SOD1[D90A] mutation. Albeit, the Daughter remained asymptomatic within a year; she had significant biological changes. The Son transitioned from asymptomatic to early symptomatic within a year, while the Father was symptomatic. Patient #2, who also had the SOD1[D90A] mutation, was more advanced. Comparison of the Son, Father, and Patient #2 suggested Fibronectin1 (FN1) as a potential pharmacokinetic biomarker, which is confirmed by ELISA.

INTERPRETATION: Exosome proteomics offer a powerful approach to interrogate disease-specific or disease-related proteins that become present in the blood. This helps define the perturbed cellular events with respect to disease progression and reveal potential pharmacokinetic biomarkers. We find FN1 levels to increase with disease progression, suggesting it may be a pharmacokinetic biomarker, especially for ALS patients with prominent UMN loss.}, } @article {pmid41024438, year = {2026}, author = {Ramesh, N and Evans, A and Wojta, K and Yang, Z and Boks, MP and Kahn, RS and de Boer, SCM and van der Lee, SJ and Pijnenburg, YAL and Reus, LM and Ophoff, RA}, title = {Accurate DNA methylation predictor for C9orf72 repeat expansion alleles in the pathogenic range.}, journal = {HGG advances}, volume = {7}, number = {1}, pages = {100522}, pmid = {41024438}, issn = {2666-2477}, mesh = {Humans ; *C9orf72 Protein/genetics ; *DNA Methylation ; *DNA Repeat Expansion ; Male ; Female ; *Amyotrophic Lateral Sclerosis/genetics ; *Alleles ; *Frontotemporal Dementia/genetics ; Middle Aged ; CpG Islands ; Aged ; }, abstract = {The hexanucleotide (G4C2) repeat expansion in the promoter region of C9orf72 is the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this study, we conducted a genome-wide DNA methylation (DNAm) analysis using EPIC version 2 (EPICv2) arrays on an FTD cohort comprising 27 carriers and 250 non-carriers of the pathogenic C9orf72 repeat expansion from the Amsterdam Dementia Cohort. We identified differentially methylated CpGs probes associated with the pathogenic C9orf72 expansion and used these findings to create a DNAm least absolute shrinkage and selection operator (LASSO) predictor to identify repeat expansion carriers. Eight CpG sites at the C9orf72 locus were significantly differentially hypermethylated in repeat expansion carriers compared to non-carriers. The LASSO model predicted repeat expansion status with an average accuracy of 98.6%. The LASSO predictor was further validated in a separate, independent validation cohort containing 1,589 subjects with bipolar disorder, 580 first-degree relatives, and 289 independent control subjects with available EPICv2 data, identifying four C9orf72 repeat expansion carriers, subsequently confirmed by repeat-primed PCR. This result highlights the accuracy and generalizability of the DNAm predictor of C9orf72 repeat expansion carriers. The identification of a highly accurate DNAm biomarker for a repeat expansion locus associated with neurodegenerative disorders may provide great value for studying this locus. The approach holds significant promise for investigating this and other repeat expansion loci, particularly given the growing interest in epigenetic epidemiological studies involving large cohorts with available DNAm data.}, } @article {pmid41024834, year = {2025}, author = {Meena, BL and Sharma, D}, title = {Are we overestimating success of salvage hepatectomy in unresectable hepatocellular carcinoma?.}, journal = {World journal of clinical oncology}, volume = {16}, number = {9}, pages = {111537}, pmid = {41024834}, issn = {2218-4333}, abstract = {The Zhang et al's study addresses an important clinical question of timing and role of salvage surgery post-downstaging procedures in patients with advanced hepatocellular carcinoma wherein different modalities like trans arterial chemoembolization, tyrosine kinase inhibitors, and anti-programmed cell death 1 antibodies have been used as downstaging procedure. Although proper selection of patients is a pre-requisite for salvage related liver failure.}, } @article {pmid41025901, year = {2025}, author = {Merbaum, P and Zwamborn, R and Hop, P and Sequencing Consortium, PMA and van Rheenen, W and Veldink, J}, title = {Dissecting epigenetic age acceleration in amyotrophic lateral sclerosis.}, journal = {Epigenomics}, volume = {17}, number = {16}, pages = {1153-1161}, pmid = {41025901}, issn = {1750-192X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Epigenesis, Genetic ; Middle Aged ; Male ; Female ; C9orf72 Protein/genetics ; *Aging/genetics ; DNA Methylation ; Aged ; Case-Control Studies ; Adult ; }, abstract = {AIM: We compared signatures of epigenetic aging in amyotrophic lateral sclerosis (ALS) patients and healthy controls to investigate the role of potential confounders and genetic subgroups.

METHODS: We used whole-blood methylome profiles for 5,146 ALS patients and 2,156 controls available for Project MinE. We predicted biological age with three generations of epigenetic clocks and estimated age acceleration by regressing our model on control individuals to evaluate case/control differences. To investigate the contribution of C9orf72 expansions, we regressed the model on C9orf72-negative ALS patients. The predicted DunedinPACE pace of aging and telomere length additionally characterized aging dynamics.

RESULTS: We found that white blood cell type proportions confound the previously observed increase in the pace of biological aging in ALS. When correcting for cell counts, there is no evidence for accelerated epigenetic aging compared to controls, except for ALS patients with the C9orf72 repeat expansion. None of the epigenetic age acceleration scores contributed to survival.

CONCLUSION: Our study revealed no significant difference in the pace of biological agingbetween ALS patients and controls, except for ALS patients carrying the C9orf72 mutation. We emphasize the importance of altered white blood cell proportions in general ALS pathophysiology as opposed to accelerated aging per se.}, } @article {pmid41026230, year = {2025}, author = {Zhang, P and Yuan, X and Liu, Y and Song, J and Liu, R and Wang, H}, title = {Deciphering the dual resistance pathways to mesosulfuron-methyl in Lolium multiflorum: target-site and non-target-site insights.}, journal = {Plant cell reports}, volume = {44}, number = {10}, pages = {228}, pmid = {41026230}, issn = {1432-203X}, support = {241111111700//Key Research and Development Project of Henan Province/ ; HN2022121//Postdoctoral research project of Henan Province/ ; 2018024//High-level Talent Introduction Project of Henan Institute of Science and Technology/ ; }, mesh = {*Sulfonylurea Compounds/pharmacology ; *Lolium/genetics/drug effects/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Acetolactate Synthase/genetics/metabolism ; Mutation/genetics ; Plant Proteins/genetics/metabolism ; China ; }, abstract = {Lolium multiflorum exhibits resistance to mesosulfuron-methyl through ALS mutations; HZ2 population also shows metabolic resistance through P450 pathways. Lolium multiflorum L., is a weed that frequently appears in wheat fields and is recognized for its strong competitive nature, where it can cause significant damage to grain production. The weeds of L. multiflorum in the wheat fields may have developed resistance to mesosulfuron-methyl. This study explored the response of L. multiflorum populations in certain areas of Henan Province, China, to mesosulfuron-methyl. The study found that, compared to the HX1 sensitive population, the HZ1 and HZ2 populations showed resistance to mesosulfuron-methyl in the full dose-response test, with resistance ratios of 12.38- and 24.19-fold, respectively. Genetic sequencing revealed novel mutations at the Pro-197-Thr and Asp-376-Glu residues of the ALS gene in both resistant populations. A critical finding was the divergent resistance mechanisms between the geographically close populations, with HZ1 resistance solely conferred by target-site mutations and HZ2 exhibiting multiple resistance driven by both target-site mutations and enhanced metabolism mediated by cytochrome P450 monooxygenases. This was conclusively demonstrated by applying the P450 inhibitors malathion and PBO, which reversed resistance in HZ2 by 66.77% and 70.53%, respectively. Furthermore, both resistant populations showed heightened sensitivity to isoproturon, suggesting a potential management strategy. Molecular docking simulations corroborated that the identified mutations reduce herbicide binding affinity. Our findings provide the first evidence of concurrent target-site and non-target-site resistance to mesosulfuron-methyl in Chinese L. multiflorum, offering crucial insights for diagnosing and managing herbicide resistance.}, } @article {pmid41026411, year = {2025}, author = {Eraslan, A and Kose, O}, title = {Prevalence and patterns of adductor lesions on MRI in athletes with osteitis pubis.}, journal = {Journal of orthopaedics and traumatology : official journal of the Italian Society of Orthopaedics and Traumatology}, volume = {26}, number = {1}, pages = {65}, pmid = {41026411}, issn = {1590-9999}, mesh = {Humans ; Male ; Adult ; *Osteitis/diagnostic imaging/epidemiology ; Retrospective Studies ; Cross-Sectional Studies ; *Magnetic Resonance Imaging ; Adolescent ; Prevalence ; Young Adult ; Middle Aged ; *Athletic Injuries/diagnostic imaging/epidemiology ; Athletes ; Tendinopathy/diagnostic imaging/epidemiology ; *Tendon Injuries/diagnostic imaging/epidemiology ; }, abstract = {PURPOSE: Adductor lesions (ALs) frequently coexist with osteitis pubis (OP) in athletes, yet the prevalence and clinical impact of different AL types have not been comprehensively evaluated. This study aimed to determine the frequency of various AL types using magnetic resonance imaging (MRI) and to investigate their association with clinical outcomes in athletes with OP.

MATERIALS AND METHODS: This retrospective cross-sectional study included male athletes aged 18-45 years with MRI-confirmed OP. ALs were classified into four types on the basis of MRI: type 1 (strain), type 2 (tendon avulsion), type 3 (tendinopathy), and type 4 (secondary cleft sign). Types 1-2 were considered acute, and types 3-4 chronic lesions. The relationships between AL types, age, symptom side, return to sport (RTS), and hip outcome score (HOS) were analyzed.

RESULTS: Among 132 athletes with OP, 90% had concurrent AL, while 10% had isolated OP. Type 3 AL was the most frequent type (77.3%), followed by type 4 (23.5%), type 1 (15.9%), and type 2 (2.3%). Logistic regression revealed that type 3 was more likely to be found in younger athletes, while types 1 and 4 were found in older athletes. Although 95% of athletes had bilateral OP, 72% reported unilateral symptoms. The symptom side showed better consistency with the AL side than the OP side (Cohen's kappa = 0.489 versus 0.057). All athletes were treated conservatively, 50 chronic AL cases were applied also injection (31 corticosteroid-CS, 19 platelet reach plasma-PRP). Athletes with isolated OP achieved a higher RTS rate than those with AL (100% versus 75%, p = 0.033). RTS rates were higher in acute AL cases than in chronic cases (91% versus 72%) and in CS injections than in PRP injections (80% versus 63%), but without statistical significance. HOS scores were comparable across groups.

CONCLUSIONS: Adductor lesions, particularly chronic types, are highly prevalent in athletes with OP. While age influences the type of AL, the symptom side is compatible with the AL side, regardless of the type. RTS rates are more satisfactory in isolated OP and acute AL cases, but chronic AL cases were less successful in RTS outcomes despite injection treatments. These findings underscore the importance of identifying and classifying ALs for prognosis and treatment strategy in athletic groin pain.

LEVEL OF EVIDENCE: level IV, retrospective cohort study.}, } @article {pmid41026994, year = {2025}, author = {Nakken, O and Vaage, AM and Stigum, H and Bjornevik, K and Holmoy, T and Meyer, HE}, title = {Duration of Current Statin Use and Amyotrophic Lateral Sclerosis Risk: A Norwegian Population-Based Cohort Study.}, journal = {Neurology}, volume = {105}, number = {8}, pages = {e214221}, doi = {10.1212/WNL.0000000000214221}, pmid = {41026994}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Norway/epidemiology ; Male ; Female ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects/administration & dosage/therapeutic use ; Middle Aged ; Adult ; Aged ; Cohort Studies ; Risk Factors ; Time Factors ; Hypercholesterolemia/drug therapy ; }, abstract = {BACKGROUND AND OBJECTIVES: Although hypercholesterolemia may contribute to long-term amyotrophic lateral sclerosis (ALS) risk, it can also seem as a secondary effect during the early, prediagnostic phase of the disease. We aimed to investigate the relationship between short-term and long-term use of statins and subsequent ALS risk.

METHODS: We designed a cohort study where information on cardiovascular risk factors among Norwegian participants in large population-based health surveys was linked to nationwide administrative data on subsequent statin use and ALS diagnosis. Duration of statin use was calculated based on cumulative defined daily doses and analyzed as time-varying exposure with 3 levels: 0-1 year (short-term), 1-5 years, and 5-17 years (long-term). In Cox regression models adjusted for sex, age, health survey participation, triglyceride and cholesterol levels, body mass index, smoking, diabetes, and hypertension, we calculated hazard ratios (HRs) for ALS according to time-varying statin exposure. In a negative control analysis, we examined whether exposure to renin-angiotensin system (RAS)-acting agents was associated with ALS risk.

RESULTS: A total of 425,564 participants (54% women), aged 40-65 years in January 2005, were followed for a mean period of 16 years (SD 2.3) during which 493 ALS cases (44% women) were identified. Compared with no current statin use, the HR for ALS was 3.56 (95% CI 2.58-4.90) for those with 0-1 year, 0.85 (95% CI 0.59-1.23) for those with 1-5 years, and 0.67 (95% CI 0.45-1.00) for those with 5-17 years of current use. The associations between both short-term and long-term statin use and ALS risk were most evident in men, with HRs for ALS of 4.03 (95% CI 2.72-5.95) and 0.47 (95% CI 0.26-0.86), respectively. There was no clear association between either short-term or long-term use of RAS-acting agents and ALS risk.

DISCUSSION: The strong association between short-term current statin use and increased ALS risk is consistent with reverse causality, where statin initiation in the prediagnostic phase may occur when lipid levels rise and individuals seek medical attention due to emerging ALS symptoms. Long-term statin use was associated with reduced risk of ALS in men.}, } @article {pmid41028049, year = {2025}, author = {Spiteri, AG and Steele, JR and Lee, HC and Zhang, H and Sun, J and Schittenhelm, RB and Yu, CH and McLean, C and Masters, CL and Goudey, B and Jin, L and Pan, Y}, title = {Proteomic analysis of brain and spinal cord tissue reveals distinct immune and mitochondrial processes between human and mouse ALS models.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {33959}, pmid = {41028049}, issn = {2045-2322}, support = {GNT2007912//National Health and Medical Research Council/ ; GNT2022203//NHMRC-AMED 2022 Dementia Collaborative Research/ ; AARF1020292//Alzheimer's Association grant/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/immunology/pathology/genetics ; *Spinal Cord/metabolism/pathology/immunology ; Humans ; Disease Models, Animal ; Mice ; *Proteomics/methods ; *Mitochondria/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Mice, Transgenic ; *Brain/metabolism/pathology/immunology ; *Proteome ; Motor Neurons/metabolism ; Male ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in the progressive loss of motor neurons in the brain and spine. More than 95% of cases are pathologically characterized by the cytoplasmic accumulation of hyperphosphorylated and ubiquitinated transactive response DNA-binding protein 43 (TDP-43). Multiple mouse models with TDP-43 accumulation have been developed, however, whether they recapitulate molecular features of ALS pathology is unclear. Given the lack of curative treatment for ALS, there is an urgent need to identify the precise biological processes contributing to disease pathogenesis for the development of effective therapeutic treatments. Thus, in this study we employed label-based untargeted proteomics to characterize the ALS proteome and related biological processes in the spinal cord and brain of TDP-43[Q331K] mice, a transgenic mouse model of ALS and the motor cortex and the cervical, thoracic, and lumbar spinal cord regions from humans. In humans, we observed highly overlapping responses across the four tissues examined, primarily related to the upregulation of immune processes and the downregulation of mitochondrial function. In contrast, TDP-43[Q331K] mice demonstrate a lack of enrichment for immune activation and the opposite regulation of mitochondrial processes. A meta-analysis of previously published mouse datasets identified the Ubqln2 knock-out mouse model as showing stronger parallels with our late-stage human ALS. Overall, this study provides in-depth analysis of the site-specific dysregulated proteomes and their associated functional processes across species. Thereby, identifying potential therapeutic targets while emphasizing the limitations of specific mouse models at certain timepoints in recapitulating ALS-related processes for future model development.}, } @article {pmid41028808, year = {2025}, author = {Rawat, A and Khurana, S and Verma, S and Dhawan, U and Gourie-Devi, M and Ganguly, NK and Taneja, V}, title = {Insights from meta-analysis and experimental validation identify exosomal miR-146a-5p as a potential biomarker for sporadic amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {33846}, pmid = {41028808}, issn = {2045-2322}, support = {2020-2641/CMB/ADHOC-BMS//Indian Council of Medical Research/ ; 3/1/2/151/Neuro/2021-NCD-I//Indian Council of Medical Research/ ; 420804-07627//Research Development Program, Sir Ganga Ram Hospital/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood/mortality ; Humans ; *MicroRNAs/genetics/blood/metabolism ; Biomarkers/blood/metabolism ; *Exosomes/genetics/metabolism ; Male ; Female ; Gene Expression Profiling ; Middle Aged ; }, abstract = {MicroRNAs (miRNAs) have emerged as key regulators in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite growing evidence that miRNAs exhibit altered expression profiles in ALS, their utility as a biomarker remains limited. To address this, we conducted a meta-analysis using the Robust Rank Aggregation package, incorporating 20 differential miRNA profiling studies. Among these, miR-146a-5p emerged as the most dysregulated and significant miRNA in ALS (P = 0.0000142, P-adj = 0.0096), particularly in extracellular vesicle-derived studies. To evaluate its diagnostic accuracy, we validated miR-146a-5p expression in serum-derived exosomes and observed a significant increase in sporadic ALS (sALS) patients (n = 22) as compared to healthy controls (n = 18). Moreover, higher levels of miR-146a-5p were strongly associated with longer survival (≥ 5 years) (P = 0.0135), with a positive correlation between miR-146a-5p expression and survival duration (P = 0.0313) in sALS patients. Further, gene set enrichment analysis of miR-146a-5p target genes highlighted critical involvement of the Immune system and NF-kappa B signaling pathways in ALS pathophysiology. These findings highlight miR-146a-5p as a potential biomarker for ALS.}, } @article {pmid41028829, year = {2025}, author = {Jiang, Q and Yang, D and Jiang, R and Wan, S and Wu, M and Xu, D and Zhou, J}, title = {Analysis of factors influencing sleep disorders in patients with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {34104}, pmid = {41028829}, issn = {2045-2322}, support = {2025AFD532//Hubei Provincial Natural Science Foundation (Joint Fund)/ ; 2024AFD279//Hubei Provincial Natural Science Foundation (Joint Fund)/ ; 2023AFD128//Hubei Provincial Natural Science Foundation (Joint Fund)/ ; GZY-KJS-2025-008//Science and Technology Special Project of State Administration of Traditional Chinese Medicine/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Female ; Middle Aged ; *Sleep Wake Disorders/etiology/epidemiology/complications ; Cross-Sectional Studies ; Aged ; Fatigue/complications ; Adult ; Sleep Quality ; Anxiety/complications ; Disease Progression ; Pain ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease frequently accompanied by sleep disorders. Conventional insomnia interventions are often unsuitable for ALS patients due to cognitive and respiratory impairments. There is a lack of targeted studies addressing sleep-related issues using multifactorial analyses specific to this group. This cross-sectional study included 266 ALS patients at the Motor Neuron Disease Rehabilitation and Treatment Center of Hubei Provincial Hospital of Traditional Chinese Medicine. Participants were evaluated using tools like the Pittsburgh Sleep Quality Index (PSQI) and ALS Functional Rating Scale-Revised (ALSFRS-R). Regression models identified factors affecting sleep disorders and quality. Patients with sleep disorders were more likely to have non-motor symptoms like anxiety, depression, pain, and excessive daytime sleepiness compared to those without. Fatigue severity and anxiety levels were identified as independent influencing factors of sleep disorders. Additionally, fatigue, anxiety, pain intensity, and disease progression rate were significantly linked to sleep quality. This study is the first comprehensive analysis of sleep-related factors in Chinese ALS patients, highlighting the crucial roles of fatigue, anxiety, pain, and disease progression rate. It provides a basis for future personalized, non-pharmacological interventions tailored to the specific needs of ALS patients.}, } @article {pmid41029500, year = {2025}, author = {Aljaberi, HA and Rahmani, S and Naji, AM}, title = {Correlation between refractive errors and ocular biometric parameters at Al-Mustaqbal University, Iraq.}, journal = {BMC ophthalmology}, volume = {25}, number = {1}, pages = {517}, pmid = {41029500}, issn = {1471-2415}, mesh = {Humans ; Male ; Female ; Cross-Sectional Studies ; Adult ; Iraq/epidemiology ; Young Adult ; *Biometry/methods ; Adolescent ; *Cornea/pathology ; *Axial Length, Eye/pathology ; *Refractive Errors/epidemiology/physiopathology/diagnosis ; *Refraction, Ocular/physiology ; Universities ; Corneal Pachymetry ; }, abstract = {PURPOSE: To establish the relationship between ocular biometry and refractive errors in young adult Iraqis by analyzing three critical biometric ocular parameters, including axial length (AL), corneal radius (CR), and central corneal thickness (CCT).

METHODS: A cross-sectional study was conducted on individuals aged 18-33 years at Al-Mustaqbal University, Iraq, including 1841 participants (3682 eyes). Quantitative measurements of AL, CR, and CCT were obtained using an Auto Kerato-Refractometer, IOL Master, and pachymetry techniques. Statistical analyses included Pearson correlation, multiple linear regression, one-way ANOVA, and independent samples t-tests to compare biometric parameters between refractive error groups. Generalized Estimating Equations (GEE) were applied to account for the correlation between fellow eyes.

RESULTS: The overall mean AL was 24.45 ± 1.10 mm, mean CR was 7.37 ± 0.77 mm, and mean CCT was 555.83 ± 50.83 μm. Myopic participants had a significantly longer AL (25.11 ± 0.42 mm) compared to hyperopic participants (22.71 ± 0.65 mm; p < 0.001). Likewise, myopic eyes had significantly thicker corneas (CCT: 565.62 ± 12.68 μm) than hyperopic eyes (495.42 ± 18.74 μm; p < 0.001), as determined by independent samples t-tests. Females exhibited slightly longer ALs than males across both myopic and hyperopic groups (p < 0.0001). Regression analysis showed that AL was the strongest predictor of spherical equivalent (SE), followed by CR and CCT. The regression model including AL and CR explained 94.5% of the variance in SE (R² = 0.945).

CONCLUSIONS: The findings confirm that AL and CCT are strongly associated with refractive errors, with AL being a primary determinant. This study highlights the role of gender differences in biometric ocular parameters and provides valuable insights into the prevalence of refractive errors in young adults in Iraq. These results can inform future public health initiatives aimed at addressing refractive errors in this population.}, } @article {pmid41030957, year = {2025}, author = {Coneys, R and Cammack, AJ and Nair, RR and Thompson, D and Mechtersheimer, J and Carcolé, M and Gupta, Y and Rech, GE and Flower, M and O'Brien, N and Ruepp, MD and Mizielinska, S and Ducotterd, F and Tabrizi, SJ and Fisher, EMC and Cunningham, TJ and Ward, M and Skarnes, WC and Isaacs, AM}, title = {Generation of C9orf72 repeat knock-in iPSC lines for modelling ALS and FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41030957}, issn = {2692-8205}, abstract = {Induced pluripotent stem cell (iPSC) models are powerful tools for neurodegenerative disease modelling, as they allow mechanistic studies in a human genetic environment and they can be differentiated into a range of neuronal and non-neuronal cells. However, these models come with inherent challenges due to line-to-line and clonal variability. To combat this issue, the iPSC Neurodegenerative Disease Initiative (iNDI) has generated an iPSC repository using a single clonal reference line, KOLF2.1J, into which disease-causing mutations and revertants are introduced via gene editing. Here we describe the generation and validation of lines carrying the most common causative mutation for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a repeat expansion in the C9orf72 gene, for the iNDI collection of neurodegenerative iPSC models. We demonstrate that these C9orf72 knock-in lines differentiate efficiently into neurons and display characteristic C9orf72-associated pathologies, including reduced C9orf72 levels and the presence of dipeptide repeat proteins (DPRs) and RNA foci, which increase in abundance over time in culture. These pathologies are not present in revertant cells lacking the repeat expansion. These repeat expansion and revertant cell lines are now available to academic and for-profit institutions through the JAX iPS cell repository and will help to facilitate and standardise iPSC-based ALS/FTD research.}, } @article {pmid41030970, year = {2025}, author = {Peethambaran Mallika, A and Yu, JG and Sitzman, O and Baghel, MS and Renganathan, S and Sinha, IR and Melnikova, T and Ling, JP and Wong, PC}, title = {Symptomatic treatment by a BBB-permeable AAV engineered to restore TDP-43 function slows motor neuron disease and prevents paralysis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41030970}, issn = {2692-8205}, support = {R01 NS095969/NS/NINDS NIH HHS/United States ; R33 NS115161/NS/NINDS NIH HHS/United States ; }, abstract = {TAR DNA-binding protein 43kDa (TDP-43) dysfunction is an early pathogenic mechanism that underlies amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder that lacks disease modifying therapies. We previously developed a mouse model in which TDP-43 is selectively deleted from motor neurons (ChAT-Cre;Tardbp [f/f]) that mimics the early stages of ALS. Here, we demonstrate that intravenous delivery of a blood-brain-barrier (BBB) permeable AAV capsid expressing our rationally designed splicing repressor CTR (AAV-PHP.eB-CTR) in symptomatic ChAT-Cre;Tardbp [f/f] mice markedly slowed disease progression and prevented paralysis. Systemic delivery of AAV-PHP.eB-CTR led to transduction of ~80% of spinal motor neurons, repression of TDP-43-associated cryptic exons within motor neurons expressing CTR, and attenuation of motor neuron loss. Notably, the addition of the TARDBP 3'UTR autoregulatory element to CTR maintained its expression within a physiological range. In control littermates that received AAV-PHP.eB-CTR and were monitored for >20 months, grip strength and body weight remained normal, and no histopathological abnormalities were observed, underscoring a favorable safety profile for this gene therapy. These results provide preclinical proof-of-concept that BBB-crossing AAV delivery of CTR can rescue motor neuron disease through the restoration of TDP-43 function, offering a promising mechanism-based therapeutic strategy for ALS.}, } @article {pmid41032491, year = {2025}, author = {Burkhill, L and Davies, TM}, title = {A case study exploring the management of dyspnoea in motor neurone disease.}, journal = {British journal of community nursing}, volume = {30}, number = {10}, pages = {488-492}, doi = {10.12968/bjcn.2025.0023}, pmid = {41032491}, issn = {1462-4753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/nursing ; Analgesics, Opioid/therapeutic use ; *Dyspnea/etiology/therapy/nursing ; *Motor Neuron Disease/complications ; Quality of Life ; United Kingdom ; }, abstract = {Motor neurone disease affects around 5000 people in the UK at any given time. It is a progressive disease with a poor prognosis and carries a high symptom burden. Dyspnoea (breathlessness) is one of its most challenging yet common symptoms and occurs because of a weakening of the muscles that control breathing. This case study explores the management of a man diagnosed with amyotrophic lateral sclerosis in the community. His advance decision to refuse treatment directive to avoid non-invasive ventilation during the day was managed through a combination of opioid medication, breath stacking, positioning and other strategies recommended by the National Institute for Health and Care Excellence. Individualised care planning and maintaining quality of life was key in his management.}, } @article {pmid41032625, year = {2025}, author = {Rosenberg, GM and Murray, KA and Sawaya, MR and Jiang, YX and Geschwind, DH and Eisenberg, DS}, title = {Genetic and structural aspects of amyloid diseases.}, journal = {Science translational medicine}, volume = {17}, number = {818}, pages = {eadp3378}, doi = {10.1126/scitranslmed.adp3378}, pmid = {41032625}, issn = {1946-6242}, support = {R01 AG048120/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyloidosis/genetics ; *Amyloid/chemistry/genetics/metabolism ; Mutation/genetics ; Animals ; }, abstract = {The conversion of proteins into insoluble fibrillar aggregates known as amyloid occurs in a wide variety of diseases, e.g., Alzheimer's disease, amyotrophic lateral sclerosis, systemic transthyretin amyloidosis, and multisystem atrophy. There are more than 60 disease-associated amyloid-forming proteins, and amyloid formation can occur sporadically or can be induced or accelerated by genetic mutations. This Review discusses structural mechanisms by which genetic changes promote amyloid formation and thereby influence disease outcomes. By dividing amyloid-forming proteins into six types according to the genetic mutations they carry and analyzing mutation-induced structural changes in amyloid fibrils, a better understanding of inheritance patterns of amyloid diseases (amyloidoses) can be obtained.}, } @article {pmid41033144, year = {2025}, author = {Bicaj, M and Oliveri, F and Rossi, C and Rosano, A and Uccelli, A and Caponnetto, C and Ferraro, PM}, title = {Development of cognitive/behavioral disturbances in motor neuron diseases with pure motor onset: can we predict it?.}, journal = {Journal of the neurological sciences}, volume = {478}, number = {}, pages = {123707}, doi = {10.1016/j.jns.2025.123707}, pmid = {41033144}, issn = {1878-5883}, mesh = {Humans ; Male ; Female ; *Motor Neuron Disease/complications/psychology/diagnosis ; Middle Aged ; Aged ; Disease Progression ; Longitudinal Studies ; *Cognition Disorders/etiology/diagnosis ; Age of Onset ; Neuropsychological Tests ; Adult ; *Mental Disorders/etiology/diagnosis ; }, abstract = {BACKGROUND: Approximately 50 % of motor neuron disease (MND) patients manifest cognitive and/or behavioral impairment (C/BI). Notably, while some patients exhibit those disturbances from disease onset, others develop them during disease course, but the determinants of such phenomenon are still largely unknown.

OBJECTIVES: This study aimed at identifying baseline predictors of subsequent C/BI development in MNDs.

METHODS: Pure motor MND cases with longitudinal Edinburgh Cognitive and Behavioral ALS screen (ECAS) exams were included (N = 80). Based on longitudinal data, patients were categorized as either remaining motor ("non-converters", N = 55) or developing C/BI ("converters", N = 25). Demographic, genetic, baseline motor and cognitive/behavioral features (with relative progression rates) were compared between groups using Mann-Whitney U and Chi-squared tests. Logistic regression models were used to identify significant predictors of C/BI development.

RESULTS: Relative to non-converters, converters cases exhibited older age at symptoms onset/first visit (p = 0.02, p = 0.01), lower frequency of right limbs onset (p = 0.02), lower ECAS alternation (p = 0.01), spelling (p = 0.02) and fluency letter S (p = 0.05) scores, as well as higher alternation (p = 0.004) and spelling (p = 0.006) progression rates, albeit those contrasts did not survive correction for multiple comparisons. All variables except for the spelling score and progression rates were predictive of C/BI development (p from 0.002 to 0.03).

DISCUSSION: While no firm conclusions can be drawn due to the lack of results surviving correction, our study suggests that specific clinical features significantly predict C/BI development in MNDs. These findings may facilitate an earlier identification of patients at risk for extra-motor symptoms development, enabling a more tailored clinical management.}, } @article {pmid41034394, year = {2025}, author = {Torres, P and Pradas, I and Fernàndez-Bernal, A and Povedano, M and Dominguez, R and Jové, M and Gonzalez-Mingot, C and Ayala, V and Ferrer, I and Pamplona, R and Portero-Otin, M}, title = {Exploring platelet metabolomics and fatty acid profiles for ALS prognosis and diagnosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {34236}, pmid = {41034394}, issn = {2045-2322}, support = {Margarita Salas//Spanish Ministry of Universities/ ; 2023 BP 00144//Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya/ ; PIRS Program//Diputació de Lleida/ ; 2017SGR696 and SLT002/16/00250//Generalitat de Catalunya/ ; RTI2018-099200-B-I00//Spanish Ministry of Science, Innovation and Universities/ ; PI20/0155//Instituto de Salud Carlos III/ ; PI23/00176//Instituto de Salud Carlos III/ ; Jack Van den Hoek Donation//Fundació Miquel Valls/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism/blood ; *Metabolomics/methods ; *Fatty Acids/metabolism/blood ; Male ; Female ; Middle Aged ; Prognosis ; Biomarkers/blood/metabolism ; *Blood Platelets/metabolism ; Aged ; Disease Progression ; Adult ; *Metabolome ; Case-Control Studies ; ROC Curve ; Gas Chromatography-Mass Spectrometry ; Chromatography, Liquid ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with heterogeneous clinical progression, reflecting distinct underlying pathological mechanisms. Early and accurate diagnosis and prognosis require reliable biomarkers to improve clinical management and therapeutic stratification. The present study explores the potential of platelet global metabolomics and fatty acid (FA) profiling as potential sources of diagnostic and prognostic biomarkers for ALS. We analysed platelets from 15 recently diagnosed ALS patients and 21 healthy controls (CTLs) using liquid chromatography-mass spectrometry (LC-MS) for metabolomics and gas chromatography-flame ionization detection (GC-FID) for FA profiling. ALS patients were classified as fast or slow progressors based on the median ALS Functional Rating Scale-Revised (ALSFRS-R) slope. While global metabolomic and FA profiles have shown limited potential for distinguishing ALS from CTL, preliminary molecular annotation based on mass and retention times disclosed specific metabolites with potential diagnostic value. Importantly, both global metabolomic and FA analyses demonstrated a marked capacity to differentiate fast progressors from slow progressors (receiver operating characteristic (ROC) curves of approximately 1), revealing distinct metabolic signatures associated with disease progression. Our findings demonstrate that platelet global metabolomics and FA profiling hold promise as prognostic biomarkers in ALS.}, } @article {pmid41034505, year = {2026}, author = {Song, X and Wu, W and Varshney, M and Roman, A and Gustafsson, JÅ and Warner, M}, title = {Role of LXRβ in oligodendrocytes in neuronal survival.}, journal = {Molecular psychiatry}, volume = {31}, number = {1}, pages = {16-26}, pmid = {41034505}, issn = {1476-5578}, mesh = {Animals ; *Oligodendroglia/metabolism/physiology ; *Liver X Receptors/metabolism/genetics ; Cell Survival/physiology/genetics ; Mice ; Mice, Knockout ; Motor Neurons/metabolism/physiology ; Brain-Derived Neurotrophic Factor/metabolism/genetics ; Cell Differentiation/genetics/physiology ; Symporters/metabolism/genetics ; Glutamate-Ammonia Ligase/metabolism/genetics ; Hydroxymethylglutaryl CoA Reductases/metabolism ; Dopaminergic Neurons/metabolism ; Neurons ; Cells, Cultured ; Spinal Cord/metabolism ; }, abstract = {We have reported that mice in which the liver X receptor β (LXRβ) gene is inactivated lose dopaminergic neurons in the substantia nigra and motor neurons in the ventral horn of the spinal cord. These mice develop progressive hind limb paralysis starting at 6 months of age. Since LXRβ is not expressed in either dopaminergic neurons or motor neurons, we have focused on LXRβ-expressing cells whose function is essential for neuron survival. We now report defects in oligodendrocyte maturation in the absence of LXRβ. At 4 months of age, long before motor neuron loss occurs, there was reduction in expression of the four following genes in oligodendrocytes: The monocarboxylate transporter 1 (MCT1), which is essential for metabolic support of motor neurons; BDNF, a motor neuron trophic factor; 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis; glutamine synthetase (GS), an enzyme crucial for the elimination of neurotoxic glutamate from synapses. Differentiation of ES cells from WT and LXRβ[-/-] mice into motor neurons/oligodendrocytes revealed that LXRβ[-/-] cultures showed less arborization of motor neurons and a reduced proportion of mature oligodendrocytes. Our study suggests that defects in glial cells can have profound effects on neuronal survival and that early defective oligodendrocyte maturation can lead to motor neuron death. The expression of LXRβ in oligodendrocytes should be investigated as a target for preventing neuronal loss in diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson's disease.}, } @article {pmid41034581, year = {2025}, author = {Michaelis, T and Lindestam Arlehamn, CS and Johansson, E and Frazier, A and Williams, GP and Berry, JD and Cudkowicz, M and Goyal, NA and Fournier, C and Snyder, A and Kwan, JY and Crook, J and Phillips, EJ and Mallal, SA and Ravits, J and Marder, KS and Sidney, J and Sulzer, D and Sette, A}, title = {Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis.}, journal = {Nature}, volume = {647}, number = {8091}, pages = {970-978}, pmid = {41034581}, issn = {1476-4687}, mesh = {*Amyotrophic Lateral Sclerosis/immunology/pathology/genetics ; *C9orf72 Protein/immunology ; Humans ; Interleukin-10/immunology/metabolism ; Female ; *Autoimmunity/immunology ; Male ; Interleukin-5/immunology/metabolism ; Middle Aged ; CD4-Positive T-Lymphocytes/immunology ; Disease Progression ; Aged ; T-Lymphocytes, Regulatory/immunology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive loss of motor neurons. Neuroinflammation is apparent in affected tissues, including increased T cell infiltration and activation of microglia, particularly in the spinal cord[1,2]. Autoimmune responses are thought to have a key role in ALS pathology, and it is hypothesized that T cells contribute to the rapid loss of neurons during disease progression[3,4]. However, until now there has been no reported target for such an autoimmune response. Here we show that ALS is associated with recognition of the C9orf72 antigen, and we map the specific epitopes that are recognized. We show that these responses are mediated by CD4[+] T cells that preferentially release IL-5 and IL-10, and that IL-10-mediated T cell responses are significantly greater in donors who have a longer predicted survival time. Our results reinforce the previous hypothesis that neuroinflammation has an important role in ALS disease progression, possibly because of a disrupted balance of inflammatory and counter-inflammatory T cell responses[4]. These findings highlight the potential of therapeutic strategies aimed at enhancing regulatory T cells[5], and identify a key target for antigen-specific T cell responses that could enable precision therapeutics in ALS.}, } @article {pmid41034691, year = {2025}, author = {Farrag, AMAS and Ota, K and Yoshimura, H and Takemoto, M and Mitarai, T and Kamikawa, T and Abo, M and Singh, VP and Cui, C and Zhou, L and Ishidate, F and Fujiwara, T and Sato, SI and Hori, Y and Ozawa, T and Kikuchi, K and Uesugi, M}, title = {Live-Cell Monitoring and Omics Analysis of Liquid-Solid Transitions of Biomolecular Condensates.}, journal = {Journal of the American Chemical Society}, volume = {147}, number = {41}, pages = {37056-37064}, doi = {10.1021/jacs.5c07340}, pmid = {41034691}, issn = {1520-5126}, mesh = {Humans ; *Biomolecular Condensates/chemistry/metabolism ; *Bacterial Proteins/chemistry/metabolism ; Flow Cytometry ; DNA-Binding Proteins/genetics/chemistry/metabolism ; Phase Transition ; Proteomics ; Photoreceptors, Microbial ; }, abstract = {Biomolecular condensates, or so-called membraneless organelles, transition from liquid into more solid-like states over time, contributing to the development of pathological conditions. The present study proposes a simple method using photoactive yellow protein (PYP) and its specific fluorescent covalent ligands to distinguish between the liquid and solid states of protein condensates in live cells. The method, compatible with fluorescence-activated cell sorting (FACS), correlates the stiffness of specific protein condensates with their accessibility to PYP ligands, enabling quantitative multicolor monitoring of condensate solidification. We applied this technique to 12 phase-separating proteins and their mutants, finding that TDP-43, particularly its A315T mutant linked to familial amyotrophic lateral sclerosis, most readily forms solid aggregates. Furthermore, this FACS-compatible strategy enabled the isolation of distinct cell populations based on condensate states, allowing for subsequent proteomic and transcriptomic analyses. Our findings demonstrate that condensate solidification is accompanied by the upregulated expression of extracellular matrix proteins, suggesting a previously unrecognized link between solid aggregate formation and extracellular matrix hardening.}, } @article {pmid41034919, year = {2025}, author = {Liu, Y and Guo, R and Wang, N and Yang, Y and Li, J and Jing, D and Cui, R and Ma, R and Ma, J}, title = {Integrated molecular data analysis confirms PDK1 as a candidate risk factor in ALS pathophysiology.}, journal = {Molecular brain}, volume = {18}, number = {1}, pages = {76}, pmid = {41034919}, issn = {1756-6606}, support = {H2023206266//the Natural Science Foundation of Hebei Province/ ; CYQD2023005//the Hebei Medical University Chunyu Project/ ; 241200073A//the Industry-University-Research Project of Universities Stationed in Hebei in collaboration with Shijiazhuang/ ; 25292401D//Hebei Province International Science and Technology Cooperation Key Project/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/physiopathology/enzymology ; Humans ; Animals ; Risk Factors ; *Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism/genetics ; HEK293 Cells ; Mice, Transgenic ; *3-Phosphoinositide-Dependent Protein Kinases/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Gene Expression Profiling ; Mice ; *Genetic Predisposition to Disease ; Gene Ontology ; }, abstract = {Combining cellular, animal, and MR analyses from three independent cohorts, we identified PDK1 as a consistent risk factor for ALS development, highlighting its potential as a therapeutic target. To further elucidate PDK1's pathogenic mechanisms, we conducted transcriptomic profiling. Samples were stratified into PDK1 high- and low-expression groups. GO and KEGG analyses demonstrated that upregulated DEGs were enriched in pathways involving β-CATENIN, cell adhesion and Ribosome, suggesting a potential role for WNT/β-catenin signaling activation in ALS pathogenesis. To further validate the consistent risk association of PDK1 with ALS across multiple datasets, we utilized 4-month-old SOD1G93A transgenic mice, 4-month-old C9orf72 transgenic mice, and SOD1-overexpressing HEK293T cells. Significant upregulation of PDK1 mRNA was observed in all models, and a significant increase in protein abundance was found in SOD1G93A. This provides strong experimental evidence for the results of the MR study. These results indicate that PDK1 may affect the pathogenesis of amyotrophic lateral sclerosis through genetic variations and transcriptional dysregulation, and may play an important role in the occurrence and development of the disease.}, } @article {pmid41035727, year = {2025}, author = {Wanner, GK and Dworkin, M and Rosenbaum, RA}, title = {Statewide Prehospital Buprenorphine in Delaware: Two-Years of Paramedic-Initiated Medication for Opioid Use Disorder After Overdose.}, journal = {Delaware journal of public health}, volume = {11}, number = {3}, pages = {24-28}, pmid = {41035727}, issn = {2639-6378}, abstract = {The Delaware Division of Public Health, Office of Emergency Medical Services (EMS) implemented the first statewide program enabling paramedics throughout the state to initiate buprenorphine treatment for opioid use disorder (OUD) in the prehospital setting. Building on a model from Camden, New Jersey, this protocol was approved in 2022 in response to rising overdose deaths and was fully implemented across Delaware's advanced life support (ALS) EMS agencies in April 2023. Eligible patients-those 18 years or older, resuscitated with naloxone, and able to consent-received up to 24 mg of sublingual buprenorphine along with ondansetron for nausea. Between April 2023 and May 2025, paramedics administered 118 buprenorphine doses to 105 patients, with improvement in withdrawal symptoms reported after 63.6% of doses. Despite a rise in patient ineligibility due to altered mental status-likely linked to sedating adulterants,such as xylazine and medetomidine,in regional street drugs-paramedics increased the percentage of eligible patients accepting offered buprenorphine from 19.0% to 22.8% between the first and second year of the program. This protocol not only addresses acute overdose management in the field but also connects patients to ongoing care, aiming to reduce mortality and expand access to medications for opioid use disorder.}, } @article {pmid41036176, year = {2025}, author = {Toro, CA and Zhao, W and Garcia Silva, P and Retamal-Santibáñez, D and Rojas, F and Pan, J and Johnson, N and Duarte, Y and Cardozo, CP and Sáez, JC and van Zundert, B}, title = {Boldine as a neuroprotective agent against motor neuron degeneration in models of amyotrophic lateral sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1640590}, pmid = {41036176}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss. Current FDA-approved treatments offer only modest benefits. Connexins (Cx), proteins that mediate intercellular communication have emerged as potential therapeutic targets, with increased Cx hemichannel (HC) activity observed in ALS models, and blocking Cx HC activity prevents motor neuron loss in vitro. Boldine, a natural compound with both Cx HC-blocking and antioxidant properties, has shown neuroprotective potential. This study investigated boldine's effects in ALS models. In vitro, spinal cord cell cultures exposed to conditioned media from mutant SOD1[G93A] astrocytes showed a 50% reduction in motor neuron survival, elevated Cx HC activity, and increased reactive oxygen species (ROS). Boldine treatment significantly reduced Cx HC activity and ROS, and increased motor neuron viability. In vivo, oral boldine was well-tolerated in male mutant SOD1[G93A] mice starting at 7 weeks of age. Mice receiving 50 mg/kg/day showed a median survival increase of 9 days (132 vs. 123 days), though not statistically significant. Functional assessments revealed delayed disease progression: in the horizontal ladder rung walk test, boldine-treated mice exhibited a 36.8% reduction in crossing time and 21.2% fewer stepping errors. Improved scores were also observed on the Basso Mouse Scale at later stages, indicating preserved locomotor function. However, boldine had no significant effect in the rotarod test. These results support boldine's neuroprotective effects in ALS, particularly in fine motor coordination and locomotor performance. Its reduction of Cx HC activity and oxidative stress highlights boldine's promise as a potential therapeutic candidate for ALS.}, } @article {pmid41037122, year = {2025}, author = {Thakur, A and Sharma, R and Sharma, R and Devi, A}, title = {Neurodegeneration and aging: pathophysiology, diagnosis, and therapeutic targets.}, journal = {Inflammopharmacology}, volume = {33}, number = {11}, pages = {6485-6505}, pmid = {41037122}, issn = {1568-5608}, mesh = {Humans ; *Aging/physiology/pathology/metabolism ; *Neurodegenerative Diseases/diagnosis/physiopathology/therapy/drug therapy ; Brain/metabolism/pathology/physiopathology ; Animals ; Oxidative Stress/physiology ; Biomarkers/metabolism ; }, abstract = {Aging is the greatest risk factor for AD, ALS, PD, FTD, and HD. Neurons in the brain experience many changes as people age, negatively affecting their structure and function. It examines the key processes behind brain aging, such as age-related death of cells, failure of the cells' powerhouses, oxidative stress, incorrect protein shapes, brain inflammation, difficulty in cleaning the brain, and deterioration of blood vessels, and shows their impact on neurodegeneration. With age, there are difficulties in brain-blood circulation, less synaptic change, and fewer new neurons, which make the disease even worse. Informed by human and animal trials, we see that mitochondria work less efficiently in aging brain cells, while oxidative damage to DNA increases doubly to triply. In addition, too much tau, amyloid-β, and α-synuclein building up is tied to declining mental abilities in the elderly. We further evaluate new tests that help with early detection and classification, for example, using biomarkers in cerebrospinal fluid (CSF), blood panels, detailed brain scans, and AI algorithms. It stresses that more aging-specific trials, better integration of multi-omics, and increased interest in research on the gut-brain axis are important. The communication between the aging of the body and the brain is also explained. This article covers the main cellular, molecular, and clinical issues linked to brain aging and highlights important future research areas needed to develop effective treatments for aging people.}, } @article {pmid41037265, year = {2025}, author = {Zhu, X and Russell, ER and Lyall, DM and Ho, F and Mackay, DF and Pell, JP and Stewart, W}, title = {Traumatic Brain Injury and Risk of Amyotrophic Lateral Sclerosis.}, journal = {JAMA network open}, volume = {8}, number = {10}, pages = {e2535119}, pmid = {41037265}, issn = {2574-3805}, support = {R01 NS094003/NS/NINDS NIH HHS/United States ; U01 NS137500/NS/NINDS NIH HHS/United States ; U54 NS115322/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/etiology ; Male ; Female ; *Brain Injuries, Traumatic/complications/epidemiology ; Middle Aged ; Retrospective Studies ; Adult ; Aged ; United Kingdom/epidemiology ; Risk Factors ; Proportional Hazards Models ; }, abstract = {IMPORTANCE: History of traumatic brain injury (TBI) or repetitive head impacts is associated with an increased risk of neurodegenerative disease. This association has attracted attention in recent years through the relationship between contact sports participation and the increased risk of a number of neurodegenerative diseases, including motor neuron disease or amyotrophic lateral sclerosis (ALS). However, to date, the association between TBI in the community and ALS risk remains uncertain.

OBJECTIVE: To leverage population-level health records to explore the association between a history of TBI and subsequent ALS risk.

This retrospective cohort study accessed UK-wide electronic health record (EHR) data from individuals 18 years or older with TBI history and age-, sex-, and area deprivation-matched general population comparators. EHR data were available from January 1, 2005, to December 31, 2020, with database interrogation performed on February 11, 2021, and data analysis conducted between June 1, 2023, and October 3, 2024.

EXPOSURE: Documented history of TBI.

MAIN OUTCOMES AND MEASURES: Outcomes were obtained by individual-level linkage to EHR data available via Clinical Practice Research Datalink. Risk of ALS was evaluated using Cox proportional hazards regression models to investigate its association with TBI.

RESULTS: Overall, 85 690 adults with a history of TBI and 257 070 matched adults with no history of TBI were included, for a total of 342 760 participants (50.1% male; mean [SD] age, 50.7 [17.6] years). During a median 5.72 (IQR, 3.07-8.82) years of follow-up, providing 2.13 million person-years of follow-up, 150 incident ALS cases were recorded, resulting in 7.05 cases per 100 000 person-years. Risk of ALS was higher among individuals with a history of TBI compared with individuals without a TBI history (hazard ratio [HR], 2.61; 95% CI, 1.88-3.63). However, this association was time dependent, with risk confined to the 2 years following TBI (HR, 6.18; 95% CI, 3.47-11.00), but not thereafter.

CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of 342 760 adults, an association between TBI and subsequent risk of ALS was identified. However, this association was confined to the 2 years immediately following injury. As such, the association between TBI and higher ALS risk may indicate reverse causality, with TBI in some individuals perhaps reflecting a consequence of early, subclinical ALS.}, } @article {pmid41038449, year = {2025}, author = {Elshehawy, M and Kadambi, M and Hughes, D and Clarke, D and Cooper, A and Inani, M and Goktas, P and Goddard, S and Diwakar, L}, title = {Emergency management of anaphylaxis and the impact of the new UK advanced life support guidelines.}, journal = {Clinical medicine (London, England)}, volume = {25}, number = {6}, pages = {100519}, pmid = {41038449}, issn = {1473-4893}, mesh = {Humans ; *Anaphylaxis/therapy/diagnosis ; Retrospective Studies ; United Kingdom ; *Practice Guidelines as Topic ; Male ; Female ; Epinephrine/therapeutic use/administration & dosage ; Middle Aged ; Adult ; Aged ; Guideline Adherence/statistics & numerical data ; Histamine Antagonists/therapeutic use ; }, abstract = {BACKGROUND: Anaphylaxis is a severe, potentially life-threatening allergic reaction that requires urgent and effective management. The UK Resuscitation Council updated its advanced life support (ALS) guidelines for anaphylaxis in 2021, emphasising early and repeated adrenaline administration, intravenous (IV) fluid use, and reduced reliance on antihistamines and steroids.

METHODS: A retrospective audit was carried out to compare the management of anaphylaxis at two English NHS hospitals, namely the University Hospital of North Midlands (UHNM) and the Shrewsbury and Telford Hospital (SATH), before (2018) and after (2022/23) the ALS guideline implementation. Adherence to NICE anaphylaxis guidance was also assessed.

RESULTS: Data from 272 patients revealed significant improvements in recognition of anaphylaxis in 2022 compared with 2018 (70.8% vs. 50%; p=0.001). The use of adrenaline and IV fluids increased, whereas the use of antihistamines and steroids declined, aligning with the new guidance. Tryptase measurement (checked in 45% of patients) and specialist referral rates (67% at UHNM vs. 3% at SATH; p=0.0001) remained suboptimal at both centres. A case example highlights the risks of misdiagnosis and adrenaline overuse in patients with recurrent urticarial presentations.

CONCLUSION: Anaphylaxis management in these centres has changed in keeping with the new ALS guidelines, although antihistamines and steroids were still used in the acute management of around 50% of the patients. Adrenaline overuse may be an unintended consequence of the guideline, which needs monitoring. There may have been some improvement in anaphylaxis recognition, but serum tryptase measurement and referral to allergy specialists remain poor.}, } @article {pmid41040165, year = {2025}, author = {Horan-Portelance, L and Acri, DJ and Mann, A and Brooks, J and Bailey, HM and Gibbs, JR and DeCasien, AR and Cookson, MR}, title = {Integrative analysis reveals generalizable human neurodegenerative disease-associated glial states.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41040165}, issn = {2692-8205}, support = {Z01 AG000953/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Disease-associated glia represent plastic transcriptional cellular states observed across neurodegenerative diseases (NDDs). In particular, microglial states have been characterized in Alzheimer's disease and mouse models of amyloidosis. Although single-cell transcriptomic technologies have increased the dimensionality of information available across cell states, few studies have systematically tested for changes in glial transcription across brain regions and disease states. Here, we report a statistical framework for glial annotation, disease association, and transcriptional profiling, which facilitate identification of generalizable glial states that are present across a spectrum of NDDs (Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Frontotemporal dementia). We identify seven astrocyte substates, 14 microglia/myeloid substates, and five oligodendrocyte substates where transcriptional variability is attributable to region, disease, or batch effects. Regional heterogeneity of astrocytes masked disease associations, even within cortical astrocytes. We found only limited oligodendrocyte transcriptional heterogeneity, resulting in few substates for further interrogation. Notably, microglia showed the strongest evidence for disease association. We show, for the first time, that this association exists across the entire NDD spectrum. Using latent factor analysis, we created a consensus human neurodegenerative disease-associated microglia (hnDAM) signature, which we experimentally validated in 11 independent sample series. We demonstrate that the hnDAM signature is a statistically testable biomarker for conserved microglial activation in NDDs by: i) comparing to murine DAM-like signatures, ii) performing transcription factor analysis, and iii) modeling transcriptional reprogramming perturbations in iPSC-derived microglia. Taken together, this work broadens our understanding of glial activation across neuropathologies and reveals hnDAM as a putative therapeutic target that can be widely generalized to patients suffering from NDDs.}, } @article {pmid41040221, year = {2025}, author = {Uyan, Ö and Sambare, S and Oomen, ME and Wightman, N and Schooley, A and Klim, JR and Belaghzal, H and Aydemir, Ö and Akgol-Oksuz, B and Uslu, ZSA and Eggan, K and Brown, RH and Dekker, J}, title = {Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41040221}, issn = {2692-8205}, support = {R01 NS104022/NS/NINDS NIH HHS/United States ; R01 NS111990/NS/NINDS NIH HHS/United States ; R21 NS139270/NS/NINDS NIH HHS/United States ; }, abstract = {We have investigated changes in chromosome conformation, nuclear organization, and transcription during differentiation and maturation of control and mutant motor neurons harboring hexanucleotide expansions in the C9orf72 gene that cause amyotrophic lateral sclerosis (ALS). Using an in vitro reprogramming, differentiation and neural maturation protocol, we obtained highly purified populations of post-mitotic motor neurons for both normal and diseased cells. As expected, as fibroblasts are reprogrammed into iPSCs, and as iPSCs differentiate into motor neurons, chromatin accessibility, chromosome conformation, and nuclear organization change along with large-scale alterations in transcriptional profiles. We find that the transcriptome changes extensively during the first three weeks of post-mitotic neuronal maturation, with thousands of genes changing expression, but then is relatively stable for the next three weeks. In contrast, chromosome conformation and nuclear organization continue to change over the entire 6-week maturation period: chromosome territoriality increases, long-range interactions along chromosomes decrease, compartmentalization strength increases, and centromeres and telomeres increasingly cluster. In motor neurons derived from ALS patients such changes in chromosome conformation were much reduced. Chromatin accessibility changes also showed delayed maturation. The transcriptome in these cells matured relatively normally but with notable changes in expression of genes involved in lipid, sterol and mitochondrial function. We conclude that neural maturation is associated with large scale post-mitotic changes in gene expression, chromosome conformation and nuclear organization, and that these processes are defective in motor neurons derived from ALS patients carrying C9orf72 hexanucleotide repeat expansions.}, } @article {pmid41040384, year = {2025}, author = {Charalampopoulou, A and Taga, A and Rust, K and Luciani, E and Marshall, K and Montgomery, E and Mansinghka, A and Singh, R and Zhao, Y and O'Keefe, C and Wang, TH and Venkatesan, A and Habela, CW and Maragakis, NJ}, title = {Development of a Human iPSC-Derived "Corticospinal Tract-on-a-Chip" for Neurodegenerative Disease Research.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.09.24.678092}, pmid = {41040384}, issn = {2692-8205}, support = {K08 NS102526/NS/NINDS NIH HHS/United States ; }, abstract = {UNLABELLED: Degeneration of the corticospinal tract is a central feature in a number of neurodegenerative disorders and leads to significant disability. However, modeling corticospinal neuron (CSN) pathology and corticospinal connectivity in neurological disorders is particularly challenging. While rodent models are important for understanding early degeneration of CSN, interspecies differences in corticospinal connectivity and challenges of in vivo study suggest that human in vitro models of corticospinal biology may be ripe for development. Human induced pluripotent stem cells (hiPSC) are promising tools for overcoming intrinsic limitations that arise from physiological differences between rodents and humans. We have developed an innovative hiPSC-based microfluidic platform for modeling human CSN and spinal motor neuron (SpMN) connectivity. The incorporation of regionally specific astrocyte subtypes (cortical and spinal) in addition to CSNs and SpMNs in this newly designed system allows for the modeling of both regional and neural cell-subtype interactions. Using this model, multielectrode array electrophysiology reveals the maturation of both cortical and spinal motor neurons over the time course of 12 weeks. Retrograde labeling methods demonstrate synaptic connectivity between corticospinal and spinal motor neurons. Optogenetic strategies to selectively activate excitatory CNs attenuated by glutamate receptor antagonism confirms the functional relevance of the model. Incorporating morphological, electrophysiological and physiological measures of corticospinal connectivity, this platform is a versatile model for use in neurodegenerative disease research and for the future development of targeted CSN therapies.

SIGNIFICANCE STATEMENT: Degeneration of the corticospinal tract is a key feature of numerous neurodegenerative diseases, yet current in vitro models lack the anatomical and functional fidelity to study this system. We developed a human iPSC-derived "Corticospinal Tract-on-a-Chip" using a multielectrode array platform that incorporates regionally patterned cortical and spinal neurons and astrocytes. This model demonstrates structural and functional synaptic connectivity and enables longitudinal electrophysiological recordings. Critically, it supports compartment-specific manipulation and real-time analysis of CST network dynamics, capabilities lacking in existing systems. By mimicking human corticospinal physiology in vitro , this platform offers a novel tool for mechanistic investigation and preclinical testing of CST-targeted therapies. It holds broad relevance for studying disorders such as ALS, hereditary spastic paraplegia, and primary lateral sclerosis.}, } @article {pmid41040684, year = {2025}, author = {Kwan, JY and Lantz, CI and Korobeynikov, VA and Snyder, A and Huang, X and Haselhuhn, T and Dore, KN and Madruga, A and Danielian, LE and Schindler, AB and Chia, R and Rasheed, M and Crook, J and Szabo, M and Portley, M and Sherer, CM and King, MC and Huang, TH and Kosa, P and Bielekova, B and Ward, ME and Grunseich, C and Shneider, NA and Traynor, BJ and Narendra, DP}, title = {Clinical, neuropathological, and biochemical characterization of ALS in a large CHCHD10 R15L family.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41040684}, support = {ZIA NS003169/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Familial forms of ALS are potential candidates for gene-directed therapies, but many recently identified genes remain poorly characterized. Here, we provide a comprehensive clinical, neuropathological, and biochemical description of fALS caused by the heterozygous p.R15L missense mutation in the gene CHCHD10. Using a cross-sectional study design, we evaluate five affected and nine unaffected individuals from a large seven-generation pedigree with at least 68 affected members. The pedigree suggests a high (68 - 81%) but incomplete disease penetrance. Through cloning of the disease-allele from distant members of the family, we establish the disease haplotype in the family. Notably, the haplotype was distinct from that of a previously reported p.R15L mutation carrier with ALS, demonstrating that the variant is in a mutational hotspot. The clinical presentation was notable for being highly stereotyped; all affected individuals presented with the rare ALS variant Flail Arm Syndrome (FAS; also known as, brachial amyotrophic diplegia or Vulpian-Bernhardt Syndrome), suggesting greater involvement of the cervical spinal cord. Consistently, neuropathology from one family member demonstrated substantially increased CHCHD10 protein aggregation and neuronal loss (though absent TDP-43 pathology) in the cervical vs. lumbar spinal cord. This FAS phenotype could be captured by a simple timed finger tapping task, suggesting potential utility for this task as a clinical biomarker. Additionally, through analysis of fibroblast lines from 12 mutation carriers, isogenic iPSC cells, and a knockin mouse model, we determined that CHCHD10 with the R15L variant is stably expressed and retains substantial function both in cultured cells and in vivo, in contrast to prior reports. Conversely, we find loss of function (LoF) variants are more common in the population but are not associated with a highly penetrant form of ALS in the UK Biobank (31 in controls; 0 in cases). Together, this argues against LoF and in favor of toxic gain-of-function as the mechanism of disease pathogenesis, similar to the myopathy-causing variants in CHCHD10 (p.G58R and p.S59L). Finally, through proteomic analysis of CSF of variant carriers, we identify that CHCHD10 protein levels are elevated approximately 2-fold in mutation carriers, and that affected and unaffected individuals are differentiated by elevation of two neurofilaments: neurofilament light chain (NfL) and Peripherin (PRPH). Collectively, our findings help set the stage for gene-directed therapy for a devasting form of fALS, by establishing the likely disease mechanism and identifying clinical and fluid biomarkers for target engagement and treatment response.}, } @article {pmid41040692, year = {2025}, author = {Schone, HR and Yoo, P and Fry, A and Chetty, N and Sawyer, A and Herbers, C and Liu, F and Moon, CH and Hill, K and Majidi, S and Harel, NY and Nogueira, RG and Levy, E and Putrino, DF and Lacomis, D and Oxley, TJ and Weber, DJ and Collinger, JL}, title = {Motor Cortex Coverage Predicts Signal Strength of a Stentrode Endovascular Brain-Computer Interface.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41040692}, support = {F32 MH139145/MH/NIMH NIH HHS/United States ; L30 NS145938/NS/NINDS NIH HHS/United States ; UH3 NS120191/NS/NINDS NIH HHS/United States ; }, abstract = {Brain-computer interfaces (BCIs) are an emerging assistive technology for individuals with motor impairments, enabling the command of digital devices using neural signals. The Stentrode BCI is an implant, positioned within the brain's neurovasculature, that can record movement-related electrocortical activity. Over 5 years, 10 participants (8 amyotrophic lateral sclerosis, 1 primary lateral sclerosis, 1 brainstem stroke) have been implanted with a Stentrode BCI and significant inter-participant variability has been observed in the recorded motor signal strength. This variability warrants a critical investigation to characterize potential predictors of signal strength to promote more successful BCI control in future participants. Therefore, we investigated the relationship between Stentrode BCI motor signal strength and a variety of user-specific factors: (1) clinical status, (2) pre-implant functional activity, (3) peri-implant neuroanatomy, (4) peri-implant neurovasculature, and (5) Stentrode device integrity. Data from 10 implanted participants, including clinical demographics, pre- and post-implant neuroimaging and longitudinal Stentrode BCI motor signal assessments were acquired over a year. Across all potential predictors, the strongest predictor of Stentrode motor signal strength was the degree to which the Stentrode BCI's deployment position overlapped with primary motor cortex (M1). These findings highlight the importance of targeting M1 during device deployment and, more generally, provides a scientific framework for investigating the role of user-specific factors on BCI device outcomes.}, } @article {pmid41040969, year = {2025}, author = {Lotesto, V and Voisine, C}, title = {Reduced insulin-like signaling restores motor and chemosensory neuron function in C. elegans expressing TDP-43, an ALS-associated protein.}, journal = {microPublication biology}, volume = {2025}, number = {}, pages = {}, pmid = {41040969}, issn = {2578-9430}, abstract = {TAR DNA-binding Protein 43 (TDP-43) is linked to the pathology of neurodegenerative diseases. We used the roundworm Caenorhabditis elegans to examine the neurotoxic impact of the pan-neuronal expression of wild-type human TDP-43 (hTDP-43) fused to a yellow fluorescent protein. Using the daf-2 (e1370) mutant allele, we sought to determine whether activating cellular stress responses in the insulin-like signaling (ILS) pathway could restore neuronal function in hTDP-43 expressing C. elegans . Using well characterized behavioral assays, our data show that manipulating the ILS pathway significantly improves functionality of motor and chemosensory neurons in animals expressing hTDP-43.}, } @article {pmid41041029, year = {2024}, author = {Zareei, A and Razeghinejad, R and Talebnejad, MR and Khalili, MR and Masoumpour, MS and Shayan, Z and Mahdaviazad, H and Keshtkar, M and Mohammadi, E and Tajbakhsh, Z and Shahmohammadi, M and Nowroozzadeh, MH}, title = {Macular Sublayer Thickness in Healthy Iranian Children: An Optical Coherence Tomography Study from the Population-Based Shiraz Pediatric Eye Study.}, journal = {Journal of current ophthalmology}, volume = {36}, number = {4}, pages = {393-399}, pmid = {41041029}, issn = {2452-2325}, abstract = {PURPOSE: To establish normative values for macular sublayer thickness in healthy Iranian children using optical coherence tomography (OCT) and to assess the effects of age and gender.

METHODS: This study was part of the population-based Shiraz pediatric eye study. Of 2400 children aged 6-12 years invited, 480 were randomly selected for optical biometry and macular spectral-domain OCT (SD-OCT) imaging. Finally, 431 OCT scans from children with medium axial length (AL; 21.5-26.5 mm) were analyzed. The OCT device automatically segmented seven retinal sublayers, and their thickness was measured across Early Treatment Diabetic Retinopathy Study (ETDRS) subfields. Thickness in the central 1-mm subfield was assessed by gender and age groups (6-9 vs. 10-12 years), adjusted for AL. Regression analysis examined the impact of age, sex, and AL on retinal sublayer thickness. Only data from the right eye were used.

RESULTS: The mean age of participants was 9.12 ± 1.59 years (range, 6-12), with 254 (58.9%) being girls. The mean AL was 22.91 ± 0.71 mm, and the mean foveal thickness was 258 ± 8 µm. A normative database was created for the total retinal thickness and the seven retinal sublayers across the nine ETDRS subfields. Boys had longer globes (by approximately 0.4 mm; P < 0.001) and thicker foveae (by about 5 µm; P = 0.001) compared to girls. Among the seven sublayers studied, boys had a thicker ganglion cell complex layer (P = 0.014) and outer nuclear layer (ONL; P = 0.012), while girls had a thicker retinal pigment epithelium (RPE; P = 0.029). The inner nuclear layer and outer plexiform layer showed no significant differences (P = 0.075 and P = 0.810, respectively). The mean AL was 22.78 ± 0.68 mm in the 6-9 age group and 23.10 ± 0.72 mm in the 10-12 age group (P < 0.001). The older age group (10-12 years) exhibited thicker ONL (P = 0.009) and RPE (P = 0.002) layers compared to the younger group.

CONCLUSIONS: This study provides normative data for macular sublayer thickness in Iranian children aged 6-12 years using Heidelberg SD-OCT. Boys had longer ALs and thicker maculae, while girls had a thicker RPE layer. Older children had longer globes and thicker retinas, mainly due to increased ONL and RPE thickness.}, } @article {pmid41041552, year = {2025}, author = {Scoles, D and Paul, S and Nguyen, H and Gandelman, M and Dansithong, W and Figueroa, K and Bonini, N and Pulst, S}, title = {A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41041552}, issn = {2693-5015}, support = {R35 NS127253/NS/NINDS NIH HHS/United States ; R01 NS137233/NS/NINDS NIH HHS/United States ; R37 NS033123/NS/NINDS NIH HHS/United States ; R21 NS128630/NS/NINDS NIH HHS/United States ; R21 NS127028/NS/NINDS NIH HHS/United States ; R33 NS124965/NS/NINDS NIH HHS/United States ; R56 NS033123/NS/NINDS NIH HHS/United States ; R35 NS097275/NS/NINDS NIH HHS/United States ; R01 NS097903/NS/NINDS NIH HHS/United States ; }, abstract = {RNA-binding proteins (RBPs) play an essential role in development, normal functioning and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire human STAU1 gene (hSTAU1) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene.}, } @article {pmid41042072, year = {2025}, author = {Trubshaw, M and Gohil, C and Edmond, E and Proudfoot, M and Yoganathan, K and Wuu, J and Northall, A and Kohl, O and Stagg, CJ and Nobre, AC and Talbot, K and Thompson, AG and Benatar, M and Woolrich, M and Turner, MR}, title = {Divergent Brain Network Activity in Asymptomatic C9orf72 and SOD1 Variant Carriers Compared With Established Amyotrophic Lateral Sclerosis.}, journal = {Human brain mapping}, volume = {46}, number = {14}, pages = {e70345}, pmid = {41042072}, issn = {1097-0193}, support = {NIHR203316//National Institute of Health Research Oxford Health Biomedical Research Centre/ ; MR/K01014X/1/MNDA_/Motor Neurone Disease Association/United Kingdom ; 4365//Muscular Dystrophy Association/ ; 203139/Z/16/Z//Wellcome Centre for Integrative Neuroimaging/ ; R01 NS105479/NS/NINDS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 NS105479/NH/NIH HHS/United States ; //National Institute of Health Research Oxford Cognitive Health Clinical Research Facility/ ; 2015//ALS Association/ ; 172123//Muscular Dystrophy Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/diagnostic imaging ; *C9orf72 Protein/genetics ; Male ; *Superoxide Dismutase-1/genetics ; Female ; Magnetoencephalography ; Middle Aged ; Adult ; *Nerve Net/physiopathology/diagnostic imaging ; Heterozygote ; Aged ; *Connectome ; }, abstract = {Understanding the presymptomatic biology in those at high risk of developing amyotrophic lateral sclerosis (ALS) is essential for the development of preventative therapeutic interventions. Approximately 10% of ALS is associated with a C9orf72 expansion or pathogenic variants in SOD1. Magnetoencephalography (MEG), combined with machine learning algorithms, can model brain network dynamics in such at-risk populations to develop pathogenic biomarkers. Individuals with symptomatic ALS (symALS, n = 61), asymptomatic C9orf72 carriers (aC9, n = 16), or pathological SOD1 carriers (aSOD, n = 12), and healthy controls (n = 84) underwent resting-state MEG recordings. Extracted metrics included regional oscillatory power, connectivity, and spectral shape. 'DyNeMo' was trained to identify six functional dynamic brain networks. Metrics were compared between groups. A classifier was trained to distinguish asymptomatic gene carriers from controls. Compared to controls, beta frequency power was decreased in both symALS and aC9 groups. The aC9 group showed a marked slowing of frontal oscillatory activity, while the aSOD group showed a marked acceleration. Dynamic network coactivation was dramatically disrupted in aC9, more than in both symALS and aSOD. The classifier accurately distinguished genetically at-risk groups from controls (receiver-operator-characteristic area-under-curve 0.89). The cerebral network dynamics of aC9 are markedly different from both aSOD and symALS, supporting the concept of profoundly different upstream pathways in SOD1 ALS, sparing wider cortical pathology when compared to C9orf72 ALS. aC9 changes may reflect chronic adaptive changes relating to neurodevelopmental factors or underpin aspects of system vulnerability that define penetrance variability. MEG metrics might provide important biomarkers of prevention therapy efficacy and phenoconversion in at-risk populations.}, } @article {pmid41042311, year = {2025}, author = {Ouyang, C and Jin, X and Zhao, H and Chen, S and Zhao, G and Li, D and Liu, W and He, X and Wu, Y and Yang, J and An, B}, title = {Generating Broad-Spectrum Resistance to ALS-Inhibiting Herbicides in Rice by CRISPR/Cas9-Mediated NHEJ.}, journal = {Rice (New York, N.Y.)}, volume = {18}, number = {1}, pages = {86}, pmid = {41042311}, issn = {1939-8425}, support = {2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; NO.ZDYF2024XDNY179//Hainan Province Science and Technology Special Fund/ ; NO.ZDYF2024XDNY179//Hainan Province Science and Technology Special Fund/ ; NO.ZDYF2024XDNY179//Hainan Province Science and Technology Special Fund/ ; NO.ZDYF2024XDNY179//Hainan Province Science and Technology Special Fund/ ; }, abstract = {Herbicides are pivotal for modern agriculture, but challenges like weed resistance and crop rotation issues necessitate the development of herbicide-resistant genetic resources. This study focused on acetolactate synthase (ALS), a key enzyme targeted by numerous herbicides. Using CRISPR/Cas9-mediated non-homologous end joining (NHEJ) and combining with whole-stage selection, we induced mutations in the OsALS gene of indica rice and identified novel in-frame mutations at the P171 and S627 sites, respectively. Among them, one mutation at the P171 site, the triple mutation P171T/R172G/M174L (ALS-TM) conferred broad-spectrum resistance to Imidazolinones Pyrimidinylthiobenzoates Sulfonylaminocarbonyltriazolinones and Sulfonylureas herbicides. Compared to wild-type (WT) rice, ALS-TM showed 1153-fold higher resistance to imazethapyr (IMT) than WT based on GR50 values (The herbicide dose causing a 50% reduction in growth), with minimal growth inhibition at 10-fold IMT treatment. Enzymatic assays revealed that ALS-TM maintained catalytic efficiency while reducing herbicide binding, which validated the resistance at the protein level. Field trials showed that ALS-TM mutant retained normal agronomic traits even after IMT spraying, indicating no yield penalty. Additionally, ALS mutations were validated as effective transgenic selection markers, enabling efficient rice transformation under different selection systems. These results demonstrated that ALS-TM could also serve as a reliable tool in basic research, facilitating the selection and identification of transgenic materials in laboratory studies. This study provided a robust method for generating herbicide-resistant rice germplasm and highlighted the potential of CRISPR-mediated NHEJ for creating novel resistant mutations.}, } @article {pmid41042334, year = {2026}, author = {Zhang, J and Han, F and Wang, X and Wu, F and Song, X and Liu, Q and Wang, J and Grecucci, A and Zhang, Y and Yi, X and Chen, BT}, title = {Brain metabolic imaging with 18 F-PET-CT and machine-learning clustering analysis reveal divergent metabolic phenotypes in patients with amyotrophic lateral sclerosis.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {53}, number = {3}, pages = {2018-2033}, pmid = {41042334}, issn = {1619-7089}, support = {No.2024PT5109//Scientific Research Program of FuRong Laboratory/ ; 2021YFA0805202//the National Key R&D Program of China/ ; STI2030-Major Projects: 2021ZD0201803//Science and Technology Innovation 2030/ ; Xiangya Hospital, Grant No. 2020LNJJ13 and 2022LNJJ09//Project Program of National Clinical Research Center for Geriatric Disorders/ ; No. 62402176//National Natural Science Foundation of China/ ; 2024JJ6191//Hunan Provincial Natural Science Foundation of China/ ; kq2402099//Changsha Municipal Natural Science Foundation/ ; 23B0626//Project Supported by Scientific Research Fund of Hunan Provincial Education Department/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging/genetics ; *Positron Emission Tomography Computed Tomography ; Male ; Female ; *Machine Learning ; Middle Aged ; *Fluorodeoxyglucose F18 ; *Brain/metabolism/diagnostic imaging ; Phenotype ; Cluster Analysis ; Aged ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by significant clinicopathologic heterogeneity. This study aimed to identify distinct ALS phenotypes by integrating brain 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (18 F-FDG PET-CT) metabolic imaging with consensus clustering data.

METHODS: This study prospectively enrolled 127 patients with ALS and 128 healthy controls. All participants underwent a brain 18 F-FDG-PET-CT metabolic imaging, psychological questionnaires, and functional screening. K-means consensus clustering was applied to define neuroimaging-based phenotypes. Survival analyses were also performed. Whole exome sequencing (WES) was utilized to detect ALS-related genetic mutations, followed by GO/KEGG pathway enrichment and imaging-transcriptome analysis based on the brain metabolic activity on the 18 F-FDG-PET-CT imaging.

RESULTS: Consensus clustering identified two metabolic phenotypes, i.e., the metabolic attenuation phenotype and the metabolic non-attenuation phenotype according to their glucose metabolic activity pattern. The metabolic attenuation phenotype was associated with worse survival (p = 0.022), poorer physical function (p = 0.005), more severe depression (p = 0.026) and greater anxiety level (p = 0.05). WES testing and neuroimaging-transcriptome analysis identified specific gene mutations and molecular pathways with each phenotype.

CONCLUSIONS: We identified two distinct ALS phenotypes with varying clinicopathologic features, indicating that the unsupervised machine learning applied to PET imaging may effectively classify metabolic subtypes of ALS. These findings contributed novel insights into the heterogeneous pathophysiology of ALS, which should inform personalized therapeutic strategies for patients with ALS.}, } @article {pmid41042380, year = {2025}, author = {Wang, S and Jiang, H and Yao, T}, title = {Integrative genomics and functional immunology reveal Clostridia species as modulators of neuroinflammation in amyotrophic lateral sclerosis.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {74}, number = {1}, pages = {136}, pmid = {41042380}, issn = {1420-908X}, support = {2020B22//Doctoral Fund of the First Affiliated Hospital of Harbin Medical University/ ; 2023ZX07D06//The key research and development project of Heilongjiang Province/ ; 2022-KYYWF-0301//Innovative Scientific Research Funding Project of Harbin Medical University/ ; PL2024H140//Natural Science Foundation of Heilongjiang Province,China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/microbiology/genetics ; *Gastrointestinal Microbiome ; Male ; Female ; Middle Aged ; Cytokines/immunology ; Genomics ; *Neuroinflammatory Diseases/immunology/microbiology/genetics ; Aged ; Myeloid-Derived Suppressor Cells/immunology ; Mendelian Randomization Analysis ; }, abstract = {OBJECTIVE: This multiomics study investigated causal relationships between the gut microbiota (GM), immune dysregulation, and amyotrophic lateral sclerosis (ALS) pathogenesis using Mendelian randomization (MR) with experimental validation.

MATERIALS: Analyses incorporated genome-wide data from 87,347 participants (GM: n = 7738; ALS: 20,806 patients, 59,804 controls; immune phenotypes: n = 3757), transcriptomic data from 71 subjects (56 ALS patients, 15 controls), and experimental validation in matched cohorts (n = 6 subjects per group).

METHODS: Two-sample bidirectional MR and mediation analysis were used to evaluate associations. Experimental validation employed flow cytometry for myeloid-derived suppressor cell quantification, enzyme-linked immunosorbent assay for cytokines, and real-time polymerase chain reaction for bacterial validation. Statistical analyses included inverse variance weighted methods with Cohen's d calculations.

RESULTS: Sixteen bacterial taxa, including p_Firmicutes.c_Clostridia, displayed protective associations with the risk of ALS, whereas sixteen showed harmful associations. Mediation analysis suggested that p_Firmicutes.c_Clostridia may confer protection through CD33+HLA-DR-myeloid-derived suppressor cell upregulation (23.8% mediation effect). Experimental validation confirmed fewer myeloid-derived suppressor cells in ALS patients (4.0 ± 0.8% vs. 7.5 ± 1.0%, p < 0.001, Cohen's d = 1.4) and lower levels of anti-inflammatory cytokines (TGF-β1: Cohen's d = 1.8, p < 0.001).

CONCLUSIONS: These findings support causal associations between gut microbial taxa and the ALS risk, which are mediated through immunoregulatory mechanisms, highlighting therapeutic targets within the gut‒immune‒brain axis.}, } @article {pmid41042709, year = {2025}, author = {Hall, HK and Austin, E and Hutchinson, K and Cheek, C and Clay-Williams, R}, title = {A Systematic Review of Management of Cramping Pain in Patients with Amyotrophic Lateral Sclerosis.}, journal = {European neurology}, volume = {88}, number = {5-6}, pages = {167-178}, pmid = {41042709}, issn = {1421-9913}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Pain Management/methods ; *Muscle Cramp/therapy/etiology ; }, abstract = {INTRODUCTION: Pain, particularly cramping, in people living with amyotrophic lateral sclerosis (ALS) is often underrecognized and under-treated. Despite affecting over 70% of people living with ALS (plwALS), cramping pain remains inadequately managed due to its complex nature and the difficulties plwALS face in communicating their symptoms as the disease progresses. This systematic review explores both pharmacological and non-pharmacological treatments for cramping pain in ALS, aiming to assess and compare their efficacy.

METHODS: The systematic review was conducted following PRISMA guidelines, and the protocol was registered with PROSPERO (ID CRD42024521649). A comprehensive search was performed across MEDLINE, Embase, Scopus, and Cochrane databases from inception until February 1, 2024, using specific search terms related to ALS and cramping.

RESULTS: The search resulted in the identification of 368 studies. After duplicates were removed, abstracts screened, and full texts reviewed, nine studies were included. Pharmacological interventions such as mexiletine demonstrated significant reductions in cramp frequency and intensity in several trials, with varying doses showing distinct levels of effectiveness. Other medications like dronabinol and levetiracetam were also tested but showed limited efficacy in reducing cramp severity. Among non-pharmacological options, supervised exercise programs, particularly those incorporating stretching and functional mobility, were effective in reducing cramping pain intensity, while unsupervised home exercise programs did not show significant improvements.

CONCLUSION: The review demonstrates the scarcity of high-quality research on cramping pain management in ALS. Mexiletine emerged as the most promising pharmacological intervention, providing notable relief, while supervised exercise therapy demonstrated beneficial effects.}, } @article {pmid41043090, year = {2025}, author = {van Rheenen, W and Harms, M and van Es, MA and Veldink, JH}, title = {Reader Response: Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.}, journal = {Neurology}, volume = {105}, number = {9}, pages = {e210115}, doi = {10.1212/WNL.0000000000210115}, pmid = {41043090}, issn = {1526-632X}, } @article {pmid41043092, year = {2025}, author = {Lewis, A and Galetta, SL}, title = {Editors' Note: Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.}, journal = {Neurology}, volume = {105}, number = {9}, pages = {e214258}, doi = {10.1212/WNL.0000000000214258}, pmid = {41043092}, issn = {1526-632X}, } @article {pmid41043093, year = {2025}, author = {Crayle, JI and Crayle, JI and Rampersaud, E and Myers, JR and Wuu, J and Wu, G and Benatar, M and Bedlack, RS}, title = {Author Response: Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.}, journal = {Neurology}, volume = {105}, number = {9}, pages = {e210166}, doi = {10.1212/WNL.0000000000210166}, pmid = {41043093}, issn = {1526-632X}, } @article {pmid41043388, year = {2025}, author = {Deniz, AA}, title = {Spheres, worms, and packing problems in the nanoscale assembly of ALS-linked protein Matrin-3.}, journal = {Molecular cell}, volume = {85}, number = {19}, pages = {3549-3550}, doi = {10.1016/j.molcel.2025.09.013}, pmid = {41043388}, issn = {1097-4164}, mesh = {Humans ; *RNA-Binding Proteins/metabolism/chemistry/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Animals ; Nuclear Matrix-Associated Proteins ; }, abstract = {Matrin-3 (MATR3) is an RNA-binding protein that forms higher-order assemblies and pathological inclusions associated with neurodegenerative diseases. In this issue of Molecular Cell, Sprunger et al.[1] explore the assembly of MATR3 and find that it forms spherical and worm-like nanoscale assemblies distinct from condensates formed by macrophase separation.}, } @article {pmid41043426, year = {2025}, author = {Ma, GM and Xia, CC and Lyu, BY and Liu, J and Luo, F and Guan, MF and Wang, JY and Sun, L and Zhang, L and Chen, Y and Mao, YW and Yu, GQ and Wang, WY}, title = {Integrated profiling of iPSC-derived motor neurons carrying C9orf72, FUS, TARDBP, or SOD1 mutations.}, journal = {Stem cell reports}, volume = {20}, number = {10}, pages = {102649}, pmid = {41043426}, issn = {2213-6711}, support = {R01 MH110504/MH/NIMH NIH HHS/United States ; U19 NS123719/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Motor Neurons/metabolism/cytology ; *C9orf72 Protein/genetics ; *RNA-Binding Protein FUS/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Mutation ; *Superoxide Dismutase-1/genetics ; *DNA-Binding Proteins/genetics ; Cell Differentiation/genetics ; Alternative Splicing ; Gene Expression Profiling ; }, abstract = {Here, we conducted temporal RNA sequencing (RNA-seq) profiling of human induced pluripotent stem cells (hiPSCs) and induced pluripotent stem cell (iPSC)-derived motor neurons (iMNs) carrying C9orf72, FUS, TARDBP, or SOD1 mutations in both patients with amyotrophic lateral sclerosis (ALS) and healthy individuals. We discovered dysregulated gene expression and alternative splicing (AS) throughout iMN development and maturation, and iMNs with mutations in ALS-associated genes displayed enrichment of cytoskeletal defects and synaptic alterations from the premature stage to mature iMNs. Our findings indicate that synaptic gene dysfunction is a common molecular hallmark of familial ALS, which may result in neuronal susceptibility and progressive motor neuron degeneration. Analysis of upstream splicing factors revealed that differentially expressed RNA-binding proteins (RBPs) in iMNs from patients with ALS may cause abnormal AS events. Overall, our research provides a comprehensive and valuable resource for gaining insights into the shared mechanisms of familial ALS pathogenesis during motor neuron development and maturation in iMN models.}, } @article {pmid41043460, year = {2025}, author = {Rasheed, S and Bennett, J and Yoo, PE and Burkitt, AN and Grayden, DB}, title = {Decoding saccadic eye movements from brain signals using an endovascular neural interface.}, journal = {Journal of neural engineering}, volume = {22}, number = {5}, pages = {}, doi = {10.1088/1741-2552/ae0f52}, pmid = {41043460}, issn = {1741-2552}, mesh = {Humans ; *Saccades/physiology ; *Brain-Computer Interfaces ; Male ; *Electroencephalography/methods ; Photic Stimulation/methods ; Middle Aged ; *Endovascular Procedures/methods ; Amyotrophic Lateral Sclerosis/physiopathology ; Female ; }, abstract = {Objective.An oculomotor brain-computer interface (BCI) records neural activity from brain regions involved in planning eye movements and translates this activity into control commands. While previous successful studies have relied on invasive implants in non-human primates or electrooculography artefacts in human electroencephalogram (EEG) data, this study aimed to demonstrate the feasibility of an oculomotor BCI using a minimally invasive endovascular Stentrode[TM]device implanted near the supplementary motor area of a patient with amyotrophic lateral sclerosis (ALS).Approach.One participant performed self-paced visually-guided and free-viewing saccade tasks in four directions (left, right, up, down) while endovascular EEG and eye gaze recordings were collected. Visually-guided saccades were cued with visual stimuli, whereas free-viewing saccades were self-directed without explicit cues. Brain signals were pre-processed to remove cardiac artefacts, downsampled, and classified using a Random Forest algorithm. For saccade onset classification (fixation vs saccade), features in time and frequency domains were extracted after xDAWN denoising, while for saccade direction classification, the downsampled time series were classified directly without explicit feature extraction.Main results.The neural responses of visually-guided saccades overlapped with cue-evoked potentials, while free-viewing saccades exhibited saccade-related potentials that began shortly before eye movement, peaked approximately 50 ms after saccade onset, and persisted for around 200 ms. In the frequency domain, these responses appeared as a low-frequency synchronisation below 15 Hz. Saccade onset classification was robust, achieving mean area under the receiver operating characteristic curve (AUC) scores of 0.88 within sessions and 0.86 across sessions. Saccade direction decoding yielded within-session AUC scores of 0.67 for four-class decoding and up to 0.75 for the best performing binary comparisons (left vs up and left vs down).Significance.This proof-of-concept study demonstrates the feasibility of an endovascular oculomotor BCI in a patient with ALS, establishing a foundation for future oculomotor BCI studies in human subjects.}, } @article {pmid41043541, year = {2025}, author = {Zhuang, J and Zhang, Z and Jin, H and Qi, J and Chen, Y and Ding, L and Fu, C and Cheng, W}, title = {C9orf72 related poly-Glycine-Alanine promotes tau phosphorylation and cell death via ERK1/2 interaction in cellular models.}, journal = {Neuroscience}, volume = {587}, number = {}, pages = {123-130}, doi = {10.1016/j.neuroscience.2025.09.053}, pmid = {41043541}, issn = {1873-7544}, mesh = {Phosphorylation ; Humans ; *C9orf72 Protein/metabolism/genetics ; *tau Proteins/metabolism ; Cell Death/physiology/drug effects ; Frontotemporal Lobar Degeneration/metabolism/pathology ; *Neurons/metabolism/pathology/drug effects ; Nitriles/pharmacology ; *MAP Kinase Signaling System/physiology ; DNA Repeat Expansion ; Mitogen-Activated Protein Kinase 3/metabolism ; Butadienes/pharmacology ; Mitogen-Activated Protein Kinase 1/metabolism ; }, abstract = {Frontotemporal lobar degeneration (FTLD), particularly cases linked to the C9ORF72 GGGGCC repeat expansion (r(G4C2)exp), is closely associated with TAR DNA-binding protein 43 (TDP-43) pathology but also exhibits concurrent tau pathology characterized by hyperphosphorylation and neurofibrillary tangles (NFTs). Despite evidence suggesting heightened tau pathology severity in C9ORF72 mutation carriers compared to other FTLD subtypes, the mechanistic interplay between r(G4C2)exp and tau dysregulation remains poorly understood. Using a cellular model, we demonstrated that (GA)50 causes significant neuronal cell death. We found that (GA)50 was shown to specifically bind to extracellular-regulated kinase 1/2 (ERK1/2) protein, leading to its hyperphosphorylation. This activation of ERK1/2 was associated with increased tau phosphorylation and aggregation. Importantly, inhibiting ERK1/2 activity with U0126 significantly reduced tau phosphorylation, aggregation, and cell death in cells overexpressing (GA)50. These in vitro findings suggest that (GA)50-driven ERK1/2 hyperphosphorylation may represent potential driver of tau pathology in C9ORF72-related FTLD, highlighting the ERK1/2 signaling or its interaction with poly-glycine-alanine (GA) as a potential therapeutic target.}, } @article {pmid41044342, year = {2025}, author = {Ionescu, A and Ankol, L and Ganapathy Subramaniam, A and Altman, T and Magen, I and Cohen, Y and Danino, Y and Gradus-Pery, T and Niv, Y and Bar Avi, O and Geller, D and Ibraheem, A and Cheng, R and Steinberg, N and Alfahel, L and Duc, P and Ergul-Ulger, Z and Arslan, D and Tan, E and Rage, F and Riva, N and Quattrini, A and Bekircan-Kurt, CE and Israelson, A and Dori, A and Hornstein, E and Perlson, E}, title = {Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models.}, journal = {Nature neuroscience}, volume = {28}, number = {11}, pages = {2201-2216}, pmid = {41044342}, issn = {1546-1726}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Animals ; *MicroRNAs/metabolism/genetics ; *Neuromuscular Junction/metabolism/pathology ; *Axons/metabolism/pathology ; Humans ; Mice ; *DNA-Binding Proteins/metabolism/genetics/biosynthesis ; *Muscle, Skeletal/metabolism ; Mice, Transgenic ; Motor Neurons/metabolism ; Disease Models, Animal ; Induced Pluripotent Stem Cells/metabolism ; Extracellular Vesicles/metabolism ; Superoxide Dismutase-1/genetics ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by neuromuscular junction (NMJ) disruption and neurodegeneration. Recent findings highlight a pivotal role for TAR DNA-binding protein 43 (TDP-43) in forming axonal pathological condensates and facilitating NMJ disruption through inhibition of local protein synthesis. However, the mechanisms that drive local TDP-43 accumulation remain unknown. Here we identify that the TDP-43 axonal accumulation in peripheral nerves of SOD1 patients and mice stems from its aberrant local synthesis. This is a non-cell-autonomous process driven by muscle-derived miR-126a-5p extracellular vesicles (EVs). Inhibiting muscle secretion of miR-126a-5p prompts presynaptic TDP-43 synthesis and accumulation, which disrupts axonal translation and causes NMJ degeneration. Introducing miR-126 to SOD1[G93A] mice, primary co-cultures and human induced pluripotent stem cell (iPSC)-derived co-cultures with ALS mutations exhibits neuroprotective effects and delays motor decline. These findings identify a transcellular communication axis between muscles and motor neurons that regulates axonal local synthesis and NMJ maintenance, offering insights into ALS onset and progression.}, } @article {pmid41046979, year = {2025}, author = {Puspita, L and Deline, M and Shim, JW}, title = {Dual SMAD inhibition as a versatile platform in human pluripotent stem cell-based regenerative medicine and disease modeling.}, journal = {Molecules and cells}, volume = {48}, number = {11}, pages = {100284}, pmid = {41046979}, issn = {0219-1032}, mesh = {Humans ; *Pluripotent Stem Cells/cytology/metabolism ; *Regenerative Medicine/methods ; *Smad Proteins/antagonists & inhibitors/metabolism ; Animals ; Signal Transduction ; Cell Differentiation ; }, abstract = {Dual SMAD inhibition is a robust and widely adopted protocol for directing human pluripotent stem cells (hPSCs) toward neuronal lineages by blocking transforming growth factor-beta and bone morphogenetic protein pathways. Suppressing transforming growth factor-beta and bone morphogenetic protein signaling enables efficient and reproducible induction of neuroectoderm, serving as the foundation for generating diverse brain region-specific neuronal subtypes. This review outlines the mechanistic basis and major achievements of the dual SMAD inhibition strategy, including its application in 2 recent clinical trials for Parkinson's disease, and its role in preclinical studies targeting conditions, such as spinal cord injury (SCI), retinal degeneration, and amyotrophic lateral sclerosis (ALS). In addition to its significant contribution to the generation of transplantation-ready grafts from hPSCs, the protocol serves as a valuable platform for disease modeling across various neurological and metabolic disorders. The key strengths include high efficiency, technical simplicity that enables precise control of cell fate using small molecules, versatility in both 2- and 3-dimensional culture systems, and reproducibility across various hPSC lines. This review also addresses key limitations, such as restricted gliogenic capacity and limited neural progenitor cell expansion. Future research should focus on incorporating emerging technologies to advance stem cell-based applications. Overall, dual SMAD inhibition represents a powerful and versatile platform for stem cell-based neuroscience and regenerative medicine.}, } @article {pmid41047006, year = {2025}, author = {Stefano, GB and Büttiker, P and Weissenberger, S and Raboch, J and Anders, M}, title = {Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.}, journal = {Frontiers in neuroendocrinology}, volume = {79}, number = {}, pages = {101217}, doi = {10.1016/j.yfrne.2025.101217}, pmid = {41047006}, issn = {1095-6808}, support = {//Cooperatio Program/ ; //Neuroscience/ ; //MH CZ – DRO VFN64165/ ; }, mesh = {Humans ; *Mitochondria/metabolism/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; *Glucagon-Like Peptides/pharmacology/therapeutic use/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Energy Metabolism/drug effects ; Glucagon-Like Peptide 1 ; Semaglutide ; }, abstract = {While mitochondria provide critical energy resources, mitochondrial dysfunction can lead to both metabolic and neurodegenerative disorders. Primary mitochondrial disorders (e.g., Leigh syndrome) are uniformly associated with profound neurodegeneration. Recent studies have also implicated mitochondrial dysfunction as a central feature of progressive neurodegenerative diseases, notably Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's Disease. In addition to its profound impact on metabolic disease, the glucagon-like peptide-1 receptor agonist, semaglutide, has significant neuroprotective features and may limit the progression of one or more of these disorders. These observations might be explained at least in part by the impact of this drug on mitochondrial function and energy production. Collectively, these observations highlight disrupted energy homeostasis as a critical feature of neurodegenerative disease and suggest novel targets for the development of much-needed new neuropharmaceutical strategies.}, } @article {pmid41050165, year = {2025}, author = {Krüger, GM and Birkeli, SG and Hansen, ØM and Faldaas, BO and Norvik, A and Lund, HJ and Egil Hautois, GL and Flage, JH and Urteaga, J and Hergum, T and Torp, H and Skogvoll, E and Ingul, CB}, title = {Realtime detection of spontaneous circulation in humans during cardiopulmonary resuscitation using a continuous hands-free carotid Doppler: a pilot study.}, journal = {Resuscitation plus}, volume = {26}, number = {}, pages = {101080}, pmid = {41050165}, issn = {2666-5204}, abstract = {BACKGROUND: The resuscitation society calls for precision-guided cardiopulmonary resuscitation (CPR), as current methods are inaccurate and time-consuming. RescueDoppler, a novel hands-free Doppler ultrasound system, continuously measures carotid blood flow during CPR. This pilot study assessed its performance, safety, and ability to detect chest compression-generated blood flow, spontaneous circulation, and return of spontaneous circulation (ROSC).

METHOD: We investigated RescueDoppler in adult cardiac arrest patients at two centres, in-hospital (IHCA) and out-of-hospital (OHCA). The cardiac arrest team placed the RescueDoppler probe over the left common carotid artery with a self-adhesive patch, collecting blinded data during CPR. Data were later interpreted and time-synchronized with defibrillator data using custom MATLAB® software.

RESULTS: RescueDoppler was used in 26 IHCA and 36 OHCA patients from October 2023 to September 2024. Carotid blood flow curves were analyzed in 36 patients and synchronized with defibrillator data in 30. The RescueDoppler identified blood flow velocities generated by chest compressions and detected spontaneous circulation during rhythm checks. ROSC was defined by the presence of systolic and diastolic blood flow. No adverse events were reported but there were 22 device deficiencies mostly related to the self-adhesive patch and connecting cable. The system is user-friendly and requires minimal training.

CONCLUSION: Real-time detection of blood flow in the carotid artery with hands-free Doppler ultrasound during CPR is safe and feasible, although the fastening patch and host unit need optimization. The RescueDoppler system detects spontaneous circulation and ROSC during rhythm checks and ongoing chest compressions. Further research is required to confirm clinical relevance.}, } @article {pmid41051197, year = {2025}, author = {}, title = {Proceedings of the 24[th] Annual Meeting of the Northeast ALS Consortium.}, journal = {Muscle & nerve}, volume = {72 Suppl 1}, number = {}, pages = {S1-S97}, doi = {10.1002/mus.70018}, pmid = {41051197}, issn = {1097-4598}, } @article {pmid41051689, year = {2025}, author = {Azam, HMH and Mumtaz, M and Rödiger, S and Schierack, P and Hussain, N and Aisha, A}, title = {MicroRNAs in neurodegenerative diseases: from molecular mechanisms to clinical biomarkers, detection methods and therapeutic strategies-advances and challenges.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {12}, pages = {6277-6319}, pmid = {41051689}, issn = {1590-3478}, mesh = {Humans ; *MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/diagnosis/therapy/genetics/metabolism ; Biomarkers/metabolism ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) pose significant challenges in early detection and treatment due to their complex pathophysiology and heterogeneous clinical presentations. MicroRNAs (miRNAs), small noncoding RNAs that regulate gene expression, have emerged as promising diagnostic biomarkers and therapeutic targets in NDDs. Pathological examination of affected tissues reveals early synaptic dysfunction, protein misfolding, and neuroinflammation occur prior to overt clinical symptoms, highlighting the importance of sensitive diagnostics approaches in prodromal stages. This review summarizes for researchers on the role of miRNAs in NDDs by examining their diagnostic potential in biofluids such as blood and cerebrospinal fluid, and their therapeutic applicability through inhibition or replacement strategies. Literature from peer-reviewed databases was assessed with a focus on recent advances in molecular detection platforms, computational modeling of miRNA-mRNA interactions, and preclinical/clinical investigations.More than 2600 human miRNAs have been identified, collectively regulating over half of mammalian protein-coding genes. Quantitative methodologies, particularly reverse transcription quantitative PCR (RT-qPCR), enable reliable miRNA profiling, facilitating early diagnosis and prognosis of NDDs. Therapeutic strategies, including antagomirs, mimics, sponges and viral or non-viral delivery systems, show promise in modulating disease pathways. However, significant challenges remain, including variability in miRNA extraction and quantification protocols, off-target effects, delivery barriers across the blood brain barrier and limited reproducibility across studies. MiRNAs represent a class of molecular tools with potential to transform diagnostics and therapeutics in NDDs. Future research should prioritize methodological standardization, validation in large multicenter cohorts, and improved computational approaches to elucidate miRNA-mediated regulatory networks in NDDs. Replication studies and translational research are essential harnessing the the full clinical utility of miRNAs in the management of Alzheimer disease, Parkinson disease and other NDDs. Graphical Abstract.}, } @article {pmid41053020, year = {2025}, author = {Gerlach, J and Pireddu, P and Zhang, X and Wetzel, S and Mennuni, M and Milenkovic, D and Nolte, H and da Silva Rodrigues, F and Branzell, N and Kaya, I and Villegas, RG and Rubalcava-Gracia, D and Alsina, D and Feederle, R and Andrén, PE and Langer, T and Svenningsson, P and Filograna, R}, title = {The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.}, journal = {Cell death & disease}, volume = {16}, number = {1}, pages = {693}, pmid = {41053020}, issn = {2041-4889}, support = {2022-01477//Vetenskapsrådet (Swedish Research Council)/ ; }, mesh = {Animals ; *Mitochondria/metabolism/pathology ; *Brain/metabolism ; Homeostasis ; *Mitochondrial Proteins/metabolism/genetics ; Mice ; Mice, Knockout ; Male ; *Lipid Metabolism ; *Transcription Factors/metabolism/genetics ; Humans ; Mice, Inbred C57BL ; DNA-Binding Proteins ; }, abstract = {The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations in the genes encoding these proteins have been linked to severe disorders, including Parkinson's disease and amyotrophic lateral sclerosis. In cultured cells, a small fraction of CHCHD2 and CHCHD10 oligomerize to form a high molecular weight complex of unknown function. Here, we generated a whole-body Chchd2 knockout mouse to investigate the in vivo role of CHCHD2 and its protein complex. We show that CHCHD2 is crucial for sustaining full motor capacity, normal striatal dopamine levels, and lipid homeostasis in the brain of adult male mice. We also demonstrate that in mouse tissues, CHCHD2 and CHCHD10 exist exclusively as a high molecular weight complex, whose levels are finely tuned under physiological conditions. In response to mitochondrial dysfunction, the abundance and size of the CHCHD2-CHCHD10 complex increase, a mechanism conserved across different tissues. Although the loss of CHCHD2 does not abolish CHCHD10 oligomerization, it enhances cell vulnerability to mitochondrial stress, suggesting that CHCHD2 is protective against mitochondrial damage. Our findings uncover the role of CHCHD2 in preserving tissue homeostasis and provide important insights into the involvement of the CHCHD2-CHCHD10 complex in human diseases.}, } @article {pmid41053519, year = {2025}, author = {Amiri, M and Afshary, H and Bezaatpour, A and Hatamikia, S and Wei, J and Boukherroub, R and Szunerits, S}, title = {A critical review on neurodegenerative biomarker diagnostics: where is the field heading to?.}, journal = {Analytical and bioanalytical chemistry}, volume = {417}, number = {24}, pages = {5435-5448}, pmid = {41053519}, issn = {1618-2650}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Biomarkers/analysis ; Nanotechnology/methods ; }, abstract = {Neurodegenerative diseases (NDD), a collection of disorders with different underlying causes and clinical presentations, are recognized as a major area of concern of our society today. The most common NDD are Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease, each one of them being characterized by the progressive degradation of nerve cells and accumulation of misfolded and aggregated proteins in the affected brain region. Diagnosing NDD is challenging, due to the heterogeneity of the disease and the overlap of symptoms. Yet, early detection and accurate diagnosis are crucial for effective NDD management. With the emergence of disease-modifying therapies for AD, monitoring disease progression and treatment success is becoming essential. The future of NND diagnostics is focusing on developing less invasive, cost-effective strategies that enable early NDD identification and detection with improved patient outcomes. The integration of biotechnology and nanotechnology is seen as crucial for advancing the analytical science aspect of NDD. The creation of these innovative tools and methodologies is on the verge of enabling new possibilities for clinical diagnostics, but is also faced with several hurdles that will be critically evaluated.}, } @article {pmid41054052, year = {2025}, author = {Uchiyama, K and Yamauchi, T and Hara, R}, title = {Validation of the Japanese version of the quality of life in life threatening illness- family carer version scale for caregivers of home-based patients with amyotrophic lateral sclerosis: A cross-sectional study.}, journal = {Medicine}, volume = {104}, number = {40}, pages = {e44799}, pmid = {41054052}, issn = {1536-5964}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/nursing/psychology/therapy ; *Caregivers/psychology ; Cross-Sectional Studies ; Home Care Services ; Japan ; Psychometrics ; *Quality of Life/psychology ; Reproducibility of Results ; Surveys and Questionnaires ; East Asian People ; }, abstract = {This study aimed to validate the Japanese version of the Quality of Life in Life-Threatening Illness-Family Carer Version (J-QOLLTI-F) tool for caregivers of ventilated home-based ALS patients. In collaboration with the Japan Amyotrophic Lateral Sclerosis (ALS) Association and the National Intractable Disease Support Center, a self-administered survey was administered to 107 caregivers of home-based ALS patients who consented to participate in this study. The survey included data concerning participant and patient characteristics derived from the J-QOLLTI-F, the 36-Item Short Form Health Survey (SF-36), and the Japanese Version of the Zarit Burden Interview (J-ZBI). This was a cross-sectional study. The Cronbach's α for the J-QOLLTI-F was 0.85. Regarding reproducibility, a strong item-total (I-T) correlation (α = 0.90) was observed. Exploratory factor analysis revealed 16 items and three factors, with eigenvalues ≥ 1 and factor loadings ≥ 0.4. A significant correlation was also found for validity using Pearson's coefficient. The reliability of the J-QOLLTI-F was confirmed through the Cronbach α coefficient and I-T correlation. Validity was confirmed through exploratory factor analysis and Pearson's correlation in relation to the SF-36 and J-ZBI. Based on these findings, this 16-item J-QOLLTI-F can be considered a valid and reliable QOL measurement scale for caregivers of home-based ALS patients.}, } @article {pmid41054101, year = {2025}, author = {Hu, W and Liu, X and Zhang, P}, title = {Rapid eye movement sleep behavior disorder (RBD) and neurodegenerative diseases: A bidirectional 2-sample Mendelian randomization study.}, journal = {Medicine}, volume = {104}, number = {40}, pages = {e44816}, pmid = {41054101}, issn = {1536-5964}, support = {2024NSFSC1608//Science and Technology Plan Project of Sichuan Province,/ ; 2024HX019)//Horizontal project of Sichuan Provincial People's Hospital/ ; 2024HX018//Horizontal project of Sichuan Provincial People's Hospital/ ; }, mesh = {Humans ; Mendelian Randomization Analysis ; *REM Sleep Behavior Disorder/genetics/epidemiology ; Polymorphism, Single Nucleotide ; *Neurodegenerative Diseases/genetics/complications/epidemiology ; Genome-Wide Association Study ; Parkinson Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Alzheimer Disease/genetics ; Frontotemporal Dementia/genetics ; Lewy Body Disease/genetics ; }, abstract = {Observational studies have documented association between rapid eye movement sleep behavior disorder (RBD) and neurodegenerative diseases, but the causal relationship remains to be established. In this study, we utilized a bidirectional 2-sample Mendelian randomization (MR) approach to assess the potential causal connection between RBD and 6 neurodegenerative conditions, including Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), multiple system atrophy (MSA), and Parkinson disease (PD). Inverse variance weighting (IVW) was performed as the main MR analysis, and additional 4 MR methods were performed to reinforce the robustness of the final MR estimates. Sensitivity analyses were conducted to detect possible heterogeneity or pleiotropy. Ten single-nucleotide polymorphisms (SNPs) for RBD, 54 SNPs for AD, 11 SNPs for ALS, 4 SNPs for DLB, 3 SNPs for MSA, and 12 SNPs for PD were selected as instrumental variables in this study. No suitable instrumental variables for FTD could be identified from genome-wide association studies dataset using a threshold of P < 5 × 10-8. Genetically predicted RBD was causally associated with an increased risk of PD (IVW: odds ratios = 1.093, 95% confidence intervals = [1.031-1.159], P = .003). In the reverse MR analysis, genetically predicted PD was found to be causally increased the incidence of RBD (IVW: odds ratios = 1.758, 95% confidence intervals = [1.355-2.281], P = 2.176 × 10-5). No heterogeneity or pleiotropy was observed in Cochran Q test, MR-Egger intercept test, or MR-PRESSSO Global test in the determination of the above 2 MR analyses. However, this bidirectional MR study did not identify any causal relationship between RBD and AD, ALS, DLB, FTD, and MSA. This MR study supported a bidirectional causal relationship between RBD and PD, mutually increasing the incidence of each. However, current genetic evidence did not support causal associations between RBD and AD, ALS, DLB, FTD, and MSA in either direction. However, these null findings should be interpreted with caution due to the limited sample sizes of the genome-wide association studies summary data used, highlighting the need for larger genetic studies to investigate these relationships further.}, } @article {pmid41056745, year = {2026}, author = {Zaichenko, V}, title = {Forensic psychiatry assessment and human rights in Ukraine: response to Butenko et al's paper 'Forensic psychiatry misuse in proceedings of administrative offenses' (2023)Type of submission.}, journal = {International journal of law and psychiatry}, volume = {104}, number = {}, pages = {102158}, doi = {10.1016/j.ijlp.2025.102158}, pmid = {41056745}, issn = {1873-6386}, mesh = {Humans ; *Forensic Psychiatry/legislation & jurisprudence ; Ukraine ; *Human Rights/legislation & jurisprudence ; }, abstract = {The paper by Butenko et al., 'Forensic psychiatry misuse in proceedings of administrative offenses' (International Journal of Law and Psychiatry, 2023) focused on the 'Case of Zaichenko v. Ukraine (No. 2)' in the European Court of Human Rights (2015). As the applicant in that case, I wish to respond to the paper by adding further context and detail to the arguments presented. My concerns centre on four areas: findings of national courts, errors and gaps in the European Court of Human Rights judgment, the constitutional consequences of mistranslation, and the broader legal chain of events. Overall, my response to all these circumstances is that intellectuals fear judges as fire, while lawyers fear knowledge and intellectuals. To explain such mutual fear only deepens the horror. This explanation may be correct and precise, but it is also too general. A more concrete half-answer might be this: let us recall (a) the overall number of cases before the Court; (b) the number of judges; (c) the principles of European Court of Human Rights staff recruitment; (d) the frequent incompatibility of member states' normative systems; and (e) their linguistic, confessional, and cultural diversity. Add to this the contradictions of regulation itself, and ordinary human weaknesses. Regulation today has grown to a scale that no single mind can contain, and is produced, not by Solons or Pericles, but by lesser hands. In such conditions, the individual who turns to the Court is often lost behind the informational avalanche. Whom or what can one trust, if not the Court's final judgment? Here I will not appeal to Popper or Lakatos, but only to a much older Athenian, himself once persecuted by a court: 'Question everything'.}, } @article {pmid41057313, year = {2025}, author = {Baklou, M and Valsecchi, V and Laudati, G and Kolici, X and Brancaccio, P and De Iesu, N and Anzilotti, S and Cieri, F and Pignataro, G}, title = {MiR-140-3p regulates axonal motor protein KIF5A and contributes to axonal transport degeneration in SMA.}, journal = {Cell death discovery}, volume = {11}, number = {1}, pages = {446}, pmid = {41057313}, issn = {2058-7716}, abstract = {Spinal muscular atrophy (SMA) is a paediatric neuromuscular disease caused by alterations of the survival motor neuron (SMN) gene, which results in progressive degeneration of motor neurons (MNs). Although effective treatments for SMA patients has been recently developed, the molecular pathway involved in selective MNs degeneration has not been yet elucidated. Disruption of axonal transport is a common feature of motor neuron diseases (MNDs); specifically, mutations at the C-terminal of the kinesin KIF5A, have been linked to neurodegenerative disorders involving MNs degeneration such as amyotrophic lateral sclerosis (ALS). Therefore, the present study attempts to investigate potential alterations of the axonal transport complex that includes KIF5A in a SMA mouse model. We demonstrated that KIF5A is downregulated in the spinal cord of SMA mice both in early and late phases of the disease. A miRNA-based strategy was developed in the attempt to prevent KIF5A downregulation, thus restoring its physiological levels. Indeed, we demonstrated that miR-140-3p was up-regulated in the spinal cord of SMA mice during disease progression and was able to negatively modulate KIF5A expression. Furthermore, the intracerebroventricular injection of an antagomir molecule, able to block miR140-3p function, resulted in a reduction of SMA severity in terms of improved behavioural performance. Based on these results, we indicated KIF5A as a distinctive mechanism of MNDs progression and suggested that developing a strategy able to prevent KIF5A downregulation could be beneficial, not only in SMA but also in other neurodegenerative diseases.}, } @article {pmid41057832, year = {2025}, author = {Heyne, S and Kuzmanova, A and Esser, P and Linse, K and Günther, R and Mehnert-Theuerkauf, A and Metelmann, M}, title = {How can we reduce psychological burden for patients of amyotrophic lateral sclerosis and their family caregivers? - Insights from the participatory multi-method study "potentiALS".}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {414}, pmid = {41057832}, issn = {1471-2377}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; Male ; *Caregivers/psychology ; Female ; Middle Aged ; Aged ; Quality of Life/psychology ; Adult ; *Cost of Illness ; Surveys and Questionnaires ; Cognitive Behavioral Therapy/methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal motor neuron disease that severely impacts patients' physical and emotional well-being, while also imposing significant burdens on family caregivers. Despite the high psychosocial demands as part of the multidimensional burden, evidence for effective interventions remains limited. This study employed a participatory approach to assess the support needs of ALS patients and caregivers and to evaluate their preferences for psychosocial therapies to derive a therapeutic framework.

METHODS: In this observational multi-method study, ALS patients, their family caregivers, and healthcare professionals (HCPs) were actively involved throughout the research process. Quantitative Data were collected through structured questionnaires assessing quality of life (e.g., MQoL, SEIQoL-Q), depression and anxiety (ADI-12, HADS), and caregiver burden (BSFC-s). Feedback was obtained through structured group sessions that combined brief introductions, practical exercises, and subsequent evaluations of four therapy approaches - cognitive behavioral therapy (CBT), psychodynamic therapy (PT), acceptance and commitment therapy (ACT), and meaning-centered therapy (MCT).

RESULTS: 14 patients, 17 caregivers and nine HCPs participated in the study. Among patients, ACT was the most frequently selected (37.5%), followed by CBT (31.3%), MCT (18.8%), and PT (12.5%) with similar distribution in caregiver attendance. Across all therapy approaches, both patients and caregivers rated the beneficial aspects highly (mean scores of 4.18, and 4.12, respectively, on a scale from 1 to 5) and identified relatively few limitations (mean scores of 2.18 and 2.09, respectively, on a scale from 1 to 5). HCPs corroborated these findings, noting that while the therapies were effective in offering emotional support and facilitating open dialogue, challenges such as time constraints and adapting interventions for speech limitations remain. Notably, caregivers showed a strong preference for individualized therapy, while patients favored a mix of individual and group formats.

CONCLUSIONS: Our study highlights the distinct yet interconnected psychosocial needs of ALS patients and their caregivers. Tailored interventions should blend emotional support, open dialogue, and a structured therapeutic framework, while also emphasizing the need for adaptable delivery models in clinical practice. These findings support the development of scalable, patient-centered psychosocial support approaches as part of the multidimensional care in ALS.

TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (number: NCT06441448, registration date: May 28, 2024).}, } @article {pmid41057901, year = {2025}, author = {Garg, P and Lenk, K and Sundaram, SM}, title = {Small molecule-mediated rapid generation of functional human astrocytes: unveiling AKT1-STAT1/3 signaling in astrocyte development.}, journal = {Stem cell research & therapy}, volume = {16}, number = {1}, pages = {542}, pmid = {41057901}, issn = {1757-6512}, support = {iBrain Graduate School, University of Dusseldorf, Germany//iBrain Graduate School, University of Dusseldorf, Germany/ ; academy of finland//academy of finland/ ; Return home grant//International Society for Neurochemistry/ ; }, mesh = {Humans ; *Astrocytes/metabolism/cytology/drug effects ; *Proto-Oncogene Proteins c-akt/metabolism ; *STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Cell Differentiation/drug effects ; *STAT1 Transcription Factor/metabolism ; Neural Stem Cells/metabolism/cytology/drug effects ; Induced Pluripotent Stem Cells/metabolism/cytology/drug effects ; }, abstract = {Astrocytes are essential for maintaining brain homeostasis, as they support neurons, regulate synaptic activity, and mediate immune responses within the central nervous system (CNS). Their role in the pathophysiology of various neurological disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis, is increasingly recognized. Thus, differentiation of astrocytes from human induced pluripotent stem cells (hiPSCs) acts as an important tool for studying disease mechanisms and advancing therapeutic development strategies. However, the prolonged time of up to six months required to generate fully mature astrocytes limits their utility, with most protocols yielding only fetal-like astrocytes or relying on artificial transcription factor overexpression. To address this challenge, we developed a small-molecule-based method using PD0325901 (PD), which enables the rapid generation of mature human astrocytes from gliogenic neural stem cells (NSCs) within a short time of 2-3 weeks, without the need for genetic modification. We found that inhibition of MEK1/2 signaling in NSCs via PD resulted in decreased proliferation, upregulation of astrocytic markers, and acquisition of functionally mature astrocytes. Mechanistically, this differentiation process involved AKT1-dependent phosphorylation and activation of STAT1/3 that is the classical pathway for astrocyte differentiation, along with the nuclear loss of the astrocytic transcriptional repressor OLIG2. Overall, our findings present a novel approach for accelerating astrocyte maturation using a small molecule and reveal a key role for AKT1-STAT1/3 signaling in astrocyte development. By significantly shortening the time required to generate mature human astrocytes, this rapid astrocyte differentiation protocol enables more efficient modeling of neurodegenerative diseases and drug screening efforts.}, } @article {pmid41057909, year = {2025}, author = {Hunter, E and Alshaker, H and Bundock, O and Weston, C and Bautista, S and Gebregzabhar, A and Virdi, A and Croxford, J and Dring, A and Powell, R and Vugrinec, D and Kingdon, C and Wilson, C and Dowrick, S and Green, J and Akoulitchev, A and Pchejetski, D}, title = {Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch[®] 3-dimensional genomic regulatory immuno-genetic profiling.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {1048}, pmid = {41057909}, issn = {1479-5876}, support = {6514//Oxford BioDynamics plc, Oxford UK/ ; }, mesh = {Humans ; *Fatigue Syndrome, Chronic/genetics/blood/diagnosis/immunology ; *Biomarkers/blood ; *Gene Expression Profiling ; *Genomics/methods ; Reproducibility of Results ; Male ; Female ; Middle Aged ; }, abstract = {Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multifactorial disorder characterised by profound fatigue, post-exertional malaise, cognitive impairments, and autonomic dysfunction. Despite its significant impact on quality of life, ME/CFS lacks definitive diagnostic biomarkers, complicating diagnosis and management. Recent evidence highlights potential blood tests for ME/CFS biomarkers in immunological, genetic, metabolic, and bioenergetic domains. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression and cross-tissue exosome signalling. We have previously developed an epigenetic assay, EpiSwitch®, that employs an algorithm-based CCs analysis. Using EpiSwitch® technology, we have shown the presence of disease-specific CCs in peripheral blood mononuclear cells (PBMCs) of patients with amyotrophic lateral sclerosis (ALS), rheumatoid arthritis (RA), prostate and colorectal cancers, diffuse Large B-cell lymphoma and severe COVID-19. In a recent paper, we have identified a profile of systemic chromosome conformations in cancer patients reflective of the predisposition to respond to immune checkpoint inhibitors, PD-1/PD-L1 antagonists, with 85% accuracy. In this Retrospective case/control study (EPI-ME, Epigenetic Profiling Investigation in Myalgic Encephalomyelitis), we used whole blood samples retrospectively collected from n = 47 patients with severe ME/CFS and n = 61 age-matched healthy control patients to perform whole-genome 3D DNA screening for CCs correlating to ME/CFS diagnosis. We identified a 200-marker model for ME/CFS diagnosis (Episwitch®CFS test). First testing on the retrospective independent validation cohort demonstrated a strong systemic ME/CFS signal with a sensitivity of 92% and a specificity of 98%.Pathways analysis revealed several likely contributors to the pathology of ME/CFS, including interleukins, TNFα, neuroinflammatory pathways, toll-like receptor signalling and JAK/STAT. Comparison with pathways involved in the action of Rituximab and glatiramer acetate (Copaxone) (therapies with potential in ME/CFS treatment) identified IL2 as a shared pathway with clear patient clustering, indicating a possibility of a potential responder group for targeted treatment.}, } @article {pmid41058966, year = {2024}, author = {Donohue, C and Perry, B and Focht Garand, KL}, title = {A Clinical Focus on Shared Decision Making in Clinical Practice When Providing Dysarthria and Dysphagia Services to Individuals With Amyotrophic Lateral Sclerosis.}, journal = {Perspectives of the ASHA special interest groups}, volume = {9}, number = {4}, pages = {1003-1015}, pmid = {41058966}, issn = {2381-4764}, support = {K23 NS123369/NS/NINDS NIH HHS/United States ; L30 NS123988/NS/NINDS NIH HHS/United States ; }, abstract = {PURPOSE: Traditional health care decision-making models center on clinicians making decisions for patients/caregivers based on the best available research evidence. However, this diminishes patient/caregiver involvement in their care and hinders the ability to align care plans with patient values and preferences. Shared decision making is a potentially beneficial process to implement with individuals with amyotrophic lateral sclerosis (ALS) to provide more holistic, patient-centered dysarthria and dysphagia treatment. Shared decision making promotes active involvement by patients/caregivers by informing them of potential treatment options, understanding their values and preferences, and aligning their desires with treatment options to determine the most optimal individualized care plan.

CONCLUSIONS: The benefits and barriers to incorporating shared decision making within ALS multidisciplinary clinics are discussed in this clinical focus article. Furthermore, a fictional case study example of how to apply shared decision making to dysarthria and dysphagia management of individuals with ALS is provided.}, } @article {pmid41060339, year = {2025}, author = {Hu, N and Qi, M and Tian, H and Ding, J and Shen, D and Yang, X and Cui, L and Niu, J and Liu, M}, title = {Fasciculation in limbs serves as the predictor of ALS progression: an ultrasound study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {12}, pages = {6575-6582}, pmid = {41060339}, issn = {1590-3478}, support = {2022ZD0118003//National Key Transform Program/ ; CIFMS 2021-I2M-1-003//Chinese Academy of Medical Sciences Initiative for Innovative Medicine/ ; 2022-PUMCH-B-017, 2022-PUMCH-D-002//National High Level Hospital Clinical Research Funding Provincial People's Hospital/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/complications ; *Fasciculation/diagnostic imaging/etiology/physiopathology ; Male ; Female ; Disease Progression ; Middle Aged ; Ultrasonography ; Aged ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Muscle Strength/physiology ; *Extremities/diagnostic imaging/physiopathology ; Adult ; Severity of Illness Index ; Follow-Up Studies ; }, abstract = {OBJECTIVE: To explore the predictive effects of fasciculation by ultrasound in amyotrophic lateral sclerosis (ALS) progression.

METHODS: Sporadic ALS patients were consecutively recruited and followed up 3 to 6 months after the initial visit. Muscle ultrasound examination was conducted at the baseline to detect the severity score of fasciculations on bilateral elbow flexor and extensor, ankle dorsiflexor and plantar flexor of each patient, the sum of which was defined as the total fasciculation score. Baseline and follow-up ALS functional research scale-revised (ALSFRS-R) score and muscle strength were collected. The progression of ALS was reflected by the decline rate of ALSFRS-R score and proportion of muscles with decreased strength.

RESULTS: Among 33 ALS patients who completed the follow-up, the total fasciculation score was positively correlated with the ALSFRS-R progression rate (rho = 0.029, p < 0.001). Patients with low levels of the total fasciculation score had a significantly lower risk of rapid ALSFRS-R progression during follow-up compared to those with high levels of the total fasciculation score (HR 0.132, 95%CI 0.037-0.476). The frequencies of decline in muscle strength at the follow up were 76.32% and 16.54% among muscles with and without high-grade fasciculation (p < 0.001) after exclusion of muscles with 0-1 the medical research council (MRC) levels of strength at the baseline.

CONCLUSION: The severity of fasciculations was correlated with the rate of decrease in ALSFRS-R score and the decline in muscle strength, which might be used as a biological marker to predict the progression rate of ALS for prognostic judgment or clinical trial grouping.}, } @article {pmid41061184, year = {2025}, author = {Farina, A and Villagrán-García, M and Abichou-Klich, A and Benaiteau, M and Bernard, E and Bouhour, F and Desestret, V and Joubert, B and Picard, G and Pinto, AL and Pons, L and Smolik, K and Thobois, S and Trouillet-Assant, S and Honnorat, J}, title = {Serum Neurofilament Light Chain Correlates With Clinical Severity and Predicts Mortality in Anti-IgLON5 Disease.}, journal = {Neurology(R) neuroimmunology & neuroinflammation}, volume = {12}, number = {6}, pages = {e200498}, pmid = {41061184}, issn = {2332-7812}, mesh = {Humans ; Male ; *Neurofilament Proteins/blood ; Female ; Aged ; Middle Aged ; Severity of Illness Index ; Biomarkers/blood ; Glial Fibrillary Acidic Protein/blood ; Aged, 80 and over ; *Cell Adhesion Molecules, Neuronal/immunology ; *Autoantibodies/blood ; Retrospective Studies ; *Autoimmune Diseases of the Nervous System/blood/mortality/diagnosis ; Prognosis ; }, abstract = {BACKGROUND AND OBJECTIVES: Anti-IgLON5 disease manifests by various neurologic symptoms, the severity of which can be evaluated using the anti-IgLON5 composite score (ICS). This study assessed the correlation of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) with the ICS and investigated these biomarkers as predictors of long-term clinical severity and mortality in anti-IgLON5 disease.

METHODS: Patients diagnosed with anti-IgLON5 disease at a national reference center (2016-2024) with available serum and CSF samples were included. NfL and GFAP concentrations were measured in these samples using Simoa assay Neurology 2-Plex B Kit. The severity of symptoms was classified according to the ICS, which was retrospectively evaluated at diagnosis, at last clinical evaluation, and at any other timepoint when samples were collected.

RESULTS: Thirty patients (60% male, median age 72 years) were included. Serum NfL concentration was significantly correlated with the total ICS (rho = 0.38, p = 0.025) and its partial bulbar score (rho = 0.39, p = 0.020); serum GFAP concentration was significantly correlated only with the bulbar ICS (rho = 0.34, p = 0.044). CSF NfL and GFAP concentrations were not significantly correlated with the total ICS nor any of its partial scores. Anti-IgLON5 antibody CSF titers, but not serum titers, showed a significant inverse correlation with the total ICS (rho = -0.44, p = 0.04). In 26 patients sampled <4 months after diagnosis, neither NfL nor GFAP predicted the total or partial ICS at last clinical evaluation (median 18 months after diagnosis), but serum NfL increased the risk of 1-year mortality independently of age (hazard ratio for each 10 pg/mL increase: 2.05, 95% CI [1.21-3.45], p = 0.007). In patients with bulbar involvement (n = 22), serum NfL concentration was lower than in 10 controls with bulbar amyotrophic lateral sclerosis (median interquartile range [IQR] 26 pg/mL [21-51] vs 158 pg/mL [100-340], p < 0.001) and higher than in 10 controls with bulbar myasthenia gravis (median [IQR] 15 pg/mL [8-26], p = 0.040).

DISCUSSION: In anti-IgLON5 disease, serum NfL and GFAP are elevated and correlate with the clinical severity, especially of bulbar symptoms. In clinical practice, serum NfL could be useful for disease monitoring and to predict the risk of death.}, } @article {pmid41061670, year = {2026}, author = {James, RE and Bekier, M and Lee, PJ and Schroeder, FA and Evans, LT and Wagner, FF and Hickman, D and Richardson, T and Hatzipetros, T and Vieira, F and Callizot, N and Modi, S and Hooker, JM and Kranz, JE and Brown, RH and Barmada, SJ and Gilbert, TM}, title = {A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {5}, pages = {1586-1603}, pmid = {41061670}, issn = {1460-2156}, support = {//Eikonizo Therapeutics, Inc/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Histone Deacetylase 6/antagonists & inhibitors/metabolism ; Animals ; *Frontotemporal Dementia/drug therapy/metabolism/genetics ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Mice ; Humans ; Mice, Transgenic ; Male ; Disease Models, Animal ; Superoxide Dismutase-1/genetics ; Mice, Inbred C57BL ; }, abstract = {Dysregulated proteostasis and intracellular transport contribute to neurodegeneration. Histone deacetylase 6 (HDAC6), a therapeutic target of interest for neurodegenerative diseases, acts at a nexus modulating both proteostasis and intracellular transport. Inhibition of HDAC6 deacetylase activity promotes autophagic clearance of protein aggregates and increases α-tubulin acetylation, thereby enhancing microtubule resiliency and motor protein-microtubule binding, which facilitates intracellular transport and, subsequently, proteostasis. Despite these benefits, advancement of HDAC6 inhibitor therapeutics for neurodegenerative disease has been hindered by inadequate selectivity and CNS-penetrance of first-generation compounds. Here, we characterize a next-generation small molecule HDAC6 inhibitor, EKZ-438, in preclinical models of amyotrophic lateral sclerosis and frontotemporal dementia. We present the pharmacological properties of EKZ-438, which demonstrate high selectivity for HDAC6 (>8500-fold selectivity for HDAC6 versus all other HDAC6 paralogues), low nanomolar potency (12 nM) for HDAC6, and importantly, CNS-penetrance (unbound brain-to-plasma partition coefficient [Kp,uu,brain] ≥ 0.55) and high oral bioavailability (fraction of dose absorbed [F%] = 70). In complementary preclinical in vitro and in vivo immunolabelling and live imaging studies we tested the hypothesis that selective inhibition of HDAC6 deacetylase activity is sufficient to improve pathophysiological proteostasis and intracellular transport deficits in animal models of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. Notably, we extended these findings to human induced pluripotent stem cell-derived neuronal cellular models, supporting the relevance of our findings to human disease. EKZ-438 treatment rescued superoxide dismutase 1 (SOD1) (q < 0.0001) and transactive response DNA binding protein 43 kDa (TDP-43) (q < 0.001) proteostasis defects following an excitotoxic glutamate challenge, and increased survival of SOD1G93A and wild-type motor neurons by 59% (q < 0.0001) and 37% (q < 0.01), respectively, demonstrating in vitro neuroprotection. In SOD1G93A mice, EKZ-438 improved axonal transport by 16% (q < 0.05), motor performance by ∼40% (q < 0.05) and decreased plasma neurofilament light chain levels by 35% (q < 0.05), demonstrating in vivo neuroprotection. In a TDP-43 mouse model, EKZ-438 reduced TDP-43 pathology by ∼30% (q < 0.05) and neuroinflammation by ∼26% (q < 0.05) in the brain, supporting HDAC6 inhibition for sporadic amyotrophic lateral sclerosis and frontotemporal dementia. Furthermore, EKZ-438 treatment improved intracellular transport by 39% (q < 0.001), rescued cytoplasmic TDP-43 accumulation by 87% (q < 0.0001) and restored nuclear TDP-43 splicing activity (P < 0.05) in human TARDBP neurons. These mechanistic improvements aligned with nearly complete rescue of human TARDBP and C9orf72 mutant neuron survival (P < 0.0001). We conclude that selective HDAC6 inhibition represents a promising therapeutic approach for potential disease modification in amyotrophic lateral sclerosis and frontotemporal dementia.}, } @article {pmid41061972, year = {2026}, author = {Mao, PC and Wei, KC and Weng, CT}, title = {Response to Bar et al's "Early initiation of hydroxychloroquine in cutaneous lupus erythematosus to prevent progression to systemic lupus erythematosus: A long-term follow-up study".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {2}, pages = {e107-e108}, doi = {10.1016/j.jaad.2025.03.108}, pmid = {41061972}, issn = {1097-6787}, } @article {pmid41062721, year = {2025}, author = {Ramasubramanian, B and Ganguly, D and Rao, RP and Ramakrishna, S}, title = {Progress, pitfalls, and prospects in emerging materials for aluminum-sulfur batteries.}, journal = {Communications chemistry}, volume = {8}, number = {1}, pages = {301}, pmid = {41062721}, issn = {2399-3669}, abstract = {Aluminium-sulfur (Al-S) batteries have emerged as a promising post-lithium alternative owing to aluminium's abundance, safety, and high theoretical capacity. However, their practical implementation is impeded by key challenges such as sluggish Al[3+] redox kinetics, polysulfide shuttle effects, and volumetric changes of the electrodes during cycling. This review critically analysis recent advancements in host structural design engineering, new electrocatalysts, and electrolyte aimed at overcoming these limitations. Advanced host frameworks include 2D/3D porous structures, MXene-based multilayers, and single-atom doped materials that facilitate efficient sulfur confinement, enhance conductivity, and catalyse redox reactions. Embedded catalysts like Mo6S8 and CoS2 within nitrogen-doped carbons lower the decomposition barrier of Al2S3, promote stable Al-polysulfide conversion, and extend cycle life. Electrolyte optimization through ionic liquids, molten salts, and halide-modified systems further enhances ion mobility, suppresses passivation, and supports stable sulfur utilization. Emerging hybrid electrolytes combining high-donicity solvents with ionic or molten salt phases offer synergistic gains in redox kinetics and thermal stability. Density functional theory (DFT) guided designs elucidate key host-electrolyte-polysulfide interactions, revealing pathways for tailored material selection and performance enhancement. These integrated strategies pave the way for high-energy, long-lasting Al-S batteries that perform reliably at both room and elevated temperatures.}, } @article {pmid41062766, year = {2025}, author = {Bordon, Y}, title = {Autoimmune T cells identified in ALS.}, journal = {Nature reviews. Immunology}, volume = {25}, number = {11}, pages = {781}, pmid = {41062766}, issn = {1474-1741}, } @article {pmid41063344, year = {2025}, author = {Ito, H and Machida, K and Fujino, Y and Hasumi, M and Sakamoto, S and Nagai, Y and Imataka, H and Taguchi, H}, title = {Canonical translation factors eIF1A and eIF5B modulate the initiation step of repeat-associated non-AUG translation.}, journal = {Nucleic acids research}, volume = {53}, number = {18}, pages = {}, pmid = {41063344}, issn = {1362-4962}, support = {JP26116002//MEXT/ ; JP18H03984//MEXT/ ; JP21H04763//MEXT/ ; JP20H05925//MEXT/ ; //AMED/ ; JP21gm1410008//CREST/ ; //JST/ ; JPMJFS2112//JSPS/ ; 24KJ1067//JSPS/ ; //Uehara Memorial Foundation/ ; //Mitsubishi Foundation/ ; //Daiichi Sankyo/ ; //KAKENHI/ ; }, mesh = {Humans ; HEK293 Cells ; *Eukaryotic Initiation Factors/genetics/metabolism/physiology ; *Eukaryotic Initiation Factor-1/genetics/metabolism/physiology ; *Peptide Chain Initiation, Translational ; *Protein Biosynthesis ; *DNA Repeat Expansion ; Codon, Initiator ; Neoplasm Proteins ; Nerve Tissue Proteins ; }, abstract = {Nucleotide repeat expansions, such as the GGGGCC repeats in C9orf72, associated with C9-ALS, are linked to neurodegenerative diseases. These repeat sequences undergo a noncanonical translation known as repeat-associated non-AUG (RAN) translation. Unlike canonical translation, RAN translation initiates from non-AUG codons and occurs in all reading frames. To identify potential regulators of RAN translation, we employed a bottom-up approach using a human factor-based reconstituted cell-free translation system to recapitulate RAN translation. This approach revealed that omission of either eIF1A or eIF5B enhanced the translation in all reading frames of C9orf72-mediated RAN translation (C9-RAN), suggesting that eIF1A and eIF5B act as repressors of RAN translation. eIF1A and eIF5B are known to contribute to the fidelity of translation initiation. In HEK293T cells, double knockdown of eIF1A and eIF5B further promoted C9-RAN compared to single knockdowns, indicating that these factors regulate C9-RAN through distinct initiation steps. Furthermore, under eIF1A knockdown conditions, the enhancement of RAN translation via the integrated stress response (ISR) was not observed in HEK293T cells, indicating that eIF1A is involved in the ISR-mediated non-AUG translation.}, } @article {pmid41063391, year = {2025}, author = {Inoue, K and Toyooka, K and Fujimura, H and Ueda, K and Kaido, M and Yamamoto, Y and Izumi, Y}, title = {Familial ALS With p. L127S (L126S) Variant of the Cu/Zn SOD1 Gene: A Report of Two New Cases and Literature Review.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {45}, number = {6}, pages = {e70028}, pmid = {41063391}, issn = {1440-1789}, support = {25wm0625126s0301//Japan Agency for Medical Research and Development/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Middle Aged ; Female ; *Superoxide Dismutase-1/genetics ; Male ; Adult ; Motor Neurons/pathology ; Inclusion Bodies/pathology ; }, abstract = {Herein, we report two autopsy cases of familial ALS with a p. L127S (L126S) SOD1 variant. Case 1 involved a 62-year-old woman who presented with lower-extremity muscle weakness with lower motor neuron signs. The patient developed bulbar palsy and died of respiratory failure 9 years after onset. Case 2 (the second son of Case 1) presented with lower-extremity muscle weakness at the age of 38 years, with upper and lower motor neuron signs and died of respiratory failure 8 years after onset. The pathological findings in both cases predominantly consisted of lower motor neuron loss and degeneration of the lateral and posterior funiculi. Numerous conglomerate hyaline inclusions (CHIs) were observed in the remaining motor neurons. Vacuole formation was observed inside the inclusions, sometimes with granular structures. Some inclusions were positive for ubiquitin, p62, and SOD1. Electron microscopy revealed that CHIs were composed of neurofilaments and expanded mitochondria. By literature review, ALS with p. L127S disclosed a male-dominant incidence rate, a variety of ages at onset, and low penetrance. The initial symptom was exclusively lower limb weakness. One-third of the patients only showed lower motor neuron signs and half did not present with bulbar symptoms. The neuropathological findings commonly observed in ALS with p. L127S variants were mainly the degeneration of lower motor neurons and the sensory system, including the posterior column, Clarke's nucleus, and the associated cerebellar system. The formation of intracytoplasmic hyaline inclusions was also a prominent feature. ALS with p. L127S variant should be included in the possible diagnosis of slowly progressive muscle weakness in the lower extremities, with or without family history or upper motor neuron signs. The loss of lower motor neurons and the accumulation of neurofilaments in the remaining neurons are key to the pathological diagnosis for ALS with p. L127S variant.}, } @article {pmid41063967, year = {2025}, author = {Yoganathan, K and Trubshaw, M and Kohl, O and Gohil, C and Echeverria-Altuna, I and Dharmadasa, T and Northall, A and Zokaei, N and Lester, D and Garcia, G and Collins, A and Amein, B and Nobre, AC and Talbot, K and Thompson, AG and Woolrich, M and Turner, MR}, title = {Reduced beta bursting underpins loss of corticomuscular coherence in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {5}, pages = {fcaf339}, pmid = {41063967}, issn = {2632-1297}, abstract = {Biomarkers of disease activity that holistically capture motor system dysfunction are needed to accelerate drug discovery in amyotrophic lateral sclerosis. Magnetoencephalography is a sensitive, non-invasive measure of cortical neurophysiology. Corticomuscular coherence reflects the functional coupling of cortical oscillations with downstream muscle activity recorded by electromyography. Cortical beta frequency bursting is known to represent a core feature of the neurophysiology underpinning movement. This study aimed to characterize disruption of beta frequency activity in both cortex and muscle to refine the understanding of corticomuscular coherence loss in amyotrophic lateral sclerosis. The study analysed 42 people living with amyotrophic lateral sclerosis and 33 healthy age-matched controls. Participants undertook an isometric hand gripping task during magnetoencephalography. Muscle contraction was measured using bipolar surface electromyography recordings at both forearms. All participants performed 120 trials of the gripper task bilaterally, and 60 trials unilaterally on each side. For each trial type, the mean corticomuscular coherence over trials was calculated for each participant and the groups were compared via cluster-based permutations tests. Beta burst metrics were calculated for the motor cortex (magnetoencephalography) and flexor forearm muscles (surface electromyography) including burst fractional occupancy, burst duration and amplitude. During muscular contraction, beta frequency corticomuscular coherence from the motor cortices contralateral to the gripper task was markedly reduced in amyotrophic lateral sclerosis patients, despite no significant difference in grip strength compared with controls. Source localization analysis showed globally reduced corticomuscular coherence in amyotrophic lateral sclerosis with significant differences in the motor regions contralateral to the engaged hand. There were no significant beta frequency activity changes in the engaged-hand electromyography signal in amyotrophic lateral sclerosis compared with controls. In contrast, analysis of the cortical motor regions revealed reduced rate of beta bursting and higher amplitude during the contraction phase of the task in amyotrophic lateral sclerosis. The corticomuscular coherence disruption in amyotrophic lateral sclerosis appears driven more by cerebral pathology than by muscle denervation. Equal grip strength during the task implies compensatory pathways in disease that are not captured by corticomuscular coherence. Interneuronal dysfunction may underlie the disruption to motor cortex beta bursting. Motor cortical beta frequency metrics have potential as secondary outcome measures in therapeutic trials and need exploration as prodromal markers in asymptomatic individuals genetically predisposed to amyotrophic lateral sclerosis.}, } @article {pmid41064708, year = {2025}, author = {Posa, A and Kornhuber, M}, title = {A Very Rare Setx Gene Variant (C.2750T>C) In a 72-year-old Man with Amyotrophic Lateral Sclerosis and an Unremarkable Family History. Should Genetic Testing be Routinely Performed in all Patients?.}, journal = {European journal of case reports in internal medicine}, volume = {12}, number = {10}, pages = {005706}, pmid = {41064708}, issn = {2284-2594}, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative multisystem disease with loss of spinal, bulbar and cortical upper and lower motor neurons resulting in progressive and generalised paralysis. Unfortunately, many aspects of this disease remain unclear. In the age of next generation sequencing, numerous gene variants have been discovered that are associated with ALS. In this article, a 72-year-old male underwent a medical history interview, clinical neurological examinations, neuropsychological tests, electrophysiological examinations (electromyography, electroneurography, somatosensory evoked potentials), computed tomography scan of the head and the cervical spine, blood and cerebrospinal fluid tests and a genetic analysis. The results of these examinations provided the definitive diagnosis of ALS. Whole-exome sequencing revealed the very rare genetic finding of the SETX Class-4 variant c.2750T>C (p.Met917Thr). The case presented here discusses the role of the SETX gene as a possible pathogenetic variant of adult-onset ALS. It demonstrates the relevance of genetic screening for gene variants of ALS in routine diagnostics. The precise classification of disease-related gene variants is of great relevance for clinical practice.

LEARNING POINTS: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative multisystem disease with loss of spinal, bulbar and cortical upper and lower motor neurons resulting in progressive and generalised paralysis.The case presented here describes a very rare variant in the SETX gene (heterozygous Class-4 variant c.2750T>C, p.Met917Thr) in an adult man with sporadic rapidly progressive ALS, with an unremarkable family history.This case demonstrates the relevance of genetic screening for gene variants of ALS in routine diagnostics, both in sporadic and familial cases. This may add to the accuracy of diagnosis and may improve genetic counselling for rare diseases.}, } @article {pmid41065069, year = {2026}, author = {Shan, Y and Jing, W and Zhang, H and Liu, Y and Wei, S and Wu, F and Pan, W}, title = {Amyotrophic lateral sclerosis rehabilitation management and non-pharmacological symptomatic treatment: A review.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {64}, number = {1}, pages = {38-46}, doi = {10.5414/CP204744}, pmid = {41065069}, issn = {0946-1965}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology/diagnosis/psychology/therapy ; Quality of Life ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that lacks effective treatment options for the prevention of progression. Relieving swallowing difficulties, reducing breathing difficulties, and alleviating muscle spasms are essential to improving the quality of life in patients with ALS. Many symptoms can be treated clinically with medication; however, the evidence level of related research is relatively low. Rehabilitation management can aid in improving various functional impairments and enhancing quality of life. This review introduces and describes the relevant evaluations of rehabilitation and nonpharmacological symptomatic treatment methods for functional disorders from the perspectives of motor and nonmotor symptoms. This review may promote the popularization of ALS rehabilitation management and provide an additional reference for ALS treatment.}, } @article {pmid41065501, year = {2025}, author = {Soleimanifard, N and Seyedalipour, B and Baziyar, P and Hosseinkhani, S}, title = {Understanding Structural Destabilization and Amyloid Aggregation in ALS-Related Neurodegenerative Disorder: An In Silico and Experimental Analysis of SOD1 Variants.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {21}, pages = {4203-4223}, doi = {10.1021/acschemneuro.5c00350}, pmid = {41065501}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; Humans ; Molecular Dynamics Simulation ; Mutation/genetics ; *Amyloid/metabolism ; *Protein Aggregation, Pathological/genetics/metabolism ; Protein Folding ; Protein Structure, Secondary ; Protein Aggregates ; }, abstract = {Protein misfolding has been reported as a common symptom in many neurodegenerative diseases, leading to the formation of protein aggregates. Metal ions (holo form) are critical for the folding and function of WT-SOD1, whereas their absence (apo form) can lead to aggregation and misfolding under physiological conditions. Therefore, this study investigates the role of mutations/metal deficiencies in the metal binding loop and how the mutations affect the SOD1 aggregation process in amyotrophic lateral sclerosis through an experimental and computational approach. Molecular dynamic (MD) simulation results show a significant difference in apo-SOD1 compared to holo-SOD, which is consistent with experimental studies. Dictionary of Secondary Structure in Proteins (DSSP), Fourier-transform infrared (FTIR), and Circular dichroism (CD) results confirmed a tendency for increased β-sheet formation in the apo-SOD1 form, which can be attributed to protein aggregation. The observed conformational changes under amyloidogenic conditions suggest that the hydrophobic pockets in apo-SOD1 are more exposed compared to holo-SOD1, as confirmed by ANS fluorescence. Thermodynamic investigations with GdnHCl demonstrated that mutation/metal deficiency are necessary to trigger the misfolding and aggregation of SOD1. Our results show that apo/holo SOD1 variants induce the formation of aggregated species under physiological conditions. These aggregates are detected by Congo red and ThT fluorescence and further validated by transmission electron microscopy (TEM) imaging. Overall, mutations in loop IV and structural abnormalities such as mutation/metal deficiency and reduced disulfide bonds synergistically lead to reduced thermodynamic stability of SOD1 variants, facilitating the formation of amyloid/amorphous aggregates. Ultimately, this study could serve as a basis for new research to develop new treatments for neurological disorders, and help to better understand the role of mutation in the formation of amyloid aggregates and identify different factors in ALS disease.}, } @article {pmid41066153, year = {2025}, author = {Su, W and Zhang, C and Sun, L and Xu, H and Zhang, G and Xue, F and Leng, Q and Niu, Y and Wu, R}, title = {Multifaceted Mechanisms of Cyprosulfamide in Mitigating Mesosulfuron-Methyl Phytotoxicity in Maize Seedlings: GST Activation, Oxidative Stress Alleviation, and Target-Site Competition.}, journal = {Journal of agricultural and food chemistry}, volume = {73}, number = {42}, pages = {26584-26594}, doi = {10.1021/acs.jafc.5c07590}, pmid = {41066153}, issn = {1520-5118}, mesh = {*Zea mays/drug effects/metabolism/genetics/enzymology/growth & development ; Oxidative Stress/drug effects ; *Herbicides/toxicity ; *Sulfonylurea Compounds/toxicity ; *Plant Proteins/metabolism/genetics ; *Glutathione Transferase/metabolism/genetics ; Seedlings/drug effects/metabolism/genetics/growth & development/enzymology ; Superoxide Dismutase/metabolism/genetics ; *Sulfonamides/pharmacology ; Malondialdehyde/metabolism ; Acetolactate Synthase/metabolism/genetics ; }, abstract = {Mesosulfuron-methyl (MS), a sulfonylurea herbicide used in wheat, poses significant residual phytotoxicity risks to subsequent maize (Zea mays L.) crops. This study evaluated the protective role of the safener cyprosulfamide (CSA) through physiological, biochemical, and molecular analyses. MS treatment drastically reduced maize shoot length and fresh weight by 80.74% and 74.24%, respectively, while CSA pretreatment significantly relieved these inhibitory effects, with the mitigation rates of shoot length and fresh weight reaching 66.3% and 63.57%, respectively. Physiologically, CSA alleviated MS-induced chlorophyll and carotenoid losses and reduced oxidative stress by lowering malondialdehyde (MDA) levels (23.39% at 6 days after sowing) while enhancing superoxide dismutase (SOD) and glutathione S-transferase (GST) activity. Molecularly, CSA upregulated nine GST genes, competitively bound to ZmALS1/2, increasing acetolactate synthase (ALS) activity by 70-146%, and reduced MS residues in shoots (4.02%) and roots (33.78%). These findings demonstrate CSA's multifunctional detoxification mechanism, combining gene activation, antioxidant regulation, and target-site competition, offering a viable strategy to mitigate herbicide carryover in crop rotations. CSA application could significantly reduce MS phytotoxicity, advancing sustainable herbicide management.}, } @article {pmid41068958, year = {2025}, author = {Benito-Casado, C and Durán-Mateos, E and Ferrer-Donato, Á and García, GB and Domínguez-Rubio, R and Povedano, M and Fernandez-Martos, CM}, title = {White adipose tissue undergoes pathological dysfunction in the TDP-43[A315T] mouse model of amyotrophic lateral sclerosis (ALS).}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {213}, pmid = {41068958}, issn = {2051-5960}, support = {LCF/PR/HR19/52160016//"la Caixa" Banking Foundation and co-funded by Fundación Luzón/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Animals ; *DNA-Binding Proteins/genetics/metabolism ; Disease Models, Animal ; *Adipose Tissue, White/pathology/metabolism ; Male ; Humans ; Mice ; Female ; Leptin/blood ; Mice, Transgenic ; Middle Aged ; Aged ; Mice, Inbred C57BL ; Obesity/pathology ; }, abstract = {White adipose tissue (WAT) has a crucial role in maintaining systemic energy homeostasis. Numerous biological pathway studies have highlighted the importance of adipokines in regulating metabolic pathways and contributing to metabolic dysfunction in animal models and patients with ALS. Despite these associations, the specific molecular mechanisms remain poorly understood. Moreover, the direct contribution of WAT to the energy metabolism abnormalities observed in ALS has yet to be clearly defined. The current study sought to identify perturbances in WAT, main source of leptin, during the clinical course of the disease in TDP-43[A315T] mice using histological, proteomic, and molecular biological techniques. We present the first evidence of a significant histological alteration in WAT prior to the symptomatic stage of the disease in TDP-43[A315T] mice, providing novel insights into pathological features earlier in the onset of symptoms, and showing WAT as a target organ for ALS. In human ALS cases, we found that circulating leptin levels at the time of diagnosis were lower in the plasma of men with ALS who were overweight or obese and had rapidly progressive ALS, emphasizing the importance of considering sex-specific approaches when analysing adipokines essential for body weight control.}, } @article {pmid41069067, year = {2025}, author = {Arshad, F and Udupi, GA and Hk, A and Somaraj, A and Jeevendra Kumar, D and Alladi, S}, title = {Expanding the genetic spectrum of corticobasal syndrome: novel CCNF p.M394L variant from a South Asian cohort.}, journal = {Neurocase}, volume = {31}, number = {5}, pages = {221-229}, doi = {10.1080/13554794.2025.2573318}, pmid = {41069067}, issn = {1465-3656}, mesh = {Female ; Humans ; Male ; Middle Aged ; *Cognitive Dysfunction/genetics ; *Corticobasal Degeneration/genetics/diagnostic imaging/physiopathology ; Mutation, Missense ; *Neurodegenerative Diseases/genetics/diagnostic imaging ; Pedigree ; South Asian People/genetics ; }, abstract = {Corticobasal syndrome (CBS) is a rare neurodegenerative disorder characterized by asymmetric motor symptoms, cognitive impairment, and cortical dysfunction. While CCNF gene mutations have been reported in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), their role in CBS spectrum remains unexplored. This study aimed to investigate a 48-year-old patient of South Asian origin, presenting with progressive cognitive decline, behavioral disturbances, and asymmetric motor symptoms characteristic of overlap CBS syndrome. Detailed cognitive and behavioral assessments were conducted, along with brain imaging and whole-exome sequencing. Structural modeling was performed to assess the functional impact of the novel CCNF variant. The family history indicated an autosomal dominant inheritance pattern of progressive cognitive decline, further suggesting genetic predisposition. Brain imaging revealed asymmetric atrophy and hypometabolism in the left temporoparietal and prefrontal regions. Genetic analysis identified a novel heterozygous missense variant (p.Met394Leu) in the CCNF gene. Structural modeling and in-silico prediction tools suggested deleterious effects, though its functional significance remains uncertain. The study reports a potential link between CCNF variants and CBS in a South Asian family, expanding the genetic spectrum of overlap CBS. While the findings suggest potential pathogenicity, further research is required to confirm this association and elucidate the underlying mechanisms.}, } @article {pmid41069215, year = {2026}, author = {Revolinski, SR and Amaral, M and Savic, M and Burke, IC}, title = {Genome-wide scan reveals CYP450 metabolism and stress response regulation underlying sulfosulfuron resistance in Bromus tectorum.}, journal = {Pest management science}, volume = {82}, number = {2}, pages = {1500-1508}, doi = {10.1002/ps.70300}, pmid = {41069215}, issn = {1526-4998}, support = {//U.S. Department of Agriculture/ ; //Washington Grain Commission/ ; }, mesh = {*Herbicide Resistance/genetics ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; Genome-Wide Association Study ; *Sulfonamides/pharmacology ; *Herbicides/pharmacology ; Polymorphism, Single Nucleotide ; *Bromus/genetics/drug effects/metabolism/physiology ; Stress, Physiological/genetics ; Plant Proteins/genetics/metabolism ; Pyrimidines ; }, abstract = {BACKGROUND: Cheatgrass (Bromus tectorum L.) is a problematic weed species in the wheat cropping systems in the rainfed crop production areas of the inland Pacific Northwest (PNW) and now is becoming resistant to multiple modes of action. To identify mechanisms of non-target site acetohydroxy-acid/acetolactase synthase (AHAS/ALS) inhibitor resistance, 123 B. tectorum accessions were treated with three sulfosulfuron treatments (3.5, 35 and 350 g ha[-1]). A genome-wide association study (GWAS) was performed using the results from the spray trials to unravel the mechanisms underlying sulfosulfuron resistance in B. tectorum.

RESULTS: A single nucleotide polymorphism (SNP) explained up to 48% of observed phenotypic variation of sulfosulfuron resistance in B. tectorum but was not located near the AHAS/ALS gene in the genome. Candidate genes included members of the cytochrome P450 (CYP450) 71 gene family, heat shock-related proteins and a regulator of a heat shock-related protein. Additionally, the analysis revealed hormonal regulators, and genes involved in abiotic stress response as candidate genes.

CONCLUSION: Non-target site resistance for sulfosulfuron is present in B. tectorum populations of the inland PNW. A heat shock-related protein 70 regulator and an auxin response factor gene was near the SNP that explained 48% of the variation in the GWAS, indicating auxin regulation and stress response pathways are involved in the resistance of B. tectorum populations to sulfosulfuron. The heat shock-factor protein 70 regulated by the heat shock-related protein 70 regulator was found on another significant SNP and the SNPs those two genes were on have a significant interaction. Additionally, the GWAS analysis indicated CYP450 genes are likely involved in resistance. © 2025 Society of Chemical Industry.}, } @article {pmid41069745, year = {2025}, author = {Hino, S and Iijima, Y and Nakayama, N and Horie, N and Kaneko, T}, title = {Macroglossia Caused by Venous Congestion in a Patient With Amyotrophic Lateral Sclerosis.}, journal = {Clinical case reports}, volume = {13}, number = {10}, pages = {e71122}, pmid = {41069745}, issn = {2050-0904}, abstract = {The macroglossia in this patient appeared largely related to impaired venous return from the tongue and neck after coil embolisation, rather than to tongue pseudohypertrophy due to denervation atrophy with fatty replacement caused by ALS.}, } @article {pmid41070136, year = {2025}, author = {Jadeja, N and Ali, N and Dratch, L and Stanislaw, C and Barvin, D and Fournier, CN and Lichten, L}, title = {Exploring Motivation and Emotional Experience in Observational Research for Individuals at Risk of ALS/FTD Spectrum Disorders.}, journal = {Neurology. Clinical practice}, volume = {15}, number = {6}, pages = {e200538}, pmid = {41070136}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: Numerous observational studies are available to asymptomatic individuals at risk to carry or known carriers of pathogenic variations associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS-FTD) spectrum disorders. Little is known about such individuals' motivations for participation or the impact on their emotional well-being.

METHODS: Asymptomatic at-risk adults, with or without genetic status known, were recruited through social media advocacy groups and by National Society of Genetic Counselors ALS-FTD special interest group members. Interviews were conducted through secure videoconferencing. Two coders independently analyzed interview transcripts, followed by thematic content analysis.

RESULTS: Twelve participants (9 status-aware and 3 status-unaware) were interviewed, representing experience with 11 observational studies. Some motivations for participation aligned with previous literature, including altruism, health focus, and intellectual interest. Motivations unique to this population stemmed from the hereditary nature of the disease, including fear of future disease onset and the desire to establish a relationship with a specialized clinical care team, reflecting individual, familial, and societal factors. Benefits of participation included meeting these motivational goals, social connection and support, psychological well-being, and practical benefits. Challenges to participation fell into research-related (e.g., struggles with the observational nature of research), disease-related (e.g., anxiety about disease risk), and logistical (e.g., travel and study procedures) categories. Compared with status-unaware participants, status-aware participants more frequently cited individual motivators for research participation and encountered more research-related challenges when their participation did not align with their anticipated personal health benefits. Interviewees found relationships with providers through research to be rewarding but noted confusion between research and clinical care as a significant challenge.

DISCUSSION: Participation in observational research helps address unmet emotional and medical needs for asymptomatic individuals who are at risk of ALS-FTD spectrum disorders. However, some of these needs are beyond the scope of research, highlighting the need for new models of clinical care for at-risk individuals.}, } @article {pmid41070481, year = {2025}, author = {Doğan, V and Şenormanci, Ö}, title = {Validity and Reliability of the Affective Lability Scale-18 (ALS-18) Turkish Form in the Non-Clinical Group.}, journal = {Turk psikiyatri dergisi = Turkish journal of psychiatry}, volume = {36}, number = {}, pages = {18}, pmid = {41070481}, issn = {2651-3463}, mesh = {Humans ; Female ; Male ; Reproducibility of Results ; Turkey ; Psychometrics ; Adult ; *Psychiatric Status Rating Scales/standards ; Middle Aged ; Young Adult ; Factor Analysis, Statistical ; Surveys and Questionnaires ; *Affective Symptoms/diagnosis/psychology ; }, abstract = {OBJECTIVE: Affective lability, which is an important aspect of mood dysregulation, is seen in many psychiatric conditions. The aim of this study is to examine the psychometric properties of the Affective Lability Scale-18 in the Turkish sample of the non-clinical group.

METHOD: A total of 615 individuals (312 females and 303 males) who did not have a past or current psychiatric disorder were included in the study. The participants were administered sociodemographic data form, Affective Lability Scale-18, Difficulties in Emotion Regulation Scale, and Beck Depression Inventory. The participants were divided into 4 groups; a pilot group, EFA (exploratory factor analysis) group, CFA (confirmatory factor analysis) group and test-retest group.

RESULTS: The factor analysis conducted for the construct validity of the scale, revealed similar results to that of the original scale. The Cronbach's alpha internal consistency coefficient was 0.92 for the EFA group and 0.92 for the CFA group. The test-retest reliability coefficient was 0.82. Difficulties in Emotion Regulation Scale (DERS) and Beck's Depression Inventory (BDI) were used tp measure validity. The correlation between the total scores of participants on the ALS-18 and their scores on the DERS and BDI was determined to be positive and moderate (r=0.38, r=41).

CONCLUSION: The Affective Lability Scale-18 in the Turkish sample, three sub-dimensions, anxiety/depression, depression/elevation, anger and the general factor all have sufficient internal consistency and it has been demonstrated that the scale can be applied in our country to evaluate the situations in which affect variability is evaluated.}, } @article {pmid41070779, year = {2026}, author = {Lewis, KN and Craig, GA and Mason, J and Tomas, D and Cuic, B and Walker, AK and Gonsalvez, DG and Turner, BJ and Barton, SK}, title = {Oligodendroglial Densities and Myelin Structure Are Altered in TDP-43 Related Amyotrophic Lateral Sclerosis.}, journal = {Glia}, volume = {74}, number = {1}, pages = {e70090}, pmid = {41070779}, issn = {1098-1136}, support = {BGRF2002//Bethlehem Griffiths Research Foundation Grant/ ; //Jane Frances Hayes and Frederick William Hayes Charitable Trust Project Grant/ ; 2001675//National Health & Medical Research Council (NHMRC) Ideas Grant/ ; DIS-202303-00887//FightMND Discovery Project Grant/ ; //Rebecca L. Cooper Al & Val Rosenstrauss Medical Research Fellowship/ ; //Motor Neuron Disease Research Australia PhD Top-Up Scholarship/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *Oligodendroglia/pathology/ultrastructure/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *Myelin Sheath/pathology/ultrastructure/metabolism ; Male ; Mice, Transgenic ; Disease Models, Animal ; Spinal Cord/pathology/ultrastructure/metabolism ; Mice ; Cell Differentiation ; Mice, Inbred C57BL ; Cell Proliferation ; Humans ; Apoptosis ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons. However, the surrounding glia, including oligodendrocytes, also exhibit ALS pathology and TDP-43 related dysfunction. Given that oligodendrocytes, the myelinating cells of the central nervous system, are essential for motor neuron function, they may play an underappreciated role in ALS. Here, we have extensively characterized the oligodendrocyte lineage and myelin integrity in the TDP-43[Q331K] mouse model of ALS. In the lumbar spinal cord of end-stage male TDP-43[Q331K] mice (TDP-43), compared to wild-type littermates (WT), oligodendrocyte precursor cell (OPC) density, oligodendrocyte proliferation, and differentiation were all increased. There was no correlative increase in the density of mature oligodendrocytes, which was determined to be due to an increase in oligodendroglial apoptosis. In end-stage mice, myelin reflectance was increased in the dorsal column of TDP-43 mice, while electron microscopy showed myelin damage and misfolding in the TDP-43 mice. Our data suggest that the oligodendrocyte lineage is impacted in TDP-43 related ALS.}, } @article {pmid41072625, year = {2025}, author = {de Natale, ER and Verghese, JP and Terry, A and Wilson, H and Khosropanah, P and Wright, H and Passamonti, L and Evans, KC and Comley, RA and Tsukada, H and Passchier, J and Searle, G and Pererva, E and Whittington, A and Gunn, R and Rabiner, EA and Politis, M}, title = {An in vivo PET/CT investigation of mitochondrial complex 1, sigma 1, and synaptic vesicle 2 A in patients with amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {216}, number = {}, pages = {107138}, doi = {10.1016/j.nbd.2025.107138}, pmid = {41072625}, issn = {1095-953X}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; Middle Aged ; *Receptors, sigma/metabolism ; Female ; Sigma-1 Receptor ; Aged ; Positron Emission Tomography Computed Tomography/methods ; Cross-Sectional Studies ; *Nerve Tissue Proteins/metabolism ; *Electron Transport Complex I/metabolism ; *Brain/metabolism/diagnostic imaging ; Adult ; Membrane Glycoproteins ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder which pathology is still largely unclear.

OBJECTIVES: To perform an in vivo cross-sectional investigation of mitochondrial complex 1 (MC1), synaptic vesicle 2 A (SV2A), and sigma-1 receptor (S1R) expression in ALS patients using the PET radioligands [[18]F]BCPP-EF, [[11]C]UCB-J, and [[11]C]SA4503.

METHODS: Sixteen ALS patients (twelve males, mean age: 57.49 ± 12.08 years) and sixteen healthy controls underwent clinical assessment, MRI, and PET imaging with [[18]F]BCPP-EF, [[11]C]UCB-J, and [[11]C]SA4503. Patients were stratified based on disease the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) progression rate into slow, and moderate/fast progressors. Volume of distribution (VT) of predefined regions of interest, corrected for partial volume effects, was the primary outcome.

RESULTS: Across the ALS cohort, [[18]F]BCPP-EF binding was reduced in the amygdala (-13.9 %, F = 4.938 p = 0.034). Moderate/fast progression ALS patients exhibited [[18]F]BCPP-EF binding loss in the hippocampus (-20.0 %), amygdala (-21.4 %), cerebellum (-19.5 %), insular cortex (-19.3 %), temporal lobe (-19.0 %), and anterior cingulate (-18.7 %) (all p < 0.05); and [[11]C]SA4503 binding loss in the caudate (-20.6 %), pallidus (-26.8 %), amygdala (-20.2 %), hippocampus (-17.4 %), insular cortex (-16.9 %), accumbens (-17.0 %), anterior cingulate (-16.4 %) and temporal lobe (-19.8 %) compared to controls (all p < 0.05). In moderate/fast progressors, [[18]F]BCPP-EF loss in the insular cortex, amygdala, anterior cingulate, and temporal lobe correlated with lower ALSFRS-R scores (p < 0.05).

CONCLUSIONS: Our findings reveal loss of MC1 and S1R in ALS, suggesting mitochondrial dysfunction associated with disease progression. This work provides initial insights of mitochondrial and receptor pathology in ALS, potentially guiding future biomarker development and therapeutic interventions.}, } @article {pmid41073116, year = {2025}, author = {Barry, C and Farquhar, M and Hawkes, M and Massey, C and Cross, JL}, title = {Understanding the complexity of living with, and managing, secretions in motor neuron disease/amyotrophic lateral sclerosis (MND/ALS/ALS): protocol for a complex intervention systematic review.}, journal = {BMJ open}, volume = {15}, number = {10}, pages = {e103704}, pmid = {41073116}, issn = {2044-6055}, mesh = {Humans ; Systematic Reviews as Topic ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/complications ; *Motor Neuron Disease/therapy/physiopathology/complications ; Research Design ; Quality of Life ; *Bodily Secretions ; }, abstract = {INTRODUCTION: Motor neuron disease/amyotrophic lateral sclerosis (MND/ALS/ALS) is an incurable disease which leads to muscle weakness that worsens over time. MND/ALS is highly heterogeneous in its presentation, with many people experiencing a rapidly progressive trajectory of symptoms. Many people living with MND/ALS (plwMND/ALS) experience a combination of flaccidity and spasticity of the muscles involved in speech, swallowing, breathing and coughing. This makes it challenging to deal with the saliva and mucous ('secretions") produced by the body. Failure to manage these problems effectively can lead to accumulation and aspiration of secretions, which may cause pneumonia and respiratory insufficiency. Knowing the best way to treat this problem is a challenge. Systematic reviews report substantive ongoing uncertainty regarding secretions management (SM). Little is known about the comparative effectiveness of secretion management interventions, their impact on quality of life and acceptability for plwMND/ALS and their unpaid/family.

METHODS AND ANALYSIS: A complex intervention systematic review of SM for plwMND/ALS and/or their carers will be conducted using an iterative logic model approach, designed in accordance with the principles and guidance laid out in a series of articles published by the Agency for Healthcare Research and Quality on complex intervention reviews . Eight electronic databases will be searched for publications between 1996 and present: Ovid Embase, EBSCO CINAHL, EBSCO Academic Search Ultimate, Scopus, EBSCO PsycInfo, Ovid MEDLINE and the Social Sciences Citation Index. This will be supplemented by hand searching of reference lists of included studies. Two reviewers will independently screen the results for potentially eligible studies using AS Review Lab (a semi-automated machine learning tool). Study selection, data extraction and risk of bias assessment, using Gough's Weight of Evidence Framework, will be independently performed by two reviewers. A framework thematic synthesis approach will be employed to analyse and report quantitative and qualitative data. The reporting will be conducted in line with the Preferred Reporting Items for Systematic Review and Meta-Analysis Complex Intervention Extension Statement and Checklist.

ETHICS AND DISSEMINATION: This review will involve the secondary analysis of published information; therefore, ethical approvals are not required. Dissemination will be via presentation at scientific meetings, presentations to MND/ALS support groups and publications in peer-reviewed journals.

PROSPERO REGISTRATION NUMBER: CRD42025102364.}, } @article {pmid41073371, year = {2025}, author = {Liu, RY and Yin, KF and He, SY and Su, WM and Duan, QQ and Wen, XJ and Chen, T and Shen, C and Li, JR and Cao, B and Chen, YP}, title = {Viral infections and the risk of neurodegenerative diseases: a comprehensive meta-analysis and systematic review.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {388}, pmid = {41073371}, issn = {2158-3188}, mesh = {Humans ; *Neurodegenerative Diseases/epidemiology/virology ; *Virus Diseases/epidemiology/complications ; *Amyotrophic Lateral Sclerosis/epidemiology/virology ; *Parkinson Disease/epidemiology/virology ; Risk Factors ; *Alzheimer Disease/epidemiology/virology ; }, abstract = {BACKGROUND: Viral infections have been implicated in the pathogenesis of neurodegenerative diseases (NDs); however, evidence linking specific viruses to Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) remains inconclusive. This study conducted a meta-analysis and systematic review to investigate these associations.

METHODS: Thorough searches were conducted across Embase, PubMed, Cochrane Library, Web of Science and Scopus until May 18, 2025, to identify observational studies investigating the relationship between viral infections and the risk of NDs, including AD, PD, and ALS. Meta-analyses were executed using a random-effects model with Stata MP18.0.

RESULTS: A total of 34,417 articles were identified, of which 73 met the eligibility criteria for inclusion in the meta-analysis, and 48 were included in the systematic review. The analysis demonstrated that infections with cytomegalovirus (CMV) (odds ratio [OR] = 1.41; 95% confidence interval [CI]: 1.03, 1.93), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (OR = 1.88; 95% CI: 1.53, 2.32), hepatitis C virus (HCV) (OR = 1.39; 95% CI: 1.14, 1.69), and human herpesvirus (HHV) (OR = 1.24; 95% CI: 1.02, 1.51) were associated with an increased risk of AD. Regarding PD, infections with hepatitis B virus (HBV) (OR = 1.18; 95% CI: 1.04, 1.35) and HCV (OR = 1.29; 95% CI: 1.18, 1.41) were identified as risk factors. Conversely, no significant correlation was found between any viral infection and the risk of ALS.

CONCLUSION: This meta-analysis supports the role of select viral infections in AD and PD pathogenesis. However, no association was found between viral infections and ALS, warranting further large, multicenter, and longitudinal studies to elucidate mechanisms and confirm causality.}, } @article {pmid41073493, year = {2025}, author = {Montazeri, S and Bijani, S and Rashidzadeh, H and Ramazani, A and Andalib, S and Kalantari-Hesari, A and Cheraghi, G and Hosseini, MJ}, title = {Application of edaravone-loaded nanogel in alleviating behavioral deficits and oxidative stress in schizophrenia rat model.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {35468}, pmid = {41073493}, issn = {2045-2322}, support = {4000397//National Institute for Medical Research Development/ ; }, mesh = {Animals ; *Oxidative Stress/drug effects ; *Schizophrenia/drug therapy/metabolism ; *Edaravone/administration & dosage/pharmacology ; Rats ; Disease Models, Animal ; *Nanogels/chemistry ; Male ; Glutathione/chemistry ; *Behavior, Animal/drug effects ; Rats, Sprague-Dawley ; Prefrontal Cortex/drug effects/metabolism ; }, abstract = {Schizophrenia is considered as a main one of the public health issues, and imposes numerous burdens on patients and society. We previously reported, the pathophysiology of schizophrenia is influenced by inflammation and mitochondrial dysfunction. Edaravone (EDV) as a potent antioxidant with neuroprotective traits, has been approved for the treatment of amyotrophic lateral sclerosis (ALS), effecting through neutralizing soluble/insoluble peroxyl radicals. However, the main disadvantages of EDV are its low stability in aqueous media, poor water solubility, and un-optimized bioavailability. To effectively address these obstacles, nanogel was utilized as the drug vehicle. The decoration of nanogel surface with glutathione (GSH) was carried out to elevate edaravone's brain delivery. The probable improvement in drug delivery of edaravone loaded GSH-nanogel is the main hypothesis of this study. In order to mimic schizophrenia-like behaviors, we applied two month of post-weaning social isolation stress (PWSI) to rodent model. The choice of PWSI model was made due to the maturation and development of prefrontal cortex and hippocampus during adolescence. In addition to causing oxidative stress and upregulating genes linked to innate immunity in the prefrontal cortex (PFC), the data showed that PWSI triggered schizophrenia-like behaviors in rats. This study demonstrated that treatment with edaravone loaded GSH-nanogel decreased the impact of PWSI on behavioral dysfunctions and oxidative stress in the PFC of rats. Edaravone loaded GSH-nanogel (GSH-PMAA-EDV) down-regulated Toll-like receptor 4 (Tlr-4) and AMP-activated protein kinase (Ampk) gene expression which are involved in inflammation and cellular energy homeostasis, respectively. Increase immunoreactivity feedback and Brain-derived neurotrophic factor (Bdnf) as direct impact in neurogenesis and neural cell plasticity was observed in EDV loaded GSH-nanogel treated groups. edaravone loaded GSH-nanogel (100 µg/kg) in comparison to free form of edaravone (5 mg/kg) revealed more beneficial effects, which might be useful for future clinical use especially for the treatment of schizophrenia.}, } @article {pmid41073781, year = {2025}, author = {Vogan, K}, title = {A plasma proteomic signature for ALS.}, journal = {Nature genetics}, volume = {57}, number = {10}, pages = {2349}, doi = {10.1038/s41588-025-02384-y}, pmid = {41073781}, issn = {1546-1718}, } @article {pmid41074071, year = {2025}, author = {Cole, A and Chege, T and Aman, R and Githuka, G and Muga, R and Aspinall, A and Kokwaro, G}, title = {Health system challenges and facilitators associated with adaptive cycling deployment of multiple first-line treatment for uncomplicated malaria: a pilot study in a malaria-endemic region of Kenya.}, journal = {Malaria journal}, volume = {24}, number = {1}, pages = {328}, pmid = {41074071}, issn = {1475-2875}, support = {PO20/00538//Medicines for Malaria Venture/ ; }, mesh = {Kenya ; Pilot Projects ; *Antimalarials/therapeutic use/administration & dosage ; Humans ; Artemisinins/therapeutic use ; *Malaria/drug therapy ; Female ; Adult ; Male ; Drug Combinations ; Young Adult ; Drug Therapy, Combination ; Adolescent ; Middle Aged ; Artemether, Lumefantrine Drug Combination/therapeutic use ; Amodiaquine/therapeutic use ; }, abstract = {BACKGROUND: Artemisinin-based combination therapy (ACT) has been first-line treatment for uncomplicated malaria in sub-Saharan Africa for over two decades. However, emerging artemisinin partial resistance threatens efficacy. Multiple first-line treatments (MFTs) represent a proposed mitigation strategy, though associated health systems challenges remain unknown. This study evaluated health systems challenges and facilitators for MFT implementation in western Kenya.

METHODS: A 2 year pilot study (June 2020-June 2022) implemented adaptive cycling of four artemisinin-based combinations: Artemether-Lumefantrine (AL), Dihydroartemisin-Piperaquine (DHA-PIP), Amodiaquine-Artesunate (ASAQ), and Pyronaridine-Artesunate (PYR-ART) in western Kenya. Homa Bay (implementation) and Migori (control) counties were compared. Implementation involved 8 month drug cycling on mainland and 12 month cycling on Mfangano Island, while control county continued AL throughout. Adult patients diagnosed with uncomplicated malaria were included (pregnant women and children < 5 years excluded). Health systems assessment used semi-structured questionnaires, key informant interviews, and exit interviews. Outcome measures included diagnostic kit availability, procurement logistics, information system alignment, human resources, stakeholder acceptance, and side effects. Costs were tracked using ingredient approach, and malaria cases compared between counties.

RESULTS: MFT was accepted by key stakeholders. One minor adverse effect (vomiting) was reported. Patients preferred simple once-daily dosing of new drugs over AL's complicated regimen. Major challenges included logistics inefficiencies in drug quantification and stock management, human resource constraints, information system reconfiguration needs, and frequent diagnostic kit stock-outs. Start-up and implementation costs were roughly equal. Economic cost per patient treated was USD 3, lower than reported elsewhere in sub-Saharan Africa. Digital health tools (SMS/WhatsApp) facilitated implementation through improved communication and follow-up. Migori (control) showed 12.5 percentage points higher malaria positivity rates (23.3% vs 10.8%) with better directional consistency. Testing efficiency differed markedly (4.3 vs 9.2 tests per positive case) between counties.

CONCLUSION: Adaptive cycling MFT implementation is feasible in Kenya with adequate planning and addressing health systems challenges. Stakeholder engagement and continuous training were critical for success. Policy implications and regional cooperation potential warrant exploration in other sub-Saharan African countries with different deployment contexts.}, } @article {pmid41074141, year = {2025}, author = {Gómez-Almería, M and Gonzalo-Consuegra, C and Rodríguez-Cueto, C and Cabañas-Cotillas, M and Jiménez-Amor, A and Machín-Díaz, I and Wittwer, MB and Dzygiel, P and Clemente, D and Grether, U and Fernández-Ruiz, J and de Lago, E}, title = {Relevance of a peripheral site of action outside the brain-blood barrier for the beneficial effects of CB2 receptor activation in experimental ALS in male mice.}, journal = {Cell communication and signaling : CCS}, volume = {23}, number = {1}, pages = {427}, pmid = {41074141}, issn = {1478-811X}, support = {CB06/05/0089//Instituto de Salud Carlos III/ ; CB06/05/0089//Instituto de Salud Carlos III/ ; CB06/05/0089//Instituto de Salud Carlos III/ ; PI24/00447//Instituto de Salud Carlos III/ ; CB06/05/0089//Instituto de Salud Carlos III/ ; PI21/00302//Instituto de Salud Carlos III/ ; PI21/00302//Instituto de Salud Carlos III/ ; CB06/05/0089//Instituto de Salud Carlos III/ ; CB06/05/0089//Instituto de Salud Carlos III/ ; RTI-2018-098885-B-100//Ministerio de Ciencia e Innovación/ ; RTI-2018-098885-B-100//Ministerio de Ciencia e Innovación/ ; RTI-2018-098885-B-100//Ministerio de Ciencia e Innovación/ ; PID2021-128906OB-I00//Ministerio de Ciencia e Innovación/ ; RTI-2018-098885-B-100//Ministerio de Ciencia e Innovación/ ; RTI-2018-098885-B-100//Ministerio de Ciencia e Innovación/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy ; *Receptor, Cannabinoid, CB2/metabolism/agonists ; Male ; *Blood-Brain Barrier/metabolism/drug effects ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/metabolism/pathology ; Superoxide Dismutase-1 ; Disease Models, Animal ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {BACKGROUND: Cannabinoid type 2 receptor (CB2) activation works against neurotoxic events that kill motor neurons in amyotrophic lateral sclerosis. Given that amyotrophic lateral sclerosis is a neuromuscular pathology with the skeletal muscle being also affected, we were interested in deciphering whether peripheral CB2 may contribute in these beneficial effects.

METHODS: To this end, we used two CB2 agonists: (i) RO-6866945, which crosses the blood-brain barrier (BBB) and acts at both Central Nervous System (CNS) and peripheral compartments; and (ii) RO-6871304, which is a peripherally-restricted ligand that activates CB2 outside the BBB. Both agonists have been evaluated in SOD-1 and TDP-43 transgenic male animals.

RESULTS: In both cases, their i.p. administration improved the neurological status of these mice, preserved their spinal motor neurons and attenuated glial reactivity. They also recovered those muscle fibers denervated by the pathology in SOD-1 transgenic mice. To confirm that the efficacy of RO-6871304 is not derived from a possible BBB damage in amyotrophic lateral sclerosis mice that may allow this agonist to reach the CNS, we analyzed their concentrations in neural tissues after acute administration in both experimental models. Our data confirmed that RO-6866945 was detected in the brain, while RO-6871304 was not, whereas both compounds were found in the plasma.

CONCLUSIONS: In summary, our data suggest that CB2 located at peripheral sites (skeletal muscle, immune cells, others) may be responsible of therapeutic effects showed by compounds targeting these receptors in amyotrophic lateral sclerosis. Our study may be of critical importance to move CB2 agonists in amyotrophic lateral sclerosis towards the clinical scenario.}, } @article {pmid41075354, year = {2025}, author = {Weinreich, M and McDonough, H and Heverin, M and Domhnaill, ÉM and Yacovzada, N and Magen, I and Cohen, Y and Harvey, C and Elazzab, A and Gornall, S and Boddy, S and Alix, JJP and Kurz, JM and Kenna, KP and Zhang, S and Iacoangeli, A and Al-Khleifat, A and Snyder, MP and Hobson, E and Chio, A and Malaspina, A and Hermann, A and Ingre, C and Costa, JV and van den Berg, L and Panadés, MP and van Damme, P and Corcia, P and de Carvalho, M and Al-Chalabi, A and Hornstein, E and Elhaik, E and Shaw, PJ and Hardiman, O and McDermott, C and Cooper-Knock, J}, title = {Optimised machine learning for time-to-event prediction in healthcare applied to timing of gastrostomy in ALS: a multi-centre, retrospective model development and validation study.}, journal = {EBioMedicine}, volume = {121}, number = {}, pages = {105962}, pmid = {41075354}, issn = {2352-3964}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/surgery/therapy ; Bayes Theorem ; Europe ; *Gastrostomy/methods ; *Machine Learning ; Retrospective Studies ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is invariably fatal but there are large variations in the rate of progression. The lack of predictability can make it difficult to plan clinical interventions. This includes the requirement for gastrostomy where early or late placement can adversely impact quality of life and survival.

METHODS: We designed a model to predict the timing of gastrostomy requirement in ALS as indicated by 5% weight loss from diagnosis. We considered >5000 different prediction model configurations including spline models and a set of deep learning (DL) models designed for time-to-event prediction. The optimal prediction model was chosen via a Bayesian framework to avoid overfitting. Model covariates were measurements routinely collected at diagnosis; a separate longitudinal model also incorporated weight at six months. We employed a training dataset of 3000 patients from Europe, and two external validation cohorts spanning distinct populations and clinical contexts (United States, n = 299; and Sweden, n = 215). Missing data was imputed using a random forest model.

FINDINGS: The optimal model configuration was a logistic hazard DL model. The optimal model achieved a median absolute error (MAE) between predicted and measured time of 3.7 months, with AUROC 0.75 for gastrostomy requirement at 12 months. To increase accuracy we updated predictions for those who had not received gastrostomy at six months after diagnosis: here MAE was 2.6 months (AUROC 0.86). Combining both models achieved MAE of 1.2 months for the modal group of patients. Prediction performance is stable across both validation cohorts. Missing data was imputed without degrading model performance.

INTERPRETATION: To enter routine clinical practice a prospective study will be required, but we have demonstrated stable performance across multiple populations and clinical contexts suggesting that our prediction model can be used to guide individualised gastrostomy decision making for patients with ALS.

FUNDING: Research Ireland (RI) and Biogen have supported the PRECISION ALS programme.}, } @article {pmid41075396, year = {2025}, author = {Tse, NY and Orlando, IF and O'Callaghan, C and Taylor, NL and Shine, JM and Zalesky, A and Tu, S and Ahmed, RM and Halliday, GM and Piguet, O and Hodges, JR and Kiernan, MC and Lewis, SJG and Devenney, EM}, title = {Susceptibility to visual hallucinations in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum: The role of dysfunctional attentional networks.}, journal = {Cortex; a journal devoted to the study of the nervous system and behavior}, volume = {192}, number = {}, pages = {213-226}, doi = {10.1016/j.cortex.2025.08.014}, pmid = {41075396}, issn = {1973-8102}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology/complications/diagnostic imaging ; Male ; Female ; Middle Aged ; *Frontotemporal Dementia/physiopathology/psychology/complications/diagnostic imaging ; *Hallucinations/physiopathology/psychology ; Magnetic Resonance Imaging/methods ; Aged ; *Attention/physiology ; Neuropsychological Tests ; Connectome ; Executive Function/physiology ; Brain/physiopathology/diagnostic imaging ; Nerve Net/physiopathology ; }, abstract = {Psychotic symptoms are well established across the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum and contribute to patient and carer distress and poorer prognosis. However, there are no objective tools to probe these symptoms and the underlying functional neurobiology has been unexplored to date. Leveraging clinical interview, neuropsychological testing, and a validated behavioural paradigm of visual misperception combined with connectome-wide fMRI analysis, we directly probed visual hallucinatory tendencies and the associated cognitive and functional connectivity signatures in ALS-FTD. In 82 participants across the ALS-FTD spectrum (24 ALS patients, 7 ALS-FTD, 31 behavioural-variant FTD [19 C9orf72 expansion carriers and 43 non-carriers] and 20 healthy controls), we showed that an ecologically valid behavioural task was sensitive to hallucinatory tendencies. We observed selective involvement of attentional deficits in visual misperception beyond the influence of executive function and psychomotor speed (r ranging from .344-.603; FDR-corrected at p < .05). Following quality control, data-driven whole-brain fMRI analysis in a subset of 26 patients converged to implicate the attentional systems, wherein abnormally heightened connectivity anchored in the attentional, default mode and executive control networks worsened as a function of visual misperception severity (FWE-corrected p = .042 with 10,000 permutations). Our findings underscore the critical role of attentional disruptions, characterised by altered interactions between top-down and bottom-up attentional, introspective, and salience detection processes, in ALS-FTD visual hallucinatory predisposition. Aligning with current models of hallucination generation postulated in schizophrenia, Parkinson's disease, and dementia with Lewy bodies, our findings point towards common neural underpinnings of psychosis vulnerability shared by ALS-FTD.}, } @article {pmid41075687, year = {2025}, author = {Liu, Y and He, S and Gao, H and Wang, X and Zhang, Q and Tian, W and Duan, B and Liu, L}, title = {Co-adsorption behavior of Cr(III) and Cd(II) via direct application of argillaceous limestone.}, journal = {Journal of chromatography. A}, volume = {1763}, number = {}, pages = {466444}, doi = {10.1016/j.chroma.2025.466444}, pmid = {41075687}, issn = {1873-3778}, mesh = {Adsorption ; *Calcium Carbonate/chemistry ; *Cadmium/chemistry/isolation & purification ; *Chromium/chemistry/isolation & purification ; Hydrogen-Ion Concentration ; *Water Pollutants, Chemical/isolation & purification/chemistry ; Kinetics ; Water Purification/methods ; }, abstract = {The study investigated the removal of Cr(Ⅲ) and Cd(Ⅱ) by argillaceous limestone (AL) in a binary adsorption system. The results indicate that AL's capacity to adsorb Cr(Ⅲ) is enhanced by the presence of Cd(Ⅱ). Conversely, the presence of Cr(Ⅲ) significantly decreases the adsorption of Cd(Ⅱ). The adsorption mechanisms involve precipitation, chelation, and ion exchange. AL's adsorption behavior was well described by the pseudo-second-order kinetic model, suggesting that the adsorption process was dominated by chemical interactions and the monolayer adsorption pattern. The pH affects adsorption primarily by altering the protonation degree of the AL surface. In the single-component system, the maximum adsorption capacity for Cr(III) reached 30.98 mg·g[-][1] at pH 7.0, while that for Cd(Ⅱ) reached 38.80 mg·g[-][1] at pH 8.0. In the binary system, Cr(Ⅲ) achieved its highest adsorption capacity (42.56 mg·g[-][1]) at pH 6.0, while Cd(Ⅱ) exhibited a maximum capacity of 19.16 mg·g[-][1] at pH 7.0. The presence of Na[+] and Ca[2][+] ions reduced the adsorption efficiency, with greater inhibition observed as ionic strength increased. This study clarifies the composite adsorption behavior of AL in multi-ion systems and can advance the direct application of natural minerals in environmental pollution remediation.}, } @article {pmid41075758, year = {2026}, author = {Gery, KL and Ramos, S and Lee, JC}, title = {Correlative Raman and immunofluorescence imaging reveals different protein abundance between stress granules induced by oxidative damage.}, journal = {Journal of inorganic biochemistry}, volume = {274}, number = {}, pages = {113091}, pmid = {41075758}, issn = {1873-3344}, support = {ZIA HL006236/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Oxidative Stress/drug effects ; *Stress Granules/metabolism/drug effects ; *Spectrum Analysis, Raman/methods ; Arsenites/toxicity/pharmacology ; Sodium Compounds/toxicity/pharmacology ; Hydrogen Peroxide/pharmacology ; Cell Line, Tumor ; Fluorescent Antibody Technique/methods ; Poly-ADP-Ribose Binding Proteins/metabolism ; Reactive Oxygen Species/metabolism ; RNA Recognition Motif Proteins/metabolism ; DNA Helicases/metabolism ; RNA Helicases ; }, abstract = {Heavy metal toxicity generates reactive oxygen species (ROS) that can contribute to neurodegeneration. Oxidative damage from exposure to metals such as sodium arsenite will activate the integrated stress response and may result in the cytosolic formation of stress granules (SGs), which have been implicated in neurodegenerative disorders such as amyotrophic lateral sclerosis. Here, two different ROS sources, sodium arsenite and hydrogen peroxide, under acute (1 h) and chronic (24 h) conditions, were used to induce SG formation in human osteosarcoma (U-2 OS) cells and investigate if characteristics of SGs could depend on the induction. Specifically, correlative Raman and immunofluorescence imaging (CRIFI) was developed to evaluate the relative protein abundance found in SGs to ascertain their potential as loci for protein accumulation. Interestingly, while there are differences in the punctate-staining phenotypes for different stressors, two types of puncta visualized by CRIFI were common to all treatment conditions, where notably a subset exhibited protein concentration above cytosolic background, indicating that only some SGs are composed of protein-rich, dense phases. Differences in protein abundance between SGs were also observed within a single cell, suggesting that individual SGs can develop differently. These results demonstrate the versatility and the strength of pairing Raman spectroscopy, which allows for probe-free detection of different chemical functional groups, with specific protein localization granted by immunofluorescence, providing new cellular insights unattainable by either modality alone.}, } @article {pmid41076779, year = {2026}, author = {Li, W and Wang, X and Zang, S and Zhou, R and Zhou, H and Yue, H and Geng, M and Zhan, Z and Xie, Z and Duan, W}, title = {Discovery of a potent and orally bioavailable 3,3-dimethyl-2-oxoindoline STING inhibitor.}, journal = {European journal of medicinal chemistry}, volume = {301}, number = {}, pages = {118232}, doi = {10.1016/j.ejmech.2025.118232}, pmid = {41076779}, issn = {1768-3254}, mesh = {Animals ; Humans ; Structure-Activity Relationship ; Mice ; *Membrane Proteins/antagonists & inhibitors/metabolism ; *Indoles/pharmacology/chemistry/administration & dosage/chemical synthesis ; Administration, Oral ; Molecular Structure ; *Drug Discovery ; Dose-Response Relationship, Drug ; Biological Availability ; STING Protein ; }, abstract = {Stimulator of interferon genes (STING) plays an imperative role in the innate immune response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Overstimulated STING axis has proven to incur multiple autoimmune or inflammatory diseases, such as Aicardi-Goutières syndrome, systematic lupus erythematosus, and amyotrophic lateral sclerosis. Here we report the discovery of a series of 3,3-dimethyl-2-oxoindoline STING inhibitors. We converted the STING agonist G10 to a STING inhibitor 8a by grafting an indole-3-yl group, and extensive structure-activity relationship (SAR) exploration of 8a allowed us to identify compound 10a as a potent and orally bioavailable STING inhibitor. Biological characterization unraveled that 10a significantly suppressed the STING signaling pathway in human monocytes and murine macrophages, potently alleviated cisplatin-induced kidney injury both in vitro and in vivo, as well as achieved robust anti-inflammatory efficacy on STING agonist-induced inflammation mice model through systemic administration. The proposed binding mode of 10a and the STING protein displays that 10a targets the transmembrane domain of STING.}, } @article {pmid41076903, year = {2025}, author = {Muhire, J and Zhang, FX and Liu, BQ and Hu, J and Wang, X and Pei, D and Di, DL}, title = {HSCCC-Tchebichef moment regression approach for enhanced quantification of oleuropein in olive leaf extracts.}, journal = {Journal of chromatography. A}, volume = {1763}, number = {}, pages = {466445}, doi = {10.1016/j.chroma.2025.466445}, pmid = {41076903}, issn = {1873-3778}, mesh = {*Plant Extracts/chemistry ; Chromatography, High Pressure Liquid/methods ; Iridoid Glucosides/chemistry ; *Regression Analysis ; }, abstract = {Oleuropein, a major bioactive phenolic compound from olive leaves, has attracted considerable interest for its health benefits. Targeted fractionation of oleuropein from crude extracts is hampered by the co-existence of numerous structurally similar metabolites, making conventional chromatographic separation inefficient. Here we describe, for the first time, a compact predictive framework that combines high-speed countercurrent chromatography (HSCCC), discrete Tchebichef moment (TM) feature extraction, and stepwise regression (SR) modelling to quantify oleuropein. Olive leaves were extracted with 80 % ethanol, and the crude extract was subjected to continuous-injection HSCCC in reverse‑phase mode using an ethyl acetate-petroleum ether-water (6:0.06:7) solvent system. HPLC analysed the resulting fractions and reference standards. Chromatograms were converted into two-dimensional matrices from which TMs up to the 20th order were computed. Forward stepwise regression identified a small set of TM coefficients that correlated strongly with oleuropein concentration and yielded a linear predictive model with high accuracy (R[2] > 0.99). In comparison to the MCR-ALS, the TM-based model achieved superior predictive performance using fewer parameters. The integrated HSCCC-TM-SR approach provides a rapid and scalable method for quantifying oleuropein and may be extended to other complex natural products.}, } @article {pmid41077137, year = {2026}, author = {Nguyen, R and Sauer, J}, title = {Response to Chen et al's "Risk of major adverse cardiovascular events and venous thromboembolic events between patients with psoriasis or psoriatic arthritis on tumor necrosis factor inhibitors, interleukin 17 inhibitors, interleukin 12/23 inhibitors, and interleukin 23 inhibitors: An emulated target trial analysis".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {2}, pages = {e119-e120}, doi = {10.1016/j.jaad.2025.08.129}, pmid = {41077137}, issn = {1097-6787}, } @article {pmid41077525, year = {2026}, author = {Campbell, N and Lilley, R and Davie, G and Morgaine, K and Dicker, B and Kool, B}, title = {Prehospital advanced versus basic life support: A cohort study comparing survival to hospital for major trauma patients in New Zealand.}, journal = {Australasian emergency care}, volume = {29}, number = {2}, pages = {138-145}, doi = {10.1016/j.auec.2025.09.008}, pmid = {41077525}, issn = {2588-994X}, mesh = {Humans ; New Zealand/epidemiology ; Male ; Female ; Middle Aged ; Adult ; *Emergency Medical Services/methods/statistics & numerical data/standards ; Cohort Studies ; *Wounds and Injuries/mortality/therapy ; Aged ; *Life Support Care/methods/statistics & numerical data/standards ; Qualitative Research ; Propensity Score ; }, abstract = {OBJECTIVE: To examine the relationship between prehospital Advanced Life Support (ALS) and survival to hospital for major trauma patients in New Zealand and explore its implications for Emergency Medical Service (EMS) practice.

METHODS: A mixed-methods explanatory design was used. Data on major trauma patients attended by road EMS (December 2016-November 2018) was analysed. A multivariable model with propensity scores estimated the odds of survival for patients receiving Advanced versus Basic Life Support (BLS). Semi-structured interviews conducted with EMS stakeholders were analysed using thematic analysis.

RESULTS: Among 1118 patients, 661 (59 %) received ALS. Only 52 (5 %) did not survive to hospital. Multivariable modeling estimated ALS recipients had 1.5 times higher odds of survival than BLS-only recipients (OR 1.49, 95 % CI 0.66-3.35). Interviews with five EMS clinical leaders highlighted two likely influences: clinical judgment and evidence use. Despite imprecise quantitative findings, stakeholders supported ALS based on clinical judgment.

CONCLUSIONS: A tension between population-level results and provision of care based on clinical judgement exists. Quantitative analysis found no evidence that ALS offers a survival benefit, although considerable uncertainty exists, whereas stakeholders perceive ALS has clinical and equity benefits. Future research should assess equity, disability, and quality of life outcomes of ALS.}, } @article {pmid41079430, year = {2025}, author = {Argelazi, RL and Graça, SC and Thomazoni, PV and Moura, CB and Gomes, AC and Kormanski, MK and de Almeida, SSC and Ferreira, YD and Santos, DH}, title = {TBK1 mutation and its role in frontotemporal dementia and amyotrophic lateral sclerosis in Brazilian families.}, journal = {Dementia & neuropsychologia}, volume = {19}, number = {}, pages = {e20240227}, pmid = {41079430}, issn = {1980-5764}, abstract = {UNLABELLED: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are progressive neurodegenerative diseases with unclear etiology. Mutations in the TBK1 gene are associated with an increased risk of both FTD and ALS, presenting a diverse phenotype that includes the behavioral variant of FTD, primary progressive aphasia, and pure ALS. This mutation is rare, and to date, only one case report on TBK1-related clinical manifestations has been published in Brazil.

OBJECTIVE: To investigate the association between TBK1 gene mutations and the clinical manifestations of FTD and ALS in a Brazilian family, documenting the clinical history and disease progression of three first-degree relatives. Additionally, to conduct a literature review to better understand the impact of this mutation and its implications for neurological practice.

METHODS: Clinical data were collected from three patients in the same family who were receiving care at Dom Pedro II Geriatric Hospital and Central Hospital of the Irmandade da Santa Casa de Misericordia de São Paulo, including information on clinical symptoms, disease progression, and complementary exams - particularly genetic testing to detect and confirm the diagnosis. A detailed analysis of the existing literature on the disease was also conducted to better understand the implications of this mutation.

RESULTS: Three siblings affected by the TBK1 gene mutation were documented, with a unique family history suggesting that this genetic alteration has affected the lineage for several generations.

CONCLUSION: Although rare, frontotemporal dementia with accompanying motor deficits is of significant relevance to neurologists due to its poor prognosis and the potential familial impact on descendants.}, } @article {pmid41079689, year = {2025}, author = {Marchal, N and Janes, WE and Marushak, S and Popescu, M and Song, X}, title = {Enhancing ALS progression tracking with semi-supervised ALSFRS-R scores estimated from ambient home health monitoring.}, journal = {Frontiers in digital health}, volume = {7}, number = {}, pages = {1657749}, pmid = {41079689}, issn = {2673-253X}, abstract = {INTRODUCTION: Clinical monitoring of functional decline in amyotrophic lateral sclerosis (ALS) relies on periodic assessments, which may miss critical changes that occur between visits when timely interventions are most beneficial.

METHODS: To address this gap, semi-supervised regression models with pseudo-labeling were developed; these models estimated rates of decline by targeting Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) trajectories with continuous in-home sensor data from a three-patient ALS case series. Three model paradigms were compared (individual batch learning and cohort-level batch vs. incremental fine-tuned transfer learning) across linear slope, cubic polynomial, and ensembled self-attention pseudo-label interpolations.

RESULTS: Results showed cohort-level homogeneity across functional domains. For ALSFRS-R subscales, transfer learning reduced the prediction error in 28 of 34 contrasts [mean root mean square error (RMSE) = 0.20 (0.14-0.25)]. However, for composite ALSFRS-R scores, individual batch learning was optimal for two of three participants [mean RMSE = 3.15 (2.24-4.05)]. Self-attention interpolation best captured non-linear progression, providing the lowest subscale-level error [mean RMSE = 0.19 (0.15-0.23)], and outperformed linear and cubic interpolations in 21 of 34 contrasts. Conversely, linear interpolation produced more accurate composite predictions [mean RMSE = 3.13 (2.30-3.95)]. Distinct homogeneity-heterogeneity profiles were identified across domains, with respiratory and speech functions showing patient-specific progression patterns that improved with personalized incremental fine-tuning, while swallowing and dressing functions followed cohort-level trends suited for batch transfer modeling.

DISCUSSION: These findings indicate that dynamically matching learning and pseudo-labeling techniques to functional domain-specific homogeneity-heterogeneity profiles enhances predictive accuracy in tracking ALS progression. As an exploratory pilot, these results reflect case-level observations rather than population-wide effects. Integrating adaptive model selection into sensor platforms may enable timely interventions as a method for scalable deployment in future multi-center studies.}, } @article {pmid41080389, year = {2025}, author = {Devanarayan, P and Sena, R and Johnson, D}, title = {Characterization and Application of Statewide Emergency Medical Services Advanced Life Support Protocols.}, journal = {Cureus}, volume = {17}, number = {9}, pages = {e92053}, pmid = {41080389}, issn = {2168-8184}, abstract = {INTRODUCTION: Many emergency medical services (EMS) systems in the United States utilize statewide protocols, but the number, type, and role of these systems in prehospital decision-making are largely unknown.

STUDY OBJECTIVE: To characterize statewide protocols and determine their role in prehospital decision-making.

METHODS: All states were queried for the presence of mandatory statewide Advanced Life Support (ALS)-level EMS protocols. Protocols were categorized as diagnosis-based, symptom-based, procedural, or non-clinical by two fellowship-trained EMS physicians. A data abstraction guide with category examples was included. Discrepancies were resolved by a third blinded EMS physician. The number and type of protocols were compiled, and simple statistics and chi-squared analysis were used to evaluate state-by-state variation.

RESULTS: Nine states have mandatory statewide ALS protocols, totaling 804 individual protocols, including 672 (83.6%) clinical and 132 (16.4%) non-clinical protocols. Symptom-based protocols accounted for 59.5% of the clinical protocols, while 13.2% were diagnosis-based and 27.2% procedural. Per state, there was a median interquartile range (IQR) of 46 (14.5) symptom-based, 8 (8) diagnosis-based, and 17 (22.5) procedural protocols. There was significant variation in the type and number of protocols by state (p < 0.001).

CONCLUSION: Significant variation exists in statewide EMS protocols. While many are symptom-based, a notable portion are diagnosis-based, challenging the notion that paramedics cannot diagnose. These findings suggest a need for higher-level clinical decision-making in EMS. Further research is warranted at other EMS training levels and to inform EMS training programs.}, } @article {pmid41082679, year = {2025}, author = {Tabor Gray, L and Sullivan, S and O'Brien, M and Costello, J and Plowman, E and Garand, KLF}, title = {International Survey of Practice Patterns of Speech-Language Pathologists Working With Patients With Amyotrophic Lateral Sclerosis.}, journal = {American journal of speech-language pathology}, volume = {34}, number = {6}, pages = {3343-3354}, doi = {10.1044/2025_AJSLP-25-00064}, pmid = {41082679}, issn = {1558-9110}, support = {R01 NS100859/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/physiopathology/complications ; *Speech-Language Pathology/trends ; *Deglutition Disorders/therapy/diagnosis/etiology/physiopathology ; *Practice Patterns, Physicians'/trends ; Health Care Surveys ; United States ; Male ; Female ; Surveys and Questionnaires ; *Communication Disorders/therapy/diagnosis/etiology ; }, abstract = {BACKGROUND: Speech-language pathologists (SLPs) evaluate and treat swallowing and communication impairments in individuals with amyotrophic lateral sclerosis (ALS). Standardized clinical practice guidelines for the evaluation and management of bulbar dysfunction in ALS have not yet been established. This study aimed to describe current international practice patterns of SLPs evaluating and treating bulbar dysfunction in ALS.

HYPOTHESIS: Significant variability in practice patterns will exist across SLPs working in different clinical settings with varied resources.

METHOD: A 26-item Qualtrics survey was electronically distributed to SLPs via e-mail, social media, and professional discussion boards.

RESULTS: Data from 245 respondents across 20 countries and 32 states within the United States were collected, with the final analysis including 214 respondents. Most respondents practiced in metropolitan areas (69%) and worked in multidisciplinary ALS clinics (41%), outpatient clinics (16%), and home health settings (17%). Cranial nerve examination (91%), swallow trials (79%), speech intelligibility tasks (85%), and diadochokinetic speech rates (65%) were frequently included in evaluations. Although 81% of clinics had access to instrumental swallowing evaluations, 32% reported performing them in fewer than 25% of patients. Communication evaluations were offered directly by 58% of clinicians, while 26% referred to an outside SLP and 16% collaborated with device representatives. Most clinicians provided patient education on swallowing (87%) and oral health (83%). However, managed practice varied widely, revealing no standardized treatment that is routinely offered. Barriers to optimal ALS care included time constraints, relevant clinical training, timing of treatment, addressing psychosocial components of care, access to resources, interdisciplinary communication, and insurance coverage (United States only).

DISCUSSION: Findings reveal little consensus on symptomatic bulbar management and intervention timing. Results emphasize the urgent need for the development of a standardized minimal data set to best guide the evaluation and management of bulbar dysfunction in ALS.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.30249997.}, } @article {pmid41083054, year = {2025}, author = {Cao, YB and Zhuang, SP and Huang, ZY and Shi, JY and Lin, HY and Chen, S and Huang, NX and Zou, ZY and Qin, W and Chen, HJ}, title = {Structural atrophy and functional disturbance in the thalamic nuclei of patients with amyotrophic lateral sclerosis.}, journal = {Brain research bulletin}, volume = {232}, number = {}, pages = {111581}, doi = {10.1016/j.brainresbull.2025.111581}, pmid = {41083054}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology/diagnostic imaging ; Male ; Female ; Middle Aged ; Atrophy/pathology ; Magnetic Resonance Imaging/methods ; *Thalamic Nuclei/pathology/physiopathology/diagnostic imaging ; Aged ; Adult ; }, abstract = {OBJECTIVE: This study investigated the structural and functional impairments in thalamic nuclei in amyotrophic lateral sclerosis (ALS) and evaluated their associations with disease severity and diagnostic value.

METHODS: This study was conducted on T1-weighted and resting-state functional magnetic resonance images from 71 ALS patients and 61 healthy controls. In each hemisphere, the thalamus was parcellated into 25 nuclei and subsequently grouped into 6 subregions. The volume and amplitude of low-frequency fluctuation (ALFF, reflecting spontaneous neural activity) in each thalamic subregion were measured and compared between groups. These metrics were then used for correlation and diagnostic analyses.

RESULTS: A volumetric reduction was observed in the bilateral anterior, intralaminar, ventral, and left medial thalamic subregions in the ALS patients (FWE-corrected P < 0.05). A decreased ALFF was observed in the right anterior and ventral thalamic subregions of patients with ALS (FWE-corrected P < 0.05). The volumes of the bilateral intralaminar (left: r = 0.304, P = 0.011; right: r = 0.281, P = 0.018) and ventral (left: r = 0.355, P = 0.003; right: r = 0.335, P = 0.005) thalamic subregions were correlated with disease severity. Compared with the whole-thalamic measurements, the volumetric and ALFF measurements of thalamic subregion demonstrated greater diagnostic performance. The combined volumetric and ALFF measurements in the thalamic subregions further resulted in a significantly increased AUC (0.865, P < 0.001).

CONCLUSIONS: Selective structural and functional damage to thalamic subregions is a feature of ALS and could potentially contribute to future diagnostic approaches and assessments of disease severity.}, } @article {pmid41083292, year = {2025}, author = {Jerath, A and Slessarev, M and Martin, C and D'Aragon, F and Carrier, FM and Senaratne, J and Meggison, H and Hooper, J and Alexandros Cavayas, Y and Goligher, EC and Couture, EJ and Randall, I and Hatzakorzian, R and Jacka, M and Wiener-Kronish, J and Xie, Z and Pinto, RL and Cuthbertson, B and , }, title = {Sedating with volatile anaesthetics for COVID-19 and non-COVID-19 acute hypoxaemic respiratory failure patients in ICU (SAVE-ICU): protocol for a randomised clinical trial.}, journal = {BMJ open}, volume = {15}, number = {10}, pages = {e108441}, pmid = {41083292}, issn = {2044-6055}, mesh = {Humans ; *COVID-19/complications/therapy ; *Respiration, Artificial/methods ; *Respiratory Insufficiency/therapy/etiology ; Intensive Care Units ; *Anesthetics, Inhalation/administration & dosage/therapeutic use ; SARS-CoV-2 ; Canada ; *Hypnotics and Sedatives/administration & dosage ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; *Hypoxia/therapy/etiology ; Pragmatic Clinical Trials as Topic ; United States ; }, abstract = {INTRODUCTION: Inhaled anaesthetics can be used in mechanically ventilated critically ill patients to provide sedation. This approach to sedation potentially improves patient and health system outcomes, but further supportive evidence is needed. The objective of the SAVE-ICU clinical trial is to compare the effectiveness of inhaled versus intravenous sedation in ventilated adults with acute hypoxaemic respiratory failure.

METHODS AND ANALYSIS: SAVE-ICU is a multicentre, open-label, pragmatic, randomised controlled trial conducted in 15 intensive care units (ICUs) in Canada and the USA. Eligible patients include mechanically ventilated and sedated adults with acute hypoxemic respiratory failure from COVID-19 or non-COVID causes with PaO2/FIO2 ratio <300 mm Hg. Patients are excluded with a history of malignant hyperthermia, allergy to sedative agents, raised intracranial pressure, need for concomitant prostacyclin, low tidal volumes (<200 mL), one-lung ventilation or pneumonectomy, severe neuromuscular disorder (eg, amyotrophic lateral sclerosis, Guillain-Barré syndrome), pregnancy or moribund status (unlikely to survive >12 hour). A hierarchy of outcomes was identified at the time of trial design, as the trial was launched during the COVID-19 pandemic when study drug shortages, staffing challenges and healthcare system pressures were prevalent and there was a requirement for rapid evidence generation and implementation on this topic. The primary outcome and highest in the hierarchy is hospital mortality (requiring 758 participants). Secondary and lower hierarchical outcomes are ventilator-free days at day 30 (200 patients), quality of life at 3 months (144 participants) and ICU-free days at day 30 (128 participants). Additional secondary outcomes include median daily oxygenation at day 3 (PaO2/FIO2 ratio), need for adjunctive acute respiratory distress syndrome therapies (prone positioning, inhaled nitric oxide, paralysis with a neuromuscular blocking agent and extracorporeal membrane oxygenation) during ICU stay, days alive and free from delirium and coma at day 14, hospital-free days at day 60 and disability score at 3 months and 12 months after enrolment.

ETHICS AND DISSEMINATION: The protocol was approved by all hospital ethics committees and by Health Canada. Informed consent will be obtained from substitute decision makers or deferred consent (as permitted by site ethics board). Trial findings will be shared at the end of the study using peer-review publications, conference presentations and social media as part of the trial knowledge translation plan.

TRIAL REGISTRATION NUMBER: NCT04415060.}, } @article {pmid41083392, year = {2025}, author = {Guo, Y and Li, CJ and Wei, H and Ding, Y and Guo, LJ and Gao, YN}, title = {[Clinical analysis of a motor neuron disease-like phenotype associated with anti-IgLON5 disease].}, journal = {Zhonghua nei ke za zhi}, volume = {64}, number = {10}, pages = {977-983}, doi = {10.3760/cma.j.cn112138-20241018-00695}, pmid = {41083392}, issn = {0578-1426}, mesh = {Aged ; Female ; Humans ; Amyotrophic Lateral Sclerosis/immunology/diagnosis ; *Autoantibodies/blood ; *Cell Adhesion Molecules, Neuronal/immunology ; Electromyography ; *Motor Neuron Disease/immunology/diagnosis ; Phenotype ; }, abstract = {We report a case of anti-IgLON5 disease with a motor neuron disease-like presentation admitted to the Department of Neurology, Xuanwu Hospital, Capital Medical University in July 2021. The patient was a 71-year-old female who presented with the chief complaint of limb weakness persisting for 4 months. She showed progressive limb weakness accompanied by muscle atrophy. Electromyography (EMG) revealed extensive neurogenic damage. Initial serum evaluation for neural-specific autoantibodies was positive for IgLON5-Ab (1∶100). Repeat testing confirmed IgLON5-Ab positivity with a titer of 1∶1 000. The patient was diagnosed with anti-IgLON5 disease and treated with methylprednisolone and immunoglobulin, leading to clinical improvement. We found four relevant articles reporting a total of 11 similar cases. Thus, in this study, we analyzed a total of 12 cases, including our patient. Based on their clinical manifestations, these cases can be categorized into two types: amyotrophic lateral sclerosis(ALS)type and isolated bulbar type. Six cases-three males and three females-presented with the ALS type. Of these, three cases had diffuse limb weakness accompanied by muscle atrophy(two cases had diffuse hyperreflexia and one had a normal tendon reflex); one case presented with neck extensor weakness and bilateral asymmetric upper extremity weakness and was hyperreflexic at the bilateral patellar tendons; one case displayed asymmetric weakness in both lower limbs with normal deep reflexes, and one case exhibited neck weakness with hyperreflexia. EMG revealed diffuse lower motor neuron disease involving two or three regions. All patients tested positive for serum anti-IgLON5 antibodies. Four were also positive for anti-IgLON5 antibodies in cerebrospinal fluid, two were negative, and six were not tested. Among the 11 patients who received immunotherapy, 4 showed partial improvement in clinical symptoms, 2 exhibited transient improvement, 2 remained stable, and 3 showed no improvement. Testing for IgLON5-Ab should be considered among patients presenting with bulbar symptoms or ALS-like features, especially those with acute or subacute onset, rapid progression, autonomic dysfunction, vocal cord paralysis requiring tracheotomy, cognitive impairment, or involuntary movements. Early diagnosis and treatment may improve clinical symptoms and reduce adverse outcomes.}, } @article {pmid41083520, year = {2025}, author = {Specht, O and Stateczny, A}, title = {A novel method for coastal zone bathymetry based on multisensor data fusion and unmanned systems.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {35637}, pmid = {41083520}, issn = {2045-2322}, support = {WN/2025/PZ/05//Uniwersytet Morski w Gdyni/ ; }, abstract = {Existing geospatial data fusion methods in hydrography do not take into account the accuracy of individual measurements when creating a bathymetric map. Consequently, geospatial data acquired by devices with low depth measurement accuracy may lead to a deterioration in the accuracy of coastal zone topography. To address this limitation, this study presents a novel method for coastal bathymetric monitoring based on the integration of multimodal geospatial data collected by unmanned platforms equipped with on-board sensors. These include Single-Beam Echo Sounder (SBES) and MultiBeam EchoSounder (MBES), a photogrammetric camera, and Light Detection and Ranging (LiDAR) from Airborne Laser Scanning (ALS) and Mobile Laser Scanning (MLS). As part of this method, bathymetric and photogrammetric data are processed using three modules: processing depth data, processing shallow-water data, and determining the coastline. After processing, the data are fused using an original weighted average data fusion method, in which weights for individual data sources are determined based on the measurement accuracy. The results demonstrate that the proposed coastal monitoring method effectively minimises redundant geospatial inputs. Notably, the model is parametric, and its accuracy depends on the appropriate selection of processing parameters and fusion settings.}, } @article {pmid41084041, year = {2025}, author = {Hassan, YM and Wanas, A and Ali, AA and El-Sayed, WM}, title = {Integrating artificial intelligence with nanodiagnostics for early detection and precision management of neurodegenerative diseases.}, journal = {Journal of nanobiotechnology}, volume = {23}, number = {1}, pages = {668}, pmid = {41084041}, issn = {1477-3155}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/therapy ; *Artificial Intelligence ; Early Diagnosis ; *Nanomedicine/methods ; *Precision Medicine/methods ; Animals ; Nanotechnology ; Intelligent Systems ; }, abstract = {BACKGROUND: Neurodegenerative diseases—including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS)—as well as autoimmune disorders with neurodegenerative features such as multiple sclerosis (MS), present an escalating global challenge. Current diagnostics often detect pathology too late, and most treatments focus on symptom relief rather than disease modification. There is an urgent need for tools that enable early detection and precision-targeted intervention. MAIN BODY: Nanotechnology offers unique advantages in this space, enabling early molecular detection, targeted drug delivery, and theranostic systems. Engineered nanocarriers, biosensors, and responsive nanodevices are being tailored to disease-specific features such as oxidative stress in AD or neuroinflammation in MS. Yet, issues like biocompatibility, clinical scalability, and long-term safety remain barriers to translation. Artificial intelligence (AI) enhances nanomedicine by improving biomarker sensitivity, stratifying patients, and enabling predictive disease modeling. From AI-guided nanoparticle design to closed-loop delivery systems and digital twin models, these technologies work synergistically to support real-time, personalized care. Still, critical challenges—including algorithmic bias, lack of explainability, heterogeneous datasets, and limited regulatory clarity—impede clinical integration. Additionally, high system complexity and cost risk excluding low-resource settings unless inclusive, scalable alternatives are pursued. CONCLUSION: The convergence of AI and nanotechnology is reshaping neurodegenerative disease care, moving from reactive to proactive, personalized neurology. Realizing this promise requires cross-sector collaboration, ethical foresight, and translational rigor to ensure these innovations are safe, equitable, and accessible to all patients.}, } @article {pmid41084991, year = {2026}, author = {Vasta, R and Callegaro, S and Canosa, A and Manera, U and Grassano, M and Palumbo, F and Cabras, S and Matteoni, E and Di Pede, F and De Mattei, F and Tafaro, S and Thakur, NM and Grosenick, R and De Marchi, F and Mazzini, L and Moglia, C and Calvo, A and Dave, KD and Chiò, A}, title = {Amyotrophic Lateral Sclerosis Prevalence Projection in 2040: A Less Rare Disease.}, journal = {Annals of clinical and translational neurology}, volume = {13}, number = {2}, pages = {379-386}, pmid = {41084991}, issn = {2328-9503}, support = {24-SI-684//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Prevalence ; Registries ; Incidence ; Middle Aged ; Female ; Aged ; Male ; Adult ; *Rare Diseases/epidemiology ; Global Health/statistics & numerical data ; Aged, 80 and over ; }, abstract = {OBJECTIVE: To project ALS prevalence across multiple countries through 2040, accounting for both population aging and increased survival.

METHODS: Data from the Piemonte and Valle d'Aosta ALS register (PARALS) was used to estimate the trends in incidence and prevalence from 2005 to 2019. Survival trends over this period were also assessed. The observed annual increase was then projected into future years up to 2040. Concurrently, the incidence for each future year was calculated using population projections. Finally, the prevalence rate for each year was estimated as the product of the projected incidence and the projected survival. We also estimated survival for fifteen countries by dividing prevalence by incidence, based on available data, and applied the same increase observed in PARALS to project prevalence in these countries up to 2040.

RESULTS: Using data from 3294 patients, we determined that ALS survival increased by 0.06 years annually from 2005 to 2019 in Piemonte and Valle d'Aosta. Considering changes in incidence due to population aging, the prevalence is projected to reach 15.72 per 100,000 population by 2040 in this area, while rising by a median of 24.9% across multiple countries worldwide. If a new drug could provide a 6-month increase in survival starting in 2025, disease prevalence would rise by 37.8% by 2040. We provided a web interface so users can model different data and assumptions.

INTERPRETATION: ALS prevalence is projected to increase significantly over the next decades. This underscores the need for careful planning and allocation of public health resources.}, } @article {pmid41085196, year = {2025}, author = {Lee, J and Kwon, I}, title = {Phase Separation of TAF15 C-Terminal LC Domain Enables RNA-Binding Protein-Mediated Transcriptional Regulation.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {39}, number = {20}, pages = {e71126}, pmid = {41085196}, issn = {1530-6860}, support = {RS-2022-NR075088//National Research Foundation of Korea (NRF)/ ; RS-2024-00336294//National Research Foundation of Korea (NRF)/ ; }, mesh = {*TATA-Binding Protein Associated Factors/metabolism/genetics/chemistry ; Humans ; RNA-Binding Protein FUS/metabolism/genetics ; Protein Domains ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; *RNA-Binding Proteins/metabolism/genetics ; *Transcription, Genetic ; Mutation ; HEK293 Cells ; *Gene Expression Regulation ; Transcriptional Activation ; Protein Binding ; Phase Separation ; }, abstract = {TAF15 is an RNA/ssDNA-binding protein and transcriptional activator implicated in diseases such as cancer and ALS. Its C-terminal low-complexity (LC) domain harbors most ALS-associated mutations, suggesting a crucial role in disease mechanisms. Here, we demonstrate that this LC domain mediates dynamic interactions with the RNA-binding protein hnRNPA0, which enhances the transcriptional activity of TAF15. Domain-swapping experiments with the related protein FUS show that the C-terminal LC domain of TAF15 is both necessary and sufficient for hnRNPA0 responsiveness. Phosphomimic mutations in the C-terminal LC domain disrupt this interaction and diminish hnRNPA0-mediated transcriptional activation. hnRNPA0 contains the RNA recognition motif and LC domain, both of which are required for hnRNPA0 to promote transcription. Furthermore, ALS-linked mutations in TAF15 impair its ability to undergo phase separation, reduce binding to hnRNPA0, and eliminate transcriptional enhancement. These findings suggest that TAF15's C-terminal LC domain connects hnRNPA0 to transcriptional regulation, and that this mechanism is disrupted in ALS-associated mutations.}, } @article {pmid41085218, year = {2025}, author = {Anzilotti, S and De Iesu, N and Gargiulo, S and Di Muraglia, N and Cicatiello, AG and Dentice, M and Panico, M and Albanese, S and Annunziato, L and Salvatore, M and Pignataro, G and Pappatà, S}, title = {TSPO Expression and [18F]DPA-714 PET/CT Imaging as Pathogenetic and Diagnostic Biomarkers in Symptomatic Stages of Skeletal Muscle Fiber Degeneration in SOD1-G93A ALS Mice.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {39}, number = {20}, pages = {e71129}, pmid = {41085218}, issn = {1530-6860}, support = {CUPE63C22002170007//PNRR, Spoke 3, MNESYS, PE00000006, M4 C2 I 1.3, finanziato dall'Unione Europea-NextGenerationEU, (to G.P.)/ ; CUPB63D22000600006//PNRR, Spoke 7, MNESYS, PE00000006, M4 C2 I 1.3, finanziato dall'Unione Europea-NextGenerationEU, (to L.A. and N.D.I.)/ ; HEALTHF22011278850FP7/2007-2013//European Union's Seventh Framework Program INMiND, (to S.P.)/ ; //Italian Ministry of Health (Ricerca Corrente Project)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging/pathology/genetics ; Mice ; *Positron Emission Tomography Computed Tomography/methods ; *Receptors, GABA/metabolism/genetics ; Mice, Transgenic ; *Pyrazoles ; *Pyrimidines ; Biomarkers/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Muscle Fibers, Skeletal/metabolism/pathology ; Fluorine Radioisotopes ; Muscle, Skeletal/metabolism/pathology ; Male ; Humans ; }, abstract = {Emerging evidence highlights the involvement of skeletal muscle in the pathogenesis of amyotrophic lateral sclerosis (ALS), through mechanisms involving inflammation and mitochondrial dysfunction in skeletal muscle fibers. The 18 kDa translocator protein (TSPO) is primarily expressed on the outer mitochondrial membrane, is implicated in inflammation, and serves as both a biomarker and a therapeutic target for neuroinflammation. This study investigated whether PET imaging targeting the TSPO, immunohistochemistry, and confocal microscopy can characterize skeletal muscle inflammation and muscular fiber damage in SOD1-G93A ALS transgenic mice. High-resolution PET/CT imaging with [18F]DPA-714 was employed to assess TSPO expression in the triceps brachii of SOD1-G93A mice at mild (age range: 98-112 days; Clinical Score (CS) range:1-1.5) and moderate-severe (age range: 120-137 days; CS range: 2-4) symptomatic stages. To support PET data, TSPO was analyzed by immunohistochemistry and confocal microscopy in the triceps skeletal muscle obtained from mild and moderate-severe SOD1-G93A mice. Inflammatory and anti-inflammatory macrophage cells in skeletal muscle tissues were detected by immunofluorescence. PET/CT revealed a progressive, significant increase of [18F]DPA-714 uptake in SOD1-G93A triceps brachii in mild and moderate-severe stages. Immunohistochemistry and confocal microscopy confirmed increased TSPO expression in the degenerating muscle fibers and in infiltrating macrophage cells. In vivo studies of TSPO expression in ALS-affected skeletal muscles may provide valuable insights into muscle inflammation and mitochondrial involvement during disease progression. In addition, TSPO and PET/CT imaging with [18F]DPA-714 might represent a noninvasive and promising diagnostic biomarker for detecting early muscle pathology in ALS.}, } @article {pmid41086149, year = {2025}, author = {Clackson, O and Hamid, MR and Wijesekera, A and Kulick, D and O'Neil, AL}, title = {Exposure to the organochlorine pesticide cis-chlordane induces ALS-like mitochondrial perturbations in stem cell-derived motor neurons.}, journal = {PloS one}, volume = {20}, number = {10}, pages = {e0332422}, pmid = {41086149}, issn = {1932-6203}, mesh = {*Chlordan/toxicity ; Pesticides/toxicity ; *Amyotrophic Lateral Sclerosis/chemically induced/pathology ; *Mitochondria/drug effects/metabolism ; *Motor Neurons/cytology/drug effects/pathology ; Reactive Oxygen Species/metabolism ; Adenosine Triphosphate/biosynthesis ; Membrane Potential, Mitochondrial/drug effects ; Oxygen Consumption/drug effects ; Sequence Analysis, RNA ; Cell Line ; Humans ; Induced Pluripotent Stem Cells ; Human Embryonic Stem Cells ; Cell Differentiation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a debilitating and incurable neurodegenerative disease with unsolved etiology. Due to the large proportion of patients lacking direct disease inheritance, understanding the environmental factors that contribute to ALS development is of high priority. Epidemiological studies have implicated pesticides and other environmental exposures as possible contributors to ALS pathogenesis. Recently, our group determined that the organochlorine pesticide cis-chlordane is toxic to human motor neurons in a dose-dependent manner, causing an ALS-like phenotype in culture and animals with a mode of action independent of its known GABAA antagonism. Here, we aimed to characterize downstream motor neuron phenotypes associated with cis-chlordane treatment. We performed bulk RNA sequencing, live imaging, immunofluorescent labeling, and real-time metabolic assays on stem cell-derived motor neurons to assess chlordane-associated phenotypes in vitro. We demonstrate that cis-chlordane treatment causes a highly altered mitochondrial phenotype in motor neurons, including increased production of reactive oxygen species, decreased oxygen consumption rate and ATP production, and loss of mitochondrial membrane potential. We further implicate cis-chlordane as a possible mediator of potent motor neuron damage, with exposure to the pesticide inducing mitochondrial phenotypes akin to those seen in ALS. Our findings contribute to the growing body of evidence that future studies of investigating the role of pesticides in ALS development should focus on organochlorine molecules.}, } @article {pmid41087397, year = {2025}, author = {Schilling, MA}, title = {The geographic association of multiple sclerosis and amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {34665}, pmid = {41087397}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Humans ; *Multiple Sclerosis/epidemiology/mortality ; Male ; Female ; Geography ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are both devastating, incurable, neurodegenerative diseases that are largely considered to be of unknown etiology. While the diseases have some similarities, they are not typically considered to be closely related. They have different pathological markers and different prognoses. Additionally, MS (but not ALS) is considered an autoimmune disease. Furthermore, MS has long been noted to have a strong north-south gradient in its distribution whereas only recently has awareness grown of such a gradient in ALS. The study here will show, however, that if the distribution of ALS and MS are analyzed using mortality data, they are extremely correlated even after controlling for gender, race and latitude. This relationship was not previously identified in part because of a Simpson's paradox in the data: strong correlations that are obvious in the data when they are separated by gender are obscured when the data are pooled across gender. The presence of a strong association in the distributions of ALS and MS suggests there is a connection between the two diseases that is not yet understood. That connection may prove valuable in helping to illuminate what causes the diseases, and whether and how they can be prevented and treated.}, } @article {pmid41087573, year = {2025}, author = {Rutkove, SB and Shah, P and Hevenor, L and Tiwari, G and Patil, D and Mourey, T and Nagy, JA and Nath, AK}, title = {Surface electrical impedance myography detects disease in an adult-onset SOD1-G93A zebrafish model of amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {35810}, pmid = {41087573}, issn = {2045-2322}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/physiopathology/pathology ; Zebrafish ; Disease Models, Animal ; Electric Impedance ; *Superoxide Dismutase-1/genetics ; Motor Neurons/pathology/metabolism ; *Myography/methods ; Muscle, Skeletal/pathology/physiopathology ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by loss of motor neurons and atrophy of skeletal muscle. Current FDA-approved drugs to treat ALS are only modestly effective at slowing the progression of the disease. Rodents have been the standard preclinical animal model for testing candidate ALS drugs; however, alternative animal models, including zebrafish, are being studied to accelerate therapeutic discovery. Here, we sought to advance a model of ALS in zebrafish with associated tools to serve as biomarkers of neuromuscular deterioration. Thus, we applied noninvasive, surface electrical impedance myography (EIM) methodology to SOD1[G93A] zebrafish and control animals to evaluate its ability to serve as an electrophysiological biomarker of disease in ALS zebrafish. Measurements were acquired from the caudal musculature of animals at 2 time points by applying an alternating current at 41 frequencies (1 kHz-1 MHz) and measuring the resulting voltages. At the first time point, SOD1[G93A] animals still exhibited normal body morphometrics, spinal cord motor neuron numbers, and skeletal muscle mass, while at the second time point, these SOD1[G93A] animals exhibited reduced weight, loss of motor neurons, type 1 and 2 myofiber atrophy, and decreased capacity for endurance swimming. We found that non-invasive surface EIM detected the alterations observed in diseased ALS zebrafish at the second time point. Specifically, EIM measurements (phase angle, reactance, and resistance) at 2 and 50 kHz were robust metrics that distinguished between healthy and diseased zebrafish. To assess the reliability of our EIM technique in healthy and ALS zebrafish, we calculated the intraclass correlation coefficient and conducted Bland-Altman analyses. The EIM methodology exhibited excellent reproducibility in both healthy and ALS zebrafish. In sum, these findings demonstrate that EIM is an effective tool to detect neuromuscular disease in symptomatic adult ALS zebrafish, and the approach described here offers a fast, noninvasive, and reliable platform that holds the potential to test candidate drug therapeutic efficacy.}, } @article {pmid41087751, year = {2025}, author = {Masrori, P and Bijnens, B and Fumagalli, L and Davie, K and Poovathingal, SK and Meese, T and Storm, A and Hersmus, N and Fazal, R and van den Biggelaar, D and Asselbergh, B and Gruel, R and Van Den Daele, J and Denton, H and Miquel, PP and Manzella, S and De Vos, WH and Chandran, S and Van Den Bosch, L and Thal, DR and Mancuso, R and Van Damme, P}, title = {C9orf72 hexanucleotide repeat expansions impair microglial response in ALS.}, journal = {Nature neuroscience}, volume = {28}, number = {11}, pages = {2217-2230}, pmid = {41087751}, issn = {1546-1726}, support = {Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; 20240019//Internationale Stichting Alzheimer Onderzoek (ISAO)/ ; ADP0144//Universiteit Antwerpen (University of Antwerp)/ ; 11PD824N//Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)/ ; G0F8516N; G065721N//Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Microglia/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; Humans ; *DNA Repeat Expansion/genetics ; Animals ; Mice ; Induced Pluripotent Stem Cells ; Spinal Cord/metabolism/pathology ; Astrocytes/metabolism ; Female ; Male ; }, abstract = {Microglia and neuroinflammation are involved in amyotrophic lateral sclerosis (ALS), but the precise underlying molecular mechanisms remain elusive. We generated single-nuclei transcriptomes from the spinal cord and motor cortex of patients with sporadic ALS (sALS) and C9orf72 ALS (C9-ALS). Here we confirmed that C9orf72 is highly expressed in microglia and observed that the hexanucleotide repeat expansion (HRE) results in haploinsufficiency. Whereas sALS microglia transitioned toward disease-associated cell states, C9orf72 HRE microglia exhibited a diminished response, with alterations in endolysosomal pathways. We confirmed these observations using a human microglia xenograft model, in which C9orf72 mutations led to a reduced activation. We also confirmed the endolysosomal alterations in C9orf72 HRE and C9orf72-deficient induced pluripotent stem cell (iPSC)-derived microglia. We also found a diminished response of C9orf72 HRE astrocytes and provided a map of dysregulated ligand-receptor pairs in microglia and astrocytes. Our data highlight variations in the cellular substrate of sporadic and inherited forms of ALS, which have implications for patient stratification and selection of appropriate treatments.}, } @article {pmid41088409, year = {2025}, author = {Ward, EL and Benowitz, L and Brunner, TM and Bu, G and Cayouette, M and Canto-Soler, V and Dá Mesquita, S and Di Polo, A and DiAntonio, A and Duan, X and Goldberg, JL and He, Z and Hu, Y and Liddelow, SA and La Torre, A and Margeta, M and Quintana, F and Shekhar, K and Stevens, B and Temple, S and Venkatesh, H and Welsbie, D and Flanagan, JG}, title = {Modeling neurodegeneration in the retina and strategies for developing pan-neurodegenerative therapies.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {108}, pmid = {41088409}, issn = {1750-1326}, support = {R01 EY034353/EY/NEI NIH HHS/United States ; P30 EY026877/EY/NEI NIH HHS/United States ; R01 EY032518/EY/NEI NIH HHS/United States ; U01 NS136405/NS/NINDS NIH HHS/United States ; R01 EY030138/EY/NEI NIH HHS/United States ; R01 EY024932/EY/NEI NIH HHS/United States ; R01 EY036943/EY/NEI NIH HHS/United States ; T32 EY007043/EY/NEI NIH HHS/United States ; }, mesh = {*Neurodegenerative Diseases/pathology/therapy ; Humans ; *Retina/pathology ; *Neuroprotection ; Disease Models, Animal ; Animals ; *Glaucoma/pathology/therapy ; Retinal Ganglion Cells ; Cellular Reprogramming ; }, abstract = {BACKGROUND: Glaucoma Research Foundation's third Catalyst for a Cure team (CFC3) was established in 2019 to uncover new therapies for glaucoma, a leading cause of blindness. In the 2021 meeting "Solving Neurodegeneration," (detailed in Mol Neurodegeneration 17(1), 2022) the team examined the failures of investigational monotherapies, issues with translatability, and other significant challenges faced when working with neurodegenerative disease models. They emphasized the need for novel, humanized models and proposed identifying commonalities across neurodegenerative diseases to support the creation of pan-neurodegenerative disease therapies. Since then, the fourth Catalyst for a Cure team (CFC4) was formed to explore commonalities between glaucoma and other neurodegenerative diseases. This review summarizes outcomes from the 2023 "Solving Neurodegeneration 2" meeting, a forum for CFC3 and CFC4 to share updates, problem solve, plan future research collaborations, and identify areas of unmet need or opportunity in glaucoma and the broader field of neurodegenerative disease research.

MAIN BODY: We summarize the recent progress in the field of neurodegenerative disease research and present the newest challenges and opportunities moving forward. While translatability and disease complexity continue to pose major challenges, important progress has been made in identifying neuroprotective targets and understanding neuron-glia-vascular cell interactions. New challenges involve improving our understanding of the disease microenvironment and timeline, identifying the optimal approach(es) to neuronal replacement, and finding the best drug combinations and synergies for neuroprotection. We propose solutions to common research questions, provide prescriptive recommendations for future studies, and detail methodologies, strategies, and approaches for addressing major challenges at the forefront of neurodegenerative disease research.

CONCLUSIONS: This review is intended to serve as a research framework, offering recommendations and approaches to validating neuroprotective targets, investigating rare cell types, performing cell-specific functional characterizations, leveraging novel adaptations of scRNAseq, and performing single-cell sorting and sequencing across neurodegenerative diseases and disease models. We focus on modeling neurodegeneration using glaucoma and other neurodegenerative pathologies to investigate the temporal and spatial dynamics of neurodegenerative disease pathogenesis, suggesting researchers aim to identify pan-neurodegenerative drug targets and drug combinations leverageable across neurodegenerative diseases.}, } @article {pmid41088992, year = {2026}, author = {Essa, SM and Khosa, NA and Kakar, A and Ozturk, B and Ibrahim, IA and Haq, N}, title = {Unraveling the Potential of Stem Cell Therapy in Motor Neuron Disease: A Narrative Review.}, journal = {CNS & neurological disorders drug targets}, volume = {25}, number = {6}, pages = {403-415}, pmid = {41088992}, issn = {1996-3181}, mesh = {Humans ; *Motor Neuron Disease/therapy ; Animals ; *Stem Cell Transplantation/methods ; *Mesenchymal Stem Cell Transplantation/methods ; }, abstract = {Motor neuron disorders (MNDs), including ALS, are deadly neurodegenerative conditions that cause progressive motor neuron degeneration. With neuroprotection and the potential for neuron regeneration employing MSCs, ESCs, iPSCs, and NSCs, stem cell treatment presents a viable alternative to current medicines, which only control a limited number of symptoms. Following PRISMA criteria, this narrative review methodically screened 1248 records from the Cochrane, Web of Science, PubMed, and Scopus databases. Following a thorough screening process, 22 studies, including preclinical models and 19 clinical trials, were analysed to assess the therapeutic mechanisms, safety, and efficacy of stem cell therapies for MNDs. Mesenchymal stem cell (MSC) therapy has shown a promising safety profile and possible therapeutic efficacy in ALS, with no substantial transplant-related toxicity noted. ALS functional rating scale-revised (ALSFRS-R) scores and forced vital capacity (FVC) assessments from clinical trials, such as those evaluating autologous bone marrow-derived MSCs, demonstrated stabilisation in ALS development. Studies have also emphasised as to how immunomodulation and neurotrophic factors play a part in MSC-based therapies. Recent data indicate that repeated intrathecal MSC injection could extend the duration of therapeutic advantages. Clinical trials have shown safety and early efficacy signals for motor neurons produced from embryonic stem cells (ESCs), especially using AstroRx®. This suggests that ESCs could be a viable option for regenerative medicine. Nonetheless, issues, like host integration and differentiation optimisation, still exist. Although clinical translation is still in its early stages, induced pluripotent stem cells (iPSCs) and their derivatives provide disease modelling and patient-specific therapeutic applications. Stem cell therapy holds promise for treating MND, with MSCs leading the way in current trials. It is necessary to enhance ESC- and iPSC-based techniques to tackle integration issues. To ensure long-term safety and efficacy, therapies must be developed using standardised protocols, patient stratification, optimised delivery, and large-scale studies.}, } @article {pmid41090678, year = {2025}, author = {Jing, W and Shan, Y and Wu, H and Li, T and Tang, H and Sun, Y and Napattharin, V and Loong, S and Qin, B and Pan, W}, title = {Integrative treatment of the motor neuron disease amyotrophic lateral sclerosis, efficacy of pharmacotherapy, traditional Chinese medicine and importance of respiratory support, life-style, and gastrostomy-assisted nutrition: A review.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {63 (Suppl. 1)}, number = {}, pages = {S14-S25}, pmid = {41090678}, issn = {0946-1965}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/etiology/physiopathology ; *Gastrostomy ; *Medicine, Chinese Traditional ; *Life Style ; *Integrative Medicine/methods ; Treatment Outcome ; }, abstract = {Currently, there are no effective treatments for amyotrophic lateral sclerosis (ALS), a chronic progressive neurodegenerative disease. Although the etiology of ALS is unknown, it is thought that factors such as diet, the environment, and lifestyle habits play a role. The pathogenesis of ALS includes alterations in glutamate neurotransmission, oxidative stress, mitochondrial dysfunction. Drugs such as riluzole, edaravone, dextromethorphan/quinidine combinations, and the administration of tofersen by injection are approved treatment options for ALS although a number of other agents are being examined in clinical trials. Despite these developments, the availability of effective treatment options is limited. This review summarizes the etiology and pathogenesis of ALS and describes treatments in detail as an integrative medicine approach and including traditional Chinese medicine together with the importance of the timing for interventions, precautions necessary for noninvasive ventilator and gastrostomy surgery, and precautions for dealing with respiratory issues with the overall aim of providing state-of-the-art clinical recommendations for the care and therapy of ALS patients.}, } @article {pmid41090725, year = {2025}, author = {Vishnumukkala, T and Che Mohd Nassir, CMN and Hein, ZM and Kalerammana Gopalakrishna, P and Karikalan, B and Alkatiri, A and Jagadeesan, S and Naik, VR and Thomas, W and Mohd Moklas, MA and Kamaruzzaman, MA}, title = {Glial Cells as Emerging Therapeutic Targets in Neurodegenerative Diseases: Mechanistic Insights and Translational Perspectives.}, journal = {Cells}, volume = {14}, number = {19}, pages = {}, pmid = {41090725}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/pathology ; *Neuroglia/metabolism/pathology/drug effects ; Animals ; *Translational Research, Biomedical ; Biomarkers/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis share converging mechanisms of neuronal dysfunction, including protein aggregation, oxidative stress, and chronic neuroinflammation. Glial cells, once considered passive supporters, are now recognized as central drivers of these processes, offering both pathogenic triggers and therapeutic opportunities. Yet, despite compelling preclinical evidence, the translation of glial-targeted therapies into clinical success has been limited. This review provides a critical synthesis of current knowledge by examining therapeutic strategies through the lens of their translational challenges and failures. This narrative review highlights how interspecies variability of glial phenotypes, shifting neuroprotective versus neurotoxic states, limited biomarker stratification, and delivery barriers have constrained trials, such as anti-triggering receptor expressed on myeloid cells 2 (anti-TREM2) antibodies in AD and glial cell line-derived neurotrophic factor (GDNF) in PD. By analyzing these obstacles across major neurodegenerative disorders, this review argue that the next stage of glial medicine requires precision approaches that integrate stage-specific phenotyping, biomarker-guided patient selection, and innovative delivery platforms. Understanding not only what has been tried but why translation has stalled is essential to chart a roadmap for effective, disease-modifying glial therapies in the aging brain.}, } @article {pmid41090732, year = {2025}, author = {Brocard, F and Dingu, N}, title = {Calpains at the Crossroads of Spinal Cord Physiology, Plasticity, and Pathology.}, journal = {Cells}, volume = {14}, number = {19}, pages = {}, pmid = {41090732}, issn = {2073-4409}, support = {ANR-24-CE16-1548//Agence National de la recherche/ ; ANR-21-CE17-0060//Agence National de la Recherche/ ; }, mesh = {*Calpain/metabolism ; Humans ; Animals ; *Spinal Cord/pathology/physiopathology/physiology/metabolism ; *Neuronal Plasticity/physiology ; }, abstract = {Calcium-dependent cysteine proteases, known as calpains, emerge as important regulators of spinal cord physiology, plasticity, and pathology. First characterized in the brain, they influence a wide range of processes in the spinal cord, maintaining neuronal homeostasis, shaping both synaptic and intrinsic plasticity, and modulating glial responses. When dysregulated, calpains contribute to the pathophysiology of traumatic and neurodegenerative spinal cord disorders, as well as to their associated motor and sensory complications, including spasticity and neuropathic pain. A recurring feature of these conditions is calpain-mediated proteolysis of ion channels, transporters, and cytoskeletal proteins, which promotes disinhibition and neuronal hyperexcitability. The resultant protein fragments are examined as prospective biomarkers for damage and disease progression. Meanwhile, promising strategies for neuroprotection and functional recovery in the clinic emerge as a result of innovative pharmacological and genetic approaches to modulate calpain activity. In this review, we present the current state of knowledge regarding the functions and regulation of calpains in the spinal cord and assess their translational potential as both therapeutic targets and effectors in spinal cord disorders.}, } @article {pmid41090760, year = {2025}, author = {Key, J and Almaguer-Mederos, LE and Kandi, AR and Fellenz, M and Gispert, S and Köpf, G and Meierhofer, D and Deller, T and Auburger, G}, title = {Conditional ATXN2L-Null in Adult Frontal Cortex CamK2a+ Neurons Does Not Cause Cell Death but Restricts Spontaneous Mobility and Affects the Alternative Splicing Pathway.}, journal = {Cells}, volume = {14}, number = {19}, pages = {}, pmid = {41090760}, issn = {2073-4409}, support = {DFG AU96/21-1//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Animals ; *Alternative Splicing/genetics ; Mice ; *Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; *Neurons/metabolism ; *Ataxin-2/metabolism/genetics ; Cell Death ; Mice, Knockout ; }, abstract = {The Ataxin-2-like (ATXN2L) protein is required to survive embryonic development, as documented in mice with the constitutive absence of the ATXN2L Lsm, LsmAD, and PAM2 domains due to knock-out (KO) of exons 5-8 with a frameshift. Its less abundant paralog, Ataxin-2 (ATXN2), has an extended N-terminus, where a polyglutamine domain is prone to expansions, mediating vulnerability to the polygenic adult motor neuron disease ALS (Amyotrophic Lateral Sclerosis) or causing the monogenic neurodegenerative processes of Spinocerebellar Ataxia Type 2 (SCA2), depending on larger mutation sizes. Here, we elucidated the physiological function of ATXN2L by deleting the LsmAD and PAM2 motifs via loxP-mediated KO of exons 10-17 with a frameshift. Crossing heterozygous floxed mice with constitutive Cre-deleter animals confirmed embryonic lethality among offspring. Crossing with CamK2a-CreERT2 mice and injecting tamoxifen for conditional deletion achieved chimeric ATXN2L absence in CamK2a-positive frontal cortex neurons and reduced spontaneous horizontal movement. Global proteome profiling of frontal cortex homogenate showed ATXN2L levels decreased to 75% and dysregulations enriched in the alternative splicing pathway. Nuclear proteins with Sm domains are critical to performing splicing; therefore, our data suggest that the Like-Sm (Lsm, LsmAD) domains in ATXN2L serve a role in splice regulation, despite their perinuclear location.}, } @article {pmid41092810, year = {2025}, author = {Lopez-Mateos, D and Harris, BJ and Hernández-González, A and Yarov-Yarovoy, V and Wulff, H}, title = {Recent advances in the pharmacology of voltage-gated ion channels.}, journal = {Pharmacological reviews}, volume = {77}, number = {6}, pages = {100090}, pmid = {41092810}, issn = {1521-0081}, support = {U54 NS127758/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Artificial Intelligence ; Drug Discovery ; *Potassium Channels, Voltage-Gated/metabolism ; *Voltage-Gated Sodium Channels/metabolism ; *Calcium Channels/metabolism ; }, abstract = {Voltage-gated ion channels (VGICs) are critical regulators of membrane potential, cellular excitability, and calcium signaling in both excitable and nonexcitable tissues and constitute important drug targets for neurological, cardiovascular, and immunological diseases. This review describes recent progress in the pharmacology of voltage-gated Na[+], voltage-gated Ca[2+], and voltage-gated K[+] channels, highlighting clinical-stage compounds, emerging therapeutic modalities, and new strategies in VGIC drug discovery, emphasizing the increasingly central role of protein structures and artificial intelligence. Several compounds targeting VGICs have progressed to clinical trials for epilepsy, atrial fibrillation, psoriasis, and difficult-to-treat disorders, such as chronic pain, schizophrenia, major depression, and amyotrophic lateral sclerosis. The therapeutic landscape for VGIC-related disorders is expanding beyond traditional small molecules and antisense oligonucleotides and gene therapies targeting VGICs at the mRNA or gene level are currently in both early and late clinical trial stages for Dravet syndrome and developmental epileptic encephalopathy. The progression of such varied modalities suggests that the extensive efforts dedicated to elucidating VGIC biophysics and structure, coupled with rigorous target validation, are beginning to translate into therapeutic advancements. Furthermore, we discuss emerging discovery strategies, including the growing impact of VGIC structures, computational structural modeling, virtual screening of focused and ultralarge libraries, and artificial intelligence-driven redesign and de novo design of biologics. Although these approaches are poised to substantially accelerate the early stages of ion channel drug discovery, the clinical stages will continue to require careful selection of indications and thoughtful clinical trial design to fully realize the long-held potential of VGICs as drug targets. SIGNIFICANCE STATEMENT: Drug development for voltage-gated ion channels is widely considered to be challenging. This article reviews recent advances in the pharmacology of voltage-gated Na[+], voltage-gated Ca[2+], and voltage-gated K[+] channels by examining compounds currently in clinical trials, including emerging new therapeutic approaches such as antisense oligonucleotides and gene therapy. We then discuss noteworthy recent developments, including the increasing availability and impact of ion channel structures, structural modeling, virtual screening, and artificial intelligence-assisted protein design, which are likely to accelerate the early stages of ion channel drug discovery. Success of the later stages will continue to rely on rigorous target validation, and proper choices of clinical candidates and clinical trial design.}, } @article {pmid41092899, year = {2025}, author = {Ruiz de Almodovar, C and Dupraz, S and Bonanomi, D}, title = {Neurovascular dynamics in the spinal cord from development to pathophysiology.}, journal = {Neuron}, volume = {113}, number = {24}, pages = {4134-4157}, doi = {10.1016/j.neuron.2025.09.017}, pmid = {41092899}, issn = {1097-4199}, mesh = {*Spinal Cord/blood supply/growth & development/physiopathology/pathology ; Humans ; Animals ; *Neurovascular Coupling/physiology ; *Spinal Cord Injuries/physiopathology/pathology ; }, abstract = {The vasculature is increasingly recognized as an active regulator of homeostasis and repair, beyond conventional roles in nutrient delivery. In the central nervous system, vascular cells adopt region-specific traits tailored to the distinct demands of the brain, retina, and spinal cord. Despite long-standing interest in the spinal cord as a model for neural development and injury, its vascular organization and properties remain understudied. The assumption that spinal cord and brain neurovascular systems are built and function in the same way has limited progress. Here, we challenge this view by examining specific properties underlying spinal cord vascular development, physiology, and pathology. We highlight unique angioarchitecture and homeostatic mechanisms, and discuss how neurovascular disruption contributes to spinal disorders and regenerative failure after injury. Identifying critical knowledge gaps, we aim to stimulate new research in spinal cord neurovascular biology, redefining its importance for health and disease.}, } @article {pmid41092967, year = {2025}, author = {Dourado Junior, MET and Dourado, LC and Santana, GC and Vale, SHL and Leite-Lais, L}, title = {Impact of weight loss and disease progression on survival in ALS: insights from a multidisciplinary care center.}, journal = {Arquivos de neuro-psiquiatria}, volume = {83}, number = {10}, pages = {1-9}, pmid = {41092967}, issn = {1678-4227}, mesh = {Brazil/epidemiology ; Delivery of Health Care, Integrated ; Retrospective Studies ; *Weight Loss/physiology ; Disease Progression ; *Amyotrophic Lateral Sclerosis/complications/mortality/physiopathology/therapy ; *Malnutrition/etiology/mortality/therapy ; Humans ; Male ; Female ; Middle Aged ; Aged ; Patient Care Team ; Prognosis ; Tracheostomy/mortality ; Gastrostomy/mortality ; Time Factors ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifaceted neurodegenerative disorder with a poor prognosis. Weight loss and malnutrition emerge as significant clinical features during disease progression.To explore how demographic and clinical characteristics relate to survival in ALS patients, emphasizing the role of weight loss percentage at the time of diagnosis.We conducted a retrospective study that used the database of a multidisciplinary ALS care center in the city of Natal, Brazil.A total of 132 patients were included in the study. The mean age of the participants at symptom onset was of 56.9 years, and most of them were male (59.8%). Older age, bulbar onset, and faster disease progression were associated with weight loss ≥ 10% at diagnosis. Among 132 patients, 72% experienced death or tracheostomy, with a median survival of 34 months. Survival was notably reduced in patients aged ≥ 60 years, those with significant weight loss, rapid disease progression, or those submitted to gastrostomy. Weight loss and the rate of disease progression were the strongest predictors of reduced survival. Potential factors relating gastrostomy with reduced survival are discussed.The present study highlights the critical impact of weight loss and disease progression on survival in ALS patients, emphasizing the importance of early nutritional and clinical interventions. These findings underscore the need for comprehensive, multidisciplinary care strategies to address key prognostic factors and improve outcomes in ALS patients.}, } @article {pmid41093062, year = {2026}, author = {Bunick, CG and Yang, K and Jafarian, F and Barbieri, JS}, title = {Response to Veenstra et al's "Benzoyl peroxide acne treatment shows no significant association with benzene-related cancers: A multicenter retrospective analysis" on statistical design.}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {2}, pages = {e125-e127}, doi = {10.1016/j.jaad.2025.10.042}, pmid = {41093062}, issn = {1097-6787}, } @article {pmid41093908, year = {2026}, author = {Wilson, E and Turner, N and Palmer, J and Davidson, S and Turner, MR and Faull, C}, title = {Living with tracheostomy ventilation for motor neurone disease: a qualitative study of family member perspectives.}, journal = {Disability and rehabilitation}, volume = {48}, number = {12}, pages = {3665-3677}, doi = {10.1080/09638288.2025.2574536}, pmid = {41093908}, issn = {1464-5165}, mesh = {Humans ; *Tracheostomy/psychology ; *Motor Neuron Disease/therapy ; *Caregivers/psychology ; Qualitative Research ; *Family/psychology ; *Quality of Life ; Female ; *Respiration, Artificial/psychology ; Male ; Middle Aged ; Decision Making ; Aged ; Interviews as Topic ; Adult ; Social Support ; }, abstract = {PURPOSE: To examine the experiences of family members caring for people with motor neurone disease (MND) who use tracheostomy ventilation.

METHODS: Drawing on a constructivist interpretivist approach, qualitative interviews with family members from England, Scotland, and Northern Ireland were conducted. Data were thematically analysed to interpret meaning and identify key themes.

RESULTS: Sixteen family members took part. Four themes are presented: (1) Decision-making and implementation: The decision about undergoing tracheostomy was driven by the person with MND. Tracheostomy ventilation was often initiated in an emergency, leaving families unprepared and distressed. (2) Impact on quality of life for family members: Responsibilities intensified once tracheostomy ventilation was in place, leading to a gradual erosion of personal autonomy for family caregivers. (3) Redefining family place and space: The continuous presence of paid carers and the medicalisation of the home impacted family dynamics. (4) Support for family members: Family members took on many roles with little support yet found meaning in the extended life of the person with MND.

CONCLUSION: Enhanced psychological, social, and practical support is urgently needed for families caring for someone with tracheostomy ventilation for MND. Greater awareness of its long-term impact, realistic home assessments, and structured support networks are essential.}, } @article {pmid41094045, year = {2025}, author = {Li, A and Huang, S and Cao, SQ and Lin, J and Zhao, L and Yu, F and Huang, M and Yang, L and Xin, J and Wen, J and Yan, L and Zhang, K and Jiang, M and Le, W and Li, P and Liu, YU and Qin, D and Lu, J and Lu, G and Shen, H and Yao, X and Fang, EF and Su, H}, title = {Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy.}, journal = {EMBO molecular medicine}, volume = {17}, number = {11}, pages = {3139-3173}, pmid = {41094045}, issn = {1757-4684}, support = {#282952; #284930//Cure Alzheimer's Fund (CAF)/ ; #281931//civitan norges forskningsfond for Alzheimer skydom/ ; #262175,#334361//research council of Norway/ ; TO01000215//Ministerstvo Práce a Sociálních Věcí České Republiky (Ministry of Labour and Social Affairs of the Czech Republic)/ ; #81971327//MOST | National Natural Science Foundation of China (NSFC)/ ; #119986//NordForsk/ ; #82271448//MOST | National Natural Science Foundation of China (NSFC)/ ; /WT_/Wellcome Trust/United Kingdom ; SKL-QRCM(UM)-2023-2025//Science and Technology Development Fund, MAR/ ; 001/2023/ALC//Science and Technology Development Fund, MAR/ ; #101073251//horizon-TMA-MSCA-DN/ ; 2020001,#2021021,#2023093//HELSE SOR-OST/ ; 269901,#261973,#262960//Høgskolen i Oslo og Akershus (HiOA)/ ; #282942//Molecule AG/VITADAO/ ; #104617//Burroughs Wellcome Fund (BWF)/ ; MYRGGRG2023-00152-ICMS-UMDF//MOST | National Natural Science Foundation of China (NSFC)/ ; 0093/2024/AFJ//Macau University of Science and Technology (MUST)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/pathology ; *Mitophagy/drug effects ; *Ubiquitin-Protein Ligases/metabolism ; Animals ; Humans ; *Protein Kinases/metabolism ; *Induced Pluripotent Stem Cells/drug effects ; Mice ; Caenorhabditis elegans ; Disease Models, Animal ; Mitochondria/drug effects/metabolism ; PTEN-Induced Putative Kinase ; }, abstract = {Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1-Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1-Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.}, } @article {pmid41094691, year = {2025}, author = {Caggiano, C and Morselli, M and Qian, X and Celona, B and Thompson, MJ and Wani, S and Tosevska, A and Taraszka, K and Heuer, G and Ngo, ST and Steyn, FJ and Nestor, PJ and Wallace, L and McCombe, P and Heggie, S and Thorpe, K and McElligott, C and English, G and Henders, A and Henderson, R and Lomen-Hoerth, C and Wray, NR and McRae, AF and Pellegrini, M and Garton, FC and Zaitlen, N}, title = {Epigenetic profiles of tissue informative CpGs inform ALS disease status and progression.}, journal = {Genome medicine}, volume = {17}, number = {1}, pages = {115}, pmid = {41094691}, issn = {1756-994X}, support = {F31 NS122538/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/diagnosis ; *DNA Methylation ; Disease Progression ; *Epigenesis, Genetic ; Female ; Male ; *CpG Islands ; Middle Aged ; Cell-Free Nucleic Acids/genetics ; C9orf72 Protein/genetics ; Aged ; Adult ; Organ Specificity ; }, abstract = {BACKGROUND: Cell-free DNA (cfDNA), derived from dying cells, has demonstrated utility across multiple clinical applications. However, its potential in neurodegenerative diseases remains underexplored, with most existing cfDNA technologies tailored to specific disease contexts like cancer or non-invasive prenatal screening.

METHODS: To address this gap, we developed a novel approach to characterize epigenetic cfDNA profiles by identifying key regions of DNA methylation that reveal the tissues origins undergoing apoptosis or necrosis. We evaluated this method in the largest cfDNA study of amyotrophic lateral sclerosis (ALS) and other neurological diseases (OND) to date, encompassing two independent cohorts (n = 192) from Australia (UQ Ncases = 48, Ncontrols = 32, NOND = 15) and the USA, (UCSF Ncases = 50, Ncontrols = 45)).

RESULTS: Our approach accurately distinguished ALS patients from controls (UQ AUC = 0.82, UCSF AUC = 0.99) and from individuals with other neurological diseases (AUC = 0.91). It also identified an asymptomatic carrier of a pathogenic C9orf72 variant, and strongly correlated with ALS disease progression measures (Pearson's R = 0.66, p = 3.71 × 10⁻⁹).

CONCLUSIONS: We identified DNA methylation signals from multiple tissue types in ALS cfDNA, highlighting diverse tissue involvement in ALS pathology. These findings promote epigenetic cfDNA analysis as a powerful tool for advancing our understanding of neurodegenerative disease.}, } @article {pmid41095229, year = {2025}, author = {Ren, J and Song, M and Bimpong, D and Wang, F and Chen, W and Ma, D and Du, L}, title = {Genomic and Functional Characterization of Acetolactate Synthase (ALS) Genes in Stress Adaptation of the Noxious Weed Amaranthus palmeri.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {19}, pages = {}, pmid = {41095229}, issn = {2223-7747}, support = {2024YFC2607600//National Key R&D Program of China/ ; 2023ZTSJJ2//Open Project Program of Key Laboratory of Integrated Pest Management on Crop in Central China, Ministry of Agriculture/Hubei Province Key Laboratory for Control of Crop Diseases, Pest and Weeds/ ; }, abstract = {Acetolactate synthase (ALS) is an important enzyme in plant branched-chain amino acid biosynthesis and the target of several major herbicide classes. Despite its agronomic importance, the role of ALS genes in stress adaptation in the invasive weed Amaranthus palmeri remains unstudied. In this study, four ApALS genes with high motif conservation were identified and analyzed in A. palmeri. Phylogenetic analysis classified ApALS and other plant ALS proteins into two distinct clades, and the ApALS proteins were predicted to localize to the chloroplast. Gene expression analysis demonstrated that ApALS genes are responsive to multiple stresses, including salt, heat, osmotic stress, glufosinate ammonium, and the ALS-inhibiting herbicide imazethapyr, suggesting roles in both early and late stress responses. Herbicide response analysis using an Arabidopsis thaliana ALS mutant (AT3G48560) revealed enhanced imazethapyr resistance, associated with higher chlorophyll retention. Furthermore, high sequence homology between AT3G48560 and ApALS1 suggests a conserved role in protecting photosynthetic function during herbicide stress. This study provides the first comprehensive analysis of the ALS gene family in A. palmeri and offers important insights into its contribution to stress resilience. These findings establish a vital foundation for developing novel strategies to control this pervasive agricultural weed and present potential genetic targets for engineering herbicide tolerance in crops.}, } @article {pmid41095520, year = {2025}, author = {Whelan, BM and Aldridge, D and Ruhle, J and Whitelock, P and Taubert, S and Collins, A and Kearney, E and Charania, S and Henderson, RD and Wallace, SJ and Mitchell, C and Stipancic, KL and Kuruvilla-Dugdale, M and Vogel, AP}, title = {To Treat or Not to Treat: A Scoping Review of Speech Treatment for Dysarthria in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Healthcare (Basel, Switzerland)}, volume = {13}, number = {19}, pages = {}, pmid = {41095520}, issn = {2227-9032}, support = {N/A//University of Queensland, School of Health and Rehabilitation Sciences, New Staff Research Start-Up Fund/ ; }, abstract = {BACKGROUND: Speech loss is recognised as one of the most devastating outcomes for individuals with ALS, yet active speech intervention is rarely targeted in this population. Clinicians face significant challenges in managing dysarthria associated with ALS due to the rapidly progressive nature of the disease, historical concerns around intensive exercise accelerating decline, and an absence of direction on restorative and compensatory intervention strategies in current clinical care guidelines. This review evaluates the scope and quality of evidence for speech treatments in ALS to identify knowledge gaps and establish research priorities to guide clinical care.

METHODS: Studies were retrieved from six electronic databases (PubMed, CINAHL, Embase, Cochrane library, Web of Science, and PsycINFO).

RESULTS: Four studies met inclusion criteria. Treatment approaches included: music-based speech therapy; multisubsystem speech rehabilitation program, tongue strengthening and articulation training; and Lee Silverman Voice Treatment-LOUD[®] combined with additional voice and articulation therapy. Sample sizes were small, with all studies demonstrating notable methodological weaknesses. The limited evidence base, marked by conflicting results and methodological flaws, prevents any reliable conclusions about treatment effectiveness.

CONCLUSIONS: Despite the prevalence and impact of dysarthria in this population, evidence for speech treatment remains sparse, of generally low quality, and provides limited guidance for clinical practice. The changing perspective on exercise in ALS warrants rigorous investigation of tailored dysarthria interventions for this population that are minimally fatiguing and enhance speech by making use of residual physiologic support.}, } @article {pmid41095781, year = {2025}, author = {Ferreira Laurentino, EK and Maldaner da Silva, VZ and Costa Meneses, WR and da Costa, LM and Otto-Yañez, M and Vera-Uribe, R and Torres-Castro, R and Carneiro de Sousa, BR and de Abreu Freitas, RP and Menezes Mateus, SR and Vasconcellos, IF and Fernandes Franco, HC and Pinto Nagem, DA and Medeiros Valentim, RA and Dourado Júnior, ME and Rodrigues Lindquist, AR and Santos Andrade, SMMD and Medeiros Fonseca, JD and Resqueti, VR and Freitas Fregonezi, G}, title = {High-Definition Transcranial Direct Current Stimulation (HD-tDCS) Therapy in Amyotrophic Lateral Sclerosis: Study Protocol for a Multicenter Randomized Controlled Clinical Trial.}, journal = {Journal of clinical medicine}, volume = {14}, number = {19}, pages = {}, pmid = {41095781}, issn = {2077-0383}, support = {1748/22//Financiadora de Estudos e Projetos/ ; 88887.692599/2022-00 (JDMF)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 305960/2021-0 (VRR)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 316937/2021-5 (GF)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 001 (EKFL)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 001 (WRCM)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 001 (LMC)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 001 (BRCS)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; }, abstract = {Background/Objectives: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by motor neuron loss, muscle weakness, and respiratory dysfunction, often culminating in ventilatory failure. Evidence suggests that High-Definition Transcranial Direct Current Stimulation (HD-tDCS) may modulate motor cortical excitability and potentially influence motor and respiratory function in ALS. This study aims to evaluate the effects of home-based HD-tDCS applied over the primary diaphragmatic motor cortex on respiratory parameters and disease progression in individuals with ALS. Methods: This is a multicenter, randomized, controlled clinical trial. Eligible participants (aged 18-80, both sexes, diagnosed with ALS) will be randomized into an active HD-tDCS group (gTDCS) or a sham group (gSham). The intervention consists of 30 min daily HD-tDCS sessions (3 mA) applied for two weeks (5 days/week), using a 4 × 1 ring configuration targeting the diaphragmatic motor cortex. Sham stimulation includes an identical setup but only delivers ramp currents (30 s) with a minimal ongoing current (0.1 mA). Results: Pre-, intra-, and post-intervention evaluations will include measures of cortical excitability, cerebral and tissue perfusion, surface electromyography, respiratory and pulmonary function, fatigue, sleep quality, pain, motor performance, dyspnea, quality of life, and adverse effects. All procedures will be conducted at participants' homes with appropriate safety monitoring. Conclusions: This study will investigate the effects of HD-tDCS on respiratory and motor function in ALS and explore the feasibility of a home-based neuromodulation intervention. The outcomes may provide insight into non-pharmacological strategies for respiratory management in ALS.}, } @article {pmid41095782, year = {2025}, author = {Maciel, ACMG and Resqueti, VR and Costa, LMD and Silva, AAMD and Fonseca, JDMD and Vieira, RGDS and Pondofe, KM and Otto-Yáñez, M and Vilaró, J and Torres-Castro, R and Vera-Uribe, R and Ribeiro-Samora, GA and Nagem, D and Valentim, RA and Dourado Júnior, MET and Fregonezi, G}, title = {The Impact of Respiratory Function on Functionality and Mortality in ALS Patients.}, journal = {Journal of clinical medicine}, volume = {14}, number = {19}, pages = {}, pmid = {41095782}, issn = {2077-0383}, support = {88887.692599/2022-00 (JMDF)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior - CAPES/ ; 316937/2021-5 (GF)//Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPQ/ ; 305960/2021-0 (VR)//Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPQ/ ; Funding Code 001 (RGSV, LMC, AAMS)//Coordenação de Aperfeiçoamento Pessoal de Nível Superior-Brazil (CAPES)/ ; TED 132/2018//Mininstério da Saúde/ ; }, abstract = {Objective: To investigate the relationship between respiratory function, functionality, and mortality in amyotrophic lateral sclerosis (ALS) patients and to determine which respiratory parameters show the strongest correlation with functionality and mortality. Methods: The study was conducted in Rio Grande do Norte, Northeast Brazil, between January 2018 and December 2023. This was a retrospective cohort, following individuals with ALS who were evaluated at the University Laboratory. Results: A total of 74 ALS patients were included in the analysis, with a mean age of 55.7 ± 13.5 years. Most were male (66.2%) and predominantly presented with spinal-onset ALS (51.3%). Respiratory variables (except peak expiratory flow (PEF)) showed a weak but significant inverse correlation with mortality (FVC% predicted (rpb = -0.260; p < 0.001), SNIP (rpb = -0.235; p = 0.001), MEP (rpb = -0.207; p = 0.007), MIP (rpb = -0.198; p = 0.009), and PEF% predicted (rpb = -0.156; p = 0.013)). When analyzing their correlation with ALSFRS-R, all variables showed a significant positive correlation (ranging from weak to moderate) with functionality. A reduction of one unit in the respiratory variables PEF% of predicted, maximal inspiratory pressure (MIP), and sniff nasal inspiratory pressure (SNIP) increased the risk of death by an average of 300% (OR = 2.99; 95% CI: 2.05-4.35), 2% (OR = 1.02; 95% CI: 1.01-1.03), and 1% (OR = 1.01; 95% CI: 1.00-1.02), respectively. Conclusions: Our findings suggest that direct measurements of respiratory function and muscle strength, particularly PEF and SNIP, may serve as more useful markers to guide early interventions such as non-invasive ventilation, thereby improving quality of life and potentially prolonging survival.}, } @article {pmid41096235, year = {2025}, author = {Savov, V and Antov, P and Kostadinova-Slaveva, A and Yusein, J and Dudeva, V and Todorova, E and Petrin, S}, title = {Development and Characterization of Sustainable Biocomposites from Wood Fibers, Spent Coffee Grounds, and Ammonium Lignosulfonate.}, journal = {Polymers}, volume = {17}, number = {19}, pages = {}, pmid = {41096235}, issn = {2073-4360}, support = {project BG05SFPR001-3.004-0010 "Development of project doctoral studies at the University of Forestry"//Programme 'Education' 2021-2027, co-funded by the European Union through the ESF+. ./ ; }, abstract = {Coffee processing generates large volumes of spent coffee grounds (SCGs), which contain 30-40% hemicellulose, 8.6-13.3% cellulose, and 25-33% lignin, making them a promising lignin-rich filler for biocomposites. Conventional wood composites rely on urea-formaldehyde (UF), melamine-urea-formaldehyde (MUF), and phenol-formaldehyde resins (PF), which dominate 95% of the market. Although formaldehyde emissions from these resins can be mitigated through strict hygiene standards and technological measures, concerns remain due to their classification as category 1B carcinogens under EU regulations. In this study, fiber-based biocomposites were fabricated from thermomechanical wood fibers, SCGs, and ammonium lignosulfonate (ALS). SCGs and ALS were mixed in a 1:1 ratio and incorporated at 40-75% of the oven-dry fiber mass. Hot pressing was performed at 150 °C under 1.1-1.8 MPa to produce panels with a nominal density of 750 kg m[-3], and we subsequently tested them for their physical properties (density, water absorption (WA), and thickness swelling (TS)), mechanical properties (modulus of elasticity (MOE), modulus of rupture (MOR), and internal bond (IB) strength), and thermal behavior and biodegradation performance. A binder content of 50% yielded MOE ≈ 2707 N mm[-2] and MOR ≈ 22.6 N mm[-2], comparable to UF-bonded medium-density fiberboards (MDFs) for dry-use applications. Higher binder contents resulted in reduced strength and increased WA values. Thermogravimetric analysis (TGA/DTG) revealed an inorganic residue of 2.9-8.5% and slower burning compared to the UF-bonded panels. These results demonstrate that SCGs and ALS can be co-utilized as a renewable, formaldehyde-free adhesive system for manufacturing wood fiber composites, achieving adequate performance for value-added practical applications while advancing sustainable material development.}, } @article {pmid41096646, year = {2025}, author = {García-Criado, F and Hurtado-García, L and Rojano, E and Esteban-Martos, Á and Pérez-García, J and Seoane, P and Ranea, JAG}, title = {Integrative Transcriptomic and Network-Based Analysis of Neuromuscular Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096646}, issn = {1422-0067}, support = {PID2019-108096RB-C21, PID2022-140047OB-C21, CPP2022-010108//Ministerio de Ciencia, Innovación y Universidades/ ; IMP/00019, ACCI-05-703, ACCI-02-770//Instituto de Salud Carlos III/ ; HORIZON-HLTH-2022-DISEASE-06, 101080580//European Union/ ; RH-0079-2021//Fundación Progreso y Salud/ ; PI RARE 24-03//Instituto de Investigación Biomédica de Málaga/ ; FPU21/01449, PRE2022/000510//Ministerio de Ciencia, Innovación y Universidades/ ; }, mesh = {Humans ; *Transcriptome ; *Neuromuscular Diseases/genetics/metabolism ; *Gene Regulatory Networks ; Protein Interaction Maps/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Gene Expression Profiling ; Muscular Dystrophy, Duchenne/genetics/metabolism ; Muscular Dystrophies, Limb-Girdle/genetics/metabolism ; Computational Biology/methods ; }, abstract = {Neuromuscular diseases (NMDs) like Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy (LGMD), and amyotrophic lateral sclerosis (ALS) are rare, progressive disorders with complex molecular mechanisms. Traditional transcriptomic analyses often struggle to capture systems-level dysregulation, especially given the small sample sizes typical of rare disease studies. Our differential expression analysis of eight public RNA-seq datasets from various cell types in DMD, LGMD, and ALS revealed not only disease-relevant pathways but also unexpected enrichments, such as renal development, suggesting systemic impacts beyond muscle tissue. To address limitations in capturing broader molecular mechanisms, we applied an integrative systems biology approach combining differential expression data, protein-protein interaction (PPI) networks, and network embedding techniques. Comparative functional enrichment revealed shared pathways, including glycosaminoglycan binding in both DMD and FUS-related ALS, implicating extracellular matrix-protein interactions in FUS mutation effects. Mapping DEGs onto the human PPI network and assessing their proximity to causal genes uncovered dysregulated non-coding RNAs, such as PAX8-AS1, SBF2-AS1, and NEAT1, potentially indicating common regulatory roles. We also found candidate genes within disease-proximal clusters, like HS3ST3A1, which may contribute to pathogenesis. Overall, this integrative approach reveals shared transcriptional programs and novel targets, advancing our understanding and potential treatment strategies for NMDs.}, } @article {pmid41096667, year = {2025}, author = {Skarlis, C and Angelopoulou, E and Rentzos, M and Papageorgiou, SG and Anagnostouli, M}, title = {Monoclonal Antibodies as Therapeutic Agents in Autoimmune and Neurodegenerative Diseases of the Central Nervous System: Current Evidence on Molecular Mechanisms and Future Directions.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096667}, issn = {1422-0067}, mesh = {Humans ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/immunology ; Animals ; *Central Nervous System Diseases/drug therapy/immunology ; Neuromyelitis Optica/drug therapy ; Central Nervous System/drug effects/immunology ; Multiple Sclerosis/drug therapy ; }, abstract = {Monoclonal antibodies (mAbs) have revolutionized the treatment landscape for neurological diseases, providing targeted, mechanism-based therapies for conditions ranging from autoimmune demyelinating disorders to neurodegenerative diseases. In multiple sclerosis (MS), mAbs against CD20, CD52, and α4-integrins offer disease-modifying efficacy by altering immune responses, depleting B cells, or blocking leukocyte migration into the central nervous system (CNS). Similarly, novel agents under investigation, such as frexalimab and foralumab, modulate T and B cell interactions and regulatory immunity. In neuromyelitis optica spectrum disorder (NMOSD), mAbs targeting IL-6, the complement cascade, and B cell lineage have demonstrated significant clinical benefit in preventing relapses and disability. In Alzheimer's disease (AD), several anti-amyloid mAbs have gained regulatory approval. Anti-tau and anti-α-synuclein antibodies, though promising, have shown limited efficacy to date in AD and parkinson's disease (PD), respectively. The evolving armamentarium of mAbs reflects a paradigm shift toward personalized neuroimmunology and neurodegeneration-targeted treatments, based on ongoing clarification of molecular and neuroinflammatory mechanisms. In this context, the present review summarizes current evidence on mAbs used in CNS disorders, with an emphasis on their pathophysiological targets, molecular mechanisms, clinical efficacy, and safety.}, } @article {pmid41096741, year = {2025}, author = {Lee, BC and Kuo, YC and Cheng, LF and Tsai, YC and Huang, JZ and Tsai, HH and Lin, JS and Huang, PY and Ting, CH and Yang, CC and Lai, HJ and Chao, CC and Tsai, LK}, title = {The Significance and Mechanism of Cerebral Enlarged Perivascular Space in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096741}, issn = {1422-0067}, support = {NHRI-112-B02)//National Health Research Institutes/ ; MS484//National Taiwan University Hospital/ ; 113-2314-B-002-100-MY3//National Science and Technology Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/metabolism ; Humans ; Male ; Female ; Animals ; Middle Aged ; *Glymphatic System/pathology/diagnostic imaging/metabolism ; Mice ; Magnetic Resonance Imaging ; Aged ; Superoxide Dismutase-1/metabolism/genetics ; Mice, Transgenic ; Adult ; Motor Neurons/metabolism/pathology ; Disease Models, Animal ; }, abstract = {Enlarged perivascular spaces (EPVS) are MRI markers of impaired glymphatic clearance and have been associated with neurodegenerative diseases. However, their clinical significance in amyotrophic lateral sclerosis (ALS) and underlying mechanisms remain poorly understood. This study investigated the prevalence, clinical relevance, and pathophysiological basis of EPVS in ALS. MRI data from 114 ALS patients and 119 matched controls were analyzed, with high-degree EPVS defined as more than 20 visible spaces. High-degree EPVS in the centrum semiovale (CSO) was more prevalent in ALS patients (49.1%) than in controls (15.1%, p < 0.001). Age, male sex, and ALS diagnosis were independent predictors, while disease severity and aggressiveness were not associated. ALS patients with high-degree CSO-EPVS were older at disease onset and MRI but showed similar clinical progression. In SOD1/G93A ALS mice, cerebral perivascular spaces were significantly enlarged at 5 months compared to wild-type and younger ALS mice. Cervical lymphatic ligation promoted misfolded SOD1 accumulation in motor neurons and cerebral vessels, further increasing perivascular space width without altering motor function. These findings suggest that about half of ALS patients exhibit high-degree CSO-EPVS, reflecting impaired protein clearance rather than disease aggressiveness.}, } @article {pmid41097004, year = {2025}, author = {Daponte, A and Koros, C and Skarlis, C and Siozios, D and Rentzos, M and Papageorgiou, SG and Anagnostouli, M}, title = {Neurofilament Biomarkers in Neurology: From Neuroinflammation to Neurodegeneration, Bridging Established and Novel Analytical Advances with Clinical Practice.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41097004}, issn = {1422-0067}, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Neurofilament Proteins/metabolism/blood ; *Neurodegenerative Diseases/metabolism/diagnosis ; *Neuroinflammatory Diseases/metabolism/diagnosis ; Animals ; }, abstract = {Neuroaxonal damage underlies permanent disability in various neurological conditions, both neuroautoimmune and neurodegenerative. It is crucial to accurately quantify and monitor axonal injury using biomarkers to evaluate disease progression and treatment effectiveness and offer prognostic insights. Neurofilaments (NFs), and especially neurofilament light chain (NfL), show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. Recent advances in ultrasensitive immunoassays enable the reliable detection of NFs in blood, transforming them from research tools into clinically applicable measures. In multiple sclerosis (MS), serum NfL correlates with disease activity, treatment response, and long-term disability, and may complement MRI in monitoring subclinical progression. In MS, NfL is primarily emerging as a marker of disease activity and treatment response; in amyotrophic lateral sclerosis (ALS), it has progressed further, being integrated into clinical trials as a pharmacodynamic endpoint and considered by regulatory agencies as a drug development tool. Additionally, NFs are increasingly being investigated in Alzheimer's disease, frontotemporal dementia, and other neurodegenerative disorders, though their disease specificity is limited. Ongoing challenges include older and novel assay harmonization, normative range interpretation, biological and analytical variability, and integration with other molecular and imaging biomarkers. This critical narrative review synthesizes the existing literature on NFs as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers and discusses their role in therapeutic development and precision medicine in neuroautoimmune and neurodegenerative diseases.}, } @article {pmid41097145, year = {2025}, author = {Tuigunov, D and Sinyavskiy, Y and Nurgozhin, T and Zholdassova, Z and Smagul, G and Omarov, Y and Dolmatova, O and Yeshmanova, A and Omarova, I}, title = {Precision Nutrition and Gut-Brain Axis Modulation in the Prevention of Neurodegenerative Diseases.}, journal = {Nutrients}, volume = {17}, number = {19}, pages = {}, pmid = {41097145}, issn = {2072-6643}, support = {Grant No. AP23489983//This research is funded by the Science Committee of the Ministry of Science and Higher Education of the Republic of Kazakhstan/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/prevention & control/microbiology ; *Gastrointestinal Microbiome/physiology ; *Brain ; *Precision Medicine/methods ; *Brain-Gut Axis/physiology ; Prebiotics/administration & dosage ; Probiotics/administration & dosage ; }, abstract = {In the recent years, the accelerating global demographic shift toward population aging has been accompanied by a marked increase in the prevalence of neurodegenerative disorders, notably Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Among emerging approaches, dietary interventions targeting the gut-brain axis have garnered considerable attention, owing to their potential to modulate key pathogenic pathways underlying neurodegenerative processes. This review synthesizes current concepts in precision nutrition and elucidates neurohumoral, immune, and metabolic regulatory mechanisms mediated by the gut microbiota, including the roles of the vagus nerve, cytokines, short-chain fatty acids, vitamins, polyphenols, and microbial metabolites. Emerging evidence underscores that dysbiotic alterations contribute to compromised barrier integrity, the initiation and perpetuation of neuroinflammatory responses, pathological protein aggregations, and the progressive course of neurodegenerative diseases. Collectively, these insights highlight the gut microbiota as a pivotal target for the development of precision-based dietary strategies in the prevention and mitigation of neurodegenerative disorders. Particular attention is devoted to key bioactive components such as prebiotics, probiotics, psychobiotics, dietary fiber, omega-3 fatty acids, and polyphenols that critically participate in regulating the gut-brain axis. Contemporary evidence on the contribution of the gut microbiota to the pathogenesis of Alzheimer's disease, Parkinson's disease, and multiple sclerosis is systematically summarized. The review further discusses the prospects of applying nutrigenomics, chrononutrition, and metagenomic analysis to the development of personalized dietary strategies. The presented findings underscore the potential of integrating precision nutrition with targeted modulation of the gut-brain axis as a multifaceted approach to reducing the risk of neurodegenerative diseases and preserving cognitive health.}, } @article {pmid41097931, year = {2025}, author = {Rutkove, S and Tiwari, G and Nath, AK}, title = {Performing Compound Motor Action Potential Measurement in Zebrafish: A Description of Methodology and a Comparison Between Healthy and ALS-Affected Animals.}, journal = {Muscle & nerve}, volume = {72}, number = {5}, pages = {1168-1177}, doi = {10.1002/mus.70009}, pmid = {41097931}, issn = {1097-4598}, support = {//Beth Israel Deaconess Medical Center/ ; }, mesh = {Animals ; Zebrafish ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics/diagnosis ; Disease Models, Animal ; *Action Potentials/physiology ; *Motor Neurons/physiology ; Animals, Genetically Modified ; Electric Stimulation ; Superoxide Dismutase/genetics ; }, abstract = {INTRODUCTION/AIMS: The compound motor action potential (CMAP) is a very well-established output from standard motor conduction studies in patients. CMAP methods have also been developed for various animal models, including mice, rats, and dogs. Here, we describe a CMAP methodology for adult zebrafish.

METHODS: Using needle stimulating electrodes placed in proximity to the caudal spinal column and a fixed two-electrode surface array placed near the dorsal fin for recording, we obtained CMAPs in wildtype (WT) and symptomatic amyotrophic lateral sclerosis (ALS) SOD1[G93A] zebrafish, assessing repeatability and the potential for identifying differences between the groups.

RESULTS: In WT animals, CMAP amplitude exhibited robust performance with a test-retest intra-class coefficient of 0.97 (95% confidence interval 0.947-0.988; p < 0.0001, n = 30). SOD1[G93A] zebrafish exhibited a 36% lower supramaximal CMAP amplitude as compared to WT (mean ± standard deviation: 7.7 ± 1.7 mV versus 12.2 ± 1.8 mV, respectively, p < 0.0001) and an 11% longer latency (1.30 ± 0.15 ms versus 1.17 ± 0.11 ms, p = 0.002). A classifier, incorporating amplitude and latency together, provided perfect discrimination between the two cohorts.

DISCUSSION: CMAP recording is a reliable technique in zebrafish and can successfully differentiate healthy WT fish from ALS-affected animals. Since CMAP is a quantitative metric that is highly sensitive to motor neuron loss or dysfunction, it will allow the zebrafish to be more effectively harnessed for physiological and clinical therapeutic studies in ALS and other neuromuscular diseases for which adult zebrafish models are available.}, } @article {pmid41098254, year = {2025}, author = {Marie, D and Miller, LE and Bhattacharyya, SK and Frankhauser, FM}, title = {Navigating End-of-Life Decisions With Amyotrophic Lateral Sclerosis: A Patient-Centered Perspective on the Clinical and Legal Barriers to Medical Aid in Dying.}, journal = {Cureus}, volume = {17}, number = {9}, pages = {e92254}, pmid = {41098254}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease that often leads to loss of speech, swallowing restrictions, respiratory failure, paralysis, and total physical dependence, despite preserved cognitive function. For some affected individuals, the anticipated decline in autonomy associated with ALS leads to the consideration of medical aid in dying (MAiD). In the United States (US), MAiD is legally permitted in 12 jurisdictions (11 states and Washington, DC); however, most require patients to self-administer the prescribed medications. This stipulation creates an inequitable barrier for people with late-stage ALS, as the ability to swallow medication or manipulate delivery devices is often lost well before the end of life. Patients with ALS who are considering MAiD and otherwise meet all eligibility criteria must weigh the decision to end their lives earlier than desired against the risk of prolonging life and becoming physically unable to self-administer MAiD. This paper, coauthored by a patient with bulbar-onset ALS, integrates clinical literature, legal analysis, and lived experience to examine how existing MAiD statutes in the US fail to accommodate the physical disabilities of otherwise eligible patients from using this option. Overall, legislative reform in the US is urgently needed to ensure that MAiD eligibility is based on informed consent and clinical criteria without unfair exclusion based on physical disability.}, } @article {pmid41098540, year = {2025}, author = {Dafsari, HS and Schuler, J and Schober, E and Möller, B and Antebi, A and Fanto, M and Jungbluth, H}, title = {The space-time continuum in neurological disorders of the autophagosome-lysosome fusion machinery.}, journal = {Autophagy reports}, volume = {4}, number = {1}, pages = {2560903}, pmid = {41098540}, issn = {2769-4127}, abstract = {Autophagy is a highly conserved cellular pathway for the degradation and recycling of defective intracellular cargo and plays a vital role in the homeostasis of post-mitotic tissues, particularly the nervous system. Autophagosome-lysosome fusion represents the final critical step in macroautophagy with a tightly regulated process mediated by a complex molecular machinery of tethering vesicles for degradation. Since the first reports of human autophagy disorders, the scientific and clinical focus condensed on severe phenotypes with biallelic-truncating genotypes as monogenic models of near-complete autophagy perturbation. Recent reports suggest a much wider disease spectrum with defective autophagy, ranging from neurodevelopmental disorders to neurodegenerative phenotypes with later manifestation due to "milder" genotypes, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). In addition, recent evidence identified molecular connections between physiological autophagy regulation during normal aging and pathophysiological hallmarks of aging-related disorders. These translational observations led to a more comprehensive understanding of autophagy at health and disease, in particular: 1) genetic location and allelism of pathogenic variants ("genomic space"); 2) protein-protein interaction in functional protein complexes ("proteomic space"); 3) metabolic autophagic flux with positive and negative regulators ("metabolomic space"); 4) age-related phenotypic progression over time. Here, we review the autophagosome-lysosome fusion machinery as a key structure both on the molecular level and with regards to the pathogenesis of the autophagy-related disease spectrum. We highlight the clinicopathological signature of disorders in the autophagosome-lysosome fusion machinery, in particular features warranting awareness from clinicians and geneticists to inform adequate diagnosis, surveillance, and patient guidance.}, } @article {pmid41099622, year = {2025}, author = {Yoshida, M and Muraki, N and Tajiri, M and Hengphasatporn, K and Sue, K and Kubo, T and Akashi, S and Shigeta, Y and Kambe, T and Furukawa, Y}, title = {Oxidative denaturation of Cu/Zn-superoxide dismutase associated with neurodegenerative diseases.}, journal = {Protein science : a publication of the Protein Society}, volume = {34}, number = {11}, pages = {e70339}, pmid = {41099622}, issn = {1469-896X}, support = {19H05765//Ministry of Education, Culture, Sports, Science and Technology/ ; 22H02768//Ministry of Education, Culture, Sports, Science and Technology/ ; 22K19389//Ministry of Education, Culture, Sports, Science and Technology/ ; 24H01329//Ministry of Education, Culture, Sports, Science and Technology/ ; }, mesh = {Humans ; Oxidation-Reduction ; *Superoxide Dismutase-1/chemistry/metabolism/genetics ; Molecular Dynamics Simulation ; Protein Denaturation ; Zinc/metabolism/chemistry ; Cysteine/chemistry/metabolism ; Protein Folding ; Hydrogen Peroxide/chemistry ; *Neurodegenerative Diseases/enzymology ; Amyotrophic Lateral Sclerosis/genetics/enzymology ; }, abstract = {Misfolding of mutant Cu/Zn-superoxide dismutase (SOD1) is a well-established pathological feature of familial amyotrophic lateral sclerosis (ALS). While amino acid substitutions in mutant SOD1 destabilize its structure and promote misfolding, oxidation has also been implicated in the pathological alterations of wild-type SOD1, particularly in neurodegenerative diseases including sporadic ALS. However, the impact of oxidation on SOD1 folding remains to be fully elucidated. Here, we demonstrate that Cys111 is primarily oxidized to sulfonic acid upon exposure of apo-SOD1 to hydrogen peroxide, as confirmed by the quantitation of thiol groups and mass spectrometry. Molecular dynamics simulations showed that sulfonylation of Cys111 disrupts the dimer interface and promotes monomerization. This monomeric form then facilitates the subsequent oxidation of buried Cys6, leading to structural disruption, as evidenced by circular dichroism spectroscopy and loss of thiol groups. SOD1 denaturation triggered by Cys111 oxidation became evident when zinc binding was impaired due to pathological mutations and/or under zinc-deficient conditions. Given that increased oxidative stress is frequently associated with many neurodegenerative diseases, modulating Cys111 oxidation may offer a potential strategy for maintaining SOD1 structural stability and preventing its pathological misfolding.}, } @article {pmid41099730, year = {2025}, author = {Rao, PP and Mishra, S}, title = {Genetic convergence in brain aging and neurodegeneration: from cellular mechanisms to therapeutic targets.}, journal = {Journal of neurogenetics}, volume = {39}, number = {4}, pages = {140-159}, doi = {10.1080/01677063.2025.2571127}, pmid = {41099730}, issn = {1563-5260}, mesh = {Humans ; *Aging/genetics/pathology ; Animals ; *Brain/pathology/metabolism ; *Neurodegenerative Diseases/genetics/therapy/pathology ; }, abstract = {The distinction between normal brain aging and neurodegeneration has traditionally been viewed as a binary classification, yet emerging evidence reveals a complex continuum of shared genetic mechanisms underlying both processes. This review synthesises current understanding of conserved molecular pathways that contribute to age-related neural decline across the spectrum from healthy aging to pathological neurodegeneration. We examine how fundamental cellular processes including protein quality control, mitochondrial dysfunction, inflammation, and synaptic maintenance are genetically regulated and become progressively dysregulated during aging. Key genetic pathways, such as insulin/IGF signalling, autophagy-lysosomal networks, and stress response mechanisms demonstrate remarkable conservation from model organisms to humans, suggesting evolutionary constraints on neural aging processes. The review highlights how genetic variants in these pathways can determine individual trajectories along the aging-neurodegeneration continuum, influencing susceptibility to diseases like Alzheimer's, Parkinson's, and ALS. We discuss evidence from comparative studies in C. elegans, Drosophila, rodents, and human populations that illuminate shared vulnerability genes and protective factors. Understanding these convergent mechanisms offers unprecedented opportunities for therapeutic intervention, as strategies targeting fundamental aging processes may simultaneously address multiple neurodegenerative conditions. This integrated perspective challenges traditional disease-centric approaches and supports the development of unified therapeutic strategies for promoting healthy brain aging while preventing neurodegeneration.}, } @article {pmid41100025, year = {2026}, author = {El Ansari, W and Elhag, W}, title = {Response to Borah et al's Comments on Manuscript: "From Outcomes to Long-Term Impact: Do Improvements in Individual Cardiometabolic Risk Factors After Sleeve Gastrectomy Translate to Reductions in Composite Indicators of Cardiovascular Risk".}, journal = {Obesity surgery}, volume = {36}, number = {2}, pages = {904-905}, pmid = {41100025}, issn = {1708-0428}, } @article {pmid41100401, year = {2025}, author = {Graco, M and Carey, KA and Russo, K and Sheers, NL and Berlowitz, DJ and , and , }, title = {Understanding the uptake and use of noninvasive ventilation among Australians living with amyotrophic lateral sclerosis: results of a national survey.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {649-658}, doi = {10.1080/21678421.2025.2529406}, pmid = {41100401}, issn = {2167-9223}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology/psychology ; Australia/epidemiology ; Cross-Sectional Studies ; *Noninvasive Ventilation/psychology/statistics & numerical data ; *Patient Acceptance of Health Care/psychology/statistics & numerical data ; Quality of Life ; Surveys and Questionnaires ; Australasian People/psychology/statistics & numerical data ; }, abstract = {Objective: Noninvasive ventilation (NIV) improves quality of life and extends survival in amyotrophic lateral sclerosis (ALS), yet NIV uptake among Australians with ALS has been estimated at 19%. This study aimed to identify demographic and disease-related factors associated with NIV uptake among people with ALS (pwALS). Methods: A national cross-sectional survey. PwALS (or their family caregivers) completed an online survey about their NIV use and healthcare experiences. Survey data were analyzed descriptively. Associations between demographic factors and three dichotomous NIV outcomes: "using NIV"; "offered and accepted NIV"; and "discussed NIV with a healthcare professional (HCP)" were investigated using multivariate logistic regression modeling. Results: A total of 224 responses were received, of which 201 completed the demographic questions. Mean (SD) age was 64 (11) years, 62% were male, and median (IQR) time since diagnosis was 2 (1-5) years. Forty-six percent were using NIV; 6% had started NIV and stopped; 4% had accepted a referral but not started; 3% had declined NIV; and 26% had never discussed NIV with a HCP. Demographic factors positively associated (p < 0.05) with at least one NIV outcome included: being male, age < 65 years, residing in a metropolitan/regional area, attending a ALS multidisciplinary clinic, and longer time since diagnosis. Conclusion: NIV uptake among Australians with ALS appears to have increased in the last decade, however this survey identified concerning disparities related to sex, age, and location of residence. Research exploring the underlying causes of these disparities is urgently required so that targeted interventions can be designed and implemented.}, } @article {pmid41100402, year = {2025}, author = {Fortuna Baptista, M and Gromicho, M and Alves, I and Oliveira Santos, M and De Carvalho, M}, title = {Predictors in late-stage amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {659-663}, doi = {10.1080/21678421.2025.2536647}, pmid = {41100402}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/mortality/therapy ; Male ; Female ; Middle Aged ; Aged ; Disease Progression ; Prognosis ; Adult ; Retrospective Studies ; }, abstract = {Aim: Prognostic factors in amyotrophic lateral sclerosis (ALS) are defined by clinical features and progression rate at first observation or over follow-up. The prognostic factors associated with late-stage disease are uncertain. We sought to identify factors predicting survival in advanced ALS. Methods: We analyzed data collected from patients followed at our clinic who progressed to late-stage ALS, defined as ALS Functional Rating Scale Revised (ALSFRS-R) ≤ 24 (group A), patients followed for at least 6 months thereafter constituted group B. We studied demographic and clinical variables, including phenotype, sex, age, diagnostic delay (disease duration at diagnosis), noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), early (from diagnosis to ALSFRS-R ≤ 24) and thereafter late functional progression rates (ΔFS), and survival. Multivariable analysis with Cox regression was performed to ascertain predictive factors for survival in late-stage. Results: Group A included 704 patients and group B 260 patients. For group A, predictors associated with shorter survival were bulbar-onset (p = 0.03), and ΔFS at diagnosis and until late stage (p < 0.001). For group B, predictors associated with shorter survival were older age (p = 0.005), bulbar-onset (p = 0.02), shorter diagnostic delay (p < 0.001), ΔFS until late stage (p < 0.02), and late stage ΔFS (p < 0.001), but not ΔFS at diagnosis. Discussion: Similar to the general ALS population, survival in late-stage patients is predicted by age, region of onset, and diagnostic delay. Although ΔFS in later stages is prognostic, the initial ΔFS at diagnosis is not. Therefore, continuous monitoring of functional decline remains crucial for patients already in advanced stages.}, } @article {pmid41101251, year = {2025}, author = {Westeneng, HJ and Nitert, AD and van Veenhuijzen, K and Wismans, C and Donatelli, G and Tan, HHG and van Hoek, W and van Es, MA and Klomp, DWJ and Bhogal, AA and Veldink, JH and Wijnen, JP and van den Berg, LH}, title = {Patterns of altered in vivo brain metabolism in patients with amyotrophic lateral sclerosis (ALS) and asymptomatic C9orf72 mutation carriers: a cross-sectional [1]H and [31]P magnetic resonance spectroscopic 7T imaging study.}, journal = {EBioMedicine}, volume = {121}, number = {}, pages = {105963}, pmid = {41101251}, issn = {2352-3964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/diagnostic imaging ; *C9orf72 Protein/genetics ; Middle Aged ; *Brain/metabolism/diagnostic imaging ; Female ; Male ; *Mutation ; Adult ; Aged ; Heterozygote ; Magnetic Resonance Imaging ; Cross-Sectional Studies ; Magnetic Resonance Spectroscopy ; }, abstract = {BACKGROUND: Processes leading to the onset of neurodegeneration in amyotrophic lateral sclerosis (ALS) are largely unknown. To gain insight into disease mechanisms, we measured brain metabolism in vivo in asymptomatic C9orf72 mutation carriers and patients with ALS.

METHODS: We enroled 15 asymptomatic family members with (AFM C9+) and 18 without a C9orf72 mutation (AFM C9-), 4 patients with ALS with (ALS C9+) and 35 without this mutation (ALS C9-), and 25 population-based controls (CO). Two-dimensional proton ([1]H) and whole-brain phosphorus ([31]P) magnetic resonance spectroscopic imaging (MRSI) data were obtained using a 7T MR scanner. 11 brain metabolites were compared between groups using weighted Bayesian linear multilevel models.

FINDINGS: Compared to AFM C9-, AFM C9+ showed evidence of neuronal dysfunction (decreased total N-acetyl aspartate/total creatine (tNAA/tCr)), widespread increased membrane breakdown product (glycerol phosphorylethanolamine/phosphocreatine (GPE/PCr)), glutamate excitotoxicity (increased glutamate + glutamine/tNAA (Glx/tNAA)) and, in frontoparietal regions, an increase in the glycogen precursor uridine diphosphoglucose/PCr (UDPG/PCr). Compared to AFM C9+, neuronal dysfunction and membrane breakdown are similar in ALS C9+, but glutamate excitotoxicity and increased glycogen precursor are more severe and widespread, also involving the primary motor region. Moreover, lower total adenosine triphosphate/PCr (tATP/PCr) emerged in ALS C9+, and signs of disturbed membrane synthesis, intracellular second messenger system and glial pathology (myo-inositol + glycine/tCr (mI + Gly/tCr)). ALS C9- is characterised by glutamate excitotoxicity, increased tATP/PCr, and lower phospholipid levels.

INTERPRETATION: [1]H and [31]P 7T MRSI can detect evolving patterns of altered brain metabolism in asymptomatic mutation carriers and patients with ALS. Abnormalities in patients with ALS C9+ appeared to be different from those in patients with ALS C9-. Metabolic markers, measured in vivo, can serve as biomarkers for inclusion or stratification as well as for drug-target engagement in clinical trials. This method can facilitate identification of new and personalised drug targets to prevent or treat this devastating disease.

FUNDING: ALS Foundation Netherlands.}, } @article {pmid41101301, year = {2025}, author = {Sasidharan, A and Somayaji, Y and Fernandes, R}, title = {Shifting Microglial Phenotypes: Targeting Disease-Associated Microglia in Neurodegeneration.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {21}, pages = {4147-4158}, doi = {10.1021/acschemneuro.5c00159}, pmid = {41101301}, issn = {1948-7193}, mesh = {Humans ; *Microglia/metabolism/pathology/immunology ; *Neurodegenerative Diseases/metabolism/pathology/immunology ; Animals ; Phenotype ; Neuroinflammatory Diseases/metabolism ; Phagocytosis/physiology ; }, abstract = {Neurodegenerative disorders are marked by the gradual degeneration of neurons and deterioration of cognitive function. One key underlying factor in these diseases is neuroinflammation. An essential component of this process is microglia, which are the innate immune cells that maintain homeostasis in the brain. A common outcome of microglial dysregulation in neurodegenerative diseases is chronic neuroinflammation, which exacerbates neuronal damage and impairs synaptic function. This review focuses on the dual roles that disease-associated microglia (DAMs) play in neural inflammation and neuroprotection as well as their distinct transcriptional profile in neurodegenerative diseases. DAMs engage in phagocytosis to remove debris, in addition to releasing cytokines that promote inflammation. To create an effective medicine, it is imperative to comprehend these dual functions. The roles of DAMs in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are discussed, along with the mechanisms (such as the TREM2-APOE pathway) causing their activation. This review attempts to highlight the important aspects that could direct future investigations and treatment development by clarifying the interactions between DAMs and neurodegenerative diseases.}, } @article {pmid41101465, year = {2026}, author = {Veenstra, J and Ozog, D and Stephens, A}, title = {Response to Bunick et al, "Response to Veenstra et al's 'Benzoyl peroxide acne treatment shows no significant association with benzene-related cancers: A multicenter retrospective analysis' on statistical design".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {2}, pages = {e129-e130}, doi = {10.1016/j.jaad.2025.09.104}, pmid = {41101465}, issn = {1097-6787}, } @article {pmid41102382, year = {2025}, author = {Wang, Q and Wang, Y and Jiang, YDD and Donahue, R and Cao, G and Yan, W and Guo, H and Li, Z and Liang, J and Hao, J and Lu, Y and Bei, F and Wang, Q and Tian, F}, title = {OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {1475}, pmid = {41102382}, issn = {2399-3642}, support = {K99 EY032181/EY/NEI NIH HHS/United States ; R00 EY032181/EY/NEI NIH HHS/United States ; EY032181//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; }, mesh = {*Retinal Ganglion Cells/metabolism/pathology ; Animals ; *Membrane Transport Proteins/metabolism/genetics ; Mice ; *Cell Cycle Proteins/genetics/metabolism ; *Optic Nerve Diseases/metabolism/pathology/genetics ; *Neuroinflammatory Diseases/metabolism/pathology/genetics ; Mice, Knockout ; Mice, Inbred C57BL ; Disease Models, Animal ; *Transcription Factor TFIIIA/genetics/metabolism ; Glaucoma ; Humans ; Male ; }, abstract = {Optineurin (OPTN) is an adaptor protein that plays a crucial role in many cellular pathways, including NF-κB signaling, programmed cell death, and vesicular trafficking. OPTN dysfunction has been implicated in the pathogenesis of several diseases, such as primary open angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS). While mutations of OPTN seem to be predominantly loss-of-function in ALS, only gain-of-function mechanisms have been reported in POAG. Here, we demonstrate that OPTN knockout in the retina contributes to short-term astrogliosis, retinal ganglion cell (RGC) loss and long-term microglial activation. Moreover, OPTN loss of function does not exacerbate RGC death induced by ocular hypertension. Integrated bioinformatics and immunofluorescence analyses reveal that OPTN dysfunction leads to neuropeptide Y (NPY) downregulation and CHOP upregulation. Overexpression of wild-type OPTN in a hypertension glaucoma model prevents the RGC loss and attenuates microglial activation. Together, our findings highlight a neuroprotective role for OPTN as a key neuroimmune modulator.}, } @article {pmid41102629, year = {2025}, author = {Masbi, M and Tavkoli, N and Payrovi, H and Dowlati, M}, title = {Special care services delivery at disaster scenes: a systematic review.}, journal = {International journal of emergency medicine}, volume = {18}, number = {1}, pages = {206}, pmid = {41102629}, issn = {1865-1372}, abstract = {BACKGROUND: Disasters create strain on health systems and require significant preparedness to reduce mortality and morbidity. Special care services; e.g. Advanced Life Support, critical care interventions (intubation; vasopressor therapy) and point of care diagnostics (ultrasound) may be provided in disaster-settings, although actual use of services is dependent on logistical, operational and contextual issues. This systematic review identifies an important gap to understand the effectiveness, feasibility and barriers to, special care services.The overall aim of this systematic review is to synthesise global evidence on the evidence-based practices and improve disaster response. METHODS: This systematic review utilized PubMed, Scopus, Web of Science, Embase, and grey literature from the time of inception of the different databases to January 2025, from which a total of 4465 records were identified. After a thorough, organized review of the identified records based on our exclusion criteria and inclusion criteria, a total of 31 articles were retained. The systematic review followed PRISMA 2020, and searched for studies on special care services in a pre-hospital disaster setting, and included primary research and review articles that described advanced interventions, and which had no time restrictions on date of publication. Articles that were waived from the cost of in-app purchasing were excluded due to limited resources and could limit the studies that were included. Quality assessment using STROBE, SANRA and checklists, along with the categories of findings using a thematic content analysis based on the dimensions of prehospital care. RESULTS: Thematic analysis revealed six broad themes: Patient Care and Clinical Management, Operational Efficiency and Logistics, Personnel and Training, Technology and Equipment, System Coordination and Preparedness, and Ethical and Contextual Considerations. Advanced functions like REBOA, ultrasound and AI-related diagnostics improved survival and neurological outcomes, However, they were restricted due to limited resources, lack of training, and lack of coordination, particularly in low resource contexts. CONCLUSIONS: The reviewed literature demonstrated that critical-care services such as Advanced Life Support (ALS), intubation, and ultrasound resulted in improved morbidity and mortality outcomes in disaster settings but were limited due to resource constraints, lack of training and inadequate coordination all the more pertinent to low-resource settings. CLINICAL TRIAL NUMBER: Not applicable.}, } @article {pmid41102689, year = {2025}, author = {Almomani, E and Tobin, J and Fernandes, S and Sullivan, J and Saadeh, O and Mustafa, E and Pattison, N and Alinier, G}, title = {A reflective learning conversation debriefing model for interprofessional simulation based education.}, journal = {BMC medical education}, volume = {25}, number = {1}, pages = {1434}, pmid = {41102689}, issn = {1472-6920}, mesh = {*Simulation Training/methods ; *Interprofessional Education/methods ; *Models, Educational ; Health Personnel ; Humans ; Interprofessional Relations ; Focus Groups ; *Cognitive Reflection ; Clinical Reasoning ; *Education, Medical/methods ; Male ; Female ; }, abstract = {BACKGROUND: Debriefing for Interprofessional Education (IPE) using Reflective Learning Conversation (RLC) methods enables learners to reflect on their actions, articulate their decisions, and benefit from peer support and the dynamics of group thinking within a team-based context. This study aims to validate a co-designed Reflective Learning Conversation (RLC) debriefing model for use in interprofessional learning groups that vary in professional seniority and clinical experience within a multicultural educational environment. The validation process focuses on enhancing clinical reasoning, clinical judgment, critical thinking skills, and self-efficacy.

METHODS: A quasi-experimental pre-test/post-test mixed method. The study sample consisted of a cohort of interprofessional healthcare providers (n = 130) who were taking part in European Resuscitation Council (ERC) Advanced Life Support (ALS) courses incorporating Simulation- Based Education (SBE) conducted at Hamad International Training Center (HITC), with the sample equally split between control and experimental groups. Data was collected through subsequent direct observations, validated questionnaires, and focus groups. Descriptive and inferential statistical analyses were performed on the quantitative data, and thematic analysis on the qualitative data.

RESULTS: The experimental group had a significantly higher level of clinical reasoning, judgment, and critical thinking skills compared to the control group at the beginning, midway, and end of simulation activities using the Clinical Reasoning Evaluation in Simulation Tool (CREST) tool, Lasater Clinical Judgment Rubric (LCJR), and Critical Thinking Rubric (CTR). The experimental group scored a significantly higher level of self-efficacy than the control group for the Self-Efficacy questionnaire subscales.

CONCLUSION: Reflective Learning Conversation (RLC) model was found to be valid for enhancing clinical reasoning, clinical judgment, critical thinking, and self-efficacy among interprofessional healthcare providers attending advanced life support simulation-based courses in multicultural learning environments. However, further research is recommended to explore how clinical experience and professional seniority interact with debriefing approaches to influence these cognitive and affective outcomes in simulation-based education.}, } @article {pmid41103971, year = {2025}, author = {Arachchige, ASPM}, title = {Rethinking ALS: Current understanding and emerging therapeutic strategies.}, journal = {AIMS neuroscience}, volume = {12}, number = {3}, pages = {391-405}, pmid = {41103971}, issn = {2373-7972}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of the upper and lower motor neurons, which leads to muscle atrophy, spasticity, and ultimately respiratory failure. The etiology of ALS remains unclear, though a combination of genetic and environmental factors is suspected. Advances in understanding ALS pathophysiology, including the role of RNA metabolism, mitochondrial dysfunction, and glutamate toxicity, have paved the way for new research directions. While Riluzole offers limited survival benefits, there is no cure, and treatment remains mostly supportive. This article summarizes the current understanding of ALS in terms of its pathophysiology, epidemiology, risk factors, clinical presentation, and treatment strategies.}, } @article {pmid41104042, year = {2025}, author = {Yassin, LK and Skrabulyte-Barbulescu, J and Alshamsi, SH and Saeed, S and Alkuwaiti, SH and Almazrouei, S and Alnuaimi, A and BaniYas, S and Aldhaheri, D and Alderei, M and Shehab, S and Hamad, MIK}, title = {The microbiota-gut-brain axis in mental and neurodegenerative disorders: opportunities for prevention and intervention.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1667448}, pmid = {41104042}, issn = {1663-4365}, abstract = {The microbiota-gut-brain axis (MGBA) is increasingly recognized as a critical regulator of brain health, influencing both neurodevelopment and age-related neurological decline. Disruptions in this axis, driven by gut dysbiosis, have been implicated in the pathogenesis of a wide range of neurodegenerative and neuropsychiatric disorders. This review synthesizes current evidence linking microbiota alterations to Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and stroke-including post-stroke cognitive impairment (PSCI), as well as major depressive disorder (MDD), bipolar disorder (BD), anxiety disorders, post-traumatic stress disorder (PTSD), and chronic fatigue syndrome (CFS). Common findings include reduced microbial diversity, depletion of short-chain fatty acid (SCFA)-producing genera, and enrichment of pro-inflammatory taxa. These changes contribute to neuroinflammation, blood-brain barrier (BBB) dysfunction, microglial activation, and neurotransmitter imbalances. The review further explores the neurotoxic effects of external factors such as radiation and xenobiotics on the MGBA. Despite disorder-specific variations, shared microbial and immunological mechanisms emerge across the spectrum of conditions. Importantly, we present current and emerging strategies aimed at restoring gut-brain communication, including dietary interventions such as fiber-rich and Mediterranean diets, SCFA supplementation, probiotics, and fecal microbiota transplantation (FMT). These approaches show promise in alleviating cognitive and emotional symptoms, modulating immune responses, and potentially slowing disease progression. By integrating mechanistic insights with therapeutic perspectives, this review underscores the gut microbiota as a modifiable factor in neuropsychiatric and neurodegenerative disease. Targeting the MGBA offers a novel, translational approach to intervention that may ultimately contribute to healthier brain aging and improved outcomes across the lifespan.}, } @article {pmid41105110, year = {2026}, author = {Wodwaski, N and Webber, E}, title = {Empowering Future Nurses: Integrating Emotional Intelligence Into Nursing Education.}, journal = {Nurse educator}, volume = {51}, number = {1}, pages = {E46-E51}, pmid = {41105110}, issn = {1538-9855}, mesh = {Humans ; *Emotional Intelligence ; *Students, Nursing/psychology ; *Education, Nursing, Baccalaureate/organization & administration/methods ; Curriculum ; Nursing Education Research ; Problem-Based Learning/methods ; Nursing Evaluation Research ; *Empowerment ; Clinical Competence ; }, abstract = {BACKGROUND: Active learning strategies (ALS) focusing on the development of emotional intelligence (EI) support the growth of interpersonal and emotional competencies in nursing. These competencies are central to the development of resilience and formation of professional nursing identity.

PROBLEM: Despite the recognized importance of EI, traditional nursing education often prioritizes technical skills and clinical knowledge, with limited focus on the intentional development of emotional and interpersonal competencies.

APPROACH: This article explores the integration of reflection, emotionally focused simulations, and communication-based exercises into a BSN (Bachelor of Science in Nursing) curriculum. Incorporating Goleman's EI model and Kolb's experiential learning cycle in the implementation of ALS is a novel approach to developing EI competencies in undergraduate nursing students.

OUTCOMES: These learning methods can help students strengthen their emotional awareness, communication skills, and self-regulation. They offer practical tools to support professional identity, resilience, and the delivery of person-centered care.

CONCLUSION: Embedding EI into nursing education through active learning fosters competencies essential for delivering compassionate, safe, and effective care. This model is adaptable across diverse learning environments.}, } @article {pmid41106144, year = {2025}, author = {Tamura, R and Taguchi, R and Yamada, T and Wada, H and Ayaki, T and Takahashi, R and Urushitani, M}, title = {Peripheral CD56[dim]CD16[+] NK cells correlate with serum NfL and ALS progression: An exploratory immunophenotyping analysis.}, journal = {Journal of neuroimmunology}, volume = {409}, number = {}, pages = {578779}, doi = {10.1016/j.jneuroim.2025.578779}, pmid = {41106144}, issn = {1872-8421}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/immunology/diagnosis ; Male ; Female ; *Killer Cells, Natural/immunology/metabolism ; Middle Aged ; *Disease Progression ; Immunophenotyping/methods ; Aged ; *Neurofilament Proteins/blood ; Biomarkers/blood ; *CD56 Antigen/blood ; Adult ; Receptors, IgG ; *Lipopolysaccharide Receptors/blood ; GPI-Linked Proteins ; }, abstract = {BACKGROUND: Peripheral immune dysregulation may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), yet, specific immunophenotypes correlated with disease progression remain unclear. We conducted an exploratory analysis to identify peripheral immune cell subsets correlated with ALS progression and serum biomarkers.

METHODS: Multicolor flow cytometry was used to evaluate 55 immune cell subsets in peripheral blood from 16 ALS patients. We assessed correlation with clinical progression (defined by monthly decline in the ALS Functional Rating Scale-Revised) and serum biomarkers: neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and estimated glomerular filtration rate (eGFR).

RESULTS: CD56[dim]CD16[+] natural killer (NK) cells were inversely correlated with both ΔALSFRS-R and serum NfL, and also showed a significant correlation with GFAP. Naive B cells positively correlated with ΔALSFRS-R. Monocyte subsets were differentially correlated with eGFR. Among all cells examined, CD56[dim]CD16[+] NK cells were the only subset significantly correlated with three clinical and biological measures.

CONCLUSIONS: CD56[dim]CD16[+] NK cells showed consistent correlations with ALS progression markers, although this exploratory study has small sample size and lacks healthy and disease controls, limiting conclusions in terms of statistical power and ALS-specificity about the observed immune alterations. These preliminary findings support the utility of immunophenotyping in ALS biomarker research and warrant validation in larger cohorts.}, } @article {pmid41107024, year = {2026}, author = {Bannwarth, S and Paquis-Flucklinger, V}, title = {Sporadic amyotrophic lateral sclerosis: what is the impact of the mitochondrial genome?.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {97}, number = {2}, pages = {199-200}, doi = {10.1136/jnnp-2025-337087}, pmid = {41107024}, issn = {1468-330X}, } @article {pmid41108075, year = {2026}, author = {Guida, N and Valsecchi, V and Anzilotti, S and Dubbioso, R and Cuomo, O and Ruggiero, S and Senerchia, G and Iuzzolino, VV and Kolici, X and De Iesu, N and Pignataro, G and Annunziato, L and Formisano, L}, title = {siRNA for REST ameliorates symptoms in ALS mice and serum REST predicts disease prognosis and survival in ALS patients.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {34}, number = {1}, pages = {367-379}, pmid = {41108075}, issn = {1525-0024}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/mortality/blood/therapy/diagnosis/pathology/metabolism ; Humans ; Mice ; Prognosis ; Disease Models, Animal ; *RNA, Small Interfering/genetics/administration & dosage ; *Repressor Proteins/genetics/blood ; Male ; Superoxide Dismutase-1/genetics/metabolism ; Female ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Middle Aged ; Biomarkers ; Spinal Cord/metabolism/pathology ; RE1-Silencing Transcription Factor ; }, abstract = {Restrictive element-1 silencing transcription factor (REST) is a key repressor of neuronal genes in stem cells and neuronal progenitor cells and its aberrant accumulation has been implicated in the pathophysiology of neurological disorders, such as Huntington's disease, epilepsy, and stroke. Herein, we investigated the role of REST in amyotrophic lateral sclerosis (ALS) pathophysiology and its potential as blood-based predictor of disease prognosis and survival in ALS patients. Intriguingly, REST protein levels were significantly increased in motor cortex, brainstem and spinal cord of superoxide dismutase 1 (SOD1)-G93A mice compared with wild-type mice, both during early and late symptomatic phases of the disease. Notably, intracerebroventricular injections of a siRNA against REST (siREST), mitigated motor neuron loss, counteracted the formation of SOD1 aggregates, and reduced astrogliosis, thus improving behavioral performance and extending the survival of SOD1-G93A mice. Interestingly, ELISA assay showed that serum REST levels were significantly elevated in ALS patients compared with healthy subjects; furthermore, the higher serum REST levels have been found in patients with shorter tracheostomy-free survival. Collectively, we demonstrated that preventing REST increase in brain areas involved in ALS disorder extended the survival of SOD1-G93A mice and showed that serum REST may represent a possible prognostic biomarker in ALS patients.}, } @article {pmid41108344, year = {2026}, author = {Freitas de Souza, G and Magalhães, RSS and Monteiro-Neto, JR and Martins, M and Follmer, C and Junqueira, M and Eleutherio, ECA}, title = {The effect of aging on post-translational modifications of wild-type human SOD1 and the A5V ALS mutant.}, journal = {GeroScience}, volume = {48}, number = {4}, pages = {5359-5377}, pmid = {41108344}, issn = {2509-2723}, support = {201.174/2022//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; E-26/010.002259/2019//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; SEI-260003/001131/2020//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; E-26/211.368/2021//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; SEI-260003/005643/202//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; 313417/2021-0//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; 88881.986154/2024-01//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 401780/2023-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 305146/2021-1//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {Humans ; *Protein Processing, Post-Translational/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Aging/genetics/metabolism ; *Mutation ; Oxidative Stress/genetics ; *Superoxide Dismutase/genetics/metabolism ; }, abstract = {Cu/Zn superoxide dismutase 1 (SOD1) is essential for maintaining neural health. Its functions include modulating metabolism, maintaining redox balance, regulating transcription, besides eliminating superoxide radicals, which are achieved through various post-translational modifications (PTMs). Consequently, unusual PTMs in SOD1 can impair its functionality and stability, leading to the accumulation of misfolded SOD1 and the increase of oxidative stress markers, hallmarks of Amyotrophic Lateral Sclerosis (ALS). Although SOD1 has been extensively studied, especially regarding its role in ALS, relatively little is known about how aging and mutations affect SOD1 PTMs. This study aimed to evaluate the effect of oxidative stress induced by chronological aging on PTMs of human SOD1: wild-type (WT) and A5V SOD1, a severe ALS-related mutant. To do this, both hSOD1 forms were expressed in Saccharomyces cerevisiae lacking the SOD1 gene, and then purified from extracts of stressed and non-stressed cells. PTMs were analyzed using mass spectrometry, observing the modification of WT and mutant human SOD1 in both conditions. We observed changes in the levels of damage, including oxidation, formylation, and carboxylation, such as oxidized tryptophan 33, associated with prion-like propagation of SOD1 misfolding. Increased levels of this PTM appeared in WT SOD1 after aging and in A5V SOD1. Acetylation and succinylation were also found on lysines. Some of these modifications already have described functions in the literature, while others still lack a defined role. Interestingly, the levels of these physiological PTMs differed between WT and mutant SOD1, providing important information for elucidating the molecular mechanisms of ALS involving SOD1.}, } @article {pmid41109359, year = {2025}, author = {Rantala, HA and Leivo-Korpela, S and Beerling, C and Helminen, M and Wijkstra, PJ and Duiverman, ML}, title = {Experienced benefits and side effects affect adherence with long-term noninvasive ventilation.}, journal = {Respiratory medicine}, volume = {249}, number = {}, pages = {108427}, doi = {10.1016/j.rmed.2025.108427}, pmid = {41109359}, issn = {1532-3064}, mesh = {Humans ; *Noninvasive Ventilation/adverse effects/methods/statistics & numerical data ; Female ; Male ; *Pulmonary Disease, Chronic Obstructive/therapy/mortality ; Retrospective Studies ; Aged ; Middle Aged ; *Patient Compliance/statistics & numerical data ; Finland/epidemiology ; *Obesity Hypoventilation Syndrome/therapy/mortality ; *Amyotrophic Lateral Sclerosis/therapy/mortality ; Netherlands/epidemiology ; }, abstract = {BACKGROUND AND OBJECTIVE: Long-term noninvasive ventilation (LT-NIV) is widely used in different diseases causing hypoventilation. We studied factors associated with adherence to LT-NIV in two hospitals in two different countries.

METHODS: This was a retrospective study including patients with chronic obstructive pulmonary disease (COPD), obesity-hypoventilation syndrome (OHS) and amyotrophic lateral sclerosis (ALS) initiating LT-NIV from January 1, 2012, to December 31, 2015, in Finland and from January 1, 2015, to December 31, 2022, in the Netherlands and followed up for two years.

RESULTS: A total of 702 patients were included: 334 patients with COPD, 158 patients with OHS and 210 patients with ALS. Six months after initiation, 78 %, 67 % and 87 % of the patients with COPD, OHS and ALS used their ventilator ≥5 h/day, respectively. Adherent COPD and ALS patients had higher ventilatory settings compared to non-adherent patients. In OHS, female patients were more often adherent. In a multivariate model, only experienced NIV benefits, side effects and the hospital where the patient was treated were associated with better adherence to NIV. The 2-year survival was best in COPD and OHS patients (median not calculated as less than 50 % died) and worst in ALS patients being 0.9 y (IQR 0.4-1.8 y). Further, survival did not differ between adherent and non-adherent COPD, OHS and ALS patients.

CONCLUSIONS: Experienced benefits and less side effects were associated with better NIV adherence. Adherence did not affect short-time survival in patients with COPD, OHS and ALS. To improve adherence, we suggest careful follow-up from the beginning to optimize ventilation.}, } @article {pmid41109388, year = {2025}, author = {Araya-Osorio, R and Dominguez, M and Thallmair, S and Marrink, SJ and Souza, PCT and Mera-Adasme, R}, title = {Allosteric pathway connects Zn(II) loss from SOD1 to known pathogenic mechanisms.}, journal = {International journal of biological macromolecules}, volume = {331}, number = {Pt 1}, pages = {148349}, doi = {10.1016/j.ijbiomac.2025.148349}, pmid = {41109388}, issn = {1879-0003}, mesh = {*Superoxide Dismutase-1/chemistry/metabolism/genetics ; *Zinc/metabolism/chemistry ; Allosteric Regulation ; Humans ; Molecular Dynamics Simulation ; Protein Folding ; Solvents/chemistry ; Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Cu,Zn superoxide dismutase (SOD1) is one of the proteins with mutations linked to hereditary forms of the amyotrophic lateral sclerosis neurodegenerative disorder. The protein is known for its enzymatic activity, but it has been shown to also have regulatory functions, which could be related to its pathogenic potential. Seemingly unrelated to its regulatory roles, the most important hypothesis on SOD1 pathogenicity is related to misfolding of the protein, specifically centered on the region corresponding to its residues 28-38. The present work explores the structural and dynamical effect of Zn(II) removal from SOD1, which is known to influence its regulatory roles, with coarse-grained simulations of 450μs per system. In agreement with experiment, we see an increased solvent exposure of the regulatory region (residues 5-18). We also see an increased solvent exposure of the misfolding-critical 28-38 region. We unveil the mechanism and interactions connecting Zn(II) loss, and solvent exposure of both regions. The present work allows for an unified understanding of two different pathogenic mechanisms of SOD1.}, } @article {pmid41109516, year = {2026}, author = {Pandya, K and Kumar, D}, title = {CRISPR/cas genome editing for neurodegenerative diseases: Mechanisms, therapeutic advances, and clinical prospects.}, journal = {Ageing research reviews}, volume = {113}, number = {}, pages = {102922}, doi = {10.1016/j.arr.2025.102922}, pmid = {41109516}, issn = {1872-9649}, mesh = {Humans ; *Gene Editing/methods/trends ; *Neurodegenerative Diseases/genetics/therapy ; *CRISPR-Cas Systems/genetics ; Animals ; *Genetic Therapy/methods/trends ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Spinocerebral Ataxia (SCA), and Huntington's disease (HD) are major global health challenges. Current treatments are only symptomatic and do not address the underlying pathogenic genetic mechanisms. The development of the CRISPR/Cas genome editing technologies, has increased possibilities for targeted repair of pathological mutations. CRISPR/Cas9, Cas12, and Cas13 systems enable targeted editing and transcriptome modulation in various preclinical models. CRISPR/Cas9 disruption of mutant APP, Tau, and LRRK2 genes, reducing toxic protein aggregration in AD models has restored normal genetic function. While correction of CAG nucleotide repeats in HD, and reduction of alpha-synuclein expression in PD. RNA targeting systems like Cas13 offers additional therapeutics potential by selectively degrading disease assciated transcript without altering genomic DNA. Advancements in engineered Cas variants with enhanced specificity, such as SpCas9-HF1, base editors and prime editors, with innovative delivery strategies including adeno-associated virus (AAVs) and nanoparticle-based systems, have improved genome editing. However, challenges remain, including off-target effects, mosaicism, and delivery across the BBB, and long-term safety. Ethical consideration focuses on somatic versus germline editing, equitable access, and regulatory oversight. While somatic editing shows acceptance in treating neurological disorders. Germline interventions face strict regulations due to potential multigeneration impacts. Collectively, these technologies are the vanguard of precision molecular medicine, advancing from symptom management towards potentially curative gene therapies for neurological disorders.}, } @article {pmid41110100, year = {2025}, author = {Yu, H and Chen, X and Yang, Y and Gu, M and Ren, K and Wei, Z}, title = {Decoding Glycosylation in Neurodegenerative Diseases: Mechanistic Insights and Therapeutic Opportunities.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {39}, number = {20}, pages = {e71160}, pmid = {41110100}, issn = {1530-6860}, support = {82301342//MOST | National Natural Science Foundation of China (NSFC)/ ; 82201455//MOST | National Natural Science Foundation of China (NSFC)/ ; 82470403//MOST | National Natural Science Foundation of China (NSFC)/ ; 82204389//MOST | National Natural Science Foundation of China (NSFC)/ ; }, mesh = {Humans ; Glycosylation ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; *Protein Processing, Post-Translational ; Animals ; Biomarkers/metabolism ; }, abstract = {Glycosylation is a highly dynamic and complex post-translational modification that plays a pivotal role in regulating protein folding, trafficking, stability, and function. Accumulating evidence indicates that aberrant glycosylation is intimately involved in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This review provides a comprehensive overview of the molecular mechanisms by which the two predominant forms of glycosylation, N-glycosylation and O-GlcNAcylation, contribute to protein misfolding, synaptic dysfunction, neuroinflammation, and impaired stress responses in the diseased nervous system. We further explore the diagnostic potential of glycosylation biomarkers and emerging therapeutic strategies targeting glycosylation pathways. Special emphasis has been placed on recent advances in glycomic technologies, artificial intelligence-driven analytics, and nanocarrier-based drug delivery platforms. By integrating mechanistic insights with translational applications, this review highlights glycosylation as both a pathological driver and a promising therapeutic target in neurodegenerative disorders.}, } @article {pmid41113424, year = {2025}, author = {Maidina, A and Wang, F}, title = {[Advances in the Structure and Function of Neurofilament Protein and Its Application in Early Diagnosis of Amyotrophic Lateral Sclerosis].}, journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition}, volume = {56}, number = {4}, pages = {1145-1151}, pmid = {41113424}, issn = {1672-173X}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Humans ; *Neurofilament Proteins/chemistry/metabolism/physiology ; Early Diagnosis ; Biomarkers ; }, abstract = {Neurofilament proteins (NFs), defined as a type Ⅳ intermediate filaments, are important components of the neuronal cytoskeleton. They play a key physiological role in maintaining the structural integrity and plasticity of axons and in ensuring the axonal transport function. Under pathological conditions, NFs detach from axons and undergo abnormal aggregation, causing axonal transport dysfunction. In addition, some components of the detached NFs leak into the peripheral circulation system. In patients with amyotrophic lateral sclerosis (ALS), the concentration of NFs is significantly elevated in the cerebrospinal fluid and blood, and the changes in NFs concentration is significantly positively correlated with the disease progression of ALS, suggesting the potential of NFs being used as early diagnostic biomarkers for ALS. In this review, we explored the relationship between NFs structure, assembly, and physiological function, focusing on the molecular mechanisms and clinical manifestations of ALS caused by abnormal assembly of NFs. We comprehensively summarized recent advances in the application of NFs as a new humoral biomarkers for early diagnosis and therapeutic monitoring of ALS. Key challenges in biomarker development-including undefined pathological neurofilament light chain (NFL) fragments, limited antibody availability, and poor assay reproducibility-are discussed. Strategies, including ultrasensitive detection technologies such as single molecule array (Simoa), antibody optimization based on pathological fragment identification, and multi-omics biomarker panels, should be integrated. These approaches may lead to breakthroughs, pave the way for precision-based ALS diagnosis, provide theoretical support for promoting its clinical translation and application, and offer ideas for future research.}, } @article {pmid41113933, year = {2025}, author = {Wang, Z and Cao, W and Fan, D}, title = {Role of lipocalin-2 in amyotrophic lateral sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1672903}, pmid = {41113933}, issn = {1663-4365}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized pathologically by degeneration of upper and lower motor neurons, ultimately leading to muscle weakness and respiratory failure. Lipocalin-2 (LCN2) is a secreted protein involved in lipid transport that plays a key role in inflammatory responses and the regulation of iron homeostasis. The role of LCN2 in ALS has attracted increasing attention, as significantly elevated LCN2 expression has been observed in the blood and postmortem tissues of ALS patients. Functionally, LCN2 participates in neuroinflammation, iron dysregulation, cell death, and peripheral immune immunity, proposing a central-peripheral linkage hypothesis mediated by LCN2. Clinically, LCN2 shows promise as both a biomarker and a therapeutic target, with multiple strategies demonstrating potential to mitigate ALS pathology. Moving forward, it is essential to integrate multi-omics to deeply decipher LCN2-mediated molecular networks, advance patient stratification, and accelerate its clinical translation.}, } @article {pmid41114097, year = {2025}, author = {Moyana, TN}, title = {Contrast-enhanced ultrasound as a non-invasive diagnostic modality for pancreatic ductal adenocarcinoma: The question of Ki67 for study validation.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {10}, pages = {110570}, pmid = {41114097}, issn = {1948-5204}, abstract = {This editorial comments on Yang et al's article that reported a correlation between dynamic contrast-enhanced ultrasound (CEUS) quantitative parameters and Ki67/tumor differentiation. The validation of CEUS as a diagnostic modality in this study deserves merit. However, it raises interesting points of discussion: (1) Since pancreatic cancer is an overarching term that includes conventional pancreatic ductal adenocarcinoma (PDAC), other subtypes, and neuroendocrine neoplasms (NENs), the inclusion/exclusion criteria require better clarification; (2) Most PDACs are grade 1-2 which contrasts with Yang et al's study where 46% were grade 3; (3) Ki67 is officially recognized for grading NENs, but not for PDAC; (4) Hotspots are selected for the Ki67 grading of NENs. However, for other tumors (e.g., breast carcinoma), the average count or hotspots are used; (5) There is no agreement for defining high-grade Ki67 cut-off for non-NENs; reports range from 10% to 50%; and (6) Ki67 reflects cellular proliferation but is not always the most important indicator for biologic aggressiveness. That notwithstanding, since the ratification of Ki67 for prognosis in NENs was based on survival outcomes, the real gold standard should be survival, instead of using Ki67 as a surrogate gold standard. In conclusion, the validation of CEUS parameters for PDAC is a work in progress. CEUS is valuable in assessing PDAC but should be viewed as augmenting other modalities such as computed tomography, magnetic resonance imaging, positron emission tomography and endoscopic ultrasound.}, } @article {pmid41114109, year = {2025}, author = {Zhou, QQ and Ren, YM and Shi, SM and Liu, TF}, title = {Microenvironmental code of pancreatic ductal adenocarcinoma: The prognostic symphony of budding, matrix and lymphocytes.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {10}, pages = {110523}, pmid = {41114109}, issn = {1948-5204}, abstract = {This editorial discusses Alpsoy et al's significant study of prognosis of pancreatic ductal adenocarcinoma (PDAC), which lacks histopathological markers. This study evaluated the synergistic prognolymphocytes. Peritumoral budding is significantly correlated with tumor volume, while intratumoral budding is closely related to lymph node metastasis. Peritumoral budding and intratumoral budding are confirmed as independent adverse prognostic factors, and their high levels of expression are associated with immature stromal phenotypes, suggesting the key role of epithelial-mesenchymal transition. These breakthrough findings provide a new multidimensional biomarker system for the prognostic assessment of PDAC, and promote the clinical transformation process of incorporating tumor budding indicators into the pathological reporting process. However, the complexity and spatiotemporal heterogeneity of the tumor microenvironment require us to go beyond traditional morphological analysis and move towards multiomics integration and dynamic monitoring. Through standardized pathological assessment, innovative treatment strategies and interdisciplinary collaboration, it is expected to transform tumor microenvironment-related markers into clinically applicable indicators, ultimately improving the treatment predicament of PDAC. This editorial intended to summarize relevant studies and share some of our views, in order to offer perspectives for future research.}, } @article {pmid41115859, year = {2025}, author = {Yap, K and Chung, TH and Hedges, EC and Nishimura, AL and Shaw, CE and Makeyev, EV}, title = {Enhanced hybridization-proximity labeling discovers protein interactomes of single RNA molecules.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {9257}, pmid = {41115859}, issn = {2041-1723}, support = {BB/Y009304/1//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; BB/V006258/1//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; BB/R001049/1//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; MR/Z506187/1//RCUK | Medical Research Council (MRC)/ ; Nishimura/Dec20/942-793//Motor Neurone Disease Association (MNDA)/ ; Shaw/Mar19/893-792//Motor Neurone Disease Association (MNDA)/ ; }, mesh = {Humans ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; C9orf72 Protein/genetics/metabolism ; *RNA/metabolism/genetics ; RNA-Binding Proteins/metabolism ; Cell Nucleus/metabolism ; RNA Precursors/metabolism/genetics ; Biotinylation ; Proteome/metabolism ; Pluripotent Stem Cells/metabolism ; }, abstract = {RNAs engage diverse protein partners and localize to specific subcellular compartments, yet dissecting proteomes associated with low-abundance or dispersed RNA molecules remains a challenge. We present an enhanced hybridization-proximity labeling (HyPro) technology for in situ proteome profiling of endogenously expressed RNA microcompartments. We re-engineer the HyPro enzyme and optimize proximity biotinylation conditions to identify proteins associated with compact RNA-containing nuclear bodies, small pre-mRNA clusters, and individual transcripts. Applying this approach to pathogenic G4C2 repeat-containing C9orf72 RNAs, retained as single-molecule foci in the nuclei of amyotrophic lateral sclerosis (ALS) patient-derived pluripotent stem cells, we reveal extensive interactions with disease-linked paraspeckle markers and a specific set of pre-mRNA splicing factors. These findings highlight early RNA processing and localization defects in ALS that may contribute to this late-onset neurodegenerative disorder. Overall, HyPro provides a broadly applicable platform for mapping RNA-protein interactions, enabling insights into RNA biology and its dysregulation in disease.}, } @article {pmid41117127, year = {2025}, author = {Kim, H and Uhm, JE and Park, J and Kim, YS and Sung, W and Lee, S and Kim, SH and Oh, KW}, title = {Monoclonal Gammopathy in Amyotrophic Lateral Sclerosis: No Impact on Clinical Progression and Immunotherapy Outcomes.}, journal = {European journal of neurology}, volume = {32}, number = {10}, pages = {e70376}, pmid = {41117127}, issn = {1468-1331}, support = {RS-2023-00265515//K-Brain Project of the National Research Foundation(NRF) Korean government (MSIT) (RS-2023-00265515)./ ; RS-2024-00348451//Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (RS-2024-00348451)./ ; }, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy/complications ; Female ; Disease Progression ; Aged ; *Immunotherapy/methods ; Middle Aged ; *Paraproteinemias/epidemiology/therapy/complications ; Republic of Korea/epidemiology ; Registries ; Prevalence ; Treatment Outcome ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND: The association between amyotrophic lateral sclerosis (ALS) and monoclonal gammopathy has been proposed, but evidence on its prevalence, clinical relevance, and treatment response remains limited, especially in Asian populations. This study aimed to investigate the prevalence of monoclonal gammopathy in Korean patients with ALS and evaluate the impact of immunotherapy.

METHODS: This registry-based study analyzed Korean patients with ALS at a tertiary referral hospital (2005-2023). All patients underwent electrophoresis and immunofixation electrophoresis to detect monoclonal gammopathy. Clinical progression was assessed using ALSFRS-R scores, disease progression rate (ΔFS), survival analysis, and electrophysiological evaluations.

RESULTS: Among 2400 patients with ALS, monoclonal gammopathy was identified in 1.0% (25/2400). Prevalence increased with age, 1.9% in patients aged ≥ 65 years and 0.7% (13/1755) aged < 65 years. Patients with ALS and monoclonal gammopathy were older (63.2 vs. 57.1; p = 0.01) and predominantly male (7.3:1 vs. 1.5:1; p < 0.01). Immunotherapy targeting monoclonal gammopathy did not significantly affect disease progression (pre-treatment ΔFS 1.00 ± 1.23 vs. post-treatment ΔFS 0.94 ± 0.86; p = 0.46) or survival outcomes (median survival 55.0 vs. 57.0 months; log-rank p = 0.93). Nerve conduction study did not correlate with clinical outcomes. IgM monoclonal gammopathy demonstrated later slower disease progression (initial ΔFS, overall ΔFS; p < 0.05) compared to IgA and IgG subtypes.

CONCLUSION: Monoclonal gammopathy in Korean patients with ALS was not more prevalent than in the general population, and immunotherapy did not impact ALS progression or survival. Clinical features may vary by immunoglobulin subtype. This collectively suggests minimal clinical significance of monoclonal gammopathy in ALS.}, } @article {pmid41117139, year = {2025}, author = {Pedro, KM and Alvi, MA and Goulart, GR and Fehlings, MG}, title = {Riluzole as a pharmacological therapy for spinal cord injury: where does this therapy stand?.}, journal = {Current opinion in neurology}, volume = {38}, number = {6}, pages = {625-634}, doi = {10.1097/WCO.0000000000001434}, pmid = {41117139}, issn = {1473-6551}, mesh = {*Riluzole/therapeutic use/pharmacology ; Humans ; *Spinal Cord Injuries/drug therapy ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; }, abstract = {PURPOSE OF REVIEW: Spinal cord injury (SCI) remains a disabling condition associated with long term neurological impairment, functional disability, and reduced quality of life. Despite decades of research, pharmacological interventions with proven clinical efficacy remain limited. This review critically evaluates the current evidence supporting riluzole as a neuroprotective agent for acute traumatic and nontraumatic SCI. We synthesize findings from preclinical and clinical studies, assess the progress towards clinical translation, and outline key challenges and research opportunities for future implementation.

RECENT FINDINGS: Riluzole, an FDA-approved agent for amyotrophic lateral sclerosis (ALS), inhibits voltage-gated sodium channels and modulates glutaminergic transmission, two mechanisms central to the pathogenesis of secondary injury in SCI and in nerve cell degeneration in nontraumatic forms of SCI, including degenerative cervical myelopathy (DCM). Preclinical studies consistently demonstrate functional and histopathological improvements following riluzole administration. Phase I/II trials have provided evidence for its safety and tolerability in acute SCI patients, while the RISCIS and CSM-PROTECT trials, two landmark multicenter randomized controlled studies, along with their secondary analyses, revealed promising multidomain improvements in motor function, independence, and quality of life indices. Sub-studies have also established pharmacokinetic and pharmacodynamic frameworks for individualized dosing, and early biomarker analysis suggests potential for predictive stratification.

SUMMARY: Riluzole represents a promising candidate for neuroprotection in traumatic and nontraumatic SCI. The consistency of favorable trends across multiple domains and strong support from preclinical studies highlight riluzole's value in orphan diseases such as SCI. Future directions should focus on refining the therapeutic window, optimizing PK/PD modeling, and identifying patient subgroups most likely to benefit. Its implementation in a multimodal treatment paradigm for acute SCI will be crucial for optimizing management protocols in this highly disabling condition.}, } @article {pmid41117267, year = {2025}, author = {Messina, C}, title = {Unraveling the Military Service-MND Connection: Time Frame, Exposures, and Phenotypic Considerations.}, journal = {European journal of neurology}, volume = {32}, number = {10}, pages = {e70392}, pmid = {41117267}, issn = {1468-1331}, } @article {pmid41117436, year = {2026}, author = {Jewett, G and Luk, C and Osman, H and Pfeffer, G}, title = {Conference proceedings from the Western Canadian Neuromuscular Conference (WCNMC) - September 27-29, 2024, Calgary, Canada.}, journal = {Journal of neuromuscular diseases}, volume = {13}, number = {4}, pages = {840-849}, pmid = {41117436}, issn = {2214-3602}, mesh = {Humans ; *Neuromuscular Diseases/therapy/diagnosis ; Canada ; }, abstract = {The Western Canadian Neuromuscular Conference (WCNMC) is a conference focused on neuromuscular medicine that was held in Calgary, Alberta from September 27-29, 2024. Although WCNMC has a history going back to 2010 as a regional event, the most recent iteration of the conference aimed to expand this as a national meeting. A collaboration with Muscular Dystrophy Canada and the Neuromuscular Network for Canada (NMD4C) helped to achieve this goal and encourage participation from across Canada. Other goals for this event were to increase the opportunities for trainees, showcase new research, and integrate new topics into the program. The sessions included a clinicopathologic case series for the first time, which was led by neuromuscular fellows from across Canada. Sessions covering topics in neuromuscular disease focused on challenging diagnostic situations, and therapeutic developments for diseases including spinal muscular atrophy, Pompe disease, and TTR amyloidosis. A separate session covered genetic neuromuscular diseases, with a focus on conditions with genetic founder effects in western Canada. Finally, a transdisciplinary session was included, which discussed patient-focused issues in neuromuscular care, as well as preliminary results from the Burden of Inherited Neuromuscular Disease (BIND) study, on the indirect costs of living with a neuromuscular disorder. A research symposium at the conclusion of the event focused on trainee-led research but also included lectures regarding antisense therapies in neuromuscular disease and updates in research on amyotrophic lateral sclerosis.}, } @article {pmid41117572, year = {2025}, author = {Soar, J and Böttiger, BW and Carli, P and Jiménez, FC and Cimpoesu, D and Cole, G and Couper, K and D'Arrigo, S and Deakin, CD and Ek, JE and Holmberg, MJ and Magliocca, A and Nikolaou, N and Paal, P and Pocock, H and Sandroni, C and Scquizzato, T and Skrifvars, MB and Verginella, F and Yeung, J and Nolan, JP}, title = {European Resuscitation Council Guidelines 2025 Adult Advanced Life Support.}, journal = {Resuscitation}, volume = {215 Suppl 1}, number = {}, pages = {110769}, doi = {10.1016/j.resuscitation.2025.110769}, pmid = {41117572}, issn = {1873-1570}, mesh = {Humans ; *Advanced Cardiac Life Support/standards/methods ; *Cardiopulmonary Resuscitation/standards/methods ; Adult ; Europe ; *Heart Arrest/therapy ; *Out-of-Hospital Cardiac Arrest/therapy ; }, abstract = {These European Resuscitation Council (ERC) Guidelines 2025 Adult Advanced Life Support (ALS) are based on the International Liaison Committee on Resuscitation (ILCOR) Consensus on Cardiopulmonary Resuscitation Science with Treatment Recommendations (CoSTR). The evidence informing the ALS Guidelines is also included. When ILCOR has not addressed a specific topic, the ERC ALS Writing Group has provided its own guidance and the evidence supporting it. This section provides recommendations for ALS for adults with in- or out-of-hospital cardiac arrest. The ERC Guidelines 2025 ALS emphasise providing early and effective ALS interventions to improve survival from cardiac arrest in adults.}, } @article {pmid41117937, year = {2025}, author = {Menge, S and Segura, I and Hartmann, M and Decker, L and Kiran, S and Danzer, KM and Iben, S and Harbauer, AB and Oeckl, P and Freischmidt, A}, title = {Comparing loss of individual fragile X proteins suggests strong links to cellular senescence and aging.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {82}, number = {1}, pages = {358}, pmid = {41117937}, issn = {1420-9071}, mesh = {Humans ; *Cellular Senescence/genetics ; *Fragile X Messenger Ribonucleoprotein 1/genetics/metabolism ; *Aging/genetics/metabolism ; *RNA-Binding Proteins/metabolism/genetics ; CRISPR-Cas Systems ; Autophagy ; Cell Line, Tumor ; Proteomics/methods ; Mitochondria/metabolism ; Fragile X Syndrome/metabolism/genetics/pathology ; Neurodegenerative Diseases/metabolism/genetics/pathology ; }, abstract = {Members of the fragile X protein (FXP) family (FMR1, FXR1 and FXR2) are differentially expressed in most types of cancer and major neurodegenerative diseases. While increased expression of FXR1 in cancer has been linked to senescence evasion and consequently tumor initiation and progression, decreased expression of FXPs in neurodegeneration may contribute to pathogenic protein aggregation and death of vulnerable neurons. However, due the causal role in fragile x syndrome, most data are available about loss of FMR1 in neurons while functions of FXR1 and especially FXR2 remain largely unexplored. To address this knowledge gap, and to directly compare functions of the FXPs, we used proteomics of CRISPR/Cas9 edited HAP1 cells carrying knockouts of the individual FXPs for identification of cellular mechanisms associated with these proteins. Further exploration of proteomic findings suggests roles of the FXPs in ribosome biogenesis, autophagy and mitochondrial health linked to organismal aging, and cellular senescence. Validation of FXP induced defects relevant for neurodegenerative diseases in neuroblastoma cell line SH-SY5Y upon FXP knockdown revealed high cell type specificity of individual FXP functions. Overall, we provide a comprehensive overview and comparison of cellular mechanisms related to the individual FXPs, as well as starting points for further studying this protein family in respective cell types of FXP associated diseases, and in aging in general.}, } @article {pmid41118343, year = {2025}, author = {Cheng, YH and Ho, MS}, title = {Disease-associated microglia in neurodegenerative diseases: Friend or foe?.}, journal = {PLoS biology}, volume = {23}, number = {10}, pages = {e3003426}, pmid = {41118343}, issn = {1545-7885}, support = {//National Yang Ming Chiao Tung University/ ; //National Natural Science Foundation of China/ ; //2030 Cross-Generation International Outstanding Young Scholars Program National Science and Technology Council Taiwan/ ; //Brain Research Center National Yang Ming Chiao Tung University/ ; }, mesh = {*Microglia/metabolism/pathology ; Humans ; Animals ; *Neurodegenerative Diseases/pathology/metabolism ; Alzheimer Disease/pathology/metabolism ; Mice ; Disease Models, Animal ; Aging ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Phagocytosis/genetics ; Lipid Metabolism ; Transcriptome ; }, abstract = {Recent advances in single-cell transcriptomics have led to the identification of disease-associated microglia (DAM) as a distinct, conserved microglia state associated with mouse models of Alzheimer's disease (AD) and amyotrophic lateral sclerosis, and with aging. DAM are characterized by downregulation of homeostatic genes and upregulation of lipid metabolism and phagocytosis genes, including key risk factors for AD in humans. Although characterized in models of AD, whether DAM acts as universal sensor across all neurodegenerative diseases remains unknown. This Essay discusses the dynamics, origins, and therapeutic potential of DAM in neurodegeneration, alongside evidence supporting a protective role for them in regulating disease processes.}, } @article {pmid41120750, year = {2025}, author = {Zeng, Y and Lovchykova, A and Akiyama, T and Rayner, SL and Maheswari Jawahar, V and Liu, C and Sianto, O and Guo, C and Calliari, A and Prudencio, M and Dickson, DW and Petrucelli, L and Gitler, AD}, title = {TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes.}, journal = {Nature neuroscience}, volume = {28}, number = {11}, pages = {2180-2189}, pmid = {41120750}, issn = {1546-1726}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; R35NS097263//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R35 NS137159/NS/NINDS NIH HHS/United States ; R01AG064690//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U54NS123743//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R35NS097273//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P01NS084974//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P01 NS084974/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; T32 AG047126/AG/NIA NIH HHS/United States ; RF1 NS120992/NS/NINDS NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; R35 NS097263/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Polyadenylation/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Neurons/metabolism ; *Cell Nucleus/metabolism/genetics ; Brain/metabolism/pathology ; Mutation/genetics ; }, abstract = {In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus of neurons in the brain and spinal cord. A key function of TDP-43 has emerged as a repressor of cryptic exon inclusion during pre-mRNA splicing, but a role for TDP-43 in other RNA-processing events remains unresolved. Here we show that loss of TDP-43 from neuronal nuclei of human brain and disease-causing mutations in TDP-43 are associated with widespread changes in alternative polyadenylation (APA). Using high-resolution polyadenylation site mapping, we comprehensively defined TDP-43-regulated APA events in human stem cell-derived neurons and found that both the strength and position of TDP-43 binding influence polyA site usage. APA events caused by loss of TDP-43 impact expression of disease-relevant genes (for example, SFPQ, NEFL and TMEM106B). These findings provide evidence that, in addition to cryptic exon inclusion, APA changes are a new facet of TDP-43 pathology.}, } @article {pmid41120751, year = {2025}, author = {Bryce-Smith, S and Brown, AL and Chien, MZYJ and Dattilo, D and Mehta, PR and Mattedi, F and Barattucci, S and Mikheenko, A and Zanovello, M and Pellegrini, F and El-Agamy, SE and Yome, M and Kargbo-Hill, SE and Qi, YA and Sun, K and Ryadnov, E and Wan, Y and , and Vargas, JNS and Birsa, N and Raj, T and Humphrey, J and Keuss, M and Wilkins, OG and Ward, M and Secrier, M and Fratta, P}, title = {TDP-43 loss induces cryptic polyadenylation in ALS/FTD.}, journal = {Nature neuroscience}, volume = {28}, number = {11}, pages = {2190-2200}, pmid = {41120751}, issn = {1546-1726}, support = {ZIA AG000535/ImNIH/Intramural NIH HHS/United States ; R00 AG080036/AG/NIA NIH HHS/United States ; K99 AG080036/AG/NIA NIH HHS/United States ; CC0102/WT_/Wellcome Trust/United Kingdom ; U01 AG068880/AG/NIA NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; *Polyadenylation/genetics ; *DNA-Binding Proteins/genetics/metabolism ; Induced Pluripotent Stem Cells/metabolism ; 3' Untranslated Regions/genetics ; Neurons/metabolism ; }, abstract = {Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 are cellular hallmarks of amyotrophic lateral sclerosis (ALS). TDP-43 nuclear loss causes de-repression of cryptic exons, yet cryptic alternative polyadenylation (APA) events have been largely overlooked. In this study, we developed a bioinformatic pipeline to reliably identify alternative last exons, 3' untranslated region (3'UTR) extensions and intronic polyadenylation APA event types, and we identified cryptic APA sites induced by TDP-43 loss in induced pluripotent stem cell (iPSC)-derived neurons. TDP-43 binding sites are enriched at sites of these cryptic events, and TDP-43 can both repress and enhance APA. All categories of cryptic APA were also identified in ALS and frontotemporal dementia (FTD) postmortem brain tissue. RNA sequencing (RNA-seq), thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) and ribosome profiling (Ribo-seq) revealed that distinct cryptic APA categories have different downstream effects on transcript levels and that cryptic 3'UTR extensions can increase RNA stability, leading to increased translation. In summary, we demonstrate that TDP-43 nuclear depletion induces cryptic APA, expanding the palette of known consequences of TDP-43.}, } @article {pmid41121754, year = {2025}, author = {Chin, ML and Choi, MMF and Tong, R and Pavlović, NM and Chan, W}, title = {Simultaneous Determination of Aristoloxazines, Aristolochic Acids, and Aristolactams Using HPLC-Fluorescence Detection with a Post-column Microreactor: Application in Identifying New Aristoloxazines.}, journal = {Journal of agricultural and food chemistry}, volume = {73}, number = {44}, pages = {28483-28492}, pmid = {41121754}, issn = {1520-5118}, mesh = {Chromatography, High Pressure Liquid/methods/instrumentation ; *Aristolochic Acids/analysis/chemistry ; Tandem Mass Spectrometry ; *Asarum/chemistry ; Fluorescence ; Mutagens/analysis ; }, abstract = {Aristoloxazines (AXs), aristolochic acids (AAs), and aristolactams (ALs) are potent genotoxins found in Asarum and Aristolochia plants, many of which are commonly used as herbal medicines. Emerging evidence indicates that these compounds contaminate arable soil during the cultivation of Aristolochiaceae herbs. Currently, no method exists for their simultaneous detection. In this study, we developed a high-performance liquid chromatography (HPLC)-based method for their determination. This method employs an iron powder-packed microreactor to convert non-fluorescent AXs and AAs into naturally fluorescent ALs, enabling fluorescence detection after HPLC separation. After being validated against LC-MS/MS analysis, the method was applied to quantify these genotoxins in herbal and soil samples, detecting AXs at concentrations as high as hundreds of μg/g in some Asarum samples. Given that Asarum plants are widely used in herbal medicine, these results reveal previously unrecognized human exposure to genotoxins that warrants the attention of both the general public and regulatory agencies.}, } @article {pmid41121980, year = {2026}, author = {Koide, S and Ikegami, I and Hanyu, R and Koike, YM and Yamagishi, T and Toyama, G and Washida, A and Tada, M and Kakita, A and Onodera, O and Sugai, A}, title = {Quantifying subpercent nuclear TDP-43 loss in cells and ALS cortex using junction-specific cryptic exon RT-qPCR.}, journal = {FEBS letters}, volume = {600}, number = {1}, pages = {119-130}, doi = {10.1002/1873-3468.70198}, pmid = {41121980}, issn = {1873-3468}, support = {KAKENHI grant / JP24K22094//Japan Society for the Promotion of Science/ ; KAKENHI grant / JP25K02462//Japan Society for the Promotion of Science/ ; JP22ek0109603//Japan Agency for Medical Research and Development/ ; SICORP grant / JP22jm0210097//Japan Agency for Medical Research and Development/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *DNA-Binding Proteins/genetics/metabolism ; *Exons/genetics ; Frontotemporal Dementia/genetics/pathology/metabolism ; Cell Line, Tumor ; *Real-Time Polymerase Chain Reaction/methods ; *Cell Nucleus/metabolism/genetics ; *Motor Cortex/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases characterised by nuclear TDP-43 loss. Its hallmark, cryptic exon (CE) splicing, is often masked in bulk tissue analyses by the low abundance of affected neurons. We developed an ultrasensitive RT-qPCR assay targeting STMN2 CE using one exon-CE junction-spanning primer and the other within the CE. The design expands the dynamic range sevenfold: TDP-43 knockdown boosted STMN2 CE levels 1395-fold in differentiated SH-SY5Y neurons. Spike-in tests set detection at 0.16% deficient cells. Crucially, the assay revealed a 42-fold CE increase in ALS motor cortex, previously missed by conventional primers. This streamlined tool enables precise quantification of TDP-43 dysfunction and sensitive pharmacodynamic monitoring for future ALS-FTD therapeutic studies. Impact statement Because cryptic-exon signals are diluted in bulk tissue, we developed a junction-spanning STMN2 RT-qPCR with sub-percent sensitivity. This deployable biomarker will aid ALS/FTD researchers and drug developers by standardizing measurements and enabling sensitive pharmacodynamic monitoring of therapies targeting nuclear TDP-43 dysfunction.}, } @article {pmid41122379, year = {2025}, author = {Takahashi, H and Kasai, T and Miyagawa-Hayashino, A and Ohara, T}, title = {Emerging roles of primary cilia in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1688839}, pmid = {41122379}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor neurons, for which effective disease-modifying therapies remain elusive. Primary cilia are solitary microtubule-based organelles critical for signal transduction and have recently been implicated in ALS pathogenesis. In this review, we provide a basic overview of the structure, dynamics, and functions of primary cilia, particularly in the brain. We highlight accumulating evidence from ALS models showing altered ciliary structure and function and explore how mutations in ALS-associated genes such as NEK1, C21orf2, and C9orf72 disrupt ciliogenesis and ciliary signaling. Moreover, we examine the interplays between primary cilia dysfunction and known ALS-related mechanisms, including loss of proteostasis, abnormal RNA metabolism, microtubule dysfunction, neuroinflammation, and mitochondrial dysfunction. Collectively, the evidence suggests a bidirectional relationship in which ciliary impairment and ALS pathomechanisms reinforce one another in a vicious cycle. We further discuss emerging therapeutic strategies targeting ciliary function, as well as the potential for primary cilia as novel clinical applications. Our review highlights primary cilia as a previously underappreciated yet potentially important component of ALS biology, offering novel insights into disease mechanisms and future therapeutic development.}, } @article {pmid41122380, year = {2025}, author = {Liu, Z and Dong, H and Yang, H and Zhou, L and Li, M and Zhang, X and Zhao, Y and Han, M and Liu, Y and Geng, Z}, title = {Glymphatic dysfunction in amyotrophic lateral sclerosis: a multimodal MRI investigation of brain-CSF functional and structural dynamics.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1666114}, pmid = {41122380}, issn = {1662-4548}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration and glial activation. The coupling of global blood oxygen level-dependent (gBOLD) signals with cerebrospinal fluid (CSF) inflow dynamics is a novel non-invasive biomarker, which is applied to assess the relationship between lymphatic function and ALS.

OBJECTIVE: The gBOLD-CSF coupling was used to assess the glymphatic system dysfunction related to ALS, and the relationship between this disease and the glymphatic system was further explored by combining the diffusion tensor imaging index of the perivascular space (DTI-ALPS) and the volume fraction of the choroid plexus (choroid plexus volume [CPV]/intracranial total volume [TIV]).

METHODS: We conducted a systematic analysis and comparative study of the imaging indicators and clinical data of 41 patients with ALS and 43 healthy controls (HC).

RESULTS: ALS patients showed significantly reduced gBOLD-CSF coupling (p < 0.001), reduced ALPS index (p < 0.001), and increased CPV fraction (p < 0.001). The area under the ROC curve (AUC) were 0.790 (gBOLD-CSF), 0.760 (ALPS index), and 0.748 (CPV fraction). A diagnostic model for ALS was developed based on gBOLD-CSF coupling, ALPS index, and CPV fraction with an AUC of 0.897 (0.830-0.964). The calibration curve demonstrates that the model exhibits strong consistency. The results of the Decision Curve Analysis (DCA) further indicate that the nomogram possesses substantial clinical utility.

CONCLUSION: This study identified that gBOLD-CSF coupling has diagnostic value for ALS and developed a diagnostic model by combining the ALPS index and CPV fraction, which has good diagnostic efficacy and clinical application value.}, } @article {pmid41123679, year = {2025}, author = {Rocha, DC and Omoregbee, MO and Contiliani, DF and Mandlik, R and Li, G and Mascoveto, J and Coleman, G and Culver, JN and Leal, DR and de Souza, AA and Qi, Y}, title = {Transgene-free genome editing in citrus and poplar trees using positive and negative selection markers.}, journal = {Plant cell reports}, volume = {44}, number = {11}, pages = {244}, pmid = {41123679}, issn = {1432-203X}, support = {IOS-2132693//Division of Integrative Organismal Systems/ ; 2224203//Division of Integrative Organismal Systems/ ; IOS-2428015//Division of Integrative Organismal Systems/ ; 2021-67013-34554//National Institute of Food and Agriculture/ ; 2020-33522-32274//National Institute of Food and Agriculture/ ; 2024-33522-42755//National Institute of Food and Agriculture/ ; 2020-70029- 33161//National Institute of Food and Agriculture/ ; DE-SC0023011//Department of Energy/ ; 2023/09068-9//FAPESP/ ; }, mesh = {*Populus/genetics ; *Gene Editing/methods ; Plants, Genetically Modified/genetics ; *Citrus/genetics ; Transgenes/genetics ; CRISPR-Cas Systems/genetics ; Genome, Plant ; Genetic Markers ; Herbicide Resistance/genetics ; }, abstract = {Transgene-free genome editing of the gene of interest in citrus and poplar has been achieved by co-editing the ALS gene via transient transgene expression of an efficient cytosine base editor. CRISPR-Cas genome editing systems have been widely used in plants. However, such genome-edited plants are nearly always transgenic in the first generation when Agrobacterium-mediated transformation is used. Transgene-free genome-edited plants are valuable for genetic analysis and breeding as well as simplifying regulatory approval. It can be challenging to generate transgene-free genome-edited plants in vegetatively propagated or perennial plants. To advance transgene-free genome editing in citrus and poplar, we investigated a co-editing strategy using an efficient cytosine base editor (CBE) to edit the ALS gene to confer herbicide resistance combined with transient transgene expression and potential mobile RNA-based movement of CBE transcripts to neighboring, non-transgenic cells. An FCY-UPP based cytotoxin system was used to select non-transgenic plants that survive after culturing on 5-FC containing medium. While the editing efficiency is higher in poplar than in citrus, our results show that the CBE-based co-editing strategy works in both citrus and poplar, albeit with low efficiency for biallelic edits. Unexpectedly, the addition of the TLS mobile RNA sequence reduced genome editing efficiency in both transgenic and non-transgenic plants. Although a small fraction of escaping plants is detected in both positive and negative selection processes, our data demonstrate a promising approach for generating transgene-free base-edited plants.}, } @article {pmid41124800, year = {2025}, author = {Sergeeva, OS and Neklesova, MV and Reushev, VA and Artemov, AV and Kuznetsova, IM and Turoverov, KK and Uversky, VN and Fonin, AV}, title = {On the potential roles of TDP-43 in the formation of membraneless organelles and their transformation into toxic aggregates.}, journal = {Biochemical and biophysical research communications}, volume = {788}, number = {}, pages = {152808}, doi = {10.1016/j.bbrc.2025.152808}, pmid = {41124800}, issn = {1090-2104}, mesh = {Humans ; *DNA-Binding Proteins/metabolism/chemistry ; *Organelles/metabolism/pathology ; Animals ; *Protein Aggregation, Pathological/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Protein Aggregates ; Frontotemporal Dementia/metabolism/pathology ; Neurodegenerative Diseases/metabolism/pathology ; *TDP-43 Proteinopathies/metabolism/pathology ; }, abstract = {Trans-activation response (TAR) DNA-binding protein 43 (TDP-43) is an RNA-binding protein involved in the processing, transport, and regulation of mRNA translation. It is distributed in many tissues, including the brain, where it is found mainly in hippocampal neurons. Abnormal localization, hyperphosphorylation, and aggregation of TDP-43 are pathological signs of a group of neurodegenerative diseases known as TDP-43 proteinopathies. Despite the growing understanding of the physiological role of TDP-43 in ensuring neuronal plasticity and the formation of long-term memory, to date, there is no comprehensive data on the molecular and cellular mechanisms of the transformation of functional membraneless organelles (MLOs) containing TDP-43 into toxic aggregates and the pathogenesis of associated diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This review is devoted to highlighting the role of MLOs in the formation of irreversible aggregates, the role of TDP-43 in the formation of MLOs and their relationship with pathological forms of TDP-43, most often found in people suffering from neurodegenerative diseases.}, } @article {pmid41126230, year = {2025}, author = {Lai, YH and Lin, KH and Huang, HK and Huang, TW and Kuo, YS}, title = {The first case of diaphragm pacing system implantation in a patient with high cervical spinal cord injury in taiwan: a case report and literature review.}, journal = {Journal of cardiothoracic surgery}, volume = {20}, number = {1}, pages = {377}, pmid = {41126230}, issn = {1749-8090}, mesh = {Humans ; *Diaphragm/innervation/physiopathology ; *Spinal Cord Injuries/complications ; Taiwan ; Male ; Laparoscopy/methods ; Middle Aged ; Cervical Vertebrae/injuries ; *Electric Stimulation Therapy/methods ; *Respiratory Insufficiency/etiology/therapy ; }, abstract = {INTRODUCTION: This report presents the first case of a patient with high cervical spinal cord injury who underwent successful laparoscopic implantation of a diaphragm pacing system in Taiwan. It also compares the pros and cons of laparoscopic and thoracoscopic implantation and discusses postoperative care.

BACKGROUND: The diaphragm pacing system (DPS) represents a substantial advancement in respiratory support technology, particularly for patients with chronic respiratory insufficiency. It electrically stimulates the phrenic nerve, which in turn activates the diaphragm-the primary muscle involved in respiration [1]. This stimulation mimics the natural neural impulses that drive diaphragmatic contractions, thereby promoting inhalation and a more efficient lung ventilation. The DPS typically consists of implanted electrodes, an external pulse generator, and connecting leads [2]. It is mainly used in patients with high spinal cord injuries, amyotrophic lateral sclerosis, and central hypoventilation syndrome. These conditions often result in compromised neural control of the diaphragm, leading to severe respiratory insufficiency. By restoring diaphragm function, DPS can enhance the patients' quality of life, reduce dependence on mechanical ventilators, and lower the risk of ventilator-associated complications [3]. Despite its benefits, DPS is not without challenges. Patient selection and the surgical approach are critical to perform successful DPS implantation for the restoration of diaphragm function [4]. This report presents the first case of a patient with cervical spine injury who underwent successful laparoscopic implantation of DPS in Taiwan. Furthermore, it discusses postoperative ICU care and reviews the pros and cons of different surgical approaches to performing DPS implantation.}, } @article {pmid41126461, year = {2025}, author = {Ayton, S and Moreau, C and Devos, D and Bush, AI}, title = {Iron on trial: recasting the role of iron in neurodegeneration.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {12}, pages = {4241-4247}, doi = {10.1093/brain/awaf398}, pmid = {41126461}, issn = {1460-2156}, support = {//National Health & Medical Research Council of Australia/ ; //Florey Institute of Neuroscience/ ; }, mesh = {Humans ; *Iron/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Brain/metabolism ; Iron Chelating Agents/therapeutic use ; Animals ; Oxidative Stress/physiology ; }, abstract = {Iron is critical for numerous neurophysiological functions, while its dysregulation is potentially hazardous for neurodegeneration through oxidative stress and ferroptosis. For decades, elevated brain iron levels observed in neurodegenerative diseases such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis was presumed to drive disease progression; a hypothesis that propelled clinical trials of strong iron chelators like deferiprone. Results from these trials, however, have challenged this paradigm, with deferiprone markedly worsening outcomes in patients with Alzheimer's disease and, in certain contexts, patients with Parkinson's disease. These findings underscore the vital role of iron for brain health and suggest functional compensatory mechanisms that could become deleterious at the extremes of iron distribution (both low and high levels). Here, we outline an evolving understanding of iron's role in neurodegeneration, and we explore pathways for therapeutic development strategies that mitigate potential iron-mediated damage, while preserving its essential functions in the brain.}, } @article {pmid41127439, year = {2025}, author = {Xu, J and van Eijk, RPA and Ellis, A and Pan, T and Nelson, LM and Roes, KCB and van Dijk, M and Sarno, M and van den Berg, LH and Tian, L and Lu, Y}, title = {On the Two-Step Hybrid Design for Augmenting Randomized Trials Using Real-World Data.}, journal = {Statistics in biopharmaceutical research}, volume = {}, number = {}, pages = {}, pmid = {41127439}, issn = {1946-6315}, support = {P01 CA257907/CA/NCI NIH HHS/United States ; R01 HL089778/HL/NHLBI NIH HHS/United States ; UM1 TR004921/TR/NCATS NIH HHS/United States ; }, abstract = {Hybrid clinical trials, which borrow real-world data (RWD) from patient registries, claims databases, or electronic health records (EHRs) to augment randomized clinical trials, are of increasing interest. Hybrid clinical trials are especially relevant for rare diseases, where the recruitment of large sample sizes may be challenging. While these trials may better use available information, they assume that the RWD and randomized control arm are exchangeable. Violating this assumption can induce bias, inflate Type I error, or adversely affect statistical power. A two-step hybrid design first tests the exchangeability between randomized control arm and external data sources before incorporating RWD as a comparator for statistical inferences (Yuan et al. 2019). This approach reduces the chance of inappropriate borrowing but may simultaneously inflate the Type I error rate. We propose four different methods to control the Type I error rate under the exchangeability assumption. Approach 1 estimates the variance of the overall test statistic and rejects the null hypothesis based on a Z-test. Approach 2 uses a numerical method to determine the exact critical value for Type I error control. Approach 3 splits the Type I error rates according to the equivalence test outcome. Approach 4 adjusts the critical value only when equivalence is established. We illustrate these methods using a hypothetical scenario in the context of amyotrophic lateral sclerosis (ALS). We evaluate the Type I error and power under various clinical trial conditions in comparison with the Bayesian power prior approach (Ibrahim et al. 2015). We demonstrate that our proposed methods and Bayesian power prior control Type I error and increase power under the exchangeability assumption, whereas the method proposed by Yuan et al. (2019) results in an increased Type I error. In the scenario where the exchangeability assumption does not hold, all methods fail to control the Type I error. Our proposed methods, however, limit a maximum Type I error inflation ranging from 6% to 8%, which compares favorably to 10% for Yuan et al. (2019) and 16% for the Bayesian power prior. All methods increase statistical power under the exchangeability condition but may lead to a loss of statistical power when the exchangeability assumption is violated.}, } @article {pmid41127961, year = {2026}, author = {De Marchi, F and Baj, A and Menegon, F and Caminiti, SP and Sacchetti, M and Sarnelli, MF and Corrado, L and Puricelli, C and Matheoud, R and Binaschi, L and Sacchetti, GM and D'Alfonso, S and Comi, C and Perani, D and Mazzini, L and Tondo, G}, title = {Profiling cognition and brain metabolism in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {6}, pages = {2046-2058}, doi = {10.1093/brain/awaf401}, pmid = {41127961}, issn = {1460-2156}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/psychology/diagnostic imaging/genetics ; *Frontotemporal Dementia/metabolism/psychology/diagnostic imaging/genetics ; Female ; Positron-Emission Tomography ; Male ; *Brain/metabolism/diagnostic imaging ; Middle Aged ; Neuropsychological Tests ; Aged ; Fluorodeoxyglucose F18 ; Biomarkers ; *Cognition/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are described as a disease continuum, given their shared clinical, genetic and pathological characteristics. Comparisons of clinical and biomarker features within the ALS and behavioural variant FTD (bvFTD) spectrum are of utmost importance for diagnostic and prognostic purposes. This study investigated biomarker differences between cognitively normal patients with ALS (ALS-cn), ALS-FTD patients and bvFTD patients. Participants, genetically screened for known ALS- and FTD-associated mutations, underwent neuropsychological assessments, CSF analysis and 18F-fluorodeoxyglucose PET (18F-FDG-PET). Neuropsychological data were analysed by calculating a composite score for each cognitive domain, averaging the rank-transformed z-scores of all tests measuring the same domain. 18F-FDG-PET was performed using a validated voxel-based SPM method at the single-subject and group levels. To evaluate the ability to differentiate ALS-cn, ALS-FTD and bvFTD using the identified markers, machine-learning models-support vector machine (SVM) and random forest (RF)-were applied, offering a streamlined, data-driven approach to improve diagnostic precision across this spectrum of disorders. Twenty ALS-cn, 19 ALS-FTD and 21 bvFTD patients were included. Neuropsychological composite z-scores revealed significant differences across groups, underlining worse performance in bvFTD regarding memory, visuospatial, language and executive functions. Brain 18F-FDG-PET showed a pattern of hypometabolism that increased from ALS-cn to ALS-FTD and reached its greatest extent in bvFTD. Specifically, brain hypometabolism was confined mainly to the sensorimotor cortices and frontobasal regions in the ALS-cn group, whereas in the ALS-FTD group, it extended to the supplementary motor area and dorsolateral frontal cortex, and in the bvFTD group, it was widespread, further affecting the frontomesial and orbitofrontal cortices. No significant differences in CSF biomarkers were observed between groups. SVM correctly classified 83% of patients, indicating good classification performance, while RF achieved perfect accuracy (100%). The two models shared eight to ten most relevant features for classification, namely age, disease duration from symptom onset to diagnosis, total composite z-score, superior frontal gyrus (left), middle frontal gyrus (left), middle frontal gyrus-pars orbitalis (left and right) and anterior cingulate cortex (left). Our study identified significant differences in biomarkers across neurodegenerative clinical groups within the same disease spectrum. These differences were evident in the neuropsychological profiles and brain hypometabolism patterns among the patient groups, providing valuable insights into the heterogeneity of the ALS-FTD continuum and highlighting distinct disease-related patterns to enhance diagnostic accuracy.}, } @article {pmid41129425, year = {2026}, author = {Radakovic, R and Gray, D and Trucco, AP and Mioshi, E and Copsey, H and Dick, D and Newton, J and Pal, S and Simmons, Z and Abrahams, S}, title = {Self-reported initiation apathy is related to worse quality of life in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {179-184}, doi = {10.1080/21678421.2025.2574684}, pmid = {41129425}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; *Quality of Life/psychology ; *Apathy/physiology ; Male ; Female ; Middle Aged ; *Self Report ; Aged ; Depression/psychology/etiology ; Adult ; Anxiety/psychology/etiology ; }, abstract = {Objective: Apathy is the most prevalent behavioral impairment or difficulty for people with ALS (pwALS), with Initiation apathy (a lack of motivation for self-generation of thoughts and/or actions) the most common subtype. Self-rated or self-perceived quality of life (sQoL) is impacted for pwALS, but the relationship to apathy subtypes is unknown. The aim was to explore the relationship between sQoL domains and apathy in pwALS. Methods: 32 pwALS were recruited and completed self-rated measures of apathy (Dimensional Apathy Scale), depression, anxiety, and emotional lability. The ALS-specific QoL short-form instrument was used to measure QoL. Cognitive functioning and functional disability were measured. Exploratory, comparative, and predictive multiple hierarchical regression analyses were performed. Results: Initiation apathy was the most common apathy subtype at 37.5% (N = 12). PwALS with Initiation apathy had higher depressive symptoms (p <.05, d = 1.11 large effect) and lower cognitive functioning (p <.05, d = 0.76 medium effect) than those without apathy. PwALS with Initiation apathy had significantly worse sQoL in domains of interaction with people and the environment (p <.05, d = 0.92, large effect) and negative emotions (p <.05, d = 0.80, large effect) than those without apathy. Regression analysis showed Initiation apathy was a significant negative predictor of the sQoL domain of interaction with people and the environment (beta =-.20, p <.01), controlling for confounders (functional disability, depression, cognitive functioning). Conclusions: Initiation apathy was associated with QoL domains of interaction with people and the environment, from the perspective of the pwALS. This emphasizes the importance of self-rating or self-perception for clinical and researcher assessment of apathy and QoL for pwALS.}, } @article {pmid41129733, year = {2025}, author = {Aouti, S and Kommu, P and Hegde, RP and Ali, A and Mm Srinivas, B and Padavattan, S and Padmanabhan, B}, title = {Structure and Molecular Basis for Inhibiting Human SOD1 Aggregation by a Promising Decan Derivative Modulator: A Potential Therapeutic Strategy for Treating Amyotrophic Lateral Sclerosis (ALS).}, journal = {ACS chemical neuroscience}, volume = {16}, number = {21}, pages = {4180-4190}, doi = {10.1021/acschemneuro.5c00168}, pmid = {41129733}, issn = {1948-7193}, mesh = {Humans ; *Superoxide Dismutase-1/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Superoxide Dismutase/metabolism/chemistry ; Crystallography, X-Ray ; Models, Molecular ; }, abstract = {Misfolding and aggregation of the human superoxide dismutase (hSOD1) protein are pathological hallmarks of amyotrophic lateral sclerosis (ALS), a motor neuron disease. The structural stabilization and enzymatic activation of hSOD1 occur upon binding to Cu/Zn ions and forming an intramolecular disulfide bond. Mutations in hSOD1 result in structural changes in the electrostatic and metal-binding loops, leading to the dissociation of Cu and/or Zn ions, which in turn triggers SOD1 oligomerization in ALS. Through X-ray studies, we have identified 1,2,10-decanetriol, a solubilizing agent commonly used in drug delivery, as a modulator that binds at the electrostatic loop and dimer interface regions of SOD1. The crystal structure of hSOD1 complexed with 1,2,10-decanetriol, refined to 1.97 Å resolution, reveals that the ligand stabilizes both loop regions as well as the dimeric structure of hSOD1. Notably, this compound exhibits a low nanomolar binding affinity of 32.40 ± 0.65 nM for hSOD1 and significantly inhibits aggregation in both metalated and demetalated wild-type and disease mutant proteins. Among the various inhibitors investigated for their ability to reduce SOD1 oligomerization, our study is the first to identify a molecule that binds at the electrostatic loop, as confirmed by in vitro experiments. These findings suggest that 1,2,10-decanetriol is a promising scaffold with potential inhibitory properties for library development against SOD1's amyloidogenic behavior.}, } @article {pmid41131452, year = {2025}, author = {Eager, KLM and Jolly, RD and Manning, L and Willet, CE and Snell, RG and Lehnert, K and Mckean, NE and Sneddon, NW and O'Rourke, BA and Dittmer, KE and Tammen, I and Littlejohn, M}, title = {A novel frameshift variant in ALS2 associated with segmental axonopathy in Merino sheep.}, journal = {Genetics, selection, evolution : GSE}, volume = {57}, number = {1}, pages = {60}, pmid = {41131452}, issn = {1297-9686}, mesh = {Animals ; *Frameshift Mutation ; Sheep/genetics ; *Sheep Diseases/genetics/pathology ; Axons/pathology ; *Neurodegenerative Diseases/genetics/veterinary/pathology ; Female ; Male ; }, abstract = {BACKGROUND: Segmental axonopathy is a recessively inherited neurodegenerative disorder that has affected Merino sheep since the early 1930s. Despite its long-standing recognition, the genetic basis of the condition remained unknown. This study aimed to identify the genetic cause of segmental axonopathy and confirm its pathological features to improve diagnostic accuracy and inform breeding strategies.

RESULTS: Whole genome sequencing and genotyping of affected and unaffected Merino sheep identified a novel homozygous frameshift variant in the ALS2 gene that segregated with disease. RNA sequencing of cerebellar peduncle tissue confirmed the nonsense consequence on the ALS2 transcript. Histological analysis highlighted the hallmarks of the disease as large, foamy eosinophilic axonal swellings predominantly in the trigeminal ganglia, with additional degenerative changes in both the brain and spinal cord. These findings support the value of targeted sampling of sensory roots of the trigeminal nerve, spinal cord tracts, and dorsal nerve rootlets to enhance diagnostic accuracy. The same ALS2 variant was found across multiple unrelated flocks in both Australia and New Zealand, indicating a broader presence within the fine-wool Merino sheep population.

CONCLUSIONS: This study identifies a novel ALS2 frameshift variant associated with segmental axonopathy in Merino sheep and provides both genetic and histological evidence supporting its role in disease pathology. The development of a DNA diagnostic test will enable more informed breeding decisions, reduce the prevalence of this condition, and improve animal welfare and productivity in the Merino industry. Moreover, the findings offer a potential large-animal model for exploring early-onset forms of human motor neuron diseases, including amyotrophic lateral sclerosis, in which ALS2 variants are implicated.}, } @article {pmid41131592, year = {2025}, author = {Theunissen, F and Flynn, L and Iacoangeli, A and Al Khleifat, A and Al-Chalabi, A and Giordano, JJ and Strømme, M and Akkari, PA}, title = {Entering the era of precision medicine to treat amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {111}, pmid = {41131592}, issn = {1750-1326}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; Humans ; *Precision Medicine/methods ; }, abstract = {With the disease modifying therapy Qalsody (tofersen) which targets the RNA product of the SOD1 gene, having been shown effective in amyotrophic lateral sclerosis (ALS), the present perspective seeks to explore progress towards the implementation of precision medicine principles in ALS drug development. We address the advances in our understanding of the complex genetic architecture of ALS, including the varying models of genetic contribution to disease, and the importance of understanding population genetics and genetic testing when considering patient selection for clinical studies. Additionally, we discuss the advances in long-read whole-genome sequencing technology and how this method can improve streamlined genetic testing and our understanding of the genetic heterogeneity in ALS. We highlight the recent advances in omics-data for understanding ALS patient sub-groups and how this knowledge should be applied to pre-clinical drug development in a proposed patient profiling workflow, particularly for gene targeted therapies. Finally, we summarise key ethical considerations that are pertinent to equitable care for patients, as we enter the era of precision medicine to treat ALS.}, } @article {pmid41131916, year = {2025}, author = {Shen, D and Liu, A and Yang, X and Liu, Q and Liu, M and Cui, L}, title = {The Impact of Bulbar and Upper Motor Neuron Involvement on Oculomotor Movement in Amyotrophic Lateral Sclerosis.}, journal = {Brain and behavior}, volume = {15}, number = {10}, pages = {e70906}, pmid = {41131916}, issn = {2162-3279}, support = {2022-PUMCH-A-069//National High Level Hospital Clinical Research Funding/ ; UHB11982//Peking Union Medical College Hospital Talent Cultivation Program (Category D)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Male ; Female ; Middle Aged ; Aged ; *Motor Neurons/physiology ; Saccades/physiology ; *Eye Movements/physiology ; Adult ; Reaction Time/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of both lower and upper motor neurons (UMN). Clinical heterogeneity manifests in subtypes such as bulbar-onset ALS (bALS) and spinal-onset ALS (sALS), with emerging evidence suggesting that oculomotor dysfunction may reflect broader multisystem involvement. This study aims to investigate oculomotor parameters across different ALS phenotypes and their associations with neuropsychological domains.

METHODS: A total of 46 patients meeting the Gold Coast Criteria for ALS were enrolled, alongside 23 age- and education-matched healthy controls (HCs). Participants were assessed for demographic variables and clinical features, and underwent cognitive and oculomotor testing using the EyeKnow system. Eye movement performance was compared between groups, and correlations between oculomotor metrics and cognitive and clinical data were examined.

RESULTS: ALS patients displayed longer reaction times in anti-saccade tasks (357.48 ± 61.28 ms vs. 316.10 ± 52.70 ms, p = 0.005) and significantly lower predictive saccade accuracy (86.77 ± 19.17% vs. 99.36 ± 2.22%, p < 0.001) compared to HCs. There is no significant difference in the eye movement parameters between sALS and bALS. Patients with bulbar involvement exhibited poorer performance in predictive saccade accuracy (77.53 ± 26.66% vs. 96.01 ± 4.92%, p < 0.001) and longer initial time in the smooth pursuit task (647.43 [402.14, 760.64] ms vs. 452.43 [131.62, 598.20] ms, U = 161.00, p = 0.037) compared to those without bulbar involvement. UMN involvement was associated with poorer performance across prosaccade, anti-saccade, and predictive saccade tasks. No significant correlation between oculomotor metrics and cognitive tests or clinical data was detected.

CONCLUSIONS: The findings highlight the impact of bulbar and UMN involvement on oculomotor dysfunction in ALS, demonstrating distinct patterns across various phenotypes. Although oculomotor metrics show sensitivity to the pathophysiology of ALS, their effectiveness as independent biomarkers needs further validation through longitudinal studies that include larger cohorts, advanced neuroimaging techniques, and multimodal assessments to capture the complex interplay between motor, cognitive, and anatomical changes in this varied disease.}, } @article {pmid41132886, year = {2025}, author = {Agüera-Morales, E and Fernández-Sánchez, VE and Navarro-Mascarell, G and Cabezas-Rodríguez, JA and Peña-Toledo, MÁ and Reyes-Rodríguez, V and Postigo-Pozo, MJ and Patrignani-Ochoa, G and Geniz-Clavijo, MÁ and Márquez-Infante, C and Tallon-Aguilar, L and Tinoco-González, J and Padillo-Ruiz, J and Valladares-Sánchez, A and Caballero-Eraso, C and López-Ramírez, C and Mata Alcázar-Caballero, R and Leyva-Fernández, L and Rodríguez-Acosta, A and Maldonado-Sánchez, R and García-Martín, ML and Somoza-Ramírez, M and Quijano-Ruiz, B and Macías-Sánchez, MDM and Carmona-Sánchez, G and Fernández-López, O and Fernández-Fernández, Ó}, title = {Adipose-derived mesenchymal stem cells for the treatment of Amyotrophic Lateral Sclerosis. A phase I/II safety and efficacy clinical trial.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1655124}, pmid = {41132886}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with few treatments available. Mesenchymal stem cells have arisen as a potential treatment option for ALS due to their immune system modulation and their neuroprotective effects. This clinical trial aimed to evaluate the safety, efficacy and feasibility of three intravenous doses of autologous adipose-derived mesenchymal stem cells (AdMSC) in ALS patients.

METHODS: A multicentre, randomized, parallel group, placebo-controlled, double-blinded clinical trial (EudraCT: 2011-006254-85) was conducted in 40 patients with ALS in treatment with riluzole. Patients were randomized 1:1:1:1 into the following treatment groups: 1 × 10[6] cells/kg, 2 × 10[6] cells/kg, 4 × 10[6] cells/kg and placebo. After a 6 month follow-up, patients in the placebo group were randomized 1:1:1 to receive one of the three doses of AdMSC and they were followed up for another 6 months. Lastly, all patients were followed-up in a 36-month open-label extension. Safety was mainly assessed through the evaluation of adverse events and their relationship with the medicinal product. Several variables were measured to assess efficacy, such as ALS Functional Rating Scale, Ashworth spasticity scale, neurophysiological and neuropsychological parameters and overall survival. The feasibility of the procedure was assessed through the evaluation of the extraction and infusion of AdMSC.

RESULTS: Safety of AdMSC was observed through all follow-up periods, with similar percentages of adverse events between groups and no significant differences between groups in the rate of adverse events related to treatment. The administration procedure was feasible for all patients. Across all analyzed measures, we observed the expected progressive decline characteristic of ALS, with no statistically significant between-group differences in the rate of change.

DISCUSSION: The results obtained in this study are consistent with the ones obtained in other clinical trials using similar doses of MSC, where safety was demonstrated and efficacy results were inconclusive, due to not reaching statistical significance. Larger studies with an increased sample size, different doses and route of administration or combination of routes, repeated dosing or larger duration and comprehensive assessment of immunological effect would be needed to analyze the efficacy of AdMSC in the treatment of ALS.

CLINICAL TRIAL REGISTRATION: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2011-006254-85.}, } @article {pmid41133655, year = {2025}, author = {Di Fronzo, P and Gaetti, G and Marcassa, D and Gervasi, V and Dardour, O and Pedretti, A and Gambolò, L}, title = {The Impact of ACLS Training in the Management of Cardiac Arrest: A Narrative Review.}, journal = {Epidemiologia (Basel, Switzerland)}, volume = {6}, number = {4}, pages = {}, pmid = {41133655}, issn = {2673-3986}, abstract = {BACKGROUND: Cardiac arrests can occur both in and out of hospital settings. Over the years, several protocols have been developed to standardize the behavior of healthcare professionals called upon to deal with these emergencies. Advanced Cardiac Life Support (ACLS) algorithms enable healthcare professionals to effectively manage cardiac arrest and achieve better patient outcomes, particularly at the time of discharge.

METHODS: We conducted a narrative review. Three databases (PubMed, Embase, Cochrane) were searched for relevant articles. The articles were screened and analyzed in accordance with the PRISMA guidelines.

RESULTS: A total of 1252 articles were initially identified. After screening, 11 papers were included in the review. From the selected studies, it has emerged that ACLS training had several positive effects, including an overall decrease in mortality rates. Adherence to ACLS protocols throughout an event is associated with increased Return of Spontaneous Circulation (ROSC) in the setting of In-Hospital Cardiac Arrest (IHCA). Advanced Life Support (ALS) response interval in out-of-hospital cardiac arrest was associated with decreased survival and a favorable neurological outcome. ALS response ≤ 10 min was associated with improved survival and favorable neurological outcomes.

CONCLUSIONS: This review underscores the importance of adherence to ALS/ACLS guidelines in the resuscitation of patients who suffer in-hospital and out-of-hospital cardiac arrest.}, } @article {pmid41133969, year = {2026}, author = {Lindenborn, P and Fabian, R and Grehl, T and Nazlican, H and Meyer, T and Bernsen, S and Weydt, P}, title = {Combination of Serum Neurofilament Light Chain and Serum Cardiac Troponin T as Biomarkers Improves Diagnostic Accuracy in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {99}, number = {2}, pages = {408-417}, pmid = {41133969}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; *Troponin T/blood ; Male ; Female ; Middle Aged ; *Neurofilament Proteins/blood ; Biomarkers/blood ; Retrospective Studies ; Aged ; Adult ; Reproducibility of Results ; ROC Curve ; }, abstract = {OBJECTIVE: We aimed to evaluate the clinical utility of serum neurofilament light chain (sNfL) and cardiac troponin T (cTnT) in amyotrophic lateral sclerosis (ALS) and assess whether their combination improves diagnostic accuracy.

METHODS: We retrospectively analyzed 293 ALS patients, 85 neurodegenerative disease controls, and 29 healthy controls. A validation cohort of 501 ALS patients was analyzed to confirm reproducibility of the results. Receiver operating characteristic (ROC) curve analysis was performed for sNfL, cTnT, and their combination, and the area under the curve (AUC) was compared across groups. An ALS-specific cTnT cut-off of 8.35ng/L was determined using the Youden index and applied in subgroup analyses, in which "biomarker-negative" ALS patients were compared to "biomarker-positive" patients regarding disease duration and progression.

RESULTS: sNfL showed excellent performance in discriminating ALS patients from healthy controls (AUC = 0.94), but only moderate performance in discriminating neurodegenerative disease controls (AUC = 0.82). Combining sNfL and cTnT improved diagnostic accuracy for ALS over neurodegenerative controls, with an AUC of 0.90, whereas cTnT alone showed an AUC of 0.77. The validation cohort showed similar AUCs. "Biomarker-negative" ALS patients had a longer disease duration (73.0 vs 18.0 months, p = 0.0003) and a lower progression rate (0.19 vs 0.70 points per months, p < 0.0001) than "biomarker-positive" patients.

INTERPRETATION: Although sNfL alone performs well in distinguishing ALS from healthy controls, repurposing cTnT for ALS provides additional value in discriminating ALS from disease controls. The combination of sNfL and cTnT improves diagnostic accuracy and may help identify prognostically distinct ALS subgroups. ANN NEUROL 2026;99:408-417.}, } @article {pmid41134896, year = {2025}, author = {Xiang, Q and Lu, Y and Wang, H and Chen, H and Chen, P and Zhao, X and Cortes Morales, L and Yang, Y and Yang, J and Zhang, T and Wang, J}, title = {ITCH regulates Golgi integrity and proteotoxicity in neurodegeneration.}, journal = {Science advances}, volume = {11}, number = {43}, pages = {eado4330}, pmid = {41134896}, issn = {2375-2548}, support = {R01 NS128494/NS/NINDS NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; R01 NS074324/NS/NINDS NIH HHS/United States ; RF1 NS074324/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; }, mesh = {*Golgi Apparatus/metabolism/pathology ; *Ubiquitin-Protein Ligases/metabolism/genetics ; Humans ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Lysosomes/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Disease Models, Animal ; Neurons/metabolism ; Alzheimer Disease/metabolism/pathology/genetics ; Mice ; Repressor Proteins ; }, abstract = {Golgi fragmentation is an early and common feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). However, whether a shared mechanism drives Golgi fragmentation across different neurodegenerative conditions remains unclear. Here, we identify the E3 ubiquitin-protein ligase Itchy homolog (ITCH) as a key regulator of proteotoxicity through its role in inducing Golgi fragmentation. Disease-associated accumulation of ITCH promotes fragmentation of both the cis- and trans-Golgi networks, disrupting protein sorting and impairing lysosomal functions. The ITCH-dependent lysosomal dysfunction compromises the clearance of misfolded proteins associated with several neurodegenerative diseases. Inhibition of ITCH protects against proteotoxicity in both mammalian neurons and Drosophila models of neurodegeneration. The accumulation of ITCH in patients with ALS and AD is attributed to up-regulation of the ubiquitin-specific protease USP11, which deubiquitinates and stabilizes ITCH. These results uncover a pathogenic pathway regulating Golgi integrity and contributing to the development of neurodegenerative diseases.}, } @article {pmid41135587, year = {2026}, author = {Patel, S and Cagino, KA and Roberts, AW and Wiley, RL and Cortes, C and Zullo, F and Mendez-Figueroa, H and Chauhan, SP}, title = {Fetal Heart Rate Tracings and Adverse Outcomes among Term Small versus Appropriate for Gestational Age.}, journal = {American journal of perinatology}, volume = {43}, number = {9}, pages = {1213-1221}, doi = {10.1055/a-2729-1189}, pmid = {41135587}, issn = {1098-8785}, mesh = {Humans ; Female ; Retrospective Studies ; *Heart Rate, Fetal/physiology ; Infant, Newborn ; Pregnancy ; *Infant, Small for Gestational Age ; Gestational Age ; Cesarean Section/statistics & numerical data ; Adult ; Birth Weight ; Pregnancy Outcome ; }, abstract = {OBJECTIVE: This study aimed to compare the patterns of fetal heart rate tracings (FHRTs), and outcomes among individuals with small (birth weight [BW] <10% for gestational age [GA]; SGA) versus appropriate (BW at 10-89% for GA; AGA) newborns at term (≥37.0 weeks).

STUDY DESIGN: Our retrospective cohort study included consecutive deliveries over 15 months at a level IV center. FHRTs were reviewed by obstetricians blinded to maternal and neonatal outcomes. The inclusion criteria were non-anomalous singletons, cataloged as SGA or AGA birth weight using Alexander et al's nomogram. In 20-minute segments, the last 120 minutes of tracing were characterized. Rates of cesarean delivery (CD) and composite neonatal adverse outcomes (CNAOs) were compared.

RESULTS: Of 5,160 deliveries, 3,029 (58.7%) met the inclusion criteria, and among them, 422 (13.9%) were SGA and 2,607 (86.1%) AGA. There were no differences in FHRT baseline, variability, or accelerations. Compared to AGA, SGA was more likely to have prolonged decelerations (11.8 vs. 8.4%, p = 0.021), and recurrent decelerations with ≥50% of contractions (21.3 vs. 16.5%, p = 0.014). Overall, the presence of category II FHRT or not was similar between the SGA (91.2%) and AGA (88.5%; p = 0.097). Persistent category II FHRT was significantly more common among SGA (37.4%) than AGA (28.1%; aOR = 1.47; 95% CI: 1.47-1.82) newborns. The rate of CD for non-reassuring FHRT was similar among the two groups. CNAO occurred in 1.4% in both SGA and AGA neonates (p = 0.95).

CONCLUSION: In our cohort of those with fetal monitoring prior to delivery at ≥37 weeks, persistent category II FHRT at the end of labor was significantly more common in SGA compared to AGA neonates; however, composite neonatal morbidity did not differ between the two groups. Our analysis provides data for shared decision-making that among SGA newborns, abnormalities of FHRT are not linked with adverse outcomes.

KEY POINTS: · There were no differences in FHRT baseline, variability, or accelerations between AGA and SGA.. · SGA was more likely to have prolonged decelerations and recurrent decelerations with ≥50% of contractions.. · Persistent category II FHRT before delivery is significantly more common with SGA than AGA.. · FHRT abnormalities, however, were not associated with CD for non-reassuring FHRT, or adverse outcomes..}, } @article {pmid40030616, year = {2024}, author = {Bista, S and Coffey, A and Mitchell, M and Fasano, A and Dukic, S and Buxo, T and Giglia, E and Heverin, M and Muthuraman, M and Carson, RG and Lowery, M and Manus, LM and Hardiman, O and Nasseroleslami, B}, title = {Abnormal EEG spectral power and coherence measures during pre-motor stage in Amyotrophic Lateral Sclerosis.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TNSRE.2024.3523109}, pmid = {40030616}, issn = {1558-0210}, abstract = {Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder characterized by progressive motor decline. Studies of electroencephalographic (EEG) activity during rest and motor execution have captured network changes in ALS. However, the nature of network-level impairment in the pre-motor activity in ALS remains unclear. Assessing the (dys)function of motor networks engaged prior to motor output is essential for understanding the motor pathophysiology in ALS. We recorded EEG in 22 people with ALS (PwALS) and 16 age-matched healthy controls during rest and isometric pincer-grip tasks. EEG spectral power and coherence were calculated during rest, pre-motor stage, and motor execution. In PwALS, significantly higher event-related spectral perturbations were observed compared to controls over electrodes representing a) contralateral prefrontal and parietal regions in theta band during pre-motor stage, b) contralateral parietal and ipsilateral motor regions in high-beta band during motor execution. Similarly, spectral coherence revealed abnormal EEG connectivity within 1) sensorimotor network during rest in theta band, 2) (pre)motor networks during pre-motor stage in low-alpha and high-beta bands, 3) Fronto-parietal networks during execution in high-beta band. Furthermore, the abnormal EEG connectivity during rest and execution (but not during pre-motor stage) showed significant negative correlation with clinical ALS-functional-rating-scale scores. Combining abnormal EEG connectivity from rest, pre-motor, and execution stages provided more powerful discrimination between patients and controls with a uniquely higher contribution of measures pertaining to the pre-motor stage. The results indicate that pre-motor functional activity reflects a different and unique aspect of network impairment, with potential for inclusion as biomarker candidates in ALS.}, } @article {pmid40030617, year = {2025}, author = {Jiang, Y and Li, K and Liang, Y and Chen, D and Tan, M and Li, Y}, title = {Daily Assistance for Amyotrophic Lateral Sclerosis Patients Based on a Wearable Multimodal Brain-Computer Interface Mouse.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {33}, number = {}, pages = {150-161}, doi = {10.1109/TNSRE.2024.3520984}, pmid = {40030617}, issn = {1558-0210}, mesh = {*Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology ; *Brain-Computer Interfaces ; Humans ; Middle Aged ; Male ; Female ; *Wearable Electronic Devices ; Wheelchairs ; Aged ; Adult ; Equipment Design ; Electroencephalography ; Communication Devices for People with Disabilities ; User-Computer Interface ; Activities of Daily Living ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic, progressive neurodegenerative disease that mainly causes damage to upper and lower motor neurons. This leads to a progressive deterioration in the voluntary mobility of the upper and lower extremities in ALS patients, which underscores the pressing need for an assistance system to facilitate communication and body movement without relying on neuromuscular function. In this paper, we developed a daily assistance system for ALS patients based on a wearable multimodal brain-computer interface (BCI) mouse. The system comprises two subsystems: a mouse system assisting the upper extremity and a wheelchair system based on the mouse system assisting the lower extremity. By wearing a BCI headband, ALS patients can control a computer cursor on the screen with slight head rotation and eye blinking, and further operate a computer and drive a wheelchair with specially designed graphical user interfaces (GUIs). We designed operating tasks that simulate daily needs and invited ALS patients to perform the tasks. In total, 15 patients with upper extremity limitations performed the mouse system task and 9 patients with lower extremity mobility issues performed the wheelchair system task. To our satisfaction, all the participants fully accomplished the tasks and average accuracies of 83.9% and 87.0% for the two tasks were achieved. Furthermore, workload evaluation using NASA Task Load Index (NASA-TLX) revealed that the participants experienced a low workload when using the system. The experimental results demonstrate that the proposed system provides ALS patients with effective daily assistance and shows promising long-term application prospects.}, } @article {pmid40030850, year = {2025}, author = {Hong, Z and Yi, S and Deng, M and Zhong, Y and Zhao, Y and Li, L and Zhou, H and Xiao, Y and Hu, X and Niu, L}, title = {Transcranial Focused Ultrasound Modifies Disease Progression in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {IEEE transactions on ultrasonics, ferroelectrics, and frequency control}, volume = {72}, number = {2}, pages = {191-201}, doi = {10.1109/TUFFC.2024.3525143}, pmid = {40030850}, issn = {1525-8955}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnostic imaging/genetics ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Ultrasonic Therapy/methods ; Superoxide Dismutase-1/genetics ; Disease Progression ; Muscle, Skeletal/physiopathology ; Male ; Motor Cortex ; Humans ; Elasticity Imaging Techniques ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressively worsening neurodegenerative condition with very few treatment options available. Ultrasound neuromodulation offers promising benefits for treating neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. However, the effects and underlying mechanisms of ultrasound neuromodulation on ALS remain unclear. A head-mounted ultrasound neuromodulation system was developed to noninvasively stimulate the motor cortex of symptomatic mice carrying the G93A human SOD1 mutation (SOD $1^{\text {G93A} } $) for four weeks. Motor performance was assessed through the rotarod locomotor test, grip strength test, and open field test. In addition, the effect of ultrasound stimulation on the elastic modulus of gastrocnemius muscle atrophy was measured using real-time shear wave elastography (SWE). Subsequently, the brain tissues of the mice were harvested. Gastrocnemius morphology was examined using hematoxylin-eosin and Gomori aldehyde-fuchsin (GAF) staining. The number of neurons and the phenotype of microglia in the motor cortex were observed by immunohistochemical analysis. Ultrasound therapy delayed disease onset by 10.7% and increased the lifespan by 6.7% in SOD $1^{\text {G93A} } $ mice by reduction of neuronal loss and enhancement of M2 microglia in the motor cortex. Furthermore, we found significant improvements in motor function for ultrasound-treated mice. More importantly, ultrasound stimulation ameliorated gastrocnemius muscle atrophy in the SOD $1^{\text {G93A} } $ mice. These results revealed the neuroprotective effects of ultrasound against the disease pathogenesis of SOD $1^{\text {G93A} } $ mice. Transcranial ultrasound neuromodulation provides an innovative tool for the intervention and treatment of neurodegenerative diseases.}, } @article {pmid40031506, year = {2024}, author = {Guo, J and Chen, D and Zeng, X and Liu, X and Wang, X and Teng, S and Ye, K and Sun, X and Zhang, S and He, J and Fan, D and Liu, Y}, title = {A Multi-branch Attention-based Deep Learning Method for ALS Identification with sMRI Data.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10782847}, pmid = {40031506}, issn = {2694-0604}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis ; Humans ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; *Spinal Cord/diagnostic imaging/pathology ; Algorithms ; *Image Processing, Computer-Assisted/methods ; }, abstract = {The structural Magnetic resonance imaging (sMRI) of spinal cord plays a significant role in the clinical diagnosis of Amyotrophic Lateral Sclerosis (ALS). But due to small cross-sectional area in the axial plane and long sagittal/coronal expansion of spinal cord, the diagnosis of ALS using sMRI of spinal cord has remained largely at the stage of morphological observation. In this study, a Multi-branch attention-based deep learning method is proposed to solve this problem. Multi-branch framework is utilized to extract general features of all levels of spinal cord for challenging of long sagittal and coronal expansion of spinal cord, and attention module coupled with multi-scale module in each branch is applied to extract multi-scale features and pay more attention to the important regions of the spinal cord in the axial plane. Experiments show that the proposed method obtains better performance in ALS identification, which implies that the proposed method can extract features of important region in the spinal cord and could be helpful to find more regions sensitive for ALS disease identification.}, } @article {pmid40032118, year = {2025}, author = {Dang, M and Wu, L and Zhang, X}, title = {Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances.}, journal = {International journal of biological macromolecules}, volume = {306}, number = {Pt 3}, pages = {141677}, doi = {10.1016/j.ijbiomac.2025.141677}, pmid = {40032118}, issn = {1879-0003}, mesh = {Humans ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; Animals ; *Neurodegenerative Diseases/metabolism/pathology/genetics/therapy ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; }, abstract = {Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a critical RNA/DNA-binding protein involved in various cellular processes, including RNA splicing, transcription regulation, and RNA stability. Mislocalization and aggregation of TDP-43 in the cytoplasm are key features of the pathogenesis of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). This review provides a comprehensive retrospective and prospective analysis of TDP-43 research, highlighting structural insights, significant milestones, and the evolving understanding of its physiological and pathological functions. We delineate five major stages in TDP-43 research, from its initial discovery as a pathological hallmark in neurodegeneration to the recent advances in understanding its liquid-liquid phase separation (LLPS) behavior and interactions with cellular processes. Furthermore, we assess therapeutic strategies targeting TDP-43 pathology, categorizing approaches into direct and indirect interventions, alongside modulating aberrant TDP-43 LLPS. We propose that future research will focus on three critical areas: targeting TDP-43 structural polymorphisms for disease-specific therapeutics, exploring dual temporal-spatial modulation of TDP-43, and advancing nano-therapy. More importantly, we emphasize the importance of understanding TDP-43's functional repertoire at the mesoscale, which bridges its molecular functions with broader cellular processes. This review offers a foundational framework for advancing TDP-43 research and therapeutic development.}, } @article {pmid40032505, year = {2025}, author = {Callegaro, S and Manera, U and Canosa, A and Grassano, M and Palumbo, F and Cabras, S and Matteoni, E and Di Pede, F and De Mattei, F and De Marchi, F and Mazzini, L and Moglia, C and Calvo, A and Chiò, A and Vasta, R}, title = {Another brick in our knowledge of ALS causes: a population-based study of residential clustering.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {8}, pages = {821-822}, doi = {10.1136/jnnp-2024-335670}, pmid = {40032505}, issn = {1468-330X}, } @article {pmid40033250, year = {2025}, author = {Lu, C and Huang, XX and Huang, M and Liu, C and Xu, J}, title = {Mendelian randomization of plasma proteomics identifies novel ALS-associated proteins and their GO enrichment and KEGG pathway analyses.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {82}, pmid = {40033250}, issn = {1471-2377}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood ; Humans ; *Mendelian Randomization Analysis/methods ; *Proteomics/methods ; Genome-Wide Association Study ; *Blood Proteins/genetics/metabolism ; Biomarkers/blood ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder with an increasing incidence rate. Despite advances in ALS research over the years, the precise etiology and pathogenic mechanisms remain largely elusive.

OBJECTIVE: To identify novel plasma proteins associated with ALS through Mendelian randomization methods in large-scale plasma proteomics and to provide potential biomarkers and therapeutic targets for ALS treatment.

METHODS: This study employed a large-scale plasma proteomic Mendelian randomization approach using genetic data from 80,610 individuals of European ancestry (including 20,806 ALS patients and 59,804 controls) derived from a genome-wide association study (GWAS). Protein quantitative trait loci (pQTLs) data were obtained from Ferkingstad et al. (2021), which measured 4,907 proteins in 35,559 Icelandic individuals. Multiple Mendelian randomization (MR) techniques were utilized, including weighted median, MR-Egger, Wald ratio, inverse-variance weighting (IVW), basic model, and weighted model. Heterogeneity was evaluated using Cochran's Q test. Horizontal pleiotropy was assessed through the MR-Egger intercept test and MR-PRESSO outlier detection. Sensitivity analysis was performed via leave-one-out analysis.

RESULTS: MR analysis revealed potential causal associations between 491 plasma proteins and ALS, identifying 19 novel plasma proteins significantly linked to the disease. Proteins such as C1QC, UMOD, SLITRK5, ASAP2, TREML2, DAPK2, ARHGEF10, POLM, SST, and SIGLEC1 showed positive correlations with ALS risk, whereas ADPGK, BTNL9, COLEC12, ADGRF5, FAIM, CRTAM, PRSS3, BAG5, and PSMD11 exhibited negative correlations. Reverse MR analyses confirmed that ALS negatively correlates with ADPGK and ADGRF5 expression. Enrichment analyses, including Gene Ontology (GO) functional analysis, indicated involvement in critical biological processes such as external encapsulating structure organization, extracellular matrix organization, chemotaxis, and taxis. KEGG pathway analysis highlighted significant enrichment in the PI3K-Akt signaling pathway, cytokine-cytokine receptor interactions, and axon guidance.

CONCLUSION: This study enhances the understanding of ALS pathophysiology and proposes potential biomarkers and mechanistic insights for therapeutic development. Future research should explore the clinical translation of these findings to improve ALS patient outcomes and quality of life.}, } @article {pmid40033457, year = {2025}, author = {Kallambettu, V and York, JD and Vasilopolous, T and Hutcheson, K and Plowman, E}, title = {Validation of the Dynamic Imaging Grade of Swallowing Toxicity for Amyotrophic Lateral Sclerosis.}, journal = {Neurogastroenterology and motility}, volume = {37}, number = {6}, pages = {e70008}, pmid = {40033457}, issn = {1365-2982}, support = {R01 CA271223/CA/NCI NIH HHS/United States ; R01 NS100859/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/physiopathology ; *Deglutition Disorders/etiology/diagnostic imaging/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Aged ; Reproducibility of Results ; Fluoroscopy/methods ; Deglutition/physiology ; Disease Progression ; Severity of Illness Index ; }, abstract = {INTRODUCTION: Although dysphagia is prevalent in persons with amyotrophic lateral sclerosis (pALS) and is associated with morbidity and mortality, no validated outcomes currently exist for the gold standard videofluoroscopy (VF) exam. We therefore sought to psychometrically validate the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale in pALS.

METHODS: One hundred pALS attended a research evaluation and underwent a standardized VF and validated clinical outcomes of oral intake (FOIS), perceived swallowing impairment (EAT-10), and ALS disease progression (ALSFRS-Revised). Duplicate, independent, and blinded VF ratings were completed using the DIGEST and MBSImP scales. Weighted kappa, ANOVAs (Tukey's HSD, Welch's correction), and Chi-square analyses were performed to determine intra- and inter-rater reliability, criterion validity, and construct validity of the DIGEST scale for use in pALS.

RESULTS: The mean age was 64.4(SD = 10.4), 50% were male, and the average ALS duration was 28.2 months (SD = 22.2). Excellent intra-rater (kappa = 0.92-1.0) and inter-rater (kappa = 0.94) reliability were noted for DIGEST ratings. DIGEST grades significantly discriminated pharyngeal pathophysiology (MBSImP, F(3,96) = 24.7, p < 0.0001), perceived dysphagia (EAT-10, F(3,40) = 20.8, p < 0.0001), oral intake (FOIS, X[2]:25.4, df = 3, p < 0.0001), ALS bulbar disease progression (ALSFRS-bulbar, F(3,93) = 20.8, p < 0.0001) with main effects noted for all analyses. Post hoc pairwise comparisons noted differences across all DIGEST grades with the exception of DIGEST 2 versus 3 (moderate vs. severe dysphagia), p > 0.05.

CONCLUSIONS: These data confirm that the DIGEST scale is a reliable and valid VF outcome for use in pALS to distinguish normal versus impaired swallowing and mild versus moderate or severe dysphagia for use in clinical practice and as a clinical trial endpoint marker.}, } @article {pmid40033997, year = {2025}, author = {Poulsen, NS and Kraglund, LR and Vissing, J}, title = {Physical training of wheelchair users with neuromuscular disorders: A systematic review.}, journal = {Journal of neuromuscular diseases}, volume = {12}, number = {3}, pages = {330-341}, pmid = {40033997}, issn = {2214-3602}, mesh = {Humans ; *Wheelchairs ; *Neuromuscular Diseases/rehabilitation ; *Exercise Therapy/methods ; }, abstract = {OBJECTIVE: Wheelchair users with neuromuscular disorders have symptoms related to the disease and complications to the sedentary lifestyle, such as constipation and lower back pain. Physical training might be beneficial. This systematic review investigates the potential benefits and harms of physical training for wheelchair users with neuromuscular disorders.

METHODS: We systematically searched PubMed including studies published until July 2024.

INCLUSION CRITERIA: 1) participants with a neuromuscular disorder, 2) at least 60% of participants in a study were wheelchair users, 3) physical training and its effects were investigated, 4) studies were prospective, and 5) English language was used. Non-peer-reviewed articles were excluded. Search results were screened by title, abstract, and full text. Two independent authors assessed the quality with the Downs and Black Quality Index.

RESULTS: We included 14 studies of 140 patients from 5 types of neuromuscular disorders (Duchenne muscular atrophy, spinal muscular atrophy, limb-girdle muscular atrophy, facioscapulohumeral muscular dystrophy, and amyotrophic lateral sclerosis). The mean quality was low (16/32) due to flaws in study design, selection bias, and power. Even though many were of low quality and lacked descriptions of adverse events, they all showed positive effects. Most studies investigated physical training of mastication or respiration with improvements in both. Other findings were improvements in endurance, extremity strength, and range of motion.

CONCLUSIONS: Physical training of wheelchair users with neuromuscular disorders is not well investigated. Physical training seems safe and beneficial, but training of respiratory and masticatory muscles is the only well-documented exercise modality that can be advised in patients with Duchenne Muscular Dystrophy or Duchenne Muscular Dystrophy/Spinal Muscular Atrophy, respectively. Larger, high-quality trials, including other neuromuscular disorders, are needed to assess the effects and adverse events of physical training.}, } @article {pmid40034089, year = {2025}, author = {Vaage, AM and Holmøy, T and Dahl, J and Stigum, H and Meyer, HE and Nakken, O}, title = {Statin Use and Amyotrophic Lateral Sclerosis Survival: A Population-Based Cohort Study.}, journal = {European journal of neurology}, volume = {32}, number = {3}, pages = {e70095}, pmid = {40034089}, issn = {1468-1331}, support = {//ALS Norway/ ; 2022050//Helse Sør-Øst RHF/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/drug therapy/epidemiology ; Female ; Male ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Middle Aged ; Norway/epidemiology ; Aged ; Cohort Studies ; Registries ; Adult ; }, abstract = {BACKGROUND: Dyslipidemia is common in amyotrophic lateral sclerosis (ALS). Statin use has been associated with both favorable and poor prognoses. We assessed whether statin use affects ALS survival.

METHODS: We linked four Norwegian health surveys (1972-2003) with mandatory national registries to obtain information on premorbid health, ALS diagnosis, and death. Using the Norwegian Prescribed Drug Registry, we identified participants who had dispensed statins pre- and post-diagnosis. We first compared pre-diagnosis statin discontinuation rates between ALS patients and matched controls. Flexible parametric models were then fitted to estimate the relationship between statin use and survival time in ALS, using restricted mean survival time and hazard ratio (HR) as effect measures.

RESULTS: A total of 524 patients (43% female) with ALS were included. Mean time from ALS diagnosis to death or end of study was 2.0 (SD 2.1) years. A substantial proportion of statin users (21%) discontinued statins during the year leading up to diagnosis. This group was characterized by poorer ALS prognosis compared to those adhering to statins and were included as statin users in our analysis. After adjusting for sex, age, birth year, riluzole use and premorbid smoking status, body mass index, and total cholesterol levels, statin use was not associated with ALS survival. The estimated mean survival difference comparing statin users to non-users was 0.74 (95% CI -5.98 to 7.47) months, corresponding to a HR of 0.97 (95% CI 0.77-1.23).

CONCLUSION: Statin use was not associated with ALS survival, suggesting that statins should not routinely be discontinued in ALS.}, } @article {pmid40034872, year = {2025}, author = {Wagner, H and Mlček, M and Krupičková, P and Popkova, M and Mejstrik, A and Boucek, T and Michálek, P and Kittnar, O and Belohlavek, J}, title = {Adrenaline has a limited effect on myocardial microvascular blood flow: A randomised experimental study in a porcine cardiac arrest model.}, journal = {Resuscitation plus}, volume = {22}, number = {}, pages = {100893}, pmid = {40034872}, issn = {2666-5204}, abstract = {BACKGROUND: Adrenaline (ADR) is a cornerstone of advanced life support (ALS) in cardiac arrest (CA), although its neurologically favourable survival outcomes remain unclear. ADR increases coronary perfusion pressure (CPP), with levels >15 mmHg associated with successful defibrillation. This study aimed to elucidate the relationship between ADR, myocardial microvascular blood flow, and resuscitation outcomes using a porcine CA model simulating refractory ventricular fibrillation (VF).

METHODS: This study involved 24 domestic pigs. After instrumentation, intubation, and baseline measurements, the animals were randomised into the ADR or control (saline) groups. VF was induced, and cardiopulmonary resuscitation was initiated using continuous mechanical chest compressions and ventilation. ADR or saline was administered following ALS guidelines. After 21 min of ALS, defibrillation was performed. Continuous measurements of arterial and venous blood pressures using an electrocardiogram and index of myocardial resistance (IMR) and transit mean time (Tmn) 1 min before and after each injection or peak blood pressure were recorded and compared between the groups. CPP-IMR, amplitude spectrum area (AMSA)-IMR, CPP-Tmn, and AMSA-Tmn correlations were assessed.

RESULTS: Compared with six animals in the control group, three in the ADR group achieved a return of spontaneous circulation. No difference was observed in IMR or AMSA; however, significant increases in CPP and arterial end-diastolic blood pressure were observed at several time points. Tmn differed between groups only at two time points.

CONCLUSION: Repeated ADR doses during prolonged ALS simulating refractory VF did not improve myocardial microvascular blood flow, as measured using IMR, despite leading to an increase in CPP.}, } @article {pmid40036368, year = {2025}, author = {Ervilha Pereira, P and De Bleecker, JL and Bogaert, E and Dermaut, B}, title = {Myopathic aggregation-prone variants in the TDP-43 prion-like domain: genetics paving the way.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {6}, pages = {1876-1887}, doi = {10.1093/brain/awaf076}, pmid = {40036368}, issn = {1460-2156}, support = {3G0H8318//Research Foundation Flanders/ ; G0AC724N//Research Foundation Flanders/ ; //Funds W. Pyleman and Cremers-Opdebeeck/ ; 2023-J1141680-231086//King Baudouin Foundation/ ; 01N10319//Ghent University Special Research Fund/ ; //Ghent University Fund/ ; }, mesh = {Humans ; *DNA-Binding Proteins/genetics/metabolism ; *TDP-43 Proteinopathies/genetics/pathology ; Animals ; *Muscular Diseases/genetics/pathology ; *Prions/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {While neuropathological and genetic studies have established the crucial involvement of TDP-43 proteinopathy in the pathogenesis of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and related neurodegenerative disorders, multiple studies have described the presence of TDP-43 inclusions in muscular disorders, including inclusion body myositis but also other related rimmed vacuole myopathies. In addition, TAR DNA-binding protein-43 (TDP-43) has been reported to be essential in normal muscle physiology as it is implicated in the formation of so-called amyloid-like myogranules during normal muscle regeneration after injury. However, genetic evidence supporting a primary role for TDP-43 proteinopathy in muscle disease has been missing. In the present review we highlight recent landmark discoveries linking novel pathogenic TDP-43 variants [p.(W385IfsX10) and p.(G376V)] within the prion-like domain with unusual aggregation-propensity and muscle rather than neuronal pathology. We discuss these studies in the context of known TDP-43-related pathways in ALS/FTD pathogenesis and show how they challenge some widely accepted views such as ALS as a pure neurogenic presynaptic neuromuscular disease and the direct correlation between TDP-43 aggregation-propensity and neurotoxicity. Finally, we discuss TDP-43 as part of a growing list of RNA-binding proteins including hnRNPA2B1 and hnRNPA1 as genetic causes of myopathies and relate this to the idea of 'multisystem proteinopathy'.}, } @article {pmid40036711, year = {2025}, author = {Nguyen, ML and Haddad, A and Law-Ye, B and Hesters, A}, title = {Uncommon Spinal Cord MRI Findings in a Patient With Early-Onset Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Neurology}, volume = {104}, number = {7}, pages = {e213503}, doi = {10.1212/WNL.0000000000213503}, pmid = {40036711}, issn = {1526-632X}, } @article {pmid40037332, year = {2025}, author = {Belbasis, L and Morris, S and van Duijn, C and Bennett, D and Walters, R}, title = {Mendelian randomization identifies proteins involved in neurodegenerative diseases.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {7}, pages = {2412-2428}, pmid = {40037332}, issn = {1460-2156}, support = {/DH_/Department of Health/United Kingdom ; //NIHR/ ; /WT_/Wellcome Trust/United Kingdom ; 203141/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; //NHS/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis/methods ; *Neurodegenerative Diseases/genetics/metabolism/blood ; Genome-Wide Association Study ; Proteomics/methods ; Male ; Parkinson Disease/genetics ; Female ; Genetic Predisposition to Disease ; }, abstract = {Proteins are involved in multiple biological functions. High-throughput technologies have allowed the measurement of thousands of proteins in population biobanks. In this study, we aimed to identify proteins related to Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis by leveraging large-scale genetic and proteomic data. We performed a two-sample cis Mendelian randomization study by selecting instrumental variables for the abundance of >2700 proteins measured by either Olink or SomaScan platforms in plasma from the UK Biobank and the deCODE Health Study. We also used the latest publicly available genome-wide association studies for the neurodegenerative diseases of interest. The potentially causal effect of proteins on neurodegenerative diseases was estimated based on the Wald ratio. We tested 13 377 protein-disease associations, identifying 169 associations that were statistically significant (5% false discovery rate). Evidence of co-localization between plasma protein abundance and disease risk (posterior probability > 0.80) was identified for 61 protein-disease pairs, leading to 50 unique protein-disease associations. Notably, 23 of 50 protein-disease associations corresponded to genetic loci not previously reported by genome-wide association studies. The two-sample Mendelian randomization and co-localization analysis also showed that APOE abundance in plasma was associated with three subcortical volumes (hippocampus, amygdala and nucleus accumbens) and white matter hyper-intensities, whereas PILRA and PILRB abundance in plasma was associated with caudate nucleus volume. Our study provided a comprehensive assessment of the effect of the human proteome that is currently measurable through two different platforms on neurodegenerative diseases. The newly associated proteins indicated the involvement of complement (C1S and C1R), microglia (SIRPA, SIGLEC9 and PRSS8) and lysosomes (CLN5) in Alzheimer's disease; the interleukin-6 pathway (CTF1) in Parkinson's disease; lysosomes (TPP1), blood-brain barrier integrity (MFAP2) and astrocytes (TNFSF13) in amyotrophic lateral sclerosis; and blood-brain barrier integrity (VEGFB), oligodendrocytes (PARP1), node of Ranvier and dorsal root ganglion (NCS1, FLRT3 and CDH15) and the innate immune system (CR1, AHSG and WARS) in multiple sclerosis. Our study demonstrates how harnessing large-scale genomic and proteomic data can yield new insights into the role of the plasma proteome in the pathogenesis of neurodegenerative diseases.}, } @article {pmid40037468, year = {2025}, author = {Peck, A and Dadi, A and Yavarow, Z and Alfano, LN and Anderson, D and Arkin, MR and Chou, TF and D'Ambrosio, ES and Diaz-Manera, J and Dudley, JP and Elder, AG and Ghoshal, N and Hart, CE and Hart, MM and Huryn, DM and Johnson, AE and Jones, KB and Kimonis, V and Kiskinis, E and Lee, EB and Lloyd, TE and Mapstone, M and Martin, A and Meyer, H and Mozaffar, T and Onyike, CU and Pfeffer, G and Pindon, A and Raman, M and Richard, I and Rubinsztein, DC and Schiava, M and Schütz, AK and Shen, PS and Southworth, DR and Staffaroni, AM and Taralio-Gravovac, M and Weihl, CC and Yao, Q and Ye, Y and Peck, N}, title = {2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy.}, journal = {Neurobiology of disease}, volume = {207}, number = {}, pages = {106861}, pmid = {40037468}, issn = {1095-953X}, support = {R01 GM127557/GM/NIGMS NIH HHS/United States ; Z99 DK999999/ImNIH/Intramural NIH HHS/United States ; R01 CA293084/CA/NCI NIH HHS/United States ; R35 GM133772/GM/NIGMS NIH HHS/United States ; R21 NS123631/NS/NINDS NIH HHS/United States ; }, mesh = {*Valosin Containing Protein/genetics/metabolism ; Humans ; Frontotemporal Dementia/genetics ; Animals ; Osteitis Deformans/genetics ; Myositis, Inclusion Body/genetics ; Congresses as Topic ; }, abstract = {Valosin-containing protein (VCP/p97) is a ubiquitously expressed AAA+ ATPase associated with numerous protein-protein interactions and critical cellular functions including protein degradation and clearance, mitochondrial homeostasis, DNA repair and replication, cell cycle regulation, endoplasmic reticulum-associated degradation, and lysosomal functions including autophagy and apoptosis. Autosomal-dominant missense mutations in the VCP gene may result in VCP-associated multisystem proteinopathy (VCP-MSP), a rare degenerative disorder linked to heterogeneous phenotypes including inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and frontotemporal dementia (FTD) or IBMPFD, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), parkinsonism, Charcot-Marie Tooth disease (CMT), and spastic paraplegia. The complexity of VCP-MSP makes collaboration among stakeholders essential and necessitates a multi-disciplinary approach. The 2024 VCP International Conference was hosted at Caltech between February 22 and 25. Co-organized by Cure VCP Disease and Dr. Tsui-Fen Chou, the meeting aimed to center the patient as a research partner, harmonize diverse stakeholder engagement, and bridge the gap between basic and clinical neuroscience as it relates to VCP-MSP. Over 100 multi-disciplinary experts attended, ranging from basic scientists to clinicians to patient advocates. Attendees discussed genetics and clinical presentation, cellular and molecular mechanisms underlying disease, therapeutic approaches, and strategies for future VCP research. The conference included three roundtable discussions, 29 scientific presentations, 32 scientific posters, nine patient and caregiver posters, and a closing discussion forum. The following conference proceedings summarize these sessions, highlighting both the identified gaps in knowledge and the significant strides made towards understanding and treating VCP diseases.}, } @article {pmid40038221, year = {2025}, author = {Mustafa, F and Mittal, S and Garg, D and Agarwal, A and Garg, A and Gupta, BK and Soneja, M and Srivastava, AK}, title = {HIV associated motor neuron disease (MND): A case series with systematic review of literature.}, journal = {Journal of neurovirology}, volume = {31}, number = {1}, pages = {1-15}, pmid = {40038221}, issn = {1538-2443}, mesh = {Humans ; *HIV Infections/drug therapy/complications/virology ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/virology/drug therapy/diagnostic imaging/pathology ; Female ; Adult ; *Motor Neuron Disease/virology/drug therapy ; Viral Load ; CD4 Lymphocyte Count ; Anti-HIV Agents/therapeutic use ; }, abstract = {Human immunodeficiency virus (HIV) associated motor neuron disease (MND) is very rare. HIV infection can cause an MND-like syndrome due to central nervous system (CNS) involvement de novo or during antiretroviral therapy (ART) due to CNS escape. We present two cases: one with a classic amyotrophic lateral sclerosis (ALS) phenotype, which was the manifestation of symptomatic CNS escape from ART, and the second with a primary lateral sclerosis (PLS) phenotype associated with underlying HIV infection. A systematic review of published literature of people living with HIV (PLHIV) who developed ALS/ MND was conducted using the PubMed, Embase, and Lilacs databases. A total of 91 cases were found, 89 of which were obtained from 37 articles, and two were included from our own case series. In patients with HIV-associated MND, 63 patients reviewed had a classic ALS phenotype followed by progressive muscular atrophy variant (12), progressive bulbar palsy (8), PLS (7) and bulbar onset ALS (1). Neuroimaging, electrophysiology, cerebrospinal fluid (CSF) analysis, CSF and serum HIV viral load, and CD4 count investigations were used for diagnosis. Following the initiation or modification of antiretroviral therapy (ART), approximately 70% exhibited an improvement or a stable disease course. HIV-associated MND is a rare condition that can occur in both ART-naive individuals and those on treatment. A proportion of cases (~ 70%) show improvement with ART. Accurate diagnosis requires the exclusion of opportunistic infections, which remains a critical yet challenging aspect of managing this condition.}, } @article {pmid40039278, year = {2024}, author = {Murphy, EK and Doussan, A and Verga, S and Stommel, EW and McIlduff, C and Halter, RJ and Rutkove, SB}, title = {Assessing Pulmonary Function in ALS using Electrical Impedance Tomography.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10781742}, pmid = {40039278}, issn = {2694-0604}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Electric Impedance ; *Tomography/methods ; *Respiratory Function Tests/methods ; Male ; Female ; Middle Aged ; Algorithms ; Aged ; *Lung/physiopathology ; Case-Control Studies ; }, abstract = {This study aimed to determine an optimal model involving thoracic electrical impedance tomography (EIT) metrics and patient geometric information to best correlate to standard pulmonary function test (PFT) measures in a cohort of 32 ALS patients and 32 age-matched healthy controls. Thoracic EIT is a non-invasive technology in which an electrode belt chest allows for real-time impedance imaging of respiratory function. The optimal form of the model was determined via a genetic algorithm a novel technique for model generation in EIT applications. Combining multiple metrics yielded optimal r[2] values of 0.62 and 0.66 for 1- and 2-term regression models optimized. The results appear very promising and further refinement of the technology appears warranted.}, } @article {pmid40039399, year = {2024}, author = {Rechichi, I and Amprimo, G and Cicolin, A and Olmo, G}, title = {Predicting Amyotrophic Lateral Sclerosis Progression: an EMG-based Survival Analysis.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10782485}, pmid = {40039399}, issn = {2694-0604}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/mortality ; *Electromyography/methods ; Disease Progression ; Survival Analysis ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease, ultimately leading to muscle inefficiency and death. A vast majority of people with ALS also suffer from sleep disorders. Previous studies highlighted the presence of REM Sleep Without Atonia (RSWA) in an ALS cohort, and suggested its strong correlation with the disease severity. This study investigates the ability of electromyography (EMG) parameters recorded during Rapid-eye Movement (REM) sleep to predict disease progress and outcome rapidity in ALS. Survival models trained on a cohort of 45 ALS patients undergoing a longitudinal study, revealed a promising predictive power for the proposed EMG-derived metrics (c-index ≥ 0.65) and encouraging goodness of fit (through c-index and χ[2]). These results suggest the possibility of employing the trained model in follow-up procedures, based on non-invasive, lightweight EMG metrics, which would significantly ease disease monitoring and help personalized symptomatic care.}, } @article {pmid40039939, year = {2024}, author = {Udhayakumar, R and Gopakumar, S and Rahman, S and Karmakar, C}, title = {Nonlinear Assessment of Gait Signal Complexity in Neurodegenerative Disorders.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10781711}, pmid = {40039939}, issn = {2694-0604}, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology/diagnosis ; Algorithms ; *Gait ; Nonlinear Dynamics ; Entropy ; *Signal Processing, Computer-Assisted ; }, abstract = {The human gait cycle undergoes discernible alterations upon the onset of neurodegenerative diseases (NDD) such as Parkinson's, Huntington's, and Amyotrophic lateral sclerosis. Each specific neurodegenerative disorder imparts a distinct influence on human gait dynamics, and precise quantification of these changes holds the potential for accurate methods of NDD detection.Nonlinear entropy algorithms, such as sample entropy (SampEn), find widespread use in physiological signal analysis. SampEn gauges signal complexity by identifying pattern matches within windowed sub-segments of the signal. However, traditional SampEn is notably dependent on user-defined parameters, particularly the tolerance parameter r, leading to inaccuracies in complexity information.SampEn profiling emerges as an alternative concept, eliminating the need for an input r parameter. This data-driven algorithm autonomously generates a set of 'r' values based on the signal's dynamics, yielding a comprehensive SampEn profile. The SampEn profile, containing extensive information about the signal's complexity, serves as a valuable resource for extracting secondary entropy features.In this study, we have contrasted the efficacy of traditional SampEn with SampEn profile-based secondary features such as Total SampEn (TSE) and Median SampEn (MSE), in identifying neurological states. Our findings consistently reveal that secondary features derived from the reduced-parametric SampEn profiling method outperform the traditional parametric SE in distinguishing control cohorts from specific Neurodegenerative Disease (NDD) cohorts.}, } @article {pmid40041912, year = {2025}, author = {Dash, UC and Bhol, NK and Swain, SK and Samal, RR and Nayak, PK and Raina, V and Panda, SK and Kerry, RG and Duttaroy, AK and Jena, AB}, title = {Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {1}, pages = {15-34}, pmid = {40041912}, issn = {2211-3835}, abstract = {Neuroprotection is a proactive approach to safeguarding the nervous system, including the brain, spinal cord, and peripheral nerves, by preventing or limiting damage to nerve cells and other components. It primarily defends the central nervous system against injury from acute and progressive neurodegenerative disorders. Oxidative stress, an imbalance between the body's natural defense mechanisms and the generation of reactive oxygen species, is crucial in developing neurological disorders. Due to its high metabolic rate and oxygen consumption, the brain is particularly vulnerable to oxidative stress. Excessive ROS damages the essential biomolecules, leading to cellular malfunction and neurodegeneration. Several neurological disorders, including Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, multiple sclerosis, and ischemic stroke, are associated with oxidative stress. Understanding the impact of oxidative stress in these conditions is crucial for developing new treatment methods. Researchers are exploring using antioxidants and other molecules to mitigate oxidative stress, aiming to prevent or slow down the progression of brain diseases. By understanding the intricate interplay between oxidative stress and neurological disorders, scientists hope to pave the way for innovative therapeutic and preventive approaches, ultimately improving individuals' living standards.}, } @article {pmid40042459, year = {2025}, author = {Lee, SM and Yoon, SJ and Park, KW and Kim, A and Kim, HJ and Jung, NY and Jang, H and Seeley, WW and Kim, YE and Moon, SY and Kim, EJ and , }, title = {Semantic variant primary progressive aphasia with ANXA11 p.D40G.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e14566}, pmid = {40042459}, issn = {1552-5279}, support = {P50 AG023501/AG/NIA NIH HHS/United States ; RS-2024-00337993//Korea Dementia Research Project through the Korea Dementia Research Center, funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; 2021-ER1004-01//Korea National Institute of Health/ ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; 2024-ER1001-00//Korea National Institute of Health/ ; }, mesh = {Humans ; *Aphasia, Primary Progressive/genetics ; Male ; Female ; Aged ; Middle Aged ; *Annexins/genetics ; Republic of Korea ; *Frontotemporal Dementia/genetics ; Cohort Studies ; High-Throughput Nucleotide Sequencing ; DNA-Binding Proteins/genetics ; }, abstract = {INTRODUCTION: Pathogenic variants of annexin A11 (ANXA11) have been identified in patients with amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). We explored ANXA11 pathogenic variants in a Korean FTD cohort to investigate the prevalence and the role of ANXA11 variation in FTD.

METHODS: We used next-generation sequencing (NGS) to search for pathogenic variants in ANXA11 in two nationwide FTD cohorts in Korea.

RESULTS: We identified a pathogenic variant in ANXA11, c.119A > G (p.D40G), in six patients with semantic variant primary progressive aphasia (svPPA), representing 5.5% of the svPPA cohort (6/109), and representing 2.3% of the FTD cohort overall (6/259). Only one patient later developed features suggestive of ALS.

DISCUSSION: This study links a rare variant in ANXA11 to a sporadic clinical syndrome in which specific TAR DNA-binding protein-43 (TDP-43) forms an obligate co-fibril with annexin A11. The variant, p.D40G, lies within the N-terminal portion of annexin A11's TDP-43 type C interacting domain, suggesting that genetic variation in that region may promote co-fibrillization.

HIGHLIGHTS: The pathogenic variant of annexin A11 (ANXA11I) is linked to frontotemporal dementia (FTD) syndrome. ANXA11 (p.D40G) may be one of the possible genetic causes of semantic variant primary progressive aphasia (svPPA). ANXA11 (p.D40G) may enhance heteromeric amyloid filaments of annexin A11 and TDP-43, promoting frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) type C.}, } @article {pmid40044193, year = {2025}, author = {Ross, WT and Buday, S and Yakel, E and Khabele, D and Balls-Berry, J and As-Sanie, S and Colditz, G and Baumann, AA}, title = {Does interdisciplinary group care for the treatment of endometriosis improve pain interference: protocol for a pilot randomised controlled trial at an urban academic medical centre.}, journal = {BMJ open}, volume = {15}, number = {3}, pages = {e097372}, pmid = {40044193}, issn = {2044-6055}, support = {K23 HD110710/HD/NICHD NIH HHS/United States ; KL2 TR002346/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Academic Medical Centers ; *Chronic Pain/therapy/etiology ; *Endometriosis/therapy/complications ; *Pain Management/methods ; Pain Measurement ; *Patient Care Team ; *Pelvic Pain/therapy/etiology ; Pilot Projects ; Quality of Life ; Randomized Controlled Trials as Topic ; }, abstract = {INTRODUCTION: Endometriosis affects 10-15% of people assigned female at birth and can cause chronic pelvic pain and impair many domains of quality of life, such as fertility, mood and bladder, bowel and sexual function. Current treatments often fail, leading to recurrent pain and the need for reintervention. As endometriosis negatively affects many domains of life, a variety of non-pharmacological treatments modestly improve symptoms. To bundle these interventions into accessible packaging, our interdisciplinary team developed a novel endometriosis intervention titled 'Peer-Empowered Endometriosis Pain Support (PEEPS)', an 8-week integrative group care intervention. Here, we present the protocol for a pilot randomised controlled trial (RCT) to evaluate the effectiveness and implementation of PEEPS for people with endometriosis-associated pain refractory to surgical management. We hypothesise that patients who complete the PEEPS programme will show a greater decrease in pain interference in daily activities at intervention completion as compared with baseline than those in the education arm.

METHODS AND ANALYSIS: This is a hybrid type 1 effectiveness-implementation mixed-methods RCT in which 60 participants will be randomised using computer-generated random numbers stratified by group in the ratio 1:1 to PEEPS plus usual versus educational handout plus usual care. The primary outcome is change in pain interference from baseline to intervention completion. Secondary outcomes include change in pain interference from baseline to 6 months and 12 months postintervention, as well as change in other quality-of-life measures as measured by nine validated questionnaires from baseline to completion, 6 months and 12 months. Proctor et al's Implementation Outcomes Framework will be used to evaluate acceptability, appropriateness and feasibility of PEEPS implementation, and the Consolidated Framework for Implementation Research will be used to guide the evaluation of barriers and facilitators of PEEPS at the patient and provider levels. Primary data analyses will follow the intention-to-treat principle. Descriptive statistics and two-sample t-tests for normally distributed values and Wilcoxon Rank-Sum test were performed for non-normally distributed values. Frequency analysis and Fisher's exact or χ[2] tests will be used for categoric variables as appropriate. Longitudinal analysis of the primary and secondary outcomes will be conducted with a mixed-effects model to investigate the effect of PEEPS compared with education. Least square means (LSMs) and the corresponding 95% CIs at each timepoint, as well as LSM differences and 95% CIs between any post-baseline and baseline will be provided for the outcomes. ORs and 95% CIs will be calculated for categorical outcomes. Qualitative data will be collected in the form of open-ended feedback, focus groups with programme completers and semistructured interviews with participants who complete two or fewer sessions. The analysis will use an embedded design-experimental model in which quantitative and qualitative outcomes will occur concurrently with weight priority given to quantitative data.

ETHICS AND DISSEMINATION: This trial was approved by the Washington University in St. Louis Institutional Review Board (protocol 202402082) on 27 March 2024 and has low risk of harm to participants. All deidentified data from this project will be shared via Digital Commons@Becker. The findings of this study will be disseminated via scientific meetings and peer-reviewed journals. The results and conclusions will be summarised for patients and the public in common language using infographics to make the findings accessible. This pilot RCT will yield the effect size for PEEPS and generate implementation context and outcomes data to guide PEEPS application to real-world practice. If PEEPS proves to be effective, this study will inform adaptation and scaling to improve the lives of people with endometriosis through a non-hormonal, fertility-preserving approach.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov; NCT06549985.}, } @article {pmid40044663, year = {2025}, author = {Abu-Rumeileh, S and Scholle, L and Mensch, A and Großkopf, H and Ratti, A and Kölsch, A and Stoltenburg-Didinger, G and Conrad, J and De Gobbi, A and Barba, L and Steinacker, P and Klafki, HW and Oeckl, P and Halbgebauer, S and Stapf, C and Posa, A and Kendzierski, T and Silani, V and Hausner, L and Ticozzi, N and Froelich, L and Weishaupt, JH and Verde, F and Otto, M}, title = {Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2019}, pmid = {40044663}, issn = {2041-1723}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/metabolism/pathology/diagnosis ; *tau Proteins/blood/metabolism ; Male ; Female ; Middle Aged ; Aged ; Phosphorylation ; Alzheimer Disease/blood/metabolism/diagnosis/pathology ; Biomarkers/blood/metabolism ; Adult ; *Muscle, Skeletal/metabolism/pathology ; Mass Spectrometry ; Case-Control Studies ; Aged, 80 and over ; Immunohistochemistry ; }, abstract = {Blood phosphorylated (p)-tau 181 and p-tau 217 have been proposed as accurate biomarkers of Alzheimer's disease (AD) pathology. However, blood p-tau 181 is also elevated in amyotrophic lateral sclerosis (ALS) without a clearly identified source. We measured serum p-tau 181 and p-tau 217 in a multicentre cohort of ALS (n = 152), AD (n = 111) cases and disease controls (n = 99) recruited from four different centres. Further, we investigated the existence of both p-tau species using immunohistochemistry (IHC) and mass spectrometry (MS) in muscle biopsies of ALS cases (IHC: n = 13, MS: n = 5) and disease controls (IHC: n = 14, MS: n = 5) from one cohort. Serum p-tau 181 and p-tau 217 were higher in AD and ALS patients compared to disease controls. IHC and MS analyses revealed the presence of p-tau 181 and 217 in muscle biopsies from both ALS cases and disease controls, with ALS samples showing increased p-tau reactivity in atrophic muscle fibres. Blood p-tau species could potentially be used to diagnose both ALS and AD.}, } @article {pmid40045432, year = {2025}, author = {Blair, K and Martinez-Serra, R and Gosset, P and Martín-Guerrero, SM and Mórotz, GM and Atherton, J and Mitchell, JC and Markovinovic, A and Miller, CCJ}, title = {Structural and functional studies of the VAPB-PTPIP51 ER-mitochondria tethering proteins in neurodegenerative diseases.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {49}, pmid = {40045432}, issn = {2051-5960}, support = {MR/X021858/1//UK Research and Innovation/ ; }, mesh = {Humans ; *Endoplasmic Reticulum/metabolism ; *Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Mitochondrial Proteins/metabolism ; *Vesicular Transport Proteins/metabolism/chemistry ; Signal Transduction/physiology ; Protein Tyrosine Phosphatases ; }, abstract = {Signaling between the endoplasmic reticulum (ER) and mitochondria regulates many of the seemingly disparate physiological functions that are damaged in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). A number of studies have now demonstrated that ER-mitochondria signaling is perturbed in these diseases and there is evidence that this may be a driving mechanism in disease onset and progression. VAPB and PTPIP51 are ER-mitochondria tethering proteins; VAPB is an ER protein and PTPIP51 is an outer mitochondrial membrane protein and the two proteins interact to enable inter-organelle signaling. The VAPB-PTPIP51 interaction is disrupted in Alzheimer's disease, Parkinson's disease, FTD and ALS. Here we review the roles of VAPB and PTPIP51 in ER-mitochondria signaling and the mechanisms by which neurodegenerative disease insults may disrupt the VAPB-PTPIP51 interaction.}, } @article {pmid40046336, year = {2025}, author = {Öztürk, MM and Emgård, J and García-Revilla, J and Fernández-Calle, R and Yang, Y and Deierborg, T and Roos, TT}, title = {The role of microglia in the prion-like transmission of protein aggregates in neurodegeneration.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf087}, pmid = {40046336}, issn = {2632-1297}, abstract = {Numerous neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis share a neuropathological hallmark: aberrant protein aggregation in the CNS. Microglia, the brain's innate immune cells, also play a pivotal role in the pathogenesis of these disorders. Multiple studies indicate that these pathological aggregates can propagate throughout the brain in a prion-like manner. A protein/peptide that adopts a prion-like conformation can induce homologous proteins to misfold into a prion-like conformation through templated seeding, enabling cell-to-cell spread and accelerating protein aggregation throughout the brain. Two important questions in the prion-like paradigm are where the prion-like misfolding occurs and how the prion-like aggregates are spread throughout the CNS. Here, we review the role of microglia and associated inflammation in the prion-like spread of pathologically aggregated proteins/peptides in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. A growing body of evidence suggests that microglia can internalize prion-like proteins and transport them to neighbouring neurons and other glial cells. Microglia may also influence the potential seeding of proteins in neurons and induce inflammatory pathways in their microenvironment. This review aims to broaden the understanding of the role of microglia in the prion-like spread of protein aggregation.}, } @article {pmid40047382, year = {2025}, author = {Murray, D and Rooney, J and Meldrum, D and Al-Chalabi, A and Bunte, TM and Chiwera, T and Choudhury, M and Chio, A and Fenton, L and Fortune, J and Maidment, L and Manera, U and McDermott, CJ and Meyjes, M and Tattersall, R and Torrieri, MC and Van Damme, P and Vanderlinden, E and Wood, C and Van Den Berg, LH and Hardiman, O}, title = {Respiratory measurements, respiratory symptoms, and quality of life in ALS: results from the REVEALS study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {467-477}, doi = {10.1080/21678421.2025.2471421}, pmid = {40047382}, issn = {2167-9223}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/psychology/epidemiology ; *Quality of Life/psychology ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; Dyspnea/etiology/physiopathology ; Fatigue/etiology ; Respiratory Function Tests ; }, abstract = {Objective: Progressing respiratory weakness throughout the course of amyotrophic lateral sclerosis (ALS) is clinically associated with distressing symptoms, including dyspnea, orthopnea, and difficulty clearing secretions. Fatigue, poor sleep, and reduced quality of life are also considered to be associated with declining respiratory function. Respiratory measurements guide prescription of interventions, which aim to alleviate symptoms. The relationships between respiratory measurements and patient reported symptoms are currently unclear. Method: The REVEALS study was a longitudinal, observational, multisite study of decline in respiratory function in people with ALS attending six European centers. Respiratory measures (forced and slow vital capacity (F/SVC), sniff nasal inspiratory pressure (SNIP), and peak cough flow) were collected, as were the presence of respiratory symptoms and simple quality of life, fatigue and sleep measures. We used Bayesian's multivariate models to explore the associations of the respiratory measures with outcome variables. Results: Two hundred and eighty participants completed in-person assessments over a median of 8 (IQR 2.3, 14.1) months, with 974 data collection timepoints. The probability of reporting symptoms including dyspnea, orthopnea, and difficulty clearing secretions increased with decreasing respiratory measurement scores. The probability of reporting moderately low quality of life and moderate fatigue also increased with decreasing test scores, but reported sleep quality was not associated with respiratory scores. Conclusion: Respiratory weakness in people with ALS was associated with symptoms including dyspnea, orthopnea, and difficulty clearing secretions. The probability of reporting symptoms increased incrementally as respiratory weakness increased, supporting the use of both respiratory measurements and the presence of symptoms in making decisions about clinical interventions.}, } @article {pmid40047927, year = {2025}, author = {Ludolph, A and Klose, V and Dreyhaupt, J and Del Tredici, K and Braak, H}, title = {The deltoid muscle and the pattern of paresis in ALS.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {253}, pmid = {40047927}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/pathology ; *Deltoid Muscle/physiopathology/pathology ; Male ; Female ; Middle Aged ; Aged ; *Paresis/etiology/physiopathology/pathology ; Adult ; *Muscle, Skeletal/physiopathology ; Aged, 80 and over ; Pyramidal Tracts/physiopathology ; Prospective Studies ; }, abstract = {There is neuroanatomical and clinical evidence that the corticospinal tract governs the patterns of pareses in sporadic ALS. These patterns are mirrored by phylogenetically young monosynaptic corticomotor neuronal connections. It is well known that, clinically, dysfunction of the deltoid muscle contributes considerably to the early disability of the ALS patient. In this study, we prospectively compared the degree of pareses of the deltoid muscle with the triceps and biceps brachii in N = 71 patients (426 muscles). We could show that the extent of involvement of the deltoid muscle early in the disease process resembles that of the biceps rather than the triceps brachii. This pattern is consistent with functional data of the corticospinal monosynaptic connectivity of all three muscles.}, } @article {pmid40048117, year = {2025}, author = {Kwon, S and Kim, B and Han, KD and Jung, W and Cho, EB and Shin, DW and Min, JH}, title = {Increased risk of ischemic stroke in amyotrophic lateral sclerosis: a nationwide cohort study in South Korea.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {6}, pages = {2687-2695}, pmid = {40048117}, issn = {1590-3478}, support = {HI20C1073//Ministry of Health and Welfare/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications ; Male ; Republic of Korea/epidemiology ; Female ; Middle Aged ; Aged ; *Ischemic Stroke/epidemiology ; Cohort Studies ; Risk Factors ; }, abstract = {BACKGROUND: We investigated the risk of ischemic stroke in ALS and analyzed the effect of ALS-related physical disability using the Korean National Health Insurance Service database.

METHODS: A total of 2,251 ALS patients diagnosed between January 1, 2012, and December 31, 2015, and 1:10 age- and sex-matched control populations were included. Cases that participated in the national health check-up programs were selected. A Cox hazard regression model was used to examine the hazard ratios (HRs) for ischemic stroke in ALS after adjusting for potential confounders.

RESULTS: A total of 681 ALS patients and 10,934 non-ALS participants were selected. ALS patients were slightly younger than the control group (60.3 ± 10.1 years vs. 61.0 ± 10.5 years, p = 0.105), and the proportion of male patients was similar between the two groups (61.6% vs. 60.9%, p = 0.722). ALS patients were more likely to have a lower body mass index (23.1 ± 2.92 vs. 24.0 ± 3.1, p < 0.001) and obstructive sleep apnea syndrome (0.59% vs. 0.06%, p < 0.001) than the controls. In ALS patients, the incidence rate of ischemic stroke was 6.32 per 1,000 person-years, and the adjusted HR of ischemic stroke was 2.58 (95% confidence interval 1.38 - 4.82) compared with the matched group. The risk of ischemic stroke did not differ by the presence of disability in ALS patients.

CONCLUSIONS: Our findings suggest that ALS patients have an increased risk of ischemic stroke compared with controls, but the risk did not differ by the presence of disability in ALS.}, } @article {pmid40048825, year = {2025}, author = {Kacker, K and Chetty, N and Feldman, AK and Bennett, J and Yoo, PE and Fry, A and Lacomis, D and Harel, NY and Nogueira, RG and Majidi, S and Opie, NL and Collinger, JL and Oxley, TJ and Putrino, DF and Weber, DJ}, title = {Motor activity in gamma and high gamma bands recorded with a Stentrode from the human motor cortex in two people with ALS.}, journal = {Journal of neural engineering}, volume = {22}, number = {2}, pages = {}, pmid = {40048825}, issn = {1741-2552}, support = {UH3 NS120191/NS/NINDS NIH HHS/United States ; }, mesh = {Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Brain-Computer Interfaces ; *Electrocorticography/methods/instrumentation ; Electrodes, Implanted ; *Gamma Rhythm/physiology ; *Motor Activity/physiology ; *Motor Cortex/physiopathology/physiology ; Movement/physiology ; *Stents ; Clinical Trials as Topic ; }, abstract = {Objective.This study examined the strength and stability of motor signals in low gamma and high gamma bands of vascular electrocorticograms (vECoG) recorded with endovascular stent-electrode arrays (Stentrodes) implanted in the superior sagittal sinus of two participants with severe paralysis due to amyotrophic lateral sclerosis.Approach.vECoG signals were recorded from two participants in the COMMAND trial, an Early Feasibility Study of the Stentrode brain-computer interface (BCI) (NCT05035823). The participants performed attempted movements of their ankles or hands. The signals were band-pass filtered to isolate low gamma (30-70 Hz) and high gamma (70-200 Hz) components. The strength of vECoG motor activity was measured as signal-to-noise ratio (SNR) and the percentage change in signal amplitude between the rest and attempted movement epochs, which we termed depth of modulation (DoM). We trained and tested classifiers to evaluate the accuracy and stability of detecting motor intent.Main results.Both low gamma and high gamma were modulated during attempted movements. For Participant 1, the average DoM across channels and sessions was 125.41 ± 17.53% for low gamma and 54.23 ± 4.52% for high gamma, with corresponding SNR values of 6.75 ± 0.37 dB and 3.69 ± 0.28 dB. For Participant 2, the average DoM was 22.77 ± 4.09% for low gamma and 22.53 ± 2.04% for high gamma, with corresponding SNR values of 1.72 ± 0.25 dB and 1.73 ± 0.13 dB. vECoG amplitudes remained significantly different between rest and move periods over the 3 month testing period, with >90% accuracy in discriminating attempted movement from rest epochs for both participants. For Participant 1, the average DoM was strongest during attempted movements of both ankles, while for Participant 2, the DoM was greatest for attempted movement of the right hand. The overall classification accuracy was 91.43% for Participant 1 and 70.37% for Participant 2 in offline decoding of multiple attempted movements and rest conditions.Significance.By eliminating the need for open brain surgery, the Stentrode offers a promising BCI alternative, potentially enhancing access to BCIs for individuals with severe motor impairments. This study provides preliminary evidence that the Stentrode can detect discriminable signals indicating motor intent, with motor signal modulation observed over the 3 month testing period reported here.}, } @article {pmid40049153, year = {2025}, author = {Cho, HW and Jung, S and Park, KH and Choi, JW and Heo, JS and Kim, J and Yun, H and Yu, D and Son, J and Choi, BM}, title = {Deep-Learning-Based Multi-Class Classification for Neonatal Respiratory Diseases on Chest Radiographs in Neonatal Intensive Care Units.}, journal = {Neonatology}, volume = {122}, number = {4}, pages = {446-454}, doi = {10.1159/000545107}, pmid = {40049153}, issn = {1661-7819}, mesh = {Humans ; Infant, Newborn ; *Deep Learning ; Intensive Care Units, Neonatal ; Retrospective Studies ; *Radiography, Thoracic ; Female ; Male ; Algorithms ; Republic of Korea ; Respiratory Distress Syndrome, Newborn/diagnostic imaging/classification ; Lung/diagnostic imaging ; *Respiratory Tract Diseases/diagnostic imaging/classification ; }, abstract = {INTRODUCTION: Accurate and timely interpretation of chest radiographs is essential for assessing respiratory distress and guiding clinical management to improve outcomes of critically ill newborns. This study aimed to introduce a deep-learning-based automated algorithm designed to classify various neonatal respiratory diseases and healthy lungs using a large dataset of high-quality, multi-class labeled chest X-ray images from neonatal intensive care units.

METHODS: Portable supine chest X-ray images for six common conditions (healthy lung, respiratory distress syndrome [RDS], transient tachypnea of the newborn [TTN], air leak syndrome [ALS], atelectasis, and bronchopulmonary dysplasia [BPD]) and demographic variables (gestational age and birth weight) were retrospectively collected from 10 university hospitals in Korea. Ground truth for manual classification of these conditions was generated by 20 neonatologists and validated by others from different hospitals. The dataset, consisting 34,598 for training, 4,370 for validation, and 4,370 for testing, was used to train a modified ResNet50-based deep-learning model for automatic classification.

RESULTS: The automatic classification algorithm showed high concordance with human-annotated classifications, achieving an overall testing accuracy of 83.96% and an F1 score of 83.68%. The F1 score for each condition was 87.38% for "healthy lung" and 92.19% for "BPD," 90.65% for "ALS," 90.30% for "RDS," 86.56% for "atelectasis," and 70.84% for "TTN."

CONCLUSION: We introduced a deep-learning-based automated algorithm to classify neonatal respiratory diseases using a large dataset of high-quality, multi-class labeled chest X-ray images, incorporating non-imaging data, which could support neonatologists in making timely and accurate decisions for critically ill newborns.}, } @article {pmid40049292, year = {2025}, author = {Faure-de Baets, J and Besnard, J and Banville, F and Cassereau, J and Allain, P}, title = {Effects of virtual reality mindfulness on cognition and well-being in ALS: A randomized trial protocol.}, journal = {Contemporary clinical trials}, volume = {152}, number = {}, pages = {107876}, doi = {10.1016/j.cct.2025.107876}, pmid = {40049292}, issn = {1559-2030}, mesh = {Humans ; *Mindfulness/methods ; *Quality of Life ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Virtual Reality ; Randomized Controlled Trials as Topic ; Anxiety/therapy ; Depression/therapy ; *Cognitive Dysfunction/therapy/etiology ; Cognition ; Female ; Male ; Middle Aged ; Adult ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease primarily affecting motor neurons but also leading to significant non-motor symptoms, including cognitive impairments, anxiety, depression, and behavioral changes, which severely impact quality of life. While mindfulness-based interventions (MBIs) have shown promise in alleviating psychological distress, their accessibility is often limited due to patients' physical impairments. Virtual reality (VR) could enhance engagement and immersion, offering a novel, more inclusive therapeutic approach. This randomized controlled trial (RCT) aims to evaluate the efficacy of a VR-based MBI compared to traditional mindfulness for ALS patients. Forty-six participants will be randomly assigned to an eight-week mindfulness program delivered either via VR or in a conventional format. The primary outcome is quality of life, assessed using the ALS-Specific Quality of Life Scale (ALSSQOL-R). Secondary outcomes include cognitive function, anxiety, depression, behavioral changes, and mindfulness propensity, evaluated at baseline, post-intervention, and three-month follow-up. The study will also examine VR usability and potential accessibility challenges for ALS patients. By addressing a critical gap in non-pharmacological psychological care, this study will provide key insights into the feasibility and benefits of VR-based MBIs. If effective, VR mindfulness could offer an innovative, scalable solution to improve emotional well-being and quality of life in ALS, making psychological support more accessible for patients with severe physical limitations.}, } @article {pmid40049531, year = {2025}, author = {Zhang, N and Dong, X}, title = {Causal relationship between gut microbiota, lipids, and neuropsychiatric disorders: A Mendelian randomization mediation study.}, journal = {Journal of affective disorders}, volume = {379}, number = {}, pages = {19-35}, doi = {10.1016/j.jad.2025.02.091}, pmid = {40049531}, issn = {1573-2517}, mesh = {Humans ; *Gastrointestinal Microbiome/genetics/physiology ; Mendelian Randomization Analysis ; *Mental Disorders/genetics/microbiology ; *Lipids/blood ; Genome-Wide Association Study ; Mediation Analysis ; }, abstract = {BACKGROUND: Numerous studies have shown an interconnection between the gut microbiota and the brain via the "gut-brain" axis. However, the causal relationships between gut microbiota, lipids, and neuropsychiatric disorders remain unclear. This study aimed to analyze potential associations among gut microbiota, lipids, and neuropsychiatric disorders-including AD, PD, ALS, MS, SCZ, MDD, and BD-using summary data from large-scale GWAS.

METHODS: Bidirectional Mendelian randomization (MR) with inverse variance weighting (IVW) was the primary method. Supplementary analyses included sensitivity analyses, Steiger tests, and Bayesian weighted MR (BWMR). Mediation analyses used two-step MR (TSMR) and multivariable MR (MVMR).

RESULTS: The analyses revealed 51 positive correlations (risk factors) (β > 0, P < 0.05) and 47 negative correlations (protective factors) (β < 0, P < 0.05) between gut microbiota and neuropsychiatric disorders. In addition, 35 positive correlations (β > 0, P < 0.05) and 22 negative correlations (β < 0, P < 0.05) between lipids and neuropsychiatric disorders were observed. Assessment of reverse causality with the seven neuropsychiatric disorders as exposures and the identified gut microbiota and lipids as outcomes revealed no evidence of reverse causality (P > 0.05). Mediation analysis indicated that the effect of the species Bacteroides plebeius on MDD is partially mediated through the regulation of phosphatidylcholine (16:0_20:4) levels (mediation proportion = 10.9 % [95 % CI = 0.0110-0.2073]).

CONCLUSION: This study provides evidence of a causal relationship between gut microbiota and neuropsychiatric disorders, suggesting lipids as mediators. These findings offer new insights into the mechanisms by which gut microbiota may influence neuropsychiatric disorders.}, } @article {pmid40050010, year = {2025}, author = {Sun, J and De Vocht, J and Stam, D and Lien, CH and Huang, YA and Lamaire, N and Laroy, M and Vansteelandt, K and D'Hondt, A and Van Den Bossche, MJA and Vandenberghe, R and Peeters, RR and Sunaert, S and van Damme, P and Vandenbulcke, M and Van den Stock, J}, title = {Neural correlates of memory deficits in premanifest C9orf72-repeat expansions.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {9}, pages = {861-869}, doi = {10.1136/jnnp-2024-335169}, pmid = {40050010}, issn = {1468-330X}, mesh = {Humans ; *C9orf72 Protein/genetics ; Male ; Magnetic Resonance Imaging ; Female ; *Memory Disorders/genetics/physiopathology/diagnostic imaging/psychology ; Middle Aged ; *DNA Repeat Expansion/genetics ; Adult ; *Brain/diagnostic imaging/physiopathology ; Neuropsychological Tests ; Recognition, Psychology/physiology ; Facial Recognition ; }, abstract = {BACKGROUND: The premanifest stage in carriers of hexanucleotide repeat expansions in the C9orf72 gene (C9RE) is associated with memory impairment. The present study examines whether the impairment is general across domains or disproportionately affects specific stimulus categories such as socioemotional events, and its underlying functional neuroanatomy.

METHODS: This task-based fMRI-study included 21 premanifest C9RE (preC9RE) carriers and 24 controls. Participants encoded stimuli of (emotional and neutral) faces and houses, followed by a recognition task. Using univariate and multivoxel pattern analyses at whole-brain level and region-of-interest level, we investigated the neural change during encoding and retrieval processes, as well as the neural pattern similarity between encoding and retrieval.

RESULTS: Compared with controls, the preC9RE group demonstrated poorer performance in memorising faces (U=104, p=0.002), while their ability to memorise houses remained intact. The preC9RE group exhibited distinct neural patterns in the anterior insula during face encoding compared with the controls (accuracy>0.765, p<0.05). During face retrieval, the preC9RE group showed an increased neural response to encoded faces versus new faces in the right anterior insula (U=394, p=0.015). Individuals with preC9RE exhibited reduced encoding-retrieval neural similarity in the salience network specifically related to face stimuli (U=120, p=0.023).

CONCLUSIONS: The findings reveal functional changes in the salience network related to impaired social memory at the premanifest stage of C9RE. The findings further underscore the high potential of multidimensional neural response patterns as a sensitive biomarker for neurodegenerative functional changes, and the salience network as biomarker for C9RE disease staging.}, } @article {pmid40050016, year = {2025}, author = {Martin, J and Johnson, R and Yemane, L and Unaka, N and Ebo, C and Hippolyte, J and Jones, M and Quinn, M and Barber, A and Floyd, B and Blankenburg, R and Hilgenberg, SL}, title = {Multi-institutional exploration of pediatric residents' perspectives on anti-racism curricula: a qualitative study.}, journal = {Medical education online}, volume = {30}, number = {1}, pages = {2474134}, pmid = {40050016}, issn = {1087-2981}, mesh = {Humans ; *Internship and Residency/organization & administration ; Qualitative Research ; Focus Groups ; *Curriculum ; *Pediatrics/education ; *Racism/prevention & control ; United States ; Female ; Male ; *Attitude of Health Personnel ; Adult ; Antiracism ; }, abstract = {BACKGROUND: Anti-racism curricula are increasingly being recognized as an integral component of medical education. To our knowledge, there has not yet been a publication exploring resident perspectives from multiple institutions and explicitly representing both underrepresented in medicine (UIM) and non-UIM perspectives.

OBJECTIVE: To explore and compare UIM and non-UIM pediatric residents' perspectives on the content and qualities of meaningful anti-racism curricula.

METHODS: We performed an IRB-approved multi-institutional, qualitative study that incorporated Sotto-Santiago et al's conceptual framework for anti-racism education. Between February and May 2021, we conducted focus groups of UIM and non-UIM pediatric residents at three large residency programs in the United States. We developed focus group guides using literature review, expert consensus, feedback from study team racial equity experts, and piloting. Focus groups were conducted virtually, audio-recorded, and transcribed verbatim. We employed thematic analysis to code transcripts, create categories, and develop themes until we reached thematic sufficiency. We completed member checking to ensure trustworthiness of themes.

RESULTS: Forty residents participated (19 UIM and 21 non-UIM) in a total of six focus groups. We identified 7 themes, summarized as: 1) racism in medicine is pervasive, therefore (2) anti-racism education is critical to the development of competent physicians, and 3) education should extend to all healthcare providers. 4) Residents desired education focused on action-oriented strategies to advance anti-racism, 5) taught by those with both learned and lived experiences with racism, 6) in a psychologically safe space for UIM residents, and 7) with adequate time and financial resources for successful implementation and engagement.

CONCLUSION: Our multi-institutional study affirms the need for pediatric resident anti-racism education, promotes co-creation as a method to affect culture change, and provides practical strategies for curricular design and implementation.}, } @article {pmid40050651, year = {2025}, author = {Gregorio-Sanz, MÁ and Marzo-Campos, JC and Segura-Heras, JV}, title = {Effects of nursing music intervention on cardiovascular patients transferred in advanced life support ambulances.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {7919}, pmid = {40050651}, issn = {2045-2322}, support = {PROMETEO/2021/063//Generalitat Valenciana/ ; }, mesh = {Humans ; Male ; Female ; *Music Therapy/methods ; *Ambulances ; Middle Aged ; Aged ; *Cardiovascular Diseases/therapy/nursing ; *Advanced Cardiac Life Support ; Case-Control Studies ; Blood Pressure ; }, abstract = {Patients with acute cardiovascular disease require out-of-hospital care during the most critical and vulnerable periods of their illness. This study aims to evaluate the influence of musical intervention in patients with acute cardiovascular disease during transfer in Advanced Life Support (ALS) ambulances using an analytical randomized controlled case-control experimental study conducted according to CONSORT guidelines. Forty-one subjects took part in the study. The patients required the administration of nitrates/antiarrhythmics (n = 11, 26.8%), (n = 5, 12.2%) antiemetics, and (n = 7, 17.1%) opioids. Statistically significant differences were found for blood pressure and the variable cardiovascular drugs between groups. The use of music therapy to complement other health measures in ALS ambulances lowers blood pressure values and reduces the need to administrate cardiovascular drugs, thus avoiding their possible side effects. It is easy to implement, has a low cost and should be monitored and controlled as a specific nursing intervention, included in the care of patients transferred by ambulances on a routine basis.}, } @article {pmid40050936, year = {2025}, author = {Jeejan, J and Rao, L and Sadasivan, S and Lopes, R and Dsouza, N}, title = {Impact of cysteine mutations on the structural dynamics and functional impairment of SOD1: insights into the pathogenicity of amyotrophic lateral sclerosis.}, journal = {Genomics & informatics}, volume = {23}, number = {1}, pages = {7}, pmid = {40050936}, issn = {1598-866X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease prevalent in American and European populations, with its onset and progression significantly influenced by mutations in the superoxide dismutase 1 (SOD1) protein. While previous studies have highlighted the effects of mutations in the metal-binding region and catalytic region and dimerisation of SOD1, the impact of mutations involving the Cysteine residue at the N-terminal end remains unexplored. This study investigates the effects of Cysteine-to-Trp, Phe, Ser, and Gly mutations at the 6th position of SOD1's N-terminal end on its structural dynamics and functional impairment. Our computational analysis using PolyPhen-2, PROVEAN, Meta-SNP, and PhD-SNP predicted mutations to be deleterious, with their negative impacts likely contributing to disease development. Furthermore, stability studies and bonding pattern changes due to the mutations, analysed by mCSM, SDM, DUET, Dynamut2, and PremPS revealed changes in free energy and disruption in intramolecular interactions. The molecular dynamics studies revealed distinct changes in stability patterns among the mutations, particularly in Cys6Trp and Cys6Phe. All the mutations primarily altered the catalytic region of the protein; additionally, Cys6Phe and Cys6Gly caused disruption in the metal-binding region. The impact of mutations on the dimerisation of SOD1, analysed using MM/PBSA showed destabilisation due to Cys6Phe mutation. These findings provide molecular insights into the clinical symptoms observed in patients, highlighting the critical impact of the Cys6Phe mutation on the metal-binding and catalytic loops of SOD1 along with destabilisation of dimer formation. Overall, our analysis offers valuable insights into the molecular mechanisms driving structural changes in SOD1 due to mutations, contributing to a deeper understanding of their role in ALS pathogenicity.}, } @article {pmid40051509, year = {2025}, author = {Syed, SA and Singh, J and Elkholy, H and Rojnić Palavra, I and Tomicevic, M and Eric, AP and Pinto da Costa, M and Guloksuz, S and Radhakrishnan, R}, title = {International perspectives on physician knowledge, attitudes, and practices related to medical cannabis.}, journal = {Frontiers in public health}, volume = {13}, number = {}, pages = {1463871}, pmid = {40051509}, issn = {2296-2565}, support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Medical Marijuana/therapeutic use ; Cross-Sectional Studies ; Female ; Male ; Adult ; *Health Knowledge, Attitudes, Practice ; *Physicians/psychology/statistics & numerical data ; Surveys and Questionnaires ; Middle Aged ; *Attitude of Health Personnel ; *Practice Patterns, Physicians'/statistics & numerical data ; *Internationality ; }, abstract = {BACKGROUND: The trends of recreational use of cannabis and the use of cannabis for medical indications (i.e., "medical cannabis") have grown in recent years. Despite that, there is still limited scientific evidence to guide clinical decision-making, and the strength of evidence for the medical use of cannabis is currently considered to be low. In contrast, there is growing evidence of negative health outcomes related to the use of cannabis. In this rapidly shifting landscape, the role of physician attitudes regarding the therapeutic value of cannabis has become essential. This study aimed to characterize knowledge/experience, attitudes, and potential predictors of clinical practice regarding medical cannabis.

METHODS: We conducted a cross-sectional survey of physicians from 17 countries between 2016 and 2018. The survey consisted of questions designed to explore physician knowledge, attitude, and practices regarding the use of medical cannabis. Descriptive statistics were used to examine willingness to recommend medical cannabis for medical and psychiatric indications, followed by regression analysis to identify the predictors of physician willingness to recommend medical cannabis.

RESULTS: A total of 323 physicians responded to the survey, among which 53% were women. The mean age was 35.4 ± 9.5 years, with 10.04 ± 8.6 years of clinical experience. Clinical experience with medical cannabis was overall limited (51.4% noted never having recommended medical cannabis and 33% noted inadequate knowledge regarding medical cannabis). The majority of respondents (84%) recognized the risk of psychosis with cannabis use, while only 23% correctly identified the risk of addiction with daily cannabis use. Overall, willingness to recommend medical cannabis was the highest for chemotherapy-induced nausea (67%), refractory chronic neuropathic pain (52%), and spasticity in amyotrophic lateral sclerosis (ALS; 51%).

CONCLUSION: This international study examining physician knowledge, attitudes, and practices related to medical cannabis revealed that there are significant gaps in domain-specific knowledge related to medical cannabis. There is a wide variability in willingness to recommend medical cannabis, which is not consistent with the current strength of evidence. This study thus highlights the need for greater education related to domain-specific knowledge about medical cannabis.}, } @article {pmid40051750, year = {2025}, author = {Dib, A and Salem, J and Fares, M}, title = {Recurrent Spontaneous Pneumothorax in the Setting of Amyotrophic Lateral Sclerosis.}, journal = {European journal of case reports in internal medicine}, volume = {12}, number = {3}, pages = {005151}, pmid = {40051750}, issn = {2284-2594}, abstract = {UNLABELLED: Spontaneous pneumothorax (SP) occurrence in amyotrophic lateral sclerosis (ALS) patients is relatively rare and may thus be under-recognised. This latter is a progressive neurodegenerative disorder, leading to muscle weakness and such respiratory complications. This article reports a case manifesting such a rare association.

LEARNING POINTS: The presence of spontaneous pneumothorax in amyotrophic lateral sclerosis patients can exacerbate respiratory insufficiency, leading to acute respiratory failure.Given the under-recognition of this latter complication, clinicians should maintain a high index of suspicion, especially in patients with amyotrophic lateral sclerosis presenting with sudden onset of dyspnoea or chest pain.Early detection and appropriate management are crucial to prevent further respiratory compromise.}, } @article {pmid40053462, year = {2025}, author = {Fazzini, L and Martis, A and Pateri, MI and Maccabeo, A and Borghero, G and Puligheddu, M and Montisci, R and Marchetti, MF}, title = {Long-term outcomes and worse clinical course in Takotsubo syndrome patients with amyotrophic lateral sclerosis.}, journal = {Journal of cardiovascular medicine (Hagerstown, Md.)}, volume = {26}, number = {4}, pages = {184-190}, pmid = {40053462}, issn = {1558-2035}, mesh = {Humans ; Female ; *Takotsubo Cardiomyopathy/mortality/therapy/diagnosis/epidemiology/physiopathology ; Aged ; Male ; Retrospective Studies ; *Amyotrophic Lateral Sclerosis/mortality/epidemiology/diagnosis/therapy ; Prevalence ; Middle Aged ; Time Factors ; Hospital Mortality ; Risk Factors ; Shock, Cardiogenic/therapy/mortality/epidemiology ; Aged, 80 and over ; Prognosis ; Risk Assessment ; }, abstract = {AIMS: Takotsubo syndrome (TTS) is usually triggered by either physical/psychological stressors or comorbidities, neurological among others. The prevalence of amyotrophic lateral sclerosis (ALS) among TTS and whether it has a worse clinical course is not known. We aim to describe ALS prevalence and its impact on clinical presentation, clinical course, and long-term mortality.

METHODS: We retrospectively screened the overall TTS population admitted and followed up at our institution between 2007 and 2020. Clinical, electrocardiographic, and echocardiographic data were collected. Kaplan-Meier method was applied for time-to-event analysis to assess the outcome of interest of all-cause death.

RESULTS: Eighty-five patients with TTS were included in our study. Overall, the mean age was 70 ± 12 years, 86% were females. Six patients (7% prevalence) were affected by ALS. At admission, patients with ALS were more likely to present left ventricular systolic dysfunction (P = 0.007). The clinical course of ALS patients was more likely complicated by cardiogenic shock (P = 0.003) which required catecholamines infusion (P = 0.001) and mechanical ventilation (P = 0.009). Despite similar in-hospital mortality rates, ALS patients exhibited significantly elevated all-cause mortality during a median 6-year follow-up (hazard ratio, 19.189, 95% confidence interval 5.639-65.296, log-rank test P < 0.001) with significantly shorter hospitalization to death time (P = 0.039).

CONCLUSIONS: Our findings highlight a notable prevalence of ALS among TTS patients, with worse clinical presentation and in-hospital course in ALS-affected individuals. While in-hospital mortality rates were comparable, highlighting the reversible nature of TTS in both groups, long-term follow-up revealed significantly heightened all-cause mortality in ALS patients, emphasizing the impact of ALS on patient prognosis.}, } @article {pmid40053600, year = {2025}, author = {Nie, Y and Szebényi, K and Wenger, LMD and Lakatos, A and Chinnery, PF}, title = {Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.}, journal = {Science advances}, volume = {11}, number = {10}, pages = {eadr0690}, pmid = {40053600}, issn = {2375-2548}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics ; *DNA, Mitochondrial/genetics ; *Brain/metabolism/pathology ; *Mutation ; *Organoids/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism ; *Frontotemporal Lobar Degeneration/genetics/pathology ; Mitochondria/genetics ; Astrocytes/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are primarily genetic in ~20% of patients. Mutations in C9ORF72 are the most frequent cause, but it is not understood why there is notable regional pathology. An increased burden of mitochondrial DNA (mtDNA) mutations in ALS-FTLD brains implicates mitochondrial mechanisms; however, it remains unclear how and when these mutations arise. To address this, we generated cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) of patients with ALS-FTLD harboring the C9ORF72 hexanucleotide repeat expansion alongside CRISPR-corrected isogenic and healthy controls. Here, we show a higher mtDNA single-nucleotide variant (mtSNV) burden in astroglia derived from C9ORF72-mutant organoids, with some de novo mtSNVs likely due to the C9ORF72 repeat and others evading selection to reach higher heteroplasmy levels. Thus, the functional consequences of the regional accumulation of mtSNVs in C9ORF72 ALS-FTLD brains are likely to manifest through astroglial mitochondrial dysfunction.}, } @article {pmid40054065, year = {2025}, author = {Tserennadmid, B and Nam, MK and Park, JH and Rhim, H and Kang, S}, title = {HAP/ClpP-mediated disaggregation and degradation of Mutant SOD1 aggregates: A potential therapeutic strategy for Amyotrophic lateral sclerosis (ALS).}, journal = {Biochemical and biophysical research communications}, volume = {756}, number = {}, pages = {151533}, doi = {10.1016/j.bbrc.2025.151533}, pmid = {40054065}, issn = {1090-2104}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; Humans ; Protein Aggregates ; Proteolysis ; *Heat-Shock Proteins/metabolism/genetics ; Mutation ; Fluorescence Resonance Energy Transfer ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by the accumulation of misfolded Cu/Zn superoxide dismutase (SOD1) protein aggregates in motor neurons, leading to progressive motor dysfunction and ultimately death. While the molecular chaperone heat shock protein 104 (Hsp104) has been shown to reduce protein misfolding by disaggregating protein aggregates, fully degrading these disaggregated proteins remains a significant challenge. In this study, we have investigated the effects of Hsp104 and its hyperactive variant, HAP, in combination with caseinolytic protease P (CIpP), on the disaggregation and degradation of SOD1 aggregates. Using laser confocal microscopy, fluorescence loss in photobleaching (FLIP), and biomolecular fluorescence complementation (BiFC)-fluorescence resonance energy transfer (FRET) assays, we demonstrate that Hsp104 effectively disaggregates SOD1 aggregates across 14 different G93 mutants, classified based on the properties of substituted amino acids, thus restoring protein mobility. Notably, the HAP/CIpP system not only disaggregates ALS-associated SOD1[G93A] aggregates but also promotes their proteolytic degradation, as evidenced by a significant reduction in high-order oligomers observed through BiFC and FRET assays. This dual mechanism of action presents. the HAP/CIpP system holds significant therapeutic potential for ALS and other neurodegenerative diseases characterized by protein aggregates, as it enables both effective disaggregation and degradation of toxic protein aggregates, thereby maintaining protein homeostasis.}, } @article {pmid40055545, year = {2025}, author = {Giblin, A and Cammack, AJ and Blomberg, N and Anoar, S and Mikheenko, A and Carcolé, M and Atilano, ML and Hull, A and Shen, D and Wei, X and Coneys, R and Zhou, L and Mohammed, Y and Olivier-Jimenez, D and Wang, LY and Kinghorn, KJ and Niccoli, T and Coyne, AN and van der Kant, R and Lashley, T and Giera, M and Partridge, L and Isaacs, AM}, title = {Author Correction: Neuronal polyunsaturated fatty acids are protective in ALS/FTD.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {913}, doi = {10.1038/s41593-025-01926-1}, pmid = {40055545}, issn = {1546-1726}, } @article {pmid40056187, year = {2025}, author = {Wiesenfarth, M and Forouhideh-Wiesenfarth, Y and Elmas, Z and Parlak, Ö and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Günther, K and Fröhlich, E and Knehr, A and Simak, T and Bachhuber, F and Regensburger, M and Petri, S and Klopstock, T and Reilich, P and Schöberl, F and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Tumani, H and Brenner, D and Dorst, J and Ludolph, AC}, title = {Correction: Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {259}, doi = {10.1007/s00415-025-12952-1}, pmid = {40056187}, issn = {1432-1459}, } @article {pmid40056296, year = {2025}, author = {Li, Z and Fan, J and Gong, Z and Tang, J and Yang, Y and Liu, M and Zhang, M}, title = {Association between cardiac autonomic dysfunction, cognitive impairment, and survival in patients with amyotrophic lateral sclerosis.}, journal = {Clinical autonomic research : official journal of the Clinical Autonomic Research Society}, volume = {35}, number = {3}, pages = {465-476}, pmid = {40056296}, issn = {1619-1560}, support = {82271478//the National Natural Science Foundation of China/ ; 2024AOXIANG05//the Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology/complications/psychology ; Male ; Female ; Middle Aged ; *Cognitive Dysfunction/physiopathology/mortality ; Aged ; *Autonomic Nervous System Diseases/physiopathology/mortality ; Heart Rate/physiology ; Electrocardiography, Ambulatory ; Adult ; }, abstract = {PURPOSE: The aim of this study was to investigate the relationship between cardiac autonomic dysfunction, cognitive impairment, and survival in patients with amyotrophic lateral sclerosis (ALS).

METHODS: The heart activity of 65 patients with ALS (28 with normal cognition [ALS-CN]; 37 with impaired cognition [ALS-CI]) and 38 healthy controls (HCs) was measured by 24-h Holter monitoring. Heart rate (HR) measures and heart rate variability (HRV) parameters were compared between the three study groups and, additionally, correlated with five Edinburgh Cognitive and Behavioral ALS Screen (ECAS) domains in the ALS subgroups. Age, gender, and educational level were adjusted. Factors associated with cognitive status were assessed using logistic regression. Survival predictors in patients with ALS were analyzed using the Kaplan-Meier estimator and Cox regression.

RESULTS: Compared to the HCs, patients with ALS-CI exhibited lower RRI (R-R-interval; P = 0.017), SDNN (standard deviation of all normal RR intervals; P = 0.013), SDNN Index (P = 0.044), and VLF power (very low-frequency power; P = 0.012). Total power was reduced in the ALS-CI group compared to the HCs (P = 0.036) and ALS-CN group (P = 0.048). In patients with ALS-CN, language negatively correlated with mean HR (P = 0.001) and positively with the RRI (P = 0.003), SDNN (P = 0.001), SDANN (standard deviation of the average NN intervals; P = 0.005), total power (P = 0.006), VLF power (P = 0.011), and low-frequency power (P = 0.026). Visuospatial function correlated positively with the SDNN Index (P = 0.041). In patients with ALS-CI, executive function (P = 0.015) and ECAS total score (P = 0.009) negatively correlated with the RMSSD (square root of mean sum-of-squares of differences between adjacent NN intervals), while visuospatial function correlated positively with normalized LF value (LFnu; P = 0.049). No associations were observed between the other cognitive domains and any of the 14 HRV/HR measures in patients with either ALS-CI or ALS-CN. SDNN ≤ 100 ms was linked to cognitive impairment (P = 0.039) and also showed a borderline association (P = 0.066) with poorer survival, while cognitive impairment (P = 0.010) was significantly linked to worse outcomes.

CONCLUSIONS: Patients with ALS with cognitive impairment demonstrated reduced cardiac autonomic modulations and altered cognitive autonomic associations. Cognitive impairment was linked to reduced survival, with baseline SDNN ≤ 100 ms identified as a potential marker.}, } @article {pmid40056413, year = {2025}, author = {Kahn, OI and Dominguez, SL and Glock, C and Hayne, M and Vito, S and Sengupta Ghosh, A and Adrian, M and Burgess, BL and Meilandt, WJ and Friedman, BA and Hoogenraad, CC}, title = {Secreted neurofilament light chain after neuronal damage induces myeloid cell activation and neuroinflammation.}, journal = {Cell reports}, volume = {44}, number = {3}, pages = {115382}, doi = {10.1016/j.celrep.2025.115382}, pmid = {40056413}, issn = {2211-1247}, mesh = {Animals ; *Neurons/metabolism/pathology ; *Neurofilament Proteins/metabolism/genetics ; Mice ; *Myeloid Cells/metabolism/pathology ; Microglia/metabolism/pathology ; Mice, Knockout ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Neuroinflammatory Diseases/pathology/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Humans ; Calpain/metabolism ; Superoxide Dismutase-1/metabolism ; }, abstract = {Neurofilament light chain (NfL) is a neuron-specific cytoskeletal protein that provides structural support for axons and is released into the extracellular space following neuronal injury. While NfL has been extensively studied as a disease biomarker, the underlying release mechanisms and role in neurodegeneration remain poorly understood. Here, we find that neurons secrete low baseline levels of NfL, while neuronal damage triggers calpain-driven proteolysis and release of fragmented NfL. Secreted NfL activates microglial cells, which can be blocked with anti-NfL antibodies. We utilize in vivo single-cell RNA sequencing to profile brain cells after injection of recombinant NfL into the mouse hippocampus and find robust macrophage and microglial responses. Consistently, NfL knockout mice ameliorate microgliosis and delay symptom onset in the SOD1 mouse model of amyotrophic lateral sclerosis (ALS). Our results show that released NfL can activate myeloid cells in the brain and is, thus, a potential therapeutic target for neurodegenerative diseases.}, } @article {pmid40056503, year = {2025}, author = {Zhan, A and Zhong, K and Zhang, K}, title = {Novel subcellular regulatory mechanisms of protein homeostasis and its implications in amyotrophic lateral sclerosis.}, journal = {Biochemical and biophysical research communications}, volume = {756}, number = {}, pages = {151582}, doi = {10.1016/j.bbrc.2025.151582}, pmid = {40056503}, issn = {1090-2104}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Proteostasis ; Animals ; Homeostasis ; Mitochondria/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disorder. Protein aggregates induce various forms of neuronal dysfunction and represent pathological hallmarks in ALS patients. Reducing protein aggregates could be a promising therapeutic strategy for ALS. While most studies have focused on cytoplasmic protein homeostasis, neurons adaptively reduce aggregates across subcellular compartments during stress through previously uncharacterized mechanisms. Here, we summarize novel compartment-specific proteostatic mechanisms: (1) the ERAD/RESET pathways, (2) HSPs-mediated nuclear sequestration, (3) mitochondrial aggregate import (MAGIC), (4) neurite-localized UPS/autophagosome and NMP, and (5) exopher-mediated extracellular disposal. These mechanisms collectively ensure cellular stress adaptation and provide novel therapeutic targets for ALS treatment.}, } @article {pmid40056552, year = {2025}, author = {Newell, ME and Babbrah, A and Aravindan, A and Kulkarni, S and Ellershaw, A and Dupati, A and Rathnam, R and Shaffer, G and Estrada, L and Curtis, C and Leneaux, J and Driver, EM and Halden, RU}, title = {Wastewater-borne markers of neurodegenerative disease: β-methylamino-L-alanine and aminomethylphosphonic acid.}, journal = {The Science of the total environment}, volume = {970}, number = {}, pages = {179032}, doi = {10.1016/j.scitotenv.2025.179032}, pmid = {40056552}, issn = {1879-1026}, mesh = {*Amino Acids, Diamino/analysis ; *Wastewater/chemistry/analysis ; Biomarkers/analysis ; *Water Pollutants, Chemical/analysis ; Cyanobacteria Toxins ; *Environmental Monitoring/methods ; *Neurodegenerative Diseases/epidemiology ; Humans ; Glycine/analogs & derivatives/analysis ; Glyphosate ; Tandem Mass Spectrometry ; Chromatography, Liquid ; Isoxazoles/analysis ; Organophosphonates ; }, abstract = {Exposure to toxic organic chemicals such as β-methylamino-L-alanine (BMAA) and glyphosate has been associated with neurodegenerative diseases (NDDs), including amyotrophic lateral sclerosis (ALS), Parkinson's Disease (PD), and Alzheimer's Disease (AD). We explored the utility of BMAA and glyphosate's metabolite aminomethylphosphonic acid (AMPA) for serving as potential markers of NDDs by comparing levels of wastewater-borne BMAA and AMPA with regional U.S. rates of NDD prevalence. Newly developed liquid chromatography tandem mass spectrometry (LC-MS/MS) methods were applied to U.S. wastewater samples (n = 87) and resultant concentrations of putative biomarkers were statistically compared to NDD prevalence rates in conjunction with environmental data on algal blooms and agricultural glyphosate use. Locations of algal blooms were found to be significantly associated (p = 0.01) with ALS prevalence rates per 100,000 people. BMAA levels in wastewater were highly correlated (p < 0.0001) with ALS prevalence rates by region. BMAA in wastewater typically peaked in summer months. We conclude that NDD biomarker detection in wastewater holds potential value, with BMAA outperforming AMPA. Furthermore, prevalence data for NDDs may have to be reported to the Centers for Disease Control and Prevention at a higher geospatial resolution to further enhance the value for the present type of analysis. Further method development is needed for AMPA to be quantified using LC-MS/MS. Future method developments focusing on metabolites (e.g., AMPA) may enable epidemiologists to determine human exposure levels rather than the mere occurrence of toxic organic chemicals in the environment.}, } @article {pmid40056685, year = {2025}, author = {Jakhar, M and Barone, V}, title = {Single atom catalysts adsorbed on reduced monolayers for enhanced kinetics in Al-S batteries.}, journal = {Journal of colloid and interface science}, volume = {689}, number = {}, pages = {137226}, doi = {10.1016/j.jcis.2025.03.015}, pmid = {40056685}, issn = {1095-7103}, abstract = {Rechargeable aluminum-sulfur (Al-S) batteries have attracted significant attention as potential next-generation energy storage devices due to their safety, the natural abundance of the elemental components, and high theoretical energy density. However, their utilization is hindered by sluggish reaction kinetics and poor reversibility. Introducing single-atom catalysts (SACs) can promote redox processes at the cathode and help in mitigating the shuttle effect of Al polysulfides (Al2Sx). While the electrochemical, thermodynamic, and thermal stabilities of SACs (Co, Fe, Ir, Ni, Pt, and Rh) have been explored in previous studies, this work focuses on their potential role in enhancing reaction kinetics in Al-S batteries. Our calculations indicate that SACs-based substrates exhibit more robust binding energies for capturing Al2Sx than the bare surfaces. Additionally, SACs lower the free energies associated with the rate-determining step during discharging and exhibit lower decomposition barriers during charging. Moreover, the interaction of soluble Al2Sx with the electrolyte reveals that SAC supported polysulfides are less likely to dissolve in the electrolyte than their pristine counterparts. The analysis of the underlying mechanisms of the interaction of molecules and the Co@ substrate reveals the ability of this substrate to accommodate large volume changes and support a sulfur loading up to 53.37 wt% during the charging and discharging cycles, without causing fractures. The mechanism driving this enhanced performance is extensively investigated through charge transfer, bond strength, and d-band center analyses. Our findings present an effective strategy for designing SACs substrates to improve the electrochemical performance of Al-S cathodes.}, } @article {pmid40057669, year = {2025}, author = {Hatcher, H and Stankeviciute, S and Learn, C and Qu, AX}, title = {Regulatory, Translational, and Operational Considerations for the Incorporation of Biomarkers in Drug Development.}, journal = {Therapeutic innovation & regulatory science}, volume = {59}, number = {3}, pages = {519-526}, pmid = {40057669}, issn = {2168-4804}, mesh = {*Drug Development/legislation & jurisprudence ; Humans ; *Biomarkers ; United States ; United States Food and Drug Administration ; Drug Approval ; }, abstract = {BACKGROUND: Biomarkers are an integral component in the drug development paradigm. According to the US Food and Drug Administration (FDA), a biomarker is "a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic intervention" (FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016-. Glossary. 2016 [Updated 2021 Nov 29, cited 2024 Apr 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK338448/ Co-published by National Institutes of Health (US), Bethesda (MD)). The European Medicines Agency (EMA) defines a biomarker as "an objective and quantifiable measure of a physiological process, pathological process or response to a treatment (excluding measurements of how an individual feels or functions" European Medicines Agency (EMA). Biomaker. 2020a. Available from: https://www.ema.europa.eu/en/glossary-terms/biomarker#:~:text=Biomarker-,Biomarker,an%20individual%20feels%20or%20functions . Several clinical biomarkers are well-documented and have been used routinely for decades in health care settings and have long been accepted as valid endpoints for drug approval (for example, blood pressure measurement as a biomarker for cardiovascular health) (European Medicines Agency (EMA). Assessment report, TAGRISSO. 2016. Available from: https://www.ema.europa.eu/en/documents/assessment-report/tagrisso-epar-public-assessment-report_en.pdf . Accessed 15 Apr 2024). Recently, novel biomarkers have been identified and validated to accelerate developing innovative therapies indicated for serious human diseases, for example targeted/immune therapies of cancer (Chen in Med Drug Discov 21:100174, 2024). As indicators of the efficacy of new pharmacological treatments or therapeutic interventions, biomarkers can improve clinical trial efficacy and reduce uncertainty in regulatory decision making (Bakker et al. in Clin Pharmacol Ther 112:69-80, 2022; Califf in Exp Biol Med 243:213-221, 2018; Parker et al. in Cancer Med 10:1955-1963, 2021).

METHODOLOGY: This article describes case studies of recent drug approvals that successfully leveraged validated and non-validated biomarkers (i.e., tofersen for the neurodegenerative disease amyotrophic lateral sclerosis (ALS) in adults; and osimertinib for treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC)).

CONCLUSIONS: Best practices for biomarker selection and strategies for health authority biomarker qualification programs are presented along with an overview of current limitations and challenges to optimizing biomarker applications along the drug development continuum from regulatory, translational, and operational perspectives.}, } @article {pmid40057753, year = {2025}, author = {Sharbafshaaer, M and Siciliano, M and Passaniti, C and Sant'Elia, V and Silvestro, M and Russo, A and Esposito, S and Tedeschi, G and Trojano, L and Trojsi, F}, title = {Screening of visuospatial abilities in amyotrophic lateral sclerosis (ALS): a pilot study using the battery for visuospatial abilities (BVA).}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {110}, pmid = {40057753}, issn = {1750-1172}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Pilot Projects ; Middle Aged ; Aged ; Neuropsychological Tests ; Space Perception/physiology ; Adult ; Visual Perception/physiology ; }, abstract = {BACKGROUND: Cognitive deficits related to frontotemporal dysfunction are common in Amyotrophic Lateral Sclerosis (ALS). Visuospatial deficits, related to posterior cerebral regions, are often underestimated in ALS, though they play a crucial role in attending daily living activities. Our pilot study aims at assessing visuospatial abilities using a domain-specific tool in ALS patients compared to healthy controls (HC).

METHODS: Twenty-three patients with early ALS and 23 age- and education-matched HC underwent the Battery for Visuospatial Abilities (BVA), including 4 visuo-perceptual and 4 visuo-representational subtests.

RESULTS: When compared to HC, ALS scored worse in 2 visuo-perceptual subtests (i.e., Line Length Judgment and Line Orientation Judgment) and 1 visuo-representational tasks (i.e., Hidden Figure Identification, HFI) (p < 0.01). No correlations arose between ALS clinical features and BVA performance. More than 80% of the ALS cohort obtained abnormal scores in the HFI subtest.

CONCLUSIONS: Our findings revealed that patients with ALS scored worse (compared to HC) on selective tests tapping "perceptual" and "representational" visuospatial abilities, since the early stages of disease. In clinical practice, our findings highlight the need for multi-domain neuropsychological assessment, for monitoring disease courses and properly organizing care management of patients with ALS.}, } @article {pmid40057796, year = {2025}, author = {Mitra, J and Kodavati, M and Dharmalingam, P and Guerrero, EN and Rao, KS and Garruto, RM and Hegde, ML}, title = {Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {54}, pmid = {40057796}, issn = {2051-5960}, support = {R03AG064266/AG/NIA NIH HHS/United States ; RF1NS112719/NS/NINDS NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; Disease Models, Animal ; Gene Knock-In Techniques ; *Cellular Senescence/physiology/genetics ; Mice, Transgenic ; *DNA Repair/physiology/genetics ; *Motor Neurons/pathology/metabolism ; Inflammation/pathology/metabolism/genetics ; *TDP-43 Proteinopathies/pathology/genetics/metabolism ; }, abstract = {TDP-43 mislocalization and aggregation are key pathological features of amyotrophic lateral sclerosis (ALS)- and frontotemporal dementia (FTD). However, existing transgenic hTDP-43 WT or ∆NLS-overexpression animal models primarily focus on late-stage TDP-43 proteinopathy. To complement these models and to study the early-stage motor neuron-specific pathology during pre-symptomatic phases of disease progression, we generated a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43∆NLS variant of mouse Tdp-43. This variant is expressed either in the whole body (WB) or specifically in the motor neurons (MNs) in two distinct models. These mice exhibit loss of nuclear Tdp-43, with concomitant cytosolic accumulation and aggregation in targeted cells, leading to increased DNA double-strand breaks (DSBs), signs of inflammation, and associated cellular senescence. Notably, unlike WT Tdp-43, which functionally interacts with Xrcc4 and DNA Ligase 4, the key DSB repair proteins in the non-homologous end-joining (NHEJ) pathway, the Tdp-43∆NLS mutant sequesters them into cytosolic aggregates, exacerbating neuronal damage in mouse brain. The mutant mice also exhibit myogenic degeneration in hindlimb soleus muscles and distinct motor deficits, consistent with the characteristics of motor neuron disease (MND). Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43∆NLS mutant, independent of Tdp-43 overexpression or other confounding factors. Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to characterize the early-stage progression of MND further and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.}, } @article {pmid40059194, year = {2025}, author = {Shang, Q and Zhou, J and Ye, J and Chen, M}, title = {Adverse events reporting of edaravone: a real-world analysis from FAERS database.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {8148}, pmid = {40059194}, issn = {2045-2322}, mesh = {*Edaravone/adverse effects ; Humans ; *Adverse Drug Reaction Reporting Systems/statistics & numerical data ; Databases, Factual ; United States ; *Amyotrophic Lateral Sclerosis/drug therapy ; United States Food and Drug Administration ; Male ; Female ; Bayes Theorem ; *Drug-Related Side Effects and Adverse Reactions/epidemiology ; }, abstract = {For individuals with amyotrophic lateral sclerosis (ALS), intravenous edaravone is approved as a disease-modifying medication; yet, there have been many reports of adverse events (AEs). We examined the AEs associated with edaravone in this study using actual data from the FDA's (Food and Drug Administration) adverse event reporting system (FAERS). By extracting large-scale data from the FAERS database, this study used the signals of edaravone-associated AEs were quantified using the multiitem gamma Poisson shrinker (MGPS) method based on disproportionality, the Bayesian confidence propagation neural network (BCPNN), the reporting odds ratio (ROR), and the proportional reporting ratio (PRR). In the FAERS database, this study extracted data between April 2017 and March 2024, and edaravone was identified as the "primary suspect (PS)" in 2,986 AE reports. AEs associated with edaravone specifically targeted 27 system organ types (SOCs). Unexpectedly serious AEs that weren't mentioned in the drug insert, include abnormal hepatic function, catheter site thrombosis, pain, cerebral hemorrhage, infection, cerebral infarction, poor venous access, disseminated intravascular coagulation, vein collapse and cerebral venous sinus thrombosis. Our research found possible signals of new AEs that may offer substantial backing for clinical surveillance and edaravone risk assessment, but further research and validation are needed, especially for those AE that may occur in actual usage scenarios but are not yet explicitly described in the instruction.}, } @article {pmid40060160, year = {2025}, author = {Mangalindan, KE and Wyatt, TR and Brown, KR and Shapiro, M and Maggio, LA}, title = {Investigating the Road to Equity: A Scoping Review of Solutions to Mitigate Implicit Bias in Assessment within Medical Education.}, journal = {Perspectives on medical education}, volume = {14}, number = {1}, pages = {92-106}, pmid = {40060160}, issn = {2212-277X}, mesh = {Humans ; *Education, Medical/methods/standards ; *Bias, Implicit ; *Educational Measurement/methods/standards ; }, abstract = {INTRODUCTION: In medical education, assessments have high-stakes implications. Yet, assessments are rife with unconscious bias, which contributes to inequitable social structures. Implicit bias in assessment must be addressed because medical educators use assessments to guide learning and promote development of physicians' careers. In this scoping review, the authors map the literature on implicit bias in assessment, as it applies to: 1) the types of implicit bias addressed, 2) the targets and types of interventions studied or proposed, and 3) how publications describe intervention efficacy.

METHODS: The authors conducted a scoping review of the literature on interventions to mitigate implicit bias that was published between January 2010 and August 2023. Author pairs independently screened articles for inclusion and extracted data. Discrepancies were resolved with discussion and consensus. Qualitative and quantitative analysis was informed by Anderson et al's three assessment orientations: fairness, assessment for inclusion (AfI), and justice.

RESULTS: 7,831 articles were identified; 54 articles were included. The majority (n = 37; 69%) of articles focus on implicit bias toward those underrepresented in medicine. Interventions to mitigate implicit bias were targeted toward admissions and applications, faculty training, recruitment, summative assessments, and evaluation templates. Interventions had fairness (n = 43; 96%) and AfI (n = 22; 49%) orientations; no articles used a justice-orientation. For the sub-set of research studies (n = 40), almost all (n = 34; 85%) examined a single program/institution.

DISCUSSION: This scoping review showed that more work is necessary to address different types of implicit biases, move scholarship beyond single-institution studies, refine existing interventions, and evaluate how efficacy is defined.}, } @article {pmid40060442, year = {2025}, author = {Deng, X and Bradshaw, G and Kalocsay, M and Mitchison, T}, title = {Tubulin Regulates the Stability and Localization of STMN2 by Binding Preferentially to Its Soluble Form.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060442}, issn = {2692-8205}, support = {R35 GM131753/GM/NIGMS NIH HHS/United States ; }, abstract = {Loss of the tubulin-binding protein STMN2 is implicated in amyotrophic lateral sclerosis (ALS) but how it protects neurons is not known. STMN2 is known to turn over rapidly and accumulate at axotomy sites. We confirmed fast turnover of STMN2 in U2OS cells and iPSC-derived neurons and showed that degradation occurs mainly by the ubiquitin-proteasome system. The membrane targeting N-terminal domain of STMN2 promoted fast turnover, whereas its tubulin binding stathmin-like domain (SLD) promoted stabilization. Proximity labeling and imaging showed that STMN2 localizes to trans-Golgi network membranes and that tubulin binding reduces this localization. Pull-down assays showed that tubulin prefers to bind to soluble over membrane-bound STMN2. Our data suggest that STMN2 interconverts between a soluble form that is rapidly degraded unless bound to tubulin and a membrane-bound form that does not bind tubulin. We propose that STMN2 is sequestered and stabilized by tubulin binding, while its neuroprotective function depends on an unknown molecular activity of its membrane-bound form.}, } @article {pmid40060539, year = {2025}, author = {Petrescu, J and Roque, CG and Jackson, CA and Daly, A and Kang, K and Casel, O and Leung, M and Reilly, L and Eschbach, J and McDade, K and Gregory, JM and Bonneau, R and Smith, C and Phatnani, H}, title = {Distinct Cellular Phenotypes of Language and Executive Decline in Amyotrophic Lateral Sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.02.26.640433}, pmid = {40060539}, issn = {2692-8205}, abstract = {Cognitive manifestations, including impairment in language and executive functions, are seen in amyotrophic lateral sclerosis (ALS), but the mechanisms that underlie these deficits remain unclear. To address this, we mapped prefrontal cortex regions from ALS patients by integrating spatial and single-nucleus transcriptomics in a cognitively stratified patient cohort. We uncover that cognitive impairment in ALS is associated with distinct patterns of neuronal dysfunction and glial-vascular dysregulation that vary by region and cognitive subtype. Executive dysfunction is linked to reduced mitochondrial and synaptic activity in neurons localized to the deeper layers of the dorsolateral prefrontal cortex, whereas language-related deficits track with a more diffuse, pan-regional response involving both glial and vascular abnormalities. Our analyses also identify signatures in the prefrontal cortex that span both motor and cognitive phenotypes, including a multicellular gliosis response. The findings reveal that the clinical heterogeneity of ALS is driven by phenotype-specific molecular and cellular interactions in motor and non-motor regions of the brain.}, } @article {pmid40060668, year = {2025}, author = {Axakova, A and Ding, M and Cote, AG and Subramaniam, R and Senguttuvan, V and Zhang, H and Weile, J and Douville, SV and Gebbia, M and Al-Chalabi, A and Wahl, A and Reuter, J and Hurt, J and Mitchell, A and Fradette, S and Andersen, PM and van Loggerenberg, W and Roth, FP}, title = {Landscapes of missense variant impact for human superoxide dismutase 1.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060668}, issn = {2692-8205}, support = {R01 HL164675/HL/NHLBI NIH HHS/United States ; RM1 HG010461/HG/NHGRI NIH HHS/United States ; UM1 HG011989/HG/NHGRI NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease for which important subtypes are caused by variation in the Superoxide Dismutase 1 gene SOD1. Diagnosis based on SOD1 sequencing can not only be definitive but also indicate specific therapies available for SOD1-associated ALS (SOD1-ALS). Unfortunately, SOD1-ALS diagnosis is limited by the fact that a substantial fraction (currently 26%) of ClinVar SOD1 missense variants are classified as "variants of uncertain significance" (VUS). Although functional assays can provide strong evidence for clinical variant interpretation, SOD1 assay validation is challenging, given the current incomplete and controversial understanding of SOD1-ALS disease mechanism. Using saturation mutagenesis and multiplexed cell-based assays, we measured the functional impact of over two thousand SOD1 amino acid substitutions on both enzymatic function and protein abundance. The resulting 'missense variant effect maps' not only reflect prior biochemical knowledge of SOD1 but also provide sequence-structure-function insights. Importantly, our variant abundance assay can discriminate pathogenic missense variation and provides new evidence for 41% of missense variants that had been previously reported as VUS, offering the potential to identify additional patients who would benefit from therapy approved for SOD1-ALS.}, } @article {pmid40061966, year = {2025}, author = {Wang, H and Jiao, Y and Ma, Q and Liu, YH}, title = {Overview of endoscopic biliary stenting in malignant obstructive jaundice.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {2}, pages = {103378}, pmid = {40061966}, issn = {1948-9366}, abstract = {This article discusses Wang et al's essay. Endoscopic biliary stenting, a less invasive alternative to surgery, is effective for malignant obstructive jaundice. This article summarizes the pathophysiology of biliary obstruction, the technical aspects of stenting, and the clinical outcomes. By comparison of endoscopic stenting with percutaneous biliary drainage, improvements and complications are focused on. Additionally, patient selection for stenting and future advancements in stent technology are important. Overall, endoscopic biliary stenting is a valuable palliative option for patients with malignant jaundice, especially those ineligibles for surgery.}, } @article {pmid40061972, year = {2025}, author = {Yi, XM and Cai, HQ and Jiao, Y}, title = {Programmed cell death receptor 1 inhibitor Pembrolizumab in the treatment of advanced gastric cancer.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {2}, pages = {100257}, pmid = {40061972}, issn = {1948-9366}, abstract = {This editorial discusses Christodoulidis et al's article, which appeared in the most recent edition. The clinical trials have demonstrated the programmed cell death receptor 1 (PD-1) inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer (AGC). Pembrolizumab combined with chemotherapy can enhance its sensitivity, and further eliminate tumor cells that develop resistance to chemotherapy. The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis. The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy, and the safety is controllable. PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.}, } @article {pmid40061974, year = {2025}, author = {Zhang, ZN and Hao, L and Han, S and Li, SS and Lin, SX and Miao, YD}, title = {Harnessing the prognostic power of preoperative systemic immune-inflammation index/albumin ratio in hepatocellular carcinoma resection.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {2}, pages = {102261}, pmid = {40061974}, issn = {1948-9366}, abstract = {The recent study by Chen et al, published in the World Journal of Gastroenterology, introduces a groundbreaking assessment tool-the preoperative systemic immune-inflammation index/albumin (SII/ALB) ratio-for patients with hepatocellular carcinoma (HCC) undergoing curative resection. This study not only establishes the independent prognostic significance of the SII/ALB ratio but also incorporates it into a predictive nomogram, enhancing its utility for clinical decision-making. The SII/ALB ratio, by integrating inflammatory and nutritional biomarkers, offers a novel lens through which the prognosis of HCC patients can be viewed, suggesting a more tailored approach to patient management. The development of the nomogram, validated for its accuracy in predicting patient outcomes, marks a pivotal advance, potentially guiding surgical decisions and postoperative care. However, the study's focus on a single-center cohort prompts the need for validation in a broader, more diverse patient population to ensure its applicability across various clinical settings. Moreover, longitudinal studies could elucidate the dynamic changes in SII/ALB post-surgery, offering insights into its potential as a continuous monitor for recurrence and long-term survival. This abstract aim to underscore the critical findings of Chen et al's study while calling for further research to explore the full potential of the SII/ALB ratio in the global management of hepatocellular carcinoma.}, } @article {pmid40063831, year = {2025}, author = {Kubinski, S and Claus, L and Schüning, T and Zeug, A and Kalmbach, N and Staege, S and Gschwendtberger, T and Petri, S and Wegner, F and Claus, P and Hensel, N}, title = {Aggregates associated with amyotrophic lateral sclerosis sequester the actin-binding protein profilin 2.}, journal = {Human molecular genetics}, volume = {34}, number = {10}, pages = {882-893}, doi = {10.1093/hmg/ddaf020}, pmid = {40063831}, issn = {1460-2083}, support = {ZE994//Deutsche Forschungsgemeinschaft/ ; }, mesh = {*Profilins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; RNA-Binding Protein FUS/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Protein Aggregates ; Mutation ; Stress Granules/metabolism/genetics ; Motor Neurons/metabolism/pathology ; Actin Cytoskeleton/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Actins/metabolism/genetics ; Protein Aggregation, Pathological/genetics ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of upper and lower motoneurons. The four most frequently mutated genes causing familial ALS (fALS) are C9orf72, FUS, SOD1, and TARDBP. Some of the related wild-type proteins comprise intrinsically disordered regions (IDRs) which favor their assembly in liquid droplets-the biophysical mechanism behind the formation of physiological granules such as stress granules (SGs). SGs assemble and dissolve dependent on the cellular condition. However, it has been suggested that transition from reversible SGs to irreversible aggregates contributes to the toxic properties of ALS-related mutated proteins. Sequestration of additional proteins within these aggregates may then result in downstream toxicity. While the exact downstream mechanisms remain elusive, rare ALS-causing mutations in the actin binding protein profilin 1 suggest an involvement of the actin cytoskeleton. Here, we hypothesize that profilin isoforms become sequestered in aggregates of ALS-associated proteins which induce subsequent dysregulation of the actin cytoskeleton. Interestingly, localization of neuronal profilin 2 in SGs was more pronounced compared with the ubiquitously expressed profilin 1. Accordingly, FUS and C9orf72 aggregates prominently sequestered profilin 2 but not profilin 1. Moreover, we observed a distinct sequestration of profilin 2 and G-actin to C9orf72 aggregates in different cellular models. On the functional level, we identified dysregulated actin dynamics in cells with profilin 2-sequestering aggregates. In summary, our results suggest a more common involvement of profilins in ALS pathomechanisms than indicated from the rarely occurring profilin mutations.}, } @article {pmid40063887, year = {2025}, author = {Hayden, CD and Murphy, BP and Gilsenan, D and Nasseroleslami, B and Hardiman, O and Murray, D}, title = {Clinical validation of a novel hand dexterity measurement device.}, journal = {PLOS digital health}, volume = {4}, number = {3}, pages = {e0000744}, pmid = {40063887}, issn = {2767-3170}, abstract = {The lack of sensitive objective outcome measures for hand dexterity is a barrier for clinical assessment of neurological conditions and has negatively affected clinical trials. Here, we clinically validate a new method for measuring hand dexterity, a novel hand worn sensor that digitises the Finger Tapping Test. The device was assessed in a cohort of 180 healthy controls and 51 people with Amyotrophic Lateral Sclerosis (ALS) and compared against rating scales and traditional measures (Nine Hole Peg test and grip dynamometry). 14 features were extracted from the device and using a logistic regression algorithm, a 0-100 dexterity performance score was generated for each participant, which accounted for age/sex differences. The device returned objective ratings of a participant's hand dexterity (dominant, non-dominant and overall score). The average overall dexterity performance score in all healthy participants was 88 ± 17 (mean ± standard deviation). The overall dexterity score was statistically significantly worse in participants with ALS (age/sex matched healthy subset: 80 ± 20, ALS: 45 ± 32, p-value < 0.0001). The device also had a higher completion rate, (94% dominant hand) compared to the traditional measures (82% dominant hand). This test and scoring system have been validated and the regression model was developed using a framework that is potentially applicable to any relevant condition. This device could act as an objective outcome measure in clinical trials and may be useful in improving patient care.}, } @article {pmid40064491, year = {2025}, author = {Izumi, Y and Nakayama, Y}, title = {[Communicating the Diagnosis of Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {3}, pages = {259-263}, doi = {10.11477/mf.188160960770030259}, pmid = {40064491}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Humans ; *Communication ; }, abstract = {When explaining amyotrophic lateral sclerosis, family members, caregivers, and other professionals are encouraged to be present with the patient's consent. Patients' perceptions vary considerably depending on their condition, personality, and home environment; therefore, the content of the explanation should be carefully considered. If the patient did not fully understand or provide consent to participate, the explanation was repeated. Depending on the patient's level of understanding and acceptance, we provided step-by-step explanations. The patients were informed that the decision could change later, even after the treatment plan had been decided. In explanations involving a multidisciplinary team, each professional explains; however, it is also important for the team leader to understand the patient's perceptions.}, } @article {pmid40064496, year = {2025}, author = {Su, Y and Yang, F and Xie, JC and Zhang, C and Luo, RX and Li, WS and Liu, BL and Su, MZ}, title = {Electroacupuncture Neural Stimulation Mitigates Bladder Dysfunction and Mechanical Allodynia in Cyclophosphamide Induced Cystitis through Downregulation of the BDNF-TrkB Signaling Pathway.}, journal = {eNeuro}, volume = {12}, number = {3}, pages = {}, pmid = {40064496}, issn = {2373-2822}, mesh = {Animals ; *Electroacupuncture/methods ; Cyclophosphamide ; *Hyperalgesia/therapy/metabolism/physiopathology/etiology ; *Brain-Derived Neurotrophic Factor/metabolism ; Signal Transduction/physiology ; *Receptor, trkB/metabolism ; Female ; *Cystitis/chemically induced/therapy/metabolism/physiopathology ; Rats, Sprague-Dawley ; Down-Regulation ; Disease Models, Animal ; Rats ; *Urinary Bladder/physiopathology/metabolism ; *Membrane Glycoproteins/metabolism ; }, abstract = {Central sensitization plays a critical role in bladder pain syndrome/interstitial cystitis (BPS/IC). Electroacupuncture (EA) nerve stimulation therapy has been broadly acknowledged as an effective means of alleviating chronic pathological pain. However, it remains to be explored whether EA is effective in mitigating pain-sensitive symptoms of BPS/IC and the mechanisms involved. This study aims to investigate the analgesic effect and mechanism of EA therapy. To achieve this goal, we employed several techniques: mechanical pain threshold tests to assess pain sensitivity, urodynamic studies to evaluate bladder function, Western blotting (WB) for protein analysis, immunofluorescence for visualizing, and transcriptomics. A rat cystitis model was established through a systemic intraperitoneal injection with cyclophosphamide (CYP). EA therapy was executed by stimulating the deep part of the hypochondriac point, where the 2nd-4th sacral nerves traverse. EA treatment was observed to effectively reduce mechanical allodynia, enhance urinary function, suppress the activation of microglial cells, and alleviate neuroinflammation. Additionally, EA demonstrated the capability to downregulate BDNF-TrkB signal transduction in the spinal dorsal horn. Transcriptome sequencing has indicated that EA therapy potentially inhibits excitatory neural transmission and modulates several pathways related to longevity. Furthermore, EA therapy has shown efficacy in treating conditions such as Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. In conclusion, by regulating the BDNF-TrkB signaling, EA nerve stimulation can effectively alleviate bladder dysfunction and mechanical allodynia in cyclophosphamide-induced cystitis model. Our research elucidates the underlying mechanisms of EA therapy in treating bladder dysfunction and offers new theoretical insights for addressing painful sensitization in BPS.Significance Statement Central sensitization is a major factor in bladder pain syndrome/interstitial cystitis (BPS/IC), making effective pain management crucial. This study explores the potential of electroacupuncture (EA) as a therapeutic approach to alleviate pain and improve bladder function in a rat model of BPS/IC induced by cyclophosphamide. Our findings demonstrate that EA therapy significantly reduces mechanical allodynia, enhances urinary function, and decreases neuroinflammation by modulating BDNF-TrkB signaling in the spinal dorsal horn. The research highlights EA's capability to inhibit excitatory neural transmission and provide relief in chronic pain conditions. These results offer new insights into the mechanisms of EA therapy, potentially improving treatment strategies for BPS/IC and similar pain syndromes.}, } @article {pmid40065552, year = {2025}, author = {Shibata, N and Kataoka, I and Okamura, Y and Murakami, K and Kato, Y and Yamamoto, T and Masui, K}, title = {Implications for soluble iron accumulation, oxidative stress, and glial glutamate release in motor neuron death associated with sporadic amyotrophic lateral sclerosis.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {45}, number = {3}, pages = {177-201}, pmid = {40065552}, issn = {1440-1789}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Oxidative Stress/physiology ; *Iron/metabolism ; *Glutamic Acid/metabolism ; *Motor Neurons/metabolism/pathology ; Male ; Female ; Middle Aged ; Aged ; Spinal Cord/metabolism/pathology ; *Neuroglia/metabolism/pathology ; Cell Death/physiology ; Microglia/metabolism ; Animals ; Astrocytes/metabolism ; Aged, 80 and over ; }, abstract = {Oxidative stress in sporadic amyotrophic lateral sclerosis (ALS) has been evidenced by accumulation of oxidatively modified products of nucleic acids, lipids, sugars, and proteins in the motor neuron system of brains and spinal cords obtained at autopsy from the patients. We recently demonstrated soluble iron accumulation in activated microglia of sporadic ALS spinal cords. This finding could indicate that iron-mediated Fenton reaction is most likely to be responsible for oxidative stress associated with this disease. The excitatory amino acid neurotoxicity hypothesis for sporadic ALS has been proposed based on increased glutamate and aspartate concentrations in cerebrospinal fluid from the patients. Initially, the increase in extracellular excitatory amino acid levels was considered to reflect excessive release from the axon terminal of upper motor neurons. However, it is a question of whether the damaged upper motor neurons continue releasing glutamate even in advanced stage of this disease. To address this issue, we hypothesized that glial cells might be a glutamate release source. Our immunohistochemical analysis on autopsied human spinal cords revealed that ferritin, hepcidin, ferroportin, aconitase 1, tumor necrosis factor-α (TNF-α), TNF-α-converting enzyme (TACE), and glutaminase-C (GAC) were expressed mainly in microglia and that cystine/glutamate antiporter (xCT) was expressed mainly in astrocytes. We next performed cell culture experiments. Cultured microglia treated with soluble iron over-released glutamate and TNF-α via aconitase 1 and TACE, respectively. Cultured microglia treated with TNF-α over-released glutamate via GAC. Cultured microglia treated with hepcidin, of which expression is known to be upregulated by TNF-α, showed downregulated expression of ferroportin. Cultured astrocytes treated with hydrogen peroxide over-released glutamate via xCT. These observations provide in vivo and in vitro evidence that microglia and astrocytes are glutamate suppliers in response to soluble iron overload and oxidative stress, respectively, in sporadic ALS.}, } @article {pmid40065553, year = {2025}, author = {Boddy, SL and Simpson, RM and Walters, SJ and Walsh, T and McDermott, CJ and , and , }, title = {Further development of a patient-reported outcome measure to assess the impact of oral secretion problems in people living with MND.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {507-515}, doi = {10.1080/21678421.2025.2469721}, pmid = {40065553}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; *Patient Reported Outcome Measures ; Middle Aged ; Aged ; Reproducibility of Results ; *Saliva/metabolism ; Longitudinal Studies ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology ; Adult ; Surveys and Questionnaires ; }, abstract = {Objective: Oral secretion problems are common yet poorly managed in people living with MND (plwMND). A validated patient-reported outcome for measuring saliva symptoms in this patient group would facilitate better monitoring of individuals. This study aimed to assess the validity, reliability and sensitivity to change of a revised version of the clinical saliva score for MND (CSS-MNDr). Methods: Data were collected as part of a longitudinal, observational saliva management study. The CSS-MNDr, ALS Functional Rating Scale, a Global Rating of Change questionnaire and saliva-specific modified Likert scale were completed at each study visit, each of which probed the severity of saliva symptoms. Construct validity, test-retest reliability and sensitivity of the CSS-MNDr were assessed and the minimal important difference of the instrument was estimated. Results: The CSS-MNDr showed excellent test-retest reliability (intraclass correlation coefficient >0.9). Construct validity showed the CSS-MNDr performed as expected, with bulbar-onset participants scoring significantly higher than those who reported limb-onset across all visits (group mean scores). Strong correlation of total scores with the ALSFRS-R saliva question was demonstrated (-0.8), with the thick subscore correlating less well (-0.5). A minimal important difference in the range of -2.5 to -3.6 over 3 months was estimated for worsening symptoms. Conclusions: The CSS-MNDr has been validated as a reliable patient reported outcome for measuring saliva problems in plwMND. With separate scores for thick and thin secretion problems, the CSS-MNDr is the most comprehensive tool for assessing salivary problems in plwMND reported to date.}, } @article {pmid40065593, year = {2025}, author = {Chen, S and Carter, D and Prier, J and Bingham, J and Patel, S and Kotay, M and Brockenbrough, PB and Gwathmey, K}, title = {Racial Disparities in ALS Progression: Time to Clinical Events Observed in a Single Center.}, journal = {Muscle & nerve}, volume = {71}, number = {6}, pages = {1086-1090}, pmid = {40065593}, issn = {1097-4598}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/ethnology/diagnosis/therapy ; Black or African American ; Disease Progression ; *Healthcare Disparities/ethnology ; Noninvasive Ventilation/statistics & numerical data ; Retrospective Studies ; Wheelchairs ; White ; }, abstract = {INTRODUCTION/AIMS: Studies examining racial differences in ALS have previously focused on diagnostic delay and disease severity. Time to critical clinical events has rarely been investigated, despite its importance in revealing differences in ALS patients' disease courses. This study explores racial disparities in time to specific clinical events in Black and non-Hispanic White ALS patients at a single center.

METHODS: We performed a retrospective analysis of 33 Black and 170 non-Hispanic White ALS patients examined at Virginia Commonwealth University between 2017 and 2023. Diagnosis dates, referral dates for wheelchair, noninvasive ventilation (NIV), augmentative and alternative communication (AAC) and hospice, along with demographic and clinical factors, were collected. We analyzed the racial difference for events occurring before or on the day of diagnosis using logistic regression models, and for events occurring after diagnosis using Cox proportional hazard models, adjusting for relevant demographic and clinical factors.

RESULTS: Black patients had significantly higher odds of acquiring a wheelchair (odds ratio = 4.06, p = 0.015) and NIV before diagnosis (odds ratio = 2.93, p = 0.017). Following diagnosis, Black patients had 1.72 times the hazards for wheelchair referral (p = 0.051), 2.17 times the hazard for NIV referral (p < 0.001), 1.84 times the hazard for AAC referral (p = 0.034), and 1.59 times the hazard for hospice referral (p = 0.24).

DISCUSSION: Our single-center findings demonstrate a large racial difference in time to clinical events for Black versus White ALS patients referred for NIV, AAC, hospice, and wheelchair, suggesting more advanced disease at the time of presentation or more rapid progression.}, } @article {pmid40066150, year = {2025}, author = {Stains, EL and Kennalley, AL and Tian, M and Boehnke, KF and Kraus, CK and Piper, BJ}, title = {Medical Cannabis in the United States: Comparing 2017 and 2024 State Qualifying Conditions to the 2017 National Academies of Sciences Report.}, journal = {Mayo Clinic proceedings. Innovations, quality & outcomes}, volume = {9}, number = {2}, pages = {100590}, pmid = {40066150}, issn = {2542-4548}, abstract = {OBJECTIVE: To compare the 2017 National Academies of Sciences, Engineering, and Medicine cannabis report to state medical cannabis (MC) laws defining approved qualifying conditions (QC) from 2017 and 2024 and to determine the evidence level of the QCs approved in each state.

PATIENTS AND METHODS: The 2017 National Academies of Sciences (NAS) report assessed therapeutic evidence for over 20 medical conditions treated with MC. We identified the QCs of 38 states (including Washington DC) where MC was legal in 2024 and compared them to the QCs listed by these states in 2017. The QCs were then categorized on the basis of NAS-established levels of evidence: limited, moderate, or substantial/conclusive evidence of effectiveness, limited evidence of ineffectiveness, or no/insufficient evidence to support or refute effectiveness. This study was completed from January 31, 2023 to June 20, 2024.

RESULTS: Most states listed at least one QC with substantial evidence-80.0% in 2017 and 97.0% in 2024. However, in 2024 only 8.3% of the QCs on states' QC lists met the standard of substantial/conclusive evidence. Of the 20 most popular QCs in the country in 2017 and 2024, one only (long-term pain) was categorized by the NAS as having substantial evidence for effectiveness. However, 7 were rated as either ineffective (eg, glaucoma) or insufficient evidence.

CONCLUSION: Most QCs lack evidence for use on the basis of the 2017 NAS report. Many states recommend QCs with little evidence (amyotrophic lateral sclerosis) or even those for which MC is ineffective (depression). These findings highlight a disparity between state-level MC recommendations and the evidence to support them.}, } @article {pmid40067754, year = {2025}, author = {, and Andrews, J and Paganoni, S and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Young, E and Chase, M and Pothier, L and Harkey, B and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Connolly, MR and Berry, JD and D'Agostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Heitzman, D and Ajroud-Driss, S and Appel, SH and Shroff, S and Katz, J and Felice, K and Maragakis, NJ and Simmons, Z and Goutman, SA and Olney, N and Miller, T and Fernandes, JA and Ilieva, H and Jawdat, O and Weiss, MD and Foster, L and Vu, T and Ladha, S and Owegi, MA and Newman, DS and Arcila-Londono, X and Jackson, CE and Swenson, A and Heiman-Patterson, T and Caress, J and Fee, D and Peltier, A and Lewis, R and Rosenfeld, J and Walk, D and Johnson, K and Elliott, M and Kasarskis, EJ and Rutkove, S and McIlduff, CE and Bedlack, R and Elman, L and Goyal, NA and Rezania, K and Twydell, P and Benatar, M and Glass, J and Cohen, JA and Jones, V and Zilliox, L and Wymer, JP and Beydoun, SR and Shah, J and Pattee, GL and Martinez-Thompson, J and Nayar, S and Granit, V and Donohue, M and Grossman, K and Campbell, DJ and Qureshi, IA and Cudkowicz, ME and Babu, S}, title = {Verdiperstat in Amyotrophic Lateral Sclerosis: Results From the Randomized HEALEY ALS Platform Trial.}, journal = {JAMA neurology}, volume = {82}, number = {4}, pages = {333-343}, pmid = {40067754}, issn = {2168-6157}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; *Enzyme Inhibitors/therapeutic use ; Treatment Outcome ; }, abstract = {IMPORTANCE: Myeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.

OBJECTIVE: To determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.

Verdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.

INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale-Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.

RESULTS: A total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, -23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.

CONCLUSIONS AND RELEVANCE: Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.

TRIAL REGISTRATION: Clinical Trial Identifiers: NCT04297683 and NCT04436510.}, } @article {pmid40067755, year = {2025}, author = {, and Shefner, JM and Oskarsson, B and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Heiman-Patterson, T and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Caress, JB and Swenson, A and Peltier, A and Lewis, RA and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Leitner, ML and Chen, K and Goldberg, YP and Cohen, Y and Geva, M and Hayden, MR and Paganoni, S and Cudkowicz, ME and , }, title = {Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.}, journal = {JAMA}, volume = {333}, number = {13}, pages = {1128-1137}, pmid = {40067755}, issn = {1538-3598}, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.

OBJECTIVE: To determine the effects of pridopidine, a σ1-receptor agonist, in ALS.

Pridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.

INTERVENTIONS: Eligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.

RESULTS: Among 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).

CONCLUSIONS AND RELEVANCE: In this 24-week study, pridopidine did not impact the progression of ALS.

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04615923.}, } @article {pmid40067821, year = {2025}, author = {, and Berry, JD and Maragakis, NJ and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Stommel, EW and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, KJ and Simmons, Z and Miller, T and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, L and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, C and Ladha, S and Heiman-Patterson, T and Caress, J and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, CE and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Rynders, A and Evan, J and Evan, J and Hartford, A and Sepassi, M and Ho, KS and Glanzman, R and Greenberg, B and Hotchkin, MT and Paganoni, S and Cudkowicz, ME and , }, title = {CNM-Au8 in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.}, journal = {JAMA}, volume = {333}, number = {13}, pages = {1138-1149}, pmid = {40067821}, issn = {1538-3598}, support = {U24 NS095871/NS/NINDS NIH HHS/United States ; }, abstract = {IMPORTANCE: Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD+, resulting in an increase of cellular adenosine triphosphate production.

OBJECTIVE: To determine the effects of CNM-Au8 on ALS disease progression.

CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses.

INTERVENTIONS: Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation.

RESULTS: Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]).

CONCLUSIONS AND RELEVANCE: No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks.

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04414345.}, } @article {pmid40067829, year = {2025}, author = {O'Neill, K and Shaw, R and Bolger, I and , and Tam, OH and Phatnani, H and Gale Hammell, M}, title = {ALS molecular subtypes are a combination of cellular and pathological features learned by deep multiomics classifiers.}, journal = {Cell reports}, volume = {44}, number = {3}, pages = {115402}, pmid = {40067829}, issn = {2211-1247}, support = {R01 NS116350/NS/NINDS NIH HHS/United States ; T32 GM065094/GM/NIGMS NIH HHS/United States ; RF1 NS118570/NS/NINDS NIH HHS/United States ; R01 NS118570/NS/NINDS NIH HHS/United States ; P30 CA045508/CA/NCI NIH HHS/United States ; R01 NS118183/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/classification ; Humans ; Transcriptome/genetics ; Neuroglia/metabolism/pathology ; Spinal Cord/pathology/metabolism ; Neurons/metabolism/pathology ; Male ; *Genomics/methods ; Female ; Microglia/metabolism/pathology ; Multiomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this heterogeneity, large-scale genomics studies revealed that ALS postmortem samples can be grouped into a small number of subtypes, defined by transcriptomic signatures of mitochondrial dysfunction and oxidative stress (ALS-Ox), microglial activation and neuroinflammation (ALS-Glia), or TDP-43 pathology and associated transposable elements (ALS-TE). In this study, we present a deep ALS neural net classifier (DANCer) for ALS molecular subtypes. Applying DANCer to an expanded cohort from the NYGC ALS Consortium highlights two subtypes that strongly correlate with disease duration: ALS-TE in cortex and ALS-Glia in spinal cord. Finally, single-nucleus transcriptomes demonstrate that ALS subtypes are recapitulated in neurons and glia, with both ALS-wide and subtype-specific alterations in all cell types. In summary, ALS molecular subtypes represent a combination of cellular and pathological features that correlate with clinical features of ALS.}, } @article {pmid40069360, year = {2025}, author = {Cheng, M and Lu, D and Li, K and Wang, Y and Tong, X and Qi, X and Yan, C and Ji, K and Wang, J and Wang, W and Lv, H and Zhang, X and Kong, W and Zhang, J and Ma, J and Li, K and Wang, Y and Feng, J and Wei, P and Li, Q and Shen, C and Fu, XD and Ma, Y and Zhang, X}, title = {Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {748-756}, pmid = {40069360}, issn = {1546-1726}, support = {2019YFA0508701//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; 2022YFA1303300//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Animals ; Rats ; Motor Neurons/metabolism/pathology ; *Electron Transport Complex IV/genetics ; *Mitochondria/metabolism/genetics ; Humans ; Disease Models, Animal ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is categorized into ~10% familial and ~90% sporadic cases. While familial ALS is caused by mutations in many genes of diverse functions, the underlying pathogenic mechanisms of ALS, especially in sporadic ALS (sALS), are largely unknown. Notably, about half of the cases with sALS showed defects in mitochondrial respiratory complex IV (CIV). To determine the causal role of this defect in ALS, we used transcription activator-like effector-based mitochondrial genome editing to introduce mutations in CIV subunits in rat neurons. Our results demonstrate that neuronal CIV deficiency is sufficient to cause a number of ALS-like phenotypes, including cytosolic TAR DNA-binding protein 43 redistribution, selective motor neuron loss and paralysis. These results highlight CIV deficiency as a potential cause of sALS and shed light on the specific vulnerability of motor neurons, marking an important advance in understanding and therapeutic development of sALS.}, } @article {pmid40069809, year = {2025}, author = {Jonsdottir, G and Vilhjalmsson, R and Sigurdardottir, V and Hjaltason, H and Klinke, ME and Jonsdottir, H}, title = {Nursing contribution to end-of-life care decision-making in patients with neurological diseases on an acute hospital ward: documentation of signs and symptoms.}, journal = {BMC nursing}, volume = {24}, number = {1}, pages = {271}, pmid = {40069809}, issn = {1472-6955}, support = {71545//Icelandic Nurses Association/ ; }, abstract = {BACKGROUND: Recognizing impending death in patients with neurological diseases presents challenges for nurses and other healthcare professionals. This study aimed to identify nursing contribution to end-of-life (EOL) care decision-making for patients with neurological diseases in an acute hospital ward and to compare signs and symptoms among subgroups of patients.

METHODS: In this retrospective study, we analyzed data from 209 patient health records using the Neurological End-Of-Life Care Assessment Tool to evaluate the care in the last 3 to 7 days of life. Key aspects included the need for EOL care, EOL care decision-making, signs and symptoms of imminent death, and communication with relatives. The patient records pertain to patients who died in an acute neurological ward between January 2011 and August 2020; 123 with ischemic stroke, 48 with hemorrhagic stroke, 27 with amyotrophic lateral sclerosis [ALS], and 11 with Parkinson's disease or extrapyramidal and movement disorders [PDoed]. Both descriptive and inferential statistical analyses were performed to analyze the data.

RESULTS: Nurses identified the need for EOL care in 36% of cases and contributed to EOL decision-making as information brokers (15%), advocates (6%), and supporters (6%). They identified disease progression in 44% of the cases. The mean number of signs and symptoms in both the acute and progressive disease groups was 6.5 and ranged from 1 to 14. Patients with stroke without a documented EOL decision had more severe symptoms, including respiratory congestion (68%) and dyspnea (37%), than those with EOL decision. A higher frequency of no food intake was documented in patients with stroke receiving EOL care (p = 0.007) compared to those without. Among patients with ALS or PDoed, those with EOL decision showed a trend toward a higher frequency of unconsciousness or limited consciousness than those without EOL decision (p = 0.067). For all groups of patients, conversations with relatives occurred in 85% instances and family meetings in 93%.

CONCLUSIONS: Nurses made substantial contributions to EOL care decision-making for patients with neurological diseases. To improve early identification of imminent death in patients with neurological diseases in acute hospital wards, healthcare professionals must investigate barriers contributing to delayed recognition.

CLINICAL TRIAL NUMBER: Not applicable.}, } @article {pmid40069959, year = {2025}, author = {Chiò, A and Foucher, J and Gwathmey, KG and Ingre, C}, title = {Minimum clinically important difference for drug effectiveness in an area of patient-oriented therapeutic goals in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {389-398}, doi = {10.1080/21678421.2025.2475893}, pmid = {40069959}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/diagnosis ; Humans ; *Minimal Clinically Important Difference ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Quality of Life ; }, abstract = {Objective: In this review, we will examine the more common endpoints incorporated in randomized controlled trials (RCTs) and their strength of evidence, focusing on the definition of what constitutes a clinically meaningful change. We will also reflect on the perspective of patients and their families regarding the design of RCTs in amyotrophic lateral sclerosis (ALS). Methods: Authors performed a scoping review of the literature around clinical meaningfulness in the ALS field and the minimum clinically important difference to deem a treatment effective. Results: The use of survival as an RCT endpoint, as well as the ALS functional rating scale-revised slope, has been criticized, and their relevance for patients remains debated. Biomarkers are promising alternatives as surrogate endpoints, but currently, only cerebrospinal fluid and plasma neurofilaments have emerged as reliable and sensitive biomarkers of disease progression. Incorporating patients' preferences and priorities for their care when treatments are selected is important to minimize the burden of care and limit the potential harms of overtreatment. Patients' interest in and acceptance of a new therapy is also determined by its impact on their quality of life. Discussion and conclusion: While scientifically sound trials must be conducted, this must be balanced with patient expectations of limiting trial burden, duration and placebo usage. An important approach in uniting these diverging needs is the inclusion of people with ALS and their organizations to advise in the design and execution of clinical trials, facilitating the design of RCTs more focused on patients' expectations while retaining a high scientific rigor.}, } @article {pmid40070688, year = {2025}, author = {Hosseini Faradonbeh, SM and Seyedalipour, B and Keivan Behjou, N and Rezaei, K and Baziyar, P and Hosseinkhani, S}, title = {Structural insights into SOD1: from in silico and molecular dynamics to experimental analyses of ALS-associated E49K and R115G mutants.}, journal = {Frontiers in molecular biosciences}, volume = {12}, number = {}, pages = {1532375}, pmid = {40070688}, issn = {2296-889X}, abstract = {Protein stability is a crucial characteristic that influences both protein activity and structure and plays a significant role in several diseases. Cu/Zn superoxide dismutase 1 (SOD1) mutations serve as a model for elucidating the destabilizing effects on protein folding and misfolding linked to the lethal neurological disease, amyotrophic lateral sclerosis (ALS). In the present study, we have examined the structure and dynamics of the SOD1 protein upon two ALS-associated point mutations at the surface (namely, E49K and R115G), which are located in metal-binding loop IV and Greek key loop VI, respectively. Our analysis was performed through multiple algorithms on the structural characterization of the hSOD1 protein using computational predictions, molecular dynamics (MD) simulations, and experimental studies to understand the effects of amino acid substitutions. Predictive results of computational analysis predicted the deleterious and destabilizing effect of mutants on hSOD1 function and stability. MD outcomes also indicate that the mutations result in structural destabilization by affecting the increased content of β-sheet structures and loss of hydrogen bonds. Moreover, comparative intrinsic and extrinsic fluorescence results of WT-hSOD1 and mutants indicated structural alterations and increased hydrophobic surface pockets, respectively. As well, the existence of β-sheet-dominated structures was observed under amyloidogenic conditions using FTIR spectroscopy. Overall, our findings suggest that mutations in the metal-binding loop IV and Greek key loop VI lead to significant structural and conformational changes that could affect the structure and stability of the hSOD1 molecule, resulting in the formation of toxic intermediate species that cause ALS.}, } @article {pmid40072076, year = {2025}, author = {Calvo, B and Schembri-Wismayer, P and Durán-Alonso, MB}, title = {Age-Related Neurodegenerative Diseases: A Stem Cell's Perspective.}, journal = {Cells}, volume = {14}, number = {5}, pages = {}, pmid = {40072076}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/therapy ; *Aging/pathology ; *Stem Cells/metabolism ; Animals ; }, abstract = {Neurodegenerative diseases encompass a number of very heterogeneous disorders, primarily characterized by neuronal loss and a concomitant decline in neurological function. Examples of this type of clinical condition are Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis. Age has been identified as a major risk in the etiology of these disorders, which explains their increased incidence in developed countries. Unfortunately, despite continued and intensive efforts, no cure has yet been found for any of these diseases; reliable markers that allow for an early diagnosis of the disease and the identification of key molecular events leading to disease onset and progression are lacking. Altered adult neurogenesis appears to precede the appearance of severe symptoms. Given the scarcity of human samples and the considerable differences with model species, increasingly complex human stem-cell-based models are being developed. These are shedding light on the molecular alterations that contribute to disease development, facilitating the identification of new clinical targets and providing a screening platform for the testing of candidate drugs. Moreover, the secretome and other promising features of these cell types are being explored, to use them as replacement cells of high plasticity or as co-adjuvant therapy in combinatorial treatments.}, } @article {pmid40072375, year = {2025}, author = {Gong, Z and Ba, L and Li, Z and Hou, H and Zhang, M}, title = {Cd16[-]Cd56[bright] NK Cells: A Protective NK Cell Subset for Progression and Prognosis in Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {17}, number = {1}, pages = {405-415}, pmid = {40072375}, issn = {2152-5250}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/diagnosis ; *Killer Cells, Natural/immunology ; Male ; Female ; Middle Aged ; Disease Progression ; *CD56 Antigen/immunology/metabolism ; Prognosis ; *Receptors, IgG/metabolism/immunology ; Aged ; Adult ; *Lymphocyte Subsets/immunology ; Case-Control Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a non-neuron-autonomous disease where peripheral immune dysregulation significantly impacts disease progression. However, the immunopathological mechanisms of natural killer (NK) cells in ALS remain largely unexplored. This study enrolled 241 ALS patients and 102 healthy controls (HC), analyzing lymphocyte subsets, including T cells, B cells, and NK cells. A sub-cohort of 81 ALS patients was followed up for one year at three-month intervals. Linear mixed and Cox proportional hazards models were used to evaluate the association between lymphocyte subsets and ALS progression and prognosis. Our results revealed significant reductions in total T cells, helper T cells (Th), and NK cells in ALS patients compared to HC (P < 0.05). Slow-progressing ALS patients exhibited higher counts of total T cells, Th, Cd16[-]Cd56[bright] NK cells, and Cd16[+]Cd56[bright] NK cells, while showing lower counts of Cd16[+]Cd56[dim] NK cells compared to fast-progressing ALS patients (P < 0.05). ALS patients with lower Cd16[-]Cd56[bright] NK cell counts experienced a faster decline in motor function than those with higher counts (P < 0.05). Elevated Cd16[-]Cd56[bright] NK cell counts were associated with improved ALS prognosis (HR, 0.73; 95% CI: 0.60-0.90; P < 0.05). This study suggests that Cd16[-]Cd56[bright] NK cells play a protective role in ALS progression and prognosis, offering a potential therapeutic target for ALS.}, } @article {pmid40073394, year = {2025}, author = {Janes, WE and Marchal, N and Song, X and Popescu, M and Mosa, ASM and Earwood, JH and Jones, V and Skubic, M}, title = {Integrating Ambient In-Home Sensor Data and Electronic Health Record Data for the Prediction of Outcomes in Amyotrophic Lateral Sclerosis: Protocol for an Exploratory Feasibility Study.}, journal = {JMIR research protocols}, volume = {14}, number = {}, pages = {e60437}, pmid = {40073394}, issn = {1929-0748}, support = {W81XWH-22-1-0491//Department of Defense/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Electronic Health Records ; Feasibility Studies ; Machine Learning ; Algorithms ; *Monitoring, Ambulatory/methods/instrumentation ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) leads to rapid physiological and functional decline before causing untimely death. Current best-practice approaches to interdisciplinary care are unable to provide adequate monitoring of patients' health. Passive in-home sensor systems enable 24×7 health monitoring. Combining sensor data with outcomes extracted from the electronic health record (EHR) through a supervised machine learning algorithm may enable health care providers to predict and ultimately slow decline among people living with ALS.

OBJECTIVE: This study aims to describe a federated approach to assimilating sensor and EHR data in a machine learning algorithm to predict decline among people living with ALS.

METHODS: Sensor systems have been continuously deployed in the homes of 4 participants for up to 330 days. Sensors include bed, gait, and motion sensors. Sensor data are subjected to a multidimensional streaming clustering algorithm to detect changes in health status. Specific health outcomes are identified in the EHR and extracted via the REDCap (Research Electronic Data Capture; Vanderbilt University) Fast Healthcare Interoperability Resource directly into a secure database.

RESULTS: As of this writing (fall 2024), machine learning algorithms are currently in development to predict those health outcomes from sensor-detected changes in health status. This methodology paper presents preliminary results from one participant as a proof of concept. The participant experienced several notable changes in activity, fluctuations in heart rate and respiration rate, and reductions in gait speed. Data collection will continue through 2025 with a growing sample.

CONCLUSIONS: The system described in this paper enables tracking the health status of people living with ALS at unprecedented levels of granularity. Combined with tightly integrated EHR data, we anticipate building predictive models that can identify opportunities for health care services before adverse events occur. We anticipate that this system will improve and extend the lives of people living with ALS.

DERR1-10.2196/60437.}, } @article {pmid40073860, year = {2025}, author = {Zhang, Z and Fu, X and Wright, N and Wang, W and Ye, Y and Asbury, J and Li, Y and Zhu, C and Wu, R and Wang, S and Sun, S}, title = {PTPσ-mediated PI3P regulation modulates neurodegeneration in C9ORF72-ALS/FTD.}, journal = {Neuron}, volume = {113}, number = {8}, pages = {1190-1205.e9}, pmid = {40073860}, issn = {1097-4199}, support = {R01 AG078948/AG/NIA NIH HHS/United States ; R21 AG072078/AG/NIA NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *C9orf72 Protein/genetics/metabolism ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; Neurons/metabolism/pathology ; Lysosomes/metabolism ; *Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism/genetics/antagonists & inhibitors ; *Phosphatidylinositol Phosphates/metabolism ; Endosomes/metabolism ; }, abstract = {The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the repeat expansion in C9ORF72. Dipeptide repeat (DPR) proteins translated from both sense and antisense repeats, especially arginine-rich DPRs (R-DPRs), contribute to neurodegeneration. Through CRISPR interference (CRISPRi) screening in human-derived neurons, we identified receptor-type tyrosine-protein phosphatase S (PTPσ) as a strong modifier of poly-GR-mediated toxicity. We showed that reducing PTPσ promotes the survival of both poly-GR- and poly-PR-expressing neurons by elevating phosphatidylinositol 3-phosphate (PI3P), accompanied by restored early endosomes and lysosomes. Remarkably, PTPσ knockdown or inhibition substantially rescues the PI3P-endolysosomal defects and improves the survival of C9ORF72-ALS/FTD patient-derived neurons. Furthermore, the PTPσ inhibitor diminishes GR toxicity and rescues pathological and behavioral phenotypes in mice. Overall, these findings emphasize the critical role of PI3P-mediated endolysosomal deficits induced by R-DPRs in disease pathogenesis and reveal the therapeutic potential of targeting PTPσ in C9ORF72-ALS/FTD.}, } @article {pmid40074390, year = {2025}, author = {Cappa, SF}, title = {Hemispheric asymmetry in neurodegenerative diseases.}, journal = {Handbook of clinical neurology}, volume = {208}, number = {}, pages = {101-112}, doi = {10.1016/B978-0-443-15646-5.00009-9}, pmid = {40074390}, issn = {0072-9752}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/physiopathology ; *Functional Laterality/physiology ; *Brain/pathology ; }, abstract = {Hemispheric asymmetry in pathologic involvement is frequently observed in neurodegenerative disorders (NDD) and is responsible for differences in cognitive and motor clinical manifestations in individual patients. While asymmetry is modest in typical Alzheimer disease (AD), atypical AD presentations with prominent language impairment [logopenic/phonologic variant of primary progressive aphasia (L/Phv-PPA)] are associated with prevalent involvement of the language-dominant hemisphere. Similarly, in the frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum, the semantic (Sv) and nonfluent/agrammatic (Nf/Av) variants of PPA are due to asymmetric pathology involving the language-dominant hemisphere. A reversed (typically right-sided) pattern of asymmetry is often found in conditions associated with prominent disorders of behavior and social cognition (i.e., behavioral variant of frontotemporal degeneration-Bv FTD). Asymmetry is generally modest and less consistent in NDD with prevalent motor manifestations, such as Parkinson disease (PD). Overall, the pattern of hemispheric involvement reflects the network-specific selectivity of NDD and is compatible with the spreading of pathology along connection pathways.}, } @article {pmid40074537, year = {2025}, author = {Mkhize, L and Marimani, M and Duze, ST}, title = {Characterization of Vibrio cholerae from the Jukskei River in Johannesburg, South Africa.}, journal = {Letters in applied microbiology}, volume = {78}, number = {3}, pages = {}, doi = {10.1093/lambio/ovaf036}, pmid = {40074537}, issn = {1472-765X}, support = {138279//National Research Foundation/ ; RKSST23//Carnegie DTA/ ; }, mesh = {South Africa ; *Rivers/microbiology ; *Vibrio cholerae/genetics/isolation & purification/classification/drug effects/pathogenicity ; Virulence Factors/genetics ; Bacterial Proteins/genetics ; Cholera/microbiology ; Drug Resistance, Bacterial/genetics ; }, abstract = {The current study aimed to isolate and characterize Vibrio cholerae isolated from the Jukskei River, one of the largest Rivers in Johannesburg, South Africa. Water samples collected from the Jukskei River were subjected to culture-based methods for the detection and isolation of V. cholerae. Twenty-four V. cholerae were isolated, confirmed using real-time PCR, and sequenced using the MInION portable nanopore-sequencing device. Reference-based genome assemblies were constructed from the raw reads using the EPI2ME software followed by bioinformatics analysis using the Centre for Genomic Epidemiology website. All the V. cholerae isolates isolated from the Jukskei River were classified as non-O1/non-O139 and none of the isolates harbored the cholera toxin gene, ctxA. All 24 V. cholerae isolates belonged to sequence type 741, virulent genes including toxR, vspD, als, hlyA, makA, and rtxA as well as the Vibrio pathogenicity island 2 were detected amongst the isolates. Antimicrobial resistance genes (parC, varG, and gyrA) were detected in 83% of isolates. Although V. cholerae non-O1/non-O139 are not associated with epidemic cholera they can still cause mild to life-threatening illnesses. Therefore, increased surveillance should be considered to better understand the public health risks to the local community.}, } @article {pmid40074931, year = {2025}, author = {Michielsen, A and van Veenhuijzen, K and Hiemstra, F and Jansen, IM and Kalkhoven, B and Veldink, JH and Kruitwagen, ET and van Es, M and van Zandvoort, MJE and van den Berg, LH and Westeneng, HJ}, title = {Cognitive impairment within and beyond the FTD spectrum in ALS: development of a complementary cognitive screen.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {268}, pmid = {40074931}, issn = {1432-1459}, support = {grant agreement no 772376- EScORIAL//H2020 European Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology/diagnosis ; Male ; Female ; *Frontotemporal Dementia/diagnosis/complications/psychology ; Middle Aged ; *Cognitive Dysfunction/diagnosis/etiology ; Aged ; *Neuropsychological Tests ; Adult ; }, abstract = {OBJECTIVE: To investigate cognitive impairments in amyotrophic lateral sclerosis (ALS), extending both within and beyond the established frontotemporal dementia (FTD) spectrum, using the Complementary Cognitive ALS Screen (C-CAS).

METHODS: The C-CAS, designed to complement the Edinburgh cognitive and behavioural ALS screen (ECAS), explores cognitive (sub)domains not investigated by the ECAS. Normative data were collected, and models adjusted for age, sex, and education level were developed. Item scores below the 5th percentile in controls were considered abnormal. A sum score was constructed, and C-CAS impairments were compared between ALS patients and controls, and to ECAS impairments.

RESULTS: Data from 314 controls and 184 ALS patients were analyzed. The C-CAS is feasible, well-tolerated, and takes 15-20 min to complete. ALS patients performed worse across all 12 items. Within the FTD spectrum, impairments in social cognition, inhibition, and cognitive flexibility were identified in up to 16%, 14%, and 12% of ALS patients, respectively, with minimal overlap with ECAS impairments. Beyond the FTD spectrum, impairments were found in visuoconstruction, incidental non-verbal memory and body orientation (13% each), with minimal overlap with ECAS memory or visuospatial impairments. Overall, 24% of the ALS patients obtained an abnormal C-CAS sum score. Compared to the ECAS, the C-CAS detected additional impairments in 15% of ALS patients. Item-specific and sum score results based on normative data can be accessed at (https://apps4mnd.com/ccas/).

INTERPRETATION: We identified cognitive impairments in ALS within and beyond the FTD spectrum not captured by existing screening tools. The C-CAS complements the ECAS, improving personalized counseling and research stratification in ALS.}, } @article {pmid40075110, year = {2025}, author = {Raas, Q and Haouy, G and de Calbiac, H and Pasho, E and Marian, A and Guerrera, IC and Rosello, M and Oeckl, P and Del Bene, F and Catanese, A and Ciura, S and Kabashi, E}, title = {TBK1 is involved in programmed cell death and ALS-related pathways in novel zebrafish models.}, journal = {Cell death discovery}, volume = {11}, number = {1}, pages = {98}, pmid = {40075110}, issn = {2058-7716}, support = {682622//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; }, abstract = {Pathogenic mutations within the TBK1 gene leading to haploinsufficiency are causative of amyotrophic lateral sclerosis (ALS). This gene is linked to autophagy and inflammation, two cellular mechanisms reported to be dysregulated in ALS patients, although its functional role in the pathogenesis could involve other players. We targeted the TBK1 ortholog in zebrafish, an optimal vertebrate model for investigating genetic defects in neurological disorders. We generated zebrafish models with invalidating tbk1 mutations using CRISPR-Cas9 or tbk1 knockdown models using antisense morpholino oligonucleotide (AMO). The early motor phenotype of zebrafish injected with tbk1 AMO beginning at 2 days post fertilization (dpf) is associated with the degeneration of motor neurons. In parallel, CRISPR-induced tbk1 mutants exhibit impaired motor function beginning at 5 dpf and increased lethality beginning at 9 dpf. A metabolomic analysis showed an association between tbk1 loss and severe dysregulation of nicotinamide metabolism, and incubation with nicotinamide riboside rescued the motor behavior of tbk1 mutant zebrafish. Furthermore, a proteomic analysis revealed increased levels of inflammatory markers and dysregulation of programmed cell death pathways. Necroptosis appeared to be strongly activated in TBK1 fish, and larvae treated with the necroptosis inhibitor necrosulfonamide exhibited improved survival. Finally, a combined analysis of mutant zebrafish and TBK1-mutant human motor neurons revealed dysregulation of the KEGG pathway "ALS", with disrupted nuclear-cytoplasmic transport and increased expression of STAT1. These findings point toward a major role for necroptosis in the degenerative features and premature lethality observed in tbk1 mutant zebrafish. Overall, the novel tbk1-deficient zebrafish models offer a great opportunity to better understand the cascade of events leading from the loss of tbk1 expression to the onset of motor deficits, with involvement of a metabolic defect and increased cell death, and for the development of novel therapeutic avenues for ALS and related neuromuscular diseases.}, } @article {pmid40075315, year = {2025}, author = {Soliman, R and Fahmy, N and Swelam, MS}, title = {Headache types and characteristics in patients with Amyotrophic Lateral Sclerosis.}, journal = {The journal of headache and pain}, volume = {26}, number = {1}, pages = {53}, pmid = {40075315}, issn = {1129-2377}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/epidemiology/physiopathology ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; Adult ; Aged ; *Migraine Disorders/etiology/epidemiology/physiopathology ; *Tension-Type Headache/etiology/epidemiology/physiopathology ; *Headache Disorders, Primary/etiology/physiopathology/epidemiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive loss of motor neurons, this result in muscle denervation, atrophy and consequently death takes place due to respiratory failure within 3-5 years of onset of symptoms.

OUR AIM: Was to investigate types and frequency of headache in ALS patients.

METHODS: This is cross sectional hospital based study. Clinically definite 100 ALS Patients (diagnosed according to El Escorial revised criteria) were recruited out of 137 ALS patients presented to the Neuromuscular Clinic in Ain Shams university Hospital from February 2022 to June 2024. Patients were screened for headache types and symptoms diagnosed according to International Headache Society criteria (IHS). Headache severity and impact were assessed using Arabic versions of Headache Impact Test (HIT) and Migraine Disability Assessment (MIDAS). Depression was also assessed via Arabic version of Beck's Depression Inventory (BDI). ALS symptoms severity was assessed via Arabic version of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). Cognitive functions were assessed via the Egyptian version of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS‑EG). Demographic data and ALS related parameters were collected.

RESULTS: Among 100 patients with clinically definite ALS, 79 patients reported headaches, 62 of them had primary headaches; with tension-type headache being the most commonly reported in 46 patients, Migraine in 16 patients. Fifteen ALS patients had secondary headaches; among them 12 had headache secondary to respiratory insufficiency and 3 patients developed headache after the initiation of Riluzole therapy. Two patients had non specific headache. Mean age for the patients at ALS presentation was 43.9 ± 13.8, Mean ALSFRS-R score 33.3 ± 9.04. The relationships between headache and clinical features of ALS were also investigated.

IN CONCLUSION: ALS patients should be evaluated for Headache; Not only headache secondary to respiratory compromise and hypercapnea, but also primary headaches which can be overlooked in patients with ALS.}, } @article {pmid40075757, year = {2025}, author = {Rizzo, GEM and Coluccio, C and Forti, E and Fugazza, A and Binda, C and Vanella, G and Di Matteo, FM and Crinò, SF and Lisotti, A and Maida, MF and Aragona, G and Mauro, A and Repici, A and Anderloni, A and Fabbri, C and Tarantino, I and On Behalf Of The I-Eus Group, }, title = {Endoscopic Ultrasound-Guided Anastomoses of the Gastrointestinal Tract: A Multicentric Experience.}, journal = {Cancers}, volume = {17}, number = {5}, pages = {}, pmid = {40075757}, issn = {2072-6694}, support = {N/A//I-EUS working group/ ; }, abstract = {This multicenter retrospective study included patients undergoing EUS-guided GI anastomoses from 2016 to 2023. Indications for EUS-guided anastomosis were GOO, ALS or patients with altered anatomy needing endoscopic interventions. The primary outcome was technical success, while secondary outcomes included clinical success, safety, lumen-apposing metal stent (LAMS) patency, and the need for reinterventions. A total of 216 patients (mean age 64.5 [±13.94] years; 49.1% males) were included. In total, 149 cases (69%) were GOO, 44 (20.4%) cases were bilioenteric anastomotic strictures or lithiasis in altered anatomy, 14 cases (6.5%) were ALS, and 9 patients (4.2%) were for ERCP in altered anatomy after EUS-GG. Overall, EUS-GE was performed in 181 patients (83.8%), EUS-JJ in 44 cases (20.4%), and EUS-GG in 10 (4.6%). Technical success was 94.91%, and clinical success was 93.66%. The adverse event (AE) rate was 11.1%. The reintervention rate was 7.69%. The median follow-up was 85 days. In conclusions, EUS-guided GI anastomoses are technically feasible and safe in both malignant and benign diseases.}, } @article {pmid40076771, year = {2025}, author = {Aguiar, B and Alfenim, AR and Machado, CS and Moreira, J and Pinto, M and Otero-Espinar, FJ and Borges, F and Fernandes, C}, title = {Exploring Nano-Delivery Systems to Enhance the Edaravone Performance in Amyotrophic Lateral Sclerosis Treatment.}, journal = {International journal of molecular sciences}, volume = {26}, number = {5}, pages = {}, pmid = {40076771}, issn = {1422-0067}, support = {2023.13291.PEX//Foundation for Science and tecnhology/ ; UIDB/00081/2020 (CIQUP)//Foundation for Science and Technology/ ; LA/P/0056/2020(IMS)//Foundation for Science and Technology/ ; 2021.04016.CEECIND/CP1655/CT0004//Foundation for Science and Technology/ ; IMPULSE: IMproving User experience, Long-term sustainability, and Services//EU-OPENSCREEN HORIZON-INFRA-2023-DEV-0/ ; 2020.08731.BD//Foundation for Science and Technology/ ; 2023.01250.BD//Foundation for Science and Technology/ ; 2024.00809.BD//Foundation for Science and Technology/ ; SFRH/BD/145637/2019//Foundation for Science and Technology/ ; }, mesh = {*Edaravone/chemistry/pharmacology/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Nanoparticles/chemistry ; *Drug Delivery Systems/methods ; Polyethylene Glycols/chemistry ; Drug Carriers/chemistry ; Cell Line, Tumor ; }, abstract = {Edaravone is one of the treatment options for Amyotrophic Lateral Sclerosis, but its therapeutic efficacy is limited due to the incapacity to cross the blood-brain barrier, as well as its short life span and poor stability, which is ultimately caused by its tautomerism in physiological condions. This work presents an overview about the use of several nanoformulations based on polymeric, protein, lipidic, or hybrid structure as suitable and stable drug delivery systems for encapsulating edaravone. We also evaluated the functionalization of nanoparticles with pegylated chains using the polyethylene glycol or tocopherol polyethylene glycol succinate and the possibility of preparing polymeric nanoparticles at different pH (7.4, 9, and 11). Edaravone was sucessfully encapsulated in polymeric, lipid-polymer hybrid, and lipidic nanoparticles. The use of higher pH values in the synthesis of polymeric nanoparticles has led to a decrease in nanoparticle size and an increase in the percentage of encapsulation efficiency. However, the resulting nanoformulations are not stable. Only polymeric and hybrid nanoparticles showed good stability over 80 days of storage, mainly at 4 °C. Overall, the nanoformulations tested did not show cytotoxicity in the SH-SY5Y cell line except the nanostructured lipid carrier formulations that showed some cytotoxicity possibly due to lipidic peroxidation. In conclusion, this work shows that edaravone can be encapsulated in different nanocarriers that could act as an interesting alternative for the treatment of Amyotrophic Lateral Sclerosis.}, } @article {pmid40077653, year = {2025}, author = {de Carvalho Vilar, MD and Coutinho, KMD and de Lima Vale, SH and Dourado Junior, MET and de Medeiros, GCBS and Piuvezam, G and Brandao-Neto, J and Leite-Lais, L}, title = {Evidence-Based Nutritional Recommendations for Maintaining or Restoring Nutritional Status in Patients with Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Nutrients}, volume = {17}, number = {5}, pages = {}, pmid = {40077653}, issn = {2072-6643}, support = {grant number 302298/2017-7 (Jose Brandao-Neto)//National Council for Scientific and Technological Development/ ; TED 132/2018//Ministry of Health (Brazil) - Laboratory of Technological Innovation in Health from the Federal University of Rio Grande do Norte - LAIS/UFRN/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy/therapy/physiopathology/complications ; *Nutritional Status ; Evidence-Based Medicine ; Nutrition Assessment ; Quality of Life ; Deglutition Disorders/etiology ; Dietary Supplements ; *Nutritional Support ; *Nutrition Therapy ; Practice Guidelines as Topic ; Gastrostomy ; }, abstract = {Background/Objectives: This study is a systematic review of guidelines that aims to synthesize evidence-based recommendations to support appropriate nutritional management for patients with amyotrophic lateral sclerosis (ALS). Methods: PubMed/MEDLINE, Embase, Scopus, SciELO, Web of Science, LILACS, ScienceDirect, and Google Scholar were searched for records published up to July 2024. Clinical practice guidelines addressing any aspect of nutritional intervention in ALS were included. No language or country of publication restrictions were applied. Data extraction was performed by two independent reviewers. The methodological quality of the reports was assessed using the AGREE II instrument. Discrepancies were resolved by consensus. Results: The findings and main recommendations were summarized narratively. A total of 837 records were identified, and 11 were included in this review. The overall AGREE II scores for the included studies ranged from 3 to 7. The summary of nutritional recommendations was organized into topics: (1) dysphagia, (2) nutritional assessment, (3) energy, (4) protein, (5) supplementation, and (6) percutaneous endoscopic gastrostomy (PEG). This review summarizes relevant and updated nutritional recommendations to maintain or restore the nutritional status of patients with ALS, contributing to their quality of life and survival time. Conclusions: These nutritional recommendations will help health professionals and caregivers to implement and standardize nutritional care according to evidence-based practice in ALS. PROSPERO registration number CRD42021233088.}, } @article {pmid40080233, year = {2025}, author = {Aydın, Ş and Özdemir, S and Adıgüzel, A}, title = {The Potential of cfDNA as Biomarker: Opportunities and Challenges for Neurodegenerative Diseases.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {1}, pages = {34}, pmid = {40080233}, issn = {1559-1166}, mesh = {Humans ; Biomarkers/blood ; *Neurodegenerative Diseases/diagnosis/genetics/blood ; *Cell-Free Nucleic Acids/blood/metabolism ; Animals ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), are characterized by the progressive and gradual degeneration of neurons. The prevalence and rates of these disorders rise significantly with age. As life spans continue to increase in many countries, the number of cases is expected to grow in the foreseeable future. Early and precise diagnosis, along with appropriate surveillance, continues to pose a challenge. The high heterogeneity of neurodegenerative diseases calls for more accurate and definitive biomarkers to improve clinical therapy. Cell-free DNA (cfDNA), including fragmented DNA released into bodily fluids via apoptosis, necrosis, or active secretion, has emerged as a promising non-invasive diagnostic tool for various disorders including neurodegenerative diseases. cfDNA can serve as an indicator of ongoing cellular damage and mortality, including neuronal loss, and may provide valuable insights into disease processes, progression, and therapeutic responses. This review will first cover the key aspects of cfDNA and then examine recent advances in its potential use as a biomarker for neurodegenerative disorders.}, } @article {pmid40084393, year = {2025}, author = {Helmold, B and Nathaniel, G and Barkhaus, P and Bertorini, T and Bromberg, M and Brown, A and Carter, GT and Chang, V and Crayle, J and Denson, K and Glass, J and Heiman-Patterson, T and Hobson, E and Jackson, C and Jhooty, S and Mallon, E and Maragakis, N and Cadavid, JM and Mcdermott, C and Pattee, G and Pierce, K and Wang, O and Wicks, P and Bedlack, R}, title = {ALSUntangled #78: Zinc.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {599-603}, doi = {10.1080/21678421.2025.2476688}, pmid = {40084393}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/diet therapy ; Humans ; *Zinc/therapeutic use/administration & dosage ; *Dietary Supplements ; Animals ; Disease Progression ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). In this review, we assess the utilization of dietary zinc supplements for modulating ALS pathology and progression. Studies in mouse models of ALS have demonstrated that high-dose zinc supplementation may be harmful, but moderate doses could potentially be beneficial. Clinical data is limited, and only one trial has explored zinc supplementation within PALS. This study reported potential benefits in slowing ALS progression but lacked statistical analyses and failed to report quantitative evidence. Numerous case reports from individual patients at varying doses have demonstrated no benefit. Zinc supplements at moderate doses are generally low cost and not associated with severe complications, but further research is required to determine the safety and efficacy of zinc supplementation within PALS. Therefore, we cannot at this time, endorse zinc supplementation to slow ALS progression.}, } @article {pmid40085521, year = {2025}, author = {Mercan, M and Seyhan, S and Yayla, V}, title = {The phenotyping dilemma in VRK1-related motor neuron disease: a Turkish family with young-onset amyotrophic lateral sclerosis caused by a novel mutation.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {573-590}, doi = {10.1080/21678421.2025.2477732}, pmid = {40085521}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging ; Male ; Turkey ; Female ; Phenotype ; Adult ; Pedigree ; *Intracellular Signaling Peptides and Proteins/genetics ; *Protein Serine-Threonine Kinases/genetics ; Middle Aged ; *Mutation/genetics ; Age of Onset ; *Motor Neuron Disease/genetics ; Exome Sequencing ; Mutation, Missense/genetics ; Magnetic Resonance Imaging ; }, abstract = {Objective: Vaccinia-related kinase 1 (VRK1)-related disease is an extremely rare autosomal recessive disorder primarily affecting the peripheral and/or central nervous system. In this report, we describe the genetic and clinical features of two siblings from a Turkish family presenting with an amyotrophic lateral sclerosis (ALS) phenotype due to a novel homozygous VRK1 mutation, and discuss the broad phenotypic spectrum associated with pathogenic variants in this gene. Methods: We analyzed the demographic data, clinical histories, neurological examinations, laboratory findings, and genetic results of 53 patients, including our cases, derived from 27 different reports. Results: Whole-exome sequencing identified a novel homozygous missense mutation, c.700A > G (p.Asn234Asp), in the VRK1 gene in two affected siblings. The characteristic features of the ALS phenotype included a recessive inheritance pattern, motor deficits with onset in the lower limbs, pyramidal tract signs, and a muscle magnetic resonance imaging (MRI) pattern demonstrating preferential involvement of the posterior compartments of the leg and thigh. The most common phenotypes associated with VRK1 mutations were ALS (18/53, 34%) and distal hereditary motor neuropathy (dHMN) (14/53, 26.4%), followed by pontocerebellar hypoplasia type 1 (7/53, 13.2%), hereditary motor and sensory neuropathy (5/53, 9.4%), autosomal recessive primary microcephaly with brain malformations (4/53, 7.5%), and spastic paraplegia (2/53, 3.8%). The ALS phenotype exhibited a significantly earlier mean age of onset compared to the dHMN phenotype (p = 0.015; 15.3 ± 11.5 and 27 ± 15.5 years, respectively). Conclusion: Our findings highlight the importance of investigating VRK1 mutations in patients with young-onset familial ALS. Furthermore, this report provides a systematic classification of the phenotype definitions associated with VRK1 mutations.}, } @article {pmid40086112, year = {2025}, author = {Liampas, I and Veltsista, D and Germeni, A and Batzikosta, P and Michou, E and Kefalopoulou, Z and Chroni, E}, title = {F waves in amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {55}, number = {4}, pages = {103061}, doi = {10.1016/j.neucli.2025.103061}, pmid = {40086112}, issn = {1769-7131}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Neural Conduction/physiology ; Ulnar Nerve/physiopathology ; Electromyography ; Muscle, Skeletal/physiopathology ; }, abstract = {OBJECTIVE: This systematic review and meta-analysis aimed to determine the pattern of F-wave abnormalities and their potential utility in the early diagnosis of amyotrophic lateral sclerosis (ALS).

METHODS: Medline and Embase were thoroughly searched. We primarily emphasized F-wave recordings from the abductor digiti minimi, following stimulation of the ulnar nerve at the wrist. Data from case-control studies involving individuals with ALS versus healthy controls (HC) or other well-defined patient groups were reviewed and -if appropriate- quantitatively synthesized.

RESULTS: Twenty-nine studies were included in this systematic review and 17 of them in the analytic part. The pattern of F-abnormalities in ALS compared to HC was as follows: decreased persistence (MD=20.25 %,15.67-24.84 %), mildly prolonged minimum latency (MD=1.59msec,1.11-2.06msec), increased maximum amplitude (MD=196μV,106-287μV) and elevated Index total Freps (MD=33.9 %,26.0-41.8 %). Affected limbs (with substantial weakness in clinical examination and/or muscle wasting and/or abnormal nerve conduction studies) exhibited more marked abnormalities in persistence, minimum latency, and Index total Freps, whereas abnormalities in these parameters were very mild in clinically unaffected limbs. More prominent increases in maximum amplitude accompanied pyramidal dysfunction. Of note, isolated upper motor neuron (UMN) disorders exhibited a comparable increase in Index total Freps without a decrease in persistence.

CONCLUSIONS: The pattern of F wave abnormalities may raise suspicion of involvement of the under-study lower motor neuron (LMN) pool in ALS. These findings may identify LMN dysfunction even at a preclinical stage and prompt extensive electromyographic investigations. UMN involvement may to some extent differentiate the profile of F wave abnormalities in ALS.}, } @article {pmid40087396, year = {2025}, author = {Omar, OMF and Kimble, AL and Cheemala, A and Tyburski, JD and Pandey, S and Wu, Q and Reese, B and Jellison, ER and Hao, B and Li, Y and Yan, R and Murphy, PA}, title = {Endothelial TDP-43 depletion disrupts core blood-brain barrier pathways in neurodegeneration.}, journal = {Nature neuroscience}, volume = {28}, number = {5}, pages = {973-984}, pmid = {40087396}, issn = {1546-1726}, support = {NS074256//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; K99 HL125727/HL/NHLBI NIH HHS/United States ; R01 NS117449/NS/NINDS NIH HHS/United States ; RF1 NS074256/NS/NINDS NIH HHS/United States ; GM135592//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; RF1 AG046929/AG/NIA NIH HHS/United States ; AG046929//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1 NS117449/NS/NINDS NIH HHS/United States ; R01 GM135592/GM/NIGMS NIH HHS/United States ; RF1-NS117449//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R00-HL125727//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R00 HL125727/HL/NHLBI NIH HHS/United States ; 23PRE1027078//American Heart Association (American Heart Association, Inc.)/ ; R01 NS074256/NS/NINDS NIH HHS/United States ; 19IPLOI34770151//American Heart Association (American Heart Association, Inc.)/ ; R01 HL150362/HL/NHLBI NIH HHS/United States ; R01 AG046929/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Blood-Brain Barrier/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism/deficiency ; Male ; Female ; Middle Aged ; Aged ; Animals ; Adult ; Aged, 80 and over ; *Neurodegenerative Diseases/pathology/metabolism ; Mice ; *Endothelial Cells/metabolism/pathology ; Young Adult ; Microglia/metabolism ; Alzheimer Disease/pathology/metabolism ; }, abstract = {Endothelial cells (ECs) help maintain the blood-brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20-98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary ECs in Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal degeneration. These capillaries exhibit reduced nuclear β-catenin and β-catenin-downstream genes, along with elevated TNF/NF-κB markers. Notably, these transcriptional changes correlate with the loss of nuclear TDP-43, an RNA-binding protein also depleted in neuronal nuclei. TDP-43 disruption in human and mouse ECs replicates these alterations, suggesting that TDP-43 deficiency in ECs is an important factor contributing to blood-brain barrier breakdown in neurodegenerative diseases.}, } @article {pmid40089090, year = {2025}, author = {Men, J and Wang, X and Zhou, Y and Huang, Y and Zheng, Y and Wang, Y and Yang, S and Chen, N and Yan, N and Duan, X}, title = {Neurodegenerative diseases: Epigenetic regulatory mechanisms and therapeutic potential.}, journal = {Cellular signalling}, volume = {131}, number = {}, pages = {111715}, doi = {10.1016/j.cellsig.2025.111715}, pmid = {40089090}, issn = {1873-3913}, mesh = {Humans ; *Epigenesis, Genetic ; *Neurodegenerative Diseases/genetics/therapy/pathology ; DNA Methylation ; Animals ; Histones/metabolism ; RNA, Untranslated/genetics/metabolism ; Chromatin Assembly and Disassembly ; }, abstract = {Neurodegenerative diseases (NDDs) are a class of diseases in which the progressive loss of subtype-specific neurons leads to dysfunction. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others. Previous studies have demonstrated that the pathogenesis of NDDs involves various mechanisms, including genetic factors, oxidative stress, apoptosis, and the immune response. Recent studies have shown that epigenetic regulation mediates the interactions between DNA methylation, chromatin remodeling, histone modification, and non-coding RNAs, thus affecting gene transcription. A growing body of research links epigenetic modifications to crucial pathways involved in the occurrence and development of NDDs. Epigenetics has also been found to regulate and maintain nervous system function, and its imbalance is closely related to the occurrence and development of NDDs. The present review summarizes focuses on the role of epigenetic modifications in the pathogenesis of NDDs and provides an overview of the key genes regulated by DNA methylation, histone modification, and non-coding RNAs in NDDs. Further, the current research status of epigenetics in NDDs is summarized and the potential application of epigenetics in the clinical diagnosis and treatment of NDDs is discussed.}, } @article {pmid40090808, year = {2025}, author = {Rosina, M and Scaricamazza, S and Fenili, G and Nesci, V and Valle, C and Ferri, A and Paronetto, MP}, title = {Hidden players in the metabolic vulnerabilities of amyotrophic lateral sclerosis.}, journal = {Trends in endocrinology and metabolism: TEM}, volume = {36}, number = {11}, pages = {1029-1042}, doi = {10.1016/j.tem.2025.02.004}, pmid = {40090808}, issn = {1879-3061}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Energy Metabolism/physiology ; Animals ; Mitochondria/metabolism ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and rapidly progressive motor neuron disorder with a fatal outcome. Despite the remarkable progress in understanding ALS pathophysiology, which has significantly contributed to clinical trial design, ALS remains a rapidly disabling and life-shortening condition. The non-motor neuron features of ALS, including nutritional status, energy expenditure, and metabolic imbalance, are increasingly gaining attention. Indeed, the bioenergetic failure and mitochondrial dysfunction of patients with ALS impact not only the high energy-demanding motor neurons but also organs and brain areas long considered irrelevant to the disease. As such, here we discuss how considering energy balance in ALS is reshaping research on this disease, opening the path to novel targetable opportunities for its treatment.}, } @article {pmid40091372, year = {2025}, author = {Jaspers Focks, RJ and Helleman, J and van den Berg, LH and Visser-Meily, JM and Gaytant, MA and Wijkstra, PJ and Beelen, A}, title = {Initiating non-invasive ventilation in patients with Amyotrophic Lateral Sclerosis in The Netherlands: A centralised approach to respiratory care.}, journal = {Journal of neuromuscular diseases}, volume = {12}, number = {3}, pages = {372-381}, pmid = {40091372}, issn = {2214-3602}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications/mortality ; *Noninvasive Ventilation/methods ; Male ; Female ; Netherlands ; Middle Aged ; Retrospective Studies ; Aged ; *Respiratory Insufficiency/therapy/etiology ; Adult ; Hypercapnia/therapy/etiology ; }, abstract = {BACKGROUND: In the Netherlands a centralised approach to respiratory care for patients with Amyotrophic Lateral Sclerosis is used based on national guidelines. Patients with Amyotrophic Lateral Sclerosis are referred to one of 4 centres for Home Mechanical Ventilation.

OBJECTIVE: Our aim was to evaluate the respiratory care according to the Dutch guideline by evaluation of reasons for starting non-invasive ventilation, timing of initiating and survival in patients with Amyotrophic Lateral Sclerosis using non-invasive ventilation.

METHOD: A retrospective chart-review was performed of 323 patients, who had been referred to centres for Home Mechanical Ventilation in 2016-2018. Data collected included symptoms of hypoventilation, forced vital capacity, blood gasses, criteria for (not) initiating non-invasive ventilation, and survival. Kaplan-Meyer curves and Multivariate Cox proportional hazard regression were used in the analysis.

RESULTS: The main criteria used for initiating non-invasive ventilation were hypercapnia (77%) and the presence of orthopnea and/or dyspnoea (25%). Median survival after starting non-invasive ventilation was 11 months, and was shorter for patients with bulbar disease onset and older age. The proportion of the total disease duration that was spent on non-invasive ventilation was not significantly affected by age, sex or site of disease. Seventy nine percent of the patients who didn't start non-invasive ventilation had reached a joint decision with their caregivers and/or physicians.

CONCLUSION: Key outcomes of the Dutch centralised respiratory care approach have shown that most patients were initiated on non-invasive ventilation due to presence of hypercapnia and/or dyspnoea/orthopnea, which is according to the Dutch guidelines. Half of patients spent at least 33% of their disease duration on non-invasive ventilation. To help find the optimal criteria and timing for non-invasive ventilation it would be useful for other countries to share their key outcomes as well.}, } @article {pmid40091916, year = {2025}, author = {Ansari, U and Wen, J and Karabala, M and Syed, B and Abed, I and Razick, DI and Lui, F}, title = {Analysis of Respiratory Muscle Strength Training in Amyotrophic Lateral Sclerosis (ALS) Patients: A Systematic Review.}, journal = {Cureus}, volume = {17}, number = {2}, pages = {e78903}, pmid = {40091916}, issn = {2168-8184}, abstract = {Respiratory muscle weakness is a significant contributor to morbidity and mortality in amyotrophic lateral sclerosis (ALS) patients. Respiratory muscle strength training (RMST) has emerged as a potential therapeutic approach to mitigate respiratory muscle weakness in ALS. Still, its efficacy and safety remain unclear due to conflicting evidence and methodological heterogeneity in existing studies. A systematic review was conducted across three databases (PubMed (United States National Library of Medicine, Bethesda, MD, USA), Embase (Elsevier, Amsterdam, Netherlands), and Cochrane Library (Cochrane, Alberta, Canada)) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess the effectiveness of RMST in ALS patients. Eligible studies included comparative studies for RMST, focusing on outcomes such as maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and ALS Functional Rating Scale (ALSFRS-R). Quality assessment was performed using the Cochrane Risk of Bias tool. This study included six studies, including 183 patients with a mean age of 58.0 years (49.6 to 63.2) and a mean follow-up time of 21.2 weeks (eight to 52). The average mean difference for ALSFRS-R (three studies), MIP (three studies), MEP (three studies), and FVC (two studies) were 2.062 (0.04 to 5.3), 2.285 (-8.145 to 10.8), 19.435 (10.86 to 21.7), and 7.23 (3.6 to 10.86), respectively. Complications related to RMST were poorly reported across studies. Secondary outcomes, such as depression scores, blood oxygen levels, and heart rate variability, showed promising trends but lacked consistency. Despite positive findings on respiratory muscle strength, RMST's efficacy in ALS management remains inconclusive. Challenges include methodological heterogeneity, limited sample sizes, and inadequate reporting of complications. Future research should focus on standardized protocols, larger sample sizes, longer follow-ups, and comprehensive assessment of adverse effects to clarify the role of RMST in ALS treatment.}, } @article {pmid40092496, year = {2025}, author = {Theuriet, J and Bohic, A and Bonjour, M and Bernard, E and Cluse, F and Svahn, J and Jomir, L and Vallet, AE and Demia, M and Roux, L and Bârsan, IC and Alves, L and Dion, M and Meens, L and Moussy, M and Bouhour, F and Péréon, Y and Pegat, A}, title = {Contralateral R1 response in blink reflex in patients with amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {10}, number = {}, pages = {47-51}, pmid = {40092496}, issn = {2467-981X}, abstract = {OBJECTIVE: This study aimed to compare the frequency of blink reflex's contralateral R1 responses (R1') between patients with amyotrophic lateral sclerosis (ALS), non-ALS motor deficit patients, and healthy volunteers.

METHODS: A total of 120 participants were prospectively recruited: 40 with ALS, 40 with a non-ALS motor deficit, and 40 healthy volunteers. Blink reflexes were recorded from orbicularis oculi muscles following supraorbital nerve stimulation.

RESULTS: R1' was more frequent in the ALS group (42.5 %) compared to healthy volunteers (12.5 %, p = 0.00588), and compared to non-ALS patients (7.5 %, p = 0.000789). Bilateral R1' was observed only in ALS patients (22.5 %). No clinically significant difference was found in the latencies or amplitudes of the R1, R2, or R1' responses among groups. R1' was more frequent in ALS patients with pseudobulbar affect (71.4 %) compared to those without (36.4 %).

CONCLUSIONS: The higher frequency of R1' in ALS highlights its potential role in distinguishing ALS from other motor disorders. Its sensitivity was low, but bilateral R1' was specific to ALS. The higher frequency of R1' among ALS patients with pseudobulbar affect potentially reflects corticobulbar neuron degeneration.

SIGNIFICANCE: The R1', especially when bilateral, could serve as an additional diagnostic biomarker for ALS, although its clinical relevance should be considered within the broader diagnostic context.}, } @article {pmid40092497, year = {2025}, author = {Fujii, Y and Kanbayashi, T and Takahashi, K and Hamada, Y and Kobayashi, S and Sonoo, M}, title = {Correlation between decremental responses in repetitive nerve stimulation and disease progression rate in patients with amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {10}, number = {}, pages = {40-46}, pmid = {40092497}, issn = {2467-981X}, abstract = {OBJECTIVE: Decrement responses in repetitive nerve stimulation (RNS) are theoretically expected to correlate with the disease progression speed in amyotrophic lateral sclerosis (ALS). However, actual results have been controversial. We investigated this issue using ΔFS calculated from the ALS functional rating scale revised version (ALSFRS-R) and the duration of illness.

METHODS: RNS results of the abductor pollicis brevis, trapezius, and deltoid muscles in our previous study were reviewed. We investigated correlations and multiple regressions regarding decremental percentage (Decr%), the amplitude of the initial compound muscle action potential (Amp), and progression speed parameters, i.e. ΔFS or ΔUL-FS, the latter being the ΔFS for the upper-limb questions in ALSFRS-R.

RESULTS: Included subjects were 124 patients with ALS, 47 of whom were upper-limb onset. Multiple regression analyses revealed that Decr% is largely determined by Amp and that Δ FS or ΔUL-FS showed no or little contributions to Decr%.

CONCLUSIONS: Decremental responses in RNS does not predict the speed of progression of the functional impairment in patients with ALS.

SIGNIFICANCE: This study suggests that the decremental responses in RNS in ALS are contributed by the impaired neuromuscular transmission in chronic sprouts following extensive reinnervation, as well as by the immature sprouts.}, } @article {pmid40092960, year = {2025}, author = {Liu, Y and Li, XF}, title = {Characteristics and therapeutic strategies for familial gastrointestinal stromal tumors.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {3}, pages = {100463}, pmid = {40092960}, issn = {1948-5204}, abstract = {This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors (GISTs). We read with great interest this article concerning the diagnosis, treatment, and post-treatment management of patients with familial GISTs. The actual incidence of GISTs may be underestimated due to diagnostic limitations and the long-term low-risk behavior of some GISTs. The molecular landscape of GISTs is primarily driven by mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. A subset of GISTs without these mutations known as wild-type GISTs, may harbor other rare mutations, impacting their response to targeted therapies. Clinically, patients with GISTs present with non-specific symptoms, often leading to delayed diagnosis. Genetic predispositions in familial GISTs provide insights into the genetic architecture and extragastrointestinal manifestations of GISTs. Management has evolved from surgical interventions to molecular-based therapies using tyrosine kinase inhibitors. The management of GISTs, especially in familial cases, requires a multidisciplinary approach. Cases of different gene mutations were reported in the same family, suggesting that incorporating genetic testing into routine clinical practice is crucial for the early identification of high-risk individuals and the implementation of tailored surveillance programs.}, } @article {pmid40093130, year = {2025}, author = {Zhou, Z and Luquette, LJ and Dong, G and Kim, J and Ku, J and Kim, K and Bae, M and Shao, DD and Sahile, B and Miller, MB and Huang, AY and Nathan, WJ and Nussenzweig, A and Park, PJ and Lagier-Tourenne, C and Lee, EA and Walsh, CA}, title = {Recurrent patterns of widespread neuronal genomic damage shared by major neurodegenerative disorders.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40093130}, issn = {2692-8205}, support = {R01 HG012573/HG/NHGRI NIH HHS/United States ; R56 AG079857/AG/NIA NIH HHS/United States ; P50 HD105351/HD/NICHD NIH HHS/United States ; DP2 AG072437/AG/NIA NIH HHS/United States ; R01 AG082346/AG/NIA NIH HHS/United States ; K01 AG051791/AG/NIA NIH HHS/United States ; R01 NS032457/NS/NINDS NIH HHS/United States ; DP2 AG086138/AG/NIA NIH HHS/United States ; R01 AG070921/AG/NIA NIH HHS/United States ; R01 AG088082/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) are common neurodegenerative disorders for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 429 neurons from three C9ORF72 ALS, six C9ORF72 FTD, seven AD, and twenty-three neurotypical control brains revealed significantly increased burdens in somatic single nucleotide variant (sSNV) and insertion/deletion (sIndel) in all three disease conditions. Mutational signature analysis identified a disease-associated sSNV signature suggestive of oxidative damage and an sIndel process, affecting 28% of ALS, 79% of FTD, and 65% of AD neurons but only 5% of control neurons (diseased vs. control: OR=31.20, p = 2.35×10[-10]). Disease-associated sIndels were primarily two-basepair deletions resembling signature ID4, which was previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Duplex sequencing confirmed the presence of sIndels and identified similar single-strand events as potential precursor lesions. TOP1-associated sIndel mutagenesis and resulting genome instability may thus represent a common mechanism of neurodegeneration.}, } @article {pmid40094392, year = {2025}, author = {Resch, M and Frickel, JS and Dischinger, K and Choo, RSW and Hell, K and Harner, ME}, title = {The Mia40 substrate Mix17 exposes its N-terminus to the cytosolic side of the mitochondrial outer membrane.}, journal = {Journal of cell science}, volume = {138}, number = {9}, pages = {}, pmid = {40094392}, issn = {1477-9137}, support = {413985647//Deutsche Forschungsgemeinschaft/ ; //LMUexcellent/ ; //Ludwig-Maximilians-Universität München/ ; }, mesh = {*Mitochondrial Membranes/metabolism ; *Saccharomyces cerevisiae Proteins/metabolism/genetics/chemistry ; *Saccharomyces cerevisiae/metabolism/genetics ; Mitochondrial Precursor Protein Import Complex Proteins ; *Cytosol/metabolism ; *Mitochondrial Membrane Transport Proteins/metabolism/genetics ; Humans ; Mitochondria/metabolism ; *Mitochondrial Proteins/metabolism/genetics ; }, abstract = {Mitochondrial architecture and the contacts between the mitochondrial outer and the inner membranes depend on the mitochondrial contact site and cristae-organizing system (MICOS) that is highly conserved from yeast to human. Variants in the mammalian MICOS subunit Mic14 (also known as CHCHD10) have been linked to amyotrophic lateral sclerosis and frontotemporal dementia, indicating the importance of this protein. Mic14 has a yeast ortholog, Mix17, a protein of unknown function, which has not been shown to interact with MICOS so far. As a first step to elucidate the function of Mix17 and its orthologs, we analyzed its interactions, biogenesis and mitochondrial sublocation. We report that Mix17 is not a stable MICOS subunit in yeast. Our data suggest that Mix17 is the first Mia40 substrate in the mitochondrial outer membrane. Unlike all other Mia40 substrates, Mix17 spans the mitochondrial outer membrane and exposes its N-terminus to the cytosol. The insertion of Mix17 into the mitochondrial outer membrane is likely to be mediated by its interaction with Tom40, the pore of the TOM complex. Moreover, we show that the exposure of Mix17 to the cytosolic side of the mitochondrial membrane depends on its N-terminus.}, } @article {pmid40095345, year = {2025}, author = {Dehghani, S and Ocakcı, O and Hatipoglu, PT and Özalp, VC and Tevlek, A}, title = {Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.}, journal = {Molecular neurobiology}, volume = {62}, number = {7}, pages = {9190-9215}, pmid = {40095345}, issn = {1559-1182}, mesh = {*Exosomes/metabolism ; Humans ; *Neurodegenerative Diseases/therapy/diagnosis/metabolism/drug therapy ; *Biomarkers/metabolism ; Animals ; Blood-Brain Barrier/metabolism ; Drug Delivery Systems ; }, abstract = {Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.}, } @article {pmid40097075, year = {2025}, author = {Cuevas, EP and Madruga, E and Valenzuela-Martínez, I and Ramírez, D and Gil, C and Nagaraj, S and Martin-Requero, A and Martinez, A}, title = {MicroRNA signature of lymphoblasts from amyotrophic lateral sclerosis patients as potential clinical biomarkers.}, journal = {Neurobiology of disease}, volume = {208}, number = {}, pages = {106871}, doi = {10.1016/j.nbd.2025.106871}, pmid = {40097075}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/diagnosis ; *MicroRNAs/metabolism/genetics ; Biomarkers/metabolism ; Middle Aged ; Female ; *Lymphocytes/metabolism ; Male ; Aged ; Superoxide Dismutase-1/genetics ; Adult ; High-Throughput Nucleotide Sequencing ; }, abstract = {MicroRNAs (miRNAs) are a class of small, non-coding RNAs involved in different cellular functions that have emerged as key regulators of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). ALS is a fatal disease that lacks of not only effective treatments, but also presents delays in its diagnosis, since reliable clinical biomarkers are unavailable. In recent years, advancements in high-throughput sequencing strategies have led to the identification of novel ALS biomarkers, facilitating earlier diagnosis and assessment of treatment efficacy. Since immortalized lymphocytes obtained from peripheral blood are a suitable model to study pathological features of ALS, we employed these samples with the aim of characterize the dysregulated miRNAs in ALS patients. Next-generation sequencing (NGS) was utilized in order to analyze the expression profiles of miRNAs in immortalized lymphocytes from healthy controls, sporadic ALS (sALS), and familial ALS with mutations in superoxide dismutase 1 (SOD1-ALS). The screening analysis of the NGS data identified a set of dysregulated miRNAs, of which nine candidates were selected for qRT-PCR validation, identifying for the first time the possible importance of hsa-miR-6821-5p as a potential ALS biomarker. Furthermore, the up-regulated miRNAs identified are predicted to have direct or indirect interactions with genes closely related to ALS, such as SIGMAR1, HNRNPA1 and TARDBP. Additionally, by Metascape enrichment analysis, we found the VEGFA/VEGFR2 signaling pathway, previously implicated in neuroprotective effects in ALS, as a candidate pathway for further analyses.}, } @article {pmid40097438, year = {2025}, author = {Ayyadurai, VAS and Deonikar, P and Kamm, RD}, title = {A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis.}, journal = {NPJ systems biology and applications}, volume = {11}, number = {1}, pages = {27}, pmid = {40097438}, issn = {2056-7189}, support = {P41 EB031772/EB/NIBIB NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology ; Humans ; *Neuromuscular Junction/metabolism/pathology/physiopathology ; Motor Neurons/metabolism/pathology ; Animals ; Schwann Cells/metabolism ; Muscle, Skeletal/pathology/metabolism ; }, abstract = {A molecular systems architecture is presented for the neuromuscular junction (NMJ) in order to provide a framework for organizing complexity of biomolecular interactions in amyotrophic lateral sclerosis (ALS) using a systematic literature review process. ALS is a fatal motor neuron disease characterized by progressive degeneration of the upper and lower motor neurons that supply voluntary muscles. The neuromuscular junction contains cells such as upper and lower motor neurons, skeletal muscle cells, astrocytes, microglia, Schwann cells, and endothelial cells, which are implicated in pathogenesis of ALS. This molecular systems architecture provides a multi-layered understanding of the intra- and inter-cellular interactions in the ALS neuromuscular junction microenvironment, and may be utilized for target identification, discovery of single and combination therapeutics, and clinical strategies to treat ALS.}, } @article {pmid40097762, year = {2025}, author = {Nabakhteh, S and Lotfi, A and Afsartaha, A and Khodadadi, ES and Abdolghaderi, S and Mohammadpour, M and Shokri, Y and Kiani, P and Ehtiati, S and Khakshournia, S and Khatami, SH}, title = {Nutritional Interventions in Amyotrophic Lateral Sclerosis: From Ketogenic Diet and Neuroprotective Nutrients to the Microbiota-Gut-Brain Axis Regulation.}, journal = {Molecular neurobiology}, volume = {62}, number = {7}, pages = {9216-9239}, pmid = {40097762}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/diet therapy/microbiology ; Humans ; *Diet, Ketogenic/methods ; *Gastrointestinal Microbiome/physiology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; *Brain/metabolism ; *Nutrients/therapeutic use ; *Neuroprotection ; *Brain-Gut Axis/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with significant challenges in diagnosis and treatment. Recent research has highlighted the complex nature of ALS, encompassing behavioral impairments in addition to its neurological manifestations. While several medications have been approved to slow disease progression, ongoing research is focused on identifying new therapeutic targets. The current review focuses on emerging therapeutic strategies and personalized approaches aimed at improving patient outcomes. Recent advancements highlight the importance of targeting additional pathways such as mitochondrial dysfunction and neuroinflammation to develop more effective treatments. Personalized medicine, including genetic testing and biomarkers, is proving valuable in stratifying patients and tailoring treatment options. Complementary therapies, such as nutritional interventions like the ketogenic diet and microbiome modulation, also show promise. This review emphasizes the need for a multidisciplinary approach that integrates early diagnosis, targeted treatments, and supportive care to address the multisystemic nature of ALS and improve the quality of life for patients.}, } @article {pmid40097890, year = {2025}, author = {Dezfouli, MA and Shalilahmadi, D and Shamsaei, G and Esmaeili, A and Majdinasab, N and Rashidi, SK}, title = {Circulating miR-223/NLRP3 axis and IL-1β level in functional disease progression of amyotrophic lateral sclerosis.}, journal = {Acta neurologica Belgica}, volume = {125}, number = {3}, pages = {783-791}, pmid = {40097890}, issn = {2240-2993}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/physiopathology ; *NLR Family, Pyrin Domain-Containing 3 Protein/blood ; Male ; Female ; *Interleukin-1beta/blood ; Middle Aged ; *MicroRNAs/blood ; *Disease Progression ; Aged ; Biomarkers/blood ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease identified by progressive motor neuron loss. NLRP3 inflammasomes induce inflammation and pyroptosis, which can lead to neurodegeneration, muscle atrophy, and respiratory decline. miR-223 targets NLRP3 and suppresses inflammasome formation. Here, miR-223, NLRP3 and IL-1β levels were evaluated as plasma biomarkers in the incidence and progression of ALS.

METHODS: 32 ALS patients and 32 healthy subjects were assessed. In all patients, the functional disability was determined by Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the respiratory dysfunction was assessed by the percent predicted forced vital capacity (ppFVC) index in spirometry examination. Plasma levels of miR-223, NLRP3 and IL-1β were assessed in ALS and control groups.

RESULTS: Compared to the healthy controls, ALS patients showed decreased miR-223 expression (P < 0.0001), increased NLRP3 expression (P = 0.0002) and increased IL-1β level (P = 0.0003). The areas under the ROC curves for miR-223, NLRP3 and IL-1β were 0.82, 0.76 and 0.75 respectively. The ALSFRS-R and ppFVC values were positively correlated with miR-223 and negatively correlated with NLRP3 and IL-1β levels.

CONCLUSION: Our results indicated that changes in miR-223, NLRP3 and IL-1β levels may correlate with the occurrence and functional progression of ALS. Additionally, therapeutic approaches based on miR-223 and inflammatory mediators can be proposed as effective strategies against disease progression.}, } @article {pmid40098659, year = {2023}, author = {Serrano-Giraldo, J and Becerra-Muñoz, MP and Tijaro-Santos, JA and Zarante, I}, title = {[Current situation of rare diseases in Bogotá: Notification to Sivigila from 2019 to 2022].}, journal = {Revista de salud publica (Bogota, Colombia)}, volume = {25}, number = {4}, pages = {107594}, pmid = {40098659}, issn = {2539-3596}, abstract = {OBJECTIVE: To analyze the reports of orphan diseases in Bogotá, in order to describe the epidemiological profile, based on the cases reported to the Public Health System (Sivigila), from January 2019 to March 2022.

METHODS: A descriptive and cross-sectional study was carried out in which the cases reported to Sivigila in Bogotá were analyzed in the period between January 2019 and March 2022. Absolute and relative frequencies, frequency distribution and prevalences and averages of different variables were calculated. notified in the notification sheets.

RESULTS: From January 2019 to March 2022, 10,399 patients with orphan diseases have been notified to Sivigila in Bogotá, of which 56.25% (5,849) are female and 43.75% (4,550) are female. male sex. 87.10% (9,060) of the cases belong to the contributory regime. The town with the highest number of reports was Suba with 15.85% (1,294). The most reported orphan diseases were: multiple sclerosis with 13.1% (1,363), amyotrophic lateral sclerosis with 4.04% (421) and Guillain-Barre syndrome with 3.6% (374). A patient with an orphan disease in Bogotá takes 61.3 months on average from the beginning of their symptoms to obtaining a diagnosis (SD 101.9).

CONCLUSIONS: From the notification to Sivigila in Bogotá, compared to the global prevalence, there is an under-registration of patients with orphan diseases and the delay in the diagnosis of these diseases is evident.}, } @article {pmid40099231, year = {2025}, author = {Hwang, DW and Ser, J and Ziabrev, K and Park, GK and Jo, MJ and Yokomizo, S and Bao, K and Yamashita, A and Cho, H and Henary, M and Kashiwagi, S and Choi, HS}, title = {Image-Guided Monitoring of Mitochondria and Blood-Brain Barrier Dysfunction in Amyotrophic Lateral Sclerosis Mice.}, journal = {Biomaterials research}, volume = {29}, number = {}, pages = {0162}, pmid = {40099231}, issn = {1226-4601}, support = {R01 CA280968/CA/NCI NIH HHS/United States ; R01 HL163273/HL/NHLBI NIH HHS/United States ; }, abstract = {Early detection of amyotrophic lateral sclerosis (ALS) progression is critical for improving disease management and therapeutic outcomes. However, the clinical heterogeneity and variability in ALS symptoms often lead to delayed diagnosis and suboptimal therapeutic interventions. Since mitochondrial dysfunction is a hallmark of ALS, we hypothesized that monitoring mitochondrial function could serve as a reliable strategy for early diagnosis and therapeutic monitoring of ALS. To address this, we synthesized and characterized 2 novel near-infrared fluorophores, ALS04 and ALS05, designed to target mitochondria and lysosomes. Their physicochemical properties, serum protein binding, fluorescence characteristics, photostability, and pharmacokinetics were systematically evaluated. We found that benzothiazole-based fluorophores exhibit excellent mitochondrial targeting, optimal optical properties, biocompatibility, and favorable biodistribution in vivo. Interestingly, ALS04 showed superior mitochondrial accumulation compared to ALS05, despite their similar physicochemical properties. This enhanced accumulation can be attributed to the lower molecular weight and higher lipophilicity of ALS04. Real-time fluorescence imaging revealed a substantial reduction in ALS04 signals in mitochondrial-rich tissues such as brown fat, highlighting its potential for monitoring mitochondrial dysfunction in early-stage ALS. Furthermore, the detection of ALS04 in the mouse brain suggests its ability to monitor blood-brain barrier hyperpermeability, another key feature of ALS pathology. These findings establish ALS04 as a promising noninvasive imaging tool for monitoring biomarkers associated with ALS progression. Its ability to detect early-stage pathophysiological changes in an ALS mouse model highlights its potential for advancing our understanding of ALS mechanisms and facilitating the identification of novel therapeutic targets.}, } @article {pmid40099353, year = {2025}, author = {Giorgio, CM and Tancredi, V and Licata, G and Moscarella, E and Argenziano, G and Fulgione, E and Babino, G and Franzese, P and Di Brizzi, EV}, title = {Cutting-edge insights: line-field confocal optical coherence tomography and 5% cyclosporine for early lichen sclerosus treatment.}, journal = {Dermatology reports}, volume = {17}, number = {4}, pages = {}, pmid = {40099353}, issn = {2036-7392}, abstract = {Dear Editor, Atrophic lichen sclerosus (ALS) is a chronic inflammatory dermatosis with significant morbidity, primarily affecting the genital area. The disease is often misdiagnosed or underdiagnosed, resulting in delayed treatment and progression to atrophic stages and permanent scars. While corticosteroids remain the first-line treatment, their long-term use may lead to adverse effects such as skin atrophy, prompting the need for alternative therapies. [...].}, } @article {pmid40099804, year = {2025}, author = {Zheng, W and Zhang, X and Chen, J and Luan, X and Wang, J and Zhang, L and Liu, K and Zhao, Y and Xu, Z}, title = {The Effect of Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex on the Amyotrophic Lateral Sclerosis Patients With Cognitive Impairment: A Double-Blinded, Randomized, and Sham Control Trial.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {3}, pages = {e70316}, pmid = {40099804}, issn = {1755-5949}, support = {20YF1436400//Shanghai Sailing program/ ; 23DZ2291500//Shanghai Science and Technology Innovation Action Plan/ ; }, mesh = {Humans ; Double-Blind Method ; Male ; Female ; *Amyotrophic Lateral Sclerosis/therapy/complications/psychology ; *Transcranial Magnetic Stimulation/methods ; Middle Aged ; *Cognitive Dysfunction/therapy/etiology/psychology ; Aged ; *Dorsolateral Prefrontal Cortex/physiology ; Treatment Outcome ; Adult ; *Prefrontal Cortex ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. A large number of ALS patients have cognitive impairment. In this double-blinded, randomized, and sham-controlled study, we aimed to investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on ALS patients with cognitive impairment.

METHODS: A total of 90 ALS patients with cognitive impairment were recruited from two cohorts; 80 participants were randomly assigned in a 1:1 ratio to receive 10 Hz rTMS or sham treatment on the bilateral dorsolateral prefrontal cortices (DLPFC) for 4 consecutive weeks. The patients were assessed by ECAS and ALSFRS-R scales. The Zarit care burden scale was administered to caregivers of ALS patients. The primary outcome measured was the rate of decline in the total ECAS score between pretreatment, 6 months post-treatment, and 12 months post-treatment. Secondary outcomes included the group difference in the slope of the Zarit score, ALSFRS-R total score, and the neurofilament light chain plasma levels.

RESULTS: The ECAS total score in the intention-to-treat population significantly changed from 79.74 ± 6.39 to 81.98 ± 6.51 and 79.22 ± 6.50 with rTMS intervention at the 6-month and 12-month follow-ups, respectively (p = 0.031, p = 0.042). The Zarit score also significantly decreased from 57.65 ± 3.42 to 52.24 ± 3.34 and 56.42 ± 3.41 at the 3-month and 6-month post-treatment time points, respectively (p = 0.003, p = 0.014). No significant differences were observed between the groups for other secondary endpoints. However, there was a trend of decreasing NF-L level rates in the treatment group over the first 6 months' follow-up.

CONCLUSIONS: rTMS could yield short-term positive effects on the ALS patients subgroup with cognitive impairment and alleviate caregivers' burden. No improvement was observed in the severity of ALS and ALS plasma biomarkers.}, } @article {pmid40099869, year = {2025}, author = {Kim, SB and Lee, JS and Lan, X and Huang, W and Taylor, DJ and Kwon, YT and Zhang, Y and Ji, CH}, title = {The structure-function relationship of ATE1 R-transferase of the autophagic Arg/N-degron pathway.}, journal = {Autophagy}, volume = {21}, number = {10}, pages = {2293-2295}, pmid = {40099869}, issn = {1554-8635}, support = {R35 GM150678/GM/NIGMS NIH HHS/United States ; }, mesh = {*Autophagy/physiology ; *Aminoacyltransferases/metabolism/chemistry/ultrastructure ; Humans ; Structure-Activity Relationship ; *Arginine/metabolism ; Sequestosome-1 Protein/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; Cryoelectron Microscopy ; Lysosomes/metabolism ; Degrons ; }, abstract = {ATE1 (arginyltransferase 1; EC 2.3.2) transfers the amino acid arginine (Arg) from Arg-tRNA[Arg] to the N-terminal (Nt) residues of proteins, such as aspartate (Asp), glutamate (Glu), and oxidized cysteine (Cys). The resulting Nt-Arg acts as an N-degron that regulates the degradation of various biomaterials via the ubiquitin/Ub-proteasome system (UPS) or the autophagy-lysosome system (ALS). In the UPS, Arg/N-degrons are recognized by cognate N-recognins, leading to substrate ubiquitination and proteasomal degradation. In the ALS, the same degrons bind the macroautophagy/autophagy receptor SQSTM1/p62 (sequestosome 1) to facilitate self-polymerization of SQSTM1 associated with cargoes and SQSTM1 interaction with LC3-II on phagophores. A key unresolved question is why only a small subset of proteins acquires Arg/N-degrons, given the rather weak binding affinity of ATE1 for Nt-substrates. In this study, we determined the cryo-EM structures of human ATE1 in complex with Arg-tRNA[Arg] and an Nt-Asp peptide. ATE1 harbors two adjacent pockets that each bind an Nt-substrate or Arg-tRNA[Arg], the latter being wrapped by a long, unstructured loop. In the apo state, two ATE1 monomers form a homodimer. ATE1 achieves the selectivity for its peptidyl-ligands through these multivalent interactions, with Kd values in the micro-molar range. These results reveal the structural principle of Nt-arginylation at the crossroads of the UPS and ALS.Abbreviations: ALS: autophagy-lysosome system; Arg: arginine; Asp: aspartate; ATE1: arginyltransferase 1; Cys: cysteine; CysO2(H): Cys sulfinic acid; Glu: glutamate; Nt: N-terminal; UBR: ubiquitin protein ligase E3 component n-recognin; UPS: ubiquitin-proteasome system; ZZ: ZZ-type zinc finger.}, } @article {pmid40100285, year = {2025}, author = {De Bertier, S and Lautrette, G and Amador, MD and Miki, T and Boillée, S and Lobsiger, CS and Bohl, D and Darios, F and Machat, S and Duchesne, M and Vourc'h, P and Fauret-Amsellem, AL and Corcia, P and Guy, N and Couratier, P and Seilhean, D and Millecamps, S}, title = {MAPT mutations in amyotrophic lateral sclerosis: clinical, neuropathological and functional insights.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {272}, pmid = {40100285}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; *tau Proteins/genetics/metabolism ; Male ; Female ; Middle Aged ; Adult ; Aged ; *Mutation/genetics ; Brain/pathology/metabolism ; Pedigree ; Exome Sequencing ; Animals ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a well-established disease continuum, underpinned by TDP43-pathology. In contrast, the clinical manifestations of Tau-linked disorders are typically limited to cognitive phenotypes or atypical parkinsonism, although few reports describe motor neuron involvement associated with MAPT (microtubule-associated protein Tau) mutations. This study aimed to investigate the contribution of MAPT to the ALS phenotype.

METHODS: We analyzed a whole-exome sequencing database comprising 470 ALS patients and explored the pathogenicity of the identified variants through familial, clinical, neuropathological, and cellular studies.

RESULTS: We identified two missense variants in the Tau repeat domains: the novel p.I308T variant, in a patient with early-onset ALS, and the p.P364S mutation in three families with spinal- or respiratory-onset ALS. Segregation of this mutation with disease could be confirmed in two affected cousins. The observation of p.P364S patient's tissue showed accumulations of hyperphosphorylated Tau in various brain regions, prominent in the motor cortex with Lewy body-like inclusions, along with a C-terminal cleaved form of Tau in muscle. In NSC-34 motor neuron cells expressing p.I308T or p.P364S mutants, Tau was discontinuous along the neurites, with clusters of mitochondria resulting from impaired mitochondrial motility.

CONCLUSION: These findings expand the molecular understanding of ALS to include MAPT mutations. MAPT analysis should be incorporated into ALS genetic screening, particularly in patients with a familial history of the disease. Recognizing the full spectrum of MAPT-linked neurodegenerative diseases is of considerable interest, given the ongoing efforts to develop MAPT-targeted therapies.}, } @article {pmid40100796, year = {2025}, author = {Giroud, M and Kuhn, B and Steiner, S and Westwood, P and Mendel, M and Mani, A and Pinard, E and Haap, W and Grether, U and Caramenti, P and Rombach, D and Zambaldo, C and Ritter, M and Schmid, P and Gasser, C and Aregger, N and Séchet, N and Topp, A and Bilyard, M and Malnight-Alvarez, A and Plitzko, I and Hilbert, M and Kalayil, S and Burger, D and Bonardi, C and Saal, W and Haider, A and Wittwer, MB and Brigo, A and Benz, J and Keaney, J}, title = {Discovery of a Potent SARM1 Base-Exchange Inhibitor with In Vivo Efficacy.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {6}, pages = {6558-6575}, doi = {10.1021/acs.jmedchem.4c03127}, pmid = {40100796}, issn = {1520-4804}, mesh = {Animals ; *Armadillo Domain Proteins/antagonists & inhibitors/metabolism ; Mice ; *Cytoskeletal Proteins/antagonists & inhibitors/metabolism ; Humans ; Structure-Activity Relationship ; Drug Discovery ; Male ; }, abstract = {Sterile alpha and TIR Motif Containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD[+]) hydrolase that plays a central role in programmed axonal degeneration. Axonal degeneration has been linked to neurodegenerative and neurological disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and peripheral neuropathies. Therefore, developing potent and selective SARM1 inhibitors could be an effective strategy to treat these disorders. We present herein the structure-guided discovery of two novel SARM1 inhibitors, 7 and 35. Compounds 7 and 35 are potent inhibitors across assays and possess favorable ADMET properties. When tested in vivo, compound 7 showed efficacy after oral dosing in a mouse model of peripheral nerve injury by decreasing plasma neurofilament light (NfL) levels at 50 mg/kg compared with vehicle-treated control mice, holding promise for the treatment of neurodegenerative and neurological disorders.}, } @article {pmid40100917, year = {2025}, author = {Thau-Habermann, N and Gschwendtberger, T and Bodemer, C and Petri, S}, title = {Parthenolide regulates microglial and astrocyte function in primary cultures from ALS mice and has neuroprotective effects on primary motor neurons.}, journal = {PloS one}, volume = {20}, number = {3}, pages = {e0319866}, pmid = {40100917}, issn = {1932-6203}, mesh = {Animals ; *Microglia/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; *Motor Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; *Sesquiterpenes/pharmacology ; Mice ; *Astrocytes/drug effects/metabolism ; Superoxide Dismutase-1 ; Superoxide Dismutase/genetics/metabolism ; Cells, Cultured ; }, abstract = {Over the last twenty years, the role of microgliosis and astrocytosis in the pathophysiology of neurodegenerative diseases has increasingly been recognized. Dysregulation of microglial and astrocyte properties and function has been described also in the fatal degenerative motor neuron disease amyotrophic lateral sclerosis (ALS). Microglia cells, the immune cells of the nervous system, can either have an immunonegative neurotoxic or immunopositive neuroprotective phenotype. The feverfew plant (Tanacetum parthenium) derived compound parthenolide has been found to be capable of interfering with microglial phenotype and properties. Positive treatment effects were shown in animal models of neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Now we were able to show that PTL has a modulating effect on primary mouse microglia cells, both wild type and SOD1, causing them to adopt a more neuroprotective potential. Furthermore, we were able to show that PTL, through its positive effect on microglia, also has an indirect positive impact on motor neurons, although PTL itself has no direct effect on these primary motor neurons. The results of our study give reason to consider PTL as a drug candidate for ALS.}, } @article {pmid40102061, year = {2025}, author = {Tran, K and Hayes, HA and Bromberg, M}, title = {A prospective observational study of decision-making by patients with amyotrophic lateral sclerosis upon recommendation for PEG enteral feeding tubes.}, journal = {Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition}, volume = {40}, number = {3}, pages = {623-629}, pmid = {40102061}, issn = {1941-2452}, mesh = {Humans ; *Enteral Nutrition/psychology/methods/instrumentation ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Prospective Studies ; *Gastrostomy/psychology/methods ; Female ; Male ; Middle Aged ; Aged ; *Decision Making ; Patient Satisfaction ; Adult ; Surveys and Questionnaires ; Intubation, Gastrointestinal ; }, abstract = {OBJECTIVE: To understand challenges surrounding acceptance of a percutaneous endoscopic gastroscopic enteral feeding tube by patients with amyotrophic lateral sclerosis: a prospective observational study.

METHODS: This was a prospective observational study of 41 patients and care partners attending a multidisciplinary Motor Neuron Disease clinic. Surveys were administered pregastrostomy tube placement (N = 23) and postplacement (N = 41). Some were not available both pre- and postplacement). For preplacement, we queried barriers affecting their decision for receiving a gastrostomy tube at the time of recommendation. For postplacement, we queried factors that influenced their decision as well as perceived benefit and satisfaction with use.

RESULTS: Patient concerns about receiving a gastrostomy tube centered on the procedure, possible pain/infection (48%), limitations on activities (44%), impact on body image, and possible extension of life. For patients who received a gastrostomy tube, satisfaction was very high (93%), and there was reduced patient (59%) and care partners (54%) stress. The average BMI was 28.6 kg/m[2] at diagnosis, and there was no net gain in weight. The average time until placement of a gastrostomy tube following recommendation was 145 days (range 13-824 days).

CONCLUSIONS: Despite counseling at multiple time points, the decision to obtain a feeding tube is often challenging for patients and care partners. Gastrostomy tube placement was perceived as a substantial benefit. Addressing these barriers may reduce concerns and promote earlier decision-making to maximize the benefits of placing a gastrostomy tube sooner.}, } @article {pmid40102416, year = {2025}, author = {Rivas-Fernández, JP and Vuillemin, M and Pilgaard, B and Klau, LJ and Fredslund, F and Lund-Hanssen, C and Welner, DH and Meyer, AS and Morth, JP and Meilleur, F and Aachmann, FL and Rovira, C and Wilkens, C}, title = {Unraveling the molecular mechanism of polysaccharide lyases for efficient alginate degradation.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2670}, pmid = {40102416}, issn = {2041-1723}, support = {315385//Norges Forskningsråd (Research Council of Norway)/ ; 226244//Norges Forskningsråd (Research Council of Norway)/ ; 294946//Norges Forskningsråd (Research Council of Norway)/ ; DFF170746//Det Frie Forskningsråd (Danish Council for Independent Research)/ ; 2021-SGR-00680//Government of Catalonia | Agència de Gestió d'Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grants)/ ; NNF10CC1016517//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; }, mesh = {*Alginates/metabolism/chemistry ; *Polysaccharide-Lyases/metabolism/chemistry/genetics ; Catalytic Domain ; Kinetics ; Crystallography, X-Ray ; Molecular Dynamics Simulation ; Substrate Specificity ; }, abstract = {Alginate lyases (ALs) catalyze the depolymerization of brown macroalgae alginates, widely used naturally occurring polysaccharides. Their molecular reaction mechanism remains elusive due to the lack of catalytically competent Michaelis-Menten-like complex structures. Here, we provide structural snapshots and dissect the mechanism of mannuronan-specific ALs from family 7 polysaccharide lyases (PL7), employing time-resolved NMR, X-ray, neutron crystallography, and QM/MM simulations. We reveal the protonation state of critical active site residues, enabling atomic-level analysis of the reaction coordinate. Our approach reveals an endolytic and asynchronous syn β-elimination reaction, with Tyr serving as both Brønsted base and acid, involving a carbanion-type transition state. This study not only reconciles previous structural and kinetic discrepancies, but also establishes a comprehensive PL reaction mechanism which is most likely applicable across all enzymes of the PL7 family as well as other PL families.}, } @article {pmid40103545, year = {2026}, author = {Sonaglioni, A and Torretta, P and Nicolosi, GL and Lombardo, M}, title = {Left ventricular mechanics assessment in amyloidosis patients: a systematic review and meta-analysis.}, journal = {Minerva cardiology and angiology}, volume = {74}, number = {1}, pages = {60-74}, doi = {10.23736/S2724-5683.24.06683-3}, pmid = {40103545}, issn = {2724-5772}, mesh = {Humans ; *Amyloidosis/physiopathology/diagnostic imaging/complications ; Echocardiography/methods ; *Ventricular Dysfunction, Left/diagnostic imaging/physiopathology/etiology ; Ventricular Function, Left ; Magnetic Resonance Imaging/methods ; Heart Ventricles/diagnostic imaging/physiopathology ; }, abstract = {BACKGROUND: Over the last decade, a small number of studies have used speckle tracking echocardiography (STE) or cardiac magnetic resonance (CMR) for measuring left ventricular (LV) mechanics in patients with amyloidosis. This systematic review and meta-analysis aimed at assessing the overall influence of amyloidosis on LV global longitudinal strain (GLS) and regional longitudinal strain at basal (BLS), mid (MLS) and apical (ALS) level, respectively.

METHODS: All imaging studies assessing LV-GLS, LV-BLS, LV-MLS and LV-ALS in amyloidosis patients versus healthy controls, selected from PubMed and EMBASE databases, were included. The risk of bias was assessed by using the National Institutes of Health (NIH) Quality Assessment of Case-Control Studies. Continuous data (LV-GLS, LV-BLS, LV-MLS and LV-ALS) were pooled as a standardized mean differences (SMDs) comparing amyloidosis group with healthy controls. The overall SMDs of LV-GLS, LV-BLS, LV-MLS and LV-ALS were calculated using the random-effect model.

RESULTS: The full-texts of 13 studies with 553 amyloidosis patients and 575 healthy controls were analyzed. STE (53.8%) and CMR (46.2%) studies were separately analyzed. Average LV-GLS magnitude was significantly impaired in amyloidosis patients vs. controls in both STE (13.8±3.9 vs. 19.8±2.7%) and CMR (12.3±4 vs. 17.9±3.5%) studies. The impairment of segmental strain detected in amyloidosis patients was prevalent at basal and mid level, with relative "apical sparing." SMDs obtained for LV-GLS (SMD -1.80, 95% CI: -2.35, -1.24, P <0.001), LV-BLS (-1.98; 95% CI: -2.51, -1.45, P <0.001) and LV-MLS (-1.84; 95% CI: -2.46, -1.23, P <0.001) assessment were significantly larger than that obtained for LV-ALS (-0.72; 95% CI: -1.31, -0.13, P=0.02) measurement. Substantial heterogeneity was found among the studies assessing LV-GLS (I[2]=92.5%), LV-BLS (I[2]=91.4%), LV-MLS (I[2]=94.3%) and LV-ALS (I[2]=94.6%). Egger's test yielded a P value of 0.10, 0.20, 0.09 and 0.55 for LV-GLS, LV-BLS, LV-MLS and LV-ALS assessment respectively, indicating no publication bias. On meta-regression analysis, none of the moderators was significantly associated with effect modification for LV-GLS, LV-BLS, LV-MLS and LV-ALS (all P<0.05).

CONCLUSIONS: Amyloidosis has a large negative effect on LV-GLS, primarily related to the deterioration of segmental longitudinal strain at the basal and mid level, with relative apical sparing.}, } @article {pmid40105198, year = {2025}, author = {Gotkine, M and Schoenfeld, DA and Cohen, I and Shefner, JM and Lerner, Y and Cohen, IR and Klein, C and Ovadia, E and Cudkowicz, ME and , }, title = {Akt Activation With IPL344 Treatment for Amyotrophic Lateral Sclerosis: First in Human, Open-Label Study.}, journal = {Muscle & nerve}, volume = {71}, number = {6}, pages = {1032-1042}, pmid = {40105198}, issn = {1097-4598}, support = {//Immunity Pharma/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/blood ; Male ; Female ; Middle Aged ; Aged ; Neurofilament Proteins/blood ; *Proto-Oncogene Proteins c-akt/metabolism ; Treatment Outcome ; Disease Progression ; Adult ; }, abstract = {INTRODUCTION/AIMS: Akt intracellular signal transduction pathway dysfunction has been reported in people with amyotrophic lateral sclerosis (ALS) providing a novel target for intervention in this devastating progressive disease. This first-in-human study evaluated the safety, tolerability, and preliminary efficacy of the Akt pathway activator, IPL344, in people with ALS.

METHODS: Nine participants with ALS and a progression rate > 0.55 points/month on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) received open-label IPL344 treatment (once-daily) for up to 36 months. Safety was assessed through adverse event (AE) reporting. Plasma neurofilament light chain (NfL) concentrations were measured before and after treatment. Clinical outcomes were compared to historical data.

RESULTS: The mean ± SD duration of IPL344 follow-up was 14.0 ± 12.5 months. One participant developed drug hypersensitivity, two had central venous catheter-related AEs, and two had serious pneumonia AEs. The unadjusted mean ± SE slope of decline in ALSFRS-R was -0.53 ± 0.15 (48% slower progression vs. historical controls, p = 0.028). Adjustment for disease stage and rate-indicating covariates indicated a 64% slower ALSFRS-R progression (p = 0.034), with increased rather than reduced body weight (p = 0.02). Eight of nine IPL344-treated participants had a significantly improved slope compared to the median slope of a matched control group (p = 0.04). Plasma NfL concentrations were lowered by 27% (n = 6). Unadjusted median survival for participants in the IPL344 group was 43.4 months [95% CI: 20.5, NA] compared with 19.1 months [17.4, 23.0] in the historical control group.

DISCUSSION: These preliminary data indicate that IPL344 was safe and well-tolerated, and possibly effective. Our findings may merit further investigation in a larger placebo-controlled clinical trial.}, } @article {pmid40105291, year = {2025}, author = {Ozeki-Hayashi, R and Wilkinson, DJC}, title = {'An Unimaginable Challenge': A Cross-Cultural Qualitative Study of Ethics and Decision-Making Around Tracheostomy Ventilation in Patients with Amyotrophic Lateral Sclerosis.}, journal = {AJOB empirical bioethics}, volume = {16}, number = {3}, pages = {172-184}, pmid = {40105291}, issn = {2329-4523}, support = {203132/WT_/Wellcome Trust/United Kingdom ; 203132/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Tracheostomy/ethics ; United Kingdom ; Qualitative Research ; Japan ; *Cross-Cultural Comparison ; United States ; *Personal Autonomy ; Female ; *Respiration, Artificial/ethics ; Male ; *Decision Making/ethics ; *Clinical Decision-Making/ethics ; Middle Aged ; *Physicians ; Adult ; Attitude of Health Personnel ; }, abstract = {BACKGROUND: The rate of tracheostomy with invasive ventilation (TIV) for patients with Amyotrophic Lateral Sclerosis (ALS) varies widely. Previous studies have shown that doctors' values may affect decision-making. There have been no previous international qualitative comparisons of medical decision-making process for TIV or why practice varies.

METHODS: We conducted semi-structured in-depth interviews with 16 doctors actively involved in the management of ALS patients from Japan (n = 7), the UK (n = 5), and the US (n = 4). We used three hypothetical cases to explore decision-making. Conversations were transcribed and thematically analyzed.

RESULTS: Our data reveals similarities but also marked differences in views between the US, the UK and Japan. Almost all participants stated that they ought to respect patient autonomy. However, their approaches varied. British participants wanted to (and felt that they should) respect patient autonomy, but they also believed that TIV was not a realistic option. US participants were likely to prioritize patient autonomy over other ethical principles, and Japanese participants were likely to limit patient autonomy indirectly. The option of TIV appeared to be heavily influenced by the availability of healthcare resources in all three countries. The high cost, limited availability and difficulty of treatment meant that particularly in the UK and the US, it is challenging to receive TIV even if patients wanted this.

CONCLUSIONS: Our study illustrates how the emphasis on autonomy varies along with variations in the way care is organized in the setting of highly resource intensive treatment and progressive severe disabling illness. There is a need to review elements of the decision-making process in all three countries. This includes the need for transparent, ideally centralized, decision-making guidelines about the provision of TIV. Although we investigated a rare neuromuscular disease, our results will be relevant to other diseases requiring highly resource-intensive treatment toward the end of life.}, } @article {pmid40105438, year = {2025}, author = {Ueha, R and Dealino, MA and Koyama, M and Yamakawa, K and Matsumoto, N and Sato, T and Goto, T and Mizukami, A and Kondo, K}, title = {Improved Pharyngeal Contraction and Oral Intake Status After Modified Central-Part Laryngectomy for Late-Stage ALS.}, journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery}, volume = {173}, number = {1}, pages = {154-161}, pmid = {40105438}, issn = {1097-6817}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/surgery/physiopathology/complications ; Male ; Retrospective Studies ; *Laryngectomy/methods ; Aged ; Middle Aged ; Female ; *Deglutition Disorders/etiology/surgery/physiopathology ; *Pharynx/physiopathology/surgery ; *Deglutition/physiology ; }, abstract = {OBJECTIVE: To investigate the effects of modified central-part laryngectomy with pharyngeal space reduction (CPL-PR) on patients with weak deglutitive pharyngeal contraction, as seen in late-stage amyotrophic lateral sclerosis (ALS).

STUDY DESIGN: Retrospective case series.

SETTING: Single-institution academic center.

METHODS: Patients with late-stage ALS confined at The University of Tokyo Hospital between 2019 and March 2024 in whom CPL-PR had been performed were identified. Patients who had undergone simultaneous pharyngeal flap surgery or had no preoperative high-resolution manofluorography done were excluded. Preoperatively, penetration-aspiration scale (PAS) scores were determined via videofluoroscopic swallowing study. Functional oral intake scale (FOIS) scores and high-resolution manometric parameters were measured and compared preoperatively and postoperatively.

RESULTS: Eighteen patients were identified with a median age of 66.5 (interquartile range [IQR]: 58.0-74.8). The median preoperative PAS score was 7.5 (IQR: 5.5-8.0), indicating severe dysphagia. There was significant improvement in oral intake status with FOIS scores increasing from 1 (IQR: 1-1) to 3 (IQR: 2-3) at 3 months postoperatively (P = .0002). Significant increases in velopharyngeal closure integral (P = .024) and mesohypopharyngeal contractile integral (P = .0001) were observed. Upper esophageal sphincter (UES) resting pressure was reduced (P = .0002), and UES relaxation time was prolonged during swallowing (P < .0001).

CONCLUSION: There were tangible improvements in pharyngeal contraction, UES bolus passage, and oral intake status following CPL-PR, which contribute to regaining oral intake in late-stage ALS. CPL-PR is an option for patients requiring tracheostomy who wish to prevent aspiration and regain their ability to take food orally.}, } @article {pmid40106466, year = {2025}, author = {Lemmers, SAM and Le Luyer, M and Stoll, SJ and Hoffnagle, AG and Ferrell, RJ and Gamble, JA and Guatelli-Steinberg, D and Gurian, KN and McGrath, K and O'Hara, MC and Smith, ADAC and Dunn, EC}, title = {Inter-rater reliability of stress signatures in exfoliated primary dentition - Improving scientific rigor and reproducibility in histological data collection.}, journal = {PloS one}, volume = {20}, number = {3}, pages = {e0318700}, pmid = {40106466}, issn = {1932-6203}, support = {R21 MH129030/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Reproducibility of Results ; *Tooth, Deciduous/pathology ; Observer Variation ; *Dental Enamel/pathology ; *Stress, Physiological ; Male ; Female ; }, abstract = {Accentuated Lines (ALs) in tooth enamel can reflect metabolic disruptions from physiological or psychological stresses during development. They can therefore serve as a retrospective biomarker of generalized stress exposure in archaeological and clinical research. However, little consensus exists on when ALs are identified and inter-rater reliability is poorly quantified across studies. Here, we sought to address this gap by examining the reliability of accentuated (AL) markings across raters, in terms of both the presence versus absence of ALs and their intensity (HAL= Highly Accentuated, MAL= Mildly Accentuated, RL= Retzius Line). Ratings were made and compared across observers (with different levels of experience) and pairs of raters (who agreed on AL coding through consensus meetings) (N = 15 teeth, eight observers). Results indicated that more experience in AL assessment does not necessarily produce higher reliability between raters. Most disagreements in intensity ratings occurred in categories other than HAL. Furthermore, when AL assessment was performed by pairs of raters, reliability was significantly higher than individual assessments (Gwet's AC1 = 0.28 to 0.56 for line presence assessment; Gwet's AC1 = 0.48 to 0.64 for line intensity assessment). Based on these results, we recommend a workflow called IRRISS (Improving Reliability and Reporting In Scoring of Stress-markers) to increase rigor and reproducibility in histological analysis of dental collections. The introduction of IRRISS is well-timed, given the surge in studies of teeth occurring across anthropological, epidemiological, medical, forensic, and climate research fields.}, } @article {pmid40108302, year = {2025}, author = {Ma, W and Polgár, E and Dickie, AC and Hajer, MA and Quillet, R and Gutierrez-Mecinas, M and Yadav, M and Hachisuka, J and Todd, AJ and Bell, AM}, title = {Anatomical characterisation of somatostatin-expressing neurons belonging to the anterolateral system.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {9549}, pmid = {40108302}, issn = {2045-2322}, support = {MR/S002987/1/MRC_/Medical Research Council/United Kingdom ; 219433/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; 304005/Z/23/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; *Somatostatin/metabolism/genetics ; Mice ; *Neurons/metabolism/cytology ; *Spinal Cord/metabolism/cytology ; Axons/metabolism ; Mice, Transgenic ; }, abstract = {Anterolateral system (ALS) spinal projection neurons are essential for pain perception. However, these cells are heterogeneous, and there has been extensive debate about the roles of ALS populations in the different pain dimensions. We recently performed single-nucleus RNA sequencing on a developmentally-defined subset of ALS neurons, and identified 5 transcriptomic populations. One of these, ALS4, consists of cells that express Sst, the gene coding for somatostatin, and we reported that these were located in the lateral part of lamina V. Here we use a Sst[Cre] mouse line to characterise these cells and define their axonal projections. We find that their axons ascend mainly on the ipsilateral side, giving off collaterals throughout their course in the spinal cord. They target various brainstem nuclei, including the parabrachial internal lateral nucleus, and the posterior triangular and medial dorsal thalamic nuclei. We also show that in the L4 segment Sst is expressed by ~ 75% of ALS neurons in lateral lamina V and that there are around 120 Sst-positive lateral lamina V cells on each side. Our findings indicate that this is a relatively large population, and based on projection targets we conclude that they are likely to contribute to the affective-motivational dimension of pain.}, } @article {pmid40109277, year = {2025}, author = {Ding, XY and Habimana, JD and Li, ZY}, title = {The role of DPP6 dysregulation in neuropathology: from synaptic regulation to disease mechanisms.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1547495}, pmid = {40109277}, issn = {1662-5102}, abstract = {As a transmembrane protein, DPP6 modulates the function and properties of ion channels, playing a crucial role in various tissues, particularly in the brain. DPP6 interacts with potassium channel Kv4.2 (KCND2), enhancing its membrane expression and channel kinetics. Potassium ion channels are critical in progressing action potential formation and synaptic plasticity. Therefore, dysfunction of DPP6 can lead to significant health consequences. Abnormal DPP6 expression has been identified in several diseases, such as amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), spinal bulbar muscular atrophy (SBMA), and idiopathic ventricular fibrillation. Recent research has indicated a connection between DPP6 and Alzheimer's disease as well. The most common symptoms resulting from DPP6 dysregulation are mental deficiency and muscle wastage. Notably, these symptoms do not always occur at the same time. Besides genetic factors, environmental factors also undoubtedly play a role in diseases related to DPP6 dysregulation. However, it remains unclear how the expression of DPP6 gets regulated. This review aims to summarize the associations between DPP6 and neurological diseases, offering insights as well as proposing hypotheses to elucidate the underlying mechanisms of DPP6 dysregulation.}, } @article {pmid40109661, year = {2025}, author = {Hong, Y and Shi, JQ and Feng, S and Huang, SQ and Yuan, ZH and Liu, S and Zhang, XH and Zhou, JS and Jiang, T and Zhao, HD and Zhang, YD}, title = {The systemic inflammation markers as potential predictors of disease progression and survival time in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1552949}, pmid = {40109661}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal and untreatable neurodegenerative disease with only 3-5 years' survival time after diagnosis. Inflammation has been proven to play important roles in ALS progression. However, the relationship between systemic inflammation markers and ALS has not been well established, especially in Chinese ALS patients. The present study aimed to assess the predictive value of systemic inflammation markers including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and systemic immune-inflammation index (SII) for Chinese amyotrophic lateral sclerosis (ALS).

METHODS: Seventy-two Chinese ALS patients and 73 controls were included in this study. The rate of disease progression was calculated as the change of Revised ALS Functional Rating Scale (ALSFRS-R) score per month. Patients were classified into fast progressors if the progression rate > 1.0 point/month and slow progressors if progression rate ≤ 1.0 point/month. The value of NLR, PLR, LMR, and SII were measured based on blood cell counts. The association between systemic inflammation markers and disease progression rate was confirmed by logistic regression analysis. Kaplan-Meier curve and Cox regression models were used to evaluate factors affecting the survival outcome of ALS patients.

RESULTS: For Chinese ALS patients, NLR, PLR and SII were higher, LMR was lower when compared with controls. All these four markers were proved to be independent correlated with fast progression of ALS. Both Kaplan-Meier curve and Cox regression analysis indicated that higher NLR and lower LMR were associated with shorter survival time in the ALS patients.

DISCUSSION: In conclusion, the systemic inflammation markers, especially NLR and LMR might be independent markers for rapid progression and shorter survival time in Chinese ALS patients.}, } @article {pmid40113485, year = {2025}, author = {Anzilotti, S and Franco, C and Valsecchi, V and Cuomo, O and Lombardi, G and Di Muraglia, N and De Iesu, N and Laudati, G and Annunziato, L and Canzoniero, LMT and Pignataro, G}, title = {Modulation of ZnT-1 by Let7a unveils a therapeutic potential in amyotrophic lateral sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {22}, number = {3}, pages = {e00571}, pmid = {40113485}, issn = {1878-7479}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics/drug therapy ; Animals ; *Cation Transport Proteins/metabolism/genetics ; Mice ; *MicroRNAs/metabolism/genetics ; Mice, Transgenic ; Spinal Cord/metabolism/pathology ; Humans ; Motor Neurons/metabolism/pathology ; Disease Models, Animal ; Microglia/metabolism ; Superoxide Dismutase/genetics ; }, abstract = {The imbalance in cellular ionic homeostasis represents a hallmark of several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). Zinc Transporter 1 (ZnT1), the first described member of the ZnT family, stands out as the sole member of the SLC30 family responsible for exporting cytosolic zinc to the extracellular space. While ZnT1 is expressed across all tissues and cell types studied, it exhibits the highest prominence within the central nervous system. In ALS SOD1[G93A] mice, a reduction in ZnT1 expression consistent with disease progression has been observed, prompting our investigation into its role in ALS pathophysiology. Remarkably, through the use of a sequence complementary to the microRNA let-7a (anti-Let-7a) able to modulate ZnT1 expression, we demonstrated in ALS mice its capability to: (1) prevent the reduction in ZnT1 levels in the spinal cord; (2) preserve motor neuron survival in the ventral spinal horn; (3) decrease astroglial and microglial activation while sparing resident microglial cells in the spinal cord; and (4) improve the lifespan and alleviate motor symptoms.}, } @article {pmid40116017, year = {2025}, author = {Addy, G and Scirocco, E and Gelevski, D and Rohrer, M and Roderick, A and McCormack, M and Weiss Sadan, A and Scalia, J and Parikh, N and Giacomelli, E and Locatelli, M and Neel, DV and D'Agostino, D and Leite, A and Yu, H and Sherman, AV and Mock, J and Kalmes, A and Luppino, S and Babu, S and Berry, J and Cudkowicz, M and Paganoni, S}, title = {An Expanded Access Protocol of RNS60 in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {72}, number = {1}, pages = {124-129}, pmid = {40116017}, issn = {1097-4598}, support = {T32 GM144273/GM/NIGMS NIH HHS/United States ; //The study drug was provided at no cost by Revalesio, and program costs were covered by philanthropic donations to the Sean M. Healey & AMG Center for ALS/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Middle Aged ; Male ; Female ; Aged ; Adult ; Pilot Projects ; Nebulizers and Vaporizers ; Treatment Outcome ; }, abstract = {AIMS: RNS60 is an investigational product in clinical development for amyotrophic lateral sclerosis (ALS). RNS60 slowed disease progression in the ALS SOD1[G93A] mouse model and was safe and well tolerated both in an open-label pilot study and a randomized, placebo-controlled, multicenter phase 2 trial in people living with ALS. The objective of this ongoing expanded access protocol (EAP) was to provide RNS60 to people living with ALS who are ineligible for controlled clinical trials and to collect data on the safety and tolerability of dosing RNS60 via twice-daily nebulization rather than the previously studied daily nebulization with weekly intravenous administration.

METHODS: Eligible participants (≥ 18 years old, diagnosed with ALS per investigator assessment, and ineligible for an ALS clinical trial testing RNS60) were treated with twice-daily nebulization of RNS60 at home. Safety was evaluated by the assessment of adverse events and routine safety labs.

RESULTS: A total of 84 participants have been treated with RNS60 via nebulization twice daily for up to 48 months so far. The most common treatment-related adverse event was increased secretions [N = 27 (32%)]. Serious adverse events (SAEs) [69 occurrences; N = 38 (45%) with at least one SAE] and deaths [N = 24 (28%)] were deemed not related to RNS60.

DISCUSSION: This EAP supports the benign side effect profile of RNS60 when administered via twice-daily nebulization and demonstrates the feasibility of long-term EAPs as a complementary approach to controlled trials in people with advanced ALS.}, } @article {pmid40116361, year = {2025}, author = {Li, C and Noonan, AM and Hays, J and Roychowdhury, S and Malalur, P and Elkhatib, R and Manne, A and Mittra, A and Rahman, S and Yan, L and Hill, K and Abbott, N and Phelps, M and Na, JY and Liang, B and Storts, H and Khan, M and Zhang, EH and Miles, W and Yildiz, V and Wei, L and Wang, JJ and Jin, N}, title = {Riluzole in Combination with mFOLFOX6 and Bevacizumab in Treating Patients with Metastatic Colorectal Cancer: A Phase I Clinical Trial.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {11}, pages = {2115-2123}, pmid = {40116361}, issn = {1557-3265}, support = {K12 CA133250/CA/NCI NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; R01 CA273924/CA/NCI NIH HHS/United States ; K12CA133250//Paul Calabresi Career Development Award for Clinical Oncology/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Bevacizumab/administration & dosage ; *Colorectal Neoplasms/drug therapy/pathology/mortality ; Fluorouracil/administration & dosage ; Leucovorin/administration & dosage ; Neoplasm Metastasis ; Organoplatinum Compounds/administration & dosage ; Riluzole/administration & dosage ; Treatment Outcome ; }, abstract = {PURPOSE: Colorectal cancer is the second leading cause of cancer-related mortality in the United States. Chemotherapies based on 5-fluorouracil (5-FU), when combined with targeted agents, remain the standard of care for patients with metastatic or locally advanced disease. New treatment strategies are needed for patients with metastatic colorectal cancer with microsatellite stable disease. Preclinical studies have shown that riluzole, an oral medicine for amyotrophic lateral sclerosis, inhibits glutamate release and synergizes with 5-fluorouracil to reduce cell viability in colorectal cancer cell lines.

PATIENTS AND METHODS: In this single-arm, phase I trial of riluzole in combination with mFOLFOX6/bevacizumab for patients with metastatic colorectal cancer, the riluzole dose started at 50 mg twice daily, escalating to 100 mg twice daily or de-escalating to 50 mg once daily. Patients received riluzole for 16 weeks in combination with mFOLFOX6/bevacizumab for eight cycles. Patients then either continued mFOLFOX6/bevacizumab or switched therapies.

RESULTS: Twelve of the 14 patients enrolled were evaluable. All patients had previously received FOLFOX, and five patients (41.7%) showed disease resistance to it. Two patients obtained partial responses, nine had stable disease, and one had progressive disease. The objective response rate was 16.7%, and the disease control rate was 91.7%. The median duration of response was 4.9 months (95% confidence interval, 1.6-9.8). Median progression-free survival and overall survival were 4.89 and 12.98 months, respectively.

CONCLUSIONS: Our study showed that riluzole plus mFOLFOX6/bevacizumab is well tolerated in patients with metastatic colorectal cancer and may have clinical activity in patients whose disease is resistant to FOLFOX.}, } @article {pmid40116377, year = {2025}, author = {Zhu, Y and Li, M and Zhou, M and Hong, D}, title = {Letter on Wine Glass Sign in Bulbar-Onset Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {97}, number = {6}, pages = {1222}, doi = {10.1002/ana.27239}, pmid = {40116377}, issn = {1531-8249}, } @article {pmid40116411, year = {2025}, author = {Albrethsen, J and Drici, L and Slot Vilmann, LM and Holmboe, SA and Thomsen, CE and Rogaczewska Groendahl, VL and Ottenheijm, ME and Nielsen, AB and Christoffersen, C and Aksglaede, L and Hagen, CP and Wewer Albrechtsen, NJ and Juul, A}, title = {Targeted proteomics of serum IGF-I, -II, IGFBP-2, -3, -4, -5, -6 and ALS.}, journal = {Clinical chemistry and laboratory medicine}, volume = {63}, number = {8}, pages = {1528-1537}, pmid = {40116411}, issn = {1437-4331}, support = {12298//TømmerhandlerVilhelm Bangs Foundation/ ; 1052-00003B//Danmarks Frie Forskningsfond/ ; //Kirsten and the Freddy Johansen Foundation/ ; MST-611-00012//Miljøstyrelsen/ ; NNF14CC0001//Novo Nordisk Fonden/ ; NNF17OC0027594//Novo Nordisk Fonden/ ; NNF19OC0055001//Novo Nordisk Fonden/ ; NNF24OC0088402//Novo Nordisk Fonden/ ; }, mesh = {Humans ; *Proteomics/methods ; Insulin-Like Growth Factor Binding Protein 2/blood ; *Insulin-Like Growth Factor I/analysis ; Insulin-Like Growth Factor Binding Protein 3/blood ; Child ; *Insulin-Like Growth Factor II/analysis ; Adolescent ; Tandem Mass Spectrometry ; Insulin-Like Growth Factor Binding Protein 5/blood ; *Insulin-Like Growth Factor Binding Proteins/blood ; *Glycoproteins/blood ; Insulin-Like Growth Factor Binding Protein 4/blood ; Male ; Female ; *Carrier Proteins/blood ; Insulin-Like Growth Factor Binding Protein 6/blood ; Chromatography, High Pressure Liquid ; }, abstract = {OBJECTIVES: The insulin-like growth factors (IGFs) regulate growth in humans. IGF-I and IGF binding protein (IGFBP)-3 are biomarkers in children with growth disorders. We investigate a targeted proteomics method for absolute quantitation of eight IGF protein family members in human serum, including the peptide hormones IGF-I and -II, and the six binding proteins IGFBP-2, -3, -4, -5, -6 and acid labile subunit (ALS).

METHODS: Serum preparation was optimized for targeted proteomics of IGF related proteins on a clinical LC-MS/MS platform (UHPLC coupled with Triple-Q MS). We created quality controls, standards and internal standards and 289 serum samples from healthy children and adolescents were measured in ten batches over two months. The method was compared to WHO reference standards, clinical and research immunoassays, and relative proteomics profiling.

RESULTS: The sensitivity and reproducibility were sufficient for most but not all IGF protein family members. Targeted proteomics correlated well with clinical immunoassays for IGF-I (R[2]=0.88) and for IGFBP-3 (R[2]=0.46), (p<0.001). The correlation between targeted proteomics and non-clinical immunoassays for IGF-II, IGFBP-2, -4, -5, -6 and ALS varied between proteins.

CONCLUSIONS: We present a method for parallel quantification of IGF-I, IGFBP-3, 5 and ALS for clinical verification studies, whereas targeted proteomics of the five remaining IGF related proteins (IGF-II, IGFBP-2, -4, and -6) require further examination. The sensitivity of our new IGF-I method suggests a possible diagnostic role for targeted proteomics of IGF-I in the management of children with extremely low levels of circulating IGF-I.}, } @article {pmid40117341, year = {2025}, author = {Koehn, LM and Steele, JR and Schittenhelm, RB and Nicolazzo, JA}, title = {Sex-Specific Markers of Neuroinflammation and Neurodegeneration in the Spinal Cord Proteome of the SOD1[G93A] Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Journal of proteome research}, volume = {24}, number = {4}, pages = {1956-1970}, doi = {10.1021/acs.jproteome.4c00990}, pmid = {40117341}, issn = {1535-3907}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Female ; *Spinal Cord/metabolism/pathology ; Mice ; Male ; Disease Models, Animal ; *Proteome/genetics/metabolism ; *Superoxide Dismutase-1/genetics ; Proteomics/methods ; Biomarkers/metabolism ; Mice, Transgenic ; *Neuroinflammatory Diseases/metabolism/pathology/genetics ; Sex Factors ; Sex Characteristics ; Superoxide Dismutase/genetics ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has no cure. The underlying mechanistic details of sex differences in the ALS spinal cord, the site of disease onset, are not understood to an extent that could guide novel drug development. To address this, the spinal cords of 120-day-old wild-type (WT) and SOD1[G93A] (familial mouse model of ALS with mutant superoxide dismutase 1) mice were subjected to untargeted, quantitative proteomics using tandem mass tag acquisition on high-resolution mass spectrometric instrumentation. Compared to WT, both male and female SOD1[G93A] spinal cords exhibited an upregulation of neuroinflammatory cascades of both peripheral and central origins, as well as a downregulation of proteins reflective of death and dysfunction of cells within the spinal cord. However, female and male SOD1[G93A] mouse spinal cords exhibited sex-specific differences in proteins compared to respective WT that related to immune response, as well as cellular structure, function, and homeostasis. The proteomic datasets presented provide entire cohort and sex-specific spinal cord drug targets and disease biomarkers in the SOD1[G93A] mouse model of ALS that may guide future drug development and sex selection in preclinical study designs utilizing the SOD1[G93A] model.}, } @article {pmid40117902, year = {2025}, author = {Wi, JH and Lee, H and Park, JM and Heo, Y and Jo, S and Lee, J and Kim, Y and Jung, C and Kim, NJ and Song, GY and Kim, P and Kim, H and Lee, S}, title = {Development of a TBK1 and ALK dual inhibitor for alleviating depressive behavior via anti-inflammatory effects.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {186}, number = {}, pages = {117991}, doi = {10.1016/j.biopha.2025.117991}, pmid = {40117902}, issn = {1950-6007}, mesh = {Animals ; *Protein Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; *Anaplastic Lymphoma Kinase/antagonists & inhibitors/metabolism ; Mice ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; *Protein Kinase Inhibitors/pharmacology ; *Depression/drug therapy/enzymology ; Lipopolysaccharides ; Humans ; Male ; Disease Models, Animal ; *Behavior, Animal/drug effects ; Mice, Inbred C57BL ; Signal Transduction/drug effects ; *Antidepressive Agents/pharmacology ; }, abstract = {Polypharmacology offers innovative strategies for treating immune and inflammatory dysregulation in complex diseases. Here, we identified ALS-04, a dual inhibitor of TANK-binding kinase 1 (TBK1) and anaplastic lymphoma kinase (ALK), which are closely linked to stimulator of interferon genes (STING)-mediated immune responses. ALS-04 effectively suppressed 2'3'-cyclic GMP-AMP (cGAMP)- and lipopolysaccharide (LPS)-induced type I interferon and pro-inflammatory responses by targeting the STING-TBK1 and STING-ALK pathways. Furthermore, ALS-04 significantly alleviated depressive symptoms, including anhedonia and behavioral despair, in an LPS-induced mouse model of depression. These findings highlight the therapeutic potential of dual TBK1 and ALK inhibition in depression by modulating immune and inflammatory pathways.}, } @article {pmid40118328, year = {2025}, author = {Mansour, HM and El-Khatib, AS}, title = {Oligonucleotide-based therapeutics for neurodegenerative disorders: Focus on antisense oligonucleotides.}, journal = {European journal of pharmacology}, volume = {998}, number = {}, pages = {177529}, doi = {10.1016/j.ejphar.2025.177529}, pmid = {40118328}, issn = {1879-0712}, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use/chemistry ; *Neurodegenerative Diseases/drug therapy/genetics/therapy ; Animals ; }, abstract = {Antisense oligonucleotides (ASOs) specifically bind to target RNA sequences and regulate protein expression through various mechanisms. ASOs are a promising therapeutic approach for treating neurodegenerative diseases. The ASO field is a growing area of drug development that focuses on targeting the root cause of diseases at the RNA level, providing a promising alternative to therapies that target downstream processes. Addressing challenges related to off-target effects and inadequate biological activity is essential to successfully develop ASO-based therapies. Researchers have investigated various chemical modifications and delivery strategies to overcome these challenges. This review discusses oligonucleotide-based therapies, particularly ASOs. We discuss the chemical modifications and mechanisms of action of ASOs. Additionally, we recap the results of preclinical and clinical studies testing different ASOs in various neurodegenerative disorders, including spinal muscular atrophy, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In conclusion, ASO drugs show promise as a therapeutic option for treating neurodegenerative diseases.}, } @article {pmid40119207, year = {2025}, author = {Cheng, M and Lu, D and Li, K and Wang, Y and Tong, X and Qi, X and Yan, C and Ji, K and Wang, J and Wang, W and Lv, H and Zhang, X and Kong, W and Zhang, J and Ma, J and Li, K and Wang, Y and Feng, J and Wei, P and Li, Q and Shen, C and Fu, XD and Ma, Y and Zhang, X}, title = {Author Correction: Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {913}, doi = {10.1038/s41593-025-01941-2}, pmid = {40119207}, issn = {1546-1726}, } @article {pmid40119776, year = {2025}, author = {Pesti, B and Langa, X and Kumpesa, N and Valdeolivas, A and Sultan, M and Rottenberg, S and Hahn, K}, title = {Mini Review: Spatial Transcriptomics to Decode the Central Nervous System.}, journal = {Toxicologic pathology}, volume = {53}, number = {4}, pages = {397-402}, doi = {10.1177/01926233251325204}, pmid = {40119776}, issn = {1533-1601}, mesh = {Humans ; Animals ; *Transcriptome ; *Central Nervous System/metabolism ; *Gene Expression Profiling/methods ; Neurodegenerative Diseases/genetics ; }, abstract = {Spatial transcriptomics (ST) is revolutionizing our understanding of the central nervous system (CNS) by providing spatially resolved gene expression data. This mini review explores the impact of ST on CNS research, particularly in neurodegenerative diseases like Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis. We describe two foundational ST methods: sequencing-based and imaging-based. Key studies are reviewed highlighting the power of ST data sets to map transcriptomes to disease-specific histomorphology, elucidate molecular mechanisms of regional and cellular vulnerability, integrate single-cell data with tissue mapping, and reveal receptor-ligand interactions. Despite current challenges like data interpretation and resolution limits, ST holds promise for identifying novel drug targets, evaluating their therapeutic potential, and bridging gaps between animal models and human studies to advance development of CNS-targeting compounds.}, } @article {pmid40120962, year = {2025}, author = {Zhang, X and Wang, J and Zhang, J and Jiang, C and Liu, X and Wang, S and Zhang, Z and Rastegar-Kashkooli, Y and Dialameh, F and Peng, Q and Tao, J and Ding, R and Wang, J and Cheng, N and Wang, M and Wang, F and Li, N and Xing, N and Chen, X and Fan, X and Wang, J and Wang, J}, title = {Humanized rodent models of neurodegenerative diseases and other brain disorders.}, journal = {Neuroscience and biobehavioral reviews}, volume = {172}, number = {}, pages = {106112}, doi = {10.1016/j.neubiorev.2025.106112}, pmid = {40120962}, issn = {1873-7528}, mesh = {Animals ; *Disease Models, Animal ; Humans ; *Neurodegenerative Diseases/genetics/pathology/physiopathology ; *Brain Diseases ; Rodentia ; }, abstract = {Central Nervous System (CNS) diseases significantly affect human health. However, replicating the onset, progression, and pathology of these diseases in rodents is challenging. To address this issue, researchers have developed humanized animal models. These models introduce human genes or cells into rodents. As a result, rodents become more suitable for studying human CNS diseases and their therapies in vivo. This review explores the preparation protocols, pathological and behavioral characteristics, benefits, significance, and limitations of humanized rodent models in researching various CNS diseases, particularly Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, glial cells-related CNS diseases, N-methyl-D-aspartic acid receptor encephalitis, and others. Humanized rodent models have expanded the opportunities for in vivo exploration of human neurodegenerative diseases, other brain disorders, and their treatments. We can enhance translational research on CNS disorders by developing, investigating, and utilizing these models.}, } @article {pmid40122396, year = {2025}, author = {Cao, Y and Xu, Y and Cao, M and Chen, N and Zeng, Q and Lai, MKP and Fan, D and Sethi, G and Cao, Y}, title = {Fluid-based biomarkers for neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {108}, number = {}, pages = {102739}, doi = {10.1016/j.arr.2025.102739}, pmid = {40122396}, issn = {1872-9649}, mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood/metabolism ; *Neurodegenerative Diseases/diagnosis/blood/cerebrospinal fluid/metabolism ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's Disease (AD), Multiple Sclerosis (MS), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are increasingly prevalent as global populations age. Fluid biomarkers, derived from cerebrospinal fluid (CSF), blood, saliva, urine, and exosomes, offer a promising solution for early diagnosis, prognosis, and disease monitoring. These biomarkers can reflect critical pathological processes like amyloid-beta (Aβ) deposition, tau protein hyperphosphorylation, α-syn misfolding, TDP-43 mislocalization and aggregation, and neuronal damage, enabling detection long before clinical symptoms emerge. Recent advances in blood-based biomarkers, particularly plasma Aβ, phosphorylated tau, and TDP-43, have shown diagnostic accuracy equivalent to CSF biomarkers, offering more accessible testing options. This review discusses the current challenges in fluid biomarker research, including variability, standardization, and sensitivity issues, and explores how combining multiple biomarkers with clinical symptoms improves diagnostic reliability. Ethical considerations, future directions involving extracellular vehicles (EVs), and the integration of artificial intelligence (AI) are also highlighted. Continued research efforts will be key to overcoming these obstacles, enabling fluid biomarkers to become crucial tools in personalized medicine for neurodegenerative diseases.}, } @article {pmid40122623, year = {2025}, author = {Ghanizada, H and Nedergaard, M}, title = {The glymphatic system.}, journal = {Handbook of clinical neurology}, volume = {209}, number = {}, pages = {161-170}, doi = {10.1016/B978-0-443-19104-6.00006-1}, pmid = {40122623}, issn = {0072-9752}, mesh = {Humans ; *Glymphatic System/metabolism/physiology ; Animals ; *Neurodegenerative Diseases ; *Brain/metabolism ; }, abstract = {The glymphatic system, a brain-wide network-supporting cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange, is essential for removing metabolic waste from the brain. This system's proper functioning is crucial for maintaining neural health and preventing the accumulation of harmful substances that can lead to neurodegenerative diseases. This chapter explores the glymphatic system's mechanisms, its dysfunction in various neurologic disorders, and potential therapeutic strategies. Recent discoveries reveal the glymphatic system's involvement in aging, sleep, cerebral edema, and conditions, such as Alzheimer, Parkinson, Huntington diseases, amyotrophic lateral sclerosis, small vessel disease, hydrocephalus, migraine, stroke, traumatic brain injury, and psychiatric disorders, where impaired waste clearance contributes to disease pathogenesis. Moreover, therapeutic interventions targeting glymphatic dysfunction present promising avenues for mitigating the effects of neurodegenerative diseases. The chapter underscores the potential of integrating glymphatic research into broader clinical practices, offering new strategies for disease management and prevention.}, } @article {pmid40124731, year = {2025}, author = {Liu, QZ and Sun, NZ}, title = {Investigation on the quality of life after anterior minimally invasive total hip arthroplasty: Commentary on recent findings.}, journal = {World journal of orthopedics}, volume = {16}, number = {3}, pages = {105318}, pmid = {40124731}, issn = {2218-5836}, abstract = {This editorial critically evaluated the recent study by Ishikura et al, which examined the impact of anterior minimally invasive total hip arthroplasty (MIS-THA) on postoperative quality of life, with a specific focus on the timeline and influencing factors for return to work and resumption of driving. Ishikura et al's research demonstrated that anterior MIS-THA could shorten recovery time, reduce postoperative pain, and significantly enhance patients' quality of life and productivity. Their findings identified occupational type and work intensity as key determinants of postoperative recovery. By synthesizing evidence from multiple studies, this analysis systematically evaluated the clinical advantages of anterior MIS-THA-including reduced soft tissue trauma and accelerated functional recovery-while acknowledging its limitations, such as a steep surgical learning curve and early postoperative complication risks. The discussion emphasized the necessity of designing personalized rehabilitation protocols that accounted for patients' occupational demands. Notably, while current findings primarily derived from retrospective analyses, the article highlighted the need for prospective cohort studies to validate these observations. The commentary also addressed ongoing debates in the field, particularly the elevated complication rates associated with the direct anterior approach compared to posterior techniques, thereby underscoring the critical role of surgeon expertise in optimizing procedural safety. Collectively, this evaluation advanced our understanding of postoperative recovery dynamics in anterior MIS-THA and provides evidence-based insights to refine clinical rehabilitation frameworks.}, } @article {pmid40124885, year = {2025}, author = {Dethier, C and Azirar, S and Verluyten, L and Boonen, H and Grosber, M and Gutermuth, J}, title = {Response to Fässler et al's "Successful treatment of refractory folliculitis decalvans with apremilast".}, journal = {JAAD case reports}, volume = {57}, number = {}, pages = {122-123}, pmid = {40124885}, issn = {2352-5126}, } @article {pmid40125691, year = {2025}, author = {Ono, D and Kawai, H and Kuwahara, H and Yokota, T}, title = {Refining Muscle Morphometry Through Machine Learning and Spatial Analysis.}, journal = {Neuropathology and applied neurobiology}, volume = {51}, number = {2}, pages = {e70012}, doi = {10.1111/nan.70012}, pmid = {40125691}, issn = {1365-2990}, mesh = {Humans ; *Machine Learning ; Retrospective Studies ; Male ; *Muscle, Skeletal/pathology ; Female ; Middle Aged ; *Neuromuscular Diseases/pathology ; Spatial Analysis ; Aged ; Adult ; Muscle Fibers, Skeletal/pathology ; *Muscular Diseases/pathology ; }, abstract = {AIMS: Muscle morphology provides important information in differentiating disease aetiology, but its measurement remains challenging because of the lack of an efficient and objective method. This study aimed to quantitatively refine the morphological features of muscle fibres in neuromuscular diseases using machine learning.

METHODS: In this retrospective study, we analysed muscle biopsy specimens on haematoxylin and eosin-staining. Machine learning-based software was developed to segment muscle fibre contours and perform automated muscle morphometry and subsequent graph theory-based spatial analysis of atrophied fibre grouping. A decision tree-based framework, LightGBM, was trained to predict underlying aetiologies based on morphometric and spatial variables.

RESULTS: The study included 100 muscle samples, including 20 normal muscles, 49 myopathies and 19 neuropathies. The fine-tuned segmentation model, YOLOv8, achieved a mask average precision of 0.819. The muscle morphometry revealed the significance of fibre circularity. The mean circularity was higher in the myopathy group, and the SD of circularity was elevated in the neuropathy group. Although most cases were consistent with textbook findings, atypical presentations, such as dermatomyositis with angular atrophy and amyotrophic lateral sclerosis with round atrophy, were objectively documented. Spatial analysis quantified grouped atrophy, showing the potential to feature specific atrophy patterns. The LightGBM model successfully predicted the final clinical diagnosis of the myopathies and neuropathies with an accuracy of 0.852, which exceeded that of 0.808 by human annotation.

CONCLUSION: Automated muscle morphometry and spatial analysis provide quantification of muscle morphology and patterns of atrophy, which will facilitate objective and efficient investigation of neuromuscular diseases.}, } @article {pmid40125702, year = {2025}, author = {Madhavan, S and Deshmukh, S and Cummings, M and Doshi, A and Rezania, K and Freels, S and Sawa, G}, title = {Home-Based Tele-tDCS in Amyotrophic Lateral Sclerosis: Feasibility, Safety, and Preliminary Efficacy.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {5}, pages = {1022-1033}, pmid = {40125702}, issn = {2328-9503}, support = {R21 HD102722/HD/NICHD NIH HHS/United States ; R21HD102722//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Female ; Male ; Middle Aged ; Pilot Projects ; Double-Blind Method ; Feasibility Studies ; Aged ; *Transcranial Direct Current Stimulation/methods/adverse effects ; Telemedicine ; Adult ; Disease Progression ; Treatment Outcome ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Transcranial direct current stimulation (tDCS) shows promise as a neuromodulatory intervention in various neurological disorders, but its application in ALS, particularly in a remote, home-based format, remains underexplored. This study investigates the feasibility, safety, and preliminary efficacy of remotely supervised tele-tDCS in ALS patients.

METHODS: This double-blinded pilot study included 14 spinal-onset ALS participants randomized into two groups: the intervention group received 72 tele-tDCS sessions over 24 weeks, and the delayed-start group received 36 sham sessions followed by 36 tele-tDCS sessions. Stimulation was delivered at 2 mA for 20 min 3 times a week. Primary outcomes included feasibility, safety, and disease progression measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Adherence and adverse effects were monitored throughout.

RESULTS: Ten participants completed the study, with an overall compliance rate of 98.3%. No serious adverse events were reported, and mild side effects, like itching and tingling, were consistent with tDCS literature. The intervention group demonstrated a significantly slower decline in ALSFRS-R scores than the delayed-start group. At 24 weeks, the intervention group had a mean ALSFRS-R change of -1.7, compared to -13.6 in the delayed-start group (p = 0.0018). Additionally, the change in ALSFRS-R between pre- and mid-intervention significantly differed between groups (p = 0.0071).

INTERPRETATION: Tele-tDCS was feasible, safe, and well-tolerated in individuals with ALS. Preliminary efficacy results suggest that tele-tDCS may slow disease progression, underscoring the potential of tele-tDCS as a promising home-based neuromodulatory intervention in ALS management.

TRIAL REGISTRATION: Clinical trial registration: NCT04866771.}, } @article {pmid40125959, year = {2025}, author = {Gupta, U and Kumar, A and Alam, MI and Balaji, PG and Sharma, A and Yadav, AK}, title = {Synthesis and characterization of protein nanohybrid systems for the brain delivery of Riluzole.}, journal = {Therapeutic delivery}, volume = {16}, number = {6}, pages = {569-579}, pmid = {40125959}, issn = {2041-6008}, mesh = {Humans ; *Riluzole/administration & dosage/chemistry ; Cell Survival/drug effects ; Particle Size ; *Brain/metabolism/drug effects ; Animals ; *Serum Albumin, Bovine/chemistry ; *Fullerenes/chemistry ; *Nanoparticles/chemistry ; Cell Line, Tumor ; *Neuroprotective Agents/administration & dosage/chemistry ; Drug Delivery Systems ; Drug Carriers/chemistry ; }, abstract = {AIMS: Synthesis and Characterization of Protein NanoHybrid Systems for the Brain Delivery of Riluzole.

METHODS/MATERIALS: Fullerene is converted into carboxylated fullerene (CF) and then, prepared RZU-loaded BSA nanoparticles conjugated with CF.

RESULTS: The particle size and zeta potential of RZU-PNH were found to be 210 ± 1.15 nm and -18.5 ± 0.615 mV respectively, and entrapment efficiency and loading efficiency of RZU-PNH were found to be 98.8 ± 0.53% and 11.6 ± 0.43%, respectively. The XRD of the RZU-PNH shows the amorphism behavior and CD revealed that secondary structure of the protein mainly consists of α-helix andβ-sheet. The MTT assay showed 88.60% and 90.84% cell viability in both SH-SY5Yand N2a cell lines at a concentration of 20 μg/ml and also, no significant nasal ciliotoxicity was observed after incubation with RZU-PNH.

CONCLUSIONS: Obtained results indicated RZU-PNH formulation to treat amyotrophic lateral sclerosis.}, } @article {pmid40126385, year = {2026}, author = {Yarlagadda, S and Hazboun, M and Vilke, G and Farah, J and Donofrio-Odmann, JJ}, title = {Epidemiology of Neonatal Prehospital Care at the San Diego (US) - Tijuana (Mexico) International Border.}, journal = {Prehospital emergency care}, volume = {30}, number = {2}, pages = {175-180}, doi = {10.1080/10903127.2025.2476196}, pmid = {40126385}, issn = {1545-0066}, mesh = {Humans ; Infant, Newborn ; Retrospective Studies ; *Emergency Medical Services/statistics & numerical data/methods ; Mexico/epidemiology ; Female ; Male ; California ; Ambulances/statistics & numerical data ; Infant ; }, abstract = {OBJECTIVES: Neonates, infants 30 days of age or younger are understudied in prehospital emergencies. Our objective was to describe prehospital assessment and care for patients <30 days of age at the San Diego-Tijuana Point of Entry (POE). Additional objectives included describing assessments, care, frequency, and level of care for newborns brought to the border by Mexican ambulances.

METHODS: This was a retrospective analysis from January 1, 2014, to January 01, 2020, of all 9-1-1 calls involving patients <30 days of age at the San Diego POEs. The 9-1-1 responses to newly delivered patients were "newborns". Patients who were not immediately post-delivery were "neonates." Patient demographics, response intervals, clinician interventions, and dispositional data were collected from electronic patient records. Descriptive statistics were applied.

RESULTS: A total of 57 patients <30 days of age were included. With 27 newborn patients, 15 were delivered by emergency medical services (EMS) personnel (27, 55.6%). Initial appearance, pulse, grimace, activity, and respiration (APGAR) scores were 8-10 in 44.4% and 5-7 in 29.6%. Procedures included newborn care (88.9%), advanced life support (ALS) assessment (63.0%), and warming (59.3%). There were five patients that had stimulation, 7 received oxygen, and 3 received Bag-Valve-Mask (BVM) ventilation. No serial heart rates were documented. Regarding 30 neonates, the predominant method of transport to the POE was Mexican ambulance (n 16, 53.3%). Medications administered included oxygen (n 16, 53.3%) and albuterol/ipratropium (n 1, 3.3%). Procedures included ALS assessment (n 19, 63.3%), pulse oximetry (n 22, 73.3%), and 3-lead electrocardiogram (n 8, 26.7%). Three patients (10%) received BVM. Mexican Ambulances brought 16 neonates. A physician or nurse was present in 37.5% of transfers, 50% were incubated, 25% intubated, 37.5% on supplemental oxygen, and 71% had preexisting intravenous access. These were not interfacility transfers but were 9-1-1 activations by U.S. border agents; and 14 neonates did not arrive via Mexican ambulance. Their complaints were respiratory distress (n 7, 50%) and Brief Resolved Unexplained Episode (n 4, 28.6%).

CONCLUSIONS: We found that 9-1-1 transports at the San Diego-Tijuana POE for patients <30 days were few and involved resuscitation, neonates in Mexican ambulances with specialized equipment, physicians, and unfamiliar medications. Neonates arriving via private transport had respiratory distress and BRUE.}, } @article {pmid40126464, year = {2025}, author = {Shefner, JM and Cudkowicz, ME and Genge, A and Hardiman, O and Al-Chalabi, A and Andrews, JA and Chio, A and Corcia, P and Couratier, P and de Carvalho, M and Heiman-Patterson, T and Henderson, RD and Ingre, C and Johnston, W and Ludolph, A and Maragakis, NJ and Miller, TM and Mora, JS and Petri, S and Simmons, Z and van den Berg, LH and Zinman, L and Kupfer, S and Malik, FI and Meng, L and Simkins, TJ and Wei, J and Wolff, AA and Rudnicki, SA and , }, title = {Reldesemtiv in Amyotrophic Lateral Sclerosis: Results From the COURAGE-ALS Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {82}, number = {5}, pages = {477-485}, pmid = {40126464}, issn = {2168-6157}, support = {UL1 TR002369/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Double-Blind Method ; Aged ; Treatment Outcome ; *Oxadiazoles/therapeutic use ; Disease Progression ; Pyrazines ; Pyrimidines ; Imidazoles ; Pyrroles ; Pyridines ; }, abstract = {IMPORTANCE: Treatment options for amyotrophic lateral sclerosis (ALS) remain suboptimal. Results from a phase 2 study of reldesemtiv in ALS suggested that it may slow disease progression.

OBJECTIVE: To assess the effect of reldesemtiv vs placebo on functional outcomes in ALS.

A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (COURAGE-ALS) was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted at 83 ALS centers in 16 countries from August 2021 to July 2023. The first 24-week period was placebo controlled vs reldesemtiv. All participants received reldesemtiv during the second 24-week period with a 4-week follow-up. Two interim analyses were planned, the first for futility and the second for futility and possible resizing. This was a hybrid decentralized trial with approximately half the trial visits performed remotely and the remaining visits in the clinic. Eligible participants met criteria for definite, probable, or possible ALS with lower motor neuron signs by modified El Escorial Criteria, ALS symptoms for 24 months or less, ALS Functional Rating Scale-Revised (ALSFRS-R) total score of 44 or less, and forced vital capacity of greater than or equal to 65% of predicted.

INTERVENTIONS: Oral reldesemtiv, 300 mg, or placebo twice daily.

MAIN OUTCOMES AND MEASURES: The primary end point was change in ALSFRS-R total score from baseline to week 24.

RESULTS: Of the 696 participants screened, 207 were screen failures. A total of 486 participants (mean [SD] age, 59.4 [10.9] years; 309 male [63.6%]) were randomized to reldesemtiv (n = 325) or placebo (n = 161); 3 randomized patients were not dosed. The second interim analysis at 24 weeks after randomization included 256 participants. The data monitoring committee recommended that the trial should end due to futility, and the sponsor agreed. The mean (SE) group difference in the ALSFRS-R score from baseline to week 24 was -1.1 (0.53; 95% CI, -2.17 to -0.08; P = .04, favoring placebo). Given excess missing data from early termination, the combined assessment assumed greater importance; it, too, failed to show a benefit from treatment with reldesemtiv (win probability was 0.44 for reldesemtiv and 0.49 for placebo, with a win ratio of 0.91; 95% CI of win ratio, 0.77-1.10; P = .11).

CONCLUSIONS AND RELEVANCE: This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04944784.}, } @article {pmid40127392, year = {2025}, author = {Vasta, R and De Mattei, F and Tafaro, S and Canosa, A and Manera, U and Grassano, M and Palumbo, F and Cabras, S and Matteoni, E and Di Pede, F and Zocco, G and Pellegrino, G and Minerva, E and Pascariu, D and Iazzolino, B and Callegaro, S and Fuda, G and Salamone, P and De Marchi, F and Mazzini, L and Moglia, C and Calvo, A and Chiò, A}, title = {Changes to Average Survival of Patients With Amyotrophic Lateral Sclerosis (1995-2018): Results From the Piemonte and Valle d'Aosta Registry.}, journal = {Neurology}, volume = {104}, number = {8}, pages = {e213467}, pmid = {40127392}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy/diagnosis ; Male ; Female ; Registries ; Middle Aged ; Aged ; Adult ; Cohort Studies ; Proportional Hazards Models ; }, abstract = {BACKGROUND AND OBJECTIVES: The average survival of patients with amyotrophic lateral sclerosis (ALS) ranges from 2 to 5 years from symptom onset. However, it remains unclear whether this estimate has improved over time. The objective of this study was to analyze the survival trend of a large population-based cohort of patients with ALS over a 24-year period.

METHODS: Patients from the Piemonte and Valle d'Aosta registry for ALS (PARALS) were categorized into the first (1995-2002), second (2003-2010), or third (2011-2018) epoch based on their diagnosis date. Survival was defined as the time from diagnosis to death, tracheostomy, or censoring date. A Cox proportional hazard model was developed with diagnosis epoch as the primary variable of interest, adjusted for sex, site of onset, age at onset, diagnostic delay, forced vital capacity at diagnosis, Δbody mass index from onset to diagnosis, noninvasive mechanical ventilation use, gastrostomy use, and site of follow-up. A subset analysis comparing the 2007-2012 and 2013-2018 cohorts was conducted, incorporating riluzole prescription, genetics, and preslope category as additional covariates.

RESULTS: A total of 3,134 patients were included, evenly distributed across the 3 epochs (990, 1,023, and 1,121, respectively). The median survival remained stable during the first and second epoch (18.6 months vs 18.3 months) but improved during the third epoch (20.1 months; p = 0.0041), with a hazard ratio (HR) of 0.76 (95% CI 0.67-0.87, p = 0.00003). In the subset analysis, the most recent epoch (2013-2018) showed a continued survival advantage (HR 0.77, 95% CI 0.65-0.90). Of interest, the survival benefit was only evident among intermediate progressors (HR 0.60, 95% CI 0.45-0.80).

DISCUSSION: In the PARALS, ALS survival increased over time. In a subset analysis, the beneficial effect of the epoch was only evident among intermediate progressors. The improvement in multidisciplinary care provided by tertiary centers may be one possible explanation for this finding, although further dedicated studies are needed to confirm this hypothesis.}, } @article {pmid40127736, year = {2025}, author = {Maetani, Y and Kurashige, T and Tada, Y and Kume, K and Watanabe, T and Sotomaru, Y and Yamanaka, K and Maruyama, H and Kawakami, H}, title = {Optineurin knock-out forms TDP-43 aggregates to regulate TDP-43 protein levels despite autophagic up-regulation and aberrant TDP-43 expression.}, journal = {Neuroscience research}, volume = {216}, number = {}, pages = {104893}, doi = {10.1016/j.neures.2025.03.005}, pmid = {40127736}, issn = {1872-8111}, mesh = {Animals ; *Autophagy/physiology ; *DNA-Binding Proteins/metabolism/genetics ; Cell Cycle Proteins/genetics ; *Membrane Transport Proteins/genetics ; Mice ; Mice, Knockout ; Mice, Transgenic ; Up-Regulation ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Spinal Cord/metabolism/pathology ; Motor Neurons/metabolism ; Mice, Inbred C57BL ; Protein Serine-Threonine Kinases/metabolism ; *Transcription Factor TFIIIA/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Optineurin is a causative gene of amyotrophic lateral sclerosis (ALS) and has many roles in processes such as autophagy and inflammation. However, it is unclear how optineurin causes ALS. Optineurin knock-out (Optn-KO) mice, which have been generated by several researchers, exhibit motor neuron degeneration and TDP-43 aggregates, but no motor deficits. Motor dysfunction in ALS model mice is associated with TDP-43 in the spinal cord. We bred Optn-KO mice with TDP-43 overexpression transgenic mice and evaluated whether increased TDP-43 protein causes motor deficits and whether Optn-KO affects TDP-43 protein level. Optn-KO mice had spinal TDP-43 protein levels and motor function comparable to wild-type mice, and TDP-43-transgenic (TDP-43-tg) mice resulted in motor dysfunction and early death. However, double-mutant TDP-43-tg / Optn-KO mice had lower TDP-43 protein levels than TDP-43-tg mice at 18 months age, and showed inhibition of the TBK1-optinerurin autophagic pathway with aging. Furthermore, Optn-KO caused TDP-43-positive cytoplasmic aggregates. TDP-43 overexpression by itself induced spinal microgliosis, but Optn-KO suppressed that microgliosis. Finally, we showed that Optn-KO mice could not exhibit behavioral dysfunction because TDP-43 protein levels were not elevated despite autophagy inhibition. Thus, downregulation of Optn may suppress TDP-43 toxicity by regulating its abundance through aggregate formation.}, } @article {pmid40128246, year = {2025}, author = {Hu, X and Wei, M and Zhang, H and Yu, M and Wang, M and Zhou, B and Luo, Y and Li, B}, title = {The experience of pain symptoms in patients with amyotrophic lateral sclerosis: a qualitative study.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {10183}, pmid = {40128246}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Pain/psychology/etiology/physiopathology ; Qualitative Research ; Pain Management ; Adaptation, Psychological ; Adult ; Pain Measurement ; }, abstract = {ALS is a progressive neurodegenerative disease that has a serious impact on patients and their caregivers. For a long time in the past, ALS was considered a painless disease that was largely ignored by clinicians. Describing the complexity and needs of pain symptoms from the perspective of patients can provide the most intuitive direction for future research. The purpose of our research is to explore the experience of pain symptoms in patients with amyotrophic lateral sclerosis (ALS), provide reference for better understanding of pain symptoms in ALS patients. From April 2023 to May 2023, 27 patients experiencing pain symptoms in Peking University Third Hospital who met the diagnostic criteria of "Chinese Guidelines for the Diagnosis and Treatment of amyotrophic lateral sclerosis" were interviewed by means of objective sampling. The content analysis method was used to describe the pain changes since the disease (amyotrophic lateral sclerosis), the factors that aggravate the pain, the measures to cope with the pain and the needs. The interview results included 3 themes and 11 subthemes. (1) Pain is diverse: the type of pain, the time when pain occurs, the change in pain intensity, and the factors that aggravate pain; (2) Individualized pain coping measures: posture adjustment, medication, physical therapy, warmth, emotional regulation; (3) Patients lack of understanding of pain: insufficient source of knowledge, the single orientation of the solution. The nature, location and aggravating factors of pain in amyotrophic lateral sclerosis patients in China are complicated, which should be paid attention to by clinical staff and scientific researchers. The situation of pain management is not optimistic, and the pain of the vast majority of patients has not been effectively alleviated. It is necessary to realize the importance of self-management and care of others in coping with pain, and conduct further research in the future to find a breakthrough in pain relief, so as to strengthen pain intervention in clinical practice.}, } @article {pmid40128823, year = {2025}, author = {Zhang, W and Huang, C and Yao, H and Yang, S and Jiapaer, Z and Song, J and Wang, X}, title = {Retrotransposon: an insight into neurological disorders from perspectives of neurodevelopment and aging.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {14}, pmid = {40128823}, issn = {2047-9158}, support = {2023TSYCCX0051//Tianshan Talent Training Program/ ; }, mesh = {Humans ; *Retroelements/genetics ; *Aging/genetics ; *Nervous System Diseases/genetics ; Animals ; }, abstract = {Neurological disorders present considerable challenges in diagnosis and treatment due to their complex and diverse etiology. Retrotransposons are a type of mobile genetic element that are increasingly revealed to play a role in these diseases. This review provides a detailed overview of recent developments in the study of retrotransposons in neurodevelopment, neuroaging, and neurological diseases. Retrotransposons, including long interspersed nuclear elements-1, Alu, SINE-VNTR-Alu, and endogenous retrovirus, play important regulatory roles in the development and aging of the nervous system. They have also been implicated in the pathological processes of several neurological diseases, including Alzheimer's disease, X-linked dystonia-parkinsonism, amyotrophic lateral sclerosis, autism spectrum disorder, and schizophrenia. Retrotransposons provide a new perspective for understanding the molecular mechanisms underlying neurological diseases and provide insights into diagnostic and therapeutic strategies of these diseases.}, } @article {pmid40128927, year = {2025}, author = {Aikawa, M and Ando, T and Shibayama, H and Kubota, M and Sonoo, M and Fukutake, T}, title = {[A case of amyotrophic lateral sclerosis complicated by syringomyelia associated with Chiari type I malformation].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {65}, number = {4}, pages = {273-277}, doi = {10.5692/clinicalneurol.cn-002045}, pmid = {40128927}, issn = {1882-0654}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/etiology/diagnosis/complications ; *Syringomyelia/surgery/complications/etiology ; Female ; Aged ; *Arnold-Chiari Malformation/complications/surgery ; Decompression, Surgical/adverse effects ; Disease Progression ; Postoperative Complications/etiology ; Foramen Magnum/surgery ; }, abstract = {The patient was a 78-year-old woman. She underwent foramen magnum decompression for syringomyelia associated with Chiari type I malformation, which had developed with difficulty in raising the left upper limb and muscle weakness in both upper limbs. One year after surgery, weight loss of 20 ‍kg, progressive muscle atrophy and weakness in the extremities, paralytic dysarthria, and fasciculation in the bilateral anterior thighs were observed, and needle electromyography showed acute denervation and chronic denervation in the medial vastus muscle. The rapid postoperative progression of symptoms and lower motor neuron symptoms in the lower extremities could not be explained by syringomyelia associated with Chiari type I malformation and were considered a possible complication of amyotrophic lateral sclerosis (ALS). It is possible that the surgery may have caused ALS progression, and attention to the rate of progression of neurologic symptoms may be important in the diagnosis of ALS complications.}, } @article {pmid40129635, year = {2025}, author = {Galaz-Araya, C and Zuñiga-Núñez, D and Salas-Sepúlveda, F and Herrera-Morande, A and Aspée, A and Poblete, H and Zamora, RA}, title = {Theoretical evaluation of a bulky ortho-thioalkyl-azobenzene as an alternative to photocontrol structural cytotoxic effects of metal-free and disulfide oxidized hSOD1 in pathogenesis of ALS.}, journal = {RSC advances}, volume = {15}, number = {12}, pages = {9018-9026}, pmid = {40129635}, issn = {2046-2069}, abstract = {This study presents a novel photopharmacological strategy to mitigate the cytotoxic effects of apo-hSOD1[S-S], a misfolded protein implicated in neurodegenerative diseases. Using quantum chemical calculations and molecular dynamics simulations, we demonstrate that ortho-thio-substituted azobenzene photoswitches (ortho-TABPs) can be employed to precisely modulate the dynamics of the crucial electrostatic loop (EL) in apo-hSOD1[S-S]. We establish that larger ortho-S-alkyl substituents on the ortho-TABP enhance its redox stability, favouring the cis conformation through the modulation of the position of the n → π* transition. This stability is crucial for operation within the reducing cellular environment. Furthermore, we demonstrate the successful and consistent photomodulation of EL conformational dynamics in apo-hSOD1[S-S] through covalent tethering of an ortho-TABP. This control is achieved by leveraging the thermodynamically stable trans conformation of the photoswitch, which allosterically influences the EL and consequently, the geometry of the Zn-binding site, a critical determinant of apo-hSOD1[S-S] cytotoxicity. This work paves the way for developing targeted therapies for neurodegenerative diseases by demonstrating the precise and effective photomodulation of apo-hSOD1[S-S] via rationally designed ortho-TABPs.}, } @article {pmid40129929, year = {2025}, author = {Liang, F and Sun, Y and Yang, J and Shen, Z and Wang, G and Zhu, J and Zhou, C and Xia, Y}, title = {Gut microbiome is associated with radiotherapy response in lung cancer patients with brain metastases.}, journal = {Frontiers in cellular and infection microbiology}, volume = {15}, number = {}, pages = {1562831}, pmid = {40129929}, issn = {2235-2988}, mesh = {Humans ; *Gastrointestinal Microbiome/radiation effects ; Male ; Female ; *Lung Neoplasms/radiotherapy/pathology ; Middle Aged ; *Brain Neoplasms/radiotherapy/secondary ; Aged ; Feces/microbiology ; RNA, Ribosomal, 16S/genetics ; *Bacteria/classification/genetics/isolation & purification ; Treatment Outcome ; DNA, Bacterial/genetics/chemistry ; }, abstract = {PURPOSE: To investigate the gut microbiome of lung cancer patients with brain metastases undergoing radiotherapy, identify key microorganisms associated with radiotherapy response, and evaluate their potential as biomarkers.

METHODS AND MATERIALS: This study enrolled 55 newly diagnosed lung cancer patients with brain metastases. Fecal samples were collected before radiotherapy and analyzed by 16S rRNA sequencing to assess the gut microbiome's composition and function. Patients were categorized into response (n=28) and non-response (n=27) groups based on treatment efficacy, and α-diversity, β-diversity, and functional pathways were compared between them. Linear Discriminant Analysis Effect Size was used to identify microbial features associated with treatment efficacy. Logistic regression analyses were performed to evaluate the predictive capacity of clinical and microbial factors for treatment outcomes.

RESULTS: No significant difference in α-diversity was observed between the groups (P > 0.05), but β-diversity differed significantly (P = 0.036). Twelve characteristic microorganisms were identified in the response group, including g_ Oscillibacter and g_ Blautia, and nine in the non-response group, such as f_ Desulfovibrionaceae and g_ Megamonas. Metabolic pathways associated with treatment response included ketone body metabolism and pathways related to amyotrophic lateral sclerosis. Multivariate analysis identified g_Flavonifractor (odds ratio [OR] = 6.680, P = 0.004), g_Negativibacillus (OR = 3.862, P = 0.014), C-reactive protein (OR = 1.054, P = 0.017), and systemic inflammation response index (OR = 1.367, P = 0.043) as independent predictors of radiotherapy response. The nomogram and microbiome models achieved area under the curve (AUC) values of 0.935 and 0.866, respectively, demonstrating excellent predictive performance. Decision curve analysis further confirmed these models provided significant net benefits across risk thresholds.

CONCLUSIONS: The composition and functional characteristics of the gut microbiome in lung cancer patients with brain metastases prior to radiotherapy are associated with therapeutic response and possess potential as predictive biomarkers. Further studies are warranted to validate these findings.}, } @article {pmid40130694, year = {2025}, author = {Burke, KM and Arulanandam, V and Scirocco, E and Royse, T and Hall, S and Weber, H and Arnold, J and Pathak, P and Walsh, C and Paganoni, S}, title = {Assistive Technology in ALS: A Scoping Review of Devices for Limb, Trunk, and Neck Weakness.}, journal = {American journal of physical medicine & rehabilitation}, volume = {104}, number = {8}, pages = {e115-e124}, pmid = {40130694}, issn = {1537-7385}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology ; *Self-Help Devices ; *Muscle Weakness/rehabilitation/etiology/physiopathology ; Activities of Daily Living ; Torso/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease affecting upper and lower motor neurons that control voluntary muscles. With no known cure, clinical care is focused on symptom management to maximize function and quality of life. Assistive technology plays a crucial role and enables some restoration of movement and function despite disease progression. This scoping review assesses the effectiveness of assistive technologies tested in people living with amyotrophic lateral sclerosis, specifically those designed to compensate for upper and lower extremity, trunk, and cervical muscle weakness. A comprehensive search was conducted across PubMed, CINAHL, ERIC, and Google Scholar and through citation chasing. We included 26 articles that tested an assistive device on at least one person living with amyotrophic lateral sclerosis and evaluated the device's effectiveness in restoring movement or providing stabilization to support functional mobility or activities of daily living. Most studies were pilot feasibility or usability trials, with small numbers of amyotrophic lateral sclerosis participants. The devices showed various benefits, including improved range of motion, function, and participation in daily activities. This review highlights the potential for assistive devices to enhance function in people living with amyotrophic lateral sclerosis and underscores the need for comprehensive studies involving larger cohorts of individuals at different stages of amyotrophic lateral sclerosis.}, } @article {pmid40131291, year = {2026}, author = {Penn, J and McAleer, R and Ziegler, C and Cheskes, S and Nolan, B and von Vopelius-Feldt, J}, title = {Effectiveness of Prehospital Critical Care Scene Response for Major Trauma: A Systematic Review.}, journal = {Prehospital emergency care}, volume = {30}, number = {2}, pages = {309-322}, doi = {10.1080/10903127.2025.2483978}, pmid = {40131291}, issn = {1545-0066}, mesh = {Humans ; *Emergency Medical Services/methods/standards ; *Critical Care/methods ; *Wounds and Injuries/therapy/mortality ; }, abstract = {OBJECTIVES: Major trauma is a leading cause of morbidity and mortality worldwide. It is unclear if the addition of a critical care response unit (CCRU) with capabilities comparable to hospital emergency departments might improve outcomes following major trauma, when added to Basic or Advanced Life Support (BLS/ALS) prehospital care. This systematic review describes the evidence for a CCRU scene response model for major trauma.

METHODS: We searched Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), CINAHL (EBSCOhost), Science Citation Index Expanded (Web of Science), Conference Proceedings Citation Index - Science (Web of Science), LILACS (Latin American and Caribbean Health Sciences Literature) for relevant publications from 2003 to 2024. We included any study that compared CCRU and BLS/ALS care at the scene of major trauma, reported patient-focused outcomes, and utilized statistical methods to reduce bias and confounding. The risk of bias was assessed by two independent reviewers, using the ROBINS-I tool. Based on our a priori knowledge of the literature, a narrative analysis was chosen. The review was prospectively registered (PROSPERO ID CRD42023490668).

RESULTS: The search yielded 5243 unique records, of which 26 retrospective cohort studies and one randomized controlled trial met inclusion criteria. Sample sizes ranged from 308 to 153,729 patients. Eighteen of the 27 included studies showed associations between CCRUs and improved survival following trauma, which appear to be more consistently found in more critically injured and adult patients, as well as those suffering traumatic cardiac arrest. The remaining nine studies showed no significant difference in outcomes between CCRU and BLS/ALS care. Most studies demonstrated critical or severe risks of bias.

CONCLUSIONS: Current evidence examining CCRU scene response for major trauma suggests potential benefits in severely injury patients but is limited by overall low quality. Further high-quality research is required to confirm the benefits from CCRU scene response for major trauma.}, } @article {pmid40131525, year = {2025}, author = {Kleinerova, J and Tahedl, M and McKenna, MC and Garcia-Gallardo, A and Hutchinson, S and Hardiman, O and Raoul, C and Ango, F and Schneider, B and Pradat, PF and Tan, EL and Bede, P}, title = {Cerebellar dysfunction in frontotemporal dementia: intra-cerebellar pathology and cerebellar network degeneration.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {289}, pmid = {40131525}, issn = {1432-1459}, support = {JPND-Cofund-2-2019-1/HRBI_/Health Research Board/Ireland ; HRB EIA-2017-019/HRBI_/Health Research Board/Ireland ; ANR France 2022-CEREBRALS//Agence Nationale de la Recherche/ ; }, mesh = {Humans ; *Frontotemporal Dementia/diagnostic imaging/pathology/physiopathology/complications ; Male ; Female ; Middle Aged ; Aged ; *Cerebellum/diagnostic imaging/pathology/physiopathology ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/physiopathology ; *Cerebellar Diseases/diagnostic imaging/pathology/etiology/physiopathology ; Magnetic Resonance Imaging ; Neural Pathways/diagnostic imaging/pathology/physiopathology ; C9orf72 Protein/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share overlapping clinical, genetic, and neuroimaging features; a spectrum of conditions commonly referred to as the ALS-FTD continuum. The majority of imaging studies focus on supratentorial pathology, and phenotype-defining motor, cognitive, and behavioural profiles are often exclusively attributed to supratentorial degeneration overlooking the contribution of cerebellar pathology.

METHODS: A multimodal neuroimaging study was conducted to evaluate phenotype-associated cerebello-cerebral connectivity profiles in ALS-FTD, behavioural variant frontotemporal dementia (bvFTD), non-fluent variant (nfvPPA), and semantic variant primary progressive aphasia (svPPA). Structural connectivity, functional connectivity, and volumetric analyses were conducted.

RESULTS: Radial diffusivity analyses detected impaired bilateral cerebello-frontal, cerebello-parietal, and cerebello-temporal connectivity in all study groups along the ALS-FTD spectrum. Cerebello-occipital disconnection was captured in ALS-FTD and nfvPPA. Spinocerebellar disconnection was detected in C9orf72 negative ALS-FTD and nfvPPA. C9orf72 positive ALS-FTD patients exhibited both anterior and posterior lobe cerebellar volume loss, while bvFTD and nfvPPA patients showed posterior cerebellar atrophy. Flocculonodular degeneration was observed in nfvPPA and cerebellar crura atrophy in bvFTD. Bilateral corticospinal tract and corpus callosum degeneration was detected in ALS-FTD, bvFTD, and nfvPPA. Primary motor cortex volume reductions were captured in both ALS-FTD and nfvPPA.

CONCLUSIONS: Our analyses capture significant cerebro-cerebellar disconnection in frontotemporal dementia. Corticospinal tract and motor cortex degeneration can be readily detected in non-ALS phenotypes. Intra-cerebellar pathology, coupled with the degeneration of cerebellar projections and the ensuing dysfunction of cerebro-cerebellar networks likely contribute to phenotype-defining clinical profiles in frontotemporal dementia. Infratentorial disease burden and cerebellar network dysfunction should, therefore, be carefully considered in FTD, and phenotype-defining neuropsychological profiles should not be solely attributed to supratentorial degeneration.}, } @article {pmid40132594, year = {2025}, author = {Zelic, M and Blazier, A and Pontarelli, F and LaMorte, M and Huang, J and Tasdemir-Yilmaz, OE and Ren, Y and Ryan, SK and Shapiro, C and Morel, C and Krishnaswami, P and Levit, M and Sood, D and Chen, Y and Gans, J and Tang, X and Hsiao-Nakamoto, J and Huang, F and Zhang, B and Berry, JD and Bangari, DS and Gaglia, G and Ofengeim, D and Hammond, TR}, title = {Single-cell transcriptomic and functional studies identify glial state changes and a role for inflammatory RIPK1 signaling in ALS pathogenesis.}, journal = {Immunity}, volume = {58}, number = {4}, pages = {961-979.e8}, doi = {10.1016/j.immuni.2025.02.024}, pmid = {40132594}, issn = {1097-4180}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics/immunology ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/genetics ; Animals ; Humans ; Mice ; Signal Transduction ; *Neuroglia/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; *Transcriptome ; Single-Cell Analysis ; Mice, Transgenic ; Superoxide Dismutase-1/genetics ; Inflammation/metabolism ; Microglia/metabolism ; Disease Models, Animal ; Spinal Cord/metabolism/pathology ; Astrocytes/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss. Microglia and astrocyte-driven neuroinflammation is prominent in ALS, but the cell state dynamics and pathways driving disease remain unclear. We performed single-nucleus RNA sequencing of ALS spinal cords and identified altered glial cell states, including increased expression of inflammatory and glial activation markers. Many of these signals converged on the inflammation and cell death regulator receptor-interacting protein kinase 1 (RIPK1) and the necroptotic cell death pathway. In superoxide dismutase 1 (SOD1)[G93A] mice, blocking RIPK1 kinase activity delayed symptom onset and motor impairment and modulated glial responses. We used human induced pluripotent stem cell (iPSC)-derived motor neuron, astrocyte, and microglia tri-cultures to identify potential biomarkers that are secreted upon RIPK1 activation in vitro and modulated by RIPK1 inhibition in the cerebrospinal fluid (CSF) of people with ALS. These data reveal ALS-enriched glial populations associated with inflammation and suggest a deleterious role for neuroinflammatory signaling in ALS pathogenesis.}, } @article {pmid40132681, year = {2025}, author = {Wang, Z and Yang, C and Wang, X and Lyu, W and Liao, H and Liu, X and Liu, H and Zhang, J and Shen, H and Zhang, L and Wang, H}, title = {Decoding stress granules dynamics: Implications for neurodegenerative disease.}, journal = {Progress in neurobiology}, volume = {248}, number = {}, pages = {102758}, doi = {10.1016/j.pneurobio.2025.102758}, pmid = {40132681}, issn = {1873-5118}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Animals ; *Stress Granules/metabolism ; }, abstract = {Stress granules (SGs) are membrane-less cytoplasmic structures formed by cells in response to external stress, primarily composed of mRNA and proteins. The dynamic properties of their assembly, maintenance, and disassembly play crucial roles in cellular homeostasis. Recent studies have increasingly revealed that aberrations in SGs dynamics are closely related to the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review summarizes the latest research progress on SGs dynamics in neurodegenerative diseases. It begins with an overview of the basic biological characteristics of SGs and their functions in neurons, followed by an in-depth exploration of the mechanisms and regulatory pathways of SGs dynamics. The review then summarizes potential therapeutic strategies targeting SGs dynamics abnormalities, particularly through small molecule drugs to modulate SGs formation and disassembly, aiming to delay or halt the progression of neurodegenerative diseases. The review also highlights the application prospects of these interventions in treating neurodegenerative diseases. Finally, the review introduces current techniques used to study SGs dynamics, discussing their advantages, limitations, and future development possibilities. This review aims to provide researchers with a comprehensive perspective to advance the understanding and clinical application of SGs dynamics in the field of neurodegenerative diseases.}, } @article {pmid40132878, year = {2025}, author = {Klickovic, U and Zampedri, L and Zafeiropoulos, N and Ziff, OJ and Sinclair, CD and Wastling, S and Dudziec, M and Allen, J and Trimmel, K and Howard, RS and Malaspina, A and Sharma, N and Sidle, KC and Shah, S and Nasel, C and Yousry, TA and Greensmith, L and Morrow, JM and Thornton, JS and Fratta, P}, title = {Muscle MRI quantifies disease progression in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {9}, pages = {908-911}, pmid = {40132878}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology/diagnosis ; Disease Progression ; Male ; *Magnetic Resonance Imaging ; Middle Aged ; Female ; *Muscle, Skeletal/pathology/physiopathology ; Longitudinal Studies ; Aged ; Muscular Atrophy/pathology ; Adult ; Muscle Strength/physiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Quantitative and operator-independent biomarkers of disease progression are urgently needed in amyotrophic lateral sclerosis (ALS) research. We assess the potential of skeletal muscle MRI as a sensitive and reliable outcome measure for future ALS clinical trials.

METHODS: In this longitudinal cohort study, muscle MRI of head-neck, upper and lower limb regions, alongside clinical and functional assessments, were acquired at three time points over the individual maximum observation period (iMOP) of 1 year in 20 patients with ALS and 16 healthy controls. Quantitative MRI parameters cross-sectional area (CSA), volume (VOL), fat fraction, functional rest muscle area and water T2 (T2m) were correlated with changes in clinical disease severity (functional rating scales and myometry).

RESULTS: Among 20 patients with ALS, 17 completed follow-up. Progressive muscle atrophy (CSA, VOL) was observed at hand (rs=0.66), head-neck (partial η²=0.47) and lower-limb level (thighs: η²=0.56, calves: η²=0.54) over iMOP. MRI changes correlated with leg muscle strength (knee extension: r=0.77; plantar flexion: r=0.78), hand grip strength (r=0.71) and functional rating scales (r=0.68).

INTERPRETATION: Our findings demonstrate the effectiveness of muscle MRI as a sensitive neuroimaging biomarker of disease progression in ALS, highlighting its potential application in clinical trials.}, } @article {pmid40133096, year = {2025}, author = {Shenouda, M and McKeever, PM and Robertson, J}, title = {The long and the short of TDP-43.}, journal = {Trends in neurosciences}, volume = {48}, number = {5}, pages = {313-314}, doi = {10.1016/j.tins.2025.03.003}, pmid = {40133096}, issn = {1878-108X}, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; Protein Isoforms/metabolism/genetics ; }, abstract = {In a recent study, Dykstra and colleagues show that shortened TAR DNA Binding Protein 43 (sTDP-43) isoforms are generated as by-products of TDP-43 autoregulation. sTDP-43 levels are regulated through nonsense-mediated decay and proteasomal and autophagic degradation, and elicit toxicity through dominant negative effects on TDP-43 splicing activity. These results identify mechanisms contributing to sTDP-43 accumulation and toxicity in disease.}, } @article {pmid40133903, year = {2025}, author = {Mitchell, G and Siwela, P and Goldstein, S and Diedericks, AM}, title = {Alcohol industry involvement in the delayed South Africa Draft Liquor Amendment Bill 2016: a case study based on freedom of information requests.}, journal = {Globalization and health}, volume = {21}, number = {1}, pages = {11}, pmid = {40133903}, issn = {1744-8603}, support = {N/A//FORUT/ ; }, mesh = {South Africa ; Humans ; *Alcoholic Beverages/legislation & jurisprudence ; Commerce/legislation & jurisprudence ; *Alcohol Drinking/legislation & jurisprudence ; *Access to Information/legislation & jurisprudence ; }, abstract = {BACKGROUND: South Africa is reported to have one of the highest per capita rates of alcohol consumption among drinkers globally, with alcohol harms exacerbating socio-economic inequalities in the country. The Draft Liquor Amendment Bill 2016 proposed new restrictions on alcohol advertising, availability, and liability of retailers and manufacturers for harm related to any contravention of the regulations. To date, the Bill has not progressed through the legislative process. The alcohol industry is known to use a diverse set of strategies to delay evidence-based policies globally.

METHODS: We aimed to explore Bill-related activity by industry within the National Economic and Development Labour Council, a multi-stakeholder forum that assesses socio-economic policies before they reach parliament. On 06 July 2023 we made a Request for Access to Record, using form two of the Promotion of Access to Information Act (PAIA), no. 2 of 2000 to the National Economic and Development Labour Council for access to minutes of all meetings, reports, and any other publications related to the Bill between January 2016 and December 2022. Informed by Ulucanlar et al's (2023) model and taxonomies of corporate political activity, we extracted data on industry Bill-related activity and thematically analysed key events, presented here as a narrative synthesis.

RESULTS: We identified activity by 14 alcohol industry organisations related to the Bill between 2016 and 2022. Industry representation on five National Economic and Development Labour Council-related committees identified between 2017 and 2021 facilitated their involvement in Bill-related discussions and supported access to other government departments. Community representation was low in all committees compared to industry, labour, and government. Industry funded two socio-economic assessments of the Bill in 2017 and 2022, despite an independent socio-economic impact assessment having already been completed. The 2017 report delayed progress of the Bill, and the 2022 're-evaluation' was more critical of the proposed measures, with the differing conclusions attributed to different methodologies. During the covid-19 pandemic, industry used a 'carrot and stick' approach of legal threats and donations to attempt to move towards self-regulation via a social compact. The National Economic and Development Labour Council confirmed in 2023 that the social compact was unsuccessful.

CONCLUSIONS: Early 'regulatory capture' gave the alcohol industry the opportunity to shape assessment of the Bill within the National Economic and Development Labour Council. Our findings are in line with previous studies on corporate influence on policy globally, and support calls for a reassessment of the role and proportion of industry representation within the National Economic and Development Labour Council locally.}, } @article {pmid40134643, year = {2025}, author = {Guo, YX and Yan, X and Liu, XC and Liu, YX and Liu, C}, title = {Artificial intelligence-driven strategies for managing renal and urinary complications in inflammatory bowel disease.}, journal = {World journal of nephrology}, volume = {14}, number = {1}, pages = {100825}, pmid = {40134643}, issn = {2220-6124}, abstract = {In this editorial, we discuss the article by Singh et al published in World Journal of Nephrology, stating the need for timely adjustments in inflammatory bowel disease (IBD) patients' long-term management plans. IBD is chronic and lifelong, with recurrence and remission cycles, including ulcerative colitis and Crohn's disease. It's exact etiology is unknown but likely multifactorial. Related to gut flora and immune issues. Besides intestinal symptoms, IBD can also affect various extraintestinal manifestations such as those involving the skin, joints, eyes and urinary system. The anatomical proximity of urinary system waste disposal to that of the alimentary canal makes early detection and the differentiation of such symptoms very difficult. Various studies show that IBD and it's first-line drugs have nephrotoxicity, impacting the patients' life quality. Existing guidelines give very few references for kidney lesion monitoring. Singh et al's plan aims to improve treatment management for IBD patients with glomerular filtration rate decline, specifically those at risk. Most of IBD patients are young and they need lifelong therapy. So early therapy cessation, taking into account drug side effects, can be helpful. Artificial intelligence-driven diagnosis and treatment has a big potential for management improvements in IBD and other chronic diseases.}, } @article {pmid40135522, year = {2025}, author = {Bai, D and Fang, Y and Tian, J and Liao, Y and Liu, M and Pan, L}, title = {Tribenuron-methyl resistance in Capsella bursa-pastoris: the co-existence of ALS target enzyme mutation (Pro-197-Ser) and overexpression of GSTF12 and ADP/ATP carrier protein.}, journal = {Pest management science}, volume = {81}, number = {8}, pages = {4365-4372}, doi = {10.1002/ps.8794}, pmid = {40135522}, issn = {1526-4998}, support = {//Scientific Research Fund of Hunan Provincial Education Department/ ; //National Natural Science Foundation of China/ ; //National Key Research and Development Program of China/ ; //China Agriculture Research System/ ; //Modern Agricultural Industrial Technology System of Hunan Province/ ; }, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Acetolactate Synthase/genetics/metabolism ; *Arylsulfonates/pharmacology ; Mutation ; *Capsella/genetics/drug effects/enzymology ; *Plant Proteins/genetics/metabolism ; }, abstract = {BACKGROUND: Capsella bursa-pastoris, a prevalent wheat-field weed in China, demonstrates substantial resistance to tribenuron-methyl, a herbicide-targeting acetolactate synthase (ALS). Understanding weed herbicide-resistance mechanisms is crucial for managing resistant weed populations. However, the genes potentially involved in nontarget-site resistance (NTSR) in herbicide-resistant C. bursa-pastoris remain poorly understood and require further investigation. This research aimed to elucidate the resistance level and underlying mechanisms of a field population (R) from Shandong Province, China, to tribenuron-methyl.

RESULTS: Whole-plant bioassays revealed that the relative resistance index (RI) of the R population was 54-fold greater than that of the tribenuron-methyl-sensitive population (S). Additionally, treatment with the cytochrome P450 (CYP450) inhibitor malathion or the glutathione S-transferase (GST) inhibitor 4-Chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) partially mitigated the resistance of the R population to tribenuron-methyl. Sequencing of the ALS target enzyme identified a substitution of proline (CCT) at position 197 with serine (TCT). RNA sequencing combined with quantitative reverse transcription polymerase chain reaction (qRT-PCR) verification identified upregulation of a candidate GST gene (GSTF12) and an ADP/ATP carrier protein in the R population. Heterologous expression of the two candidate genes in yeast cells demonstrated enhanced growth in the presence of tribenuron-methyl.

CONCLUSION: We first identified that, in tribenuron-methyl-resistant C. bursa-pastoris, the Pro-197-Ser mutation in the ALS gene, along with GSTF12 and ADP/ATP carrier protein overexpression, jointly mediate its resistance. This enhances our understanding of herbicide-resistance mechanisms and offers a novel perspective for managing tribenuron-methyl-resistant weeds in agricultural practices. © 2025 Society of Chemical Industry.}, } @article {pmid40135564, year = {2025}, author = {Liang, W and Zhang, C and Wang, D and Su, X and Tan, X and Yang, Y and Cong, C and Wang, Y and Huo, D and Wang, H and Wang, S and Wang, X and Feng, H}, title = {Inhibition of Salt-Inducible Kinase 2 Protects Motor Neurons From Degeneration in ALS by Activating Autophagic Flux and Enhancing mTORC1 Activity.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {3}, pages = {e70341}, pmid = {40135564}, issn = {1755-5949}, support = {2023-KYYWF-0195//Innovative Scientific Research Fund of Harbin Medical University/ ; 82271450//National Natural Science Foundation of China/ ; 82301599//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Motor Neurons/pathology/metabolism ; *Autophagy/physiology/drug effects ; *Protein Serine-Threonine Kinases/antagonists & inhibitors/metabolism/genetics ; Mice ; *Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice, Transgenic ; Humans ; Male ; Mice, Inbred C57BL ; *Nerve Degeneration/pathology/metabolism ; }, abstract = {OBJECTIVES: Autophagic impairment has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Salt-inducible kinase 2 (SIK2), a member of the AMP-activated protein kinase (AMPK) family widely expressed in the central nervous system, plays critical roles in neuronal survival, neurogenesis, and the regulation of autophagy. This study aims to investigate the effects and underlying mechanisms of SIK2 in the pathogenesis of ALS.

METHODS: In our work, we used both in vivo and in vitro models of ALS to study the effect of SIK2. Protein and RNA levels were assessed by Western blot, RT-qPCR, immunofluorescence, and immunohistochemistry. Cell viability and apoptosis were evaluated using CCK-8 assay and flow cytometry. Transmission electron microscopy was employed to examine autophagic vacuoles. Additionally, lentivirus particles carrying shRNA targeting SIK2 (sh-SIK2) were injected into the lateral ventricle of ALS mice at 60 days of age. Motor performance was evaluated by the rotarod test.

RESULTS: We observed that increased expression of SIK2 significantly contributed to the degeneration of motor neurons in both the cellular model and the hSOD1[G93A] transgenic mice model of ALS. SIK2 knockdown enhanced neuronal survival and restored mTORC1 activity. Furthermore, SIK2 suppression facilitated the clearance of mutant SOD1 accumulation by activating autophagic flux and enhancing lysosomal acidification. Conversely, SIK2 overexpression impaired mTORC1 activity, exacerbating autophagy dysfunction by inhibiting lysosomal function, and ultimately led to motor neuron degeneration. In vivo, SIK2 deficiency delayed disease onset and extended the lifespan of ALS mice by enhancing autophagy-mediated clearance of mutant SOD1 aggregates.

CONCLUSIONS: Our findings reveal that SIK2 regulates autophagic flux by modulating lysosomal acidification, thereby influencing the degradation of mutant SOD1 aggregates. SIK2 suppression enhances autophagy-mediated clearance of toxic protein aggregates and protects motor neurons, highlighting its potential as a therapeutic target for ALS.}, } @article {pmid40135631, year = {2025}, author = {Novy, C and Tysnes, OB and Busk, ØL and Jaioun, K and Holmøy, T and Holla, ØL and Høyer, H}, title = {Association of UNC13A with increased amyotrophic lateral sclerosis risk, bulbar onset, and lower motor neuron involvement in a Norwegian ALS cohort.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {566-572}, doi = {10.1080/21678421.2024.2447922}, pmid = {40135631}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Norway/epidemiology ; Female ; Middle Aged ; Aged ; *Genetic Predisposition to Disease/genetics ; Cohort Studies ; *Motor Neurons/pathology ; *Nerve Tissue Proteins/genetics ; *Polymorphism, Single Nucleotide/genetics ; Genotype ; Gene Frequency ; Adult ; }, abstract = {Objective: Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by the loss of motor neurons, has limited treatment options available. Treatments targeting specific ALS genes, including UNC13A, have attracted considerable attention. The UNC13A rs12608932 variant has been associated with an increased risk of ALS, shorter survival, and more frequent bulbar onset. Methods: In this study, we investigated the allele frequency of rs12608932 among 500 Norwegian ALS patients, divided into three groups: patients with a genetic cause, patients without a genetic cause, and the entire ALS population. The three groups were compared to two independent control groups. The patients carrying UNC13A genotypes AA, AC, and CC were further clinically characterized and compared using additive, recessive, and dominant models. Results: The frequency of the rs12608932 C allele was higher in the patients with ALS (0.438) than in the controls (0.365; p < 0.001). Among ALS patients without a known genetic cause, individuals with the CC genotype exhibited higher frequencies of bulbar onset (p = 0.015) and prominent lower motor neuron involvement (p = 0.007) than those with the AA and AC genotypes. Conclusions: The CC genotype of rs12608932 is associated with an increased risk of ALS. Additionally, it acts as a modifier of the ALS phenotype, increasing the risk of bulbar onset and dominant lower motor neuron involvement, specifically in patients without a genetic cause in known ALS genes.}, } @article {pmid40135721, year = {2025}, author = {Fayaz, MU and Wang, Q and Xu, M and Chen, D and Pan, F and Song, C}, title = {Compressive Strain-Induced Uphill Hydrogen Distribution in Strontium Ferrite Films.}, journal = {ACS applied materials & interfaces}, volume = {17}, number = {14}, pages = {21371-21379}, doi = {10.1021/acsami.4c21825}, pmid = {40135721}, issn = {1944-8252}, abstract = {Hydrogen incorporation into metal oxides enhances their electrochemical properties, making them highly suitable for various energy conversion applications. The controlled distribution of hydrogen ions in material systems and their conduction at elevated temperatures have garnered significant attention for various energy storage and environmental monitoring applications, including fuel cells, smart windows, and sensor technologies. In this work, cost-effective, high-concentration hydrogen-doped SrFeO3-δ (HSrFeO3-δ) films were prepared under ambient conditions by treating Al(s)|SrFeO3-δ(s) films with KOH(aq), utilizing electron-proton codoping to investigate hydrogen distribution. The uphill hydrogen distributions in SrFeO3-δ films with compressive strain, in contrast to the density gradient behavior under tensile strain, suggest the fundamental role of the strain states in the hydrogen accommodation. Compressively strained films with a rich Al source follow an anomalous uphill feature of hydrogen distribution, highlighting their potential use as electrolyte for fuel cells. The strain significantly influences the structure, chemical lattice coupling, and consequently the ionic transport in SrFeO3-δ. Ionic conductivity measurements reveal that compressively strained HSrFeO3-δ films with uphill hydrogen distributions exhibit a significant ionic conductivity of 0.189 S/cm at 413 K, with an activation energy of approximately 0.29 eV, making them suitable for low-temperature electrochemical applications. These findings provide a promising approach for tuning material properties and valuable insights for building iontronic devices.}, } @article {pmid40136528, year = {2025}, author = {Chen, X and Wang, Y and Zhang, Y and Li, X and Zhang, L and Gao, S and Zhang, C}, title = {Neural Excitatory/Inhibitory Imbalance in Motor Aging: From Genetic Mechanisms to Therapeutic Challenges.}, journal = {Biology}, volume = {14}, number = {3}, pages = {}, pmid = {40136528}, issn = {2079-7737}, support = {C2406001//the Shenzhen Medical Research Fund/ ; 2024TJCR023//the Tongji Hospital High Quality Clinical Research Fund/ ; 32020103007//the Major International (Regional) Joint Research Project/ ; 2022YFA1206000//the National Key Research and Development Program of China/ ; 32371189, 32300984//the National Natural Science Foundation of China/ ; }, abstract = {Neural excitatory/inhibitory (E/I) imbalance plays a pivotal role in the aging process. However, despite its significant impact, the role of E/I imbalance in motor dysfunction and neurodegenerative diseases has not received sufficient attention. This review explores the mechanisms underlying motor aging through the lens of E/I balance, emphasizing genetic and molecular factors that contribute to this imbalance (such as SCN2A, CACNA1C, GABRB3, GRIN2A, SYT, BDNF…). Key regulatory genes, including REST, vps-34, and STXBP1, are examined for their roles in modulating synaptic activity and neuronal function during aging. With insights drawn from ALS, we discuss how disruptions in E/I balance contribute to the pathophysiology of age-related motor dysfunction. The genes discussed above exhibit a certain association with age-related motor neuron diseases (like ALS), a relationship that had not been previously recognized. Innovative genetic therapies, such as gene editing technology and optogenetic manipulation, are emerging as promising tools for restoring E/I balance, offering hope for ameliorating motor deficits in aging. This review explores the potential of these technologies to intervene in aging-related motor diseases, despite challenges in their direct application to human conditions.}, } @article {pmid40136670, year = {2025}, author = {Bond, S and Saxena, S and Sierra-Delgado, JA}, title = {Microglia in ALS: Insights into Mechanisms and Therapeutic Potential.}, journal = {Cells}, volume = {14}, number = {6}, pages = {}, pmid = {40136670}, issn = {2073-4409}, support = {//Rare Village/ ; //Radala Foundation/ ; //University of Missouri- Columbia, School of Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/pathology/immunology ; Humans ; *Microglia/pathology/metabolism ; Animals ; Motor Neurons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons, leading to escalating muscle weakness, atrophy, and eventually paralysis. While neurons are the most visibly affected, emerging data highlight microglia-the brain's resident immune cells-as key contributors to disease onset and progression. Rather than existing in a simple beneficial or harmful duality, microglia can adopt multiple functional states shaped by internal and external factors, including those in ALS. Collectively, these disease-specific forms are called disease-associated microglia (DAM). Research using rodent models, patient-derived cells, and human postmortem tissue shows that microglia can transition into DAM phenotypes, driving inflammation and neuronal injury. However, these cells can also fulfill protective roles under certain conditions, revealing their adaptable nature. This review explores recent discoveries regarding the multifaceted behavior of microglia in ALS, highlights important findings that link these immune cells to motor neuron deterioration, and discusses emerging therapies-some already used in clinical trials-that aim to recalibrate microglial functions and potentially slow disease progression.}, } @article {pmid40136713, year = {2025}, author = {Gao, J and Sikal, A and Hankin, R and Zheng, Y and Sterling, E and Chan, K and Yao, Y}, title = {Extracellular Vesicles from Regenerating Skeletal Muscle Mitigate Muscle Atrophy in an Amyotrophic Lateral Sclerosis Mouse Model.}, journal = {Cells}, volume = {14}, number = {6}, pages = {}, pmid = {40136713}, issn = {2073-4409}, support = {startup//University of Georgia/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/complications/therapy ; *Extracellular Vesicles/metabolism/transplantation ; *Muscular Atrophy/pathology/therapy ; *Muscle, Skeletal/pathology/metabolism ; Disease Models, Animal ; *Regeneration ; Mice ; NF-kappa B/metabolism ; Macrophages/metabolism ; Mice, Inbred C57BL ; Cell Differentiation ; Humans ; Male ; Myoblasts/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by progressive motor neuron degeneration and muscle atrophy, with no effective treatments available. Chronic inflammation, which impairs muscle regeneration and promotes proteolysis, is a key contributor to ALS-related muscle atrophy and a promising therapeutic target. Here, we applied extracellular vesicles (EVs) derived from regenerating skeletal muscles 14 days post-acute injury (CTXD14SkM-EVs), which possess a unique anti-inflammatory profile, to target muscle defects in ALS. We found that CTXD14SkM-EVs enhanced myoblast differentiation and fusion in a cellular muscle-wasting model induced by pro-inflammatory cytokine tumor necrosis factor alpha. Intramuscular administration of these EVs into an ALS mouse model mitigated muscle atrophy by promoting muscle regeneration, shifting macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 state, and suppressing the aberrant Nuclear Factor Kappa B (NF-κB) signaling, a key driver of muscle protein degradation. These results underscore the therapeutic potential of regenerating muscle-derived EVs for combating muscle atrophy in ALS.}, } @article {pmid40137226, year = {2025}, author = {Stella, R and Bertoli, A and Lopreiato, R and Peggion, C}, title = {A Twist in Yeast: New Perspectives for Studying TDP-43 Proteinopathies in S. cerevisiae.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {40137226}, issn = {2309-608X}, abstract = {TAR DNA-binding protein 43 kDa (TDP-43) proteinopathies are a group of neurodegenerative diseases (NDs) characterized by the abnormal accumulation of the TDP-43 protein in neurons and glial cells. These proteinopathies are associated with several NDs, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and some forms of Alzheimer's disease. Yeast models have proven valuable in ND research due to their simplicity, genetic tractability, and the conservation of many cellular processes shared with higher eukaryotes. For several decades, Saccharomyces cerevisiae has been used as a model organism to study the behavior and toxicity of TDP-43, facilitating the identification of genes and pathways that either exacerbate or mitigate its toxic effects. This review will discuss evidence showing that yeast models of TDP-43 exhibit defects in proteostasis, mitochondrial function, autophagy, and RNA metabolism, which are key features of TDP-43-related NDs. Additionally, we will explore how modulating proteins involved in these processes reduce TDP-43 toxicity, aiding in restoring normal TDP-43 function or preventing its pathological aggregation. These findings highlight potential therapeutic targets for the treatment of TDP-43-related diseases.}, } @article {pmid40137505, year = {2025}, author = {Calderón-Garcidueñas, L and González-Maciel, A and Reynoso-Robles, R and Cejudo-Ruiz, FR and Silva-Pereyra, HG and Gorzalski, A and Torres-Jardón, R}, title = {Alzheimer's, Parkinson's, Frontotemporal Lobar Degeneration, and Amyotrophic Lateral Sclerosis Start in Pediatric Ages: Ultrafine Particulate Matter and Industrial Nanoparticles Are Key in the Early-Onset Neurodegeneration: Time to Invest in Preventive Medicine.}, journal = {Toxics}, volume = {13}, number = {3}, pages = {}, pmid = {40137505}, issn = {2305-6304}, abstract = {Billions of people are exposed to fine particulate matter (PM2.5) levels above the USEPA's annual standard of 9 μg/m[3]. Common emission sources are anthropogenic, producing complex aerosolized toxins. Ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs) have major detrimental effects on the brain, but the USA does not measure UFPM on a routine basis. This review focuses on the development and progression of common neurodegenerative diseases, as diagnosed through neuropathology, among young residents in Metropolitan Mexico City (MMC). MMC is one of the most polluted megacities in the world, with a population of 22 million residents, many of whom are unaware of the brain effects caused by their polluted atmosphere. Fatal neurodegenerative diseases (such as Alzheimer's and Parkinson's) that begin in childhood in populations living in air polluted environments are preventable. We conclude that UFPM/NPs are capable of disrupting neural homeostasis and give rise to relentless neurodegenerative processes throughout the entire life of the highly exposed population in MMC. The paradigm of reaching old age to have neurodegeneration is no longer supported. Neurodegenerative changes start early in pediatric ages and are irreversible. It is time to invest in preventive medicine.}, } @article {pmid40138021, year = {2025}, author = {Vaughan, DP and Real, R and Jensen, MT and Fumi, RG and Hodgson, M and Jabbari, E and Lux, D and Wu, L and , and , and Warner, TT and Jaunmuktane, Z and Revesz, T and Rowe, JB and Rohrer, J and Morris, HR}, title = {Analysis of C9orf72 repeat length in progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, and atypical parkinsonism.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {293}, pmid = {40138021}, issn = {1432-1459}, support = {220258/WT_/Wellcome Trust/United Kingdom ; T033371/1/MRC_/Medical Research Council/United Kingdom ; MC_UU_00030/14//Cambridge Centre for Parkinson-Plus/ ; /WT_/Wellcome Trust/United Kingdom ; NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; PROSPECT2//Progressive Supranuclear Palsy Association/ ; }, mesh = {Humans ; C9orf72 Protein/genetics ; *Supranuclear Palsy, Progressive/genetics ; Male ; Female ; Aged ; *DNA Repeat Expansion/genetics ; *Parkinsonian Disorders/genetics ; Middle Aged ; *Corticobasal Degeneration/genetics ; Aged, 80 and over ; Cohort Studies ; }, abstract = {BACKGROUND: Pathogenic hexanucleotide repeat expansions in C9orf72 are the commonest genetic cause of frontotemporal dementia and/or amyotrophic lateral sclerosis. There is growing interest in intermediate repeat expansions in C9orf72 and their relationship to a wide range of neurological presentations, including Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, corticobasal degeneration, and corticobasal syndromes.

AIMS: To assess the prevalence of intermediate C9orf72 repeat expansions in a large cohort of prospectively-recruited patients clinically diagnosed with progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and atypical parkinsonism (APS), compared with healthy controls. We also sought to replicate the association between C9orf72 repeat length and CBD in neuropathologically confirmed cases.

METHODS: 626 cases, including PSP (n = 366), CBS (n = 130), and APS (n = 53) from the PROSPECT study, and 77 cases with pathologically confirmed CBD were screened for intermediate repeat expansions in C9orf72 using repeat-primed PCR. These were compared to controls from the PROSPECT-M-UK study and from the 1958 Birth Cohort.

RESULTS: There was no difference in the mean or largest allele size in any affected patient group compared with controls. A higher proportion of our affected cohort had large C9orf72 repeat expansions compared to controls, but there was no difference when comparing the frequency of intermediate expansions between affected patients and controls. There was no relationship between repeat length and age at onset, level of disability, or survival.

CONCLUSIONS: Intermediate expansions in C9orf72 do not appear to be a genetic risk factor for PSP, CBS, CBD, or atypical parkinsonism. They are not associated with age at onset, disability, or survival in our study.}, } @article {pmid40138119, year = {2025}, author = {Ali, N and Sayeed, U and Shahid, SMA and Akhtar, S and Khan, MKA}, title = {Molecular mechanisms and biomarkers in neurodegenerative disorders: a comprehensive review.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {337}, pmid = {40138119}, issn = {1573-4978}, mesh = {Humans ; *Biomarkers/metabolism/cerebrospinal fluid ; *Neurodegenerative Diseases/metabolism/genetics/diagnosis ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; alpha-Synuclein/metabolism/cerebrospinal fluid ; Parkinson Disease/metabolism/genetics ; tau Proteins/metabolism/cerebrospinal fluid ; Alzheimer Disease/metabolism/genetics ; Huntington Disease/genetics/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Dopamine Plasma Membrane Transport Proteins/metabolism ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD), are significant global health challenges, owing to their profound impact on cognitive, motor, and behavioral functions. The etiology and progression of these disorders are influenced by a complex interplay of environmental factors and genetic predispositions with specific genetic markers, such as mutations in the APOE and HTT genes, which play pivotal roles. Current therapeutic interventions predominantly focus on symptom management; however, emerging strategies, including gene therapies, anti-amyloid agents, and neuroprotective approaches, are designed to directly target the underlying disease mechanisms. Advances in biomarker discovery and imaging methodologies have emerged as essential tools for early diagnosis and monitoring of therapeutic efficacy in these disorders. In the context of AD, cerebrospinal fluid (CSF) amyloid-beta (Aβ) and tau levels, along with positron emission tomography (PET) imaging, are well-established biomarkers. Similarly, CSF alpha-synuclein and dopamine transporter (DAT) imaging have been employed as diagnostic tools for PD. Moreover, emerging biomarkers, such as blood-based tau and the Aβ42/40 ratio for AD, as well as the neurofilament light chain (NfL) for ALS and PD, hold promise for enhancing early diagnostic accuracy and facilitating the longitudinal assessment of disease progression. This study comprehensively examined the molecular mechanisms underlying these neurodegenerative disorders, focusing on amyloid-beta plaque deposition and tau protein aggregation in AD, alpha-synuclein misfolding in PD, and aberrant protein aggregation in ALS and HD, thereby contributing to a deeper understanding of the pathophysiological basis of these disorders.}, } @article {pmid40138872, year = {2025}, author = {Liang, T and Jiang, T and Liang, Z and Li, L and Chen, Y and Chen, T and Yang, L and Zhang, N and Dong, B and Xie, X and Gu, B and Wu, Q}, title = {Gut microbiota-driven BCAA biosynthesis via Staphylococcus aureus -expressed acetolactate synthase impairs glycemic control in type 2 diabetes in South China.}, journal = {Microbiological research}, volume = {296}, number = {}, pages = {128145}, doi = {10.1016/j.micres.2025.128145}, pmid = {40138872}, issn = {1618-0623}, mesh = {*Diabetes Mellitus, Type 2/microbiology/metabolism ; *Gastrointestinal Microbiome/physiology ; *Staphylococcus aureus/enzymology/genetics/metabolism ; *Amino Acids, Branched-Chain/biosynthesis ; *Acetolactate Synthase/metabolism/genetics ; Humans ; Animals ; Mice ; China ; Male ; Insulin Resistance ; Female ; Middle Aged ; *Glycemic Control ; Blood Glucose ; Feces/microbiology ; Staphylococcal Infections/microbiology ; Metagenomics ; Prediabetic State/microbiology ; Metabolomics ; Insulin ; }, abstract = {An increase in branched-chain amino acid (BCAA) levels can result in insulin resistance at different stages of type 2 diabetes (T2D), however, the causes of this increase are unclear. We performed metagenomics and metabolomics profiling in patients with prediabetes (PDM), newly diagnosed diabetes (NDDM), and post-medication type 2 diabetes (P2DM) to investigate whether altered gut microbes and metabolites could explain the specific clinical characteristics of different disease stages of T2D. Here we identify acetolactate synthase (ALS) a BCAA biosynthesis enzyme in Staphylococcus aureus as a cause of T2D insulin resistance. Compared with healthy peoples, patients with PDM, NDDM, and P2DM groups, especially in P2DM group, have increased faecal numbers of S. aureus. We also demonstrated that insulin administration may be a risk factor for S. aureus infection in T2D. The presence of ALS-positive S. aureus correlated with the levels of BCAAs and was associated with an increased fasting blood glucose (FBG) and insulin resistance. Humanized microbiota transplantation experiment indicated that ALS contributes to disordered insulin resistance mediated by S. aureus. We also found that S. aureus phage can reduced the FBG levels and insulin resistance in db/db mice. The ALS-positive S. aureus are associated with insulin resistance in T2D, opening a new therapeutic avenue for the prevention or treatment of diabetes.}, } @article {pmid40139174, year = {2026}, author = {Toraih, EA and Siddiqui, S and Siddiqui, S and Shirini, K and Elfezzani, N and Abdelmaksoud, A and Elshazli, RM and Hussein, MH and Elmorsy, EM and Fawzy, MS}, title = {Thyroid Disorders as a Risk Factor for Neurodegenerative Proteinopathies: A Large-Scale Propensity Score-Matched Analysis.}, journal = {Neuroepidemiology}, volume = {60}, number = {2}, pages = {290-302}, doi = {10.1159/000545369}, pmid = {40139174}, issn = {1423-0208}, mesh = {Humans ; *Thyroid Diseases/epidemiology/surgery/complications ; Male ; Female ; Propensity Score ; *Neurodegenerative Diseases/epidemiology ; Aged ; Risk Factors ; Middle Aged ; Retrospective Studies ; Thyroidectomy ; Alzheimer Disease/epidemiology ; Lewy Body Disease/epidemiology ; }, abstract = {BACKGROUND: The relationship between thyroid disorders and neurodegenerative diseases remains poorly understood. This large-scale retrospective cohort study aimed to investigate the association between thyroid disorders and various neurodegenerative diseases, as well as the potential impact of thyroidectomy.

METHODS: We analyzed data from 3,719,666 patients with thyroid disorders and 2,945,438 controls from 120 healthcare organizations (TriNetX database). After propensity score matching, each group included 2,033,096 patients. We compared the risk of neurodegenerative diseases between these groups and examined the effect of thyroidectomy in a subgroup analysis of 31,753 matched pairs.

RESULTS: Patients with thyroid disorders showed significantly higher risks of Alzheimer's disease (RR = 1.15, 95% CI: 1.110-1.195), Parkinson's disease (RR = 1.25, 95% CI: 1.187-1.318), amyotrophic lateral sclerosis (RR = 1.35, 95% CI: 1.131-1.622), frontotemporal dementia (RR = 1.44, 95% CI: 1.219-1.702), Lewy body dementia (RR = 1.15, 95% CI: 1.107-1.186), progressive supranuclear palsy (RR = 1.41, 95% CI: 1.095-1.819), vascular dementia (RR = 1.32, 95% CI: 1.266-1.369), Niemann-Pick disease type C (RR = 1.34, 95% CI: 1.092-1.638), and Wilson's disease (RR = 1.26, 95% CI: 1.056-1.507). Interestingly, the risk of multiple sclerosis was lower (RR = 0.80, 95% CI: 0.738-0.862). Thyroidectomy was associated with a 44.2% lower risk of Lewy body dementia (RR = 0.558, 95% CI: 0.339-0.919, p = 0.020).

CONCLUSIONS: Thyroid disorders are significantly associated with an increased risk of several neurodegenerative diseases. Thyroidectomy may have a protective effect against Lewy body dementia. These findings suggest a complex relationship between thyroid function and neurodegeneration, emphasizing the need for neurological monitoring in patients with thyroid disorders and further research into thyroid-brain interactions.}, } @article {pmid40139318, year = {2025}, author = {Lai, IC and Wei, JC}, title = {Comment on Vera et al's "Interleukin-23 inhibition associates with lower incidence of cardiovascular risk factor type diseases compared to biologic naïve patients with psoriasis: A retrospective cohort study.".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {2}, pages = {e51-e52}, doi = {10.1016/j.jaad.2024.12.054}, pmid = {40139318}, issn = {1097-6787}, } @article {pmid40140376, year = {2025}, author = {Megat, S and Marques, C and Hernán-Godoy, M and Sellier, C and Stuart-Lopez, G and Dirrig-Grosch, S and Gorin, C and Brunet, A and Fischer, M and Keime, C and Kessler, P and Mendoza-Parra, MA and Zwamborn, RAJ and Veldink, JH and Scholz, SW and Ferrucci, L and Ludolph, A and Traynor, B and Chio, A and Dupuis, L and Rouaux, C}, title = {CREB3 gain of function variants protect against ALS.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2942}, pmid = {40140376}, issn = {2041-1723}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *Cyclic AMP Response Element-Binding Protein/genetics/metabolism ; Humans ; Mice ; Male ; Motor Neurons/metabolism/pathology ; *Gain of Function Mutation ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Motor Cortex/metabolism/pathology ; Disease Models, Animal ; Female ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly evolving neurodegenerative disease arising from the loss of glutamatergic corticospinal neurons (CSN) and cholinergic motoneurons (MN). Here, we performed comparative cross-species transcriptomics of CSN using published snRNA-seq data from the motor cortex of ALS and control postmortem tissues, and performed longitudinal RNA-seq on CSN purified from male Sod1[G86R] mice. We report that CSN undergo ER stress and altered mRNA translation, and identify the transcription factor CREB3 and its regulatory network as a resilience marker of ALS, not only amongst vulnerable neuronal populations, but across all neuronal populations as well as other cell types. Using genetic and epidemiologic analyses we further identify the rare variant CREB3[R119G] (rs11538707) as a positive disease modifier in ALS. Through gain of function, CREB3[R119G] decreases the risk of developing ALS and the motor progression rate of ALS patients.}, } @article {pmid40140608, year = {2025}, author = {Dubey, SK and Bellen, HJ}, title = {A neuroprotective role of polyunsaturated fatty acids in C9orf72-ALS/FTD.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {710-712}, pmid = {40140608}, issn = {1546-1726}, } @article {pmid40140666, year = {2025}, author = {de Bernardo, N and de la Rubia Ortí, JE and Villarón-Casales, C and Privado, J and Maset-Roig, R and Cañabate, M and Sancho-Cantus, D and Sanz, IO and Fernández, RF and Proaño, B and Tvarijonaviciute, A and Rubio, CP and Benlloch, M and Menargues-Ramírez, R and Alarcón-Jiménez, J}, title = {Autonomic nervous system and mediating role of respiratory function in patients with ALS.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {10513}, pmid = {40140666}, issn = {2045-2322}, support = {2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Autonomic Nervous System/physiopathology ; Aged ; Cross-Sectional Studies ; Adult ; Cognition/physiology ; *Respiration ; Oxidative Stress ; Heart Rate/physiology ; Antioxidants/metabolism ; }, abstract = {Patients with Amyotrophic Lateral Sclerosis (ALS) exhibit altered patterns of respiratory rate and heart rhythm that are directly related to autonomic nervous system (ANS) activity. This study aimed to analyze the role of the ANS in respiratory function, cognition, functionality, and antioxidant capacity in patients with ALS through a predictive model that assesses the mediating activity of respiration. This quantitative, observational, analytical, and cross-sectional clinical study was conducted using a sample of 75 patients diagnosed with ALS. ANS activity, respiratory function, cognition, functionality, and antioxidant capacity were also measured. Using these values, a structural equation model was developed using AMOS V.23 software. The mediational predictive model showed that increased sympathetic nervous system (SNS) activity, in turn, increased respiratory function, whereas the role of the parasympathetic nervous system in respiration was very weak and had the opposite effect. Furthermore, SNS activity increased respiratory function values, which, in turn, improved functional capacity, cognition, and antioxidant power in patients with ALS, with respiratory function playing a mediating role. The mediating effect of respiratory function was observed primarily between ANS and functional disability. For oxidative stress, respiratory function showed a high mediating effect, such that greater respiratory function corresponded to greater antioxidant capacity. Additionally, for cognitive activity, a moderate direct effect of the ANS was observed; however, it was greatly enhanced by respiratory disability. Finally, differences were only found based on sex, with respiratory capacity and antioxidant power being higher in men.}, } @article {pmid40140908, year = {2025}, author = {Wang, KS and Smeyers, J and Eggan, K and Budnik, B and Mordes, DA}, title = {C9ORF72 poly-PR disrupts expression of ALS/FTD-implicated STMN2 through SRSF7.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {67}, pmid = {40140908}, issn = {2051-5960}, support = {K08 NS104270/NS/NINDS NIH HHS/United States ; K08NS104270/NS/NINDS NIH HHS/United States ; R01 NS089742/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Serine-Arginine Splicing Factors/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Axons/metabolism ; Neurons/metabolism ; DNA Repeat Expansion ; }, abstract = {A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and combined ALS/FTD. The repeat is transcribed in the sense and the antisense directions to produce several dipeptide repeat proteins (DPRs) that have toxic gain-of-function effects; however, the mechanisms by which DPRs lead to neural dysfunction remain unresolved. Here, we observed that poly-proline-arginine (poly-PR) was sufficient to inhibit axonal regeneration of human induced pluripotent stem cell (iPSC)-derived neurons. Global phospho-proteomics revealed that poly-PR selectively perturbs nuclear RNA binding proteins (RBPs). In neurons, we found that depletion of one of these RBPs, SRSF7 (serine/arginine-rich splicing factor 7), resulted in decreased abundance of STMN2 (stathmin-2), though not TDP-43. STMN2 supports axon maintenance and repair and has been recently implicated in the pathogenesis of ALS/FTD. We observed that depletion of SRSF7 impaired axonal regeneration, a phenotype that could be rescued by exogenous STMN2. We propose that antisense repeat-encoded poly-PR perturbs RBPs, particularly SRSF7, resulting in reduced STMN2 and axonal repair defects in neurons. Hence, we provide a potential link between DPRs gain-of-function effects and STMN2 loss-of-function phenotypes in neurodegeneration.}, } @article {pmid40140966, year = {2025}, author = {Balaban, E and Köse, TE and Günaçar, DN and Naralan, ME and Gonca, M}, title = {Comparison of methods for detecting mandibular lingula and can antilingula be used in lingula mandibula detection?.}, journal = {BMC oral health}, volume = {25}, number = {1}, pages = {430}, pmid = {40140966}, issn = {1472-6831}, support = {02025001021255//Recep Tayyip Erdoğan University Development Foundation/ ; }, mesh = {Humans ; Female ; Male ; Retrospective Studies ; Adult ; *Cone-Beam Computed Tomography/methods ; Middle Aged ; *Mandible/diagnostic imaging/anatomy & histology/surgery ; Aged ; Adolescent ; Young Adult ; Aged, 80 and over ; *Orthognathic Surgical Procedures/methods ; Anatomic Landmarks ; Mandibular Nerve ; }, abstract = {OBJECTIVE: The aim of this study is to evaluate the relationship between anatomical reference points used during orthognathic surgery and to minimize the risks of iatrogenic neurovascular damage.

MATERIALS AND METHODS: This retrospective study included cone-beam computed tomography (CBCT) images involving the mandible from patients who visited Recep Tayyip Erdoğan University Faculty of Dentistry between January 2018 and September 2023. The age range of the included individuals was set between 18 and 80 years. Horizontal and vertical distances between mandibular anatomical structures, such as the lingula mandibula (LM), mandibular foramen (MF), antilingula (AL), and surrounding structures were measured using CBCT software. Individuals with intraosseous pathology, insufficient image quality, or a history of surgical/orthodontic treatment were excluded from the study.

RESULTS: A total of 240 hemimandibles from 120 patients were analyzed (55.83% female, 44.17% male; mean age: 46.78 ± 15.30 years). Significant differences were identified in LM positions according to different AL types. The LM was found to be more inferior and posterior relative to hill and ridge type ALs, while it was more anterior relative to plateau type ALs. In 26.25% of mandibular rami, AL was not detected.

CONCLUSION: The position of the AL can serve as a guide in determining the osteotomy line during inferior vertical ramus osteotomy (IVRO). However, relying solely on AL as a reference point may increase the risk of inferior alveolar nerve (IAN) injury. Preoperative tomographic evaluations to determine the relationships among LM, MF, and AL can provide a safer approach in surgical planning, reduce complications, and help protect neurovascular structures.}, } @article {pmid40141149, year = {2025}, author = {Zheng, MY and Luo, LZ}, title = {The Role of IL-17A in Mediating Inflammatory Responses and Progression of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {6}, pages = {}, pmid = {40141149}, issn = {1422-0067}, support = {No. 2023D022//the Fujian Provincial Natural Science Foundation/ ; No. 3502Z202473076//the Science and Technology Program of Xiamen City/ ; No. 2019-WJ-30//the Fujian Province Health Education Joint Research Project/ ; }, mesh = {Humans ; *Interleukin-17/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/immunology ; Animals ; *Inflammation/metabolism/pathology ; Signal Transduction ; Disease Progression ; Blood-Brain Barrier/metabolism ; }, abstract = {IL-17A has been implicated as a critical pro-inflammatory cytokine in the pathogenesis of autoimmune and neurodegenerative disorders. Emerging evidence indicates its capacity to activate microglial cells and astrocytes, subsequently inducing the production of inflammatory mediators that exacerbate neuronal injury and functional impairment. Clinical observations have revealed a demonstrated association between IL-17A concentrations and blood-brain barrier (BBB) dysfunction, creating a pathological feedback loop that amplifies neuro-inflammatory responses. Recent advances highlight the cytokine's critical involvement in neurodegenerative disorders through multiple molecular pathways. Therapeutic interventions utilizing monoclonal antibodies (mAbs) against IL-17A or its cognate receptor (IL-17R) have shown promising clinical potential. This review systematically examines the IL-17A-mediated neuro-inflammatory cascades; the mechanistic contributions to neurodegenerative pathology in the established disease models including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis; and current therapeutic strategies targeting the IL-17A signaling pathways. The analysis provides novel perspectives on optimizing cytokine-directed therapies while identifying the key challenges and research priorities for translational applications in neurodegeneration.}, } @article {pmid40141987, year = {2025}, author = {Russo, A and Putaggio, S and Tellone, E and Calderaro, A and Cirmi, S and Laganà, G and Ficarra, S and Barreca, D and Patanè, GT}, title = {Emerging Ferroptosis Involvement in Amyotrophic Lateral Sclerosis Pathogenesis: Neuroprotective Activity of Polyphenols.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {6}, pages = {}, pmid = {40141987}, issn = {1420-3049}, mesh = {*Ferroptosis/drug effects ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/etiology ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Polyphenols/pharmacology/therapeutic use ; Animals ; Reactive Oxygen Species/metabolism ; Lipid Peroxidation/drug effects ; Mitochondria/metabolism/drug effects ; Oxidative Stress/drug effects ; Iron/metabolism ; }, abstract = {Neurodegenerative diseases are a group of diseases that share common features, such as the generation of misfolded protein deposits and increased oxidative stress. Among them, amyotrophic lateral sclerosis (ALS), whose pathogenesis is still not entirely clear, is a complex neurodegenerative disease linked both to gene mutations affecting different proteins, such as superoxide dismutase 1, Tar DNA binding protein 43, Chromosome 9 open frame 72, and Fused in Sarcoma, and to altered iron homeostasis, mitochondrial dysfunction, oxidative stress, and impaired glutamate metabolism. The purpose of this review is to highlight the molecular targets common to ALS and ferroptosis. Indeed, many pathways implicated in the disease are hallmarks of ferroptosis, a recently discovered type of iron-dependent programmed cell death characterized by increased reactive oxygen species (ROS) and lipid peroxidation. Iron accumulation results in mitochondrial dysfunction and increased levels of ROS, lipid peroxidation, and ferroptosis triggers; in addition, the inhibition of the Xc[-] system results in reduced cystine levels and glutamate accumulation, leading to excitotoxicity and the inhibition of GPx4 synthesis. These results highlight the potential involvement of ferroptosis in ALS, providing new molecular and biochemical targets that could be exploited in the treatment of the disease using polyphenols.}, } @article {pmid40141996, year = {2025}, author = {Kodama, TS and Furuita, K and Kojima, C}, title = {Beyond Static Tethering at Membrane Contact Sites: Structural Dynamics and Functional Implications of VAP Proteins.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {6}, pages = {}, pmid = {40141996}, issn = {1420-3049}, support = {JP22H05536, JP22K19184, JP23H02416, and JP23K18030//Ministry of Education, Culture, Sports, Science and Technology/ ; NMR Platform//Ministry of Education, Culture, Sports, Science and Technology/ ; CR-24-05//Institute for Protein Research, Osaka University/ ; JP24ama121001//Japan Agency for Medical Research and Development/ ; }, mesh = {Humans ; *Vesicular Transport Proteins/metabolism/chemistry/genetics ; Animals ; *Cell Membrane/metabolism ; }, abstract = {The membranes surrounding the eukaryotic cell and its organelles are continuously invaginating, budding, and undergoing membrane fusion-fission events, which enable them to perform functions not found in prokaryotic cells. In addition, organelles come into close contact with each other at membrane contact sites (MCSs), which involve many types of proteins, and which regulate the signaling and transport of various molecules. Vesicle-associated membrane protein (VAMP)-associated protein (VAP) is an important factor involved in the tethering and contact of various organelles at MCSs in almost all eukaryotes and has attracted attention for its association with various diseases, mainly neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, the detailed mechanism of its functional expression remains unclear. In this review, we quantitatively discuss the structural dynamics of the entire molecule, including intrinsically disordered regions and intramolecular and intermolecular interactions, focusing on the vertebrate VAP paralogs VAPA and VAPB. Molecular phylogenetic and biophysical considerations are the basis of the work.}, } @article {pmid40143051, year = {2025}, author = {Zou, Y and Zhang, J and Chen, L and Xu, Q and Yao, S and Chen, H}, title = {Targeting Neuroinflammation in Central Nervous System Diseases by Oral Delivery of Lipid Nanoparticles.}, journal = {Pharmaceutics}, volume = {17}, number = {3}, pages = {}, pmid = {40143051}, issn = {1999-4923}, support = {82100892//Hong Chen/ ; 82300929//Jing Zhang/ ; }, abstract = {Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson's disease, Alzheimer's disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently induce neuronal death and accelerate the progression of neurodegeneration. Therefore, mitigating excessive neuroinflammation has emerged as a promising strategy for the treatment of CNS diseases. Despite advancements in drug discovery and the development of novel therapeutics, the effective delivery of these agents to the CNS remains a serious challenge due to the restrictive nature of the blood-brain barrier (BBB). This underscores the need to develop a novel drug delivery system. Recent studies have identified oral lipid nanoparticles (LNPs) as a promising approach to efficiently deliver drugs across the BBB and treat neurological diseases. This review aims to comprehensively summarize the recent advancements in the development of LNPs designed for the controlled delivery and therapeutic modulation of CNS diseases through oral administration. Furthermore, this review addresses the mechanisms by which these LNPs overcome biological barriers and evaluate their clinical implications and therapeutic efficacy in the context of oral drug delivery systems. Specifically, it focuses on LNP formulations that facilitate oral administration, exploring their potential to enhance bioavailability, improve targeting precision, and alleviate or manage the symptoms associated with a range of CNS diseases.}, } @article {pmid40143800, year = {2025}, author = {Heylen, A and Vermeiren, Y and De Deyn, PP and Van Dam, D}, title = {Monoaminergic Alterations at the Subregional Cervical and Thoracic Spinal Cord Level of Patients Within the FTD-ALS Continuum and Early-Onset AD: Low Thoracic Dopaminergic Activity in ALS.}, journal = {Journal of neurochemistry}, volume = {169}, number = {3}, pages = {e70046}, doi = {10.1111/jnc.70046}, pmid = {40143800}, issn = {1471-4159}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Female ; Male ; *Frontotemporal Dementia/metabolism ; Aged ; Middle Aged ; *Dopamine/metabolism ; *Spinal Cord/metabolism ; *Alzheimer Disease/metabolism ; *Biogenic Monoamines/metabolism ; *Cervical Cord/metabolism ; Thoracic Vertebrae ; }, abstract = {Early-onset neurodegeneration leads to cognitive and behavioral symptoms in frontotemporal dementia (FTD) and motor disturbances in amyotrophic lateral sclerosis (ALS). Despite distinct clinical profiles, more than half of FTD patients experience ALS-related symptoms and vice versa. Spinal cord monoamine neurotransmitter alterations were reported in ALS, but not yet in FTD. Therefore, we compared monoaminergic turnover across the FTD-ALS continuum. Reversed-phase, ultra-high-performance liquid chromatography with electrochemical detection was used to measure levels of the monoamines (nor)adrenaline ((N)A), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) and their metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in five cervical and thoracic spinal cord regions in 10 FTD, 14 ALS, 6 mixed FTD-ALS, 14 early-onset Alzheimer's disease (EOAD), and 7 control (CONTR) individuals. At the cervical level, NA levels were lower in FTD-ALS versus CONTR, whereas the HVA/5-HIAA ratio was higher in ALS versus EOAD in the lateral funiculus. In the dorsal horn-intermediate gray matter, DA levels were decreased in FTD-ALS compared to FTD. At the thoracic level, DOPAC was lower in ALS than in FTD-ALS patients in the ventral and lateral funiculus, ventral horn, and dorsal horn-intermediate gray matter, as was the DOPAC/DA ratio in the lateral funiculus and dorsal horn-intermediate gray matter. Contrarily, HVA/DA turnover was lower in FTD-ALS than in FTD in the dorsal and ventral funiculus. We observed lower NA levels in FTD-ALS than in FTD in the ventral funiculus, and lower MHPG/NA turnover in the dorsal horn-intermediate gray matter. A levels were lower in ALS versus FTD. This study indicates differences in monoaminergic turnover across the FTD-ALS continuum, at the cervical and thoracic levels, with primarily a decrease in dopaminergic activity in ALS. Characterizing disease-specific neurochemical profiles for FTD, ALS, or FTD-ALS could contribute to the identification of novel interesting pharmacological targets.}, } @article {pmid40143847, year = {2025}, author = {Meyer, J and Gaur, N and von der Gablentz, J and Friedrich, B and Roediger, A and Grosskreutz, J and Steinbach, R}, title = {Phosphorylated neurofilament heavy chain (pNfH) concentration in cerebrospinal fluid predicts overall disease aggressiveness (D50) in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1536818}, pmid = {40143847}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, characterized by tremendous clinical heterogeneity that necessitates reliable biomarkers for the trajectory of the disease. The potential of phosphorylated Neurofilament-Heavy-chain (pNfH) measured in cerebrospinal fluid (CSF) to mirror disease progressiveness has repeatedly been suggested but is not applicable as outcome on an individual patient-level. This potential was probably obfuscated before due to imprecise clinical measures of disease progression that assumed a linear decline of motoric function over time. The primary objective was therefore to study if disease aggressiveness, as quantified via the D50 model, would reveal more stable correlations with pNfH.

METHODS: ELISA-quantified pNfH CSF levels of 108 patients with ALS were comparatively analyzed in relation to three different measures of disease progression speed via analyses of covariance, linear and non-linear regressions, respectively. These were (a) the D50, depicting a patient's overall disease aggressiveness, (b) cFL, the calculated functional loss-rate as locally derived parameter of progression speed, and (c) DPR, the disease progression-rate as more commonly used linear approximation of points lost per month in the ALS functional rating scale since symptom onset.

RESULTS: All analyses of covariance showed a significant main impact of the respective disease progression-speed parameter on pNfH, independent of disease phase, presence of frontotemporal dementia, analyzing laboratory, sex or clinical onset type, while only age revealed borderline additional influence. Notably, CSF pNfH concentration was independent of how far the disease had progressed, as neither disease phase nor a direct regression with the quantified disease accumulation at the time of lumbar puncture revealed a significant correlation. However, the parameter D50 quantifying aggressiveness showed the most significant impact on pNfH-levels, as compared to the cFL and even more evident in contrast to the DPR. This superiority of D50 was confirmed in direct linear and most evident in non-linear regressions with pNfH.

CONCLUSION: Overall disease aggressiveness in ALS, as quantified by D50, most robustly correlated with CSF pNfH-levels, independent of the time of collection during symptomatic disease. This opens perspectives to use CSF pNfH as a prognostic outcome measure for future therapeutic interventions in the sense of precision medicine.}, } @article {pmid40145976, year = {2026}, author = {Wang, Z and Cao, W and Chen, L and Zhang, S and Tang, L and Cui, W and Kong, M and Yu, L and Fan, D and Zheng, W}, title = {The role of the peripheral immune system in mediating axonal dysfunction in early-stage amyotrophic lateral sclerosis: An age- and sex-based analysis.}, journal = {Neural regeneration research}, volume = {21}, number = {7}, pages = {3156-3162}, pmid = {40145976}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons. Early-stage axonal dysfunction, rather than central nervous system injury, plays a key role in the disease process. However, the molecular mechanisms underlying this dysfunction remain unclear. To investigate the relationship between peripheral immune dysregulation and axonal dysfunction in amyotrophic lateral sclerosis, we recruited 372 patients within the first 12 months of sporadic amyotrophic lateral sclerosis onset between January 2018 and May 2024. We collected peripheral immune markers at baseline, including total leukocytes, lymphocytes, monocytes, neutrophils, basophils, eosinophils, and platelets. We also calculated four derived ratios: neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and systemic immune inflammation index. Multivariate analysis, adjusted for confounding factors, revealed that higher counts of total leukocytes and neutrophils, as well as higher neutrophil-related ratios, including the neutrophil to lymphocyte ratio and the systemic immune inflammation index, were significantly correlated with higher compound muscle action potential scores. Stratified analyses revealed that these associations varied by age and sex. Furthermore, mediation analysis demonstrated that axonal dysfunction plays a significant role in the relationship between immune markers and disease progression. These findings emphasize the critical role that peripheral immune dysregulation plays in amyotrophic lateral sclerosis progression by mediating peripheral nerve injury, particularly in the early stages of the disease. This study highlights the importance of the peripheral nervous system in the early stages of amyotrophic lateral sclerosis and provides new insights into disease mechanisms and potential therapeutic targets.}, } @article {pmid40145977, year = {2026}, author = {Zhao, W and Liu, Z and Wu, J and Liu, A and Yan, J}, title = {Potential targets of microglia in the treatment of neurodegenerative diseases: Mechanism and therapeutic implications.}, journal = {Neural regeneration research}, volume = {21}, number = {4}, pages = {1497-1511}, pmid = {40145977}, issn = {1673-5374}, abstract = {For diverse neurodegenerative disorders, microglial cells are activated. Furthermore, dysfunctional and hyperactivated microglia initiate mitochondrial autophagy, oxidative stress, and pathological protein accumulation, ending with neuroinflammation that exacerbates damage to dopaminergic neurons and contributes significantly to the pathology of neurodegenerative disorder. Microglial over-activation is closely associated with the secretion of pro-inflammatory cytokines, the phagocytosis of injured neurons, and the modulation of neurotoxic environments. This review summarizes the role of microglia neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, cortical degeneration, Lewy body dementia, and Huntington's disease. It also discusses novel forms of cell death such as ferroptosis, cuproptosis, disulfidptosis, and parthanatos (poly(adenosine diphosphate ribose) polymerase 1-dependent cell death), as well as the impact of regulatory factors related to microglial inflammation on microglial activation and neuroinflammation. The aim is to identify potential targets for microglial cell therapy in neurodegenerative diseases.}, } @article {pmid40147067, year = {2025}, author = {Jiang, T and Ding, W and Li, X}, title = {Serum creatine kinase dynamics in amyotrophic lateral sclerosis: Predictive role of male sex, limb onset, and intermediate disease duration for stratified monitoring.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {135}, number = {}, pages = {111203}, doi = {10.1016/j.jocn.2025.111203}, pmid = {40147067}, issn = {1532-2653}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; Male ; *Creatine Kinase/blood ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Biomarkers/blood ; Adult ; Disease Progression ; Sex Factors ; }, abstract = {OBJECTIVE: To investigate serum creatine kinase (CK) levels in amyotrophic lateral sclerosis (ALS) patients and their associations with disease characteristics, exploring its utility as a biomarker for disease progression.

METHODS: This retrospective study included 81 definitive ALS patients and 99 matched controls. Serum CK levels were analyzed against sex, age, onset site, disease duration, and ALSFRS-R scores using Mann-Whitney U tests, Kruskal-Wallis tests, and multivariate regression.

RESULTS: ALS patients exhibited significantly elevated CK levels compared to controls (233.92 ± 216.91 vs. 101.81 ± 34.28 IU/L, P < 0.05), with 65.43 % exceeding gender-specific ranges. Multivariate analysis identified male sex (β = 0.32, 95 % CI: 0.21-0.43; P < 0.05), limb onset (vs. bulbar: β = 0.41, 95 % CI: 0.29-0.53; P < 0.05), and intermediate disease duration (1-3 years: β = 0.32, P < 0.05) as independent predictors. CK levels peaked in limb-onset patients (lower limb: 342.40 ± 283.53 IU/L vs. bulbar: 96.20 ± 49.39 IU/L; P < 0.05). Higher CK was associated with moderate disease severity (ALSFRS-R 36-40 vs. ≤ 35: P < 0.05).

CONCLUSION: Serum CK elevation in ALS is strongly linked to male sex, limb onset, and intermediate disease duration (1-3 years), though long-duration cases (>3 years) were underrepresented (n = 4). These findings highlight CK's potential as a cost-effective biomarker for personalized monitoring, particularly in limb-onset males with moderate functional impairment. Further validation in larger cohorts is warranted.}, } @article {pmid40148057, year = {2025}, author = {De Marchi, F and Spinelli, EG and Bendotti, C}, title = {Neuroglia in neurodegeneration: Amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Handbook of clinical neurology}, volume = {210}, number = {}, pages = {45-67}, doi = {10.1016/B978-0-443-19102-2.00004-1}, pmid = {40148057}, issn = {0072-9752}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Frontotemporal Dementia/pathology ; *Neuroglia/pathology/metabolism ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases sharing significant pathologic and genetic overlap, leading to consider these diseases as a continuum in the spectrum of their pathologic features. Although FTD compromises only specific brain districts, while ALS involves both the nervous system and the skeletal muscles, several neurocentric mechanisms are in common between ALS and FTD. Also, recent research has revealed the significant involvement of nonneuronal cells, particularly glial cells such as astrocytes, oligodendrocytes, microglia, and peripheral immune cells, in disease pathology. This chapter aims to provide an extensive overview of the current understanding of the role of glia in the onset and advancement of ALS and FTD, highlighting the recent implications in terms of prognosis and future treatment options.}, } @article {pmid40148124, year = {2025}, author = {Beckers, D and Kretz, F and Glandorf, K and Abdassalam, S and Amer, M and Breyer, DRH and Kaymak, H and Klabe, K and Beckers, L}, title = {Automated Comprehensive Analysis of Preoperative Biometric Parameters in Cataract Patients: A Retrospective Study of over 6000 Eyes.}, journal = {Klinische Monatsblatter fur Augenheilkunde}, volume = {242}, number = {5}, pages = {555-561}, doi = {10.1055/a-2541-4942}, pmid = {40148124}, issn = {1439-3999}, mesh = {Humans ; Female ; Male ; Retrospective Studies ; *Biometry/methods ; *Cataract/epidemiology/diagnosis/pathology ; Aged ; Middle Aged ; *Cataract Extraction/statistics & numerical data ; Germany/epidemiology ; Aged, 80 and over ; *Preoperative Care/statistics & numerical data/methods ; Reproducibility of Results ; Sensitivity and Specificity ; Adult ; }, abstract = {Cataract surgery is one of the most successful surgical procedures, improving vision and quality of life for millions globally. An accurate preoperative measurement is crucial for predicting outcomes, particularly in minimizing postoperative refractive errors through precise intraocular lens (IOL) selection. This study aimed to analyze preoperative biometric data in cataract patients to identify key parameters relevant for clinical decision-making. The study also sought to understand patient demographics and biometrics in a representative population. An automated retrospective analysis was conducted on the preoperative biometric data of 6 163 eyes from 3 118 patients who underwent cataract or clear lens extraction (CLE) surgery in a German clinic over the past 2 years. All measurements were taken using the IOL Master 700 (Carl Zeiss Meditec, Jena, Germany), and data were automatically transferred for analysis using a dedicated software tool. Biometric parameters assessed included axial length (AL), keratometry values (K, TK), anterior chamber depth (ACD), lens thickness (LT), and vitreous length (VL). The age and gender distribution of the cohort was also considered. The biometric data from this large patient cohort largely aligns with published norms for cataract patients. The majority of eyes exhibited ALs and corneal curvatures within expected ranges, supporting accurate IOL power calculations. The study also confirmed a high prevalence of mild astigmatism, suggesting that toric IOLs could address residual astigmatism for better visual outcomes. This study's large sample size adds valuable insights into preoperative cataract patient data and shows the value of an automated analysis.}, } @article {pmid40149017, year = {2025}, author = {Suk, TR and Part, CE and Zhang, JL and Nguyen, TT and Heer, MM and Caballero-Gómez, A and Grybas, VS and McKeever, PM and Nguyen, B and Ali, T and Callaghan, SM and Woulfe, JM and Robertson, J and Rousseaux, MWC}, title = {A stress-dependent TDP-43 SUMOylation program preserves neuronal function.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {38}, pmid = {40149017}, issn = {1750-1326}, support = {PJT-195691//CIHR/Canada ; }, mesh = {*Sumoylation/physiology ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; *Neurons/metabolism ; Mice ; Amyotrophic Lateral Sclerosis/metabolism ; Male ; Frontotemporal Dementia/metabolism ; Female ; Aging/metabolism ; *Stress, Physiological/physiology ; TDP-43 Proteinopathies/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are overwhelmingly linked to TDP-43 dysfunction. Mutations in TDP-43 are rare, indicating that the progressive accumulation of exogenous factors - such as cellular stressors - converge on TDP-43 to play a key role in disease pathogenesis. Post translational modifications such as SUMOylation play essential roles in response to such exogenous stressors. We therefore set out to understand how SUMOylation may regulate TDP-43 in health and disease. We find that TDP-43 is regulated dynamically via SUMOylation in response to cellular stressors. When this process is blocked in vivo, we note age-dependent TDP-43 pathology and sex-specific behavioral deficits linking TDP-43 SUMOylation with aging and disease. We further find that SUMOylation is correlated with human aging and disease states. Collectively, this work presents TDP-43 SUMOylation as an early physiological response to cellular stress, disruption of which may confer a risk for TDP-43 proteinopathy.}, } @article {pmid40149460, year = {2025}, author = {Ghezzi, A and Gianferrari, G and Baldassarri, E and Zucchi, E and Martinelli, I and Vacchiano, V and Bonan, L and Zinno, L and Nuredini, A and Canali, E and Gizzi, M and Terlizzi, E and Medici, D and Sette, E and Currò Dossi, M and Morresi, S and Santangelo, M and Patuelli, A and Longoni, M and De Massis, P and Ferro, S and Fini, N and Simonini, C and Carra, S and Zamboni, G and Mandrioli, J}, title = {Phenotypical Characterization of C9ALS Patients from the Emilia Romagna Registry of ALS: A Retrospective Case-Control Study.}, journal = {Genes}, volume = {16}, number = {3}, pages = {}, pmid = {40149460}, issn = {2073-4425}, support = {00000000//Emilia Romagna Regional Health Authority/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/epidemiology ; Male ; Female ; Middle Aged ; *C9orf72 Protein/genetics ; Registries ; Aged ; Case-Control Studies ; Phenotype ; Retrospective Studies ; Disease Progression ; Adult ; Prognosis ; Italy/epidemiology ; }, abstract = {BACKGROUND/OBJECTIVES: C9ORF72 expansion is associated with significant phenotypic heterogeneity. This study aimed to characterize the clinical features of C9ALS patients from the Emilia Romagna ALS registry (ERRALS) and compare them with non-mutated ALS (nmALS) patients matched for sex, age at onset, and diagnostic delay, sourced from the same register.

METHODS: In total, 67 C9ALS patients were compared to 201 nmALS. Clinical data, phenotype, and prognostic factors were analyzed in the two groups and within the C9ALS group after stratification by sex.

RESULTS: C9ALS patients displayed a higher disease progression rate and shorter times to gastrostomy and invasive ventilation, despite no differences in overall survival. Female C9ALS had a more severe bulbar and upper motor neuron involvement compared to males. Cognitive and behavioral symptoms were more common in the C9ALS group, and the former was an independent prognostic factor. Prevalences of, autoimmune diseases, and dyslipidemia were significantly higher among C9ALS patients.

CONCLUSIONS: In our dataset, we show an overall increased disease progression rate in C9ALS patients and hint at sex-specific discrepancies in some phenotypical characteristics. We also suggest a possible clinically relevant involvement of C9ORF72 expansion in metabolism and autoimmunity.}, } @article {pmid40149536, year = {2025}, author = {Kleinerova, J and Chipika, RH and Tan, EL and Yunusova, Y and Marchand-Pauvert, V and Kassubek, J and Pradat, PF and Bede, P}, title = {Sensory Dysfunction in ALS and Other Motor Neuron Diseases: Clinical Relevance, Histopathology, Neurophysiology, and Insights from Neuroimaging.}, journal = {Biomedicines}, volume = {13}, number = {3}, pages = {}, pmid = {40149536}, issn = {2227-9059}, support = {JPND-Cofund-2-2019-1 & HRB EIA-2017-019//HRB/ ; }, abstract = {Background: The clinical profiles of MNDs are dominated by inexorable motor decline, but subclinical proprioceptive, nociceptive and somatosensory deficits may also exacerbate mobility, dexterity, and bulbar function. While extra-motor pathology and frontotemporal involvement are widely recognised in motor neuron diseases (MNDs), reports of sensory involvement are conflicting. The potential contribution of sensory deficits to clinical disability is not firmly established and the spectrum of sensory manifestations is poorly characterised. Methods: A systematic review was conducted to examine the clinical, neuroimaging, electrophysiology and neuropathology evidence for sensory dysfunction in MND phenotypes. Results: In ALS, paraesthesia, pain, proprioceptive deficits and taste alterations are sporadically reported and there is also compelling electrophysiological, histological and imaging evidence of sensory network alterations. Gait impairment, impaired dexterity, and poor balance in ALS are likely to be multifactorial, with extrapyramidal, cerebellar, proprioceptive and vestibular deficits at play. Human imaging studies and animal models also confirm dorsal column-medial lemniscus pathway involvement as part of the disease process. Sensory symptoms are relatively common in spinal and bulbar muscular atrophy (SBMA) and Hereditary Spastic Paraplegia (HSP), but are inconsistently reported in primary lateral sclerosis (PLS) and in post-poliomyelitis syndrome (PPS). Conclusions: Establishing the prevalence and nature of sensory dysfunction across the spectrum of MNDs has a dual clinical and academic relevance. From a clinical perspective, subtle sensory deficits are likely to impact the disability profile and care needs of patients with MND. From an academic standpoint, sensory networks may be ideally suited to evaluate propagation patterns and the involvement of subcortical grey matter structures. Our review suggests that sensory dysfunction is an important albeit under-recognised facet of MND.}, } @article {pmid40149599, year = {2025}, author = {Yang, W and Xiao, W and Liu, X and Li, H and Huang, T and Fan, D}, title = {Testosterone Supplementation: A Potential Therapeutic Strategy for Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {13}, number = {3}, pages = {}, pmid = {40149599}, issn = {2227-9059}, support = {82071426//National Natural Science Foundation of China/ ; }, abstract = {Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by the degeneration of spinal cord and brain neurons. Proteomics combined with Mendelian randomization (MR) is an effective method for finding disease treatment targets. Methods: We aimed to seek new therapeutic targets for ALS. A large-scale GWAS on proteomics (4907 circulatory protein) with 35,559 individuals was included as the exposure data; a GWAS with 138,086 ALS patients was used as the outcome data; we found that a high level of sex hormone-binding globulin (SHBG) is a risk factor by MR analysis. Colocalization analyses were used to validate the causality between SHBG and ALS further. Functional enrichment found a high level of SHBG was associated with a low level of bioavailable testosterone. Two-sample MR confirmed the association of SHBG (400,210 samples), bioavailable testosterone (367,289 samples), and ALS. Results: A high level of SHBG, and a low level of bioavailable testosterone are risk factors for ALS. Conclusions: A low level of bioavailable testosterone is a risk factor for ALS. Although our study is relatively limited and cannot fully confirm that testosterone supplementation has a therapeutic effect on ALS, it offers a promising direction for ALS therapy.}, } @article {pmid40149779, year = {2025}, author = {Ginanneschi, F and Casali, S and Cioni, C and Righi, D and Emmanuello, E and Toccaceli, C and Plantone, D and De Stefano, N}, title = {Does Lumbar Puncture Still Have Clinical Value for Patients with Amyotrophic Lateral Sclerosis?.}, journal = {Brain sciences}, volume = {15}, number = {3}, pages = {}, pmid = {40149779}, issn = {2076-3425}, abstract = {Background: The relationship between routine cerebrospinal fluid (CSF) testing and clinical and prognostic data in amyotrophic lateral sclerosis (ALS) remains unclear. Additionally, biochemical data have never been correlated with markers of neurodegeneration. The purpose of this study is to determine whether lumbar puncture may still have clinical utility in ALS. Methods: We collected the CSF profiles of 140 ALS subjects. CSF protein, albumin, IgG, IgG index, albumin quotient (QAlb), t-tau, p-tau, and Aβ42 were analyzed. Results: Approximately one-quarter of ALS patients had elevated levels of protein, albumin, and QAlb in the CSF, but these were not associated with clinical or survival data. Among the neurodegeneration markers, the percentage of patients with abnormal values ranged from 26.3% to 35.4%. The p-tau/t-tau ratio and Aβ42 were correlated with both the ALS progression rate and the time from diagnosis to death. Aβ42 was the prognostic marker most strongly associated with survival. Conclusions: The lack of correlation between biochemical CSF findings and the clinical and/or prognostic status of ALS suggests that these markers have no clinical value. However, neurodegeneration markers that are easily measurable in clinical laboratories, particularly Aβ42, may be useful at the time of diagnosis for predicting ALS survival and progression rate.}, } @article {pmid40150989, year = {2025}, author = {Matsumoto, S and Tateishi-Karimata, H and Ohyama, T and Sugimoto, N}, title = {Controlling the Local Conformation of RNA G-Quadruplex Results in Reduced RNA/Peptide Cytotoxic Accumulation Associated with C9orf72 ALS/FTD.}, journal = {Small methods}, volume = {9}, number = {6}, pages = {e2401630}, doi = {10.1002/smtd.202401630}, pmid = {40150989}, issn = {2366-9608}, mesh = {*G-Quadruplexes/drug effects ; Humans ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *RNA/chemistry/metabolism/genetics ; *Peptides/metabolism/chemistry ; *Frontotemporal Dementia/genetics/metabolism ; Cell Line, Tumor ; DNA Repeat Expansion ; Nucleic Acid Conformation ; }, abstract = {Repeat expansion of d(G4C2) in the noncoding region of the C9orf72 gene contributes to neurodegenerative diseases. The repeat expansion transcript r(G4C2) induces RNA/peptide accumulation, which, in turn, induces cytotoxicity and accelerates the development of neurodegenerative diseases. Such cytotoxic accumulation is triggered by peptide aggregation. Here, a technique is developed to prevent accumulation by regulating RNA interactions, assuming that RNA structure is important for peptide interactions. A screening method is used to identify compounds that suppress RNA accumulation of r(G4C2) repeats. The four compounds are identified with wide π-planes containing hydroxyl, methoxy, and cyclic ether groups that suppressed RNA accumulation. Interestingly, these compounds also suppressed RNA/peptide accumulation in neuroblastoma cells, indicating that RNA accumulation is a key regulator of RNA/peptide cytotoxic aggregate formation. In vitro and in silico physicochemical analyses reveal that these compounds bind to the loop region of the G-quadruplex via hydrogen bonds or CH-π interactions, resulting in an altered loop conformation. Importantly, these conformational changes inhibited RNA G-quadruplex associations. These results show that conformational changes are promising for controlling the interactions between G-quadruplexes and further RNA accumulation. These findings may be useful in the development of therapeutic strategies for the treatment of neurodegenerative diseases.}, } @article {pmid40151398, year = {2025}, author = {Roy, SM and Acquarone, E and Argyrousi, EK and Zhang, H and Staniszewski, A and Inoue, A and Ziarek, JJ and Arancio, O and Watterson, DM}, title = {Optimized 5-HT2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70073}, pmid = {40151398}, issn = {2352-8737}, support = {R01 AG031311/AG/NIA NIH HHS/United States ; U01 AG066722/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Neuropsychiatric syndromes such as anxiety and agitation are clinical presentations common to diverse neurodegenerative diseases and brain injury sequelae. They are a concern due to the impact on cognition, social interactions, and non-pharmacological treatments. Cognitive or behavioral disturbances occur at early disease stages and increase with disease progression. Coincident pathologies include the loss of serotonin (5-HT) neurons and appearance of neurofibrillary tangles in the raphe nucleus. Brain 5-HT2b receptor (5-HT2bR) levels are increased in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and post-stroke morbidity. HTR2B gene variants are implicated in psychiatric disorders. 5-HTRs are associated with atypical neurotropic drug mechanisms and behavioral dysfunction in drug abuse. The accumulating body of evidence suggests that selective 5-HT2bR inhibition might mitigate neuropsychiatric syndromes and the associated cognitive dysfunction. Atypical neurotropic drugs interact with a variety of monoamine receptors and outcomes are viewed as a combination of 5-HT and dopamine D2 receptor mediated actions. Clearly, there is a need for insight into precision 5-HT2bR inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia.

METHODS: Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5-HT2bR activity and β-arrestin-1 recruitment that is devoid of dopamine receptor recognition and risk of 5-HT2bR agonist activity.

RESULTS: MW073 ameliorates amyloid and tau induction of behavioral dysfunction in preventive or disease stage intervention paradigms. Using MW073 as a standard of comparison, risperidone was shown to be a dose-dependent inhibitor 5-HT2bR activity and β-arrestin-1 recruitment.

DISCUSSION: Selective inhibition of 5-HT2bR activity is a viable mechanism for the treatment of neuropsychiatric syndromes with synaptic dysfunction as a root cause and is a previously unrealized pharmacodynamic mechanism potentially embedded in current neurotherapeutics.

HIGHLIGHTS: A new highly selective 5-HT2bR antagonist, MW073, is described and used as a reference standard.MW073 attenuates synaptic and behavioral dysfunctions an animal models of neuropsychatric syndromes.Risperidone is a dose dependent inhibitor of 5-HT2bR activity and arrestin recruitment.}, } @article {pmid40151693, year = {2025}, author = {Tariq, D and Madhusudan, R and Guntupalli, Y and Karumanchi Anantha Venkata Sai, S and Vejandla, B and Lnu, M}, title = {A Cross-Sectional Study Comparing Patient Information Guides for Amyotrophic Lateral Sclerosis, Myasthenia Gravis, and Guillain-Barré Syndrome Produced by ChatGPT-4 and Google Gemini 1.5.}, journal = {Cureus}, volume = {17}, number = {2}, pages = {e79646}, pmid = {40151693}, issn = {2168-8184}, abstract = {INTRODUCTION: Patient education for amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG), and Guillain-Barré syndrome (GBS) is essential for effective symptom management, improving quality of life, and enabling informed care decisions. AI tools enhance healthcare and patient education through personalized care and improved diagnostics.

METHODS:  In this study, ChatGPT (OpenAI, San Francisco, CA, USA) and Google Gemini (Mountain View, CA, USA) generated patient education guides for ALS, MG, and GBS. Variables included word count, sentence count, average words and syllables per sentence, grade level, ease score using the Flesch-Kincaid calculator, similarity score using QuillBot, and reliability using a modified DISCERN score. Statistical analysis was done using R version 4.3.2 (2023; R Foundation for Statistical Computing, Vienna, Austria).

RESULTS: ChatGPT-generated brochures for patient education on ALS, MG, and GBS had a higher grade level and lower ease score compared to those generated by Google Gemini. Although both models had similar reliability and similarity percentages, ChatGPT produced more content with greater complexity and slightly higher reliability.

CONCLUSION:  This study found no significant difference in the average ease, grade, and reliability scores between the two AI tools when generating patient information brochures on ALS, MG and GBS. However, a statistically significant difference was observed in the mean word counts generated by the tools.}, } @article {pmid40151753, year = {2025}, author = {Carqueja, I and Montenegro Sá, F and Monteiro, S}, title = {Ventricular Arrhythmias Caused by Left Main Coronary Artery Vasospasm: A Diagnostic Challenge in a Cardiac Arrest Victim.}, journal = {Cureus}, volume = {17}, number = {2}, pages = {e79554}, pmid = {40151753}, issn = {2168-8184}, abstract = {Sudden cardiac death (SCD) is a common cause of cardiovascular deaths. It may be caused by primary electrical diseases, cardiomyopathies, myocarditis, valvular heart diseases, or coronary artery disease (including acute coronary syndrome). Coronary artery vasospasm is defined as a transient total or subtotal coronary artery obstruction, associated with angina symptoms and ischemic findings on electrocardiogram (ECG). It is a cause of myocardial infarction, life-threatening arrhythmias, atrioventricular block, and SCD. A 55-year-old man presented to the hospital after an out-of-hospital cardiac arrest (OHCA). He had a previous history of cardiovascular risk factors, excessive alcohol intake, non-obstructive coronary artery disease, and paroxysmic atrial fibrillation. On the day of the OHCA, he had a sudden collapse while exercising, with ventricular fibrillation and return of spontaneous circulation (ROSC) after advanced life support (ALS). No ECG or echocardiographic anomalies were identified on hospital admission. The patient suffered three more episodes of cardiac arrest during the hospital stay, with atypical arrhythmic presentations. No ECG or echocardiographic abnormalities were observed after ROSC. The fourth cardiac arrest had concomitant segmental ST changes and de novoechocardiographic segmental motility abnormalities suggestive of left main coronary artery occlusion. These findings were transient, with a normal ECG and echocardiogram obtained one hour after ROSC. No electrolyte abnormalities or other causes of cardiac arrest were identified. The hypothesis of left main coronary vasospasm was raised as the likely diagnosis. Coronary artery vasospasm is a possible cause of major cardiac events. Diagnosis can be challenging due to the transient findings and varied manifestations, often in patients with normal coronary arteries. The correct diagnosis and treatment of coronary artery vasospasm can have a determinant effect on prognosis and mortality, as appropriate treatment can lead to prolonged event-free survival. Provocative coronary vasospasm tests performed in patients with atypical cardiovascular manifestations can allow for the timely diagnosis of vasospasm and avoid critical events. The authors aim to raise awareness of the different clinical presentations of coronary artery vasospasm and its consequences. The performance of provocative tests in selected patients should be considered to promote early diagnosis and potentially avoid major events.}, } @article {pmid40152389, year = {2025}, author = {Belosludtseva, NV and Ilzorkina, AI and Dubinin, MV and Mikheeva, IB and Belosludtsev, KN}, title = {Comparative Study of Structural and Functional Rearrangements in Skeletal Muscle Mitochondria of SOD1-G93A Transgenic Mice at Pre-, Early-, and Late-Symptomatic Stages of ALS Progression.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {30}, number = {3}, pages = {28260}, doi = {10.31083/FBL28260}, pmid = {40152389}, issn = {2768-6698}, support = {23-25-00286//Russian Science Foundation/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology/genetics ; Mice, Transgenic ; Mice ; *Superoxide Dismutase/genetics/metabolism ; *Muscle, Skeletal/ultrastructure/pathology/metabolism/physiopathology ; *Mitochondria, Muscle/ultrastructure/metabolism/pathology ; Male ; Disease Progression ; Superoxide Dismutase-1 ; Disease Models, Animal ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive multisystem disease characterized by limb and trunk muscle weakness that is attributed, in part, to abnormalities in mitochondrial ultrastructure and impaired mitochondrial functions. This study investigated the time course of structural and functional rearrangements in skeletal muscle mitochondria in combination with motor impairments in Tg (copper-zinc superoxide dismutase enzyme (SOD1) G93A) dl1/GurJ (referred to as SOD1-G93A/low) male mice, a familial ALS model, as compared with non-transgenic littermates.

METHODS: The neurological status and motor functions were assessed weekly using the paw grip endurance method and the grid suspension test with two-limb and four-limb suspension tasks. Transmission electron microscopy followed by quantitative analysis was performed to study ultrastructural alterations in the quadriceps femoris. Functional analysis of skeletal muscle mitochondria was performed using high-resolution Oxygraph-2k (O2K) respirometry and methods for assessing the calcium retention capacity index and the content of lipid peroxidation products in freshly isolated preparations.

RESULTS: Based on the behavioral phenotyping data, specific age groups were identified: postnatal day 56 (P56) (n = 10-11), 84 (P84) (n = 10-11), and 156 (P154) (n = 10-12), representing the pre-symptomatic, early-symptomatic and late-symptomatic stages of ALS progression in SOD1-G93A/low mice, respectively. Electron microscopy showed mosaic destructive changes in subsarcolemmal mitochondria in fibers of the quadriceps femoris from 84-day-old SOD1-G93A/low mice. Morphometric analysis revealed an elevation in the mean size of the mitochondria in SOD1-G93A mice at P84 and P154. In addition, the P154 transgenic group demonstrated a decrease in sarcomere width and the number of mitochondria per unit area. At the symptomatic stage, SOD1-G93A mice exhibited a decreased respiratory control ratio, ADP-stimulated, and uncoupled respiration rates of mitochondria isolated from the quadriceps femoris muscle, as measured by high-resolution respirometry. In parallel, the mitochondria showed lower calcium retention capacity and increased levels of lipid peroxidation products compared with the control.

CONCLUSIONS: Taken together, these results indicate stage-dependent changes in skeletal muscle mitochondrial ultrastructure and functions associated with defective oxidative phosphorylation, impaired calcium homeostasis, and oxidative damage in the SOD1-G93A/low mouse model, which appears to be a promising direction for the development of combination therapies for ALS.}, } @article {pmid40152605, year = {2025}, author = {Yuan, C and Dong, H and Wu, C and Liu, J and Wang, Z and Wang, X and Ren, H and Wang, Z and Lu, Q}, title = {EPG-5 regulates TGFB/TGF-β and WNT signalling by modulating retrograde endocytic trafficking.}, journal = {Autophagy}, volume = {21}, number = {9}, pages = {1995-2008}, pmid = {40152605}, issn = {1554-8635}, mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; *Transforming Growth Factor beta/metabolism ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Endocytosis/physiology ; *Wnt Signaling Pathway ; Endosomes/metabolism ; Protein Transport ; Autophagy ; Autophagosomes/metabolism ; Lysosomes/metabolism ; Humans ; Vesicular Transport Proteins/metabolism ; rab GTP-Binding Proteins/metabolism ; }, abstract = {The Vici syndrome protein EPG5 acts as a tethering factor determining the fusion specificity of autophagosomes with late endosomes/lysosomes. Here we demonstrated that during C. elegans development, EPG-5 modulates SMA and MAB TGFB/TGF-β signaling in controlling body size and also WNT signaling in regulating cell migration. EPG-5 is required for retrograde trafficking of the TGFB receptor SMA-6 and WLS/Wntless homolog MIG-14. In epg-5 mutants, SMA-6 and MIG-14 are trapped within hybrid endosomal structures, which colocalize with SNX-1- and SNX-3-labeled vesicles, respectively. Basolateral recycling processes of transmembrane cargos H.s.TFR/hTfR and H.s.IL2RA/hTAC are also defective in epg-5 mutants. Depletion of EPG-5 causes defective RAB-5 and RAB-7, and RAB-5 and RAB-10 conversion, leading to the formation of these hybrid vesicles. The defects in endocytic trafficking and autophagy in epg-5 mutants are ameliorated by knocking down components of the HOPS complex. Our study demonstrates the intersection between the autophagy pathway and the endocytic pathway, providing insights into the pathogenesis of amyotrophic lateral sclerosis (ALS) and Vici syndrome.Abbreviations: ALM: anterior lateral microtubule; ATG: autophagy related; AVM: anterior ventral microtubule; CORVET: class C core vacuole/endosome tethering; DAF-4: abnormal dauer formation 4; DIC: differential interference contrast; EPG: ectopic PGL granules; EPG-5: ectopic P granules 5; GAP: GTPase activating protein; GFP: green fluorescent protein; HOPS: homotypic fusion and vacuole protein sorting; H.s.IL2RA/hTAC: human interleukin 2 receptor subunit alpha; H.s.TFR/hTfR: human transferrin receptor; L1/L4: the first/fourth larval; mCh: mCherry; MIG-14: abnormal cell migration 14; PLM: posterior lateral microtubule; PVM: posterior ventral microtubule; RAB: ras-related protein; RFP: red fluorescent protein; RME-1: receptor mediated endocytosis 1; SMA-6: small 6; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNX: sorting nexin; TBC-2: TBC1 (Tre-2/Bub2/Cdc16) domain family 2; TGFB/TGF-β: transforming growth factor beta; TGN: trans-Golgi network; VPS: related to yeast vacuolar protein sorting factor; WT: wild type.}, } @article {pmid40152938, year = {2025}, author = {Yu, L and Yang, Z and Ming, Z and Zhou, Q and Zeng, S}, title = {Impaired Aortic Biomechanical Properties in Patients With Severe Obstructive Sleep Apnea Syndrome.}, journal = {Echocardiography (Mount Kisco, N.Y.)}, volume = {42}, number = {4}, pages = {e70135}, doi = {10.1111/echo.70135}, pmid = {40152938}, issn = {1540-8175}, support = {kq2208343//Natural Science Foundation of Changsha City/ ; 2024JJ8122//Natural Science Foundation of Hunan Province/ ; }, mesh = {Humans ; *Sleep Apnea, Obstructive/physiopathology/complications/diagnostic imaging ; Male ; Female ; Middle Aged ; *Aorta/physiopathology/diagnostic imaging ; Biomechanical Phenomena ; *Echocardiography/methods ; Adult ; Severity of Illness Index ; }, abstract = {PURPOSE: Evaluating the biomechanical properties of the aorta is crucial for assessing cardiovascular risk and preventing disease progression. The aim of this study was to evaluate the biomechanical properties of the ascending aorta (AA) in severe obstructive sleep apnea syndrome (OSAS) patients with or without hypertension (HT) via velocity vector imaging (VVI).

METHODS: A total of 68 patients with severe OSAS were selected, 35 of whom were included in the simple OSAS group and 33 of whom were included in the OSAS + HT group, and 40 volunteers without these two disorders who were taken as the control group. AA biomechanical properties, that is, AA longitudinal strain (ALS), AA circumferential strain (ACS), and fractional area change (FAC), were evaluated via VVI. Pulsed Doppler early transmitral peak flow velocity (E), early diastolic mitral annular velocity (e'), left ventricular (LV) global longitudinal strain (GLS), and the AA dimension (AD) were also measured.

RESULTS: ALS (mean ± SD; 32.8% ± 11.9% and 19.7% ± 7.6% vs. 40.6% ± 15.6%, p = 0.006), ACS (mean ± SD; 11.8% ± 3.5% and 8.6% ± 2.7% vs. 16.5% ± 5.8%, p = 0.02), and FAC (mean ± SD; 21.0% ± 5.3% and 12.4% ± 3.8% vs. 32.8% ± 9.7%, p = 0.004) were significantly lower in the patient groups (OSAS and OSAS + HT, respectively) than in the control group. LV systolic and diastolic functions were also impaired in the patient groups. Compared with volunteers without OSAS and HT, these patients had a greater AD and E/e' ratio and a lower GLS (p < 0.01). The aortic biomechanical properties were strongly correlated with the LV function and sleep parameters.

CONCLUSION: AA biomechanical properties are impaired in patients with severe OSAS, especially those with HT. Impairments in these aortic biomechanical properties are associated with diminished LV function and abnormal sleep parameters. This discovery may help clinicians identify and manage potential cardiovascular risks in OSAS patients. Further large-scale longitudinal studies are needed to confirm the potential predictive value of aortic events (e.g., aortic aneurysm or dissection) in patients with OSAS.}, } @article {pmid40153582, year = {2024}, author = {Norata, D and Capone, F and Motolese, F and Marano, M and Rossi, M and Calandrelli, R and Sacchetti, M and Mantelli, F and Di Lazzaro, V and Pilato, F}, title = {1953-2023. Seventy Years of the Nerve Growth Factor: A Potential Novel Treatment in Neurological Diseases?.}, journal = {Aging and disease}, volume = {16}, number = {4}, pages = {2293-2314}, pmid = {40153582}, issn = {2152-5250}, mesh = {Humans ; *Nerve Growth Factor/therapeutic use ; Animals ; *Nervous System Diseases/therapy/drug therapy ; History, 20th Century ; History, 21st Century ; }, abstract = {Rita Levi-Montalcini's 1953 discovery of nerve growth factor (NGF) in mouse sarcoma tumors marked a groundbreaking moment in neuroscience. NGF, a key signaling molecule, became the first identified neurotrophic factor, influencing the growth, differentiation, and survival of neurons in both peripheral and central nervous systems. NGF and related neurotrophic factors hold therapeutic potential for various neurological disorders, such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis, spinal cord injuries, neuropathies, traumatic brain injuries, and stroke. However, despite promising in vitro studies and animal models findings, NGF efficacy in patients remains unproven. Indeed, its use as a therapeutic agent faces challenges in delivery and clinical translation. This review delves into these challenges, exploring ongoing research on refined delivery methods, dosages, and safety profiles. Innovative strategies, including molecular mimicking, combination therapies, gene therapy, and coupling with neuromodulation techniques like transcranial magnetic stimulation and vagal nerve stimulation, are discussed. Incorporating nerve growth factor (NGF) into a comprehensive strategy may prove beneficial, particularly in non-neurodegenerative conditions such as stroke, trauma, and neuropathies. In these instances, NGF holds promise for promoting tissue regeneration and repair. Challenges persist in addressing the complexity of neurodegenerative pathologies for a combined therapeutic approach.}, } @article {pmid40155564, year = {2025}, author = {Tang, J and Zhao, Y and Chen, Y and Yang, Y and Gong, Z and Li, Z and Zhang, M and Zhang, J}, title = {White matter integrity mediated the effect of plasma uric acid levels on cognitive function in ALS patients.}, journal = {Brain imaging and behavior}, volume = {19}, number = {3}, pages = {678-689}, pmid = {40155564}, issn = {1931-7565}, support = {82271478//National Natural Science Foundation of China/ ; 2024AOXIANG05//the Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital/ ; }, mesh = {Humans ; *Uric Acid/blood ; *White Matter/diagnostic imaging/pathology ; *Amyotrophic Lateral Sclerosis/blood/diagnostic imaging/physiopathology/psychology ; Male ; Female ; Middle Aged ; Diffusion Tensor Imaging/methods ; *Cognition/physiology ; Aged ; Brain/diagnostic imaging ; Executive Function/physiology ; Adult ; Neuropsychological Tests ; }, abstract = {OBJECTIVE: To investigate the association between plasma uric acid levels and white matter microstructural alterations in amyotrophic lateral sclerosis (ALS) patients and to explore the potential mediating role of white matter microstructural alterations in the protective effect of plasma uric acid on cognitive function in ALS patients.

METHODS: 73 right-handed ALS patients were recruited for this study. Plasma uric acid levels were measured, diffusion tensor imaging scans were performed to assess white matter integrity, and cognition was evaluated using the Edinburgh Cognitive and Behavioral Screen. The relationships among plasma uric acid, white matter integrity, and cognitive function were examined through multivariate linear regression analysis. Additionally, mediation analysis was performed to investigate whether white matter integrity mediated the relationship between uric acid levels and cognitive function.

RESULTS: The findings revealed a positive correlation between plasma uric acid levels and extensive preservation of white matter microstructure in various regions, including the fornix, cerebellar, internal capsule, frontotemporal and frontooccipital lobe bundles among ALS patients. Mediation analysis indicated that fractional anisotropy in the hippocampal portion of the cingulum fully mediated the effects of plasma uric acid levels on executive function in ALS patients.

INTERPRETATION: Our results suggested that elevated plasma uric acid may preserve the integrity of white matter microstructure in ALS patients. Furthermore, we have identified evidence supporting the mediating influence of the hippocampal portion of the cingulum in linking plasma uric acid levels to cognitive function among ALS patients.}, } @article {pmid40155688, year = {2025}, author = {Fan, X and Zeng, Y and Zhang, F and Xu, Y and Duan, Q and Long, S and Lin, Y and Wang, K and Jiang, L}, title = {Genetic effects of circulating hormone and proteome on amyotrophic lateral sclerosis identified by Mendelian randomization.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {10782}, pmid = {40155688}, issn = {2045-2322}, support = {82201242//National Natural Science Foundation of China/ ; 82470903//National Natural Science Foundation of China/ ; LY24C110001//Natural Science Foundation of Zhejiang Province/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood ; Humans ; *Mendelian Randomization Analysis ; *Proteome/genetics ; Testosterone/blood/genetics ; Biomarkers/blood ; Male ; Insulin-Like Growth Factor I/genetics/metabolism ; Risk Factors ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Proteomics ; Female ; *Hormones/blood/genetics ; }, abstract = {Altered circulating hormones in ALS patients have been widely reported by previous observational studies, but whether these relationships are causal is unclear. Moreover, the potential therapeutic targets for ALS and the effects of plasma protein fluctuation on ALS progression are not fully understood. Therefore, we conducted a Mendelian randomization (MR) study to evaluate the causal role of 5 hormonal risk factors (insulin-like growth factor-1, IGF-1; sex hormone-binding globulin, SHBG; free testosterone, FT; total testosterone, TT; and estradiol) in ALS risk. Furthermore, we screened up to 90 circulating proteins including cytokines, chemokines, growth factors, and interferons, to identify potential therapeutic targets for ALS. Our MR analysis found genetically predicted higher level of FT was associated with a 23% lowered risk of ALS. Further screening of proteomic traits found that 12 plasma proteins were causally associated with ALS. These findings suggest that higher FT potentially exerts a protective effect on ALS risk. Several proteins may act as potential circulating biomarkers and therapeutic targets for ALS. In the future, high-throughput proteomic analyses and experimental explorations are likely needed to clarify the regulated role and mechanistic pathways.}, } @article {pmid40156516, year = {2025}, author = {Gorgich, EA and Heidari, Z and Mahmoudzadeh-Sagheb, H and Rustamzadeh, A and Shabani, A and Amirzadeh, A and Haghi Ashtiani, B}, title = {Brain Metabolite Profiles are Associated with Selective Neuronal Vulnerability and Underlying Mechanisms in Amyotrophic Lateral Sclerosis.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {8}, pages = {1469-1480}, doi = {10.1021/acschemneuro.4c00593}, pmid = {40156516}, issn = {1948-7193}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; Male ; Female ; Middle Aged ; Case-Control Studies ; Aged ; *Motor Cortex/metabolism/diagnostic imaging ; *Brain/metabolism ; Disease Progression ; Proton Magnetic Resonance Spectroscopy ; Adult ; *Neurons/metabolism ; Magnetic Resonance Imaging ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurological syndrome accompanied by selective degeneration of somatic motor neurons and neurochemistry alterations. Nevertheless, eye movement's nuclei are relatively spared from ALS damage. This survey was to probe metabolite changes in the primary motor cortex (PMC) and interstitial nucleus of Cajal (INC) of ALS patients using proton magnetic resonance spectroscopy ([1]H-MRS). In this case-control study, 20 patients with ALS and 20 healthy controls underwent 1.5 T MRI and multivoxel [1]H-MRS. [1]H-MRS spectra to determine metabolite profiles including tNAA, mIns, tCr, tCho, and also tNAA/tCr, tNAA/tCho, and mIns/tNAA metabolite ratios from the PMC and INC were quantified via a point resolved spectroscopy pulse (PRESS) sequence in two groups. Further, the associations between [1]H-MRS markers with forced vital capacity (FVC), ALS functional rating scale (ALSFRS-R), and disease progression rate (ΔFS) were investigated. In the PMC, tNAA and tNAA/tCr were significantly lower in ALS patients than the healthy controls, but mIns and mIns/tNAA were significantly greater in these patients (p < 0.05). In the INC, tCho and mIns concentrations, and mIns/tNAA ratio were significantly increased (p < 0.05) in ALS patients, while tNAA and tNAA/tCr ratio did not show significant discriminations between the two groups (p > 0.05). The PMC tNAA/Cr ratio is associated with ALSFRS-R (p = 0.001, r = 0.71), FVC (p = 0.03, r = 0.58), and ΔFS (p = 0.01, r = -0.33). The mIns/tNAA ratio in PMC is also associated with ΔFS (p = 0.02, r = 0.41). In the INC, tCho concentrations (p = 0.04, r = -0.54) and mIns/tNAA ratio (p = 0.02, r = -0.38) were negatively associated with ALSFRS-R and positively correlated with ΔFS (p = 0.01, r = 0.33) and (p = 0.001, r = 0.61), respectively. The study suggests that neurochemistry changes in ALS patients' brains are linked to selective neuronal vulnerability and the underlying pathophysiology of the disease.}, } @article {pmid40157354, year = {2025}, author = {Klickstein, JA and Johnson, MA and Antonoudiou, P and Maguire, J and Paulo, JA and Gygi, SP and Weihl, C and Raman, M}, title = {ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons.}, journal = {Stem cell reports}, volume = {20}, number = {5}, pages = {102478}, doi = {10.1016/j.stemcr.2025.102478}, pmid = {40157354}, issn = {2213-6711}, support = {R01 GM127557/GM/NIGMS NIH HHS/United States ; R21 NS123631/NS/NINDS NIH HHS/United States ; }, } @article {pmid40157355, year = {2025}, author = {Scialò, C and Zhong, W and Jagannath, S and Wilkins, O and Caredio, D and Hruska-Plochan, M and Lurati, F and Peter, M and De Cecco, E and Celauro, L and Aguzzi, A and Legname, G and Fratta, P and Polymenidou, M}, title = {Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures.}, journal = {Neuron}, volume = {113}, number = {10}, pages = {1614-1628.e11}, doi = {10.1016/j.neuron.2025.03.008}, pmid = {40157355}, issn = {1097-4199}, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Frontotemporal Dementia/pathology/metabolism/genetics ; *Protein Aggregation, Pathological/pathology/metabolism/genetics ; *Neurons/metabolism/pathology ; Inclusion Bodies/metabolism/pathology ; }, abstract = {Neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) results from both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43, but their mechanistic connection remains unclear. Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade. We developed a robust TDP-43-seeding platform for quantitative assessment of TDP-43 aggregate uptake, cell-to-cell spreading, and loss of function within living cells, while they progress toward pathology. We show that both patient-derived and recombinant TDP-43 pathological aggregates were abundantly internalized by human neuron-like cells, efficiently recruited endogenous TDP-43, and formed cytoplasmic inclusions reminiscent of ALS/FTD pathology. Combining a fluorescent reporter of TDP-43 function with RNA sequencing and proteomics, we demonstrated aberrant cryptic splicing and a loss-of-function profile resulting from TDP-43-templated aggregation. Our data highlight known and novel pathological signatures in the context of seed-induced TDP-43 loss of function.}, } @article {pmid40157356, year = {2025}, author = {Rummens, J and Khalil, B and Yıldırım, G and Silva, P and Zorzini, V and Peredo, N and Wojno, M and Ramakers, M and Van Den Bosch, L and Van Damme, P and Davie, K and Hendrix, J and Rousseau, F and Schymkowitz, J and Da Cruz, S}, title = {TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss of function of TDP-43.}, journal = {Neuron}, volume = {113}, number = {10}, pages = {1597-1613.e8}, doi = {10.1016/j.neuron.2025.03.004}, pmid = {40157356}, issn = {1097-4199}, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; *Cytoplasm/metabolism/pathology ; *Cell Nucleus/metabolism/pathology ; *Neurons/metabolism/pathology ; *Protein Aggregation, Pathological/metabolism/pathology ; TDP-43 Proteinopathies/metabolism/pathology ; Amyloid/metabolism ; Inclusion Bodies/metabolism ; Protein Aggregates ; }, abstract = {Cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) are hallmarks of several neurodegenerative disorders. Yet, recapitulating both features in cellular systems has been challenging. Here, we produced amyloid-like fibrils from recombinant TDP-43 low-complexity domain and demonstrate that sonicated fibrils trigger TDP-43 pathology in human cells, including induced pluripotent stem cell (iPSC)-derived neurons. Fibril-induced cytoplasmic TDP-43 inclusions acquire distinct biophysical properties, recapitulate pathological hallmarks such as phosphorylation, ubiquitin, and p62 accumulation, and recruit nuclear endogenous TDP-43, leading to its loss of function. A transcriptomic signature linked to both aggregation and nuclear loss of TDP-43, including disease-specific cryptic splicing, is identified. Cytoplasmic TDP-43 aggregates exhibit time-dependent heterogeneous morphologies as observed in patients-including compacted, filamentous, or fragmented-which involve upregulation/recruitment of protein clearance pathways. Ultimately, cell-specific progressive toxicity is provoked by seeded TDP-43 pathology in human neurons. These findings identify TDP-43-templated aggregation as a key mechanism driving both cytoplasmic gain of function and nuclear loss of function, offering a valuable approach to identify modifiers of sporadic TDP-43 proteinopathies.}, } @article {pmid40157434, year = {2025}, author = {Pu, L and Steele, JR and Phillips, CR and Violi, JP and Rodgers, KJ}, title = {The cyanobacterial toxins BMAA and 2,4-DAB perturb the l-serine biosynthesis pathway and induce systemic changes in energy metabolism in human neuroblastoma cells: A proteomic study.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {106}, number = {}, pages = {106058}, doi = {10.1016/j.tiv.2025.106058}, pmid = {40157434}, issn = {1879-3177}, mesh = {*Amino Acids, Diamino/toxicity ; Humans ; Cyanobacteria Toxins ; *Serine/biosynthesis ; Energy Metabolism/drug effects ; Cell Line, Tumor ; Proteomics ; Neuroblastoma/metabolism ; *Aminobutyrates/toxicity ; *Bacterial Toxins/toxicity ; }, abstract = {Blue-green algae (cyanobacteria), an ancient phylum of bacteria, produce a wide array of secondary metabolites that are toxic to humans. Rapid growth of cyanobacteria in an aquatic environment can result in algal blooms capable of turning waterways green and increasing toxin levels in the environment. Cyanobacterial toxins were first linked to the high incidence of a complex neurodegenerative disorder reported on the island of Guam in the 1940s but more recently have been linked to clusters of sporadic amyotrophic lateral sclerosis (sALS) worldwide. The non-protein amino acid β-N-methylamino-L-alanine (BMAA) and its isomer L-2,4-diaminobutyric acid (2,4-DAB) are produced concurrently by most cyanobacterial species. We carried out proteomic analysis on human neuroblastoma cells treated with BMAA and 2,4-DAB to determine the underlying mechanisms of toxicity resulting from exposure to these cyanotoxins and identified significant changes in the l-serine biosynthesis pathway as well as pathways associated with energy production in the cell such as fatty acid ß-oxidation and glycolysis. The impact on the serine biosynthetic pathway was supported by demonstrating a significant decrease in both mRNA and protein levels of the enzyme 3-phosphoglycerate dehydrogenase (PHGDH) the first committed step in serine biosynthesis. PHGDH uses 3-phospho-D-glycerate (3PG) an intermediate in the glycolytic pathway as a substrate, and co-incubation of cells with l-serine restored expression levels of PHGDH as did cell pre-treatment with the glycolytic product pyruvate. This is the first study to link exposure to BMAA and 2,4-DAB to impairments in the l-serine biosynthesis pathway and broad disturbances in energy metabolism.}, } @article {pmid40157684, year = {2025}, author = {Yu, T and Li, M and Li, M and Zhang, Q and Zhang, H and Jiang, Z and Wang, S and Mao, H and Li, D and Fan, L and Hu, C and Xu, X}, title = {Zebrafish TDP43 positively regulates p65-mediated apoptotic pathway.}, journal = {International journal of biological macromolecules}, volume = {308}, number = {Pt 3}, pages = {142599}, doi = {10.1016/j.ijbiomac.2025.142599}, pmid = {40157684}, issn = {1879-0003}, mesh = {Animals ; *Zebrafish/metabolism/genetics/virology ; *Apoptosis/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Transcription Factor RelA/metabolism ; *Zebrafish Proteins/metabolism/genetics ; Signal Transduction ; Reoviridae/physiology ; Rhabdoviridae ; Reactive Oxygen Species/metabolism ; Phosphorylation ; Humans ; }, abstract = {TAR DNA-binding protein 43 (TDP43) is a multifunctional RNA/DNA binding protein that serves as a hallmark of neurodegeneration in amyotrophic lateral sclerosis (ALS) and is associated with the inflammatory response related to nuclear factor κB (NF-κB) pathway. However, the relationship between TDP43 and NF-κB is not well known. In this study, zebrafish TDP43 (DrTDP43) can be induced by grass carp reovirus (GCRV) or spring viremia of carp virus (SVCV). DrTDP43 enhances the nuclear factor-kappaB (NF-κB) activity and the expression of p65 and TNFα, as well as promotes the phosphorylation of p65 in response to stimulation of GCRV and SVCV. Further assays indicate that DrTDP43 primarily resides in the nucleus and interacts with p65 via its RRM1. DrTDP43 is required for p65 to induce pro-inflammatory cytokine production (IL-6, IL-10, TNFα, IL-1β). It disrupts mitochondrial membrane potential and exacerbates apoptosis via downregulating Bcl2 and upregulating Bax, caspase3, and eIF2α. Moreover, knockdown of TDP43 decreases the content of reactive oxygen species (ROS) and the number of apoptotic cells in zebrafish larvae, which is attributed to the lower lever of p65 phosphorylation and expression of TNFα, Bax and cleaved-caspase3. In a word, these results establish TDP43 as a critical activator of the NF-κB-mediated apoptotic pathway during antiviral responses, which reveals a previously unrecognized host defense mechanism.}, } @article {pmid40157939, year = {2025}, author = {Rossi, S and Milani, M and Della Valle, I and Bisegna, S and Durante, V and Addesse, M and D'Avorio, E and Di Salvio, M and Serafino, A and Cestra, G and Apolloni, S and D'Ambrosi, N and Cozzolino, M}, title = {Cytoplasmic accumulation of a splice variant of hnRNPA2/B1 contributes to FUS-associated toxicity in a mouse model of ALS.}, journal = {Cell death & disease}, volume = {16}, number = {1}, pages = {219}, pmid = {40157939}, issn = {2041-4889}, support = {Nutrage, IFT DBA.AD005.225//Consiglio Nazionale delle Ricerche (National Research Council)/ ; SpliceALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SwitchALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism/genetics ; *RNA-Binding Protein FUS/metabolism/genetics ; Disease Models, Animal ; Mice ; *Cytoplasm/metabolism ; Humans ; *Alternative Splicing/genetics ; Motor Neurons/metabolism/pathology ; Exons ; Stress Granules/metabolism ; }, abstract = {Genetic and experimental findings point to a crucial role of RNA dysfunction in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Evidence suggests that mutations in RNA binding proteins (RBPs) such as FUS, a gene associated with ALS, affect the regulation of alternative splicing. We have previously shown that the overexpression of wild-type FUS in mice, a condition that induces ALS-like phenotypes, impacts the splicing of hnRNP A2/B1, a protein with key roles in RNA metabolism, suggesting that a pathological connection between FUS and hnRNP A2/B1 might promote FUS-associated toxicity. Here we report that the expression and distribution of different hnRNP A2/B1 splice variants are modified in the affected tissues of mice overexpressing wild-type FUS. Notably, degenerating motor neurons are characterized by the cytoplasmic accumulation of splice variants of hnRNP A2/B1 lacking exon 9 (hnRNP A2b/B1b). In vitro studies show that exon 9 skipping affects the nucleocytoplasmic distribution of hnRNP A2/B1, promoting its localization into stress granules (SGs), and demonstrate that cytoplasmic localization is the primary driver of hnRNP A2b recruitment into SGs and cell toxicity. Finally, boosting exon 9 skipping using splicing switching oligonucleotides exacerbates disease phenotypes in wild-type FUS mice. Altogether, these findings reveal that alterations of the nucleocytoplasmic distribution of hnRNP A2/B1, driven by FUS-induced splicing changes, likely contribute to motor neuron degeneration in ALS.}, } @article {pmid40159068, year = {2025}, author = {Wang, HF and Wang, HR and Lin, YC and Bai, JM and Li, M and Huang, XS}, title = {[Analysis of serum 25-hydroxyvitamin D3 levels and prognosis in patients with amyotrophic lateral sclerosis].}, journal = {Zhonghua nei ke za zhi}, volume = {64}, number = {4}, pages = {325-332}, doi = {10.3760/cma.j.cn112138-20240728-00481}, pmid = {40159068}, issn = {0578-1426}, support = {2023124//Tianjin Municipal Health and Health Commission Traditional Chinese Medicine and Integrative Medicine Research Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; Prognosis ; Male ; Female ; Middle Aged ; *Calcifediol/blood ; Prospective Studies ; Cross-Sectional Studies ; Risk Factors ; Aged ; Biomarkers/blood ; }, abstract = {Objective: To evaluate serum 25-hydroxyvitamin D3 [25(OH)D3] as a potential biomarker for amyotrophic lateral sclerosis (ALS) severity and to identify risk factors influencing ALS prognosis. Methods: This study included 217 ALS patients hospitalized at the Department of Neurology, First Medical Center, Chinese PLA General Hospital, between October 2018 and October 2021, who met the revised El Escorial diagnostic criteria. A cross-sectional analysis assessed differences in clinical indicators-including the ALS Functional Rating Scale-Revised (ALSFRS-R) and forced vital capacity percentage (FVC%)-across different serum 25(OH)D3 levels. The correlation between 25(OH)D3 levels and individual ALSFRS-R components was also examined. Conduct a prospective cohort study to identify independent risk factors affecting the survival time of ALS patients. Results: Among three groups categorized by serum 25(OH)D3 levels, there were significant differences in the proportion of males (χ[2]=10.51, P<0.05). Serum 25(OH)D3 levels correlated positively with lower limb function scores in the ALSFRS-R (r=0.05, P<0.05), but they were not identified as an independent risk factor for survival (HR=0.98, 95%CI 0.93-1.04, P>0.05). In contrast, delayed diagnosis(HR=0.94, 95%CI 0.89-0.99, P<0.05) and reduced FVC%(HR=0.94, 95%CI 0.97-0.99, P<0.05) were independent predictors of shorter survival. Conclusion: Serum 25(OH)D3 levels differ by gender distribution and may be linked to better lower limb function in ALS patients. However, their role in prolonging survival remains uncertain.}, } @article {pmid40161216, year = {2025}, author = {Scarcella, S and Brambilla, L and Quetti, L and Rizzuti, M and Melzi, V and Galli, N and Sali, L and Costamagna, G and Comi, GP and Corti, S and Gagliardi, D}, title = {Unveiling amyotrophic lateral sclerosis complexity: insights from proteomics, metabolomics and microbiomics.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf114}, pmid = {40161216}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is the most common motor neuron disease and manifests as a clinically and genetically heterogeneous neurodegenerative disorder mainly affecting the motor systems. To date, despite promising results and accumulating knowledge on the pathomechanisms of amyotrophic lateral sclerosis, a specific disease-modifying treatment is still not available. In vitro and in vivo disease models coupled with multiomics techniques have helped elucidate the pathomechanisms underlying this disease. In particular, omics approaches are powerful tools for identifying new potential disease biomarkers that may be particularly useful for diagnosis, prognosis and assessment of treatment response. In turn, these findings could support physicians in stratifying patients into clinically relevant subgroups for the identification of the best therapeutic targets. Here, we provide a comprehensive review of the most relevant literature highlighting the importance of proteomics approaches in determining the role of pathogenic misfolded/aggregated proteins and the molecular mechanisms involved in the pathogenesis and progression of amyotrophic lateral sclerosis. In addition, we explored new findings arising from metabolomic and lipidomic studies, which can aid to elucidate the intricate metabolic alterations underlying amyotrophic lateral sclerosis pathology. Moreover, we integrated these insights with microbiomics data, providing a thorough understanding of the interplay between metabolic dysregulation and microbial dynamics in disease progression. Indeed, a greater integration of these multiomics data could lead to a deeper understanding of disease mechanisms, supporting the development of specific therapies for amyotrophic lateral sclerosis.}, } @article {pmid40162390, year = {2025}, author = {Xie, Y and Xie, H and Wang, RL}, title = {Enhancing palliative care in malignant obstructive jaundice: A critical care perspective on endoscopic biliary stenting.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {3}, pages = {103431}, pmid = {40162390}, issn = {1948-9366}, abstract = {This letter responds to Wang et al's recent publication on endoscopic biliary stenting for malignant obstructive jaundice (MOJ) by offering constructive feedback and suggestions for future research. We commend the authors for their comprehensive study design and execution, which included a clear delineation of study groups and a robust set of outcome measures. We suggest that future studies incorporate additional biomarkers, such as serum levels of liver enzymes and bilirubin, to provide a more nuanced understanding of liver function changes post-intervention. The study's focus on short-term survival rates is appreciated, but we recommend exploring longer-term follow-up periods to capture the full spectrum of survival outcomes. Additionally, the inclusion of quality of life assessments using validated instruments could offer a more holistic view of patient outcomes. From a critical care perspective, we advocate for the integration of advanced imaging techniques to better characterize biliary anatomy and potentially predict treatment response or complications. We believe that incorporating these suggestions could enhance the understanding of endoscopic biliary stenting's role in MOJ management and its impact on patient outcomes, influencing future clinical guidelines and practice.}, } @article {pmid40163151, year = {2025}, author = {Wadan, AS and Shaaban, AH and El-Sadek, MZ and Mostafa, SA and Moshref, AS and El-Hussein, A and Ellakwa, DE and Mehanny, SS}, title = {Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {398}, number = {9}, pages = {11357-11386}, pmid = {40163151}, issn = {1432-1912}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/physiopathology/therapy ; *Mitochondria/drug effects/metabolism/pathology ; Animals ; Oxidative Stress ; }, abstract = {Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.}, } @article {pmid40164574, year = {2025}, author = {Gómez-Gálvez, P and Navarro, V and Castro, AM and Paradas, C and Escudero, LM}, title = {Computational Analysis of SOD1-G93A Mouse Muscle Biomarkers for Comprehensive Assessment of ALS Progression.}, journal = {Neuropathology and applied neurobiology}, volume = {51}, number = {2}, pages = {e70014}, doi = {10.1111/nan.70014}, pmid = {40164574}, issn = {1365-2990}, support = {//Margarita Salas Fellowship - NextGenerationEU/ ; CB18/05/00028//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; PI13/01347//National Institute of Health Carlos III/ ; PI23/01892//National Institute of Health Carlos III/ ; FORT23/00008//National Institute of Health Carlos III/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics ; *Muscle, Skeletal/pathology ; Disease Progression ; Mice ; Disease Models, Animal ; Mice, Transgenic ; Biomarkers ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase/genetics ; }, abstract = {AIMS: To identify potential image biomarkers of neuromuscular disease by analysing morphological and network-derived features in skeletal muscle biopsies from a murine model of amyotrophic lateral sclerosis (ALS), the SOD1[G93A] mouse and wild-type (WT) controls at distinct stages of disease progression.

METHODS: Using the NDICIA computational framework, we quantitatively evaluated histological differences between skeletal muscle biopsies from SOD1[G93A] and WT mice. The process involved the selection of a subset of features revealing these differences. A subset of discriminative features was selected to characterise these differences, and their temporal dynamics were assessed across disease stages.

RESULTS: Our findings demonstrate that muscle pathology in the mutant model evolves from early alterations in muscle fibre arrangement, detectable at the presymptomatic stage through graph theory features, to the subsequent development of the typical morphological pattern of neurogenic atrophy at more advanced disease stages.

CONCLUSIONS: Our assay identifies a neurogenic signature in mutant muscle biopsies, even when the disease is phenotypically imperceptible.}, } @article {pmid40165742, year = {2025}, author = {Fernández Soberón, S and Gómez Escobar, T and Caravaca Puchades, A and Andrés-Benito, P and Vázquez-Costa, JF and Mora Pardina, J and Juntas Morales, R and Povedano, M}, title = {Yentl syndrome, a real phenomenon in amyotrophic lateral sclerosis (ALS)?.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {211-214}, doi = {10.1080/21678421.2024.2432030}, pmid = {40165742}, issn = {2167-9223}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Databases, Factual ; Retrospective Studies ; Spain/epidemiology ; }, abstract = {Introduction: ALS, a neurodegenerative disorder, exhibits variable incidence and prevalence across various databases consulted. Among these, PRO-ACT stands out as the most extensive publicly accessible repository of aggregated ALS clinical trial information. The estimated male-female ratio is greater for men at younger ages, which tends to equalize with aging. If specific measures are not taken to address this, this higher male prevalence could result in a higher inclusion of men in clinical trials, which could lead to biases in the observed results, preventing the proper assessment of differences between sexes. Our aim was to describe the demographic dates of the population included in ALS clinical trials in the last 8 years at Spanish national reference centers, with special interest in female participation. Methodology: Retrospective and descriptive observational study using databases of national reference centers. Results: We analyzed the databases of 4 neurological Spanish reference centers during a period of 8 years. A total number of 426 subjects were included. A greater participation of the male sex was evident in all the studies evaluated, representing 64.55% of the subjects included. This predominance has not varied significantly over the last 8 years. Our results correlate with the data published in PRO-ACT to date, where men represent 60% of the total number of participants. Conclusion: The predominance of the male sex in ALS clinical trials is a consistent and invariable finding and is known as Yentl's syndrome. This phenomenon prevents the principle of neutrality of medicine, allowing for purely partial knowledge.}, } @article {pmid40166559, year = {2025}, author = {Lorincz-Comi, N and Cheng, F}, title = {Bayesian inference of genetic pleiotropy identifies drug targets and repurposable medicines for human complex diseases.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40166559}, support = {R21 AG083003/AG/NIA NIH HHS/United States ; R01 AG082118/AG/NIA NIH HHS/United States ; R56 AG074001/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; RF1 NS133812/NS/NINDS NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; R01 AG076448/AG/NIA NIH HHS/United States ; }, abstract = {Complex diseases share heritable components which can be leveraged to identify drug targets with low side effect or high repurposing potential, but current methods cannot efficiently make these inferences at scale using public data. We introduce a Bayesian model to estimate the polygenic structure of a trait using GWAS summary data (BPACT). Across 32 complex traits, we estimated that 69.5 to 97.5% of disease-associated druggable genes are shared between multiple traits. We observed that targeting KIT for ALS prevention may increase triglyceride levels, but that targeting TBK1 and SCN11B may be safer because of they were not pleiotropic. We additionally found 21 candidate repurposable drug targets for Alzheimer's disease (AD) (e.g., PLEKHA1, PPIB) and 5 for ALS (e.g., GAK, DGKQ) based on the directionality of their pleiotropy. Our results demonstrate that modeling shared genetic architecture across traits can uncover safer therapeutic targets and highlight opportunities for drug repurposing in complex diseases.}, } @article {pmid40166606, year = {2025}, author = {de-Winton Cummings, PJ and Gonzalez Bravo, C and Dukes, KC and Wilks, AD and Ahlers, CD and Casado Castillo, FE and Courtney, A and Elliott-Wherry, AN and Knobbe, JE and Pineiro-Falcon, NM and Schaeffer, SE and Tillinghast, S and Tovar, EF and Villa, AT and Carvour, ML}, title = {Modifiable social and structural factors influence COVID-19 vaccine intention among frontline workers in the Midwestern USA: a community-engaged survey study.}, journal = {BMJ public health}, volume = {3}, number = {1}, pages = {e000859}, pmid = {40166606}, issn = {2753-4294}, support = {KL2 TR002536/TR/NCATS NIH HHS/United States ; T32 AI007485/AI/NIAID NIH HHS/United States ; T32 GM139776/GM/NIGMS NIH HHS/United States ; UM1 TR004403/TR/NCATS NIH HHS/United States ; }, abstract = {INTRODUCTION: COVID-19 vaccines have been a crucial measure in the pandemic response, yet vaccine uptake has been variable across the population. We sought to identify social and structural factors associated with COVID-19 vaccine intention among adults in the Midwestern USA who worked in one or more frontline industries during the COVID-19 pandemic.

METHODS: A community-engaged, cross-sectional online survey study was conducted between May and July 2022 among 889 workers. Guided by Thomas and Penchasky's 5As theory of access and Thomson et al's 5As taxonomy of vaccine uptake, we assessed modifiable social and structural factors related to access (transportation and convenient locations), affordability (time and incentives), activation (reminders), acceptability (experiences in a healthcare setting, political confidence and vaccine confidence) and accommodation (language inclusion and flexible appointments). Multinomial logistic regression was used to identify potentially modifiable factors that may influence vaccine intention among more than 200 surveyed workers who had not yet been vaccinated.

RESULTS: Workers who intended not to receive the vaccine were at least three times more likely to report transportation challenges, limited time off work and inflexible vaccine appointments compared with those who intended to vaccinate. Interest in financial incentives was strongly endorsed among workers who did not intend to vaccinate and among those who were undecided. Concerns about vaccine safety or side effects did not influence intention, whereas concerns about vaccine effectiveness were more common among workers who did not intend to vaccinate. Mistrust in government leaders was associated with positive vaccine intention.

CONCLUSIONS: Vaccine intention among frontline workers is strongly influenced by social and structural factors and not solely by hesitancy about the vaccine itself.}, } @article {pmid40166719, year = {2025}, author = {Xiong, J and Chen, X and Huang, K and Pan, Y}, title = {Successful Guselkumab Treatment in a Patient with Comorbid Psoriasis and Amyotrophic Lateral Sclerosis: A Case Study and Literature Review.}, journal = {Clinical, cosmetic and investigational dermatology}, volume = {18}, number = {}, pages = {735-741}, pmid = {40166719}, issn = {1178-7015}, abstract = {Psoriasis is genetically influenced and can be triggered by factors such as infections, stress, and lifestyle. Chronic plaque psoriasis, the most prevalent form, involves key roles for IL-17 and IL-23 in its pathogenesis. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons, resulting in muscle weakness and atrophy. Currently, there is no cure for ALS, and treatment is symptomatic, aimed at improving quality of life. The combination of psoriasis and ALS is relatively rare. Although biologic agents have shown remarkable efficacy in the treatment of chronic plaque psoriasis, we have not found any case reports regarding the use of biologic agents for treating psoriasis accompanied by ALS. Our study presents a patient with severe plaque psoriasis and ALS who exhibited a positive response to Guselkumab, without worsening of ALS symptoms, suggesting a promising therapeutic strategy. This could provide a treatment option for patients with psoriasis combined with ALS.We conducted a comprehensive review of the literature on the comorbidity of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and ALS, with plaque psoriasis. This review highlights the differential impact of treatment modalities. Specifically, we found that TNF-α inhibitors may have adverse effects in MS but could provide protective benefits in AD and PD. In ALS patients with psoriasis, IL-17A and IL-23 inhibitors, exemplified by Guselkumab, are suggested as a more suitable alternative due to their lower risk of worsening ALS symptoms.}, } @article {pmid40167598, year = {2025}, author = {Shi, Y and Wan, Y and Wang, Y and Fang, K and Yang, J and Lu, Y and Xie, X and Pan, J and Gao, D and Wang, H and Qu, H}, title = {Quantitative [1]H NMR optimization for high-throughput metabolite analysis in industrial bioprocess monitoring.}, journal = {Analytical and bioanalytical chemistry}, volume = {417}, number = {14}, pages = {3047-3059}, pmid = {40167598}, issn = {1618-2650}, support = {2023C03116//Key Research and Development Program of Zhejiang Province/ ; }, mesh = {CHO Cells ; Cricetulus ; Animals ; *High-Throughput Screening Assays/methods ; *Proton Magnetic Resonance Spectroscopy/methods ; Limit of Detection ; *Metabolomics/methods ; Cricetinae ; }, abstract = {Quantitative [1]H NMR ([1]H qNMR) is an ideal tool for bioprocess monitoring because it can comprehensively detect and quantify diverse metabolites that significantly influence bioprocess performance. However, the long experiment time associated with the [1]H qNMR, due to the long longitudinal relaxation time (T1) of some metabolites, does not meet the requirements for high-throughput analysis. We developed a high-throughput [1]H qNMR method for bioprocess analysis using a short relaxation delay (D1) to reduce analytical time and a correction factor (k) to compensate for incomplete relaxation. A total of 27 metabolites were quantified using spectral deconvolution via a peak fitting algorithm and MCR-ALS. Methodological validation results indicated that the precision and accuracy of the developed qNMR method were consistently high across different D1 values, with LOQs ranging from 0.008 to 0.13 mM and LODs ranging from 0.024 to 0.38 mM. Notably, a longer D1 value generally resulted in lower LODs and LOQs for most metabolites. A D1 value of 4 s was optimal for balancing analysis time and performance. The method is broadly applicable for bioprocess monitoring and control, offering valuable guidance for optimizing CHO cell culture processes and improving yield.}, } @article {pmid40169452, year = {2025}, author = {Hou, X and Jiang, J and Deng, M}, title = {Exploring epigenetic modifications as potential biomarkers and therapeutic targets in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {304}, pmid = {40169452}, issn = {1432-1459}, support = {82273915//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/diagnosis ; *Epigenesis, Genetic ; Biomarkers/metabolism ; DNA Methylation ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. Whole-genome sequencing has identified many novel ALS-associated genes, but genetics alone cannot fully explain the onset of ALS and an effective treatment is still lacking. Moreover, we need more biomarkers for accurate diagnosis and assessment of disease prognosis. Epigenetics, which includes DNA methylation and hydroxymethylation, histone modifications, chromatin remodeling, and non-coding RNAs, influences gene transcription and expression by affecting chromatin accessibility and transcription factor binding without altering genetic information. These processes play a role in the onset and progression of ALS. Epigenetic targets can serve as potential biomarkers and more importantly, the reversibility of epigenetic changes supports their potential role as versatile therapeutic targets in ALS. This review summarized the alterations in different epigenetic modulations in ALS. Additionally, given the close association between aberrant metabolic profiles characterized by hypoxia and high glycolytic metabolism in ALS and epigenetic changes, we also integrate epigenetics with metabolomics. Finally, we discuss the application of therapies based on epigenetic mechanisms in ALS. Our data integration helps to identify potential diagnostic and prognostic biomarkers and support the development of new effective therapies.}, } @article {pmid40169538, year = {2025}, author = {Iyer, KA and Tenchov, R and Sasso, JM and Ralhan, K and Jotshi, J and Polshakov, D and Maind, A and Zhou, QA}, title = {Rare Diseases, Spotlighting Amyotrophic Lateral Sclerosis, Huntington's Disease, and Myasthenia Gravis: Insights from Landscape Analysis of Current Research.}, journal = {Biochemistry}, volume = {64}, number = {8}, pages = {1698-1719}, pmid = {40169538}, issn = {1520-4995}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/metabolism ; *Myasthenia Gravis/genetics/therapy/pathology/metabolism ; *Rare Diseases/genetics/therapy ; *Huntington Disease/genetics/therapy/pathology/metabolism ; Animals ; }, abstract = {Rare diseases are a diverse group of disorders that, despite each individual condition's rarity, collectively affect a significant portion of the global population. Currently approximately 10,000 rare diseases exist globally, with 80% of these diseases being identified as having genetic origins. In this Review, we examine data from the CAS Content Collection to summarize scientific progress in the area of rare diseases. We examine the publication landscape in the area in an effort to provide insights into current advances and developments. We then discuss the evolution of key concepts in the field, genetic associations, as well as the major technologies and development pipelines of rare disease treatments. We focus our attention on three specific rare diseases: (i) amyotrophic lateral sclerosis, a terminal neurodegenerative disease affecting the central nervous system resulting in progressive loss of motor neurons that control voluntary muscles; (ii) Huntington's disease, another terminal neurodegenerative disease that causes progressive degeneration of nerve cells in the brain, with a wide impact on a person's functional abilities; and (iii) myasthenia gravis, a chronic autoimmune synaptopathy leading to skeletal muscle weakness. While the pathogenesis of these rare diseases is being elucidated, there is neither a cure nor preventative treatment available, only symptomatic treatment. The objective of the paper is to provide a broad overview of the evolving landscape of current knowledge on rare diseases and specifically on the biology and genetics of the three spotlighted diseases, to outline challenges and evaluate growth opportunities, an aim to further efforts in solving the remaining challenges.}, } @article {pmid40169635, year = {2025}, author = {D'Amico, A and Cucunato, R and Salemi, G and Bella, V and Aridon, P}, title = {A population based study to analyse amyotrophic lateral sclerosis as a multi-step process.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {11189}, pmid = {40169635}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/pathology/genetics ; Female ; Male ; Middle Aged ; Aged ; Adult ; Sicily/epidemiology ; Incidence ; Disease Progression ; }, abstract = {Recent studies suggest that Amyotrophic Lateral Sclerosis (ALS) follows a multistep process. We evaluated this hypothesis in a well-defined ALS population in Palermo, Sicily, almost entirely followed by our ALS Clinical Center. Incident data from the ALS Center (2014-2023) were analyzed, including both sporadic and familial ALS forms of the disease. To evaluate the multistep process, we regressed the natural log of age-specific incidence against the natural log of patient age We identified 216 ALS patients. We obtained a slope of 5 (r[2] = 0.93); the 95% CI ranged from 2.51 to 7.60, remaining relatively wide due to the small sample size, with a p-value of 0.008. The slope estimate was consistent with a 6-step process. In the Palermo ALS population, the multistep analysis confirms a process consistent with a 6-step model. This data, obtained in a relatively homogeneous population, further highlights the probability of strict interaction between environmental and genetic variables in the disease. Our data offer insights into the complexity of the mechanisms involved in the pathogenesis of the disease, particularly during its asymptomatic phase. This study supports the hypothesis that a single therapeutic silver bullet would probably be insufficient to arrest or slow the disease's progression.}, } @article {pmid40169784, year = {2025}, author = {Simonini, C and Zucchi, E and Martinelli, I and Gianferrari, G and Lunetta, C and Sorarù, G and Trojsi, F and Pepe, R and Piras, R and Giacchino, M and Banchelli, F and Mandrioli, J}, title = {Neurodegenerative and neuroinflammatory changes in SOD1-ALS patients receiving tofersen.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {11034}, pmid = {40169784}, issn = {2045-2322}, support = {Ricerca Corrente funding scheme of the Italian Ministry of Health//Ministero della Salute/ ; Ricerca Finalizzata bando 2021 (RF-2021-12373036)//Ministero della Salute/ ; bando FAR 2021, Progetti di ricerca Interdisciplinari Mission Oriented, NEURALS project)//Università Degli Studi di Modena e Reggio Emila/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; alpha 1-Antitrypsin/cerebrospinal fluid/blood ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Biomarkers/cerebrospinal fluid/blood ; Chitinase-3-Like Protein 1/cerebrospinal fluid/blood ; Disease Progression ; Neurofilament Proteins/cerebrospinal fluid/blood ; *Neuroinflammatory Diseases ; *Oligonucleotides/therapeutic use ; *Superoxide Dismutase-1/genetics ; }, abstract = {The initiation of tofersen, a new specific antisense oligonucleotide (ASO) for SOD1 pathology, marked a significant turning point for SOD1-ALS patients. While clinical trials and early access program studies reported a significant reduction in plasma and cerebrospinal fluid (CSF) neurofilament levels, neuroinflammation following prolonged treatment was never assessed. In this multicenter study, we evaluated a cohort of 18 SOD1-ALS patients treated with tofersen, analyzing correlations between biomarkers of neurodegeneration/neuroinflammation and clinical variables indicative of disease progression. NfL, NfH, CHI3L1, and Serpina1 levels in serum and CSF were determined by semi-automated immunoassays (Ella™ technology). Generalized linear mixed models were employed to investigate longitudinal trends of these biomarkers. Our data highlighted a progressive decrease in CSF neurofilament levels during tofersen treatment (MR = 0.97, 95% CI 0.94-0.99, p = 0.006 and MR = 0.98, 95% CI 0.95-1.00, p = 0.076 for NfL and NfH in CSF, respectively). Conversely, CSF levels of SerpinA1 and CHI3L1 increased over time (MR = 1.12, 95% CI 1.08-1.16, p < 0.0001 and MR = 1.039, 95% CI 1.015-1.062, p = 0.001 for SerpinA1 and CHI3L1 in CSF, respectively), but these modifications were most apparent after six and twelve months of therapy, respectively. Disease progression rate did not correlate with these biomarker trends. We observed a significant decrease in neurofilament levels during Tofersen treatment, alongside an increase in neuroinflammatory markers, potentially linked to an immune response triggered by ASO treatment. Given the limited data on tofersen's long-term efficacy in ALS due to its recent introduction, identifying biomarkers that predict clinical outcomes such as diminished therapeutic response or adverse effects is crucial. These biomarkers may help to better understand the underlying pathomechanisms of ALS and tofersen's role in modulating disease progression.}, } @article {pmid40170672, year = {2025}, author = {Schneck, D and Arguedas, A and Xenopoulos-Oddsson, A and Arcila-Londono, X and Lunetta, C and Wymer, J and Olney, N and Gwathmey, K and Ajroud-Driss, S and Hayat, G and Heiman-Patterson, T and Cerri, F and Fournier, C and Glass, J and Sherman, A and Fiecas, M and Walk, D}, title = {Time-to-event prediction in ALS using a landmark modeling approach, using the ALS Natural History Consortium dataset.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {417-425}, doi = {10.1080/21678421.2025.2482943}, pmid = {40170672}, issn = {2167-9223}, support = {R01 FD007630/FD/FDA HHS/United States ; R01-0007630/FD/FDA HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy/physiopathology/epidemiology ; Male ; Female ; *Disease Progression ; Middle Aged ; Aged ; Longitudinal Studies ; Time Factors ; Noninvasive Ventilation ; }, abstract = {BACKGROUND AND OBJECTIVES: Times to clinically relevant events are a valuable outcome in observational and interventional studies, complementing linear outcomes such as functional rating scales and biomarkers. In ALS, there are several clinically relevant events. We developed dynamic prediction models for several of these times to events that can be used for clinical trial modeling and personal planning.

METHODS: Landmark time-to-event analysis was implemented to determine the effect of patient characteristics on disease progression. Longitudinal data from 1557 participants in the ALS Natural History Consortium dataset were used. Five outcomes in the ALS disease progression were considered: loss of ambulation, loss of speech, gastrostomy, noninvasive ventilation (NIV) use, and continuous NIV use. Covariates in our models include age at diagnosis, sex, onset location, riluzole use, diagnostic delay, ALSFRS-R scores at the landmark time, and ALSFRS-R rates of change from baseline. Internal and external validation techniques were used.

RESULTS: For each of our models and landmark times, we present risk prediction intervals for random sets of patient characteristics. We demonstrate our models' application for an individual's personal predicted time-to-event. Our internal and external validation metrics indicate good concordance and overall performance. The time to loss of speech models perform the best for each metric in terms of both internal and external validation.

DISCUSSION: Landmarking is an efficient, individualized risk prediction model that is intuitive for both clinicians and patients. Importantly, landmarking can be used for clinical trial modeling, personal planning, and development of real-world evidence of the impacts of treatment interventions.}, } @article {pmid40170896, year = {2025}, author = {Wang, Y and Mi, Y and Wang, H and Jiang, J and Mao, L and Heng, Y and Li, X and Deng, M}, title = {Combined impact of CHCHD10 p.Gly66Val and three other variants suggests oligogenic contributions to ALS.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1438207}, pmid = {40170896}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Genetic factors are known to play important roles in ALS and concomitant presence of rare variants in ALS patients have been increasingly reported.

METHODS: In order to explore the genetic variants in ALS patients within the context of oligogenic inheritance and to elucidate the clinical heterogeneity observed in these patients, we conducted whole-genome sequencing on 34 familial ALS (FALS) probands.

RESULTS: In one proband, we identified a CHCHD10 p.Gly66Val variant, along with three additional variants: UNC13A p.Leu1034Val, SUSD1 p.Trp704Ser, and SQSTM1 p.His359del. This patient exhibited a slow disease progression and a prolonged survival duration, consistent with the clinical features of ALS patients with CHCHD10 variants. This suggests that the CHCHD10 p.Gly66Val variant may play a predominant role in shaping the patient's phenotype, while the other variants may primarily contribute to ALS occurrence.

DISCUSSION: Variants in CHCHD10 have been found in ALS and other neurodegenerative diseases, exhibiting significant clinical variability. However, the combinatorial effect of CHCHD10 and other ALS-related gene variants has not been fully studied. Our findings suggest that the combined impact of these four variants contributes to this patient's ALS phenotype, distinguishing it from other, less severe neuromuscular disorders associated with CHCHD10 mutations. Overall, this study further supports the oligogenic pathogenic basis of ALS and offers new insights into understanding the intricate clinical presentations associated with CHCHD10 variants.}, } @article {pmid40171058, year = {2025}, author = {Husted, C and Tubman, G}, title = {Case Study: The Benefits of the Neubie Direct Current Electrical Stimulation Device for Pain, Spasticity, and Movement in Amyotrophic Lateral Sclerosis.}, journal = {Integrative medicine (Encinitas, Calif.)}, volume = {24}, number = {2}, pages = {25-29}, pmid = {40171058}, issn = {1546-993X}, abstract = {This case study reports the impact of the Neubie direct current electrical stimulation device in helping restore nerve conduction and function in a 65-year-old woman with sporadic ALS. Use of the Neubie began 12 months after her sudden onset of symptoms. By then, she could not move her fingers or toes, had drop foot, had lost considerable weight and muscle mass, and was in pain. After her first Neubie session, she could wiggle her toes and that movement persisted. After two months she had no hip pain and was moving her fingers, toes, hands, and feet. The Master Reset protocol was used to facilitate the calming of the nervous system and required a sequential increase of settings. She then developed tight, painful shoulders from being in a wheelchair and Neubie treatments on her shoulders ultimately allowed her to become pain-free and regain some range of motion to increase her shoulder flexibility. Her voice then became soft due to a weak diaphragm. After two months she could feel the Neubie treatments increase the innervation of her diaphragm. At the time of this data collection and work, she was pain-free, had increased movement and range of motion, and had more energy. She showed improvements in muscle activation and strength in her legs and was able to stand with assistance. The results of this case study support the need to further study the impact of the Neubie in ALS, especially early in the course of the disease.}, } @article {pmid40171495, year = {2024}, author = {Oviedo, BJ and Arroyo-Hernandez, J and Gutiérrez-Bolaños, MJ and Alvarado-Pérez, H and Mora-Monestel, E and Rojas-Alvarado, A and Álvarez-Valverde, V and Jiménez-Bonilla, P}, title = {Assesment of chemometric analysis utilizing Multivariate Curve Resolution Alternating Least Squares (MCRALS) for examination of thermal and photodegradation of fern extracts.}, journal = {... IEEE International Conference on Bioinspired Processing}, volume = {2024}, number = {}, pages = {}, pmid = {40171495}, support = {D43 TW011403/TW/FIC NIH HHS/United States ; T37 MD001452/MD/NIMHD NIH HHS/United States ; }, abstract = {This study focuses on refining Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) for chromatographic profiling to analyze chemical changes in Serpocaulon sessilifolium extracts from the Costa Rican rainforest. High-Performance Liquid Chromatography (HPLC) with a diode array detector (DAD) and Mass Detector were employed, where traditional analyses often discard valuable spectral data beyond the maximum absorption wavelength. To optimize the analysis, Principal Component Analysis (PCA) were used to select the optimal number of components for MCR-ALS. Fern extracts, stored under varying conditions -refrigeration, warm temperatures, and UV light exposure- are analyzed over time to study their chemical stability. The decomposition identifies key chemical constituents, revealing that warmer conditions and UV exposure accelerate degradation, with significant shifts in chemical composition observed over time. MCR-ALS analysis allows detailed tracking of chemical changes, showing emerging peaks and shifts in concentration, particularly in the more reactive compounds, enhancing resolution and overcoming challenges such as peak interference and co-elution. The study highlights the differences between UV-absorption data and mass spectrometry, where mass spectrometry offers more detailed resolution but requiring greater computational resources. The use of both methods provides a comprehensive understanding of the chemical dynamics of the extracts. This research demonstrates the potential of MCR-ALS, combined with advanced statistical tools, for improving chromatographic analysis and contributing to botanical and natural product research.}, } @article {pmid40171534, year = {2025}, author = {Burg, T and Tzeplaeff, L and Cassel, R and Lingor, P}, title = {Editorial: Innovative approaches to catalyze preclinical and clinical research on amyotrophic lateral sclerosis (ALS) and related disorders.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1582539}, pmid = {40171534}, issn = {1662-4548}, } @article {pmid40171862, year = {2025}, author = {Bierowski, AE and Comber, PC and Kuc, A and Shah, A and Carroll, G}, title = {The Effect of Prehospital Protocol Modification during COVID-19 on First-Pass Intubation Success Rates.}, journal = {Prehospital and disaster medicine}, volume = {40}, number = {2}, pages = {73-76}, pmid = {40171862}, issn = {1945-1938}, mesh = {Humans ; *COVID-19/epidemiology ; *Intubation, Intratracheal/statistics & numerical data/standards/methods ; Retrospective Studies ; *Emergency Medical Services ; Male ; Female ; Middle Aged ; *Airway Management/methods ; *Clinical Protocols ; SARS-CoV-2 ; Adult ; Aged ; }, abstract = {INTRODUCTION: Many Emergency Medical Services (EMS) agencies modified their protocols during the height of the COVID-19 pandemic, particularly those involving procedures that lead to an increased risk of airborne exposure, such as intubation. In 2020, local Advanced Life Support (ALS) providers' first-line airway management device was the supraglottic airway (SGA), and tracheal intubations (TIs) were rarely performed.

OBJECTIVE: This study's aim was to investigate the potential clinical effect of this pandemic-related protocol change on first-pass TI success rates and on overall initial advanced airway placement success.

METHODS: This study was a retrospective prehospital chart review for all ALS encounters from a single urban EMS agency that resulted in the out-of-hospital placement of at least one advanced airway per encounter from January 1, 2019 through June 30, 2021 (n = 452). Descriptive statistics and chi square tests were used to evaluate data. Statistical significance was defined at P < .05.

RESULTS: Significantly fewer TIs were attempted in 2020 (n = 16) compared to 2019 (n = 80; P < .001), and first-pass TI success rates significantly decreased in 2021 (n = 22; 61.1%) compared to 2019 (n = 63; 78.8%; P = .047). Also, SGA placement constituted 91.2% of all initial airway management attempts in 2020 (n = 165), more than both 2019 (n = 114; 58.8%; P < .001) and 2021 (n = 87; 70.7%; P < .001). Overall first-attempt advanced airway placement success, encompassing both supraglottic and TI, increased from 2019 (n = 169; 87.1%) to 2020 (n = 170; 93.9%; P = .025). Conversely, overall first attempt advanced airway placement success decreased from 2020 to 2021 (n = 104; 84.6%; P = .0072).

CONCLUSIONS: Lack of exposure to TI during the COVID-19 pandemic likely contributed to this local agency's decreased first-pass TI success in 2021. Moving forward, agencies should utilize simulation labs and other continuing education efforts to help maintain prehospital providers' proficiency in performing this critical procedure, particularly when protocol changes temporarily hinder or prohibit field-based psychomotor skill development.}, } @article {pmid40172690, year = {2025}, author = {Mathis, S and Beauvais, D and Duval, F and Barnay, M and Strub, V and Géfard-Gontier, E and Solé, G and Le Masson, G}, title = {When neuromuscular disorders become stars.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {305}, pmid = {40172690}, issn = {1432-1459}, mesh = {Humans ; *Neuromuscular Diseases/history ; Retrospective Studies ; History, 20th Century ; Motion Pictures/history ; }, abstract = {This retrospective study identified 125 audio-visual works from cinema and television, including films, TV series, and documentaries, depicting neuromuscular disorders since 1910. Motor neuron disorders, including amyotrophic lateral sclerosis (ALS), had the highest representation (69.3%), followed by myopathies (20%). The predominant genre was documentary (48%), which offered more factual representation than fictional works. ALS was overrepresented due to its dramatic nature and association with notable figures, including the American baseball player Lou Gehrig and British theoretical physicist Stephen Hawking; other neuromuscular disorders, such as Duchenne muscular dystrophy, were depicted less frequently. Despite inaccuracies in some portrayals, these works raise public awareness and contribute to a greater understanding of rare diseases, such as neuromuscular disorders, among the general public.}, } @article {pmid40174325, year = {2025}, author = {Farndale, L and Insall, R and Yuan, K}, title = {TriDeNT : Triple deep network training for privileged knowledge distillation in histopathology.}, journal = {Medical image analysis}, volume = {102}, number = {}, pages = {103479}, doi = {10.1016/j.media.2025.103479}, pmid = {40174325}, issn = {1361-8423}, mesh = {Humans ; *Deep Learning ; Immunohistochemistry ; }, abstract = {Computational pathology models rarely utilise data that will not be available for inference. This means most models cannot learn from highly informative data such as additional immunohistochemical (IHC) stains and spatial transcriptomics. We present TriDeNT , a novel self-supervised method for utilising privileged data that is not available during inference to improve performance. We demonstrate the efficacy of this method for a range of different paired data including immunohistochemistry, spatial transcriptomics and expert nuclei annotations. In all settings, TriDeNT outperforms other state-of-the-art methods in downstream tasks, with observed improvements of up to 101%. Furthermore, we provide qualitative and quantitative measurements of the features learned by these models and how they differ from baselines. TriDeNT offers a novel method to distil knowledge from scarce or costly data during training, to create significantly better models for routine inputs.}, } @article {pmid40176466, year = {2025}, author = {Zhang, Y and Robinson, K and Xia, Y and Sun, J}, title = {Synergistic Effects of Riluzole and Sodium Butyrate on Barrier Function and Disease Progression of Amyotrophic Lateral Sclerosis Through the Gut-Neuron Axis.}, journal = {Comprehensive physiology}, volume = {15}, number = {2}, pages = {e70009}, pmid = {40176466}, issn = {2040-4603}, support = {I01BX004824-06//U.S. Department of Veterans Affairs/ ; R01DK134343/NH/NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; I01 BX004824/BX/BLRD VA/United States ; R01DK105118/NH/NIH HHS/United States ; R01DK114126/NH/NIH HHS/United States ; R01 DK105118/DK/NIDDK NIH HHS/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Riluzole/pharmacology/therapeutic use/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology ; Mice ; *Butyric Acid/pharmacology/therapeutic use ; Disease Progression ; *Neuroprotective Agents/pharmacology ; Male ; Mice, Transgenic ; Drug Synergism ; Disease Models, Animal ; *Neurons/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Emerging evidence has shown that gut-brain barrier dysfunction occurs at the early stages of ALS. Previous studies demonstrated that sodium butyrate significantly prolonged the life span of ALS mice. Riluzole is the first FDA-approved drug for ALS treatment. We hypothesize that Riluzole and sodium butyrate combined treatment further decreases aggregation of the h-SOD1[G93A], restores the gut-brain barrier function, and delays ALS progression. SOD1[G93A] mice (9-10-week-old) were treated with Riluzole (10 mg/kg, I.P. daily), sodium butyrate (2% in drinking water), or Riluzole and sodium butyrate combination for 6 weeks. The Riluzole/butyrate combination showed a significantly longer rotarod time, increased grip strength, and enhanced intestinal barrier, as compared with Riluzole or sodium butyrate-only treatment. More reduction of h-SOD1[G93A] aggregation was observed in the colon, spinal cord lumbar, and brain cortex with Riluzole and sodium butyrate combination, compared with Riluzole or sodium butyrate-only treatment. Tight junction proteins (ZO-1 and Claudin-5) significantly increased in the colon, spinal cord lumbar, and brain cortex of mice with Riluzole and sodium butyrate treatment. The Riluzole and sodium butyrate combination reduced serum lipopolysaccharides and h-SOD1[G93A] aggregation, and inflammatory cytokines more than those in Riluzole or sodium butyrate-only treatment. Overall, Riluzole and sodium butyrate treatment is more effective than either Riluzole or sodium butyrate-only in delaying ALS progress. It provides a potential therapeutic strategy and mechanism by restoring barrier function through the gut-brain axis for ALS.}, } @article {pmid40177728, year = {2025}, author = {Liu, S and Lun, J and Zhan, Y and Li, Z and Tian, J and Zhang, C and Pan, L}, title = {CRISPR/Cas12a Combined with RAA for On-Site Detection of ALS W574L Mutation in Three Alopecurus Species: A Visual Approach for Herbicide Resistance Monitoring.}, journal = {Journal of agricultural and food chemistry}, volume = {73}, number = {15}, pages = {8907-8914}, doi = {10.1021/acs.jafc.5c02188}, pmid = {40177728}, issn = {1520-5118}, mesh = {*Herbicide Resistance ; CRISPR-Cas Systems ; *Acetolactate Synthase/genetics/metabolism ; *Herbicides/pharmacology ; *Plant Proteins/genetics/metabolism ; Mutation ; *Poaceae/genetics/drug effects/enzymology ; Plant Weeds/genetics/drug effects/enzymology ; }, abstract = {The genus Alopecurus encompasses several weed species, including Alopecurus japonicus, Alopecurus aequalis, and Alopecurus myosuroides, which represent significant threats to agricultural productivity, particularly in wheat and oilseed rape fields. ALS-inhibiting herbicides have been extensively used for controlling Alopecurus weeds. However, the widespread use of these herbicides has led to the rapid emergence of resistance in Alopecurus populations with the Trp-574-Leu (W574L) mutation in the ALS gene being one of the most common resistance mechanisms. This study aims to develop a novel molecular detection method combining recombinase-aided amplification (RAA) with CRISPR/Cas12a technology to detect the W574L mutation in Alopecurus species. The method was optimized for key parameters, balancing efficiency with experimental costs, and was evaluated for specificity, sensitivity, and field applicability. This approach offers a rapid, accurate, and visual tool for identifying W574L target-site resistance in A. japonicus, A. aequalis, and A. myosuroides, with significant potential for monitoring resistance and enhancing weed management strategies.}, } @article {pmid40178078, year = {2025}, author = {Castro, J and de Carvalho, M}, title = {Letter on "Synaptic dynamics linked to widespread elevation of H-reflex before peripheral denervation in amyotrophic lateral sclerosis".}, journal = {Journal of neurophysiology}, volume = {133}, number = {4}, pages = {1146-1147}, doi = {10.1152/jn.00582.2024}, pmid = {40178078}, issn = {1522-1598}, } @article {pmid40178484, year = {2025}, author = {Gao, Y and Lu, Y and Chen, R and Zhao, S and Liu, J and Zhang, S and Bai, X and Zhang, J}, title = {Skin pathology in ALS: Diagnostic implications and biomarker potential.}, journal = {Biomolecules & biomedicine}, volume = {26}, number = {3}, pages = {368-376}, pmid = {40178484}, issn = {2831-090X}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/diagnosis/metabolism ; Humans ; Biomarkers/metabolism ; *Skin/pathology/metabolism ; Animals ; alpha-Synuclein/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons in the spinal cord and brain, resulting in motor deficits and muscle atrophy. Approximately 5-10% of ALS patients are familial (fALS), while the rest are sporadic (sALS). Currently, early diagnosis of ALS cannot be achieved based on clinical manifestations and electromyography due to the lack of effective and easily available biomarkers. The skin and central nervous system (CNS) share the same embryonic origin. Several skin biomarkers have been found in many neurodegenerative diseases, such as abnormal deposition of pathological α-synuclein (α-Syn) in Parkinson's disease. Thus, molecular changes in the skin associated with ALS-specific pathological events could readily be detected and become biomarkers for ALS through skin testing. Here, we summarize the literature on pathological changes in the skin of ALS patients and animal models, including structural abnormalities of the skin, reduced density of skin nerve fibers, abnormal protein aggregation, altered mitochondrial morphology and function, and dysregulation of skin inflammation, which may be useful for early diagnosis and monitoring of ALS progression.}, } @article {pmid40179249, year = {2025}, author = {Traynor, BJ}, title = {The interneuron hypothesis of amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {4}, pages = {1045-1046}, pmid = {40179249}, issn = {1460-2156}, support = {/NH/NIH HHS/United States ; 1ZIAAG000933/AG/NIA NIH HHS/United States ; }, } @article {pmid40179811, year = {2025}, author = {Li, B and Mu, H and Shan, D and Yang, Y and Wang, Y and Li, J and Wang, H and Sun, X and Ji, X and Zhan, Z and Jiao, Y and Tang, Y and Kong, B and Gao, B and Wang, Y and Sun, P and Liu, F}, title = {Generation of an induced pluripotent stem cell (iPSC) line (INNDSUi009-A) from a patient with amyotrophic lateral sclerosis due to SOD1 mutation.}, journal = {Stem cell research}, volume = {85}, number = {}, pages = {103704}, doi = {10.1016/j.scr.2025.103704}, pmid = {40179811}, issn = {1876-7753}, mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism/cytology/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Superoxide Dismutase-1/genetics ; *Mutation ; Cell Differentiation ; Cell Line ; Fibroblasts/metabolism/cytology ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of nerve cells in the spinal cord and brain. We generated and characterized a human induced pluripotent stem cell (iPSC) line from skin fibroblasts of a patient with ALS due to SOD1 Mutation. The pluripotency of these iPSCs was verified by the expression of several pluripotency markers at both RNA and protein levels, as well as their capability to differentiate into all three germ layers.}, } @article {pmid40180127, year = {2025}, author = {Kaltchenko, M and Kim, E and Radtke, S and Wan, J}, title = {Response to Li et al's "Comments on 'Dupilumab and neuropsychiatric outcomes in pediatric atopic dermatitis: A real-world cohort analysis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {1}, pages = {e41-e43}, doi = {10.1016/j.jaad.2025.03.081}, pmid = {40180127}, issn = {1097-6787}, } @article {pmid40180646, year = {2025}, author = {Temiz, K and Gul, A and Gov, E}, title = {5-Repurposed Drug Candidates Identified in Motor Neurons and Muscle Tissues with Amyotrophic Lateral Sclerosis by Network Biology and Machine Learning Based on Gene Expression.}, journal = {Neuromolecular medicine}, volume = {27}, number = {1}, pages = {24}, pmid = {40180646}, issn = {1559-1174}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Humans ; *Machine Learning ; *Motor Neurons/metabolism/drug effects ; *Drug Repositioning/methods ; Transcriptome ; Gene Expression Profiling ; *Muscle, Skeletal/metabolism ; Gene Regulatory Networks ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to motor neuron degeneration, muscle weakness, and respiratory failure. Despite ongoing research, effective treatments for ALS are limited. This study aimed to apply network biology and machine learning (ML) techniques to identify novel repurposed drug candidates for ALS. In this study, we conducted a meta-analysis using 4 transcriptome data in ALS patients (including motor neuron and muscle tissue) and healthy controls. Through this analysis, we uncovered common shared differentially expressed genes (DEGs) separately for motor neurons and muscle tissue. Using common DEGs as proxies, we identified two distinct clusters of highly clustered differential co-expressed cluster genes: the 'Muscle Tissue Cluster' for muscle tissue and the 'Motor Neuron Cluster' for motor neurons. We then evaluated the performance of the nodes of these two modules to distinguish between diseased and healthy states with ML algorithms: KNN, SVM, and Random Forest. Furthermore, we performed drug repurposing analysis and text-mining analyses, employing the nodes of clusters as drug targets to identify novel drug candidates for ALS. The potential impact of the drug candidates on the expression of cluster genes was predicted using linear regression, SVR, Random Forest, Gradient Boosting, and neural network algorithms. As a result, we identified five novel drug candidates for the treatment of ALS: Nilotinib, Trovafloxacin, Apratoxin A, Carboplatin, and Clinafloxacin. These findings highlight the potential of drug repurposing in ALS treatment and suggest that further validation through experimental studies could lead to new therapeutic avenues.}, } @article {pmid40180687, year = {2025}, author = {Ms, S and Banerjee, S and D'Mello, SR and Dastidar, SG}, title = {Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis.}, journal = {Molecular neurobiology}, volume = {62}, number = {8}, pages = {10091-10117}, pmid = {40180687}, issn = {1559-1182}, support = {SAN No: 102/IFD/SAN/2549/2019-20//DBT RLS/ ; CRG/2022/005004//Science and Engineering Research Board/ ; LBRN//Louisiana Biomedical Research Network/ ; IIRPIG-2023-0001508//Indian Council of Medical Research/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Proteostasis/physiology ; Animals ; *Cytoplasm/metabolism ; Endoplasmic Reticulum Stress ; Endoplasmic Reticulum/metabolism ; Golgi Apparatus/metabolism ; Protein Transport/physiology ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease characterized by the pathological loss of upper and lower motor neurons. Whereas most ALS cases are caused by a combination of environmental factors and genetic susceptibility, in a relatively small proportion of cases, the disorder results from mutations in genes that are inherited. Defects in several different cellular mechanisms and processes contribute to the selective loss of motor neurons (MNs) in ALS. Prominent among these is the accumulation of aggregates of misfolded proteins or peptides which are toxic to motor neurons. These accumulating aggregates stress the ability of the endoplasmic reticulum (ER) to function normally, cause defects in the transport of proteins between the ER and Golgi, and impair the transport of RNA, proteins, and organelles, such as mitochondria, within axons and dendrites, all of which contribute to the degeneration of MNs. Although dysfunction of a variety of cellular processes combines towards the pathogenesis of ALS, in this review, we focus on recent advances concerning the involvement of defective ER stress, vesicular transport between the ER and Golgi, and axonal transport.}, } @article {pmid40180875, year = {2025}, author = {Li, H and Cheng, M and Zhang, N and Wang, S and Ye, C and Li, H and Wang, S and Wang, Z and Yang, X and Liu, Z and Zhang, X and Xu, J and Xu, Q and Wang, J}, title = {The role of serum vitamins in mediating the effect of neurodegenerative diseases on subcortical brain volume.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {6}, pages = {100155}, pmid = {40180875}, issn = {2426-0266}, mesh = {Humans ; Animals ; *Neurodegenerative Diseases/pathology/blood/genetics ; *Brain/pathology ; *Vitamins/blood ; Atrophy/pathology ; Genome-Wide Association Study ; Mice ; Mendelian Randomization Analysis ; Alzheimer Disease/pathology/blood/genetics ; *Vitamin D/blood ; Male ; Hippocampus/pathology ; Parkinson Disease/pathology/blood ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDs) lead to a progressive loss of neuronal cells and link to atrophy of subcortical brain structures, but the causal intermediates are not known. To test whether major NDs (Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis) causally affects subcortical atrophy, and whether serum vitamin level play a mediating role in this process.

METHODS: Using large-scale genome-wide association study (GWAS) summary data, we performed two-sample Mendelian randomization (MR) to assess the causal effect of NDs on the volume of seven subcortical structures, and then adopted two-step multivariable MR approach to quantify the proportion of the effect of NDs on the volume of subcortical regions mediated by serum vitamin level. Finally, we utilized animal experiments to validate results and explored the potential molecular mechanisms.

RESULTS: Genetically predicted AD was associated with atrophy of the nucleus accumbens (NAc) (β = -0.09; p = 5.13 × 10[-5]), amygdala (β = -0.07; p = 8.44 × 10[-4]), and hippocampus (β = -0.07; p = 0.001), as well as with low serum vitamin D level (β = -0.02; p = 6.84 × 10[-6]). Specifically, decreased serum vitamin D level mediated 3.99 % (95 % CI: -0.006 to -5.82 × 10[-5]) and 3.97 % (95 % CI: -0.007 to -2.94 × 10[-4]) of the total effect of AD on hippocampal and NAc atrophy, respectively. Animal experiments further confirmed significant delays in hippocampal and NAc atrophy, a significant reduction of β-amyloid deposits and an increase of vitamin D receptor expression in hippocampus in AD mice with high-dose vitamin D diet.

CONCLUSIONS: These findings provide important insights into the effect sizes of vitamin D-mediated roles in AD and atrophy of subcortical structures. Interventions to increase serum vitamin D levels at a population level might attenuate damage to hippocampus in patients with AD.}, } @article {pmid40181198, year = {2025}, author = {Manolopoulos, A and Yao, PJ and Kapogiannis, D}, title = {Extracellular vesicles: translational research and applications in neurology.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {5}, pages = {265-282}, pmid = {40181198}, issn = {1759-4766}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Translational Research, Biomedical/methods ; Biomarkers/metabolism ; *Nervous System Diseases/therapy/diagnosis/metabolism ; Animals ; *Neurology/methods/trends ; }, abstract = {Over the past few decades, extensive basic, translational and clinical research has been devoted to deciphering the physiological and pathogenic roles of extracellular vesicles (EVs) in the nervous system. The presence of brain cell-derived EVs in the blood, carrying diverse cargoes, has enabled the development of predictive, diagnostic, prognostic, disease-monitoring and treatment-response biomarkers for various neurological disorders. In this Review, we consider how EV biomarkers can bring us closer to understanding the complex pathogenesis of neurological disorders such as Alzheimer disease, Parkinson disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis and multiple sclerosis. We describe how translational research on EVs might unfold bidirectionally, proceeding from basic to clinical studies but also in the opposite direction, with biomarker findings in the clinic leading to novel hypotheses that can be tested in the laboratory. We demonstrate the potential value of EVs across all stages of the therapeutic development pipeline, from identifying therapeutic targets to the use of EVs as reporters in model systems and biomarkers in clinical research. Finally, we discuss how the cargo and physicochemical properties of naturally occurring and custom-engineered EVs can be leveraged as novel treatments and vehicles for drug delivery, potentially revolutionizing neurotherapeutics.}, } @article {pmid40181571, year = {2025}, author = {Yoganathan, K and Dharmadasa, T and Northall, A and Talbot, K and Thompson, AG and Turner, MR}, title = {Asymmetry in amyotrophic lateral sclerosis: Clinical, neuroimaging and histological observations.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {8}, pages = {2605-2615}, pmid = {40181571}, issn = {1460-2156}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology/diagnostic imaging ; *Neuroimaging/methods ; *Brain/pathology/diagnostic imaging ; Disease Progression ; Spinal Cord/pathology/diagnostic imaging ; *Functional Laterality/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor system marked by significant phenotypic heterogeneity. Motor symptoms in the limbs consistently emerge focally and asymmetrically and, whilst variable, the pattern of regional progression related to the balance of clinical upper and lower motor neuron signs, upper versus lower limb onset and hand dominance to some extent. The neurobiological mechanisms and pathological correlates for this lateralized onset and non-random progression are uncertain. Cerebral neuroimaging studies have commonly reported structural and functional asymmetries in ALS, but the limited analysis of the pre-symptomatic phase has limited their implications. Post-mortem study of spinal cord provided strong evidence for focal pathology at symptom onset in ALS. Histopathological staging of molecular pathology in post-mortem tissue lacks clinical correlation and an ordered, sequential temporal progression in life cannot be assumed. The development of integrated brain and cord MRI holds the hope of deepening understanding of the relationship between focal symptomatology and histopathological progression. This review considers the nature and implications of asymmetry in ALS across clinical, neuroimaging and post-mortem histopathology, highlighting the current gaps in knowledge and the need for a broader investigative framework.}, } @article {pmid40182859, year = {2025}, author = {Kobayakawa, Y and Ko, S and Tashiro, T and Maimaitijiang, G and Kira, JI and Kishimoto, J and Yamasaki, R and Isobe, N}, title = {FVC-DiP correlates with neurofilament light chain levels in serum and cerebrospinal fluid in patients with ALS.}, journal = {BMJ neurology open}, volume = {7}, number = {1}, pages = {e001012}, pmid = {40182859}, issn = {2632-6140}, abstract = {BACKGROUND: We previously reported a scale to assess the disease progression rate in patients with amyotrophic lateral sclerosis (ALS), the forced vital capacity decline pattern scale (FVC-DiP). In this study, we investigated the association between FVC-DiP scores and neurofilament light chain (NfL) in the serum and cerebrospinal fluid (CSF) in patients with ALS.

METHODS: We performed a retrospective study to examine the association between NfL levels and the rate of disease progression (N=41). The disease progression rate was assessed using three methods: the FVC-DiP score determined using the percentage of predicted FVC (%FVC) and disease duration at the %FVC measurement, the rate of decline in the ALS Functional Rating Scale Revised (ALSFRS-R) score (ΔFS) and the rate of decline in the %FVC (Δ%FVC).

RESULTS: The FVC-DiP scores were significantly correlated with NfL levels in both the serum and CSF (serum, R[2]=0.274, p<0.001; CSF, R[2]=0.274, p=0.001). Patients assessed as rapidly progressing by the FVC-DiP had high NfL levels, and patients assessed as slowly progressing had low NfL levels. In the group with a low ΔFS and/or Δ%FVC, although the disease progression rate assessed by the FVC-DiP may have differed from the assessments obtained using the ALSFRS-R and/or %FVC, the correlation between FVC-DiP scores and serum NfL levels remained consistent.

CONCLUSIONS: The FVC-DiP was significantly associated with NfL levels in the serum and CSF, suggesting that the FVC-DiP is a reasonable scale to assess the rate of ALS progression.}, } @article {pmid40183173, year = {2025}, author = {Zulueta, A and Piras, R and Azzolino, D and Mariani, P and Sideri, R and Garrè, C and Federico, G and Lucchi, T and Magni, P and Parati, EA and Lunetta, C}, title = {Neurofilament Light Chain Levels, Skeletal Muscle Loss, and Nutritional Decline: Key Prognostic Factors in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {72}, number = {1}, pages = {49-55}, pmid = {40183173}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/metabolism/blood ; Male ; Female ; Middle Aged ; Aged ; *Neurofilament Proteins/metabolism/blood ; Disease Progression ; *Malnutrition/diagnosis/etiology ; Prognosis ; *Nutritional Status/physiology ; *Muscle, Skeletal/metabolism/pathology ; Body Composition/physiology ; Adult ; Body Mass Index ; }, abstract = {INTRODUCTION/AIMS: Hypermetabolism and weight loss are established negative prognostic factors in amyotrophic lateral sclerosis (ALS). However, the role of individualized body composition parameters in predicting ALS progression has been underexplored. This study aimed to investigate the correlation between nutritional parameters, neurofilament light chain (NfL) levels, and disease progression in ALS patients.

METHODS: The Global Leadership Initiative on Malnutrition criteria were used to define malnutrition in this study. Nutritional status was assessed using body mass index and bioelectrical impedance analysis. The rate of disease progression was defined by the change in the Revised ALS Functional Rating Scale score (ΔFRS). NfL was quantified using single molecule array technology. Spearman's analyses were used to assess correlations.

RESULTS: Sixty of 110 ALS patients were classified as malnourished. There was a strong positive correlation between NfL and ΔFRS (r = 0.71), and a moderate negative correlation with disease duration (r = -0.55). The correlations between NfL and body composition parameters were statistically significant, although weak. NfL levels were significantly higher in fast progressors (p < 0.0001 compared to slow progressors) and in malnourished patients (p = 0.0001). Of the 34 fast progressor patients, 28 (82%) exhibited some degree of malnutrition.

DISCUSSION: Our findings indicate that poor nutritional status, particularly reduced skeletal muscle mass-both independently and in combination with fat mass loss-is associated with elevated NfL levels and faster ALS progression. NfL, combined with nutritional parameters, could serve as a valuable biomarker for disease severity. Further research is warranted to clarify the role of skeletal muscle abnormalities in ALS progression.}, } @article {pmid40183433, year = {2025}, author = {Jiang, J and Li, X and Mi, Y and Wang, Y and Heng, Y and Li, Z and Deng, M}, title = {Real-world evidence of riluzole on survival and ALSFRS change in a Chinese ALS cohort.}, journal = {Neurodegenerative disease management}, volume = {15}, number = {2-3}, pages = {77-87}, pmid = {40183433}, issn = {1758-2032}, mesh = {Humans ; *Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/mortality ; Female ; Male ; Middle Aged ; *Neuroprotective Agents/therapeutic use ; Aged ; China ; Adult ; Cohort Studies ; Kaplan-Meier Estimate ; Treatment Outcome ; East Asian People ; }, abstract = {AIMS: This study aimed to evaluate the effects of riluzole on survival and changes in ALS Functional Rating Scale (ALSFRS) among Chinese patients with Amyotrophic Lateral Sclerosis (ALS).

PATIENTS & METHODS: Propensity score matching was used to balance baseline variables between the riluzole group (n = 238) and control group (n = 454). Survival was analyzed using Kaplan - Meier curves and Cox regression, while multivariable linear regression assessed ALSFRS changes at 6 and 12 months. Subgroup analyses were conducted to identify potential responders.

RESULTS: Riluzole did not significantly improve survival (p = 0.478) or ALSFRS changes at 6 months (p = 0.380) or 12 months (p = 0.175). Subgroup analyses revealed no survival benefit in any subgroup, and further stratification showed inconsistent adverse effects on ALSFRS scores.

CONCLUSIONS: Riluzole neither prolonged survival nor slowed functional decline in Chinese ALS patients, with no subgroup demonstrating a better response.}, } @article {pmid40183526, year = {2025}, author = {Dorst, J and Dreyhaupt, J and Wernecke, D and Weiland, U and Parlak, Ö and Wiesenfarth, M and Elmas, Z and Herrmann, C and Bäzner, H and Boertlein, A and Dempewolf, S and Foerch, C and Hecht, M and Kohler, A and Opherk, C and Althaus, K and Clauer-Bredt, M and Lindner, A and Ruf, W and Brenner, D and Witzel, S and Peter, RS and Schuster, J and Ludolph, AC and Rosenbohm, A and Nagel, G}, title = {Population-Based Versus Hospital-Based Data in Amyotrophic Lateral Sclerosis-A Factor to Consider?.}, journal = {European journal of neurology}, volume = {32}, number = {4}, pages = {e70137}, pmid = {40183526}, issn = {1468-1331}, support = {577631//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/therapy ; Male ; Female ; Middle Aged ; Aged ; *Registries ; Selection Bias ; *Hospitals/statistics & numerical data ; }, abstract = {BACKGROUND: Over the past years, some studies in amyotrophic lateral sclerosis (ALS) have provided heterogeneous findings regarding demographic and clinical data as well as the impact of various prognostic factors. It is well known that these inconsistencies might be caused by a selection bias in hospital-based data sets. In this study, we sought to further characterize this selection bias.

METHODS: We compared hospital-based data from the ALS center at Ulm University (UC; n = 3833; 1997-2021) with the population-based ALS registry Swabia (SR; n = 852; 2010-2020).

RESULTS: Patients from UC were younger (age of onset 60.9 [IQR 52.4-68.9] vs. 65.0 [57.0-72.7]), had a higher share of males (60.5% vs. 56.3%), a longer diagnostic delay (10.5 [IQR 6.4-18.4] months vs. 6.9 [IQR 3.4-12.1] months), a higher prevalence of the "definite" category according to El Escorial diagnostic criteria (60.9% vs. 11.2%), a higher share of familial cases (12.9% vs. 6.3%), a slower progression rate (points of ALS functional rating scale revised lost per month -0.54 [IQR -1.02 to -0.28] vs. -0.79 [IQR -1.47 to -0.43]), and (among all deceased patients) a higher share of percutaneous endoscopic gastrostomy (26.7% vs. 17.7%) and non-invasive ventilation (34.3% vs. 25.3%).

CONCLUSIONS: The observed differences likely indicate a selection bias in hospital-based data, which may be attributed, among others, to the willingness to travel large distances to a specialized center, the desire to participate in clinical studies, and the attitude toward life-prolonging measures. These differences must be considered when interpreting and generalizing study results from hospital-based populations.}, } @article {pmid40184012, year = {2025}, author = {Chowdhury, MR and Reddy, RVS and Nampoothiri, NK and Erva, RR and Vijaykumar, SD}, title = {Exploring bioactive natural products for treating neurodegenerative diseases: a computational network medicine approach targeting the estrogen signaling pathway in amyotrophic lateral sclerosis and Parkinson's disease.}, journal = {Metabolic brain disease}, volume = {40}, number = {4}, pages = {169}, doi = {10.1007/s11011-025-01585-y}, pmid = {40184012}, issn = {1573-7365}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; *Parkinson Disease/drug therapy/metabolism/genetics ; *Signal Transduction/drug effects/physiology ; Computational Biology/methods ; *Estrogens/metabolism ; *Biological Products/therapeutic use/pharmacology ; Protein Interaction Maps/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Gene Regulatory Networks/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) share overlapping molecular mechanisms, including estrogen signaling dysregulation, oxidative stress, and neuroinflammation. Standard treatments often lead to adverse effects due to unintended cross-talk with the estrogen signaling pathway. Identifying key regulatory genes and bioactive plant-derived compounds that modulate estrogen signaling without interfering with standard therapies offers a promising neuroprotective strategy. A network medicine and systems biology approach was used, beginning with the screening of 29 medicinal plants for ALS and 49 for PD, identifying 12 shared plants with neuroprotective potential. Bioactive compounds were screened for gene, protein, and pathway interactions, leading to target prediction (846 ALS-related and 690 PD-related targets) and disease association mining, which identified 93 overlapping genes (OGs). Protein-protein interaction (PPI) network analysis and MCODE clustering revealed ESR1, EGFR, and SRC as key hub-bottleneck (HB) genes, further validated via differential gene expression analysis. Gene ontology (GO) and pathway enrichment analyses revealed significant enrichment in estrogen signaling confirming the involvement of HB genes in neurodegenerative disease progression. Differential expression analysis confirmed ESR1 upregulation in ALS but downregulation in PD, suggesting a converse disease-specific regulatory pattern. Gene regulatory network (GRN) analysis identified hsa-miR-145-5p (ALS) and hsa-miR-181a-5p (PD) as key regulators, while FOXC1, GATA2, and TP53 emerged as crucial transcription factors (TFs) influencing disease progression. Molecular docking and MD simulations validated strong and stable interactions of Eupalitin (CYP19A1, -9.0 kcal/mol), Hesperetin (ESR1, -8.1 kcal/mol), and Sumatrol (PIK3CA, -8.9 kcal/mol). These phytochemicals, derived from Rosmarinus officinalis, Artemisia scoparia, Ocimum tenuiflorum, and Indigofera tinctoria, maintained stable hydrogen bonding and hydrophobic interactions for over 30% of a 25 ns simulation, supporting their therapeutic potential. The identification of ESR1, EGFR, and SRC as key targets, alongside estrogen signaling involvement, highlights the need for targeted nutraceutical interventions. These findings pave the way for safer, plant-based therapies that mitigate neurodegeneration while preserving estrogen signaling integrity, offering a promising adjuvant strategy alongside existing treatments.}, } @article {pmid40184864, year = {2025}, author = {Deloncle, R and Guillard, O and Pineau, A}, title = {Copper in human health: From COVID 19 to neurodegenerative diseases.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {89}, number = {}, pages = {127636}, doi = {10.1016/j.jtemb.2025.127636}, pmid = {40184864}, issn = {1878-3252}, mesh = {*Copper/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism ; *COVID-19/metabolism ; Animals ; SARS-CoV-2 ; Brain/metabolism ; }, abstract = {Copper (Cu) exists in two oxidation states Cu+I and Cu+II yielding formation of enzymes involved in biological processes. In higher concentrations, by oxidative process and ROS production, Cu is toxic towards plants, humans and animals livers as observed in Wilson disease or sheep scrapie. Fighting according to the Fenton reaction against bacteria and viruses, has been proposed as a mean of combatting nosocomial diseases and complementary to COVID19 vaccination. In humans, Cu is stocked in liver, muscle or bound to brain protein as ß-APP, tau-protein, α-synuclein, ubiquitin or prion which present antioxidant properties when Cu-bonded. In abnormal ß-sheet conformation, they can trigger neurodegenerative diseases such as Alzheimer(AD), Parkinson(PD) and ALS. In these diseases, blood copper increase correlated with brain copper decrease has been described. In AD, abnormal D-serine has been detected in blood and cerebrospinal fluid. D-glutamate and D-alanine blood levels have been found in AD and could also be controlled with Cu and ceruloplasmin in a possible disease screening test. This abnormal D-conformation might result from epimerization of physiologically L-conformation brain peptides into protease-resistant D-enantiomers. This has previously been experimentally demonstrated for Bovine Spongiform Encephalopathy in a free Cu reductive medium with UV-induced free radicals. The Cu brain protective effect against free radicals was restored with cupric addition in oxidizing medium. Cupric supplementation in the brain, might restore Cu protection and slow down neurodegenerative processes. To lower side effects, Cu amino-acid complexes able to cross the blood brain barrier might be suggested for a Cu transfer to the brain.}, } @article {pmid40185066, year = {2025}, author = {Fujii, T and Honda, H and Yoshidomi, S and Kashu, KY and Yamasaki, R and Yoshimura, M and Sasagasako, N and Iwaki, T and Isobe, N}, title = {Plexin D1 accumulation in the spinal motor neurons of patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {472}, number = {}, pages = {123483}, doi = {10.1016/j.jns.2025.123483}, pmid = {40185066}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Male ; Female ; Middle Aged ; *Motor Neurons/metabolism/pathology ; *Spinal Cord/metabolism/pathology ; Aged ; *Nerve Tissue Proteins/metabolism ; DNA-Binding Proteins/metabolism ; Endothelial Cells/metabolism ; Adult ; }, abstract = {BACKGROUND: Plexin D1 in endothelial cells (ECs) in the spinal cord (SC) has emerged as a key protein in spinal motor neuron (MN) maturation. Here, we pathologically investigated plexin D1 expression in the SCs of patients with sporadic amyotrophic lateral sclerosis (sALS) to clarify the association between plexin D1 expression in ECs and MN degeneration.

METHODS: We measured plexin D1 expression in the ECs of lumbar SC tissue samples from 11 patients with sALS and 8 age- and sex-matched patients with other non-inflammatory neurological diseases (OND) by immunohistochemistry. Additionally, the number and percentage of plexin D1-positive MNs in lumbar MNs were assessed in each case. We also evaluated the immunoreactivity of TAR DNA binding protein (TARDBP) in plexin D1-positive MNs.

RESULTS: Immunohistochemistry showed that there was no obvious difference in plexin D1 expression in ECs between sALS and OND cases. Unexpectedly, plexin D1 accumulation was greater in MNs of patients with sALS compared with those with OND. The number and percentage of plexin D1-positive MNs in patients with sALS were significantly greater than in patients with OND (median [interquartile range], 6 [1-11] vs. 1 [0-3.3], p = 0.0349; and 12.9 % [5.5-15.5] vs. 1.1 % [0-3.5], p = 0.0032, respectively). Plexin D1-positive MNs showed TARDBP cytoplasmic mislocalization and aggregation.

CONCLUSIONS: Plexin D1 was similarly expressed in ECs between sALS and OND cases, but accumulated in the degenerated MNs of patients with sALS. Plexin D1 accumulation in MNs may provide new insights into the mechanism of MN degeneration in ALS.}, } @article {pmid40185386, year = {2025}, author = {Lei, S and Liu, Y}, title = {Identifying blood mitochondrial DNA copy number as a biomarker for development of neurodegenerative diseases: Evidence from Mendelian randomization analysis.}, journal = {Neuroscience}, volume = {573}, number = {}, pages = {421-429}, doi = {10.1016/j.neuroscience.2025.04.003}, pmid = {40185386}, issn = {1873-7544}, mesh = {Humans ; *DNA, Mitochondrial/blood/genetics ; Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/blood ; *DNA Copy Number Variations/genetics ; Genome-Wide Association Study ; Biomarkers/blood ; }, abstract = {Mitochondrial dysfunction has been associated with neurodegenerative diseases (NDDs). This study aimed to explore the association between blood mitochondrial DNA copy number (mtDNA-CN) and development of NDDs. This study was based on two-sample Mendelian randomization (MR) analysis. The genome wide association study (GWAS) data of NDDs including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), age-related macular degeneration (AMD), multiple sclerosis (MS), Parkinson's disease (PD), primary open-angle glaucoma (POAG), and vascular dementia (VD) was obtained from FinnGen consortium. Inverse-variance weighted (IVW) was applied as the primary approach for MR estimation. MR results revealed that blood mtDNA-CN exhibited a significant relationship with the incidence of AD (IVW-P = 0.011, odds ratio [OR] = 0.65) and AMD (IVW-P = 0.038, OR = 0.64). However, there was no significant association observed between blood mtDNA-CN and other NDDs (IVW-P > 0.05). Our findings supported the relationship between mitochondrial dysfunction and development of AD and AMD, and that blood mtDNA-CN may serve as a potential biomarker for the incidence of these two NDDs.}, } @article {pmid40185536, year = {2025}, author = {Uzgiris, AJ and Ladic, LA and Pfister, SX}, title = {Advances in neurofilament light chain analysis.}, journal = {Advances in clinical chemistry}, volume = {126}, number = {}, pages = {31-71}, doi = {10.1016/bs.acc.2025.01.006}, pmid = {40185536}, issn = {2162-9471}, mesh = {*Neurofilament Proteins/analysis ; Humans ; Biomarkers/analysis ; *Nervous System Diseases/diagnosis/metabolism ; }, abstract = {This chapter provides a comprehensive summary of clinical laboratory testing for neurofilament light chain (NfL) in neurologic disease. A primer on the NfL structure and function is presented with its potential use as a biomarker. The most widely utilized methods for NfL in biologic samples are highlighted and examined. Limitations of current knowledge are considered, as are outstanding questions related to dissemination and standardization of testing. Herein we focus on methods available today and those in development for clinical use. In the final section, a broad vision is presented of how NfL may be utilized in the future to improve diagnosis and treatment of neurologic diseases as well as for maintaining health.}, } @article {pmid40185615, year = {2025}, author = {Dawson, M}, title = {Marxism on Musk: reflections on Baum et al's 'Twenty-First Century Alienation and Health'.}, journal = {Journal of epidemiology and community health}, volume = {79}, number = {7}, pages = {477-478}, doi = {10.1136/jech-2025-223762}, pmid = {40185615}, issn = {1470-2738}, } @article {pmid40185700, year = {2025}, author = {Yang, T and Pang, D and Huang, J and Xiao, Y and Li, C and Wei, Q and Ou, R and Cheng, Y and Lin, J and Che, N and Fu, J and Jiang, Q and Wang, S and Liu, J and Zhang, S and Shang, H}, title = {Association between sleep and ALS-FTSD: A Prospective Cohort Study based on 396,918 UK biobank participants.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {123}, pmid = {40185700}, issn = {2158-3188}, support = {82371430//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; United Kingdom/epidemiology ; Prospective Studies ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Sleep Wake Disorders/epidemiology/complications ; Aged ; Risk Factors ; Biological Specimen Banks ; *Sleep/physiology ; Incidence ; Adult ; Proportional Hazards Models ; *Frontotemporal Dementia/epidemiology ; UK Biobank ; }, abstract = {Amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) is a fatal neurodegenerative condition, and identifying its modifiable risk factors is a critical public health issue. This large-scale prospective cohort study investigated the role of sleep-related factors in ALS-FTSD risk using data from 396,918 UK Biobank participants. Eight sleep-related exposures were assessed, and Cox proportional hazards regression was employed to evaluate their associations with ALS-FTSD incidence. Subgroup and sensitivity analyses were conducted to validate the robustness of our findings. At baseline, participants had a mean age of 56.31 ± 8.12 years, with 47.5% being male. In the fully adjusted Cox model, organic sleep disorders (G47) (HR: 1.81, 95% CI: 1.21, 2.72, P = 0.004), hypersomnia (G47.1) (HR: 36.53, 95% CI: 9.04, 147.55, P < 0.001), and extreme short sleep (<5 h per day) (HR: 2.09, 95% CI: 1.09, 3.99, P = 0.046) were significantly associated with increased ALS-FTSD risk. In conclusions, these findings revealed the relationship between sleep and the risk of ALS-FTSD, identifying new modifiable risk factors and potential preventive possibilities for ALS-FTSD. Further research is warranted to elucidate the mechanistic links between sleep disturbances and ALS-FTSD pathogenesis.}, } @article {pmid40185982, year = {2025}, author = {Cummings, JL and Teunissen, CE and Fiske, BK and Le Ber, I and Wildsmith, KR and Schöll, M and Dunn, B and Scheltens, P}, title = {Biomarker-guided decision making in clinical drug development for neurodegenerative disorders.}, journal = {Nature reviews. Drug discovery}, volume = {24}, number = {8}, pages = {589-609}, doi = {10.1038/s41573-025-01165-w}, pmid = {40185982}, issn = {1474-1784}, support = {P20 GM109025/GM/NIGMS NIH HHS/United States ; R35 AG071476/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Drug Development/methods ; *Neurodegenerative Diseases/drug therapy/diagnosis ; Clinical Trials as Topic/methods ; Animals ; Alzheimer Disease/drug therapy ; }, abstract = {Neurodegenerative disorders are characterized by complex neurobiological changes that are reflected in biomarker alterations detectable in blood, cerebrospinal fluid (CSF) and with brain imaging. As accessible proxies for processes that are difficult to measure, biomarkers are tools that hold increasingly important roles in drug development and clinical trial decision making. In the past few years, biomarkers have been the basis for accelerated approval of new therapies for Alzheimer disease and amyotrophic lateral sclerosis as surrogate end points reasonably likely to predict clinical benefit.Blood-based biomarkers are emerging for Alzheimer disease and other neurodegenerative disorders (for example, Parkinson disease, frontotemporal dementia), and some biomarkers may be informative across multiple disease states. Collection of CSF provides access to biomarkers not available in plasma, including markers of synaptic dysfunction and neuroinflammation. Molecular imaging is identifying an increasing array of targets, including amyloid plaques, neurofibrillary tangles, inflammation, mitochondrial dysfunction and synaptic density. In this Review, we consider how biomarkers can be implemented in clinical trials depending on their context of use, including providing information on disease risk and/or susceptibility, diagnosis, prognosis, pharmacodynamic outcomes, monitoring, prediction of response to therapy and safety. Informed choice of increasingly available biomarkers and rational deployment in clinical trials support drug development decision making and de-risk the drug development process for neurodegenerative disorders.}, } @article {pmid40186067, year = {2025}, author = {Maranzano, A and Gentile, F and Passaretti, M and Doretti, A and Colombo, E and Wall, AK and Treddenti, M and Patisso, V and De Lorenzo, A and Gendarini, C and Cocuzza, A and Maio, AD and Pierro, S and Poletti, B and Cinnante, CM and Morelli, C and Messina, S and Pereira, JB and Hardiman, O and Silani, V and Verde, F and Ticozzi, N}, title = {Rate of change in upper and lower motor neuron burden is associated with survival in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {315}, pmid = {40186067}, issn = {1432-1459}, support = {2022-12375731//Ministero della Salute/ ; E3-2022-23683266//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/pathology/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Motor Neurons/pathology ; Retrospective Studies ; Aged ; Disease Progression ; Adult ; Severity of Illness Index ; Cohort Studies ; ROC Curve ; }, abstract = {BACKGROUND: We hypothesize that the rate of change in upper (ΔUMN) and lower (ΔLMN) motor neuron signs from symptom onset to first clinical assessment represent best predictors of survival and disease progression in amyotrophic lateral sclerosis (ALS) compared to singular quantification of UMN and LMN involvement.

METHODS: A retrospective inpatient cohort of 1000 ALS patients was evaluated. The burden of UMN and LMN signs was assessed using the Penn Upper Motor Neuron Score and Lower Motor Neuron Score, respectively. For 421 patients, we compute the ENCALS survival model. Univariate and regularized Cox regressions were conducted to estimate the effect of the aforementioned variables on survival. The ROC curve analysis was then employed to a training sub-cohort to identify a ΔLMN cut-off value discriminating ALS patients with prolonged vs short survival. This cut-off value was then cross validated on a test sub-cohort. A multinomial regression model was used to compare different ΔUMN and ΔLMN scores among ENCALS groups.

RESULTS: ΔUMN and ΔLMN showed a negative association with survival (ΔUMN: HR = 1.30; ΔLMN: HR = 4.22). A cut-off value of 0.22 for ΔLMN was identified to predict patients with estimated short vs prolonged survival. ENCALS groups characterized by shorter survival presented significantly higher ΔUMN and ΔLMN scores compared to those with longer survival. No significant association of PUMNS or LMNS gross scores with the above-mentioned variables was observed.

CONCLUSION: By reflecting the progressing degeneration of the two distinct motor neuron subpopulations, ΔUMN and ΔLMN might represent reliable and easily measurable clinical indexes to estimate survival in ALS.}, } @article {pmid40187044, year = {2025}, author = {Fu, Y and Zhang, J and Qin, R and Ren, Y and Zhou, T and Han, B and Liu, B}, title = {Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases.}, journal = {Pharmacological reviews}, volume = {77}, number = {3}, pages = {100053}, doi = {10.1016/j.pharmr.2025.100053}, pmid = {40187044}, issn = {1521-0081}, mesh = {Humans ; *Autophagy/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Animals ; *Protein Aggregates/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; }, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.}, } @article {pmid40188375, year = {2025}, author = {Prajapati, JL and Dhurandhar, Y and Singh, AP and Gupta, DK and Baghel, VS and Kushwaha, U and Namdeo, KP}, title = {Redox chemical delivery system: an innovative strategy for the treatment of neurodegenerative diseases.}, journal = {Expert opinion on drug delivery}, volume = {22}, number = {6}, pages = {805-822}, doi = {10.1080/17425247.2025.2489558}, pmid = {40188375}, issn = {1744-7593}, mesh = {Humans ; *Drug Delivery Systems ; *Neurodegenerative Diseases/drug therapy/physiopathology ; Oxidation-Reduction ; Blood-Brain Barrier/metabolism ; Animals ; *Central Nervous System Agents/administration & dosage/pharmacokinetics ; Brain/metabolism ; }, abstract = {INTRODUCTION: It is anticipated that the prevalence of illnesses affecting the central nervous system (CNS) will rise significantly due to longer lifespans and changing demography. Age-related decline in brain function and neuronal death are features of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, which provide formidable treatment challenges. Because most therapeutic drugs cannot across the blood-brain barrier (BBB) to reach the brain, there are still few treatment alternatives available despite a great deal of research.

AREAS COVERED: This study explores the role of redox chemical delivery systems in CNS drug delivery and addresses challenges associated with neurodegenerative disease (ND). Redox Chemical Delivery System offers a promising approach to enhancing leveraging redox reactions that facilitate the transport of therapeutic agents across the BBB. Through the optimization of medication delivery pathways to the brain, this technology has the potential to greatly improve the treatment of ND.

EXPERT OPINION: As our understanding of the biological underpinnings of ND deepens, the potential for effective interventions increases. Refining drug delivery strategies, such as RCDS, is essential for advancing CNS therapies from research to clinical practice. These advancements could transform the management of ND, improving both treatment efficacy and patient outcomes.}, } @article {pmid40188740, year = {2025}, author = {Kuo, YC and Yang, CC and Tsai, LK}, title = {Exploring CSF biomarkers in amyotrophic lateral sclerosis: Highlighting the significance of TDP-43.}, journal = {Journal of the neurological sciences}, volume = {472}, number = {}, pages = {123479}, doi = {10.1016/j.jns.2025.123479}, pmid = {40188740}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood/physiopathology/diagnosis ; Male ; Female ; *DNA-Binding Proteins/cerebrospinal fluid/blood ; Middle Aged ; Biomarkers/cerebrospinal fluid/blood ; Neurofilament Proteins/cerebrospinal fluid ; Aged ; tau Proteins/cerebrospinal fluid ; Disease Progression ; Cohort Studies ; Adult ; Severity of Illness Index ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the existence of the TAR DNA-binding protein 43 (TDP-43) aggregates in motor neurons. This study investigated specific cerebrospinal fluid (CSF) biomarkers, including TDP-43, as diagnostic or prognostic biomarkers for ALS.

METHODS: The study included a hospital-based cohort of sporadic ALS patients (N = 30) and age-matched controls (N = 19). Using immunomagnetic reduction technology, CSF levels of TDP-43, neurofilament light chain (NfL), phosphorylated tau 181 (p-tau181), and total tau (t-tau) were assessed. Plasma levels of TDP-43 were also measured. The association of the different biomarkers with disease severity was investigated using ALS Functional Rating Scale-Revised (ALSFRS-R) scores, forced vital capacity (FVC), and compound muscle action potential (CMAP) amplitudes. The rate of disease progression was evaluated by measuring decline in ALSFRS-R over time.

RESULTS: ALS patients had higher CSF NfL and lower ratio of p-tau181/t-tau than control subjects. No significant difference between groups was observed in CSF TDP-43. In ALS patients, CSF levels of any biomarker, including TDP-43, were not associated with ALSFRS-R scores, FVC, or mean CMAP amplitudes. However, CSF TDP-43 positively correlated with the rate of decline in ALSFRS-R (p = 0.042). ALS patients with high CSF TDP-43 levels (>5 pg/mL) showed larger decline in ALSFRS-R (14.0 ± 11.90 vs. 8.8 ± 5.48 per year; p = 0.045) than those with lower TDP-43. Plasma TDP-43 levels did not correlate with CSF TDP-43 or any clinical parameter.

CONCLUSION: CSF TDP-43 is associated with the rate of disease progression and may be a prognostic biomarker in patients with sporadic ALS.}, } @article {pmid40188806, year = {2025}, author = {Saller, R and Schwabl, H and Rostock, M and Dal Cero, M}, title = {[Vom Spezifischen zum Systemischen - am Beispiel Tormentill/Blutwurz, der Heilpflanze des Jahres 2024].}, journal = {Complementary medicine research}, volume = {32}, number = {3}, pages = {260-263}, doi = {10.1159/000545128}, pmid = {40188806}, issn = {2504-2106}, mesh = {Humans ; Anti-Inflammatory Agents/therapeutic use ; *Phytotherapy ; *Plant Extracts/therapeutic use ; *Plants, Medicinal/chemistry ; }, abstract = {Am Beispiel des in verschiedenen lokalen Traditionen genutzten Blutwurz, auch Tormentill (Potentilla erecta L.), wird exemplarisch eine offensichtliche Kluft zwischen üblichen indikationsgetriebenen Zulassungsverfahren und der empirischen Realität sowie dem Potential vieler Heilpflanzen aufgezeigt. Für Tormentillae rhizoma ist ein breites Spektrum an Inhaltsstoffen und das mit dem Vielstoffgemisch einhergehende Wirkprofil einer u.a. vielfältig antiinflammatorisch wirkenden systemischen Droge experimentell belegt. Die traditionelle Empirie der dämpfenden Effekte im Entzündungsgeschehen wird dadurch plausibilisiert. Die moderne Forschung liefert also Daten für einen sinnvollen Einsatz einer gut verträglichen Heilpflanze mit vielfältigen Anwendungsmöglichkeiten für Haut und Schleimhaut (innerlich und äusserlich). Auf dem Markt gibt es aber, abgesehen von vereinzelten topischen Spezialitäten und Arzneitees, kaum Zubereitungen als zugelassene Arzneispezialität. Denn die derzeitige Praxis der Arzneimittelzulassung bevorzugt die spezifischen und organbezogenen Wirkungen und übersieht dabei das systemische Potential, die Modulationsfähigkeit dieser natürlichen Stoffgemische, wie sie durch traditionelle und empirische Belege angezeigt wird. Systemische Wirkungen zeigen ihre Stärke gerade im Zusammenspiel mit anderen Therapien insbesondere beim additiven Einsatz mit Spezifika, indem sie bestimmte Wirkungen verstärken bzw. abschwächen oder die Verträglichkeit der Spezifika erhöhen bzw. deren Nebenwirkungen abmildern. Die Kombination von spezifisch wirkenden Arzneimitteln mit solchen Systemmitteln (wie z.B. Blutwurz/Tormentill) stellt damit eine weitere Therapieoption dar, die als sinnvolle Ergänzung, wenn nicht sogar als Grundlage bei Prävention, Therapie und Lebensgestaltung zu werten ist. The example of tormentil (Potentilla erecta L.), which is used in various local traditions, is taken to illustrate an obvious gap between the common indication-driven authorization procedures and the empirical reality and potential of many medicinal plants. For Tormentillae rhizoma, a broad spectrum of active compounds and the active profile of a systemic drug with multiple anti-inflammatory effects have been experimentally proven. The traditional empiricism of the dampening effects in the inflammatory process is thus made plausible. Modern research, therefore, provides data for the effective use of a well-tolerated medicinal plant with a wide range of possible applications for the skin and mucous membranes (internally and externally). However, apart from a few topical specialties and medicinal teas, there are hardly any preparations on the market as authorized medicinal specialties. This is because the current practice of marketing authorization favors the specific and organ-related effects and overlooks the systemic potential, the modulation capacity of these natural substance mixtures, as indicated by traditional and empirical evidence. Systemic effects show their strength particularly in combination with other therapies, especially when used additively with specific agents, in that they strengthen or weaken certain effects or increase the tolerability of the specific agents or minimize their side effects. The combination of specific drugs with such systemic drugs (e.g., bloodroot/tormentil) therefore represents a further therapeutic option that can be seen as a valuable addition, if not a basis for prevention, therapy and lifestyle.}, } @article {pmid40188980, year = {2025}, author = {Chong, ZZ and Souayah, N}, title = {Pathogenic TDP-43 in amyotrophic lateral sclerosis.}, journal = {Drug discovery today}, volume = {30}, number = {5}, pages = {104351}, doi = {10.1016/j.drudis.2025.104351}, pmid = {40188980}, issn = {1878-5832}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; Animals ; Mutation ; Protein Processing, Post-Translational ; }, abstract = {The aberrant expression of the transactive response DNA-binding protein of 43 kDa (TDP-43) has been closely associated with amyotrophic lateral sclerosis (ALS). Cytoplasmic inclusions containing TDP-43 can be found in the brain and spinal cord in up to 97% of ALS cases. Mutations in the TARDBP gene promote the nuclear export of TDP-43, increase cytoplasmic aggregation, and predispose TDP-43 to post-translational modifications. Cleavage of TDP-43 and the resulting C- and N-terminal fragments also contribute to the development of ALS. Cellularly, the resulting impairment of autophagy and mitochondria aggravates cellular damage and neurodegeneration. Given the contribution of pathogenic TDP-43 to the development of ALS, elucidating the mechanisms related to TDP-43 will facilitate finding therapeutic targets for the disease.}, } @article {pmid40189519, year = {2025}, author = {Tseng, PT and Zeng, BY and Hsu, CW and Hung, CM and Carvalho, AF and Stubbs, B and Chen, YW and Chen, TY and Lei, WT and Chen, JJ and Su, KP and Shiue, YL and Liang, CS}, title = {The pharmacodynamics-based prophylactic benefits of GLP-1 receptor agonists and SGLT2 inhibitors on neurodegenerative diseases: evidence from a network meta-analysis.}, journal = {BMC medicine}, volume = {23}, number = {1}, pages = {197}, pmid = {40189519}, issn = {1741-7015}, mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists/pharmacology/therapeutic use ; Hypoglycemic Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/prevention & control/drug therapy ; Randomized Controlled Trials as Topic ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; }, abstract = {BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a new generation of antihyperglycemic agents that operate through mechanisms distinct from conventional diabetes treatments. Beyond their metabolic effects, these medications have demonstrated neuroprotective properties in preclinical studies. While clinical trials have explored their therapeutic potential in established neurodegenerative conditions, their role in disease prevention remains unclear. We conducted a network meta-analysis (NMA) to comprehensively evaluate the prophylactic benefits of these agents across multiple neurodegenerative diseases and identify the most promising preventive strategies.

METHODS: We systematically searched PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ProQuest, ScienceDirect, Web of Science, and ClinicalTrials.gov through October 24th, 2024, for randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors. Our primary outcome was the incidence of seven major neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, Lewy body dementia, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington's disease. Secondary outcomes included safety profiles assessed through dropout rates. We performed a frequentist-based NMA and evaluated risk of bias with Risk of Bias tool. The main result of the primary outcome in the current study would be re-affirmed via sensitivity test with Bayesian-based NMA.

RESULTS: Our analysis encompassed 22 RCTs involving 138,282 participants (mean age 64.8 years, 36.4% female). Among all investigated medications, only dapagliflozin demonstrated significant prophylactic benefits, specifically in preventing Parkinson's disease (odds ratio = 0.28, 95% confidence intervals = 0.09 to 0.93) compared to controls. Neither GLP-1 receptor agonists nor other SGLT2 inhibitors showed significant preventive effects for any of the investigated neurodegenerative conditions. Drop-out rates were comparable across all treatments.

CONCLUSIONS: This comprehensive NMA reveals a novel and specific prophylactic effect of dapagliflozin against Parkinson's disease, representing a potential breakthrough in preventive neurology. The specificity of dapagliflozin's protective effect to Parkinson's disease might rely on its highly selective inhibition to SGLT2. These findings provide important direction for future research and could inform preventive strategies for populations at risk of Parkinson's disease.

TRIAL REGISTRATION: PROSPERO CRD42021252381.}, } @article {pmid40189941, year = {2025}, author = {Padigos, J and Murray, L and Bredhauer, O and Jaspers, J and Bethune, S}, title = {Extending the interval for changing flushing solutions for central venous and arterial line systems in the intensive care unit: An evidence-based quality improvement project.}, journal = {Nursing in critical care}, volume = {30}, number = {3}, pages = {e70034}, pmid = {40189941}, issn = {1478-5153}, mesh = {Humans ; *Quality Improvement ; *Intensive Care Units/organization & administration ; Queensland ; *Catheterization, Central Venous/methods ; Time Factors ; Catheter-Related Infections/prevention & control ; }, abstract = {BACKGROUND: Central venous lines (CVLs) and arterial lines (ALs) are commonly used for patients in the intensive care units (ICUs) to facilitate the administration of medications and haemodynamic monitoring. In an ICU in Queensland, Australia (AU), saline (sodium chloride 0.9%) flush bags used for these lines were routinely changed every 24 h following organizational policy that all intravenous fluid bags are to be changed within a 24-h period.

AIM: This quality improvement (QI) project aimed to evaluate current practice guided by the Plan-Do-Study-Act (PDSA) model of QI and implementation science. Benchmarking practices with other ICUs was conducted.

STUDY DESIGN: A narrative literature review focused on evaluating the safe interval for changing flush solutions every 24 h was performed using EBSCO Medline, CINAHL, Cochrane Library, Embase and Google Scholar databases for citations up to November 2022. Bloodstream infection rates attributed to CVLs and/or ALs were monitored. Economic analysis was performed. End-user feedback was sought. A change of practice was implemented for a 1-year study period (March 2023 - March 2024) to extend dwell times of flushing solutions for CVLs and ALs from every 24 h to every 96 h.

RESULTS: One-year post-implementation, no bloodstream infections were linked to CVLs or ALs. A simplified economic analysis was performed based on costs of 0.9% sodium chloride 500-mL fluid bags, which revealed that changing the fluid bags once every 96 h resulted in a per patient saving of AU$3.21 for any individual AL or CVL and up to AU$6.42 per patient where both an AL and CVL are in situ, based on fluid bag cost at AU$1.07 per bag. This saving excludes potential savings from reduced nursing time, infection-related costs and recycling costs.

CONCLUSION: A sustainable practice change based on evidence was implemented in the local ICU. The use of the PDSA model of the QI process and the principles of implementation science strengthened the buy-in and implementation of the project.

This practice change was examined through lenses of evidence-based practice, environmental sustainability (minimizing environmental footprint by limiting plastic bag usage), patient safety, cost minimization, and reduced nursing workload.}, } @article {pmid40192272, year = {2025}, author = {Kurashige, T and Murao, T and Kanaya, Y and Dodo, Y and Sugiura, T and Kuraoka, K and Ohshita, T}, title = {Intramuscular Nerve Bundles Reflect TDP-43 Pathology in the Medulla and Spinal Cord of ALS Patients.}, journal = {Neuropathology and applied neurobiology}, volume = {51}, number = {2}, pages = {e70016}, pmid = {40192272}, issn = {1365-2990}, support = {//SENSHIN Medical Research Foundation/ ; //ALS foundation by Japan ALS Association/ ; //Tsuchiya Foundation/ ; //Takeda Science Foundation/ ; //Japan ALS Association/ ; //Daiichi Sankyo Foundation of Life Science/ ; //Kato Memorial Trust for Nanbyo Research/ ; //Kurozumi Medical Foundation/ ; //Okinaka Memorial Institute for Medical Research/ ; //Takeda Science Foundation, and Tsuchiya Foundation/ ; }, } @article {pmid40192904, year = {2025}, author = {Kodirov, SA}, title = {Comparison of Superoxide Dismutase Activity at the Cell, Organ, and Whole-Body Levels.}, journal = {Cell biochemistry and biophysics}, volume = {83}, number = {3}, pages = {2713-2726}, pmid = {40192904}, issn = {1559-0283}, mesh = {*Superoxide Dismutase/metabolism ; Humans ; Animals ; Amyotrophic Lateral Sclerosis/enzymology/metabolism ; Male ; }, abstract = {Superoxide dismutase (SOD) can be considered an antitoxic metalloenzyme that facilitates the production of oxygen and hydrogen peroxide from superoxide anions. Four classes have been identified depending on selective binding of metals, namely Cu,Zn-SOD, Fe-SOD, Mn-SOD, and Ni-SOD. The established isoforms are SOD1, SOD2, and SOD3 in various cells and tissues of eukaryotes. The relatively newer type Ni-SOD binds nickel and is observed in bacteria, including the genus Streptomyces. The Fe-SOD and Mn-SOD are also present in bacteria. Cu,Zn superoxide dismutase (SOD1) activity correlates with various pathophysiological states of organs. SOD2 binds manganese (Mn) and is located in the mitochondria. The SOD3, similar to the SOD1, binds copper and zinc, which are also expressed in the brain. The assay relies on several methods, including the enzyme activities, expression, field potential, and patch-clamp electrophysiology. The effects of SOD activity are emphasized at organ and whole-body levels depending on animal models. The antioxidant properties and behavior of SOD are compared based on responses among females and males to diet and toxic substances. However, in humans with amyotrophic lateral sclerosis (ALS), the mean SOD activity in both erythrocytes and muscles was comparable to controls. The detailed comparisons between the catalase and SOD activities are one of the aspects of this review. Also, modulation of excitability and synaptic plasticity in neurons by SOD is highlighted.}, } @article {pmid40196013, year = {2025}, author = {Viteri, JA and Kerr, NR and Brennan, CD and Kick, GR and Wang, M and Ketabforoush, A and Snyder, HK and Moore, PJ and Darvishi, FB and Dashtmian, AR and Ayyagari, SN and Rich, K and Zhu, Y and Arnold, WD}, title = {Targeting senescence in Amyotrophic Lateral Sclerosis: senolytic treatment improves neuromuscular function and preserves cortical excitability in a TDP-43[Q331K] mouse model.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40196013}, issn = {2693-5015}, support = {R01 AG078129/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron degeneration in the primary motor cortex (PMC) and spinal cord. Aging is a key factor in ALS onset and progression, with evidence suggesting that biological aging-a process involving cellular decline- far outpaces chronological aging in ALS. This promotes senescent cell accumulation-marked by irreversible cell-cycle arrest, impaired apoptosis, and chronic inflammation-disrupting tissue homeostasis and impairing neuronal support functions. Thus, targeting senescence presents a novel therapeutic strategy for ALS. Here, we investigated the senolytic combination Dasatinib and Quercetin (D&Q) in TDP-43[Q331K] ALS mice. D&Q improved neuromuscular function and reduced plasma neurofilament light chain, a biomarker of axonal damage. The most pronounced improvement was the improved cortical excitability, accompanied by reductions in senescence and TDP-43 in the PMC. These findings highlight the potential of senolytics to mitigate ALS-related dysfunction, supporting their viability as a therapeutic strategy.}, } @article {pmid40196659, year = {2025}, author = {Ramesh, N and Evans, A and Wojta, K and Yang, Z and Boks, MM and Kahn, RS and de Boer, SCM and van der Lee, SJ and Pijnenburg, YAL and Reus, LM and Ophoff, RA}, title = {Accurate DNA Methylation Predictor for C9orf72 Repeat Expansion Alleles in the Pathogenic Range.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.03.20.643775}, pmid = {40196659}, issn = {2692-8205}, abstract = {The hexanucleotide (G 4 C 2) repeat expansion in the promoter region of C9orf72 is the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this study, we conducted a genome-wide DNA methylation (DNAm) analysis using EPIC version 2 (EPICv2) arrays on an FTD cohort comprising 27 carriers and 250 non-carriers of the pathogenic C9orf72 repeat expansion from the Amsterdam Dementia Cohort. We identified differentially methylated CpGs probes associated with the pathogenic C9orf72 expansion and used these findings to create a DNAm Least Absolute Shrinkage and Selection Operator (LASSO) predictor to identify repeat expansion carriers. Eight CpG sites at the C9orf72 locus were significantly differentially hypermethylated in repeat expansion carriers compared to non-carriers. The LASSO model predicted repeat expansion status with an average accuracy of 98.6%. The LASSO predictor was further validated in an independent cohort of 2,548 subjects with available EPICv2 data, identifying four C9orf72 repeat expansion carriers, subsequently confirmed by repeat-primed PCR. This result not only illustrates the accuracy of the DNAm predictor of C9orf72 repeat expansion carriers but also suggests that repeat expansion carriers may be more prevalent than expected. The identification of a highly accurate DNAm biomarker for a repeat expansion locus associated with neurodegenerative disorders may provide great value for studying this locus. The approach holds significant promise for investigating this and other repeat expansion loci, particularly given the growing interest in epigenetic epidemiological studies involving large cohorts with available DNAm data.}, } @article {pmid40196899, year = {2025}, author = {Li, S and Pandat, T and Chi, B and Moon, D and Mas, M}, title = {Management Approaches to Spastic Gait Disorders.}, journal = {Muscle & nerve}, volume = {72}, number = {2}, pages = {179-200}, doi = {10.1002/mus.28402}, pmid = {40196899}, issn = {1097-4598}, mesh = {Humans ; *Gait Disorders, Neurologic/therapy/etiology/diagnosis/physiopathology ; *Muscle Spasticity/therapy/complications/physiopathology/diagnosis ; *Disease Management ; }, abstract = {Spastic gait presents clinically as the net mechanical consequence of neurological impairments of spasticity, weakness, and abnormal synergies and their interactions with the ground reaction force in patients with upper motor neuron syndromes and with some neuromuscular diseases. It is critical to differentiate whether the primary problem is weakness or spasticity, thus better understanding different phenotypes of spastic gait disorders. Pelvic girdle abnormality plays a pivotal role in determining the clinical presentation of gait disorders, since it determines the body vector and compensatory kinetic chain reactions in the knee and ankle joints. Knee joint abnormality can be a mechanical compensation for hip and/or ankle and foot abnormality. Diagnostic nerve blocks and instrumented gait analysis may be needed for diagnosing the underlying problems and developing an individualized plan of care. A wide spectrum of treatment options has been used to manage spastic gait disorders. Some are in early and investigational stages, such as neuromodulation modalities, while others are well-developed, such as therapeutic exercise, ankle-foot orthoses, botulinum toxin treatment, and surgical interventions. Physicians and other healthcare providers who manage spastic gait disorders should be familiar with these treatment options and should employ appropriate interventions concurrently rather than serially. The most effective treatments can be selected based on careful evaluation, inputs from patients, family, and therapists, along with appropriate goal setting. Treatment plans need to be re-evaluated for effectiveness, relevance, and in concordance with disease progress. This is particularly important for patients with progressive neuromuscular diseases such as amyotrophic lateral sclerosis.}, } @article {pmid40198473, year = {2025}, author = {Seok, HY}, title = {Critical issues in the use of edaravone for the treatment of amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {8}, pages = {3427-3430}, pmid = {40198473}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Edaravone/therapeutic use ; *Neuroprotective Agents/therapeutic use ; *Free Radical Scavengers/therapeutic use ; Disease Progression ; Riluzole/therapeutic use ; }, abstract = {Edaravone, along with riluzole, is a key treatment for amyotrophic lateral sclerosis (ALS), with evidence supporting its efficacy in slowing disease progression, particularly in patients with early-stage ALS. Despite its approval and increasing clinical use, several critical questions about its use remain unanswered: Can edaravone be effective as monotherapy? Is it beneficial for patients who fall outside the inclusion criteria of pivotal trials? What is the optimal duration of treatment as ALS progresses? In addition, does edaravone provide clinical benefit to patients with familial ALS? Answering these questions is essential to optimize the use of edaravone in clinical practice and to further our understanding of its role in the treatment of ALS. This review synthesizes the current evidence to address these questions and identifies areas that require further investigation.}, } @article {pmid40198794, year = {2025}, author = {Corucci, G and Vadukul, DM and Paracini, N and Laux, V and Batchu, KC and Aprile, FA and Pastore, A}, title = {Membrane Charge Drives the Aggregation of TDP-43 Pathological Fragments.}, journal = {Journal of the American Chemical Society}, volume = {147}, number = {16}, pages = {13577-13591}, pmid = {40198794}, issn = {1520-5126}, mesh = {*DNA-Binding Proteins/chemistry/metabolism ; Humans ; *Lipid Bilayers/chemistry/metabolism ; Protein Aggregates ; }, abstract = {TDP-43 protein is an RNA-binding protein linked to amyotrophic lateral sclerosis, frontotemporal dementia, and Alzheimer disease. While normally a protein that shuttles between the nucleus and cytoplasm, TDP-43 has recently been found also in extracellular vesicles. These are an important medium for cell-cell communication that allows the transfer of lipids, proteins, and genetic material among cells. An increasing concern in neurodegenerative diseases, however, is the possibility that extracellular vesicles can also provide an effective way to spread misfolded proteins that could "infect" other cells according to a "prion-like" mechanism. To characterize the interaction of TDP-43 with lipid membranes, we carried out a systematic biophysical study using a TDP-43 fragment lacking the first 84 N-terminal residues, called M85, and synthetic model phospholipid membranes. We utilized standard techniques, such as fluorescence and microscopy, complemented by neutron reflectivity measurements. Our results show that lipid charge affects the modality by which M85 interacts with membranes: a higher negative charge induces the protein to bind to the bilayer surface, promoting protein aggregation and decreasing lipid bilayer damage that this interaction causes. Thus, we speculate that the M85-lipid membrane interaction could play an important and previously undefined role in TDP-43-related neurodegenerative diseases.}, } @article {pmid40199586, year = {2025}, author = {Fyrberg, E and Learnard, H and Lee, S and Jun, YW and Gao, FB}, title = {New Mouse Lines That Drive Tetracycline-Controlled Gene Expression in a Small Subset of Spinal Cord Dorsal Horn Neurons.}, journal = {eNeuro}, volume = {12}, number = {4}, pages = {}, pmid = {40199586}, issn = {2373-2822}, support = {R01 NS101986/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; RF1 AG082478/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Posterior Horn Cells/metabolism/drug effects ; *Tetracycline/pharmacology ; Mice, Transgenic ; Mice ; Promoter Regions, Genetic ; Disease Models, Animal ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Gene Expression/drug effects ; Spinal Cord/metabolism ; Mice, Inbred C57BL ; Transcription Factors ; Homeodomain Proteins ; }, abstract = {Mouse lines with tetracycline-controlled gene expression in specific neuronal populations provide valuable tools for studying their development, function, connectivity, and pathology in vivo. Our initial goal was to generate a mouse model that could express amyotrophic lateral sclerosis-associated genes specifically in spinal cord motor neurons under the control of the HB9 promoter. However, HB9-tTA mice unexpectedly direct target gene expression in a small subset of dorsal horn neurons. These mice represent a new tool for scientists who are interested in studying these spinal cord neurons.}, } @article {pmid40200352, year = {2025}, author = {Li, J and Tang, S and Li, J and Huang, X and Liu, Y and Zeng, J and Fan, Y}, title = {Incidence and health burden of 20 rare neurological diseases in South China from 2016 to 2022: a hospital-based observational study.}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {163}, pmid = {40200352}, issn = {1750-1172}, support = {202007030010//Guangzhou Science and Technology Program Key Projects/ ; 2020B1212060017//Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases/ ; 2020B1111170002//Guangdong Provincial Clinical Research Center for Neurological Diseases/ ; }, mesh = {Humans ; China/epidemiology ; Male ; Female ; *Nervous System Diseases/epidemiology ; Incidence ; Adult ; Middle Aged ; *Rare Diseases/epidemiology ; Adolescent ; Child ; Aged ; Young Adult ; Hospitals ; }, abstract = {BACKGROUND: Rare neurological diseases (RNDs) result in severe health burdens worldwide. Data from China are limited. We aimed to investigate the health burden of 20 RNDs in Guangdong Province (GD), which contains two-thirds of the population of South China.

METHODS: The hospitalization data of 20 RNDs were described using hospital-based front sheet data from 3,037 hospitals of GD from 2016 to 2022. The 20 RNDs included amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth Disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, congenital myotonia, congenital myasthenic syndrome, Dravet syndrome, Fabry disease, hereditary spastic paraplegia, Huntington disease, Leber hereditary optic neuropathy, mitochondrial encephalopathy (ME), multi-focal motor neuropathy, myotonic dystrophy, primary hereditary dystonia, progressive muscular dystrophy (PMD), spinal and bulbar muscular atrophy, spinal muscular atrophy (SMA), spinocerebellar ataxia, Wilson disease (WD) and X-linked adrenoleukodystrophy. Age were presented as mean and standard deviation while length of hospital stay as median and interquartile range (25th and 75th percentiles). The other variables were described as number and percentage. The data were analyzed by Joinpoint regression.

RESULTS: There were 9,351 cases, including 330 ICU and 155 death cases. The average age was 33.7 ± 22.0 y, and 63.8% of patients were male. From 2016 to 2022, the number of RND (and juvenile RND) cases were 1034 (184), 1174 (293), 1443 (374), 1422 (320), 1331 (337), 1432 (409) to 1515 (515). ICU (and juvenile ICU) cases rose from 28 (3), 34 (6), 24 (4), 38 (11), 46 (13), 54 (24) to 106 (56). Joinpoint regression showed significant upward trend in percentages of juvenile and juvenile ICU cases (APC = 8.13, P< 0.05; APC = 28.42, P< 0.05). The fop five RNDs were WD, ASL, PMD, ME, and SMA, which accounted for 79.7% of all, 99.1% of ICU, and 94.8% of death cases.

CONCLUSIONS: We demonstrated that the increase in health burden of RNDs was mainly evident in juveniles in South China from 2016 to 2022. The top 5 RNDs accounted for majority of the critical patients.}, } @article {pmid40200520, year = {2025}, author = {Nikiema, SLW and Barro, SG and Kantagba, YMK and Kouraogo, BAJ and Staccini, P}, title = {Design and Development of a Virtual Reality Tool for Adult Basic Life Support Training.}, journal = {Studies in health technology and informatics}, volume = {323}, number = {}, pages = {414-418}, doi = {10.3233/SHTI250123}, pmid = {40200520}, issn = {1879-8365}, mesh = {*Virtual Reality ; Humans ; *Cardiopulmonary Resuscitation/education/instrumentation ; Adult ; *User-Computer Interface ; }, abstract = {The research introduces a Virtual Reality (VR) instrument for Adult Basic Life Support (ABLS) training, employing Blender for 3D modeling, Unity3D for VR environment creation, XChart for data visualization, and the Oculus Quest 2 as the principal VR headset. The device replicates authentic emergency situations, offering immediate feedback on CPR execution. Preliminary findings indicate enhancements in technical proficiency and user engagement; nonetheless, issues like as motion sickness and scalability remain unresolved. Future improvements will concentrate on sophisticated haptic feedback and ALS scenarios.}, } @article {pmid40200577, year = {2025}, author = {Winkelsas, A and Apfel, A and Johnson, B and Harmison, G and Perez, KD and Li, D and Cheung, VG and Grunseich, C}, title = {Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.}, journal = {HGG advances}, volume = {6}, number = {3}, pages = {100435}, pmid = {40200577}, issn = {2666-2477}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Alleles ; HEK293 Cells ; *Mutation ; *RNA Helicases/genetics ; *Multifunctional Enzymes/genetics ; RNA, Small Interfering/genetics ; *Gene Silencing ; DNA Helicases/genetics ; RNA Interference ; }, abstract = {Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope-tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels while having minimal effect on the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele while sparing the wild-type allele and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference.}, } @article {pmid40200760, year = {2025}, author = {Herrmann, C and Uzelac, Z and Michels, S and Weber, A and Richter, L and Elmas, Z and Jagodzinski, L and Wurster, C and Schuster, J and Dreyhaupt, J and Dorst, J}, title = {Alterations of Fat and Ketone Body Metabolism in ALS and SMA-A Prospective Observational Study.}, journal = {European journal of neurology}, volume = {32}, number = {4}, pages = {e70132}, pmid = {40200760}, issn = {1468-1331}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Adipose Tissue/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Energy Metabolism/physiology ; Fatty Acids, Nonesterified/metabolism/blood ; *Ketone Bodies/metabolism ; *Muscular Atrophy, Spinal/metabolism ; Prospective Studies ; Young Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerdosis (ALS) and spinal muscular atrophy (SMA) are motor neuron diseases associated with distinct metabolic alterations. ALS patients feature an increased resting energy expenditure (REE) causing weight loss and cachexia. In SMA, a disturbed utilization of free fatty acids has been described. These metabolic alterations negatively affect prognosis in both diseases. The objective of this study was to further characterize these changes to identify potential therapeutic targets.

METHODS: Between 11/2020 and 08/2022, 112 ALS patients, 77 SMA patients, and 50 controls were recruited in the Department of Neurology of Ulm University. Standardized blood and urinary samples were collected to analyze fat and ketone metabolism.

RESULTS: Ketone body levels were higher in ALS and SMA compared to controls. In both diseases, patients with higher BMI featured higher ketone bodies and free fatty acids compared to those with lower BMI, while in controls we found the opposite phenomenon. In SMA, more severe disease types were associated with higher ketone body levels. Compared to ALS, SMA patients featured higher ketone body and free fatty acid levels.

CONCLUSIONS: Our data suggest that already during early disease stages, ALS patients produce ketone bodies to compensate for the energy deficit. In SMA, on the other hand, the persistence of ketogenesis may indicate an upregulation of all available metabolic pathways for energy production due to the disturbance of fatty acid utilization. Therefore, the application of additional sources of energy, such as ketone bodies, might constitute a promising therapeutic option in both diseases.}, } @article {pmid40202498, year = {2025}, author = {Gu, J and Yang, M and Zhang, L and Liu, Y and Yan, R and Pan, D and Qian, X and Hu, H and Chu, D and Hu, C and Liu, F and Cui, H}, title = {Rhythmic TDP-43 affects RNA splicing of USP13, resulting in alteration of BMAL1 ubiquitination.}, journal = {The Journal of cell biology}, volume = {224}, number = {5}, pages = {}, pmid = {40202498}, issn = {1540-8140}, support = {32171258//National Natural Science Foundation of China/ ; BK20211329//Natural Science Foundation of Jiangsu Province/ ; //Co-Innovation Center of Neuroregeneration/ ; //Nantong University/ ; }, mesh = {Animals ; *ARNTL Transcription Factors/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Ubiquitination ; *Circadian Rhythm/genetics ; Humans ; Mice ; *RNA Splicing/genetics ; *Ubiquitin-Specific Proteases/genetics/metabolism ; Mice, Inbred C57BL ; Male ; HEK293 Cells ; }, abstract = {Circadian rhythm disorders are common characteristics of neurodegenerative diseases. The pathological aggregation of transactive response DNA-binding protein 43 (TDP-43) is associated with multiple neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, the relationship between TDP-43 and circadian rhythm remains unknown. Here, we found that TDP-43 is rhythmically expressed both in vivo and in vitro. TDP-43 knockdown affected the expression of circadian genes, including BMAL1, CLOCK, CRY1, and PER2, and impaired autonomous circadian wheel behavior, cognitive functions, and balance abilities in mice. Furthermore, TDP-43 knockdown induced aberrant splicing of ubiquitin-specific peptidase 13 (USP13) and blocked USP13 rhythmic expression, enhancing the ubiquitination of BMAL1. Meanwhile, TDP-43 knockdown altered the rhythmic expression of phospho-AMPKα (Thr172) and platelet-type phosphofructokinase (PFKP), which may change cellular glucose uptake and ATP production. Our findings further the understanding of the role of TDP-43 dysfunction in circadian rhythm disruption in neurodegenerative diseases and provide new mechanistic evidence supporting the interaction between circadian rhythm disruption and neurodegeneration.}, } @article {pmid40202704, year = {2025}, author = {Oyovwi, MO and Chijiokwu, EA and Ben-Azu, B and Atere, AD and Joseph, UG and Ogbutor, UG and Udi, OA}, title = {Potential Roles of Natural Antioxidants in Modulating Neurodegenerative Disease Pathways.}, journal = {Molecular neurobiology}, volume = {62}, number = {8}, pages = {10367-10397}, pmid = {40202704}, issn = {1559-1182}, mesh = {Humans ; *Antioxidants/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Animals ; Oxidative Stress/drug effects ; Neuroprotective Agents/therapeutic use/pharmacology ; *Signal Transduction/drug effects ; *Biological Products/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are increasingly prevalent among aging populations. Oxidative stress contributes to these diseases, leading to cellular damage and neuronal death. Natural antioxidants are being explored as preventive measures. This study aims to assess the effectiveness of natural antioxidants in delaying the onset or progression of neurodegenerative diseases by identifying their specific mechanisms of action. A comprehensive review of existing literature was conducted, focusing on studies that examine the role of natural antioxidants in neuroprotection. Key natural antioxidants, including flavonoids, polyphenls, vitamins C and E, and omega-3 fatty acids, were reviewed and analyzed for their bioavailability, mechanisms of action, and outcomes in both in vitro and in vivo studies. Additionally, clinical trials involving human subjects were considered to provide insights into the translational implications of antioxidant consumption. The findings suggest that several natural antioxidants exhibit neuroprotective properties by modulating oxidative stress, reducing inflammation, and promoting neuronal survival. For instance, flavonoids such as quercetin and resveratrol have shown promise in enhancing cognitive function and mitigating the pathophysiological alterations associated with neurodegeneration. In clinical studies, higher intakes of dietary antioxidants were correlated with a reduced risk of developing neurodegenerative disorders. Natural antioxidants offer potential for preventing neurodegenerative diseases by counteracting oxidative stress and maintaining cellular integrity. Overall, our report recommends that further research is needed to optimize dosages and understand their long-term benefits.}, } @article {pmid40202986, year = {2025}, author = {Askarova, A and Yaa, RM and Marzi, SJ and Nott, A}, title = {Genetic risk for neurodegenerative conditions is linked to disease-specific microglial pathways.}, journal = {PLoS genetics}, volume = {21}, number = {4}, pages = {e1011407}, pmid = {40202986}, issn = {1553-7404}, mesh = {Humans ; *Microglia/metabolism/pathology ; *Genetic Predisposition to Disease ; Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/pathology ; Schizophrenia/genetics/pathology ; Neurons/metabolism/pathology ; Alzheimer Disease/genetics/pathology ; Multiple Sclerosis/genetics/pathology ; Parkinson Disease/genetics/pathology ; Oligodendroglia/metabolism/pathology ; Chromatin/genetics ; Linkage Disequilibrium/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Promoter Regions, Genetic/genetics ; Brain/metabolism/pathology ; Polymorphism, Single Nucleotide ; }, abstract = {Genome-wide association studies have identified thousands of common variants associated with an increased risk of neurodegenerative disorders. However, the noncoding localization of these variants has made the assignment of target genes for brain cell types challenging. Genomic approaches that infer chromosomal 3D architecture can link noncoding risk variants and distal gene regulatory elements such as enhancers to gene promoters. By using enhancer-to-promoter interactome maps for human microglia, neurons, and oligodendrocytes, we identified cell-type-specific enrichment of genetic heritability for brain disorders through stratified linkage disequilibrium score regression. Our analysis suggests that genetic heritability for multiple neurodegenerative disorders is enriched at microglial chromatin contact sites, while schizophrenia heritability is predominantly enriched at chromatin contact sites in neurons followed by oligodendrocytes. Through Hi-C coupled multimarker analysis of genomic annotation (H-MAGMA), we identified disease risk genes for Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and schizophrenia. We found that disease-risk genes were overrepresented in microglia compared to other brain cell types across neurodegenerative conditions and within neurons for schizophrenia. Notably, the microglial risk genes and pathways identified were largely specific to each disease. Our findings reinforce microglia as an important, genetically informed cell type for therapeutic interventions in neurodegenerative conditions and highlight potentially targetable disease-relevant pathways.}, } @article {pmid40203806, year = {2025}, author = {Johnson, AM and Lukens, JR}, title = {Glia get RIPped in ALS.}, journal = {Immunity}, volume = {58}, number = {4}, pages = {778-780}, doi = {10.1016/j.immuni.2025.03.013}, pmid = {40203806}, issn = {1097-4180}, support = {F31 AG089911/AG/NIA NIH HHS/United States ; RF1 AG078684/AG/NIA NIH HHS/United States ; T32 NS115657/NS/NINDS NIH HHS/United States ; R01 AG087406/AG/NIA NIH HHS/United States ; R01 AG071996/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/pathology/metabolism ; Humans ; Animals ; *Neuroglia/immunology/metabolism ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/immunology ; *Microglia/immunology/metabolism ; *Astrocytes/immunology/metabolism ; Mice ; Neuroinflammatory Diseases/immunology ; Disease Models, Animal ; }, abstract = {While neuroinflammatory responses driven by microglia and astrocytes have been extensively linked to neurodegenerative disease progression in amyotrophic lateral sclerosis (ALS), the specific pathways that coordinate glial cell-dependent neuroinflammation in ALS remain poorly defined. In this issue of Immunity, Zelic et al.[1] identified RIPK1 as a pivotal regulator of glial cell-driven neuroinflammation in multiple ALS models.}, } @article {pmid40203833, year = {2025}, author = {Shen, D and Vincent, A and Udine, E and Buhidma, Y and Anoar, S and Tsintzas, E and Maeland, M and Xu, D and Carcolé, M and Osumi-Sutherland, D and Aleyakpo, B and Hull, A and Martínez Corrales, G and Woodling, N and Rademakers, R and Isaacs, AM and Frigerio, C and van Blitterswijk, M and Lashley, T and Niccoli, T}, title = {Differential neuronal vulnerability to C9orf72 repeat expansion driven by Xbp1-induced endoplasmic reticulum-associated degradation.}, journal = {Cell reports}, volume = {44}, number = {4}, pages = {115459}, doi = {10.1016/j.celrep.2025.115459}, pmid = {40203833}, issn = {2211-1247}, mesh = {Animals ; *Neurons/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *X-Box Binding Protein 1/metabolism/genetics ; *Drosophila Proteins/metabolism/genetics ; Drosophila melanogaster/metabolism/genetics ; *Endoplasmic Reticulum/metabolism ; *DNA Repeat Expansion/genetics ; Humans ; Unfolded Protein Response ; Disease Models, Animal ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Proteolysis ; DNA-Binding Proteins ; }, abstract = {Neurodegenerative diseases are characterized by the localized loss of neurons. Why cell death is triggered only in specific neuronal populations and whether it is the response to toxic insults or the initial cellular state that determines their vulnerability is unknown. To understand individual cell responses to disease, we profiled their transcriptional signatures throughout disease development in a Drosophila model of C9orf72 (G4C2) repeat expansion (C9), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. We identified neuronal populations specifically vulnerable or resistant to C9 expression and found an upregulation of protein homeostasis pathways in resistant neurons at baseline. Overexpression of Xbp1s, a key regulator of the unfolded protein response and a central node in the resistance network, rescues C9 toxicity. This study shows that neuronal vulnerability depends on the intrinsic transcriptional state of neurons and that leveraging resistant neurons' properties can boost resistance in vulnerable neurons.}, } @article {pmid40204667, year = {2025}, author = {Parajuli, S and McDonald, MR and Adhikari, L and Wolyn, DJ}, title = {Genetic architecture of anthocyanin pigment traits and purple spot (Stemphylium vesicarium) resistance in an F1 pseudo-testcross population of asparagus.}, journal = {The plant genome}, volume = {18}, number = {2}, pages = {e70028}, pmid = {40204667}, issn = {1940-3372}, support = {ASC-18/19//Canadian Agri-Science Cluster for Horticulture 3/ ; //Asparagus Farmers of Ontario/ ; //Agriculture and Agri-Food Canada/ ; UofGT2-2019-27360//Ontario Ministry of Agriculture Food and Rural Affairs/ ; }, mesh = {*Anthocyanins/genetics/metabolism ; Quantitative Trait Loci ; *Plant Diseases/microbiology/genetics ; *Disease Resistance/genetics ; *Asparagus Plant/genetics/microbiology/metabolism ; *Ascomycota/pathogenicity/physiology ; Phenotype ; Crosses, Genetic ; Plant Leaves/genetics/microbiology ; }, abstract = {Stemphylium vesicarium (Wallr.) Simmons is a plant pathogenic fungus causing purple spot in both fern and spears of asparagus (Asparagus officinalis L.). Although the fern can be sprayed with fungicides to control the disease, pesticide applications during spear harvest are restricted. Infected spears can develop prominent pigmentation at lesion sites, reducing marketable yield. Breeding resistant asparagus cultivars with decreased lesion numbers and reduced purpling at the site of infection is considered the most economical and sustainable approach to combat this disease. The objectives of this study were to determine the genetic architectures of, and relationships among, anthocyanin pigment expression in spear scale leaves (ALS) and spear lesions (APS) and purple spot levels in spears (NPS) and fern (PSF). Traits were phenotyped over 2 years under natural conditions in an F1 pseudo-testcross population, and quantitative trait loci (QTL) were mapped. ALS, APS, NPS, and PSF were not correlated, suggesting independent regulation of the anthocyanin pathway in scale leaves and lesions and no relationship between pigment and disease. Segregation, 3 red:1 purple and 3 red:13 purple, was observed in scale leaves and lesions, respectively. Two stable QTL for each of ASL, APS, and NPS, one tentative QTL for ASL, four tentative QTL for APS, two tentative QTL for NPS, and three tentative QTL for PSF were identified. Candidate genes were found for four loci. This study advances the genetic understanding of anthocyanin pigmentation at a tissue-specific level, and purple spot disease severity in spears and fern, supporting future breeding efforts.}, } @article {pmid40204975, year = {2025}, author = {Wolmer, PS and de Borba, FC and de Rezende, TJR and González-Salazar, C and Pedroso, JL and Barsottini, OGP and Kleinerova, J and Bede, P and Marques, W and França, MC}, title = {Distinct patterns of cerebral and spinal pathology along the spectrum of ATXN2-related disorders.}, journal = {Journal of neurology}, volume = {272}, number = {5}, pages = {330}, pmid = {40204975}, issn = {1432-1459}, support = {2013/07559-3//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; }, mesh = {Humans ; Male ; *Ataxin-2/genetics ; Female ; Middle Aged ; *Spinocerebellar Ataxias/pathology/genetics/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/pathology/genetics/diagnostic imaging ; Adult ; Magnetic Resonance Imaging ; Aged ; *Spinal Cord/pathology/diagnostic imaging ; *Brain/pathology/diagnostic imaging ; Neuroimaging ; }, abstract = {BACKGROUND: The ATXN2 gene contains a polymorphic CAG-rich region encoding a polyglutamine tract in ataxin- 2. Normal alleles have fewer than 27 CAG repeats, 27-34 repeats pose a risk for ALS (ATXN2-ALS), and > 34 repeats cause spinocerebellar ataxia type 2 (SCA2). The striking phenotypic differences between these two ATXN2-related conditions are not yet fully understood.

OBJECTIVE: To characterize and compare the distinguishing radiological signatures of ATXN2-ALS, SCA2, sporadic ALS (sALS) and healthy controls in vivo using quantitative computational neuroimaging techniques.

METHODS: Four groups were defined: healthy controls (n = 34), sALS (n = 17), ATXN2-ALS (n = 16), and SCA2 (n = 17). Cortical, subcortical, brainstem, cerebellar and spinal regions were segmented based on T1-weighted data using validated segmentation tools and their volumes estimated. Group-specific morphometric data were correlated with cerebral ATXN2 expression maps from the Allen Human Brain Atlas.

RESULTS: Study groups were age and sex-matched. sALS, ATXN2-ALS and SCA2 have distinct structural CNS signatures, with disease burden restricted to the precentral gyri in the sALS group, to the spinal cord and brainstem in the ATXN2-ALS group and more diffusely distributed in the subcortical structures in the SCA2 group. Brain ATXN2 expression correlated with the structural signature of SCA2, but not with that of ATXN2-ALS.

CONCLUSIONS: Neuroimaging signatures differ in ATXN2-ALS and SCA2, indicating distinct mechanisms of ATXN2-mediated neurodegeneration. sALS and ATXN2-ALS also exhibit distinct patterns of CNS involvement. The unique imaging signatures and clinical profiles along the spectrum of ATXN2-related disorders raise important questions regarding the pathophysiology of the disease and have practical clinical ramifications.}, } @article {pmid40205152, year = {2025}, author = {Mohan, M and Mannan, A and Singh, TG}, title = {Unravelling the role of protein kinase R (PKR) in neurodegenerative disease: a review.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {377}, pmid = {40205152}, issn = {1573-4978}, mesh = {Humans ; *eIF-2 Kinase/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics ; Animals ; Parkinson Disease/metabolism/genetics ; Huntington Disease/genetics/metabolism ; Alzheimer Disease/metabolism/genetics ; Mitochondria/metabolism ; }, abstract = {Protein Kinase R is an essential regulator of many cell activities and belongs to one of the largest and most functionally complex gene families. These are found all over the body, and by adding phosphate groups to the substrate proteins, they regulate their activity and coordinate the action of almost all cellular processes. Recent research has illuminated the involvement of PKR in the pathogenesis of neurodegenerative disorders (NDs), thereby expanding our understanding of intricate molecular mechanisms underlying disease progression. Through their inhibition or activation, they hold potential therapeutic targets for the pathogenesis or protection of NDs. In the case of AD (AD), PKR contributes to the protection or elevation of Aβ accumulation, neuroinflammation, synaptic plasticity alterations, and neuronal excitability. Similarly, in Parkinson's disease (PD), PKR again has a dual role in dopaminergic neuronal loss, gene mutations, and mitochondrial dysfunction via various pathways. Notably, neuronal excitotoxicity, as well as genetic mutations, have been linked to ALS. In Huntington's disease (HD), PKR is associated with decreased or increased mutated genes, striatal neuron degeneration, neuroinflammation, and excitotoxicity. This review emphasizes strategies that target PKR for the treatment of neurodegenerative disorders. Doing so offers valuable insights that can guide future research endeavors and the development of innovative therapeutic approaches.}, } @article {pmid40207633, year = {2025}, author = {Luteijn, MJ and Bhaskar, V and Trojer, D and Schürz, M and Mahboubi, H and Handl, C and Pizzato, N and Pfeifer, M and Dafinca, R and Voshol, H and Giorgetti, E and Manneville, C and Garnier, IPM and Müller, M and Zeng, F and Buntin, K and Markwalder, R and Schröder, H and Weiler, J and Khar, D and Schuhmann, T and Groot-Kormelink, PJ and Keller, CG and Farmer, P and MacKay, A and Beibel, M and Roma, G and D'Ario, G and Merkl, C and Schebesta, M and Hild, M and Elwood, F and Vahsen, BF and Ripin, N and Clery, A and Allain, F and Labow, M and Gabriel, D and Chao, JA and Talbot, K and Nash, M and Hunziker, J and Meisner-Kober, NC}, title = {High-throughput screen of 100 000 small molecules in C9ORF72 ALS neurons identifies spliceosome modulators that mobilize G4C2 repeat RNA into nuclear export and repeat associated non-canonical translation.}, journal = {Nucleic acids research}, volume = {53}, number = {7}, pages = {}, pmid = {40207633}, issn = {1362-4962}, support = {EFRE/IWB 20102-F1900731-KZP//European Funds for Regional Development/ ; WISS2025 F2200397-KZP//Salzburger Landesregierung/ ; }, mesh = {Humans ; *Spliceosomes/drug effects/metabolism/genetics ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Protein Biosynthesis/drug effects ; Active Transport, Cell Nucleus/drug effects ; Serine-Arginine Splicing Factors/metabolism ; *Neurons/metabolism/drug effects ; High-Throughput Screening Assays ; *Small Molecule Libraries/pharmacology ; DNA Repeat Expansion ; RNA/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Cell Nucleus/metabolism ; }, abstract = {An intronic G4C2 repeat expansion in the C9ORF72 gene is the major known cause for Amyotrophic Lateral Sclerosis (ALS), with current evidence for both, loss of function and pathological gain of function disease mechanisms. We screened 96 200 small molecules in C9ORF72 patient iPS neurons for modulation of nuclear G4C2 RNA foci and identified 82 validated hits, including the Brd4 inhibitor JQ1 as well as novel analogs of Spliceostatin-A, a known modulator of SF3B1, the branch point binding protein of the U2-snRNP. Spliceosome modulation by these SF3B1 targeted compounds recruits SRSF1 to nuclear G4C2 RNA, mobilizing it from RNA foci into nucleocytoplasmic export. This leads to increased repeat-associated non-canonical (RAN) translation and ultimately, enhanced cell toxicity. Our data (i) provide a new pharmacological entry point with novel as well as known, publicly available tool compounds for dissection of C9ORF72 pathobiology in C9ORF72 ALS models, (ii) allowing to differentially modulate RNA foci versus RAN translation, and (iii) suggest that therapeutic RNA foci elimination strategies warrant caution due to a potential storage function, counteracting translation into toxic dipeptide repeat polyproteins. Instead, our data support modulation of nuclear export via SRSF1 or SR protein kinases as possible targets for future pharmacological drug discovery.}, } @article {pmid40209306, year = {2025}, author = {Meanti, R and Bresciani, E and Rizzi, L and Molteni, L and Coco, S and Omeljaniuk, RJ and Torsello, A}, title = {Cannabinoid Receptor 2 (CB2R) as potential target for the pharmacological treatment of neurodegenerative diseases.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {186}, number = {}, pages = {118044}, doi = {10.1016/j.biopha.2025.118044}, pmid = {40209306}, issn = {1950-6007}, mesh = {Humans ; *Receptor, Cannabinoid, CB2/metabolism/agonists ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Endocannabinoids/metabolism ; Molecular Targeted Therapy ; Cannabinoid Receptor Agonists/therapeutic use ; }, abstract = {The endocannabinoid system (ECS) is a ubiquitous physiological system that plays a crucial role in maintaining CNS homeostasis and regulating its functions. It includes cannabinoid receptors (CBRs), endogenous cannabinoids (eCBs), and the enzymes responsible for their synthesis and degradation. In recent years, growing evidence has highlighted the therapeutic potential of the ECS and CBRs, in a wide range of severe diseases and pathological conditions, including Alzheimer's and Parkinson's diseases, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Huntington's Disease, HIV-1 associated neurocognitive disorders, neuropathic pain and migraine. Targeting the cannabinoid type 2 receptor (CB2R) has gained attention due to its ability to (i) mitigate neuroinflammatory responses, (ii) regulate mitochondrial function and (iii) provide trophic support, all without eliciting the psychotropic actions associated with CB1R activation. This review aims to explore the potential of CB2R modulation as a strategy for the prevention and treatment of neurologic disorders, exploring both preclinical and clinical findings.}, } @article {pmid40209696, year = {2025}, author = {Nashwan, AJ and Hawas, Y and Hamad, AA and Meshref, M and Elbehary, M and Mohamed, RG and Elshahat, A and Mabrouk, MA and Nashwan, AJ and Fouda, BH}, title = {Clinical Features, Diagnostic Implications, and Outcomes of Amyotrophic Lateral Sclerosis and Myasthenia Gravis Overlap Syndrome: A Systematic Review.}, journal = {Medical principles and practice : international journal of the Kuwait University, Health Science Centre}, volume = {34}, number = {5}, pages = {432-442}, pmid = {40209696}, issn = {1423-0151}, mesh = {Humans ; *Myasthenia Gravis/diagnosis/complications/physiopathology/epidemiology/therapy ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/physiopathology/therapy/epidemiology ; Middle Aged ; Aged ; Adult ; Aged, 80 and over ; Male ; }, abstract = {UNLABELLED:

Objective: This review aimed to summarize the current evidence of reported myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) overlap syndrome regarding clinical and laboratory features, diagnostic implications, management, outcomes, and comorbid conditions to raise awareness among healthcare providers and aid in proper care provision.

METHODS: Recently, a few cases of an unusual association between both diseases have been reported. PubMed, Scopus, and Web of Science were searched from inception until May 2024 to identify eligible studies. After the screening and data extraction, 20 studies with 42 cases suffering from ALS and MG were included.

RESULTS: Forty-two cases were categorized into four groups as follows: the first group had 26 cases with MG onset (age range 26-82 years) preceding ALS (age range 46-83 years). The second group had 9 cases with ALS onset (age range 34-89 years) preceding MG (age range 40-89 years). The third group comprised 5 cases of ALS with positive acetylcholine receptor antibodies but without clinical manifestations of MG. The fourth group involved 2 cases of ALS with initial ocular symptoms that were unresponsive to MG treatments.

CONCLUSION: The onset of new ptosis or diplopia in ALS patients should prompt clinicians to consider the possibility of a coexisting condition or alternative diagnosis. Additionally, positive acetylcholine receptor antibodies alone are insufficient to diagnose MG if ALS coexists. In patients with ALS, repetitive nerve stimulation tests may be less sensitive for detecting MG. Thus, diagnosing MG in ALS patients should rely on clinical presentation and response to empirical treatment.

.}, } @article {pmid40210682, year = {2025}, author = {Perciballi, E and Bovio, F and Ferro, S and Forcella, M and Rosati, J and Carletti, RM and D'Anzi, A and Gelati, M and La Bella, V and Innocenti, M and Spataro, R and Pecoraro, M and Lombardi, I and Vulcano, E and Ruotolo, G and Mercurio, S and Sabatelli, M and Lattante, S and Malm, T and Ohtonen, S and Vescovi, AL and Fusi, P and Ferrari, D}, title = {Mitochondrial and energy metabolism dysfunctions are hallmarks of TDP-43[G376D] fibroblasts from members of an Amyotrophic Lateral Sclerosis family.}, journal = {Cell death & disease}, volume = {16}, number = {1}, pages = {272}, pmid = {40210682}, issn = {2041-4889}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Fibroblasts/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; *Mitochondria/metabolism/pathology/genetics ; *Energy Metabolism/genetics ; Male ; Female ; Middle Aged ; Mutation/genetics ; Glycolysis ; Pedigree ; Adult ; Cell Proliferation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease, causing degeneration of motor neurons, paralysis, and death. About 5-10% of cases are associated with gene mutations inherited from a family member (fALS). Among them, mutations in the transactive-response (TAR)-DNA-binding protein (TARDBP), which encodes for the TAR DNA binding protein 43 (TDP-43) are responsible for 4-5% of fALS but the molecular mechanisms that initiate and sustain the neurodegenerative process are largely unknown. Metabolic impairments might be involved in the pathogenesis of ALS and are currently under investigation. In order to correlate biochemical and metabolic alterations with disease progression, here, we established the metabolic fingerprint of dermal fibroblasts derived from symptomatic and asymptomatic members of a family with fALS cases carrying to the p.G376D mutation in TDP-43. We found that increased proliferation, unbalanced oxidative homeostasis and higher ATP production rate coupled with enhanced metabolic activity are underlying traits of this family. Fibroblasts from carrier individuals deploy several mechanisms to increase mitochondrial respiration to meet increasing energy demands. This is accompanied by an upregulation of glycolysis corresponding to a metabolic reprograming towards a glycolytic phenotype for ATP production during ALS progression, particularly in late disease stages. In summary, we uncover alterations in energy metabolism in TDP43[G376D] patient-derived primary fibroblasts that may be used as risk biomarkers and/or to monitor ALS progression.}, } @article {pmid40210846, year = {2025}, author = {Joyce, EE and Yin, W and Löf, M and Wirdefeldt, K and Sandin, S and Fang, F}, title = {Mediterranean dietary pattern and risk of neurodegenerative diseases in a cohort of Swedish women.}, journal = {NPJ Parkinson's disease}, volume = {11}, number = {1}, pages = {71}, pmid = {40210846}, issn = {2373-8057}, support = {R01 TS000324/TS/ATSDR CDC HHS/United States ; 802091/ERC_/European Research Council/International ; 2019-01088//Vetenskapsrådet/ ; R01TS000324-01-00/CC/CDC HHS/United States ; }, abstract = {Mediterranean dietary patterns (MDP) may be neuroprotective. Using a large population-based cohort of 42,582 Swedish women, this study examined the association between MDP adherence and the risk of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). During 1991-1992, women in the Women's Lifestyle and Health Study reported dietary intake, and MDP adherence was calculated. Incident neurodegenerative diseases were identified using the Swedish National Patient Register through 2022. Women who reported high MDP adherence had a lower risk of PD (HR: 0.69, 95% CI: 0.49-0.95), primarily over age 60 (HR: 0.68, 95% CI: 0.47-0.97). A moderate-high MDP adherence was associated with a lower risk of ALS before age 60 (HR: 0.44, 95% CI: 0.19-0.99), but not overall. We observed no association between MDP adherence and AD. Our findings suggest higher adherence to a MDP may be protective against PD above age 60, and ALS before age 60.}, } @article {pmid40212027, year = {2025}, author = {Menezes, AT and Nagasse, HY and Lopes, HRM and Coltri, PP}, title = {Design of a GFP reporter for splicing analysis in mammalian cells.}, journal = {Biotechnology reports (Amsterdam, Netherlands)}, volume = {46}, number = {}, pages = {e00887}, pmid = {40212027}, issn = {2215-017X}, abstract = {Eukaryotic genes are formed by exons and introns. Pre-mRNA splicing promotes exon ligation and intron removal and is performed by a specialized macromolecular machinery named spliceosome, composed of five small ribonucleoprotein particles (snRNPs) and more than one hundred proteins. The activity of this complex is highly accurate due to the coordinated activity of its components. Altered splicing has been related to the development of several diseases, including neurodegenerative disorders, such as amyotrophic lateral sclerosis, and different types of cancer. Detailed understanding of splicing regulation in eukaryotic cells can be achieved using splicing reporter systems. We designed a reporter plasmid suitable for splicing analysis in cultured mammalian cells. Our reporter is based on GFP expression, and the splicing outcome can be easily visualized by fluorescence microscopy. We quantified splicing activity in two human cell lines, HEK-293T and MDA-MB-231, confirming its suitability for use in live cells in culture.}, } @article {pmid40212206, year = {2025}, author = {Basnet, P and Singh, PR and Pudasaini, KR and Shrestha, S and Kc, A}, title = {A rare case of symmetric quadriplegia in a patient with Japanese encephalitis: a case report.}, journal = {Annals of medicine and surgery (2012)}, volume = {87}, number = {4}, pages = {2430-2433}, pmid = {40212206}, issn = {2049-0801}, abstract = {INTRODUCTION AND IMPORTANCE: Acute flaccid paralysis is a rare neurological complication of Japanese encephalitis (JE) infection, which may involve one or multiple limbs. Symmetric involvement of upper and lower limbs such as in this case is rarely reported.

PRESENTATION OF CASE: We present a case of a 30-year-old male from Terai region of Nepal who presented with fever, altered level of consciousness, and symmetrical quadriplegia. Based on these clinical findings, cerebrospinal fluid (CSF) analysis was done which came back negative. And based on results, polymerase chain reaction for herpes simplex virus types I and II was done which came out negative. Other neurological conditions such as amyotrophic lateral sclerosis and spinal dystrophy were ruled out because of the presence of fever and altered mental status. He was eventually diagnosed with JE based on his CSF analysis and positive result for JE serology/IgM Antibody Capture Enzyme-Linked Immunosorbent Assay test.

CLINICAL DISCUSSION: The patient presented with fever, altered mental status, and symmetrical flaccid paralysis of the bilateral upper and lower limb. Symmetrical involvement of the upper and the lower limbs is unusual in most cases of JE.

CONCLUSION: This case highlights the importance of awareness on the part of the clinician about the possibilities of atypical presentation in JE. It also emphasizes that Japanese encephalitis should be a part of the differential in patients with atypical neurological presentation in endemic areas.}, } @article {pmid40213632, year = {2025}, author = {Dezawa, M}, title = {Macrophage- and pluripotent-like reparative Muse cells are unique endogenous stem cells distinct from other somatic stem cells.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {13}, number = {}, pages = {1553382}, pmid = {40213632}, issn = {2296-4185}, abstract = {Muse cells are endogenous reparative stem cells with dual characteristics: pluripotent-like and macrophage-like. They can be identified by the pluripotent surface marker stage-specific embryonic antigen-3-positive (SSEA-3 (+)) cells in the bone marrow, peripheral blood, and various organs, including the umbilical cord and amnion. Muse cells can differentiate into ectodermal, endodermal, and mesodermal lineage cells, self-renew, and selectively migrate to damaged sites by sensing one of the universal tissue damage signals, sphingosine-1-phosphate (S1P). At these sites, they phagocytose damaged/apoptotic cells and differentiate into the same cell type as the phagocytosed cells. In this manner, Muse cells replace damaged/apoptotic cells with healthy, functioning cells, thereby repairing tissues. Due to their specific immunosuppressive and immunotolerant mechanism, clinical trials have been conducted for acute myocardial infarction (AMI), subacute ischemic stroke, epidermolysis bullosa, amyotrophic lateral sclerosis (ALS), cervical spinal cord injury, neonatal hypoxic-ischemic encephalopathy (HIE), and COVID-19 acute respiratory distress syndrome. These trials involved the intravenous injection of ∼1.5 × 10[7] donor Muse cells without human leukocyte antigen (HLA) matching or immunosuppressant treatment, and they demonstrated safety and therapeutic efficacy. Thus, donor Muse cell treatment does not require gene manipulation, differentiation induction, or surgical intervention. These unique characteristics distinguish Muse cells from other somatic stem cells, such as mesenchymal stem cells, VSEL stem cells, and marrow-isolated adult multi-lineage inducible (MIAMI) cells.}, } @article {pmid40213728, year = {2025}, author = {Grigore, A and Goebel, LJ}, title = {Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: A Case Report and Clinical Insights.}, journal = {Cureus}, volume = {17}, number = {3}, pages = {e80329}, pmid = {40213728}, issn = {2168-8184}, abstract = {Primary care providers are often the first contact for patients with neurodegenerative illnesses, however, they may not be aware of the relationship of certain diseases that may have an impact on their patients' longevity. This case report reminds clinicians of the association between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Physicians should be aware of the association, because FTD commonly occurs first and may prepare clinicians to be alert to the signs of ALS in these patients, leading to earlier detection of ALS and the prescription of disease-modifying medication that may extend the lifespan of people with these diseases. We describe the case of a 61-year-old female patient initially presenting with cognitive decline most likely due to FTD who subsequently developed ALS.}, } @article {pmid40214138, year = {2025}, author = {Reus, LM and Willemse, SW and de Boer, SCM and De Houwer, J and Hartog, WL and Mol, MO and van Rooij, JGJ and Tesi, N and Donker Kaat, L and Hulsman, M and Vijverberg, EGB and Holstege, H and van Rheenen, W and Veldink, JH and van den Berg, LH and van Swieten, JC and Seelaar, H and van der Lee, SJ and van Es, MA and Pijnenburg, YAL}, title = {UNC13A Polymorphism Influences Survival in Patients with Frontotemporal Dementia.}, journal = {Annals of neurology}, volume = {97}, number = {6}, pages = {1062-1066}, pmid = {40214138}, issn = {1531-8249}, mesh = {Humans ; *Frontotemporal Dementia/genetics/mortality ; Male ; Female ; Middle Aged ; Aged ; *Nerve Tissue Proteins/genetics ; *Polymorphism, Single Nucleotide/genetics ; Genotype ; }, abstract = {UNC13A (rs12608932-CC) is associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and shortens survival in ALS. We aim to describe the association for UNC13A and survival in FTD. We included 626 patients with FTD from Dutch memory clinics, including a subcohort of 150 patients with TDP-43 pathology. Survival analyses were performed using Cox proportional hazard models in a recessive manner. Homozygosity for rs12608932-C in UNC13A was associated with a shorter survival compared with other genotypes (hazard ratio [HR] = 1.28, 95% confidence interval [CI] = 1.02-1.60, p = 0.033), which has implications for patient counselling and trial design. ANN NEUROL 2025;97:1062-1066.}, } @article {pmid40214652, year = {2025}, author = {Yu, G and Liu, X and Huang, W and Wang, S and Zhan, J and Ma, L and Li, H and Lin, X and Liu, T and Amine, K and Li, H}, title = {Ferromagnetic Atomic d-p Orbital Hybridization for Promoting Al-S Batteries.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {37}, number = {24}, pages = {e2418784}, doi = {10.1002/adma.202418784}, pmid = {40214652}, issn = {1521-4095}, support = {tsqn202211118//Taishan Scholar Program of Shandong Province/ ; ZR2023YQ008//Excellent Youth Science Fund Project of Shandong China/ ; 2021KJ020//Outstanding Youth Innovation Team of Universities in Shandong Province/ ; 51804173//National Natural Science Foundation (NSFC) of China/ ; DE-SC0012704//Brookhaven National Laboratory under contract/ ; }, abstract = {Rechargeable aluminum-sulfur batteries (Al-S) are emerging as a promising alternative energy storage system beyond lithium-ion batteries due to their high energy density, abundant material resources, and economic efficiency. However, their practical application remains challenged by sluggish conversion kinetics, polysulfide shuttling, and low sulfur cathode utilization. While extensive studies have focused on enhancing polysulfide adsorption through catalytic strategies, the roles of electronic structure in dictating catalytic performance remain underexplored. Here, this work unveils the critical effect of unpaired electronic structure on the catalytic performance of single atom ferromagnetic transition metals through a systematic evaluation of three typical atomically dispersed ferromagnetic single atoms-Fe, Co, and Ni-supported on porous carbon (denoted as PC-SAFAs). Comprehensive characterizations and density functional theory (DFT) calculations reveal that the PC-SAFe catalysts, exhibiting the highest spin polarization arising from unpaired electrons, demonstrate the strongest interactions with polysulfide, thereby facilitating rapid and reversible polysulfide conversion reactions. Consequently, Al-S batteries incorporating the optimized PC-SAFe cathode achieve an impressive specific capacity of 508.8 mAh g[-1] at 1.0 A g[-1] after 500 cycles, along with much improved rate capability. This work provides a deeper understanding of the role of electronic structure in catalytic chemistry, and offers new insights for developing high-performance Al-S batteries.}, } @article {pmid40215589, year = {2025}, author = {Yaguchi, H and Miyagawa, S and Nakada, R and Yamamoto, S and Sakuta, K}, title = {Speech-swallow dissociation in velopharyngeal closure for differentiating amyotrophic lateral sclerosis and myasthenia gravis.}, journal = {Auris, nasus, larynx}, volume = {52}, number = {3}, pages = {239-242}, doi = {10.1016/j.anl.2025.03.003}, pmid = {40215589}, issn = {1879-1476}, mesh = {Humans ; Male ; Female ; Middle Aged ; Retrospective Studies ; Laryngoscopy ; *Myasthenia Gravis/diagnosis/physiopathology/complications ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; *Velopharyngeal Insufficiency/physiopathology/diagnosis/etiology ; Aged ; Diagnosis, Differential ; Adult ; *Deglutition Disorders/physiopathology/etiology ; Phonation ; Logistic Models ; *Speech ; }, abstract = {OBJECTIVE: Speech-swallow dissociation (SSD) in velopharyngeal closure on laryngoscopy is a sign of pseudobulbar palsy. We hypothesized that this finding could differentiate amyotrophic lateral sclerosis (ALS) from myasthenia gravis (MG). This study aimed to identify laryngoscopic findings useful in differentiating these two diseases.

METHODS: ALS and MG patients with bulbar symptoms who underwent fiberoptic laryngoscopy in our hospital were retrospectively examined. The following laryngoscopic items were evaluated: velopharyngeal incompetence (VPI) in phonation and swallowing, pharyngeal constriction, vocal cord movement, and salivary status.

RESULTS: One hundred seven patients (70 with ALS and 37 with MG) were included for analysis. The prevalence of VPI in phonation was significantly higher in the ALS group (40 % vs. 19 %; P = 0.027). The prevalence of SSD in velopharyngeal closure was also significantly higher in the ALS group (33 % vs. 3 %; P < 0.001). The other laryngoscopic findings did not differ between the groups. Multivariate logistic regression showed that SSD in velopharyngeal closure was independently associated with ALS (odds ratio, 26.64; 95 % confidence interval, 2.24-317.58; P = 0.009).

CONCLUSION: SSD in velopharyngeal closure is useful for differentiating ALS from MG.}, } @article {pmid40216201, year = {2025}, author = {Cagalinec, M and Mohd, A and Borecka, S and Bultynck, G and Choubey, V and Yanovsky-Dagan, S and Ezer, S and Gasperikova, D and Harel, T and Jurkovicova, D and Kaasik, A and Liévens, JC and Maurice, T and Peviani, M and Richard, EM and Skoda, J and Skopkova, M and Tarot, P and Van Gorp, R and Zvejniece, L and Delprat, B}, title = {Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.}, journal = {Biochimica et biophysica acta. Molecular cell research}, volume = {1872}, number = {5}, pages = {119954}, doi = {10.1016/j.bbamcr.2025.119954}, pmid = {40216201}, issn = {1879-2596}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/therapy/genetics ; *Endoplasmic Reticulum/metabolism/pathology ; *Mitochondria/metabolism/pathology ; *Neoplasms/metabolism/pathology/therapy/genetics ; Animals ; Receptors, sigma/metabolism ; Calcium Signaling ; Sigma-1 Receptor ; *Intracellular Membranes/metabolism ; Unfolded Protein Response ; Mitochondrial Membranes/metabolism ; }, abstract = {Membrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca[2+] signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca[2+], reactive oxygen species and lipids. Particularly, IP3 receptors, intracellular Ca[2+]-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.}, } @article {pmid40216746, year = {2025}, author = {Rezaei, A and Kocsis-Jutka, V and Gunes, ZI and Zeng, Q and Kislinger, G and Bauernschmitt, F and Isilgan, HB and Parisi, LR and Kaya, T and Franzenburg, S and Koppenbrink, J and Knogler, J and Arzberger, T and Farny, D and Nuscher, B and Katona, E and Dhingra, A and Yang, C and Gouna, G and LaClair, KD and Janjic, A and Enard, W and Zhou, Q and Hagan, N and Ofengeim, D and Beltrán, E and Gokce, O and Simons, M and Liebscher, S and Edbauer, D}, title = {Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {3442}, pmid = {40216746}, issn = {2041-1723}, support = {390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 407495230//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 423957469//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 101057649//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; 101117710//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; }, mesh = {Animals ; Female ; Mice ; *Oligodendroglia/metabolism/drug effects ; *Lipid Metabolism/drug effects/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy/pathology ; *C9orf72 Protein/genetics/metabolism ; Disease Models, Animal ; Male ; Cholesterol/metabolism ; Humans ; *2-Hydroxypropyl-beta-cyclodextrin/pharmacology ; Mice, Transgenic ; Myelin Sheath/metabolism ; Spinal Cord/metabolism/pathology ; Longevity/drug effects/genetics ; }, abstract = {Clinical and genetic research links altered cholesterol metabolism with ALS development and progression, yet pinpointing specific pathomechanisms remain challenging. We investigated how cholesterol dysmetabolism interacts with protein aggregation, demyelination, and neuronal loss in ALS. Bulk RNAseq transcriptomics showed decreased cholesterol biosynthesis and increased cholesterol export in ALS mouse models (GA-Nes, GA-Camk2a GA-CFP, rNLS8) and patient samples (spinal cord), suggesting an adaptive response to cholesterol overload. Consequently, we assessed the efficacy of the cholesterol-binding drug 2-hydroxypropyl-β-cyclodextrin (CD) in a fast-progressing C9orf72 ALS mouse model with extensive poly-GA expression and myelination deficits. CD treatment normalized cholesteryl ester levels, lowered neurofilament light chain levels, and prolonged lifespan in female but not male GA-Nes mice, without impacting poly-GA aggregates. Single nucleus transcriptomics indicated that CD primarily affected oligodendrocytes, significantly restored myelin gene expression, increased density of myelinated axons, inhibited the disease-associated oligodendrocyte response, and downregulated the lipid-associated genes Plin4 and ApoD. These results suggest that reducing excess free cholesterol in the CNS could be a viable ALS treatment strategy.}, } @article {pmid40217081, year = {2025}, author = {Baek, SH and Tae, WS and Auer, D and Kim, BJ}, title = {Brain diffusion tensor imaging changes linked to the split hand phenomenon in amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {12450}, pmid = {40217081}, issn = {2045-2322}, mesh = {*Diffusion Tensor Imaging ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *White Matter/diagnostic imaging/physiopathology ; Prospective Studies ; Nerve Conduction Studies ; Humans ; Male ; Female ; Aged ; Middle Aged ; Aged, 80 and over ; }, abstract = {The split-hand phenomenon is an early and specific feature of amyotrophic lateral sclerosis (ALS). This study aimed to investigate whether the split-hand phenomenon in ALS is associated with the white matter degeneration of the brain. Patients diagnosed with clinically definite or probable ALS were prospectively recruited and underwent both nerve conduction studies to assess the split-hand index (SHI) and brain diffusion tensor imaging (DTI). Demographic, clinical, and electrophysiological data were all collected. A total of 35 patients with ALS (18 male; median age, 66.0 years) were enrolled in this study. The axial diffusivity (AD) and mode of anisotropy (MO) values of DTI in the corticospinal tract (CST) positively correlated with the SHI. However, there were no significant correlations between the SHI and the fraction anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) scalars. In addition, patients having ALS with bilateral split-hand phenomenon showed reduced AD values in the left CST and reduced MO values in the bilateral CST compared with those without the split-hand phenomenon. However, there were no significant differences in FA, MD, and RD scalars. Our findings suggest that the split-hand phenomenon is associated with degenerative brain changes, particularly in the CST.}, } @article {pmid40218232, year = {2025}, author = {Iglesias, M and Cascón, JA and Maimó, A and Albaladejo, A and Andreo, F and Fernández, AS and Palazón, MM and González-Posada, IM and García, RG and Cordovilla, R}, title = {Evaluation of Diaphragmatic Ultrasound in Respiratory Functional Assessment in Patients with ALS.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {7}, pages = {}, pmid = {40218232}, issn = {2075-4418}, support = {becaPII2019//SOCIEDAD ESPAÑOLA DE NEUMOLOGÍA Y CIRUGÍA TORÁCICA (SEPAR)/ ; }, abstract = {Background: Diaphragmatic ultrasound emerges as a valuable non-invasive method for assessing diaphragm functionality in patients with amyotrophic lateral sclerosis (ALS). This study aimed to evaluate diaphragmatic ultrasound parameters in ALS, compare them with respiratory function tests, and determine whether they are associated with the need for non-invasive ventilation (NIV). Methods: This was a prospective, descriptive, and multicenter study across five centers, enrolling patients with recent diagnoses of ALS. At three-monthly visits, participants underwent both diaphragmatic ultrasound and pulmonary function testing. The following variables were analyzed: withdrawal from this study due to NIV or death, excursion, velocity, thickness, thickening fraction, and spirometric and respiratory muscle function values. Results: A total of 41 patients were included. A total of 24 (61.5%) patients left this study before the final year: 17 due to initiation of NIV, 4 due to clinical deterioration without NIV, and 3 due to death. Statistically significant moderate correlations were observed between diaphragmatic excursion and velocity and FVC and supine FVC (p < 0.001) and with MIP and the SNIP test (p < 0.05). No correlation was observed with thickening fraction. Additionally, lower baseline values in excursion were significantly associated with study withdrawal, along with reduced lung function (FVC, supine FVC, and MEP (p < 0.001). Conclusions: assessing diaphragmatic excursion by ultrasonography may serve as a useful tool for monitoring patients with ALS.}, } @article {pmid40219902, year = {2025}, author = {Lapp, HS and Günther, R}, title = {SOD1-ALS mimicking an inflammatory neuropathy: a case report.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {591-594}, doi = {10.1080/21678421.2025.2488296}, pmid = {40219902}, issn = {2167-9223}, mesh = {Humans ; Adult ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Diagnosis, Differential ; Male ; *Superoxide Dismutase-1/genetics ; Disease Progression ; }, abstract = {We present the case of a 36-year-old patient with a rapidly progressing SOD1-ALS, who was initially diagnosed as inflammatory acute motor axonal neuropathy due to contrast-enhancement of the lumbar spinal cord and a pure secondary motor neuron phenotype. Since the initiation of tofersen, disease progression and neurofilament levels impressively declined.}, } @article {pmid40220686, year = {2025}, author = {Coloma, L and Aramendia, J and Amigo, JM and Población, I and Alberquilla, F and Gorla, G and Huidobro, J and Torre-Fdez, I and Arana, G and Madariaga, JM}, title = {Analysis and interpretation of organic compounds in Martian meteorites with Raman imaging and chemometrics.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {338}, number = {}, pages = {126194}, doi = {10.1016/j.saa.2025.126194}, pmid = {40220686}, issn = {1873-3557}, abstract = {One of the focuses of the research being developed on Mars (and consequently in samples from Mars) is the detection and study of organic compounds. Perseverance rover, currently analysing the Martian surface, is equipped with top-level instrumentation to detect mostly organic molecules. One of the techniques being used is Raman spectroscopy, due to its capability to analyse both inorganic and organic compounds simultaneously and its non-destructive and non-invasive properties. Unfortunately, it becomes cumbersome to determine the belonging of specific Raman bands in complex mixtures composed of an undetermined number of organic and inorganic molecules. Therefore, the study of this mixed information must be carried out with dedicated Chemometrics methods in order to understand the number of compounds present in a mixture (using Principal Component Analysis - PCA) and to obtain the pure spectra and the relative intensity of each compound (using spectral unmixing methods like Multivariate Curve Resolution - MCR). This manuscript presents an analysis of specific areas from the NWA 6148 Martian Nakhlite using Raman imaging, coupled with principal component analysis (PCA) and multivariate curve resolution (MCR), to determine the spatial distribution and spectral signatures of all organic and inorganic molecules present in these areas. The proposed methodology could be applied to the laboratory study of the future Mars-returned samples and other extraterrestrial samples returned to Earth.}, } @article {pmid40220918, year = {2025}, author = {Key, J and Almaguer-Mederos, LE and Kandi, AR and Sen, NE and Gispert, S and Köpf, G and Meierhofer, D and Auburger, G}, title = {ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation.}, journal = {Neurobiology of disease}, volume = {209}, number = {}, pages = {106903}, doi = {10.1016/j.nbd.2025.106903}, pmid = {40220918}, issn = {1095-953X}, mesh = {Animals ; Mice ; *Ataxin-2/metabolism/genetics ; Humans ; *RNA-Binding Proteins/metabolism ; Fibroblasts/metabolism ; Spinocerebellar Ataxias/metabolism/genetics ; *Nerve Tissue Proteins/metabolism/genetics ; Peptides/metabolism/genetics ; Mice, Knockout ; }, abstract = {The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations in this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. In contrast, Ataxin-2-like (ATXN2L) is predominantly perinuclear, more abundant, and essential for embryonic life. Its sequestration into ATXN2 aggregates may contribute to disease. In this study, we utilized two approaches to clarify the roles of ATXN2L. First, we identified interactors through co-immunoprecipitation in both wild-type and ATXN2L-null murine embryonic fibroblasts. Second, we assessed the proteome profile effects using mass spectrometry in these cells. Additionally, we examined the accumulation of ATXN2L interactors in the SCA2 mouse model, Atxn2-CAG100-KnockIn (KIN). We observed that RNA-binding proteins, including PABPN1, NUFIP2, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, and HNRNPDL, exhibit a stronger association with ATXN2L compared to established interactors like ATXN2, PABPC1, LSM12, and G3BP2. Additionally, ATXN2L interacted with components of the actin complex, such as SYNE2, LMOD1, ACTA2, FYB, and GOLGA3. We noted that oxidative stress increased HNRNPK but decreased SYNE2 association, which likely reflects the relocalization of SG. Proteome profiling revealed that NUFIP2 and SYNE2 are depleted in ATXN2L-null fibroblasts. Furthermore, NUFIP2 homodimers and SYNE1 accumulate during the ATXN2 aggregation process in KIN 14-month-old spinal cord tissues. The functions of ATXN2L and its interactors are therefore critical in RNA granule trafficking and surveillance, particularly for the maintenance of differentiated neurons.}, } @article {pmid40222004, year = {2025}, author = {Oliveri, F and Bicaj, M and Cillerai, M and Cabona, C and Gemelli, C and Uccelli, A and Schenone, A and Ferraro, PM}, title = {Prevalence of cognitive impairment in motor neuron diseases: alternative norming methods lead to considerably diverse estimates.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {535-540}, doi = {10.1080/21678421.2025.2488294}, pmid = {40222004}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Cognitive Dysfunction/epidemiology/diagnosis/etiology ; Aged ; Prevalence ; *Motor Neuron Disease/epidemiology/complications/psychology ; Neuropsychological Tests ; Italy/epidemiology ; Amyotrophic Lateral Sclerosis/epidemiology ; Adult ; Aged, 80 and over ; }, abstract = {Objectives: Cognitive impairment (CI) is frequently observed in motor neuron diseases (MNDs), and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) represents the most widely used measure to evaluate it. For the Italian ECAS, two norming approaches are currently available: the "regression-based" (R) and the "2 standard deviation-based" (2SD). In this study, we therefore aimed at comparing those two methods for the detection of CI in MNDs. Methods: Raw ECAS scores from 160 MND patients were corrected using both the R and the 2SD methods. According to Strong's criteria, patients were then categorized as either cognitively normal (CN), with CI (ALSci), with behavioral impairment (ALSbi), or both (ALScbi). Results: Using the R approach, the frequency of below-cutoff performances was 3.12% for the ECAS total, 4.37% for the ALS specific, and 3.75% for the ALS nonspecific score. Using the 2SD method, the prevalence increased to 25.62% for the ECAS total, 21.25% for the ALS specific, and 23.12% for the ALS nonspecific score. The same increase was observed across all single tasks except for the digit span backward. The R-based frequency of Strong's diagnoses was 7.50% for ALSci, 15.62% for ALSbi, and 3.14% for ALScbi, which became 24.38% for ALSci, 8.75% for ALSbi and 10% for ALScbi with the 2SD method. Conclusions: The norming approach has a significant impact on the estimated prevalence of CI in MNDs, with the R method representing the most conservative one. These findings highlight the need for harmonized protocols in future studies evaluating CI in MNDs.}, } @article {pmid40222103, year = {2025}, author = {Lum, JS and Brown, ML and Farrawell, NE and Bartlett, R and Chisholm, CG and Gorman, J and Dosseto, A and Dux, F and McInnes, LE and Ecroyd, H and McAlary, L and Crouch, PJ and Donnelly, PS and Yerbury, JJ}, title = {A polytherapy approach demonstrates therapeutic efficacy for the treatment of SOD1 associated amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {115}, number = {}, pages = {105692}, pmid = {40222103}, issn = {2352-3964}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; Humans ; Organoselenium Compounds/pharmacology/administration & dosage/therapeutic use ; Isoindoles ; Animals ; Mice ; Azoles/pharmacology/administration & dosage ; Cell Line ; Drug Therapy, Combination ; Mutation ; Disease Models, Animal ; Cell Survival/drug effects ; Protein Folding ; Motor Neurons/metabolism/drug effects ; }, abstract = {BACKGROUND: SOD1 mutations are a significant contributor of familial amyotrophic lateral sclerosis (ALS) cases. SOD1 mutations increase the propensity for the protein to misfold and aggregate into insoluble proteinaceous deposits within motor neurons and neighbouring cells. The small molecule, CuATSM, has repeatedly shown in mouse models to be a promising therapeutic treatment for SOD1-associated ALS and is currently in Phase II/III clinical trials for the treatment of ALS. We have previously shown CuATSM stabilises various ALS-associated variants of the SOD1 protein, reducing misfolding and toxicity. Two additional FDA-approved small molecules, ebselen and telbivudine, have also been identified to reduce mutant SOD1 toxicity, providing additional potential therapeutic candidates that could be used in combination with CuATSM. Here, we aimed to investigate if CuATSM, ebselen and telbivudine (CET) polytherapy could improve on the therapeutic efficacy of CuATSM monotherapy for the treatment of SOD1-associated ALS.

METHODS: We utilised a 3D checkerboard approach to investigate whether a matrix of different concentrations CuATSM, ebselen and telbivudine could provide therapeutic improvements on cell survival, SOD1 folding and aggregation in SOD1[G93A]-transfected NSC-34 cells, compared to CuATSM alone. To progress the preclinical development of CET polytherapy, we evaluated the bioavailability and safety of in vivo polytherapy administration. Furthermore, we assessed and compared the effects of CET- and CuATSM-treatment on disease onset, motor function, survival and neuropathological features in SOD1[G93A] mice.

FINDINGS: CET polytherapy reduced inclusion formation and increased cell survival of NSC-34 cells overexpressing SOD1[G93A] compared to higher concentrations of CuATSM monotherapy. In addition, CET administration was bioavailable and tolerable in mice. CET treatment in SOD1[G93A] mice delayed disease onset, reduced motor impairments, and increased survival compared to vehicle- and CuATSM-treated mice. In line with these findings, biochemical analysis of lumbar spinal cords showed CET administration improved SOD1 folding, decreased misfolded SOD1 accumulation, and reduced motor neuron loss.

INTERPRETATION: These findings support CET polytherapy as an advantageous alternative compared to CuATSM monotherapy and highlight the potential of utilising small molecules targeting SOD1 as a polytherapy avenue for the treatment of SOD1-associated ALS.

FUNDING: This work was supported by a FightMND Drug Development Grant, an Australian National Health and Medical Research Council (NHMRC) Investigator Grant (No. 1194872) and a Motor Neuron Disease Research Institute of Australia Bill Gole Postdoctoral Fellowship.}, } @article {pmid40222791, year = {2025}, author = {Bhardwaj, I and Singh, S and Ansari, AH and Rai, SP and Singh, D}, title = {Effect of stress on neuronal cell: Morphological to molecular approach.}, journal = {Progress in brain research}, volume = {291}, number = {}, pages = {469-502}, doi = {10.1016/bs.pbr.2025.01.010}, pmid = {40222791}, issn = {1875-7855}, mesh = {Humans ; Animals ; *Neurons/pathology/metabolism/physiology ; *Stress, Psychological/pathology/metabolism ; *Brain/pathology ; }, abstract = {Stress can be characterized as any perceived or actual threat that necessitates compensatory actions to maintain homeostasis. It can alter an organism's behavior over time by permanently altering the composition and functionality of brain circuitry. The amygdala and prefrontal cortex are two interrelated brain regions that have been the focus of initial research on stress and brain structural and functional plasticity, with the hippocampus serving as the entry point for most of this knowledge. Prolonged stress causes significant morphological alterations in important brain regions such as the hippocampus, amygdala, and prefrontal cortex. Memory, learning, and emotional regulation are among the cognitive functions that are adversely affected by these changes, including neuronal shrinkage, dendritic retraction, and synaptic malfunction. Stress perturbs the equilibrium of neurotransmitters, neuronal plasticity, and mitochondrial function at the molecular level. On the other hand, chronic stress negatively impacts physiology and can result in neuropsychiatric diseases. Recent molecular research has linked various epigenetic processes, such as DNA methylation, histone modifications, and noncoding RNAs, to the dysregulation of genes in the impacted brain circuits responsible for the pathophysiology of chronic stress. Numerous disorders, including neurodegenerative diseases (NDDs) including Alzheimer's, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, multiple sclerosis, and Parkinson's disease, have been linked to oxidative stress as a possible cause.}, } @article {pmid40225153, year = {2023}, author = {Fiorini, MR and Dilliott, AA and Farhan, SMK}, title = {Evaluating the Utility of REVEL and CADD for Interpreting Variants in Amyotrophic Lateral Sclerosis Genes.}, journal = {Human mutation}, volume = {2023}, number = {}, pages = {8620557}, pmid = {40225153}, issn = {1098-1004}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Computational Biology/methods ; *Genetic Predisposition to Disease ; *Genetic Variation ; *Software ; Genetic Association Studies ; Mutation ; Databases, Genetic ; Genetic Testing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease affecting approximately two per 100,000 individuals globally. While there are many benefits to offering early genetic testing to people with ALS, this has also led to an increase in the yield of novel variants of uncertain significance in ALS-associated genes. Computational (in silico) predictors, including REVEL and CADD, are widely employed to provide supporting evidence of pathogenicity for variants in conjunction with clinical, molecular, and other genetic evidence. However, in silico predictors are developed to be broadly applied across the human genome; thus, their ability to evaluate the consequences of variation in ALS-associated genes remains unclear. To resolve this ambiguity, we surveyed 20 definitive and moderate ClinGen-defined ALS-associated genes from two large, open-access ALS sequencing datasets (total people with ALS = 8,230; controls = 9,671) to investigate REVEL and CADD's ability to predict which variants are most likely to be disease-causing in ALS. While our results indicate a predetermined pathogenicity threshold for REVEL that could be of clinical value for classifying variants in ALS-associated genes, an accurate threshold was not evident for CADD, and both in silico predictors were of limited value for resolving which variants of uncertain significance (VUS) may be likely pathogenic in ALS. Our findings allow us to provide important recommendations for the use of REVEL and CADD scores for variants and indicate that both tools should be used with caution when attempting to evaluate the pathogenicity of VUSs in ALS genetic testing.}, } @article {pmid40226510, year = {2025}, author = {Ufarry Alvarado, AJ and Zaidi Pons, MA and Plaza Hernández, J and Torres Ortiz, C}, title = {Improvements of Paraquat Treatment in Liquid Media for Behavior and Neurodegenerative Tests.}, journal = {microPublication biology}, volume = {2025}, number = {}, pages = {}, pmid = {40226510}, issn = {2578-9430}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a disease characterized by misfolded and aggregated proteins that have toxic effects on motor neurons. The missense mutation, G85R, of the sod-1 gene associated with ALS displays locomotor impairments in Caenorhadbitis elegans (C. elegans). We treated the sod-1 (G85R) strain with 0 and 2.5 mM Paraquat treatments in a liquid M9 buffer for 4 hours and in solid NGM media for 18 hours. In both methodologies, the locomotion defects and neurodegeneration were significantly increased with 2.5 mM Paraquat. Our work provides evidence of methodology that is more cost effective, rapid and reproducible to perform behavior and neurodegenerative assay in worms.}, } @article {pmid40228660, year = {2025}, author = {Veenstra, J and Ozog, D and Stephens, A}, title = {Response to Barbieri, "Response to Veenstra et al's 'Benzoyl peroxide acne treatment shows no significant association with benzene-related cancers: A multicenter retrospective analysis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {2}, pages = {e71-e72}, doi = {10.1016/j.jaad.2025.03.090}, pmid = {40228660}, issn = {1097-6787}, } @article {pmid40229296, year = {2025}, author = {Kumar, P and Bishnoi, R and Priyadarshini, P and Chhuneja, P and Singla, D}, title = {Understanding the structural basis of ALS mutations associated with resistance to sulfonylurea in wheat.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {12855}, pmid = {40229296}, issn = {2045-2322}, mesh = {*Acetolactate Synthase/genetics/chemistry/metabolism ; *Triticum/genetics/enzymology/drug effects ; *Sulfonylurea Compounds/pharmacology/chemistry ; *Herbicide Resistance/genetics ; Molecular Docking Simulation ; Herbicides/pharmacology ; *Plant Proteins/genetics/chemistry/metabolism ; Molecular Dynamics Simulation ; *Mutation ; Pyridines/pharmacology/chemistry ; }, abstract = {Developing herbicide-tolerant wheat varieties is highly desirable for effective weed management and improved crop yield. The enzyme acetolactate synthase (ALS) is the target enzyme for the sulfonylurea class of herbicides. The structural analysis of mutable sites in ALS is crucial for the generation of herbicide-resistant crops. Previous studies indicated that mutant lines of Triticum aestivum ALS (TaALS) with amino acid substitutions at P174, G631, and G632 residues provided resistance to sulfonylurea herbicide, nicosulfuron. The present study aimed to provide structural insights into mutable residues causing sulfonylurea herbicide resistance to TaALS enzyme through in-silico molecular docking and simulation approaches. The molecular docking analysis suggested a single point mutation at TaALS-P174S, its double mutant conformations (TaALS-G632S/P174S and TaALS-G631D/G632S) and associated triple mutant conformation (TaALS-G631D/G632S/P174S) to have the lowest binding affinity with nicosulfuron than the wild-type conformation of TaALS. Furthermore, the molecular dynamic simulation study confirms the weakest and more stable binding of the triple mutant conformation with nicosulfuron. Our computational study identifies a triple mutant conformation (TaALS-G631D/G632S/P174S) to be more effective in developing sulfonylurea herbicide-resistant wheat crops.}, } @article {pmid40229540, year = {2025}, author = {Ghimire, S and Kreilaus, F and Rosa Porto, R and Anderson, LL and Yerbury, JJ and Arnold, JC and Karl, T}, title = {Behavioural effects of oral cannabidiol (CBD) treatment in the superoxide dismutase 1 G93 A (SOD1[G93 A]) mouse model of amyotrophic lateral sclerosis.}, journal = {Psychopharmacology}, volume = {242}, number = {9}, pages = {2077-2095}, pmid = {40229540}, issn = {1432-2072}, mesh = {Animals ; *Cannabidiol/pharmacology/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/physiopathology/psychology ; Female ; Male ; Mice ; Disease Models, Animal ; Superoxide Dismutase-1/genetics ; Mice, Transgenic ; *Behavior, Animal/drug effects ; Social Behavior ; Administration, Oral ; Prepulse Inhibition/drug effects ; Fear/drug effects ; Mice, Inbred C57BL ; Motor Activity/drug effects ; Superoxide Dismutase ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting voluntary muscle movement as well as cognitive and other behavioural domains at later disease stages. No effective treatment for ALS is currently available. Elevated neuroinflammation, oxidative stress and alterations to the endocannabinoid system are evident in ALS. The phytocannabinoid cannabidiol (CBD) has anti-inflammatory and anti-oxidant properties. Thus, we evaluated the remedial effects of chronic oral cannabidiol (CBD) treatment on ALS-relevant behavioural domains in the copper-zinc superoxide dismutase 1 (SOD1) mouse model of ALS that carries a G93A mutation (SOD1[G93A]).

METHODS: Male and female SOD1[G93A] and wild type-like (WT) littermates were fed either a control (CHOW) or CBD-enriched chow diet (equivalent to a dose of 36 mg/kg per day) beginning from 10 weeks of age. Bodyweight and motor performance were recorded weekly from 11 to 19 weeks and open field behaviours at 12 and 18 weeks. Mice were also tested for prepulse inhibition (PPI), social behaviours, as well as fear-associated memory.

RESULTS: CBD treatment ameliorated the bodyweight loss in female SOD1[G93A] mice, tended to reinstate sociability in SOD1[G93A] males, strengthened social recognition memory in SOD1[G93A] females, and improved the PPI response in younger SOD1[G93A] females at higher prepulse intensities. CBD had no effect on motor impairments but instead reversed the anxiolytic-like phenotype of 12-week-old male SOD1[G93A] mice and decreased the acoustic startle response and strengthened cue freezing in male mice.

CONCLUSION: Thus, the current remedial oral dose of CBD delayed disease progression (inferred by bodyweight) in both male and female mice and improve specific cognitive deficits of SOD1[G93A] mice in a sex specific manner without altering the motor phenotype.}, } @article {pmid40229738, year = {2025}, author = {Abdoalsadig, E and Hamid, M and Peck, A and Johar, L and Kimonis, V}, title = {Utilization of CoRDS registry to monitor quality of life in patients with VCP multisystem proteinopathy.}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {178}, pmid = {40229738}, issn = {1750-1172}, support = {R01 AR050236/AR/NIAMS NIH HHS/United States ; }, mesh = {Humans ; Registries ; *Quality of Life ; Female ; Male ; *Valosin Containing Protein/genetics/metabolism ; Middle Aged ; Aged ; Myositis, Inclusion Body/genetics ; Adult ; Amyotrophic Lateral Sclerosis/genetics ; Osteitis Deformans/genetics ; Frontotemporal Dementia/genetics ; }, abstract = {BACKGROUND: VCP disease, also known as multisystem proteinopathy, is a rare, autosomal dominant, adult-onset, neuromuscular disease that is caused by variants in the valosin-containing protein (VCP) gene. VCP disease may exhibit one or more of the following primary features: inclusion body myopathy, Paget's disease of bone (PDB), Frontotemporal dementia, and amyotrophic lateral sclerosis. Due to its progressive nature, death normally occurs in their sixties due to respiratory and cardiac failure. The purpose of this study is to utilize the Cure VCP Disease patient registry hosted by the Coordination of Rare Diseases at Sanford (CoRDS) to conduct a prospective natural history study.

METHODS: Seventy-nine participants enrolled in the patient registry and answered demographic, VCP variant type, Patient-reported outcome measures (PROMs), and quality of life (QOL) questionnaires over the course of 3 years. We additionally investigated if any sex differences existed and if genotype-phenotype correlations affected the rate of progression of the varying clinical manifestations.

RESULTS: Overall, participants' mobility declined significantly as the disease progressed. Participants reported a 0.6% decline in upper extremity function, 1.2% decline in lower extremity function, and 0.3% decline in cognitive function per year of age. Furthermore, participants reported a 1.6% decline in upper and lower extremity function and a 0.1% decline in cognitive function per year of disease duration. The highest PROMs correlations were noted between overall health and lower extremity function, upper extremity function, fatigue, and the ability to perform vigorous activities. Genotype-phenotype correlations revealed no significant differences except for the absence of PDB in the p.Arg159Cys group.

CONCLUSION: The VCP CoRDS Registry was found to be a valuable tool for monitoring the QOL in patients with VCP disease and capturing patient perspectives for future clinical trials.}, } @article {pmid40230758, year = {2025}, author = {Bossei, AA and Al Zahrani, HA and Bossei, FA and Saadi, SM and Alsaedi, AS and Al Sulami, AQ and Al Asmari, EH and Aalam, AA and Khojah, IM}, title = {Emergency Physicians' Perceptions, Knowledge, and Attitudes Toward Family Presence During Resuscitation in the Emergency Department: A Multicenter Survey-Based Cross-Sectional Study.}, journal = {Cureus}, volume = {17}, number = {3}, pages = {e80612}, pmid = {40230758}, issn = {2168-8184}, abstract = {BACKGROUND: Cardiac arrest remains a significant public health issue, with high incidence rates in both in-hospital and out-of-hospital settings. The practice of family presence during resuscitation (FPDR) has gained attention for its potential benefits to patients and their families. This study evaluates the perceptions, knowledge, and attitudes of emergency physicians (EPs) regarding FPDR in the emergency department (ED) and aims to inform policy development at King Abdulaziz University Hospital in Jeddah, Saudi Arabia.

METHODS:  A multicenter cross-sectional study was conducted from January to April 2023, surveying EPs from multiple EDs across the western region of Saudi Arabia. Participants, certified in basic (BLS) or advanced life support (ALS), completed an anonymous online survey adapted from previous studies.

RESULTS: Our study surveyed 122 EPs, with 112 completing the survey. Of the participants, 49.1% were aged 25-29 years, 61.6% were men, and 58.9% had 1-4 years of work experience. Awareness of FPDR was reported by 67.9% (n = 76) of participants. Only 3.6% (n = 4) had a policy allowing FPDR, while 6.3% (n = 7) had a policy prohibiting it. Additionally, 49.1% (n = 55) supported implementing an FPDR policy. Awareness of FPDR was significantly higher among younger, male, and more experienced physicians (p < 0.05). Higher perception and practice scores were observed among those aware of FPDR, those who had participated in CPR with a family member, and those without a prohibiting policy (p < 0.05).

CONCLUSION: EPs in the western region of Saudi Arabia generally support FPDR, recognizing its potential benefits. However, concerns about its impact on performance and medicolegal issues warrant further exploration. To implement effective FPDR policies, these concerns must be addressed, along with efforts to promote awareness and training. Future research should expand to include broader healthcare settings and multidisciplinary teams to develop comprehensive, evidence-based guidelines.}, } @article {pmid40231293, year = {2025}, author = {Smyth, BR and Patwardhan, S and Turner, EL and McLintock, S}, title = {Using Functional Resonance Analysis Method (FRAM) Modelling to Assess the Factors That Slow or Prevent Clinicians in Performing Advanced Life Support (ALS) During Crash Calls to Park House Mental Health Hospital.}, journal = {Cureus}, volume = {17}, number = {4}, pages = {e82231}, pmid = {40231293}, issn = {2168-8184}, abstract = {This Quality Improvement Project (QIP) aimed to improve the response system for crash calls at Park House Mental Health Hospital, supported by the North Manchester General Hospital Crash Team. Using a functional resonance analysis method (FRAM), the team identified inefficiencies in the Advanced Life Support (ALS) process, with delayed responses increasing patient mortality risks. Interviews with staff helped create "work-as-imagined" (WAI) and "work-as-done" (WAD) models, highlighting the underperformed functions like ward entry protocols, and fully stocked crash trolleys. Recommendations, including access cards, stock changes, and live simulations, were implemented, in an aim to improve ALS provision.}, } @article {pmid40231507, year = {2025}, author = {Tecalco-Cruz, AC and Ramirez-Jarquin, JO and Medina Abreu, KH and Palacios-Serrato, EG and Lopez-Canovas, L and Zepeda-Cervantes, J and Oropeza-Martínez, E}, title = {Molecular Interplay of ISG15/ISGylation in Neuropathologies.}, journal = {CNS & neurological disorders drug targets}, volume = {24}, number = {10}, pages = {723-730}, pmid = {40231507}, issn = {1996-3181}, support = {CCyT-2024-CON-07//CCyT-UACM/ ; }, mesh = {Humans ; *Ubiquitins/metabolism ; Animals ; *Cytokines/metabolism ; *Neurodegenerative Diseases/metabolism ; }, abstract = {ISG15 is a 15 kDa ubiquitin-like protein that covalently associates with its target proteins by a sequential enzymatic process known as ISGylation. Research on protein ISGylation has increased in recent years, and some studies have suggested that ISG15 is involved in neuroprotection and neurodegeneration mechanisms. This review outlines the current state of research on the implications of ISG15/ISGylation in other neuropathies such as malignant tumors, ataxia telangiectasia, ischemia, depression, and neurodegenerative diseases such as Alzheimer's, Parkinson's diseases, multiple sclerosis, and amyotrophic lateral sclerosis. Based on the studies reported to date, ISG15/ ISGylation promotes the progression of brain tumors such as glioblastoma. Moreover, ISG15/ ISGylation seems to play a dual role in neuropathies, demonstrating a neuroprotective effect when there is acute brain damage, but ISG15/ISGylation is associated with reduced neuroprotection when there is chronic damage, such as in neurodegenerative diseases.}, } @article {pmid40232308, year = {2025}, author = {Wu, J and Xu, Y and Yin, T and Zhang, N and Fan, D and Ye, S}, title = {Unveiling structural damage of the corpus callosum in amyotrophic lateral sclerosis through diffusion tensor imaging and spread direction perspectives.}, journal = {Annals of medicine}, volume = {57}, number = {1}, pages = {2490822}, pmid = {40232308}, issn = {1365-2060}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/physiopathology ; *Corpus Callosum/pathology/diagnostic imaging ; *Diffusion Tensor Imaging/methods ; Male ; Female ; Middle Aged ; Aged ; Adult ; Motor Cortex/pathology/diagnostic imaging ; }, abstract = {OBJECTIVE: Damage to the corpus callosum (CC) in amyotrophic lateral sclerosis (ALS) patients has been confirmed via electrophysiological, neuroimaging, and autopsy studies. Additionally, the CC is hypothesized to serve as a pathway for the spread of pathological information. This study aimed to investigate whether the CC plays a mediating role in the symptomatic spread of ALS.

METHODS: In this observational study, diffusion tensor imaging (DTI) data were acquired from 45 individuals with the upper motor neuron-dominant (UMN-D) phenotype of ALS. The UMN-D ALS patients were categorized into two groups based on the direction of symptom spread, including 25 patients with horizontal spread (group H) and 20 patients with vertical spread (group V). Diffusivity indices were derived through whole-brain analysis and probabilistic fiber tracking.

RESULTS: According to the voxel-based analysis and tract-based spatial statistics, differences in axial diffusivity (AD) in the CC were observed between disease subgroups, with patients in group H showing higher AD values than those in group V. Fiber tracking analysis revealed persistent differences in the AD indices of CC-primary motor cortex (PMC) fibers between the two disease subgroups.

CONCLUSION: In UMN-D ALS patients, the direction of symptom spread may be related to the degree of CC involvement. The AD metric may be a more specific indicator of CC damage.}, } @article {pmid40232582, year = {2025}, author = {Mehrnoosh, F and Rezaei, D and Pakmehr, SA and Nataj, PG and Sattar, M and Shadi, M and Ali-Khiavi, P and Zare, F and Hjazi, A and Al-Aouadi, RFA and Sapayev, V and Zargari, F and Alkhathami, AG and Ahmadzadeh, R and Khedmatgozar, M and Hamzehzadeh, S}, title = {The role of Panax ginseng in neurodegenerative disorders: mechanisms, benefits, and future directions.}, journal = {Metabolic brain disease}, volume = {40}, number = {4}, pages = {183}, pmid = {40232582}, issn = {1573-7365}, mesh = {Humans ; *Panax ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Ginsenosides/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Plant Extracts/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Multiple sclerosis (MS), and Huntington's disease (HD) represent a growing global health challenge, especially with aging populations. Characterized by progressive neuronal loss, these diseases lead to cognitive, motor, and behavioral impairments, significantly impacting patients' quality of life. Current therapies largely address symptoms without halting disease progression, underscoring the need for innovative, disease-modifying treatments. Ginseng, a traditional herbal medicine with well-known adaptogenic and neuroprotective properties, has gained attention as a potential therapeutic agent for neurodegeneration. Rich in bioactive compounds called ginsenosides, ginseng exhibits antioxidant, anti-inflammatory, and anti-apoptotic effects, making it a promising candidate for addressing the complex pathology of neurodegenerative diseases. Recent studies demonstrate that ginsenosides modulate disease-related processes such as oxidative stress, protein aggregation, mitochondrial dysfunction, and inflammation. In AD models, ginsenosides have been shown to reduce amyloid-beta accumulation and tau hyperphosphorylation, while in PD, they help protect dopaminergic neurons and mitigate motor symptoms. Ginseng's effects in ALS, MS, and HD models include improving motor function, extending neuronal survival, and reducing cellular toxicity. This review provides a comprehensive overview of the neuroprotective mechanisms of ginseng, emphasizing its therapeutic potential across various neurodegenerative diseases and discussing future research directions for its integration into clinical practice.}, } @article {pmid40232694, year = {2024}, author = {Ichikawa, Y and Sato, B and Hirano, SI and Takefuji, Y and Satoh, F}, title = {Hydrogen inhalation therapy may ameliorate amyotrophic lateral sclerosis.}, journal = {Medical gas research}, volume = {14}, number = {3}, pages = {149-150}, pmid = {40232694}, issn = {2045-9912}, } @article {pmid40234116, year = {2025}, author = {McHale-Owen, H and Faller, KME and Chaytow, H and Gillingwater, TH}, title = {Phosphoglycerate kinase 1 as a therapeutic target in neurological disease.}, journal = {Trends in molecular medicine}, volume = {31}, number = {12}, pages = {1077-1088}, doi = {10.1016/j.molmed.2025.03.008}, pmid = {40234116}, issn = {1471-499X}, mesh = {Humans ; *Phosphoglycerate Kinase/metabolism/genetics/antagonists & inhibitors ; Animals ; *Nervous System Diseases/drug therapy/enzymology/metabolism ; Molecular Targeted Therapy ; Parkinson Disease/drug therapy/metabolism/enzymology ; }, abstract = {Phosphoglycerate kinase 1 (PGK1) is a highly conserved enzyme that catalyzes the initial ATP-producing step in glycolysis. Improving cellular energy production by increasing PGK1 activity may be beneficial in multiple neurological conditions where cell metabolism is dysregulated, including Parkinson's disease (PD) and motor neuron disease (MND). This review examines recent evidence that suggests increasing PGK1 activity may be beneficial in multiple neurological conditions and discusses the current challenges surrounding the development of PGK1-focused therapies. PGK1 has considerable therapeutic potential, but novel PGK1 activators are needed to maximize the benefit for patients.}, } @article {pmid40234916, year = {2025}, author = {Park, KH and Yu, E and Choi, S and Kim, S and Park, C and Lee, JE and Kim, KW}, title = {Optogenetic induction of TDP-43 aggregation impairs neuronal integrity and behavior in Caenorhabditis elegans.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {20}, pmid = {40234916}, issn = {2047-9158}, support = {P40 OD010440/OD/NIH HHS/United States ; NRF-2022R1A2C1003766//Ministry of Education, Science and Technology/ ; RS-2024-00331685//Ministry of Food and Drug Safety/ ; }, mesh = {Animals ; Caenorhabditis elegans ; *Optogenetics/methods ; *DNA-Binding Proteins/metabolism/genetics ; *TDP-43 Proteinopathies/metabolism/pathology/genetics ; *Neurons/metabolism/pathology ; *Protein Aggregation, Pathological/metabolism/pathology ; Disease Models, Animal ; Animals, Genetically Modified ; Protein Aggregates/physiology ; Caenorhabditis elegans Proteins/metabolism ; *Behavior, Animal/physiology ; }, abstract = {BACKGROUND: Cytoplasmic aggregation of TAR DNA binding protein 43 (TDP-43) in neurons is one of the hallmarks of TDP-43 proteinopathy. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are closely associated with TDP-43 proteinopathy; however, it remains uncertain whether TDP-43 aggregation initiates the pathology or is a consequence of it.

METHODS: To demonstrate the pathology of TDP-43 aggregation, we applied the optoDroplet technique in Caenorhabditis elegans (C. elegans), which allows spatiotemporal modulation of TDP-43 phase separation and assembly.

RESULTS: We demonstrate that optogenetically induced TDP-43 aggregates exhibited insolubility similar to that observed in TDP-43 proteinopathy. These aggregates increased the severity of neurodegeneration, particularly in GABAergic motor neurons, and exacerbated sensorimotor dysfunction in C. elegans.

CONCLUSIONS: We present an optogenetic C. elegans model of TDP-43 proteinopathy that provides insight into the neuropathological mechanisms of TDP-43 aggregates. Our model serves as a promising tool for identifying therapeutic targets for TDP-43 proteinopathy.}, } @article {pmid40234983, year = {2025}, author = {Xie, Q and Li, K and Chen, Y and Li, Y and Jiang, W and Cao, W and Yu, H and Fan, D and Deng, B}, title = {Gene therapy breakthroughs in ALS: a beacon of hope for 20% of ALS patients.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {19}, pmid = {40234983}, issn = {2047-9158}, support = {81901273//National Natural Science Foundation of China/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; *Genetic Therapy/methods/trends ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that remains incurable. Although the etiologies of ALS are diverse and the precise pathogenic mechanisms are not fully understood, approximately 20% of ALS cases are caused by genetic factors. Therefore, advancing targeted gene therapies holds significant promise, at least for the 20% of ALS patients with genetic etiologies. In this review, we summarize the main strategies and techniques of current ALS gene therapies based on ALS risk genes, and review recent findings from animal studies and clinical trials. Additionally, we highlight ALS-related genes with well-understood pathogenic mechanisms and the potential of numerous emerging gene-targeted therapeutic approaches for ALS.}, } @article {pmid40235273, year = {2025}, author = {Scelsa, SN and MacGowan, DJL}, title = {Disease Modification in SOD1-ALS With Tofersen May Result in Serious CNS Inflammation.}, journal = {Muscle & nerve}, volume = {71}, number = {6}, pages = {928-931}, doi = {10.1002/mus.28413}, pmid = {40235273}, issn = {1097-4598}, } @article {pmid40235752, year = {2025}, author = {Huang, NX and Zeng, JY and Huang, HW and Fang, SY and Chen, S and Li, JQ and Chen, HJ and Zou, ZY}, title = {Association of glymphatic system disturbance with neural dysfunction in amyotrophic lateral sclerosis.}, journal = {Quantitative imaging in medicine and surgery}, volume = {15}, number = {4}, pages = {3445-3457}, pmid = {40235752}, issn = {2223-4292}, abstract = {BACKGROUND: Formation and aggregation of pathological proteins in the brain constitutes a critical hallmark of amyotrophic lateral sclerosis (ALS). However, the role of the glymphatic system in the clearance of pathological proteins in ALS remains unclear. The purpose of this cross-sectional study was to evaluate glymphatic system disturbance in ALS and its relation to neural function.

METHODS: This study included 38 healthy controls (HCs) and 30 patients with ALS who underwent diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI). The disease severity, duration, and progression rate of ALS were recorded. Glymphatic system function was indirectly evaluated by DTI analysis along the perivascular space (ALPS) surrounding the deep medullary vein. Neural activity was examined in sensorimotor-related brain areas by measuring amplitude of low-frequency fluctuation (ALFF) based on rs-fMRI. A two-sample t-test or Mann-Whitney test was used to examine between-group differences in ALPS, diffusivities measured along the x-, y-, and z-axis in the association (Dxx_association, Dyy_association, Dzz_association) and projection (Dxx_projection, Dyy_projection, Dzz_projection) fiber areas, and ALFF indices. The associations between ALPS, diffusivities, ALFF, and clinical assessments were determined via Spearman correlation analysis, and diagnostic performance was evaluated with receiver operating characteristic curve analysis.

RESULTS: Patients with ALS exhibited significantly decreased ALPS and increased diffusivities (Dyy_association and Dyy_projection) as compared to HCs (all P values <0.05). Patients with ALS showed decreased ALFF in sensorimotor-related regions, including the bilateral primary motor and somatosensory areas (all P values <0.001) and left supplementary motor area (P=0.031). ALPS and diffusivities were correlated with ALFF in the sensorimotor-motor regions (all P values <0.05), and ALPS and ALFF correlated with disease severity and duration (all P values <0.05). ALPS, diffusivities, and ALFF showed moderate ability to diagnose ALS.

CONCLUSIONS: The glymphatic system function was impaired in ALS. This may contribute to spontaneous neural activity disturbance and could represent a mechanism for the development of sensorimotor deficits frequently observed in patients with ALS.}, } @article {pmid40235786, year = {2025}, author = {Wang, LP and Yang, C and Fu, JY and Zhang, XY and Shen, XM and Shi, NL and Wu, HL and Gao, XR}, title = {A preliminary study of steady-state visually-evoked potential-based non-invasive brain-computer interface technology as a communication aid for patients with amyotrophic lateral sclerosis.}, journal = {Quantitative imaging in medicine and surgery}, volume = {15}, number = {4}, pages = {3469-3479}, pmid = {40235786}, issn = {2223-4292}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, leading to severe disability and ultimately death. Communication difficulties are common in ALS patients as the disease progresses; thus, alternative communication aids need to be explored. This study sought to examine the use and effect of steady-state visually-evoked potential (SSVEP)-based non-invasive brain-computer interface (BCI) technology as a communication aid for patients with ALS and to examine possible influencing factors.

METHODS: In total, 12 patients with ALS were selected, and a 40-character target selection was performed using SSVEP-based non-invasive BCI technology. The patients were presented with specific visual stimuli, and nine-lead electroencephalogram (EEG) signals in the occipital region were acquired when the patients were looking at the target. Using the feature recognition analysis method, the final output was the characters recognized by the patients. The basic clinical data of the patients (e.g., age, gender, course of disease, affected area, and ALS functional scale score) were collected, and the BCI accuracy rate, information transmission rate, and average SSVEP recognition time were calculated.

RESULTS: The results revealed that the recognition efficiency of the ALS patients varied. The accuracy potential increased as the stimulus duration extended, highlighting the possibility for improvement via further optimization. The results also showed that the experimental design schedules typically used for healthy individuals may not be entirely suitable for ALS patients, which presents an exciting opportunity to tailor future studies to better meet the unique needs of ASL patients. Further, the results revealed the necessity of using customized experimental schedules in future studies, which could lead to more relevant and effective data collection for ALS patients.

CONCLUSIONS: The study found that SSVEP-based non-invasive BCI technology has promising potential as a communication aid for ALS patients. While further algorithm optimization and comprehensive studies with larger sample sizes are necessary, the initial findings are encouraging, and could lead to the development of more effective communication solutions that are specifically tailored to address the challenges faced by ALS patients.}, } @article {pmid40235867, year = {2025}, author = {Sundararaju, U and Rajakumar, HK}, title = {Prognostic value of neutrophil-to-lymphocyte ratio in gastric cancer: Enhancing clinical relevance.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {4}, pages = {103128}, pmid = {40235867}, issn = {1948-5204}, abstract = {Gastric cancer (GC) is a leading cause of cancer-related deaths, highlighting the need for reliable prognostic biomarkers to guide treatment. Wei et al's systematic review and meta-analysis evaluates the neutrophil-to-lymphocyte ratio (NLR) as a potential biomarker for GC patients undergoing neoadjuvant chemotherapy. NLR is a simple and cost-effective measure of systemic inflammation that shows promise in predicting treatment response and survival outcomes, including overall survival and progression-free survival. However, variations in NLR thresholds and timing of measurements affect its accuracy and clinical utility. Moreover, the studies reviewed primarily involved Asian populations, which may limit the generalizability of the findings. To improve NLR's clinical relevance, future research should focus on standardizing NLR thresholds, refining measurement timing, and incorporating additional inflammatory markers like platelet-to-lymphocyte ratio and Glasgow prognostic score. Addressing confounders and including diverse patient populations will help improve NLR's reliability as a prognostic marker for GC.}, } @article {pmid40235960, year = {2025}, author = {Basgaran, A and Lymberopoulos, E and Burchill, E and Reis-Dehabadi, M and Sharma, N}, title = {Machine learning determines the incidence of Alzheimer's disease based on population gut microbiome profile.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf059}, pmid = {40235960}, issn = {2632-1297}, abstract = {The human microbiome is a complex and dynamic community of microbes, thought to have symbiotic benefit to its host. Influences of the gut microbiome on brain microglia have been identified as a potential mechanism contributing to neurodegenerative diseases, such as Alzheimer's disease, motor neurone disease and Parkinson's disease (Boddy SL, Giovannelli I, Sassani M, et al. The gut microbiome: A key player in the complexity of amyotrophic lateral sclerosis (ALS). BMC Med. 2021;19(1):13). We hypothesize that population level differences in the gut microbiome will predict the incidence of Alzheimer's disease using machine learning methods. Cross-sectional analyses were performed in R, using two large, open-access microbiome datasets (n = 959 and n = 2012). Countries in these datasets were grouped based on Alzheimer's disease incidence and the gut microbiome profiles compared. In countries with a high incidence of Alzheimer's disease, there is a significantly lower diversity of the gut microbiome (P < 0.05). A permutational analysis of variance test (P < 0.05) revealed significant differences in the microbiome profile between countries with high versus low incidence of Alzheimer's disease with several contributing taxa identified: at a species level Escherichia coli, and at a genus level Haemophilus and Akkermansia were found to be reproducibly protective in both datasets. Additionally, using machine learning, we were able to predict the incidence of Alzheimer's disease within a country based on the microbiome profile (mean area under the curve 0.889 and 0.927). We conclude that differences in the microbiome can predict the varying incidence of Alzheimer's disease between countries. Our results support a key role of the gut microbiome in neurodegeneration at a population level.}, } @article {pmid40236149, year = {2025}, author = {Strell, P and Waldron, MA and Johnson, S and Shetty, A and Crane, AT and Steer, CJ and Low, WC}, title = {Characterization of the intraspecies chimeric mouse brain at embryonic day 12.5.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.03.31.646380}, pmid = {40236149}, issn = {2692-8205}, support = {R01 AI173804/AI/NIAID NIH HHS/United States ; }, abstract = {Incidence of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis have increased dramatically as life expectancy at birth has risen year-over-year and the population ages. Neurological changes within the central nervous system, specifically the brain, include cell loss and deterioration that impact motor function, memory, executive function, and mood. Available treatments are limited and often only address symptomatic manifestations of the disease rather than disease progression. Cell transplantation therapy has shown promise for treating neurodegenerative diseases, but a source of autologous cells is required. Blastocyst complementation provides an innovative method for generating those autologous neural cells. By injecting mouse induced pluripotent stem cells (iPSCs) into a wild type (WT) mouse blastocyst, we generated a chimeric mouse brain derived of both donor and host neuronal and non-neuronal cells. An embryonic day 12.5 (E12.5), automated image analysis of mouse-mouse chimeric brains showed the presence of GFP-labeled donor-derived dopaminergic and serotonergic neuronal precursors. GFP-labeled donor-derived cholinergic precursor neurons and non-neuronal microglia-like and macrophage-like cells were also observed using more conventional imaging analysis software. This work demonstrates that the generation of mouse-mouse chimeric neural cells is possible; and that characterization of early neuronal and non-neuronal precursors provides a first step towards utilizing these cells for cell transplantation therapies for neurodegenerative diseases.}, } @article {pmid40236412, year = {2025}, author = {Jude, JJ and Levi-Aharoni, H and Acosta, AJ and Allcroft, SB and Nicolas, C and Lacayo, BE and Card, NS and Wairagkar, M and Brandman, DM and Stavisky, SD and Willett, FR and Williams, ZM and Simeral, JD and Hochberg, LR and Rubin, DB}, title = {An intuitive, bimanual, high-throughput QWERTY touch typing neuroprosthesis for people with tetraplegia.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.04.01.25324990}, pmid = {40236412}, support = {I01 RX003803/RX/RRD VA/United States ; I50 RX002864/RX/RRD VA/United States ; U01 NS123101/NS/NINDS NIH HHS/United States ; R01 DC014034/DC/NIDCD NIH HHS/United States ; I01 RX004820/RX/RRD VA/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; }, abstract = {Recognizing keyboard typing as a familiar, high information rate communication paradigm, we developed an intracortical brain computer interface (iBCI) typing neuroprosthesis providing bimanual QWERTY keyboard functionality for people with paralysis. Typing with this iBCI involves only attempted finger movements, which are decoded accurately with as few as 30 calibration sentences. Sentence decoding is improved using a 5-gram language model. This typing neuroprosthesis performed well for two iBCI clinical trial participants with tetraplegia - one with ALS and one with spinal cord injury. Typing speed is user-regulated, reaching 110 characters per minute, resulting in 22 words per minute with a word error rate of 1.6%. This resembles able-bodied typing accuracy and provides higher throughput than current state-of-the-art hand motor iBCI decoding. In summary, a typing neuroprosthesis decoding finger movements, provides an intuitive, familiar, and easy-to-learn paradigm for individuals with impaired communication due to paralysis.}, } @article {pmid40237114, year = {2025}, author = {Thompson, OL and Russell, JA and Stockman, SK and Swall, JL and Simmons, T}, title = {Assessing the effectiveness of alternate light sources in the search for skeletal remains.}, journal = {Journal of forensic sciences}, volume = {70}, number = {4}, pages = {1501-1508}, pmid = {40237114}, issn = {1556-4029}, mesh = {Humans ; Swine ; Animals ; Deer ; *Bone and Bones ; *Lighting/instrumentation ; Forensic Anthropology/methods ; *Body Remains ; Fluorescence ; Models, Animal ; *Light ; }, abstract = {Many search and recovery operations for human skeletal remains are unsuccessful due to difficulties recognizing bones in outdoor environments even when evidence indicates the last known whereabouts of missing individuals. Though the collagen component of bone is known to emit fluorescence, this property has not been leveraged consistently during skeletal remains searches. Thirty-six mock searches were completed in 5000 ft[2] zones of eastern deciduous forest by volunteers associated with the Virginia Department of Emergency Management. Pig and deer bones were scattered and partially concealed under brush and leaf cover. Pairs of volunteers were allowed up to 1 h to conduct searches in their usual pattern. Nighttime searches were conducted with handheld alternate light source (ALS) devices (uvBeast™, Crime-lite[®], ForenScope, and Labino AB), which produced ultraviolet (385-395 nm), violet (395-425 nm), blue (~455 nm), cyan (~510 nm), or green (~530 nm) lights. Filtered safety glasses were paired with appropriate ALS. Daytime searches were conducted under the same parameters, without ALS. Results indicated that (1) nighttime searches with ALS produced a recovery rate more than triple that of daytime searches (p < 0.0001) and that they were often completed more quickly, and (2) the violet Crime-lite[®], due to breadth of illumination and strength of fluorescent response, consistently produced the highest recovery rate (95%). Data suggest that nighttime searches with ALS can be used both as the primary search method for locating and recovering human skeletal remains, and as a secondary method for recovering any bones expected to be present but not found during daylight searches.}, } @article {pmid40237254, year = {2025}, author = {Russek, M and Peltner, J and Haenisch, B}, title = {Supplementing Single-Arm Trials with External Control Arms-Evaluation of German Real-World Data.}, journal = {Clinical pharmacology and therapeutics}, volume = {118}, number = {6}, pages = {1443-1450}, pmid = {40237254}, issn = {1532-6535}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Germany ; *Breast Neoplasms/drug therapy ; Female ; *Research Design ; *Clinical Trials as Topic/methods ; Registries ; }, abstract = {As single-arm trials (SATs) are increasingly used in pharmaceutical research, the validity of such study designs needs to be critically assessed. We characterize the feasibility of supplementing SATs with real-world data (RWD)-derived external control arms by determining the proportion of SATs on breast cancer and amyotrophic lateral sclerosis (ALS) for which an external control arm based on RWD can be constructed. The main outcome measure is the number and percentage of trials for which all important eligibility criteria and at least one primary endpoint could be identified in one of five German RWD sources. We surveyed all SATs concerning breast cancer or ALS treatment registered in the European Union's clinical trial registers between 2004 and 2023. Ten out of 379 breast cancer SATs and 2 of 11 ALS SATs could feasibly be supplemented with RWD-derived external control arms, if all important eligibility criteria and a primary endpoint have to be identifiable in the RWD source. Ninety-three breast cancer trials had at least one outcome ascertainable in a RWD source, and 35 trials had all important eligibility criteria recorded in a RWD source. Nine ALS trials had at least one primary endpoint ascertainable in RWD sources, and 2 had all important eligibility criteria recorded in a RWD source. Our study shows that SATs with RWD-derived external control arms will rarely be suitable to establish treatment effects of medicines in the current setting for the investigated phenotypes and that SATs should be designed with limitations of the source of external controls in mind.}, } @article {pmid40238886, year = {2025}, author = {Cheemala, A and Kimble, AL and Burrage, EN and Helming, SB and Tyburski, JD and Leclair, NK and Omar, OM and Zuberi, AR and Murphy, M and Jellison, ER and Reese, B and Hu, X and Lutz, CM and Yan, R and Murphy, PA}, title = {Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects.}, journal = {Science advances}, volume = {11}, number = {16}, pages = {eads0505}, pmid = {40238886}, issn = {2375-2548}, support = {R00 HL125727/HL/NHLBI NIH HHS/United States ; K99 HL125727/HL/NHLBI NIH HHS/United States ; P30 CA034196/CA/NCI NIH HHS/United States ; RF1 NS074256/NS/NINDS NIH HHS/United States ; R01 NS074256/NS/NINDS NIH HHS/United States ; RF1 AG046929/AG/NIA NIH HHS/United States ; RF1 NS117449/NS/NINDS NIH HHS/United States ; U54 OD020351/OD/NIH HHS/United States ; R01 NS117449/NS/NINDS NIH HHS/United States ; R01 HL150362/HL/NHLBI NIH HHS/United States ; R01 AG046929/AG/NIA NIH HHS/United States ; }, mesh = {*Blood-Brain Barrier/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Mice ; *Mutation ; Humans ; *Endothelial Cells/metabolism/pathology ; Disease Models, Animal ; Brain/metabolism/pathology ; }, abstract = {Mutations in the TARDBP gene encoding TDP-43 protein are linked to loss of function in neurons and familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We recently identified reduced nuclear TDP-43 in capillary endothelial cells (ECs) of donors with ALS-FTD. Because blood-brain barrier (BBB) permeability increases in ALS-FTD, we postulated that reduced nuclear TDP-43 in ECs might contribute. Here, we show that nuclear TDP-43 is reduced in ECs of mice with an ALS-FTD-associated mutation in TDP-43 (Tardbp[G348C]) and that this leads to cell-autonomous loss of junctional complexes and BBB integrity. Targeted excision of TDP-43 in brain ECs recapitulates BBB defects and loss of junctional complexes and ultimately leads to fibrin deposition, gliosis, phospho-Tau accumulation, and impaired memory and social interaction. Transcriptional changes in TDP-43-deficient ECs resemble diseased brain ECs. These data show that nuclear loss of TDP-43 in brain ECs disrupts the BBB and causes hallmarks of FTD.}, } @article {pmid40240969, year = {2025}, author = {Xia, H and Wang, ZH and Wang, XB and Gao, MR and Jiang, S and Du, XY and Yang, XL}, title = {Investigating the genetic association of mitochondrial DNA copy number with neurodegenerative diseases.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {160}, pmid = {40240969}, issn = {1471-2377}, support = {2023B03003//Autonomous Region Key Research and Development Project/ ; 2022TSYCLJ0066//the Tian-Shan Talent Program/ ; 82371258//the National Natural Science Foundation of China/ ; ZYYD2022C17//the Central Guiding Local Science and Technology Development Special Fund Project/ ; }, mesh = {Humans ; *DNA, Mitochondrial/genetics ; *Neurodegenerative Diseases/genetics ; *DNA Copy Number Variations/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Genetic Predisposition to Disease/genetics ; Male ; Cohort Studies ; Female ; }, abstract = {OBJECTIVE: This study aims to investigate the causal relationship between Mitochondrial DNA (mtDNA) copy number and several common neurodegenerative diseases (NDs).

METHODS: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis using data from genome-wide association studies (GWAS) as instrumental variables (IVs). After screening for relevance and potential confounders, we estimated the association between mtDNA copy number and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS). Additionally, we validated our findings using GWAS data on mtDNA copy number from Longchamps et al., sourced from the Genetics Epidemiology Consortium and the UK Biobank (UKB) aging study cohort.

RESULTS: A GWAS analysis of 395,718 UKB participants found no significant association between mtDNA copy number and the risk of NDs, including AD (OR = 0.956, P = 0.708), PD (OR = 1.223, P = 0.179), ALS (OR = 0.972, P = 0.374), and MS (OR = 0.932, P = 0.789). Similarly, reverse MR analysis revealed no significant relationship between genetic predictions of NDs and mtDNA copy number: AD (OR = 0.987, P = 0.062), PD (OR = 0.997, P = 0.514), ALS (OR = 0.974, P = 0.706), and MS (OR = 1.003, P = 0.181).

CONCLUSION: Although mitochondrial dysfunction is implicated in the pathogenesis of NDs, no clear evidence supports a causal role for mtDNA copy number. The relationship between mtDNA copy number and NDs is likely mediated by more complex molecular regulatory mechanisms. Further research is required to elucidate these intricate interactions.}, } @article {pmid40241786, year = {2025}, author = {Hernández-Gloria, JJ and Jaramillo-Gonzalez, A and Savić, AM and Mrachacz-Kersting, N}, title = {Toward brain-computer interface speller with movement-related cortical potentials as control signals.}, journal = {Frontiers in human neuroscience}, volume = {19}, number = {}, pages = {1539081}, pmid = {40241786}, issn = {1662-5161}, abstract = {Brain Computer Interface spellers offer a promising alternative for individuals with Amyotrophic Lateral Sclerosis (ALS) by facilitating communication without relying on muscle activity. This study assessed the feasibility of using movement related cortical potentials (MRCPs) as a control signal for a Brain-Computer Interface speller in an offline setting. Unlike motor imagery-based BCIs, this study focused on executed movements. Fifteen healthy subjects performed three spelling tasks that involved choosing specific letters displayed on a computer screen by performing a ballistic dorsiflexion of the dominant foot. Electroencephalographic signals were recorded from 10 sites centered around Cz. Three conditions were tested to evaluate MRCP performance under varying task demands: a control condition using repeated selections of the letter "O" to isolate movement-related brain activity; a phrase spelling condition with structured text ("HELLO IM FINE") to simulate a meaningful spelling task with moderate cognitive load; and a random condition using a randomized sequence of letters to introduce higher task complexity by removing linguistic or semantic context. The success rate, defined as the presence of an MRCP, was manually determined. It was approximately 69% for both the control and phrase conditions, with a slight decrease in the random condition, likely due to increased task complexity. Significant differences in MRCP features were observed between conditions with Laplacian filtering, whereas no significant differences were found in single-site Cz recordings. These results contribute to the development of MRCP-based BCI spellers by demonstrating their feasibility in a spelling task. However, further research is required to implement and validate real-time applications.}, } @article {pmid40241787, year = {2025}, author = {Wölfel, SM and Widmann, CN and Castro-Gomez, S and Weydt, P and Tacik, P and Heneka, MT}, title = {Cognitive capacity in amyotrophic lateral sclerosis: the value of diagnostic markers in cerebrospinal fluid and the influence of nutrition and pulmonary function.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf137}, pmid = {40241787}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is an incurable neurodegenerative disease that is fatal with a median of 3-4 years. It is characterized by degeneration of the first and second motor neurons. In addition to physical limitations, neuropsychological abnormalities occur in more than 50% of cases. This leads to a rapid loss of autonomy and increases the need for care. An individual prognosis for the course of the disease, in particular the development of cognitive and behavioural abnormalities, is not yet possible As part of our investigations, we focused on cognitive performance and behavioural abnormalities measured by the Edinburgh Cognitive and Behavioural ALS Screen in patients with amyotrophic lateral sclerosis and investigated possible prognostic biomarkers in cerebrospinal fluid as well as modifiable factors such as nutrition and lung function. A retrospective data analysis of 99 patients with amyotrophic lateral sclerosis cases examined between 2018 and 2021 at the Department for Neurodegenerative Diseases and Gerontopsychiatry at the University Hospital of Bonn, using Edinburgh Cognitive and Behavioural ALS Screen, revealed that elevated levels of total tau and phospho-tau 181 were associated with diminished performance of patients with amyotrophic lateral sclerosis on the Edinburgh Cognitive and Behavioural ALS Screen. Additionally, weight loss during the course of the disease has been observed to have a deleterious impact on cognitive performance. Moreover, we were able to demonstrate a previously insufficiently described correlation between abnormalities in the Edinburgh Cognitive and Behavioural ALS Screen and low-normal thiamine levels in serum. The hypothesis that reduced lung function has a negative effect on cognitive performance was not supported by our findings. The initial onset of amyotrophic lateral sclerosis, whether bulbar or spinal, does not appear to affect cognition and behaviour measured using Edinburgh Cognitive and Behavioural ALS Screen. Furthermore, our findings confirm the utility of the Edinburgh Cognitive and Behavioural ALS Screen in identifying a behavioural variant frontotemporal dementia in amyotrophic lateral sclerosis patients who have been previously diagnosed by experienced neurologists using the Rascovsky criteria. This development facilitates a more precise utilization of complex diagnostic instruments. Our results provide insight into the prognosis of patients with amyotrophic lateral sclerosis in terms of cognitive performance and behavioural abnormalities as the disease progresses, as well as potential therapeutic approaches to stabilize and support neuropsychological abnormalities. The importance of total tau as a widely available prognostic marker should be emphasized. Additionally, new avenues of research are emerging, particularly regarding the role of thiamine in amyotrophic lateral sclerosis.}, } @article {pmid40243463, year = {2025}, author = {Fan, X and Diao, W and Wang, H and Yin, X and Qian, W}, title = {Interferon Regulatory Factors as a Potential Therapeutic Target for Neuroinflammation: A Focus on Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, pmid = {40243463}, issn = {1422-0067}, support = {82473926//National Natural Science Foundation of China/ ; 81872875//National Natural Science Foundation of China/ ; 81170317//National Natural Science Foundation of China/ ; 81473218//National Natural Science Foundation of China/ ; 81503077//National Natural Science Foundation of China/ ; JC2023042//the project of Nantong Natural Science Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Animals ; *Interferon Regulatory Factors/metabolism/genetics ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Signal Transduction ; Inflammation/metabolism ; }, abstract = {Interferon Regulatory Factors (IRFs) are critical modulators of immune and inflammatory responses, yet their roles in Alzheimer's disease (AD) and other neurodegenerative disorders remain incompletely understood. While IRFs are recognized for their regulatory functions in neuroinflammation, microglial activation, and neuronal survival, their dual roles as both drivers of pathological inflammation and mediators of neuroprotective pathways underscore a sophisticated regulatory paradox in neurodegenerative disorders. This review aims to synthesize current evidence on IRF-mediated neuroinflammation in AD and related diseases, focusing on the multifaceted functions of key IRF family members, including IRF1, IRF3, and IRF7. We critically evaluate their divergent roles: IRF1 and IRF3, for instance, exacerbate neuroinflammatory cascades and amyloid-beta (Aβ) pathology in AD, whereas IRF7 may paradoxically suppress inflammation under specific conditions. Additionally, we explore IRF dysregulation in Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease, emphasizing shared and distinct mechanisms across neurodegenerative disorders. Restoring IRF balance through genetic manipulation, small-molecule inhibitors, or microbiome-derived modulators could attenuate neuroinflammation, enhance Aβ clearance, and protect neuronal integrity. Ultimately, this work provides a framework for future research to harness IRF signaling pathways in the development of precision therapies for AD and other neurodegenerative diseases.}, } @article {pmid40243477, year = {2025}, author = {Romano, R and Del Fiore, VS and Ruotolo, G and Mazzoni, M and Rosati, J and Conforti, FL and Bucci, C}, title = {Lysosomal Dysfunction in Amyotrophic Lateral Sclerosis: A Familial Case Linked to the p.G376D TARDBP Mutation.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, pmid = {40243477}, issn = {1422-0067}, support = {PRIN2022 N. 2022XTM2S3//Ministero dell'università e della ricerca/ ; PRIN2022 PNRR N. P2022FBZXY//Ministero dell'università e della ricerca/ ; D.M. n. 737 of 25.06.2021//Ministero dell'università e della ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Lysosomes/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; Motor Neurons/metabolism/pathology ; *Mutation ; Fibroblasts/metabolism/pathology ; Male ; Female ; Induced Pluripotent Stem Cells/metabolism ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Consequent to the loss of these cells, neuromuscular functions decline, causing progressive weakness, muscle wasting, and paralysis, leading to death in 2 to 5 years. More than 90% of ALS cases are sporadic, while the remaining 10% of cases are familial, due to mutations in 40 different genes. One of the most common genes to be mutated in ALS is TARDBP (transactive response DNA binding protein 43), which encodes TDP-43 (TAR DNA-binding protein 43). A mutation in exon 6 of TARDBP causes the aminoacidic substitution G376D in the C-terminal region of TDP-43, leading to its cytoplasmic mislocalization and aggregation. In fibroblasts derived from patients carrying this mutation, we found a strong increase in lysosome number, with overexpression and higher nuclear translocation of the transcription factor TFEB. In contrast, lysosomal functionality was deeply compromised. Interestingly, lysosomal activity was unaffected at an early stage of the disease, worsening in more advanced stages. Moreover, we observed the same pathological phenotype in iPSC (induced pluripotent stem cells)-derived patient motor neurons carrying the G376D mutation. Therefore, this mutation compromises the functionality of lysosomes, possibly contributing to neurodegeneration.}, } @article {pmid40243699, year = {2025}, author = {Xu, R and Kang, Q and Yang, X and Yi, P and Zhang, R}, title = {Unraveling Molecular Targets for Neurodegenerative Diseases Through Caenorhabditis elegans Models.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, pmid = {40243699}, issn = {1422-0067}, support = {32270739//National Natural Science Foundation of China/ ; }, mesh = {*Caenorhabditis elegans/genetics/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/genetics/drug therapy/pathology ; *Disease Models, Animal ; Humans ; Caenorhabditis elegans Proteins/metabolism/genetics ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and prion disease, represent a group of age-related disorders that pose a growing and formidable challenge to global health. Despite decades of extensive research that has uncovered key genetic factors and biochemical pathways, the precise molecular mechanisms underlying these diseases and effective therapeutic strategies remain elusive. Caenorhabditis elegans (C. elegans) has emerged as a powerful model organism for studying NDDs due to its unique biological features such as genetic tractability, conserved molecular pathways, and ease of high-throughput screening. This model provides an exceptional platform for identifying molecular targets associated with NDDs and developing novel therapeutic interventions. This review highlights the critical role of C. elegans in elucidating the complex molecular mechanisms of human NDDs, with a particular focus on recent advancements and its indispensable contributions to the discovery of molecular targets and therapeutic strategies for these NDDs.}, } @article {pmid40243810, year = {2025}, author = {Flores, SV and Lillo, P and Levi-Monsalve, A and Roco-Videla, Á and Montaña, R}, title = {Genetic ancestry and risk allele C9orf72 rs3849942 T for amyotrophic lateral sclerosis in Latin American populations.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {379-381}, doi = {10.1080/21678421.2024.2447459}, pmid = {40243810}, issn = {2167-9223}, mesh = {Female ; Humans ; Male ; Middle Aged ; Alleles ; *Amyotrophic Lateral Sclerosis/genetics/ethnology ; *C9orf72 Protein/genetics ; *Genetic Predisposition to Disease/genetics ; Latin America/epidemiology ; *Polymorphism, Single Nucleotide/genetics ; White People/genetics ; *South American People/genetics ; }, abstract = {This study examines the relationship between genetic ancestry and the rs3849942 T allele, linked to ALS, in 347 Latin American individuals from the 1000 Genomes Project. Ancestry proportions were estimated using 446 AIMs, and associations were analyzed via logistic regression. Higher Native American ancestry significantly reduced the likelihood of carrying the T allele, while European ancestry increased it. These findings emphasize the importance of incorporating genetic diversity into ALS research.}, } @article {pmid40244061, year = {2025}, author = {Tseriotis, VS and Liampas, A and Lazaridou, IZ and Karachrysafi, S and Vavougios, GD and Hadjigeorgiou, GM and Papamitsou, T and Kouvelas, D and Arnaoutoglou, M and Pourzitaki, C and Mavridis, T}, title = {Repulsive Guidance Molecule-A as a Therapeutic Target Across Neurological Disorders: An Update.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, pmid = {40244061}, issn = {1422-0067}, mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Nerve Tissue Proteins/metabolism/antagonists & inhibitors/genetics ; *GPI-Linked Proteins/metabolism/antagonists & inhibitors/genetics ; Molecular Targeted Therapy ; Neurodegenerative Diseases/metabolism/drug therapy ; }, abstract = {Repulsive guidance molecule-a (RGMa) has emerged as a significant therapeutic target in a variety of neurological disorders, including neurodegenerative diseases and acute conditions. This review comprehensively examines the multifaceted role of RGMa in central nervous system (CNS) pathologies such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuromyelitis optica spectrum disorder, spinal cord injury, stroke, vascular dementia, auditory neuropathy, and epilepsy. The mechanisms through which RGMa contributes to neuroinflammation, neuronal degeneration, and impaired axonal regeneration are herein discussed. Evidence from preclinical studies associate RGMa overexpression with negative outcomes, such as increased neuroinflammation and synaptic loss, while RGMa inhibition, particularly the use of agents like elezanumab, has shown promise in enhancing neuronal survival and functional recovery. RGMa's responses concerning immunomodulation and neurogenesis highlight its potential as a therapeutic avenue. We emphasize RGMa's critical role in CNS pathology and its potential to pave the way for innovative treatment strategies in neurological disorders. While preclinical findings are encouraging so far, further clinical trials are needed to validate the safety and efficacy of RGMa-targeted therapies.}, } @article {pmid40244186, year = {2025}, author = {Hu, C and Jiang, Y and Ma, C and Xu, F and Cui, C and Du, X and Chen, J and Zhu, L and Yu, S and He, X and Yu, W and Wang, Y and Xu, X}, title = {Decreased Cdk2 Activity Hindered Embryonic Development and Parthenogenesis Induction in Silkworm, Bombyx mori L.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, pmid = {40244186}, issn = {1422-0067}, support = {2021C02072//Technological Grant of Zhejiang for Breeding New Agricultural Varieties/ ; 32100377//National Natural Science Foundation of China/ ; CARS-18//Key Scientific and the China Agriculture Research System of MOF and MARA/ ; }, mesh = {Animals ; *Bombyx/embryology/genetics/enzymology ; *Parthenogenesis/drug effects ; *Cyclin-Dependent Kinase 2/metabolism/antagonists & inhibitors/genetics ; *Embryonic Development/drug effects ; *Insect Proteins/metabolism/genetics/antagonists & inhibitors ; Female ; }, abstract = {Cyclin-dependent protein kinase 2 (Cdk2), an important member of the serine/threonine-specific protein kinase family, plays a critical regulatory role in biological processes. Previous studies have demonstrated that Cdk2 is involved in the arrest and resumption of meiosis in mammalian oocytes. In this study, we explored the function of Cdk2 through parthenogenetic lines (PLs) and corresponding amphigonic lines (ALs) in a model lepidopteran insect silkworm, Bombyx mori L. Our findings revealed a positive correlation between Cdk2 activity and the parthenogenesis induction rate. The pharmacological inhibition of Cdk2 using the specific inhibitor AUZ454 not only significantly reduced the parthenogenesis induction rate but also caused developmental delays in embryos. These results demonstrate that Cdk2 is essential for parthenogenesis success and is a potential target gene for biological reproductive regulation.}, } @article {pmid40244212, year = {2025}, author = {Zhang, M and Zhou, H and Pan, Y and Wei, L}, title = {A pregnant woman with a 5-year history of amyotrophic lateral sclerosis: A case report.}, journal = {International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics}, volume = {171}, number = {1}, pages = {463-464}, doi = {10.1002/ijgo.70173}, pmid = {40244212}, issn = {1879-3479}, support = {202414030736//Medical and Health Science and Technology Project of Shandong Province/ ; ZHKY202423//Chinese Nursing Association Scientific Research Project/ ; QDFY+X 2023125//the Clinical Medicine +X Project of the Affiliated Hospital of Qingdao University/ ; }, } @article {pmid40245393, year = {2025}, author = {Musson, LS and Mitic, N and Leigh-Valero, V and Onambele-Pearson, G and Knox, L and Steyn, FJ and Holdom, CJ and Dick, TJ and van Eijk, RP and van Unnik, JW and Botman, LC and Beswick, E and Murray, D and Griffiths, A and McDermott, C and Hobson, E and Chaouch, A and Hodson-Tole, E}, title = {The Use of Digital Devices to Monitor Physical Behavior in Motor Neuron Disease: Systematic Review.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e68479}, pmid = {40245393}, issn = {1438-8871}, mesh = {Humans ; *Exercise ; *Motor Neuron Disease/diagnosis/physiopathology ; *Wearable Electronic Devices ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a progressive and incurable neurodegenerative disease. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is the primary clinical tool for assessing disease severity and progression in MND. However, despite its widespread use, it does not adequately capture the extent of physical function decline. There is an urgent need for sensitive measures of disease progression that can be used to robustly evaluate new treatments. Measures of physical function derived from digital devices are beginning to be used to assess disease progression. There is value in establishing a consensus approach to standardizing the use of such devices.

OBJECTIVE: We aimed to explore how digital devices are being used to quantify free-living physical behavior in MND. We evaluated the feasibility and assessed the implications for monitoring physical behavior for future clinical trials and clinical practice.

METHODS: Systematic searches of 4 databases were performed in October 2023 and June 2024. Peer-reviewed English-language articles (including preprints) that examined how people living with MND used digital devices to assess their free-living physical behavior were included. Study reporting quality was assessed using a 22-item checklist (maximum possible score=44 points).

RESULTS: In total, 12 articles met the inclusion criteria for data extraction. All studies were longitudinal and observational in design, but data collection, analysis, and reporting protocols varied. Quality assessment scores ranged between 19 and 40 points. Sample sizes ranged between 10 and 376 people living with MND at baseline, declining over the course of the study. Most studies used an accelerometer device worn on the wrist, chest, hip, or ankle. Participants were typically asked to continuously wear devices for 1 to 8 days at 1- to 4-month intervals, with studies running for 12 weeks to 24 months. Some studies asked participants to wear the device continuously for the full duration. Studies derived traditional end points focusing on duration, intensity, and frequency of physical activity or nontraditional end points focusing on features of an individual's movement patterns. The correlation coefficients (r) between physical behavior end points and ALSFRS-R ranged from 0.31 to 0.78. Greater monitoring frequencies and improved end point sensitivity were shown to provide smaller sample size requirements and shorter durations for hypothetical clinical trials. People living with MND found using devices acceptable and reported a low burden. Adherence assessed in 8 (67%) studies was good, ranging from approximately 86% to 96%, with differences evident between wear locations. The perspectives of other end users and implications on clinical practice were not explored.

CONCLUSIONS: Remote monitoring of free-living physical behavior in MND is in its infancy but has the potential to quantify physical function. It is essential to develop a consensus statement, working toward agreed and standardized methods for data collection, analysis, and reporting.}, } @article {pmid40247229, year = {2025}, author = {Samudi Raju, C and Kono, M and Looi, KW and Ong, JX and Tan, CA and Ang, CS and Tan, PHY and Shamnugam, H and Sekaran, SDKC and Syed Omar, SF and Lum, LCS}, title = {Low atypical lymphocyte score as a predictor of non-severe dengue.}, journal = {BMC infectious diseases}, volume = {25}, number = {1}, pages = {551}, pmid = {40247229}, issn = {1471-2334}, mesh = {Humans ; *Dengue/diagnosis/blood/immunology/pathology ; Prospective Studies ; Male ; Female ; Adult ; Middle Aged ; *Lymphocytes/pathology ; Lymphocyte Count ; Severity of Illness Index ; Young Adult ; Prognosis ; Aged ; Adolescent ; }, abstract = {BACKGROUND: Severe dengue has been linked to the presence of atypical lymphocytes, which can be quantified using the Q-flag parameter on a hematology analyzer. A higher atypical lymphocyte count has previously been associated with severe dengue. We aimed to evaluate the feasibility of the atypical lymphocyte score to provide an early prognosis for dengue severity.

METHOD: A prospective observational study enrolled adult patients admitted to the Infectious Disease ward with a febrile illness of less than 7 days. Blood samples obtained daily until discharge, were processed with XN-20 hematology analyzer with specific attention given to atypical lymphocyte score. Severe dengue cases were classified according to the 2009 World Health Organization Classification.

RESULTS: A total of 287 cases of laboratory-confirmed dengue, including 25 severe cases, were included. Dengue fever compared to non-dengue patients manifested increased lymphocytes within the high fluorescent zone on Day 6, The atypical lymphocyte score (ALS) of severe dengue showed an early rise, reaching a saturation point of 300 and remaining stable within the timeframe of days 4 to 8 post-fever onset. All but one severe dengue patient had a score exceeding 100 on day 4 post fever onset.

CONCLUSION: An atypical lymphocyte score below 100 on day 4 post fever onset, may serve as a predictive indicator that severe dengue is less likely to develop, potentially allowing for a lower level of medical intervention. These findings may contribute to more efficient resource allocation during outbreaks.

TRIAL REGISTRATION: The study was registered under National Medical Research Registration of Malaysia, (NMRR-18-3347-45473, 1 Sept 2019).}, } @article {pmid40247237, year = {2025}, author = {Pehlivanidis, A and Kouklari, EC and Kalantzi, E and Korobili, K and Tagkouli, E and Papanikolaou, K}, title = {Self-reported symptoms of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and affective lability in discriminating adult ADHD, ASD and their co-occurrence.}, journal = {BMC psychiatry}, volume = {25}, number = {1}, pages = {391}, pmid = {40247237}, issn = {1471-244X}, mesh = {Humans ; *Attention Deficit Disorder with Hyperactivity/diagnosis/psychology/complications ; *Autism Spectrum Disorder/diagnosis/psychology/complications ; Male ; Adult ; Female ; Self Report ; Diagnosis, Differential ; Middle Aged ; Young Adult ; Psychiatric Status Rating Scales ; *Affective Symptoms/diagnosis/psychology ; Comorbidity ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: To diagnose and manage adults with Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), or their co-occurrence (ADHD + ASD), clinicians must identify specific features that differentiate these diagnostic categories. Self-report questionnaires targeting specific features are widely used and, together with clinical assessments, provide reliable diagnoses. Although affective lability is present in various psychiatric disorders, it lacks specificity when screening for ADHD in the general population, and its discriminant value for ADHD, ASD, and ADHD + ASD has not been studied.

METHODS: This study involved 300 adults without intellectual developmental disorder (188 male) who received an ADHD (n = 174), ASD (n = 68), or ADHD + ASD (n = 58) diagnosis after a multidisciplinary consensus decision according to DSM-5 criteria. Before clinical assessment, all patients requesting evaluation for one of these diagnoses completed questionnaires on an online platform. The assessment instruments included a modified version of the Barkley Adult ADHD Rating Scale (BAARS IV) for ADHD, the Autism Spectrum Quotient (AQ) and the Empathy Quotient (EQ) for ASD features, and the Affective Lability Scale (ALS) for affective lability. Total scores and sub-scores of the instruments were compared among the three groups. Additionally, stepwise logistic regression analyses were conducted to identify specific measures that contribute to group discrimination.

RESULTS: Results revealed distinct patterns in symptomatology as expected. The ADHD and the ADHD + ASD groups presented significantly higher ALS total score compared to ASD. Stepwise logistic regression analyses identified specific measures contributing to group differentiation. ASD vs. ADHD + ASD discrimination included BAARS IV current total score and EQ total score. The subscale anger from ALS in addition with BAARS IV past total score and AQ total score were the factors that discriminated ADHD diagnosis from the co-occurrence of ADHD and ASD. Finally, BAARS IV past total score, BAARS IV current inattention, AQ total score, and EQ total score were found to differentiate ADHD from ASD.

CONCLUSIONS: The study highlights the significance of incorporating emotional dimensions in diagnostic frameworks and may contribute valuable insights for clinicians differentiating neurodevelopmental conditions.}, } @article {pmid40248372, year = {2025}, author = {Dai, ZS and Zhang, M and Deng, YY and Zhou, N and Tian, Y}, title = {Efficacy of a novel artificial liver versatile plasma purification system in patients with acute-on-chronic liver failure.}, journal = {World journal of gastroenterology}, volume = {31}, number = {14}, pages = {103892}, pmid = {40248372}, issn = {2219-2840}, mesh = {Humans ; *Acute-On-Chronic Liver Failure/mortality/therapy/blood ; Female ; Male ; Middle Aged ; Prospective Studies ; *Liver, Artificial ; Treatment Outcome ; Aged ; Patient Readmission/statistics & numerical data ; Adult ; Length of Stay/statistics & numerical data ; Kaplan-Meier Estimate ; Follow-Up Studies ; Peritonitis/epidemiology/etiology ; China/epidemiology ; }, abstract = {BACKGROUND: We have innovatively amalgamated membrane blood purification and centrifugal blood cell separation technologies to address the limitations of current artificial liver support (ALS) models, and develop a versatile plasma purification system (VPPS) through centrifugal plasma separation.

AIM: To investigate the influence of VPPS on long-term rehospitalization and mortality rates among patients with acute-on-chronic liver failure (ACLF).

METHODS: This real-world, prospective study recruited inpatients diagnosed with ACLF from the Second Xiangya Hospital of Central South University between October 2021 and March 2024. Patients were categorized into the VPPS and non-VPPS groups based on the distinct ALS models administered to them. Self-administered questionnaires, clinical records, and self-reported data served as the primary methods for data collection. The laboratory results were evaluated at six distinct time points. All patients were subjected to follow-up assessments for > 12 months. Kaplan-Meier survival analyses and Cox proportional hazards models were used to evaluate the risks of hospitalization and mortality during the follow-up period.

RESULTS: A cohort of 502 patients diagnosed with ACLF was recruited, with 260 assigned to the VPPS group. On comparing baseline characteristics, the VPPS group exhibited a significantly shorter length of stay, higher incidence of spontaneous peritonitis and pulmonary aspergillosis compared to the non-VPPS group (P < 0.05). Age [hazard ratio (HR) = 1.142, 95%CI: 1.01-1.23, P = 0.018), peritonitis (HR = 2.825, 95%CI: 1.07-6.382, P = 0.026), albumin (HR = 0.67, 95%CI: 0.46-0.942, P = 0.023), total bilirubin (HR = 1.26, 95%CI: 1.01-3.25, P = 0.021), international normalized ratio (HR = 1.97, 95%CI: 1.21-2.908, P = 0.014), and VPPS/non-VPPS (HR = 3.24, 95%CI: 2.152-4.76, P < 0.001) were identified as significant independent predictors of mortality in both univariate and multivariate analyses throughout the follow-up period. Kaplan-Meier survival analyses demonstrated significantly higher rehospitalization and mortality rates in the non-VPPS group compared to the VPPS group during follow-up of ≥ 2 years (log-rank test, P < 0.001).

CONCLUSION: These findings suggest that VPPS is safe and has a positive influence on prognostic outcomes in patients with ACLF.}, } @article {pmid40249895, year = {2025}, author = {Vaage, AM and Nakken, O}, title = {Author Response: Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study.}, journal = {Neurology}, volume = {104}, number = {9}, pages = {e209962}, doi = {10.1212/WNL.0000000000209962}, pmid = {40249895}, issn = {1526-632X}, } @article {pmid40249896, year = {2025}, author = {Kawada, T}, title = {Reader Response: Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study.}, journal = {Neurology}, volume = {104}, number = {9}, pages = {e209943}, doi = {10.1212/WNL.0000000000209943}, pmid = {40249896}, issn = {1526-632X}, } @article {pmid40249897, year = {2025}, author = {Siegler, JE and Galetta, SL}, title = {Editors' Note: Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study.}, journal = {Neurology}, volume = {104}, number = {9}, pages = {e213609}, doi = {10.1212/WNL.0000000000213609}, pmid = {40249897}, issn = {1526-632X}, } @article {pmid40250093, year = {2025}, author = {Casiraghi, V and Pellegrini, E and Brusati, A and Peverelli, S and Invernizzi, S and Santangelo, S and Colombrita, C and Verde, F and Ticozzi, N and Silani, V and Ratti, A}, title = {Characterization of human healthy i[3] lower motor neurons exposed to CSF from ALS patients stratified by UNC13A and C9ORF72 genotype.}, journal = {Journal of the neurological sciences}, volume = {473}, number = {}, pages = {123508}, doi = {10.1016/j.jns.2025.123508}, pmid = {40250093}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/genetics/pathology ; *C9orf72 Protein/genetics ; *Motor Neurons/drug effects/metabolism/pathology ; Induced Pluripotent Stem Cells ; *Nerve Tissue Proteins/genetics ; Male ; Genotype ; Female ; Polymorphism, Single Nucleotide/genetics ; Middle Aged ; Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons. Neurodegeneration in ALS might be driven by proteotoxicity or neuroinflammation, which have also been proposed to be promoted by toxic components of the cerebrospinal fluid (CSF). We investigated the possible toxicity of ALS CSF on healthy induced pluripotent stem cells (iPSC)-derived integrated, inducible, and isogenic lower motor neurons (i[3]LMNs). CSFs were obtained from ALS patients homozygous for the risk UNC13A rs12608932 single nucleotide polymorphism (CC) and for the corresponding major allele (AA), ALS patients with C9ORF72 hexanucleotide repeat expansion, and individuals affected by normal pressure hydrocephalus as non-disease controls (ND). A chronic and low-dose sodium arsenite (ARS) treatment was used as positive control of oxidative stress. We found that 10 % ALS CSF treatment for 48 h was not sufficient to induce significant alterations in viability, autophagic flux, axonal degeneration, DNA damage, and Golgi apparatus integrity in healthy i[3]LMNs, in contrast to ARS treatment. Only UNC13A CC CSF significantly increased protein aggregation and Golgi apparatus fragments dimension. RNA-sequencing revealed that all ALS and ND CSFs induced expression changes of few genes, while chronic ARS deregulated the expression of thousands of genes, mostly involved in inflammation and synapse biology. In this work, we demonstrated that in our experimental settings only CSF from UNC13A CC patients induced some ALS-associated pathological features in healthy i[3]LMNs. Further studies will be required to elucidate the mechanistic link between the risk UNC13A genotype and CSF composition and toxicity.}, } @article {pmid40250284, year = {2025}, author = {Calma, AD and Pavey, N and Silva, CS and van den Bos, MAJ and Yiannikas, C and Farrar, MA and Kiernan, MC and Menon, P and Vucic, S}, title = {Diagnostic utility of threshold tracking TMS paradigms in early amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {174}, number = {}, pages = {105-113}, doi = {10.1016/j.clinph.2025.03.044}, pmid = {40250284}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Transcranial Magnetic Stimulation/methods ; Male ; Female ; Middle Aged ; Aged ; *Evoked Potentials, Motor/physiology ; Adult ; Motor Cortex/physiopathology ; Prospective Studies ; }, abstract = {OBJECTIVE: Threshold tracking transcranial magnetic stimulation (TMS) has exhibited utility as a diagnostic technique in Amyotrophic Lateral Sclerosis (ALS). Different threshold tracking paradigms have recently been proposed. The present study assessed the diagnostic utility of serial ascending and parallel threshold tracking TMS in ALS.

METHODS: Threshold tracking TMS was undertaken on 90 prospectively recruited participants suspected of ALS. Short interval intracortical inhibition (SICI) was recorded with serial ascending and parallel threshold tracking paradigms between Interstimulus Interval (ISI) 1-to-7 ms. The primary outcome measure was differences in diagnostic utility of the paradigms in differentiating ALS from ALS mimicking disorders using receiver operating characteristic (ROC) analysis (DeLong statistical method).

RESULTS: Reduction in SICI reliably differentiated ALS from mimic disorders, irrespective of the threshold tracking paradigm. Comparison of area under the curve (AUC) established a significantly higher value for mean SICI (1-7 ms) with the serial ascending SICI paradigm (0.81, 95 % confidence interval 0.72-0.91) compared to the parallel paradigm (SICI 0.72, 95 % confidence interval 0.61-0.83, p = 0.0065). The better diagnostic utility of serial ascending paradigm was evident for SICI recorded between 1-to-5 ms, and was maintained irrespective of disease onset site, degree of functional impairment, and the degree of lower motor neuron dysfunction. A comparable diagnostic utility across threshold tracking paradigms was evident in ALS participants who presented with a relative paucity of upper motor neuron signs.

CONCLUSION: While threshold tracking TMS reliably differentiated ALS from mimic disorders, the present study established better diagnostic utility with the serial ascending threshold tracking TMS paradigm.

SIGNIFICANCE: The serial ascending threshold tracking TMS should be used in a clinical setting as a diagnostic tool for ALS.}, } @article {pmid40251218, year = {2025}, author = {Abid, MN and Siming, L and Chao, H and Amin, M and Sarwer, S}, title = {Enhancing faculty teaching performance through constructive leadership with a mediating role of job satisfaction.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {13454}, pmid = {40251218}, issn = {2045-2322}, mesh = {*Job Satisfaction ; *Leadership ; Humans ; Male ; Female ; Cross-Sectional Studies ; *Teaching ; Adult ; *Faculty/psychology ; Universities ; Pakistan ; Middle Aged ; Surveys and Questionnaires ; }, abstract = {This study explored the impact of constructive leadership styles including transformational leadership (TLS), authentic leadership (ALS), and servant leadership (SLS) on faculty teaching performance (FTP), with job satisfaction (JS) acting as a critical mediator. Using a cross-sectional design and convenience sampling, data were collected from 346 faculty members across six universities in Lahore, Pakistan. Structural equation modeling (SEM) and regression analysis revealed that all three leadership styles significantly enhanced FTP, with transformational leadership showing the strongest influence. Authentic and servant leadership also demonstrated robust positive effects. Job satisfaction emerged as a pivotal mediator, strengthening the relationship between CLS and FTP.These findings highlight the transformative potential of constructive leadership in improving teaching performance and emphasize the critical role of department heads in fostering such practices. By prioritizing strategies to enhance employee motivation and satisfaction, institutions can improve retention, productivity, and overall academic excellence. This study reinforces existing literature on leadership and teaching performance while providing novel insights into the mediating role of job satisfaction, offering actionable implications for academic leadership and organizational development.}, } @article {pmid40251832, year = {2025}, author = {Bresque, M and Esteve, D and Balmer, G and Hamilton, HL and Stephany, JS and Pehar, M and Vargas, MR}, title = {FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.}, journal = {Glia}, volume = {73}, number = {8}, pages = {1627-1641}, pmid = {40251832}, issn = {1098-1136}, support = {R01 NS122973/NS/NINDS NIH HHS/United States ; R01 NS132760/NS/NINDS NIH HHS/United States ; R01NS132760/NH/NIH HHS/United States ; R01NS122973/NH/NIH HHS/United States ; }, mesh = {*Astrocytes/metabolism/drug effects ; Animals ; *Fatty Acid-Binding Protein 7/metabolism/genetics ; Mice ; Humans ; *Endotoxemia/metabolism/chemically induced ; Lipopolysaccharides/toxicity ; Cells, Cultured ; Mice, Inbred C57BL ; Male ; Coculture Techniques ; Tumor Suppressor Proteins ; }, abstract = {Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression in vivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.}, } @article {pmid40252655, year = {2025}, author = {Dame, PS}, title = {The four most common genetic subtypes of amyotrophic lateral sclerosis: state of the art and future directions.}, journal = {The Lancet. Neurology}, volume = {24}, number = {5}, pages = {380-381}, doi = {10.1016/S1474-4422(25)00117-6}, pmid = {40252655}, issn = {1474-4465}, } @article {pmid40252666, year = {2025}, author = {Balendra, R and Sreedharan, J and Hallegger, M and Luisier, R and Lashuel, HA and Gregory, JM and Patani, R}, title = {Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy.}, journal = {The Lancet. Neurology}, volume = {24}, number = {5}, pages = {456-470}, pmid = {40252666}, issn = {1474-4465}, support = {/WT_/Wellcome Trust/United Kingdom ; CC0103/CRUK_/Cancer Research UK/United Kingdom ; R01 NS127186/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *TDP-43 Proteinopathies/genetics/pathology ; *Mutation/genetics ; }, abstract = {Mutations in the TARDBP gene, which encodes the TDP-43 protein, account for only 3-5% of familial cases of amyotrophic lateral sclerosis and less than 1% of cases that are apparently idiopathic. However, the discovery of neuronal inclusions of TDP-43 as the neuropathological hallmark in the majority of cases of amyotrophic lateral sclerosis has transformed our understanding of the pathomechanisms underlying neurodegeneration. An individual TARDBP mutation can cause phenotypic heterogeneity. Most mutations lie within the C-terminus of the TDP-43 protein. In pathological conditions, TDP-43 is mislocalised from the nucleus to the cytoplasm, where it can be phosphorylated, cleaved, and form insoluble aggregates. This mislocalisation leads to dysfunction of downstream pathways of RNA metabolism, proteostasis, mitochondrial function, oxidative stress, axonal transport, and local translation. Biomarkers for TDP-43 dysfunction and targeted therapies are being developed, justifying cautious optimism for personalised medicine approaches that could rescue the downstream effects of TDP-43 pathology.}, } @article {pmid40252901, year = {2025}, author = {Baidya, AT and Dante, D and Das, B and Wang, L and Darreh-Shori, T and Kumar, R}, title = {Discovery and characterization of novel pyridone and furan substituted ligands of choline acetyltransferase.}, journal = {European journal of pharmacology}, volume = {998}, number = {}, pages = {177638}, doi = {10.1016/j.ejphar.2025.177638}, pmid = {40252901}, issn = {1879-0712}, mesh = {*Choline O-Acetyltransferase/metabolism/antagonists & inhibitors/chemistry ; Humans ; Ligands ; *Furans/chemistry/pharmacology/metabolism ; Molecular Dynamics Simulation ; *Drug Discovery ; *Pyridones/chemistry/pharmacology/metabolism ; Molecular Docking Simulation ; *Enzyme Inhibitors/pharmacology/chemistry/metabolism ; Structure-Activity Relationship ; Animals ; }, abstract = {The key to the management of two devastating diseases, namely Alzheimer's Disease (AD) and Amyotrophic Lateral Sclerosis (ALS) lies in an early diagnosis, which is difficult due to its multifactorial nature. However, a common hallmark of AD and ALS is degeneration of cholinergic system. Choline acetyltransferase (ChAT) has been proposed as a potential target for development of cholinergic-specific biomarker. However, lack of selective, potent, brain permeable molecular probes of ChAT hinder development of ChAT biomarkers. In this study, we have successfully utilised structure-based virtual screening approach and identified two ChAT inhibitors from a database of 1.4 million compounds. The compounds were then subjected to rigorous in vitro characterization. Compound V6 showed Ki value of 11 μM and IC50 value of 21.73 μM, while V15 showed Ki and IC50 values of 4.5 and 9.42 μM, respectively for ChAT enzyme. V6 and V15 showed good solubility of 0.21 mg/mL and 0.17 mg/mL respectively and cytotoxicity analysis indicated no toxicity. We also performed a 200 ns molecular dynamics simulation, which revealed the intricate interaction dynamics for V6 and V15 with ChAT binding pocket. Moreover, the Tanimoto similarity analysis indicated the novelty and structural diversity of the hits. In conclusion, these validated hits provide a platform to develop potent, selective, blood-brain barrier permeable small molecules as chemical probes of ChAT or as Positron Emission Tomography tracer for early diagnosis and/or in vivo monitoring of the effect of new therapeutic candidates in spectrum of neurodegenerative disorders, in which cholinergic deficit is one of the hallmarks.}, } @article {pmid40253599, year = {2025}, author = {Malik, M and Bhatti, T and Hodson-Tole, E and Onambele-Pearson, G and Chaouch, A}, title = {Physical activity in amyotrophic lateral sclerosis: a systematic review of the methodologies used to assess a possible association.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {605-622}, doi = {10.1080/21678421.2025.2488298}, pmid = {40253599}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/epidemiology/diagnosis ; *Exercise/physiology ; Surveys and Questionnaires ; Reproducibility of Results ; }, abstract = {Growing evidence suggests that strenuous physical activity (PA) may be associated with an increased risk of developing Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease. However, there are inconsistent findings across studies that may reduce our understanding of any potential associations. We propose that these differences may reflect the tools used to record historical PA. We conducted a systematic review evaluating the risk of developing ALS due to PA. The inclusion criteria were met by 22/113 studies, and an association between increasing PA and ALS was found in 15 studies. Studies that found a positive association were more likely to have longer recall periods and convert data into Metabolic Equivalent of Task values. Studies that did not find an association with increasing PA were more likely to use questionnaires with no validity or reliability data. Questionnaires with validity data all showed at least a moderate correlation of PA compared to objective measures, with reliability ranging from poor to good. Study designs included prospective cohort and case-control, which may also contribute to heterogeneity in findings. This work highlights the need for consensus on the type of questionnaire to use to assess potential associations between PA and ALS.}, } @article {pmid40254133, year = {2025}, author = {Turner-Ivey, B and Jenkins, DP and Carroll, SL}, title = {Multiple Roles for Neuregulins and Their v-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog Receptors in Neurodegenerative Disease Pathogenesis and Therapy.}, journal = {The American journal of pathology}, volume = {195}, number = {11}, pages = {2015-2031}, pmid = {40254133}, issn = {1525-2191}, support = {P30 NS057098/NS/NINDS NIH HHS/United States ; P50 AG016582/AG/NIA NIH HHS/United States ; P50 DC000422/DC/NIDCD NIH HHS/United States ; R01 NS109655/NS/NINDS NIH HHS/United States ; }, abstract = {The role that neurotrophins, such as nerve growth factor, play in the pathogenesis of neurodegenerative diseases has long been appreciated. However, the neuregulin (NRG) family of growth factors and/or their v-erb-B2 avian erythroblastic leukemia viral oncogene homolog (ERBB) receptors have also been implicated in the pathogenesis of conditions, such as Alzheimer disease (AD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). In this review, we consider the structural variability of NRG isoforms generated by alternative RNA splicing, the use of multiple promoters and proteolysis, and the impact of this structural variability on neuronal and glial physiology during development and adulthood. We discuss the NRG receptors ERBB2, ERBB3, and ERBB4, how activation of each of these receptors further diversifies NRG actions in the central nervous system, and how dementia-related proteins, such as γ-secretase modulate the action of NRGs and their ERBB receptors. We then turn to the abnormalities in NRG and ERBB expression and function evident in human AD and mouse AD models, how these abnormalities affect brain function, and attempts to use NRGs to treat AD. Finally, we discuss the effects of NRG on the survival and function of neurons relevant to FTLD and ALS, alterations in NRG/ERBB signaling identified in these conditions, and the recent discovery of multiple human pedigrees in which autosomal dominant FTLD/ALS potentially results from point mutations in ERBB4.}, } @article {pmid40254295, year = {2025}, author = {Epel, ES and White, KE and Brownell, KD and Rodin, J and Hollis, AL and Diefenbach, MA and Alegria, KE and Fromer, E and Czajkowski, SM and Bacon, SL and Revenson, TA and Ruiz, J and Maibach, E and , }, title = {Transforming Health Psychology and Behavioral Medicine to Address the Climate Crisis: A Call for Strategic Research and Advocacy.}, journal = {Annals of behavioral medicine : a publication of the Society of Behavioral Medicine}, volume = {59}, number = {1}, pages = {}, pmid = {40254295}, issn = {1532-4796}, mesh = {Humans ; *Climate Change ; *Behavioral Medicine ; *Health Behavior ; Social Change ; }, abstract = {OBJECTIVE: The climate crisis poses the largest threat to human health and survival and has been a public health emergency for many years. It is causing harmful consequences for physical and mental health and is amplifying existing health inequities. In this call to action, we highlight the relevance of the health psychology and behavioral medicine communities in addressing the health impacts of climate change.

METHOD: We identify mitigation and adaptation climate health behaviors and social changes needed that underlie the three essential objectives to address climate change and its associated health consequences: (a) rapid decarbonization, (b) drawdown of atmospheric heat-trapping gases (sequestration), and (c) adap- tation.

RESULTS: To advance the behavioral and systemic changes necessary to protect health, we propose a 1-2-3 Transformational Model in which the larger field of health psychology and behavioral medicine promotes (1) One Health, human and planetary health by (2) targeting climate health behaviors, and (3) social change across major professional areas, including research, interventions, and education/advo- cacy. We urge the adoption of the social quantum change paradigm, a systems approach to understanding the process of social change, where systemic change is viewed as local to global, and the individual has an influential role.

DISCUSSION: These shifts in views, priorities, and methods will bolster hope, collective efficacy, and action to support the next generation of health psychology and behavioral medicine profession- als. With these changes, the health psychology and behavioral medicine communities can have a more immediate and meaningful impact on the climate crisis and its associated health consequences.}, } @article {pmid40254405, year = {2025}, author = {Shevchuk, DV and Tukhvatulin, AI and Dzharullaeva, AS and Berdalina, IA and Zakharova, MN}, title = {Molecular Biomarkers of Neurodegeneration in Amyotrophic Lateral Sclerosis.}, journal = {Biochemistry. Biokhimiia}, volume = {90}, number = {2}, pages = {276-288}, doi = {10.1134/S0006297924604039}, pmid = {40254405}, issn = {1608-3040}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnosis/pathology/blood ; Biomarkers/metabolism/blood ; Male ; Female ; Middle Aged ; Aged ; Amyloid beta-Peptides/metabolism/blood ; Adult ; tau Proteins/metabolism/blood ; Clusterin ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disease. However, definitive diagnosis could be delayed by up to 12 months due to the lack of specific and sensitive biomarkers for ALS. In our study, conducted for the first time on a large cohort of ALS patients (n = 100) within the Russian population, we assessed key biomarkers of neurodegenerative pathology, including β-amyloids (Aβ40 and Aβ42) and tau proteins (Tau-total and Tau-p181), as well as other pathogenetically relevant, promising biomarkers such as FGF-21, Kallikrein-6 (KLK-6), NCAM-1, Neurogranin (NRGN), TDP-43, Apolipoprotein E4, Clusterin (Apo J), Complement Factor H, Fetuin-A, α2-Macroglobulin, Apo AI, Apo CIII, Apo E, Complement C3, GDNF, sRAGE, and S100B protein. Significant differences between the ALS patients and the control group were observed for Aβ40 (p = 0.044), Aβ42 (p < 0.001), FGF-21 (p < 0.001), Tau-total (p = 0.001), Tau-p181 (p = 0.014), Clusterin (p < 0.001), Complement C3 (p = 0.001), and S100B (p = 0.024). A significant direct correlation was found between the ALSFRS-R score and concentrations of Aβ40 and Aβ42. Changes in the complement system (Complement C3 and Complement Factor H) were identified, highlighting critical role of neuroinflammatory processes in ALS pathogenesis. Additionally, increased levels of FGF-21 were observed in the patients with the bulbar onset of ALS. Significant increase in the concentration of the chaperone protein clusterin in the patients with rapid disease progression suggests its potential as a prognostic biomarker for motor neuron disease. Furthermore, its role in maintaining proteostasis could provide novel therapeutic targets.}, } @article {pmid40255098, year = {2025}, author = {Regnault, R and Kouach, M and Goossens, L and Thuru, X and Bailly, C and Goossens, JF}, title = {HR-MS Analysis of the Covalent Binding of Edaravone to 5-Formylpyrimidine Bases and a DNA Oligonucleotide Containing a 5-Formylcytidine Residue.}, journal = {Rapid communications in mass spectrometry : RCM}, volume = {39}, number = {14}, pages = {e10050}, pmid = {40255098}, issn = {1097-0231}, support = {//Comité de l'Oise de la Ligue Contre le Cancer/ ; //French Ligue Against Cancer/ ; }, mesh = {Edaravone/chemistry ; *Mass Spectrometry/methods ; *Oligonucleotides/chemistry/metabolism ; *Pyrimidines/chemistry ; *DNA/chemistry ; *Cytidine/chemistry/analogs & derivatives ; Cytosine/analogs & derivatives ; }, abstract = {RATIONALE: Edaravone (EDA) is a radical scavenger and an antioxidant drug approved to treat amyotrophic lateral sclerosis and used as a research tool to explore treatment of neurodegenerative diseases and cancers. It is also a reactive agent, known as PMP (1-phenyl-3-methyl-5-pyrazolone), used for the analysis of polysaccharides composition. EDA can react with sugars and aromatic aldehydes. In this context, we have investigated the reactivity of EDA toward the biologically relevant formylated nucleobases, nucleosides, and an oligonucleotide containing a formylated residue.

METHODS: The formation of both mono- and bis-adducts between EDA and the formylated nucleobases (5-formyluracil (5fU) and 5-formylcytosine (5fC)) or the corresponding nucleosides 5-fdU and 5-fdC was characterized using high-resolution mass spectrometry (HR-MS). Similarly, the covalent binding of EDA to an 8-mer palindromic oligonucleotide d (TATG[*C]ATA) containing a single 5-fdC residue [*C] under physiological conditions was investigated using mass spectrometry.

RESULTS: For the first time, EDA is shown to react with formylated pyrimidines. Covalent and stable adducts were identified. EDA was found to react efficiently with the formylated oligonucleotide to generate mono- and bis-adducts. The rate of formation of the mono-adduct was five times higher than that of the bis-adduct. The reaction of EDA with aldehydic DNA modifications such as 5fU/5fC may have important consequences in terms of gene expression.

CONCLUSIONS: These observations raise implications for an epigenetic contribution to the mechanism of action of EDA. The biological implications of our in vitro results are discussed, notably in the frame of neurodegenerative diseases and cancers.}, } @article {pmid40256588, year = {2024}, author = {Ahmady, H and Afrand, M and Motaqi, M and Meftahi, GH}, title = {Utilizing Sertoli Cell Transplantation as a Therapeutic Technique for the Management of Neurodegenerative Diseases.}, journal = {Archives of Razi Institute}, volume = {79}, number = {4}, pages = {701-710}, pmid = {40256588}, issn = {2008-9872}, mesh = {*Neurodegenerative Diseases/therapy ; Humans ; Male ; Animals ; *Sertoli Cells/transplantation ; }, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are defined by aberrant protein accumulation, brain atrophy, and gradual decline of neuronal function. Despite the considerable endeavors devoted to discovering treatments for NDs in recent decades, the demand for efficient therapeutic agents persists. Sertoli cells (SCs) play a crucial role in providing a supportive structure and environment for the development of germ cells. SCs, whether transplanted as xenogeneic or allogeneic cells, present a viable choice for enhancing graft persistence via the release of immunomodulatory and trophic factors, including neurturin (NTN), platelet-derived growth factor, Fas (CD95) ligand (FasL), glial-derived neurotrophic factor, interleukin 1 (IL1), brain-derived neurotrophic factor, interleukin 6 (IL6), transforming growth factors, and vascular growth factor, that protect replaced cells and tissues from the immune system. However, there is currently no cohesive evidence regarding the neuroprotective influence of the transplantation of SCs on NDs. Therefore, this review focuses on assessing stem cells' neuroprotective impact on neurodegenerative diseases in pre-clinical settings and presenting cohesive information. A comprehensive search was conducted between 2000 and 2022. In the identification stage, after a comprehensive search across databases, including Web of Science, Scopus, and PubMed/Medline, 103 papers were obtained. The search conducted in the present study yielded a total of nine relevant papers on the therapeutic effect of the transplantation of SCs on NDs. It was found that the transplantation of SCs exhibits a promising impact on enhancing the symptoms of neurological diseases in rats. The findings highlight the need for multiple standardized pre-clinical trials to find reliable information to confirm the utilization of the transplantation of SCs and the reduction of the symptoms of neurodegenerative diseases.}, } @article {pmid40258293, year = {2025}, author = {Elsayyid, M and Tanis, JE and Yu, Y}, title = {Simple In-Cell Processing Enables Deep Proteome Analysis of Low-Input Caenorhabditis elegans.}, journal = {Analytical chemistry}, volume = {97}, number = {17}, pages = {9159-9167}, pmid = {40258293}, issn = {1520-6882}, support = {T32 GM133395/GM/NIGMS NIH HHS/United States ; R01 GM135433/GM/NIGMS NIH HHS/United States ; P20 GM103446/GM/NIGMS NIH HHS/United States ; S10 OD030321/OD/NIH HHS/United States ; P20 GM139760/GM/NIGMS NIH HHS/United States ; P20 GM104316/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism/chemistry ; *Proteome/analysis ; *Caenorhabditis elegans Proteins/analysis/metabolism ; *Proteomics/methods ; Chromatography, Liquid ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Caenorhabditis elegans is a widely used genetic model organism; however, the worm cuticle complicates extraction of intracellular proteins, a prerequisite for typical bottom-up proteomics. Conventional physical disruption procedures are not only time-consuming but can also cause significant sample loss, making it difficult to perform proteomics with low-input samples. Here, for the first time, we present an on-filter in-cell (OFIC) processing approach that can digest C. elegans proteins directly in the cells of the organism after methanol fixation. With OFIC processing and single-shot LC-MS analysis, we identified over 9400 proteins from a sample of only 200 worms, the largest C. elegans proteome reported to date that did not require fractionation or enrichment. We systematically evaluated the performance of the OFIC approach by comparing it to conventional lysis-based methods. Our data suggest superior performance of OFIC processing for C. elegans proteome identification and quantitation. We further evaluated the OFIC approach with even lower-input samples, including single worms. Then, we used this method to determine how the proteome is impacted by loss of superoxide dismutase sod-1, the ortholog of human SOD1, a gene associated with amyotrophic lateral sclerosis. Analysis of 8800 proteins from only 50 worms as the initial input showed that loss of sod-1 affects the abundance of proteins required for stress response, ribosome biogenesis, and metabolism. In conclusion, our streamlined OFIC approach, which can be broadly applied to other systems, minimizes sample loss while offering the simplest workflow reported to date for C. elegans proteomics.}, } @article {pmid40259624, year = {2025}, author = {Finsterer, J}, title = {Homogeneous ALS Cohorts in Terms of Etiology, onset type, and Vaccination Status Are Required to Assess the Outcome of Their COVID Infection.}, journal = {European journal of neurology}, volume = {32}, number = {4}, pages = {e70161}, pmid = {40259624}, issn = {1468-1331}, } @article {pmid40259632, year = {2025}, author = {García-Casanova, PH and Pérez-Martínez, P and Sevilla, T and Doménech, R and León, M and Vázquez-Costa, JF}, title = {In Response to "Homogeneous ALS Cohorts in Terms of Etiology, Onset Type and Vaccination Status Are Required to Assess the Outcome of Their COVID Infection".}, journal = {European journal of neurology}, volume = {32}, number = {4}, pages = {e70162}, pmid = {40259632}, issn = {1468-1331}, } @article {pmid40260387, year = {2025}, author = {Guo, N and Huang, W and Huang, J and Liu, Y and Zhu, K and Gao, W}, title = {Global research trends in biomarkers, therapeutic targets, and drugs for amyotrophic lateral sclerosis: a bibliometric and visualization analysis.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1588968}, pmid = {40260387}, issn = {1663-9812}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons, marked by complex pathological mechanisms and a lack of effective treatments. Despite substantial global research efforts, no comprehensive bibliometric analysis has systematically mapped the evolution of ALS biomarkers, therapeutic targets, and pharmacological advancements.

METHODS: This study, based on 4,250 publications retrieved from the Web of Science Core Collection (2005-2025), employs bibliometric tools such as CiteSpace and VOSviewer to conduct the first multidimensional analysis of global trends in ALS biomarkers, therapeutic targets, and drug research.

RESULTS: The results revealed contributions from 20,168 authors across 92 countries, with annual publications growing at an average rate of 16.5%. The United States dominated research output, accounting for 34.07% (n=1,448, TLCS=7,100), while the United Kingdom achieved the highest research impact with an average of 68 citations per article. Leading institutions, including the University of Oxford and the University of Milan, consistently produced high-impact studies. Pioneering scholars such as Turner MR and Kiernan MC made significant contributions to advancing therapeutic targets and drug discovery. The interdisciplinary integration of molecular biology and genetics emerged as a core driver of progress in ALS research. Neurofilament light chain (NfL), antisense oligonucleotide (ASO) drugs, transcranial magnetic stimulation (TMS), oxygen free radicals (oxidative stress), and gene therapy have consistently remained central research focuses in the ALS therapeutic field. Looking ahead, stem cell therapy, blood-brain barrier (BBB) penetration technologies, and skeletal muscle targeting are poised to emerge as prominent research directions.

CONCLUSION: The United States dominates ALS research productivity, whereas the United Kingdom demonstrates superior citation influence. Despite China's substantial publication volume, its limited citation impact underscores the necessity for enhanced methodological rigor and strategic international collaboration. Current research priorities encompass NfL, TMS, and ASO therapies, with emerging innovations in stem cell therapy, BBB penetration technologies and skeletal muscle targeting showing therapeutic promise. Future directions should prioritize biomarker standardization, optimization of drug delivery systems, and Clinical Translation.}, } @article {pmid40260525, year = {2025}, author = {Ganapule, A and Garg, D and Agarwal, A and Gupta, A and Rajan, R and Desai, S and Chandarana, M and Sidharth, S and Tripathi, M and Garg, A and Radhakrishnan, DM and Srivastava, AK}, title = {The Expanding Spectrum of Anti-IgLON5 Disease: A Case Series from an Indian Cohort.}, journal = {Annals of Indian Academy of Neurology}, volume = {28}, number = {3}, pages = {440-444}, pmid = {40260525}, issn = {0972-2327}, abstract = {Anti-IgLON5 disease is an evolving entity that lies at the confluence of autoimmunity and neurodegeneration. Reports from India remain sparse. In this series, we describe seven Indian patients with anti-IgLON5-related disease. Patients presented across the fifth to eighth decades with a mean duration of illness of 16 months. All had movement disorders, which included gait ataxia, parkinsonism, and chorea. Six patients had sleep disturbances. Five had a frontal dysexecutive dementia phenotype. Two had epilepsy. Bulbar involvement was present in four, and one had amyotrophic lateral sclerosis (ALS)-like features. Magnetic resonance imaging was abnormal in two cases. Positron emission tomography of the brain also contributed to diagnosis. Combination immunotherapies were used in most of the patients, with three showing a sustained response and two deaths reported due to sepsis-related complications. It is important to recognize the increasing spectrum of IgLON5-related disease to enable timely initiation of immunotherapy before marked degeneration occurs.}, } @article {pmid40261114, year = {2025}, author = {Abati, E}, title = {Regulatory T Cell-Based Therapies - A New Piece of the ALS Therapeutic Puzzle?.}, journal = {NEJM evidence}, volume = {4}, number = {5}, pages = {EVIDe2500078}, doi = {10.1056/EVIDe2500078}, pmid = {40261114}, issn = {2766-5526}, } @article {pmid40261116, year = {2025}, author = {Shneider, NA and Nesta, AV and Rifai, OM and Yasek, J and Elyaman, W and Aziz-Zaman, S and Lyu, MA and Levy, SHS and Hoover, BN and Vlad, G and Huang, M and Zeng, K and Sadeghi, T and Reddy, A and Flowers, CR and Parmar, S}, title = {Clinical Safety and Preliminary Efficacy of Regulatory T Cells for ALS.}, journal = {NEJM evidence}, volume = {4}, number = {5}, pages = {EVIDoa2400249}, doi = {10.1056/EVIDoa2400249}, pmid = {40261116}, issn = {2766-5526}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Middle Aged ; *T-Lymphocytes, Regulatory/transplantation ; Female ; Male ; Aged ; Adult ; Biomarkers/blood ; Treatment Outcome ; Neurofilament Proteins/blood ; }, abstract = {BACKGROUND: Peripheral and neuroinflammation have been previously associated with progression in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease involving progressive loss of motor neurons. We hypothesize that regulatory T cell (Treg) therapy can resolve inflammation and preserve function in those patients with ALS.

METHODS: Participants with ALS received infusions of a fixed dose (100×10[6] cells) of umbilical cord blood-derived, allogeneic, nonhuman leukocyte antigen-matched, cryopreserved Treg product (TREG), administered as four weekly infusions followed by six monthly infusions. No lymphodepletion, immunosuppression, or interleukin 2 was administered. The primary outcome was dose-limiting toxicity, including infusion reaction within 24 hours (as graded by National Cancer Institute - Common Terminology Criteria for Adverse Events, Version 4.0) and/or regimen-related death, or grade 3 or 4 cytokine release syndrome within 14 days postinfusion. We measured clinical response using the Revised ALS Functional Rating Scale (ALSFRS-R; range 0 to 48, with lower numbers indicating lower functional ability). Exploratory analyses measured serum and plasma neurofilament light (NfL) and inflammatory biomarkers.

RESULTS: Six participants with a median age of 48.5 years (range 27 to 66 years) and baseline ALSFRS-R score of 31.5 (range 23 to 43) were treated with a median of 11 (range 6 to 22) TREG infusions in an ambulatory setting. No dose-limiting toxicity was observed. In participants with sufficient data points (n=4), the mean ALSFRS-R slope of decline was -1.66±1.03 points/month before treatment, -0.41±0.45/month during treatment, and -0.60±0.59/month posttreatment. Biomarkers including NfL and inflammatory markers MIP-1δ (macrophage inflammatory protein-1 delta), CTACK (cutaneous T cell-attracting chemokine), and GROα (growth-regulated oncogene alpha) exhibited different relationships with ALSFRS-R score between participants.

CONCLUSIONS: This study demonstrates the preliminary safety of "off-the-shelf", allogeneic Treg-cell therapy.}, } @article {pmid40261626, year = {2025}, author = {Lum, JS and Brown, ML and Suters, SC and Yerbury, JJ and McAlary, L}, title = {In-Gel Zymography of Amyotrophic Lateral Sclerosis-Associated Variants of Superoxide Dismutase-1.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2918}, number = {}, pages = {221-228}, pmid = {40261626}, issn = {1940-6029}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/enzymology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; Humans ; *Enzyme Assays/methods ; *Electrophoresis, Polyacrylamide Gel/methods ; }, abstract = {In-gel zymography allows the separation of protein via electrophoresis and subsequent measurement of enzymatic activity of enzymes from biological mixtures. The antioxidant enzyme superoxide dismutase 1 (SOD1) is an important cytosolic oxygen radical scavenging enzyme that has been implicated in a range of pathologies, including cancer, metabolic and neurodegenerative diseases, most notably amyotrophic lateral sclerosis (ALS). Here, we describe a method to detect and compare SOD1 activity from both cell and tissue samples. This method can be utilized to compare differences between ALS-associated SOD1 genetic variants and pharmacologically treated biological samples.}, } @article {pmid40262277, year = {2025}, author = {Turner, N and Palmer, J and Faull, C and Davidson, S and Turner, MR and Wilson, E}, title = {Tracheostomy ventilation in ALS: healthcare practitioner perspectives on quality of life and implications for decision-making.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {444-451}, doi = {10.1080/21678421.2025.2495014}, pmid = {40262277}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Quality of Life/psychology ; *Tracheostomy/psychology/methods ; Male ; Female ; *Decision Making ; *Health Personnel/psychology ; Qualitative Research ; Middle Aged ; *Attitude of Health Personnel ; *Respiration, Artificial/psychology/methods ; Adult ; }, abstract = {Objectives: This qualitative study aimed to increase understanding of how healthcare practitioners (HCPs) perceive quality of life for people with ALS who use tracheostomy ventilation (TV) and the extent to which such views inform discussions regarding future treatment and care. Methods: A thematic analysis was applied to data derived from online semi-structured interviews with a professionally diverse group of 24 HCPs with experience of supporting people with ALS to use TV. Results: Four main themes relating to TV use emerged: i) Positive benefits; ii) Risks and challenges; iii) Factors influencing HCP perspectives; iv) Concepts informing HCP discussions. HCPs acknowledged that TV has the potential to extend life but were concerned with prolonging a serious decline in physical and cognitive functioning. HCPs tried to identify the 'tipping point' between quantity and quality of life for the individual and their family, taking into account the likelihood of a higher burden of care. HCPs drew on prior experience to assess anticipated quality of life, yet most HCPs in the UK have limited experience of TV for this group. HCPs also drew on principles of person-centered care, patient autonomy and value for money to guide their approach to discussing TV. Conclusions: HCP experience of positive outcomes of TV can foster a more proactive approach to initiating conversations about its potential use. Sharing best practice and improving guidance for HCPs may support early and on-going future care planning and enable people with ALS to make choices which are informed and in their best interests.}, } @article {pmid40262704, year = {2025}, author = {Kim, HB and Ehsan, MF and Alshawabkeh, AN and Kim, JG}, title = {Electrochemical activation of alum sludge for the adsorption of lead (Pb(II)) and arsenic (As): Mechanistic insights and machine learning (ML) analysis.}, journal = {Bioresource technology}, volume = {430}, number = {}, pages = {132563}, pmid = {40262704}, issn = {1873-2976}, support = {P42 ES017198/ES/NIEHS NIH HHS/United States ; }, mesh = {Adsorption ; *Lead/isolation & purification/chemistry ; *Machine Learning ; *Sewage/chemistry ; *Alum Compounds/chemistry ; *Arsenic/isolation & purification/chemistry ; *Water Pollutants, Chemical/isolation & purification ; *Electrochemical Techniques/methods ; Water Purification/methods ; }, abstract = {Alum sludge (AlS) has emerged as an effective adsorbent for anionic contaminants, with traditional activation methods like acid/base treatments and calcination employed to enhance its adsorption capacity. However, these approaches encounter significant drawbacks, including excessive waste generation, structural degradation, and limited efficacy for cationic contaminants. To overcome these challenges, this study proposes electrochemical activation as a sustainable method to enhance alum sludge adsorption performance by generating oxygen-containing functional groups (O-FGs) on its surface. In particular, cathodic activated AlS (E-AlS) leads to the formation of hydroxyl (-OH) and carboxyl (-COOH) groups, which served as key active sites for Pb(II) adsorption through complexation mechanisms. E-AlS effectively removed both Pb(II) and As within 4 h, showcasing its dual functionality for cationic and anionic contaminants. While HCl- and KOH-activated AlS also achieved 100 % Pb(II) removal, they caused substantial aluminum (Al) leaching, exceeding 1,000 mg/L, due to structural instability. In contrast, E-AlS minimized Al leaching, preserved structural integrity, and exhibited a 6.5-fold higher Pb(II) adsorption capacity than raw AlS. X-ray photoelectron spectroscopy (XPS) and machine learning (ML) validated the enhanced adsorption performance of E-AlS. These findings highlight electrochemical activation as a cost-effective and environmentally friendly remediation.}, } @article {pmid40262868, year = {2025}, author = {Shi, Y and Wu, Z and Cheng, R and Zhang, L and Guo, X and Li, X and Bi, Y}, title = {The Trp-574-Leu mutations together with enhanced metabolism contribute to cross-resistance to ALS inhibiting herbicides in Fimbristylis littoralis.}, journal = {Pesticide biochemistry and physiology}, volume = {210}, number = {}, pages = {106385}, doi = {10.1016/j.pestbp.2025.106385}, pmid = {40262868}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Herbicides/pharmacology ; *Herbicide Resistance/genetics ; Mutation ; Molecular Docking Simulation ; *Plant Proteins/genetics/metabolism/antagonists & inhibitors ; Sulfonylurea Compounds/pharmacology ; Piperonyl Butoxide/pharmacology ; }, abstract = {Fimbristylis littoralis Gaudich., an important weed in Chinese paddy fields, has caused significant yield losses in rice and other crops. Acetolactate synthase (ALS) inhibitors, such as halosulfuron-methyl, are widely used for weed control. This study identified a highly resistant population (R23-1) of F. littoralis to halosulfuron-methyl, with an exceptionally high resistance index (RI) of 3441.66. The resistant mechanisms of F. littoralis to ALS inhibitors have not been reported previously. We employed a comprehensive approach to address this, including whole-plant bioassay, ALS target gene sequencing, molecular docking, synergistic tests with metabolic enzyme inhibitors, glutathione S-transferases (GSTs) activity assays, and cross-resistance testing. The results revealed the first report of a Trp-574-Leu mutation in the ALS gene of the R23-1 population, which significantly increased binding energy, as shown by molecular docking analysis. Synergistic tests demonstrated that the cytochrome P450 monooxygenase (P450) inhibitor piperonyl butoxide (PBO) and the GSTs inhibitor 4-chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) markedly enhanced the sensitivity of the R23-1 population to halosulfuron-methyl, with synergistic ratios of 4.11 and 8.15, respectively, while malathion had no effect. GST activity decreased in both populations after halosulfuron-methyl treatment, with the R23-1 population consistently showing significantly higher levels, peaking on day five. Furthermore, the R23-1 population demonstrated cross-resistance to multiple ALS inhibitors. These findings provide novel insights into the resistance mechanisms of F. littoralis and lay a theoretical foundation for developing effective strategies to mitigate or delay the evolution of resistance.}, } @article {pmid40263468, year = {2025}, author = {Su, Y and Schwartz, M and Fayad, I and García, M and Zavala, MA and Tijerín-Triviño, J and Astigarraga, J and Cruz-Alonso, V and Liu, S and Zhang, X and Chen, S and Ritter, F and Besic, N and d'Aspremont, A and Ciais, P}, title = {Canopy height and biomass distribution across the forests of Iberian Peninsula.}, journal = {Scientific data}, volume = {12}, number = {1}, pages = {678}, pmid = {40263468}, issn = {2052-4463}, support = {ANR-22-FAI1-0002//Agence Nationale de la Recherche (French National Research Agency)/ ; ANR-22-FAI1-0002//Agence Nationale de la Recherche (French National Research Agency)/ ; ANR-22-FAI1-0002//Agence Nationale de la Recherche (French National Research Agency)/ ; ANR-22-FAI1-0002//Agence Nationale de la Recherche (French National Research Agency)/ ; }, mesh = {*Forests ; *Biomass ; Spain ; Remote Sensing Technology ; *Trees ; Ecosystem ; Climate Change ; Deep Learning ; }, abstract = {Accurate mapping of vegetation canopy height and biomass distribution is essential for effective forest monitoring, climate change mitigation, and sustainable forestry. Here we present high-resolution remote sensing-based canopy height (10 m resolution) and above ground biomass (AGB, 50 m resolution) maps for the forests of the Iberian Peninsula from 2017 to 2021, using a deep learning framework that integrates Sentinel-1, Sentinel-2, and LiDAR data. Two UNET models were developed: one trained on Airborne Laser Scanning (ALS) data (MAE: 1.22 m), while another using Global Ecosystem Dynamics Investigation (GEDI) footprints (MAE: 3.24 m). External validation with 6,308 Spanish National Forest Inventory (NFI) plots (2017-2019) confirmed canopy height reliability, showing MAEs of 2-3 m in tree-covered areas. AGB estimates were obtained through Random Forest models that linked UNET derived height predictions to NFI AGB data, achieves an MAE of ~29 Mg/ha. The creation of high-resolution maps of canopy height and biomass across various forest landscapes in the Iberian Peninsula provides a valuable new tool for environmental researchers, policy makers, and forest management professionals, offering detailed insights that can inform conservation strategies, carbon sequestration efforts, and sustainable forest management practices.}, } @article {pmid40264898, year = {2024}, author = {Kumar, J and Varela-Ramirez, A and Narayan, M}, title = {Development of novel carbon-based biomedical platforms for intervention in xenotoxicant-induced Parkinson's disease onset.}, journal = {BMEmat}, volume = {2}, number = {4}, pages = {}, pmid = {40264898}, issn = {2751-7446}, support = {G12 MD007592/MD/NIMHD NIH HHS/United States ; R16 GM145575/GM/NIGMS NIH HHS/United States ; }, abstract = {Chronic exposure to herbicides, weedicides, and pesticides is associated with the onset and progress of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we have investigated whether quinic- and chlorogenic-acid-derived Carbon Quantum Dots (QACQDs and ChACQDs, respectively) protect against a (pesticide) paraquat-insult model of PD. Our results indicated that both types of CQDs intervened in the soluble-to-toxic transformation of the amyloid-forming model protein Hen Egg White Lysozyme (HEWL). Furthermore, QACQDs and ChACQDs demonstrated antioxidant activity while remaining biocompatible in a human neuroblastoma-derived cell line (SH-SY5Y) up to 5 mg/ml and protected the cell line from the environmental neurotoxicant (paraquat). Importantly, both CQDs were found to protect dopaminergic neuronal ablation in a paraquat model of Parkinson's disease using the nematode C. elegans. Our results are significant because both plant-derived organic acids cross the blood-brain barrier, making them attractive for developing CQD architectures. Furthermore, since the synthesis of these CQDs was performed using green chemistry methods from precursor acids that cross the BBB, these engineered bionanomaterial platforms are tantalizing candidates for preventing neurodegenerative disorders associated with exposure to environmental neurotoxicants.}, } @article {pmid40265276, year = {2025}, author = {Mendonça, IP and Peixoto, CA}, title = {The Double-Edged Sword: The Complex Function of Enteric Glial Cells in Neurodegenerative Diseases.}, journal = {Journal of neurochemistry}, volume = {169}, number = {4}, pages = {e70069}, doi = {10.1111/jnc.70069}, pmid = {40265276}, issn = {1471-4159}, support = {CNPq;#301891/2022-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; IAM-PROEP# 005-FIO-22//Instituto Aggeu Magalhães/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism ; *Neuroglia/metabolism/pathology/physiology ; Animals ; *Enteric Nervous System/pathology/metabolism ; }, abstract = {Over the past two decades, a growing number of studies have been conducted on the role of bidirectional communication through the gut-brain axis in the development of neurodegenerative diseases. These studies were driven by the curious fact that all of these diseases present varying degrees of intestinal involvement included in their wide range of symptoms. A population of cells belonging to the ENS, called enteric glial cells (EGCs), appears to actively participate in this communication between the intestine and the brain, but acting in a dualistic manner, sometimes in reactive gliosis releasing inflammatory mediators, sometimes promoting homeostasis and resilience in the face of inflammatory injuries. To date, the intracellular mechanisms that define the transcriptional profile expressed in EGCs in each situation have not yet been elucidated. This review proposes a discussion on: (1) the complex role of distinct phenotypes of enteric glial cells involved in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS); and (2) innovative strategies such as IDO/TDO inhibitors, Brazil nuts, caffeic acid, polyphenols, among others, that act on EGCs and have the potential to treat neurodegenerative diseases.}, } @article {pmid40265300, year = {2025}, author = {Xu, IQ and Guo, L and Xu, J and Setiawan, S and Deng, X and Lo, YL and Chai, JYH and Simmons, Z and Ramasamy, S and Yeo, CJJ}, title = {Predictive Analysis of Amyotrophic Lateral Sclerosis Progression and Mortality in a Clinic Cohort From Singapore.}, journal = {Muscle & nerve}, volume = {72}, number = {1}, pages = {71-81}, pmid = {40265300}, issn = {1097-4598}, support = {C210112024//Agency for Science, Technology and Research/ ; IRNMR21CPGJJ//National Neuroscience Institute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/epidemiology ; Singapore/epidemiology ; Male ; Female ; Middle Aged ; Aged ; *Disease Progression ; Registries ; Retrospective Studies ; Cohort Studies ; Machine Learning ; Adult ; }, abstract = {INTRODUCTION: There is currently no comprehensive Amyotrophic Lateral Sclerosis (ALS) patient database in Singapore comparable to those available in Europe and the United States. We established the Singapore ALS registry (SingALS) to draw meaningful inferences about the ALS population in Singapore through developing statistical and machine learning-based predictive models.

METHODS: The SingALS registry was established through the retrospective collection of demographic, clinical, and laboratory data from 72 ALS patients at Tan Tock Seng Hospital (TTSH) and combining it with demographic and clinical data from 71 patients at Singapore General Hospital (SGH). The SingALS was compared against international ALS registries. Using comparative studies including survival and temporal feature analysis, we identified key factors influencing ALS survival and developed a machine learning model to predict survival outcomes.

RESULTS: Compared to Caucasian-dominant registries, such as the German Swabia registry, SingALS patients had longer average survival (50.51 vs. 31.0 months), younger age of onset (56.18 vs. 66.6 years), and lower bulbar onset prevalence (20.98% vs. 34.10%). Singaporean males had poorer outcomes compared to females, with a hazard ratio (HR) of 3.12 (p = 0.008). Patients who died within 24 months had an earlier need for being bedbound (p < 0.004), percutaneous endoscopic gastrostomy (PEG) insertion (p = 0.004) and non-invasive ventilation (NIV) (p < 0.001). Machine learning and statistical analysis indicated that a steeper ALSFRS-R slope, higher alkaline phosphatase (ALP), white blood cell (WBC), absolute neutrophil counts, and creatinine levels are associated with worse mortality.

DISCUSSION: We developed a comprehensive Singaporean ALS registry and identified key factors influencing survival.}, } @article {pmid40267187, year = {2025}, author = {Guillaud, L and Garanzini, A and Zakhia, S and De la Fuente, S and Dimitrov, D and Boerner, S and Terenzio, M}, title = {Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.}, journal = {Science advances}, volume = {11}, number = {17}, pages = {eadq6077}, pmid = {40267187}, issn = {2375-2548}, mesh = {*Adenosine Triphosphate/metabolism ; Humans ; Animals ; *Protein Aggregation, Pathological/metabolism/pathology ; Mice ; *Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Axons/metabolism ; Viscosity ; Mitochondria/metabolism ; Protein Aggregates ; Parkinson Disease/metabolism/pathology ; DNA-Binding Proteins/metabolism ; Alzheimer Disease/metabolism/pathology ; }, abstract = {Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) condensed and underwent ATP-dependent liquid phase separation in vitro. Human inducible pluripotent stem cell-derived neurons from patients with PD and ALS displayed reduced axoplasmic fluidity and decreased intracellular ATP. Last, nicotinamide mononucleotide treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from patients with PD and ALS and reduced TAR DNA-binding protein 43 (TDP-43) aggregation in human motor neurons derived from a patient with ALS. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis under both physiological and pathological conditions.}, } @article {pmid40267236, year = {2025}, author = {Zhong, H and Zhu, J and Liu, S and Zhou, D and Long, Q and Wu, C and Zhao, B and Cheng, C and Yang, Y and Wu, Q and Wu, Y and Li, C and Wang, Z and Wu, J and Guo, X and Zhi, D and Deng, Y and Wu, L}, title = {Linking DNA methylation in brain regions to Alzheimer's disease risk: a Mendelian randomization study.}, journal = {Human molecular genetics}, volume = {34}, number = {12}, pages = {1026-1033}, pmid = {40267236}, issn = {1460-2083}, support = {P30 CA071789/CA/NCI NIH HHS/United States ; R01 CA269764/CA/NCI NIH HHS/United States ; //University of Hawai'i Cancer Center/ ; }, mesh = {Humans ; *DNA Methylation/genetics ; *Alzheimer Disease/genetics/pathology/metabolism ; Mendelian Randomization Analysis ; Quantitative Trait Loci/genetics ; Polymorphism, Single Nucleotide/genetics ; *Brain/metabolism/pathology ; Genetic Predisposition to Disease ; Male ; Female ; CpG Islands/genetics ; Aged ; Genome-Wide Association Study ; Risk Factors ; }, abstract = {AIM: DNA methylation in brain regions represents a potential mechanism linking genetic variation to Alzheimer's disease (ad) risk, yet most studies have focused on blood-derived methylation markers. In this study, we conducted a systematic Mendelian randomization (MR) study to evaluate associations between predicted brain region-specific DNA methylation levels and ad risk, using methylation quantitative trait loci (mQTL) as genetic instruments.

METHODS: We analyzed mQTLs from five human brain regions: cerebellum (CRBLM), frontal cortex (FCTX), causal pons (PONS), and temporal cortex (TCTX) from 600 individuals in Gibbs et al's study, as well as mQTLs from dorsolateral prefrontal cortex (DLPFC) of 543 participants in the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). In our MR analyses, we integrated these mQTLs with single nucleotide polymorphisms (SNP)-ad risk summary statistics derived from 85 934 ad-related cases and 401 577 normal controls.

RESULTS: Among 62 554 cytosine-guanine dinucleotide (CpG) sites, we identified 597 CpG sites (CpGs) significantly associated with ad risk (false discovery rate (FDR) < 0.05). Of these, 289 were confirmed through colocalization and summary-based MR (SMR) analyses, including one CpG site in CRBLM, 285 in DLPFC, one in FCTX, two in PONS, and one in TCTX. By integrating gene expression data, we identified 19 CpG sites with consistent associations across methylation levels, expression of eight target genes, and ad risk, including novel regulatory mechanisms involving RITA1's modulation of cg11558705 and PCGF3's regulation of cg10009224.

CONCLUSION: Our findings highlight brain region-specific DNA methylation as a mediator of genetic risk for ad, offering insights into ad pathogenesis and identifying potential therapeutic targets.}, } @article {pmid40267619, year = {2025}, author = {Garnés-Camarena, O and Mahíllo-Fernández, I and Martínez-Ulloa, P and Mandeville, R and Lorenzo, O and Stashuk, DW}, title = {Towards early diagnosis of amyotrophic lateral sclerosis using near fibre EMG.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {174}, number = {}, pages = {114-122}, doi = {10.1016/j.clinph.2025.04.006}, pmid = {40267619}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Electromyography/methods ; Male ; Female ; Middle Aged ; Aged ; Retrospective Studies ; Early Diagnosis ; Adult ; Motor Neurons/physiology ; Muscle, Skeletal/physiopathology/innervation ; *Muscle Fibers, Skeletal/physiology ; Action Potentials/physiology ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons and diagnosis is usually delayed several months. The continuous denervation and reinnervation associated with ALS are manifest in EMG signals as changes in motor unit potential (MUP) size, temporal dispersion and instability. Near Fibre EMG is a novel method to assess early changes in MUP temporal dispersion and instability using routinely recorded EMG signals in a semi-automated manner.

METHODS: Near Fibre EMG values from 2318 MUs, retrospectively sampled at the time of ALS diagnosis, from 96 muscles of 15 patients were compared with values from 3954 MUs sampled from 109 muscles of 84 reference subjects.

RESULTS: 30.1% and 46.1% of ALS MUs had MUPs with increased complexity or instability, respectively, and 17.4% had both. The potential importance and heightened sensitivity of NFEMG was highlighted when analyzing normal-sized motor units; as many as 24% of the normal-sized MUPs actually had significant instability, while 14% had increased complexity, and 7.4% had both.

CONCLUSIONS: Near Fibre EMG can characterize motor unit electrophysiological status and hence help quantify the degree, and course of denervation and reinnervation.

SIGNIFICANCE: Near-Fiber EMG offers the potential to facilitate earlier ALS diagnosis, which, as promising therapies become available, can be consequential.}, } @article {pmid40267658, year = {2025}, author = {Orsucci, D and Vista, M and Santorelli, FM}, title = {Conversational AI in neurogenetics. The example of FUS gene.}, journal = {Journal of the neurological sciences}, volume = {473}, number = {}, pages = {123511}, doi = {10.1016/j.jns.2025.123511}, pmid = {40267658}, issn = {1878-5883}, } @article {pmid40268233, year = {2025}, author = {Basak, B and Holzbaur, ELF}, title = {Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.}, journal = {Journal of molecular biology}, volume = {437}, number = {18}, pages = {169161}, doi = {10.1016/j.jmb.2025.169161}, pmid = {40268233}, issn = {1089-8638}, mesh = {*Mitophagy ; Humans ; *Neurons/metabolism ; *Homeostasis ; *Mitochondria/metabolism ; Animals ; Ubiquitin-Protein Ligases/metabolism/genetics ; Protein Kinases/metabolism ; *Mitochondrial Turnover ; Parkinson Disease/metabolism ; PTEN-Induced Putative Kinase ; }, abstract = {Mitochondrial quality control is instrumental in regulating neuronal health and survival. The receptor-mediated clearance of damaged mitochondria by autophagy, known as mitophagy, plays a key role in controlling mitochondrial homeostasis. Mutations in genes that regulate mitophagy are causative for familial forms of neurological disorders including Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). PINK1/Parkin-dependent mitophagy is the best studied mitophagy pathway, while more recent work has brought to light additional mitochondrial quality control mechanisms that operate either in parallel to or independent of PINK1/Parkin mitophagy. Here, we discuss our current understanding of mitophagy mechanisms operating in neurons to govern mitochondrial homeostasis. We also summarize progress in our understanding of the links between mitophagic dysfunction and neurodegeneration, and highlight the potential for therapeutic interventions to maintain mitochondrial health and neuronal function.}, } @article {pmid40271071, year = {2025}, author = {Luo, H and Wei, S and Fu, S and Han, L}, title = {Role of Achyranthes aspera in neurodegenerative diseases: current evidence and future directions.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1511011}, pmid = {40271071}, issn = {1663-9812}, abstract = {Neurodegenerative diseases are caused by the progressive degeneration of neurons and/or their myelin sheaths, ultimately leading to cognitive and motor dysfunction. Due to their complex pathogenesis and the limited efficacy of therapeutic drugs, these diseases have attracted significant attention. Achyranthes aspera, belongs to family Amaranthaceae, has been extensively used in the traditional and folk medicines for the treatment of various ailments. Modern research has revealed that Achyranthes aspera possesses various pharmacological effects, including cardiocerebrovascular protection, immune regulation, antioxidation, and anti-aging. Furthermore, the neuroprotective effects of Achyranthes aspera have been confirmed by numerous scientific studies. This review focuses on the primary pharmacological effects and mechanisms of Achyranthes aspera in the prevention and treatment of neurodegenerative diseases, as well as their potential application prospects. This review aims to provide insights into the potential clinical applications and research directions of Achyranthes aspera in neurodegenerative diseases.}, } @article {pmid40271315, year = {2025}, author = {Honda, N and Watanabe, Y and Honda, H and Uemoto, M and Fukuhara, H and Hanajima, R}, title = {Implications of Mutant SOD1 on RNA Processing and Interferon Responses in Amyotrophic Lateral Sclerosis: Omics Data Analysis.}, journal = {Cureus}, volume = {17}, number = {3}, pages = {e81045}, pmid = {40271315}, issn = {2168-8184}, abstract = {INTRODUCTION: Cytoplasmic inclusions are observed in motor neurons in amyotrophic lateral sclerosis (ALS) associated with the Cu/Zn superoxide dismutase mutation (mtSOD1). Although these inclusions are a hallmark of the disorder, degeneration is not necessarily initiated in the cytoplasm, nor are these structures the culprit of ALS. The nucleus stores genetic material and acts as the cell's control center, and a small fraction of mtSOD1 is reported to be distributed in the nucleus. We hypothesized that mtSOD1 in the nucleus contributes to motor neuron degeneration.

METHODS: We explored the roles of mtSOD1 in relation to nuclear proteins, chromosomal DNA, and mRNA expression. An immortalized cell line derived from a transgenic ALS mouse model expressing mtSOD1-L126delTT with a FLAG was used for stable immunoprecipitation of mtSOD1-binding molecules using shotgun proteomics and chromatin immunoprecipitation-sequencing (ChIP-seq). We also examined mRNA expression by silencing whole SOD1 (innate mouse Sod1 and mtSOD1) or mtSOD1 alone and compared these patterns against those in non-silenced counterparts.

RESULTS: We identified 392 mtSOD1-interacting proteins in the nucleus. Gene ontology (GO) revealed these proteins to be enriched for "mRNA processing." Notably, more than 11% of mtSOD1-interacting proteins were expressed concurrently with previously reported wild-type TAR DNA-binding protein 43 (TDP-43)-interacting proteins. ChIP-seq revealed that mtSOD1-interacting DNA portions showed a preference for zinc finger protein-binding motifs. GO analysis of the ChIP-seq data revealed that "mRNA processing" was again enriched among the genes harboring mtSOD1-binding domains. RNA expression analyses revealed that the presence of mouse Sod1 and mtSOD1 induced the overexpression of molecules related to "type 1 IFN responses."

CONCLUSIONS: We revealed that mtSOD1 interacted with nuclear proteins and specific DNA segments and that RNA expression was notably altered when mouse Sod1 and mtSOD1 were silenced. These interactions could play a pivotal role in motor neuron degeneration.}, } @article {pmid40271431, year = {2025}, author = {Rana, A and Katiyar, A and Arun, A and Berrios, JN and Kumar, G}, title = {Natural sulfur compounds in mental health and neurological disorders: insights from observational and intervention studies.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1534000}, pmid = {40271431}, issn = {2296-861X}, abstract = {Over the years, the global disease burden of neurological disorders (NDs) and mental disorders (MDs) has significantly increased, making them one of the most critical concerns and challenges to human health. In pursuit of novel therapies against MD and ND, there has been a growing focus on nutrition and health. Dietary sulfur, primarily derived from various natural sources, plays a crucial role in numerous physiological processes, including brain function. This review offers an overview of the chemical composition of several natural sources of the sulfur-rich substances such as isothiocyanates, sulforaphane, glutathione, taurine, sulfated polysaccharides, allyl sulfides, and sulfur-containing amino acids, all of which have neuroprotective properties. A multitude of studies have documented that consuming foods that are high in sulfur enhances brain function by improving cognitive parameters and reduces the severity of neuropathology by exhibiting antioxidant and anti-inflammatory properties at the molecular level. In addition, the growing role of natural sulfur compounds in repairing endothelial dysfunction, compromising blood-brain barrier and improving cerebral blood flow, are documented here. Furthermore, this review covers the encouraging results of supplementing sulfur-rich diets in many animal models and clinical investigations, along with their molecular targets in MD, such as schizophrenia, depression, anxiety, bipolar disorder, and autism spectrum disorder, and ND, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS). The prospects of natural sulfur compounds show great promise as they have potential applications in nutraceuticals, medicines, and functional foods to enhance brain function and prevent diseases. However, additional research is required to clarify the mechanisms by which it works, enhance its bioavailability, and evaluate its long-term safety for broad use.}, } @article {pmid40272376, year = {2025}, author = {Nguyen, THV and Ferron, F and Murakami, K}, title = {Neurotoxic Implications of Human Coronaviruses in Neurodegenerative Diseases: A Perspective from Amyloid Aggregation.}, journal = {ACS chemical biology}, volume = {20}, number = {5}, pages = {983-992}, doi = {10.1021/acschembio.5c00153}, pmid = {40272376}, issn = {1554-8937}, mesh = {Humans ; *Neurodegenerative Diseases/virology/metabolism ; *Amyloid/metabolism/chemistry ; *Coronavirus/metabolism/pathogenicity ; *Coronavirus Infections/complications/virology ; }, abstract = {Human coronaviruses (HCoVs) include seven species: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1, and SARS-CoV-2. The last three, classified as Betacoronaviruses, are highly transmissible and have caused severe pandemics. HCoV infections primarily affect the respiratory system, leading to symptoms such as dry cough, fever, and breath shortness, which can progress to acute respiratory failure and death. Beyond respiratory effects, increasing evidence links HCoVs to neurological dysfunction. However, distinguishing direct neural complications from preexisting disorders, particularly in the elderly, remains challenging. This study examines the association between HCoVs and neurodegenerative diseases like Alzheimer disease, Parkinson disease, Lewy body dementia, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease. It also presents the long-term neurological effects of HCoV infections and their differential impact across age groups and sexes. A key aspect of this study is the investigation of the sequence and structural similarities between amyloidogenic and HCoV spike proteins, which can provide insights into potential neuropathomechanisms.}, } @article {pmid40273110, year = {2025}, author = {Souza, AA and Silva, STD and Régis, AMP and Aires, DN and Pondofe, KM and Melo, LP and Valentim, RAM and Lindquist, ARR and Macedo, LRD and Ribeiro, TS}, title = {Muscle strengthening in individuals with Amyotrophic Lateral Sclerosis: a systematic review with meta-analyses.}, journal = {PloS one}, volume = {20}, number = {4}, pages = {e0320788}, pmid = {40273110}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation/therapy ; *Muscle Strength/physiology ; *Resistance Training/methods ; *Exercise Therapy/methods ; }, abstract = {Despite the observed benefits of properly prescribed exercises for people with Amyotrophic Lateral Sclerosis (ALS), the scarcity of studies and lack of consensus on the effects of muscle-strengthening exercises on this population has a negative impact on their rehabilitation. This study aimed to evaluate the effects of muscle-strengthening interventions in individuals with ALS. This systematic review of intervention studies included clinical trials that performed non-respiratory muscle strengthening in people with ALS compared to non-strengthening interventions, usual care, or placebo. Such studies were obtained from the MEDLINE, EMBASE, Cochrane Library, SPORTDiscus, and Physiotherapy Evidence Database databases, with no language or publication date restrictions. The outcomes considered were peripheral muscle strength, functionality, fatigue, and adverse events. The Physiotherapy Evidence Database scale was used to analyze the risk of bias, while the Grading of Recommendations Assessment, Development and Evaluation system was used to evaluate the quality of the evidence. Searches were conducted in October 2023 and eight studies were included, totaling 296 individuals. Seven of the eight studies showed superiority of the experimental intervention over the control, but this was not supported in the meta-analyses. Small sample size and high heterogeneity in the primary studies contributed significantly to the low quality of the evidence. There was no evidence of the superiority of interventions for muscle strengthening compared to interventions not aimed at strengthening, usual care, or placebo in terms of the outcomes analyzed immediately after the intervention. The quality of the evidence ranged from low to very low. Five of the studies evaluated adverse events, without reporting serious events. Interventions for muscle strengthening did not prove to be more effective when compared to the control group in the short term nor seem to produce serious adverse events. The low quality of the evidence indicates the need for studies with greater methodological rigor in this population, to more assertively assess the impacts of this intervention over the short, medium, and long term.}, } @article {pmid40275359, year = {2025}, author = {Grima, N and Smith, AN and Shepherd, CE and Henden, L and Zaw, T and Carroll, L and Rowe, DB and Kiernan, MC and Blair, IP and Williams, KL}, title = {Multi-region brain transcriptomic analysis of amyotrophic lateral sclerosis reveals widespread RNA alterations and substantial cerebellum involvement.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {40}, pmid = {40275359}, issn = {1750-1326}, support = {Discovery Grant//FightMND/ ; Grant-in-Aid//Motor Neurone Disease Research Australia/ ; R28AA012725/AA/NIAAA NIH HHS/United States ; Investigator Grant 1176913//National Health and Medical Research Council/ ; R28 AA012725/AA/NIAAA NIH HHS/United States ; Not applicable//Neuroscience Research Australia/ ; Angie Cunningham PhD Scholarship and Project Grant-In-Aid Award//FightMND/ ; Ideas Grant 2011120//National Health and Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Cerebellum/metabolism/pathology ; Male ; Female ; Middle Aged ; Aged ; *Transcriptome/genetics ; *Brain/metabolism/pathology ; Gene Expression Profiling/methods ; Motor Cortex/metabolism/pathology ; Aged, 80 and over ; *RNA/genetics/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor neurons, causing progressive muscle weakness and paralysis. While research has focused on understanding pathological mechanisms in the motor cortex and spinal cord, there is growing evidence that extra-motor brain regions may also play a role in the pathogenesis or progression of ALS.

METHODS: We generated 165 sample-matched post-mortem brain transcriptomes from 22 sporadic ALS patients with pTDP-43 pathological staging and 11 non-neurological controls. For each individual, five brain regions underwent mRNA sequencing: motor cortex (pTDP-43 inclusions always present), prefrontal cortex and hippocampus (pTDP-43 inclusions sometimes present), and occipital cortex and cerebellum (pTDP-43 inclusions rarely present). We examined gene expression, cell-type composition, transcript usage (% contribution of a transcript to total gene expression) and alternative splicing, comparing ALS-specific changes between brain regions. We also considered whether post-mortem pTDP-43 pathological stage classification defined ALS subgroups with distinct gene expression profiles.

RESULTS: Significant gene expression changes were observed in ALS cases for all five brain regions, with the cerebellum demonstrating the largest number of total (> 3,000) and unique (60%) differentially expressed genes. Pathway enrichment and predicted activity were largely concordant across brain regions, suggesting that ALS-linked mechanisms, including inflammation, mitochondrial dysfunction and oxidative stress, are also dysregulated in non-motor brain regions. Switches in transcript usage were identified for a small set of genes including increased usage of a POLDIP3 transcript, associated with TDP-43 loss-of-function, in the cerebellum and a XBP1 transcript, indicative of unfolded protein response activity, in the motor cortex. Extensive variation in RNA splicing was identified in the ALS brain, with 26-41% of alternatively spliced genes unique to a given brain region. This included detection of TDP-43-associated cryptic splicing events such as the STMN2 cryptic exon which was shown to have a pTDP-43 pathology-specific expression pattern. Finally, ALS patients with stage 4 pTDP-43 pathology demonstrated distinct gene and protein expression changes in the cerebellum.

CONCLUSIONS: Together our findings highlighted widespread transcriptome alterations in ALS post-mortem brain and showed that, despite the absence of pTDP-43 pathology in the cerebellum, extensive and pTDP-43 pathological stage-specific RNA changes are evident in this brain region.}, } @article {pmid40275673, year = {2025}, author = {Olmstead, AJ and Lee, J and Skrzat, S and Simmons, Z}, title = {Everyday Communication Experiences of Persons With Amyotrophic Lateral Sclerosis and Their Caregivers: Implications for Novel Speech Interventions.}, journal = {Muscle & nerve}, volume = {72}, number = {1}, pages = {158-165}, pmid = {40275673}, issn = {1097-4598}, support = {R01 DC021714/DC/NIDCD NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology ; Male ; Female ; *Caregivers/psychology ; Middle Aged ; Aged ; *Speech Intelligibility/physiology ; *Dysarthria/etiology/rehabilitation/psychology ; *Speech Therapy/methods ; *Communication ; Adult ; Surveys and Questionnaires ; }, abstract = {INTRODUCTION/AIMS: Speech intelligibility decline is a common in dysarthria secondary to amyotrophic lateral sclerosis (ALS). However, interventions that focus on improving speech may not be able to counteract decline as the disease progresses. Researchers have suggested interventions that help PALS's communication partners tune their speech perception systems to PALS's production. In the current study, we take a first step to establishing the need and enthusiasm for such interventions on the part of PALS and their caregivers (CPALS).

METHODS: PALS and CPALS recruited from the Greater Philadelphia chapter of the ALS association completed novel questionnaires probing their everyday speech communication and speech intervention experiences. Questions focused especially on changes in communication partners' ability to understand PALS' speech. Both quantitative and qualitative data were recorded.

RESULTS: PALS (n = 21) and CPALS (n = 22) reported speech as a primary mode of communication despite declines in intelligibility. However, most also indicated variability in PALS's speech intelligibility depending on the communication partner, indicating that frequent communication partners were better able to understand PALS's speech. Both groups reported interest in interventions supporting speech intelligibility and were most interested in speech interventions that included PALS and CPALS together.

DISCUSSION: PALS and especially CPALS in our study expressed interest in speech interventions that involved both parties. Thus, there is both a need for and a desire in the community for interactive speech interventions that support intelligibility. Additionally, our findings lend support to clinical approaches targeting frequent communication partners in addition to PALS.}, } @article {pmid40276468, year = {2025}, author = {Zhang, G and Chen, Y and Tang, L and Bai, L and Zhang, H and Liu, H and Fan, D}, title = {Impact of sleep quality on disease progression in early-stage amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1545463}, pmid = {40276468}, issn = {1664-2295}, abstract = {Non-motor symptoms are clinical manifestations of amyotrophic lateral sclerosis (ALS). However, few studies have examined these symptoms in patients with early-stage ALS. We conducted a cross-sectional study to explore non-motor symptoms in 69 patients with ALS within 18 months of disease onset. The Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), and the Hospital Anxiety and Depression Scale (HADS) were used to evaluate sleep quality, daytime sleepiness, and anxiety and depression, respectively. Differences in the abovementioned non-motor symptoms between ALS patients and age-/sex-matched caregivers were examined, and correlations between these symptoms and the clinical features of ALS were analyzed. Compared to caregivers, ALS patients were more likely to report poor sleep [odds ratio (OR) and 95% confidence interval (95% CI) = 2.664, 1.276-5.560; p = 0.009] and excessive daytime sleepiness (EDS) [OR and 95% CI = 5.135, 1.640-16.072; p = 0.005]. The PSQI scores in ALS patients correlated significantly with the disease progression rate [ΔFS = (48-score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, ALSFRS-R)/disease duration] [β(95% CI) = 2.867 (0.397, 5.336), p = 0.024] and plasma neurofilament light chain (NfL) levels [β (95% CI) = 0.041 (0.012, 0.070), p = 0.008). Our results revealed that the patients with early-stage ALS experienced poor sleep quality and daytime sleepiness and suggested that low sleep quality may be related to more rapid disease progression. Confounders were not obvious in the early stage of ALS, and our results suggested that these symptoms may be related to more severe and extensive pathological changes in the central nervous system.}, } @article {pmid40276954, year = {2025}, author = {Manini, A and Vasta, R and Brusati, A and Scheveger, F and Peverelli, S and Maranzano, A and Doretti, A and Gentile, F and Colombo, E and Brunetti, M and Moglia, C and Canosa, A and Manera, U and Grassano, M and Gentilini, D and Messina, S and Verde, F and Morelli, C and Landers, JE and Traynor, BJ and Chiò, A and Silani, V and Calvo, A and Ratti, A and Ticozzi, N}, title = {KIF5A p.Pro986Leu Risk Variant and Accelerated Progression of Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {7}, pages = {1499-1503}, pmid = {40276954}, issn = {2328-9503}, support = {2018-12367768//Italian Ministry of Health/ ; //Intramural Research Program of the National Institutes of Health/ ; /AG/NIA NIH HHS/United States ; //Aldo Ravelli Center for Neurotechnology/ ; RF-2021-12374238//Italian Ministry of Health/ ; ZIA AG000935/ImNIH/Intramural NIH HHS/United States ; //Dept. of Pathophysiology and Transplantation, Università degli Studi di Milano/ ; //Italian Ministry of Education/ ; //Università degli Studi di Milano/ ; //Experimental Brain Therapeutics/ ; PNC-E3-2022-23683266//Italian Ministry of Health/ ; }, abstract = {This study explored the impact of KIF5A rs113247976 (p.Pro986Leu), a risk allele for amyotrophic lateral sclerosis (ALS), on phenotypic variability in two Italian ALS cohorts (discovery, n = 865; replication, n = 1174). The minor allele (T) frequency was 0.015. No patients were homozygous (TT), allowing comparison between wild type and heterozygous carriers only. Heterozygous carriers showed faster disease progression (ALSFRS-R preslope). Findings were validated across both cohorts. Multiple linear regression identified p.Leu986 and age at onset as ALSFRS-R preslope predictors. In conclusion, heterozygous p.Leu986 in KIF5A is associated with faster ALS progression, supporting its consideration for genetic screening in clinical trials.}, } @article {pmid40277009, year = {2026}, author = {Rohrbaugh, MK and Houseman, G and Cunningham, A and Dobak, S and Ilieva, H and Kreher, M}, title = {The Impact of Cognitive Impairment on Advance Care Planning and Healthcare Utilization in People With ALS.}, journal = {The American journal of hospice & palliative care}, volume = {43}, number = {5}, pages = {470-473}, doi = {10.1177/10499091251337464}, pmid = {40277009}, issn = {1938-2715}, mesh = {Humans ; *Advance Care Planning/statistics & numerical data ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; *Cognitive Dysfunction/psychology ; Retrospective Studies ; Aged ; Middle Aged ; *Patient Acceptance of Health Care/statistics & numerical data/psychology ; Decision Making ; Aged, 80 and over ; Tracheostomy/statistics & numerical data ; Advance Directives/statistics & numerical data ; Gastrostomy/statistics & numerical data ; Hospitalization/statistics & numerical data ; }, abstract = {ObjectiveHalf of people with amyotrophic lateral sclerosis (PALS) develop cognitive impairment and/or behavioral changes, which may affect decision-making ability and participation in advance care planning (ACP) discussions. We aimed to determine the impact cognitive impairment, as measured by the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), has on PALS' ACP discussions and healthcare utilization.MethodsPALS from a retrospective chart review were categorized into 2 groups: cognitively intact or cognitively impaired (ALS Specific Score < 77, ALS Nonspecific Score < 24, ECAS Total Score < 105, and/or ECAS Behavior or Psychosis Score 1+). Documented advance directives (AD); ACP discussions; and rates of percutaneous endoscopic gastrostomy (PEG) placement, tracheostomy placement, hospitalization within 2 weeks of death, death in hospital, and hospice utilization were recorded. Late disease stage was defined as ALS Functional Rating Scale-Revised (ALSFRS-R) score ≤ 38. Group comparisons were completed using chi-square tests, Fisher's exact test, and independent samples t-tests with P < .05 significance.ResultsThirty-three (47.1%) of 70 PALS met ECAS criteria for cognitive impairment. Rates of AD for PEG placement, AD for tracheostomy placement, hospitalization within 2 weeks of death, death in hospital, and hospice enrollment were not significantly different between groups (P = .41, .62, .32, .30, .06, respectively) despite ALSFRS-R score ≥/< 38 (all P > .05). Conclusions: ACP discussions and healthcare utilization were not affected by cognitive impairment despite disease stage. It is unknown if cognitive impairment affects healthcare decision-making processes for PALS/families. Further research examining the effect of various provider communication strategies on outcomes is needed.}, } @article {pmid40277369, year = {2025}, author = {Kyheng, M and Babykina, G and Duhamel, A}, title = {Joint Latent Class Models: A Tutorial on Practical Applications in Clinical Research.}, journal = {Statistics in medicine}, volume = {44}, number = {8-9}, pages = {e70047}, pmid = {40277369}, issn = {1097-0258}, mesh = {Humans ; *Latent Class Analysis ; Software ; Longitudinal Studies ; Disease Progression ; *Models, Statistical ; *Biomedical Research/methods ; Linear Models ; Data Interpretation, Statistical ; Survival Analysis ; Computer Simulation ; }, abstract = {Joint latent class model is a statistical approach allowing to simultaneously account for two outcomes related to disease progression: A longitudinal measure (for example a biomarker) and time-to-event, in the context of a heterogeneous population. Within this approach, the linear mixed model, describing the longitudinal measure, is connected to the survival model, describing the risk of event occurrence, via a model for latent classes, describing an unobserved population heterogeneity; thus, the behavior of the two outcomes is assumed to be specific to each latent class. The theoretical properties of the model are established and the model is implemented in software. However, its complexity makes it difficult to manipulate by clinicians. In this paper, we propose a detailed tutorial for clinicians and applied statisticians on how to specify the model in R software in order to respond to concrete clinical questions, how to explore, manipulate, interpret the provided results. The tutorial is based on a real clinical dataset; for each clinical question the mathematical model specification and the R script for implementation are provided, and the estimation results and goodness-of-fit measures are detailed and interpreted.}, } @article {pmid40278411, year = {2025}, author = {Di Sarno, A and Romano, F and Arianna, R and Serpico, D and Lavorgna, M and Savastano, S and Colao, A and Di Somma, C}, title = {Lipid Metabolism and Statin Therapy in Neurodegenerative Diseases: An Endocrine View.}, journal = {Metabolites}, volume = {15}, number = {4}, pages = {}, pmid = {40278411}, issn = {2218-1989}, abstract = {Background/aim: A growing body of evidence suggests a link between dyslipidemias and neurodegenerative diseases, highlighting the crucial role of lipid metabolism in the health of the central nervous system. The aim of our work was to provide an update on this topic, with a focus on clinical practice from an endocrinological point of view. Endocrinologists, being experts in the management of dyslipidemias, can play a key role in the prevention and treatment of neurodegenerative conditions, through precocious and effective lipid profile optimization. Methods: The literature was scanned to identify clinical trials and correlation studies on the association between dyslipidemia, statin therapy, and the following neurodegenerative diseases: Alzheimer's disease (AD), Parkisons's disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Results: Impaired lipid homeostasis, such as that frequently observed in patients affected by obesity and diabetes, is related to neurodegenerative diseases, such as AD, PD, and other cognitive deficits related to aging. AD and related dementias are now a real priority health problem. In the United States, there are approximately 7 million subjects aged 65 and older living with AD and related dementias, and this number is projected to grow to 12 million in the coming decades. Lipid-lowering therapy with statins is an effective strategy in reducing serum low-density lipoprotein cholesterol to normal range concentrations and, therefore, cardiovascular disease risk; moreover, statins have been reported to have a positive effect on neurodegenerative diseases. Conclusions: Several pieces of research have found inconsistent information following our review. There was no association between statin use and ALS incidence. More positive evidence has emerged regarding statin use and AD/PD. However, further large-scale prospective randomized control trials are required to properly understand this issue.}, } @article {pmid40279084, year = {2026}, author = {Singh, P and Borkar, M and Doshi, G}, title = {Network pharmacology approach to unravel the neuroprotective potential of natural products: a narrative review.}, journal = {Molecular diversity}, volume = {30}, number = {1}, pages = {59-100}, pmid = {40279084}, issn = {1573-501X}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Biological Products/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Network Pharmacology/methods ; Animals ; Aging ; }, abstract = {Aging is a slow and irreversible biological process leading to decreased cell and tissue functions with higher risks of multiple age-related diseases, including neurodegenerative diseases. It is widely accepted that aging represents the leading risk factor for neurodegeneration. The pathogenesis of these diseases involves complex interactions of genetic mutations, environmental factors, oxidative stress, neuroinflammation, and mitochondrial dysfunction, which complicate treatment with traditional mono-targeted therapies. Network pharmacology can help identify potential gene or protein targets related to neurodegenerative diseases. Integrating advanced molecular profiling technologies and computer-aided drug design further enhances the potential of network pharmacology, enabling the identification of biomarkers and therapeutic targets, thus paving the way for precision medicine in neurodegenerative diseases. This review article delves into the application of network pharmacology in understanding and treating neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and spinal muscular atrophy. Overall, this article emphasizes the importance of addressing aging as a central factor in developing effective disease-modifying therapies, highlighting how network pharmacology can unravel the complex biological networks associated with aging and pave the way for personalized medical strategies.}, } @article {pmid40279947, year = {2025}, author = {de Carvalho, M and Oliveira Santos, M and Swash, M}, title = {Subclinical involvement of small hand muscles in early amyotrophic lateral sclerosis: Selective susceptibility leads to 'split hand' phenomenon.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {174}, number = {}, pages = {173-177}, doi = {10.1016/j.clinph.2025.04.007}, pmid = {40279947}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Hand/physiopathology/innervation ; *Muscle, Skeletal/physiopathology ; Aged ; Electromyography/methods ; Adult ; Motor Neurons/physiology ; }, abstract = {OBJECTIVES: Split-hand phenomenon is common in patients with amyotrophic lateral sclerosis (ALS), but it is unknown if first dorsal interosseous (FDI) and abductor pollicis brevis (ABP) are affected earlier than abductor digiti minimi (ADM). We aimed to address this issue.

METHODS: One clinically normal hand from ALS patients was investigated, including needle EMG of the FDI, motor amplitude, distal latency, F-waves, neurophysiological index (NI) and split-hand index (SHI). Hands were categorised as G1 (normal FDI) and G2 (FDI with neurogenic changes). In patients who agreed EMG of the 3 muscles was done. A subset of G1 patients underwent a second evaluation 4-5 months later.

RESULTS: We studied 133 patients; EMG of the 3 muscles was done in 77 patients. There was no evidence for an earlier loss of motor units in FDI/ABP. In G2 patients, CMAP amplitude and NI were significantly lower (p < 0.001), but ADM changes were minor. Reassessment of G1 patients confirmed significant SHI, and amplitude and NI decrease in all muscles, but F-waves frequency remained stable in ADM.

CONCLUSIONS: Loss of motor units in the 3 hand muscles began in parallel, but ADM spinal motoneurons showed stronger resistance to degeneration.

SIGNIFICANCE: Dysfunction of intrinsic spinal circuits can influence split-hand phenomenon.}, } @article {pmid40280150, year = {2025}, author = {Singer-Clark, T and Hou, X and Card, NS and Wairagkar, M and Iacobacci, C and Peracha, H and Hochberg, LR and Stavisky, SD and Brandman, DM}, title = {Speech motor cortex enables BCI cursor control and click.}, journal = {Journal of neural engineering}, volume = {22}, number = {3}, pages = {}, pmid = {40280150}, issn = {1741-2552}, support = {DP2 DC021055/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; Male ; Middle Aged ; Amyotrophic Lateral Sclerosis/physiopathology ; *Brain-Computer Interfaces ; Electrodes, Implanted ; Electroencephalography/methods ; *Motor Cortex/physiology ; *Speech/physiology ; }, abstract = {Objective.Decoding neural activity from ventral (speech) motor cortex is known to enable high-performance speech brain-computer interface (BCI) control. It was previously unknown whether this brain area could also enable computer control via neural cursor and click, as is typically associated with dorsal (arm and hand) motor cortex.Approach.We recruited a clinical trial participant with amyotrophic lateral sclerosis and implanted intracortical microelectrode arrays in ventral precentral gyrus (vPCG), which the participant used to operate a speech BCI in a prior study. We developed a cursor BCI driven by the participant's vPCG neural activity, and evaluated performance on a series of target selection tasks.Main results.The reported vPCG cursor BCI enabled rapidly-calibrating (40 s), accurate (2.90 bits per second) cursor control and click. The participant also used the BCI to control his own personal computer independently.Significance.These results suggest that placing electrodes in vPCG to optimize for speech decoding may also be a viable strategy for building a multi-modal BCI which enables both speech-based communication and computer control via cursor and click. (BrainGate2 ClinicalTrials.gov ID NCT00912041).}, } @article {pmid40280271, year = {2025}, author = {Kopalli, SR and Behl, T and Baldaniya, L and Ballal, S and Joshi, KK and Arya, R and Chaturvedi, B and Chauhan, AS and Verma, R and Patel, M and Jain, SK and Wal, A and Gulati, M and Koppula, S}, title = {Neuroadaptation in neurodegenerative diseases: compensatory mechanisms and therapeutic approaches.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {139}, number = {}, pages = {111375}, doi = {10.1016/j.pnpbp.2025.111375}, pmid = {40280271}, issn = {1878-4216}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/physiopathology/metabolism/pathology ; *Neuronal Plasticity/physiology ; Animals ; *Adaptation, Physiological/physiology ; *Brain/physiopathology/pathology/metabolism ; }, abstract = {Progressive neuronal loss is a hallmark of neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, and Amyotrophic Lateral Sclerosis (ALS), which cause cognitive and motor impairment. Delaying the onset and course of symptoms is largely dependent on neuroadaptation, the brain's ability to restructure in response to damage. The molecular, cellular, and systemic processes that underlie neuroadaptation are examined in this study. These mechanisms include gliosis, neurogenesis, synaptic plasticity, and changes in neurotrophic factors. Axonal sprouting, dendritic remodelling, and compensatory alterations in neurotransmitter systems are important adaptations observed in NDDs; nevertheless, these processes may shift to maladaptive plasticity, which would aid in the advancement of the illness. Amyloid and tau pathology-induced synaptic alterations in Alzheimer's disease emphasize compensatory network reconfiguration. Dopamine depletion causes a major remodelling of the basal ganglia in Parkinson's disease, and non-dopaminergic systems compensate. Both ALS and Huntington's disease rely on motor circuit rearrangement and transcriptional dysregulation to slow down functional deterioration. Neuroadaptation is, however, constrained by oxidative stress, compromised autophagy, and neuroinflammation, particularly in elderly populations. The goal of emerging therapy strategies is to improve neuroadaptation by pharmacologically modifying neurotrophic factors, neuroinflammation, and synaptic plasticity. Neurostimulation, cognitive training, and physical rehabilitation are instances of non-pharmacological therapies that support neuroplasticity. Restoring compensating systems may be possible with the use of stem cell techniques and new gene treatments. The goal of future research is to combine biomarkers and individualized medicines to maximize neuroadaptive responses and decrease the course of illness. In order to reduce neurodegeneration and enhance patient outcomes, this review highlights the dual function of neuroadaptation in NDDs and its potential as a therapeutic target.}, } @article {pmid40280333, year = {2025}, author = {Kearney, CA and Needle, CD and Brinks, AL and Shapiro, J and Lacouture, ME and Lo Sicco, KI}, title = {Response to Venkatesh et al's "Analysis of breast health outcomes in women on oral 5-alpha reductase inhibitors: A single-center retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {2}, pages = {e73-e76}, doi = {10.1016/j.jaad.2025.03.091}, pmid = {40280333}, issn = {1097-6787}, } @article {pmid40280464, year = {2025}, author = {Gritsiuta, AI and Reep, G and Parupudi, S and Petrov, RV}, title = {Optimizing the management of anastomotic leaks after esophagectomy: a narrative review of salvage strategies and outcomes.}, journal = {Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract}, volume = {29}, number = {7}, pages = {102069}, doi = {10.1016/j.gassur.2025.102069}, pmid = {40280464}, issn = {1873-4626}, mesh = {Humans ; *Esophagectomy/adverse effects ; *Anastomotic Leak/therapy/etiology ; *Salvage Therapy/methods ; Drainage/methods ; Treatment Outcome ; Nutritional Support ; Anti-Bacterial Agents/therapeutic use ; }, abstract = {BACKGROUND: Anastomotic leaks (ALs) after esophagectomy remain a major postoperative complication, leading to increased morbidity, prolonged hospital stays, and higher mortality. Despite advancements in surgical techniques and perioperative care, AL management lacks standardized protocols. This review aimed to evaluate current salvage strategies, including conservative, endoscopic, and surgical approaches, to optimize outcomes and reduce complications.

METHODS: A comprehensive literature search was conducted using PubMed, Scopus, Cochrane Library, and Google Scholar databases to identify studies published between 2000 and 2025 on AL management after esophagectomy. Peer-reviewed clinical trials, guidelines, and expert consensus reports were reviewed, focusing on minimally invasive and surgical interventions, patient outcomes, and emerging treatment strategies.

RESULTS: AL management strategies were classified into 3 primary approaches. Conservative management includes nutritional support, antibiotic therapy, and percutaneous drainage, particularly for contained leaks. Endoscopic interventions, such as self-expanding metal stents and endoscopic vacuum-assisted closure, have shown high success rates, with vacuum-assisted closure achieving superior closure outcomes. Hybrid techniques, including stent-over-sponge and vacuum-assisted closure-stent, are emerging as promising alternatives. Surgical interventions remain the gold standard for severe or refractory leaks with options, including primary repair, esophageal diversion, and delayed conduit reconstruction.

CONCLUSION: A multidisciplinary approach is crucial for optimizing AL management, incorporating enhanced recovery protocols, early risk assessment, and individualized treatment plans. Endoscopic techniques have reduced the need for surgical revisions, but surgical intervention remains necessary for severe cases. Future research should focus on refining treatment algorithms, integrating novel technologies, and establishing standardized guidelines to improve patient survival and quality of life.}, } @article {pmid40281113, year = {2025}, author = {Sasaki, D and Tenda, M and Sohma, Y}, title = {Semi-synthesis of TDP-43 reveals the effects of phosphorylation in N-terminal domain on self-association.}, journal = {Communications chemistry}, volume = {8}, number = {1}, pages = {125}, pmid = {40281113}, issn = {2399-3669}, support = {JP21H02602, JP24K02153, JP24H01787, JP24K09344//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; }, abstract = {TDP-43, a nucleocytoplasmic shuttle protein consisting of 414 residues, forms self-association in the nucleus for physiological gene regulation, while aggregation into amyloid (consisting of aberrant β-sheets) in the cytoplasm causes neurodegenerative diseases such as amyotrophic lateral sclerosis. Post-translational phosphorylation of TDP-43 alters the self-association properties, which affects both the physiological function in the nucleus and the amyloidogenic potential in the cytoplasm, thereby impacting upon disease progression. However, insight into the role of per-residue phosphorylation in the self-association remains limited due to the difficulty in obtaining site-specifically phosphorylated TDP-43. Here, we demonstrate semi-synthesis of full-length TDP-43 that is uniformly phosphorylated at the 48th serine residue (designated as TDP1-414[pS48]). The synthetic scheme consisting of native chemical ligation followed by His-tag affinity chromatography efficiently gave TDP1-414(pS48) with a high purity. Interestingly, unlike non-phosphorylated TDP-43, the phosphorylated TDP-43 was found to have weak self-association property and to form aggregates that were not typical amyloid fibrils. Furthermore, chemical synthesis and three-dimensional structure analysis of the N-terminal domain (NTD, corresponding to TDP1-80) suggested that the phosphate ion at Ser48 weakens the inter-NTD interaction by inducing electrostatic repulsion. It significantly advances understanding of the pathological mechanisms involved in the post-translational modifications of TDP-43 associated with the neurodegenerative diseases.}, } @article {pmid40281300, year = {2025}, author = {Upadhayay, S and Soni, D and Dhureja, M and Temgire, P and Kumar, V and Arthur, R and Kumar, P}, title = {Role of Fibroblast Growth Factors in Neurological Disorders: Insight into Therapeutic Approaches and Molecular Mechanisms.}, journal = {Molecular neurobiology}, volume = {62}, number = {11}, pages = {14367-14386}, pmid = {40281300}, issn = {1559-1182}, mesh = {Humans ; *Nervous System Diseases/metabolism/therapy/drug therapy ; Animals ; *Fibroblast Growth Factors/metabolism ; Signal Transduction/physiology ; }, abstract = {In the last few decades, the incidence and progression of neurological disorders have consistently increased, which mainly occur due to environmental pollution, genetic abnormalities, and modern lifestyles. Several case reports suggested that these factors enhanced oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis, leading to neurological disease. The pathophysiology of neurological disorders is still not understood, mainly due to the diversity within affected populations. Existing treatment options primarily provide symptomatic relief but frequently come with considerable side effects, including depression, anxiety, and restlessness. Fibroblast growth factors (FGFs) are key signalling molecules regulating various cellular functions, including cell proliferation, differentiation, electrical excitability, and injury responses. Hence, several investigations claimed a relationship between FGFs and neurological disorders, and their findings indicated that they could be used as therapeutic targets for neurological disorders. The FGFs are reported to activate various signalling pathways, including Ras/MAPK/PI3k/Akt, and downregulate the GSK-3β/NF-κB pathways responsible for anti-oxidant, anti-inflammatory, and anti-apoptotic effects. Therefore, researchers are interested in developing novel treatment options for neurological disorders. The emergence of unreported FGFs contributes to our understanding of their involvement in these conditions and encourages further exploration of innovative therapeutic approaches. All the data were obtained from published articles using PubMed, Web of Science, and Scopus databases using the search terms Fibroblast Growth Factor, PD, HD, AD, ALS, signalling pathways, and neurological disorders.}, } @article {pmid40282131, year = {2025}, author = {Monteiro, A and Ali, AM and Laranjeira, C}, title = {Lived Experiences of Physiotherapists in Caring for People with Advanced Amyotrophic Lateral Sclerosis in Portugal: A Phenomenological Study.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {15}, number = {4}, pages = {}, pmid = {40282131}, issn = {2076-328X}, support = {(UIDB/05704/2020 and UIDP/05704/2020)-and under the Scientific Employment Stimu-lus-Institutional Call (https://doi.org/10.54499/CEECINST/00051/2018/CP1566/CT0012, accessed on 1 March 2025).//Fundação para a Ciência e Tecnologia/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease that has a multidimensional impact on a person's life, with symptoms associated with a significant loss of autonomy. Specialized palliative care (PC) should be provided early and throughout the course of the disease. Indeed, physiotherapists should be understood as integral members of the multidisciplinary team in PC, in the care and improvement of the quality of life of these people. This study aimed to describe the lived experience of physiotherapists in the context of intervention in people with advanced ALS and their families. Descriptive phenomenology was employed as a framework for conducting semi-structured interviews to reveal experiences. Sixteen physiotherapists who performed interventions on at least one person with advanced ALS in the last 2 years were included in the study. The study involved conducting semi-structured individual interviews, through the Zoom[®] videoconferencing platform (version 6.4.3). Data were analyzed according to Giorgi's five-stage approach and managed using webQDA software (Version 3.0, University of Aveiro, Aveiro, Portugal). The COREQ checklist was applied in the study. Participants were mostly female (n = 12) and aged between 26 and 55 years (M = 36.81; SD = 6.75). Four constituents were identified: (1) undulating course of a complex disease; (2) barriers to person-centered care; (3) enablers of person-centered care; (4) transition between curative and palliative care. The findings illustrate the multidimensional impact of the disease trajectory on the person and their family. This study highlights the need to invest in specialized training for physiotherapists, contributing to a person-centered PC practice with an impact on promoting comfort and quality of life.}, } @article {pmid40282285, year = {2025}, author = {Hohman, G and Watson, A and Eldeeb, MA}, title = {A Novel Approach to Relocate Misplaced Proteins in Cells.}, journal = {Biology}, volume = {14}, number = {4}, pages = {}, pmid = {40282285}, issn = {2079-7737}, abstract = {Proper cellular function hinges on appropriate subcellular protein localization. When cellular proteins become mislocalized, they can accumulate, cause cellular damage, and disrupt many biochemical and cellular processes. Notably, mislocalized protein accumulation and the resulting cytotoxic effects are salient features of neurodegenerative diseases including Alzheimer's, Parkinson's disease, and ALS. The detrimental cellular consequences of mislocalized proteins accumulation make it crucial to develop techniques and approaches that counteract this malfunction. Remarkably, a recent study by Ng et al. introduced targeted relocalization-activating molecules (TRAMs) as a novel molecular tool for relocalizing endogenous target proteins to counteract disease-associated mislocalized proteins. The authors developed a quantitative single-cell analysis to evaluate the strength and relocalization capability of TRAMs by coupling a target protein and a shuttle protein. Herein, we briefly highlight and discuss the potential molecular implications for targeted protein relocalization as an effective approach for correcting mislocalized proteins.}, } @article {pmid40282367, year = {2025}, author = {Watanabe, Y and Nakagawa, T and Nakagawa, M and Nakayama, K}, title = {The Molecular Intersection of NEK1, C21ORF2, Cyclin F, and VCP in ALS Pathogenesis.}, journal = {Genes}, volume = {16}, number = {4}, pages = {}, pmid = {40282367}, issn = {2073-4425}, support = {23K06367//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *NIMA-Related Kinase 1/genetics/metabolism ; *Valosin Containing Protein/genetics/metabolism ; *Cyclins/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Animals ; DNA Damage ; Mutation ; DNA Repair ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive degeneration of motor neurons, leading to muscle weakness, paralysis, and death. Although significant progress has been made in understanding ALS, its molecular mechanisms remain complex and multifactorial. This review explores the potential convergent mechanisms underlying ALS pathogenesis, focusing on the roles of key proteins including NEK1, C21ORF2, cyclin F, VCP, and TDP-43. Recent studies suggest that mutations in C21ORF2 lead to the stabilization of NEK1, while cyclin F mutations activate VCP, resulting in TDP-43 aggregation. TDP-43 aggregation, a hallmark of ALS, impairs RNA processing and protein transport, both of which are essential for neuronal function. Furthermore, TDP-43 has emerged as a key player in DNA damage repair, translocating to DNA damage sites and recruiting repair proteins. Given that NEK1, VCP, and cyclin F are also involved in DNA repair, this review examines how these proteins may intersect to disrupt DNA damage repair mechanisms, contributing to ALS progression. Impaired DNA repair and protein homeostasis are suggested to be central downstream mechanisms in ALS pathogenesis. Ultimately, understanding the interplay between these pathways could offer novel insights into ALS and provide potential therapeutic targets. This review aims to highlight the emerging connections between protein aggregation, DNA damage repair, and cellular dysfunction in ALS, fostering a deeper understanding of its molecular basis and potential avenues for intervention.}, } @article {pmid40283201, year = {2025}, author = {González-Sánchez, M and Ramírez-Expósito, MJ and Martínez-Martos, JM}, title = {Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies.}, journal = {Life (Basel, Switzerland)}, volume = {15}, number = {4}, pages = {}, pmid = {40283201}, issn = {2075-1729}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis, and respiratory failure. This comprehensive review synthesizes the current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, and evolving therapeutic strategies. Mechanistically, ALS arises from complex interactions between genetic mutations (e.g., in C9orf72, SOD1, TARDBP (TDP-43), and FUS) and dysregulated cellular pathways, including impaired RNA metabolism, protein misfolding, nucleocytoplasmic transport defects, and prion-like propagation of toxic aggregates. Phenotypic heterogeneity, manifesting as bulbar-, spinal-, or respiratory-onset variants, complicates its early diagnosis, which thus necessitates the rigorous application of the revised El Escorial criteria and emerging biomarkers such as neurofilament light chain. Clinically, ALS intersects with frontotemporal dementia (FTD) in up to 50% of the cases, driven by shared TDP-43 pathology and C9orf72 hexanucleotide expansions. Epidemiological studies have revealed a lifetime risk of 1:350, with male predominance (1.5:1) and peak onset between 50 and 70 years. Disease progression varies widely, with a median survival of 2-4 years post-diagnosis, underscoring the urgency for early intervention. Approved therapies, including riluzole (glutamate modulation), edaravone (antioxidant), and tofersen (antisense oligonucleotide), offer modest survival benefits, while dextromethorphan/quinidine alleviates the pseudobulbar affect. Non-pharmacological treatment advances, such as non-invasive ventilation (NIV), prolong survival by 13 months and improve quality of life, particularly in bulb-involved patients. Multidisciplinary care-integrating physical therapy, respiratory support, nutritional management, and cognitive assessments-is critical to addressing motor and non-motor symptoms (e.g., dysphagia, spasticity, sleep disturbances). Emerging therapies show promise in preclinical models. However, challenges persist in translating genetic insights into universally effective treatments. Ethical considerations, including euthanasia and end-of-life decision-making, further highlight the need for patient-centered communication and palliative strategies.}, } @article {pmid40283578, year = {2025}, author = {Mantle, D and Hargreaves, I}, title = {Coenzyme Q10 and the Blood-Brain Barrier: An Overview.}, journal = {Journal of clinical medicine}, volume = {14}, number = {8}, pages = {}, pmid = {40283578}, issn = {2077-0383}, abstract = {Mitochondrial dysfunction is a common factor known to be involved in the pathogenesis of a number of neurological disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Given the importance of coenzyme Q10 (CoQ10) in promoting normal mitochondrial function, and the deficiency of CoQ10 reported in such neurological disorders, there is a rationale for investigating the potential therapeutic role of supplementary CoQ10. However, while there is evidence for the efficacy of CoQ10 supplementation in animal models of the above disorders, randomised controlled clinical trials supplementing CoQ10 in PD, AD, or ALS have had disappointing outcomes. This in turn may be a reflection of the current uncertainty as to whether CoQ10 can access the blood-brain barrier in human subjects. In an attempt to further elucidate the disparity in outcomes of such preclinical and clinical studies, in this article we have reviewed evidence from the peer-reviewed literature to establish the ability of CoQ10 to access the brain via the BBB.}, } @article {pmid40283933, year = {2025}, author = {Martín-Ruiz, J and Maset-Roig, R and Caplliure-Llopis, J and Villarón-Casales, C and Alarcón-Jiménez, J and de Bernardo, N and Proaño, B and Menargues-Ramírez, R and Selvi-Sabater, P and de la Rubia-Ortí, JE}, title = {Enhanced Acute Muscle Activation in ALS Patients Following Liposomal Curcumin, Resveratrol, and Dutasteride Administration.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {4}, pages = {}, pmid = {40283933}, issn = {1424-8247}, abstract = {Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of electrical activity and motor control at the muscular level. Therapeutic alternatives, such as the polyphenolic antioxidants curcumin and resveratrol in liposome form, or the drug dutasteride, could be effective for muscular activity. Objective: To measure the acute change in electrical muscle activation after administration of a combination of curcumin in liposomal form, resveratrol, and dutasteride in patients with ALS. Materials and methods: Patients with bulbar and spinal ALS were selected and randomly distributed into an intervention group (IG), which received an oral combination of curcumin in liposomal form/resveratrol[®] and dutasteride for 2 months, and a control group (CG), which received a placebo. Electrical activity to determine basal muscle activation and fasciculations was measured before and after the intervention using surface electromyography of the biceps brachii (BB), triceps brachii (TB), rectus femoris (RF), and tibialis anterior (TA). Within comparisons of pre and post-muscular variations in each group were conducted. Results: Electrical basal activity increased only for the IG in the right (p = 0.05; g = -0.45) and left (p = 0.004; g = -0.74) hemibody muscles and also presented less variation among them after treatment in the IG. For fasciculations, there was an increase in the total activation of the upper muscles in the IG (p = 0.017; g = -0.86) and for the lower muscles in the CG (p = 0.037; g = -0.68). The pattern of muscle activation remained constant in the IG but experienced variations in the CG.}, } @article {pmid40283960, year = {2025}, author = {Salomon-Zimri, S and Kerem, N and Linares, GR and Russek-Blum, N and Ichida, JK and Tracik, F}, title = {Elucidating the Synergistic Effect of the PrimeC Combination for Amyotrophic Lateral Sclerosis in Human Induced Pluripotent Stem Cell-Derived Motor Neurons and Mouse Models.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {4}, pages = {}, pmid = {40283960}, issn = {1424-8247}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the involvement of multiple pathways and mechanisms. The complexity of its pathophysiology is reflected in the diverse hypotheses relating to its underlying causes. Given this intricate interplay of processes, a combination therapy approach offers a promising strategy. Combination therapies have demonstrated significant success in treating complex diseases, where they aim to achieve synergistic therapeutic effects and reduce drug dosage. PrimeC is an oral combination treatment composed of a patented novel formulation consisting of specific and unique doses of two well-characterized drugs (ciprofloxacin and celecoxib). It aims to synergistically inhibit the progression of ALS by addressing key elements of its pathophysiology. Objectives: Demonstrating the synergistic effect of the PrimeC combination compared to each of its individual components, celecoxib and ciprofloxacin, and assessing its ability to improve the drug concentration profile and efficacy. Methods: The efficacy of the PrimeC combination was assessed in a survival assay using human induced pluripotent stem cell (iPSC)-derived motor neurons. Additionally, a drug profiling study was conducted, measuring drug levels in the brain and serum of C57BL mice treated with a single compound versus the combination. Results: Motor neurons modeling ALS treated with the PrimeC combination exhibited better survival rates compared to treatment with either individual compound alone. The enhanced efficacy of the combination was further supported by a drug concentration profiling study in rodents, demonstrating that the PrimeC combination resulted in increased ciprofloxacin concentrations in both brain tissue and serum-highlighting the optimized interaction and synergistic potential of its two comprising agents. Conclusions: Our findings support the potential of combination therapy as an effective strategy for ALS treatment. Specifically, the PrimeC combination demonstrated promising therapeutic effects, providing a strong rationale for its ongoing development as a targeted treatment for ALS.}, } @article {pmid40284157, year = {2025}, author = {Sousa-Catita, D and Mascarenhas, P and Oliveira, C and Grunho, M and Santos, CA and Cabrita, J and Correia, P and Fonseca, J}, title = {Nutrition and Survival of 150 Endoscopic Gastrostomy-Fed Patients with Amyotrophic Lateral Sclerosis.}, journal = {Nutrients}, volume = {17}, number = {8}, pages = {}, pmid = {40284157}, issn = {2072-6643}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy/complications ; *Gastrostomy/methods/mortality ; Male ; Female ; Aged ; *Enteral Nutrition/methods/mortality ; *Nutritional Status ; Middle Aged ; Kaplan-Meier Estimate ; Aged, 80 and over ; }, abstract = {Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons in the brain and spinal cord, leading to muscle weakness, atrophy, and paralysis. Treatment focuses on symptom management, using medication, physiotherapy, and nutritional support. In this context, endoscopic gastrostomy (PEG) can provide adequate feeding, hopefully improving nutrition and preventing complications. Methods: We studied ALS patients undergoing PEG over three months post-procedure, using anthropometry ((BMI)-body mass index; (MUAC)-mid-upper arm circumference; (TSF)-tricipital skinfold; (MAMC)-mid-arm muscle circumference) and laboratory data (Albumin; Transferrin; total cholesterol and hemoglobin), evaluating survival, complications, and nutritional/clinical status. Statistical analysis included Kaplan-Meier survival estimation and Cox regression to assess nutritional markers associated with survival. Results: 150 ALS patients underwent gastrostomy, mostly older adults (mean age: 66.1 years; median: 67). Mean survival was 527 [95% CI: 432-622] days, median 318 [95% CI: 236-400]. ALS bulbar subtype, MUAC and MAMC positively impacted PEG-feeding survival time (p < 0.05, Wald test). During the first three months of PEG feeding, each unit increase (cm) in MUAC and MAMC lowered death risk by 10% and 11%, respectively, highlighting the importance of nutrition care for survival. The bulbar subtype showed higher PEG feeding survival, with a 55.3% lower death hazard than the spinal subtype. There were no major PEG complications. Conclusions: ALS patients present a high risk of malnutrition. Patients that improved MAMC and MUAC in the first three PEG-fed months presented longer survival. Early PEG nutrition, even when some oral feeding is still possible, may reinforce the preventative role of enteral feeding in maintaining nutrition and potentially improving survival.}, } @article {pmid40284160, year = {2025}, author = {Fernandez-Pombo, A and Izquierdo, AG and Canton-Blanco, A and Garcia-Sobrino, T and Hervás, D and Martínez-Olmos, MA and Pardo, J and Crujeiras, AB}, title = {Blood DNA Methylation in Nuclear and Mitochondrial Sequences Links to Malnutrition and Poor Prognosis in ALS: A Longitudinal Study.}, journal = {Nutrients}, volume = {17}, number = {8}, pages = {}, pmid = {40284160}, issn = {2072-6643}, support = {CPII22/00008//Instituto de Salud Carlos III/ ; CIBEROBN//Instituto de Salud Carlos III/ ; IN607B-20240301//Xunta de Galicia/ ; CPII22/00008//Instituto de Salud Carlos III/ ; JR23/00042//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *DNA Methylation ; *Amyotrophic Lateral Sclerosis/genetics/complications/blood/mortality ; Male ; Female ; Middle Aged ; *Malnutrition/genetics/blood/complications ; Longitudinal Studies ; Aged ; Prognosis ; Disease Progression ; Nutritional Status ; Biomarkers/blood ; *DNA, Mitochondrial/blood/genetics ; Oxidative Stress ; Epigenesis, Genetic ; }, abstract = {Background: Malnutrition in amyotrophic lateral sclerosis (ALS) is associated with disease severity, and epigenetic regulation may be involved. The aim of this study was to assess the methylation levels of specific DNA sequences from the nuclear and mitochondrial genomes in a population with ALS to elucidate their relationship with nutritional status and the evolution of the disease. Methods: Patients with ALS were evaluated between 2013 and 2021 (n = 66). They were categorized according to their nutritional status, using the Global Leadership Initiative on Malnutrition (GLIM) criteria, and disease progression, using the ALS Functional Rating (ALSFRS-R) Scale. DNA samples were extracted from leukocytes at the time of diagnosis for analysis of DNA methylation levels of markers of oxidative stress, mitochondrial function and global methylation (D-loop, GSTP1, and LINE-1). Results: According to the GLIM criteria, 29 (43.9%) patients had malnutrition (22.7%-moderate; 21.2%-severe), which was positively correlated with ALS disease progression (r = 0.414; p < 0.01) and death (r = 0.687; p < 0.01). Mortality occurred in 43.9% of the patients (median time to death, 18.7 (1.7-82.7) months). A significant association was observed between DNA methylation levels of the D-loop, GSTP1, and the CpG1 site of LINE-1 and malnutrition, disease progression at diagnosis, and death. The D-loop was the best predictor of malnutrition (AUC, 0.79; p < 0.01), disease progression (AUC, 0.70; p < 0.01), and mortality (AUC, 0.71; p < 0.01). Conclusions: This study revealed, for the first time, the early detection of D-loop methylation levels as a potential biomarker of nutritional status in patients with ALS, which may be useful for personalized nutritional management aimed at counteracting disease progression.}, } @article {pmid40284406, year = {2025}, author = {Ansari, UA and Srivastava, A and Srivastava, AK and Pandeya, A and Vatsa, P and Negi, R and Singh, A and Pant, AB}, title = {Targeting TDP-43 Proteinopathy in hiPSC-Derived Mutated hNPCs with Mitoxantrone Drugs and miRNAs.}, journal = {Pharmaceutics}, volume = {17}, number = {4}, pages = {}, pmid = {40284406}, issn = {1999-4923}, support = {5/4-5/3/9/DHR/Neuro/2021-NCD-1//Indian Council of Medical Research/ ; }, abstract = {Background/Objectives: TDP-43 mutation-driven Amyotrophic Lateral Sclerosis (ALS) motor neuron disease is one of the most prominent forms (approximately 97%) in cases of sporadic ALS. Dysfunctional autophagy and lysosomal function are the prime mechanisms behind ALS. Mitoxantrone (Mito), a synthetic doxorubicin analog, is an inhibitor of DNA and RNA synthesis/repair via intercalating with nitrogenous bases and inhibiting topoisomerase II. The therapeutic potential of miRNAs associated with disease conditions has also been reported. This study explores the therapeutic potential of Mito along with miRNAs against mutated TDP-43 protein-induced proteinopathy in human-induced pluripotent stem cell (hiPSC)-derived human neural progenitor cells (hNPCs). Methods: HiPSCs mutated for TDP-43 were differentiated into hNPCs and used to explore the therapeutic potential of Mito at a concentration of 1 μM for 24 h (the identified non-cytotoxic dose). The therapeutic effects of Mito on miRNA expression and various cellular parameters such as mitochondrial dynamics, autophagy, and stress granules were assessed using the high-throughput Open Array technique, immunocytochemistry, flow cytometry, immunoblotting, and mitochondrial bioenergetic assay. Results: Mutated TDP-43 protein accumulation causes stress granule formation (G3BP1), mitochondrial bioenergetic dysfunction, SOD1 accumulation, hyperactivated autophagy, and ER stress in hNPCs. The mutated hNPCs also show dysregulation in six miRNAs (miR-543, miR-34a, miR-200c, miR-22, miR-29b, and miR-29c) in mutated hNPCs. A significant restoration of TDP-43 mutation-induced alterations could be witnessed upon the exposure of mutated hNPCs to Mito. Conclusions: Our study indicates that miR-543, miR-29b, miR-22, miR-200c, and miR-34a have antisense therapeutic potential alone and in combination with Mitoxantrone.}, } @article {pmid40284554, year = {2025}, author = {Tamai, R and Kiyoura, Y}, title = {Candida Infections: The Role of Saliva in Oral Health-A Narrative Review.}, journal = {Microorganisms}, volume = {13}, number = {4}, pages = {}, pmid = {40284554}, issn = {2076-2607}, support = {21K10233, 23K09511//KAKEN/ ; }, abstract = {Candida species, particularly Candida albicans, are causative agents of oral infections to which immunocompromised patients are especially susceptible. Reduced saliva flow (xerostomia) can lead to Candida overgrowth, as saliva contains antibacterial components such as histatins and β-defensins that inhibit fungal growth and adhesion to the oral mucosa. Candida adheres to host tissues, forms biofilms, and secretes enzymes required for tissue invasion and immune evasion. Secretory asparaginyl proteinases (Saps) and candidalysin, a cytolytic peptide toxin, are vital to Candida virulence, and agglutinin-like sequence (Als) proteins are crucial for adhesion, invasion, and biofilm formation. C. albicans is a risk factor for dental caries and may increase periodontal disease virulence when it coexists with Porphyromonas gingivalis. Candida infections have been suggested to heighten the risk of oral cancer based on a relationship between Candida species and oral squamous cell carcinoma (OSCC) or oral potentially malignant disorder (OPMD). Meanwhile, β-glucan in the Candida cell wall has antitumor effects. In addition, Candida biofilms protect viruses such as herpesviruses and coxsackieviruses. Understanding the intricate interactions between Candida species, host immune responses, and coexisting microbial communities is essential for developing preventive and therapeutic strategies against oral Candida infections, particularly in immunocompromised individuals.}, } @article {pmid40285121, year = {2025}, author = {Chatragadda, L and Fletcher, A and Zhong, S and Vargas, FA and Bhagat, N and Mankodiya, K and Delmonico, MJ and Solanki, D}, title = {Development and Assessment of a Soft Wearable for sEMG-Based Hand Grip Detection and Control of a Virtual Environment.}, journal = {Sensors (Basel, Switzerland)}, volume = {25}, number = {8}, pages = {}, pmid = {40285121}, issn = {1424-8220}, support = {N/A//Office of Undergraduate Research and Innovation, University of Rhode Island/ ; }, mesh = {Humans ; *Electromyography/methods/instrumentation ; *Hand Strength/physiology ; *Wearable Electronic Devices ; Male ; Female ; Middle Aged ; Adult ; Neurodegenerative Diseases/physiopathology ; Aged ; Hand/physiology ; Feasibility Studies ; }, abstract = {BACKGROUND: As the number of individuals diagnosed with neurodegenerative disorders (NDs) rises, there is a growing need to enhance both the quantity and quality of approaches used to treat these debilitating conditions. The progression of NDs can cause muscle weakness in the lower or upper limbs. We particularly focus on the area of the upper limb, specifically grip rehabilitation, by developing a system (VRGrip) that can reliably record electromyography (EMG) events of the hand flexor muscles to control an adaptive and engaging game using grip exertion. The purpose of this study was to determine the feasibility of using the VRGrip system.

METHODS: We prototyped a three-component wearable system consisting of an e-textile forearm band (E-band), data acquisition module (DAM), and a computer game. This allows participants to play a game by squeezing their dominant hand. A feasibility study was completed with 9 individuals who self-reported an ND (including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), and essential tremor (ET)) and 12 individuals who self-reported to be relatively healthy (RH). Each participant completed 15 min of gameplay (three trials of five minutes), where they would squeeze a resistive ball to trigger in-game actions. The user experience was then evaluated via a User Satisfaction Evaluation Questionnaire (USEQ; scored 0-30, with 30 being best).

RESULTS: Analysis of the grip detection reliability during the feasibility study resulted in an F1 score of 0.8343 ± 0.1208 for the healthy participant group and 0.8401 ± 0.1034 for the ND participant group. The USEQ (Avg. score: 4.65 ± 0.51) indicated that participants found the system comfortable, engaging, and enjoyable. Additionally, we potentially identified age-related changes in muscle fatigue.

CONCLUSION: The results of this study demonstrate that our VRGrip system could be used for hand grip detection in a virtual environment. In the future, we aim to conduct longitudinal studies to determine if repeated use of the system has merit for grip rehabilitation.}, } @article {pmid40285624, year = {2025}, author = {Vasta, R and Koumantakis, E and Canosa, A and Manera, U and Grassano, M and Palumbo, F and Cabras, S and Matteoni, E and Di Pede, F and De Mattei, F and Vergnano, F and Mandrioli, J and Simonini, C and Martinelli, I and De Marchi, F and Mazzini, L and Moglia, C and Calvo, A and Chiò, A}, title = {Phosphatemia is an Independent Prognostic Factor in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {98}, number = {2}, pages = {286-293}, pmid = {40285624}, issn = {1531-8249}, support = {2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 259867//European Commission's Health Seventh Framework Programme/ ; 101137074//European Union's Horizon 2020 research and innovation programme/ ; GA101017598//European Union's Horizon 2020 research and innovation programme/ ; PNRR-MAD-2022-12375731//Ministero della Salute/ ; RF-2016-02362405//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/mortality ; Male ; Female ; Middle Aged ; Prognosis ; Aged ; Biomarkers/blood ; Creatinine/blood ; *Hyperphosphatemia/blood/diagnosis ; Adult ; *Phosphates/blood ; Phosphorus/blood ; }, abstract = {OBJECTIVE: The objective of this study was to evaluate the prognostic value of several muscle damage biomarkers.

METHODS: Data from Piemonte and Valle d'Aosta Amyotrophic Lateral Sclerosis (PARALS) were considered for this study. Survival was defined as the time from diagnosis to death, tracheostomy, or the censoring date. Blood levels of potassium, creatinine, creatine kinase, phosphorus, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) diagnosis were evaluated as potential prognostic biomarkers. A Cox model was developed for each biomarker and adjusted for sex, onset age, onset site, and diagnostic delay. Significant findings from PARALS were evaluated in the Pooled Resource Open-Access Amyotrophic Lateral Sclerosis Clinical Trials (PRO-ACT) database. Additionally, a joint model was constructed to evaluate the prognostic role of phosphatemia slope over time using longitudinal data from PRO-ACT.

RESULTS: A total of 1,444 and 1,023 patients were included in the PARALS and PRO-ACT cohorts, respectively. Only creatinine (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.50-0.85) and phosphorus (HR = 1.14, 95% CI = 1.04-1.24) showed a significant association with survival in the PARALS cohort. These findings were further validated in the PRO-ACT cohort (creatinine HR = 0.21, 95% CI = 0.13-0.35, p < 0.0001; phosphorus HR = 2.35, 95% CI = 1.13-4.88, p = 0.02). Longitudinal data from the PRO-ACT database showed that an increase of 0.1 mmol/l per month in phosphate levels was also associated with a HR of 8.26 (95% CI = 1.07-96.6, p = 0.044).

INTERPRETATION: Creatininemia was confirmed as a prognostic marker in amyotrophic lateral sclerosis (ALS). Additionally, both phosphatemia levels at diagnosis and its rate of change over time were identified as a potential prognostic marker for ALS. As with other blood biomarkers, phosphate levels are cost-effective and minimally invasive to measure, supporting their potential use in clinical trials. ANN NEUROL 2025;98:286-293.}, } @article {pmid40285687, year = {2025}, author = {Altemus, JJ and Lay, MA and Thompson, VF and Schwartz, JC}, title = {Purification of Low-Complexity Domain Proteins FUS, EWSR1, and Their Fusions.}, journal = {Current protocols}, volume = {5}, number = {4}, pages = {e70136}, pmid = {40285687}, issn = {2691-1299}, support = {R01 CA259570/CA/NCI NIH HHS/United States ; }, mesh = {*RNA-Binding Protein FUS/isolation & purification/chemistry/genetics/metabolism ; *RNA-Binding Protein EWS/isolation & purification/chemistry/genetics/metabolism ; Humans ; *Oncogene Proteins, Fusion/isolation & purification/chemistry ; Protein Domains ; }, abstract = {FET proteins are large multifunctional proteins that have several key roles in biology. The FET family of proteins, including FUS, EWSR1, and TAF15, play critical roles in transcription regulation, RNA processing, and DNA damage repair. These multifunctional RNA- and DNA-binding proteins are ubiquitously expressed and conserved across vertebrate species. They contain low-complexity (LC) domains that allow them to assemble and phase separate but also makes the proteins prone to aggregation. Aberrations in FET proteins, such as point mutations, aggregation, or translocations leading to fusion proteins, have been implicated in several pathologies, including frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Ewing sarcoma. In vitro study of FET proteins is hampered by their propensity to aggregate, their disordered structure, and their susceptibility to proteolysis, making high-yield production difficult. Here, we present optimized methods for the purification of full-length FUS, EWSR1, and their fusion proteins. These protocols enable researchers to overcome issues related to aggregation and solubility, facilitating biochemical and biophysical studies of these critical yet complex proteins. © 2025 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Purification of EWSR1 and FUS proteins Alternate Protocol: Purification for fusion proteins.}, } @article {pmid40286795, year = {2025}, author = {Murdock, BJ and Zhao, B and Webber-Davis, IF and Teener, SJ and Pawlowski, KD and Famie, JP and Piecuch, CE and Jang, DG and Feldman, EL and Zhao, L and Goutman, SA}, title = {Early immune system changes in amyotrophic lateral sclerosis correlate with later disease progression.}, journal = {Med (New York, N.Y.)}, volume = {6}, number = {8}, pages = {100673}, pmid = {40286795}, issn = {2666-6340}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; R01 TS000339/TS/ATSDR CDC HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R21 NS102960/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/blood/diagnosis/immunology ; Disease Progression ; Case-Control Studies ; Biomarkers/blood ; Flow Cytometry ; Longitudinal Studies ; *Immunity, Cellular ; Humans ; Male ; Female ; Middle Aged ; Aged ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no cure and limited treatment options. The immune system is implicated in disease pathology, unlocking a potential therapeutic avenue. However, it is unclear whether immune changes are a cause or consequence of disease progression.

METHODS: Peripheral immune cells were longitudinally measured at monthly intervals in 55 ALS and 50 control participants. 22 peripheral immune markers in the blood were assessed using flow cytometry, and clinical progression was assessed using the revised ALS functional rating scale (ALSFRS-R). Individual immune markers, their trajectories, and overall variability were compared in ALS versus control participants; ALS participants were also stratified by clinical progression rates and assessed similarly across progression groups. Finally, a novel, lagged linear regression model correlated the rate of immune changes to subsequent downstream ALSFRS-R changes.

FINDINGS: Numerous immune markers were dysregulated in ALS versus control participants, with altered levels, trajectories, or variability in immune populations and surface markers. ALS participants had increased immune variability relative to control participants; within ALS participants, faster progressors overall had decreased marker variability. Finally, natural killer (NK) cell numbers, NK cell subpopulations, and NK cell surface markers were significantly associated with downstream ALS progression.

CONCLUSIONS: The immune system is dysregulated in ALS and more consistently dysregulated in faster ALS progression, and immune dysregulation occurs upstream of clinical changes. These findings suggest that the immune system is a causal factor of ALS progression in human patients.

FUNDING: CReATe Consortium, NIH, Target ALS, DoD, ALSA.}, } @article {pmid40286820, year = {2025}, author = {Cepica, TB and Xie, L and Faden, DF and Stone, CJ and Feng, R and Werth, VP and Chong, BF}, title = {Regarding Wu et al's "response to Cepica et al's 'smoking status is a negative predictor of 6-month cutaneous lupus activity trends: A prospective cohort study'".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {2}, pages = {e89-e90}, doi = {10.1016/j.jaad.2025.04.050}, pmid = {40286820}, issn = {1097-6787}, } @article {pmid40287045, year = {2025}, author = {Dudzisz, K and Wandzik, I}, title = {Antisense oligonucleotides: A promising advancement in neurodegenerative disease treatment.}, journal = {European journal of pharmacology}, volume = {999}, number = {}, pages = {177644}, doi = {10.1016/j.ejphar.2025.177644}, pmid = {40287045}, issn = {1879-0712}, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use ; *Neurodegenerative Diseases/genetics/drug therapy/therapy ; Animals ; Clinical Trials as Topic ; }, abstract = {Antisense oligonucleotides (ASOs) are a class of therapeutics designed to modulate gene expression and have shown promise in the treatment of various neurodegenerative diseases. As of March 2025, four ASO-based therapies have received approval for the treatment of neurodegenerative diseases, including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and hereditary transthyretin amyloidosis (ATTR). These approvals underscore the therapeutic potential of ASOs as effective treatments for neurodegenerative diseases by addressing specific genetic abnormalities. This is best demonstrated by clinical studies in more than a dozen ASOs, which could pave the way for the development of new therapeutics soon. Moreover, the ongoing extended clinical studies, which target presymptomatic carriers, have significant potential to cure familial ALS based on the SOD1 gene mutation. This review provides an update on clinical trials, highlighting promising results and the challenges encountered.}, } @article {pmid40287755, year = {2025}, author = {Vizziello, M and Dellarole, IL and Ciullini, A and Pascuzzo, R and Lombardo, A and Bellandi, F and Celauro, L and Battipaglia, C and Ciusani, E and Rizzo, A and Catania, M and Devigili, G and Della Seta, SA and Margiotta, V and Consonni, M and Faltracco, V and Tiraboschi, P and Riva, N and Portaleone, SMS and Zanusso, G and Legname, G and Lauria, G and Dalla Bella, E and Moda, F}, title = {TDP-43 seeding activity in the olfactory mucosa of patients with amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {49}, pmid = {40287755}, issn = {1750-1326}, support = {GR-2021-12372019//Ministero della Salute/ ; PNRR-MAD-2022-12376035//Ministero della Salute/ ; 5M-2018-23680266//Ministero della Salute/ ; RC//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism ; Male ; Female ; Middle Aged ; Aged ; *Olfactory Mucosa/metabolism/pathology ; Frontotemporal Dementia/metabolism ; Adult ; }, abstract = {BACKGROUND: In recent years, the seed amplification assay (SAA) has enabled the identification of pathological TDP-43 in the cerebrospinal fluid (CSF) and olfactory mucosa (OM) of patients with genetic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we investigated the seeding activity of TDP-43 in OM samples collected from patients with sporadic ALS.

METHODS: OM samples were collected from patients with (a) sporadic motor neuron diseases (MND), including spinal ALS (n = 35), bulbar ALS (n = 18), primary lateral sclerosis (n = 10), and facial onset sensory and motor neuronopathy (n = 2); (b) genetic MND, including carriers of C9orf72[exp] (n = 6), TARDBP (n = 4), SQSTM1 (n = 3), C9orf72[exp] + SQSTM1 (n = 1), OPTN (n = 1), GLE1 (n = 1), FUS (n = 1) and SOD1 (n = 4) mutations; (c) other neurodegenerative disorders (OND), including Alzheimer's disease (n = 3), dementia with Lewy bodies (n = 8) and multiple system atrophy (n = 6); and (d) control subjects (n = 22). All samples were subjected to SAA analysis for TDP-43 (TDP-43_SAA). Plasmatic levels of TDP-43 and neurofilament-light chain (NfL) were also assessed in a selected number of patients.

RESULTS: TDP-43_SAA was positive in 29/65 patients with sporadic MND, 9/21 patients with genetic MND, 6/17 OND patients and 3/22 controls. Surprisingly, one presymptomatic individual also tested positive. As expected, OM of genetic non-TDP-43-related MND tested negative. Interestingly, fluorescence values from non-MND samples that tested positive were consistently and significantly lower than those obtained with sporadic and genetic MND. Furthermore, among TDP-43-positive samples, the lag phase observed in MND patients was significantly longer than that in non-MND patients. Plasma TDP-43 levels were significantly higher in sporadic MND patients compared to controls and decreased as the disease progressed. Similarly, plasma NfL levels were higher in both sporadic and genetic MND patients and positively correlated with disease progression rate (ΔFS). No significant correlations were detected between TDP-43_SAA findings and the biological, clinical, or neuropsychological parameters considered.

CONCLUSIONS: The OM of a subset of patients with sporadic MND can trigger seeding activity for TDP-43, as previously observed in genetic MND. Thus, TDP-43_SAA analysis of OM can improve the clinical characterization of ALS across different phenotypes and enhance our understanding of these diseases. Finally, plasma TDP-43 could serve as a potential biomarker for monitoring disease progression. However, further research is needed to confirm and expand these findings.}, } @article {pmid40288540, year = {2025}, author = {He, M and Jia, H}, title = {Enhancing access to scalp cooling therapy: How can we move forward? A response to Novice et al's "the financial burden of scalp cooling therapy: A nonprofit organization data analysis".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {2}, pages = {e81}, doi = {10.1016/j.jaad.2025.03.093}, pmid = {40288540}, issn = {1097-6787}, } @article {pmid40288591, year = {2025}, author = {Servi, R and Akkoç, RF and Aksu, F and Servi, S}, title = {Therapeutic potential of enzymes, neurosteroids, and synthetic steroids in neurodegenerative disorders: A critical review.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {251}, number = {}, pages = {106766}, doi = {10.1016/j.jsbmb.2025.106766}, pmid = {40288591}, issn = {1879-1220}, mesh = {Humans ; *Neurosteroids/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Steroids/therapeutic use ; *Neuroprotective Agents/therapeutic use/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Neurodegenerative disorders present a significant challenge to healthcare systems, mainly due to the limited availability of effective treatment options to halt or reverse disease progression. Endogenous steroids synthesized in the central nervous system, such as pregnenolone (PREG), dehydroepiandrosterone (DHEA), progesterone (PROG), and allopregnanolone (ALLO), have been identified as potential therapeutic agents for neurodegenerative diseases. Neurosteroids such as ALLO, DHEA, and PROG, as well as their synthetic analogs like Ganaxolene, Fluasterone, and Olexoxime, offer promising effects for conditions such as Alzheimer's disease (AD) and depression. Moreover, Brexanolone and Ganaxolone are synthetic steroids approved for the treatment of postpartum depression and epilepsy, respectively. Neurosteroids such as ALLO are crucial in modulating GABAergic neurotransmission and reducing neuroinflammation. These compounds enhance the activity of GABA-A receptors, leading to increased inhibitory signaling in the brain, which can help regulate mood, cognition, and neuroprotection. Small clinical trials and observational studies indicate that ALLO may have cognitive benefits, but no large-scale, definitive meta-analysis confirms a 20 % improvement in AD patients. Mitochondrial dysfunction plays a vital role in the pathogenesis of numerous neurological diseases due to the high-energy demand and sensitivity of neurons to oxidative stress. Reduced mitochondrial function leads to amyloid-beta plaques and tau tangles accumulation in AD. In Parkinson's disease (PD), mitochondrial dysfunction resulting from the PINK1 or Parkin genes leads to energy deficiencies and the accumulation of toxic byproducts. Mutations in genes such as SOD1, C9orf72, and TDP-43 have been associated with mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS). Moreover, studies on these neurodegenerative diseases suggest that inflammation is not merely a consequence of neurodegeneration but is also an essential factor in this process. Many neurological disorders involve multifaceted interactions between genetics, the environment, and immune responses, making it difficult to pinpoint their exact causes. Future research aims to overcome these hurdles through genetic advances, regenerative medicine, and personalized therapies. Cutting-edge technologies such as artificial intelligence and high-throughput screening are expected to accelerate drug discovery and improve diagnostic accuracy. Increasing collaboration between interdisciplinary fields such as bioinformatics, neuroscience, and immunology will lead to innovative treatment strategies. This comprehensive review discusses the therapeutic effects of enzymes, neurosteroids, and synthetic steroids in different neurodegenerative diseases, particularly AD, PD, ALS, and MS. Potential challenges in the therapeutic use of neurosteroids, such as the limited bioavailability and off-target effects of synthetic steroids, are also discussed, and an up-to-date and comprehensive review of the impact of these steroids on neurodegenerative disorders is presented.}, } @article {pmid40288877, year = {2025}, author = {Alcaraz, MR and Montemurro, M and Pisano, PL and Lombardi, JM and Bortolato, SA}, title = {Functional data analysis, a comprehensive framework for processing non-quadrilinear and low-selective data provided by four-way liquid chromatography analysis.}, journal = {Analytica chimica acta}, volume = {1356}, number = {}, pages = {344044}, doi = {10.1016/j.aca.2025.344044}, pmid = {40288877}, issn = {1873-4324}, abstract = {The chemometric treatment of higher-order chromatographic (LC) data often crashes due to two main effects: the chromatographic band shifts/warpings across samples and quasi-full overlaps between component signals, affecting their analytical selectivities. From a chemometric point of view, these phenomena have independent effects, although they can jointly contribute to the failure of the algorithms: 1) data multilinearity breaking, leading to the poor performance of multilinear decomposition algorithms, and 2) linear dependence between the analytes signals, causing the failure of folded models. Under this scenario, making chemometric processing feasible involves defining specific experimental conditions that minimize these effects or increasing the number of instrumental ways to deal with selectivity lost. This work presents the Functional Aligned of Pure Vectors (FAPV) algorithm for restoring four-way chromatographic data multilinearity and bearing the spectral overlap trouble. Simulated and experimental four-way data were used to test the FAPV analytical efficiency, covering a wide range of chromatographic artifacts. Based on a multi-injection procedure, the experimental case implied the chromatographic determination of two analytes with uncalibrated interferents in aqueous samples. Both data systems were subjected to FAPV and then processed by PARAFAC. Therefore, a comprehensive comparison was made with the most widely used chemometric models for non-multilinear chromatographic data (MCR-ALS and PARAFAC2). Moreover, the performance of the FAPV approach was compared with commonly used alignment procedures, e.g., correlation-optimized warping. The results (c.a. REPs of 10 % in both analytes from the experimental case) show the efficiency of the FAPV algorithm in solving the troubles observed in chromatographic/spectral data.}, } @article {pmid40289140, year = {2025}, author = {Meyer, T and Boentert, M and Großkreutz, J and Weydt, P and Bernsen, S and Reilich, P and Steinbach, R and Rödiger, A and Wolf, J and Weyen, U and Ludolph, AC and Weishaupt, J and Petri, S and Lingor, P and Günther, R and Löscher, W and Weber, M and Münch, C and Maier, A and Grehl, T}, title = {Motor phenotypes of amyotrophic lateral sclerosis - a three-determinant anatomical classification based on the region of onset, propagation of motor symptoms, and the degree of upper and lower motor neuron dysfunction.}, journal = {Neurological research and practice}, volume = {7}, number = {1}, pages = {27}, pmid = {40289140}, issn = {2524-3489}, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS), heterogeneity of motor phenotypes is a fundamental hallmark of the disease. Distinct ALS phenotypes were associated with a different progression and survival. Despite its relevance for clinical practice and research, there is no broader consensus on the classification of ALS phenotypes.

METHODS: An expert consensus process for the classification of ALS motor phenotypes was performed from May 2023 to December 2024. A three-determinant anatomical classification was proposed which is based on the (1) region of onset (O), (2) the propagation of motor symptoms (P), and (3) the degree of upper (UMN) and/or lower motor neuron (LMN) dysfunction (M). Accordingly, this classification is referred to as the "OPM classification".

RESULTS: Onset phenotypes differentiate the site of first motor symptoms: O1) head onset; O2d) distal arm onset; O2p) proximal arm onset; O3r) trunk respiratory onset; O3a) trunk axial onset; O4d) distal leg onset; O4p) proximal leg onset. Propagation phenotypes differentiate the temporal propagation of motor symptoms from the site of onset to another, vertically distant body region: PE) earlier propagation (within 12 months of symptom onset); PL) later propagation (without propagation within 12 months of symptom onset), including the established phenotypes of "progressive bulbar paralysis" (O1, PL), "flail-arm syndrome" (O2p, PL), and "flail-leg syndrome" (O4d, PL); PN) propagation not yet classifiable as time since symptom onset is less than 12 months. Phenotypes of motor neuron dysfunction differentiate the degree of UMN and/or LMN dysfunction: M0) balanced UMN and LMN dysfunction; M1d) dominant UMN dysfunction; M1p) pure UMN dysfunction ("primary lateral sclerosis", PLS); M2d) dominant LMN dysfunction; M2p) pure LMN dysfunction ("progressive muscle atrophy", PMA); M3) dissociated motor neuron dysfunction with dominant LMN and UMN dysfunction of the arms and legs ("brachial amyotrophic spastic paraparesis"), respectively.

CONCLUSION: This consensus process aimed to standardize the clinical description of ALS motor phenotypes in clinical practice and research - based on the onset region, propagation pattern, and motor neuron dysfunction. This "OPM classification" contributes to specifying the prognosis, to defining the inclusion or stratification criteria in clinical trials and to correlate phenotypes with the underlying disease mechanisms of ALS.}, } @article {pmid40289884, year = {2025}, author = {Janelidze, S and Ashton, NJ and Orduña Dolado, A and Nordström, U and Bali, D and Forsberg, KME and Keskin, I and Mastrangelo, A and Vacchiano, V and Liguori, R and Blennow, K and Zetterberg, H and Mattsson-Carlgren, N and Gonzalez-Ortiz, F and Parchi, P and Andersen, PM and Hansson, O}, title = {A comparison of p-tau assays for the specificity to detect tau changes in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {4}, pages = {e70208}, pmid = {40289884}, issn = {1552-5279}, mesh = {Humans ; *tau Proteins/blood/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/blood/diagnosis ; Female ; Male ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood/diagnosis ; Aged ; Sensitivity and Specificity ; Middle Aged ; Biomarkers/blood/cerebrospinal fluid ; Aged, 80 and over ; Immunoassay ; Phosphorylation ; }, abstract = {INTRODUCTION: We evaluated differences in p-tau levels between Alzheimer's disease (AD), a condition with brain-specific changes in p-tau, and amyotrophic lateral sclerosis (ALS), a condition associated with increases in peripheral p-tau levels.

METHODS: Cerebrospinal fluid and plasma from 668 participants were analyzed using immunoassays specific for the low-molecular-weight (LMW) tau isoforms present in the brain (i.e., p-tau217Lilly, p-tau181Lilly) and those that detect both LMW- and high-molecular-weight (HMW) tau expressed in the peripheral nervous system (i.e., p-tau217AlzPath, p-tau181UGOT).

RESULTS: Increases in plasma p-tau in ALS versus controls were significantly smaller for the LMW-specific p-tau assays (15.9%-20.5%) compared with non-specific assays (92.0%-121.3%). The LMW-specific p-tau assays showed significantly larger plasma p-tau increases in AD versus ALS, discriminating AD from ALS with areas under the curve (AUCs; 0.890.93) higher than the AUCs of the non-specific assays (0.54-0.74).

DISCUSSION: LMW-specific p-tau assays could be more useful in the diagnostic workup of AD, especially in population-based communities where conditions causing peripheral neuropathy are frequent.

HIGHLIGHTS: Increases in plasma phosphorylated tau (p-tau) in amyotrophic lateral sclerosis (ALS) versus controls were significantly smaller for low-molecular-weight (LMW)-specific p-tau assays (i.e., p-tau217Lilly, p-tau181Lilly) compared with p-tau assays that also detect high-molecular-weight (HMW) assays (i.e., p-tau217AlzPath, p-tau181UGOT). The LMW-specific p-tau assays showed significantly larger increases in plasma p-tau in AD versus ALS compared with the non-specific assays. The LMW-specific p-tau assays discriminated AD from ALS with higher precision, showing significantly better performance than the non-specific assays. LMW-specific p-tau assays could be more useful in the diagnostic workup of AD, especially in population-based communities where conditions causing peripheral neuropathy (such as ALS) are frequent.}, } @article {pmid40290120, year = {2025}, author = {Hong, Y and Song, Y and Wang, W and Shi, J and Chen, X}, title = {Mitochondrial DNA editing: Key to the treatment of neurodegenerative diseases.}, journal = {Genes & diseases}, volume = {12}, number = {4}, pages = {101437}, pmid = {40290120}, issn = {2352-3042}, abstract = {Neuronal death is associated with mitochondrial dysfunction caused by mutations in mitochondrial DNA. Mitochondrial DNA becomes damaged when processes such as replication, repair, and nucleotide synthesis are compromised. This extensive accumulation of damaged mitochondrial DNA subsequently disrupts the normal function of mitochondria, leading to aging, degeneration, or even death of neurons. Mitochondrial dysfunction stands as a pivotal factor in the development of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Recognizing the intricate nature of their pathogenesis, there is an urgent need for more effective therapeutic interventions. In recent years, mitochondrial DNA editing tools such as zinc finger nucleases, double-stranded DNA deaminase toxin A-derived cytosine base editors, and transcription activator-like effector ligand deaminases have emerged. Their emergence will revolutionize the research and treatment of mitochondrial diseases. In this review, we summarize the advancements in mitochondrial base editing technology and anticipate its utilization in neurodegenerative diseases, offering insights that may inform preventive strategies and therapeutic interventions for disease phenotypes.}, } @article {pmid40290679, year = {2025}, author = {Li, ZY and Li, T and Cai, HQ}, title = {Overview of serrated polyposis syndrome from pathophysiology, diagnosis, and management.}, journal = {World journal of clinical oncology}, volume = {16}, number = {4}, pages = {103343}, pmid = {40290679}, issn = {2218-4333}, abstract = {This editorial discusses Thompson et al's original article, which is published in the most recent edition of the World Journal of Clinical Oncology and sheds critical light on the intertwined issues of health anxiety and work loss in individuals diagnosed with serrated polyposis syndrome (SPS). SPS is rare, characterized by the development of multiple serrated colorectal polyps. This editorial provides an overview of SPS, including its pathophysiology, clinical presentation, diagnostic criteria, management strategies, and the psychosocial impact. SPS is linked to molecular alterations, which drive carcinogenesis. Colonoscopy and histological analysis are used for diagnosis. Genetic testing is also considered where there is a family history. Quality of life can be greatly impacted by the psychosocial effects of SPS, especially health anxiety. Further understanding of the molecular mechanisms and creating individualized surveillance are required.}, } @article {pmid40290690, year = {2025}, author = {Cao, YK and Yang, SL and Wei, ZQ}, title = {Is the use of a transanal drainage tube effective in treating anastomotic leakage for mid-low rectal cancer.}, journal = {World journal of clinical oncology}, volume = {16}, number = {4}, pages = {99801}, pmid = {40290690}, issn = {2218-4333}, abstract = {BACKGROUND: Anastomotic leakage (AL) is a severe surgical complication for mid-low rectal cancers. The efficacy of transanal drainage tube (TDT) has rarely been reported.

AIM: To evaluate the efficacy of TDT after AL.

METHODS: A retrospective analysis was conducted on 68 patients with mid-low rectal cancer who underwent laparoscopic low anterior resection (LAR) and developed ALs. Leakage were identified using imaging studies and digital rectal examinations when local abscesses or systemic infections were present. In each patient, the leakage site was determined using the index finger and a drainage tube was inserted transanally to drain the abscesses and exudates outside the anus. The clinical outcomes of the patients following transanal drainage were analyzed.

RESULTS: A total of 43 patients received TDT treatment, while 25 patients did not receive TDT treatment. Among the patients in the TDT group, 9 required reoperation compared to 12 in the non-TDT group. In the TDT group, 76.74% of the patients were able to restore intestinal continuity, whereas only 40% of the patients in the non-TDT group achieved restored intestinal continuity. In the TDT group, 48.48% of patients developed LAR syndrome (LARS), whereas in the non-TDT group, 90% of patients developed LARS. The median drainage time was 7 days, the median postoperative hospital stay was 21 days, the median fasting time was 6.5 days, and the median hospitalization cost was 109205.93 RMB.

CONCLUSION: TDT use lowered reoperation rate but did not increase hospitalization expenses. After ≥ 1 year of follow-up, its use improved intestinal patency rate and reduced the incidence of LARS.}, } @article {pmid40291645, year = {2025}, author = {Xie, L and Zhu, Y and Hurtle, BT and Wright, M and Robinson, JL and Mauna, JC and Brown, EE and Ngo, M and Bergmann, CA and Xu, J and Merjane, J and Gleixner, AM and Grigorean, G and Liu, F and Rossoll, W and Lee, EB and Kiskinis, E and Chikina, M and Donnelly, CJ}, title = {Context-dependent Interactors Regulate TDP-43 Dysfunction in ALS/FTLD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40291645}, issn = {2692-8205}, support = {R01 EY030546/EY/NEI NIH HHS/United States ; R21 NS133676/NS/NINDS NIH HHS/United States ; RF1 AG068581/AG/NIA NIH HHS/United States ; R01 AG068581/AG/NIA NIH HHS/United States ; RF1 AG065341/AG/NIA NIH HHS/United States ; R01 HG009299/HG/NHGRI NIH HHS/United States ; R01 NS105756/NS/NINDS NIH HHS/United States ; R01 AG077771/AG/NIA NIH HHS/United States ; U24 DK112331/DK/NIDDK NIH HHS/United States ; R01 AG076122/AG/NIA NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; RF1 AG076122/AG/NIA NIH HHS/United States ; R21 AG085314/AG/NIA NIH HHS/United States ; R21 NS141767/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; }, abstract = {TDP-43 mislocalization, aggregation, and loss of splicing function are neuropathological hallmarks in over 97% of Amyotrophic Lateral Sclerosis (ALS), 45% of Frontotemporal Lobar Degeneration (FTLD), and 60% of Alzheimer's Disease, which has been reclassified as LATE-NC. However, the mechanisms underlying TDP-43 dysfunction remain elusive. Here, we utilize APEX2-driven proximity labeling and mass spectrometry to characterize the context-dependent TDP-43 interactome in conditions of cytoplasmic mislocalization, impaired RNA-binding contributing to aggregation, and oxidative stress. We describe context-dependent interactors, including disrupted interactions with splicing-related proteins and altered biomolecular condensate (BMC) associations. By integrating ALS and FTLD snRNA-seq data, we uncover disease-relevant molecular alterations and validate our dataset through a functional screen that identifies key TDP-43 regulators. We demonstrate that disrupting nuclear speckle integrity, particularly through the downregulation of the splicing factor SRRM2, promotes TDP-43 mislocalization and loss of function. Additionally, we identify NUFIP2 as an interactor associated with mislocalization that sequesters TDP-43 into cytoplasmic aggregates and co-localizes with TDP-43 pathology in patient tissue. We also highlight HNRNPC as a potent TDP-43 splicing regulator, where precise modulation of TDP-43 or HNRNPC can rescue cryptic exon splicing. These findings provide mechanistic insights and potential therapeutic targets for TDP-43 dysfunction.}, } @article {pmid40291709, year = {2025}, author = {Gao, G and Sumrall, ER and Walter, NG}, title = {Nanoscale domains govern local diffusion and aging within FUS condensates.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40291709}, issn = {2692-8205}, support = {R01 NS097542/NS/NINDS NIH HHS/United States ; R35 GM131922/GM/NIGMS NIH HHS/United States ; }, abstract = {Biomolecular condensates regulate cellular physiology by sequestering and processing RNAs and proteins, yet how these processes are locally tuned within condensates remains unclear. Moreover, in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), condensates undergo liquid-to-solid phase transitions, but capturing early intermediates in this process has been challenging. Here, we present a surface multi-tethering approach to achieve intra-condensate single-molecule tracking of fluorescently labeled RNA and protein molecules within liquid-like condensates. Using RNA-binding protein Fused in Sarcoma (FUS) as a model for condensates implicated in ALS, we discover that RNA and protein diffusion is confined within distinct nanometer-scale domains, or nanodomains, which exhibit unique connectivity and chemical environments. During condensate aging, these nanodomains reposition, facilitating FUS fibrilization at the condensate surface, a transition enhanced by FDA-approved ALS drugs. Our findings demonstrate that nanodomain formation governs condensate function by modulating biomolecule sequestration and percolation, offering insights into condensate aging and disease-related transitions.}, } @article {pmid40291716, year = {2025}, author = {Hnath, B and Dokholyan, NV}, title = {Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.04.07.647611}, pmid = {40291716}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease resulting in paralysis and death within three to five years. Mutations in over forty different proteins have been linked to ALS, leading to controversy whether ALS is one disease or many diseases with a similar phenotype. Mutations in Cu,Zn superoxide dismutase 1 (SOD1) are only found in 2-3% of ALS cases, yet misfolded SOD1 is found in both sporadic (sALS) and familial (fALS) patients. Yet, mutations in TDP-43 or FUS increase the level of misfolded SOD1 on extracellular vesicles (EVs). Additionally, small EVs isolated from ALS patient samples caused cell death of wild type motor neurons and myotubules. The toxicity and protein alterations of ALS EVs have led to the theory that EVs are responsible for the spread of ALS. We hypothesize that previously-identified toxic trimeric SOD1 is spreading on EVs in ALS and altering the spread of other ALS-related proteins, linking them to a common mechanism. To test our hypothesis, we isolate EVs from motor neuron-like cells expressing trimer stabilizing mutations and perform a sandwich enzyme-linked immunoassay (ELISA) (CD9 capture antibody) to quantify whether misfolded SOD1 and 17 other ALS-related proteins increase or decrease on EVs with trimer stabilization. We identify which EV release pathway is being affected by trimeric SOD1 utilizing endocytosis and exocytosis inhibitors, and determine if any specific EV-related proteins are altered with trimer stabilization. We establish that VAPB, VCP, and Stathmin-2 increase on EVs with trimer stabilization. The common pathway between SOD1 and three other ALS-associated proteins is affected by multiple pathways, including the Caveolae endocytosis pathway, suggesting a novel hybrid pathway of EV release present in ALS.}, } @article {pmid40291738, year = {2025}, author = {Zhu, B and Van, R and Wang, H and Kuang, S and Jia, Y and Leon, EC and Yang, F and Zhang, J and Yang, J and Hong, H and Fleur Marie, L and Yu, A and Wang, J and Tanzi, RE and Zhang, CM and Mao, XM and Shao, Y and Ran, C}, title = {Highly sensitive chemiluminescence imaging of misfolded proteins in neurodegenerative models.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.04.12.648090}, pmid = {40291738}, issn = {2692-8205}, abstract = {Protein misfolding is a crucial pathological phenomenon driving neurodegenerative diseases that affect millions of people. Visualizing misfolded proteins would greatly facilitate early diagnosis, etiology elucidation, and therapy monitoring of neurodegeneration. Although several probes have been reported, versatile and sensitive detection in vivo is still challenging. We demonstrated that both generic and precise detection of misfolded proteins could be achieved with a chemiluminescence probe, ADLumin-1. For generic aspect, ADLumin-1 was highly sensitive to various misfolded proteins, showing up to 127.73-fold higher signal-to-noise ratio than gold standard dye of Thioflavin T. ADLumin-1 could also non-invasively visualize misfolded proteins in mouse models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. For precise aspects, ADLumin-1 can selectively detect α-synuclein in CSF at the femtomolar level by combining with protein misfolding cyclic amplification technology in vitro. In addition, ADLumin-1 enables selective in vivo imaging of misfolded α-synuclein in transgenic mice models by employing bioorthogonal chemiluminescence resonance energy transfer strategy. Combining generality and precision, our findings could be widely applied in preclinical and clinical studies of neurodegenerative diseases.}, } @article {pmid40293530, year = {2025}, author = {Shahidehpour, RK and Katsumata, Y and Dickson, DW and Ghayal, NB and Aung, KZ and Wu, X and Phe, P and Jicha, GA and Neltner, AM and Archer, JRC and Corrada, MM and Kawas, CH and Ahmad Sajjadi, S and Woodworth, DC and Bukhari, SA and Montine, TJ and Fardo, DW and Nelson, PT}, title = {LATE-NC Stage 3: a diagnostic rubric to differentiate severe LATE-NC from FTLD-TDP.}, journal = {Acta neuropathologica}, volume = {149}, number = {1}, pages = {38}, pmid = {40293530}, issn = {1432-0533}, support = {P50 AG008671/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; R01 AG057187/AG/NIA NIH HHS/United States ; P30 AG013854/AG/NIA NIH HHS/United States ; P50 MH060451/MH/NIMH NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; R01 AG022374/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; U01 HG006375/HG/NHGRI NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; RC2 AG036528/AG/NIA NIH HHS/United States ; R01 AG021055/AG/NIA NIH HHS/United States ; P30 AG028377/AG/NIA NIH HHS/United States ; P50 AG005142/AG/NIA NIH HHS/United States ; R01 AG061111/AG/NIA NIH HHS/United States ; R01 AG035137/AG/NIA NIH HHS/United States ; R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; P50 AG005131/AG/NIA NIH HHS/United States ; P50 AG005128/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; R01 AG031581/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; P50 AG005146/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; R01 AG019085/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; R01 AG013616/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; R01 AG030146/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; RF1 NS118584/NS/NINDS NIH HHS/United States ; UL1 RR029893/RR/NCRR NIH HHS/United States ; U01 AG016976/AG/NIA NIH HHS/United States ; P50 NS039764/NS/NINDS NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P30 AG008051/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG013846/AG/NIA NIH HHS/United States ; RC2 AG036502/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; R01 MH080295/MH/NIMH NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG012300/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; R01 AG012101/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; P50 AG016570/AG/NIA NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG008017/AG/NIA NIH HHS/United States ; U24 AG041689/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG062706/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; R01 AG033193/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; R37 AG015473/AG/NIA NIH HHS/United States ; U24 AG026395/AG/NIA NIH HHS/United States ; P50 AG005133/AG/NIA NIH HHS/United States ; U01 AG010483/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P01 AG002219/AG/NIA NIH HHS/United States ; R01 CA129769/CA/NCI NIH HHS/United States ; T32 AG078110/AG/NIA NIH HHS/United States ; U01 AG006781/AG/NIA NIH HHS/United States ; R01 AG041797/AG/NIA NIH HHS/United States ; P50 AG005144/AG/NIA NIH HHS/United States ; P01 AG010491/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; R01 AG021547/AG/NIA NIH HHS/United States ; R01 AG041232/AG/NIA NIH HHS/United States ; R01 AG019757/AG/NIA NIH HHS/United States ; R01 AG020688/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R01 AG030653/AG/NIA NIH HHS/United States ; R01 AG027944/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; R01 AG017173/AG/NIA NIH HHS/United States ; R01 AG025259/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; U01 HG004610/HG/NHGRI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG010129/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; R01 AG041718/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P50 AG016582/AG/NIA NIH HHS/United States ; RF1 AG082339/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; P30 AG028383/AG/NIA NIH HHS/United States ; R01 AG082730/AG/NIA NIH HHS/United States ; R01 AG026916/AG/NIA NIH HHS/United States ; P50 AG033514/AG/NIA NIH HHS/United States ; R01 NS059873/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Aged ; *Frontotemporal Lobar Degeneration/pathology/diagnosis/genetics ; *TDP-43 Proteinopathies/pathology/diagnosis/genetics ; Diagnosis, Differential ; Aged, 80 and over ; DNA-Binding Proteins/metabolism/genetics ; Middle Aged ; *Brain/pathology ; Inclusion Bodies/pathology ; Dementia ; }, abstract = {A diagnostic rubric is required to distinguish between limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In LATE-NC Stage 3, TDP-43 proteinopathy is present in the middle frontal gyrus (MFG), thus posing a potential diagnostic challenge in differentiating these severe LATE-NC cases from FTLD-TDP. LATE-NC Stage 3 cases and other TDP-43 proteinopathies were analyzed from the University of Kentucky (total n = 514 with TDP-43 pathology assessed), The 90+ Study at the University of California Irvine (n = 458), and the Mayo Clinic (n = 5067) brain banks. Digital pathology was used to quantify pathology burden in a select subset of cases (n = 51), complemented by a previously-described manual counting method and expert neuropathologic examinations to evaluate qualitative features such as FTLD-TDP types and subtypes of neuronal cytoplasmic inclusions (NCIs). To evaluate clinical and genetic characteristics of LATE-NC Stage 3, data were analyzed from the National Alzheimer's Coordinating Center (NACC) Neuropathology Data set and correlated with findings from the Alzheimer's Disease Genetics Consortium (ADGC). When using TDP-43 proteinopathy quantification in the MFG as a diagnostic criterion, more than 90% of cases could be classified as either LATE-NC Stage 3 or FTLD-TDP. Diagnostically challenging scenarios included a subset of FTLD-TDP Type B cases with relatively mild MFG TDP-43 pathology and a novel non-LATE-NC, non-FTLD-TDP pathologic subtype with severe MFG TDP-43 pathology. Taking these potential pitfalls into account, a classification schema was developed that could correctly diagnose all included cases. There was no difference in the Alzheimer's disease pathological load in LATE-NC Stages 2 versus 3. In genetic analyses, the GRN (rs5848) risk allele was preferentially associated with LATE-NC Stage 3, whereas TMEM106B and APOE risk-associated variants were not. In conclusion, LATE-NC Stage 3 could be differentiated reliably from FTLD-TDP and other TDP-43-opathies, based on a data-driven diagnostic rubric.}, } @article {pmid40294152, year = {2025}, author = {Alfano, LN and Iammarino, MA and Reash, NF and Lowes, LP and Pietruszewski, L and Adderley, K and Humphrey, L and Knight, AB and Steiner, CL and Smith, MA and Sahenk, Z and Connolly, AM and Almomen, M and D'Ambrosio, ES and Peck, N and Peck, A}, title = {Validity and Reliability of Clinical and Patient-Reported Outcomes in Multisystem Proteinopathy 1.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {7}, pages = {1324-1333}, pmid = {40294152}, issn = {2328-9503}, support = {//Cure VCP Disease Inc/ ; }, mesh = {Humans ; *Patient Reported Outcome Measures ; Male ; Female ; Middle Aged ; Aged ; Reproducibility of Results ; *Valosin Containing Protein/genetics ; *Outcome Assessment, Health Care/standards ; Adult ; }, abstract = {OBJECTIVE: Valosin-containing protein (VCP)-associated multisystem proteinopathy 1 (MSP1) is caused by variants in the VCP gene. MSP1 results in various phenotypes including progressive myopathy, Paget's disease of bone, frontotemporal dementia, amyotrophic lateral sclerosis, and parkinsonism, among others. Our study aimed to validate functional clinical outcome assessments (COA) and patient-reported outcomes (PRO) to inform clinical care practices and future clinical trial design. In addition, we evaluated the test-retest reliability of these COAs within clinics and remote environments.

METHODS: Patients completed a battery of COA and PRO across a 2-day traditional onsite visit and a 2-day remote visit within their home environment. All COA and PRO deemed safe and feasible to complete based on participants' level of function and/or home environment were collected at each visit.

RESULTS: Forty-six total patients enrolled in our study, 34 in our full study and 12 in an expanded remote-only cohort. Functional COA measured decline over reported disease duration in this cross-sectional group and significantly correlated with PRO (rho > 0.5, p < 0.001). Differences in lower and upper extremity involvement were noted across variant groups. Performance of functional COA was reliable and safe within and across onsite and remote testing environments (ICC > 0.7, p < 0.001).

INTERPRETATION: Functional COA and PRO are valid and reliable to measure abilities in participants with MSP1. Testing can be completed reliably within the home, which could expand equitable access to clinical care and/or future clinical trial participation. Prospective longitudinal data collection is ongoing to understand outcome sensitivity and meaningful change over time.}, } @article {pmid40294208, year = {2025}, author = {Winek, K and Soreq, H}, title = {Emerging roles of transfer RNA fragments in the CNS.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {8}, pages = {2631-2645}, pmid = {40294208}, issn = {1460-2156}, support = {5P01AG014449-21/GF/NIH HHS/United States ; 11183//Israel Science Foundation/ ; 835/23//Israel Science Foundation/ ; P01 AG014449/AG/NIA NIH HHS/United States ; 3213/19//Israel Science Foundation/ ; 1770/20//Israel Science Foundation/ ; }, mesh = {Humans ; *RNA, Transfer/metabolism/genetics ; Animals ; *Central Nervous System/metabolism ; *Central Nervous System Diseases/genetics/metabolism ; *RNA, Small Untranslated/metabolism/genetics ; }, abstract = {Transfer RNA-derived small RNAs (tsRNAs), previously considered inactive tRNA degradation products, have now been shown to be functional small non-coding RNAs. They may play important roles within the CNS and in brain-body interactions, both during normal developmental stages as well as in diverse brain pathologies. Among the cell types found in the CNS, tsRNAs are particularly abundant in neurons. Correspondingly, neurons show cell type specific tRNA expression profiles when compared to other cells of the CNS under homeostatic conditions and defects in tRNA processing may lead to neurological disorders. Disease-specific tsRNA profiles have been identified in a number of CNS disorders, including amyotrophic lateral sclerosis and epilepsy. Elevated levels of specific tsRNAs have been found in the blood before the onset of epileptic seizures; and age-related, sex-specific loss of mitochondrial genome-originated tsRNAs in the nucleus accumbens of female patients is correlated with accelerated cognitive deterioration in Alzheimer's disease. Disease-related tsRNA signatures have also been identified in the CSF of patients with Parkinson's disease, and nucleated blood cells from ischaemic stroke patients show specific elevation of cholinergic-targeted tsRNAs. The mechanisms of action of tsRNAs are still being elucidated but include targeting complementary mRNA to impact RNA levels and translation in a miRNA-like manner, direct interaction with RNA binding proteins, or interference with translation machinery. The function of tsRNAs may be affected by the chemical modifications they inherit from the originating tRNA molecules, which impact tsRNAs production and may modulate their interactions with proteins. Research on the genetics, biochemical properties and regulatory roles of tsRNAs has expanded rapidly in recent years, facilitated by novel sequencing strategies, which include the removal of tRNA modifications and chemically blocked ends that hinder amplification and adapter ligation. Future in-depth profiling of tsRNAs levels, mode(s) of function, and identification of interacting proteins and RNAs may together shed light on the impact of tsRNAs on neuronal function, and enable novel diagnostics/therapeutics avenues for brain diseases in age, sex and disease-specific manner.}, } @article {pmid40294721, year = {2025}, author = {Natala, SR and Habas, A and Stocking, EM and Orry, A and Abagyan, R and Makale, MT and Wrasidlo, W}, title = {Structure based design, synthesis and identification of novel covalent reversible dual TLR2/TLR9 small molecule antagonists.}, journal = {Bioorganic & medicinal chemistry letters}, volume = {124}, number = {}, pages = {130259}, doi = {10.1016/j.bmcl.2025.130259}, pmid = {40294721}, issn = {1464-3405}, mesh = {*Toll-Like Receptor 2/antagonists & inhibitors/metabolism ; Humans ; *Drug Design ; *Toll-Like Receptor 9/antagonists & inhibitors/metabolism ; *Small Molecule Libraries/pharmacology/chemistry/chemical synthesis ; Molecular Structure ; Structure-Activity Relationship ; Animals ; Dose-Response Relationship, Drug ; }, abstract = {Inflammation is a key driver of the onset and progression of neurodegenerative diseases and cancer and can be caused by aggregated proteins, injured neurons or synapses, dysregulation of inflammatory control mechanisms, and other factors. Tolllike receptors (TLRs) are important mediators of inflammatory pathways, and their activation leads to pro-inflammatory cytokine release by immune cells in the periphery or in the central nervous system (CNS). TLR2 and TLR9 are implicated in the inflammatory pathogenesis of CNS degenerative diseases such as Parkinson's Disease (PD) and amyotrophic lateral sclerosis (ALS). They are also held to be important in the etiology of certain malignancies like inflammatory pancreatic ductal adenocarcinoma and glioblastoma. Inactivation of TLR2/9 in animal models of neurodegeneration has reduced pathological markers and diminished neuronal loss, while in animal models of cancer it has suppressed tumors. Therefore, TLR2 and TLR9 may be potential targets for the treatment of neurodegenerative disorders and cancers. We identified for the first time a key binding locus in TLR2/9 TIR domain which guided reversible covalent drug (RCD) design of a novel, first-in class series of dual TLR2/9 antagonists. Sub-micromolar antagonist concentrations potently inhibited TLR2 and TLR9 signaling induced by TLR2/9 specific agonists. Importantly, this series of antagonists did not discernably activate other TLRs and exhibited favorable in-vitro ADME and safety. The analogs described here may help realize effective TLR2/9 antagonism as a viable therapeutic strategy for inflammation driven CNS diseases and various malignancies with an inflammatory etiology.}, } @article {pmid40295049, year = {2025}, author = {Keul, J and Sperling, S and Rohde, V and Ninkovic, M}, title = {Advantages and Disadvantages of Drug Combination Treatment: Riluzole, Metformin and Dexamethasone Effect on Glioblastoma Cell.}, journal = {Anticancer research}, volume = {45}, number = {5}, pages = {1813-1823}, doi = {10.21873/anticanres.17561}, pmid = {40295049}, issn = {1791-7530}, mesh = {Humans ; *Glioblastoma/drug therapy/pathology/metabolism/genetics ; *Metformin/pharmacology/administration & dosage ; *Dexamethasone/pharmacology/administration & dosage ; Cell Line, Tumor ; *Riluzole/pharmacology/administration & dosage ; *Brain Neoplasms/drug therapy/pathology/metabolism ; Cell Movement/drug effects ; Cell Survival/drug effects ; *Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Matrix Metalloproteinase 2/metabolism ; Drug Synergism ; Cell Proliferation/drug effects ; }, abstract = {BACKGROUND/AIM: In glioblastoma multiforme (GBM), a deadly brain tumor, glucose is one of the main fuels for accelerated growth. Patients with GBM are also exposed to excess glucose through hyperglycemia in diabetes mellitus. In addition, dexamethasone (Dex), a corticosteroid commonly administered for controlling cerebral oedema, causes additional excess glucose. Therefore, targeting glucose metabolism is an attractive therapeutic intervention for GBM treatment. We have recently shown that riluzole (Ril), a drug used to treat amyotrophic lateral sclerosis (ALS), has an effect on some detrimental Dex-induced metabolic changes in GBM. Therefore, we examined the effect of the combination of metformin (Met), widely used to treat type 2 diabetes, and Ril on GBM cells.

MATERIALS AND METHODS: The 3-(4, 5-dimethylthiazol)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to determine cell viability of U87MG after treatment with Ril, Met, Ril plus Met (Ril+Met) and the addition of Dex to this co-treatment. Cell migration was assessed by the xCELLigence system, matrix metalloproteinase 2 (MMP2) activation by zymography assay and gene expression by real-time polymerase chain reaction (RT-PCR).

RESULTS: Co-treatment with Ril and Met was effective in killing GBM cells and reducing the expression of genes involved in glucose and stem cell metabolism. Furthermore, combination of Ril and Met reduced MMP2 activation. But co-administration increased the migration of U87MG cells. The addition of Dex to this combination reversed the unfavorable effects of Ril+Met on cell migration.

CONCLUSION: Ril+Met co-treatment had a positive effect in terms of GBM cell death, decreased expression of genes involved in glucose metabolism and stemness, and reduced MMP2 activation. Disadvantage of Ril+Met treatment was increased cell migration. Taken together, these drug combinations may also allow the reduction of the concentration of Dex to minimize its side effects.}, } @article {pmid40295163, year = {2025}, author = {Miyachi, S and Oshima, Y and Yazaki, K and Futaki, N and Shirai, Y and Tanei, ZI and Ikebe, Y and Iwata, I and Ujiie, H and Onozawa, M and Hirano, S and Tanaka, S and Yabe, I}, title = {An Autopsy Case of Amyotrophic Lateral Sclerosis With Sudden Death Showed Histological Features of Lewy Body Disease.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {45}, number = {4}, pages = {e70009}, doi = {10.1111/neup.70009}, pmid = {40295163}, issn = {1440-1789}, support = {//Mitsubishi Foundation Research Grant for Social Welfare Activities/ ; }, mesh = {Humans ; Male ; Aged, 80 and over ; *Amyotrophic Lateral Sclerosis/pathology/complications ; *Lewy Body Disease/pathology/complications ; Autopsy ; *Death, Sudden/etiology/pathology ; Fatal Outcome ; *Brain/pathology ; }, abstract = {We present the case of an 81-year-old man diagnosed with probable amyotrophic lateral sclerosis (ALS) based on the Updated Awaji criteria. The patient exhibited progressive motor neuron degeneration with muscle weakness, atrophy, and fasciculations primarily in the right lower limb and later extending to the right upper limb. Three months after being referred to a home care clinic, he collapsed in front of his family members and died. An autopsy revealed phosphorylated TDP-43 pathology consistent with ALS, with involvement of the hypoglossal nucleus, facial nerve nucleus, and medulla oblongata. Interestingly, widespread a-synuclein pathology indicative of diffuse neocortical type Lewy body disease (LBD; Braak stage 6) was identified, despite the absence of clinical parkinsonism or dementia with Lewy bodies (DLB) during his lifetime. The presence of autonomic symptoms such as constipation and urinary retention shortly before death may be attributable to a-synuclein pathology affecting the autonomic nervous system. The coexistence of ALS and LBD underscores the clinical challenge of diagnosing overlapping pathologies, as motor symptoms may obscure signs of LBD. Dopamine transporter imaging or MIBG myocardial scintigraphy might aid in identifying preclinical LBD in ALS patients with atypical symptoms. The patient died of respiratory failure due to extensive organizing pneumonia, but the possibility of sudden cardiac arrest could not be excluded. This case highlights the potential for coexisting neurodegenerative pathologies in ALS, emphasizing the importance of comprehensive evaluation when autonomic symptoms or other atypical features are present.}, } @article {pmid40295825, year = {2025}, author = {Hu, X and Xu, Y and Li, C and Mao, H and Liu, Z and Xiao, Y and Li, Y and Yang, X}, title = {A five-year examination into the occurrence of herbicide-resistant barnyardgrass populations in paddy from Jiangsu Province, China.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {14781}, pmid = {40295825}, issn = {2045-2322}, support = {2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; }, mesh = {*Herbicide Resistance/genetics ; China ; *Herbicides/pharmacology ; *Echinochloa/drug effects/genetics ; *Oryza/growth & development ; Quinolines ; }, abstract = {To assess resistance situation and evolutionary risks, 510 Echinochloa populations from 13 rice-growing regions in Jiangsu Province (2018-2022) were tested against seven herbicides (penoxsulam, quinclorac, cyhalofop-butyl, bispyribac-sodium, pretilachlor, metamifop, and florpyrauxifen-benzyl), with cross- and multiple-resistance patterns analyzed. Penoxsulam resistance increased ninefold over five years, while quinclorac resistance consistently exceeded 40% annually for four years. Cyhalofop-butyl and bispyribac-sodium resistance frequencies also rose annually, with the strongest resistance to penoxsulam and bispyribac-sodium observed in southern Jiangsu, particularly in Suzhou, Wuxi, Changzhou, and Zhenjiang. In northern Jiangsu, Huaian showed the highest resistance to multiple herbicides, while quinclorac resistance was widespread across all regions. Pretilachlor and metamifop resistance remained low, with only sporadic outbreaks, indicating that they continued to be used. However, prolonged use of single-site herbicides, particularly ALS inhibitors and ACCase inhibitors, has led to cross-resistance evolution. Multiple-resistance analysis indicated that quinclorac, penoxsulam, and cyhalofop-butyl should not be used in binary or ternary mixtures to control resistant Echinochloa. Notably, 14 populations exhibited florpyrauxifen-benzyl resistance, with 13 also showing quinclorac resistance, suggesting a potential link between prior quinclorac resistance and florpyrauxifen-benzyl resistance evolution, which warrants further investigation. This study clarifies herbicide resistance patterns in Echinochloa in Jiangsu Province, offering critical insights for resistance management strategies.}, } @article {pmid40295933, year = {2025}, author = {Yu, SF and Michon, M and Lingappa, AF and Paulvannan, K and Solas, D and Staats, K and Ichida, J and Dey, D and Rosenfeld, J and Lingappa, VR}, title = {An ALS assembly modulator signature in peripheral blood mononuclear cells: implications for ALS pathophysiology, therapeutics, and diagnostics.}, journal = {Clinical proteomics}, volume = {22}, number = {1}, pages = {16}, pmid = {40295933}, issn = {1542-6416}, support = {IL-2023-C4-L1//Target ALS/ ; W81XWH2210721//DOD CDMRP/ ; }, abstract = {Assembly modulators are a new class of allosteric site-targeted therapeutic small molecules, some of which are effective at restoring nuclear localization of TDP-43 in ALS cellular models, and which display efficacy in a variety of ALS animal models. These compounds have been shown to bind selectively to a small subset of protein disulfide isomerase (PDI), a protein implicated in ALS pathophysiology. The targeted subset of PDI is found within a novel, transient and energy-dependent multi-protein complex that includes other important members of the ALS interactome, such as TDP-43, RanGTPase, and selective autophagy receptor p62/SQSTM1. We demonstrate here that a similar multi-protein complex drug target is present in PBMCs as isolated by energy-dependent drug resin affinity chromatography (eDRAC) and characterized by mass spectrometry and by Western blot (WB). Signature alterations in the composition of the multi-protein complex in PBMCs from ALS patients compared to PBMCs from healthy individuals were identified by WB of eDRAC bound proteins, thereby extending earlier literature suggesting PBMC dysfunction in ALS. Changes in the PBMC drug target in ALS patients compared to healthy individuals include diminished p62/SQSTM1 and appearance of a 17 kDa post-translationally modified form of RanGTPase. These changes are not readily apparent from analysis of whole cell extracts, as the individual protein components within the drug target multi-protein complex comprise only small percentages of the total of those component proteins in the extract. Furthermore, whole blood from ALS patients shows a distinctive degradation of total RanGTPase not observed in blood from healthy individuals. This degradation appears to be rescued by treatment of whole blood from ALS patients for 72 h with ALS-active assembly modulator small molecules. Our findings are consistent with the hypothesis that ALS is fundamentally a disorder of homeostasis that can be detected early, prior to disability, in blood by the methods described, and restored to the healthy state by assembly modulator drug treatment.}, } @article {pmid40296625, year = {2025}, author = {Barabadi, T and Mirjalili, ES and Mohamadi-Zarch, SM and Rahimi, H and Keshmirshekan, F and Bagheri, SM}, title = {Cell-Free DNA, a Noninvasive Biomarker for Prediction and Detection of Neurodegenerative Diseases, New Insights, and Perspectives.}, journal = {CNS & neurological disorders drug targets}, volume = {24}, number = {10}, pages = {731-742}, pmid = {40296625}, issn = {1996-3181}, support = {18535//Shahid Sadoughi University of Medical Science and Health Services/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/blood ; Biomarkers/blood ; *Cell-Free Nucleic Acids/blood/metabolism ; Parkinson Disease/diagnosis ; Animals ; }, abstract = {Neurodegenerative diseases pose serious threats to public health worldwide. Biomarkers for neurodegenerative disorders are essential to enhance the diagnostic process in clinical settings and to aid in the creation and assessment of effective disease-modifying treatments. In recent times, affordable and readily available blood-based biomarkers identifying the same neurodegenerative disease pathologies have been created, potentially transforming the diagnostic approach for these disorders worldwide. Emerging relevant biomarkers for α-synuclein pathology in Parkinson's disease include blood-based indicators of overall neurodegeneration and glial activation. Cell-free DNA (cfDNA), an encouraging non-invasive biomarker commonly utilized in oncology and pregnancy, has demonstrated significant potential in clinical uses for diagnosing neurodegenerative disorders. In this section, we explore the latest cfDNA studies related to neurodegenerative disorders. Moreover, we present a perspective on the possible role of cfDNA as a diagnostic, therapeutic, and prognostic indicator for neurodegenerative disorders. This review provides a summary of the most recent progress in biomarkers for neurodegenerative disorders such as Alzheimer's, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and traumatic brain injury.}, } @article {pmid40297747, year = {2025}, author = {Nara, T and Shibuya, K and Ikeda, S and Kuroiwa, R and Otani, R and Ogushi, M and Suichi, T and Shiko, Y and Takahashi, K and Misawa, S and Murata, A and Kuwabara, S}, title = {Different patterns of fasciculation in spinal and bulbar muscular atrophy and amyotrophic lateral sclerosis: a muscle ultrasonographic study.}, journal = {BMJ neurology open}, volume = {7}, number = {1}, pages = {e001065}, pmid = {40297747}, issn = {2632-6140}, abstract = {BACKGROUND: The usefulness of muscle ultrasonography for detection of fasciculations has been increasingly recognised, particularly in amyotrophic lateral sclerosis (ALS). This study aimed to elucidate distributions and characteristics of fasciculations in spinal and bulbar muscular atrophy (SBMA) and to compare the results of those in ALS.

METHODS: In 24 SBMA and 16 ALS patients, muscle ultrasonography was systematically performed in the tongue, upper limb muscles (biceps brachii, triceps brachii, first dorsal interosseous (FDI), abductor pollicis brevis and abductor digiti minimi), trunk muscles (Th10 paraspinals and rectus abdominis) and lower limb muscles (vastus lateralis, biceps femoris, tibialis anterior and gastrocnemius). We assessed the presence of fasciculations and the fasciculation intensity (scored from 0 to 3) for each muscle.

RESULTS: All SBMA and ALS patients showed fasciculations at least in two muscles. In SBMA patients, fasciculations were most frequently found in the tongue (100%), FDI (93%) and tibialis anterior (80%), whereas less frequently present in the proximal limb and trunk muscles, irrespective of age, disease duration and CAG repeat numbers. By contrast, in ALS patients, fasciculations were more diffusely distributed including the proximal limb and trunk muscles. When fasciculations were present, the intensity was higher in ALS patients, except for the tongue.

CONCLUSIONS: Whereas both diseases exhibit extensive fasciculations, the distribution and intensity are different. SBMA is characterised by prominent involvement in the tongue and distal limb muscles, suggesting different pathophysiology of motor neuronal death in SBMA and ALS.}, } @article {pmid40298207, year = {2025}, author = {Radakovic, R and Gray, D and Trucco, AP and Bregola, A and Mioshi, E and Copsey, H and Dick, D and Newton, J and Colville, S and Pal, S and Chandran, S and Simmons, Z and Abrahams, S}, title = {Impact of apathy over the course of disease in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {516-525}, doi = {10.1080/21678421.2025.2495020}, pmid = {40298207}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; *Apathy/physiology ; Female ; Middle Aged ; *Quality of Life/psychology ; *Caregivers/psychology ; Aged ; Disease Progression ; Adult ; }, abstract = {Objective: Apathy is a common syndrome in amyotrophic lateral sclerosis (ALS), particularly Initiation apathy (lack of motivation for self-generated thoughts and/or actions). The aim was to determine how apathy subtypes change over time, and their impact on individuals' quality of life (QoL), caregiver-wellbeing and burden or strain. Methods: Forty-nine people living with ALS (pwALS) and their caregiver participated in interviews at three time-points (3-month intervals). They completed the Dimensional Apathy Scale (DAS), and assessments of depression, anxiety and emotional lability, cognitive-behavioral functioning and functional disability. PwALS QoL, caregiver burden or strain, caregiver-wellbeing and care-related QoL were measured. Results: At baseline, Initiation apathy was most common (38.8%, N = 19) followed by Emotional apathy (16.3%, N = 8). Lower caregiver-wellbeing was observed in Initiation apathy (p < 0.05) and Mixed-emotional apathy (p < 0.001) groups, where only Initiation apathy had higher caregiver burden or strain (p < 0.05) than those with no apathy. Over three visits (N = 31), there was an increase in Initiation apathy (p < 0.01) and Executive apathy (p < 0.05) over time. While controlling for functional disability, only increasing Emotional apathy was associated with increasing caregiver burden or strain (p < 0.05), decreasing caregiver-wellbeing (p < 0.001), and decreasing care-related QoL (p < 0.05). Conclusion: Initiation and Emotional apathy were variably associated with higher levels of caregiver burden or strain and decreased caregiver-wellbeing in ALS. As ALS progresses, Initiation and Executive apathy increased, while Emotional apathy has been shown to impact care-related QoL, caregiver-wellbeing and burden or strain. This has implications for understanding the progression of apathy subtypes and the interplay of caregiver-wellbeing, QoL, burden, or strain.}, } @article {pmid40298692, year = {2025}, author = {Petito, G and Del Fiore, VS and Cuomo, A and Cioffi, F and Cobellis, G and Lanni, A and Guerra, F and Bucci, C and Senese, R and Romano, R}, title = {Dysfunctional Mitochondria Characterize Amyotrophic Lateral Sclerosis Patients' Cells Carrying the p.G376D TARDBP Pathogenetic Substitution.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, pmid = {40298692}, issn = {2076-3921}, support = {PRIN2022 PNRR N. P2022FBZXY//Ministero dell'università e della ricerca/ ; D.M. n. 737 of 25.06.2021//Ministero dell'università e della ricerca/ ; PRIN2022 N. 2022XTM2S3//Ministero dell'università e della ricerca/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the degeneration of upper and lower motor neurons in the brain, brainstem and spinal cord. About 10% of familial ALS cases are linked to pathogenetic substitution in TARDBP, the gene encoding the TDP-43 protein. A novel rare causative variant in TARDBP (p.G376D) was recently reported in ALS patients. It leads to TDP-43 cytoplasmic mislocalization, increased oxidative stress and reduced cell viability. However, functional studies on the effects of this molecular defect have not yet been carried out. Mitochondria are highly dynamic organelles, and their deregulation has emerged as a key factor in many diseases, among which is ALS. Therefore, this study aimed at determining the impact of this causative variant on mitochondria. In cellular models expressing TDP-43[G376D] and in fibroblasts derived from patients carrying this molecular defect, we observed alterations of mitochondrial functionality. We demonstrated increased localization of the mutated protein to mitochondria and a reduced abundance of subunits of complex I and complex II of the mitochondrial respiratory chain, associated with a decrease in mitochondrial membrane potential, in cellular respiration and in cytochrome C oxidase (COX) activity. Moreover, ALS cells showed increased mitochondrial fragmentation and reduced abundance of antioxidant enzymes causing increased oxidative stress. These results expand our knowledge about the molecular mechanisms underlying ALS pathogenesis associated with TDP-43 p.G376D and could help to identify new therapeutic strategies to counteract this disease.}, } @article {pmid40298821, year = {2025}, author = {Bortolotti, M and Polito, L and Battelli, MG and Bolognesi, A}, title = {Xanthine Oxidoreductase: A Double-Edged Sword in Neurological Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, pmid = {40298821}, issn = {2076-3921}, abstract = {Non-communicable neurological disorders are the second leading cause of death, and their burden continues to increase as the world population grows and ages. Oxidative stress and inflammation are crucially implicated in the triggering and progression of multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and even stroke. In this narrative review, we examine the role of xanthine oxidoreductase (XOR) activities and products in all the above-cited neurological diseases. The redox imbalance responsible for oxidative stress could arise from excess reactive oxygen and nitrogen species resulting from the activities of XOR, as well as from the deficiency of its main product, uric acid (UA), which is the pivotal antioxidant system in the blood. In fact, with the exception of stroke, serum UA levels are inversely related to the onset and progression of these neurological disorders. The inverse correlation observed between the level of uricemia and the presence of neurological diseases suggests a neuroprotective role for UA. Oxidative stress and inflammation are also caused by ischemia and reperfusion, a condition in which XOR action has been recognized as a contributing factor to tissue damage. The findings reported in this review could be useful for addressing clinical decision-making and treatment optimization.}, } @article {pmid40299083, year = {2025}, author = {Levison, LS and Blicher, JU and Andersen, H}, title = {Correction: Incidence and mortality of ALS: a 42-year population-based nationwide study.}, journal = {Journal of neurology}, volume = {272}, number = {5}, pages = {365}, doi = {10.1007/s00415-025-13076-2}, pmid = {40299083}, issn = {1432-1459}, } @article {pmid40299101, year = {2025}, author = {Sarkar, S and Porel, P and Kosey, S and Aran, KR}, title = {Unraveling the role of CGRP in neurological diseases: a comprehensive exploration to pathological mechanisms and therapeutic implications.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {436}, pmid = {40299101}, issn = {1573-4978}, mesh = {Humans ; *Calcitonin Gene-Related Peptide/metabolism/genetics ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; *Nervous System Diseases/metabolism ; Signal Transduction ; Receptors, Calcitonin Gene-Related Peptide/metabolism ; Oxidative Stress ; }, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Spinal muscular atrophy (SMA) are neurodegenerative diseases (NDDs) characterized by progressive neuronal degeneration. Recent studies provide compelling information regarding the contribution of Calcitonin Gene-Related Peptide (CGRP), a potent neuropeptide, in regulating neuroinflammation, vasodilation, and neuronal survival in these disorders. This review systematically delves into the multidimensional aspects of CGRP as both a neuroprotective agent and a neurotoxic factor in NDDs. The neuroprotective effects of CGRP include suppression of inflammation, regulation of intracellular signaling pathways, and promotion of neuronal growth and survival. However, under pathological conditions, its overexpression or dysregulation is associated with oxidative stress, excitotoxicity, and neuronal death. The therapeutic use of CGRP and its receptor antagonists in migraine provides substantial evidence for CGRP's therapeutic potential, which can be further explored for the management of NDDs. However, since the bidirectional nature of CGRP effects is evident, it is crucial to gain an accurate insight into its mechanisms to target only the neuropeptide's beneficial effects while completely avoiding the undesired consequences. Further studies should focus on understanding the context-dependent activity of CGRP in the hope of designing targeted therapy for NDDs, which could gradually transform the current pharmacological management of NDDs.}, } @article {pmid40299102, year = {2025}, author = {Zhang, G and Huang, S and Wei, M and Wu, Y and Wang, J}, title = {Excitatory Amino Acid Transporters as Therapeutic Targets in the Treatment of Neurological Disorders: Their Roles and Therapeutic Prospects.}, journal = {Neurochemical research}, volume = {50}, number = {3}, pages = {155}, pmid = {40299102}, issn = {1573-6903}, support = {2023JJB140089//Guangxi Youth Science Foundation Project/ ; 82201694//the National Natural Scientific Foundation of China/ ; 2022AC21033//Guangxi Science and technology base and talent project/ ; 2022KY0349//Guangxi university young and middle-aged teachers' basic ability improvement project/ ; }, mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Glutamate Plasma Membrane Transport Proteins/metabolism ; Glutamic Acid/metabolism ; }, abstract = {Excitatory amino acid transporters (EAATs) are pivotal regulators of glutamate homeostasis in the central nervous system and orchestrate synaptic glutamate clearance through transmembrane transport and the glutamine‒glutamate cycle. The five EAAT subtypes (GLAST/EAAT1, GLT-1/EAAT2, EAAC1/EAAT3, EAAT4, and EAAT5) exhibit spatiotemporal-specific expression patterns in neurons and glial cells, and their dysfunction is implicated in diverse neurological pathologies, including epilepsy, amyotrophic lateral sclerosis (ALS), schizophrenia, depression, and retinal degeneration. Mechanistic studies revealed that astrocytic GLT-1 deficiency disrupts glutamate clearance in ALS motor neurons, whereas GLAST genetic variants are linked to both epilepsy susceptibility and glaucomatous retinal ganglion cell degeneration. Three major challenges persist in ongoing research: ① subtype-specific regulatory mechanisms remain unclear; ② compensatory functions of transporters vary significantly across disease models; and ③ clinical translation lacks standardized evaluation criteria. The interaction mechanisms and dynamic roles of EAATs in neurological disorders were systematically investigated in this study, and an integrated approach combining single-cell profiling, stem cell-based disease modeling, and drug screening platforms was proposed. These findings lay the groundwork for novel therapeutic strategies targeting glutamate homeostasis.}, } @article {pmid40299512, year = {2025}, author = {Eslami, M and Adampour, Z and Fadaee Dowlat, B and Yaghmayee, S and Motallebi Tabaei, F and Oksenych, V and Naderian, R}, title = {A Novel Frontier in Gut-Brain Axis Research: The Transplantation of Fecal Microbiota in Neurodegenerative Disorders.}, journal = {Biomedicines}, volume = {13}, number = {4}, pages = {}, pmid = {40299512}, issn = {2227-9059}, abstract = {The gut-brain axis (GBA) represents a sophisticated bidirectional communication system connecting the central nervous system (CNS) and the gastrointestinal (GI) tract. This interplay occurs primarily through neuronal, immune, and metabolic pathways. Dysbiosis in gut microbiota has been associated with multiple neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). In recent years, fecal microbiota transplantation (FMT) has gained attention as an innovative therapeutic approach, aiming to restore microbial balance in the gut while influencing neuroinflammatory and neurodegenerative pathways. This review explores the mechanisms by which FMT impacts the gut-brain axis. Key areas of focus include its ability to reduce neuroinflammation, strengthen gut barrier integrity, regulate neurotransmitter production, and reinstate microbial diversity. Both preclinical and clinical studies indicate that FMT can alleviate motor and cognitive deficits in PD and AD, lower neuroinflammatory markers in MS, and enhance respiratory and neuromuscular functions in ALS. Despite these findings, several challenges remain, including donor selection complexities, uncertainties about long-term safety, and inconsistencies in clinical outcomes. Innovations such as synthetic microbial communities, engineered probiotics, and AI-driven analysis of the microbiome hold the potential to improve the precision and effectiveness of FMT in managing neurodegenerative conditions. Although FMT presents considerable promise as a therapeutic development, its widespread application for neurodegenerative diseases requires thorough validation through well-designed, large-scale clinical trials. It is essential to establish standardized protocols, refine donor selection processes, and deepen our understanding of the molecular mechanisms behind its efficacy.}, } @article {pmid40299664, year = {2025}, author = {Nogueira-Machado, JA and Rocha-Silva, F and Gomes, NA}, title = {The Role of mTOR in Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {13}, number = {4}, pages = {}, pmid = {40299664}, issn = {2227-9059}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a rare, progressive, and incurable disease characterized by muscle weakness and paralysis. Recent studies have explored a possible link between ALS pathophysiology and mTOR signaling. Recent reports have linked the accumulation of protein aggregates, dysfunctional mitochondria, and homeostasis to the development of ALS. mTOR plays a pivotal role in controlling autophagy and affecting energy metabolism, in addition to supporting neuronal growth, plasticity, and the balance between apoptosis and autophagy, all of which are important for homeostasis. Aim: This mini-review approaches the regulatory roles of mTOR signaling pathways, their interaction with other metabolic pathways, and their potential to modulate ALS progression. Significance: It discusses how these metabolic signaling pathways affect the neuromuscular junction, producing symptoms of muscle weakness and atrophy similar to those seen in patients with ALS. The discussion includes the concepts of neurocentric and peripheral and the possible connection between mTOR and neuromuscular dysfunction in ALS. Conclusions: It highlights the therapeutic potential of mTOR signaling and interconnections with other metabolic routes, making it a promising biomarker and therapeutic target for ALS.}, } @article {pmid40300213, year = {2025}, author = {Sun, Y and Vermulst, M}, title = {The hidden costs of imperfection: transcription errors in protein aggregation diseases.}, journal = {Current opinion in genetics & development}, volume = {93}, number = {}, pages = {102350}, pmid = {40300213}, issn = {1879-0380}, support = {R01 AG054641/AG/NIA NIH HHS/United States ; R01 AG075130/AG/NIA NIH HHS/United States ; R01 AG083065/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Transcription, Genetic/genetics ; *Protein Aggregation, Pathological/genetics/pathology ; Protein Folding ; *Alzheimer Disease/genetics/pathology ; *Neurodegenerative Diseases/genetics/pathology ; *Protein Aggregates/genetics ; Amyloid/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Aging/genetics/pathology ; Prions/genetics ; Mutation ; }, abstract = {At first glance, biological systems appear to operate with remarkable precision and order. Yet, closer examination reveals that this perfection is an illusion, biological processes are inherently prone to errors. Here, we describe recent evidence that indicates that errors that occur during transcription play an important role in neurological diseases. These errors, though transient, can have lasting consequences when they generate mutant proteins with amyloid or prion-like properties. Such proteins can seed aggregation cascades, converting wild-type counterparts into misfolded conformations, ultimately leading to toxic deposits seen in diseases like Alzheimer's and amyotrophic lateral sclerosis. These observations help to paint a fuller picture of the origins of neurodegenerative diseases in aging humans and suggest a unified mechanism by which they may arise.}, } @article {pmid40300682, year = {2025}, author = {Li, Z and Xing, J}, title = {Role of sirtuins in cerebral ischemia-reperfusion injury: Mechanisms and therapeutic potential.}, journal = {International journal of biological macromolecules}, volume = {310}, number = {Pt 4}, pages = {143591}, doi = {10.1016/j.ijbiomac.2025.143591}, pmid = {40300682}, issn = {1879-0003}, mesh = {Humans ; *Sirtuins/metabolism/genetics ; *Reperfusion Injury/metabolism/drug therapy/pathology ; Animals ; *Brain Ischemia/metabolism/drug therapy/pathology ; }, abstract = {The high incidence and mortality rate of cardiac arrest (CA) establishes it as a critical clinical challenge in emergency medicine globally. Despite continuous advances in advanced life support (ALS) technology, the prognosis for patients experiencing cardiac arrest remains poor, with cerebral ischemia and reperfusion injury (CIRI) being a significant determinant of adverse neurological outcomes and increased mortality. Sirtuins (SIRTs) are a class of highly evolutionarily conserved NAD[+]-dependent histone deacylenzymes capable of regulating the expression of various cytoprotective genes to play a neuroprotective role in CIRI. SIRTs mainly regulate the levels of downstream proteins such as PGC 1-α, Nrf 2, NLRP 3, FoxOs, and PINK 1 to inhibit inflammatory response, attenuate oxidative stress, improve mitochondrial dysfunction, promote angiogenesis, and inhibit apoptosis while reducing CIRI. Natural active ingredients are widely used in regulating the protein level of SIRTs in the body because of their multi-components, multi-pathway, multi-target, and minimal toxic side effects. However, these naturally active ingredients still face many challenges related to drug targeting, pharmacokinetic properties, and drug delivery. The emergence and vigorous development of new drug delivery systems, such as nanoparticles, micromilk, and exosomes, provide strong support for solving the above problems. In the context of the rapid development of molecular biology technology, non-coding RNA (NcRNA), represented by miRNA and LncRNA, offers great potential for achieving gene-level precision medicine. In the context of multidisciplinary integration, combining SIRTs proteins with biotechnology, omics technologies, artificial intelligence, and material science will strongly promote the deepening of their basic research and expand their clinical application. This review describes the major signaling pathways of targeting SIRTs to mitigate CIRI, as well as the current research status of Chinese and Western medicine and medical means for the intervention level of SIRTs. Meanwhile, the challenges and possible solutions in the clinical application of targeted drugs are summarized. In the context of medical and industrial crossover, the development direction of SIRTs in the future is discussed to provide valuable reference for basic medical researchers and clinicians to improve the clinical diagnosis and treatment effects of CIRI.}, } @article {pmid40301025, year = {2025}, author = {Yamahara, N and Yoshikura, N and Yuhei, I and Shimohata, T}, title = {[Intravenous glucose infusion may have caused refeeding syndrome in a patient with advanced amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {65}, number = {5}, pages = {372-375}, doi = {10.5692/clinicalneurol.cn-002086}, pmid = {40301025}, issn = {1882-0654}, mesh = {Humans ; Female ; Aged ; *Refeeding Syndrome/etiology/chemically induced ; *Glucose/adverse effects/administration & dosage ; *Amyotrophic Lateral Sclerosis/complications ; Infusions, Intravenous/adverse effects ; Fluid Therapy ; Treatment Outcome ; }, abstract = {We present the case of a 69-year-old woman who underwent tracheostomy for advanced amyotrophic lateral sclerosis. The patient was treated with furosemide for leg edema. Body mass index was stable at 21.5 ‍kg/m[2]. The patient was admitted to our hospital after vomiting because of biliary infection. Fluid therapy with 286 ‍kcal/day of glucose was administered, followed by acute deterioration, including tachycardia (120 bpm), glucose intolerance, abdominal pain, hypophosphatemia (required intravenous phosphate supply; 60 ‍mmol/day), and hypokalemia (required intravenous potassium supply; 60 mEq/day). Refeeding syndrome was suspected, and the patient recovered with adjustments in serum electrolyte levels. We demonstrated that glucose infusion can cause refeeding syndrome in patients with advanced amyotrophic lateral sclerosis without low nutritional intake.}, } @article {pmid40301152, year = {2025}, author = {Armas, JMB and Taoro-González, L and Fisher, EMC and Acevedo-Arozena, A}, title = {Challenges of modelling TDP-43 pathology in mice.}, journal = {Mammalian genome : official journal of the International Mammalian Genome Society}, volume = {36}, number = {2}, pages = {465-481}, pmid = {40301152}, issn = {1432-1777}, mesh = {Animals ; *DNA-Binding Proteins/genetics/metabolism ; Mice ; *Disease Models, Animal ; *TDP-43 Proteinopathies/genetics/pathology/metabolism ; Humans ; Mutation ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Cell Nucleus/genetics/metabolism ; Cytoplasm/metabolism/genetics ; }, abstract = {TDP-43 is a normally nuclear RNA binding protein that under pathological conditions may be excluded from the nucleus and deposited in the cytoplasm in the form of insoluble polyubiquitinated and polyphosphorylated inclusions. This nuclear exclusion coupled with cytoplasmic accumulation is called TDP-43 pathology and contributes to a range of disorders collectively known as TDP-43 proteinopathies. These include the great majority of amyotrophic lateral sclerosis (ALS) cases, all limbic-predominant age-related TDP-43 encephalopathy (LATE), as well as up to 50% of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) cases. Thus, TDP-43 pathology is a common feature underlying a wide range of neurodegenerative conditions. However, modelling it has proven to be challenging, particularly generating models with concomitant TDP-43 loss of nuclear function and cytoplasmic inclusions. Here, focussing exclusively on mice, we discuss TDP-43 genetic models in terms of the presence of TDP-43 pathology, and we consider other models with TDP-43 pathology due to mutations in disparate genes. We also consider manipulations aimed at producing TDP-43 pathology, and we look at potential strategies to develop new, much needed models to address the many outstanding questions regarding how and why TDP-43 protein leaves the nucleus and accumulates in the cytoplasm, causing downstream dysfunction and devastating disease.}, } @article {pmid40301571, year = {2025}, author = {Dragoni, F and Gerlando, RD and Diamanti, L and Rizzo, B and Bordoni, M and Scarian, E and Viola, C and Cerchia, G and Zucca, S and Pansarasa, O and Gagliardi, S}, title = {Cross-tissue MiRNA profiling of extracellular vesicles and PBMCs from amyotrophic lateral sclerosis patients.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {14976}, pmid = {40301571}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *MicroRNAs/genetics/metabolism ; *Extracellular Vesicles/metabolism/genetics ; *Leukocytes, Mononuclear/metabolism ; Male ; Female ; Gene Expression Profiling ; Middle Aged ; Aged ; Transcriptome ; }, abstract = {RNA-mediated toxicity, which can be controlled by alteration of gene expression, is considered a key event in Amyotrophic Lateral Sclerosis (ALS). Transcriptomic deregulation of miRNAs expression can spread via "horizontal" RNA transfer through extracellular vesicles (EVs) to act in conjunction with proteins, leading to changes in mRNA, which can provide early signals to indicate forthcoming neuropathological changes in the brain. The aim of this work is to compare expression profiles (obtained by miRNA-seq) from different tissues to highlight commonly expressed and tissue-specific miRNAs. miRNA species from plasma EVs were correlated with miRNA profiles obtained from peripheral blood mononuclear cells (PBMCs). Each tissue from ALS patients was compared to controls, revealing 159 deregulated (DE) miRNAs in Exosomes (EXOs), 247 DE miRNAs in PBMCs and 162 DE miRNAs in Microvesicles (MVs). Next, data were filtered to include only miRNAs expressed in disease samples (not in healthy subjects), to reduce the number of tissue- and ALS- specific miRNAs (EXO n = 22, MV = 11, PBMCs n = 8). We identified specific miRNAs and pathways related to each tissue. Interestingly, in PBMCs we found mainly neuro-linked pathways, such as neurotransmitters, brain and neuron development, while in EXOs, we found miRNAs implicated in MAPK and ERB signaling. In contrast, the altered pathways in MVs were not specific. This study shows that the composition of small RNA differs significantly between blood cells and its respective EVs fraction. Differentially expressed miRNAs can target definite transcripts in different cellular and molecular fractions. It is evident that, in terms of miRNAs cargo, MVs are not specific to ALS. Therefore, future studies will focus on the interaction between cells and EXOs.}, } @article {pmid40302786, year = {2025}, author = {Vijayaraghavan, M and Murali, SP and Thakur, G and Li, XJ}, title = {Role of glial cells in motor neuron degeneration in hereditary spastic paraplegias.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1553658}, pmid = {40302786}, issn = {1662-5102}, support = {R01 NS118066/NS/NINDS NIH HHS/United States ; }, abstract = {This review provides a comprehensive overview of hereditary spastic paraplegias (HSPs) and summarizes the recent progress on the role of glial cells in the pathogenesis of HSPs. HSPs are a heterogeneous group of neurogenetic diseases characterized by axonal degeneration of cortical motor neurons, leading to muscle weakness and atrophy. Though the contribution of glial cells, especially astrocytes, to the progression of other motor neuron diseases like amyotrophic lateral sclerosis (ALS) is well documented, the role of glial cells and the interaction between neurons and astrocytes in HSP remained unknown until recently. Using human pluripotent stem cell-based models of HSPs, a study reported impaired lipid metabolisms and reduced size of lipid droplets in HSP astrocytes. Moreover, targeting lipid dysfunction in astrocytes rescues axonal degeneration of HSP cortical neurons, demonstrating a non-cell-autonomous mechanism in axonal deficits of HSP neurons. In addition to astrocytes, recent studies revealed dysfunctions in HSP patient pluripotent stem cell-derived microglial cells. Increased microgliosis and pro-inflammation factors were also observed in HSP patients' samples, pointing to an exciting role of innate immunity and microglia in HSP. Building upon these recent studies, further investigation of the detailed molecular mechanism and the interplay between glial cell dysfunction and neuronal degeneration in HSP by combining human stem cell models, animal models, and patient samples will open avenues for identifying new therapeutic targets and strategies for HSP.}, } @article {pmid40303507, year = {2025}, author = {Verma, S and Khurana, S and Gourie-Devi, M and Anand, I and Vats, Y and Singh, A and Jothiramajayam, M and Kshetrapal, P and Sharma, A and Wajid, S and Ganguly, NK and Chakraborti, P and Taneja, V}, title = {Multiomics Approach Reveal Novel Insights in FUS Driven Juvenile Amyotrophic Lateral Sclerosis: A Family Quartet Analysis.}, journal = {Annals of neurosciences}, volume = {32}, number = {2}, pages = {78-89}, pmid = {40303507}, issn = {0972-7531}, abstract = {BACKGROUND: Juvenile amyotrophic lateral sclerosis (JALS) is a rare and severe form of motor neuron disease characterized by progressive loss of upper and lower motor neurons with an early onset (<25 years).

PURPOSE: Due to complex etiology and clinical heterogeneity, it is indispensable to unravel molecular mechanisms underlying JALS pathology. The study aimed to identify disease-specific signatures in a 14-years-old sporadic JALS patient.

METHODS: Genomic, transcriptomic, and metabolomic analysis of proband and first-degree relatives (FDR).

RESULTS: Exome sequencing identified a novel de novo frameshift variation (c.1465dupG: p.D490Gfs*26) in the fused in sarcoma (FUS) gene in proband. Interestingly, rare and potentially deleterious, disease-modifying variations in DDHD domain containing 1 (DDHD1) and fibrillin 2 (FBN2) were observed. Differentially expressed genes (DGEs) enriched in neuromuscular transmission and inflammatory response were identified by RNA-sequencing. In addition, alterations in purine and pyrimidine, vitamin B6, and sphingolipid metabolism reflect the involvement of inflammatory process in disease pathobiology.

CONCLUSION: Our findings suggest the involvement of multiple genetic factors coupled with hampered neuromuscular transmission and systemic inflammation in the onset and disease course of JALS.}, } @article {pmid40303620, year = {2025}, author = {Basiri, K and Paydari, H and Abbasi, F and Ansari, B}, title = {Upper Extremity Peripheral Nerve Ultrasonography, as a Diagnostic Aid in Amyotrophic Lateral Sclerosis.}, journal = {Advanced biomedical research}, volume = {14}, number = {}, pages = {22}, pmid = {40303620}, issn = {2277-9175}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a life-threatening progressive motor neuron disease whose diagnosis is challenging because of lacking specific diagnostic means. The current study aims to assess the value of upper extremity peripheral nerves ultrasonography in ALS detection.

MATERIALS AND METHODS: In this case-control study, 30 ALS subjects were assessed regarding the cross-sectional area (CSA) of the proximal (at distal part of arm or the proximal of elbow) and distal (at wrist level) median and ulnar nerves, assessed via ultrasonography. Similarly, 30 age- and gender-matched healthy controls were evaluated. The receiver operating curve (ROC) was depicted to determine a cut-point for ALS-associated peripheral nerve involvement.

RESULTS: Proximal CSA and the proximal-to-distal ratio of the median nerve was remarkably lower in both upper extremities of the ALS subjects compared to the controls (P value < 0.05), while the distal median nerve CSAs did not differ between the groups (P value > 0.05). Distal ulnar nerve CSA in the right hand (P value = 0.007) and the proximal ulnar nerve CSA in the left hand (P value = 0.001) were remarkably lower in the cases than the controls, but the other measurements did not differ (P value > 0.05). There was no significant cut-points to differentiate ALS-affected peripheral nerves from the healthy controls (P value > 0.05).

CONCLUSION: Based on this study, CSA of the proximal median nerve in the cubital fossa seems a rational and valuable means to diagnose ALS; but the distal parts of the median nerve and the ulnar nerve in its all length remained a matter of debate.}, } @article {pmid40304712, year = {2025}, author = {Freisem, D and Hoenigsperger, H and Catanese, A and Sparrer, KMJ}, title = {Inborn errors of canonical autophagy in neurodegenerative diseases.}, journal = {Human molecular genetics}, volume = {34}, number = {R1}, pages = {R23-R34}, pmid = {40304712}, issn = {1460-2083}, support = {CA 2915/4-1//German Research Foundation/ ; CRC1506//German Research Foundation/ ; CRC1279//German Research Foundation/ ; SP 1600/7-1//German Research Foundation/ ; SP 1600/9-1//German Research Foundation/ ; }, mesh = {Humans ; *Autophagy/genetics ; *Neurodegenerative Diseases/genetics/pathology/metabolism ; Animals ; Mitophagy/genetics ; Parkinson Disease/genetics/pathology ; Mutation ; Proteostasis/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology ; }, abstract = {Neurodegenerative disorders (NDDs), characterized by a progressive loss of neurons and cognitive function, are a severe burden to human health and mental fitness worldwide. A hallmark of NDDs such as Alzheimer's disease, Huntington's disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and prion diseases is disturbed cellular proteostasis, resulting in pathogenic deposition of aggregated protein species. Autophagy is a major cellular process maintaining proteostasis and integral to innate immune defenses that mediates lysosomal protein turnover. Defects in autophagy are thus frequently associated with NDDs. In this review, we discuss the interplay between NDDs associated proteins and autophagy and provide an overview over recent discoveries in inborn errors in canonical autophagy proteins that are associated with NDDs. While mutations in autophagy receptors seems to be associated mainly with the development of ALS, errors in mitophagy are mainly found to promote PD. Finally, we argue whether autophagy may impact progress and onset of the disease, as well as the potential of targeting autophagy as a therapeutic approach. Concludingly, understanding disorders due to inborn errors in autophagy-"autophagopathies"-will help to unravel underlying NDD pathomechanisms and provide unique insights into the neuroprotective role of autophagy, thus potentially paving the way for novel therapeutic interventions.}, } @article {pmid40304918, year = {2025}, author = {Anjum, F and Alsharif, A and Bakhuraysah, M and Shafie, A and Hassan, MI and Mohammad, T}, title = {Discovering Novel Biomarkers and Potential Therapeutic Targets of Amyotrophic Lateral Sclerosis Through Integrated Machine Learning and Gene Expression Profiling.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {2}, pages = {61}, pmid = {40304918}, issn = {1559-1166}, support = {KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Machine Learning ; Receptors, Nicotinic/genetics/metabolism ; Gene Expression Profiling ; Biomarkers/metabolism ; Tumor Suppressor Proteins/genetics/metabolism ; Transcriptome ; Membrane Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has multiple factors that make its molecular pathogenesis difficult to understand and its diagnosis and treatment during the early stages difficult to determine. Discovering novel biomarkers in ALS for diagnostic and therapeutic potential has become important. Consequently, bioinformatics and machine learning algorithms are useful for identifying differentially expressed genes (DEGs) and potential biomarkers, as well as understanding the molecular mechanisms and intricacies of diseases such as ALS. To achieve the aim of the present study, six datasets obtained from the Gene Expression Omnibus (GEO) were utilized and analyzed using an integrative bioinformatics and machine learning approach. Log transformation was done during data preprocessing, RMA normalization was performed, and the batch effect was corrected. Differential expression analysis identified 206 DEGs that were significantly associated with different biological processes, including muscle function, energy metabolism, and mitochondrial membrane activity. Functional enrichment analysis highlighted pathways, including those related to prion disease, Parkinson's disease, and ATP synthesis via chemiosmotic coupling. We employed a multi-step machine learning framework incorporating random forest, LASSO regression, and SVM-RFE to identify robust biomarkers. This approach identified three key genes, CHRNA1, DLG5, and PLA2G4C, which could be explored as promising biomarkers for ALS after further validation. The internal validation, including principal component analysis (PCA) and ROC-AUC analysis, demonstrated strong diagnostic potential of these hub genes, achieving an AUC of 0.96. This work highlights the utility of bioinformatics and machine learning in identifying key genes as biomarkers for diagnostic and therapeutic potential in ALS.}, } @article {pmid40305176, year = {2025}, author = {Erichsen, PA and Henriksen, EE and Nielsen, JE and Ejlerskov, P and Simonsen, AH and Toft, A}, title = {Immunological Fluid Biomarkers in Frontotemporal Dementia: A Systematic Review.}, journal = {Biomolecules}, volume = {15}, number = {4}, pages = {}, pmid = {40305176}, issn = {2218-273X}, support = {0084960//Novo Nordisk Foundation/ ; R450-2023-989//Lundbeck Foundation/ ; }, mesh = {Humans ; *Frontotemporal Dementia/immunology/blood/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid/blood ; Alzheimer Disease/immunology/blood/cerebrospinal fluid ; Amyotrophic Lateral Sclerosis/blood/immunology/cerebrospinal fluid ; Chitinase-3-Like Protein 1/cerebrospinal fluid/blood ; Glial Fibrillary Acidic Protein/cerebrospinal fluid/blood ; Chemokine CCL2/cerebrospinal fluid/blood ; }, abstract = {Dysregulated immune activation plays a key role in the pathogenesis of neurodegenerative diseases, including frontotemporal dementia (FTD). This study reviews immunological biomarkers associated with FTD and its subtypes. A systematic search of PubMed and Web of Science was conducted for studies published before 1 January 2025, focusing on immunological biomarkers in CSF or blood from FTD patients with comparisons to healthy or neurological controls. A total of 124 studies were included, involving 6686 FTD patients and 202 immune biomarkers. Key findings include elevated levels of GFAP and MCP1/CCL2 in both CSF and blood and consistently increased CHIT1 and YKL-40 in CSF. Complement proteins from the classical activation pathway emerged as promising targets. Distinct immune markers were found to differentiate FTD from Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), with GFAP, SPARC, and SPP1 varying between FTD and AD and IL-15, HERV-K, NOD2, and CHIT1 differing between FTD and ALS. A few markers, such as Galectin-3 and PGRN, distinguished FTD subtypes. Enrichment analysis highlighted IL-10 signaling and immune cell chemotaxis as potential pathways for further exploration. This study provides an overview of immunological biomarkers in FTD, emphasizing those most relevant for future research on immune dysregulation in FTD pathogenesis.}, } @article {pmid40305762, year = {2025}, author = {Manohar, R and Yang, FX and Stephen, CD and Schmahmann, JD and Eklund, NM and Gupta, AS}, title = {At-home wearables and machine learning capture motor impairment and progression in adult ataxias.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {10}, pages = {3623-3634}, pmid = {40305762}, issn = {1460-2156}, support = {R01 NS117826/NS/NINDS NIH HHS/United States ; R01 NS117826/NH/NIH HHS/United States ; //Friedreich's Ataxia Research Alliance/ ; R01 NS134597/NH/NIH HHS/United States ; }, mesh = {Humans ; Male ; Disease Progression ; Female ; Middle Aged ; *Wearable Electronic Devices ; *Machine Learning ; Adult ; Aged ; Cross-Sectional Studies ; Longitudinal Studies ; *Spinocerebellar Ataxias/physiopathology/diagnosis ; *Multiple System Atrophy/physiopathology/diagnosis ; Accelerometry ; }, abstract = {A significant barrier to developing disease-modifying therapies for spinocerebellar ataxias (SCAs) and multiple system atrophy of the cerebellar type (MSA-C) is the scarcity of tools to measure disease progression sensitively in clinical trials. Wearable sensors worn continuously during natural behaviour at home have the potential to produce ecologically valid and precise measures of motor function by leveraging frequent and numerous high-resolution samples of behaviour. Here we test whether movement building block characteristics (i.e. submovements), obtained from the wrist and ankle during natural behaviour at home, can capture disease progression sensitively in SCAs and MSA-C, as recently shown in amyotrophic lateral sclerosis and ataxia telangiectasia. Remotely collected cross-sectional (n = 76) and longitudinal (n = 27) data were analysed from individuals with ataxia (SCAs 1, 2, 3 and 6, MSA-C) and controls. Machine learning models were trained to produce composite outcome measures based on submovement properties. Two models were trained on data from individuals with ataxia to estimate ataxia rating scale scores. Two additional models, previously trained entirely on longitudinal amyotrophic lateral sclerosis data to optimize sensitivity to change, were also evaluated. All composite outcomes from both wrist and ankle sensor data had moderate to strong correlations with ataxia rating scales and self-reported function, showed differences between ataxia and control groups with high effect size, and had high within-week reliability. The composite outcomes trained on longitudinal amyotrophic lateral sclerosis data most strongly captured disease progression over time. These data demonstrate that outcome measures based on accelerometers worn at home can capture the ataxia phenotype accurately and measure disease progression sensitively. This assessment approach is scalable and can be used in clinical or research settings with relatively low individual burden.}, } @article {pmid40306255, year = {2025}, author = {Bu, Y and Yuan, Y and Hu, F and Zhao, Q and He, C and Tang, L and Li, Y and Liu, Z and Weng, L and Du, J and Guo, J and Shen, L and Li, J and Yi, J and Cao, W and Xu, R and Tang, B and Wang, J}, title = {Retinal alterations induced by amyotrophic lateral sclerosis: An analysis using optical coherence tomography.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {136}, number = {}, pages = {111268}, doi = {10.1016/j.jocn.2025.111268}, pmid = {40306255}, issn = {1532-2653}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/complications/pathology ; *Tomography, Optical Coherence/methods ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; *Retina/diagnostic imaging/pathology ; Aged ; Adult ; Disease Progression ; Nerve Fibers/pathology ; }, abstract = {OBJECTIVE: In this study, we aimed to investigate retinal changes in a large cohort of amyotrophic lateral sclerosis (ALS) patients and healthy controls (HCs) to further elucidate their relationship with ALS.

METHODS: This was a cross-sectional observational study. We evaluated retinal layer thickness in 134 ALS patients and 66 HCs using optical coherence tomography (OCT). Particularly, we focused on the macular region and peripapillary retinal nerve fiber layer (p-RNFL).

RESULTS: The examination of retinal layers in ALS patients revealed a significant change in the inner nuclear layer (INL), with a pattern of initial thickening followed by thinning, which correlated with disease stages, most notably in the inner nasal quadrant. Moreover, the p-RNFL in the temporal quadrant was thinner in ALS patients compared to HCs. In addition, ALS patients who developed bulbar symptoms exhibited marginally thinner p-RNFL in the temporal quadrant compared to those without bulbar symptoms. Interestingly, a thinner p-RNFL in the temporal quadrant did not correlate with faster disease progression.

CONCLUSION: This study reveals notable changes in the INL and p-RNFL thickness in ALS patients, highlighting the intricate relationship between retinal changes and ALS progression. Despite these retinal alterations, no correlation with disease progression rate was observed. These findings suggest that while OCT shows potential in monitoring ALS, its role in predicting disease course requires further investigation with long-term longitudinal studies and diverse patient cohorts.}, } @article {pmid40306441, year = {2025}, author = {Chen, Y and Sun, S and Gao, N and Bai, Z and Yu, W and Zhao, B and Yun, Y and Sun, X and Lin, P and Li, W and Zhao, Y and Yan, C and Liu, S}, title = {Proximity extension assay reveals serum inflammatory biomarkers in two amyotrophic lateral sclerosis cohorts.}, journal = {Neurobiology of disease}, volume = {211}, number = {}, pages = {106933}, doi = {10.1016/j.nbd.2025.106933}, pmid = {40306441}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/genetics ; Biomarkers/blood ; Male ; Female ; Middle Aged ; Cohort Studies ; Aged ; *Inflammation/blood ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with both clinical and hereditary heterogeneity. Inflammation has been suggested to play an important role in ALS pathophysiology. In this study, we aimed to identify serum inflammatory alterations and develop effective inflammatory biomarkers to assist in the diagnosis of ALS. Through proximity extension assay (PEA), we investigated serum inflammatory alterations in two ALS cohorts compared with healthy controls (HCs), including sporadic ALS patients and genetic ALS patients. We found that CHIT1, OSM, SIRT2, CDCP1 and 5 other factors were significantly increased in sporadic ALS patients in both cohorts and that SIRT2, CDCP1 and 6 other factors were different between genetic ALS patients and HCs. Using XGBoost and binary logistic regression analysis, we developed a two-serum protein diagnostic panel (CHIT1 and CDCP1), and the area under the curve (AUC) was 0.904 in the original cohort and 0.907 in the replication cohort. Based on Mendelian Randomization (MR), OSM and SIRT2 are significantly associated with the risk of ALS. In conclusion, our study revealed a consistent and replicable serum inflammatory profile and developed a biomarker panel that can differentiate ALS patients from HCs in two cohorts, which may play an important role in advancing our current understanding of the inflammatory process and identifying novel therapeutic strategies for ALS patients.}, } @article {pmid40307231, year = {2025}, author = {Yen, YP and Lung, TH and Liau, ES and Wu, CC and Huang, GL and Hsu, FY and Chang, M and Yang, ZD and Huang, CY and Zheng, Z and Zhao, W and Hung, JH and He, C and Nie, Q and Chen, JA}, title = {The motor neuron m6A repertoire governs neuronal homeostasis and FTO inhibition mitigates ALS symptom manifestation.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4063}, pmid = {40307231}, issn = {2041-1723}, support = {NHRI-EX113-11330NI//National Health Research Institutes (NHRI)/ ; AS-GCP-113-L02//Academia Sinica/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *Motor Neurons/metabolism/pathology ; *Methyltransferases/metabolism/genetics ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Mice ; *Adenosine/analogs & derivatives/metabolism ; *Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism/antagonists & inhibitors/genetics ; Homeostasis ; Disease Models, Animal ; Mice, Knockout ; Male ; Methylation ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a swiftly progressive and fatal neurodegenerative ailment marked by the degenerative motor neurons (MNs). Why MNs are specifically susceptible in predominantly sporadic cases remains enigmatic. Here, we demonstrated N[6]-methyladenosine (m[6]A), an RNA modification catalyzed by the METTL3/METTL14 methyltransferase complex, as a pivotal contributor to ALS pathogenesis. By conditional knockout Mettl14 in murine MNs, we recapitulate almost the full spectrum of ALS disease characteristics. Mechanistically, pervasive m[6]A hypomethylation triggers dysregulated expression of high-risk genes associated with ALS and an unforeseen reduction of chromatin accessibility in MNs. Additionally, we observed diminished m[6]A levels in induced pluripotent stem cell derived MNs (iPSC~MNs) from familial and sporadic ALS patients. Restoring m[6]A equilibrium via a small molecule or gene therapy significantly preserves MNs from degeneration and mitigates motor impairments in ALS iPSC~MNs and murine models. Our study presents a substantial stride towards identifying pioneering efficacious ALS therapies via RNA modifications.}, } @article {pmid40309037, year = {2025}, author = {Yu, Q and Mohammed Nazar, RB and Chen, S and Qian, Q and Wang, J and Chen, X}, title = {A novel SIGMAR1 missense mutation leads to distal hereditary motor neuropathy phenotype mimicking juvenile ALS: a case report of China.}, journal = {Frontiers in genetics}, volume = {16}, number = {}, pages = {1477518}, pmid = {40309037}, issn = {1664-8021}, abstract = {We present the case of a 16-year-old East Asian Chinese girl with a novel mutation in the SIGMAR1 gene, initially diagnosed as juvenile amyotrophic lateral sclerosis (JALS). At the age of five, she began to exhibit gait abnormalities while walking, a condition that persisted for 4 years until muscle weakness and atrophy emerged, predominantly affecting her distal muscles symmetrically. Electromyography (EMG) initially revealed early abonormal motor conduction, and subsequent examinations indicated neurogenic damage accompanied by localized denervation potentials. Whole-exome sequencing identified compound heterozygous mutations in the SIGMAR1 gene. Throughout the course of her illness, the patient exhibited slow disease progression without cognitive impairment or scoliosis development. We ultimately revised the diagnosis to distal hereditary motor neuropathy (dHMN). This study reports the case of SIGMAR1 new locus mutation leading to dHMN in China, contributing to the expansion of the dHMN genetic database. In our patient, the initial EMG findings indicated issues with neurogenic conduction, followed by a slow progression of the disease. Subsequently, EMG results revealed axonal damage and denervation potentials. These clinical features can easily lead to confusion with JALS. This insight is valuable for improving diagnostic accuracy and understanding the clinical spectrum of dHMN related to SIGMAR1 mutations.}, } @article {pmid40309514, year = {2025}, author = {Li, V and Huang, Y}, title = {Oligonucleotide therapeutics for neurodegenerative diseases.}, journal = {NeuroImmune pharmacology and therapeutics}, volume = {4}, number = {1}, pages = {1-11}, pmid = {40309514}, issn = {2750-6665}, support = {R44 DC018463/DC/NIDCD NIH HHS/United States ; R44 DC018762/DC/NIDCD NIH HHS/United States ; }, abstract = {Recently there has been a surge in interest involving the application of oligonucleotides, including small interfering RNA (siRNA) and antisense oligonucleotides (ASOs), for the treatment of chronic diseases that have few available therapeutic options. This emerging class of drugs primarily operates by selectively suppressing target genes through antisense and/or RNA interference mechanisms. While various commercial medications exist for delivering oligonucleotides to the hepatic tissue, achieving effective delivery to extra hepatic tissues remains a formidable challenge. Here, we review recent advances in oligonucleotide technologies, including nanoparticle delivery, local administration, and 2'-O-hexadecyl (C16)-conjugation that work to extend the applicability of siRNAs and ASOs to nerve tissues. We discuss critical factors pivotal for the successful clinical translations of these modified or engineered oligonucleotides in the context of treating neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis.}, } @article {pmid40309789, year = {2025}, author = {Khan, S and Kallis, L and Mee, H and El Hadwe, S and Barone, D and Hutchinson, P and Kolias, A}, title = {Invasive Brain-Computer Interface for Communication: A Scoping Review.}, journal = {Brain sciences}, volume = {15}, number = {4}, pages = {}, pmid = {40309789}, issn = {2076-3425}, abstract = {BACKGROUND: The rapid expansion of the brain-computer interface for patients with neurological deficits has garnered significant interest, and for patients, it provides an additional route where conventional rehabilitation has its limits. This has particularly been the case for patients who lose the ability to communicate. Circumventing neural injuries by recording from the intact cortex and subcortex has the potential to allow patients to communicate and restore self-expression. Discoveries over the last 10-15 years have been possible through advancements in technology, neuroscience, and computing. By examining studies involving intracranial brain-computer interfaces that aim to restore communication, we aimed to explore the advances made and explore where the technology is heading.

METHODS: For this scoping review, we systematically searched PubMed and OVID Embase. After processing the articles, the search yielded 41 articles that we included in this review.

RESULTS: The articles predominantly assessed patients who had either suffered from amyotrophic lateral sclerosis, cervical cord injury, or brainstem stroke, resulting in tetraplegia and, in some cases, difficulty speaking. Of the intracranial implants, ten had ALS, six had brainstem stroke, and thirteen had a spinal cord injury. Stereoelectroencephalography was also used, but the results, whilst promising, are still in their infancy. Studies involving patients who were moving cursors on a screen could improve the speed of movement by optimising the interface and utilising better decoding methods. In recent years, intracortical devices have been successfully used for accurate speech-to-text and speech-to-audio decoding in patients who are unable to speak.

CONCLUSIONS: Here, we summarise the progress made by BCIs used for communication. Speech decoding directly from the cortex can provide a novel therapeutic method to restore full, embodied communication to patients suffering from tetraplegia who otherwise cannot communicate.}, } @article {pmid40309798, year = {2025}, author = {de Carvalho, M}, title = {Developments in Neurodegenerative Disorders: Highly Cited Articles Published in Brain Sciences in 2023-2024.}, journal = {Brain sciences}, volume = {15}, number = {4}, pages = {}, pmid = {40309798}, issn = {2076-3425}, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), pose a significant and growing health concern, particularly in developed countries [...].}, } @article {pmid40309800, year = {2025}, author = {Manai, AL and Caria, P and Noli, B and Contini, C and Manconi, B and Etzi, F and Cocco, C}, title = {VGF and Its Derived Peptides in Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {15}, number = {4}, pages = {}, pmid = {40309800}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive degeneration in the neurons of the frontal cortex, spinal cord, and brainstem, altering the correct release of neurotransmitters. The disease affects every muscle in the body and could cause death three to five years after symptoms first occur. There is currently no efficient treatment to stop the disease's progression. The lack of identification of potential therapeutic strategies is a consequence of the delayed diagnosis due to the absence of accurate ALS early biomarkers. Indeed, neurotransmitters altered in ALS are not measurable in body fluids at quantities that allow for testing, making their use as diagnostic tools a challenge. Contrarily, neuroproteins and neuropeptides are chemical messengers produced and released by neurons, and most of them have the potential to enter bodily fluids. To find out new possible ALS biomarkers, the research of neuropeptides and proteins is intensified using mass spectrometry and biochemical-based assays. Neuropeptides derived from the proVGF precursor protein act as signaling molecules within neurons. ProVGF and its derived peptides are expressed in the nervous and endocrine systems but are also widely distributed in body fluids such as blood, urine, and cerebrospinal fluid, making them viable options as disease biomarkers. To highlight the proVGF and its derived peptides' major roles as ALS diagnostic biomarkers, this review provides an overview of the VGF peptide alterations in spinal cord and body fluids and outlines the limitations of the reported investigations.}, } @article {pmid40310263, year = {2025}, author = {Alidoost, M and Huang, JY and Dermentzaki, G and Blazier, AS and Gaglia, G and Hammond, TR and Frau, F and McCorry, MC and Ofengeim, D and Wilson, JL}, title = {Uncovering New Therapeutic Targets for Amyotrophic Lateral Sclerosis and Neurological Diseases Using Real-World Data.}, journal = {Clinical pharmacology and therapeutics}, volume = {118}, number = {1}, pages = {242-251}, pmid = {40310263}, issn = {1532-6535}, support = {//Sanofi iDEA-TECH/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/mortality ; Humans ; *Drug Repositioning/methods ; *Nervous System Diseases/drug therapy ; Retrospective Studies ; Molecular Targeted Therapy ; Electronic Health Records ; Complement System Proteins/metabolism ; }, abstract = {Although attractive for relevance to real-world scenarios, real-world data (RWD) is typically used for drug repurposing and not therapeutic target discovery. Repurposing studies have identified few effective options in neurological diseases such as the rare disease, amyotrophic lateral sclerosis (ALS), which has no disease-modifying treatments available. We previously reclassified drugs by their simulated effects on proteins downstream of drug targets and observed class-level effects in the EHR, implicating the downstream protein as the source of the effect. Here, we developed a novel ALS-focused network medicine model using data from patient samples, the public domain, and consortia. With this model, we simulated drug effects on ALS and measured class effects on overall survival in retrospective EHR studies. We observed an increased but non-significant risk of death for patients taking drugs with complement system proteins downstream of their targets and experimentally validated drug effects on complement activation. We repeated this for six protein classes, three of which, including multiple chemokine receptors, were associated with a significantly increased risk for death, suggesting that targeting proteins such as CXCR5, CXCR3, chemokine signaling generally, or neuropeptide Y (NPY) could be advantageous therapeutic targets for these patients. We expanded our analysis to the neuroinflammatory condition, myasthenia gravis, and neurodegenerative disease, Parkinson's, and recovered similar effect sizes. We demonstrated the utility of network medicine for testing novel therapeutic effects using RWD and believe this approach may accelerate target discovery in neurological diseases, addressing the critical need for new therapeutic options.}, } @article {pmid40310478, year = {2025}, author = {de Moura-Silva, IA and Rodrigues, BJS and Posso, DA and Bacarin, MA and Borella, J}, title = {Growth inhibition of Pontederia crassipes to imidazolinones herbicides-group exposure.}, journal = {Ecotoxicology (London, England)}, volume = {34}, number = {6}, pages = {958-972}, pmid = {40310478}, issn = {1573-3017}, support = {001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 21/2551-0000621-8//Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul/ ; }, mesh = {*Herbicides/toxicity ; *Water Pollutants, Chemical/toxicity ; *Nicotinic Acids/toxicity ; *Imidazoles/toxicity ; Plant Leaves/drug effects ; Oxidative Stress ; Niacin/analogs & derivatives ; }, abstract = {ALS-inhibiting imidazolinone herbicides are widely used for selective weed control in Clearfield[®] cropping systems. However, their physicochemical properties promote dispersion into adjacent aquatic environments, posing risks to non-target organisms such as aquatic macrophytes. This study aimed to elucidate the toxicological effects of the commercial formulation Kifix[®] (a mixture of imazapyr and imazapic) on Pontederia crassipes, with emphasis on its biochemical and physiological responses. Two experiments were conducted using herbicide concentrations ranging from 0.2-1.0 mg L[-1], alongside untreated controls. Multiple parameters were evaluated in leaves and roots at 7 and 14 days after application, including visual symptoms, chlorophyll index, growth parameters, chlorophyll a fluorescence, gas exchange, epidermal anatomy, reactive oxygen species, lipid peroxidation, electrolyte leakage, antioxidant enzyme activity, glycolate oxidase, glutathione S-transferase, and acetolactate synthase activity, as well as carbohydrate, amino acid, and protein content. Upon exposure, mature leaves exhibited photochemical impairment, compromising carbon assimilation and photorespiration, and leading to carbohydrate accumulation. Stomatal aperture and conductance were also negatively affected. Oxidative stress responses and antioxidant enzyme activity changed in both leaves and roots. Notably, acetolactate synthase activity increased in treated plants, while protein and amino acid contents remained unchanged. Overall, Kifix[®] significantly impaired P. crassipes, particularly by inhibiting the development of new tissues-such as leaves and plantlets essential for reproduction and spread-while also triggering physiological and biochemical disturbances in mature tissues.}, } @article {pmid40310505, year = {2025}, author = {Gautam, P and Yadav, R and Vishwakarma, RK and Pathak, A and Singh, C}, title = {Metabolic dysregulation in amyotrophic lateral sclerosis: insights from [1]H NMR-based metabolomics in a tertiary care center in India.}, journal = {Metabolic brain disease}, volume = {40}, number = {5}, pages = {196}, pmid = {40310505}, issn = {1573-7365}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; *Metabolomics/methods ; Male ; Female ; India ; Middle Aged ; Case-Control Studies ; Adult ; Tertiary Care Centers ; Biomarkers/blood/metabolism ; Aged ; Pilot Projects ; Proton Magnetic Resonance Spectroscopy/methods ; Magnetic Resonance Spectroscopy/methods ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron loss, leading to severe physical impairment and mortality. Despite available treatments like Riluzole and Edaravone, their limited efficacy highlights the need for improved understanding of ALS pathology. This study has explored metabolic alterations in North Indian ALS patients using [1]H Nuclear Magnetic Resonance (NMR)-based metabolomics. A case-control study, involving 45 ALS patients and 30 healthy controls (HCs) was performed. Serum samples were analyzed using 600-MHz NMR spectrometer, revealing significant metabolic differences between ALS and HC groups. Multivariate analyses identified nine dysregulated metabolites-pyruvate, glutamine, histidine, isoleucine, leucine, imidazole, arginine, creatinine, and choline-with ROC analysis showing isoleucine as a promising biomarker (AUC 83%). Pathway enrichment analysis highlighted disruptions in key metabolic pathways, including the Glucose-Alanine Cycle, Urea Cycle, Ammonia Recycling, and the Warburg Effect, suggesting potential links to neuroinflammatory and mitochondrial dysfunction in ALS pathogenesis. This pilot study provides insight into ALS-specific metabolic alterations in Indian cohort and demonstrates the potential of these metabolites as diagnostic biomarkers. Our findings identify potential biomarkers that require validation in larger, multi-centric cohorts to support diagnosis, prognosis, and improved management of ALS.}, } @article {pmid40311013, year = {2025}, author = {Xu, Z and Yi, W and Guan, L and Tang, J and Feng, D and Zou, Y}, title = {Deciphering the Inhibitory Mechanism of ALS-Associated N352S and S352p Variants against TDP-43 Aggregation and Its Destabilization Effect on TDP-43 Protofibrils.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {10}, pages = {1898-1908}, doi = {10.1021/acschemneuro.5c00045}, pmid = {40311013}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism/chemistry ; Humans ; Molecular Dynamics Simulation ; Phosphorylation ; Mutation/genetics ; Protein Aggregates/genetics ; *Protein Aggregation, Pathological/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is closely related to ubiquitin-positive inclusions formed by transactive response deoxyribonucleic acid (DNA) binding protein of 43 kDa (TDP-43). Previous experiments identified that the ALS-linked familial variant, N352S (asparagine substituted by serine), and subsequent phosphorylation of S352 (S352p) are associated with the aggregation of TDP-43. However, the underlying molecular mechanisms are still not fully understood. By performing all-atom explicit-solvent replica exchange molecular dynamics (REMD) simulations with a total simulation time of 100.8 μs, we scrutinized the impact of the N352S mutation and its phosphorylation variant S352p on the conformational ensembles of the TDP-43342-366 dimer. Our simulation results show that both the N352S and S352p variants could promote the formation of unstructured conformation and impede the formation of β-structure and helix content, and the inhibitive effect of S352P is more obvious. Further analyses suggest that the H-bonding and hydrophobic interaction among TDP-43342-366 peptides, as well as the R361-E362 salt bridge, are attenuated by N352S and S352p variants. Additional MD simulations show that N352S and S352p variants reduce the structural stability of the hydrophobic region and lower the number of H-bonds and contacts of two hydrophobic clusters, thus possessing a destabilization effect on the TDP-43282-360 protofibrils. Our results unmask the molecular mechanism of the N352S mutation and its phosphorylation variant S352p toward the inhibition of TDP-43342-366 aggregation and prove the protofibril-destabilizing effects of these two variants, which may be helpful for designing drugs for the treatment of ALS.}, } @article {pmid40311553, year = {2025}, author = {Dulski, J and Pant, DC and Hoffman-Zacharska, D and Kwaśniak-Butowska, M and Wszolek, ZK and Sławek, J}, title = {KIF5A variant in familial dystonia: A clinicogenetic study of a large Roma kindred.}, journal = {Parkinsonism & related disorders}, volume = {135}, number = {}, pages = {107825}, doi = {10.1016/j.parkreldis.2025.107825}, pmid = {40311553}, issn = {1873-5126}, mesh = {Humans ; *Kinesins/genetics ; Male ; Female ; Pedigree ; Adult ; Middle Aged ; *Dystonic Disorders/genetics ; Mutation, Missense ; Young Adult ; }, abstract = {BACKGROUND: Mutations in the KIF5A gene were associated with several neurological diseases, including hereditary spastic paraplegia type 10, Charcot-Marie-Tooth type 2, amyotrophic lateral sclerosis, and neonatal intractable myoclonus. To date, none of the KIF5A variants was linked with dystonia. This study presents the first family with autosomal-dominant dystonia exhibiting incomplete penetrance, potentially linked to a KIF5A variant.

METHODS: Seven family members were recruited between 2017 and 2024. Detailed medical history and neurological examination were conducted for all. Genetic screening, including Sanger sequencing, MLPA analysis of SGCE, and PCR RFLP/BseRI for the common dystonia TOR1A mutation (c.907-909del), followed by whole exome sequencing, was performed on the proband and one affected relative. The genetic status of the remaining five individuals was assessed with Sanger sequencing.

RESULTS: A missense variant in the KIF5A c.118G > A was found in four affected and one asymptomatic individual, while it was absent in two non-affected individuals. The variant is rare in the general population (0.00001 in gnomAD 4.0), affects a highly conserved amino acid, and in silico models (M-CAP) indicates it is pathogenic. It was classified as likely pathogenic per ACMG criteria (PM1, PM2, PP2, PP3).

CONCLUSIONS: Our study suggests that KIF5A could represent a potential dystonia gene and sheds light on the broader role of motor proteins in human health and disease. This further expands the phenotypes associated with KIF5A and highlights the importance for clinicians to include this variant in their screening panels, as it tends to be underrepresented in current databases.}, } @article {pmid40311838, year = {2025}, author = {Recher, M and Canon, V and Lockhart-Bouron, M and Hubert, H and Javaudin, F and Leteurtre, S and Mitha, A and , }, title = {The peak end-tidal carbon dioxide concentration recorded during cardiopulmonary resuscitation as an indicator of survival: a nationwide cohort study of pediatric out-of-hospital cardiac arrests.}, journal = {Resuscitation}, volume = {212}, number = {}, pages = {110626}, doi = {10.1016/j.resuscitation.2025.110626}, pmid = {40311838}, issn = {1873-1570}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/mortality/therapy/etiology ; *Cardiopulmonary Resuscitation/methods/mortality ; *Carbon Dioxide/analysis/metabolism ; Male ; Female ; Child ; Child, Preschool ; Infant ; Registries ; Adolescent ; Cohort Studies ; Tidal Volume ; France/epidemiology ; Return of Spontaneous Circulation ; ROC Curve ; }, abstract = {BACKGROUND: Although the end-tidal carbon dioxide concentration (ETCO2) recorded during resuscitation has been reported as an indicator of survival in a few studies of pediatric in-hospital cardiac arrest, the relationship between ETCO2 and survival in pediatric out-of-hospital cardiac arrest (OHCA) has not previously been investigated (particularly with regard to the cause of the OHCA). This study aimed to determine whether quantitative measurement of ETCO2 during resuscitation is predictive of survival in cases of pediatric OHCA.

METHOD: This nationwide, population-based cohort study analyzed data from the French RéAC OHCA registry, including all patients under 18 years of age with trauma-related OHCA or medical OHCA from 2011 to 2023. The highest ETCO2 value was recorded during advanced cardiopulmonary resuscitation. The main outcomes were return of spontaneous circulation (ROSC) and day (d)30 survival. Discriminant ability was evaluated using the area under the receiver operating characteristic curve (AUROC), and the Youden index was used to determine the optimal ETCO2 cut-off value.

RESULTS: A total of 1209 pediatric OHCAs (226 (19%) trauma-related and 983 (81%) medical) were included. The victims' median [interquartile range] age was 6 [0;14] years. ROSC was achieved in 347 (29%) cases and d30 survival was achieved in 61 (5%) cases. In both trauma-related and medical OHCAs, the peak recorded ETCO2 value was higher in patients who achieved ROSC and in d30 survivors. The AUROC [95% confidence interval] for the highest ETCO2 that predicted ROSC and d30 survival were respectively 0.808 [0.745-0.872] and 0.854 [0.761-0.947] for the trauma-related OHCA group and 0.803 [0.774-0.831] and 0.732 [0.676-0.787] for the medical OHCA group. In both groups, the probability of ROSC and d30 survival increased with higher ETCO2 values, with optimal cut-offs of 21 and 29 mmHg for trauma-related OHCA and 27 and 26 mmHg for medical OHCA, respectively.

CONCLUSIONS: Further studies are necessary to clarify the use of ETCO2 in optimizing pediatric ALS.}, } @article {pmid40312429, year = {2025}, author = {Ludolph, AC and Grandjean, H and Reviers, E and De Micheli, V and Bianchi, C and Cardosi, L and Russ, H and Silani, V}, title = {Author Correction: The preferences of people with amyotrophic lateral sclerosis on riluzole treatment in Europe.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {15297}, doi = {10.1038/s41598-025-95009-7}, pmid = {40312429}, issn = {2045-2322}, } @article {pmid40312886, year = {2025}, author = {Spisto, M and Moretta, P and Senerchia, G and Iuzzolino, VV and Aruta, L and Salvatore, E and Santangelo, G and Trojano, L and Dubbioso, R}, title = {Identifying Mild Behavioral and Neurocognitive Impairment in Amyotrophic Lateral Sclerosis (MBNI-ALS) Provides Key Prognostic Insights.}, journal = {European journal of neurology}, volume = {32}, number = {5}, pages = {e70171}, pmid = {40312886}, issn = {1468-1331}, support = {E53D23019760001//PRIN-PNRR2022/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/psychology ; Male ; Female ; *Cognitive Dysfunction/diagnosis/etiology ; Middle Aged ; Aged ; Prognosis ; Disease Progression ; Prospective Studies ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disease encompassing cognitive and behavioral impairments. The Revised Diagnostic Criteria for ALS-frontotemporal spectrum disorder (ALS-FTDS), while widely adopted, may overlook subtle impairments such as memory and visuospatial deficits, limiting their prognostic value.

OBJECTIVES: This study aimed to apply the Mild Behavioral and Neurocognitive Impairment (MBNI) approach, adapted from other neurodegenerative diseases, to ALS patients and assess its prognostic utility for survival and disease progression.

METHODS: A prospective cohort of 201 ALS patients was evaluated between January 2018 and July 2024. Participants underwent comprehensive cognitive and behavioral assessments. The MBNI approach identified patients with mild cognitive impairment (MCI), mild behavioral impairment (MBI), or combined cognitive-behavioral impairment (MCBI). Prognostic value was analyzed using Kaplan-Meier survival curves, Cox proportional hazards models, and logistic regression for disease progression.

RESULTS: Mild cognitive and/or behavioral impairments were detected in 67% of patients classified as cognitively normal by ALS-FTDS criteria. At a median follow-up of 15 months, these patients showed shorter tracheostomy-free survival (all p < 0.005). MCI (HR5.3; CI 1.10-25.41; p = 0.038) and frontotemporal dementia (HR6.2; Confidence Interval: 1.34-28.40; p = 0.019) independently predicted poor outcomes. Logistic regression confirmed that MCBI and frontotemporal dementia were associated with rapid progression (both p < 0.019).

CONCLUSION: The MBNI approach enhances the detection of mild cognitive and behavioral impairments in ALS, providing prognostic insights and improving stratification over the Revised Diagnostic Criteria for ALS-FTDS. This framework supports personalized care and the design of clinical trials targeting early disease stages.}, } @article {pmid40313084, year = {2026}, author = {Zhang, T and Yin, Y and Xia, X and Que, X and Liu, X and Zhao, G and Chen, J and Chen, Q and Xu, Z and Tang, Y and Qin, Q}, title = {Regulation of synaptic function and lipid metabolism.}, journal = {Neural regeneration research}, volume = {21}, number = {3}, pages = {1037-1057}, pmid = {40313084}, issn = {1673-5374}, abstract = {Synapses are key structures involved in transmitting information in the nervous system, and their functions rely on the regulation of various lipids. Lipids play important roles in synapse formation, neurotransmitter release, and signal transmission, and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases. The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention, but their specific mechanisms remain to be fully understood. This review aims to explore how lipids regulate synaptic activity in the central nervous system, focusing on their roles in synapse formation, neurotransmitter release, and signal transmission. Additionally, it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation. This review shows that within the central nervous system, lipids are essential components of the cell membrane bilayer, playing critical roles in synaptic structure and function. They regulate presynaptic vesicular trafficking, postsynaptic signaling pathways, and glial-neuronal interactions. Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts. Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles. Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis. Fatty acids are vital for energy metabolism and the synthesis of signaling molecules. Abnormalities in lipid metabolism may lead to impairments in synaptic function, affecting information transmission between neurons and the overall health of the nervous system. Therapeutic strategies targeting lipid metabolism, particularly through cholesterol modulation, show promise for treating these conditions. In neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, and amyotrophic lateral sclerosis, dysregulation of lipid metabolism is closely linked to synaptic dysfunction. Therefore, lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs. Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.}, } @article {pmid40313114, year = {2026}, author = {Zhou, M and Zheng, M and Liang, S and Li, M and Ma, J and Zhang, S and Song, X and Hu, Y and Lyu, Y and Ou, X and Yue, C}, title = {Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {21}, number = {4}, pages = {1409-1427}, pmid = {40313114}, issn = {1673-5374}, abstract = {The cure rate for chronic neurodegenerative diseases remains low, creating an urgent need for improved intervention methods. Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases. This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases, aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options. We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy, inhibiting mitochondrial fission, enhancing mitochondrial biogenesis, applying mitochondria-targeting antioxidants, and transplanting mitochondria. Each method has unique advantages and potential limitations, making them suitable for various therapeutic situations. Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression, especially in the early stages. In contrast, those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism. Mitochondrial transplantation, while still experimental, holds great promise for restoring the function of damaged cells. Future research should focus on exploring the mechanisms and effects of these intervention strategies, particularly regarding their safety and efficacy in clinical settings. Additionally, the development of innovative mitochondria-targeting approaches, such as gene editing and nanotechnology, may provide new solutions for treating chronic neurodegenerative diseases. Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.}, } @article {pmid40313273, year = {2025}, author = {Dergai, O and Wuu, J and Koziczak-Holbro, M and Malaspina, A and Granit, V and Hernandez, JP and Cooley, A and Sachdev, R and Yu, L and Bidinosti, M and Flotte, L and Nash, M and Jennings, LL and Berry, JD and Bruijn, LI and Brachat, S and Benatar, M}, title = {Skeletal muscle biomarkers of amyotrophic lateral sclerosis: a large-scale, multi-cohort proteomic study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40313273}, support = {/WT_/Wellcome Trust/United Kingdom ; U01 NS107027/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Biomarkers with clear contexts-of-use are important tools for ALS therapy development. Understanding their longitudinal trajectory in the untreated state is key to their use as potential markers of pharmacodynamic response. To this end, we undertook a large-scale proteomic study in well-phenotyped cohorts to identify biomarker candidates of ALS disease state and disease progression.

METHODS: Clinical phenotypic data and biofluid samples, collected from patients with ALS and healthy controls through multiple longitudinal natural history studies, were used to identify biomarker candidates. SOMAmer (Slow Off-rate Modified Aptamer)-based relatively quantitative measurement of ~7,000 proteins was performed in plasma and CSF, with immunoassay validation of candidates of interest.

RESULTS: We identified 329 plasma proteins significantly differentially regulated between ALS and controls (adjusted p-value <0.05), with 25 showing >40% relative abundance. PDLIM3, TNNT2, and MYL11 had the greatest log-fold elevation, while ANTXR2 and ART3 had the greatest log-fold reduction. A similar set of plasma proteins was found to increase (e.g. PDLIM3, TNNT2, MYL11) or decrease (e.g. ANTXR2, ART3, MSTN) with disease progression. CSF proteins with the greatest log-fold elevation included NEFL, NEFH, CHIT1, CA3, MYL11 and GPNMB. These results were confirmed in an independent replication cohort. Moreover, tissue-specific signature enrichment suggests a significant contribution of muscle as a source of these biomarkers. Immunoassays provided orthogonal validation of plasma TNNT2 and CSF GPNMB.

CONCLUSION: We identified an array of novel biomarkers with the potential to serve as response biomarkers to aid therapy development, as well as to shed light on the underlying biology of disease.}, } @article {pmid40314217, year = {2026}, author = {Ju, T and Zhang, Y and Liu, L and Zhao, X and Li, X and Liu, C and Sun, S and Wu, LA}, title = {The role of gut microbiota-mitochondria crosstalk in neurodegeneration: Underlying mechanisms and potential therapies.}, journal = {Neural regeneration research}, volume = {21}, number = {6}, pages = {2238-2253}, pmid = {40314217}, issn = {1673-5374}, abstract = {Emerging evidence suggests that the gut microbiota is closely associated with the pathological manifestations of multiple neurodegenerative diseases via the gut-brain axis, which refers to the crosstalk between the gut and the central nervous system. More importantly, mitochondria have been considered prominent mediators of the interplay between the gut microbiota and the brain. Intestinal microbes may modulate mitochondrial function in the central nervous system to affect the progression of neurodegenerative diseases. Mitochondria are essential for meeting the host's substantial neuronal metabolic demands, maintaining excitability, and facilitating synaptic transmission. Dysfunctional mitochondria are considered critical hallmarks of various neurodegenerative diseases. Therefore, this review provides novel insights into the intricate roles of gut microbiota-mitochondrial crosstalk in the underlying mechanisms during the progression of neurodegeneration, as well as the existing potential therapeutic strategies for neurodegenerative disorders. These suggest intestinal microbiota-mitochondrial interaction play a crucial role in the occurrence and development of neurodegenerative diseases, and targeting this interaction may be a promising therapeutic approach to neurodegenerative diseases. However, this review found that there was relatively little research on the effect of this crosstalk on other neurodegenerative diseases, such as Huntington's disease and Multiple sclerosis, and the potential therapeutic strategies were translated into clinical trials, which face many challenges in developing personalized treatment plans based on the unique gut microbiota of different individuals.}, } @article {pmid40314791, year = {2025}, author = {Iuzzolino, VV and Scaravilli, A and Carignani, G and Senerchia, G and Pontillo, G and Dubbioso, R and Cocozza, S}, title = {Mapping motor and extra-motor gray and white matter changes in ALS: a comprehensive review of MRI insights.}, journal = {Neuroradiology}, volume = {67}, number = {7}, pages = {1683-1696}, pmid = {40314791}, issn = {1432-1920}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *White Matter/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; *Gray Matter/diagnostic imaging/pathology ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor neurons, yet with substantial clinical variability. Furthermore, beyond motor symptoms, ALS patients also show non-motor features, reflecting its classification as a multi-system disorder. The identification of reliable biomarkers is a critical challenge for improving diagnosis, tracking disease progression, and predicting patient outcomes. This review explores macro- and microstructural alterations in ALS, focusing on gray matter (GM) and white matter (WM) as observed through Magnetic Resonance Imaging (MRI). This approach synthesizes not only the expected involvement of motor areas but also highlights emerging evidence that these changes extend to extra-motor areas, such as the frontal and temporal lobes, underscoring the complex pathophysiology of ALS. The review emphasizes the potential of MRI as a non-invasive tool to provide new biomarkers by assessing both GM and WM integrity, a key advancement in ALS research. Additionally, it addresses existing discrepancies in findings and stresses the need for standardized imaging protocols. It also highlights the role of multi-modal MRI approaches in deepening our understanding of ALS pathology, emphasizing the importance of combining structural and diffusion MRI techniques to offer more comprehensive insights into ALS progression, ultimately advancing the potential for personalized treatment strategies and improving patient outcomes.}, } @article {pmid40316175, year = {2025}, author = {Iguchi, Y and Takahashi, Y and Li, J and Amakusa, Y and Kawakami, Y and Yoshimura, T and Chikuchi, R and Iida, M and Yokoi, S and Katsuno, M}, title = {Truncation mutation of CHMP2B disrupts late endosome function but reduces TDP-43 aggregation through HSP70 upregulation.}, journal = {Neurochemistry international}, volume = {187}, number = {}, pages = {105982}, doi = {10.1016/j.neuint.2025.105982}, pmid = {40316175}, issn = {1872-9754}, mesh = {Humans ; *Endosomes/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *HSP70 Heat-Shock Proteins/biosynthesis/genetics ; *Mutation/genetics ; Up-Regulation/physiology ; *Endosomal Sorting Complexes Required for Transport/genetics ; HEK293 Cells ; Frontotemporal Dementia/genetics ; Protein Aggregation, Pathological/genetics/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43)-positive cytoplasmic aggregation is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). This aggregation contributes substantially to the neurodegeneration of ALS and FTLD. The endosome, a key component of membrane trafficking in eukaryotic cells and is involved in the autophagy-lysosome pathway. Endosome-related genes such as CHMP2B, Alsin, and TMEM106B, are either causative or act as genetic modifiers in ALS and FTLD. However, the association between endosomal functions and TDP-43 aggregations remain poorly understood. The C-terminal truncation mutation CHMP2B, which causes frontotemporal dementia associated with chromosome 3 (FTD3), disrupts late endosome (LE)-lysosomes fusion. Nevertheless, FTD3 does not induce TDP-43 pathology. In this study, we showed that CHMP2B mutation-induced LE dysfunction promotes TDP-43 aggregate degradation through enhanced recruitment to juxtanuclear quality control compartments. Transcriptomic analysis revealed that CHMP2B[intron5] overexpression upregulates HSP70 expression. New insights into the connection between CMHP2B and HSP70 as well as the role of HSP70-mediated membrane trafficking in TDP-43 aggregation, offer a valuable understanding of the disease mechanism of ALS and FTLD.}, } @article {pmid40317297, year = {2025}, author = {Faltacco, V and Dalla Bella, E and Nigri, A and Telesca, A and Gandini, G and Riva, N and Vizziello, M and Medina, JP and Demichelis, G and Grisoli, M and Usai, S and Lauria, G and Consonni, M}, title = {Pathological laugher and crying in motor neuron diseases: a matter of bulbar and neurobehavioral involvement with sex imbalance.}, journal = {Journal of neurology}, volume = {272}, number = {5}, pages = {372}, pmid = {40317297}, issn = {1432-1459}, support = {2015-0023//Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia/ ; 1157625//Fondo Europeo di Sviluppo Regionale, Regione Lombardia (POR FESR 2014-2020)/ ; }, mesh = {Humans ; Female ; Male ; *Crying/psychology/physiology ; Middle Aged ; *Motor Neuron Disease/physiopathology/psychology/diagnostic imaging/complications/pathology ; Aged ; *Laughter/physiology/psychology ; Magnetic Resonance Imaging ; *Affective Symptoms/etiology/physiopathology ; *Sex Characteristics ; Adult ; }, abstract = {BACKGROUND: Emotional lability (EL), also known as pathological laughter and crying, is a common but understudied symptom in motor neuron diseases (MND): amyotrophic lateral sclerosis and primary lateral sclerosis. This study aimed to investigate the prevalence of EL in MND and to explore the independent frequency components of laughter and crying in relation to motor, cognitive, neuropsychiatric, and neuroimaging factors.

METHODS: A total of 198 incident MND patients were enrolled. The Centre of Neurological Study-Lability Scale was used to measure EL. Associations between EL and motor function, mood, neuropsychological variables, and structural MRI were examined, with cortical thinning measured on a subset of 48 patients.

RESULTS: EL was identified in 36% of patients showing more severe motor functional disabilities, heightened depressive and anxiety symptoms and behavioral changes than those without EL. Women exhibited more severe EL and altered mood with frequent crying episodes than men. EL was strongly correlated with bulbar involvement. Crying episodes were associated with mood disorders, while laughter correlated with disinhibition and emotional regulation difficulties. EL had a specific association with the thinning of frontal regions, including the right pars orbitalis, which was also linked to altered emotional and behavioral regulation.

CONCLUSION: These findings underscore the role of corticobulbar and frontal pathways in EL pathophysiology. The study highlights the distinct mechanisms underlying pathological crying and laughter and their independency from general cognitive decline. It emphasizes the need for clinicians to recognize EL as an independent symptom, necessitating targeted management strategies to improve patient outcomes and support caregivers.}, } @article {pmid40317507, year = {2025}, author = {Garret, MA and Namiranian, D and Milone, M and Varadhachary, A and Ho, D}, title = {Atypical Facial Onset Weakness in SOD1 ALS.}, journal = {Muscle & nerve}, volume = {72}, number = {3}, pages = {520-522}, doi = {10.1002/mus.28428}, pmid = {40317507}, issn = {1097-4598}, } @article {pmid40319325, year = {2025}, author = {Mehdizadeh, S and Mamaghani, M and Hassanikia, S and Pilehvar, Y and Ertas, YN}, title = {Exosome-powered neuropharmaceutics: unlocking the blood-brain barrier for next-gen therapies.}, journal = {Journal of nanobiotechnology}, volume = {23}, number = {1}, pages = {329}, pmid = {40319325}, issn = {1477-3155}, mesh = {*Exosomes/metabolism/chemistry ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; Animals ; *Drug Delivery Systems/methods ; *Neuropharmacology/methods ; Drug Carriers/chemistry ; }, abstract = {BACKGROUND: The blood-brain barrier (BBB) presents a formidable challenge in neuropharmacology, limiting the delivery of therapeutic agents to the brain. Exosomes, nature's nanocarriers, have emerged as a promising solution due to their biocompatibility, low immunogenicity, and innate ability to traverse the BBB. A thorough examination of BBB anatomy and physiology reveals the complexities of neurological drug delivery and underscores the limitations of conventional methods.

MAIN BODY: This review explores the potential of exosome-powered neuropharmaceutics, highlighting their structural and functional properties, biogenesis, and mechanisms of release. Their intrinsic advantages in drug delivery, including enhanced stability and efficient cellular uptake, are discussed in detail. Exosomes naturally overcome BBB barriers through specific translocation mechanisms, making them a compelling vehicle for targeted brain therapies. Advances in engineering strategies, such as genetic and biochemical modifications, drug loading techniques, and specificity enhancement, further bolster their therapeutic potential. Exosome-based approaches hold immense promise for treating a spectrum of neurological disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), brain tumors, stroke, and psychiatric conditions.

CONCLUSION: By leveraging their innate properties and engineering innovations, exosomes offer a versatile platform for precision neurotherapeutics. Despite their promise, challenges remain in clinical translation, including large-scale production, standardization, and regulatory considerations. Future research directions in exosome nanobiotechnology aim to refine these therapeutic strategies, unlocking new avenues for treating neurological diseases. This review underscores the transformative impact of exosome-based drug delivery, paving the way for next-generation therapies that can effectively penetrate the BBB and revolutionize neuropharmacology.}, } @article {pmid40320052, year = {2025}, author = {Nadeem, A and Sharma, P and Gupta, P and Sandeep, P and Sharma, B and Sharma, N and Yadav, M and Dhiman, N}, title = {Exploring Neuregulin3: From physiology to pathology, a novel target for rational drug design.}, journal = {Biochemical pharmacology}, volume = {238}, number = {}, pages = {116964}, doi = {10.1016/j.bcp.2025.116964}, pmid = {40320052}, issn = {1873-2968}, mesh = {Humans ; Animals ; *Drug Design ; *Neuregulins/metabolism/genetics ; Neoplasms/drug therapy/metabolism/pathology ; *Drug Delivery Systems/methods/trends ; }, abstract = {Neuregulin 3 (NRG3) is an epidermal growth factor related protein that binds to and stimulates the Erb-B2 receptor tyrosine kinase 4 (ErbB4). NRG3 is a multifunctional protein with fifteen alternative splicing isoforms categorized into four classes. Numerous physiological processes, such as the formation of cortical plate, cortical patterning, synaptic development, neuronal proliferation, regulation of neurotransmission, control of impulsive behavior, mammary gland morphogenesis, spermatogonial proliferation and cardiac homeostasis are influenced by NRG3. Besides its physiological roles, NRG3 also modulates anxiogenic phenotypes. It is a susceptibility gene for schizophrenia, autism spectrum disorder and Hirschsprung's Disease. Furthermore, anxiety during nicotine withdrawal is dependent on NRG3-ErbB4 signaling. Research on a range of solid carcinomas, such as brain tumors, ovarian cancer, gastrointestinal cancer and breast cancer, has demonstrated NRG3 gene as a therapeutic target. NRG3 also has potential involvement in epilepsy, angular limb malformation in Rambouillet rams, amyotrophic lateral sclerosis and polythelia. Nevertheless, little is known about the molecular characteristics, activities specific to isoforms, and molecular mechanisms of NRG3. Examining its potential involvement in a range of physiological processes and pathological states is a unique area that needs in-depth study and may offer new mechanistic insights and comprehension of these elements. Thus, the purpose of this review is to shed light on the utility of NRG3 as a potential target in various health and disease conditions.}, } @article {pmid40320859, year = {2025}, author = {Watanabe, S and Yamanaka, K}, title = {Mitochondria and Endoplasmic Reticulum Contact Site as a Regulator of Proteostatic Stress Responses in Neurodegenerative Diseases.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {47}, number = {7}, pages = {e70016}, pmid = {40320859}, issn = {1521-1878}, support = {23K06826//Ministry of Education, Culture, Sports, Science and Technology, Japan/Japan Society for the Promotion of Science/ ; 19KK0214//Ministry of Education, Culture, Sports, Science and Technology, Japan/Japan Society for the Promotion of Science/ ; 22H00467//Ministry of Education, Culture, Sports, Science and Technology, Japan/Japan Society for the Promotion of Science/ ; JP22ek0109426//Japan Agency for Medical Research and Development/ ; JP24wm0425014//Japan Agency for Medical Research and Development/ ; JP24wm0625301//Japan Agency for Medical Research and Development/ ; //Takeda Science Foundation/ ; //Mochida Memorial Foundation for Medical and Pharmaceutical Research/ ; //Kowa Life Science Foundation/ ; //Novartis Foundation/ ; }, mesh = {Humans ; *Mitochondria/metabolism ; *Endoplasmic Reticulum/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Proteostasis ; Calcium/metabolism ; Autophagy ; Amyotrophic Lateral Sclerosis/metabolism ; Mitochondrial Membranes/metabolism ; Alzheimer Disease/metabolism ; }, abstract = {Recent evidence indicates that the mitochondria-endoplasmic reticulum (ER) contact site is a novel microdomain essential for cellular homeostasis. Various proteins are accumulated at the mitochondria-associated membrane (MAM), an ER subcomponent closely associated with the mitochondria, contributing to Ca[2+] transfer to the mitochondria, lipid synthesis, mitochondrial fission/fusion, and autophagy. These functions are disrupted in the diseases, particularly in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In this review, we summarize the disruption of protein homeostasis in various neurodegenerative diseases, present recent works on the mechanisms of MAM aberration, including ours mainly focused on ALS, and then discuss challenges and prospects for future MAM-targeted therapies in neurodegenerative diseases.}, } @article {pmid40321197, year = {2025}, author = {Rennels, CF and Rosow, L and Pantilat, S and Bell, BK and Lomen-Hoerth, C and Cohen, E and Bischoff, KE}, title = {Characteristics and Motivations of People With Amyotrophic Lateral Sclerosis Who Pursue Medical Aid in Dying in California.}, journal = {Neurology. Clinical practice}, volume = {15}, number = {3}, pages = {e200478}, pmid = {40321197}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: People with amyotrophic lateral sclerosis (ALS) disproportionately pursue medical aid in dying (MAID). We described characteristics and motivations of patients with ALS who sought MAID in California.

METHODS: This is a retrospective cohort study of patients followed in the ALS and Palliative Care clinics at the University of California, San Francisco, between September 2017 and October 2023 who obtained a MAID prescription under California's End of Life Option Act. We abstracted demographic and clinical information from the electronic health record. We reviewed clinician notes to gather salient themes regarding patients' motivations for MAID and calculated the frequencies of motivations reported by prescribing physicians on standardized forms.

RESULTS: Thirty-seven patients obtained a MAID prescription. The median age at first documented inquiry about MAID was 64.0 years, 51.4% identified as women, 83.8% were White, and 10.8% had Medicaid. All spoke English and had a care partner. Most (70.3%) had limb-onset ALS. The median ALS Functional Rating Scale-Revised score was 28.5/48 and the median forced vital capacity was 41.5% at time of first inquiry about MAID. Most patients (70.3%) inquired about MAID during their first visit with palliative care. Physicians wrote MAID prescriptions at a median of 76 days after first inquiry. Most patients (73.0%) took MAID medications to end their lives, at a median of 39.5 days after the prescription was written.Clinician notes revealed that patients were commonly motivated to pursue MAID by concerns about current and future suffering, loss of autonomy and enjoyable activities, and desire for control at the end of life. On standardized forms completed after patients died, physicians documented that "persistent and uncontrollable pain and suffering" was a less common reason that patients pursued MAID.

DISCUSSION: Patients with ALS who requested MAID were largely White and English speaking. Most patients inquired about MAID when they had moderate-stage ALS and were early in their course of palliative care. Motivations for pursuing MAID often involved the accumulated losses characterizing ALS and worries about the future. Future studies should incorporate diverse patient voices, explore barriers to accessing MAID, and consider whether any interventions can ameliorate issues driving requests for MAID in people with ALS.}, } @article {pmid40321778, year = {2025}, author = {Gao, G and Sumrall, ER and Walter, NG}, title = {Nanoscale domains govern local diffusion and aging within FUS condensates.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40321778}, issn = {2693-5015}, support = {R01 NS097542/NS/NINDS NIH HHS/United States ; R35 GM131922/GM/NIGMS NIH HHS/United States ; }, abstract = {Biomolecular condensates regulate cellular physiology by sequestering and processing RNAs and proteins, yet how these processes are locally tuned within condensates remains unclear. Moreover, in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), condensates undergo liquid-to-solid phase transitions, but capturing early intermediates in this process has been challenging. Here, we present a surface multi-tethering approach to achieve intra-condensate single-molecule tracking of fluorescently labeled RNA and protein molecules within liquid-like condensates. Using RNA-binding protein Fused in Sarcoma (FUS) as a model for condensates implicated in ALS, we discover that RNA and protein diffusion is confined within distinct nanometer-scale domains, or nanodomains, which exhibit unique connectivity and chemical environments. During condensate aging, these nanodomains reposition, facilitating FUS fibrilization at the condensate surface, a transition enhanced by FDA-approved ALS drugs. Our findings demonstrate that nanodomain formation governs condensate function by modulating biomolecule sequestration and percolation, offering insights into condensate aging and disease-related transitions.}, } @article {pmid40323286, year = {2025}, author = {Zhao, N and Jiang, J and Zhu, T and Wang, Z and Hu, W and Yin, F and Cao, H and Liao, M}, title = {First Report on Resistance to ALS-Inhibiting Herbicides in the Broadleaved Weed Common Vetch (Vicia sativa L.) and Visual Detection of the Associated ALS Resistance Mutation.}, journal = {Journal of agricultural and food chemistry}, volume = {73}, number = {19}, pages = {11606-11617}, doi = {10.1021/acs.jafc.5c01785}, pmid = {40323286}, issn = {1520-5118}, mesh = {*Herbicide Resistance ; *Herbicides/pharmacology ; *Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism/chemistry ; *Plant Proteins/genetics/metabolism/chemistry/antagonists & inhibitors ; Mutation ; *Plant Weeds/drug effects/genetics/enzymology ; Molecular Docking Simulation ; *Enzyme Inhibitors/pharmacology ; China ; Arylsulfonates/pharmacology ; }, abstract = {Common vetch (Vicia sativa L.), an economically significant crop, is also a detrimental weed in wheat fields in the middle and lower reaches of the Yangtze River, China. A population of V. sativa (AHLQ-1) exhibiting high resistance (>10-fold) to ALS inhibitors, tribenuron-methyl and florasulam, was identified. All resistant plants carried a Pro-197-Ser substitution in their ALS genes, rendering their ALS enzymes 16.89 times less sensitive. Molecular docking revealed that the binding energies between ALS active sites and tribenuron-methyl or florasulam were reduced by over 80% due to the mutation at codon position 197. A LAMP method was successfully developed to visually detect this mutation, and a dCAPS assay was established to distinguish specific resistance mutations between homozygotes and heterozygotes. Additionally, cytochrome P450 activity was significantly elevated in resistant plants, enhancing the herbicide metabolism and resistance. This is the first global report of ALS resistance naturally occurring in V. sativa. These findings will aid in breeding herbicide-resistant V. sativa and improve resistance management.}, } @article {pmid40324158, year = {2025}, author = {Tabor Gray, L and Shune, S and Perry, S and Kosty, D and Namasivayam-MacDonald, A}, title = {Dysphagia Symptoms Contribute to Greater Care Partner Burden in Neurodegenerative Disease.}, journal = {American journal of speech-language pathology}, volume = {34}, number = {4}, pages = {2053-2061}, doi = {10.1044/2025_AJSLP-24-00529}, pmid = {40324158}, issn = {1558-9110}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/psychology ; Canada ; *Caregiver Burden/psychology ; *Caregivers/psychology ; *Cost of Illness ; *Deglutition Disorders/psychology/etiology/diagnosis/physiopathology ; *Neurodegenerative Diseases/psychology/complications ; New Zealand ; *Parkinson Disease/psychology ; Severity of Illness Index ; United States ; }, abstract = {PURPOSE: Providing care for family members with neurodegenerative diseases entails significant physical and psychosocial costs, increasing caregiver burden. Limited research exists on the factors contributing to dysphagia-related burden, particularly across disease trajectories. This study aimed to (a) determine if dysphagia-related burden predicts general caregiver burden, (b) identify predictors of dysphagia-related burden, and (c) examine relationships between dysphagia severity, disease severity, and dysphagia-related burden.

METHOD: Care partners (N = 211; 80% female; Mage = 60 ± 14 years) from clinics in Canada, New Zealand, and the United States participated. Care recipients included those with amyotrophic lateral sclerosis (ALS; n = 48), dementia (n = 110), and Parkinson's disease (PD; n = 53). General burden was measured using the Zarit Burden Interview, while dysphagia-related burden was assessed via the Caregiver Assessment of Reported Experiences with Swallowing Difficulties. Multiple regression analyses examined predictors of general and dysphagia-related burden and their relationships to dysphagia and disease severity.

RESULTS: Higher general burden was associated with female caregivers (β = -.19, p = .05), higher education (β = .16, p = .03), caring for someone with dementia (β = .36, p = .01), and greater dysphagia-related burden (β = .33, p = .01). Predictors of dysphagia-related burden included working caregivers (β = .15, p = .01), increased dysphagia symptoms (β = .77, p < .01), and caring for individuals with ALS or dementia (vs. PD; β = -.16, p = .02). Dysphagia burden varied by disease severity and diet tolerance (p < .01).

CONCLUSIONS: Managing dysphagia independently contributes to caregiver burden, potentially increasing burnout and nonadherence to clinical recommendations. Early, proactive inquiry about dysphagia-related care partner burden and provision of support to minimize burden should be considered early in disease management.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.28843055.}, } @article {pmid40324960, year = {2025}, author = {Simkins Lead, T and Shefner, JM and Kupfer, S and Malik, FI and Meng, L and Rudnicki, SA and Wei, J and van Eijk, RP}, title = {Application of the ENCALS predictive survival model in assessing the effect of the 24/44 inclusion criteria in FORTITUDE-ALS.}, journal = {Journal of neuromuscular diseases}, volume = {12}, number = {5}, pages = {679-682}, pmid = {40324960}, issn = {2214-3602}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/drug therapy/diagnosis ; Female ; Male ; Middle Aged ; Aged ; Disease Progression ; }, abstract = {FORTITUDE-ALS was a study evaluating reldesemtiv in people living with ALS. Post-hoc analysis identified larger treatment effects in those with symptom onset ≤24 months and baseline ALSFRS-R ≤ 44 (24/44 criteria). Using the ENCALS risk score (RS), we analyzed how the 24/44 criteria changed the eligible population. Of the 272 participants meeting the 24/44 criteria, 73% had very short to intermediate RS compared to 18% not meeting the criteria. Though the 24/44 criteria enriched the FORTITUDE-ALS population with rapidly progressing patients, they did not completely exclude all patients with a very long predicted survival.}, } @article {pmid40324968, year = {2025}, author = {Gomathy, SB and Macken, WL and Rani, N and Agarwal, A and Singh, R and Dhamne, M and Nair, SS and Reyaz, A and Ahmed, T and Dalal, A and Muthulakshmi, M and Wilson, L and Vijayaraghavan, A and , and Bhatia, R and Pitceathly, RDS and Thangaraj, K and Reilly, MM and Srivastava, PM and Hanna, MG and Vishnu, VY}, title = {Kennedy's disease from India: An Indian Cohort with multisystemic manifestations.}, journal = {Journal of neuromuscular diseases}, volume = {12}, number = {4}, pages = {513-522}, pmid = {40324968}, issn = {2214-3602}, mesh = {Humans ; Male ; India ; Middle Aged ; Adult ; Retrospective Studies ; *Bulbo-Spinal Atrophy, X-Linked/genetics/physiopathology/complications/diagnosis ; Cohort Studies ; }, abstract = {BackgroundKennedy's disease (KD) is a rare, insidiously progressive lower motor neuron syndrome characterised by amyotrophy involving the appendicular or bulbar musculature of adult males in their fourth to fifth decade. There are no large series from the Indian subcontinent describing the clinical-genetic and laboratory spectrum of KD.AimTo describe the clinical, electrophysiologic, metabolic and genetic profile of patients with KD.MethodsWe conducted a retrospective review of ten genetically confirmed KD patients.ResultsThe mean age of the cohort was 47 years, with a mean age of onset of illness at 41.3 ± 9.9 years. The median duration of symptoms before presentation was 5 (3-12) years. The most common referral diagnosis was ALS. The majority presented with symmetric proximal limb weakness with bulbar symptoms and were found to have gynecomastia, lower motor neuron (LMN) facial weakness, and facial and lingual fasciculations. Electrophysiology revealed sensory neuropathy in five patients and chronic neurogenic changes consistent with anterior horn cell disease in all. Metabolic profile showed impaired glycemia, hyperlipidemia and evidence of non-alcoholic fatty liver disease in the majority. All had elevated serum creatine kinase. Genetic testing revealed a median of 46 CAG repeats. The phenotypes of our patients aligned with global data that is predominantly derived from participants of European ancestry.ConclusionWe describe a series of patients with KD from India with significant multisystemic involvement.}, } @article {pmid40325332, year = {2025}, author = {Liu, S and Feng, A and Li, Z}, title = {Neuron-Derived Extracellular Vesicles: Emerging Regulators in Central Nervous System Disease Progression.}, journal = {Molecular neurobiology}, volume = {62}, number = {11}, pages = {14585-14612}, pmid = {40325332}, issn = {1559-1182}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Disease Progression ; Animals ; *Central Nervous System Diseases/metabolism/pathology ; *Neurons/metabolism/pathology ; Blood-Brain Barrier/metabolism ; Biomarkers/metabolism ; }, abstract = {The diagnosis and exploration of central nervous system (CNS) diseases remain challenging due to the blood-brain barrier (BBB), complex signaling pathways, and heterogeneous clinical manifestations. Neurons, as the core functional units of the CNS, play a pivotal role in CNS disease progression. Extracellular vesicles (EVs), capable of crossing the BBB, facilitate intercellular and cell-extracellular matrix (ECM) communication, making neuron-derived extracellular vesicles (NDEVs) a focal point of research. Recent studies reveal that NDEVs, carrying various bioactive substances, can exert either pathogenic or protective effects in numerous CNS diseases. Additionally, NDEVs show significant potential as biomarkers for CNS diseases. This review summarizes the emerging roles of NDEVs in CNS diseases, including Alzheimer's disease, depression, traumatic brain injury, schizophrenia, ischemic stroke, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. It aims to provide a novel perspective on developing therapeutic and diagnostic strategies for CNS diseases through the study of NDEVs.}, } @article {pmid40326218, year = {2025}, author = {Yan, G and Tang, H and Shen, Y and Han, L and Han, Q}, title = {AI-Generated Ammonium Ligands for High-Efficiency and Stable 2D/3D Heterojunction Perovskite Solar Cells.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {37}, number = {26}, pages = {e2503154}, doi = {10.1002/adma.202503154}, pmid = {40326218}, issn = {1521-4095}, support = {2020YFB1506400//National Key R&D Program of China/ ; 2021YFB3800100//National Key R&D Program of China/ ; U20A20245//National Natural Science Foundation of China/ ; U21A20171//National Natural Science Foundation of China/ ; 11834011//National Natural Science Foundation of China/ ; 12074245//National Natural Science Foundation of China/ ; }, abstract = {The 2D/3D heterojunction perovskite solar cells (PSCs) exhibit remarkable stability, but the quantum well in the 2D perovskite capping layer hinders the carrier transport, thereby lowering the power conversion efficiency (PCE). The relationship between the transport barrier and the complex structure of ammonium ligands (ALs) is currently poorly understood, thus leading to the one-sided approach and inefficient process in the development of 2D perovskite. Here, a machine learning procedure is established to comprehensively explore the relationship and combined it with an artificial intelligence (AI) model based on reinforcement learning algorithm to accelerate the generation of ALs. Finally, the AI-designed ALs improved the carrier transport performance of the 2D perovskite capping layer, and we achieved a certified PCE of 26.12% in inverted PSCs. The devices retained 96.79% of the initial PCE after 2000 h operation in maximum power point tracking under 1-sun illumination at 85°C.}, } @article {pmid40326912, year = {2025}, author = {McFarlane, R and Opie-Martin, S and Caravaca Puchades, A and Chiò, A and Corcia, P and Galvin, M and Heverin, M and Hobin, F and Holmdahl, O and Ingre, C and Lamaire, N and Mac Domhnaill, É and Manera, U and Mcdermott, CJ and McDonough, H and Mouzouri, M and Ombelet, F and Panadés, MP and Sennfält, S and Shaw, P and Terrafeta Pastor, C and Veldink, JH and Van Damme, P and van den Berg, L and Van Eijk, RPA and Vasta, R and Weemering, DN and Al-Chalabi, A and Hardiman, O}, title = {Clinical trajectories of genetic variants in ALS: a European observational study within PRECISION-ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {41-49}, doi = {10.1080/21678421.2025.2450805}, pmid = {40326912}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/diagnosis ; Male ; Female ; *C9orf72 Protein/genetics ; Middle Aged ; *RNA-Binding Protein FUS/genetics ; Europe/epidemiology ; *Superoxide Dismutase-1/genetics ; Aged ; *DNA-Binding Proteins/genetics ; *Genetic Variation/genetics ; Adult ; Age of Onset ; Registries ; Genetic Testing ; }, abstract = {OBJECTIVE: To investigate the association between C9orf72, SOD1, FUS and TARDBP variants on the clinical trajectory of ALS patients in Europe.

METHODS: Nine ALS centers with population-based registries provided data on demographic and disease characteristics - at diagnosis and longitudinally - as part of PRECISION ALS. These data were harmonized and collated for analysis.

RESULTS: 21,820 ALS patients were identified, 9,887 underwent genetic testing for at least one of the 4 genes of interest. 9.8% of patients carried a hexanucleotide expansion in C9orf72; 2.9% carried a pathogenic variant in SOD1; 1.4% carried a pathogenic variant in TARDBP; and 0.8% carried a pathogenic variant in FUS. Only one p.A5V variant was identified in this dataset. The most frequently identified SOD1 variant was p.D91A, with evidence of other variant clusters in Belgium, Italy and the United Kingdom. TARDBP variants were clustered in the Netherlands and Italy. Earlier ages of onset were demonstrated compared to wild-type populations; C9orf72 59.58 (IQR 62.5, p < 2.2e-16), SOD1 54.19 (IQR 19.4, p = 6.304e-14), TARDBP 58.30 (IQR 16.23, p = 0.00024) and FUS 51.16 (IQR 25.08, p = 1.58e-06). C9orf72 was more bulbar (p < 0.0001) in onset and SOD1 more spinal (p < 0.0001). Those carrying variants spent distinctly different periods in each of the King's stages.

CONCLUSIONS: Genetic forms of ALS have an earlier age of onset, have distinct patterns in their sites of disease onset, and progress differently as compared to populations without such major-effect genes. There is also evidence of disease clusters across Europe suggestive of founder effects.}, } @article {pmid40326913, year = {2025}, author = {McDonough, H and McFarlane, R and Caravaca Puchades, A and Chiò, A and Corcia, P and Galvin, M and Heverin, M and Hobin, F and Holmdahl, O and Ingre, C and Lamaire, N and Mac Domhnaill, É and Manera, U and Mouzouri, M and Ombelet, F and Opie-Martin, S and Povedano Panadés, M and Sennfält, S and Terrafeta Pastor, C and Veldink, JH and van Damme, P and van Den Berg, L and van Eijk, RPA and Vasta, R and Weemering, DN and Al-Chalabi, A and Shaw, P and McDermott, CJ and Hardiman, O}, title = {Examining changing working status and caregiver assistance in amyotrophic lateral sclerosis (ALS) using large-scale European databases as part of PRECISION-ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {20-29}, doi = {10.1080/21678421.2024.2448536}, pmid = {40326913}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/psychology/therapy/nursing ; *Caregivers/psychology/statistics & numerical data ; Female ; Male ; Middle Aged ; Europe/epidemiology ; *Employment/statistics & numerical data/trends ; Aged ; Adult ; Databases, Factual ; Cohort Studies ; Longitudinal Studies ; }, abstract = {OBJECTIVE: To examine the working status of people living with ALS (plwALS), the identity of their caregivers, the amount of informal care provided to them, and how these factors change over time.

METHODS: Data from nine specialist European ALS centers and previously funded projects, such as ALSCarE, were collated. The cohort was stratified into progression groups based on the calculated ΔFRS and compared longitudinally.

RESULTS: Twenty-one thousand eight hundred and twenty patients were identified at the time of data analysis. One thousand one hundred and eighty-four had working status data. Two hundred and thirty-seven patients in this group were followed in the form of semi-structured interviews. Within the 1184 patient group, 45% were identified as in "paid employment" prior to diagnosis, taking a median of 12 months to leave the workforce post-onset. Eighty-three percent of patients were no longer working 20 months post-diagnosis. Informal care hours increased over time, and were primarily provided by spouses and children. In those less than 12 months from symptom onset, the median number of care hours per week was 15.0 (IQR 63.8), rising to 60.0 (IQR 154.0) 48-96 months after onset. There was a significant relationship between ALSFRS-R total score and hours of care delivered (r = -0.47, p < 0.001).

CONCLUSION: Up to 45% of plwALS are working prior to diagnosis and their working status changes rapidly, taking an average of 12 months to leave the workforce. Caregiver input increases over time, proportional to ALSFRS-R score. Caregivers are primarily spouses and children. Further work is needed to comprehensively capture this information and calculate its true socioeconomic impact.}, } @article {pmid40326914, year = {2025}, author = {Vasta, R and Ombelet, F and Hobin, F and Manera, U and Ammar, AC and Caravaca Puchades, A and Corcia, P and Galvin, M and Hardiman, O and Heverin, M and Holmdahl, O and Ingre, C and Lamaire, N and McDermott, C and Mac Domhnaill, É and McDonough, H and McFarlane, R and Mouzouri, M and Sarah, OM and Povedano Panadés, M and Sennfält, S and Shaw, P and Terrafeta Pastor, C and van den Berg, LH and van Eijk, RPA and Veldink, JH and Weemering, DN and Van Damme, P and Chiò, A}, title = {Real-world prognostic role of riluzole use in ALS: a multi-center study from PRECISION-ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {50-60}, doi = {10.1080/21678421.2025.2472889}, pmid = {40326914}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/mortality/diagnosis ; Male ; Female ; Middle Aged ; *Neuroprotective Agents/therapeutic use ; Retrospective Studies ; Aged ; Prognosis ; Disease Progression ; Adult ; Kaplan-Meier Estimate ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) remains an incurable disease, with limited treatment options, and riluzole is the most widely available drug. We evaluated survival in a large cohort of patients with ALS, comparing those treated with riluzole to those who were not.

METHODS: Using data from the PRECISION-ALS database, we retrospectively analyzed patients with ALS who were treated with 100 mg of riluzole daily at the time of diagnosis. ALSFRS-R slope from onset to diagnosis (ΔFRS) was calculated. Based on the ΔFRS distribution, we defined fast progressors as patients having a ΔFRS > 1.17, intermediate progressors as those with 1.17 > ΔFRS > 0.31 and slow progressors as those with a ΔFRS < 0.31 points per month. We used Kaplan-Meier curves and Cox proportional hazards model to explore the association of riluzole use with patient survival since diagnosis.

RESULTS: Out of the 5842 patients with available riluzole data, 4847 (82.9%) received riluzole. The overall survival significantly differed between patients treated and not treated with riluzole (HR 0.70, 95%CI 0.69, 0.79), independently of sex, site of onset, age at onset and diagnostic delay. Patients treated with riluzole exhibited a 7 month longer median survival than those who did not receive riluzole (17.6 months, IQR 9.7, 29.9 vs 10.7 months, IQR 4.3, 23.4; p = 2 × 10[-16]). The relationship between riluzole use and extended survival varied across ΔFRS strata, being only evident among fast progressors (HR = 0.50, 95% 0.40, 0.63).

CONCLUSIONS: Treatment with riluzole is an independent prognostic factor in ALS. The extended survival related to riluzole use was only evident among fast-progressing patients.}, } @article {pmid40326915, year = {2025}, author = {Caravaca Puchades, A and McDonough, HE and Al-Chalabi, A and Chiò, A and Corcia, P and Galvin, M and Hardiman, O and Heverin, M and Hobin, F and Holmdahl, O and Ingre, C and Lamaire, N and Mac Domhnaill, É and Manera, U and McFarlane, R and Mouzouri, M and Ombelet, F and Opie-Martin, S and Sennfält, S and Terrafeta Pastor, C and Veldink, JH and Van Damme, P and van den Berg, L and van Eijk, RPA and Vasta, R and Weemering, DN and Shaw, P and McDermott, CJ and Povedano Panadés, M}, title = {Mapping the natural history of amyotrophic lateral sclerosis: time-to-event analysis of clinical milestones in the pan-European, population-based PRECISION-ALS cohort.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {8-19}, doi = {10.1080/21678421.2024.2448535}, pmid = {40326915}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/epidemiology/therapy/mortality ; Male ; Middle Aged ; Female ; Europe/epidemiology ; Aged ; Disease Progression ; Cohort Studies ; Age of Onset ; Prognosis ; Adult ; C9orf72 Protein/genetics ; Gastrostomy ; Noninvasive Ventilation ; Superoxide Dismutase-1/genetics ; }, abstract = {OBJECTIVE: Map time to key clinical milestones in amyotrophic lateral sclerosis (ALS), highlighting underlying genotypic and phenotypic prognostic factors.

BACKGROUND: Understanding the ALS disease trajectory and factors influencing the heterogeneous disease course is important to guide clinical care and stratify individuals to effectively assess therapeutics in clinical trials.

METHODS: Population-based datasets from nine European ALS care centers were collated. Time-to-event analysis was conducted for key clinical milestones: symptom onset, diagnosis, gastrostomy insertion, noninvasive ventilation (NIV) initiation, and survival. Independent prognostic factors were determined.

RESULTS: 21,820 people with ALS from nine ALS centers were included. Median age of symptom onset was 63.9 years. Median diagnostic delay was 1.0 years, with median survival of 33.7 months from onset. Prognostic factors for survival included age at onset, baseline vital capacity, progression rate, diagnostic delay, site of onset, and C9orf72-positive status. SOD1 variants D91A and G94C had protective prognostic effects in the whole cohort. Median time from diagnosis to gastrostomy insertion in bulbar-onset disease was 2.34 years. Median time from diagnosis to NIV initiation in those diagnosed between 2010 and 2019 was 3.61 years. Significant differences between ALS clinical center cohorts were seen in time to gastrostomy insertion, time to NIV initiation, and in overall survival time.

CONCLUSION: Our analysis of a large, well-defined, population-based European cohort provides detailed insight into the natural history of ALS, highlighting phenotypic and genetic factors affecting time to key clinical milestones. Further study is needed to determine the drivers in observed differences between ALS clinical center cohorts in time to clinical interventions and overall survival.}, } @article {pmid40326916, year = {2025}, author = {Sennfält, S and Al-Chalabi, A and Caravaca Puchades, A and Chiò, A and Corcia, P and Galvin, M and Hardiman, O and Heverin, M and Hobin, F and Holmdahl, O and Lamaire, N and Mac Domhnaill, É and McDonough, H and Manera, U and McDermott, CJ and McFarlane, R and Mouzouri, M and Ombelet, F and Opie-Martin, S and Povedano Panadés, M and Shaw, P and Terrafeta Pastor, C and Van Damme, P and van den Berg, L and van Eijk, RPA and Vasta, R and Veldink, JH and Weemering, DN and Ingre, C}, title = {Respiratory function, survival, and NIV prevalence over time in ALS - a PRECISION ALS study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {61-72}, doi = {10.1080/21678421.2025.2454923}, pmid = {40326916}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy/physiopathology/genetics/epidemiology/complications ; Male ; Female ; Middle Aged ; *Noninvasive Ventilation/statistics & numerical data/trends ; Aged ; Prevalence ; Prospective Studies ; *Respiratory Insufficiency/therapy/etiology ; Adult ; Disease Progression ; Cohort Studies ; C9orf72 Protein/genetics ; }, abstract = {INTRODUCTION: Respiratory function typically deteriorates as ALS progresses and is associated with shorter survival. This study aims to describe respiratory function and the prevalence of noninvasive ventilation (NIV) along the disease trajectory using prospective data from the PRECISION ALS project.

METHODS: We included 3449 ALS patients from six European population-based cohorts. All had comparable assessments of vital capacity, percent predicted (VC%) (58.1% had multiple assessments) and 56% had assessments of the revised ALS Functional Rating Scale (ALSFRS-R). The data were analyzed in relation to survival, NIV, and genetic status (C9orf72, SOD1, FUS, and TARDBP).

RESULTS: In those with a survival time of 1-4 years from diagnosis, the median VC% declined from 91 to 97% at the first assessment to 47-50% at the last assessment 6 months before death. In those with longitudinal assessments, the median VC% declined an average of 24 percentage points per year. Over time, there was an increase in respiratory symptoms relative to general functional impairment, as measured by the ALSFRS-R, and VC% was strongly associated with shorter survival. The confirmed prevalence of NIV was approximately 3%, 15%, and 25% in patients with a VC% of >80, 50-80, and <50, respectively.

CONCLUSION: There was a trend of worsening respiratory function over time and an increase in respiratory symptoms relative to general functional impairment. Survival was strongly associated with respiratory function. In those with impaired respiratory function, there was significant variation in the introduction of NIV.}, } @article {pmid40326917, year = {2025}, author = {van Eijk, RPA and Weemering, DN and Opie-Martin, S and van Unnik, JWJ and Caravaca Puchades, A and Chiò, A and Corcia, P and Galvin, M and Hardiman, O and Heverin, M and Hobin, F and Holmdahl, O and Ingre, C and Lamaire, N and Mac Domhnaill, É and McDonough, H and Manera, U and McDermott, CJ and McFarlane, R and Mouzouri, M and Ombelet, F and Povedano Panadés, M and Sennfält, S and Shaw, PJ and Terrafeta Pastor, C and Van Damme, P and Vasta, R and Veldink, JH and Al-Chalabi, A and van den Berg, LH}, title = {Natural history of the revised ALS functional rating scale and its association with survival: the PRECISION-ALS Extant Study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {30-40}, doi = {10.1080/21678421.2024.2443985}, pmid = {40326917}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Disease Progression ; Aged ; Longitudinal Studies ; Cohort Studies ; Adult ; Severity of Illness Index ; Survival Rate/trends ; }, abstract = {OBJECTIVE: To characterize the natural history of the revised ALS functional rating scale (ALSFRS-R) over a 24-month period following initial assessment, and to assess its associations with survival.

METHODS: Longitudinal ALSFRS-R measurements and survival data were obtained from seven population-based, European cohorts. Different models for the ALSFRS-R trajectory were evaluated, including tests for linearity and between-cohort differences. We employed a joint modeling framework to factor in mortality, thereby aiming to derive a more precise estimate of the population's rate of decline, while simultaneously delineating its relationship with survival.

RESULTS: In total, 7,030 patients were included who produced 31,746 ALSFRS-R measurements during a follow-up period of 10,285 person-years. There was substantial evidence for a non-linear time trend within all cohorts (all p < 0.001), with faster progression rates at the beginning of follow-up. The average rate over 24 months was 0.89 points per month; 95% of the patients had a rate between 0.04 and 1.96. Overall, two components of the ALSFRS-R trajectory were found to be associated with survival: (1) the actual value of the ALSFRS-R total score and (2) the rate of change at any given time (both p < 0.001).

CONCLUSIONS: Functional loss in ALS follows a decelerating trajectory, where the current functional status and the rate of change have a direct impact on the patient' s probability of survival. Given the pivotal role of the ALSFRS-R in drug development, these results help to separate treatment benefit from the disease's natural trajectory and to estimate the impact on survival.}, } @article {pmid40327885, year = {2025}, author = {Malik, T and Sidisky, JM and Jones, S and Winters, A and Hocking, B and Rotay, J and Huhulea, EN and Moran, S and Connors, B and Babcock, DT}, title = {Synaptic defects in adult drosophila motor neurons in a model of amyotrophic lateral sclerosis.}, journal = {Human molecular genetics}, volume = {34}, number = {14}, pages = {1204-1215}, doi = {10.1093/hmg/ddaf068}, pmid = {40327885}, issn = {1460-2083}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/physiopathology ; Animals ; *Motor Neurons/metabolism/pathology ; Disease Models, Animal ; *RNA-Binding Protein FUS/genetics/metabolism ; *Synapses/metabolism/pathology/genetics ; Humans ; Drosophila/genetics ; Drosophila melanogaster/genetics ; Drosophila Proteins/genetics/metabolism ; Mutation ; Neuromuscular Junction ; Optogenetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons in the brain and spinal cord. Like other neurodegenerative diseases, defects in synaptic integrity are among the earliest hallmarks of ALS. However, the specific impairments to synaptic integrity remain unclear. To better understand synaptic defects in ALS, we expressed either wild-type or mutant Fused in Sarcoma (FUS), an RNA binding protein that is often mis-localized in ALS, in adult motor neurons. Using optogenetic stimulation of the motor neurons innervating the Ventral Abdominal Muscles (VAMs), we found that expression of mutant FUS disrupted the functional integrity of these synapses. This functional deficit was followed by disruption of synaptic gross morphology, localization of pre- and post-synaptic proteins, and cytoskeleton integrity. We found similar synaptic defects using the motor neurons innervating the Dorsal Longitudinal Muscles (DLMs), where expression of mutant FUS resulted in a progressive loss of flight ability along with disruption of active zone distribution. Our findings uncover defects in synaptic function that precede changes in synaptic structure, suggesting that synaptic function is more sensitive to this ALS model. Highlighting the earliest synaptic defects in this disease model should help to identify strategies for preventing later stages of disease progression.}, } @article {pmid40328052, year = {2025}, author = {Mirveis, Z and Patil, N and Byrne, HJ}, title = {Exploring cellular metabolic kinetics through spectroscopic analysis of extracellular environments.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {340}, number = {}, pages = {126308}, doi = {10.1016/j.saa.2025.126308}, pmid = {40328052}, issn = {1873-3557}, mesh = {Spectroscopy, Fourier Transform Infrared/methods ; Kinetics ; Glucose/metabolism/analysis ; Glutamine/metabolism ; Lactic Acid/metabolism/analysis ; Glycolysis ; Least-Squares Analysis ; Humans ; *Extracellular Space/metabolism ; }, abstract = {Studying the kinetics of metabolic pathways, such as glycolysis and glutaminolysis, is valuable due to their fundamental links to various diseases, including cancer. This study explores the potential of Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy for analysing low concentrations of metabolites in extracellular media. It also evaluates the use of the Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) method to data mine the kinetic evolution of the spectroscopic signatures of the glycolysis metabolic pathway and to explore the impact of the presence of glutamine on it. By extracting samples at specific time intervals and drying them on the ATR crystal, ATR-FTIR could effectively measure individual metabolites of glucose, glutamine and lactate at low concentrations, providing clear spectra with strong correlations between peak absorbance and metabolite concentrations. In data mining, MCR-ALS successfully resolved two components, glucose and lactate, from time-series data of cellular glucose metabolism (glycolysis), showing approximately 28 % glucose consumption and 1 mM lactate production at a constant rate of 0.0016 min[-1]. However, when glutamine was introduced as a third component, the overlap of the peaks of glutamine and lactate limited the method's ability to deconvolute the data, highlighting constraints of MCR-ALS in complex mixtures.}, } @article {pmid40328131, year = {2025}, author = {Amorim, RM and Gaudie-Ley, LW and Aguiar, M and Sant'Anna, PDS and Freitas, ADS and Caetano, LF and Póvoa, AA and Santos, CSG and Folly, E and Silva, EC and Neto, JAB}, title = {The role of bioremediation in mitigating urban expansion impacts on coastal lagoons: A comparative study of Araçatiba and Padre Lagoons, Rio de Janeiro.}, journal = {Marine pollution bulletin}, volume = {217}, number = {}, pages = {118048}, doi = {10.1016/j.marpolbul.2025.118048}, pmid = {40328131}, issn = {1879-3363}, mesh = {Brazil ; *Biodegradation, Environmental ; *Environmental Monitoring ; Eutrophication ; Seawater/chemistry ; Geologic Sediments/chemistry ; Nitrogen/analysis ; Phosphorus/analysis ; Animals ; *Urban Renewal ; }, abstract = {This study examines the impact of urban expansion on organic matter gradients in two coastal lagoons, Araçatiba (AL) and Padre (PL), in Rio de Janeiro, Brazil, using benthic macrofauna as ecological indicators. To mitigate the effects of organic enrichment, a microbial consortium (Lactobacillus casei, Lactobacillus acidophilus, and Saccharomyces cerevisiae) was applied in AL for nine months prior to sampling, while PL remained untreated. Sediment samples were collected from 43 stations and analyzed for Total Organic Carbon (TOC), Total Nitrogen (TN), and Total Phosphorus (TP), alongside water column parameters (e.g., dissolved oxygen, salinity, chlorophyll-a) and benthic macrofaunal composition. Results indicated higher macrofaunal abundance and diversity in AL compared to PL, where organic pollution and eutrophication were more severe. Canonical Correspondence Analysis (CCA) identified salinity and eutrophication as primary drivers of community structure, with taxa such as Capitella spp. and Streblospio sp. tolerating high organic loads and hypoxia. AL's benthic community was dominated by mollusks (Heleobia australis, Mytilopsis leucophaeata), while PL was dominated by annelids (oligochaetes, Alitta succinea), reflecting divergent environmental conditions. The AMBI index classified PL as moderately to severely disturbed and AL as slightly to moderately disturbed, aligning with geochemical data showing higher TOC and nutrient concentrations in PL sediments. Microbial bioremediation in AL correlated with improved water quality (higher WQI, lower BOD) and benthic health, underscoring its potential as a management tool. The study highlights the need for tailored strategies to address anthropogenic pressures and restore ecological balance in coastal lagoons.}, } @article {pmid40328418, year = {2025}, author = {Lai, IC and Wei, JC}, title = {Comment on Kaltchenko et al's "Dupilumab and neuropsychiatric outcomes in pediatric atopic dermatitis: A real-world cohort analysis".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {3}, pages = {e109-e110}, doi = {10.1016/j.jaad.2025.02.101}, pmid = {40328418}, issn = {1097-6787}, } @article {pmid40328546, year = {2025}, author = {Kleinerova, J and Tan, EL and Delaney, S and Smyth, M and Bede, P}, title = {Advances and research priorities in the respiratory management of ALS: Historical perspectives and new technologies.}, journal = {Revue neurologique}, volume = {181}, number = {6}, pages = {525-534}, doi = {10.1016/j.neurol.2025.04.008}, pmid = {40328546}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications/history ; *Biomedical Research/trends ; History, 19th Century ; History, 20th Century ; History, 21st Century ; Noninvasive Ventilation/methods ; Respiratory Insufficiency/therapy/etiology ; }, abstract = {Respiratory involvement has been identified as a cardinal feature of amyotrophic lateral sclerosis (ALS) since its earliest descriptions in the 19th century. Since these initial reports, considerable research has been undertaken to clarify the pathophysiology and progression rates associated with respiratory compromise and effective management strategies have been developed. Clinical trials routinely incorporate respiratory measures as study end points, non-invasive ventilation is now widely used in the home setting, cough-assist techniques are commonly used, advanced neurophysiology techniques and wearable technologies have been integrated into respiratory monitoring protocols, and palliative guidelines have been developed to effectively manage respiratory distress. Despite the widespread implementation of these interventions, epidemiology studies are inconsistent and some studies suggest that survival in ALS has not improved significantly with the introduction of these measures. The outcomes of diaphragmatic pacing trials have been disappointing, advanced neurophysiology techniques are not routinely utilised, spinal and brainstem imaging are not commonly undertaken and significant geographical differences exist in proceeding to tracheostomy. The worldwide COVID pandemic has given impetus for remote monitoring, connected devices, video-consultations, and timely vaccinations in ALS; lessons that are invaluable long after the pandemic. Respiratory monitoring and management in ALS is a swiftly evolving facet of ALS care with considerable quality of life benefits.}, } @article {pmid40328798, year = {2025}, author = {Wu, X and Yang, Z and Zou, J and Gao, H and Shao, Z and Li, C and Lei, P}, title = {Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery.}, journal = {Signal transduction and targeted therapy}, volume = {10}, number = {1}, pages = {146}, pmid = {40328798}, issn = {2059-3635}, support = {32070961//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/enzymology/genetics/pathology ; *Drug Discovery ; *Protein Kinases/genetics/metabolism ; *Protein Kinase Inhibitors/therapeutic use ; Signal Transduction/drug effects/genetics ; Phosphorylation ; Animals ; }, abstract = {Neurodegenerative diseases (e.g., Alzheimer's, Parkinson's, Huntington's disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase-kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.}, } @article {pmid40329780, year = {2025}, author = {Mohammadi, S and Ghaderi, S and Fatehi, F and Kalra, S and Batouli, SAH}, title = {Pathological Aging of Patients With Amyotrophic Lateral Sclerosis: A Preliminary Longitudinal Study.}, journal = {Brain and behavior}, volume = {15}, number = {5}, pages = {e70484}, pmid = {40329780}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology/diagnostic imaging/psychology ; Male ; Longitudinal Studies ; Female ; Middle Aged ; *Aging/pathology/physiology ; Aged ; Magnetic Resonance Imaging/methods ; *Brain/pathology/diagnostic imaging/physiopathology ; Neuropsychological Tests ; Cognition/physiology ; Cognitive Dysfunction/physiopathology ; Executive Function/physiology ; Disease Progression ; Adult ; }, abstract = {OBJECTIVE: This longitudinal study investigated pathological brain aging in amyotrophic lateral sclerosis (ALS) by evaluating disparities between chronological age and deep learning-derived brain structure age (BSA) and exploring associations with cognitive and functional decline.

METHODS: Ten limb-onset ALS patients (seven males) and 10 demographically matched healthy controls (HCs) underwent structural magnetic resonance imaging (sMRI) and cognitive assessments at baseline and follow-up. The BSA was estimated using the validated volBrain platform. Cognitive domains (language, verbal fluency, executive function, memory, and visuospatial skills) and global cognition (Persian adaptive Edinburgh Cognitive and Behavioral ALS Screen [ECAS] total score) were assessed along with functional status (ALSFRS-R).

RESULTS: ALS patients exhibited significant BSA-chronological age disparities at baseline (Δ = +7.31 years, p = 0.009) and follow-up (Δ = +8.39 years, p = 0.003), with accelerated BSA progression over time (p = 0.004). The HCs showed no such disparities (p = 0.931). Longitudinal BSA increases were correlated with executive function decline (r = -0.651, p = 0.042). Higher education predicted preserved language (r = 0.831, p = 0.003) and verbal fluency (r = 0.738, p = 0.015). ALSFRS-R decline paralleled visuospatial (r = 0.642, p = 0.045) and global cognitive deterioration (r = 0.667, p = 0.035).

CONCLUSIONS: ALS is characterized by accelerated structural brain aging that progresses independently of chronological age and is correlated with executive dysfunction. Education may mitigate cognitive decline, while motor functional deterioration aligns with visuospatial and global cognitive impairments. BSA has emerged as a potential biomarker for tracking pathological aging trajectories in ALS, warranting validation using larger cohorts.}, } @article {pmid40330290, year = {2025}, author = {Pérez-Holanda, S}, title = {Life-threatening bleeding caused by artery pseudoaneurysm after endoscopic procedure successfully treated by artery embolization.}, journal = {World journal of clinical cases}, volume = {13}, number = {13}, pages = {99278}, pmid = {40330290}, issn = {2307-8960}, abstract = {The Kakinuma et al's case report shows that non-pregnancy-related arterial pseudoaneurysm is a relatively rare, little known by some gynecologists, endoscopists, surgeons or radiologists, which can cause massive bleeding. Arterial pseudoaneurysm is a condition in which the wall of a blood vessel collapses due to some invasive event, and the resulting leaked blood is engulfed by soft tissues, forming a cavity that is in communication with the vessel. It is a potentially life-threatening complication that could occurs after some deliveries and some gynecological invasive procedures. Remarkably, an undetermined percentage of pseudoaneurysms are asymptomatic, and in an asymptomatic patient it is difficult to predict the risk of haemorrhage and the attitude to follow, which depends on several factors, such as, the size and location of the vessel involved, changes in the size of the pseudoaneurysm, or the available therapeutic resources to be offered to patients, among others circumstances. The management of abdominal arterial pseudoaneurysm does not have consistent scientific evidence, but it seems that, regardless of the associated circumstances, the pseudoaneurysm could be treated at least initially, and mainly, through endovascular procedures, as done by Kakinuma et al.}, } @article {pmid40330963, year = {2025}, author = {Kayabaşi, M and Köksaldi, S and Demirel, N and Saatci, AO}, title = {The Effect of Axial Length on Macular Vascular Density in Eyes with High Myopia.}, journal = {Romanian journal of ophthalmology}, volume = {69}, number = {1}, pages = {88-100}, pmid = {40330963}, issn = {2501-2533}, mesh = {Humans ; *Tomography, Optical Coherence/methods ; Female ; Male ; *Retinal Vessels/pathology/diagnostic imaging ; *Axial Length, Eye/pathology/diagnostic imaging ; Middle Aged ; Fluorescein Angiography/methods ; Adult ; *Myopia, Degenerative/diagnosis/physiopathology ; *Macula Lutea/blood supply/pathology ; Retrospective Studies ; Visual Acuity ; Fundus Oculi ; Choroid/blood supply/pathology ; Microvascular Density ; Fovea Centralis ; Follow-Up Studies ; }, abstract = {OBJECTIVE: To evaluate the relationship between optical coherence tomography angiography (OCTA) findings and axial length (AL) in eyes with high myopia.

MATERIALS AND METHODS: A total of 122 eyes from 78 patients were included. Seventy-five eyes with an AL ranging between 26.00 and 27.49 mm comprised Group 1, and 47 with an AL of ≥ 27.50 mm comprised Group 2. Spectral-domain OCT was performed to measure the central macular thickness, subfoveal choroidal thickness (SCT) and swept-source OCTA was utilized to obtain the data on foveal avascular zone (FAZ) and vascular density (VD) values at the superficial and deep capillary plexuses (SCP and DCP), outer retina (OuR), and choriocapillaris (CC) segments.

RESULTS: While no significant differences were found in terms of the mean superficial-FAZ and deep-FAZ areas (p=0.284 and p=0.952, respectively), there were significant differences between the groups in terms of the mean foveal VD in the SCP (p=0.001), the mean total VD (p=0.045) and foveal VD in the DCP (p<0.001), the mean foveal VD (p=0.019) and superior parafoveal VD in the OuR (p=0.008), the mean total (p=0.005), temporal parafoveal (p=0.034), inferior parafoveal (p=0.029), and nasal parafoveal VDs in the CC segments (p=0.005).

DISCUSSION: The findings of the present study highlight the complex interplay between axial elongation and retinal microvasculature, suggesting that factors beyond mechanical stretching may contribute to these alterations. The variability in the existing literature on this topic arises from inconsistencies in the definition of high myopia, the use of different OCTA devices, and heterogeneous study populations. By including eyes with myopic maculopathy and employing axial length-based classification, this study provides a broad representation of high myopia. However, its retrospective design, single-center setting, and monoracial cohort represent limitations. Future large-scale, prospective studies involving diverse populations are needed to elucidate further the pathophysiology of high myopia and its impact on retinal and choroidal microcirculation.

CONCLUSIONS: Our study revealed that high-myopic eyes with longer ALs exhibited increased total VD in the DCP and increased foveal VD in the SCP, DCP, and OuR segments, while they showed decreased total VD and temporal, inferior, and nasal parafoveal VDs in the CC segment compared to high-myopic eyes with shorter ALs.}, } @article {pmid40331424, year = {2025}, author = {Santoro, F and D'Amico, E and Brunetti, ND}, title = {Amyotrophic lateral sclerosis and Takotsubo syndrome: a call for action!.}, journal = {Journal of cardiovascular medicine (Hagerstown, Md.)}, volume = {26}, number = {5}, pages = {255-256}, doi = {10.2459/JCM.0000000000001724}, pmid = {40331424}, issn = {1558-2035}, } @article {pmid40331673, year = {2025}, author = {Ma, W and Dickie, AC and Polgár, E and Yadav, M and Quillet, R and Gutierrez-Mecinas, M and Bell, AM and Todd, AJ}, title = {Expression of Tacr1 and Gpr83 by spinal projection neurons.}, journal = {Molecular pain}, volume = {21}, number = {}, pages = {17448069251342409}, pmid = {40331673}, issn = {1744-8069}, support = {/WT_/Wellcome Trust/United Kingdom ; 219433/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; *Receptors, G-Protein-Coupled/metabolism/genetics ; *Spinal Cord/metabolism/cytology ; *Neurons/metabolism ; Mice ; *Receptors, Neurokinin-1/metabolism ; Mice, Transgenic ; Male ; Axons/metabolism ; Mice, Inbred C57BL ; }, abstract = {Anterolateral system (ALS) projection neurons underlie perception of pain, itch and skin temperature. These cells are heterogeneous, and there have therefore been many attempts to define functional populations. A recent study identified two classes of ALS neuron in mouse superficial dorsal horn (SDH) based on expression of the G protein-coupled receptors Tacr1 or Gpr83. It was reported that cells expressing these receptors formed largely non-overlapping populations, and that ~60% of ALS cells in SDH expressed Tacr1. An additional finding was that while Tacr1- and Gpr83-expressing ALS cells projected to several brain nuclei, their axons did not reach the ventral posterolateral (VPL) thalamic nucleus, which is reciprocally connected to the primary somatosensory cortex. These results were surprising, because we had reported that ~90% of SDH ALS neurons in the mouse possess the neurokinin 1 receptor (NK1r), which is encoded by Tacr1, and in addition the VPL is thought to receive input from lamina I ALS cells. Here we use retrograde and anterograde labelling in Tacr1[CreERT2] and Gpr83[CreERT2] mice to reinvestigate the expression of the receptors by ALS neurons and to reassess their projection patterns. We find that ~90% of ALS neurons in SDH express Tacr1, with 40%-50% expressing Gpr83. We also show that axons of both Tacr1- and Gpr83-expressing ALS neurons reach the VPL. These results suggest that ALS neurons in the SDH that express these GPCRs show considerable overlap, and that they are likely to contribute to the sensory-discriminative dimension of pain through their projections to VPL.}, } @article {pmid40332015, year = {2025}, author = {Duță, C and Dogaru, CB and Muscurel, C and Stoian, I}, title = {Nanozymes: Innovative Therapeutics in the Battle Against Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {8}, pages = {}, pmid = {40332015}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Oxidative Stress/drug effects ; Animals ; Antioxidants/therapeutic use/chemistry/pharmacology ; *Nanostructures/chemistry/therapeutic use ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), represent a significant challenge to global health due to their progressive nature and the absence of curative treatments. These disorders are characterized by oxidative stress, protein misfolding, and neuroinflammation, which collectively contribute to neuronal damage and death. Recent advancements in nanotechnology have introduced nanozymes-engineered nanomaterials that mimic enzyme-like activities-as promising therapeutic agents. This review explores the multifaceted roles of nanozymes in combating oxidative stress and inflammation in neurodegenerative conditions. By harnessing their potent antioxidant properties, nanozymes can effectively scavenge reactive oxygen species (ROS) and restore redox balance, thereby protecting neuronal function. Their ability to modify surface properties enhances targeted delivery and biocompatibility, making them suitable for various biomedical applications. In this review, we highlight recent findings on the design, functionality, and therapeutic potential of nanozymes, emphasizing their dual role in addressing oxidative stress and pathological features such as protein aggregation. This synthesis of current research underscores the innovative potential of nanozymes as a proactive therapeutic strategy to halt disease progression and improve patient outcomes in neurodegenerative disorders.}, } @article {pmid40332510, year = {2025}, author = {Stacchiotti, C and Mazzella di Regnella, S and Cinotti, M and Spalloni, A and Volpe, E}, title = {Neuroinflammation and Amyotrophic Lateral Sclerosis: Recent Advances in Anti-Inflammatory Cytokines as Therapeutic Strategies.}, journal = {International journal of molecular sciences}, volume = {26}, number = {8}, pages = {}, pmid = {40332510}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/immunology ; *Cytokines/therapeutic use/metabolism ; Animals ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Blood-Brain Barrier/metabolism ; Inflammation ; }, abstract = {Neuroinflammation is an inflammatory response occurring within the central nervous system (CNS). The process is marked by the production of pro-inflammatory cytokines, chemokines, small-molecule messengers, and reactive oxygen species. Microglia and astrocytes are primarily involved in this process, while endothelial cells and infiltrating blood cells contribute to neuroinflammation when the blood-brain barrier (BBB) is damaged. Neuroinflammation is increasingly recognized as a pathological hallmark of several neurological diseases, including amyotrophic lateral sclerosis (ALS), and is closely linked to neurodegeneration, another key feature of ALS. In fact, neurodegeneration is a pathological trigger for inflammation, and neuroinflammation, in turn, contributes to motor neuron (MN) degeneration through the induction of synaptic dysfunction, neuronal death, and inhibition of neurogenesis. Importantly, resolution of acute inflammation is crucial for avoiding chronic inflammation and tissue destruction. Inflammatory processes are mediated by soluble factors known as cytokines, which are involved in both promoting and inhibiting inflammation. Cytokines with anti-inflammatory properties may exert protective roles in neuroinflammatory diseases, including ALS. In particular, interleukin (IL)-10, transforming growth factor (TGF)-β, IL-4, IL-13, and IL-9 have been shown to exert an anti-inflammatory role in the CNS. Other recently emerging immune regulatory cytokines in the CNS include IL-35, IL-25, IL-37, and IL-27. This review describes the current understanding of neuroinflammation in ALS and highlights recent advances in the role of anti-inflammatory cytokines within CNS with a particular focus on their potential therapeutic applications in ALS. Furthermore, we discuss current therapeutic strategies aimed at enhancing the anti-inflammatory response to modulate neuroinflammation in this disease.}, } @article {pmid40333317, year = {2025}, author = {Simula, ER and Jasemi, S and Cossu, D and Fais, M and Cossu, I and Chessa, V and Canu, M and Sechi, LA}, title = {Human Endogenous Retroviruses as Novel Therapeutic Targets in Neurodegenerative Disorders.}, journal = {Vaccines}, volume = {13}, number = {4}, pages = {}, pmid = {40333317}, issn = {2076-393X}, support = {PNRR-MCNT1-2023-12376993//Ministero della Salute/ ; 2022BP837R//MUR, PRIN 2022/ ; 22//Regione Autonoma Sardegna grant: legge regionale 12 22 December 2022/ ; e.INS Ecosystem of Innovation for Next Generation Sardinia spoke n 5//European Union/ ; }, abstract = {Human Endogenous Retroviruses comprise approximately 8% of the human genome, serving as fragments of ancient retroviral infections. Although they are generally maintained in a silenced state by robust epigenetic mechanisms, specific HERV groups, particularly HERV-W and HERV-K, can become derepressed under specific pathological conditions, thereby contributing to the initiation and progression of neuroinflammatory and neurodegenerative processes. Preclinical studies and clinical trials, such as those investigating monoclonal antibodies, indicate that directly targeting these elements may offer a novel therapeutic strategy. In this review, we provide an overview of HERVs' biology, examine their role in neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, and Parkinson's disease, and explore their therapeutic prospects, highlighting both the challenges and the potential future research directions needed to translate these approaches into clinical interventions.}, } @article {pmid40333935, year = {2025}, author = {Vanderlinden, G and Carron, C and Van Weehaeghe, D and De Vocht, J and Ombelet, F and Masrori, P and De Weerdt, C and James, RE and Evans, LT and Schroeder, FA and Hooker, JM and Koole, M and Kranz, JE and Gilbert, TM and Van Damme, P and Van Laere, K}, title = {Histone Deacetylase 6 Brain PET in Amyotrophic Lateral Sclerosis-Frontotemporal Spectrum Disorder.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {7}, pages = {1350-1359}, pmid = {40333935}, issn = {2328-9503}, support = {//Association for Frontotemporal Degeneration/ ; //Target ALS/ ; //Eikonizo Therapeutics/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Middle Aged ; Female ; Male ; *Positron-Emission Tomography/methods ; Aged ; *Histone Deacetylase 6/metabolism ; *Frontotemporal Dementia/diagnostic imaging/metabolism ; *Brain/diagnostic imaging/metabolism ; *Cognitive Dysfunction/diagnostic imaging/metabolism/etiology ; }, abstract = {OBJECTIVE: [[18]F]EKZ-001 is a positron emission tomography (PET) tracer targeting histone deacetylase 6 (HDAC6), an enzyme responsible for intracellular transport and clearance of misfolded proteins. HDAC6 modulation is a promising treatment strategy in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Apart from motor symptoms, people with ALS (pwALS) can show a variable degree of cognitive impairment as part of the ALS-frontotemporal spectrum disorder (ALS-FTSD). This work assessed [[18]F]EKZ-001 binding in pwALS with variable involvement of FTSD.

METHODS: Twenty-four pwALS (13M/11F, 61 ± 10 years) and 12 healthy controls (HC) (6M/6F, 58 ± 3 years) were included. Thirteen pwALS were cognitively normal (ALS-CN), and eleven pwALS presented with FTSD (ALS-FTSD) ranging from mild cognitive or behavioral impairment to FTD, according to their performance on the Edinburgh cognitive and behavioral ALS screen (ECAS). All subjects underwent dynamic PET-MR imaging with arterial sampling, and regional distribution volumes (VT) were calculated using a Logan graphical analysis.

RESULTS: [[18]F]EKZ-001 VT was significantly lower in pwALS compared to HC. For ALS-CN, the largest reduction was found in the brainstem. For ALS-FTSD, reductions were more widespread in both gray and white matter. No differences in VT were found between pwALS with and without a C9orf72 mutation. [[18]F]EKZ-001 VT was not correlated with ECAS scores, age, or disease duration.

INTERPRETATION: [[18]F]EKZ-001 binding is lower throughout the brain in pwALS compared to HC. This may be related to a compensatory mechanism to repair intracellular transport defects in ALS or to reduced HDAC6 enzyme availability for [[18]F]EKZ-001 binding due to sequestration of HDAC6 within protein aggregates.}, } @article {pmid40334711, year = {2025}, author = {Sucker, C and Koscielny, J and Kappert, G}, title = {Ausgewählte Beiträge der BDDH-Veranstaltung im Rahmen der 69. Jahrestagung der Gesellschaft für Thrombose- und Hämostaseforschung (GTH) am 18.02.2025 in Lausanne.}, journal = {Hamostaseologie}, volume = {45}, number = {2}, pages = {209-211}, doi = {10.1055/a-2447-6517}, pmid = {40334711}, issn = {2567-5761}, mesh = {Humans ; *Hemostasis ; *Thrombosis ; }, abstract = {DHR -2025, WAS GIBT ES NEUES?: Die DHR-Webseite (www.pei.de/DE/regulation/melden/dhr/dhr-node.html) beinhaltet neben fünf Publikationen, die letzte von 2020, einen Jahresbericht 2022/2023. Die Daten aus 2023 sind als vorläufig gekennzeichnet. Veröffentlicht sind die Anzahlen gemeldeter Fälle (Hämophilie A/B nach Schweregrad, von Willebrand Syndrom Typ 3 und andere, seltene Faktoren und Hemmkörper bei Kindern und Erwachsenen), sowie der Verbrauch bis 2022. Klinisch relevante Daten, wie z.B. Blutungen, die Teil der Einzelmeldung sind, finden sich nicht.}, } @article {pmid40334920, year = {2025}, author = {Perez, OD and Lin, MJ and Pomeranz, MK and Chiu, ES and Lu, CP and Petukhova, L}, title = {Response to Andersen et al's "A genome-wide association meta-analysis links hidradenitis suppurativa to common and rare sequence variants causing disruption of the Notch and Wnt/β-catenin signaling pathways".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {3}, pages = {e113-e114}, doi = {10.1016/j.jaad.2025.04.064}, pmid = {40334920}, issn = {1097-6787}, } @article {pmid40335898, year = {2025}, author = {Kim, JH and Whitaker, VM and Lee, S}, title = {A haplotype-phased genome characterizes the genomic architecture and causal variants for RXf1 conferring resistance to Xanthomonas fragariae in strawberry (F. × ananassa).}, journal = {BMC genomics}, volume = {26}, number = {1}, pages = {453}, pmid = {40335898}, issn = {1471-2164}, support = {#2022-51181-38328//National Institute of Food and Agriculture/ ; #2022-51181-38328//National Institute of Food and Agriculture/ ; #2022-51181-38328//National Institute of Food and Agriculture/ ; }, mesh = {*Fragaria/genetics/microbiology ; *Disease Resistance/genetics ; *Haplotypes ; *Plant Diseases/microbiology/genetics ; *Xanthomonas/physiology ; *Genome, Plant ; Chromosome Mapping ; *Genomics ; Chromosomes, Plant/genetics ; }, abstract = {BACKGROUND: Cultivated octoploid strawberry (Fragaria × ananassa) is one of the most economically important fruits worldwide due to its flavor, texture, and health benefits. However, bacterial angular leaf spot (ALS) causes economic losses in fruit production and plant nurseries. All commercial strawberry varieties are susceptible to ALS. A major resistance locus, RXf1, has been reported, but the genomic structure and candidate genes underlying this resistance remain known.

RESULTS: Fine-mapping was performed using three segregating populations containing 663 individuals that were genotyped with subgenome specific seven high-resolution melting (HRM) markers to narrow the RXf1 region to a 486-kb interval on chromosome 6C. We assembled a haplotype-phased chromosome-scale genome of ALS-resistant breeding selection FL17.68-110 using highly accurate long-read sequencing and trio-binning with parental short reads. The 1.62 Gbp genome containing two haplotypes, 56 chromosomes and 193,072 annotated genes. Transcriptome analysis in response to the ALS pathogen identified a candidate gene, Resistance gene analogue 3 (RGA3), associated with the RXf1 resistance. The gene structure and sequence variations within FaRGA3 were identified between resistant and susceptible genotypes.

CONCLUSIONS: Our results narrowed the RXf1 region, identified structural variations within this locus and pointed to FaRGA3 as a promising candidate gene. This information will be useful for breeders toward developing ALS-resistant strawberry varieties, and the high-quality genome will be a valuable resource for further genomics research in octoploid strawberry.}, } @article {pmid40338003, year = {2025}, author = {Chen, X and Chen, X and Lin, X and Zhou, W and Hu, H and Jiang, H}, title = {Unveiling ten novel SETX mutations: implications for ALS pathogenesis and clinical diversity.}, journal = {Somatosensory & motor research}, volume = {42}, number = {3-4}, pages = {107-114}, doi = {10.1080/08990220.2025.2500940}, pmid = {40338003}, issn = {1369-1651}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Male ; Female ; *Mutation/genetics ; *RNA Helicases/genetics ; Middle Aged ; Multifunctional Enzymes/genetics ; Adult ; *DNA Helicases/genetics ; Cohort Studies ; Aged ; Disease Progression ; Neural Conduction/physiology ; }, abstract = {OBJECTIVE: To investigate the relationship between newly identified senataxin (SETX) gene mutations and the clinical manifestation of Amyotrophic Lateral Sclerosis (ALS), enhancing understanding of the genetic underpinnings associated with this disorder.

METHODS: A cohort study was conducted at Nanfang Hospital, involving comprehensive genetic sequencing of ALS patients to identify novel SETX mutations. Homology modelling and structural analysis were employed to predict the functional impacts of these mutations on the senataxin protein. Clinical assessments, including symptom evaluation, age of onset, and progression rate, were integrated with electrophysiological studies to establish correlations between genetic variants and clinical outcomes.

RESULTS: Ten novel SETX mutations were identified, expanding the genetic landscape of ALS. These mutations exhibited diverse impacts on clinical presentations, with patients showing variability in onset age, symptom severity, and progression rates. Computational modelling suggested that certain mutations cause significant structural changes in senataxin, potentially affecting its RNA/DNA helicase function. Electrophysiological findings consistently revealed nerve conduction abnormalities, indicating that these mutations may influence neuronal excitability and contribute to ALS pathogenesis.

CONCLUSION: The discovery of novel SETX mutations provides valuable insights into the genetic and clinical complexity of ALS. This study underscores the importance of genetic screening for SETX mutations and suggests potential personalised therapeutic approaches targeting senataxin dysfunction. By elucidating genotype-phenotype correlations, these findings contribute to the broader understanding of ALS and offer pathways for developing targeted interventions to address the challenges posed by this disabling disease.}, } @article {pmid40338888, year = {2025}, author = {Faisal, M and Khosa, I and Waris, A and Gilani, SO and Khan, MJ and Hazzazi, F and Ijaz, MA}, title = {RETRACTED: Optimizing the impact of time domain segmentation techniques on upper limb EMG decoding using multimodal features.}, journal = {PloS one}, volume = {20}, number = {5}, pages = {e0322580}, pmid = {40338888}, issn = {1932-6203}, mesh = {Humans ; *Electromyography/methods ; *Upper Extremity/physiology ; Male ; Adult ; Female ; Movement/physiology ; Signal Processing, Computer-Assisted ; Support Vector Machine ; Young Adult ; }, abstract = {Neurological disorders, such as stroke, spinal cord injury, and amyotrophic lateral sclerosis, result in significant motor function impairments, affecting millions of individuals worldwide. To address the need for innovative and effective interventions, this study investigates the efficacy of electromyography (EMG) decoding in improving motor function outcomes. While existing literature has extensively explored classifier selection and feature set optimization, the choice of preprocessing technique, particularly time-domain windowing techniques, remains understudied posing a significant knowledge gap. This study presents upper limb movement classification by providing a comprehensive comparison of eight time-domain windowing techniques. For this purpose, the EMG data from volunteers is recorded involving fifteen distinct movements of fingers. The rectangular window technique among others emerged as the most effective, achieving a classification accuracy of 99.98% while employing 40 time-domain features and a L-SVM classifier, among other classifiers. This optimal combination has implications for the development of more accurate and reliable myoelectric control systems. The achieved high classification accuracy demonstrates the feasibility of using surface EMG signals for accurate upper limb movement classification. The study's results have the potential to improve the accuracy and reliability of prosthetic limbs and wearable sensors and inform the development of personalized rehabilitation programs. The findings can contribute to the advancement of human-computer interaction and brain-computer interface technologies.}, } @article {pmid40339566, year = {2025}, author = {Parameswaran, J and McEachin, ZT}, title = {PI3P: Rising to the (DPR) challenge in C9-ALS/FTD.}, journal = {Neuron}, volume = {113}, number = {9}, pages = {1301-1303}, doi = {10.1016/j.neuron.2025.04.007}, pmid = {40339566}, issn = {1097-4199}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Humans ; C9orf72 Protein ; *Phosphatidylinositol Phosphates/metabolism ; *DNA Repeat Expansion/genetics ; *Proteins/genetics ; Animals ; *Dipeptides/genetics/metabolism ; }, abstract = {A hexanucleotide G4C2 repeat expansion in C9orf72 causes accumulation of dipeptide repeat (DPR) proteins and is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In a recent issue of Neuron, Zhang et al.[1] report that elevating PI3P levels mitigates endolysosomal deficits and DPR-associated neurotoxicity.}, } @article {pmid40339618, year = {2025}, author = {Zhou, C and Hardin, EJ and Zimmer, TS and Jackvony, S and Barnett, D and Khobrekar, N and Giacomelli, E and Studer, L and Orr, AL and Orr, AG}, title = {Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology.}, journal = {Neurobiology of disease}, volume = {211}, number = {}, pages = {106939}, pmid = {40339618}, issn = {1095-953X}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 NS118569/NS/NINDS NIH HHS/United States ; F31 AG079616/AG/NIA NIH HHS/United States ; RF1 NS118569/NS/NINDS NIH HHS/United States ; F31 AG084165/AG/NIA NIH HHS/United States ; T32 GM152349/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Astrocytes/metabolism/pathology/immunology ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; *Signal Transduction/physiology ; Humans ; *Stress Granules/metabolism/pathology/immunology ; NF-kappa B/metabolism ; Mice, Inbred C57BL ; *Neuroimmunomodulation/physiology ; *TDP-43 Proteinopathies/pathology/metabolism/immunology ; }, abstract = {Alterations in transactivating response region DNA-binding protein 43 (TDP-43) are prevalent in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurological disorders. TDP-43 influences neuronal functions and might also affect glial cells. However, specific intracellular effects of TDP-43 alterations on glial cells and underlying mechanisms are not clear. We report that TDP-43 dysregulation in mouse and human cortical astrocytes causes nucleoporin mislocalization, nuclear envelope remodeling, and changes in nucleocytoplasmic protein transport. These effects are dependent on interleukin-1 (IL-1) receptor activity and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and are associated with the formation of cytoplasmic stress granules. Stimulation of IL-1 receptors and NF-κB signaling are necessary and sufficient to induce astrocytic stress granules and rapid nucleocytoplasmic changes, which are broadly alleviated by inhibition of the integrated stress response. These findings establish that TDP-43 alterations and neuroimmune factors can induce nucleocytoplasmic changes through NF-κB signaling, revealing mechanistic convergence of proteinopathy and neuroimmune pathways onto glial nucleocytoplasmic disruptions that may occur in diverse neurological conditions.}, } @article {pmid40340591, year = {2026}, author = {Ward, AL and Nooijen, C and Bernstein, J}, title = {Power wheelchair users with ALS: Impact of an alerting system on complications with prolonged sitting and power feature utilization.}, journal = {Assistive technology : the official journal of RESNA}, volume = {38}, number = {5}, pages = {421-430}, doi = {10.1080/10400435.2025.2497865}, pmid = {40340591}, issn = {1949-3614}, mesh = {Humans ; *Wheelchairs/adverse effects ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology/complications ; *Sitting Position ; Female ; Male ; Middle Aged ; *Pressure Ulcer/prevention & control ; Aged ; *Mobile Applications ; Adult ; }, abstract = {An interventional technology called Virtual Seating Coach (VSC) provided alerts via an app to perform pressure redistribution using power wheelchair seat functions. The objective was whether alerts can contribute to more function utilization and thereby reduce pressure injuries and pain. Thirty-nine individuals with Amyotrophic Lateral Sclerosis (ALS) participated, 14 consented to use VSC, and 25 controls. The duration of the study was 27 months, with follow-up at 1 month or 3 months. Due to multiple technological and disease-related difficulties, three of those consented for the VSC received alerts once per hour to move into prescribed positions for one minute. These participants were able to use the VSC through the study end, and two of the three adhered to performing pressure redistribution after receiving alerts. The three using the VSC did not report pressure injuries; 12 of 21 controls reported development of a pressure injury. Furthermore, those using VSC noted a decrease in pain; most controls showed an increase during the same time period. The study thus highlighted the potential for such alerting technology while at the same time revealing many limitations due to disease progression and diminishing access to wheelchair controls.}, } @article {pmid40340620, year = {2025}, author = {Shen, D and Liu, A and Yang, X and Liu, Q and Liu, M and Cui, L}, title = {Exploring oculomotor challenges in amyotrophic lateral sclerosis: a comprehensive review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {478-484}, doi = {10.1080/21678421.2025.2501690}, pmid = {40340620}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; *Ocular Motility Disorders/etiology/physiopathology/diagnosis ; *Eye Movements/physiology ; Disease Progression ; *Cognitive Dysfunction/physiopathology/etiology ; }, abstract = {Traditionally understood as a motor neuron disease, amyotrophic lateral sclerosis (ALS) is now recognized to involve broader neurodegenerative processes, including the oculomotor system. This narrative review summarizes current evidence on oculomotor dysfunction in ALS, with a focus on its relationship to disease-related motor and cognitive impairments. Specifically, the review examines key eye-tracking (ET) metrics, including saccades, smooth pursuit, and fixation, highlighting their potential to reflect both motor and extramotor degeneration. Notably, patients with bulbar-onset ALS exhibit more pronounced oculomotor impairments. By synthesizing findings on the connection between oculomotor dysfunction and cognitive decline, this review underscores the potential of ET as a noninvasive tool for assessing ALS progression. Oculomotor metrics, as part of a broader understanding of ALS's impact on multiple neural networks, may offer valuable insights to refine patient assessment and care strategies, particularly in advanced disease stages.}, } @article {pmid40340943, year = {2025}, author = {Kellett, EA and Bademosi, AT and Walker, AK}, title = {Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {53}, pmid = {40340943}, issn = {1750-1326}, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; Phosphorylation/physiology ; Animals ; *Neurodegenerative Diseases/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Increased phosphorylation of TDP-43 is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the regulation and roles of TDP-43 phosphorylation remain incompletely understood. A variety of techniques have been utilized to understand TDP-43 phosphorylation, including kinase/phosphatase manipulation, phosphomimic variants, and genetic, physical, or chemical inducement in a variety of cell cultures and animal models, and via analyses of post-mortem human tissues. These studies have produced conflicting results: suggesting incongruously that TDP-43 phosphorylation may either drive disease progression or serve a neuroprotective role. In this review, we explore the roles of regulators of TDP-43 phosphorylation including the putative TDP-43 kinases c-Abl, CDC7, CK1, CK2, IKKβ, p38α/MAPK14, MEK1, TTBK1, and TTBK2, and TDP-43 phosphatases PP1, PP2A, and PP2B, in disease. Building on recent studies, we also examine the consequences of TDP-43 phosphorylation on TDP-43 pathology, especially related to TDP-43 mislocalisation, liquid-liquid phase separation, aggregation, and neurotoxicity. By comparing conflicting findings from various techniques and models, this review highlights both the discrepancies and unresolved aspects in the understanding of TDP-43 phosphorylation. We propose that the role of TDP-43 phosphorylation is site and context dependent, and includes regulation of liquid-liquid phase separation, subcellular mislocalisation, and degradation. We further suggest that greater consideration of the normal functions of the regulators of TDP-43 phosphorylation that may be perturbed in disease is warranted. This synthesis aims to build towards a comprehensive understanding of the complex role of TDP-43 phosphorylation in the pathogenesis of neurodegeneration.}, } @article {pmid40341287, year = {2025}, author = {Merler, M and Agurto, C and Peller, J and Roitberg, E and Taitz, A and Trevisan, MA and Navar, I and Berry, JD and Fraenkel, E and Ostrow, LW and Cecchi, GA and Norel, R}, title = {Clinical assessment and interpretation of dysarthria in ALS using attention based deep learning AI models.}, journal = {NPJ digital medicine}, volume = {8}, number = {1}, pages = {260}, pmid = {40341287}, issn = {2398-6352}, abstract = {Speech dysarthria is a key symptom of neurological conditions like ALS, yet existing AI models designed to analyze it from audio signal rely on handcrafted features with limited inference performance. Deep learning approaches improve accuracy but lack interpretability. We propose an attention-based deep learning AI model to assess dysarthria severity based on listener effort ratings. Using 2,102 recordings from 125 participants, rated by three speech-language pathologists on a 100-point scale, we trained models directly from recordings collected remotely. Our best model achieved R[2] of 0.92 and RMSE of 6.78. Attention-based interpretability identified key phonemes, such as vowel sounds influenced by 'r' (e.g., "car," "more"), and isolated inspiration sounds as markers of speech deterioration. This model enhances precision in dysarthria assessment while maintaining clinical interpretability. By improving sensitivity to subtle speech changes, it offers a valuable tool for research and patient care in ALS and other neurological disorders.}, } @article {pmid40341849, year = {2025}, author = {Neuhaus, D and Wendebourg, MJ and Deigendesch, N and Berger, C and Bauer, M and Haas, T and Scheurer, E and Schlaeger, R and Lenz, C}, title = {Exploring Potential Biomarkers for Amyotrophic Lateral Sclerosis Using Postmortem In Situ Magnetic Resonance Imaging.}, journal = {NMR in biomedicine}, volume = {38}, number = {6}, pages = {e70059}, doi = {10.1002/nbm.70059}, pmid = {40341849}, issn = {1099-1492}, support = {//Neuromuscular Research Association Basel/ ; //Stiftung zur Foerderung der gastroenterologischen und der allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Biomarkers/metabolism ; Male ; *Magnetic Resonance Imaging ; Female ; Middle Aged ; Aged ; Brain/diagnostic imaging/pathology ; Autopsy ; }, abstract = {There is an urgent need for reliable magnetic resonance imaging (MRI) biomarkers for the diagnosis, prognosis or therapy management of amyotrophic lateral sclerosis (ALS). The aim of this study was to explore potential biomarkers for ALS by conducting postmortem (PM) in situ MRI, allowing for a non-invasive evaluation of the disease's end-stage without the effects of formalin fixation. PM in situ MRI whole-brain scans of five deceased patients with clinically definite ALS and seven deceased healthy controls (HC) without known neurological disorders were performed at 3 Tesla. Fractional anisotropy, mean diffusivity, T1, T2 and T2* were assessed for cortex, deep grey matter, white matter, whole brain and hippocampus. For the validation of the MRI DTI data, the focus was placed on the hippocampus, where the myelin density was evaluated by analysing histological samples from the dentate gyrus. A custom python script was developed for the quantification of the myelin density in histological data. Comparing ALS to HC values suggested potential reductions of mean diffusivity, T1 (after outlier removal) and T2* in white matter and of T2 in deep grey matter in the ALS group. Furthermore, mean diffusivity was potentially reduced in the hippocampus of patients with ALS (after outlier removal), whereas no difference in myelin density was found by histopathological assessment. The results of this exploratory study suggest potential differences in diffusivity and relaxometry between PM in situ brains of patients with ALS and HC. Understanding these variations at the end-stage of ALS might contribute to the development of novel MRI prognostic and diagnostic biomarkers for ALS. However, larger sample sizes and complementary histological examinations are needed to confirm these results and to clarify the underlying mechanisms.}, } @article {pmid40342184, year = {2025}, author = {Ribeiro, VHV and Gallagher, J and Mallory-Smith, C and Barroso, J and Brunharo, CACG}, title = {Multiple Origins or Widespread Gene Flow in Agricultural Fields? Regional Population Genomics of Herbicide Resistance in Bromus tectorum.}, journal = {Molecular ecology}, volume = {34}, number = {11}, pages = {e17791}, pmid = {40342184}, issn = {1365-294X}, support = {//Oregon Wheat Commission/ ; //College of Agricultural Sciences, Pennsylvania State University/ ; Project#PEN04859,Accession#7005632//USDA National Institute of Food and Agriculture/ ; }, mesh = {*Herbicide Resistance/genetics ; *Gene Flow ; Acetolactate Synthase/genetics/antagonists & inhibitors ; Herbicides/pharmacology ; *Bromus/genetics/drug effects ; *Genetics, Population ; Mutation ; Genetic Variation ; Agriculture ; }, abstract = {The repeated evolution of herbicide resistance in agriculture provides an unprecedented opportunity to understand how organisms rapidly respond to strong anthropogenic-driven selection pressure. We recently identified agricultural populations of the grass species Bromus tectorum L. with resistance to multiple herbicides. To understand the evolutionary origins and spread of resistance, we investigated the resistance mechanisms to acetolactate synthase (ALS) inhibitors and photosystem II inhibitors, two widely used herbicide modes of action, in 49 B. tectorum populations. We assessed the genetic diversity, structure and relatedness in a subset of 21 populations. Resistance to ALS inhibitors was associated with multiple nonsynonymous mutations in ALS, the target site gene, despite the relatively small geographic region where populations originated, suggesting ALS inhibitor resistance evolution occurred multiple times in the region. We also found evidence that mechanisms not related to the target site evolved and were common in the populations studied. Resistance to photosystem II inhibitors was confirmed in two populations and was conferred by nonsynonymous mutations in the plastid gene psbA. Population genomics analyses suggested that ALS resistance in most populations, at the nucleotide level, spread via gene flow, except for one population where we found evidence that Pro-197-His mutations may have evolved in three separate events. Our results suggest that both gene flow via pollen and/or seed dispersal and multiple local evolutionary events were involved in the spread of herbicide-resistant B. tectorum. Our results provide an empirical example of the rapid repeated evolution of a trait under strong anthropogenic selection and elucidate the evolutionary origins of herbicide resistance in a plant species of agricultural importance.}, } @article {pmid40344624, year = {2025}, author = {Temme, N and Haehre, T and Boyher, C and Hoppe, L and Davenport, C and Stumo, Z and Prenzler, K and Maeser, A and Pflugmacher, M and Koch, K and Stahl, DJ}, title = {Host-induced gene silencing of the amino acid biosynthesis gene acetolactate synthase of Phytophthora infestans caused strong enhanced late blight resistance of potato in the field.}, journal = {Plant biotechnology journal}, volume = {23}, number = {8}, pages = {3054-3067}, pmid = {40344624}, issn = {1467-7652}, support = {Forschungsvorhaben 0315701C//Bundesministerium für Bildung und Forschung/ ; GABI-PLANT-KBBE II//Bundesministerium für Bildung und Forschung/ ; }, mesh = {*Phytophthora infestans/genetics/enzymology ; *Solanum tuberosum/microbiology/genetics/immunology ; *Acetolactate Synthase/genetics/metabolism ; *Plant Diseases/microbiology/genetics/immunology ; *Disease Resistance/genetics ; *Gene Silencing ; *Amino Acids/biosynthesis ; }, abstract = {Late blight caused by Phytophthora infestans is the most serious disease of potatoes. Here we present the effectiveness of the host-induced gene silencing (HIGS) technology against an amino acid biosynthesis gene of the pathogen to increase the resistance against the plant-infecting oomycete in the field. A RNAi hairpin construct directed against the acetolactate synthase (ALS) gene of Phytophthora infestans was transferred into potato. HIGS-ALS potato lines displayed efficient target gene silencing revealed by a luciferase reporter gene assay. Plant-derived siRNAs targeting the oomycete's ALS gene were detected by small RNA sequencing. ALS gene expression of P. infestans was reduced during the early infection stages of HIGS-ALS potatoes, as shown by qRT-PCR. HIGS-ALS plants revealed an enhanced late blight resistance in detached leaf assays. ALS gene silencing also conferred strong enhanced late blight resistance to the HIGS lines in trials under near-field conditions in Europe and in field trials in the USA against European and US P. infestans isolates, respectively. These results demonstrated the value of the HIGS technology for the development of a new quantitative resistance source for potato against Phytophthora infestans.}, } @article {pmid40344633, year = {2025}, author = {Tang, S and Shi, J and Li, X and Yang, M and Li, C and Zhang, D and Yang, S and Mei, C and Luo, Z and Zhang, L and Zhang, W and Zhang, C and Zhu, C and Ma, X and Xia, R and Chen, Y and Zhang, J and Chen, Q and Chen, S and Xie, Q and Yu, F}, title = {Development and Breeding of Herbicide-Resistant Sorghum for Effective Cereal-Legume Intercropping.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {27}, pages = {e2503083}, pmid = {40344633}, issn = {2198-3844}, support = {YZGG-04//Sorghum Seed Industry Innovation and Improved Joint Research Project of Shanxi Province/ ; 2023YFD1200700//National Key R&D Program of China/ ; 2023YFF1001400//National Key R&D Program of China/ ; 32222010//National Natural Science Foundation of China/ ; 32430077//National Natural Science Foundation of China/ ; }, mesh = {*Sorghum/genetics/drug effects/growth & development ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Edible Grain/genetics/drug effects ; *Plant Breeding/methods ; Acetolactate Synthase/genetics ; Imidazoles/pharmacology ; }, abstract = {Weeds bring a serious challenge to crop production, and herbicides is the most effective and economic way to manage it in field. Sorghum is a critical crop for staple food, fodder, and biofuel. However, the lack of herbicide-resistant sorghum germplasm severely impedes its production. Here, we conducted a large-scale screening and identified 13 sorghum mutant lines resistant to imidazolinone (IMI) herbicides. Two unique mutation sites in SbALS (acetolactate synthase), thus namely Sbals-1 (A93T) and Sbals-2 (S624N) are discovered, both enhance sorghum tolerance to imazamox. Notably, under high concentrations of imazamox, sbals-1 presented a superior growth phenotype and elevated SbALS activity than sbals-2, a difference that can be attributed to the predicted protein structures. Breeding with Sbals, both grain- and grass-type sorghum, shows great weed control and field performance. The herbicide imazamox resistance is further evaluated in a soybean population for sorghum-soybean strip intercropping, identifying 123 highly resistant soybean varieties. Field intercropping tests indicated health growth of both soybean and sorghum lines post-imazamox treatment, which enhance field clearance of weed. This study, therefore, provides valuable insights not only for herbicide-resistant sorghum breeding but also for the successful implementation of efficient and sustainable cereal-legume intercropping systems.}, } @article {pmid40344943, year = {2025}, author = {Zhou, ZD and Yi, L and Popławska-Domaszewicz, K and Chaudhuri, KR and Jankovic, J and Tan, EK}, title = {Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges.}, journal = {Pharmacological research}, volume = {216}, number = {}, pages = {107770}, doi = {10.1016/j.phrs.2025.107770}, pmid = {40344943}, issn = {1096-1186}, mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use ; *Hypoglycemic Agents/therapeutic use ; Glucagon-Like Peptide-1 Receptor/metabolism ; }, abstract = {Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T2DM) and obesity and have systemic effects on various organs, including the brain, liver, pancreas, heart, and the gut. Patients with T2DM have a higher risk of developing neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), accompanied by more severe motor deficits and faster disease progression, suggesting dysregulation of insulin signaling in these diseases. Experimental studies have shown that GRA have protective effects to modulate neuroinflammation, oxidative stress, mitochondrial and autophagic functions, and protein misfolding. Hence the compounds have generated enormous interest as novel therapeutic agents against NDs. To date, clinical trials have shown that three GRA, exenatide, liraglutide and lixisenatide can improve motor deficits as an add-on therapy in PD patients and liraglutide can improve cognitive function in AD patients. The neuroprotective effects of these and other GRA, such as PT320 (a sustained-released exenatide) and semaglutide, are still under investigation. The dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists have been demonstrated to have beneficial effects in AD and PD mice models. Overall, GRA are highly promising novel drugs, but future clinical studies should identify which subsets of patients should be targeted as potential candidates for their symptomatic and/or neuroprotective benefits, investigate whether combinations with other classes of drugs can further augment their efficacy, and evaluate their long-term disease-modifying and adverse effects.}, } @article {pmid40345155, year = {2025}, author = {Liu, X and Liu, X and Zhan, J and Yuan, W and Zhu, Y and Huang, W and Li, H and Liu, T and Amine, K and Li, H and Yu, G}, title = {High-Performance Al-S Batteries by Spin Polarization Modulation via Catalytic Ni-MoS2 Nanosheets.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {64}, number = {29}, pages = {e202503835}, doi = {10.1002/anie.202503835}, pmid = {40345155}, issn = {1521-3773}, support = {51804173//National Natural Science Foundation of China/ ; F-1861//Welch Foundation/ ; }, abstract = {Aluminum-sulfur (Al-S) batteries catalysts with adsorption and catalytic capabilities can effectively improve the slow redox kinetics, but the current research often ignores the effect of optimizing the electronic structure of the catalyst on improving charge transfer and adsorption. Here, Ni-doped monolayer MoS2 nanosheets are synthesized and used as a catalytic additive for the sulfur cathode. The addition of Ni promotes spin splitting of 4d orbital of Mo, thereby affecting polarization degree of the basal plane sulfur and making it change from a low spin state to a high spin one. This high spin configuration raises the electron energy level and provides an active electron state to react with aluminum polysulfides (AlPSs), which optimizes the adsorption energy. At the same time, it accelerates electron transfer and lowers the energy barrier for the overall conversion of the polysulfides. Benefiting from these features, Al-S batteries based on rationally designed S@Ni-MoS2/C cathodes exhibit a high initial capacity (1603.0 mAh g[-1] at 0.5 A g[-1]) and extraordinary cycling stability (0.035% capacity decay rate during 2000 cycles). This study showcases a spin-polarized electronic structure control strategy to enhance catalytic activity, providing a viable approach for developing efficient catalysts for practical Al-S batteries.}, } @article {pmid40345169, year = {2025}, author = {Meng, Y and Li, W and Zhang, Y and Li, Y and He, Y and Zhang, N}, title = {ANXA11 Mutations in the FTD Spectrum: A Novel Finding in a Patient With Semantic Variant Primary Progressive Aphasia.}, journal = {European journal of neurology}, volume = {32}, number = {5}, pages = {e70187}, pmid = {40345169}, issn = {1468-1331}, support = {24JCYBJC00650//Natural Science Foundation of Tianjin Municipality/ ; 2022ZD0211605//Science and Technology Innovation 2030 Major Projects/ ; }, mesh = {Aged ; Humans ; *Annexins/genetics ; *Aphasia, Primary Progressive/genetics ; *Frontotemporal Dementia/genetics ; *Mutation/genetics ; }, abstract = {BACKGROUND: Semantic variant primary progressive aphasia (svPPA) is typically a sporadic disorder, and few cases have been linked to ANXA11 mutations. Comprehensive analyses of genetic mutations in svPPA are limited. Furthermore, the clinical and genetic distinctions between typical svPPA and right temporal variant frontotemporal dementia (rtvFTD) are poorly understood.

METHODS: A 68-year-old patient with svPPA carrying a heterozygous ANXA11 c.119A>G (p.D40G) mutation underwent comprehensive neuropsychological, neuroimaging, and genetic assessments at baseline and at the one-year follow-up timepoint. Additionally, systematic reviews were conducted to identify reported cases of ANXA11 mutations in the FTD spectrum and the genetic mutations associated with svPPA. Clinical-genetic profiles of typical svPPA and rtvFTD were compared based on data from the literature.

RESULTS: Thirty-two patients with ANXA11 mutations were identified, including 11 with pure FTD phenotypes and the majority exhibiting FTD-amyotrophic lateral sclerosis (ALS). Among 167 svPPA-related cases, MAPT, GRN, and C9ORF72 mutations were most frequently implicated; ANXA11 mutations were primarily identified in East Asian patients. Comparative analysis revealed overlapping age at onset, disease duration, sex distribution, and APOE ε4 allele frequencies between typical svPPA and rtvFTD but differing clinical presentations.

CONCLUSIONS: This study reports a case of typical svPPA in China associated with the ANXA11 p.D40G mutation without ALS-related features. Our findings highlight the importance of ANXA11 mutations in FTD pathogenesis.}, } @article {pmid40345258, year = {2025}, author = {Sepulveda, M and Martínez Traub, F and Ojeda, P and Perez, V and Ojeda, J and Mella, J and Diaz, R and Rozas, P and Mansilla-Jaramillo, M and Zuleta, A and Diaz, G and Kerr, B and Woehlbier, U and Henríquez, JP and Medinas, DB and Hetz, C}, title = {Expression of protein disulfide isomerase A3Q481K variant associated with amyotrophic lateral sclerosis triggers disease features in mice.}, journal = {Neurobiology of disease}, volume = {212}, number = {}, pages = {106947}, doi = {10.1016/j.nbd.2025.106947}, pmid = {40345258}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Protein Disulfide-Isomerases/genetics/metabolism ; Mice, Transgenic ; Mice ; Motor Neurons/pathology/metabolism ; Endoplasmic Reticulum Stress/genetics ; Spinal Cord/pathology/metabolism ; Humans ; Neuromuscular Junction/pathology ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motoneurons and compromised proteostasis. Dysfunction of the endoplasmic reticulum (ER) has been identified as a transversal pathogenic mechanism associated with motoneurons vulnerability in ALS. Protein disulfide isomerases (PDIs) are key enzymes catalyzing protein folding at the ER that are altered in the disease, involving biochemical and genetic perturbations. In ALS cases, we previously identified variants in the gene encoding PDIA3 (also known as Grp58 or ERp57), which were associated with altered neurite outgrowth in cell culture and abnormal motoneuron connectivity in zebrafish. Here, we report the generation of transgenic mice expressing the ALS-associated PDIA3[Q481K] variant. Moderate PDIA3[Q481K] overexpression resulted in altered motor capacity accompanied by decreased motoneuron number. The adverse effects of PDIA3[Q481K] expression were associated with induction of ER stress in the spinal cord and subtle morphological changes in neuromuscular junctions. Our results suggest that the PDIA3[Q481K] variant is likely pathogenic and its overexpression in mice recapitulate some ALS features, further supporting the concept that altered proteostasis due to PDI dysfunction may predispose an individual to develop the disease.}, } @article {pmid40346135, year = {2025}, author = {Abril, SP and Rincón-Díaz, N and Puyana, M and Castellanos, L and Ramos, FA}, title = {Photoprotective activity from Colombian Caribbean brown algae using HPLC-DAD metabolic profiling by MCR-ALS data analysis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {16204}, pmid = {40346135}, issn = {2045-2322}, support = {1101-852-69964//Ministerio de Ciencia, Tecnología e Innovación/ ; 1101-852-69964//Ministerio de Ciencia, Tecnología e Innovación/ ; 1101-852-69964//Ministerio de Ciencia, Tecnología e Innovación/ ; 1101-852-69964//Ministerio de Ciencia, Tecnología e Innovación/ ; 1101-852-69964//Ministerio de Ciencia, Tecnología e Innovación/ ; }, mesh = {Chromatography, High Pressure Liquid/methods ; *Phaeophyceae/metabolism/chemistry ; Antioxidants/pharmacology/chemistry ; *Metabolomics/methods ; Ultraviolet Rays/adverse effects ; Caribbean Region ; *Sunscreening Agents/pharmacology/chemistry ; *Metabolome ; }, abstract = {Although synthetic UV filters are widely used for skin photoprotection, growing concerns about their environmental and health impacts underscore the need for new, effective photoprotective products. This study aimed to develop a screening methodology for selecting brown macroalgae extracts with potential photoprotective activity. The approach integrates in vitro photoprotection assays, antioxidant TLC-DPPH assays, and HPLC-DAD metabolic profiling of 17 algal samples from the Dictyota, Canistrocarpus, Stypopodium, Sargassum, Lobophora, Padina, and Turbinaria genera. The results revealed concentration-dependent sun protection factor (SPF) values ranging from 0.403 to 2.915, UVA ratios (UVAr) ranging from 0.167 to 3.623, critical wavelengths (λc) ranging from 335 to 393 nm, and antioxidant DPPH-TLC activity in 10 of the evaluated extracts. These findings were correlated with the HPLC-DAD metabolic profile using the Multivariate Curve Resolution- Alternating Least Squares (MCR-ALS) algorithm and multivariate data analysis tools. Extracts from Canistrocarpus cervicornis (CCe) and Stypopodium zonale (SS) presented the most promising photoprotective activity. Through NMR and MS analysis, 2,5,7-trihydroxy-2-pentadecylchroman-4-one (1), fucoxanthin, pheophytin a, and pheophorbide a were identified as the main contributors to this activity. This methodology was successfully implemented and could be further used to screen for photoprotective activity in algal species.}, } @article {pmid40346540, year = {2025}, author = {Lombardi, I and Ferrero, C and Vulcano, E and Rasà, DM and Gelati, M and Pastor, D and Carletti, RM and de la Morena, S and Profico, DC and Longobardi, S and Lazzarino, E and Perciballi, E and Rosati, JD and Martinez, S and Vercelli, A and Vescovi, AL and Boido, M and Ferrari, D}, title = {Safety and efficacy evaluation of intracerebroventricular human neural stem cell transplantation in SOD1 mice as a novel approach for ALS.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {529}, pmid = {40346540}, issn = {1479-5876}, support = {Fondazione Revert Onlus//Fondazione Revert Onlus/ ; 2019-ATESP-0028//Università degli Studi di Milano-Bicocca/ ; Dipartimenti di Eccellenza 2023-2027 to Department of Neuroscience "Rita Levi Montalcini"//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; R24-5x1000 to Fondazione IRCCS Casa Sollievo della Sofferenza//Ministero della Salute/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/pathology/physiopathology ; *Neural Stem Cells/transplantation/cytology ; Humans ; *Superoxide Dismutase-1/metabolism ; Mice ; Disease Models, Animal ; Mice, Transgenic ; Injections, Intraventricular ; *Stem Cell Transplantation ; Treatment Outcome ; Spinal Cord/pathology ; }, abstract = {BACKGROUND: Neural stem cell (NSC) transplantation holds promising therapeutic potential for neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). However, pre-clinical studies and early-phase clinical trials have faced challenges hindering the effective clinical translation of this approach. Crucial hurdles include the side-effects of prolonged immunosuppression, concerns regarding cell origin and transplantation dosage, identification of the most appropriate therapeutic window, and invasiveness of surgical procedures. Here, we assessed the safety and efficacy of intracerebroventricular (ICV) hNSC transplantation as a novel and possibly more effective experimental approach for ALS.

METHODS: We evaluated the safety of administering up to 1 × 10[6] hNSCs in immunodeficient mice and assessed their potential efficacy in reducing ALS hallmarks employing the SOD1[G93A] mouse model. Both transient (15 days) and prolonged immunosuppression regimens, at low (15 mg/kg) and high (30 mg/kg) doses, were tested along with two different cell dosages (3 × 10[5] and 1 × 10[6]).

RESULTS: Our study suggests that: (i) a bilateral ICV transplantation of 1 × 10[6] hNSCs is safe and non-tumorigenic in immunodeficient hosts; (ii) sustained and high-dose immunosuppression is essential for ensuring cell survival in immunocompetent SOD1[G93A] mice; and (iii) hNSCs may delay motor symptom progression and reduce spinal cord microgliosis in SOD1[G93A] mice when administered in the lateral ventricles under prolonged high-dose (30 mg/kg) immunosuppression.

CONCLUSIONS: ICV transplantation of hNSCs emerges as a safe and promising strategy for ALS, demonstrating potential to delay motor decline and reduce spinal cord microgliosis. However, sustained high-dose immunosuppression is crucial for therapeutic efficacy, emphasizing the need for further optimization to overcome translational challenges and achieve durable clinical benefits.}, } @article {pmid40346885, year = {2025}, author = {Tahedl, M and Kleinerova, J and Doherty, MA and Hengeveld, JC and McLaughlin, RL and Hardiman, O and Tan, EL and Bede, P}, title = {Progressive Thalamo-Cortical Disconnection in Amyotrophic Lateral Sclerosis Genotypes: Structural Degeneration and Network Dysfunction of Thalamus-Relayed Circuits.}, journal = {European journal of neurology}, volume = {32}, number = {5}, pages = {e70146}, pmid = {40346885}, issn = {1468-1331}, support = {17/CDA/4737/SFI_/Science Foundation Ireland/Ireland ; SFI SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; HRB EIA-2017-019 & JPND-Cofund-2-2019-1/HRBI_/Health Research Board/Ireland ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/diagnostic imaging/physiopathology ; *Thalamus/pathology/diagnostic imaging/physiopathology ; Male ; Female ; Middle Aged ; Aged ; C9orf72 Protein/genetics ; Neural Pathways/pathology/diagnostic imaging/physiopathology ; Magnetic Resonance Imaging ; *Cerebral Cortex/pathology/diagnostic imaging/physiopathology ; Genotype ; Adult ; Prospective Studies ; *Nerve Net/pathology/diagnostic imaging/physiopathology ; Longitudinal Studies ; }, abstract = {BACKGROUND: The thalamus is a key subcortical hub of numerous corticobasal and corticocortical circuits mediating a wealth of cognitive, behavioural, sensory and motor processes. While thalamic pathology is increasingly recognised in amyotrophic lateral sclerosis, its degeneration is often assessed in isolation instead of adopting a network-wise perspective and assessing the integrity of its rich cortical projections.

METHODS: A prospective imaging study was conducted in a cohort of genetically stratified patients to assess the structural and functional integrity of thalamo-cortical circuits and volumetric alterations longitudinally.

RESULTS: The white matter integrity of thalamic projections to the anterior cingulate cortex, cerebellum, dorsolateral prefrontal cortex (DLPFC), Heschl's gyrus, medial frontal gyrus (MFG), orbitofrontal cortex, parietal cortex, postcentral gyrus and precentral gyrus (PreCG) is affected at baseline in ALS, which is more marked in C9orf72 hexanucleotide repeat carriers. Precentral gyrus and cerebellar grey matter volumes are also reduced, particularly in C9orf72. Longitudinal analyses capture progressive disconnection between the thalamus and frontal regions (DLPFC and MFG) in both C9orf72 positive and sporadic patients and progressive thalamo-PreCG disconnection in the sporadic C9orf72 negative cohort. Functional connectivity analyses revealed increasing thalamo-cerebellar connectivity in sporadic ALS and increasing thalamo-DLPFC connectivity in intermediate-length CAG repeat expansion carriers in ATXN2 over time.

DISCUSSION: Our data provide evidence of extensive thalamo-cortical connectivity alterations in ALS. Corticobasal circuits mediating extrapyramidal, somatosensory, cognitive and behavioural functions are increasingly affected as the disease progresses. The degeneration of thalamic projections support the conceptualisation of ALS as a 'network disease' and the notion of 'what wires together degenerates together'.}, } @article {pmid40346939, year = {2025}, author = {Santibanez, RCG and Fournier, CN}, title = {The Necessity of Overcoming Racial Disparities in Amyotrophic Lateral Sclerosis Care and Research.}, journal = {Muscle & nerve}, volume = {72}, number = {1}, pages = {5-6}, doi = {10.1002/mus.28433}, pmid = {40346939}, issn = {1097-4598}, } @article {pmid40346952, year = {2025}, author = {Çelik, F}, title = {Xenon in ALS Treatment: What Are We Waiting for?.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {5}, pages = {e70435}, pmid = {40346952}, issn = {1755-5949}, } @article {pmid40347374, year = {2025}, author = {Varshney, V and Gabble, BC and Bishoyi, AK and Varma, P and Qahtan, SA and Kashyap, A and Panigrahi, R and Nathiya, D and Chauhan, AS}, title = {Exploring Exosome-Based Approaches for Early Diagnosis and Treatment of Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {62}, number = {11}, pages = {14683-14705}, pmid = {40347374}, issn = {1559-1182}, mesh = {Humans ; *Exosomes/metabolism ; *Neurodegenerative Diseases/diagnosis/therapy/metabolism ; Early Diagnosis ; Animals ; Biomarkers/metabolism ; }, abstract = {Neurodegenerative diseases (NDs), like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), present an increasingly significant global health burden, primarily due to the lack of effective early diagnostic tools and treatments. Exosomes-nano-sized extracellular vesicles secreted by nearly all cell types-have emerged as promising candidates for both biomarkers and therapeutic agents in NDs. This review examines the biogenesis, molecular composition, and diverse functions of exosomes in NDs. Exosomes play a crucial role in mediating intercellular communication. They are capable of reflecting the biochemical state of their parent cells and have the ability to cross the blood-brain barrier (BBB). In doing so, they facilitate the propagation of pathological proteins, such as amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn), while also enabling the targeted delivery of neuroprotective compounds. Recent advancements in exosome isolation and engineering have opened up new possibilities for diagnostic and therapeutic strategies. These range from the discovery of non-invasive biomarkers to innovative approaches in gene therapy and drug delivery systems. However, challenges related to standardization, safety, and long-term effects must be addressed before exosomes can be translated into clinical applications. This review highlights both the promising potential and the obstacles that must be overcome to leverage exosomes in the treatment of NDs and the transformation of personalized medicine.}, } @article {pmid40347946, year = {2025}, author = {Blazev, R and Zee, BM and Peckham, H and Ng, YK and Lewis, CTA and Zhang, C and McNamara, JW and Goodman, CA and Gregorevic, P and Ochala, J and Steyn, FJ and Ngo, ST and Stokes, MP and Parker, BL}, title = {Site-specific quantification of the in vivo UFMylome reveals myosin modification in ALS.}, journal = {Cell reports methods}, volume = {5}, number = {5}, pages = {101048}, pmid = {40347946}, issn = {2667-2375}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; Animals ; Mice ; *Myosins/metabolism ; Muscle, Skeletal/metabolism/pathology ; Ubiquitination ; Protein Processing, Post-Translational ; *Ubiquitins/metabolism ; Mass Spectrometry ; }, abstract = {UFMylation is a ubiquitin-like protein modification of Ubiquitin Fold Modifier 1 (UFM1) applied to substrate proteins and regulates several cellular processes such as protein quality control. Here, we describe the development of an antibody-based enrichment approach to immunoprecipitate remnant UFMylated peptides and identification by mass spectrometry. We used this approach to identify >200 UFMylation sites from various mouse tissues, revealing extensive modification in skeletal muscle. In vivo knockdown of the E2 ligase, UFC1, followed by enrichment and analysis of remnant UFMylated peptides quantified concomitant down-regulation and validation of a subset of modification sites, particularly myosin UFMylation. Furthermore, we show that UFMylation is increased in skeletal muscle biopsies from people living with amyotrophic lateral sclerosis (plwALS). Quantification of UFMylation sites in these biopsies with multiplexed isotopic labeling reveal prominent increases in myosin UFMylation. Our data suggest that in vivo UFMylation is more complex than previously thought.}, } @article {pmid40348049, year = {2025}, author = {Reda, A and Khalil, H and Bahgat, EA and Fawzy, MG}, title = {Univariate versus multivariate approaches for resolving the overlapped spectra of azelastine hydrochloride and mometasone furoate.}, journal = {Analytical biochemistry}, volume = {704}, number = {}, pages = {115902}, doi = {10.1016/j.ab.2025.115902}, pmid = {40348049}, issn = {1096-0309}, mesh = {*Mometasone Furoate/analysis/chemistry ; *Phthalazines/analysis/chemistry ; Multivariate Analysis ; Principal Component Analysis ; Least-Squares Analysis ; }, abstract = {Azelastine hydrochloride (AZE) and Mometasone furoate (MOM) combination is used to treat allergic rhinitis' symptoms. The aim of this work is to qualitatively and quantitatively analyze both medications using univariate and multivariate spectrophotometric techniques in a comparative study. Regarding univariate approaches; AZE was quantified by direct measurement at 291 nm within (5-60 μg/mL) concentration range. While, MOM was assayed by absorption correction (AC) approach at 250 nm within the range of (2-18 μg/mL). The LOD values for AZE and MOM were (0.79 μg/mL) and (0.21 μg/mL), respectively. Classical least squares (CLS), partial least squares (PLS), principal component regression (PCR), multivariate curve resolution-alternating least squares (MCR-ALS) and artificial neural networks (ANN) were the applied multivariate chemometric models. The proposed methods were utilized for analyzing the binary mixture in laboratory-synthetic mixtures and pharmaceutical preparation with correlation coefficients values ≥ 0.9996. No statistically significant variation was found between the applied methods and the reported HPLC one. The methods' sustainability was assessed using blue applicability grade index (BAGI) and Red-Green-Blue 12 (RGB12) metrics. The obtained findings revealed that the suggested methodologies are safer option than the published HPLC technique for the conventional pharmaceutical analysis of the studied medications.}, } @article {pmid40348172, year = {2025}, author = {Xin, Z and Xin, C and Huo, J and Liu, Q and Dong, H and Li, X and Liu, Y and Li, R}, title = {Stage-dependent efficacy of short-chain fatty acids in amyotrophic lateral sclerosis: Insights into autophagy and neuroprotection.}, journal = {Life sciences}, volume = {374}, number = {}, pages = {123686}, doi = {10.1016/j.lfs.2025.123686}, pmid = {40348172}, issn = {1879-0631}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Animals ; *Autophagy/drug effects ; Mice ; *Fatty Acids, Volatile/pharmacology/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Superoxide Dismutase-1/metabolism/genetics ; Spinal Cord/metabolism/pathology/drug effects ; Humans ; *Neuroprotection/drug effects ; Male ; *Neuroprotective Agents/pharmacology ; Propionates/pharmacology ; Butyrates/pharmacology ; Mice, Inbred C57BL ; }, abstract = {AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited therapeutic options. Previously, we have shown that a combination of multiple probiotic strains can regulate intestinal flora, increase serum short-chain fatty acids (SCFAs), reduce abnormal protein accumulation in the spinal cord, and protect neurons. It is necessary to explore the mechanism to provide therapeutic targets for ALS.

MATERIALS AND METHODS: This study utilizes live cell imaging, mouse behavioral research, immunofluorescence, Electron microscopy, Western Blot, and polymerase chain reaction to explore the impact of various SCFAs on ALS animal and cell models, as well as their underlying mechanisms.

KEY FINDINGS: We found SCFAs, including butyrate and propionate can increase the levels of acetylated histones, enhance the expression of autophagy-related genes and regulate autophagy, leading to a decrease in abnormal SOD1 aggregation, reduction of cell damage, and enhancement of cell proliferation in NSC34-SOD1[G93A] cells. Furthermore, systemic administration of butyrate and propionate can regulate autophagy, reduce SOD1 aggregation, and protect spinal cord neurons in SOD1[G93A] mice. However, these favorable effects of butyrate and propionate are greatly decreased at later stages of the disease process in SOD1[G93A] mice.

SIGNIFICANCE: Our study revealed that the positive impact of SCFAs in autophagy could be a promising focus for ALS therapy. However, this effect might have different impacts in different stages of ALS.}, } @article {pmid40349108, year = {2025}, author = {Weiss, A and Gilbert, JW and Rivera Flores, IV and Belgrad, J and Ferguson, C and Dogan, EO and Wightman, N and Mocarski, K and Echeverria, D and Harkins, AL and Summers, A and Bramato, B and McHugh, N and Furgal, R and Yamada, N and Cooper, D and Monopoli, K and Godinho, BMDC and Hassler, MR and Yamada, K and Greer, P and Henninger, N and Brown, RH and Khvorova, A}, title = {RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {8}, pages = {3917-3938}, pmid = {40349108}, issn = {1525-0024}, support = {R01 NS104022/NS/NINDS NIH HHS/United States ; R21 NS131756/NS/NINDS NIH HHS/United States ; T32 AI095213/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/mortality/pathology/metabolism ; *Superoxide Dismutase-1/genetics/antagonists & inhibitors ; Mice ; Disease Models, Animal ; *RNA Interference ; Mice, Transgenic ; Humans ; *RNA, Small Interfering/genetics/administration & dosage ; Gene Silencing ; Motor Neurons/metabolism/pathology ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2%-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene suppression a promising approach, supported by preclinical data and the 2023 Federal Drug Administration (FDA) approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo. With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo. Administered intraventricularly, di-siRNA[SOD1] extended survival in SOD1-G93A ALS mice, increasing survival beyond that previously seen in these mice by ASO modalities, slowed disease progression according to the standard ALS preclinical endpoints, and attenuated ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders.}, } @article {pmid40349338, year = {2025}, author = {Hölbling, BV and Gupta, Y and Marchi, PM and Atilano, ML and Flower, M and Ureña, E and Goulden, RA and Dobbs, HK and Katona, E and Mikheenko, A and Giblin, A and Awan, AR and Fisher-Ward, CL and O'Brien, N and Vaizoglu, D and Kempthorne, L and Wilson, KM and Gittings, LM and Carcolé, M and Ruepp, MD and Mizielinska, S and Partridge, L and Fratta, P and Tabrizi, SJ and Selvaraj, BT and Chandran, S and Armstrong, E and Whiting, P and Isaacs, AM}, title = {A multimodal screening platform for endogenous dipeptide repeat proteins in C9orf72 patient iPSC neurons.}, journal = {Cell reports}, volume = {44}, number = {5}, pages = {115695}, doi = {10.1016/j.celrep.2025.115695}, pmid = {40349338}, issn = {2211-1247}, mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; *Neurons/metabolism ; *Dipeptides/metabolism/genetics ; Animals ; DNA Repeat Expansion ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Frontotemporal Dementia/genetics ; }, abstract = {Repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. Repeat-associated non-AUG (RAN) translation generates neurotoxic dipeptide repeat proteins (DPRs). To study endogenous DPRs, we inserted the minimal HiBiT luciferase reporter downstream of sense repeat derived DPRs polyGA or polyGP in C9orf72 patient iPSCs. We show these "DPReporter" lines sensitively and rapidly report DPR levels in lysed and live cells and optimize screening in iPSC neurons. Small-molecule screening showed the ERK1/2 activator periplocin dose dependently increases DPR levels. Consistent with this, ERK1/2 inhibition reduced DPR levels and prolonged survival in C9orf72 repeat expansion flies. CRISPR knockout screening of all human helicases revealed telomere-associated helicases modulate DPR expression, suggesting common regulation of telomeric and C9orf72 repeats. These DPReporter lines allow investigation of DPRs in their endogenous context and provide a template for studying endogenous RAN-translated proteins, at scale, in other repeat expansion disorders.}, } @article {pmid40349639, year = {2025}, author = {Maiocchi, A and Pedrini, M and Ferrari, V and Carreira, ASA and D'Amore, VM and Santoro, F and Di Porzio, A and Bosetti, M and Cristofani, R and Silvani, A and Brancaccio, D and Marinelli, L and Di Leva, FS and Provenzani, A and Poletti, A and Seneci, P}, title = {Design, synthesis and characterization of aryl bis-guanyl hydrazones as RNA binders of C9orf72 G4C2 extended repeats.}, journal = {European journal of medicinal chemistry}, volume = {293}, number = {}, pages = {117736}, doi = {10.1016/j.ejmech.2025.117736}, pmid = {40349639}, issn = {1768-3254}, mesh = {Humans ; *C9orf72 Protein/genetics/metabolism ; *Drug Design ; *Hydrazones/chemistry/pharmacology/chemical synthesis ; *RNA/metabolism/chemistry ; Structure-Activity Relationship ; G-Quadruplexes/drug effects ; Molecular Structure ; Dose-Response Relationship, Drug ; Amyotrophic Lateral Sclerosis/drug therapy/genetics ; }, abstract = {Expanded G4C2 repeats derived from mutations of the C9orf72 gene are causative factors in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, leading to multiple pathological events. Bis thiophene para dinicotinimidamide 2a was reported to preferentially stabilize G-quadruplex G4C2 RNA structures at sub-micromolar concentrations. We replaced its amidine groups with BBB-compliant guanyl hydrazones, and carried out scaffold variations to improve water solubility. An eight-membered array was built around bis-thiophene- (4b-6a), bis-oxazole- (7b), diphenylurea diamide- (8b) and phenyldioxy ditriazolephenyl scaffolds (9a,b). Biological profiling of the array identified 4b as a promising, drug-like hit, active in cellular assays on ALS patient-derived cells.}, } @article {pmid40350140, year = {2025}, author = {Amin, MA and Zehravi, M and Sweilam, SH and Shatu, MM and Durgawale, TP and Qureshi, MS and Durgapal, S and Haque, MA and Vodeti, R and Panigrahy, UP and Ahmad, I and Khan, SL and Emran, TB}, title = {Neuroprotective potential of epigallocatechin gallate in Neurodegenerative Diseases: Insights into molecular mechanisms and clinical Relevance.}, journal = {Brain research}, volume = {1860}, number = {}, pages = {149693}, doi = {10.1016/j.brainres.2025.149693}, pmid = {40350140}, issn = {1872-6240}, mesh = {Humans ; *Catechin/analogs & derivatives/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; Clinical Relevance ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis pose significant challenges due to their complex pathophysiology and lack of effective treatments. Green tea, rich in the epigallocatechin gallate (EGCG) polyphenolic component, has demonstrated potential as a neuroprotective agent with numerous medicinal applications. EGCG effectively reduces tau and Aβ aggregation in ND models, promotes autophagy, and targets key signaling pathways like Nrf2-ARE, NF-κB, and MAPK. This review explores the molecular processes that underlie EGCG's neuroprotective properties, including its ability to regulate mitochondrial dysfunction, oxidative stress, neuroinflammation, and protein misfolding. Clinical research indicates that EGCG may enhance cognitive and motor abilities, potentially inhibiting disease progression despite absorption and dose optimization limitations. The substance has been proven to slow the amyloidogenic process, prevent protein aggregation, decrease amyloid cytotoxicity, inhibit fibrillogenesis, and restructure fibrils for synergistic therapeutic effects. The review highlights the potential of EGCG as a natural, multi-targeted strategy for NDs but emphasizes the need for further clinical trials to enhance its therapeutic efficacy.}, } @article {pmid40350485, year = {2025}, author = {Rofail, D and Chladek, M and Williams, B and Patel, N and Nowell, WB and Karantzoulis, S and Levy, O}, title = {Advancing Future Amyotrophic Lateral Sclerosis Medicines by Incorporating The Patient Voice Into Patient-Centered Holistic Measurement Strategies for Clinical and Real-World Studies: Results from Targeted Literature Reviews.}, journal = {Neurology and therapy}, volume = {14}, number = {4}, pages = {1311-1343}, pmid = {40350485}, issn = {2193-8253}, abstract = {INTRODUCTION: This analysis sought to understand the patient experience in amyotrophic lateral sclerosis (ALS) and to assess whether commonly used clinical outcome assessments (COAs) reliably and validly capture that experience.

METHODS: Two targeted literature reviews were conducted to identify and describe key concepts potentially important to patients (signs, symptoms, impacts), and identify commonly used COAs in ALS. Insights gained were used to map target COAs to concepts identified as potentially relevant to patients and their caregivers. COAs of interest were further examined to evaluate evidence of their validity and reliability within ALS.

RESULTS: Forty-three articles were identified for concept extraction. Signs and symptoms were identified across multiple themes: motor; non-motor; respiratory; cognitive; and behavioral. Patient impacts were identified across multiple themes: physical; functional; emotional; social; and other aspects of well-being. Caregiver impacts were identified across four themes: general; emotional; social; and physical. Of 236 unique COAs identified, 6 were found to provide the greatest coverage of potentially important concepts. Closer examination of these showed some evidence gaps supporting content validity and/or psychometric properties.

CONCLUSIONS: Several concepts related to ALS were identified that are relevant to patients in their daily lives. We identified and reviewed COAs commonly used in assessing these concepts, and found gaps in their content validity and/or psychometric properties. These findings suggest the need for further testing/refinement of existing tools, and the opportunity to use other instruments alongside those most frequently used (e.g., ALSFRS-R) to comprehensively capture the patient experience of ALS in future clinical trial and real-world studies.}, } @article {pmid40350531, year = {2025}, author = {Woo, TG and Han, J and Kim, Y and Hwang, YJ and Lee, M and Kang, SM and Park, S and Ji, Y and Chung, YH and Baek, S and Shin, E and Minju-Kim, and Jang, H and Shin, YJ and Kwon, Y and Kim, BH and Park, BJ}, title = {Inhibition of SOD1 trimerization is a novel drug target for ALS disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {21}, pmid = {40350531}, issn = {2047-9158}, support = {RS-2024-00399681//Ministry of Science and ICT, South Korea/ ; RS-2024-00339289//Ministry of Science and ICT, South Korea/ ; RS-2023-00258714//Korea Drug Development Fund/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; *Superoxide Dismutase-1/metabolism/genetics/antagonists & inhibitors ; Animals ; Humans ; Mice ; Mice, Transgenic ; *Protein Multimerization/drug effects ; Disease Models, Animal ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that begins with motor neuron death in the spinal cord and cerebral cortex, ultimately resulting in death from respiratory distress (breathing failure). About 90% of ALS cases are sporadic, and 10% of ALS cases are of the inherited type with a genetic cause. About 150 different gene mutations have been reported so far. SOD1 is a well-identified gene associated with ALS. Indeed, SOD1 aggregation has been reported in ALS patients, but the mechanism of SOD1 aggregation remains unclear. Our previous work showed that inhibiting SOD1 aggregation with a hit compound (PRG-A-01) could reduce the SOD1-induced cytotoxicity and extend the lifespan of ALS mouse model (SOD1[G93A-Tg]). However, the low bioavailability and rapid degradation of the compound in vivo necessitates the development of a more effective candidate. We generated different derivatives and finally obtained the most potential drug candidate, PRG-A-04.

METHODS: Neuronal cell lines were transfected with the mutant SOD1 expression vector and incubated with PRG-A-04. SOD1 aggregation was examined by SOD1 oligomerization assay, immunofluorescence and dot blot assay. The interaction between GST-conjugated SOD1 recombinant proteins and PRG-A-04 was identified using LC-MS/MS and GST pull-down assay. To check the in vivo therapeutic effect of PRG-A-04, SOD1[G93A-Tg] mice were injected with PRG-A-04; then behavioral test, histological analysis and microarray were performed.

RESULTS: PRG-A-04 demonstrated favorable pharmacokinetics including high bioavailability and significant blood-brain barrier penetration. Indeed, oral administration of PRG-A-04 in ALS mouse model inhibited the aggregation of SOD1 in the spinal cord, protected against neuronal loss, and extended the lifespan of ALS mice by up to 3 weeks. In vitro, PRG-A-04 selectively bound to the mutant form of SOD1, but not the wild type, and efficiently inhibited the aggregation caused by SOD1-G147P (a SOD1 trimer stabilizer).

CONCLUSIONS: Our findings underscore the potential of targeting trimeric SOD1 in ALS treatment, positioning PRG-A-04 as a strong drug candidate for both familial and sporadic ALS.}, } @article {pmid40350633, year = {2025}, author = {Ishiura, H}, title = {[Genetics of Motor Neuron Diseases and Hereditary Spastic Paraplegia].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {5}, pages = {481-491}, doi = {10.11477/mf.188160960770050481}, pmid = {40350633}, issn = {1881-6096}, mesh = {Humans ; *Spastic Paraplegia, Hereditary/genetics/diagnosis/therapy ; *Motor Neuron Disease/genetics/diagnosis ; }, abstract = {Motor neuron diseases encompass a range of phenotypes, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), and spinal muscular atrophy (SMA). Related conditions include spinal and bulbar muscular atrophy (SBMA) and hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). Hereditary spastic paraplegia (HSP)-a group of disorders primarily affecting the corticospinal tract-also exhibits diverse clinical manifestations. This review summarizes the genetic basis of these diseases, along with their clinical characteristics, diagnostic approaches, and disease-specific therapies.}, } @article {pmid40350723, year = {2025}, author = {Kuznetsova, DR and Kutlubaev, MA and Pervushina, EV}, title = {[Oculomotor disorders in patients with amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {125}, number = {4}, pages = {7-12}, doi = {10.17116/jnevro20251250417}, pmid = {40350723}, issn = {1997-7298}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Ocular Motility Disorders/etiology/physiopathology/diagnosis ; Saccades ; Eye Movements ; }, abstract = {Oculomotor disorders are not typical manifestations of amyotrophic lateral sclerosis (ALS). Occasionally, this disease is associated with vertical gaze paresis, presenting a distinct type as «ALS+progressive supranuclear palsy». Studies using eye-tracking methods have revealed a variety of subclinical oculomotor disorders in this disease. These disorders can manifest as changes in reflex and voluntary saccades, antisaccades, smooth tracking eye movements, and fixations. A significant association between oculomotor disorders and clinical manifestations of ALS was reported. The occurrence of oculomotor disorders indicates the involvement of broader neuroanatomical structures, including the prefrontal cortex and basal ganglia. The lack of consistency in the data from different studies and their limited number emphasize the need for further research in this area.}, } @article {pmid40350993, year = {2025}, author = {Vedeler, A and Tartaglia, GG and Pastore, A}, title = {Annexin, a Protein for All Seasons: From Calcium Dependent Membrane Metabolism to RNA Recognition.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {47}, number = {7}, pages = {e70019}, pmid = {40350993}, issn = {1521-1878}, support = {ASTRA_855923//ERC / ; PNRRCN00000041andEPNRRCN3//Piano Nazionale di Ripresa e Resilienza of Italian MUR/ ; IVBM4PAP_101098989//EIC Pathfinder/ ; ARUK_PG2019B-020//ARUK / ; }, mesh = {*Annexins/metabolism/chemistry ; Humans ; *Calcium/metabolism ; Animals ; *Cell Membrane/metabolism ; *RNA/metabolism ; *RNA-Binding Proteins/metabolism ; Protein Binding ; }, abstract = {Annexins are a protein family well known to bind to phospholipids in a calcium-dependent way. They are involved in several different crucial cellular processes such as cell division, calcium signaling, membrane repair, vesicle trafficking, and apoptosis. Although RNA binding for some members of the family was reported long ago, it was only recently that it was shown that a common feature of the family is also the ability to bind RNA, a discovery that has added significantly to our perception of the cellular role of these proteins. In the present review, we discuss the properties of annexins under an updated light and the current knowledge on the RNA binding properties of annexins. We then focus specifically on annexin A11, because this is a less characterized member of the family but, at the same time, a potentially important component of the mRNA transport machinery in neurons. We hope to offer to the reader a more complete picture of the annexins' binding properties and new tools to evaluate the multifaceted functions of this important protein family.}, } @article {pmid40351442, year = {2025}, author = {Khanal, P and Chikhale, R and Machhi, J}, title = {Editorial: Targeting neuroinflammation for novel therapeutics in neurodegenerative diseases.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1602495}, doi = {10.3389/fphar.2025.1602495}, pmid = {40351442}, issn = {1663-9812}, } @article {pmid40352904, year = {2025}, author = {Quizhpilema, JC and Legarda, A and Hidalgo, JM and Lecumberri, P and Jerico, I and Cabada, T}, title = {Asymmetric white matter degeneration in amyotrophic lateral sclerosis: a diffusion kurtosis imaging study of motor and extra-motor pathways.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1581719}, pmid = {40352904}, issn = {1662-4548}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that lacks effective early biomarkers. This study investigated the potential of diffusion kurtosis imaging (DKI) as a non-invasive biomarker for detecting and monitoring ALS progression through a comprehensive analysis of white matter alterations.

METHODS: We performed a cross-sectional analysis of magnetic resonance images with advanced diffusion imaging techniques in ALS patients recruited from a neurodegenerative consultation service over a 3-year period and healthy controls. Our methodology employed multi-shell multi-tissue constrained spherical deconvolution (MSMT-CSD) for tract reconstruction and diffusion kurtosis imaging for microstructural analysis. The study focused particularly on the corticospinal tract and associated pathways, utilizing both tract-specific Bundle Analytics (BUAN) and whole-brain Tract-Based Spatial Statistics (TBSS) approaches.

RESULTS: The study included 33 ALS patients and 37 controls with no significant differences in age or gender. ALS patients predominantly presented with spinal onset and exhibited moderate functional impairment (ALSFRS-R: 39.09 ± 5). Whole-brain TBSS revealed widespread white matter alterations, with increased MD, RD, and AD, and decreased FA notably in the corona radiata, internal capsule, and corticospinal tracts. Detailed fiber tracking of the corticospinal tracts showed significant microstructural changes, with the left CST displaying pronounced increases in MD and AD alongside reduced FA, while the right CST exhibited distinctive regional variations. Additionally, analyses of the frontopontine and parietopontine tracts uncovered further alterations in diffusion metrics. Despite imaging findings, clinical-radiological correlations with functional scores and disease progression were not statistically significant.

CONCLUSIONS: This study explores DKI as a potential biomarker for ALS pathology, revealing microstructural changes in both motor and extra-motor pathways. Using whole-brain TBSS analysis and tractography with DIPY, we identified an asymmetric pattern of degeneration and involvement of integrative neural networks, providing new insights into ALS pathophysiology. These findings contribute to our understanding of the complex structural alterations in ALS and suggest that DKI-derived metrics may have utility in characterizing the disease process.}, } @article {pmid40353188, year = {2025}, author = {Liu, Y and Topsakal, M and Zheng, K and Betancourt, LE and Woods, M and Roy, S and Patra, N and Leshchev, D and Halstenberg, P and Maltsev, DS and Dai, S and Ivanov, AS and Bryantsev, VS and Wishart, JF and Gakhar, R and Frenkel, AI and Gill, SK}, title = {Correlative analysis of Ni(ii) coordination states in molten salts using a combination of X-ray and optical spectroscopies and simulations.}, journal = {Chemical science}, volume = {16}, number = {23}, pages = {10414-10423}, pmid = {40353188}, issn = {2041-6520}, abstract = {Understanding the factors that control the speciation of metal ions in molten salts is crucial for the successful deployment of molten salts in both concentrated solar power and nuclear energy applications. The speciation of the Ni(ii) ion is of interest because it is a common corrosion product, and the distribution of coordination states it occupies is highly sensitive to the molten salt matrix. We employ in situ X-ray absorption spectroscopy (XAS), optical spectroscopy, and ab initio molecular dynamics (AIMD) simulations to investigate and understand the heterogeneities of Ni(ii) coordination in LiCl-KCl, NaCl-MgCl2, and LiCl-ZnCl2 molten salt systems. The main challenge lies in identifying the population distribution of Ni(ii) coordination states as a function of temperature and melt composition. We combined the multivariate curve resolution - alternating least squares (MCR-ALS) analysis of the XAS data and principal component analysis (PCA) of the optical spectra to determine the number of unique coordination states coexisting in the molten state, extract X-ray spectra for each state, and obtain their mixing fractions at different temperatures and for different salt mixtures. AIMD simulations were essential in identifying the coordination states corresponding to the deconvoluted spectra. The differences in the coordination states of Ni(ii) in different salt systems are discussed in terms of the effects of the varying polarizing powers of the cations in the host salt matrix on chloride ion coordination to Ni(ii). Such elucidation of the local structure adopted by metal ions enables a better understanding of the factors controlling the speciation of ions and their effect on molten salt properties.}, } @article {pmid40353466, year = {2025}, author = {Dhasmana, S and Dhasmana, A and Khan, S and Narula, AS and Haque, S and Yallapu, MM and Chauhan, SC}, title = {Excessive Urinary p75ecd is a Potential Indicator of Amyotrophic Lateral Sclerosis: An American Cohort Study.}, journal = {Current neuropharmacology}, volume = {23}, number = {12}, pages = {1621-1630}, pmid = {40353466}, issn = {1875-6190}, support = {U54 MD019970/MD/NIMHD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/urine/diagnosis ; Male ; Female ; Middle Aged ; Biomarkers/urine ; Cohort Studies ; Aged ; Adult ; Neurofilament Proteins/urine ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, and rapidly progressive neurodegenerative disease. At present, neurofilament light (NFL) and phosphorylated neurofilament heavy (pNfH) proteins in biological fluids are commonly known prognostic biomarkers, but their levels stabilize over time. Thus, there is a critical gap in the field to identify unique biomarkers that can aid disease diagnosis, progression and monitoring the therapy response.

AIMS: To evaluate the presence of extracellular domain of p75 (p75ecd) in urine of ALS patients and healthy control volunteers in the North American cohort.

METHODS: An enzyme-linked immunoassay (ELISA) and creatinine assay was used to determine the levels of p75ecd and creatinine in the urine of ALS patients and healthy control volunteers respectively. This assay demonstrated clear discrimination in the levels of the p75ecd in the urine samples of ALS patients as compared to healthy individuals.

RESULTS: It was found that the concentration of p75ecd in ALS samples was significantly higher than that of healthy controls group. Additionally, high p75ecd levels were segregated with respect to age, sex, family history, occupation and drug treatment, medication status. Moreover, we observed differential expression patterns among the different stages of the disease. Our results followed the pattern that was observed in the Chinese, and Australian cohort. c Conclusion: Altogether, our results indicate that the development of an efficient system for the detection of elevated levels of p75ecd in the urine could serve as a useful modality for early ALS diagnosis, disease progression, and monitoring the effectiveness of therapeutic interventions.}, } @article {pmid40353906, year = {2025}, author = {Kleinerova, J and Querin, G and Pradat, PF and Siah, WF and Bede, P}, title = {New developments in imaging in ALS.}, journal = {Journal of neurology}, volume = {272}, number = {6}, pages = {392}, pmid = {40353906}, issn = {1432-1459}, support = {JPND-Cofund-2-2019-1/HRBI_/Health Research Board/Ireland ; HRB EIA-2017-019/HRBI_/Health Research Board/Ireland ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; *Neuroimaging/methods/trends ; *Brain/diagnostic imaging ; Magnetic Resonance Imaging ; }, abstract = {Neuroimaging in ALS has contributed considerable academic insights in recent years demonstrating genotype-specific topological changes decades before phenoconversion and characterising longitudinal propagation patterns in specific phenotypes. It has elucidated the radiological underpinnings of specific clinical phenomena such as pseudobulbar affect, apathy, behavioural change, spasticity, and language deficits. Academic concepts such as sexual dimorphism, motor reserve, cognitive reserve, adaptive changes, connectivity-based propagation, pathological stages, and compensatory mechanisms have also been evaluated by imaging. The underpinnings of extra-motor manifestations such as cerebellar, sensory, extrapyramidal and cognitive symptoms have been studied by purpose-designed imaging protocols. Clustering approaches have been implemented to uncover radiologically distinct disease subtypes and machine-learning models have been piloted to accurately classify individual patients into relevant diagnostic, phenotypic, and prognostic categories. Prediction models have been developed for survival in symptomatic patients and phenoconversion in asymptomatic mutation carriers. A range of novel imaging modalities have been implemented and 7 Tesla MRI platforms are increasingly being used in ALS studies. Non-ALS MND conditions, such as PLS, SBMA, and SMA, are now also being increasingly studied by quantitative neuroimaging approaches. A unifying theme of recent imaging papers is the departure from describing focal brain changes to focusing on dynamic structural and functional connectivity alterations. Progressive cortico-cortical, cortico-basal, cortico-cerebellar, cortico-bulbar, and cortico-spinal disconnection has been consistently demonstrated by recent studies and recognised as the primary driver of clinical decline. These studies have led the reconceptualisation of ALS as a "network" or "circuitry disease".}, } @article {pmid40354780, year = {2025}, author = {Delivoria, DC and Konia, E and Matis, I and Skretas, G}, title = {Optimization of a High-Throughput Screen for Monitoring Disease-Associated Protein Misfolding and Aggregation in Bacteria.}, journal = {ACS synthetic biology}, volume = {14}, number = {6}, pages = {2283-2293}, pmid = {40354780}, issn = {2161-5063}, mesh = {Humans ; *Escherichia coli/metabolism/genetics ; Protein Folding ; *High-Throughput Screening Assays/methods ; Green Fluorescent Proteins/genetics/metabolism ; Protein Aggregates ; Tumor Suppressor Protein p53/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Amyloid beta-Peptides/metabolism/genetics ; }, abstract = {Protein misfolding and aggregation are central features of a wide range of diseases, including neurodegenerative disorders, systemic amyloidoses, and cancer. The identification of compounds that can modulate protein folding and aggregation is a key step toward developing effective therapies. High-throughput screening methods are essential for efficiently identifying such compounds. In this study, we optimized a previously developed high-throughput genetic screen for monitoring protein misfolding and aggregation in bacteria. This system is based on monitoring the fluorescence of Escherichia coli cells expressing fusions of human misfolding-prone and disease-related proteins (MisPs) with the green fluorescent protein. We systematically tested a variety of experimental conditions, such as overexpression conditions and MisP-GFP fusion formats, to identify key parameters that affect the sensitivity and dynamic range of the assay. Using misfolding-prone, cancer-associated variants of human p53 as a model system, we found that strong overexpression conditions, such as high copy number vectors, strong promoters, high inducer concentrations, and high overexpression temperatures, can yield optimal assay performance. These optimized assay conditions were also validated with additional MisPs, such as the Alzheimer's disease-associated amyloid-β peptide and variants of superoxide dismutase 1 associated with amyotrophic lateral sclerosis. At the same time, we observed that certain conditions, such as inducer concentrations and overexpression temperature, may need to be precisely fine-tuned for each new MisP target to yield optimal assay performance. Our findings provide a framework for standardizing MisP-GFP screening assays, facilitating their broad application in the discovery of therapeutic agents targeting protein misfolding and aggregation.}, } @article {pmid40354799, year = {2025}, author = {Bensimon, G and Leigh, PN and Tree, T and Malaspina, A and Payan, CA and Pham, HP and Klaassen, P and Shaw, PJ and Al Khleifat, A and Amador, MDM and Attarian, S and Bell, SM and Beltran, S and Bernard, E and Camu, W and Corcia, P and Corvol, JC and Couratier, P and Danel, V and Debs, R and Desnuelle, C and Dimitriou, A and Ealing, J and Esselin, F and Fleury, MC and Gorrie, GH and Grapperon, AM and Hesters, A and Juntas-Morales, R and Kolev, I and Lautrette, G and Le Forestier, N and McDermott, CJ and Pageot, N and Salachas, F and Sharma, N and Soriani, MH and Sreedharan, J and Svahn, J and Verber, N and Verschueren, A and Yildiz, O and Suehs, CM and Saker-Delye, S and Muller, C and Masseguin, C and Hajduchova, H and Kirby, J and Garlanda, C and Locati, M and Zetterberg, H and Asselain, B and Al-Chalabi, A and , }, title = {Efficacy and safety of low-dose IL-2 as an add-on therapy to riluzole (MIROCALS): a phase 2b, double-blind, randomised, placebo-controlled trial.}, journal = {Lancet (London, England)}, volume = {405}, number = {10492}, pages = {1837-1850}, doi = {10.1016/S0140-6736(25)00262-4}, pmid = {40354799}, issn = {1474-547X}, mesh = {Humans ; Female ; Male ; *Riluzole/administration & dosage/therapeutic use/adverse effects ; Middle Aged ; Double-Blind Method ; *Amyotrophic Lateral Sclerosis/drug therapy/mortality ; Adult ; Aged ; *Interleukin-2/administration & dosage/adverse effects/therapeutic use ; *Neuroprotective Agents/administration & dosage/therapeutic use/adverse effects ; Treatment Outcome ; Drug Therapy, Combination ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a life-threatening disease characterised by progressive loss of motor neurons with few therapeutic options. The MIROCALS study tested the hypothesis that low-dose interleukin-2 (IL-2LD) improves survival and function in ALS.

METHODS: In this randomised, double-blind, placebo-controlled trial, male and female riluzole-naive participants, with either a possible, laboratory-supported probable, probable, or definite ALS diagnosis (revised El Escorial criteria), aged 18-76 years, with symptom duration of 24 months or fewer, and slow vital capacity of 70% or more, underwent a riluzole-only 12-18 week run-in period before randomisation in a 1:1 ratio to either 2 million international units (MIU) IL-2LD or placebo by subcutaneous injection daily for 5 days every 28 days over 18 months. The primary endpoint was survival at 640 days (21 months). Secondary outcomes included safety, ALS Functional Rating Scale-Revised (ALSFRS-R) score, and biomarker measurements including regulatory T-cells (Tregs), cerebrospinal fluid (CSF)-phosphorylated-neurofilament heavy-chain (CSF-pNFH), and plasma and CSF-chemokine ligand 2 (CCL2). The primary endpoint analysis used unadjusted log-rank and Cox's model adjusted analyses using pre-defined prognostic covariates to control for the disease and treatment response heterogeneity. The study was 80% powered to detect a two-fold decrease in the risk of death by the log-rank test in the intention-to-treat (ITT) population, including all randomly allocated participants. MIROCALS is registered with ClinicalTrials.gov (NCT03039673) and is complete.

FINDINGS: From June 19, 2017, to Oct 16, 2019, 304 participants were screened, of whom 220 (72%) met all criteria for random allocation after the 12-to-18-week run-in period on riluzole. 136 (62%) of participants were male and 84 participants (38%) were female. 25 (11%) of the 220 randomly allocated participants were defined as having possible ALS under El Escorial criteria. At the cutoff date there was no loss to follow-up, and all 220 patients who were randomly allocated were documented as either deceased (90 [41%]) or alive (130 [59%]), so all participants were included in the ITT and safety populations. The primary endpoint unadjusted analysis showed a non-significant 19% decrease in risk of death with IL-2LD (hazard ratio 0·81 [95% CI 0·54-1·22], p=0·33), failing to demonstrate the expected two-fold decrease in risk of death. The analysis of the primary endpoint adjusted on prognostic covariates, all measured at time of random allocation, showed a significant decrease of the risk of death with IL-2LD (0·32 [0·14-0·73], p=0·007), with a significant treatment by CSF-pNFH interaction (1·0003 [1·0001-1·0005], p=0·001). IL-2LD was safe, and significantly increased Tregs and decreased plasma-CCL2 at all timepoints. Stratification on CSF-pNFH levels measured at random allocation showed that IL-2LD was associated with a significant 48% decrease in risk of death (0·52 [0·30-0·89], p=0·016) in the 70% of the population with low (750-3700 pg/mL) CSF-pNFH levels, while in the 21% with high levels (>3700 pg/mL), there was no significant difference (1·37 [0·68-2·75], p=0·38).

INTERPRETATION: With this treatment schedule, IL-2LD resulted in a non-significant reduction in mortality in the primary unadjusted analysis. However, the difference between the results of unadjusted and adjusted analyses of the primary endpoint emphasises the importance of controlling for disease heterogeneity in ALS randomised controlled trials. The decrease in risk of death achieved by IL-2LD therapy in the trial population with low CSF-pNFH levels requires further investigation of the potential benefit of this therapy in ALS.

FUNDING: European Commission H2020 Programme; French Health Ministry PHRC2014; and Motor Neurone Disease Association.}, } @article {pmid40354800, year = {2025}, author = {Benatar, M and McDermott, MP}, title = {Examining the evidence for IL-2 in amyotrophic lateral sclerosis.}, journal = {Lancet (London, England)}, volume = {405}, number = {10492}, pages = {1793-1795}, doi = {10.1016/S0140-6736(25)00901-8}, pmid = {40354800}, issn = {1474-547X}, } @article {pmid40355001, year = {2025}, author = {Ognard, J and El Hajj, G and Verma, O and Ghozy, S and Kadirvel, R and Kallmes, DF and Brinjikji, W}, title = {Advances in endovascular brain computer interface: Systematic review and future implications.}, journal = {Journal of neuroscience methods}, volume = {420}, number = {}, pages = {110471}, doi = {10.1016/j.jneumeth.2025.110471}, pmid = {40355001}, issn = {1872-678X}, mesh = {*Brain-Computer Interfaces/trends ; Animals ; Humans ; *Endovascular Procedures/methods/trends ; *Brain/physiology ; Electrodes, Implanted ; }, abstract = {BACKGROUND: Brain-computer interfaces (BCIs) translate neural activity into real-world commands. While traditional invasive BCIs necessitate craniotomy, endovascular BCIs offer a minimally invasive alternative using the venous system for electrode placement.

NEW METHOD: This systematic review evaluates the technical feasibility, safety, and clinical outcomes of endovascular BCIs, discussing their future implications. A systematic review was conducted per PRISMA guidelines. The search spanned PubMed, Web of Science, and Scopus databases using keywords related to neural interfaces and endovascular approaches. Studies were included if they reported on endovascular BCIs in preclinical or clinical settings. Dual independent screening and extraction focused on electrode material, recording capabilities, safety parameters, and clinical efficacy.

RESULTS: From 1385 initial publications, 26 met the inclusion criteria. Seventeen studies investigated the Stentrode device. Among the 24 preclinical studies, 16 used ovine or rodent models, and 9 addressed engineering or simulation aspects. Two clinical studies reported six ALS patients successfully using an endovascular BCI for digital communication. Preclinical data established the endovascular ovine model, demonstrating stable neural recordings and vascular changes with long-term implantation. Key challenges include thrombosis risk, long-term electrode stability, and anatomical variability.

Endovascular BCI reduced invasiveness, improved safety profiles, with comparable neural recording fidelity to invasive methods, and promising preliminary clinical outcomes in severely paralyzed patients.

CONCLUSIONS: Early results are promising, but clinical data remain scarce. Further research is needed to optimize signal processing, enhance electrode biocompatibility, and refine endovascular procedures for broader clinical applications.}, } @article {pmid40355776, year = {2025}, author = {Hirose, S and Kobatake, Y and Tada, N and Kandeel, M and Itoh, A and Oh-Hashi, K}, title = {NanoBiT-based Analysis of Canine SOD1 Protein Dynamics: Understanding the Role of CCS and Ebselen Derivatives as Potential Therapeutics for Canine Degenerative Myelopathy.}, journal = {Cell biochemistry and biophysics}, volume = {83}, number = {3}, pages = {3945-3958}, pmid = {40355776}, issn = {1559-0283}, support = {KFU241899//Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University/ ; }, mesh = {Dogs ; Isoindoles ; *Organoselenium Compounds/chemistry/pharmacology/therapeutic use/metabolism ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; Animals ; *Azoles/chemistry/pharmacology/therapeutic use/metabolism ; Molecular Docking Simulation ; *Spinal Cord Diseases/drug therapy/veterinary/metabolism ; Mutation ; Humans ; Amyotrophic Lateral Sclerosis/drug therapy ; }, abstract = {Canine degenerative myelopathy (DM) is a progressive neurodegenerative disorder that shares common pathological features with amyotrophic lateral sclerosis (ALS) in humans. Both diseases are linked to mutations in the superoxide dismutase 1 (SOD1) gene. Understanding the molecular differences between wild-type (WT) and mutant SOD1 proteins is critical for developing therapeutic strategies. In this study, we employed the NanoLuc complementation (NanoBiT) reporter system to investigate the expression and functional differences between WT and E40K mutant canine SOD1 to assess the therapeutic potential of copper chaperone for SOD1 (CCS) and ebselen derivatives. E40K cSOD1 displayed significantly reduced luciferase activity compared to WT cSOD1 in all NanoBiT-tagged combinations, indicating altered homodimerization and protein stability. Co-transfection with CCS increased both WT and mutant cSOD1 protein levels and reporter activities, with a more pronounced effect on the E40K mutant. Ebselen treatment enhanced luciferase activity, particularly in E40K cSOD1-expressing cells. Two compounds (compounds 2 and 5) were stronger than the parent compound in improving mutant cSOD1-derived NanoBiT activities. Additionally, molecular docking simulations revealed stronger binding affinities of ebselen and its derivatives to E40K cSOD1, suggesting potential therapeutic benefits. In conclusion, the NanoLuc reporter system offers a valuable tool for screening potential therapeutics for SOD1-linked neurodegenerative diseases. CCS and ebselen derivatives exhibited promising effects on SOD1 activity, providing a basis for future therapeutic strategies targeting both DM and ALS.}, } @article {pmid40356623, year = {2025}, author = {Mori, S and Zhou, H and Omura, T and Tsumoto, H and Miura, Y and Shigemoto, K}, title = {Muscle-specific kinase levels in blood are an early diagnostic biomarker for SOD1-93A mouse model of ALS.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1556120}, pmid = {40356623}, issn = {1664-2295}, abstract = {Neuromuscular junction (NMJ) denervation is an early event preceding motor neuron loss in amyotrophic lateral sclerosis (ALS). Progressive loss of the NMJ leads to irreversible muscle weakness and atrophy. Muscle-specific kinase (MuSK), locally expressed at the postsynaptic membrane of the NMJ, is activated by agrin released from motor nerve terminals and is essential for NMJ maintenance and regeneration. Here, we found that the progression of NMJ denervation prior to the onset of muscle weakness in SOD1-93A mouse model of ALS correlated with increased serum MuSK immunoreactivity and elevated MuSK expression throughout the skeletal muscle. Our results suggest that neuromuscular failure associated with the onset of muscle weakness increases MuSK expression throughout the muscle, which is subsequently cleaved by proteolytic enzymes to increase MuSK immunoreactivity in the blood. These results demonstrate that the level of serum MuSK immunoreactivity may indicate the early phase of NMJ denervation and serve as a biomarker for assessing the progression of other types of ALS and therapeutic benefits in preclinical studies.}, } @article {pmid40358443, year = {2025}, author = {Choi, SJ and Kim, JS and Jeong, SY and Son, H and Sung, JJ and Park, CM and Choi, KS}, title = {Association of Deep Learning-based Chest CT-derived Respiratory Parameters with Disease Progression in Amyotrophic Lateral Sclerosis.}, journal = {Radiology}, volume = {315}, number = {2}, pages = {e243463}, doi = {10.1148/radiol.243463}, pmid = {40358443}, issn = {1527-1315}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/mortality ; Male ; Female ; Retrospective Studies ; Aged ; *Deep Learning ; Disease Progression ; *Tomography, X-Ray Computed/methods ; Middle Aged ; Vital Capacity ; Lung/diagnostic imaging/physiopathology ; Respiratory Muscles/diagnostic imaging/physiopathology ; }, abstract = {Background Forced vital capacity (FVC) is a standard measure of respiratory function in patients with amyotrophic lateral sclerosis (ALS) but has limitations, particularly for patients with bulbar impairment. Purpose To determine the value of deep learning-based chest CT-derived respiratory parameters in predicting ALS progression and survival. Materials and Methods This retrospective study included patients with ALS diagnosed between January 2010 and July 2023 who underwent chest CT at a tertiary hospital. Deep learning-based software was used to measure lung and respiratory muscle volume, normalized for height as the lung volume index (LVI) and respiratory muscle index (RMI). Differences in these parameters across King clinical stages were assessed using ordinal logistic regression. Tracheostomy-free survival was evaluated using Cox regression and time-dependent receiver operating characteristic analysis. Subgroup analysis was conducted for patients with bulbar impairment. In addition, a Gaussian process regressor model was developed to estimate FVC based on lung volume, respiratory muscle volume, age, and sex. Results A total of 261 patients were included in the study (mean age, 65.2 years ± 11.9 [SD]; 156 male patients). LVI and RMI decreased with increasing King stage (both P < .001). The high LVI and high RMI groups had better survival (both P < .001). After adjustment, LVI (hazard ratio [HR] = 0.998 [95% CI: 0.996, 1.000]; P = .021) and RMI (HR = 0.992 [95% CI: 0.988, 0.996]; P < .001) remained independent prognostic factors. In patients with bulbar impairment, LVI (HR = 0.998 [95% CI: 0.996, 1.000]; P = .029) and RMI (HR = 0.991 [95% CI: 0.987, 0.996]; P < .001) were independent prognostic factors. Time-dependent receiver operating characteristic curve analysis revealed no significant differences in survival prediction performance among LVI, RMI, and FVC. The Gaussian process regressor model estimated FVC with approximately 8% error. Conclusion The deep learning-derived CT metrics LVI and RMI reflected ALS stage, enabled FVC prediction, and supported assessment in patients with limited respiratory function. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Rahsepar and Bedayat in this issue.}, } @article {pmid40358451, year = {2025}, author = {Rahsepar, AA and Bedayat, A}, title = {Beyond Spirometry: AI-Driven Chest CT Analysis, a New Frontier in Monitoring Amyotrophic Lateral Sclerosis.}, journal = {Radiology}, volume = {315}, number = {2}, pages = {e250988}, doi = {10.1148/radiol.250988}, pmid = {40358451}, issn = {1527-1315}, } @article {pmid40360159, year = {2025}, author = {Li, Z and Li, Y and Zhao, J and Zhang, F and Dang, W and Jia, Y and Guo, F and Guo, L}, title = {Association among blood pressure, antihypertensive drugs, and amyotrophic lateral sclerosis.}, journal = {Arquivos de neuro-psiquiatria}, volume = {83}, number = {5}, pages = {1-8}, pmid = {40360159}, issn = {1678-4227}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/etiology/prevention & control ; *Antihypertensive Agents/therapeutic use ; *Blood Pressure/drug effects/genetics ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Hypertension/drug therapy/genetics/complications ; Risk Factors ; Male ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Female ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease. The impacts of antihypertensive drugs and blood pressure (BP) on ALS are currently debatable.

OBJECTIVE: To evaluate the causal relationship involving antihypertensive drugs, BP, and ALS through a Mendelian randomization (MR) analysis.

METHODS: The causal relationship between BP and ALS was evaluated by a bidirectional two-sample MR analysis. Then, a sensitivity analysis was performed using a secondary BP genome-wide association study. The drug-target MR was employed to evaluate the impact of antihypertensive drugs on ALS. Furthermore, we used cis-expression quantitative trait loci (cis-eQTLs) data from brain tissue and blood to validate the positive results by a summary-based MR method.

RESULTS: We found that an increment in systolic BP (SBP) could elevate the risk of ALS (inverse-variance weighted [IVW] odds ratio [OR] = 1.003; 95% confidence interval [95%CI]: 1.001-1.006; per 10-mmHg increment) and ALS might be protected by angiotensin-converting enzyme inhibitors (ACEIs; OR = 0.970; 95%CI: 0.956-0.984; p = 1.96 × 10[-5]; per 10-mmHg decrement). A causal relationship was not observed between diastolic BP and other antihypertensive drugs in ALS.

CONCLUSION: In the present study, genetic support for elevated SBP serves as a risk factor for ALS. Besides, ACEIs hold promise as a candidate for ALS.}, } @article {pmid40360341, year = {2025}, author = {Lin, W and Huang, C and Tan, Z and Xu, H and Wei, W and Wang, L}, title = {Cu[II]-bis(thioureido) Complex: A Potential Radiotracer for Detecting Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases.}, journal = {Seminars in nuclear medicine}, volume = {55}, number = {4}, pages = {577-586}, doi = {10.1053/j.semnuclmed.2025.03.008}, pmid = {40360341}, issn = {1558-4623}, mesh = {Humans ; *Oxidative Stress ; *Neurodegenerative Diseases/diagnostic imaging/metabolism/complications ; Animals ; *Copper/chemistry ; *Neuroinflammatory Diseases/diagnostic imaging/metabolism/complications ; Positron-Emission Tomography ; Radioactive Tracers ; *Thiosemicarbazones/chemistry ; }, abstract = {Neurodegenerative diseases, characterized by progressive neuronal degeneration and associated with neuroinflammation and oxidative stress, present significant challenges in diagnosis and treatment. This review explores the potential of copper(II)-bis(thiosemicarbazone) complexes, particularly Cu-ATSM, as a dual-purpose radiopharmaceutical for imaging and therapeutic interventions. Cu-ATSM exhibits unique redox-dependent retention in pathological microenvironments, driven by mitochondrial dysfunction and hyper-reductive states, which enables the noninvasive detection of oxidative stress via positron emission tomography (PET). Preclinical studies demonstrate its efficacy in mitigating neuroinflammation by suppressing glial activation, reducing the secretion of pro-inflammatory cytokines (e.g., TNF-α, MCP-1), and increasing the expression of neuroprotective metallothionein-1 (MT1). Some Clinical research reveals elevated [64]Cu-ATSM uptake in Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) patients, correlating with disease severity and regional oxidative stress markers. Furthermore, Cu-ATSM derivatives show promise in modulating blood-brain barrier (BBB) permeability, enhancing amyloid-β clearance, and restoring copper homeostasis in ALS models. Despite these advances, limitations such as small cohort sizes and heterogeneity in clinical studies underscore the need for larger-scale validation. Multimodal imaging integrating PET and MRI, alongside novel structural analogs targeting Aβ plaques and redox imbalances, emerges as a strategic direction for future research. Collectively, Cu-ATSM represents a transformative tool for elucidating neuropathological mechanisms and advancing therapeutic strategies in neurodegenerative disorders.}, } @article {pmid40362304, year = {2025}, author = {Shiryaeva, O and Tolochko, C and Alekseeva, T and Dyachuk, V}, title = {Targets and Gene Therapy of ALS (Part 1).}, journal = {International journal of molecular sciences}, volume = {26}, number = {9}, pages = {}, pmid = {40362304}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics/pathology ; *Genetic Therapy/methods ; Animals ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; Mutation ; Gene Editing ; RNA-Binding Protein FUS/genetics ; Oligonucleotides, Antisense/therapeutic use ; CRISPR-Cas Systems ; DNA-Binding Proteins/genetics ; RNA Interference ; MicroRNAs/genetics ; Disease Models, Animal ; RNA, Small Interfering/genetics ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons, which causes muscle atrophy. Genetic forms of ALS are recorded only in 10% of cases. However, over the past decade, studies in genetics have substantially contributed to our understanding of the molecular mechanisms underlying ALS. The identification of key mutations such as SOD1, C9orf72, FUS, and TARDBP has led to the development of targeted therapy that is gradually being introduced into clinical trials, opening up a broad range of opportunities for correcting these mutations. In this review, we aimed to present an extensive overview of the currently known mechanisms of motor neuron degeneration associated with mutations in these genes and also the gene therapy methods for inhibiting the expression of their mutant proteins. Among these, antisense oligonucleotides, RNA interference (siRNA and miRNA), and gene-editing (CRISPR/Cas9) methods are of particular interest. Each has shown its efficacy in animal models when targeting mutant genes, whereas some of them have proven to be efficient in human clinical trials.}, } @article {pmid40362464, year = {2025}, author = {Yapici, I and Tokur, AG and Sever, B and Ciftci, H and Basak, AN and DeMirci, H}, title = {Structural Insights into the Dynamics of Water in SOD1 Catalysis and Drug Interactions.}, journal = {International journal of molecular sciences}, volume = {26}, number = {9}, pages = {}, pmid = {40362464}, issn = {1422-0067}, support = {122Z429//Scientific and Technological Research Council of Turkey (TÜBİTAK)/ ; 101061939//European Union's Horizon Europe research and innovation programme under the Marie Sktodowska-Curie grant agreement/ ; }, mesh = {*Superoxide Dismutase-1/chemistry/metabolism/antagonists & inhibitors/genetics ; *Water/chemistry/metabolism ; Humans ; Molecular Docking Simulation ; Catalytic Domain ; Hydrogen Bonding ; Catalysis ; Molecular Dynamics Simulation ; Amyotrophic Lateral Sclerosis/drug therapy ; Crystallography, X-Ray ; Protein Conformation ; }, abstract = {Superoxide dismutase 1 (SOD1) is a crucial enzyme that protects cells from oxidative damage by converting superoxide radicals into H2O2 and O2. This detoxification process, essential for cellular homeostasis, relies on a precisely orchestrated catalytic mechanism involving the copper cation, while the zinc cation contributes to the structural integrity of the enzyme. This study presents the 2.3 Å crystal structure of human SOD1 (PDB ID: 9IYK), revealing an assembly of six homodimers and twelve distinct active sites. The water molecules form a complex hydrogen-bonding network that drives proton transfer and sustains active site dynamics. Our structure also uncovers subtle conformational changes that highlight the intrinsic flexibility of SOD1, which is essential for its function. Additionally, we observe how these dynamic structural features may be linked to pathological mutations associated with amyotrophic lateral sclerosis (ALS). By advancing our understanding of hSOD1's mechanistic intricacies and the influence of water coordination, this study offers valuable insights for developing therapeutic strategies targeting ALS. Our structure's unique conformations and active site interactions illuminate new facets of hSOD1 function, underscoring the critical role of structural dynamics in enzyme catalysis. Moreover, we conducted a molecular docking analysis using SOD1 for potential radical scavengers and Abelson non-receptor tyrosine kinase (c-Abl, Abl1) inhibitors targeting misfolded SOD1 aggregation along with oxidative stress and apoptosis, respectively. The results showed that CHEMBL1075867, a free radical scavenger derivative, showed the most promising docking results and interactions at the binding site of hSOD1, highlighting its promising role for further studies against SOD1-mediated ALS.}, } @article {pmid40362512, year = {2025}, author = {Chong, ZZ and Souayah, N}, title = {Targeting Gene C9orf72 Pathogenesis for Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {26}, number = {9}, pages = {}, pmid = {40362512}, issn = {1422-0067}, mesh = {*C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/therapy ; Humans ; DNA Repeat Expansion ; Animals ; Mutation ; Autophagy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal adult neurodegenerative disorder. Since no cure has been found, finding effective therapeutic targets for ALS remains a major challenge. Gene C9orf72 mutations with the formation of hexanucleotide repeat (GGGGCC) expansion (HRE) have been considered the most common genetic pathogenesis of ALS. The literature review indicates that the C9orf72 HRE causes both the gain-of-function toxicity and loss of function of C9ORF72. The formation of RNA foci and dipeptide repeats (DPRs) resulting from HRE is responsible for toxic function gain. The RNA foci can interfere with RNA processing, while DPRs directly bind to and sequester associated proteins to disrupt processes of rRNA synthesis, mRNA translation, autophagy, and nucleocytoplasmic transport. The mutations of C9orf72 and HRE result in the loss of functional C9ORF72. Under physiological conditions, C9ORF72 binds to Smith-Magenis chromosome region 8 and WD repeat-containing protein and forms a protein complex. Loss of C9ORF72 leads to autophagic impairment, increased oxidative stress, nucleocytoplasmic transport impairment, and inflammatory response. The attempted treatments for ALS have been tried by targeting C9orf72 HRE; however, the outcomes are far from satisfactory yet. More studies should be performed on pharmacological and molecular modulators against C9orf72 HRE to evaluate their efficacy by targeting HRE.}, } @article {pmid40362582, year = {2025}, author = {Kitaoka, Y and Uchihashi, T and Kawata, S and Nishiura, A and Yamamoto, T and Hiraoka, SI and Yokota, Y and Isomura, ET and Kogo, M and Tanaka, S and Spigelman, I and Seki, S}, title = {Role and Potential of Artificial Intelligence in Biomarker Discovery and Development of Treatment Strategies for Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {26}, number = {9}, pages = {}, pmid = {40362582}, issn = {1422-0067}, support = {24K13154//Japan Society for the Promotion of Science/ ; 21K10091//Japan Society for the Promotion of Science/ ; 24K13113//Japan Society for the Promotion of Science/ ; 23K09351//Japan Society for the Promotion of Science/ ; 24K13112//Japan Society for the Promotion of Science/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis/metabolism ; Humans ; *Biomarkers/metabolism ; *Artificial Intelligence ; Proteomics/methods ; Neuroimaging/methods ; Deep Learning ; }, abstract = {Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), present significant challenges owing to their complex pathologies and a lack of curative treatments. Early detection and reliable biomarkers are critical but remain elusive. Artificial intelligence (AI) has emerged as a transformative tool, enabling advancements in biomarker discovery, diagnostic accuracy, and therapeutic development. From optimizing clinical-trial designs to leveraging omics and neuroimaging data, AI facilitates understanding of disease and treatment innovation. Notably, technologies such as AlphaFold and deep learning models have revolutionized proteomics and neuroimaging, offering unprecedented insights into ALS pathophysiology. This review highlights the intersection of AI and ALS, exploring the current state of progress and future therapeutic prospects.}, } @article {pmid40362586, year = {2025}, author = {Zhang, R and Azhir, A and McGrath, MS}, title = {Respiratory Function Improvement and Lifespan Extension Following Immunotherapy with NP001 Support the Concept That Amyotrophic Lateral Sclerosis (ALS) Is an Immuno-Neurologic Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {9}, pages = {}, pmid = {40362586}, issn = {1422-0067}, support = {Neuvivo-NP001//Neuvivo, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/drug therapy/physiopathology/mortality/therapy ; Middle Aged ; Male ; Female ; Aged ; *Immunotherapy/methods ; Body Mass Index ; Adult ; Vital Capacity/drug effects ; Immunity, Innate/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease that involves progressive loss of voluntary muscle and ultimately, respiratory function, which is the primary cause of death in ALS patients. Respiratory vital capacity (VC) measurements are objective, reproducible, and directly related to survival. Respiratory function is known to be negatively affected in individuals with excess abdominal fat contributing to a chronic innate immune inflammatory state. To test whether ALS patients might have a body mass index (BMI) related VC response to the innate immune system regulator NP001, clinical results from two NP001 phase 2 trials were evaluated in an intent-to-treat manner, stratified by BMI measurements. Slowing of progressive VC loss and extension of overall survival (OS) occurred primarily in ALS patients who were overweight with a BMI ≥ 25 (70% of patients in the phase 2 trials). Innate immune dysfunction is a characteristic of ALS patients ≤ 65 years of age, and in this group both VC and OS changes in response to NP001 were most significant. This study represents a novel approach to ALS, wherein VC and OS were both significantly improved through immunologic, not neurologic modulation with NP001, a precursor to the dominant regulator of inflammation, taurine chloramine.}, } @article {pmid40362746, year = {2025}, author = {Moțățăianu, A and Mănescu, IB and Șerban, G and Ion, V and Bălașa, R and Andone, S}, title = {The Effects of a Mediterranean Diet on Metabolic Hormones and Cytokines in Amyotrophic Lateral Sclerosis Patients: A Prospective Interventional Study.}, journal = {Nutrients}, volume = {17}, number = {9}, pages = {}, pmid = {40362746}, issn = {2072-6643}, support = {PN-III-P1-1.1-TE-2021-0960//Ministry of Research, Innovation and Digitization, CNCS - UEFISCDI/ ; }, mesh = {Humans ; *Diet, Mediterranean ; *Amyotrophic Lateral Sclerosis/diet therapy/blood ; Male ; Female ; Prospective Studies ; Middle Aged ; *Cytokines/blood ; Aged ; Leptin/blood ; Glucagon-Like Peptide 1/blood ; Insulin/blood ; Disease Progression ; *Gastrointestinal Hormones/blood ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a prevalent neurodegenerative disease but lacks effective treatments. Dietary interventions, notably the Mediterranean diet, promise to modulate disease pathways. This study aimed to investigate the impact of the Mediterranean diet on gut hormones and cytokines in patients with amyotrophic lateral sclerosis (ALS). Methods: We conducted a 12-month, single-center prospective study on a total of 44 ALS patients. After a 6-month observation period, the patients were placed on a dairy-free Mediterranean diet for the next 6 months. We evaluated the patients at baseline (T0), 6 months (T1), and 12 months (T2). We measured the ALS Functional Rating Scale-Revised (ALSFRS-R) scores and a panel of metabolic hormones and cytokines. Results: The ALSFRS-R scores declined over 12 months (37.59 ± 6.32 at T0 vs. 30.23 ± 8.91 at T2, p < 0.001), indicating expected disease progression with no significant difference in the rate of decline before and after the dietary intervention. The leptin levels significantly decreased from T0 to T1 (T0: 4956 ± 3994 pg/mL vs. T1: 3196 ± 2807 pg/mL, p = 0.038). The insulin and GLP-1 levels showed significant drops at T2 (insulin T0: 480 ± 369 vs. T2: 214 ± 213 pmol/L, p < 0.01; GLP-1 T0: 118 ± 76 vs. T2: 60 ± 57 pg/mL, p < 0.01). C-peptide increased at T2 (T0: 3814 ± 1967 vs. T2: 9532 ± 4000 pg/mL, p < 0.001). Among the cytokines, the levels of IL-12P70, IL-13, IL-9, and IL-2 significantly decreased from T0 to T2 (all p < 0.05), while IL-17A and TNFα significantly increased between T1 and T2 (p < 0.01). Conclusions: The Mediterranean diet intervention in ALS patients modulated several metabolic hormones and cytokines but with no evidence of impacting the disease's evolution or of a slowed clinical progression. These findings suggest a potential role for dietary intervention, particularly the Mediterranean diet, in modulating gut hormones and cytokines in ALS patients, but its impact on disease course is unclear. Future randomized studies are needed to confirm these changes and to determine whether dietary intervention can have any benefit in ALS.}, } @article {pmid40362907, year = {2025}, author = {Christopher, CJ and Morgan, KH and Tolleson, CM and Trudell, R and Fernandez-Romero, R and Rice, L and Abiodun, BA and Vickery, Z and Jones, KA and Woodall, BM and Nagy, C and Mieczkowski, PA and Bowen, G and Campagna, SR and Ellis, JC}, title = {Specific Bacterial Taxa and Their Metabolite, DHPS, May Be Linked to Gut Dyshomeostasis in Patients with Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis.}, journal = {Nutrients}, volume = {17}, number = {9}, pages = {}, pmid = {40362907}, issn = {2072-6643}, support = {N/A//The Cole Family who support Parkinson's care and research at the Cole Center for Parkinson's Disease and Movement Disorders/ ; N/A//University of Tennessee at Knoxville's Human Health & Wellness Program/ ; N/A//Laboratory Directed Research and Development Program at Oak Ridge National Laboratory, managed by UT-Battelle, LLC, for the U.S. Department of Energy/ ; N/A//A philanthropic donor to ALS research at the University of Tennessee Medical Center/ ; }, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Parkinson Disease/microbiology/metabolism ; *Alzheimer Disease/microbiology/metabolism ; *Dysbiosis/microbiology ; Male ; Female ; *Amyotrophic Lateral Sclerosis/microbiology/metabolism ; Aged ; Middle Aged ; Feces/microbiology ; *Bacteria/metabolism/classification ; Homeostasis ; Metabolomics ; Case-Control Studies ; }, abstract = {Background: Neurodegenerative diseases (NDDs) are multifactorial disorders frequently associated with gut dysbiosis, oxidative stress, and inflammation; however, the pathophysiological mechanisms remain poorly understood. Methods: Using untargeted mass spectrometry-based metabolomics and 16S sequencing of human stool, we investigated bacterial and metabolic dyshomeostasis in the gut microbiome associated with early disease stages across three NDDs-amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD)-and healthy controls (HC). Results: We discovered a previously unrecognized link between a microbial-derived metabolite with an unknown role in human physiology, 2,3-dihydroxypropane-1-sulfonate (DHPS), and gut dysbiosis in NDDs. DHPS was downregulated in AD, ALS, and PD, while bacteria involved in DHPS metabolism, Eubacterium and Desulfovibrio, were increased in all disease cohorts. Additionally, select taxa within the Clostridia class had strong negative correlations to DHPS, suggesting a potential role in DHPS metabolism. A catabolic product of DHPS is hydrogen sulfide, and when in excess, it is known to promote inflammation, oxidative stress, mitochondrial damage, and gut dysbiosis, known hallmarks of NDDs. Conclusions: These findings suggest that cryptic sulfur metabolism via DHPS is a potential missing link in our current understanding of gut dysbiosis associated with NDD onset and progression. As this was a hypothesis generating study, more work is needed to elucidate the role of DHPS in gut dysbiosis and neurodegenerative diseases.}, } @article {pmid40363964, year = {2025}, author = {Niemann, BR and Murthy, J and Breinholt, C and Swords, J and Stevens, A and Garland-Kledzik, M and Mayers, K and Groves, E and Train, K and Murken, D}, title = {Postoperative C-Reactive Protein Trend Is a More Accurate Predictor of Anastomotic Leak than Absolute Values Alone.}, journal = {Journal of clinical medicine}, volume = {14}, number = {9}, pages = {}, pmid = {40363964}, issn = {2077-0383}, abstract = {Background/Objectives: An anastomotic leak (AL) following colorectal surgery is one of the most feared complications due to its associated morbidity and mortality. Early detection of ALs remains difficult, as the development of clinical signs of deterioration can be a late finding. This is particularly problematic in patients with poor access to care after discharge. C-reactive protein (CRP) is a systemic marker of inflammation that has been proposed as an early AL screening. However, absolute cut-off values have been shown to have limited sensitivity and specificity. We propose the use of CRP trends for early AL detection. Methods: A retrospective chart review of patients undergoing surgery requiring at least one anastomosis at a single tertiary care center was performed. Patients with two or fewer postoperative CRP values were excluded. Postoperative CRP trends were compared between control and AL patients using a mixed model with a Geisser-Greenhouse correction. Results: CRP trends differed significantly between AL and control patients, with a 10% CRP increase after postoperative day two showing 100% sensitivity and 84% specificity for an AL as well as a 100% negative predictive value. Accepted CRP cut-off values on postoperative days three and four had sensitivities of only 71.4% and 80% and specificities of 70.0% and 76.5%, respectively. CRP trends differed in AL versus control patients despite the surgical approach or presence of additional procedures. Conclusions: Daily monitoring of CRP trends (versus absolute cut-offs) may enhance early anastomotic leak detection and aid in discharge decision-making, particularly important in rural settings with limited healthcare access.}, } @article {pmid40364088, year = {2025}, author = {Plotti, F and Martinelli, A and Terranova, C and De Cicco Nardone, C and Montera, R and Luvero, D and Guzzo, F and Di Donato, V and Cundari, GB and Manco, S and Angioli, R}, title = {Laparoscopic Lateral Suspension (LLS) for Pelvic Organ Prolapse (POP): Update and Systematic Review of Prospective and Randomised Trials.}, journal = {Journal of clinical medicine}, volume = {14}, number = {9}, pages = {}, pmid = {40364088}, issn = {2077-0383}, abstract = {Background: Pelvic organ prolapse (POP) significantly impacts women's quality of life, especially in postmenopausal patients. Although laparoscopic sacrocolpopexy (LSC) is the gold standard for advanced apical prolapse, its complexity and risk of complications have led to alternative approaches like laparoscopic lateral suspension (LLS), a minimally invasive technique with promising results. Methods: A comprehensive search using PubMed databases was performed. The search was conducted from June 2024 to September 2024. The search string used was as follows: (pelvic organ prolapse) AND (lateral suspension) OR (laparoscopic lateral suspension). We included randomized controlled trials, prospective cohort studies, prospective observational studies, and case studies. We excluded retrospective studies, small case series, case reports, and articles not published in English. All selected articles were screened based on the titles and abstracts. Relevant data were extracted and tabulated. Results: An overall number of 12 studies were included in our analysis. LLS demonstrated high anatomical success rates: 91.15% for the anterior, 94.95% for the central, and 86.55% for the posterior compartments. The randomized controlled studies exhibit comparable effectiveness between both methods (LLS vs. LSC) and LLS appears to be the best option for anterior repair or anterior-apical repair. Patient satisfaction rates exceeded 90%, with reduced operative times (123 ± 33 min and 193 ± 55.6 min for ALS and ASC, respectively). According to the Claiven-Dindo scale, 0.17% of postoperative complications were graded more than III. The rate of mesh erosion was 0% to 10%. The technique showed particular benefit for uterine preservation and in obese patients but was less effective for severe posterior prolapse. Conclusions: Laparoscopic lateral suspension offers a safe, effective alternative for POP management, with significant anatomical and functional benefits. Its minimally invasive nature, shorter surgery time, and high satisfaction rates make it suitable for tailored patient care. Further studies should standardize evaluation metrics and assess long-term outcomes. The review was not registered. No funding was received. The authors declare no competing interests.}, } @article {pmid40364629, year = {2026}, author = {Sepehrimanesh, M and Xu, W and Ding, B}, title = {Comparative analysis of chemical and lentiviral approaches in the generation of human induced pluripotent stem cell-derived motor neurons.}, journal = {Neural regeneration research}, volume = {21}, number = {7}, pages = {2968-2974}, pmid = {40364629}, issn = {1673-5374}, support = {R21 NS112910/NS/NINDS NIH HHS/United States ; R56 NS133252/NS/NINDS NIH HHS/United States ; }, abstract = {The generation of human induced pluripotent stem cell–derived motor neurons overcomes limited access to human tissues and offers an unprecedented approach to modeling motor neuron diseases such as dystonia and amyotrophic lateral sclerosis. Motor neurons generated through different strategies may exhibit substantial differences in purity, maturation, characterization, and even neuronal identity, leading to variable outcomes in disease modeling and drug screening. However, very few comparative studies have been conducted to determine the similarities and differences among motor neurons prepared via different protocols. In this study, we prepared human induced pluripotent stem cell–derived motor neurons via lentiviral delivery of transcription factors and chemical induction and performed a systematic comparative analysis. We found that motor neurons generated by both approaches showed typical motor neuron morphology and robustly expressed motor neuron-specific markers, such as nuclear homeobox transcription factor 9 and choline acetyltransferase. The chemical induction protocol utilizes a combination of small molecules to induce motor neuron differentiation, offering a significantly faster maturation time of 35 days compared to 46 days with lentiviral delivery of transcription factors. Additionally, while lentiviral delivery of transcription factors are suitable for downstream biochemical analysis, chemical induction are more applicable for therapeutic approaches as they avoid the use of lentiviruses. Both approaches produce motor neurons with high purity (> 95%) and yield. No significant differences were found between chemical induction and lentiviral delivery of transcription factors in terms of motor neuron markers and maturation markers. These robust methodologies offer researchers powerful tools for investigating motor neuron diseases and potential therapeutic strategies.}, } @article {pmid40364643, year = {2026}, author = {Wen, X and Lan, T and Su, W and Cao, B and Wang, Y and Chen, Y}, title = {Latest progress and challenges in drug development for degenerative motor neuron diseases.}, journal = {Neural regeneration research}, volume = {21}, number = {5}, pages = {1849-1863}, pmid = {40364643}, issn = {1673-5374}, abstract = {Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions. They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage. The main types include amyotrophic lateral sclerosis, progressive muscular atrophy, primary lateral sclerosis, and progressive bulbar palsy, the pathological processes of which are largely identical, with the main disparity lying in the location of the lesions. Amyotrophic lateral sclerosis is the representative condition in this group of diseases, while other types are its variants. Hence, this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases. Although the precise pathogenesis remains elusive, recent advancements have shed light on various theories, including gene mutation, excitatory amino acid toxicity, autoimmunology, and neurotrophic factors. The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis: riluzole, edaravone, AMX0035, and tofersen, with the latter being the most recent to receive approval. However, following several phase III trials that failed to yield favorable outcomes, AMX0035 has been voluntarily withdrawn from both the US and Canadian markets. This article presents a comprehensive summary of drug trials primarily completed between January 1, 2023, and June 30, 2024, based on data sourced from clinicaltrials.gov. Among these trials, five are currently in phase I, seventeen are in phase II, and eleven are undergoing phase III evaluation. Notably, 24 clinical trials are now investigating potential disease-modifying therapy drugs, accounting for the majority of the drugs included in this review. Some promising drugs being investigated in preclinical studies, such as ATH-1105, are included in our analysis, and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases. This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs, with the aim of highlighting the latest potentialities for clinical therapy.}, } @article {pmid40364652, year = {2025}, author = {Gonçalves Netto, A and Ribeiro, VHV and Nicolai, M and Lopez Ovejero, RF and Silva, VFV and Junior, GJP and Brunharo, C}, title = {Genetic diversity and population structure of ALS-resistant Amaranthus hybridus across Brazil's primary soybean-growing regions.}, journal = {Pest management science}, volume = {81}, number = {9}, pages = {5394-5402}, pmid = {40364652}, issn = {1526-4998}, mesh = {*Amaranthus/genetics/drug effects/enzymology ; *Herbicide Resistance/genetics ; Brazil ; *Acetolactate Synthase/antagonists & inhibitors/genetics ; *Genetic Variation ; *Herbicides/pharmacology ; Glycine max/growth & development ; *Plant Proteins/genetics/metabolism/antagonists & inhibitors ; }, abstract = {BACKGROUND: Resistance to acetolactate synthase (ALS)-inhibiting herbicides has emerged in Amaranthus hybridus populations across Brazil's soybean-growing regions. To gain insights into the evolutionary origins and spread of resistance, this study (1) investigated the ALS inhibitor resistance mechanisms in nine A. hybridus populations and (2) assessed their genetic diversity, structure, and relatedness.

RESULTS: Resistance to the ALS inhibitor chlorimuron in A. hybridus was associated with two distinct target-site mutations: Trp-574-Leu and Asp-376-Glu. Population genetics revealed low levels of genetic diversity (HE = 0.00117 to 0.16019; π = 0.00126 to 0.17421) and inbreeding (FIS = 0.0015 to 0.13157). Principal component analysis differentiated A. hybridus by geographical region, while ADMIXTURE analysis revealed population structure with evidence of admixture between genetic clusters in three groups of populations.

CONCLUSION: The results suggest multiple local and independent evolutionary origins of resistance. The spread of resistance is primarily driven by local herbicide selection pressure and gene flow through seed dispersal. © 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid40365751, year = {2025}, author = {Connaghan, KP and Eshghi, M and Haenssler, AE and Green, JR and Wang, J and Scheier, Z and Keegan, M and Clark, A and Onnela, JP and Burke, KM and Berry, JD}, title = {A Preliminary Investigation of Acoustic Features for Remote Monitoring of Respiration in ALS.}, journal = {Muscle & nerve}, volume = {72}, number = {2}, pages = {321-326}, pmid = {40365751}, issn = {1097-4598}, support = {K23 DC019179/DC/NIDCD NIH HHS/United States ; R15DC018944/NH/NIH HHS/United States ; R15 DC018944/DC/NIDCD NIH HHS/United States ; K24DC06312/NH/NIH HHS/United States ; K23DC019179/NH/NIH HHS/United States ; F32DC020896/NH/NIH HHS/United States ; K24 DC016312/DC/NIDCD NIH HHS/United States ; //ALS Association/ ; F32 DC020896/DC/NIDCD NIH HHS/United States ; K24DC06312/NH/NIH HHS/United States ; K23DC019179/NH/NIH HHS/United States ; R15DC018944/NH/NIH HHS/United States ; F32DC020896/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Female ; Male ; Middle Aged ; Aged ; *Respiration ; Adult ; *Acoustics ; Monitoring, Physiologic/methods ; Vital Capacity/physiology ; Smartphone ; Respiratory Function Tests/methods ; }, abstract = {INTRODUCTION/AIMS: There is a substantial need to establish reliable approaches for low-burden at-home monitoring of respiratory function for people with amyotrophic lateral sclerosis (PALS). This preliminary study assessed the potential of acoustic features extracted from a smartphone passage reading task to serve as clinically meaningful outcome measures reflecting instrumental and self-reported respiratory function measures.

METHODS: Thirty-six PALS completed an in-clinic slow vital capacity (SVC) task, followed by at-home completion of surveys and audio recording of a reading passage using a smartphone application. Speaking rate and pause features were extracted offline. Correlation analysis evaluated the relationship between the acoustic features and both instrumental (SVC) and self-reported (respiratory subscale of the self-entry version of the ALS Functional Rating Scale-Revised; ALSFRS-RSE) measures of respiratory function. Receiver operator characteristic (ROC) with area under the curve (AUC) analysis evaluated the utility of acoustic features for classifying participants with and without respiratory involvement.

RESULTS: SVC and respiratory self-ratings were significantly correlated with pause, but not rate, measures. Percent pause time was the most strongly correlated acoustic feature with both SVC (r = -0.62) and ALSFRS-RSE respiratory subscale ratings (r = -0.43). ROC analysis revealed that percent pause time classified participants presenting with respiratory involvement based on instrumentation (SVC < 70% predicted [AUC = 0.70]; SVC < 50% predicted [AUC = 0.88]) and self-ratings when using the respiratory ALSFRS-RSE score cut-off of < 11 (AUC = 0.78), but not < 12 (AUC = 0.61).

DISCUSSION: Percent pause time, extracted from a smartphone-recorded passage reading, offers a promising index for remote assessment and monitoring of respiratory function in PALS.}, } @article {pmid40365763, year = {2025}, author = {Cheng, F and Chapman, T and Venturato, J and Davidson, JM and Polido, SA and Rosa-Fernandes, L and San Gil, R and Suddull, HJ and Zhang, S and Macaslam, CY and Szwaja, P and Chung, R and Walker, AK and Rayner, SL and Morsch, M and Lee, A}, title = {Proteomics Analysis of the TDP-43 Interactome in Cellular Models of ALS Pathogenesis.}, journal = {Journal of neurochemistry}, volume = {169}, number = {5}, pages = {e70079}, pmid = {40365763}, issn = {1471-4159}, support = {IG2308//Motor Neurone Disease Research Australia/ ; //FightMND/ ; AL230125//U.S. Department of Defense/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Proteomics/methods ; Animals ; Oxidative Stress/physiology ; }, abstract = {Cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) is a hallmark pathology of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). However, the protein interactome of TDP-43 remains incompletely defined. In this study, we aimed to identify putative TDP-43 protein partners within the nucleus and the cytoplasm and with different disease models of TDP-43 by comparing TDP-43 interaction partners in three different cell lines. We verified the levels of interaction of protein partners under stress conditions as well as after introducing TDP-43 variants containing ALS missense mutations (G294V and A315T). Overall, we identified 58 putative wild-type TDP-43 interactors, including novel binding partners responsible for RNA metabolism and splicing. Oxidative stress exposure broadly led to changes in TDP-43[WT] interactions with proteins involved in mRNA metabolism, suggesting a dysregulation of the transcriptional machinery early in disease. Conversely, although G294V and A315T mutations are both located in the C-terminal domain of TDP-43, both mutants presented different interactome profiles with most interaction partners involved in translational and transcriptional machinery. Overall, by correlating different cell lines and disease-simulating interventions, we provide a list of high-confidence TDP-43 interaction partners, including novel and previously reported proteins. Understanding pathological changes to TDP-43 and its specific interaction partners in different models of stress is critical to better understand TDP-43 proteinopathies and provide novel potential therapeutic targets and biomarkers.}, } @article {pmid40365999, year = {2025}, author = {Gao, Z and Qiu, R and Dave, DR and Chandravanshi, P and Soares, GP and Smith, CS and Ortega, JA and Palmer, LC and Álvarez, Z and Stupp, SI}, title = {Supramolecular Copolymerization of Glycopeptide Amphiphiles and Amyloid Peptides Improves Neuron Survival.}, journal = {Journal of the American Chemical Society}, volume = {147}, number = {21}, pages = {17710-17724}, doi = {10.1021/jacs.5c00105}, pmid = {40365999}, issn = {1520-5126}, mesh = {Humans ; *Neurons/cytology/drug effects ; Cell Survival/drug effects ; *Amyloid beta-Peptides/chemistry ; Polymerization ; *Glycopeptides/chemistry/pharmacology ; *Surface-Active Agents/chemistry/pharmacology ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis are characterized by progressive neuronal loss and the accumulation of misfolded proteins including amyloid proteins. Current therapeutic options include the use of antibodies for these proteins, but novel chemical strategies need to be developed. The disaccharide trehalose has been widely reported to prevent misfolding and aggregation of proteins, and we therefore investigated the conjugation of this moiety to biocompatible peptide amphiphiles (TPAs) known to undergo supramolecular polymerization. Using X-ray scattering, circular dichroism, and infrared spectroscopy, we found that trehalose conjugation destabilized the internal β-sheet structures within the TPA supramolecular polymers as evidenced by a lower thermal transition. Thioflavin T fluorescence showed that these metastable TPA nanofibers suppressed A42 aggregation. Interestingly, we found that the suppression involved supramolecular copolymerization of TPA polymers with Aβ42, which effectively trapped the peptides within the filamentous structures. In vitro assays with human induced pluripotent stem cell-derived neurons demonstrated that these TPAs significantly improved neuron survival compared to other conditions. Our study highlights the potential of properly tuned supramolecular polymerizations of monomers to safely remove amyloidogenic proteins in neurodegeneration.}, } @article {pmid40366590, year = {2025}, author = {Wu, H and He, Q and Wang, Q}, title = {Histochemical Assays for Analyzing Abscission Layer Development and Function in Rice.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2916}, number = {}, pages = {99-107}, pmid = {40366590}, issn = {1940-6029}, mesh = {*Oryza/growth & development/physiology/metabolism/genetics ; *Histocytochemistry/methods ; Gene Expression Regulation, Plant ; }, abstract = {This chapter outlines detailed methods and protocols for studying the structure and mechanisms of abscission layers (ALs) in rice. Utilizing rice spikelets as a primary example, these protocols provide comprehensive techniques for analyzing AL development, including tissue preparation, microscopy, and histochemical assays. The AL is a specialized tissue where cell separation takes place, and it is crucial for processes such as organ shedding and fruit drop. By examining the AL, researchers can uncover the physiological and genetic factors governing plant organ separation. These insights are pertinent for advancing agricultural practices and crop improvement, as understanding the dynamics of the AL can lead to the development of rice varieties with enhanced traits related to abscission and grain retention. These improvements can result in better yield stability and reduced post-harvest losses, which are essential for meeting the food demands of a growing global population. By focusing on the genetic and physiological mechanisms governing the AL, researchers can develop innovative strategies to optimize rice production and contribute to food security.}, } @article {pmid40366870, year = {2025}, author = {Arguedas, A and Schneck, D and Cui, E and Xenopoulos-Oddsson, A and Arcila-Londono, X and Lunetta, C and Wymer, J and Olney, N and Gwathmey, K and Ajroud-Driss, S and Hayat, G and Heiman-Patterson, T and Cerri, F and Fournier, C and Glass, J and Sherman, A and Walk, D and Fiecas, M}, title = {Risk prediction for ALS using semi-competing risk models with applications to the ALS Natural History Consortium dataset.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {550-557}, doi = {10.1080/21678421.2025.2500359}, pmid = {40366870}, issn = {2167-9223}, support = {R01 FD007630/FD/FDA HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/therapy ; Female ; Male ; Disease Progression ; Middle Aged ; Aged ; Risk Assessment/methods ; Gastrostomy ; Risk Factors ; }, abstract = {Background and objectives: Important landmarks in progression of amyotrophic lateral sclerosis (ALS) can occur prior to death. Predictive models for the risk of these events can assist in clinical trial design and personal planning. We propose a predictive model, using a semi-competing risks modeling approach, for five important disease progression landmarks in ALS. Methods: Data on 1508 participants from the ALS Natural History Consortium (ALS NHC) were used, including baseline characteristics and the ALS Functional Rating Scale-Revised (ALSFRS-R) score collected at clinic visits. A semi-competing risks modeling approach was used to study the time to disease progression landmarks, accounting for the possibility of death. Specifically, time to gastrostomy, use of noninvasive ventilation (NIV), continuous use of NIV, loss of speech, and loss of ambulation were chosen and modeled individually. To measure the predictive capabilities of the model, the integrated Brier score was computed for each model using cross-validation for the NHC data. Data from Emory University were used for external validation of the models. Results: We present model results using gastrostomy as the intermediate outcome. Similar trends in disease progression groups were found across all model pathways. Diagnostic delay, age, and site of onset were the most important covariates. Predictive metrics in both internal and external validation are presented across all models and for different pathways. Conclusion: Semi-competing risks modeling is a flexible approach to studying disease progression. The models have good predictive capabilities across different outcomes and pathways. These are replicated in the external validation dataset.}, } @article {pmid40369342, year = {2025}, author = {Uechi, H and Sridharan, S and Nijssen, J and Bilstein, J and Iglesias-Artola, JM and Kishigami, S and Casablancas-Antras, V and Poser, I and Martinez, EJ and Boczek, E and Wagner, M and Tomschke, N and de Jesus Domingues, AM and Pal, A and Doeleman, T and Kour, S and Anderson, EN and Stein, F and Lee, HO and Zhang, X and Fritsch, AW and Jahnel, M and Fürsch, J and Murthy, AC and Alberti, S and Bickle, M and Fawzi, NL and Nadler, A and David, DC and Pandey, UB and Hermann, A and Stengel, F and Davis, BG and Baldwin, AJ and Savitski, MM and Hyman, AA and Wheeler, RJ}, title = {Small-molecule dissolution of stress granules by redox modulation benefits ALS models.}, journal = {Nature chemical biology}, volume = {21}, number = {10}, pages = {1577-1588}, pmid = {40369342}, issn = {1552-4469}, support = {103261/Z/13/Z//Wellcome Trust (Wellcome)/ ; R01 GM147677/GM/NIGMS NIH HHS/United States ; 390729961//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; /WT_/Wellcome Trust/United Kingdom ; R01GM147677//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; STE 2517/1-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; EP/V011359/1//RCUK | Engineering and Physical Sciences Research Council (EPSRC)/ ; STE 2517/5-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics/pathology ; Oxidation-Reduction/drug effects ; Humans ; Animals ; *Stress Granules/metabolism/drug effects ; *Small Molecule Libraries/pharmacology/chemistry ; Mice ; Disease Models, Animal ; }, abstract = {Neurodegenerative diseases, such as amyotrophic lateral sclerosis, are often associated with mutations in stress granule proteins. Aberrant stress granule condensate formation is associated with disease, making it a potential target for pharmacological intervention. Here, we identified lipoamide, a small molecule that specifically prevents cytoplasmic condensation of stress granule proteins. Thermal proteome profiling showed that lipoamide stabilizes intrinsically disordered domain-containing proteins, including SRSF1 and SFPQ, which are stress granule proteins necessary for lipoamide activity. SFPQ has redox-state-specific condensate dissolving behavior, which is modulated by the redox-active lipoamide dithiolane ring. In animals, lipoamide ameliorates aging-associated aggregation of a stress granule reporter protein, improves neuronal morphology and recovers motor defects caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants. Thus, lipoamide is a well-tolerated small-molecule modulator of stress granule condensation, and dissection of its molecular mechanism identified a cellular pathway for redox regulation of stress granule formation.}, } @article {pmid40370030, year = {2025}, author = {Fusaro, L and Bangari, DS and Pasterkamp, RJ and Fernández-Ruiz, J and Youssef, SA and Sharma, AK}, title = {Neurodegenerative Diseases: Pathogenesis and Preclinical Models for Translational Drug Discovery.}, journal = {Toxicologic pathology}, volume = {53}, number = {4}, pages = {364-371}, doi = {10.1177/01926233251339105}, pmid = {40370030}, issn = {1533-1601}, mesh = {*Neurodegenerative Diseases/drug therapy/pathology ; Animals ; Humans ; *Disease Models, Animal ; *Drug Discovery/methods ; Translational Research, Biomedical ; Drug Evaluation, Preclinical ; }, abstract = {The fourth session of the 2024 European Society of Toxicologic Pathology (ESTP) Congress brought together lectures focused on the use of in vitro and in vivo models to investigate neurodegenerative diseases. Four presentations highlighted various aspects of neurodegenerative diseases including dementia, immune-mediated conditions, and neuromuscular disorders. The session began with an overview of animal models of dementia underscoring their critical role in understanding disease pathogenesis and supporting the development of effective therapeutic drugs. Subsequent presentations investigated immunological self-tolerance in autoimmune neurodegenerative diseases, such as multiple sclerosis and Guillain-Barré syndrome, and the application of in vitro models to study neuromuscular diseases such as amyotrophic lateral sclerosis. The final presentation examined cannabinoid-based therapeutic options for treating neurodegenerative diseases, highlighting their potential in neuroprotection and neurorepair. This session provided valuable insights into the latest research and advancements in neurodegenerative disease modeling and therapy, offering promising directions for improved modeling and therapeutic strategies.}, } @article {pmid40373480, year = {2025}, author = {Jih, KY and Fang, SY and Tsai, YS and Sytwu, HP and Liao, YC and Lee, YC}, title = {TARDBP variants in Taiwanese ALS patients: Genetic spectrum, clinical features, and founder effects.}, journal = {Journal of the neurological sciences}, volume = {474}, number = {}, pages = {123531}, doi = {10.1016/j.jns.2025.123531}, pmid = {40373480}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Female ; Middle Aged ; Taiwan/epidemiology ; *DNA-Binding Proteins/genetics ; *Founder Effect ; Aged ; Adult ; Polymorphism, Single Nucleotide/genetics ; Haplotypes ; Cohort Studies ; *Genetic Predisposition to Disease ; Age of Onset ; }, abstract = {BACKGROUND: TARDBP is one of the most commonly implicated genes in amyotrophic lateral sclerosis (ALS). It encodes TAR DNA-binding protein 43 (TDP-43), a protein critical to ALS pathology, whose pathogenic variants disrupt its nuclear-cytoplasmic translocation, leading to aggregation. This study aimed to investigate the role of TARDBP variants in a Taiwanese ALS cohort.

METHODS: We analyzed the coding regions of TARDBP using Sanger sequencing in 650 unrelated ALS patients recruited between 2000 and 2024. The cohort included 388 men and 262 women, with an average age of onset of 56 ± 13 years. Approximately 20 % presented with bulbar-onset ALS. Haplotype analysis was conducted using single nucleotide polymorphism and short tandem repeat markers flanking TARDBP.

RESULTS: Pathogenic TARDBP variants were identified in 17 probands and 11 of their relatives, with an average age of onset of 49.1 ± 10.3 years, 32 % of whom had bulbar-onset disease. Six probands carried the p.M337V variant, five had p.S375G, two had p.N378D, and one each carried p.G348C, p.G348V, p.G376D, or p.I383V. Haplotype analysis suggested a common founder for the p.S375G variant and most families with p.M337V. Asymptomatic carriers were also identified, suggesting incomplete penetrance.

CONCLUSIONS: Our study revealed that pathogenic TARDBP variants are a significant genetic contributor to ALS in Taiwan, associated with earlier disease onset but reduced penetrance. The recurrent M337V and p.S375G variants likely reflect a founder effect.}, } @article {pmid40373575, year = {2025}, author = {de Carvalho, M}, title = {The F-wave fingerprint of amyotrophic lateral sclerosis.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {55}, number = {4}, pages = {103080}, doi = {10.1016/j.neucli.2025.103080}, pmid = {40373575}, issn = {1769-7131}, } @article {pmid40373763, year = {2025}, author = {Wu, J and Song, H and Arkin, M and Zhang, S and Huang, X and Fan, D and Xu, Y}, title = {Characteristics of Neuromuscular Ultrasound in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Neuro-degenerative diseases}, volume = {25}, number = {4}, pages = {169-179}, pmid = {40373763}, issn = {1660-2862}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; Male ; Female ; Middle Aged ; Ultrasonography ; Aged ; Fasciculation/diagnostic imaging/physiopathology ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Adult ; Electromyography ; }, abstract = {INTRODUCTION: Neuromuscular ultrasound has been increasingly used in the detection and diagnosis of amyotrophic lateral sclerosis (ALS), commonly characterized by peripheral nerve atrophy, degeneration, and muscle fasciculations. The aim of this study was to assess the ultrasound characteristics of ALS patients.

METHODS: A total of 67 consecutive patients with sporadic ALS and 19 with ALS mimics (63.16% peripheral neuropathy) were recruited. Ultrasound and electrophysiological examinations were performed; the peripheral nerve cross-sectional area (CSA) and fasciculation grades were compared between the groups, and correlations between ultrasound and electrophysiological data in ALS patients were determined.

RESULTS: ALS patients had smaller proximal median and ulnar nerve CSAs than those of ALS mimics, who exhibited asymmetric changes. Fasciculation differences in the trapezius, triceps brachii, extensor digitorum communis, thenar, and first dorsal interosseous muscles were observed. In ALS patients, the CSA and fasciculation relative scores were correlated with electrophysiological indicators.

CONCLUSION: Ultrasound is a valuable tool for monitoring peripheral nerve CSA and muscle fasciculations, both of which correlate with electrophysiological indices, in ALS patients.}, } @article {pmid40374720, year = {2025}, author = {Usategui-Martín, R and Esteban-López, V and Chantre-Fortes, E and Sánchez-Martín, M and Riancho, JA and López, DE and González-Sarmiento, R}, title = {The p.R321C mutation in the p62 protein is associated with abnormalities in the central nervous system.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {16929}, pmid = {40374720}, issn = {2045-2322}, mesh = {Animals ; *Sequestosome-1 Protein/genetics/metabolism ; Mice ; Humans ; Autophagy/genetics ; *Mutation ; *Central Nervous System/metabolism/pathology/abnormalities ; Disease Models, Animal ; NF-kappa B/metabolism ; Male ; Seizures/genetics/pathology ; }, abstract = {SQSTM1/p62 has an essential role in autophagy, a catabolic pathway that is vital for maintaining cell homeostasis. p62 alterations have been observed in multiple pathological conditions, including neurodegenerative diseases and bone metabolism alterations. The p.R321C p62 protein mutation has been described in patients with amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Paget's disease of bone. In vitro studies associated the p62-321C variant with a blockade of autophagy and with the activation of the NF-kB pathway. We aimed to provide a deeper understating of the pathophysiological consequences of the p.R321C p62 mutation using a humanized mouse model. Micro-computed tomography, immunohistochemistry, and western blot analysis studied the functional consequences of the p. R321C p62 mutation. Statistical analyses were performed using SPSS software. The results showed that the p62-321C mice developed seizures after tactile-vestibular stimulation, probably associated with a blockage of the autophagy and NF-kB activation. Changes in expression of cFos and p62 were found in the amygdala, hypothalamic nuclei, and hippocampi nuclei. In addition, numerous degenerating motor neurons were observed in the spinal cord of the p62-321C mice. We report that the blockage of the autophagy, caused by p.R321C p62 mutation, is associated with abnormalities in the central nervous system, mainly seizures after tactile-vestibular stimulation and degeneration of the motor neurons of the spinal cord but not with bone abnormalities in a humanized mouse model.}, } @article {pmid40374755, year = {2025}, author = {Krishnan, D and Talbot, DL and Ashhurst, JF and Park, SB and Vucic, S and Timmins, HC and Kiernan, MC}, title = {Longitudinal assessment of cortical motor function in amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {16978}, pmid = {40374755}, issn = {2045-2322}, support = {1156093//National Health and Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Motor Cortex/physiopathology ; Male ; Female ; Middle Aged ; Transcranial Magnetic Stimulation ; Longitudinal Studies ; Evoked Potentials, Motor/physiology ; Aged ; Adult ; Disease Progression ; Prospective Studies ; }, abstract = {Background Short interval intracortical inhibition (SICI) remains the most sensitive parameter to assess motor cortical function in amyotrophic lateral sclerosis (ALS). While an initial value of SICI has been utilised to support a diagnosis of ALS, less is known about progression of change. Methods Motor cortex function was prospectively assessed in ALS patients, through serial threshold tracking transcranial magnetic stimulation (TMS) assessment over more than 12 months. Motor cortical potentials were recorded from the abductor pollicis brevis (APB). Demographic information and clinical variables were analysed. Results A cohort of 52 ALS patients (69.2% limb-onset disease; 47.2% right-side) were assigned to undergo longitudinal assessment of cortical motor function. Mean ALSFRS-R score at baseline was 39.5 ± 1.0 denoting relatively milder clinical deficits at study commencement. Cortical motor dysfunction was evident at baseline, with reduction in averaged SICI (p = 0.004) when compared to healthy controls. In terms of disease trajectory, ALS patients experienced a significant decline in averaged SICI overtime. When compared to initial assessment, averaged SICI was significantly reduced after 12 months (p = 0.004). There was no significant main effect of site of onset on averaged SICI (p = 0.78). The progressive change in averaged SICI was more robust in the dominant hemisphere, with the proportion of ALS patients who demonstrated a clinically abnormal averaged SICI value (< 5.5%) increasing by 50%, compared to 15.4% for the non-dominant hemisphere. Conclusion ALS patients demonstrate progressive cortical motor abnormalities, evident through longitudinal assessment. While SICI represents a diagnostic biomarker, the rate of decline in the present series is consistent with disease progression, suggesting a potential role to monitor the efficacy of therapeutic intervention.}, } @article {pmid40374790, year = {2025}, author = {Verma, KK and Gaur, PK and Gupta, SL and Lata, K and Kaushik, R and Sharma, V}, title = {Metabolomics: a new frontier in neurodegenerative disease biomarker discovery.}, journal = {Metabolomics : Official journal of the Metabolomic Society}, volume = {21}, number = {3}, pages = {67}, pmid = {40374790}, issn = {1573-3890}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/diagnosis ; *Biomarkers/metabolism/analysis ; *Metabolomics/methods ; Animals ; }, abstract = {BACKGROUND: Neurodegenerative disorders are a group of debilitating diseases affecting the central nervous system, and are characterized by the progressive loss of neurons, leading to declines in cognitive function, movement, and overall quality of life. While the exact causes remain elusive, it's believed that a combination of genetic, environmental, and lifestyle factors contribute to their development. Metabolites, the end products of cellular processes, reflect the physiological state of an organism. By analysing these molecules, researchers can gain a deeper understanding of the underlying metabolic changes associated with neurodegenerative disorders.

AIM OF REVIEW: This review aims to explore the possibilities between metabolites and their association with neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS) and Huntington's disease (HD).

Metabolomic studies could potentially illuminate altered biochemical pathways, facilitating earlier detection and treatment of these conditions. Metabolomic investigations have revealed the role of oxidative stress, alterations in glucose and fat metabolism, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity and alterations in myelin composition in neurodegenerative disorders. The common metabolic biomarkers identified includes glutamate, taurine, uric acid, branched chain amino acids, acylcarnitine, creatinine, choline, with some more amino acids and lipids. Metabolomics offers valuable insights into disease mechanisms and potential therapeutic targets by identifying biochemical and metabolic alterations, but still there are several aspects to be explored for accurate mapping of metabolites with specific pathway involved in the disease.}, } @article {pmid40375307, year = {2025}, author = {Trautwig, AN and Fox, EJ and Dammer, EB and Shantaraman, A and Ping, L and Duong, DM and Watson, CM and Wu, F and Asress, S and Guo, Q and Levey, AI and Lah, JJ and Verde, F and Doretti, A and Ratti, A and Ticozzi, N and Ly, CV and Miller, TM and Garret, MA and Berry, JD and Thomas, EV and Fournier, CN and McEachin, ZT and Seyfried, NT and Glass, JD}, title = {Network analysis of the cerebrospinal fluid proteome reveals shared and unique differences between sporadic and familial forms of amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {58}, pmid = {40375307}, issn = {1750-1326}, support = {R01 NS138499./NH/NIH HHS/United States ; No grant ID//Muscular Dystrophy Association/ ; RF-2021-12374238//Italian Ministry of Health/ ; 1RO1NS137434/NH/NIH HHS/United States ; NS097816/NH/NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 NS138499/NS/NINDS NIH HHS/United States ; No Grant ID//Italian Ministry of Education and Research/ ; AG070937/NH/NIH HHS/United States ; P01NS084974/NS/NINDS NIH HHS/United States ; No grant ID//Association of Frototemporal Dementia/ ; P30AG066511//National Institute of Aging/ ; No Grant ID//Biogen, Inc/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/genetics ; Male ; Female ; Middle Aged ; *Proteome ; C9orf72 Protein/genetics ; Proteomics/methods ; Biomarkers/cerebrospinal fluid ; Aged ; Superoxide Dismutase-1/genetics ; Adult ; Cohort Studies ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3-5 years of disease onset. Although roughly 10% of cases can be linked to a specific inherited mutation (e.g., C9orf72 hexanucleotide repeat expansion or SOD1 mutation), the cause(s) of most cases are unknown. Consequently, there is a critical need for biomarkers that reflect disease onset and progression across ALS subgroups.

METHODS: We employed tandem mass tag mass spectrometry (TMT-MS) based proteomics on cerebrospinal fluid (CSF) to identify and quantify 2105 proteins from sporadic, C9orf72, and SOD1 ALS patients, asymptomatic C9orf72 expansion carriers, and controls (N = 101). To verify trends in our Emory University cohort we used data-independent acquisition (DIA-MS) on an expanded, four center cohort. This expanded cohort of 259 individuals included 50 sporadic ALS (sALS), 43 C9orf72 ALS, 22 SOD1 ALS, 72 asymptomatic gene carriers (59 C9orf72 and 13 SOD1) and 72 age-matched controls. We identified 2330 proteins and used differential protein abundance and network analyses to determine how protein profiles vary across disease subtypes in ALS CSF.

RESULTS: Differential abundance and co-expression network analysis identified proteomic differences between ALS and control, as well as differentially abundant proteins between sporadic, C9orf72 and SOD1 ALS. A panel of proteins differentiated forms of ALS that are indistinguishable in a clinical setting. An additional panel differentiated asymptomatic from symptomatic C9orf72 and SOD1 mutation carriers, marking a pre-symptomatic proteomic signature of genetic forms of ALS. Leveraging this large, multicenter cohort, we validated our ALS CSF network and identified ALS-specific proteins and network modules.

CONCLUSIONS: This study represents a comprehensive analysis of the CSF proteome across sporadic and genetic causes of ALS that resolves differences among these ALS subgroups and also identifies proteins that distinguish symptomatic from asymptomatic gene carriers. These new data point to varying pathogenic pathways that result in an otherwise clinically indistinguishable disease.}, } @article {pmid40375549, year = {2025}, author = {Kuiper, MM and Kruithof, WJ and Broekman-Peters, N and Schröder-van den Nieuwendijk, DL and Visser-Meily, JMA and Beelen, A}, title = {Nutritional care practices in ALS: perspectives of healthcare professionals and people with ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {452-466}, doi = {10.1080/21678421.2025.2501681}, pmid = {40375549}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy/epidemiology/complications ; Male ; Female ; *Health Personnel/psychology ; Middle Aged ; Surveys and Questionnaires ; Nutritional Status ; Aged ; Netherlands ; *Malnutrition/etiology/diagnosis ; *Nutrition Therapy/methods ; Adult ; }, abstract = {Objective: To map nutritional care provided to people with ALS, PMA and PLS (pwALS) and identify barriers encountered by healthcare professionals and pwALS. Methods: Two online questionnaires, addressing current nutritional management of ALS in the Netherlands, were sent to healthcare professionals of the 36 certified ALS care teams and pwALS drawn from a population-based registry. Topics were: 1) contact between pwALS and their ALS care team, 2) monitoring nutritional status, 3) nutritional advice provided or received, and 4) satisfaction with current nutritional care and barriers encountered. Results: In total, 100 healthcare professionals and 372 pwALS completed the questionnaires. Dietitian responses (n = 36/100) showed that 28% utilized malnutrition screening tools and 17% measured body composition. Dietitians used different predictive equations to estimate energy and protein requirements. Patient responses showed that 50% had contact with a dietitian, 7% indicated body composition had been measured and 25% reported never being weighed or weighing themselves. Healthcare professionals and pwALS highlighted the need for comprehensive, up-to-date information on nutrition and ALS, national consensus on nutritional advice and monitoring methods, patient information material, training for healthcare professionals and personalized nutritional advice for pwALS. Conclusions: Practice variation was observed in the assessment and monitoring of nutritional status and the provision of nutritional advice. Suboptimal monitoring of nutritional status and estimation of nutritional requirements may result in delayed detection of malnutrition and inaccurate dietary recommendations. Further research and national consensus on monitoring methods and nutritional advice is required.}, } @article {pmid40378471, year = {2025}, author = {Birylo, M and Błaszczak-Bąk, W and Suchocki, C}, title = {Application of GLDAS models and ALS point clouds in assessing the impact of modified evapotranspiration on the water budget.}, journal = {Water research}, volume = {283}, number = {}, pages = {123746}, doi = {10.1016/j.watres.2025.123746}, pmid = {40378471}, issn = {1879-2448}, mesh = {*Water ; Climate Change ; Rain ; Models, Theoretical ; Hydrology ; Seasons ; Environmental Monitoring ; }, abstract = {Monitoring and assessing the water budget is crucial, especially in the context of climate change and increasing occurrences of extreme weather events. The water budget is influenced by precipitation, evapotranspiration, and surface runoff, which are shaped by meteorological conditions. Additionally, terrain topography and land cover structure play a significant role, although they are often overlooked in water budget calculations. This study presents the integration of data from the Global Land Data Assimilation System (GLDAS) and airborne laser scanning (ALS) point clouds, enabling a comprehensive analysis of hydrological processes. The results highlight that modified evapotranspiration significantly affects water availability, particularly in regions with diverse topography, where terrain features influence local hydrological conditions. The findings confirm that precipitation remains the dominant factor in the water budget, but terrain-driven variations in evapotranspiration contribute to seasonal and spatial differences. The study demonstrates that incorporating ALS-derived vegetation and terrain data into hydrological modeling improves the accuracy of water budget assessments, which is crucial for sustainable water resource management.}, } @article {pmid40378485, year = {2025}, author = {Keating, ME and Byrne, HJ}, title = {Seeding multivariate algorithms for spectral analysis, a data augmentation approach to enhance analytical performance.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {340}, number = {}, pages = {126369}, doi = {10.1016/j.saa.2025.126369}, pmid = {40378485}, issn = {1873-3557}, mesh = {Humans ; *Algorithms ; Principal Component Analysis ; Multivariate Analysis ; *Spectrum Analysis, Raman/methods ; Least-Squares Analysis ; A549 Cells ; Discriminant Analysis ; Cisplatin/pharmacology ; }, abstract = {Seeding spectral datasets by augmenting the data matrix with either the full spectrum or selected spectral features in order to bias multivariate analysis towards the solution of interest is explored. It is demonstrated that such seeding can have a profound effect on the endpoint of the analysis. Using Raman spectroscopic data of human lung adenocarcinoma cells (A549) in vitro, systematic perturbations to the spectra are introduced to simulate dose dependent exposure to a drug (cisplatin), and/or cellular response, representing reduced viability. Taking Principal Components Analysis (PCA) as the first example, seeding with the known spectral profiles of the drug exposure is demonstrated to greatly increase the ability of the algorithm to differentiate two distinct data subsets, representing control and exposed. The improved differentiation is quantified by further Linear Discriminant Analysis of the PCA data. Other examples of where seeding may be applied include, simulated datasets consisting of simultaneous changes in the spectral markers of exposure dose and cellular response, which are used for Multivariate Curve Resolution - Alternating Least Squares analysis (MCR-ALS). In the example presented, adding pure components to the dataset improves the ability of the algorithm to both model the systematic variation of concentration dependent data and extract the component spectra more accurately than the unseeded dataset. The seeded approach thus provides improved performance for differential analysis of datasets, as well as spectral unmixing analyses, to monitor, for example, the kinetic evolution of a reaction mixture, or metabolic pathway.}, } @article {pmid40378897, year = {2025}, author = {Fontanelli, L and Nisini, N and Pirola, S and Recchia, FA}, title = {Neuromuscular and cardiac organoids and assembloids: Advanced platforms for drug testing.}, journal = {Pharmacology & therapeutics}, volume = {272}, number = {}, pages = {108876}, doi = {10.1016/j.pharmthera.2025.108876}, pmid = {40378897}, issn = {1879-016X}, support = {R01 HL151345/HL/NHLBI NIH HHS/United States ; }, mesh = {*Organoids/drug effects ; Humans ; Animals ; Induced Pluripotent Stem Cells/cytology ; Drug Evaluation, Preclinical/methods ; *Neuromuscular Junction/drug effects ; }, abstract = {The inherent technical difficulties, ethical/regulatory issues and costs of experimental studies in animal models is prompting investigators to replace as much as possible living organisms with in vitro physiological models named organoids and assembloids. Generated from induced pluripotent stem cells, these three-dimensional structures approximate the complexity of tissues and their interactions, enabling personalized disease modelling and drug testing. The integration of multiple components in assembloids further enhances their predictive value for multi-system interactions and toxicities. This review describes how neuromuscular organoids, incorporating functional neuromuscular junctions and contractile muscle tissue, have been used to replicate, in vitro, complex neuromuscular morpho-functional structures, offering very valuable platforms to study molecular mechanisms and drug effects in models of incurable diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis. In the cardiological field, cardiac organoids and assembloids are proving reliable models for testing drug effects at molecular, morphological, electrophysiological and mechanical level. Recently, the integration of neuronal components into cardiac organoids has provided a potential approach to investigate autonomic function, a fundamental aspect of many neurological, neuromuscular and cardiac diseases. Challenges and limitations still remain, including the non-uniform differentiation protocols across studies, the incomplete maturation of cell phenotypes, and the lack of integrated pharmacokinetic modelling. We discussed some future developments aimed at overcoming such hurdles. Despite their current limitations, organoids and assembloids clearly hold great promises and will help advancing many fields of biomedicine.}, } @article {pmid40379219, year = {2025}, author = {Konopka, A and Jamali, MS and Fowler, M and Mehta, P and Parakh, S and Takalloo, Z and Farzana, F and Mumtaz, N and Hunter, J and Shadfar, S and Rogers, ML and Atkin, JD}, title = {Pathological forms of TDP-43 in amyotrophic lateral sclerosis (ALS) promote aberrant telomere elongation.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1871}, number = {7}, pages = {167906}, doi = {10.1016/j.bbadis.2025.167906}, pmid = {40379219}, issn = {1879-260X}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Animals ; *DNA-Binding Proteins/genetics/metabolism ; Mice ; Telomeric Repeat Binding Protein 2/metabolism/genetics ; *Telomere/metabolism/genetics/pathology ; Humans ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Male ; Neurons/metabolism/pathology ; Mice, Transgenic ; *Telomere Homeostasis ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons. TAR DNA-binding protein 43 (TDP-43) mis-localisation from the nucleus to the cytoplasm is the major pathological characteristic of ALS. Telomeres are repetitive DNA sequences found in complex with proteins at chromosomal ends. The shelterin protein complex protects telomeres from DNA damage by producing characteristic t-loop structures, and telomere repeat binding factor 2 (TRF2) has an essential role in this process. Telomere dysregulation is reported in ALS, but conflicting findings have been obtained. Here we examined if telomere dysregulation is present in cortical neurons in a mouse model with pathological mis-localisation of TDP-43 to the cytoplasm - TDP-43 rNLS - compared to controls, and in cortical primary neurons expressing TDP-43 ALS associated mutations (A315T, A90V). We demonstrate that telomeres are significantly longer and of more variable in length in the TDP-43 rNLS model compared to controls. This was proceeded by downregulation of TRF2 in early disease stages with subsequent upregulation of TRF2 at advanced disease in TDP-43 rNLS mice. Longer telomeres were also present in primary cortical neurons expressing mutant TDP-43. A trend towards TRF2 upregulation was also present in human ALS spinal cord lysates. We detected dysregulation of catalytic subunit of telomerase, TERT, and a trend towards upregulation of telomere interacting protein, Rif 1 in these mice and human ALS spinal cord lysates. The longer telomeres were independent of the alternative lengthening of telomeres (ALT) mechanism of maintaining telomere length. Similarly, no DNA damage at telomere sites was detected. Our findings imply that telomere protection is compromised in ALS, leading to longer telomeres in neurons in ALS associated with TDP-43 pathology.}, } @article {pmid40379483, year = {2025}, author = {Lester, DG and Thompson, AG and Talbot, K and Turner, MR}, title = {Progression and life expectancy in primary lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {10}, pages = {1008-1011}, pmid = {40379483}, issn = {1468-330X}, mesh = {Humans ; Male ; Female ; *Life Expectancy ; Middle Aged ; Aged ; Retrospective Studies ; Disease Progression ; *Motor Neuron Disease/mortality/physiopathology ; Adult ; Aged, 80 and over ; Age of Onset ; Amyotrophic Lateral Sclerosis/mortality ; }, abstract = {OBJECTIVES: To characterise the clinical characteristics and longitudinal outcomes in primary lateral sclerosis (PLS), including median survival from symptom onset and age at death.

METHODS: The authors retrospectively reviewed electronic health records of patients diagnosed with PLS referred to a specialised motor neuron disorders clinic from 2002 to 2024, analysed longitudinal Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) assessments using joint models and used Kaplan-Meier methods and life tables to calculate median survival and age at death compared with population-based values.

RESULTS: Of 52 patients, 34 (65%) were male, 41 (79%) first noted symptoms in the lower limbs and 10 (19%) in corticobulbar function. Median age of symptom onset was 53 years. The mean annual rate of functional decline was -1.92 ALSFRS-R points (95% CI -3.03 to -0.78), with equal highest rates of decline in fine and gross motor subscores. Five patients (10%) received gastrostomy and three (6%) non-invasive ventilation. Median survival from symptom onset was 23.1 years (22.7 to not reached), and median age at death was 79.5 years (77.8 to not reached) compared with a population-based reference mean of 81.9 years (81.1 to 82.8).

DISCUSSION: PLS may be commensurate with near-normal life expectancy. Significant disability arises from limb motor dysfunction, with a minority of patients requiring nutritional or respiratory support. This has important implications for counselling and trial design.}, } @article {pmid40381165, year = {2025}, author = {Esperante, I and Banzan, C and Munuera, JZ and Lima, A and Hunt, H and De Kloet, ER and Deniselle, MCG and De Nicola, AF and Meyer, M}, title = {The Selective Glucocorticoid Receptor Modulator Cort125329 Decreases Neuroinflammation and Gliosis and Enhances Myelination in the Wobbler Model of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {62}, number = {9}, pages = {12252-12269}, pmid = {40381165}, issn = {1559-1182}, support = {PIP 2017PIP 2019 #11220170100002CO//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PICT 2021 00389//Ministry of Science, Technology and Innovative Production of Argentina/ ; AFDN grant//CORCEPT Therapeutics/ ; 20020170100224BA)//Universidad de Buenos Aires/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism/complications ; *Receptors, Glucocorticoid/metabolism ; *Gliosis/drug therapy/pathology/complications/metabolism ; Disease Models, Animal ; *Neuroinflammatory Diseases/drug therapy/pathology/complications/metabolism ; *Myelin Sheath/drug effects/metabolism ; Mice ; Motor Neurons/drug effects/pathology/metabolism ; Mice, Inbred C57BL ; Male ; }, abstract = {The Wobbler mouse is a genetic model of familial amyotrophic lateral sclerosis. Wobblers show spinal cord neurodegeneration associated with gliosis, neuroinflammation, and demyelination. Like human neurodegenerative diseases, Wobblers show high levels of corticosterone in the blood and the nervous system. The role of glucocorticoids in neuropathology is suggested by the observation that pathological signs attenuate with treatment with glucocorticoid receptor (GR) antagonists/modulators. In the present study, we demonstrated in 5-month-old clinically afflicted Wobbler mice that the selective GR modulator CORT125329 decreased motoneuron degeneration, astro- and microgliosis, and levels of pro-inflammatory factors (HMGB1, toll-like receptor 4, tumor necrosis factor α, and its receptor). In addition, CORT125329 increased the acetylcholine-producing enzyme choline acetyltransferase, the neurotrophin brain-derived neurotrophic factor, and their cellular colocalization. Furthermore, the increased oligodendrocyte number and a healthier myelin ultrastructure are consistent with the enhanced axonal myelination after CORT125329 treatment. Finally, the high expression of immunoreactive protein and mRNA levels of aquaporin4 in Wobblers was decreased by CORT125329 treatment, implying this water channel is a glucocorticoid target involved in neuropathology. The beneficial effects of CORT125329 correlated with enhanced motor behavioral performance and trophic changes of the forelimbs. In conclusion, our results support further preclinical and clinical studies on GR modulators in sporadic amyotrophic lateral sclerosis.}, } @article {pmid40381433, year = {2025}, author = {Begh, MZA and Zehravi, M and Bhuiyan, MAK and Molla, MR and Raman, K and Emran, TB and Ullah, MH and Ahmad, I and Osman, H and Khandaker, MU}, title = {Recent advances in stem cell approaches to neurodegeneration: A comprehensive review with mechanistic insight.}, journal = {Pathology, research and practice}, volume = {271}, number = {}, pages = {156013}, doi = {10.1016/j.prp.2025.156013}, pmid = {40381433}, issn = {1618-0631}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; Animals ; }, abstract = {The progressive nature of neurodegenerative diseases (NDs), such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, presents substantial problems because current treatments are still obscure. Stem cell-based treatments are emerging as a viable solution to address the significant gaps in treating these severe diseases. This study provides a comprehensive analysis of the latest advancements in stem cell research, focusing on the treatment of NDs. Various types of stem cells, such as adult, induced pluripotent, and embryonic stem cells, and their potential applications in immunomodulation, neurotrophic factor release, and neuronal development are also discussed. Recent clinical studies reveal outcomes, challenges, and solutions, with advancements in disease-specific neural cell production, gene editing, and improved stem cell transplantation transport strategies. The review discussed future perspectives on developing more effective stem cell-based interventions. Biomaterials are being used for cell distribution and personalized medicine techniques to improve treatment outcomes, while exploring stem cell treatments for NDs and identifying areas for further research.}, } @article {pmid40382904, year = {2025}, author = {Montemerlo, AE and Azcarate, SM and Camiña, JM and Messina, G}, title = {Development of a chemometrics-assisted electrochemical sensor applied to gallic acid quantification in food samples.}, journal = {Food chemistry}, volume = {487}, number = {}, pages = {144737}, doi = {10.1016/j.foodchem.2025.144737}, pmid = {40382904}, issn = {1873-7072}, mesh = {*Gallic Acid/analysis ; *Electrochemical Techniques/methods/instrumentation ; *Chemometrics/methods/instrumentation ; Fruit/chemistry ; *Food Analysis/instrumentation/methods ; Tea/chemistry ; Limit of Detection ; }, abstract = {Gallic acid (GA) is an abundant natural phenolic compound found in foods such as tea, fruits, and beverages. Quantifying GA remains a key research area in analytical chemistry. Traditional methods, such as liquid chromatography, are time-consuming, highlighting the need for faster and more efficient techniques to quantify GA concentration. This study proposes an approach based on the MCR-ALS algorithm to model second-order voltammetric data obtained by varying the scan rate. Data preprocessing and subsequent mathematical modeling enabled the quantification of GA with a detection limit of 5.9 mg L[-1], below the stipulated concentrations for the analyte in various food matrices. Quantification was achieved even in the presence of unmodeled interferences, leveraging the second-order capabilities of multivariate calibration methods. This approach allows for accurate results to be obtained in a direct, fast, and reliable manner, representing a breakthrough in food industry quality control and opening new perspectives for food quality assessment.}, } @article {pmid40383620, year = {2025}, author = {Ibáñez-Cervantes, JL and Vargas-de León, C and Veléz-Reséndiz, JM and Fernández-Sánchez, V and Saavedra-Bravo, R and Bandala, C and Olvera-Gómez, I and Mancilla-Ramírez, J and Ibáñez-Cervantes, G}, title = {Association of ALS genes in strains of the genus Candida with cervical cytological alterations.}, journal = {Indian journal of medical microbiology}, volume = {54}, number = {}, pages = {100795}, doi = {10.1016/j.ijmmb.2025.100795}, pmid = {40383620}, issn = {1998-3646}, mesh = {Humans ; Female ; Adult ; Mexico ; *Candidiasis, Vulvovaginal/microbiology/pathology ; Middle Aged ; *Candida/genetics/isolation & purification/classification/enzymology ; *Cervix Uteri/pathology/microbiology ; Young Adult ; *Fungal Proteins/genetics ; Polymerase Chain Reaction ; Candida albicans/genetics/isolation & purification ; Aged ; }, abstract = {PURPOSE: Fungi are an important cause of human infection and include infections caused by Candida species. Vaginal candidiasis is a mycosis caused by several species of the genus Candida. In Mexico, it is considered the only mycosis that must be reported to health authorities. The participation and/or contribution of Candida ALS genes to the presence of cervical cytological alterations is currently unknown. The purpose of this study was to elucidate the frequency of Candida ALS genes and their association with clinical characteristics.

METHODS: The number of randomly selected samples was 697, of which 53 were Candida positive. Samples were selected from women attending gynaecological outpatient clinics for cervical cancer screening at Hospital Juarez de Mexico. These strains were identified, and genomic DNA was obtained from each isolate. Molecular assays were performed by endpoint PCR amplification of ALS genes.

RESULTS: The predominant Candida species identified in the study were Candida tropicalis and Candida albicans. ALS1 12 (22.6 %) and ALS3 19 (35.8 %) genes were found. ALS2, ALS4, ALS5, ALS6, ALS7, and ALS9 genes were not detected. ALS1 was the gene that was associated with patients using corticosteroids.

CONCLUSIONS: Vulvovaginitis remains one of the most prevalent conditions in patients in their 20s and 30s, and it is a real public health problem. Further studies are needed to determine the direct involvement of the identified ALS genes in the pathogen's ability to adhere and how it causes transient change in vaginal cytology.}, } @article {pmid40383997, year = {2025}, author = {Foucher, J and Wellander, T and Lovik, A and Öijerstedt, L and Juto, A and Fang, F and Ingre, C}, title = {Venous Bicarbonate as a Prognostic Biomarker and Proposed Proxy for Vital Capacity to Be Used as an Eligibility Criterion in Amyotrophic Lateral Sclerosis Clinical Trials.}, journal = {Brain and behavior}, volume = {15}, number = {5}, pages = {e70570}, pmid = {40383997}, issn = {2162-3279}, support = {//Demensförbundet/ ; //Neuro Sweden/ ; //R01TS000324-02-01/ ; //Svenska Frimurarorden/ ; //Ulla-Carin Lindquists stiftelse för ALS-forskning/ ; R01 TS000324/TS/ATSDR CDC HHS/United States ; /CC/CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/physiopathology/diagnosis/mortality ; Male ; Female ; Middle Aged ; Biomarkers/blood ; Prognosis ; *Bicarbonates/blood ; Aged ; Vital Capacity/physiology ; Sweden ; Registries ; Clinical Trials as Topic ; }, abstract = {BACKGROUND: Clinical trials for people living with ALS (pALS) all list vital capacity (VC) as an important eligibility criterion. However, VC measures are challenging to perform among pALS, especially bulbar pALS. Additionally, since the disease rapidly changes, the VC can change in a short duration of time, making it unreliable.

OBJECTIVE: We aimed to investigate the association of venous bicarbonate with VC as an alternative criterion for trial eligibility. We also wanted to examine whether venous bicarbonate could be used as a prognostic biomarker for survival in ALS.

METHODS: We included pALS from the Swedish ALS/MND Registry between January 1, 2019 and July 31, 2022. pALS had to have serum bicarbonate values and ALSFRS-R available close to diagnosis. Spearman correlations, Kaplan-Meier curves, and Cox proportional hazard regressions were used to assess the associations of venous bicarbonate with VC, other clinical characteristics, and survival.

RESULTS: Among the 117 pALS included in the study, we observed a negative correlation between venous bicarbonate and VC among spinal and bulbar pALS (ρ = -0.346, p = 0.002 and ρ = -0.367, p = 0.024, respectively). Venous bicarbonate negatively correlated with ALSFRS-R (ρ = -0.377, p < 0.001), specifically among bulbar pALS (ρ = -0.595, p < 0.001), but positively correlated with KING's stage (ρ = 0.248, p = 0.007). High level of venous bicarbonate appeared to be associated with shorter survival.

CONCLUSIONS: Venous bicarbonate appears to be a prognostic biomarker for survival among pALS. This cheap and easily accessible measure could potentially be an alternative for VC as an eligibility criterion in ALS trials.}, } @article {pmid40384011, year = {2025}, author = {Changqing, L and Leying, Y and Caiyun, M and Hebao, W and Laiguo, H and Xiaojiang, Z}, title = {Causal Relationships Between the Gut Microbiota, Inflammatory Cytokines, and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Analysis.}, journal = {Brain and behavior}, volume = {15}, number = {5}, pages = {e70571}, pmid = {40384011}, issn = {2162-3279}, support = {//Philosophy and Social Sciences Foundation of the Anhui Higher Education Institutions of China/ ; //Provincial Quality Engineering Project of Higher Education Institutions of Anhui Province/ ; //Natural Science Foundation of the Higher Education Institutions of Anhui Province/ ; 202310367042//National College Students Innovation and Entrepreneurship Training Program/ ; //innovation and entrepreneurship training program for college students/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/microbiology ; Humans ; Mendelian Randomization Analysis ; *Gastrointestinal Microbiome/genetics/physiology ; *Cytokines/metabolism/genetics ; Genome-Wide Association Study ; Inflammation ; }, abstract = {BACKGROUND: The relationship between gut microbiota (GM) and amyotrophic lateral sclerosis (ALS) is well-documented. However, the causal nature of this association and the potential mediating role of inflammatory cytokines (ICs) have yet to be elucidated.

METHODS: We performed Mendelian randomization (MR) analyses utilizing data derived from genome-wide association studies (GWAS) of GM, ICs, and ALS. Initially, we conducted bidirectional two-sample MR analysis to determine the causal relationships between GM, ICs, and ALS. Subsequently, a two-step MR mediation analysis was performed to investigate the role of ICs as mediators. The primary statistical approach was the inverse variance weighted (IVW) method.

RESULTS: Through MR analysis, we identified one positive causal relationship and three negative causal relationships between GM and ALS. There was one positive association and one negative association between ICs and ALS. In addition, ICs do not appear to mediate the pathway from GM to ALS.

CONCLUSION: This study established a causal relationship between GM, ICs, and ALS, suggesting that ICs do not function as mediators in the pathway from GM to ALS. These findings provide new perspectives on potential ALS prevention and treatment strategies.}, } @article {pmid40384352, year = {2025}, author = {Yuan, Y and Fu, Y and Wang, X and Hu, F and Zhao, Q and He, C and Tang, L and Li, Y and Bu, Y and Song, X and Liu, Q and Liu, Z and Xu, R and Cao, W and Zhang, Y and Yi, X and Wang, J and Chen, BT}, title = {Shape Alterations of Subcortical Nuclei Correlate With Amyotrophic Lateral Sclerosis Progression.}, journal = {Brain and behavior}, volume = {15}, number = {5}, pages = {e70495}, pmid = {40384352}, issn = {2162-3279}, support = {81300981//National Natural Science Foundation of China/ ; 81671120//National Natural Science Foundation of China/ ; 82171431//National Natural Science Foundation of China/ ; U22A20377//National Natural Science Foundation of China/ ; 2021ZD0201803//Science and Technology Innovation 2030/ ; 2020LNJJ13;2022LNJJ09//Project Program of National Clinical Research Center for Geriatric Disorders (Xiangya hospital)/ ; 2022JJ30979//Natural Science Foundation of Hunan Province/ ; 2021YFA0805202//National Key Research and Development Program of China/ ; 2022M713536//China Post-Doctoral Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/physiopathology ; Male ; Female ; Disease Progression ; Middle Aged ; Magnetic Resonance Imaging/methods ; Aged ; Brain Stem/pathology/diagnostic imaging ; Neuroimaging/methods ; Basal Ganglia/pathology/diagnostic imaging ; Adult ; Thalamus/pathology/diagnostic imaging ; Brain/pathology/diagnostic imaging ; Prospective Studies ; }, abstract = {BACKGROUND: Neuroimaging has been increasingly used to assess brain structural alterations in patients with amyotrophic lateral sclerosis (ALS). We aimed to investigate alterations in brain sub-cortical structures and to identify potential neuroimaging biomarkers for disease progression for patients with ALS.

METHODS: A total of 61 patients with ALS were prospectively enrolled and were divided into three subgroups according to disease progression, i.e., fast, intermediate, and slow progression. Sixty-one matched healthy controls (HCs) were also recruited. All participants acquired a brain structural magnetic resonance imaging scan for subcortical volumetric and shape analyses. Neuropsychological testing and functional assessment were performed.

RESULTS: Patients with fast progression showed significant shape alterations in basal ganglia and brainstem as compared to the HCs group. In ALS patients with fast progression, shape contractions with atrophic changes were noted in bilateral nucleus accumbens, left caudate, left thalamus, and brainstem; while shape expansion with hypertrophy was noted in the left caudate, left thalamus, and left pallidum (all p < 0.05). There were significant positive correlations of the shape changes of the left thalamus with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALS-FRS-R) total and limb scores and with disease duration (all p < 0.05). There were positive correlations of left pallidum with anxiety or with disease duration, and of left nucleus accumbens with ALS-FRS-R total or bulbar score, and of brainstem with mini-mental state examination score (all p < 0.05).

CONCLUSION: Extensive shape alterations of subcortical nuclei were noted in patients with fast progression of ALS, implicating subcortical shape being a potential neuroimaging biomarker for ALS progression.}, } @article {pmid40384575, year = {2025}, author = {Vogt, C and Weber, M and Schneider, U and Neuwirth, C}, title = {Quinine Sulfate for Muscle Cramps in Amyotrophic Lateral Sclerosis: A Randomized, Double-Blind Crossover Trial.}, journal = {Muscle & nerve}, volume = {72}, number = {2}, pages = {267-273}, doi = {10.1002/mus.28440}, pmid = {40384575}, issn = {1097-4598}, support = {//Swiss ALS foundation/ ; //Hänseler AG/ ; }, mesh = {Humans ; *Quinine/therapeutic use ; Double-Blind Method ; *Muscle Cramp/drug therapy/etiology ; Male ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; Female ; Cross-Over Studies ; Middle Aged ; Aged ; Adult ; Treatment Outcome ; Muscle Relaxants, Central/therapeutic use ; }, abstract = {INTRODUCTION/AIMS: Many patients with amyotrophic lateral sclerosis (ALS) experience muscle cramps during the course of the disease. This study aimed to evaluate the efficacy of orally administered quinine sulfate for muscle cramps in ALS patients.

METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial in ALS patients experiencing daily muscle cramps. After a two-week run-in period, patients were assigned to receive 250 mg quinine sulfate once daily, followed by a placebo or vice versa. Each treatment period lasted 2 weeks and was followed by a 4-week washout period. Patients used a daily diary to rate muscle cramp intensity on the numeric rating scale (NRS) and record muscle cramp frequency. The primary outcome measure was change in cramp intensity; coprimary outcome measures were number of muscle cramps during daytime and nighttime.

RESULTS: Data from four women and three men were included in the analysis, all of whom reported a notable reduction in cramp intensity and frequency, leading them to continue the medication. Quinine sulfate was well-tolerated, with two patients reporting mild tinnitus. Cramp intensity was significantly reduced by 48% (p = 0.042). Further, the number of daytime muscle cramps declined significantly (p = 0.024).

DISCUSSION: Our findings suggest the potential efficacy of quinine sulfate in reducing muscle cramp intensity and frequency in ALS patients. However, the small sample size (n = 7) limits generalizability. Larger, multicenter studies are needed to confirm these results and fully assess its safety, serious adverse events, and therapeutic potential.}, } @article {pmid40384653, year = {2025}, author = {Bai, C and Leng, Y and Xiao, H and Li, L and Cui, W and Li, T and Dong, Y and Zheng, J and Cai, X}, title = {A deep-learning model for predicting post-stroke cognitive impairment based on brain network damage.}, journal = {Quantitative imaging in medicine and surgery}, volume = {15}, number = {5}, pages = {3964-3981}, pmid = {40384653}, issn = {2223-4292}, abstract = {BACKGROUND: Post-stroke cognitive impairment (PSCI) is a common and severe complication following acute lacunar stroke (ALS). Due to the limitations of current assessment tools and imaging methods, the early diagnosis of PSCI within 3 months of ALS remaining challenging. This study aimed to develop an effective, reliable, and accurate deep-learning method to predict PSCI within 3 months of ALS.

METHODS: In total, 100 ALS patients were enrolled in the study, of whom 39 were diagnosed with PSCI and 61 were non-PSCI. First, we quantified three-dimensional (3D) gray-matter damage and white-matter tract disconnection, providing both regional damage (RD) and structural disconnection (SDC) higher-dimensional insights into brain network disruption. Second, we developed a novel deep-learning model based on ResNet18, integrating 3D RD, SDC, and diffusion-weighted imaging (DWI) to provide a comprehensive analysis of brain network integrity and predict PSCI. Finally, we compared the performance of our method with other methods, and visualized brain network damage associated with PSCI.

RESULTS: Our model showed strong predictive performance and had a mean accuracy (ACC) of 0.820±0.024, an area under the curve (AUC) of 0.795±0.068, a sensitivity (SEN) of 0.746±0.121, a specificity (SPE) of 0.869±0.044, and a F1-score (F1) of 0.760±0.050 in the five-fold cross-validation, outperforming existing models. In the PSCI patients, brain network damage significantly affected the salience, default mode, and somatic motor networks.

CONCLUSIONS: This study not only established a model that can accurately predict PSCI, it also identified potential targets for symptom-based treatments, offering new insights into PSCI.}, } @article {pmid40385376, year = {2025}, author = {Chamoun, S and Imrell, S and Upate, Z and Kläppe, U and Öijerstedt, L and Yazdani, S and Andersson Franko, M and Foucher, J and Azizi, L and Lovik, A and Samuelsson, K and Press, R and Fang, F and Svennberg, E and Juto, A and Ingre, C}, title = {Plasma troponin T reflects lower motor neuron involvement on electromyography in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {3}, pages = {fcaf177}, pmid = {40385376}, issn = {2632-1297}, abstract = {Cardiac troponin T (cTnT) is elevated in neuromuscular conditions without apparent cardiac disease, including Amyotrophic Lateral Sclerosis (ALS). The reason for this increase is unclear. Since cTnT is found in both cardiomyocytes and skeletal muscle cells, we aimed to investigate the latter as a possible cTnT source. We examined the correlation of cTnT in venous blood to lower motor neuron (LMN) involvement on Electromyography (EMG). A positive correlation between EMG findings and cTnT levels would indicate that cTnT is a biomarker for LMN involvement in ALS. This observational cohort study was conducted on a tertiary referral centre for neuromuscular diseases in Stockholm, Sweden. Consecutive patients with ALS were included. EMG was performed during diagnostic work-up, and high-sensitive cardiac troponin T (hs-cTnT), plasma creatine kinase (CK), and serum neurofilament light (NfL) were analysed within 6 months of the EMG. King's stage and score on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) closest to hs-cTnT sampling were noted. In total, 50 ALS patients diagnosed between 1 January 2014 and 31 December 2018 were included and followed until death, invasive ventilation, or the 14 August 2024. Hs-cTnT correlated positively with the number of muscular regions involved (τ = 0.283, P = 0.009) and percentage of muscles involved on EMG (ρ = 0.367, P = 0.009). Hs-cTnT was associated with the percentage of muscles involved in EMG in the adjusted linear regression. Patients with higher hs-cTnT had more advanced King's stage, both when numerical hs-cTnT and subgrouping high (≥15 nanogram/L) versus normal hs-cTnT was used (τ = 0.253, P = 0.021 and U = 197.5, P = 0.022, respectively). Hs-cTnT was neither correlated to ALSFRS-R total score (ρ = -0.176, P = 0.220 and U = 249.5, P = 0.233, respectively) nor ALSFRS-R excluding respiratory domain score (ρ = -0.069, P = 0.632 and U = 280.5, P = 0.558, respectively). High versus normal hs-cTnT did not predict survival (univariate analysis, HR = 1.824, P = 0.060). Numerical hs-cTnT was associated with shorter survival (univariate analysis, HR = 1.635, P = 0.017) but not after adjusting for age at diagnosis (HR = 1.413, P = 0.105). This study illustrates that ALS patients with higher hs-cTnT have more spread disease as evidenced by the positive correlation between hs-cTnT and both EMG and King's stage. This is not true for established biomarkers of muscle damage (CK) and neuroaxonal damage (NfL). These findings need to be confirmed in larger studies but suggest that hs-cTnT is a biomarker of LMN involvement in patients with ALS and could be used in clinical trials.}, } @article {pmid40385805, year = {2025}, author = {Moutinho, A and Fontes, J and Ferreira, L and Lopes, J and Martins, F and Mega, S and Gil, M and Barros, F and Correia, AM}, title = {Sepsis Alerts in the Pre-hospital Setting: An Observational Retrospective Study of Emergency Medical Services' Response in Portugal (2020-2023).}, journal = {Cureus}, volume = {17}, number = {4}, pages = {e82528}, pmid = {40385805}, issn = {2168-8184}, abstract = {Background Sepsis is a life-threatening condition that demands prompt recognition and intervention to enhance patient outcomes. Early identification and timely treatment, particularly in the prehospital setting, are essential. Objective This study aims to characterize sepsis pre-alerts issued by the Portuguese Emergency Medical Services (EMS) early warning system between May 2020 and December 2023, focusing on adult patients. It provides an overview of the alert system and examines associated clinical data, therapeutic interventions, and hospital referrals. Methods A retrospective analysis was conducted on sepsis pre-alerts from the Portuguese EMS database. Data collected included patient demographics, comorbidities, National Early Warning Score (NEWS), interventions administered, and outcomes. Results A total of 537 sepsis alerts were identified, with a median patient age of 83 years. The majority of patients had significant cardiovascular and neurological comorbidities. The average NEWS was 11.74. Advanced Life Support (ALS) or Integrated Life Support (ILS) teams were required in 76.9% (N=413) of cases. Interventions included intravenous fluid administration in 49.3% (N=265), oxygen therapy in 46.2% (N=248), and vasopressor use in 3.9% (N=14). Conclusions Effective prehospital sepsis management is crucial for improving patient outcomes. Challenges such as delayed hospital transfers, often due to regional constraints, highlight the need for enhanced integration between EMS and hospital care. Future efforts should focus on optimizing early sepsis management, fostering collaboration between EMS and hospital teams, and exploring the feasibility of prehospital antibiotic administration.}, } @article {pmid40385899, year = {2025}, author = {Panganiban, ELC and Rosales, RL}, title = {Multiple System Atrophy (Cerebellar Type) With Overlapping Progressive Muscular Atrophy Features and Genetic Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4) Amyotrophic Lateral Sclerosis Variant: A Case Report.}, journal = {Cureus}, volume = {17}, number = {4}, pages = {e82509}, pmid = {40385899}, issn = {2168-8184}, abstract = {Multiple system atrophy (MSA) is a progressive disease with Parkinsonism, dysautonomia, and cerebellar symptoms wherein patients can present with a broad range of confusing and overlapping findings attributable to various neuroanatomical substrates. Although possible, weakness is an unusual primary complaint, warranting further work-up for another neurodegenerative disease. The involvement of the more central structures, such as the locus coeruleus, pontine micturition center, and the cerebellum, can explain the wide range of symptoms. While Onuf's nucleus contributes to the urinary symptoms, anterior horn cells can implicate a motor neuron disease. Taking the varied neuroanatomical substrates into consideration, patients can present with a plethora of dysregulated motor symptoms. The authors share the course of a patient with clinically established MSA-cerebellar type and lower motor neuron disease findings at par with progressive muscular atrophy (PMA), but tested positive for an ERBB4 gene mutation, which is linked to an amyotrophic lateral sclerosis (ALS) variant. A 65-year-old Chinese female manifested with bilateral leg weakness and urinary incontinence. Over the next five years, she developed recurrent pre-syncopal attacks, asymmetric limb tremors, memory lapses, laughing fits, and a staccato-like voice. Medical management with anti-Parkinsonism drugs did not help her condition. Repeated annual non-contrast enhanced cranial magnetic resonance imaging (MRI) revealed gradual cerebellar atrophy, and an eventual prominent "hot-cross bun" sign. Because of episodes of orthostatic hypotension, with a systolic blood pressure as low as 50 mmHg, she gradually became bedridden with progressive arm weakness and sleep issues. These prompted her admission. Saccadic dysmetria and ataxic dysarthria aided in the diagnosis of MSA-cerebellar type, while motor neuron disease findings included tongue fasciculation, asymmetric leg atrophy, and polyminimyoclonus, suggestive of PMA. Neurophysiological studies confirmed this, while whole genome sequencing yielded an ERBB4 gene ALS variant of uncertain significance. She remained compliant with physical therapy during her admission. Although she was prescribed fludrocortisone for symptomatic relief and a two-week course of edaravone, she was discharged with minimal improvement and wheelchair-bound. However, the patient eventually expired two years afterward due to systemic complications. Although suspicion for a certain movement disorder can be initially made with physical examination, diagnostics can shed further light on the patient's pathology, exemplifying the uniqueness of this case report and how varying neurodegenerative movement disorders can coexist in a single patient.}, } @article {pmid40386966, year = {2025}, author = {Honig, A and Dayan, R and Knaani, A and Levine, H and Gotkine, M}, title = {Military Service Roles and ALS Among Veterans: A Matched Case-Control Study.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {8}, pages = {1702-1705}, pmid = {40386966}, issn = {2328-9503}, abstract = {While military service is an established risk factor for amyotrophic lateral sclerosis (ALS), it remains unclear whether this association is linked to combat. We conducted a matched case-control study comparing 191 ALS patients who were veterans of the Israeli Defense Forces (IDF) with known military service type and 1910 matched controls. The ALS group had higher rates of combat service (46.0% vs. 22.7%) and parachuting (10.5% vs. 1.1%) in comparison with controls (p < 0.001 for both). In a multivariate model, combat service was associated with ALS (odds ratio 2.49, confidence interval [1.49-4.16], p < 0.01). The higher prevalence of combat roles among ALS patients expands our understanding of military service factors that contribute to ALS risk.}, } @article {pmid40388191, year = {2025}, author = {De Marchi, F and Lombardi, I and Bombaci, A and Diamanti, L and Olivero, M and Perciballi, E and Tornabene, D and Vulcano, E and Ferrari, D and Mazzini, L}, title = {Recent therapeutic advances in the treatment and management of amyotrophic lateral sclerosis: the era of regenerative medicine.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {7}, pages = {773-789}, doi = {10.1080/14737175.2025.2508781}, pmid = {40388191}, issn = {1744-8360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Regenerative Medicine/methods ; Genetic Therapy/methods ; Stem Cell Transplantation/methods ; Animals ; }, abstract = {INTRODUCTION: Despite decades of research, effective disease-modifying treatments for Amyotrophic Lateral Sclerosis (ALS) remain scarce. The emergence of regenerative medicine presents a new frontier for ALS treatment.

AREAS COVERED: This review is based on a comprehensive literature search using PubMed, Scopus and clinical trials databases on the recent therapeutic advancements in ALS, giving focus to regenerative medicine. The article includes coverage of stem cell-based therapies, including mesenchymal, neural and induced pluripotent stem cells; all of which may offer potential neuroprotective and immunomodulatory effects. Gene therapy, particularly antisense oligonucleotides targeting ALS-related mutations, has gained traction, with tofersen becoming the first FDA-approved genetic therapy for ALS. The article also covers emerging approaches such as extracellular vesicles, immune-modulating therapies, and bioengineering techniques, including CRISPR-based gene editing and cellular reprogramming, that hold promise for altering disease progression.

EXPERT OPINION: While regenerative medicine provides hope for ALS patients, significant challenges remain. Biomarkers will play a crucial role in guiding personalized treatment strategies, ensuring targeted interventions. Future research should prioritize optimizing combinatory approaches, integrating different therapy strategies to maximize patient outcomes. Although regenerative medicine is still in its early clinical stages, its integration into ALS treatment paradigms could redefine disease management and alter its natural course.}, } @article {pmid40388677, year = {2025}, author = {de Vries, BS and de Boer, EMJ and Brugman, F and Van Damme, P and Veldink, JH and van Es, MA and van den Berg, LH}, title = {Primary Lateral Sclerosis: Implications for Diagnostic Criteria From a Natural History Study in the Netherlands.}, journal = {Neurology}, volume = {104}, number = {11}, pages = {e213461}, pmid = {40388677}, issn = {1526-632X}, mesh = {Humans ; Female ; Middle Aged ; Male ; *Motor Neuron Disease/diagnosis/epidemiology/physiopathology ; Aged ; Netherlands/epidemiology ; Disease Progression ; Amyotrophic Lateral Sclerosis/diagnosis ; Follow-Up Studies ; Adult ; Cohort Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: Primary lateral sclerosis (PLS) is a rare disease characterized by upper motor neuron (UMN) degeneration. We aimed to elucidate the natural history in patients with UMN syndromes suggestive of PLS and validate the most recent diagnostic (consensus) criteria.

METHODS: A validation study of a long-term follow-up cohort was conducted, including adults with UMN syndromes and disease durations ≥6 months. Patients were assessed at baseline (T1), at 3 years (T2), and when possible after 13 years (T3). Diagnostic categorization followed the 2020 PLS consensus criteria. Main outcomes included diagnostic classification at follow-up and survival.

RESULTS: The study comprised 86 patients (34 women [40%], mean age 58.9 ± 10.1 years), of whom 43 met the PLS consensus criteria at baseline (6 probable, 37 definite). Eight patients had a disease duration <2 years, and 35 patients presented with UMN symptoms localized to 1 region (1 bulbar, 34 legs). Change of initial diagnosis occurred in 14% of patients with PLS, and 49% of patients presenting with UMN symptoms in 1 region progressed to PLS. Seven patients developed amyotrophic lateral sclerosis (ALS), and for 7 patients, diagnosis was revised to hereditary spastic paraplegia (HSP). Survival was shorter for patients with a disease duration <4 years. In the probable PLS group, 33% converted to ALS. Converters had a steeper Amyotrophic Lateral Sclerosis Functional Rating Scale slope (p = 0.023) and shorter symptom duration (p < 0.001) at inclusion. Of patients presenting with leg symptoms, diagnosis was revised between T2 and T3 in 29%. Introducing a 4-year minimal disease duration for PLS diagnosis and categorization based on regions involved resulted in 86% of PLS diagnoses remaining within the PLS category, 5% transitioning to ALS (slow variant), and 9% to HSP. Survival was longest for patients presenting with symptoms confined to arms and legs or legs only, followed by those with bulbar involvement at baseline, while patients with disease durations between 6 months and 4 years exhibited the shortest survival.

DISCUSSION: Our findings suggest that a diagnosis of PLS should be deferred until 4 years after symptom onset because shorter durations correlate with higher ALS conversion rates and shorter survival. Categorization by regional involvement may facilitate more effective monitoring of patients with UMN syndromes.}, } @article {pmid40389086, year = {2025}, author = {Pu, K and Yang, S and Sheng, R and Chen, J and Dai, Y and Wood, IC and Zhong, Z and Xu, S}, title = {Chuanxiong-Danggui herb pair alleviated cognitive deficits of APP/PS1 mice by promoting mitophagy.}, journal = {Journal of ethnopharmacology}, volume = {350}, number = {}, pages = {119988}, doi = {10.1016/j.jep.2025.119988}, pmid = {40389086}, issn = {1872-7573}, mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Mice, Inbred C57BL ; *Mitophagy/drug effects ; *Cognitive Dysfunction/drug therapy ; Mice ; *Alzheimer Disease/drug therapy/pathology ; Amyloid beta-Protein Precursor/genetics ; Hippocampus/drug effects/pathology/metabolism ; Mice, Transgenic ; Male ; *Neuroprotective Agents/pharmacology ; Disease Models, Animal ; Presenilin-1/genetics ; Cell Line ; Dendritic Spines/drug effects ; Maze Learning/drug effects ; }, abstract = {Disruption of receptor-mediated mitophagy contributes to neuronal damage in Alzheimer's disease (AD). Chuanxiong-Danggui herb pair (CDHP) is classic herbal pair applied to treating neurodegenerative diseases including AD, Amyotrophic Lateral Sclerosis, Parkinson's disease. Though studies have demonstrated the neuroprotective effects of CDHP, the underlying mechanisms by which CDHP attenuates neuronal impairment of AD remains to be elucidated.

AIM OF THE STUDY: The objective of this work was to investigate the anti-AD mechanism of CDHP in APP/PS1 mice.

MATERIALS AND METHODS: Behavioral assessments were conducted on C57BL/6J and APP/PS1 mice following CDHP treatment, alongside an evaluation of neuronal morphology in the hippocampal region. In vitro, HT-22 cells were induced by Aβ25-35 before being treated with CDHP. The mechanisms of CDHP were investigated using transmission electron microscopy, Golgi staining, immunofluorescence, and Western blot analysis.

RESULTS: Results from the passive avoidance test and the Morris water maze (MWM) indicated that CDHP significantly mitigated cognitive deficits of APP/PS1 mice, accompanied by a reduction of pathological damage in the CA1 and CA3 regions of hippocampus. Further testing found that a significant reduction in dendritic spines density was rescued by CDHP. Synaptophysin (SYN) and postsynaptic density protein 95 (PSD-95) were elevated in the CDHP group, while β-amyloid (Aβ) plaques deposition was significantly reduced. Simultaneously, CDHP markedly inhibited neuronal apoptosis through a decrease of the levels of Cleaved Caspase-12 and enhanced expression of Bcl-2/Bax, both in vivo and in vitro. Additionally, CDHP improved mitochondrial morphology and function in the AD model by decreasing abnormal mitochondria and increasing the expression of COXIV. Transmission electron microscopy (TEM) revealed that clear mitophagy-autophagosomes were nearly absent in APP/PS1 mice, while the expression of p62 and LC3B were elevated following CDHP treatment. Furthermore, CDHP increased the expression of the FUNDC1 and PGAM5 in APP/PS1 mice and AD-like cell models.

CONCLUSION: These findings suggest that CDHP mitigated cognitive dysfunction in APP/PS1 mice by enhancing mitophagy to reduce neuronal injury.}, } @article {pmid40389143, year = {2025}, author = {Tan, X and Su, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Wang, S and Wang, J and Feng, H}, title = {COMM domain containing 4 inhibits hephaestin and ferroportin to enhance neuronal ferroptosis by disturbing the Cu-Fe balance in amyotrophic lateral sclerosis.}, journal = {Brain research}, volume = {1861}, number = {}, pages = {149707}, doi = {10.1016/j.brainres.2025.149707}, pmid = {40389143}, issn = {1872-6240}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; *Ferroptosis/physiology ; Ferroportin ; Animals ; *Copper/metabolism ; *Cation Transport Proteins/metabolism ; Humans ; Iron/metabolism ; Neurons/metabolism ; *Membrane Proteins/metabolism ; Mice ; *Adaptor Proteins, Signal Transducing/metabolism ; Male ; Disease Models, Animal ; }, abstract = {Dysregulation of copper and iron homeostasis contributes to the progression of amyotrophic lateral sclerosis (ALS), but the role and mechanism of COMM domain containing 4 (COMMD4) in ALS remains unclear. In this research, we showed that the expression of COMMD4 was upregulated in ALS cells and animal models. The increased COMMD4 induced neuronal ferroptosis by disrupting the Cu-Fe balance. Mechanistic studies indicated that COMMD4 inhibited ferroportin (FPN)-mediated neuronal iron efflux by inhibiting intracellular copper and hephaestin (HEPH). Our findings demonstrated that COMMD4 depletion exerts neuroprotective effects on ALS by increasing intracellular copper and activating HEPH/FPN pathway, rather than affecting the interaction between HEPH and FPN. Targeting COMMD4 and its downstream signaling pathways may offer potential therapeutic avenues for ALS.}, } @article {pmid40389171, year = {2025}, author = {Das, D and Das, A and Bhattacharya, K and Koch, KP and Deuri, DJ and Saikia, D and Chanu, NR and Deka, S}, title = {Xanthones as neuroprotective agents: A comprehensive review of their role in the prevention and treatment of neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {109}, number = {}, pages = {102772}, doi = {10.1016/j.arr.2025.102772}, pmid = {40389171}, issn = {1872-9649}, mesh = {*Xanthones/therapeutic use/pharmacology/chemistry ; Humans ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/prevention & control ; Animals ; }, abstract = {Over the recent years, numerous research efforts have been focused toward xanthones, a class of heterocyclic compounds characterized by a three-ring core structure and a diverse range of biological activities. Despite extensive studies, no xanthone-based molecule has successfully progressed through clinical trials to reach pharmaceutical applications. Xanthones belong to the class of secondary metabolites that exist naturally, found in various plant species, and their structural diversity has been further expanded through synthetic modifications to enhance their pharmacological efficacy. This review provides a comprehensive description of the therapeutic potential of xanthone derivatives within the scope of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and neuroinflammation. Existing literature has been rigorously examined to highlight the pharmacological relevance of xanthones in these disorders. Additionally, the pathophysiological aspects of each disease are discussed in detail to establish a mechanistic understanding of how xanthone derivatives may exert neuroprotective effects. Furthermore, the SAR of xanthones is explored to elucidate key molecular features responsible for their bioactivity, providing insights into rational drug design. By synthesizing and critically analyzing the existing research, this review is focused in highlighting the therapeutic relevance of xanthones in neurodegenerative diseases and their potential as lead candidates for further drug development.}, } @article {pmid40389397, year = {2025}, author = {Schweingruber, C and Nijssen, J and Mechtersheimer, J and Reber, S and Lebœuf, M and O'Brien, NL and Mei, I and Hedges, E and Keuper, M and Benitez, JA and Radoi, V and Jastroch, M and Ruepp, MD and Hedlund, E}, title = {Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4633}, pmid = {40389397}, issn = {2041-1723}, support = {2020-01049//Vetenskapsrådet (Swedish Research Council)/ ; }, mesh = {*RNA-Binding Protein FUS/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Mitochondria/metabolism/genetics/pathology ; Humans ; Single-Cell Analysis ; Induced Pluripotent Stem Cells/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Mutation ; Sequence Analysis, RNA ; Axons/metabolism ; C9orf72 Protein/genetics/metabolism ; Animals ; }, abstract = {Mutations in FUS and TARDBP cause amyotrophic lateral sclerosis (ALS), but the precise mechanisms of selective motor neuron degeneration remain unresolved. To address if pathomechanisms are shared across mutations and related to either gain- or loss-of-function, we performed single-cell RNA sequencing across isogenic induced pluripotent stem cell-derived neuron types, harbouring FUS P525L, FUS R495X, TARDBP M337V mutations or FUS knockout. Transcriptional changes were far more pronounced in motor neurons than interneurons. About 20% of uniquely dysregulated motor neuron transcripts were shared across FUS mutations, half from gain-of-function. Most indicated mitochondrial impairments, with attenuated pathways shared with mutant TARDBP M337V as well as C9orf72-ALS patient motor neurons. Mitochondrial motility was impaired in ALS motor axons, even with nuclear localized FUS mutants, demonstrating shared toxic gain-of-function mechanisms across FUS- and TARDBP-ALS, uncoupled from protein mislocalization. These early mitochondrial dysfunctions unique to motor neurons may affect survival and represent therapeutic targets in ALS.}, } @article {pmid40389567, year = {2025}, author = {Wu, WL and Gong, XX and Qin, ZH and Wang, Y}, title = {Molecular mechanisms of excitotoxicity and their relevance to the pathogenesis of neurodegenerative diseases-an update.}, journal = {Acta pharmacologica Sinica}, volume = {46}, number = {12}, pages = {3129-3142}, pmid = {40389567}, issn = {1745-7254}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; Animals ; *Glutamic Acid/metabolism/toxicity ; Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Glutamate excitotoxicity is intricately linked to the pathogenesis of neurodegenerative diseases, exerting a profound influence on cognitive functions such as learning and memory in mammals. Glutamate, while crucial for these processes, can lead to neuronal damage and death when present in excessive amounts. Our previous review delved into the cascade of excitotoxic injury events and the underlying mechanisms of excitotoxicity. Building on that foundation, this update summarizes the latest research on the role of excitotoxicity in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, as well as new cutting-edge techniques applied in the study of excitotoxicity. We also explore the mechanisms of action of various excitotoxicity inhibitors and their clinical development status. This comprehensive analysis aims to enhance our understanding of the nexus between excitotoxicity and neurodegenerative diseases, offering valuable insights for therapeutic strategies in these conditions.}, } @article {pmid40389989, year = {2025}, author = {Noh, MY and Oh, SI and Kim, YE and Cha, SJ and Sung, W and Oh, KW and Park, Y and Mun, JY and Ki, CS and Nahm, M and Kim, SH}, title = {Mutations in NEK1 cause ciliary dysfunction as a novel pathogenic mechanism in amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {59}, pmid = {40389989}, issn = {1750-1326}, support = {RS-2023-00265515//Ministry of Science and ICT/ ; RS-2023-00265515//Ministry of Science and ICT/ ; 24-BR-02-04//Ministry of Science and ICT/ ; 25-BR-04-01//Ministry of Science and ICT, South Korea/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *NIMA-Related Kinase 1/genetics/metabolism ; *Cilia/metabolism/pathology/genetics ; Mutation/genetics ; Female ; Male ; Middle Aged ; Motor Neurons/metabolism ; Fibroblasts/metabolism ; Adult ; }, abstract = {BACKGROUND: Neuronal primary cilia, vital for signaling and cell-cycle regulation, have been implicated in maintaining neuronal identity. While a link between primary ciliary defects and neurodegenerative diseases is emerging, the precise pathological mechanisms remain unclear.

METHODS: We studied the genetic contribution of NEK1 to ALS pathogenesis by analyzing the exome sequences of 920 Korean patients with ALS. To understand the disease contribution of NEK1 variants in ALS, we performed a series of functional studies using patient fibroblasts focusing on primary cilia and microtubule-related phenotypes. In addition, these findings were validated in iPSC-derived motor neurons (iPSC-MNs).

RESULTS: NIMA-related kinase 1 (NEK1), a gene encoding a serine/threonine kinase involved in cell cycle regulation, has been identified as a risk gene for amyotrophic lateral sclerosis (ALS). Here, we report that mutations in NEK1 cause primary ciliary abnormality, cell cycle re-entry, and disrupted tubulin acetylation in ALS. We analyzed the whole-exome sequences of 920 Korean patients with sporadic ALS and identified 16 NEK1 variants in 23 patients. We found that two novel variants, p.E853Rfs*9 and p.M1?, reduced NEK1 expression, resulting in loss-of-function (LOF) and one synonymous splicing variant (p.Q132=) exhibited an aberrant isoform lacking exon 5. All three NEK1 variants exhibited abnormal primary ciliary structure, impaired sonic hedgehog signaling, and altered cell-cycle progression. Furthermore, the ALS-linked variants induced intracellular calcium overload followed by Aurora kinase A (AurA)-histone deacetylase (HDAC)6 activation, resulting in ciliary disassembly. These defects were restored by treatment with the intracellular Ca[2+] chelator, BAPTA. We also found that NEK1 variants cause decreased α-tubulin acetylation, mitochondrial alteration, and impaired DNA damage response (DDR). Notably, drug treatment to inhibit HDAC6 restored the NEK1-dependent deficits in patient fibroblasts. And, we confirmed that data found in patient fibroblasts were reproduced in iPSC-MNs model.

CONCLUSIONS: Our results suggest that NEK1 contributes to ALS pathogenesis through the LOF mechanism, and HDAC6 inhibition provides an attractive therapeutic strategy for NEK1 variants associated ALS treatment.}, } @article {pmid40390638, year = {2025}, author = {Oh, J and Chu, HS}, title = {Self-care mobile application for people with Amyotrophic Lateral Sclerosis: a development and usability test.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {683-690}, doi = {10.1080/21678421.2025.2507169}, pmid = {40390638}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; *Mobile Applications ; *Self Care/methods ; Female ; Male ; Middle Aged ; Aged ; Caregivers/psychology ; Adult ; }, abstract = {OBJECTIVE: Mobile technology can significantly enhance self-care for individuals with amyotrophic lateral sclerosis (ALS). This study aims to develop and evaluate the usability of a mobile application that provides relevant information and manages disease-related data for ALS patients and their families.

METHODS: A mobile application compatible with Android and iOS platforms was developed following the four phases of the System Development Life Cycle. The content was derived from a literature review, stakeholder focus group interviews, and in-depth interviews with ALS patients, family members, and healthcare professionals. The final application was validated by experts (n = 7), tested for usability by ALS patients and caregivers (n = 18), and evaluated using the System Usability Scale (SUS) to assess effectiveness and user satisfaction.

RESULTS: The application includes features such as tailored health data visualization, symptom tracking, text-to-speech functionality, and access to information customized based on the overall the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, thereby supporting patient-centered care and daily disease management. The mean SUS score was 75.00 ± 9.57 for expert panel members and 63.75 ± 10.26 for the target users, indicating an acceptable level of usability.

CONCLUSIONS: The mobile application was evaluated as practical, acceptable, and feasible for ALS patients and their caregivers, with positive feedback on its usability and potential to improve self-care management.}, } @article {pmid40390742, year = {2025}, author = {Franconieri, F and Fayolle, S and Raviol, P}, title = {Non-diabetic Ketoacidosis in a Patient With Amyotrophic Lateral Sclerosis: The Role of Stewart's Approach in Analyzing Acid-Base Disorders.}, journal = {Cureus}, volume = {17}, number = {4}, pages = {e82585}, pmid = {40390742}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is often complicated by severe malnutrition, increasing the risk of metabolic disturbances. Non-diabetic ketoacidosis (NDKA) is a rare but serious complication, typically related to prolonged fasting or catabolic states. A 62-year-old female patient with ALS and hypothyroidism presented with pneumonia and tetraplegia. Her body mass index (BMI) was 17 kg/m[2]. Laboratory findings showed a high anion gap (AG) metabolic acidosis (pH 7.23, bicarbonate 13 mmol/L, partial pressure of carbon dioxide (pCO2) 28 mmHg) without hyperlactatemia, but with significant ketonemia (5 mmol/L), severe hypophosphatemia, and signs of systemic inflammation. Upon admission, she received an intravenous infusion of 4.2% sodium bicarbonate. The simplified strong ion difference (SID) was preserved, excluding dilutional or hyperchloremic causes. Stewart's physicochemical approach, supported by a Gamblegram, revealed an acidosis due to unmeasured fixed acids, specifically ketone bodies. In light of this, bicarbonate therapy was discontinued, and nutritional correction with glucose hydration led to rapid clinical and biochemical improvement. This case illustrates the diagnostic and therapeutic value of Stewart's model in complex acid-base disturbances and underscores the need for early nutritional assessment in ALS patients. To our knowledge, this is the first reported case of NDKA in ALS, highlighting a rare but clinically relevant metabolic complication.}, } @article {pmid40391540, year = {2025}, author = {Massey, C and Hobson, E and Griffiths, AW and Musson, L and McDermott, C}, title = {Exploring mechanisms of behavior change for healthcare professionals in cough and secretion management in ALS.}, journal = {Neurodegenerative disease management}, volume = {15}, number = {4}, pages = {149-160}, pmid = {40391540}, issn = {1758-2032}, support = {NIHR301648//National Institute for Health and Care Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Cough/therapy/etiology ; *Health Personnel/psychology ; Female ; Male ; Focus Groups ; Middle Aged ; Qualitative Research ; Adult ; }, abstract = {OBJECTIVES: To explore healthcare professionals' experiences managing cough and secretion problems in Amyotrophic Lateral Sclerosis (ALS).

METHODS: A qualitative study was completed with 23 individuals participating in four focus groups. Data was analyzed using reflexive thematic analysis and COM-B and theoretical domains framework (TDF) behavior change frameworks.

RESULTS: This study found that roles, responsibilities, and expectations needed to be clearly defined and that building relationships was important to support care delivery. Barriers identified included limited access to specialist care, equipment, and opportunities to gain knowledge and skills. A structured clinical assessment was highlighted to enable good-quality care. Data mapped most commonly to the environmental context/resources, knowledge, skills (TDF), and physical capability (COM-B) behavior change domains.

CONCLUSION: Cough and secretion management in ALS is complex due to the multifaceted nature of the disease. This study emphasizes the need for future development of clinical interventions to support care.}, } @article {pmid40392845, year = {2025}, author = {Beccari, MS and Arnold-Garcia, O and Baughn, MW and Artates, JW and McAlonis-Downes, M and Lim, J and Leyva-Cázares, DF and Rubio-Lara, HI and Ramirez-Rodriguez, A and Bernal-Buenrostro, CN and Murgia-Bay, B and Rangel, CK and Kim, DH and Melamed, Z and Lutz, CM and Lagier-Tourenne, C and Corbett, KD and López-Erauskin, J and Cleveland, DW}, title = {Stathmin-2 enhances motor axon regeneration after injury independent of its binding to tubulin.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {21}, pages = {e2502294122}, pmid = {40392845}, issn = {1091-6490}, support = {R35 GM144121/GM/NIGMS NIH HHS/United States ; T32 AG066596/AG/NIA NIH HHS/United States ; P30 NS047101/NS/NINDS NIH HHS/United States ; R35GM144121//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; T32GM008666//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01NS112503//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P30NS047101//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; T32 GM008666/GM/NIGMS NIH HHS/United States ; R01 NS112503/NS/NINDS NIH HHS/United States ; R37 NS112503/NS/NINDS NIH HHS/United States ; N/A//Muscular Dystrophy Association (MDA)/ ; RF1 NS124203/NS/NINDS NIH HHS/United States ; T32AG066596//HHS | NIH | National Institute on Aging (NIA)/ ; R01 NS124203/NS/NINDS NIH HHS/United States ; N/A//NOMIS Stiftung (NOMIS Foundation)/ ; RF1NS124203//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *Stathmin/metabolism/genetics ; *Axons/metabolism/physiology/pathology ; *Motor Neurons/metabolism/physiology/pathology ; Mice ; *Tubulin/metabolism ; *Nerve Regeneration/physiology ; Mice, Knockout ; Protein Binding ; Neuromuscular Junction/metabolism/pathology ; Humans ; Microtubules/metabolism ; }, abstract = {Stathmin-2 (also known as SCG10) is encoded by the STMN2 gene, whose mRNA is one of the most abundantly expressed in human motor neurons. In almost all instances of ALS and other TDP-43 proteinopathies, stathmin-2 encoding mRNAs are cryptically spliced and polyadenylated in motor neurons, a pathogenic consequence of nuclear loss of function of the RNA binding protein TDP-43. While stathmin-2 has been shown to enhance regeneration after axonal injury to axons of cultured motor neurons, here, we show that after crush injury within the adult murine nervous system of wild-type or stathmin-2-null mice, the presence of stathmin-2 reduces axonal and neuromuscular junction degeneration and stimulates reinnervation and functional recovery. Mechanistically, although stathmin-2 has been proposed to function through direct binding to α/β tubulin heterodimers and correspondingly to affect microtubule assembly and dynamics, stathmin-2's role in axon regeneration after axotomy is shown to be independent of its tubulin binding abilities.}, } @article {pmid40394046, year = {2025}, author = {Ge, R and Chen, M and Wu, S and Huang, S and Zhou, P and Cao, M and Zhang, F and Zang, J and Zhu, Y and Li, J and Ni, G and Yang, Z and Li, Q and Pan, W and Zhang, L and Liu, M and Xuan, C and Yu, H and Zhou, J and Xie, S}, title = {DNA nanoflower Oligo-PROTAC for targeted degradation of FUS to treat neurodegenerative diseases.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4683}, pmid = {40394046}, issn = {2041-1723}, support = {32270892//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32200613//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; *RNA-Binding Protein FUS/metabolism/genetics ; Animals ; Proteolysis ; *DNA/chemistry ; *Neurodegenerative Diseases/genetics/therapy/metabolism ; Blood-Brain Barrier/metabolism ; *Oligonucleotides ; Mice ; Brain/metabolism ; Receptors, Transferrin/metabolism ; Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Oligonucleotide-based medicine faces challenges in efficiently crossing the blood-brain barrier and rapidly reducing toxic proteins. To address these challenges, here we establish an integrated modality, brain-penetrant DNA nanoflowers incorporated with oligonucleotide-based proteolysis targeting chimeras. Using FUS as a proof-of-concept, mutations of which cause frontotemporal dementia and amyotrophic lateral sclerosis, we demonstrate that a FUS-engaging RNA oligonucleotide crosslinked to a ligand for Cereblon efficiently degrade FUS and its cytoplasmic disease-causing mutants through a ubiquitin-proteasomal pathway. The DNA nanoflower contains hundreds of oligonucleotide binding sites and transferrin receptor-engaging aptamers, allowing efficient loading of the oligonucleotide-based degrader and engaging transferrin receptors for brain delivery. A single dose intravenous injection of this modality reaches brain parenchyma within 2 h and degrades 80% FUS protein there, sustained for two weeks without noticeable toxicity. DNA nanoflower oligonucleotide-based degrader is a therapeutic strategy for neurodegenerative diseases that leverages the advantages of designer oligonucleotides and targeted protein degradation.}, } @article {pmid40395088, year = {2025}, author = {Zhang, S and Gu, J and Yang, Y and Li, J and Ni, L}, title = {Evolution Trend of Brain Science Research: An Integrated Bibliometric and Mapping Approach.}, journal = {Brain and behavior}, volume = {15}, number = {5}, pages = {e70451}, pmid = {40395088}, issn = {2162-3279}, support = {2020Z388//Jiangsu Postdoctoral Research Foundation/ ; //Top Talent Support Program for young and middle-aged people of the Wuxi Health Committee/ ; M202033//Wuxi Health Commission Scientific Research Project/ ; 24CC00903//Beijing Academy of Science and Technology Think Tank Research Project/ ; ZYYB05//Wuxi Administration of Traditional Chinese Medicine/ ; }, mesh = {*Bibliometrics ; Humans ; *Biomedical Research/trends ; *Neurosciences/trends ; *Brain/physiology ; United States ; China ; }, abstract = {BACKGROUND: Brain science research is considered the crown jewel of 21st-century scientific research; the United States, the United Kingdom, and Japan have elevated brain science research to a national strategic level. This study employs bibliometric analysis and knowledge graph visualization to map global trends, research hotspots, and collaborative networks in brain science, providing insights into the field's evolving landscape and future directions.

METHODS: We analyzed 13,590 articles (1990-2023) from the Web of Science Core Collection using CiteSpace and VOSviewer. Metrics included publication volume, co-authorship networks, citation patterns, keyword co-occurrence, and burst detection. Analytical tools such as VOSviewer, CiteSpace, and online bibliometric platforms were employed to facilitate this investigation.

RESULTS: The United States, China, and Germany dominated research output, with China's publications rising from sixth to second globally post-2016, driven by national initiatives like the China Brain Project. However, China exhibited limited international collaboration compared to the United States and European Union. Key journals included Human Brain Mapping and Journal of Neural Engineering, while emergent themes centered on "task analysis," "deep learning," and "brain-computer interfaces" (BCIs). Research clusters revealed three focal areas: (1) Brain Exploration (e.g., fMRI, diffusion tensor imaging), (2) Brain Protection (e.g., stroke rehabilitation, amyotrophic lateral sclerosis therapies), and (3) Brain Creation (e.g., neuromorphic computing, BCIs integrated with AR/VR). Despite China's high output, its influence lagged in highly cited scholars, reflecting a "quantity-over-quality" challenge.

CONCLUSION: Brain science research is in a golden period of development. This bibliometric analysis offers the first comprehensive review, encapsulating research trends and progress in brain science. It reveals current research frontiers and crucial directions, offering a strategic roadmap for researchers and policymakers to navigate countries when planning research layouts.}, } @article {pmid40395127, year = {2026}, author = {Ghannizadeh, M and Rustamzadeh, A and Homayoun, M and Aliakbari, Z and Zamani, S}, title = {Premotor cortex and frontal eye field region metabolite alteration in human amyotrophic lateral sclerosis patients: A quantitative survey.}, journal = {The neuroradiology journal}, volume = {39}, number = {1}, pages = {78-86}, pmid = {40395127}, issn = {2385-1996}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; Male ; Female ; Middle Aged ; *Motor Cortex/metabolism/diagnostic imaging ; Magnetic Resonance Spectroscopy/methods ; *Frontal Lobe/metabolism/diagnostic imaging ; Aspartic Acid/analogs & derivatives/metabolism ; Aged ; Choline/metabolism ; Creatine/metabolism ; Adult ; Case-Control Studies ; Superoxide Dismutase-1/metabolism ; Inositol/metabolism ; }, abstract = {IntroductionAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive upper and lower motor neuron degeneration, leading to muscle weakness, respiratory failure, and mortality. The premotor cortex (PMC), including the frontal eye field (FEF), shows greater resistance, with limb function declining earlier than eye movement. This study utilizes magnetic resonance spectroscopy (MRS) to investigate metabolite ratio changes in these regions for potential early ALS diagnosis.Methods and MaterialsFourteen ALS patients and healthy controls underwent MRS to assess neurometabolite levels, including N-acetyl aspartate (NAA), creatine (Cr), myo-inositol (mIns), and choline (Cho) in the PMC and FEF. ELISA measured superoxide dismutase-1 (SOD1) enzyme levels. Group differences were analyzed statistically using t-tests to evaluate significant variations.ResultIn ALS patients, a significant decrease in NAA/Cr (p = .045) and an increase in mIns/Cr (p < .0001) concentrations were observed in the PMC. No significant differences in Cho/Cr (p = .215) were detected between the FEF and PMC regions in ALS patients. Compared to the control group, NAA/Cr levels in the PMC and FEF regions of ALS patients were significantly lower (p = .004, .001), while mIns/Cr values were significantly higher (p = .001). However, no significant changes were observed in the Cho/Cr ratio in the FEF between ALS patients and controls. Additionally, SOD1 enzyme levels were significantly reduced in ALS patients (p < .0001).ConclusionThe findings suggest that neurometabolites levels in the PMC and FEF may be a promising candidate for clinical and pathological changes in ALS.}, } @article {pmid40395318, year = {2023}, author = {Sun, S and Wang, H and Ma, Q and Li, N and Cao, M and Tam, KY and Ying, Z}, title = {PRKN regulates inner mitochondrial membrane PHB2 during mitophagy.}, journal = {Autophagy reports}, volume = {2}, number = {1}, pages = {2164643}, pmid = {40395318}, issn = {2769-4127}, abstract = {PINK1 (PTEN induced kinase 1) and PRKN-mediated mitophagy is an important mitochondrial quality control pathway which selectively degrades damaged mitochondria and is tightly associated with neurodegenerative diseases, including Parkinson disease and amyotrophic lateral sclerosis. The current model of PINK1-PRKN-mediated mitophagy is that PRKN ubiquitinates multiple outer mitochondrial membrane (OMM) proteins, and then the ubiquitin chains on the OMM interact with autophagy receptors which bind Atg8-family protein labeled phagophores. However, little work has been focused on the PRKN-mediated ubiquitination of inner mitochondrial membrane (IMM) proteins during mitophagy. Our recent work revealed that PRKN binds and ubiquitinates PHB2 (prohibitin 2), an essential IMM protein which was previously recognized as a mitophagy receptor, after the OMM is ruptured by proteasomal degradation. Using biochemical and microscopy approaches, we found that mutations of PRKN-targeted ubiquitination sites on PHB2 decrease the recognition of damaged mitochondria by the phagophore and the clearance of damaged mitochondria. In conclusion, our findings revealed a critical role for PRKN-PHB2 interaction in mitochondrial quality control by regulating IMM-associated recognition of mitochondria by the autophagy machinery.}, } @article {pmid40395512, year = {2024}, author = {Tanaka, Y and Ito, SI and Suzuki, G}, title = {TDP-43 Secretion via Extracellular Vesicles Is Regulated by Macroautophagy.}, journal = {Autophagy reports}, volume = {3}, number = {1}, pages = {2291250}, pmid = {40395512}, issn = {2769-4127}, abstract = {The pathological accumulation of the nuclear protein TDP-43 (TAR DNA-binding protein 43 kDa) in the cytoplasm is characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), and its spread through the brain and spinal cord is closely associated with the progression of these two diseases. However, the mechanisms through which the TDP-43 pathology propagates throughout the central nervous system remain unclear. We recently reported the role of (macro)autophagy in the secretion of TDP-43 via extracellular vesicles (EVs). We found that among the autophagy modulators, bafilomycin A1 (Baf) and GRN (granulin precursor) deficiency impair the formation of autolysosomes and promote the secretion of TDP-43 by EVs. TDP-43 loading on EVs involves autophagy-related proteins and the knockdown of TDP-43 augmented Baf-induced EV release. Thus, our results suggest that the loss-of-function of TDP-43 accelerates release of EVs possibly derived from autophagosomes, which may mediate cell-to-cell spread of the TDP-43 pathology.}, } @article {pmid40395537, year = {2024}, author = {Zhang, J and Pan, L}, title = {Mechanistic insights into the interaction between optineurin with RAB8A.}, journal = {Autophagy reports}, volume = {3}, number = {1}, pages = {2432848}, pmid = {40395537}, issn = {2769-4127}, abstract = {OPTN (optineurin), an amyotrophic lateral sclerosis (ALS)-associated modifier, plays vital roles in autophagy and cellular vesicular transport in mammals. OPTN can associate with RAB8A and the GTPase-activating protein TBC1D17, and facilitate the negative regulation of RAB8A by TBC1D17 (TBC domain family member 17). Recently, we reported the biochemical and structural characterizations of the interactions between OPTN, RAB8A and TBC1D17. We determined the crystal structure of the leucine-zipper domain (LZD) of OPTN with the GTP-bound active RAB8A and uncovered the molecular mechanism underpinning the specific interaction of OPTN with RAB8A. Moreover, we revealed that OPTN LZD and the TBC (Tre-2/Bub2/Cdc16) domain of TBC1D17 competitively bind to active RAB8A, while the central coiled-coil domain of OPTN and the active RAB8A can simultaneously interact with TBC1D17 TBC. In summary, our study provided mechanistic insights into the interaction of OPTN with RAB8A, and revealed the interaction relationship among OPTN, RAB8A and TBC1D17.}, } @article {pmid40395632, year = {2025}, author = {Gerring, ZF and Bhalala, OG and Fearnley, LG and Oikari, LE and White, AR and Derks, EM and Watson, R and Yassi, N and Bahlo, M and Reay, WR}, title = {Drug repurposing candidates for amyotrophic lateral sclerosis using common and rare genetic variants.}, journal = {Brain communications}, volume = {7}, number = {3}, pages = {fcaf184}, pmid = {40395632}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition for which novel disease modifying therapies are urgently needed. Given the increasing bottlenecks in drug discovery pipelines, repurposing existing drugs for ALS may represent a path to expedite translation and improve disease outcomes. However, ALS is a heterogeneous disease for which the aetiology remains poorly characterized, complicating efforts to effectively repurpose drugs. We propose that the polygenic architecture of ALS genetic liability, which ranges from ultra-rare, high-impact variation to common frequency loci of small-individual effect, could be leveraged to prioritize drug repurposing candidates which are more generalizable to the ALS clinical population. Here, we utilize common and rare frequency ALS genetic risk with a novel approach to uncover therapeutic classes that may be prospective repurposing opportunities in ALS. The common variant-led analyses integrated both positional-based and functional gene-based tests on SNP-genotype data from a genome-wide association study of ALS and implicated mitogen-activated protein kinase signalling related downregulation through B-Raf inhibitors as a prospective target for repurposing. The rare variant-led approaches leveraged rare variant burden testing of exonic variation on whole genome-sequencing data from a subset of the common variant genome-wide association study cohort and prioritized B-vitamin related candidates, such as cobalamin and niacin. Clinical characterization of these putative repurposing opportunities revealed genetic support to existing biology for which related compounds are actively proceeding through ALS clinical studies. Moreover, leveraging transcriptomic data from ALS derived cell lines carrying a selection of pathogenic variants in genes that cause familial forms of ALS (C9orf72, SOD1, FUS and TARDBP) suggested that the action of B-Raf inhibitors may be of particular relevance to C9orf72 carriers, whilst the signal for B-vitamin signalling related targets was strongest in SOD1 carriers. In summary, we demonstrate the importance of considering the therapeutic actionability of both common and rare-variant mediated risk for ALS given the immense biological heterogeneity of this disorder. Future pre-clinical and clinical studies are now warranted to further characterize the tractability of these prioritized compounds.}, } @article {pmid40395983, year = {2025}, author = {Beckers, J and Van Damme, P}, title = {The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).}, journal = {Autophagy reports}, volume = {4}, number = {1}, pages = {2474796}, pmid = {40395983}, issn = {2769-4127}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two extremes of a neurodegenerative disease spectrum characterised by overlapping genetic, clinical, and neuropathological features. This review covers the intricate relationship between both ALS and FTD and defects in the autophagy and endolysosomal pathway as recent evidence has pointed towards alterations in these pathways as being a root cause of disease pathogenesis. Here, we review the current knowledge on the interplay between ALS/FTD and lysosomebased proteostasis pathways and carefully asses the steps of the autophagy and endolysosomal pathways that are impaired by ALS or FTDcausing variants. Finally, we present a comprehensive overview of therapeutic strategies aimed at restoring autophagic and lysosomal function as potential avenues for mitigating the impact of these devastating diseases. Through this review, we aim to enhance the understanding of the pathophysiological mechanisms involving autophagy and/or the endolysosomal system that underlie the ALS-FTD spectrum and underscore the necessity for specific therapeutic approaches that target these shared vulnerabilities.}, } @article {pmid40396030, year = {2022}, author = {Ichimura, Y and Komatsu, M}, title = {Considering the mechanism by which droplets of ALS-FTD-associated SQSTM1/p62 mutants cause pathology.}, journal = {Autophagy reports}, volume = {1}, number = {1}, pages = {9-13}, pmid = {40396030}, issn = {2769-4127}, abstract = {Large numbers of point mutations in SQSTM1/p62 have been identified in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). SQSTM1 interacts with ubiquitinated proteins, undergoing liquid-liquid phase separation, and the resulting SQSTM1-droplets are degraded by macroautophagy/autophagy. SQSTM1 also serves as a multiple signaling hub for processes including selective autophagy and the anti-oxidative stress response. Such diverse functions are modulated by multiple domains and regions throughout the protein. Because mutations in SQSTM1 have been identified throughout its gene, including regions encoding the domains and motifs, the effects of these mutations on disease onset have been thought to be complicated. Recently, we thoroughly investigated how 7 mutations around the LC3-interacting region and KEAP1-interacting region (amino acids 335-356) affected autophagic degradation of SQSTM1, the anti-oxidative stress response, the KEAP1-NFE2L2/Nrf2 pathway, and the dynamics of SQSTM1 droplets. We found that reduced inner fluidity of the droplets is a unique, shared defect among all mutants, suggesting a link between qualitative changes in SQSTM1 liquid droplets and ALS-FTD. In this punctum article, we discuss the mechanism whereby reduced inner fluidity of mutant SQSTM1 droplets causes ALS-FTD pathology.}, } @article {pmid40396429, year = {2025}, author = {Keipert, LM and Wurster, CD and Uzelac, Z and Dorst, J and Schuster, J and Wollinsky, K and Ludolph, A and Lulé, D}, title = {Pain in adult and adolescent patients with 5q-associated Spinal Muscular Atrophy - an often underrated phenomenon.}, journal = {Journal of neuromuscular diseases}, volume = {12}, number = {5}, pages = {662-669}, pmid = {40396429}, issn = {2214-3602}, mesh = {Humans ; Male ; Adult ; Female ; Cross-Sectional Studies ; *Muscular Atrophy, Spinal/complications/genetics/psychology ; Adolescent ; Middle Aged ; Young Adult ; Quality of Life ; Prospective Studies ; *Pain/etiology/epidemiology ; Pain Measurement ; Depression ; }, abstract = {BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disorder leading to progressive muscle weakness and atrophy. Pain in SMA may be the consequence of the underlying neuromuscular disease but has hardly been investigated so far.

OBJECTIVE: To assess pain in SMA and its interaction with patient's wellbeing.

METHODS: In a prospective, cross-sectional study design, 70 adult and adolescent SMA patients (median age 30 years, IQR 21-49 years, types I-IV) were assessed at the Department of Neurology, Ulm University hospital. Pain was evaluated with a self-adapted Pain Scale, depressiveness with the ALS-Depression-Inventory-12-Items (ADI-12) and global Quality of Life (gQoL) with the Anamnestic Comparative Self-Assessment (ACSA).

RESULTS: We found an intermittent frequency of pain in 80% in SMA patients with more than half of the patients experience pain at least once a week. The mean pain intensity score estimated by pain frequency and strength was 24 on a scale of 0 to 240, indicating a frequently appearing mild to moderate pain. Pain was mostly located in the lumbar spine, hip, and thoracic spine. The pain intensity score was independent from demographics (age, gender) or clinical parameters (SMA type, physical state), but, instead, it was associated to depressiveness. Depressiveness was more prevalent in older SMA patients. gQoL was rather independent from pain intensity or physical state.

CONCLUSIONS: The study provides evidence for a prevalence of mild to moderate pain in 80% of adult and adolescent SMA patients. Pain was not simply caused by physical deficits and did not severely interfere with patients' quality of life, but, instead, was closely interrelated with patients' affective state.}, } @article {pmid40396430, year = {2025}, author = {Yang, J and Xiao, F and Liu, Y and Bai, J and Tan, S}, title = {Nerve Conduction Study and the Prognosis of Amyotrophic Lateral Sclerosis: Exploration of Additional Neuroelectrophysiological Parameters.}, journal = {European journal of neurology}, volume = {32}, number = {5}, pages = {e70209}, pmid = {40396430}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/mortality ; *Neural Conduction/physiology ; Middle Aged ; Male ; Female ; Prognosis ; Aged ; Adult ; Action Potentials/physiology ; Aged, 80 and over ; Median Nerve/physiopathology ; Nerve Conduction Studies ; }, abstract = {OBJECTIVE: To investigate the correlation between nerve conduction study (NCS) parameters and the prognosis of patients with amyotrophic lateral sclerosis (ALS).

METHODS: NCS parameters were recorded from the median, ulnar, peroneal, tibial, and superficial peroneal nerves of 114 sporadic patients with ALS. The main endpoint was death or tracheostomy. Univariate Cox regression analysis was conducted for all the NCS parameters. Subsequently, multivariate analysis was performed using Cox stepwise regression, incorporating factors identified in the univariate analysis and known prognostic factors. Kaplan-Meier curves and log-rank tests were used for survival analysis. Receiver operating characteristic (ROC) curves were used to assess the predictive capabilities of NCS parameters.

RESULTS: The distal compound muscle action potential (dCMAP) negative peak area and the sensory nerve action potential (SNAP) amplitude of the median nerve were identified as prognostic factors for ALS. Further stratified analyses showed that larger median dCMAP negative peak area significantly correlated with better prognosis in elderly (> 61 years) patients with limb-onset ALS. Conversely, higher median SNAP amplitudes indicated worse prognosis in younger (≤ 61 years) patients with limb-onset ALS.

CONCLUSION: The current study showed that the dCMAP negative peak area and SNAP amplitude of the median nerve are independent prognostic factors for sporadic ALS patients.}, } @article {pmid40396445, year = {2025}, author = {Hu, X and Cheng, J and Yuan, R and Zhou, Y and Rao, J and Wan, Y and Li, Y and Zhang, X and Li, R}, title = {Gold nanoparticles: diagnostic and therapeutic applications in neurodegenerative disorders.}, journal = {Journal of drug targeting}, volume = {33}, number = {9}, pages = {1511-1528}, doi = {10.1080/1061186X.2025.2509287}, pmid = {40396445}, issn = {1029-2330}, mesh = {Humans ; *Gold/chemistry/administration & dosage ; *Metal Nanoparticles/chemistry/administration & dosage ; *Neurodegenerative Diseases/drug therapy/diagnosis ; Blood-Brain Barrier/metabolism ; Animals ; Drug Delivery Systems/methods ; }, abstract = {Neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and prion diseases, pose a significant and escalating health challenge in the context of an ageing population. Gold nanoparticles (GNPs) have emerged as promising agents in the diagnostic and therapeutic realms of NDDs, due to their unique ability to enhance drug delivery across the blood-brain barrier (BBB). This paper presents a comprehensive review of the application of GNPs in the context of NDDs diagnosis and therapy, highlighting their potential to transform patient management. Additionally, we systematically address the critical challenges associated with the use of GNPs in the treatment and diagnosis of NDDs, focusing on pharmacokinetics and metabolism, toxicity, long-term biocompatibility, regulatory challenges and cost-effectiveness. Furthermore, we synthesise ongoing clinical studies to provide a holistic perspective on the current state of research in this field. We also explore the prospective trajectories and clinical translational potential of GNPs, which may usher in a new era in the treatment of NDDs.}, } @article {pmid40398050, year = {2025}, author = {Hirschbeck, SS and Sawaya, MR and Lindberg, ET and Limbach, MN and Jang, JH and Lazar Cantrell, KL and Eisenberg, DS and Do, TD}, title = {Amyloid Oligomers: Expediting Crystal Growth and Revisiting the Corkscrew Structures.}, journal = {Journal of the American Chemical Society}, volume = {147}, number = {22}, pages = {18594-18605}, doi = {10.1021/jacs.5c00656}, pmid = {40398050}, issn = {1520-5126}, mesh = {*Superoxide Dismutase-1/chemistry/genetics ; Humans ; Crystallography, X-Ray ; *Amyloid/chemistry ; Models, Molecular ; Crystallization ; }, abstract = {Crystallizing soluble amyloid oligomers (AOs) presents a major challenge in studying disease-related mutations associated with amyloid diseases. The G37R mutation in superoxide dismutase 1 (SOD1) is linked to early onset amyotrophic lateral sclerosis (ALS), yet its toxic mechanism remains unclear. The transient nature and low solubility of AOs often complicate the production of high-quality crystals required for X-ray crystallography (XRC) analysis. To address these challenges, we employ native ion mobility spectrometry-mass spectrometry (IMS-MS) to screen SOD1 peptides and examine correlations between structural features that reflect AO stability, their sequence length, and specific mutations. In particular, previous studies showed that the P28K mutation in SOD1(28-38) enhances solubility, thus allowing the capture of AO corkscrew structures for both SOD1(28-38)[P28K] and SOD1(28-38)[P28K, G37R]. Building on these findings, we expanded our screening to include SOD1 peptides with longer sequences, identifying structural features in IMS-MS spectra that correlate with improved crystallization potential. This approach enabled us to distinguish the stabilizing effects of G37R from those of P28K, culminating in the successful determination of the first crystal structure of the SOD1 corkscrew containing the native proline.}, } @article {pmid40398193, year = {2025}, author = {Carra, S and Fabian, B and Taghavi, H and Milanetti, E and Giliberti, V and Ruocco, G and Shepherd, J and Vendruscolo, M and Fuxreiter, M}, title = {Virus-like particles of retroviral origin in protein aggregation and neurodegenerative diseases.}, journal = {Molecular aspects of medicine}, volume = {103}, number = {}, pages = {101369}, doi = {10.1016/j.mam.2025.101369}, pmid = {40398193}, issn = {1872-9452}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/virology/pathology ; *Protein Aggregates ; *Endogenous Retroviruses/metabolism/genetics ; *Protein Aggregation, Pathological/metabolism/virology ; Animals ; *Virion/metabolism ; Protein Folding ; }, abstract = {A wide range of human diseases are associated with protein misfolding and amyloid aggregates. Recent studies suggest that in certain neurological disorders, including Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD) and various tauopathies, protein aggregation may be promoted by virus-like particles (VLPs) formed by endogenous retroviruses (ERVs). The molecular mechanisms by which these VLPs contribute to protein aggregation, however, remain enigmatic. Here, we discuss possible molecular mechanisms of ERV-derived VLPs in the formation and spread of protein aggregates. An intriguing possibility is that liquid-like condensates may facilitate the formation of both protein aggregates and ERV-derived VLPs. We also describe how RNA chaperoning, and the encapsulation and trafficking of misfolded proteins, may contribute to protein homeostasis through the elimination of protein aggregates from cells. Based on these insights, we discuss future potential therapeutic opportunities.}, } @article {pmid40399476, year = {2025}, author = {Rasà, DM and Stoppa, I and Bérenger-Currias, N and Pasho, E and Ciura, S and Kabashi, E and Martinat, C and Boido, M}, title = {Stress exposure affects amyotrophic lateral sclerosis pathogenesis via PI3K/Akt and focal adhesion pathways: evidence from three experimental models.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {17583}, pmid = {40399476}, issn = {2045-2322}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics/etiology ; *Proto-Oncogene Proteins c-akt/metabolism ; *Phosphatidylinositol 3-Kinases/metabolism ; Disease Models, Animal ; Mice ; Humans ; *Focal Adhesions/metabolism ; *Signal Transduction ; Male ; Superoxide Dismutase-1/genetics/metabolism ; Female ; Motor Neurons/metabolism/pathology ; Mice, Transgenic ; *Stress, Physiological ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial motor neuron (MN) disease, characterized by several cellular dysfunctions, many of which are shared by different neurodegenerative diseases. Here, we investigated whether a stressful lifestyle might exacerbate the altered mechanisms and affect the disease progression in ALS-predisposed conditions. To model stress in vivo, SOD1[G93A] mice underwent a chronic unpredicted mild stress protocol. This resulted in a significant impairment in body weight gain and motor performance, in a gender-specific manner. Moreover, the gene expression of Col1a1, Col1a2 and Il6 was strongly dysregulated in motor cortex and/or spinal cord of stressed mice. To assess the direct impact of stress on MNs, NSC-34 hSOD1[G93A] cells underwent oxygen and glucose deprivation. Compared to NSC-34 hSOD1[WT], mutated MNs exhibited a reduced capacity to cope with stress. By performing gene expression, protein-protein interaction, gene ontology and pathway enrichment analyses, we also revealed the pivotal role of the PI3K/Akt and focal adhesion pathways (triggered by Gsk3b, Il6, Igf1 and/or collagen) in mediating stress response. Similar results were observed in stressed human iPSCs-derived TARDBP[G298S] MNs. In conclusion, our results suggest that the PI3K/Akt and focal adhesion pathways play a crucial role in stress response across different ALS-predisposed models: the study paves the way for novel therapeutic targets and highlights the relevance of a healthy lifestyle.}, } @article {pmid40399998, year = {2025}, author = {Xu, L and Wang, Y and Li, X and Hu, Q and Adamkova, V and Xu, J and Harris, CJ and Ausin, I}, title = {H3K4me3 binding ALFIN-LIKE proteins recruit SWR1 for gene-body deposition of H2A.Z.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {137}, pmid = {40399998}, issn = {1474-760X}, support = {URF\R1\201016//Royal Society, UK/ ; URF\R1\201016//Royal Society, UK/ ; URF\R1\201016//Royal Society, UK/ ; EP/X025306/1/ERC_/European Research Council/International ; EP/X025306/1/ERC_/European Research Council/International ; EP/X025306/1/ERC_/European Research Council/International ; 321703059 and 32370580//National Science Foundation of China/ ; 321703059 and 32370580//National Science Foundation of China/ ; 321703059 and 32370580//National Science Foundation of China/ ; 321703059 and 32370580//National Science Foundation of China/ ; 321703059 and 32370580//National Science Foundation of China/ ; }, mesh = {*Histones/metabolism/genetics ; *Arabidopsis Proteins/metabolism/genetics ; *Arabidopsis/genetics/metabolism ; Gene Expression Regulation, Plant ; Protein Binding ; *Adenosine Triphosphatases/metabolism ; }, abstract = {BACKGROUND: The H2A.Z histone variant is highly enriched over gene bodies, playing an essential role in several genome-templated processes, including transcriptional regulation and epigenetic patterning across eukaryotes. Deposition of H2A.Z is mediated by the SWR1 remodeling complex. How SWR1 is directed to gene bodies is largely unknown.

RESULTS: Here, we show that ALFIN-LIKE (AL) proteins are responsible for H2A.Z gene body patterning in Arabidopsis. AL proteins encode H3K4me3-binding PHD domains, and by ChIP-seq, we confirm preferential binding of AL5 to H3K4me3 over H3K4me1/2 in planta. We observe a global reduction in H2A.Z in al septuple mutants (al7m), especially over H3K4me3-enriched genic regions. While MBD9 recruits SWR1 to nucleosome-free regions, ALs act non-redundantly with MBD9 for deposition of H2A.Z. Notably, al7m mutants show severe developmental abnormalities and upregulation of H2A.Z gene body-enriched responsive genes.

CONCLUSIONS: Therefore, we propose a model whereby AL proteins direct gene body enrichment of H2A.Z by recruiting SWR1 to H3K4me3-containing responsive genes.}, } @article {pmid40400037, year = {2025}, author = {Harjuhaahto, S and Jokela, M and Rajendran, J and Rokka, M and Hu, B and Kvist, J and Zhang, F and Zárybnický, T and Haimilahti, K and Euro, L and Pirinen, E and Huber, N and Herukka, SK and Haapasalo, A and Kuuluvainen, E and Gopalakrishnan, S and Katajisto, P and Hietakangas, V and Burg, T and Van Den Bosch, L and Huang, X and Narendra, DP and Kuure, S and Ylikallio, E and Tyynismaa, H}, title = {Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {111}, pmid = {40400037}, issn = {2051-5960}, mesh = {Animals ; Humans ; Mice ; *Mitochondrial Proteins/genetics/metabolism ; *Creatine/metabolism ; Male ; Motor Neurons/metabolism ; Female ; Disease Models, Animal ; *Motor Neuron Disease/genetics/metabolism ; Energy Metabolism/genetics ; Mice, Transgenic ; Mutation ; Muscular Atrophy, Spinal/genetics/metabolism ; }, abstract = {Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle disease phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by heterozygous p.G66V variant. While most disease variants lead to aggregation of CHCHD10 and activation of proteotoxic stress responses, the pathogenic mechanisms of the p.G66V variant are less clear. Here we report the first homozygous CHCHD10 patient, and show that the variant dosage dictates the severity of the motor neuron disease in SMAJ. We demonstrate that the amount of the mutant CHCHD10 is reduced, but the disease mechanism of p.G66V is not full haploinsufficiency as residual mutant CHCHD10 protein is present even in a homozygous state. Novel knock-in mouse model recapitulates the dose-dependent reduction of mutant CHCHD10 protein and the slow disease progression of SMAJ. With metabolome analysis of patients' primary fibroblasts and patient-specific motor neurons, we show that CHCHD10 p.G66V dysregulates energy metabolism, leading to altered redox balance and energy buffering by creatine metabolism.}, } @article {pmid40400199, year = {2025}, author = {Ramgopal, S and Callaway, CW and Martin-Gill, C and Okubo, M}, title = {Using Life-Saving Interventions to Determine Optimal Vital Sign Ranges among Adults Encountered by Emergency Medical Services.}, journal = {Prehospital and disaster medicine}, volume = {40}, number = {3}, pages = {129-135}, doi = {10.1017/S1049023X25001542}, pmid = {40400199}, issn = {1945-1938}, mesh = {Humans ; Retrospective Studies ; *Emergency Medical Services ; *Vital Signs ; Male ; Female ; Adult ; Middle Aged ; Aged ; }, abstract = {BACKGROUND: Vital signs are an essential component of the prehospital assessment of patients encountered in an emergency response system and during mass-casualty disaster events. Limited data exist to define meaningful vital sign ranges to predict need for advanced care.

STUDY OBJECTIVES: The aim of this study was to identify vital sign ranges that were maximally predictive of requiring a life-saving intervention (LSI) among adults cared for by Emergency Medical Services (EMS).

METHODS: A retrospective study of adult prehospital encounters that resulted in hospital transport by an Advanced Life Support (ALS) provider in the 2022 National EMS Information System (NEMSIS) dataset was performed. The outcome was performance of an LSI, a composite measure incorporating critical airway, medication, and procedural interventions, categorized into eleven groups: tachydysrhythmia, cardiac arrest, airway, seizure/sedation, toxicologic, bradycardia, airway foreign body removal, vasoactive medication, hemorrhage control, needle decompression, and hypoglycemia. Cut point selection was performed in a training partition (75%) to identify ranges for heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), oxygen saturation, and Glasgow Coma Scale (GCS) by using an approach intended to prioritize specificity, keeping sensitivity constrained to at least 25%.

RESULTS: Of 18,259,766 included encounters (median age 63 years; 51.8% male), 6.3% had at least one LSI, with the most common being airway interventions (2.2%). Optimal ranges for vital signs included 47-129 beats/minute for HR, 8-30 breaths/minute for RR, 96-180mmHg for SBP, >93% for oxygen saturation, and >13 for GCS. In the test partition, an abnormal vital sign had a sensitivity of 75.1%, specificity of 66.6%, and positive predictive value (PPV) of 12.5%. A multivariable model encompassing all vital signs demonstrated an area under the receiver operator characteristic curve (AUROC) of 0.78 (95% confidence interval [CI], 0.78-0.78). Vital signs were of greater accuracy (AUROC) in identifying encounters needing airway management (0.85), needle decompression (0.84), and tachydysrhythmia (0.84) and were lower for hemorrhage control (0.52), hypoglycemia management (0.68), and foreign body removal (0.69).

CONCLUSION: Optimal ranges for adult vital signs in the prehospital setting were statistically derived. These may be useful in prehospital protocols and medical alert systems or may be incorporated within prediction models to identify those with critical illness and/or injury for patients with out-of-hospital emergencies.}, } @article {pmid40400898, year = {2025}, author = {Aziz, S and Anbreen, S and Shahzad, S and Ahmed, MS and Sharma, V and Yang, J and Ali, L}, title = {Investigating nanoparticle's utilization in stem cell therapy for neurological disorders.}, journal = {American journal of stem cells}, volume = {14}, number = {1}, pages = {1-13}, pmid = {40400898}, issn = {2160-4150}, abstract = {Stem cell therapy is a promising area of regenerative medicine, offering potential treatments for various life-threatening disorders. Stem cells are classified based on their differentiation potential into totipotent, pluripotent, and multipotent stem cells. Among them, mesenchymal stem cells (MSCs) are widely used in regenerative medicine due to their tissue regeneration capabilities and ability to differentiate into multiple cell types. Stem cells are being explored for treating neurodegenerative disorders like Parkinson's, Alzheimer's, Huntington's, and amyotrophic lateral sclerosis (ALS). These conditions result from progressive neuronal degeneration, leading to irreversible damage. Challenges such as cell survival, immune rejection, tumor formation, and ethical concerns related to embryonic stem cells need to be addressed. Nanotechnology is emerging as a tool for enhancing stem cell therapy, improving targeted delivery and effectiveness. Nanoparticles possess the ability to create microenvironments as substrates, facilitate targeted administration, and enable real-time, precise imaging of stem cells. This review explores the integration of stem cells and nanotechnology as regenerative medicine tool for neurodegenerative disease treatment, analyzing current strategies and therapeutic approaches. Integrating nanotechnology with stem cell therapy may significantly improve targeted delivery and enhance regenerative outcomes for neurodegenerative disorders.}, } @article {pmid40401027, year = {2025}, author = {Libonati, L and Cambieri, C and Ceccanti, M and Moret, F and Di Giulio, M and Palma, E and Inghilleri, M}, title = {Twitch force in human Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1590950}, pmid = {40401027}, issn = {1664-2295}, abstract = {INTRODUCTION: This study investigated differences in muscle twitch force between slow and fast progressors of amyotrophic lateral sclerosis (ALS) to better understand disease heterogeneity and identify potential biomarkers of disease progression.

METHODS: Forty-four ALS patients were classified as slow or fast progressors based on disease progression rates. Electrophysiological assessments, including compound muscle action potential (CMAP) and muscle force measurements, were conducted. Creatine kinase (CK) levels were also evaluated.

RESULTS: Slow progressors demonstrated significantly higher muscle peak force and area under the curve (AUC) compared to fast progressors, reflecting greater muscle strength and endurance. CK levels were also elevated in slow progressors.

DISCUSSION: Despite similar CMAp values, slow progressors retained greater muscle strength, possibly due to a reduced degeneration of fast-twitch fibers and compensatory axonal sprouting. These adaptations may preserve muscle function and elevate CK levels, suggesting better muscle integrity in slow progressors.

CONCLUSION: Muscle function profiles and CK levels are promising indicators of ALS progression. These findings could enhance early detection of disease progression and lead to targeted interventions to preserve muscle function. Further research is needed to validate these results and explore the underlying functional mechanisms of disease heterogeneity.}, } @article {pmid40401739, year = {2025}, author = {Perera, ND and De Silva, S and Tomas, D and Cuic, B and Turner, BJ}, title = {Mapping Glial Autophagy Dynamics in an Amyotrophic Lateral Sclerosis Mouse Model Reveals Microglia and Astrocyte Autophagy Dysfunction.}, journal = {Glia}, volume = {73}, number = {9}, pages = {1860-1882}, pmid = {40401739}, issn = {1098-1136}, support = {IG 2132//Motor Neurone Disease Research Australia/ ; 2020-2024//Stafford Fox Medical Research Foundation/ ; Early Career Researcher Grant 2020//University of Melbourne/ ; ID 2202//Bethlehem Griffiths Research Foundation Grant 2022/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Autophagy/physiology ; *Astrocytes/pathology/metabolism ; Mice ; *Microglia/pathology/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase-1/genetics/metabolism ; *Neuroglia/pathology/metabolism ; Spinal Cord/pathology ; Motor Neurons/pathology ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is defined by motor neuron death. However, recent research has identified non-cell-autonomous mechanisms, with significant involvement of glia in disease progression. We link previous observations of intracellular protein aggregates in glia to the autophagy pathway, the primary mediator of intracellular degradation of large protein aggregates. While dysfunctional autophagy is reported in ALS motor neurons, pre-clinical and clinical outcomes of autophagy modulators have been inconsistent, indicating the need for a nuanced understanding of autophagy dynamics across CNS cell types and ALS-affected regions. We hypothesized that glial autophagy is defective in ALS, with glial-type-specific dysfunction. To investigate in vivo autophagy dynamics, we intercrossed SOD1[G93A] mice with transgenic RFP-EGFP-LC3 autophagy reporter mice, enabling the quantification of autophagy degradation, termed flux. Investigation of autophagy dynamics in SOD1 oligodendrocytes, microglia, and astrocytes at key disease stages uncovered useful insights. While oligodendrocytes seemed to mount effective compensatory autophagic responses to combat mutant SOD1, significantly increased autophagy flux was observed in symptomatic spinal microglia and astrocytes in comparison to controls. Symptomatic SOD1 astrocytes displayed greater autophagy dysfunction compared to microglia, with subcellular analysis revealing cell compartment-specific, transient autophagy defects that returned to control levels by end stage. Interestingly, spinal glia showed more pronounced and earlier autophagy dysfunction compared to motor cortex glia, where autophagy dysfunction emerged later in disease end stage, aligning with greater spinal cord pathology reported in this model. Our results suggest that cell-type- and time-specific targeting might be essential when developing autophagy therapeutics for ALS, with prioritization of astrocytic autophagy modulation.}, } @article {pmid40403503, year = {2025}, author = {Dhapola, R and Paidlewar, M and Kumari, S and Sharma, P and Vellingiri, B and Medhi, B and HariKrishnaReddy, D}, title = {cGAS-STING and neurodegenerative diseases: A molecular crosstalk and therapeutic perspective.}, journal = {International immunopharmacology}, volume = {159}, number = {}, pages = {114902}, doi = {10.1016/j.intimp.2025.114902}, pmid = {40403503}, issn = {1878-1705}, mesh = {Humans ; *Nucleotidyltransferases/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism/immunology ; *Membrane Proteins/metabolism ; Animals ; Signal Transduction ; STING Protein ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS) and Frontotemporal Dementia (FTD) share key pathological features, including neuroinflammation, oxidative stress, mitochondrial dysfunction, autophagic dysfunction, and DNA damage. By identifying cytosolic DNA and triggering the type I interferon response, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway regulates neuroinflammation. Dysregulated cGAS-STING signaling has been linked to neuroinflammation and neuronal degeneration across multiple neurodegenerative conditions. In many neurodegenerative disorders, neuroinflammation is mediated by the cGAS-STING pathway. Mitochondrial malfunction and impaired autophagy cause cytosolic DNA buildup in Huntington's, Parkinson's, and Alzheimer's diseases, which activates cGAS-STING and drives chronic inflammation. This pathway is triggered by TDP-43 pathology and nucleic acid dysregulation in ALS and FTD, which leads to neuronal destruction. Both central demyelination and peripheral immunological responses are linked to cGAS-STING activation in multiple sclerosis. Various inhibitors, such as RU.521, H-151, and naturally occurring compounds like metformin, potentially attenuate cGAS-STING-mediated neuroinflammation and associated pathologies. H-151 significantly decreased the expression of pro-inflammatory markers in murine macrophage J774 cells activated with cGAMP: TNF-α by 68 %, IFN-β by 84 %, and CXCL10 by 96 %. cGAS-STING inhibitors target neuroinflammation, offering a disease-modifying approach unlike current symptomatic treatments. However, challenges like blood-brain barrier penetration, off-target effects, and immune suppression hinder clinical translation, necessitating optimized drug delivery and immune modulation. With a focus on its potential for future clinical applications, this review explores the role of the cGAS-STING pathway in neurodegeneration and new treatment approaches.}, } @article {pmid40403623, year = {2025}, author = {Chtourou, M and Osuna, MD and Vázquez-García, JG and De Prado, R and Lozano-Juste, J and Marín, GM and Hada, Z and Souissi, T and Torra, J}, title = {Several point mutations and metabolism confer cross-resistance to ALS-inhibiting herbicides in Tunisian wild mustard.}, journal = {Plant physiology and biochemistry : PPB}, volume = {225}, number = {}, pages = {110043}, doi = {10.1016/j.plaphy.2025.110043}, pmid = {40403623}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/antagonists & inhibitors/genetics/metabolism ; *Herbicides/pharmacology ; *Herbicide Resistance/genetics ; Tunisia ; *Point Mutation/genetics ; *Sinapis/genetics/drug effects/metabolism/enzymology ; *Plant Proteins/genetics/metabolism/antagonists & inhibitors ; }, abstract = {A growing number of weed biotypes showing resistance to acetolactate synthase (ALS)-inhibitors have been reported in several species, notably including Sinapis arvensis L. Two putative resistant (R) populations of S. arvensis from Tunisia were subjected to greenhouse and laboratory investigations to validate resistance to ALS-inhibitors and to determinate the mechanisms involved. The results indicated that both populations were resistant to four distinct ALS-inhibiting herbicides, tribenuron-methyl (TM), florasulam, flucarbazone and imazamox (IMZ), thereby confirming cross-resistance between them. The dose of (TM) required to achieve a 50 % reduction in plant growth (ED50) and 50 % mortality (LC50) in R populations of S. arvensis was found to be at least 60 times greater than the recommended field dose (18.7 g ai ha[-1]) applied in cereal crops in Tunisia, indicating a significantly elevated resistance factor. Synergist experiments using malathion as a cytochrome P450 (Cyt-P450) inhibitor demonstrated a reduction in resistance to imazamox (IMZ) in both resistant (R) biotypes, indicating that Cyt-P450 plays a partial role in the resistance mechanism. In addition, ALS gene analysis identified three key point mutations, Pro197Ala, Asp376Glu and Trp574Leu, in both R populations. The docking analysis demonstrated that Asp376Glu mutation in S. arvensis could confer cross-resistance to IMZ and TM herbicides. CAPS and dCAPS methods were developed for detecting the Trp574Leu and Asp376Glu mutations, respectively, in S arvensis and it was shown that work efficiently. Fortunately, the study also confirmed that 2,4-D still effectively controlled S. arvensis populations. This study provides valuable insights into the mechanisms underlying herbicide resistance in S.arvensis populations from Tunisia, demonstrating that both target-site resistance (TSR) and non-target-site resistance (NTSR) contribute to the species' broad-spectrum resistance against four dissimilar ALS-inhibitors.}, } @article {pmid40403957, year = {2025}, author = {Zeng, L and Yang, J and Zhang, C and Zhu, J and Zhong, S and Liu, X and Xie, H and Wang, L and Chen, L and Zhong, M and Hua, F and Liang, W}, title = {Miro1: A potential target for treating neurological disorders.}, journal = {Neuroscience}, volume = {577}, number = {}, pages = {228-239}, doi = {10.1016/j.neuroscience.2025.05.019}, pmid = {40403957}, issn = {1873-7544}, mesh = {Humans ; Animals ; *rho GTP-Binding Proteins/metabolism ; *Nervous System Diseases/metabolism/drug therapy ; *Mitochondria/metabolism ; *Mitochondrial Proteins/metabolism ; Neurons/metabolism ; }, abstract = {The Miro1 protein is a member of the mitochondrial Rho GTPase (Miro) protein family and plays a crucial role in regulating the dynamic processes of mitochondria and participating in cellular movement and mitochondrial transport. In the nervous system, it ensures adequate energy supply for normal neuronal function and synaptic transmission. Additionally, Miro1 actively participates in the regulation of mitochondrial quality control and stress responses within neurons. Its primary function is to sense intracellular stress signals to regulate mitochondrial movement and metabolism, thereby adapting to environmental changes. Multiple studies have indicated that the Miro1 protein is associated with the pathogenesis of various neurological disorders, such as Alzheimer's Disease(AD), Parkinson's Disease(PD), and Amyotrophic Lateral Sclerosis(ALS). This article reviews the mechanistic role of Miro1 in these diseases and summarizes the latest research on its involvement in neurological disorders. These efforts aim to provide unified treatment strategies for certain neurological disorders and explore the potential for treating complex neurological diseases.}, } @article {pmid40404809, year = {2025}, author = {Morando, MA and D'Alessandro, V and Spinello, A and Sollazzo, M and Monaca, E and Sabbatella, R and Volpe, MC and Gervaso, F and Polini, A and Mizielinska, S and Alfano, C}, title = {Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {17879}, pmid = {40404809}, issn = {2045-2322}, support = {CUP F85F20000260006//Programma Operativo Nazionale Ricerca e Innovazione 2014-2020 (CCI 2014IT16M2OP005), Fondo Sociale Europeo, Azione I.1 "Dottorati Innovativi con caratterizzazione Industriale"/ ; CUP B73C21001300006//Italian Ministry of University and Research/ ; }, mesh = {*Catechin/analogs & derivatives/pharmacology/chemistry/metabolism ; *DNA-Binding Proteins/metabolism/chemistry ; Humans ; Protein Binding ; *Protein Aggregates/drug effects ; *RNA Recognition Motif ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Transactive response DNA-binding Protein 43 (TDP-43) aggregation is a key pathological feature in Amyotrophic Lateral Sclerosis and related neurodegenerative diseases. This study investigates the inhibitory effects of Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, on TDP-43 aggregation. Using a combination of fluorescence assays, NMR spectroscopy, and computational modeling, we demonstrate that Epigallocatechin-3-gallate significantly delays the nucleation phase of TDP-43 aggregation process, thus inhibiting the formation of TDP-43 aggregates in vitro. Additionally, we proved a direct interaction of the compound with the RNA recognition motifs of TDP-43 and modeled the mechanism of interaction. Our findings reveal that EGCG stabilizes the RRM domains, counteracting aggregation by interfering with the early stages of the amyloidogenic pathway. Furthermore, EGCG's stability under experimental conditions was ensured using reducing agents, highlighting the importance of maintaining its reduced form for reproducible results. These insights underscore the therapeutic potential of EGCG in TDP-43 proteinopathies and provide a foundation for developing targeted treatments for ALS and related disorders.}, } @article {pmid40405223, year = {2025}, author = {Yoonesi, S and Abedi Azar, R and Arab Bafrani, M and Yaghmayee, S and Shahavand, H and Mirmazloumi, M and Moazeni Limoudehi, N and Rahmani, M and Hasany, S and Idjadi, FZ and Aalipour, MA and Gharedaghi, H and Salehi, S and Asadi Anar, M and Soleimani, MS}, title = {Facial expression deep learning algorithms in the detection of neurological disorders: a systematic review and meta-analysis.}, journal = {Biomedical engineering online}, volume = {24}, number = {1}, pages = {64}, pmid = {40405223}, issn = {1475-925X}, mesh = {Humans ; *Deep Learning ; *Facial Expression ; *Nervous System Diseases/diagnosis ; }, abstract = {BACKGROUND: Neurological disorders, ranging from common conditions like Alzheimer's disease that is a progressive neurodegenerative disorder and remains the most common cause of dementia worldwide to rare disorders such as Angelman syndrome, impose a significant global health burden. Altered facial expressions are a common symptom across these disorders, potentially serving as a diagnostic indicator. Deep learning algorithms, especially convolutional neural networks (CNNs), have shown promise in detecting these facial expression changes, aiding in diagnosing and monitoring neurological conditions.

OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the performance of deep learning algorithms in detecting facial expression changes for diagnosing neurological disorders.

METHODS: Following PRISMA2020 guidelines, we systematically searched PubMed, Scopus, and Web of Science for studies published up to August 2024. Data from 28 studies were extracted, and the quality was assessed using the JBI checklist. A meta-analysis was performed to calculate pooled accuracy estimates. Subgroup analyses were conducted based on neurological disorders, and heterogeneity was evaluated using the I[2] statistic.

RESULTS: The meta-analysis included 24 studies from 2019 to 2024, with neurological conditions such as dementia, Bell's palsy, ALS, and Parkinson's disease assessed. The overall pooled accuracy was 89.25% (95% CI 88.75-89.73%). High accuracy was found for dementia (99%) and Bell's palsy (93.7%), while conditions such as ALS and stroke had lower accuracy (73.2%).

CONCLUSIONS: Deep learning models, particularly CNNs, show strong potential in detecting facial expression changes for neurological disorders. However, further work is needed to standardize data sets and improve model robustness for motor-related conditions.}, } @article {pmid40405476, year = {2025}, author = {Ma, C and Tian, G and Liu, Y and Wang, P and Meng, C and Liu, J and Guo, S and Qi, D}, title = {Highly Stretchable and Conductive Wrapping-Entanglement Coupling Network for All-Carbon-Based Soft Bioelectrode.}, journal = {Nano letters}, volume = {25}, number = {22}, pages = {9061-9069}, doi = {10.1021/acs.nanolett.5c01522}, pmid = {40405476}, issn = {1530-6992}, mesh = {*Carbon/chemistry ; Animals ; Electric Conductivity ; Rats ; Magnetic Resonance Imaging ; Electrodes ; Electromyography/instrumentation ; Polymers/chemistry ; Electrocardiography ; *Nanostructures/chemistry ; }, abstract = {Carbon-based materials are ideal for MRI-compatible bioelectrodes, essential for monitoring electromyographic signals and delivering electrical stimulation in diseases like ALS and MG. However, conventional stretchable carbon electrodes struggle with balancing electrical and mechanical properties. This paper proposes a new method of using a wrapping-entanglement coupling carbon network with multiple carbon nanomaterials in a polymer matrix, achieving high conductivity (454.5 S/m, several to dozens of times higher than that of electrodes made from other carbon materials embedded in polymers) and exceptional elongation at break (>3000%, carbon-based stretchable electrodes typically have a stretch rate of <500%). This electrode demonstrates remarkable durability, withstanding over 10,000 cycles at 20% strain (carbon-based stretchable electrodes can typically withstand <2500 cycles), outperforming existing carbon-polymer electrodes. It can be conformally attached to the skin and used as multichannel electrodes for ECG and EMG monitoring, matching the performance of Ag/AgCl electrodes. Implanted in rat models, it successfully recorded electrophysiological signals while reducing MRI artifacts compared to Pt electrodes in a 9.4 T MRI scanner. This innovation offers significant potential for advanced medical diagnostics and treatments.}, } @article {pmid40405710, year = {2025}, author = {Clift, A and Rowen, D and Knox, L and Griffiths, AW and McDermott, CJ}, title = {A Systematic Review of Attributes Influencing Preferences for Treatments and Interventions in People With Amyotrophic Lateral Sclerosis (ALS).}, journal = {Muscle & nerve}, volume = {72}, number = {3}, pages = {359-382}, pmid = {40405710}, issn = {1097-4598}, support = {//National Institute for Health and Care Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; *Patient Preference/psychology ; Quality of Life/psychology ; Patient-Centered Care ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that has no cure, and treatments predominantly focus on improving quality of life. Patient-centred care is central to bringing about meaningful improvements to quality of life. This review addresses the lack of consolidated evidence on what matters most to people with ALS (pwALS) by synthesizing 44 preference-based studies covering six different treatment and intervention categories. Data-based convergent synthesis identified five overarching factors influencing preferences: ease of use, accessibility, making life easier, autonomy, and safety/reliability. Simplifying and enhancing accessibility of treatment delivery across disease stages aligns with the nature of neurodegenerative disorders such as ALS, where function declines as the disease progresses. The value in perceived and real control reflects the profound impact ALS has on an individual's independence. Safety and reliability are crucial for people with ALS and are recognized as fundamental requirements for quality healthcare. The themes identified in this review can inform the attributes of preference elicitation methods. Systematically varying the levels of these attributes elicits quantitative measures of preferences. These findings can be used to inform and develop healthcare policy and clinical practice in ALS care. Specifically, preferences related to drug treatments can then be integrated into target product profiles (TPPs) to align drug development with the needs and values of pwALS. Integrating patient preferences into clinical practice promotes patient-centred care, increasing both patient satisfaction and treatment effectiveness.}, } @article {pmid40406043, year = {2025}, author = {Wang, L and Ma, L and Gao, Z and Wang, Y and Qiu, J}, title = {Significance of gene therapy in neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1515255}, pmid = {40406043}, issn = {1662-4548}, abstract = {Gene therapy is an approach that employs vectors to deliver genetic material to target cells, aiming to correct genes with pathogenic mutations and modulate one or more genes responsible for disease progression. It holds significant value for clinical applications and offers broad market potential due to the large patient population affected by various conditions. For instance, in 2023, the Food and Drug Administration (FDA) approved 55 new drugs, including five specifically for gene therapy targeting hematologic and rare diseases. Recently, with advancements in understanding the pathogenesis and development of neurodegenerative diseases (NDDs), gene therapy has emerged as a promising avenue for treating Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA), particularly in personalized medicine. Notably, the FDA has approved three clinical applications for combating SMA, utilizing viral vectors delivered via intravenous and intrathecal injections. However, gene therapy for other NDDs remains in clinical trials, necessitating improvements in viral vectors, exploration of new vectors, optimization of delivery routes, and further investigation into pathogenesis to identify novel targets. This review discusses recent advancements in gene therapy for NDDs, offering insights into developing new therapeutic strategies.}, } @article {pmid40406897, year = {2025}, author = {Li, J and Zi, X and Fang, J and Liang, M and Ju, M and Sun, Z and Shen, B and Zhang, X}, title = {Endoplasmic Reticulum Stress Induces Liquid-Liquid Phase Separation of GRP78 and Modulates Protein Aggregation Dynamics.}, journal = {ACS sensors}, volume = {10}, number = {6}, pages = {4535-4543}, doi = {10.1021/acssensors.5c00807}, pmid = {40406897}, issn = {2379-3694}, mesh = {Endoplasmic Reticulum Chaperone BiP ; Humans ; *Endoplasmic Reticulum Stress ; *Protein Aggregates ; Superoxide Dismutase-1/metabolism/chemistry/genetics ; *Heat-Shock Proteins/metabolism/chemistry ; Fluorescent Dyes/chemistry/chemical synthesis ; Phase Separation ; }, abstract = {Abnormal protein aggregation is a hallmark of neurodegenerative diseases, disrupting cellular homeostasis. Glucose-regulated protein 78 (GRP78), a key endoplasmic reticulum (ER) chaperone, plays a crucial role in protein folding and the ER stress response. Recent studies suggest that GRP78 undergoes liquid-liquid phase separation (LLPS) to form dynamic condensates; however, its functional implications under pathological conditions remain unclear. In this study, we designed and synthesized two fluorescent probes (ER-Pro and Agg-Pro) for specifically labeling GRP78 and monitoring microenvironmental polarity changes during protein phase transition. By integrating fluorescence lifetime imaging microscopy and confocal microscopy, we demonstrated that GRP78 undergoes LLPS under ER stress and recruits the amyotrophic lateral sclerosis-associated mutant protein SOD1(A4V), influencing its aggregation dynamics. Further investigations revealed that SOD1(A4V) aggregation is accompanied by local polarity changes, highlighting a potential role for GRP78 LLPS in protein quality control. Our findings provide new insights into ER homeostasis regulation and the pathogenesis of neurodegenerative diseases, offering potential strategies for early diagnosis and therapeutic intervention.}, } @article {pmid40407286, year = {2025}, author = {Steenkjær, CH and Heintzelmann, MB and Obál, I and Andersen, G and Blicher, JU}, title = {An adapted Danish translation of the Center for Neurologic Study Lability scale.}, journal = {Danish medical journal}, volume = {72}, number = {5}, pages = {}, doi = {10.61409/A07240497}, pmid = {40407286}, issn = {2245-1919}, mesh = {Humans ; Denmark ; *Amyotrophic Lateral Sclerosis/psychology/complications/diagnosis ; *Multiple Sclerosis/psychology/complications/diagnosis ; *Translations ; Surveys and Questionnaires ; Female ; Male ; Middle Aged ; Adult ; Aged ; Translating ; }, abstract = {INTRODUCTION: Pathological crying and/or laughing (pseudobulbar affect (PBA)) are socially debilitating symptoms seen in many neurological diseases, such as stroke, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). One method for measuring the degree of PBA is the Center for Neurologic Study-Lability Scale (CNS-LS), a seven-item questionnaire validated for quantifying symptoms and supporting PBA diagnoses in ALS and MS. The aim of this study was to provide a Danish translation of the CNS-LS inspired by international guidelines on cross-cultural translation and adaptation of self-report measurements.

METHODS: Through a six-step process, the CNS-LS was translated and back-translated by four certified translators, followed by an expert committee examination. The translation was then field-tested by interviewing patients with ALS and MS after they had completed the CNS-LS. If at least 20% of participants found an item "unclear", it would be reevaluated.

RESULTS: Twelve patients with ALS patients and 30 patients with MS were tested and interviewed. None of the questionnaire items exceeded the 20% threshold for lack of clarity.

CONCLUSION: We present a Danish translation of the CNS-LS to facilitate better diagnosis and quantification of PBA symptoms in Danish patients with ALS or MS.

FUNDING: This study received funding from the PhD fellowship grant of Neuroscience Academy Denmark.

TRIAL REGISTRATION: Not relevant.}, } @article {pmid40407667, year = {2025}, author = {Pérez-Bonilla, M and Díaz Borrego, P and Mora-Ortiz, M and Fernández-Baillo, R and Muñoz-Alcaraz, MN and Mayordomo-Riera, FJ and Girela López, E}, title = {Relationship Between Voice Analysis and Functional Status in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Audiology research}, volume = {15}, number = {3}, pages = {}, pmid = {40407667}, issn = {2039-4330}, abstract = {Background: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper and lower motor neurons, with bulbar dysfunction manifesting in up to 80% of patients. Dysarthria, characterized by impaired speech production, is common in ALS and often correlates with disease severity. Voice analysis has emerged as a promising tool for detecting disease progression and monitoring functional status. Methods: This study investigates acoustic and biomechanical voice alterations in ALS patients and their association with clinical measures of functional independence. A descriptive observational case series study was conducted, involving 43 ALS patients and 43 age and sex matched controls with non-neurological voice disorders. Sustained vowel /a/ recordings were obtained and analyzed using Voice Clinical Systems[®] and Praat software (version 6.2.22). Biomechanical and acoustic parameters were correlated with ALS Functional Rating Scale-Revised (ALSFRS-R) and Barthel Index scores. Results: Significant differences were observed between ALS and control groups (elevated muscle force and tension and interedge distance in non-ALS individuals). Between bulbar and spinal ALS subtypes, elevated values were observed in certain parameters in Bulbar ALS patients, indicating irregular vocal fold contact and weakened phonatory control, while spinal ALS exhibited increased values, suggesting higher phonatory muscle tension. Elevated biomechanical parameters were significantly correlated with low ALSFRS-R scores, suggesting a possible relationship between voice measures and functional decline. However, acoustic measurements showed no relationship with performance status. Conclusions: These results highlight the potential of voice analysis as a non-invasive, objective tool for monitoring ALS stage and differentiating between subtypes. Further research is needed to validate these findings and explore their clinical applications.}, } @article {pmid40409302, year = {2025}, author = {Fan, D}, title = {Innovative trial designs in amyotrophic lateral sclerosis: balancing efficiency and precision.}, journal = {The Lancet. Neurology}, volume = {24}, number = {6}, pages = {473-474}, doi = {10.1016/S1474-4422(25)00150-4}, pmid = {40409302}, issn = {1474-4465}, } @article {pmid40409314, year = {2025}, author = {, and , }, title = {Safety and efficacy of trehalose in amyotrophic lateral sclerosis (HEALEY ALS Platform Trial): an adaptive, phase 2/3, double-blind, randomised, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {24}, number = {6}, pages = {500-511}, doi = {10.1016/S1474-4422(25)00173-5}, pmid = {40409314}, issn = {1474-4465}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; Disease Progression ; Double-Blind Method ; Edaravone/therapeutic use ; *Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Treatment Outcome ; *Trehalose/therapeutic use/adverse effects/administration & dosage ; }, abstract = {BACKGROUND: Trehalose is a disaccharide that activates autophagy pathways in animal models of neurodegenerative diseases, with the potential to catalyse clearance of toxic, misfolded proteins in motor neurons and slow disease progression in amyotrophic lateral sclerosis (ALS). We aimed to evaluate the safety and efficacy of trehalose in individuals with ALS.

METHODS: The HEALEY ALS Platform Trial is a perpetual, adaptive, phase 2/3, randomised, double-blind, multi-regimen trial conducted at 60 geographically diverse sites in the USA. In the current regimen, adults with clinically possible, probable, laboratory-supported probable, or definite ALS, defined by the revised El Escorial criteria, were randomly allocated (3:1), stratified by use of edaravone and riluzole, to receive trehalose 0·75 g per kg intravenously weekly over 24 weeks, or matching placebo. The primary outcome was a composite of the relative rate of disease progression, as measured by the Revised ALS Functional Rating Scale (ALSFRS-R), and survival over 24 weeks, estimated in a Bayesian shared-parameter model. The study included prespecified stopping rules for futility; interim analyses occurred every 12 weeks. The primary outcome was analysed according to the intention-to-treat principle in all participants in the trehalose group, the placebo group within the regimen, and placebo groups from other contributing regimens; the safety analysis population was comprised of all participants who initiated treatment. This study is registered with ClinicalTrials.gov, NCT05136885.

FINDINGS: Between Feb 21, 2022, and Feb 17, 2023, 1021 participants were screened for the platform trial and 171 were assigned to the trehalose regimen. Of these, 161 participants met eligibility criteria, with 120 randomly allocated to trehalose and 41 to regimen-specific placebo. 164 participants randomly allocated to placebo in other regimens were added for analysis (totalling 205 placebo recipients). The disease rate ratio for change in ALSFRS-R and survival was 0·87 (95% credible interval 0·665-1·102, posterior probability of superiority 0·877). Serious adverse events occurred in 19 (16%) participants in the trehalose group and three (7%) participants in the regimen-only placebo group, leading to premature discontinuations in 14 (12%) versus one (2%), respectively. Fatal treatment-emergent adverse events occurred in seven participants in the trehalose group and none in the regimen-only placebo group. No death was considered related to the trial drug. The most common cause of death was respiratory failure, consistent with the natural history of ALS.

INTERPRETATION: Trehalose was well tolerated but there was no evidence to suggest a difference in ALS disease progression compared with placebo in this study. No statistical benefit was seen in secondary clinical or biomarker measures, suggesting that trehalose at this dosage is unlikely to be efficacious for treatment of ALS.

FUNDING: AMG Charitable Foundation, Tackle ALS, the ALS Association, ALS Finding a Cure, the Muscular Dystrophy Association, ALS ONE, the Arthur M Blank Family Foundation, I AM ALS, Tambourine ALS Collaborative, and other community fundraising initiatives and donors. Study drug and partial regimen-related funding was provided by Seelos.}, } @article {pmid40409555, year = {2025}, author = {Ma, G and Ruan, X and Yang, B and Li, N and Su, D and Sun, S and Chen, S and Xu, K and Ying, Z and Wang, H}, title = {Abnormal regulation of membrane-less organelles contributes to profilin1-associated ALS.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {7}, pages = {110259}, pmid = {40409555}, issn = {1083-351X}, mesh = {*Profilins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; Stress Granules/metabolism/pathology/genetics ; *Coiled Bodies/metabolism/pathology/genetics ; Actin Cytoskeleton/metabolism ; Animals ; }, abstract = {Profilin 1 (PFN1) is a key cytoskeletal protein that regulates actin dynamics by incorporating monomeric actin into linear filaments. PFN1 deletion or mutations have been linked to numerous neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the contribution of PFN1 to neurodegenerative pathologies is poorly understood. Recent studies have implicated the role of aberrant cellular membrane-less organelles (MLOs) in neurodegenerative pathogenesis. Here, we demonstrate that PFN1 is involved in the assembly of MLOs, including Cajal bodies and Stress granules. Specifically, depletion of PFN1 leads to abnormal Cajal body accumulation and accelerated maturation into a gel-like state, consequently dysregulating snRNP biogenesis and impairing pre-mRNA splicing efficiency in both neuronal and non-neuronal cells. Similarly, we show that PFN1 knockdown accelerates the assembly of Stress granules in stressed cells. Furthermore, we demonstrate that the ALS-linked PFN1-C71 G mutant exhibits a loss of function in the context of MLO biogenesis. We further reveal that the PFN1 deficiency-induced Cajal body dysregulation, but not Stress granule assembly, is caused by cellular actin filament depolymerization. Importantly, the actin filament agonist CN04 rescues Cajal body properties in PFN1-depleted cells. Taken together, our findings shed light on the role of PFN1 in MLO biogenesis and suggest its involvement in neurodegenerative pathogenesis.}, } @article {pmid40411245, year = {2026}, author = {Giacobbe, A and Hiana, J and Wang, O and Benatar, M and Wicks, P and Mascias Cadavid, J and Jhooty, S and McDermott, C and Pattee, G and Bertorini, T and Heiman-Patterson, T and Ratner, D and Barkhaus, P and Carter, G and Jackson, C and Denson, K and Brown, A and Armon, C and Sun, Y and Nguyen, A and Bedlack, R and Li, X}, title = {ALSUntangled #79: alpha-lipoic acid.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {233-237}, doi = {10.1080/21678421.2025.2507166}, pmid = {40411245}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Thioctic Acid/therapeutic use ; *Antioxidants/therapeutic use ; Animals ; }, abstract = {Alpha-lipoic acid (ALA) is a naturally occurring fatty acid. It serves as an essential cofactor for enzymatic reactions in mitochondrial energy production, is a potent antioxidant and has anti-inflammatory effects, which are plausible mechanisms in slowing ALS progression. In ALS preclinical studies, ALA slowed motor function decline and improved survival. There were self-reported cases of improved muscle strength in ALS patients when ALA was taken with numerous additional supplements, making it difficult to discern its efficacy. One small, 6-month open-label study showed improved quality of life, fatigue, and mood after participants took it with B vitamins and amino acids for the first 3 months. So far, no clinical trials have been published in people living with amyotrophic lateral sclerosis (PALS). Given the insufficient clinical data, we cannot endorse ALA and will support more research on its efficacy in slowing ALS progression.}, } @article {pmid40411682, year = {2025}, author = {Jain, S and Das, D and Mukherjee, A and Roy, I}, title = {Inhibition of PolyGA Dipeptide Repeat Protein Aggregation by Nucleic Acid Aptamers in C9 Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Models.}, journal = {Molecular neurobiology}, volume = {62}, number = {10}, pages = {12445-12460}, pmid = {40411682}, issn = {1559-1182}, support = {BT/PR30896/BRB/10/1747/2018//Department of Biotechnology/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy/pathology ; *Frontotemporal Dementia/drug therapy/genetics/metabolism/pathology ; *Aptamers, Nucleotide/pharmacology/therapeutic use ; Humans ; *Dipeptides/metabolism ; *C9orf72 Protein/metabolism/genetics ; *Protein Aggregates/drug effects ; *Peptides/metabolism ; *Protein Aggregation, Pathological/drug therapy ; Cell Survival/drug effects ; Autophagy/drug effects ; Neurons/metabolism/drug effects/pathology ; Oxidative Stress/drug effects ; }, abstract = {Hexanucleotide (GGGGCC) repeat expansion in non-coding region of C9ORF72 is the main genetic cause of amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Gain of toxic function, via RNA or proteins, or loss of function via haploinsufficiency, are probable mechanisms of disease progression. Expanded GGGGCC repeat codes for dipeptide repeat (DPR) proteins which form inclusions in the brain. Among all the dipeptides, aggregates formed by polyGA sequence are the most toxic. In this work, inhibition of aggregation of polyGA DPRs using aptamers has been explored as a therapeutic strategy to delay disease progression. Target-specific, high-affinity RNA aptamers were selected against monomeric (GA)30. Selected aptamers showed significant inhibition of aggregation of (GA)30 in vitro. Inhibitory RNA sequences were seen to form typical secondary structures which was missing in a non-inhibitory sequence. Some of the RNA aptamers showed increased solubilisation of DPRs formed by (GA)30 and (GA)60 in a neuronal cell model of ALS-FTD. Decreased aggregation was accompanied by lower oxidative stress and improved cell survival. Importantly, expression level of one of the markers of autophagy was significantly enhanced in the presence of aptamers, explaining lower aggregation observed in these cells. Thus, aptamers may be developed as potential therapeutic agents in C9 ALS-FTD.}, } @article {pmid40412267, year = {2025}, author = {Tian, H and Huang, N and Chen, C and Yu, H and Ge, C}, title = {Flavor profiles and genetic basis differences of Lacticaseibacillus paracasei isolates from different isolations in fermented milk.}, journal = {International journal of food microbiology}, volume = {440}, number = {}, pages = {111274}, doi = {10.1016/j.ijfoodmicro.2025.111274}, pmid = {40412267}, issn = {1879-3460}, mesh = {*Cultured Milk Products/microbiology ; *Flavoring Agents/metabolism/chemistry ; Taste ; *Lacticaseibacillus paracasei/genetics/isolation & purification/metabolism/classification ; Fermentation ; Animals ; Food Microbiology ; Volatile Organic Compounds/metabolism/analysis ; *Milk/microbiology ; Ketones/metabolism/analysis ; Multigene Family ; }, abstract = {Lacticaseibacillus paracasei from diverse traditional fermented foods exhibit unique flavor profiles in dairy products. In this study, 101 Lacticaseibacillus isolates were categorized into four distinct classes, with those originating from fermented dairy products demonstrating the highest flavor diversity. Multivariate statistical analyses identified diacetyl, acetoin, and 2-nonanone as key volatile compounds characterizing ketone-type isolates. Further examination of two ketone-type isolates and one non-ketone-type isolate, isolated from kurut, sour porridge, and Huangjiu mash respectively, revealed their specific abilities to produce ketones, lactones, and alcohols. Genome comparison of ketone-type and non-ketone-type L. paracasei isolates revealed disparities in the cit gene cluster, als, and but genes within the citrate metabolic pathway. These findings provide novel insights into the flavor diversity and help identify potential key genes involved in flavor formation in L. paracasei isolates, thereby facilitating the application of L. paracasei isolates in fermented dairy products.}, } @article {pmid40412392, year = {2025}, author = {Yan, X and Kuster, D and Mohanty, P and Nijssen, J and Pombo-García, K and Garcia Morato, J and Rizuan, A and Franzmann, TM and Sergeeva, A and Ly, AM and Liu, F and Passos, PM and George, L and Wang, SH and Shenoy, J and Danielson, HL and Ozguney, B and Honigmann, A and Ayala, YM and Fawzi, NL and Dickson, DW and Rossoll, W and Mittal, J and Alberti, S and Hyman, AA}, title = {Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates.}, journal = {Cell}, volume = {188}, number = {15}, pages = {4123-4140.e18}, pmid = {40412392}, issn = {1097-4172}, support = {R01 NS114289/NS/NINDS NIH HHS/United States ; R01 NS116176/NS/NINDS NIH HHS/United States ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry/genetics ; Humans ; Animals ; Mice ; *Stress Granules/metabolism ; *Protein Aggregation, Pathological/metabolism ; Oxidative Stress ; Protein Aggregates ; Disease Models, Animal ; Motor Neurons/metabolism ; Neurodegenerative Diseases/metabolism/pathology ; Protein Domains ; }, abstract = {Cytosolic aggregation of the nuclear protein TAR DNA-binding protein 43 (TDP-43) is associated with many neurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstrate that TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond a threshold, and the other is oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to a dynamic TDP-43-enriched phase within stress granules, which subsequently transition into pathological aggregates. Intra-condensate demixing of TDP-43 is observed in iPS-motor neurons, a disease mouse model, and patient samples. Mechanistically, intra-condensate demixing is triggered by local unfolding of the RRM1 domain for intermolecular disulfide bond formation and by increased hydrophobic patch interactions in the C-terminal domain. By engineering TDP-43 variants resistant to intra-condensate demixing, we successfully eliminate pathological TDP-43 aggregates in cells. We suggest that up-concentration inside condensates followed by intra-condensate demixing could be a general pathway for protein aggregation.}, } @article {pmid40412724, year = {2025}, author = {Xu, Y and Hou, W and Gao, J and Wei, JC and Zhang, L}, title = {Letter to Alameddine et al's "Celiac disease associated with alopecia areata: A multicenter case-control study".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {3}, pages = {e115-e116}, doi = {10.1016/j.jaad.2025.05.1405}, pmid = {40412724}, issn = {1097-6787}, } @article {pmid40413059, year = {2025}, author = {Lopes, AMDS and Giacomini, S and Ulahannan, A and Darnac, C and Bugeia, S and Gutknecht, G and Colomer-Lahiguera, S and Spurrier-Bernard, G and Latifyan, S and Addeo, A and Michielin, O and Eicher, M}, title = {Acceptability of an Electronic Patient-Reported Outcomes-Based Model of Care to Monitor Symptoms Related to Cancer Treatment with Immune Checkpoint Inhibitors: Results from the IePRO Randomized Controlled Trial.}, journal = {Seminars in oncology nursing}, volume = {41}, number = {4}, pages = {151903}, doi = {10.1016/j.soncn.2025.151903}, pmid = {40413059}, issn = {1878-3449}, mesh = {Humans ; *Neoplasms/drug therapy ; *Patient Reported Outcome Measures ; Female ; Male ; *Immune Checkpoint Inhibitors/adverse effects/therapeutic use ; Middle Aged ; Aged ; Adult ; *Mobile Applications ; Telemedicine ; Aged, 80 and over ; }, abstract = {OBJECTIVES: This study analyzed the acceptability of an electronic patient-reported outcomes measures-based model of care (IePRO MoC) and the usability of its complementary ePROM mobile app to monitor and manage symptoms related to immune checkpoint inhibitors. In this MoC, symptoms reported by patients treated at an outpatient clinic were reviewed by oncology triage nurses who provided symptom management interventions by telephone.

METHODS: As part of a larger intervention trial (ClinicalTrials.gov.NCT05530187) we conducted an abductive, semantic thematic analysis through semistructured interviews of patients participating in the intervention arm. Acceptability was deduced from Sekhon et al's (2017) Theoretical Framework of Acceptability completed with inductively generated themes. Usability analysis was guided by the mHealth App Usability Questionnaire's domains by Zhoul et al (2019).

RESULTS: A total of 17 interviews were performed. The IePRO MoC was reported to be an acceptable intervention. Patients expressed feeling safe and empowered due to continuous monitoring and timely support from nurses. Personalized support motivated patients to use the MoC throughout treatment. Some questioned the predefined response options of the app, and the standardized approach regarding notifications and monitoring requirements. Despite high app usability, some expressed discomfort from being frequently reminded of their illness and being confronted with questions about their sexuality and other intimate themes.

CONCLUSIONS: The feedback loop between patients and nurses facilitated the acceptability of the IePRO MoC. The app's usability further facilitated adherence to the MoC. A more personalized approach regarding the frequency of assessments and the way symptoms are conveyed is recommended to decrease discomfort and support the implementation of similar MoCs in the future.}, } @article {pmid40413303, year = {2025}, author = {Yang, W and Luo, Z and Tang, X and Guo, J and Chen, X and Dong, Y and Sun, YM and Fan, D and Xu, K and Chen, Y and Zhang, M}, title = {Protein Structure-based FUS Mutational Subtypes Are Associated With Protein Mislocalization in Amyotrophic Lateral Sclerosis Patients.}, journal = {Molecular neurobiology}, volume = {62}, number = {10}, pages = {12461-12472}, pmid = {40413303}, issn = {1559-1182}, support = {32301018//National Natural Science Foundation of China/ ; 82071430, 82371878//National Natural Science Foundation of China/ ; 2021YFA1302200//National Key Research and Development Program of China/ ; 22ZR1466400//Shanghai Municipal Natural Science Foundation General Program/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *RNA-Binding Protein FUS/genetics/metabolism/chemistry ; *Mutation/genetics ; Middle Aged ; Female ; Protein Transport ; Male ; Adult ; Cell Nucleus/metabolism ; Nuclear Localization Signals ; Aged ; Young Adult ; }, abstract = {The mislocalization of RNA-binding proteins (RBPs) from nucleus to cytoplasm and the formation of aggregates are hallmarks of neurodegeneration. Amyotrophic lateral sclerosis (ALS) disease-causing mutations in the fused in sarcoma (FUS) gene, encoding an RNA-binding protein, cluster at the C-terminal proline/tyrosine-nuclear localization signal (PY-NLS) domain, which is crucial for mediating nucleus-cytoplasm translocation by binding to Transportin-1. However, the mechanisms underlying heterogeneous protein mislocalization and age at onset (AAO) of ALS cases carrying FUS PY-NLS mutations remain unclear. Here, we screened FUS mutations in 416 ALS patients, and identified 12 patients carrying four FUS mutations at the p.R521 locus of PY-NLS domain (p.R521P, p.R521C, p.R521G, p.R521H), exhibiting highly variable AAO (20-56 years). AlphaFold-2 predicted protein structures classified FUS p.R521 mutants into alpha-helix containing (p.R521C, p.R521H) and alpha-helix disrupted (p.R521P, p.R521G) subgroups. Isothermal titration calorimetry experiment showed that the FUS alpha-helix disrupted subgroup had a reduced binding affinity with transportin-1, which is essential for mediating the nucleus-cytoplasm translocation. Furthermore, immunofluorescence in HEK-293 T and SH-SY5Y cells revealed more protein mislocalization in the FUS alpha-helix disrupted subgroup compared to the alpha-helix containing subgroup. FUS mislocalization status is also significantly associated with ALS AAO. Finally, the alpha-helix structure based FUS-ALS subgroups exhibited significantly different AAO (P = 0.036) in our cohort, but not in a Chinese cohort including published dataset. In summary, we showed highly diverse phenotypes in ALS patients with FUS R521 mutants, and implicated a link between genetic mutation related C-terminal structure with the status of FUS protein mislocalization.}, } @article {pmid40413526, year = {2025}, author = {Hawley, ZCE and Li, X and Bodnar, D and Gu, Y and Luo, Y and Ferretti, D and Sheehy, A and Driscoll, R and Zavodszky, MI and Cao, S and Isaza, I and Jandreski, L and Liu, Y and Carlile, T and Lo, SC and Grimard, A and Bourque, S and Utturkar, A and Desmarais, S and Arnold, HM and Huh, D and Guilmette, E and Kwon, DY}, title = {Viral-mediated knockdown of Atxn2 attenuates TDP-43 pathology and muscle dysfunction in the PFN1[C71G] ALS mouse model.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {116}, pmid = {40413526}, issn = {2051-5960}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *Profilins/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Ataxin-2/genetics/metabolism ; Humans ; Spinal Cord/pathology/metabolism ; Gene Knockdown Techniques ; Muscle, Skeletal/pathology/metabolism ; Male ; Motor Neurons/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss and muscle atrophy. Hyperphosphorylated aggregation of the RNA-binding protein, TDP-43, in the motor cortex and spinal cord are defining molecular features of ALS, suggesting TDP-43 dysfunction underlies disease pathogenesis. This phenomenon, however, has been difficult to recapitulate endogenously in animal models, impeding characterization of TDP-43 pathobiology in neurodegeneration. In this study, we report age-dependent accumulation of TDP-43 pathology in the spinal cord and progressive muscle-related deficits in transgenic mice expressing the ALS-associated PFN1[C71G] mutant protein. We show that transgenic neuronal expression of PFN1[C71G] induces early hyperphosphorylation of endogenous TDP-43 in the spinal cord that augments over time, preceding accumulation of insoluble non-phosphorylated TDP-43 and the manifestation of muscle denervation and motor dysfunction. Sustained knockdown of Atxn2 in the central nervous system (CNS) in pre-symptomatic PFN1[C71G] mice by AAV-driven expression of an artificial microRNA (AAV-amiR-Atxn2) reduces aberrant TDP-43 in the spinal cord, while delaying neurodegeneration and improving muscle and motor function. RNA-sequencing analysis of spinal cord samples from PFN1[C71G] mice and ALS donors show shared patterns of transcriptional perturbation, including a pro-inflammatory gene signature that is attenuated by AAV-amiR-Atxn2. Notably, impaired regulation of the PFN1[C71G] skeletal muscle transcriptome exceeds that of the spinal cord and is also improved by Atxn2 reduction in the CNS. Lastly, we find significant gene co-expression network homology between PFN1[C71G] mice and human ALS, with shared dysregulation of modules related to neuroinflammation and neuronal function and uncover novel hub genes that provide biological insight into ALS and potential drug targets that can be further investigated in this mouse model.}, } @article {pmid40413670, year = {2025}, author = {Montero-Odasso, M and Pieruccini-Faria, F and Black, SE and Binns, MA and Freedman, M and Grimes, DA and Hegele, RA and Haddad, SH and Lang, AE and Masellis, M and Mandzia, J and Beaton, D and Ramirez, J and Roberts, AC and McIlroy, W and Pasternak, SH and Zinman, L and Abrahao, A and Swartz, RH and Symons, S and Tan, B and Tartaglia, C and Son, S and Sakurai, R and Dilliott, A and Cornish, BF and Hezam, A and Strong, MJ and , and Bartha, R}, title = {Association between vascular risk factors burden and neurodegenerative diseases: results from ONDRI.}, journal = {Journal of neurology}, volume = {272}, number = {6}, pages = {418}, pmid = {40413670}, issn = {1432-1459}, mesh = {Humans ; Male ; Female ; Aged ; Cross-Sectional Studies ; *Neurodegenerative Diseases/epidemiology/diagnostic imaging/pathology ; Risk Factors ; Middle Aged ; *White Matter/diagnostic imaging/pathology ; *Cerebrovascular Disorders/epidemiology/diagnostic imaging ; Cognitive Dysfunction/epidemiology/diagnostic imaging ; Aged, 80 and over ; Cohort Studies ; Ontario/epidemiology ; Magnetic Resonance Imaging ; Diffusion Tensor Imaging ; }, abstract = {BACKGROUND: Vascular risk factors are common in older adults and contribute to brain damage, can manifest as increased white matter hyperintensities (WMH), and associated with future risk of stroke and dementia. However, their prevalence, effect across different neurodegenerative diseases, and association with WMH remains underexplored.

OBJECTIVE: To investigate the association between vascular risk burden, and brain white matter integrity, across five neurodegenerative conditions.

METHODS: Cross-sectional study including 520 participants from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) cohorts: 126 with amnestic Mild Cognitive Impairment/Alzheimer's Disease (MCI/AD), 53 with Frontotemporal Dementia (FTD), 161 with Cerebrovascular Disease (CVD), 140 with Parkinson's Disease (PD), and 40 with Amyotrophic Lateral Sclerosis (ALS), along with 41 cognitively healthy controls. A vascular risk index (VRI, range 0-5) assessed hypertension, diabetes, dyslipidemia, obesity (BMI ≥ 30), and smoking history. Macro (WMH volume) and micro (Diffusion tensor imaging) white matter integrity were evaluated using 3-Tesla MRI. Associations were analyzed using multinomial logistic regression and ANCOVA, adjusting for age, sex, education, and APOE ε4 allele status.

RESULTS: Vascular risk factors, particularly hypertension and hypercholesterolemia, were more prevalent in the disease cohorts than controls. A higher VRI was significantly associated with MCI/AD (1.5-fold, p = 0.05), FTD (1.7-fold, p =0 .02), and CVD (2.6-fold, p < 0.005) cohorts. High VRI was associated with reduced macro and microstructural white matter integrity in the pooled sample (macro: p = 0.005; micro: p = 0.003), and separately in CVD (macro: p = 0.04; micro: p = 0.002). APOE ε4 status only mildly attenuated these associations.

CONCLUSION: Vascular risk burden is prevalent in neurocognitive syndromes including MCI/AD, FTD and CVD, and impacts white matter integrity. Future studies are needed to explore if vascular risk management may mitigate the consequences of neurodegeneration in these clinical groups.}, } @article {pmid40414239, year = {2025}, author = {Shneider, NA and Harms, MB and Korobeynikov, VA and Rifai, OM and Hoover, BN and Harrington, EA and Aziz-Zaman, S and Singleton, J and Jamil, A and Madan, VR and Lee, I and Andrews, JA and Smiley, RM and Alam, MM and Black, LE and Shin, M and Watts, JK and Walk, D and Newman, D and Pascuzzi, RM and Weber, M and Neuwirth, C and Da Cruz, S and Soriano, A and Lane, R and Henry, S and Mathews, J and Jafar-Nejad, P and Norris, D and Rigo, F and Brown, RH and Miller, S and Crean, R and Bennett, CF}, title = {Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series.}, journal = {Lancet (London, England)}, volume = {405}, number = {10494}, pages = {2075-2086}, pmid = {40414239}, issn = {1474-547X}, support = {75N95023C00015/DA/NIDA NIH HHS/United States ; R01 NS111990/NS/NINDS NIH HHS/United States ; TL1 TR001875/TR/NCATS NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; R01 NS106236/NS/NINDS NIH HHS/United States ; U24 MH100931/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *RNA-Binding Protein FUS/genetics ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Oligonucleotides, Antisense/therapeutic use/administration & dosage/adverse effects ; Injections, Spinal ; Adult ; *Oligonucleotides/therapeutic use/administration & dosage/adverse effects ; Treatment Outcome ; Aged ; }, abstract = {BACKGROUND: Pathogenic variants of fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (FUS-ALS), with evidence of gain of function. Jacifusen is an antisense oligonucleotide targeting FUS pre-mRNA, previously shown to delay neurodegeneration in a mouse model and potentially slow functional decline in a first-in-human study. Here, we sought to further evaluate use of jacifusen as a treatment for FUS-ALS.

METHODS: This expanded access programme was conducted through a series of single-patient investigational new drug applications at five sites (four hospitals in the USA and one in Switzerland). Participants carried a FUS variant and had clinical evidence of motor neuron disease onset or electrophysiological abnormalities, if not a diagnosis of ALS. Participants were ineligible if chronically ventilated with tracheostomy. Enrolled sequentially, participants received serial intrathecal injections of jacifusen over 2·8-33·9 months. Based on multiple ascending doses of jacifusen (from 20 mg to 120 mg), successive protocols were modified as safety and other data were acquired, with the last participants enrolled receiving 120 mg doses monthly from the start of their treatment. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.0 and standard cerebrospinal fluid (CSF) metrics. Concentration of neurofilament light chain (NfL) in CSF was used as a biomarker of axonal injury and neurodegeneration, and the ALS Functional Rating Scale-Revised (ALSFRS-R) score was used as an overall measure of motor function. Biochemical analysis and immunohistochemical staining were done on post-mortem CNS tissues to quantify FUS protein expression and assess the burden of FUS pathology.

FINDINGS: Between June 11, 2019, and June 2, 2023, we recruited 12 participants (median age 26 years [range 16-45]; seven [58%] were female and five [42%] were male) into the expanded access programme. Transient elevations in cell counts or total protein concentration in CSF (six [50%] participants) were unrelated to treatment duration. The most common adverse events were back pain (six [50%]), headache (four [33%]), nausea (three [25%]), and post-lumbar puncture headache (three [25%]). Two participant deaths were recorded during the programme, both thought to be unrelated to the investigational drug. The concentration of NfL in CSF was reduced by up to 82·8% after 6 months of treatment. Although most participants had continued functional decline (as measured by ALSFRS-R) after starting treatment with jacifusen, one showed unprecedented, objective functional recovery after 10 months, and another remained asymptomatic, with documented improvement in electromyographic abnormalities. Biochemical and immunohistochemical analysis of CNS tissue samples from four participants showed reduced FUS protein levels and an apparent decrease in the burden of FUS pathology.

INTERPRETATION: The findings suggest the safety and possible efficacy of jacifusen for treating FUS-ALS. The efficacy of jacifusen is being further evaluated in an ongoing clinical trial.

FUNDING: ALS Association, Project ALS, Ionis Pharmaceuticals, Tow Foundation, Nancy D Perlman and Thomas D Klingenstein Innovation Fund for Neurodegenerative Disease, National Institutes of Health, Angel Fund for ALS Research, Cellucci Fund for ALS Research, Max Rosenfeld ALS Fund, University of Minnesota, and the Muscular Dystrophy Association.}, } @article {pmid40414240, year = {2025}, author = {Suzuki, N and Nishiyama, A and Ebihara, S and Aoki, M}, title = {Jacifusen for FUS-ALS: molecular effects and clinical outcomes in a case series.}, journal = {Lancet (London, England)}, volume = {405}, number = {10494}, pages = {2028-2030}, doi = {10.1016/S0140-6736(25)01038-4}, pmid = {40414240}, issn = {1474-547X}, } @article {pmid40414644, year = {2025}, author = {Manusha, S and Varsha, N and Varshini, R and Sivamani, Y and Pokkuluri, KS and Elayaperumal, S}, title = {Altered microbiome influence on the enteric neuromuscular system in amyotrophic lateral sclerosis (ALS).}, journal = {International review of neurobiology}, volume = {180}, number = {}, pages = {95-123}, doi = {10.1016/bs.irn.2025.04.006}, pmid = {40414644}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/physiopathology ; Humans ; *Gastrointestinal Microbiome/physiology ; *Enteric Nervous System/physiopathology/microbiology ; *Dysbiosis/physiopathology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease marked by the degeneration of motor neurons, leading to muscle weakness and paralysis. While the cause of ALS is uncertain, research indicates that changes in the gut microbiome may influence the disease's progression. This chapter explores how alterations in gut microbiota affect the enteric neuromuscular system (ENS) in ALS. In ALS patients, disrupted gut microbiota are linked to the brain-gut axis, impacting both gastrointestinal function and neuronal health. Studies show that microbial changes are associated with inflammation, immune instability, and neurodegeneration, which exacerbate the disease. Gastrointestinal issues like constipation and dysphagia in ALS are tied to ENS dysregulation. Understanding the connections between the gut microbiome, ENS, and central nervous system (CNS) may lead to novel therapies targeting neurodegeneration and microbial dysbiosis in ALS.}, } @article {pmid40414828, year = {2025}, author = {Kim, MS and Yoo, SH and Kim, KH and Cho, B and Lee, SY}, title = {Telemedicine Experiences of People Living with Amyotrophic Lateral Sclerosis at Home in South Korea.}, journal = {Yonsei medical journal}, volume = {66}, number = {6}, pages = {366-373}, pmid = {40414828}, issn = {1976-2437}, support = {RS-2021-KH120239//Patient-Centered Clinical Research Coordinating Center (PACEN)/Korea ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Republic of Korea ; *Telemedicine ; Middle Aged ; Female ; Male ; Aged ; Cross-Sectional Studies ; Retrospective Studies ; Home Care Services ; }, abstract = {PURPOSE: Telemedicine is advantageous in providing medical care to patients with mobility difficulties. This single-center study aimed to report on the provision of video televisits to people living with amyotrophic lateral sclerosis (pALS, ALS) who were registered with a home-based medical care (HBMC) team in a tertiary hospital in South Korea.

MATERIALS AND METHODS: A retrospective cross-sectional study was conducted for pALS provided with video televisits by the HBMC team between July 2020 and February 2023. The patients' demographics, disease status, mobility level, and supportive care equipment were investigated. The main issues discussed at televisits were investigated.

RESULTS: During the 32-month study period, video televisits were provided to 69 (81.2%) of the 85 pALS registered with the HBMC team. Their median (interquartile range) age was 66 (57-71) years, and 66.7% were aged 60 years or older. At the time of the televisits, 71.0% were non-ambulatory and 27.5% were at an assisted ambulatory level. Furthermore, 82.6% were receiving nutritional support with a nasogastric or gastrostomy tube, and 78.3% had received either non-invasive positive pressure ventilation (43.5%) or tracheostomy invasive ventilation (34.8%). Common issues addressed on televisits were disease-related symptoms (100%), management of supportive care equipment (92.8%), acute health issues (52.2%), and advance care planning (ACP) including goal of care discussion (14.5%).

CONCLUSION: Video telemedicine is feasible for pALS, including older adults with limited mobility due to muscle weakness or reliance on various supportive care equipment. Video televisits allow for a variety of discussions, ranging from acute health issues to ACP.}, } @article {pmid40415381, year = {2025}, author = {Pretalli, JB and Vernerey, D and Evrard, P and Pozet, A and Clairet, AL and Benoist, S and Karoui, M and Cotte, E and Heyd, B and Lakkis, Z and , }, title = {Intraoperative indocyanine green fluorescence angiography in colorectal surgery to prevent anastomotic leakage: A single-blind phase III multicentre randomized controlled trial (FLUOCOL-01/FRENCH 21/GRECCAR 19 intergroup trial).}, journal = {Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland}, volume = {27}, number = {5}, pages = {e70119}, pmid = {40415381}, issn = {1463-1318}, support = {PHRC-K-20-044//Programme Hospitalier de Recherche Clinique-Cancer/ ; //French Ministry of Health/ ; }, mesh = {Female ; Humans ; Male ; Anastomosis, Surgical/adverse effects/methods ; *Anastomotic Leak/prevention & control/etiology ; Clinical Trials, Phase III as Topic ; Colon/surgery/blood supply ; *Colorectal Neoplasms/surgery ; Colorectal Surgery/methods ; Coloring Agents ; *Fluorescein Angiography/methods ; France ; *Indocyanine Green ; *Intraoperative Care/methods ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; Single-Blind Method ; }, abstract = {AIM: Anastomotic leak (AL) is a major problem in colorectal surgery, and its prevention is crucial for patient safety. The scientific literature shows that optimal anastomotic perfusion is essential for anastomotic healing. However, in cases of left colon or rectal cancer requiring high vessel ligation for oncological reasons, anastomotic blood supply relies mainly on the pericolic arterial arcades. Consequently, assessing anastomotic perfusion using intraoperative fluorescence angiography with indocyanine green might be relevant to reduce the risk of AL. Although evidence of its positive impact on the risk of AL is growing in the literature, most studies are descriptive prospective cohorts or retrospective comparative series with controversial findings. Furthermore, no other studies specifically address left-sided colon or high rectal tumours. FLUOCOL-1 is a large multicentre randomized controlled trial (RCT) that aims to demonstrate that assessing anastomotic perfusion using intraoperative fluorescence angiography with indocyanine green will reduce ALs in left-sided or high anterior resections with intraperitoneal anastomosis METHOD: FLUOCOL-1 is a French multicentre, single-blind, randomized, two-arm, phase III superiority clinical trial. Patients will be randomized in a 1:1 ratio to either the intervention group (FLUO+) or the control group (FLUO-). A total of 1010 patients will be randomized. The primary endpoint is the occurrence of an AL within 90 days postsurgery. AL is defined as any anastomotic dehiscence with leakage into the pelvic cavity diagnosed by imaging or surgical exploration, or any isolated pelvic organ-space infection with no evidence of fistula, as defined by the International Study Group of Rectal Cancer.

DISCUSSION: Prevention of AL is one of the most important questions to be addressed in colorectal surgery. The FLUOCOL-1 multicentre RCT described herein aims to demonstrate that assessment of anastomotic perfusion using intraoperative fluorescence angiography with indocyanine green will reduce ALs in certain resections with intraperitoneal anastomosis.}, } @article {pmid40415670, year = {2025}, author = {Uskun, E and Turkmenel, N and Kutluhan, S}, title = {Cross-cultural adaptation and psychometric evaluation of a Turkish version of the Amyotrophic Lateral Sclerosis-Specific Quality of Life-Short Form.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {526-534}, doi = {10.1080/21678421.2025.2507177}, pmid = {40415670}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis ; *Quality of Life/psychology ; Female ; Male ; Middle Aged ; Turkey ; *Psychometrics/methods ; Reproducibility of Results ; Adult ; Aged ; *Cross-Cultural Comparison ; Surveys and Questionnaires ; }, abstract = {Objective: This study aimed to evaluate the validity and reliability of the Turkish version of the Amyotrophic Lateral Sclerosis Specific Quality of Life Instrument Short Form (ALSSQOL-SF), a quality-of-life scale originally developed by Simons et al., for Turkish Amyotrophic Lateral Sclerosis (ALS) patients. Methods: Using a rigorous six-step translation process, the scale was adapted without altering any items to maintain linguistic and cultural equivalence. The study included 100 patients diagnosed with ALS, aged 18 years and older, and native Turkish speakers. Results: Psychometric evaluations revealed strong content validity (CVI: 100%) and high internal consistency (Cronbach's alpha: 0.86 for the overall scale, 0.74-0.95 for subscales). Item-total correlation coefficients, except for three items, exceeded 0.20, and removing these items did not improve the scale's reliability, preserving the scale's integrity. Construct validity was supported by significant correlations with the Short Form 12 Health Survey Questionnaire (SF-12) and ALS Functional Rating Scale Revised (ALSFRS-R), confirming the scale's ability to assess physical and mental health in ALS patients. Exploratory factor analysis showed a 6-factor structure consistent with the original structure. Conclusion: Turkish version of ALSSQOL-SF (ALSSQOL-SF-Tr) is a reliable and valid instrument for assessing the quality of life in Turkish ALS patients. Its application in clinical and research settings can help evaluate patient needs and improve disease management.}, } @article {pmid40417478, year = {2024}, author = {Marchal, N and Janes, WE and Earwood, JH and Mosa, ASM and Popescu, M and Skubic, M and Song, X}, title = {Integrating Multi-sensor Time-series Data for ALSFRS-R Clinical Scale Predictions in an ALS Patient Case Study.}, journal = {AMIA ... Annual Symposium proceedings. AMIA Symposium}, volume = {2024}, number = {}, pages = {788-797}, pmid = {40417478}, issn = {1942-597X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Monitoring, Ambulatory/methods ; Pilot Projects ; }, abstract = {Clinical tools for tracking functional decline in amyotrophic lateral sclerosis (ALS) rely on in-clinic guided assessments, such as the gold standard ALS Functional Rating Scale Revised (ALSFRS-R) instrument, thus limiting the frequency of collection and potentially delaying needed treatments. As such, ALS clinicians may miss subtle yet critical shifts inpatient health -pointing to the needfor objective and continuous capturing of day-to-day functional status. In-home health sensors could supplement clinical instruments with more frequent, quantitative measurements as early indicators of change. Using the XGBoost regressor in base learning, we explore interpolation techniques for aligning monthly ALSFRS-R assessment targets with high frequency sensor-based health features. We evaluated 9 interpolation models, which demonstrate superior prediction of ALSFRS-R scores compared to traditional clinical scale estimates based on linear slope. This pilot work provides a practical approach of modeling mixed-frequency data and shows the potential of using sensor-based health estimates as sensitive prognostic markers.}, } @article {pmid40417702, year = {2025}, author = {Hoang, K and Prayotamornkul, S and Kuo, CY and Jang, H and Shi, L}, title = {Optical imaging of metabolic dynamics in ALS under methionine regulation.}, journal = {Journal of biomedical optics}, volume = {30}, number = {Suppl 2}, pages = {S23906}, pmid = {40417702}, issn = {1560-2281}, support = {R21 NS125395/NS/NINDS NIH HHS/United States ; R01 NS111039/NS/NINDS NIH HHS/United States ; U01 AI167892/AI/NIAID NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; *Methionine/metabolism/pharmacology ; Humans ; *Optical Imaging/methods ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; Spectrum Analysis, Raman/methods ; Cytochromes c/metabolism ; Imaging, Three-Dimensional ; Oxidation-Reduction ; }, abstract = {SIGNIFICANCE: Excessive reactive oxygen species (ROS) in dysfunctional mitochondria, combined with inefficient antioxidant defenses, can drive amyotrophic lateral sclerosis (ALS) progression. L-methionine (Met) can neutralize ROS by modulating metabolism and activating antioxidants; however, its impact on ALS remains unknown.

AIM: We aim to investigate the influence of excess Met on cellular metabolism and ROS accumulation and its role in ALS using multimodal optical imaging techniques.

APPROACH: We applied deuterium oxide-probed stimulated Raman scattering imaging to study metabolic changes of lipids, proteins, and cytochrome c and two-photon excitation fluorescence imaging to assess mitochondrial redox state (nicotinamide adenine dinucleotide and flavin adenine dinucleotide ratio) in ALS cellular models under excess Met treatment. With three-dimensional (3D) image reconstruction, we investigated morphological changes of lipid droplets (LDs) and stress granules (SGs) in ALS models.

RESULTS: Excess Met not only promoted syntheses of lipids and unsaturated lipid membranes but also reduced protein synthesis, cytochrome c oxidation, and oxidative stress. Moreover, 3D image reconstruction showed that LDs increased in volume and number to promote cellular repair, whereas SGs decreased in volume but increased in number in response to reduced cellular stress.

CONCLUSIONS: Excess Met offers a protective mechanism against oxidative stress and promotes cellular repair in ALS.}, } @article {pmid40419749, year = {2025}, author = {Monteiro Neto, JR and de Souza, GF and Dos Santos, VM and de Holanda Paranhos, L and Ribeiro, GD and Magalhães, RSS and Queiroz, DD and Eleutherio, ECA}, title = {SOD1, A Crucial Protein for Neural Biochemistry: Dysfunction and Risk of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {62}, number = {11}, pages = {14966-14986}, pmid = {40419749}, issn = {1559-1182}, support = {201.174/2022//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/enzymology/metabolism/pathology/genetics ; Humans ; *Superoxide Dismutase-1/metabolism ; Animals ; *Neurons/metabolism/pathology ; Oxidative Stress/physiology ; Risk Factors ; }, abstract = {Neurons are very susceptible to oxidative stress. They are the major consumers of oxygen in the brain, which is used to provide energy through oxidative phosphorylation, the major source of reactive oxygen species (ROS). In addition, compared to other tissues, neurons have lower levels of catalase and glutathione and increased susceptibility to lipid peroxidation due to the elevated levels of unsaturated fatty acids. These characteristics increasingly emphasize the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) to maintain neuronal redox homeostasis. In the last decade, SOD1 gained additional roles which are also important to the metabolism of neurons. SOD1 controls the production of ROS by the electron transport chain, activates the expression of genes involved in the protection against oxidative stress, and regulates the shift from oxidative to fermentative metabolism involved in astrocyte-neuron metabolic cooperation. Furthermore, impaired interaction between the phosphatase calcineurin and SOD1 seems to result in TDP-43 hyperphosphorylation, the main proteinopathy found in amyotrophic lateral sclerosis (ALS) patients. However, this enzyme is ubiquitously expressed, mutated, and damaged forms of SOD1 cause disease in motor neurons. In this review, we discuss the pivotal functions of SOD1 in neuronal biochemistry and their implications for ALS.}, } @article {pmid40420561, year = {2025}, author = {Harkey, BA and Distefano, S and Pagliaro, JA and Heyd, L and Chase, M and Igne, C and Yu, H and Sherman, AV and Dagostino, D and Tustison, E and Changkuon, G and Hall, M and Kittle, G and Connolly, MR and Giacomelli, E and Scirocco, E and Berry, JD and Babu, S and Shefner, J and Macklin, EA and Chibnik, LB and De Mattos, A and Drake, K and Kamp, C and McGarry, A and Torti, M and Small, C and Bulat, A and Cudkowicz, ME and Paganoni, S and , }, title = {Operational Development and Launch of an Adaptive Platform Trial in Amyotrophic Lateral Sclerosis: Processes and Learnings From the First Four Regimens of the HEALEY ALS Platform Trial.}, journal = {Muscle & nerve}, volume = {72}, number = {2}, pages = {294-305}, doi = {10.1002/mus.28442}, pmid = {40420561}, issn = {1097-4598}, support = {//Sean M. Healey and AMG Center/ ; //Tackle ALS/ ; //ALS Finding a Cure/ ; //The ALS Association/ ; //ALS ONE/ ; //The Arthur M. Blank Family Foundation/ ; //Muscular Dystrophy Association/ ; //UCB/ ; //Biohaven Pharmaceuticals Inc/ ; //Clene Nanomedicine/ ; //Prilenia Therapeutics/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Male ; Female ; *Adaptive Clinical Trials as Topic/methods ; }, abstract = {INTRODUCTION/AIMS: Platform trials present several advantages over traditional interventional clinical trials. Here, we provide a detailed description of the operational framework of the HEALEY ALS Platform Trial.

METHODS: Platform-level procedures for regulatory oversight, safety, and site management were developed prior to trial launch. Central vendors and a single Institutional Review Board (sIRB) were used. An Investigational New Drug (IND) application was submitted for the master protocol, and each regimen was added as an amendment.

RESULTS: The HEALEY ALS Platform Trial was launched in 2020. Fifty-four geographically diverse sites from the Northeast ALS Consortium (NEALS), all highly experienced in ALS care and research, were selected. Three investigational products were selected to launch concurrently at the start of the trial as individual regimens. A fourth investigational product was selected and added to the trial after the initial launch. The Master Protocol and the first three regimens (Regimens A-C) were sIRB approved in 120 days. sIRB amendment for Regimen D was approved in 21 days. Enrollment for regimens A-C was completed in 15 months, whereas Regimen D was completed in 11 months from the start of enrollment. Results of all regimens were available within approximately 2 years from the initial trial launch.

DISCUSSION: The HEALEY ALS Platform Trial capitalized on the benefits of the platform approach, including an adaptable operational infrastructure, concurrent enrollment into four distinct regimens, and an accelerated start-up time for a new regimen added after initial trial launch.}, } @article {pmid40420932, year = {2025}, author = {Farsakoury, R and Nashwan, AJ}, title = {Revitalizing upper blepharoplasty: Preserving volume.}, journal = {World journal of clinical cases}, volume = {13}, number = {15}, pages = {100563}, pmid = {40420932}, issn = {2307-8960}, abstract = {Blepharoplasty is a frequently performed aesthetic surgery today aimed at enhancing eyelid appearance and correcting age-related changes. The traditional method of subtraction blepharoplasty, which involved removing fat and excess skin, is now considered outdated. This letter explores Gorgy et al's commentary on Miotti et al's study, highlighting a shift in upper eyelid blepharoplasty towards a more conservative, volume-preserving approach. The study systematically reviewed 10 publications, including three retrospective studies, five comparative studies, and two clinical trials. It emphasizes the trend towards preserving the patient's natural anatomy and focusing on enhancement rather than alteration. However, the study's limitations, such as the lack of long-term comparative research, a relatively small sample size, and a single-center design, indicate that further research with extended follow-up is necessary to validate the safety and effectiveness of these techniques. The focus is increasingly on preserving and augmenting volume in upper blepharoplasty rather than removing tissue.}, } @article {pmid40421380, year = {2025}, author = {Park, S and Park, SK and Blair, P and Liebman, SW}, title = {An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases.}, journal = {Microbial cell (Graz, Austria)}, volume = {12}, number = {}, pages = {119-130}, pmid = {40421380}, issn = {2311-2638}, support = {P20 GM130459/GM/NIGMS NIH HHS/United States ; R35 GM136229/GM/NIGMS NIH HHS/United States ; }, abstract = {TDP-43 is linked to human diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Expression of TDP-43 in yeast is known to be toxic, cause cells to elongate, form liquid-like aggregates, and inhibit autophagy and TOROID formation. Here, we used the apt1∆ aah1∆ yeast model of inborn errors of metabolism, previously shown to lead to intracellular adenine accumulation and adenine amyloid-like fiber formation, to explore interactions with TDP-43. Results show that the double deletion shifts the TDP-43 aggregates from liquid-like droplets toward a more amyloid-like state. At the same time the deletions reduce TDP-43's effects on toxicity, cell morphology, autophagy, and TOROID formation without affecting the level of TDP-43. This suggests that the liquid-like droplets rather than amyloid-like TDP-43 aggregates are responsible for the deleterious effects in yeast. How the apt1∆ aah1∆ deletions alter TDP-43 aggregate formation is not clear. Possibly, it results from adenine and TDP-43 fiber interactions as seen for other heterologous fibers. This work offers new insights into the potential interactions between metabolite-based amyloids and pathological protein aggregates, with broad implications for understanding protein misfolding diseases.}, } @article {pmid40422183, year = {2025}, author = {Verde, EM and Secco, V and Ghezzi, A and Mandrioli, J and Carra, S}, title = {Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses.}, journal = {Cells}, volume = {14}, number = {10}, pages = {}, pmid = {40422183}, issn = {2073-4409}, support = {SUMOsolvable//AriSLA/ ; AHA MCA 2022//Giovanni Armenise-Harvard Foundation and AirAlzh/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Frontotemporal Dementia/metabolism/pathology/genetics ; *Protein Aggregates ; *Protein Aggregation, Pathological/metabolism ; Animals ; Protein Processing, Post-Translational ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders that share common genes and pathomechanisms and are referred to as the ALS-FTD spectrum. A hallmark of ALS-FTD pathology is the abnormal aggregation of proteins, including Cu/Zn superoxide dismutase (SOD1), transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), and dipeptide repeat proteins resulting from C9orf72 hexanucleotide expansions. Genetic mutations linked to ALS-FTD disrupt protein stability, phase separation, and interaction networks, promoting misfolding and insolubility. This review explores the molecular mechanisms underlying protein aggregation in ALS-FTD, with a particular focus on TDP-43, as it represents the main aggregated species inside pathological inclusions and can also aggregate in its wild-type form. Moreover, this review describes the protective mechanisms activated by the cells to prevent protein aggregation, including molecular chaperones and post-translational modifications (PTMs). Understanding these regulatory pathways could offer new insights into targeted interventions aimed at mitigating cell toxicity and restoring cellular function.}, } @article {pmid40422218, year = {2025}, author = {Saxena, S and Arnold, WD}, title = {Current Challenges in Elucidating ALS Disease Mechanisms and Therapeutic Advances.}, journal = {Cells}, volume = {14}, number = {10}, pages = {}, pmid = {40422218}, issn = {2073-4409}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy/pathology/genetics ; }, abstract = {As a researcher and a physician working together to combat amyotrophic lateral sclerosis (ALS), we are acutely aware of both the urgent need for innovation and the persistent divide between laboratory discoveries and clinical care [...].}, } @article {pmid40424855, year = {2025}, author = {Mrkela, M and Rodrigues, M and Naidoo, S and Devaux, JBL and Kirk, SE and Vinnakota, C and Buchanan, CM and Mulroy, D and Fraser, H and Jacobsen, JC and Wyatt, H and Drake, K and Parker, E and Potter, H and Henden, L and McCann, EP and Williams, KL and Henders, AK and Roxburgh, RH and Scotter, EL}, title = {The genetics of motor neuron disease in New Zealand.}, journal = {Journal of the neurological sciences}, volume = {474}, number = {}, pages = {123472}, doi = {10.1016/j.jns.2025.123472}, pmid = {40424855}, issn = {1878-5883}, mesh = {Humans ; New Zealand/epidemiology ; Male ; Female ; *Motor Neuron Disease/genetics/epidemiology ; Middle Aged ; Aged ; Superoxide Dismutase-1/genetics ; Adult ; C9orf72 Protein/genetics ; *Genetic Predisposition to Disease/genetics ; Dynactin Complex/genetics ; Aged, 80 and over ; }, abstract = {Motor neuron disease (MND) is a group of adult-onset neurodegenerative diseases characterised by progressive motor neuron degeneration, of which amyotrophic lateral sclerosis (ALS) is the most common. MND is clinically heterogeneous with complex etiology, caused by or associated with over 40 different genes and multiple environmental risk factors. New Zealand has one of the highest global incidence and mortality rates of MND, however the reasons are unknown. We sought to identify the frequencies of genetic variants in known MND-linked genes among people with MND in New Zealand. We enrolled 184 participants: 149 with a clinical diagnosis of MND (128 sporadic, 21 familial) and 35 clinically unaffected but at-risk individuals. Participants' DNA was screened for genetic variation in 46 MND-associated genes using Sanger sequencing, Illumina SNP microarray, repeat-primed PCR for C9orf72, and an Invitae gene panel. Clinical phenotypes mirrored European trends: males and spinal-onset cases had earlier disease onset. Thirty-three participants (17.9%) carried known pathogenic variants: 24 had C9orf72 repeat expansions, and 9 had pathogenic SOD1 variants (p.(Ile114Thr) and p.(Glu101Gly)). All New Zealand SOD1 p.(Ile114Thr) cases (n = 4) were distantly related to each other and to over 30 Australian cases with the same variant. Variants of interest were found in 14 participants with the splicing variants DCTN1:c.279+1G>C and ATP13A2:c.2412G>A, p.(Lys804=) subject to further study. Notably, 48.4% of pathogenic variants were in pre-symptomatic, unaffected individuals with family history, highlighting the importance of offering cascade testing and symptom surveillance for families, particularly as gene-specific treatments emerge.}, } @article {pmid40424919, year = {2025}, author = {Yamazaki, H and Takamatsu, N and Matsubara, T and Tani, M and Fukushima, K and Yoshida, T and Osaki, Y and Oki, R and Fujita, K and Nodera, H and Izumi, Y}, title = {Evaluation of the diagnostic performance of brachial plexus ultrasound in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {175}, number = {}, pages = {2110741}, doi = {10.1016/j.clinph.2025.2110741}, pmid = {40424919}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; Male ; Female ; Middle Aged ; *Brachial Plexus/diagnostic imaging/physiopathology ; Cross-Sectional Studies ; Ultrasonography/methods/standards ; Aged ; Retrospective Studies ; Adult ; }, abstract = {OBJECTIVE: This study aimed to assess the diagnostic performance of brachial plexus cross-sectional area (BP-CSA) measured by nerve ultrasound (NUS) for differentiating amyotrophic lateral sclerosis (ALS) from controls.

METHODS: A retrospective, cross-sectional study was conducted including patients with ALS and control patients who underwent NUS evaluation of the BP-CSA and the cervical nerve root CSA (C-CSA). Reference values for BP-CSA were built using reference cohort. Receiver operating characteristic curve analysis was performed in independent discovery and validation cohorts to assess the diagnostic performance of BP-CSA.

RESULTS: A total of 244 patients (114 ALS and 130 controls) were included. BP-CSA significantly correlated with body weight (coefficient = 0.50, p < 0.001). After adjusting for body weight, BP-CSA values were significantly lower in patients with ALS than controls (p < 0.001). Adjusted BP-CSA showed superior diagnostic performance compared to C-CSA, with area under the curve values of 0.75 (95 % CI: 0.64-0.86) and 0.78 (95 % CI: 0.68-0.88) in the discovery and validation cohorts, respectively.

CONCLUSIONS: BP-CSA, when adjusted for body weight, shows reliable performance in diagnosing ALS.

SIGNIFICANCE: This study highlights the clinical value of BP-CSA as a potential ALS diagnostic biomarker and underscores its superiority over cervical nerve root measurements.}, } @article {pmid40426231, year = {2025}, author = {Bergh, S and Casadei, N and Gabery, S and Simonsson, O and Duarte, JMN and Kirik, D and Nguyen, HP and Petersén, Å}, title = {TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {119}, pmid = {40426231}, issn = {2051-5960}, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Hypothalamus/pathology/metabolism ; Mice, Transgenic ; Mice ; Humans ; Neurons/pathology/metabolism ; Male ; Orexins/metabolism ; Hypothalamic Hormones/metabolism ; Melanins/metabolism ; Pituitary Hormones/metabolism ; Oxytocin/metabolism ; *Behavior, Animal/physiology ; Disease Models, Animal ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) pathology is linked to the neurodegenerative disorders amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Huntington disease (HD). Dysregulation of metabolism and emotion is shared across these disorders and may be caused by hypothalamic pathology. Inclusions with TDP-43 are present in the hypothalamus in clinical ALS, as well as selective loss of hypothalamic neurons expressing the metabolism and emotion regulating neuropeptides hypocretin (orexin), melanin-concentrating hormone (MCH) and oxytocin. We aimed to investigate whether there is a casual link between the effects of TDP-43 in the hypothalamus and the development of neuropathology, as well as changes in metabolism and behavior. We generated an adeno-associated viral (AAV) vector expressing human TDP-43 under the neuronal-specific synapsin promoter, which was injected bilaterally into the hypothalamus of wild-type FVB/N mice. TDP-43 overexpression resulted in hypothalamic pathology in a dose-dependent fashion replicating clinical pathology with hypothalamic atrophy and loss of hypocretin-, MCH- and oxytocin-expressing neurons. Nuclear and cytoplasmic inclusions of TDP-43 were found in the hypothalamus. Mice overexpressing TDP-43 in the hypothalamus developed metabolic dysregulation with hyperglycaemia independent of food intake. Additionally, mice overexpressing TDP-43 in the hypothalamus exhibited reduced motor activity and nesting ability, suggesting the development of an apathy-like phenotype. Taken together, AAV-vector mediated TDP-43 overexpression in the hypothalamus leads to neuropathology with the development of metabolic dysfunction and apathy-like behavior. These results indicate that TDP-43 can exert direct pathological effects in the hypothalamus, which may contribute to the development of the non-motor phenotype in TDP-43 proteinopathies.}, } @article {pmid40426669, year = {2025}, author = {Eisen, A}, title = {Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy.}, journal = {Brain sciences}, volume = {15}, number = {5}, pages = {}, pmid = {40426669}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS/MND) is considered a uniquely human complex neurodegenerative disorder, presenting with a variety of clinical phenotypes, which include frontotemporal dementia [...].}, } @article {pmid40426848, year = {2025}, author = {Spargo, TP and Iacoangeli, A and Ryten, M and Forzano, F and Pearce, N and Al-Chalabi, A}, title = {Modelling Population Genetic Screening in Rare Neurodegenerative Diseases.}, journal = {Biomedicines}, volume = {13}, number = {5}, pages = {}, pmid = {40426848}, issn = {2227-9059}, abstract = {Importance: Genomic sequencing enables the rapid identification of a breadth of genetic variants. For clinical purposes, sequencing for small genetic variations is considered a solved problem, while challenges remain for structural variants, given the lower sensitivity and specificity. Interest has recently risen among governing bodies in developing protocols for population-wide genetic screening. However, usefulness is constrained when the probability of being affected by a rare disease remains low, despite a positive genetic test. This is a common scenario in neurodegenerative disorders. The problem is recognised among statisticians and statistical geneticists but is less well-understood by clinicians and researchers who will act on these results, and by the general public who might access screening services directly without the appropriate support for interpretation. Observations: We explore the probability of subsequent disease following genetic screening of several variants, both single nucleotide variants (SNVs) and larger repeat expansions, for two neurological conditions, Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), comparing these results with screening for phenylketonuria, which is well-established. The risk following a positive screening test was 0.5% for C9orf72 in ALS and 0.4% for HTT in HD when testing repeat expansions, for which the test had sub-optimal performance (sensitivity = 99% and specificity = 90%), and 12.7% for phenylketonuria and 10.9% for ALS SOD1 when testing pathogenic SNVs (sensitivity = 99.96% and specificity = 99.95%). Subsequent screening confirmation via PCR for C9orf72 led to a 2% risk of developing ALS as a result of the reduced penetrance (44%). Conclusions and Relevance: We show that risk following a positive screening test result can be strikingly low for rare neurological diseases, even for fully penetrant variants such as HTT, if the test has sub-optimal performance. Accordingly, to maximise the utility of screening, it is vital to prioritise protocols with very high sensitivity and specificity, and a careful selection of markers for screening, giving regard to clinical interpretability, actionability, high penetrance, and secondary testing to confirm positive findings.}, } @article {pmid40426973, year = {2025}, author = {Ivantsik, O and Exarchos, TP and Vrahatis, AG and Vlamos, P and Krokidis, MG}, title = {Exploring Protein Misfolding in Amyotrophic Lateral Sclerosis: Structural and Functional Insights.}, journal = {Biomedicines}, volume = {13}, number = {5}, pages = {}, pmid = {40426973}, issn = {2227-9059}, support = {TAEDR-0535850.//This work was partially supported by the European Union-Next Generation EU, Greece 2.0 Na-tional Recovery and Resilience Plan Flagship program TAEDR-0535850./ ; }, abstract = {Protein functionality depends on its proper folding, making protein misfolding crucial for the function of proteins and, by extension, cells and the whole organism. Increasing evidence supports the role of protein misfolding in the pathogenesis of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). ALS is a rapidly progressive disease diagnosed at a prevalence of 5 cases per 100,000, with approximately 2-3 patients per 100,000 diagnosed each year. To date, there is no cure, and the disease usually leads to death within 2 to 5 years from diagnosis. There are two types of the disorder: familial ALS (fALS), accounting for approximately 10% of cases, and sporadic (sALS), accounting for the remaining 90%. The hallmark of ALS, regardless of type, is the protein aggregates found in patients' tissues. This suggests that the disruption of proteostasis plays a critical role in the development of the disease. Herein, we stress the distinct factors that lead to protein misfolding and aggregate formation in ALS. Specifically, we highlight several triggering factors affecting protein misfolding, namely mutations, errors in the processes of protein production and trafficking, and failures of folding and chaperone machinery. Gaining a deeper understanding of protein aggregation will improve our comprehension of disease pathogenesis and potentially uncover new therapeutic approaches.}, } @article {pmid40427436, year = {2025}, author = {Minuti, A and Raffaele, I and Scuruchi, M and Lui, M and Muscarà, C and Calabrò, M}, title = {Role and Functions of Irisin: A Perspective on Recent Developments and Neurodegenerative Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {5}, pages = {}, pmid = {40427436}, issn = {2076-3921}, support = {Current Research Funds 2025 (RRC-2025-23686388)//Ministero della Salute/ ; }, abstract = {Irisin is a peptide derived from fibronectin type III domain-containing protein 5 (FNDC5) and is primarily produced by muscle fibers under the regulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) during exercise. Irisin has been the subject of extensive research due to its potential as a metabolic regulator and its antioxidant properties. Notably, it has been associated with protective actions within the brain. Despite growing interest, many questions remain regarding the molecular mechanisms underlying its effects. This review summarizes recent findings on irisin, highlighting its pleiotropic functions and the biological processes and molecular cascades involved in its action, with a particular focus on the central nervous system. Irisin plays a crucial role in neuron survival, differentiation, growth, and development, while also promoting mitochondrial homeostasis, regulating apoptosis, and facilitating autophagy-processes essential for normal neuronal function. Emerging evidence suggests that irisin may improve conditions associated with non-communicable neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and multiple sclerosis. Given its diverse benefits, irisin holds promise as a novel therapeutic agent for preventing and treating neurological diseases.}, } @article {pmid40427878, year = {2025}, author = {Batterman, SA and Islam, MK and Jang, DG and Feldman, EL and Goutman, SA}, title = {Life Course Exposure to Cyanobacteria and Amyotrophic Lateral Sclerosis Survival.}, journal = {International journal of environmental research and public health}, volume = {22}, number = {5}, pages = {}, pmid = {40427878}, issn = {1660-4601}, support = {1K23ES027221-02D2/NH/NIH HHS/United States ; 3P30ES017885-03D3/NH/NIH HHS/United States ; (no number)//NeuroNetwork for Emerging Therapies/ ; (no number)//Robert and Katherine Jacobs Environmental Health Initiative Fund/ ; 1R01NS127188-04D4/NH/NIH HHS/United States ; 1R01ES030049-03A3/NH/NIH HHS/United States ; (no number)//Scott L. Pranger ALS Clinic Fund/ ; P30 ES017885/ES/NIEHS NIH HHS/United States ; (no number)//Andrea and Lawrence Wolfe Brain Health Initiative/ ; (no number)//Coleman Therapeutic Discovery Fund/ ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/mortality/epidemiology ; Humans ; *Cyanobacteria ; *Environmental Exposure ; *Microcystins/toxicity ; Middle Aged ; *Harmful Algal Bloom ; Female ; Male ; Aged ; Adult ; }, abstract = {Cyanobacterial harmful algal blooms (cyanoHABs) occur worldwide and can cause ingestion and inhalation exposure to microcystin and other potent toxins. This study develops life course exposure measures for cyanobacteria for application in population studies and then associates these measures with the survival of individuals with amyotrophic lateral sclerosis (ALS). The exposure measures utilize an individual's residence history, date of disease onset, and satellite data from the Cyanobacteria Assessment Network. Residence duration for selected exposure windows referenced to disease onset date was used to weight cyanobacteria concentrations in water bodies within 0.25 to 10 km of each residence. Different concentration metrics, buffer sizes, and exposure windows were evaluated. The 2.5 and 5 km buffers best balanced the likelihood and plausibility of exposure while still resolving exposure contrasts. Over their lifetime, most study participants lived within 5 km of cyanobacteria blooms, and the exposure was associated with up to 0.89 years shorter survival, with significant interactions for individuals reporting swimming, fishing, and private wells. Our findings suggest a new and modifiable risk factor for ALS survival, and a need to confirm exposures and epidemiological findings. These cyanoHAB exposure estimates can facilitate population studies that can discover new relationships with neurodegenerative and other diseases.}, } @article {pmid40428092, year = {2025}, author = {Vaccarino, F and Quattrocchi, CC and Parillo, M}, title = {Susceptibility-Weighted Imaging (SWI): Technical Aspects and Applications in Brain MRI for Neurodegenerative Disorders.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {40428092}, issn = {2306-5354}, abstract = {Susceptibility-weighted imaging (SWI) is a magnetic resonance imaging (MRI) sequence sensitive to substances that alter the local magnetic field, such as calcium and iron, allowing phase information to distinguish between them. SWI is a 3D gradient-echo sequence with high spatial resolution that leverages both phase and magnitude effects. The interaction of paramagnetic (such as hemosiderin and deoxyhemoglobin), diamagnetic (including calcifications and minerals), and ferromagnetic substances with the local magnetic field distorts it, leading to signal changes. Neurodegenerative diseases are typically characterized by the progressive loss of neurons and their supporting cells within the neurovascular unit. This cellular decline is associated with a corresponding deterioration of both cognitive and motor abilities. Many neurodegenerative disorders are associated with increased iron accumulation or microhemorrhages in various brain regions, making SWI a valuable diagnostic tool in clinical practice. Suggestive SWI findings are known in Parkinson's disease, Lewy body dementia, atypical parkinsonian syndromes, multiple sclerosis, cerebral amyloid angiopathy, amyotrophic lateral sclerosis, hereditary ataxias, Huntington's disease, neurodegeneration with brain iron accumulation, and chronic traumatic encephalopathy. This review will assist radiologists in understanding the technical framework of SWI sequences for a correct interpretation of currently established MRI findings and for its potential future clinical applications.}, } @article {pmid40428327, year = {2025}, author = {Papapanagiotou, AP and Alvanou, MV and Giantsis, IA and Vasilakoglou, I and Eleftherohorinos, IG}, title = {Characterization of the Giant Foxtail's (Setaria faberi) ALS Gene and Its Enhanced Metabolism-Based Cross-Resistance to Nicosulfuron and Rimsulfuron.}, journal = {Genes}, volume = {16}, number = {5}, pages = {}, pmid = {40428327}, issn = {2073-4425}, mesh = {*Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Sulfonylurea Compounds/pharmacology ; *Herbicide Resistance/genetics ; *Pyridines/pharmacology ; Herbicides/pharmacology ; *Setaria Plant/genetics/drug effects/enzymology ; *Plant Proteins/genetics/metabolism ; Zea mays/genetics/drug effects ; }, abstract = {BACKGROUND: Weed herbicide resistance is a serious problem in crop protection globally. Giant foxtail (Setaria faberi R.A.N. Herrm.) populations cannot be controlled by acetolactate synthase (ALS)-inhibiting herbicides in a few corn (Zea mays L.) monoculture fields.

METHODS: Five putative resistant giant foxtail populations, originating from corn monoculture fields in northeastern Greece, were evaluated for possible evolution of ALS-inhibitor resistance (nicosulfuron, rimsulfuron). The resistance ratio, the underlying resistance mechanism, and its impact on competitive ability against corn were studied.

RESULTS: The whole-plant rate-response assays showed that these populations were resistant (R) to the sulfonylureas nicosulfuron and rimsulfuron, but susceptible (S) to imidazolinone imazamox, triketone 4-hydroxyphenylpyruvate dioxygenase inhibitor tembotrione, and acetyl-CoA carboxylase inhibitor cycloxydim. The sequencing of the ALS gene did not reveal the presence of resistance-associated point mutations, indicating that the resistance was probably not target-site mediated. This was confirmed by the application of piperonyl butoxide two hours before nicosulfuron application, which reversed the resistance in all R giant foxtail populations, supporting the evidence of enhanced metabolism-mediated resistance. The competition study between corn and R or S giant foxtail populations indicated no stable trend reduction in corn traits, suggesting that the resistance mechanism was not associated with the competitive ability of the R populations. The novel ALS genotype in S. faberi, characterized for the first time and submitted to the GenBank database with accession number PV016837, indicated a closer genetic relationship with the S. viridis ALS gene than with S. italica.

CONCLUSIONS: Five giant foxtail populations have evolved metabolism-based resistance to the ALS-inhibiting herbicides nicosulfuron and rimsulfuron.}, } @article {pmid40428407, year = {2025}, author = {Škarica, M and Acsadi, G and Živković, SA}, title = {Pontocerebellar Hypoplasia Type 1 and Associated Neuronopathies.}, journal = {Genes}, volume = {16}, number = {5}, pages = {}, pmid = {40428407}, issn = {2073-4425}, mesh = {Humans ; *Olivopontocerebellar Atrophies/genetics/pathology ; *Cerebellar Diseases/genetics/pathology ; }, abstract = {Pontocerebellar hypoplasia is a rare neurodegenerative syndrome characterized by severe hypoplasia or atrophy of pons and cerebellum that may be associated with other brain malformations, microcephaly, optic nerve atrophy, dystonia, ataxia and neuromuscular disorders. At this time, there are 17 variants of PCH distinguished by clinical presentation and distinctive radiological and biochemical features in addition to pontine and cerebellar hypoplasia. PCH1 is defined as PCH variant associated with anterior horn degeneration in the spinal cord with muscle weakness and hypotonia, and is associated with recessive variants in genes VRK1, EXOSC3, EXOSC8, EXOSC9 and SLC25A46. Neuromuscular manifestations may clinically present as amyotrophic lateral sclerosis (ALS), motor neuropathy (HMN) or neuronopathy (non-5q spinal muscular atrophy; SMA) or sensorimotor polyneuropathy (HMSN). Physiologic functions of PCH1-associated genes include regulation of RNA metabolism, mitochondrial fission and neuronal migration. Overall, complex phenotypes associated with PCH1 gene variants ranging from PCH and related neurodevelopmental disorders combined with neuromuscular disorders to isolated neuromuscular disorders have variable outcomes with isolated neuromuscular disorders typically having later onset with better outcomes. Improved understanding of pathogenesis of pontocerebellar hypoplasia and its association with motor neuronopathies and peripheral neuropathies may provide us with valuable insights and lead to potential new therapeutic targets for neurodegenerative disorders.}, } @article {pmid40428860, year = {2025}, author = {Laucius, O and Drūteika, J and Vanagas, T and Balnytė, R and Radžiūnas, A and Vaitkus, A}, title = {Ultrasonography of the Vagus Nerve for ALS Patients: Correlations with Clinical Data and Dysfunction of the Autonomic Nervous System.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {61}, number = {5}, pages = {}, pmid = {40428860}, issn = {1648-9144}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnostic imaging ; Male ; Female ; *Vagus Nerve/diagnostic imaging/physiopathology ; Middle Aged ; Aged ; Ultrasonography/methods ; *Autonomic Nervous System/physiopathology ; Prospective Studies ; Cohort Studies ; }, abstract = {Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons, leading to the rapid decline of motor function. In recent years, dysfunction of the autonomic nervous system (ANS) has also been increasingly recognized as a contributing factor in various neurodegenerative diseases, including ALS. This study is the second publication from our ALS research cohort at Kaunas Clinics. Our previous work examined ultrasonographic changes in the phrenic nerve as a supplementary diagnostic approach for ALS. Materials and Methods: In the present study, we investigated ultrasonographic alterations of the vagus nerve within the same ALS cohort, aiming to explore correlations with ANS involvement. We performed high-resolution ultrasonography of the vagus nerve (VN), collected clinical data, conducted heart rate monitoring, and evaluated respiratory function. Results: We prospectively included 32 ALS patients meeting "Gold Coast" criteria and 64 age- and sex-matched control patients. The average onset of ALS was 57.97 ± 9.22 years, and the duration of the disease was15.41 ± 9.04 months. For ALS patients, we found significantly reduced vagus nerve cross-sectional area (CSA) at the level of the carotid artery bifurcation bilaterally compared to controls (right VN 1.86 ± 0.21 vs. 2.07 ± 0.18 mm[2], p < 0.001; left VN 1.69 ± 0.21 vs. 1.87 ± 0.21 mm[2], p < 0.001). Reduced values of the left VN positively correlated with the reduced values of FEV1% and sO2. Conclusions: Our findings revealed a significant bilateral reduction in vagus nerve size in ALS patients compared to controls, suggesting that vagal atrophy may serve as a potential marker of autonomic dysfunction in ALS.}, } @article {pmid40429496, year = {2025}, author = {Watt, NA and Hockley, N and Armitage, JA}, title = {Exploring the Risk: Peripheral Retinal Degenerations in Young Australian Adults.}, journal = {Journal of clinical medicine}, volume = {14}, number = {10}, pages = {}, pmid = {40429496}, issn = {2077-0383}, abstract = {Background/Objectives: Peripheral retinal degenerations (PRDs) are structural anomalies in the outer regions of the retina, typically emerging in adolescence and early adulthood. Early detection is crucial, as some PRDs can lead to sight-threatening complications, such as retinal detachment, if left unmanaged. Due to a paucity of research regarding PRDs and their association with axial length (AL) and refractive error (RE) in young Australian adults, this study aimed to investigate the prevalence of PRDs in this population and establish whether AL and RE could help predict the likelihood of PRD occurrence. Methods: A cross-sectional study was conducted on a mixed population (n = 221) of Australian adults aged 18 to 40. Demographic data, RE, AL, and a series of ultra-widefield (UWF) retinal images were obtained from participants' undilated eyes using the Zeiss Clarus[TM] 500. Results: The overall PRD prevalence was 8.15% (n = 442 eyes). Binary logistic regression revealed that a longer AL was a more significant factor in increasing the risk of PRD development across all myopia classifications compared to emmetropia than RE. The likelihood of a PRD was 50% at an AL of 26.9 mm and -6.50D of myopia, and 95% at 29.6 mm and -11.00D. Conclusions: PRD prevalence was lower than reported in other global studies, perhaps reflecting the diverse ethnic makeup of the cohort. While our study supports the conventional understanding that longer ALs, and high myopia are key risk factors for developing a PRD, it also provides new insights into the likelihood of detecting a PRD at a given AL or RE in a mixed population. This information is crucial for eye care practitioners, enabling early identification of at-risk individuals and screening for PRDs that may increase the risk of retinal detachment.}, } @article {pmid40429767, year = {2025}, author = {Bokulic Panichi, L and Stanca, S and Dolciotti, C and Bongioanni, P}, title = {The Role of Oligodendrocytes in Neurodegenerative Diseases: Unwrapping the Layers.}, journal = {International journal of molecular sciences}, volume = {26}, number = {10}, pages = {}, pmid = {40429767}, issn = {1422-0067}, mesh = {Humans ; *Oligodendroglia/metabolism/pathology ; *Neurodegenerative Diseases/pathology/metabolism/etiology ; Animals ; Myelin Sheath/metabolism/pathology ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis/motor neuron disease, and multiple sclerosis, are characterized by progressive loss of neuronal structure and function, leading to severe cognitive, motor, and behavioral impairments. They pose a significant and growing challenge due to their rising prevalence and impact on global health systems. The societal and emotional toll on patients, caregivers, and healthcare infrastructures is considerable. While significant progress has been made in elucidating the pathological hallmarks of these disorders, the underlying cellular and molecular mechanisms remain incompletely understood. Increasing evidence implicates oligodendrocytes and their progenitors-oligodendrocyte progenitor cells (OPCs)-in the pathogenesis of several NDs, beyond their traditionally recognized role in demyelinating conditions such as MS. Oligodendrocytes are essential for axonal myelination, metabolic support, and neural circuit modulation in the central nervous system. Disruptions in oligodendrocyte function and myelin integrity-manifesting as demyelination, hypomyelination, or dysmyelination-have been associated with disease progression in various neurodegenerative contexts. This review consolidates recent findings on the role of OPCs in NDs, explores the concept of myelin plasticity, and discusses therapeutic strategies targeting oligodendrocyte dysfunction. By highlighting emerging research in oligodendrocyte biology, this review aims to provide a short overview of its relevance to neurodegenerative disease progression and potential therapeutic advances.}, } @article {pmid40429802, year = {2025}, author = {Carnaroli, M and Deriu, MA and Tuszynski, JA}, title = {Computational Search for Inhibitors of SOD1 Mutant Infectivity as Potential Therapeutics for ALS Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {10}, pages = {}, pmid = {40429802}, issn = {1422-0067}, mesh = {*Superoxide Dismutase-1/genetics/chemistry/antagonists & inhibitors/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; *Mutation ; Protein Multimerization ; }, abstract = {Familial amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective degeneration of motor neurons. Among the main genetic causes of ALS, over 200 mutations have been identified in the Cu/Zn superoxide dismutase (SOD1) protein, a dimeric metalloenzyme essential for converting superoxides from cellular respiration into less toxic products. Point mutations in SOD1 monomers can induce protein misfolding, which spreads to wild-type monomers through a prion-like mechanism, leading to dysfunctions that contribute to the development of the disease. Understanding the structural and functional differences between the wild-type protein and its mutated variants, as well as developing drugs capable of inhibiting the propagation of misfolding, is crucial for identifying new therapeutic strategies. In this work, seven SOD1 mutations (A4V, G41D, G41S, D76V, G85R, G93A, and I104F) were selected, and three-dimensional models of SOD1 dimers composed of one wild-type monomer and one mutated monomer were generated, along with a control dimer consisting solely of wild-type monomers. Molecular dynamics simulations were conducted to investigate conformational differences between the dimers. Additionally, molecular docking was performed using a library of ligands to identify compounds with high affinity for the mutated dimers. The study reveals some differences in the mutated dimers following molecular dynamics simulations and in the docking of the selected ligands with the various dimers.}, } @article {pmid40430989, year = {2025}, author = {Li, Z and Sun, X and Yu, S and Sun, H and Lian, L and Peng, X and Jin, T and Liu, W and Wang, H}, title = {Baseline Sensitivity of Echinochloa crus-galli (L.) P.Beauv. and Leptochloa chinensis (L.) Nees to Flusulfinam, a New 4-Hydroxyphenylpyruvate Dioxygenase (HPPD)-Inhibiting Herbicide in Rice, in China.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {40430989}, issn = {2223-7747}, support = {ZR2024QC067//Shandong Provincial Natural Science Foundation/ ; 32202353//National Natural Science Foundation of China/ ; 2021CXGC010811//Key R&D Program of Shandong Province, China/ ; 2023YFD1400501//National Key R&D Program of China/ ; }, abstract = {Flusulfinam is a 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicide applied post-emergence (POST) to control Echinochloa crus-galli (L.) P.Beauv., Leptochloa chinensis (L.) Nees, Digitaria sanguinalis (Linn.) Scop. and other annual weeds in directly seeded and transplanted paddy fields in China, registered in September 2024. Notably, compared with other HPPD inhibitors in rice, flusulfinam exhibits consistently high safety in both japonica and indica rice varieties. Meanwhile, flusulfinam has no target-site cross-resistance with traditional acetolactate synthase (ALS)-inhibiting, acetyl-CoA carboxylase (ACCase)-inhibiting, and auxin herbicides. Moreover, as the only heterocyclic-amide-structured herbicide in the HPPD inhibitors, it poses a low risk of metabolic cross-resistance with the other HPPD inhibitors, making it a promising candidate for managing herbicide-resistant weeds in rice fields. In this study, the baseline sensitivity to flusulfinam of E. crus-galli and L. chinensis in paddy fields in China was established using dose-response assays between June and October 2023. Thirty-nine populations of E. crus-galli and forty-three populations of L. chinensis, collected from rice fields across various major rice-producing regions in China, exhibited susceptibility to flusulfinam. The GR50 values ranged from 0.15 to 19.39 g active ingredient (a.i.) ha[-1] for E. crus-galli and from 7.82 to 49.92 g a.i. ha[-1] for L. chinensis, respectively, far below the field recommended rate of flusulfinam. Meanwhile, the GR50 values of E. crus-galli and L. chinensis to flusulfinam were both distributed as a unimodal curve, with baseline sensitivity (GR50b) of 6.48 g a.i. ha[-1] and 22.38 g a.i. ha[-1], respectively. The SI50 value showed 129.27-fold and 6.38-fold variability in flusulfinam sensitivity among the 39 E. crus-galli field populations and 43 L. chinensis filed populations, while the variability declined to 2.99-fold and 2.23-fold when the SI50b value was used. This study substantiated the efficacy of flusulfinam against E. crus-galli and L. chinensis in Chinese paddy fields and furnished a benchmark for monitoring temporal variations in the susceptibility of field populations of E. crus-galli and L. chinensis to flusulfinam.}, } @article {pmid40431070, year = {2025}, author = {Trebol-Aizpurua, E and Eceiza, MV and Jimenez-Martinez, C and Marí, AI and Royuela, M and Zabalza, A and Gil-Monreal, M}, title = {Resistance to Amino Acid Biosynthesis Inhibiting-Herbicides in Amaranthus palmeri Populations from Aragon (Spain).}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {40431070}, issn = {2223-7747}, support = {2020 117723-RB-I00//Spanish Ministry of Science and Innovation/ ; PhD fellowship//Basque Government/ ; Investigo programme//Public University of Navarre-Government of Navarre/ ; postgraduate research fellowship (call 2024)//Sociedad Española de Malherbología/ ; }, abstract = {Amaranthus palmeri is a highly problematic agricultural weed due to its rapid growth, high seed production, and strong tendency to develop herbicide resistance. In Spain, the initial colonization of A. palmeri began in 2007, when populations were detected at various locations in the province of Lleida (Catalonia). Since then, new infestations have been reported in other regions of the country, primarily infesting maize fields. Although resistance to glyphosate or to acetolactate synthase (ALS) inhibitors has been documented in several populations from Catalonia and Extremadura, little is known about the resistance profile of populations from Aragon. The main objective of this study was to characterize the putative resistance of five populations from Aragon to 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) inhibitors (glyphosate) and ALS inhibitors (nicosulfuron and imazamox). Sensitivity to both mechanisms of action was measured by root growth in vertical plates and shikimate accumulation for glyphosate. Target-site resistance was evaluated by analyzing EPSPS and ALS gene copy numbers and ALS gene mutations. The populations showed high variability, with no multiple resistance detected. The Bujaraloz population showed moderate resistance to glyphosate due to EPSPS gene amplification. In three populations, mutations in the ALS gene conferring resistance were detected. The Trp574Leu mutation was detected in approximately half of the individuals from the Albelda, Tamarite de Litera, and Caspe populations. In the latter, the Pro197Thr mutation was also present. This study reveals significant genetic variability within each population and provides evidence for the spread of herbicide resistance across different regions of Spain.}, } @article {pmid40431734, year = {2025}, author = {Kim, DH and Kim, JH and Jeon, MT and Kim, KS and Kim, DG and Choi, IS}, title = {The Role of TDP-43 in SARS-CoV-2-Related Neurodegenerative Changes.}, journal = {Viruses}, volume = {17}, number = {5}, pages = {}, pmid = {40431734}, issn = {1999-4915}, support = {25-BR-02-03//Korea Brain Research Institute/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *COVID-19/complications/metabolism/virology/pathology ; *SARS-CoV-2/physiology ; *Neurodegenerative Diseases/metabolism/virology/pathology/etiology ; Virus Replication ; Animals ; }, abstract = {The coronavirus disease 2019 (COVID-19) pandemic has been linked to long-term neurological effects with multifaceted complications of neurodegenerative diseases. Several studies have found that pathological changes in transactive response DNA-binding protein of 43 kDa (TDP-43) are involved in these cases. This review explores the causal interactions between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and TDP-43 from multiple perspectives. Some viral proteins of SARS-CoV-2 have been shown to induce pathological changes in TDP-43 through its cleavage, aggregation, and mislocalization. SARS-CoV-2 infection can cause liquid-liquid phase separation and stress granule formation, which accelerate the condensation of TDP-43, resulting in host RNA metabolism disruption. TDP-43 has been proposed to interact with SARS-CoV-2 RNA, though its role in viral replication remains to be fully elucidated. This interaction potentially facilitates viral replication, while viral-induced oxidative stress and protease activity accelerate TDP-43 pathology. Evidence from both clinical and experimental studies indicates that SARS-CoV-2 infection may contribute to long-term neurological sequelae, including amyotrophic lateral sclerosis-like and frontotemporal dementia-like features, as well as increased phosphorylated TDP-43 deposition in the central nervous system. Biomarker studies further support the link between TDP-43 dysregulation and neurological complications of long-term effects of COVID-19 (long COVID). In this review, we presented a novel integrative framework of TDP-43 pathology, bridging a gap between SARS-CoV-2 infection and mechanisms of neurodegeneration. These findings underscore the need for further research to clarify the TDP-43-related neurodegeneration underlying SARS-CoV-2 infection and to develop therapeutic strategies aimed at mitigating long-term neurological effects in patients with long COVID.}, } @article {pmid40432760, year = {2025}, author = {Simkin, RL and Rhymes, ER and Lang, Q and Birsa, N and Sleigh, JN}, title = {Dissection and Whole-Mount Immunofluorescent Staining of Mouse Hind Paw Muscles for Neuromuscular Junction Analysis.}, journal = {Bio-protocol}, volume = {15}, number = {10}, pages = {e5315}, pmid = {40432760}, issn = {2331-8325}, abstract = {The neuromuscular junction (NMJ) is a peripheral synaptic connection between a lower motor neuron and skeletal muscle fibre that enables muscle contraction in response to neuronal stimulation. NMJ dysfunction and morphological abnormalities are commonly observed in neurological conditions, including amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, and spinal muscular atrophy. Employing precise and reproducible techniques to visualise NMJs in mouse models of neuromuscular disorders is crucial for uncovering aspects of neuropathology, revealing disease mechanisms, and evaluating therapeutic approaches. Here, we present a method for dissecting the deep lumbrical and flexor digitorum brevis (FDB) muscles of the mouse hind paw and describe the process of whole-mount immunofluorescent staining for morphological analysis of NMJs. Similar whole-mount techniques have been applied to other muscles, such as the diaphragm; however, dense connective tissue in adult samples often impedes antibody penetration. Moreover, large hind limb muscles, including the gastrocnemius and tibialis anterior, are commonly used to examine NMJs but require embedding and cryosectioning. These additional steps increase the complexity and duration of the protocol and can introduce sectioning artefacts, including transection of NMJs and disruption of morphology. Using small hind paw muscles enables whole-mounting, which completely eliminates the requirement for embedding and cryosectioning. As a result, the entire neuromuscular innervation pattern can be visualised, allowing a more accurate assessment of NMJ development, denervation, and regeneration in mouse models of neurological disease and nerve injury, which can be applied across all postnatal ages. Key features • Small muscles of the mouse hind paw, i.e., lumbrical and FDB muscles, can be rapidly dissected for whole-mount immunofluorescent analysis without the need for cryosectioning. • This protocol allows visualisation of the entire neuromuscular innervation pattern using axonal (anti-tubulin βIII), pre-synaptic (anti-synaptophysin), and post-synaptic (α-bungarotoxin) markers. • Whole-mount immunofluorescence of hind paw muscles enables assessment of developmental, degenerative, and regenerative phenotypes in young and adult mice across disease and injury models. • High-throughput analysis can be performed using NMJ-Analyser or NMJ-morph to evaluate diverse morphological features of the NMJ.}, } @article {pmid40433509, year = {2025}, author = {Baek, SH and Tae, WS and Park, JW and Kim, BJ}, title = {Assessment of the glymphatic dysfunction in amyotrophic lateral sclerosis using the diffusion tensor imaging along the perivascular spaces index: a pilot study.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1570327}, pmid = {40433509}, issn = {1663-4365}, abstract = {BACKGROUND: The glymphatic system plays a critical role in clearing interstitial waste from the brain. Dysfunction of this system has been linked to various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The diffusion tensor imaging-along the perivascular space (DTI-ALPS) index has emerged as a potential neuroimaging biomarker for evaluating glymphatic function. This study investigates whether glymphatic function differs in individuals with ALS compared to those with Parkinson's disease (PD) and normal controls (NCs), using the DTI-ALPS index.

METHODS: This study included 35 ALS patients, 35 age- and sex-matched PD patients, and 13 NCs. Diffusion tensor imaging (DTI) was conducted, and the DTI-ALPS index was calculated. Clinical assessments included demographic data, disease duration, cognitive status, and functional scales. Group comparisons and correlation analyses were performed to assess the relationship between the DTI-ALPS index and clinical parameters.

RESULTS: The ALS group exhibited a significantly lower right-side DTI-ALPS index than the NC group (p = 0.037), while no differences were observed between the ALS and PD groups. The DTI-ALPS index was negatively correlated with age in ALS and PD groups but showed no correlation with clinical measures in the ALS group. Women in the ALS group had a significantly higher DTI-ALPS index than in men.

CONCLUSION: Glymphatic dysfunction may contribute to the pathogenesis of ALS, as evidenced by a reduced DTI-ALPS index compared to NCs. However, its clinical relevance and specificity for ALS remain uncertain. Further studies with larger cohorts are warranted to validate these findings.}, } @article {pmid40436373, year = {2025}, author = {Vosough, M and Drees, F and Sieber, G and Stach, TL and Beisser, D and Probst, AJ and Boenigk, J and Schmidt, TC}, title = {Integrative Analysis of Nontargeted LC-HRMS and High-Throughput Metabarcoding Data for Aquatic Environmental Studies Using Combined Multivariate Statistical Approaches.}, journal = {Analytical chemistry}, volume = {97}, number = {22}, pages = {11563-11571}, pmid = {40436373}, issn = {1520-6882}, mesh = {Chromatography, Liquid ; Mass Spectrometry ; Multivariate Analysis ; Wastewater/chemistry/analysis ; RNA, Ribosomal, 16S/genetics ; *Water Pollutants, Chemical/analysis ; *High-Throughput Screening Assays ; *DNA Barcoding, Taxonomic ; }, abstract = {Significant progress in high-throughput analytical techniques has paved the way for novel approaches to integrating data sets from different compartments. This study leverages nontarget screening (NTS) via liquid chromatography-high-resolution mass spectrometry (LC-HRMS), a crucial technique for analyzing organic micropollutants and their transformation products, in combination with biological indicators. We propose a combined multivariate data processing framework that integrates LC-HRMS-based NTS data with other high-throughput data sets, exemplified here by 18S V9 rRNA and full-length 16S rRNA gene metabarcoding data sets. The power of data fusion is demonstrated by systematically evaluating the impact of treated wastewater (TWW) over time on an aquatic ecosystem through a controlled mesocosm experiment. Highly compressed NTS data were compiled through the implementation of the region of interest-multivariate curve resolution-alternating least-squares (MCR-ALS) method, known as ROIMCR. By integrating ANOVA-simultaneous component analysis with structural learning and integrative decomposition (SLIDE), the innovative SLIDE-ASCA approach enables the decomposition of global and partial common, as well as distinct variation sources arising from experimental factors and their possible interactions. SLIDE-ASCA results indicate that temporal variability explains a much larger portion of the variance (74.6%) than the treatment effect, with both contributing to global shared space variation (41%). Design structure benefits include enhanced interpretability, improved detection of key features, and a more accurate representation of complex interactions between chemical and biological data. This approach offers a greater understanding of the natural and wastewater-influenced temporal patterns for each data source, as well as reveals associations between chemical and biological markers in an exemplified perturbed aquatic ecosystem.}, } @article {pmid40436457, year = {2025}, author = {Peace, A and White, DA and Hackney, G and Bradburn, M and Norman, P and White, S and Al-Chalabi, A and Baird, W and Beever, D and Cade, J and Coates, E and Cooper, C and Ezaydi, N and Halliday, V and Maguire, C and Shaw, PJ and Stavroulakis, H and Waterhouse, S and Young, TA and McDermott, CJ and , }, title = {Randomised controlled trial with parallel process evaluation and health economic analysis to evaluate a nutritional management intervention, OptiCALS, for patients with amyotrophic lateral sclerosis: study protocol.}, journal = {BMJ open}, volume = {15}, number = {5}, pages = {e096098}, pmid = {40436457}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy/economics ; Cost-Benefit Analysis ; Energy Intake ; Ireland ; Nutrition Therapy/methods ; Quality of Life ; United Kingdom ; Equivalence Trials as Topic ; Multicenter Studies as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating illness that leads to muscle weakness and death usually within around 3 years of diagnosis. People with ALS (pwALS) often lose weight due to raised energy requirements and symptoms of the disease presenting significant challenges to taking adequate oral diet, with those who lose more weight being at a greater chance of earlier death. There is also some evidence to suggest that a higher calorie diet may benefit the disease course in pwALS, but further research is needed.

METHODS AND ANALYSIS: Two armed, parallel group, superiority, open labelled, randomised controlled trial, with internal pilot, to assess the effectiveness of an early high calorie diet on functional outcomes in ALS, comprising two treatment arms: (1) standard care, (2) standard care with additional active management using the OptiCALS complex intervention to achieve a high calorie diet (initially randomised 1:1, then 1:2 following a protocol amendment). Using a food first approach, pwALS will be encouraged and supported to follow a diet that meets an individualised calorie target from food before prescribing oral nutritional supplements. 259 pwALS will be recruited from up to 20 ALS centres across the United Kingdom and Ireland and followed up for a period of 12 months. Primary outcome is functional change measured over 12 months, using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Secondary end points include measures of functional health, quality of life, calorie intake and weight, as well as time to gastrostomy and survival. A health economic analysis and process evaluation will also be undertaken. Participant recruitment is expected to complete in September 2025, and participant follow-up is expected to complete in September 2026. The results of this study are expected in March 2027.

ETHICS AND DISSEMINATION: The trial was approved by Greater Manchester-North West Research Ethics Committee, reference 20/NW/0334 on 8 September 2020. We will publish the study findings in peer-reviewed academic journals and present at local, national and international conferences where possible.

TRIAL REGISTRATION NUMBER: ISRCTN30588041.}, } @article {pmid40437235, year = {2025}, author = {Modafferi, S and Farina, S and Esposito, F and Brandi, O and Di Salvio, M and Della Valle, I and D'Uva, S and Scarian, E and Cicio, G and Riccardi, A and Pisati, F and Garbelli, A and Santini, T and Pansarasa, O and Morlando, M and D'Ambrosi, N and Cozzolino, M and Cestra, G and d'Adda di Fagagna, F and Gioia, U and Francia, S}, title = {DNA damage response defects induced by the formation of TDP-43 and mutant FUS cytoplasmic inclusions and their pharmacological rescue.}, journal = {Cell death and differentiation}, volume = {32}, number = {12}, pages = {2309-2322}, pmid = {40437235}, issn = {1476-5403}, support = {RIPREI2023_7c8ae10d783c//Istituto Superiore di Sanità (ISS)/ ; PRIN 2020 CXFL4T//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; MNESYS (PE0000006)//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; CN00000041 CN3 RNA//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PNRR-CN3//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; 2021 DDR&ALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; 2016 DDRNA&ALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SwitchALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; DBA.AD005.225-NUTRAGE-FOE2021//Consiglio Nazionale delle Ricerche (National Research Council)/ ; Flagship Project Interomics//Consiglio Nazionale delle Ricerche (National Research Council)/ ; TELORNAGING-835103//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; AIRC-IG(21762)//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; AIRC 5×1000//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; GGP17111//Fondazione Telethon (Telethon Foundation)/ ; POR FESR 2014-2020//Regione Lombardia (Region of Lombardy)/ ; Ricerca Corrente 2022 - 2024//Ministero della Salute (Ministry of Health, Italy)/ ; }, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; *RNA-Binding Protein FUS/metabolism/genetics ; Humans ; Mice ; *DNA Damage ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Inclusion Bodies/metabolism/drug effects ; Ataxia Telangiectasia Mutated Proteins/metabolism/antagonists & inhibitors ; DNA Repair/drug effects ; DNA Breaks, Double-Stranded/drug effects ; Mutation ; }, abstract = {Formation of cytoplasmic inclusions (CIs) of TDP-43 and FUS, along with DNA damage accumulation, is a hallmark of affected motor neurons in Amyotrophic Lateral Sclerosis (ALS). However, the impact of CIs on DNA damage response (DDR) and repair in this pathology remains unprobed. Here, we show that CIs of TDP-43 and FUS[P525L], co-localizing with stress granules, lead to a dysfunctional DDR activation associated with physical DNA breakage. Inhibition of the activity of the DDR kinase ATM, but not of ATR, abolishes DDR signaling, indicating that DNA double-strand breaks (DSBs) are the primary source of DDR activation. In addition, cells with TDP-43 and FUS[P525L] CIs exhibit reduced DNA damage-induced RNA synthesis at DSBs. We previously showed that the two endoribonucleases DROSHA and DICER, also known to interact with TDP-43 and FUS during small RNA processing, contribute to DDR signaling at DSBs. Treatment with enoxacin, which stimulates DDR and repair by boosting the enzymatic activity of DICER, restores a proficient DDR and reduces DNA damage accumulation in cultured cells with CIs and in vivo in a murine model of ALS. In Drosophila melanogaster, Dicer-2 overexpression rescues TDP-43-mediated retinal degeneration. In summary, our results indicate that the harmful effects caused by TDP-43 and FUS CIs include genotoxic stress and that the pharmacological stimulation of the DNA damage signaling and repair counteracts it.}, } @article {pmid40438583, year = {2025}, author = {Li, H and Peng, Y and Wu, Y and Chen, Y and Li, J and He, Y and Wang, H and Luo, C and Mo, Z}, title = {Cardiomyocyte-derived exosomes carrying miR-181a-5p facilitate heart-brain crosstalk and exacerbate methamphetamine dependence in rats.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1541442}, pmid = {40438583}, issn = {1663-9812}, abstract = {BACKGROUND: Methamphetamine (MA) is one of the most harmful synthetic drugs, yet the mechanisms underlying its addiction and relapse remain incompletely understood. This study investigates how cardiomyocyte-derived exosomes carrying miRNAs facilitate heart-brain crosstalk and contribute to MA dependence.

MATERIALS AND METHODS: A conditioned place preference (CPP) model of MA dependence was established in rats. High-throughput sequencing were employed to identify candidate miRNAs in cardiac exosomes and brain tissues. Behavioral assessments, real-time PCR, nanoparticle tracking analysis, in vivo imaging, in vitro uptake assays, network pharmacology, and dual-luciferase reporter assays were used to explore the role of cardiomyocyte-derived exosomes in MA dependence.

RESULTS: MA induced significant CPP in rats. miR-181a-5p was markedly upregulated in cardiac exosomes and brain tissue, with higher levels observed in cardiac exosomes. In vivo biodistribution showed that cardiomyocyte-derived exosomes cross the blood-brain barrier and accumulate in the brain. In vitro uptake assays demonstrated that SH-SY5Y cells internalized these exosomes, leading to increased miR-181a-5p expression. Tail vein injections of miR-181a-5p-enriched exosomes enhanced MA CPP behavior in rats. Network pharmacology revealed 108 potential targets of miR-181a-5p, enriched in processes such as steroid biosynthesis, amide metabolism, and apoptosis, involving pathways related to the endoplasmic reticulum, MAPK signaling, and amyotrophic lateral sclerosis. Molecular docking identified stable interactions between MA and 12 targets, including HSP90B1, TNF, and MAP2K1, with miR-181a-5p binding to the 3'-UTR regions of these targets. Dual-luciferase assays confirmed the negative regulation of six targets by miR-181a-5p.

CONCLUSION: This study reveals that cardiomyocyte-derived exosomes transport miR-181a-5p, facilitating heart-brain crosstalk and exacerbating MA CPP behavior in rats. These effects are mediated through the regulation of key brain targets, including HSP90B1, TNF, and MAP2K1, providing new insights into the molecular mechanisms of MA addiction and potential therapeutic targets.}, } @article {pmid40439808, year = {2025}, author = {Singh, H and Gupta, R and Gupta, M and Ahmad, A}, title = {Aging-induced alterations in microglial cells and their impact on neurodegenerative disorders.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {515}, pmid = {40439808}, issn = {1573-4978}, mesh = {Humans ; *Microglia/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Aging/pathology/metabolism ; Animals ; Brain/metabolism/pathology ; Cellular Senescence ; }, abstract = {Senescence causes deterioration in the functioning and physiology of an organism. Microglia, the standing resident immune brain cells transform from neuroprotective to neurotoxic with age. Rapid process motility and cellular migration of microglia in the developing brain, and other characteristics are regarded to be crucial for immunological defense and tissue repair. As they mature, microglia not only differ in their morphology but also in their functioning. However, the exact mechanism related to the atrophies caused by aged microglia or their role in neurodegenerative diseases is still uncertain. The aim of this updated review is to provide insights of how aging microglial cells change and how this influences the development of neurodegenerative diseases. As life expectancy rises, there is an increase in the accumulation of iron, ROS/NOS, protein misfolding and insufficient clearing of debris. This is attributed to the age-dependent alterations in the genes linked to energy metabolism, mitochondrial and lysosome function, and neuroinflammation. Aging microglia often shifts towards a pro-inflammatory state with a reduction of anti-inflammatory cytokines. Aging microglia fail to clear amyloid-beta plaques, accelerates tau-pathology and enhances the chronic neuroinflammation, exacerbating the α-synuclein aggregation. These changes significantly impacted the onset of various neurogenerative disorders such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease etc. However, it is important to note that these microglial aging effects might not be perceived as absolute, due to various limitations such as microglial heterogeneity, intercellular complexity across brain regions and variability in human aging owing to genetic and epigenetic variations. Regardless of this the future perspective of such insights are of immense relevance as novel therapeutic approaches can be formulated if the molecular and cellular mechanisms of aging microglial perturbations are understood. Future research should focus on restoring microglial homeostasis to mitigate the effects of aging on the brain and slowing the progression of neurodegenerative diseases.}, } @article {pmid40439916, year = {2025}, author = {Porel, P and Hunjan, G and Kaur, N and Sharma, V and Kaur, M and Mittal, Y and Kaur, R and Aran, KR}, title = {Unlocking the neuroprotective potential of peptide nucleic acids 5 (PNA5) in neurological diseases: molecular mechanisms to therapeutic approaches.}, journal = {Metabolic brain disease}, volume = {40}, number = {5}, pages = {213}, pmid = {40439916}, issn = {1573-7365}, mesh = {Humans ; *Peptide Nucleic Acids/therapeutic use/pharmacology ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Blood-Brain Barrier/drug effects/metabolism ; }, abstract = {Peptide nucleic acids (PNAs) are synthetic nucleic acid analogues offering distinct structural and functional advantages over conventional RNA and DNA, positioning them as powerful molecules in molecular biology. Recently, PNAs have gained significant attention for their potential in the prevention and management of neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury (TBI), spinal cord injury (SCI), depression, and anxiety. PNA5, a specific PNA variant, is highly expressed in neocortical association regions, particularly in primates, and plays a critical role in high-level cognitive functions such as reasoning, decision-making, and problem-solving. It can form stable, sequence-specific hybridizations with nucleic acids, resist nuclease degradation, and efficiently cross cellular membranes, making them ideal candidates for targeting disease-related genes in the brain. PNA5 has shown neuroprotective properties by improving cognitive function, reducing neuroinflammation, and preserving the integrity of the blood-brain barrier (BBB). Additionally, it supports critical processes such as neural migration, axon guidance, and synaptogenesis, which are vital for maintaining proper brain function. This review explores the mechanisms by which PNAs, particularly PNA5, exert therapeutic effects in neurological disorders. It highlights their role in gene modulation, protein regulation, and potential strategies for enhancing PNA delivery to the central nervous system (CNS) and its related disorders.}, } @article {pmid40440345, year = {2025}, author = {Krull, F and Hosseini, S and Bleyer, M and Brenig, B}, title = {Findings from transcriptomics and immunohistochemistry indicate an autoimmune disease targeting brainstem inhibitory interneurons in bovine spastic paresis.}, journal = {PloS one}, volume = {20}, number = {5}, pages = {e0324633}, pmid = {40440345}, issn = {1932-6203}, mesh = {*Paraparesis, Spastic/genetics/immunology/veterinary ; Animals ; Cattle ; *Gene Expression Profiling ; *Immunohistochemistry ; *Autoimmune Diseases/genetics/veterinary ; Interneurons/physiology ; Brain Stem/physiology ; Animal Husbandry/economics/methods/statistics & numerical data ; Dairying/economics/methods/statistics & numerical data ; Pregnancy Proteins/genetics ; Interleukin-21/blood ; Cholecystokinin/genetics/metabolism ; Neuropeptide Y/genetics/metabolism ; Somatostatin/genetics/metabolism ; Shotgun Sequencing ; RNA, Messenger/genetics/metabolism ; Metabolic Networks and Pathways/physiology ; Male ; Female ; }, abstract = {Bovine spastic paresis (BSP) is a progressive neuromuscular disease of unknown origin that causes persistent stiffness of the hind limbs. The symptoms are similar to those of human motor neuron diseases such as primary (PLS) or amyotrophic lateral sclerosis (ALS). BSP occurs worldwide in cattle production with an estimated prevalence of <1%. For Germany, this means that around 20,000 Holstein cattle are affected. BSP is generally considered a hereditary disease, but there is no prevention through breeding programs. As a result, BSP not only affects animal welfare but also leads to economic losses in milk and beef production. Here, we used transcriptomics to analyse the brainstem, spinal cord and affected gastrocnemius muscle tissue of eight animals affected by BSP and eight control animals from slaughterhouses to gain new insights into the molecular mechanisms underlying BSP. We found that the expression of several genes was significantly different in animals affected by BSP compared to control animals. Specific genes for inhibitory neurons were downregulated in the brainstems of the affected animals, namely CCK (cholecystokinin), NPY (neuropeptide Y), and SST (somatostatin). These inhibitory neurotransmitters influence cerebral movement control, among other processes. Furthermore, OOSP2 (oocyte secreted protein 2) was found to be significantly upregulated in the affected animals in all tissues. This expression could best be explained by the presence of T-follicular-helper cells which, through interleukin 21, can trigger a TH-2-dominated immune response and lead to autoimmune encephalitis. Further cases were sampled for confirmation and we detected cell infiltrates of activated microglia and T-cells in the brainstem using immunohistochemistry. Microglial foci were significantly more abundant in animals affected by BSP than control animals. We conclude that BSP is caused by an autoimmune reaction directed against inhibitory interneurons in the brainstem and is due to a combination of genetics and environmental influences. This may result in lost controlling influence on the upper motor neurons via extrapyramidal pathways and therefore triggers the specific symptoms of motor neuron disease.}, } @article {pmid40441139, year = {2025}, author = {Workman, MJ and Lim, RG and Wu, J and Frank, A and Ornelas, L and Panther, L and Galvez, E and Perez, D and Meepe, I and Lei, S and Valencia, V and Gomez, E and Liu, C and Moran, R and Pinedo, L and Tsitkov, S and Ho, R and Kaye, JA and , and Thompson, T and Rothstein, JD and Finkbeiner, S and Fraenkel, E and Sareen, D and Thompson, LM and Svendsen, CN}, title = {Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects.}, journal = {Neuron}, volume = {113}, number = {12}, pages = {2028}, doi = {10.1016/j.neuron.2025.05.022}, pmid = {40441139}, issn = {1097-4199}, support = {R35 NS132179/NS/NINDS NIH HHS/United States ; }, } @article {pmid40441157, year = {2025}, author = {Das, T and Zaidi, FK and Farag, M and Ruff, KM and Mahendran, TS and Singh, A and Gui, X and Messing, J and Taylor, JP and Banerjee, PR and Pappu, RV and Mittag, T}, title = {Tunable metastability of condensates reconciles their dual roles in amyloid fibril formation.}, journal = {Molecular cell}, volume = {85}, number = {11}, pages = {2230-2245.e7}, pmid = {40441157}, issn = {1097-4164}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; R01 NS121114/NS/NINDS NIH HHS/United States ; R35 GM138186/GM/NIGMS NIH HHS/United States ; R35 NS097974/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyloid/metabolism/genetics/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mutation ; *Stress Granules/metabolism/genetics ; *Heterogeneous Nuclear Ribonucleoprotein A1/genetics/metabolism/chemistry ; Protein Domains ; Protein Binding ; }, abstract = {Stress granules form via co-condensation of RNA-binding proteins (RBPs) containing prion-like low-complexity domains (PLCDs) with RNA molecules. Homotypic interactions among PLCDs can drive amyloid fibril formation that is enhanced by amyotrophic lateral sclerosis (ALS)-associated mutations. We report that condensation- versus fibril-driving homotypic interactions are separable for A1-LCD, the PLCD of hnRNPA1. These separable interactions lead to thermodynamically metastable condensates and globally stable fibrils. Interiors of condensates suppress fibril formation, whereas interfaces have the opposite effect. ALS-associated mutations enhance the stability of fibrils and weaken condensate metastability, thus enhancing the rate of fibril formation. We designed mutations to enhance A1-LCD condensate metastability and discovered that stress granule disassembly in cells can be restored even when the designed variants carry ALS-causing mutations. Therefore, fibril formation can be suppressed by condensate interiors that function as sinks. Condensate sink potentials are influenced by their metastability, which is tunable through separable interactions even among minority components of stress granules.}, } @article {pmid40441681, year = {2025}, author = {Sarasate, M and Córdoba-Izquierdo, A and Farrero, E and López-Lisbona, R and Díez-Ferrer, M and Trias-Sabrià, P and Plana, M and Povedano, M and Santos, S and Prats, E}, title = {Effect of Noninvasive Ventilation on the Upper Airway in Patients With Amyotrophic Lateral Sclerosis: The Role of Upper-Airway Endoscopy.}, journal = {Respiratory care}, volume = {70}, number = {9}, pages = {1075-1083}, doi = {10.1089/respcare.12791}, pmid = {40441681}, issn = {1943-3654}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/physiopathology ; *Noninvasive Ventilation/methods/adverse effects ; Male ; Prospective Studies ; Middle Aged ; Female ; Aged ; *Airway Obstruction/etiology/therapy/diagnosis ; *Endoscopy/methods ; }, abstract = {Background: Upper-airway obstruction (UAO) in amyotrophic lateral sclerosis (ALS) may reduce the efficacy of noninvasive ventilation (NIV). NIV can cause or worsen this obstruction, further worsening the disease prognosis. This study aims to describe UAO in ALS patients using upper-airway endoscopy (UA-End) during spontaneous breathing (SB) and NIV and to evaluate the usefulness of UA-End in adjusting NIV parameters to correct any observed obstruction. Methods: This prospective study (2017-2019) involved subjects with ALS and indications for NIV. After optimizing ventilation following standardized procedures, an awake UA-End was performed, first during SB and then during NIV. Endoscopic assessments included identification of the site of UAO using the VOTE classification, assessment of vocal cords, and adjustments of NIV settings to correct any identified obstructions. Afterward, a post hoc analysis was conducted comparing gasometrical and nocturnal oximetry variables between the groups with and without NIV obstruction at 3 and 6 months. Results: In total, 25 subjects were enrolled. UAO was observed in 9 cases (37%) during SB, whereas 12 cases (50%) showed obstruction during NIV, 7 newly appearing. Hypopharyngeal constriction and backward movement of the epiglottis were the most frequent findings. Adjustments in NIV settings during endoscopy improved UAO in all but one case. Survival rates were similar after UA-End adjustments for subjects on NIV, both with and without UAO. Conclusions: This study is, to the best of our knowledge, the first to show the usefulness of UA-End in assessing and correcting UAO in subjects with ALS at NIV initiation. Furthermore, correction of such events through UA-End may have a positive impact on ventilation control and survival.}, } @article {pmid40441800, year = {2025}, author = {Mehmood, N and Riaz, A and Ghuffar, S and Anwaar, S and Jabeen, N and Shaheen, I and Qasim, M and Khan, SS and Rauf, M and Anwar, T and Qureshi, H and Abusalim, GS and Zaman, W and Ansari, MJ and Iqbal, R}, title = {Epidemiology and genetic characterization of Alternaria alternata causing leaf spot in Fragaria × ananassa.}, journal = {Fungal biology}, volume = {129}, number = {4}, pages = {101589}, doi = {10.1016/j.funbio.2025.101589}, pmid = {40441800}, issn = {1878-6146}, mesh = {*Fragaria/microbiology ; *Alternaria/genetics/isolation & purification/classification/pathogenicity ; *Plant Diseases/microbiology ; Phylogeny ; Pakistan/epidemiology ; Incidence ; DNA, Fungal/genetics/chemistry ; Prevalence ; Sequence Analysis, DNA ; Plant Leaves/microbiology ; DNA, Ribosomal Spacer/genetics/chemistry ; }, abstract = {Alternaria leaf spot (ALS), caused by Alternaria alternata, is a major disease threatening strawberry (Fragaria × ananassa) production globally, including in Pakistan. This study investigated the incidence and prevalence of ALS in key strawberry-producing regions of Pakistan and characterized the pathogen using morphological and molecular techniques. Surveys were conducted during the 2014-2015 and 2015-2016 seasons across 182 farms in Punjab, Khyber Pakhtunkhwa, and Islamabad. Disease prevalence was 100% across all regions, with incidence rates ranging from 17.25% in cooler Islamabad to 55% in Mardan, KPK. Pathogenicity tests confirmed A. alternata as the causal agent. Morphological traits and sequencing of the ITS and endoPG genes further validated its identity. Phylogenetic analysis showed close genetic relatedness to known A. alternata isolates. This is the first comprehensive report of ALS in strawberries in Pakistan, confirming A. alternata as the primary pathogen. The widespread occurrence and high incidence highlight the urgent need for effective control measures. Integrated disease management, including resistant cultivars and targeted fungicide use, is strongly recommended. Further research should investigate environmental factors influencing disease spread and severity to support long-term sustainable management of ALS in strawberry cultivation.}, } @article {pmid40443183, year = {2025}, author = {Gonçalves, F and Teixeira, MI and Rego, F and Magalhães, B}, title = {The role of spiritual care management - Needs and resources in people with amyotrophic lateral sclerosis: Insights from a mixed-methods study.}, journal = {Palliative & supportive care}, volume = {23}, number = {}, pages = {e111}, pmid = {40443183}, issn = {1478-9523}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/therapy ; Male ; Female ; Middle Aged ; Aged ; Surveys and Questionnaires ; Qualitative Research ; Adult ; *Spirituality ; Psychometrics/methods/instrumentation ; *Spiritual Therapies/methods/standards ; }, abstract = {OBJECTIVES: To explore the spiritual needs and resources of People with Amyotrophic Lateral Sclerosis (PALS) at different stages of its trajectory and to characterize the experiences of the current state of the disease.

METHODS: A convergent mixed-methods study was conducted using qualitative and quantitative approaches. Participants were assessed using the clinical and sociodemographic data, ALSFRS-R (function assessment), and the GES Questionnaire to evaluate spiritual needs and resources. Data were collected through in-person or online interviews, transcribed and coded. The qualitative analysis was based on the content analysis method. Statistical analysis was performed using SPSS software. Both datasets were integrated during data analysis.

RESULTS: Twenty-four patients were interviewed, with a duration of the illness ranging from 1 year to 12 years. Participants were at different stages of functional dependence. Analyzing the open questions of the GES questionnaire, six categories were established related to the inner world of PALS: Concern, Nuisance, Help, Support, Safety, and Valorization. Contrary to what was hypothesized, no correlations were found between functionality and the spiritual dimensions. Spiritual needs and resources tend to vary with age, with younger ages presenting a more fragile spiritual dimension overall. Also, the intrapersonal and interpersonal dimension seems to play a central role in the lives of PALS. A negative correlation was identified between the feeling of connection to a supreme/transcendent reality and the level of educational qualifications.

SIGNIFICANCE OF RESULTS: Spirituality often provides crucial emotional support, meaning, and resilience during challenging times. Despite its importance, it is often overlooked in clinical settings. The study emphasizes the need for personalized, holistic care, which should include spiritual care support, regardless of the functional state, highlighting the importance of addressing both intrapersonal and interpersonal domains, resources and needs from early phases. Allowing to create a structured care plan that meets patients' individual spiritual needs, that can contribute to a better QoL and reduce suffering.}, } @article {pmid40443243, year = {2025}, author = {Adhya, A and Uppula, S and Raidas, S and Gupta, A and Singh, RK and Vibha, D and Garg, A and Tripathi, M}, title = {Midbrain Atrophy in Mills Syndrome: A Rare Finding Pointing to Diagnosis.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-2}, doi = {10.1017/cjn.2025.10135}, pmid = {40443243}, issn = {0317-1671}, } @article {pmid40446399, year = {2025}, author = {Holdom, CJ and Pilkar, R and Guo, CC and Eijk, RPAV and Sethi, N and Henderson, RD and Ngo, ST and Steyn, FJ}, title = {Identification of passive wrist-worn accelerometry outcomes for improved disease monitoring and trial design in motor neuron disease.}, journal = {EBioMedicine}, volume = {117}, number = {}, pages = {105779}, pmid = {40446399}, issn = {2352-3964}, mesh = {Humans ; *Accelerometry/methods/instrumentation ; Male ; Female ; Middle Aged ; Aged ; *Wrist ; *Motor Neuron Disease/diagnosis/physiopathology ; Longitudinal Studies ; Disease Progression ; Adult ; Clinical Trials as Topic ; }, abstract = {BACKGROUND: Motor neuron disease (MND) leads to progressive functional decline, making reliable measures of disease progression critical for patient care and clinical trials. Current clinical outcome measures lack the ability to continuously and objectively track functional decline in daily life of patients with MND. This study assessed and validated wrist-worn accelerometry outcome measures for continuous monitoring in MND, with the potential to refine clinical trial outcomes.

METHODS: This longitudinal study included 95 patients with MND who wore an ActiGraph GT9X Link device on their non-dominant wrist for 8 days, with follow-up every 3-4 months. Accelerometer data were processed using ActiLife and GGIR. Joint models were used to simultaneously investigate the longitudinal change in ALS Functional Rating Scale-Revised (ALSFRS-R) scores and accelerometer-derived outcomes alongside their relationship with overall survival. Sample size estimates for clinical trials were generated using both accelerometer- and ALSFRS-R-based outcomes, and principal component analysis (PCA) explored outcome relationships.

FINDINGS: Accelerometer outcomes showed a slower rate of decline (-0.03 to -0.07 SD/month) compared to ALSFRS-R (-0.10 SD/month) and had stronger correlations with ALSFRS-R motor subdomains (partial r: 0.60-0.73). PCA revealed that longitudinal measures of accelerometry were distinct from the ALSFRS-R, highlighting the complementary nature of these measures. Peak 6-min activity predicted smaller clinical trial sample sizes for studies over 12 months. Accelerometer-derived outcomes were not significantly associated with survival.

INTERPRETATION: Wrist-worn accelerometry offers a practical solution for continuous monitoring in MND, complementing ALSFRS-R. Measures of peak performance, and specifically peak 6-min activity shows promise, potentially reducing sample sizes and improving disease tracking over longer duration studies. Further refinement and validation are needed to adopt actigraphy measures as clinical assessment outcomes.

FUNDING: This study was supported by Wesley Medical Research (2016-32), the Honda Foundation, Motor Neurone Disease Research Australia, and FightMND. CJH received a Higher Degree Research Scholarship from UQ. STN received support from the Scott Sullivan Fellowship (MND and Me Foundation/RBWH Foundation), a FightMND Mid-Career Fellowship, and the AIBN.}, } @article {pmid40446958, year = {2025}, author = {Yuan, L and Yang, Y and Guo, Y and Deng, H}, title = {Genetic architecture of amyotrophic lateral sclerosis: a comprehensive review.}, journal = {Journal of genetics and genomics = Yi chuan xue bao}, volume = {52}, number = {10}, pages = {1155-1176}, doi = {10.1016/j.jgg.2025.05.008}, pmid = {40446958}, issn = {1673-8527}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; Animals ; *Genetic Predisposition to Disease ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS), one of the most prevalent neurodegenerative disorders, is pathologically characterized by the progressive degeneration of both upper and lower motor neurons, leading to muscle weakness, paralysis, and death within 2-4 years post-diagnosis. ALS is categorized into familial ALS (FALS) and sporadic ALS, with FALS accounting for approximately 10% of ALS cases. As a genetically heterogeneous disease, ALS exhibits diverse inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked transmission, and genetic factors play pivotal roles in disease pathogenesis. To date, at least 34 disease-causing loci and 32 genes for ALS have been identified. The investigations of mutant protein products and the establishment of animal models have unraveled potential pathogenic pathways, offering insights into the mechanisms of neurodegeneration in ALS. This review focuses on ALS clinical characteristics, neuropathological features, causative loci/genes, genetic susceptibility factors, animal models, and pathogenic mechanisms, with particular attention to recent advances in genetic findings and pathogenic pathways of ALS. Elucidation of the genetic basis of ALS could provide the scientific foundation for personalized treatments to address this recalcitrant disease.}, } @article {pmid40449058, year = {2025}, author = {Zhang, Q and Ding, Y and Zhang, Y and Li, Q and Shi, S and Liu, Y and Chen, S and Wu, Q and Xu, X and Wu, F and Cheng, X and Niu, Q}, title = {Early cortical alterations and neuropsychological mechanisms in amyotrophic lateral sclerosis.}, journal = {NeuroImage. Clinical}, volume = {47}, number = {}, pages = {103809}, pmid = {40449058}, issn = {2213-1582}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/psychology/pathology/complications ; Male ; Female ; Middle Aged ; Magnetic Resonance Imaging/methods ; Aged ; *Cerebral Cortex/diagnostic imaging/physiopathology/pathology ; Neuropsychological Tests ; Adult ; Support Vector Machine ; Neurofilament Proteins/blood ; }, abstract = {OBJECTIVE: This study investigates the characteristics of cortical structural and functional alterations in amyotrophic lateral sclerosis (ALS) patients and their modulation of emotional and cognitive functions, as well as to discuss their diagnostic value in early-stage ALS.

METHODS: Fifty-nine ALS patients (28 in ALS 1 and 31 in ALS 2, categorized using King's College Staging) and 31 healthy controls were evaluated using multiparametric MRI, motor and neuropsychological assessments, and serum neurofilament light chain (NfL) levels. Mediation analyses were performed to examine how cortical alterations influence the relationship between emotional and cognitive functions. Support vector machine (SVM) classification models were constructed to assess the diagnostic utility of differential cortical parameters.

RESULTS: ALS 1 patients exhibited increased cortical thickness (CT) and functional activity in the cingulate and frontotemporal regions, correlating with neuropsychological performance and NfL levels. Mediation analysis revealed that perigenual and frontotemporal functional activity significantly modulated the relationship between depressive symptoms and cognitive function. SVM classification showed that the combined altered regions with Amplitude of Low Frequency Fluctuations (ALFF) model achieved slightly better performance (AUC = 0.853, 95 %CI: 0.687-1.000, p < 0.001) compared to CT (AUC = 0.779, 95 %CI: 0.587-0.972, p < 0.001), although both models showed limited efficacy in differentiating between ALS 1 and ALS 2 groups.

CONCLUSIONS: Cortical structural and functional alterations in ALS mediate the impact of depression on cognitive function, offering insights into the neuropsychological mechanisms of the disease and potential biomarkers for early-stage diagnosis.}, } @article {pmid40449630, year = {2025}, author = {Vu Trung, K and Abou-Ali, E and Gulla, A and Soares, K and Caillol, F and Paik, WH and Napoleon, B and Halimi, A and Masaryk, V and Bruno, MJ and Pérez-Cuadrado-Robles, E and Bolm, L and Seyfried, S and Petrone, MC and Yilmaz, B and Vollmer, C and Berger, A and Maggino, L and Schemmer, P and Wichmann, D and Karam, E and Dugic, A and Kunovsky, L and Regner, S and Gaujoux, S and Hollenbach, M and , }, title = {Development and validation of the SDLD score: a simplified tool to predict successful endoscopic papillectomy in ampullary lesions.}, journal = {Gastrointestinal endoscopy}, volume = {102}, number = {4}, pages = {602-606}, doi = {10.1016/j.gie.2025.03.1333}, pmid = {40449630}, issn = {1097-6779}, mesh = {Humans ; *Ampulla of Vater/surgery/pathology ; Female ; Male ; Aged ; *Common Bile Duct Neoplasms/surgery/pathology ; Middle Aged ; *Sphincterotomy, Endoscopic ; ROC Curve ; Pancreatic Ducts/pathology ; Logistic Models ; Aged, 80 and over ; *Adenoma/surgery/pathology ; Retrospective Studies ; Cholangiopancreatography, Endoscopic Retrograde ; }, abstract = {BACKGROUND AND AIMS: Endoscopic papillectomy (EP) is the standard treatment for noninvasive ampullary lesions (ALs), whereas advanced cases require surgery. Managing ALs is challenging and may lead to over- or undertreatment. We developed a score to identify the best candidates for endoscopic or surgical treatment.

METHODS: We analyzed 447 patients who underwent EP. The cohort was randomly split into a training set (n = 325) and validation set (n = 122). Logistic regression identified predictors for incomplete resection (R1), which were incorporated into a 4-item score. Performance was assessed using the area under the receiver-operating characteristic curve (AUROC).

RESULTS: Independent predictors for R1 included size ≥30 mm (S), high-grade dysplasia and/or invasive cancer (D), laterally spreading-lesion (L), and bile or pancreatic duct dilation (D), which we named the SDLD score. ALs with 0 to 1 points had the highest complete resection rates (training, 86.0%; validation, 88.5%), whereas ≥2 points significantly increased R1 rates (training, 52.0%; validation, 57.7%; P < .001). The AUROC was 0.792 (training) and 0.708 (validation).

CONCLUSIONS: The SDLD score predicts R1 in EP and aids in treatment decisions.}, } @article {pmid40450581, year = {2025}, author = {Tokuda, E and Leykam, L and Zetterström, P and Brännström, T and Andersen, PM and Marklund, SL}, title = {Diverse effects of coexpression of human SOD1 variants on motor neuron disease.}, journal = {Human molecular genetics}, volume = {34}, number = {16}, pages = {1380-1391}, pmid = {40450581}, issn = {1460-2083}, support = {56103-7002829//Västerbotten County Council/ ; 223-2808-12//Torsten and Ragnar Söderberg Foundation, Umeå University Insamlingsstiftelsen/ ; 223-1881-13//Torsten and Ragnar Söderberg Foundation, Umeå University Insamlingsstiftelsen/ ; 2.1.12-1605-14//Torsten and Ragnar Söderberg Foundation, Umeå University Insamlingsstiftelsen/ ; 2012.0091//Knut and Alice Wallenberg Foundation/ ; 2014.0305//Knut and Alice Wallenberg Foundation/ ; 2020.0232//Knut and Alice Wallenberg Foundation/ ; 2012-3167//Swedish Research Council/ ; 2017-03100//Swedish Research Council/ ; 2012-0262//Swedish Brain Foundation/ ; 2012-0305//Swedish Brain Foundation/ ; 2013-0279//Swedish Brain Foundation/ ; 2016-0303//Swedish Brain Foundation/ ; 2018-0310//Swedish Brain Foundation/ ; 2020-0353//Swedish Brain Foundation/ ; 2022-0309//Swedish Brain Foundation/ ; }, mesh = {Animals ; *Superoxide Dismutase-1/genetics/metabolism ; Humans ; Mice, Transgenic ; Mice ; Disease Models, Animal ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Mutation ; *Motor Neuron Disease/genetics ; Motor Neurons/metabolism/pathology ; *Superoxide Dismutase/genetics/metabolism ; }, abstract = {Mutations in superoxide dismutase-1 (SOD1) are a common cause of amyotrophic lateral sclerosis (ALS). Inheritance is as a rule dominant, but in carriers of the most common mutation, D90A, disease can develop in both homozygous and, more rarely, in heterozygous individuals with unexplained differences in clinical presentation. There is mounting evidence that prion-like spread of SOD1 aggregation is the primary cause of the disease. Two different strains of aggregates have been found to arise in human SOD1 (hSOD1) transgenic mouse models of ALS. Strain A is formed by most mutants including hSOD1G85R and hSOD1WT, whereas hSOD1D90A transgenic mice form a distinct strain B in addition to A. To explore the effects of aggregate strain propensities when hSOD1 variants are coexpressed, we generated digenic hSOD1G85R/WT and hSOD1G85R/D90A mice. Coexpression of hSOD1WT considerably shortened the lifespan of hSOD1G85R mice to the extent expected from the neurotoxicities of the variants alone. In contrast, coexpression of hSOD1D90A had a minimal effect on survival, far smaller than expected. Moreover, time from onset to the end stage was markedly prolonged in the hSOD1G85R/D90A mice. Aggregation of hSOD1 developed concomitantly with motor neuron disease, and the aggregates contained large amounts of both coexpressed variants in both digenic models. Our findings suggest that hSOD1WT has high a capacity to coaggregate with mutants and enhance neurotoxicity. Such interactions may be restricted by differences in strain propensities, which may contribute to the primarily recessive inheritance associated with the hSOD1D90A mutation.}, } @article {pmid40450587, year = {2025}, author = {Mehta, P and Raymond, J and Nair, T and Han, M and Punjani, R and Larson, T and Berry, J and Mohidul, S and Xue, S and Horton, DK}, title = {Incidence of ALS in all 50 states in the United States, data from the National ALS Registry, 2012-2019.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {758-766}, doi = {10.1080/21678421.2025.2506448}, pmid = {40450587}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; United States/epidemiology ; *Registries ; Incidence ; Male ; Aged ; Female ; Middle Aged ; Aged, 80 and over ; Adult ; Risk Factors ; }, abstract = {OBJECTIVE: To summarize amyotrophic lateral sclerosis (ALS) incidence in all 50 states and the District of Columbia from 2012 to 2019. In 2010, the Agency for Toxic Substances and Disease Registry (ATSDR) launched the congressionally mandated National ALS Registry (Registry) to determine the incidence and prevalence of ALS within the United States, characterize demographics, and identify potential risk factors. This is the first analysis of state-level ALS incidence estimates for all 50 states and the District of Columbia.

METHODS: ALS is not a notifiable disease in the United States. As such, the Registry identifies cases using existing national administrative databases (Medicare, Veterans Health Administration, and Veterans Benefits Administration), and a secure web portal that identifies cases not included in the national databases. Confirmed and likely cases are deduplicated and counted as incident cases for the first year they are identified using a validated algorithm. Incident counts, incident rates, and rate ratios were then calculated.

RESULTS: State-level age-adjusted overall incidence rates for 2012 to 2019 ranged from 0.65 per 100,000 persons (Alaska) to 2.25 per 100,000 persons (Vermont), with an overall incidence of 1.44 per 100,000 persons in the United States. New England and the upper Midwest regions had higher incidence rates than national rates.

CONCLUSIONS: These findings summarize the incidence of ALS for all 50 states from 2012 to 2019. This is a continuing effort to identify ALS cases nationally. The establishment of the Registry allows for epidemiological analyses of ALS data and the assessment of potential risk factors.}, } @article {pmid40451302, year = {2025}, author = {Thang, CJ and Garate, D and Sánchez-Feliciano, A and Barbieri, JS}, title = {Response to Cho et al's "GLP-1 receptor agonist use is associated with increased rates of acne vulgaris diagnosis in non-diabetic obese women but not men: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {3}, pages = {e121-e122}, doi = {10.1016/j.jaad.2025.03.102}, pmid = {40451302}, issn = {1097-6787}, } @article {pmid40451305, year = {2025}, author = {Cho, SW and Sontam, T and Chen, A and Limmer, EE and Tolkachjov, SN}, title = {Response to Thang et al's "Response to Cho et al's 'GLP-1 receptor agonist use is associated with increased rates of acne vulgaris diagnosis in non-diabetic obese women but not men: A retrospective cohort study'".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {3}, pages = {e123-e124}, doi = {10.1016/j.jaad.2025.04.085}, pmid = {40451305}, issn = {1097-6787}, } @article {pmid40452867, year = {2025}, author = {Labarre, A and Guitard, E and Tossing, G and Parker, JA}, title = {Suppression of har-1/CHCHD10 phenotypes for ALS-FTD therapy discovery.}, journal = {microPublication biology}, volume = {2025}, number = {}, pages = {}, pmid = {40452867}, issn = {2578-9430}, abstract = {Mutations in CHCHD10 are linked to a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). The Caenorhabditis elegans orthologue of CHCHD10 is har-1 , and we investigated whether har-1 mutants could be used for therapeutic discovery in ALS-FTD. Our results show that the small molecule pioglitazone and the probiotic Lacticaseibacillus rhamnosus HA-114 can alleviate har-1 mutant phenotypes. These findings suggest that har-1 mutants are suitable for modifier screens and could be adapted for high-throughput drug screening and microbiome studies to aid in discovering therapies for ALS-FTD.}, } @article {pmid40452868, year = {2025}, author = {Labarre, A and Guitard, E and Tossing, G and Parker, JA}, title = {har-1/CHCHD10 mutations induce neurodegeneration and mitochondrial fragmentation in Caenorhabditis elegans.}, journal = {microPublication biology}, volume = {2025}, number = {}, pages = {}, pmid = {40452868}, issn = {2578-9430}, abstract = {CHCHD10 encodes a mitochondrial protein that plays a role in cristae morphology and oxidative phosphorylation, with mutations associated with neurodegenerative diseases, including the spectrum of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). The Caenorhabditis elegans ortholog of CHCHD10 is har-1 , which can be used to model CHCHD10-related neurodegenerative diseases. We focused on two har-1 mutant strains: one featuring a 260 bp deletion (gk3124) and the other with a G73E point mutation (ad2155). Both har-1 mutants displayed progressive paralysis, degeneration of GABAergic motor neurons, and mitochondrial fragmentation. These strains may be valuable tools for investigating pathogenic mechanisms and therapeutic strategies for neurodegenerative diseases.}, } @article {pmid40453369, year = {2025}, author = {Slagt, C and Van Kuijk, SMJ and Bruhn, J and Van Geffen, GJ and Mommers, L}, title = {First Results of Our Local Practice Guide Used During the Late Phase of Resuscitation in Patients with Refractory VF in Out of Hospital Cardiac Arrest.}, journal = {Open access emergency medicine : OAEM}, volume = {17}, number = {}, pages = {203-213}, pmid = {40453369}, issn = {1179-1500}, abstract = {OBJECTIVE: Treatment of refractory ventricular fibrillation (rVF) is a clinical challenge. If rVF is still present after standard advanced life support (ALS) guideline care, including amiodaron administration, other therapeutic options might be necessary. Based on the available evidence and expertise, our Helicopter Emergency Medical Service (HEMS) team developed a local practice guide for the prolonged resuscitation of patients in rVF and implemented this as standard HEMS care in March 2022.

METHODS: This database study contains all patients treated with our local practice guide during out of hospital cardiac arrest (OHCA) with rVF beyond the fifth regular ALS shock-block. This local practice HEMS treatment algorithm consisted of, among others, cessation of epinephrine and alternating administration of esmolol and norepinephrine combined with enoximone. Data were derived from the HEMS database and the treating hospitals. Primary outcome was the return of spontaneous circulation. Secondary outcome was defined as survival to hospital discharge and cerebral performance. This outcome was compared to the literature to analyze for inferiority of treatment.

RESULTS: In a 21-month period, HEMS was 761 times deployed for OHCA. Nineteen patients were treated with the local practice guide, nine patients (47%) were admitted to hospital with return of spontaneous circulation. Median resuscitation time was 22min. Hospital survival with good neurology was achieved in 42% vs 17% as expected. Exact Clopper-Pearson and logistic regression analysis revealed non-inferiority of the local practice guide. Withholding epinephrine was achieved in 84% of patients. A total of 79% and 90% of patients received esmolol and norepinephrine/enoximone mixture, respectively. Alternative defibrillation positions were indicated in 18 patients but applied in only 6 (33%).

CONCLUSION: In patients with persisting VF despite prolonged advanced life support care, a multifaceted bundle of care approach shows promising results and warrants further research. Alternative drug administrations were found to be substantially easier to achieve compared to alternative defibrillation positions.}, } @article {pmid40453434, year = {2025}, author = {Voosala, S and Sandhya, M and Mathuranath, PS and Mahale, RR}, title = {Autoimmune Encephalitis Pattern on PET-MRI in a Patient with Amyotrophic Lateral Sclerosis.}, journal = {Indian journal of nuclear medicine : IJNM : the official journal of the Society of Nuclear Medicine, India}, volume = {40}, number = {1}, pages = {22-25}, pmid = {40453434}, issn = {0972-3919}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive primary motor neuron disorder whose etiology is a subject of debate even today. Interplay between multiple genetic and environmental factors and co-existent/antecedent infection, inflammation, and malignancy have all been hypothesized as potentially causative for this disease. Owing to its hybrid diagnostic capability, fluorodeoxyglucose positron emission tomography-magnetic resonance imaging is highly valuable in detecting varied autoimmune encephalitis patterns, one of which we report in a patient with ALS providing insight into autoimmunity as a potential etiology in the pathogenesis of this disease.}, } @article {pmid40454469, year = {2025}, author = {Arnold, FJ and Cui, Y and Michels, S and Colwin, MR and Stockford, CM and Ye, W and Maheswari Jawahar, V and Jansen-West, K and Philippe, J and Gulia, R and Gou, Y and Tam, OH and Menon, S and Situ, WG and Cazarez, SL and Zandi, A and Ehsani, KC and Howard, S and Dickson, DW and Gale Hammell, M and Prudencio, M and Petrucelli, L and Li, W and La Spada, AR}, title = {TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {The Journal of clinical investigation}, volume = {135}, number = {11}, pages = {}, pmid = {40454469}, issn = {1558-8238}, support = {R56 NS118570/NS/NINDS NIH HHS/United States ; R35 NS122140/NS/NINDS NIH HHS/United States ; RF1 NS118570/NS/NINDS NIH HHS/United States ; R01 NS118570/NS/NINDS NIH HHS/United States ; T32 AG000096/AG/NIA NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; RF1 NS120992/NS/NINDS NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; R01 CA193466/CA/NCI NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Polyadenylation ; tau Proteins/metabolism/genetics ; }, abstract = {Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) are observed in many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 dysregulation of splicing has emerged as a key event in these diseases, TDP-43 can also regulate polyadenylation; yet this has not been adequately studied. Here, we applied the dynamic analysis of polyadenylation from an RNA-Seq (DaPars) tool to ALS/FTD transcriptome datasets and report extensive alternative polyadenylation (APA) upon TDP-43 alteration in ALS/FTD cell models and postmortem ALS/FTD neuronal nuclei. Importantly, many identified APA genes highlight pathways implicated in ALS/FTD pathogenesis. To determine the functional relevance of APA elicited by TDP-43 nuclear depletion, we examined microtubule affinity regulating kinase 3 (MARK3). Nuclear loss of TDP-43 yielded increased expression of MARK3 transcripts with longer 3' UTRs, corresponding with a change in the subcellular distribution of MARK3 and increased neuronal tau S262 phosphorylation. Our findings define changes in polyadenylation site selection as a previously understudied feature of TDP-43-driven disease pathology in ALS/FTD and highlight a potentially important mechanistic link between TDP-43 dysfunction and tau regulation.}, } @article {pmid40454605, year = {2025}, author = {Zheng, X and Zhang, K and Zhao, X and Zhou, J and Shen, H and Kong, J and Guo, Y}, title = {Achieving High-Yield Conversion of Janus Transition Metal Dichalcogenides on Diverse Substrates.}, journal = {ACS nano}, volume = {19}, number = {22}, pages = {20744-20752}, doi = {10.1021/acsnano.5c02687}, pmid = {40454605}, issn = {1936-086X}, abstract = {Janus transition metal dichalcogenides (TMDCs) with intrinsic broken mirror symmetry and vertical dipole moment provide an additional degree of freedom to manipulate material symmetry down to atomic-layer thickness. However, despite advances in synthesis strategies, fundamental understanding of this atomic substitution process remains limited, which has impeded their implementation in advanced devices. Here, by using a room-temperature atomic-layer substitution (RT-ALS) strategy, we systematically investigate the critical factors facilitating the high-yield conversion of Janus TMDCs on diverse substrates. Combining Raman spectroscopy probes, X-ray photoelectron spectroscopy (XPS) measurements, and density functional theory (DFT) calculations, we demonstrate that substrates with enhanced electron doping or larger surface polarity substantially benefit the conversion of Janus TMDCs reaching a near-unity yield. Intriguingly, the strong affinity between Janus TMDCs and substrates (e.g., Au) brings about abnormal Raman spectroscopic phenomena. These findings highlight the significance of substrates in achieving the reliable synthesis of Janus two-dimensional materials with improved homogeneity on various substrates. In addition, this takes us one step closer to utilizing Janus TMDCs as a versatile platform in next-generation optoelectronic devices, sensors, and quantum technologies.}, } @article {pmid40454774, year = {2025}, author = {Madrer, N and Perera, ND and Uccelli, NA and Abbondanza, A and Andersen, JV and Carsana, EV and Demmings, MD and Fernandez, RF and de Fragas, MG and Gbadamosi, I and Kulshrestha, D and Lima-Filho, RAS and Marian, OC and Markussen, KH and McGovern, AJ and Neal, ES and Sarkar, S and Šimončičová, E and Soto-Verdugo, J and Yandiev, S and Fernández-Moncada, I}, title = {Neural Metabolic Networks: Key Elements of Healthy Brain Function.}, journal = {Journal of neurochemistry}, volume = {169}, number = {6}, pages = {e70084}, pmid = {40454774}, issn = {1471-4159}, mesh = {Humans ; *Brain/metabolism ; Animals ; *Nerve Net/metabolism ; *Energy Metabolism/physiology ; *Metabolic Networks and Pathways/physiology ; *Neurons/metabolism ; }, abstract = {Neural networks are responsible for processing sensory stimuli and driving the synaptic activity required for brain function and behavior. This computational capacity is expensive and requires a steady supply of energy and building blocks to operate. Importantly, the neural networks are composed of different cell populations, whose metabolic profiles differ between each other, thus endowing them with different metabolic capacities, such as, for example, the ability to synthesize specific metabolic precursors or variable proficiency to manage their metabolic waste. These marked differences likely prompted the emergence of diverse intercellular metabolic interactions, in which the shuttling and cycling of specific metabolites between brain cells allows the separation of workload and efficient control of energy demand and supply within the central nervous system. Nevertheless, our knowledge about brain bioenergetics and the specific metabolic adaptations of neural cells still warrants further studies. In this review, originated from the Fourth International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Schmerlenbach, Germany (2022), we describe and discuss the specific metabolic profiles of brain cells, the intercellular metabolic exchanges between these cells, and how these bioenergetic activities shape synaptic function and behavior. Furthermore, we discuss the potential role of faulty brain metabolic activity in the etiology and progression of Alzheimer's disease, Parkinson disease, and Amyotrophic lateral sclerosis. We foresee that a deeper understanding of neural networks metabolism will provide crucial insights into how higher-order brain functions emerge and reveal the roots of neuropathological conditions whose hallmarks include impaired brain metabolic function.}, } @article {pmid40454831, year = {2025}, author = {Santos Silva, C and Pavey, N and Calma, AD and Kiernan, MC and Menon, P and van den Bos, M and Vucic, S}, title = {Utility of Cortical Inhibitory and Facilitatory Neuronal Circuits in Amyotrophic Lateral Sclerosis Diagnosis.}, journal = {European journal of neurology}, volume = {32}, number = {6}, pages = {e70203}, pmid = {40454831}, issn = {1468-1331}, support = {//Motor Neurone Disease Research Institute of Australia/ ; 1024915//National Health and Medical Research Council of Australia/ ; 1055778//National Health and Medical Research Council of Australia/ ; 233//National Health and Medical Research Council of Australia/ ; 510//National Health and Medical Research Council of Australia/ ; GIA 1726//National Health and Medical Research Council of Australia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Transcranial Magnetic Stimulation/methods ; Cross-Sectional Studies ; Aged ; *Neural Inhibition/physiology ; *Evoked Potentials, Motor/physiology ; Adult ; *Motor Cortex/physiopathology ; }, abstract = {BACKGROUND: Cortical hyperexcitability is an early feature of amyotrophic lateral sclerosis (ALS), linked to dysfunction in inhibitory and facilitatory cortical circuits, measurable using paired-pulse transcranial magnetic stimulation (TMS). Short-interval intracortical inhibition (SICI) is a robust biomarker of inhibitory function and an ALS diagnostic marker. Short interval intracortical facilitation (SICF) serves as a biomarker of facilitatory function, while the index of excitation assesses the contribution of these circuits to hyperexcitability. This study aimed to evaluate the diagnostic effectiveness of SICF and the index of excitation in distinguishing ALS from non-ALS mimic disorders.

METHODS: This cross-sectional study assessed cortical excitability in participants with suspected ALS from two Sydney centres, classified using the Gold Coast criteria. Threshold tracking TMS measured SICI, SICF, and the index of excitation. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis, with sensitivity, specificity, and optimal cut-off values determined.

RESULTS: Of 154 participants, 95 were diagnosed with ALS and 48 with non-ALS mimics. SICI demonstrated a marginally higher diagnostic accuracy (AUC 0.84, 95% CI:0.77-0.89) compared to SICF (AUC 0.77, 95% CI:0.68-0.84, p = 0.028). The index of excitation showed comparable accuracy to SICI (AUC 0.82, 95% CI: 0.75-0.88, p = 0.328). The optimal SICF cut-off (≤ -13.6%) provided 70.5% sensitivity and 70.8% specificity, while the index of excitation cut-off (≥ 64.5%) yielded 71.6% sensitivity and 70.8% specificity.

CONCLUSIONS: The present study established modest diagnostic potential of increased SICF and index of excitation in differential ALS from mimic disorders, thereby enhancing understanding of the role of inhibitory and facilitatory cortical circuits in ALS diagnosis.}, } @article {pmid40456907, year = {2025}, author = {Rhine, K and Li, R and Kopalle, HM and Rothamel, K and Ge, X and Epstein, E and Mizrahi, O and Madrigal, AA and Her, HL and Gomberg, TA and Hermann, A and Schwartz, JL and Daniels, AJ and Manor, U and Ravits, J and Signer, RAJ and Bennett, EJ and Yeo, GW}, title = {Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress.}, journal = {Nature neuroscience}, volume = {28}, number = {6}, pages = {1174-1184}, pmid = {40456907}, issn = {1546-1726}, support = {R35 GM148339/GM/NIGMS NIH HHS/United States ; DGE-2038238//National Science Foundation (NSF)/ ; P30-CA014195//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; R01 NS069566/NS/NINDS NIH HHS/United States ; R01-HG004659//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; T32 GM145427/GM/NIGMS NIH HHS/United States ; U01 CA267031/CA/NCI NIH HHS/United States ; P30-AG068635//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; 23-PDF-639//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; P30 AG068635/AG/NIA NIH HHS/United States ; R01 HG004659/HG/NHGRI NIH HHS/United States ; U01-CA267031//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; R35-GM148339//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; T32 CA067754/CA/NCI NIH HHS/United States ; R01 NS103172/NS/NINDS NIH HHS/United States ; R01-NS103172//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P30 CA014195/CA/NCI NIH HHS/United States ; IL-2023-C2-L4//Target ALS (Target ALS Foundation)/ ; T32-CA067754//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, mesh = {Humans ; Animals ; *Neurons/metabolism/pathology ; Mice ; *Aging/metabolism/pathology ; *RNA-Binding Proteins/metabolism ; *Stress, Physiological/physiology ; *Cellular Senescence/physiology ; Cells, Cultured ; DNA-Binding Proteins/metabolism ; Aged ; Fibroblasts/metabolism ; Mice, Inbred C57BL ; }, abstract = {Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging hallmarks, and we verified key findings in aged human and mouse brain tissue. Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins-like the dementia- and ALS-associated protein TDP-43-mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components are typically recruited to stress granules, but aged neurons suffer from chronic cellular stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity and the failure to respond to new stress events. Together, our data demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.}, } @article {pmid40456951, year = {2025}, author = {Douglas, AGL}, title = {Penetrance and pleiotropy in ATXN2-related amyotrophic lateral sclerosis.}, journal = {European journal of human genetics : EJHG}, volume = {33}, number = {9}, pages = {1093-1095}, pmid = {40456951}, issn = {1476-5438}, support = {HMR04192 HM40.01//DH | National Institute for Health Research (NIHR)/ ; }, } @article {pmid40457327, year = {2025}, author = {Gilchrist, L and Mutz, J and Hysi, P and Legido-Quigley, C and Kõks, S and Lewis, CM and Proitsi, P}, title = {Evaluating metabolome-wide causal effects on risk for psychiatric and neurodegenerative disorders.}, journal = {BMC medicine}, volume = {23}, number = {1}, pages = {326}, pmid = {40457327}, issn = {1741-7015}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Mendelian Randomization Analysis ; *Metabolome ; *Mental Disorders/genetics/metabolism ; Bayes Theorem ; Risk Factors ; }, abstract = {BACKGROUND: Evidence indicates phenotypic and biological overlap between psychiatric and neurodegenerative disorders. Further identification of underlying mutual and unique biological mechanisms may yield novel multi-disorder and disorder-specific therapeutic targets. The metabolome represents an important domain for target identification as metabolites play critical roles in modulating a diverse range of biological processes.

METHODS: We used Mendelian randomisation (MR) to test the causal effects of ~ 1000 plasma metabolites and ~ 300 metabolite ratios on anxiety, bipolar disorder, depression, schizophrenia, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and multiple sclerosis. Follow-up analyses were conducted using statistical colocalisation, multivariable Bayesian model averaging MR (MR-BMA) and polygenic risk score analysis in the UK Biobank.

RESULTS: MR analyses identified 85 causal effects involving 77 unique metabolites passing FDR correction and robust sensitivity analyses (IVW-MR OR range 0.73-1.48; pFDR < 0.05). No evidence of reverse causality was identified. Multivariable MR-BMA analyses implicated sphingolipid metabolism in psychiatric disorder risk and carnitine derivatives in risk for amyotrophic lateral sclerosis and multiple sclerosis. Although polygenic risk scores for prioritised metabolites showed limited prediction in the UK Biobank, those nominally significant were directionally consistent with MR estimates. Downstream colocalisation in regions containing influential variants identified greater than suggestive evidence (PP.H4 ≥ 0.6) for a shared causal variant for 29 metabolite/psychiatric disorder trait-pairs on chromosome 11 at the FADS gene cluster. Most of these metabolites were lipids containing linoleic or arachidonic acid. Additional colocalisation was identified between the ratio of histidine-to-glutamine, glutamine, Alzheimer's disease and SPRYD4 gene expression on chromosome 12.

CONCLUSIONS: Although no single metabolite had a causal effect on both a psychiatric and a neurodegenerative disease, results suggest a broad effect of lipids across brain disorders, with a particular role for lipids containing linoleic or arachidonic acid in psychiatric disorders. The metabolites identified here may help inform future targeted interventions.}, } @article {pmid40457619, year = {2025}, author = {Alaydin, HC and Kocak, OK and Arslan, I and Kılınc, H and Boran, HE and Tankisi, H and Cengiz, B}, title = {Assessing MScanFit MUNE in Amyotrophic Lateral Sclerosis: Influence of Nerve Conduction Distance and Temporal Dispersion.}, journal = {Muscle & nerve}, volume = {72}, number = {3}, pages = {408-415}, doi = {10.1002/mus.28446}, pmid = {40457619}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Neural Conduction/physiology ; *Action Potentials/physiology ; Aged ; Electromyography/methods ; Adult ; Ulnar Nerve/physiopathology ; *Muscle, Skeletal/physiopathology ; Electric Stimulation ; *Motor Neurons/physiology ; }, abstract = {INTRODUCTION/AIMS: MScanFit is a promising method for motor unit number estimation (MUNE) based on compound muscle action potential (CMAP) scanning. Considering that CMAP morphology may be altered by temporal dispersion associated with nerve conduction distance, it is important to evaluate the potential impact of these changes on MScanFit measurements. Therefore, we aimed to investigate the effect of nerve conduction distance on MScanFit MUNE in patients with amyotrophic lateral sclerosis (ALS).

METHODS: MScanFit MUNE was recorded from the abductor digiti minimi (ADM) muscle by stimulating the ulnar nerve at the wrist and elbow in twenty-three ALS patients. Consistency of MScanFit MUNE and size parameters, CMAP amplitude, and CMAP duration were evaluated using intraclass correlation coefficients (ICC).

RESULTS: Significant differences were noted in CMAP amplitudes (6.35 ± 2.5 mV vs. 5.7 ± 2.4 mV; p = 0.003) and CMAP durations (5.8 ± 0.7 ms vs. 6.2 ± 0.8 ms; p < 0.001), reflecting temporal dispersion effects. MUNE values showed high consistency between wrist and elbow stimulations (61 ± 32.4 vs. 61.1 ± 30.7; p = 0.99), with an ICC of 0.86. Similar repeatability was also observed for MScanFit size parameters.

DISCUSSION: The reliability of MScanFit MUNE in determining motor unit values in ALS patients remains consistent regardless of the stimulation distance. Our findings highlight the effectiveness of MScanFit MUNE in evaluating motor unit loss of ALS patients and demonstrate its resilience to temporal dispersion effects. Proximal stimulation serves as a viable alternative, enhancing the utility of MScanFit in clinical settings.}, } @article {pmid40457777, year = {2025}, author = {Martin, EM and Cichon, C and Choudhury, R and Day, SR and Fatemi, Y and Luther, VP and Stillwell, T and Sung, A}, title = {Society for Healthcare Epidemiology of America (SHEA) infectious diseases fellow infection prevention and control and healthcare epidemiology curriculum.}, journal = {Infection control and hospital epidemiology}, volume = {46}, number = {8}, pages = {773-782}, pmid = {40457777}, issn = {1559-6834}, mesh = {Humans ; *Curriculum ; *Infection Control ; *Epidemiology/education ; Fellowships and Scholarships ; United States ; Cross Infection/prevention & control ; }, abstract = {With the rapid expansion of the Infection Prevention Control/Healthcare Epidemiology (IPC/HE) fields over recent decades, the pivotal roles of IPC/HE in hospital regulation, quality improvement, patient safety, and healthcare finances have become increasingly apparent. Consequently, the demand for effective IPC/HE leaders has surged.[1,2] Training in IPC/HE is essential for all infectious diseases (ID) fellows (both adult and pediatric), including those planning a career in hospital epidemiology as well as those planning to focus on general ID, transplant, HIV, etc. ID fellows, however, have historically felt ill-prepared in IPC/HE. Joiner et al's survey highlighted this gap, revealing that only half of respondents felt adequately trained in infection control, despite half of them participating in infection control in their practice.[3] IPC/HE fellow education is not currently standardized, and most IPC/HE training is led by individual mentors and healthcare facilities.}, } @article {pmid40458045, year = {2025}, author = {Weng, R and Li, X and Yue, H and Xu, Y and Wei, Z and Xu, S and Li, B and Zhang, Z}, title = {A Missense Mutation in Close Proximity of ALS-linked PFN1 Mutations Causes Only Early-onset Paget Disease of Bone.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {111}, number = {1}, pages = {93-106}, pmid = {40458045}, issn = {1945-7197}, support = {2018YFA0800801//National Key Research and Development Program of China/ ; 82100941//National Natural Science Foundation of China/ ; 82300985//National Natural Science Foundation of China/ ; 81974126//National Natural Science Foundation of China/ ; 82200988//National Natural Science Foundation of China/ ; 2023M732309//China Postdoctoral Science Foundation/ ; }, mesh = {*Osteitis Deformans/genetics/drug therapy/pathology ; *Profilins/genetics ; Humans ; *Mutation, Missense ; Animals ; Mice ; Male ; Female ; *Amyotrophic Lateral Sclerosis/genetics ; Pedigree ; Middle Aged ; Denosumab/therapeutic use ; Disease Models, Animal ; Adult ; Age of Onset ; Bone Density Conservation Agents/therapeutic use ; Osteoclasts ; }, abstract = {CONTEXT: Paget disease of bone (PDB) is a metabolic disorder characterized by abnormal osteoclast activation. Recently, mutations in the PFN1 gene, which encodes Profilin 1, an actin-binding protein controlling actin dynamics and cell movement, have been linked to early-onset PDB. Interestingly, mutations in PFN1 (C71G, T109M, M114T, E117G, G118V, etc.) are associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting motor neurons.

OBJECTIVE: To provide insights into the underlying molecular mechanism of early-onset PDB.

METHODS: We observed the clinical responses to denosumab in early-onset PDB patients. Additionally, a mouse model carrying the c.335T>C mutation in the Pfn1 gene was generated.

RESULTS: We reported a second Chinese family affected by early-onset PDB with malignant giant cell tumors, in which we identified the same heterozygous missense mutation (c.335T>C/p. L112P) in PFN1 that we have reported previously in another family. Despite its proximity to ALS-linked PFN1 mutations, the PFN1 L112P mutation did not induce ALS in affected individuals. These early-onset PDB patients exhibited a significantly poorer response to denosumab compared to typical PDB patients. The heterozygous mice displayed PDB-like phenotypes, including skeletal deformities and focal osteoclastic lesions with giant osteoclasts, and did not show ALS-like phenotypes. We further show that mutation of Pfn1 leads to enhanced actin ring-like structures at the bone surfaces without affecting nuclear factor-κB activation in osteoclast cultures.

CONCLUSION: The observation of recurrent mutations highlights the causative role of PFN1 (L112P) in early-onset PDB/giant cell tumor within the Chinese population and provides insights into the physio-pathological functions of Profilin 1.}, } @article {pmid40459635, year = {2025}, author = {Abraham, I and Martin, P and Vaghela, S and Klein, T and Chow, E and Rush, M and Morlock, R and Huang, H}, title = {Budget impact analysis of revumenib for the treatment of relapsed or refractory acute leukemias with a KMT2A translocation in the United States.}, journal = {Journal of managed care & specialty pharmacy}, volume = {31}, number = {7}, pages = {680-693}, pmid = {40459635}, issn = {2376-1032}, mesh = {Humans ; United States ; *Myeloid-Lymphoid Leukemia Protein/genetics ; *Histone-Lysine N-Methyltransferase/genetics ; *Leukemia, Myeloid, Acute/drug therapy/economics/genetics ; Budgets ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/economics/genetics ; Translocation, Genetic ; *Antineoplastic Agents/economics/therapeutic use ; Adult ; Recurrence ; Drug Costs ; Benzamides ; Spiro Compounds ; }, abstract = {BACKGROUND: Acute leukemias (ALs), including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), are heterogeneous diseases characterized by different phenotypic, genetic, and molecular alterations that can guide treatment decisions. ALs harboring lysine methyltransferase 2A gene translocation (KMT2t), previously known as mixed-lineage leukemia, are associated with high rates of relapsed or refractory (R/R) disease. Revumenib, a first-in-class oral menin inhibitor, has shown improved clinical outcomes in patients with R/R KMT2At ALs.

OBJECTIVE: To estimate, using a budget impact model (BIM), the financial impact of introducing revumenib for the treatment of adult patients with R/R KMT2At ALs on the formulary of a hypothetical US 1-million-member commercial health plan.

METHODS: The BIM compared scenarios with or without revumenib and the resulting impact on commercial US third-party payers over a 3-year time horizon. Although no other therapies specifically targeted for R/R KMT2At ALs were approved during BIM development, 11 additional pharmacotherapies for R/R ALs (5 for AML and 6 for ALL, not including revumenib) were included as treatment options in the model. Clinical data included adverse event (AE) rates, duration of treatment, time to subsequent treatment, and survival outcomes. Cost inputs (USD 2024) included in the model comprised drug acquisition and administration, grade 3 or greater AEs, treatment-related supportive care and monitoring, subsequent treatment, and end-of-life costs. The differential cost per member per month (PMPM) was estimated. One-way sensitivity analyses varying the costs of drug acquisition and toxicity by ±20% and scenario analyses varying uptake of revumenib and epidemiology inputs, as well as excluding costs related to supportive care and posttreatment discontinuation, were performed.

RESULTS: An estimated 1.7 adult patients (AML, 1.1; ALL, 0.6) were treatment eligible annually. Estimated 3-year total plan costs without and with revumenib were $2,146,564 and $2,126,919, respectively, for savings of -$19,646. Including revumenib was estimated to yield a differential PMPM cost of -$0.0005 over 3 years. The total number of grade 3 or greater AEs was lower over 3 years (10.82 vs 10.99, respectively) in the plan with revumenib vs without. Sensitivity and scenario analyses validated the robustness of the model.

CONCLUSIONS: The BIM demonstrated that including revumenib in a formulary for adult patients with R/R KMT2At ALs was approximately cost neutral, offering patients access to a targeted treatment with potential for improved clinical outcomes.}, } @article {pmid40459673, year = {2025}, author = {Dengri, C and Mayberry, W and Koriesh, A and Nouh, A}, title = {Neurology of Androgens and Androgenic Supplements.}, journal = {Current neurology and neuroscience reports}, volume = {25}, number = {1}, pages = {39}, pmid = {40459673}, issn = {1534-6293}, mesh = {Humans ; *Androgens/metabolism/therapeutic use ; *Nervous System Diseases/drug therapy/metabolism ; *Dietary Supplements ; Receptors, Androgen/metabolism ; Animals ; Testosterone/therapeutic use ; }, abstract = {PURPOSE OF REVIEW: This article explores the intricate relationship between androgens, androgen receptors, and the central nervous system. We examine the role of physiologically derived androgens and androgenic supplements in neurodevelopment and neuroplasticity and delve into the involvement of androgen pathways in the pathogenesis of various neurological disorders.

RECENT FINDINGS: This review highlights the increasing recognition of testosterone and androgen signaling in various neurological conditions, with evidence of both protective and harmful effects depending on dosage and context. Although limited to experimental use, testosterone replacement therapy (TRT) may serve potential benefits in the management of multiple sclerosis, epilepsy, headache, Duchenne muscular dystrophy, amyotrophic lateral sclerosis, and Parkinson disease. On the other hand, androgen-blocking treatments may help alter disease progression in spinal and bulbar muscular atrophy. Testosterone supplementation can have potential adverse events when used at a supratherapeutic level, and prenatal testosterone exposure is believed to contribute to the pathogenesis of neurodevelopmental disease. Additionally, androgen-blocking agents could increase the risk of neurodegenerative conditions, such as Parkinson disease and Alzheimer disease. Despite the above findings, there is no established indication of TRT or androgen-blocking medication in neurological disorders. The body of evidence highlighting the involvement of androgens and androgen receptors (ARs) in pathogenesis of neurological diseases is growing. This includes ongoing research exploring the potential therapeutic targets involving the androgen signaling pathway for management of neurological disorders. Future placebo-controlled clinical trials are essential to determine the efficacy and safety of TRT or androgen-blocking therapies in managing neurological disease.}, } @article {pmid40460337, year = {2025}, author = {van Unnik, JWJ and Ing, L and Oliveira Santos, M and McDermott, CJ and de Carvalho, M and van Eijk, RPA}, title = {Remote Monitoring of Amyotrophic Lateral Sclerosis Using Digital Health Technologies: Shifting Toward Digitalized Care and Research?.}, journal = {Neurology}, volume = {105}, number = {1}, pages = {e213738}, pmid = {40460337}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis ; *Telemedicine ; Wearable Electronic Devices ; Videoconferencing ; Digital Technology ; *Biomedical Technology ; Monitoring, Physiologic/methods ; Digital Health ; }, abstract = {Current care and research pathways for amyotrophic lateral sclerosis (ALS) primarily rely on regularly scheduled visits to specialized centers. These visits provide intermittent clinical information to health care professionals and require patients to travel to the clinic. Digital health technologies enable continuous data collection directly from the patient's home, bringing new opportunities for personalized, timely care and a refined assessment of disease severity in clinical trials. In this review, we summarize the state of the art in digital health technologies for remote monitoring of patients with ALS, ranging from televisits through videoconferencing to sensor-based wearable devices. We explore how these technologies can benefit clinical care and advance treatment development. Despite significant progress, real-world adoption of these technologies remains limited. An overview is provided of the key barriers hindering their widespread implementation and the opportunities to advance the field. Significantly, there is an urgent need for harmonization across stakeholders through consensus guidelines and consortia. These efforts are essential to accelerate progress and harness the full potential of digital health technologies to better meet the needs of patients.}, } @article {pmid40460399, year = {2025}, author = {Pommée, T and Bouvier, L and Barnett-Tapia, C and Maffei, MF and Gutz, SE and Tilton-Bolowsky, VE and Martino, R and Berry, JD and Abrahao, A and Zinman, L and Green, JR and Yunusova, Y}, title = {Construct Validity of the Amyotrophic Lateral Sclerosis Bulbar Dysfunction Index-Remote.}, journal = {American journal of speech-language pathology}, volume = {34}, number = {4}, pages = {2189-2211}, pmid = {40460399}, issn = {1558-9110}, support = {F31 DC020108/DC/NIDCD NIH HHS/United States ; R01 DC017291/DC/NIDCD NIH HHS/United States ; T32 DC013017/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/complications ; Male ; Female ; Middle Aged ; Aged ; Reproducibility of Results ; Severity of Illness Index ; Adult ; Disability Evaluation ; Predictive Value of Tests ; Speech Intelligibility ; }, abstract = {PURPOSE: The Amyotrophic Lateral Sclerosis Bulbar Dysfunction Index-Remote (ALSBDI-R) is a clinician-administered tool designed to assess bulbar dysfunction remotely in patients with amyotrophic lateral sclerosis (ALS). This study aimed to evaluate the construct validity of the ALSBDI-R by examining its correlation with established clinical measures and its ability to discriminate among different bulbar disease severities.

METHOD: A total of 92 patients with ALS were recruited from two multidisciplinary clinics. Participants were assessed using the ALSBDI-R, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), the Center for Neurologic Study Bulbar Function Scale (CNS-BFS), the Sentence Intelligibility Test, and the Eating Assessment Tool (EAT-10). Construct validity was established through Spearman correlations and comparison of ALSBDI-R scores across bulbar severity groups (asymptomatic, mild, moderate, severe).

RESULTS: Strong correlations were found between ALSBDI-R total scores and bulbar-specific measures such as ALSFRS-R bulbar subscore (r = -.85), CNS-BFS (r = .85), and EAT-10 (r = .77). The ALSBDI-R effectively discriminated between severity groups, supporting its construct validity. Severity bins were created based on median ALSBDI-R total scores for each group.

CONCLUSIONS: The ALSBDI-R is a valid tool for remotely assessing bulbar dysfunction in patients with ALS. Despite several limitations, its ability to capture varying degrees of severity makes it valuable for clinical use and research, offering a standardized approach to monitor disease progression remotely.}, } @article {pmid40461666, year = {2025}, author = {Orologio, I and Russo, A and Trojsi, F and Todisco, V and Cirillo, M and Tessitore, A and Silvestro, M}, title = {A case of rapidly progressive juvenile amyotrophic lateral sclerosis associated with a pathogenetic heterozygous de novo variant in the FUS gene.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {10}, pages = {5469-5475}, pmid = {40461666}, issn = {1590-3478}, } @article {pmid40462117, year = {2025}, author = {Akif, A and Nguyen, TTM and Liu, L and Xu, X and Kulkarni, A and Jiang, J and Zhang, Y and Hao, J}, title = {Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.}, journal = {Fluids and barriers of the CNS}, volume = {22}, number = {1}, pages = {55}, pmid = {40462117}, issn = {2045-8118}, support = {R01 NS105787/NS/NINDS NIH HHS/United States ; R21 NS133895/NS/NINDS NIH HHS/United States ; R01NS105787//National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS133895-01//National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors/metabolism/drug effects ; Mice ; *Dementia, Vascular/drug therapy/metabolism ; *Signal Transduction/drug effects ; *Sulfonylurea Compounds/pharmacology ; *Cognitive Dysfunction/drug therapy/metabolism ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Carotid Stenosis/complications ; Brain/drug effects/metabolism ; }, abstract = {BACKGROUND: As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD.

METHODS: In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50th day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-4 (IL-4) in the blood were measured using ELISA.

RESULTS: AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-α and IL-1β levels, while increasing the anti-inflammatory IL-4 level in the blood.

CONCLUSIONS: The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.

CLINICAL TRIAL NUMBER: Not applicable.}, } @article {pmid40462477, year = {2025}, author = {Shaka, Z and Mojtabavi, H and Taebi, M and Mahmoodi-Bakhtiari, B and Sarraf, P}, title = {Examining cognitive decline over time in Iranian ALS patients: Adapting successive versions B and C of the Edinburgh cognitive and behavioral screen to Persian.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {709-719}, doi = {10.1080/21678421.2025.2509615}, pmid = {40462477}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology/diagnosis/epidemiology ; Male ; Female ; Iran/epidemiology ; *Cognitive Dysfunction/diagnosis/etiology/psychology ; Middle Aged ; Aged ; *Neuropsychological Tests/standards ; *Mental Status and Dementia Tests/standards ; Reproducibility of Results ; Adult ; }, abstract = {OBJECTIVE: To adapt successive versions B and C of the Edinburgh Cognitive and Behavioral Screen (ECAS) into Persian and evaluate cognitive and behavioral changes over time in Iranian ALS patients.

METHODS: This study included 38 ALS patients in the ECAS-B group and 29 in the ECAS-C group, diagnosed between May 2021 and February 2023 at the Iranian Center of Neurological Research, Imam Khomeini Hospital, Tehran, Iran. Additionally, 59 age- and education-matched healthy controls were enrolled (30 for ECAS-B and 29 for ECAS-C). The Montreal Cognitive Assessment (MoCA) was used to validate the ECAS versions.

RESULTS: The Persian versions of ECAS-B and ECAS-C demonstrated strong internal consistency (Cronbach's alpha: 0.88 for ECAS-B and 0.89 for ECAS-C) and a positive correlation with MoCA and ALS-FRS-r scores. The area under the ROC curve was 0.851 for ECAS-B and 0.861 for ECAS-C. ECAS-C scores were significantly lower than ECAS-B scores, suggesting a faster cognitive decline over time. Optimal cutoff values of 72 for ECAS-B and 78 for ECAS-C were identified for detecting cognitive impairment. Cognitive impairment was observed in 10 patients (26.31%) in the ECAS-B group and 15 patients (51.72%) in the ECAS-C group.

CONCLUSIONS: The Persian versions of ECAS-B and ECAS-C demonstrate good validity and reliability for detecting cognitive impairment and tracking cognitive decline in ALS patients.}, } @article {pmid40462656, year = {2025}, author = {Gong, Z and Cao, R and Zhu, H}, title = {Exploring the Causal Association Between 91 Circulating Inflammatory Proteins and Neurodegenerative Diseases: A Bidirectional Two-Sample Mendelian Randomization and Bioinformatics Analysis.}, journal = {Brain and behavior}, volume = {15}, number = {6}, pages = {e70586}, pmid = {40462656}, issn = {2162-3279}, support = {2025JJ70054//Natural Science Foundation of Hunan Province/ ; }, mesh = {Humans ; Mendelian Randomization Analysis/methods ; Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/blood ; Computational Biology ; CD40 Antigens/genetics ; Polymorphism, Single Nucleotide ; Amyotrophic Lateral Sclerosis/genetics ; Quantitative Trait Loci ; Parkinson Disease/genetics ; Multiple Sclerosis/genetics ; Alzheimer Disease/genetics ; Inflammation/genetics ; }, abstract = {BACKGROUND: Circulating inflammatory proteins play a significant role in the pathogenesis of neurodegenerative diseases (NDDs). However, the precise causal relationship and the underlying mechanisms of their interaction remain elusive.

METHODS: Genome-wide association study (GWAS) data for 91 circulating inflammatory proteins were obtained from the GWAS Catalog. Additionally, GWAS data for Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and ischemic stroke (IS) were acquired from the IEU Open GWAS Project. Four Mendelian randomization (MR) methods were employed to analyze causal effects, accompanied by sensitivity and pleiotropy analyses. Expression quantitative trait loci (eQTL) analyses for CD40 and MS-associated SNPs were performed. Transcriptomic data from the peripheral blood of MS patients were used to identify differentially expressed genes (DEGs) in relapsing-remitting MS (RRMS). RRMS patients were divided into two subgroups (C1 and C2) based on CD40 expression levels for comparative analysis. A single gene set enrichment analysis (GSEA) was conducted to investigate potential molecular mechanisms through which CD40 influences MS.

RESULTS: MR analyses indicated that CD40 ligand receptor (CD40) is associated with a reduced risk of MS (OR, 0.78; 95% CI, 0.72-0.84; PFDR = 8.75E-07). No statistically significant bidirectional causal relationships were found between other inflammatory proteins and PD, AD, ALS, or IS, and the findings were robust. Functional enrichment analysis revealed that these eQTLs primarily relate to transcriptional regulation, herpes simplex virus 1 (HSV-1) infection, and bile and fatty acid metabolism. In MS peripheral blood microarray data, CD40 is significantly downregulated in RRMS. Intergroup comparisons revealed elevated levels of resting memory CD4[+] T cells, activated NK cells, and neutrophils in C1, alongside increased autophagy, apoptosis, multiple immune responses, and upregulation of transforming growth factor-β (TGF-β) signaling pathways. Conversely, C2 exhibited higher levels of Tregs, resting NK cells, and activated dendritic cells, as well as upregulation in processes such as cholesterol homeostasis, glucose metabolism, and CD4/CD8 downregulation. Single-GSEA results suggest that CD40 promotes nucleotide metabolism, mitochondrial calcium ion transport, unfolded protein response (UPR), and adaptive immune regulation, while inhibiting androgen response and TGF-β signaling pathways, thereby influencing the progression of RRMS.

CONCLUSION: CD40 may exert neuroprotective effects in MS patients via diverse cellular and molecular pathways, potentially representing a novel target for MS intervention.}, } @article {pmid40462740, year = {2025}, author = {DeCastro, J and Mehta-Doshi, A and Liu, C and Ray, A and Aran, K}, title = {Red Blood Cell-Derived Exosomes as Mediators of Age-Related Neurodegeneration.}, journal = {Rejuvenation research}, volume = {28}, number = {4}, pages = {184-194}, pmid = {40462740}, issn = {1557-8577}, mesh = {*Exosomes/metabolism ; Animals ; MicroRNAs/genetics/metabolism ; *Neurodegenerative Diseases/genetics/pathology/blood ; *Aging/pathology/genetics ; *Erythrocytes/metabolism ; Mice ; Biomarkers/metabolism ; Mice, Inbred C57BL ; Male ; }, abstract = {Age-associated neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are marked by progressive degeneration of the nervous system. Current diagnostic approaches, such as neuroimaging and cerebrospinal fluid biomarkers, are invasive, costly, and lack early diagnostic reliability. Recent studies highlight the potential of extracellular vesicles, particularly exosomes, derived from erythrocytes or red blood cells (RBCs), as emerging indicators of aging and age-associated diseases. Exosomes carry noncoding RNA, lipid, and protein molecules, and modulate cellular pathways at distant sites, providing neuroprotective and anti-inflammatory effects. In this study, we isolated RBC-derived exosomes of young and old mice. MicroRNA sequencing analysis revealed differential expression of several miRNA species between young and old mice. We report an upregulation of miR-125a-5p and a downregulation of miR-302a-5p in old mice that are potentially linked to neurodegenerative pathways. This study underscores the potential of RBC-derived exosomes as noninvasive biomarkers for NDDs.}, } @article {pmid40462869, year = {2025}, author = {Acan, D and Cakar, BB and Karahan, E}, title = {Low anterior chamber volume as a risk factor in non-arteritic anterior ischemic optic neuropathy.}, journal = {Frontiers in ophthalmology}, volume = {5}, number = {}, pages = {1554279}, pmid = {40462869}, issn = {2674-0826}, abstract = {PURPOSE: This study aimed to compare the anterior chamber depth (ACD), anterior chamber volume (ACV), and iridocorneal angle (ICA) of the eyes of patients with non-arteritic anterior ischemic optic neuropathy (NAION) and normal eyes.

METHODS: In this cross-sectional study, 28 patients with NAION who were admitted to our institution were examined. Central corneal thickness (CCT), ACV, ACD, and ICA of all eyes were measured using corneal topography (Sirius, CSO, Italy). Axial lengths (ALs) were measured using an IOL-Master 500 (Carl Zeiss, Meditec). The eyes of these patients were compared with the eyes of 29 healthy individuals of similar age and gender.

RESULTS: The mean ALs of the eyes with NAION and those in the control group were not statistically different, measuring 22.95 ± 0.68 mm and 23.13 ± 0.80mm, respectively (p=0.651). While the average ACV was 137.93 ± 41.01 mm[3] in the control group, it was significantly lower at 117.86 ± 22.23 mm[3] in the patients with NAION (p=0.038). The mean ACD, ICA, and CCT values in the control and study groups were not statistically different, with 2.82 ± 0.57 mm and 2.64 ± 0.31 mm, 41.62 ± 6.99° and 40.14 ± 7.04°, and 542.48 ± 19.39µm and 544.68 ± 31.26 µm, respectively (p1 = 0.236, p2 = 0.693, and p3 = 0.959). No statistical differences were found between the eyes with NAION and their fellow eyes in terms of AL, CCT, ACD, ACV, and ICA (p>0.05).

CONCLUSION: Differences in anterior segment morphology were observed in eyes with NAION compared to healthy eyes. Decreased ACV may be a risk factor for NAION.}, } @article {pmid40463522, year = {2025}, author = {Cohen, Y and Sinai, I and Magen, I and Danino, YM and Wuu, J and Malaspina, A and Benatar, M and Hornstein, E}, title = {IsomiR Utility in Amyotrophic Lateral Sclerosis Prognostication.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40463522}, support = {U01 NS107027/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. IsomiRs are microRNA (miRNA) isoforms that arise from alternative processing or editing events during miRNA biogenesis. While isomiRs may carry distinct biological and clinical relevance, their potential as cell-free biomarkers in neurodegeneration remains largely unexplored.

METHOD: Here we investigated the prognostic utility of plasma isomiRs in ALS, using next-generation sequencing and two orthogonal statistical approaches.

FINDINGS: We profiled cell-free isomiRs in 154 ALS patients from a British cohort and identified higher levels of one isomiR, let-7g-5p.t, to be associated with longer survival. This finding was independently validated in an international ALS cohort of 200 patients. let-7g-5p.t prognostic utility was comparable to that of neurofilament light chain (NfL) or miR-181.

CONCLUSION: These results establish isomiRs as a novel class of blood-based biomarkers in ALS with potential to refine prognostication in clinical trials for neurodegenerative diseases.

FUNDING: Target ALS, Israel Science Foundation (ISF 3497/21, 424/22) and the CReATe Consortium. All additional funding can be found in the Acknowledgements section of this paper.}, } @article {pmid40463912, year = {2025}, author = {Liu, T and Sun, W and Guo, S and Yuan, Z and Zhu, M and Lu, J and Chen, T and Qu, Y and Feng, C and Yang, T}, title = {Role of mitochondrial quality control in neurodegenerative disease progression.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1588645}, pmid = {40463912}, issn = {1662-5102}, abstract = {Neurodegenerative diseases are a diverse group of neurological disorders, in which abnormal mitochondrial function is closely associated with their development and progression. This has generated significant research interest in the field. The proper functioning of mitochondria relies on the dynamic regulation of the mitochondrial quality control system. Key processes such as mitochondrial biogenesis, mitophagy, and mitochondrial dynamics (division/fusion) are essential for maintaining this balance. These processes collectively govern mitochondrial function and homeostasis. Therefore, the mitochondrial quality control system plays a critical role in the onset and progression of neurodegenerative diseases. This article provides a concise overview of the molecular mechanisms involved in mitochondrial biogenesis, mitophagy, and mitochondrial dynamics, explores their interactions, and summarizes current research progress in understanding the mitochondrial quality control system in the context of neurodegenerative diseases.}, } @article {pmid40464332, year = {2025}, author = {Naim, A and Farooqui, AM and Badruddeen, and Khan, MI and Akhtar, J and Ahmad, A and Islam, A}, title = {The Role of Kinases in Neurodegenerative Diseases: From Pathogenesis to Treatment.}, journal = {The European journal of neuroscience}, volume = {61}, number = {11}, pages = {e70156}, doi = {10.1111/ejn.70156}, pmid = {40464332}, issn = {1460-9568}, mesh = {Humans ; *Neurodegenerative Diseases/enzymology/drug therapy/metabolism ; Animals ; *Protein Kinases/metabolism ; Protein Kinase Inhibitors/therapeutic use ; }, abstract = {Neurodegenerative diseases are characterized by progressive neuronal loss and dysfunction, with protein kinases playing crucial roles in their pathogenesis. This article explores the involvement of protein kinases in these disorders, focusing on their contributions to disease mechanisms, potential as therapeutic targets and challenges in developing effective treatments. In Alzheimer's disease, kinases such as CDK5, GSK3β and MARK4 are implicated in tau hyperphosphorylation and the formation of neurofibrillary tangles. Kinases also regulate amyloid-β processing and plaque formation. In Parkinson's disease, LRRK2, PINK1 and other kinases contribute to α-synuclein pathology, mitochondrial dysfunction and neuroinflammation. LRRK2 inhibitors and PROTACs have shown promise in preclinical models. Huntington's disease involves altered kinase activity, with CK2, GSK3 and MAPK pathways influencing mutant huntingtin toxicity and aggregation. Kinases are also implicated in less common neurodegenerative diseases, such as ALS and spinocerebellar ataxias. Despite the therapeutic potential of targeting kinases, challenges remain, including the complexity of kinase networks, blood-brain barrier permeability and the lack of robust biomarkers. Emerging technologies, such as covalent inhibitors, targeted protein degradation and combination therapies, offer new avenues for addressing these challenges and developing more effective treatments for neurodegenerative diseases.}, } @article {pmid40464500, year = {2025}, author = {Dedoni, S and Avdoshina, V and Olianas, MC and Onali, P}, title = {Role of Lysophosphatidic Acid in Neurological Diseases: From Pathophysiology to Therapeutic Implications.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {30}, number = {5}, pages = {28245}, doi = {10.31083/FBL28245}, pmid = {40464500}, issn = {2768-6698}, mesh = {Humans ; *Lysophospholipids/metabolism ; *Nervous System Diseases/physiopathology/metabolism/drug therapy ; Animals ; Receptors, Lysophosphatidic Acid/metabolism ; Signal Transduction ; }, abstract = {Lysophosphatidic acid (LPA), a bioactive lipid molecule, has been identified as a critical regulator of several cellular processes in the central nervous system, with significant impacts on neuronal function, synaptic plasticity, and neuroinflammatory responses. While Alzheimer's disease, Multiple Sclerosis, and Parkinson's disease have garnered considerable attention due to their incidence and socioeconomic significance, many additional neurological illnesses remain unclear in terms of underlying pathophysiology and prospective treatment targets. This review synthesizes evidence linking LPA's function in neurological diseases such as traumatic brain injury, spinal cord injury, cerebellar ataxia, cerebral ischemia, seizures, Huntington's disease, amyotrophic lateral sclerosis, Hutchinson-Gilford progeria syndrome, autism, migraine, and human immunodeficiency virus (HIV)-associated complications Despite recent advances, the specific mechanisms underlying LPA's actions in various neurological disorders remain unknown, and further research is needed to understand the distinct roles of LPA across multiple disease conditions, as well as to investigate the therapeutic potential of targeting LPA receptors in these pathologies. The purpose of this review is to highlight the multiple functions of LPA in the aforementioned neurological diseases, which frequently share the same poor prognosis due to a scarcity of truly effective therapies, while also evaluating the role of LPA, its receptors, and signaling as promising actors for the development of alternative therapeutic strategies to those proposed today.}, } @article {pmid40464816, year = {2025}, author = {Savran, Z and Baltaci, SB and Aladag, T and Mogulkoc, R and Baltaci, AK}, title = {Vitamin D and Neurodegenerative Diseases Such as Multiple Sclerosis (MS), Parkinson's Disease (PD), Alzheimer's Disease (AD), and Amyotrophic Lateral Sclerosis (ALS): A Review of Current Literature.}, journal = {Current nutrition reports}, volume = {14}, number = {1}, pages = {77}, pmid = {40464816}, issn = {2161-3311}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Vitamin D/metabolism ; Multiple Sclerosis ; Alzheimer Disease ; Parkinson Disease ; Receptors, Calcitriol/metabolism ; Amyotrophic Lateral Sclerosis ; Oxidative Stress/drug effects ; Animals ; Cholecalciferol ; }, abstract = {PURPOSE OF REVIEW: This review explores the role of Vitamin D3 and its derivatives as inhibitors of pathological metabolic modifications in neurodegenerative diseases. The manuscript investigates how Vitamin D3 impacts neuronal calcium regulation, antioxidative pathways, immunomodulation, and neuroprotection during detoxification, beyond its known functions in intestinal, bone, and kidney calcium and phosphorus absorption, as well as bone mineralization.

RECENT FINDINGS: Recent studies have highlighted the synthesis of the active metabolite 1,25(OH)2D3 (vitamin D) in glial cells via the hydroxylation process of CY-P24A1, an enzyme in the cytochrome P450 system in the brain. The effects of vitamin D occur through the vitamin D receptor (VDR), a nuclear steroid receptor, which has been identified in various brain regions, including the cerebellum, thalamus, hypothalamus, basal ganglia, hippocampus, olfactory system, temporal, and orbital regions. Neurodegeneration is primarily associated with oxidative stress, protein aggregation, neuroinflammation, mitochondrial dysfunction, apoptosis, and autophagy changes, all of which Vitamin D and VDR are believed to influence. Vitamin D and VDR are recognized as both environmental and genetic factors in the etiopathogenesis of neurodegenerative diseases such as Multiple Sclerosis (MS), Parkinson's Disease (PD), Alzheimer's Disease (AD), and Amyotrophic Lateral Sclerosis (ALS). A deficiency in Vitamin D is postulated to have detrimental effects on the brain and other diseases throughout various stages of life. This review consolidates findings from clinical and experimental studies, as well as past publications, focusing on the implications of Vitamin D deficiency in these neurodegenerative conditions. Current articles published in PubMed were extensively considered for this review.}, } @article {pmid40465292, year = {2025}, author = {Chourpiliadis, C and Lovik, A and Ingre, C and Press, R and Samuelsson, K and Valdimarsdottir, U and Fang, F}, title = {Use of Common Psychiatric Medications and Risk and Prognosis of Amyotrophic Lateral Sclerosis.}, journal = {JAMA network open}, volume = {8}, number = {6}, pages = {e2514437}, pmid = {40465292}, issn = {2574-3805}, support = {R01 TS000324/TS/ATSDR CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Male ; Female ; Case-Control Studies ; Middle Aged ; Sweden/epidemiology ; Aged ; Prognosis ; *Antidepressive Agents/adverse effects/therapeutic use ; *Hypnotics and Sedatives/adverse effects/therapeutic use ; *Mental Disorders/drug therapy ; *Anti-Anxiety Agents/adverse effects/therapeutic use ; Risk Factors ; Registries ; Disease Progression ; *Psychotropic Drugs/adverse effects/therapeutic use ; }, abstract = {IMPORTANCE: Although several studies have shown an increased risk of subsequent amyotrophic lateral sclerosis (ALS) diagnosis for individuals with a history of psychiatric disorders, the evidence of an association between use of common psychiatric medications and ALS is scarce and inconclusive.

OBJECTIVE: To examine whether there is an association of prescribed use of common psychiatric medications, namely anxiolytics, hypnotics and sedatives, and antidepressants, with the risk and disease progression of ALS.

This nationwide register-based case-control study was conducted in Sweden among all patients diagnosed with ALS from January 1, 2015, to July 1, 2023, according to the Swedish Motor Neuron Disease Quality Registry, who were age- and sex-matched with as many as 5 individuals with no ALS as well as their full siblings and spouses. Patients with ALS were followed up for a median (IQR) of 1.33 (0.64-2.37) years after diagnosis.

EXPOSURES: At least 2 prescriptions of the studied psychiatric medications before ALS diagnosis.

MAIN OUTCOMES AND MEASURES: The risk of ALS diagnosis associated with prediagnostic prescribed use of common psychiatric medications was estimated using conditional logistic regression models, comparing patients with ALS with population or relative control participants. Patients with ALS were followed up from diagnosis to assess the association of prediagnostic prescribed use of common psychiatric medications with disease progression. The association of mortality (or use of invasive ventilation) with the use of common psychiatric medications was estimated with a joint longitudinal-survival model accounting for the longitudinal changes of ALS Functional Rating Scale-Revised (ALSFRS-R) in the time-to-event analysis.

RESULTS: Among the 1057 case participants and 5281 population control participants, the mean (SD) age at diagnosis of the case participants (ie, date of selection of the control participants) was 67.5 (11.5) years, and 3363 (53.1%) were male. In the population comparison, prescribed use of common psychiatric medications across all studied time windows before ALS diagnosis was associated with a higher risk of ALS (eg, among individuals prescribed hypnotics and sedatives 0-1 year before diagnosis: odds ratio [OR], 6.10; 95% CI, 3.77-9.88; prescribed anxiolytics 1-5 years before diagnosis: OR, 1.60; 95% CI, 1.15-2.23; prescribed antidepressants >5 years before diagnosis: OR, 1.21; 95% CI, 1.02-1.44). Excluding the year before diagnosis from the analysis, prescribed use of anxiolytics (OR, 1.34; 95% CI, 1.12-1.60), hypnotics and sedatives (OR, 1.21; 95% CI, 1.02-1.43), or antidepressants (OR, 1.26; 95% CI, 1.06-1.49) was associated with an increased risk of ALS. Similar results were noted in the comparison with relative control participants, partially alleviating the concern on familial confounding, with the exception of hypnotics and sedatives. Shorter survival was demonstrated among patients with ALS who had prediagnostic use of anxiolytics (hazard ratio [HR], 1.52; 95% CI, 1.12-2.05) or antidepressants (HR, 1.72; 95% CI, 1.30-2.29), compared with patients with ALS without such experience.

CONCLUSIONS AND RELEVANCE: In this case-control study, prescribed use of anxiolytics, hypnotics and sedatives, or antidepressants was associated with a higher subsequent risk of ALS. Prediagnostic use of such medications was also associated with a poor prognosis after ALS diagnosis.}, } @article {pmid40466410, year = {2025}, author = {Guillen-Sola, A and Bertran-Recasens, B and Martinez-Llorens, J and Balaña, A and Villatoro, M and Rubio, MA}, title = {[Use of tongue pressure to determine the indication for instrumental swallowing assessment in patients with spinal ALS].}, journal = {Rehabilitacion}, volume = {59}, number = {3}, pages = {100917}, doi = {10.1016/j.rh.2025.100917}, pmid = {40466410}, issn = {1578-3278}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Female ; Middle Aged ; *Tongue/physiopathology ; *Deglutition Disorders/diagnosis/etiology/physiopathology ; Cross-Sectional Studies ; Aged ; Pressure ; Prospective Studies ; Adult ; }, abstract = {OBJECTIVE: Systematic swallowing assessment in amyotrophic lateral sclerosis (ALS) is essential, as approximately 85% of patients will develop dysphagia, and 8% of these cases may remain clinically silent. Although instrumental diagnostic tools exist, they are not always accessible. Recent studies suggest that lingual pressure measurements may be valuable for early detection of bulbar dysfunction. This study aims to establish lingual pressure cutoff points for early screening of such dysfunction.

DESIGN: Transversal study based on prospectively collected data from patients with spinal-onset ALS at the Motor Neuron Unit, Hospital del Mar (Barcelona).

MATERIALS AND METHODS: A total of 58 patients were included. Anterior (PA) and posterior (PP) lingual pressures were measured using the IOPI system and analyzed alongside the ALSFRS-R scale. Statistical analysis included descriptive statistics, Spearman correlation, and ROC curve analysis (SPSS v25).

RESULTS: A moderate correlation was found between lingual strength and ALSFRS-R scores (PA: r=.634, P<.001; PP: r=.539, P<.001). Identified cutoff values: PA: 39.5kPa (AUC=.766; 95%CI: .700-.831; P<.001), sensitivity 64.6%, specificity 76.4%. PP: 37.0kPa (AUC=.726; 95%CI: .653-.799; P<.001), sensitivity 55.1%, specificity 72.2%.

CONCLUSION: In spinal-onset ALS, a moderate correlation exists between global functionality and lingual pressures. Cutoff points of PA=39.5kPa and PP=37.0kPa are proposed for early screening of bulbar dysfunction.}, } @article {pmid40468389, year = {2025}, author = {Rummens, J and Da Cruz, S}, title = {RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {64}, pmid = {40468389}, issn = {1750-1326}, support = {G064721N//Fonds Wetenschappelijk Onderzoek/ ; 1S15218N//Fonds Wetenschappelijk Onderzoek/ ; 962700//Muscular Dystrophy Association/ ; SAO-FRA 20230035//Alzheimer's Research Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Frontotemporal Dementia/metabolism/pathology/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Animals ; DNA-Binding Proteins/metabolism ; RNA-Binding Protein FUS/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative disorders with overlapping clinical, genetic and pathological features. A large body of evidence highlights the critical role of RNA-binding proteins (RBPs) - in particular TAR DNA-binding protein 43 (TDP-43) and Fused in sarcoma (FUS) - in the pathogenesis of these diseases. These RBPs normally regulate various key aspects of RNA metabolism in the nervous system (by assembling into transient biomolecular condensates), but undergo cytoplasmic mislocalization and pathological aggregation in ALS and FTD. Furthermore, emerging evidence suggests that RBP-containing aggregates may propagate through the nervous system in a prion-like manner, driving the progression of these neurodegenerative diseases. In this review, we summarize the genetic and neuropathological findings that establish RBP dysfunction as a central theme in ALS and FTD, and discuss the role of disease-associated RBPs in health and disease. Furthermore, we review emerging evidence regarding the prion-like properties of RBP pathology, and explore the downstream mechanisms that drive neurodegeneration. By unraveling the complex role of RBPs in ALS and FTD, we ultimately aim to provide insights into potential avenues for therapeutic intervention in these incurable disorders.}, } @article {pmid40468914, year = {2025}, author = {Cao, Y and Yuan, B and Jiang, X and Xie, C and Wu, D and Zhang, Z}, title = {Quantification of Skeletal Muscle at the First Lumbar Level for Prognosis in Amyotrophic Lateral Sclerosis.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {16}, number = {3}, pages = {e13827}, pmid = {40468914}, issn = {2190-6009}, support = {81830040//National Natural Science Key Foundation of China/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/mortality/pathology/diagnostic imaging/diagnosis ; *Lumbar Vertebrae/diagnostic imaging ; *Muscle, Skeletal/diagnostic imaging/pathology ; Prognosis ; Tomography, X-Ray Computed ; }, abstract = {BACKGROUND: Skeletal muscle parameters at the first lumbar vertebra (L1) level on computed tomography (CT) are common indicators for muscle mass. However, their relationship with the severity and prognosis of amyotrophic lateral sclerosis (ALS) patients remains unclear.

METHODS: This cohort study included ALS patients who underwent chest CT scans between January 2018 and January 2022 and healthy controls (HCs) matched for gender and age. Overall survival (OS) was determined from the date of chest CT to death, tracheal intubation or 1 January 2024. Using ImageJ software, skeletal muscle area and density (L1 SMA/SMD), skeletal muscle index (L1 SMI), paraspinal muscle area and density (L1 PMA/PMD) and subcutaneous fat area and density (L1 SFA/SFD) at L1 were quantified. The relationships between the quantified muscle parameters and both King's clinical stages and the Revised ALS Functional Rating Scale (ALSFRS-R) were analysed. The Cox proportional hazard model was used to evaluate the hazard ratio (HR) of skeletal muscle parameters as risk factors for outcome events, and to construct a nomogram.

RESULTS: Muscle parameters in ALS patients (n = 102; 36.27% female; mean age, 60.85 ± 10.58 years) were significantly lower compared with HCs (p < 0.001). L1 SMD (p = 0.047) and L1 PMD (p = 0.003) both differed significantly across the King's clinical stages. ALSFRS-R scores correlated with L1 SMA (r = 0.35, p < 0.001), L1 SMI (r = 0.34, p < 0.001), L1 PMA (r = 0.27, p = 0.007) and L1 PMD (r = 0.27, p = 0.007). Multivariate Cox regression analysis revealed that L1 SMA (HR = 0.96, 95% confidence interval [CI] = 0.94-0.98, p = 0.001), L1 SMD (HR = 0.92, 95% CI = 0.88-0.96, p < 0.001) and L1 PMA (HR = 1.06, 95% CI = 1.01-1.11, p = 0.022) significantly influenced ALS survival, with area under the curves (AUCs) of 0.687 and 0.851 for 1- and 3-year OS prediction. The consistency index (C-index) for the nomogram was 0.72 (95% CI = 0.641-0.793).

CONCLUSIONS: Skeletal muscle parameters at L1 level on CT are significantly associated with clinical severity and prognosis in ALS.

TRIAL REGISTRATION: Chinese Clinical Trial Registration Center: ChiCTR230078702.}, } @article {pmid40469844, year = {2025}, author = {Shen, D and Yang, X and He, D and Zhang, K and Liu, S and Sun, X and Li, J and Cai, Z and Liu, M and Zhang, X and Liu, Q and Cui, L}, title = {Genetic analysis of ERBB4 gene in Chinese patients with amyotrophic lateral sclerosis: a single-center study and systematic review of published literature.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1584541}, pmid = {40469844}, issn = {1663-4365}, abstract = {BACKGROUND: Rare ERBB4 variants have been implicated in amyotrophic lateral sclerosis (ALS), but their prevalence and clinical significance remain poorly understood, particularly across different ethnic populations.

METHODS: We performed genetic screening of ERBB4 in 1627 Chinese ALS patients using whole-exome sequencing. A systematic review and meta-analysis of the published literature were conducted to evaluate the global frequency of ERBB4 variants and their clinical correlations.

RESULTS: We identified 14 missense variants and 6 splice region variants in 23 unrelated patients, with four variants classified as damaging (p.R782P, p.M799T, p.R847C, and p.S997R). The splice variant c.1490-3C > T, associated with a 50% reduction in ERBB4 mRNA expression, was maternally inherited by a male ALS patient, while its presence in his asymptomatic mother suggests the involvement of potential genetic modifiers. ERBB4 variant carriers demonstrated earlier disease onset compared to non-carriers (46.9 ± 10.3 vs. 52.6 ± 11.2 years; p = 0.015), though survival duration remained comparable. Meta-analysis revealed a pooled ERBB4 variant frequency of 0.83% (95% CI, 0.56-1.10%) in ALS patients globally, with notable ethnic differences (1.36% in Chinese, 0.66% in European, and 1.44% in American populations).

CONCLUSION: Our findings establish the prevalence of ERBB4 variants in ALS across different populations and suggest their potential role as disease modifiers, particularly affecting the age of onset. The ethnic variation in mutation frequency highlights the importance of population-specific genetic screening strategies in ALS.}, } @article {pmid40470490, year = {2025}, author = {Ren, S and Che, X and Hu, S and Feng, X and Zhang, J and Shi, P}, title = {The effect of exercise intervention on amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1499407}, pmid = {40470490}, issn = {1664-2295}, abstract = {OBJECTIVE: Quantitative evaluation of the effect of exercise intervention in amyotrophic lateral sclerosis (ALS).

METHODS: The CNKI, WOS, PubMed, and Scopus databases were searched by computer, and randomized controlled trials (RCTs) of exercise intervention in ALS were screened out according to the inclusion and exclusion criteria of the PICOS principle. Stata 12.0 software was used for statistical analysis.

RESULTS: A total of 12 RCTs including 430 participants were included. Meta-analysis results show that exercise intervention can significantly improve the overall function, walking test (WT) distance and maximum expiratory pressure (MEP) of ALS patients (p < 0.05). However, exercise interventions did not show significant effects on fatigue, maximum inspiratory pressure (MIP), forced vital capacity (FVC), and peak expiratory flow (PEF) in ALS patients (p > 0.05). Subgroup analysis showed that resistance exercise is the most effective intervention for improving the function of ALS patients, while aerobic exercise is the most effective intervention for improving FVC in ALS patients.

CONCLUSION: Exercise intervention in ALS has a positive effect, but due to the small number of included studies and possible heterogeneity, risk of bias and sensitivity issues, further research is needed.}, } @article {pmid40473122, year = {2025}, author = {Mueller, KA and Suneby, EG and Ferola, MH and Moreno, AJ and Kidd, JD and Thompson, K and Vieira, FG and Valdez, G and Hatzipetros, T}, title = {Comprehensive characterization and validation of the Prp-hPFN1[G118V] mouse model: Guidelines for preclinical therapeutic testing for ALS.}, journal = {Neurobiology of disease}, volume = {212}, number = {}, pages = {106975}, doi = {10.1016/j.nbd.2025.106975}, pmid = {40473122}, issn = {1095-953X}, support = {T32 GM136566/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology/drug therapy ; *Disease Models, Animal ; Mice ; Mice, Transgenic ; Female ; *Profilins/genetics ; Male ; Humans ; Drug Evaluation, Preclinical/methods ; Motor Neurons/pathology ; Spinal Cord/pathology ; Neuromuscular Junction/pathology ; }, abstract = {The hPFN1[G118V] mouse model, overexpressing mutant human profilin1 linked to a rare form of ALS, was comprehensively characterized to assess its suitability for preclinical drug testing. Using a large cohort of nearly 250 transgenic and wild-type mice in a longitudinal study, we combined behavioral, electrophysiological, and neuropathological assessments to define the chronology of pathological events and assess inherent subject variability. The early stage of the disease in this model was characterized by elevated plasma neurofilament light chain levels, an effect that persisted and progressed throughout the course of the disease, followed by spinal cord neuroinflammation, suggesting that axonal pathology is the initiating event. The middle stage of the disease involved progressive neuromuscular decline, including reductions in compound muscle action potential (CMAP) and grip strength, accompanied by neuromuscular junction degeneration. The end-stage of the disease was characterized by the onset of visible changes such as weight loss, gait abnormalities and hindlimb paresis that quickly progressed to paralysis. At end-stage we also observed spinal motor neuron loss and TDP-43 pathology. The average humane endpoint was 213 days for females and 237 days for males. Our findings demonstrate that hPFN1[G118V] mice recapitulate key ALS features with moderate disease progression and a reproducible disease course, making them a valuable model for therapeutic testing. Recommendations are provided to optimize study design for preclinical testing, emphasizing survival duration as the primary endpoint, with CMAP and plasma NFL as key secondary readouts.}, } @article {pmid40473505, year = {2026}, author = {Song, W and Huang, Q and Jiang, Z}, title = {Clinical efficacy of athletic taping-assisted physiotherapy for plantar fasciitis: A systematic evaluation and meta-analysis.}, journal = {Foot and ankle surgery : official journal of the European Society of Foot and Ankle Surgeons}, volume = {32}, number = {1}, pages = {11-25}, doi = {10.1016/j.fas.2025.05.013}, pmid = {40473505}, issn = {1460-9584}, mesh = {Humans ; *Fasciitis, Plantar/therapy ; *Athletic Tape ; Randomized Controlled Trials as Topic ; Pain Measurement ; Treatment Outcome ; *Physical Therapy Modalities ; }, abstract = {BACKGROUND: Plantar fasciitis is a common sports injury with long-term chronic pain in the heel as the main symptom, and athletic taping has achieved certain therapeutic effects to improve it, but the clinical efficacy of the problem is still controversial, which was evaluated by Meta-analysis to evaluate the clinical efficacy of the athletic taping technique on patients with plantar fasciitis.

METHODS: The Cochrane Library, Embase, PubMed, Web of Science, CNKI, Wanfang, and Vip databases were searched by computer for randomized controlled trial on the clinical efficacy of exercise taping in patients with PF from the time of construction to 1 September 2024, and the PRISMA 2020 checklist was strictly followed. Quality was assessed using the cochrane 2.0 randomized controlled trials scale by two independent reviewers. Endings were meta-analysis using RevMan 5.4.1 analysis software to analyse the data.

RESULTS: Eleven randomized controlled trial with a total of 395 patients were included. On VAS scores, KT effectively reduced VAS pain scores (MD=-0.79,95 % CI -1.10,-0.48, P < 0.00001); on AOFAS scores, KT improved AOFAS function scores (MD=6.58, 95 % CI 5.03,8.13, P < 0.00001) and the results remained consistent across intervention durations; on plantar fascia thickness measurements, KT significantly reduced plantar fascia thickness (MD=-0.33, 95 % CI -0.56,-0.10, P = 0.005); on BBS scores, KT significantly improved BBS scores [MD= 4.75, 95 % CI (3.17, 6.32), P < 0.00001]; on FFI-FPS scores, KT effectively improved FFI-FPS scores [MD = -2.59, 95 % CI (-3.50, -1.69), P < 0.00001]; on FFI-FDS scores, there was a significant improvement on FFI-FDS scores; on FFI-ALS scores, KT had a significant improvement on the FFI-ALS score had a significant effect [MD= -11.03, 95 % CI (-14.79, -7.27), P < 0.00001]; and on VAS scores after follow-up, the pain relief effect was sustained (MD=-1.03, 95 % CI -1.21, -0.85, P < 0.00001).

CONCLUSION: Based on the available evidence, preliminary analyses suggest that KT combined with conventional rehabilitation may have some advantages in improving pain, ankle-hindfoot function, and plantar fascia thickness in patients with plantar fasciitis, and some of the efficacy is short-term sustained. However, due to the heterogeneity and sample size of the included studies, the above conclusions need to be further validated by more high-quality studies.}, } @article {pmid40473629, year = {2025}, author = {Li, Y and Fang, J and Ding, Y and Zhang, X and Liu, Y and Qiu, W and Xu, H and Kang, Y and Chen, J and Gao, Y and Zhao, YG and Yang, P and Wang, B and Tian, W and Chen, Y and Bi, W and Zhang, P}, title = {β-propeller protein-associated neurodegeneration protein WDR45 regulates stress granule disassembly via phase separation with Caprin-1.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {5227}, pmid = {40473629}, issn = {2041-1723}, support = {20240484503//Beijing Nova Program/ ; 7244365//Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)/ ; 32471202//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32270856//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; *Stress Granules/metabolism ; RNA Recognition Motif Proteins/metabolism/genetics ; *Cell Cycle Proteins/metabolism/genetics ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Carrier Proteins/metabolism/genetics ; Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Poly-ADP-Ribose Binding Proteins/metabolism/genetics ; RNA Helicases/metabolism/genetics ; Animals ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mutation ; Mice ; HEK293 Cells ; Phase Separation ; DNA Helicases ; }, abstract = {β-propeller protein-associated neurodegeneration (BPAN) is a rare X-linked neurodegenerative disorder caused by mutations in the WDR45 gene, yet its molecular mechanisms remain poorly understood. Here, we identify a role for WDR45 in stress granule (SG) disassembly, mediated through its phase separation with Caprin-1. We demonstrate that WDR45 forms gel-like condensates via its WD5 domain, which competitively displaces G3BP1 from Caprin-1 to promote SG disassembly. BPAN-associated WDR45 mutations impair condensate formation and Caprin-1 interaction, leading to delayed SG disassembly, which correlates with earlier disease onset. WDR45 depletion also exacerbates amyotrophic lateral sclerosis-associated pathological SGs, highlighting its broader relevance to neurodegenerative diseases. Using iPSC-derived midbrain neurons from a BPAN patient, we demonstrate delayed SG recovery, directly linking WDR45 dysfunction to neurodegeneration. These findings establish WDR45 as a critical regulator of SG dynamics, uncover a potential molecular basis of BPAN pathogenesis, and identify therapeutic targets for neurodegenerative diseases associated with SG dysregulation.}, } @article {pmid40474686, year = {2025}, author = {Rothstein, J and Genge, A and De Silva, S and Zinman, L and Chum, M and Chio, A and Sobue, G and Aoki, M and Yoshino, H and Doyu, M and Selness, D and Todorovic, V and Sasson, N and Hirai, M and Takahashi, F and Salah, A and Wamil, A and Apple, S}, title = {Efficacy and Safety of Once Daily Dosing vs. Approved On/Off Dosing of Edaravone Oral Suspension Up to 48 Weeks in Patients With Amyotrophic Lateral Sclerosis (Study MT-1186-A02).}, journal = {Muscle & nerve}, volume = {72}, number = {3}, pages = {433-442}, pmid = {40474686}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/administration & dosage ; Male ; Female ; Middle Aged ; Double-Blind Method ; Aged ; Administration, Oral ; Treatment Outcome ; *Free Radical Scavengers/administration & dosage/adverse effects/therapeutic use ; Adult ; Drug Administration Schedule ; Suspensions ; }, abstract = {INTRODUCTION/AIMS: An On/Off dosing regimen of intravenous (IV) edaravone and edaravone oral suspension is approved in the US for the treatment of amyotrophic lateral sclerosis (ALS). Placebo-controlled clinical trials showed IV edaravone slows the rate of physical functional decline. This study evaluated whether investigational daily dosing displayed superior efficacy vs. approved on/off dosing of edaravone oral suspension, and assessed safety and tolerability, over 48 weeks in patients with ALS.

METHODS: Study MT-1186-A02 (NCT04569084) was a multicenter, phase 3b, double-blind, parallel group, superiority study that randomized patients to edaravone oral suspension (105-mg dose) administered Once Daily or the same edaravone oral suspension dose administered according to the approved On/Off regimen including placebo to mimic daily drug dosing. Patients had definite or probable ALS, baseline forced vital capacity ≥ 70%, and baseline disease duration ≤ 2 years. The primary endpoint was a combined assessment of function and survival (CAFS) at week 48, which included change in ALS Functional Rating Scale-Revised (ALSFRS-R) and time to death.

RESULTS: CAFS at week 48 indicated Once Daily dosing did not show a statistically significant difference vs. approved on/off dosing (p = 0.777). Both dosing regimens provided comparable change from baseline ALSFRS-R total score to week 48 (least squares mean difference: 0.27 [95% CI -1.43 to 1.97]). Edaravone oral suspension was well tolerated, and no new safety concerns were identified in either group.

DISCUSSION: Daily edaravone oral suspension did not show superiority and had equivalent safety and tolerability vs. the approved On/Off regimen, reinforcing the appropriateness of the approved dosing regimen.}, } @article {pmid40475252, year = {2025}, author = {Seyedi Asl, FS and Malverdi, N and Ataei Kachouei, FS and Zarei, F and Ghiabi, S and Baziyar, P and Nabi-Afjadi, M}, title = {Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS disease.}, journal = {Frontiers in chemistry}, volume = {13}, number = {}, pages = {1569777}, pmid = {40475252}, issn = {2296-2646}, abstract = {Protein misfolding and aggregation in superoxide dismutase 1 (SOD1) are linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). SOD1 mutations have a significant role in the pathophysiology and fast behavior of protopathic proteins in ALS illness. The E100K mutation may be useful in uncovering the pathogenic mechanism of SOD1 associated with ALS. According to several studies, giving small molecule inhibitors made from polyphenolic flavonoid compounds may be a viable treatment strategy for neurological conditions. Using molecular docking and MD simulations, we have identified a potential flavonoid drug that may successfully inhibit SOD1's amyloidogenic activity. Puerarin, Fisetin, and Peonidin provided intriguing pharmacological hints during the initial screening of flavonoids. The Fisetin-E100K complex had a larger residual energy contribution and substantial binding than other flavonoid compounds. The findings showed that, unlike other materials, Fisetin increased the structural stability, hydrophobicity, and flexibility of the mutant while reducing the amount of β-sheets. Furthermore, to distinguish aggregation in the mutant (unbound/bound) states, we displayed modifications in the free energy landscape (FEL). As a result, Fisetin was identified as having therapeutic potential against the E100K, which might make it a viable pharmacological option for the creation of inhibitors that lower the chance of ALS death.}, } @article {pmid40476303, year = {2025}, author = {Mustafa, MA and Bansal, P and Pallavi, MS and Panigrahi, R and Nathiya, D and Kumar, S and Al-Hasnaawei, S and Chauhan, AS and Singla, S}, title = {Exploring the Role of NLRP3 in Neurodegeneration: Cutting-Edge Therapeutic Strategies and Inhibitors.}, journal = {Developmental neurobiology}, volume = {85}, number = {3}, pages = {e22982}, doi = {10.1002/dneu.22982}, pmid = {40476303}, issn = {1932-846X}, mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors ; Humans ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Inflammasomes/metabolism ; *Neuroprotective Agents/pharmacology ; }, abstract = {Inflammasomes, particularly the NLRP3 inflammasome, play a pivotal role in mediating neuroinflammation in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Huntington's disease (HD). Recent findings indicate that the activation of the NLRP3 inflammasome in microglia and astrocytes triggers the release of pro-inflammatory cytokines, including IL-1β and IL-18, which contribute to chronic inflammation and neuronal damage. This process accelerates neurodegeneration and exacerbates disease progression. Misfolded protein aggregates, mitochondrial dysfunction, and oxidative stress are key factors in the pathological activation of the NLRP3 inflammasome in these diseases. Recent studies have highlighted that targeting the NLRP3 inflammasome, either through direct inhibitors like MCC950 or natural compounds such as oridonin and β-hydroxybutyrate, shows promise in mitigating neuroinflammation and protecting neuronal integrity. These inhibitors have demonstrated neuroprotective effects in animal models of AD, PD, and MS, presenting a new therapeutic approach for halting disease progression. However, the complexity of NLRP3 regulation requires further investigation to balance its inflammatory and protective roles. This review examines the recent advancements in NLRP3 inflammasome research and discusses potential strategies for modulating inflammasome activity to slow or prevent the progression of neurodegenerative diseases.}, } @article {pmid40476320, year = {2025}, author = {Bombaci, A and De Marco, G and Casale, F and Salamone, P and Marchese, G and Fuda, G and Calvo, A and Chiò, A}, title = {Peripherin: A Novel Early Diagnostic and Prognostic Plasmatic Biomarker in Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {32}, number = {6}, pages = {e70241}, pmid = {40476320}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; Male ; Female ; Middle Aged ; *Peripherins/blood ; Biomarkers/blood ; Aged ; Prognosis ; Disease Progression ; Adult ; Early Diagnosis ; }, abstract = {BACKGROUND: Motor neuron diseases (MND) are heterogeneous and complex neurodegenerative disorders. Biomarkers could facilitate early diagnosis, prognosis determination, and patient stratification. Among the most studied biomarkers are neurofilaments, with peripherin (PRPH), a specific type predominantly expressed in the peripheral nervous system, gaining attention. To date, no studies have evaluated PRPH in human plasma.

METHODS: Sandwich-ELISA was used to quantify plasma peripherin from 120 MND (100 ALS, 4 PMA, 15 PLS), 73 MND-mimics, and 38 healthy-controls (HCs). Plasma was collected at diagnosis or some months earlier. 41 ALS were evaluated longitudinally. ALSFRSr, MRC, spirometry, genetic tests, disease progression rate (PR), blood examinations, and neuropsychological tests were performed. Statistical analyses included Kruskal-Wallis, Mann-Whitney, Cox regression, and Kaplan-Meier curves.

RESULTS: Plasma PRPH levels differed significantly among groups (p < 0.0001), showing higher values in MND participants than MND mimics and HCs. Moreover, PRPH levels were elevated in PLS compared with HSP patients (p = 0.0001). Differences persisted after adjusting for age and sex. ROC curve demonstrated that PRPH discriminated MND from MND mimics (AUC = 0.85). Elevated PRPH correlated positively with ALSFRSr and lower motor neuron index, whereas inversely with disease progression rate. Higher PRPH levels at the beginning of the disease were associated with longer survival.

DISCUSSION: Plasma PRPH is raised in MND, particularly ALS, from the earliest stages, distinguishing MND from mimics and correlating with clinical parameters and survival. This suggests PRPH may reflect an endogenous response of lower motor neuron to injury. Further multicenter studies are required to refine the diagnostic and prognostic utility of PRPH in MND.}, } @article {pmid40478288, year = {2025}, author = {Wilbert, D and Voigt, M and Jaeger, M}, title = {A process analyzer assembly for real-time automated near-infrared, Raman, and proton nuclear magnetic resonance spectroscopic monitoring enhanced by heterocovariance spectroscopy and chemometry applied to a Schiff base formation.}, journal = {Analytical and bioanalytical chemistry}, volume = {417}, number = {25}, pages = {5703-5713}, pmid = {40478288}, issn = {1618-2650}, abstract = {Process analytical technology (PAT) plays a key role in enhancing the efficiency and resulting quality of chemical processes. Hitherto, suitable methods enable real-time analysis and provide meaningful and robust data and models. Spectroscopic techniques, e.g., vibrational or absorption, offer in situ insight into reaction progress but may require advanced data analysis to interpret the complex spectra. In this study, inline and online monitoring by spectroscopic techniques was applied to a Schiff base formation as an illustrative example and enhanced by data analysis. Two-dimensional heterocorrelation spectroscopy was used to identify and select relevant spectral regions. The results allowed data reduction and data fusion for model building and process description. First, qualitative process representation was achieved through principal component analysis (PCA). Quantitative prediction models were then developed using multivariate curve resolution-alternating least squares (MCR-ALS) with evolving factor analysis (EFA), partial least squares (PLS), and supporting vector regression (SVR) analysis. The low- and mid-level data fusion based on the spectroscopic data and the multivariate models enabled the development of accurate predictive models, with the best prediction achieved by PLS models from low-level data fusion. The results demonstrate the strength of the combination of spectroscopy, multivariate data analysis, and-in the field of PAT rarely exploited-heterocovariance transformation and data fusion to obtain process understanding and reaction models. The methodology may provide further contributions to automatable process control in industrial applications.}, } @article {pmid40480222, year = {2025}, author = {Oldani, EG and Reynolds Caicedo, KM and Spaeth Herda, ME and Sachs, AH and Chapman, EG and Kumar, S and Linseman, DA and Horowitz, S}, title = {The effect of G-quadruplexes on TDP43 condensation, distribution, and toxicity.}, journal = {Structure (London, England : 1993)}, volume = {33}, number = {8}, pages = {1294-1303.e5}, doi = {10.1016/j.str.2025.05.006}, pmid = {40480222}, issn = {1878-4186}, mesh = {*G-Quadruplexes ; Humans ; *DNA-Binding Proteins/metabolism/chemistry/genetics ; HEK293 Cells ; Oxidative Stress ; Mice ; Animals ; Protein Aggregates ; Protein Binding ; Saccharomyces cerevisiae/metabolism ; RNA/chemistry/metabolism ; }, abstract = {Many proteins implicated in neurodegenerative diseases (e.g., trans-active response DNA binding protein 43 kDa [TDP43]) interact with nucleic acids, including RNA G-quadruplexes (G4s). We here investigate whether RNA G4s play a role in TDP43 condensation in biophysical and cellular models. We find that G4s modulate TDP43 aggregation in vitro and condensation in multiple cell types, including yeast, HEK293T, and motor-neuron-like NSC-34 cells. In yeast cells, treatment with G4s causes increased TDP43 accumulation in cells before cellular death. In HEK293T cells expressing TDP43, incubation with G4-binding small molecules causes an increase in G4 stability that also stabilizes TDP43 and reduces TDP43 condensation induced by proteasomal or oxidative stress. Finally, in NSC-34 cells overexpressing exogenous TDP43, we show that G4s co-localize with TDP43 condensates under stress conditions, and treatment with G4-binding small molecules decreases TDP43-mediated toxicity. Together, these findings suggest exploring treating protein misfolding diseases by targeting specific RNA structures such as G4s.}, } @article {pmid40480424, year = {2025}, author = {Lin, CY and Wu, HC and Fu, RH and Weng, EF and Hsieh, WC and Su, TP and Wu, HE and Wang, SM}, title = {Sigma-1R-Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS.}, journal = {Neurobiology of disease}, volume = {212}, number = {}, pages = {106992}, doi = {10.1016/j.nbd.2025.106992}, pmid = {40480424}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Receptors, sigma/metabolism/genetics ; *C9orf72 Protein/genetics/metabolism ; Sigma-1 Receptor ; Mice ; Humans ; *Active Transport, Cell Nucleus/physiology ; *Nuclear Pore Complex Proteins/metabolism/genetics ; Activating Transcription Factor 3/metabolism ; Mice, Transgenic ; Disease Models, Animal ; }, abstract = {Nucleocytoplasmic transport disruption contributes to the pathogenesis of C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Among the dipeptide repeat proteins translated from G4C2-repeat RNA, poly-PR is particularly toxic, compromising nuclear envelope integrity and transport. Here, we revealed that poly-PR reduced expression of the nucleoporin Pom121 in NSC-34 cells and in an AAV-mediated poly-PR42 mouse model, resulting in cytoplasmic mislocalization of the neuroprotective transcription factor ATF3 and nuclear envelope damage. Pom121 overexpression restored nuclear ATF3 localization and alleviated poly-PR-induced toxicity. We further identified Sigma-1 receptor (Sigma-1R) as a stabilizer of Pom121 that preserved nuclear integrity and ATF3 function under oxidative stress. Overexpression of Sigma-1R, Pom121, or ATF3 rescued poly-PR-induced cytotoxicity. Our findings defined a protective Sigma-1R/Pom121/ATF3 axis and suggested this pathway as a therapeutic target in C9orf72-linked ALS.}, } @article {pmid40480675, year = {2025}, author = {Reitzle, L and Rohmann, JL and Kurth, T and Audebert, HJ and Piccininni, M}, title = {External validation of risk prediction models for post-stroke mortality in Berlin.}, journal = {BMJ open}, volume = {15}, number = {6}, pages = {e089320}, pmid = {40480675}, issn = {2044-6055}, mesh = {Humans ; Male ; Female ; Aged ; Berlin/epidemiology ; Registries ; Risk Assessment/methods ; *Stroke/mortality ; Hospital Mortality ; Aged, 80 and over ; Middle Aged ; Risk Factors ; }, abstract = {OBJECTIVES: Prediction models for post-stroke mortality can support medical decision-making. Although numerous models have been developed, external validation studies determining the models' transportability beyond the original settings are lacking. We aimed to assess the performance of two prediction models for post-stroke mortality in Berlin, Germany.

DESIGN: We used data from the Berlin-SPecific Acute Treatment in Ischaemic or hAemorrhagic stroke with Long-term follow-up (B-SPATIAL) registry.

SETTING: Multicentre stroke registry in Berlin, Germany.

PARTICIPANTS: Adult patients admitted within 6 hours after symptom onset and with a 10th revision of the International Classification of Diseases discharge diagnosis of ischaemic stroke, haemorrhagic stroke or transient ischaemic attack at one of 15 hospitals with stroke units between 1 January 2016 and 31 January 2021.

PRIMARY OUTCOME MEASURES: We evaluated calibration (calibration-in-the-large, intercept, slope and plot) and discrimination performance (c-statistic) of Bray et al's 30-day mortality and Smith et al's in-hospital mortality prediction models. Information on mortality was supplemented by Berlin city registration office records.

RESULTS: For the validation of Bray et al's model, we included 7879 patients (mean age 75; 55.0% men). We observed 763 (9.7%) deaths within 30 days of stroke compared with 680 (8.6%) predicted. The model's c-statistic was 0.865 (95% CI: 0.851 to 0.879). For Smith et al's model, we performed the validation among 1931 patients (mean age 75; 56.2% men), observing 105 (5.4%) in-hospital deaths compared with the 92 (4.8%) predicted. The c-statistic was 0.891 (95% CI: 0.864 to 0.918). The calibration plots of both models revealed an underestimation of the mortality risk for high-risk patients.

CONCLUSIONS: Among Berlin stroke patients, both models showed good calibration performance for low and medium-risk patients and high discrimination while underestimating risk among high-risk patients. The acceptable performance of Bray et al's model in Berlin illustrates how a small number of routinely collected variables can be sufficient for valid prediction of post-stroke mortality.}, } @article {pmid40480719, year = {2025}, author = {Fuentes, CA and Montoya, D and Öztop, M and Rojas-Rioseco, M and Bravo, M and González, F and Castillo, RDP}, title = {Interval resonance analysis (InRA): A versatile tool for automated untargeted [1]H NMR fingerprinting - A case study in sugar beet field authentication.}, journal = {Analytica chimica acta}, volume = {1363}, number = {}, pages = {344175}, doi = {10.1016/j.aca.2025.344175}, pmid = {40480719}, issn = {1873-4324}, mesh = {*Beta vulgaris/chemistry ; *Proton Magnetic Resonance Spectroscopy/methods ; Least-Squares Analysis ; Software ; Automation ; Multivariate Analysis ; Algorithms ; }, abstract = {BACKGROUND: The extraction of relevant information from proton nuclear magnetic resonance ([1]H NMR) spectra through preprocessing and multivariate analysis requires integrating multiple software tools and extensive manual intervention, compromising efficiency and reproducibility when the technique is used. Consequently, the development of automated, versatile, and reliable methodologies has become imperative to streamline workflows, improve analytical performance, and broaden the applicability of multivariate methods for the analysis of diverse sample types and experimental conditions.

RESULTS: This work presents the development and application of Interval Resonance Analysis (InRA), an alternative software tool focused on [1]H NMR multivariate analysis. InRA includes a novel algorithm for resonance signal detection (intervals), specifically designed to operate with flexibility across diverse [1]H NMR spectra. All intervals are integrated using multivariate curve resolution with alternating least squares (MCR-ALS) and analyzed by exploratory analysis. The performance of InRA was tested by evaluating the [1]H NMR spectra of hydrophilic sugar beet root extracts cultivated in three different fields and their discrimination by partial least squares - discriminant analysis (PLS-DA). The workflow provided by InRA yielded consistent results regarding the distribution of samples according to their field, enabling the identification of subtle sources of variation and achieving classification accuracies ≥ 88.9 %.

SIGNIFICANCE: The proposed methodology represents an advancement in the multivariate analysis of [1]H NMR spectra for untargeted studies and enhances analytical efficiency by reducing manual intervention and reliance on analyst experience. InRA is versatile and can be applied to various sample types and analytical objectives, as it is not restricted by specific experimental conditions.}, } @article {pmid40481583, year = {2025}, author = {Johnson, B and Gibson, G and Baskerville, D and Castellano, G and de Courcy, J and Iqbal, H and Piercy, J and Williams, A and Pinedo-Villanueva, R and Rylands, A}, title = {Health-related quality of life and productivity burden for non-professional caregivers of adults with rare diseases: a real-world study.}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {282}, pmid = {40481583}, issn = {1750-1172}, mesh = {Humans ; *Quality of Life ; *Caregivers/psychology ; Male ; Female ; Middle Aged ; *Rare Diseases ; Adult ; Efficiency ; Aged ; Surveys and Questionnaires ; Cost of Illness ; }, abstract = {BACKGROUND: Rare diseases present a substantial patient burden, but the impact on non-professional caregivers is poorly understood. We explored the health-related quality of life (HRQoL) and productivity burden on caregivers of adults with rare diseases.

METHODS: We analysed physician- and caregiver-reported real-world data from France, Germany, Italy, Spain, the United Kingdom, and the United States of America collected July 2017-March 2021 via Adelphi Disease Specific Programmes™ in amyotrophic lateral sclerosis (ALS), eosinophilic esophagitis (EoE), graft versus host disease (GvHD), Huntington's disease (HD), myasthenia gravis (MG), and progressive supranuclear palsy (PSP). Non-professional caregivers completed the EQ-5D-5L and Work Productivity and Activity Impairment questionnaire. Multivariate regression analysis modelled the relationship of care recipient/caregiver characteristics with caregiver HRQoL and productivity.

RESULTS: Data were provided by 365 caregivers; 114, 89, 75, 32, 29 and 26 in GvHD, PSP, ALS, MG, EoE and HD, respectively. Care recipients' mean (standard deviation [SD]) age was 58.7 (15.6) years, 59% were male and 23% had both professional and non-professional caregivers. Patients' mean (SD) EuroQol visual analogue scale (EQ VAS) score was 50.9 (23.3) and mean EQ-5D utility was 0.460 (0.350). Caregivers' mean age was 55.8 (13.8) years, 66% were female. Caregivers' EQ-5D-5L indicated their greatest problems in anxiety/depression. Overall, 45% of caregivers were employed, mostly part-time. In the past 7 days, mean (SD) caregiver absenteeism was 5.2% (13.1%), presenteeism was 28.0% (23.7%), and activity impairment was 43.1% (27.2%). Regressions identified multiple significant associations with caregivers' HRQoL and productivity. Caregivers' HRQoL (EQ-5D utility and EQ VAS) was associated with care recipients' EQ-5D utility and caregivers' age. Outcomes relating to caregivers' employment and productivity (hours spent caring, employment status, hours in employment, hours of employment missed, absenteeism, presenteeism, work impairment and activity impairment) were most frequently associated with care recipients' EQ-5D utility, caregivers' age and sex, caregiver living with the care recipient, the presence of a professional caregiver, and the care recipient having HD.

CONCLUSIONS: The substantial burden of providing non-professional caregiving to adults with rare diseases is associated with multiple factors. Interventions improving care recipient HRQoL could enhance caregiver HRQoL and productivity.}, } @article {pmid40482451, year = {2025}, author = {Attiq, A and Afzal, S and Raman, H and Ahmad, W}, title = {Neuroinflammation to neurodegeneration: Boulevard of broken nerves.}, journal = {International immunopharmacology}, volume = {161}, number = {}, pages = {115015}, doi = {10.1016/j.intimp.2025.115015}, pmid = {40482451}, issn = {1878-1705}, mesh = {Humans ; Animals ; *Neuroinflammatory Diseases/immunology/drug therapy/therapy ; *Neurodegenerative Diseases/immunology/drug therapy/therapy ; *Anti-Inflammatory Agents/therapeutic use ; Cytokines/metabolism ; }, abstract = {Neuroinflammation is caused by various factors, such as the activation of glial cells, the excessive release of chemokines and cytokines, and the accumulation of blood cells in the brain parenchyma. The inflammatory processes occur in acute and chronic phases, with traumatic brain injuries triggering the release of neurotoxins from CNS-specific glial cells. Furthermore, activation of microglia, astrocytes, and mast cells worsens the situation by producing pro-inflammatory cytokines, chemokines and glia maturation factors. Chronic activation of astroglia and microglial cells promotes loss of neurons, memory, and impaired learning capacity, leading to neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. These implications have led to a rational search for inflammatory druggable targets. Based on various preclinical and clinical studies, NSAIDs (aspirin, ibuprofen, diclofenac, and mefenamic acid), SSRIs (fluoxetine and sertraline), antipsychotics (risperidone), corticosteroids (dexamethasone), antidiabetics (metformin and rosiglitazone), and statins (simvastatin and atorvastatin) have exhibited promising results. These drugs have anti-inflammatory and neuromodulation activities that enhance neuroplasticity and effectively manage neurodegenerative symptoms. In addition, non-pharmacological interventions such as art creation and physical exercise have been linked with improving neural development and stimulating the production of anti-inflammatory cytokines, which can attenuate disease progression and promote synaptic plasticity. Hence, it is imperative to understand the complex interplay between glial cells, inflammatory signalling and neural pathways. We reviewed the interconnected pathways between neuroinflammation and neurodegeneration. Moreover, recommendations for pharmacological and non-pharmacological interventions to address these issues are discussed herein.}, } @article {pmid40482593, year = {2025}, author = {Tankisi, H and Jacobsen, AB and Fanella, G and Cengiz, B and Kılınç, H and Matamala, JM and Moreno-Roco, J and Abrahao, A and Zinman, L and Koltzenburg, M and Howells, J and Samusyte, G and Awiszus, F and Bostock, H}, title = {Short-interval intracortical inhibition and facilitation in amyotrophic lateral sclerosis related to disease phenotype.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {176}, number = {}, pages = {2110770}, doi = {10.1016/j.clinph.2025.2110770}, pmid = {40482593}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Evoked Potentials, Motor/physiology ; Transcranial Magnetic Stimulation/methods ; *Neural Inhibition/physiology ; Aged ; *Motor Cortex/physiopathology ; *Phenotype ; Adult ; Electromyography ; }, abstract = {OBJECTIVE: To investigate the relationship between short-interval intracortical inhibition (SICI), short-interval intracortical facilitation (SICF) and amyotrophic lateral sclerosis (ALS) phenotype, using threshold-tracking transcranial magnetic stimulation (TMS).

METHODS: A new paired-pulse TMS protocol was applied to 49 patients with ALS and 49 age-matched healthy controls. Motor evoked potentials (MEPs) were recorded from first dorsal interosseus muscle, while paired pulses were delivered at interstimulus intervals (ISI) of 1.0, 2.5 or 3.0 ms, with stimuli related to the resting motor threshold for a 200 µV MEP. For each ISI, 6 SICI and 3 SICF pulse pairs with different conditioning stimuli were randomised and interleaved with test-alone stimuli.

RESULTS: ALS phenotypes were characterised as Pyramidal (n = 12, with prominent upper motor neuron signs), Classic (n = 20, with limb onset), or Bulbar (n = 17). Compared with healthy controls, Bulbar patients had significantly less inhibition at all ISIs, while SICI in Pyramidal patients was normal, and in Classic patients intermediate. The only SICF abnormalities independent of the changes in SICI were less facilitation in Pyramidal patients at ISIs 1 and 3 ms.

CONCLUSION: Changes in SICI and SICF depend on ALS phenotype.

SIGNIFICANCE: ALS phenotypes should be matched between treatment and placebo arms of clinical trials.}, } @article {pmid40482730, year = {2025}, author = {Mori, H and Sato, T and Tsuboguchi, S and Takahashi, M and Nakamura, Y and Hoshina, K and Kato, T and Fujii, M and Onodera, O and Ueno, M}, title = {TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model.}, journal = {Neurobiology of disease}, volume = {212}, number = {}, pages = {106988}, doi = {10.1016/j.nbd.2025.106988}, pmid = {40482730}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism/toxicity ; Disease Progression ; Mice ; Disease Models, Animal ; *Axonal Transport/physiology ; Mutation/genetics ; *Frontotemporal Lobar Degeneration/pathology/metabolism/genetics ; Mice, Transgenic ; Neurons/metabolism/pathology ; Cells, Cultured ; Protein Aggregation, Pathological/metabolism/genetics/pathology ; Humans ; Mice, Inbred C57BL ; }, abstract = {TDP-43 accumulates and forms inclusions in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) and is assumed to cause neurodegenerative processes. The morphologies and cellular and areal distributions of accumulated TDP-43 inclusions are pathologically diverse among ALS/FTLD patients; however, whether and how different types of TDP-43 affect the process and severity of disease progression are not fully understood. Here, we compared the pathological events evoked by TDP-43 mutations, which have different aggregation properties, in cultured neurons and the cerebral cortex in mice. We selected TDP-43[C173/175S] and TDP-43[G298S] as aggregation-prone and nonprone mutants, respectively. Cytoplasmically expressed TDP-43[C173/175S] induced insoluble inclusions more robustly than TDP-43[G298S] did. In contrast, TDP-43[G298S] induced cell death more severely than TDP-43[C173/175S]. TDP-43[G298S] was further found to be efficiently transported in axons and led to axon degeneration, while this effect was not obvious in TDP-43[C173/175S]. Instead, TDP-43[C173/175S] was frequently trapped in the axon initial segments. Finally, TDP-43[G298S] was secreted in exosomes and transferred to oligodendrocyte-lineage cells in vitro more efficiently than TDP-43[C173/175S] to induce cell death. The transfer further evoked cytokine responses in microglial cells. These data revealed that different aggregation properties of TDP-43 cause distinct pathological events. These findings may explain the differences in the neurodegenerative progression and distribution observed among patients with ALS and FTLD.}, } @article {pmid40482733, year = {2025}, author = {Ting, CH and Tai, ST and Chang, HY and Huang, PY and Cheng, LF and Lai, HJ and Kuo, YC and Kao, CH and Wang, IF and Tsai, LK}, title = {Baicalein benefits amyotrophic lateral sclerosis via reduction of Intraneuronal misfolded protein.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1869}, number = {8}, pages = {130831}, doi = {10.1016/j.bbagen.2025.130831}, pmid = {40482733}, issn = {1872-8006}, mesh = {*Flavanones/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; *Superoxide Dismutase-1/metabolism/genetics ; Mice ; Protein Folding/drug effects ; *Motor Neurons/drug effects/metabolism/pathology ; Humans ; Mice, Transgenic ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by muscle weakness and atrophy, with limited treatment options. The accumulation of misfolded proteins, such as misfolded superoxide dismutase 1 (mSOD1), contributes significantly to neuronal degeneration in ALS. Therapies targeting misfolded proteins represent a promising strategy. Baicalein, a flavonoid compound with neuroprotective properties, has shown efficacy in clearing misfolded proteins and improving behaviors in rodent models of Alzheimer's and Parkinson's diseases. However, its effects in ALS remain largely unexplored. This study demonstrated that baicalein treatment reduced total and misfolded SOD1 protein levels in both soluble and insoluble fractions of a motor neuron cell line overexpressing mutant SOD1. Baicalein also reduced intracellular SOD1 aggregates in cultured motor neurons transfected with SOD1/G93A, preserving neurite length. In an ALS mouse model expressing the SOD1/G93A transgene, baicalein treatment decreased mSOD1 aggregation, increased spinal motor neuron density, and reduced neuromuscular junction denervation. Furthermore, baicalein partially improved motor behaviors, as assessed by the rotarod test. These findings highlight baicalein's potential as a therapeutic agent for ALS, targeting intraneuronal misfolded proteins to ameliorate pathological changes and preserve motor function.}, } @article {pmid40482900, year = {2025}, author = {La Cognata, V and Guarnaccia, M and Morello, G and Gentile, G and Cavallaro, S}, title = {Predicting amyotrophic lateral sclerosis in the pre-symptomatic phase: Insights from SOD1G93A mouse gene expression profiles.}, journal = {Experimental neurology}, volume = {392}, number = {}, pages = {115329}, doi = {10.1016/j.expneurol.2025.115329}, pmid = {40482900}, issn = {1090-2430}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/metabolism ; Mice, Transgenic ; Mice ; *Superoxide Dismutase-1/genetics ; Gene Expression Profiling/methods ; *Transcriptome/genetics ; Disease Models, Animal ; Spinal Cord/metabolism ; Superoxide Dismutase/genetics ; Humans ; Disease Progression ; Male ; Motor Neurons/metabolism ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fast-paced fatal disease that requires immediate intervention to slow down the course of pathology and improve patients' quality of life. However, in most cases, ALS is diagnosed too late. For this reason, an accurate diagnostic test is urgently needed to identify ALS patients early, enabling a timely introduction of novel therapeutics and effective monitoring of disease progression. To address this significant unmet medical need, we explored a transcriptome-based signature to predict ALS during the preclinical phase. Using publicly available gene expression profiles from central nervous system (lumbar isolated motor neurons and spinal cord homogenates) of transgenic SOD1G93A mice with different genetic background and their respective control littermates, covering pre-symptomatic to late stages of the disease, we identified 463 differentially expressed genes (DEGs), primarily involved in immune response and metabolic processes. Based on this ALS gene-associated signature, we tested three machine learning binary classifiers (Support Vector Machine, Neural Network and Linear Discriminant Analysis), which demonstrated highly significant predictive power in discriminating mutant SOD1G93A from controls mice, even at pre-symptomatic stages. This was evident in both the discovery cohort and in two additional peripheral cross-tissue validation datasets from preclinical SOD1G93A sciatic nerve and muscles. Our study provides the first proof of concept for early ALS detection using a machine learning-based transcriptomic classifier. This could lead to earlier diagnosis, potentially enabling effective monitoring of disease progression and earlier interventions.}, } @article {pmid40482989, year = {2025}, author = {Qin, J and He, Y and Yu, W and Zhang, Z and Chen, X and Hu, Y and Jiang, H}, title = {Knockdown of OPTN modulates miRNA-125b-5p expression via NF-κB pathways in amyotrophic lateral sclerosis.}, journal = {Archives of biochemistry and biophysics}, volume = {771}, number = {}, pages = {110499}, doi = {10.1016/j.abb.2025.110499}, pmid = {40482989}, issn = {1096-0384}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *MicroRNAs/genetics/metabolism ; Mice ; Membrane Transport Proteins ; Cell Cycle Proteins ; Microglia/metabolism/pathology ; Exosomes/metabolism ; *NF-kappa B/metabolism ; Signal Transduction ; *Transcription Factor TFIIIA/genetics/metabolism ; Apoptosis ; Cell Line ; Gene Knockdown Techniques ; Gene Expression Regulation ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease characterized by severe dysfunction in upper and lower motor neurons. Previous studies have reported that the optineurin gene (OPTN) downregulation is one of the causative genetic factors for ALS, leading to the dysfunction of optineurin (OPTN), a multifunctional protein implicated in several cellular processes. Herein, we found that conditional knockout of the Optn gene in mouse microglia leads to activation of microglia. In subsequent studies, we also found that OPTN knockdown in BV2 cells leads to the activation of BV2 cells and promotes the apoptosis of co-cultured NSC34 cells via exosomes derived from BV2 cells in vitro. In contrast, OPTN knockdown in NSC34 cells did not cause apoptosis of the NSC34 cells themselves. It was suggested that microglia activation is involved in ALS initiation and development, but the nature of microglial-neuronal interactions remained elusive, requiring further exploration. Exosomes have been proven to be essential mediators. Notably, increased miRNA-125b-5p expression was uncovered in BV2 cells with the OPTN gene silenced, their derived exosomes, as well as the cocultured NSC34 cells. Interestingly, we proved that increased miRNA-125b-5p enhanced the apoptosis of NSC34 cells. We further noted that the overexpression of miRNA-125b-5p in BV2 cells can be regulated by an NF-κB activator (LPS) or inhibitor (withaferin A). Altogether, this study showed that silencing the OPTN gene may overexpress miRNA-125b-5p levels via the classical NF-κB pathway in BV2 cells. Up-regulated miRNA-125b-5p might be transmitted from exosomes to NSC34 cells, resulting in NSC34 cells apoptosis. Microglial-neuronal interactions mediated by exosomes were the crucial mechanism of OPTN gene downregulation leading to ALS, and this conclusion had been verified in cell models.}, } @article {pmid40484835, year = {2025}, author = {Zhao, JR and Pang, XY and Bai, JM and Zhang, JH and Wang, HF and Li, M and Chen, ZH and Cheng, HM and Ling, L and Huang, XS}, title = {[Progression patterns of lower motor neuron involvement in the lower medulla oblongata and cervical spinal cord of amyotrophic lateral sclerosis patients].}, journal = {Zhonghua yi xue za zhi}, volume = {105}, number = {21}, pages = {1721-1727}, doi = {10.3760/cma.j.cn112137-20241229-02957}, pmid = {40484835}, issn = {0376-2491}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology ; *Medulla Oblongata/pathology ; Male ; Female ; *Cervical Cord/pathology ; Electromyography ; *Motor Neurons/pathology ; Middle Aged ; Disease Progression ; Adult ; Aged ; *Spinal Cord/pathology ; }, abstract = {Objective: To investigate the lower motor neuron (LMN) involvement patterns in the lower medulla oblongata and cervical spinal cord in amyotrophic lateral sclerosis (ALS) patients. Methods: The needle electromyography (EMG) data of 200 patients with non-thoracic onset sporadic ALS, hospitalized in the Neurology Department of the First Medical Center of the Chinese PLA General Hospital from September 2022 to December 2023, were retropectively analyzed. All participants met the EI Escorial-Revised diagnostic criteria. According to the onset site, the patients were divided into the lower medulla oblongata onset group(34 cases), the spinal cord onset group(166 cases) [including the lower cervical spinal cord onset group (92 cases) and the lumbosacral spinal cord onset group (74 cases)]. Electromyography (EMG) abnormalities in the muscles innervated by the lower medulla oblongata and cervical cord were counted, and the characteristics of LMN involvement were analyzed. The binomial distribution test was used to determine whether the progression of LMN involvement to the second central nervous system segment was random. Results: Among 200 ALS patients, there were 111 males (55.5%) and 89 females (44.5%), with an age onset of 28-86 (56±11) years. 20 (10.0%) cases with normal sternocleidomastoid (SCM)-EMG or trapezius (TRA)-EMG results, and 7 (3.5%) cases with normal SCM-EMG and TRA-EMG results were observed in patients with LMN involvement in both the lower medulla oblongata and lower cervical spinal cord. The abnormal rates of EMG at the onset of lower cervical spinal cord were tongue muscle (GEN)-EMG (88.2%, 30/34), TRA-EMG (70.6%, 24/34) and SCM-EMG (67.6%, 23/34), respectively. The abnormal rates of EMG at the onset of lower cervical spinal cord were TRA-EMG (72.8%, 67/92), SCM-EMG (38.0%, 35/92) and GEN-EMG (32.6%, 30/92), respectively. The binomial distribution test showed that the progression of LMN involvement to the second segment of the central nervous system was not random (all P<0.05). In low bulbar onset patients, the abnormal rate of LMN involvement was higher in the lower cervical spinal cord segment [100.0% (34/34)], and lower in the lumbosacral spinal cord segment[91.2% (31/34)]. In the lower cervical spinal cord onset group, the abnormal rate of LMN involvement was lower in the the low medulla obliterum[32.6% (30/92)] and high in the lumbosacral spinal cord [96.7% (89/92)].In the lumbosacral spinal cord onset group, the abnormal rate of LMN involvement was low in the low medulla oblata [27.0% (20/74)] and high in the lower cervical spinal cord [94.6% (70/74)]. Conclusions: The progression of LMN involvement in the lower medulla oblongata and cervical spinal cord is primarily continuous, while a discontinuous progression pattern was also observed. The lower medulla oblongata of ALS patients with spinal onset is relatively less involved in disease progression.}, } @article {pmid40485494, year = {2025}, author = {Genge, A and Pattee, GL and Sobue, G and Aoki, M and Yoshino, H and Couratier, P and Lunetta, C and Petri, S and Selness, D and Todorovic, V and Sasson, N and Hirai, M and Takahashi, F and Salah, A and Apple, S and Wamil, A and Kalin, A and Jackson, CE}, title = {Safety Extension Study of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis for up to an Additional 96 Weeks of Treatment.}, journal = {Muscle & nerve}, volume = {72}, number = {3}, pages = {450-454}, pmid = {40485494}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America Inc/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/administration & dosage/adverse effects/therapeutic use ; Male ; Female ; Middle Aged ; Aged ; Administration, Oral ; *Free Radical Scavengers/administration & dosage/adverse effects/therapeutic use ; Adult ; Suspensions ; Treatment Outcome ; }, abstract = {INTRODUCTION/AIMS: Edaravone intravenous (IV) and oral suspension have been shown to have similar pharmacokinetics, safety, and slowing of functional decline in patients with amyotrophic lateral sclerosis (ALS). Study MT-1186-A01 indicated that edaravone oral suspension was well-tolerated over 48 weeks, with no new safety concerns identified relative to existing safety data of IV edaravone, including Study MCI186-19. The aim of this study was to assess the long-term safety and tolerability of edaravone oral suspension in patients with ALS.

METHODS: Study MT-1186-A03 (NCT04577404) was a phase 3, open-label, multi-center, extension study that evaluated the long-term safety of edaravone oral suspension over an additional 96 weeks in patients with ALS who have completed the initial 48 weeks of Study MT-1186-A01, for a total of up to 144 weeks of treatment. Patients received a 105-mg dose of edaravone administered in treatment cycles identical to the approved edaravone on/off dosing schedule. Patients had definite, probable, probable-laboratory-supported, or possible ALS.

RESULTS: In Study MT-1186-A03, edaravone oral suspension was well tolerated with no new safety concerns. The most common treatment-emergent adverse events (TEAEs) were fall, muscular weakness, dyspnea, constipation, and dysphagia. These TEAEs were consistent with the safety profile for edaravone from previous clinical trials.

DISCUSSION: These results help establish the long-term safety and tolerability profile of edaravone oral suspension.}, } @article {pmid40485533, year = {2025}, author = {Alves, I and Gromicho, M and Pronto-Laborinho, AC and Lopes, D and Oliveira Santos, M and De Carvalho, M}, title = {Federated sport activity in amyotrophic lateral sclerosis: a case-control study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {767-774}, doi = {10.1080/21678421.2025.2511124}, pmid = {40485533}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/physiopathology ; Male ; Case-Control Studies ; Female ; Middle Aged ; *Sports ; Aged ; Adult ; Risk Factors ; Surveys and Questionnaires ; }, abstract = {Amyotrophic lateral sclerosis (ALS) develops in a multistep process combining environmental variables and genes. Among the identified risk factors, the role of regular vigorous physical activity is still debatable. Objective: This case-control study investigated the relationship between ALS and different degrees of sports engagement, with federated status as a proxy for strenuous activity. Methods: 586 ALS patients and 558 controls were consecutively assessed by using a standard questionnaire. Due to low female participation in regular or intensive sports activity, the study focused on men (327 with ALS and 314 controls). Results: Overall, football (soccer) had the most practitioners (n = 137, 35.8%), accounting for 62.1% of ALS and 32.3% of control federated athletes. Male football players have a 3.07-fold increased ALS risk (95% CI: 1.82-5.19) compared to other men (p < 0.0001) and 3.43-fold increase (95% CI: 1.77-6.68) compared to those federated in other sports (p = 0.0003). After controlling for age and trauma, football players still had 2.91-fold (95% CI: 1.70-5.01) increased risk compared to non-federated and non-participants in contact sports intensively. No significant ALS risk difference existed for other sports practiced with identical intensity and contact levels. Clinical characteristics of ALS federated football players were similar to other ALS patients. Conclusion: Our results suggest ALS susceptibility is not linked to general physical activity, but specifically to competitive football, regardless of a history of head and neck trauma. Given football's popularity, even a small risk increase could impact many. Further research is required to understand the mechanisms linking football to ALS, and why this association is not observed in other sports.}, } @article {pmid40485888, year = {2025}, author = {Liu, Y and Ren, Y and Song, P}, title = {Traditional Chinese medicine for intractable and rare diseases: Research progress and future strategies.}, journal = {Intractable & rare diseases research}, volume = {14}, number = {2}, pages = {109-121}, pmid = {40485888}, issn = {2186-3644}, abstract = {Rare diseases have become a global public health challenge due to their low prevalence, difficult diagnosis, and limited treatment options. Intractable diseases are more common but often involve complex mechanisms, treatment with limited efficacy, and high medical costs, placing a heavy burden on patients and healthcare systems. In recent years, traditional Chinese medicine (TCM) has demonstrated unique advantages in the treatment of intractable and rare diseases and has gradually become an important complementary treatment. The current work is a systematic review of the progress of clinical and experimental research on TCM in typical rare diseases such as amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus (SLE), mitochondrial encephalomyopathy, aplastic anemia (AA), and Wilson's disease (WD). It focuses on the multi-target therapeutic mechanisms of key Chinese herbal compound formulas, including immune regulation, antioxidative stress, and neuroprotection. The core TCM theories of "syndrome differentiation", "different treatments for the same disease" and the "same treatment for different diseases" are also discussed in the context of personalized medicine. In recent years, China has continuously promoted the development of TCM through a series of national plans and supportive policies, such as the 14th Five-Year Plan for TCM development, funding for key special projects, expedited approval pathways, and expanded coverage by medical insurance. These efforts have provided strong support for the clinical translation of TCM and technological innovation in the field of intractable and rare diseases. Notwithstanding the encouraging advances, the field of Chinese medicine continues to grapple with numerous challenges. In the future, the enhancement of mechanistic studies and quality multicenter clinical trials needs to be promoted while further enhancing policy support and international collaboration to substantiate the scientific basis and clinical value of TCM in the prevention and treatment of intractable and rare diseases.}, } @article {pmid40486953, year = {2025}, author = {Lehrer, S and Rheinstein, PH}, title = {Insulin and Metformin are Associated With Reduced Risk of Amyotrophic Lateral Sclerosis.}, journal = {Chronic diseases and translational medicine}, volume = {11}, number = {2}, pages = {148-155}, pmid = {40486953}, issn = {2589-0514}, abstract = {BACKGROUND: Type 2 diabetes (T2D), but not type 1, protected against amyotrophic lateral sclerosis (ALS). In T2D serum insulin is normal or elevated in the early stages. Type 1 diabetes, characterized by a total lack of insulin, is associated with an increased risk of ALS. The antidiabetic metformin also protects against ALS. Connexin 43 (Cx43), an astrocyte protein, operates as an open channel via which toxic substances from astrocytes reach motor neurons to cause ALS.

METHODS: In the current study we analyzed FDA MedWatch data to determine whether insulin or metformin could reduce the risk of ALS. We performed in silico molecular docking studies and molecular dynamics simulation with Cx43 to determine if insulin or metformin dock within the Cx43 channel and can block it effectively, again reducing risk of ALS.

RESULTS: In MedWatch, Insulin use is associated with a significantly reduced risk of ALS (Proportional Reporting Ratio 0.401). Metformin use is associated with a significantly reduced risk of ALS (PRR 0.567). The Human insulin heterodimer docked within center of the Cx43 channel, effectively blocking it. Molecular dynamics simulation showed that the block is highly stable and may be responsible for the protective effect of T2D on ALS. Metformin docks within the Cx43 channel, but the relatively small size of the metformin molecule may not allow it to obstruct the passage of toxic substances from astrocytes to motor neurons.

CONCLUSION: MedWatch data indicate that both insulin and metformin reduce risk of ALS. The results of our in silico docking study and molecular dynamics simulation corroborate our previous findings with Cx31. Insulin docks within the open hemichannel of hexameric Cx43, potentially blocking it. Molecular dynamics simulation showed that the block is stable and may be responsible for the protective effect of T2D and insulin on ALS.}, } @article {pmid40487949, year = {2025}, author = {Kumar, S}, title = {Nomogram-based strategy to predict relapse-free survival in patients with gastrointestinal stromal tumor using inflammatory indicators.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {5}, pages = {103127}, pmid = {40487949}, issn = {1948-5204}, abstract = {Zhao et al's investigation on the assessment of inflammatory markers prognostic value for relapse-free survival in patients with gastrointestinal stromal tumor (GIST) using a nomogram-based approach is a scientific approach. This study explored the potential of an inflammatory marker-based nomograph model, highlighting the relapse-free survival-associated risk factors prognostic potential in patients with GIST. The author assessed 124 samples from patients with GIST to find an association between inflammatory markers and tumor size in a retrospective study using multivariate regression analysis. Further, a nomogram model was developed to identify the independent risk factors for the prognosis. GIST clinical treatment can use preoperative monocyte/lymphocyte ratio and platelet/lymphocyte ratio for relapse-free survival prognosis as independent factors.}, } @article {pmid40488178, year = {2025}, author = {Benetton, C and Preuilh, A and Khamaysa, M and Chaumon, M and Lackmy-Vallée, A and Er, A and Pélégrini-Issac, M and Querin, G and Rouaux, C and Pradat, PF and Marchand-Pauvert, V}, title = {Encephalography cross-frequency coupling and brain alteration in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {3}, pages = {fcaf192}, pmid = {40488178}, issn = {2632-1297}, abstract = {The diagnosis of amyotrophic lateral sclerosis requires identifying degeneration in both brain and bulbospinal motor neurons. However, detecting cortical dysfunction remains challenging, as peripheral symptoms often overshadow upper motor neuron signs. Although transcranial magnetic stimulation and MRI are valuable tools, transcranial magnetic stimulation is challenged as disease progresses but also at early stage in some patients, and brain MRI shows in most cohorts no significant change at the time of diagnosis. This emphasizes the need for neuromarkers facilitating detection of cortical dysfunction and longitudinal monitoring. EEG offers promising avenues. Accordingly, we recently identified altered theta-gamma phase-amplitude coupling in amyotrophic lateral sclerosis. The present study aimed to further explore phase-amplitude coupling in patients, focusing not only on theta and gamma bands but also on alpha and beta bands, and the link with handedness and brain structure. Resting-state EEG was recorded in 26 patients with amyotrophic lateral sclerosis and 26 age- and sex-matched controls, alongside anatomical and diffusion MRI. PAC was calculated between slow and gamma oscillations at five sensorimotor electrodes bilaterally. Grey and white matter integrity was evaluated through cortical thickness measurements and diffusion metrics along the corticospinal tract. Results revealed significantly decreased theta-gamma PAC in the dominant hemisphere of patients, without changes in band powers or other frequency couplings. MRI confirmed well-known handedness-related brain structural asymmetry in both groups, although it was less pronounced in patients. Specifically, diffusion metrics were altered in the most caudal segment (brainstem level) of the pyramidal tract within the dominant hemisphere in patients. These findings align with lateralized theta-gamma PAC alterations and the greater vulnerability of the dominant hemisphere to amyotrophic lateral sclerosis. No correlation was found between electrophysiological and diffusion metrics, likely because they are related to different mechanisms: PAC alteration being presumably linked to excitation/inhibition imbalance preceding upper motor neuron degeneration. Moreover, theta-gamma PAC was found to be particularly altered in patients with altered cognitive scores, consistent with previous findings in patients with mild cognitive impairment. Lastly, receiver operating characteristic analyses demonstrated that PAC outperformed diffusion MRI in diagnostic accuracy, underscoring its potential as a very sensitive marker of cortical dysfunction in amyotrophic lateral sclerosis. Although these results need validation in a larger cohort at different stages of the disease and across different forms (sporadic and familial), they confirm that PAC can detect cortical dysfunctions in amyotrophic lateral sclerosis.}, } @article {pmid40488385, year = {2025}, author = {Hermann, A and Prudlo, J and Kasper, E and Synofzik, M and Peters, O and Priller, J and Dinter, E and Wiltfang, J and Zerr, I and Flöel, A and Bürger, K and Höglinger, GU and Levin, J and Düzel, E and Teipel, S and Beichert, L and Brosseron, F and Wagner, M and Frommann, I and Ramirez, A and Yakupov, R and Schmid, M and Lingor, P and Haass, C and , and Spottke, A and Günther, R and Weydt, P and Neumann, M and Schneider, A}, title = {"The DESCRIBE-ALS-FTD study: a prospective multicenter observational study of the ALS-FTD spectrum".}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {720-728}, doi = {10.1080/21678421.2025.2509617}, pmid = {40488385}, issn = {2167-9223}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/physiopathology ; Cross-Sectional Studies ; Disease Progression ; *Frontotemporal Dementia/diagnosis/genetics/physiopathology ; Prospective Studies ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit significant clinical, genetic and neuropathological abnormalities, and are regarded as belonging to a common disease spectrum, referred to as the ALS-FTD spectrum disorders. Our understanding of the underlying mechanisms of these diseases has advanced significantly, including molecular neuropathology, genetics and molecular pathophysiology. The heterogeneity of these diseases poses significant challenges to translational research and drug development, particularly in sporadic cases. Consequently, there is an urgent need to improve patient stratification for the successful execution of future clinical trials. Methods/Results: We here describe the study design of the DESCRIBE-ALS/FTD study which aims to address this research gap by undertaking a systematic sampling of patients from the ALS FTD spectrum, encompassing all possible disease variants. The main objective of the study is to systematically document detailed cross-sectional phenotyping and the temporal progression of motor and neuropsychological abnormalities that occur in both ALS and FTD. Additionally, it seeks to systematically correlate these abnormalities with genetics and potentially predictive biomarkers including longitudinal biomaterial sampling, brain imaging and brain banking. Furthermore, first-degree relatives of patients with disease-causing gene variants undergo the same assessments to also sample presymptomatic risk gene carriers. Conclusion: With this prospective registry study we aim to generate datasets which will help researchers identifying different disease traits in people with sporadic and genetic ALS and FTD and to develop biomarkers to identify preclinical and prodromal disease stages.}, } @article {pmid40488544, year = {2025}, author = {Benzo-Iglesias, MJ and Rocamora-Pérez, P and Valverde-Martínez, MLÁ and García-Luengo, AV and Benzo-Iglesias, PM and López-Liria, R}, title = {Efficacy of respiratory muscle training in improving pulmonary function and survival in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Therapeutic advances in respiratory disease}, volume = {19}, number = {}, pages = {17534666251346095}, pmid = {40488544}, issn = {1753-4666}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/therapy/diagnosis ; *Respiratory Muscles/physiopathology ; *Breathing Exercises/adverse effects/methods ; Randomized Controlled Trials as Topic ; Quality of Life ; Muscle Strength ; *Lung/physiopathology ; Treatment Outcome ; Recovery of Function ; Male ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, resulting in muscle weakness, loss of function, and ultimately death due to respiratory failure. Due to the lethal prognosis of ALS, respiratory muscle training has been proposed as a potentially beneficial intervention.

OBJECTIVES: To systematically review the efficacy of respiratory muscle training on lung function and respiratory muscle strength in ALS patients.

DESIGN: A systematic review and meta-analysis of randomized controlled trials.

DATA SOURCES AND METHODS: Articles published in PubMed, PEDro, Scopus, and Web of Science databases up to July 2024. The Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement guideline was followed. Included studies had (1) ALS patients, (2) respiratory muscle training, (3) physical exercise, usual care or no intervention were provided as a comparison group, (4) assessments of lung function, respiratory muscle strength, quality of life, survival, fatigue, and functional capacity outcome measures, and (5) a randomized controlled trial design. Methodological quality was analyzed using the PEDro scale, and risk of bias with the Cochrane Collaboration Risk of Bias Tool. Meta-analyses were performed with Review Manager software.

RESULTS: Five randomized controlled trials with 170 participants were included. The results showed that respiratory muscle training improved muscle strength, particularly maximum expiratory and inspiratory pressures. One study suggested inspiratory muscle training as a survival predictor in ALS patients. No significant effects were observed in forced vital capacity or quality of life. No adverse effects were reported.

CONCLUSION: Respiratory muscle training improves ventilatory function, particularly respiratory muscle strength, in people with ALS. While evidence is limited, it shows promise as an adjuvant therapy to enhance quality of life and survival. It has been registered in the PROSPERO (CRD42024568235).}, } @article {pmid40488711, year = {2025}, author = {Tang, IW and Knekt, P and Rantakokko, P and Heliövaara, M and Rissanen, H and Ruokojärvi, P and Mukherjee, R and Weisskopf, MG}, title = {Pre-disease biomarkers of persistent organic pollutants (POPs) and amyotrophic lateral sclerosis (ALS) risk in Finland.}, journal = {Environmental health perspectives}, volume = {}, number = {}, pages = {}, doi = {10.1289/EHP16539}, pmid = {40488711}, issn = {1552-9924}, support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND: Persistent organic pollutants (POPs) are toxic chemicals that bioaccumulate and were used in pesticides and industrial products/processes. POP-exposed occupations and environmental exposure to POPs have been associated with amyotrophic lateral sclerosis (ALS), but no study has evaluated the association with ALS when measuring POPs in samples collected before ALS onset.

OBJECTIVES: This study examined the relationship between pre-disease POP exposure and ALS risk.

METHODS: We conducted a nested case-control study pooling three Finnish cohorts (n=56,862). During a median follow-up of 27 years, 97 incident ALS cases were identified (mean age at ALS=68). Within each cohort, two controls per case were selected by individual matching for age, sex, municipality, and serum freeze-thaw cycles. Thirteen polychlorinated biphenyls (PCB) and nine organochlorine pesticides (OCP) were determined in serum samples collected at baseline and stored at -20C. We considered these POPs both in groups (similar congener, isomer, metabolite groups) and separately. Odds ratios and 95% confidence intervals were estimated using a conditional logistic model in a two-stage approach, further adjusting for smoking, occupation, marital status, BMI, and serum cholesterol level in primary models.

RESULTS: In the main model hexachlorobenzene (HCB) showed a positive association with ALS occurrence. In contrast, Σnon-dioxin-like (NDL) PCB and ΣDDT were significantly inversely associated with ALS incidence. Most other POP groups were non-significantly inversely associated with ALS risk. In co-pollutant models, the only notable changes were that Σdioxin-like PCB and ΣHCH showed large non-significant, elevated, ORs, suggesting some negative co-pollutant confounding. There were some suggestions of stronger findings when limiting to some subgroups.

DISCUSSION: We found little evidence that POPs were associated with ALS, but we identified a suggestive positive association with HCB and HCH. ΣNDL PCB and ΣDDT were inversely associated with ALS. This could suggest protective mechanisms or uncontrolled confounding by neuroprotective factors (e.g. fish oils). https://doi.org/10.1289/EHP16539.}, } @article {pmid40488810, year = {2025}, author = {Kulkarni, SR and Thokchom, B and Abbigeri, MB and Bhavi, SM and Singh, SR and Metri, N and Yarajarla, RB}, title = {The role of L-DOPA in neurological and neurodegenerative complications: a review.}, journal = {Molecular and cellular biochemistry}, volume = {480}, number = {10}, pages = {5221-5242}, pmid = {40488810}, issn = {1573-4919}, mesh = {Humans ; *Levodopa/therapeutic use/pharmacokinetics/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Animals ; Blood-Brain Barrier/metabolism ; *Parkinson Disease/drug therapy/metabolism ; }, abstract = {L-DOPA remains a cornerstone treatment for Parkinson's disease and is increasingly recognized for its role in various neurological and neurodegenerative disorders. As a direct precursor to dopamine, L-DOPA is synthesized from L-tyrosine through the action of tyrosine hydroxylase and is subsequently converted into dopamine via aromatic L-amino acid decarboxylase. Its ability to cross the blood-brain barrier (BBB) makes it a crucial therapeutic agent for restoring dopaminergic neurotransmission, thereby influencing motor function, cognition, and neuroprotection. Beyond Parkinson's, L-DOPA's therapeutic potential extends to neurodegenerative conditions such as Alzheimer's disease, Huntington's disease, multiple sclerosis, Lewy body dementia, and amyotrophic lateral sclerosis, where dopamine modulation plays a critical role. Furthermore, L-DOPA has demonstrated efficacy in neurological disorders including epilepsy, peripheral neuropathy, cerebrovascular diseases, and traumatic brain injury, suggesting broader neurobiological applications. However, long-term use is associated with challenges such as motor fluctuations, dyskinesias, and loss of therapeutic efficacy due to progressive neurodegeneration and alterations in dopaminergic pathways. Recent advancements in drug delivery systems, combination therapies, and nanotechnology, including plant-derived carbon dots, offer promising strategies to enhance L-DOPA's effectiveness while mitigating its limitations. This comprehensive review explores L-DOPA's synthesis, pharmacokinetics, mechanism of action, and its evolving role in neurological diseases, while highlighting ongoing challenges and future directions for optimizing its clinical application.}, } @article {pmid40489211, year = {2025}, author = {Gautam, P and Yadav, R and Vishwakarma, RK and Shekhar, S and Pathak, A and Singh, C}, title = {An Integrative Analysis of Metagenomic and Metabolomic Profiling Reveals Gut Microbiome Dysbiosis and Metabolic Alterations in ALS: Potential Biomarkers and Therapeutic Insights.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {14}, pages = {2691-2706}, doi = {10.1021/acschemneuro.5c00254}, pmid = {40489211}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/microbiology ; Humans ; *Gastrointestinal Microbiome/physiology ; *Dysbiosis/metabolism/microbiology ; Male ; *Metabolomics/methods ; Female ; Middle Aged ; Biomarkers/metabolism ; Aged ; Metagenomics/methods ; Feces/microbiology ; }, abstract = {ALS is a severe neurodegenerative disorder characterized by motor neuron degeneration, gut dysbiosis, immune dysregulation, and metabolic disturbances. In this study, shotgun metagenomics and [1]H nuclear magnetic resonance (NMR)-based metabolomics were employed to investigate the altered gut microbiome and metabolite profiles in individuals with ALS, household controls (HCs), and nonhousehold controls (NHCs). The principal component analysis (PCA) explained 33% of the variance, and the partial least-squares discriminant analysis (PLS-DA) model demonstrate R[2] and Q[2] values of 0.97 and 0.84, respectively, indicating an adequate model fit. The relative bacterial abundance was 99.34% in the ALS group and 98.94% in the HC group. Among the ten identified genera, Bifidobacterium, Lactobacillus, and Enterococcus were more prevalent in ALS individuals, while Lactiplantibacillus and Klebsiella were more abundant in the HC group. We identified 70 metabolites, including short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), carbohydrates, and aromatic compounds, using NMR. Orthogonal partial least-squares discriminant analysis (O-PLS-DA) explained 15.8% of the variance, with a clear separation between the ALS and HC groups. Univariate receiver operating characteristic (ROC) analysis identified three fecal metabolites with AUC values above 0.70, including butyrate (0.798), propionate (0.727), and citrate (0.719). These metabolites may serve as potential biomarkers for ALS. The statistical model for metabolic pathway analysis revealed interconnected pathways, highlighting the complexity of metabolic dysregulation, as well as potential microbial and metabolic biomarkers in ALS. These results highlight the role of gut microbiome alterations in ALS and suggest potential avenues for therapeutic intervention.}, } @article {pmid40489271, year = {2025}, author = {Li, B and Han, Y and Zhang, S and Wang, H and Zhao, Z and Zhai, Y}, title = {High-Precision Edge Detection Guided byFlow Fields.}, journal = {IEEE transactions on image processing : a publication of the IEEE Signal Processing Society}, volume = {34}, number = {}, pages = {3674-3688}, doi = {10.1109/TIP.2025.3572763}, pmid = {40489271}, issn = {1941-0042}, abstract = {Edge detection is frequently employed to support downstream visual tasks. However, current edge detection methods still encounter two significant challenges: extracting complex textured targets and capturing valuable information from complex backgrounds. We propose FFED, a flow field-guided edge detection model. FFED integrates the three components of our design. FFED incorporates three designed components: the Feature Broadcast Module (FBM), the Antagonistic Bio-inspired Spatial Attention Module (ABSAM), a novel pixel difference convolution named ALS. The FBM serves as an implementation mode of the flow field, with its input pair selection strategy inspired by video processing. The FBM broadcasts high-level semantic features to high-resolution ones, preserving more meaningful texture details. Inspired by biological studies, we propose the ABSAM. ABSAM extracts valuable information from complex backgrounds by optimizing spatial modeling of data. The ALS exhibits enhanced capability in extracting gradient information and capturing subtle texture details that are easily overlooked. Experimental results demonstrate that FFED achieved competitive detection results on NYUD, BSDS500, and BIPED datasets, as well as good performance on industrial datasets. Additionally, the experiment verified the auxiliary effect of FFED on downstream visual tasks. The code is available at https://github.com/hanyuchen2022/Flow-field-guided-edge-detection-FFED-.}, } @article {pmid40489721, year = {2025}, author = {Levison, L and Jepsen, P and Blicher, JU and Andersen, H}, title = {Hospital-Diagnosed Traumatic Head Injury and Associated Risk of Developing ALS: A Nationwide Population-Based Case-Control Study.}, journal = {Neurology}, volume = {105}, number = {1}, pages = {e213809}, doi = {10.1212/WNL.0000000000213809}, pmid = {40489721}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/etiology/diagnosis ; Male ; Female ; Case-Control Studies ; Middle Aged ; Aged ; Risk Factors ; *Craniocerebral Trauma/epidemiology/complications/diagnosis ; Registries ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND AND OBJECTIVES: Previous studies have suggested that traumatic head injury (THI) may be a risk factor of amyotrophic lateral sclerosis (ALS) development, yet the association remains unclear. We aimed to determine whether hospital-diagnosed THI is an important ALS risk factor, and we investigated the magnitude and duration of associated ALS risk.

METHODS: In this population-based case-control study, we used individual-level data linkage across nationwide health registers from 1980 to 2021 to identify patients with hospital-diagnosed ALS. Each patient was matched 1:10 with individuals from the general population by age, sex, and diagnostic index date. We used conditional logistic regression to examine the relative risk of ALS associated with having previous hospital-diagnosed THI. To avoid the effect of reverse causation, we investigated ALS risk within several time windows and repeated all analyses after restricting THI exposures to more than 3 years before the date of ALS diagnosis.

RESULTS: THI was observed in 4.7% of 5,943 ALS cases vs 3.7% of 59,426 controls, with a matched odds ratio (OR) of 1.3 (95% CI 1.1-1.4). However, the risk of ALS declined considerably with increasing time since head injury, with a high OR of 4.5 (95% CI 2.8-7.3) observed within the 6 months before ALS diagnosis. If head injury was suffered 6-12 months before ALS diagnosis, the OR was 2.4 (95% CI 1.4-4.0). Restricting the analysis to THI suffered more than 3 years before ALS diagnosis, we found no association with an OR of 1.1 (95% CI 1.0-1.3).

DISCUSSION: Although a strong association of ALS with THI experienced ≤1 year before ALS diagnosis was evident, our results suggest that this is due to reverse causation. When restricting the analysis to a period deemed relevant for causative events leading to ALS development, no association was observed. Consequently, we do not consider THI an important ALS risk factor. This study was limited by the inability to consider minor THIs not receiving hospital attendance. Future research should explore alternative models to unfold this possible ALS risk factor.}, } @article {pmid40489798, year = {2025}, author = {Huang, J and Zhao, L and Xiang, P and Zhang, F and Yang, Y and Chao, L and Liu, W and Li, H and Zhang, X}, title = {Aminated Lignin/Cellulose-Based Hydrogel with High Adhesion for Wearable Sensors.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {41}, number = {24}, pages = {15484-15493}, doi = {10.1021/acs.langmuir.5c01389}, pmid = {40489798}, issn = {1520-5827}, mesh = {*Hydrogels/chemistry ; *Lignin/chemistry/analogs & derivatives ; *Cellulose/chemistry ; *Wearable Electronic Devices ; Nanoparticles/chemistry ; Animals ; Swine ; }, abstract = {Hydrogels play a significant role in the flexibility, stretchability, and conductivity of wearable sensors. However, it is still a challenge to achieve multifunctional hydrogel sensors with excellent mechanical strength, outstanding self-adhesion, and high stimulus responsiveness for meeting various demands of practical applications. Here, this work presents a one-pot method to prepare a conductive hydrogel with multifunction by introducing aminated lignosulfonate (A-LS) and aminated cellulose nanocrystals (A-CNC) into the hydrogel matrix. Benefiting from the synergistic effect of dynamic reversible noncovalent bond network with the introduction of nanoparticles in the system, the resultant hydrogel showed excellent mechanical properties. In addition, the prepared hydrogels exhibited remarkable adhesion strength (pig skin: 24 kPa) with sustainable adhesion, which still maintained an adhesion strength above 18 kPa after 20 cycles of adhesion/separation. The resultant hydrogel sensor showed a wide operating range (0-200%), high sensitivity (GF = 0.71 at 0-100% strain; GF = 3.15 at 100-200% strain), and fast response time (320 ms). The high-value utilization of renewable forest biomass resources is conducive to the sustainable development of green chemistry.}, } @article {pmid40489983, year = {2025}, author = {The Lancet Neurology, }, title = {Honouring the amyotrophic lateral sclerosis research pledge.}, journal = {The Lancet. Neurology}, volume = {24}, number = {7}, pages = {557}, doi = {10.1016/S1474-4422(25)00166-8}, pmid = {40489983}, issn = {1474-4465}, } @article {pmid40490178, year = {2025}, author = {Akkum, FI and Ozbas, CE and Damar, M and Uversky, VN and Fayetorbay, R and Kang, DE and Woo, JA and Coskuner-Weber, O}, title = {Impacts of pathogenic mutations on the structures of the CHCHD10 monomer: An AlphaFold3 study linked to the generation of conformational ensembles.}, journal = {International journal of biological macromolecules}, volume = {318}, number = {Pt 2}, pages = {144970}, doi = {10.1016/j.ijbiomac.2025.144970}, pmid = {40490178}, issn = {1879-0003}, mesh = {Humans ; *Mitochondrial Proteins/genetics/chemistry ; *Mutation ; Models, Molecular ; Protein Conformation ; Protein Structure, Secondary ; }, abstract = {CHCHD10, a member of the coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein family, plays a critical role in mitochondrial function. The link between pathological mutations and CHCHD10 is important and increasingly recognized, especially due to mitochondrial dysfunction and its association with neurodegenerative diseases. Several mutations in CHCHD10 have been directly linked to human diseases, such as Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), mitochondrial myopathies, and Spinal Muscular Atrophy-Jokela type (SMAJ). In this study, we investigate the structural properties of wild-type and mutant CHCHD10 proteins using AlphaFold3 linked to the generation of conformational ensembles. Structural changes may modulate interactions, flexibility, and aggregation tendencies, potentially influencing neurodegenerative disease pathogenesis linked to mitochondrial dysfunction. Notably, disease-associated mutations like R15S, P23L, and S59L alter secondary structure formations such as 310-helices and β-sheets. Despite, we find that the compactness of CHCHD10 is not significantly altered by genetic mutations since radius of gyration values range between 32.69 Å and 35.94 Å. All in all, we find that the compactness is not but the secondary and tertiary structure properties are affected by pathological mutations. We propose that evolution may have optimized CHCHD10 to maintain a suitable radius of gyration that provides sufficient flexibility through its intrinsically disordered region while ensuring efficient interaction with diverse molecules. Thus, alterations in secondary and tertiary structures through mutations might be a mechanism for fine-tuning the protein's functionality while preserving its optimal state. These characteristics might be related to the pathologies of neurodegenerative diseases linked to mitochondrial dysfunction.}, } @article {pmid40491248, year = {2025}, author = {Bernsen, S and Fabian, R and Koc, Y and Schumann, P and Körtvélyessy, P and Castro-Gomez, S and Meyer, T and Weydt, P}, title = {Serum Cardiac Troponin T Levels as a Therapy Response Marker in Tofersen-Treated ALS.}, journal = {Muscle & nerve}, volume = {72}, number = {3}, pages = {509-514}, pmid = {40491248}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/drug therapy/genetics ; *Troponin T/blood ; Male ; Female ; Middle Aged ; Aged ; Biomarkers/blood ; *Oligonucleotides/therapeutic use ; Treatment Outcome ; Neurofilament Proteins ; Superoxide Dismutase-1/genetics ; Cohort Studies ; Adult ; Creatine Kinase/blood ; }, abstract = {INTRODUCTION/AIMS: Cardiac troponin T (cTnT) levels are elevated in the majority of persons with amyotrophic lateral sclerosis (ALS) and increase over time. Neurofilament light chain (NfL) is an established therapy response biomarker in ALS as superoxide dismutase1 (SOD1)-ALS patients treated with the antisense oligonucleotide tofersen show a decrease in NfL. In this study, we assess cTnT levels in SOD1-ALS at baseline and during tofersen treatment.

METHODS: cTnT was analyzed at baseline and during tofersen treatment in 23 SOD1-ALS patients at two specialized ALS centers in Germany and compared to a control cohort of 74 ALS patients without SOD1 variants.

RESULTS: cTnT levels increased in the control ALS cohort over time (p < 0.0001) but not in the tofersen group (p = 0.36). Creatine kinase (CK) and CK-MB levels did not show significant changes over time. The median monthly increase of cTnT was 0.045 points (IQR 0.02-0.08) in the control ALS cohort and 0.01 points (IQR -0.01-0.03) in the tofersen group (p = 0.0013). A significantly lower fold change in cTnT levels was observed in the tofersen-treated cohort (median 1.2; IQR 0.77-1.59) relative to the control group (median 1.89; IQR 1.35-2.75) (p = 0.0003). Nine (39%) patients treated with tofersen experienced a reduction in cTnT levels.

DISCUSSION: In this study, we describe a response signal of cTnT to tofersen treatment, which supports the value of cTnT as an independent biomarker in ALS. These results contribute to the notion that cTnT may provide additional value as a progression and treatment response biomarker in ALS complementary to NfL and warrant further investigation.}, } @article {pmid40491620, year = {2025}, author = {Sue, S and Yamazaki, S and Sue, K and Kinoshita, T and Yoshida, K}, title = {Combined Effects of Lung Volume Recruitment Training and Mechanical Insufflation-Exsufflation in a Patient With Advanced Amyotrophic Lateral Sclerosis Receiving Long-Term Mechanical Ventilation: A Case Report.}, journal = {Cureus}, volume = {17}, number = {5}, pages = {e83823}, pmid = {40491620}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) degenerates both upper and lower motor neurons. Most patients with ALS require respiratory support due to deterioration of their respiratory muscles. Mechanical insufflation-exsufflation (MI-E) is one option that can help patients with weak cough strength to clear the airway, and it may potentially increase survival time. Another option is lung volume recruitment training (LVRT), a technique commonly used to maintain lung and chest wall flexibility. However, it requires specific equipment, such as one-way valves, to be applied to patients with ALS who undergo invasive mechanical ventilation with tracheostomy. Only limited studies have indicated the effectiveness of LVRT for patients with ALS. Moreover, no study is currently available on the effect of combining LVRT with MI-E. As the disease progresses, treatment options become increasingly limited, making it crucial to explore new therapeutic approaches for patients at the advanced stage. Here, we examined the effects of a combination of LVRT and MI-E in a 74-year-old female patient with ALS who had survived under invasive mechanical ventilation for nine years. We measured tidal volume (TV) and dynamic lung compliance (Cdyn) as respiratory parameters three months before and after the initiation of the combined therapy. Following the intervention, TV improved from 750.15 L/min (standard deviation (SD) ± 34.60) to 859.14 L/min (SD ± 75.63), and Cdyn increased from 24.18 cmH2O (SD ± 2.84) to 26.54 cmH2O (SD ± 2.92). These results suggest that MI-E combined with LVRT may improve lung compliance even in patients with ALS receiving long-term invasive mechanical ventilation.}, } @article {pmid40492022, year = {2025}, author = {Ennis, R and Husted, C}, title = {Case Report: Treating Atrial Fibrillation with the Neubie Direct Current Electrical Stimulation.}, journal = {Medical devices (Auckland, N.Z.)}, volume = {18}, number = {}, pages = {291-295}, pmid = {40492022}, issn = {1179-1470}, abstract = {INTRODUCTION: A novel Neuro-Bio-Electric-Stimulation device (Neubie, Neufit, Austin, Texas, USA) using Direct Current (DC) has been used to treat various neurological conditions (ALS, MS, peripheral neuropathy, chronic pain) and functional limitations such as limited range of motion. One method, called the Master Reset Protocol, is thought to stimulate the vagus nerve system, impacting heart rate, digestion and other vital systems.

PURPOSE: We used the Master Reset Protocol on a subject experiencing paroxysmal Atrial Fibrillation (AFib) to assess whether this treatment might be effective in reversing a cardiac arrhythmia.

SUBJECT AND METHODS: A single subject is reported in this Case Report. The subject is a 62-year-old healthy, athletic male, 6'2″ tall, 165 lbs. with a good diet and is not obese nor has other exacerbating underlying conditions related to heart disease. The subject experiences arrhythmia approximately 1-2 times per month lasting generally 3 or more days per the subject. The Master Reset Method was initiated within 12 hours of arrhythmia onset, and arrhythmia before and after treatment was confirmed through subject observation and confirmed with pulse readings. A total of ten treatments were conducted over 7 months.

RESULTS: Reversal of arrhythmia was confirmed during or within 24 hours of treatment with DC application for all 10 treatments (100%). Two of the more severe cases of AFib required two treatments on the same day with confirmed reversal of AFib.

CONCLUSION: Treatment with Direct Current suggests a good correlation with reversal of arrhythmia. Further studies are planned to determine if similar, regular, treatments can be effective in preventing arrhythmia.}, } @article {pmid40492044, year = {2025}, author = {Roshni, J and Mahema, S and Janakiraman, V and Ahmad, SF and Al-Mazroua, HA and Ahmed, SSSJ}, title = {Effect of bovine milk-derived peptide on SNAP-25 of the neurotransmitter system in treating the sialorrhoea in chronic neurological diseases.}, journal = {Food science and biotechnology}, volume = {34}, number = {11}, pages = {2601-2610}, pmid = {40492044}, issn = {2092-6456}, abstract = {Sialorrhea is a prominent symptom of chronic neurological disorders like amyotrophic lateral sclerosis, Parkinson's disease, motor neuron disease, cerebral palsy, and stroke. Synaptosome-Associated Protein-25 (SNAP-25) plays a key role in triggering involuntary saliva secretion. This study aimed to identify SNAP-25-targeting bovine milk-derived peptides to mitigate sialorrhea, using computational and quantum atomistic simulation approach. Among 8559 bovine milk-derived peptides, 8499 were non-toxic, 7749 non-allergenic, 911 with blood-brain barrier crossing potential, and 175 with cell-penetrating capabilities. Using HAPPENN program, 20 non-hemolytic peptides were screened, while PeptideRanker predicted two physiologically active peptides. Protein-peptide docking followed by de novo structural modeling showed that CMPTFQFFK has a stronger inhibitory affinity (- 7.45 kcal/mol) for SNAP-25 than botulinum toxin. Additionally, dynamic simulations, free energy and quantum chemical studies confirmed the stability of CMPTFQFFK's with SNAP-25. Our study recommends CMPTFQFFK as a potential inhibitor of SNAP-25 for sialorrhea treatment, with further in vitro testing needed to confirm efficacy.}, } @article {pmid40492096, year = {2025}, author = {Tzeplaeff, L and Galhoz, A and Meijs, C and Gomes, LC and Kovac, A and Menzel, A and Değirmenci, H and Alaamel, A and Kaya, HC and Çelik, AG and Dinçer, S and Korucuk, M and Karaüzüm, SB and Bayraktar, E and Çiftçi, V and Bilge, U and Koç, F and Demleitner, AF and Buchberger, A and von Heynitz, R and Gmeiner, V and Knellwolf, C and Mouzouri, M and Wuu, J and Başak, AN and Andersen, PM and Kohlmayer, F and Ashton, NJ and Kuban, W and Lenz, C and Rogers, ML and Zilka, N and Corcia, P and Lerner, Y and Weber, M and Koprusakova, MT and Uysal, H and Benatar, M and Menden, MP and Lingor, P}, title = {Identification of a presymptomatic and early disease signature for Amyotrophic Lateral Sclerosis (ALS): protocol of the premodiALS study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40492096}, support = {R01 NS105479/NS/NINDS NIH HHS/United States ; }, abstract = {The median time to diagnosis of amyotrophic lateral sclerosis (ALS) is approximately 12 months after the onset of first symptoms. This diagnostic delay is primarily due to the nonspecific nature of early symptoms and the clinical challenges in differentiating ALS from its mimics. Therefore, the discovery of reliable biomarkers for the early and accurate diagnosis of ALS represents a critical medical need. A total of 330 participants will be recruited across six international study sites. The cohort will include (1) pre-symptomatic gene mutation carriers, (2) symptomatic individuals up to 12 months after symptom onset with either ALS, ALS mimics, or a pure motor syndrome with yet unclear assignment, and (3) healthy controls. Participants will engage in a one-year longitudinal study, consisting of an initial evaluation at baseline visit and a follow-up visit 12 months later. Assessments will include an environmental and medical history questionnaire, neurological examinations, olfactory testing, cognitive/behavioral evaluations, and the collection of biological samples (serum, plasma, urine, tear fluid, and cerebrospinal fluid). Proteomic, metabolomic, and lipidomic analyses will be performed using mass spectrometry and targeted immunoassays, with all samples processed under standardized protocols. The resulting multimodal dataset will be systematically integrated in an effort to uncover a clinico-molecular signature characteristic of presymptomatic and early ALS. These findings may have relevance to early ALS diagnosis and future clinical practice.}, } @article {pmid40493155, year = {2025}, author = {Kang, A and Qiao, Y and Pan, S and Yan, F and Chen, H and Bai, Y}, title = {From RIPK1 to Necroptosis: Pathogenic Mechanisms in Neurodegenerative Diseases.}, journal = {Neurochemical research}, volume = {50}, number = {3}, pages = {194}, pmid = {40493155}, issn = {1573-6903}, support = {24JRRA346//Natural Science Foundation of Gansu Province/ ; CY2023-QN-B03//"Cuiying Science and Technology Program" of the Second Hospital of Lanzhou University/ ; (23)0207//Foundation for International Medical Exchanges/ ; (23)1263//China Health Promotion Foundation/ ; }, mesh = {Humans ; *Necroptosis/physiology/drug effects ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; Animals ; Signal Transduction/physiology ; }, abstract = {Receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis, a newly identified mode of regulated cell death, represents a significant pathogenic mechanism in multiple neurodegenerative disorders. Substantial experimental evidence indicates that RIPK1 regulates necroptotic cell death pathways in both neuronal and glial cell populations through activation of the canonical RIPK3-MLKL signaling cascade, thereby exacerbating neuroinflammatory responses and accelerating neurodegenerative progression. The pathological relevance of this molecular pathway has been extensively validated across multiple major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Pharmacological interventions targeting RIPK1 or its downstream effectors-particularly RIPK3 and MLKL-have demonstrated significant efficacy in mitigating disease-associated pathological manifestations. This highlights the RIPK1 signaling axis as a promising therapeutic target for neuroprotective strategies. Consequently, thorough investigation of RIPK1-mediated necroptosis in neurodegenerative settings holds considerable translational potential. Such inquiry deepens mechanistic understanding of disease pathogenesis while accelerating the advancement of innovative therapeutic approaches with direct clinical relevance.}, } @article {pmid40493233, year = {2025}, author = {Russo, T and Domi, T and Schito, P and Falzone, YM and Pozzi, L and Locatelli, M and Riva, N and Spinelli, EG and Agosta, F and Filippi, M and Quattrini, A}, title = {Osteopontin levels in the serum reflect anatomical disease progression in patients with amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {7}, pages = {452}, pmid = {40493233}, issn = {1432-1459}, support = {Age-It: "Ageing Well in an Ageing Society"//Ministero dell'Università e della Ricerca/ ; RF-2021-12374238//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/pathology/diagnosis ; *Osteopontin/blood ; Male ; Female ; *Disease Progression ; Middle Aged ; Aged ; Retrospective Studies ; Biomarkers/blood ; Neurofilament Proteins/blood ; Adult ; Longitudinal Studies ; Severity of Illness Index ; Cohort Studies ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) lacks biomarkers for diagnosis, prognostic stratification, and evaluation of response to potential treatments. Previous research supported the role of serum osteopontin (OPN) levels as a potential biomarker in ALS. However, the associations of OPN serum levels with clinical features and their trend over the disease course have not been explored yet.

METHODS: We measured OPN serum levels in a retrospective cohort of 110 well-characterized patients with ALS, using a commercial ELISA kit, and analyzed their association with demographic and clinical features, as well as with other serum biomarkers. For a subset of patients, longitudinal measurements were available.

RESULTS: OPN serum levels differed significantly between patients with ALS and a cohort of 45 age and sex-matched healthy controls. However, when considering potential differential diagnoses, elevated OPN serum levels were not specific for ALS. Patients with an advanced disease stage (King's stage 3 or 4) exhibited significantly higher OPN serum levels compared to patients at earlier disease stages, whereas we did not observe any correlation with ALSFRS-R and progression rate. We observed an inverse correlation between OPN serum levels and BMI at diagnosis. Higher OPN serum levels predicted a shorter survival time and a shorter time to King's stage 4. No significant association between serum OPN and serum neurofilament light or glial fibrillary acid protein levels was observed. OPN serum levels were substantially stable over a 9-month observation time.

CONCLUSION: Our findings indicate that serum OPN is an informative biomarker in ALS, providing valuable prognostic insights, potentially reflecting the extent of disease, and demonstrating potential applications in clinical trials.}, } @article {pmid40493543, year = {2025}, author = {Lucassen, HJ and Prinsen, EC and Asseln, M and van Vliet, RO and Tuijthof, GJM}, title = {Assistive devices for ALS patients: exploring wishes and values through focus groups.}, journal = {Disability and rehabilitation. Assistive technology}, volume = {20}, number = {8}, pages = {2960-2972}, doi = {10.1080/17483107.2025.2516628}, pmid = {40493543}, issn = {1748-3115}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/psychology ; *Self-Help Devices ; Male ; Focus Groups ; Female ; Middle Aged ; Aged ; Activities of Daily Living ; Adult ; Upper Extremity/physiopathology ; Qualitative Research ; }, abstract = {PURPOSE: Amyotrophic Lateral Sclerosis (ALS) is a progressive disease leading to loss of muscle strength and control, and as such limiting patients' independence. Assistive devices can help individuals with ALS; however, their use by ALS patients is limited. To increase use rates, we expect that devices need to be tailored to ALS patients. The aim of this study was to identify wishes, requirements and values of ALS patients regarding assistive devices for the upper extremity through focus groups involving ALS patients, their relatives and medical professionals.

METHODS AND MATERIALS: Four focus groups were conducted, recorded and transcribed. Two focus groups with ALS patients and their relatives contained a "Day in a Life" and "Empathy map" method, while during two focus groups with medical professionals, "Day in the Life" method and "Provoking statements" were used. Activities mentioned were counted and categorized into "Daily activities" and "Elective activities".

RESULTS: Qualitative analysis of transcripts yielded three themes: (1) ALS patients' considerations on use and wishes for assistive devices, (2) external factors influencing the use of assistive devices and (3) change in ALS patients' needs over time. In addition to maintaining independence in activities of daily living, the results highlight that retaining the ability to perform elective activities such as hobbies, is important. Moreover, there is a clear need for assistive devices designed for ALS patients with limited upper extremity strength, but who are not confined to a wheelchair.

CONCLUSION: These findings can guide the development of assistive devices tailored to the needs of ALS patients.}, } @article {pmid40493571, year = {2025}, author = {Nathan Kochen, N and Murray, M and Zafari, S and Vunnam, N and Liao, EE and Chen, L and Braun, AR and Sachs, JN}, title = {Fluorescence Lifetime-Based FRET Biosensors for Monitoring N Terminal Domain-Dependent Interactions of TDP-43 in Living Cells: A Novel Approach for ALS and FTD Drug Discovery.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {13}, pages = {2450-2462}, pmid = {40493571}, issn = {1948-7193}, mesh = {Humans ; *Biosensing Techniques/methods ; *Fluorescence Resonance Energy Transfer/methods ; *DNA-Binding Proteins/metabolism/genetics ; *Frontotemporal Dementia/metabolism/drug therapy ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *Drug Discovery/methods ; Animals ; Ketoconazole/pharmacology ; High-Throughput Screening Assays ; HEK293 Cells ; Caenorhabditis elegans ; }, abstract = {Pathological aggregates of TDP-43 are implicated in Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. While therapeutic efforts have traditionally focused on mitigating end-stage TDP-43 aggregation, recent evidence highlights an upstream and potentially targetable event: the loss of functional nuclear TDP-43 multimers due to disrupted N-terminal domain (NTD) interactions. To address this, we developed fluorescence lifetime (FLT)-based FRET biosensors to monitor TDP-43 multimerization in living cells that couple a full-length TDP-43 FLT-FRET biosensor screen with an NTD-deletion counter screen, forming the foundation of a novel high-throughput screening (HTS) platform. Screening the 2682 compound FDA-approved Selleck library, we identified the small molecule ketoconazole, which stabilizes functional nuclear TDP-43 multimers in an NTD-dependent manner with low micromolar potency. Ketoconazole rescues TDP-43 mislocalization and aggregation, restores SREBP2 mRNA levels under TDP-43 overexpression, improves neuronal health, and partially restores motor function in a TDP-43 C. elegans model. These findings establish both the biosensors and the HTS platform as innovative tools for TDP-43 drug discovery and support an exciting translational approach for targeting TDP-43 proteinopathies.}, } @article {pmid40494757, year = {2025}, author = {Luu, S and McGuiness, O and Menadue, C and Piper, AJ and Wong, K and Yee, BJ and Gray, EL}, title = {Inter-Night Variability of Nocturnal Pulse Oximetry in People Living With Motor Neuron Disease: A Retrospective Observational Study.}, journal = {Respirology (Carlton, Vic.)}, volume = {30}, number = {10}, pages = {995-1002}, pmid = {40494757}, issn = {1440-1843}, mesh = {Humans ; *Oximetry/methods ; Retrospective Studies ; Male ; Female ; Middle Aged ; *Motor Neuron Disease/physiopathology/complications ; Aged ; Reproducibility of Results ; Noninvasive Ventilation ; Oxygen Saturation/physiology ; *Circadian Rhythm/physiology ; }, abstract = {BACKGROUND AND OBJECTIVE: Nocturnal pulse oximetry (NPO) is a simple and inexpensive assessment tool that has previously been shown to correlate with prognosis and timing of non-invasive ventilation (NIV) initiation in people living with motor neuron disease (plwMND). However, the optimal number of nights for measuring NPO has not been defined for this population, with other respiratory conditions exhibiting both low and high night-to-night variability in NPO parameters. This study aims to determine the inter-night variability in NPO data over three nights in plwMND.

METHODS: We conducted a retrospective analysis of 132 studies in which plwMND underwent three consecutive nights of NPO. Intraclass correlation coefficients (ICC) were used to assess the reliability of key NPO parameters, including mean percentage of total recording time with oxygen saturation (SpO2) < 90% (T90), oxygen desaturation index (ODI), basal SpO2 and nadir SpO2. The proportion of plwMND meeting NIV criteria based on single-night versus multi-night assessments was also compared.

RESULTS: Excellent reliability was observed for T90 (ICC(1) = 0.940) and ODI (ICC(1) = 0.901), while basal SpO2 (ICC(1) = 0.845) and nadir SpO2 (ICC(1) = 0.768) demonstrated good reliability. However, relying on a single-night NPO assessment failed to identify 12% of plwMND who met NIV criteria when evaluated over three nights.

CONCLUSION: Despite good to excellent inter-night variability of NPO data in plwMND, multi-night NPO monitoring improves the accuracy of identifying plwMND requiring NIV. These findings support the need for multi-night assessments to enhance clinical decision-making in MND management.}, } @article {pmid40495157, year = {2025}, author = {Gonsalves, GS}, title = {Still we rise: research on bias and discrimination will endure.}, journal = {International journal for equity in health}, volume = {24}, number = {1}, pages = {167}, pmid = {40495157}, issn = {1475-9276}, mesh = {Humans ; Racism ; Boston ; *Prejudice ; United States ; *Social Discrimination ; *Vaping/epidemiology ; Smoking/epidemiology ; Bias ; Sexism ; }, abstract = {This is a commentary on Reisner et al's Analyzing multiple types of discrimination using implicit and explicit measures, comparing target vs. Dominant groups, in a study of smoking/vaping among community health center members in Boston, Massachusetts (2020-2022). This manuscript is a study of the intersection of multiple forms of discrimination-racism, sexism, heterosexism, cissexism, ageism, and sizeism-and measures of implicit and explicit bias in the context of current smoking and vaping behavior among patients from targeted versus dominant groups at community health centers in Boston, Massachusetts (USA) from 2020 to 2022. The authors used logistic regression to assess smoking and vaping behavior with each type of discrimination, and then extended this analysis employing a meta-regression approach to better understand relationships across all types of discrimination under consideration in their study. Recently, the grant from the US National Institutes of Health, which supported this research was terminated in progress for ideological reasons by the current US administration under President Donald J. Trump for simply focusing on discrimination. While this study was among the first to be terminated by the Trump administration, hundreds of grants from the NIH and other US research funders have been cancelled in the first half of 2025. Reisner et al's paper is an important piece of research, but it represents the start of a sophisticated inquiry into discrimination and bias, and future work by this team and in this area of research is necessary and sadly, now impossible to do with federal scientific funding. Work on discrimination and bias has always faced obstacles, but the scope and scale of attacks on science in the US require all scientists to push back against this censorship and political interference in the funding and conduct of research.}, } @article {pmid40495464, year = {2025}, author = {Majtan, T and Mijatovic, E and Petrosino, M}, title = {Understanding the Impact of Mutations in the Cystathionine Beta-Synthase Gene: Towards Novel Therapeutics for Homocystinuria.}, journal = {Molecular and cellular biology}, volume = {45}, number = {8}, pages = {327-342}, doi = {10.1080/10985549.2025.2511338}, pmid = {40495464}, issn = {1098-5549}, mesh = {Humans ; *Homocystinuria/genetics/drug therapy/enzymology ; *Cystathionine beta-Synthase/genetics/metabolism/chemistry ; Animals ; *Mutation ; Protein Folding ; Molecular Chaperones/therapeutic use ; }, abstract = {Protein misfolding and conformational instability drive protein conformational disorders, causing either accelerated degradation and loss-of-function, as in inherited metabolic disorders like lysosomal storage disorders, or toxic aggregation and gain-of-function, as in neurodegenerative diseases like Alzheimer's disease or amyotrophic lateral sclerosis. Classical homocystinuria (HCU), an inborn error of sulfur amino acid metabolism, results from cystathionine beta-synthase (CBS) deficiency. CBS regulates methionine conversion into metabolites critical for redox balance (cysteine, glutathione) and signaling (H2S). Pathogenic missense mutations in the CBS gene often impair folding, cofactor binding, stability or oligomerization rather than targeting the key catalytic residues of the CBS enzyme. Advances in understanding of CBS folding and assembly as well as CBS interactions with cellular proteostasis network offer potential for therapies using pharmacological chaperones (PCs), i.e., compounds facilitating proper folding, assembly or cellular trafficking. This review discusses progress in identifying PCs for HCU, including chemical chaperones, cofactors, and proteasome inhibitors. We outline future directions, focusing on high-throughput screening and structure-based drug design to develop CBS-specific PCs. These could stabilize mutant CBS, enhance its stability and restore activity, providing new treatments for HCU and possibly other conditions related to dysregulated CBS, such as cancer or Down's syndrome.}, } @article {pmid40495844, year = {2025}, author = {Byeon, H}, title = {Unveiling the invisible: How cutting-edge neuroimaging transforms adolescent depression diagnosis.}, journal = {World journal of psychiatry}, volume = {15}, number = {5}, pages = {102953}, pmid = {40495844}, issn = {2220-3206}, abstract = {Yu et al's study has advanced the understanding of the neural mechanisms underlying major depressive disorder (MDD) in adolescents, emphasizing the significant role of the amygdala. While traditional diagnostic methods have limitations in objectivity and accuracy, this research demonstrates a notable advancement through the integration of machine learning techniques with neuroimaging data. Utilizing resting-state functional magnetic resonance imaging (fMRI), the study investigated functional connectivity (FC) in adolescents with MDD, identifying notable reductions in regions such as the left inferior temporal gyrus and right lingual gyrus, alongside increased connectivity in Vermis-10. The application of support vector machines (SVM) to resting-state fMRI (rs-fMRI) data achieved an accuracy of 83.91%, sensitivity of 79.55%, and specificity of 88.37%, with an area under the curve of 0.6765. These results demonstrate how SVM analysis of rs-fMRI data represents a significant improvement in diagnostic precision, with reduced FC in the right lingual gyrus emerging as a particularly critical marker. These findings underscore the critical role of the amygdala in MDD pathophysiology and highlight the potential of rs-fMRI and SVM as tools for identifying reliable neuroimaging biomarkers.}, } @article {pmid40496257, year = {2025}, author = {Ding, LH and Wu, PF and Sun, NZ}, title = {Investigation of clinical outcomes in conservative management of hook fractures: Commentary on recent findings.}, journal = {World journal of orthopedics}, volume = {16}, number = {5}, pages = {106881}, pmid = {40496257}, issn = {2218-5836}, abstract = {This editorial critically evaluates the landmark study by Tanaka and Yoshii, which demonstrated a 100% union rate with conservative management of hamate hook fractures, challenging the historical preference for surgical intervention. In contrast to Scheufle et al's report of 90%-100% failure rates with early surgical approaches, Tanaka and Yoshii's protocol achieved universal healing despite delayed diagnoses in 25% of cases. Central to this success is the systematic integration of high-resolution computed tomography for early diagnosis and dynamic monitoring of trabecular bone regeneration, significantly reducing missed diagnoses and guiding personalized immobilization timelines. The patient-centered strategy-allowing temporary splint removal during low-risk activities-balanced fracture stability with joint mobility preservation, avoiding post-treatment stiffness. However, limitations such as small sample size (n = 16), selection bias, and insufficient long-term functional data (e.g., grip strength, return-to-sport metrics) underscore the need for comparative trials. Emerging trends, including adjunct therapies like low-intensity pulsed ultrasound and biologics (e.g., teriparatide), are proposed to accelerate healing while minimizing immobilization risks. This work redefines conservative fracture management paradigms, emphasizing innovation without compromising efficacy. Overall, this assessment deepens our understanding of the conservative management of hook fractures and provides evidence-based insights for improved clinical decision-making.}, } @article {pmid40496269, year = {2025}, author = {Liu, QZ and Zeng, L and Sun, NZ}, title = {Linguistic exclusion in orthopedic research: Cultural adaptation, multilingual innovations, and pathways to global health equity.}, journal = {World journal of orthopedics}, volume = {16}, number = {5}, pages = {106951}, pmid = {40496269}, issn = {2218-5836}, abstract = {This editorial critically evaluated the recent study by AlMousa et al, which examined the impact of the Arabic version of the American Academy of Orthopedic Surgeons Foot and Ankle Outcomes Questionnaire (AAOS-FAOQ) on postoperative quality of life and recovery in Arabic-speaking patients with traumatic foot and ankle injuries. In the context of systemic linguistic exclusion in orthopedic research-where English-language journals dominated most publications and non-English-speaking populations faced dual barriers of trial underrepresentation and semantic distortions (e.g., mistranslations of terms like "joint instability" in Arabic)-AlMousa et al's work highlighted the transformative potential of culturally adapted methodologies. Their rigorous four-stage adaptation framework validated the Arabic AAOS-FAOQ as a reliable tool, enhancing ecological validity and reducing bias in patient-reported outcomes. However, limitations such as regional specificity (Gulf-centric sampling) and short follow-up periods (4 months) underscored broader challenges in non-English research: Redundant studies, prolonged hospital stays for limited English proficiency patients, and underrepresentation of certain ethnic groups in trials. To dismantle linguistic hegemony, we proposed semantic reconstruction (e.g., integrating culturally specific indicators like "prayer posture"), dialect-aware neural translation, and World Health Organization led terminology standardization. In line with these proposed solutions, AlMousa et al's study exemplified how language-sensitive adaptations could bridge equity gaps, while future efforts would need to balance cultural specificity with cross-study comparability through AI-driven multilingual databases and policy mandates for cultural adaptation roadmaps.}, } @article {pmid40496636, year = {2025}, author = {Qiao, H and Cheng, X and Tian, H and Zhao, C and Sun, X and Zhao, J}, title = {Lower cervical C6/C7 andersson lesion with upper cervical C1/C2 fracture in ankylosing spondylitis: a case report and literature review.}, journal = {Frontiers in surgery}, volume = {12}, number = {}, pages = {1568553}, pmid = {40496636}, issn = {2296-875X}, abstract = {Cervical andersson lesions (ALs) are rare in patients with ankylosing spondylitis (AS), and even more rare in patients with simultaneous superior cervical atlantoaxial fracture and dislocation. Here, we present a case of C1 Jefferson fracture (C1 bilateral posterior arch fracture), C2 odontoid, lateral mass, vertebral fracture (nonclassic C2 hangman fracture), traumatic posterior atlantoaxial dislocation (AAD) and C6/C7 AL in a long-standing AS cervical spine. The patient with traumatic AS-related cervical fractures underwent a two-stage surgery. The stage I surgery involved a posterior atlantoaxial reduction and fixation surgery combined with C5/C6/T1/T2 posterior pedicle screw fixation plus C6/C7 decompression. One week later, C6/C7 anterior cervical corpectomy decompression and fusion (ACCF) with long anterior plate stabilization combined with iliac crest bone graft transplantation was performed for stage II surgery. The patient recovery observed during follow-up was satisfactory. Nine-month postoperative radiological images revealed fracture union of the upper and lower cervical spine with optimal reduction of the atlantoaxial segment. In conclusion, lower cervical ALs with simultaneous upper cervical C1/C2 fractures in the AS are very rare. Posterior C1-C2 fixation combined with C6-C7 AL corpectomy/fusion and posterior pedicle screw fixation may offer a desirable alternative approach for this complex case of cervical trauma. During treatment, complete decompression, effective reduction, and potent stabilization can comprehensively improve the clinical prognosis.}, } @article {pmid40497426, year = {2025}, author = {Bao, J and Zhou, J and Xie, Z and Zou, M and Napier, R and Li, J}, title = {CYP99A2 from Aegilops tauschii metabolizes pyroxsulam but not mesosulfuron-methyl, causing different natural sensitivity to two herbicides.}, journal = {Pest management science}, volume = {81}, number = {10}, pages = {6210-6219}, doi = {10.1002/ps.8967}, pmid = {40497426}, issn = {1526-4998}, support = {2021YFD1700100//National Key Research and Development Program/ ; }, mesh = {*Herbicides/pharmacology/metabolism ; *Sulfonylurea Compounds/metabolism/pharmacology ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; *Herbicide Resistance ; *Plant Proteins/metabolism/genetics ; Acetolactate Synthase/antagonists & inhibitors ; *Poaceae/genetics/metabolism/drug effects/enzymology ; Plant Weeds/drug effects ; }, abstract = {BACKGROUND: Weed tolerance to herbicides poses a major threat to agricultural production. Aegilops tauschii has promising prospects for genetic development; however, the fact that this plant is invasive in China and other countries is often ignored owing to its pronounced adaptability. Among the current acetolactate synthase (ALS) inhibitors, only mesosulfuron-methyl (MM) can control A. tauschii, and pyroxsulam (P) is ineffective. However, a knowledge gap remains regarding differences in sensitivity of A. tauschii to these two ALS inhibitors.

RESULTS: We hypothesized that differences in sensitivity of A. tauschii to the ALS inhibitors MM and P are mediated by metabolic enzymes. Whole-plant experiments showed that the P450s inhibitor 1-Aminobenzotriazole (ABT) significantly increased the sensitivity of A. tauschii to P compared with MM. In A. tauschii, the P metabolism rate was higher than that of MMl, as detected by liquid chromatography with tandem mass spectrometry. Transcriptome sequencing and quantitative real-time polymerase chain reaction identified seven differentially expressed P450s after P and MM treatments, three of which were upregulated after P treatment and were unaffected by MM. AtCYP99A2 reduced plant sensitivity to P by metabolizing P without affecting MM by overexpressing it in Arabidopsis and inducing in vitro protein expression.

CONCLUSION: To the best of our knowledge, this is the first report on P450 involvement in A. tauschii sensitivity to two ALS-inhibitor herbicides. This study deepens current understandings of A. tauschii and facilitates subsequent screening of specific metabolic enzyme inhibitors to be used as synergists in combination with herbicides, which will provide new avenues for weed control. © 2025 Society of Chemical Industry.}, } @article {pmid40498024, year = {2025}, author = {Pisoni, L and Donini, L and Gagni, P and Pennuto, M and Ratti, A and Verde, F and Ticozzi, N and Mandrioli, J and Calvo, A and Basso, M}, title = {Barriers in the Nervous System: Challenges and Opportunities for Novel Biomarkers in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {14}, number = {11}, pages = {}, pmid = {40498024}, issn = {2073-4409}, support = {MUR PNRR project iNEST - Interconnected Nord-Est Innovation Ecosystem (ECS00000043)//NextGenerationEU/ ; PERMEALS - PNRR-MAD-2022-12375731//Ministero della Salute/ ; CUP E53D23019700001, project "MYSTICALS"//European Union - Next Generation EU, Mission 4, Component 1/ ; RF-2016-02361616//Ministero della Salute/ ; EVTestInALS//AriSLA/ ; Aldo Ravelli Center for Neurotechnology and Experimental Brain Therapeutics//Università degli Studi di Milano/ ; MUR-PRIN 2022 project EV-PRINT 2022CS9H53//Next Generation EU/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/diagnosis ; *Biomarkers/metabolism ; Extracellular Vesicles/metabolism ; Animals ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by wide phenotypic heterogeneity. Despite efforts to carefully define and stratify ALS patients according to their clinical and genetic features, prognosis prediction still remains unreliable. Biomarkers that reflect changes in the central nervous system would be useful, but the physical impossibility of direct sampling and analysis of the nervous system makes them challenging to validate. A highly explored option is the identification of neuronal-specific markers that could be analyzed in peripheral biofluids. This review focuses on the description of the physical and biological barriers to the central nervous system and of the composition of biofluids in which ALS disease biomarkers are actively searched. Finally, we comment on already validated biomarkers, such as the neurofilament light chain, and show the potential of extracellular vesicles (EVs) and cell-free DNA as additional biomarkers for disease prediction.}, } @article {pmid40498122, year = {2025}, author = {Doronzio, PN and Lattante, S and Bernardo, D and Patanella, AK and Bisogni, G and Meleo, E and Del Giudice, E and Colavito, D and Porro, LM and Sabatelli, E and Conte, A and Zollino, M and Sabatelli, M and Marangi, G}, title = {Burden of pathogenetic and likely pathogenetic variants in SPG7, SPG11 and AP4 genes in Amyotrophic Lateral Sclerosis. A case-control study.}, journal = {Journal of neurology}, volume = {272}, number = {7}, pages = {455}, pmid = {40498122}, issn = {1432-1459}, support = {Linea D1//Catholic University of Sacred Hearth/ ; Linea D1//Catholic University of Sacred Hearth/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; Case-Control Studies ; Aged ; Adult ; *Genetic Predisposition to Disease/genetics ; *Adaptor Protein Complex 4/genetics ; *Proteins/genetics ; Spastic Paraplegia, Hereditary/genetics ; Genetic Variation/genetics ; ATPases Associated with Diverse Cellular Activities ; Metalloendopeptidases ; }, abstract = {BACKGROUND: There is evidence that some Hereditary Spastic Paraplegia (HSP) genes are linked to Amyotrophic Lateral Sclerosis (ALS). In particular, KIF5A and SPG11 genes, which cause two different forms of HSP, are also associated with adult-onset and Juvenile ALS, respectively.

OBJECTIVES: To study the frequencies of pathogenetic and likely pathogenetic variants in HSP genes in ALS patients and to determine whether they act as predisposing factors.

METHODS: We analysed 72 HSP-associated genes in 1024 ALS and 44 Primary Lateral Sclerosis patients and applied customized ACMG criteria to identify pathogenic and likely pathogenic variants. Based on the frequency of identified variants, six genes, including SPG7, SPG11 and the four genes encoding the subunits of the AP4 adaptor protein, were selected for analysis in an additional cohort of 481 ALS patients. Overall results on 1549 patients were compared with 1138 controls.

RESULTS: The frequency of variants in SPG7 gene was 0.45% (7/1549) in patients vs 0.18% (2/1138) in controls (p = 0.19), in SPG11 was 0.77% (12/1549) in cases and 0.26% (3/1138) in controls (p = 0.06), in AP4 genes was 0.64% (10/1549) in patients and 0.26% (3/1138) in controls (p = 0.13). The total number of variants detected across SPG7, SPG11 and AP4 genes was statistically different between patients and controls (1.87% vs 0.7%; p = 0.006).

CONCLUSIONS: We found a significant enrichment of variants in a set of HSP genes, including SPG7, SPG11 and AP4 genes, in a large cohort of ALS patients, suggesting that they may act as predisposing factors for ALS.}, } @article {pmid40498248, year = {2025}, author = {Pahwa, R and Molho, E and Lew, M and Dashtipour, K and Gil, RA and Revilla, FJ and Clinch, T and Qin, P and Isaacson, SH and , }, title = {Long-Term Safety and Efficacy of Repeated Cycles of RimabotulinumtoxinB in the Treatment of Chronic Sialorrhea: Results of the OPTIMYST Trial.}, journal = {Neurology and therapy}, volume = {14}, number = {4}, pages = {1553-1567}, pmid = {40498248}, issn = {2193-8253}, abstract = {INTRODUCTION: Botulinum toxin injections into the salivary glands inhibit saliva production by reducing the release of acetylcholine at the parasympathetic nerve terminals within the salivary gland. The phase 3 study reported here assessed the safety, tolerability, and effectiveness of repeated cycles of rimabotulinumtoxinB (RIMA) injections in adults with troublesome sialorrhea.

METHODS: In this phase 3, open-label multicenter study, 187 adult participants with troublesome sialorrhea due to Parkinson disease (65.8%), amyotrophic lateral sclerosis (13.9%), and other etiologies (20.3%) received up to 4 cycles of RIMA treatment (3500 U every 11-15 weeks).

RESULTS: Participants (69% male, 31% female; mean age 64.1 years) had sialorrhea for a mean of 3.2 years at baseline with a mean Unstimulated Salivary Flow Rate (USFR) of 0.63 ± 0.49 g/min. During the first treatment cycle, RIMA significantly reduced the mean±standard deviation (SD) USFR from baseline to week 4 by - 0.34 ± 0.37 g/min (p < 0.0001), and efficacy was maintained through week 13 (- 0.14 ± 0.29 g/min; p < 0.0001). Reductions were maintained at subsequent injection cycles 2-4, with mean absolute USFRs at weeks 4 and 13 of each cycle similar to those of cycle 1. Most adverse events (AEs) were mild, and the most commonly reported AEs in each cycle that were considered to be treatment-related were dry mouth (≤ 15.5% participants/cycle) and dental caries (≤ 6.0% participants/cycle).

CONCLUSION: This study demonstrates that RIMA 3500 U safely reduces saliva production over repeated treatment cycles through 1 year, thereby supporting its utility in the management of troublesome sialorrhea in adults.

GOV IDENTIFIER: NCT02610868.}, } @article {pmid40498717, year = {2025}, author = {Komolafe, OO and Mustofa, J and Daley, MJ and Walton, D and Tawiah, A}, title = {Current applications and outcomes of AI-driven adaptive learning systems in physical rehabilitation science education: A scoping review protocol.}, journal = {PloS one}, volume = {20}, number = {6}, pages = {e0325649}, pmid = {40498717}, issn = {1932-6203}, mesh = {Scoping Reviews as Topic ; Humans ; *Artificial Intelligence ; *Rehabilitation/education ; *Learning ; }, abstract = {Rationale Integrating artificial intelligence (AI) into education has introduced transformative possibilities, particularly through adaptive learning systems. Rehabilitation science education stands to benefit significantly from the integration of AI-driven adaptive learning systems. However, the application of these technologies remains underexplored. Understanding the current applications and outcomes of AI-driven adaptive learning in broader healthcare education can provide valuable insights into how these approaches can be effectively adapted to enhance multimodal case-based learning in Rehabilitation Science education. Methods The scoping review is based on the Joanne Briggs Institute (JBI) framework. It is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRIMSA-ScR). A comprehensive search strategy will be used to find relevant papers in Scopus, PubMed, CINAHL, Education Resources Information Center (ERIC), Association for Computing Machinery (ACM), ProQuest Education Journal, Web of Science, ProQuest Dissertations & Theses Global, and IEEE Digital Library. This review will include all types of studies that describe or evaluate our outcomes of interest: AI models used, learning and teaching methods, effective implementation, outcomes, and challenges of ALS's in rehabilitation health science education. Data will be extracted using a pre-piloted data extraction sheet and synthesized narratively to identify themes and patterns. Discussion This scoping review will synthesize the applications of AI models in rehabilitation science education. It will provide evidence for educators, healthcare professionals, and policymakers to incorporate AI into educational curricula effectively. The protocol is registered on Open Science Framework registries at https://osf.io/e46s3.}, } @article {pmid40499018, year = {2025}, author = {Yadav, V and Singh, R and Chaturvedi, M and Siddhanta, S and Chaturvedi, R}, title = {Multivariate and Machine Learning-Derived Virtual Staining and Biochemical Quantification of Cancer Cells through Raman Hyperspectral Imaging.}, journal = {Analytical chemistry}, volume = {97}, number = {24}, pages = {12660-12668}, doi = {10.1021/acs.analchem.5c01028}, pmid = {40499018}, issn = {1520-6882}, mesh = {*Spectrum Analysis, Raman/methods ; Humans ; *Machine Learning ; Principal Component Analysis ; Multivariate Analysis ; Neural Networks, Computer ; *Hyperspectral Imaging/methods ; Staining and Labeling ; Least-Squares Analysis ; Lipids/analysis ; Algorithms ; Collagen/analysis ; Cell Line, Tumor ; }, abstract = {Advances in virtual staining and spatial omics have revolutionized our ability to explore cellular architecture and molecular composition with unprecedented detail. Virtual staining techniques, which rely on computational algorithms to map molecular or structural features, have emerged as powerful tools to visualize cellular components without the need for physical dyes, thereby preserving sample integrity. Similarly, spatial omics enable the mapping of biomolecules across tissue or cell surfaces, providing spatially resolved insights into biological processes. However, traditional dye-based staining methods, while widely used, come with significant limitations. In this context, Raman spectroscopy offers a robust, label-free alternative for probing molecular composition at a high resolution. We present a novel algorithm that reconstructs super-resolved Raman images by extracting spectral patterns from surrounding pixels, enabling detailed, label-free visualization of cellular structures. By employing Raman spectroscopy in conjunction with chemometric tools such as principal component analysis (PCA), multivariate curve resolution-alternating least squares (MCR-ALS), and artificial neural network (ANN), we performed a quantitative analysis of key biomolecular components, including collagen, lipids, glycogen, and nucleic acids, and classify the different cancer cell lines with an accuracy of nearly 99%. This approach not only enabled the identification of distinct molecular fingerprints across the different cancer types but also provided a powerful tool for understanding the biochemical variations that underlie tumor heterogeneity. This innovative combination of virtual staining, spatial omics, and advanced chemometrics highlights the potential for more accurate diagnostics and personalized treatment strategies in oncology.}, } @article {pmid40500504, year = {2025}, author = {Niu, J and Verkhratsky, A and Butt, A and Yi, C}, title = {Oligodendroglia in Ageing and Age-Dependent Neurodegenerative Diseases.}, journal = {Advances in neurobiology}, volume = {43}, number = {}, pages = {363-405}, pmid = {40500504}, issn = {2190-5215}, mesh = {Humans ; *Oligodendroglia/pathology/physiology/metabolism ; *Neurodegenerative Diseases/pathology/physiopathology/metabolism ; *Aging/pathology/physiology ; Animals ; }, abstract = {The central nervous system is susceptible to gradual decline with age, affecting all types of glial cells in the process. Compared to other glial cells, the oligodendroglial lineage is highly vulnerable to ageing and undergoes significant characteristic changes that impact upon its structure and impair its physiological functions. Therefore, the ageing and degeneration of oligodendroglia become major risk factors for neurodegenerative diseases. During the age-related disease process, changes in oligodendroglia lead to a decline in their ability to regenerate myelin and respond to the aged microenvironment, which are closely linked to the pathogenesis of neurodegenerative diseases, facilitating the emergence of these diseases in older populations. In this chapter, we introduce the physiological changes of oligodendroglia during ageing and the related mechanisms and then summarise their pathophysiological contributions to age-related cognitive disorders. Finally, we discuss potential therapeutic strategies that target oligodendroglia for future research on neurodegenerative diseases.}, } @article {pmid40501419, year = {2025}, author = {Bischoff, KE and Kojimoto, G and O'Riordan, DL and Leavell, YL and Maiser, S and Grouls, A and Smith, AK and Pantilat, SZ and Kluger, BM and Mehta, AK}, title = {Strengths and Opportunities: Clinicians' Perspectives on Palliative Care for Amyotrophic Lateral Sclerosis (ALS) in the United States.}, journal = {Muscle & nerve}, volume = {72}, number = {3}, pages = {455-463}, pmid = {40501419}, issn = {1097-4598}, support = {/AG/NIA NIH HHS/United States ; //ALS Association/ ; /AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/epidemiology/psychology ; Humans ; *Palliative Care/methods ; United States/epidemiology ; Male ; Female ; *Attitude of Health Personnel ; Surveys and Questionnaires ; Middle Aged ; }, abstract = {INTRODUCTION/AIMS: Little is known about the state of palliative care (PC) for people with ALS (pALS) in the U.S. We aimed to examine current practice regarding PC for pALS and how it can be improved.

METHODS: ALS and PC clinicians completed surveys about: (1) strengths and limitations of PC for pALS provided by ALS and PC teams, (2) reasons for and barriers to referring to specialty PC, and (3) how PC could be improved.

RESULTS: One hundred forty-one ALS clinicians from 72 institutions and 242 PC clinicians from 96 institutions in 30 states completed surveys. Half of ALS clinicians reported they are able to manage patients' pain (55%) and mood symptoms (52%) "very well." Fewer reported managing care partner needs (43%) and spiritual/existential distress (29%) "very well." Fifty-eight percent of pALS are referred to outpatient PC and 69% to hospice at some point in the illness. Barriers to referring include that PC programs are not sufficiently available to pALS. ALS clinicians generally felt satisfied with PC teams' care, but PC clinicians were less confident managing motor symptoms (51% confident) and helping care partners understand how to provide care (51%) and use equipment (25%). Most clinicians felt the quality of PC provided by ALS (77%) and PC (90%) teams is good/excellent. However, qualitative comments highlighted that both ALS and PC clinicians have knowledge gaps, and collaboration between ALS and PC clinicians should increase.

DISCUSSION: Clinician education, expansion of PC services, strengthened collaboration, and further research about PC for pALS are needed.}, } @article {pmid40501554, year = {2025}, author = {Trautwig, AN and Shantaraman, A and Chung, M and Dammer, EB and Ping, L and Duong, DM and Petrucelli, L and Ward, ME and Glass, JD and Nelson, PT and Levey, AI and McEachin, ZT and Seyfried, NT}, title = {Molecular subtyping based on hippocampal cryptic exon burden reveals proteome-wide changes associated with TDP-43 pathology across the spectrum of LATE and Alzheimer's Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40501554}, issn = {2692-8205}, support = {P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; R01 NS132330/NS/NINDS NIH HHS/United States ; U01 AG061357/AG/NIA NIH HHS/United States ; }, abstract = {TDP-43 pathology is a defining feature of Limbic-Predominant Age-Related TDP-43 Encephalopathy neuropathologic change (LATE-NC) and is frequently comorbid with Alzheimer's disease neuropathologic change (ADNC). However, the molecular consequences of co-occurring LATE-NC and ADNC pathology (TDP-43, β-amyloid, and tau protein pathologies) remain unclear. Here, we conducted a comparative biochemical, molecular, and proteomic analysis of hippocampal tissue from 90 individuals spanning control, LATE-NC, ADNC, and ADNC+LATE-NC groups to assess the impact of cryptic exon (CE) inclusion, phosphorylated TDP-43 pathology (pTDP-43), and AD-related pathologies (β-amyloid, and tau) on the proteome. ADNC+LATE-NC cases exhibited the highest burden of CE inclusion as quantified by measuring the levels of known TDP-43 regulated CEs within eight transcripts: STMN2, UNC13A, ELAVL3, KALRN, ARHGAP32, CAMK2B, PFKP, and SYT7. While CE levels correlated with pTDP-43 pathology, they were more strongly correlated with each other, suggesting that the molecular signature of CE inclusion may serve as a more sensitive measure of TDP-43 dysfunction than pTDP-43 pathology alone. Unbiased classification based on the relative abundance of these eight CEs stratified individual cases into low, intermediate, and high CE burden subtypes, largely independent of β-amyloid and tau pathology. Proteome-wide correlation analysis revealed a bias toward reduced protein levels from genes harboring TDP-43-regulated CEs in cases with high cumulative CE burden. Notably, proteins significantly decreased under high CE burden included canonical STMN2, ELAVL3, and KALRN, as well as kinesin proteins that are genetically associated with amyotrophic lateral sclerosis. Co-expression network analysis identified both shared and distinct biological processes across CE subtypes and pathways associated with pTDP-43, tau, β-amyloid pathologies, and CE accumulation in the hippocampus. Protein modules associated with TDP-43 loss of function were prioritized by integrating proteomic data from TDP-43-depleted human neurons with the hippocampal co-expression network. Specifically, we observed decreased endosomal vesicle, microtubule-binding, and synaptic modules, alongside an increase in RNA-binding modules. These results provide new insights into the proteomic impact of CE burden across the spectrum of LATE and AD pathological severity, highlighting the molecular consequences of TDP-43 dysfunction in neurodegenerative disease.}, } @article {pmid40501612, year = {2025}, author = {Bhuiyan, P and Yi, Y and Wei, B and Yan, A and Dong, L and Wei, H}, title = {Intranasal Dantrolene Nanoparticles for Treatment of Amyotrophic Lateral Sclerosis as a Disease-Modifying Drug.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40501612}, issn = {2692-8205}, support = {R01 AG061447/AG/NIA NIH HHS/United States ; }, abstract = {Calcium dysregulation, caused by pathological activation of ryanodine receptors, contributes to motor neuron degeneration, motor dysfunction, and muscle weakness in SOD1-G93A transgenic amyotrophic lateral sclerosis (ALS) mice. This study investigates the therapeutic efficacy of intranasally administered dantrolene nanoparticles, a ryanodine receptor antagonist, on motor neuron function, muscle strength, spinal cord degeneration, and survival outcomes. Male and female C57BL/6SJLF1 non-transgenic control and SOD1-G93A ALS transgenic mice were assigned to one of three experimental groups: 1) NO TX: No treatment control; 2) IN-DAN: Intranasal administration of dantrolene in the Ryanodex formulation vehicle (RFV), at a dosage of 5mg/kg, administered daily from ages 90-120 days; 3) IN-VEH: Intranasal administration of RFV alone (as a vehicle control), following the same dosing schedule as the IN-DAN condition. Body weight and general motor function were monitored weekly, with survival recorded daily throughout the treatment period. At the treatment conclusion, neurological function was comprehensively evaluated using a standardized neurological scoring system. Motor coordination and balance were assessed using the balance beam test (beam widths of 12 mm and 6 mm) and the rotarod test. Muscle strength was evaluated by measuring grip force using the Kondziela inverted screen test. After behavioral testing, spinal cord tissues were collected for analysis. The levels of neurofilament light chain (NFL), a skeletal neuron protein, and spinal cord weight were determined to measure spinal cord degeneration. Compared to non-transgenic control mice, SOD1-G93A mice exhibited significantly elevated neurological scores, indicating severely impaired neurological function. This deterioration was robustly and significantly ameliorated by IN-DAN treatment by 90% (P<0.0001). Similarly, ALS mice demonstrated impairments in motor coordination and balance on the beam balance test, with dramatic and significant increases in crossing time and the number of foot slips. These impairments were greatly and significantly mitigated by IN-DAN treatment, by 78% in crossing time (P<0.0001) and 84% in the number of slips (P<0.0001) on the 12 mm-wide beam, but not by the vehicle control. ALS mice demonstrated progressive body weight loss as well, which was similarly reversed by IN-DAN treatment, but not by the vehicle control. Muscle strength, as measured by grip force, was significantly reduced in ALS mice but robustly preserved IN-DAN treatment, which prevented the decrease by 213% (P<0.0001), while the vehicle control had no effect. Spinal cord weight was significantly reduced in ALS mice, a trend reversed by intranasal dantrolene nanoparticle treatment, but not by the vehicle control. Survival analysis revealed that 100% of control mice survived through the 30-day treatment period (up to 120 days of age), while survival in untreated or vehicle-treated ALS mice dropped to 67%. In contrast, ALS mice treated with intranasal dantrolene nanoparticles demonstrated a significantly improved survival rate of 89%. Thus, intranasal dantrolene nanoparticle treatment significantly and robustly improved neurological outcomes in SOD1-G93A ALS mice, inhibiting neurological impairment, motor dysfunction, balance deficits, and muscle weakness. These improvements were associated with a marked inhibition of spinal cord weight loss. Additionally, dantrolene treatment reversed body weight loss and significantly improved survival probability in ALS mice.}, } @article {pmid40502095, year = {2025}, author = {Poch, D and Mukherjee, C and Mallik, S and Todorow, V and Kuiper, EFE and Dhingra, N and Surovtseva, YV and Schlieker, C}, title = {Integrative Chemical Genetics Platform Identifies Condensate Modulators Linked to Neurological Disorders.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.06.07.658469}, pmid = {40502095}, issn = {2692-8205}, abstract = {UNLABELLED: Aberrant biomolecular condensates are implicated in multiple incurable neurological disorders, including Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and DYT1 dystonia. However, the role of condensates in driving disease etiology remains poorly understood. Here, we identify myeloid leukemia factor 2 (MLF2) as a disease-agnostic biomarker for phase transitions, including stress granules and nuclear condensates associated with dystonia. Exploiting fluorophore-derivatized MLF2 constructs, we developed a high-content platform and computational pipeline to screen modulators of NE condensates across chemical and genetic space. We identified RNF26 and ZNF335 as protective factors that prevent the buildup of nuclear condensates sequestering K48-linked polyubiquitinated proteins. Chemical screening identified four FDA-approved drugs that potently modulate condensates by resolving polyubiquitinated cargo and MLF2 accumulation. Our exploratory integrated chemical-genetics approach suggests that modulation of zinc, and potentially autophagy and oxidative stress, is critical for condensate modulation and nuclear proteostasis, offering potential therapeutic strategies for neurological disorders. Application of our platform to a genome-wide CRISPR KO screen identified strong enrichment of candidate genes linked to primary microcephaly and related neurodevelopmental disorders. Two hypomorphic microcephaly-associated alleles of ZNF335 failed to rescue nuclear condensate accumulation in ZNF335 KO cells, suggesting that aberrant condensates and impaired nuclear proteostasis may contribute to the pathogenesis of microcephaly.

HIGHLIGHTS: MLF2 emerges as a disease-agnostic condensate biomarker co-localizing with TDP-43 and G3BP1FDA-approved drugs target condensates linked to perturbed proteostasis.RNF26 and ZNF335 are identified as modulators of nuclear phase transitions.Microcephaly patient disease alleles fail to counteract aberrant condensates.}, } @article {pmid40502754, year = {2025}, author = {Lorincz-Comi, N and Song, W and Chen, X and Paz, IR and Hou, Y and Zhou, Y and Xu, J and Martin, W and Barnard, J and Pieper, AA and Haines, JL and Chung, M and Cheng, F}, title = {Combining xQTL and genome-wide association studies from ethnically diverse populations improves druggable gene discovery.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40502754}, issn = {2693-5015}, support = {R21 AG083003/AG/NIA NIH HHS/United States ; R01 AG082118/AG/NIA NIH HHS/United States ; R56 AG074001/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; RF1 NS133812/NS/NINDS NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; R01 AG076448/AG/NIA NIH HHS/United States ; }, abstract = {Repurposing existing medicines to target disease-associated genes represents a promising strategy for developing new treatments for complex diseases. However, progress has been hindered by a lack of viable candidate drug targets identified through genome-wide association studies (GWAS). Gene-based association tests provide a more powerful alternative to traditional single nucleotide polymorphism (SNP)-based methods, yet current approaches often fail to leverage shared heritability across populations and to effectively integrate functional genomic data. To address these challenges, we developed GenT and its various extensions, comprising a framework of gene-based tests utilizing summary-level GWAS data. Using GenT, we identified 16, 15, 35, and 83 druggable genes linked to Alzheimer's disease (AD), amyotrophic lateral sclerosis, major depression, and schizophrenia, respectively. Additionally, our multi-ancestry gene-based test (MuGenT) uncovered 28 druggable genes associated with type 2 diabetes that previous trans-ancestry or ancestry-specific GWAS had missed. By integrating brain expression and protein quantitative trait loci (e/pQTLs) into our analysis, we identified 43 druggable genes (e.g., RIPK2, NTRK1, RIOK1) associated with AD that had supporting xQTL evidence. Notably, experimental assays demonstrated that the NTRK1 protein inhibitor GW441756 significantly reduced tau hyper-phosphorylation (including p-tau181 and p-tau217) in AD patient-derived iPSC neurons, thus providing mechanistic support for our predictions. Overall, our findings underscore the power of gene-based association testing as a strategic tool for informed drug target discovery and validation based on human genetic and genomic data for complex diseases.}, } @article {pmid40502782, year = {2025}, author = {White, MA and Crowley, L and Massenzio, F and Li, X and Niblock, M and Coleman, MP and Barmada, SJ and Sreedharan, J}, title = {Inhibiting glycogen synthase kinase 3 suppresses TDP-43-mediated neurotoxicity in a caspase-dependent manner.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40502782}, issn = {2693-5015}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 NS097542/NS/NINDS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive and ultimately fatal diseases characterised by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Current disease modifying drugs have modest effects and novel therapies are sorely needed. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration in Drosophila. Here, we investigated the potential of GSK3 inhibition to ameliorate TDP-43-mediated toxicity in mammalian neurons. Expression of TDP-43 both activated GSK3 and promoted caspase mediated cleavage of TDP-43. Conversely, GSK3 inhibition reduced the abundance of full-length and cleaved TDP-43 in neurons expressing wild-type or disease-associated mutant TDP-43, ultimately ameliorating neurotoxicity. Our results suggest that TDP-43 turnover is promoted by GSK3 inhibition in a caspase-dependent manner, and that targeting GSK3 activity has therapeutic value.}, } @article {pmid40503807, year = {2025}, author = {Rudnicki, SA and Al-Chalabi, A and Andrews, JA and Chio, A and Corcia, P and Couratier, P and Cudkowicz, ME and De Carvalho, M and Genge, A and Hardiman, O and Heiman-Patterson, T and Henderson, RD and Ingre, C and Johnston, W and Ludolph, A and Maragakis, NJ and Miller, TM and Mora, JS and Petri, S and Simmons, Z and Van Den Berg, LH and Zinman, L and Herder, KE and Kupfer, S and Malik, FI and Meng, L and Simkins, TJ and Wei, J and Wolff, AA and Shefner, JM and , }, title = {Hospitalizations as an outcome measure in COURAGE-ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {802-811}, doi = {10.1080/21678421.2025.2515907}, pmid = {40503807}, issn = {2167-9223}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/epidemiology ; Double-Blind Method ; *Hospitalization/statistics & numerical data ; *Outcome Assessment, Health Care/methods ; }, abstract = {Objective: To describe the development of a methodology to characterize hospitalizations and their relationship to amyotrophic lateral sclerosis (ALS) and provide results using this process in a phase 3 trial of reldesemtiv in ALS. Methods: ALS clinical trialists assisted in developing a classification system to determine if a hospitalization was related to ALS (HR-ALS), unrelated (HU-ALS), or if the relationship was indeterminate (HI-ALS) and this was applied by the investigators to hospitalizations in COURAGE-ALS. Time to first hospitalization and number of hospitalizations were compared between those assigned reldesemtiv or placebo for up to 48 weeks. Demographic and clinical features were evaluated for prediction of hospitalization risk; this analysis was limited to those participants who completed the first 24-week double-blind placebo-controlled portion of the trial. Results: COURAGE-ALS terminated early due to futility. Time to first hospitalization was similar in the reldesemtiv compared to placebo arms as was the incidence, with 86 of the participants (17.6% of those originally assigned placebo and 18.0% originally on reldesemtiv) experiencing an event. The largest percentage of events was classified as HR-ALS for both placebo (64%, 18/28) and reldesemtiv (76%, 44/58). In a multivariate model, only bulbar or respiratory onset disease was a significant risk factor for hospitalization. Conclusion: While most hospitalizations in COURAGE-ALS were HR-ALS, HU-ALS and HI-ALS also occurred. When using hospitalization as an endpoint in an ALS clinical trial, recording its relationship to ALS provides additional details to characterize disease burden and clinical meaningfulness of the endpoint.}, } @article {pmid40504117, year = {2025}, author = {Morgan, KJ and Carley, E and Coyne, AN and Rothstein, JD and Lusk, CP and King, MC}, title = {Visualizing nuclear pore complex plasticity with pan-expansion microscopy.}, journal = {The Journal of cell biology}, volume = {224}, number = {9}, pages = {}, pmid = {40504117}, issn = {1540-8140}, support = {R01 NS122236/NH/NIH HHS/United States ; F31 HL158119/NH/NIH HHS/United States ; F31 HL158119/HL/NHLBI NIH HHS/United States ; R35 GM153474/GM/NIGMS NIH HHS/United States ; R35 GM15374/NH/NIH HHS/United States ; R01 NS122236/NS/NINDS NIH HHS/United States ; R01 GM129308/GM/NIGMS NIH HHS/United States ; 2420904//National Science Foundation/ ; R01 GM129308/NH/NIH HHS/United States ; }, mesh = {*Nuclear Pore/metabolism/ultrastructure ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism ; Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Nuclear Envelope/metabolism ; *Microscopy/methods ; Membrane Glycoproteins ; }, abstract = {The exploration of cell-type and environmentally responsive nuclear pore complex (NPC) plasticity requires new, accessible tools. Using pan-expansion microscopy (pan-ExM), NPCs were identified by machine learning-facilitated segmentation. They exhibited a large range of diameters with a bias for dilated NPCs at the basal nuclear surface in clusters suggestive of local islands of nuclear envelope tension. Whereas hyperosmotic shock constricted NPCs analogously to those found in annulate lamellae, depletion of LINC complexes specifically eliminated the modest nuclear surface diameter biases. Therefore, LINC complexes may contribute locally to nuclear envelope tension to toggle NPC diameter between dilated, but not constricted, states. Lastly, POM121 shifts from the nuclear ring to the inner ring of the NPC specifically in induced pluripotent stem cell-derived neurons from a patient with C9orf72 amyotrophic lateral sclerosis. Thus, pan-ExM is a powerful tool to visualize NPC plasticity in physiological and pathological contexts at single NPC resolution.}, } @article {pmid40504265, year = {2025}, author = {Torres-Villaros, H and Streho, M and Hoa, D and Giocanti-Aurégan, A}, title = {STARGUS: a comparative study of a new swept-source biometer and B-mode ultrasound in dense cataracts.}, journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie}, volume = {263}, number = {9}, pages = {2577-2584}, pmid = {40504265}, issn = {1435-702X}, support = {IIT #69445453//Alcon/ ; }, mesh = {Humans ; *Cataract/diagnosis ; Male ; Female ; Aged ; *Axial Length, Eye/diagnostic imaging/pathology ; *Biometry/instrumentation/methods ; Middle Aged ; Ultrasonography/methods ; *Lens, Crystalline/diagnostic imaging/pathology ; Reproducibility of Results ; Aged, 80 and over ; *Anterior Chamber/diagnostic imaging/pathology ; Retrospective Studies ; Equipment Design ; }, abstract = {PURPOSE: This study aimed to compare a new swept-source biometer to the gold standard B-mode ultrasound biometer for measuring the axial length (AL) when standard optical biometers failed due to cataract density.

METHODS: Patients with advanced cataracts whose AL could not be measured using optical biometers available in our clinics, including the Lenstar LS-900 and IOLMaster 500 and 700, were included. The AL, anterior chamber depth (ACD), and lens thickness (LT) were measured using a new swept-source biometer (SSB) (Argos[®], Alcon) and B-mode ultrasound. The Enhanced Retinal Visualization (ERV) mode of the new SSB was used when the standard mode did not provide reliable AL measurements.

RESULTS: AL measurements failed in 183 eyes due to cataract density using available biometers. The new SSB allowed successfully measuring the AL in 89.6% of cases, and the ERV mode was needed in 15.8% of eyes. The ALs measured with the new SSB and B-mode ultrasound were comparable, with an excellent intraclass correlation coefficient (ICC) of 0.99. No significant differences in ACD measurements were observed between new SSB and ultrasound or conventional biometers, with ICC of 0.81 and 0.87, respectively. However, the LT tended to be thinner with the new SSB compared to ultrasound, suggesting a potential source of error, but no significant difference was observed with conventional biometers (ICC of 0.88).

CONCLUSIONS: The new SSB Argos[®], in particular when the ERV mode is used, could be a reliable alternative to B-mode ultrasound for measuring AL in eyes with dense cataracts. It is as effective as ultrasound in measuring the AL, and it could help to improve cataract surgery planning and outcomes.}, } @article {pmid40504748, year = {2025}, author = {Andersen, TM and Conde, B and Vollsæter, M}, title = {Seeing in Synchrony: Toward Personalized Noninvasive Ventilation in Amyotrophic Lateral Sclerosis Through Dynamic Upper-Airway Visualization.}, journal = {Respiratory care}, volume = {70}, number = {9}, pages = {1193-1195}, doi = {10.1089/respcare.13193}, pmid = {40504748}, issn = {1943-3654}, } @article {pmid40505784, year = {2025}, author = {Tang, J and Kang, Y and Chen, Q and Zhang, B and Shang, N and Lan, J and Wu, L and Peng, Y}, title = {TIMP1 inhibits Rac1-mediated ROS production to ameliorate blood-spinal cord barrier disruption in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {213}, number = {}, pages = {106987}, doi = {10.1016/j.nbd.2025.106987}, pmid = {40505784}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; *rac1 GTP-Binding Protein/metabolism ; *Tissue Inhibitor of Metalloproteinase-1/metabolism/genetics ; *Spinal Cord/metabolism/pathology ; *Reactive Oxygen Species/metabolism ; Mice ; Endothelial Cells/metabolism ; Mice, Transgenic ; Humans ; Mice, Inbred C57BL ; Male ; Neuropeptides ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive degeneration of motor neurons, for which therapeutic strategies and pharmacological interventions remain limited. Disruption of the blood-spinal cord barrier (BSCB) has been identified as a significant factor that may exacerbate motor neuron damage. Tissue inhibitor of metalloproteinase-1 (TIMP1), a molecule known for its dual roles in inhibiting matrix metalloproteinase (MMP) activity and exerting cytokine-like effects via receptor interactions, has been demonstrated to ameliorate endothelial barrier damage in various diseases. Here, we explored the potential of TIMP1 to restore BSCB integrity as a strategy to slow the ALS progression. Specifically, the expression of TIMP1 or its mutant variant AlaTIMP1, which lacks MMP-inhibitory activity, in spinal cord microvascular endothelial cells (SCMECs) prior to disease onset significantly reduces BSCB leakage in mice with ALS, thereby alleviating motor function deficits and delaying disease progression. Additionally, TIMP1 expression restores the expression of junctional complexes in SCMECs, as demonstrated in both in vivo and in vitro ALS models. Mechanistic studies revealed that TIMP1 suppresses ALS injury-induced integrin β1 activation independent of MMP inhibition, blocking downstream Rac1 translocation to the membrane to form a complex with NOX2. The inhibition of NOX2 activity reduces ROS-induced cytoskeletal remodeling, consequently stabilizing overall junctional alignment and preserving the BSCB integrity. Overall, our findings elucidate an MMP-independent mechanism through which TIMP1 regulates BSCB integrity in ALS context, suggesting that TIMP1 could serve as a novel tool for the treatment of ALS, particularly for prophylactic treatment in patients with familial ALS.}, } @article {pmid40506548, year = {2025}, author = {Wairagkar, M and Card, NS and Singer-Clark, T and Hou, X and Iacobacci, C and Miller, LM and Hochberg, LR and Brandman, DM and Stavisky, SD}, title = {An instantaneous voice-synthesis neuroprosthesis.}, journal = {Nature}, volume = {644}, number = {8075}, pages = {145-152}, pmid = {40506548}, issn = {1476-4687}, support = {DP2 DC021055/DC/NIDCD NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; }, mesh = {*Brain-Computer Interfaces ; Humans ; Male ; *Voice/physiology ; *Speech/physiology ; Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation/complications ; Dysarthria/rehabilitation/physiopathology ; *Neural Prostheses ; Electrodes, Implanted ; Microelectrodes ; Communication Devices for People with Disabilities ; }, abstract = {Brain-computer interfaces (BCIs) have the potential to restore communication for people who have lost the ability to speak owing to a neurological disease or injury. BCIs have been used to translate the neural correlates of attempted speech into text[1-3]. However, text communication fails to capture the nuances of human speech, such as prosody and immediately hearing one's own voice. Here we demonstrate a brain-to-voice neuroprosthesis that instantaneously synthesizes voice with closed-loop audio feedback by decoding neural activity from 256 microelectrodes implanted into the ventral precentral gyrus of a man with amyotrophic lateral sclerosis and severe dysarthria. We overcame the challenge of lacking ground-truth speech for training the neural decoder and were able to accurately synthesize his voice. Along with phonemic content, we were also able to decode paralinguistic features from intracortical activity, enabling the participant to modulate his BCI-synthesized voice in real time to change intonation and sing short melodies. These results demonstrate the feasibility of enabling people with paralysis to speak intelligibly and expressively through a BCI.}, } @article {pmid40506843, year = {2025}, author = {Ashford, BA and Simpson, JE and Dawson, C and Boche, D and Cooper-Knock, J and Heath, PR and Fillingham, D and Appleby-Mallinder, C and Wei, W and Dunning, M and Highley, JR}, title = {Human amyotrophic lateral sclerosis/motor neuron disease: The disease-associated microglial pathway is upregulated while APOE genotype governs risk and survival.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {35}, number = {6}, pages = {e70019}, pmid = {40506843}, issn = {1750-3639}, support = {//Bruker Spatial Biology/ ; //British Neuropathological Society/ ; //Pathological Society of Great Britain and Ireland/ ; }, mesh = {Transcriptome ; *Spinal Cord Ventral Horn/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Motor Cortex/metabolism ; Biomarkers/metabolism ; *Apolipoproteins E/genetics/metabolism ; Neuroinflammatory Diseases/metabolism ; Humans ; Male ; Female ; Aged ; Macrophages/pathology ; Microglia/pathology ; Membrane Glycoproteins ; Membrane Proteins ; Receptors, Immunologic ; Adaptor Proteins, Signal Transducing ; }, abstract = {A key role for inflammation in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) has been identified. It is vital to assess which central nervous system structures are most affected and which inflammatory processes are responsible in humans. The inflammatory transcriptome was characterized in the cervical spinal cord and motor cortex in post-mortem frozen and formalin-fixed paraffin-embedded specimens from human sporadic ALS/MND and control cases using the nCounter® Neuroinflammation Panel. Archival data were reanalyzed and compared with the nCounter data. Immunohistochemistry was used to examine the inflammatory response in the spinal cord and motor cortex and validate changes found during transcriptomic analyses. In the spinal cord, marked inflammation was observed, while less inflammation was detected in the motor cortex. Examination of differentially expressed genes in the spinal cord highlighted TREM2, TYROBP, APOE, and CD163, as well as phagocytic pathways. In sporadic ALS/MND spinal cord, significant microglial reactivity and involvement of TREM2, ApoE (encoded by APOE), and TYROBP were confirmed, suggesting the involvement of the disease-associated microglial (DAM) phenotype. The corticospinal tracts showed greater inflammation than the ventral horns. The precentral gyrus of ALS/MND again showed less immune reactivity to disease when compared to controls. Finally, in the largest cohort assessed to date, we demonstrate an association between the APOE variant and ALS/MND risk, age of onset, and survival. We find confirmed associations between APOE ε3/ε3 and disease and between ε2/ε2 and absence of disease. Further, ε4/ε4 appears to be associated with earlier disease onset and a more aggressive course. We conclude that while there is widespread inflammation in the CNS in sporadic ALS/MND, this is more marked in the spinal cord, especially the corticospinal tract. The specific markers stress the DAM phenotype as having a key role together with a possible influx of somatic macrophages. In addition, APOE function and genotype may be relevant in ALS/MND.}, } @article {pmid40507679, year = {2025}, author = {Zhou, Y and Ni, Y and Lan, L and Wan, H and Luo, F}, title = {Association Between Allostatic Load and Delirium in ICU Patients: A Retrospective Analysis of the MIMIC-IV Database.}, journal = {Journal of clinical medicine}, volume = {14}, number = {11}, pages = {}, pmid = {40507679}, issn = {2077-0383}, support = {82300118//National Natural Science Foundation of China/ ; }, abstract = {Background: Allostatic load reflects the cumulative physiological effects of chronic and repeated stress on the body and is associated with dysregulation of multiple systems. This study aimed to examine the association between the allostatic load score (ALS) and the development of delirium in intensive care unit (ICU) patients. Method: The adult patients from the Medical Information Mart for Intensive Care (MIMIC-IV) database were screened and included in this study. Allostatic load was scored by hemoglobin A1c, high-density lipoprotein, total cholesterol, systolic blood pressure, diastolic blood pressure, body mass index, C-reactive protein, and serum albumin, and varied from 0 to 8. Restricted cubic spline and multivariate logistic regression were used to assess the relationship between ALS and delirium risk in the ICU. The threshold of the ALS was determined by the decision tree approach. A sensitivity analysis was also conducted. Results: A total of 656 patients were included in the study, and the incidence of delirium was 50.6% (n = 332). In a fully adjusted restricted cubic spline model, an increase in ALS was linearly positively correlated with the occurrence of delirium in the ICU (p-overall = 0.039, p-nonlinear = 0.506). The threshold for ALS was determined to be 3. ALS ≥ 3 was associated with increased delirium rates (p < 0.001), longer hospital stays (p < 0.001), and higher in-hospital mortality (p = 0.002). Subgroup analyses revealed no significant interactions (all p values for interactions > 0.05). Conclusions: Higher ALS was linearly associated with increased risk of ICU delirium. An ALS ≥ 3 identified patients with greater delirium incidence, longer hospital stays, and higher mortality.}, } @article {pmid40508048, year = {2025}, author = {Tolochko, C and Shiryaeva, O and Alekseeva, T and Dyachuk, V}, title = {Amyotrophic Lateral Sclerosis: Pathophysiological Mechanisms and Treatment Strategies (Part 2).}, journal = {International journal of molecular sciences}, volume = {26}, number = {11}, pages = {}, pmid = {40508048}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/drug therapy/metabolism/therapy/etiology/pathology ; Humans ; Oxidative Stress/drug effects ; Animals ; Antioxidants/therapeutic use/pharmacology ; Motor Neurons/metabolism/pathology/drug effects ; Glutamic Acid/metabolism ; Neuroprotective Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with damage to motor neurons and leading to severe muscle weakness and, eventually, death. Over the past decade, understanding of the key pathogenetic links of ALS, including glutamate-mediated excitotoxicity and oxidative stress, has significantly advanced. This review considers the recent evidence on molecular mechanisms of these processes, as well as the therapeutic strategies aimed at their modulation. Special attention is paid to antiglutamatergic and antioxidant drugs as approaches to the ALS pathogenetic therapy.}, } @article {pmid40509360, year = {2025}, author = {Chang, B and Huang, J and Xie, Q and Ruan, Y and Liu, R}, title = {Identification, Geographical Traceability, and Thermal Oxidation and Photodegradation Studies of Camellia Oil Based on Raman Spectroscopy.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {11}, pages = {}, pmid = {40509360}, issn = {1420-3049}, support = {2024KY0802, 2023KY0217,XJ21KT29//the Middle-aged and Young Teachers' Basic Ability Promotion Project of Guangxi，The Guilin University of Aerospace Technology School Fund/ ; No. AD25069073//Guangxi Science and Technology Program Project/ ; }, mesh = {*Spectrum Analysis, Raman/methods ; *Plant Oils/chemistry/analysis ; *Camellia/chemistry ; Oxidation-Reduction ; Photolysis ; Carotenoids/chemistry/analysis ; Temperature ; Least-Squares Analysis ; Discriminant Analysis ; }, abstract = {Camellia oil, rich in monounsaturated fatty acids, squalene, tocopherols, and polyphenols, is highly valued for its nutritional benefits. However, its high market value and regional variations have led to frequent adulteration, highlighting the need for rapid, non-destructive methods for authentication, geographical traceability, and quality assessment. This study employed portable Raman spectroscopy combined with Partial Least Squares Discriminant Analysis (PLS-DA) and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to differentiate camellia oil from other edible oils and evaluate its thermal and photo-oxidative stability. PLS-DA, based on VIP-selected spectral variables, effectively distinguished camellia oil, with Raman bands near 1250 cm[-1] and 1650 cm[-1] contributing significantly. A unique peak at 1525 cm[-1], observed in samples from Gongcheng, Guangxi, was associated with carotenoids and served as a potential marker for geographical traceability. MCR-ALS modeling revealed significant reductions in the 1650 cm[-1] and 1525 cm[-1] peaks when temperatures exceeded 150 °C, indicating degradation of unsaturated fatty acids and carotenoids. Under UV exposure, the 1525 cm[-1] peak declined sharply and nearly disappeared after 24 h, suggesting rapid carotenoid degradation via photooxidation. Extended UV treatment also affected the 1650 cm[-1] peak and led to oxidative product accumulation. Overall, this study demonstrates the feasibility of integrating Raman spectroscopy with chemometric analysis for efficient oil classification, traceability, and stability monitoring, offering a valuable tool for food quality control and market supervision.}, } @article {pmid40510202, year = {2025}, author = {Li, L and Lv, L and Wang, Z and Liu, X and Wang, Q and Zhu, H and Jiang, B and Han, Y and Pan, X and Zhou, X and Ren, L and Chang, Z}, title = {From copper homeostasis to cuproptosis: a new perspective on CNS immune regulation and neurodegenerative diseases.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1581045}, pmid = {40510202}, issn = {1664-2295}, abstract = {Copper, an essential trace element for the human body, plays a key role in energy metabolism, mitochondrial respiration, redox reactions, and neural signal transmission. The recently proposed concept of "cuproptosis" has further revealed the unique status of copper in cellular regulation: when copper abnormally accumulates within cells, it can directly bind to the lipoylated proteins of the mitochondrial TCA cycle, triggering protein aggregation and metabolic disorders, ultimately leading to cell death. This form of cell death plays an important role in various neurodegenerative diseases of the central nervous system, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and stroke. This review summarizes recent research on the mechanisms of cuproptosis, providing new perspectives and a theoretical basis for understanding the pathogenesis of these neurodegenerative diseases.}, } @article {pmid40510242, year = {2025}, author = {Pfaff, AL and Bubb, VJ and Quinn, JP and Kõks, S}, title = {The landscape of non-reference SINE-VNTR-Alus in amyotrophic lateral sclerosis.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {250}, number = {}, pages = {10600}, pmid = {40510242}, issn = {1535-3699}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Minisatellite Repeats/genetics ; Genetic Predisposition to Disease ; Male ; Female ; *Short Interspersed Nucleotide Elements/genetics ; Middle Aged ; Gene Frequency ; }, abstract = {The fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS), leads to the degeneration of motor neurons in the brain and spinal cord. Many different genetic variants are known to increase the risk of developing ALS, however much of the disease heritability is still to be identified. To identify novel genetic factors, we characterised SINE-VNTR-Alu (SVA) presence/absence variation in 4403 genomes from the New York Genome Center (NYGC) ALS consortium. SVAs are a type of retrotransposon able to mobilise in the human genome generating new insertions that can modulate gene expression and mRNA splicing and to date 33 insertions are known to cause a range of genetic diseases. In the NYGC ALS consortium sequence data 2831 non-reference genome SVAs were identified and 95% of these insertions were rare with an insertion allele frequency of less than 0.01. Association analysis of the common SVAs with ALS risk, age at onset and survival did not identify any SVAs that survived correction for multiple testing. However, there were three different rare SVA insertions in the ALS associated gene NEK1 identified in four different individuals with ALS. The frequency of these rare insertions in NEK1 was significantly higher in the individuals with ALS from the NYGC ALS consortium compared to the gnomAD SV non-neuro controls (p = 0.0002). This study was the first to characterise non-reference SVA presence/absence variation in a large cohort of ALS individuals identifying insertions as potential candidates involved in disease development for further investigation.}, } @article {pmid40511793, year = {2026}, author = {Parks, ASE and Gotlib Conn, L and Amog, K and Bodmer, NS and King, JW and McLaren, AMR and Reid, M and Kishibe, T and Abrahao, A and Zinman, L and Sale, JEM}, title = {Age and life stage in the experience of amyotrophic lateral sclerosis: a scoping review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {1-27}, doi = {10.1080/21678421.2025.2515914}, pmid = {40511793}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Age Factors ; *Aging/psychology ; *Quality of Life/psychology ; Adult ; Middle Aged ; Aged ; Male ; Female ; }, abstract = {Objective: Understanding the experiences of people living with amyotrophic lateral sclerosis (plwALS) is necessary to appreciate their unique needs. Age and stage in the life course influence how illness is experienced; however, the extent to which age-specific complexities of living with ALS have been examined remains unexplored. This review aims to map the available evidence exploring age, age-graded role, or life-course transition with regards to the experience of ALS and to identify age-specific gaps in the literature. Methods: A scoping review guided by Joanna Briggs Institute methodology was undertaken. Eligible articles included peer-reviewed primary research studies, published in English from 2010 onward, investigating illness experience of adults with ALS with consideration for how age, age-graded roles, or life-course transitions influenced experience. Database sources included: Ovid's Medline, Embase, and PsycINFO; EBSCO CINAHL; and ProQuest Sociological Abstracts. Findings related to ALS experience and dimensions of age were summarized descriptively and categorized using qualitative content analysis. Results: Six thousand one hundred and eighty individual records were identified and screened. Forty-five articles, reporting 42 studies, were included. Findings regarding thoughts, feelings, or emotions of plwALS were most common and varied depending on whether they were in reference to chronological age or age-graded role. Despite the importance of life-course transitions for illness experience, they were not routinely considered. Conclusion: Numerous aspects of the experience of plwALS have been reported in reference to age; however, the significance of age-graded roles and life-course transitions warrants further examination. Recognition of age-related complexities of living with ALS will facilitate more personalized ALS care.}, } @article {pmid40511876, year = {2025}, author = {Yeole, A and Khanna, L and Doshi, M and Sharma, A and Uttarwar, P and Doshi, S and Kaushik Kumar, R and Venkataramana, N and Parmar, D}, title = {A phase 2, proof-of-concept, placebo-controlled, randomized, multicenter, double-blind study to evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of Usnoflast (ZYIL1) in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {794-801}, doi = {10.1080/21678421.2025.2515900}, pmid = {40511876}, issn = {2167-9223}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; Dose-Response Relationship, Drug ; Double-Blind Method ; Neurofilament Proteins/cerebrospinal fluid/blood ; *Organic Chemicals/administration & dosage/adverse effects/pharmacokinetics ; Proof of Concept Study ; Treatment Outcome ; }, abstract = {Objective: To assess the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of Usnoflast (ZYIL1) in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients with a probable or definite ALS diagnosis were randomized to receive twice daily oral doses (for 12 weeks) of Usnoflast (25 mg, 50 mg, or 75 mg) or placebo. The primary outcome was the change in ALS functional rating scale-revised (ALSFRS-R) total score from baseline to week 12. Secondary outcomes were assessment of PK, change in slow vital capacity (SVC) and serum and cerebrospinal fluid (CSF) levels of neurofilament light (NfL) chain from baseline to week 12, and safety up to 12 weeks. Results: Total 24 patients were enrolled; 71% of those who received Usnoflast had the drug above therapeutic concentration in CSF. In the modified intent-to-treat (mITT) population, least square mean changes (ANCOVA) in ALSFRS-R total score from baseline to week 12 were -1.91 for Usnoflast 25 mg, -3.84 for Usnoflast 50 mg, 0.52 for Usnoflast 75 mg, and -2.26 for placebo arm. Though not significant (p > 0.05), compared with placebo, Usnoflast 75 mg demonstrated a difference of 2.78 (mITT) and 3.28 (per-protocol) in ALSFRS-R total score. Statistical non-significant differences were also observed in changes of SVC% and CSF NfL levels. Usnoflast was well-tolerated at tested doses, and there was no treatment-emergent serious adverse event or death during the study duration. Conclusion: Usnoflast 50 and 75 mg doses were well-tolerated in ALS patients, providing rationale for further studies of Usnoflast in ALS.}, } @article {pmid40513028, year = {2025}, author = {Bromberg, MB}, title = {What Is in the Literature.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {4}, pages = {176-183}, doi = {10.1097/CND.0000000000000526}, pmid = {40513028}, issn = {1537-1611}, mesh = {Humans ; *Motor Neuron Disease/therapy/diagnosis ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis ; }, abstract = {This issue of What Is in the Literature focuses on articles over the past year on clinical aspects of motor neuron disease, including amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). Disease-modifying treatment for ALS remains a challenge as 2 formal drug trials did not hold up to retesting. There are new thoughts based on a multistep model to partially explain why ALS develops relatively late in life. New information on fluid biomarkers, sex differences, efficacy of medical marijuana for common symptoms, and cognitive dysfunction are discussed. For the clinic, there are updated guidelines for multidisciplinary management. Other articles address how frequently the topic of sexual health is brought up in the clinic, and insights into how patients view end-of-life issues and quality of life when using tracheal ventilation. PLS has diagnostic challenges and practical aspects, which are reviewed.}, } @article {pmid40513650, year = {2025}, author = {Ho, CY and Chang, YJ and Yang, CW and Shih, O and Jeng, US and Hwang, IS and Huang, WC and Chen, YR}, title = {Membrane Disruption Properties of Poly-Glycine Arginine Dipeptide Repeats Affected by Peptide Repeats Continuity and Membrane Composition.}, journal = {Journal of molecular biology}, volume = {437}, number = {17}, pages = {169296}, doi = {10.1016/j.jmb.2025.169296}, pmid = {40513650}, issn = {1089-8638}, mesh = {*Cell Membrane/metabolism/chemistry ; Humans ; C9orf72 Protein/genetics ; *Peptides/chemistry/metabolism ; *Dipeptides/chemistry/metabolism ; Liposomes/chemistry/metabolism ; Animals ; Mice ; }, abstract = {C9ORF72 hexanucleotide expansion is the most common genetic mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTD). This expansion can be translated into dipeptide repeats (DPRs) through repeat-associated non-ATG (RAN) translation. Arginine-rich DPRs, i.e., poly-glycine arginine (poly-GR) and poly-proline arginine (poly-PR) are considered the most toxic ones among the five types of DPRs. We recently discovered that poly-GR forms helical conformation and is able to penetrate cell membranes, leading to cytotoxicity, but the mechanism remains unclear. Here, we investigated the membrane disruption mechanism of poly-GR related to its sequence and membrane composition. To test this, we stopped its continuously repeated sequence by inserting several proline residues to disrupt its helical structure. We found that the modification reduced its cytotoxicity and membrane disruption capability. Next, we examined the influence of lipid composition on the membrane-disrupting ability of poly-GR using various liposomes. Poly-GR caused higher leakage in the negatively charged liposomes compared to the neutral or positively charged ones. Cholesterol content affected the extent of disruption, while gangliosides had no significant effect. Using small-angle x-ray scattering (SAXS), total internal reflection fluorescence (TIRF) microscopy, and atomic force microscopy (AFM), we observed the behavior of poly-GR on lipid membranes. Finally, we directly treated mouse neuroblastoma to modulate the cholesterol content and found that cholesterol depletion inhibited the internalization of poly-GR into the cells and reduced cytotoxicity. These findings reveal that the conformation of poly-GR and the lipid composition influence its membrane penetration, offering insights into potential therapeutic strategies for C9ORF72-related diseases.}, } @article {pmid40514097, year = {2025}, author = {Artuğ, NT and Sirin, NG and Baslo, SA and Orhan, EK and Baslo, MB and Oge, AE}, title = {Automated step analysis algorithm for CMAP scan study.}, journal = {Medical engineering & physics}, volume = {141}, number = {}, pages = {104353}, doi = {10.1016/j.medengphy.2025.104353}, pmid = {40514097}, issn = {1873-4030}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; *Algorithms ; Automation ; *Action Potentials ; Aged ; Adult ; Software ; Reproducibility of Results ; Case-Control Studies ; *Electromyography/methods ; }, abstract = {OBJECTIVE: To create an automated method for step analysis in compound muscle action potential (CMAP) scan curves and compare the step parameters calculated using the conventional semi-automated and the new automated method between patients with amyotrophic lateral sclerosis (ALS) and controls.

METHODS: Twenty ALS patients and fifteen controls were enrolled into the study. Median nerve was stimulated at the wrist to record CMAP scans from abductor pollisis brevis muscle. Automated step analysis software revealed gaps on CMAP scan graphics by using new parameters indicating the steps. New parameters were calculated and compared with the conventional semi-automated step analysis. Intra-class correlation coefficients (ICC) were measured for reliability between methods.

RESULTS: Step parameters calculated by two methods showed no significant difference in patients with ALS, except step%, but their similarities were less favorable in controls. The reliability of parameters between two methods was good-to-excellent in patient group, but controls did not show a significant ICC for any of the parameters.

CONCLUSION: A completely new automated step analysis software was developed. Analyses were done within 5 s. New step parameters were presented with supporting graphics. Results of automated step analysis were in concordance with semi-automated one for ALS patients, but not in controls.}, } @article {pmid40514455, year = {2025}, author = {Hu, YQ and Zhang, XX and Zhao, TT and Wu, XH}, title = {Using proteomics and single-cell sequencing to analyze the pathogenesis of recurrent implantation failure associated with uterine natural killer cells.}, journal = {Archives of gynecology and obstetrics}, volume = {312}, number = {3}, pages = {885-900}, pmid = {40514455}, issn = {1432-0711}, support = {H2023106006//Natural Science Foundation of Hebei Province/ ; 213777102D//The Key Research and Development project of Hebei Province/ ; 20251109//Medical Science Research Project of Hebei/ ; }, mesh = {Humans ; Female ; *Killer Cells, Natural/metabolism ; Proteomics ; Single-Cell Analysis ; *Endometrium/metabolism/immunology ; *Embryo Implantation/immunology/genetics ; Adult ; *Infertility, Female/genetics ; Case-Control Studies ; }, abstract = {PROBLEM: Recurrent implantation failure (RIF) affects about 10% of infertility patients and may involve mid-luteal phase endometrial natural killer (NK) cells. The pathogenesis of NK cells in RIF remains unclear.

METHOD OF STUDY: Our study integrated proteomics data from endometrial tissues of six RIF patients and six controls, with single-cell sequencing insights.

RESULTS: Our proteomics analysis identified 1366 differentially expressed proteins (DEPs) between RIF and control groups, highlighting alterations in cellular processes, such as cytoplasmic translation and mRNA processing. Functional enrichment analysis revealed significant associations with pathways involved in amyotrophic lateral sclerosis and proteasomes. The DEPs were transformed into differentially expressed genes1 (DEGs1) by ID-transformation. 33 candidate genes were detected when ID-transformed 1210 DEGs1 were intersected with 752 DEGs2 from NK cells. After that, the proteomics sequencing data validation showed that the expression of AMPD3, H6PD, and PAK2 was consistent and significantly different from the GSE111974 dataset and classified as crucial genes. In addition, analysis of single-cell sequencing data annotated fibroblast-like stromal cells, NK cells, T cells, and endothelial cells, and these three essential genes showed that they were expressed in NK cells. Crossing the signaling pathways of key genes with those enriched for DEPs yielded the 'Escherichia coli infection' possibly associated with RIF. Finally, the transcription factor HR had a strong regulatory effect on the PAK2.

CONCLUSION: Finally, identifying three key genes (AMPD3, H6PD and PAK2) associated with RIF and the regulatory solid roles of HR and PAK2 provided a basis for understanding the molecular mechanism of RIF. Our findings may pave the way for developing targeted therapies to improve pregnancy outcomes in patients with RIF.}, } @article {pmid40515812, year = {2026}, author = {Jellinger, KA}, title = {Prevalence and impact of comorbidities in amyotrophic lateral sclerosis.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {133}, number = {3}, pages = {379-396}, pmid = {40515812}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Comorbidity ; Prevalence ; *Cardiovascular Diseases/epidemiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of multifaceted nature and variable progression that poses considerable challenges to our understanding of its evolution and interplay with different comorbid conditions. The etiopathogenesis of ALS is still unexplained and multimorbidity is common, but its influence on the ALS susceptibility and disease course is a matter of discussion. This study using medical databases tries to find diseases associated with ALS and their impact on disease onset and progression. Diseases associated with the risk of ALS include diabetes mellitus, dyslipidemias and cardiovascular comorbidities that may play an important role in the prognosis of ALS. Hypometabolic disorders and cardiovascular diseases may have a protective effect on ALS incidence, while coronary heart disease and hypertension have a negative effect on disease progression. Other comorbidities include Parkinson disease, TDP-43 pathology, progressive supranuclear palsy, progressive aphasia, myasthenia gravis, cancer and autoimmune disorders, while there is no evidence for a shared genetic background of common risk variants in ALS and multiple sclerosis. Among non-motor manifestations of ALS, cognitive and behavioral impairments are important. Other comorbidities include sleep disorders, traumatic encephalopathy, sarcoidosis, prionopathies, schizophrenia, cervical spondylotic myelopathy, psoriasis and others. The tremendous heterogeneity of concomitant pathologies and comorbidities observed across the ALS spectrum may be caused by a complex interplay between genetic, pathogenetic, inflammatory and other risk factors that are still poorly understood. Further research should provide increasing insight into their relationship with motor system disorders in order to find better diagnostic tools and probable effective therapies for these disease-modifying comorbidities.}, } @article {pmid40515975, year = {2025}, author = {Zhu, Y and Neyrinck, K and Burg, T and Chai, YC and Nami, F and Ahuja, K and Swinnen, JV and Van Den Bosch, L and Verfaillie, C}, title = {Altered Lipid Homeostasis in Mutant FUS[R521H] Astrocytes from HiPSCs.}, journal = {Molecular neurobiology}, volume = {62}, number = {9}, pages = {11025-11029}, pmid = {40515975}, issn = {1559-1182}, support = {201908440360//China Scholarship Council/ ; 12AIK24N//Fonds Wetenschappelijk Onderzoek/ ; FWO-SBO-S001221N -ORGAN-ID//Fonds Wetenschappelijk Onderzoek/ ; C14-17-107//University of Leuven C1 grants/ ; }, mesh = {*Astrocytes/metabolism ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; *Lipid Metabolism ; *Homeostasis ; *Mutation/genetics ; *RNA-Binding Protein FUS/genetics/metabolism ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss, leading to paralysis and death. Mutations in the fused in sarcoma (FUS) gene cause early-onset ALS with rapid disease progression. Although motor neuron degeneration is central to ALS, recent studies highlight a significant role for dysfunctional glial cells, particularly astrocytes, in disease progression. In this study, we generated astrocytes from FUS[R521H] mutant and isogenic human induced pluripotent stem cells (hiPSCs) by inducible overexpressing SOX9. Lipidomic analysis revealed marked glycerophospholipid deficiencies in FUS[R521H] mutant astrocytes, especially reduced phosphatidylcholine (PC) and phosphatidylinositol (PI) levels. This reduction in PC was also observed in FUS[R521H] mutant oligodendroglial progenitors and motor neurons, suggesting a potential dysregulation of glycerophospholipid metabolism across multiple central nervous system (CNS) cell types in FUS-ALS. These observations highlight the need for further investigation into lipid dysregulation and its relevance to FUS-ALS pathogenesis.}, } @article {pmid40516449, year = {2025}, author = {Yadav, AJ and Padhi, AK}, title = {Synergizing multiresolution simulations, interface redesign, and hotspot mapping to decipher pathogenic mutation-driven structural modulation in VCP.}, journal = {Computers in biology and medicine}, volume = {194}, number = {}, pages = {110560}, doi = {10.1016/j.compbiomed.2025.110560}, pmid = {40516449}, issn = {1879-0534}, mesh = {*Valosin Containing Protein/genetics/chemistry/metabolism ; Humans ; *Molecular Dynamics Simulation ; *Mutation, Missense ; Mutation ; }, abstract = {Valosin-containing protein (VCP/p97), a pivotal AAA[+] ATPase, orchestrates proteostasis via ER-associated degradation (ERAD), ubiquitin-mediated proteolysis, and organelle surveillance. Pathogenic missense mutations, notably Arg95Gly (R95G) within the evolutionarily conserved double-ψ β-barrel (DPBB) of its N-terminal domain, are implicated in proteinopathies including IBMPFD and ALS. To decode the structural-dynamics perturbations underpinning R95G-driven dysfunction, we integrated AlphaFold3-based modeling, protein-peptide docking, and multiscale enhanced-sampling molecular dynamics (MD) simulations-spanning 1.2 μs all-atom, 12 μs coarse-grained, and umbrella sampling regimes. Our findings reveal that R95G disrupts the β-barrel integrity, destabilizes long-range domain coupling, and engenders conformational heterogeneity deleterious to gp78 cofactor recruitment. Free-energy landscapes of the mutant highlight enthalpically disfavored, low-occupancy binding conformers, corroborated by MM/PBSA-based end-state binding free energy and potential of mean force (PMF) analyses, which indicate impaired binding thermodynamics. Interface hotspot mapping pinpoints dynamic perturbations at critical residues that propagate allosteric decoupling and morphological distortion of the binding interface. Collectively, our results delineate a mechanistic cascade-from local β-barrel destabilization to global interaction network disruption-underlying VCP's functional impairment in disease states. This work provides a computationally derived structural framework to inform targeted biophysical validation and the rational design of therapeutic strategies aimed at rescuing VCP function in IBMPFD and ALS.}, } @article {pmid40516596, year = {2025}, author = {Kitamura, K and Tsukui, I and Sasaki, F and Shiramasa, Y and Arayama, M and Morishita, M and Oshima, A and Kitazawa, S and Kameda, T and Kitahara, R}, title = {ATP as a Key Modulator of Fused-in-sarcoma Phase Separation and Aggregation: Insights into Amyotrophic Lateral Sclerosis Pathogenesis.}, journal = {Journal of molecular biology}, volume = {437}, number = {17}, pages = {169295}, doi = {10.1016/j.jmb.2025.169295}, pmid = {40516596}, issn = {1089-8638}, mesh = {*RNA-Binding Protein FUS/metabolism/chemistry/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Adenosine Triphosphate/metabolism/chemistry ; Humans ; Molecular Dynamics Simulation ; Protein Aggregates ; *Protein Aggregation, Pathological/metabolism ; Phase Separation ; }, abstract = {Fused in sarcoma (FUS) is an RNA-binding protein, the aberrant aggregation of which is linked to amyotrophic lateral sclerosis (ALS). Liquid-liquid phase separation (LLPS) of FUS facilitates functional condensate formation and can drive pathological aggregation under certain conditions. The aggregation-inhibitory effects of ATP, a key cellular hydrotrope, have been reported for multiple proteins; however, how ATP, present at approximately 1-12 mM concentrations in cells, regulates LLPS and amyloid fibril formation remains unclear. Therefore, we investigated how ATP modulates the LLPS behavior and aggregation of FUS and its ALS-linked variants, R495X and P525L. ATP destabilized both normal LLPS and aberrant high-pressure LLPS (HP-LLPS), with a relatively strong inhibitory effect on HP-LLPS. Pressure-jump experiments demonstrated that ATP reduced the irreversible aggregation propensity of HP-LLPS, particularly in ALS variants that exhibited enhanced aggregation compared to that by wild-type FUS. Molecular dynamic simulations further revealed that the triphosphate and adenosine moieties of ATP synergistically disrupted intermolecular interactions that were crucial for phase separation, leveraging its amphipathic properties. Notably, ATP concentrations within the physiological range (1-12 mM) significantly inhibited FUS aggregation, suggesting a protective role in cellular environments. These results indicate that decreased intracellular ATP levels may exacerbate aberrant phase transitions of FUS, contributing to ALS onset. This study underscores the potential of ATP as a therapeutic modulator of protein phase separation and aggregation, providing valuable insights into the molecular mechanisms of ALS. Our findings open new avenues for targeting ATP-regulated pathways for treating neurodegenerative disorders.}, } @article {pmid40516772, year = {2025}, author = {Rawat, E and Sharma, S and Vyas, S and Alsaidan, OA and Kapoor, DU and Prajapati, BG}, title = {Advances in alginate-based nanoformulations: Innovative and effective strategies for targeting and treating brain disorders.}, journal = {International journal of pharmaceutics}, volume = {681}, number = {}, pages = {125851}, doi = {10.1016/j.ijpharm.2025.125851}, pmid = {40516772}, issn = {1873-3476}, mesh = {*Alginates/chemistry/administration & dosage ; Humans ; *Brain Diseases/drug therapy ; Animals ; *Drug Delivery Systems/methods ; *Nanoparticles/chemistry/administration & dosage ; Blood-Brain Barrier/metabolism ; Drug Carriers/chemistry ; }, abstract = {Brain disorders, encompassing neurodegenerative conditions and intracranial neoplasms, present formidable obstacles in the realm of pharmacological delivery due to the existence of athe blood-brain barrier (BBB) and the restricted bioavailability of therapeutic agents. Alginate-derived nanoformulations have emerged as highly promising systems for drug delivery, offering attributes such as biocompatibility, regulated release, and improved targeting efficacies. This review investigates contemporary advancements in alginate-based nanoformulations, with a particular emphasis on their efficacy in surmounting obstacles to successful pharmacological delivery to the brain. Initially, we furnish a comprehensive overview of alginate, underscoring its pertinent properties, biomedical applications, and inherent limitations. Subsequently, the discourse progresses to strategies for nanoformulation, which encompass lipid-based, polymeric, and inorganic methodologies, with a focus on their benefits in relation to cerebral targeting. Moreover, this review entails the therapeutic potential of alginate-based nanoformulations in addressing significant neurological disorders, including Alzheimer's disease, Parkinson's disease, brain tumours, traumatic brain injury, epilepsy, and amyotrophic lateral sclerosis. By amalgamating cutting-edge nanotechnology with the distinctive properties of alginate, these formulations signify a promising pathway for the advancement of efficacious therapies aimed at brain targeting. Additionally, prospective research trajectories and challenges associated with the optimization of alginate-based nanocarriers for clinical applications are also elucidated.}, } @article {pmid40517187, year = {2026}, author = {Haro-Martínez, E and Muscolino, E and Moral, N and Duran, J and Fornaguera, C}, title = {Crossing the blood-brain barrier: nanoparticle-based strategies for neurodegenerative disease therapy.}, journal = {Drug delivery and translational research}, volume = {16}, number = {3}, pages = {797-824}, pmid = {40517187}, issn = {2190-3948}, support = {2021 SGR 00537//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; 2024-LLAV-00042//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; ICREA Acadèmia 2024//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; 202207-31//Fundació la Marató de TV3/ ; PID2020-118699GB-100//Agencia Estatal de Investigación/ ; Not specified//Fundación Ramón Areces/ ; FISDUR-2024//Departament d'Universitats, Recerca i Societat de la Informació/ ; }, mesh = {Humans ; *Blood-Brain Barrier/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Nanoparticles/administration & dosage/chemistry ; Drug Delivery Systems ; Drug Carriers/chemistry ; }, abstract = {Neurodegenerative conditions, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's disease, represent a critical medical challenge due to their increasing prevalence, severe consequences, and absence of curative treatments. Beyond the need for a deeper understanding of the fundamental mechanisms underlying neurodegeneration, the development of effective treatments is hindered by the blood-brain barrier, which poses a major obstacle to delivering therapeutic agents to the central nervous system. This review provides a comprehensive analysis of the current landscape of nanoparticle-based strategies to overcome the blood-brain barrier and enhance drug delivery for the treatment of neurodegenerative diseases. The nanocarriers reviewed in this work encompass a diverse array of nanoparticles, including polymeric nanoparticles (e.g. micelles and dendrimers), inorganic nanoparticles (e.g. superparamagentic iron oxide nanoparticles, mesoporous silica nanoparticles, gold nanoparticles, selenium and cerium oxide nanoparticles), lipid nanoparticles (e.g. liposomes, solid lipid nanoparticles, nanoemulsions), as well as quantum dots, protein nanoparticles, and hybrid nanocarriers. By examining recent advancements and highlighting future research directions, we aim to shed light on the promising role of nanomedicine in addressing the unmet therapeutic needs of these diseases.}, } @article {pmid40518263, year = {2025}, author = {Alali, S and Dubin, J and Hobin, F and Das, S and Lambrechts, C and Stoops, E and Vanmechelen, E and van Damme, P and Poesen, K}, title = {Serum neuronal pentraxin 2 levels are associated with shorter survival in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {11}, pages = {1126-1128}, pmid = {40518263}, issn = {1468-330X}, } @article {pmid40518671, year = {2025}, author = {Val, GD and Gauye, F and Audrain, M and Menant, S and Ratnam, M and Chevalier, E and Ollier, R and Bhatia, D and Seredenina, T and Afroz, T and Pfeifer, A and Kosco-Vilbois, M and Nevoltris, D}, title = {A single dose of a vectorized mAb targeting TDP-43 potently inhibits the neuropathology in a model of ALS/FTD.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {9}, pages = {4360-4380}, pmid = {40518671}, issn = {1525-0024}, support = {P01 AG019724/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/pathology/metabolism/genetics ; *DNA-Binding Proteins/immunology/antagonists & inhibitors/genetics/metabolism ; *Frontotemporal Dementia/therapy/pathology/metabolism/genetics ; Mice ; Disease Models, Animal ; Humans ; *Antibodies, Monoclonal/genetics/administration & dosage/immunology ; *Genetic Vectors/genetics/administration & dosage ; Dependovirus/genetics ; Brain/metabolism/pathology ; }, abstract = {Transactive response DNA binding protein-43 (TDP-43)-mediated pathology is a hallmark of devastating neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Thus, monoclonal antibodies (mAbs) are being developed to target the pathological forms of this protein. To improve mAb exposure within the central nervous system, a potent anti-TDP-43 mAb, ACI-5891, was generated as a vectorized full-length antibody (vmAb) and evaluated for brain delivery using adeno-associated virus 9 (AAV9). Among the expression cassettes explored, the selected construct utilized an internal ribosome entry site (IRES), which produced high expression yields in vitro (>200 mg/L) with comparable quality, binding, and functional properties to the conventionally produced mAb. A single intracisternal administration of vmAb ACI-5891 demonstrated a broad brain distribution and sustained expression (i.e., months) in the serum, cerebrospinal fluid, and brain of mice. In a mouse model of ALS/FTD, treatment with a vmAb reduced the amount of pathological phospho-TDP-43 in neurons by 58% and 68% when expressed using either a ubiquitous promoter or a brain-selective promoter, respectively. This innovative approach sufficiently delivers effective immunotherapy with a single dose and illustrates the enormous potential of using vectorized antibodies to target neuropathology, including TDP-43 in patients suffering from ALS, FTD, and other TDP-43 proteinopathies.}, } @article {pmid40518845, year = {2025}, author = {Erdal, Y and Mahmutoglu, AS and Yavuz, N and Mahmutoglu, O and Emre, U}, title = {Assessment of cervical skeletal muscle index in early and late phases of amyotrophic lateral sclerosis.}, journal = {Neurological research}, volume = {47}, number = {12}, pages = {1239-1244}, doi = {10.1080/01616412.2025.2520010}, pmid = {40518845}, issn = {1743-1328}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; Magnetic Resonance Imaging ; Retrospective Studies ; Aged ; *Muscle, Skeletal/diagnostic imaging/pathology ; Cervical Vertebrae/diagnostic imaging ; *Neck Muscles/diagnostic imaging ; Adult ; }, abstract = {OBJECTIVES: The diagnosis of Amyotrophic Lateral Sclerosis (ALS) can be challenging when clinical and electrophysiological findings are insufficient. We aimed to investigate the potential role of cervical Skeletal Muscle Index (SMI), as a supportive diagnostic marker in ALS, particularly in relation to disease duration.

METHODS: A total of 22 ALS patients and 25 age- and sex-matched controls were retrospectively included. The cross-sectional area (CSA) of cervical muscles was measured on axial T1-weighted magnetic resonance imaging (MRI) at the C3 vertebra level. SMI was calculated by normalizing the total CSA to patient height (mm[2]/m[2]). ALS patients were stratified based on the timing of MRI: within six months of symptom onset and after six months.

RESULTS: There were no significant differences in age, sex, BMI, or total muscle volume between patients and controls. Although mean SMI was slightly lower in ALS patients (p = 0.177), this difference was not statistically significant. Among ALS patients, those who underwent MRI more than six months after symptom onset had significantly lower SMI values compared to both those who underwent MRI within six months and controls (respectively, p = 0.014, p = 0.018). No significant SMI difference was observed between ALS patients who underwent MRI within six months and controls (p = 0.626).

CONCLUSION: Cervical SMI measurements at the C3 vertebral level may support ALS diagnosis, particularly in patients with longer disease duration. SMI may also provide insight into early muscle loss due to denervation.}, } @article {pmid40519505, year = {2025}, author = {Funo, K and Fukutake, T and Takeuchi, R and Uzawa, Y}, title = {Importance of Individualized Pressure Settings in Mechanical Insufflation-Exsufflation for Lung Volume Recruitment: A Case Report.}, journal = {Cureus}, volume = {17}, number = {5}, pages = {e84211}, pmid = {40519505}, issn = {2168-8184}, abstract = {Lung volume recruitment (LVR) has been proposed as a treatment to maintain respiratory health in patients with neuromuscular diseases who frequently develop restrictive ventilatory impairment due to muscle weakness. LVR applies noninvasive mechanical pressure techniques to maintain and improve pulmonary and chest wall compliance and to preserve vital capacity. Various methods of LVR have been developed, which can be classified into two types: the stacked-breath method and the single-breath method. Mechanical insufflation-exsufflation (MI-E) is one approach categorized under the single-breath method. Although the clinical use of pressure settings in MI-E varies, inspiratory pressure levels around 40 cmH2O are sometimes applied in practice. However, such settings may result in patient discomfort and raise safety concerns. Given the limited clinical guidance available, it may be more appropriate to determine individualized settings based on each patient's impairment level, pulmonary mechanics, and tolerance. This case report describes such an approach to LVR using the single-breath method with MI-E in a patient with amyotrophic lateral sclerosis (ALS). To determine the optimal inspiratory pressure, three parameters were assessed at each pressure level: expiratory volume, subjective perception of lung expansion, and immediate subjective effects following inspiration. As the patient reported discomfort at 30 cmH2O, the final inspiratory pressure was set at 25 cmH2O. This level of inspiratory assistance led to improvements in vocal loudness and alleviated breathlessness during speech. These positive effects contributed to the patient's acceptance of the intervention and its continued use after discharge to home care. This case highlights the importance of tailoring LVR settings to optimize effectiveness, patient comfort, and safety, based on pulmonary mechanics, bedside volume assessment, and patient-reported respiratory status.}, } @article {pmid40520109, year = {2025}, author = {Evangelista, BA and Ragusa, JV and Pellegrino, K and Wu, Y and Quiroga-Barber, IY and Cahalan, SR and Arooji, OK and Madren, JA and Schroeter, S and Cozzarin, J and Xie, L and Chen, X and White, KK and Ezzell, JA and Iannone, MA and Cohen, S and Phanstiel, DH and Meeker, RB and Cohen, TJ}, title = {ALS-associated TDP-43 aggregates drive innate and adaptive immune cell activation.}, journal = {iScience}, volume = {28}, number = {6}, pages = {112648}, pmid = {40520109}, issn = {2589-0042}, support = {R01 AG066871/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common and fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, transactive response DNA binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 aggregates elicit immune responses remains underexplored. In this study, we demonstrate that TDP-43 aggregates are internalized by antigen-presenting cell populations, cause vesicle rupture, and drive innate and adaptive immune cell activation by way of antigen presentation. Using a multiplex imaging platform, we observed enrichment of activated microglia/macrophages in ALS white matter that correlated with phosphorylated TDP-43 accumulation, CD8 T cell infiltration, and major histocompatibility complex expression. Taken together, this study sheds light on a novel cellular response to TDP-43 aggregates through an immunological lens.}, } @article {pmid40521002, year = {2025}, author = {Wei, Y and Rhee, H and Najafi, H and Blair, S and Kim, NC and Kim, WJ}, title = {Glial subtype-specific modulation of disease pathogenesis in Drosophila models of ALS.}, journal = {Genes & diseases}, volume = {12}, number = {5}, pages = {101631}, pmid = {40521002}, issn = {2352-3042}, } @article {pmid40522761, year = {2026}, author = {Fan, T and Peng, J and Liang, H and Chen, W and Wang, J and Xu, R}, title = {Potential common pathogenesis of several neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {21}, number = {3}, pages = {972-988}, pmid = {40522761}, issn = {1673-5374}, abstract = {With the gradual advancement of research methods and technologies, various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases. However, current descriptions of these biological processes do not fully explain the onset, progression, and development of these conditions. Therefore, exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research. This review summarizes the potential common pathogeneses of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, frontotemporal lobar dementia, and Lewy body disease. Research findings have indicated that several common biological processes, including aging, genetic factors, progressive neuronal dysfunction, neuronal death and apoptosis, protein misfolding and aggregation, neuroinflammation, mitochondrial dysfunction, axonal transport defects, and gut microbiota dysbiosis, are involved in the pathogenesis of these six neurodegenerative diseases. Based on current information derived from diverse areas of research, these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases. Furthermore, promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed. Hence, these potential common biological processes may represent only very small, limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases. In clinical treatment, interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases. Therefore, future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks, rather than isolating individual biological processes. Based on this, therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions, as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.}, } @article {pmid40523537, year = {2025}, author = {Risby-Jones, G and Marallag, J and Jagaraj, CJ and Atkin, JD and Walker, AK and Woodruff, TM and Lee, JD and Fung, JN}, title = {IL-6 trans-signalling is elevated in ALS models and drives TDP-43 induced inflammatory responses in microglia.}, journal = {Brain, behavior, and immunity}, volume = {129}, number = {}, pages = {296-304}, doi = {10.1016/j.bbi.2025.06.021}, pmid = {40523537}, issn = {1090-2139}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/immunology ; *Microglia/metabolism ; *Interleukin-6/metabolism ; Mice ; Mice, Transgenic ; Signal Transduction/physiology ; *DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Humans ; Inflammation/metabolism ; Spinal Cord/metabolism ; Receptors, Interleukin-6/metabolism ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by chronic inflammation in both the central nervous system (CNS) and peripheral tissues. Interleukin-6 (IL-6) has been implicated in ALS pathology; however, IL-6 exhibits both anti-inflammatory and pro-inflammatory functions. Notably, IL-6 trans-signalling possesses pro-inflammatory properties and is emerging as a key contributor to neuroinflammation during neurodegeneration. In this study, we aimed to characterize the expression of the IL-6 trans-signalling pathway in ALS mouse models and investigate its role in ALS protein aggregate-mediated inflammation in microglia and peripheral immune cells. Our results revealed that the protein expression level of a key IL-6 trans-signalling component, soluble IL-6 receptor (sIL-6R), was significantly increased in the spinal cord and tibialis anterior (TA) muscles of both SOD1[G93A] and rNLS8 TDP-43 transgenic mice. Additionally, using mouse primary microglia, human monocyte-derived microglia-like cells (MDMi), and blood peripheral immune cells, we demonstrated that recombinant TDP-43 protein elicits robust pro-inflammatory cytokine responses, including IL-6, TNF-α, IL-23, and MCP-1. These responses were attenuated when treated with a specific IL-6 trans-signalling inhibitor, sgp130Fc. Our findings suggest that the TDP-43-induced inflammatory response is, in part, IL-6 trans-signalling-dependent and highlight the role of IL-6 trans-signalling as a potential driver of chronic inflammation contributing to ALS pathology. These results support IL-6 trans-signalling as a promising therapeutic target for mitigating inflammation and slowing disease progression. Future research should explore the broader implications of modulating IL-6 trans-signalling in ALS.}, } @article {pmid40523602, year = {2025}, author = {Horikawa, I and Yamada, L and Harris, BT and Harris, CC}, title = {Δ133p53α-mediated inhibition of astrocyte senescence and neurotoxicity as a possible therapeutic approach for neurodegenerative diseases.}, journal = {Neuroscience}, volume = {580}, number = {}, pages = {54-61}, pmid = {40523602}, issn = {1873-7544}, support = {ZIA BC011496/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Astrocytes/metabolism/drug effects/pathology ; *Cellular Senescence/physiology ; *Tumor Suppressor Protein p53/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; Animals ; Protein Isoforms/metabolism ; }, abstract = {Non-neuronal glial cells in the brain, such as astrocytes, play essential roles in maintaining the functional integrity of neuronal cells. A growing body of evidence suggests that cellular senescence of astrocytes, characterized by loss of proliferative potential and secretion of neurotoxic cytokines, makes significant contribution to neurotoxicity in Alzheimer's disease and a wide range of other neurodegenerative diseases. This review discusses the beneficial effects of Δ133p53α, a natural p53 protein isoform that inhibits p53-mediated cellular senescence, thereby protecting astrocytes from senescence, highlights its potential as a therapeutic target, and underscores the need for continued research in this area. Both in senescent human astrocytes in culture, whether induced by replicative exhaustion, irradiation or exposure to amyloid-β, and in brain tissues with increased senescent astrocytes from patients with Alzheimer's disease, the expression levels of endogenous Δ133p53α protein were consistently and significantly reduced. The lentiviral vector-driven expression of Δ133p53α protected cultured human astrocytes from cellular senescence and neurotoxic secretory phenotype, leading to their cellular reprogramming to a neuroprotective state associated with neurotrophic growth factors. We thus propose that Δ133p53α is worth testing as a therapeutic target that can be enhanced in a wide range of neurodegenerative diseases with accumulated senescent astrocytes, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and chronic traumatic encephalopathy due to traumatic brain injury. We hypothesize that a Δ133p53α-mediated cellular reprogramming approach and a senolytic or senomorphic approach, both targeting non-neuronal cells, may be complementary with each other, and may cooperate with neuron-protecting or amyloid-β-targeting therapies currently in use.}, } @article {pmid40524081, year = {2025}, author = {Uygun, Ö and Unkun, R and Asan, F and Gündüz, A}, title = {Facial onset sensory-motor neuronopathy: diagnostic challenges and insights from a case report.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {10}, pages = {5555-5557}, pmid = {40524081}, issn = {1590-3478}, } @article {pmid40524084, year = {2025}, author = {Ticozzi, N and Padovani, A and Filosto, M and , }, title = {ALS global day 2025: research and clinical advances.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {8}, pages = {3359-3361}, pmid = {40524084}, issn = {1590-3478}, } @article {pmid40524150, year = {2025}, author = {Cozzi, M and Tedesco, B and Ferrari, V and Chierichetti, M and Pramaggiore, P and Cornaggia, L and Magdalena, R and Brodnanova, M and Mohamed, A and Milioto, C and Piccolella, M and Galbiati, M and Rusmini, P and Crippa, V and Gellera, C and Magri, S and Taroni, F and Cristofani, R and Poletti, A}, title = {One gene, many phenotypes: the role of KIF5A in neurodegenerative and neurodevelopmental diseases.}, journal = {Cell communication and signaling : CCS}, volume = {23}, number = {1}, pages = {287}, pmid = {40524150}, issn = {1478-811X}, support = {PRIN- Progetti di ricerca di interesse nazionale - bando 2022, PNRR finanziato dall'Unione europea- Next Generation EU, componente M4C2, investimento 1.1 n. P20225R4Y5//Ministero dell'Università e della Ricerca/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2022EFLFL8//Ministero dell'Università e della Ricerca/ ; 23236//AFM-Téléthon/ ; 739510//European Network for Rare Neurological Disorders/ ; piano di sviluppo della ricerca (PSR) UNIMI//Università degli Studi di Milano/ ; R21 AR080407/AR/NIAMS NIH HHS/United States ; Travelling Fellowship n. JCSTF2205742//Company of Biologists/ ; R21AR080407/AR/NIAMS NIH HHS/United States ; RF-2018-12367768//Ministero della Salute/ ; . 2021-1544//Fondazione Cariplo/ ; Scientific Exchange Grant n. 9643//European Molecular Biology Organization/ ; 2025 grant//CureHSPB8,USA/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2020PBS5MJ//Ministero dell'Università e della Ricerca/ ; CP 20/2018 (Care4NeuroRare)//Fondazione Regionale per la Ricerca Biomedica/ ; 2020 grant//Kennedy's Disease Association/ ; 2018 grant//Kennedy's Disease Association/ ; }, mesh = {Humans ; *Kinesins/genetics/chemistry/metabolism ; Phenotype ; Animals ; *Neurodevelopmental Disorders/genetics ; *Neurodegenerative Diseases/genetics ; Mutation ; }, abstract = {Kinesin family member 5 A (KIF5A) is a neuron-specific molecular motor involved in anterograde transport. KIF5A mediates a wide range of trafficking processes that are only partially shared with the other members of the KIF5 family. Since 2002, several disease-causing mutations have been found in the KIF5A gene and a link between the specific domain in the encoded protein affected by mutations and the associated phenotype has become evident. Point mutations targeting KIF5A motor and stalk domains, that are expected to impair KIF5A motility, mainly associate with spastic paraplegia type 10 (SPG10) and axonal Charcot-Marie-Tooth (CMT) disease. Oppositely, translational frameshifts causing the elongation of KIF5A tail enhance KIF5A migration towards cell periphery, induce kinesin aggregation, and are linked to amyotrophic lateral sclerosis (ALS) or neonatal intractable myoclonus (NEIMY). This review correlates KIF5A structure and roles in neuronal trafficking with its involvement in the above-mentioned neurodegenerative and neurodevelopmental conditions.}, } @article {pmid40525139, year = {2025}, author = {Abou Izzeddine, N and Ahmad, K and Bacha, C and Jabbour, M and Najjar, M and Salhab, S and Ghadieh, HE and Kanaan, A and Azar, S and Khattar, ZA and Harb, F}, title = {The microbial guardians: Unveiling the role of gut microbiota in shaping neurodegenerative disease.}, journal = {IBRO neuroscience reports}, volume = {19}, number = {}, pages = {17-37}, pmid = {40525139}, issn = {2667-2421}, abstract = {The gut microbiota, a complex community of microorganisms residing in the digestive tract, plays a pivotal role in human health. Recent studies have highlighted its significant impact on neurodegenerative diseases, conditions that pose profound challenges to affected individuals and society at large. This review explores the intricate relationship between gut microbiota and the progression of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. We delve into the dynamic ecosystem of gut microbiota, examining factors influencing its composition and the bidirectional communication established via the gut-brain axis. Emerging evidence suggests that gut microbiota can modulate neurodegenerative disease progression through mechanisms including inflammatory responses, production of neuroactive substances, and regulation of neurotransmitters. Furthermore, we discuss the potential therapeutic implications of targeting gut microbiota with probiotics, prebiotics, and postbiotics. While promising, these interventions face challenges and limitations that must be addressed through ongoing research. Understanding the role of gut microbiota in neurodegenerative diseases is crucial for developing innovative therapeutic strategies and improving patient outcomes.}, } @article {pmid40527446, year = {2025}, author = {Zhang, Z and Guo, X and Liu, Y and Ke, P and Meng, Y and Gu, J and Hu, L and Yuan, Z and Duan, R and Luo, J and Xiao, F}, title = {PKM2 alleviates mitochondrial oxidative stress and neuronal apoptosis through metabolic and non-metabolic pathways to protect SOD1[G93A] mice.}, journal = {Free radical biology & medicine}, volume = {238}, number = {}, pages = {1-16}, doi = {10.1016/j.freeradbiomed.2025.06.012}, pmid = {40527446}, issn = {1873-4596}, mesh = {Animals ; Oxidative Stress/drug effects ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/drug therapy ; *Mitochondria/metabolism/pathology/drug effects ; Apoptosis/drug effects ; *Pyruvate Kinase/genetics/metabolism/antagonists & inhibitors ; NF-E2-Related Factor 2/genetics/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Motor Neurons/metabolism/pathology/drug effects ; Humans ; Disease Models, Animal ; Mice, Transgenic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motor neuron death. Dysregulated energy metabolism is implicated in ALS pathogenesis, yet the role of pyruvate kinase M2 (PKM2), a key glycolytic enzyme, remains elusive. Here, we demonstrated that PKM2 expression was upregulated in the spinal neurons of SOD1[G93A] mice during early stages of disease. Pharmacological inhibition of PKM2 with compound 3k (C3k) shortened survival times, exacerbated motor deficits, and amplified mitochondrial oxidative stress and neuronal apoptosis in mice with ALS. Mechanistically, PKM2 mitigated mitochondrial dysfunction via its enzymatic activity, promoting lactate metabolism to reduce reactive oxygen species (ROS) accumulation. Concurrently, nuclear PKM2 directly bound to the Nrf2 promoter, enhancing Nrf2 transcription to strengthen antioxidant defenses. Our findings unveil PKM2 as a multifunctional neuroprotectant in ALS, offering novel therapeutic directions through metabolic and transcriptional modulation.}, } @article {pmid40527529, year = {2025}, author = {Cassidy-Seyoum, SA and Adhikari, B and Chheng, K and Chanpheakdey, P and Meershoek, A and Hsiang, MS and von Seidlein, L and Tripura, R and Ley, B and Price, RN and Dysoley, L and Thriemer, K and Engel, N}, title = {Acceptability and feasibility of glucose-6-phosphate dehydrogenase (G6PD) testing using SD Biosensor by village malaria workers in Cambodia: a qualitative study.}, journal = {BMJ global health}, volume = {10}, number = {6}, pages = {}, pmid = {40527529}, issn = {2059-7908}, mesh = {Humans ; Cambodia ; Qualitative Research ; Feasibility Studies ; *Glucosephosphate Dehydrogenase/blood/analysis ; Female ; *Community Health Workers ; *Biosensing Techniques/methods ; Focus Groups ; Male ; *Glucosephosphate Dehydrogenase Deficiency/diagnosis ; *Patient Acceptance of Health Care/statistics & numerical data ; *Malaria, Vivax/drug therapy ; Adult ; Interviews as Topic ; Point-of-Care Testing ; Middle Aged ; Malaria ; Primaquine/therapeutic use ; }, abstract = {INTRODUCTION: Plasmodium vivax is the predominant cause of malaria in the Greater Mekong Subregion. To ensure safe treatment with primaquine, point-of-care glucose-6-phosphate dehydrogenase (G6PD) testing was rolled out in Cambodia at the health facility level, although most malaria patients are diagnosed in the community. The current study aims to explore the acceptability and feasibility of implementing community-level G6PD testing in Cambodia.

METHODS: Semistructured interviews and focus group discussions (FGD) were conducted. Across eight study sites in three provinces, 142 respondents, including policymakers, programme officers, healthcare providers and patients, participated in 67 interviews and 19 FGDs in 2022 and 2023. Data were analysed thematically using an adapted framework derived from Bowen et al's feasibility framework and Sekhon et al's acceptability framework.

RESULTS: All stakeholders attributed value to the intervention. Acknowledging an intervention's different values can help discern policy implications for an intervention's successful implementation. Building and maintaining confidence in the device, end users, infrastructure and health systems were found to be key elements of acceptability. In general, health centre workers and village malaria workers (VMWs) had confidence that VMWs could conduct the test and administer treatment given appropriate initial training, monthly refresher training and the test's repeated use. More is required to build policymakers' confidence, while some implementation challenges, including the test's regulatory approval, stability above 30°C and cost, need to be overcome.

CONCLUSION: Implementation of G6PD testing at the community level in Cambodia is an acceptable and potentially feasible option but requires addressing implementation challenges and building and maintaining confidence among stakeholders.}, } @article {pmid40527647, year = {2025}, author = {Thijs, Z and Calzada, A and Sosa, M and Dumican, M}, title = {The Association Between Bilingualism and Voice Quality in Spanish-English Bilingual Speakers: A Systematic Review.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2025.05.027}, pmid = {40527647}, issn = {1873-4588}, abstract = {OBJECTIVE/HYPOTHESIS: The vast majority of the global population speaks more than one language. In the United States, Spanish-English bilingual speakers are the largest bilingual group. Yet, the potential effect of being bilingual, specifically a Spanish-English speaker, on voice quality is poorly understood. The current study consequently set out to systematically review the literature on the association between being a Spanish-English bilingual speaker and voice quality.

STUDY DESIGN: Systematic review.

METHODS: A systematic review of association was conducted using Moola et al's guidelines. A search string was developed and run in May 2024 across three databases: MEDLINE (via PubMed), CINAHL via EBSCOhost, and Scopus. After duplicate removal, title, and abstract screening, full-text screening was performed, and peer-reviewed articles considering voice quality measures in Spanish-English bilingual speakers were included. Data were extracted and presented in table format, and the quality of the articles was assessed using the Checklist for Analytical Cross-Sectional Studies.

RESULTS: In total, 685 records were retrieved, with 485 remaining after duplicate removal. After title and abstract screening, 25 full texts were screened, including 8 articles in the review. Five studies included acoustic measures describing voice quality, with only three including auditory-perceptual analysis. The most commonly considered vocal trait in Spanish-English bilinguals was vocal fry, with the included studies pointing to increased vocal fry use when speaking English.

CONCLUSIONS: Only a few articles discuss potential vocal changes in Spanish-English bilinguals. Further research is needed to elucidate any potential vocal changes related to being a bilingual speaker, as the current small number of studies and mixed findings make drawing conclusions difficult. More standardization across voice and language assessment could be beneficial.}, } @article {pmid40528238, year = {2025}, author = {Huang, X and Zhang, Z and Chen, L and Yang, S and Liu, X and Bi, J and Zhang, Z and Wang, Y and Wei, N and Zhu, W and Chen, N and Hua, L and Li, Y and Wang, Y and Jing, J and Pan, H}, title = {Diagnostic value of the motor band sign in amyotrophic lateral sclerosis: a 7T magnetic resonance imaging study.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {30}, pmid = {40528238}, issn = {2047-9158}, } @article {pmid40528459, year = {2025}, author = {Yang, M and Zhang, A and Chen, M and Cao, J}, title = {Advances in Circulating Biomarkers for Neurodegenerative Diseases, Traumatic Brain Injuries, and Central Nervous System Tumors.}, journal = {Annals of laboratory medicine}, volume = {45}, number = {4}, pages = {381-390}, pmid = {40528459}, issn = {2234-3814}, mesh = {Humans ; *Brain Injuries, Traumatic/diagnosis/blood ; *Neurodegenerative Diseases/diagnosis/blood ; *Biomarkers/blood/cerebrospinal fluid ; *Central Nervous System Neoplasms/diagnosis/blood ; Enzyme-Linked Immunosorbent Assay ; tau Proteins/blood/cerebrospinal fluid ; }, abstract = {Neurological disorders, including neurodegenerative diseases, traumatic brain injuries (TBI), and central nervous system (CNS) tumors, are complex conditions that significantly impact patients globally. Timely diagnosis and monitoring are critical for improving outcomes, driving the need for reliable biomarkers. Specifically, biomarkers detectable in cerebrospinal fluid (CSF) and blood offer important insights into disease presence and progression. This review explores the evolution of circulating blood biomarkers for neurodegenerative diseases, TBI, and CNS tumors, highlighting advanced detection technologies from enzyme-linked immunosorbent assays (ELISAs) to electrochemiluminescence (ECL) assays, single-molecule arrays (Simoa), and mass spectrometry. Advanced technologies with enhanced sensitivity and specificity, particularly in detecting low-abundance analytes, facilitate the investigation of CSF biomarkers for various neurological disorders. We also describe the progress in blood-based biomarkers for , emerging as less invasive alternatives to CSF sampling. Clinically, the implementation of Alzheimer's disease (AD) blood biomarkers Aβ42/Aβ40 ratio and Apolipoprotein E isoform-specific peptide can aid the diagnosis, while p-tau181 and p-tau217 differentiates AD dementia from non-AD neurodegenerative diseases. Blood glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 are used in ruling out mild TBI. Despite these innovations, challenges remain, including assay standardization, sensitivity/specificity trade-offs, and the requirement for longitudinal studies to understand biomarker utility over time. Future research should focus on addressing these challenges to fully realize the potential of blood-based biomarkers in neurological disorder diagnostics and patient care.}, } @article {pmid40529392, year = {2025}, author = {Pfaff, AL and Kõks, S}, title = {Retrotransposition-competent L1s are increased in the genomes of individuals with amyotrophic lateral sclerosis.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {250}, number = {}, pages = {10575}, pmid = {40529392}, issn = {1535-3699}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Long Interspersed Nucleotide Elements/genetics ; *Genome, Human ; Female ; Male ; Middle Aged ; Genetic Predisposition to Disease ; Retroelements ; }, abstract = {An individual's genetics contributes to their risk of developing amyotrophic lateral sclerosis (ALS); however, there is still a large proportion of the heritability of ALS to be understood. Part of this missing heritability may lie in complex variants, such as the long interspersed element 1 (L1) retrotransposon, which have yet to be evaluated. The majority of L1 insertions in the human genome are no longer able to retrotranspose, but to date 279 retrotransposition-competent (RC) L1s have been reported. Many RC-L1s are polymorphic for their presence/absence; therefore, each individual will have a different number and complement of RC-L1s. These elements have been hypothesized to be involved in disease processes by multiple mechanisms such as somatic mutation by retrotransposition, the triggering of neuroinflammation and DNA damage. We hypothesize that L1s may influence disease development either through their effects on endogenous genes or through the properties that enable them to retrotranspose. Whole genome sequencing data from the New York Genome Center ALS consortium were used to characterize L1 variation identifying 2,803 polymorphic L1 elements and association analysis was performed in European individuals (ALS/ALS with other neurological disorder (ALSND) n = 2,653, controls n = 320). There were no individual L1 elements associated with disease, but we did identify a significant increase in the number of RC-L1s in ALS/ALSND genomes (p = 0.01) and the presence of ≥46 RC-L1s showed the most significant association (OR = 1.09 (1.02-1.16), p = 0.01) with disease. Analysis of individual L1s and their association with age at onset and survival identified one L1 whose presence was significantly associated with a lower age at onset (52.7 years) compared to homozygous absent individuals (59.2 years) (padj = 0.009). Our study has identified novel genetic factors for both disease risk and age at onset in ALS providing further evidence for the role of L1 retrotransposons in neurodegenerative diseases.}, } @article {pmid40530462, year = {2026}, author = {Raymond, J and Oskarsson, B and Larson, T and Mohidul, S and Horton, DK and Mehta, P}, title = {Place of Death in Patients with Motor Neuron Disease and the Association with Comorbidities During the Coronavirus Disease 2019 Pandemic: A Population-Based Analysis.}, journal = {Journal of palliative care}, volume = {41}, number = {2}, pages = {159-165}, doi = {10.1177/08258597251349627}, pmid = {40530462}, issn = {2369-5293}, mesh = {Humans ; *COVID-19/epidemiology/mortality ; *Motor Neuron Disease/mortality/epidemiology ; Female ; Male ; Middle Aged ; Comorbidity ; Aged ; United States/epidemiology ; Cross-Sectional Studies ; Adult ; Aged, 80 and over ; Young Adult ; SARS-CoV-2 ; Nursing Homes/statistics & numerical data ; Pandemics ; }, abstract = {ObjectiveMotor neuron disease (MND) is a progressive neurological disorder with no known cure that damages motor neurons. The purpose of this analysis is to examine the place of death for MND patients in the United States during the coronavirus disease 2019 (COVID-19) pandemic and to investigate the extent of specific comorbidities.MethodsWe obtained death certificate and associated comorbidities data for all U.S. MND deaths from 2018 to 2021 and conducted a population-based cross-sectional analysis of the deaths pre-COVID-19 (2018-2019) and during COVID-19 (2020-2021). We hypothesized that place of death and comorbidities associated with place of death for MND patients in the United States were altered during the COVID-19 pandemic in comparison to the 2 years period before the pandemic.ResultsWe analyzed 30 066 MND deaths (14 562 pre-COVID-19 and 15 504 during COVID-19) aged 20 years and older. During COVID-19, MND deaths at home increased (54.4% vs 45.5% pre-COVID). Hispanic individuals had an increased likelihood of dying at home compared to a nursing home or hospice (OR = 1.57, 95%CI: 1.22-2.02), but a decreased likelihood compared to a hospital (OR = 0.61, 95% CI: 0.51-0.72). Among the top comorbidities listed, there was a 27.8% increase in diabetes mellitus and a 20.2% increase in essential hypertension during COVID-19. During COVID-19, diabetes mellitus was more commonly reported as a comorbidity for deaths occurring in hospitals (OR = 1.40, 95%CI: 1.03-1.89) or at home (OR = 1.26, 95%CI: 1.03-1.55), while essential hypertension was more commonly reported with deaths at home (OR = 1.17, 95%CI: 1.01-1.36).ConclusionOur analysis showed an increase in at-home MND deaths as well as certain comorbidities during the COVID-19 pandemic, suggesting MND patients had a higher likelihood of death from non-COVID-19 comorbidities.}, } @article {pmid40531483, year = {2025}, author = {Endo, M and Kami, M}, title = {CNM-Au8 in Amyotrophic Lateral Sclerosis.}, journal = {JAMA}, volume = {334}, number = {3}, pages = {277-278}, doi = {10.1001/jama.2025.5822}, pmid = {40531483}, issn = {1538-3598}, } @article {pmid40531486, year = {2025}, author = {Berry, JD and Maragakis, N and Paganoni, S}, title = {CNM-Au8 in Amyotrophic Lateral Sclerosis-Reply.}, journal = {JAMA}, volume = {334}, number = {3}, pages = {278}, doi = {10.1001/jama.2025.5825}, pmid = {40531486}, issn = {1538-3598}, } @article {pmid40531650, year = {2026}, author = {Zeng, W and Peng, Z and Chen, Y and Du, S}, title = {Multi-Scale Temporal Analysis With a Dual-Branch Attention Network for Interpretable Gait-Based Classification of Neurodegenerative Diseases.}, journal = {IEEE journal of biomedical and health informatics}, volume = {30}, number = {4}, pages = {3089-3101}, doi = {10.1109/JBHI.2025.3580944}, pmid = {40531650}, issn = {2168-2208}, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology/classification/diagnosis ; *Deep Learning ; *Gait/physiology ; *Gait Analysis/methods ; *Signal Processing, Computer-Assisted ; *Gait Disorders, Neurologic/diagnosis/physiopathology/classification ; Male ; }, abstract = {The accurate diagnosis of neurodegenerative diseases (NDDs), such as Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and Parkinson's Disease (PD), remains a clinical challenge due to the complexity and subtlety of gait abnormalities. This paper proposes the Dual-Branch Attention-Enhanced Residual Network (DAERN), a novel deep learning architecture that integrates Dilated Causal Convolutions (DCCBlock) for local gait pattern extraction and Multi-Head Self-Attention (MHSA) for long-range dependency modeling. A Cross-Attention Fusion module enhances feature integration, while SHapley Additive exPlanations (SHAP) and Integrated Gradients (IG) improve interpretability, providing clinically relevant insights into gait-based NDD classification. Uniform Manifold Approximation and Projection (UMAP) visualizations reveal well-separated clusters corresponding to distinct NDDs categories, demonstrating the model's ability to capture discriminative features. Comprehensive ablation studies validate the contributions of model components and preprocessing strategies, highlighting the significance of each in achieving state-of-the-art classification performance. Experimental evaluations on the Gait in Neurodegenerative Disease (GaitNDD) dataset demonstrate that DAERN achieves an accuracy of 99.64%, an F1-score of 99.65%, and an AUC of 0.9997, significantly outperforming conventional deep learning and machine learning baselines. These findings suggest that DAERN could be a valuable and interpretable tool for clinical gait assessment, aiding in early-stage monitoring and automated screening of NDDs, with potential applications in real-time wearable sensor-based gait analysis.}, } @article {pmid40531663, year = {2025}, author = {Ralston, CY and Gupta, S and Del Mundo, JT and Soe, AC and Russell, B and Rad, B and Tyler, J and Paul, S and Kahan, DN and Kristensen, LG and Subramanian, S and Kidd, S and Burnett, K and Sankaran, B and Classen, S and Prigozhin, DM and Taylor, JR and Dickert, JM and Royal, KB and Rozales, A and Ortega, SL and Allaire, M and Nix, JC and Hura, GL and Holton, JM and Hammel, M and Adams, PD}, title = {ALS-ENABLE: creating synergy and opportunity at the Advanced Light Source synchrotron structural biology beamlines.}, journal = {Journal of synchrotron radiation}, volume = {32}, number = {Pt 4}, pages = {1059-1067}, pmid = {40531663}, issn = {1600-5775}, support = {S10 OD032212/OD/NIH HHS/United States ; P30 GM124169/GM/NIGMS NIH HHS/United States ; GM126218//National Institutes of Health, National Institute of General Medical Sciences/ ; GM124169//National Institutes of Health, National Institute of General Medical Sciences/ ; R01 GM124149/GM/NIGMS NIH HHS/United States ; DE-AC02-05CH1123//US Department of Energy, Office of Science/ ; R01 GM126218/GM/NIGMS NIH HHS/United States ; }, mesh = {*Synchrotrons/instrumentation ; Scattering, Small Angle ; Crystallography, X-Ray/instrumentation ; Mass Spectrometry ; X-Ray Diffraction ; }, abstract = {ALS-ENABLE is an integrated NIH P30 resource at the Advanced Light Source synchrotron at Lawrence Berkeley National Laboratory in Berkeley, California, USA. The resource provides a single portal to the combined mature structural biology technologies of macromolecular crystallography, small-angle X-ray scattering and X-ray footprinting mass spectrometry, and includes beamlines 2.0.1, 3.3.1, 4.2.2, 5.0.1, 5.0.2, 5.0.3, 8.2.1, 8.2.2, 8.3.1 and 12.3.1. This paper describes the organizational structure and the technologies of ALS-ENABLE. A case study showcasing the main technologies of the resource applied to the characterization of the SpyCatcher-SpyTag protein system is presented.}, } @article {pmid40533880, year = {2025}, author = {Liu, W and Wang, S and Zhang, T and Zhu, H and Chang, N and Zhang, L and Hu, Z}, title = {A Review of Preparation of Low-Carbon Cementitious Materials from Chemically Activated Red Mud: Synergy, Hydration Mechanism, Rheological Properties and Applications.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {41}, number = {25}, pages = {15735-15751}, doi = {10.1021/acs.langmuir.5c01088}, pmid = {40533880}, issn = {1520-5827}, abstract = {Red mud, a byproduct of the alumina refining process, is generated at a rate of 1-2.5 tonnes per tonne of alumina produced. In 2022, China's alumina production totaled 77.475 million tonnes, contributing over 4 billion tonnes of accumulated red mud, which is the third-largest industrial solid waste in the country. Red mud's high alkalinity and presence of toxic elements pose environmental challenges, particularly in terms of disposal. This review provides a comprehensive examination of red mud-based cementitious materials, focusing on their preparation, properties, and environmental impact. By combining red mud with high-calcium and silica-aluminum solid wastes and enhancing its reactivity through mechanical grinding or thermal activation, red mud's cementitious activity can be significantly improved. Optimized compositions, with a Ca/Si ratio of 2.05 and Al/S ratio of 0.70, have achieved compressive strengths of up to 63.9 MPa at 28 day. Durability studies highlight the material's resistance to chloride ion penetration and sulfate attack, with reduced permeability enhancing long-term performance. Additionally, environmental assessments confirm that stabilization and solidification techniques effectively mitigate heavy metal leaching, ensuring compliance with EPA standards. Despite these advancements, challenges remain in optimizing red mud activation processes, improving rheological properties, and reducing production costs. Future research should focus on refining activation methods, enhancing hydration mechanisms, and developing scalable industrial applications. By addressing these gaps, red mud-based cementitious materials can become a sustainable solution for eco-friendly construction, supporting global efforts to repurpose industrial byproducts into low-carbon, durable building materials.}, } @article {pmid40534528, year = {2025}, author = {Ertural, B and Çiçek, BN and Kurnaz, IA}, title = {RNA Therapeutics: Focus on Antisense Oligonucleotides in the Nervous System.}, journal = {Biomolecules & therapeutics}, volume = {33}, number = {4}, pages = {572-581}, pmid = {40534528}, issn = {1976-9148}, abstract = {RNA therapeutics represent a disruptive technology that has transformed drug discovery and manufacturing, gaining significant prominence during the COVID-19 pandemic. RNA therapeutics encompass diverse molecules like antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), RNA aptamers, and messenger RNAs (mRNAs), which can function through different mechanisms. RNA therapeutics are increasingly used to treat various diseases, including neurological disorders. For example, ASO therapies such as nusinersen for spinal muscular atrophy and eteplirsen for Duchenne muscular dystrophy are successful applications of RNA-based treatment. Emerging ASO treatments for Huntington's disease and amyotrophic lateral sclerosis are also promising, with ongoing clinical trials demonstrating significant reductions in disease-associated proteins. Still, delivery of these molecules remains a pivotal challenge in RNA therapeutics, especially for ASOs in penetrating the blood-brain barrier to target neurological disorders effectively. Nanoparticle-based formulations have emerged as leading strategies to enhance RNA stability, reduce immunogenicity, and improve cellular uptake. Despite these advances, significant hurdles remain, including optimizing pharmacokinetics, minimizing off-target effects, and ensuring sustained therapeutic efficacy. Regulatory frameworks are evolving to accommodate the unique challenges of RNA-based therapies, including ASOs with efforts underway to establish comprehensive guidelines for RNA therapeutics, yet there are also sustainable manufacturing issues that need to be considered for long-term feasibility. By addressing these challenges, RNA therapeutics hold immense potential to revolutionize treatment paradigms for neurological disorders. Looking forward, the future of RNA therapeutics in neurology appears promising but requires continued interdisciplinary collaboration and technological innovation.}, } @article {pmid40534726, year = {2025}, author = {Kissling, WD and Mulder, W and Wang, J and Shi, Y}, title = {Data of vegetation structure metrics retrieved from airborne laser scanning surveys for European demonstration sites.}, journal = {Data in brief}, volume = {60}, number = {}, pages = {111548}, pmid = {40534726}, issn = {2352-3409}, abstract = {This dataset provides a standardized collection of rasterized Light Detection And Ranging (LiDAR) metrics in GeoTIFF format, derived from country-wide airborne laser scanning (ALS) data across seven demonstration sites in five European countries: Mols Bjerge National Park (Denmark), Reserve Naturelle Nationale du Bagnas (France), Oostvaardersplassen (Netherlands), Salisbury Plain (United Kingdom), Knepp Estate (United Kingdom), Monks Wood (United Kingdom), and the island of Comino (Malta). The sites range in areal size from 0.08 km[2] to 54 km[2] and include habitat types such as forests, broadleaf and conifer woodlands, small plantations, dry and wet grasslands, marshes, reedbeds, arable fields, farmland, scrublands and mediterranean garigue. A total of 35 LiDAR metrics were calculated, of which 28 represent vegetation structural attributes. These include vegetation height (seven metrics), vegetation cover (fourteen metrics), and vegetation vertical variability (seven metrics). Additionally, seven metrics describe point density (one metric), eigenvalues (three metrics), and normal vectors (three metrics). The rasterized LiDAR metrics have a spatial resolution of 10 m, with coverage and extent defined by shapefiles corresponding to each demonstration site. The raw ALS point clouds were clipped to the site boundaries and processed with the 'Laserfarm' workflow, a standardized computational workflow that includes modular pipelines for re-tiling, normalization, feature extraction, and rasterization. Laserfarm employs the feature extraction module of the open-source 'Laserchicken' software to compute the LiDAR metrics. The workflow was implemented using the IT services of the Dutch national facility for information and communication technology, SURF. The clipped LiDAR point clouds are available through a public repository, except for the LiDAR point clouds from Comino, Malta, which are not publicly available. The 35 rasterized LiDAR metrics (GeoTIFF files, 10 m resolution) from all sites, including Comino, as well as the corresponding site boundary shapefiles (geospatial vector format), are provided in a Zenodo repository. Additionally, the Jupyter Notebooks with Python code for executing the Laserfarm workflow are available to facilitate reproducibility and further computational applications. Users should note that the rasterized LiDAR metrics may contain zero or NA values, particularly over water surfaces, with the pulse penetration ratio metric potentially indicating false high vegetation cover over water. Users may reclassify or mask areas with zero values accordingly. Some pixels exhibit abnormal vegetation height values, which can be filtered before analysis. Certain striping patterns, likely resulting from overlapping flight lines and increased point density, are present in some metrics, though their overall impact appears minimal. This dataset enables diverse applications, including canopy height measurements, mapping of hedgerows, treelines, and forest patches, as well as characterizing vegetation density, vertical stratification, and habitat openness. It supports landscape-scale habitat analysis and contributes to the standardization of vegetation metrics from ALS data for site-specific ecological monitoring (e.g., Natura 2000). Moreover, the dataset demonstrates the automated execution of LiDAR data processing workflows, which is crucial for establishing a transnational and multi-site biodiversity and ecosystem observation network.}, } @article {pmid40535632, year = {2025}, author = {Tang, X and Wang, C and Tian, S and Wen, H and Zhang, H}, title = {Acupuncture for neurodegenerative diseases: mechanisms, efficacy, and future research directions.}, journal = {American journal of translational research}, volume = {17}, number = {5}, pages = {3703-3717}, pmid = {40535632}, issn = {1943-8141}, abstract = {In recent years, acupuncture has shown good therapeutic efficacy in treating neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Studies have demonstrated that acupuncture alleviates symptoms primarily by suppressing neuroinflammation, enhancing autophagy, improving synaptic plasticity, and optimizing mitochondrial function. As molecular research advances, the underlying mechanisms of acupuncture in these conditions have become increasingly clear. This review summarizes recent progress in understanding the efficacy and molecular mechanisms of acupuncture in neurodegenerative diseases, providing a theoretical support for its clinical application.}, } @article {pmid40536530, year = {2025}, author = {Pensato, V and Peverelli, S and Tiloca, C and Magri, S and Brusati, A and Pingue, M and Morelli, C and Dalla Bella, E and Manini, A and Tannorella, P and Doretti, A and Mandrioli, J and Terenghi, F and Prelle, A and Riva, N and Verde, F and Eleopra, R and Taroni, F and Lauria Pinter, G and Silani, V and Ticozzi, N and Gellera, C and Ratti, A}, title = {Exploring NEK1 genetic variability in Italian amyotrophic lateral sclerosis patients.}, journal = {Journal of neurology}, volume = {272}, number = {7}, pages = {469}, pmid = {40536530}, issn = {1432-1459}, support = {GR-2016-02364373//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *NIMA-Related Kinase 1/genetics ; Male ; Female ; Italy ; Middle Aged ; Aged ; Adult ; Mutation/genetics ; *Genetic Variation/genetics ; Cohort Studies ; Genetic Predisposition to Disease ; }, abstract = {BACKGROUND: Mutations in NEK1, encoding for a serine/threonine kinase which regulates several biological processes, are associated with amyotrophic lateral sclerosis (ALS).

METHODS: NEK1 was analysed by amplicon deep sequencing in a cohort of 1016 Italian sporadic and familial ALS patients previously screened for C9orf72, SOD1, TARDBP and FUS mutations.

RESULTS: We identified 28 rare NEK1 variants in 29 patients (2.85%) of whom 20/782 were sporadic (2.5%), 6/107 familial (5%) and 3/127 of unknown aetiology (2.3%). Variants were classified as pathogenic (P; n = 1), likely pathogenic (LP; n = 6 in 7 patients) and of unknown significance (VUS; n = 21) according the American College of Medical Genetics and Genomics criteria. Notably, 64% of the identified variants (18/28, including 4 LP and 14 VUS) were novel. Among the 29 patients with rare NEK1 variants, 7 (of whom 5 were familial cases) had additional variants in one of the four main ALS causative genes. Moreover, 23 patients carried the already reported NEK1 p.Arg261His risk variant (VUS) alone or in addition to SOD1 mutations (n = 1) or C9orf72 repeat expansion (n = 2) and to the NEK1 p.Asp128Val variant (n = 1). Genotype-phenotype correlation analysis showed no significant differences in age at onset or survival in NEK1 variant carriers, independently on the variant type. No flail arm phenotype, but atypical features, including sensory symptoms, were present in NEK1 carriers.

CONCLUSION: Our study further expands NEK1 genetic variability by identifying novel rare variants and confirming ALS oligogenic nature since 19.6% of NEK1 patients also carried mutations in one of the four main ALS-associated genes.}, } @article {pmid40536931, year = {2026}, author = {Li, K and Chen, R and Wang, R and Fan, W and Zhao, N and Yang, Z and Yan, J}, title = {Neuroinflammation in neurodegenerative diseases: Focusing on the mediation of T lymphocytes.}, journal = {Neural regeneration research}, volume = {21}, number = {5}, pages = {1864-1889}, pmid = {40536931}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system, leading to a decline in patients' cognitive, motor, and emotional abilities. Neuroinflammation plays a significant role in the progression of these diseases. However, there is limited research on therapeutic approaches to specifically target neuroinflammation. The role of T lymphocytes, which are crucial mediators of the adaptive immune response, in neurodegenerative diseases has been increasingly recognized. This review focuses on the involvement of T lymphocytes in the neuroinflammation associated with neurodegenerative diseases. The pathogenesis of neurodegenerative diseases is complex, involving multiple mechanisms and pathways that contribute to the gradual degeneration of neurons, and T cells are a key component of these processes. One of the primary factors driving neuroinflammation in neurodegenerative diseases is the infiltration of T cells and other neuroimmune cells, including microglia, astrocytes, B cells, and natural killer cells. Different subsets of CD4 + T cells, such as Th1, Th2, Th17, and regulatory T cells, can differentiate into various cell types and perform distinct roles within the neuroinflammatory environment of neurodegenerative diseases. Additionally, CD8 + T cells, which can directly regulate immune responses and kill target cells, also play several important roles in neurodegenerative diseases. Clinical trials investigating targeted T cell therapies for neurodegenerative diseases have shown that, while some patients respond positively, others may not respond as well and may even experience adverse effects. Targeting T cells precisely is challenging due to the complexity of immune responses in the central nervous system, which can lead to undesirable side effects. However, with new insights into the pathophysiology of neurodegenerative diseases, there is hope for the establishment of a solid theoretical foundation upon which innovative treatment strategies that target T cells can be developed in the future.}, } @article {pmid40536996, year = {2026}, author = {Yañez, IM and Torres-Cuevas, I and Corral-Debrinski, M}, title = {Neuroglobin: A promising candidate to treat neurological diseases.}, journal = {Neural regeneration research}, volume = {21}, number = {4}, pages = {1292-1303}, pmid = {40536996}, issn = {1673-5374}, abstract = {Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide. Altogether, the burden of neurological disorders has increased considerably over the past 30 years because of population aging. Overall, neurological diseases significantly impair cognitive and motor functions and their incidence will increase as societies age and the world's population continues to grow. Autism spectrum disorder, motor neuron disease, encephalopathy, epilepsy, stroke, ataxia, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease represent a non-exhaustive list of neurological illnesses. These affections are due to perturbations in cellular homeostasis leading to the progressive injury and death of neurons in the nervous system. Among the common features of neurological handicaps, we find protein aggregation, oxidative stress, neuroinflammation, and mitochondrial impairment in the target tissues, e.g., the brain, cerebellum, and spinal cord. The high energy requirements of neurons and their inability to produce sufficient adenosine triphosphate by glycolysis, are responsible for their dependence on functional mitochondria for their integrity. Reactive oxygen species, produced along with the respiration process within mitochondria, can lead to oxidative stress, which compromises neuronal survival. Besides having an essential role in energy production and oxidative stress, mitochondria are indispensable for an array of cellular processes, such as amino acid metabolism, iron-sulfur cluster biosynthesis, calcium homeostasis, intrinsic programmed cell death (apoptosis), and intraorganellar signaling. Despite the progress made in the last decades in the understanding of a growing number of genetic and molecular causes of central nervous diseases, therapies that are effective to diminish or halt neuronal dysfunction/death are rare. Given the genetic complexity responsible for neurological disorders, the development of neuroprotective strategies seeking to preserve mitochondrial homeostasis is a realistic challenge to lastingly diminish the harmful evolution of these pathologies and so to recover quality of life. A promising candidate is the neuroglobin, a globin superfamily member of 151 amino acids, which is found at high levels in the brain, the eye, and the cerebellum. The protein, which localizes to mitochondria, is involved in electron transfer, oxygen storage and defence against oxidative stress; hence, possessing neuroprotective properties. This review surveys up-to-date knowledge and emphasizes on existing investigations regarding neuroglobin physiological functions, which remain since its discovery in 2000 under intense debate and the possibility of using neuroglobin either by gene therapy or its direct delivery into the brain to treat neurological disorders.}, } @article {pmid40537251, year = {2025}, author = {Verde, F and Vávra, J and Dorst, J and Elmas, Z and Wiesenfarth, M and De Gobbi, A and Ratti, A and Poletti, B and Tumani, H and Weishaupt, J and Silani, V and Ticozzi, N and Otto, M and Ludolph, AC and Oeckl, P}, title = {CSF levels of the somatodendritic protein MAP2 are increased in ALS and predict shorter survival.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {12}, pages = {1132-1143}, doi = {10.1136/jnnp-2025-336208}, pmid = {40537251}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/mortality/genetics ; Male ; Female ; Middle Aged ; Biomarkers/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; Aged ; Retrospective Studies ; *Microtubule-Associated Proteins/cerebrospinal fluid ; Disease Progression ; C9orf72 Protein/genetics ; Adult ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Previous proteomic work has identified the somatodendritic protein MAP2 as a new candidate cerebrospinal fluid (CSF) biomarker for amyotrophic lateral sclerosis (ALS).

METHODS: We measured CSF levels of MAP2 and neurofilament light chain (NFL) in a retrospective cohort of 251 patients with ALS and 108 neurological controls (NCs).

RESULTS: Patients with ALS had a higher median CSF MAP2 level compared with NCs, leading to an area under the curve (AUC) of 0.7080 (p<0.0001). They also had a higher median CSF NFL level (p<0.0001), resulting in an excellent diagnostic performance (AUC=0.9641; p<0.0001). Among patients with ALS, CSF MAP2 correlated with disease progression rate (DPR) (r=0.3099; p<0.0001) and was negatively associated with survival (HR=3.174). CSF NFL also correlated with DPR (r=0.4936; p<0.0001) and was negatively associated with survival (HR=2.759). The association of MAP2 with DPR was independent from NFL (p=0.0037). Stratifying patients based on median levels of both biomarkers resulted in significant differences in median survival times (low NFL/low MAP2, 66 months; high NFL/low MAP2 and vice versa, 35 months; high NFL/high MAP2, 26 months; p<0.0001). MAP2 was also associated with genetic status in patients with ALS, as patients with no mutations in C9ORF72 or in SOD1, as well as C9ORF72-positive ones, had higher median levels compared with NCs (p<0.0001), while patients with SOD1 mutations did not significantly differ from NCs (p>0.9999).

CONCLUSIONS: Our study shows that the somatodendritic protein MAP2 is a promising candidate CSF biomarker for ALS.}, } @article {pmid40538061, year = {2025}, author = {Guo, Z and Zhang, X and Li, Y and Chen, Y and Xu, Y}, title = {Splicing to keep splicing: A feedback system for cellular homeostasis and state transition.}, journal = {Clinical and translational medicine}, volume = {15}, number = {6}, pages = {e70369}, pmid = {40538061}, issn = {2001-1326}, support = {82173292//National Natural Science Foundation of China/ ; 62171365//National Natural Science Foundation of China/ ; 62471378//National Natural Science Foundation of China/ ; 2024SF-GJHX-40//the Key Research and Development Projects of Shaanxi Province/ ; QCYRCXM-2022-209//the Key Research and Development Projects of Shaanxi Province/ ; YX6J021//Young Talent Support Plan of Xi'an Jiaotong University/ ; 2022-11//Basic-Clinical Medical Integration & Innovation Project of Xi'an Jiaotong University/ ; }, mesh = {Humans ; *Homeostasis/genetics ; *Alternative Splicing/genetics ; Feedback, Physiological ; Nonsense Mediated mRNA Decay ; }, abstract = {BACKGROUND: Alternative splicing (AS) plays a crucial role in regulating gene expression and governing proteomic diversity by generating multiple protein isoforms from a single gene. Increasing evidence has highlighted the regulation for pre-mRNA splicing of the splicing factors (SFs). This review aims to examine featured mechanisms and examples of SF regulation by AS, focusing on paradigmatic feedback loops and their biological implications.

MAIN BODY OF THE ABSTRACT: We specifically focus on the autoregulation and inter-regulation of SFs through AS machinery. These interactions give rise to a feedback system, where the negative feedback loops aid in maintaining cellular homeostasis, and the positive feedback loops play roles in triggering cellular state transitions. We examine the growing evidence highlighting the specific mechanisms employed by SFs to autoregulate their own splicing, including AS-coupled nonsense-mediated mRNA decay (AS-NMD), nuclear retention, and alternative 3'UTR regulation. We showcase the influence of AS feedback in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and cancer. Furthermore, we discuss how master splicing factors can dominantly orchestrate splicing cascades, leading to widespread impacts in cellular processes. We also discuss how non-coding RNAs, particularly circular RNAs and microRNAs, engage in the splicing regulatory networks. Lastly, we showcase how negative and positive feedback loops can collaboratively achieve remarkable biological functions during the cell fate decision.

SHORT CONCLUSION: This review highlights the regulation of SFs by AS, providing enriched information for future investigations that aim at deciphering the intricate interplay within splicing regulatory networks.

KEY POINTS: Negative feedback of alternative splicing maintains cellular homeostasis. Positive feedback of alternative splicing triggers cellular state transitions. Alternative splicing forms integrated feedback networks with circRNAs and microRNAs to reciprocally regulate their expression and function. The coordinated interplay of distinct splicing feedback mechanisms orchestrates precise cell fate transitions. Future directions and therapeutic possibilities that could transform alternative splicing research into treatments.}, } @article {pmid40539764, year = {2025}, author = {Adler, GL and Kiernan, MC and Tan, RH}, title = {The FindMNDBiomarker Program: Protein Changes in Motor Neuron Disease/Amyotrophic Lateral Sclerosis Postmortem Tissue and Biofluids.}, journal = {Annals of neurology}, volume = {98}, number = {4}, pages = {788-800}, pmid = {40539764}, issn = {1531-8249}, support = {IM-202403-01257//FightMND/ ; MCR-77//FightMND/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Biomarkers/metabolism/cerebrospinal fluid ; *Proteomics/methods ; *Motor Neuron Disease/metabolism ; }, abstract = {OBJECTIVE: Biomarkers of disease pathogenesis are critically needed for amyotrophic lateral sclerosis (ALS) to facilitate diagnosis and patient stratification into appropriate therapeutic trials. Proteomic studies offer significant potential to advance this, but reproducibility across laboratories is a key component toward identifying protein changes that can be translated into clinical applications.

METHODS: A combined analysis of 25 proteomic studies in human ALS biospecimens was performed to identify proteins consistently altered in ALS postmortem tissue, cerebrospinal fluid, or blood, as well as across primary regions of ALS pathology and peripheral biofluids. We consolidated these datasets into a user-friendly database "FindMND Biomarker," which is an accessible search tool that allows users to quickly determine how often, and in which biospecimen types, their proteins of interest are dysregulated in patients with ALS.

RESULTS: Our combined analysis identified 1,458 altered proteins in ALS, and revealed consistent dysregulation in mitochondrial, cytoplasmic, and RNA binding proteins in primary and later affected regions of ALS pathology. Remarkable consistency in the direction and dysregulation of chitinases and gelsolin proteins were observed across ALS biofluids. Comparisons of postmortem tissue and biofluids reinforce several known protein changes, and highlighted novel proteins of interest that may drive disease pathogenesis.

INTERPRETATION: The biospecimen type in which protein dysregulation is most consistently identified provides important insight into disease, and whether these represent potential measures of disease pathogenesis or systemic changes. By streamlining proteins by reproducibility and biospecimen type, FindMNDBiomarker is a useful resource that provides new mechanistic insights, and facilitates the prioritization of ALS-associated proteins for further validation and investigation. ANN NEUROL 2025;98:788-800.}, } @article {pmid40540128, year = {2025}, author = {Bonan, L and Bombardi, M and Di Lionardo, A and Vitiello, M and Morresi, S and Longoni, M}, title = {Co-occurence of amyotrophic lateral sclerosis and sarcoidosis: a case report and systematic review of the literature.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {9}, pages = {4209-4217}, pmid = {40540128}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Male ; Middle Aged ; *Sarcoidosis/complications/diagnosis/drug therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons, with 90% of cases being sporadic. Sarcoidosis is an inflammatory disease affecting multiple organs, with neurological complications occurring in 5-10% of patients. Only isolated cases of this extremely rare combination of the two diseases have been reported.

METHODS: We present the case of a 45-year-old man diagnosed with ALS after a 2-year history of progressive upper limb weakness who was incidentally found to be affected by thoraco-abdominal lymphadenopathy. The biopsy confirmed the co-presence of sarcoidosis. We also make a systematic review of the literature of this rare combination.

RESULTS: The patient showed stabilization of the neurological condition and the pneumological disease after administration of immunosuppressive treatment.

CONCLUSION: Our case report and literature review highlight peculiar clinical characteristics of this extremely rare combination of diseases, deepening the understanding of this peculiar phenotype.}, } @article {pmid40540646, year = {2025}, author = {Au, CK and Chin, ML and Luk, WL and Wong, KW and Che, LY and Yuan, BF and Ilić, G and Pavlović, M and Chan, HW and Yu, JZ and Pavlović, NM and Cai, Z and Chan, W}, title = {Analysis of Honey and Environmental Samples from BEN Endemic Villages in Serbia: Identification of a Novel Human Exposure Pathway for Aristolochic Acids and Aristolactams.}, journal = {Journal of agricultural and food chemistry}, volume = {73}, number = {26}, pages = {16293-16300}, pmid = {40540646}, issn = {1520-5118}, mesh = {Serbia/epidemiology ; Humans ; *Aristolochic Acids/analysis/toxicity/metabolism ; *Balkan Nephropathy/epidemiology/etiology ; *Aristolochia/chemistry/metabolism ; *Honey/analysis ; *Air Pollutants/analysis ; }, abstract = {Dietary exposure to aristolochic acids (AAs) through AA-tainted flour is closely linked to the development of Balkan endemic nephropathy (BEN), a chronic kidney disease that is prevalent in rural farming villages in the Balkan region; however, additional exposure pathways would better explain the incidence rate of BEN. This study reveals for the first time that inhalation of AA-contaminated air, which often contains aristolactams (ALs)─genotoxic metabolites of AAs─represents an unrecognized exposure route. The presence of AAs was confirmed in local honey, and subsequent analysis of face masks worn by volunteers near flowering Aristolochia clematitis (A. clematitis) weeds indicated that AAs may be airborne. Further investigation into the transport of AA-containing particles was conducted by analyzing outdoor residential surfaces (e.g., windowsills) in Serbia, detecting AA-I or AL-I in more than 20% of the samples, with concentrations ranging from 13 to 2470 pg and 1 to 8985 pg per 225 cm[2], respectively. Additionally, it was found that burning A. clematitis generates particle-bound ALs. Given that A. clematitis weeds are often burned alongside wheat remnants for cooking, heating, and fertilizer production, these findings highlight airborne AAs and ALs as potentially key agents in the induction of BEN. In conjunction with the WHO's notice that biomass burning significantly contributes to the high prevalence of respiratory diseases in the Balkans, this study identifies AAs and their analogs as air pollutants. Therefore, it is imperative to eliminate A. clematitis weeds from affected areas and to cease their use as heating and cooking fuel.}, } @article {pmid40541176, year = {2025}, author = {Sonustun, B and Vahsen, BF and Ledesma-Terrón, M and Li, Z and Tuffery, L and Xu, N and Calder, EL and Jungverdorben, J and Weber, L and Zhong, A and Miguez, DG and Monetti, M and Zhou, T and Giacomelli, E and Studer, L}, title = {Telmisartan is neuroprotective in a hiPSC-derived spinal microtissue model for C9orf72 ALS via inhibition of neuroinflammation.}, journal = {Stem cell reports}, volume = {20}, number = {7}, pages = {102535}, pmid = {40541176}, issn = {2213-6711}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {*Telmisartan/pharmacology ; Humans ; *Induced Pluripotent Stem Cells/metabolism/cytology/drug effects ; *Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism/genetics ; *Neuroprotective Agents/pharmacology ; Microglia/drug effects/metabolism ; Motor Neurons/drug effects/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *Spinal Cord/pathology/drug effects/metabolism ; *Neuroinflammatory Diseases/drug therapy/pathology ; Inflammation/drug therapy/pathology ; Astrocytes/drug effects/metabolism ; Angiotensin II Type 1 Receptor Blockers/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron (MN) loss. The most common genetic cause, a hexanucleotide repeat expansion in C9orf72 (C9-ALS), disrupts microglial function, contributing to neuroinflammation, a key disease driver. To investigate this, we developed a three-dimensional spinal microtissue (SM) model incorporating human induced pluripotent stem cell (hiPSC)-derived MNs, astrocytes, and microglia. Screening 190 Food and Drug Administration (FDA)-approved compounds, we identified sartans-angiotensin II receptor I blockers (ARBs)-as potent inhibitors of neuroinflammation. Telmisartan, a highly brain-penetrant ARB, significantly reduced the levels of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 and rescued MN loss in C9-ALS SMs. Our findings suggest that C9-ALS microglia drive MN toxicity and that telmisartan can effectively mitigate inflammation and preserve MN viability. This work lays the groundwork for modeling disease-related neuroinflammation and points to telmisartan as a therapeutic candidate worth further exploration for treating C9-ALS.}, } @article {pmid40541245, year = {2025}, author = {Vázquez, MC and Perna, A and Legnani, M and Saona, G}, title = {Prognostic factors in ALS: different approaches to the same problem.}, journal = {Arquivos de neuro-psiquiatria}, volume = {83}, number = {6}, pages = {1-7}, pmid = {40541245}, issn = {1678-4227}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis ; Female ; Male ; Middle Aged ; Prognosis ; Uruguay/epidemiology ; Aged ; Disease Progression ; Adult ; Kaplan-Meier Estimate ; Age of Onset ; Proportional Hazards Models ; Time Factors ; }, abstract = {The natural history of amyotrophic lateral sclerosis (ALS), the prognoses, and the survival times are fields of considerable interest that are scarcely studied in South American countries.To describe the survival of a representative cohort of Uruguayan ALS patients, and to identify covariates associated with survival using different analyses.Survival was assessed using the Kaplan-Meier method. Different Cox proportional hazards functions were used to identify independent prognostic predictors since the diagnosis: classic, stratified, and truncated.We included 166 definite and probable ALS patients. The median follow-up was of 13.6 years. An analysis was performed according to the recruitment groups: prevalent, exhaustive incident, and non-exhaustive incident cases. The median survival since the diagnosis was longer in the prevalent group (33 months) than in the exhaustive incident (22 months) and non-exhaustive incident (14 months) groups. The median survival time of the entire cohort from onset to death was 37 months and 23 months from the diagnosis. Factors related to survival from diagnosis to death were: age at onset, bulbar region onset, clinical form, and progression rate.The present study described the role of clinical and demographic factors in ALS survival in the Uruguayan population and shed light on differences involving survival models and the temporal bias produced by the lack of precision in determining the onset of the disease.}, } @article {pmid40541317, year = {2025}, author = {Frecska, E and Kovács, A and Szabo, A}, title = {The protective effect of DMT against neurodegeneration.}, journal = {International review of neurobiology}, volume = {181}, number = {}, pages = {395-420}, doi = {10.1016/bs.irn.2025.04.010}, pmid = {40541317}, issn = {2162-5514}, mesh = {Humans ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy/prevention & control ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Receptors, sigma/agonists/metabolism ; *Reperfusion Injury/metabolism/drug therapy ; Sigma-1 Receptor ; }, abstract = {This paper explores the therapeutic potential of DMT in neuroprotective strategies, particularly concerning ischemia-reperfusion injury (IRI) and neurodegenerative disorders. Besides its potent serotonin receptor actions, DMT is also an endogenous agonist of the sigma-1 receptor (Sig-1R). Sigma receptors are a unique family of proteins with high expression in the brain and spinal cord and have been involved in the etiology, symptom course and treatment of several central nervous system disorders. Our previous theoretical and experimental work strongly suggest that targeting sigma (and serotonin) receptors via DMT may be particularly useful for treatment in a number of neurological conditions like stroke, global brain ischemia, Alzheimer's disease, and amyotrophic lateral sclerosis. In this article, we briefly overview the function of Sig1-R in cellular bioenergetics with a focus on the processes involved in IRI and summarize the results of our previous preclinical (in vitro and in vivo) DMT studies aiming at mitigating IRI and related cellular neuropathologies. We conclude that the effect of DMT may involve a universal role in cellular protective mechanisms suggesting therapeutic potentials against different components and types of IRIs emerging in local and generalized brain ischemia after stroke or cardiac arrest. The multiple neuroprotective mechanisms facilitated by DMT may position it as a model molecule for developing pharmacological treatments for neurodegenerative disorders.}, } @article {pmid40542104, year = {2025}, author = {Temp, AGM and Tarakdjian, GN and Kasper, E and Machts, J and Kaufmann, J and Vielhaber, S and Prudlo, J and Cole, JH and Dyrba, M and Teipel, S and Hermann, A}, title = {The role of cognitive and brain reserve in the clinical presentation and progression of amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {20232}, pmid = {40542104}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology/pathology ; *Cognitive Reserve/physiology ; Disease Progression ; Male ; Female ; Middle Aged ; *Brain/physiopathology/pathology ; Aged ; Cognitive Dysfunction/physiopathology ; *Cognition ; Frontotemporal Dementia/physiopathology ; }, abstract = {Recent research has shown that cognitive reserve is associated with better cognitive abilities in ALS/MND, and that a slow brain ageing speed is associated with intact cognition in ALS. This study compares the effects of cognitive reserve and the predicted brain age difference (PAD) on the risk of being diagnosed with ALS, the risk of having cognitive or behavioral impairment, or even fronto-temporal dementia, and on disease duration.Our results indicated that neither PAD nor cognitive reserve was associated with an increased risk of ALS, but that higher PAD was associated with an increased risk of cognitive impairments and FTD, as well as a shortened disease duration. Higher cognitive reserve on the other hand was associated with a lower risk of cognitive impairment and a longer disease duration.Brain age as a proxy of brain reserve influences disease progression and presentation more strongly than cognitive reserve.}, } @article {pmid40542195, year = {2025}, author = {Zhang, J and Hu, J and Liu, R and Zhou, T and Luo, X and Liang, P and Xie, Z and Zhao, Q and Chen, Y and Du, D and Liu, C and Zheng, Y and Li, D and Wang, B}, title = {YAP maintains the dynamics of TDP-43 condensates and antagonizes TDP-43 pathological aggregates.}, journal = {Nature cell biology}, volume = {27}, number = {7}, pages = {1148-1160}, pmid = {40542195}, issn = {1476-4679}, support = {32470726//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32000727//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82188101//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32171236//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32370731//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32170683//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82372788//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2023J01024//Natural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)/ ; JCYJ20220531100204010//Shenzhen Science and Technology Innovation Commission/ ; 20XD1425000//Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)/ ; 22JC1410400//Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; YAP-Signaling Proteins ; Phosphorylation ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; Transcription Factors/metabolism ; Drosophila Proteins/metabolism/genetics ; HEK293 Cells ; Drosophila melanogaster/metabolism/genetics ; Animals, Genetically Modified ; Cell Cycle Proteins ; Stress Granules/metabolism/pathology ; Protein Aggregation, Pathological/metabolism ; Mice ; *Phosphoproteins/metabolism/genetics ; Nuclear Proteins/metabolism/genetics ; Disease Models, Animal ; *Biomolecular Condensates/metabolism ; }, abstract = {Recent studies exploring the underlying pathomechanisms of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, have focused on biomolecular condensates. Here we reveal an unexpected function for YAP, a central component of the Hippo pathway, in regulating the dynamic behaviour of stress granules and TDP-43 condensates, a role that is independent of its transcriptional activity in the Hippo pathway. YAP directly binds to TDP-43. This interaction directly promotes the homotypic multimerization and phase separation of TDP-43 while inhibiting its hyperphosphorylation and solidification under stress conditions. Remarkably, YAP, whose messenger RNA levels are reduced in patients with ALS, is found to co-localize with pathological hyperphosphorylated TDP-43 aggregates in the brains of patients with ALS. In addition, elevation of YAP/Yorkie (a fly homologue of mammalian YAP) expression substantially reduces TDP-43 toxicity in primary neuron and transgenic fly models of ALS. Our findings highlight an unexpected role of YAP in managing ALS-associated biomolecular condensates, presenting important implications for potential ALS treatments.}, } @article {pmid40543321, year = {2025}, author = {Zou, T and Hou, M and Han, H and Wang, X and Chen, H and Tang, Y and Li, R and Hu, S}, title = {Medulla oblongata dominated synaptic density network degeneration in amyotrophic lateral sclerosis.}, journal = {NeuroImage. Clinical}, volume = {47}, number = {}, pages = {103814}, pmid = {40543321}, issn = {2213-1582}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Female ; Male ; Middle Aged ; Aged ; *Medulla Oblongata/diagnostic imaging/pathology ; *Synapses/pathology ; *Nerve Net/diagnostic imaging/pathology ; Positron-Emission Tomography/methods ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a brain network disorder closely associated with synaptic loss in the upper and lower motor neurons. However, the in vivo synaptic network changes and their progressive processes remain unclear. Here, we aim to investigate the synaptic density network connectivity and the likely sequences of synaptic loss in patients with ALS.

METHODS: We examined data from 21 patients diagnosed with ALS and 25 sex- and age-matched healthy controls (HCs) who underwent PET imaging with the SV2A radioligand [[18]F]SynVesT-1. The individual synaptic density similarity network was constructed for each patient by calculating the similarity between interregional synaptic density distributions. The synaptic network connectivity changes were investigated, followed by an examination of the local synaptic density in regions that showed significant network alterations. Finally, we constructed the voxel-wise and ROI-wise causal synaptic covariance network (cSCN) by applying Granger causality analysis. This allowed us to identify the sequence of synaptic loss in these brain regions.

RESULTS: We observed an overall decrease in synaptic density network connectivity in ALS patients compared to controls, with the highest nodal degree in the right medulla oblongata. Specifically, the reduced connections were dominantly between the medulla oblongata and the striatum, frontal lobe, occipital lobe, as well as between the striatum and the frontal lobe, occipital lobe. Furthermore, patients with ALS displayed significantly synaptic loss in those brain regions. The cSCN analyses showed that as the disease progresses, the cortical synaptic loss sequences of ALS extend from the medulla oblongata to the regions including the striatum, frontal lobe, occipital lobe, and parietal lobe.

CONCLUSIONS: These findings suggest that synaptic density network degeneration in ALS may follow a bottom-up transmission pattern, primarily involving in the medulla oblongata-striatum-neocortex network, which have the potential to capture new network-based targets for clinical therapy in the progression of ALS.}, } @article {pmid40543477, year = {2025}, author = {Scott, J and Crook-Rumsey, M and Carobin, A and Bilgorai, J and Kelly, G and Sreedharan, J and Shaw, C and Bashford, J}, title = {Noninvasive quantification of fasciculations to track tofersen therapy in superoxide dismutase 1 amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {177}, number = {}, pages = {2110791}, doi = {10.1016/j.clinph.2025.2110791}, pmid = {40543477}, issn = {1872-8952}, } @article {pmid40543671, year = {2025}, author = {Kim, RW and Mesinkovska, NA and Min, MS}, title = {Limitations in insurance coverage for management of alopecia, a response to Brinks et al's letter.}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {4}, pages = {e153-e154}, doi = {10.1016/j.jaad.2025.06.043}, pmid = {40543671}, issn = {1097-6787}, } @article {pmid40544342, year = {2026}, author = {Rodríguez-García, V and Venta-Sobero, JA and Chima-Galán, MDC}, title = {A novel heterozygous variant of FUS gene associated with juvenile ALS and premature tremor onset: a case report.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {230-232}, doi = {10.1080/21678421.2025.2522403}, pmid = {40544342}, issn = {2167-9223}, mesh = {Humans ; *RNA-Binding Protein FUS/genetics ; Female ; *Tremor/genetics ; *Amyotrophic Lateral Sclerosis/genetics/complications/diagnosis ; *Mutation/genetics ; Heterozygote ; }, abstract = {Juvenile amyotrophic lateral sclerosis (JALS) is neurodegenerative disease of the upper and lower motor neurons of rare incidence. Although fused in sarcoma (FUS) mutations in JALS patients have been associated with movement disorders, here we described the case of a young girl with very early onset of tremor, years before commencement of weakness; once symptoms of JALS were stablished, a typical rapid disease progression from spinal to bulbar symptoms were noticed. Genetic testing revealed a novel mutation in FUS gene causative of a protein dysfunction. This case emphasizes the fact that some mutations within the FUS in JALS patients may produce a symptom onset with tremor.}, } @article {pmid40544604, year = {2025}, author = {Jonk, SM and Nicol, A and Chrysostomou, V and Lardner, E and Yu, SC and Stålhammar, G and Crowston, JG and Tribble, JR and Swoboda, P and Williams, PA}, title = {Metabolic analysis of sarcopenic muscle identifies positive modulators of longevity and healthspan in C. elegans.}, journal = {Redox biology}, volume = {85}, number = {}, pages = {103732}, pmid = {40544604}, issn = {2213-2317}, mesh = {Animals ; *Longevity ; *Caenorhabditis elegans/metabolism/genetics/physiology ; *Sarcopenia/metabolism/pathology ; Mice ; *Muscle, Skeletal/metabolism/pathology ; *Metabolomics/methods ; *Metabolome ; Aging/metabolism ; Mice, Inbred C57BL ; }, abstract = {Sarcopenia is the age-related degeneration of skeletal muscle, resulting in loss of skeletal muscle tone, mass, and quality. Skeletal muscle is a source of systemic metabolites and macromolecules important for neuronal health, function, and healthy neuronal aging. Age-related loss of skeletal muscle might result in decreased metabolite and macromolecule availability, resulting in reduced neuronal function or increased susceptibility to unhealthy aging and neurodegenerative diseases. We aimed to identify muscle metabolite candidates that regulate healthy aging. C57BL/6J mice were aged to young adult (4 months) and old age (25 months) and skeletal muscle was collected. Age-related muscle loss was confirmed by reduced muscle mass, muscle fiber degeneration, reduced myosin intensity, in addition to a metabolic shift and increased DNA damage in skeletal muscle. Using a low molecular weight enriched metabolomics protocol, we assessed the metabolic profile of skeletal muscle from young adult and old age mice and identified 20 metabolites that were significantly changed in aged muscle. These metabolite candidates were tested in C. elegans assays of lifespan, healthspan, muscle, and mitochondrial morphology under normal and stressed conditions. We identified four metabolite candidates (beta-alanine, 4-guanidinobutanoic acid, 4-hydroxyproline, pantothenic acid) that, when supplemented in C. elegans provided robust gero- and mitochondrial protection. These candidates also affected life-, and health- span in C. elegans models of amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD). Our findings support that aging muscle can be used to identify novel metabolite modulators of lifespan and health and may show promise for future treatments of neurodegenerative and neuromuscular disorders.}, } @article {pmid40544661, year = {2025}, author = {Zelek, WM and Tenner, AJ}, title = {Complement therapeutics in neurodegenerative diseases.}, journal = {Immunobiology}, volume = {230}, number = {4}, pages = {153089}, doi = {10.1016/j.imbio.2025.153089}, pmid = {40544661}, issn = {1878-3279}, mesh = {Humans ; *Neurodegenerative Diseases/immunology/therapy/drug therapy/metabolism/etiology ; *Complement System Proteins/metabolism/immunology ; Animals ; Brain/immunology ; Complement Activation/drug effects ; }, abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis pose considerable therapeutic challenges, not only due to their complex pathophysiology, but also because any effective drug must be capable of penetrating the brain. Inflammation is a key feature of NDDs. Increasingly, the complement system, long studied in the context of host defence, has emerged as a central player in the brain, with roles extending far beyond its classical immune functions. Complement contributes to synaptic pruning and immune surveillance, but when dysregulated, it can drive chronic inflammation, synapse loss, and neurodegeneration. Complement is also implicated in neurodevelopmental and neuropsychiatric diseases, including schizophrenia and mood disorders, where overactivation of the cascade impacts brain maturation and circuit stability. In this review, we take a broad view of roles of the complement system in both health and disease in the central nervous system (CNS). We summarise key mechanisms through which complement contributes to pathology, discuss emerging therapeutic strategies, and consider major hurdles in CNS drug development, including brain delivery and the need for patient stratification. As our understanding of the pathological roles of the complement system in the brain advances, it is becoming clear that complement therapeutics may offer a novel approach in slowing neurodegeneration, and in addressing a broader spectrum of disorders affecting the brain.}, } @article {pmid40544973, year = {2025}, author = {Thakur, N and Kumar, T and Singh, C and Kumar, R and Kumar, A}, title = {Cell membrane-coated nanoparticles for neurodegenerative disorders management.}, journal = {International journal of pharmaceutics}, volume = {681}, number = {}, pages = {125875}, doi = {10.1016/j.ijpharm.2025.125875}, pmid = {40544973}, issn = {1873-3476}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Cell Membrane/metabolism/chemistry ; *Nanoparticles/chemistry/administration & dosage ; Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism ; Drug Carriers/chemistry ; *Nanoparticle Drug Delivery System/chemistry ; }, abstract = {Neurodegenerative disorders (ND) are accompanied by neuronal death because of progressive destruction in neuronal structure and function. Due to various neurological conditions, there is a significant number of deaths every year around the world. The healthcare burden is also increasing each year. Development and progress in nanotechnology enable the creation of nanocarriers that transport drugs to the site of disease, thereby enhancing the therapeutic performance of the drug. However, the transport of nanocarrier-based therapeutics to the brain is restricted by barriers such as the Blood-Brain Barrier (BBB) and Blood-Cerebrospinal Fluid Barrier (BCFB), which are further impeded by P-glycoproteins. Hence, current research and development focus on overcoming these obstacles. A biomimetic drug delivery system is one of the best ways to overcome these challenges. One of the promising biomimetic drug delivery systems is cell membrane-coated nanoparticles. In this review, we have comprehensively reviewed the recent progress and development in various cell membrane coated nanoparticle-based drug delivery systems for the effective management of a range of neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, Glioblastoma, Ischemic Stroke, Huntington's Disease, Amyotrophic Lateral Sclerosis, Glioma, Peripheral Nerve Injury, and Motor Neuron Disorder. We also reviewed the challenges associated with cell membrane-coated nanoparticles, such as biosafety hurdles, toxicity, regulatory requirements, and clinical translation. Ultimately, we provided the conclusions and future research directions that must be investigated to overcome the current limitations.}, } @article {pmid40545904, year = {2025}, author = {Mitsumoto, H and Cheung, K and Oskarsson, B and Jang, GE and Andrews, HF and Johnson, S and Shah, JS and Fernandes, JA and Andrews, JA and Rao, M and McElhiney, M}, title = {Placebo-Controlled, Randomized Double-Blind N-Of-1 Trial to Study Safety and Potential Efficacy of TJ-68 for Improving Muscle Cramps in Patients With Amyotrophic Lateral Sclerosis: A Pilot Study.}, journal = {Muscle & nerve}, volume = {72}, number = {3}, pages = {485-492}, pmid = {40545904}, issn = {1097-4598}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; Cross-Over Studies ; Double-Blind Method ; *Muscle Cramp/drug therapy/etiology ; Pilot Projects ; Treatment Outcome ; Single-Case Studies as Topic ; }, abstract = {INTRODUCTION/AIMS: Muscle cramps are a common symptom in amyotrophic lateral sclerosis (ALS). Ameliorating muscle cramps may improve quality of life in devastating diseases like ALS. A traditional Japanese medicine (Kampo, TJ-68) is widely prescribed in Japan for muscle cramps. However, it is not available in the USA. This study evaluated the safety, tolerability, and efficacy of TJ-68 in ALS.

METHODS: This study was a double-blind, randomized, placebo-controlled crossover trial, consisting of four periods, conducted at three centers in the USA. Safety was evaluated using multiple measures. The primary efficacy outcome was the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity (item #5 of the Muscle Cramp Scale (MCS)). The secondary outcomes included the remaining items of the MCS and the Clinical Global Impression of Changes (CGIC), among others. The study was planned to enroll 22 participants with ALS within 2 years.

RESULTS: The enrollment was slow and was completed with 11 participants. There were no serious safety issues and TJ-68 was well tolerated. Although the primary outcome measure did not reach statistical significance (p = 0.35), several secondary measures showed significant results: MCS #1 triggering of cramps (p = 0.01), MCS #2 cramp frequency (p = 0.03), MCS Additional 1 change of motor behaviors (p = 0.02), and CGIC assessed by the evaluator (p = 0.009). Other outcome measures did not reach statistical significance.

DISCUSSION: The study revealed that N-of-1 trial design can detect changes in a small sample size, and TJ-68 appeared to be safe. Larger studies are needed to confirm the efficacy of TJ-68.}, } @article {pmid40547142, year = {2025}, author = {Kumar, S}, title = {Esophageal squamous cell carcinoma susceptibility of activin A receptor type 1C variants in Chinese population.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {6}, pages = {102687}, pmid = {40547142}, issn = {1948-5204}, abstract = {Lin et al's investigation on the association of activin A receptor type 1C (ACVR1C) (transforming growth factor beta type I receptor) single nucleotide polymorphisms (SNPs) with esophageal squamous cell carcinoma (ESCC) risk in the Chinese population is a scientific approach. This study explores the susceptibility of ACVR1C polymorphism towards ESCC in the Chinese population, highlighting the polymorphism's potentiality as an early diagnostic and therapeutic target. The author assessed about a thousand ESCC Chinese patients' samples for ACVR1C SNPs in a hospital-based cohort study using the ligation detection reaction method. Further, the hypothesis was tested using appropriate statistical genetic models and stratified analysis. ACVR1C SNPs can help assess ESCC susceptibility stratification and provide valuable information for individual diagnosis and treatment of ESCC patients. In order to account for confounding variables, find genuine SNP-disease relationships, boost statistical power, and make biological interpretation easier, it is imperative that genetic association studies of ESCC incorporate pertinent clinical aspects.}, } @article {pmid40548824, year = {2025}, author = {Leykam, L and Jonsson, PA and Forsberg, KME and Andersen, PM and Brännström, T and Marklund, SL and Zetterström, P}, title = {SOD1 Protein Content in Human Central Nervous System and Peripheral Tissues.}, journal = {Journal of neurochemistry}, volume = {169}, number = {6}, pages = {e70136}, pmid = {40548824}, issn = {1471-4159}, support = {//Olsson och Olsson Välgörenhetsstiftelse/ ; //King Gustaf V:s and Queen Victoria's Freemason's Foundation/ ; //Fort Knox Välgörenhetsstiftelse/ ; 2.1.12-1605-14//Umeå University Insamlingsstiftelsen/ ; 2.1.6-452-20//Umeå University Insamlingsstiftelsen/ ; 223-1881-13//Umeå University Insamlingsstiftelsen/ ; 223-2808-12//Umeå University Insamlingsstiftelsen/ ; //Västerbotten Läns Landsting/ ; //Ulla-Carin Lindquists stiftelse för ALS-forskning/ ; //Neuroförbundet/ ; 2012-3167//Vetenskapsrådet/ ; 2017-03100//Vetenskapsrådet/ ; 2012.0091//Knut och Alice Wallenbergs Stiftelse/ ; 2014.0305//Knut och Alice Wallenbergs Stiftelse/ ; 2020.0232//Knut och Alice Wallenbergs Stiftelse/ ; 2012-0262//Swedish brain foundation/ ; 2012-0305//Swedish brain foundation/ ; 2013-0279//Swedish brain foundation/ ; 2016-0303//Swedish brain foundation/ ; 2020-0353//Swedish brain foundation/ ; }, mesh = {Humans ; *Superoxide Dismutase-1/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/enzymology ; Male ; Female ; *Central Nervous System/enzymology/metabolism ; Middle Aged ; Aged ; Adult ; *Superoxide Dismutase/metabolism ; Muscle, Skeletal/enzymology ; }, abstract = {Gene silencing therapy is an effective treatment for amyotrophic lateral sclerosis (ALS) patients carrying mutations in the superoxide dismutase-1 (SOD1) gene aiming to reduce noxious forms of SOD1 in the central nervous system (CNS). The normal steady-state level of SOD1 protein in human CNS is therefore of interest but is contested. In this work we have analyzed SOD1 protein content, total protein content, and SOD1 enzymatic activity in six areas of the CNS as well as in four peripheral tissues from sporadic and familial ALS patients and non-ALS controls. Our results show that SOD1 in the human CNS constitutes around 100 μg/g wet weight corresponding to about 0.16% of the total protein in the studied areas. Of the peripheral tissues analyzed, kidney and erythrocytes contain roughly equal amounts, liver higher, and skeletal muscle lower levels of SOD1 compared to the CNS. This data shows SOD1 protein levels around 10 times lower compared to previously published figures. However, SOD1 can still be considered an abundant protein considering that > 12 000 proteins are expressed in human cells. There was no difference in SOD1 protein content between sporadic or familial ALS patients and control individuals. The level and activity of SOD1 are not deviating in the areas of the CNS that are most vulnerable to ALS. Instead, insufficient control of SOD1 structure and aggregation could be important factors behind the vulnerability of motor areas to SOD1 proteotoxicity.}, } @article {pmid40550045, year = {2025}, author = {Lei, C and Chen, J and Chen, Z and Xiao, Y and Chen, J and Ma, C and Yang, M and Wu, D and Xie, L}, title = {Amyotrophic lateral sclerosis and neurodegenerative diseases: A Mendelian randomization study.}, journal = {Medicine}, volume = {104}, number = {25}, pages = {e42847}, pmid = {40550045}, issn = {1536-5964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/epidemiology ; Parkinson Disease/genetics ; Alzheimer Disease/genetics ; Frontotemporal Dementia/genetics ; }, abstract = {In this study, we used the Mendelian randomization (MR) method to systematically examine whether there is a bidirectional causal relationship between amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). We analyzed data from 6,44,924 participants using MR to evaluate causality. We employed inverse variance weighted and MR-Egger regression tests for MR analysis. Additionally, we performed sensitivity analyses using the MR-Egger test and Mendelian Randomization Pleiotropy RESidual Sum and Outlier. The inverse variance weighted analysis found no evidence of a risk effect between ALS and the neurodegenerative diseases AD, PD, FTD, MSA, and DLB. However, the MR-Egger analysis showed that both AD (odds ratio: 1.079, 95% confidence interval: 1.017-1.145, P = .029) and PD (odds ratio: 1.210, 95% confidence interval: 1.046-1.401, P = .020) have a risk effect on ALS, indicating that AD and PD increase the risk of ALS. Our MR analysis suggests that AD and PD may have a potential causal relationship with ALS. Conversely, ALS does not appear to have a causal relationship with the other neurodegenerative diseases examined (FTD, MSA, DLB).}, } @article {pmid40550228, year = {2025}, author = {Tiwari, A and Singh, B and Singh, GK and Meena, J and Agrawal, AK and Kumar, S and Modi, G}, title = {Unveiling Exosome Potential: Transforming Treatments for Neurodegeneration.}, journal = {ACS applied bio materials}, volume = {8}, number = {7}, pages = {5406-5423}, doi = {10.1021/acsabm.5c00096}, pmid = {40550228}, issn = {2576-6422}, mesh = {*Exosomes/chemistry/metabolism ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Biocompatible Materials/chemistry ; Drug Delivery Systems ; }, abstract = {Exosomes, tiny extracellular vesicles, hold significant potential as biological nanocarriers for diverse therapeutic agents due to their exceptional ability to navigate through the barriers of biological systems. This comprehensive review delves into the capability of exosomes in the therapy of neurodegenerative disorders, concentrating on their potential for targeted drug delivery. It examines the complex processes involved in exosome-mediated drug delivery, including targeting, cellular uptake, intracellular trafficking, and therapeutic release. Insights from preclinical studies and clinical trials are exploited, highlighting the impactful applications of exosomes, particularly in the treatment of Parkinson's, Alzheimer's, ALS, and Huntington's diseases. The review also addresses challenges such as immunogenicity, scalability, and regulatory obstacles while exploring emerging technologies like advanced exosome engineering, personalized medicine, and the integration of nanotechnology. Overall, this review accentuates the potential impact of exosome-based treatments in biomedicine alongside the critical need to overcome existing barriers.}, } @article {pmid40551967, year = {2025}, author = {Berdyński, M and Safranow, K and Andersen, PM and Żekanowski, C}, title = {Phenotypic Characterization of ALS-Causing SOD1 Mutations Affecting Polypeptide Length.}, journal = {Human mutation}, volume = {2025}, number = {}, pages = {9792233}, pmid = {40551967}, issn = {1098-1004}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/mortality ; Humans ; *Superoxide Dismutase-1/genetics/chemistry ; Phenotype ; *Mutation ; Middle Aged ; Female ; Male ; Adult ; Age of Onset ; Aged ; }, abstract = {Background: Some 234 mutations in the small SOD1 gene have been reported to cause amyotrophic lateral sclerosis. However, the pathogenic mechanisms, particularly of those mutations affecting polypeptide length, are contested. It is presently unknown whether all reported nonsense mutations in SOD1 are causative for ALS. The emergence of promising new anti-SOD1 drugs has made it imperative to gain further insight into clinical-genetic aspects of ALS for deciding which patients to treat in clinical practice and include in drug trials. Objective: This study is aimed at comprehensively analyzing the clinical phenotypes associated with ALS-causing SOD1 mutations that alter the polypeptide length. The specific focus is on the age at which symptoms manifest and the survival duration. Methods: Data were collected from web databases, published reports, conference presentations, and personal communications up to November 2023. The clinical endpoints, including age at symptom onset and age at death, were subjected to survival analysis. Comparative analyses were performed between frameshift and nonframeshift variants. Results: A cohort of 146 ALS patients harboring 38 different nonmissense SOD1 variants was analyzed. The mean age of disease onset was 46.9 years, with a mean survival duration of 49 months. Significant heterogeneity was observed in clinical outcomes, with earlier disease onset and reduced survival associated with specific mutations. Notably, frameshift mutations proximal to the N-terminus showed a higher risk of early ALS onset compared to more distal mutations. Conclusions: The clinical phenotypes of ALS patients with nonmissense SOD1 mutations are highly variable and dependent on the specific mutation. These findings underscore the necessity of including diverse SOD1 mutation carriers in therapeutic trials and suggest that both loss-of-function and gain-of-function mechanisms may contribute to ALS pathology.}, } @article {pmid40553535, year = {2025}, author = {Ramachandra, K and Narayana, AR and Induraj, A and Pai, R}, title = {Unilateral Vocal Cord Palsy as Presenting Feature of Amyotrophic Lateral Sclerosis.}, journal = {The Journal of the Association of Physicians of India}, volume = {73}, number = {5}, pages = {83-84}, doi = {10.59556/japi.73.0931}, pmid = {40553535}, issn = {0004-5772}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/complications ; Aged ; *Vocal Cord Paralysis/etiology/diagnosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative pathology marked by the degeneration of upper and lower motor neurons, resulting in muscle weakness and atrophy, impairing motor function. Bulbar-onset ALS is a distinct clinical subtype, with initial involvement of bulbar motor neurons, often causing severe speech and swallowing difficulties. Despite its impact, bulbar-onset ALS, especially with rare symptoms like unilateral vocal cord palsy (UVCP), lacks extensive research. Here, we detail the case of a 79-year-old nonambulatory diabetic male with a 1-year history of hoarseness of voice, diagnosed with bulbar-onset ALS with UVCP. This underscores the importance of recognizing unusual presentations of ALS, particularly in geriatric populations, urging tailored medical evaluations for optimal care and improved outcomes in this challenging neurological condition.}, } @article {pmid40553568, year = {2025}, author = {Bekier, ME and Pinarbasi, E and Krishnan, G and Mesojedec, JJ and Hurley, M and Harikumar Sheela, H and Collins, CA and Ghaffari, L and de Majo, M and Ullian, EM and Koontz, M and Coleman, S and Li, X and Tank, EM and Waksmacki, J and Gao, FB and Barmada, SJ}, title = {Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS.}, journal = {The Journal of clinical investigation}, volume = {135}, number = {17}, pages = {}, pmid = {40553568}, issn = {1558-8238}, support = {UL1 TR000433/TR/NCATS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; R44 NS124457/NS/NINDS NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R56 NS069844/NS/NINDS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS069844/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology/enzymology ; *DNA-Binding Proteins/metabolism/genetics ; Active Transport, Cell Nucleus ; *Protein Serine-Threonine Kinases/metabolism/genetics ; Animals ; Mice ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; *Cell Nucleus/metabolism/genetics ; Neurons/metabolism/pathology ; }, abstract = {Cytoplasmic transactive response DNA-binding protein 43 (TDP43) mislocalization and aggregation are pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the initial cellular insults that lead to TDP43 mislocalization remain unclear. In this study, we demonstrate that nemo-like kinase (NLK) - a proline-directed serine-threonine kinase - promotes the mislocalization of TDP43 and other RNA-binding proteins by disrupting nuclear import. NLK levels were selectively elevated in neurons exhibiting TDP43 mislocalization in tissues from patients with ALS, and genetic reduction of NLK reduced toxicity in human neuron models of ALS. Our findings suggest that NLK is a promising therapeutic target for neurodegenerative diseases.}, } @article {pmid40554439, year = {2025}, author = {Fan, Y and Wang, Z and Wu, M and Lin, L and Chen, L and Zheng, B}, title = {Bidirectional Causal Relationship Between Myopia and Neurodegenerative Diseases: Two-Sample Mendelian Randomization Analyses.}, journal = {British journal of hospital medicine (London, England : 2005)}, volume = {86}, number = {6}, pages = {1-19}, doi = {10.12968/hmed.2025.0183}, pmid = {40554439}, issn = {1759-7390}, mesh = {Humans ; Mendelian Randomization Analysis ; *Myopia/genetics/epidemiology ; Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/epidemiology ; Genetic Predisposition to Disease ; Parkinson Disease/genetics/epidemiology ; Polymorphism, Single Nucleotide ; Alzheimer Disease/genetics/epidemiology ; Amyotrophic Lateral Sclerosis/genetics/epidemiology ; }, abstract = {Aims/Background Myopia is highly prevalent in certain neurodegenerative diseases (NDDs), and both conditions demonstrate genetic susceptibility. This study investigated the potential bidirectional causal relationships between myopia and four NDDs, Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), using Mendelian randomization (MR). We aimed to determine whether myopia contributes to the risk of NDDs and vice versa. Methods We analyzed data from two independent, large-scale genome-wide association study (GWAS) cohorts on myopia, comprising 212,571 participants in the first cohort (finn-b-H7_MYOPIA) and 95,619 in the second (GCST009521). GWAS summary statistics for the four NDDs, encompassing 589,439 samples, were also incorporated. Bidirectional MR was employed to investigate causal relationships between myopia and each of the four NDDs. The inverse variance-weighted (IVW) method served as the primary analytical approach. Sensitivity analyses, including MR-Egger regression, weighted median, weighted mode, and simple mode, were conducted to assess the robustness of the findings. Horizontal pleiotropy was evaluated using the MR-Egger regression intercept test and the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) global test, while heterogeneity was assessed via Cochran's Q test. Leave-one-out analyses were conducted to evaluate the influence of individual single nucleotide polymorphisms (SNPs). Odds ratios (ORs) with 95% confidence intervals (CIs) were reported, and statistical significance was set at p < 0.05. Results MR analyses identified no evidence of a causal relationship between myopia and refractive error and increased risk of any of the four NDDs (all p > 0.05). Similarly, none of the NDDs were associated with an increased risk of myopia or refractive error (all p > 0.05). Sensitivity analyses revealed no SNPs with significant influence on the causal associations (all p > 0.05), supporting the robustness of the findings. Conclusion This study provides no evidence of a bidirectional causal relationship between myopia and the four NDDs among individuals of European ancestry. Future research should extend beyond direct causal inference to investigate potential mediating biological mechanisms.}, } @article {pmid40554516, year = {2026}, author = {Castro, J and de Carvalho, M}, title = {Nerve Conduction Studies of Phrenic Nerve: Normative Data.}, journal = {Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society}, volume = {43}, number = {2}, pages = {176-182}, doi = {10.1097/WNP.0000000000001181}, pmid = {40554516}, issn = {1537-1603}, mesh = {Humans ; Male ; Female ; *Phrenic Nerve/physiology ; Middle Aged ; Adult ; *Neural Conduction/physiology ; Aged ; Aged, 80 and over ; Young Adult ; *Diaphragm/physiology/innervation ; Reference Values ; Action Potentials/physiology ; Electric Stimulation ; Electromyography ; Nerve Conduction Studies ; }, abstract = {INTRODUCTION: In neuromuscular diseases, respiratory failure is a major complication. Pulmonary function tests are generally used to assess respiratory function but can be influenced by a number of factors. Nerve conduction studies of the phrenic nerve (PN) is a simple, noninvasive, and safe method to assess diaphragm compromise in neuromuscular diseases.

METHODS: A group of 132 (78 males) healthy subjects, aged between 23 and 90 years, was studied, with bilateral stimulation of the PN, with recording of diaphragm motor responses. Anthropometric variables (sex, age, height, and weight) were collected, and their influence on diaphragm motor response was assessed. Side-to-side differences were also analyzed.

RESULTS: PN compound muscle action potential (CMAP) had significantly higher amplitude and area on the left side. Men had longer latency, and higher amplitude and area when compared with women, on both sides. Age was a significant factor influencing CMAP latency, with an average increase of 0.25 ms per decade of life. In men, a latency longer than 9.5 ms and a CMAP amplitude lower than 0.62 mV should be considered abnormal, while in women, the values are 8.5 ms and 0.48 mV, respectively.

CONCLUSIONS: PN conduction studies offer a simple and reliable technique readily applicable in clinical settings. Diaphragm CMAP parameters are significantly influenced by the anthropometric variables of sex and age. Notably, CMAP amplitude and area are greater for the left PN.}, } @article {pmid40555284, year = {2025}, author = {Park, KH and Kim, KW}, title = {Optogenetics to biomolecular phase separation in neurodegenerative diseases.}, journal = {Molecules and cells}, volume = {48}, number = {8}, pages = {100247}, pmid = {40555284}, issn = {0219-1032}, mesh = {*Optogenetics/methods ; Humans ; *Neurodegenerative Diseases/metabolism/genetics ; Animals ; Phase Separation ; }, abstract = {Neurodegenerative diseases involve toxic protein aggregation. Recent evidence suggests that biomolecular phase separation, a process in which proteins and nucleic acids form dynamic, liquid-like condensates, plays a key role in this aggregation. Optogenetics, originally developed to control neuronal activity with light, has emerged as a powerful tool to investigate phase separation in living systems. This is achieved by fusing disease-associated proteins to light-sensitive oligomerization domains, enabling researchers to induce or reverse condensate formation with precise spatial and temporal control. This review highlights how optogenetic systems such as OptoDroplet are being used to dissect the mechanisms of neurodegenerative disease. We examine how these tools have been applied in models of neurodegenerative diseases, such as amyotrophic lateral sclerosis, Alzheimer's, Parkinson's, and Huntington's disease. These studies implicate small oligomeric aggregates as key drivers of toxicity and highlight new opportunities for therapeutic screening. Finally, we discuss advances in light-controlled dissolution of condensates and future directions for applying optogenetics to combat neurodegeneration. By enabling precise, dynamic control of protein phase behavior in living systems, optogenetic approaches provide a powerful framework for elucidating disease mechanisms and informing the development of targeted therapies.}, } @article {pmid40555518, year = {2025}, author = {Zanella, P and Loss, I and Parlato, R and Weishaupt, JH and Sala, C and Verpelli, C and Boeckers, TM and Catanese, A}, title = {ALS Mutations Shift the Isoelectric Point of the KIF5A C Terminal Inducing Protein Aggregation and TDP-43 Mislocalization.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {45}, number = {31}, pages = {}, pmid = {40555518}, issn = {1529-2401}, mesh = {*Kinesins/genetics/metabolism/chemistry ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Mutation/genetics ; Motor Neurons/metabolism ; Animals ; *Protein Aggregation, Pathological/genetics/metabolism ; Cells, Cultured ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by death of lower and upper motor neurons. Although the mechanism behind the selective neuron loss is still unclear, several heterogeneous genes have been causally linked to ALS. KIF5A encodes for a neuronally enriched kinesin involved in protein transport, and mutations within this gene have been causally linked to different motor neuron diseases. The mutations identified in ALS patients are mostly predicted to alter its mRNA splicing, leading to a frameshift mutation and an aberrant 39-aa-long sequence in the C-terminal domain of KIF5A. Here we found that ALS-related KIF5A mutations induce the accumulation of the mutant form of the protein in human motoneurons, which are also characterized by the cytosolic mislocalization of TDP-43. This ALS hallmark was even exacerbated upon overexpression of the ALS-KIF5A protein in cells differentiated from healthy controls and primary neurons, suggesting a pathological connection between the cellular load of the mutant protein and TDP-43 pathology. While the terminal domain of the WT isoform is characterized by an acid isoelectric point (pI), the ALS variant presents a basic pI due to the altered aminoacidic composition of this sequence. We thus generated a KIF5A-ALS isoform that retained part of the aberrant sequence but with lower pI. The overexpression of this mutated variant led to significantly lower protein aggregation and TDP-43 mislocalization than the ALS mutant. Our data show that re-establishing the correct pI rescues KIFA aggregation and significantly reduces the cytoplasmic mislocalization of TDP-43.}, } @article {pmid40555967, year = {2025}, author = {Ahmed, AB and Draz, ME and Asad, H and Naguib, IA and Edrees, FH}, title = {Innovative Synchronous Spectrofluorometric Method for Assessing a Novel Drug Combination in Amyotrophic Lateral Sclerosis: In Vivo Human Application With Greenness and Sustainability Evaluation.}, journal = {Luminescence : the journal of biological and chemical luminescence}, volume = {40}, number = {6}, pages = {e70222}, doi = {10.1002/bio.70222}, pmid = {40555967}, issn = {1522-7243}, support = {TU-DSPP-2024-49//Taif University/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Spectrometry, Fluorescence/methods ; *Celecoxib/analysis/therapeutic use/administration & dosage/blood ; *Ciprofloxacin/analysis/therapeutic use/blood/administration & dosage ; Drug Combinations ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurological disorder that causes damage to sensory neurons, then paralysis and death. A novel combination of celecoxib (CXP) and ciprofloxacin (CIP) has recently been used to enhance both motor performance and CNS cell morphology, alterations in the rate of disease progression, quality of life, and survival, which passed phase IIb RCT study. Celecoxib is classified as a non-steroidal anti-inflammatory drug; ciprofloxacin is a fluoroquinolone antibiotic that has a synergistic effect for the treatment of ALS, which is a severe neurological disorder. A new sustainable, simple, sensitive, and environmentally friendly synchronous spectrofluorimetric approach (SSF) was established to simultaneously estimate celecoxib and ciprofloxacin in pure form and biological fluids. The approach depends on synchronous fluorescence spectroscopy, where CXP and CIP were detected at 364 and 438 nm, correspondingly, using Δλ of 80-nm utilizing sodium dodecyl sulphate (SDS) micellar system, which considerably improved synchronous fluorescence intensity. The approach was validated and revealed excellent linearity with concentrations varying from 10 to 10,000 and 5 to 20,000 ng/mL for CXP and CIP; correspondingly, CXP and CIP showed extremely low limits of detection (LODs) 0.58-0.24 ng/mL, which guarantee the sensitivity of the proposed approach. The suggested approach was successfully implemented to analyze the co-administered pharmaceuticals in their pure form and actual human plasma after concurrent oral administration of both drugs, which may be employed in an inquiry on the pharmacokinetics and bioavailability of human plasma to the new coming PrimeC pharmaceutical formulation. Ultimately, the method's remarkable greenness was proved by evaluating its greenness profile using various assessment strategies. The findings revealed that the SSF approach is a sustainable and environmentally friendly analytical approach.}, } @article {pmid40557915, year = {2025}, author = {Ranieri, F and Senerchia, G and Bonan, L and Casali, S and Cabona, C and Cantone, M and De Marchi, F and Diamanti, L and Doretti, A and Fini, N and Filosto, M and Fortuna, A and Iovino, A and Iuzzolino, VV and Lanza, G and Lunetta, C and Maderna, L and Mandrioli, J and Mazzini, L and Musumeci, G and Nuredini, A and Sorarù, G and Toriello, A and Ticozzi, N and Todisco, M and Vacchiano, V and Zinno, L and Silani, V and Rossi, S and Di Lazzaro, V and Dubbioso, R and , }, title = {Cortical Excitability as a Prognostic and Phenotypic Stratification Biomarker in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {98}, number = {4}, pages = {801-813}, pmid = {40557915}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/mortality ; Male ; Female ; Middle Aged ; Aged ; Retrospective Studies ; Phenotype ; Prognosis ; *Evoked Potentials, Motor/physiology ; *Cortical Excitability/physiology ; Biomarkers ; Motor Neurons/physiology ; Adult ; Action Potentials/physiology ; Disease Progression ; }, abstract = {OBJECTIVE: Despite its clinical heterogeneity, amyotrophic lateral sclerosis is unified by early and prominent alterations in cortical excitability, increasingly recognized as contributors to disease progression. This study assessed whether the ratio between motor evoked potential (MEP) amplitude, reflecting upper motor neuron integrity, and compound muscle action potential (CMAP) amplitude, indexing lower motor neuron function, could provide an accessible marker of corticospinal excitability to stratify patients by phenotype, stage, and survival.

METHODS: In this multicenter retrospective study, 743 amyotrophic lateral sclerosis patients from 16 tertiary centers in Italy were analyzed. The MEP:CMAP ratio, recorded from upper limb muscles, was categorized as hyperexcitable, normal, or hypoexcitable. Phenotypes included progressive muscular atrophy (or lower motor neuron), flail arm/leg, classic, bulbar, patient with predominant upper motor neuron signs (or pyramidal), and primary lateral sclerosis. Disease stage was assessed using King's staging. Survival was analyzed using Kaplan-Meier curves and Cox regression models.

RESULTS: The MEP:CMAP ratio differed significantly across phenotypes (p < 0.0001), with hyperexcitability predominating in lower motor neuron, flail, classic, and bulbar forms, and hypoexcitability in pyramidal and primary lateral sclerosis. Hypoexcitability increased in advanced King's stages (p < 0.0001). Hyperexcitable patients had shorter survival (p = 0.004), including when tested within 1 year of onset (p = 0.006). Cox regression identified the MEP:CMAP ratio as an independent survival predictor (HR 1.84, 95% CI 1.12-3.03, p = 0.016).

INTERPRETATION: This real-world study supports the clinical value of the MEP:CMAP ratio as a scalable biomarker of cortical excitability in amyotrophic lateral sclerosis, with prognostic relevance across phenotypes and disease stages. ANN NEUROL 2025;98:801-813.}, } @article {pmid40558500, year = {2025}, author = {Mai, HA and Thomas, CM and Nge, GG and Elefant, F}, title = {Modulating Cognition-Linked Histone Acetyltransferases (HATs) as a Therapeutic Strategy for Neurodegenerative Diseases: Recent Advances and Future Trends.}, journal = {Cells}, volume = {14}, number = {12}, pages = {}, pmid = {40558500}, issn = {2073-4409}, support = {R01 NS095799/NS/NINDS NIH HHS/United States ; RF1 NS095799/NS/NINDS NIH HHS/United States ; 2RF1NS095799//National Institutes of Health NINDS/ ; 2RF1NS095799/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/therapy/enzymology/drug therapy ; *Histone Acetyltransferases/metabolism ; *Cognition/physiology ; Animals ; Protein Processing, Post-Translational ; Histones/metabolism ; Epigenesis, Genetic ; Acetylation ; Aging ; }, abstract = {Recent investigations into the neuroepigenome of the brain are providing unparalleled understanding into the impact of post-translational modifications (PTMs) of histones in regulating dynamic gene expression patterns required for adult brain cognitive function and plasticity. Histone acetylation is one of the most well-characterized PTMs shown to be required for neuronal function and cognition. Histone acetylation initiates neural circuitry plasticity via chromatin control, enabling neurons to respond to external environmental stimuli and adapt their transcriptional responses accordingly. While interplay between histone acetylation and deacetylation is critical for these functions, dysregulation during the aging process can lead to significant alterations in the neuroepigenetic landscape. These alterations contribute to impaired cognitive functions, neuronal cell death, and brain atrophy, all hallmarks of age-related neurodegenerative disease. Significantly, while age-related generation of DNA mutations remains irreversible, most neuroepigenetic PTMs are reversible. Thus, manipulation of the neural epigenome is proving to be an effective therapeutic strategy for neuroprotection in multiple types of age-related neurodegenerative disorders (NDs) that include Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Here, we highlight recent progress in research focusing on specific HAT-based neuroepigenetic mechanisms that underlie cognition and pathogenesis that is hallmarked in age-related NDs. We further discuss how these findings have potential to be translated into HAT-mediated cognitive-enhancing therapeutics to treat these debilitating disorders.}, } @article {pmid40559225, year = {2025}, author = {Elgenidy, A and Hassan, IA and Hamed, Y and Hashem, HA and Abuel-Naga, O and Abdel-Rahman, HI and Mohamed, KR and Hamed, BM and Shehab, MA and Zeyada, M and Kassab, S and Abdelgawad, SSA and Ibrahim, AI and Hasanin, EH and Elhoufey, AA and Mahmoud, KH and Saad, K}, title = {Sonographic Evaluation of Peripheral Nerves and Cervical Nerve Roots in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Medical sciences (Basel, Switzerland)}, volume = {13}, number = {2}, pages = {}, pmid = {40559225}, issn = {2076-3271}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Ultrasonography/methods ; *Peripheral Nerves/diagnostic imaging/pathology ; *Spinal Nerve Roots/diagnostic imaging/pathology ; Middle Aged ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that leads to nerve atrophy. Ultrasonography has a significant role in the diagnosis of ALS.

AIM: We aimed to sonographically assess the size of all peripheral nerves and cervical nerve roots in ALS compared to controls.

METHODS: We searched MEDLINE (PubMed), Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and Scopus using comprehensive MeSH terms for the keywords nerve, ultrasound, and ALS. We extracted data regarding cross-sectional area (CSA) or diameter for the following nerves: vagus, phrenic, tibial, fibular, sural, radial, ulnar, and median nerves, and the roots of C5, C6, C7, and C8 in both ALS patients and controls.

RESULTS: Our study included 2683 participants, of which 1631 were ALS patients (mean age = 60.36), 792 were healthy controls (mean age = 57.79), and 260 were patients with other neurological disorders. ALS patients had significantly smaller nerve size compared to controls. Nerve size differences were observed in the vagus nerve [MD = -0.23], phrenic nerve [MD = -0.25], C5 nerve root [SMD = -0.94], C6 nerve root [SMD = -1.56], C7 nerve root [SMD = -1.18], C8 nerve root [MD = -1.9], accessory nerve [MD = -0.32], sciatic nerve [MD = -11], tibial nerve [MD = -0.68], sural nerve [MD = -0.32,], ulnar nerve [MD = -0.80], and median nerve [MD = -1.21].

CONCLUSIONS: Our findings showed that ALS patients have a sonographically smaller nerve size than healthy controls. Therefore, this is a potential marker for neuronal diseases.}, } @article {pmid40559965, year = {2025}, author = {Kim, WW and Zarus, G and Alman, B and Ruiz, P and Han, M and Mehta, P and Ji, C and Qureshi, H and Antonini, J and Shoeb, M}, title = {Metal-Induced Genotoxic Events: Possible Distinction Between Sporadic and Familial ALS.}, journal = {Toxics}, volume = {13}, number = {6}, pages = {}, pmid = {40559965}, issn = {2305-6304}, abstract = {Metal exposure is a potential risk factor for amyotrophic lateral sclerosis (ALS). Increasing evidence suggests that elevated levels of DNA damage are present in both familial (fALS) and sporadic (sALS) forms of ALS, characterized by the selective loss of motor neurons in the brain, brainstem, and spinal cord. However, identifying and differentiating initial biomarkers of DNA damage response (DDR) in both forms of ALS remains unclear. The toxicological profiles from the Agency for Toxic Substances and Disease Registry (ATSDR) and our previous studies have demonstrated the influence of metal exposure-induced genotoxicity and neurodegeneration. A comprehensive overview of the ATSDR's toxicological profiles and the available literature identified 15 metals (aluminum (Al), arsenic (As), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), mercury (Hg), nickel (Ni), selenium (Se), uranium (U), vanadium (V), and zinc (Zn)) showing exposure-induced genotoxicity indicators associated with ALS pathogenesis. Genetic factors including mutations seen in ALS types and with concomitant metal exposure were distinguished, showing that heavy metal exposure can exacerbate the downstream effect of existing genetic mutations in fALS and may contribute to motor neuron degeneration in sALS. Substantial evidence associates heavy metal exposure to genotoxic endpoints in both forms of ALS; however, a data gap has been observed for several of these endpoints. This review aims to (1) provide a comprehensive overview of metal exposure-induced genotoxicity in ALS patients and experimental models, and its potential role in disease risk, (2) summarize the evidence for DNA damage and associated biomarkers in ALS pathogenesis, (3) discuss possible mechanisms for metal exposure-induced genotoxic contributions to ALS pathogenesis, and (4) explore the potential distinction of genotoxic biomarkers in both forms of ALS. Our findings support the association between metal exposure and ALS, highlighting under or unexplored genotoxic endpoints, signaling key data gaps. Given the high prevalence of sALS and studies showing associations with environmental exposures, understanding the mechanisms and identifying early biomarkers is vital for developing preventative therapies and early interventions. Limitations include variability in exposure assessment and the complexity of gene-environment interactions. Studies focusing on longitudinal exposure assessments, mechanistic studies, and biomarker identification to inform preventative and therapeutic strategies for ALS is warranted.}, } @article {pmid40560468, year = {2025}, author = {Sumra, V and Hadian, M and Dilliott, AA and Farhan, SMK and Frank, AR and Lang, AE and Roberts, AC and Troyer, A and Arnott, SR and Marras, C and Tang-Wai, DF and Finger, E and Rogaeva, E and Orange, JB and Ramirez, J and Zinman, L and Binns, M and Borrie, M and Freedman, M and Ozzoude, M and Bartha, R and Swartz, RH and Munoz, D and Masellis, M and Black, SE and Dixon, RA and Dowlatshahi, D and Grimes, D and Hassan, A and Hegele, RA and Kumar, S and Pasternak, S and Pollock, B and Rajji, T and Sahlas, D and Saposnik, G and Tartaglia, MC and , }, title = {Regional free-water diffusion is more strongly related to neuroinflammation than neurodegeneration.}, journal = {Journal of neurology}, volume = {272}, number = {7}, pages = {478}, pmid = {40560468}, issn = {1432-1459}, mesh = {Humans ; Male ; Aged ; Female ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; *Diffusion Magnetic Resonance Imaging/methods ; *Neuroinflammatory Diseases/diagnostic imaging/metabolism ; Middle Aged ; Neurofilament Proteins/blood ; Glial Fibrillary Acidic Protein/blood ; Biomarkers/blood ; Aged, 80 and over ; Cognitive Dysfunction/diagnostic imaging ; }, abstract = {INTRODUCTION: Recent research has suggested that neuroinflammation may be important in the pathogenesis of neurodegenerative diseases. Free-water diffusion (FWD) has been proposed as a non-invasive neuroimaging-based biomarker for neuroinflammation.

METHODS: Free-water maps were generated using diffusion MRI data in 367 patients from the Ontario Neurodegenerative Disease Research Initiative (108 Alzheimer's Disease/Mild Cognitive Impairment, 42 Frontotemporal Dementia, 37 Amyotrophic Lateral Sclerosis, 123 Parkinson's Disease, and 58 vascular disease-related Cognitive Impairment). The ability of FWD to predict neuroinflammation and neurodegeneration from biofluids was estimated using plasma glial fibrillary-associated protein (GFAP) and neurofilament light chain (NfL), respectively.

RESULTS: Recursive Feature Elimination (RFE) performed the strongest out of all feature selection algorithms used and revealed regional specificity for areas that are the most important features for predicting GFAP over NfL concentration. Deep learning models using selected features and demographic information revealed better prediction of GFAP over NfL.

DISCUSSION: Based on feature selection and deep learning methods, FWD was found to be more strongly related to GFAP concentration (measure of astrogliosis) over NfL (measure of neuro-axonal damage), across neurodegenerative disease groups, in terms of predictive performance. Non-invasive markers of neurodegeneration such as MRI structural imaging that can reveal neurodegeneration already exist, while non-invasive markers of neuroinflammation are not available. Our results support the use of FWD as a non-invasive neuroimaging-based biomarker for neuroinflammation.}, } @article {pmid40560475, year = {2025}, author = {Bamber, R and Stavroulakis, T and McDermott, C and Carlton, J}, title = {Health-related quality of life of informal carers in ALS: a systematic review of person reported outcome measures.}, journal = {Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation}, volume = {34}, number = {10}, pages = {2731-2744}, pmid = {40560475}, issn = {1573-2649}, support = {NIHR301648//National Institute for Health and Care Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/nursing ; *Quality of Life/psychology ; *Caregivers/psychology ; *Patient Reported Outcome Measures ; Psychometrics ; Reproducibility of Results ; }, abstract = {PURPOSE: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition with swift progression. The devastating impact of ALS affects the health-related quality of life (HRQoL) of informal carers. Various person reported outcome measures (PROMs) have been used to assess HRQoL in informal carers in ALS, yet their validity remains unclear. This review aimed to identify and evaluate the content validity of HRQoL PROMs for informal carers in ALS.

METHODS: This review was conducted according to best practice COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology. Two literature searches were conducted in November 2023 and April 2024 across MEDLINE, PsycINFO, Embase, CINAHL, the Cochrane Database of Systematic Reviews, CENTRAL and Google Scholar, to identify HRQoL PROMs used with informal carers in ALS, PROM development articles, and psychometric literature. Evidence synthesis followed COSMIN guidance.

RESULTS: 12,276 articles were screened, and 109 PROMs were identified, with 43 undergoing full COSMIN assessment. Content validity ratings were 'Inconsistent' or 'Insufficient' for all PROMs. All PROMs, except the CarerQoL, were rated 'Insufficient' for comprehensiveness. Only 18.6% of PROMs included informal carers in development. Quality of evidence supporting content validity ratings was 'Very Low' for 93% of PROMs.

CONCLUSION: HRQoL PROMs used with informal carers in ALS lack evidence to support their content validity, restricting their utility for this purpose. Existing literature on the impact of caring in ALS on informal carers' HRQoL should be interpreted cautiously. Further research is required to establish the content validity of HRQoL PROMs used for this cohort.}, } @article {pmid40560963, year = {2025}, author = {Pang, C and Li, Y and Jiang, W and Xie, H and Cao, W and Yu, H and Lin, Z and Cheng, Y and Fan, D and Deng, B}, title = {Analysis of retinal markers and incident amyotrophic lateral sclerosis: An optical coherence tomography-based cohort study.}, journal = {PLoS medicine}, volume = {22}, number = {6}, pages = {e1004545}, pmid = {40560963}, issn = {1549-1676}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnostic imaging/diagnosis/pathology ; *Tomography, Optical Coherence ; Male ; Female ; Middle Aged ; *Retina/diagnostic imaging/pathology ; Biomarkers ; Aged ; Incidence ; Cohort Studies ; Adult ; United Kingdom/epidemiology ; Risk Factors ; }, abstract = {BACKGROUND: Biomarkers are widely recognized as crucial breakthroughs in tackling amyotrophic lateral sclerosis (ALS). Among them, retina markers may hold promise due to the close retina-brain connection and non-invasive, portable detection methods. Thus, using optical coherence tomography (OCT), we investigated the link between baseline cell-level retinal features and future ALS risk.

METHODS AND FINDINGS: Participants from the UK Biobank underwent OCT scans to assess retinal layers, macula, and optic disc parameters. Follow-up commenced two years after the baseline period (2006-2010), during which ALS cases were identified using International Classification of Diseases (ICD) codes from medical and assessment records. Cox proportional hazards models were applied to examine the relationship between retinal markers and incident ALS. Over a median follow-up of 14.11 years, 70 ALS cases occurred among 53,824 participants (incidence 10.58 per 100,000 person-years). Most participants were White (94.6%), 44.8% male, with a median age of 58 years. After adjusting for demographics and comorbidities affecting the retina, a standard deviation (SD) decrease of 15.19 µm in photoreceptor layer (PRL) thickness was associated with a 19% (95% confidence interval [7, 29]; p = 0.002) increased risk of ALS, while a SD increase of 26.11 µm in retinal pigment epithelium (RPE) thickness corresponded to a 20% (95% CI [7, 34]; p = 0.002) higher risk. Sensitivity analyses excluding follow-ups of less than 4 and 6 years yielded consistent results. Subgroup analyses showed these findings were more pronounced in smokers. The main limitation of this study is its single time point observational design.

CONCLUSION: A thinner PRL and thicker RPE may precede the clinical diagnosis of ALS, offering potential clues for early diagnosis and insights into the disease's pathogenesis.}, } @article {pmid40562033, year = {2025}, author = {Lall, D and Workman, MJ and Sances, S and Ondatje, BN and Bell, S and Lawless, G and Woodbury, A and West, D and Meyer, A and Matlock, A and Vaibhav, V and Van Eyk, JE and Svendsen, CN}, title = {An organ-chip model of sporadic ALS using iPSC-derived spinal cord motor neurons and an integrated blood-brain-like barrier.}, journal = {Cell stem cell}, volume = {32}, number = {7}, pages = {1139-1153.e7}, pmid = {40562033}, issn = {1875-9777}, support = {UG3 NS105703/NS/NINDS NIH HHS/United States ; UG3 TR003264/TR/NCATS NIH HHS/United States ; UH3 NS105703/NS/NINDS NIH HHS/United States ; UH3 TR003264/TR/NCATS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; Humans ; *Induced Pluripotent Stem Cells/metabolism/pathology/cytology ; *Motor Neurons/pathology/metabolism ; *Blood-Brain Barrier/pathology/metabolism ; *Spinal Cord/pathology ; *Lab-On-A-Chip Devices ; Cell Differentiation ; *Models, Biological ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder in which motor neurons (MNs) of the brain and spinal cord degenerate, leading to paralysis. Generating MNs from patient-specific induced pluripotent stem cells (iPSCs) may help elucidate early stages of disease. Here, we combined MNs from patients with early-onset disease with brain microvascular endothelial-like cells in a microfluidic device we termed spinal cord chips (SC-chips) and added media flow, which enhanced neuronal maturation and improved cellular health. Bulk transcriptomic and proteomic analyses of SC-chips revealed differences between control and ALS samples, including increased levels of neurofilaments. Single-nuclei RNA sequencing revealed the presence of two MN subpopulations and an ALS-specific dysregulation of glutamatergic and synaptic signaling. This ALS SC-chip model generates a diversity of mature MNs to better understand ALS pathology in a model that has an active blood-brain barrier-like system for future drug screening.}, } @article {pmid40562281, year = {2025}, author = {Sharma, J and Thakur, A and Rain, M and Khosla, R and Maity, K and Mathur, GR and Anand, A}, title = {Interplay between exercise and neuregulin in providing neuroprotection.}, journal = {Behavioural brain research}, volume = {493}, number = {}, pages = {115710}, doi = {10.1016/j.bbr.2025.115710}, pmid = {40562281}, issn = {1872-7549}, mesh = {Humans ; Animals ; *Neuroprotection/physiology ; *Neurodegenerative Diseases/metabolism/prevention & control ; *Neuregulins/metabolism/therapeutic use ; *Exercise/physiology ; *Neuroprotective Agents ; }, abstract = {Exercise has been shown to have a positive impact on brain health including neuroprotective function. It has been demonstrated to increase the synthesis of neurotrophic factors, support neuronal survival, and improve neuroplasticity. Concurrently, neuregulin plays a vital role in the development, maintenance, and repair of both the central and peripheral nervous system. The link between exercise and neuregulin in mediating neuroprotection has been the subject of increased research to better understand the possible applications for the deterrence of neurodegenerative disorders. Understanding this link is of great interest because it has the potential to lead to new strategies for preventing or slowing the progression of neurodegenerative diseases. With an emphasis on exercise-induced neuregulin-mediated neuroprotection, this article reviews the literature on the neuroprotective effects of exercise and neuregulin. The synergistic effects of exercise and neuregulin on neuroprotection will be clarified and valuable insights will be gained from this review, with potential implications for the development of novel therapeutic strategies for neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD) and Huntington's disease (HD).}, } @article {pmid40562529, year = {2025}, author = {Ferese, R and Suppa, A and Campopiano, R and Scala, S and Sammarone, F and Di Pilla, L and Di Pardo, A and Chiaravalloti, MA and Griguoli, AM and Cannella, M and D'Alessio, C and Storto, M and Fanelli, M and Zampogna, A and Patera, M and Inghilleri, M and Ceccanti, M and Cambieri, C and Buttari, F and Peconi, C and Giardina, E and Zampatti, S and Centonze, D and Gambardella, S}, title = {New variants and genotype-phenotype correlation in KIF5A mutation: the contribution of a large Italian cohort.}, journal = {Journal of medical genetics}, volume = {62}, number = {10}, pages = {641-646}, pmid = {40562529}, issn = {1468-6244}, mesh = {Humans ; *Kinesins/genetics ; *Genetic Association Studies ; Male ; Female ; Italy/epidemiology ; *Mutation ; Middle Aged ; Adult ; Phenotype ; *Charcot-Marie-Tooth Disease/genetics/pathology ; Pedigree ; Cohort Studies ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Spastic Paraplegia, Hereditary/genetics/pathology ; Aged ; Genotype ; }, abstract = {BACKGROUND: Variants in the Kinesin-family member 5A (KIF5A) gene are associated with a range of motor diseases, and a strong correlation between the protein domains (motor, stalk and tail) and the clinical phenotype has been proposed. However, several studies have reported exceptions contributing to a complex genotype-phenotype correlation in recent years. Further studies are needed to improve our knowledge about the prevalence of KIF5A variants and their genotype-phenotype correlation.

METHODS: 390 patients (220 hereditary spastic paraplegia, 80 Charcot-Marie-Tooth disease type 2 and 90 amyotrophic lateral sclerosis) have been selected for next-generation sequencing Clinical Exome.

RESULTS: Five patients have been found to carry causative variants in the KIF5A gene. Of these, three are familiar cases, and two are sporadic. Segregation analysis was performed on the familiar probands. The five patients with pathogenic variants represent 4% of the studied population, and the clinical and genetic analysis of these five families allowed us to examine different scenarios.Some of these data support the hypothesis of a complex correlation between domains and disease.

CONCLUSION: These data confirm the complex genotype-phenotype correlation, both in terms of clinical heterogeneity associated with a specific domain and variability within the members of the same family, but also suggest a strong genotype-phenotype correlation, both intrafamiliar and interfamiliar, produced by a few variants.}, } @article {pmid40562771, year = {2025}, author = {Amado, DA and Robbins, AB and Whiteman, KR and Smith, AR and Chillon, G and Chen, Y and Fuller, JA and Patty, NA and Izda, A and Cheng, C and Nelson, S and Dichter, AI and Mazzoni, EO and Monteys, AM and Davidson, BL}, title = {AAV-based delivery of RNAi targeting ataxin-2 improves survival and pathology in TDP-43 mice.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {5334}, pmid = {40562771}, issn = {2041-1723}, support = {K08 NS114106/NS/NINDS NIH HHS/United States ; UH2 NS094355/NS/NINDS NIH HHS/United States ; UH3 NS094355/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/metabolism ; *Dependovirus/genetics ; Motor Neurons/metabolism/pathology ; Mice ; *Ataxin-2/genetics/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Humans ; *RNA Interference ; Genetic Vectors ; Disease Models, Animal ; Genetic Therapy/methods ; Male ; MicroRNAs/genetics ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) involves motor neuron death due to mislocalized TDP-43. Pathologic TDP-43 associates with stress granules (SGs), and lowering the SG-associated protein ataxin-2 (ATXN2) using Atxn2-targeting antisense oligonucleotides prolongs survival in TAR4/4 sporadic ALS mice but failed in clinical trials likely due to poor target engagement. Here we show that an AAV with potent motor neuron transduction delivering Atxn2-targeting miRNAs reduces Atxn2 throughout the central nervous system at doses 40x lower than published work. In TAR4/4 mice, miAtxn2 increased survival (50%) and strength, and reduced motor neuron death, inflammation, and phosphorylated TDP-43. TAR4/4 transcriptomic dysregulation recapitulated ALS gene signatures that were rescued by miAtxn2, identifying potential therapeutic mechanisms and biomarkers. In slow progressing hemizygous mice, miAtxn2 slowed disease progression, and in ALS patient-derived lower motor neurons, our AAV vector transduced >95% of cells and potently reduced ATXN2 at MOI 4 logs lower than previously reported. These data support AAV-RNAi targeting ATXN2 as a translatable therapy for sporadic ALS.}, } @article {pmid40563288, year = {2025}, author = {Dibwe, DF and Oba, S and Monde, S and Hui, SP}, title = {Inhibition of Triacylglycerol Accumulation and Oxidized Hydroperoxides in Hepatocytes by Allium cepa (Bulb).}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, pmid = {40563288}, issn = {2076-3921}, abstract = {Recent studies have demonstrated that dietary plant extracts can inhibit the development of lipid droplets (LDs) and oxidized LDs (oxLDs) in hepatic cells. These findings suggest that such extracts may be beneficial in combating metabolic dysfunction-associated fatty liver disease (MAFLD) and its more advanced stage, metabolic dysfunction-associated steatohepatitis (MASH). We examined nine Allium extracts (ALs: AL1-9) to assess their capacity to decrease lipid droplet accumulation (LDA) and oxidative stress by suppressing lipid formation and oxidation in liver cells. Among the Allium extracts tested, AL6 exhibited significant inhibitory effects against LDA. Furthermore, we employed our lipidomic method to assess the accumulation and suppression of intracellular triacylglycerol (TAG) and oxidized TAG hydroperoxide [TG (OOH) n = 3] by AL6 in liver cells under oleic acid (OA) and linoleic acid (LA) loading conditions. These findings indicate that foods derived from Allium species prevent the formation of lipid droplets by decreasing intracellular lipids and lipid hydroperoxides in the hepatocytes. Analysis of the metabolome of bioactive lipid droplet accumulation inhibition (LDAI) AL6 using LC-MS/MS and 1D-NMR [[1]H, [13]C, DEPT 90, and 135] techniques revealed that AL6 is primarily composed of carbohydrates, glucosidic metabolites, and organosulfur compounds, with small amounts of polyols, fatty acyls, small peptides, and amino acids. This implies that AL6 could be a valuable resource for developing functional foods and drug discovery targeting metabolic dysfunction-associated fatty liver disease (MAFLD)/metabolic dysfunction-associated steatohepatitis (MASH) and related disorders.}, } @article {pmid40563328, year = {2025}, author = {Chong, ZZ and Souayah, N}, title = {Oxidative Stress: Pathological Driver in Chronic Neurodegenerative Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, pmid = {40563328}, issn = {2076-3921}, abstract = {Oxidative stress has become a common impetus of various diseases, including neurodegenerative diseases. This review introduces the generation of reactive oxygen species (ROSs) in the nervous system, the cellular oxidative damage, and the high sensitivity of the brain to ROSs. The literature review focuses on the roles of oxidative stress in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Oxidative stress occurs when excessively produced free radicals are beyond the capability of endogenous antioxidants to scavenge, leading to the oxidation of proteins, lipids, and nucleic acids, stimulating neuroinflammatory responses, causing neuronal dysfunction, senescence, and death. The dysfunctional mitochondria and aberrant activities of metabolic enzymes are the major source of ROSs. The high vulnerability of the nervous system to ROSs underlies the critical roles of oxidative stress in neurodegenerative diseases. Gene mutations and other risk factors promote the generation of ROSs, which have been considered a crucial force causing the main pathological features of AD, PD, HD, and ALS. As a result, antioxidants hold therapeutic potential in these neurodegenerative diseases. The elucidation of the pathogenic mechanisms of oxidative stress will facilitate the development of antioxidants for the treatment of these diseases.}, } @article {pmid40563439, year = {2025}, author = {Marini, C and Riondato, M and Dighero, E and Democrito, A and Losacco, S and Emionite, L and Nobbio, L and Di Patrizi, I and Camera, M and Ghersi, C and Ghelardoni, M and Lanfranchi, F and Vitale, F and Carta, S and Chiesa, S and Torazza, C and Milanese, M and Bauckneht, M and Hamedani, M and Zaottini, F and Schenone, A and Martinoli, C and Grillo, F and Sambuceti, G}, title = {Increased [[18]F]DPA-714 Uptake in the Skeletal Muscle of SOD1[G93A] Mice: A New Potential of Translocator Protein 18 kDa Imaging in Amyotrophic Lateral Sclerosis.}, journal = {Biomolecules}, volume = {15}, number = {6}, pages = {}, pmid = {40563439}, issn = {2218-273X}, support = {RF-2018-12366238//Italian Ministry of Health/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/genetics/pathology ; Mice ; Mice, Transgenic ; *Muscle, Skeletal/metabolism/diagnostic imaging ; Positron-Emission Tomography/methods ; *Receptors, GABA/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Pyrimidines/pharmacokinetics ; *Pyrazoles/pharmacokinetics ; Fluorine Radioisotopes ; Disease Models, Animal ; Humans ; Tissue Distribution ; Brain/metabolism/diagnostic imaging ; Male ; }, abstract = {PURPOSE: The skeletal muscle has been proposed to contribute to the progressive loss of motor neurons typical of amyotrophic lateral sclerosis (ALS). However, this mechanism has not yet been clarified due to the lack of suitable imaging tools. Here, we aimed to verify whether PET imaging of the translocator protein 18 kDa (TSPO) can detect a muscular abnormality in an experimental model of ALS.

METHODS: In vivo biodistribution and kinetics of [[18]F]DPA-714 were analyzed in skeletal muscle and brain of SOD1[G93A] transgenic mice and in wildtype (WT) littermates. Both cohorts were divided into three groups (n = 6 each) to be studied at 60, 90 and 120 days. After microPET imaging, animals were sacrificed to evaluate inflammatory infiltrates by hematoxylin/eosin staining and TSPO expression by immunohistochemistry and Western blot in both quadriceps and brain.

RESULTS: [[18]F]DPA-714 uptake was higher in the skeletal muscles of SOD1[G93A] than in WT mice in the preclinical phase (60 and 90 days) and further increased up to the symptomatic late stage (120 days). Inflammatory cells were absent in the quadriceps of SOD1[G93A] mice whose myocytes, instead, showed a progressive increase in TSPO expression with advancing age. By contrast, brain tracer uptake and TSPO expression were comparably low in both groups, regardless of age and genotype.

CONCLUSION: Upregulation of TSPO expression is characteristic of skeletal muscle, but not the brain, in the experimental SOD1[G93A] mouse model of ALS. Tracers targeting this pathway have been mostly proposed for the evaluation of inflammatory processes within the central nervous system. Nevertheless, the ubiquitous nature of TSPO expression and its responsiveness to various signals may broaden the diagnostic potential of these tracers to include disease conditions beyond inflammation.}, } @article {pmid40563772, year = {2025}, author = {Artioli, G and Guardamagna, L and Succi, N and Guasconi, M and Diamanti, O and Dellafiore, F}, title = {Relational, Ethical, and Care Challenges in ALS: A Systematic Review and Qualitative Metasynthesis of Nurses' Perspectives.}, journal = {Brain sciences}, volume = {15}, number = {6}, pages = {}, pmid = {40563772}, issn = {2076-3425}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to severe functional decline and death, imposing significant physical, emotional, and ethical burdens on patients and healthcare providers. With no curative treatment, ALS care depends on the early and sustained integration of palliative care to address complex and evolving needs. Nurses play a pivotal role in this process, yet their lived experiences remain underexplored. This study aimed to synthesize qualitative evidence on nurses' experiences in ALS care, with a focus on emotional, ethical, and palliative dimensions.

METHODS: A meta-synthesis of qualitative studies was conducted using Sandelowski and Barroso's four-step method. A systematic search across five databases identified eight studies exploring nurses' experiences with ALS care. Thematic synthesis was applied to extract overarching patterns.

RESULTS: Three core themes emerged: (1) Relational Dimension: From challenges to empathy and Trust and mistrust-emphasizing communication barriers and the value of relational trust; (2) Care Dimension: Competence, Palliative care needs, and Rewarding complexity-highlighting the emotional demands of care, the need for timely palliative integration, and the professional meaning derived from ALS care; (3) Ethical Dimension: Medical interventionism and Patient-centered values-exploring dilemmas around life-sustaining treatments, patient autonomy, and end-of-life decisions.

CONCLUSION: Nurses in ALS care face complex emotional and ethical challenges that call for strong institutional support and palliative training. Enhancing palliative care integration from diagnosis, alongside targeted education and psychological support, is crucial to improving care quality and sustaining the well-being of both patients and nurses.}, } @article {pmid40563773, year = {2025}, author = {Swash, M and de Carvalho, M}, title = {Dynamics of Onset and Progression in Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {15}, number = {6}, pages = {}, pmid = {40563773}, issn = {2076-3425}, abstract = {This review focuses on the complexities of amyotrophic lateral sclerosis (ALS) onset, highlighting the insidious nature of the disease and the challenges in defining its precise origin and early pathogenic mechanisms. The clinical presentation of ALS is characterised by progressive muscle weakness and wasting, often with widespread fasciculations, reflecting lower motor neuron hyperexcitability. The disease's pathogenesis involves a prolonged preclinical phase of neuronal proteinopathy, particularly TDP-43 accumulation, which eventually leads to motor neuron death and overt ALS. This review discusses the difficulties in detecting this transition and the implications for early therapeutic intervention. It also addresses the involvement of both the upper and lower motor neuron systems, as well as the importance of following presymptomatic patients with genetic mutations. The significance of understanding the distinct processes of TDP-43 deposition and subsequent neuronal degeneration in developing effective treatments is emphasised.}, } @article {pmid40563824, year = {2025}, author = {Hasan, A and Scuderi, SA and Capra, AP and Giosa, D and Bonomo, A and Ardizzone, A and Esposito, E}, title = {An Updated and Comprehensive Review Exploring the Gut-Brain Axis in Neurodegenerative Disorders and Neurotraumas: Implications for Therapeutic Strategies.}, journal = {Brain sciences}, volume = {15}, number = {6}, pages = {}, pmid = {40563824}, issn = {2076-3425}, abstract = {The gut-brain axis (GBA) refers to the biochemical bidirectional communication between the central nervous system (CNS) and the gastrointestinal tract, linking brain and gut functions. It comprises a complex network of interactions involving the endocrine, immune, autonomic, and enteric nervous systems. The balance of this bidirectional pathway depends on the composition of the gut microbiome and its metabolites. While the causes of neurodegenerative diseases (NDDs) vary, the gut microbiome plays a crucial role in their development and prognosis. NDDs are often associated with an inflammation-related gut microbiome. However, restoring balance to the gut microbiome and reducing inflammation may have therapeutic benefits. In particular, introducing short-chain fatty acid-producing bacteria, key metabolites that support gut homeostasis, can help counteract the inflammatory microbiome. This strong pathological link between the gut and NDDs underscores the gut-brain axis (GBA) as a promising target for therapeutic intervention. This review, by scrutinizing the more recent original research articles published in PubMed (MEDLINE) database, emphasizes the emerging notion that GBA is an equally important pathological marker for neurological movement disorders, particularly in Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease and neurotraumatic disorders such as traumatic brain injury and spinal cord injury. Additionally, the GBA presents a promising therapeutic target for managing these diseases.}, } @article {pmid40564128, year = {2025}, author = {Drewes, N and Fang, X and Gupta, N and Nie, D}, title = {Pharmacological and Pathological Implications of Sigma-1 Receptor in Neurodegenerative Diseases.}, journal = {Biomedicines}, volume = {13}, number = {6}, pages = {}, pmid = {40564128}, issn = {2227-9059}, abstract = {Originally identified as a potential receptor for opioids, the sigma-1 receptor is now recognized as an intracellular chaperone protein associated with mitochondria-associated membranes at the endoplasmic reticulum (ER). Over the past two decades, extensive research has revealed that the sigma-1 receptor regulates many cellular processes, such as calcium homeostasis, oxidative stress responses, protein folding, and mitochondrial function. The various functions of the sigma-1 receptor highlight its role as a central modulator of neuronal health and may be a promising pharmacological target across multiple neurodegenerative conditions. Herein, we provide an overview of the current pharmacological understanding of the sigma-1 receptor with an emphasis on the signaling mechanisms involved. We examine its pathological implications in common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. We then highlight how sigma-1 receptor modulation may influence disease progression as well as potential pharmacological mechanisms to alter disease outcomes. The translational potential of sigma-1 receptor therapies is discussed, as well as the most up-to-date results of ongoing clinical trials. This review aims to clarify the therapeutic potential of the sigma-1 receptor in neurodegeneration and guide future research in these diseases.}, } @article {pmid40564215, year = {2025}, author = {Yoo, JK and Kwon, SH and Yoon, SH and Lee, JE and Chun, JU and Chung, JH and Lee, SY and Lee, JH and Chae, YR}, title = {Multi-Metal Exposure Profiling in ALS Patients in South Korea via Hair Analysis: A Cross-Sectional Study.}, journal = {Biomedicines}, volume = {13}, number = {6}, pages = {}, pmid = {40564215}, issn = {2227-9059}, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with an unclear etiology. This study aimed to assess chronic heavy metal exposure in ALS patients in South Korea by comparing hair concentrations of common (Hg, Pb, Cd) and rare (U, Th, Pt) metals with healthy controls.

METHODS: Hair samples were collected from 66 ALS patients and 70 healthy individuals at Rodem Hospital between 2022 and 2025. Metal concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS) following standardized washing and digestion protocols.

RESULTS: ALS patients showed significantly higher levels of Hg, Pb, Cd, Al, As, and U than controls (p < 0.05). Notably, 40% of ALS patients had Hg levels exceeding 50% of the reference upper limit, compared to only 10% of controls. Elevated levels of uranium and other rare metals were also observed in specific ALS cases.

CONCLUSIONS: These findings suggest a possible association between heavy metal exposure and ALS in South Korea. Hair analysis may serve as a useful tool for identifying environmental factors contributing to ALS pathogenesis.}, } @article {pmid40565135, year = {2025}, author = {Bono, N and Fruzzetti, F and Farinazzo, G and Candiani, G and Marcuzzo, S}, title = {Perspectives in Amyotrophic Lateral Sclerosis: Biomarkers, Omics, and Gene Therapy Informing Disease and Treatment.}, journal = {International journal of molecular sciences}, volume = {26}, number = {12}, pages = {}, pmid = {40565135}, issn = {1422-0067}, support = {//Italian Ministry of Health (RRC)/ ; T4-AN-09 prog. ZRPOS2//CALabria HUB per Ricerca Innovativa ed Avanzata- CALHUB.RIA "Creazione di Hub delle Sci-enze della Vita"/ ; ZRA124//AriSLA foundation, "Bulb-Omics"/ ; PNRR-MCNT2-2023-12377336//the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics/diagnosis/metabolism ; Humans ; *Genetic Therapy/methods ; *Biomarkers/metabolism ; C9orf72 Protein/genetics ; Animals ; Gene Editing ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. Despite advances in understanding its genetic basis, particularly mutations in Chromosome 9 Open Reading Frame 72 (C9orf72), superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP), and Fused in Sarcoma (FUS) gene, current diagnostic methods result in delayed intervention, and available treatments offer only modest benefits. This review examines innovative approaches transforming ALS research and clinical management. We explore emerging biomarkers, including the fluid-based markers such as neurofilament light chain, exosomes, and microRNAs in biological fluids, alongside the non-fluid-based biomarkers, including neuroimaging and electrophysiological markers, for early diagnosis and patient stratification. The integration of multi-omics data reveals complex molecular mechanisms underlying ALS heterogeneity, potentially identifying novel therapeutic targets. We highlight current gene therapy strategies, including antisense oligonucleotides (ASOs), RNA interference (RNAi), and CRISPR/Cas9 gene editing systems, alongside advanced delivery methods for crossing the blood-brain barrier. By bridging molecular neuroscience with bioengineering, these technologies promise to revolutionize ALS diagnosis and treatment, advancing toward truly disease-modifying interventions for this previously intractable condition.}, } @article {pmid40565514, year = {2025}, author = {Roque-Ramírez, B and Ríos-López, KE and López-Hernández, LB}, title = {Decoding Neuromuscular Disorders: The Complex Role of Genetic and Epigenetic Regulators.}, journal = {Genes}, volume = {16}, number = {6}, pages = {}, pmid = {40565514}, issn = {2073-4425}, mesh = {Humans ; *Epigenesis, Genetic ; *Neuromuscular Diseases/genetics ; DNA Methylation/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Animals ; }, abstract = {Neuromuscular disorders (NMDs), such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and muscular dystrophies (e.g., Duchenne muscular dystrophy, DMD), are primarily driven by genetic mutations but are critically modulated by epigenetic mechanisms such as DNA methylation, histone modifications, and noncoding RNA activity. These epigenetic processes contribute to phenotypic variability and disease progression, and emerging evidence suggests that environmental factors, particularly nutrition and exercise, may further influence the molecular pathways that modulate these diseases. Dietary bioactive compounds (e.g., polyphenols and omega-3 fatty acids) exhibit epigenetic modulatory properties, which could mitigate oxidative stress, inflammation, and muscle degeneration in NMDs. For example, the inhibition of DNMTs and HDACs by curcumin in ALS models and the promyogenic effects of green tea catechins in DMD suggest plausible, though still requiring investigation, therapeutic avenues. However, the clinical application of nutriepigenetic interventions is preliminary and requires further validation. This review examines the interaction of genetic and epigenetic factors in ALS, SMA, and muscular dystrophies, highlighting their combined role in the heterogeneity of these diseases. Integrative therapeutic strategies combining gene therapies, epigenetic modulators, and lifestyle interventions may offer a multidimensional approach to the management of NMD. A deeper understanding of these interactions will be essential for advancing precision medicine and improving patient outcomes.}, } @article {pmid40565515, year = {2025}, author = {Falduti, A and Giovinazzo, A and Lo Feudo, E and Rocca, V and Brighina, F and Messina, A and Conforti, FL and Iuliano, R}, title = {The Role of Non-Coding RNAs in ALS.}, journal = {Genes}, volume = {16}, number = {6}, pages = {}, pmid = {40565515}, issn = {2073-4425}, support = {Project P20225J5NB//Project P20225J5NB "Identifying pathogenic pathways in sporadic Amyotrophic Lateral Sclerosis: a genetic, omics and functional study" PRIN PNRR/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; *RNA, Long Noncoding/genetics ; *MicroRNAs/genetics ; *RNA, Circular/genetics ; Motor Neurons/metabolism/pathology ; Animals ; *RNA, Untranslated/genetics ; Biomarkers/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventually death. The pathogenesis of ALS is influenced by genetic factors, environmental factors, and age-related dysfunctions. These factors, taken together, are responsible for sporadic cases of ALS, which account for approximately 85-90% of ALS cases, while familial ALS accounts for the remaining 10-15% of cases, usually with dominant traits. Despite advances in understanding and studying the disease, the cause of the onset of ALS remains unknown. Emerging evidence suggests that non-coding RNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play crucial roles in the pathogenesis of the disease. An abnormal expression of these molecules is implicated in various ALS-related processes, including motor neuron survival, protein aggregation, and inflammation. Here, we describe the dysregulation of non-coding RNAs in the pathogenic mechanism of ALS, highlighting the potential roles of miRNAs, lncRNAs, and circRNAs as biomarkers or therapeutic targets to examine the progression of the disease.}, } @article {pmid40565582, year = {2025}, author = {Rother, F and Parmar, AR and Bodenhagen, JS and Marvaldi, L and Hartmann, E and Bader, M}, title = {Deficiency in KPNA4, but Not in KPNA3, Causes Attention Deficit/Hyperactivity Disorder like Symptoms in Mice.}, journal = {Genes}, volume = {16}, number = {6}, pages = {}, pmid = {40565582}, issn = {2073-4425}, support = {2021 Grant//Rita Levi Montalcini 2021 Grant (MIUR, Italy)/ ; MIUR project "Dipartimenti di Eccellenza 2023-2027"//Ministero dell'Istruzione dell'Università e della Ricerca/ ; }, mesh = {Animals ; *alpha Karyopherins/genetics/deficiency ; *Attention Deficit Disorder with Hyperactivity/genetics/pathology/metabolism ; Mice ; Mice, Knockout ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Male ; }, abstract = {Nucleocytoplasmic transport is crucial for neuronal cell physiology and defects are involved in neurodegenerative diseases like amyotrophic lateral sclerosis and Alzheimer's disease, but also in ageing. Recent studies have suggested, that the classic nuclear import factor adapters KPNA3 (also named importin alpha4) and KPNA4 (also named importin alpha3) could be associated with the development of motor neuron diseases, a condition specifically affecting the neurons projecting from brain to spinal cord or from spinal cord to the muscles. Here we set out to analyze the neuronal function of mice deficient in KPNA3 (Kpna3-KO) or KPNA4 (Kpna4-KO). The motoric abilities and locomotion at different time points in ageing were tested to study the role of these two genes on motor neuron function. While we did not find deficits related to motor neurons in both mouse models, we discovered a hypermotoric phenotype in KPNA4-deficient mice. Attention deficit/hyperactivity disorder (ADHD) is caused by a combination of genetic, environmental and neurobiological factors and a number of genes have been suggested in genome-wide association studies to contribute to ADHD, including KPNA4. Here we provide supportive evidence for KPNA4 as a candidate pathogenic factor in ADHD, by analysing Kpna4-KO mice which show ADHD-like symptoms.}, } @article {pmid40566588, year = {2025}, author = {Martinelli, I and Gianferrari, G and Santarelli, R and Zucchi, E and Simonini, C and Fini, N and Ghezzi, A and Gessani, A and Ferri, L and Smolik, K and Ferraro, D and Bedin, R and Gizzi, M and Sette, E and Vacchiano, V and Bonan, L and Zinno, L and De Massis, P and Canali, E and Medici, D and Terlizzi, E and Morresi, S and Santangelo, M and Patuelli, A and Currò Dossi, M and Longoni, M and Pugliatti, M and Filippini, T and Ferro, S and Errals Study Group, and Mandrioli, J}, title = {Exploring the Role of Diabetes in ALS: A Population-Based Cohort Study.}, journal = {Life (Basel, Switzerland)}, volume = {15}, number = {6}, pages = {}, pmid = {40566588}, issn = {2075-1729}, support = {GPG/2022/1343//The Emilia Romagna Registry for ALS (ERRALS) is supported by a grant from the Emilia Romagna Regional Health Authority/ ; }, abstract = {Type 2 diabetes mellitus (T2DM) as a comorbidity in amyotrophic lateral sclerosis (ALS) has sparked interest for its potential impact on disease expression and prognosis. In this retrospective cohort study, we investigated the prevalence and clinical correlates of T2DM in a large cohort of patients from the ALS registry of a Northern Italy region, Emilia Romagna, established in 2009. Out of 1756 ALS patients enrolled up to 2021, 145 were affected by T2DM (diALS). Patients with diALS were older than those without T2DM (ndALS) (71.56 vs. 65.76 years, p < 0.001), had a higher body mass index (25.63 vs. 24.23, p < 0.001), but experienced greater weight loss at diagnosis (6.87% vs. 5.44%, p < 0.007). Respiratory onset (6.2% vs. 2.6%, p = 0.013) and respiratory phenotype (4.2% vs. 1.4%, p = 0.04) were more frequent among diALS. Coherently, diALS presented a lower forced vital capacity (74.9% vs. 87.9%, p ≤ 0.001) and more frequently adopted Non-Invasive Ventilation (NIV) (50.35% vs. 37.61%, p = 0.003), with significant influence on time to NIV (HR 1.71, 95% CI 1.07-2.74, p = 0.024). Exploring genetic background, among all the genes examined C9ORF72 emerged as underrepresented among diALS (7.64% in ndALS vs. 0% in diALS, p = 0.039). In conclusion, we confirmed a more severe respiratory dysfunction in diALS, suggesting a specific frailty in respiratory muscles, together with some peculiar clinical features consistent with the previous literature data, such as a later onset. The lower prevalence of C9ORF72 expansion in this population may hint towards a specific role of the gene in metabolism and inflammation, granting more space to non-genetic causes, warranting further studies for confirmation.}, } @article {pmid40566744, year = {2025}, author = {Bai, J and Cheng, K and Zhang, N and Chen, Y and Ni, J and Wang, Z}, title = {Research advances in dysphagia animal models.}, journal = {Animal models and experimental medicine}, volume = {8}, number = {9}, pages = {1579-1589}, pmid = {40566744}, issn = {2576-2095}, support = {82172531//National Natural Science Foundation of China/ ; 2021Y9105//Joint Funds for the Innovation of Science and Technology, Fujian Province/ ; }, mesh = {Animals ; *Deglutition Disorders/etiology/physiopathology ; *Disease Models, Animal ; Dogs ; Amyotrophic Lateral Sclerosis/complications ; Parkinson Disease/complications ; Swine ; Stroke/complications ; Humans ; }, abstract = {Dysphagia is a common complication of stroke, Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). The construction of animal models of dysphagia is an important way to explore its pathogenesis and treatment. At present, the animal models of dysphagia mainly include rodents, nonhuman primates, and other mammals, such as pigs and dogs. This review systematically summarizes the establishment and evaluation of dysphagia animal models in stroke, PD, and ALS in three kinds of experimental animals, providing a basis for the selection of appropriate animal models of dysphagia.}, } @article {pmid40566837, year = {2025}, author = {Massey, C and Griffiths, AW and McDermott, C and Hobson, E}, title = {How healthcare professionals support cough and secretion management in amyotrophic lateral sclerosis (ALS): a UK national survey.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {637-648}, doi = {10.1080/21678421.2025.2522401}, pmid = {40566837}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/epidemiology ; *Cough/etiology/therapy ; United Kingdom/epidemiology ; Cross-Sectional Studies ; Male ; Female ; *Health Personnel ; Surveys and Questionnaires ; Middle Aged ; Adult ; }, abstract = {OBJECTIVE: To understand the practices of healthcare professionals supporting people with Amyotrophic Lateral Sclerosis (ALS) to manage cough and secretion issues. This includes utilization of and confidence in assessment and treatment techniques and barriers and enablers of care.

METHODS: An online cross-sectional survey was distributed to UK healthcare professionals involved in cough and/or secretion management care in people with ALS.

RESULTS: A total of 113 responses were analyzed, over half were from physiotherapists (52%). The majority (71%) of respondents reported a role managing saliva and secretions. Just under two thirds (60%) routinely assessed cough and almost all (89%) routinely assessed secretions. Healthcare professionals reported reduced confidence assessing secretions compared with cough and very few (5%) used validated secretion outcome measures. Participants reported lower confidence implementing all treatment strategies than recommending them. Multiple barriers to care were identified, including access to specialist care and equipment, education and skills training and a lack of evidence-based care guidelines.

CONCLUSION: Cough and secretion management is complex and involves numerous professional groups. There is a need for clinical and educational interventions that address knowledge and skill gaps in managing cough and secretion issues, which will help increase healthcare professionals' confidence in assessing and treating these complex problems.}, } @article {pmid40566997, year = {2025}, author = {Wu, J and Yan, S and Bian, Y and Liu, R and Lyu, X and Zhang, Z and Huang, S and Chen, T and Cheng, L}, title = {The Impact of Splicing Dysregulation on Neuromuscular Disorders and Current Neuromuscular Genetic Therapies.}, journal = {Journal of neurochemistry}, volume = {169}, number = {6}, pages = {e70133}, doi = {10.1111/jnc.70133}, pmid = {40566997}, issn = {1471-4159}, support = {ZR2022QC052//Natural Science Foundation of Shandong Province/ ; 32200464//National Natural Science Foundation of China/ ; ZD2021036//Science and Technology Project of Hebei Education Department/ ; }, mesh = {Humans ; *Genetic Therapy/methods/trends ; *Neuromuscular Diseases/genetics/therapy ; Animals ; *RNA Splicing/genetics ; Alternative Splicing ; }, abstract = {Eukaryotic genes contain non-coding segments known as introns, which interrupt coding sequences. Consequently, eukaryotic transcription produces precursor messenger RNA (pre-mRNA) that relies on precise splicing to remove highly diverse introns from the genome and to generate the mature mRNA essential for maintaining normal cellular activities. The extensive heterogeneity of neurons necessitates complex splicing regulation, particularly alternative splicing, to ensure the accuracy of gene expression in neurogenesis, signal transduction, and synaptic function and to maintain stability and adaptability in the nervous system. With the improvement of genetic testing technology, aberrant splicing has been identified as a contributing factor to the pathogenesis of neuromuscular disorders (NMDs) such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), myotonic dystrophy (DM), Charcot-Marie-Tooth disease (CMT), myasthenia gravis (MG), and multiple sclerosis (MS). Studying the correlation between splicing defects and neuromuscular disorders is crucial for gaining a more comprehensive understanding of the pathogenesis of these diseases and for developing effective therapies. In this review, we introduce the intricate process and key factors of pre-mRNA splicing, with a focus on aberrant splicing and pathogenesis in several major neuromuscular disorders, providing an overview of the latest therapeutic strategies.}, } @article {pmid40568026, year = {2025}, author = {Peggion, C and Bonadio, RS and Stella, R and Scalabrin, S and Pasetto, L and Millino, C and Camporeale, L and Pacchioni, B and Bonetto, V and Bertoli, A and Cagnin, S and Massimino, ML}, title = {Restoration of myogenesis in ALS-myocytes through miR-26a-5p-mediated Smad4 inhibition and its impact on motor neuron development.}, journal = {Molecular therapy. Nucleic acids}, volume = {36}, number = {3}, pages = {102581}, pmid = {40568026}, issn = {2162-2531}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset paralytic disorder, characterized primarily by a progressive loss of motor neurons (MNs) in which degeneration skeletal muscle involvement has been demonstrated. Skeletal muscle is a plastic tissue that responds to insults through proliferation and differentiation of satellite cells. Skeletal muscle degeneration and regeneration are finely regulated by signals that regulate satellite cell proliferation and differentiation. It is known that satellite cell differentiation is impaired in ALS, but little is known about the involvement of microRNAs (miRNAs) and their role in intercellular communication in ALS. Here we demonstrated impaired differentiation of satellite cells derived from ALS mice related to the impairment of myogenic p38MAPK and protein kinase A (PKA)/pCREB signaling pathways that can be regulated by miR-882 and -134-5p. These miRNAs participate in autocrine signaling in association with miR-26a-5p that, secreted from wild-type (WT) and captured by ALS myoblasts, enhances ALS-related myoblast differentiation by repressing Smad4-related signals. Moreover, miR-26a-5p and -431-5p work in a paracrine way ameliorating motoneuron differentiation. These findings emphasize the need to better understand intercellular communication and its role in ALS pathogenesis and progression. They also suggest that miRNAs could be targeted or used as therapeutic agents for myofiber and MN regeneration.}, } @article {pmid40568112, year = {2025}, author = {Calco, B and Sweeney, CL and Steiner, J and Wang, T and Markowitz, TE and Paul, S and Palicha, B and Dinges, S and Yoo, K and Henderson, L and McDonald, V and De Ravin, SS and Greenberg, B and Zerbe, CS and Notarangelo, LD and Holland, SM and Nath, A and Safavi, F}, title = {A novel frameshift mutation in Phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1) causes immunodeficiency and Amyotrophic Lateral Sclerosis (ALS).}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40568112}, issn = {2692-8205}, abstract = {Mutations in PIK3R1, a regulatory subunit of Class I PI3K, are implicated in immune disorders and neurological conditions. We identified a novel heterozygous pathogenic frameshift mutation (c.1710dup) in PIK3R1 in a patient with common variable immunodeficiency who developed slowly progressive Amyotrophic Lateral Sclerosis. Induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs) demonstrated that this mutation resulted in PIK3R1 haploinsufficiency, with downstream activation of AKT, disruption of neuronal electrical function and increased apoptosis in iPSC-derived motor neurons. Single-cell RNA sequencing (scRNA-seq) and pathway analysis of differentially expressed genes showed apoptosis pathways were upregulated in neuronal clusters from iMNs harboring the PIK3R1c.1710 dup mutation. Mutated iPSC-derived brain organoids were smaller than matched controls. scRNA-seq of brain organoids showed more active apoptosis in neuronal clusters of patient-derived brain organoids. These findings identify a critical and novel role for PIK3R1 haploinsufficiency in neuronal function and survival.}, } @article {pmid40568280, year = {2025}, author = {Bouabdallaoui, A and Taouihar, S and Yahya, N and Adali, N and Nassik, H}, title = {Bulbar-Onset Amyotrophic Lateral Sclerosis Unmasked by General Anesthesia: A Case Report.}, journal = {Cureus}, volume = {17}, number = {5}, pages = {e84823}, pmid = {40568280}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects the motor neurons in the brain and spinal cord, resulting in severe muscular weakness, atrophy, and loss of motor control. Patients with ALS are often highly sensitive to anesthetic drugs, specifically neuromuscular blocking agents, which can exacerbate muscle weakness and contribute to prolonged postoperative recovery times. In this article, we report a case of bulbar ALS diagnosed after postoperative extubation failure in a 51-year-old patient. Practitioners should consider this disease in cases of difficult postoperative ventilatory weaning and should be aware of the impact of surgery and anaesthesia on disease progression.}, } @article {pmid40569409, year = {2025}, author = {Thissen, J and Klassen, MD and Fischer, B and Hacker, MC and Breitkreutz, J and Teutenberg, T and Cunha, R}, title = {StreamFind: data processing workflows for qualification and quantification of biopharmaceutical drug products analyzed by size exclusion chromatography coupled to capillary-enhanced Raman spectroscopy.}, journal = {Analytical and bioanalytical chemistry}, volume = {417}, number = {19}, pages = {4469-4480}, pmid = {40569409}, issn = {1618-2650}, support = {16DKWN138//Bundesministerium für Bildung und Forschung/ ; KK5312603KA1//Bundesministerium für Wirtschaft und Klimaschutz/ ; }, mesh = {*Spectrum Analysis, Raman/methods ; *Chromatography, Gel/methods ; Principal Component Analysis ; *Software ; Workflow ; *Antibodies, Monoclonal/analysis ; *Biological Products/analysis ; Pharmaceutical Preparations/analysis ; Least-Squares Analysis ; }, abstract = {Innovative hyphenated technologies, such as size exclusion chromatography coupled with capillary-enhanced Raman spectroscopy (SEC-CERS), enable more comprehensive analyses of biopharmaceutical drug products. However, specialized software for processing and analyzing data from these advanced techniques is often lacking. This study introduces the R package StreamFind, which is designed to help users seamlessly process both chromatographic and Raman spectroscopic data within an integrated workflow. We detail the implementation and structure of StreamFind and demonstrate its ability in the in-depth analysis of biopharmaceutical products. The study shows its capability to differentiate monoclonal antibodies and entire biopharmaceutical formulations and to quantify various components based on their Raman spectra. Principal component analysis (PCA) identified significant differences among the biopharmaceutical products analyzed, while multivariate curve resolution-alternating least squares (MCR-ALS) proved to be an effective method for quantifying different components within these products. The StreamFind platform is designed to be extensible, to facilitate contributions from new users and to support the future integration of additional algorithms to process different types of complex analytical data.}, } @article {pmid40569529, year = {2025}, author = {Shin, M and Ha, T and Lee, S and Li, C and Choi, JH and Choi, JW}, title = {Biohybrid motor neuron spheroid composed of graphene/HUVEC/neural cell for 3D biosensing system to evaluate drug of amyotrophic lateral sclerosis.}, journal = {Nano convergence}, volume = {12}, number = {1}, pages = {29}, pmid = {40569529}, issn = {2196-5404}, support = {RS-2023-00259341//the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT/ ; RS-2024-00344633//the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)/ ; NRF-2022M3H4A1A01005271//the National R&D Program through the NRF funded by the Ministry of Science and ICT/ ; }, abstract = {A 3D motor neuron (MN) spheroid has been developed to investigate neurodegenerative and neuromuscular junction (NMJ) disease. However, core necrosis and reduced neurogenesis, impairing neural network formation, were observed as the MN spheroid matured. In this study, to enhance neural network formation, a biohybrid MN spheroid composed of neural cells/reduced graphene oxide (rGO)/human umbilical vein endothelial cells (HUVECs) was generated for the first time and applied to 3D biosensing system for MNJ disease. By incorporating rGO and HUVECs at the onset of human neural stem cell (hNSC) culture, rGO and HUVECs were evenly distributed within MN spheroid generated by differentiation of hNSC, which improved oxygen- and nutrient- supply by reduction of core necrosis, and enhanced neurogenesis. The fabricated biohybrid MN spheroid improved neural network formation and electrophysiological signal. This method was also applied to generate biohybrid cerebral organoids from human induced pluripotent stem cells (hiPSCs), emphasizing its versatility for diverse 3D neural models. Then, a 3D NMJ biosensing system was fabricated by positioning the biohybrid MN spheroid with muscle bundles to evaluate its utility in neuromuscular disease modeling. Biohybrid MN spheroids generated from induced pluripotent stem cells of sporadic amyotrophic lateral sclerosis (ALS) patients were used to make NMJ. Reduced contraction of the connected muscle bundle due to ALS could be restored by upon treatment with the bosutinib, ALS drug, demonstrating the potential use for drug screening. The method to generate biohybrid spheroid can be applied to generation of various biohybrid brain organoids, and the proposed 3D NMJ biosensing system can be used to drug screening of diverse neuromuscular diseases.}, } @article {pmid40571082, year = {2025}, author = {Saucier, D and Bélanger, M and Liu, Z and Lavigne, E and O'Connell, C}, title = {Associations between long-term air pollution exposure and the development of amyotrophic lateral sclerosis: A matched case-control study.}, journal = {Environmental research}, volume = {284}, number = {}, pages = {122232}, doi = {10.1016/j.envres.2025.122232}, pmid = {40571082}, issn = {1096-0953}, mesh = {*Air Pollution/statistics & numerical data ; *Air Pollutants/analysis/toxicity ; Case-Control Studies ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Inhalation Exposure/statistics & numerical data ; Nitrogen Dioxide/analysis/toxicity ; Sulfur Dioxide/analysis/toxicity ; Humans ; Male ; Female ; Middle Aged ; Aged ; Particulate Matter/analysis/toxicity ; }, abstract = {There is increasing evidence of an association between air pollution, particularly nitrogen dioxide (NO2), and the development of amyotrophic lateral sclerosis (ALS). However, investigation into sulfur dioxide (SO2) remains understudied. Also, empirical identification of confounding variables to adjust for in ALS environmental studies is largely absent. Thus, we created a multifactorial database, mapped hypothesized direct effects of air pollutants, and conducted a matched case-control study in New Brunswick, Canada to investigate the association between long-term exposure to various air pollutants and the development of ALS. Odds of ALS onset was significantly associated with increased SO2 exposure (OR = 1.23; 95 % CI: 1.02-1.47, per IQR increase of 0.14 ppb) in adjusted direct effect models, but not associated with exposure to NO2 (OR = 1.09; 95 % CI: 0.87-1.41, per IQR increase of 2.79 ppb), ozone (O3) (OR = 0.99; 95 % CI: 0.80-1.22, per IQR increase of 2.31 ppb), fine particulate matter (PM2.5) (OR = 0.99; 95 % CI: 0.80-1.23, per IQR increase of 0.52 μg/m[3]) or PM2.5(smoke) (OR = 1.05; 95 % CI: 0.83-1.35, per IQR increase of 0.68 μg/m[3]). As for recency models, SO2 remained significantly associated with ALS in both 5-year (OR = 1.21; 95 % CI: 1.03-1.43) and 10-year prior to onset sensitivity models (OR = 1.23; 95 % CI: 1.02-1.47). Our findings support the association between long-term exposure to air pollutants, particularly SO2, and the development of ALS, supporting the need for improved air pollution control measures.}, } @article {pmid40571609, year = {2026}, author = {Watanabe, Y and Uemoto, M and Otsuki, M and Fukuhara, H and Tajiri, Y and Murakami, T and Hanajima, R}, title = {Can Language Characteristics Contribute to the Classification of Neurodegenerative Disorders? -An Exploratory Study.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {65}, number = {1}, pages = {103-110}, pmid = {40571609}, issn = {1349-7235}, mesh = {Humans ; Male ; Female ; Aged ; *Neurodegenerative Diseases/classification/diagnosis/psychology/complications ; *Language ; Middle Aged ; Amyotrophic Lateral Sclerosis/diagnosis ; Alzheimer Disease/diagnosis ; Aged, 80 and over ; Parkinson Disease/diagnosis ; *Language Disorders/diagnosis ; Supranuclear Palsy, Progressive/diagnosis ; Language Tests ; }, abstract = {Objective Evaluating language symptoms is challenging owing to their varied presentations. We developed a Japanese Language Screen (JLS) to assess 11 language aspects, including agrammatism, impairment of articulation and prosody (IAP), word recall, syntactic comprehension, meaning of proverbs, and writing, considering the unique features of the Japanese language. Methods Using the JLS, we assessed the language functions in patients with Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and healthy controls (HC) to identify language symptoms specific to each condition and determine whether the JLS can differentiate between diseases and HC. Results The study included 168 participants. The total JLS score categorized the participants' language status as normal or impaired. According to the total score, PSP patients had more severe language deficits than AD patients, despite comparable cognitive scores. Substantial differences were found in the 11 assessed items for each disease. Patients with AD and PSP showed decreased performance in more than half of the items compared to HC, with the PSP group being more impaired. ALS patients showed decreases in IAP and writing, notably in the meaning of proverbs, whereas PD was closely comparable to HC. Conclusion This study suggests that while the JLS is useful for understanding the language symptoms associated with neurodegenerative disorders, its ability to classify them remains limited.}, } @article {pmid40571717, year = {2025}, author = {Khan, R and Rahman, N and Prasannan, A and Ganiyeva, K and Chakrabortty, S and Sangaraju, S}, title = {Phase transition and bandgap modulation in TiO2 nanostructures for enhanced visible-light activity and environmental applications.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {20309}, pmid = {40571717}, issn = {2045-2322}, abstract = {Due to its wide-ranging applications in the climate and energy fields, enhancing the visible-light photoactivity of TiO2 nanoparticles remains a crucial challenge in photocatalysis. Interestingly, this work examined the phase transition, structural, optical, and photocatalytic characteristics of TiO2 nanoparticles doped with Al[3][+]/Al[2][+] and S[6+] ions. It was observed that the anatase phase (AP) dominates in pure TiO2 (100%) nanoparticles, whereas the rutile phase (RP) content increases in doped samples, reaching 20 ± 2.1% for X1 (Al = 2%, S = 2%) and falling to 12 ± 1.2% in X4 (Al = 2%, S = 8%). The introduction of Al[3][+]/Al[2][+] and S[6+] induces oxygen vacancies (Ovs) and alters the phase stability, as evidenced by the reduction of transformation energy to - 0.033 eV, facilitating the AP to RP transition. The effective integration of dopants indicates that a redshift and intensity in the Photoluminescence spectrum reduced by X-series nanoparticles is due to band gap reductions (from 3.23 eV for pure TiO2 to 1.98 eV for X4) and distortions in the lattice generated by Al/S doping. Raman spectroscopy results show peak broadening and shifts due to lattice strain from dopants, which validates dopant incorporation via peak shifts in Fourier-transform infrared spectroscopy. ESR study reveals paramagnetic centers in Ti[3][+]-Ovs complexes, indicating defect-induced magnetic characteristics. When methylene blue (MB) dye is photocatalyzed under visible light exhibits increased activity and degradation efficiencies that are higher than pure TiO2. The pseudo-first-order kinetic results show that co-doping effectively improves photocatalytic activity. Rate constants of 0.017 min[-][1] for X4 are found to be much higher than 7.28 × 10[-][4] min[-][1] for pure TiO2 nanoparticles. Finally, anatase X-series samples degraded MB at a maximum rate of 96.4% in 150 min, outperforming undoped TiO2 (15%) and rutile-TiO2 nanoparticles (65% degradation). The fundamental mechanism explains that the photocatalytic characteristics of TiO2 are modulated by co-doping, which is why these compounds are potential candidates for environmental remediation applications.}, } @article {pmid40571723, year = {2025}, author = {Li, TY and Gao, AW and Yang, R and Sun, Y and Lei, Y and Li, X and Chen, L and Liu, YJ and Arey, RN and Morales, K and Liu, RB and Wang, W and Zhou, A and Zhao, TJ and Li, W and Lalou, A and Wang, Q and Lima, T and Houtkooper, RH and Auwerx, J}, title = {A lysosomal surveillance response to stress extends healthspan.}, journal = {Nature cell biology}, volume = {27}, number = {7}, pages = {1083-1097}, pmid = {40571723}, issn = {1476-4679}, support = {ERC-AdG-787702//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; SNSF 31003A_179435; Sinergia CRSII5_202302//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; NRF 2017K1A1A2013124//National Research Foundation of Korea (NRF)/ ; LT000731/2018-L//Human Frontier Science Program (HFSP)/ ; PF-19-0232//United Mitochondrial Disease Foundation (UMDF)/ ; 82300708//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {*Lysosomes/metabolism/genetics ; *Caenorhabditis elegans/genetics/metabolism ; Animals ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Longevity/genetics ; *Stress, Physiological ; Vacuolar Proton-Translocating ATPases/genetics/metabolism ; Humans ; Proteolysis ; Disease Models, Animal ; }, abstract = {Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H[+]-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity and enhanced clearance of protein aggregates in worm models of Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis, thereby improving fitness. The GATA transcription factor ELT-2 governs the LySR programme and its associated beneficial effects. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan.}, } @article {pmid40571936, year = {2025}, author = {Evans, DM and Smith, GD and Moen, GH}, title = {Woolf et al's "GWAS by subtraction" is not useful for cross-generational Mendelian randomization studies.}, journal = {BMC research notes}, volume = {18}, number = {1}, pages = {247}, pmid = {40571936}, issn = {1756-0500}, support = {2017942//National Health and Medical Research Council/ ; MC_UU_00011/1/MRC_/Medical Research Council/United Kingdom ; DE220101226//Australian Research Council/ ; 325640//Norges Forskningsråd/ ; }, mesh = {Humans ; *Genome-Wide Association Study/methods ; *Mendelian Randomization Analysis/methods ; Phenotype ; }, abstract = {Mendelian randomization (MR) is an epidemiological method that can be used to strengthen causal inference regarding the relationship between a modifiable environmental exposure and a medically relevant trait and to estimate the magnitude of this relationship [1]. Recently, there has been considerable interest in using MR to examine potential causal relationships between parental phenotypes and outcomes amongst their offspring [2–4] (interestingly one of the earliest exemplars of MR was confirmation that antenatal maternal folate was protective against offspring neural tube defects [1]). In a recent issue of BMC Research Notes, Woolf, Sallis, Munafo and Gill (2023) [5] (abbreviated as WSMG from now on) present a method they call “GWAS by subtraction” (not to be confused with GWAS by subtraction via genomic SEM [6, 7]), to derive genome-wide summary statistics for paternal smoking and other “paternal phenotypes” with the goal that these estimates can then be used in downstream (including two sample) MR studies [8]. Whilst a potentially useful goal, WSMG (2023) focus on the wrong parameter of interest for useful genome-wide association studies (GWAS) and downstream cross-generational MR studies, and the estimator that they derive is neither efficient nor appropriate for such use.}, } @article {pmid40574759, year = {2025}, author = {Kalawatia, M and Lucke-Wold, B and Mehrunkar, A}, title = {Closer look at the cardiovascular and metabolic predictors of postpartum depression.}, journal = {World journal of psychiatry}, volume = {15}, number = {6}, pages = {106283}, pmid = {40574759}, issn = {2220-3206}, abstract = {Postpartum depression (PPD) is a severe mental health disorder affecting 10% to 15% of postpartum women worldwide. Pre-eclampsia is a hypertensive disorder of pregnancy that has been identified as a significant factor for PPD due to its vascular dysfunction, systemic inflammation and neurobiological alterations. The neuroinflammatory mechanisms common to both pre-eclampsia and PPD, that contribute to depressive symptoms include elevated proinflammatory cytokines (interleukin-6, tumor necrosis factor-alpha), activation of the kynurenine pathway, and oxidative stress. To critically evaluate Wu et al's study, which investigates blood pressure variability (BPV) and gestational body mass index (BMI) as independent predictors of PPD. To integrate recent findings on the metabolic and cardiovascular links between depression, pre-eclampsia, and postpartum mental health outcomes. Pre-pregnancy BMI is found to be a stronger predictor of PPD than gestational weight gain. A vascular-neuropsychiatric connection has been indicated in pre-eclamptic women, indicating a significant correlation between BPV and depressive postpartum symptoms. There is increased susceptibility to depression due to neuroinflammation contributed by blood pressure fluctuations and metabolic dysregulation. The incidence of PPD could be reduced by early identification and intervention for BP fluctuations. Early detection and intervention in high-risk pregnancies should be conducted through public health strategies that prioritize awareness, education, and accessibility to mental health care.}, } @article {pmid40574761, year = {2025}, author = {Yıldız, GN and Çiftçi, B}, title = {Interplay between insomnia, anxiety, and depression.}, journal = {World journal of psychiatry}, volume = {15}, number = {6}, pages = {104796}, pmid = {40574761}, issn = {2220-3206}, abstract = {Insomnia, anxiety, and depression have become critical mental health issues exacerbated by the coronavirus disease 2019 pandemic, highlighting the importance of understanding their interrelationships. This article evaluates the study by Li et al, which investigates the links between insomnia, anxiety, and depression while examining the mediating role of cognitive failures and the moderating effect of neuroticism. The study employed a cross-sectional design with 1011 participants, using validated scales to measure insomnia severity, neuroticism, cognitive failures, and mental health indicators. Li et al found that approximately 40% of participants exhibited symptoms of anxiety, depression, and insomnia, with most cases being mild. The results demonstrated that cognitive failures play a mediating role in the relationship between insomnia and both anxiety and depression. Furthermore, neuroticism moderated the relationship between insomnia and cognitive failures, with a stronger effect observed in individuals with lower levels of neuroticism. These findings underscore the importance of considering personality traits and cognitive processes in understanding mental health outcomes. This study emphasizes the critical need for interventions aimed at reducing cognitive failures and enhancing emotional stability to mitigate the impact of insomnia on mental health. Strategies to improve sleep quality, boost cognitive resilience, and regulate emotional responses could significantly enhance individuals' mental well-being. Moreover, integrating personality assessments into mental health services could facilitate more effective and personalized interventions. This article provides an original perspective on the effects of the coronavirus disease 2019 pandemic on global mental health. The content of the article addresses the complex relationships between sleep disorders, cognitive function losses, and neuroticism in light of data compiled from existing literature and current research. In addition, how these relationships have deepened during the pandemic and the effectiveness of proposed treatment methods for these phenomena are discussed in comparison with previous studies. The arguments in the article offer new perspectives and suggestions aimed at filling gaps in the literature, and make an important contribution to both clinical practice and public health policies. Li et al's study provides a comprehensive framework for understanding the connections between insomnia, cognitive failures, and neuroticism, as well as their influence on anxiety and depression. The findings offer valuable implications for public health strategies, emphasizing the necessity of holistic approaches to address post-pandemic mental health challenges.}, } @article {pmid40574889, year = {2025}, author = {Kulshreshtha, NN and Barthélémy, P}, title = {Lock and key: locked G quadruplexes could be the key to new modalities in nucleic acid therapeutics.}, journal = {RSC medicinal chemistry}, volume = {16}, number = {8}, pages = {3336-3343}, pmid = {40574889}, issn = {2632-8682}, abstract = {G quadruplexes are secondary structures formed by G-rich sequences in DNA/RNA. They are critical regulatory centres for gene activation and chromosome stability. Malfunctions in their number or topology often results in ailments such as frontotemporal dementia, amyotrophic lateral sclerosis, coronary heart disease, anaemia, and various cancers. Proteins and ligands can bind to them only if the quadruplex topology matches their requirements. Hence, stabilizing or destabilizing this topology can have profound implications in therapeutics. Novel nucleic acid modalities involving intra-conjugated G4s are an interesting prospect as they have a fixed topology without the use of additional ligand stabilizers. They could also efficiently bind to G4-associated proteins and have important consequences in clinical research and development. In this opinion, a justification for the development of these modalities is presented by highlighting their advantages and the potential applications that can be unlocked by locking G4 sequences.}, } @article {pmid40574975, year = {2025}, author = {Lehto, A and Schumacher, J and Teipel, S and Machts, J and Vielhaber, S and Hermann, A and Prudlo, J and Kasper, E}, title = {Cerebellar grey matter volume is associated with semantic fluency performance in amyotrophic lateral sclerosis patients.}, journal = {Brain communications}, volume = {7}, number = {3}, pages = {fcaf230}, pmid = {40574975}, issn = {2632-1297}, abstract = {The cerebellum has been shown to contribute to different cognitive functions such as verbal fluency and different aspects of executive functioning, which are also commonly impaired in amyotrophic lateral sclerosis (ALS) patients. Whereas cerebellar involvement has been indicated in ALS patients in general, its relative contribution to the patients' specific cognitive deficits remains unclear. In the current analyses, the demographic, clinical, neuropsychological and imaging data of 120 ALS patients and 88 healthy controls were analysed. Grey matter volume (GMV) and white matter (WM) fractional anisotropy were extracted for a comprehensive list of cerebral and cerebellar regions and bootstrapped elastic net regularized regression analyses were employed to identify regional structural metrics that were related to various cognitive scores. We further examined the stability of predictor variables selection and the regression coefficient distributions across the bootstrap samples. Both regional GMV and WM integrity are featured as informative predictors for patients' cognitive scores. The GMV of cerebellar lobules V and VIIIa were related to semantic fluency, but cerebellar regions did not reliably contribute to other cognitive outcomes. The GMV of pallidum was positively correlated with fluency outcomes and working memory, whereas hippocampus volume was positively related to fluency and episodic memory outcomes. Unsurprisingly, educational achievement emerged as the most general and reliable predictor of cognitive performance. Based on the current findings, cerebellar GMV seems to be specifically associated with semantic fluency performance in ALS patients but not any of the other cognitive measures. Further cognitive functions were associated with both cerebral grey matter (GM) and WM metrics. Future investigations could examine the possible involvement of the cerebellum in the affective and social-emotional dysfunction present in a subset of ALS patients.}, } @article {pmid40575450, year = {2025}, author = {Barker, MS and Shneider, NA and Manoochehri, M and Huey, ED and Lindenberger, EC}, title = {Excessive emotional reactivity in a case of behavioral variant frontotemporal dementia with amyotrophic lateral sclerosis.}, journal = {Psychiatry research case reports}, volume = {4}, number = {1}, pages = {}, pmid = {40575450}, issn = {2773-0212}, support = {R01 NS076837/NS/NINDS NIH HHS/United States ; U01 AG079850/AG/NIA NIH HHS/United States ; R00 NS060766/NS/NINDS NIH HHS/United States ; R01 MH120794/MH/NIMH NIH HHS/United States ; R01 AG062268/AG/NIA NIH HHS/United States ; }, abstract = {Although amyotrophic lateral sclerosis (ALS) is defined as a neuromuscular disease, cognitive and/or behavioral symptoms are relatively common, and a portion of ALS patients will meet criteria for behavioral variant frontotemporal dementia (bvFTD). In this report, we describe the case of a man with ALS with bvFTD (ALS-FTD) presenting with excessive emotional reactivity, including severe anger, aggression, and obsessive thoughts. We contrast this case with the decreased emotional reactivity that is usually observed in patients with bvFTD without ALS. We discuss possible explanations including that: 1) the behavioral symptoms of bvFTD and ALS-FTD are the same, but the motor dysfunction influences the clinical manifestations of the behavioral symptoms in ALS-FTD; 2) the emotional and behavioral symptoms of bvFTD and ALS-FTD are the same, but ALS-FTD patients come to clinical attention earlier in the course of their FTD than bvFTD patients without ALS; and 3) the emotional and behavioral symptoms of bvFTD and ALS-FTD could differ.}, } @article {pmid40575640, year = {2025}, author = {Ahmed, S and Nashwan, AJ}, title = {Rising adult hepatitis A in Pakistan: Shifting trends and public health solutions.}, journal = {World journal of virology}, volume = {14}, number = {2}, pages = {102519}, pmid = {40575640}, issn = {2220-3249}, abstract = {This letter evaluates Shahid et al's study in 2025 on the rising hepatitis A virus (HAV) among adults in Pakistan, highlighting a shift in the virus's epidemiology. Once primarily a childhood disease in low-income regions, HAV is now increasingly affecting adults, also seen globally due to improved sanitation. The study highlights public health challenges from adult HAV infections, which can lead to complications like coagulopathy and acute liver failure. It also has limitations, including being a single-center study and lacking seroprevalence and socioeconomic data, indicating the need for further research. This letter calls for urgent public health measures to extend adult vaccination programs and improve sanitation to address the increasing HAV infection in adult populations.}, } @article {pmid40575894, year = {2025}, author = {Eliasdottir, OJ}, title = {[Antisense oliconucleotides-potential treatment for familial Amyotrophic lateral sclerosis (ALS).].}, journal = {Laeknabladid}, volume = {111}, number = {7-08}, pages = {311}, doi = {10.17992/lbl.2025.0708.846}, pmid = {40575894}, issn = {1670-4959}, } @article {pmid40575896, year = {2025}, author = {Thorarinsson, BL and Halldorsdottir, KE and Hilmarsson, A and Sveinsson, OA}, title = {[Treatment of familial ALS with the drug tofersen].}, journal = {Laeknabladid}, volume = {111}, number = {7-08}, pages = {314-317}, doi = {10.17992/lbl.2025.0708.848}, pmid = {40575896}, issn = {1670-4959}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/diagnosis/cerebrospinal fluid ; Treatment Outcome ; Mutation ; Male ; Middle Aged ; Female ; Superoxide Dismutase-1/genetics ; Neurofilament Proteins/cerebrospinal fluid ; Injections, Spinal ; Iceland ; Genetic Predisposition to Disease ; *Oligonucleotides/administration & dosage/therapeutic use ; Adult ; Biomarkers/cerebrospinal fluid ; *Oligonucleotides, Antisense/administration & dosage ; Phenotype ; Hospitals, University ; Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe and progressive neurodegenerative disorder. We describe four cases of familial ALS based on SOD1 mutations who received intrathecal treatment with the antisense oligonucleotide tofersen at Landspítali University Hospital Iceland. Since initiation of treatment, there has not been any significant deterioration, and three patients have shown signs of cinical improvement. The cerebrospinal fluid concentration of neurofilament light chain (Nf-L), a biomarker of neuronal axonal damage, has decreased to the reference range of healthy individuals. No serious side effects have been observed.}, } @article {pmid40576049, year = {2025}, author = {Rudnicki, SA and Gebrehiwet, P and Kupfer, S and Malik, FI and Meng, L and Simkins, T and Wei, J and Wolff, AA and Shefner, JM}, title = {Participant, site personnel and sponsor perspectives on decentralized trial features in COURAGE-ALS: a randomized clinical trial.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {812-820}, doi = {10.1080/21678421.2025.2523941}, pmid = {40576049}, issn = {2167-9223}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/psychology ; Double-Blind Method ; }, abstract = {OBJECTIVES: To describe participant, site personnel (SP) and sponsor perspectives regarding their experiences with a decentralized clinical trial (DCT).

METHODS: COURAGE-ALS was a 48-week, double-blind, randomized, phase III, hybrid DCT of reldesemtiv versus placebo for ALS. Fifty participants completed semi-structured interviews at Week ∼22; the majority provided feedback on DCT features. Subsequently, a planned interim analysis led to termination of COURAGE-ALS for futility; 486 participants were randomized and dosed. SP completed an online survey focusing on operational aspects of the hybrid design.

RESULTS: RVs influenced the decision to pursue the trial in 13/31 participants. Remotely performing forced vital capacity (FVC) was a concern for 17/43 (40%). Survey response rate for SP was 41% (141/344). The trial was viewed as less time/labour for the site versus a traditional design by 52/136 (38%) of SP. Twenty percent (25/125) agreed their participants liked doing remote FVC assessments; 6% (7/109) of SP reported no challenges in obtaining FVC remotely. Technological problems were commonly reported by SP (71/109, 65%). Biospecimen collection and Revised Amyotrophic Lateral Sclerosis Functional Rating Scale done at in-clinic visits (ICVs) and return visits (RVs) had similar completion rates, FVCs were missed more often at RVs than ICVs (completion rates 82% vs. 96%, p < 0.001).

CONCLUSIONS AND RELEVANCE: Participants and SP viewed RVs favorably, despite common technical challenges. RV FVC assessments were more likely to be missed. COURAGE-ALS demonstrated that an interventional hybrid DCT is feasible in ALS but limitations remain that will need to be considered when designing future DCTs.

TRIAL REGISTRATION: ClinicalTrials.gov (NCT04944784).}, } @article {pmid40576748, year = {2026}, author = {Gupta, MK and Chauhan, K and Bhardwaj, S and Srivastava, R}, title = {Innovative Interventions: Postbiotics and Psychobiotics in Neurodegenerative Disease Treatment.}, journal = {Probiotics and antimicrobial proteins}, volume = {18}, number = {2}, pages = {2818-2837}, pmid = {40576748}, issn = {1867-1314}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/drug therapy ; *Probiotics/administration & dosage/therapeutic use ; Gastrointestinal Microbiome/drug effects ; Animals ; }, abstract = {Neurodegenerative disorders, including Huntington's disease, Amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease, create more challenges as the population gets older and there are no curative therapies available. Recent advances in gut microbiome research have spotlighted postbiotics and psychobiotics as innovative therapeutic strategies targeting the gut-brain axis to alleviate neurodegenerative symptoms and slow disease progression. Postbiotics, which are metabolites and cellular components released by probiotic bacteria, and psychobiotics, a class of probiotics with potential mental health benefits, offer novel approaches to neuroprotection. This chapter examines the ways in which postbiotics and psychobiotics modulate inflammation, oxidative stress, neurotrophic factors, and gut barrier integrity to provide neuroprotective effects. We review scientific research that highlights the efficacy of specific microbial strains and their metabolites in enhancing cognitive function and reducing neurodegeneration. In addition, we explore the consequences of diet and specific nutrition on strengthening the therapeutic results of these medications. The purpose of this chapter is to provide a detailed analysis of the existing data supporting the use of postbiotics and psychobiotics in both the prevention and management of neurological diseases. By integrating perspectives from microbiology, neurology, and clinical nutrition, we highlight the potential of these interventions to enhance patient outcomes and quality of life. In addition, we discuss the translational limitations and future research approaches required to successfully transition these microbiome-based treatments from the laboratory to clinical practice, emphasizing the importance of a holistic and personalized approach in combating neurodegenerative diseases.}, } @article {pmid40577240, year = {2025}, author = {O'Brien, D and Alhathli, E and Harwood, C and Bhattacharya, D and Gupta, K and Julian, T and Weinreich, M and West, RJH and Wang, D and Byrne, RP and McLaughlin, RL and Wuu, J and Benatar, M and Cooper-Knock, J and Shaw, PJ}, title = {Extreme exercise in males is linked to mTOR signalling and onset of amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {10}, pages = {3652-3664}, pmid = {40577240}, issn = {1460-2156}, support = {DOD/14/43//My Name'5 Doddie Foundation/ ; NF-SI-0617-10077//NIHR/ ; 23-PP-664//ALS Association/ ; 894-791//MND Association/ ; //TargetALS/ ; //Tambourine's ALS Breakthrough Research Fund/ ; //Milken Institute/ ; NIHR 203321//NIHR Sheffield Biomedical Research Centre/ ; 879-791//NIHR Sheffield Clinical Research Facility/ ; 979-799//NIHR Sheffield Clinical Research Facility/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Male ; *TOR Serine-Threonine Kinases/genetics/metabolism ; *Exercise/physiology ; Female ; Middle Aged ; *Signal Transduction/genetics/physiology ; Aged ; Prospective Studies ; Mendelian Randomization Analysis ; Cohort Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is thought to be caused by interaction between genetic and environmental factors leading to motor neuron (MN) degeneration. Physical exercise has been linked to ALS but controversy remains. A key question is to determine which individuals might be at risk of exercise-associated ALS, because unnecessary avoidance of exercise could be harmful. We implemented complementary strategies including Mendelian randomization (MR) and multiple questionnaire-based measures of physical exercise in different cohorts. We include a prospective study involving UK Biobank participants where we could test for a relationship between exercise and the timing of future ALS symptom onset. To interrogate the molecular basis of our observations we performed a genetic association study of 'extreme' exercise, equivalent to >6 h of strenuous exercise or >12 h of any leisure-time exercise per week. Our data suggest that the link between increased physical exercise and ALS is particularly important for males who perform the most activity; with no evidence of a link in females. We determined that extreme exercise in males is associated with loss-of-function genetic variants within a number of mammalian target of rapamycin (mTOR) signalling genes that are also differentially expressed in ALS spinal cord. Activity-induced mTOR signalling has been shown to selectively benefit MN. Therefore, our findings could imply that moderate exercise is neuroprotective via enhanced mTOR signalling, but extreme exercise in men is associated with neurotoxicity and ALS via a failure of this mechanism. There was no significant overlap between genes associated with extreme exercise and those associated with ALS risk, consistent with a true gene-environment interaction rather than a shared genetic basis. We are not yet able to make individual-level recommendations regarding exercise and risk of ALS, but our conclusions should provide focus for future investigation.}, } @article {pmid40578028, year = {2025}, author = {Yang, JL and Qian, SY and Chen, ML and Wang, LX and Wang, Y and Liu, JJ and Xi, CS and Yang, YX and Li, Y and Gao, C and Zheng, GQ}, title = {Skeletal muscle, neuromuscular organoids and assembloids: a scoping review.}, journal = {EBioMedicine}, volume = {118}, number = {}, pages = {105825}, pmid = {40578028}, issn = {2352-3964}, mesh = {*Organoids/cytology/metabolism ; Humans ; *Neuromuscular Junction/metabolism ; *Muscle, Skeletal/metabolism/cytology ; Cell Differentiation ; Animals ; Motor Neurons/metabolism/cytology ; Induced Pluripotent Stem Cells/cytology/metabolism ; }, abstract = {Skeletal muscle organoids (SKMOs), neuromuscular organoids (NMOs), and assembloids have emerged as powerful in vitro models that simulate the intricate cellular interactions between muscle and nerve, offering a promising approach to study function, development, and disease at the neuromuscular junction (NMJ). Given the relevance of NMJ dysfunction in diseases such as amyotrophic lateral sclerosis (ALS), these models provide insights into disease modelling. Scoping reviews are particularly valuable when exploring broad or emerging areas, as they help identify key concepts and evolving methodologies. Here, we conducted a scoping review by searching five databases, ultimately including 17 studies focussing on the development and application of SKMOs, NMOs, and assembloids in muscle function modelling. We highlight recent advancements and summarise various differentiation protocols, primarily utilising the Wnt signalling pathway agonist CHIR99021 and basic fibroblast growth factor (bFGF) to induce pluripotent stem cells into 2D neuromesodermal progenitors, further differentiated into SKMOs, NMOs, and assembloids. We also reviewed their cellular compositions, including motor neurons, neural stem cells, terminal Schwann cells, and astrocytes, alongside related research outcomes. Additionally, we discuss key challenges such as iPSC donor selection, standardisation, vascularisation, and 3D organoid imaging. This scoping review provides a foundation for future research on muscle function modelling.}, } @article {pmid40580199, year = {2025}, author = {Allen, MD and Van Eijk, RPA and Knox, L and Carlton, J and Hobson, E and Mcdermott, CJ and Murray, D and Berry, J and Meyer, T and Genge, A}, title = {Variability across versions of the self-administered ALSFRS-R: a review and call for harmonization.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {631-636}, doi = {10.1080/21678421.2025.2522400}, pmid = {40580199}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; *Disability Evaluation ; Severity of Illness Index ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease predominantly affecting motor neurons resulting in substantial, progressive disability. The amyotrophic lateral sclerosis functional rating scale - revised (ALSFRS-R) is commonly used to assess and monitor functional status in patients with ALS. Additionally, it is the current regulatory accepted primary outcome measure documenting functional status in ALS clinical trials. The ALSFRS-R was originally designed to be administered to a patient by a trained professional. But over time it has been adapted to be performed independently by patients or their caregivers without assistance. Several different versions of the self-administered ALSFRS-R have been created over the past two decades, each with subtle but important differences. Some of these differences are related to language used in item wording or the platform for which the scale was intended to be administered (e.g. digitally). These differences across versions of the self-administered scale may be problematic as they could increase the heterogeneity of data collected across clinical trials or complicate interpretation of results across trials. Therefore, we highlight the need for a harmonized version of the self-administered ALSFRS-R to be used across all clinics and clinical trial sites internationally.}, } @article {pmid40580203, year = {2026}, author = {Pirozzi, MA and Canale, F and Di Nardo, F and Sharbafshaaer, M and Passaniti, C and Siciliano, M and Cirillo, M and Tessitore, A and Tedeschi, G and Esposito, F and Trojsi, F}, title = {Quantitative susceptibility mapping for investigating brain iron deposits in amyotrophic lateral sclerosis: correlations with clinical phenotype and disease progression.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {133-141}, doi = {10.1080/21678421.2025.2522406}, pmid = {40580203}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging/pathology ; Male ; Middle Aged ; Female ; Disease Progression ; *Iron/metabolism ; Phenotype ; *Brain/metabolism/diagnostic imaging/pathology ; Aged ; Magnetic Resonance Imaging ; *Brain Mapping/methods ; }, abstract = {Objective: Perturbation of iron homeostasis is a potential key mechanism involved in neurodegeneration across many neurological disorders, including amyotrophic lateral sclerosis (ALS). We hypothesized that changes in quantitative susceptibility mapping (QSM) could capture perturbations in brain iron concentration in subgroups of ALS patients stratified by clinical phenotype and disease progression. Method: We enrolled 38 ALS patients (23 males - mean age: 58.7 ± 9.8), screened by clinical (ALS functional rating scale-revised, ALSFRS-R) and neuropsychological scales. Patients were a posteriori classified as fast (n = 16) or slow (n = 22) progressors. Two subgroups were also considered: pyramidal (or upper motor neuron+, UMN+) patients (n = 18), and patients with other phenotypes (n = 20). Results: Comparing fast vs. slow progressors, significant differences in iron deposits were observed in the left (p = 0.028) and right amygdala (p = 0.022), and in susceptibility distribution on the right hippocampus (p = 0.0011). Comparing UMN+ vs. other phenotypes, significant susceptibility differences emerged in the left thalamus (p = 0.0014) and right amygdala (p = 0.001). QSM changes were associated with baseline ALSFRS-R (rho = 0.36, p = 0.026) in the left paracentral cortex, and iron concentration with UMN score (rho = 0.35, p = 0.034). Moreover, the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) was associated with iron deposits in the left thalamus (rho=-0.46, p = 0.0041). Conclusions: We confirmed that QSM alterations in extra-motor areas and subcortical regions may be distinctive hallmarks of neurodegeneration in pure/dominant UMN phenotypes of ALS. Moreover, we showed that QSM could be a valuable tool to differentiate patients with different progression rates and phenotypes, suggesting that QSM may support a prognostically useful early stratification of ALS patients.}, } @article {pmid40580315, year = {2026}, author = {Jellinger, KA}, title = {Co-occurrence of amyotrophic lateral sclerosis and multiple sclerosis: a rare but interesting association.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {133}, number = {1}, pages = {1-13}, pmid = {40580315}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications/genetics ; *Multiple Sclerosis/epidemiology/complications/genetics ; }, abstract = {Multiple sclerosis (MS) is an inflammatory demyelinating disease with highly variable clinical course and usual onset in younger age, caused by genetic and environmental factors. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects motor neurons in the brain and spinal cord, resulting in gradual loss of voluntary muscle and respiratory control. Both ALS and MS exhibit distinct underlying causes and disease mechanisms, despite some shared clinical effects. About 10% of ALS are linked to genetic factors, such as C9orf72, the remaining sporadic ones being potentially influenced by environmental, toxic and oxidative stress, while MS is an autoimmune disorder where the immune system leads to inflammation and attacks the myelin sheath, genetic predisposition and viral infections playing a role in its susceptibility. The co-occurrence of ALS and MS is extremely rare, with 46 cases being reported in the available literature from 1986 to 2024, while in the earlier literature, cases with coincidental muscular atrophy simulating ALS were described. In the overwhelming majority, ALS manifested between one and 41 years after the onset of MS; only in four cases was ALS present before detection of MS. The concurrence of MS and ALS can be explained by similarities in their pathogenesis related to neurodegeneration, inflammation, and/or genetic susceptibility. The role of rare genetic ALS forms in this comorbidity deserves further studies. The shared inflammatory component with a cascade of oxidative stress and other noxious mechanisms leads to progressive motor and bulbar or other symptoms that underscore the potential for cross-disease research to yield insights applicable to both conditions and their relations to immune-mediated disorders.}, } @article {pmid40580336, year = {2025}, author = {Wang, T and Wang, Y and Yang, Y and Wang, S and Wang, X and Feng, H}, title = {Fisetin Attenuates Mutant SOD1 Aggregation in Amyotrophic Lateral Sclerosis via Nrf2-Mediated Autophagy Activation.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {3}, pages = {84}, pmid = {40580336}, issn = {1559-1166}, support = {2020B11//the First Affiliated Hospital of Harbin Medical University Research Innovation Fund/ ; 2020B11//the First Affiliated Hospital of Harbin Medical University Research Innovation Fund/ ; 2020-127//the Health Commission Scientific Research Foundation of Heilongjiang Province of China/ ; 21042240013//2024 Heilongjiang Province Postdoctoral Research Start-up Fund/ ; }, mesh = {*NF-E2-Related Factor 2/metabolism/genetics ; *Autophagy ; Flavonols ; *Flavonoids/pharmacology ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Animals ; Motor Neurons/metabolism/drug effects ; Humans ; Cell Line ; Sequestosome-1 Protein/metabolism/genetics ; *Neuroprotective Agents/pharmacology ; Protein Aggregates ; Protein Aggregation, Pathological ; }, abstract = {Dysregulated autophagy and copper/zinc superoxide dismutase (SOD1) protein aggregation play a crucial role in amyotrophic lateral sclerosis (ALS). Here, we used stably transfected NSC34 motor neuron-like cells: (1) SOD1[G93A] mutants (G93A), (2) wild-type SOD1 (WT) controls, and (3) empty vector (EV) controls to observe the effects of fisetin. Pharmacological autophagy inhibition (Bafilomycin A1, 40 nM) and nuclear factor erythroid 2-related factor 2 (Nrf2) gene silencing (siRNA transfection) were employed to dissect molecular pathways. Protein aggregation dynamics and autophagy markers (LC3, p62/SQSTM1) were quantified through immunofluorescence and immunoblotting. SOD1[G93A] models exhibited impaired autophagic flux evidenced by elevated LC3-II and p62 levels, correlating with increased detergent-insoluble SOD1 aggregates. Fisetin treatment (1-10 μ M) dose-dependently reduced both soluble and aggregated SOD1[G93A] protein, concomitantly with restored autophagic flux. Mechanistically, fisetin promoted nuclear translocation while decreasing cytoplasmic Nrf2. After administration of an autophagy inhibitor and interference with Nrf2, the regulation of fisetin on p62 and mutant hSOD1 protein was inhibited. Our findings demonstrate that fisetin ameliorates mutant SOD1 proteotoxicity through coordinated activation of Nrf2-mediated autophagy pathways, suggesting therapeutic potential for SOD1-associated ALS pathologies.}, } @article {pmid40580685, year = {2025}, author = {Deng, Z and Chen, H and Chen, J and Du, Z and Zhou, W and Yuan, Z}, title = {Multifaceted roles of extracellular vesicles in the interplay of neuroinflammation and neurodegenerative diseases.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1871}, number = {7}, pages = {167960}, doi = {10.1016/j.bbadis.2025.167960}, pmid = {40580685}, issn = {1879-260X}, mesh = {Humans ; *Extracellular Vesicles/metabolism/pathology ; *Neurodegenerative Diseases/pathology/metabolism ; Animals ; *Neuroinflammatory Diseases/pathology/metabolism ; Blood-Brain Barrier/metabolism/pathology ; Biomarkers/metabolism ; Cell Communication ; }, abstract = {Despite advances in understanding neurodegenerative disease mechanisms, effective treatments remain elusive. Extracellular vesicles (EVs), key mediators of intercellular communication within the central nervous system (CNS), are increasingly recognized for their involvement in the pathogenesis of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington's disease (HD). In vivo studies demonstrate EVs' crucial role in maintaining CNS homeostasis, modulating neuroinflammatory responses, and influencing tissue repair and regeneration following injury, thereby impacting disease progression and recovery. Their unique properties, including small size and ability to cross the blood-brain barrier (BBB), position them as promising candidates for both biomarkers and therapeutics in CNS diseases. This review delves into the significant impact of neuroinflammation on neurodegenerative conditions, specifically focusing on the multifaceted contributions of EVs and their intricate interplay with the inflammatory landscape. We explore EV biogenesis, cargo composition, diverse roles in neuroinflammation (including intercellular communication and neuroprotection), their potential as biomarkers and drug delivery vehicles across the BBB for diagnosis or treatment of neuroinflammation implemented neurodegenerative diseases.}, } @article {pmid40580876, year = {2025}, author = {García-Toscano, L and Rodríguez-Cueto, C and Furiano, A and Hind, W and de Lago, E and Fernández-Ruiz, J}, title = {Preclinical evaluation of cannabidiolic acid as a neuroprotective agent in TDP-43 transgenic mice, an experimental model of amyotrophic lateral sclerosis.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {189}, number = {}, pages = {118288}, doi = {10.1016/j.biopha.2025.118288}, pmid = {40580876}, issn = {1950-6007}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/genetics/physiopathology/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Disease Models, Animal ; Male ; Mice, Transgenic ; Mice ; Motor Neurons/drug effects/pathology/metabolism ; Microglia/drug effects/metabolism/pathology ; Spinal Cord/drug effects/pathology/metabolism ; *Cannabinoids/pharmacology ; *DNA-Binding Proteins/genetics/metabolism ; Dose-Response Relationship, Drug ; Motor Activity/drug effects ; Riluzole/pharmacology ; }, abstract = {Plant-derived cannabinoids, including Δ[9]-THC, cannabinol, and Sativex-like combinations, have shown neuroprotection in preclinical ALS models. However, minor phytocannabinoids like cannabidiolic acid (CBDA) remain unexplored. This study evaluated the neuroprotective effects of CBDA, cannabidivarin, CBD, Δ[9]-THC, and Δ[9]-tetrahydrocannabidivarin in Prp-hTDP-43(A315T) transgenic male mice from early symptomatic (day 65) to advanced stages (day 90). CBDA proved the most effective, improving motor coordination (rotarod test) and reducing neuronal cell death, gliosis, microglial reactivity, and pro-inflammatory mediators in the spinal cord. A dose-response study confirmed that 10 mg/kg CBDA improved motor performance and preserved motor neurons, while lower doses were less effective and higher doses caused toxicity. Flow cytometry revealed a shift from an M1 proinflammatory to an M2 anti-inflammatory phenotype in microglial cells after CBDA treatment, mirroring effects in BV2 cells exposed to LPS. Comparing CBDA with riluzole (standard ALS therapy), CBDA showed superior neuroprotection, except for rotarod performance, where no improvement was observed. A combination of CBD and riluzole failed to enhance efficacy and even weakened microglial response benefits. In conclusion, CBDA was the most effective of the five phytocannabinoids studied and outperformed riluzole in ALS models. These findings support further clinical evaluation of CBDA for ALS treatment.}, } @article {pmid40581291, year = {2025}, author = {Ha, T and Ganesh, S and Narendran, K and Uduman, MS and Rajan, R and Sankaridurg, P and Nguyen, N and Tran, H}, title = {Comparison of axial length measurements of myopic eyes from ocular biometers versus axial length estimator.}, journal = {Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus}, volume = {29}, number = {4}, pages = {104254}, doi = {10.1016/j.jaapos.2025.104254}, pmid = {40581291}, issn = {1528-3933}, mesh = {Humans ; Child ; Cross-Sectional Studies ; *Axial Length, Eye/pathology ; *Myopia/diagnosis/ethnology ; Adolescent ; Retrospective Studies ; *Biometry/instrumentation/methods ; Child, Preschool ; Female ; Male ; Refraction, Ocular/physiology ; Vietnam ; India ; Reproducibility of Results ; }, abstract = {PURPOSE: To compare axial length (AL) estimates of myopic eyes obtained using an axial length estimator (ALE) and AL measurements made with the IOLMaster 700 in India and the Lenstar 900 in Vietnam.

METHODS: This multicenter retrospective cross-sectional study analyzed masked data of both eyes from myopic children (<18 years of age). Estimated AL was derived from mean keratometry and refraction values using ALE. Differences between actual and estimated ALs and their correlation were assessed using Bland-Altman plots and intraclass correlation coefficients (ICCs).

RESULTS: A total of 237 myopic children (474 eyes) aged 5-16 years were included: 90 Indian and 147 Vietnamese children. ALE estimates on average exceeded actual AL measurements, with mean differences of -0.26 mm (95% limits of agreement, -1.25 to 0.73 mm) for ALE formula, and -0.21 mm (95% limits of agreement, -1.14 to 0.71 mm) for ALE data input. ICCs showed strong agreement: 0.90 (95% CI, 0.83-0.93) for actual AL versus ALE data input and 0.89 (95% CI, 0.78-0.93) for actual AL versus ALE formula. Indian children had shorter actual AL than Vietnamese children (24.56 ± 0.90 vs 24.91 ± 0.86 mm [P < 0.001]) and exhibited slightly smaller differences between actual and estimated AL (-0.13 vs -0.27 mm for ALE data input; -0.17 vs -0.31 mm for ALE formula).

CONCLUSIONS: In our cohorts, ALE demonstrated strong agreement with IOLMaster 700 and Lenstar 900 AL measurements in myopic children. ALE may be a useful clinical tool for this population when direct measurements of AL are unavailable.}, } @article {pmid40581642, year = {2025}, author = {Sanadgol, N and Samadi, M and Voelz, C and Khalseh, R and Amini, J and Beyer, C and Kipp, M and Clarner, T}, title = {Genomic ncRNAs regulating mitochondrial function in neurodegeneration: a neglected clue in the complex etiopathogenesis of multiple sclerosis.}, journal = {Cell & bioscience}, volume = {15}, number = {1}, pages = {93}, pmid = {40581642}, issn = {2045-3701}, abstract = {Multiple sclerosis (MS), the most prevalent myelinopathy with unclear etiology, involves mitochondrial dysfunction that critically contributes to oligodendrocyte damage and neurodegeneration. Recent interest has surged around the role of inflammatory non-coding RNAs (ncRNAs) in mitochondrial function, particularly in the context of neurodegenerative diseases (NDs), where neuroinflammation is a hallmark feature. This review highlights the collection and characterization of mitochondrial-related ncRNAs (MRncRNAs) that have been extensively studied in the context of NDs. Through a literature review, we identified 35 MRncRNAs (23 miRNAs, 8 LncRNAs, and 4 circRNAs) across Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), and Huntington's disease (HD). Notably, the inflammatory miRNAs miR-34a and miR-146a were commonly dysregulated in both PD and AD, while in HD, only a single miRNA, miR-196a, was identified. As expected, due to the mitochondrial nature of PD, the majority of MRncRNAs (9 miRNAs, 8 lncRNAs, and 3 circRNAs) were associated with this disorder. Further bioinformatic analysis of MRmiRNAs revealed that miR-124-5p, -146a-3p, and -15b-3p target mitochondrial genes more than others, and mRNA of pro-apoptotic protein BCL2L11 is the most targeted. Notably, the link between these MRncRNAs and mitochondrial function in MS remains unidentified. By evaluating upregulated MS-related ncRNAs in patients and comparing them with identified MRncRNAs, we found nine overlapping miRNAs (miR-15b, miR-21, miR-27b, miR-34a, miR-124, miR-137, miR-146a, miR-155, and miR-92a) as well as two shared lncRNAs, MALAT1 and HOTAIR (called MS/MRncRNAs). Further bioinformatic analysis of MS/MRmiRNAs revealed that the autophagy pathway is the most involved. Six of these miRNAs are significantly involved in MR diseases. Notably, miR-34a-5p showed a connection to oligodendrocyte mitochondria, while miR-15b targeted two MR hub genes, SDHC and BCL2. Moreover, several hub proteins (HIF1A, STAT3, MAPK1, GSK3B) targeted by these miRNAs are well-known regulators of inflammatory pathways and mitochondrial homeostasis: These findings highlight the critical roles of ncRNAs in mitochondrial dysfunction and neurodegeneration, emphasizing the urgent need for experimental studies on MRmiRNAs, particularly in the context of MS and other myelinopathies.}, } @article {pmid40581653, year = {2025}, author = {Lin, LT and Shenouda, M and McGoldrick, P and Lau, A and Robertson, J}, title = {C9orf72 deficiency impairs the autophagic response to aggregated TDP-25 and exacerbates TDP-25-mediated neurodegeneration in vivo.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {136}, pmid = {40581653}, issn = {2051-5960}, support = {#189242, #507996, #20012625//ALS Society of Canada/ ; 2023-001//Association for Frontotemporal Degeneration/ ; MOP-137005//CIHR/Canada ; AL161011//Weston Brain Institute/ ; }, mesh = {Animals ; *C9orf72 Protein/deficiency/genetics ; *Autophagy/physiology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; Humans ; Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Mice, Transgenic ; Frontotemporal Dementia/pathology/genetics/metabolism ; Disease Models, Animal ; Male ; Neurons/pathology/metabolism ; Brain/pathology/metabolism ; *Nerve Degeneration/pathology/metabolism ; }, abstract = {Cytoplasmic aggregates of the predominantly nuclear TAR DNA-binding protein 43 (TDP-43) are a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases caused by G4C2 hexanucleotide repeat expansions in C9orf72 (C9-ALS/FTD). While these repeat expansions are associated with both gain- and loss-of-function mechanisms, the contribution of C9orf72 loss of function to disease pathogenesis remains unclear. C9orf72 has been shown to regulate autophagy, and its deficiency has been shown to exacerbate phenotypes in gain-of-function G4C2 models, implicating impaired autophagic clearance in disease pathogenesis. Here, we directly test whether C9orf72 deficiency exacerbates TDP-43 pathology and neurodegeneration in vivo. Using AAV9-vectors to drive neuron-specific expression of pathologically relevant C-terminal species of TDP-43, TDP-35 and TDP-25, we established models of TDP-43 pathology that recapitulate key disease features, including cytoplasmic aggregates, motor and cognitive decline, and neuronal loss. TDP-25 expression in particular produced robust, abnormally phosphorylated, ubiquitinated and p62-labelled cytoplasmic aggregates, modelling TDP-43 pathology in disease. Loss of C9orf72 in TDP-25-expressing mice accelerated the onset of motor deficits, increased neurodegeneration, and impaired the autophagic response to TDP-25 expression. These findings reveal that C9orf72 deficiency disrupts autophagy and exacerbates TDP-25-mediated toxicity in vivo, supporting a contributory role for C9orf72 loss-of-function in driving neurodegeneration in C9-ALS/FTD.}, } @article {pmid40581671, year = {2025}, author = {Ono, S and Nakamura, M and Ikegami, T and Kajiyama, Y and Kume, K and Takahashi, Y and Takahashi, M and Mochizuki, H and Mizusawa, H and Kawakami, H and Yakushiji, Y}, title = {Spinocerebellar ataxia type 2 followed by amyotrophic lateral sclerosis due to a pure CAG repeat expansion in ATXN2: a case report and literature review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {10}, pages = {5417-5421}, pmid = {40581671}, issn = {1590-3478}, mesh = {Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/complications/diagnostic imaging ; Female ; *Ataxin-2/genetics ; *Spinocerebellar Ataxias/genetics/complications/diagnostic imaging ; *Trinucleotide Repeat Expansion/genetics ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia caused by abnormal CAG expansions (≥ 34 repeats) in the ATXN2 gene (ATXN2), whereas intermediate CAG expansions (27-33 repeats) have been linked to amyotrophic lateral sclerosis (ALS).

CASE DESCRIPTION: A 53-year-old woman with longstanding cerebellar ataxia developed progressive upper limb weakness and muscle atrophy at the age of 51 years. On neurological examination, she was found to have ataxic dysarthria, slow saccadic eye movements, tongue atrophy with fasciculations, muscle atrophy and weakness in both upper limbs, hyperreflexia with Babinski's sign, and limb and gait ataxia. Brain magnetic resonance imaging (MRI) showed brainstem and cerebellar atrophy. Genetic analysis identified an expanded CAG-repeat of 39/22 in ATXN2, and screening for other known ALS-related gene mutations was negative, leading to a diagnosis of both SCA2 and ALS associated with ATXN2.

CONCLUSIONS: SCA2 is typically associated with uninterrupted CAG-repeat expansions, whereas ALS-related ATXN2 expansions usually contain at least one CAA triplet. However, despite carrying an uninterrupted CAG-repeat expansion, this patient developed ALS. This case shows that ALS can emerge several decades after SCA2 onset, even in patients with pure CAG-repeats, underscoring the need for long-term monitoring in SCA2 patients. Further research is needed to clarify the roles of repeat length, CAA interruptions, and other factors in ATXN2-related ALS.}, } @article {pmid40581791, year = {2025}, author = {Al Ojaimi, Y and Osman, S and Alarcan, H and Emond, P and Veyrat-Durebex, C and Lanznaster, D and Meme, S and Clemencon, R and Galineau, L and Corcia, P and Andres, C and Vourc'h, P and Masse, F and Trovero, F and Blasco, H}, title = {Identification of disease-associated molecular signatures in the Prp-TDP-43A315T mouse model of ALS: Toward preclinical biomarker development.}, journal = {Journal of neuropathology and experimental neurology}, volume = {84}, number = {10}, pages = {911-927}, doi = {10.1093/jnen/nlaf071}, pmid = {40581791}, issn = {1554-6578}, support = {//Région Centre Val de Loire/ ; //French National Research Agency/ ; //ARSLA/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/diagnostic imaging ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Biomarkers/metabolism ; Mice, Inbred C57BL ; *DNA-Binding Proteins/genetics/metabolism ; Male ; Female ; Brain/metabolism/pathology ; Disease Progression ; }, abstract = {Identifying disease-related molecular signatures that can be used as biomarkers is critical for the development of preclinical therapies for amyotrophic lateral sclerosis (ALS). In this study, we focused on the Prp-TDP-43A315T transgenic mouse model of ALS to explore peripheral and central molecular alterations associated with disease progression. Prp-TDP-43A315T transgenic (Tg) and C57BL/6J wild-type mice were monitored from 50 to 400 postnatal days. One cohort assessed phenotypic parameters and MRI activity at 3 timepoints, ie, before (T0), at disease onset (T1), and at end-stage (T2). A second cohort validated findings from the first using omics analyses of tissues to examine ALS-related markers. Tg mice showed reduced body weight, decreased grip strength and tail position, and increased gait impairment at T1. Changes in (p)TDP-43, NRF2, GFAP, and pAMPK expression were noted in brain samples from the second cohort at T1. Metabolomic and lipidomic analyses revealed shifts in specific molecules in the brain and muscle of Tg mice. These data highlight individual differences in ALS pathology and adaptive responses to TDP-43-induced damage. This model provides valuable insights into TDP-43 proteinopathies and presents an innovative method for analyzing pathophysiological pathways through dried blood spot analysis, thereby expanding its applicability across various research fields.}, } @article {pmid40582511, year = {2025}, author = {Wei, JH and Hirsch, Y and Lehrer, LW and Hoyer, S}, title = {Response to Gordon et al's "Part 2: Management of intraoperative and perioperative bleeding".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {4}, pages = {e163}, doi = {10.1016/j.jaad.2025.05.1458}, pmid = {40582511}, issn = {1097-6787}, } @article {pmid40583130, year = {2025}, author = {Yang, M and Wang, Q and Kang, D and Wang, S and Jiang, Y and Wang, JZ and Ming, C and Liu, R and Gu, J and Wang, X}, title = {Cryptic Splicing of GAP43 mRNA is a Novel Hallmark of TDP-43-Associated ALS and AD.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {36}, pages = {e12054}, pmid = {40583130}, issn = {2198-3844}, support = {82330041//National Natural Science Foundation of China/ ; 92049107//National Natural Science Foundation of China/ ; 32171258//National Natural Science Foundation of China/ ; 2022-72-18//Science and Technology Innovation Team project from Department of Science and Technology of Hubei Province/ ; //Co-lnnovation Center of Neuroregeneration, Nantong University/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *DNA-Binding Proteins/genetics/metabolism ; *GAP-43 Protein/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; *RNA Splicing/genetics ; Induced Pluripotent Stem Cells/metabolism ; Exons/genetics ; }, abstract = {Cytoplasmic aggregation of transactive response DNA-binding protein 43 (TDP-43) is a hallmark of amyotrophic lateral sclerosis (ALS) and occurs in 57% of Alzheimer's disease (AD) cases. TDP-43 regulates RNA processing, including cryptic exon splicing. Here, we demonstrate that TDP-43 directly controls growth-associated protein (GAP43) expression by binding to its pre-mRNA. Loss or hyperphosphorylation of TDP-43 disrupts this binding, leading to the inclusion of cryptic exon 4a1, which introduces premature stop codons and reduces GAP43 protein levels. RNA sequencing analysis of ALS and AD brains revealed GAP43 downregulation, while 4a1 is upregulated in AD cases with phosphorylated TDP-43. TDP-43 knockdown impaired axonal regeneration in induced pluripotent stem cell (iPSC)-derived motor neurons, whereas GAP43 restoration rescued this defect. These findings suggest that the loss of GAP43 contributes to neurodegeneration in ALS and AD. The inclusion of GAP43 cryptic exon 4a1 may serve as a hallmark of TDP-43 proteinopathies, highlighting a mechanistic link between TDP-43 dysfunction and neuronal vulnerability.}, } @article {pmid40583472, year = {2025}, author = {Salehirozveh, M and Dehghani, P and Mijakovic, I}, title = {Nanopore-Based Neurotransmitter Detection: Advances, Challenges, and Future Perspectives.}, journal = {ACS nano}, volume = {19}, number = {27}, pages = {24404-24424}, pmid = {40583472}, issn = {1936-086X}, mesh = {*Nanopores ; *Neurotransmitter Agents/analysis ; Humans ; *Nanotechnology/methods ; *Biosensing Techniques/methods ; Animals ; }, abstract = {Neurotransmitters play a pivotal role in neural communication, synaptic plasticity, and overall brain function. Disruptions in neurotransmitter homeostasis are closely linked to various neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, schizophrenia, depression, and amyotrophic lateral sclerosis. This review explores the critical role of neurotransmitters in neurological disorders and highlights recent advances in nanopore-based neurotransmitter detection. Solid-state nanopores (SSNs), with their superior mechanical and chemical durability, have emerged as highly sensitive molecular sensors capable of real-time monitoring of neurotransmitter dynamics. We discuss the integration of SSNs into diagnostic frameworks, emphasizing their potential for early disease detection and personalized therapeutic interventions. Additionally, we examine the complementary role of nanopipettes in neurotransmitter detection, focusing on their high spatial resolution and real-time monitoring capabilities. The review also addresses the challenges and future perspectives of nanopore-based sensing technology, including the need for improved sensitivity, stability, and reproducibility. By integrating insights from neuroscience, bioengineering, and nanotechnology, this review aims to provide a comprehensive overview of how nanopore sensing can revolutionize neurotransmitter analysis and contribute to the development of next-generation diagnostic and therapeutic approaches for neurological diseases.}, } @article {pmid40583561, year = {2025}, author = {Magarotto, M and Gawne, RT and Vilkaite, G and Beltrami, M and Mason, AS and Chen, HJ}, title = {Familial ALS/FTD-associated RNA-binding deficient TDP-43 mutants cause neuronal and synaptic transcript dysregulation in vitro.}, journal = {Human molecular genetics}, volume = {34}, number = {17}, pages = {1480-1494}, doi = {10.1093/hmg/ddaf111}, pmid = {40583561}, issn = {1460-2083}, support = {SBF006\1088//British Heart Foundation and Diabetes UK/ ; //ASM's York Against Cancer (York, UK)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Neurons/metabolism/pathology ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Mutation ; RNA-Binding Proteins/genetics/metabolism ; Synapses/metabolism/genetics/pathology ; Cell Line, Tumor ; Cell Differentiation/genetics ; }, abstract = {TDP-43 is an RNA-binding protein constituting the pathological inclusions observed in ~ 95% of ALS and ~ 50% of FTD patients. In ALS and FTD, TDP-43 mislocalises to the cytoplasm and forms insoluble, hyperphosphorylated and ubiquitinated aggregates that enhance cytotoxicity and contribute to neurodegeneration. Despite its primary role as an RNA/DNA-binding protein, how RNA-binding deficiencies contribute to disease onset and progression are little understood. Among many identified familial mutations in TDP-43 causing ALS/FTD, only two mutations cause an RNA-binding deficiency, K181E and K263E. In this study, we used CRISPR/Cas9 to knock-in the two disease-linked RNA-binding deficient mutations in SH-SY5Y cells, generating both homozygous and heterozygous versions of the mutant TDP-43 to investigate TDP-43-mediated neuronal disruption. Significant changes were identified in the transcriptomic profiles of these cells, in particular, between K181E homozygous and heterozygous cells, with the most affected genes involved in neuronal differentiation and synaptic pathways. This result was validated in cell studies where the neuronal differentiation efficiency and neurite morphology were compromised in TDP-43 cells compared to unmodified control. Interestingly, divergent neuronal regulation was observed in K181E-TDP-43 homozygous and heterozygous cells, suggesting a more complex signalling network associated with TDP-43 genotypes and expression level which warrants further study. Overall, our data using cell models expressing the ALS/FTD disease-causing RNA-binding deficient TDP-43 mutations at endogenous levels show a robust impact on transcriptomic profiles at the whole gene and transcript isoform level that compromise neuronal differentiation and processing, providing further insights on TDP-43-mediated neurodegeneration.}, } @article {pmid40583986, year = {2025}, author = {Shobe, SM and Melka, D and Mulugeta, M and Adane, L}, title = {Bright tongue sign as a radiological clue of bulbar onset amyotrophic lateral sclerosis: A case report.}, journal = {Radiology case reports}, volume = {20}, number = {9}, pages = {4338-4341}, pmid = {40583986}, issn = {1930-0433}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by degeneration of motor neurons, with the tongue often involved in clinical presentation. In this case, a 60-year-old female presented with progressive choking episodes and speech slurring over 9 months, exhibiting dysarthria, prominent tongue atrophy, fasciculations, and hyperreflexia. Needle electromyography (EMG) showed diffuse chronic neurogenic changes with signs of active denervation changes prominent on the tongue and right arm with normal sensory nerve studies. Magnetic resonance imaging (MRI) brain imaging revealed a Diffuse T1 Weighted image (T1WI) hyperintense of tongue known as "bright tongue sign" indicating fatty infiltration of tongue muscles, consistent with neurogenic atrophy. This case underscores the importance of recognizing this characteristic tongue hyperintensity as a valuable radiological clue in diagnosing bulbar-onset ALS and highlights the potential for early diagnosis to improve patient management and outcomes.}, } @article {pmid40584177, year = {2025}, author = {Wu, Q and Yang, J and Duan, Y and Ma, Y and Zhang, Y and Tan, S and Wang, J and Wang, Y and Liu, B and Zhang, J and Liu, X}, title = {Environmental risk factors, protective factors, and biomarkers for amyotrophic lateral sclerosis: an umbrella review.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1541779}, pmid = {40584177}, issn = {1663-4365}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the rapid loss of motor neurons. Given the significant global economic impact of ALS, effective preventive measures are urgently needed to reduce the incidence of this devastating disease. Recent meta-analyses have explored potential links between environmental factors, biomarkers, and ALS occurrence. However, the findings of these studies have been inconsistent and controversial. Therefore, we present a comprehensive umbrella review of recent meta-analyses to systematically summarize the available epidemiological evidence and evaluate its credibility.

METHODS: A systematic search was conducted in PubMed and Embase from inception until 01 October 2024, to identify meta-analyses of observational studies examining associations between environmental risk factors, protective factors, biomarkers, and ALS susceptibility. For each meta-analysis, summary effect estimates, 95% confidence intervals (CIs), 95% prediction intervals, study heterogeneity, small study effects, and excess significance biases were calculated independently by two investigators. The methodological quality was evaluated using the AMSTAR 2 criteria. The strength of the epidemiological evidence was categorized into five levels based on predefined criteria.

RESULTS: Out of 1,902 articles identified, 43 met the inclusion criteria, resulting in 103 included meta-analyses. These analyses covered 46 environmental risk and protective factors (344,597 cases, 71,415,574 population) and 57 cerebrospinal fluid (CSF) and serum biomarkers (30,941 cases, 2,180,797 population). The evidence was classified as convincing (Class I) for the regular use of antihypertensive drugs (OR: 0.85, 95% CI: 0.81-0.88) and highly suggestive (Class II) for premorbid body mass index (OR: 0.97, 95% CI: 0.95 to 0.98), trauma (OR: 1.51, 95% CI: 1.32 to 1.73), CSF NFL levels (SMD: 2.06, 95% CI: 1.61 to 2.51), serum NFL levels (SMD: 1.57, 95% CI: 1.29 to 1.85), ferritin levels (SMD: 0.66, 95% CI: 0.50 to 0.83), and uric acid levels (SMD: -0.72; 95% CI: -0.98 to -0.46).

DISCUSSION: This umbrella review offers new insights into the epidemiological evidence regarding the associations between environmental factors, biomarkers, and ALS susceptibility. We aim for our study to enhance the understanding of the roles of environmental factors and biomarkers in ALS occurrence and assist clinicians in developing evidence-based prevention and control strategies.}, } @article {pmid40584588, year = {2025}, author = {Odenbring, Y and Lindén, L}, title = {Reaching everyone: school nurses' experiences of including refugee and migrant students in the extended school-based HPV vaccination programme in Sweden.}, journal = {Journal of research in nursing : JRN}, volume = {30}, number = {4}, pages = {359-370}, pmid = {40584588}, issn = {1744-988X}, abstract = {BACKGROUND: In Sweden, providing a free-of-charge national child vaccination programme is part of national public health work to promote health and prevent illness. Yet Sweden is no exception when it comes to systematic societal inequality. Research worldwide has shown that childhood vaccination coverage is lower among refugee and migrant children than among non-migrant children.

AIM: The aim of this study is to explore how school nurses working in one of Sweden's largest regions reflect on their strategies and experiences of including children with refugee or migrant backgrounds in the school-based extended HPV vaccination programme.

METHODS: The study draws from semi-structured individual interviews with 21 school nurses. Analysis drew on Braun et al's (2011) four contextual dimensions: 1) the situated context; 2) the professional context; 3) material contexts; 4) external contexts. Thematic analysis was undertaken (Braun and Clarke, 2006; Clarke and Braun, 2013).

RESULTS: Three themes were identified: 1) social and economic deprivation; 2) ways of communicating; 3) gratitude. According to the school nurses, mapping the families' social situation and building trusting relationships are essential. Providing written information about the vaccination in diverse languages and/or involving an interpreter are also important strategies to reach refugee and migrant parents. Despite the families' often marginalised position, the children and their parents favour the HPV vaccination, which could be interpreted as vaccine confidence.

CONCLUSIONS: Meeting the needs of children and families with refugee or migrant backgrounds requires that school nursing practice take a holistic perspective. The study contributes new insights regarding these issues.}, } @article {pmid40584972, year = {2025}, author = {Khandelwal, N and Sanchirico, M and Ajibade, A and Munshi, K and Vu, M and Engel-Nitz, N and Steiger, C and Anderson, AJ and Karam, C}, title = {Characteristics, Treatment Patterns, Healthcare Resource Utilization, and Costs Among Patients with Multifocal Motor Neuropathy: A US Claims Database Cohort Study.}, journal = {Journal of health economics and outcomes research}, volume = {12}, number = {1}, pages = {261-268}, pmid = {40584972}, issn = {2327-2236}, abstract = {Background: Multifocal motor neuropathy (MMN) is a rare, slowly progressive nerve disorder characterized by asymmetric limb weakness without sensory abnormalities. MMN is often misdiagnosed due to similarities in clinical symptoms with conditions including amyotrophic lateral sclerosis (ALS), making diagnosis and treatment challenging. Objectives: This study assessed patient characteristics, treatment patterns, and the economic burden of MMN in the United States. Methods: Using the Optum Research Database, this retrospective analysis included patients with ≥1 diagnostic or nondiagnostic medical claim with an MMN diagnosis code between 2016 and 2020 (date of first diagnosis-related claim =index date), and continuous enrollment for 12 months preindex and postindex. Patients with MMN within this group were identified using more specific criteria; ≥2 MMN nondiagnostic claims separated by ≥30 days, with no subsequent ALS diagnosis during follow-up. All patients who did not meet these criteria were included in the MMN-mimic cohort. Outcomes included treatment patterns, differential diagnoses, healthcare utilization, and costs. Results: Of 904 patients identified, 37% had MMN and 63% had an MMN-mimic condition. Patients with MMN were significantly younger than patients in the MMN-mimic cohort (mean, 64.9 vs 66.8 years; P = .047). At preindex, significantly more patients with MMN received MMN-related medications than patients in the MMN-mimic cohort (20.5% vs 9.0%, respectively; P < .001). Intravenous immunoglobulin (IVIG) was the most common MMN-related medication. At postindex, more patients with MMN used IVIG (28.0%) compared with preindex (16.4%). In the 12 months preindex and postindex, >70% of patients had ≥1 differential diagnosis. The MMN cohort had higher all-cause total costs than the MMN-mimic cohort (mean preindex, 58 974 v s 48 132, respectively [P = .100]; mean postindex, 74 187 v s 50 652 [P = .002]); they also had significantly higher MMN-related healthcare costs (mean preindex, 23 625 v s 12 890 [P = .011]; mean postindex, 39 521 v s 11 938 [P < .001]). Discussion: This study showed that most patients with initial MMN diagnoses had an alternative disorder after subsequent evaluation/follow-up, and patients with MMN incurred higher costs. Many patients with MMN did not receive IVIG, suggesting that undertreatment or misattribution of diagnosis codes are common. Conclusions: Further education is needed regarding accurate diagnosis of MMN to ensure patient access to guideline-recommended treatment.}, } @article {pmid40585089, year = {2025}, author = {Shen, T and Spencer, BE and Kuksa, PP and Van Deerlin, VM and Phatnani, H and , and Lee, EB and McMillan, CT}, title = {Unraveling temporal dynamics of the post-mortem transcriptome in amyotrophic lateral sclerosis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.06.10.25329061}, pmid = {40585089}, support = {P01 AG066597/AG/NIA NIH HHS/United States ; }, abstract = {Human tissue transcriptomics are crucial for understanding neurodegeneration but limited by cross-sectional post-mortem sampling, which represents end-stage disease. Subtype and Stage Inference (SuStaIn) modeling addresses these limitations by inferring temporal gene expression dynamics while also identifying potential transcriptomic subtypes. Applied to bulk RNA-seq data from post-mortem lumbar spinal cord in amyotrophic lateral sclerosis (ALS), SuStaIn unraveled that more advanced transcriptomic stages were associated with higher microglia and reduced neuron proportions, which mapped onto two ALS subtypes: Immune/Apoptosis/Proteostasis subtype with early immune/apoptotic/proteostatic dysregulation, worse prognosis and higher microglia proportions; Synapse/RNA-Metabolism subtype with early synaptic/RNA-processing deficits, lower male prevalence and neuron loss. Lumbar patterns demonstrated high concordance with cervical patterns and a strong correlation in staging across regional tissues. These findings revealed subtype-specific mechanisms underlying ALS heterogeneities, prioritized key genes driving subtyping/staging as potential therapeutic targets. More broadly, we established a framework to decode temporal dynamics from traditionally constrained post-mortem transcriptomic studies.}, } @article {pmid40585174, year = {2025}, author = {Cassel, R and Lorenc, F and Bombardier, A and DE Tapia, C and Dieterle, S and Gouveia Roque, C and Jackson, CA and Stuart-Lopez, G and Rouaux, C and Guillot, SJ and Birling, MC and Kessler, P and Grassano, M and Traynor, B and Chio, A and Roy, R and Shorter, J and Waldron, FM and Gregory, JM and Phatnani, H and Dupuis, L and Megat, S}, title = {FUS Mislocalization Rewires a Cortical Gene Network to Drive Cognitive and Behavioral Impairment in ALS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40585174}, support = {ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Cognitive and behavioral impairment affects up to half of individuals with amyotrophic lateral sclerosis (ALS), but their molecular origin remains unresolved. Here, we identify mislocalization of the RNA-binding protein FUS in cortical neurons as a defining feature in ALS patients with cognitive impairment (ALS-ci). Selective mislocalization of FUS in adult cortical projection neurons in mice is sufficient to trigger ALS-ci- and ALS with behavioral impairment (ALS-bi)-like phenotypes, including deficits in sociability, and neurodegeneration. Single-nucleus transcriptomics reveal a conserved FUS-dependent gene network downregulated in these mice and ALS-ci patients. This regulon is enriched for ALS genetic risk factors and newly implicates FBXO16 in ALS-bi. Carriers of protein-truncating FBXO16 variants display behavioral abnormalities, frontotemporal atrophy, and increased levels of dementia-linked biomarkers. These findings define a neuron-intrinsic mechanism for cognitive and behavioral dysfunction in ALS and nominate FUS mislocalization and its downstream gene network as therapeutic targets.}, } @article {pmid40585304, year = {2025}, author = {Cesaro, G and Baruzzo, G and Tussardi, G and Di Camillo, B}, title = {Differential cellular communication inference framework for large-scale single-cell RNA-sequencing data.}, journal = {NAR genomics and bioinformatics}, volume = {7}, number = {2}, pages = {lqaf084}, pmid = {40585304}, issn = {2631-9268}, mesh = {*Single-Cell Analysis/methods ; *Cell Communication/genetics ; Humans ; *Sequence Analysis, RNA/methods ; *Transcriptome ; *Software ; Gene Expression Profiling/methods ; Computational Biology/methods ; }, abstract = {Single-cell transcriptomics data have been widely used to characterize biological systems, particularly in studying cell-cell communication, which plays a significant role in many biological processes. Despite the availability of various computational tools for inferring cellular communication, quantifying variations across different experimental conditions at both intercellular and intracellular levels remains challenging. Moreover, available methods are in general limited in terms of flexibility in analyzing different experimental designs and the ability to visualize results in an easily interpretable way. Here, we present a generalizable computational framework designed to infer and support differential cellular communication analysis across two experimental conditions from large-scale single-cell transcriptomics data. The scSeqCommDiff tool employs a statistical and network-based computational approach for characterizing altered cellular cross-talk in a fast and memory-efficient way. The framework is complemented with CClens, a user-friendly Shiny app to facilitate interactive analysis of inferred cell-cell communication. Validation through spatial transcriptomics data, comparison with other tools, and application to large-scale datasets (including a cell atlas) confirms the reliability, scalability, and efficiency of the framework. Moreover, the application to a single-nucleus transcriptomics dataset shows the validity and ability of the proposed workflow to support and unravel alterations in cell-cell interactions among patients with amyotrophic lateral sclerosis and healthy subjects.}, } @article {pmid40585363, year = {2025}, author = {Wang, C and Xu, J and Pan, K and Xu, Y and Yu, J}, title = {Relationship between endocrine disruptors and neurodegenerative diseases: Systematic review and meta-analysis.}, journal = {iScience}, volume = {28}, number = {7}, pages = {112779}, pmid = {40585363}, issn = {2589-0042}, abstract = {We conducted a meta-analysis to evaluate relevant literature published between January 2003 and December 2023 in order to provide updated epidemiological evidence on the relationship between endocrine-disrupting chemicals (EDCs) and neurodegenerative diseases (NDs). A systematic search of related studies was conducted in PubMed, Web of Science, and Embase. A total of 21 studies were included, with 286,610 subjects for meta-analysis. Analysis revealed that exposure to polychlorinated biphenyls (odds ratio [OR] = 1.08, 95% confidence interval [CI]: 1.03-1.14) posed a risk for NDs, while organochlorine pesticide (OR = 1.11, 95% CI: 1.05-1.17) exposure exhibited a positive correlation with ND risk. Subgroup analysis by disease indicated a positive association between EDC exposure and Alzheimer's disease (OR = 1.03, 95% CI: 1.00-1.07) and amyotrophic lateral sclerosis (OR = 1.02, 95% CI: 1.01-1.03) risk. Our meta-analysis indicates that human exposure to EDCs has adverse effects on NDs.}, } @article {pmid40585370, year = {2025}, author = {Maurel, C and Scherer, NM and Luu, L and Radford, RA and Hogan, A and Merjane, J and Vidal-Itriago, A and Don, EK and Chapman, T and Cull, S and Vourc'h, P and Lisowski, L and Lee, A and Chung, RS and Morsch, M}, title = {Critical impact of lysine 136 in TDP-43 phase separation, compartmentalization, and aggregation in living vertebrates.}, journal = {iScience}, volume = {28}, number = {7}, pages = {112761}, pmid = {40585370}, issn = {2589-0042}, support = {R21 DA056320/DA/NIDA NIH HHS/United States ; }, abstract = {TDP-43 is a nuclear RNA-binding protein that undergoes liquid-liquid phase separation (LLPS) and forms insoluble aggregates in neurodegenerative diseases. By studying TDP-43 in living vertebrates, we confirmed that TDP-43 undergoes LLPS and forms dynamic biomolecular condensates in spinal motor neurons. We validated in vivo that interfering with the lysine residue at position 136 altered the phase separation behavior of TDP-43 by reducing cytoplasmic mislocalization and aggregation. These alterations were post-translational modification (PTM) independent, highlighting that residue 136 is a key structural regulator of TDP-43 function. We further established an adeno-associated virus (AAV)-mediated expression approach in mice that confirmed altered nuclear condensation characteristics of lysine-modified TDP-43. These assessments exposed the formation of dynamic nuclear TDP-43 condensates and emphasize the important role of lysine 136 in maintaining TDP-43 function. Altogether, we establish lysine 136 as a molecular regulator for phase separation and TDP-43 aggregation in amyotrophic lateral sclerosis (ALS) in two in vivo platforms.}, } @article {pmid40585388, year = {2025}, author = {Wang, X and Sun, Y and Han, C and Meng, X and Wen, K and Wu, J and Min, P and Li, K and Zhang, Y}, title = {Research trends of piezoelectric materials in neurodegenerative disease applications.}, journal = {Bioactive materials}, volume = {52}, number = {}, pages = {366-392}, pmid = {40585388}, issn = {2452-199X}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and huntington's disease, pose significant threats to human health, with current treatment options remaining limited. Piezoelectric materials, known for their ability to convert mechanical energy into electrical signals at the nanoscale, hold great promise in the diagnosis and treatment of neurodegenerative diseases due to their excellent electromechanical properties, environmental stability, and sensitivity. This review systematically outlines the working principles and classifications of piezoelectric materials. Subsequently, the recent advances in piezoelectric materials and their applications in the diagnosis and treatment of neurodegenerative diseases are highlighted. Finally, the challenges and perspectives regarding the development of future piezoelectric materials are discussed. This review aims to provide a comprehensive reference for the further application of piezoelectric materials in neurodegenerative diseases.}, } @article {pmid40585720, year = {2025}, author = {Kato, T and Yorimoto, K and Ariake, Y and Shimizu-Motohashi, Y and Hara, T}, title = {Acute Respiratory Distress Syndrome Exacerbated by Inappropriate Use of Mechanical Insufflation-Exsufflation Following Infection in a Patient With Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Cureus}, volume = {17}, number = {5}, pages = {e84991}, pmid = {40585720}, issn = {2168-8184}, abstract = {Mechanical insufflation-exsufflation (MI-E) is widely used to assist airway secretion clearance in patients with neuromuscular disorders such as amyotrophic lateral sclerosis (ALS). While MI-E is generally considered safe when used intermittently for cough augmentation, its prolonged and unsupervised use as a substitute for invasive ventilation is discouraged by current clinical guidelines, including those issued by the American College of Chest Physicians and the American Academy of Neurology. We report the case of a 53-year-old man with advanced ALS, diagnosed approximately 10 years earlier, who developed acute respiratory distress syndrome (ARDS) exacerbated by inappropriate use of MI-E following a recent respiratory infection. The patient had previously relied on tracheostomy invasive ventilation (TIV) but chose to suspend its use, instead employing MI-E continuously for 62 hours (28,234 cycles), based on prior positive experiences and personal preference. Upon hospital admission, the patient was diagnosed with mild ARDS, bacterial pneumonia, and influenza B infection. Although the respiratory infection was likely the primary cause of deterioration, MI-E-related pressure changes may have exacerbated pulmonary injury, particularly in the context of acute infection. Rapid improvement in gas exchange and imaging findings within 48 hours of MI-E discontinuation further supports this hypothesis. We discuss possible mechanisms linking excessive MI-E usage to lung injury, including barotrauma and negative pressure pulmonary edema. We also emphasize the importance of clearly defined device indications, structured caregiver education, and regular clinical supervision in home respiratory care. To our knowledge, this may be the first reported case of ARDS potentially resulting from the combined effects of infection and inappropriate MI-E application, highlighting the need for multidisciplinary coordination and proper device supervision in managing advanced neuromuscular respiratory failure at home.}, } @article {pmid40585812, year = {2025}, author = {Barbier, M and Gareau, T and Camuzat, A and Guillaud-Bataille, M and Boluda, S and Clot, F and Araktingi, L and Borroni, B and van der Zee, J and Ghidoni, R and Bellini, S and Galimberti, D and Rossi, G and Nacmias, B and De la Casa-Fages, B and Pastor, P and , and Latouche, M and le Guern, E and Durr, A and Laquerrière, A and Moccia, R and Seilhean, D and Alvarez, V and Le Ber, I}, title = {Analysis of short tandem repeats linked to polyglutamine diseases from whole-genome sequencing reveals intermediate alleles of HTT associated with an early disease onset in C9orf72 carriers.}, journal = {Brain communications}, volume = {7}, number = {3}, pages = {fcaf220}, pmid = {40585812}, issn = {2632-1297}, abstract = {Carriers of the GGGGCC pathogenic expansion in C9orf72 can develop symptoms of frontotemporal dementia and/or amyotrophic lateral sclerosis, with variable and unpredictable ages at onset. Previous studies aiming to decipher the genetic bases of the clinical variability in this rare disease included bi-allelic polymorphisms, excluding short tandem repeats. Whole-genome sequencing data of 195 C9orf72 patients were used to consider all short tandem repeats linked to polyglutamine disorders as potential genetic modifiers given the existing links between C9orf72 and polyglutamine diseases. Intermediate alleles of HTT encoding huntingtin were associated with an earlier age at onset among C9orf72 carriers in the discovery cohort (n = 195, P = 0.0003) and in a European replication cohort (n = 145, P = 0.006). In the merged cohort (n = 340), the average difference of age at disease onset was 9.42 ± 2.14 years (P = 1.3 × 10[e-5]) between carriers and non-carriers of HTT-intermediate alleles. Neuropathology of one C9orf72 case heterozygous for HTT-intermediate allele showed typical TDP-43 inclusions related to the C9orf72 pathogenic expansion and was negative for polyglutamine inclusion. No somatic expansion of HTT was detected in blood of all C9orf72exp/HTT-intermediate carriers. If this study reinforces potential biological links between huntingtin and C9orf72 that remain to be explored, the results also illustrate the interest of considering short tandem repeats from whole-genome data in association studies which paves the way to more exhaustive approaches to explore the trait heritability due to short-tandem-repeats still hidden in the genome.}, } @article {pmid40585924, year = {2025}, author = {Almuhanna, Z and Bohulaigah, Z and Alkhawaja, H and Aljafar, H}, title = {Posterior trachea wall erosion: a case report and literature review of a catastrophic complication of cuff overinflation.}, journal = {Journal of surgical case reports}, volume = {2025}, number = {6}, pages = {rjaf361}, pmid = {40585924}, issn = {2042-8812}, abstract = {Tracheostomy complications range from early to late complications. One of the late complications can be seen with cuff over-inflation that exceeds tracheal capillary perfusion pressure, which leads to segmental tracheomalacia and rarely, tracheal wall erosion. A 40-year-old male with amyotrophic lateral sclerosis and mechanical ventilation dependence was found to have a persistent ventilatory leak. Endoscopic examination revealed a large posterior tracheal wall erosion that was confirmed by computed tomography. Conservative management by the placement of a long endotracheal tube through the tracheostoma was chosen. Cuff pressure over 20-25 cm H2O, which exceeds tracheal capillary perfusion pressure, increases the risk of tracheal mucosal ischemia. Preventive strategies such as the use of pressure-limiting devices and careful tube selection, should be implemented. Regular implementation of preventive measures along with early identification are essential for avoiding tracheostomy tube complications. This case demonstrates the importance of strict cuff pressure maintenance to avoid tracheal wall injuries.}, } @article {pmid40586110, year = {2025}, author = {Appukuttan, S and Grapperon, AM and El Mendili, MM and Dary, H and Guye, M and Verschueren, A and Ranjeva, JP and Attarian, S and Zaaraoui, W and Gilson, M}, title = {Evaluating machine learning pipelines for multimodal neuroimaging in small cohorts: an ALS case study.}, journal = {Frontiers in neuroinformatics}, volume = {19}, number = {}, pages = {1568116}, pmid = {40586110}, issn = {1662-5196}, abstract = {Advancements in machine learning hold great promise for the analysis of multimodal neuroimaging data. They can help identify biomarkers and improve diagnosis for various neurological disorders. However, the application of such techniques for rare and heterogeneous diseases remains challenging due to small-cohorts available for acquiring data. Efforts are therefore commonly directed toward improving the classification models, in an effort to optimize outcomes given the limited data. In this study, we systematically evaluated the impact of various machine learning pipeline configurations, including scaling methods, feature selection, dimensionality reduction, and hyperparameter optimization. The efficacy of such components in the pipeline was evaluated on classification performance using multimodal MRI data from a cohort of 16 ALS patients and 14 healthy controls. Our findings reveal that, while certain pipeline components, such as subject-wise feature normalization, help improve classification outcomes, the overall influence of pipeline refinements on performance is modest. Feature selection and dimensionality reduction steps were found to have limited utility, and the choice of hyperparameter optimization strategies produced only marginal gains. Our results suggest that, for small-cohort studies, the emphasis should shift from extensive tuning of these pipelines to addressing data-related limitations, such as progressively expanding cohort size, integrating additional modalities, and maximizing the information extracted from existing datasets. This study provides a methodological framework to guide future research and emphasizes the need for dataset enrichment to improve clinical utility.}, } @article {pmid40586230, year = {2026}, author = {Knudsen, LF and Nikolajevic-Pujic, S}, title = {Prevalence and predictors of prolonged grief disorder, anxiety and depression in bereaved ALS family caregivers: a national survey of distress and support needs after bereavement.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {142-153}, doi = {10.1080/21678421.2025.2523948}, pmid = {40586230}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; *Caregivers/psychology ; Middle Aged ; *Amyotrophic Lateral Sclerosis/psychology/epidemiology/nursing ; Prevalence ; Cross-Sectional Studies ; *Depression/epidemiology/psychology ; *Bereavement ; *Anxiety/epidemiology/psychology ; Adult ; Aged ; *Grief ; Denmark/epidemiology ; Adaptation, Psychological ; Surveys and Questionnaires ; Social Support ; }, abstract = {OBJECTIVE: The distress of amyotrophic lateral sclerosis (ALS) family caregivers may not end after bereavement. Yet, the prevalence of psychological distress and support needs after bereavement are unclear. This study examined the prevalence and predictors of prolonged grief disorder (PGD), anxiety and depression, and level of needed and received support after bereavement.

METHODS: We conducted a cross-sectional online survey of a national cohort of bereaved ALS family caregivers recruited through the National Rehabilitation Center for Neuromuscular Diseases in Denmark. Questions included disease-related factors, care involvement, burden (Zarit Burden Inventory), loneliness (Three-Item Loneliness Scale), coping style (CSQ-37), PGD (PG-13), anxiety/depression (HADS), time since bereavement, needed and received support during and after ALS.

RESULTS: A total of 162 caregivers (46.4%) with a median of 24 months since bereavement responded. PGD prevalence was 5.6%, anxiety 22.2%, depression 16.0%. PGD was predicted by more caregiving hours. Anxiety and depression by high emotional coping and not receiving the needed information post bereavement and, anxiety, also by a more recent bereavement. Half of the participants had needed information about ALS after bereavement with 17.4% receiving it to a small degree and 32.3% not at all. Nearly 80% had needed emotional support with 31.0% receiving it to a small degree/not at all.

CONCLUSIONS: Caregivers may be distressed for a long time. Healthcare professionals should offer information about ALS to bereaved caregivers and screen caregivers for PGD, anxiety, depression, and coping style to offer targeted interventions post bereavement. Future longitudinal studies should investigate predictors for post-loss psychological distress including pre-loss anxiety/depression and formal care.}, } @article {pmid40587112, year = {2025}, author = {Regev, S and Talmy, T and Gelikas, S and Mitchnik, IY}, title = {Impact of ongoing clinical experience on advanced life support provider performance in multicasualty simulations.}, journal = {The journal of trauma and acute care surgery}, volume = {99}, number = {3S Suppl 1}, pages = {S32-S38}, doi = {10.1097/TA.0000000000004697}, pmid = {40587112}, issn = {2163-0763}, mesh = {Humans ; *Clinical Competence ; Israel ; *Advanced Trauma Life Support Care/standards ; *Simulation Training ; Male ; Female ; *Military Medicine/education ; Military Personnel ; Adult ; }, abstract = {BACKGROUND: Effective response to multicasualty events may depend on the performance of advanced life support (ALS) providers. This study examines the relationship between ALS training, clinical skill maintenance through a Competency Maintenance Program, and provider performance in multicasualty event simulations.

METHODS: Military medical teams, led by Israel Defense Forces (IDF) Military Trauma Life Support (MTLS)-trained providers (physicians or paramedics), participated in a multicasualty scenario simulation. Performance was assessed using a task checklist and the Trauma Non-Technical Skills scale. Data were collected on MTLS training and participation in the Competency Maintenance Program, which mandates ALS providers to complete hospital and ambulance shifts for continuous skill maintenance. Regression analyses were conducted to evaluate the impact of these variables on simulation performance.

RESULTS: The study included 25 teams, the majority of which were led by paramedics (78%). Clinical experience in hospitals and ambulance services showed moderate correlations with simulation performance (R = 0.562, p = 0.009, and R = 0.664, p = 0.003, respectively). However, ALS provider type (physician vs. paramedic) and MTLS course performance did not correlate with simulation performance (R = 0.009, p = 0.952, and R = 0.390, p = 0.054, respectively). Simulation performance was also correlated with the teams' nontechnical skills (R = 0.550, p < 0.001, β = 0.393, p = 0.014), which functioned as both an independent factor and a partial mediator in the relationship between ALS providers' attributes and simulation performance (R2 = 0.725, R2 change = 0.475). Specifically, clinical experience in hospitals was directly linked to performance, whereas ambulance experience was indirectly associated with performance through its impact on nontechnical skills.

CONCLUSION: Clinical skill maintenance through hospital and ambulance experience may enhance ALS providers' performance in multicasualty event simulations. These findings suggest that structured skill maintenance programs could better prepare teams for managing complex scenarios.

LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.}, } @article {pmid40587259, year = {2025}, author = {Hattori, Y and Kumashiro, M and Kumeta, H and Kyo, T and Kawagoe, S and Matsusaki, M and Saio, T}, title = {A Disease-Associated Mutation Impedes PPIA through Allosteric Dynamics Modulation.}, journal = {Biochemistry}, volume = {64}, number = {14}, pages = {2971-2975}, pmid = {40587259}, issn = {1520-4995}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/enzymology/metabolism ; Allosteric Regulation ; *Peptidylprolyl Isomerase/genetics/chemistry/metabolism ; *Mutation ; Kinetics ; NIMA-Interacting Peptidylprolyl Isomerase ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration. Peptidylprolyl cis-trans isomerase A (PPIA) is a molecular chaperone involved in protein folding, and its dysfunction has been linked to ALS pathogenesis, as proline is recognized as a key residue for maintaining proper folding of ALS-related proteins. A recent study identified a K76E mutation in PPIA in sporadic ALS patients, but its effect on protein function and structure remain unclear. In this study, we used biochemical and biophysical techniques to investigate the structural and functional consequences of the K76E mutation. Our results show that K76E significantly reduces enzyme activity without affecting structure, monodispersity, or substrate recognition. Significant effects of K76E mutation were identified by relaxation dispersion NMR experiments, showing that K76E disrupts key protein dynamics and alters an allosteric network essential for isomerase activity. Corroborated by theoretical kinetic analysis, these dynamics data, revealing the exchange process for K76E to be approximately 1 order of magnitude slower than that of the wild type, explain the reduced cis-trans isomerase activity of the K76E mutant. These findings suggest that the pathogenic effect of K76E arises primarily from impaired protein dynamics rather than direct structural disruption. Our study provides new insights into the molecular mechanisms underlying ALS-associated mutations and their impact on protein function.}, } @article {pmid40587877, year = {2025}, author = {Moalefshahri, R and Hashemy, SI and Hosseini, H and Sahebkar, A}, title = {Neuroprotective effect of Kaempferol through modulation of autophagy.}, journal = {Nutritional neuroscience}, volume = {28}, number = {12}, pages = {1463-1479}, doi = {10.1080/1028415X.2025.2524702}, pmid = {40587877}, issn = {1476-8305}, mesh = {*Kaempferols/pharmacology ; *Autophagy/drug effects ; *Neuroprotective Agents/pharmacology ; Humans ; Animals ; }, abstract = {Objective: Autophagy is a critical cellular mechanism that ensures the breakdown of damaged or unnecessary components. This process helps ensure cellular health by maintaining cellular balance, protecting cells from stress, and providing an alternative energy source during metabolic stress. Disruptions in autophagy have been linked to neurological disorders.Method: In this review, the neuroprotective effects of Kaempferol through autophagy modulation are elaborated. Methods: An electronic search in scientific databases was performed to find relevant studies exploring the neuroprotective effects of kaempferol mediated via modulation of autophagy.Results: Kaempferol, a natural flavonoid found in fruits, vegetables, and plant-based products like tea, has been shown to demonstrate a variety of health-promoting properties, including antimicrobial, antioxidant, and antiinflammatory effects. This review summarizes the current understanding of how Kaempferol modulates autophagy and discusses its potential impact on various neurological disorders, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ischemic stroke, and depression. Studies increasingly indicate that Kaempferol could be a vital factor in maintaining neural health by influencing autophagy mechanisms.Conclusion: Numerous studies have established Kaempferol's neuroprotective potential through autophagy regulation, which suggests opprotunities for potential therapeutic applications.}, } @article {pmid40589142, year = {2025}, author = {Tiwari, R and Paswan, A and Tiwari, G and Reddy, VJS and Posa, MK}, title = {Perspectives on Fecal Microbiota Transplantation: Uses and Modes of Administration.}, journal = {Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology}, volume = {41}, number = {}, pages = {e20250014}, doi = {10.62958/j.cjap.2025.014}, pmid = {40589142}, issn = {1000-6834}, mesh = {*Fecal Microbiota Transplantation/methods ; Humans ; *Gastrointestinal Microbiome ; Feces/microbiology ; *Nervous System Diseases/therapy ; }, abstract = {Fecal microbiota Transplantation (FMT), often referred to as stool transplantation, fecal transfusion, and fecal bacteria therapy, is considered one of the most medical innovations of the 20th century. Fecal microbiota Transplantation entails filtering and dilution of a healthy donor's feces before injecting it into the recipient's digestive system. In China, it was first administered orally in the fourth century for diarrhea and food poisoning under the name "Yellow Soup." It has recently been widely employed in a variety of clinical settings, including cases of Clostridium difficile infection that are recurring and resistant. By replacing the unhealthy intestinal microbiota with a healthy bacterial community, the FMT treatment aims to enhance the intestinal flora. It also looks at neurological conditions where alterations in gut microbiota are prevalent. We have discussed FMT in the context of its use in conditions affecting the nerve system, such as neurological and other conditions (multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, epilepsy, Amyotrophic lateral sclerosis, Tourette syndrome, neuropathic pain, Huntington's diseases, etc.), as well as the role of gut microbiota in many neurological disorders.}, } @article {pmid40589421, year = {2025}, author = {Ravera, F and Efeoglu, E and Byrne, HJ}, title = {Monitoring the kinetic evolution of mesenchymal stem cell differentiation using Raman microspectroscopy.}, journal = {The Analyst}, volume = {150}, number = {15}, pages = {3445-3456}, doi = {10.1039/d4an01509f}, pmid = {40589421}, issn = {1364-5528}, mesh = {*Spectrum Analysis, Raman/methods ; *Mesenchymal Stem Cells/cytology ; *Cell Differentiation ; Kinetics ; Animals ; Collagen/chemistry ; Chondrocytes/cytology ; Hydrogels/chemistry ; Least-Squares Analysis ; Cells, Cultured ; Chondrogenesis ; Humans ; }, abstract = {Raman microspectroscopy (RMS) offers a powerful, non-destructive approach for in situ monitoring of dynamic biochemical processes within cells. However, the ability to reliably data-mine the spectroscopic signatures and their evolution and extract meaningful information can be challenging. Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) regression analysis is a powerful chemometric technique that can potentially address this challenge by deconvoluting the spectra into individual component spectra, each representing a specific biochemical species, and regressing the solutions against kinetic constraints. In this study, MCR-ALS analysis was performed on spectral data of differentiation process of mesenchymal stem cells into chondrocytes, carried out on two different substrates, collagen 3-dimensional hydrogel and the conventional 2-dimensional culture model at time intervals of 1-7, 14, 21 days. The kinetic evolution of the chondrogenesis was modelled according to a phenomenological rate equation model, in an attempt to describe the biochemical evolution of the cell composition within the process. Moreover, the ability of the algorithm to faithfully extract the correct reaction rates and spectral profiles has been explored. The results indicated that the differentiation process originates in the nucleolar regions, subsequently extending to the nuclear and cytoplasmic compartments and corroborated a more rapid differentiation rate in cell cultures grown on 3D collagen hydrogels compared to 2D substrates. The combination of Raman microspectroscopy and MCR-ALS offers a powerful approach for elucidating the complex mechanisms underlying chondrogenesis and developing innovative strategies for regenerative medicine.}, } @article {pmid40589786, year = {2025}, author = {Arreola-Aldape, CA and Moran-Guerrero, JA and Pons-Monnier, GK and Flores-Salcido, RE and Martinez-Ledesma, E and Ruiz-Manriquez, LM and Razo-Alvarez, KR and Mares-Custodio, D and Avalos-Montes, PJ and Figueroa-Sanchez, JA and Ortiz-Lopez, R and Martínez, HR and Cuevas-Diaz Duran, R}, title = {A systematic review and functional in-silico analysis of genes and variants associated with amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1598336}, pmid = {40589786}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by the deterioration of upper and lower motor neurons. Affected patients experience progressive muscle weakness, including difficulty in swallowing and breathing; being respiratory failure the main cause of death. However, there is considerable phenotypic heterogeneity, and its diagnosis is based on clinical criteria. Moreover, most ALS cases remain unexplained, suggesting a complex genetic background.

METHODS: To better understand the molecular mechanisms underlying ALS, we comprehensively analyzed, filtered and classified genes from 4,293 abstracts retrieved from PubMed, 7,343 variants from ClinVar, and 33 study accessions from GWAS catalog. To address the importance of ALS-associated genes and variants, we performed diverse bioinformatic analyses, including gene set enrichment, drug-gene interactions, and differential gene expression analysis using public databases.

RESULTS: Our analysis yielded a catalog of 300 genes with 479 ALS-associated variants. Most of these genes and variants are found in coding regions and their proteins are allocated to the cytoplasm and the nucleus, underscoring the relevance of toxic protein aggregates. Moreover, protein-coding genes enriched ALS-specific pathways, for example spasticity, dysarthria and dyspnea. ALS-associated genes are targeted by commonly used drugs, including Riluzole and Edaravone, and by the recently approved antisense oligonucleotide therapy (Tofersen). Moreover, we observed transcriptional dysregulation of ALS-associated genes in peripheral blood mononuclear cell and postmortem cortex samples.

CONCLUSION: Overall, this ALS catalog can serve as a foundational tool for advancing early diagnosis, identifying biomarkers, and developing personalized therapeutic strategies.}, } @article {pmid40589992, year = {2025}, author = {Yue, Y and Chang, N and Shi, Z}, title = {Nonlinear characteristics of gait signals in neurodegenerative diseases.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1607273}, pmid = {40589992}, issn = {1664-2295}, abstract = {Based on the asymmetric characteristics of left and right movements in patients with neurodegenerative diseases and their inherent coupling relationships, as well as the inevitable internal connection between them according to the principles of mechanical kinematics, and a processing method for the ratio of gait signals to left and right limb data is proposed. Using gait time series data collected from left and right limbs via pressure-sensitive insoles, a comparison was conducted among patients with Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), and a healthy control group (Ctrl) in terms of the average, standard deviation, and coefficient of variation of the left and right sequences, as well as the ratios between them. It was discovered that there exists a close correlation between the ratios of left to right sequences and the actual standard deviation and coefficient of variation of these sequences. These ratios can be utilized for identifying the categories of PD, ALS, and HD patients. After using a median filter (n = 3) to filter four sets of stride ratio data (Ctr1, A1s, PD, and HD), it was found that the data before filtering generally showed significant fluctuations, with many peaks and valleys, indicating that the original data may contain a lot of noise or outliers. In contrast, the filtered data showed relatively smaller fluctuations and a smoother curve, indicating that the filtering process effectively reduced noise in the data and enhanced its stability. The raw data distribution for the left and right limbs of patients with PD, ALS, HD, and the Ctrl was relatively large, posing certain difficulties in analyzing the patients' diseases. The use of the ratio of left to right data effectively improves the discreteness of the data. The ranking of CO complexity features from highest to lowest is ALS, HD, PD, and Ctrl. The ranking of sample entropy features from largest to smallest is ALS, HD, PD, and Ctrl. The ranking of wavelet coefficient features from largest to smallest is ALS, PD, HD, and Ctrl.}, } @article {pmid40590340, year = {2025}, author = {Takahashi, F and Genge, A and Hirai, M and Selness, D and Todorovic, V and Wamil, A and Sasson, N and Apple, S and Ushirogawa, Y and , }, title = {Analysis of Long-Term Function and Survival of Edaravone Oral Suspension-Treated Patients With Amyotrophic Lateral Sclerosis Using PRO-ACT Data as Historical Placebo Controls.}, journal = {Muscle & nerve}, volume = {72}, number = {4}, pages = {586-596}, pmid = {40590340}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/mortality/physiopathology ; *Edaravone/administration & dosage/therapeutic use ; Male ; Female ; Middle Aged ; Administration, Oral ; Aged ; *Free Radical Scavengers/administration & dosage/therapeutic use ; Treatment Outcome ; *Neuroprotective Agents/administration & dosage ; Suspensions ; Adult ; }, abstract = {INTRODUCTION/AIMS: On/Off dosing of intravenous (IV) edaravone and edaravone oral suspension was US Food and Drug Administration (FDA)-approved for Amyotrophic Lateral Sclerosis (ALS) treatment. Placebo-controlled trials showed that IV edaravone slows the rate of physical functional decline in patients with ALS. Here, the impact of edaravone oral suspension on function and survival was assessed.

METHODS: Edaravone oral suspension was investigated in clinical trials MT-1186-A01/A02/A03/A04. Patients from Studies MT-1186-A02/A04 (prespecified analysis) and Studies MT-1186-A01/A02/A03/A04 (post hoc analysis) were propensity score matched 1:1 on 10 baseline variables with historical Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) placebo patients (not receiving active investigational treatment in their trials) to assess the impact of edaravone oral suspension on function and survival.

RESULTS: In the prespecified analysis, 78 edaravone oral suspension-treated patients from Studies MT-1186-A02/A04 demonstrated a survival benefit versus 78 matched PRO-ACT placebo patients (p = 0.005). Baseline risk-adjusted hazard ratio showed an 84% decreased risk of death in edaravone oral suspension versus PRO-ACT placebo patients (p = 0.005). ALS Functional Rating Scale-Revised (ALSFRS-R) total score change from baseline at Week 48 was -8.4 points for edaravone oral suspension versus -14.1 points for PRO-ACT placebo patients (p < 0.001). In the post hoc analysis, patients from Studies MT-1186-A01/A02/A03/A04 (n = 210) propensity score matched to PRO-ACT placebo patients (n = 210) showed statistically significantly longer time to death and smaller ALSFRS-R change from baseline at Week 48; restricted mean survival time showed a 7.3-month improvement (p < 0.001).

DISCUSSION: This suggests edaravone oral suspension significantly increases survival time and decreases physical functional decline versus PRO-ACT placebo patients.}, } @article {pmid40593943, year = {2025}, author = {Gbadamosi, I and Binias, S and Gielniewski, B and Magno, R and Duarte, I and Jawaid, A}, title = {Coding and non-coding RNA expression in NSC34 cells following TDP-43 depletion and mutant TDP-43 M337V expression.}, journal = {Scientific data}, volume = {12}, number = {1}, pages = {1110}, pmid = {40593943}, issn = {2052-4463}, support = {TREMENDOS; UMO-2022/04/Y/NZ5/00122//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; }, mesh = {*DNA-Binding Proteins/genetics ; Mutation ; *Amyotrophic Lateral Sclerosis/genetics ; Mice ; *Motor Neurons/metabolism ; Animals ; Humans ; Cell Line ; *RNA, Untranslated/genetics ; Transcriptome ; RNA Interference ; }, abstract = {Several neurodegenerative disorders (NDDs), notably amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by pathological cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) in neurons and glia. Primarily localized in the nucleus under physiological conditions, TDP-43 is a critical regulator of RNA processing and metabolism. Therefore, RNA changes induced by TDP-43 depletion or mutation could play an important role in the pathogenesis of ALS and other TDP-43 related NDDs.To investigate these effects in NSC34 motor neuron-like cells, a commonly used cellular model of ALS, we used RNA interference to knock down TDP-43 and overexpressed the ALS-associated TDP-43 M337V mutation. RNA from both these experiments was enriched for small and large transcripts and subsequently analyzed via next-generation sequencing.The resulting transcriptomics datasets offer a valuable resource for studying the impact of TDP-43 depletion and mutant over-expression in motor neurons. These data enable comprehensive differential expression analyses and functional enrichment studies, identifying cellular pathways affected by TDP-43 depletion or mutation. Additionally, the inclusion of non-coding RNAs facilitates the construction of gene regulatory networks, providing insights into the interplay between coding and non-coding RNAs in gene expression regulation under TDP-43 loss-of-function or pathogenic mutation conditions.}, } @article {pmid39457505, year = {2024}, author = {Seta, Y and Kimura, K and Masahiro, G and Tatsumori, K and Murakami, Y}, title = {SHED-CM: The Safety and Efficacy of Conditioned Media from Human Exfoliated Deciduous Teeth Stem Cells in Amyotrophic Lateral Sclerosis Treatment: A Retrospective Cohort Analysis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457505}, issn = {2227-9059}, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive and irreversible neurodegenerative disease with limited treatment options. Advances in regenerative medicine have opened up new treatment options. The primary and exploratory objectives of this retrospective cohort study were to evaluate the safety and efficacy of stem cells from human exfoliated deciduous teeth-conditioned media (SHED-CM).

METHODS: Safety assessments included adverse events, vital signs, and laboratory test changes before and after administration, and efficacy was measured using the ALS Functional Rating Scale-Revised (ALSFRS-R), grip strength, and forced vital capacity in 24 patients with ALS treated at a single facility between 1 January 2022, and 30 November 2023.

RESULTS: While ALSFRS-R scores typically decline over time, the progression rate in this cohort was slower, suggesting a potential delay in disease progression. Alternatively, improvements in muscle strength and mobility were observed in some patients. Although adverse events were reported in only 3% of cases (no serious allergic reactions), the treatment-induced changes in vital signs and laboratory results were not clinically significant.

CONCLUSIONS: The SHED-CM treatment is a safe and potentially effective therapeutic option for patients with ALS. Further research is needed to optimize the SHED-CM treatment; however, this study lays the groundwork for future exploration of regenerative therapies for ALS.}, } @article {pmid39457513, year = {2024}, author = {Montiel-Troya, M and Mohamed-Mohamed, H and Pardo-Moreno, T and González-Díaz, A and Ruger-Navarrete, A and de la Mata Fernández, M and Tovar-Gálvez, MI and Ramos-Rodríguez, JJ and García-Morales, V}, title = {Advancements in Pharmacological Interventions and Novel Therapeutic Approaches for Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457513}, issn = {2227-9059}, support = {PID2019-110960GB-I00//Ministry of Science and Innovation, Spain./ ; }, abstract = {(1) Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which the patient suffers from an affection of both upper and lower motor neurons at the spinal and brainstem level, causing a progressive paralysis that leads to the patient's demise. Gender is also considered a predisposing risk factor for developing the disease. A brief review of the pathophysiological mechanisms of the disease is also described in this work. Despite the fact that a cure for ALS is currently unknown, there exists a variety of pharmacological and non-pharmacological therapies that can help reduce the progression of the disease over a certain period of time and alleviate symptoms. (2) We aim to analyze these pharmacological and non-pharmacological therapies through a systematic review. A comprehensive, multidisciplinary approach to treatment is necessary. (3) Drugs such as riluzole, edaravone, and sodium phenylbutyrate, among others, have been investigated. Additionally, it is important to stay updated on research on new drugs, such as masitinib, from which very good results have been obtained. (4) Therapies aimed at psychological support, speech and language, and physical therapy for the patient are also available, which increase the quality of life of the patients.}, } @article {pmid39457678, year = {2024}, author = {Forrest, BD and Goyal, NA and Fleming, TR and Bracci, PM and Brett, NR and Khan, Z and Robinson, M and Azhir, A and McGrath, M}, title = {The Effectiveness of NP001 on the Long-Term Survival of Patients with Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457678}, issn = {2227-9059}, support = {01//Neuvivo, Inc./ ; }, abstract = {BACKGROUND/OBJECTIVES: The aim of this study was to estimate the effect of a 6 months' treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with amyotrophic lateral sclerosis.

METHODS: Blinded survival data were retrospectively collected for 268 of the 273 patients who had participated in two phase 2 placebo-controlled clinical trials of NP001 (ClinicalTrials.gov: NCT01281631 and NCT02794857) and received at least one dose of either 1 mg/kg or 2 mg/kg of NP001 as chlorite based on actual body weight, or placebo. Kaplan-Meier methods were used on the intent-to-treat population to estimate survival probabilities.

RESULTS: In the overall population, the median OS was 4.8 months (2.7 years [95% CI: 2.3, 3.5] in the 2 mg/kg NP001group and 2.3 years [95% CI: 1.8, 2.9] in the placebo group). Hazard ratio (HR): 0.77 (95% CI: 0.57, 1.03), p = 0.073. Among patients aged ≤ 65 years, the median OS for the 2 mg/kg NP001 group was 10.8 months (3.3 years [95% CI: 2.4, 3.8] in the 2 mg/kg NP001 group and 2.4 years [95% CI: 1.7, 3.3] in the placebo group). HR: 0.69 (95% CI: 0.50, 0.95). No differences were observed in the 1 mg/kg NP001 group or in patients aged > 65 years.

CONCLUSIONS: The findings from this study suggest that a 6 months' treatment course of NP001 resulted in a 4.8-month increase in overall survival in patients with ALS. The findings from this study indicate that targeting inflammation associated with the innate immune system may provide a pathway for new therapeutic options for the treatment of ALS.}, } @article {pmid39457680, year = {2024}, author = {McGrath, MS and Zhang, R and Bracci, PM and Azhir, A and Forrest, BD}, title = {Systemic Innate Immune System Restoration as a Therapeutic Approach for Neurodegenerative Disease: Effects of NP001 on Amyotrophic Lateral Sclerosis (ALS) Progression.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457680}, issn = {2227-9059}, support = {Neuvivo-NP001//Neuvivo, Inc./ ; }, abstract = {BACKGROUND/OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a diagnosis that incorporates a heterogeneous set of neurodegenerative processes into a single progressive and uniformly fatal disease making the development of a uniformly applicable therapeutic difficult. Recent multinational ALS natural history incidence studies have identified systemic chronic activation of the innate immune system as a major risk factor for developing ALS. Persistent immune activation in patients with ALS leads to loss of muscle and lowering of serum creatinine. The goal of the current study was to test whether the slowing of nerve and muscle destruction in NP001-treated ALS patients compared with controls in phase 2 studies would lead to extension of survival.

METHODS: Phase 2 clinical studies with NP001, an intravenously administered form of the innate immune system regulator NaClO2, are now reporting long-term survival benefits for drug recipients vs. placebo controls after only six months of intermittent treatment. As a prodrug, NP001 is converted by macrophages to taurine chloramine, a long-lived regulator of inflammation. We performed a pooled analysis of all patients who had completed the studies in two six-month NP001 phase 2 trials. Changes in respiratory vital capacity and the muscle mass product, creatinine, defined treated patients who, compared to placebo, had up to a year of extended survival.

CONCLUSIONS: The observed longer survival in ALS patients with the greatest inflammation-associated muscle loss provides further evidence that ALS is a disease of ongoing innate immune dysfunction and that NP001 is a disease-modifying drug with sustained clinical activity.}, } @article {pmid39458862, year = {2024}, author = {Palacıoğlu, G}, title = {Chitosan, Methyl Jasmonate, and Silicon Induce Resistance to Angular Leaf Spot in Common Bean, Caused by Pseudocercospora griseola, with Expression of Defense-Related Genes and Enzyme Activities.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {20}, pages = {}, pmid = {39458862}, issn = {2223-7747}, abstract = {This study assessed the efficacy of chitosan, methyl jasmonate, and silicon in the reduction of disease severity and the induction of defense responses in common bean plants against angular leaf spot caused by Pseudocercospora griseola. The expression level of several pathogenesis-related (PR) proteins, PR1, PR2 (β-1,3-glucanase), and PR3 (chitinase), and defense-related enzymes, phenylalanine ammonia-lyase, peroxidase, and lipoxygenase, was analyzed at different time points in common bean plants after different treatments. Elicitor treatments significantly reduced disease severity 21 days after inoculation, with silicon at a 2 mM concentration proving most effective with 38.93% disease control, followed by 1 mM MeJA and 2% chitosan, respectively. Treatments with chitosan, methyl jasmonate, and silicon, regardless of pathogen infection, significantly elevated PR1, PR2, and PR3 gene expressions at 48 h after inoculation (hpi). PAL and POD activities were similarly increased following elicitor treatments and pathogen infection, especially at 48 hpi. Chemical elicitors applied post-inoculation induced PR proteins, PAL, and POD enzyme activities at 48 hpi, while LOX activity exhibited a variable fluctuation with treatments. These findings suggested that chemical elicitors, especially silicon, were effective in reducing ALS disease severity in common beans, with improved resistance associated with the expression of pathogen-responsive genes. This study is the first to analyze the expression profiles of defense-related genes in common beans treated with chemical elicitors prior to P. griseola infection.}, } @article {pmid39458929, year = {2024}, author = {Giannakou, M and Akrani, I and Tsoka, A and Myrianthopoulos, V and Mikros, E and Vorgias, C and Hatzinikolaou, DG}, title = {Discovery of Novel Inhibitors against ALS-Related SOD1(A4V) Aggregation through the Screening of a Chemical Library Using Differential Scanning Fluorimetry (DSF).}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {10}, pages = {}, pmid = {39458929}, issn = {1424-8247}, support = {MIS-5000432//state scholarship foundation (GR)/ ; }, abstract = {BACKGROUND: Cu/Zn Superoxide Dismutase 1 (SOD1) is a 32 kDa cytosolic dimeric metalloenzyme that neutralizes superoxide anions into oxygen and hydrogen peroxide. Mutations in SOD1 are associated with ALS, a disease causing motor neuron atrophy and subsequent mortality. These mutations exert their harmful effects through a gain of function mechanism, rather than a loss of function. Despite extensive research, the mechanism causing selective motor neuron death still remains unclear. A defining feature of ALS pathogenesis is protein misfolding and aggregation, evidenced by ubiquitinated protein inclusions containing SOD1 in affected motor neurons. This work aims to identify compounds countering SOD1(A4V) misfolding and aggregation, which could potentially aid in ALS treatment.

METHODS: The approach employed was in vitro screening of a library comprising 1280 pharmacologically active compounds (LOPAC[®]) in the context of drug repurposing. Using differential scanning fluorimetry (DSF), these compounds were tested for their impact on SOD1(A4V) thermal stability.

RESULTS AND CONCLUSIONS: Dimer stability was the parameter chosen as the criterion for screening, since the dissociation of the native SOD1 dimer is the step prior to its in vitro aggregation. The screening revealed one compound raising protein-ligand Tm by 6 °C, eleven inducing a higher second Tm, suggesting a stabilization effect, and fourteen reducing Tm from 10 up to 26 °C, suggesting possible interactions or non-specific binding.}, } @article {pmid39459030, year = {2024}, author = {Al-Khayri, JM and Ravindran, M and Banadka, A and Vandana, CD and Priya, K and Nagella, P and Kukkemane, K}, title = {Amyotrophic Lateral Sclerosis: Insights and New Prospects in Disease Pathophysiology, Biomarkers and Therapies.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {10}, pages = {}, pmid = {39459030}, issn = {1424-8247}, support = {GRANT0000//Deanship of Scientific Research, King Faisal University/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disorder marked by the gradual loss of motor neurons, leading to significant disability and eventual death. Despite ongoing research, there are still limited treatment options, underscoring the need for a deeper understanding of the disease's complex mechanisms and the identification of new therapeutic targets. This review provides a thorough examination of ALS, covering its epidemiology, pathology, and clinical features. It investigates the key molecular mechanisms, such as protein aggregation, neuroinflammation, oxidative stress, and excitotoxicity that contribute to motor neuron degeneration. The role of biomarkers is highlighted for their importance in early diagnosis and disease monitoring. Additionally, the review explores emerging therapeutic approaches, including inhibitors of protein aggregation, neuroinflammation modulators, antioxidant therapies, gene therapy, and stem cell-based treatments. The advantages and challenges of these strategies are discussed, with an emphasis on the potential for precision medicine to tailor treatments to individual patient needs. Overall, this review aims to provide a comprehensive overview of the current state of ALS research and suggest future directions for developing effective therapies.}, } @article {pmid39459490, year = {2024}, author = {Banciu, C and Chiriac, S and Pojoga, C and Marian, L and Fabian, A and Gogulescu, A and Simu, M and Parvanescu, R and Mioc, A and Racoviceanu, R and Munteanu, A}, title = {An Uncommon Overlap Syndrome Between Ankylosing Spondylitis and Amyotrophic Lateral Sclerosis-Case Report.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {10}, pages = {}, pmid = {39459490}, issn = {1648-9144}, support = {//"Victor Babes" University of Medicine and Pharmacy Timisoara/ ; }, mesh = {Humans ; *Spondylitis, Ankylosing/complications/drug therapy ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Middle Aged ; Etanercept/therapeutic use ; Tumor Necrosis Factor-alpha/antagonists & inhibitors ; Syndrome ; }, abstract = {This case report describes an uncommon overlap syndrome between ankylosing spondylitis (AS) and amyotrophic lateral sclerosis (ALS). Initially, the patient was diagnosed with AS, for which he received various specific treatments, including TNF-α inhibitors. After five years of treatment with TNF-α inhibitor etanercept, the patient was referred for a full neurological assessment after he reported balance disturbances, postural instability, muscle weakness, and other neurological symptoms that indicated the presence of a neurological disorder. After a thorough investigation, the patient was diagnosed with ALS. This case report aims to contribute to the limited literature by providing a detailed case study regarding the crosstalk between AS and ALS while also exploring the potential underlying mechanisms and the possible link between TNF-α inhibitors therapy and ALS.}, } @article {pmid39459534, year = {2024}, author = {Nakhal, MM and Yassin, LK and Alyaqoubi, R and Saeed, S and Alderei, A and Alhammadi, A and Alshehhi, M and Almehairbi, A and Al Houqani, S and BaniYas, S and Qanadilo, H and Ali, BR and Shehab, S and Statsenko, Y and Meribout, S and Sadek, B and Akour, A and Hamad, MIK}, title = {The Microbiota-Gut-Brain Axis and Neurological Disorders: A Comprehensive Review.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {39459534}, issn = {2075-1729}, support = {12M159//UAEU/ ; G00004325//UAEU/ ; 12M142//UAEU/ ; }, abstract = {Microbes have inhabited the earth for hundreds of millions of years longer than humans. The microbiota-gut-brain axis (MGBA) represents a bidirectional communication pathway. These communications occur between the central nervous system (CNS), the enteric nervous system (ENS), and the emotional and cognitive centres of the brain. The field of research on the gut-brain axis has grown significantly during the past two decades. Signalling occurs between the gut microbiota and the brain through the neural, endocrine, immune, and humoral pathways. A substantial body of evidence indicates that the MGBA plays a pivotal role in various neurological diseases. These include Alzheimer's disease (AD), autism spectrum disorder (ASD), Rett syndrome, attention deficit hyperactivity disorder (ADHD), non-Alzheimer's neurodegeneration and dementias, fronto-temporal lobe dementia (FTLD), Wilson-Konovalov disease (WD), multisystem atrophy (MSA), Huntington's chorea (HC), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), temporal lobe epilepsy (TLE), depression, and schizophrenia (SCZ). Furthermore, the bidirectional correlation between therapeutics and the gut-brain axis will be discussed. Conversely, the mood of delivery, exercise, psychotropic agents, stress, and neurologic drugs can influence the MGBA. By understanding the MGBA, it may be possible to facilitate research into microbial-based interventions and therapeutic strategies for neurological diseases.}, } @article {pmid39459584, year = {2024}, author = {Silva, F and Silva, J and Salgueira, S and Mendes, A and Matos, E and Conde, B}, title = {Sleep Disturbances in Amyotrophic Lateral Sclerosis and Prognostic Impact-A Retrospective Study.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {39459584}, issn = {2075-1729}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with sleep disturbance, namely insomnia and sleep-disordered breathing. This study aims to evaluate the overall sleep characteristics of ALS patients, their association with lung function tests, and possible predictive survival factors. We conducted a retrospective observation study among ALS patients monitored during a pulmonology consultation. Type one polysomnography (PSG) and lung function tests were performed once the patients presented with sleep-related symptoms, and the relationship between their parameters was assessed, as well as a survival analysis. We included 35 patients, with an overall diminished sleep efficiency, a partially conserved forced vital capacity (FVC), and low maximal inspiratory pressure (MIP). A positive correlation between FVC and REM sleep percentage was observed. A survival analysis showed that a normal rapid eye movement (REM) sleep percentage and respiratory disturbance index (RDI) ≥ 15/h were independent predictors of survival. We observed a trend for higher sleep quality in patients with conserved lung function. A better sleep quality was associated with a higher survival. Obstructive events (reduced or absence of airflow associated with continued or increased inspiratory effort) did not seem to impact survival.}, } @article {pmid39460670, year = {2025}, author = {Gondim, FAA and Fernandes, JMA}, title = {ALS due to c.1189 + 1G > T (splice donor) TBK1 mutation.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {180}, doi = {10.1080/21678421.2024.2421754}, pmid = {39460670}, issn = {2167-9223}, } @article {pmid39461320, year = {2024}, author = {Didcote, L and Vitoratou, S and Al-Chalabi, A and Goldstein, LH}, title = {The reliability and validity of in-person and remote behavioural screening tools for people with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123282}, doi = {10.1016/j.jns.2024.123282}, pmid = {39461320}, issn = {1878-5883}, support = {GOLDSTEIN/OCT17/892-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Male ; Female ; Middle Aged ; Reproducibility of Results ; Aged ; *Psychometrics/methods/standards ; Surveys and Questionnaires/standards ; Neuropsychological Tests/standards ; Adult ; }, abstract = {OBJECTIVE: This study aimed to assess the psychometric properties of and relationships between total scores on different screening tools assessing behavioural change for people with amyotrophic lateral sclerosis (ALS), and whether administering the screens as online questionnaires (rather than on paper, in-person) influences total scores.

METHODS: The behavioural component of the Edinburgh Cognitive and Behavioural ALS Screen (ECASb); the behavioural component of the ALS Cognitive Behavioural Screen (ALS-CBSb), the ALS-Frontotemporal Dementia Questionnaire (ALS-FTD-Q), the Beaumont Behavioural Inventory (BBI), and the Motor Neuron Disease Behavioural Instrument (MiND-B) were administered to 35 informants on paper. Online questionnaire versions of the behavioural screens were administered to 49 informants. Forward stepwise linear regressions were conducted to assess whether scores on behavioural screens were predicted by scores on the other behavioural screens and to assess whether total scores were predicted by the mode of administration (paper or online) of the screens.

RESULTS: Behavioural screening tools, except the ECASb, had good internal consistency but mixed item-total correlations. All regression models assessing whether behavioural screen scores predict other behavioural screen scores were significant. The BBI performed best and the ECASb performed worst in terms of their predictive relationships with other screening tools. The administration mode of the questionnaires did not significantly affect total scores.

CONCLUSIONS: The psychometric properties of the scales varied. The scales predicted each other's scores, supporting convergent validity. Online and paper versions performed similarly, and demographics did not predict scores.}, } @article {pmid39461630, year = {2024}, author = {Kouhi, ZH and Seyedalipour, B and Hosseinkhani, S and Chaichi, MJ}, title = {Bisdemethoxycurcumin, a novel potent polyphenolic compound, effectively inhibits the formation of amyloid aggregates in ALS-associated hSOD1 mutant (L38R).}, journal = {International journal of biological macromolecules}, volume = {282}, number = {Pt 2}, pages = {136701}, doi = {10.1016/j.ijbiomac.2024.136701}, pmid = {39461630}, issn = {1879-0003}, mesh = {*Diarylheptanoids/chemistry/pharmacology ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism ; *Protein Aggregates/drug effects ; *Amyloid/metabolism/chemistry ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Mutation ; *Molecular Dynamics Simulation ; *Molecular Docking Simulation ; Curcumin/pharmacology/analogs & derivatives/chemistry ; Polyphenols/pharmacology/chemistry ; Protein Aggregation, Pathological/genetics/drug therapy ; Hemolysis/drug effects ; Hydrophobic and Hydrophilic Interactions ; }, abstract = {Protein misfolding is a biological process that leads to protein aggregation. Anomalous misfolding and aggregation of human superoxide dismutase (hSOD1) into amyloid aggregates is a characteristic feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative illness. Thus, focusing on the L38R mutant may be a wise decision to comprehend the SOD1 disease process in ALS. We suggest that Bisdemethoxycurcumin (BDMC) may be a strong anti-amyloidogenic polyphenol against L38R mutant aggregation. Protein stability, hydrophobicity, and flexibility were altered when BDMC was bound to the L38R mutant, as shown by molecular dynamic (MD) simulations and molecular docking. FTIR data shows α-Helix dominance in BDMC-containing samples, with reduced β-sheet and disordered peaks, indicating the decrease of aggregate species. ThT aggregation kinetics curves show BDMC reduces L38R mutant aggregation dose-dependently, with higher BDMC concentrations yielding greater reductions. TEM images showed various quantities of amorphous aggregates, but notably, 60 μM BDMC markedly reduced aggregate density, underscoring BDMC's inhibitory effect. Hemolysis tests revealed aggregate species in BDMC-treated samples were less toxic than in L38R mutant samples alone at the same concentrations and exposure times. Overall, BDMC has substantial potential to develop highly effective inhibitors that mitigate the risk of fatal ALS.}, } @article {pmid39461864, year = {2024}, author = {Imamura, K and Izumi, Y and Egawa, N and Ayaki, T and Nagai, M and Nishiyama, K and Watanabe, Y and Murakami, T and Hanajima, R and Kataoka, H and Kiriyama, T and Nanaura, H and Sugie, K and Hirayama, T and Kano, O and Nakamori, M and Maruyama, H and Haji, S and Fujita, K and Atsuta, N and Tatebe, H and Tokuda, T and Takahashi, N and Morinaga, A and Tabuchi, R and Oe, M and Kobayashi, M and Lobello, K and Morita, S and Sobue, G and Takahashi, R and Inoue, H}, title = {Protocol for a phase 2 study of bosutinib for amyotrophic lateral sclerosis using real-world data: induced pluripotent stem cell-based drug repurposing for amyotrophic lateral sclerosis medicine (iDReAM) study.}, journal = {BMJ open}, volume = {14}, number = {10}, pages = {e082142}, pmid = {39461864}, issn = {2044-6055}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Aniline Compounds/therapeutic use ; Clinical Trials, Phase II as Topic ; *Drug Repositioning ; Induced Pluripotent Stem Cells ; Japan ; Multicenter Studies as Topic ; *Nitriles/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; *Quinolines/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive, severe neurodegenerative disease caused by motor neuron death. Development of a medicine for ALS is urgently needed, and induced pluripotent cell-based drug repurposing identified a Src/c-Abl inhibitor, bosutinib, as a candidate for molecular targeted therapy of ALS. A phase 1 study confirmed the safety and tolerability of bosutinib in a 12-week treatment of ALS patients. The objectives of this study are to evaluate the efficacy and longer-term safety of bosutinib in ALS patients.

METHODS AND ANALYSIS: An open-label, multicentre phase 2 study was designed. The study consisted of a 12-week observation period, a 1-week transitional period, a 24-week study treatment period and a 4-week follow-up period. Following the transitional period, patients whose total Revised ALS Functional Rating Scale (ALSFRS-R) score declined by 1 to 4 points during the 12-week observation period were to receive bosutinib for 24 weeks. In this study, 25 ALS patients will be enrolled; patients will be randomly assigned to the following groups: 12 patients in the 200 mg quaque die (QD) group and 13 patients in the 300 mg QD group of bosutinib. The safety and exploratory efficacy of bosutinib in ALS patients for 24 weeks will be assessed. Efficacy using the ALSFRS-R score will be compared with the external published data from an edaravone study (MCI186-19) and registry data from a multicentre ALS cohort study, the Japanese Consortium for Amyotrophic Lateral Sclerosis Research.

ETHICS AND DISSEMINATION: This study was approved by the ethics committees of Kyoto University, Tokushima University, Kitasato University, Tottori University, Nara Medical University School of Medicine, Toho University and Hiroshima University. The findings will be disseminated in peer-reviewed journals and at scientific conferences.

TRIAL REGISTRATION NUMBER: jRCT2051220002; Pre-results, NCT04744532; Pre-results.}, } @article {pmid39462509, year = {2024}, author = {Dauer, LT and Mumma, MT and Lima, JC and Cohen, SS and Andresen, D and Bahadori, AA and Bellamy, M and Bierman, DA and Blattnig, S and French, B and Giunta, E and Held, K and Hertel, N and Keohane, L and Leggett, R and Lipworth, L and Miller, KB and Norman, RB and Samuels, C and Thomas, KS and Tolmachev, SY and Walsh, L and Boice, JD}, title = {A Million Person Study Innovation: Evaluating Cognitive Impairment and other Morbidity Outcomes from Chronic Radiation Exposure Through Linkages with the Centers for Medicaid and Medicare Services Assessment and Claims Data.}, journal = {Radiation research}, volume = {202}, number = {6}, pages = {847-861}, pmid = {39462509}, issn = {1938-5404}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; UE2 EH001315/EH/NCEH CDC HHS/United States ; 80NSSC17M0016/NASA/NASA/United States ; 80NSSC19M0161/NASA/NASA/United States ; DE-AU0000042//US Department of Energy/ ; DE-AU0000046//US Department of Energy/ ; 5NUE1EH001315//US Naval Sea Systems Command/ ; }, mesh = {Humans ; United States/epidemiology ; *Radiation Exposure/adverse effects ; Centers for Medicare and Medicaid Services, U.S. ; Male ; Medicare ; Female ; Cognition Disorders/epidemiology/etiology ; }, abstract = {The study of One Million U.S. Radiation Workers and Veterans, the Million Person Study (MPS), examines the health consequences, both cancer and non-cancer, of exposure to ionizing radiation received gradually over time. Recently the MPS has focused on mortality patterns from neurological and behavioral conditions, e.g., Parkinson's disease, Alzheimer's disease, dementia, and motor neuron disease such as amyotrophic lateral sclerosis. A fuller picture of radiation-related late effects comes from studying both mortality and the occurrence (incidence) of conditions not leading to death. Accordingly, the MPS is identifying neurocognitive diagnoses from fee-for-service insurance claims from the Centers for Medicare and Medicaid Services (CMS), among Medicare beneficiaries beginning in 1999 (the earliest date claims data are available). Linkages to date have identified ∼540,000 workers with available health information. Such linkages provide individual information on important co-factor and confounding variables such as smoking, alcohol consumption, blood pressure, obesity, diabetes and many other health and demographic characteristics. The total person-level set of time-dependent variables, outcomes, organ-specific dose measures, co-factors, and demographics will be massive and much too large to be evaluated with standard software. Thus, development of specialized open-source software designed for large datasets (Colossus) is nearly complete. The wealth of information available from CMS claims data, coupled with individual dose reconstructions, will thus greatly enhance the quality and precision of health evaluations for this new field of low-dose radiation and neurocognitive effects.}, } @article {pmid39462586, year = {2024}, author = {Kurita, H and Hirasawa, N and Yabe, S and Okuda, A and Murakami, T and Ohuchi, K and Ogata, A and Yoshioka, H and Kakita, A and Hozumi, I and Inden, M}, title = {MicroRNA-5572 Is Associated with Endoplasmic Reticulum Stress Responses in Low Zinc Treated and SOD1 G85R-Transfected HEK293 Cells.}, journal = {Biological & pharmaceutical bulletin}, volume = {47}, number = {10}, pages = {1717-1725}, doi = {10.1248/bpb.b24-00418}, pmid = {39462586}, issn = {1347-5215}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Endoplasmic Reticulum Stress/drug effects/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; *Zinc/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; HEK293 Cells ; Transfection ; Tunicamycin/toxicity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fetal neurodegenerative disease. The mechanism of sporadic ALS onset remains unclarified in detail. Disruption of zinc homeostasis could be related to sporadic ALS. Previously, we first reported miR-5572 as a microRNA (miRNA) among those identified in the spinal cords of patients with sporadic ALS. However, since its function in ALS remained unknown, this study further examined the role of miR-5572 in low-zinc status and ALS model cells which transfected with causative gene, Cu/Zn superoxide dismutase 1 (SOD1) G85R mutant vector. The miR-5572 level was increased by low-zinc condition accompanied by increase of endoplasmic reticulum (ER) stress. In addition, increase of miR-5572 enhanced the cellular toxicity induced by low-zinc treatment. The expression of miR-5572 was also increased, which was accompanied by an increase of ER stress markers associated with SOD1 aggregation formation. Cell death and ER stress makers levels induced by tunicamycin treatment were further increased in miR-5572 mimic-transfected cells. This study showed that miR-5572 exacerbated ER stress toxicity associated with low-zinc status and mutant SOD1 aggregates in ALS.}, } @article {pmid39463426, year = {2025}, author = {Yang, SF and Patel, PN}, title = {Invited Commentary on: Youssefi et al's 3D Smartphone Photography During Rhinoplasty Surgery.}, journal = {Facial plastic surgery & aesthetic medicine}, volume = {27}, number = {2}, pages = {199-200}, doi = {10.1089/fpsam.2024.0265}, pmid = {39463426}, issn = {2689-3622}, } @article {pmid39464100, year = {2024}, author = {Du, M and Akerman, SC and Fare, CM and Ruan, L and Vidensky, S and Mamedova, L and Lee, J and Rothstein, JD}, title = {Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39464100}, issn = {2692-8205}, support = {P50 AG005146/AG/NIA NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.}, } @article {pmid39464461, year = {2024}, author = {Karunakaran, V and Dadgar, S and Paidi, SK and Mordi, AF and Lowe, WA and Mim, UM and Ivers, JD and Rodriguez Troncoso, JI and McPeake, JA and Fernandes, A and Tripathi, SD and Barman, I and Rajaram, N}, title = {Investigating In Vivo Tumor Biomolecular Changes Following Radiation Therapy Using Raman Spectroscopy.}, journal = {ACS omega}, volume = {9}, number = {42}, pages = {43025-43033}, pmid = {39464461}, issn = {2470-1343}, support = {P20 GM139768/GM/NIGMS NIH HHS/United States ; P41 EB015871/EB/NIBIB NIH HHS/United States ; R01 CA238025/CA/NCI NIH HHS/United States ; R15 CA238861/CA/NCI NIH HHS/United States ; }, abstract = {Treatment resistance is a major bottleneck in the success of cancer therapy. Early identification of the treatment response or lack thereof in patients can enable an earlier switch to alternative treatment strategies that can enhance response rates. Here, Raman spectroscopy was applied to monitor early tumor biomolecular changes in sensitive (UM-SCC-22B) and resistant (UM-SCC-47) head and neck tumor xenografts for the first time in in vivo murine tumor models in response to radiation therapy. We used a validated multivariate curve resolution-alternating least-squares (MCR-ALS) model to resolve complex multicomponent Raman spectra into individual pure spectra and their respective contributions. We observed a significant radiation-induced increase in the contributions of lipid-like species (p = 0.0291) in the radiation-sensitive UM-SCC-22B tumors at 48 h following radiation compared to the nonradiated baseline (prior to commencing treatment). We also observed an increase in the contribution of collagen-like species in the radiation-resistant UM-SCC-47 tumors at 24 h following radiation compared to the nonradiated baseline (p = 0.0125). In addition to the in vivo analysis, we performed ex vivo confocal Raman microscopic imaging of frozen sections derived from the same tumors. A comparison of all control and treated tumors revealed similar trends in the contributions of lipid-like and collagen-like species in both in vivo and ex vivo measurements; however, when evaluated as a function of time, longitudinal trends in the scores of collagen-like and lipid-like components were not consistent between the two data sets, likely due to sample numbers and differences in sampling depth at which information is obtained. Nevertheless, this study demonstrates the potential of fiber-based Raman spectroscopy for identifying early tumor microenvironmental changes in response to clinical doses of radiation therapy.}, } @article {pmid39464638, year = {2024}, author = {Altuwaijri, F and Alrabiah, A and Alqarni, A and Habash, AK and Alghofili, M and Alotaibi, O and Altuwaijri, M}, title = {Comparison Between the Advanced Cardiac Life Support and Adult Advanced Life Support Protocols: A Simulation-Based Pilot Study.}, journal = {Emergency medicine international}, volume = {2024}, number = {}, pages = {6696879}, pmid = {39464638}, issn = {2090-2840}, abstract = {Introduction: Cardiac arrest is a public health concern associated with unfavorable disease outcomes. Cardiopulmonary resuscitation (CPR) of optimal quality is widely acknowledged as an indispensable technique in restoring spontaneous circulation. In order to perform advanced cardiac life support (ACLS), chest compression must be paused twice: once to assess the rhythm and again to administer the shock. Australian advanced life support (ALS) recommends that the defibrillator needs to be precharged in order to administer the shock during a solitary interval in chest compressions. While performing chest compressions, precharging defibrillators can decrease hands-off time without posing a risk of injury. Aim: To compare chest compression fraction (CCF)-which is the cumulative time spent providing chest compressions divided by the total time taken for the entire resuscitation-by calculating the hands-off time duration in cardiac arrest between the Australian Resuscitation Council (ARC) and American Heart Association (AHA) protocols for CPR. Methods: A simulation-based pilot study was designed using a Laerdal Resusci Anne mannequin and a LIFEPACK 20 defibrillator. The study included six participants recruited from King Khalid University Hospital in Riyadh, Saudi Arabia, where three participants were certified ACLS providers and there were certified ALS providers. Participants were divided into two groups, ALS and ACLS, each following one protocol. For each scenario, a random job was assigned to each participant, regardless of their role as assistant, team leader, or performer of CPR. Each case's shockable and nonshockable rhythms were hidden from the team leader and the chest compressor. Ten trials of CPR were performed, each for four cycles with a total time of 8 min. The simulation was video recorded for hands-off time counting. Comparison between CCF (seconds) per cycle between the two protocols was performed using an independent sample t-test. A p value of 0.05 was used to measure statistical significance. Results: Comparing CCF in shockable rhythms between ARC and AHA protocols, it was observed that the CCF of ALS-ARC was significantly higher than ACLS-AHA in all cycles; the first cycle: t = 3.782, p=0.004; the second cycle: t = 3.380, p=0.007; the third cycle: t = 3.803, p=0.003; and the fourth cycle: t = 4.341, p=0.001. Conclusion: Precharging a defibrillator before a rhythm check during chest compression, in anticipation of a potentially shockable rhythm, reduces the time required for defibrillation and limits interruptions in chest compression during CPR. This practice effectively enhances the CCF. Enhancing the continuity of chest compressions can potentially improve survival rates in ARC.}, } @article {pmid39465642, year = {2024}, author = {Erdaş, ÇB and Sümer, E}, title = {CNN-Based Neurodegenerative Disease Classification Using QR-Represented Gait Data.}, journal = {Brain and behavior}, volume = {14}, number = {10}, pages = {e70100}, pmid = {39465642}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/classification/diagnosis/physiopathology ; *Huntington Disease/diagnosis/physiopathology/classification ; *Parkinson Disease/classification/diagnosis/physiopathology ; *Neurodegenerative Diseases/classification/diagnosis/physiopathology ; Male ; Middle Aged ; Female ; Neural Networks, Computer ; Gait/physiology ; Aged ; Deep Learning ; Gait Analysis/methods ; Adult ; }, abstract = {PURPOSE: The primary aim of this study is to develop an effective and reliable diagnostic system for neurodegenerative diseases by utilizing gait data transformed into QR codes and classified using convolutional neural networks (CNNs). The objective of this method is to enhance the precision of diagnosing neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Huntington's disease (HD), through the introduction of a novel approach to analyze gait patterns.

METHODS: The research evaluates the CNN-based classification approach using QR-represented gait data to address the diagnostic challenges associated with neurodegenerative diseases. The gait data of subjects were converted into QR codes, which were then classified using a CNN deep learning model. The dataset includes recordings from patients with Parkinson's disease (n = 15), Huntington's disease (n = 20), and amyotrophic lateral sclerosis (n = 13), and from 16 healthy controls.

RESULTS: The accuracy rates obtained through 10-fold cross-validation were as follows: 94.86% for NDD versus control, 95.81% for PD versus control, 93.56% for HD versus control, 97.65% for ALS versus control, and 84.65% for PD versus HD versus ALS versus control. These results demonstrate the potential of the proposed system in distinguishing between different neurodegenerative diseases and control groups.

CONCLUSION: The results indicate that the designed system may serve as a complementary tool for the diagnosis of neurodegenerative diseases, particularly in individuals who already present with varying degrees of motor impairment. Further validation and research are needed to establish its wider applicability.}, } @article {pmid39465944, year = {2024}, author = {Chen, C and Rafael, KA and Cho, G and Lim, Y}, title = {Split-Luciferase Reassembly Assay to Measure Endoplasmic Reticulum-Mitochondria Contacts in Live Cells.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {212}, pages = {}, pmid = {39465944}, issn = {1940-087X}, support = {R01 NS113516/NS/NINDS NIH HHS/United States ; }, mesh = {*Endoplasmic Reticulum/metabolism ; *Mitochondria/metabolism ; Humans ; Luciferases/metabolism/genetics ; Animals ; Mitochondria Associated Membranes ; }, abstract = {Endoplasmic reticulum (ER)-mitochondria contact sites play a critical role in cell health and homeostasis, such as the regulation of Ca[2+] and lipid homeostasis, mitochondrial dynamics, autophagosome and mitophagosome biogenesis, and apoptosis. Failure to maintain normal ER-mitochondrial coupling is implicated in many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and hereditary spastic paraplegia. It is of considerable significance to explore how the dysregulation of ER-mitochondrial contacts could lead to cell death and whether repairing these contacts to the normal level could ameliorate neurodegenerative conditions. Thus, improved assays that measure the level of these contacts could help to illuminate the pathogenic mechanisms of these diseases. Ultimately, establishing simple and reliable assays will facilitate the development of new therapeutic strategies. Here we describe a split-luciferase assay to quantitatively measure the level of ER-mitochondria contacts in live cells. This assay can be used to study the pathophysiological role of these contacts as well as to identify their modulators in high-throughput screening.}, } @article {pmid39466798, year = {2025}, author = {Correa, T and Owen, SR}, title = {Invited Commentary on: Santamaría-Gadea et al's "Non-Surgical Rhinoplasty After Rhinoplasty: A Systematic Review of the Technique, Results, and Complications".}, journal = {Facial plastic surgery & aesthetic medicine}, volume = {27}, number = {1}, pages = {75-76}, doi = {10.1089/fpsam.2024.0267}, pmid = {39466798}, issn = {2689-3622}, } @article {pmid39467933, year = {2025}, author = {Kang, M and Kim, BJ and Nguyen, B and Park, JS}, title = {Computed tomography-based radiological gynecomastia in SBMA as an independent differential diagnostic biomarker: a retrospective study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {2}, pages = {783-789}, doi = {10.1007/s10072-024-07820-1}, pmid = {39467933}, issn = {1590-3478}, mesh = {Humans ; *Gynecomastia/diagnostic imaging/etiology ; Retrospective Studies ; Middle Aged ; Male ; Diagnosis, Differential ; *Tomography, X-Ray Computed/methods ; Aged ; Adult ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/complications ; *Bulbo-Spinal Atrophy, X-Linked/diagnostic imaging/complications ; }, abstract = {BACKGROUND: Spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) are motor neuron disorders that demonstrate overlapping clinical features, especially in the early stage. Therefore, the aim of this study was to investigate the utility of chest tomography (CT) imaging in distinguishing between SBMA and ALS.

METHODS: This was a retrospective study reviewing CT images from patients with SBMA and sporadic ALS and those in the control group. The CT images were assessed to measure the diameter and morphology of glandular tissue associated with gynecomastia. We compared CT-measured gynecomastia between the SBMA, ALS, and control groups. Additionally, correlation analyses were performed between the quantitative measurements of gynecomastia obtained from CT scans and various clinical/laboratory parameter in the SBMA group.

RESULTS: 15 chest CT images were collected from SBMA, 41 from ALS, and 29 from control group. No statistical differences were observed in BMI, functional scales, or age at the time of CT scans between the SBMA and ALS groups. Despite similar functional scales and age in both groups, the mean glandular tissue diameter of breast tissue observed in chest CT imaging differed significantly between SBMA, ALS, and controls: 32.22 ± 12.57 mm, 15.91 ± 4.81 mm, and 15.76 ± 7.26 mm, respectively. This disparity allowed for the differentiation of SBMA from ALS and controls with statistical significance. Clinical gynecomastia was 80%, while radiological gynecomastia was 93.3% in SBMA. A significantly higher prevalence of diffuse glandular morphology pattern in SBMA (50%) was observed, contrasting with the predominance of nodular morphology in ALS and controls (9.1% and 20%). Correlative analysis between glandular tissue diameter and other clinical/laboratory parameters within the SBMA group showed no specific finding.

CONCLUSION: CT-based radiological gynecomastia effectively differentiated SBMA from ALS. These findings support the usefulness of radiological gynecomastia as a potential differential diagnostic marker for SBMA, especially in the early stages.}, } @article {pmid39468607, year = {2024}, author = {Liu, C and Wu, Y and Wang, F and Sun, S and Wei, J and Tao, L}, title = {Cost-utility analysis for sublingual versus intravenous edaravone in the treatment of amyotrophic lateral sclerosis.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {400}, pmid = {39468607}, issn = {1750-1172}, mesh = {*Edaravone/therapeutic use/economics/administration & dosage ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/economics ; *Cost-Benefit Analysis ; Administration, Sublingual ; Antipyrine/analogs & derivatives/therapeutic use/economics/administration & dosage ; Free Radical Scavengers/therapeutic use/economics/administration & dosage ; Administration, Intravenous ; Male ; }, abstract = {BACKGROUND: Edaravone has been widely used in amyotrophic lateral sclerosis (ALS) treatment, and a sublingual (SL) tablet has been developed to offer a more convenient alternative for injection. We present a cost-utility analysis to comprehensively evaluate the costs and health outcomes of oral and intravenous edaravone for the treatment of ALS in Chinese medical context.

METHODS: Cost-utility analysis of SL tablets of edaravone versus intravenous edaravone at home was performed by constructing a 20-year Markov model of ALS stage 1-4 and death. The data were extracted from the literature with model assumptions. Typical sensitivity analysis and scenario analysis for administering SL tablets at home versus intravenous tablets at the hospital were performed.

RESULTS: In the base case analysis, with SL tablets and intravenous injections both at home, the model estimated an additional cost of ¥12,670.04 and an additional 0.034 QALYs over 20 years (life time) of modeling analysis, and the ICER was ¥372,648.24 per QALY. However, in the scenario of intravenous administration at the hospital, SL tablet was demonstrated dominance to intravenous injection.

CONCLUSIONS: Using 3 times the GDP per capita of China in 2023 as the threshold, the SL tablet edaravone was not cost-effective in the context of home treatment for both formulationst, but was dominance to intravenous injection in hospital treatment. The results highlighted the importance of treatment context for health economic analysis.}, } @article {pmid39470153, year = {2024}, author = {Xu, R}, title = {Overview of nomenclature and diagnosis of amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2422572}, pmid = {39470153}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/classification/physiopathology ; Humans ; *Terminology as Topic ; Electromyography/methods ; Motor Neurons/pathology ; }, abstract = {The nomenclature of amyotrophic lateral sclerosis (ALS) currently is blurred, indistinct and no accurate and haven't been properly updated since the first description, which is far from being suitable for the current implementation of clinical practise and scientific research of ALS, and urgently need an solution. Furthermore, the current diagnostic criteria need also further been improved, because the current clinical diagnosis of ALS majorly depends on the clinical manifestations yet. Up to now, no any objective clinical auxiliary examination can be helpful to diagnose ALS besides the electromyogram identifying the lower motor neuron damage, which isn't conducive to early diagnosis and prolongs the time of ALS confirmed diagnosis. In this mini review, we discussed the current doubt about the nomenclature and diagnostic criteria of ALS, and prospected in order to further improve and normalize the nomenclature and diagnosis of ALS.}, } @article {pmid39470585, year = {2024}, author = {Lin, W and Wu, X and Ou, G}, title = {Causal association of circulating inflammatory proteins on neurodegenerative diseases: Insights from a mendelian randomization study.}, journal = {Journal of cellular and molecular medicine}, volume = {28}, number = {20}, pages = {e70176}, pmid = {39470585}, issn = {1582-4934}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/blood ; *Genome-Wide Association Study ; *Cytokines/blood/genetics ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Alzheimer Disease/genetics/blood ; Amyotrophic Lateral Sclerosis/genetics/blood ; Inflammation/genetics/blood ; Multiple Sclerosis/genetics/blood ; Parkinson Disease/genetics/blood ; }, abstract = {Neuroinflammation is increasingly recognized as a pivotal factor in the development and progression of neurodegenerative disorders. While correlations between inflammatory cytokines and these diseases are documented, the definitive causal dynamics remain to be elucidated. We explored the causal association between 91 circulating inflammatory cytokines and Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Parkinson's disease (PD) through Mendelian randomization analysis. Leveraging genetic variants from the most comprehensive genome-wide association studies (GWAS) available for these cytokines, AD, ALS, MS and PD, we sought to uncover the causality. Our study validated a causal influence of genetically determined cytokine levels on the susceptibility to AD, with notable cytokines including C-X-C motif chemokine 1 (OR = 0.9993, p = 0.0424), Interleukin-18 (OR = 0.9994, p = 0.0186), Leukaemia inhibitory factor receptor (OR = 0.9993, p = 0.0122) and Monocyte chemoattractant protein-1 (OR = 0.9992, p = 0.0026) in risk attenuation. Additionally, a positive causal relationship was identified between two cytokines-C-C motif chemokine 19 (OR = 1.0005, p = 0.0478) and Fms-related tyrosine kinase 3 ligand (OR = 1.0005, p = 0.0210)-and AD incidence. Conversely, transforming growth factor-alpha (OR = 0.8630, p = 0.0298), CD40L receptor (OR = 0.7737, p = 1.1265E-09) and Interleukin-12 subunit beta (OR = 0.8987, p = 0.0333) showed inverse associations with ALS, MS and PD, respectively. The consistency observed in various MR analyses, alongside sensitivity analysis, underscored the absence of horizontal pleiotropy, thus supporting our causal findings. This study reveals, for the first time, a genetically anchored causal nexus between levels of circulating inflammatory cytokines and the risk of neurodegenerative diseases.}, } @article {pmid39470847, year = {2025}, author = {Jellinger, KA}, title = {Mild cognitive impairment in amyotrophic lateral sclerosis: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {3}, pages = {357-368}, pmid = {39470847}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Cognitive Dysfunction/etiology/diagnosis ; *Brain/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multi-system neurodegenerative disorder with no effective treatment or cure. Although primarily characterized by motor degeneration, cognitive dysfunction is an important non-motor symptom that has a negative impact on patient and caregiver burden. Mild cognitive deficits are present in a subgroup of non-demented patients with ALS, often preceding motor symptoms. Detailed neuropsychological assessments reveal deficits in a variety of cognitive domains, including those of verbal fluency and retrieval, language, executive function, attention and verbal memory. Mild cognitive impairment (MCI), a risk factor for developing dementia, affects between 10% and over 50% of ALS patients. Neuroimaging revealed atrophy of frontal and temporal cortices, disordered white matter Integrity, volume reduction in amygdala and thalamus, hypometabolism in the frontal and superior temporal gyrus and anterior insula. Neuronal loss in non-motor brain areas, associated with TDP-43 deposition, one of the morphological hallmarks of ALS, is linked to functional disruption of frontostriatal and frontotemporo-limbic connectivities as markers for cognitive deficits in ALS, the pathogenesis of which is still poorly understood. Early diagnosis by increased cerebrospinal fluid or serum levels of neurofilament light/heavy chain or glial fibrillary acidic protein awaits confirmation for MCI in ALS. These fluid biomarkers and early detection of brain connectivity signatures before structural changes will be helpful not only in establishing early premature diagnosis but also in clarifying the pathophysiological mechanisms of MCI in ALS, which might serve as novel targets for prohibition/delay and future adequate treatment of this debilitating disorder.}, } @article {pmid39470866, year = {2025}, author = {Liu, Y and Fu, R and Jia, H and Yang, K and Ren, F and Zhou, MS}, title = {GHRH and its analogues in central nervous system diseases.}, journal = {Reviews in endocrine & metabolic disorders}, volume = {26}, number = {3}, pages = {427-442}, pmid = {39470866}, issn = {1573-2606}, support = {82270434//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Growth Hormone-Releasing Hormone/analogs & derivatives/metabolism/therapeutic use ; Animals ; *Central Nervous System Diseases/metabolism/drug therapy ; Insulin-Like Growth Factor I/metabolism ; }, abstract = {Growth hormone-releasing hormone (GHRH) is primarily produced by the hypothalamus and stimulates the release of growth hormone (GH) in the anterior pituitary gland, which subsequently regulates the production of hepatic insulin-like growth factor-1 (IGF-1). GH and IGF-1 have potent effects on promoting cell proliferation, inhibiting cell apoptosis, as well as regulating cell metabolism. In central nerve system (CNS), GHRH/GH/IGF-1 promote brain development and growth, stimulate neuronal proliferation, and regulate neurotransmitter release, thereby participating in the regulation of various CNS physiological activities. In addition to hypothalamus-pituitary gland, GHRH and GHRH receptor (GHRH-R) are also expressed in other brain cells or tissues, such as endogenous neural stem cells (NSCs) and tumor cells. Alternations in GHRH/GH/IGF-1 axis are associated with various CNS diseases, for example, Alzheimer's disease, amyotrophic lateral sclerosis and emotional disorders manifest GHRH, GH or IGF-1 deficiency, and GH or IGF-1 supplementation exerts beneficial therapeutic effects on these diseases. CNS tumors, such as glioma, can express GHRH and GHRH-R, and activating this signaling pathway promotes tumor cell growth. The synthesized GHRH antagonists have shown to inhibit glioma cell growth and may hold promising as an adjuvant therapy for treating glioma. In addition, we have shown that GHRH agonist MR-409 can improve neurological sequelae after ischemic stroke by activating extrapituitary GHRH-R signaling and promoting endogenous NSCs-derived neuronal regeneration. This article reviews the involvement of GHRH/GH/IGF-1 in CNS diseases, and potential roles of GHRH agonists and antagonists in treating CNS diseases.}, } @article {pmid39471269, year = {2024}, author = {Stenson, K and Chew, S and Dong, S and Heithoff, K and Wang, MJ and Rosenfeld, J}, title = {Health care resource utilization and costs across stages of amyotrophic lateral sclerosis in the United States.}, journal = {Journal of managed care & specialty pharmacy}, volume = {30}, number = {11}, pages = {1239-1247}, pmid = {39471269}, issn = {2376-1032}, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy ; Humans ; United States ; Male ; Female ; Middle Aged ; Aged ; *Patient Acceptance of Health Care/statistics & numerical data ; *Health Care Costs/statistics & numerical data ; Adult ; Health Resources/economics/statistics & numerical data ; Severity of Illness Index ; Retrospective Studies ; Disease Progression ; Cost of Illness ; Databases, Factual ; }, abstract = {BACKGROUND: People living with ALS (plwALS) experience motor control loss, speech/swallowing difficulties, respiratory insufficiency, and early death. Advancing disease stage is typically associated with a greater burden on the health care system, and delays in diagnosis can result in substantial health care resource utilization (HCRU).

OBJECTIVE: To estimate HCRU and cost burden of plwALS across disease stages from a US payer perspective we assessed HCRU and costs in early-, mid-, and late-stage ALS.

METHODS: Using insurance claims data from the IBM MarketScan Databases between January 2013 and December 2019, we identified plwALS as having at least 2 claims at least 27 days apart with an ALS International Classification of Diseases, Ninth or Tenth Revision diagnosis code (335.20/G12.21) or at least 1 ALS diagnosis code and prescription filled for riluzole/edaravone. Eligible plwALS were aged at least 18 years and had at least 12 months of enrollment data before and at least 6 months after the index date (date diagnosis criteria met). plwALS were grouped into disease stages using an ALS severity-based staging algorithm developed using ALS symptom and staging survey data from 142 neurologists reporting on 880 plwALS. The starting date of each severity stage was defined as the first date of an ALS symptom within the early-, mid-, and late-stage categories, respectively. The ending date for a severity stage was defined as the day before the first date of an ALS symptom from a more severe category. plwALS could transition to more severe stages, with reverse transition of severity excluded. Mixed regression modeling was used to assess differences in HCRU and costs per person-year between severity stages, adjusted for age and sex.

RESULTS: 2,273 plwALS were included in the total ALS study sample, with 1,215 early-stage, 1,511 midstage, and 1,186 late-stage plwALS. 90% of early-stage plwALS had ALS symptoms before diagnosis, and 27% of late-stage plwALS had a late-stage symptom before diagnosis. In the evaluation period, later-stage ALS groups had more overall hospital admissions (early = 0.15, middle = 0.23, and late = 0.74; P < 0.01), outpatient visits/service (early = 26.81, middle = 32.78, and late = 48.54; P < 0.01), emergency department visits (early = 0.46, middle = 0.69, and late = 1.03; P < 0.01), and total prescription count (early = 9.23, middle = 11.37, and late = 12.72; P < 0.01) over 12 months. Annualized costs increased as ALS progressed (early = $31,411, middle = $51,481, and late = $121,903; P < 0.01), which was primarily driven by higher frequency of and cost per hospital admission.

CONCLUSIONS: HCRU and costs increased with ALS progression, with diagnosis frequently occurring even after experiencing late-stage symptoms. These findings highlight the potential value of delaying progression into a more resource-intensive stage by diagnosing and adequately treating plwALS earlier in the disease course.}, } @article {pmid39471842, year = {2024}, author = {Ferro, F and Wolf, CR and Henstridge, C and Inesta-Vaquera, F}, title = {Novel in vivo TDP-43 stress reporter models to accelerate drug development in ALS.}, journal = {Open biology}, volume = {14}, number = {10}, pages = {240073}, pmid = {39471842}, issn = {2046-2441}, support = {//MND Scotland/ ; //ARUK/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics/pathology ; Animals ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; *Disease Models, Animal ; Humans ; *Mice, Transgenic ; *Genes, Reporter ; Oxidative Stress/drug effects ; NF-E2-Related Factor 2/metabolism/genetics ; Drug Development ; DNA Damage ; Biomarkers ; }, abstract = {The development of therapies to combat neurodegenerative diseases is widely recognized as a research priority. Despite recent advances in understanding their molecular basis, there is a lack of suitable early biomarkers to test selected compounds and accelerate their translation to clinical trials. We have investigated the utility of in vivo reporters of cytoprotective pathways (e.g. NRF2, p53) as surrogate early biomarkers of the ALS degenerative disease progression. We hypothesized that cellular stress observed in a model of ALS may precede overt cellular damage and could activate our cytoprotective pathway reporters. To test this hypothesis, we generated novel ALS-reporter mice by crossing the hTDP-43tg model into our oxidative stress/inflammation (Hmox1; NRF2 pathway) and DNA damage (p21; p53 pathway) stress reporter models. Histological analysis of reporter expression in a homozygous hTDP-43tg background demonstrated a time-dependent and tissue-specific activation of the reporters in tissues directly associated with ALS, before moderate clinical signs are observed. Further work is warranted to determine the specific mechanisms by which TDP-43 accumulation leads to reporter activation and whether therapeutic intervention modulates reporters' expression. We anticipate the reporter strategy could be of great value in developing treatments for a range of degenerative disorders.}, } @article {pmid39471924, year = {2024}, author = {Xu, Y and Xu, T and Huang, C and Liu, L and Kwame, AW and Zhu, Y and Ren, J}, title = {Preventive intervention with Agaricus blazei murill polysaccharide exerts anti-tumor immune effect on intraperitoneal metastasis colorectal cancer.}, journal = {International journal of biological macromolecules}, volume = {282}, number = {Pt 3}, pages = {136810}, doi = {10.1016/j.ijbiomac.2024.136810}, pmid = {39471924}, issn = {1879-0003}, mesh = {Animals ; *Agaricus/chemistry ; *Colorectal Neoplasms/pathology/immunology/prevention & control/drug therapy ; Mice ; Cell Line, Tumor ; Tumor Microenvironment/drug effects ; Peritoneal Neoplasms/secondary/drug therapy/prevention & control/immunology ; Fungal Polysaccharides/pharmacology/chemistry ; CD8-Positive T-Lymphocytes/drug effects/immunology ; Polysaccharides/pharmacology/chemistry ; Antineoplastic Agents/pharmacology ; }, abstract = {Agaricus blazei murill (ABM) mainly exerts its antitumor effect via modulation of the immune system. However, the immunomodulatory role of the ABM polysaccharide (ABMP) in mice with subcutaneously and intraperitoneally implanted MC38 tumor remains to be explored. This study aimed to define the progression effect of inhibiting tumor of ABMP in subcutaneous and intraperitoneal models and its effect on tumor microenvironment (TME) metabolism. In vitro experiments showed that ABMP could significantly promote the activity of CD8+ T immune cells in the co-culture system and promoted their colorectal cancer killing function (p < 0.05). In vivo animal exploration further showed that ABMP could inhibit the growth of intraperitoneal but not subcutaneous tumors. MCR-ALS analysis revealed a significant reduction in the signal of lipid-related spectral components in the TME of peritoneal tumors after ABMP intervention. In addition, preventive intervention with ABMP increased ω-3 polyunsaturated fatty acids content in intraperitoneal TME, revealing that ABMP shifted the metabolic landscape of the TME to promote T cell function and achieved immune regulation. These results suggest that the inhibitory effect of ABMP on colon cancer may be tumor stage-dependent, and that remodeling of fatty acid composition may be an important determinant of its action at any given stage.}, } @article {pmid39472796, year = {2024}, author = {Zheng, K and Chen, M and Xu, X and Li, P and Yin, C and Wang, J and Liu, B}, title = {Chemokine CXCL13-CXCR5 signaling in neuroinflammation and pathogenesis of chronic pain and neurological diseases.}, journal = {Cellular & molecular biology letters}, volume = {29}, number = {1}, pages = {134}, pmid = {39472796}, issn = {1689-1392}, support = {82474625//National Natural Science Foundation of China/ ; 82305368//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Chemokine CXCL13/metabolism/genetics ; *Chronic Pain/metabolism/immunology ; *Receptors, CXCR5/metabolism ; *Signal Transduction ; *Nervous System Diseases/metabolism ; Animals ; *Neuroinflammatory Diseases/metabolism ; }, abstract = {Chronic pain dramatically affects life qualities of the sufferers. It has posed a heavy burden to both patients and the health care system. However, the current treatments for chronic pain are usually insufficient and cause many unwanted side effects. Chemokine C-X-C motif ligand 13 (CXCL13), formerly recognized as a B cell chemokine, binds with the cognate receptor CXCR5, a G-protein-coupled receptor (GPCR), to participate in immune cell recruitments and immune modulations. Recent studies further demonstrated that CXCL13-CXCR5 signaling is implicated in chronic pain via promoting neuroimmune interaction and neuroinflammation in the sensory system. In addition, some latest work also pointed out the involvement of CXCL13-CXCR5 in the pathogenesis of certain neurological diseases, including ischemic stroke and amyotrophic lateral sclerosis. Therefore, we aim to outline the recent findings in regard to the involvement of CXCL13-CXCR5 signaling in chronic pain as well as certain neurological diseases, with the focus on how this chemokine signaling contributes to the pathogenesis of these neurological diseases via regulating neuroimmune interaction and neuroinflammation. Strategies that can specifically target CXCL13-CXCR5 signaling in distinct locations may provide new therapeutic options for these neurological diseases.}, } @article {pmid39472842, year = {2024}, author = {Guazzo, A and Atzeni, M and Idi, E and Trescato, I and Tavazzi, E and Longato, E and Manera, U and Chió, A and Gromicho, M and Alves, I and de Carvalho, M and Vettoretti, M and Di Camillo, B}, title = {Predicting clinical events characterizing the progression of amyotrophic lateral sclerosis via machine learning approaches using routine visits data: a feasibility study.}, journal = {BMC medical informatics and decision making}, volume = {24}, number = {Suppl 4}, pages = {318}, pmid = {39472842}, issn = {1472-6947}, support = {GA01017598//HORIZON EUROPE Health/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Feasibility Studies ; *Disease Progression ; *Machine Learning ; Male ; Middle Aged ; Female ; Aged ; Prognosis ; Noninvasive Ventilation ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in death within a short time span (3-5 years). One of the major challenges in treating ALS is its highly heterogeneous disease progression and the lack of effective prognostic tools to forecast it. The main aim of this study was, then, to test the feasibility of predicting relevant clinical outcomes that characterize the progression of ALS with a two-year prediction horizon via artificial intelligence techniques using routine visits data.

METHODS: Three classification problems were considered: predicting death (binary problem), predicting death or percutaneous endoscopic gastrostomy (PEG) (multiclass problem), and predicting death or non-invasive ventilation (NIV) (multiclass problem). Two supervised learning models, a logistic regression (LR) and a deep learning multilayer perceptron (MLP), were trained ensuring technical robustness and reproducibility. Moreover, to provide insights into model explainability and result interpretability, model coefficients for LR and Shapley values for both LR and MLP were considered to characterize the relationship between each variable and the outcome.

RESULTS: On the one hand, predicting death was successful as both models yielded F1 scores and accuracy well above 0.7. The model explainability analysis performed for this outcome allowed for the understanding of how different methodological approaches consider the input variables when performing the prediction. On the other hand, predicting death alongside PEG or NIV proved to be much more challenging (F1 scores and accuracy in the 0.4-0.6 interval).

CONCLUSIONS: In conclusion, predicting death due to ALS proved to be feasible. However, predicting PEG or NIV in a multiclass fashion proved to be unfeasible with these data, regardless of the complexity of the methodological approach. The observed results suggest a potential ceiling on the amount of information extractable from the database, e.g., due to the intrinsic difficulty of the prediction tasks at hand, or to the absence of crucial predictors that are, however, not currently collected during routine practice.}, } @article {pmid39472924, year = {2024}, author = {Stikvoort García, DJL and Sleutjes, BTHM and Mugge, W and Plouvier, JJ and Goedee, HS and Schouten, AC and van der Helm, FCT and van den Berg, LH}, title = {Instrumented assessment of lower and upper motor neuron signs in amyotrophic lateral sclerosis using robotic manipulation: an explorative study.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {193}, pmid = {39472924}, issn = {1743-0003}, support = {AV20180012//Stichting ALS Nederland/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; *Robotics/instrumentation/methods ; *Electromyography/methods/instrumentation ; Aged ; *Motor Neurons/physiology ; *Muscle, Skeletal/physiopathology/physiology ; Torque ; Wrist Joint/physiopathology ; Adult ; Muscle Strength/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a lethal progressive neurodegenerative disease characterized by upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Their varying degree of involvement results in a clinical heterogenous picture, making clinical assessments of UMN signs in patients with ALS often challenging. We therefore explored whether instrumented assessment using robotic manipulation could potentially be a valuable tool to study signs of UMN involvement.

METHODS: We examined the dynamics of the wrist joint of 15 patients with ALS and 15 healthy controls using a Wristalyzer single-axis robotic manipulator and electromyography (EMG) recordings in the flexor and extensor muscles in the forearm. Multi-sinusoidal torque perturbations were applied, during which participants were asked to either relax, comply or resist. A neuromuscular model was used to study muscle viscoelasticity, e.g. stiffness (k) and viscosity (b), and reflexive properties, such as velocity, position and force feedback gains (kv, kp and kf, respectively) that dominated the responses. We further obtained clinical signs of LMN (muscle strength) and UMN (e.g. reflexes, spasticity) dysfunction, and evaluated their relation with the estimated neuromuscular model parameters.

RESULTS: Only force feedback gains (kf) were elevated in patients (p = 0.033) compared to controls. Higher kf, as well as the resulting reflexive torque (Tref), were both associated with more severe UMN dysfunction in the examined arm (p = 0.040 and p < 0.001). Patients with UMN symptoms in the examined arm had increased kf and Tref compared to controls (both p = 0.037). Neither of these measures was related to muscle strength, but muscle stiffness (k) was lower in weaker patients (p = 0.012). All these findings were obtained from the relaxed test. No differences were observed during the instructions comply and resist.

CONCLUSIONS: This findings are proof-of-concept that instrumented assessment using robotic manipulation is a feasible technique in ALS, which may provide quantitative, operator-independent measures relating to UMN symptoms. Elevated force feedback gains, driving larger reflexive muscle torques, appear to be particularly indicative of clinically established levels of UMN dysfunction in the examined arm.}, } @article {pmid39473221, year = {2024}, author = {Ito, D and Okada, K}, title = {Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {12}, pages = {3054-3063}, pmid = {39473221}, issn = {2328-9503}, support = {21H02812//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Oligonucleotides, Antisense/administration & dosage/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide-based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on-target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis.}, } @article {pmid39473462, year = {2024}, author = {Zhang, Y and Xu, N and Yan, C and Zhou, X and Qiao, Q and Miao, L and Xu, Z}, title = {Live-Cell Imaging to Resolve Salt-Induced Liquid-Liquid Phase Separation of FUS Protein by Dye Self-Labeling.}, journal = {Chemical & biomedical imaging}, volume = {2}, number = {1}, pages = {70-80}, pmid = {39473462}, issn = {2832-3637}, abstract = {The aggregation of fusion in sarcoma (FUS) in the cytoplasm and nucleus is a pathological feature of Amyotrophic lateral sclerosis (ALS) and Frontotemporal Dementia (FTD). Genetic mutations, abnormal protein synthesis, environmental stress, and aging have all been implicated as causative factors in this process. Salt ions are essential to many physiological processes in the body, and the imbalance of them is an important environmental stress factor in cells. However, their effect on liquid-liquid phase separation (LLPS) of FUS proteins in living cells is not well understood. Here, we map the various salt-induced LLPS of FUS in living cells by genetically coding and self-labeling FUS with organic dyes. The brightness and photostability of the dyes enable long-term imaging to track the mechanism of the assembly and disappearance of FUS phase separation. The FUS protein showed a better phase separation tendency under 0.3 M salt stimulation, and there was a large amount of FUS shuttling from the nucleus to the cytoplasm. At this concentration, various salt solutions displayed different effects on the phase separation of FUS protein, following the Hofmeister effects. We further observed that the assembly of FUS droplets underwent a process of rapid formation of small droplets, plateaus, and mutual fusion. Strikingly, The CsCl-stimulated FUS droplets were not completely reversible after washing, and some solid-like granules remained in the nucleus. Taken together, these results help broaden our understanding of the LLPS of FUS proteins in cellular stress responses.}, } @article {pmid39473490, year = {2024}, author = {Fei, Y and Ding, Y}, title = {The role of ferroptosis in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1475934}, pmid = {39473490}, issn = {1662-5102}, abstract = {Ferroptosis represents an iron[-] and lipid peroxidation (LPO)-mediated form of regulated cell death (RCD). Recent evidence strongly suggests the involvement of ferroptosis in various neurodegenerative diseases (NDs), particularly Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), among others. The treatment of ferroptosis poses both opportunities and challenges in the context of ND. This review provides a comprehensive overview of characteristic features, induction and inhibition of ferroptosis, highlighting the ferroptosis inhibitor and the underlying mechanisms responsible for its occurrence. Moreover, the review explores how these mechanisms contribute to the pathogenesis and progression of major neurodegenerative disorders. Additionally, it presents novel insights into the role of ferroptosis in ND and summarizes recent advancements in the development of therapeutic approaches targeting ferroptosis. These insights and advancements hold potential to guide future strategies aimed at effectively managing these debilitating medical conditions.}, } @article {pmid39473802, year = {2024}, author = {Lukac, M and Luben, H and Martin, AE and Simmons, Z and Geronimo, A}, title = {Spatial-Temporal Analysis of Gait in Amyotrophic Lateral Sclerosis Using Foot-Worn Inertial Sensors: An Observational Study.}, journal = {Digital biomarkers}, volume = {8}, number = {1}, pages = {22-29}, pmid = {39473802}, issn = {2504-110X}, support = {R44 TR000045/TR/NCATS NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that alters gait and increases the risk of falls. The current model of care involves in-person multidisciplinary clinic visits to, in part, assess alterations in gait, evaluate safety, and make recommendations for management. Clinic visits, however, are relatively infrequent, and multidisciplinary evaluations can be physically demanding for patients. To better understand how gait changes over time in those with ALS and enable healthcare providers to properly respond to these changes, remote monitoring of functional mobility would be advantageous.

METHODS: The objective of this study was to remotely track long-term changes in walking speed using wearable inertial measurement units (IMUs). Nine ALS patients and 6 healthy controls submitted twice-weekly home walking recordings for 24 and 4 weeks, respectively. An IMU data processing method was developed and validated against laboratory-measured walking speed.

RESULTS: For both ALS patients and healthy controls, home walking speed was less than clinic walking speed by an average of 0.19 m/s (p = 0.0024). Over 24 weeks, home walking speed significantly decreased for 5 of 9 ALS patients at an average of -0.021 m/s/months (p = 0.005). Those who eventually transitioned to using assistive device (AD) while on the study demonstrated a greater decrease in walking speed than those who did not.

CONCLUSIONS: Remote longitudinal gait monitoring of ALS patients is feasible with the use of an IMU. Decreases in walking speed were detected in the majority of patients, most strongly in those who eventually transitioned to an AD. Home walking speed may more accurately represent the walking abilities of ALS patients in their real-life environments, a finding which further supports the case for remote monitoring in ALS.}, } @article {pmid39473807, year = {2024}, author = {Oliveira, GC and Ngo, QC and Passos, LA and Oliveira, LS and Stylianou, S and Papa, JP and Kumar, D}, title = {Video Assessment to Detect Amyotrophic Lateral Sclerosis.}, journal = {Digital biomarkers}, volume = {8}, number = {1}, pages = {171-180}, pmid = {39473807}, issn = {2504-110X}, abstract = {INTRODUCTION: Weakened facial movements are early-stage symptoms of amyotrophic lateral sclerosis (ALS). ALS is generally detected based on changes in facial expressions, but large differences between individuals can lead to subjectivity in the diagnosis. We have proposed a computerized analysis of facial expression videos to detect ALS.

METHODS: This study investigated the action units obtained from facial expression videos to differentiate between ALS patients and healthy individuals, identifying the specific action units and facial expressions that give the best results. We utilized the Toronto NeuroFace Dataset, which includes nine facial expression tasks for healthy individuals and ALS patients.

RESULTS: The best classification accuracy was 0.91 obtained for the pretending to smile with tight lips expression.

CONCLUSION: This pilot study shows the potential of using computerized facial expression analysis based on action units to identify facial weakness symptoms in ALS.}, } @article {pmid39473991, year = {2024}, author = {Hobro, AJ and Sakaguchi, T and Akira, S and Smith, NI}, title = {Correlative Quantitative Raman Chemical Imaging and MCR-ALS in Mouse NASH Model Reveals Direct Relationships between Diet and Resultant Liver Pathology.}, journal = {Chemical & biomedical imaging}, volume = {2}, number = {8}, pages = {577-583}, pmid = {39473991}, issn = {2832-3637}, abstract = {Raman imaging has the capability to provide unlabeled, spatially aware analysis of chemical components, with no a priori assumptions. Several lifestyle diseases such as nonalcoholic steatohepatitis (NASH) can appear in the liver as changes in the nature, abundance, and distribution of lipids, proteins, and other biomolecules and are detectable by Raman imaging. In order to identify which of these liver-associated changes occur as a direct result of the diet and which are secondary effects, we developed correlative imaging and analysis of diet and liver samples. Oleic acid was found to be a direct contributor to NASH liver composition, whereas protein and collagen distributions were found to be affected in a manner consistent with early fibrotic transformation, as a secondary consequence of the high-fat diet.}, } @article {pmid39474168, year = {2024}, author = {Sandler, AB and Wells, ME and Tran, C and Arakawa, R and Klahs, KJ and Scanaliato, JP and Green, CK and Hettrich, CM and Dunn, JC and Adler, A and Parnes, N}, title = {High rates of return to sport after suprascapular nerve decompression: an updated systematic review.}, journal = {JSES reviews, reports, and techniques}, volume = {4}, number = {4}, pages = {654-661}, pmid = {39474168}, issn = {2666-6391}, abstract = {BACKGROUND: Suprascapular nerve decompression (SSND) remains a controversial procedure. In 2018, Momaya et al published the first systematic review of SSND noting satisfactory outcomes with low rates of complications; however, numerous studies published since have noted no benefit in routinely adding SSND to other arthroscopic surgeries, contributing to existing contention regarding the procedure. The purpose of this study is to provide an updated assessment of outcomes after SSND.

METHODS: To conduct this updated systematic review, a search of PubMed (MEDLINE) for relevant studies published prior to January 21, 2023 was conducted. Outcomes including patient-reported clinical outcomes, return to sport, preoperative and postoperative electrodiagnostic testing, and adverse events were collected and pooled for assessment. Studies were eligible for inclusion if they met Momaya et al's inclusion criteria and/or reported outcomes following SSND at either the suprascapular notch or spinoglenoid notch.

RESULTS: In total, 730 patients from 33 studies were eligible for inclusion. All patient-reported outcome measure scores including American Shoulder Elbow Surgeon Standardized Shoulder Assessment; Constant-Murley score; Disabilities of the Arm, Shoulder, and Hand; Subjective Shoulder Value; University of California-Los Angeles shoulder; and visual analog scale pain scores improved significantly postoperatively, with improvements ranging from 53.5% to 102.6% of preoperative values. Ultimately, 98% (n = 90/92) of patients returned to sport or military duty and 96% of these patients returned at their previous level of activity (n = 48/50) without heterogeneity among rates between studies (P = .176, P = .238, respectively). Preoperative electrodiagnostic testing was conducted in 93% of patients, and 90% had associated abnormal findings. Continued symptoms were noted among 12% of patients (n = 39/322) with significantly different rates observed between studies. Complications from operative management not limited to SSND occurred in 11% of patients (n = 64/576) and reoperations occurred in 3.3% of patients (n = 15/455).

CONCLUSION: Suprascapular neuropathy treated with SSND significantly improves patient-reported outcomes and is noninferior to similar procedures without SSND. Appropriate clinical diagnosis of suprascapular neuropathy is required as opposed to a routine adjunct procedure with other arthroscopic shoulder surgery. Ultimately, SSND is associated with high rates of return to sport and relatively low rates of adverse events; however, the risk of continued symptoms and electrodiagnostic test-related complications is an important point on preoperative counseling.}, } @article {pmid39474398, year = {2024}, author = {Goyal, O and Goyal, MK}, title = {Critical analysis of the effects of proton pump inhibitors on inflammatory bowel disease: An updated review.}, journal = {World journal of gastroenterology}, volume = {30}, number = {37}, pages = {4160-4162}, pmid = {39474398}, issn = {2219-2840}, mesh = {Humans ; *Colitis, Ulcerative/drug therapy/immunology/diagnosis ; *Crohn Disease/diagnosis/drug therapy/immunology ; *Proton Pump Inhibitors/therapeutic use/adverse effects ; Treatment Outcome ; Review Literature as Topic ; }, abstract = {This letter critically evaluates the effects of proton pump inhibitors (PPIs) on inflammatory bowel disease, particularly focusing on Crohn's disease (CD) and ulcerative colitis (UC), as discussed in Liang et al's recent review. While the review provides significant insights, it relies heavily on cross-sectional and observational studies, which limits the ability to draw causal inferences. The heterogeneous study populations and inconsistent definitions of long-term PPI use further complicate the findings. This letter also highlights the need for rigorous control of confounding factors and considers the potential publication bias in the existing literature. The implications of these issues are discussed in the context of both CD and UC, and future research directions are proposed to address these shortcomings.}, } @article {pmid39475135, year = {2024}, author = {Jackowski, T and Horodnicka-Józwa, A and Berus, E and Walczak, M and Petriczko, E}, title = {An analysis of acid-labile subunit (ALS) levels in children with short stature born with normal weight.}, journal = {Endokrynologia Polska}, volume = {75}, number = {5}, pages = {548-557}, doi = {10.5603/ep.100285}, pmid = {39475135}, issn = {2299-8306}, mesh = {Humans ; Child ; Female ; Male ; *Glycoproteins ; Growth Disorders/diagnosis ; Carrier Proteins ; Child, Preschool ; Insulin-Like Growth Factor I/metabolism/analysis ; Insulin-Like Growth Factor Binding Protein 3/blood ; Body Height ; }, abstract = {INTRODUCTION: The acid-labile subunit (ALS) is a protein best known for its function in stabilising the insulin like growth factor-1/2-insulin-like growth factor-1 binding protein 3/5 (IGF-1/2-IGFBP3/5) binary complex by creating the ternary complex and in consequence regulating the biological activity of IGF-1. The aim of the study was to assess ALS concentrations in a chosen population of children with short stature taking into account their clinical diagnosis.

MATERIAL AND METHODS: A total of 109 prepubertal children were involved in the study - 85 children in the study group and 24 in controls. In all the children IGF-1, IGFBP3, and ALS were measured. The study group was divided according to diagnosis into groups: growth hormone deficiency (GHD), constitutional delay of growth and puberty (CDGP), idiopathic short stature (ISS), and familial short stature (FSS).

RESULTS: In the control group the ALS concentration ranged from 4.81 to 13.66 μg/mL. In the whole study group the ALS concentration ranged from 2.73 to 15.81 μg/mL. The difference between both groups was statistically significant (p < 0.0001, R = 0.39). A strong, statistically significant correlation between ALS levels and age was observed, but only in the study group (p < 0.0001, r = 0.59). The ALS standard deviation score (SDS) was not significantly different between the control and CDGP children (p = 0.0644). The ALS concentration was significantly lower in children with short stature. There was, however, no difference between the subgroups of the study group.

CONCLUSION: There was no significant difference in ALS SDS between the control group and children with constitutional delay of growth and development. The usefulness of ALS in routine short stature diagnostics is uncertain, but it might play a role in the diagnosis of children with ISS and CDGP in the future.}, } @article {pmid39475283, year = {2025}, author = {Ziser, L and van Eijk, RPA and Kiernan, MC and McRae, A and Henderson, RD and Schultz, D and Needham, M and Mathers, S and McCombe, P and Talman, P and Vucic, S}, title = {Amyotrophic lateral sclerosis established as a multistep process across phenotypes.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16532}, pmid = {39475283}, issn = {1468-1331}, support = {//National Health and Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Middle Aged ; *Phenotype ; Male ; Female ; Aged ; *Registries ; *Age of Onset ; Australia/epidemiology ; Disease Progression ; Incidence ; Adult ; }, abstract = {BACKGROUND AND PURPOSE: Given the accepted multistep process of disease causation in amyotrophic lateral sclerosis (ALS), the present study was undertaken to determine the number of steps required for disease onset across each of the ALS phenotypes.

METHODS: Clinical and demographic data were prospectively accumulated using the Australian Motor Neurone Disease Registry (2005-2016), and age-specific incidence rates were calculated. Poisson regression was utilized to assess the relationship between log age-specific incidence and log age of onset, with McFadden's R[2] used to assess the goodness of fit of the model.

RESULTS: In total, 2647 ALS patients were included, with mean disease-onset age being 62.2 ± 12.1 years. A linear relationship between log incidence and log age was established across ALS phenotypes, with variable slope estimates: bulbar 5.1 (95% confidence interval [CI] 4.6-5.6); cervical 2.7 (95% CI 2.3-3.0); lumbar 3.5 (95% CI 3.2-3.9); flail arm 4.7 (95% CI 3.9-5.5); flail leg 3.6 (95% CI 2.6-4.5); primary lateral sclerosis 2.7 (95% CI 1.8-3.7). Slope estimates were significantly higher in the bulbar compared to the cervical, lumbar and primary lateral sclerosis phenotypes. McFadden's R[2] values were >0.4 for all phenotypes indicating excellent model fit.

DISCUSSION: A multistep process has been established across all ALS phenotypes with variable slope estimates, suggesting that the number of steps to develop disease is different across clinical presentations. Identification of mechanisms underlying slope estimate variability could exert pathophysiological significance.}, } @article {pmid39475611, year = {2024}, author = {Wang, LQ and Ma, Y and Zhang, MY and Yuan, HY and Li, XN and Xia, W and Zhao, K and Huang, X and Chen, J and Li, D and Zou, L and Wang, Z and Le, W and Liu, C and Liang, Y}, title = {Amyloid fibril structures and ferroptosis activation induced by ALS-causing SOD1 mutations.}, journal = {Science advances}, volume = {10}, number = {44}, pages = {eado8499}, pmid = {39475611}, issn = {2375-2548}, mesh = {*Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Amyloid/metabolism ; *Mutation ; *Ferroptosis/genetics ; Cryoelectron Microscopy ; Models, Molecular ; Mitochondria/metabolism ; }, abstract = {Over 200 genetic mutations in copper-zinc superoxide dismutase (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). Among these, two ALS-causing mutants, histidine-46→arginine (H46R) and glycine-85→arginine (G85R), exhibit a decreased capacity to bind metal ions. Here, we report two cryo-electron microscopy structures of amyloid fibrils formed by H46R and G85R. These mutations lead to the formation of amyloid fibrils with unique structures distinct from those of the native fibril. The core of these fibrils features a serpentine arrangement with seven or eight β strands, secured by a hydrophobic cavity and a salt bridge between arginine-85 and aspartic acid-101 in the G85R fibril. We demonstrate that these mutant fibrils are notably more toxic and capable of promoting the aggregation of wild-type SOD1 more effectively, causing mitochondrial impairment and activating ferroptosis in cell cultures, compared to wild-type SOD1 fibrils. Our study provides insights into the structural mechanisms by which SOD1 mutants aggregate and induce cytotoxicity in ALS.}, } @article {pmid39478194, year = {2024}, author = {Yang, M and You, D and Liu, G and Lu, Y and Yang, G and O'Brien, T and Henshall, DC and Hardiman, O and Cai, L and Liu, M and Shen, S}, title = {Polyethyleneimine facilitates the growth and electrophysiological characterization of iPSC-derived motor neurons.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {26106}, pmid = {39478194}, issn = {2045-2322}, support = {16/RC/3948/SFI_/Science Foundation Ireland/Ireland ; C2024205026//Natural Science Foundation of Hebei Province/ ; L2024B36//Doctoral Research Initiation Fund Project of Hebei Normal University/ ; GJHZ20200731095005016//International Scientific and Technological Cooperation Foundation of Shenzhen/ ; 00000326//Medical-Engineering Interdisciplinary Research Foundation of ShenZhen University/ ; }, mesh = {*Polyethyleneimine/pharmacology ; *Electrophysiology ; *Induced Pluripotent Stem Cells/drug effects ; *Cell Proliferation/drug effects ; Motor Neurons/drug effects ; Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Cells, Cultured ; Cell Differentiation ; }, abstract = {Induced pluripotent stem cell (iPSC) technology, in combination with electrophysiological characterization via multielectrode array (MEA), has facilitated the utilization of iPSC-derived motor neurons (iPSC-MNs) as highly valuable models for underpinning pathogenic mechanisms and developing novel therapeutic interventions for motor neuron diseases (MNDs). However, the challenge of MN adherence to the MEA plate and the heterogeneity presented in iPSC-derived cultures raise concerns about the reproducibility of the findings obtained from these cellular models. We discovered that one novel factor modulating the electrophysiological activity of iPSC-MNs is the extracellular matrix (ECM) used in the coating to support in vitro growth, differentiation and maturation of iPSC-MNs. The current study showed that two coating conditions, namely, Poly-L-ornithine/Matrigel (POM) and Polyethyleneimine (PEI) strongly promoted attachment of iPSC-MNs on MEA culture dishes compared to three other coating conditions, and both facilitated the maturation of iPSC-MNs as characterized by the detection of extensive electrophysiological activities from the MEA plates. POM coating accelerated the maturation of the iPSC-MNs for up to 5 weeks, which suits modeling of neurodevelopmental disorders. However, the application of PEI resulted in more even distribution of the MNs on the culture dish and reduced variability of electrophysiological signals from the iPSC-MNs in 7-week cultures, which permitted the detection of enhanced excitability in iPSC-MNs from patients with amyotrophic lateral sclerosis (ALS). This study provides a comprehensive comparison of five coating conditions and offers POM and PEI as favorable coatings for in vitro modeling of neurodevelopmental and neurodegenerative disorders, respectively.}, } @article {pmid39478664, year = {2025}, author = {Ropert, B and Bannwarth, S and Genin, EC and Vaillant-Beuchot, L and Lacas-Gervais, S and Madji Hounoum, B and Bernardin, A and Dinh, N and Mauri-Crouzet, A and D'Elia, MA and Augé, G and Lespinasse, F and Di Giorgio, A and Meira, W and Bonnefoy, N and Monassier, L and Schiff, M and Sago, L and Kilinc, D and Brau, F and Redeker, V and Bohl, D and Tribouillard-Tanvier, D and Procaccio, V and Azoulay, S and Ricci, JE and Delahodde, A and Paquis-Flucklinger, V}, title = {Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {5}, pages = {1665-1679}, doi = {10.1093/brain/awae348}, pmid = {39478664}, issn = {1460-2156}, support = {ANR-16-CE16-0024-01//Agence Nationale de la Recherche/ ; //Association Française contre les Myopathies/ ; //la Ligue Nationale contre le Cancer/ ; //la ville de Nice/ ; FDT202012010694//Fondation pour la Recherche Médicale/ ; MND202004011475//Fondation pour la Recherche Médicale/ ; P-21-03626//French RENATECH network/ ; }, mesh = {Humans ; *Mitochondrial Proteins/genetics/metabolism ; *Hydroxybenzoates/pharmacology ; *Mitochondria/drug effects/metabolism ; Motor Neurons/drug effects/metabolism ; Fibroblasts/drug effects/metabolism ; Induced Pluripotent Stem Cells/drug effects ; Mitochondria Associated Membranes ; Nitrofurans ; }, abstract = {The identification of a point mutation (p.Ser59Leu) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease. Since then, we have shown that this mutation leads to the disorganization of the MItochondrial contact site and Cristae Organizing System (MICOS) complex that maintains the mitochondrial cristae structure. Here, we generated yeast mutant strains mimicking MICOS instability and used them to test the ability of more than 1600 compounds from two repurposed libraries to rescue the growth defect of those cells. Among the hits identified, we selected nifuroxazide, a broad-spectrum antibacterial molecule. We show that nifuroxazide rescues mitochondrial network fragmentation and cristae abnormalities in CHCHD10S59L/+ patient fibroblasts. This molecule also decreases caspase-dependent death of human CHCHD10S59L/+ induced pluripotent stem cell-derived motor neurons. Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons. Our findings strengthen the MICOS-mitochondrial transport connection. Nifuroxazide and analogues emerge as potential therapeutics for MICOS-related disorders like motor neuron disease. Its impact on syntaphilin hints at broader neurological disorder applicability for nifuroxazide.}, } @article {pmid39480562, year = {2025}, author = {Cao, G and Wang, S and Yu, J and Wang, X and Shi, X and Yang, L and Zhang, X and Tong, P and Tan, H}, title = {Outcomes of combined single-bundle anterior cruciate ligament reconstruction and anterolateral structure reconstruction through a modified single femoral tunnel.}, journal = {International orthopaedics}, volume = {49}, number = {1}, pages = {83-91}, pmid = {39480562}, issn = {1432-5195}, support = {82104896//National Natural Science Foundation of China/ ; 242102310025//Henan Provincial Science and Technology Research Project/ ; 2024HLTJ17//Heluo Youth Talent Support Program/ ; }, mesh = {Humans ; Male ; Female ; *Anterior Cruciate Ligament Reconstruction/methods ; Adult ; Middle Aged ; Young Adult ; Adolescent ; *Femur/surgery ; *Anterior Cruciate Ligament Injuries/surgery ; Treatment Outcome ; Arthroscopy/methods ; Hamstring Tendons/transplantation ; Transplantation, Autologous/methods ; }, abstract = {PURPOSE: To explore the clinical outcomes of combining anterior cruciate ligament (ACL) reconstruction and anterolateral structure (ALS) reconstruction through a modified single femoral tunnel in patients with high risk of clinical failure.

METHODS: From December 2018 to August 2022, a total of 62 patients with ACL injury in our institution were enrolled in this study. All patients were associated with high risk of clinical failure, meeting the indications of ALS reconstruction. All patients accepted arthroscopic single-bundle ACL reconstruction and ALS reconstruction using hamstring autograft through a modified single femoral tunnel. Perioperative clinical outcome measurements consisted of functions, stability and safety evaluation at different time points (preoperative, postoperative three month, six month, one year, two year, three year and more). Functional evaluation included Lysholm score, Tegner activity scale, subjective and objective International Knee Documentation Committee (IKDC) score.

RESULTS: All patients, including 47 males and 15 females, aged 16-52 years with an average age of 29.3 ± 9.2 years, were followed up for 12-58 months. At the last follow-up, the Lysholm, subjective IKDC and Tegner activity scale (93.8 ± 7.0, 88.8 ± 10.7 and 5.8 ± 1.4 respectively) were significantly higher than those before surgery (65.0 ± 20.8, 51.2 ± 21.1 and 2.3 ± 1.3 respectively)(P < 0.05). Postoperative pivot shift and Lachman test were markedly improved (P < 0.05). One patient still had grade II pivot shift, defined as clinical failure. During follow-up, no graft rupture occurred according to magnetic resonance imaging and physical examination, no lateral compartment osteoarthritis were found in all patients.

CONCLUSIONS: Combined single bundle ACL reconstruction and ALS reconstruction through a modified single femoral tunnel could significantly improve knee function and stability with low related risk in patients with high risk of failure in ACL injury.}, } @article {pmid39480764, year = {2024}, author = {Perrin, S and Ladha, S and Maragakis, N and Rivner, MH and Katz, J and Genge, A and Olney, N and Lange, D and Heitzman, D and Bodkin, C and Jawdat, O and Goyal, NA and Bornstein, JD and Mak, C and Appel, SH and Paganoni, S}, title = {Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial.}, journal = {PLoS medicine}, volume = {21}, number = {10}, pages = {e1004469}, pmid = {39480764}, issn = {1549-1676}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology ; Antibodies, Monoclonal/adverse effects/administration & dosage/therapeutic use ; Antibodies, Monoclonal, Humanized/adverse effects/administration & dosage/therapeutic use/pharmacokinetics ; Biomarkers/blood ; CD40 Ligand/blood ; Disease Progression ; Dose-Response Relationship, Drug ; Neurofilament Proteins/blood ; Pyrazines ; Treatment Outcome ; Imidazoles ; }, abstract = {BACKGROUND: The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS).

METHODS AND FINDINGS: In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation.

CONCLUSIONS: Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS.

TRIAL REGISTRATION: Clintrials.gov ID:NCT04322149.}, } @article {pmid39483234, year = {2024}, author = {Fujimoto, A and Kinjo, M and Kitamura, A}, title = {Short Repeat Ribonucleic Acid Reduces Cytotoxicity by Preventing the Aggregation of TDP-43 and Its 25 KDa Carboxy-Terminal Fragment.}, journal = {JACS Au}, volume = {4}, number = {10}, pages = {3896-3909}, pmid = {39483234}, issn = {2691-3704}, abstract = {TAR DNA/RNA-binding protein 43 kDa (TDP-43) proteinopathy is a hallmark of neurodegenerative disorders, such as amyotrophic lateral sclerosis, in which cytoplasmic aggregates containing TDP-43 and its C-terminal fragments, such as TDP-25, are observed in degenerative neuronal cells. However, few reports have focused on small molecules that can reduce their aggregation and cytotoxicity. Here, we show that short RNA repeats of GGGGCC and AAAAUU are aggregation suppressors of TDP-43 and TDP-25. TDP-25 interacts with these RNAs, as well as TDP-43, despite the lack of major RNA-recognition motifs using fluorescence cross-correlation spectroscopy. Expression of these RNAs significantly decreases the number of cells harboring cytoplasmic aggregates of TDP-43 and TDP-25 and ameliorates cell death by TDP-25 and mislocalized TDP-43 without altering the cellular transcriptome of molecular chaperones. Consequently, short RNA repeats of GGGGCC and AAAAUU can maintain proteostasis by preventing the aggregation of TDP-43 and TDP-25.}, } @article {pmid39483635, year = {2024}, author = {Murakami, Y and Ando, M and Imamura, A and Oketani, R and Leproux, P and Honjoh, S and Kano, H}, title = {Molecular Fingerprinting of Mouse Brain Using Ultrabroadband Coherent Anti-Stokes Raman Scattering (CARS) Microspectroscopy Empowered by Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS).}, journal = {Chemical & biomedical imaging}, volume = {2}, number = {10}, pages = {689-697}, pmid = {39483635}, issn = {2832-3637}, abstract = {The Raman fingerprint spectral region provides abundant structural information on molecules. However, analyzing vibrational images within this region using coherent Raman imaging remains challenging due to the small Raman cross section and congested spectral features. In this study, we combined ultrabroadband coherent anti-Stokes Raman scattering (CARS) microspectroscopy across the spectral range of 500-4000 cm[-1] with multivariate curve resolution-alternating least-squares (MCR-ALS) to reveal hidden Raman bands in the fingerprint region. Applying this method to mouse brain tissue, we extracted information on cholesterol and collagen, leveraging their distinctive molecular signatures, as well as on key molecules such as lipids, proteins, water, and nucleic acids. Moreover, the simultaneous detection of second harmonic generation facilitated label-free visualization of organelles, including arachnoid membrane and Rootletin filaments.}, } @article {pmid39484239, year = {2024}, author = {Leinders, S and Aarnoutse, EJ and Branco, MP and Freudenburg, ZV and Geukes, SH and Schippers, A and Verberne, MSW and van den Boom, M and van der Vijgh, B and Crone, NE and Denison, T and Ramsey, NF and Vansteensel, MJ}, title = {DO NOT LOSE SLEEP OVER IT: IMPLANTED BRAIN-COMPUTER INTERFACE FUNCTIONALITY DURING NIGHTTIME IN LATE-STAGE AMYOTROPHIC LATERAL SCLEROSIS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39484239}, support = {U01 DC016686/DC/NIDCD NIH HHS/United States ; UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Brain-computer interfaces (BCIs) hold promise as augmentative and alternative communication technology for people with severe motor and speech impairment (locked-in syndrome) due to neural disease or injury. Although such BCIs should be available 24/7, to enable communication at all times, feasibility of nocturnal BCI use has not been investigated. Here, we addressed this question using data from an individual with amyotrophic lateral sclerosis (ALS) who was implanted with an electrocorticography-based BCI that enabled the generation of click-commands for spelling words and call-caregiver signals.

METHODS: We investigated nocturnal dynamics of neural signal features used for BCI control, namely low (LFB: 10-30Hz) and high frequency band power (HFB: 65-95Hz). Additionally, we assessed the nocturnal performance of a BCI decoder that was trained on daytime data by quantifying the number of unintentional BCI activations at night. Finally, we developed and implemented a nightmode decoder that allowed the participant to call a caregiver at night, and assessed its performance.

RESULTS: Power and variance in HFB and LFB were significantly higher at night than during the day in the majority of the nights, with HFB variance being higher in 88% of nights. Daytime decoders caused 245 unintended selection-clicks and 13 unintended caregiver-calls per hour when applied to night data. The developed nightmode decoder functioned error-free in 79% of nights over a period of ±1.5 years, allowing the user to reliably call the caregiver, with unintended activations occurring only once every 12 nights.

DISCUSSION: Reliable nighttime use of a BCI requires decoders that are adjusted to sleep-related signal changes. This demonstration of a reliable BCI nightmode and its long-term use by an individual with advanced ALS underscores the importance of 24/7 BCI reliability.

TRIAL REGISTRATION: This trial is registered in clinicaltrials.gov under number NCT02224469 (https://clinicaltrials.gov/study/NCT02224469?term=NCT02224469&rank=1). Date of submission to registry: August 21, 2014. Enrollment of first participant: September 7, 2015.}, } @article {pmid39484675, year = {2022}, author = {Chopra, N and Menounos, S and Choi, JP and Hansbro, PM and Diwan, AD and Das, A}, title = {Blood-Spinal Cord Barrier: Its Role in Spinal Disorders and Emerging Therapeutic Strategies.}, journal = {NeuroSci}, volume = {3}, number = {1}, pages = {1-27}, pmid = {39484675}, issn = {2673-4087}, abstract = {The blood-spinal cord barrier (BSCB) has been long thought of as a functional equivalent to the blood-brain barrier (BBB), restricting blood flow into the spinal cord. The spinal cord is supported by various disc tissues that provide agility and has different local immune responses compared to the brain. Though physiologically, structural components of the BSCB and BBB share many similarities, the clinical landscape significantly differs. Thus, it is crucial to understand the composition of BSCB and also to establish the cause-effect relationship with aberrations and spinal cord dysfunctions. Here, we provide a descriptive analysis of the anatomy, current techniques to assess the impairment of BSCB, associated risk factors and impact of spinal disorders such as spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), peripheral nerve injury (PNI), ischemia reperfusion injury (IRI), degenerative cervical myelopathy (DCM), multiple sclerosis (MS), spinal cavernous malformations (SCM) and cancer on BSCB dysfunction. Along with diagnostic and mechanistic analyses, we also provide an up-to-date account of available therapeutic options for BSCB repair. We emphasize the need to address BSCB as an individual entity and direct future research towards it.}, } @article {pmid39486415, year = {2024}, author = {Al-Azzam, N and To, JH and Gautam, V and Street, LA and Nguyen, CB and Naritomi, JT and Lam, DC and Madrigal, AA and Lee, B and Jin, W and Avina, A and Mizrahi, O and Mueller, JR and Ford, W and Schiavon, CR and Rebollo, E and Vu, AQ and Blue, SM and Madakamutil, YL and Manor, U and Rothstein, JD and Coyne, AN and Jovanovic, M and Yeo, GW}, title = {Inhibition of RNA splicing triggers CHMP7 nuclear entry, impacting TDP-43 function and leading to the onset of ALS cellular phenotypes.}, journal = {Neuron}, volume = {112}, number = {24}, pages = {4033-4047.e8}, pmid = {39486415}, issn = {1097-4199}, support = {R01 HG012216/HG/NHGRI NIH HHS/United States ; P30 AG068635/AG/NIA NIH HHS/United States ; U24 HG009889/HG/NHGRI NIH HHS/United States ; R01 HG004659/HG/NHGRI NIH HHS/United States ; R35 GM128802/GM/NIGMS NIH HHS/United States ; R01 AG071869/AG/NIA NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; *RNA Splicing ; *Motor Neurons/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Cell Nucleus/metabolism ; Phenotype ; Active Transport, Cell Nucleus ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is linked to the reduction of certain nucleoporins in neurons. Increased nuclear localization of charged multivesicular body protein 7 (CHMP7), a protein involved in nuclear pore surveillance, has been identified as a key factor damaging nuclear pores and disrupting transport. Using CRISPR-based microRaft, followed by gRNA identification (CRaft-ID), we discovered 55 RNA-binding proteins (RBPs) that influence CHMP7 localization, including SmD1, a survival of motor neuron (SMN) complex component. Immunoprecipitation-mass spectrometry (IP-MS) and enhanced crosslinking and immunoprecipitation (CLIP) analyses revealed CHMP7's interactions with SmD1, small nuclear RNAs, and splicing factor mRNAs in motor neurons (MNs). ALS induced pluripotent stem cell (iPSC)-MNs show reduced SmD1 expression, and inhibiting SmD1/SMN complex increased CHMP7 nuclear localization. Crucially, overexpressing SmD1 in ALS iPSC-MNs restored CHMP7's cytoplasmic localization and corrected STMN2 splicing. Our findings suggest that early ALS pathogenesis is driven by SMN complex dysregulation.}, } @article {pmid39486473, year = {2024}, author = {Wang, HE and Daya, MR and Schmicker, R and Nassal, M and Okubo, M and Aramendi, E and Alonso, E and Idris, A and Panchal, AR and Jaureguibeitia, X and Aufderheide, T and Carlson, J and Nichol, G}, title = {Vasopressor or advanced airway first in cardiac arrest?.}, journal = {Resuscitation}, volume = {205}, number = {}, pages = {110422}, pmid = {39486473}, issn = {1873-1570}, support = {K08 HL168330/HL/NHLBI NIH HHS/United States ; UH2 HL125163/HL/NHLBI NIH HHS/United States ; UH3 HL125163/HL/NHLBI NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Airway Management/methods ; *Cardiopulmonary Resuscitation/methods ; Epinephrine/administration & dosage ; Intubation, Intratracheal/methods ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Return of Spontaneous Circulation ; *Vasoconstrictor Agents/therapeutic use/administration & dosage ; Vasopressins/therapeutic use/administration & dosage ; }, abstract = {BACKGROUND: While resuscitation guidelines emphasize early vasopressor administration and advanced airway management, their optimal sequence remains unclear. We sought to determine the associations between vasopressor-airway resuscitation sequence and out-of-hospital cardiac arrest (OHCA) outcomes in the Pragmatic Airway Resuscitation Trial (PART).

METHODS: We analyzed data from the PART trial. For each patient we determined times of first vasopressor administration (epinephrine or vasopressin), and successful advanced airway insertion (laryngeal tube or endotracheal tube). We classified each case as vasopressor-first or advanced airway-first. We used Generalized Estimating Equations to determine associations between vasopressor-airway sequence and outcomes (72-hour survival, return of spontaneous circulation (ROSC) on emergency department arrival, survival to hospital discharge, hospital survival with favorable neurologic status) and CPR outside of recommended parameters (chest compression fraction <0.8, chest compression rate <100 or >120 per min, or ventilation rate <8 or >12 breaths/min), adjusting for confounders.

RESULTS: Of 3,004 patients in the parent trial, we analyzed 2,404, including 1,821 vasopressor-first and 583 advanced airway-first. Median intervention times: ALS arrival-to-vasopressor 8 min (IQR 6-11) and ALS arrival-to-airway 11 min (8-15). Compared with airway-first, vasopressor-first sequence was not associated with 72-hour survival (adjusted OR 0.96; 95% CI: 0.71-1.31), ROSC (0.83; 0.66-1.06), hospital survival (1.09; 0.68-1.73), or hospital survival with favorable neurologic status (0.97; 0.53-1.78). Vasopressor-first sequence was not associated with non-compliance with recommended CPR performance parameters.

CONCLUSIONS: Vasopressor-airway resuscitation sequence was not associated with OHCA outcomes or CPR quality.}, } @article {pmid39486621, year = {2024}, author = {Stephani, C and Krämer, H and Chakalov, I and Bähr, M and Paulus, W and Antal, A and Koch, JC}, title = {Static transcranial magnetic stimulation does not alter cortical excitability in patients with amyotrophic lateral sclerosis on riluzole.}, journal = {Brain stimulation}, volume = {17}, number = {6}, pages = {1244-1246}, doi = {10.1016/j.brs.2024.10.013}, pmid = {39486621}, issn = {1876-4754}, } @article {pmid39486809, year = {2024}, author = {Van Loon, FT and Seitidis, G and Mavridis, D and van Unnik, JWJ and Weemering, DN and van den Berg, LH and Bethani, I and Nikolakopoulos, S and van Eijk, RPA}, title = {Living systematic review and comprehensive network meta-analysis of ALS clinical trials: study protocol.}, journal = {BMJ open}, volume = {14}, number = {10}, pages = {e087970}, pmid = {39486809}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Clinical Trials as Topic ; Disease Progression ; Research Design ; Systematic Reviews as Topic ; Network Meta-Analysis as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurogenerative disease with no effective treatment to date. Despite numerous clinical trials, the majority of studies have been futile in their effort to significantly alter the course of the disease. However, these studies may still provide valuable information for identifying patient subgroups and generating new hypotheses for future research. Additionally, synthesising evidence from these studies may help overcome the limitations of individual studies. Network meta-analysis may refine the assessment of efficacy in specific patient subgroups, evaluate intervention characteristics such as mode of administration or biological mechanisms of action, and rank order promising therapeutic areas of interest. Therefore, we aim to synthesise the available evidence from ALS clinical trials.

METHODS AND ANALYSIS: We will conduct a systematic review to identify all clinical trials that assessed disease-modifying pharmaceutical therapies, cell therapies, or supplements in patients with ALS. Outcomes of interest are clinical disease progression outcomes and survival. We will conduct this search in the period Q4 2024 in three databases: PubMed, Embase and ClinicalTrials.gov for studies from 1999 to 2023. Individual patient data and aggregate data will be collected and subsequentially synthesised in meta-analytical models. The final model will be presented as an open-source web application with biannual updates of the underlying data, thereby providing a 'living' overview of the ALS clinical trial landscape.

ETHICS AND DISSEMINATION: No ethics approvals are required. Findings will be presented at relevant conferences and submitted to peer-reviewed journals. Data will be stored anonymously in secure repositories.}, } @article {pmid39487163, year = {2024}, author = {Cai, S and Venugopalan, S and Seaver, K and Xiao, X and Tomanek, K and Jalasutram, S and Morris, MR and Kane, S and Narayanan, A and MacDonald, RL and Kornman, E and Vance, D and Casey, B and Gleason, SM and Nelson, PQ and Brenner, MP}, title = {Using large language models to accelerate communication for eye gaze typing users with ALS.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9449}, pmid = {39487163}, issn = {2041-1723}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Communication Devices for People with Disabilities ; Female ; Male ; Pilot Projects ; *Fixation, Ocular/physiology ; Language ; Adult ; User-Computer Interface ; Middle Aged ; Communication ; }, abstract = {Accelerating text input in augmentative and alternative communication (AAC) is a long-standing area of research with bearings on the quality of life in individuals with profound motor impairments. Recent advances in large language models (LLMs) pose opportunities for re-thinking strategies for enhanced text entry in AAC. In this paper, we present SpeakFaster, consisting of an LLM-powered user interface for text entry in a highly-abbreviated form, saving 57% more motor actions than traditional predictive keyboards in offline simulation. A pilot study on a mobile device with 19 non-AAC participants demonstrated motor savings in line with simulation and relatively small changes in typing speed. Lab and field testing on two eye-gaze AAC users with amyotrophic lateral sclerosis demonstrated text-entry rates 29-60% above baselines, due to significant saving of expensive keystrokes based on LLM predictions. These findings form a foundation for further exploration of LLM-assisted text entry in AAC and other user interfaces.}, } @article {pmid39487328, year = {2024}, author = {Paganoni, S and Harkey, B and Giacomelli, E and Cudkowicz, M and , }, title = {Lessons from the HEALEY adaptive platform trial in amyotrophic lateral sclerosis.}, journal = {Nature aging}, volume = {4}, number = {11}, pages = {1512-1515}, pmid = {39487328}, issn = {2662-8465}, } @article {pmid39487710, year = {2025}, author = {van Veenhuijzen, K and Tan, HHG and Nitert, AD and van Es, MA and Veldink, JH and van den Berg, LH and Westeneng, HJ}, title = {Longitudinal Magnetic Resonance Imaging in Asymptomatic C9orf72 Mutation Carriers Distinguishes Phenoconverters to Amyotrophic Lateral Sclerosis or Amyotrophic Lateral Sclerosis With Frontotemporal Dementia.}, journal = {Annals of neurology}, volume = {97}, number = {2}, pages = {281-295}, pmid = {39487710}, issn = {1531-8249}, support = {//Stichting ALS Nederland/ ; 772376-EScORIAL//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/pathology ; *C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics/diagnostic imaging/pathology ; Male ; Female ; Magnetic Resonance Imaging ; Middle Aged ; Longitudinal Studies ; Aged ; Mutation/genetics ; Adult ; Heterozygote ; Atrophy ; Prospective Studies ; Brain/diagnostic imaging/pathology ; }, abstract = {OBJECTIVE: We prospectively studied asymptomatic C9orf72 mutation carriers, identifying those developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD).

METHODS: We enrolled 56 asymptomatic family members (AFM) with a C9orf72 mutation (AFM C9+), 132 non-carriers (AFM C9-), and 359 population-based controls. Using 3 T magnetic resonance imaging, we measured cortical thickness, gyrification, and subcortical volumes longitudinally. Linear mixed-effects models on non-converting AFM C9+ scans (n = 107) created a reference for these measurements, establishing individual atrophy patterns. Atrophy patterns from presymptomatic phenoconverters (n = 10 scans) served as a template for group comparisons and similarity assessments. Similarity with phenoconverters was quantified using Dice similarity coefficient (DSC) for cortical and Kullback-Leibler similarity (KLS) for subcortical measures. Using longitudinal similarity assessments, we predicted when participants would reach the average similarity level of phenoconverters at their first post-onset scan.

RESULTS: Five AFM C9+ converted to ALS or ALS-FTD. Up to 6 years before symptoms, these phenoconverters exhibited significant atrophy in frontal, temporal, parietal, and cingulate cortex, along with smaller thalamus, hippocampus, and amygdala compared to other AFM C9+. Some non-converted AFM C9+ had high DSC and KLS, approaching values of phenoconverters, whereas others, along with AFM C9- and controls, had lower values. At age 80, we predicted 27.9% (95% confidence interval, 13.2-40.1%) of AFM C9+ and no AFM C9- would reach the same DSC as phenoconverters.

INTERPRETATION: Distinctive atrophy patterns are visible years before symptom onset on presymptomatic scans of phenoconverters. Combining baseline and follow-up similarity measures may serve as a promising imaging biomarker for identifying those at risk of ALS or ALS-FTD. ANN NEUROL 2025;97:281-295.}, } @article {pmid39488863, year = {2024}, author = {Lopes, M and Swash, M and de Carvalho, M}, title = {F-waves responses derived from low-intensity electrical stimulation: A method to explore split-hand pathogenesis.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {54}, number = {6}, pages = {103018}, doi = {10.1016/j.neucli.2024.103018}, pmid = {39488863}, issn = {1769-7131}, mesh = {Humans ; Male ; Female ; *Hand/physiopathology ; Adult ; *Muscle, Skeletal/physiopathology/physiology ; *Electric Stimulation/methods ; Middle Aged ; Motor Neurons/physiology ; Electromyography ; Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Young Adult ; Evoked Potentials, Motor/physiology ; Aged ; }, abstract = {OBJECTIVES: The "split-hand syndrome" is a common clinical sign in amyotrophic lateral sclerosis (ALS), being characterized by more severe atrophy of the hand muscles on the radial side of the hand compared to the ulnar side. We aimed to investigate possible physiological differences between relevant hand muscles using low-intensity F-wave stimulation to assess spinal motoneuron excitability.

METHODS: We recruited 36 healthy volunteers. F-waves were recorded from the abductor pollicis brevis (APB), first dorsal interosseous (FDI) and abductor digiti minimi (ADM), using 20 supramaximal stimuli followed by 20 stimuli at a low-intensity required to obtain M-waves with 10 % amplitude of maximal CMAP. We evaluated the following F-wave parameters: F-M latency, chronodispersion, persistence, amplitude, F/CMAP amplitude ratio and number of F-wave repeaters (with low-intensity). In 10 subjects, low-intensity stimulation F-waves were compared after 20 and 50 stimuli in each muscle.

RESULTS: Low-intensity stimulation resulted in lower F-wave amplitude and persistence and higher F/CMAP amplitude ratios. There were no significant differences in F-wave latencies and chronodispersion. When comparing the three muscles, we found higher F-wave persistence and F/CMAP amplitude ratios when recording over the ADM and APB compared to the FDI. We also found a higher number of F-wave repeaters in the ADM with low-intensity stimulation. Results from 20 to 50 low-intensity stimuli were similar.

DISCUSSION: A small number of low-intensity stimuli is appropriate to study F-wave latencies and chronodispersion. We found differences in some physiological properties of the ADM spinal motoneuron pool compared to other hand muscles.}, } @article {pmid39489397, year = {2024}, author = {Desouky, MA and Michel, HE and Elsherbiny, DA and George, MY}, title = {Recent pharmacological insights on abating toxic protein species burden in neurological disorders: Emphasis on 26S proteasome activation.}, journal = {Life sciences}, volume = {359}, number = {}, pages = {123206}, doi = {10.1016/j.lfs.2024.123206}, pmid = {39489397}, issn = {1879-0631}, mesh = {*Proteasome Endopeptidase Complex/metabolism ; Humans ; Animals ; Neurodegenerative Diseases/metabolism/drug therapy ; Nervous System Diseases/drug therapy/metabolism ; Proteolysis/drug effects ; Signal Transduction/drug effects ; Proteostasis/drug effects ; Ubiquitin/metabolism ; }, abstract = {Protein homeostasis (proteostasis) refers to the plethora of mechanisms that safeguard the proper folding of the newly synthesized proteins. It entails various intricately regulated cues that demolish the toxic protein species to prevent their aggregation. The ubiquitin-proteasome system (UPS) is recognized as a salient protein degradation system, with a substantial role in maintaining proteostasis. However, under certain circumstances the protein degradation capacity of the UPS is overwhelmed, leading to the accumulation of misfolded proteins. Several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington disease, and amyotrophic lateral sclerosis are characterized with the presence of protein aggregates and proteinopathy. Accordingly, enhancing the 26S proteasome degradation activity might delineate a pioneering approach in targeting various proteotoxic disorders. Regrettably, the exact molecular approaches that enhance the proteasomal activity are still not fully understood. Therefore, this review aimed to underscore several signaling cascades that might restore the degradation capacity of this molecular machine. In this review, we discuss the different molecular components of the UPS and how 26S proteasomes are deleteriously affected in many neurodegenerative diseases. Moreover, we summarize different signaling pathways that can be utilized to renovate the 26S proteasome functional capacity, alongside currently known druggable targets in this circuit and various classes of proteasome activators.}, } @article {pmid39489870, year = {2024}, author = {Van Weehaeghe, D and Devrome, M and de Vocht, J and Masrori, P and Schramm, G and Deckers, W and Baete, K and De Weerdt, C and Van Damme, P and Koole, M and Van Laere, K}, title = {Combined brain and spinal FDG PET in the differentiation between ALS and ALS mimics - correction and additional validation study.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {52}, number = {1}, pages = {109-112}, pmid = {39489870}, issn = {1619-7089}, } @article {pmid39490400, year = {2024}, author = {Zhang, Y and Zou, M and Wu, H and Zhu, J and Jin, T}, title = {The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106710}, doi = {10.1016/j.nbd.2024.106710}, pmid = {39490400}, issn = {1095-953X}, mesh = {Humans ; *Nucleotidyltransferases/metabolism ; *Membrane Proteins/metabolism ; *Neurodegenerative Diseases/metabolism ; *Signal Transduction/physiology ; Animals ; *Neuroinflammatory Diseases/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; }, abstract = {Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by progressive damage to specific cell populations in the nervous system, ultimately leading to disability or death. Effective treatments for these diseases are still lacking, due to a limited understanding of their pathogeneses, which involve multiple cellular and molecular pathways. The triggering of an immune response is a common feature in neurodegenerative disorders. A critical challenge is the intricate interplay between neuroinflammation, neurodegeneration, and immune responses, which are not yet fully characterized. In recent years, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway, a crucial immune response for intracellular DNA sensing, has gradually gained attention. However, the specific roles of this pathway within cellular types such as immune cells, glial and neuronal cells, and its contribution to ND pathogenesis, remain not fully elucidated. In this review, we systematically explore how the cGAS-STING signaling links various cell types with related cellular effector pathways under the context of NDs for multifaceted therapeutic directions. We emphasize the discovery of condition-dependent cellular heterogeneity in the cGAS-STING pathway, which is integral for understanding the diverse cellular responses and potential therapeutic targets. Additionally, we review the pathogenic role of cGAS-STING activation in Parkinson's disease, ataxia-telangiectasia, and amyotrophic lateral sclerosis. We focus on the complex bidirectional roles of the cGAS-STING pathway in Alzheimer's disease, Huntington's disease, and multiple sclerosis, revealing their double-edged nature in disease progression. The objective of this review is to elucidate the pivotal role of the cGAS-STING pathway in ND pathogenesis and catalyze new insights for facilitating the development of novel therapeutic strategies.}, } @article {pmid39490682, year = {2024}, author = {Leykam, L and Forsberg, KME and Nordström, U and Hjertkvist, K and Öberg, A and Jonsson, E and Andersen, PM and Marklund, SL and Zetterström, P}, title = {Specific analysis of SOD1 enzymatic activity in CSF from ALS patients with and without SOD1 mutations.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106718}, doi = {10.1016/j.nbd.2024.106718}, pmid = {39490682}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid ; *Superoxide Dismutase-1/genetics ; Male ; *Mutation ; Female ; Middle Aged ; Superoxide Dismutase/genetics/cerebrospinal fluid ; Adult ; Aged ; }, abstract = {Mutations in superoxide dismutase-1 (SOD1) are a cause of hereditary amyotrophic lateral sclerosis (ALS) through a gain-of-function mechanism involving unfolded mutant SOD1. Intrathecal gene therapy using the antisense-oligo-nucleotide drug tofersen to reduce SOD1 expression delays disease progression and has recently been approved in the United States and the European Union. However, the discovery of children homozygous for inactivating SOD1 mutations developing the SOD1 Deficiency Syndrome (ISODDES) with injury to the motor system suggests that a too low SOD1 antioxidant activity may be deleterious in humans. Measuring SOD1 activity in cerebrospinal fluid (CSF) in tofersen-treated patients is recommended but difficult due to low concentration and the presence of the isoenzyme SOD3. We here present a sensitive method to assess SOD1 activity by removing SOD3 from CSF samples using highly specific immobilized antibodies and subsequent measurement of the SOD activity. We validated the method on 171 CSF samples from ALS patients with and without mutations and controls and used paired erythrocyte samples for comparison. We found that in ALS patients with wildtype SOD1, the SOD1 activity in CSF was equal to controls, but patients with mutant SOD1 show lower activity in CSF, even for patients with mutants previously reported to have full activity in erythrocytes. Activity variation in CSF was large among patients carrying the same SOD1 mutation and larger than in erythrocytes and in post-mortem nervous tissue. Additionally, we identified a discrepancy between the SOD1 activity and protein level measured with ELISA in both CSF and erythrocytes. Since antibodies used for SOD1 ELISA-quantification are raised against the natively folded wildtype SOD1, the concentration of mutant SOD1s may be underestimated. Analysis of SOD1 enzymatic activity in CSF is therefore a more reliable way to monitor the effect of SOD1-lowering drugs.}, } @article {pmid39490684, year = {2024}, author = {Liu, YJ and Lee, CW and Liao, YC and Huang, JJ and Kuo, HC and Jih, KY and Lee, YC and Chern, Y}, title = {The role of adiponectin-AMPK axis in TDP-43 mislocalization and disease severity in ALS.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106715}, doi = {10.1016/j.nbd.2024.106715}, pmid = {39490684}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Adiponectin/metabolism ; *DNA-Binding Proteins/metabolism ; Male ; Female ; Middle Aged ; *AMP-Activated Protein Kinases/metabolism ; Aged ; Motor Neurons/metabolism ; Severity of Illness Index ; }, abstract = {Hypermetabolism is a prominent characteristic of ALS patients. Aberrant activation of AMPK, an energy sensor regulated by adiponectin, is known to cause TDP-43 mislocalization, an early event in ALS pathogenesis. This study aims to evaluate the association between key energy mediators and clinical severity in ALS patients. We found that plasma adiponectin levels were significantly higher in ALS patients with ALSFRS-R scores below 38 compared to controls (p = 0.047). Additionally, adiponectin concentration was inversely correlated with ALSFRS-R scores (p = 0.021). Immunofluorescence staining of PBMCs revealed negative associations between AMPK activation, TDP-43 mislocalization, and ALSFRS-R scores. We then examined the hypothesis that adiponectin may activate the AMPK-TDP-43 axis in motor neurons. Our results demonstrated that adiponectin treatment of NSC34 cells and HiPSC-MNs induced AMPK activation and TDP-43 mislocalization in an adiponectin receptor-dependent manner. Collectively, these findings suggest that elevated plasma adiponectin may enhance AMPK activation, leading to TDP-43 mislocalization in both PBMCs and motor neurons of ALS patients. This highlights the potential involvement of the adiponectin-AMPK-TDP-43 axis in the dysregulated energy balance observed in ALS.}, } @article {pmid39491120, year = {2023}, author = {Stachel, SJ and Wang, D and Ginnetti, AT and Niroomand, S and Ma, L and Hu, Y and Fay, JF and Lemaire, W and Krosky, DJ and Ramirez, AD and Zariwala, HA and Coleman, PJ}, title = {Virtual screening for early identification of potent and selective histone deacetylase 6 inhibitor series.}, journal = {Bioorganic & medicinal chemistry letters}, volume = {}, number = {}, pages = {129537}, doi = {10.1016/j.bmcl.2023.129537}, pmid = {39491120}, issn = {1464-3405}, abstract = {Virtual screening was leveraged to identify novel series of histone deacetylase 6 (HDAC6) inhibitors prior to conducting a high-throughput screen. The virtual screen was designed to augment and expand on chemical matter that would otherwise be unavailable for high-throughput screening. Through this effort we succeeded in identifying four novel, potent and highly selective HDAC6 inhibitor series. These series displayed favorable ligand binding efficiencies and good potential for further optimization. The virtual design specifications and results are discussed herein.}, } @article {pmid39491419, year = {2023}, author = {Talebi, M and Sadoughi, MM and Ayatollahi, SA and Ainy, E and Kiani, R and Zali, A and Miri, M}, title = {Therapeutic potentials of cannabidiol: Focus on the Nrf2 signaling pathway.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {168}, number = {}, pages = {115805}, doi = {10.1016/j.biopha.2023.115805}, pmid = {39491419}, issn = {1950-6007}, abstract = {Cannabidiol (CBD), a cannabinoid that does not create psychoactive activities, has been identified as having a multitude of therapeutic benefits. This study delves into the chemical properties, pharmacokinetics, safety and toxicity, pharmacological effects, and most importantly, the association between the therapeutic potential of CBD and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The relationship between Nrf2 and CBD is closely linked to certain proteins that are associated with cardiovascular dysfunctions, cancers, and neurodegenerative conditions. Specifically, Nrf2 is connected to the initiation and progression of diverse health issues, including nephrotoxicity, bladder-related diseases, oral mucositis, cancers, obesity, myocardial injury and angiogenesis, skin-related inflammations, psychotic disorders, neuropathic pain, Huntington's disease, Alzheimer's disease, Parkinson's disease, neuroinflammation, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. The association between CBD and Nrf2 is a zone of great interest in the medical field, as it has the potential to significantly impact the treatment and prevention of wide-ranging health conditions. Additional investigation is necessary to entirely apprehend the mechanisms underlying this crucial interplay and to develop effective therapeutic interventions.}, } @article {pmid39491634, year = {2024}, author = {Tedeschi, V and Nele, V and Valsecchi, V and Anzilotti, S and Vinciguerra, A and Zucaro, L and Sisalli, MJ and Cassiano, C and De Iesu, N and Pignataro, G and Canzoniero, LMT and Pannaccione, A and De Rosa, G and Secondo, A}, title = {Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel.}, journal = {Pharmacological research}, volume = {210}, number = {}, pages = {107491}, doi = {10.1016/j.phrs.2024.107491}, pmid = {39491634}, issn = {1096-1186}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology ; Animals ; *Transient Receptor Potential Channels/metabolism ; *Lysosomes/drug effects/metabolism ; *Motor Neurons/drug effects/metabolism ; *Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Transgenic ; Humans ; Mice ; Phosphatidylinositols/metabolism ; Phosphatidylinositol Phosphates/metabolism ; Male ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease currently incurable, in which motor neuron degeneration leads to voluntary skeletal muscle atrophy. Molecularly, ALS is characterized by protein aggregation, synaptic and organellar dysfunction, and Ca[2+] dyshomeostasis. Of interest, autophagy dysfunction is emerging as one of the main putative targets of ALS therapy. A tune regulation of this cleansing process is affordable by a proper stimulation of TRPML1, one of the main lysosomal channels. However, TRPML1 activation by PI(3,5)P2 has low open probability to remain in an active conformation. To overcome this drawback we developed a lipid-based formulation of PI(3,5)P2 whose putative therapeutic potential has been tested in in vitro and in vivo ALS models. Pharmacodynamic properties of PI(3,5)P2 lipid-based formulations (F1 and F2) on TRPML1 activity have been characterized by means of patch-clamp electrophysiology and Fura-2AM video-imaging in motor neuronal cells. Once selected for the ability to stabilize TRPML1 activity, the most effective preparation F1 was studied in vivo to measure neuromuscular function and survival of SOD1[G93A] ALS mice, thereby establishing its therapeutic profile. F1, but not PI(3,5)P2 alone, stabilized the open state of the lysosomal channel TRPML1 and increased the persistence of intracellular calcium concentration ([Ca[2+]]i). Then, F1 was effective in delaying motor neuron loss, improving innervated endplants and muscle performance in SOD1[G93A] mice, extending overall lifespan by an average of 10 days. Of note F1 prevented gliosis and autophagy dysfunction in ALS mice by restoring PI(3,5)P2 level. Our novel self-assembling lipidic formulation for PI(3,5)P2 delivery exerts a neuroprotective effect in preclinical models of ALS mainly regulating dysfunctional autophagy through TRPML1 activity stabilization.}, } @article {pmid39491718, year = {2024}, author = {Sharma, R and Khan, Z and Mehan, S and Das Gupta, G and Narula, AS}, title = {Unraveling the multifaceted insights into amyotrophic lateral sclerosis: Genetic underpinnings, pathogenesis, and therapeutic horizons.}, journal = {Mutation research. Reviews in mutation research}, volume = {794}, number = {}, pages = {108518}, doi = {10.1016/j.mrrev.2024.108518}, pmid = {39491718}, issn = {1388-2139}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Mutation/genetics ; RNA-Binding Protein FUS/genetics ; C9orf72 Protein/genetics ; Animals ; Superoxide Dismutase-1/genetics ; DNA-Binding Proteins/genetics ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease, primarily impairs upper and lower motor neurons, leading to debilitating motor dysfunction and eventually respiratory failure, widely known as Lou Gehrig's disease. ALS presents with diverse symptomatology, including dysarthria, dysphagia, muscle atrophy, and hyperreflexia. The prevalence of ALS varies globally, with incidence rates ranging from 1.5 to 3.8 per 100,000 individuals, significantly affecting populations aged 45-80. A complex interplay of genetic and environmental factors underpins ALS pathogenesis. Key genetic contributors include mutations in chromosome 9 open reading frame 72 (C9ORF72), superoxide dismutase type 1 (SOD1), Fusedin sarcoma (FUS), and TAR DNA-binding protein (TARDBP) genes, accounting for a considerable fraction of both familial (fALS) and sporadic (sALS) cases. The disease mechanism encompasses aberrant protein folding, mitochondrial dysfunction, oxidative stress, excitotoxicity, and neuroinflammation, contributing to neuronal death. This review consolidates current insights into ALS's multifaceted etiology, highlighting the roles of environmental exposures (e.g., toxins, heavy metals) and their interaction with genetic predispositions. We emphasize the polygenic nature of ALS, where multiple genetic variations cumulatively influence disease susceptibility and progression. This aspect underscores the challenges in ALS diagnosis, which currently lacks specific biomarkers and relies on symptomatology and familial history. Therapeutic strategies for ALS, still in nascent stages, involve symptomatic management and experimental approaches targeting molecular pathways implicated in ALS pathology. Gene therapy, focusing on specific ALS mutations, and stem cell therapy emerge as promising avenues. However, effective treatments remain elusive, necessitating a deeper understanding of ALS's genetic architecture and the development of targeted therapies based on personalized medicine principles. This review aims to provide a comprehensive understanding of ALS, encouraging further research into its complex genetic underpinnings and the development of innovative, effective treatment modalities.}, } @article {pmid39492095, year = {2023}, author = {Mohammadi, S and Mohammadi, M and Ghaderi, S}, title = {Sleep-related regions in neurodegenerative diseases by central nervous system localization using magnetic resonance imaging.}, journal = {Psychiatry research. Neuroimaging}, volume = {336}, number = {}, pages = {111727}, doi = {10.1016/j.pscychresns.2023.111727}, pmid = {39492095}, issn = {1872-7506}, abstract = {Sleep disruptions associated with neurodegenerative diseases (NDDs) damage the brain's sleep-regulating regions. Advanced magnetic resonance imaging (MRI) techniques can characterize the signature of each neurodegenerative pathology. We performed an evaluation of sleep-related regions in NDDs using MRI to localize the central nervous system (CNS). In the initial search, 61 related papers were discovered using predetermined inclusion and exclusion criteria. Finally, 30 articles were included in this study. The study included patients with Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), rapid eye movement (REM) sleep behavior disorder (RBD), idiopathic RBD (iRBD), amyotrophic lateral sclerosis (ALS), and mild cognitive impairment (MCI). Sleep-related regions recognized by CNS localization in NDDs can be linked to important regions. MRI also revealed cortical thinning, GM atrophy, WM, and tract loss, changes in diffusion tensor imaging (DTI) biomarkers (fractional anisotropy (FA), axial diffusivity (Da), and radial diffusivity (Dr)), a decrease in DMN connectivity, a reduction in functional connectivity (FC), and amplitude of low-frequency fluctuation (ALFF) alterations. Sleep plays an important role in predicting future risks for the development of NDDs. Other neuroimaging, cognitive-behavioral, and clinical research can use the information found in this research about the brain regions, MRI biomarker changes, and their relationships.}, } @article {pmid39492438, year = {2023}, author = {Hamzeh, O and Rabiei, F and Shakeri, M and Parsian, H and Saadat, P and Rostami-Mansoor, S}, title = {Mitochondrial dysfunction and inflammasome activation in neurodegenerative diseases: Mechanisms and therapeutic implications.}, journal = {Mitochondrion}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.mito.2023.10.003}, pmid = {39492438}, issn = {1872-8278}, abstract = {Impaired mitochondrial function is crucial to the pathogenesis of several neurodegenerative diseases. It causes the release of mitochondrial DNA (mtDNA), mitochondrial reactive oxygen species (mtROS), ATP, and cardiolipin, which activate the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. NLRP3 inflammasome is an important innate immune system element contributing to neuroinflammation and neurodegeneration. Therefore, targeting the NLRP3 inflammasome has become an interesting therapeutic approach for treating neurodegenerative diseases. This review describes the role of mitochondrial abnormalities and over-activated inflammasomes in the progression of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Friedrich ataxia (FRDA). We also discuss the therapeutic strategies focusing on signaling pathways associated with inflammasome activation, which potentially alleviate neurodegenerative symptoms and impede disease progression.}, } @article {pmid39492487, year = {2023}, author = {Xu, L and Ma, Y and Ji, Y and Ma, Y and Wang, Y and Zhao, X and Ge, S}, title = {Obesity exacerbates postoperative cognitive dysfunction by activating the PARP1/NAD[+]/SIRT1 axis through oxidative stress.}, journal = {Experimental gerontology}, volume = {}, number = {}, pages = {112320}, doi = {10.1016/j.exger.2023.112320}, pmid = {39492487}, issn = {1873-6815}, abstract = {The purposes of this study were to explore the impact of obesity on postoperative cognitive dysfunction (POCD) and to investigate the underlying mechanism by which obesity exacerbates POCD. In this study, fifteen-month-old male C57BL/6 J mice were fed a High-fat diet for three months to establish obesity models. Internal fixation of tibial fractures under isoflurane inhalation was performed to construct a POCD animal model. Three days after surgery, mice were subjected to the Morris water maze (MWM) experiment to evaluate their learning and memory abilities. The findings from the MWM experiment revealed that in comparison to the Ad Libitum Surgical group (ALS), mice in the High-fat Surgical group (HFS) exhibited prolonged escape latencies and reduced platform crossings. These outcomes suggest the potential exacerbating role of obesity in cognitive impairment within the POCD mouse models. Immunofluorescence (IF) findings demonstrate that obesity intensifies anesthesia and surgery-induced oxidative stress levels within the hippocampus. Compared to the Ad Libitum Control group (ALC), an elevation in PARP1 expression and a reduction in the NAD[+]/NADH ratio and SIRT1 expression were observed in the hippocampus of mice from the ALS. Moreover, when contrasting the HFS group with the ALS group, increased PARP1 expression along with decreased NAD[+]/NADH ratio and SIRT1 expression were evident. In vitro studies found that compared with the Control group (CON), oil red staining and BODIPY probe staining showed significant lipid droplet aggregation in the palmitic acid (PA) group. IF results demonstrated that HT22 cells in the PA group experienced oxidative stress and activation of the PARP1/NAD[+]/SIRT1 axis in contrast to the CON group. Moreover, manipulation of PARP1 expression in HT22 cells through PARP1 lentivirus-based silencing or overexpression revealed a converse relationship between PARP1 expression levels and the NAD[+]/NADH ratio as well as SIRT1 expression levels. This study concludes that obesity may exacerbate POCD by triggering activation of the oxidative stress-induced PARP1/NAD[+]/SIRT1 axis.}, } @article {pmid39492846, year = {2024}, author = {Matera, AG and Steiner, RE and Mills, CA and McMichael, BD and Herring, LE and Garcia, EL}, title = {Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.}, journal = {Frontiers in RNA research}, volume = {2}, number = {}, pages = {}, pmid = {39492846}, issn = {2813-7116}, support = {P30 CA016086/CA/NCI NIH HHS/United States ; R35 GM136435/GM/NIGMS NIH HHS/United States ; }, abstract = {INTRODUCTION: Molecular chaperones and co-chaperones are highly conserved cellular components that perform a variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an assembly chaperone and serves as a paradigm for studying how specific RNAs are identified and paired with their client substrate proteins to form RNPs. SMN is the eponymous component of a large complex, required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs), that localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN protein forms the oligomeric core of this complex, and missense mutations in the human SMN1 gene are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known. However, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood.

METHODS: Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. We carried out affinity purification mass spectrometry (AP-MS) of Drosophila SMN complexes using fly lines exclusively expressing either wildtype or SMA-causing missense alleles.

RESULTS: Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially associated with SMA-causing alleles of SMN.

DISCUSSION: Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and Drosophila ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.}, } @article {pmid39493687, year = {2024}, author = {Kato, N and Hashida, G and Kobayashi, M and Sahara, W}, title = {Characteristics and factors associated with independence in the activities of daily living of patients with amyotrophic lateral sclerosis at diagnosis.}, journal = {Journal of physical therapy science}, volume = {36}, number = {11}, pages = {692-698}, pmid = {39493687}, issn = {0915-5287}, abstract = {[Purpose] To investigate the characteristics and factors associated with independence in the activities of daily living in patients with amyotrophic lateral sclerosis at diagnosis based on clinical phenotypes. [Participants and Methods] Fifty-seven participants diagnosed with amyotrophic lateral sclerosis were assessed using the Barthel Index. Participants were classified into three clinical phenotypes (bulbar-onset, upper limb-onset, and lower limb-onset), and the total and subitem scores were compared. To statistically examine factors associated with independence in the activities of daily living, the participants were divided into two groups: Barthel Index of 100 and ≤95. [Results] The total, bulbar-onset, upper limb-onset, and lower limb-onset Barthel Index scores were 87.9 ± 17.7, 96.7 ± 5.9, 92.5 ± 11.9, and 70.0 ± 22.2, respectively. The Total Barthel Index and lower limb-related activities of daily living scores were significantly lower in the lower limb-onset group, and knee extension muscle strength was identified as a factor associated with independence, with a cutoff value of 32.0%. [Conclusion] Patients with lower limb onset had more impairments in lower limb-related activities of daily living than those with other clinical phenotypes. To maintain independence in patients with amyotrophic lateral sclerosis at diagnosis, it is necessary to improve knee extension muscle strength through exercise and perform environment adjustments using the cutoff values as indicators.}, } @article {pmid39494098, year = {2024}, author = {Xu, AX and Zhao, ZF and Zhu, L and Zhang, YH and Li, Y and Wei, YF and Zhang, BY and Jiang, B and Gao, TZ and Li, MS and Liu, JY}, title = {Promise and challenges of traditional Chinese medicine, specifically Calculus bovis, in liver cancer treatment.}, journal = {World journal of gastroenterology}, volume = {30}, number = {40}, pages = {4380-4385}, pmid = {39494098}, issn = {2219-2840}, mesh = {Humans ; Drugs, Chinese Herbal/therapeutic use ; *Liver Neoplasms/therapy/pathology/mortality ; *Medicine, Chinese Traditional/methods ; Neoplasm Staging ; Quality of Life ; Treatment Outcome ; }, abstract = {Liver cancer, one of the most common malignancies worldwide, ranks sixth in incidence and third in mortality. Liver cancer treatment options are diverse, including surgical resection, liver transplantation, percutaneous ablation, transarterial chemoembolization, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and traditional Chinese medicine (TCM). A multidisciplinary team (MDT) is essential to customize treatment plans based on tumor staging, liver function, and performance status (PS), ensuring individualized patient care. Treatment decisions require a MDT to tailor strategies based on tumor staging, liver function, and PS, ensuring personalized care. The approval of new first-line and second-line drugs and the establishment of standard treatments based on immune checkpoint inhibitors have significantly expanded treatment options for advanced liver cancer, improving overall prognosis. However, many patients do not respond effectively to these treatments and ultimately succumb to the disease. Modern oncology treatments, while extending patient survival, often come with severe side effects, resistance, and damage to the body, negatively impacting quality of life. Huang et al's study published at World Journal of Gastroenterology rigorously validates the anticancer properties of Calculus bovis, enhancing our understanding of TCM and contributing to new liver cancer treatment strategies. For over 5000 years, TCM has been used in East Asian countries like China to treat various diseases, including liver conditions. Analysis of real-world clinical data suggests that for patients with advanced-stage tumors lacking effective treatments, integrated TCM therapies could provide significant breakthroughs.}, } @article {pmid39494508, year = {2024}, author = {Mariani, D and Setti, A and Castagnetti, F and Vitiello, E and Stufera Mecarelli, L and Di Timoteo, G and Giuliani, A and D'Angelo, A and Santini, T and Perego, E and Zappone, S and Liessi, N and Armirotti, A and Vicidomini, G and Bozzoni, I}, title = {ALS-associated FUS mutation reshapes the RNA and protein composition of stress granules.}, journal = {Nucleic acids research}, volume = {52}, number = {21}, pages = {13269-13289}, pmid = {39494508}, issn = {1362-4962}, support = {ERC-2019-SyG 855923-ASTRA//ERC/ ; IG 2019 Id. 23053//Associazione Italiana per la Ricerca sul Cancro/ ; CN00000041//NextGenerationEU/ ; //Istituto Italiano di Tecnologia/ ; }, mesh = {*RNA-Binding Protein FUS/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Mutation ; *Stress Granules/metabolism/genetics ; Cell Line, Tumor ; Transcriptome ; RNA/metabolism/genetics ; RNA, Messenger/metabolism/genetics ; RNA-Binding Proteins/metabolism/genetics ; Cytoplasmic Granules/metabolism/genetics ; }, abstract = {Stress granules (SG) are part of a cellular protection mechanism where untranslated messenger RNAs and RNA-binding proteins are stored upon conditions of cellular stress. Compositional variations due to qualitative or quantitative protein changes can disrupt their functionality and alter their structure. This is the case of different forms of amyotrophic lateral sclerosis (ALS) where a causative link has been proposed between the cytoplasmic de-localization of mutant proteins, such as FUS (Fused in Sarcoma), and the formation of cytotoxic inclusions. Here, we describe the SG transcriptome in neuroblastoma cells and define several features for RNA recruitment in these condensates. We demonstrate that SG dynamics and RNA content are strongly modified by the incorporation of mutant FUS, switching to a more unstructured, AU-rich SG transcriptome. Moreover, we show that mutant FUS, together with its protein interactors and their target RNAs, are responsible for the reshaping of the mutant SG transcriptome with alterations that can be linked to neurodegeneration. Our data describe the molecular differences between physiological and pathological SG in ALS-FUS conditions, showing how FUS mutations impact the RNA and protein composition of these condensates.}, } @article {pmid39494512, year = {2024}, author = {Donohoe, MN and Upadhyay, A and Pratt, DA}, title = {Ligand-Based Radical Reactivity of Metal Thiosemicarbazones Prompts the Identification of Platinum(II)-Based Cytoprotectants.}, journal = {Journal of the American Chemical Society}, volume = {146}, number = {45}, pages = {31307-31320}, doi = {10.1021/jacs.4c12713}, pmid = {39494512}, issn = {1520-5126}, mesh = {*Thiosemicarbazones/chemistry/pharmacology ; Ligands ; *Platinum/chemistry/pharmacology ; *Coordination Complexes/chemistry/pharmacology/chemical synthesis ; Humans ; Antioxidants/chemistry/pharmacology ; Lipid Peroxidation/drug effects ; Molecular Structure ; Copper/chemistry ; Neuroprotective Agents/chemistry/pharmacology/chemical synthesis ; }, abstract = {CuATSM, a copper(II) complex of a bis(thiosemicarbazone) of diacetyl, prevents oxidative cell death and acts as a neuroprotectant in vivo, prompting its evaluation to treat amyotrophic lateral sclerosis and other neurodegenerative conditions in the clinic. We recently demonstrated that CuATSM functions as a potent radical-trapping antioxidant (RTA), inhibiting lipid peroxidation and associated ferroptotic cell death by a noncanonical mechanism based on radical addition to the ligand backbone. Herein we report our investigations of the generality of this reactivity, which include studies of corresponding complexes of various other metals, including Co, Ru, Ni, Pd, Pt, and Au. Inhibited autoxidations of styrene and dioxane reveal that most of these complexes exhibit RTA activity, consistent with ligand-based reactivity, but the identity of the metal atom nevertheless plays a role. In particular, analyses of the electronic structures of the complexes of metals within the same group (i.e., the group 10 metals Ni, Pd and Pt) highlight how the metal atom can modulate the ligand-based reactivity by enabling spin delocalization to the other thiosemicarbazone moiety. The RTA activity determined in organic solution largely translates to phospholipid bilayers and mammalian cells, where most complexes inhibited lipid peroxidation and associated ferroptotic cell death. A preliminary structure-activity study revealed Pt complexes with potencies eclipsing those of archetype ferroptosis inhibitors ferrostatin-1 and liproxstatin-1, suggesting that Pt (and to a lesser extent Ni) bis(thiosemicarbazone)s may be better suited to optimization for therapeutic development than those based on Cu.}, } @article {pmid39494632, year = {2025}, author = {Uzunçakmak-Uyanık, H and Tan, E and Temuçin, ÇM and Yıldız, FG}, title = {Lack of habituation in somatosensory cortex but not in visual cortex of ALS patients.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {93-102}, doi = {10.1080/21678421.2024.2421747}, pmid = {39494632}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Somatosensory Cortex/physiopathology ; *Habituation, Psychophysiologic/physiology ; Aged ; *Evoked Potentials, Somatosensory/physiology ; *Visual Cortex/physiopathology ; *Evoked Potentials, Visual/physiology ; Adult ; Electroencephalography ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a multisystem degenerative disease with extra-motor components. In ALS, there is also hyperexcitability of extra-motor areas. Habituation is defined as ''a response decrement" caused by repeated stimulations. Studies on evoked potential habituation can be conducted to detect cortical excitability. This study aimed to explore lack of habituation in non-motor cortical structures in ALS.

METHODS: Twenty-one ALS patients and 14 controls were enrolled. Recordings were obtained in 3 and 10 consecutive blocks (each containing 100 responses) during right median somatosensory evoked potential (SEP) and bilateral visual evoked potential (VEP), respectively. "Habituation" and "lack of habituation" were defined as the amount of increase or decrease in the average N20 or N75-P100 amplitude of the last blocks compared to the first blocks, respectively. Comparative analyses were performed between patient and control groups, as well as the first and last block within groups.

RESULTS: Paired sample t-test showed that in control group N20 peak amplitude of last blocks were significantly lower than first block values (p = 0.025) that indicate the physiological habituation as expected. On the other hand, there was not such a difference in ALS group (p = 0.239) which indicated lack of habituation.

CONCLUSIONS: Our study results suggest somatosensory hyperexcitability in line with cortical reorganization in ALS patients.}, } @article {pmid39494653, year = {2025}, author = {Springer, SA}, title = {Commentary on Gregory et al.: Fear of precipitated opioid withdrawal should not prevent buprenorphine initiation.}, journal = {Addiction (Abingdon, England)}, volume = {120}, number = {1}, pages = {21-22}, pmid = {39494653}, issn = {1360-0443}, support = {DP1 DA056106/DA/NIDA NIH HHS/United States ; NIDA DP1DA056106/DA/NIDA NIH HHS/United States ; }, abstract = {Provision of buprenorphine treatment for opioid use disorder is often stymied by clinicians’ concerns for precipitated opioid withdrawal. Gregory et al’s systematic review identified a low level of precipitated withdrawal with buprenorphine induction even among persons who reported fentanyl use. Evidence, not fear should guide treatment.}, } @article {pmid39494889, year = {2024}, author = {Ito, SI and Tanaka, Y}, title = {Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {212}, pages = {}, doi = {10.3791/67385}, pmid = {39494889}, issn = {1940-087X}, mesh = {*Extracellular Vesicles/metabolism ; Humans ; *Microtubule-Associated Proteins/metabolism/genetics ; Autophagy/physiology ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {(Macro)autophagy represents a fundamental cellular degradation pathway. In this process, double-membraned vesicles known as autophagosomes engulf cytoplasmic contents, subsequently fusing with lysosomes for degradation. Beyond the canonical role, autophagy-related genes also modulate a secretory pathway involving the release of inflammatory molecules, tissue repair factors, and extracellular vesicles (EVs). Notably, the process of disseminating pathological proteins between cells, particularly in neurodegenerative diseases affecting the brain and spinal cord, underscores the significance of understanding this phenomenon. Recent research suggests that the transactive response DNA-binding protein 43 kDa (TDP-43), a key player in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, is released in an autophagy-dependent manner via EVs enriched with the autophagosome marker microtubule-associated proteins 1A/1B light chain 3B-II (LC3-II), especially when autophagosome-lysosome fusion is inhibited. To elucidate the mechanism underlying the formation and release of LC3-II-positive EVs, it is imperative to establish an accessible and reproducible method for evaluating both intracellular and extracellular LC3-II-positive vesicles. This study presents a detailed protocol for assessing LC3-II levels via immunoblotting in cellular and EV fractions obtained through differential centrifugation. Bafilomycin A1 (Baf), an inhibitor of autophagosome-lysosome fusion, serves as a positive control to enhance the levels of intracellular and extracellular LC3-II-positive vesicles. Tumor susceptibility gene 101 (TSG101) is used as a marker for multivesicular bodies. Applying this protocol, it is demonstrated that siRNA-mediated knockdown of syntaxin-6 (STX6), a genetic risk factor for sporadic Creutzfeldt-Jakob disease, augments LC3-II levels in the EV fraction of cells treated with Baf while showing no significant effect on TSG101 levels. These findings suggest that STX6 may negatively regulate the extracellular release of LC3-II via EVs, particularly under conditions where autophagosome-lysosome fusion is impaired. Combined with established methods for evaluating autophagy, this protocol provides valuable insights into the role of specific molecules in the formation and release of LC3-II-positive EVs.}, } @article {pmid39495912, year = {2024}, author = {Wheeler, HB and Madrigal, AA and Chaim, IA}, title = {Mapping the future of oxidative RNA damage in neurodegeneration: Rethinking the status quo with new tools.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {46}, pages = {e2317860121}, pmid = {39495912}, issn = {1091-6490}, support = {R00 NS121511/NS/NINDS NIH HHS/United States ; T32 GM133351/GM/NIGMS NIH HHS/United States ; 4R00NS121511-03//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *RNA/metabolism/genetics ; *Oxidation-Reduction ; Oxidative Stress ; RNA-Binding Proteins/metabolism/genetics ; Proteomics/methods ; Animals ; }, abstract = {Over two decades ago, increased levels of RNA oxidation were reported in postmortem patients with ALS, Alzheimer's, Parkinson's, and other neurodegenerative diseases. Interestingly, not all cell types and transcripts were equally oxidized. Furthermore, it was shown that RNA oxidation is an early phenomenon, altogether indicating that oxidative RNA damage could be a driver, and not a consequence, of disease. Despite all these exciting observations, the field appears to have stagnated since then. We argue that this is a consequence of the shortcomings of technologies to model these diseases, limiting our understanding of which transcripts are being oxidized, which RNA-binding proteins are interacting with these RNAs, what their implications are in RNA processing, and as a result, what their potential role is in disease onset and progression. Here, we discuss the limits of previous technologies and propose ways by which advancements in iPSC-derived disease modeling, proteomics, and sequencing technologies can be combined and leveraged to answer new and decades-old questions.}, } @article {pmid39496035, year = {2024}, author = {Xu, W and Zhao, X and Wang, J and Guo, Y and Ren, Z and Cai, L and Wu, S and Zhou, M}, title = {Different intensities of physical activity for amyotrophic lateral sclerosis and Parkinson disease: A Mendelian randomization study and meta-analysis.}, journal = {Medicine}, volume = {103}, number = {44}, pages = {e40141}, pmid = {39496035}, issn = {1536-5964}, support = {ZYYLJRC201911//the Anhui Province Traditional Chinese Medicine Leading Talents Construction Project/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Amyotrophic Lateral Sclerosis/genetics ; *Parkinson Disease/genetics/epidemiology ; *Exercise ; Genome-Wide Association Study ; }, abstract = {BACKGROUND: The causal relationships between amyotrophic lateral sclerosis (ALS), Parkinson disease and different intensities of physical activity (PA) are still inconclusive. To evaluate the causal impact of PA on ALS and Parkinson disease (PD), this study integrates evidence from Mendelian randomization (MR) using a meta-analysis approach.

METHODS: MR analyses on genetically predicted levels of PA (compose of self-reported moderate-to-vigorous physical activity [MVPA], self-reported vigorous physical activity [VPA], and strenuous sports or other exercises [SSOE]) regarding ALS and PD published up to July 27, 2024, were obtained from PubMed, Scopus, Web of Science, and Embase. De novo MR studies were analyzed utilizing publicly accessible datasets from genome-wide association studies and then meta-analyses were performed to pool the results.

RESULTS: Meta-analyses of results of 12 de novo MR studies analyses and 2 published MR studies indicated that genetic predicted levels of MVPA (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.08-1.38), VPA (OR: 1.32, 95% CI: 1.08-1.60), and SSOE (OR: 1.35, 95% CI: 1.07-1.70) were related to a raised risk of ALS, but not causally with PD.

CONCLUSION: Our findings showed no causal relationships between MVPA, VPA, SSOE, and PD, while MVPA, VPA, and SSOE were associated with increased ALS risk, highlighting the need for targeted PA recommendations for disease management.}, } @article {pmid39496465, year = {2025}, author = {Baker, MR and Maitland, S}, title = {Response to: 'Cortical Inexcitability in ALS: Correlating a Clinical Phenotype'.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {3}, pages = {208}, doi = {10.1136/jnnp-2024-334587}, pmid = {39496465}, issn = {1468-330X}, } @article {pmid39496878, year = {2025}, author = {Yang, T and Wei, Q and Pang, D and Cheng, Y and Huang, J and Lin, J and Xiao, Y and Jiang, Q and Wang, S and Li, C and Shang, H}, title = {Mutation Screening of ATXN1, ATXN2, and ATXN3 in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {62}, number = {4}, pages = {4854-4865}, pmid = {39496878}, issn = {1559-1182}, support = {82371430//National Natural Science Foundation of China/ ; 2022ZDZX0023//Sichuan Science and Technology Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Ataxin-1/genetics ; *Ataxin-3/genetics ; *Ataxin-2/genetics ; Male ; Female ; Middle Aged ; *Ataxins/genetics ; *Genetic Predisposition to Disease ; *Mutation/genetics ; DNA Mutational Analysis ; Aged ; *Genetic Testing ; Adult ; Repressor Proteins ; }, abstract = {Emerging evidence suggests potential disease modifying roles of ATXN1, ATXN2, and ATXN3 in amyotrophic lateral sclerosis (ALS). We aimed to provide a comprehensive variants profile of the ATXN1, ATXN2, and ATXN3 genes and examine the association of these variants with the risk and clinical characteristics of ALS. We screened and analyzed the rare variants in a cohort of 2220 ALS patients from Southwest China, using controls from the Genome Aggregation Database (gnomAD) and the China Metabolic Analytics Project (ChinaMAP). The over-representation of rare variants and their association with disease risk in ALS patients were assessed using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis was employed to explore the relationship between the distribution of variants and survival. A total of 62 eligible rare missense variants were identified, comprising 32 from ATXN1, 21 from ATXN2, and 9 from ATXN3. Allelic association testing revealed a significant enrichment of the ATXN1 (c.2122C > G, p.Leu708Val) variant and the ATXN2 (c.3778C > G, p.Pro1260Ala) variant in ALS. Gene burden analysis indicated that variants in the ATXN1 and ATXN3 genes had a higher burden in ALS. Substantial heterogeneity in survival time was observed among patients carrying different variants within the same gene. However, there were no significant differences in survival between ALS patients grouped by N-terminal or C-terminal distribution. Our results provided a genetic variation profile of ATXN1, ATXN2, and ATXN3 in ALS patients, along with the clinical characteristics of individuals carrying these variations. This information might offer valuable insights for the ongoing ALS disease-modifying treatments.}, } @article {pmid39500483, year = {2024}, author = {Piotrkiewicz, M}, title = {Possible changes in motor neuron discharge characteristics in presymptomatic amyotrophic lateral sclerosis.}, journal = {The Journal of physiology}, volume = {602}, number = {24}, pages = {6631-6635}, doi = {10.1113/JP287788}, pmid = {39500483}, issn = {1469-7793}, } @article {pmid39500920, year = {2024}, author = {Yu, M and Xu, J and Dutta, R and Trapp, B and Pieper, AA and Cheng, F}, title = {Network medicine informed multiomics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis.}, journal = {NPJ systems biology and applications}, volume = {10}, number = {1}, pages = {128}, pmid = {39500920}, issn = {2056-7189}, support = {R21 AG083003/AG/NIA NIH HHS/United States ; R01 AG082118/AG/NIA NIH HHS/United States ; R56 AG074001/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; RF1 NS133812/NS/NINDS NIH HHS/United States ; RF1NS133812//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; U01 AG073323/AG/NIA NIH HHS/United States ; U01AG073323//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG082118//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG066707//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG066707/AG/NIA NIH HHS/United States ; R01AG076448//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R21AG083003//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG076448/AG/NIA NIH HHS/United States ; RF1AG082211//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG084250//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism ; Humans ; *Quantitative Trait Loci/genetics ; Genome-Wide Association Study/methods ; Drug Repositioning/methods ; Genomics/methods ; Protein Interaction Maps/genetics/drug effects ; Multiomics ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. We developed a network medicine methodology via integrating human brain multi-omics data to prioritize drug targets and repurposable treatments for ALS. We leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on human brain expression quantitative trait loci (QTL) (eQTL), protein QTL (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Using a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in known ALS pathobiological pathways. Applying network proximity analysis of predicted ALS-associated genes and drug-target networks under the human protein-protein interactome (PPI) model, we identified potential repurposable drugs (i.e., Diazoxide and Gefitinib) for ALS. Subsequent validation established preclinical evidence for top-prioritized drugs. In summary, we presented a network-based multi-omics framework to identify drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.}, } @article {pmid39501102, year = {2025}, author = {Howard, J and Chaouch, A and Douglas, AGL and MacLeod, R and Roggenbuck, J and McNeill, A}, title = {Genetic testing for monogenic forms of motor neuron disease/amyotrophic lateral sclerosis in unaffected family members.}, journal = {European journal of human genetics : EJHG}, volume = {33}, number = {1}, pages = {7-13}, pmid = {39501102}, issn = {1476-5438}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Family ; Genetic Counseling ; *Genetic Testing/methods/standards ; *Motor Neuron Disease/genetics/diagnosis ; }, abstract = {Motor neuron disease (MND), also referred to as amyotrophic lateral sclerosis (ALS), is a monogenic disease in a minority of cases, with autosomal dominant inheritance. Increasing numbers of people with MND are requesting genetic testing, and indeed receiving a genetic diagnosis. Consequently, requests for genetic counselling and predictive testing (i.e. of unaffected family members) are similarly expected to rise, alongside pre-symptomatic clinical trials. Despite this, there is no evidence-based guideline for predictive genetic testing in MND. This paper provides an overview of the genomic basis of MND, focusing specifically on the most common monogenic causes of MND. It then lays out the complexities of MND predictive testing, including the genetic landscape characterised by incomplete penetrance, clinical and genetic heterogeneity, and an oligogenic mechanism of pathogenesis in some cases. Additionally, there is limited research on the psychosocial impact of predictive genetic testing for MND, with studies suggesting potential difficulty in adjusting to the news, in part due to a lack of support and follow-up. This underscores a case for evidence-based, disease-specific guidance for predictive testing in MND.}, } @article {pmid39501538, year = {2024}, author = {Bampton, A and McHutchison, C and Talbot, K and Benatar, M and Thompson, AG and Turner, MR}, title = {The Basis of Cognitive and Behavioral Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Brain and behavior}, volume = {14}, number = {11}, pages = {e70115}, pmid = {39501538}, issn = {2162-3279}, support = {MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; Thompson/Jan20/952-795//Motor Neurone Disease Association Lady Edith Wolfson Clinician Scientist Fellowship/ ; //Foulkes Foundation/ ; //National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Cognitive Dysfunction/etiology/physiopathology ; }, abstract = {OBJECTIVE: To summarize and evaluate evidence pertaining to the clinical, genetic, histopathological, and neuroimaging correlates of cognitive and behavioral dysfunction in amyotrophic lateral sclerosis (ALS).

METHODOLOGY: We comprehensively reviewed the literature on cognitive and behavioral manifestations of ALS, narrating findings from both cross-sectional and longitudinal studies. We discussed knowledge gaps in the evidence base and key limitations affecting studies to date, before formulating a framework for future research paradigms aimed at investigating clinicopathological correlates of neuropsychological dysfunction in ALS.

RESULTS: Studies have demonstrated clinical associations with cognitive dysfunction in ALS e.g., bulbar-onset of symptoms, pathological associations (extramotor TDP-43 deposition), and imaging associations (frontotemporal involvement). The most common behavioral deficit, apathy, is highly associated with verbal fluency, but longitudinal studies assessing behavioral dysfunction in ALS are comparatively lacking.

CONCLUSION: Longitudinal studies have been helpful in identifying several potential correlates of cognitive and behavioral dysfunction but have frequently been confounded by selection bias and inappropriate testing platforms. This review provides a framework for more robust assessment of clinicopathological associations of neuropsychological abnormalities in ALS in the future, advocating for greater utilization of pre-symptomatic C9orf72 repeat expansion-carrying cohorts.}, } @article {pmid39502740, year = {2024}, author = {Nishiyama, A and Niihori, T and Suzuki, N and Izumi, R and Akiyama, T and Kato, M and Funayama, R and Nakayama, K and Warita, H and Aoki, Y and Aoki, M}, title = {Updated Genetic Analysis of Japanese Familial ALS Patients Carrying SOD1 Variants Revealed Phenotypic Differences for Common Variants.}, journal = {Neurology. Genetics}, volume = {10}, number = {6}, pages = {e200196}, pmid = {39502740}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease. Approximately 10% of ALS cases are familial, and more than 20 causative genes have been identified. As we have previously reported, SOD1 variants are the most common causes of familial ALS in Japan. Because antisense oligonucleotides for SOD1-linked ALS are being used in practical applications, the types of variants and the clinical features of patients need to be updated.

METHODS: We consecutively recruited 160 families with familial ALS in Japan. We performed genetic analyses, focusing on SOD1-linked ALS as the most common in our cohort, updated their genotypes, and characterized clinical phenotypes.

RESULTS: A total of 26 SOD1 variants in 56 patients and 49 families (30.6%) were collected, with the 3 most common (p.His47Arg [the conventional numbering; H46R], p.Leu127Ser [L126S], p.Asn87Ser [N86S]) accounting for 38.8% of all families. We also identified 2 novel variants (p.Ile36Phe [I35F] and p.Asn132Argfs*3 [N131Rfs*3]). The mean age at onset was 48.9 ± 12.2 (mean ± SD) years for all patients with SOD1-linked ALS. Lower limb onset comprised 70% of cases. The mean disease duration was 64.7 ± 82 months, and the median survival was 71.5 months. Some variants led to a relatively homogeneous phenotype, although clinical characteristics differed among types of variants and families. Patients with p.His47Arg (H46R) showed slower progression with lower limb onset and a predominance of lower motor neuron involvement. The p.Leu127Ser (L126S) variant led to varying degrees of progression in heterozygous or homozygous states and presented incomplete penetrance. Intrafamilial phenotypic differences were observed in families carrying p.Asn87Ser (N86S). Four variants (p.Cys7Gly [C6G], p.His44Arg [H43R], p.Leu85Val [L84V], and p.Cys147Arg [C146R]) were found to be associated with rapid disease progression.

DISCUSSION: The genetic basis of familial ALS, at least for SOD1 variants, still differed by geographic and ethnic background. Understanding these clinical profiles will help optimize evaluation in targeted gene therapy worldwide and benefit efficient diagnosis, leading to precise application in clinical practice.}, } @article {pmid39503018, year = {2024}, author = {Rennie, O and Sharma, M and Helwa, N}, title = {Hepatobiliary anastomotic leakage: a narrative review of definitions, grading systems, and consequences of leaks.}, journal = {Translational gastroenterology and hepatology}, volume = {9}, number = {}, pages = {70}, pmid = {39503018}, issn = {2415-1289}, abstract = {BACKGROUND AND OBJECTIVE: Hepatobiliary diseases are a longstanding and significant medical challenge which, despite advances in surgical techniques, still carry risks for postoperative complications such as anastomotic leaks (ALs), which can include both postoperative pancreatic fistula (POPF) and bile leaks (BL). These complications incur significant human and economic costs on all those involved, including the patient, healthcare providers, and hospital systems. The aim of this study was to construct a narrative review of literature surrounding definitions and grading systems for ALs in the context of hepato-pancreato-biliary (HPB) procedures, and consequences of POPF and BL.

METHODS: A literature review was conducted by examining databases including PubMed, Web of Science, OVID Embase, Google Scholar, and Cochrane library databases. Searches were performed with the following search criteria: (((((((anastomosis) OR (anastomotic leak*)) OR (postoperative pancreatic fistula)) OR (bile leak*)) OR (pancreaticoduodenectomy)) OR (whipple)) AND ((hepatobiliary) OR (hepato-pancreato-biliary)) AND ((definition) OR (grading system*) OR (consequences) OR (outcomes) OR (risk factor*) OR (morbidity) OR (mortality))). Publications that were retrieved underwent further assessment to ensure other relevant publications were identified and included.

KEY CONTENT AND FINDINGS: A universally accepted definition and grading system for POPF and BL continues to be lacking, leading to variability in reported incidence in the literature. Various groups have worked to publish guidelines for defining and grading POPF and BL, with the International Study Group in Pancreatic Surgery (ISGPS) and International Study Group for Liver Surgery (ISGLS) definitions the current most recommended definitions for POPF and BL, respectively. The burden of AL on patients, healthcare providers, and hospitals is well documented in evidence from leak consequences, such as increased morbidity and mortality, higher reoperation rates, and increased readmission rates, among others.

CONCLUSIONS: AL remains a significant challenge in HPB surgery, despite medical advancements. Understanding the progress made in defining and grading leaks, as well as the range of negative outcomes that arise from AL, is crucial in improving patient care, reduce surgical mortality, and drive further advancements in earlier detection and treatment of AL.}, } @article {pmid39503319, year = {2024}, author = {Bedlack, R and Li, X and Evangelista, BA and Panzetta, ME and Kwan, J and Gittings, LM and Sattler, R}, title = {The Scientific and Therapeutic Rationale for Off-Label Treatments in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {97}, number = {1}, pages = {15-27}, pmid = {39503319}, issn = {1531-8249}, support = {//ALS Association/ ; }, abstract = {There are no dramatically effective pharmacological treatments for most patients with amyotrophic lateral sclerosis, a complex disease with multiple underlying mechanisms, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, microbiome alteration, and antiretroviral activity. We sifted through 15 years of reviews by a group called ALSUntangled to identify 8 alternative and off-label treatments that target ≥1 of these mechanisms, and have ≥1 human trial suggesting meaningful benefits. Given the overlapping pathological mechanisms of the highlighted products, we suggest that combinations of these treatments targeting diverse mechanisms might be worthwhile for future amyotrophic lateral sclerosis therapy development. ANN NEUROL 2024.}, } @article {pmid39503423, year = {2025}, author = {Alfahel, L and Rajkovic, A and Israelson, A}, title = {Translational challenges in amyotrophic lateral sclerosis therapy with macrophage migration inhibitory factor.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2583-2584}, pmid = {39503423}, issn = {1673-5374}, } @article {pmid39503426, year = {2025}, author = {Shimizu, M and Okuno, T}, title = {Disruption of neuronal actin barrier promotes the entry of disease-implicated proteins to exacerbate amyotrophic lateral sclerosis pathology.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2589-2590}, pmid = {39503426}, issn = {1673-5374}, } @article {pmid39505137, year = {2024}, author = {Abbasi, H and Jourabchi-Ghadim, N and Asgarzade, A and Mirshekari, M and Ebrahimi-Mameghani, M}, title = {Unveiling the veil of adipokines: A meta-analysis and systematic review in amyotrophic lateral sclerosis.}, journal = {Neuroscience}, volume = {563}, number = {}, pages = {1-9}, doi = {10.1016/j.neuroscience.2024.11.003}, pmid = {39505137}, issn = {1873-7544}, mesh = {*Amyotrophic Lateral Sclerosis/blood/metabolism ; Humans ; *Adipokines/blood ; Ghrelin/blood ; Leptin/blood ; Adiponectin/blood ; Disease Progression ; }, abstract = {BACKGROUND: Adipokines are proposed to be associated with ALS progression through assorted pathways. Therefore, The present meta-analysis explored the link between various adipokines and ALS progression.

METHOD: International database like PubMed, Scopus, and Web of Science databases were searched to achieve eligible papers published before December 2023. The following PICO structure was utilized: Population (patients with ALS); Intervention (serum concentrations of ghrelin, leptin, and adiponectin), Comparison (with or without controls), and Outcome (ALS progression). the risk of bias of selected papers was assessed through the Newcastle-Ottawa Scale (NOS) tool.

RESULTS: 11 out of 240 papers were selected for this study which were published between 2010 and 2024. Lower serum leptin concentrations were detected in the ALS compared to control groups (WMD: -0.91, 95% CI:-1.77, -0.05). Serum concentrations of adiponectin were higher in ALS compared to control groups (WMD: 0.41, 95% CI:-0.7, 0.89). Ultimately, The serum concentrations of ghrelin in the ALS groups were lower than control groups (WMD: -1.21, 95% CI: -2.95, 0.53).

CONCLUSION: Our findings revealed that serum concentrations of ghrelin and leptin were higher in ALS patients compared to control, unlike adiponectin.}, } @article {pmid39505319, year = {2024}, author = {Lee, J and Kim, A and Choi, SJ and Cho, E and Seo, J and Oh, SI and Jung, J and Kim, JS and Sung, JJ and Abrahams, S and Hong, YH}, title = {Erratum: Development and Validation of the Korean Version of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS-K).}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {20}, number = {6}, pages = {637}, doi = {10.3988/jcn.2022.0403e}, pmid = {39505319}, issn = {1738-6586}, abstract = {This corrects the article on p. 454 in vol. 19, PMID: 37488957.}, } @article {pmid39505881, year = {2024}, author = {Li, J and Jaiswal, MK and Chien, JF and Kozlenkov, A and Jung, J and Zhou, P and Gardashli, M and Pregent, LJ and Engelberg-Cook, E and Dickson, DW and Belzil, VV and Mukamel, EA and Dracheva, S}, title = {Author Correction: Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9588}, doi = {10.1038/s41467-024-53972-1}, pmid = {39505881}, issn = {2041-1723}, } @article {pmid39506789, year = {2024}, author = {Niccolai, E and Di Gloria, L and Trolese, MC and Fabbrizio, P and Baldi, S and Nannini, G and Margotta, C and Nastasi, C and Ramazzotti, M and Bartolucci, G and Bendotti, C and Nardo, G and Amedei, A}, title = {Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1[G93A] mice.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {174}, pmid = {39506789}, issn = {2051-5960}, support = {SG-2019-12371083//Italian Ministry of Health/ ; PE0000006//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Animals ; *Gastrointestinal Microbiome/physiology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/microbiology/pathology ; Mice ; *Mice, Transgenic ; *Lipid Metabolism/genetics ; Inflammation/metabolism/pathology ; Mice, Inbred C57BL ; Superoxide Dismutase-1/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, with genetic and environmental factors contributing to its complex pathogenesis. Dysregulated immune responses and altered energetic metabolism are key features, with emerging evidence implicating the gut microbiota (GM) in disease progression. We investigated the interplay among genetic background, GM composition, metabolism, and immune response in two distinct ALS mouse models: 129Sv_G93A and C57Ola_G93A, representing rapid and slow disease progression, respectively.Using 16 S rRNA sequencing and fecal metabolite analysis, we characterized the GM composition and metabolite profiles in non-transgenic (Ntg) and SOD1[G93A] mutant mice of both strains. Our results revealed strain-specific differences in GM composition and functions, particularly in the abundance of taxa belonging to Erysipelotrichaceae and the levels of short and medium-chain fatty acids in fecal samples. The SOD1 mutation induces significant shifts in GM colonization in both strains, with C57Ola_G93A mice showing changes resembling those in 129 Sv mice, potentially affecting disease pathogenesis. ALS symptom progression does not significantly alter microbiota composition, suggesting stability.Additionally, we assessed systemic immunity and inflammatory responses revealing strain-specific differences in immune cell populations and cytokine levels.Our findings underscore the substantial influence of genetic background on GM composition, metabolism, and immune response in ALS mouse models. These strain-specific variations may contribute to differences in disease susceptibility and progression rates. Further elucidating the mechanisms underlying these interactions could offer novel insights into ALS pathogenesis and potential therapeutic targets.}, } @article {pmid39506867, year = {2024}, author = {Ishihara, T and Koyama, A and Atsuta, N and Tada, M and Toyoda, S and Kashiwagi, K and Hirokawa, S and Hatano, Y and Yokoseki, A and Nakamura, R and Tohnai, G and Izumi, Y and Kaji, R and Morita, M and Tamura, A and Kano, O and Aoki, M and Kuwabara, S and Kakita, A and Sobue, G and Onodera, O}, title = {SMN2 gene copy number affects the incidence and prognosis of motor neuron diseases in Japan.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {263}, pmid = {39506867}, issn = {1755-8794}, support = {17K09750//Scientific Research from the Japan Society for the Promotion of Science/ ; 21K07272//Scientific Research from the Japan Society for the Promotion of Science/ ; 17ek0109284h0001//Japan Agency for Medical Research and Development/ ; 17ek0109284h0001//Japan Agency for Medical Research and Development/ ; 17ek0109284h0001//Japan Agency for Medical Research and Development/ ; 26117006//Scientific Research on Innovative Areas from MEXT/ ; JPMH23FC1008//MHLW Research on rare and intractable diseases Program/ ; }, mesh = {Humans ; *Survival of Motor Neuron 2 Protein/genetics ; Male ; Japan/epidemiology ; Middle Aged ; Female ; Prognosis ; *Motor Neuron Disease/genetics ; *Gene Dosage ; Incidence ; Amyotrophic Lateral Sclerosis/genetics ; Aged ; Adult ; Case-Control Studies ; DNA Copy Number Variations ; }, abstract = {BACKGROUND: The copy number status (CNS) of the survival motor neuron (SMN) gene may influence the risk and prognosis of amyotrophic lateral sclerosis (ALS) and lower motor neuron diseases (LMND) other than spinal muscular atrophy (SMA). However, previous studies of this association, mainly from Europe, have yielded controversial results, suggesting possible regional differences. Here, we investigated the effect of the SMN gene in Japanese patients with ALS and LMND.

METHODS: We examined the SMN copy numbers and clinical histories of 487 Japanese patients with sporadic ALS (281 men; mean age at onset 61.5 years), 50 with adult LMND (50 men; mean age at onset 58.4 years) and 399 Japanese controls (171 men; mean age 62.2 years). Patients with pathogenic mutations in ALS-causing genes were excluded. SMN1 and SMN2 copy numbers were determined using the droplet digital polymerase chain reaction.

RESULTS: The frequency of a copy number of one for the SMN2 gene was higher in patients with ALS (38.0%) than in healthy controls (30.8%) (odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.04-1.82, p < 0.05). The SMN2 copy number affected the survival time of patients with ALS (median time: 0 copies, 34 months; 1 copy, 39 months; 2 copies, 44 months; 3 copies, 54 months; log-rank test, p < 0.05). Cox regression analysis revealed that the SMN2 copy number was associated with increased mortality (hazard ratio = 0.84, 95% CI = 0.72-0.98, p < 0.05). Also, null SMN2 cases were significantly more frequent in the LMND group (12.0%) than in the control group (4.8%) (OR = 2.73, 95% CI = 1.06-6.98, p < 0.05).

CONCLUSIONS: Our findings suggest that SMN2 copy number reduction may adversely affect the onset and prognosis of MND, including ALS and LMND, in Japanese.}, } @article {pmid39508106, year = {2024}, author = {Gao, XF and Chen, AQ and Tang, HY and Kong, XQ and Zhang, H and Wang, ZM and Lu, W and Wang, LG and Wang, F and Zhou, WY and Gu, Y and Zuo, GF and Ge, Z and Zhang, JJ and Chen, SL}, title = {m[6]A Modification of Profilin-1 in Vascular Smooth Muscle Cells Drives Phenotype Switching and Neointimal Hyperplasia via Activation of the p-ANXA2/STAT3 Pathway.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {44}, number = {12}, pages = {2543-2559}, pmid = {39508106}, issn = {1524-4636}, mesh = {Animals ; *Neointima ; *Muscle, Smooth, Vascular/metabolism/pathology ; *Hyperplasia ; *Phenotype ; *STAT3 Transcription Factor/metabolism/genetics ; *Myocytes, Smooth Muscle/metabolism/pathology ; *Signal Transduction ; *Disease Models, Animal ; *Proto-Oncogene Mas ; Male ; *Profilins/metabolism/genetics ; *Mice, Knockout ; *Adenosine/metabolism/analogs & derivatives ; Humans ; Mice ; Mice, Inbred C57BL ; Rats ; Cells, Cultured ; Rats, Sprague-Dawley ; Phosphorylation ; Coronary Restenosis/metabolism/pathology/genetics/etiology ; Carotid Stenosis/metabolism/pathology/genetics ; Cell Proliferation ; }, abstract = {BACKGROUND: In-stent restenosis is characterized by a significant reduction in lumen diameter within the stented segment, primarily attributed to excessive proliferation of vascular smooth muscle cells (VSMCs) and neointimal hyperplasia. PFN1 (profilin-1), an actin-sequestering protein extensively studied in amyotrophic lateral sclerosis, remains less explored in neointimal hyperplasia.

METHODS: Utilizing single-cell RNA sequencing alongside data from in-stent restenosis patients and various experimental in-stent restenosis models (swine, rats, and mice), we investigated the role of PFN1 in promoting VSMC phenotype switching and neointimal hyperplasia.

RESULTS: Single-cell RNA sequencing of stenotic rat carotid arteries revealed a critical role for PFN1 in neointimal hyperplasia, a finding corroborated in stented swine coronary arteries, in-stent restenosis patients, PFN1[SMC-IKO] (SMC-specific PFN1 knockout) mice, and PFN1 overexpressed mice. PFN1 deletion was shown to suppress VSMC phenotype switching and neointimal hyperplasia in PFN1[SMC-IKO] mice subjected to a wire-injured model. To elucidate the observed discordance in PFN1 mRNA and protein levels, we identified that METTL3 (N[6]-methyladenosine methyltransferase) and YTHDF3 (YTH N6-methyladenosine RNA binding protein F3; N[6]-methyladenosine-specific reader) enhance PFN1 translation efficiency in an N[6]-methyladenosine-dependent manner, confirmed through experiments involving METTL3 knockout and YTHDF3 knockout mice. Furthermore, PFN1 was mechanistically found to interact with the phosphorylation of ANXA2 (annexin A2) by recruiting Src (SRC proto-oncogene, nonreceptor tyrosine kinase), promoting the phosphorylation of STAT3 (signal transducer and activator of transcription 3), a typical transcription factor known to induce VSMC phenotype switching.

CONCLUSIONS: This study unveils the significance of PFN1 N[6]-methyladenosine modification in VSMCs, demonstrating its role in promoting phenotype switching and neointimal hyperplasia through the activation of the p-ANXA2 (phospho-ANXA2)/STAT3 pathway.}, } @article {pmid39508354, year = {2025}, author = {Bhatele, P and Pai, AR}, title = {Wine Glass Sign in Bulbar Onset Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {97}, number = {3}, pages = {558-560}, doi = {10.1002/ana.27131}, pmid = {39508354}, issn = {1531-8249}, } @article {pmid39508663, year = {2024}, author = {}, title = {Platform Communications: Abstract Book 35th International Symposium on ALS/MND (Complete printable file).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {sup1}, pages = {1-92}, doi = {10.1080/21678421.2024.2403293}, pmid = {39508663}, issn = {2167-9223}, } @article {pmid39508675, year = {2024}, author = {}, title = {DSP-01 conversion from PLS to ALS: a Dutch cohort study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {sup1}, pages = {262-279}, doi = {10.1080/21678421.2024.2403307}, pmid = {39508675}, issn = {2167-9223}, } @article {pmid39509425, year = {2024}, author = {Deng, YC and Liu, JW and Ting, HC and Kuo, TC and Chiang, CH and Lin, EY and Harn, HJ and Lin, SZ and Chang, CY and Chiou, TW}, title = {n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0311573}, pmid = {39509425}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; *Induced Pluripotent Stem Cells/metabolism/drug effects ; Humans ; *Motor Neurons/drug effects/metabolism/pathology ; *Calcium/metabolism ; *Homeostasis/drug effects ; *Superoxide Dismutase-1/genetics/metabolism ; *Phthalic Anhydrides/pharmacology ; Cell Differentiation/drug effects ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that causes muscle atrophy and primarily targets motor neurons (MNs). Approximately 20% of familial ALS cases are caused by gain-of-function mutations in superoxide dismutase 1 (SOD1), leading to MN degeneration and ion channel dysfunction. Previous studies have shown that n-Butylidenephthalide (BP) delays disease progression and prolongs survival in animal models of ALS. However, no studies have been conducted on models from human sources. Herein, we examined the protective efficacy of BP on MNs derived from induced pluripotent stem cells (iPSCs) of an ALS patient harboring the SOD1G85R mutation as well as on those derived from genetically corrected iPSCs (SOD1G85G). Our results demonstrated that the motor neurons differentiated from iPSC with SOD1G85R mutation exhibited characteristics of neuron degeneration (as indicated by the reduction of neurofilament expression) and ion channel dysfunction (in response to potassium chloride (KCl) and L-glutamate stimulation), in contrast to those derived from the gene corrected iPSC (SOD1G85G). Meanwhile, BP treatment effectively restored calcium ion channel function by reducing the expression of glutamate receptors including glutamate ionotropic receptor AMPA type subunit 3 (GluR3) and glutamate ionotropic receptor NMDA type subunit 1 (NMDAR1). Additionally, BP treatment activated autophagic pathway to attenuate neuron degeneration. Overall, this study supports the therapeutic effects of BP on ALS patient-derived neuron cells, and suggests that BP may be a promising candidate for future drug development.}, } @article {pmid39510439, year = {2024}, author = {Tan, X and Su, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Feng, H}, title = {BRD7 regulates cellular senescence and apoptosis in ALS by modulating p21 expression and p53 mitochondrial translocation respectively.}, journal = {Neuroscience}, volume = {563}, number = {}, pages = {51-62}, doi = {10.1016/j.neuroscience.2024.11.004}, pmid = {39510439}, issn = {1873-7544}, mesh = {*Cellular Senescence/physiology ; *Apoptosis/physiology ; *Tumor Suppressor Protein p53/metabolism/genetics ; Humans ; *Cyclin-Dependent Kinase Inhibitor p21/metabolism/genetics ; *Mitochondria/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Motor Neurons/metabolism/pathology ; Chromosomal Proteins, Non-Histone/metabolism/genetics ; Male ; Female ; Middle Aged ; Aged ; Bromodomain Containing Proteins ; }, abstract = {Cellular senescence is involved in the progression of neurodegenerative diseases. Motor neurons exhibit senescence-like alterations in ALS. BRD7, identified as a regulatory factor associated with cellular senescence, its function in ALS remains unclear. This study aims to investigate the potential role and mechanisms of BRD7 in ALS. We analyzed RNA levels using qRT-PCR, protein levels through immunofluorescence and western blot, and apoptosis via TUNEL staining. Cell transfection was conducted for in vitro experiments. The level of β-galactosidase was measured by β-galactosidase activity detection kit. ALS motor neurons exhibited senescence-like alterations, characterized by increased activity of p53, p21, and β-galactosidase, as well as reduced lamin B1 staining. Additionally, the expression of BRD7 was upregulated and induced cellular senescence and apoptosis. Downregulation of BRD7 alleviates the cellular senescence by inhibiting p21 rather than p53. Knockdown of BRD7 inhibited p53 mitochondrial translocation, leading to reduced apoptosis. Our results suggest that BRD7 plays an important role in the survival of ALS motor neurons. BRD7 knockdown can reduce cellular senescence and apoptosis by inhibiting p21 and p53 mitochondrial translocation.}, } @article {pmid39510899, year = {2024}, author = {Kaul, M and Mukherjee, D and Weiner, HL and Cox, LM}, title = {Gut microbiota immune cross-talk in amyotrophic lateral sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {6}, pages = {e00469}, pmid = {39510899}, issn = {1878-7479}, support = {P51 OD011133/OD/NIH HHS/United States ; R01 NS115951/NS/NINDS NIH HHS/United States ; R21 NS126866/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/microbiology ; *Gastrointestinal Microbiome/immunology/physiology ; Humans ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons. While there has been significant progress in defining the genetic contributions to ALS, greater than 90 % of cases are sporadic, which suggests an environmental component. The gut microbiota is altered in ALS and is an ecological factor that contributes to disease by modulating immunologic, metabolic, and neuronal signaling. Depleting the microbiome worsens disease in the SOD1 ALS animal model, while it ameliorates disease in the C9orf72 model of ALS, indicating critical subtype-specific interactions. Furthermore, administering beneficial microbiota or microbial metabolites can slow disease progression in animal models. This review discusses the current state of microbiome research in ALS, including interactions with different ALS subtypes, evidence in animal models and human studies, key immunologic and metabolomic mediators, and a path toward microbiome-based therapies for ALS.}, } @article {pmid39511225, year = {2024}, author = {Silvestri, B and Mochi, M and Mawrie, D and de Turris, V and Colantoni, A and Borhy, B and Medici, M and Anderson, EN and Garone, MG and Zammerilla, CP and Simula, M and Ballarino, M and Pandey, UB and Rosa, A}, title = {HuD impairs neuromuscular junctions and induces apoptosis in human iPSC and Drosophila ALS models.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9618}, pmid = {39511225}, issn = {2041-1723}, support = {RP123188EC9F2349//Sapienza Università di Roma (Sapienza University of Rome)/ ; R01 NS081303/NS/NINDS NIH HHS/United States ; 2022BYB33L//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; RM12117A5DE7A45B//Sapienza Università di Roma (Sapienza University of Rome)/ ; CN00000041//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; LT0024/2022-L//Human Frontier Science Program (HFSP)/ ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Neuromuscular Junction/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *Apoptosis/genetics ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; *RNA-Binding Protein FUS/metabolism/genetics ; *Disease Models, Animal ; *ELAV-Like Protein 4/metabolism/genetics ; Mutation ; Oxidative Stress ; Drosophila Proteins/metabolism/genetics ; Drosophila melanogaster/genetics ; Female ; Male ; Drosophila ; }, abstract = {Defects at the neuromuscular junction (NMJ) are among the earliest hallmarks of amyotrophic lateral sclerosis (ALS). According to the "dying-back" hypothesis, NMJ disruption not only precedes but also triggers the subsequent degeneration of motoneurons in both sporadic (sALS) and familial (fALS) ALS. Using human induced pluripotent stem cells (iPSCs), we show that the RNA-binding protein HuD (ELAVL4) contributes to NMJ defects and apoptosis in FUS-ALS. HuD overexpression mimics the severe FUS[P525L] mutation, while its knockdown rescues the FUS[P525L] phenotypes. In Drosophila, neuronal overexpression of the HuD ortholog, elav, induces motor dysfunction, and its knockdown improves motor function in a FUS-ALS model. Finally, we report increased HuD levels upon oxidative stress in human motoneurons and in sALS patients with an oxidative stress signature. Based on these findings, we propose that HuD plays a role downstream of FUS mutations in fALS and in sALS related to oxidative stress.}, } @article {pmid39511709, year = {2025}, author = {Fontaine, M and Horowitz, K and Anoja, N and Genge, A and Salmon, K}, title = {How the prospect of a clinical trial impacts decision-making for predictive genetic testing in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {343-351}, doi = {10.1080/21678421.2024.2423718}, pmid = {39511709}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/psychology ; *Genetic Testing/methods ; Male ; Female ; Middle Aged ; *Decision Making ; Adult ; Aged ; Genetic Counseling/psychology ; *Clinical Trials as Topic/psychology ; C9orf72 Protein/genetics ; Surveys and Questionnaires ; Genetic Predisposition to Disease ; Superoxide Dismutase-1/genetics ; }, abstract = {Objective: Genetic testing practices are rapidly evolving for people living with, or at-risk for, amyotrophic lateral sclerosis (ALS), due to emerging genotype-driven therapies. This study explored how individuals at-risk for familial ALS (fALS) perceive the opportunity to participate in a clinical trial, and to better understand how that may influence the decision-making process for predictive genetic testing. Methods: This study used both quantitative and qualitative data analyses. Data were collected through an online questionnaire, followed by semi-structured interviews conducted with twelve (n = 12) individuals at-risk for either SOD1- or C9orf72-ALS who had predictive testing prior to study participation. Interview data were analyzed using reflexive thematic analysis. Results: Three overarching themes were conceptualized from the data: i) the psychosocial impact of fALS; ii) perspectives of at-risk individuals on research involvement; and iii) predictive genetic counseling and testing considerations. These results contribute perspectives of the lived experience to inform predictive genetic counseling and testing practices for individuals at-risk for fALS. Conclusion: Individuals at-risk for fALS view potential participation in a presymptomatic clinical trial as an actionable measure that may increase their desire for predictive genetic testing. Genetic counseling was identified as a critical component of the predictive testing process given the life-changing implications associated with a positive result. Increased access to predictive genetic counseling, and in a timely manner, is a significant need in the ALS population given potential access to gene-specific therapies in the presymptomatic stage.}, } @article {pmid39511821, year = {2025}, author = {Grady, A and Lorch, R and Giles, L and Lamont, H and Anderson, A and Pearson, N and Romiti, M and Lum, M and Stuart, A and Leigh, L and Yoong, SL}, title = {The impact of early childhood education and care-based interventions on child physical activity, anthropometrics, fundamental movement skills, cognitive functioning, and social-emotional wellbeing: A systematic review and meta-analysis.}, journal = {Obesity reviews : an official journal of the International Association for the Study of Obesity}, volume = {26}, number = {2}, pages = {e13852}, pmid = {39511821}, issn = {1467-789X}, support = {APP1170042//National Health and Medical Research Council/ ; Heart Foundation Postdoctoral Fellowship 102518//National Heart Foundation of Australia/ ; Heart Foundation Future Leader Fellowship 106654//National Heart Foundation of Australia/ ; }, mesh = {Humans ; *Cognition ; Child, Preschool ; *Exercise/psychology ; Child ; Infant ; Motor Skills/physiology ; Pediatric Obesity/psychology/prevention & control ; Anthropometry ; Early Intervention, Educational ; }, abstract = {This review assessed the effectiveness of ECEC-based interventions to improve child physical activity, and intervention impact on child weight-based anthropometrics, fundamental movement skills (FMS), cognitive functioning, and social-emotional wellbeing. Adverse effects and costs were assessed. Finch et al's 2014 systematic review was updated. Electronic databases were searched 10 September 2014 to 27 October 2022. Included studies were randomized controlled trials of ECEC interventions targeting physical activity among children aged 0-6 years. The methodological quality of studies was assessed using Cochrane's Risk of Bias tool v2. Standardized mean differences (SMD) were calculated for each outcome with meta-analysis undertaken; otherwise, findings were described narratively. Fifty-three studies were included. ECEC-based interventions were found to significantly improve child physical activity (SMD 0.193, 95% confidence interval [CI] 0.09 to 0.3; p < 0.001) and FMS (SMD 0.544, 95% CI 0.1 to 0.98; p = 0.015), compared to control. Small positive, but non-significant, effects were found for weight-based anthropometrics, cognitive functioning, and social-emotional wellbeing. Few studies reported adverse effects (n = 10), and no studies reported formal economic analyses. While ECEC-based interventions can significantly improve child physical activity and FMS, further evidence of their impact on cognitive functioning, social-emotional wellbeing, and the cost-effectiveness of such interventions is required to inform policy and practice.}, } @article {pmid39511939, year = {2025}, author = {Eisen, A and Vucic, S and Kiernan, MC}, title = {Amyotrophic lateral sclerosis represents corticomotoneuronal system failure.}, journal = {Muscle & nerve}, volume = {71}, number = {4}, pages = {499-511}, pmid = {39511939}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Humans ; Animals ; *Motor Neurons/pathology/physiology ; *Motor Cortex/pathology/physiopathology ; }, abstract = {Several decades have passed since the anterograde corticomotoneuronal hypothesis for amyotrophic lateral sclerosis (ALS) was proposed. The intervening years have witnessed its emergent support based on anatomical, pathological, physiological, neuroimaging, and molecular biological studies. The evolution of an extensive corticomotoneuronal system appears restricted to the human species, with ALS representing a uniquely human disease. While some, very select non-human primates have limited corticomotoneuronal projections, these tend to be absent in all other animals. From a general perspective, the early clinical features of ALS may be considered to reflect failure of the corticomotoneuronal system. The characteristic loss of skilled motor dexterity involving the limbs, and speech impairment through progressive bulbar dysfunction specifically involve those motor units having the strongest corticomotoneuronal projections. A similar explanation likely underlies the unique "split phenotypes" that have now been well characterized in ALS. Large Betz cells and other pyramidal corticomotoneuronal projecting neurons, with their extensive dendritic arborization, are particularly vulnerable to the elements of the ALS exposome such as aging, environmental stress and lifestyle changes. Progressive failure of the proteosome impairs nucleocytoplasmic shuffling and induces toxic but soluble TDP-43 to aggregate in corticomotoneurons. Betz cell failure is further accentuated through dysfunction of its profuse dendritic arborizations. Clarification of system specific genomes and neural networks will likely promote the initiation of precision medicine approaches directed to support the key structure that underlies the neurological manifestations of ALS, the corticomotoneuronal system.}, } @article {pmid39511965, year = {2025}, author = {Bhai, S and Levine, T and Moore, D and Bowser, R and Heim, AJ and Walsh, M and Shibani, A and Simmons, Z and Grogan, J and Goyal, NA and Govindarajan, R and Hussain, Y and Papsdorf, T and Schwasinger-Schmidt, T and Olney, N and Goslin, K and Pulley, M and Kasarskis, E and Weiss, M and Katz, SW and Moser, S and Jabari, D and Jawdat, O and Statland, J and Dimachkie, MM and Barohn, R and , }, title = {A 40-week phase 2B randomized, multicenter, double-blind, placebo-controlled study evaluating the safety and efficacy of memantine in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {71}, number = {1}, pages = {63-72}, pmid = {39511965}, issn = {1097-4598}, support = {R01 FD003937/FD/FDA HHS/United States ; R01FD003937//FDA-OPD/ ; //U.S. Food and Drug Administration/ ; }, mesh = {Humans ; *Memantine/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Double-Blind Method ; Middle Aged ; Aged ; Adult ; Aged, 80 and over ; *Disease Progression ; Treatment Outcome ; Young Adult ; Excitatory Amino Acid Antagonists/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no known cure, limited treatment options with minimal benefits, and significant unmet need for disease modifying therapies.

AIMS: This study investigated memantine's impact on ALS progression, with an additional focus on the effects of memantine on cognitive and behavioral changes associated with the disease.

METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2018 to September 2020. ALS patients were enrolled in-person and remotely across 13 sites in the United States. Participants were randomized to memantine (20 mg twice daily) or placebo in a 2:1 ratio and completed 36 weeks of treatment. The primary outcome of disease progression was assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and blood was collected for biomarker analysis.

RESULTS: Of the 99 participants enrolled in the study, 89 were randomized to memantine or placebo (ages 24-83 years, male-to-female ratio ~3:2). Fifty-two participants completed the study treatment with no significant differences in disease progression, biomarker changes (including neurofilament light chain [NfL]), or neuropsychiatric testing noted between the groups. Initial NfL values correlated with the rate of ALSFRS-R decline.

DISCUSSION: In this study, memantine did not impact ALS disease progression or neuropsychiatric symptoms. Trials with remote enrollment may help trial participation and success.}, } @article {pmid39512085, year = {2025}, author = {White, CG and Hancewicz, TM and Fasasi, A and Wright, J and Lavine, BK}, title = {Alternating and Modified Alternating Least Squares Applied to Raman Spectra of Finished Gasolines.}, journal = {Applied spectroscopy}, volume = {79}, number = {5}, pages = {808-815}, doi = {10.1177/00037028241292649}, pmid = {39512085}, issn = {1943-3530}, abstract = {Extraction of components from individual refinery streams (e.g., reformates and alkylates) in finished gasoline was undertaken using Raman spectroscopy to characterize the chemical content of the finished product. Modified alternating least squares (MALS) was used for separating Raman spectroscopic data sets of the finished product into its pure individual components. The advantages of MALS over alternating least squares (ALS) for multicomponent resolution are highlighted in this study using three Raman spectroscopic data sets which provide a suitable benchmark for comparing the performance of these two methods. MALS is superior to ALS in terms of accuracy and can better resolve components than ALS, and it is also more robust toward collinear data. Finally, components near the noise level usually cannot be extracted by ALS because of instability when inverting the covariance structure which inflates the noise present in the data. However, these same components can be extracted by MALS due to the stabilization of the least squares regression with respect to the matrix inversion using modified techniques from ridge regression.}, } @article {pmid39512134, year = {2025}, author = {Pattee, GL}, title = {Gastrostomy in Amyotrophic Lateral Sclerosis: Timing Enhances Survival.}, journal = {Muscle & nerve}, volume = {71}, number = {1}, pages = {3-5}, doi = {10.1002/mus.28294}, pmid = {39512134}, issn = {1097-4598}, } @article {pmid39513379, year = {2025}, author = {Simkins, TJ and Kupfer, S and Malik, FI and Meng, L and Rudnicki, SA and Wei, J and Shefner, JM and Bowser, R}, title = {Plasma neurofilament analysis in VITALITY-ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {103-112}, doi = {10.1080/21678421.2024.2423707}, pmid = {39513379}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/blood/drug therapy/diagnosis ; Double-Blind Method ; Disease Progression ; *Neurofilament Proteins/blood ; Aged ; Biomarkers/blood ; *Intermediate Filaments/metabolism ; Longitudinal Studies ; Adult ; }, abstract = {OBJECTIVE: To evaluate correlations between neurofilament (Nf) concentrations and clinical characteristics and disease progression using a large longitudinal dataset from VITALITY-ALS (ClinicalTrials.gov identifier: NCT02496767), a 48-week, randomized, double-blind, placebo-controlled clinical trial of tirasemtiv in people with ALS (pALS).

METHODS: Plasma was collected at baseline and every 8 weeks thereafter. Results were compared between treatment groups and evaluated by clinical characteristics and over time. Pearson's correlation coefficients (r) were calculated to evaluate associations between Nf concentrations and slow vital capacity (SVC), Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score, and pre-study/in-study rates of disease progression (psRDP/isRDP).

RESULTS: Nf measurements were available from 101 placebo- and 161 tirasemtiv-treated people with ALS (pALS). There were no significant differences in Nf between placebo and tirasemtiv groups at any time point; further analyses grouped all samples. At baseline, Nf concentration did not differ by multiple clinical characteristics. Baseline Nf light chain (NfL) concentration correlated with the psRDP (r = 0.50, p < 0.001) and isRDP (r = 0.53, p < 0.0001). Phosphorylated Nf heavy chain (pNfH) demonstrated a similar, but less robust, pattern of results. Baseline Nf concentration correlated with change in SVC and ALSFRS-R score over time. Plasma pNfH concentration continuously decreased over time. There was no meaningful change in plasma NfL concentration over the study period.

CONCLUSIONS: In this large longitudinal study, baseline NfL concentration correlated with multiple markers of disease progression. The findings suggest Nfs show promise primarily as prognostic markers for pALS, particularly for those with rapid disease progression.}, } @article {pmid39514515, year = {2024}, author = {Ohnari, K and Mafune, K and Adachi, H}, title = {Fasciculation potentials are related to the prognosis of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0313307}, pmid = {39514515}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/diagnosis ; Male ; Female ; Middle Aged ; Prognosis ; *Fasciculation/physiopathology/diagnosis ; *Electromyography ; Aged ; Retrospective Studies ; Disease Progression ; Adult ; Biomarkers/blood ; }, abstract = {Some prognostic biomarkers of amyotrophic lateral sclerosis (ALS) have been described; however, they are inadequate for satisfactorily predicting individual patient outcomes. Fasciculation potentials (FPs) on electromyography (EMG) are useful for the early diagnosis of ALS, and complex FPs are associated with shorter survival in ALS. In this study, we investigated the relationship between the proportion of muscles with FPs, biochemical markers, and the prognosis of ALS. 89 Patients with ALS were retrospectively classified into three groups based on the interval from onset to death or tracheostomy (less than 1 year: fast progression; from 1 year to less than 3 years: average progression; 3 years or more: slow progression). We performed statistical analysis of the electrophysiological findings, including the percentage of examined muscles with FPs, and biochemical markers evaluated on admission. Patients with fast ALS progression had a higher percentage of muscles with FPs (93.1% vs. 37.9%, P<0.001) and lower uric acid (UA) levels (male: 4.19 mg/dl vs 5.55 mg/dl, P<0.001; female: 3.71 mg/dl vs 5.41 mg/dl, P<0.001) than patients with slow progression. Survival curves demonstrated a relationship between these factors and the survival time in patients with ALS. Furthermore, UA levels were correlated with the percentage of muscles with FPs. Our electrophysiological findings suggest that ALS presents with multisystem neurological manifestations, and these manifestations differed among the groups classified by disease progression. The percentage of muscles with FPs on EMG and serum UA levels were especially associated with the prognosis of ALS.}, } @article {pmid39515011, year = {2024}, author = {Mauri, L and Taccaliti, F and Lingua, E}, title = {Modeling the interaction between wildfires and windthrows: A pilot case study for Italian Alps.}, journal = {Journal of environmental management}, volume = {371}, number = {}, pages = {123150}, doi = {10.1016/j.jenvman.2024.123150}, pmid = {39515011}, issn = {1095-8630}, mesh = {*Wildfires ; Italy ; *Forests ; Pilot Projects ; Models, Theoretical ; Ecosystem ; Wind ; }, abstract = {Wildland fires and windthrows represent relevant disturbances for forest ecosystems worldwide. In this context, especially for Italian catchments, the interaction between windthrows and changes in wildfire behaviour starting from ALS data processing is scarcely investigated. Therefore, this research aims to compute a multi-temporal analysis of the interaction between windthrows and wildfire behaviour in a forested area (Veneto region, northern Italy), recently affected by the renamed Vaia windstorm. The semi-empirical FlamMap model was applied, starting from ALS data processing implemented in R for mapping the spatial distribution of forest attributes and fuels within the catchment. The role of windthrows in altering wildfire behaviour was investigated considering ALS point clouds acquired before and after the occurrence of the storm Vaia. Digital Terrain Models (DTMs), Canopy Height Models (CHMs), topographic data and metrics describing forest structure were extracted from ALS data for both scenarios at 5 m resolution, to compare changes in wildfire behaviour over time. Differences in Rate of Spread (RoS), flame length (FL), midflame windspeed (WS) and arrival time (AT) were assessed, and their correlation with windstorm damages was investigated at the catchment detail. , An increase of RoS, FL, and WS greater than 30 m/min, 3 m and 1.1 m/s were respectively estimated in windthrown areas, as well as a decrease of AT greater than 30 min, attesting the key role of windthrows in altering wildfire behaviour over time. The correlation between windthrows and changes in wildfire attributes was finally modeled by computing regression analysis, with R[2] of 0.86, 0.93, 0.62, and 0.91 resulted for RoS, FL, WS and AT. This research represents a pilot case study for better detecting changes in wildfires behaviour due to windthrows occurrence, therefore proposing and carrying out effective planning and management strategies for disturbed forest stands over time.}, } @article {pmid39517754, year = {2024}, author = {Ciou, TS and Lin, CH and Wang, CK}, title = {Airborne LiDAR Point Cloud Classification Using Ensemble Learning for DEM Generation.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {21}, pages = {}, pmid = {39517754}, issn = {1424-8220}, abstract = {Airborne laser scanning (ALS) point clouds have emerged as a predominant data source for the generation of digital elevation models (DEM) in recent years. Traditionally, the generation of DEM using ALS point clouds involves the steps of point cloud classification or ground point filtering to extract ground points and labor-intensive post-processing to correct the misclassified ground points. The current deep learning techniques leverage the ability of geometric recognition for ground point classification. However, the deep learning classifiers are generally trained using 3D point clouds with simple geometric terrains, which decrease the performance of model inferencing. In this study, a point-based deep learning model with boosting ensemble learning and a set of geometric features as the model inputs is proposed. With the ensemble learning strategy, this study integrates specialized ground point classifiers designed for different terrains to boost classification robustness and accuracy. In experiments, ALS point clouds containing various terrains were used to evaluate the feasibility of the proposed method. The results demonstrated that the proposed method can improve the point cloud classification and the quality of generated DEMs. The classification accuracy and F1 score are improved from 80.9% to 92.2%, and 82.2% to 94.2%, respectively, by using the proposed methods. In addition, the DEM generation error, in terms of mean squared error (RMSE), is reduced from 0.318-1.362 m to 0.273-1.032 m by using the proposed ensemble learning.}, } @article {pmid39518442, year = {2024}, author = {Laucius, O and Drūteika, J and Balnytė, R and Palačionytė, J and Ališauskienė, M and Petrikonis, K and Vaitkus, A}, title = {Phrenic Nerve Sonography Alterations in Patients with ALS: Insight with Clinical and Neurophysiological Findings.}, journal = {Journal of clinical medicine}, volume = {13}, number = {21}, pages = {}, pmid = {39518442}, issn = {2077-0383}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, and although the diagnosis is primarily based on clinical criteria, ENMG, as the "gold standard", does not always show detectable changes. Therefore, our study suggests that alterations in echogenicity and heterogeneity of the phrenic nerve (PN) may serve as potential additional diagnostic tools for ALS. Methods: Our study included 32 patients in the ALS group and 64 individuals in the control group. Each participant underwent an interview and completed questionnaires to collect clinical and demographic data, including age, gender, height, body mass index (BMI), hip and waist circumference, duration of illness, ALS-FRS-R score, comorbidities, and medication use. Ultrasound examinations of the PN were performed by two authors using a high-resolution "Philips EPIQ 7" ultrasound machine equipped with a linear 4-18 MHz transducer. The ALS group participants underwent PN sonography and conduction examinations, arterial blood gas (ABG) analysis, respiratory function tests (RFT), and electroneuromyography (ENMG). Results: The study demonstrated that the phrenic nerve is significantly smaller on both sides in patients with ALS compared to the control group (p < 0.01). Changes in the homogeneity and echogenicity of the PN were also observed on both sides. On the right side, 43.8% of the nerves showed heterogeneity, 40.6% were isoechoic, and 21.9% were hyperechoic. On the left side, 59.4% of the nerves exhibited heterogeneity, 34.4% were isoechoic, and 28.1% were hyperechoic. Moreover, sonography on both sides showed significant correlation with ALS-FRS-R, COMPASS-31, and ENMG results. Conclusions: Our study highlights the importance of phrenic nerve ultrasound as a promising supplementary diagnostic tool for ALS. The significant differences in phrenic nerve size, echogenicity, and homogeneity between patients with ALS and the control group demonstrate that ultrasound imaging can detect morphological changes in the phrenic nerve. Incorporating phrenic nerve ultrasound into routine diagnostic protocols could improve early detection, enhance disease monitoring, and offer a more comprehensive understanding of the neurodegenerative processes in ALS.}, } @article {pmid39519209, year = {2024}, author = {Firdaus, Z and Li, X}, title = {Epigenetic Explorations of Neurological Disorders, the Identification Methods, and Therapeutic Avenues.}, journal = {International journal of molecular sciences}, volume = {25}, number = {21}, pages = {}, pmid = {39519209}, issn = {1422-0067}, support = {R01 DK126662/DK/NIDDK NIH HHS/United States ; R01 DK129241/DK/NIDDK NIH HHS/United States ; DK129241 DK126662/GF/NIH HHS/United States ; }, mesh = {Humans ; *Epigenesis, Genetic ; *DNA Methylation ; Neurodegenerative Diseases/genetics/therapy ; Animals ; Nervous System Diseases/genetics/therapy ; Histones/metabolism/genetics ; Epigenomics/methods ; Histone Code/genetics ; }, abstract = {Neurodegenerative disorders are major health concerns globally, especially in aging societies. The exploration of brain epigenomes, which consist of multiple forms of DNA methylation and covalent histone modifications, offers new and unanticipated perspective into the mechanisms of aging and neurodegenerative diseases. Initially, chromatin defects in the brain were thought to be static abnormalities from early development associated with rare genetic syndromes. However, it is now evident that mutations and the dysregulation of the epigenetic machinery extend across a broader spectrum, encompassing adult-onset neurodegenerative diseases. Hence, it is crucial to develop methodologies that can enhance epigenetic research. Several approaches have been created to investigate alterations in epigenetics on a spectrum of scales-ranging from low to high-with a particular focus on detecting DNA methylation and histone modifications. This article explores the burgeoning realm of neuroepigenetics, emphasizing its role in enhancing our mechanistic comprehension of neurodegenerative disorders and elucidating the predominant techniques employed for detecting modifications in the epigenome. Additionally, we ponder the potential influence of these advancements on shaping future therapeutic approaches.}, } @article {pmid39519213, year = {2024}, author = {Bova, V and Mannino, D and Capra, AP and Lanza, M and Palermo, N and Filippone, A and Esposito, E}, title = {CK and LRRK2 Involvement in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {21}, pages = {}, pmid = {39519213}, issn = {1422-0067}, mesh = {Humans ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics ; Animals ; Mutation ; Phosphorylation ; Autophagy/genetics ; }, abstract = {Neurodegenerative diseases (NDDs) are currently the most widespread neuronal pathologies in the world. Among these, the most widespread are Alzheimer's disease (AD), dementia, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD)-all characterized by a progressive loss of neurons in specific regions of the brain leading to varied clinical symptoms. At the basis of neurodegenerative diseases, an emerging role is played by genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene that cause increased LRRK2 activity with consequent alteration of neuronal autophagy pathways. LRRK2 kinase activity requires GTPase activity which functions independently of kinase activity and is required for neurotoxicity and to potentiate neuronal death. Important in the neurodegeneration process is the upregulation of casein kinase (CK), which causes the alteration of the AMPK pathway by enhancing the phosphorylation of α-synuclein and huntingtin proteins, known to be involved in PD and HD, and increasing the accumulation of the amyloid-β protein (Aβ) for AD. Recent research has identified CK of the kinases upstream of LRRK2 as a regulator of the stability of the LRRK2 protein. Based on this evidence, this review aims to understand the direct involvement of individual kinases in NDDs and how their crosstalk may impact the pathogenesis and early onset of neurodegenerative diseases.}, } @article {pmid39520508, year = {2024}, author = {Larose, A and Miller, CCJ and Mórotz, GM}, title = {The lemur tail kinase family in neuronal function and disfunction in neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {447}, pmid = {39520508}, issn = {1420-9071}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism/enzymology ; Animals ; *Neurons/metabolism/pathology ; Cyclin-Dependent Kinase 5/metabolism/genetics ; Signal Transduction ; Synapses/metabolism/pathology ; Protein-Tyrosine Kinases/metabolism/genetics ; Phosphorylation ; Axonal Transport ; Glycogen Synthase Kinase 3 beta/metabolism ; }, abstract = {The complex neuronal architecture and the long distance of synapses from the cell body require precisely orchestrated axonal and dendritic transport processes to support key neuronal functions including synaptic signalling, learning and memory formation. Protein phosphorylation is a major regulator of both intracellular transport and synaptic functions. Some kinases and phosphatases such as cyclin dependent kinase-5 (cdk5)/p35, glycogen synthase kinase-3β (GSK3β) and protein phosphatase-1 (PP1) are strongly involved in these processes. A primary pathological hallmark of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal dementia, is synaptic degeneration together with disrupted intracellular transport. One attractive possibility is that alterations to key kinases and phosphatases may underlie both synaptic and axonal transport damages. The brain enriched lemur tail kinases (LMTKs, formerly known as lemur tyrosine kinases) are involved in intracellular transport and synaptic functions, and are also centrally placed in cdk5/p35, GSK3β and PP1 signalling pathways. Loss of LMTKs is documented in major neurodegenerative diseases and thus can contribute to pathological defects in these disorders. However, whilst function of their signalling partners became clearer in modulating both synaptic signalling and axonal transport progress has only recently been made around LMTKs. In this review, we describe this progress with a special focus on intracellular transport, synaptic functions and neurodegenerative diseases.}, } @article {pmid39520580, year = {2024}, author = {Hyldgaard Andersen, S and Harsløf, S and Tøttrup, A}, title = {Laparoscopic ileopexy for afferent loop syndrome after restorative proctocolectomy-a retrospective case series.}, journal = {International journal of colorectal disease}, volume = {39}, number = {1}, pages = {180}, pmid = {39520580}, issn = {1432-1262}, mesh = {Humans ; *Proctocolectomy, Restorative/adverse effects ; *Laparoscopy/adverse effects ; Female ; Male ; Retrospective Studies ; Middle Aged ; Adult ; *Afferent Loop Syndrome/surgery/etiology ; *Ileum/surgery ; Aged ; Treatment Outcome ; Postoperative Complications/etiology/surgery ; }, abstract = {BACKGROUND: To study the effect of laparoscopic ileopexy in patients with afferent-loop syndrome (ALS) after restorative proctocolectomy (RP).

METHOD: Ileopexy has been the treatment of choice in patients with ALS for the last 5 years at our department. All patients who had undergone ileopexy for ALS between January 2019 and August 2023 were identified. Data were extracted from the medical records. All patients were contacted and asked standardized questions regarding symptoms of ALS. A symptom score was calculated and compared before surgery and at the last follow-up.

RESULTS: Ten patients, who had undergone ileopexy for ALS, were identified. Eight of these (80%) had been admitted with small bowel obstruction due to ALS. The remaining 2 patients had other symptoms indicative of ALS. In all patients, ileopexy was immediately effective in reducing symptoms. Symptoms recurred after 16.5 weeks (2-80) in 8 patients. Repeat laparoscopy showed that the ileopexy had slipped in 6 of these. Six had a new ileopexy with mesh. Later, one of these developed recurrent symptoms and had a new mesh ileopexy performed. No mesh complications were seen. Symptom score was reduced from 6.5 (1-9) to 2 (0-7) (p = 0.02) at the last follow-up.

CONCLUSIONS: In this study, ileopexy is effective in reducing symptoms of ALS after RP. In a high proportion of patients, it is necessary to use mesh to ensure long-term fixation of the ileum.}, } @article {pmid39521135, year = {2025}, author = {Sajid, SL and Ur Rehman, MA and Sajid, SA and Shahid, N}, title = {Response to Valerio Nardone et al's "Previous radiotherapy increases the efficacy of cemiplimab in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma: A retrospective analysis".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e53-e54}, doi = {10.1016/j.jaad.2024.08.084}, pmid = {39521135}, issn = {1097-6787}, } @article {pmid39521994, year = {2024}, author = {Liang, H and Zhou, X and Zhang, J and Xu, W and Liu, Y and Wang, X and Hu, Y and Xu, R and Li, X}, title = {The therapeutic potential of Apigenin in amyotrophic lateral sclerosis through ALDH1A2/Nrf2/ARE signaling.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {206}, pmid = {39521994}, issn = {1528-3658}, support = {81960244//National Natural Science Foundation of China/ ; 20212BAB216026//Jiangxi Natural Science Foundation/ ; 202110016//Science and Technology Plan of Jiangxi Provincial Health Commission/ ; 2022B975//Science and Technology Plan of Jiangxi Provincial Administration of Traditional Chinese Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; Animals ; *Apigenin/pharmacology/therapeutic use ; Mice ; *Signal Transduction/drug effects ; *Mice, Transgenic ; *Disease Models, Animal ; *NF-E2-Related Factor 2/metabolism/genetics ; Oxidative Stress/drug effects ; Aldehyde Dehydrogenase 1 Family/metabolism/genetics ; Humans ; Apoptosis/drug effects ; Retinal Dehydrogenase/metabolism/genetics ; Cell Line ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss leading to muscle weakness and atrophy. Apigenin (APG), known for its antioxidant properties, holds potential as a therapeutic compound in ALS.

METHODS: We used the Tg(SOD1*G93A)1Gur/J transgenic mouse model of ALS to investigate the therapeutic effects of APG. Key measured included motor function via the ALSTDI score, molecular markers of oxidative stress (OS) and apoptosis in spinal cord tissues. Techniques used included pathological, Western blotting, flow cytometry, and qRT-PCR to assess the effect of ALDH1A2.

RESULTS: APG treatment attenuated weight loss and improved motor function scores in ALS mice compared to untreated ALS models. Molecular analyses revealed a significant upregulation of ALDH1A2 in APG-treated groups, along with a reduction in markers of OS and apoptosis. In vitro studies in NSC34 cells further confirmed the protective effects of APG against SOD1*G93A mutation-induced cytotoxicity. In addition, suppression of ALDH1A2 by shRNA exacerbated disease markers that were ameliorated by APG treatment.

CONCLUSIONS: Our results suggest that APG attenuates the progression of ALS pathology by regulating OS and apoptosis through ALDH1A2. These results support further investigation of APG as a potential therapeutic agent for the treatment of ALS.}, } @article {pmid39522672, year = {2025}, author = {Shapiro, O and Woods, C and Gleixner, AM and Sannino, S and Ngo, M and McDaniels, MD and Wipf, P and Hukriede, NA and Donnelly, CJ and Brodsky, JL}, title = {Assays to measure small molecule Hsp70 agonist activity in vitro and in vivo.}, journal = {Analytical biochemistry}, volume = {697}, number = {}, pages = {115712}, pmid = {39522672}, issn = {1096-0309}, support = {U54 DK137329/DK/NIDDK NIH HHS/United States ; R01 DK112652/DK/NIDDK NIH HHS/United States ; P30 DK079307/DK/NIDDK NIH HHS/United States ; R01 DK069403/DK/NIDDK NIH HHS/United States ; R35 GM131732/GM/NIGMS NIH HHS/United States ; R21 NS133676/NS/NINDS NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; R01 NS105756/NS/NINDS NIH HHS/United States ; R01 HD053287/HD/NICHD NIH HHS/United States ; }, mesh = {*HSP70 Heat-Shock Proteins/metabolism/agonists ; Animals ; *Zebrafish ; Humans ; Small Molecule Libraries/pharmacology/chemistry ; Optogenetics/methods ; DNA-Binding Proteins/agonists/metabolism ; }, abstract = {Hsp70 prevents protein aggregation and is cytoprotective, but sustained Hsp70 overexpression is problematic. Therefore, we characterized small molecule agonists that augment Hsp70 activity. Because cumbersome assays were required to assay agonists, we developed cell-based and in vivo assays in which disease-associated consequences of Hsp70 activation can be quantified. One assay uses an optogenetic system in which the formation of TDP-43 inclusions can be controlled, and the second assay employs a zebrafish model for acute kidney injury (AKI). These complementary assays will facilitate future work to identify new Hsp70 agonists as well as optimized agonist derivatives.}, } @article {pmid39522697, year = {2024}, author = {Gao, L and Yang, XN and Dong, YX and Han, YJ and Zhang, XY and Zhou, XL and Liu, Y and Liu, F and Fang, JS and Ji, JL and Gao, ZR and Qin, XM}, title = {The potential therapeutic strategy in combating neurodegenerative diseases: Focusing on natural products.}, journal = {Pharmacology & therapeutics}, volume = {264}, number = {}, pages = {108751}, doi = {10.1016/j.pharmthera.2024.108751}, pmid = {39522697}, issn = {1879-016X}, mesh = {Humans ; *Biological Products/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and Multiple sclerosis (MS), pose a significant global health challenge due to their intricate pathology and limited therapeutic interventions. Natural products represent invaluable reservoirs for combating these neurodegenerative diseases by targeting key pathological hallmarks such as protein aggregation, synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, inflammation, and neuronal cell death. This review provides an in-depth analysis of the mechanisms and therapeutic targets of natural products for their neuroprotective effects. Furthermore, it elucidates the current progress of clinical trials investigating the potential of natural products in delaying neurodegeneration. The objective of this review is to enhance the comprehension of natural products in the prevention and treatment of neurodegenerative diseases, offering new insights and potential avenues for future pharmaceutical research.}, } @article {pmid39522723, year = {2025}, author = {Nardone, V and Esposito, A and D'Ippolito, E and Argenziano, G and Reginelli, A and Troiani, T}, title = {Response to Sajid et al's "Response to Valerio Nardone et al's 'Previous radiotherapy increases the efficacy of cemiplimab in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma: A retrospective analysis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e55-e56}, doi = {10.1016/j.jaad.2024.10.058}, pmid = {39522723}, issn = {1097-6787}, } @article {pmid39522725, year = {2025}, author = {Tsai, SY}, title = {Response to Narayanan et al's "Adverse events in cemiplimab therapy for locally advanced or metastatic cSCC: A global propensity-matched retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e57}, doi = {10.1016/j.jaad.2024.08.085}, pmid = {39522725}, issn = {1097-6787}, } @article {pmid39522728, year = {2025}, author = {Lauck, KC and Narayanan, D and Tolkachjov, SN}, title = {Regarding response to Narayanan et al's "Adverse events in cemiplimab therapy for locally advanced or metastatic cSCC: A global propensity-matched retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e59-e60}, doi = {10.1016/j.jaad.2024.10.059}, pmid = {39522728}, issn = {1097-6787}, } @article {pmid39523613, year = {2024}, author = {Fukutake, T}, title = {[Diagnosis, Notification, and Managements of ALS: A Personal Perspective from 40 years of Experience as a Clinical Neurologist].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1205-1216}, doi = {10.11477/mf.1416202762}, pmid = {39523613}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Humans ; *Neurologists ; Female ; Middle Aged ; Male ; Aged ; }, abstract = {This narrative summary presents the author's 40-year experience as a clinical neurologist who treated patients with amyotrophic lateral sclerosis (ALS). Five representative cases from the author's first 20 years at Chiba University Hospital and its affiliated hospitals were selected, including a patient of respiratory-onset who was ignorantly extubated by a female relative for patient's distress to the intratracheal tube. Based on the latter 20 years of experience at the author's current hospital, the author first describes a famous patient with ALS who was being treated at this medical center before the author was assigned to this hospital and fought against ALS for 31 years before eventually succumbing to total locked-in syndrome. Thereafter, the author has summarized the ages, sex, phenotypes, comorbidities, responses to the available treatment options, and total number of years that have elapsed for the 24 patients that the author initially examined in the outpatient clinic. In terms of diagnostic delay, the author describes "foot drop" in patients who developed lower limb symptoms, and hoarseness in those who developed bulbar palsy. Furthermore, the author discusses issues regarding family caregiving capacity, patient's and families' understanding of notification, and medical management (i.e., medications, rehabilitation for ADL, nutrition and respiration, complications of frontotemporal dementia, and medical cooperation with other clinics and hospitals).}, } @article {pmid39523614, year = {2024}, author = {Yamakawa, I and Urushitani, M}, title = {[Gold Coast Criteria: A New Diagnostic Paradigm in the Era of Disease-Modifying Therapy for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1217-1223}, doi = {10.11477/mf.1416202763}, pmid = {39523614}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Humans ; }, abstract = {Significant progress has been made in the development of disease-modifying drugs for amyotrophic lateral sclerosis (ALS), with the introduction of tofersen, an antisense oligonucleotide drug for familial ALS, marking a turning point in the treatment. These drugs are most effective when administered early in the disease course, highlighting the need for improved diagnostic sensitivity. The 2020 Gold Coast Diagnostic Criteria allow ALS diagnosis in cases without upper motor neuron symptoms, potentially increasing early detection rates. However, careful differential diagnoses are necessary when applying these criteria to maintain diagnostic specificity. This review outlines the key points to consider when using the Gold Coast Criteria, balancing the need for an early diagnosis with caution to avoid overdiagnosis.}, } @article {pmid39523615, year = {2024}, author = {Ogino, M}, title = {[Palliative Care for Persons with Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1225-1232}, doi = {10.11477/mf.1416202764}, pmid = {39523615}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Analgesics, Opioid/administration & dosage ; Japan ; *Palliative Care ; }, abstract = {Palliative care in Japan is available mainly for patients with cancer, and palliative care specialists do not have sufficient experience with management of palliation in persons with amyotrophic lateral sclerosis (ALS). Treatment of ALS symptoms is an important component of palliative care, and it is important that neurologists and home care physicians familiarize themselves with palliative care for ALS in consultation with palliative care specialists. Notably, the use of opioids at the end of life differs from that of pain relief for cancer. Physicians should be mindful that opioids are not a perfect solution for palliative care of persons with ALS.}, } @article {pmid39523616, year = {2024}, author = {Ishiguro, T and Nagata, T and Yokota, T}, title = {[Current Landscape of Tofersen in SOD-1-associated Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1233-1239}, doi = {10.11477/mf.1416202765}, pmid = {39523616}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; Humans ; *Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Since the identification, in 1993, of the causative gene for familial amyotrophic lateral sclerosis (ALS), which is associated with SOD1 mutations, research has focused on the pathogenesis and therapeutics of ALS for more than 30 years. Tofersen, a highly anticipated gene-specific therapy that has been aligned with the disease-specific pathology, has been approved for marketing by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) However, as significant data on tofersen's safety and efficacy are required, the evaluation of this treatment is ongoing. This paper introduces the current clinical and commercial status of Tofersen, along with expectations for its approval in Japan.}, } @article {pmid39523617, year = {2024}, author = {Iguchi, Y and Katsuno, M}, title = {[Current Status of Drug Development for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1241-1249}, doi = {10.11477/mf.1416202766}, pmid = {39523617}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Drug Development ; Clinical Trials as Topic ; Animals ; Riluzole/therapeutic use ; Neuroprotective Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease of motor neuron. Although riluzole and edaravone have been approved for the treatment of ALS, it remains a lethal disease that causes rapid motor impairment, and there is an urgent need to develop more effective treatments. Advances in understanding the pathomechanisms of ALS, efficient clinical trial design, and research support programs have led to many clinical trials for ALS both domestically and internationally.}, } @article {pmid39524179, year = {2024}, author = {Trinh, QD and Mai, HN and Pham, DT}, title = {Application of mesenchymal stem cells for neurodegenerative diseases therapy discovery.}, journal = {Regenerative therapy}, volume = {26}, number = {}, pages = {981-989}, pmid = {39524179}, issn = {2352-3204}, abstract = {Neurodegenerative diseases are central or peripheral nervous system disorders associated with progressive brain cell degeneration. Common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis have been widely studied. However, current therapeutics only reduce the symptoms and do not ameliorate the pathogenesis of these diseases. Recent studies suggested the roles of neuroinflammation, apoptosis, and oxidative stress in neurodegenerative diseases. Mesenchymal stem cells (MSCs) exert anti-apoptotic, anti-inflammatory, and antioxidative effects. Therefore, investigating the effects of MSCs and their applications may lead to the discovery of more effective therapies for neurodegenerative diseases. In this study, we review different approaches used to identify therapies for neurodegenerative diseases using MSCs.}, } @article {pmid39525702, year = {2024}, author = {Ravichandran, VV and Coleman, E and Brown, A and Boh, E}, title = {Response to Rodríguez-Cuadrado et al's "Clinical, histopathologic, immunohistochemical, and electron microscopic findings in cutaneous monkeypox: A multicenter retrospective case series in Spain".}, journal = {JAAD case reports}, volume = {53}, number = {}, pages = {149-150}, pmid = {39525702}, issn = {2352-5126}, } @article {pmid39526716, year = {2024}, author = {Šljivo, A and Jevtić, T and Siručić, I and Terzić-Salihbašić, S and Abdulkhaliq, A and Reiter, L and Salihbašić, F and Bečar-Alijević, A and Alijević, A and Dadić, I and Gavrankapetanović, F}, title = {Out-of-hospital cardiac arrest (OHCA) in Bosnia and Herzegovina in the period 2018-2022: current trends, usage of automated external defibrillators (AED) and bystanders' involvement.}, journal = {Medicinski glasnik : official publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina}, volume = {21}, number = {2}, pages = {267-273}, doi = {10.17392/1719-21-2}, pmid = {39526716}, issn = {1840-2445}, abstract = {AIM: To investigate out-of-hospital cardiac arrest (OHCA) trend, provided advanced life support (ALS) measures, automated external defibrillator (AEDs) utilization and bystanders' involvement in cardiopulmonary resuscitation (CPR) during OHCA incidents.

METHODS: This cross-sectional study encompassed data pertaining to all OHCA incidents attended to by the Emergency Medical Service of Canton Sarajevo, Bosnia and Herzegovina, covering the period from January 2018 to December 2022.

RESULTS: Among a total of 1131 OHCA events, 236 (20.8 %) patients achieved return of spontaneous circulation (ROSC); there were 175 (74.1%) males and 61 (25.9%) females. The OHCA incidence was 54/100,000 inhabitants per year. After a 30-day period post-ROSC, 146 (61.9%) patients fully recovered, while 90 (38.1%) did not survive during this timeframe. Younger age (p<0.05), initial rhythm of ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) (p<0.05), and faster emergency medical team (EMT) response time (p<0.05) were significantly associated with obtaining ROSC. Only 38 (3.3%) OHCA events were assisted by bystanders, who were mostly medical professionals, 25 (65.7%), followed by close family members, 13 (34.3%). There was no report of AED usage.

CONCLUSION: This follow-up study showed less ROSC achievement, similar bystanders' involvement, similar factors associated with achieving ROSC (age, EMT response time), and a decline in OHCA events (especially in year 2021 and 2022) compared to our previous study (2015-2019). There was an extremely low rate of bystander engagement and no AEDs usage. Governments and health organizations must swiftly improve public awareness, promote better practice (basic life support), and actively encourage bystander participation.}, } @article {pmid39528814, year = {2024}, author = {Ovchinnikova, LA and Dzhelad, SS and Simaniv, TO and Zakharova, MN and Lomakin, YA and Gabibov, AG and Illarioshkin, SN}, title = {Development of a Panel of Biomarkers for Differential Diagnosis of Multiple Sclerosis.}, journal = {Doklady. Biochemistry and biophysics}, volume = {519}, number = {1}, pages = {593-596}, pmid = {39528814}, issn = {1608-3091}, mesh = {Humans ; Biomarkers/metabolism/blood ; Diagnosis, Differential ; *Multiple Sclerosis/diagnosis/metabolism/blood ; Amyotrophic Lateral Sclerosis/diagnosis ; Male ; Female ; Middle Aged ; Neuromyelitis Optica/diagnosis/blood ; Adult ; }, abstract = {Demyelinating diseases are a group of heterogeneous pathologies that affect the nervous system and reduce the quality of life. One of such diseases is multiple sclerosis (MS), an inflammatory autoimmune neurodegenerative disease of the central nervous system (CNS). At the initial stages, MS can mimic some infectious, neoplastic, genetic, metabolic, vascular, and other pathologies. Accurate differential diagnosis of this disease is important to improve the quality of life of patients and reduce possible irreversible damage to the central nervous system. In this work, we confirmed the possibility of using our previously proposed candidate panel of MS biomarkers to distinguish MS from neuromyelitis optica spectrum disorder (NMOSD) and amyotrophic lateral sclerosis (ALS). We have shown that our proposed panel (SPTAN1601-644 + PRX451-494 + PTK6301-344 + LMP1285-330) allows us to distinguish MS from ALS (AUC = 0.796) and NMOSD (AUC = 0.779).}, } @article {pmid39529471, year = {2025}, author = {Trojsi, F and Canna, A and Sharbafshaaer, M and di Nardo, F and Canale, F and Passaniti, C and Pirozzi, MA and Silvestro, M and Orologio, I and Russo, A and Cirillo, M and Tessitore, A and Siciliano, M and Esposito, F}, title = {Brain neurovascular coupling in amyotrophic lateral sclerosis: Correlations with disease progression and cognitive impairment.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16540}, pmid = {39529471}, issn = {1468-1331}, support = {NRRP project MNESYS (PE0000006, to NT)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; *Disease Progression ; Middle Aged ; *Cognitive Dysfunction/physiopathology/etiology/diagnostic imaging ; Aged ; *Magnetic Resonance Imaging ; *Neurovascular Coupling/physiology ; Adult ; *Brain/physiopathology/diagnostic imaging/blood supply ; Nerve Net/diagnostic imaging/physiopathology ; Default Mode Network/physiopathology/diagnostic imaging ; }, abstract = {BACKGROUND AND PURPOSE: 'Neurovascular coupling' (NVC) alterations, assessing the interplay between local cerebral perfusion and neural activity within a given brain region or network, may reflect neurovascular unit impairment in amyotrophic lateral sclerosis (ALS). The aim was to explore NVC as a correlation between the functional connectivity and cerebral blood flow within the large-scale resting-state functional magnetic resonance imaging brain networks in a sample of ALS patients compared to healthy controls (HCs).

METHODS: Forty-eight ALS patients (30 males; mean age 60.64 ± 9.62 years) and 32 HC subjects (14 males; mean age 55.06 ± 16 years) were enrolled and underwent 3 T magnetic resonance imaging. ALS patients were screened by clinical and neuropsychological scales and were retrospectively classified as very fast progressors (VFPs), fast progressors and slow progressors (SPs).

RESULTS: Neurovascular coupling reduction within the default mode network (DMN) (p = 0.005) was revealed in ALS patients compared to HCs, observing, for this network, significant NVC differences between VFP and SP groups. Receiver operating characteristic curve analysis showed that impaired NVC in the DMN at baseline best discriminated VFPs and SPs (area under the curve 75%). Significant correlations were found between NVC and the executive (r = 0.40, p = 0.01), memory (r = 0.32, p = 0.04), visuospatial ability (r = 0.40, p = 0.01) and non-ALS-specific (r = 0.40, p = 0.01) subscores of the Edinburgh Cognitive and Behavioural ALS Screen.

CONCLUSIONS: The reduction of brain NVC in the DMN may reflect largely distributed abnormalities of the neurovascular unit. NVC alterations in the DMN could play a role in anticipating a faster clinical progression in ALS patients, aiding patient selection and monitoring during clinical trials.}, } @article {pmid39531940, year = {2024}, author = {Pioro, EP and Brooks, BR and Liu, Y and Zhang, J and Apple, S}, title = {Efficacy of Radicava® IV (intravenous edaravone) in subjects with differing trajectories of disease progression in amyotrophic lateral sclerosis: Use of a novel statistical approach for post hoc analysis of a pivotal phase 3 clinical trial.}, journal = {Journal of the neurological sciences}, volume = {467}, number = {}, pages = {123290}, doi = {10.1016/j.jns.2024.123290}, pmid = {39531940}, issn = {1878-5883}, mesh = {Humans ; *Edaravone/therapeutic use/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Disease Progression ; Male ; Female ; Middle Aged ; Aged ; Treatment Outcome ; Double-Blind Method ; Free Radical Scavengers/therapeutic use/administration & dosage ; Administration, Intravenous ; }, abstract = {INTRODUCTION: Subjects with amyotrophic lateral sclerosis (ALS) treated with Radicava® (edaravone) IV (intravenous; Mitsubishi Tanabe Pharma America [MTPA], hereafter "MTPA IV edaravone") in Study MCI186-19 had a significantly slower physical functional decline vs placebo-treated subjects as measured by the revised ALS Functional Rating Scale (ALSFRS-R) and analyzed by the linear mixed model for repeated measures (MMRM). This Study 19 post hoc analysis of MTPA IV edaravone-treated and placebo-treated subjects evaluated linear and nonlinear latent class mixed models defining trajectories based on identifying the model with the lowest Bayesian information criterion. The best model differentiated 4 nonlinear trajectories in ALS subjects. ALSFRS-R total score in MTPA IV edaravone-treated and placebo-treated subjects was evaluated for these 4 nonlinear latent class trajectory groups.

METHODS: Disease trajectories of MCI186-19 MTPA IV edaravone-treated or placebo-treated ALS subjects who completed the double-blind period were investigated using latent class analysis (LCA) statistical models to identify potential unique nonlinear ALSFRS-R disease trajectories.

RESULTS: ALSFRS-R trajectories revealed 4 unique nonlinear trajectory latent classes per treatment group in MTPA IV edaravone-treated and placebo-treated ALS subjects completing the MCI186-19 double-blind period. Latent classes 2-4 had statistically significant slowing of ALSFRS-R total score decline in the predicted nonlinear trajectories of MTPA IV edaravone-treated vs placebo-treated ALS subjects.

CONCLUSIONS: This post hoc analysis suggests MTPA IV edaravone treatment results in slower ALSFRS-R decline vs placebo in most predicted nonlinear trajectories. LCA is a novel approach that may benefit future trial analyses.}, } @article {pmid39531950, year = {2025}, author = {Kacem, I and Sghaier, I and Ben Rhouma, H and Ratti, A and Ticozzi, N and Silani, V and Gouider-Khouja, N and Gouider, R}, title = {Association of Amyotrophic Lateral Sclerosis and Dopa-responsive dystonia in a Tunisian patient.}, journal = {Parkinsonism & related disorders}, volume = {130}, number = {}, pages = {107171}, doi = {10.1016/j.parkreldis.2024.107171}, pmid = {39531950}, issn = {1873-5126}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications ; *Dystonic Disorders/genetics/drug therapy ; GTP Cyclohydrolase/genetics ; Tunisia ; }, abstract = {Dopa-responsive dystonia (DRD) is an autosomal dominant disease with parkinsonian and dystonic symptoms caused by GCH1 gene pathogenic variants affecting dopamine synthesis. The present case report is the first to link DRD with childhood-onset with ALS, suggesting that complex inheritance patterns in the North African population may contribute to multiple disorders.}, } @article {pmid39534022, year = {2024}, author = {Li, Y and Bhinge, A and Inoue, S and Garcia, G}, title = {Editorial: Noncoding RNAs in neurodegenerative disorders: from current insights and future directions to translational modeling and therapeutic approaches.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1497673}, pmid = {39534022}, issn = {1662-4548}, } @article {pmid39534418, year = {2024}, author = {Wang, WL and Tam, PKH and Chen, Y}, title = {Abnormally activated wingless/integrated signaling modulates tumor-associated macrophage polarization and potentially promotes hepatocarcinoma cell growth.}, journal = {World journal of gastroenterology}, volume = {30}, number = {41}, pages = {4490-4495}, pmid = {39534418}, issn = {2219-2840}, mesh = {Humans ; *Carcinoma, Hepatocellular/pathology/metabolism ; *Liver Neoplasms/pathology/metabolism ; *Tumor-Associated Macrophages/metabolism/immunology ; *Cell Proliferation ; *Wnt Signaling Pathway ; *Tumor Microenvironment ; Cell Movement ; Animals ; Disease Progression ; Macrophage Activation ; }, abstract = {In this article, we comment on the article by Huang et al. The urgent development of new therapeutic strategies targeting macrophage polarization is critical in the fight against liver cancer. Tumor-associated macrophages (TAMs), primarily of the M2 subtype, are instrumental in cellular communication within the tumor microenvironment and are influenced by various signaling pathways, including the wingless/integrated (Wnt) pathway. Activation of the Wnt signaling pathway is pivotal in promoting M2 TAMs polarization, which in turn can exacerbate hepatocarcinoma cell proliferation and migration. This manuscript emphasizes the burgeoning significance of the Wnt signaling pathway and M2 TAMs polarization in the pathogenesis and progression of liver cancer, highlighting the potential therapeutic benefits of inhibiting the Wnt pathway. Lastly, we point out areas in Huang et al's study that require further research, providing guidance and new directions for similar studies.}, } @article {pmid39534483, year = {2024}, author = {Sbarigia, C and Rome, S and Dini, L and Tacconi, S}, title = {New perspectives of the role of skeletal muscle derived extracellular vesicles in the pathogenesis of amyotrophic lateral sclerosis: the 'dying back' hypothesis.}, journal = {Journal of extracellular biology}, volume = {3}, number = {11}, pages = {e70019}, pmid = {39534483}, issn = {2768-2811}, abstract = {Amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord, and is characterized by muscle weakness, paralysis and ultimately, respiratory failure. The exact causes of ALS are not understood, though it is believed to combine genetic and environmental factors. Until now, it was admitted that motor neurons (MN) in the brain and spinal cord degenerate, leading to muscle weakness and paralysis. However, as ALS symptoms typically begin with muscle weakness or stiffness, a new hypothesis has recently emerged to explain the development of the pathology, that is, the 'dying back hypothesis', suggesting that this degeneration starts at the connections between MN and muscles, resulting in the loss of muscle function. Over time, this damage extends along the length of the MN, ultimately affecting their cell bodies in the spinal cord and brain. While the dying back hypothesis provides a potential framework for understanding the progression of ALS, the exact mechanisms underlying the disease remain complex and not fully understood. In this review, we are positioning the role of extracellular vesicles as new actors in ALS development.}, } @article {pmid39534515, year = {2024}, author = {Watanabe, S and Sekiguchi, K and Suehiro, H and Yoshikawa, M and Noda, Y and Kamiyama, N and Matsumoto, R}, title = {Decreased diaphragm moving distance measured by ultrasound speckle tracking reflects poor prognosis in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {252-260}, pmid = {39534515}, issn = {2467-981X}, abstract = {OBJECTIVE: Decreased cephalocaudal diaphragm movement may indicate respiratory dysfunction in amyotrophic lateral sclerosis (ALS). We aimed to evaluate diaphragm function in ALS using ultrasound speckle tracking, an image-analysis technology that follows similar pixel patterns.

METHODS: We developed an offline application that tracks pixel patterns of recorded ultrasound video images using speckle-tracking methods. Ultrasonography of the diaphragm movement during spontaneous quiet respiration was performed on 19 ALS patients and 21 controls to measure the diaphragm moving distance (DMD) in the cephalocaudal direction during a single respiration. We compared respiratory function measures and analyzed the relationship between the clinical profiles and DMD.

RESULTS: DMD was significantly lower in ALS patients than in the control group (0.6 ± 1.4 mm vs 2.2 ± 2.2 mm, p < 0.01) and positively correlated with phrenic nerve compound motor action potential amplitude (R = 0.63, p = 0.01). DMD was negatively correlated with the change in the ALS Functional Rating Scale-Revised scores per month after the exam (R = -0.61, p = 0.02), and those with a larger rate of decline had a significantly lower DMD (p = 0.03).

CONCLUSIONS: Diaphragm ultrasound speckle tracking enabled the detection of diaphragm dysfunction in ALS.

SIGNIFICANCE: Diaphragm ultrasound speckle tracking may be useful for predicting prognosis.}, } @article {pmid39535924, year = {2024}, author = {Hannestad, J and Smith, S and Lam, A and Hurt, J and Harada, N and Kim, R and Das, A and Brunello, J and Whitaker, G and Chalmers, D and Senjoti, F and Lin, W and Coghill, J and Bansal, Y and Sidhu, S and Zann, V and Liu, E}, title = {A randomized, placebo-controlled first-in-human study of oral TQS-168 in healthy volunteers: Assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect.}, journal = {Clinical and translational science}, volume = {17}, number = {11}, pages = {e70064}, pmid = {39535924}, issn = {1752-8062}, mesh = {Humans ; Male ; *Food-Drug Interactions ; Adult ; Administration, Oral ; *Healthy Volunteers ; Young Adult ; Middle Aged ; Area Under Curve ; Double-Blind Method ; Dose-Response Relationship, Drug ; Methylcellulose/administration & dosage/analogs & derivatives/chemistry ; Spray Drying ; Suspensions ; Cross-Over Studies ; Placebos/administration & dosage ; }, abstract = {TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. Cmax and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median Tmax for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (T1/2) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 Cmax but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies.}, } @article {pmid39535960, year = {2025}, author = {Soares, RV and Pedrosa, RBDS and Sandars, J and Cecilio-Fernandes, D}, title = {The importance of combined use of spacing and testing effects for complex skills training: A quasi-experimental study.}, journal = {Medical teacher}, volume = {47}, number = {8}, pages = {1296-1303}, doi = {10.1080/0142159X.2024.2427735}, pmid = {39535960}, issn = {1466-187X}, support = {GRANT NUMBER 2018/15642-1//FAPESP – São Paulo Research Foundation/ ; }, mesh = {Humans ; *Clinical Competence ; Female ; Male ; *Educational Measurement/methods ; Students, Nursing/psychology ; Retention, Psychology ; *Simulation Training/methods ; Adult ; Young Adult ; }, abstract = {INTRODUCTION: A major challenge is retention of complex clinical skills. Spacing training and testing have been demonstrated to increase knowledge and skill retention but the combination has not been previously investigated in complex clinical skills. The aim of our study was to compare the effectiveness of combined spacing and testing for Basic Life Support (BLS) and Advance Life Support (ALS) simulation training in one group (intervention group), with combined spacing and testing, and another group (control) that received simulation training in a single-session simulation training without testing.

METHODS: A quasi-experimental study.

RESULTS: Thirteen nursing students were in the intervention group and 18 in the control group. After three months, there was no significant reduction in retention of BLS knowledge (p > 0.05) or BLS skills (p < 0.05) in the intervention group, but there was a significant reduction in both (p < 0.05) in the control group. We found no significant reduction in retention of ALS knowledge in the control group (p > 0.05), but there was a significant reduction in the intervention group (p < 0.05). There was no significant decay of ALS skills in both groups (p < 0.05).

DISCUSSION: This is the first study to demonstrate that combined spacing and testing could be highly effective for complex skills simulation training to increase retention after three months.}, } @article {pmid39536438, year = {2024}, author = {Henderson, NL and Ortiz-Olguin, E and Bourne, G and Pywell, C and Rose, JB and Williams, GR and Nipp, RD and Rocque, GB}, title = {Implementation of ePROs Into Multidisciplinary Tumor Board Discussions for Patients With Pancreatic Cancer: The INSPIRE Intervention.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {9}, pages = {602-609}, doi = {10.6004/jnccn.2024.7052}, pmid = {39536438}, issn = {1540-1413}, support = {T32 CA047888/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Pancreatic Neoplasms/therapy ; Female ; Male ; *Patient Reported Outcome Measures ; Aged ; Middle Aged ; Patient Care Team/standards ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: The incorporation of electronic patient-reported outcomes (ePROs), such as the Geriatric Assessment (GA) and treatment preferences, into decision-making for pancreatic cancer has been limited by clinician- and system-level barriers concerning workflow. We hypothesized that ePRO inclusion within multidisciplinary tumor boards (MDTBs) would circumvent barriers and provide a venue for systematic consideration of critical patient-provided information.

PATIENTS AND METHODS: The INtegrating Systematic PatIent-Reported Evaluations (INSPIRE) intervention consists of (1) patient survey completion, including GA and patient preferences, and (2) screensharing patient ePROs during MDTBs. Proctor et al's implementation outcomes were assessed, with penetration (the proportion of consented patients who were presented at MDTBs) acting as the primary outcome (considered successful at 70%). Secondary outcomes included adoption, feasibility, acceptability, appropriateness, cost, and sustainability, assessed by clinician post-MDTB exit surveys, clinician postintervention surveys, clinician postintervention semistructured interviews, and time-coding analysis of recorded and transcribed historical (November 2021-February 2022) and intervention (September 2022-June 2023) MDTBs.

RESULTS: A total of 50 patients completed surveys and all were presented at MDTBs (penetration=100%). All eligible clinicians (n=9) enrolled patients (adoption=100%) and reported that ePROs were useful in 90% and led to a change in treatment plan in 30% of cases. In postintervention surveys and interviews, clinicians primarily responded positively to feasibility, acceptability, and appropriateness questions. Time-coding analysis found a modest time cost of an additional 51.1 seconds in mean discussion time-per-patient between preintervention (mean [SD], 172.7 [111.4] seconds) and intervention patients (mean [SD], 223.8 [107.1] seconds); 86% of clinicians reported the intervention did not take too much time. All surveyed clinicians reported interest in continuing the intervention and suggested adaptations to further promote sustainability.

CONCLUSIONS: The integration of ePROs into pancreatic MDTBs was feasible and acceptable, providing a potential approach to increase the utilization of ePROs by clinical teams in their management of patients with pancreatic cancer.}, } @article {pmid39536963, year = {2025}, author = {Casiraghi, V and Sorce, MN and Santangelo, S and Invernizzi, S and Bossolasco, P and Lattuada, C and Battaglia, C and Venturin, M and Silani, V and Colombrita, C and Ratti, A}, title = {Modeling of TDP-43 proteinopathy by chronic oxidative stress identifies rapamycin as beneficial in ALS patient-derived 2D and 3D iPSC models.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {115057}, doi = {10.1016/j.expneurol.2024.115057}, pmid = {39536963}, issn = {1090-2430}, mesh = {Humans ; *Induced Pluripotent Stem Cells/drug effects ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; *Oxidative Stress/drug effects/physiology ; *Sirolimus/pharmacology ; *TDP-43 Proteinopathies/pathology/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Arsenites/toxicity/pharmacology ; Sodium Compounds/toxicity/pharmacology ; Motor Neurons/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized neuropathologically by TDP-43 proteinopathy with loss of TDP-43 nuclear splicing activity and formation of cytoplasmic TDP-43 aggregates. The lack of suitable experimental models of TDP-43 proteinopathy has hampered the discovery of effective therapies. We already showed that chronic and mild oxidative insult by sodium arsenite (ARS) triggered TDP-43 cytoplasmic aggregation and stress granules (SGs) formation in ALS patient-derived fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs). However, whether this insult induces a reduction of TDP-43 splicing activity in the nucleus, thus recapitulating both gain and loss of function pathomechanisms, still remains to be determined. In this study we first showed that chronic ARS in human neuroblastoma cells triggered TDP-43 cytoplasmic mislocalization, SGs formation and defective splicing of TDP-43 target genes UNC13A and POLDIP3 as functional readouts of TDP-43 proteinopathy. Additionally, a dysregulation of autophagy and senescence markers was observed in this condition. In a preliminary drug screening approach with autophagy-promoting drugs, namely rapamycin, lithium carbonate and metformin, only rapamycin prevented ARS-induced loss of TDP-43 splicing activity. We then demonstrated that, in addition to TDP-43 cytoplasmic aggregation, chronic ARS triggered TDP-43 loss of splicing activity also in ALS patient-derived primary fibroblasts and iPSC-MNs and that rapamycin was beneficial to reduce these TDP-43 pathological features. By switching to a neuro-glial 3D in vitro model, we observed that treatment of ALS iPSC-brain organoids with chronic ARS also induced a defective TDP-43 splicing activity which was prevented by rapamycin. Collectively, we established different human cell models of TDP-43 proteinopathy which recapitulate TDP-43 gain and loss of function, prevented by rapamycin administration. Human neuroblastoma cells and patient-derived fibroblasts and 2D- and 3D-iPSC models exposed to chronic oxidative stress represent therefore suitable in vitro platforms for future drug screening approaches in ALS.}, } @article {pmid39537536, year = {2025}, author = {Zou, J and Meng, X and Hong, Z and Rao, Y and Wang, K and Li, J and Yu, H and Wang, C}, title = {Cas9-PE: a robust multiplex gene editing tool for simultaneous precise editing and site-specific random mutation in rice.}, journal = {Trends in biotechnology}, volume = {43}, number = {2}, pages = {433-446}, doi = {10.1016/j.tibtech.2024.10.012}, pmid = {39537536}, issn = {1879-3096}, mesh = {*CRISPR-Associated Protein 9/genetics/metabolism ; *Gene Editing/instrumentation/methods ; *Oryza/genetics ; Mutation ; *Mutagenesis, Site-Directed ; Acetolactate Synthase/genetics ; Herbicide Resistance/genetics ; }, abstract = {In molecular design breeding, the simultaneous introduction of desired functional genes through specific nucleotide modifications and the elimination of genes regulating undesired phenotypic traits or agronomic components require advanced gene editing tools. Due to limited editing efficiency, even with the use of highly precise editing tools, such as prime editing (PE), simultaneous editing of multiple mutation types poses a challenge. Here, we replaced Cas9 nickase (nCas9) with Cas9 to construct a Cas9-mediated PE (Cas9-PE) system in rice. This system not only enables precise editing, but also allows for site-specific random mutation. Moreover, leveraging the precision of Cas9-PE, we established a transgene-free multiplex gene editing system using a co-editing strategy. This strategy involved the Agrobacterium-mediated transient expression of the precise editing rice endogenous acetolactate synthase gene ALS[S627I] to confer herbicide bispyribac-sodium (BS) resistance as a selection marker. This study provides a versatile and efficient multiplex gene editing tool for molecular design breeding.}, } @article {pmid39538124, year = {2024}, author = {Sun, Y and Hu, S and Lan, Y and Wang, R and Wei, S and Huang, H and Cui, H and Li, X and Huang, Z}, title = {Investigation of resistance mechanisms to flucarbazone-sodium in wild oat (Avena fatua L.) from China.}, journal = {BMC plant biology}, volume = {24}, number = {1}, pages = {1073}, pmid = {39538124}, issn = {1471-2229}, mesh = {*Avena/genetics/drug effects ; China ; Herbicide Resistance/genetics ; Herbicides/pharmacology ; Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Plant Weeds/genetics/drug effects ; }, abstract = {BACKGROUND: Wild oat (Avena fatua L.) is a self-pollinating, allohexaploid species in the family Gramineae (grasses), which is a malignant weed that mainly harms crops such as wheat. In recent years, a decline in the control efficiency of flucarbazone-sodium against wild oat has occurred in some regions of China.

RESULTS: We identified an ALS-resistant A. fatua population (R population). Whole-plant response assays revealed that the R population exhibited a moderate level of resistance (5.9-fold) to flucarbazone-sodium. Pre-treatment with malathion significantly reduced flucarbazone-sodium resistance in the R population. The known mutation sites and ALS gene relative expression that confer resistance to ALS inhibitor herbicides were not found in R population. Following flucarbazone-sodium treatment, the expression of eight genes related to metabolic enzymes was investigated using quantitative real-time PCR (qRT-PCR). CYP92A6 and the Aldo/keto reductase family were highly expressed in the R population after the application of flucarbazone-sodium.

CONCLUSIONS: The mechanism of flucarbazone-sodium resistance in A. fatua is mediated by NTSR, nor TSR. Two genes, CYP92A6 and the Aldo/keto reductase family, were discovered to be possibly related in the metabolism of NTSR in the A. fatua population, justifying more functional studies. The results will serve as a data resource for further studies on the molecular mechanisms of A. fatua to flucarbazone-sodium.}, } @article {pmid39538364, year = {2025}, author = {Terra, R and Éthier, V and Busque, L and Morin-Quintal, A and D'Angelo, G and Hébert, J and Wang, X and Lépine, G and LeBlanc, R and Bergeron, J}, title = {Improved identification of clinically relevant Acute Leukemia subtypes using standardized EuroFlow panels versus non-standardized approach.}, journal = {Cytometry. Part B, Clinical cytometry}, volume = {108}, number = {2}, pages = {116-127}, doi = {10.1002/cyto.b.22213}, pmid = {39538364}, issn = {1552-4957}, support = {//BD Biosciences/ ; }, mesh = {Humans ; *Flow Cytometry/methods/standards ; Immunophenotyping/methods ; *Leukemia, Myeloid, Acute/diagnosis/pathology/genetics ; Dendritic Cells/pathology ; Female ; Male ; Middle Aged ; *Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis/pathology ; Adult ; Aged ; }, abstract = {Rare acute leukemia (AL) components or subtypes such as blastic plasmacytoid dendritic cell neoplasm (BPDCN) or early T-cell precursor acute Lymphoblastic Leukemia (ETP-ALL) can be difficult to detect by routine flow cytometry due to their immunophenotypes overlapping with other poorly differentiated AL. We hypothesized that using standardized EuroFlow™ Consortium approach could better diagnose such entities among cases that previously classified as acute myeloid leukemia (AML)-M0, AML with minimal differentiation, AML with myelodysplasia-related changes without further lineage differentiation, and AL of ambiguous lineage. In order to confirm this hypothesis and assess whether these AL subtypes such as BPDCN and ETP-ALL had previously gone undetected, we reanalyzed 49 banked cryopreserved sample cases using standardized EuroFlow™ Consortium panels. We also performed target sequencing to capture the mutational commonalities between these AL subtypes. Reanalysis led to revised or refined diagnoses for 23 cases (47%). Of these, five diagnoses were modified, uncovering 3 ETP-ALL and 2 typical BPDCN cases. In 12 AML cases, a variable proportion of immature plasmacytoid dendritic cell and/or monocytic component was newly identified. In one AML case, we have identified a megakaryoblastic differentiation. Finally, in five acute lymphoblastic leukemia (ALL) cases, we were able to more precisely determine the maturation stage. The application of standardized EuroFlow flow cytometry immunophenotyping improves the diagnostic accuracy of ALs and could impact treatment decisions.}, } @article {pmid39539269, year = {2024}, author = {Risen, S and Sharma, S and Gilberto, VS and Brindley, S and Aguilar, M and Brown, JM and Chatterjee, A and Moreno, JA and Nagpal, P}, title = {Large- and Small-Animal Studies of Safety, Pharmacokinetics, and Biodistribution of Inflammasome-Targeting Nanoligomer in the Brain and Other Target Organs.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {11}, pages = {3439-3451}, pmid = {39539269}, issn = {2575-9108}, abstract = {Immune malfunction or misrecognition of healthy cells and tissue, termed autoimmune disease, is implicated in more than 80 disease conditions and multiple other secondary pathologies. While pan-immunosuppressive therapies like steroids can offer limited relief for systemic inflammation for some organs, many patients never achieve remission, and such drugs do not cross the blood-brain barrier, making them ineffective for tackling neuroinflammation. Especially in the brain, unintended activation of microglia and astrocytes is hypothesized to be directly or indirectly responsible for multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Recent studies have also shown that targeting inflammasomes and specific immune targets can be beneficial for these diseases. Furthermore, our previous studies have shown targeting NF-κB and NLRP3 through brain penetrant Nanoligomer cocktail SB_NI_112 (abbreviated as NI112) can be therapeutic for several neurodegenerative diseases. Here, we show safety-toxicity studies, followed by pharmacokinetics and biodistribution in small- (mice) and large-animal (dog) studies of this inflammasome-targeting Nanoligomer cocktail NI112. We conducted studies using four different routes of administration: intravenous, subcutaneous, intraperitoneal, and intranasal, and identified the drug concentration over time using inductively coupled plasma mass spectrometry in the blood serum, the brain (including different brain regions), and other target organs such as liver, kidney, and colon. Our results indicate that the Nanoligomer cocktail has a strong safety profile and shows high biodistribution (F ∼ 0.98) and delivery across multiple routes of administration. Further analysis showed high brain bioavailability with a ratio of NI112 in brain tissue to blood serum of ∼30%. Our model accurately shows dose scaling, translation between different routes of administration, and interspecies scaling. These results provide an excellent platform for human clinical translation and prediction of therapeutic dosage between different routes of administration.}, } @article {pmid39541203, year = {2024}, author = {Russo, A and Maiorano, G and Cortese, B and D'Amone, S and Invidia, A and Quattrini, A and Romano, A and Gigli, G and Palamà, IE}, title = {Optimizing TDP-43 silencing with siRNA-loaded polymeric nanovectors in neuronal cells for therapeutic applications: balancing knockdown and function.}, journal = {Nanoscale}, volume = {16}, number = {48}, pages = {22337-22349}, doi = {10.1039/d4nr03159h}, pmid = {39541203}, issn = {2040-3372}, mesh = {*DNA-Binding Proteins/metabolism/genetics/chemistry ; *RNA, Small Interfering/chemistry/metabolism ; Humans ; *Neurons/metabolism/pathology ; Amyotrophic Lateral Sclerosis/therapy/metabolism/pathology/genetics ; Polymers/chemistry ; Nanoparticles/chemistry ; Gene Knockdown Techniques ; Cell Line, Tumor ; Gene Silencing ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed DNA/RNA binding protein critical for regulating gene expression, including transcription, splicing, mRNA stability, and protein translation. Aggregation of pathological TDP-43 proteins in the cytoplasm of neurons and glial cells appears to be a common feature of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases such as frontotemporal dementia (FTD), contributing to motor neuron degeneration and clinical symptoms. Downregulation of TDP-43 expression to prevent or reduce the formation of pathological aggregates is a potential therapeutic approach for treating TDP-43-related diseases. However, therapeutic strategies to reduce TDP-43 aggregation face significant challenges, as the downregulation of TDP-43 must balance the need to maintain its normal functions, which are essential for RNA metabolism and cellular homeostasis. In this study, we developed novel polymeric nanovectors for the delivery of TDP-43 siRNAs in neuronal cells. These nanovectors were designed to provide adequate TDP-43 silencing to achieve the desired functional reduction of TDP-43 levels, thereby optimizing its impact on cellular functions. Our results demonstrate that the polymeric nanovector formulations effectively reduced TDP-43 mRNA and protein levels to an extent comparable to those observed with traditional lipid-based systems. Concurrently, the polymeric nanovectors exhibited an enhanced capacity to reduce stress granules (SG) formation and facilitate TDP-43-containing SG disassembly, while preserving its essential cellular functions. This study provides the first evidence that polymeric nanovectors may be a valuable tool for developing therapeutic strategies to treat TDP-43 protein diseases, such as ALS and FTD, by directly silencing TDP-43 to reduce its aggregation.}, } @article {pmid39541975, year = {2025}, author = {Márquez-Moñino, MÁ and Santiveri, CM and de León, P and Camero, S and Campos-Olivas, R and Jiménez, MÁ and Sáiz, M and González, B and Pérez-Cañadillas, JM}, title = {The ALS drug riluzole binds to the C-terminal domain of SARS-CoV-2 nucleocapsid protein and has antiviral activity.}, journal = {Structure (London, England : 1993)}, volume = {33}, number = {1}, pages = {39-50.e6}, doi = {10.1016/j.str.2024.10.025}, pmid = {39541975}, issn = {1878-4186}, mesh = {*SARS-CoV-2/drug effects/metabolism ; *Antiviral Agents/pharmacology/chemistry ; Binding Sites ; Humans ; *Riluzole/pharmacology/chemistry/metabolism ; *Protein Binding ; Crystallography, X-Ray ; Coronavirus Nucleocapsid Proteins/chemistry/metabolism ; Phosphoproteins/metabolism/chemistry ; Protein Domains ; COVID-19 Drug Treatment ; Models, Molecular ; }, abstract = {Nucleoproteins (N) play an essential role in virus assembly and are less prone to mutation than other viral structural proteins, making them attractive targets for drug discovery. Using an NMR fragment-based drug discovery approach, we identified the 1,3-benzothiazol-2-amine (BZT) group as a scaffold to develop potential antivirals for SARS-CoV-2 nucleocapsid (N) protein. A thorough characterization of BZT derivatives using NMR, X-ray crystallography, antiviral activity assays, and intrinsic fluorescence measurements revealed their binding in the C-terminal domain (CTD) domain of the N protein, to residues Arg 259, Trp 330, and Lys 338, coinciding with the nucleotide binding site. Our most effective compound exhibits a slightly better affinity than GTP and the ALS drug riluzole, also identified during the screening, and displays notable viral inhibition activity. A virtual screening of 218 BZT-based compounds revealed a potential extended binding site that could be exploited for the future development of new SARS-CoV-2 antivirals.}, } @article {pmid39542047, year = {2024}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Okhovat, AA and Nafissi, S and Mohammadi, S and Batouli, SAH}, title = {Metabolite alterations in the left dorsolateral prefrontal cortex and its association with cognitive assessments in amyotrophic lateral sclerosis: A longitudinal magnetic resonance spectroscopy study.}, journal = {Brain research bulletin}, volume = {219}, number = {}, pages = {111125}, doi = {10.1016/j.brainresbull.2024.111125}, pmid = {39542047}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; Male ; Female ; Middle Aged ; *Magnetic Resonance Spectroscopy/methods ; Longitudinal Studies ; Aged ; *Cognition/physiology ; *Dorsolateral Prefrontal Cortex/metabolism ; Choline/metabolism ; Creatine/metabolism ; Neuropsychological Tests ; Adult ; Cognitive Dysfunction/metabolism/diagnostic imaging ; Aspartic Acid/analogs & derivatives/metabolism ; Prefrontal Cortex/metabolism/diagnostic imaging ; }, abstract = {OBJECTIVE: To characterize the longitudinal metabolite profile of the left dorsolateral prefrontal cortex (DLPFC) in amyotrophic lateral sclerosis (ALS) using magnetic resonance spectroscopy (MRS) and to examine its correlation with cognitive assessments.

METHODS: Thirteen patients at baseline and ten at follow-up, along with 14 age-, sex-, and handedness-matched healthy controls (HCs), were recruited. Three Tesla with a 64-channel coil, Point-RESolved Spectroscopy (PRESS) sequence (TR=1500 ms and TE=140 ms) was used. Metabolites in the left DLPFC were quantified using LCModel. Cognitive performance and functional impairment were assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) and Revised ALS Functional Rating Scale (ALSFRS-R), respectively. Group comparisons were adjusted for multiple comparisons (p < 0.05, Bonferroni correction). The links between the brain metabolites and cognitive function were investigated using relevant correlation tests (Pearson's or Spearman's).

RESULTS: Our analysis revealed a significant difference in the choline-to-creatine ratio (tCho/tCr) among the three groups. Baseline ALS patients showed a higher tCho/tCr ratio than HCs (p = 0.033, Bonferroni-corrected). Interestingly, the total N-acetyl aspartate (tNAA)/tCr ratio, a marker of neuronal health, was strongly positively correlated with visuospatial cognitive scores at baseline and follow-up. Furthermore, at follow-up, tNAA/tCr was positively correlated with the total scores and specific sub-scores on the ECAS, encompassing both ALS-specific and non-specific cognitive domains. At follow-up, positive correlations emerged between tNAA/tCr and the total language and executive function scores.

CONCLUSIONS: Metabolite alterations and correlations with cognition were observed in the left DLPFC of ALS patients, supporting extra-motor involvement and its association with cognitive decline.}, } @article {pmid39542176, year = {2024}, author = {Tian, Z and Zhang, Q and Wang, L and Li, M and Li, T and Wang, Y and Cao, Z and Jiang, X and Luo, P}, title = {Progress in the mechanisms of pain associated with neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102579}, doi = {10.1016/j.arr.2024.102579}, pmid = {39542176}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Pain/physiopathology/metabolism/etiology ; Animals ; Neuroinflammatory Diseases ; }, abstract = {Neurodegenerative diseases (NDDs) represent a class of neurological disorders characterized by the progressive degeneration or loss of neurons, impacting millions of individuals globally. In addition to the typical manifestations, pain is a prevalent symptom associated with NDDs, seriously impacting the quality of life for patients. The pathogenesis of pain associated with NDDs is intricate and multifaceted. Currently, the clinical management of NDDs-related pain symptoms predominantly relies on conventional pharmacological agents or physical therapy. However, these approaches often fail to produce satisfactory outcomes. This article summarizes the underlying mechanisms of major NDDs-associated pain: Neuroinflammation, Brain and spinal cord dysfunctions, Mitochondrial dysfunction, Risk gene and pathological protein, as well as Receptor, channel, and neurotransmitter. While numerous studies have investigated the downstream pathological processes associated with these mechanisms, there remains a significant gap in identifying the key initiating factors. Specifically, there is insufficient evidence for the upstream elements that activate microglia and astrocytes in neuroinflammation leading to pain in NDDs. Likewise, there is an absence of upstream factors elucidating how dysfunctions in the brain and spinal cord, as well as mitochondrial impairments, contribute to the development of pain. Furthermore, the specific mechanisms through which hallmark pathological proteins related to NDDs contribute to these pathological processes remain inadequately understood. The objective of this article is to synthesize the existing mechanisms underlying pain associated with NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Schizophrenia, Amyotrophic lateral sclerosis, and Multiple sclerosis, while also identifying gaps and deficiencies in these mechanisms. This paper offers insights for future research trajectories. Given the intricate pathogenesis of NDDs-related pain, it emphasizes that a promising short-term strategy is combination therapy-intervening concurrently in multiple pathological processes-akin to the cocktail approach utilized in treating acquired immunodeficiency syndrome (AIDS). For long-term advancements, achieving breakthroughs in the treatment of the NDDs themselves will remain essential for alleviating accompanying pain symptoms.}, } @article {pmid39544700, year = {2024}, author = {Parnianpour, P and Steinbach, R and Buchholz, IJ and Grosskreutz, J and Kalra, S}, title = {T1-weighted MRI texture analysis in amyotrophic lateral sclerosis patients stratified by the D50 progression model.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae389}, pmid = {39544700}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis, a progressive neurodegenerative disease, presents challenges in predicting individual disease trajectories due to its heterogeneous nature. This study explores the application of texture analysis on T1-weighted MRI in patients with amyotrophic lateral sclerosis, stratified by the D50 disease progression model. The D50 model, which offers a more nuanced representation of disease progression than traditional linear metrics, calculates the sigmoidal curve of functional decline and provides independent quantifications of disease aggressiveness and accumulation. In this research, a representative cohort of 116 patients with amyotrophic lateral sclerosis was studied using the D50 model and texture analysis on MRI images. Texture analysis, a technique used for quantifying voxel intensity patterns in MRI images, was employed to discern alterations in brain tissue associated with amyotrophic lateral sclerosis. This study examined alterations of the texture feature autocorrelation across sub-groups of patients based on disease accumulation, aggressiveness and the first site of onset, as well as in direct regressions with accumulation/aggressiveness. The findings revealed distinct patterns of the texture-derived autocorrelation in grey and white matter, increase in bilateral corticospinal tract, right hippocampus and left temporal pole as well as widespread decrease within motor and extra-motor brain regions, of patients stratified based on their disease accumulation. Autocorrelation alterations in grey and white matter, in clusters within the left cingulate gyrus white matter, brainstem, left cerebellar tonsil grey matter and right inferior fronto-occipital fasciculus, were also negatively associated with disease accumulation in regression analysis. Otherwise, disease aggressiveness correlated with only two small clusters, within the right superior temporal gyrus and right posterior division of the cingulate gyrus white matter. The findings suggest that texture analysis could serve as a potential biomarker for disease stage in amyotrophic lateral sclerosis, with potential for quick assessment based on using T1-weighted images.}, } @article {pmid39544780, year = {2024}, author = {Silva, JF and de Souza, WM and Mello, JDC and Ceccato, HD and Oliveira, PSP and Ayrizono, MLS and Leal, RF}, title = {Evidence linking gut-brain axis and Crohn's disease, focusing on neurotrophic dysfunctions and radiological imaging analysis - a systematic review.}, journal = {American journal of translational research}, volume = {16}, number = {10}, pages = {6029-6040}, pmid = {39544780}, issn = {1943-8141}, abstract = {OBJECTIVE: To conduct a systematic review (SR) to find evidence for a connection between Crohn's disease (CD) and the gut-brain axis (GBA).

METHODS: This study conducted a systematic review (SR) employing a search strategy and strict inclusion criteria. It was conducted by searching for studies published between 2017 and 2024 in the following databases: PUBMED, PUBMED PMC, BVS-BIREME, SCOPUS, WEB OF SCIENCE, EMBASE, and COCHRANE.

RESULTS: Fifty original research articles were included. Among these, 20 studies addressed neuroimaging methods to evaluate CD patients' functional or structural brain changes. Neurodegenerative diseases were the second most addressed topic in the studies, with 18 articles related to different diseases such as Parkinson's disease, Alzheimer's disease, dementia, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Multiple System Atrophy. Eight articles addressed sleep disorders related to CD; two explored Electroencephalography changes; one investigated Brain-Derived Neurotrophic Factor serum levels and one correlated vagotomy with CD.

CONCLUSION: Interest in the link between CD and GBA is increasing, but studies remain varied and inconclusive, spanning from epidemiology to brain imaging and neglecting to investigate a mechanistic relationship. This SR underscores the need for further research to better understand the potential role of GBA in the prognosis and etiology of CD, highlighting its complexity.}, } @article {pmid39545045, year = {2024}, author = {Xu, X and Huang, Y and Zhu, Y and Jin, Q}, title = {Association between dietary patterns and the prognosis of amyotrophic lateral sclerosis in China: a cross-sectional study.}, journal = {Frontiers in nutrition}, volume = {11}, number = {}, pages = {1437521}, pmid = {39545045}, issn = {2296-861X}, abstract = {BACKGROUND: Recently, a growing number of studies have specifically examined the impact of dietary variables on the development and progression of amyotrophic lateral sclerosis (ALS). The purpose of this study was to investigate the correlation between different dietary patterns and Chinese ALS patients' prognosis.

METHODS: A retrospective study was conducted by recruiting 590 patients with ALS who attended and were regularly followed at hospitals in Nanjing from 2016 to 2023. Nutrient intake was calculated using dietary information collected through the food frequency questionnaire (FFQ), and patients were divided into a control group and special diet groups, including a high-calorie group (HC), a high-protein group (HP), and a ketogenic diet group (KD), based on their specific intake. And used the Kaplan-Meier product limiting distribution to compare the time required to transition between phases of different dietary patterns and to estimate cumulative survival probabilities.

RESULTS: Patients in the HP had a better nutritional status. And the disease progression rate (ΔFS) was significantly associated with dietary patterns, with the KD group having the lowest ΔFS. Meanwhile, special diets extended the survival time of stage 4 patients but had no effect on the overall survival of the disease.

CONCLUSION: A special diet can be one of effective options for patients with advanced ALS. Patients with poor nutritional status may choose the HP diet, whereas those with underlying conditions should consider the ketogenic diet with caution.}, } @article {pmid39545606, year = {2024}, author = {A Virata, MC and Catahay, JA and Lippi, G and Henry, BM}, title = {Neurofilament light chain: a biomarker at the crossroads of clarity and confusion for gene-directed therapies.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {6}, pages = {227-239}, pmid = {39545606}, issn = {1758-2032}, mesh = {Humans ; *Biomarkers/blood ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/diagnosis/drug therapy/genetics ; *Neurofilament Proteins/blood ; }, abstract = {Neurofilament light chain (NfL) is a promising biomarker for neurodegenerative diseases, measurable in both CSF and blood upon neuroaxonal damage. While CSF analysis was traditionally used, blood-based assays now offer a less invasive alternative. NfL levels correlate with disease severity and progression in conditions like Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and Huntington's disease. Clinical trials demonstrate its utility as a pharmacodynamic biomarker in MS and ALS. The FDA's approval of Tofersen for SOD1-ALS based on NfL reduction underscores its growing acceptance as surrogate marker. However, challenges remain in standardizing assays, interpreting clinical correlations, low specificity and understanding the dynamics between CSF and blood NfL levels. Addressing these issues is crucial for maximizing NfL's potential in neurodegenerative disease management.}, } @article {pmid39545975, year = {2024}, author = {Eickhoff, C and Schöne-Seifert, B and Kettemann, D and Bormann, E and Grehl, T and Boentert, M and Koch, JC and Schmitt, C and Schrank, B and Schröter, C and Meyer, T}, title = {[End of life perspectives: a systematic survey of patients with amyotrophic lateral sclerosis].}, journal = {Der Nervenarzt}, volume = {95}, number = {12}, pages = {1131-1138}, pmid = {39545975}, issn = {1433-0407}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/psychology ; Humans ; Male ; Female ; Middle Aged ; *Terminal Care/psychology ; Aged ; *Advance Directives/psychology ; Surveys and Questionnaires ; Germany ; Adult ; Aged, 80 and over ; Noninvasive Ventilation ; Palliative Care ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease that still has to be primarily treated symptomatically or palliatively. It is therefore all the more important, in addition to initiating treatment, such as percutaneous endoscopic gastrostomy (PEG), noninvasive ventilation therapy (NIVT) and invasive ventilation therapy via tracheotomy (IVT), to discuss the possible termination of these measures early on.

QUESTION: What is the importance of advance directives for those affected and where are possible deficits in therapy planning for the end of life?

MATERIAL AND METHOD: Between March 2017 and January 2019 patients with a clinically confirmed diagnosis of ALS at six treatment centers were asked to fill out a questionnaire. A total of 328 people returned the completed forms.

RESULTS: Of the participants 72% had already made an advance directive (AD), 25% planned to fill one out and only 3% refused to do so. In composing the AD most patients (90%) had support, although 56% lacked medical counselling and only 18% had drawn up the will together with the doctor and relatives, with the majority of the rest also wanting support from a doctor. A total of 37% of all patients wanted a contact person to talk about their illness but only 40% of them had such a contact person. Of the patients 22% stated that they had considered suicide and of these only 55% stated that they had no contact person for the psychological stress caused by the illness but 31% wished to have such a person.

DISCUSSION AND CONCLUSION: A coordinated care of ALS patients, which also takes the psychosocial aspects into account is urgently needed.}, } @article {pmid39546178, year = {2025}, author = {Li, N and Zhang, Z and Shen, L and Song, G and Tian, J and Liu, Q and Ni, J}, title = {Selenium metabolism and selenoproteins function in brain and encephalopathy.}, journal = {Science China. Life sciences}, volume = {68}, number = {3}, pages = {628-656}, pmid = {39546178}, issn = {1869-1889}, mesh = {*Selenoproteins/metabolism ; Humans ; *Selenium/metabolism/deficiency ; *Brain/metabolism ; Animals ; *Brain Diseases/metabolism ; Neurodegenerative Diseases/metabolism ; }, abstract = {Selenium (Se) is an essential trace element of the utmost importance to human health. Its deficiency induces various disorders. Se species can be absorbed by organisms and metabolized to hydrogen selenide for the biosynthesis of selenoproteins, selenonucleic acids, or selenosugars. Se in mammals mainly acts as selenoproteins to exert their biological functions. The brain ranks highest in the specific hierarchy of organs to maintain the level of Se and the expression of selenoproteins under the circumstances of Se deficiency. Dyshomeostasis of Se and dysregulation of selenoproteins result in encephalopathy such as Alzheimer's disease, Parkinson's disease, depression, amyotrophic lateral sclerosis, and multiple sclerosis. This review provides a summary and discussion of Se metabolism, selenoprotein function, and their roles in modulating brain diseases based on the most currently published literature. It focuses on how Se is utilized and transported to the brain, how selenoproteins are biosynthesized and function physiologically in the brain, and how selenoproteins are involved in neurodegenerative diseases. At the end of this review, the perspectives and problems are outlined regarding Se and selenoproteins in the regulation of encephalopathy.}, } @article {pmid39547816, year = {2024}, author = {Salmerón-Mendoza, AN and Aguilar-Vázquez, CA and Aguilar-Castillo, SJ}, title = {[Electromyography in atypical variants of motor neuron disease: a case series].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {62}, number = {4}, pages = {1-6}, pmid = {39547816}, issn = {2448-5667}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Electromyography ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Adult ; Aged, 80 and over ; Motor Neuron Disease/diagnosis/physiopathology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both the upper and lower motor neurons, it has a heterogeneous clinical presentation, there are atypical variants that differ from the classic form of the disease. The criteria for diagnosis have evolved over time, with the support of electromyography (EMG), we present a patient series with these variants in which EMG was crucial to make the diagnosis.

CLINICAL CASES: Six cases are described with atypical presentation of motor neuron disease, for the isolated bulbar ALS phenotype, three cases are reported: two male patients (68 and 62 years old) and one woman (33 years old), with initial symptoms in the bulbar segment and late progression. to a second segment, corroborating characteristic findings by EMG. For the variant of Vulpian-Bernhardt syndrome (VBS), two male patients aged 82 and 72 years are reported, with initial symptoms in the thoracic segment with electromyographic support for the diagnosis; Finally, a case of amyotrophic diplegia of the legs (APD) is described in a 50-year-old female patient with symptoms isolated to the pelvic limbs, with a slow clinical evolution, corroborated by EMG with involvement of other spinal segments.

CONCLUSIONS: ALS a spectrum of motor neuron disease, a neurodegenerative disease of the CNS, without curative treatment and one with a fatal outcome, the diagnosis of ELA is complex and becomes more complex for atypical phenotypes, as observed in the presented cases EMG is an essential part of the approach and part of the diagnostic criteria.}, } @article {pmid39547910, year = {2025}, author = {Khamaysa, M and El Mendili, M and Marchand, V and Querin, G and Pradat, PF}, title = {Quantitative spinal cord imaging: Early ALS diagnosis and monitoring of disease progression.}, journal = {Revue neurologique}, volume = {181}, number = {3}, pages = {172-183}, doi = {10.1016/j.neurol.2024.10.005}, pmid = {39547910}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/diagnostic imaging/pathology ; Disease Progression ; *Spinal Cord/diagnostic imaging/pathology ; Early Diagnosis ; *Neuroimaging/methods ; Magnetic Resonance Imaging/methods ; Prognosis ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons in the cortex, brainstem, and spinal cord. This degeneration leads to muscular weakness, progressively impairing motor functions and ultimately resulting in respiratory failure. The clinical, genetic, and pathological heterogeneity of ALS, combined with the absence of reliable biomarkers, significantly challenge the efficacy of therapeutic trials. Despite these hurdles, neuroimaging, and particularly spinal cord imaging, has emerged as a promising tool. It provides insights into the involvement of both upper and lower motor neurons. Quantitative spinal imaging has the potential to facilitate early diagnosis, enable accurate monitoring of disease progression, and refine the design of clinical trials. In this review, we explore the utility of spinal cord imaging within the broader context of developing spinal imaging biomarkers in ALS. We focus on a both diagnostic and prognostic biomarker in ALS, highlighting its pivotal role in elucidating the disease's underlying pathology. We also discuss the existing limitations and future avenues for research, aiming to bridge the translational gap between academic research and its application in clinical practice and therapeutic trials.}, } @article {pmid39548226, year = {2024}, author = {Qin, J and Wang, X and Fan, G and Zhang, W and Wu, X and Wang, B and Liu, Y}, title = {Identifying amyotrophic lateral sclerosis using diffusion tensor imaging, and correlation with neurofilament markers.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28110}, pmid = {39548226}, issn = {2045-2322}, support = {202103021224405//the Basic Research Project of Shanxi Province/ ; 201903D321049//the Key Research and Development Project Plan of Shanxi Province concerning social advancement/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/cerebrospinal fluid/blood/pathology ; *Diffusion Tensor Imaging/methods ; Middle Aged ; Male ; Female ; *Neurofilament Proteins/cerebrospinal fluid/blood ; *Biomarkers/blood/cerebrospinal fluid ; Aged ; Adult ; ROC Curve ; Case-Control Studies ; Anisotropy ; Pyramidal Tracts/diagnostic imaging/pathology ; }, abstract = {To determine diagnostic value of diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS) patients and investigate the association between DTI and neurofilaments (NFs), including serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH). Forty-three clinically diagnosed ALS patients and 32 control subjects without neurological disorders underwent routine MRI (magnetic resonance imaging) and DTI scans. DTI parameters (mean diffusivity [MD] and fractional anisotropy [FA]) at axial levels of internal capsules and cerebral peduncles along the corticospinal tract (CST) were measured. The study compared the differences of DTI parameters between ALS patients and controls using the Mann-Whitney U test. Diagnostic efficacy of each DTI metric was evaluated using the receiver operating characteristic (ROC) curve. NFs (NFL and pNFH levels in serum and CSF) were measured by enzyme-linked immunosorbent assay. Correlation analyses were conducted between DTI parameters and NFs. Capsule-MD and Peduncle-MD in ALS patients were higher than those in controls; whereas Capsule-FA and Peduncle-FA in ALS patients were lower than those in controls (all, p < 0.05). The area under curve (AUC) was 0.730 for Capsule-FA, 0.828 for Capsule-MD, 0.890 for Peduncle-FA, and 0.896 for Peduncle-MD. Capsule-FA was negatively correlated with CSF-NFL (r = - 0.813, p < 0.001), Serum-NFL (r = - 0.493, p = 0.001), CSF-pNFH (r = - 0.637, p < 0.001), and Serum-pNFH (r = - 0.672, p < 0.001); Peduncle-FA negatively with CSF-NFL (r = - 0.562, p < 0.001), CSF-pNFH (r = - 0.506, p = 0.001), and Serum-pNFH (r = - 0.488, p = 0.001); Peduncle-MD positively with CSF-NFL (r = 0.516, p < 0.001), CSF-pNFH (r = 0.494, p = 0.001). DTI had superior performance in identifying ALS patients and could serve as a reliable predictor. DTI parameters related to neurofilament markers, and Capsule-FA may become a robust surrogate biomarker indicating disease severity and progression rate for ALS patients.}, } @article {pmid39548409, year = {2024}, author = {Ruan, K and Cheng, D and Zhu, X and Sun, S and Bao, F and Zhu, J and Li, F and Shen, M and Ye, Y}, title = {Corneal higher-order aberrations and their relationship with choroid in myopic patients.}, journal = {BMC ophthalmology}, volume = {24}, number = {1}, pages = {500}, pmid = {39548409}, issn = {1471-2415}, support = {81900910//Innovative Research Group Project of the National Natural Science Foundation of China/ ; LQ19H120003//Natural Science Foundation of Zhejiang Province/ ; Y2023809, Y20190638//Basic Scientific Research Project of Wenzhou/ ; }, mesh = {Humans ; Female ; Male ; *Choroid/pathology/diagnostic imaging/blood supply ; Adult ; *Myopia/physiopathology/complications ; *Corneal Wavefront Aberration/physiopathology ; *Tomography, Optical Coherence/methods ; Young Adult ; *Cornea/pathology/diagnostic imaging ; Axial Length, Eye/pathology/diagnostic imaging ; Refraction, Ocular/physiology ; Visual Acuity/physiology ; Corneal Topography ; Middle Aged ; Cross-Sectional Studies ; }, abstract = {BACKGROUND: To investigate corneal higher-order aberrations (HOAs) and choroidal characteristics in myopic individuals and explore the association between HOAs and choroidal parameters.

METHODS: Myopic participants were categorized into three groups based on axial lengths (ALs). We compared corneal HOAs, including spherical (Z4[0]), comatic (Z3 [- 1] and Z3[1]), and trefoil (Z3 [- 3] and Z3[3]) aberrations, as well as choroidal vascularity index (CVI) and choroidal thickness (CT). Linear regression analysis was used to assess the relationships among corneal HOAs, CVI, CT, spherical equivalent, and AL.

RESULTS: Groups 1, 2, and 3 included 105, 98, and 118 eyes, respectively. Group 3 exhibited lower spherical HOA root mean square and Z4[0] values than group 1(p < 0.05). Group 1 showed lower Z3[1] levels than other groups (p < 0.001). Groups 1 and 2 had higher mean, central, and I2 vertical CVIs than group 3 (p < 0.05). Group 1 had a larger vertical S1 CVI than group 3 (p < 0.05). Group 3 had smaller horizontal CVI values in all regions except N2 (p < 0.05). Both the mean and CT in all regions decreased as AL increased (p < 0.001). The comatic (Z3[1]) and trefoil (Z3[3]) components were predictors of mean horizontal CVI, and the comatic (Z3[1]) component was correlated with both mean vertical and horizontal CT.

CONCLUSION: Longer AL myopic patients exhibited lower absolute values of spherical aberration and horizontal coma. Alterations in choroid in myopic patients correlated with corneal HOAs. Our results suggest a potential connection between the optical quality and ocular perfusion in myopia.}, } @article {pmid39548508, year = {2024}, author = {Panei, FP and Di Rienzo, L and Zacco, E and Armaos, A and Tartaglia, GG and Ruocco, G and Milanetti, E}, title = {Synchronized motion of interface residues for evaluating protein-RNA complex binding affinity: Application to aptamer-mediated inhibition of TDP-43 aggregates.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {12}, pages = {e5201}, pmid = {39548508}, issn = {1469-896X}, support = {855923//ERC-2019-Synergy Grant (ASTRA, 855923)/ ; ivBM4PAP,101098989//EIC-2022-PathfinderOpen/ ; CN00000041//National Center for Gene Therapy and Drugs Based on RNA Technology/ ; CUPj33C22001130001//Potenziamento Strutture di Ricerca e Creazione di Campioni Nazionali Di R&S/ ; }, mesh = {*Aptamers, Nucleotide/chemistry/metabolism ; *Molecular Dynamics Simulation ; Humans ; *DNA-Binding Proteins/chemistry/metabolism ; *Protein Binding ; RNA/chemistry/metabolism ; Molecular Docking Simulation ; }, abstract = {Investigating the binding between proteins and aptamers, such as peptides or RNA molecules, is of crucial importance both for understanding the molecular mechanisms that regulate cellular activities and for therapeutic applications in several pathologies. Here, a new computational procedure, employing mainly docking, clustering analysis, and molecular dynamics simulations, was designed to estimate the binding affinities between a protein and some RNA aptamers, through the investigation of the dynamical behavior of the predicted molecular complex. Using the state-of-the-art software catRAPID, we computationally designed a set of RNA aptamers interacting with the TAR DNA-binding protein 43 (TDP-43), a protein associated with several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We thus devised a computational protocol to predict the RNA-protein molecular complex, so that the structural and dynamical behavior of such a complex can be investigated through extensive molecular dynamics simulation. We hypothesized that the coordinated and synchronized motion of the protein-binding residues, when in contact with RNA molecule, is a critical requisite in order to have a stable binding. Indeed, we calculated the motion covariance exhibited by the interface residues during molecular dynamics simulation: we tested the results against experimental measurements of binding affinity (in this case, the dissociation constant) for six RNA molecules, resulting in a linear correlation of about 0.9. Our findings suggest that the synchronized movement of interface residues plays a pivotal role in ensuring the stability within RNA-protein complexes, moreover providing insights into the contribution of each interface residue. This promising pipeline could thus contribute to the design of RNA aptamers interacting with proteins.}, } @article {pmid39548731, year = {2024}, author = {Shino, Y and Muraki, N and Kobatake, Y and Kamishina, H and Kato, R and Furukawa, Y}, title = {Disulfide-mediated oligomerization of mutant Cu/Zn-superoxide dismutase associated with canine degenerative myelopathy.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {12}, pages = {e5210}, pmid = {39548731}, issn = {1469-896X}, support = {JP21am0101083//Japan Agency for Medical Research and Development/ ; 19H05765//The Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 22H02768//The Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 22K19389//The Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 23EXC334//Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences/ ; }, mesh = {Animals ; Dogs ; *Disulfides/chemistry/metabolism ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; Protein Multimerization ; Dog Diseases/genetics ; Spinal Cord Diseases/genetics/metabolism ; Amino Acid Substitution ; Zinc/metabolism/chemistry ; Mutation ; Mutation, Missense ; Copper/metabolism/chemistry ; }, abstract = {A homozygous E40K mutation in the gene coding canine Cu/Zn-superoxide dismutase (cSOD1) causes degenerative myelopathy (DM) in dogs. A pathological hallmark of DM with the cSOD1 mutation is the aggregation of mutant cSOD1 proteins in neurons. The amino acid substitution E40K disrupts a salt bridge between Glu40 and Lys91 and is considered to destabilize the native state of cSOD1; however, the mechanism by which mutant cSOD1 aggregates remains unclear. Here, we show that mutant cSOD1 losing a copper and zinc ion forms oligomers crosslinked via disulfide bonds. The E40K substitution was found to result in the increased solvent exposure of the Cys7 side chain, which then attacked the disulfide bond (Cys57-Cys146) in cSOD1 to form disulfide-linked oligomers. We also successfully prevented the Cys7 exposure and thus the oligomerization of mutant cSOD1 by a fragment antibody that specifically recognizes the region around the mutation site. The fragment antibody covered the β-plug region, reinforcing the interactions compromised by the E40K substitution and thus contributing to the maintenance of the structural integrity of the β-barrel core of cSOD1. Taken together, we propose that the Cys7 exposure in cSOD1 upon the salt bridge disruption plays a central role in the aggregation mechanism of DM-associated mutant cSOD1.}, } @article {pmid39548852, year = {2025}, author = {Dellar, ER and Vendrell, I and Amein, B and Lester, DG and Edmond, EC and Yoganathan, K and Dharmadasa, T and Sogorb-Esteve, A and Fischer, R and Talbot, K and Rohrer, JD and Turner, MR and Thompson, AG}, title = {Elevated Cerebrospinal Fluid Ubiquitin Carboxyl-Terminal Hydrolase Isozyme L1 in Asymptomatic C9orf72 Hexanucleotide Repeat Expansion Carriers.}, journal = {Annals of neurology}, volume = {97}, number = {3}, pages = {449-459}, pmid = {39548852}, issn = {1531-8249}, support = {2018-I2M-2-002//Chinese Academy of Medical Sciences Innovation Fund for Medical Science/ ; Lester/2450/795/MNDA_/Motor Neurone Disease Association/United Kingdom ; Thompson/Jan20/952-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; MR/Y001095/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid ; Aged ; *Frontotemporal Dementia/genetics/cerebrospinal fluid ; DNA Repeat Expansion/genetics ; Adult ; Heterozygote ; Biomarkers/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; }, abstract = {OBJECTIVE: To identify biochemical changes in individuals at higher risk of developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) via C9orf72 hexanucleotide repeat expansion (HRE) heterozygosity.

METHODS: Cross-sectional observational study of 48 asymptomatic C9orf72 HRE carriers, 39 asymptomatic non-carrier controls, 19 people with sporadic ALS, 10 with C9orf72 ALS, 14 with sporadic FTD, and 10 with C9orf72 FTD. Relative abundance of 30 pre-defined cerebrospinal fluid biomarkers of ALS and FTD were compared in asymptomatic C9orf72 HRE carriers and age-matched non-carrier controls. Differential abundance of these proteins was quantified using data independent acquisition mass spectrometry or electro chemiluminescent assay for neurofilament light chain. Unbiased analysis of the entire cerebrospinal fluid proteome was then carried out.

RESULTS: Ubiquitin carboxyl-hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age-matched non-carriers (log2fold change 0.20, FDR-adjusted p-value = 0.034), whereas neurofilament light chain levels did not significantly differ. Ubiquitin carboxyl-hydrolase isozyme L1 levels remained elevated after matching of groups by neurofilament levels (p = 0.011), and after adjusting for age, sex, and neurofilament levels. A significant difference was also observed when restricting analysis to younger participants (<37) matched by neurofilament level (p = 0.007).

INTERPRETATION: Elevated cerebrospinal fluid ubiquitin carboxyl-hydrolase isozyme L1 levels in C9orf72 HRE carriers can occur in the absence of increased neurofilament levels, potentially reflecting either compensatory or pathogenic mechanisms preceding rapid neuronal loss. This brings forward the window on changes associated with the C9orf72 HRE carrier state, with potential to inform understanding of penetrance and approaches to prevention. ANN NEUROL 2025;97:449-459.}, } @article {pmid39550435, year = {2024}, author = {Wang, Z and Cao, W and Deng, B and Fan, D}, title = {Lower creatinine-to-cystatin c ratio associated with increased risk of incident amyotrophic lateral sclerosis in the prospective UK biobank cohort.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28289}, pmid = {39550435}, issn = {2045-2322}, support = {81873784//National Natural Science Foundation of China/ ; BYSYDL2019002//Peking University Third Hospital/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/blood/epidemiology ; Humans ; Male ; Female ; *Creatinine/blood ; Middle Aged ; United Kingdom/epidemiology ; Aged ; Incidence ; Prospective Studies ; *Cystatin C/blood ; Risk Factors ; *Biological Specimen Banks ; *Biomarkers/blood ; Proportional Hazards Models ; Adult ; UK Biobank ; }, abstract = {Reduced muscle mass has been associated with the progression and prognosis of amyotrophic lateral sclerosis (ALS). However, it remains unclear whether decreased muscle mass is a risk factor for ALS or a consequence of motor neuron degeneration. Recently, serum creatinine-to-cystatin C ratio (CCR) have emerged as promising biomarkers for assessing muscle mass. We aimed to explore the association between CCR and the incidence of ALS using data from the UK Biobank. Between 2006 and 2010, 446,945 participants were included in the baseline. CCR was calculated as the ratio of serum creatinine to cystatin C. Cox regression models were used to analyze the relationship between CCR and ALS incidence. Furthermore, subgroup analyses were conducted to investigate potential covariates in these relationships. After adjusting for all covariates, the multivariate Cox regression analysis revealed a significant association between decreased CCR and an increased risk of ALS (hazard ratio (HR) = 0.990, 95% confidence interval (CI): 0.982-0.999, P = 0.026). Participants were stratified into groups based on CCR tertiles. Compared with participants in the highest tertiles of CCR, those in the lowest (HR = 1.388, 95% CI: 1.032-1.866, P = 0.030) and medium tertiles (HR = 1.348, 95% CI: 1.045-1.739, P = 0.021) had an increased risk of ALS incidence. Subgroup analysis showed that the relationship between CCR and ALS incidence was particularly significant among participants aged < 65 years (CCR tertile 1: HR = 1.916, 95% CI: 1.366-2.688, P < 0.001; CCR tertile 2: HR = 1.699, 95% CI: 1.267-2.278, P < 0.001). The present results demonstrate that lower CCR is significantly associated with a higher risk of ALS.}, } @article {pmid39550606, year = {2024}, author = {Rabadi, MH and Russell, KA and Xu, C}, title = {Analysis of Mortality Causes and Locations in Veterans with ALS: A Decade Review.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {30}, number = {}, pages = {e945816}, pmid = {39550606}, issn = {1643-3750}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology ; *Veterans ; Male ; Female ; Middle Aged ; Aged ; *Cause of Death ; Retrospective Studies ; United States/epidemiology ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that leads to rapid degeneration of nerves in the brain and spinal cord, with eventual loss of voluntary movements, including breathing. This retrospective study of medical record data from 105 US veterans diagnosed with ALS at the Oklahoma City VA Medical Center between 2010 and 2021 aimed to identify patient demographics, and the causes and places of death for these veterans. MATERIAL AND METHODS Data from 105 US veterans diagnosed with ALS by the El Escorial criteria and supported by neurophysiology testing was reviewed. The information about the place and cause of death was obtained from each patient's care provider and death certificate. Crude mortality rates (per 100 person-years) and standardized mortality ratios (SMRs) were calculated for the causes of death, by sex, age group, and location of death. RESULTS During the 11-year follow-up period, 80 (76.2%) veterans with ALS died. The mean (SD) follow-up time was 4.53 (4.55) years. Most of the deaths were due to respiratory failure and pneumonia (n=43, mortality rate=9.21 per 100 person-years). Most patients died at home (n=71, 88.7%). The annual crude mortality rate was 16.7 and the all-cause death SMR was 25.63 (95% CI, 20.32-31.55). CONCLUSIONS This study's findings are that in veterans with ALS, the main cause of death is respiratory disease (failure). The main location of death was the home, with their family members. The all-cause mortality rate among veterans with ALS was 26 times greater than for the general Oklahoma population.}, } @article {pmid39551138, year = {2024}, author = {Yang, C and Leifer, C and Lammerding, J and Hu, F}, title = {Regulation of TAR DNA binding protein 43 (TDP-43) homeostasis by cytosolic DNA accumulation.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {12}, pages = {107999}, pmid = {39551138}, issn = {1083-351X}, support = {R21 AG078741/AG/NIA NIH HHS/United States ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; *Cytosol/metabolism ; Humans ; Animals ; *Homeostasis ; DNA/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Cytoplasm/metabolism ; beta Karyopherins/metabolism/genetics ; Neurons/metabolism/pathology ; Mice ; Cell Nucleus/metabolism ; Oligodeoxyribonucleotides/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA binding protein predominantly localized in the nucleus under physiological conditions. TDP-43 proteinopathy, characterized by cytoplasmic aggregation and nuclear loss, is associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Thus it is crucial to understand the molecular mechanism regulating TDP-43 homeostasis. Here, we show that the uptake of oligodeoxynucleotides (ODNs) from the extracellular space induces reversible TDP-43 cytoplasmic puncta formation in both neurons and glia. ODNs facilitate the liquid-liquid phase separation of TDP-43 in vitro. Importantly, persistent accumulation of DNA in the cytoplasm leads to nuclear depletion of TDP-43 and enhanced production of a short isoform of TDP-43 (sTDP-43). In addition, in response to ODN uptake, the nuclear import receptor karyopherin subunit β1 (KPNB1) is sequestered in the cytosolic TDP-43 puncta. ALS-linked Q331K mutation decreases the dynamics of cytoplasmic TDP-43 puncta and increases the levels of sTDP-43. Moreover, the TDP-43 cytoplasmic puncta are induced by DNA damage and by impaired nuclear envelope integrity due to Lamin A/C deficiency. In summary, our data support that abnormal DNA accumulation in the cytoplasm may be one of the key mechanisms leading to TDP-43 proteinopathy and provides novel insights into molecular mechanisms of ALS caused by TDP-43 mutations.}, } @article {pmid39551139, year = {2024}, author = {Liu, C and Chen, IS and Barri, M and Murrell-Lagnado, R and Kubo, Y}, title = {Structural determinants of M2R involved in inhibition by Sigma-1R.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {12}, pages = {108006}, pmid = {39551139}, issn = {1083-351X}, mesh = {*Receptors, sigma/metabolism/genetics ; Humans ; *Sigma-1 Receptor ; HEK293 Cells ; *Receptor, Muscarinic M2/metabolism/genetics ; Animals ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism/genetics ; }, abstract = {Sigma-1 receptor (S1R) is a multimodal chaperone protein that is implicated in various pathophysiological conditions including drug addiction, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). S1R interacts with various ion channels and receptors on the endoplasmic reticulum or plasma membrane (PM). It has been reported that S1R colocalizes with the M2-muscarinic acetylcholine receptor (M2R) on the soma of motoneurons, although a functional interaction between these two proteins has not been established. Here, we investigated the regulation of M2R signaling by S1R using electrophysiological recordings of GIRK currents in HEK293T cells. We observed that S1R strongly inhibited M2R-mediated activation of GIRK1/2, but the disease mutant linked to ALS, S1R E102Q, did not. The inhibitory effect of S1R was selective for M2R and wasn't seen when S1R was co-expressed with other Gi/o coupled receptors including M4R. Chimeric and mutant receptors of M2R and M4R were generated and analyzed, and this highlighted Ala401 in the transmembrane 6 domain (TM6) of M2R and Glu172 as well as Glu175 in the extracellular loop 2 regions of M2R, as essential for the inhibition by S1R. Co-immunoprecipitation confirmed the physical interaction between M2R and S1R. Immunocytochemical labeling of M2R and S1R expressed in HeLa cells, HEK293T cells, and cultured hippocampal neurons, showed clear PM expression of M2R throughout the cell which was decreased by coexpression with S1R but was still apparent. Taken together, our results show that S1R interacts with M2R to reduce both its PM expression and function, and this involves TM6 and the extracellular loop 2.}, } @article {pmid39551156, year = {2025}, author = {Chen, LC and Martin, A and Senna, MM}, title = {Response to Truel J. et al's "Response to 'Topical tofacitinib for patients with lichen planopilaris and/or frontal fibrosing alopecia'".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e69}, doi = {10.1016/j.jaad.2024.11.011}, pmid = {39551156}, issn = {1097-6787}, } @article {pmid39551782, year = {2024}, author = {Labrador, L and Rodriguez, L and Beltran, S and Hernandez, F and Gomez, L and Ojeda, P and Bergmann, C and Calegaro-Nassif, M and Kerr, B and Medinas, DB and Manque, P and Woehlbier, U}, title = {Overexpression of autophagy enhancer PACER/RUBCNL in neurons accelerates disease in the SOD1[G93A] ALS mouse model.}, journal = {Biological research}, volume = {57}, number = {1}, pages = {86}, pmid = {39551782}, issn = {0717-6287}, support = {1200459//Agencia Nacional de Investigación y Desarrollo/ ; 1150743//Agencia Nacional de Investigación y Desarrollo/ ; 11160288//Agencia Nacional de Investigación y Desarrollo/ ; 1191538//Agencia Nacional de Investigación y Desarrollo/ ; 1230905//Agencia Nacional de Investigación y Desarrollo/ ; ACT210039//Agencia Nacional de Investigación y Desarrollo/ ; 11240328//Agencia Nacional de Investigación y Desarrollo/ ; 1240176//Agencia Nacional de Investigación y Desarrollo/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Autophagy/genetics/physiology ; Mice ; Humans ; Superoxide Dismutase-1/genetics ; Motor Neurons/pathology ; Superoxide Dismutase/genetics ; Neurons/pathology ; Male ; Female ; Autophagy-Related Proteins/genetics/metabolism ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal paralytic disorder associated with motor neuron death. Mutant superoxide dismutase 1 (SOD1) misfolding and aggregation have been linked to familial ALS, with the accumulation of abnormal wild-type SOD1 species being also observed in postmortem tissue of sporadic ALS cases. Both wild-type and mutated SOD1 are reported to contribute to motoneuron cell death. The autophagic pathway has been shown to be dysregulated in ALS. Recent evidence suggests a dual time-dependent role of autophagy in the progression of the disease. PACER, also called RUBCNL (Rubicon-like), is an enhancer of autophagy and has been found diminished in its levels during ALS pathology in mice and humans. Pacer loss of function disturbs the autophagy process and leads to the accumulation of SOD1 aggregates, as well as sensitizes neurons to death. Therefore, here we investigated if constitutive overexpression of PACER in neurons since early development is beneficial in an in vivo model of ALS. We generated a transgenic mouse model overexpressing human PACER in neurons, which then was crossbred with the mutant SOD1[G93A] ALS mouse model. Unexpectedly, PACER/SOD1[G93A] double transgenic mice exhibited an earlier disease onset and shorter lifespan than did littermate SOD1[G93A] mice. The overexpression of PACER in neurons in vivo and in vitro increased the accumulation of SOD1 aggregates, possibly due to impaired autophagy. These results suggest that similar to Pacer loss-of function, Pacer gain-of function is detrimental to autophagy, increases SOD1 aggregation and worsens ALS pathogenesis. In a wider context, our results indicate the requirement to maintain a fine balance of PACER protein levels to sustain proteostasis.}, } @article {pmid39551788, year = {2024}, author = {Sadeghdoust, M and Das, A and Kaushik, DK}, title = {Fueling neurodegeneration: metabolic insights into microglia functions.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {300}, pmid = {39551788}, issn = {1742-2094}, support = {MS220110//U.S. Department of Defense/ ; 916184//Multiple Sclerosis Society of Canada/ ; }, mesh = {*Microglia/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; }, abstract = {Microglia, the resident immune cells of the central nervous system, emerge in the brain during early embryonic development and persist throughout life. They play essential roles in brain homeostasis, and their dysfunction contributes to neuroinflammation and the progression of neurodegenerative diseases. Recent studies have uncovered an intricate relationship between microglia functions and metabolic processes, offering fresh perspectives on disease mechanisms and possible treatments. Despite these advancements, there are still significant gaps in our understanding of how metabolic dysregulation affects microglial phenotypes in these disorders. This review aims to address these gaps, laying the groundwork for future research on the topic. We specifically examine how metabolic shifts in microglia, such as the transition from oxidative phosphorylation and mitochondrial metabolism to heightened glycolysis during proinflammatory states, impact the disease progression in Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Additionally, we explore the role of iron, fatty and amino acid metabolism in microglial homeostasis and repair. Identifying both distinct and shared metabolic adaptations in microglia across neurodegenerative diseases could reveal common therapeutic targets and provide a deeper understanding of disease-specific mechanisms underlying multiple CNS disorders.}, } @article {pmid39552337, year = {2024}, author = {Baindoor, S and Gibriel, HAY and Venø, MT and Su, J and Morrissey, EP and Jirström, E and Woods, I and Kenny, A and Alves, M and Halang, L and Fabbrizio, P and Bilen, M and Engel, T and Hogg, MC and Bendotti, C and Nardo, G and Slack, RS and Kjems, J and Prehn, JHM}, title = {Distinct fingerprints of tRNA-derived small non-coding RNA in animal models of neurodegeneration.}, journal = {Disease models & mechanisms}, volume = {17}, number = {11}, pages = {}, pmid = {39552337}, issn = {1754-8411}, support = {17/JPND/3455//Research Ireland/ ; //European Regional Development Fund/ ; //FutureNeuro/ ; //Precision ALS/ ; 18/CRT/6214//Research Ireland Centre for Research Training in Genomics Data Science/ ; //EU Joint Programme - Neurodegenerative Disease Research/ ; CUP E48I20000000007//Regione Lombardia/ ; SG-2018-12366226//Ministero della Salute/ ; //Royal College of Surgeons in Ireland/ ; }, mesh = {Animals ; *Disease Models, Animal ; *RNA, Transfer/genetics/metabolism ; *RNA, Small Untranslated/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Neurodegenerative Diseases/genetics/pathology ; Mice ; Humans ; Mice, Transgenic ; Parkinson Disease/genetics/pathology ; Frontotemporal Dementia/genetics/pathology ; }, abstract = {Transfer RNA-derived small RNAs (tsRNAs) - categorized as tRNA-derived fragments (tRFs), tRNA-derived stress-induced RNAs (tiRNAs) and internal tRF (itRF) - are small non-coding RNAs that participate in various cellular processes such as translation inhibition and responses to cellular stress. We here identified tsRNA profiles within susceptible tissues in animal models of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Parkinson's disease (PD) to pinpoint disease-specific tsRNAs and those shared across neurodegenerative diseases. We performed small RNA sequencing in the SOD1G93A and TDP43A315T mouse models of ALS (spinal cord), the TauP301S model of FTD (hippocampus), and the parkin/POLG model of PD (substantia nigra). Bioinformatic analysis showed higher expression of 5' tiRNAs selectively in the two ALS models, lower expression of 3' tRFs in both the ALS and FTD mouse models, and lower expression of itRF Arg in the PD model. Experimental validation confirmed the expression of tsRNAs. Gene Ontology analysis of targets associated with validated 3' tRFs indicated functions in the regulation of synaptic and neuronal pathways. Our profiling of tsRNAs indicates disease-specific fingerprints in animal models of neurodegeneration, which require validation in human disease.}, } @article {pmid39552508, year = {2025}, author = {Zhong, R and Dionela, DLA and Kim, NH and Harris, EN and Geisler, JG and Wei-LaPierre, L}, title = {Micro-Doses of DNP Preserve Motor and Muscle Function with a Period of Functional Recovery in Amyotrophic Lateral Sclerosis Mice.}, journal = {Annals of neurology}, volume = {97}, number = {3}, pages = {542-557}, pmid = {39552508}, issn = {1531-8249}, support = {R56 NS117429/NS/NINDS NIH HHS/United States ; NS99545/NS/NINDS NIH HHS/United States ; R01 NS127858/NS/NINDS NIH HHS/United States ; R21 NS099545/NS/NINDS NIH HHS/United States ; NS117429/NS/NINDS NIH HHS/United States ; NS127858/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology/genetics ; *2,4-Dinitrophenol/pharmacology/administration & dosage/therapeutic use ; Mice ; *Muscle, Skeletal/drug effects/physiopathology ; Mice, Transgenic ; *Recovery of Function/drug effects ; Disease Models, Animal ; Muscle Contraction/drug effects ; *Uncoupling Agents/pharmacology/administration & dosage ; Male ; Neuromuscular Junction/drug effects ; }, abstract = {OBJECTIVE: Mitochondrial dysfunction is one of the earliest pathological events observed in amyotrophic lateral sclerosis (ALS). The aim of this study is to evaluate the therapeutic efficacy of 2,4-dinitrophenol (DNP), a mild mitochondrial uncoupler, in an ALS mouse model to provide preclinical proof-of-concept evidence of using DNP as a potential therapeutic drug for ALS.

METHODS: hSOD1[G93A] mice were treated with 0.5-1.0 mg/kg DNP through daily oral gavage from presymptomatic stage or disease onset until 18 weeks old. Longitudinal behavioral studies were performed weekly or biweekly from 6 to 18 weeks old. In situ muscle contraction measurements in extensor digitorum longus muscles were conducted to evaluate the preservation of contractile force and motor unit numbers in hSOD1[G93A] mice following DNP treatment. Muscle innervation and inflammatory markers were assessed using immunostaining. Extent of protein oxidation and activation of Akt pathway were also examined.

RESULTS: DNP delayed disease onset; improved motor coordination and muscle performance in vivo; preserved muscle contractile function, neuromuscular junction morphology, and muscle innervation; and reduced inflammation and protein oxidation at 18 weeks old in hSOD1[G93A] mice. Strikingly, symptomatic hSOD1[G93A] mice exhibited a period of recovery in running ability at 20 cm/s several weeks after 2,4-dinitrophenol treatment started at disease onset, offering the first observation in disease phenotype reversal using a small molecule.

INTERPRETATION: Our results strongly support that micro-dose DNP may be used as a potential novel treatment for ALS patients, with a possibility for recovery, when used at optimal doses and time of intervention. ANN NEUROL 2025;97:542-557.}, } @article {pmid39553255, year = {2024}, author = {Zeinali, M and Almasi Dooghaee, M and Ziaee, M and Haghi Ashtiani, B}, title = {Evaluation of Relationship Between Laboratory, Electrodiagnostic, and Functional Parameters in Patients With Amyotrophic Lateral Sclerosis; A Cross Sectional Study.}, journal = {Basic and clinical neuroscience}, volume = {15}, number = {4}, pages = {553-560}, pmid = {39553255}, issn = {2008-126X}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a poor prognosis that leads to limb and or bulbar muscle degeneration. Several demographic and biological factors have prognostic importance, but little data exist on the relationship between clinical, electrodiagnostic, and laboratory markers as predictors of disease progression. We aimed to assess the relationships between different aspects of ALS patients' clinical, electrodiagnostic, and laboratory features and their level of functioning.

METHODS: We included 27 ALS patients diagnosed within the last two years. A neurology resident conducted clinical assessment and electrodiagnostic studies. The motor unit number index (MUNIX) and compound motor action potential (CMAP) were used to measure motor unit loss. Serum creatinine, urea, albumin, and creatine kinase were measured as laboratory markers. We used the Persian version of the ALS functional rating scale (ALS-FRS) as the main outcome measure. The Pearson correlation coefficient was calculated to assess the correlations using the SPSS software, version 16.

RESULTS: None of the demographic or laboratory parameters were correlated with ALSFRS. Patients with the onset of disease in the limbs had a higher MUNIX score than those with bulbar onset. Also, increased body mass index (BMI) was associated with lower CMAP and MUNIX scores (P=0.02). Higher serum creatinine levels were significantly associated with higher lower limb MUNIX (P=0.04). Higher lower limb MUNIX was associated with a higher lower limb functional score.

CONCLUSION: Decreased serum creatinine may indicate lower limb motor unit loss in patients with ALS. Also, MUNIX scores may be used as substitutes for ALS-FRS in ALS trials. Further research is needed to elucidate the clinical application of these findings.}, } @article {pmid39556113, year = {2025}, author = {Yeganeh Markid, T and Pourahmadiyan, A and Hamzeh, S and Sharifi-Bonab, M and Asadi, MR and Jalaiei, A and Rezazadeh, M and Ghafouri-Fard, S}, title = {A special focus on polyadenylation and alternative polyadenylation in neurodegenerative diseases: A systematic review.}, journal = {Journal of neurochemistry}, volume = {169}, number = {2}, pages = {e16255}, doi = {10.1111/jnc.16255}, pmid = {39556113}, issn = {1471-4159}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; *Polyadenylation/physiology ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) are one of the prevailing conditions characterized by progressive neuronal loss. Polyadenylation (PA) and alternative polyadenylation (APA) are the two main post-transcriptional events that regulate neuronal gene expression and protein production. This systematic review analyzed the available literature on the role of PA and APA in NDDs, with an emphasis on their contributions to disease development. A comprehensive literature search was performed using the PubMed, Scopus, Cochrane, Google Scholar, Embase, Web of Science, and ProQuest databases. The search strategy was developed based on the framework introduced by Arksey and O'Malley and supplemented by the inclusion and exclusion criteria. The study selection was performed by two independent reviewers. Extraction and data organization were performed in accordance with the predefined variables. Subsequently, quantitative and qualitative analyses were performed. Forty-seven studies were included, related to a variety of NDDs, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Disease induction was performed using different models, including human tissues, animal models, and cultured cells. Most investigations were related to PA, although some were related to APA or both. Amyloid precursor protein (APP), Tau, SNCA, and STMN2 were the major genes identified; most of the altered PA patterns were related to mRNA stability and translation efficiency. This review particularly underscores the key roles of PA and APA in the pathogenesis of NDDs through their mechanisms that contribute to gene expression dysregulation, protein aggregation, and neuronal dysfunction. Insights into these mechanisms may lead to new therapeutic strategies focused on the modulation of PA and APA activities. Further research is required to investigate the translational potential of targeting these pathways for NDD treatment.}, } @article {pmid39556393, year = {2024}, author = {Ishii, J and Nishikimi, M and Kikutani, K and Ohki, S and Ota, K and Anzai, T and Takahashi, K and Okubo, M and Ohshimo, S and Iwami, T and Shime, N}, title = {Resuscitation Attempt and Outcomes in Patients With Asystole Out-of-Hospital Cardiac Arrest.}, journal = {JAMA network open}, volume = {7}, number = {11}, pages = {e2445543}, pmid = {39556393}, issn = {2574-3805}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality/epidemiology ; Male ; Female ; Aged ; Middle Aged ; Japan/epidemiology ; *Cardiopulmonary Resuscitation/methods ; *Registries ; *Emergency Medical Services/statistics & numerical data ; Aged, 80 and over ; Advanced Cardiac Life Support/methods ; Prospective Studies ; Epinephrine/therapeutic use/administration & dosage ; Treatment Outcome ; Cohort Studies ; }, abstract = {IMPORTANCE: Little is known about the epidemiology of out-of-hospital cardiac arrest (OHCA) in patients with asystole in countries where prehospital resuscitation is not withheld or terminated.

OBJECTIVE: To investigate the secular trends in the patient outcomes and advanced life support (ALS) procedures and evaluate the association of ALS procedures with favorable outcomes among patients with OHCA and asystole.

This cohort study analyzed data from a nationwide prospective OHCA registry in Japan. OHCA occurred from June 1, 2014, to December 31, 2020. Adults with an initial rhythm of asystole and OHCA were included in the analysis, which was conducted between July 29, 2022, and August 24, 2024.

EXPOSURES: Year of OHCA and prehospital ALS procedures (advanced airway management [AAM] and intravenous epinephrine administration).

MAIN OUTCOMES AND MEASURES: Trends in prehospital and in-hospital ALS procedures and patient outcomes were described using the Jonckheere-Terpstra trend test for continuous variables and the Cochran-Armitage trend test for categorical variables. The primary outcome was a favorable neurological outcome at 30 days. The secondary outcomes included a favorable neurological outcome at 90 days and survival at 30 and 90 days. Associations between prehospital procedures and outcomes were analyzed using time-dependent propensity score and risk-set matching.

RESULTS: Of 60 349 patients with OHCA, 35 843 (59.4%) presented with asystole (median age, 77 [IQR, 64-85] years; 20 573 [57.4%] men). Among these, 33 674 patients (93.9%) underwent ALS procedures, with 67 (0.2%) achieving a favorable neurological outcome at 30 days. No significant trends in the outcomes were noted, except for a decline in return of spontaneous circulation (424 of 1848 [22.9%] to 1178 of 5892 [20.0%]; P = .003). Neither AAM (odds ratio [OR], 1.27 [95% CI, 0.76-2.12]; P = .36) nor intravenous epinephrine administration (OR, 0.53 [95% CI, 0.24-1.13]; P = .10) was associated with a favorable neurological outcome at 30 days, although both were associated with survival at 30 days (ORs, 1.45 [95% CI, 1.21-1.74] and 1.81 [95% CI, 1.44-2.27], respectively; P < .001 for both).

CONCLUSIONS AND RELEVANCE: In this cohort study of patients with OHCA presenting with asystole, the proportion with a favorable neurological outcome at 30 days was substantially low, and no prehospital ALS procedure was associated with a favorable neurological outcome. These findings suggest that discussions regarding implementation of a termination of resuscitation rule for such patients are warranted.}, } @article {pmid39556975, year = {2024}, author = {Yu, Z and Qi, J and Liu, S and Zhao, X and Huang, H}, title = {Evaluating forest aboveground biomass estimation model using simulated ALS point cloud from an individual-based forest model and 3D radiative transfer model across continents.}, journal = {Journal of environmental management}, volume = {372}, number = {}, pages = {123287}, doi = {10.1016/j.jenvman.2024.123287}, pmid = {39556975}, issn = {1095-8630}, mesh = {*Biomass ; *Forests ; Models, Theoretical ; Computer Simulation ; Trees/growth & development ; Algorithms ; }, abstract = {Area-based approach (ABA) has been widely employed for estimating forest aboveground biomass (AGB) using airborne laser scanning (ALS) data. However, its scalability is limited due to challenges in model generalization across different forest types and regions. The selection of sensitive variables from ALS data is crucial for constructing robust forest AGB estimation models, yet this selection varies significantly among forest types and regions. Traditionally, assessing the influence of variable selection is hindered by the lack of accurate reference forest AGB values. Computer simulation-based method provides a perspective for exploring these challenges. This study employs an individual-based forest growth process model, FORMIND, coupled with a 3D radiative transfer model (RTM), LESS, to evaluate the transferability of ABA-based forest AGB estimation models and the generalization of ALS-derived variables. We used six virtual 3D forest scenes and two real-world forest sites, representing a range of global forest types, along with their simulated ALS data, to develop a forest AGB estimation model using the random forest algorithm, which allowed us to analyze the importance of various variables. We assessed model transferability through cross-comparison. Additionally, we validated the model using field plots and ALS data collected from two distinct regions. The results showed that the canopy surface area and volume extracted using the α-shape algorithm and parameters fitted from the Weibull distribution are vital variables when using ALS for forest AGB estimation across forest types and regions. Incorporating these variables into the model significantly improves the accuracy of forest AGB estimation. The optimized model achieved a R[2] of 0.945, a RMSE of 34.22 t/ha, and a MAE of 20.53 t/ha. Our study not only deepens the understanding of the relationship between forest vertical structural metrics and AGB but also highlights the potential of computer simulation as a tool for refining the estimation of forest structural parameters.}, } @article {pmid39557152, year = {2025}, author = {Yu, H and Ren, K and Jin, Y and Zhang, L and Liu, H and Huang, Z and Zhang, Z and Chen, X and Yang, Y and Wei, Z}, title = {Mitochondrial DAMPs: Key mediators in neuroinflammation and neurodegenerative disease pathogenesis.}, journal = {Neuropharmacology}, volume = {264}, number = {}, pages = {110217}, doi = {10.1016/j.neuropharm.2024.110217}, pmid = {39557152}, issn = {1873-7064}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/immunology ; *Neuroinflammatory Diseases/metabolism/immunology/pathology ; Animals ; *Mitochondria/metabolism ; *Alarmins/metabolism ; Inflammasomes/metabolism ; DNA, Mitochondrial/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are increasingly linked to mitochondrial dysfunction and neuroinflammation. Central to this link are mitochondrial damage-associated molecular patterns (mtDAMPs), including mitochondrial DNA, ATP, and reactive oxygen species, released during mitochondrial stress or damage. These mtDAMPs activate inflammatory pathways, such as the NLRP3 inflammasome and cGAS-STING, contributing to the progression of neurodegenerative diseases. This review delves into the mechanisms by which mtDAMPs drive neuroinflammation and discusses potential therapeutic strategies targeting these pathways to mitigate neurodegeneration. Additionally, it explores the cross-talk between mitochondria and the immune system, highlighting the complex interplay that exacerbates neuronal damage. Understanding the role of mtDAMPs could pave the way for novel treatments aimed at modulating neuroinflammation and slowing disease progression, ultimately improving patient outcome.}, } @article {pmid39557859, year = {2024}, author = {Pamphlett, R and Parkin Kullmann, J}, title = {Early life events may be the first steps on the multistep path to amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28497}, pmid = {39557859}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/etiology/genetics ; Humans ; Female ; Male ; Middle Aged ; Risk Factors ; Adult ; Aged ; Case-Control Studies ; Surveys and Questionnaires ; }, abstract = {A combination of multiple genetic and environmental factors appear to be required to trigger the onset of amyotrophic lateral sclerosis (ALS). Early life environmental exposures have been reported to be risk factors for a variety of adult-onset diseases, so we used data from an online international ALS case-control questionnaire to estimate whether any of these could be risk factors for the clinical onset of ALS. Responses were obtained from 1,049 people aged 40 years or more, 568 with ALS and 481 controls. People with ALS were more likely to have been born and lived longer in a country area than in a city area, to have younger parents, and to have lower educational attainment and fewer years of education. No ALS-control differences were found in sibling numbers, birth order, adult height, birth weight, parent smoking, Cesarean delivery, or age of starting smoking. In conclusion, early life events and conditions may be part of a group of polyenvironmental risk factors that act together with polygenetic variants to trigger the onset of ALS. Reducing exposure to adverse environmental factors in early life could help to lower the risk of later developing ALS.}, } @article {pmid39558635, year = {2024}, author = {Pillai, M and Patil, AD and Das, A and Jha, SK}, title = {Pathological Mutations D169G and P112H Electrostatically Aggravate the Amyloidogenicity of the Functional Domain of TDP-43.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {23}, pages = {4267-4283}, doi = {10.1021/acschemneuro.4c00372}, pmid = {39558635}, issn = {1948-7193}, mesh = {Humans ; *DNA-Binding Proteins/genetics/metabolism/chemistry ; *Static Electricity ; *Amyloid/metabolism/genetics ; Mutation ; Protein Domains/genetics ; Hydrogen-Ion Concentration ; Protein Aggregation, Pathological/genetics/metabolism ; }, abstract = {Aggregation of TDP-43 is linked to the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Notably, electrostatic point mutations such as D169G and P112H, located within the highly conserved functional tandem RNA recognition motif (RRM) domains of the TDP-43 protein (TDP-43[tRRM]), have been identified in diseased patients as well. In this study, we address how the electrostatic mutations alter both the native state stability and aggregation propensity of TDP-43[tRRM]. The mutants D169G and P112H show increased chemical stability compared to the TDP-43[tRRM] at physiological pH. However, at low pH, both the mutants undergo a conformational change to form amyloid-like fibrils, though with variable rates─the P112H mutant being substantially faster than the other two sequences (TDP-43[tRRM] and D169G mutant) showing comparable rates. Moreover, among the three sequences, only the P112H mutant undergoes a strong ionic strength-dependent aggregability trend. These observations signify the substantial contribution of the excess charge of the P112H mutant to its unique aggregation process. Complementary simulated observables with atomistic resolution assign the experimentally observed sequence-, pH-, and ionic strength-dependent aggregability pattern to the degree of thermal lability of the mutation site-containing RRM1 domain and its extent of dynamical anticorrelation with the RRM2 domain whose combination eventually dictate the extent of generation of aggregation-prone partially unfolded conformational ensembles. Our choice of a specific charge-modulated pathogenic mutation-based experiment-simulation-combination approach unravels the otherwise hidden residue-wise contribution to the individual steps of this extremely complicated multistep aggregation process.}, } @article {pmid39559551, year = {2024}, author = {Wang, J and Chi, L and Liu, S and Yin, J and Zhang, Y and Shen, J and Wang, X}, title = {Overlooked role of long capping time and environmental factors in the plateau lake for impairing lanthanum-modified-bentonite's immobilization to phosphate.}, journal = {Water research X}, volume = {25}, number = {}, pages = {100272}, pmid = {39559551}, issn = {2589-9147}, abstract = {Lanthanum-modified-bentonite(LMB) has been applied for eutrophication management as a phosphate(P)-binding agent in many lakes. However, re-eutrophication took place several years or decades later after the first practice of capping due to dynamic environmental factors in the plateau lake. Here, we investigated the effect of long-term capping and integrated environmental factors in the plateau lake including alkalinity, organic matter, disturbance and photodegradation to the LMB immobilization. Long-term LMB immobilization exhibited C accumulation(82.3%), La depletion(53.5%) and lager size effect in the sediment particle, indicating the breakage of La-O-P bonds and the formation of La-O-C bonds over immobilization time. Additionally, pH(8-10) in the plateau lake could enhance the P desorption and decrease P adsorption through electrostatic repulsion enhancement with the zeta potential reduction(7.2 mV). Further disturbance experiment indicated a significant releasing trend of active P and DGT-labile P from the solid phase, pore water to the overlying water after disturbances due to resuspended releasing, particle size and amorphous Fe, Mn and Al's redistribution. Moreover, [31]P NMR and EPR results indicated photodegradation after disturbance converted diester phosphate into orthophosphate with long-term LMB immobilization via the oxidation of ·OH in the sediment of the plateau lake. Therefore, management issues for Xingyun Lake may apply to other plateau lakes with low external P input, intermediate depth and intense disturbance.}, } @article {pmid39560839, year = {2024}, author = {Wu, R and Ramakrishnan, S and Lin, H and Dong, Z and Liu, M and Qiang, L}, title = {Development and validation a novel FEZF2 based fluorescent reporter for corticospinal motor neurons.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {17}, pmid = {39560839}, issn = {1573-7365}, support = {R01 NS115977/NS/NINDS NIH HHS/United States ; 4100083087//the CURE program via Drexel University College of Medicine/ ; 32070725//the National Natural Science Foundation/ ; }, mesh = {Animals ; *Motor Neurons/metabolism ; Mice ; Nerve Tissue Proteins/genetics/metabolism ; Pyramidal Tracts/metabolism ; Green Fluorescent Proteins/genetics/metabolism ; Genes, Reporter ; Cells, Cultured ; DNA-Binding Proteins ; }, abstract = {Corticospinal motor neurons (CSMNs), also named upper motor neurons, are the giant pyramidal neurons called Betz cells. In mammals, the majority of CSMNs reside within layer V of the primary motor cortex, where they extend long axon bundles named the pyramidal tract into the brainstem and the spinal cord to control voluntary movement. CSMN lesions are implicated in a variety of neurodegenerative disorders, such Amyotrophic Lateral Sclerosis, Primary Lateral Sclerosis and Hereditary Spastic paraplegia. Although FEZF2-CTIP2 genetic axis have been indicated as the cardinal molecular pathway underlying the development of CSMNs, these proteins are transcription factors that are mostly used to label the nuclei of CSMNs in the fixed cells and tissues. Therefore, a fluorescent reporter to mark CSMNs will be invaluable in identifying living CSMNs, including their extended processes, for time-lapse imaging and high-throughput molecular analyses with much more improved specificity. Based on the in-silico analysis, we identified a putative region within the promoter sequence of FEZF2 and assembled it with an indispensable enhancer motif at its downstream of the gene to form a complex promoter that drives the expression of reporter GFP. The plasmid and virus of FEZF2:eGFP reporter constructs were further validated for its use in specifically labeling CSMNs in primary neuronal cultures from the embryonic rat motor cortex, postnatal mouse cortex. This innovative molecular labeling tool has the potential to offer indispensable support in diverse experimental setups, enabling a comprehensive understanding of the susceptibility and specificity of CSMNs in a wide array of neurological disorders.}, } @article {pmid39561111, year = {2025}, author = {Rohrer, C and Palumbo, A and Paul, M and Reese, E and Basu, S}, title = {Neurotransmitters and neural hormone-based probes for quadruplex DNA sequences associated with neurodegenerative diseases.}, journal = {Nucleosides, nucleotides & nucleic acids}, volume = {44}, number = {12}, pages = {1124-1147}, doi = {10.1080/15257770.2024.2431145}, pmid = {39561111}, issn = {1532-2335}, mesh = {*G-Quadruplexes ; *Neurotransmitter Agents/chemistry/metabolism ; Humans ; *DNA/chemistry ; *Neurodegenerative Diseases/genetics ; Molecular Docking Simulation ; *Serotonin/chemistry/metabolism ; *Melatonin/chemistry/metabolism ; gamma-Aminobutyric Acid/chemistry/metabolism ; Spectrum Analysis, Raman ; }, abstract = {The potential of neurotransmitters and neural hormones as possible G-quadruplex DNA binders was analyzed using fluorescence spectroscopy, surface-enhanced Raman spectroscopy (SERS), DNA melting analysis, and molecular docking. G-quadruplex sequences, (GGC)3 and G4C2, with roles in Fragile X syndrome and amyotrophic lateral sclerosis (ALS), respectively, were selected, and their interactions with melatonin, serotonin, and gamma-aminobutyric acid (GABA), were studied. Both melatonin and serotonin demonstrated strong interactions with the DNA sequences with hydrogen bonding being the primary mode of interaction, with some non-intercalative interactions involving the π systems. GABA demonstrated much weaker interactions and may not be a suitable candidate as a probe for low concentrations of G-quadruplex DNA.}, } @article {pmid39562594, year = {2024}, author = {Tahmasebi, BK and Zand, E and Yousefi, A and Babaei, S and Sadeghpour, A}, title = {Surveillance and mapping of tribenuron-methyl-resistant weeds in wheat fields.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28626}, pmid = {39562594}, issn = {2045-2322}, mesh = {*Plant Weeds/drug effects ; *Triticum/drug effects/genetics/growth & development ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Arylsulfonates/pharmacology ; Iran ; Weed Control/methods ; }, abstract = {Tribenuron-methyl (TBM) is among the herbicides that are widely used for controlling broadleaf weeds in wheat fields in Iran due to its low mammalian toxicity and environmental risk, use at low doses, the broad spectrum of weed control, and low price compared to other herbicides. However, wheat farmers' repeated application and dissatisfaction with the optimal and effective control of the TBM herbicide have led to investigating broadleaf weed resistance in Iranian wheat fields. For this purpose, through a national call in 2018, a total of 240 broadleaf weed populations belonging to 13 species and 7 plant families were collected from 153 wheat fields in 72 counties across 14 provinces suspected to be resistant to the TBM herbicide. Then, a screening test was conducted in a completely randomized design with 5 replications of each biotype using the recommended dose of 25 g a.i. ha[- 1] of TBM in the greenhouse. Overall, the results indicated that 124 (51.7%) of the screened populations were resisted to TBM. Specifically, 44 populations (81%) of Sinapis arvensis L., 18 populations (45%) of Malva neglecta Wallr., 25 populations (45%) of Silybum marianum (L.) Gaertn, 2 populations (66.6%) of Ammi majus L., 1 population (50%) of Rapistrum rugosum L., 3 populations (21%) of Descurainia Sophia (L.) Webb ex Prantl, 9 populations (36%) of Vaccaria hispanica Mill., 8 populations (48%) of Galium aparine L., 9 populations (75%) of Melilotus indicus L. According to the Adkins and Maas evaluation, 4 populations (100%) of Raphanus raphanistrum L. were classified as resistant to TBM. This study is the first comprehensive investigation of broadleaf weed resistance to TBM across Iranian wheat fields, providing crucial insights for future herbicide management strategies. Given the high incidence of resistance, continued use of TBM in Iranian wheat fields may lead to increased yield loss and environmental pollution. Additionally, it is necessary to investigate cross-resistance in resistant populations to other ALS-inhibiting herbicides.}, } @article {pmid39562997, year = {2024}, author = {Zheng, W and Xia, T and Zhang, X and Han, J and Li, Y and Tian, N and Zheng, G and Wang, J and Peng, Y and Yao, D and Long, F}, title = {Tailoring Multifunctional Amine Salts Based on Anisole Liquid Soaking for Fabricating Efficient and Stable Perovskite Solar Cells.}, journal = {ACS applied materials & interfaces}, volume = {16}, number = {48}, pages = {66643-66654}, doi = {10.1021/acsami.4c12455}, pmid = {39562997}, issn = {1944-8252}, abstract = {The post-treatment based on spin-coating (SC) organic amine salts is commonly used for surface modification of perovskite films to eliminate defects. However, there is still a lack of systematic study and a unified understanding of the functions and mechanisms of different organic amine salts. The SC method is also not conducive to the industrialization of solar cells. In this work, we study three different organic amine salts, and a passivation strategy for perovskite films based on green anisole liquid soaking (ALS) has been developed. Phenylethylammonium iodide (PEAI), diethylamine hydroiodide (DEAI), and guanidine hydroiodide (GAI) organic amine salt passivators are selected to modify perovskite films, and their effect and working mechanism are also systematically estimated. It is found that PEAI passivates shallow-level defects on the surface of perovskite films, while DEAI incorporates into the perovskite lattice to suppress point defects, and GAI eliminates excess PbI2 residuals in perovskite films. These three organic-amine-salt-modified devices achieve enhanced power conversion efficiencies (PCE) of 21.82% (PEAI-ALS), 21.74% (DEAI-ALS), and 22.21% (GAI-ALS), which is much higher than that of the pristine device without treatment (19.95%). The PCE of the PEAI-ALS device retains nearly 94% of the initial efficiency after 1200 h in unpackaged conditions and about 40% ambient humidity, achieving the best stability performance. Particularly, the PEAI-ALS device has the best comprehensive performance in efficiency and stability. And PEAI is estimated by the SC method and ALS method, and it is found that the PEAI-ALS device achieves a higher PCE compared to the PEAI-SC device (21.51%). We believe that the post-treatment based on a combination of appropriate amine salts and ALS enables a universal approach for fabrication of perovskite solar cells with enhanced photovoltaic performance.}, } @article {pmid39563026, year = {2025}, author = {Hawley, ZCE and Pardo, ID and Cao, S and Zavodszky, MI and Casey, F and Ferber, K and Luo, Y and Hana, S and Chen, SK and Doherty, J and Costa, R and Cullen, P and Liu, Y and Carlile, TM and Chowdhury, T and Doyle, B and Clarner, P and Mangaudis, K and Guilmette, E and Bourque, S and Koske, D and Nadella, MVP and Trapa, P and Hawes, ML and Raitcheva, D and Lo, SC}, title = {Dorsal root ganglion toxicity after AAV intra-CSF delivery of a RNAi expression construct into non-human primates and mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {1}, pages = {215-234}, pmid = {39563026}, issn = {1525-0024}, mesh = {Animals ; *Dependovirus/genetics ; Mice ; *MicroRNAs/genetics ; *Ganglia, Spinal/metabolism ; *Genetic Vectors/administration & dosage/genetics ; *RNA Interference ; Superoxide Dismutase-1/genetics ; Humans ; Neurons/metabolism ; Male ; }, abstract = {Dorsal root ganglion (DRG) toxicity has been consistently reported as a potential safety concern after delivery of adeno-associated viruses (AAVs) containing gene-replacement vectors but has yet to be reported for RNAi-based vectors. Here, we report DRG toxicity after AAV intra-CSF delivery of an RNAi expression construct-artificial microRNA targeting superoxide dismutase 1 (SOD1)-in non-human primates (NHPs) and provide evidence that this can be recapitulated within mice. Histopathology evaluation showed that NHPs and mice develop DRG toxicity after AAV delivery, including DRG neuron degeneration and necrosis and nerve-fiber degeneration that were associated with increases in cerebrospinal fluid (CSF) and serum phosphorylated neurofilament heavy chain (pNF-H). RNA-sequencing analysis of DRGs showed that dysregulated pathways were preserved between NHPs and mice, including increases in innate/adaptive immune responses and decreases in mitochondrial- and neuronal-related genes, following AAV treatment. Finally, endogenous miR-21-5p was upregulated in DRGs of AAV-treated NHPs and mice. Increases in miR-21-5p were also identified within the CSF of NHPs, which significantly correlated with pNF-H, implicating miR-21-5p as a potential biomarker of DRG toxicity in conjunction with other molecular analytes. This work highlights the importance of assessing safety concerns related to DRG toxicity when developing RNAi-based AAV vectors for therapeutic purposes.}, } @article {pmid39563746, year = {2024}, author = {Moyana, TN}, title = {Metabolic dysfunction-associated steatotic liver disease: The question of long-term high-normal alanine aminotransferase as a screening test.}, journal = {World journal of gastroenterology}, volume = {30}, number = {42}, pages = {4576-4582}, pmid = {39563746}, issn = {2219-2840}, mesh = {Humans ; *Alanine Transaminase/blood ; *Biomarkers/blood ; Mass Screening/methods/standards ; Fatty Liver/diagnosis/blood/epidemiology ; Obesity/complications/diagnosis/epidemiology ; Early Diagnosis ; Reference Values ; Male ; Liver/pathology ; Non-alcoholic Fatty Liver Disease/diagnosis/blood/epidemiology ; }, abstract = {The growing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is being driven by the obesity epidemic. The quest for solutions continues particularly with regard to early detection. This editorial comments on the utility of long-term high-normal alanine aminotransferase (ALT) in screening for MASLD. Chen et al found that new onset MASLD can be detected by repetitively high normal ALT. Implicit in this concept is the question of what should be the accepted upper limit of normal (ULN) for ALT. It was previously set at 40 IU/L based on studies that included people with subclinical liver disease but the new consensus is 30/19 U/L in healthy males/females. Thus, when Chen et al defines the ULN as 40 U/L, others may view it as excessively high. It is important to recognize the variables affecting ULN e.g. instrumentation, diurnal variations, exercise and ageing. These variables matter when the distinctions are subtle e.g. normal vs high-normal. In this regard, the utility of long-term high normal ALT as a disease marker could be enhanced by combining it with other biomarkers, imaging and MASLD genetics to create machine learning classifiers. All in all, Chen et al's work on long-term high normal ALT as a marker of new-onset MASLD deserves merit.}, } @article {pmid39564171, year = {2024}, author = {Byeon, H}, title = {Holistic approaches to mitigating psychological distress in gynecological cancer patients.}, journal = {World journal of psychiatry}, volume = {14}, number = {11}, pages = {1766-1771}, pmid = {39564171}, issn = {2220-3206}, abstract = {This article delves into the psychological impact of gynecological malignancies and suggests pathways to improve the quality of life (QoL) for affected patients. Building on Shang et al's comprehensive analysis, this piece integrates insights from various studies to highlight the profound influence of psychological and physical symptoms on patients undergoing treatment for gynecological cancers. The study underscores that anxiety and depression significantly exacerbate the disease's toll. Factors such as physical exercise and digital and interactive health interventions show promise in mitigating these adverse effects. The article emphasizes the necessity for a holistic care approach that addresses both physical and emotional needs. Recommendations include enhanced training for healthcare providers, public awareness campaigns, streamlined diagnostic pathways, and improved access to specialist care. These integrated strategies aim to ensure that women facing gynecological cancers can maintain an optimal QoL through comprehensive and multidisciplinary care models.}, } @article {pmid39564190, year = {2024}, author = {Cavaliere, F and Hermann, DM and Magliaro, C}, title = {Editorial: Human brain organoids to model neurodegenerative diseases at the BOSS23 Brain Organoid Summer School.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1501036}, doi = {10.3389/fncel.2024.1501036}, pmid = {39564190}, issn = {1662-5102}, } @article {pmid39565466, year = {2025}, author = {Crowley, PD and Mira, P and Saleh, OMA}, title = {Minocycline susceptibility in Stenotrophomonas maltophilia: a closer look at institutional data amid CLSI breakpoint revisions.}, journal = {European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology}, volume = {44}, number = {2}, pages = {459-460}, doi = {10.1007/s10096-024-04995-5}, pmid = {39565466}, issn = {1435-4373}, mesh = {*Stenotrophomonas maltophilia/drug effects/isolation & purification ; *Anti-Bacterial Agents/pharmacology ; *Minocycline/pharmacology ; Humans ; Microbial Sensitivity Tests/standards ; Gram-Negative Bacterial Infections/microbiology/drug therapy ; }, abstract = {In this letter we respond Bakthavatchalam et al's brief report on susceptibility of Stenotrophomonas maltophilia to Minocycline in the setting of new susceptibility breakpoints. We outline our institution's experience with this organism and new data of susceptibility with the breakpoint of < 1 mg/L from the past 5 months showing 93.8% of 144 isolates remained susceptible.}, } @article {pmid39567371, year = {2024}, author = {Nuzum, ND and Deady, C and Kittel-Schneider, S and Cryan, JF and O'Mahony, SM and Clarke, G}, title = {More than just a number: the gut microbiota and brain function across the extremes of life.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2418988}, pmid = {39567371}, issn = {1949-0984}, mesh = {*Gastrointestinal Microbiome/physiology ; Humans ; *Brain/microbiology ; Animals ; Brain-Gut Axis/physiology ; Alzheimer Disease/microbiology/physiopathology ; Neurodegenerative Diseases/microbiology ; }, abstract = {Understanding the interrelationship between the gut microbiota and host physiology, although still in its relative infancy, has taken important steps forward over the past decade. In the context of brain disorders including those characterized by neurodevelopmental and neurodegenerative changes there have been important advances. However, initially research involved correlational analyses, had limited translational scope, and lacked functional assessments. Thus, largescale longitudinal clinical investigations that assess causation and underlying mechanisms via in depth analysis methods are needed. In neurodegeneration research, strong causal evidence now links the gut microbiome to Alzheimer's (AD), and Parkinson's Disease (PD), as supported by human-to-animal transplantation studies. Longitudinal interventions are being conducted in AD, PD, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Neurodevelopmental research has also seen a boon in microbiome-related clinical research including in autism, Attention-deficit/hyperactivity disorder, and schizophrenia, which is confirming prior animal model work regarding the key time-windows in the gut microbiome important for infant cognition. While recent research advances represent important progress, fundamental knowledge gaps and obstacles remain. Knowing how and why the gut microbiome changes at the extremes of life will develop our mechanistic understanding and help build the evidence base as we strive toward counteracting microbial missteps with precision therapeutic interventions.}, } @article {pmid39567497, year = {2024}, author = {Zhu, Z and Song, M and Ren, J and Liang, L and Mao, G and Chen, M}, title = {Copper homeostasis and cuproptosis in central nervous system diseases.}, journal = {Cell death & disease}, volume = {15}, number = {11}, pages = {850}, pmid = {39567497}, issn = {2041-4889}, mesh = {Humans ; *Copper/metabolism ; *Homeostasis ; *Central Nervous System Diseases/metabolism/pathology ; Animals ; }, abstract = {Copper (Cu), an indispensable micronutrient for the sustenance of living organisms, contributes significantly to a vast array of fundamental metabolic processes. The human body maintains a relatively low concentration of copper, which is mostly found in the bones, liver, and brain. Despite its low concentration, Cu plays a crucial role as an indispensable element in the progression and pathogenesis of central nervous system (CNS) diseases. Extensive studies have been conducted in recent years on copper homeostasis and copper-induced cell death in CNS disorders, including glioma, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease, and stroke. Cuproptosis, a novel copper-induced cell death pathway distinct from apoptosis, necrosis, pyroptosis, and ferroptosis, has been identified as potentially intricately linked to the pathogenic mechanisms underlying various CNS diseases. Therefore, a systematic review of copper homeostasis and cuproptosis and their relationship with CNS disorders could deepen our understanding of the pathogenesis of these diseases. In addition, it may provide new insights and strategies for the treatment of CNS disorders.}, } @article {pmid39568060, year = {2024}, author = {Abbas, AEF and Abdelshafi, NA and Gamal, M and Halim, MK and Said, BAM and Naguib, IA and Mansour, MMA and Morshedy, S and Salem, YA}, title = {Simultaneously quantifying a novel five-component anti- migraine formulation containing ergotamine, propyphenazone, caffeine, camylofin, and mecloxamine using UV spectrophotometry and chemometric models.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {233}, pmid = {39568060}, issn = {2661-801X}, support = {TU-DSPP-2024-49//Taif University/ ; }, abstract = {This study presents a new method for simultaneously quantifying a complex anti-migraine formulation containing five components (ergotamine, propyphenazone, caffeine, camylofin, and mecloxamine) using UV spectrophotometry and chemometric models. The formulation presents analytical challenges due to the wide variation in component concentrations (ERG: PRO: CAF: CAM: MEC ratio of 0.075:20:8:5:4) and highly overlapping UV spectra. To create a comprehensive validation dataset, the Kennard-Stone Clustering Algorithm was used to address the limitations of arbitrary data partitioning in chemometric methods. Three different chemometric models were evaluated: Classical Least Squares (CLS), Partial Least Squares (PLS), and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). Among these, MCR-ALS demonstrated excellent performance, achieving recovery values of 98-102% for all components, accompanied by minimal root mean square errors of calibration (0.072-0.378) and prediction (0.077-0.404). Moreover, the model exhibited high accuracy, with relative errors ranging from 1.936 to 3.121%, bias-corrected mean square errors between 0.074 and 0.389, and a good sensitivity (0.2097-1.2898 μg mL[-1]) for all components. The Elliptical Joint Confidence Region analysis further confirmed the predictive performance of the models, with MCR-ALS consistently showing the smallest ellipses closest to the ideal point (slope = 1, intercept = 0) for most analytes, indicating superior accuracy and precision. The approach's sustainability was rigorously assessed using six advanced metrics, validating its environmental friendliness, economic viability, and practical application. This approach effectively resolves complex pharmaceutical formulations, contributing to sustainable development objectives in quality control processes.}, } @article {pmid39568376, year = {2025}, author = {Held-Bradford, EC and Sells, M and Longhurst, JK and Doherty, M}, title = {Variation in amyotrophic lateral sclerosis presentation and outcomes based on phenotype and physical therapy movement system diagnosis: a case series.}, journal = {Physiotherapy theory and practice}, volume = {41}, number = {7}, pages = {1519-1528}, doi = {10.1080/09593985.2024.2430745}, pmid = {39568376}, issn = {1532-5040}, mesh = {Aged ; Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/therapy/rehabilitation ; Disability Evaluation ; Disease Progression ; Phenotype ; *Physical Therapy Modalities ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neuron disease and presentation varies. There is limited description of this variability and how physical therapy (PT) specific movement system diagnoses (MSD) may impact care.

PURPOSE: The purpose of this case series is to describe the variability of ALS presentation longitudinally across early, middle, and late stages of ALS based on phenotype and MSD.

METHODS: Four individuals were selected from an ALS clinic chart review representing a unique combination of phenotypes and MSDs (Case 1: bulbar onset force production deficit (FPD), Case 2: bulbar onset fractionated movement deficit (FMD), Case 3: limb onset FPD, Case 4: limb onset FMD). Descriptions of care over 9 years included outcomes of disability (ALS Functional Rating scale-revised), activity (10 Meter Walk Test, Five Times Sit to Stand Test, Trunk Impairment Scale-version 2), and impairment (strength and spasticity).

RESULTS: Persons with ALS were seen every 3 to 6 months (10 to 19 visits total). Determination of MSD was hardest to complete in early stage bulbar onset ALS. Patterns of decline through stages varied by MSD and phenotype, most notably in length of time in middle stage. Limb onset FMD had the slowest progression. Falls and fall related injuries were most frequent in limb onset ALS but falls occurred in all cases.

CONCLUSION: The combination of MSD and phenotype enhanced variability description offers new insights into clinical decision-making in ALS care.}, } @article {pmid39568840, year = {2024}, author = {Souayah, N and Chong, ZZ and Patel, T and Nasar, A and Pahwa, A and W Sander, H}, title = {Regression equation analysis enhances detection of conduction slowing beyond axonal loss in diabetic neuropathy.}, journal = {Heliyon}, volume = {10}, number = {21}, pages = {e39712}, pmid = {39568840}, issn = {2405-8440}, abstract = {OBJECTIVES: To evaluate the utility of regression analysis in the assessment of conduction slowing in diabetic distal symmetrical polyneuropathy (DSP) and in identifying superimposed demyelination beyond fiber loss.

BACKGROUND: Causes of conduction slowing beyond pure axonal loss has been attributed to an additional demyelinating component. We therefore evaluated the utility of regression analysis in the assessment of conduction slowing in diabetic DSP and in identifying superimposed demyelination beyond fiber loss.

METHODS: We previously established regression analysis to develop confidence intervals that assess the range of conduction slowing from primary demyelination in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). In this study, by using the regression equations, we analyzed conduction slowing in patients with diabetic DSP.

RESULTS: Mean conduction velocity (CV) was significantly slower in diabetic DSP than in the non-diabetic DSP for all tested nerves. More patients were found to fulfill the regression equation criteria in the diabetic group compared to the non-diabetic group (47.0 % vs. 23.3 %). The estimated likelihood of having more than two motor nerves with CV slowing in the demyelination range by American Academy of Neurology or regression equations criteria was significantly higher in the diabetic DSP (0.73) compared to non-diabetic DSP (0.52).

CONCLUSIONS: Conduction slowing in diabetic DSP beyond what is expected exclusively from axonal loss could be identified by regression analysis.}, } @article {pmid39569145, year = {2024}, author = {Mirceta, M and Schmidt, MHM and Shum, N and Prasolava, TK and Meikle, B and Lanni, S and Mohiuddin, M and Mckeever, PM and Zhang, M and Liang, M and van der Werf, I and Scheers, S and Dion, PA and Wang, P and Wilson, MD and Abell, T and Philips, EA and Sznajder, ŁJ and Swanson, MS and Mehkary, M and Khan, M and Yokoi, K and Jung, C and de Jong, PJ and Freudenreich, CH and McGoldrick, P and Yuen, RKC and Abrahão, A and Keith, J and Zinman, L and Robertson, J and Rogaeva, E and Rouleau, GA and Kooy, RF and Pearson, CE}, title = {C9orf72 expansion creates the unstable folate-sensitive fragile site FRA9A.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.10.26.620312}, pmid = {39569145}, issn = {2692-8205}, abstract = {The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72 Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. C9orf72 Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immuno-stimulatory or damaged DNA is unknown. Here, we show C9orf72 Exp in pre-symptomatic and ALS-FTD patient cells and brains cause the folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33kb of C9orf72 as highly-compacted chromatin embedded in an 8.2Mb fragility zone spanning 9p21, encompassing 46 genes, making FRA9A one of the largest fragile sites. C9orf72 Exp cells show chromosomal instability, heightened global- and Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s and Chr9-containing micronuclei, providing endogenous sources of damaged and immunostimulatory DNA. Cells from one C9orf72 Exp patient contained highly-rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic C9orf72 Exp repeat instability and chromosomal fragility are sensitive to folate-deficiency. Age-dependent repeat instability, chromosomal fragility, and chromosomal instability can be transferred to CNS and peripheral tissues of transgenic C9orf72 Exp mice, implicating C9orf72 Exp as the source. Our results highlight unappreciated effects of C9orf72 expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere.}, } @article {pmid39569650, year = {2025}, author = {Luo, S and Wang, X and Ma, B and Liu, D and Li, L and Wang, L and Ding, N and Zou, L and Wang, J and Pan, J and Sang, D and Zhou, H and Qu, H and Lu, Y and Yang, L}, title = {Therapeutic potential of simvastatin in ALS: Enhanced axonal integrity and motor neuron survival through Apoa4 and Alb modulation.}, journal = {Biomolecules & biomedicine}, volume = {25}, number = {3}, pages = {632-647}, pmid = {39569650}, issn = {2831-090X}, mesh = {*Simvastatin/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Motor Neurons/drug effects/pathology ; Cell Survival/drug effects/genetics ; Mice, Inbred C57BL ; Animals ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase-1/genetics ; *Apolipoproteins A/genetics/metabolism ; Gene Expression Regulation/drug effects ; *Albumins/genetics/metabolism ; Axons/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using hematoxylin and eosin staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression.}, } @article {pmid39569894, year = {2024}, author = {Brannigan, JFM and Liyanage, K and Horsfall, HL and Bashford, L and Muirhead, W and Fry, A}, title = {Brain-computer interfaces patient preferences: a systematic review.}, journal = {Journal of neural engineering}, volume = {21}, number = {6}, pages = {}, doi = {10.1088/1741-2552/ad94a6}, pmid = {39569894}, issn = {1741-2552}, mesh = {*Brain-Computer Interfaces ; Humans ; *Patient Preference ; Adult ; Middle Aged ; Spinal Cord Injuries/rehabilitation/psychology/physiopathology ; Amyotrophic Lateral Sclerosis/psychology/rehabilitation/physiopathology ; }, abstract = {Objective. Brain-computer interfaces (BCIs) have the potential to restore motor capabilities and functional independence in individuals with motor impairments. Despite accelerating advances in the performance of implanted devices, few studies have identified patient preferences underlying device design, and each study typically captures a single aetiology of motor impairment. We aimed to characterise BCI patient preferences in a large cohort across multiple aetiologies.Approach. We performed a systematic review of all published studies reporting patient preferences for BCI devices, including both qualitative and quantitative data. We searched MEDLINE, Embase, and CINAHL from inception to 18 April 2023. Two reviewers independently screened articles and extracted data on demographic information, device use, invasiveness preference, device design, and functional preferences.Main results. From 1316 articles identified, 28 studies met inclusion criteria, capturing preferences from 1701 patients (mean age 42.1-64.3 years). The most represented conditions were amyotrophic lateral sclerosis (n= 15 studies, 53.6%) and spinal cord injury (n= 13 studies 46.4%). Individuals with motor impairments prioritised device accuracy over other design characteristics. In four studies where patients ranked performance characteristics, accuracy was ranked first each time. We found that the speed and accuracy of BCI systems in recent publications exceeds reported patient preferences, however this performance has been achieved with a level of training and setup burden that would not be tolerated by most patients. Preferences varied by disease aetiology and severity; amyotrophic lateral sclerosis patients typically prioritised communication functions, whereas spinal cord injury patients emphasised limb control and sphincteric functions.Significance.Our findings highlight that despite advances in BCI performance exceeding patient expectations, there remains a need to reduce training and setup burdens to enhance usability. Moreover, patient preferences differ across conditions and impairment severities, underscoring the importance of personalised BCI configurations and tailored training regimens to meet individual needs.}, } @article {pmid39570437, year = {2025}, author = {Maity, D and Kaundal, RK}, title = {Exploring dysregulated miRNAs in ALS: implications for disease pathogenesis and early diagnosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {4}, pages = {1661-1686}, pmid = {39570437}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Humans ; *MicroRNAs/metabolism/genetics ; Early Diagnosis ; Biomarkers/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor neuron degeneration, leading to muscle weakness and paralysis, with no effective treatments available. Early diagnosis could slow disease progression and optimize treatment. MicroRNAs (miRNAs) are being investigated as potential biomarkers due to their regulatory roles in cellular processes and stability in biofluids. However, variability across studies complicates their diagnostic utility in ALS. This study aims to identify significantly dysregulated miRNAs in ALS through meta-analysis to elucidate disease mechanisms and improve diagnostic strategies.

METHODS: We systematically searched PubMed, Google Scholar, and the Cochrane Library, following predefined inclusion and exclusion criteria. The primary effect measure was the standardized mean difference (SMD) with a 95% confidence interval, analyzed using a random-effects model. Additionally, we used network pharmacology to examine the targets of dysregulated miRNAs and their roles in ALS pathology.

RESULTS: Analysing 34 studies, we found significant upregulation of hsa-miR-206, hsa-miR-133b, hsa-miR-23a, and hsa-miR-338-3p, and significant downregulation of hsa-miR-218, hsa-miR-21-5p, and hsa-let-7b-5p in ALS patients. These miRNAs are involved in ALS pathophysiology, including stress granule formation, nuclear pore complex, SMCR8 and Sig1R dysfunction, histone methyltransferase complex alterations, and MAPK signaling perturbation, highlighting their critical role in ALS progression.

CONCLUSION: This study identifies several dysregulated miRNAs in ALS patients, offering insights into their role in the disease and potential as diagnostic biomarkers. These findings enhance our understanding of ALS mechanisms and may inform future diagnostic strategies. Validating these results and exploring miRNA-based interventions are crucial for improving ALS diagnosis and treatment outcomes.}, } @article {pmid39570667, year = {2025}, author = {Burks, CA and Brenner, MJ}, title = {Commentary on Von Sneidern et al's "Evaluation and Treatment of Acute Facial Palsy: Opportunities for Optimization at a Single Institution."-Bridging the Gap Between Guidelines and Practice.}, journal = {Facial plastic surgery & aesthetic medicine}, volume = {27}, number = {4}, pages = {319-320}, doi = {10.1089/fpsam.2024.0263}, pmid = {39570667}, issn = {2689-3622}, } @article {pmid39571211, year = {2025}, author = {Wang, Z and Wu, P and Zhao, Y and Li, X and Kong, D}, title = {Application of excitation-emission matrix fluorescence spectroscopy and chemometrics for quantitative analysis of emulsified oil concentration.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {328}, number = {}, pages = {125423}, doi = {10.1016/j.saa.2024.125423}, pmid = {39571211}, issn = {1873-3557}, abstract = {Emulsified oil concentration is an important index for quantitative analysis of sea surface oil spill pollution, and the development of a fast and effective quantitative analysis method for emulsified oil concentration plays a crucial role in the estimation of oil spill volume and post-spill assessment. A quantitative analysis method for emulsified oil concentration based on excitation-emission matrix (EEM) fluorescence spectroscopy and chemometrics was proposed. Firstly, the EEM fluorescence spectra of two emulsified oils were measured using a FLS1000 fluorescence spectrometer. Then, the measured EEM fluorescence spectra were decomposed by parallel factor analysis (PARAFAC), and several key excitation wavelengths were filtered from the loading matrix obtained from the decomposition. Subsequently, the three-band fluorescence index (TBFI) at these excitation wavelengths was calculated and combined with the optimal band selection algorithm, from which the optimal emission band combinations were selected. Finally, the selected optimal emission bands were combined with partial least squares regression (PLSR) to establish a prediction model for emulsified oil concentration. By comparing the prediction results with those based on PARAFAC-PLSR and multivariate curve resolved-alternating least squares (MCR-ALS)-PLSR models, the TBFI-PLSR model showed the best results in the quantitative analysis of emulsified oil concentration. The coefficient of determination, mean square relative error, and ratio of performance to interquartile distance for the gasoline and diesel fuel emulsion validation sets were 0.93, 3.67%, 4.72, and 0.93, 3.72%, 4.60, respectively.}, } @article {pmid39571437, year = {2025}, author = {Parastar, H and Yazdanpanah, H and Weller, P}, title = {Non-targeted volatilomics for the authentication of saffron by gas chromatography-ion mobility spectrometry and multivariate curve resolution.}, journal = {Food chemistry}, volume = {465}, number = {Pt 2}, pages = {142074}, doi = {10.1016/j.foodchem.2024.142074}, pmid = {39571437}, issn = {1873-7072}, mesh = {*Crocus/chemistry ; *Ion Mobility Spectrometry/methods ; Food Contamination/analysis ; Gas Chromatography-Mass Spectrometry ; Volatile Organic Compounds/chemistry/analysis ; Discriminant Analysis ; Multivariate Analysis ; Principal Component Analysis ; Least-Squares Analysis ; Iran ; }, abstract = {In the present contribution, a novel non-targeted volatilomic study based on headspace GC-IMS (HS-GC-IMS) was developed for the authentication and geographical origin discrimination of saffron. In this regard, multivariate curve resolution-alternating least squares (MCR-ALS) was employed to recover the pure GC elution and IMS profiles of saffron metabolites. Iranian saffron samples from seven important areas were analyzed by HS-GC-IMS. The resulting second-order GC-IMS datasets were organized in a augmented matrix and processed using MCR-ALS with various constraints. The MCR-ALS resolved GC profiles were analyzed by different pattern recognition techniques; principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and data driven-soft independent modeling of class analogy (DD-SIMCA). The saffron samples were assigned to their seven geographical origins with an accuracy of 89.0 %. Additionally, four adulterants (style, safflower, madder and calendula) were reliably detected with over 94.0 % accuracy. In this context, GC-IMS substantially outperformed the commonly used FT-NIR spectroscopy approach.}, } @article {pmid39572209, year = {2025}, author = {Grassano, M}, title = {Navigating the presymptomatic frontier in genetic ALS and FTD.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {3}, pages = {205-207}, doi = {10.1136/jnnp-2024-334924}, pmid = {39572209}, issn = {1468-330X}, } @article {pmid39572211, year = {2025}, author = {Benatar, M and Heiman-Patterson, TD and Cooper-Knock, J and Brickman, D and Casaletto, KB and Goutman, SA and Vinceti, M and Dratch, L and Arias, JJ and Swidler, J and Turner, MR and Shefner, J and Westeneng, HJ and van den Berg, LH and Al-Chalabi, A and , }, title = {Guidance for clinical management of pathogenic variant carriers at elevated genetic risk for ALS/FTD.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {3}, pages = {209-218}, pmid = {39572211}, issn = {1468-330X}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; RF1 NS105479/NS/NINDS NIH HHS/United States ; U01 NS107027/NS/NINDS NIH HHS/United States ; R01 NS105479/NS/NINDS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; 216596/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Frontotemporal Dementia/genetics/therapy ; *Genetic Predisposition to Disease ; Genetic Testing ; Heterozygote ; }, abstract = {There is a growing understanding of the presymptomatic stages of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and nascent efforts aiming to prevent these devastating neurodegenerative diseases have emerged. This progress is attributable, in no small part, to the altruism of people living with pathogenic variants at elevated genetic risk for ALS/FTD via their willingness to participate in natural history studies and disease prevention trials. Increasingly, this community has also highlighted the urgent need to develop paradigms for providing appropriate clinical care for those at elevated risk for ALS and FTD. This manuscript summarises recommendations emanating from a multi-stakeholder Workshop (Malvern, Pennsylvania, 2023) that aimed to develop guidance for at-risk carriers and their treating physicians. Clinical care recommendations span genetic testing (including counselling and sociolegal implications); monitoring for the emergence of early motor, cognitive and behavioural signs of disease; and the use of Food and Drug Administration-approved small molecule drugs and gene-targeting therapies. Lifestyle recommendations focus on exercise, smoking, statin use, supplement use, caffeine intake and head trauma, as well as occupational and environmental exposures. While the evidence base to inform clinical and lifestyle recommendations is limited, this guidance document aims to appraise carriers and clinicians of the issues and best available evidence, and also to define the research agenda that could yield more evidence-informed guidelines.}, } @article {pmid39572390, year = {2025}, author = {Morales, JMN and Alcaraz, MR and Loto, A and Parellada, EA and Tulli, F and Morán Vieyra, FE and Borsarelli, CD}, title = {Chemometric modeling of spectroscopic data for characterizing the visible-light-driven photocatalytic N-dealkylation of rhodamine B on a TiO2 film.}, journal = {Photochemistry and photobiology}, volume = {101}, number = {4}, pages = {1000-1012}, doi = {10.1111/php.14043}, pmid = {39572390}, issn = {1751-1097}, support = {PIP-2020-101043CO//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PUE-2018-035//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PICT-2019-02052//Fondo para la Investigación Científica y Tecnológica/ ; 23A/254//Universidad Nacional de Santiago del Estero/ ; }, abstract = {The green-light driven photocatalytic N-deethylation reaction of Rhodamine B (RhB) on a TiO2 film was investigated by UV-vis absorption and fluorescence emission spectroscopies, in addition to HPLC and HR-MS, to ascertain the nature of the reaction products. The evolution of the photocatalytic reaction was chemometrically analyzed using Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) of the spectroscopic data to obtain the kinetic and spectral decomposition of the RhB derivatives involved in the reaction. This was then compared with the results obtained by standard HPLC analysis. The MCR-ALS analysis yielded satisfactory spectral and kinetic profiles for RhB and the fully deethylated product, Rhodamine 110. However, the spectral profiles for the N-triethyl (3EtRh) and the mixture of the two isomeric N-diethyl (2EtRh) derivatives exhibited some spectral distortions due to significant spectral overlap between these compounds. In contrast to the HPLC analysis, the MCR-ALS could not resolve the N-ethylrhodamine (EtRh) derivative. The deethylation reactions occurred via independent zero-order steps at the surface of TiO2, indicating that the RhB degradation reaction is governed by the adsorption-desorption equilibrium of the dye and derivatives on the photocatalyst surface, thereby enhancing the diffusion of compounds on the surface.}, } @article {pmid39572918, year = {2025}, author = {Changkakoti, L and Rajabalaya, R and David, SR and Balaraman, AK and Sivasubramanian, H and Mukherjee, AK and Bala, A}, title = {Exploration of the Role of Vitamins in Preventing Neurodegenerative Diseases: Comprehensive Review on Preclinical and Clinical Findings.}, journal = {Current neuropharmacology}, volume = {23}, number = {5}, pages = {547-563}, pmid = {39572918}, issn = {1875-6190}, mesh = {Humans ; *Neurodegenerative Diseases/prevention & control ; Animals ; *Vitamins/therapeutic use ; }, abstract = {Neurodegenerative diseases (NDDs) are a multifaceted and heterogeneous group of complex diseases. Unfortunately, a cure for these conditions has yet to be found, but there are ways to reduce the risk of developing them. Studies have shown that specific vitamins regulate the brain molecules and signaling pathways, which may help prevent degeneration. This review focuses on examining the role of vitamins in preventing five significant types of neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS). This review also highlights promising and controversial findings about the potential impact of vitamins on this group of diseases. Several developed countries standardize daily dietary vitamin intake to meet nutrient requirements, improve health, and prevent chronic diseases like NDDs. However, more research is necessary to gain a more comprehensive understanding of their therapeutic benefits, including studies exploring different drug-dose paradigms, diverse humanized animal models, and clinical trials conducted in various locations.}, } @article {pmid39574440, year = {2024}, author = {Kaur, N and Verma, AK and Girdhar, M and Kumar, A and Siddiqui, MA and Al-Khedhairy, AA and Malik, T and Mohan, A}, title = {Genome-wide analysis of the Cannabis sativa cytochrome P450 monooxygenase superfamily and uncovering candidate genes for improved herbicide tolerance.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1490036}, pmid = {39574440}, issn = {1664-462X}, abstract = {Cannabis sativa is an economically important crop, yet weed management remains a significant challenge due to limited herbicide options. Cytochrome P450 enzymes play crucial roles in plant metabolism, including herbicide detoxification. This study aimed to identify and characterize the CYP gene family in Cannabis and investigate their potential role in herbicide metabolism. We identified 225 CYP proteins encoded by 221 genes in the Cannabis genome, classified into 9 clans and 47 families. The majority of CsCYPs were predicted to be located in endomembrane system and chromosomal mapping revealed that they were present in all the chromosomes. Motif and gene structure analysis supported the results from phylogenetic analysis. The gene duplication analysis results showed that tandem duplication plays a pivotal role in evolutionary expansion of CsCYP superfamily. Promoter analysis revealed various cis-acting elements involved in stress, light, hormone and development responses. Molecular docking simulations identified several CsCYPs with strong binding affinities to ALS-inhibiting herbicides, particularly bispyribac-sodium, propoxycarbazone-sodium, and pyriftalid. CsCYP_215, CsCYP_213, CsCYP_217 and CsCYP_14 emerged as promising candidates for herbicide metabolism. Analysis of binding site residues revealed the importance of hydrophobic and aromatic interactions in herbicide binding. This study provides the first comprehensive characterization of the CYP gene family in C. sativa and offers new insights into their potential roles in herbicide metabolism. The identification of promising herbicide-metabolizing CYP candidates opens new avenues for developing herbicide-tolerant Cannabis varieties, potentially addressing key challenges in weed management and crop productivity.}, } @article {pmid39574607, year = {2024}, author = {Fürtjes, AE and Foote, IF and Xia, C and Davies, G and Moodie, J and Taylor, A and Liewald, DC and Redmond, P and Corley, J and McIntosh, AM and Whalley, HC and Maniega, SM and Hernández, MV and Backhouse, E and Ferguson, K and Bastin, ME and Wardlaw, J and de la Fuente, J and Grotzinger, AD and Luciano, M and Hill, WD and Deary, IJ and Tucker-Drob, EM and Cox, SR}, title = {Lifetime brain atrophy estimated from a single MRI: measurement characteristics and genome-wide correlates.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39574607}, issn = {2692-8205}, support = {MR/M013111/1/MRC_/Medical Research Council/United Kingdom ; P2C HD042849/HD/NICHD NIH HHS/United States ; R01 AG073593/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 MH120219/MH/NIMH NIH HHS/United States ; P30 AG066614/AG/NIA NIH HHS/United States ; U54 MH091657/MH/NIMH NIH HHS/United States ; }, abstract = {A measure of lifetime brain atrophy (LBA) obtained from a single magnetic resonance imaging (MRI) scan could be an attractive candidate to boost statistical power in uncovering novel genetic signals and mechanisms of neurodegeneration. We analysed data from five young and old adult cohorts (MRi-Share, Human Connectome Project, UK Biobank, Generation Scotland Subsample, and Lothian Birth Cohort 1936 [LBC1936]) to test the validity and utility of LBA inferred from cross-sectional MRI data, i.e., a single MRI scan per participant. LBA was simply calculated based on the relationship between total brain volume (TBV) and intracranial volume (ICV), using three computationally distinct approaches: the difference (ICV-TBV), ratio (TBV/ICV), and regression-residual method (TBV~ICV). LBA derived with all three methods were substantially correlated with well-validated neuroradiological atrophy rating scales (r = 0.37-0.44). Compared with the difference or ratio method, LBA computed with the residual method most strongly captured phenotypic variance associated with cognitive decline (r = 0.36), frailty (r = 0.24), age-moderated brain shrinkage (r = 0.45), and longitudinally-measured atrophic changes (r = 0.36). LBA computed using a difference score was strongly correlated with baseline (i.e., ICV; r = 0.81) and yielded GWAS signal similar to ICV (rg = 0.75). We performed the largest genetic study of LBA to date (N = 43,110), which was highly heritable (h [2] SNP GCTA = 41% [95% CI = 38-43%]) and had strong polygenic signal (LDSC h [2] = 26%; mean χ2 = 1.23). The strongest association in our genome-wide association study (GWAS) implicated WNT16, a gene previously linked with neurodegenerative diseases such as Alzheimer, and Parkinson disease, and amyotrophic lateral sclerosis. This study is the first side-by-side evaluation of different computational approaches to estimate lifetime brain changes and their measurement characteristics. Careful assessment of methods for LBA computation had important implications for the interpretation of existing phenotypic and genetic results, and showed that relying on the residual method to estimate LBA from a single MRI scan captured brain shrinkage rather than current brain size. This makes this computationally-simple definition of LBA a strong candidate for more powerful analyses, promising accelerated genetic discoveries by maximising the use of available cross-sectional data.}, } @article {pmid39574800, year = {2024}, author = {Bouajila, N and Domenighetti, C and Aubin, HJ and Naassila, M}, title = {Alcohol consumption and its association with cancer, cardiovascular, liver and brain diseases: a systematic review of Mendelian randomization studies.}, journal = {Frontiers in epidemiology}, volume = {4}, number = {}, pages = {1385064}, pmid = {39574800}, issn = {2674-1199}, abstract = {BACKGROUND: The health effects of alcohol consumption, particularly regarding potential protective benefits of light to moderate intake compared to abstinence, remain a subject of ongoing debate. However, epidemiological studies face limitations due to imprecise exposure measurements and the potential for bias through residual confounding and reverse causation. To address these limitations, we conducted a systematic review of Mendelian Randomization (MR) studies examining the causal relationship between alcohol consumption and cancers, cardiovascular, liver, and neurological diseases.

METHODOLOGY: We searched PubMed, ScienceDirect and Embase and Europe PMC up to 05/2024 for MR studies investigating the association of genetically predicted alcohol consumption with cancers, cardiovascular, liver and neurological diseases. We assessed methodological quality based on key elements of the MR design a genetic association studies tool.

RESULTS: We included 70 MR studies that matched our inclusion criteria. Our review showed a significant association of alcohol consumption with multiple cancers such as oral and oropharyngeal, esophageal, colorectal cancers, hepatocellular carcinoma and cutaneous melanoma. While the available studies did not consistently confirm the adverse or protective effects of alcohol on other cancers, such as lung cancer, as suggested by observational studies. Additionally, MR studies confirmed a likely causal effect of alcohol on the risk of hypertension, atrial fibrillation, myocardial infraction and vessels disease. However, there was no evidence to support the protective effects of light to moderate alcohol consumption on cognitive function, Alzheimer's disease, and amyotrophic lateral sclerosis, as reported in observational studies while our review revealed an increased risk of epilepsy and multiple sclerosis. The available studies provided limited results on the link between alcohol consumption and liver disease.

CONCLUSIONS: Despite the valuable insights into the causal relationship between alcohol consumption and various health outcomes that MR studies provided, it is worth noting that the inconsistent ability of genetic instrumental variables to distinguish between abstainers, light and moderate drinkers makes it difficult to differentiate between U or J-shaped vs. linear relationships between exposure and outcome. Additional research is necessary to establish formal quality assessment tools for MR studies and to conduct more studies in diverse populations, including non-European ancestries.

www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021246154, Identifier: PROSPERO (CRD42021246154).}, } @article {pmid39574866, year = {2024}, author = {Manohar, R and Yang, FX and Stephen, CD and Schmahmann, JD and Eklund, NM and Gupta, AS}, title = {At-home wearables and machine learning capture motor impairment and progression in adult ataxias.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39574866}, support = {R01 NS117826/NS/NINDS NIH HHS/United States ; R01 NS134597/NS/NINDS NIH HHS/United States ; }, abstract = {A significant barrier to developing disease-modifying therapies for spinocerebellar ataxias (SCAs) and multiple system atrophy of the cerebellar type (MSA-C) is the scarcity of tools to sensitively measure disease progression in clinical trials. Wearable sensors worn continuously during natural behavior at home have the potential to produce ecologically valid and precise measures of motor function by leveraging frequent and numerous high-resolution samples of behavior. Here we test whether movement-building block characteristics (i.e., submovements), obtained from the wrist and ankle during natural behavior at home, can sensitively capture disease progression in SCAs and MSA-C, as recently shown in amyotrophic lateral sclerosis (ALS) and ataxia telangiectasia (A-T). Remotely collected cross-sectional (n = 76) and longitudinal data (n = 27) were analyzed from individuals with ataxia (SCAs 1, 2, 3, and 6, MSA-C) and controls. Machine learning models were trained to produce composite outcome measures based on submovement properties. Two models were trained on data from individuals with ataxia to estimate ataxia rating scale scores. Two additional models, previously trained entirely on longitudinal ALS data to optimize sensitivity to change, were also evaluated. All composite outcomes from both wrist and ankle sensor data had moderate to strong correlations with ataxia rating scales and self-reported function, strongly separated ataxia and control populations, and had high within-week reliability. The composite outcomes trained on longitudinal ALS data most strongly captured disease progression over time. These data demonstrate that outcome measures based on accelerometers worn at home can accurately capture the ataxia phenotype and sensitively measure disease progression. This assessment approach is scalable and can be used in clinical or research settings with relatively low individual burden.}, } @article {pmid39575564, year = {2025}, author = {Olofsson, J and Bergström, S and Mravinacová, S and Kläppe, U and Öijerstedt, L and Zetterberg, H and Blennow, K and Ingre, C and Nilsson, P and Månberg, A}, title = {Cerebrospinal fluid levels of NfM in relation to NfL and pNfH as prognostic markers in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {113-123}, doi = {10.1080/21678421.2024.2428930}, pmid = {39575564}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/mortality ; *Neurofilament Proteins/cerebrospinal fluid ; Male ; Female ; Middle Aged ; Prognosis ; Biomarkers/cerebrospinal fluid ; Aged ; Disease Progression ; Adult ; Cohort Studies ; Sweden ; }, abstract = {OBJECTIVE: To evaluate the prognostic potential of neurofilament medium chain (NfM) in CSF from patients with ALS and explore its relationship with the extensively studied neurofilament light chain (NfL) and phosphorylated heavy chain (pNfH).

METHOD: CSF levels of NfL, NfM, and pNfH were analyzed in 235 samples from patients with ALS, ALS mimics, and healthy controls in a well-characterized cohort from Karolinska ALS Clinical Research Center in Stockholm, Sweden. NfM levels were analyzed using an antibody-based suspension bead-array and NfL and pNfH levels were measured using ELISA. Clinical data, including ALS Revised Functional Rating Scale (ALSFRS-R), and survival outcomes were utilized for disease progression estimations.

RESULT: Increased NfM levels were observed in patients with ALS compared with mimics and healthy controls. Similarly, higher NfM levels were found in fast compared with slow progressing patients for baseline and longitudinal progression when evaluating both total and subscores of ALSFRS-R. These findings were consistent with the results observed for NfL and pNfH. All three proteins, used individually as well as in combination, showed comparable performance when classifying fast vs slow progressing patients (AUCs 0.78-0.85). For all neurofilaments, higher survival probability was observed for patients with low CSF levels.

CONCLUSION: Based on this cross-sectional study, the prognostic value provided by NfM aligns with the more established markers, NfL and pNfH. Additional investigations with independent cohorts and longitudinal studies are needed to further assess the potential added value of NfM.}, } @article {pmid39575748, year = {2024}, author = {Xu, Z and He, S and Begum, MM and Han, X}, title = {Myelin Lipid Alterations in Neurodegenerative Diseases: Landscape and Pathogenic Implications.}, journal = {Antioxidants & redox signaling}, volume = {41}, number = {16-18}, pages = {1073-1099}, pmid = {39575748}, issn = {1557-7716}, support = {P30 AG013319/AG/NIA NIH HHS/United States ; P30 AG044271/AG/NIA NIH HHS/United States ; R01 AG061729/AG/NIA NIH HHS/United States ; R01 AG085545/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Myelin Sheath/metabolism ; *Lipid Metabolism ; Animals ; Lipids ; }, abstract = {Significance: Lipids, which constitute the highest portion (over 50%) of brain dry mass, are crucial for brain integrity, energy homeostasis, and signaling regulation. Emerging evidence revealed that lipid profile alterations and abnormal lipid metabolism occur during normal aging and in different forms of neurodegenerative diseases. Moreover, increasing genome-wide association studies have validated new targets on lipid-associated pathways involved in disease development. Myelin, the protective sheath surrounding axons, is crucial for efficient neural signaling transduction. As the primary site enriched with lipids, impairments of myelin are increasingly recognized as playing significant and complex roles in various neurodegenerative diseases, beyond simply being secondary effects of neuronal loss. Recent Advances: With advances in the lipidomics field, myelin lipid alterations and their roles in contributing to or reflecting the progression of diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others, have recently caught great attention. Critical Issues: This review summarizes recent findings of myelin lipid alterations in the five most common neurodegenerative diseases and discusses their implications in disease pathogenesis. Future Directions: By highlighting myelin lipid abnormalities in neurodegenerative diseases, this review aims to encourage further research focused on lipids and the development of new lipid-oriented therapeutic approaches in this area. Antioxid. Redox Signal. 00, 000-000.}, } @article {pmid39577115, year = {2024}, author = {Abdian, S and Fakhri, S and Moradi, SZ and Khirehgesh, MR and Echeverría, J}, title = {Saffron and its major constituents against neurodegenerative diseases: A mechanistic review.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {135}, number = {}, pages = {156097}, doi = {10.1016/j.phymed.2024.156097}, pmid = {39577115}, issn = {1618-095X}, mesh = {Animals ; Humans ; *Carotenoids/pharmacology/therapeutic use ; *Crocus/chemistry ; Cyclohexenes/pharmacology ; Glucosides/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/chemistry/pharmacology ; Phytochemicals/pharmacology ; *Plant Extracts/chemistry/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Terpenes/pharmacology ; Vitamin A/analogs & derivatives ; }, abstract = {BACKGROUND: Neurodegeneration has been recognized as the main pathophysiological alteration in the majority of brain-related diseases. Despite contemporary attempts to provide acceptable medicinal therapies, the conclusion has not been much beneficial. Besides, the complex pathophysiological mechanisms behind neurodegenerative diseases (NDDs) urge the needs for finding novel multi-target agents. Accordingly, saffron with major active constituents and as multi-targeting agents have shown beneficial effects in modulating NDDs with higher efficacy and lower side effects.

PURPOSE: The present study provides a systematic and comprehensive review of the existing in vitro, in vivo, and clinical data on the effectiveness, and signaling pathways of saffron and its key phytochemical components in the management of NDDs. The need to develop novel saffron delivery systems is also considered.

METHODS: Studies were identified through a systematic and comprehensive search in Science Direct, PubMed, and Scopus databases through April 30, 2024. The whole saffron major constituents (e.g., saffron, crocin, crocetin, picrocrocin, and safranal) and NDDs (e.g., neuro*, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Huntington*, Parkinson*, Alzheimer*, and brain) were selected as keywords to find related studies. In the systematic analysis, 64 articles were directly included in the current study. Additional reports were added within the comprehensive studies in the review.

RESULTS: Saffron and its active metabolites crocin, crocetin, safranal, and picrocrocin have shown acceptable efficacy in managing NDDs like Alzheimer's disease, Parkinson's disease, Attention deficit hyperactivity disorder, depression, and other NDDs via modulating apoptotic (e.g., caspases, Bax/Bcl-2, cytochrome c, and death receptors), inflammatory (e.g., NF-κB, IL-1β, IL-6, TNF-α, and COX-2), and oxidative strass (e.g., Nrf2, GSH, GPx, CAT, SOD, MDA, ROS, and nitrite) signaling pathways. The presented in vitro, in vivo, and clinical evidences showed us a better future of controlling NDDs with higher efficacy, while decreasing associated side effects with no significant toxicity. Additionally, employing novel delivery systems could increase the efficacy of saffron phytoconstituents to resolve the issues pharmacokinetic limitations.

CONCLUSION: Saffron and its major constituents employ anti-inflammatory, anti-apoptotic and antioxidant mechanisms in modulating several dysregulated-signaling pathways in NDDs. However, further research is necessary to elucidate the precise underlying mechanisms in exploring the feasibility of using saffron active compounds against NDDs. More studies should focus on dose-response relationships, long-term effects, highlighting key mechanisms, and designing more well-controlled clinical trials. Additionally, developing stable and cost-benefit novel delivery systems in future works helps to remove the pharmacokinetic limitations of saffron major constituents.}, } @article {pmid39577228, year = {2025}, author = {Sojdeh, S and Safarkhani, M and Daneshgar, H and Aldhaher, A and Heidari, G and Nazarzadeh Zare, E and Iravani, S and Zarrabi, A and Rabiee, N}, title = {Promising breakthroughs in amyotrophic lateral sclerosis treatment through nanotechnology's unexplored frontier.}, journal = {European journal of medicinal chemistry}, volume = {282}, number = {}, pages = {117080}, doi = {10.1016/j.ejmech.2024.117080}, pmid = {39577228}, issn = {1768-3254}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Nanotechnology ; Genetic Therapy ; Animals ; Drug Delivery Systems ; Neuroprotective Agents/chemistry/therapeutic use/pharmacology ; }, abstract = {This review explores the transformative potential of nanotechnology in the treatment and diagnosis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder characterized by motor neuron degeneration, muscle weakness, and eventual paralysis. Nanotechnology offers innovative solutions across various domains, including targeted drug delivery, neuroprotection, gene therapy and editing, biomarker detection, advanced imaging techniques, and tissue engineering. By enhancing the precision and efficacy of therapeutic interventions, nanotechnology facilitates key advancements such as crossing the blood-brain barrier, targeting specific cell types, achieving sustained therapeutic release, and enabling combination therapies tailored to the complex pathophysiology of ALS. Despite its immense promise, the clinical translation of these approaches faces challenges, including potential cytotoxicity, biocompatibility, and regulatory compliance, which must be addressed through rigorous research and testing. This review emphasizes the application of nanotechnology in targeted drug delivery and gene therapy/editing for ALS, drawing on the author's prior work with various nanotechnological platforms to illustrate strategies for overcoming similar obstacles in drug and gene delivery. By bridging the gap between cutting-edge technology and clinical application, this article aims to highlight the vital role of nanotechnology in shaping the future of ALS treatment.}, } @article {pmid39577621, year = {2025}, author = {Reiche, L and Plaack, B and Lehmkuhl, M and Weyers, V and Gruchot, J and Picard, D and Perron, H and Remke, M and Knobbe-Thomsen, C and Reifenberger, G and Küry, P and Kremer, D}, title = {HERV-W envelope protein is present in microglial cells of the human glioma tumor microenvironment and differentially modulates neoplastic cell behavior.}, journal = {Microbes and infection}, volume = {27}, number = {5-6}, pages = {105460}, doi = {10.1016/j.micinf.2024.105460}, pmid = {39577621}, issn = {1769-714X}, mesh = {Humans ; *Microglia/virology/metabolism ; *Tumor Microenvironment ; *Endogenous Retroviruses ; Cell Line, Tumor ; *Glioma/virology/pathology ; Cell Movement ; Cell Proliferation ; *Gene Products, env/metabolism ; Cytokines/metabolism ; Coculture Techniques ; }, abstract = {Gliomas are the most common parenchymal tumors of the central nervous system (CNS). With regard to their still unclear etiology, several recent studies have provided evidence of a new category of pathogenic elements called human endogenous retroviruses (HERVs) which seem to contribute to the evolution and progression of many neurological diseases such as amyotrophic lateral sclerosis (ALS), schizophrenia, chronic inflammatory polyneuropathy (CIDP) and, particularly, multiple sclerosis (MS). In these diseases, HERVs exert effects on cellular processes such as inflammation, proliferation, and migration. In previous studies, we demonstrated that in MS, the human endogenous retrovirus type-W envelope protein (HERV-W ENV) interferes with lesion repair through the activation of microglia (MG), the innate myeloid immune cells of the CNS. Here, we now show that HERV-W ENV is also present in the microglial cells (MG) of the tumor microenvironment (TME) in gliomas. It modulates the behavior of glioblastoma (GBM) cell lines in GBM/MG cocultures by altering their gene expression, secreted cytokines, morphology, proliferation, and migration properties and could thereby contribute to key tumor properties.}, } @article {pmid39577687, year = {2025}, author = {Li, Z and Zhang, Y and Li, D and Du, X and Chen, L and Guo, Y}, title = {Microglial upregulation of CD109 expression in spinal cord of amyotrophic lateral sclerosis mouse model and its role in modulating inflammation and TGFβ/SMAD pathway.}, journal = {Neuroscience}, volume = {564}, number = {}, pages = {202-213}, doi = {10.1016/j.neuroscience.2024.11.053}, pmid = {39577687}, issn = {1873-7544}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Microglia/metabolism ; *Spinal Cord/metabolism/pathology ; *Up-Regulation ; Mice ; *Smad Proteins/metabolism ; *Signal Transduction/physiology ; *Disease Models, Animal ; *Antigens, CD/metabolism ; *Transforming Growth Factor beta/metabolism ; Mice, Transgenic ; Inflammation/metabolism ; Lipopolysaccharides/pharmacology ; Transforming Growth Factor beta1/metabolism ; }, abstract = {CD109 is a multifunctional coreceptor, whose function has been widely studied in tumor progression and metastasis. One of the reported primary roles of CD109 involves down-regulating TGFβ signaling. However, the role of CD109 in central nervous system, especially neurodegenerative disease, is barely known. Here, we examined the expression changes and cellular location of CD109 and TGFβ/SMAD pathway molecules in lumbar spinal cord of SOD1-G93A mice, and explored the role and mechanism of CD109 on LPS-treated BV2 microglia and primary microglia derived from SOD1-G93A mice. Our results showed an increased expression of CD109 and TGFβ/SMAD pathway molecules in lumbar spinal cord of SOD1-G93A mice. Further cellular localization analysis demonstrated that proliferating microglia contributed mainly to the upregulation of CD109 and TGFβ1. Moreover, CD109 intervention in vitro partially reduced inflammatory response and TGFβ/SMAD pathway activation in both LPS-treated BV2 microglia and primary SOD1-G93A microglia. Thus, CD109 was involved in pathogenesis of ALS mice, and interventions targeting on CD109 modulation could be a potential therapeutic strategy for ALS.}, } @article {pmid39577774, year = {2025}, author = {Olesen, MA and Villavicencio-Tejo, F and Cuevas-Espinoza, V and Quintanilla, RA}, title = {Unknown roles of tau pathology in neurological disorders. Challenges and new perspectives.}, journal = {Ageing research reviews}, volume = {103}, number = {}, pages = {102594}, doi = {10.1016/j.arr.2024.102594}, pmid = {39577774}, issn = {1872-9649}, mesh = {Humans ; *tau Proteins/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; Tauopathies/metabolism/pathology ; Aging/metabolism/pathology ; }, abstract = {Aging presents progressive changes that increase the susceptibility of the central nervous system (CNS) to suffer neurological disorders (NDs). Several studies have reported that an aged brain suffering from NDs shows the presence of pathological forms of tau protein, a microtubule accessory protein (MAP) critical for neuronal function. In this context, accumulative evidence has shown a pivotal contribution of pathological forms of tau to Alzheimer's disease (AD) and tauopathies. However, current investigations have implicated tau toxicity in other NDs that affect the central nervous system (CNS), including Parkinson's disease (PD), Huntington's disease (HD), Traumatic brain injury (TBI), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). These diseases are long-term acquired, affecting essential functions such as motor movement, cognition, hearing, and vision. Previous evidence indicated that toxic forms of tau do not have a critical contribution to the genesis or progression of these diseases. However, recent studies have shown that these tau forms contribute to neuronal dysfunction, inflammation, oxidative damage, and mitochondrial impairment events that contribute to the pathogenesis of these NDs. Recent studies have suggested that these neuropathologies could be associated with a prion-like behavior of tau, which induces a pathological dissemination of these toxic protein forms to different brain areas. Moreover, it has been suggested that this toxic propagation of tau from neurons into neighboring cells impairs the function of glial cells, oligodendrocytes, and endothelial cells by affecting metabolic function and mitochondrial health and inducing oxidative damage by tau pathology. Therefore, in this review, we will discuss current evidence demonstrating the critical role of toxic tau forms on NDs not related to AD and how its propagation and induced-bioenergetics failure may contribute to the pathogenic mechanism present in these NDs.}, } @article {pmid39577830, year = {2025}, author = {Morikawa, K and Izumiya, Y and Takashio, S and Kawano, Y and Oguni, T and Kuyama, N and Oike, F and Yamamoto, M and Tabata, N and Ishii, M and Hanatani, S and Hoshiyama, T and Kanazawa, H and Matsuzawa, Y and Usuku, H and Yamamoto, E and Ueda, M and Tsujita, K}, title = {Early experience with daratumumab-containing regimens in patients with light-chain cardiac amyloidosis.}, journal = {Journal of cardiology}, volume = {85}, number = {6}, pages = {440-446}, doi = {10.1016/j.jjcc.2024.11.003}, pmid = {39577830}, issn = {1876-4738}, mesh = {Humans ; Male ; Aged ; Female ; *Immunoglobulin Light-chain Amyloidosis/drug therapy/mortality ; *Antibodies, Monoclonal/administration & dosage/therapeutic use ; Middle Aged ; Retrospective Studies ; Survival Rate ; Treatment Outcome ; *Heart Diseases/drug therapy/mortality ; }, abstract = {BACKGROUND: Immunoglobulin light-chain (AL) amyloidosis is a lethal condition resulting from misfolded immunoglobulin ALs produced by clonal CD38-positive plasma cells. Treatment with daratumumab, an anti-human CD38 monoclonal antibody, led to higher frequencies of complete hematologic response and better clinical outcomes compared with conventional treatment. This study sought to evaluate the survival benefit of daratumumab-containing regimens in patients with AL cardiac amyloidosis.

METHODS AND RESULTS: We examined 65 consecutive patients with AL cardiac amyloidosis (mean age: 67.2 ± 10.4 years, male: 69 %) who underwent chemotherapy. We divided patients into a daratumumab group, which used daratumumab-containing regimens before second-line treatment (n = 32), and a conventional treatment group (n = 33). Compared with the conventional treatment group, the daratumumab group tended to be older, but there were no significant differences between groups in biomarkers and echocardiographic parameters. A total of 26 patients (40 %) died (median follow-up duration: 395 days). Kaplan-Meier survival analysis showed that the daratumumab group had significantly lower mortality compared with the conventional treatment group (p = 0.04; log-rank test). Cox hazard analysis revealed that use of daratumumab-containing regimens was associated with lower mortality after adjustment for the revised Mayo staging of AL amyloidosis (hazard ratio: 0.32; 95 % confidence interval: 0.12 to 0.85; p = 0.02).

CONCLUSION: Daratumumab-containing regimens may be associated with improved survival in patients with AL cardiac amyloidosis.}, } @article {pmid39578133, year = {2025}, author = {Travaglia, A and Lal, S and Pullagura, SR}, title = {Advancing ALS research: public-private partnerships to accelerate drug and biomarker development.}, journal = {Trends in neurosciences}, volume = {48}, number = {1}, pages = {1-2}, doi = {10.1016/j.tins.2024.10.008}, pmid = {39578133}, issn = {1878-108X}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Public-Private Sector Partnerships ; Biomarkers ; *Drug Development ; *Drug Discovery ; *Biomedical Research ; }, abstract = {Developing effective treatments for amyotrophic lateral sclerosis (ALS) has been hindered by both the complexity of the disease and decentralized research efforts. By fostering collaboration, standardization, and inclusivity, the Accelerating Medicines Partnership® (AMP®) ALS initiative aims to lay the foundation for future discoveries in ALS biomarkers and treatments.}, } @article {pmid39578404, year = {2025}, author = {Phrathep, DD and Abdo, Z and Tadros, M and Lewandowski, E and Evans, J}, title = {The role of osteopathic manipulative treatment for dystonia: a literature review.}, journal = {Journal of osteopathic medicine}, volume = {125}, number = {4}, pages = {203-211}, pmid = {39578404}, issn = {2702-3648}, mesh = {Humans ; *Manipulation, Osteopathic/methods ; *Dystonia/therapy ; }, abstract = {CONTEXT: Dystonia is a movement disorder that causes involuntary muscle contractions leading to abnormal movements and postures, such as twisting. Dystonia is the third most common movement disorder in the United States, with as many as 250,000 people affected. Because of its complexity, dystonia presents a significant challenge in terms of management and treatment. Despite limited research, osteopathic manipulative treatment (OMT) has been considered as an adjunctive treatment due to its inexpensive and noninvasive nature, as opposed to other modalities such as botulinum toxin injections, deep brain stimulation (DBS), and transcranial magnetic stimulation, which are often expensive and inaccessible. OMT treatments performed in case studies and series such as balanced ligamentous tension/articular ligamentous strain (BLT/ALS), muscle energy (ME), high-velocity low-amplitude (HVLA), and myofascial release (MFR) have shown reduction of pain and muscle hypertonicity, including in patients with dystonia.

OBJECTIVES: The studies reviewed in this paper provide a snapshot of the literature regarding the current evidence of OMT's role for dystonia.

METHODS: A medical reference librarian conducted a thorough literature search across multiple databases including PubMed and Google Scholar to find articles relevant to the use of OMT for dystonia. The search employed a combination of Medical Subject Headings (MeSH) terms and keywords related to osteopathic medicine and dystonia to ensure precise retrieval of relevant articles within the last 20 years. Despite limited research on the topic, all four relevant reports found in the literature were selected for review.

RESULTS: Of the four relevant reports, case series and studies highlighted the potential benefits of OMT in managing dystonia, particularly cervical dystonia and foot dystonia. OMT has shown promising results addressing pain, stiffness, and impaired motor function. In cases of foot dystonia in Parkinson's disease, OMT has helped improve gait and reduce pain by targeting somatic dysfunctions (SDs) associated with dystonia, such as abnormalities in foot progression angle (FPA) and musculoskeletal imbalances. Also, OMT has been found to alleviate symptoms of cervical dystonia, including tremors, muscle spasms, and neck stiffness. These interventions performed in case studies and series led to improvements in gait biomechanics in foot dystonia and overall symptom severity in patients with cervical dystonia.

CONCLUSIONS: Currently, botulinum toxin, oral medications, physical therapy, and rehabilitation are commonly utilized in managing dystonia. The studies reviewed in this paper suggest that these treatments may lead to improvements in pain and muscle hypertonicity in patients with dystonia. It is important to investigate whether factors such as the type of dystonia (eg, focal vs. segmental) and its underlying cause (eg, idiopathic, trauma, infection, autoimmune, medication side effects) influence treatment outcomes. Further research is recommended to explore the role of OMT in managing dystonia.}, } @article {pmid39579350, year = {2024}, author = {Alfahel, L and Rajkovic, A and Israelson, A}, title = {Protocol for handling and using SOD1 mice for amyotrophic lateral sclerosis pre-clinical studies.}, journal = {STAR protocols}, volume = {5}, number = {4}, pages = {103459}, pmid = {39579350}, issn = {2666-1667}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Superoxide Dismutase-1/genetics/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; Female ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that has no proper cure. Pre-clinical studies on ALS mice are an essential milestone toward clinical trials. Here, we present a protocol for handling and using SOD1[G37R] mice for ALS pre-clinical studies. We describe steps for breeding, genotyping, monitoring, and behavioral testing of mice. We then detail procedures for perfusion, organ harvesting, and immunostaining for postmortem analysis. This protocol can be easily modified for other mouse lines. For complete details on the use and execution of this protocol, please refer to Alfahel et al.[1].}, } @article {pmid39579963, year = {2024}, author = {Carracedo, S and Launay, A and Dechelle-Marquet, PA and Faivre, E and Blum, D and Delarasse, C and Boué-Grabot, E}, title = {Purinergic-associated immune responses in neurodegenerative diseases.}, journal = {Progress in neurobiology}, volume = {243}, number = {}, pages = {102693}, doi = {10.1016/j.pneurobio.2024.102693}, pmid = {39579963}, issn = {1873-5118}, mesh = {Humans ; *Neurodegenerative Diseases/immunology/metabolism ; Animals ; *Receptors, Purinergic/metabolism ; }, abstract = {The chronic activation of immune cells can participate in the development of pathological conditions such as neurodegenerative diseases including Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, compelling evidence indicates that purinergic signaling plays a key role in neuro-immune cell functions. The extracellular release of adenosine 5'-triphosphate (ATP), and its breakdown products (ADP and adenosine) provide the versatile basis for complex purinergic signaling through the activation of several families of receptors. G-protein coupled adenosine A2A receptors, ionotropic P2X and G-protein coupled P2Y receptors for ATP and other nucleotides are abundant and widely distributed in neurons, microglia, and astrocytes of the central nervous system as well as in peripheral immune cells. These receptors are strongly linked to inflammation, with a functional interplay that may influence the intricate purinergic signaling involved in inflammatory responses. In the present review, we examine the roles of the purinergic receptors in neuro-immune cell functions with particular emphasis on A2AR, P2X4 and P2X7 and their possible relevance to specific neurodegenerative disorders. Understanding the molecular mechanisms governing purinergic receptor interaction will be crucial for advancing the development of effective immunotherapies targeting neurodegenerative diseases.}, } @article {pmid39579996, year = {2025}, author = {Watanabe, Y and Yamaguchi, Y}, title = {Regarding response to Yamaguchi et al's "Anti-SS-A antibody is a potential predictor of severe Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e73-e74}, doi = {10.1016/j.jaad.2024.11.030}, pmid = {39579996}, issn = {1097-6787}, } @article {pmid39579998, year = {2025}, author = {Baroukhian, J and Seiffert-Sinha, K and Sinha, AA}, title = {Response to Kasperkiewicz et al's "Pemphigus following herpes simplex infection: A global comprehensive cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {4}, pages = {e99-e100}, doi = {10.1016/j.jaad.2024.07.1536}, pmid = {39579998}, issn = {1097-6787}, } @article {pmid39580792, year = {2025}, author = {Kaplan, E and Weissbach, A and Kadmon, G and Nahum, E and Stein, J}, title = {Plasma exchange using peripheral arterial and venous access in the pediatric intensive care unit.}, journal = {Transfusion}, volume = {65}, number = {1}, pages = {152-158}, pmid = {39580792}, issn = {1537-2995}, mesh = {Humans ; *Plasma Exchange/methods ; Retrospective Studies ; Child, Preschool ; Child ; *Intensive Care Units, Pediatric ; Female ; Male ; Infant ; *Catheterization, Peripheral/methods ; Adolescent ; Radial Artery ; }, abstract = {OBJECTIVE: Therapeutic plasma exchange (TPE) is a vital therapeutic modality in pediatric intensive care units (PICU) for various indications. Traditionally, pediatric TPE is performed via a large bore, double lumen catheter, whose insertion necessitates deep sedation, and poses risk of hemorrhagic and thrombotic complications. Building on our previous success utilizing percutaneous radial artery catheters (ALs) for apheresis procedures, we present our experience with ALs for TPE procedures in the PICU.

METHODS: A retrospective cohort study, conducted in the PICU of a tertiary, university affiliated pediatric hospital, including all children aged 19 years and younger, who underwent TPE using an AL for vascular access, between 2018 and 2023. TPE procedures were evaluated for utility (the procedure was performed as planned) and safety.

RESULTS: A total of 72 procedures were performed on 20 children, using ALs for inlet access and peripheral intra-venous catheters for blood return. Procedure success rate was 94%, with AL malfunction causing transient delays in 6%. All were successfully completed following AL replacement. ALs were mostly 20 and 22 gauge, predominantly located in the radial artery. AL gauge did not significantly affect flow rate or procedure duration.

CONCLUSIONS: Our findings support AL use for vascular access, as a viable alternative to the traditional large bore, double lumen catheters most often used for TPE in children. Benefits of AL use may include a decrease in sedation requirements and a lower risk of vascular complications. Further investigation is warranted, for consideration as routine practice in PICUs.}, } @article {pmid39580968, year = {2024}, author = {Lewandowski, SA and Kular, L and Jagodic, M}, title = {Epigenetic age acceleration as a biomarker of amyotrophic lateral sclerosis severity?.}, journal = {EBioMedicine}, volume = {110}, number = {}, pages = {105470}, pmid = {39580968}, issn = {2352-3964}, } @article {pmid39581338, year = {2025}, author = {Kokona, B and Cunningham, NR and Quinn, JM and Jacobsen, DR and Garcia, FJ and Galindo, SM and Petrucelli, L and Stafford, WF and Laue, TM and Fairman, R}, title = {Studying C9orf72 dipeptide repeat polypeptide aggregation using an analytical ultracentrifuge equipped with fluorescence detection.}, journal = {Analytical biochemistry}, volume = {697}, number = {}, pages = {115720}, pmid = {39581338}, issn = {1096-0309}, support = {P40 OD018537/OD/NIH HHS/United States ; R15 NS081681/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *C9orf72 Protein/genetics ; *Caenorhabditis elegans/genetics ; *Dipeptides/chemistry ; Ultracentrifugation ; Drosophila melanogaster/genetics ; Humans ; Protein Aggregates ; Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics ; Peptides/chemistry/genetics/analysis ; Fluorescence ; }, abstract = {Sedimentation velocity, using an analytical ultracentrifuge equipped with fluorescence detection, and electrophoresis methods are used to study aggregation of proteins in transgenic animal model systems. Our previous work validated the power of this approach in an analysis of mutant huntingtin aggregation. We demonstrate that this method can be applied to another neurodegenerative disease studying the aggregation of three dipeptide repeats (DPRs) produced by aberrant translation of mutant c9orf72 containing large G4C2 hexanucleotide repeats. These repeat expansions are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We analyzed the aggregation patterns of (Gly-Pro)47, (Gly-Ala)50, and (Gly-Arg)50 fused to fluorescent proteins in samples prepared from D. melanogaster, and (Gly-Ala)50 in C. elegans, using AU-FDS and SDD-AGE. Results suggest that (GP)47 is largely monomeric. In contrast, (GA)50 forms both intermediate and large-scale aggregates. (GR)50 is partially monomeric with some aggregation noted in SDD-AGE analysis. The aggregation of this DPR is likely to represent co-aggregated states with DNA and/or RNA. The power of these methods is the ability to gather data on aggregation patterns and characteristics in animal model systems, which may then be used to interpret the mitigation of aggregation through genetic or molecular therapeutic interventions.}, } @article {pmid39581840, year = {2025}, author = {Hannaford, A and Pavey, N and Menon, P and van den Bos, MAJ and Kiernan, MC and Simon, N and Vucic, S}, title = {Muscle ultrasound aids diagnosis in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {170}, number = {}, pages = {234-243}, doi = {10.1016/j.clinph.2024.11.008}, pmid = {39581840}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; Male ; Middle Aged ; Female ; Ultrasonography/methods ; Aged ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Cohort Studies ; Adult ; Prospective Studies ; }, abstract = {OBJECTIVE: There is a need for improved diagnostic tools in Amyotrophic Lateral Sclerosis (ALS). Our objective was to assess muscle ultrasound as a diagnostic tool in patients with ALS and determine a simplified screening protocol to aid implementation in clinical practice.

METHODS: Ultrasound of bulbar and limb muscles was prospectively performed on all patients referred to a single centre with suspected ALS. Clinical measures of disease severity and upper motor neuron impairment were also recorded. Receiver operating characteristic (ROC) curves were calculated to assess the diagnostic utility of muscle ultrasound.

RESULTS: 94 patients initially suspected of ALS were recruited to this observational cohort study. Forty-four were subsequently diagnosed as ALS and 50 as disease mimics. ALS patients demonstrated a higher frequency and more generalised distribution of fasciculations compared to mimics. A simplified 5 muscle screening protocol exhibited an AUC of 0.94 (95 %CI 0.89-0.99) in discriminating ALS from mimics. The presence of ≥ 3 fasciculating muscles detected using this screening protocol was 89 % sensitive and 88 % specific for the diagnosis of ALS.

CONCLUSIONS: Muscle ultrasound, screening as few as 5 muscles, has diagnostic utility in ALS.

SIGNIFICANCE: Muscle ultrasound enhances clinical diagnosis in ALS.}, } @article {pmid39582565, year = {2024}, author = {Byeon, H}, title = {Glymphatic system function in diverse glucose metabolism states.}, journal = {World journal of diabetes}, volume = {15}, number = {11}, pages = {2245-2250}, pmid = {39582565}, issn = {1948-9358}, abstract = {The rising prevalence of diabetes and prediabetes globally necessitates a deeper understanding of associated complications, including glymphatic system dysfunction. The glymphatic system, crucial for brain waste clearance, is implicated in cognitive decline and neurodegenerative diseases like Alzheimer's disease. This letter explores recent research on glymphatic function across different glucose metabolism states. Tian et al's study reveals significant glymphatic dysfunction in type 2 diabetes mellitus patients, evidenced by lower diffusion tensor imaging analysis along perivascular space indices compared to those with normal glucose metabolism and prediabetes. The research also reveals a link between glymphatic dysfunction and cognitive impairment. Additional research underscores the role of glymphatic impairment in neurodegenerative diseases. These findings highlight the importance of integrating glymphatic health into diabetes management and suggest potential biomarkers for early diagnosis and targeted therapeutic interventions.}, } @article {pmid39583905, year = {2024}, author = {Townley, MA}, title = {Spinneret spinning field ontogeny and life history observations in the spider Palpimanus uncatus (Araneae: Palpimanidae).}, journal = {The Journal of arachnology}, volume = {52}, number = {1}, pages = {41-70}, pmid = {39583905}, issn = {0161-8202}, support = {P20 GM113131/GM/NIGMS NIH HHS/United States ; }, abstract = {As in other Palpimanidae, two pairs of posterior spinnerets present in typical Araneomorphae are vestigial in Palpimanus uncatus Kulczyński, 1909, with only the anterior lateral spinneret (ALS) pair prominent. Nevertheless, in late juvenile and adult females, spigots appear in the ancestral posterior spinneret region (PS). Consistent with these spigots serving cylindrical silk glands, females construct substantial egg sacs. While juveniles and adults exhibit a compressed PS, in postembryos it is fully extended. Piriform silk gland (PI) spigots form a linear array on ALSs from the 1[st] stadium, increasing in number during ontogeny by addition of PIs of the tartipore-accommodated (T-A) subtype (i.e., functional during proecdyses). The number of T-A PIs added from one stadium to the next and locations occupied by their spigots often exhibit a stereotypic pattern, especially consistent in early instars. The number of non-T-A PIs remains constant through ontogeny from the 1[st] stadium: one per ALS rather than the two per ALS inferred in a few araneoids. The secondary major ampullate silk gland (2° MaA) spigot, primitively uni-shafted among araneomorphs, has become modified into a multi-shafted spigot with extended base, the number of shafts increasing during ontogeny. However, the multiple ducts that connect to the shafts continue to be accommodated during proecdysis by a single enormous tartipore. Sexual dimorphism is present, with late stadium females having greater numbers of T-A PI spigots and 2° MaA spigot shafts. Observations are presented pertaining to feeding behavior, sexual cannibalism (absent), habitat, winter diapause, numbers of molts, and longevity.}, } @article {pmid39584466, year = {2025}, author = {Daneshpour, A and Rezvanimehr, A and Niktalab, P and Sharif, H and Yazdanpanah, N and Saleki, K and Rezaei, N}, title = {Exploring the role of vault complex in the nervous system: a literature review.}, journal = {Reviews in the neurosciences}, volume = {36}, number = {3}, pages = {327-338}, pmid = {39584466}, issn = {2191-0200}, mesh = {Humans ; Animals ; *Vault Ribonucleoprotein Particles/metabolism/genetics ; *Nervous System/metabolism ; Major Vault Protein ; }, abstract = {Vault RNAs (vtRNAs) are a novel group of non-coding RNAs that are involved in various signaling mechanisms. vtRNAs are joined by three proteins major vault protein (MVP), vault poly (ADP-ribose) polymerase (VPARP), and telomerase-associated protein 1 (TEP1) to form the vault complex. In humans, only four vtRNA including vtRNA 1-1, vtRNA 1-2, vtRNA 1-3, vtRNA 2-1) have been discovered. In nerve cells, vtRNA is involved in synapse formation through MAPK signaling. vtRNA travels to the distal area of neurites as a key unit in the vault complex. Moreover, tRNA is detached from the vault complex in the neurite via a mitotic kinase Aurora-A-reliant MVP phosphorylation. Several molecules contribute to the formation of vtRNAs. For instance, SRSF2 and NSUN2 and their attachment to vtRNA1-1 determines the production of small-vtRNAs. Through the same factors, vtRNAs could play a role in neurodevelopmental deficits. Addition the role of vtRNA expression and vault proteins has been recently studied in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as well as brain cancers. While the mechanisms of vtRNA involvement in neurological disorders is not well-demonstrated, we believe this could be related to the impact of vtRNA regulation in autophagy, immunoregulation, RNA stability, cellular stress, apoptosis, and regulation of other epigenetic pathways. The present review captures the state-of-the-art regarding the role of vtRNAs in neurodevelopment, normal nervous system function, and neurological disorders.}, } @article {pmid39585060, year = {2024}, author = {Magni, E and Hochsprung, A and Cáceres-Matos, R and Pabón-Carrasco, M and Heredia-Camacho, B and Solís-Marcos, I and Luque-Moreno, C}, title = {Effects of Respiratory Training on Pulmonary Function, Cough, and Functional Independence in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Neurology international}, volume = {16}, number = {6}, pages = {1332-1342}, pmid = {39585060}, issn = {2035-8385}, abstract = {BACKGROUND: Respiratory complications in patients with amyotrophic lateral sclerosis (ALS), due to the involvement of respiratory muscles, are the leading cause of death, and respiratory physiotherapy (RP) focuses on addressing these complications.

OBJECTIVES: The objective was to evaluate the effectiveness of an RP intervention that combines the four specific techniques (inspiratory muscle training, lung volume recruitment, manually assisted coughing, and diaphragmatic breathing training) in patients with ALS.

METHODS: A quasi-experimental study was carried out, and a specific RP programme was implemented in 15 patients with ALS (12 sessions, 30 min/session, one session/week, duration of three months), based on directed ventilation techniques, lung volume recruitment, manually assisted coughing, and the use of incentive spirometry and a cough assist device, along with a daily home exercise programme. Respiratory functions were assessed (pre- and post-intervention, with follow-up at three months) using Forced Vital Capacity (FVC) and Peak Expiratory Cough Flow (PECF); functionality was assessed using the Revised ALS Functional Rating Scale (ALSFRS-R) and the Modified Barthel Index by Granger.

RESULTS: FVC experienced an increase after three months of the intervention initiation (p = 0.30), which was not sustained at the three-month follow-up after the intervention ended. All other variables remained practically constant after treatment, with their values decreasing at follow-up.

CONCLUSION: A specific RP intervention could have beneficial effects on respiratory functions, potentially preventing pulmonary infections and hospitalisations in patients with ALS. It may improve FVC and help stabilize the patient's functional decline. Considering the progressive and degenerative nature of the disease, this finding could support the usefulness of these techniques in maintaining respiratory function.}, } @article {pmid39585162, year = {2024}, author = {Savvidis, C and Kouroglou, E and Kallistrou, E and Ragia, D and Dionysopoulou, S and Gavriiloglou, G and Tsiama, V and Proikaki, S and Belis, K and Ilias, I}, title = {IGFBP-2 in Critical Illness: A Prognostic Marker in the Growth Hormone/Insulin-like Growth Factor Axis.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {31}, number = {4}, pages = {621-630}, pmid = {39585162}, issn = {1873-149X}, abstract = {Critical illness (CI) triggers complex disruptions in the growth hormone (GH)/insulin-like growth factor (IGF) axis, significantly affecting the dynamics of insulin-like growth-factor-binding proteins (IGFBPs). Among these, IGFBP-2 shows a sustained elevation during CI, which inversely correlates with serum levels of IGF-1, IGFBP-3, and the acid-labile subunit (ALS). Although IGFBP-2 does not directly interact with ALS, it may influence the availability of IGFs by competing with other IGFBPs for binding to IGF-1 and IGF-2. Research suggests that this persistent elevation of IGFBP-2 is largely driven by cytokine activity during CI, reflecting an adaptive response rather than a direct result of GH/IGF axis dysregulation. The clinical importance of IGFBP-2 is emphasized by its correlation with disease severity in conditions like sepsis and coronavirus disease 2019 (COVID-19), where its levels are markedly elevated compared to healthy controls and are similar to those observed in sepsis from various causes. Beyond its role in endocrine regulation, IGFBP-2 appears to play a part in metabolic and inflammatory pathways. Elevated IGFBP-2 levels have been linked to increased mortality and longer hospital stays, indicating its potential utility as a prognostic marker. Furthermore, measuring plasma IGFBP-2 may have other diagnostic applications, aiding in the assessment of CI when traditional biomarkers are inconclusive.}, } @article {pmid39587229, year = {2025}, author = {Wang, C and Wang, S and Xue, Y and Zhong, Y and Li, H and Hou, X and Kang, DD and Liu, Z and Tian, M and Wang, L and Cao, D and Yu, Y and Liu, J and Cheng, X and Markovic, T and Hashemi, A and Kopell, BH and Charney, AW and Nestler, EJ and Dong, Y}, title = {Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system.}, journal = {Nature biotechnology}, volume = {43}, number = {11}, pages = {1783-1789}, pmid = {39587229}, issn = {1546-1696}, mesh = {*Blood-Brain Barrier/metabolism ; Animals ; Mice ; Humans ; Administration, Intravenous ; *Central Nervous System/metabolism ; Transcytosis ; *Oligonucleotides/administration & dosage/pharmacokinetics ; Biological Transport ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; }, abstract = {Delivery of biomacromolecules to the central nervous system (CNS) remains challenging because of the restrictive nature of the blood-brain barrier (BBB). We developed a BBB-crossing conjugate (BCC) system that facilitates delivery into the CNS through γ-secretase-mediated transcytosis. Intravenous administration of a BCC10-oligonucleotide conjugate demonstrated effective transportation of the oligonucleotide across the BBB and gene silencing in wild-type mice, human brain tissues and an amyotrophic lateral sclerosis mouse model.}, } @article {pmid39588282, year = {2024}, author = {Dash, BP and Freischmidt, A and Helferich, AM and Ludolph, AC and Andersen, PM and Weishaupt, JH and Hermann, A}, title = {Upregulated miR-10b-5p as a potential miRNA signature in amyotrophic lateral sclerosis patients.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1457704}, pmid = {39588282}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset disease marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Death in most patients usually occurs within 2-4 years after symptoms onset. Despite promising progress in delineating underlying mechanisms, such as disturbed proteostasis, DNA/RNA metabolism, splicing or proper nucleocytoplasmic shuttling, there are no effective therapies for the vast majority of cases. A reason for this might be the disease heterogeneity and lack of substantial clinical and molecular biomarkers. The identification and validation of such pathophysiology driven biomarkers could be useful for early diagnosis and treatment stratification. Recent advances in next generation RNA-sequencing approaches have provided important insights to identify key changes of non-coding RNAs (ncRNAs) implicated with ALS disease. Especially, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression to target several genes/pathways by degrading messenger RNAs (mRNAs) or repressing levels of gene expression. In this study, we expand our previous work to identify top-regulated differentially expressed (DE)-miRNAs by combining different normalizations to search for important and generalisable pathomechanistic dysregulations in ALS as putative novel biomarkers of the disease. For this we performed a consensus pipeline of existing datasets to investigate the transcriptomic profile (mRNAs and miRNAs) of MN cell lines from iPSC-derived SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to identify potential signatures and their related pathways associated with neurodegeneration. Transcriptional profiling of miRNA-mRNA interactions from MN cell lines in ALS patients revealed differential expression of genes showed greater vulnerability to KEAP1-NRF2 stress response pathway, sharing a common molecular denominator linked to both disease conditions. We also reported that mutations in above genes led to significant upregulation of the top candidate miR-10b-5p, which we could validate in immortalized lymphoblast cell lines (LCLs) derived from sporadic and familial ALS patients and postmortem tissues of familial ALS patients. Collectively, our findings suggest that miRNA analysis simultaneously performed in various human biological samples may reveal shared miRNA profiles potentially useful as a biomarker of the disease.}, } @article {pmid39589160, year = {2025}, author = {Wang, Y and Li, D and Xu, K and Wang, G and Zhang, F}, title = {Copper homeostasis and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3124-3143}, pmid = {39589160}, issn = {1673-5374}, abstract = {Copper, one of the most prolific transition metals in the body, is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine, and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline, along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.}, } @article {pmid39589178, year = {2025}, author = {Peng, Y and Zhou, L and Jin, Y and Wu, D and Chen, N and Zhang, C and Liu, H and Li, C and Ning, R and Yang, X and Mao, Q and Liu, J and Zhang, P}, title = {Calcium bridges built by mitochondria-associated endoplasmic reticulum membranes: potential targets for neural repair in neurological diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {12}, pages = {3349-3369}, pmid = {39589178}, issn = {1673-5374}, abstract = {The exchange of information and materials between organelles plays a crucial role in regulating cellular physiological functions and metabolic levels. Mitochondria-associated endoplasmic reticulum membranes serve as physical contact channels between the endoplasmic reticulum membrane and the mitochondrial outer membrane, formed by various proteins and protein complexes. This microstructural domain mediates several specialized functions, including calcium (Ca 2+) signaling, autophagy, mitochondrial morphology, oxidative stress response, and apoptosis. Notably, the dysregulation of Ca 2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes is a critical factor in the pathogenesis of neurological diseases. Certain proteins or protein complexes within these membranes directly or indirectly regulate the distance between the endoplasmic reticulum and mitochondria, as well as the transduction of Ca 2+ signaling. Conversely, Ca 2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes influences other mitochondria-associated endoplasmic reticulum membrane-associated functions. These functions can vary significantly across different neurological diseases-such as ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-and their respective stages of progression. Targeted modulation of these disease-related pathways and functional proteins can enhance neurological function and promote the regeneration and repair of damaged neurons. Therefore, mitochondria-associated endoplasmic reticulum membranes-mediated Ca 2+ signaling plays a pivotal role in the pathological progression of neurological diseases and represents a significant potential therapeutic target. This review focuses on the effects of protein complexes in mitochondria-associated endoplasmic reticulum membranes and the distinct roles of mitochondria-associated endoplasmic reticulum membranes-mediated Ca 2+ signaling in neurological diseases, specifically highlighting the early protective effects and neuronal damage that can result from prolonged mitochondrial Ca 2+ overload or deficiency. This article provides a comprehensive analysis of the various mechanisms of Ca 2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes in neurological diseases, contributing to the exploration of potential therapeutic targets for promoting neuroprotection and nerve repair.}, } @article {pmid39589500, year = {2025}, author = {Apolloni, S and D'Ambrosi, N}, title = {Biochemical dissection of STAT3 signaling in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3229-3230}, pmid = {39589500}, issn = {1673-5374}, } @article {pmid39589881, year = {2024}, author = {Jean Gregoire, M and Sirtori, R and Donatelli, L and Morgan Potts, E and Collins, A and Zamor, D and Katenka, N and Fallini, C}, title = {Early disruption of the CREB pathway drives dendritic morphological alterations in FTD/ALS cortical neurons.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {49}, pages = {e2406998121}, pmid = {39589881}, issn = {1091-6490}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; Early Career Development Award//RI-INBRE/ ; R01NS116143//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P20GM103430//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 NS116143/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Dendrites/metabolism ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Frontotemporal Dementia/metabolism/genetics/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Neurons/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Signal Transduction ; C9orf72 Protein/genetics/metabolism ; Phosphorylation ; Cerebral Cortex/metabolism/pathology ; }, abstract = {Synaptic loss and dendritic degeneration are common pathologies in several neurodegenerative diseases characterized by progressive cognitive and/or motor decline, such as Alzheimer's disease (AD) and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). An essential regulator of neuronal health, the cAMP-dependent transcription factor CREB positively regulates synaptic growth, learning, and memory. Phosphorylation of CREB by protein kinase A (PKA) and other cellular kinases promotes neuronal survival and maturation via transcriptional activation of a wide range of downstream target genes. CREB pathway dysfunction has been strongly implicated in AD pathogenesis, and recent data suggest that impaired CREB activation may contribute to disease phenotypes in FTD/ALS as well. However, the mechanisms behind reduced CREB activity in FTD/ALS pathology are not clear. In this study, we found that cortical-like neurons derived from iPSC lines carrying the hexanucleotide repeat expansion in the C9ORF72 gene, a common genetic cause of FTD/ALS, displayed a diminished activation of CREB, resulting in decreased dendritic and synaptic health. Importantly, we determined such impairments to be mechanistically linked to an imbalance in the ratio of regulatory and catalytic subunits of the CREB activator PKA and to be conserved in C9-ALS patient's postmortem tissue. Modulation of cAMP upstream of this impairment allowed for a rescue of CREB activity and an amelioration of dendritic morphology and synaptic protein levels. Our data elucidate the mechanism behind early CREB pathway dysfunction and discern a feasible therapeutic target for the treatment of FTD/ALS and possibly other neurodegenerative diseases.}, } @article {pmid39589981, year = {2024}, author = {Mohaček-Grošev, V and Škrabić, M and Gebavi, H and Blažek Bregović, V and Marić, I and Amendola, V and Grdadolnik, J}, title = {Binding of Glutamic Acid to Silver and Gold Nanoparticles Investigated by Surface-Enhanced Raman Spectroscopy.}, journal = {Biosensors}, volume = {14}, number = {11}, pages = {}, pmid = {39589981}, issn = {2079-6374}, support = {croatian-slovenian bilateral project//Ministry of Scirence and Education of the Republic of Croatia/ ; }, mesh = {*Spectrum Analysis, Raman ; *Glutamic Acid/chemistry ; *Silver/chemistry ; *Gold/chemistry ; *Metal Nanoparticles/chemistry ; Hydrogen-Ion Concentration ; }, abstract = {Glutamate is the most important excitatory neurotransmitter, which is relevant for the study of several diseases such as amyotrophic lateral sclerosis and Alzheimer. It is the form L-glutamic acid (Glu) takes at physiologically relevant pHs. The surface-enhanced Raman spectra of Glu obtained at pH values ranging from 3.3 to 12 are collected in the presence of silver and gold colloids and on solid substrates. The observed bands are compared with the positions of calculated normal modes for free neutral glutamic acid, glutamic acid monohydrate, glutamic acid bound to gold and silver atoms, and sodium glutamate. Although gold atoms prefer to bind to the NH2 group as compared to carbonyl groups, silver atoms prefer binding to hydroxyl groups more than binding to the amino group. SERS spectra of glutamic acid solutions with a pH value of 12, in which both carboxylic groups are deprotonated, indicate a complexation of the glutamic acid dianion with the sodium cation, which was introduced into the solution to adjust the pH value. Further research towards an optimal substrate is needed.}, } @article {pmid39589985, year = {2024}, author = {Tkachenko, K and González-Saíz, JM and Calvo, AC and Lunetta, C and Osta, R and Pizarro, C}, title = {Comparative Blood Profiling Based on ATR-FTIR Spectroscopy and Chemometrics for Differential Diagnosis of Patients with Amyotrophic Lateral Sclerosis-Pilot Study.}, journal = {Biosensors}, volume = {14}, number = {11}, pages = {}, pmid = {39589985}, issn = {2079-6374}, support = {N· 801586//European Union's H2020/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/blood ; Humans ; Pilot Projects ; Diagnosis, Differential ; Spectroscopy, Fourier Transform Infrared ; Middle Aged ; Female ; Male ; Aged ; Adult ; Biomarkers/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neurodegenerative disease characterized by poor prognosis. Currently, screening and diagnostic methods for ALS remain challenging, often leading to diagnosis at an advanced stage of the disease. This delay hinders the timely initiation of therapy, negatively impacting patient well-being. Additionally, misdiagnosis with other neurodegenerative disorders that present similar profiles often occurs. Therefore, there is an urgent need for a cost-effective, rapid, and user-friendly tool capable of predicting ALS onset. In this pilot study, we demonstrate that infrared spectroscopy, coupled with chemometric analysis, can effectively identify and predict disease profiles from blood samples drawn from ALS patients. The selected predictive spectral markers, which are used in various discriminant models, achieved an AUROC sensitivity of almost 80% for distinguishing ALS patients from controls. Furthermore, the differentiation of ALS at both the initial and advanced stages from other neurodegenerative disorders showed even higher AUROC values, with sensitivities of 87% (AUROC: 0.70-0.97). These findings highlight the elevated potential of ATR-FTIR spectroscopy for routine clinical screening and early diagnosis of ALS.}, } @article {pmid39591907, year = {2024}, author = {Bajpai, A and Bharathi, V and Kumawat, R and Tomar, RS and Patel, BK}, title = {Activation of the yeast MAP kinase, Slt2, protects against TDP-43 and TDP-25 toxicity in the Saccharomyces cerevisiae proteinopathy model.}, journal = {Biochemical and biophysical research communications}, volume = {741}, number = {}, pages = {151062}, doi = {10.1016/j.bbrc.2024.151062}, pmid = {39591907}, issn = {1090-2104}, mesh = {*Saccharomyces cerevisiae/metabolism/genetics ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Unfolded Protein Response/drug effects ; *Mitogen-Activated Protein Kinases/metabolism/genetics ; TDP-43 Proteinopathies/metabolism/genetics/pathology ; Humans ; Enzyme Activation ; Oxidative Stress/drug effects ; }, abstract = {TDP-43 proteinopathy is observed in human neurodegenerative diseases like ALS. Heterologous TDP-43 expression in the yeast model also mimics several proteinopathy features such as cytotoxicity, cytoplasmic mis-localization and oxidative stress. Among the pathways implicated in modulating the TDP-43 toxicity in yeast, the unfolded protein response (UPR) activation was also identified. Here, we examine the role of stress-regulated yeast MAP kinase, Slt2, which also links cellular stress with UPR activation, in modulating the toxicities of the full-length TDP-43 and its 25 kDa C-terminal fragment, TDP-25. We find enhancement in the cytotoxicity of TDP-43, as well as TDP-25, in the yeast cells deleted for the MAP kinase, Slt2, but not in those lacking other yeast MAP kinases, Kss1 and Fus3. Unlike in the wild-type yeast, upon treatment with an antioxidant N-acetyl cysteine, the TDP-43 toxicity could not be mitigated in the slt2Δ yeast but the TDP-25 toxicity was significantly rescued suggesting oxidative stress as an important contributor to the TDP-25 toxicity. Notably, TDP-43 as well as TDP-25 expressions could cause significant phosphorylation of Slt2 suggesting activation of this MAP Kinase due to their toxicities. Interestingly, in the slt2Δ cells, lacking the MAP Kinase activity, a treatment with low concentrations of an UPR activator molecule, DTT, caused significant reduction in the toxicities of both TDP-43 as well as TDP-25. Taken together, these findings suggest that TDP-43 and TDP-25 toxicity-induced stress-mediated activation of the MAP kinase Slt2 helps in mitigating their toxicities in the yeast model possibly through UPR activation.}, } @article {pmid39592063, year = {2024}, author = {Lorenc, F and Dupuis, L and Cassel, R}, title = {Impairments of inhibitory neurons in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Neurobiology of disease}, volume = {203}, number = {}, pages = {106748}, doi = {10.1016/j.nbd.2024.106748}, pmid = {39592063}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology ; *Frontotemporal Dementia/pathology/physiopathology ; Humans ; Animals ; *Neurons/pathology ; *Neural Inhibition/physiology ; }, abstract = {Amyotrophic lateral sclerosis and frontotemporal dementia are two fatal neurodegenerative disorders. They are part of a pathophysiological continuum, displaying clinical, neuropathological, and genetic overlaps. There is compelling evidence that neuronal circuit dysfunction is an early feature of both diseases. Impaired neuronal excitability, imbalanced excitatory and inhibitory influences, and altered functional connectivity have been reported. These phenomena are likely due to combined alterations in the various cellular components involved in the functioning of neuronal networks. This review focuses on one of these cellular components: inhibitory neurons. We assess the evidence for inhibitory neuron impairments in amyotrophic lateral sclerosis and frontotemporal dementia, as well as the mechanisms leading to the loss of inhibition. We also discuss the contributions of these alterations to symptoms, and the potential therapeutic strategies for targeting inhibitory neuron deficits.}, } @article {pmid39592088, year = {2025}, author = {Mahakalakar, N and Mohariya, G and Taksande, B and Kotagale, N and Umekar, M and Vinchurney, M}, title = {"Nattokinase as a potential therapeutic agent for preventing blood-brain barrier dysfunction in neurodegenerative disorders".}, journal = {Brain research}, volume = {1849}, number = {}, pages = {149352}, doi = {10.1016/j.brainres.2024.149352}, pmid = {39592088}, issn = {1872-6240}, mesh = {*Blood-Brain Barrier/drug effects/metabolism ; Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Subtilisins/therapeutic use/pharmacology ; *Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are characterized by progressive destruction of neurons and cognitive impairment, and thorough studies have provided evidence that these pathologies have a close relationship to the failure of the blood-brain barrier (BBB). Nattokinase (NK), a protease found in fermented soybeans, has been extensively studied because it displays powerful neuroprotective abilities, which is why current research was reviewed in the present article. It was concluded that there is enough evidence in preclinical studies using experimental animals that NK supplementation can alleviate the condition related to BBB dysfunction, reduce brain inflammation, and improve cognitive ability. Furthermore, the study of NK on the cardiovascular system leads to certain assumptions, which include the impact on vasculature function and the ability to manage blood flow, which is the key feature of BBB integrity. Such assumed mechanisms are fibrinolytic action, anti-inflammatory and antioxidant action, and endothelium function modulation. There are many positive research findings, and it seems that NK may serve as an effective opponent for BBB breakdown; however, a new research level should be taken to disclose the application and therapeutic use of NK in brain neurodegenerative disease.}, } @article {pmid39593143, year = {2024}, author = {Clarke, BE and Ziff, OJ and Tyzack, G and Petrić Howe, M and Wang, Y and Klein, P and Smith, CA and Hall, CA and Helmy, A and Howell, M and Kelly, G and Patani, R}, title = {Human VCP mutant ALS/FTD microglia display immune and lysosomal phenotypes independently of GPNMB.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {90}, pmid = {39593143}, issn = {1750-1326}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Microglia/metabolism ; *Membrane Glycoproteins/metabolism/genetics ; *Valosin Containing Protein/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Animals ; *Lysosomes/metabolism ; Mice ; Mutation/genetics ; Phenotype ; Motor Neurons/metabolism/pathology ; Astrocytes/metabolism ; }, abstract = {BACKGROUND: Microglia play crucial roles in maintaining neuronal homeostasis but have been implicated in contributing to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the role of microglia in ALS/FTD remains incompletely understood.

METHODS: Here, we generated highly enriched cultures of VCP mutant microglia derived from human induced pluripotent stem cells (hiPSCs) to investigate their cell autonomous and non-cell autonomous roles in ALS pathogenesis. We used RNA-sequencing, proteomics and functional assays to study hiPSC derived VCP mutant microglia and their effects on hiPSC derived motor neurons and astrocytes.

RESULTS: Transcriptomic, proteomic and functional analyses revealed immune and lysosomal dysfunction in VCP mutant microglia. Stimulating healthy microglia with the inflammatory inducer lipopolysaccharide (LPS) showed partial overlap with VCP mutant microglia in their reactive transformation. LPS-stimulated VCP mutant microglia displayed differential activation of inflammatory pathways compared with LPS-stimulated healthy microglia. Conserved gene expression changes were identified between VCP mutant microglia, SOD1 mutant mice microglia, and postmortem ALS spinal cord microglial signatures, including increased expression of the transmembrane glycoprotein GPNMB. While knockdown of GPNMB affected inflammatory and phagocytosis processes in microglia, this was not sufficient to ameliorate cell autonomous phenotypes in VCP mutant microglia. Secreted factors from VCP mutant microglia were sufficient to activate the JAK-STAT pathway in hiPSC derived motor neurons and astrocytes.

CONCLUSIONS: VCP mutant microglia undergo cell autonomous reactive transformation involving immune and lysosomal dysfunction that partially recapitulate key phenotypes of microglia from other ALS models and post mortem tissue. These phenotypes occur independently of GPNMB. Additionally, VCP mutant microglia elicit non cell autonomous responses in motor neurons and astrocytes involving the JAK-STAT pathway.}, } @article {pmid39593881, year = {2024}, author = {Favier, G and Rocha, DS}, title = {Overview of Tensor-Based Cooperative MIMO Communication Systems-Part 2: Semi-Blind Receivers.}, journal = {Entropy (Basel, Switzerland)}, volume = {26}, number = {11}, pages = {}, pmid = {39593881}, issn = {1099-4300}, abstract = {Cooperative MIMO communication systems play an important role in the development of future sixth-generation (6G) wireless systems incorporating new technologies such as massive MIMO relay systems, dual-polarized antenna arrays, millimeter-wave communications, and, more recently, communications assisted using intelligent reflecting surfaces (IRSs), and unmanned aerial vehicles (UAVs). In a companion paper, we provided an overview of cooperative communication systems from a tensor modeling perspective. The objective of the present paper is to provide a comprehensive tutorial on semi-blind receivers for MIMO one-way two-hop relay systems, allowing the joint estimation of transmitted symbols and individual communication channels with only a few pilot symbols. After a reminder of some tensor prerequisites, we present an overview of tensor models, with a detailed, unified, and original description of two classes of tensor decomposition frequently used in the design of relay systems, namely nested CPD/PARAFAC and nested Tucker decomposition (TD). Some new variants of nested models are introduced. Uniqueness and identifiability conditions, depending on the algorithm used to estimate the parameters of these models, are established. Two families of algorithms are presented: iterative algorithms based on alternating least squares (ALS) and closed-form solutions using Khatri-Rao and Kronecker factorization methods, which consist of SVD-based rank-one matrix or tensor approximations. In a second part of the paper, the overview of cooperative communication systems is completed before presenting several two-hop relay systems using different codings and configurations in terms of relaying protocol (AF/DF) and channel modeling. The aim of this presentation is firstly to show how these choices lead to different nested tensor models for the signals received at destination. Then, by capitalizing on these models and their correspondence with the generic models studied in the first part, we derive semi-blind receivers to jointly estimate the transmitted symbols and the individual communication channels for each relay system considered. In a third part, extensive Monte Carlo simulation results are presented to compare the performance of relay systems and associated semi-blind receivers in terms of the symbol error rate (SER) and channel estimate normalized mean-square error (NMSE). Their computation time is also compared. Finally, some perspectives are drawn for future research work.}, } @article {pmid39594452, year = {2024}, author = {Dibwe, DF and Oba, S and Monde, S and Hui, SP}, title = {Inhibition of Accumulation of Neutral Lipids and Their Hydroperoxide Species in Hepatocytes by Bioactive Allium sativum Extract.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {39594452}, issn = {2076-3921}, abstract = {Our ongoing research suggests that extracts from plant-based foods inhibit the accumulation of lipid droplets (LDs) and oxidized lipid droplets (oxLDs) in liver cells. These findings suggest their potential use in the alleviation of metabolic dysfunction-associated fatty liver disease (MAFLD) and its most severe manifestation, metabolic dysfunction-associated steatohepatitis (MASH). Allium extracts (ALs: AL1-AL9) were used to assess their ability to reduce lipid droplet accumulation (LDA) and oxidized lipid droplet accumulation (oxLDA) by inhibiting neutral lipid accumulation and oxidation in LD. Among the tested Allium extracts, AL1, AL3, and AL6 demonstrated substantial inhibitory effects on the LDA. Furthermore, AL1 extract showed real-time inhibition of LDA in HepG2 cells in DMEM supplemented with oleic acid (OA) within 12 h of treatment. Our lipidomic approach was used to quantify the accumulation and inhibition of intracellular triacylglycerol (TAG) and oxidized TAG hydroperoxide [TG (OOH) n = 3] species in hepatocytes under OA and linoleic acid loading conditions. These results suggest that Allium-based foods inhibit LD accumulation by decreasing intracellular lipids and lipid hydroperoxides in the hepatocytes. The metabolomic analysis of AL1-the bioactive LDAI extract-using both LC-MS/MS and 1D-NMR [[1]H, [13]C, and Dept (135 and 90)] approaches revealed that AL1 contains mainly carbohydrates and glucoside metabolites, including iridoid glucosides, as well as minor amino acids, organosulfur compounds, and organic acids such as the antioxidant ascorbic acid (KA2 = S13), and their derivatives, suggesting that AL1 could be a potential resource for the development of functional foods and in drug discovery targeting MAFLD/MASH and other related diseases.}, } @article {pmid39595127, year = {2024}, author = {Cardona, F}, title = {Special Issue "Mechanisms and Novel Therapeutic Approaches for Neurodegenerative Diseases".}, journal = {Biomedicines}, volume = {12}, number = {11}, pages = {}, pmid = {39595127}, issn = {2227-9059}, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are among the major health problems of the elderly, and represent a major global health challenge due to their increasing prevalence and complex pathophysiological mechanisms [...].}, } @article {pmid39595543, year = {2024}, author = {Stoccoro, A and Coppedè, F}, title = {Exposure to Metals, Pesticides, and Air Pollutants: Focus on Resulting DNA Methylation Changes in Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {14}, number = {11}, pages = {}, pmid = {39595543}, issn = {2218-273X}, mesh = {*DNA Methylation/drug effects ; Humans ; *Pesticides/toxicity/adverse effects ; *Neurodegenerative Diseases/genetics/metabolism/chemically induced ; *Epigenesis, Genetic/drug effects ; *Air Pollutants/toxicity/adverse effects ; Environmental Exposure/adverse effects ; Animals ; Metals, Heavy/toxicity/adverse effects ; Metals/toxicity/metabolism/adverse effects ; }, abstract = {Individuals affected by neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are dramatically increasing worldwide. Thus, several efforts are being made to develop strategies for stopping or slowing the spread of these illnesses. Although causative genetic variants linked to the onset of these diseases are known, they can explain only a small portion of cases. The etiopathology underlying the neurodegenerative process in most of the patients is likely due to the interplay between predisposing genetic variants and environmental factors. Epigenetic mechanisms, including DNA methylation, are central candidates in translating the effects of environmental factors in genome modulation, and they play a critical role in the etiology of AD, PD, and ALS. Among the main environmental exposures that have been linked to an increased risk for these diseases, accumulating evidence points to the role of heavy metals, pesticides, and air pollutants. These compounds could trigger neurodegeneration through different mechanisms, mainly neuroinflammation and the induction of oxidative stress. However, increasing evidence suggests that they are also capable of inducing epigenetic alterations in neurons. In this article, we review the available literature linking exposure to metals, pesticides, and air pollutants to DNA methylation changes relevant to neurodegeneration.}, } @article {pmid39595812, year = {2024}, author = {Zhang, S and Yang, Y and Lv, X and Zhou, X and Zhao, W and Meng, L and Zhu, S and Zhang, Z and Wang, Y}, title = {Exosome Cargo in Neurodegenerative Diseases: Leveraging Their Intercellular Communication Capabilities for Biomarker Discovery and Therapeutic Delivery.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595812}, issn = {2076-3425}, support = {82171871//National Natural Science Foundation of China/ ; BK20230488//Youth Fund Project of the Jiangsu Province Basic Research Program (Natural Science Foundation)/ ; None//Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)/ ; }, abstract = {The inexorable progression of neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, is closely related to irreversible brain decline. Accurately characterizing pathophysiological features and identifying reliable biomarkers for early diagnosis and optimized treatment are critical. Hindered by the blood-brain barrier (BBB), obtaining sensitive monitoring indicators for disease progression and achieving efficient drug delivery remain significant challenges. Exosomes, endogenous nanoscale vesicles that carry key bioactive substances, reflect the intracellular environment and play an important role in cell signaling. They have shown promise in traversing the BBB, serving dual roles as potential biomarkers for NDs and vehicles for targeted drug delivery. However, the specific mechanisms by which exosome influence NDs are not fully understood, necessitating further investigation into their attributes and functionalities in the context of NDs. This review explores how exosomes mediate multifaceted interactions, particularly in exacerbating pathogenic processes such as oxidative stress, neuronal dysfunction, and apoptosis integral to NDs. It provides a comprehensive analysis of the profound impact of exosomes under stress and disease states, assessing their prospective utility as biomarkers and drug delivery vectors, offering new perspectives for tackling these challenging diseases.}, } @article {pmid39595816, year = {2024}, author = {Shandiz, E and Fernandes, GL and Henkin, JS and McCombe, PA and Trajano, GS and Henderson, RD}, title = {Assessing the Effect of Riluzole on Motor Unit Discharge Properties.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595816}, issn = {2076-3425}, abstract = {Background. This study aims to determine if Riluzole usage can change the function and excitability of motor neurons. Methods. The clinical data and indices of motor neuron excitability were assessed using high-density surface EMG parameters from 80 ALS participants. The persistent inward current was assessed using the discharge rate from paired motor units obtained from the tibialis anterior muscle. This enabled the discharge rate at recruitment, peak discharge rates and the hysteresis of the recruitment-derecruitment frequencies (also known as delta F) to be calculated. Limbs were classified according to their strength. Results. No differences in these motor neuron discharge properties were found according to whether Riluzole was used. Conclusions. The possible interpretations of this finding are discussed.}, } @article {pmid39595818, year = {2024}, author = {Ferullo, L and Risi, B and Caria, F and Olivieri, E and Poli, L and Gazzina, S and Leggio, U and Bertella, E and Giovanelli, G and Labella, B and Padovani, A and Filosto, M}, title = {Gold Coast Criteria in ALS Diagnosis: A Real-World Experience.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595818}, issn = {2076-3425}, abstract = {Background: Revised El Escorial (rEEC) and Awaji criteria are currently used for diagnosing and categorizing amyotrophic lateral sclerosis (ALS). However, they are complex; their sensitivity is still not optimal for research purposes, and they present high inter-rater variability in clinical practice. To address these points, in 2019, a new set of diagnostic criteria was proposed, namely the Gold Coast criteria (GCC), characterized by a dichotomous diagnostic categorization, i.e., ALS or not ALS. Methods: In order to investigate the sensitivity, specificity, and clinical usefulness of GCC in a practical clinical setting, we retrospectively evaluated 131 patients diagnosed with ALS and 104 control subjects. ALSFRS-R score, electrophysiological tests, neuroradiological investigations, and CSF analysis were obtained. rEEC, Awaji, and GCC were applied at the first and last evaluations. Results: The sensitivity of GCC (93.1%; 96.1%) was greater than rEEC (71.8%; 87%) and Awaji criteria (77.8%; 89.3%) both at the first visit and last follow-up. The GCC's specificity (28.8%) is lower than that of the other two criteria (rEEC 45.2%; Awaji 43.3%). Conclusions: Our study suggests that in a real-world setting, the GCC are more sensitive and have substantially lower risk of false negative diagnoses than rEEC and Awaji criteria. Although rEEC had the highest specificity, they may delay the diagnosis. Systematically using the GCC could help to achieve an earlier diagnosis and quickly refer patients to the correct management. The low specificity of GCC is likely to not significantly impact patient recruitment in clinical trials; therefore, its use might allow a faster and earlier enrollment.}, } @article {pmid39595845, year = {2024}, author = {Rocha, PS and Bento, N and Svärd, H and Lopes, DM and Hespanhol, S and Folgado, D and Carreiro, AV and de Carvalho, M and Miranda, B}, title = {Voice Assessment in Patients with Amyotrophic Lateral Sclerosis: An Exploratory Study on Associations with Bulbar and Respiratory Function.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595845}, issn = {2076-3425}, support = {PTDC/MEC-NEU/6855/202//Fundação para a Ciência e Tecnologia/ ; }, abstract = {BACKGROUND: Speech production is a possible way to monitor bulbar and respiratory functions in patients with amyotrophic lateral sclerosis (ALS). Moreover, the emergence of smartphone-based data collection offers a promising approach to reduce frequent hospital visits and enhance patient outcomes. Here, we studied the relationship between bulbar and respiratory functions with voice characteristics of ALS patients, alongside a speech therapist's evaluation, at the convenience of using a simple smartphone.

METHODS: For voice assessment, we considered a speech therapist's standardized tool-consensus auditory-perceptual evaluation of voice (CAPE-V); and an acoustic analysis toolbox. The bulbar sub-score of the revised ALS functional rating scale (ALSFRS-R) was used, and pulmonary function measurements included forced vital capacity (FVC%), maximum expiratory pressure (MEP%), and maximum inspiratory pressure (MIP%). Correlation coefficients and both linear and logistic regression models were applied.

RESULTS: A total of 27 ALS patients (12 males; 61 years mean age; 28 months median disease duration) were included. Patients with significant bulbar dysfunction revealed greater CAPE-V scores in overall severity, roughness, strain, pitch, and loudness. They also presented slower speaking rates, longer pauses, and higher jitter values in acoustic analysis (all p < 0.05). The CAPE-V's overall severity and sub-scores for pitch and loudness demonstrated significant correlations with MIP% and MEP% (all p < 0.05). In contrast, acoustic metrics (speaking rate, absolute energy, shimmer, and harmonic-to-noise ratio) significantly correlated with FVC% (all p < 0.05).

CONCLUSIONS: The results provide supporting evidence for the use of smartphone-based recordings in ALS patients for CAPE-V and acoustic analysis as reliable correlates of bulbar and respiratory function.}, } @article {pmid39595895, year = {2024}, author = {Pongrácová, E and Buratti, E and Romano, M}, title = {Prion-like Spreading of Disease in TDP-43 Proteinopathies.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595895}, issn = {2076-3425}, abstract = {TDP-43 is a ubiquitous nuclear protein that plays a central role in neurodegenerative disorders collectively known as TDP-43 proteinopathies. Under physiological conditions, TDP-43 is primarily localized to the nucleus, but in its pathological form it aggregates in the cytoplasm, contributing to neuronal death. Given its association with numerous diseases, particularly ALS and FTLD, the mechanisms underlying TDP-43 aggregation and its impact on neuronal function have been extensively investigated. However, little is still known about the spreading of this pathology from cell to cell. Recent research has unveiled the possibility that TDP-43 may possess prion-like properties. Specifically, misfolded TDP-43 aggregates can act as templates inducing conformational changes in native TDP-43 molecules and propagating the misfolded state across neural networks. This review summarizes the mounting and most recent evidence from in vitro and in vivo studies supporting the prion-like hypothesis and its underlying mechanisms. The prion-like behavior of TDP-43 has significant implications for diagnostics and therapeutics. Importantly, emerging strategies such as small molecule inhibitors, immunotherapies, and gene therapies targeting TDP-43 propagation offer promising avenues for developing effective treatments. By elucidating the mechanisms of TDP-43 spreading, we therefore aim to pave the way for novel therapies for TDP-43-related neurodegenerative diseases.}, } @article {pmid39596445, year = {2024}, author = {Jiang, LL and Zhang, XL and Hu, HY}, title = {Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, pmid = {39596445}, issn = {1422-0067}, support = {31670782, 31700669//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *DNA-Binding Proteins/metabolism ; *Protein Aggregation, Pathological/metabolism ; Animals ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Protein Aggregates ; }, abstract = {Pathological aggregation of a specific protein into insoluble aggregates is a common hallmark of various neurodegenerative diseases (NDDs). In the earlier literature, each NDD is characterized by the aggregation of one or two pathogenic proteins, which can serve as disease-specific biomarkers. The aggregation of these specific proteins is thought to be a major cause of or deleterious result in most NDDs. However, accumulating evidence shows that a pathogenic protein can interact and co-aggregate with other pathogenic proteins in different NDDs, thereby contributing to disease onset and progression synergistically. During the past years, more than one type of NDD has been found to co-exist in some individuals, which may increase the complexity and pathogenicity of these diseases. This article reviews and discusses the biochemical characteristics and molecular mechanisms underlying the co-aggregation and co-pathologies associated with TDP-43 pathology. The TDP-43 aggregates, as a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), can often be detected in other NDDs, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and spinocerebellar ataxia type 2 (SCA2). In many cases, TDP-43 is shown to interact and co-aggregate with multiple pathogenic proteins in vitro and in vivo. Furthermore, the co-occurrence and co-aggregation of TDP-43 with other pathogenic proteins have important consequences that may aggravate the diseases. Thus, the current viewpoint that the co-aggregation of TDP-43 with other pathogenic proteins in NDDs and their relevance to disease progression may gain insights into the patho-mechanisms and therapeutic potential of various NDDs.}, } @article {pmid39596581, year = {2024}, author = {Paubel, A and Marouillat, S and Dangoumau, A and Maurel, C and Haouari, S and Blasco, H and Corcia, P and Laumonnier, F and Andres, CR and Vourc'h, P}, title = {Dynamic Expression of Genes Encoding Ubiquitin Conjugating Enzymes (E2s) During Neuronal Differentiation and Maturation: Implications for Neurodevelopmental Disorders and Neurodegenerative Diseases.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596581}, issn = {2073-4425}, mesh = {Animals ; *Ubiquitin-Conjugating Enzymes/genetics/metabolism ; Mice ; *Neurons/metabolism ; *Neurodevelopmental Disorders/genetics/pathology ; *Neurodegenerative Diseases/genetics ; *Hippocampus/metabolism ; *Cell Differentiation/genetics ; Neurogenesis/genetics ; Cells, Cultured ; N-Methylaspartate/pharmacology/metabolism ; }, abstract = {Background: The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families. Objectives: We analyzed by real-time PCR the expression dynamics of all known E2 genes during an in vitro differentiation of mouse hippocampal neuronal cultures, and after, we analyzed their stimulation with N-methyl-D-aspartate (NMDA). Results: We found that 36 of the 38 E2 genes were expressed in hippocampal neurons. Many were up-regulated during neuritogenesis and/or synaptogenesis stages, such as Ube2h, Ube2b, and Aktip. Rapid and delayed responses to NMDA stimulation were associated with the increased expression of several E2 genes, such as Ube2i, the SUMO-conjugating E2 enzyme. We also observed similar expression profiles within the same E2 gene family, consistent with the presence of similar transcription factor binding sites in their respective promoter sequences. Conclusions: Our study indicates that specific expression profiles of E2 genes are correlated with changes in neuronal differentiation and activity. A better understanding of the regulation and function of E2s is needed to better understand the role played by the ubiquitination process in physiological mechanisms and pathophysiological alterations involved in neurodevelopmental or neurodegenerative diseases.}, } @article {pmid39596609, year = {2024}, author = {Luglio, A and Maggi, E and Riviello, FN and Conforti, A and Sorrentino, U and Zuccarello, D}, title = {Hereditary Neuromuscular Disorders in Reproductive Medicine.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596609}, issn = {2073-4425}, support = {PNRR-MR1-2022-12376108//European Union/ ; }, mesh = {Humans ; *Neuromuscular Diseases/genetics/diagnosis ; Female ; Pregnancy ; Reproductive Medicine/methods ; Genetic Testing/methods ; Prenatal Diagnosis ; Preimplantation Diagnosis ; Muscular Atrophy, Spinal/genetics ; Charcot-Marie-Tooth Disease/genetics/diagnosis ; }, abstract = {Neuromuscular disorders (NMDs) encompass a broad range of hereditary and acquired conditions that affect motor units, significantly impacting patients' quality of life and reproductive health. This narrative review aims to explore in detail the reproductive challenges associated with major hereditary NMDs, including Charcot-Marie-Tooth disease (CMT), dystrophinopathies, Myotonic Dystrophy (DM), Facioscapulohumeral Muscular Dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Limb-Girdle Muscular Dystrophy (LGMD), and Amyotrophic Lateral Sclerosis (ALS). Specifically, it discusses the stages of diagnosis and genetic testing, recurrence risk estimation, options for preimplantation genetic testing (PGT) and prenatal diagnosis (PND), the reciprocal influence between pregnancy and disease, potential obstetric complications, and risks to the newborn.}, } @article {pmid39596615, year = {2024}, author = {Papapanagiotou, AP and Anthimidou, EA and Eleftherohorinos, IG and Giantsis, IA}, title = {Comparison of Molecularly Identified Resistant and Susceptible Johnsongrass (Sorghum halepense L.) Populations at ALS Gene, in the Absence and Presence of Field Crops.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596615}, issn = {2073-4425}, mesh = {*Herbicide Resistance/genetics ; *Acetolactate Synthase/genetics ; *Sorghum/genetics/growth & development ; *Herbicides/pharmacology ; Plant Weeds/genetics/growth & development/drug effects ; Plant Proteins/genetics ; Zea mays/genetics/growth & development ; Crops, Agricultural/genetics/growth & development ; Genotype ; Biomass ; Helianthus/genetics/growth & development ; }, abstract = {BACKGROUND/OBJECTIVES: Johnsongrass (Sorghum halepense) is an erect tetraploid, perennial, C4 grass weed species categorized among the world's most noxious weeds due to its high competitive ability against crops and the increased number of field-evolved herbicide-resistant populations. The aim of the present study was to assess the growth rate and performance of resistant (R) johnsongrass genotypes hosting Trp574Leu target-site cross-resistance at ALS gene, inhibiting various herbicides, compared to susceptible (S) conspecific weeds, in the absence and presence of corn or sunflower antagonism.

METHODS: The aboveground biomass, tiller, and rhizome production ability of one S and one R johnsongrass population with a Trp574-Leu substitution conferring cross-resistance to ALS-inhibiting herbicides were compared under non-competitive conditions. Furthermore, the competitive ability of these two johnsongrass populations against corn or sunflower was determined in a target-neighborhood design.

RESULTS: The S and R johnsongrass populations displayed similar growth rates concerning aboveground biomass and tiller number, whereas the R population displayed a slightly greater growth rate for rhizome production compared to the S population. Both populations grown with corn produced more aboveground biomass than the ones grown with sunflowers. The aboveground biomass of corn was reduced to a greater extent than sunflower by the presence of both johnsongrass populations, while both crops were affected more by the S than by the R population.

CONCLUSIONS: Although the inheritance and the genetic background of plant materls were not addressed, the findings of this study indicate clearly that the growth rate and competitive ability of the ALS-resistant johnsongrass population are not associated with the resistance mechanism involved.}, } @article {pmid39596631, year = {2024}, author = {Sneha, NP and Dharshini, SAP and Taguchi, YH and Gromiha, MM}, title = {Tracing ALS Degeneration: Insights from Spinal Cord and Cortex Transcriptomes.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596631}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Transcriptome ; *Spinal Cord/metabolism/pathology ; Frontal Lobe/metabolism/pathology ; Gene Regulatory Networks ; Motor Neurons/metabolism/pathology ; }, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons. Key factors contributing to neuronal death include mitochondrial energy damage, oxidative stress, and excitotoxicity. The frontal cortex is crucial for action initiation, planning, and voluntary movements whereas the spinal cord facilitates communication with the brain, walking, and reflexes. By investigating transcriptome data from the frontal cortex and spinal cord, we aim to elucidate common pathological mechanisms and pathways involved in ALS for understanding the disease progression and identifying potential therapeutic targets.

METHODS: In this study, we quantified gene and transcript expression patterns, predicted variants, and assessed their functional effects using computational tools. It also includes predicting variant-associated regulatory effects, constructing functional interaction networks, and performing a gene enrichment analysis.

RESULTS: We found novel genes for the upregulation of immune response, and the downregulation of metabolic-related and defective degradation processes in both the spinal cord and frontal cortex. Additionally, we observed the dysregulation of histone regulation and blood pressure-related genes specifically in the frontal cortex.

CONCLUSIONS: These results highlight the distinct and shared molecular disruptions in ALS, emphasizing the critical roles of immune response and metabolic dysfunction in neuronal degeneration. Targeting these pathways may provide new therapeutic avenues to combat neurodegeneration and preserve neuronal health.}, } @article {pmid39596864, year = {2024}, author = {McKenna, MC and Kleinerova, J and Power, A and Garcia-Gallardo, A and Tan, EL and Bede, P}, title = {Quantitative and Computational Spinal Imaging in Neurodegenerative Conditions and Acquired Spinal Disorders: Academic Advances and Clinical Prospects.}, journal = {Biology}, volume = {13}, number = {11}, pages = {}, pmid = {39596864}, issn = {2079-7737}, support = {2023//Spastic Paraplegia Foundation/ ; }, abstract = {Introduction: Quantitative spinal cord imaging has facilitated the objective appraisal of spinal cord pathology in a range of neurological conditions both in the academic and clinical setting. Diverse methodological approaches have been implemented, encompassing a range of morphometric, diffusivity, susceptibility, magnetization transfer, and spectroscopy techniques. Advances have been fueled both by new MRI platforms and acquisition protocols as well as novel analysis pipelines. The quantitative evaluation of specific spinal tracts and grey matter indices has the potential to be used in diagnostic and monitoring applications. The comprehensive characterization of spinal disease burden in pre-symptomatic cohorts, in carriers of specific genetic mutations, and in conditions primarily associated with cerebral disease, has contributed important academic insights. Methods: A narrative review was conducted to examine the clinical and academic role of quantitative spinal cord imaging in a range of neurodegenerative and acquired spinal cord disorders, including hereditary spastic paraparesis, hereditary ataxias, motor neuron diseases, Huntington's disease, and post-infectious or vascular disorders. Results: The clinical utility of specific methods, sample size considerations, academic role of spinal imaging, key radiological findings, and relevant clinical correlates are presented in each disease group. Conclusions: Quantitative spinal cord imaging studies have demonstrated the feasibility to reliably appraise structural, microstructural, diffusivity, and metabolic spinal cord alterations. Despite the notable academic advances, novel acquisition protocols and analysis pipelines are yet to be implemented in the clinical setting.}, } @article {pmid39598025, year = {2024}, author = {Vacchiano, V and Morabito, F and Bonan, L and Teodorani, L and Faini, C and Rizzo, G and Liguori, R}, title = {Reverse Split Hand as a Neurophysiological Hallmark of Spinal Muscular Atrophy.}, journal = {Journal of clinical medicine}, volume = {13}, number = {22}, pages = {}, pmid = {39598025}, issn = {2077-0383}, abstract = {Objective: Motor unit number estimation (MUNE) methods are crucial for estimating lower motor neuron loss in motor neuron diseases. The MScanFit MUNE (MScanFit) is a novel method that estimates MUNE values from compound motor action potential (CMAP) scans, demonstrating high sensitivity and reproducibility in detecting motor unit loss in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we aimed to characterize the pattern of motor unit loss in the hand intrinsic muscles of SMA patients compared to ALS patients and healthy controls (HC) using MScanFit MUNE. Methods: Patients diagnosed with ALS, adult SMA patients, and HC were prospectively enrolled. MScanFit examinations were performed on the abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. To focus on the different patterns of motor neuron degeneration in the intrinsic hand muscles, the ratio of CMAP amplitude of APB to ADM (CMAP ratio) and the ratio of MUNE values of APB to those of the ADM muscle (MUNE ratio) were calculated. Results: The study included 46 ALS patients, 16 SMA patients, and 23 HC. MScanFit MUNE revealed distinct patterns of motor unit degeneration in SMA patients, notably more severe in the ADM than in the APB muscle, indicating a "reverse" split-hand phenomenon. Both CMAP and MUNE ratios demonstrated high diagnostic accuracy in distinguishing ALS from SMA, with the MUNE ratio performing better. Conclusions: MScanFit MUNE is a valuable tool for exploring distinct patterns of motor neuron degeneration in patients with different types of motor neuron diseases.}, } @article {pmid39598374, year = {2024}, author = {Li, Y and Fu, J and Wang, H}, title = {Advancements in Targeting Ion Channels for the Treatment of Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {11}, pages = {}, pmid = {39598374}, issn = {1424-8247}, support = {2023YFF1205500//National Key Research and Development Program of China/ ; 82471465//NSFC/ ; C2024202005//Distinguished Young Scholars Science Fund of the Natural Science Foundation of Hebei Province/ ; JZX2023002//Technology Project of Hebei Education Department/ ; 22JCQNJC01110//Tianjin Applied Basic Research Project/ ; 236Z2602G, 246Z2605G, 236Z2401G//the central government guides local funds for science and technology development for Hebei Province/ ; NV20230015//The Key Laboratory of Neural and Vascular Biology, Ministry of Education/ ; }, abstract = {Ion channels are integral membrane proteins embedded in biological membranes, and they comprise specific proteins that control the flow of ion transporters in and out of cells, playing crucial roles in the biological functions of different cells. They maintain the homeostasis of water and ion metabolism by facilitating ion transport and participate in the physiological processes of neurons and glial cells by regulating signaling pathways. Neurodegenerative diseases are a group of disorders characterized by the progressive loss of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Despite significant progress in understanding the pathophysiological processes of various neurological diseases in recent years, effective treatments for mitigating the damage caused by these diseases remain inadequate. Increasing evidence suggests that ion channels are closely associated with neuroinflammation; oxidative stress; and the characteristic proteins in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Therefore, studying the pathogenic mechanisms closely related to ion channels in neurodegenerative diseases can help identify more effective therapeutic targets for treating neurodegenerative diseases. Here, we discuss the progress of research on ion channels in different neurodegenerative diseases and emphasize the feasibility and potential of treating such diseases from the perspective of ion channels.}, } @article {pmid39601192, year = {2025}, author = {Sørensen, DM and Tankisi, H}, title = {Reliability of MScanFit Motor Unit Number Estimation in the Trapezius Muscle.}, journal = {Muscle & nerve}, volume = {71}, number = {2}, pages = {166-170}, doi = {10.1002/mus.28303}, pmid = {39601192}, issn = {1097-4598}, support = {//Aage & Johanne Louis-Hansens Foundation/ ; //Grosserer L. F. Foghts Foundation/ ; //Dagmar Marshalls Fond/ ; //The Jascha Foundation,/ ; //Lundbeck Foundation/ ; }, mesh = {Humans ; Male ; *Superficial Back Muscles/physiology ; Female ; Reproducibility of Results ; Adult ; *Electromyography/methods ; *Action Potentials/physiology ; Motor Neurons/physiology ; Young Adult ; Middle Aged ; Recruitment, Neurophysiological/physiology ; Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; }, abstract = {INTRODUCTION/AIMS: MScanFit motor unit number estimation (MUNE) is the most recent MUNE method which has shown promising results in extremity muscles, but it has not been applied to bulbar muscles. Bulbar muscles are particularly important in the diagnosis of amyotrophic lateral sclerosis (ALS). This study aimed to investigate the feasibility and reliability of MScanFit MUNE in the accessory nerve and trapezius muscles.

METHODS: A total of twenty healthy participants were examined twice within 1-2 weeks. We extracted the MScanFit MUNE and size parameter, and compound muscle action potential (CMAP) amplitude values. The reliability of these parameters was assessed using the intra-rater coefficient of variation (CoV), intraclass correlation coefficient (ICC), and Bland-Altman plots. We also correlated MUNE values with CMAP amplitudes using correlation coefficients.

RESULTS: Mean MUNE values (Day 1 = 132.1 and Day 2 = 137.4), CMAP amplitudes (Day 1 = 9.71 mV and Day 2 = 10.10 mV) and size parameters did not differ between the two sessions (p > 0.05). CoV showed excellent reliability for MUNE values, size parameters, and CMAP amplitudes (CoV < 7%) whereas ICCs showed moderate reliability for MUNE values (ICC = 0.619), poor to moderate reliability for size parameters (between 0.393 and 0.689), and good reliability for CMAP amplitude (ICC = 0.864) There was no correlation between MUNE values and CMAP amplitudes.

DISCUSSION: MScanFit MUNE is applicable and mostly reliable in the trapezius muscle. Further studies in patients are needed to investigate the sensitivity of MScanFit in this muscle in detecting motor unit loss, particularly in ALS.}, } @article {pmid39602508, year = {2024}, author = {Lynch, EM and Pittman, S and Daw, J and Ikenaga, C and Chen, S and Dhavale, DD and Jackrel, ME and Ayala, YM and Kotzbauer, P and Ly, CV and Pestronk, A and Lloyd, TE and Weihl, CC}, title = {Seeding-competent TDP-43 persists in human patient and mouse muscle.}, journal = {Science translational medicine}, volume = {16}, number = {775}, pages = {eadp5730}, pmid = {39602508}, issn = {1946-6242}, support = {RF1 NS110436/NS/NINDS NIH HHS/United States ; R35 GM153303/GM/NIGMS NIH HHS/United States ; R01 NS138499/NS/NINDS NIH HHS/United States ; F32 NS124841/NS/NINDS NIH HHS/United States ; K24 AR073317/AR/NIAMS NIH HHS/United States ; R01 AG031867/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; *DNA-Binding Proteins/metabolism ; Mice ; *Muscle, Skeletal/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Myositis, Inclusion Body/metabolism/pathology ; Disease Models, Animal ; }, abstract = {TAR DNA binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous systems of some patients with neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy. TDP-43 aggregates from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis, and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding-competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with sporadic inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and ALS, we found that TDP-43 seeding capacity was specific to IBM. TDP-43 seeding capacity anticorrelated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.}, } @article {pmid39602529, year = {2024}, author = {Jin, S and Tian, Y and Hacker, J and Chen, X and Bertolio, M and Reynolds, C and Jarvis, R and Hu, J and Promes, V and Halim, D and Gao, FB and Yang, Y}, title = {Inflammatory cytokines disrupt astrocyte exosomal HepaCAM-mediated protection against neuronal excitotoxicity in the SOD1G93A ALS model.}, journal = {Science advances}, volume = {10}, number = {48}, pages = {eadq3350}, pmid = {39602529}, issn = {2375-2548}, support = {R37 NS057553/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; R01 AG078728/AG/NIA NIH HHS/United States ; R01 NS118747/NS/NINDS NIH HHS/United States ; R01 NS125490/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Astrocytes/metabolism ; *Exosomes/metabolism ; Mice ; Humans ; *Cytokines/metabolism ; *Disease Models, Animal ; *Superoxide Dismutase-1/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism ; }, abstract = {Astrocyte secreted signals substantially affect disease pathology in neurodegenerative diseases. It remains little understood about how proinflammatory cytokines, such as interleukin-1α/tumor necrosis factor-α/C1q (ITC), often elevated in neurodegenerative diseases, alter astrocyte-secreted signals and their effects in disease pathogenesis. By selectively isolating astrocyte exosomes (A-Exo.) and employing cell type-specific exosome reporter mice, our current study showed that ITC cytokines significantly reduced A-Exo. secretion and decreased spreading of focally labeled A-Exo. in diseased SOD1G93A mice. Our results also found that A-Exo. were minimally associated with misfolded SOD1 and elicited no toxicity to mouse spinal and human iPSC-derived motor neurons. In contrast, A-Exo. were neuroprotective against excitotoxicity, which was completely diminished by ITC cytokines and partially abolished by SOD1G93A expression. Subsequent proteomic characterization of A-Exo. and genetic analysis identified that surface expression of glial-specific HepaCAM preferentially mediates A-Exo's axon protection effect. Together, our study defines a cytokine-induced loss-of-function mechanism of A-Exo. in protecting neurons from excitotoxicity in amyotrophic lateral sclerosis.}, } @article {pmid39603486, year = {2025}, author = {Krus, KL and Benitez, AM and Strickland, A and Milbrandt, J and Bloom, AJ and DiAntonio, A}, title = {Two cardinal features of ALS, reduced STMN2 and pathogenic TDP-43, synergize to accelerate motor decline in mice.}, journal = {Experimental neurology}, volume = {384}, number = {}, pages = {115068}, pmid = {39603486}, issn = {1090-2430}, support = {R37 NS065053/NS/NINDS NIH HHS/United States ; R01 NS087632/NS/NINDS NIH HHS/United States ; RF1 AG013730/AG/NIA NIH HHS/United States ; R01 NS119812/NS/NINDS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Stathmin/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Mice, Transgenic ; Mice, Inbred C57BL ; Male ; }, abstract = {Pathological TDP-43 loss from the nucleus and cytoplasmic aggregation occurs in almost all cases of ALS and half of frontotemporal dementia patients. Stathmin2 (Stmn2) is a key target of TDP-43 regulation and aberrantly spliced Stmn2 mRNA is found in patients with ALS, frontotemporal dementia, and Alzheimer's Disease. STMN2 participates in the axon injury response and its depletion in vivo partially replicates ALS-like symptoms including progressive motor deficits and distal NMJ denervation. The interaction between STMN2 loss and TDP-43 dysfunction has not been studied in mice because TDP-43 regulates human but not murine Stmn2 splicing. Therefore, we generated trans-heterozygous mice that lack one functional copy of Stmn2 and express one mutant TDP-43[Q331K] knock-in allele to investigate whether reduced STMN2 function exacerbates TDP-43-dependent pathology. Indeed, we observe synergy between these two alleles, resulting in an early onset, progressive motor deficit. Surprisingly, this behavioral defect is not accompanied by detectable neuropathology in the brain, spinal cord, peripheral nerves or at neuromuscular junctions (NMJs). However, the trans-heterozygous mice exhibit abnormal mitochondrial morphology in their distal axons and NMJs. As both STMN2 and TDP-43 affect mitochondrial dynamics, and neuronal mitochondrial dysfunction is a cardinal feature of many neurodegenerative diseases, this abnormality likely contributes to the observed motor deficit. These findings demonstrate that partial loss of STMN2 significantly exacerbates TDP-43-associated phenotypes, suggesting that STMN2 restoration could ameliorate TDP-43 related disease before the onset of degeneration.}, } @article {pmid39603574, year = {2024}, author = {Wen, J and Li, Y and Qin, Y and Yan, L and Zhang, K and Li, A and Wang, Z and Yu, F and Lai, J and Yang, W and Liu, YU and Qin, D and Su, H}, title = {Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis.}, journal = {Pharmacological research}, volume = {210}, number = {}, pages = {107518}, doi = {10.1016/j.phrs.2024.107518}, pmid = {39603574}, issn = {1096-1186}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Phenanthridines/pharmacology/therapeutic use ; *Amaryllidaceae Alkaloids/pharmacology/therapeutic use ; *Caenorhabditis elegans/drug effects/metabolism ; *Motor Neurons/drug effects/pathology/metabolism ; Humans ; *Disease Models, Animal ; TDP-43 Proteinopathies/drug therapy/metabolism/pathology ; DNA-Binding Proteins/metabolism/genetics ; Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; }, abstract = {Aggregation of TAR-DNA binding protein-43 (TDP-43) is a pathological feature present in nearly 97 % cases of amyotrophic lateral sclerosis (ALS), making it an attractive target for pathogenic studies and drug screening. Here, we have performed a high-throughput screening of 1500 compounds from a natural product library and identified that lycorine, a naturally occurring alkaloid, significantly decreases the level of TDP-43[A315T] in a cellular model. We further demonstrate that lycorine reduces the level of TDP-43[A315T] both through inhibiting its synthesis and by promoting its degradation by the ubiquitin-proteasome system (UPS). Importantly, treatment with lycorine significantly attenuates TDP-43 proteinopathy and improves functional recovery in TDP-43[A315T]-expressing Caenorhabditis elegans and mouse models. These findings suggest that lycorine is a promising lead compound that has therapeutic potential for ALS.}, } @article {pmid39604641, year = {2025}, author = {Mi, Y and Zhang, P and Hou, X and Ding, Y and Wang, Y and Du, H and Deng, M}, title = {A rare genetic variant in APEX1 is associated with familial amyotrophic lateral sclerosis with slow progression.}, journal = {Acta neurologica Belgica}, volume = {125}, number = {1}, pages = {191-203}, pmid = {39604641}, issn = {2240-2993}, support = {No. 82273915//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; *DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; Disease Progression ; Adult ; Aged ; Pedigree ; Mutation, Missense ; Genetic Variation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of motor neurons and progressive muscle weakness. We aimed to identify the pathogenic genetic variants in familial ALS (fALS) pedigrees and to elucidate their impact on the disease phenotype. Through the analysis of whole-genome sequencing data of 34 fALS probands that screened negative for mutations in the most common ALS-causing genes, we identified a rare missense variant in APEX1 (NM_001641.4: c.22G > A, p.Gly8Arg) associated with ALS in one pedigree. Fluorescence microscopy images using green fluorescent protein (GFP)-fusion proteins suggested that this amino acid substitution could cause an impairment in nuclear localization of the protein. We described the clinical characteristics of this cohort analyzed and found that patients carrying this variant exhibit lower motor neuron onset and prolonged survival. The relation between APEX1 and ALS occurrence has been elusive despite evidence of a neuroprotective role for the gene. This study provides evidence linking an APEX1 variant with fALS and information on the distinct clinical manifestation. This study contributes to the understanding of the genetic basis of ALS, as well as a potential mechanism leading to loss of neurons, highlighting possible opportunities of targeted treatment harnessing the DNA repair process or ameliorating the oxidative stress.}, } @article {pmid39605053, year = {2024}, author = {Horiuchi, M and Watanabe, S and Komine, O and Takahashi, E and Kaneko, K and Itohara, S and Shimada, M and Ogi, T and Yamanaka, K}, title = {ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {184}, pmid = {39605053}, issn = {2051-5960}, support = {JP23K06826//Japan Society for the Promotion of Science/ ; JP19KK0214//Japan Society for the Promotion of Science/ ; JP22H00467//Japan Society for the Promotion of Science/ ; JP22ek0109426//Japan Agency for Medical Research and Development/ ; JP24wm0425014//Japan Agency for Medical Research and Development/ ; JP24wm0625301//Japan Agency for Medical Research and Development/ ; }, mesh = {Animals ; *Oligodendroglia/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Mice, Transgenic ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mutation ; Spinal Cord/metabolism/pathology ; Mice, Inbred C57BL ; }, abstract = {Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and its pathogenic mechanism is mediated by both loss-of-function and gain-of-toxicity of TDP-43. However, the role of TDP-43 gain-of-toxicity in oligodendrocytes remains unclear. To investigate the impact of excess TDP-43 on oligodendrocytes, we established transgenic mice overexpressing the ALS-linked mutant TDP-43[M337V] in oligodendrocytes through crossbreeding with Mbp-Cre mice. Two-step crossbreeding of floxed TDP-43[M337V] and Mbp-Cre mice resulted in the heterozygous low-level systemic expression of TDP-43[M337V] with (Cre-positive) or without (Cre-negative) oligodendrocyte-specific overexpression of TDP-43[M337V]. Although Cre-negative mice also exhibit subtle motor dysfunction, TDP-43[M337V] overexpression in oligodendrocytes aggravated clasping signs and gait disturbance accompanied by myelin pallor in the corpus callosum and white matter of the lumbar spinal cord in Cre-positive mice. RNA sequencing analysis of oligodendrocyte lineage cells isolated from whole brains of 12-month-old transgenic mice revealed downregulation of myelinating oligodendrocyte marker genes and cholesterol-related genes crucial for myelination, along with marked upregulation of apoptotic pathway genes. Immunofluorescence staining showed cleaved caspase 3-positive apoptotic oligodendrocytes surrounded by activated microglia and astrocytes in aged transgenic mice. Collectively, our findings demonstrate that an excess amount of ALS-linked mutant TDP-43 expression in oligodendrocytes exacerbates motor dysfunction in mice, likely through oligodendrocyte dysfunction and neuroinflammation. Therefore, targeting oligodendrocyte protection, particularly through ameliorating TDP-43 pathology, could represent a potential therapeutic approach for ALS.}, } @article {pmid39605399, year = {2024}, author = {Tuddenham, JF and Fujita, M and Khairallah, A and Harbison, C and Flowers, XE and Coronas-Samano, G and Maniatis, S and Daly, A and Schneider, JA and Teich, AF and Vonsattel, JPG and Sims, PA and Elyaman, W and Bradshaw, EM and Phatnani, H and Shneider, N and Bennett, DA and De Jager, PL and Przedborski, S and Menon, V and Olah, M}, title = {Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.12.623183}, pmid = {39605399}, issn = {2692-8205}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; R25 MH129256/MH/NIMH NIH HHS/United States ; }, abstract = {Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.}, } @article {pmid39605556, year = {2024}, author = {Singer-Clark, T and Hou, X and Card, NS and Wairagkar, M and Iacobacci, C and Peracha, H and Hochberg, LR and Stavisky, SD and Brandman, DM}, title = {Speech motor cortex enables BCI cursor control and click.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39605556}, issn = {2692-8205}, support = {DP2 DC021055/DC/NIDCD NIH HHS/United States ; }, abstract = {Decoding neural activity from ventral (speech) motor cortex is known to enable high-performance speech brain-computer interface (BCI) control. It was previously unknown whether this brain area could also enable computer control via neural cursor and click, as is typically associated with dorsal (arm and hand) motor cortex. We recruited a clinical trial participant with ALS and implanted intracortical microelectrode arrays in ventral precentral gyrus (vPCG), which the participant used to operate a speech BCI in a prior study. We developed a cursor BCI driven by the participant's vPCG neural activity, and evaluated performance on a series of target selection tasks. The reported vPCG cursor BCI enabled rapidly-calibrating (40 seconds), accurate (2.90 bits per second) cursor control and click. The participant also used the BCI to control his own personal computer independently. These results suggest that placing electrodes in vPCG to optimize for speech decoding may also be a viable strategy for building a multi-modal BCI which enables both speech-based communication and computer control via cursor and click.}, } @article {pmid39605661, year = {2024}, author = {Zimyanin, V and Dash, BP and Großmann, D and Simolka, T and Glaß, H and Verma, R and Khatri, V and Deppmann, C and Zunder, E and Redemann, S and Hermann, A}, title = {Axonal transcriptome reveals upregulation of PLK1 as a protective mechanism in response to increased DNA damage in FUS [P525L] spinal motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.20.624439}, pmid = {39605661}, issn = {2692-8205}, support = {R01 NS091617/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in the gene FUSED IN SARCOMA (FUS) are among the most frequently occurring genetic forms of amyotrophic lateral sclerosis (ALS). Early pathogenesis of FUS -ALS involves impaired DNA damage response and axonal degeneration. However, it is still poorly understood how these gene mutations lead to selective spinal motor neuron (MN) degeneration and how nuclear and axonal phenotypes are linked. To specifically address this, we applied a compartment specific RNA-sequencing approach using microfluidic chambers to generate axonal as well as somatodendritic compartment-specific profiles from isogenic induced pluripotent stem cells (iPSCs)-derived MNs. We demonstrate high purity of axonal and soma fractions and show that the axonal transcriptome is unique and distinct from that of somas including significantly fewer number of transcripts. Functional enrichment analysis revealed that differentially expressed genes (DEGs) in axons were mainly enriched in key pathways like RNA metabolism and DNA damage, complementing our knowledge of early phenotypes in ALS pathogenesis and known functions of FUS. In addition, we demonstrate a strong enrichment for cell cycle associated genes including significant upregulation of polo-like kinase 1 (PLK1) in FUS [P525L] mutant MNs. PLK1 was increased upon DNA damage induction and PLK1 inhibition further increased the number of DNA damage foci in etoposide-treated cells, an effect that was diminished in case of FUS mutant MNs. In contrast, inhibition of PLK1 increased late apoptotic or necrosis-induced neuronal cell death in mutant neurons. Taken together, our findings provide insights into compartment-specific transcriptomics in human FUS -ALS MNs and we propose that specific upregulation of PLK1 might represent an early event in the pathogenesis of ALS, possibly modulating DNA damage response and other associated pathways.}, } @article {pmid39606178, year = {2024}, author = {Tröger, J and Dörr, F and Schwed, L and Linz, N and König, A and Thies, T and Barbe, MT and Orozco-Arroyave, JR and Rusz, J}, title = {Corrigendum: An automatic measure for speech intelligibility in dysarthrias-validation across multiple languages and neurological disorders.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1488178}, doi = {10.3389/fdgth.2024.1488178}, pmid = {39606178}, issn = {2673-253X}, abstract = {[This corrects the article DOI: 10.3389/fdgth.2024.1440986.].}, } @article {pmid39606446, year = {2024}, author = {Du, M and Akerman, SC and Fare, CM and Ruan, L and Vidensky, S and Mamedova, L and Lee, J and Rothstein, JD}, title = {Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39606446}, issn = {2693-5015}, support = {P50 AG005146/AG/NIA NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.}, } @article {pmid39608571, year = {2025}, author = {Diggins, L and Ross, D and Bhanot, S and Corallo, R and Daley, R and Patel, K and Lewis, O and Donahue, S and Thaddeus, J and Hiers, L and Syed, C and Eagerton, D and Mohanty, BK}, title = {CD spectra reveal the state of G-quadruplexes and i-motifs in repeated and other DNA sequences.}, journal = {Biophysical reports}, volume = {5}, number = {1}, pages = {100187}, pmid = {39608571}, issn = {2667-0747}, mesh = {*G-Quadruplexes ; *Circular Dichroism ; *DNA/chemistry/genetics ; Hydrogen-Ion Concentration ; Humans ; *Nucleotide Motifs ; Base Sequence ; *Repetitive Sequences, Nucleic Acid ; Temperature ; }, abstract = {The B-DNA of the genome contains numerous sequences that can form various noncanonical structures including G-quadruplex (G4), formed by two or more stacks of four guanine residues in a plane, and intercalating motif (i-motif [iM]) formed by alternately arranged C-C[+] pairs. One of the easy yet sensitive methods to study G4s and iMs is circular dichroism (CD) spectroscopy, which generates characteristic G4 and iM peaks. We have analyzed and compared the effects of various environmental factors including pH, buffer composition, temperature, flanking sequences, complimentary DNA strands, and single-stranded DNA binding protein (SSB) on the CD patterns of G4s and iMs generated by two groups of DNA molecules, one containing tandem repeats of GGGGCC and CCCCGG from the C9ORF72 gene associated with amyotrophic lateral sclerosis and frontotemporal dementia, and the second containing polyG/polyC clusters from oncogene promoter-proximal regions without such tandem repeats. Changes in pH caused drastic changes in CCCCGG-iM and GGGGCC-G4 and the changes were dependent on repeat numbers and G-C basepairing. In contrast, with the DNA sequences from the promoter-proximal regions of oncogenes, iMs disassembled upon pH changes with the peak slowly shifting to lower wavelength but the G4s did not show significant change. Complementary DNA strands and flanking DNA sequences also regulate G4 and iM formation. The SSB disassembled both G4s and iMs formed by almost all sequences suggesting an in vivo role for SSBs in the disassembly of G4s and iMs during DNA replication and other DNA transactions.}, } @article {pmid39608699, year = {2025}, author = {Kale, MB and Wankhede, NL and Bishoyi, AK and Ballal, S and Kalia, R and Arya, R and Kumar, S and Khalid, M and Gulati, M and Umare, M and Taksande, BG and Upaganlawar, AB and Umekar, MJ and Kopalli, SR and Fareed, M and Koppula, S}, title = {Emerging biophysical techniques for probing synaptic transmission in neurodegenerative disorders.}, journal = {Neuroscience}, volume = {565}, number = {}, pages = {63-79}, doi = {10.1016/j.neuroscience.2024.11.055}, pmid = {39608699}, issn = {1873-7544}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/physiopathology ; *Synaptic Transmission/physiology ; Animals ; Synapses/metabolism/pathology/physiology ; }, abstract = {Plethora of research has shed light on the critical role of synaptic dysfunction in various neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Synapses, the fundamental units for neural communication in the brain, are highly vulnerable to pathological conditions and are central to the progression of neurological diseases. The presynaptic terminal, a key component of synapses responsible for neurotransmitter release and synaptic communication, undergoes structural and functional alterations in these disorders. Understanding synaptic transmission abnormalities is crucial for unravelling the pathophysiological mechanisms underlying neurodegeneration. In the quest to probe synaptic transmission in NDDs, emerging biophysical techniques play a pivotal role. These advanced methods offer insights into the structural and functional changes occurring at nerve terminals in conditions like AD, PD, HD & ALS. By investigating synaptic plasticity and alterations in neurotransmitter release dynamics, researchers can uncover valuable information about disease progression and potential therapeutic targets. The review articles highlighted provide a comprehensive overview of how synaptic vulnerability and pathology are shared mechanisms across a spectrum of neurological disorders. In major neurodegenerative diseases, synaptic dysfunction is a common thread linking these conditions. The intricate molecular machinery involved in neurotransmitter release, synaptic vesicle dynamics, and presynaptic protein regulation are key areas of focus for understanding synaptic alterations in neurodegenerative diseases.}, } @article {pmid39608855, year = {2024}, author = {Budworth, L and Wilson, B and Sutton-Klein, J and Basu, S and O'Keeffe, C and Mason, SM and Ang, A and Anne-Wilson, S and Reynard, K and Croft, S and Shah, AD and Bank, S and Conner, M and Lawton, R}, title = {Is emergency doctors' tolerance of clinical uncertainty on a novel measure associated with doctor well-being, healthcare resource use and patient outcomes?.}, journal = {Emergency medicine journal : EMJ}, volume = {42}, number = {1}, pages = {}, pmid = {39608855}, issn = {1472-0213}, abstract = {INTRODUCTION: Emergency doctors routinely face uncertainty-they work with limited patient information, under tight time constraints and receive minimal post-discharge feedback. While higher uncertainty tolerance (UT) among staff is linked with reduced resource use and improved well-being in various specialties, its impact in emergency settings is underexplored. We aimed to develop a UT measure and assess associations with doctor-related factors (eg, experience), patient outcomes (eg, reattendance) and resource use (eg, episode costs).

METHODS: From May 2021 to February 2022, emergency doctors (specialty trainee 3 and above) from five Yorkshire (UK) departments completed an online questionnaire. This included a novel UT measure-an adapted Physicians' Reaction to Uncertainty scale collaboratively modified within our team according to Hillen et al's (2017) UT model. The questionnaire also included well-being-related measures (eg, Brief Resilience Scale) and assessed factors like doctors' seniority. Patient encounters involving prespecified 'uncertainty-inducing' problems (eg, headache) were analysed. Multilevel regression explored associations between doctor-level factors, resource use and patient outcomes.

RESULTS: 39 doctors were matched with 384 patients. The UT measure demonstrated high reliability (Cronbach's α=0.92) and higher UT was significantly associated with better psychological well-being including greater resilience (Pearson's r=0.56; 95% CI=0.30 to 0.74) and lower burnout (eg, Cohen's d=-2.98; -4.62 to -1.33; mean UT difference for 'no' vs 'moderate/high' burnout). UT was not significantly associated with resource use (eg, episode costs: β=-0.07; -0.32 to 0.18) or patient outcomes including 30-day readmission (eg, OR=0.82; 0.28 to 2.35).

CONCLUSIONS: We developed a reliable UT measure for emergency medicine. While higher UT was linked to doctor well-being, its impact on resource use and patient outcomes remains unclear. Further measure validation and additional research including intervention trials are necessary to confirm these findings and explore the implications of UT in emergency practice.}, } @article {pmid39610104, year = {2025}, author = {Bar Avi, O and Perlson, E}, title = {Navigating the pathways: TAR-DNA-binding-protein-43 aggregation, axonal transport, and local synthesis in amyotrophic lateral sclerosis pathology.}, journal = {Neural regeneration research}, volume = {20}, number = {10}, pages = {2921-2922}, pmid = {39610104}, issn = {1673-5374}, } @article {pmid39611137, year = {2024}, author = {Valančius, D and Burnytė, B and Masaitienė, R and Morkūnienė, A and Klimašauskienė, A}, title = {Rapidly Progressing and Early-Onset Forms of Amyotrophic Lateral Sclerosis Caused by a Novel SOD1 Variant in a Lithuanian Family.}, journal = {Neurology. Genetics}, volume = {10}, number = {6}, pages = {e200217}, pmid = {39611137}, issn = {2376-7839}, abstract = {OBJECTIVES: To describe a novel familial variant of superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS) in a Lithuanian family, highlighting its variable progression and implications for treatment inclusion criteria.

METHODS: This study presents the clinical and genetic findings of a family with the novel SOD1 variant, including one member diagnosed with early-onset ALS (onset <40 years) and one with a particularly rapidly progressing course of ALS.

RESULTS: The SOD1 variant NM_000454.5:c.446T>C, NP_000445.1:p.(Val149Ala) was identified in affected family members and 4 asymptomatic members aged 32-56 years. We present detailed disease course of the affected family members obtained during follow-up. Clinically, this variant is associated with variable disease progression, with the time from symptom onset to death ranging from 5 to 77 months.

DISCUSSION: The novel SOD1 variant p.Val149Ala in this Lithuanian family causes ALS of variable onset and course, including a case of early-onset ALS and one case of rapidly progressing ALS, necessitating recognition by the scientific community and development of tailored therapeutic approaches.}, } @article {pmid39611310, year = {2025}, author = {Diaz, F and Thornton, JS and Wastling, SS and Asaab, A and Morrow, JM and Zafeiropoulos, N and Bresee, C and Allred, P and Avalos, P and Lewis, RA and Baloh, RH and Svendsen, CN}, title = {Longitudinal Quantitative MRI Provides Responsive Outcome Measures for Early and Late Muscle Changes in ALS.}, journal = {Muscle & nerve}, volume = {71}, number = {2}, pages = {171-182}, doi = {10.1002/mus.28306}, pmid = {39611310}, issn = {1097-4598}, support = {CLIN2-09284//This study was supported with funding from The California Institute of Regenerative Medicine./ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; *Disease Progression ; Longitudinal Studies ; *Magnetic Resonance Imaging ; Muscle Strength/physiology ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Outcome Assessment, Health Care ; Clinical Trials, Phase I as Topic ; }, abstract = {INTRODUCTION/AIMS: Studies have demonstrated the potential of muscle MRIs to measure disease progression in ALS. However, the responsiveness and utility of quantitative muscle MRIs in an ALS clinical trial remain unknown. This study aimed to determine the responsiveness of quantitative muscle MRIs to measure disease progression in ALS.

METHODS: Longitudinal quantitative muscle MRIs were obtained in an ALS study that delivered human neural progenitor cells to the spinal cord (NCT02943850). Participants underwent MRIs at baseline, 1, 3, 6, 9, and 12 months. MRI measures included fat fraction (ff), water T2 (T 2m), cross-sectional area (CSA), and remaining muscle area (RMA). Non-MRI measures included strength via Accurate Test of Limb Isometric Strength (ATLIS) and the ALSFRS-R. Standardized response means (SRM) were calculated at 1, 3, 6, and 12 months.

RESULTS: Significant increases in muscle FF and decreases in CSA and RMA were seen as early as 1 month from baseline. At 6 months, the most responsive measures were muscle FF (SRMthigh = 1.85, SRMcalf = 1.39), T 2m (SRMthigh = 1.2, SRMcalf = 1.71), CSA (SRMthigh = -1.58, SRMcalf = -1.14), RMA (SRMthigh = -1.77, SRMcalf = -1.28), and strength tested via ATLIS (SRMknee extension = -1.79, SRMknee flexion = -1.3). The ALSFRS-R was the least responsive at 6 months (SRM = -0.85). Muscle FF and T 2m correlated with ALSFRS-R leg subscores and MRI measures demonstrated varying degrees of correlation with strength.

DISCUSSION: High responsiveness and low variability make quantitative muscle MRI a novel and complementary outcome measure for ALS clinical trials.}, } @article {pmid39611550, year = {2025}, author = {Veyrat-Durebex, C and Osman, S and Al Ojaimi, Y and Gosset, P and Dupuy, C and Lefevre, A and Emond, P and Vourc'h, P and Corcia, P and Mereghetti, L and Kempf, F and Raoul, C and Blasco, H}, title = {Gut metabolomic and microbiota analyses in ALS mice reveal specific metabolites despite the absence of significant gut dysbiosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {368-374}, doi = {10.1080/21678421.2024.2433578}, pmid = {39611550}, issn = {2167-9223}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/microbiology ; *Gastrointestinal Microbiome/physiology ; Mice ; *Dysbiosis/metabolism ; Disease Models, Animal ; Metabolomics ; Feces/microbiology ; Mice, Transgenic ; Male ; Female ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase/genetics ; }, abstract = {OBJECTIVE: Over the past years, interest in the role of gut microbiota in neurodegenerative diseases has emerged. Despite numerous publications over the past decade, both in human and pre-clinical studies, there is no clear consensus on the microbiota's role or involvement in ALS. Few studies on mouse models of ALS highlighted a correlation between specific bacteria species and the prognostic or severity of the disease. Still these results lack reproducibility and remain controverted. In this article we present a study of fecal microbiota in the SOD1[G93A] mouse model associated with a metabolomic analysis of cecum content, compared to controls.

METHODS: Intestinal metabolomic profile and fecal microbiota were assessed in two cohorts of SOD[G93A] mice compared to wildtype controls at the terminal stage of the ALS disease.

RESULTS: Results showed a significant difference in metabolomic profile in SOD1[G93A] mice compared to controls but without a marked change in composition and diversity of fecal microbiota. Nevertheless, we observed an increase of Lachnospiraceae family, which are butyrate-producer bacteria, in SOD1[G93A] mice. Moreover, some metabolites with significantly different intestinal concentrations are partially produced and linked with intestinal bacteria, such as riboflavin, hippurate, and N-acetylputrescine, leaving us convinced of the interest in looking further into the role of the microbiota in ALS.

CONCLUSIONS: Despite an alteration of the intestinal metabolome in SOD1[G93A] mice, microbiota data did not show significant changes, underlying the need for further research.}, } @article {pmid39612643, year = {2024}, author = {Egorov, VV and Grudinina, NA and Polyakov, DS and Zabrodskaya, YA and Gavrilova, NV and Shavlovsky, MM}, title = {Spontaneous formation of different forms of alpha-synuclein fibrils from a recombinant protein.}, journal = {Biochemical and biophysical research communications}, volume = {741}, number = {}, pages = {151068}, doi = {10.1016/j.bbrc.2024.151068}, pmid = {39612643}, issn = {1090-2104}, mesh = {*alpha-Synuclein/metabolism/chemistry ; *Recombinant Proteins/chemistry/metabolism/genetics ; Humans ; *Amyloid/chemistry/metabolism ; Protein Processing, Post-Translational ; Protein Conformation ; }, abstract = {Alpha-synuclein is a protein, the conformational changes of which lead to the development of such socially significant diseases as Parkinson's disease and amyotrophic lateral sclerosis. The methods for differential diagnostics of these diseases based on the use of alpha-synuclein in a non-native conformation obtained from patients as a seed for inducing fibrillogenesis and studying the morphology of the resulting amyloid-like fibrils were described in a number of studies. The authors associate such properties of the seed with the presence of post-translational modifications in the protein obtained from patients. At the same time, the production of fibrils differing in morphology from recombinant alpha-synuclein under various conditions of fibrillogenesis is also described. In this work, we show that the formation of morphologically distinct fibril types from recombinant alpha-synuclein lacking post-translational modifications is possible under the same conditions, and that spontaneously arising different fibril types, when used as a seed for fibrillogenesis, lead to the formation of recombinant protein fibrils morphological similar to the parental seed. The results of the work can be used both in studying the fundamental mechanisms of conformation transfer and in developing test systems for synucleinopathies.}, } @article {pmid39612826, year = {2025}, author = {Xu, H and Cheng, J and Leng, Q and Cao, R and Su, W and Sun, L and Xue, F and Han, Y and Wu, R}, title = {Characterization of acetolactate synthase genes and resistance mechanisms of multiple herbicide resistant Lolium multiflorum.}, journal = {Plant physiology and biochemistry : PPB}, volume = {219}, number = {}, pages = {109324}, doi = {10.1016/j.plaphy.2024.109324}, pmid = {39612826}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Herbicide Resistance/genetics ; *Lolium/genetics/enzymology/drug effects ; *Herbicides/pharmacology ; *Plant Proteins/genetics/metabolism ; Imidazoles/pharmacology ; Genes, Plant ; Mutation ; }, abstract = {Combining imidazolinone-tolerant wheat with imazamox presents an effective solution to combat weed resistance. However, Lolium multiflorum, a troublesome resistant weed infesting wheat fields, may have developed resistance to imazamox, and the potential resistance mechanisms are intriguing. In this study, we explored the susceptibility of L. multiflorum to imazamox and investigated the resistance mechanisms, including the contribution of the target enzyme acetolactate synthase (ALS) to resistance and the presence of non-target-site resistance (NTSR). Eight L. multiflorum populations suspected of being resistant to imazamox were collected, and six populations exhibited resistance, ranging from 2.45-fold to 16.32-fold. The LmALS1 gene from susceptible population D3 plants and multiple copies of the LmALS gene (LmALS1, LmALS2, LmALS2α, LmALS3, LmALS3α, LmALS3β) from resistant populations D5 and D8 plants were separately amplified. Two mutations (Pro/Gln197 to Thr, Trp574 to Leu) were found in LmALS1 in the resistant populations. Compared to D3, LmALS1 was overexpressed in D5 but not in D8. The presence of LmALS1 mutants (LmALS1-Thr197 and LmALS1- Leu574), along with LmALS2, LmALS3, and their subunits, contribute to the resistance phenotype by increasing bonding energies, weakening hydrogen bonds, or decreasing protein binding pocket volumes and surface area. Additionally, D5 and D8 populations exhibited multiple resistance (>40-fold) to three other ALS inhibitors: pyroxsulam, flucarbazone-sodium, and mesosulfuron-methyl. Pre-treatment with malathion and 4-chloro-7-nitrobenzoxadiazole (cytochrome P450 monooxygenase and glutathione S-transferase inhibitors respectively) reversed the resistance of the D8 population and partially reversed the resistance of the D5 population to imazamox. This study characterizes ALS genes and extends our knowledge into the ALS resistance mechanisms involved in L. multiflorum. It also deepens our understanding of the complex diversification resistance mechanisms, thereby facilitating advances in weed resistance management strategies in wheat fields.}, } @article {pmid39614020, year = {2025}, author = {Shi, DL and Grifone, R and Zhang, X and Li, H}, title = {Rbm24-mediated post-transcriptional regulation of skeletal and cardiac muscle development, function and regeneration.}, journal = {Journal of muscle research and cell motility}, volume = {46}, number = {1}, pages = {53-65}, pmid = {39614020}, issn = {1573-2657}, support = {23545//the French Muscular Dystrophy Association/ ; }, mesh = {*RNA-Binding Proteins/metabolism/genetics ; Humans ; Animals ; *Muscle, Skeletal/metabolism/physiology ; *Regeneration/physiology ; *Muscle Development/physiology/genetics ; *Myocardium/metabolism ; *RNA Processing, Post-Transcriptional ; Cell Differentiation ; }, abstract = {RNA-binding proteins are critically involved in the post-transcriptional control of gene expression during embryonic development and in adult life, contributing to regulating cell differentiation and maintaining tissue homeostasis. Compared to the relatively well documented functions of transcription factors, the regulatory roles of RNA-binding proteins in muscle development and function remain largely elusive. However, deficiency of many RNA-binding proteins has been associated with muscular defects, neuromuscular disorders and heart diseases, such as myotonic dystrophy, amyotrophic lateral sclerosis, and cardiomyopathy. Rbm24 is highly conserved among vertebrates and is one of the best characterized RNA-binding proteins with crucial implication in the myogenic and cardiomyogenic programs. It presents the distinctive particularity of displaying highly restricted expression in both skeletal and cardiac muscles, with changes in subcellular localization during the process of differentiation. Functional analyses using different vertebrate models have clearly demonstrated its requirement for skeletal muscle differentiation and regeneration as well as for myocardium organization and cardiac function, by regulating the expression of both common and distinct target genes in these tissues. The challenge remains to decipher the dynamic feature of post-transcriptional circuits regulated by Rbm24 during skeletal myogenesis, cardiomyogenesis, and muscle repair. This review discusses current understanding of its function in striated muscles and its possible implication in human disease, with the aim of identifying research gaps for future investigation.}, } @article {pmid39615150, year = {2025}, author = {Garbey, M and Lesport, Q and Öztosun, G and Ghodasara, V and Kaminski, HJ and Bayat, E}, title = {Improving care for amyotrophic lateral sclerosis with artificial intelligence and affective computing.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123328}, doi = {10.1016/j.jns.2024.123328}, pmid = {39615150}, issn = {1878-5883}, support = {U54 NS115054/NS/NINDS NIH HHS/United States ; R43 NS124329/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/physiopathology/diagnosis ; Male ; Female ; *Artificial Intelligence ; Middle Aged ; Aged ; *Emotions/physiology ; Natural Language Processing ; Adult ; }, abstract = {BACKGROUND: Patients with ALS often face difficulties expressing emotions due to impairments in facial expression, speech, body language, and cognitive function. This study aimed to develop non-invasive AI tools to detect and quantify emotional responsiveness in ALS patients, providing objective insights. Improved understanding of emotional responses could enhance patient-provider communication, telemedicine effectiveness, and clinical trial outcome measures.

METHODS: In this preliminary exploratory study, fourteen patients with ALS had audio recordings performed during routine clinic visits while wearing a wireless pulse oximeter. Emotion-triggering questions related to symptom progression, breathing, mobility, feeding tube, and financial burden were randomly asked. The same questions were posed in separate psychiatric evaluations. Natural language processing (NLP) was used to analyze transcriptions, topic classifications, sentiment, and emotional states, combining pulse and speech data. AI-generated reports summarized the findings.

RESULTS: Pulse alterations consistent with emotional arousal were identified, with longer consultations and positive communication reducing pulse fluctuations. Financial concerns triggered the strongest emotional response, while discussions about breathing, mobility, and feeding tube increased anxiety. AI-generated reports prioritized patient concerns and streamlined documentation for providers.

CONCLUSIONS: This study introduces a novel approach to linking pulse and speech analysis to evaluate emotional responses in ALS patients. AI and affective computing provide valuable insights into emotional responses and disease progression, with potential applications for other neurological disorders. This approach could augment clinical trial outcomes by offering a more comprehensive view of patient well-being.}, } @article {pmid39616446, year = {2025}, author = {Rutkove, SB and McIlduff, CE and Stommel, E and Levy, S and Smith, C and Gutierrez, H and Verga, S and Samaan, S and Yator, C and Nanda, A and Sonbas-Cobb, B and Capella, T and Pastel, L and Doussan, A and Phipps, K and Murphy, E and Halter, R}, title = {Thoracic electrical impedance tomography for assessing progression of pulmonary dysfunction in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {296-302}, pmid = {39616446}, issn = {2167-9223}, support = {R21 NS118434/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/diagnostic imaging ; Female ; *Electric Impedance ; Middle Aged ; *Tomography/methods ; Disease Progression ; Aged ; Vital Capacity/physiology ; Respiratory Function Tests/methods ; *Lung Diseases/etiology/diagnostic imaging/physiopathology ; Longitudinal Studies ; Adult ; *Lung/physiopathology/diagnostic imaging ; }, abstract = {Objective: We compared thoracic electrical impedance tomography (EIT) with slow vital capacity (SVC) to determine if EIT could monitor pulmonary function in ALS patients longitudinally. Methods: Of 32 ALS patients and 32 age- and sex-matched healthy controls (HCs) initially enrolled in the Pulmonary Function via Impedance Tomography (PuFIT) study, 22 ALS and 20 HCs returned for a follow-up visit ∼3.9 months later. All participants had thoracic EIT measurements performed simultaneously with standard SVC in upright and supine positions at both visits. EIT data from each measurement were summarized as a single parameter, the impedance-SVC (zSVC), representing an averaged impedance change across both lungs. We assessed alterations over time for both cohorts of participants. Results: Sufficient quality EIT and SVC data were available for 18 of the patients with ALS and 19 HCs. Over time, mean upright SVC significantly declined by 5% in the ALS group and did not change in the healthy group. Supine SVC showed no change in either group. Although mean trajectories of zSVC mirrored mean SVC trajectories in both participant cohorts, changes in zSVC in ALS patients did not reach significance, due to greater variability in the repeated measures. Conclusion: Despite strong cross-sectional correlations to SVC, EIT did not detect a decline in pulmonary function over approximately four months. Increased variability in EIT data explains the lack of sensitivity to change. Technological improvements and special care with electrode placement will be needed for EIT to reach its full potential in longitudinal assessment of pulmonary function in ALS.}, } @article {pmid39616922, year = {2024}, author = {Santurtún, A and Medín, P and Riancho, JA and Santiago-Setién, M and Ortiz, F and López de Munain, A and Almendra, R and Riancho, J}, title = {Temporo-spatial analysis of amyotrophic lateral sclerosis in Spain: Altitude and land use as new determinants of the disease.}, journal = {The Science of the total environment}, volume = {957}, number = {}, pages = {177796}, doi = {10.1016/j.scitotenv.2024.177796}, pmid = {39616922}, issn = {1879-1026}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Spain/epidemiology ; Humans ; Male ; Female ; *Altitude ; Spatio-Temporal Analysis ; Middle Aged ; Aged ; Incidence ; Adult ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Currently, ALS is conceived as the result of the interaction between genetics, environmental factors, and aging. This study analyzed the spatial and temporal patterns of ALS in Spain, delving into the potential relationships between altitude, land cover, and this disease.

METHODOLOGY: ALS death data were collected over a 19-year period, including information on sex, age and municipality of residence. The standardized mortality rate was calculated for each municipality of residencia, and Anselin's local Moran's I statistic was used to identify clusters of high and low incidence. Altitude data were sourced from the Copernicus Land Monitoring Services, while land cover data came from CORINE satellite images and national agricultural statistics.

RESULTS: The average annual incidence of ALS deaths among adults was 2.5 per 100,000 people. Higher mortality rates were noted in males (2.8) than in females (2.3), with both sexes exhibiting a rising mortality trend in a temporal analysis. Cluster analysis revealed that high mortality areas were mostly located in the North and Northeast of the country. Municipalities in these clusters had significantly lower median altitudes and larger areas of Permanently Irrigated Arable Land and Broad-Leaved Forest.

CONCLUSION: This study provides new evidence about the increase in ALS cases in European countries during the last decades, reporting for the first time altitude and certain agricultural land uses as potential geographic determinants of the disease.}, } @article {pmid39617118, year = {2025}, author = {Liang, YF and Niu, ZX and Wu, ZW and Zhang, QY and Zhao, XY and Chao, LL and Li, H and Gao, WY}, title = {Catalytic insights of acetolactate synthases from different bacteria.}, journal = {Archives of biochemistry and biophysics}, volume = {764}, number = {}, pages = {110248}, doi = {10.1016/j.abb.2024.110248}, pmid = {39617118}, issn = {1096-0384}, mesh = {*Acetolactate Synthase/chemistry/metabolism/genetics ; *Bacillus subtilis/enzymology ; Molecular Docking Simulation ; *Klebsiella pneumoniae/enzymology ; *Listeria/enzymology ; Pyruvic Acid/metabolism/chemistry ; Substrate Specificity ; *Bacterial Proteins/chemistry/metabolism/genetics ; Amino Acid Sequence ; Butyrates ; }, abstract = {Acetolactate synthase (ALS) is an essential enzyme involved in the biosynthesis of platform chemicals acetoin and 2,3-butanediol in several microorganisms. In this study, we investigated the catalytic differences among three bacterial ALSs involved in the ligation of two molecules of pyruvate or 2-ketobutyrate. Based on the findings, we predicted three amino acid residues in each enzyme that caused a discrepancy in accordance with the multi-sequence alignment and molecular docking experiments: I398, A402, and T480 in Bacillus subtilis ALS; V400, Y404, and S482 in Listeria seleigeri serovar 1/2b ALS; and M394, H398, and G476 in Klebsiella pneumoniae ALS. Subsequently, we mutually mutated the residues in the three ALSs. The data obtained confirmed our inference that these three residues in each enzyme are truly correlated with substrate recognition, particularly in recognizing compounds that are larger than pyruvate, such as 2-ketobutyrate, benzaldehyde, and nitrosobenzene. This study further clarifies the biochemical traits of ALSs derived from various bacteria and expands the scope of ALS research.}, } @article {pmid39617896, year = {2024}, author = {Feng, R and Zhu, Q and Wang, A and Wang, H and Wang, J and Chen, P and Zhang, R and Liang, D and Teng, J and Ma, M and Ding, X and Wang, X}, title = {Effect of fecal microbiota transplantation on patients with sporadic amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled trial.}, journal = {BMC medicine}, volume = {22}, number = {1}, pages = {566}, pmid = {39617896}, issn = {1741-7015}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Fecal Microbiota Transplantation/methods ; Double-Blind Method ; Female ; Male ; Middle Aged ; Aged ; Gastrointestinal Microbiome/physiology ; Treatment Outcome ; Quality of Life ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the progressive loss of motor neurons. Recent insights into ALS pathogenesis underscore the pivotal role of the gut microbiome, prompting an investigation into the potential therapeutic impact of fecal microbiota transplantation (FMT) on sporadic ALS patients.

METHODS: Conducted as a double-blind, placebo-controlled, parallel-group, randomized clinical trial, the study enrolled 27 participants from October 2022 to April 2023. The participants were followed up for 6 months from February 2023 to October 2023, during in-person visits at baseline, week 15, week 23, and week 35. The participants, evenly randomized, received either healthy donor FMT (FMT, n = 14) or a mixture of 0.9% saline and food coloring (E150c) as sham transplantation (placebo, n = 13). The primary outcome measured the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score from baseline to week 35. Secondary outcomes included changes in gastrointestinal and respiratory functions, muscle strength, autonomic function, cognition, quality of life, intestinal microbiome composition, and plasm neurofilament light chain protein (NFL). Efficacy and safety outcomes were assessed in the intention-to-treat population.

RESULTS: A total of 27 randomized patients (47% women; mean age, 67.2 years), 24 participants completed the entire study. Notably, ALSFRS-R score changes exhibited no significant differences between FMT (6.1 [SD, 3.11]) and placebo (6.41[SD, 2.73]) groups from baseline to week 35. Secondary efficacy outcomes, encompassing respiratory function, muscle strength, autonomic function, cognition, quality of life, and plasm NFL, showed no significant differences. Nevertheless, the FMT group exhibited improvements in constipation, depression, and anxiety symptoms. FMT induced a shift in gut microbiome community composition, marked by increased abundance of Bifidobacterium, which persisted until week 15 (95% CI, 0.04 to 0.28; p = 0.01). Gastrointestinal adverse events were the primary manifestations of FMT-related side effects.

CONCLUSIONS: In this clinical trial involving 27 sporadic ALS patients, FMT did not significantly slow the decline in ALSFRS-R score. Larger multicenter trials are needed to confirm the efficacy of FMT in sporadic ALS patients and to explore the underlying biological mechanisms.

TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR 2200064504.}, } @article {pmid39620262, year = {2025}, author = {Chen, Y and Sun, S and Yun, Y and Sun, X and Xin, J and Shao, K and Lin, P and Yu, D and Yan, C and Liu, S}, title = {Connectivity-based striatal subregion microstructural changes in sporadic amyotrophic lateral sclerosis patients: Relation to motor disability, cognitive deficits, and serum biomarkers.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16577}, pmid = {39620262}, issn = {1468-1331}, support = {2020M672067//China Postdoctoral Science Foundation/ ; NSFC82001354//National Natural Science Foundation of China/ ; NSFC82471395//National Natural Science Foundation of China/ ; ZR2023LSW020//Shandong Provincial Natural Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; Aged ; *Biomarkers/blood ; *Cognitive Dysfunction/blood/etiology/diagnostic imaging/pathology/physiopathology ; Retrospective Studies ; *Corpus Striatum/diagnostic imaging/pathology ; Adult ; Neurofilament Proteins/blood ; Diffusion Tensor Imaging ; Diffusion Magnetic Resonance Imaging ; }, abstract = {BACKGROUND AND PURPOSE: To date, no previous studies have used multishell diffusion MRI to identify striatal microstructural damage in vivo in amyotrophic lateral sclerosis (ALS) patients. Thus, in the present study, we aimed to comprehensively explore connectivity-based selective striatal subregion microstructural damage in sporadic ALS patients and its associations with motor disability, cognitive deficits, and serum biomarkers.

METHODS: In this retrospective study, 79 ALS patients and 53 healthy controls (HCs) who underwent clinical assessment, serum neurofilament light (NfL) measurement, genetic testing, and multishell diffusion MRI scanning were included. Using a probabilistic tractography approach, the striatum was segmented into six subregions based on their corticostriatal connectivity. Three neurite orientation dispersion and density imaging (NODDI) parameters, the neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISO), of the connectivity-based striatal subregions were measured.

RESULTS: Compared with HCs, ALS patients had a significantly lower NDI in the bilateral motor and right frontal subregions, a significantly lower ODI in the right motor and frontal subregions, and a significantly higher ISO in the bilateral motor and frontal subregions of the striatum after familywise error (p < 0.05). Moreover, striatal subregion microstructural damage was significantly correlated with motor disabilities, cognitive deficits, and serum NfL levels in ALS patients (p = 0.020-0.002).

CONCLUSIONS: Our study provides clear evidence demonstrating that connectivity-based selective striatal subregion microstructural damage is a definite feature of sporadic ALS patients and suggesting that striatal damage may play an important role in motor disability and cognitive deficits in ALS patients.}, } @article {pmid39621126, year = {2024}, author = {Mikhailova, MM and Klein, OI and Patsaev, TD and Panteleyev, AA}, title = {Co-culture of postnatal mouse spinal cord and skeletal muscle explants as an experimental model of neuromuscular interactions.}, journal = {Histochemistry and cell biology}, volume = {163}, number = {1}, pages = {15}, pmid = {39621126}, issn = {1432-119X}, support = {1п.2.3//National Research Center "Kurchatov Institute"/ ; 1п.2.3//National Research Center "Kurchatov Institute"/ ; 1п.2.3//National Research Center "Kurchatov Institute"/ ; 1п.2.3//National Research Center "Kurchatov Institute"/ ; }, mesh = {Animals ; Mice ; *Muscle, Skeletal/metabolism ; *Coculture Techniques ; *Spinal Cord/metabolism ; Mice, Inbred C57BL ; Animals, Newborn ; }, abstract = {The intercommunication between nerves and muscles plays an important role in the functioning of our body, and its failure leads to severe neuromuscular disorders such as spinal muscular atrophy and amyotrophic lateral sclerosis. Understanding the cellular and molecular mechanisms underlying nerve-muscle interactions and mediating their mutual influence is an integral part of strategies aimed at curing neuromuscular diseases. Here, we propose a novel ex vivo experimental model for the spinal cord (SC) and skeletal muscle interactions which for the first time utilizes only fully formed (but not yet quite functional) postnatal tissues. The model represents an organotypic co-culture comprising a longitudinal slice of the mouse postnatal SC and an extensor digitorum longus (EDL) muscle explant placed in the "damage zone" of transversally dissected longitudinal slice of the SC. Using this model, we have shown that SC tissue stimulates muscle contractions and reduces the area occupied by acetylcholine receptors on muscle surface. In turn, EDL muscles stimulate the growth of SC-derived neurites. Thus, our organotypic model allows one to assess the mutual influence of neurons and muscles in a nearly natural setting which maintains the architecture and cellular composition of intact tissues. Therefore, this model may provide an effective platform for studying molecular and cellular mechanisms linked to defective neuromuscular interactions in associated pathologies.}, } @article {pmid39621188, year = {2025}, author = {Gerometta, M and Henderson, RD and Friend, R and Cooper, LT and Zhao, J and Boyd, AW and Bartlett, PF}, title = {Evaluation of NUN-004, a Novel Engineered Ephrin Antagonist, in Healthy Volunteers and Patients with Amyotrophic Lateral Sclerosis: A Phase I/Ib, Open-Label, Escalating Dose and Extended Access Study.}, journal = {Clinical drug investigation}, volume = {45}, number = {1}, pages = {17-28}, pmid = {39621188}, issn = {1179-1918}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Adult ; Dose-Response Relationship, Drug ; Aged ; Healthy Volunteers ; *Receptor, EphA4/antagonists & inhibitors ; Half-Life ; Young Adult ; *Recombinant Fusion Proteins/pharmacokinetics/adverse effects/administration & dosage/therapeutic use ; }, abstract = {BACKGROUND: Erythropoietin-producing hepatocellular carcinoma A4 (EphA4) is implicated in the pathophysiology of amyotrophic lateral sclerosis. EphA4 fusion protein (EphA4-Fc) inhibits EphA4 function in vivo but is too short-lived for prolonged therapy. NUN-004 (mEphA4-Fc) is a modified EphA4-Fc engineered for an extended half-life.

OBJECTIVE: This first-in-human phase I/Ib study evaluated the safety, tolerability, pharmacokinetics, immunogenicity and efficacy of NUN-004 in healthy volunteers and patients with amyotrophic lateral sclerosis.

METHODS: In this open-label study, Part 1 enrolled 20 healthy volunteers in five single ascending dose cohorts (1, 3, 10, 20 and 30 mg/kg), followed by Part 2, which enrolled eight patients with amyotrophic lateral sclerosis in two multiple ascending dose cohorts (cycle 1: 15 and 30 mg/kg) who could continue into an extended access phase (cycles 2-6: 15 mg/kg) for a total of 6 months' treatment. All participants received intravenous NUN-004; multiple dosing was administered weekly in 28-day cycles. Primary endpoints included safety assessments, single-dose and multiple-dose pharmacokinetics, and anti-drug antibodies. Efficacy assessments were Amyotrophic Lateral Sclerosis Function Rating Score Revised (ALSFRS-R) and forced vital capacity.

RESULTS: NUN-004 was well tolerated, with no serious adverse events or discontinuations. NUN-004 exposure generally increased with dose. Single-dose half-life was 111.7 (± 22.8) h in healthy volunteers (n = 20) and 74.4 (± 19.4) h in patients (n = 6). Steady state was observed in patients by day 8. Steady-state half-life (cycle 1 doses 2-4) was 83.7 (± 26.6) to 101.1 (± 46.0) h. No antibody response was observed. ALSFRS-R showed a slight improvement (+0.09 points/month) to cycle 4 and a slight decline (-0.35 points/month) over the whole study. Forced vital capacity trends were consistent with ALSFRS-R.

CONCLUSIONS: This study supports the safety, tolerability and extended half-life of NUN-004, and provides preliminary evidence for its ability to ameliorate disease progression in an amyotrophic lateral sclerosis cohort.

CLINICAL TRIAL REGISTRATION: Registered on ANZCTR under identifier ACTRN12621000514808 (3 May, 2021).}, } @article {pmid39621705, year = {2024}, author = {Foldvari, KM and Stolee, P and Neiterman, E and Boscart, V and Tong, C}, title = {"…but I know something's not right here": Exploring the diagnosis and disclosure experiences of persons living with ALS.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0301249}, pmid = {39621705}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis ; Female ; Male ; Middle Aged ; Aged ; *Caregivers/psychology ; Disclosure ; Focus Groups ; Truth Disclosure ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), an incurable motor neuron disease, primarily affects those between the ages of 60-79, and has an approximate post-diagnosis life-expectancy of only two to five years. The condition has an unpredictable but ultimately terminal trajectory that poses challenges for patients, caregivers and healthcare providers. While the diagnosis and disclosure are critical periods for intervention and support, knowledge regarding the relational, communicational and psychodynamic forces that occur within the process of diagnostic disclosure is relatively limited.

OBJECTIVES: The purpose of this study was to explore the experiences of persons living with ALS in the diagnosis and disclosure of the condition, with the support of their caregivers.

METHODS: We conducted a focus group and in-depth individual interviews with people living with ALS (n = 9), and caregivers (n = 9). The interviews were transcribed, cleaned, and anonymized, and then entered into NVivo 11 for thematic analysis.

RESULTS: Participants discussed the diagnostic process, including inklings and subtle changes prior to diagnosis, attempts at self-diagnosis, and the lengthy assessment process. Time was also a consideration in the diagnostic disclosure process, in which participants shared how the disclosure was the product of longstanding conversations with their care providers. It was described as rarely a shock to finally have confirmation. Participants shared their information seeking strategies and needs for a diagnosis that, for them, typically came with insufficient information on the disease, prognosis, and next steps.

SIGNIFICANCE: This project serves as a step in bridging the relevant gaps in our knowledge and understanding towards improved person-centered care practices in the diagnosis and disclosure of ALS.}, } @article {pmid39621905, year = {2024}, author = {Van Nerom, M and Ahmed, J and Lazar, T and Meszaros, A and Galand, Q and De Malsche, W and Van Lindt, J and Pancsa, R and Maes, D and Tompa, P}, title = {C9orf72-linked arginine-rich dipeptide repeats aggravate pathological phase separation of G3BP1.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {50}, pages = {e2402847121}, pmid = {39621905}, issn = {1091-6490}, support = {952334//EC | Horizon 2020 Framework Programme (H2020)/ ; 778247//EC | Horizon 2020 Framework Programme (H2020)/ ; K124670//National Research, Development and Innovation Office/ ; K131702//National Research, Development and Innovation Office/ ; SRP51//Vrije Universiteit Brussel (VUB)/ ; A0-2004-070//European Space Agency (ESA)/ ; FWOSB77//Fonds Wetenschappelijk Onderzoek (FWO)/ ; 11D2522N//Fonds Wetenschappelijk Onderzoek (FWO)/ ; HBC.2022.0194//Agentschap Innoveren en Ondernemen (VLAIO)/ ; FK-142285//National Research, Development and Innovation Office/ ; BO/00174/22//Magyar Tudományos Akadémia (MTA)/ ; 184018//Tempus Közalapítvány (TPF)/ ; }, mesh = {*RNA Recognition Motif Proteins/metabolism/genetics/chemistry ; *Poly-ADP-Ribose Binding Proteins/metabolism/genetics/chemistry ; Humans ; *C9orf72 Protein/genetics/metabolism ; *RNA Helicases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Dipeptides/metabolism/chemistry ; *DNA Helicases/metabolism/genetics ; *Arginine/metabolism/chemistry ; *Nucleophosmin/genetics ; Frontotemporal Dementia/metabolism/genetics/pathology ; Stress Granules/metabolism ; DNA-Binding Proteins/metabolism/genetics/chemistry ; Heterogeneous Nuclear Ribonucleoprotein A1/metabolism/genetics ; Protein Binding ; Phase Separation ; }, abstract = {The toxic effects of C9orf72-derived arginine-rich dipeptide repeats (R-DPRs) on cellular stress granules in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia remain unclear at the molecular level. Stress granules are formed through the switch of Ras GTPase-activating protein-binding protein 1 (G3BP1) by RNA from a closed inactive state to an open activated state, driving the formation of the organelle by liquid-liquid phase separation (LLPS). We show that R-DPRs bind G3BP1 a thousand times stronger than RNA and initiate LLPS much more effectively. Their pathogenic effect is underscored by the slow transition of R-DPR-G3BP1 droplets to aggregated, ThS-positive states that can recruit ALS-linked proteins hnRNPA1, hnRNPA2, and TDP-43. Deletion constructs and molecular simulations show that R-DPR binding and LLPS are mediated via the negatively charged intrinsically disordered region 1 (IDR1) of the protein, allosterically regulated by its positively charged IDR3. Bioinformatic analyses point to the strong mechanistic parallels of these effects with the interaction of R-DPRs with nucleolar nucleophosmin 1 (NPM1) and underscore that R-DPRs interact with many other similar nucleolar and stress-granule proteins, extending the underlying mechanism of R-DPR toxicity in cells. Our results also highlight characteristic differences between the two R-DPRs, poly-GR and poly-PR, and suggest that the primary pathological target of poly-GR is not NPM1 in nucleoli, but G3BP1 in stress granules in affected cells.}, } @article {pmid39622292, year = {2025}, author = {Ojo, O and Boateng, J and Pacella, R and Hanrahan, A and Essex, R and Dibley, L}, title = {Factors Influencing the Care and Management of Diabetic Foot Ulcers: A Scoping Review.}, journal = {Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists}, volume = {31}, number = {3}, pages = {380-389}, doi = {10.1016/j.eprac.2024.11.010}, pmid = {39622292}, issn = {1530-891X}, mesh = {Humans ; *Diabetic Foot/therapy ; *Health Knowledge, Attitudes, Practice ; Patient Education as Topic ; Disease Management ; }, abstract = {OBJECTIVE: The objective of this scoping review is to explore the experiences of patients' and healthcare practitioners on the factors that influence the care and management of diabetes-related foot ulcers (DFUs).

METHODS: Levac et al's 6-stage framework and the Preferred Reporting Items for Systematic Review and Meta-analysis extension for scoping reviews, guided the review. The SPIDER tool was used to define key elements of the review question. Searches for relevant articles were conducted in electronic databases (PUBMED, CINAHL, AMED, Embase, Cochrane Database of Systematic Reviews, and PsycINFO), Google Scholar, and hand searches of reference lists.

RESULTS: Eight articles met the inclusion criteria and were included in the review. Three themes were identified: Communication and Education about DFUs; Challenges of managing DFUs; and Barriers to treatment and management. The themes are presented as a narrative synthesis.

CONCLUSION: Inadequate knowledge of diabetic foot care by patients and inconsistent communication by healthcare professionals were primary factors affecting the effective management of diabetes-related foot ulcers. Consistent, patient-focused education that is supported by knowledgeable health care professionals should form the foundation of effective diabetic foot ulcer care.}, } @article {pmid39623474, year = {2024}, author = {Hoyle, AC and Stevenson, R and Leonhardt, M and Gillett, T and Martinez-Hernandez, U and Gompertz, N and Clarke, C and Cazzola, D and Metcalfe, BW}, title = {Exploring the 'EarSwitch' concept: a novel ear based control method for assistive technology.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {210}, pmid = {39623474}, issn = {1743-0003}, mesh = {Humans ; Female ; Male ; Adult ; Middle Aged ; *Self-Help Devices ; Aged ; Tensor Tympani/physiology ; Young Adult ; Nervous System Diseases/rehabilitation ; Adolescent ; Motor Neuron Disease/rehabilitation ; Communication Devices for People with Disabilities ; Muscle Contraction/physiology ; Multiple Sclerosis/rehabilitation ; }, abstract = {BACKGROUND: Loss of communication with loved ones and carers is one of the most isolating and debilitating effects of many neurological disorders. Assistive technology (AT) supports individuals with communication, but the acceptability of AT solutions is highly variable. In this paper a novel ear based control method of AT, the concept of 'EarSwitch', is presented. This new approach is based on detecting ear rumbling, which is the voluntary contraction of the tensor tympani muscle (TTM), resulting in observable movement of the eardrum and a dull rumbling sound. 'EarSwitch' has the potential to be a discreet method that can complement existing AT control methods. However, only a subset of the population can ear rumble and little is known about the ability of rumbling in populations with neurological disorders.

METHODS: To explore the viability of the 'EarSwitch' concept as an AT control method we conducted in-depth online surveys with (N=1853) respondents from the general population and (N=170) respondents with self-declared neurological disorders including Motor Neurone Disease (MND) and Multiple Sclerosis (MS).This is the largest ever study to explore ear rumbling and the first to explore whether rumbling is preserved among individuals with neurological disorders. In addition, we validated rumbling, and investigated usability of the 'EarSwitch' concept as a control input, using in-person otoscopic examination with a subset of participants.

RESULTS: A significant proportion of the population with neurological disorders could benefit from 'EarSwitch' controllable AT. The upper bound prevalence of the ability to rumble without accompanying movements was 55% in the general population, 38% in the neurological population, and 20% of participants with MND (N=95) reported this ability. During the validation procedure, participants achieved high accuracy in self-reporting the ability to rumble (80%) and proved concept of using the 'EarSwitch' method to control a basic interface.

DISCUSSION: 'EarSwitch' is a potential new AT control method control, either by itself or as a supplement to other existing methods. Results demonstrate self-reported ear rumbling is present among patients with different neurological disorders, including MND. Further research should explore how well the ability to rumble is preserved in different types and stages of neurological disorders.}, } @article {pmid39623504, year = {2024}, author = {Gupta, R and Bhandari, M and Grover, A and Al-Shehari, T and Kadrie, M and Alfakih, T and Alsalman, H}, title = {Predictive modeling of ALS progression: an XGBoost approach using clinical features.}, journal = {BioData mining}, volume = {17}, number = {1}, pages = {54}, pmid = {39623504}, issn = {1756-0381}, support = {RSP2024R244//King Saud University/ ; }, abstract = {This research presents a predictive model aimed at estimating the progression of Amyotrophic Lateral Sclerosis (ALS) based on clinical features collected from a dataset of 50 patients. Important features included evaluations of speech, mobility, and respiratory function. We utilized an XGBoost regression model to forecast scores on the ALS Functional Rating Scale (ALSFRS-R), achieving a training mean squared error (MSE) of 0.1651 and a testing MSE of 0.0073, with R[2] values of 0.9800 for training and 0.9993 for testing. The model demonstrates high accuracy, providing a useful tool for clinicians to track disease progression and enhance patient management and treatment strategies.}, } @article {pmid39624674, year = {2024}, author = {Nakamura, K and Fujita, K and Suzuki, M and Kunugi, A and Hirozane, Y and Kunikata, T and Takahashi, B and Narazaki, G and Kondo, H and Haji, S and Hirai, K and Izumi, Y}, title = {Neuroinflammation and glycosylation-related cerebrospinal fluid proteins for predicting functional decline in amyotrophic lateral sclerosis: a proteomic study.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1418320}, pmid = {39624674}, issn = {1664-2295}, abstract = {BACKGROUND: The rate of disease progression varies widely among patients with amyotrophic lateral sclerosis (ALS). Prognostic assessment using biomarkers is highly anticipated to improve clinical trial design. We aimed to explore the cerebrospinal fluid (CSF) for prognostic biomarkers to predict future functional decline in patients with ALS.

METHODS: We collected CSF samples from 64 patients with ALS and 25 disease controls. The prospective progression rate was calculated using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) at CSF collection and in 6 months. The ALS patients were classified into slow, intermediate, and fast progression groups. We performed comprehensive proteomic analyses of the CSF samples. Factors with significant changes between slow and fast progression groups were investigated via receiver operating characteristic curve analyses. Moreover, the correlation of the CSF factors with progression rate was evaluated by multiple regression analyses.

RESULTS: In total, 26 proteins changed significantly (p < 0.05 and q < 0.10), with levels varying within a large dynamic range (fold change of >1.5 or < 0.5). A receiver operating characteristic curve analyses showed that the following proteins showed high discrimination power between slow and fast progression groups: glycoprotein non-metastatic melanoma protein B (GPNMB; area under the curve [AUC], 0.88), glial fibrillary acidic protein (AUC, 0.81), glypican-1 (GPC1; AUC, 0.79), alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase (AUC, 0.74), and chitinase-3-like protein 2 (CHI3L2; AUC, 0.73). Of these, GPNMB, GPC1, and CHI3L2 were significantly correlated to prognostic progression rate.

CONCLUSION: This study demonstrated that CSF levels of neuroinflammation and glycosylation-related proteins were significantly correlated with prospective progression rates in patients with ALS. These proteins could be useful prognostic biomarkers for ALS.}, } @article {pmid39624969, year = {2024}, author = {Yuan, D and Jiang, S and Xu, R}, title = {Clinical features and progress in diagnosis and treatment of amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2399962}, pmid = {39624969}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy/epidemiology/genetics ; Humans ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the central nervous system. Despite a large number of studies, the current prognosis of ALS is still not ideal. This article briefly describes the clinical features including epidemiology, genetic structure and clinical manifestations, as well as the progress of new diagnostic criteria and treatment of ALS. Meanwhile, we also discussed further both developments and improvements to enhance understanding and accelerating the introduction of the effective treatments of ALS.}, } @article {pmid39627617, year = {2024}, author = {Wiersema, AF and Rennenberg, A and Smith, G and Varderidou-Minasian, S and Pasterkamp, RJ}, title = {Shared and distinct changes in the molecular cargo of extracellular vesicles in different neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {479}, pmid = {39627617}, issn = {1420-9071}, support = {XS grant//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; GoALS//Stichting ALS Nederland/ ; TOTALS//Stichting ALS Nederland/ ; MUSALS//Stichting ALS Nederland/ ; ATAXALS//Stichting ALS Nederland/ ; MAXOMOD//E-rare3/ ; INTEGRALS//Rare-3/ ; TRIAGE//JPND/ ; }, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Biomarkers/analysis/metabolism ; *Cell Communication ; *Extracellular Vesicles/metabolism ; MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/diagnosis/metabolism/pathology ; Parkinson Disease/metabolism/pathology ; tau Proteins/metabolism ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) affect millions of people worldwide. Curative treatment for these neurodegenerative disorders is still lacking and therefore a further understanding of their cause and progression is urgently needed. Extracellular vesicles (EVs) are nanosized vesicles loaded with cargo, such as proteins and miRNAs, that are released by cells and play an important role in intercellular communication. Intercellular communication through EVs can contribute to the spread of pathological proteins, such as amyloid-beta and tau, or cause pathogenesis through other mechanisms. In addition, EVs may serve as potential biomarkers for diagnosis and for monitoring disease progression. In this review, we summarize and discuss recent advances in our understanding of the role of EVs in AD, ALS an PD with an emphasis on dysregulated cargo in each disease. We highlight shared dysregulated cargo between these diseases, discuss underlying pathways, and outline future implications for therapeutic strategies.}, } @article {pmid39627937, year = {2024}, author = {Gielas, AM}, title = {Wounds and Vulnerabilities. The Participation of Special Operations Forces in Experimental Brain-Computer Interface Research.}, journal = {Cambridge quarterly of healthcare ethics : CQ : the international journal of healthcare ethics committees}, volume = {}, number = {}, pages = {1-22}, doi = {10.1017/S096318012400063X}, pmid = {39627937}, issn = {1469-2147}, abstract = {Brain-computer interfaces (BCIs) exemplify a dual-use neurotechnology with significant potential in both civilian and military contexts. While BCIs hold promise for treating neurological conditions such as spinal cord injuries and amyotrophic lateral sclerosis in the future, military decisionmakers in countries such as the United States and China also see their potential to enhance combat capabilities. Some predict that U.S. Special Operations Forces (SOF) will be early adopters of BCI enhancements. This article argues for a shift in focus: the U.S. Special Operations Command (SOCOM) should pursue translational research of medical BCIs for treating severely injured or ill SOF personnel. After two decades of continuous military engagement and on-going high-risk operations, SOF personnel face unique injury patterns, both physical and psychological, which BCI technology could help address. The article identifies six key medical applications of BCIs that could benefit wounded SOF members and discusses the ethical implications of involving SOF personnel in translational research related to these applications. Ultimately, the article challenges the traditional civilian-military divide in neurotechnology, arguing that by collaborating more closely with military stakeholders, scientists can not only help individuals with medical needs, including servicemembers, but also play a role in shaping the future military applications of BCI technology.}, } @article {pmid39628659, year = {2024}, author = {Ye, Q and Li, X and Gao, W and Gao, J and Zheng, L and Zhang, M and Yang, F and Li, H}, title = {Role of Rho-associated kinases and their inhibitor fasudil in neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1481983}, pmid = {39628659}, issn = {1662-4548}, abstract = {Neurodegenerative diseases (NDDs) are prevalent in the elderly. The pathogenesis of NDDs is complex, and currently, there is no cure available. With the increase in aging population, over 20 million people are affected by common NDDs alone (Alzheimer's disease and Parkinson's disease). Therefore, NDDs have profound negative impacts on patients, their families, and society, making them a major global health concern. Rho-associated kinases (ROCKs) belong to the serine/threonine protein kinases family, which modulate diverse cellular processes (e.g., apoptosis). ROCKs may elevate the risk of various NDDs (including Huntington's disease, Parkinson's disease, and Alzheimer's disease) by disrupting synaptic plasticity and promoting inflammatory responses. Therefore, ROCK inhibitors have been regarded as ideal therapies for NDDs in recent years. Fasudil, one of the classic ROCK inhibitor, is a potential drug for treating NDDs, as it repairs nerve damage and promotes axonal regeneration. Thus, the current review summarizes the relationship between ROCKs and NDDs and the mechanism by which fasudil inhibits ROCKs to provide new ideas for the treatment of NDDs.}, } @article {pmid39628898, year = {2024}, author = {Stansberry, WM and Fiur, NC and Robins, MM and Pierchala, BA}, title = {Analysis of translatomic changes in the Ubqln2[P497S] model of ALS reveals that motor neurons express muscle-associated genes in non-disease states.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1491415}, pmid = {39628898}, issn = {1664-2295}, support = {R01 NS089585/NS/NINDS NIH HHS/United States ; T32 AG071444/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressively worsening motor symptoms that lead to eventual fatal paralysis. The number of gene mutations associated with ALS have increased dramatically in recent years, suggesting heterogeneity in the etiology of ALS and the need to develop new models of the disease that encompass these pathologies. In 2011, mutations in the UBQLN2 gene were identified in families with both ALS and frontotemporal dementia (FTD) and have since been linked to ubiquitinated TDP43 inclusion pathology. The involvement of UBQLN2 in ubiquitination and proteasome function suggests an important role in proteostasis, which is reported to be impaired in ALS.

METHODS: A UBQLN2 mouse model was generated for the P497S mutation and recapitulates some of the motor symptoms of ALS. We utilized ribosomal profiling followed by mRNA sequencing of associated transcripts to characterize gene expression changes of motor neurons in the Ubqln2[P497S] model and evaluated ALS phenotypes in these animals.

RESULTS: At 12 months of age, we observed reduced motor neuron survival and neuromuscular junction denervation in these mice that translated into motor deficits observed in locomotor behavioral trials. The sequencing of motor neuron transcripts revealed that Wnt pathways and muscle-related transcripts were downregulated in Ubqln2[P497S] mice, while metabolic pathways were upregulated.

DISCUSSION: Surprisingly, genes often reported to be muscle-specific, such as Desmin and Acta1, were expressed in motor neurons and were dramatically downregulated in symptomatic Ubqln2[P497S] mice. The expression of muscle transcripts by motor neurons suggests their potentially supportive role in skeletal muscle maintenance.}, } @article {pmid39629626, year = {2025}, author = {Boutin, RCT and Shobeirian, F and Adam, S and Lehman, A and Salvarinova, R and Friedman, JM}, title = {Immune Dysregulation in a Child With SOD1-Related Neurological Disease.}, journal = {American journal of medical genetics. Part A}, volume = {197}, number = {4}, pages = {e63949}, doi = {10.1002/ajmg.a.63949}, pmid = {39629626}, issn = {1552-4833}, support = {//Mining for Miracles (BCCH Foundation)/ ; //Genome British Columbia/ ; }, mesh = {Humans ; Male ; *Superoxide Dismutase-1/genetics ; Homozygote ; Young Adult ; Phenotype ; *Nervous System Diseases/genetics/immunology/pathology ; *Quadriplegia/genetics/pathology/immunology ; Child ; Mutation ; }, abstract = {Spastic tetraplegia and axial hypotonia (STAHP) associated with biallelic SOD1 deficiency is a recently described neurological disorder affecting children. Five studies have described a total of nine cases thus far, all characterized by the onset of progressive spastic tetraplegia beginning before 2 years of age. All but two of these cases are associated with homozygosity for the same genetic variant (NM_000454.4:c.335dupG; NP_000445.1:p.Cys112Trpfs*11) that leads to a non-functional enzyme product. More recently, a homozygous 3-base pair in-frame deletion (NM_000454.5: c.357_357+2delGGT) and a truncating frameshift variant (NM_000454.5: c.52_56del5ins154) in SOD1 have been described in similarly affected patients lacking SOD1 activity. Here we expand on the neurological and extra-neuronal phenotypes of STAHP in a patient with a novel homozygous SOD1 variant predicted to result in disrupted calcium- and zinc-binding activity of the encoded enzyme. We describe a 19-year-old male born to consanguineous parents who is homozygous for an NM_000454.4:c.369_371del SOD1 variant. The patient had progressive neuromuscular degeneration with onset before 1 year of age, consistent with a diagnosis of STAHP. Brain MRI at 7 years of age showed cerebellar atrophy, as has previously been described in this condition, as well as small optic nerves and a hypoplastic optic chiasm, which have not been reported previously. Our patient also exhibited clinical features of immune dysregulation with treatment-refractory inflammatory bowel disease, asthma, recurrent infections, and dermatitis. Overall, the early-onset progressive neurological disorder in our patient, found in association with homozygosity for an SOD1 variant that is predicted to result in impaired function of the transcribed protein, is consistent with a diagnosis of STAHP. Our patient also demonstrates optic atrophy and disrupted immune homeostasis, which have not been previously described as part of this condition. Taken together with previous case studies in children carrying loss-of-function variants of SOD1, this case highlights a possible role for antioxidant therapy in slowing disease progression in patients lacking SOD1 activity. These cases also draw attention to the need for careful consideration of possible harmful neuronal and extra-neuronal complications of proposed SOD1 knockdown therapies against ALS.}, } @article {pmid39630042, year = {2024}, author = {Zinman, L and Duni, E and Abrahao, A}, title = {Rethinking Drug Reimbursement Criteria in Amyotrophic Lateral Sclerosis.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {51}, number = {5}, pages = {606-607}, doi = {10.1017/cjn.2023.320}, pmid = {39630042}, issn = {0317-1671}, } @article {pmid39630626, year = {2024}, author = {Szeky, B and Jurakova, V and Fouskova, E and Feher, A and Zana, M and Karl, VR and Farkas, J and Bodi-Jakus, M and Zapletalova, M and Pandey, S and Kucera, R and Lochman, J and Dinnyes, A}, title = {Efficient derivation of functional astrocytes from human induced pluripotent stem cells (hiPSCs).}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0313514}, pmid = {39630626}, issn = {1932-6203}, mesh = {*Astrocytes/cytology/metabolism ; Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Cell Differentiation ; *S100 Calcium Binding Protein beta Subunit/metabolism ; Cytokines/metabolism ; Aquaporin 4/metabolism ; Glial Fibrillary Acidic Protein/metabolism ; Cells, Cultured ; }, abstract = {Astrocytes are specialized glial cell types of the central nervous system (CNS) with remarkably high abundance, morphological and functional diversity. Astrocytes maintain neural metabolic support, synapse regulation, blood-brain barrier integrity and immunological homeostasis through intricate interactions with other cells, including neurons, microglia, pericytes and lymphocytes. Due to their extensive intercellular crosstalks, astrocytes are also implicated in the pathogenesis of CNS disorders, such as ALS (amyotrophic lateral sclerosis), Parkinson's disease and Alzheimer's disease. Despite the critical importance of astrocytes in neurodegeneration and neuroinflammation are recognized, the lack of suitable in vitro systems limits their availability for modeling human brain pathologies. Here, we report the time-efficient, reproducible generation of astrocytes from human induced pluripotent stem cells (hiPSCs). Our hiPSC-derived astrocytes expressed characteristic astrocyte markers, such as GFAP, S100b, ALDH1L1 and AQP4. Furthermore, hiPSC-derived astrocytes displayed spontaneous calcium transients and responded to inflammatory stimuli by the secretion of type A1 and type A2 astrocyte-related cytokines.}, } @article {pmid39631325, year = {2024}, author = {Zhang, Y and Liu, Q and Xie, H and Zhang, W and Lin, X and Zhang, H and Yu, H and Ma, Y and Zhang, C and Geng, H and Shi, N and Cui, L and Li, B and Li, YF}, title = {Fecal microbiota transplantation as an effective way in treating methylmercury-poisoned rats.}, journal = {The Science of the total environment}, volume = {957}, number = {}, pages = {177850}, doi = {10.1016/j.scitotenv.2024.177850}, pmid = {39631325}, issn = {1879-1026}, mesh = {Animals ; *Methylmercury Compounds/metabolism ; *Fecal Microbiota Transplantation ; Rats ; *Gastrointestinal Microbiome ; Male ; Feces/microbiology ; }, abstract = {Methylmercury (MeHg) can cause devastating neurotoxicity in animals and human beings. Gut microbiota dysbiosis has been found in MeHg-poisoned animals. Fecal microbiota transplantation (FMT) has been shown to improve clinical outcomes in a variety of diseases such as epilepsy, amyotrophic lateral sclerosis (ALS) and autism. The aim of this study was to investigate the effects of FMT on MeHg-poisoned rats. FMT treatment was applied to MeHg-poisoned rats for 14 days. The neurobehavior, weight changes, dopamine (DA), the total Hg and MeHg level were evaluated. Besides, the gut microbiota and metabolites change in feces were also checked. It was found that FMT helped weight gain, alleviated the neurological disorders, enhanced fecal mercury excretion and MeHg demethylation, reconstructed gut microbiome and promoted the production of gut-brain axis related-metabolites in MeHg-poisoned rats. This study elaborates on the therapeutic efficacy of FMT in treating of MeHg-poisoned rats, which sheds lights on the treatment of neurological diseases like Minamata Disease and even Parkinson's Disease.}, } @article {pmid39633494, year = {2024}, author = {Ko, VI and Ong, K and Kwon, DY and Li, X and Pietrasiewicz, A and Harvey, JS and Lulla, M and Bhat, G and Cleveland, DW and Ravits, JM}, title = {CK1δ/ε-mediated TDP-43 phosphorylation contributes to early motor neuron disease toxicity in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {187}, pmid = {39633494}, issn = {2051-5960}, support = {P30 NS047101/NS/NINDS NIH HHS/United States ; S10 OD026929/OD/NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Phosphorylation ; *DNA-Binding Proteins/metabolism/genetics ; *Casein Kinase Idelta/metabolism/genetics ; *Casein Kinase 1 epsilon/metabolism/genetics ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Humans ; Motor Neurons/metabolism/pathology/drug effects ; Mice, Inbred C57BL ; Male ; Mice, Knockout ; }, abstract = {Hyperphosphorylated TDP-43 aggregates in the cytoplasm of motor neurons is a neuropathological signature of amyotrophic lateral sclerosis (ALS). These aggregates have been proposed to possess a toxic disease driving role in ALS pathogenesis and progression, however, the contribution of phosphorylation to TDP-43 aggregation and ALS disease mechanisms remains poorly understood. We've previously shown that CK1δ and CK1ε phosphorylate TDP-43 at disease relevant sites, and that genetic reduction and chemical inhibition could reduce phosphorylated TDP-43 (pTDP-43) levels in cellular models. In this study, we advanced our findings into the hTDP-43-ΔNLS in vivo mouse model of ALS and TDP-43 proteinopathy. This mouse model possesses robust disease-relevant features of ALS, including TDP-43 nuclear depletion, cytoplasmic pTDP-43 accumulation, motor behavior deficits, and shortened survival. We tested the effect of homozygous genetic deletion of Csnk1e in the hTDP-43-ΔNLS mouse model and observed a delay in the formation of pTDP-43 without significant ultimate rescue of TDP-43 proteinopathy or disease progression. Homozygous genetic deletion of Csnk1d is lethal in mice, and we were unable to test the role of CK1δ alone. We then targeted both CK1δ and CK1ε kinases by way of CK1δ/ε-selective PF-05236216 inhibitor in the hTDP-43-ΔNLS mouse model, reasoning that inhibiting CK1ε alone would be insufficient as shown by our Csnk1e knockout mouse model study. Treated mice demonstrated reduced TDP-43 phosphorylation, lowered Nf-L levels, and improved survival in the intermediate stages. The soluble TDP-43 may have been more amenable to the inhibitor treatment than insoluble TDP-43. However, the treatments did not result in improved functional measurements or in overall survival. Our results demonstrate that phosphorylation contributes to neuronal toxicity and suggest CK1δ/ε inhibition in combination with other therapies targeting TDP-43 pathology could potentially provide therapeutic benefit in ALS.}, } @article {pmid39633896, year = {2024}, author = {Bhaskaran, S and Piekarz, KM and Brown, J and Yang, B and Ocañas, SR and Wren, JD and Georgescu, C and Bottoms, C and Murphy, A and Thomason, J and Saunders, D and Smith, N and Towner, R and Van Remmen, H}, title = {The nitrone compound OKN-007 delays motor neuron loss and disease progression in the G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1505369}, pmid = {39633896}, issn = {1662-4548}, support = {I21 BX005619/BX/BLRD VA/United States ; IK6 BX005234/BX/BLRD VA/United States ; P30 AG050911/AG/NIA NIH HHS/United States ; }, abstract = {Our study investigated the therapeutic potential of OKN-007 in the SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS). The impact of OKN-007, known for its antioxidant, anti-inflammatory, and neuroprotective properties, was tested at two doses (150 mg/kg and 300 mg/kg) at onset and late-stage disease. Results demonstrated a significant delay in disease progression at both doses, with treated mice showing a slower advance to early disease stages compared to untreated controls. Motor neuron counts in the lumbar spinal cord were notably higher in OKN-007 treated mice at the time of disease onset, suggesting neuroprotection. Additionally, OKN-007 reduced microglial activation and preserved reduced neuromuscular junction fragmentation, although it did not significantly alter the increase in astrocyte number or the decline in hindlimb muscle mass. MR spectroscopy (MRS) revealed improved spinal cord perfusion and normalized myo-inositol levels in treated mice, supporting reduced neuroinflammation. While the expression of several proteins associated with inflammation is increased in spinal cord extracts from G93A mice, OKN-007 dampened the expression of IL-1β, IL-1ra and IL-1α. Despite its promising effects on early-stage disease progression, in general, the beneficial effects of OKN-007 diminished over longer treatment durations. Further, we found no improvement in muscle atrophy or weakness phenotypes in OKN-007 treated G93A mice, and no effect on mitochondrial function or lifespan. Overall, our findings suggest that OKN-007 holds potential as a disease-modifying treatment for ALS, although further research is needed to optimize dosing regimens and understand its long-term effects.}, } @article {pmid39634573, year = {2024}, author = {Braimah, RO and Taiwo, AO and Olasoji, HO and Legbo, JN and Amundson, M and Ibikunle, AA and Suleiman, IK and Bala, M and Ile-Ogedengbe, BO}, title = {Braimah-Taiwo et al New Classification System and Treatment Algorithm of Mandibulo-Maxillary Synostosis Related to Noma. Field Experience From Noma Children Hospital Sokoto, Nigeria.}, journal = {Craniomaxillofacial trauma & reconstruction}, volume = {17}, number = {4}, pages = {279-290}, pmid = {39634573}, issn = {1943-3875}, abstract = {STUDY DESIGN: This was a retrospective study at Noma Children Hospital, Sokoto, Nigeria, from January 2018 to December 2021.

OBJECTIVE: The main objective of this appraisal was to present Braimah-Taiwo et al's new classification system for mandibulo-maxillary synostosis secondary to noma and also to provide a guide to their treatment.

METHODS: Noma with mandibulo-maxillary synostosis was the main inclusion criteria. Excluded were cases of acute noma and noma without mandibulo-maxillary synostosis. Data retrieved include demographics of patients and extent of bony ankylosis and mandibulo-maxillary synostosis.

RESULTS: A total of 64 patients (30 (46.9%) males and 34 (53.1%) females) were managed. Ages ranged from 6 to 40 years with mean ± SD (18.2 ± 7.6) years. Regarding the new classification system of mandibulo-maxillary synostosis, 6 (9.4%) patients presented with Type 1 (Mild joint obliteration)±Soft tissue scarring, 24 (37.5%) presented with Type II (Total joint obliteration)±Soft tissue scarring, 21 (32.8%) presented with Type III (Coronoid, zygoma and maxilla) ±Soft tissue scarring, 4 (6.3%) presented with Type IV (Condyle, glenoid fossa, coronoid, sigmoid notch and zygoma) ±Soft tissue scarring, 7 (10.9%) presented with Type V (Condyle, glenoid fossa, coronoid, sigmoid notch, zygoma and pterygo-maxilla) ±Soft tissue scarring, while 2 (3.1%) patients presented with Type VI (condyle, glenoid fossa, coronoid, sigmoid notch, zygoma, pterygo-maxilla and the orbit) ±Soft tissue scarring.

CONCLUSIONS: Pattern of tissue destruction in noma patients is complex involving both soft and hard tissues. This new classification will guide surgeons in the effective management of these patients.}, } @article {pmid39635310, year = {2024}, author = {Yuan, J and Zhang, YJ and Wen, W and Liu, XC and Chen, FL and Yang, Y}, title = {Afferent loop syndrome of a patient with recurrent fever: A case report.}, journal = {World journal of radiology}, volume = {16}, number = {11}, pages = {678-682}, pmid = {39635310}, issn = {1949-8470}, abstract = {BACKGROUND: Afferent loop syndrome (ALS) is a rare complication, Aoki et al reported that the incidence of distal gastrectomy in Billroth-II is 0.3%-1.0%. The clinical manifestations of ALS are atypical, which can manifest as severe abdominal pain, vomiting, obstructive jaundice, malnutrition, etc.

CASE SUMMARY: The patient was a 58-year-old man who complained of recurrent high fever for more than 1 week. Laboratory tests showed an increase in neutrophil ratio, procalcitonin, C-reactive protein, and abnormal liver function. Enhanced computed tomography scan of the abdomen showed small intestinal obstruction between the anastomosis of the gastrojejunum, bile duct, and pancreaticoduodenum. Gastroscopy revealed significant narrowing of the lumen 15 cm from the anastomosis into the afferent loop. After performing balloon dilation and placement of the nutrition tube, the patient did not experience further fever.

CONCLUSION: ALS is relatively rare after pancreaticoduodenectomy, and the treatment depends on the nature of the obstructive lesion. The traditional treatment method is surgery, and in recent years, endoscopy has provided a new treatment method for ALS.}, } @article {pmid39636698, year = {2025}, author = {Nona, RJ and Henderson, RD and Mccombe, PA}, title = {Routine blood biochemical biomarkers in amyotrophic lateral sclerosis: Systematic review and cohort analysis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {303-321}, doi = {10.1080/21678421.2024.2435976}, pmid = {39636698}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality/diagnosis ; *Biomarkers/blood ; Cohort Studies ; Creatine Kinase/blood ; Creatinine/blood ; Uric Acid/blood ; }, abstract = {Introduction: Blood biochemical biomarkers, including urate, creatinine, albumin, and creatine kinase, have been shown to be useful in ALS. To provide further information about the roles of these four biomarkers roles we performed a systematic review. In addition, we also performed a new study of the role of these biomarkers in predicting survival, using data from our local ALS cohort. Methods: (1) Using established databases and other sources, we searched for papers about the use of urate, creatinine, albumin, and creatine kinase as biomarkers in ALS. Included articles were reviewed for information about biomarker levels in ALS and controls, association with markers of functional decline, and survival. (2) For our local ALS cohort, we performed survival analysis, Cox-proportionate-hazard ratio and ROC curves to investigate the use of these biomarkers in predicting survival. Results: (1) For systematic review, 104 papers were included. There was some variability in the findings. For urate, there was evidence of decreased levels in ALS, with higher levels associated ith longer survival. For creatinine, there was evidence of decreased levels in ALS, and higher levels correlated with longer survival. For albumin, some reports of reduced levels in ALS, but no consistent association with survival. For creatine kinase, some reports of increased levels in ALS, with inconsistent association with survival. (2) For the local ALS cohort there was evidence that urate and creatinine were associated with survival, but no significant association with survival. There was less evidence for albumin and CK. Discussion: This study provides support for further studies of these readily available biochemical measurement as bioamerkers in ALS.}, } @article {pmid39636751, year = {2025}, author = {Desai, AB and Agarwal, A and Mohamed, AS and Mohamed, KH and Middlebrooks, EH and Bhatt, AA and Gupta, V and Kumar, N and Sechi, E and Flanagan, EP and López Chiriboga, S}, title = {Motor Neuron Diseases and Central Nervous System Tractopathies: Clinical-Radiologic Correlation and Diagnostic Approach.}, journal = {Radiographics : a review publication of the Radiological Society of North America, Inc}, volume = {45}, number = {1}, pages = {e240067}, doi = {10.1148/rg.240067}, pmid = {39636751}, issn = {1527-1323}, mesh = {Humans ; *Motor Neuron Disease/diagnostic imaging ; Diagnosis, Differential ; Magnetic Resonance Imaging/methods ; Pyramidal Tracts/diagnostic imaging ; }, abstract = {White matter tracts within the central nervous system are organized into ascending and descending pathways that transmit sensory input and motor output, respectively. Tractopathy, or damage to these tracts, can impair sensory or motor functions. Motor neuron diseases are pathologic processes affecting the upper or lower motor neurons. Amyotrophic lateral sclerosis (ALS) is the most common form of acquired motor neuron disease. Traditionally, ALS has affected upper and lower motor neurons of the extremities, torso, and head and neck. There are several ALS variants, some of which affect only the upper motor neurons (eg, primary lateral sclerosis), lower motor neurons (eg, progressive muscular atrophy), or motor neurons of the head and neck (eg, progressive bulbar palsy). Characteristic imaging features of ALS include abnormal T2 hyperintensity within the brain along the corticospinal tract, as well as cortical susceptibility signal intensity along the precentral gyrus, termed the "motor band" sign. Spinal muscular atrophy is a less common primary motor neuron disease and appears on images as atrophy of the anterior horn of the spinal cord, as well as proximal muscle atrophy. In addition to pure motor neuron diseases, there are numerous toxic and metabolic conditions, genetic disorders, infectious diseases, and immune-mediated disorders that can secondarily affect the corticospinal tracts (corticospinal tractopathies), producing symptoms of upper motor neuron injury. These tractopathies are visible at MRI as T2-hyperintense lesions along varying segments of the corticospinal tract. A comprehensive diagnostic approach that integrates clinical symptoms with radiologic and laboratory findings is crucial to distinguish among these varied conditions. [©]RSNA, 2024 Supplemental material is available for this article.}, } @article {pmid39637982, year = {2025}, author = {Vallée, S and Deneux, V and Funaro, D and Marcoux, D and Powell, J and Hatami, A and Coulombe, J and Piram, M and McCuaig, CC}, title = {Long-term evolution of prepubertal-onset anogenital lichen sclerosus: A 35-year retrospective and cross-sectional study from a single tertiary care maternal and pediatric center.}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {5}, pages = {1010-1014}, doi = {10.1016/j.jaad.2024.09.086}, pmid = {39637982}, issn = {1097-6787}, mesh = {Humans ; Retrospective Studies ; Female ; Child ; Cross-Sectional Studies ; Puberty ; *Vulvar Lichen Sclerosus/diagnosis ; Adolescent ; Quality of Life ; Tertiary Care Centers ; Age of Onset ; *Lichen Sclerosus et Atrophicus/diagnosis ; Disease Progression ; Follow-Up Studies ; Child, Preschool ; Time Factors ; }, abstract = {BACKGROUND: Anogenital lichen sclerosus (ALS) in children may persist after puberty with potential clinical repercussions.

OBJECTIVE: The purpose of this study was to evaluate postpubertal evolution of girls with ALS diagnosed in the prepubertal period based on physical examination, the persistence of functional symptoms, and the effect on quality of life.

METHODS: We retrospectively reviewed 65 cases of girls with prepubertal-onset ALS. Onset, signs/symptoms, photos, evolution, and treatment were collected from the medical records. Subsequently, 30 of these 65 patients were assessed for persistence of signs/symptoms by physical examination and/or standardized questionnaire.

RESULTS: Signs of active disease after puberty based on physical examination were present in 92% (N = 23) of examined patients. A high proportion of cases with persistent ALS after puberty were asymptomatic (47%, N = 14).

LIMITATIONS: This is a single-center retrospective study with a limited number of patients. Half of our original cohort could not be reached or declined a follow-up visit.

CONCLUSION: Prepubertal lichen sclerosus is a chronic condition that can be asymptomatic after puberty despite continued disease activity. We recommend long-term follow-up of patients with prepubertal ALS to prevent associated morbidity.}, } @article {pmid39638270, year = {2025}, author = {Ruzzante, B and Fruzzetti, F and Cattaneo, M and Lauria Pinter, G and Marcuzzo, S and Candiani, G and Bono, N}, title = {Harnessing osmotic shock for enhanced intracellular delivery of (nano)cargos.}, journal = {International journal of pharmaceutics}, volume = {669}, number = {}, pages = {125008}, doi = {10.1016/j.ijpharm.2024.125008}, pmid = {39638270}, issn = {1873-3476}, mesh = {*Osmotic Pressure ; Humans ; *Cell Survival/drug effects ; Nanoparticles/administration & dosage/chemistry ; Drug Delivery Systems/methods ; Fibroblasts/drug effects/metabolism ; Animals ; Cell Size ; Cell Line ; Cells, Cultured ; }, abstract = {Efficient intracellular delivery of exogenous (nano)materials is critical for both research and therapeutic applications. The physicochemical properties of the cargo play a crucial role in determining internalization efficacy. Consequently, significant research efforts are focused on developing innovative and effective methodologies to optimize (nano)material delivery. In this study, we utilized osmotic shock to enhance (nano)cargos internalization. We examined the effects of hypotonic/hypertonic shock on both primary and cell lines, assessing parameters such as cell viability, cell volume, membrane tension changes, and particle uptake. Our results indicate that short-lived osmotic shock does not harm cells. Hypotonic shock induced temporary shape changes lasting up to 5 min, followed by a 15-minute recovery period. Importantly, hypotonic shock increased the uptake of 100-nm and 500-nm particles by ∼ 3- and ∼ 5-fold, respectively, compared to isotonic conditions. In contrast, the hypertonic shock did not impact cell behavior or particle uptake. Notably, the internalization mechanisms triggered by osmotic shock operate independently of active endocytic pathways, making hypotonic stimulation particularly beneficial for hard-to-treat cells. When primary fibroblasts derived from amyotrophic lateral sclerosis (ALS)-patients were exposed to hypotonic shock in the presence of the therapeutic cargo icerguastat, there was an increased expression of miR-106b-5p compared to isotonic conditions. In conclusion, osmotic shock presents a promising strategy for improving drug delivery within cells and, potentially, in tissues such as muscles or skin, where localized drug administration is preferred.}, } @article {pmid39638345, year = {2025}, author = {Webster, CP and Hall, B and Crossley, OM and Dauletalina, D and King, M and Lin, YH and Castelli, LM and Yang, ZL and Coldicott, I and Kyrgiou-Balli, E and Higginbottom, A and Ferraiuolo, L and De Vos, KJ and Hautbergue, GM and Shaw, PJ and West, RJ and Azzouz, M}, title = {RuvBL1/2 reduce toxic dipeptide repeat protein burden in multiple models of C9orf72-ALS/FTD.}, journal = {Life science alliance}, volume = {8}, number = {2}, pages = {}, pmid = {39638345}, issn = {2575-1077}, support = {MR/V000470/1/MRC_/Medical Research Council/United Kingdom ; MR/V030140/1/MRC_/Medical Research Council/United Kingdom ; MR/W00416X/1/MRC_/Medical Research Council/United Kingdom ; /ERC_/European Research Council/International ; }, mesh = {Animals ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Humans ; Mice ; *Disease Models, Animal ; *Dipeptides/metabolism ; *ATPases Associated with Diverse Cellular Activities/metabolism/genetics ; *DNA Helicases/genetics/metabolism ; *Mice, Transgenic ; DNA Repeat Expansion/genetics ; Carrier Proteins/metabolism/genetics ; Motor Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Male ; }, abstract = {A G4C2 hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Bidirectional transcription and subsequent repeat-associated non-AUG (RAN) translation of sense and antisense transcripts leads to the formation of five dipeptide repeat (DPR) proteins. These DPRs are toxic in a wide range of cell and animal models. Therefore, decreasing RAN-DPRs may be of therapeutic benefit in the context of C9ALS/FTD. In this study, we found that C9ALS/FTD patients have reduced expression of the AAA+ family members RuvBL1 and RuvBL2, which have both been implicated in aggregate clearance. We report that overexpression of RuvBL1, but to a greater extent RuvBL2, reduced C9orf72-associated DPRs in a range of in vitro systems including cell lines, primary neurons from the C9-500 transgenic mouse model, and patient-derived iPSC motor neurons. In vivo, we further demonstrated that RuvBL2 overexpression and consequent DPR reduction in our Drosophila model was sufficient to rescue a number of DPR-related motor phenotypes. Thus, modulating RuvBL levels to reduce DPRs may be of therapeutic potential in C9ALS/FTD.}, } @article {pmid39639468, year = {2024}, author = {Arango-Cortes, ML and Giraldo-Cadavid, LF and Latorre Quintana, M and Forero-Cubides, JD and Gonzalez-Bermejo, J}, title = {Diaphragm pacing compared with mechanical ventilation in patients with chronic respiratory failure caused by diaphragmatic dysfunction: a systematic review and meta-analysis.}, journal = {Expert review of respiratory medicine}, volume = {18}, number = {12}, pages = {1101-1111}, doi = {10.1080/17476348.2024.2421846}, pmid = {39639468}, issn = {1747-6356}, mesh = {Humans ; Chronic Disease/therapy ; *Diaphragm/physiopathology ; *Electric Stimulation Therapy/methods/statistics & numerical data ; Length of Stay/statistics & numerical data ; Quality of Life ; *Respiration, Artificial/adverse effects/methods/statistics & numerical data ; *Respiratory Paralysis/etiology/mortality/physiopathology/therapy ; Spinal Cord Injuries/complications/mortality/physiopathology/therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: The effectiveness of diaphragmatic electrical stimulation (DES) compared to mechanical ventilation (MV) in improving clinical outcomes such as quality-of-life (QOL) and hospital stay remains inconsistent.

METHODS: We conducted a systematic review and meta-analysis by searching PubMed, Scopus, Google Scholar, LILACS, and IEEE Xplore. We included comparative studies (randomized controlled trials and observational studies) of DES administered via the phrenic nerve or intramuscular electrodes, compared with MV in adults with diaphragmatic paralysis or paresis. Two authors independently extracted data and assessed bias, with discrepancies resolved by a senior author. Results were pooled using the inverse variance method.

RESULTS: Out of 1,290 articles, nine were included in the systematic review, totaling 852 subjects. In spinal cord injury (SCI), one study reported lower mortality with DES, while three found no difference compared to MV. In these patients, DES was associated with shorter hospital stay, similar QOL, and heterogeneous results on respiratory infections. In amyotrophic lateral sclerosis (ALS), DES was associated with higher mortality and similar QOL compared to MV. Most SCI studies had a serious risk of bias.

CONCLUSION: DES shows potential in reducing hospital stay and respiratory infections in SCI but is associated with higher mortality in ALS.}, } @article {pmid39640633, year = {2024}, author = {Nikafshan Rad, H and Su, Z and Trinh, A and Hakim Newton, MA and Shamsani, J and Nygc Als Consortium, and Karim, A and Sattar, A}, title = {Amyotrophic lateral sclerosis diagnosis using machine learning and multi-omic data integration.}, journal = {Heliyon}, volume = {10}, number = {20}, pages = {e38583}, pmid = {39640633}, issn = {2405-8440}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex and rare neurodegenerative disorder characterized by significant genetic, molecular, and clinical heterogeneity. Despite numerous endeavors to discover the genetic factors underlying ALS, a significant number of these factors remain unknown. This knowledge gap highlights the necessity for personalized medicine approaches that can provide more comprehensive information for the purposes of diagnosis, prognosis, and treatment of ALS. This work utilizes an innovative approach by employing a machine learning-facilitated, multi-omic model to develop a more comprehensive knowledge of ALS. Through unsupervised clustering on gene expression profiles, 9,847 genes associated with ALS pathways are isolated and integrated with 7,699 genes containing rare, presumed pathogenic genomic variants, leading to a comprehensive amalgamation of 17,546 genes. Subsequently, a Variational Autoencoder is applied to distil complex biomedical information from these genes, culminating in the creation of the proposed Multi-Omics for ALS (MOALS) model, which has been designed to expose intricate genotype-phenotype interconnections within the dataset. Our meticulous investigation elucidates several pivotal ALS signaling pathways and demonstrates that MOALS is a superior model, outclassing other machine learning models based on single omic approaches such as SNV and RNA expression, enhancing accuracy by 1.7 percent and 6.2 percent, respectively. The findings of this study suggest that analyzing the relationships within biological systems can provide heuristic insights into the biological mechanisms that help to make highly accurate ALS diagnosis tools and achieve more interpretable results.}, } @article {pmid39640847, year = {2024}, author = {Raineri, D and De Marchi, F and Vilardo, B and Barbero Mazzucca, C and Scotti, L and Kustrimovic, N and Mazzini, L and Cappellano, G and Chiocchetti, A}, title = {Circulating GLAST[+] EVs are increased in amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular biosciences}, volume = {11}, number = {}, pages = {1507498}, pmid = {39640847}, issn = {2296-889X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, hallmarked by the gradual deterioration of motor neurons, culminating in muscle weakness and fatal paralysis. The exact etiology of ALS remains elusive, and there is a critical need for reliable biomarkers to aid in diagnosis and monitoring of disease progression. Extracellular vesicles (EVs) have emerged as promising candidates for biomarker discovery in neurodegenerative diseases such as ALS, giving access to pathologically relevant tissues otherwise typically challenging or invasive to sample. Indeed, EVs can derive by many cell types within the central nervous system, cross the blood-brain barrier and reach the blood, where they can be easily measured. One of the central mechanisms implicated in ALS pathology is glutamate excitotoxicity, which involves excessive glutamate accumulation due to impaired uptake by astrocytes and other glial cells, leading to neuronal damage. GLAST is a key glutamate transporter responsible for maintaining extracellular gluta-mate levels, and its dysregulation is thought to contribute significantly to ALS development and associated neuropathogenesis. Here, we applied a quick and validated method, to evaluate GLAST[+] EVs in ALS patients' plasma and age-matched healthy controls. We found an increase in GLAST[+] EVs that holds promise for uncovering novel diagnostic and therapeutic avenues in ALS research.}, } @article {pmid39641521, year = {2025}, author = {Manera, U and Callegaro, S and Canosa, A and Palumbo, F and Grassano, M and Bombaci, A and Dagliati, A and Bosoni, P and Daviddi, M and Casale, F and Cabras, S and Matteoni, E and De Marchi, F and Mazzini, L and Moglia, C and Vasta, R and Calvo, A and Chiò, A}, title = {Croplands proximity is associated with amyotrophic lateral sclerosis incidence and age at onset.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16464}, pmid = {39641521}, issn = {1468-1331}, support = {//Dipartimenti di Eccellenza/ ; //EU Joint Programme - Neurodegenerative Disease Research/ ; 259867//Seventh Framework Programme/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; RF-2016-02362405//Ministero della Salute/ ; GA101017598//Horizon 2020 Framework Programme/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology ; Humans ; Incidence ; *Age of Onset ; Female ; Male ; Middle Aged ; Aged ; *Crops, Agricultural ; Adult ; Registries ; Italy/epidemiology ; Risk Factors ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from an intricate interplay between genetics and environmental factors. Many studies have explored living in rural areas as a possible risk factor for ALS, without focusing simultaneously on incidence, age at onset and phenotypic features.

OBJECTIVE: To evaluate the effect of croplands residential proximity on ALS incidence and phenotype, focusing on age of onset, site of onset and progression rate.

METHODS: The address history of ALS patients belonging to the population-based Piemonte and Valle d'Aosta registry (PARALS), diagnosed between 2007 and 2014, was obtained for the 20 years prior to the onset date. The smoothed ALS incidence per year (im) was compared with the percentage of area covered by each crop for each municipality. A proximity score was calculated for each cropland by geolocation, measuring the percentage of area surrounding patients' residence for variable radii, and was used to compare croplands exposure and phenotype.

RESULTS: We observed an increased ALS incidence in the municipalities with a higher percentage of area covered by arable crops (R = 0.191, p < 0.001). Age at onset was significantly lower in those patients who lived near arable crops, with a median anticipation ranging from 1.8 to 3.4 years; using historical data, a significant anticipation was found also for patients living near vineyards.

DISCUSSION: Our study proved a direct association between arable crops and ALS risk and an inverse association between arable crops and vineyards proximity and age at onset, suggesting the possible causative role of specific environmental contaminants.}, } @article {pmid39641862, year = {2024}, author = {Zhang, J and Zhang, X and Xiao, B and Ouyang, J and Wang, P and Peng, X}, title = {Mendelian randomization study of causal link from Cerebrospinal fluid metabolomics to neurodegenerative diseases.}, journal = {Neurogenetics}, volume = {26}, number = {1}, pages = {15}, pmid = {39641862}, issn = {1364-6753}, support = {No. YZ2020MS04//President Foundation of The Fifth Affiliated Hospital, Southern Medical University/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/cerebrospinal fluid ; *Metabolomics/methods ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid ; Multiple Sclerosis/genetics/cerebrospinal fluid ; Alzheimer Disease/genetics/cerebrospinal fluid ; Parkinson Disease/genetics/cerebrospinal fluid ; Polymorphism, Single Nucleotide ; }, abstract = {To investigate the causal relationships between cerebrospinal fluid (CSF) metabolites and various neurodegenerative diseases (NDDs), we conducted a two-sample Mendelian randomization (MR) analysis. This study utilized summary statistics from genome-wide association studies (GWAS) of CSF metabolites and four common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). MR methods were employed to determine causal associations, with the inverse variance weighted method as the primary approach. Additionally, different GWAS summary data for NDDs were used to validate the initial results and perform sensitivity analyses to enhance the robustness of the findings. Finally, reverse MR analyses were conducted to assess the possibility of reverse causation. Combining results from the initial and replication phases of MR analysis, we identified potential causal relationships between various CSF metabolites and different NDDs. Specifically, we found potential causal relationships between five CSF metabolites and AD, six CSF metabolites and MS, and thirteen CSF metabolites and ALS. Further sensitivity analyses confirmed the robustness of these associations. Reverse MR analysis indicated causal effects of AD on glucuronate and ALS on acetylcarnitine (C2). Our study, through genetic means, demonstrates close causal associations between the specific types of CSF metabolites and the risk of NDDS (AD, PD, MS, and ALS), providing useful guidance for future clinical researches.}, } @article {pmid39642451, year = {2025}, author = {He, X}, title = {Hyperspectral Raman imaging with multivariate curve resolution-alternating least square (MCR-ALS) analysis for xylazine-containing drug mixtures.}, journal = {Forensic science international}, volume = {367}, number = {}, pages = {112314}, doi = {10.1016/j.forsciint.2024.112314}, pmid = {39642451}, issn = {1872-6283}, mesh = {*Xylazine/analysis/chemistry ; *Spectrum Analysis, Raman/methods ; Least-Squares Analysis ; Humans ; Mannitol/chemistry ; Acetaminophen/chemistry ; *Hyperspectral Imaging ; Multivariate Analysis ; Excipients/chemistry ; }, abstract = {Xylazine, increasingly implicated in illicit opioid overdose deaths, poses a significant public health threat due to its synergistic effects with fentanyl and resistance to naloxone reversal. Despite its rising prevalence, xylazine is not classified as a controlled substance, leading to its exclusion from routine forensic screening. This study introduces a novel analytical method combining Raman hyperspectral imaging with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to detect xylazine in drug mixtures containing common excipients such as acetaminophen, dipyrone, and mannitol. Utilizing only non-negativity constraints, MCR-ALS successfully resolved the Raman spectrum of xylazine at levels as low as 5 % without reference spectra. The method demonstrated robust performance, with percent variance explained (R[2]) values of 99.60 %, 99.80 %, and 99.91 % for the drug mixtures containing 25 %, 10 %, and 5 % xylazine, respectively.}, } @article {pmid39643926, year = {2025}, author = {Wang, J and Du, Y and Zhang, L and Deng, Y and Wang, T and Wang, S and Ji, M}, title = {Pro-197-Ser mutation combinations in acetolactate synthase (ALS) homoeologous genes affect ALS inhibitor herbicide resistance levels in Monochoria korsakowii.}, journal = {Pest management science}, volume = {81}, number = {4}, pages = {1894-1902}, doi = {10.1002/ps.8586}, pmid = {39643926}, issn = {1526-4998}, support = {32372594//National Natural Science Foundation of China/ ; }, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Plant Proteins/genetics/metabolism/antagonists & inhibitors ; Mutation ; Sulfonylurea Compounds/pharmacology ; *Poaceae/genetics/drug effects/enzymology ; Nicotinic Acids/pharmacology ; Sulfonamides ; Uridine/analogs & derivatives ; }, abstract = {BACKGROUND: Monochoria korsakowii is a common broadleaf weed found in rice (Oryza sativa) fields. Acetolactate synthase (ALS) inhibitor herbicides are commonly used to control broadleaf weeds in rice fields. However, prolonged herbicide use has exacerbated resistance issues. In this study, we evaluated the resistance to ALS inhibitors in populations where the same mutation occurred separately and simultaneously in the two ALS homoeologous genes (ALS1 and ALS2) and investigated the resistance mechanisms in M. korsakowii.

RESULTS: Monochoria korsakowii exhibited high resistance to bensulfuron-methyl, low resistance to penoxsulam, and sensitivity to imazethapyr. Three resistant populations were identified: M-1 and M-2, which independently evolved the Pro-197-Ser mutation in ALS1 and ALS2, respectively, and M-3, which harbored this mutation in both ALS1 and ALS2. The sensitivity of ALS isolated from these populations to herbicide inhibition corresponded to the whole-plant resistance levels. Subsequently, we cloned and transformed Pro-197-Ser-mutated ALS1 and ALS2 into Arabidopsis thaliana. The resistance of homozygous A. thaliana to bensulfuron-methyl and penoxsulam aligned with bioassay trends. Furthermore, we measured the ploidy, relative expression, and copy number of ALS1 and ALS2, and found no significant differences, suggesting that the evolution of resistance was primarily attributed to the Pro-197-Ser mutation. Finally, we developed a derived cleaved amplified polymorphic sequence marker for detecting Pro-197-Ser mutation in ALS.

CONCLUSION: The same mutation occurring separately in homoeologous genes resulted in similar resistance levels, whereas simultaneous mutations in homoeologous genes led to increased resistance levels. © 2024 Society of Chemical Industry.}, } @article {pmid39643934, year = {2025}, author = {Farrokhzad, R and Seyedalipour, B and Baziyar, P and Hosseinkhani, S}, title = {Insight Into Factors Influencing the Aggregation Process in Wild-Type and P66R Mutant SOD1: Computational and Spectroscopic Approaches.}, journal = {Proteins}, volume = {93}, number = {4}, pages = {885-907}, doi = {10.1002/prot.26765}, pmid = {39643934}, issn = {1097-0134}, mesh = {*Superoxide Dismutase-1/chemistry/genetics/metabolism ; Humans ; Molecular Dynamics Simulation ; Protein Aggregates ; Hydrophobic and Hydrophilic Interactions ; Mutation ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Protein Folding ; Spectroscopy, Fourier Transform Infrared ; Amyloid/chemistry/metabolism ; Protein Conformation, beta-Strand ; Recombinant Proteins/chemistry/genetics/metabolism ; }, abstract = {Disturbances in metal ion homeostasis associated with amyotrophic lateral sclerosis (ALS) have been described for several years, but the exact mechanism of involvement is not well understood. To elucidate the role of metalation in superoxide dismutase (SOD1) misfolding and aggregation, we comprehensively characterized the structural features (apo/holo forms) of WT-SOD1 and P66R mutant in loop IV. Using computational and experimental methodologies, we assessed the physicochemical properties of these variants and their correlation with protein aggregation at the molecular level. Modifications in apo-SOD1 compared to holo-SOD1 were more pronounced in flexibility, stability, hydrophobicity, and intramolecular interactions, as indicated by molecular dynamics simulations. The enzymatic activities of holo/apo-WT SOD1 were 1.30 and 1.88-fold of the holo/apo P66R mutant, respectively. Under amyloid-inducing conditions, decreased ANS fluorescence intensity in the apo-form relative to the holo-form suggested pre-fibrillar species and amyloid aggregate growth due to occluded hydrophobic pockets. FTIR spectroscopy revealed that apo-WT-SOD1 and apo-P66R exhibited a mixture of parallel and intermolecular β-sheet structures, indicative of aggregation propensity. Aggregate species were identified using TEM, Congo red staining, and ThT/ANS fluorescence spectroscopy. Thermodynamic analyses with GdnHCl demonstrated that metal deficit, mutation, and intramolecular disulfide bond reduction are essential for initiating SOD1 misfolding and aggregation. These disruptions destabilize the dimer-monomer equilibrium, promoting dimer dissociation into monomers and decreasing the thermodynamic stability of SOD1 variants, thus facilitating amyloid/amorphous aggregate formation. Our findings offer novel insights into protein aggregation mechanisms in disease pathology and highlight potential therapeutic strategies against toxic protein aggregation, including SOD1.}, } @article {pmid39644798, year = {2025}, author = {Toko, M and Ohshita, T and Nakamori, M and Ueno, H and Akiyama, Y and Maruyama, H}, title = {Myelin measurement in amyotrophic lateral sclerosis with synthetic MRI: A potential diagnostic and predictive method.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123337}, doi = {10.1016/j.jns.2024.123337}, pmid = {39644798}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Magnetic Resonance Imaging/methods ; *Myelin Sheath/pathology ; Aged ; Adult ; Predictive Value of Tests ; *Brain/diagnostic imaging ; }, abstract = {BACKGROUND: Myelin damage has recently been highlighted as a major causative factor of amyotrophic lateral sclerosis (ALS). Although myelin damage has been pathologically identified in ALS, it has not been clinically evaluated. This study aimed to quantify myelin volume using synthetic MRI to evaluate myelin damage in patients with ALS, and determine its association with clinical parameters.

METHODS: We evaluated patients with ALS (n = 35) and individuals (n = 16) without intracranial disease using synthetic magnetic resonance imaging (MRI) and measured total myelin volume (TMV), myelin fraction (MYF), and myelin partial volume (VMY) in the cerebral peduncle and the posterior limb of the internal capsule (PLIC). We also investigated factors associated with acquired quantitative values.

RESULTS: The TMV was significantly lower in the patients with ALS than in the control group (P = 0.045). The TMV (r = 0.42, P = 0.013) and MYF (r = 0.34, P = 0.047) significantly correlated with Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores in the patients, and MYF was independent of the traditional white matter lesion grading score. The VMY of the PLIC was significantly lower in the ALS than the control group (P = 0.018), and the ALS group significantly correlated with ALSFRS-R scores (r = 0.36, P = 0.033).

CONCLUSIONS: Myelin damage can be quantified by synthetic MRI as reduced myelin volume, with the possibility of predicting prognoses in patients with ALS. Furthermore, myelin measurements in the PLIC might be a novel diagnostic marker for ALS.}, } @article {pmid39644980, year = {2025}, author = {Guerra San Juan, I and Brunner, JW and Eggan, K and Toonen, RF and Verhage, M}, title = {KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.}, journal = {Neurobiology of disease}, volume = {204}, number = {}, pages = {106759}, doi = {10.1016/j.nbd.2024.106759}, pmid = {39644980}, issn = {1095-953X}, support = {R01 NS089742/NS/NINDS NIH HHS/United States ; }, mesh = {*Kinesins/metabolism/genetics ; *Axonal Transport/physiology ; Humans ; *Mitochondria/metabolism ; *Motor Neurons/metabolism ; *Axons/metabolism ; PTB-Associated Splicing Factor/metabolism ; Nerve Regeneration/physiology ; Cells, Cultured ; Neuronal Outgrowth/physiology ; }, abstract = {Mutations in the microtubule-binding motor protein kinesin 5 A (KIF5A) are implicated in several adult-onset motor neuron diseases, including Amyotrophic Lateral Sclerosis, Spastic Paraplegia Type 10 and Charcot-Marie-Tooth Disease Type 2. While KIF5 family members transport a variety of cargos along axons, the specific cargos affected by KIF5A mutations remain poorly understood. Here, we generated KIF5Anull mutant human motor neurons and analyzed the impact on axonal transport and motor neuron outgrowth and regeneration in vitro. KIF5A deficiency caused reduced neurite complexity in young neurons (DIV14) and defects in axonal regeneration. KIF5A deficiency did not affect neurofilament transport but impaired mitochondrial motility and anterograde speed at DIV42. Notably, KIF5A deficiency strongly reduced anterograde transport of splicing factor proline/glutamine-rich (SFPQ)-associated RNA granules in DIV42 axons. Hence, KIF5A plays a critical role in promoting axonal regrowth after injury and in driving the anterograde transport of mitochondria and especially SFPQ-associated RNA granules in mature neurons.}, } @article {pmid39645043, year = {2025}, author = {Needle, C and Brinks, A and Shapiro, J and Lo Sicco, K}, title = {Response to Chen et al's "Emergence of Janus kinase inhibitors led to increase in proportion of severe alopecia areata patients receiving treatment: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {4}, pages = {e119-e120}, doi = {10.1016/j.jaad.2024.10.118}, pmid = {39645043}, issn = {1097-6787}, } @article {pmid39645085, year = {2025}, author = {Ediriweera, GR and Sivaram, AJ and Cowin, G and Brown, ML and McAlary, L and Lum, JS and Fletcher, NL and Robinson, L and Simpson, JD and Chen, L and Wasielewska, JM and Byrne, E and Finnie, JW and Manavis, J and White, AR and Yerbury, JJ and Thurecht, KJ and Vine, KL}, title = {Lipid nanoparticles and transcranial focused ultrasound enhance the delivery of SOD1 antisense oligonucleotides to the murine brain for ALS therapy.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {378}, number = {}, pages = {221-235}, doi = {10.1016/j.jconrel.2024.11.074}, pmid = {39645085}, issn = {1873-4995}, mesh = {Animals ; *Oligonucleotides, Antisense/administration & dosage/pharmacokinetics ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy/genetics ; *Superoxide Dismutase-1/genetics ; Mice, Inbred C57BL ; *Nanoparticles/administration & dosage/chemistry ; *Brain/metabolism ; Mice, Transgenic ; Lipids/chemistry/administration & dosage ; Mice ; Microbubbles ; Spinal Cord/metabolism ; Male ; Blood-Brain Barrier/metabolism ; Liposomes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with extremely limited therapeutic options. One key pathological feature of ALS is the abnormal accumulation of misfolded proteins within motor neurons. Hence, reducing the burden of misfolded protein has emerged as a promising therapeutic approach. Antisense oligonucleotides (ASOs) have the potential to effectively silence proteins with gain-of-function mutations, such as superoxide dismutase 1 (SOD1). However, ASO delivery to the central nervous system (CNS) is hindered by poor blood-brain barrier (BBB) penetration and the invasiveness of intrathecal administration. In the current study, we demonstrate effective systemic delivery of a next-generation SOD1 ASO (Tofersen) into the brain of wildtype and G93A-SOD1 transgenic C57BL/6 mice using calcium phosphate lipid nanoparticles (CaP lipid NPs). We show that transcranial focused ultrasound (FUS) with intravenously administered microbubbles can significantly enhance ASO-loaded nanoparticle delivery into the mouse brain. Magnetic resonance imaging (MRI) and immunohistological analysis showed reduced SOD1 expression in the FUS-exposed brain regions and increased motor neuron count in the spinal cord of treated mice suggesting decreased motor neuron degeneration. Importantly, the BBB opening was transient without evidence of structural changes, neuroinflammation or damage to the brain tissue, indicating that the treatment is well tolerated. Overall, our results highlight FUS-assisted nanoparticle delivery of ASOs as a promising non-invasive therapeutic strategy for the treatment of ALS and CNS diseases more broadly.}, } @article {pmid39645221, year = {2025}, author = {Bajpai, A and Bharathi, V and Patel, BK}, title = {Therapeutic targeting of the oxidative stress generated by pathological molecular pathways in the neurodegenerative diseases, ALS and Huntington's.}, journal = {European journal of pharmacology}, volume = {987}, number = {}, pages = {177187}, doi = {10.1016/j.ejphar.2024.177187}, pmid = {39645221}, issn = {1879-0712}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; *Antioxidants/pharmacology/therapeutic use ; *Huntington Disease/metabolism/drug therapy/pathology/genetics ; Molecular Targeted Therapy/methods ; Neurodegenerative Diseases/metabolism/drug therapy/pathology ; *Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative disorders are characterized by a progressive decline of specific neuronal populations in the brain and spinal cord, typically containing aggregates of one or more proteins. They can result in behavioral alterations, memory loss and a decline in cognitive and motor abilities. Various pathways and mechanisms have been outlined for the potential treatment of these diseases, where redox regulation is considered as one of the most common druggable targets. For example, in amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) pathology, there is a downregulation of the antioxidant response nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. TDP-43 proteinopathy in ALS is associated with elevated levels of reactive oxygen species and mitochondrial dyshomeostasis. In ALS with mutant FUS, poly ADP ribose polymerase-dependent X ray repair cross complementing 1/DNA-ligase recruitment to the sites of oxidative DNA damage is affected, thereby causing defects in DNA damage repair. Oxidative stress in Huntington's disease (HD) with mutant huntingtin accumulation manifests as protein oxidation, metabolic energetics dysfunction, metal ion dyshomeostasis, DNA damage and mitochondrial dysfunction. The impact of oxidative stress in the progression of these diseases further warrants studies into the role of antioxidants in their treatment. While an antioxidant, edaravone, has been approved for therapeutics of ALS, numerous antioxidant molecules failed to pass the clinical trials despite promising initial studies. In this review, we summarize the oxidative stress pathways and redox modulators that are investigated in ALS and HD using various models.}, } @article {pmid39645528, year = {2024}, author = {Ríos-López, AL and Garza-Velásquez, MF and González, GM and Becerril-García, MA and Flores-Maldonado, O}, title = {Prevalence, virulence factors and antifungal susceptibility of oral isolates of Candida albicans from patients with cystic fibrosis in Mexico.}, journal = {Revista iberoamericana de micologia}, volume = {41}, number = {2-3}, pages = {31-36}, doi = {10.1016/j.riam.2024.09.001}, pmid = {39645528}, issn = {2173-9188}, mesh = {Humans ; *Cystic Fibrosis/microbiology/complications ; *Virulence Factors/genetics ; *Candida albicans/drug effects/isolation & purification/genetics ; Mexico/epidemiology ; *Antifungal Agents/pharmacology ; *Microbial Sensitivity Tests ; Female ; Male ; Adult ; Young Adult ; Adolescent ; *Candidiasis, Oral/microbiology/epidemiology ; Prevalence ; Child ; Drug Resistance, Fungal ; Biofilms/growth & development ; Mouth/microbiology ; Child, Preschool ; }, abstract = {BACKGROUND: Candida species are frequently isolated from the oral cavity of patients with cystic fibrosis. However, the information on the role of Candida in cystic fibrosis is scarce.

AIMS: This study aimed to evaluate the prevalence, virulence profile and antifungal susceptibility of oral isolates of Candida albicans recovered from patients with cystic fibrosis.

METHODS: Oropharyngeal swab samples were collected from sixty-five cystic fibrosis patients and sixty-five healthy individuals. Candida isolates were identified by MALDI-TOF VITEK-MS. Proteinase, phospholipase and esterase activity, biofilm production and level expression of ALS, SAP and PLB genes in C. albicans were evaluated. Minimal inhibitory concentration values were determined by means of an antifungal susceptibility test.

RESULTS: Oral Candida colonization in cystic fibrosis patients was 66.15%, while in healthy individuals was 36.92%. C. albicans was the most frequently isolated species. C. albicans strains from cystic fibrosis patients were high producers of protease and biofilm, and had higher expression levels of adhesin and protease-associated genes in comparison with healthy subjects. Among the C. albicans strains isolated from cystic fibrosis patients, 18.91% were resistant to itraconazole, while 16.21% exhibited resistance to ketoconazole and fluconazole, and only one strain was resistant to voriconazole.

CONCLUSIONS: This work represents a surveillance study on virulence patterns and antifungal susceptibility of Candida from the oropharyngeal tract in cystic fibrosis.}, } @article {pmid39647703, year = {2025}, author = {Watters, JJ and Bell, MC and Que, SKT}, title = {Regarding response to Watters et al's "Educational intervention targeting primary care residents improves skin cancer recognition in patients with skin of color".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {4}, pages = {e105-e106}, doi = {10.1016/j.jaad.2024.11.051}, pmid = {39647703}, issn = {1097-6787}, } @article {pmid39649175, year = {2024}, author = {Harvey, C and Nowak, A and Zhang, S and Moll, T and Weimer, AK and Barcons, AM and Dos Santos Souza, C and Ferraiuolo, L and Kenna, K and Zaitlen, N and Caggiano, C and Shaw, PJ and Snyder, MP and Mill, J and Hannon, E and Cooper-Knock, J}, title = {Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39649175}, issn = {2693-5015}, support = {R01 HL101388/HL/NHLBI NIH HHS/United States ; P50 HL083800/HL/NHLBI NIH HHS/United States ; P30 DK116074/DK/NIDDK NIH HHS/United States ; R01 HL122939/HL/NHLBI NIH HHS/United States ; UM1 HG009442/HG/NHGRI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity to develop a sensitive and specific biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we have performed whole genome bisulfite sequencing (WGBS) of iPSC-derived MN from neurologically normal individuals. By comparing MN methylation with an atlas of tissue methylation we have derived a MN-specific signature of hypomethylated genomic regions, which accords with genes important for MN function. Through simulation we have optimised the selection of regions for biomarker detection in plasma and CSF cell-free DNA (cfDNA). However, we show that MN-derived DNA is not detectable via WGBS in plasma cfDNA. In support of our experimental finding, we show theoretically that the relative sparsity of lower MN sets a limit on the proportion of plasma cfDNA derived from MN which is below the threshold for detection of WGBS. Our findings are important for the ongoing development of ALS biomarkers. The MN-specific hypomethylated genomic regions we have derived could be usefully combined with more sensitive detection methods and perhaps with study of CSF instead of plasma. Indeed we demonstrate that neuronal-derived DNA is detectable in CSF. Our work is relevant for all diseases featuring death of rare cell-types.}, } @article {pmid39649550, year = {2024}, author = {Han, S and Li, RH and Gao, P}, title = {Gut microbiota participates and remodels host metabolism: From treating patients to treating their gut flora.}, journal = {World journal of gastroenterology}, volume = {30}, number = {45}, pages = {4839-4843}, pmid = {39649550}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; Animals ; Uric Acid/blood/metabolism ; Hyperuricemia/microbiology/drug therapy/blood/metabolism ; Metabolomics/methods ; Feces/microbiology ; }, abstract = {In this editorial, we comment on Liu et al's article published in the recent issue of the World Journal of Gastroenterology. Biochemically and pathologically, Liu et al proved that the urate-lowering activity of leech total protein (LTP) was mainly attributed to the rectification of gut microbiota. Specifically, we noticed the change in Bacteroides and Akkermansia after LTP administration. Both bacteria have been reported to alleviate metabolic dysfunction-associated steatohepatitis and other chronic metabolic diseases. LTP was administrated through intragastric manners. Most possibly, LTP would be digested by the gut microbiota further. The anti-hyperuricemia effects should, to the most possible extent, be exerted by the peptides or their secondary metabolic products. Human gut microbiota communicates with other organs through metabolites generated by the microbes or co-metabolized with the host. Whether the anti-hyperuricemia effect could be partially ascribed to the microbiota metabolites also deserves to be discussed. Although metabolomics analysis was performed for serum samples, fecal metabolomics was highly advocated which could facilitate exact mechanism explanation. This study implied that gut microbiota contains many unexplored targets with different therapeutic potentials. It is foreseeable that utilizing these targets can avoid the impairment or side effects of directly using human targets to some extent.}, } @article {pmid39650285, year = {2024}, author = {Hu, Y and Deeba, E and Kläppe, U and Öijerstedt, L and Andersson, J and Ruffin, N and Piehl, F and Ingre, C and Fang, F and Seitz, C}, title = {Immune cells and the trajectories of depression, anxiety, and cognitive function among people with amyotrophic lateral sclerosis.}, journal = {Brain, behavior, & immunity - health}, volume = {42}, number = {}, pages = {100907}, pmid = {39650285}, issn = {2666-3546}, support = {R01 TS000324/TS/ATSDR CDC HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) represents a complex syndrome characterized by motor, psychiatric, and cognitive symptoms, where associations between cellular immune features and non-motor manifestations remain unknown.

METHODS: In this cohort study, we enrolled 250 incident people with ALS (pwALS) assessed with the Hospital Anxiety and Depression Scale, and 226 pwALS with the Montreal Cognitive Assessment, including 218 overlapping pwALS. All individuals were diagnosed between January 2015 and January 2023 in Stockholm, Sweden. We applied joint latent class models to delineate distinct trajectories of anxiety, depression, and cognition, incorporating survival outcomes. A majority of the pwALS had data on leukocyte counts and flow cytometric analyses using a comprehensive T cell panel. We then used immune cell subtypes measured at diagnosis to predict trajectories of these outcomes following ALS diagnosis.

RESULTS: We identified two distinct trajectories for anxiety, depression, and cognitive function following ALS diagnosis. PwALS with longer survival displayed more stable trajectories, while those with shorter survival showed decreasing anxiety symptom, increasing depressive symptom, and declining cognitive function. Higher count of leukocytes at the time of ALS diagnosis tended to associate with anxiety and depression trajectories related to shorter survival. Among T cell subpopulations, several CD8[+] T cell subsets were associated with a stable trajectory of depressive symptom, and, in turn, better survival.

CONCLUSION: ALS-associated psychiatric and cognitive trajectories vary significantly between pwALS with different prognosis. Certain T cell subsets measured at diagnosis might be indicative of depression trajectories post-diagnosis.}, } @article {pmid39651147, year = {2024}, author = {Fleming, AC and Rao, NR and Wright, M and Savas, JN and Kiskinis, E}, title = {The ALS-associated co-chaperone DNAJC7 mediates neuroprotection against proteotoxic stress by modulating HSF1 activity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39651147}, issn = {2692-8205}, support = {F31 NS132580/NS/NINDS NIH HHS/United States ; R01 NS104219/NS/NINDS NIH HHS/United States ; R21 NS131713/NS/NINDS NIH HHS/United States ; S10 OD032464/OD/NIH HHS/United States ; }, abstract = {The degeneration of neurons in patients with amyotrophic lateral sclerosis (ALS) is commonly associated with accumulation of misfolded, insoluble proteins. Heat shock proteins (HSPs) are central regulators of protein homeostasis as they fold newly synthesized proteins and refold damaged proteins. Heterozygous loss-of-function mutations in the DNAJC7 gene that encodes an HSP co-chaperone were recently identified as a cause for rare forms of ALS, yet the mechanisms underlying pathogenesis remain unclear. Using mass spectrometry, we found that the DNAJC7 interactome in human motor neurons (MNs) is enriched for RNA binding proteins (RBPs) and stress response chaperones. MNs generated from iPSCs with the ALS-associated mutation R156X in DNAJC7 exhibit increased insolubility of its client RBP HNRNPU and associated RNA metabolism alterations. Additionally, DNAJC7 haploinsufficiency renders MNs increasingly susceptible to proteotoxic stress and cell death as a result of an ablated HSF1 stress response pathway. Critically, expression of HSF1 in mutant DNAJC7 MNs is sufficient to rescue their sensitivity to proteotoxic stress, while postmortem ALS patient cortical neurons exhibit a reduction in the expression of HSF1 pathway genes. Taken together, our work identifies DNAJC7 as a crucial mediator of HNRNPU function and stress response pathways in human MNs and highlights HSF1 as a therapeutic target in ALS.}, } @article {pmid39651197, year = {2024}, author = {Grant, OA and Iacoangeli, A and Zwamborn, RAJ and van Rheenen, W and Byrne, R and Van Eijk, KR and Kenna, K and van Vugt, JJFA and Cooper-Knock, J and Kenna, B and Vural, A and Topp, S and Campos, Y and Weber, M and Smith, B and Dobson, R and van Es, MA and Vourc'h, P and Corcia, P and de Carvalho, M and Gotkine, M and Panades, MP and Mora, JS and Mill, J and Garton, F and McRae, A and Wray, NR and Shaw, PJ and Landers, JE and Glass, JD and Shaw, CE and Basak, N and Hardiman, O and Van Damme, P and McLaughlin, RL and van den Berg, LH and Veldink, JH and Al-Chalabi, A and Al Khleifat, A}, title = {Sex-specific DNA methylation differences in Amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.22.624866}, pmid = {39651197}, issn = {2692-8205}, abstract = {Sex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigenome-wide association study meta-analysis in 9274 individuals after stringent quality control (5529 males and 3975 females). We identified a total of 226 ALS saDMPs (sex-associated DMPs) annotated to a total of 159 unique genes. These ALS saDMPs were depleted at transposable elements yet significantly enriched at enhancers and slightly enriched at 3'UTRs. These ALS saDMPs were enriched for transcription factor motifs such as ESR1 and REST. Moreover, we identified an additional 10 genes associated with ALS saDMPs through chromatin loop interactions, suggesting a potential regulatory role for these saDMPs on distant genes. Furthermore, we investigated the relationship between DNA methylation at specific CpG sites and overall survival in ALS using Cox proportional hazards models. We identified two ALS saDMPs, cg14380013 and cg06729676, that showed significant associations with survival. Overall, our study reports a reliable catalogue of sex-associated ALS saDMPs in ALS and elucidates several characteristics of these sites using a large-scale dataset. This resource will benefit future studies aiming to investigate the role of sex in the incidence, progression and risk for ALS.}, } @article {pmid39651224, year = {2024}, author = {Kodavati, M and Maloji Rao, VH and Mitra, J and Hegde, ML}, title = {Selective Inhibition of Cytosolic PARylation via PARG99: A Targeted Approach for Mitigating FUS-associated Neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.25.625276}, pmid = {39651224}, issn = {2692-8205}, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) are characterized by complex etiologies, often involving disruptions in functions of RNA/DNA binding proteins (RDBPs) such as FUS and TDP-43. The cytosolic mislocalization and aggregation of these proteins are linked to accumulation of unresolved stress granules (SGs), which exacerbate the disease progression. Poly-ADP-ribose polymerase (PARP)-mediated PARylation plays a critical role in this pathological cascade, making it a potential target for intervention. However, conventional PARP inhibitors are limited by their detrimental effects on DNA repair pathways, which are already compromised in ALS. To address this limitation, we investigated a strategy focused on targeting the cytosolic compartment by expressing the cytosol-specific, natural PAR- glycohydrolase (PARG) isoform, PARG99. Using ALS patient derived FUS mutant induced pluripotent cells (iPSCs) and differentiated neurons, we observed elevated levels of FUS in insoluble fractions in mutant cells compared to mutation-corrected isogenic lines. The insoluble FUS as well as TDP-43 levels increased further in sodium arsenite-treated or oxidatively stressed cells, correlating with accumulation of unresolved SGs. Notably, both PARG99 and PARP inhibitors reduced SG formation and insoluble FUS levels, however, PARG99 treated cells exhibited significantly lower DNA damage markers and improved viability under oxidative and arsenite stress. This study highlights the potential of PARG99 as a cytosol-specific intervention to mitigate FUS-associated toxicity while preserving critical nuclear DNA repair mechanisms, offering a promising strategy for addressing the underlying pathology of ALS and potentially other SG-associated neurodegenerative diseases.}, } @article {pmid39651269, year = {2024}, author = {O'Neill, K and Shaw, R and Bolger, I and , and Tam, O and Phatnani, H and Hammell, MG}, title = {ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.07.19.603731}, pmid = {39651269}, issn = {2692-8205}, support = {R01 NS118570/NS/NINDS NIH HHS/United States ; RF1 NS118570/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this general heterogeneity, several common factors have been identified. For example, nearly all patients show pathological accumulations of phosphorylated TDP-43 protein in affected regions of the motor cortex and spinal cord. Moreover, large patient cohort studies have revealed that most patient samples can be grouped into a small number of ALS subtypes, as defined by their transcriptomic profiles. These ALS molecular subtypes can be grouped by whether postmortem motor cortex samples display signatures of: mitochondrial dysfunction and oxidative stress (ALS-Ox), microglial activation and neuroinflammation (ALS-Glia), or dense TDP-43 pathology and associated transposable element de-silencing (ALS-TE). In this study, we have built a deep layer ALS neural network classifier (DANcer) that has learned to accurately assign patient samples to these ALS subtypes, and which can be run on either bulk or single-cell datasets. Upon applying this classifier to an expanded ALS patient cohort from the NYGC ALS Consortium, we show that ALS Molecular Subtypes are robust across clinical centers, with no new subtypes appearing in a cohort that has quadrupled in size. Signatures from two of these molecular subtypes strongly correlate with disease duration: ALS-TE signatures in cortex and ALS-Glia signatures in spinal cord, revealing molecular correlates of clinical features. Finally, we use single nucleus RNA sequencing to reveal the cell type-specific contributions to ALS subtype, as determined by our single-cell classifier (scDANCer). Single-cell transcriptomes reveal that ALS molecular subtypes are recapitulated in neurons and glia, with both ALS-wide shared alterations in each cell type as well as ALS subtype-specific alterations. In summary, ALS molecular subtypes: (1) are robust across large cohorts of sporadic and familial ALS patient samples, (2) represent a combination of cellular, genetic, and pathological features, and (3) correlate with clinical features of ALS.}, } @article {pmid39654532, year = {2025}, author = {Dave, KD and Oskarsson, B and Yersak, J and Krauss, R and Heiman-Patterson, T and Lomen-Hoerth, C and Selig, WKD and Halpern Paul, I and Schaeffer, M and Garcia-Trujillo, B and Waldo, D and Thakur, N and Babu, S}, title = {Contributions of neurologists to diagnostic timelines of ALS and thinkALS as an early referral instrument for clinicians.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {215-224}, doi = {10.1080/21678421.2024.2432034}, pmid = {39654532}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Referral and Consultation ; *Neurologists ; United States ; Male ; Female ; Medicare ; Aged ; Time Factors ; Delayed Diagnosis ; }, abstract = {Objectives: To evaluate neurologists and other clinicians' contributions to U.S. ALS diagnostic timelines. Background: Over the past two decades, the average time to ALS diagnosis in the U.S. has remained unchanged at 12 months. ALS patients see 3-4 clinicians prior to referral to an ALS specialist for diagnosis confirmation and/or treatment initiation. There is an urgent need to identify where delays occur, so that targeted clinician awareness may be raised about early suspicion and referrals. Methods: Review of Medicare claims database for health care utilization patterns by ALS beneficiaries during diagnostic journey. Survey of typical clinic wait times for new consultations reported by 75-78 ALS Certified Treatment Centers of Excellence (2019-2021). Results: During 2011-2021, 78,520 Medicare beneficiaries were diagnosed with ALS (T0). The mean (median) timelines between first neurologist ambulatory visit and T0, is 16.5 (11.0) months; mean ± SD for ALS/neuromuscular providers being 9.6 ± 12.6 months versus 16.7 ± 17.5 months for non-neuromuscular neurologists. During the 12-months preceding T0, an ALS patient undergoes median(max) 1.5(4.0) brain-MRIs, 1.6(6.0) spine-MRIs, and 1.3(4.0) electromyography studies. Greater than 75% of ALS centers consistently report ≤ 4 week wait times for new ALS consults. This study introduces "thinkALS," an easy-to-use clinical diagnostic and referral guide for non-ALS neurologists to tackle this challenge. Conclusions: This study is the first to provide metrics on how non-neuromuscular/ALS specialists contribute to ALS diagnostic timelines in the U.S.}, } @article {pmid39654963, year = {2024}, author = {Sun, P and Niu, L and He, P and Yu, H and Chen, J and Cui, H and Li, X}, title = {Trp-574-Leu and the novel Pro-197-His/Leu mutations contribute to penoxsulam resistance in Echinochloa crus-galli (L.) P. Beauv.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1488976}, pmid = {39654963}, issn = {1664-462X}, abstract = {Recently, due to the widespread use of the acetolactate synthase (ALS)-inhibiting herbicide penoxsulam in paddy fields in China, Echinochloa crus-galli (L.) P. Beauv. has become a problematic grass weed that is frequently not controlled, posing a threat to weed management and rice yield. There are many reports on target-site mutations of ALS inhibiting herbicides; however, the detailed penoxsulam resistance mechanism in E. crus-galli remains to be determined. Greenhouse and laboratory studies were conducted to characterize target-site resistance mechanisms in JL-R, AH-R, and HLJ-R suspected resistant populations of E. crus-galli survived the field-recommended dose of penoxsulam. The whole-plant dose-response testing of E. crus-galli to penoxsulam confirmed the evolution of moderate-level resistance in two populations, JL-R (9.88-fold) and HLJ-R (8.66-fold), and a high-level resistance in AH-R (59.71-fold) population. ALS gene sequencing identified specific mutations in resistant populations, including Pro-197-His in ALS1 for JL-R, Trp-574-Leu in ALS1 for AH-R, and Pro-197-Leu in ALS2 for HLJ-R. In vitro ALS activity assays demonstrated a significantly higher activity in AH-R compared to the susceptible population (YN-S). Molecular docking studies revealed that Trp-574-Leu mutation primarily reduced the enzyme's ability to bind to the triazole-pyrimidine ring of penoxsulam due to decreased π-π stacking interactions, while Pro-197-His/Leu mutations impaired binding to the benzene ring by altering hydrogen bonds and hydrophobic interactions. Additionally, the Pro-197-His/Leu amino acid residue changes resulted in alterations in the shape of the active channel, impeding the efficient entry of penoxsulam into the binding site in the ALS protein. The three mutant ALS proteins expressed via the Bac-to-Bac baculovirus system exhibited notably lower activity inhibition rates than the non-mutant ALS proteins to penoxsulam, indicating all three ALS mutations reduce sensitivity to penoxsulam. This study elucidated the distinct impacts of the Pro-197-His/Leu and Trp-574-Leu mutations in E. crus-galli to penoxsulam resistance. Notably, the Trp-574-Leu mutation conferred stronger resistance to penoxsulam compared to the Pro-197-His/Leu mutations in E. crus-galli. The Pro-197-His/Leu mutations were first detected in E. crus-galli conferring penoxsulam resistance. These findings provide deeper insights into the molecular mechanisms underlying target-site resistance to penoxsulam in E. crus-galli.}, } @article {pmid39655131, year = {2024}, author = {Mori, Y and Kenzaka, T}, title = {Systemic Amyloid Light Chain Amyloidosis With Repeated Syncope Due to Severe Orthostatic Hypotension Caused by Autonomic Neuropathy: A Case Report.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e73320}, pmid = {39655131}, issn = {2168-8184}, abstract = {Amyloid light chain (AL) amyloidosis is a disease in which ALs, which are proteins with fibrous structures, are deposited in systemic organs, causing functional impairment. Diagnosis is often difficult because of non-specific and varied symptoms. We report a case of systemic AL amyloidosis that was diagnosed as a result of repeated syncope. A 76-year-old woman was brought to the emergency room with multiple episodes of loss of consciousness over the past five years. She visited the major hospital, where pulmonary thromboembolism and symptomatic epilepsy were considered possible causes. Orthostatic hypotension was observed after being transferred to our hospital for rehabilitation. We performed diagnostic tests, including blood tests, imaging, and a head-up tilt test, which confirmed severe orthostatic hypotension. A gastrointestinal biopsy with Congo red staining confirmed the presence of amyloid deposits. AL amyloidosis (λ) was diagnosed using immunohistochemical staining. Given her age and prolonged bed rest, she was determined that she could not tolerate chemotherapy and was discharged upon her request. To the best of our knowledge, this is the first report of systemic AL amyloidosis presenting with orthostatic hypotension severe enough to cause syncope due to autonomic neuropathy. Autonomic neuropathy should be considered, and amyloidosis should be included in the differential diagnosis when a patient presents with recurrent syncope.}, } @article {pmid39655175, year = {2024}, author = {Palm, A and Ekström, M and Emilsson, Ö and Ersson, K and Ljunggren, M and Sundh, J and Grote, L}, title = {Control of hypercapnia and mortality in home mechanical ventilation: the population-based DISCOVERY study.}, journal = {ERJ open research}, volume = {10}, number = {6}, pages = {}, pmid = {39655175}, issn = {2312-0541}, abstract = {BACKGROUND: Studies on the survival of patients with home mechanical ventilation (HMV) are sparse. We aimed to analyse the impact of controlled hypercapnia on survival over 27 years among patients with HMV in Sweden.

STUDY DESIGN AND METHODS: Population-based cohort study of adult patients starting HMV in the Swedish Registry for Respiratory Failure (Swedevox) during 1996-2022 cross-linked with the National Cause of Death registry. Mortality risk factors were analysed using crude and multivariable Cox regression models, including adjustments for anthropometrics, comorbidities, the underlying diagnosis causing chronic hypercapnic respiratory failure (CRF) and the control of hypercapnia (P aCO2 ≤6.0 kPa) at follow-up.

RESULTS: We included 10 190 patients (50.1% women, age 62.9±14.5 years). Control of hypercapnia at follow-up after 1.3±0.9 years was associated with lower mortality, hazard ratio (HR) 0.74 (95% CI 0.68-0.80) and the association was strongest in those with pulmonary disease, restrictive thoracal disease (RTD), obesity hypoventilation syndrome (OHS) and amyotrophic lateral sclerosis (ALS). Predictors for increased mortality included age, Charlson Comorbidity Index, supplemental oxygen therapy and acute start of HMV therapy. Median survival varied between 0.8 years (95% CI 0.8-0.9 (n=1401)) for ALS and 7.6 years (95% CI 6.9-8.6 (n=1061)) for neuromuscular disease. Three-year survival decreased from 76% (95% CI 71-80) between 1996 and 1998 to 52% (95% CI 50-55) between 2017 and 2019. When adjusting for underlying diagnosis and age, the association between start year and decreased survival disappeared, HR 1.00 (95% CI 0.99-1.01).

CONCLUSION: Controlling P aCO2 is a key treatment goal for survival in HMV therapy. Survival differed markedly between diagnosis and age groups, and survival rates have declined as the patient group has aged.}, } @article {pmid39655539, year = {2025}, author = {Canosa, A and Martino, A and Manera, U and Giuliani, A and Vasta, R and Palumbo, F and Grassano, M and Morbelli, SD and Pardini, M and Chiaravalloti, A and Schillaci, O and Leenders, KL and Kogan, RV and Polverari, G and Zocco, G and Pede, FD and Mattei, F and Cabras, S and Matteoni, E and Moglia, C and Calvo, A and Chiò, A and Pagani, M}, title = {Sex-related differences in amyotrophic lateral sclerosis: A 2-[[18]F]FDG-PET study.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16588}, pmid = {39655539}, issn = {1468-1331}, support = {//Dipartimenti di Eccellenza/ ; RF-2016- 02362405//Ministero della Salute/ ; 259867//Seventh Framework Programme/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; //Fondation Thierry Latran/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Male ; Female ; Middle Aged ; *Positron-Emission Tomography ; *Fluorodeoxyglucose F18 ; Aged ; *Sex Characteristics ; *Brain/diagnostic imaging/metabolism ; Adult ; }, abstract = {PURPOSE: We investigated sex-related brain metabolic differences in Amyotrophic Lateral Sclerosis (ALS) and healthy controls (HC).

METHODS: We collected two equal-sized groups of male (m-ALS) and female ALS (f-ALS) patients (n = 130 each), who underwent 2-[[18]F]FDG-PET at diagnosis, matched for site of onset, cognitive status and King's stage. We included 168 age-matched healthy controls, half female (f-HC) and half male (m-HC). We compared brain metabolism of males and females separately for ALS and HC, including age as covariate. A differential network analysis was performed to evaluate brain connectivity.

RESULTS: M-ALS showed relative hypometabolism of bilateral medial frontal, parietal and occipital cortices, and left temporal cortex, compared to f-ALS. In node-wise comparison, f-ALS showed significantly higher connectivity in right middle cingulate cortex and left superior and medial frontal gyrus. In HC we did not find any sex-related differences.

CONCLUSION: Sex resulted a major determinant of brain metabolism and connectivity in ALS patients.}, } @article {pmid39655696, year = {2025}, author = {Di Iacovo, A and D'Agostino, C and Bhatt, M and Romanazzi, T and Giovannardi, S and Cinquetti, R and Roseti, C and Bossi, E}, title = {The kinase LRRK2 is required for the physiological function and expression of the glial glutamate transporter EAAT2 (SLC1A2).}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16265}, pmid = {39655696}, issn = {1471-4159}, support = {860954//H2020 Marie Skłodowska-Curie Actions/ ; }, mesh = {Animals ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics/metabolism/biosynthesis ; *Excitatory Amino Acid Transporter 2/metabolism/genetics/biosynthesis ; *Xenopus laevis ; Humans ; Oocytes/metabolism ; Female ; Neuroglia/metabolism ; }, abstract = {Neurotransmitter transporters (NTTs) control synaptic responses by modulating the concentration of neurotransmitters at the synaptic cleft. Glutamate is the most abundant excitatory neurotransmitter in the brain and needs to be finely tuned in time and space to maintain a healthy brain and precise neurotransmission. The glutamate transporter EAAT2 (SLC1A2) is primarily responsible for glutamate clearance. EAAT2 impairment has been associated with Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both monogenic and sporadic forms of PD, of which the common substitution Gly2019Ser is associated with a significant deficit in EAAT2 expression. The role of pathological mutants of the LRRK2 is intensively studied and reviewed. Here we have focused the attention on the physiological role of LRRK2 on EAAT2, comparing the activity of NTTs with or without the LRRK2 kinase. By heterologous expression in Xenopus laevis oocytes and two-electrode voltage clamp, the current amplitudes of the selected NTTs and kinetic parameters have been collected in the presence and absence of LRRK2. The results show that EAAT2 expression and function are impaired in the absence of the kinase and also under its pharmacological inhibition via MLi-2 treatment. LRRK2 stabilizes EAAT2 expression increasing the amount of transporter at the plasma membrane. Interestingly, the LRRK2 action is EAAT2-specific, as we observed no significant changes in the transport current amplitude and kinetic parameters obtained for the other excitatory and inhibitory NTTs studied. This study, for the first time, demonstrates the physiological importance of LRRK2 in EAAT2 function, highlighting the specificity of LRRK2-mediated modulation of EAAT2 and suggesting a potential role for the kinase as a checkpoint for preserving neurons from excitotoxicity. In brain conditions associated with impaired glutamate clearance, targeting LRRK2 for EAAT2 regulation may offer novel therapeutic opportunities.}, } @article {pmid39656022, year = {2024}, author = {Prentiss, AM and Baggio, C and Pagett, J and Kulinich, AO and Ethell, IM and Muzzarelli, K and Assar, Z and Pellecchia, M}, title = {Constrained β-Hairpins Targeting the EphA4 Ligand Binding Domain.}, journal = {Journal of medicinal chemistry}, volume = {67}, number = {24}, pages = {22245-22253}, pmid = {39656022}, issn = {1520-4804}, support = {R01 CA168517/CA/NCI NIH HHS/United States ; P41 GM103311/GM/NIGMS NIH HHS/United States ; R01 NS129555/NS/NINDS NIH HHS/United States ; P20 CA242620/CA/NCI NIH HHS/United States ; R01 NS107479/NS/NINDS NIH HHS/United States ; }, mesh = {*Receptor, EphA4/metabolism/antagonists & inhibitors/chemistry ; Ligands ; Humans ; Binding Sites ; Protein Binding ; Peptides, Cyclic/chemistry/pharmacology/metabolism/chemical synthesis ; Drug Design ; Protein Domains/drug effects ; Models, Molecular ; }, abstract = {The activity of the receptor tyrosine kinase EphA4 has been implicated in several pathologies including oncology (gastric and pancreatic cancers) and neurodegenerative diseases (amyotrophic lateral sclerosis and Alzheimer's disease). However, advances in validating EphA4 as a possible drug target have been limited by the lack of suitable pharmacological inhibitors. Recently, we reported on the design of potent EphA4 agonistic agents targeting its ligand binding domain (LBD). Based on previous studies with a phage display cyclic peptide inhibitor, we designed a β-hairpin mimetic with high affinity for EphA4-LBD. These agents hold great promise for further validation and development of EphA4-based therapeutics. Moreover, our studies introduce a possible strategy for the design of constrained β-hairpin peptides.}, } @article {pmid39656589, year = {2024}, author = {Nascimento, F and Özyurt, MG and Halablab, K and Bhumbra, GS and Caron, G and Bączyk, M and Zytnicki, D and Manuel, M and Roselli, F and Brownstone, R and Beato, M}, title = {Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration.}, journal = {Cell reports}, volume = {43}, number = {12}, pages = {115046}, pmid = {39656589}, issn = {2211-1247}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 NS110953/NS/NINDS NIH HHS/United States ; 221610/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; MR/V003607/1/MRC_/Medical Research Council/United Kingdom ; BB/S005943/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; *Motor Neurons/metabolism/pathology ; Mice ; *Homeostasis ; *Disease Models, Animal ; *Spinal Cord/pathology/metabolism ; Synaptic Transmission/physiology ; Receptors, Glycine/metabolism ; Nerve Degeneration/pathology ; Mice, Inbred C57BL ; Renshaw Cells/metabolism ; }, abstract = {In many neurological conditions, early-stage neural circuit adaptation preserves relatively normal behavior. In some diseases, spinal motoneurons progressively degenerate yet movement remains initially preserved. This study investigates whether these neurons and associated microcircuits adapt in a mouse model of progressive motoneuron degeneration. Using a combination of in vitro and in vivo electrophysiology and super-resolution microscopy, we find that, early in the disease, neurotransmission in a key pre-motor circuit, the recurrent inhibition mediated by Renshaw cells, is reduced by half due to impaired quantal size associated with decreased glycine receptor density. This impairment is specific and not a widespread feature of spinal inhibitory circuits. Furthermore, it recovers at later stages of disease. Additionally, an increased probability of release from proprioceptive afferents leads to increased monosynaptic excitation of motoneurons. We reveal that, in this motoneuron degenerative condition, spinal microcircuits undergo specific multiphasic homeostatic compensations that may contribute to preservation of force output.}, } @article {pmid39656857, year = {2024}, author = {Alvarado, M and Gómez-Navajas, JA and Blázquez-Muñoz, MT and Gómez-Molero, E and Fernández-Sánchez, S and Eraso, E and Munro, CA and Valentín, E and Mateo, E and de Groot, PWJ}, title = {The good, the bad, and the hazardous: comparative genomic analysis unveils cell wall features in the pathogen Candidozyma auris typical for both baker's yeast and Candida.}, journal = {FEMS yeast research}, volume = {24}, number = {}, pages = {}, pmid = {39656857}, issn = {1567-1364}, support = {PID2020-117983RB-I00//Agencia Estatal de Investigación/ ; SBPLY/23/180225/000029//UCLM/ ; //European Regional Development Fund/ ; JDC2023-051226-I//European Social Fund Plus/ ; }, mesh = {*Cell Wall/metabolism ; *Saccharomyces cerevisiae/genetics/metabolism ; Computational Biology ; Genomics ; Candida auris/genetics/metabolism/drug effects ; beta-Glucans/metabolism ; Genome, Fungal ; Fungal Proteins/genetics/metabolism ; Glycosylphosphatidylinositols/metabolism/genetics ; Candida albicans/genetics/pathogenicity ; Candida/genetics/metabolism/pathogenicity ; }, abstract = {The drug-resistant pathogenic yeast Candidozyma auris (formerly named Candida auris) is considered a critical health problem of global importance. As the cell wall plays a crucial role in pathobiology, here we performed a detailed bioinformatic analysis of its biosynthesis in C. auris and related Candidozyma haemuli complex species using Candida albicans and Saccharomyces cerevisiae as references. Our data indicate that the cell wall architecture described for these reference yeasts is largely conserved in Candidozyma spp.; however, expansions or reductions in gene families point to subtle alterations, particularly with respect to β--1,3--glucan synthesis and remodeling, phosphomannosylation, β-mannosylation, and glycosylphosphatidylinositol (GPI) proteins. In several aspects, C. auris holds a position in between C. albicans and S. cerevisiae, consistent with being classified in a separate genus. Strikingly, among the identified putative GPI proteins in C. auris are adhesins typical for both Candida (Als and Hyr/Iff) and Saccharomyces (Flo11 and Flo5-like flocculins). Further, 26 putative C. auris GPI proteins lack homologs in Candida genus species. Phenotypic analysis of one such gene, QG37_05701, showed mild phenotypes implicating a role associated with cell wall β-1,3-glucan. Altogether, our study uncovered a wealth of information relevant for the pathogenicity of C. auris as well as targets for follow-up studies.}, } @article {pmid39657109, year = {2025}, author = {Benatar, M and McDermott, C and Turner, MR and van Eijk, RPA}, title = {Rethinking phase 2 trials in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {4}, pages = {1106-1111}, pmid = {39657109}, issn = {1460-2156}, support = {/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; *Clinical Trials, Phase II as Topic/methods ; }, abstract = {There is a long history in amyotrophic lateral sclerosis (ALS) of promoting therapies based on phase 2 data, which then fail in phase 3 trials. Experience suggests that studies of 6 months in duration are too short, especially with function-based outcome measures. Multiplicity poses a serious threat to data interpretation, and strategies to impute missing data may not be appropriate for ALS where progression is always expected. Emerging surrogate markers of clinical benefit such as reduction of neurofilament light chain levels may be better suited to phase 2 go/no-go decisions. Over-interpretation of phase 2 data, and overly optimistic communication of exploratory analyses must be avoided to ensure optimal prioritization for the investment needed for definitive phase 3 trials and to minimize the harm of false hope for people living with ALS. Delivering on advances in understanding of the neurobiology of ALS requires urgent attention to phase 2 design and implementation.}, } @article {pmid39659205, year = {2026}, author = {Alzahrani, AK and A S, A and Imran, M}, title = {Unraveling the molecular mechanisms of ALS: a network biology and structural modeling approach of investigating the impact of C9orf72 mutations.}, journal = {Journal of biomolecular structure & dynamics}, volume = {44}, number = {3}, pages = {1362-1375}, doi = {10.1080/07391102.2024.2437682}, pmid = {39659205}, issn = {1538-0254}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *C9orf72 Protein/genetics/chemistry/metabolism ; Humans ; *Mutation ; Molecular Dynamics Simulation ; Protein Interaction Maps ; Protein Binding ; Molecular Docking Simulation ; Protein Conformation ; Models, Molecular ; }, abstract = {C9orf72 is a major genetic factor in Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disorder affecting brain and spinal cord neurons, and comprehending its mutational impact is crucial for developing ALS therapies. Therefore, the current study's protein-protein interaction (PPI) network for C9orf72 was meticulously mapped to identify key interactors that might influence the disease mechanism. Among the identified proteins, SMCR8 emerged as a prominent candidate due to its high connectivity (total network contribution = 7.896) within the C9orf72-associated network, suggesting a potential role in modulating the effects of C9orf72 mutations. Analysis of C9orf72 mutations highlighted the I525T mutation, which significantly destabilizes the protein, as indicated by a ΔΔG value of -2.02 kcal/mol. Further investigation involved comparing the structural dynamics of the wild-type C9orf72 and its mutant variants through molecular docking and dynamics simulations. The wild-type demonstrated more stable structural conformation over time, as shown by its RMSD profile than its mutant counterpart. However, after 80 nanoseconds, the mutant variant achieved a similar RMSD stability level. Intriguingly, the mutant formed a more stable complex with SMCR8, evident from its lower binding free energy (-64.18 kcal/mol compared to the wild type's -34.82 kcal/mol). Moreover, per-residue decomposition analysis further revealed critical interactions at specific residues. The wild-type protein showed a significant stabilizing interaction at Arg785, whereas the mutant favored Arg262, indicating a potential shift in binding affinity and site due to the mutation. This shift suggests an altered binding landscape in the mutant C9orf72, which might contribute to the dysregulated protein interactions and cellular processes associated with ALS pathology. The study thus underscores the pathological hyper-stability of the mutant C9orf72, highlighting its potential role in the progression of ALS.}, } @article {pmid39659885, year = {2024}, author = {Wan, H and Qian, W and Wei, B and Tian, K and Chen, Z and Zhang, J and Chen, F}, title = {A bibliometric analysis of gene editing and amyotrophic lateral sclerosis (from 2004 to 2024).}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1499025}, pmid = {39659885}, issn = {1662-4548}, abstract = {OBJECTIVE: To learn more about gene editing and ALS, and to provide a comprehensive view of gene editing for further treatment of amyotrophic lateral sclerosis.

METHODS: We searched 1981 records from Web of Science core collection and Pubmed, Scopus, of which 1,292 records were obtained after exclusion. We then scientifically and metrologically analyzed these records for spatial and temporal distribution, author distribution, subject categories, subject distribution, references, and keywords using R, software CiteSpace and VOSviewer.

RESULTS: Our analysis provides basic information about research in the field, suggests that the field has stabilized over the past decade, and identifies potential partners for interested researchers. Current research in this area is focused on inflammatory mechanisms, immune mechanisms, related diseases, and associated cytokines in ALS.

CONCLUSION: RNA Editing, Antisense Bligonucleotide, and Glycine Receptor are cutting-edge research topics in this field, which is undergoing rapid development. We hope that this work will provide new ideas for advancing the scientific research and clinical application of ALS.}, } @article {pmid39659975, year = {2024}, author = {Kim, HJ and Ban, JJ and Kang, J and Im, HR and Ko, SH and Sung, JJ and Park, SH and Park, JE and Choi, SJ}, title = {Single-cell analysis reveals expanded CD8[+] GZMK [high] T cells in CSF and shared peripheral clones in sporadic amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae428}, pmid = {39659975}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the brain and spinal cord. Despite the crucial role of aberrant immune responses in ALS pathogenesis, studies investigating immunological profiles in the cerebrospinal fluid (CSF) of patients with ALS have reported inconsistent findings. Herein, we explored the intrathecal adaptive immune response and features of circulating T cells between CSF and blood of patients with ALS using single-cell RNA and T-cell receptor (TCR) sequencing. This study comprised a total of 11 patients with apparently sporadic ALS and three controls with non-inflammatory diseases. We collected CSF from all participants, and for three patients with ALS, we additionally obtained paired samples of peripheral blood mononuclear cells (PBMCs). Utilizing droplet-based single-cell RNA and TCR sequencing, we analysed immunological profiles, gene expression characteristics and clonality. Furthermore, we examined T-cell characteristics in both PBMC and CSF samples, evaluating the shared T-cell clones across these compartments. In the CSF, patients with ALS exhibited a lower proportion of CD4[+] T cells (45.2 versus 61.2%, P = 0.005) and a higher proportion of CD8[+] GZMK [hi] effector memory T cells (TEMs) than controls (21.7 versus 16.8%, P = 0.060). Higher clonality was observed in CD8[+] TEMs in patients with ALS compared with controls. In addition, CSF macrophages of patients with ALS exhibited a significant increase in chemokines recruiting CD8[+] TEMs. Immunohistochemical analysis showed slightly higher proportions of T cells in the perivascular and parenchymal spaces in patients with ALS than in controls, and CD8[+] TEMs co-localized with neurons or astrocytes in the motor cortices of patients with ALS. Clonally expanded CD8[+] GZMK [hi] TEMs primarily comprised shared T-cell clones between CSF and PBMCs. Moreover, the shared CD8[+] TEMs of PBMCs exhibited gene expression profiles similar to CSF T cells. Patients with ALS showed an increase in proportion and clonality of CD8[+] GZMK [hi] TEMs and activated features of macrophages in CSF. The shared T-cell clone between CSF and blood was mainly composed of expanded CD8[+] GZMK [hi] TEMs. In conclusion, single-cell immune profiling provided novel insights into the pathogenesis of ALS, characterized by activated macrophages and clonally expanded CD8[+] T cells potentially communicating with the central nervous system and peripheral circulation.}, } @article {pmid39660938, year = {2025}, author = {Kashiwagi-Hakozaki, M and Ikemura, M and Naruse, H and Takahashi, Y and Toda, T and Ushiku, T}, title = {An autopsy case report of amyotrophic lateral sclerosis with unusual basophilic inclusions exhibiting immunopositivity for optineurin.}, journal = {Pathology international}, volume = {75}, number = {2}, pages = {121-123}, doi = {10.1111/pin.13501}, pmid = {39660938}, issn = {1440-1827}, } @article {pmid39662462, year = {2025}, author = {Huang, C and Qiu, L and Zhou, W and Shao, C and Wang, X and Zhang, Q and Chen, W and Xiong, M and Huang, M and Tang, M and Zou, L and Xu, X}, title = {A human-induced pluripotent stem cell (iPSC) line (SMUSHi006-A) from an ALS patient carrying a mutation c.1126C > T in the FUS gene.}, journal = {Stem cell research}, volume = {82}, number = {}, pages = {103604}, doi = {10.1016/j.scr.2024.103604}, pmid = {39662462}, issn = {1876-7753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *RNA-Binding Protein FUS/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism/pathology/cytology ; *Mutation ; Cell Line ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Four major genes associated with ALS-SOD1, TARDBP, FUS, and C9orf72-have been identified, with the fused in sarcoma (FUS) gene demonstrating considerable genetic heterogeneity. Our research group has previously established an induced pluripotent stem (iPS) cell line harboring the c.1562G > A mutation in the FUS gene. The objective of this study is to create another iPS cell line featuring the pathogenic c.1126C > T mutation in the FUS gene. This research aims not only to establish a disease model for ALS linked to FUS mutations but also to pave the way for potential therapeutic interventions.}, } @article {pmid39662532, year = {2025}, author = {Bayansan, O and Bhan, P and Chang, CY and Barmaver, SN and Shen, CP and Wagner, OI}, title = {UNC-10/SYD-2 links kinesin-3 to RAB-3-containing vesicles in the absence of the motor's PH domain.}, journal = {Neurobiology of disease}, volume = {204}, number = {}, pages = {106766}, doi = {10.1016/j.nbd.2024.106766}, pmid = {39662532}, issn = {1095-953X}, mesh = {Animals ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Caenorhabditis elegans/metabolism ; *rab3 GTP-Binding Proteins/metabolism/genetics ; *Synaptic Vesicles/metabolism ; Kinesins/metabolism/genetics ; Intracellular Signaling Peptides and Proteins/metabolism/genetics ; Animals, Genetically Modified ; Pleckstrin Homology Domains ; Nerve Tissue Proteins ; Intercellular Signaling Peptides and Proteins ; }, abstract = {Kinesin-3 KIF1A (UNC-104 in C. elegans) is the major axonal transporter of synaptic vesicles and mutations in this molecular motor are linked to KIF1A-associated neurological disorders (KAND), encompassing Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis and hereditary spastic paraplegia. UNC-104 binds to lipid bilayers of synaptic vesicles via its C-terminal PH (pleckstrin homology) domain. Since this interaction is relatively weak and non-specific, we hypothesize that other, more specific, interaction schemes exist. From the literature, it is evident that UNC-104 regulator SYD-2 interacts with UNC-10 and that UNC-10 itself interacts with RAB-3 bound to synaptic vesicles. RT-PCR and Western blot experiments expose genetic relationships between unc-10 and syd-2, but not between unc-10 and rab-3. Also, neither unc-10 nor rab-3 affects UNC-104 expression. However, co-immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays reveal functional interactions between UNC-104, SYD-2, UNC-10 and RAB-3. Though both SNB-1 and RAB-3 are actively transported by UNC-104, motility of RAB-3 is facilitated in the presence of SYD-2 and UNC-10. Deletion of UNC-104's PH domain did not affect UNC-104/RAB-3 colocalization, but significantly affected UNC-104/SNB-1 colocalization. Similarly, motility of RAB-3-labeled vesicles is only slightly altered in nematodes carrying a point mutation in the PH domain, whereas movement of SNB-1 is significantly reduced in this mutant. Western blots from purified fractions of synaptic vesicles reveal strong reduction of UNC-104 in rab-3/unc-10 double mutants. Our findings suggest that the UNC-10/SYD-2 complex acts as a functional linker to connect UNC-104 to RAB-3-containing vesicles. Thus, this linker complex contributes to the specificity of motor/cargo interactions.}, } @article {pmid39662651, year = {2025}, author = {Keethedeth, N and Anantha Shenoi, R}, title = {Mitochondria-targeted nanotherapeutics: A new frontier in neurodegenerative disease treatment.}, journal = {Mitochondrion}, volume = {81}, number = {}, pages = {102000}, doi = {10.1016/j.mito.2024.102000}, pmid = {39662651}, issn = {1872-8278}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Mitochondria/drug effects/metabolism ; Animals ; *Drug Delivery Systems/methods ; Nanoparticles ; }, abstract = {Mitochondria are the seat of cellular energy and play key roles in regulating several cellular processes such as oxidative phosphorylation, respiration, calcium homeostasis and apoptotic pathways. Mitochondrial dysfunction results in error in oxidative phosphorylation, redox imbalance, mitochondrial DNA mutations, and disturbances in mitochondrial dynamics, all of which can lead to several metabolic and degenerative diseases. A plethora of studies have provided evidence for the involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Hence mitochondria have been used as possible therapeutic targets in the regulation of neurodegenerative diseases. However, the double membranous structure of mitochondria poses an additional barrier to most drugs even if they are able to cross the plasma membrane. Most of the drugs acting on mitochondria also required very high doses to exhibit the desired mitochondrial accumulation and therapeutic effect which in-turn result in toxic effects. Mitochondrial targeting has been improved by direct conjugation of drugs to mitochondriotropic molecules like dequalinium (DQA) and triphenyl phosphonium (TPP) cations. But being cationic in nature, these molecules also exhibit toxicity at higher doses. In order to further improve the mitochondrial localization with minimal toxicity, TPP was conjugated with various nanomaterials like liposomes. inorganic nanoparticles, polymeric nanoparticles, micelles and dendrimers. This review provides an overview of the role of mitochondrial dysfunction in neurodegenerative diseases and various nanotherapeutic strategies for efficient targeting of mitochondria-acting drugs in these diseases.}, } @article {pmid39662855, year = {2025}, author = {Yang, ZF and Jiang, XC and Gao, JQ}, title = {Present insights into the progress in gene therapy delivery systems for central nervous system diseases.}, journal = {International journal of pharmaceutics}, volume = {669}, number = {}, pages = {125069}, doi = {10.1016/j.ijpharm.2024.125069}, pmid = {39662855}, issn = {1873-3476}, mesh = {Humans ; *Genetic Therapy/methods ; *Central Nervous System Diseases/therapy ; Animals ; *Gene Transfer Techniques ; *Genetic Vectors/administration & dosage ; Dependovirus/genetics ; }, abstract = {Central nervous system (CNS) diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), spinal cord injury (SCI), and ischemic strokes and certain rare diseases, such as amyotrophic lateral sclerosis (ALS) and ataxia, present significant obstacles to treatment using conventional molecular pharmaceuticals. Gene therapy, with its ability to target previously "undruggable" proteins with high specificity and safety, is increasingly utilized in both preclinical and clinical research for CNS ailments. As our comprehension of the pathophysiology of these conditions deepens, gene therapy stands out as a versatile and promising strategy with the potential to both prevent and treat these diseases. Despite the remarkable progress in refining and enhancing the structural design of gene therapy agents, substantial obstacles persist in their effective and safe delivery within living systems. To surmount these obstacles, a diverse array of gene delivery systems has been devised and continuously improved. Notably, Adeno-Associated Virus (AAVs)-based viral gene vectors and lipid-based nanocarriers have each advanced the in vivo delivery of gene therapies to various extents. This review aims to concisely summarize the pathophysiological foundations of CNS diseases and to shed light on the latest advancements in gene delivery vector technologies. It discusses the primary categories of these vectors, their respective advantages and limitations, and their specialized uses in the context of gene therapy delivery.}, } @article {pmid39663989, year = {2025}, author = {Das, U and Gayan, A and Biswas, R}, title = {A highly sensitive facile plasmonic scheme for assessment of melamine in raw milk.}, journal = {Analytical methods : advancing methods and applications}, volume = {17}, number = {3}, pages = {552-561}, doi = {10.1039/d4ay01764a}, pmid = {39663989}, issn = {1759-9679}, mesh = {*Triazines/analysis ; *Milk/chemistry ; Animals ; Metal Nanoparticles/chemistry ; Gold/chemistry ; Limit of Detection ; Silver/chemistry ; *Food Contamination/analysis ; Colorimetry/methods/instrumentation ; }, abstract = {This work presents two novel devices with a microcontroller and two different light sensors, namely, Light Dependent Resistor (LDR) and Ambient Light Sensor (ALS), which can provide a quantitative output from the colorimetric variations of citrate capped borohydride reduced silver nanoparticles (AgNPs) and citrate capped gold nanoparticles (AuNPs) upon addition of melamine adulterated milk. The limit of detection (LOD) of the LDR setup with AgNPs and AuNPs was found to be 1.24 ppm and 1.68 ppm, respectively, and the corresponding recovery rates were 92.86% and 88.57%, respectively. The device fabricated with the ALS with AgNPs displayed a recovery rate of 97.14% with a LOD value of 0.64 ppm.}, } @article {pmid39664295, year = {2024}, author = {Chen, LX and Zhang, MD and Xu, HF and Ye, HQ and Chen, DF and Wang, PS and Bao, ZW and Zou, SM and Lv, YT and Wu, ZY and Li, HF}, title = {Single-Nucleus RNA Sequencing Reveals the Spatiotemporal Dynamics of Disease-Associated Microglia in Amyotrophic Lateral Sclerosis.}, journal = {Research (Washington, D.C.)}, volume = {7}, number = {}, pages = {0548}, pmid = {39664295}, issn = {2639-5274}, abstract = {Disease-associated microglia (DAM) are observed in neurodegenerative diseases, demyelinating disorders, and aging. However, the spatiotemporal dynamics and evolutionary trajectory of DAM during the progression of amyotrophic lateral sclerosis (ALS) remain unclear. Using a mouse model of ALS that expresses a human SOD1 gene mutation, we found that the microglia subtype DAM begins to appear following motor neuron degeneration, primarily in the brain stem and spinal cord. Using reverse transcription quantitative polymerase chain reaction, RNAscope in situ hybridization, and flow cytometry, we found that DAM increased in number as the disease progressed, reaching their peak in the late disease stage. DAM responded to disease progression in both SOD1[G93A] mice and sporadic ALS and C9orf72-mutated patients. Motor neuron loss in SOD1[G93A] mice exhibited 2 accelerated phases: P90 to P110 (early stage) and P130 to P150 (late stage). Some markers were synchronized with the accelerated phase of motor neuron loss, suggesting that these proteins may be particularly responsive to disease progression. Through pseudotime trajectory analysis, we tracked the dynamic transition of homeostatic microglia into DAM and cluster 6 microglia. Interestingly, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia in SOD1[G93A] mice and observed that DAM survival is independent of CSF1R. An in vitro phagocytosis assay directly confirmed that DAM could phagocytose more beads than other microglia subtypes. These findings reveal that the induction of the DAM phenotype is a shared cross-species and cross-subtype characteristic in ALS. Inducing the DAM phenotype and enhancing its function during the early phase of disease progression, or the time window between P130 and P150 where motor neuron loss slows, could serve as a neuroprotective strategy for ALS.}, } @article {pmid39664805, year = {2025}, author = {Xing, H and McGregor, SKM and Batista, BD and Whitefield, C and Stone, ISJ and Murray, CE and Hurst, RM and Liu, Y and Chow, S and Fahrenhorst-Jones, T and Zhao, Q and Houston, SD and Hu, SH and Lonhienne, T and Nouwens, A and Burns, JM and Savage, GP and Walter, GH and Guddat, LW and Rafter, MA and Williams, CM}, title = {In search of herbistasis: COT-metsulfuron methyl displays rare herbistatic properties.}, journal = {Chemical science}, volume = {16}, number = {2}, pages = {649-658}, pmid = {39664805}, issn = {2041-6520}, abstract = {Weed management is an essential intervention for maintaining food security and protecting biodiversity but is heavily reliant on chemical control measures (i.e., herbicides). Concerningly, only one herbicide has been developed with a new mode of action (MOA) since the 1980s. Therefore, alternative strategies for preventing weed growth need to be explored. The lesser-known concept of halting weed growth through herbistasis could be one strategy to alleviate the lack of success in obtaining new MOA leads, but this type of activity has rarely been investigated. Herein reported is a bioisosteric cyclooctatetraene (COT) for phenyl ring replacement tactic, using the commercial acetolactate synthase (ALS) inhibitor metsulfuron methyl, that has unearthed a rare agent displaying herbistatic properties against the weed, Cryptostegia grandiflora (rubber vine).}, } @article {pmid39665821, year = {2025}, author = {Serneels, PJ and De Schutter, JD and De Groef, L and Moons, L and Bergmans, S}, title = {Oligodendroglial heterogeneity in health, disease, and recovery: deeper insights into myelin dynamics.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3179-3192}, pmid = {39665821}, issn = {1673-5374}, abstract = {Decades of research asserted that the oligodendroglial lineage comprises two cell types: oligodendrocyte precursor cells and oligodendrocytes. However, recent studies employing single-cell RNA sequencing techniques have uncovered novel cell states, prompting a revision of the existing terminology. Going forward, the oligodendroglial lineage should be delineated into five distinct cell states: oligodendrocyte precursor cells, committed oligodendrocyte precursor cells, newly formed oligodendrocytes, myelin-forming oligodendrocytes, and mature oligodendrocytes. This new classification system enables a deeper understanding of the oligodendroglia in both physiological and pathological contexts. Adopting this uniform terminology will facilitate comparison and integration of data across studies. This, including the consolidation of findings from various demyelinating models, is essential to better understand the pathogenesis of demyelinating diseases. Additionally, comparing injury models across species with varying regenerative capacities can provide insights that may lead to new therapeutic strategies to overcome remyelination failure. Thus, by standardizing terminology and synthesizing data from diverse studies across different animal models, we can enhance our understanding of myelin pathology in central nervous system disorders such as multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis, all of which involve oligodendroglial and myelin dysfunction.}, } @article {pmid39666071, year = {2024}, author = {de Boer, EMJ and de Vries, BS and Van Hecke, W and Mühlebner, A and Vincken, KL and Mol, CP and van Rheenen, W and Westeneng, HJ and Veldink, JH and Höglinger, GU and Morris, HR and Litvan, I and Raaphorst, J and Ticozzi, N and Corcia, P and Vandenberghe, W and Pijnenburg, YAL and Seelaar, H and Ingre, C and Van Damme, P and van den Berg, LH and van de Warrenburg, BPC and van Es, MA}, title = {Diagnosing primary lateral sclerosis: a clinico-pathological study.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {46}, pmid = {39666071}, issn = {1432-1459}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/diagnosis/pathology/genetics ; Autopsy ; Brain/pathology/diagnostic imaging ; Diagnosis, Differential ; *Motor Neuron Disease/diagnosis/pathology ; DNA-Binding Proteins ; }, abstract = {BACKGROUND: Primary lateral sclerosis (PLS) is a rare motor neuron disease characterized by upper motor neuron degeneration, diagnosed clinically due to the absence of a (neuropathological) gold standard. Post-mortem studies, particularly TDP-43 pathology analysis, are limited.

METHODS: This study reports on 5 cases in which the diagnostic criteria for PLS were met, but in which neuropathology findings showed (partially) conflicting results. These discrepancies prompted us to perform a clinico-pathology study focussing on diagnostic challenges and accuracy in PLS. To this end, all cases were reviewed by an international panel of 11 experts using an e-module and structured questionnaires.

RESULTS: Autopsy exhibited neuropathological findings consistent with amyotrophic lateral sclerosis (ALS) in one case, while two cases exhibited similar, but more limited lower motor neuron involvement, hinting at PLS or ALS overlap. Another case displayed tau-pathology indicative of progressive supranuclear palsy. The final case displayed extensive myelin loss without a proteinopathy or a clear diagnosis. The expert panel identified 24 different ancillary investigations lacking across cases (e.g. genetic testing, DAT scans, neuropsychological evaluation), listed 28 differential diagnoses, and identified 13 different conditions as the most likely diagnosis. Autopsy results led panel members to change their final diagnosis in 42% of the cases.

CONCLUSIONS: This study underscores the diagnostic challenges posed by diverse underlying pathologies resulting in upper motor neuron phenotypes. Despite adhering to the same diagnostic criteria, consensus amongst experts was limited. Ensuring the diagnostic consistency is crucial for advancing understanding and treatment of PLS. Explicit guidelines for excluding potential mimics along with a neuropathological gold standard are imperative.}, } @article {pmid39666103, year = {2024}, author = {Zimmermann, M and Mengel, D and Raupach, K and Haack, T and Neumann, M and Synofzik, M}, title = {Frequency and neuropathology of HTT repeat expansions in FTD/ALS: co-existence rather than causation.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {58}, pmid = {39666103}, issn = {1432-1459}, mesh = {Humans ; *Frontotemporal Dementia/genetics/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Male ; Female ; *Huntingtin Protein/genetics ; Middle Aged ; Aged ; *Trinucleotide Repeat Expansion/genetics ; Brain/pathology/diagnostic imaging ; }, abstract = {INTRODUCTION: While ≥ 40 CAG repeat expansions in HTT present a well-established cause of Huntington's disease (HD), an enrichment of HTT repeat expansions was recently reported also in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including FTD/ALS patients with additional HD neuropathology. This raises the question whether the phenotypic spectrum of HTT expansions can be extended to ALS and FTD, and whether HTT should be considered as a new causative gene of FTD/ALS. If HTT repeat expansions were indeed systematically related to FTD/ALS, one would expect an increased frequency of HTT carriers in FTD/ALS, who can clinically/neuropathologically not be explained better than by the presence of the HTT repeat expansions.

METHODS: Screening of HTT repeat expansions in 249 consecutive patients with ALS or FTD by short-read genome sequencing took place. The post-mortem neuropathological examination was performed in the identified HTT repeat expansion carrier.

RESULTS: One HTT repeat expansion [40/22 repeats (± 1)] was identified in an ALS patient, giving a frequency of 0.4% (1/249) (frequency in the general population: 0.03-0.18%). This patient showed a classic ALS phenotype, but no clinical or imaging signs of HD. Post-mortem brain examination revealed-in addition to ALS-typical degeneration of upper and lower motor neurons with TDP-43 inclusions-HD-typical polyQ-aggregates in gyrus cinguli, striatum and frontal lobe, yet without evidence of striatal degeneration.

CONCLUSIONS: Our study does not support the notion of an increased frequency of HTT repeat expansions in FTD/ALS. Moreover, the phenotype of the HTT carrier identified can be better explained by two co-existent, but independent diseases: (i) ALS and (ii) presymptomatic HD, which-given the low repeat number-is likely to become manifest only later in life. These findings corroborate the concept that HTT repeat expansions are likely co-existent/coincidental, but not causative in FTD/ALS.}, } @article {pmid39666115, year = {2024}, author = {Psychogios, I and Hu, Y and Seitz, C and Joyce, EE and Lovik, A and Ingre, C and Fang, F}, title = {Exploring clinical chemistry markers in amyotrophic lateral sclerosis: insights into survival and disease trajectories.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {7}, pmid = {39666115}, issn = {1432-1459}, support = {2019-01088//Swedish Research Council/ ; 2023-02428//Swedish Research Council/ ; MegaALS 802091//European Research Council Starting Grant/ ; R01 TS000324/TS/ATSDR CDC HHS/United States ; R01TS000324-01-00/CC/CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Biomarkers/blood ; Aged ; *Disease Progression ; Cohort Studies ; Sweden ; Adult ; Prognosis ; }, abstract = {OBJECTIVE: Commonly measured clinical chemistry markers might be indicative of survival and disease progression in amyotrophic lateral sclerosis (ALS).

METHODS: In a cohort study of 270 ALS patients diagnosed from April 2014 to May 2021 in Stockholm, Sweden, we examined the link between 29 clinical chemistry markers at diagnosis and mortality risk at 6 months, 1 year, and 3 years after diagnosis. Summary variables from exploratory factor analysis (EFA) assessed the markers' collective impact on survival. We integrated ALS functional rating scale-revised (ALSFRS-R) scores with survival data using a joint latent class model to identify patterns of functional decline. Multinomial logistic regression determined how the EFA-derived factors predicted the decline trajectories post-diagnosis.

RESULTS: Higher levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and albumin at diagnosis were linked to lower mortality in ALS patients, while increased neurofilament light chain (NfL), leukocyte count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and carbon dioxide (CO2) levels indicated higher mortality. The 'Red blood cell profile' factor, derived from EFA, emerged as a significant predictor of survival, independent of other prognostic indicators. The joint latent class model identified three distinct patient groups based on functional decline, with 'Red blood cell profile' suggesting a lower likelihood of being in the groups with slower progression.

CONCLUSION: Clinical chemistry markers, including NfL, lipids, albumin, leukocyte count, MCV, MCH, CO2, and the 'Red blood cell profile,' were associated with ALS survival. As these markers represent broader bodily functions, integrating them in ALS patient care could improve disease management.}, } @article {pmid39666121, year = {2024}, author = {Okubo, S and Naruse, H and Ishiura, H and Sudo, A and Esaki, K and Mitsui, J and Matsukawa, T and Satake, W and Greimel, P and Shingai, N and Oya, Y and Yoshikawa, T and Tsuji, S and Toda, T}, title = {Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {36}, pmid = {39666121}, issn = {1432-1459}, support = {JPMH23FC1008//Ministry of Health, Labour and Welfare/ ; JP23ek0109673//Japan Agency for Medical Research and Development/ ; JP23ek0109617//Japan Agency for Medical Research and Development/ ; JP23ek0109631//Japan Agency for Medical Research and Development/ ; JP24K18698//Japan Society for the Promotion of Science/ ; JP23K27514//Japan Society for the Promotion of Science/ ; 21K07512//Japan Society for the Promotion of Science/ ; Glyco-lipidologue Initiative Program//RIKEN/ ; }, mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood ; Mutation ; Pedigree ; *Serine C-Palmitoyltransferase/genetics ; Sphingolipids/blood ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor system. Pathogenic variants in SPTLC1, encoding a subunit of serine palmitoyltransferase, cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), and have recently been associated with juvenile ALS. SPTLC1 variants associated with ALS cause elevated levels of sphinganines and ceramides. Reports on ALS associated with SPTLC1 remain limited. This study aimed to investigate the frequency of SPTLC1 variants in ALS and relevant clinical characteristics.

METHODS: We analyzed whole-exome and whole-genome sequence data from 40 probands with familial ALS and 413 patients with sporadic ALS without previously identified causative variants. Reverse transcription polymerase chain reaction (RT-PCR) analysis and droplet digital PCR (ddPCR) were used to assess splicing and mosaicism, respectively. Plasma sphingolipid levels were quantified to analyze biochemical consequences.

RESULTS: The heterozygous c.58G>A, p.Ala20Thr variant was identified in a 21-year-old Japanese female patient presenting with symmetric weakness which slowly progressed over 15 years. RT-PCR analysis showed no splice defects. Plasma sphingolipid levels in the patient were significantly increased compared to her asymptomatic parents. ddPCR revealed that the asymptomatic father harbored a mosaic variant with 17% relative mutant allele abundance in peripheral blood leukocytes.

CONCLUSIONS: We identified a pathogenic c.58G>A, p.Ala20Thr SPTLC1 variant in a patient with juvenile ALS, likely inherited from an asymptomatic parent with mosaicism. Lipid analysis results are consistent with previous findings on SPTLC1-associated ALS. Further studies are necessary to determine the clinical effect of mosaic variants of SPTLC1.}, } @article {pmid39666144, year = {2024}, author = {Levison, LS and Blicher, JU and Andersen, H}, title = {Incidence and mortality of ALS: a 42-year population-based nationwide study.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {44}, pmid = {39666144}, issn = {1432-1459}, support = {A3520//Health Research Fund of Central Denmark Region/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Male ; Female ; Incidence ; Middle Aged ; Denmark/epidemiology ; Aged ; Adult ; Aged, 80 and over ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND AND AIM: Recent studies have suggested that the incidence rate (IR) and the rate of death (MR) of amyotrophic lateral sclerosis (ALS) are increasing. Still, it remains unclear whether this is due to improved case ascertainment or represents a true increase. We examined the development in the incidence and mortality of ALS in Denmark for 42 years.

METHODS: We retrieved individual-level data of all patients aged above 18 years with first-time ALS diagnosed at any Danish department of neurology. The IR and MR were calculated based on data from 1980 to 2021, stratified by gender and age.

RESULTS: We identified 5,943 patients with ALS and identified a total of 5,069 deaths in the nationwide population. Overall, the IR was 3.4 per 100,000 persons per year (95% CI 3.4-3.5). ALS incidence rose gradually during the study period, and the IR was 2.8 times higher (95% CI 2.4-3.2) when comparing the latest period (2018-2021) with the first (1980-1983). Parallel to the IR, the MR increased over time and was associated with male gender and rose with age at diagnosis, peaking in the 70-79-year age group.

CONCLUSION: In Denmark, the IR and MR of ALS increased threefold from 1980 to 2021, with steadily increasing risk related to male gender and in particular to higher age. Considering our aging societies, the number of elderly patients with ALS can be expected to increase considerably.}, } @article {pmid39666202, year = {2024}, author = {van Eijk, RPA and van Loon, FT and van Unnik, JWJ and Weemering, DN and Seitidis, G and Mavridis, D and van den Berg, LH and Nikolakopoulos, S}, title = {Attrition and discontinuation in amyotrophic lateral sclerosis clinical trials: a meta-analysis.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {40}, pmid = {39666202}, issn = {1432-1459}, support = {EVIDENCE//Stichting ALS Nederland/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Randomized Controlled Trials as Topic ; Patient Dropouts/statistics & numerical data ; }, abstract = {OBJECTIVES: Attrition due to adverse events and disease progression impacts the integrity and generalizability of clinical trials. The aim of this study is to provide evidence-based estimates of attrition for clinical trials in amyotrophic lateral sclerosis (ALS), and identify study-related predictors, through a comprehensive systematic review and meta-analysis.

METHODS: We systematically reviewed the literature to identify all randomized, placebo-controlled clinical trials in ALS and determined the number of patients who discontinued the study per randomized arm. Subsequently, we meta-analyzed attrition rates across studies, evaluated the difference between study arms, and explored the impact of study-level characteristics. Finally, a meta-regression model predicting study discontinuation for future clinical trials was translated into a web application.

RESULTS: In total, 60 randomized placebo-controlled clinical trials were included in the meta-analysis, randomizing 14,493 patients with ALS. Attrition varied significantly between studies, ranging from 3.1% to 75.7% of all randomized patients, with a pooled effect of 32.0% (90% prediction interval 6.1% to 66.3%). Attrition was similar between the intervention and placebo arm (odds ratio 1.08, 95% CI 0.89 to 1.31, p = 0.43). The follow-up duration was identified as the sole study-level predictor (0.032, 95% CI 0.026 to 0.039, p < 0.001), resulting in predicted attrition of 19.3% for 6-month, 36.4% for 12-month, and 55.6% for 18-month clinical trials.

CONCLUSIONS: ALS clinical trials encounter high attrition, which increases with the follow-up duration. These findings underscore the need to refine our strategies to manage attrition, preserving the integrity and generalizability of ALS clinical trials.}, } @article {pmid39667295, year = {2025}, author = {Spencer, PS and Berntsson, SG and Buguet, A and Butterfield, P and Calne, DB and Calne, SM and Giménez-Roldán, S and Hugon, J and Kahlon, S and Kisby, GE and Lagrange, E and Landtblom, AE and Ludolph, AC and Nunn, PB and Palmer, VS and Reis, J and Román, GC and Sipilä, JOT and Spencer, SS and Angues, RV and Vernoux, JP and Yabushita, M}, title = {Brain health: Pathway to primary prevention of neurodegenerative disorders of environmental origin.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123340}, doi = {10.1016/j.jns.2024.123340}, pmid = {39667295}, issn = {1878-5883}, mesh = {Humans ; *Neurodegenerative Diseases/prevention & control/etiology/epidemiology ; *Primary Prevention/methods ; *Brain ; *Environmental Exposure/adverse effects ; }, abstract = {While rising global rates of neurodegenerative disease encourage early diagnosis and therapeutic intervention to block clinical expression (secondary prevention), a more powerful approach is to identify and remove environmental factors that trigger long-latencybrain disease (primary prevention) by acting on a susceptible genotype or acting alone. The latter is illustrated by the post-World War II decline and disappearance of Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC), a prototypical often-familial neurodegenerative disease formerly present in very high incidence on the island of Guam. Lessons learned from 75 years of investigation on the etiology of ALS/PDC include: the importance of focusing field research on the disease epicenter and patients with early-onset disease; soliciting exposure history from patients, family, and community to guide multidisciplinary biomedical investigation; recognition that disease phenotype may vary with exposure history, and that familial brain disease may have a primarily environmental origin. Furthermore, removal from exposure to the environmental trigger effects primary disease prevention.}, } @article {pmid39667814, year = {2025}, author = {Rousseau, JA and Maier, M and Ait-Mohand, S and Dumulon-Perreault, V and Sarrhini, O and Tremblay, S and Rousseau, E and Salzmann, M and Guérin, B}, title = {Antibody-Based PET Imaging of Misfolded Superoxide Dismutase 1 in an Amyotrophic Lateral Sclerosis Mouse Model.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {66}, number = {1}, pages = {130-135}, pmid = {39667814}, issn = {1535-5667}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Mice ; *Superoxide Dismutase-1/metabolism/genetics ; *Positron-Emission Tomography/methods ; *Disease Models, Animal ; *Zirconium/chemistry ; Protein Folding ; Mice, Transgenic ; Deferoxamine/chemistry ; Antibodies/chemistry ; Radioisotopes ; Tissue Distribution ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease characterized by motor neuron loss in the motor cortex, brain stem, and spinal cord. Mutations in the superoxide dismutase 1 (SOD1) gene, resulting in misfolding of its protein product, are a common cause of ALS. Currently, there is no approved ALS diagnostic tool. Here, we present the development of a PET radiotracer, [[89]Zr]Zr-desferoxamine (DFO)-α-miSOD1, targeting selectively misfolded SOD1 (misSOD1). Methods: DFO-α-miSOD1 was prepared by conjugating α-miSOD1 antibody with DFO and labeled with [89]Zr. A longitudinal imaging study was performed to identify the optimal mouse age and time after administration of [[89]Zr]Zr-DFO-α-miSOD1 for the detection of misSOD1 aggregation in transgenic mice overexpressing misSOD1 and in wild-type mice. Subsets of mice were either coinjected with an excess of α-miSOD1 or imaged with deglycosylated [[89]Zr]Zr-DFO-α-miSOD1 to assess target specificity. The internal radiation dose for [[89]Zr]Zr-DFO-α-miSOD1 was estimated by extrapolating data from mouse biodistribution experiments. Results: Imaging with [[89]Zr]Zr-DFO-α-miSOD1 was optimal in 136-d-old transgenic mice on day 10 after administration. Significant accumulation of [[89]Zr]Zr-DFO-α-miSOD1 was detected in the spinal cord and cartilage of ALS transgenic mice compared with the wild-type mice (P = 0.01). The radiotracer accumulation is selective and blockable with an excess of α-miSOD1. Deglycosylated [[89]Zr]Zr-DFO-α-miSOD1 results in high-contrast detection of misSOD1 but is prone to aggregation. The dosimetry for [[89]Zr]Zr-DFO-α-miSOD1 is comparable to that for other [89]Zr-based tracers currently used in humans. Conclusion: This work thus establishes that [[89]Zr]Zr-DFO-α-miSOD1 PET can detect misSOD1 in transgenic mice, paving the way for application in early diagnosis of ALS and therapeutic monitoring.}, } @article {pmid39669124, year = {2024}, author = {Mirceta, M and Schmidt, MHM and Shum, N and Prasolava, TK and Meikle, B and Lanni, S and Mohiuddin, M and McKeever, PM and Zhang, M and Liang, M and van der Werf, I and Scheers, S and Dion, PA and Wang, P and Wilson, MD and Abell, T and Philips, EA and Sznajder, ŁJ and Swanson, MS and Mehkary, M and Khan, M and Yokoi, K and Jung, C and de Jong, PJ and Freudenreich, CH and McGoldrick, P and Yuen, RKC and Abrahão, A and Keith, J and Zinman, L and Robertson, J and Rogaeva, E and Rouleau, GA and Kooy, RF and Pearson, CE}, title = {C9orf72 repeat expansion creates the unstable folate-sensitive fragile site FRA9A.}, journal = {NAR molecular medicine}, volume = {1}, number = {4}, pages = {ugae019}, pmid = {39669124}, issn = {2976-856X}, support = {P50 NS048843/NS/NINDS NIH HHS/United States ; R01 GM122880/GM/NIGMS NIH HHS/United States ; R35 GM144215/GM/NIGMS NIH HHS/United States ; U54 NS048843/NS/NINDS NIH HHS/United States ; }, abstract = {The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. C9orf72Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immunostimulatory or damaged DNA is unknown. Here, we show C9orf72Exp in pre-symptomatic and amyotrophic lateral sclerosis-frontotemporal dementia patient cells and brains cause the folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33 kb of C9orf72 as highly compacted chromatin embedded in an 8.2 Mb fragility zone spanning 9p21, encompassing 46 genes, making FRA9A one of the largest fragile sites. C9orf72Exp cells show chromosomal instability, heightened global- and Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s and Chr9-containing micronuclei, providing endogenous sources of damaged and immunostimulatory DNA. Cells from one C9orf72Exp patient contained a highly rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic C9orf72Exp repeat instability and chromosomal fragility are sensitive to folate deficiency. Age-dependent repeat instability, chromosomal fragility and chromosomal instability can be transferred to CNS and peripheral tissues of transgenic C9orf72Exp mice, implicating C9orf72Exp as the source. Our results highlight unappreciated effects of C9orf72 expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere.}, } @article {pmid39669591, year = {2024}, author = {Beauregard-Lacroix, É and Scott, A and Nguyen, TTM and Wierenga, KJ and Purcarin, G and Karstensen, AB and Carvalho, DR and Alessandri, JL and Payet, F and Girisha, KM and Ferron, M and Campeau, PM}, title = {Exploring the phenotypic spectrum and osteopenia mechanisms in Yunis-Varón syndrome.}, journal = {Genetics in medicine open}, volume = {2}, number = {}, pages = {101837}, pmid = {39669591}, issn = {2949-7744}, abstract = {PURPOSE: Biallelic variants in FIG4 or VAC14 are associated with Yunis-Varón syndrome (YVS), which is characterized by multisystem involvement including skeletal findings, craniofacial dysmorphisms and central nervous system anomalies. Pathogenic variants in those same genes have also been associated with a predominantly neurological phenotype and with nonsyndromic conditions, such as Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. By describing 5 new cases of FIG4-associated YVS and reviewing the literature, we better delineate the clinical phenotype associated with loss of function of those genes. We also explore osteopenia mechanisms by assessing bone physiologic parameters in a mouse model.

METHODS: Exome sequencing or Sanger sequencing was performed in 5 unrelated individuals. Bone histomorphometry was performed in Fig4 [plt/plt] mice and compared with wild type. Relevant literature from the last 10 years was reviewed.

RESULTS: All individuals presented a phenotype overlapping the typical YVS and the brain anomalies and neurologic syndrome. Clinical features included developmental delay, structural brain malformations, and skeletal anomalies, such as osteopenia. Biallelic FIG4 variants were identified in each individual. In mice, bone histomorphometry parameters suggested that osteopenia might be secondary to reduced bone formation rather than increased bone degradation.

CONCLUSION: This study contributes to a better understanding of the phenotypic variability caused by pathogenic variants in FIG4 or VAC14 and suggests an important overlap between previously described phenotypes. The brain anomalies and neurologic syndrome is likely in the same spectrum as classical YVS. Further studies are still needed to clarify the effects of partial loss-of-function (hypomorphic) variants and to identify genotype-phenotype correlations.}, } @article {pmid39670112, year = {2024}, author = {Pinkerton, M and Adler, GL and Ledger, M and Ni, CY and Yang, Y and Tan, RH}, title = {Heterogeneous nuclear ribonucleoprotein D - an understudied subfamily affected in sporadic TDP-43 proteinopathies.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae352}, pmid = {39670112}, issn = {2632-1297}, abstract = {Despite the recognition that heterogeneous nuclear ribonucleoproteins (hnRNPs) modulate TDP-43 and can limit aberrant splicing events to compensate for TDP-43 loss, their role in TDP-43 proteinopathies remains poorly understood and studies in patient tissue are lacking. This study assesses seven heterogeneous nuclear ribonucleoproteins from the A/B, C, D and H subfamilies in two cortical regions implicated in early TDP-43 dysfunction versus late TDP-43 dysfunction in sporadic amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration. Our results reveal significant nuclear loss of hnRNPD, hnRNPC and hnRNPA1 in the frontal cortex of frontotemporal lobar degeneration compared to amyotrophic lateral sclerosis but not in the motor cortical neurons or Betz cells of amyotrophic lateral sclerosis cases. Cytoplasmic co-occurrence was observed between hnRNPA1 and hnRNPC but not with phosphorylated TDP-43 (pTDP-43). Interestingly, nuclear hnRNPD loss associated with increasing cytoplasmic pTDP-43, highlighting an understudied subfamily in sporadic TDP-43 proteinopathies. In summary, this study identifies the nuclear loss of hnRNPD, C and A1 in a predilection brain region of TDP-43 in frontotemporal lobar degeneration compared to amyotrophic lateral sclerosis cases without significant pTDP-43 in this region. This highlights the need for further investigation into the involvement of these heterogeneous nuclear ribonucleoproteins in disease pathogenesis and potential to serve as modulatory targets and/or proximal markers of TDP-43 dysfunction in sporadic TDP-43 proteinopathies.}, } @article {pmid39670345, year = {2025}, author = {D'Anna, L and Wragg, D and Mauro, D and Rubino, S and Terenzi, A and Barone, G and Thomas, SR and Casini, A and Bonsignore, R and Spinello, A}, title = {Unraveling the Molecular Basis for G-Quadruplex-Binders to ALS/FTD-Associated G4C2 Repeats of the C9orf72 Gene.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {26}, number = {8}, pages = {e202400974}, pmid = {39670345}, issn = {1439-7633}, support = {PNRR-M4C2-I1.3//European Union-NextGenerationEU/ ; PE_00000019//European Union-NextGenerationEU/ ; B73C22001250006//European Union-NextGenerationEU/ ; }, mesh = {*G-Quadruplexes/drug effects ; *C9orf72 Protein/genetics/chemistry ; *Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Frontotemporal Dementia/genetics ; Fluorescence Resonance Energy Transfer ; }, abstract = {The most recurrent familial cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of an abnormal number of intronic GGGGCC (G4C2) repetitions in the C9orf72 gene, which has been proposed to drive ALS/FTD pathogenesis. Recently, it has been shown that such G4C2 repetitions can fold into G-quadruplex (G4) secondary structures. These G4s have been selectively stabilized by small-molecule binders, furnishing proof-of-principle that targeting these non-canonical nucleic acid sequences represents a novel and effective therapeutic strategy to tackle neurodegenerative disorders. However, precise information on the mechanism of action of these compounds is still lacking. Here, by performing in silico investigations, we unraveled the molecular basis for the selectivity of a series of known structurally related C9orf72 G4-binders. Moreover, we investigated the binding properties of a strong and selective metal-based G4 stabilizer, the Au[I] bis-N-heterocyclic carbene (NHC) complex - Au(TMX)2 - showing that it moderately stabilizes G4C2 G4 RNA by Förster resonance energy transfer (FRET) DNA melting assays. Using metadynamics (metaD) simulations, the Au(TMX)2 binding mode and the associated free-energy landscape were also evaluated. This information paves the way for developing improved compounds to tackle ALS/FTD neurodegenerative disorders.}, } @article {pmid39670434, year = {2025}, author = {Piga, G and Fadda, L and Borghero, G and Maccabeo, A and Pala, F and Murru, MR and Giglio, S and Puligheddu, M and Floris, G}, title = {Semantic behavioral variant frontotemporal dementia and semantic dementia associated with TARDBP mutations.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {358-367}, doi = {10.1080/21678421.2024.2439448}, pmid = {39670434}, issn = {2167-9223}, mesh = {Humans ; *Frontotemporal Dementia/genetics/diagnosis ; Male ; Female ; Middle Aged ; Aged ; *DNA-Binding Proteins/genetics ; *Mutation/genetics ; Cohort Studies ; Semantics ; }, abstract = {Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, characterized by varying clinical and pathological features. TARDBP gene has been described worldwide within the FTD/ALS spectrum but its association with right and left temporal variant of FTD (tvFTD) is still unclear. This study aimed to reclassify a Sardinian FTD cohort according to proposed criteria for the semantic behavioral variant FTD (sbvFTD), explore TARDBP mutations' association with tvFTD, and review related literature. From our FTD cohort of 94 patients, ten fulfilled the criteria for sbvFTD. Therefore, in light of the diagnostic reclassification carried out, we describe the largest series of unrelated patients with TARDBP p.A382T missense mutation, including four new cases of tvFTD: two sbvFTD and two svPPA, exhibiting semantic and behavioral disorders and showing predominant right and left anterior temporal lobe involvement, respectively. We present for the first time two sbvFTD cases carrying the pA382T TARDBP mutation. Comparison with C9orf72 and non-mutated patients revealed lower age at onset (p = 0.006), and a higher prevalence of tvFTD, particularly sbvFTD (p < 0.001), and motor neuron disease in TARDBP carriers (p < 0.001). Our findings along with a review of the literature highlighted TARDBP mutations' association with sbvFTD and semantic dementia, suggesting a genetic role in temporal variants of FTD and emphasizing the need for TARDBP mutation screening in these cases. Reclassifying FTD cohorts, including the sbvFTD phenotype, could aid in better defining the clinical spectrum of tvFTD and guide differential diagnosis across different FTD populations with TARDBP or other FTD-related mutations.}, } @article {pmid39670820, year = {2025}, author = {Lagiakos, HR and Zou, Y and Igawa, H and Therrien, E and Lawrenz, M and Kato, M and Svensson, M and Gray, F and Jensen, K and Dahlgren, MK and Pelletier, RD and Dingley, K and Bell, JA and Liu, Z and Jiang, Y and Zhou, H and Skene, RJ and Nie, Z}, title = {In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {3}, pages = {2720-2741}, doi = {10.1021/acs.jmedchem.4c02074}, pmid = {39670820}, issn = {1520-4804}, mesh = {Animals ; *Neurodegenerative Diseases/drug therapy ; Humans ; Mice ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use/chemical synthesis ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis ; MAP Kinase Kinase Kinases/antagonists & inhibitors/metabolism ; Neurons/drug effects/pathology/metabolism ; Drug Discovery ; Computer Simulation ; Structure-Activity Relationship ; Rats ; }, abstract = {Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.}, } @article {pmid39671140, year = {2025}, author = {Ikehata, A}, title = {Extension of the molar absorption coefficient for non-ideal mixtures: an application to aqueous monovalent alcohol solutions.}, journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry}, volume = {41}, number = {4}, pages = {353-363}, pmid = {39671140}, issn = {1348-2246}, abstract = {The hydration state of the alcohols was investigated using the extended molar absorption coefficient, which redefines the molar absorption coefficient as a differential coefficient of concentration. The extended molar absorption coefficient is a function of the concentration calculated from the difference in absorbance, and is consistent with the conventional molar absorption coefficient, allowing a complete quantitative comparison. The quantitative performance was verified using IR and NIR absorption spectra of aqueous solutions of monovalent alcohols (methanol, ethanol, 1-propanol, 2-propanol, and tert-butanol) that were soluble in water at any mixing ratio. Extended molar absorption coefficient spectra were calculated for the combination bands of water, which were further separated by multivariate curve resolution-alternating least squares (MCR-ALS) into molecular species with different peak wavenumbers: strongly hydrogen-bonded (SHB), weakly hydrogen-bonded (WHB), and free OH species. The number of water species that change when one alcohol molecule increases, i.e., the perturbed hydration number (PHN), was calculated by comparison with the conventional molar absorption coefficient of pure water. The calculated PHN indicates that the numbers of SHB and WHB species are reversed at approximately 20 wt%, and that the free OH species increase at higher alcohol concentrations and are more pronounced for alcohols with bulky alkyl groups. These results provide a quantitative answer to the long-debated question of anomalies in water-alcohol mixing.}, } @article {pmid39671291, year = {2024}, author = {Lin, J and Carman, PJ and Gambogi, CW and Kendsersky, NM and Chuang, E and Gates, SN and Yokom, AL and Rizo, AN and Southworth, DR and Shorter, J}, title = {Design principles to tailor Hsp104 therapeutics.}, journal = {Cell reports}, volume = {43}, number = {12}, pages = {115005}, pmid = {39671291}, issn = {2211-1247}, support = {R01 GM099836/GM/NIGMS NIH HHS/United States ; R01 GM110001/GM/NIGMS NIH HHS/United States ; R01 GM138690/GM/NIGMS NIH HHS/United States ; T32 GM008076/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Adenosine Triphosphate/metabolism ; Saccharomyces cerevisiae Proteins/metabolism/genetics ; HSP40 Heat-Shock Proteins/metabolism/genetics ; HEK293 Cells ; Adenosine Diphosphate/metabolism ; Protein Binding ; }, abstract = {The hexameric AAA+ disaggregase, Hsp104, collaborates with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated proteins. However, how ATP- or ADP-specific MD configurations regulate Hsp104 hexamers remains poorly understood. Here, we define an ATP-specific network of interprotomer contacts between nucleotide-binding domain 1 (NBD1) and MD helix L1, which tunes Hsp70 collaboration. Manipulating this network can (1) reduce Hsp70 collaboration without enhancing activity, (2) generate Hsp104 hypomorphs that collaborate selectively with class B Hsp40s, (3) produce Hsp70-independent potentiated variants, or (4) create species barriers between Hsp104 and Hsp70. Conversely, ADP-specific intraprotomer contacts between MD helix L2 and NBD1 restrict activity, and their perturbation frequently potentiates Hsp104. Importantly, adjusting an NBD1:MD helix L1 rheostat via rational design enables finely tuned collaboration with Hsp70 to safely potentiate Hsp104, minimize off-target toxicity, and counteract FUS and TDP-43 proteinopathies in human cells. Thus, we establish design principles to tailor Hsp104 therapeutics.}, } @article {pmid39671529, year = {2025}, author = {Katzman, D and Kalman, G and Almog, O and Fogel, I}, title = {Deployment of Physician Resources and Innovative Medical Strategies in the 2023-2024 Israel-Hamas War: Israel's Strategy to Deliver Advanced Life Support and Whole Blood Transfusion to the Battlefield via Forward Medical Teams and the Impact on the Case Fatality Rate.}, journal = {Military medicine}, volume = {190}, number = {9-10}, pages = {226-230}, doi = {10.1093/milmed/usae553}, pmid = {39671529}, issn = {1930-613X}, mesh = {Humans ; Israel/epidemiology ; *Blood Transfusion/methods/statistics & numerical data/trends ; *Warfare/statistics & numerical data ; *Physicians/statistics & numerical data/trends ; Military Medicine/methods ; }, abstract = {The 2023-2024 Israel-Hamas War, which began following a Hamas attack on Israel on October 7, 2023, has seen a case fatality rate (CFR) among the lowest in the history of warfare. In resultant ground maneuvers, the Israel Defense Forces Medical Corps (IDF-MC) doctrine for the delivery of combat casualty care has been battle tested. We suggest the decreased CFR in part reflects a paradigm shift in combat deployment of medical resources, so as to introduce life-saving strategies not previously seen on the battlefield in large scale to date. These changes, which began in the 2006 Lebanon war and have been in evolution since, include strategic physician deployment to positions more forward than in previous wars and in teams smaller than the previous standard. These forward medical teams have replaced the battalion aid station in the Gaza theater of operations and serve to increase the availability of Advanced Life Support (ALS) level care at the point of injury, wherever a casualty might be on a multidimensional battlefield. These forward medical teams deploy with advanced medical capabilities, including in some cases the ability to transfuse low titer O whole blood. This article reviews aspects of the IDF-MC combat casualty care doctrine as implemented during the current war, the role and advantages of transfusion-capable ALS forward medical teams, and the apparent impact on the CFR thereof.}, } @article {pmid39672208, year = {2025}, author = {Liu, Y and Wu, L and Peng, W and Mao, X}, title = {Glial polarization in neurological diseases: Molecular mechanisms and therapeutic opportunities.}, journal = {Ageing research reviews}, volume = {104}, number = {}, pages = {102638}, doi = {10.1016/j.arr.2024.102638}, pmid = {39672208}, issn = {1872-9649}, mesh = {Humans ; *Neuroglia/pathology/metabolism/physiology ; *Nervous System Diseases/therapy/pathology/metabolism ; Animals ; *Cell Polarity/physiology ; Microglia/metabolism/pathology ; }, abstract = {Glial cell polarization plays a pivotal role in various neurological disorders. In response to distinct stimuli, glial cells undergo polarization to either mitigate neurotoxicity or facilitate neural repair following injury, underscoring the importance of glial phenotypic polarization in modulating central nervous system function. This review presents an overview of glial cell polarization, focusing on astrocytes and microglia. It explores the involvement of glial polarization in neurological diseases such as Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis and meningoencephalitis. Specifically, it emphasizes the role of glial cell polarization in disease pathogenesis through mechanisms including neuroinflammation, neurodegeneration, calcium signaling dysregulation, synaptic dysfunction and immune response. Additionally, it summarizes various therapeutic strategies including pharmacological treatments, dietary supplements and cell-based therapies, aimed at modulating glial cell polarization to ameliorate brain dysfunction. Future research focused on the spatio-temporal manipulation of glial polarization holds promise for advancing precision diagnosis and treatment of neurological diseases.}, } @article {pmid39672239, year = {2025}, author = {Cocozza, G and Busdraghi, LM and Chece, G and Menini, A and Ceccanti, M and Libonati, L and Cambieri, C and Fiorentino, F and Rotili, D and Scavizzi, F and Raspa, M and Aronica, E and Inghilleri, M and Garofalo, S and Limatola, C}, title = {GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis.}, journal = {Brain, behavior, and immunity}, volume = {124}, number = {}, pages = {280-293}, doi = {10.1016/j.bbi.2024.12.010}, pmid = {39672239}, issn = {1090-2139}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; *Growth Differentiation Factor 15/metabolism ; *Weight Loss/physiology ; *Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism/genetics ; Mice ; Disease Models, Animal ; Signal Transduction/physiology ; *Lipid Metabolism/physiology ; Humans ; Brain Stem/metabolism ; Male ; Mice, Transgenic ; Microglia/metabolism ; Adipose Tissue/metabolism ; Female ; }, abstract = {Weight loss is a common early sign in amyotrophic lateral sclerosis (ALS) patients and negatively correlates with survival. In different cancers and metabolic disorders, high levels of serum growth differentiation factor 15 (GDF15) contribute to a decrease of food intake and body weight, acting through GDNF family receptor alpha-like (GFRAL). Here we report that GDF15 is highly expressed in the peripheral blood of ALS patients and in the hSOD1[G93A] mouse model and that GFRAL is upregulated in the brainstem of hSOD1[G93A] mice. We demonstrate that the localized GFRAL silencing by shRNA in the area postrema/nucleus tractus solitarius of hSOD1[G93A] mice induces weight gain, reduces adipose tissue wasting, ameliorates the motor function and muscle atrophy and prolongs the survival time. We report that microglial cells could be involved in mediating these effects because their depletion with PLX5622 reduces brainstem GDF15 expression, weight loss and the expression of lipolytic genes in adipose tissue. Altogether these results reveal a key role of GDF15-GFRAL signaling in regulating weight loss and the alteration of and lipid metabolism in the early phases of ALS.}, } @article {pmid39673548, year = {2026}, author = {Alzahrani, AK and Imran, M and Alshrari, AS}, title = {Investigating the impact of SOD1 mutations on amyotrophic lateral sclerosis progression and potential drug repurposing through in silico analysis.}, journal = {Journal of biomolecular structure & dynamics}, volume = {44}, number = {1}, pages = {300-315}, doi = {10.1080/07391102.2024.2439577}, pmid = {39673548}, issn = {1538-0254}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/pathology ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; *Drug Repositioning ; Humans ; Molecular Dynamics Simulation ; *Mutation ; Protein Binding ; Molecular Docking Simulation ; Thermodynamics ; Protein Conformation ; Binding Sites ; Computer Simulation ; }, abstract = {Superoxide dismutase 1 (SOD1) is a vital enzyme responsible for attenuating oxidative stress through its ability to facilitate the dismutation of the superoxide radical into oxygen and hydrogen peroxide. The progressive loss of motor neurons characterize amyotrophic lateral sclerosis (ALS), a crippling neurodegenerative disease that is caused by mutations in the SOD1 gene. In this study, in silico mutational analysis was performed to study the various mutations, the pathogenicity and stability ΔΔG (binding free energy) of the variant of SOD1. x in the protein variant analysis showed a considerable destabilizing effect with a ΔΔG value of -4.2 kcal/mol, signifying a notable impact on protein stability. Molecular dynamics simulations were conducted on both wild-type and C146R mutant SOD1. RMSD profiles indicated that both maintained consistent structural conformation over time. Additionally, virtual screening of 3067 FDA-approved drugs against the mutant SOD1 identified two potential binders, Tucatinib (51039094) and Regorafenib (11167602), which interacted with Leu106, similar to the control drug, Ebselen. Further simulations assessed the dynamic properties of SOD1 in monomeric and dimeric forms while bound to these compounds. 11167602 maintained stable interaction with the monomeric SOD1 mutant, whereas 51039094 and Ebselen dissociated from the monomeric protein's binding site. However, all three compounds were stably bound to the dimeric SOD1. MM/GBSA analysis revealed similar negative binding free energies for 11167602 and 51039094, identifying them as strong binders due to their interaction with Cys111. Experimental validation, including in vitro, cell-based, and in vivo assays are essential to confirm these candidates before advancing to clinical trials.}, } @article {pmid39673573, year = {2024}, author = {Riaz, S and Steinsland, H and Andersen, AZ and Boysen, A and Hanevik, K}, title = {Proportions of IgA antibodies targeting glycosylated epitopes of secreted Escherichia coli mucinase YghJ in initial plasmablast response differ from salivary and intestinally secreted IgA.}, journal = {Medical microbiology and immunology}, volume = {214}, number = {1}, pages = {2}, pmid = {39673573}, issn = {1432-1831}, support = {234364//Research Council of Norway/ ; 234364//Research Council of Norway/ ; 234364//Research Council of Norway/ ; 7041-00220//Innovation Fund Denmark/ ; 7041-00220//Innovation Fund Denmark/ ; }, mesh = {Humans ; Glycosylation ; *Saliva/immunology ; *Epitopes/immunology ; Enterotoxigenic Escherichia coli/immunology ; Escherichia coli Proteins/immunology ; Antibodies, Bacterial/immunology/blood ; Plasma Cells/immunology ; Immunoglobulin A, Secretory/immunology ; Immunoglobulin A/immunology/blood ; Adult ; Male ; Female ; Escherichia coli Infections/immunology ; Young Adult ; }, abstract = {Mucosal infections normally cause an immune response including activation of antigen-specific B cells in regional mucosa-associated lymphoid tissue. After recirculation of plasmablasts, and maturation at mucosal surfaces or bone marrow, plasma cells produce secretory or systemic IgA. It remains uncertain to what extent secretory and systemic IgA share the same target specificities. For vaccine candidate optimization, it is important to know whether IgA targeting of glycosylated epitopes of a protein antigen vary between mucosal and systemic sites. We evaluated glycosylated epitope specificity of systemic and mucosally secreted IgA against YghJ, a potential vaccine candidate antigen secreted by most pathogenic Escherichia coli. IgA from intestinal lavage, saliva, serum, and blood-derived antibody in lymphocyte supernatants (ALS) were collected from 21 volunteers following experimental infection with enterotoxigenic E. coli. Methods for preparing IgA from saliva and ALS were developed, and multiplex bead flow cytometric immunoassays were used to determine levels of IgA targeting natively glycosylated YghJ and estimating what proportion of these antibodies specifically targeted glycosylated epitopes. Following infection, anti-YghJ IgA levels increased substantially for most volunteers across all four specimen types. Target specificity of ALS IgA correlated well with serum IgA, but not with mucosally secreted IgA. Furthermore, glycosylation-specific proportion of salivary IgA was higher than, and did not correlate with, intestinally secreted IgA. These results indicate a new degree of complexity to our understanding of epitope-targeting and tissue specificity of mucosal antibody responses. Our findings also suggest that all features of an intestinal IgA response may not be well reflected in serum, saliva, or ALS, which are commonly used proxy specimens for evaluating intestinal immune responses.}, } @article {pmid39674307, year = {2025}, author = {Pistolesi, A and Ranieri, G and Calvani, M and Guasti, D and Chiarugi, A and Buonvicino, D}, title = {Microglial suppression by myeloperoxidase inhibitor does not delay neurodegeneration in a mouse model of progressive multiple sclerosis.}, journal = {Experimental neurology}, volume = {385}, number = {}, pages = {115095}, doi = {10.1016/j.expneurol.2024.115095}, pmid = {39674307}, issn = {1090-2430}, mesh = {Animals ; Mice ; *Microglia/drug effects ; Disease Models, Animal ; *Peroxidase/antagonists & inhibitors/metabolism ; Mice, Inbred NOD ; Female ; *Multiple Sclerosis, Chronic Progressive/pathology/drug therapy ; Disease Progression ; Reactive Oxygen Species/metabolism ; *Propionates/pharmacology/therapeutic use ; *Enzyme Inhibitors/therapeutic use/pharmacology ; Mitochondria/drug effects/metabolism ; *Nerve Degeneration/pathology/drug therapy ; Spinal Cord/pathology/drug effects ; Aminopyridines ; Pyrroles ; }, abstract = {Drugs able to efficiently counteract the progression of multiple sclerosis (MS) are still an unmet need. Numerous preclinical evidence indicates that reactive oxygen-generating enzyme myeloperoxidase (MPO), expressed by neutrophils and microglia, might play a key role in neurodegenerative disorders. Then, the MPO inhibition has been evaluated in clinical trials in Parkinson's and multiple system atrophy patients, and a clinical trial for the treatment of amyotrophic lateral sclerosis is underway. The effects of MPO inhibition on MS patients have not yet been explored. In the present study, by adopting the NOD mouse model of progressive MS (PMS), we evaluated the pharmacological effects of the MPO inhibitor verdiperstat (also known as AZD3241) on functional, immune, and mitochondrial parameters during disease evolution. We found that daily treatment with verdiperstat did not affect the pattern of progression as well as survival, despite its ability to reduce mitochondrial reactive oxygen species and microglia activation in the spinal cord of immunized mice. Remarkably, verdiperstat did not affect adaptive immunity, neutrophils invasion as well as mitochondrial derangement in the spinal cords of immunized mice. Data suggest that microglia suppression is not sufficient to prevent disease evolution, corroborating the hypothesis that immune-independent components drive neurodegeneration in progressive MS.}, } @article {pmid39674407, year = {2025}, author = {Xue, S and Bao, W and Lyu, J and Wang, C and Zhang, Y and Li, H and Chen, D and Lu, Y}, title = {In vitro nephrotoxicity and structure-toxicity relationships of eight natural aristolactams.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {254}, number = {}, pages = {108214}, doi = {10.1016/j.toxicon.2024.108214}, pmid = {39674407}, issn = {1879-3150}, mesh = {Humans ; Structure-Activity Relationship ; *Aristolochic Acids/toxicity/chemistry ; Reactive Oxygen Species/metabolism ; Cell Survival/drug effects ; Cell Line ; Epithelial Cells/drug effects ; Transforming Growth Factor beta1/metabolism ; Hepatitis A Virus Cellular Receptor 1/metabolism ; }, abstract = {The structural similarity between aristolactams (ALs) and aristolochic acids (AAs) raises constant concerns about the safety of ALs-containing plants. Natural ALs are distributed more extensively than AAs, leading to a higher risk of ALs exposure in daily consumption. This study aimed to evaluate and compare the in vitro nephrotoxicity on human renal tubular epithelial cells (HK-2 cells) of eight natural ALs with different substituents on the phenanthrene ring and amide ring, including aristolactam Ⅰ (AL Ⅰ), AL BⅡ, velutinam, AL AⅡ, sauristolactam, AL AⅠa, AL FⅠ and N-methyl piperolactam A. Their IC50 values of cell viability were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of kidney injury molecule-1 (KIM-1), transforming growth factor-β1 (TGF-β1) and fibronectin (FN). The reactive oxygen species (ROS) assay was used to detect the intracellular oxidative stress level. The results showed that the eight ALs all had specific nephrotoxicity on HK-2 cells. Particularly, AL Ⅰ, AL BⅡ and velutinam exhibited more potent cytotoxicity on HK-2 cells (IC50 = 2.49-2.78 μM) than the other five ALs (IC50 = 12.33-43.84 μM). The structure-toxicity relationships indicated that both methylenedioxy (-OCH2O-) and methoxy (-OCH3) were positively contributing functional groups of ALs on nephrotoxicity, while the hydroxy group (-OH) and methyl substitution on nitrogen (N-CH3) accounted for a detrimental effect conversely. Consistent with this structure-toxicity relationship, the eight ALs increased KIM-1 levels in the same trend as their cytotoxicity at the same concentration of 2.5 μg/mL, associating with different levels of ROS generation. And the four most toxic ALs, AL Ⅰ, AL BⅡ, velutinam and AL AⅡ, could also induce fibrosis by increasing TGF-β1 and FN levels.}, } @article {pmid39676614, year = {2025}, author = {Roscoe, S and Allen, SP and McDermott, C and Stavroulakis, T}, title = {Exploring the role of anthropometric measurements to assess nutritional status in amyotrophic lateral sclerosis: a longitudinal prospective cohort study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {225-238}, pmid = {39676614}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Nutritional Status/physiology ; *Anthropometry/methods ; Aged ; Longitudinal Studies ; Prospective Studies ; Adult ; Body Mass Index ; Cohort Studies ; Body Weight/physiology ; Skinfold Thickness ; }, abstract = {OBJECTIVE: To observe longitudinal correlations between limb anthropometry against weight, BMI and functional decline in patients with amyotrophic lateral sclerosis.

METHODS: A longitudinal, prospective, cohort study was undertaken. Four consecutive measurements of weight, height, triceps skinfold thickness (TSF), mid-upper arm (MUAC) and calf circumferences were collected at three-monthly intervals. Fat- and lean body mass were estimated using measurements of TSF and derivations of arm muscle area, respectively. Correlation analyses indicated associations between anthropometric assessments and functional decline (ALSFRS-R). Longitudinal changes were assessed using repeated measures analyses.

RESULTS: Data from 18 participants was analyzed. At enrollment, weight positively correlated with MUAC (n = 17, p = 0.0001), arm muscle area (n = 17, p = 0.04) and calf circumference (n = 17, p < 0.0001). The ALSFRS-R score negatively correlated with weight (n = 17, p = 0.03), MUAC (n = 18, p = 0.01), TSF (n = 18, p = 0.04), and calf circumference (n = 18, p = 0.003). Function significantly declined by a difference of 6.3 points per month (p = 0.009). A positive correlation was observed between the changes in weight and calf circumference over nine months (r = 0.70, p = 0.02, n = 10).

CONCLUSION: Limb anthropometric measurements may be surrogate indicators of weight and BMI; TSF may be a practical, reliable indicator of fat mass, whilst changes in calf circumference may be alternatively used to monitor changes in nutritional status in the clinic.}, } @article {pmid39677625, year = {2024}, author = {Li, A and Dong, L and Li, X and Yi, J and Ma, J and Zhou, J}, title = {ALDH3A1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to denervation and Amyotrophic Lateral Sclerosis progression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39677625}, issn = {2692-8205}, support = {R01 NS105621/NS/NINDS NIH HHS/United States ; R01 NS129219/NS/NINDS NIH HHS/United States ; }, abstract = {Different muscles exhibit varied susceptibility to degeneration in Amyotrophic Lateral Sclerosis (ALS), a fatal neuromuscular disorder. Extraocular muscles (EOMs) are particularly resistant to ALS progression and exploring the underlying molecular nature may deliver great therapeutic value. Reactive aldehyde 4-hydroxynonenal (HNE) is implicated in ALS pathogenesis and ALDH3A1 is an inactivation-resistant intracellular detoxifier of 4-HNE protecting eyes against UV-induced oxidative stress. Here we detected prominently higher levels of ALDH3A1 in mouse EOMs than other muscles under normal physiological conditions. In an ALS mouse model (hSOD1[G93A]) reaching end-stage, ALDH3A1 expression was sustained at high level in EOMs, whereas substantial upregulation of ALDH3A1 occurred in soleus and diaphragm. The upregulation was less pronounced in extensor digitorum longus (EDL) muscle, which endured the most severe pathological remodeling as demonstrated by unparalleled upregulation of a denervation marker ANKRD1 expression. Interestingly, sciatic nerve transection in wildtype mice induced ALDH3A1 and ANKRD1 expression in an inverse manner over muscle type and time. Adeno-associated virus enforced overexpression of ALDH3A1 protected myotubes from 4-HNE-induced DNA fragmentation, plasma membrane leakage and restored MG53-mediated membrane repair. Our data indicate that ALDH3A1 may contribute to distinct muscle resistance to ALS through detoxifying reactive aldehydes.}, } @article {pmid39677629, year = {2024}, author = {Park, S and Park, SK and Liebman, SW}, title = {A model of inborn metabolism errors associated with adenine amyloid-like fiber formation reduces TDP-43 aggregation and toxicity in yeast.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.12.03.626668}, pmid = {39677629}, issn = {2692-8205}, abstract = {TDP-43 is linked to human diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Expression of TDP-43 in yeast is known to be toxic, cause cells to elongate, form liquid-like aggregates, and inhibit autophagy and TOROID formation. Here, we used the apt1Δ aah1Δ yeast model of disorders of inborn errors of metabolism, previously shown to lead to intracellular adenine accumulation and adenine amyloid-like fiber formation, to explore interactions with TDP-43. Results show that the double deletion shifts the TDP-43 aggregates from a liquid-like, toward a more amyloid-like, state. At the same time the deletions reduce TDP-43's effects on toxicity, cell morphology, autophagy, and TOROID formation without affecting the level of TDP-43. This suggests that the liquid-like and not amyloid-like TDP-43 aggregates are responsible for the deleterious effects in yeast. How the apt1Δ aah1Δ deletions alter TDP-43 aggregate formation is not clear. Possibly, it results from adenine/TDP-43 fiber interactions as seen for other heterologous fibers. The work offers new insights into the potential interactions between metabolite-based amyloids and pathological protein aggregates, with broad implications for understanding protein misfolding diseases.}, } @article {pmid39677679, year = {2024}, author = {Chen, L and Smith, M and Roe, DR and Miranda-Quintana, RA}, title = {Extended Quality (eQual): Radial threshold clustering based on n-ary similarity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39677679}, issn = {2692-8205}, support = {R35 GM150620/GM/NIGMS NIH HHS/United States ; }, abstract = {We are transforming Radial Threshold Clustering (RTC), an O (N 2) algorithm, into Extended Quality Clustering, an O (N) algorithm with several novel features. Daura et al's RTC algorithm is a partitioning clustering algorithm that groups similar frames together based on their similarity to the seed configuration. Two current issues with RTC is that it scales as O (N 2) making it inefficient at high frame counts, and the clustering results are dependent on the order of the input frames. To address the first issue, we have increased the speed of the seed selection by using k -means++ to select the seeds of the available frames. To address the second issue and make the results invariant with respect to frame ordering, whenever there is a tie in the most populated cluster, the densest and most compact cluster is chosen using the extended similarity indices. The new algorithm is able to cluster in linear time and produce more compact and separate clusters.}, } @article {pmid39678053, year = {2024}, author = {Finsterer, J and Mehri, S}, title = {The Causality Spectrum of Dropped Head Syndrome is Broad and Includes Myopathy, Neurodegenerative Disorders, and Varia.}, journal = {Noro psikiyatri arsivi}, volume = {61}, number = {4}, pages = {382-383}, pmid = {39678053}, issn = {1300-0667}, abstract = {Dropped head syndrome is a common complication of various neurological disorders. Most commonly, dropped head syndrome is due to primary or secondary myopathy. However, neurodegenerative diseases and various other conditions can also be complicated by dropped head syndrome. Among the primary myopathies, dropped head occurs most commonly in association with mitochondrial disorders, congenital myasthenic syndrome, and axial myopathies. Among the secondary myopathies, dropped occurs most commonly in association with inflammatory myopathies. Myasthenia is the most common transmission disorder associated with dropped head syndrome. The neurodegenerative disorder most commonly associated with dropped head syndrome is Parkinson syndrome. The diagnosis and treatment of dropped head syndrome from any cause requires a multidisciplinary approach. Outcome varies considerably but early diagnosis and early treatment are associated with a more favourable outcome.}, } @article {pmid39678056, year = {2024}, author = {Baslo, SA and Şirin, NG and Orhan, EK and Baslo, MB and Öge, AE}, title = {Selective Muscle Involvement in Amyotrophic Lateral Sclerosis: Evidence Inferred from the Point of Motor Unit Firing Rates.}, journal = {Noro psikiyatri arsivi}, volume = {61}, number = {4}, pages = {296-305}, pmid = {39678056}, issn = {1300-0667}, abstract = {INTRODUCTION: The aim of the study is to determine the role of upper motor neuron (UMN) or lower motor neuron (LMN) dysfunction as the primary initiator of distal-proximal and lateral-medial gradients of muscle involvement in amyotrophic lateral sclerosis (ALS).

METHODS: Concentric needle electromyography recordings were performed in deltoid, abductor digiti minimi, and first dorsal interosseous (FDI) muscles in patients with ALS and controls during slight voluntary contraction needed to activate two motor units (MU). Five motor unit potential (MUP) pairs were recorded from each muscle. Motor unit potential analyses were performed offline using Multi-MUP analysis program. Quantitative MUP parameters, MU firing rate (FR), FR variability (FRV), and mean consecutive difference (MCD) were calculated. Motor-evoked potentials and the triple stimulation technique (TST) were performed to evaluate UMN involvement.

RESULTS: Twenty patients with ALS along with 20 age and sex-matched healthy volunteers were enrolled. Quantitative MUP parameters compatible with denervation and reinnervation were found in patients with ALS, who also showed higher FR, FRV, and MCD values, most prominently in FDI. First dorsal interosseous FRV was lower in patients with abnormal central motor conduction time (CMCT). Firing rate and FRV were negatively correlated with CMCT, but not with TST.

CONCLUSION: Distal limb muscles, particularly FDI, revealed more prominent FR abnormalities in patients with ALS in parallel with the distal-proximal and lateral-medial gradients of the selective muscle involvement pattern which seems predominantly to be correlated with LMN dysfunction. Reduced FRV may be associated with the presence of UMN dysfunction in ALS.}, } @article {pmid39678223, year = {2025}, author = {Banos, M and Preuilh, A and Pradat, PF and Lackmy-Vallée, A and Marchand-Pauvert, V}, title = {Exercises and Brain Stimulation to Preserve Function in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Neurology. Clinical practice}, volume = {15}, number = {1}, pages = {e200408}, pmid = {39678223}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to the loss of motor function and muscle strength. Nonpharmacologic neuromodulative therapeutic approaches such as active exercise may contribute to preserve motor functions in ALS, but this hypothesis remains debated. The present meta-analysis first aimed to evaluate the effect of active exercise on function and muscle strength preservation. Moreover, since the responsiveness to induced neuroplasticity of patients with ALS is being discussed, the second objective was to review the analogous effects of noninvasive brain stimulation (NIBS).

METHODS: Following PRISMA guidelines, we systematically reviewed PubMed, CENTRAL, NIH PMC, PEDro, ScienceDirect, and Web of Science databases from the period between January 10 and July 1, 2023. Criteria limited inclusion to randomized controlled trials comparing active exercise (aerobic or resistance) with usual care or NIBS with sham. The primary outcome was assessed based on functional assessment scores reported on validated clinical scales, and the secondary outcome analysis included muscle strength and neurophysiologic changes. Methodologic quality of the selected studies was assessed using the Physiotherapy Evidence-Based (PEDro) scale. Relative risk (RR) and heterogeneity (I[2]) were calculated with Revman software, and evidence quality was estimated by the GRADE quality scale.

RESULTS: Thirteen studies were included. Analysis involved 393 patients among whom 164 underwent active exercise and 155 received usual care, 41 received NIBS and 33 underwent sham stimulations. The nature of active exercise was consistent across studies but varied in frequency. NIBS parameters were consistent for stimulation sites and session frequency. Function was significantly preserved in 5 of 9 studies on active exercise and 2 of 4 NIBS trials. Meta-analysis on functional scales indicated a moderate quality of evidence for the effectiveness of active exercises (RR = 0.61 [0.18, 1.04] with I[2] = 69%) compared with usual care and very low quality of evidence for NIBS (RR = -1.41 [-0.44, 3.26] with I[2] = 89%). Only 1 NIBS study revealed neuroplastic changes in the brain.

DISCUSSION: Active exercise likely slows functional loss in ALS, but the effects of NIBS need further investigation to support their neuroprotective effectiveness. Moreover, both interventions require further neurophysiologic investigation to elucidate ALS neuroplasticity.

This review has been registered in PROSPERO (CRD42023408121).}, } @article {pmid39678458, year = {2024}, author = {Sulek, A}, title = {Secretome - the role of extracellular vesicles in the pathogenesis and therapy of neurodegenerative diseases.}, journal = {Postepy psychiatrii neurologii}, volume = {33}, number = {3}, pages = {147-162}, pmid = {39678458}, issn = {2720-5371}, abstract = {PURPOSE: Extracellular vesicles are the subject of many studies in various medical specialties. Their role in neurodegenerative diseases is increasing and they worth introducing in more detail.

METHODS: This review was performed following an electronic search of the database PubMed/Medline and Web of Science for English-language articles between 2010 and 2024 in the fields of medicine, molecular biology, and biochemistry. Keywords searches included combinations of the following terms: "extracellular vesicles" OR "exosomes" AND "neurodeg*" AND "microRNA" OR "miRNA" AND "AD" OR "PD" OR "ALS" OR "HD". Articles had to be original work or reviews.

RESULTS: The classification of extracellular vesicles is based on their size or origin. Their content is of key importance in communication between cells and can be treated as a physiological determinant of the normal or pathological condition of a body. The cargo transported in the extracellular space and over longer distances in various body fluids is diversified and may be nucleic acids (DNA, RNA, miRNA) as well as proteins and lipids, and, in the case of apoptotic bodies also a cell's organelles. Exosomes are the most thoroughly studied extracellular vesicles and the most often considered for therapeutic applications. Vesicles carrying biological substances in the body perform three basic functions: participation in a pathological mechanism, a biomarker role that also has diagnostic and prognostic functions, and a role in therapeutic activities. In the case of neurodegenerative diseases, it appears that extracellular vesicles can transport misfolded proteins, initiating pathological processes in previously normal cells.

CONCLUSIONS: The transport of various substances enclosed in vesicles seems to be very promising in therapeutic prospects in various diseases, and the possibility of their crossing the blood-brain barrier particularly indicates diseases of the central nervous system. Despite many years of research on extracellular vesicles in the context of neurodegenerative diseases, their practical use is currently limited to studies on animal and cellular models, and their practical application in clinical trials in neurodegenerative diseases is to date extremely rare.}, } @article {pmid39678608, year = {2024}, author = {Dong, F}, title = {Bioinformatic materials science reconsidered.}, journal = {American journal of translational research}, volume = {16}, number = {11}, pages = {7200-7204}, pmid = {39678608}, issn = {1943-8141}, abstract = {Bioinformatic materials science integrates medical science, materials science, informatics, and other disciplines, aiming to maintain the balance of tissues and organs in the human body. This paper explores the relationship between structural information and the structures synthesized through regulated gene expression. Specifically, it describes the transformation of information into substances via biological structural systems, using mathematical formulas to develop bioinformatic materials. These materials have applications in medical treatments, functional foods for preventive healthcare, and cosmetic products for health maintenance. Notably, bioinformatic materials have been applied in treating acromegaly, a rare and life-threatening disease of unknown etiology, and have improved the neurofilament light chain (NFL) index and typical symptoms of Amyotrophic Lateral Sclerosis (ALS). In summary, bioinformatic materials science holds potential for enhancing human health and contributing to advances in medicine.}, } @article {pmid39679063, year = {2024}, author = {Kodavati, M and Hegde, ML}, title = {A Commentary on Mitochondrial Dysfunction and Compromised DNA Repair in Neurodegeneration: The Emerging Role of FUS in ALS.}, journal = {Neuroscience insights}, volume = {19}, number = {}, pages = {26331055241305151}, pmid = {39679063}, issn = {2633-1055}, support = {R01 NS088645/NS/NINDS NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {Mitochondrial dysfunction plays a pivotal role in the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, and Parkinson's disease. Recent discoveries have highlighted the involvement of DNA damage and repair processes, particularly mitochondrial DNA (mtDNA) damage, in these conditions. This commentary reflects on our recent findings, demonstrating the RNA/DNA binding protein fused in sarcoma (FUS)'s crucial role in maintaining mtDNA integrity through interactions with mitochondrial DNA ligase IIIα (mtLig3). Our studies provide direct evidence of increased mtDNA damage in ALS-linked FUS mutant cells, emphasizing the potential of targeting DNA repair pathways to mitigate neurodegeneration. Furthermore, the restoration of mitochondrial function through targeted expression of human DNA ligase 1 (Lig1) in FUS mutant models showcases the therapeutic promise of DNA repair mechanisms in neurodegenerative diseases. These insights offer new molecular understanding and open up future avenues for therapeutic interventions, particularly in FUS-associated ALS and related disorders.}, } @article {pmid39679928, year = {2024}, author = {Bhattacharjee, T and Vengalil, S and Belur, Y and Atchayaram, N and Ghosh, PK}, title = {Inter-speaker acoustic differences of sustained vowels at varied dysarthria severities for amyotrophic lateral sclerosis.}, journal = {JASA express letters}, volume = {4}, number = {12}, pages = {}, doi = {10.1121/10.0034613}, pmid = {39679928}, issn = {2691-1191}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Dysarthria/etiology/physiopathology ; *Speech Acoustics ; Male ; Female ; Middle Aged ; Aged ; Severity of Illness Index ; Phonetics ; }, abstract = {We study inter-speaker acoustic differences during sustained vowel utterances at varied severities of Amyotrophic Lateral Sclerosis-induced dysarthria. Among source attributes, jitter and standard deviation of fundamental frequency exhibit enhanced inter-speaker differences among patients than healthy controls (HCs) at all severity levels. Though inter-speaker differences in vocal tract filter attributes at most severity levels are higher than those among HCs for close vowels /i/ and /u/, these are comparable with or lower than those among HCs for the relatively more open vowels /a/ and /o/. The differences typically increase with severity except for a few parameters for /a/ and /i/.}, } @article {pmid39680215, year = {2024}, author = {Wu, H and Erenay, FS and Özaltın, OY and Dalgıç, ÖO and Sır, MY and He, QM and Crum, BA and Pasupathy, KS and , }, title = {Prognostic factors affecting ALS progression through disease tollgates.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {69}, pmid = {39680215}, issn = {1432-1459}, support = {2018-06596//NSERC (Natural Sciences and Engineering Research Council of Canada)/ ; 2017-04001//NSERC (Natural Sciences and Engineering Research Council of Canada)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Disease Progression ; Male ; Female ; Prognosis ; Middle Aged ; Aged ; }, abstract = {BACKGROUND AND OBJECTIVES: Understanding factors affecting the timing of critical clinical events in ALS progression.

METHODS: We captured ALS progression based on the timing of critical events (tollgates), by augmenting 6366 patients' data from the PRO-ACT database with tollgate-passed information using classification. Time trajectories of passing ALS tollgates after the first visit were derived using Kaplan-Meier analyses. The significant prognostic factors were found using log-rank tests. Decision-tree-based classifications identified significant ALS phenotypes characterized by the list of body segments involved at the first visit.

RESULTS: Standard (e.g., gender and onset type) and tollgate-related (phenotype and initial tollgate level) prognostic factors affect the timing of ALS tollgates. For instance, by the third year after the first visit, 80-100% of bulbar-onset patients vs. 43-48% of limb-onset patients, and 65-73% of females vs. 42-49% of males lost the ability to talk and started using a feeding tube. Compared to the standard factors, tollgate-related factors had a stronger effect on ALS progression. The initial impairment level significantly impacted subsequent ALS progression in a segment while affected segment combinations further characterized progression speed. For instance, patients with normal speech (Tollgate Level 0) at the first visit had less than a 10% likelihood of losing speech within a year, while for patients with Tollgate Level 1 (affected speech), this likelihood varied between 23 and 53% based on additional segment (leg) involvement.

CONCLUSIONS: Tollgate- and phenotype-related factors have a strong effect on the timing of ALS tollgates. All factors should be jointly considered to better characterize patient groups with different progression aggressiveness.}, } @article {pmid39680524, year = {2024}, author = {Rocha, PS and Bento, N and Folgado, D and Carreiro, AV and Santos, MO and de Carvalho, M and Miranda, B}, title = {Evaluation of smartphone-based cough data in amyotrophic lateral sclerosis as a potential predictor of functional disability.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0301734}, pmid = {39680524}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; *Cough/physiopathology ; Male ; Female ; *Smartphone ; Middle Aged ; Case-Control Studies ; Aged ; Cross-Sectional Studies ; Support Vector Machine ; Adult ; }, abstract = {OBJECTIVES: Cough dysfunction is a feature of patients with amyotrophic lateral sclerosis (ALS). The cough sounds carry information about the respiratory system and bulbar involvement. Our goal was to explore the association between cough sound characteristics and the respiratory and bulbar functions in ALS.

METHODS: This was a single-center, cross-sectional, and case-control study. On-demand coughs from ALS patients and healthy controls were collected with a smartphone. A total of 31 sound features were extracted for each cough recording using time-frequency signal processing analysis. Logistic regression was applied to test the differences between patients and controls, and in patients with bulbar and respiratory impairment. Support vector machines (SVM) were employed to estimate the accuracy of classifying between patients and controls and between patients with bulbar and respiratory impairment. Multiple linear regressions were applied to examine correlations between cough sound features and clinical variables.

RESULTS: Sixty ALS patients (28 with bulbar dysfunction, and 25 with respiratory dysfunction) and forty age- and gender-matched controls were recruited. Our results revealed clear differences between patients and controls, particularly within the frequency-related group of features (AUC 0.85, CI 0.79-0.91). Similar results were observed when comparing patients with and without bulbar dysfunction. Sound features related to intensity displayed the strongest correlation with disease severity, and were the most significant in distinguishing patients with and without respiratory dysfunction.

DISCUSSION: We found a good relationship between specific cough sound features and clinical variables related to ALS functional disability. The findings relate well with some expected impact from ALS on both respiratory and bulbar contributions to the physiology of cough. Finally, our approach could be relevant for clinical practice, and it also facilitates home-based data collection.}, } @article {pmid39681698, year = {2025}, author = {Aschemacher, NA and Siano, ÁS and Teglia, CM and Goicoechea, HC}, title = {Development, optimization and comparison of solid-liquid and liquid-liquid microextraction for the determination of four flavonols in Schinus molle L. using high-performance liquid chromatography coupled with second-order data modeling.}, journal = {Analytical and bioanalytical chemistry}, volume = {417}, number = {7}, pages = {1381-1392}, pmid = {39681698}, issn = {1618-2650}, support = {PICT 2020-0304//Fondo para la Investigación Científica y Tecnológica/ ; }, mesh = {Chromatography, High Pressure Liquid/methods ; *Liquid Phase Microextraction/methods ; *Flavonols/analysis/isolation & purification ; Limit of Detection ; Flavonoids/analysis ; *Solid Phase Microextraction/methods ; Quercetin/analysis/analogs & derivatives ; Plant Extracts/chemistry/analysis ; Schinus ; }, abstract = {Flavonoids are particularly interesting because they have a broad spectrum of biological effects, including antioxidant and free radical scavenging activities. In this work, solid-liquid microextraction and dispersive liquid-liquid microextraction enhanced by ultrasound were developed and compared with the conventional method (Soxhlet extraction) to optimize the extraction of four flavonoids: rutin, quercitrin, quercetin, and myricetin in samples of Schinus molle (Aguaribay). During the development of the analytical method, different chemometric tools were used to optimize the microextraction procedure. In addition, an analytical method based on high-performance liquid chromatography with diode array detector (HPLC-DAD) and second order calibration using multivariate curve resolution-alternating least square (MCR-ALS) is presented to quantify the flavonoids with limits of quantification between 0.011 and 0.082 µg mL[-1]. Finally, solid-liquid microextraction using 4.00 mL water/ethanol (54.3:45.7%), 14 s vortex, and 45 min was selected as the most suitable method due to its high recovery rate and environmental friendliness (with a greenness score of 0.78). After the optimization step, the concentrations found in the plant samples were 1825.3, 632.6, 110.2, and 18.9 µg g[-1] for rutin, quercitrin, quercetin, and myricetin, respectively. The present work is the first achievement of simultaneously determining these four analytes with exceptional sensitivity, demonstrating lower LOQs compared to previous reports.}, } @article {pmid39681722, year = {2025}, author = {Weiner, HL}, title = {Immune mechanisms and shared immune targets in neurodegenerative diseases.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {2}, pages = {67-85}, pmid = {39681722}, issn = {1759-4766}, mesh = {Animals ; Humans ; Amyotrophic Lateral Sclerosis/immunology ; *Immunotherapy/methods ; Microglia/immunology ; Multiple Sclerosis/immunology ; *Neurodegenerative Diseases/immunology/therapy ; }, abstract = {The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.}, } @article {pmid39682764, year = {2024}, author = {Huang, R and Xia, H and Lin, W and Wang, Z and Li, L and Deng, J and Ye, T and Li, Z and Yang, Y and Huang, Y}, title = {Riluzole Reverses Blood-Testis Barrier Loss to Rescue Chemotherapy-Induced Male Infertility by Binding to TRPC.}, journal = {Cells}, volume = {13}, number = {23}, pages = {}, pmid = {39682764}, issn = {2073-4409}, support = {No. U22A20277, 32170865, and 82071634//National Natural Science Foundation of China/ ; No. 2022A1515012178//Natural Science Foundation of Guangdong Province/ ; No. 202103030003//Guangzhou Key R&D Program/ ; No.2022B1111080007//Kea-Area Research and Development Program of Guangdong Province/ ; }, mesh = {Male ; *Riluzole/pharmacology/therapeutic use ; Animals ; *Blood-Testis Barrier/drug effects/metabolism ; *Infertility, Male/chemically induced/drug therapy/pathology ; Mice ; TRPC Cation Channels/metabolism ; Busulfan/pharmacology/adverse effects ; Antineoplastic Agents/pharmacology/adverse effects ; Mice, Inbred C57BL ; Molecular Docking Simulation ; Protein Binding/drug effects ; }, abstract = {Cancer treatments, including cytotoxic therapy, often result in male infertility, necessitating the development of safe and effective strategies to preserve male reproductive potential during chemotherapy. Notably, our study uncovers the potential of repurposing riluzole, an FDA-approved drug for amyotrophic lateral sclerosis (ALS), in enhancing spermatogenesis. Hence, this research aims to explore the feasibility of utilizing riluzole to alleviate male infertility induced by busulfan (BSF), a commonly used chemotherapy drug. We established a BSF-induced oligospermia model in 4-week-old male mice and found that riluzole could effectively counter the detrimental effects of BSF on sperm production in mice with oligospermia. By restoring blood-testis barrier (BTB) functionality, riluzole improves sperm quality and reduces testicular atrophy. Through transcriptomic and molecular docking analyses, we identify transient receptor potential canonical subfamily member 5 (TRPC5) as a potential target for riluzole-mediated regulation of blood-testis barrier function. These findings propose riluzole as a promising therapeutic option for chemotherapy-induced male infertility, thereby addressing the fertility challenges associated with cancer treatments. Moreover, repurposing riluzole could streamline the drug development process, providing a cost-effective approach with reduced risk compared to developing entirely new drugs.}, } @article {pmid39684197, year = {2024}, author = {García-González, N and Gonçalves-Sánchez, J and Gómez-Nieto, R and Gonçalves-Estella, JM and López, DE}, title = {Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684197}, issn = {1422-0067}, mesh = {Humans ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics ; Animals ; Amyotrophic Lateral Sclerosis/therapy/genetics ; }, abstract = {This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable conclusions. The efficacy of various gene therapies was evaluated for Parkinson's disease (n = 12), spinal muscular atrophy (n = 8), Huntington's disease (n = 3), Alzheimer's disease (n = 3), and amyotrophic lateral sclerosis (n = 6). For each condition, we assessed the therapeutic approach, curative or disease-modifying potential, delivery methods, advantages, drawbacks, and side effects. Results indicate that gene therapies targeting specific genes are particularly effective in monogenic disorders, with promising clinical outcomes expected in the near future. In contrast, in polygenic diseases, therapies primarily aim to promote cell survival. A major challenge remains: the translation of animal model success to human clinical application. Additionally, while intracerebral delivery methods enhance therapeutic efficacy, they are highly invasive. Despite these hurdles, gene therapy represents a promising frontier in the treatment of neurodegenerative diseases, underscoring the need for continued research to refine and personalize treatments for each condition.}, } @article {pmid39684308, year = {2024}, author = {Ścibior, A and Llopis, J and Dobrakowski, PP and Męcik-Kronenberg, T}, title = {Magnesium (Mg) and Neurodegeneration: A Comprehensive Overview of Studies on Mg Levels in Biological Specimens in Humans Affected Some Neurodegenerative Disorders with an Update on Therapy and Clinical Trials Supplemented with Selected Animal Studies.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684308}, issn = {1422-0067}, mesh = {Humans ; *Magnesium/therapeutic use ; Animals ; *Neurodegenerative Diseases/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Clinical Trials as Topic ; Disease Models, Animal ; Neuroprotective Agents/therapeutic use/pharmacology ; Parkinson Disease/drug therapy/metabolism ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Neurodegenerative diseases, characterized by neuron loss, are a group of neurological disorders that adversely affect the lives of millions of people worldwide. Although several medicines have been approved for managing neurodegenerative diseases, new therapies allowing for a significant slowdown in the progression of neurodegenerative syndromes are constantly being sought. Magnesium (Mg), a crucial mineral necessary for the functioning of organisms, is important to normal central nervous system (CNS) activity. Although the effects of this bioelement on the CNS are relatively well recognized, its role in the pathophysiology of neurological disorders in humans is not yet well characterized. Therefore, the main goal of this review is to collect data about a possible association between Mg and neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's Disease (PD), and Amyotrophic lateral sclerosis (ALS) in humans. Hence, the levels of Mg in blood, cerebrospinal fluid (CSF), urine, and hair from subjects with AD, PD, and ALS are compiled to detect possible variations in the levels of this mineral in the biological specimens of people with neurodegenerative illnesses. Additionally, the findings from an animal model are summarized to offer the reader a deeper insight into studies on Mg in the context of neuroprotection and neurodegeneration. Data provided in the present review indicate that Mg, due to its neuroprotective, antioxidant, anti-inflammatory, and mitochondrial-supportive properties, could be a potential therapeutic agent for AD, PD, and ALS. However, more epidemiological studies with standardized methods of dietary assessment and Mg measurement are necessary to recognize its exact role in neurodegenerative disorders. Moreover, extensive well-designed clinical trials are also needed to establish definitive therapeutic protocols and optimal dosages, and to ensure long-term safety of this mineral supplementation in AD, PD, and ALS patients.}, } @article {pmid39684324, year = {2024}, author = {Toader, C and Tataru, CP and Munteanu, O and Serban, M and Covache-Busuioc, RA and Ciurea, AV and Enyedi, M}, title = {Decoding Neurodegeneration: A Review of Molecular Mechanisms and Therapeutic Advances in Alzheimer's, Parkinson's, and ALS.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684324}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/genetics ; *Parkinson Disease/therapy/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism ; Animals ; Neurodegenerative Diseases/therapy/metabolism/genetics ; Drug Delivery Systems ; Gene Editing ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene in these once-intractable conditions. This review synthesizes the latest insights into the underlying molecular dynamics of neurodegeneration, revealing how intertwined pathways drive the course of these diseases. With an eye on the most promising advances, we explore innovative therapies emerging from cutting-edge research: nanotechnology-based drug delivery systems capable of navigating the blood-brain barrier, gene-editing tools like CRISPR designed to correct harmful genetic variants, and stem cell strategies that not only replace lost neurons but foster neuroprotective environments. Pharmacogenomics is reshaping treatment personalization, enabling tailored therapies that align with individual genetic profiles, while molecular diagnostics and biomarkers are ushering in an era of early, precise disease detection. Furthermore, novel perspectives on the gut-brain axis are sparking interest as mounting evidence suggests that microbiome modulation may play a role in reducing neuroinflammatory responses linked to neurodegenerative progression. Taken together, these advances signal a shift toward a comprehensive, personalized approach that could transform neurodegenerative care. By integrating molecular insights and innovative therapeutic techniques, this review offers a forward-looking perspective on a future where treatments aim not just to manage symptoms but to fundamentally alter disease progression, presenting renewed hope for improved patient outcomes.}, } @article {pmid39684507, year = {2024}, author = {Tournezy, J and Léger, C and Klonjkowski, B and Gonzalez-Dunia, D and Szelechowski, M and Garenne, A and Mathis, S and Chevallier, S and Le Masson, G}, title = {The Neuroprotective Effect of the X Protein of Orthobornavirus Bornaense Type 1 in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684507}, issn = {1422-0067}, support = {Evaluation of the therapeutic potential of the Borna virus X protein and X-derived peptides in ALS//Association pour la recherche sur la Sclérose Latérale Amyotrophique/ ; Award Fabrice Le Mouaher 2020//Fondation pour la Recherche Médicale/ ; trampoline grant 20219//Association Francaise contre les Myopathies/ ; X protein and ALS//Rotary Club of Bergerac/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Motor Neurons/metabolism/pathology ; Mice ; *Neuroprotective Agents/pharmacology ; *Disease Models, Animal ; Adenosine Triphosphate/metabolism ; Viral Proteins/metabolism/genetics ; Mice, Transgenic ; Humans ; }, abstract = {In amyotrophic lateral sclerosis (ALS), early mitochondrial dysfunction may contribute to progressive motor neuron loss. Remarkably, the ectopic expression of the Orthobornavirus bornaense type 1 (BoDV-1) X protein in mitochondria blocks apoptosis and protects neurons from degeneration. Therefore, this study examines the neuroprotective effects of X protein in an ALS mouse model. We first tested in vitro the effect of the X-derived peptide (PX3) on motoneurons primary cultures of SOD1[G93A] mice. The total intracellular adenosine triphosphate (ATP) content was measured after incubation of the peptide. We next tested in vivo the intramuscular injection of X protein using a canine viral vector (CAV2-X) and PX3 intranasal administrations in SOD1[G93A] mice. Disease onset and progression were assessed through rotarod performance, functional motor unit analysis via electrophysiology, and motor neuron survival by immunohistochemistry. The results showed that in vitro PX3 restored the ATP level in SOD1[G93A] motor neurons. In vivo, treated mice demonstrated better motor performance, preserved motor units, and higher motor neuron survival. Although life expectancy was not extended in this severe mouse model of motor neuron degeneration, the present findings clearly demonstrate the neuroprotective potential of X protein in a model of ALS. We are convinced that further studies may improve the therapeutic impact of X protein with optimized administration methods.}, } @article {pmid39686920, year = {2025}, author = {Sodagari, S and Sodagari, N}, title = {Examining vaccination-related adverse events in frequent neurodegenerative diseases.}, journal = {Brain, behavior, & immunity - health}, volume = {43}, number = {}, pages = {100902}, pmid = {39686920}, issn = {2666-3546}, abstract = {This study investigates adverse events following vaccination in patients with four neurodegenerative diseases: Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Multiple Sclerosis (MS), and Parkinson's disease. We applied advanced data processing techniques to analyze symptom patterns and severity scores across these disease groups. Patients were identified through filtering, and symptom clusters were extracted to group similar symptoms into distinct clusters, and severity scores were computed based on hospitalization and death reports. A chi-squared test was performed to assess the statistical significance of adverse event distributions among the diseases for different vaccines. The results reveal that ALS patients exhibit severe respiratory symptoms post-vaccination, while Alzheimer's patients report significant respiratory and gastrointestinal issues. MS patients commonly experience general symptoms such as fatigue, while Parkinson's patients face exacerbated motor symptoms. Notably, our analysis showed no significant difference in adverse event reporting rates between COVID-19 and pneumococcal vaccines across these disease groups. This research provides new insights into disease-specific responses to vaccines, emphasizing the importance of personalized monitoring and treatment strategies to mitigate risks and improve clinical outcomes in these vulnerable populations.}, } @article {pmid39687198, year = {2024}, author = {Pappalardo, XG and Jansen, G and Amaradio, M and Costanza, J and Umeton, R and Guarino, F and De Pinto, V and Oliver, SG and Messina, A and Nicosia, G}, title = {Inferring gene regulatory networks of ALS from blood transcriptome profiles.}, journal = {Heliyon}, volume = {10}, number = {23}, pages = {e40696}, pmid = {39687198}, issn = {2405-8440}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {One of the most robust approaches to the prediction of causal driver genes of complex diseases is to apply reverse engineering methods to infer a gene regulatory network (GRN) from gene expression profiles (GEPs). In this work, we analysed 794 GEPs of 1117 human whole-blood samples from Amyotrophic Lateral Sclerosis (ALS) patients and healthy subjects reported in the GSE112681 dataset. GRNs for ALS and healthy individuals were reconstructed by ARACNe-AP (Algorithm for the Reconstruction of Accurate Cellular Networks - Adaptive Partitioning). In order to examine phenotypic differences in the ALS population surveyed, several datasets were built by arranging GEPs according to sex, spinal or bulbar onset, and survival time. The designed reverse engineering methodology identified a significant number of potential ALS-promoting mechanisms and putative transcriptional biomarkers that were previously unknown. In particular, the characterization of ALS phenotypic networks by pathway enrichment analysis has identified a gender-specific disease signature, namely network activation related to the radiation damage response, reported in the networks of bulbar and female ALS patients. Also, focusing on a smaller interaction network, we selected some hub genes to investigate their inferred pathological and healthy subnetworks. The inferred GRNs revealed the interconnection of the four selected hub genes (TP53, SOD1, ALS2, VDAC3) with p53-mediated pathways, suggesting the potential neurovascular response to ALS neuroinflammation. In addition to being well consistent with literature data, our results provide a novel integrated view of ALS transcriptional regulators, expanding information on the possible mechanisms underlying ALS and also offering important insights for diagnostic purposes and for developing possible therapies for a disease yet incurable.}, } @article {pmid39687363, year = {2024}, author = {Stal, C and Covătaru, C and De Wolf, Q and Ignat, T and Pecheniuk, D and Lazăr, C}, title = {Towards a spatial data repository for archaeological research in the Romanian Mostiștea Basin and Danube Valley.}, journal = {Data in brief}, volume = {57}, number = {}, pages = {111119}, doi = {10.1016/j.dib.2024.111119}, pmid = {39687363}, issn = {2352-3409}, abstract = {Spatial data are crucial in archaeological research, where orthophotos, digital elevation models, and 3D models are widely used for mapping, documenting, and monitoring archaeological sites. The introduction of affordable and compact unmanned aerial vehicles (UAVs) has significantly advanced the use of UAV-based photogrammetry in the past 20 years. Recently, compact airborne systems have also enabled the capture of thermal, multispectral, and aerial laser scanning data. This paper presents the data acquired with different platforms and sensors at Chalcolithic archaeological sites in Romania's Mostiștea Basin and Danube Valley. Since laser scanning and photogrammetry generate large data volumes, data storage and dissemination must also be carefully considered. Based on a thorough study of system performance, data acquisition and processing methods, and data outputs, a workflow for the systematic mapping and documentation of sites has been proposed. Given the experience obtained in the last 5 summer campaigns (2018-2023), 19 sites have been accurately mapped, of which 5 sites are mapped using airborne laser scanning. 18 sites are documented using multispectral photogrammetry, and for 17 sites, interactive image-based 3D models are acquired using true-color photogrammetry. All data are stored on a publicly accessible website for visualization, as well as on an open-data platform for data exchange. For the multispectral data, a raster tile service has been implemented, allowing the use of the data in a GIS environment.}, } @article {pmid39688317, year = {2025}, author = {Tseriotis, VS and Eleftheriadou, K and Mavridis, T and Konstantis, G and Falkenburger, B and Arnaoutoglou, M}, title = {Is the Swallow Tail Sign a Useful Imaging Biomarker in Clinical Neurology? A Systematic Review.}, journal = {Movement disorders clinical practice}, volume = {12}, number = {2}, pages = {134-147}, pmid = {39688317}, issn = {2330-1619}, support = {//Hellenic Academic Libraries Link/ ; }, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Parkinson Disease/diagnostic imaging ; *Substantia Nigra/diagnostic imaging/pathology ; Biomarkers ; *Parkinsonian Disorders/diagnostic imaging ; }, abstract = {BACKGROUND: Loss of dorsolateral nigral hyperintensity (DNH) in iron-sensitive sequences of Magnetic Resonance Imaging (MRI), also described as "swallow tail sign" (STS) loss, has shown promising diagnostic value in Parkinson's Disease (PD) and Atypical Parkinsonian Syndromes (APS).

OBJECTIVE: To conduct a bibliometric analysis on substantia nigra MRI and a systematic review on the clinical utility of STS visual assessment on Susceptibility-Weighted Imaging in various clinical entities.

METHODS: VOSviewer's keyword co-occurrence network was employed using Web of Science (WOS). Complying with the PRISMA statement, we searched MEDLINE, WOS, SCOPUS, ProQuest and Google Scholar for peer-reviewed studies conducted in vivo, excluding quantitative imaging techniques.

RESULTS: DNH is a relatively novel parameter in substantia nigra MRI literature. Our SWI-focused review included 42 studies (3281 patients). Diagnostic accuracy of STS loss for PD/APS differentiation from controls and for Lewy Body Dementia differentiation from other dementias was 47.8-98.5% and 76-90%, respectively, with poorer capacity, however, in delineating PD from APS. STS evaluation in idiopathic REM sleep behavior disorder, a sign of prodromal PD, was typically concordant with nuclear scans, identifying subjects with high conversion risk. Iron deposition can affect STS in Multiple Sclerosis and STS loss in Amyotrophic Lateral Sclerosis is linked with multisystem degeneration, with poorer prognosis. In healthy individuals iron-induced microvessel changes are suspected for false positive results.

CONCLUSION: STS assessment exhibits potential in different settings, with a possibly intermediate role in the diagnostic work-up of various conditions. Its clinical utility should be explored further, through standardized MRI protocols on larger cohorts.}, } @article {pmid39688717, year = {2024}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Mohammadi, S and Batouli, SAH}, title = {Involvement of the left uncinate fasciculus in the amyotrophic lateral sclerosis: an exploratory longitudinal multi-modal neuroimaging and neuropsychological study.}, journal = {Brain structure & function}, volume = {230}, number = {1}, pages = {8}, pmid = {39688717}, issn = {1863-2661}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/physiopathology ; Female ; Male ; Middle Aged ; *Diffusion Tensor Imaging/methods ; Longitudinal Studies ; *Magnetic Resonance Imaging ; Aged ; Neuropsychological Tests ; Adult ; Neural Pathways/diagnostic imaging/physiopathology/pathology ; White Matter/diagnostic imaging/pathology ; Neuroimaging/methods ; Multimodal Imaging ; }, abstract = {To investigate the microstructural integrity, tract volume analysis, and functional connectivity (FC) alterations of the left uncinate fasciculus (UF) in patients with amyotrophic lateral sclerosis (ALS) compared to healthy controls (HCs). Fourteen limb-onset ALS patients were recruited at baseline and ten at follow-up, along with 14 HCs. All participants underwent 3D T1-weighted, diffusion tensor imaging and kurtosis imaging (DTI/DKI), and resting-state functional MRI (rs-fMRI) using a 3 Tesla scanner with 64-channel coils. Eight metrics of diffusion, rs-FC of the left UF, and graph theory analyses were extracted. Statistical group comparisons and correlation analysis for significant diffusion metrics were also conducted. Significantly lower radial kurtosis (RK), mean kurtosis (MK), and higher DTI diffusivity metrics were observed in the left UF of ALS patients than in HCs. RK and MK were correlated with various cognitive scores, particularly executive function and visuospatial ability. The volume of the left UF was positively correlated only with RK and MK at follow-up. While rs-FC analysis did not reveal group differences, a negative functional link between the left UF and cerebellum was observed in HCs but not in patients. Graph theory analysis suggested decreased connectivity in baseline patients and potential compensatory effects during the follow-up. Our study reveals microstructural abnormalities and potential network changes in left UF. DKI metrics, especially RK and MK, may be more sensitive biomarkers than DTI metrics, particularly longitudinally. Diffusion changes appear to precede volume and functional connectivity alterations, suggesting diffusion as a potential early biomarker.}, } @article {pmid39688956, year = {2024}, author = {Spargo, TP and Gilchrist, L and Hunt, GP and Dobson, RJB and Proitsi, P and Al-Chalabi, A and Pain, O and Iacoangeli, A}, title = {Statistical examination of shared loci in neuropsychiatric diseases using genome-wide association study summary statistics.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {39688956}, issn = {2050-084X}, support = {DRIVE-Health Centre for Doctoral Training//King's College London/ ; 772376-EScORIAL//Horizon 2020/ ; ES/L008238/1//Economic and Social Research Council/ ; 633413//Horizon 2020/ ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; 259867//European Community's Health Seventh Framework Programme/ ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; 10.35802/222811/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Genome-Wide Association Study ; Genetic Predisposition to Disease ; Mental Disorders/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Schizophrenia/genetics ; Genetic Loci ; Parkinson Disease/genetics ; Alzheimer Disease/genetics ; }, abstract = {Continued methodological advances have enabled numerous statistical approaches for the analysis of summary statistics from genome-wide association studies. Genetic correlation analysis within specific regions enables a new strategy for identifying pleiotropy. Genomic regions with significant 'local' genetic correlations can be investigated further using state-of-the-art methodologies for statistical fine-mapping and variant colocalisation. We explored the utility of a genome-wide local genetic correlation analysis approach for identifying genetic overlaps between the candidate neuropsychiatric disorders, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Parkinson's disease, and schizophrenia. The correlation analysis identified several associations between traits, the majority of which were loci in the human leukocyte antigen region. Colocalisation analysis suggested that disease-implicated variants in these loci often differ between traits and, in one locus, indicated a shared causal variant between ALS and AD. Our study identified candidate loci that might play a role in multiple neuropsychiatric diseases and suggested the role of distinct mechanisms across diseases despite shared loci. The fine-mapping and colocalisation analysis protocol designed for this study has been implemented in a flexible analysis pipeline that produces HTML reports and is available at: https://github.com/ThomasPSpargo/COLOC-reporter.}, } @article {pmid39689069, year = {2024}, author = {Junedahl, E and Lundgren, P and Andersson, E and Gupta, V and Råmunddal, T and Rawshani, A and Riva, G and Arnetorp, I and Hessulf, F and Herlitz, J and Djärv, T and Rawshani, A}, title = {The evidence supporting AHA guidelines on adult cardiopulmonary resuscitation (CPR).}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0309241}, pmid = {39689069}, issn = {1932-6203}, mesh = {Humans ; *Cardiopulmonary Resuscitation/standards/methods ; *American Heart Association ; Adult ; *Practice Guidelines as Topic ; United States ; *Heart Arrest/therapy ; Evidence-Based Medicine/standards ; }, abstract = {BACKGROUND: Guidelines for the management of cardiac arrest play a crucial role in guiding clinical decisions and care. We examined the strength and quality of evidence underlying these recommendations in order to elucidate strengths and gaps in knowledge.

METHODS: Using the 2020 American Heart Association (AHA) Guidelines for Adult CPR, we subdivided all recommendations into advanced life support (ALS), basic life support (BLS), and recovery after cardiac arrest, as well as a more granular categorization by topic (i.e. the intervention or evaluation recommended). The Class of Recommendation (COR) and Level of Evidence (LOE) for each were reviewed. Additionally, we reviewed the 2023 guidelines to ensure the inclusion of the most recent updates.

RESULTS: We noted 254 recommendations, of which 181 were ALS, 69 were BLS, and 4 were recovery after resuscitation. In total, only 2 (1%) had the most robust evidence (LOE A), while 23% were at LOE B-NR (Non-Randomized), 15% at LOE B-R (Randomized), 50% at LOE C-LD (Limited Data), and 12% relied on expert opinion LOE C-EO (Expert Opinion). Despite the strength of ALS recommendations (Class 1, 2a, or 2b), none had LOE A. In BLS, no recommendations were supported by LOE A. For BLS, 7% of recommendations had LOE C (C-LD or C-EO). The evidence for specific BLS topics, such as airway management, was notably low. Among ALS topics, neurological prognostication had relatively stronger evidence.

CONCLUSIONS: Only 26 out of the 81 COR 1 recommendations (32%) were supported by LOE A or B, indicating a strong discrepancy between the strength of recommendation and the underlying evidence in cardiac arrest guidelines. The findings underscore a pressing need for more rigorous research, particularly randomized trials.}, } @article {pmid39690343, year = {2025}, author = {Lamichhane, S and Seo, JE and Jeong, JH and Lee, S and Lee, S}, title = {Ideal animal models according to multifaceted mechanisms and peculiarities in neurological disorders: present and challenges.}, journal = {Archives of pharmacal research}, volume = {48}, number = {1}, pages = {62-88}, pmid = {39690343}, issn = {1976-3786}, support = {Research grant 2024//Chung-Ang University/ ; NRF-2016R1A6A1A03011325//Ministry of Education/ ; }, mesh = {Animals ; *Disease Models, Animal ; Humans ; *Nervous System Diseases/physiopathology/pathology/drug therapy ; Translational Research, Biomedical/methods ; }, abstract = {Neurological disorders, encompassing conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), pose a significant global health challenge, affecting millions worldwide. With an aging population and increased life expectancy, the prevalence of these disorders is escalating rapidly, leading to substantial economic burdens exceeding trillions of dollars annually. Animal models play a crucial role in understanding the underlying mechanisms of these disorders and developing effective treatments. Various species, including rodents, non-human primates, and fruit flies, are utilized to replicate specific aspects of human neurological conditions. However, selecting the ideal animal model requires careful consideration of its proximity to human disease conditions and its ability to mimic disease pathobiology and pharmacological responses. An Animal Model Quality Assessment (AMQA) tool has been developed to facilitate this selection process, focusing on assessing models based on their similarity to human conditions and disease pathobiology. Therefore, integrating intrinsic and extrinsic factors linked to the disease into the study's objectives aids in constructing a biological information matrix for comparing disease progression between the animal model and human disease. Ultimately, selecting an ideal animal disease model depends on its predictive, face, and construct validity, ensuring relevance and reliability in translational research efforts.}, } @article {pmid39690447, year = {2025}, author = {Koch, R and Nagoshi, E}, title = {Examining the potential involvement of NONO in TDP-43 proteinopathy in Drosophila.}, journal = {The European journal of neuroscience}, volume = {61}, number = {1}, pages = {e16632}, pmid = {39690447}, issn = {1460-9568}, support = {310030_189169//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; 310030_189169//The Swiss National Science Foundation/ ; }, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; *TDP-43 Proteinopathies/metabolism/pathology/genetics ; *Drosophila Proteins/metabolism/genetics ; RNA-Binding Proteins/metabolism/genetics ; Drosophila ; Neurons/metabolism ; Longevity ; Cell Nucleus/metabolism ; }, abstract = {The misfolding and aggregation of TAR DNA binding protein-43 (TDP-43), leading to the formation of cytoplasmic inclusions, emerge as a key pathological feature in a spectrum of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). TDP-43 shuttles between the nucleus and cytoplasm but forms nuclear bodies (NBs) in response to stress. These NBs partially colocalise with nuclear speckles and paraspeckles that sequester RNAs and proteins, thereby regulating many cellular functions. The laboratory of Steven Brown has recently found that the non-POU domain-containing octamer-binding protein (NONO), a component of paraspeckles, forms novel nuclear speckle-like structures in mouse cortical neurons in response to stress and sleep deprivation. These findings suggest the possibility of a functional link between NONO and TDP-43, potentially contributing to TDP-43 proteinopathy. Here, we demonstrate that pathological phenotypes caused by TDP-43 gain of function-locomotor defects and life span shortening-are exacerbated by silencing the Drosophila homolog of NONO, no on or off transient A (NonA). Additionally, NonA silencing results in an increase in nuclear TDP-43 NBs. These results provide supporting evidence for the functional link between NONO and TDP-43 and lay the foundation for dissecting underlying mechanisms.}, } @article {pmid39691422, year = {2024}, author = {Fang, K}, title = {Modulation of the central nervous system immune response and neuroinflammation via Wnt signaling in health and neurodegenerative diseases.}, journal = {Ibrain}, volume = {10}, number = {4}, pages = {462-476}, pmid = {39691422}, issn = {2769-2795}, abstract = {The immune response in the central nervous system (CNS) is a highly specialized and tightly regulated process essential for maintaining neural health and protecting against pathogens and injuries. The primary immune cells within the CNS include microglia, astrocytes, T cells, and B cells. They work together, continuously monitor the CNS environment for signs of infection, injury, or disease, and respond by phagocytosing debris, releasing cytokines, and recruiting other immune cells. In addition to providing neuroprotection, these immune responses must be carefully balanced to prevent excessive inflammation that can lead to neuronal damage and contribute to neurodegenerative diseases. Dysregulated immune responses in the CNS are implicated in various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Wnt signaling is a crucial pathway in the CNS that regulates various cellular processes critical for brain development, function, and maintenance. Despite enhancing immune responses in the health CNS, dysregulated Wnt signaling exacerbates neuroinflammation in the neurodegenerative brains. This review summarized the role of Wnt signaling in regulating immune response under different conditions. We then examined the role of immune response in healthy brains and during the development of neurodegenerative diseases. We also discussed therapeutic intervention in various neurodegenerative diseases through the modulation of the Wnt signaling pathway and neuroinflammation and highlighted challenges and limitations in current clinical trials.}, } @article {pmid39691755, year = {2025}, author = {Sood, A and Mishra, GV and Kar, P and Khandelwal, S and Gaur, S and Manuja, N}, title = {Amyotrophic lateral sclerosis in a tricenarian female.}, journal = {Radiology case reports}, volume = {20}, number = {2}, pages = {1121-1123}, pmid = {39691755}, issn = {1930-0433}, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by the progressive degeneration of the upper and lower motor neurons. This disease is mostly observed in patients of the 6th decade or above, and it is extremely rare to observe this pathology in patients less than 50 years of age. This manuscript depicts the magnetic resonance imaging findings of ALS showing a wine glass sign in a 31-year-old female from a rural area with complaints of progressive limb weakness and muscle wasting.}, } @article {pmid39693632, year = {2024}, author = {Hausmann, F and Caldi Gomes, L and Hänzelmann, S and Khatri, R and Oller, S and Gebelin, M and Parvaz, M and Tzeplaeff, L and Pasetto, L and Zhou, Q and Zelina, P and Edbauer, D and Pasterkamp, RJ and Rehrauer, H and Schlapbach, R and Carapito, C and Bonetto, V and Bonn, S and Lingor, P}, title = {A dataset profiling the multiomic landscape of the prefrontal cortex in amyotrophic lateral sclerosis.}, journal = {GigaScience}, volume = {13}, number = {}, pages = {}, pmid = {39693632}, issn = {2047-217X}, support = {01GM1917A//Bundesministerium für Bildung und Forschung/ ; CRC1192//DFG/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Prefrontal Cortex/metabolism/pathology ; Humans ; Female ; Mice ; Male ; Animals ; Mice, Transgenic ; Transcriptome ; Proteome ; Disease Models, Animal ; Aged ; Gene Expression Profiling/methods ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, which still lacks effective disease-modifying therapies. Similar to other neurodegenerative disorders, such as Alzheimer and Parkinson disease, ALS pathology is presumed to propagate over time, originating from the motor cortex and spreading to other cortical regions. Exploring early disease stages is crucial to understand the causative molecular changes underlying the pathology. For this, we sampled human postmortem prefrontal cortex (PFC) tissue from Brodmann area 6, an area that exhibits only moderate pathology at the time of death, and performed a multiomic analysis of 51 patients with sporadic ALS and 50 control subjects. To compare sporadic disease to genetic ALS, we additionally analyzed PFC tissue from 4 transgenic ALS mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS) using the same methods. This multiomic data resource includes transcriptome, small RNAome, and proteome data from female and male samples, aimed at elucidating early and sex-specific ALS mechanisms, biomarkers, and drug targets.}, } @article {pmid39693933, year = {2025}, author = {Taisei Ito, and Ohuchi, K and Kurita, H and Murakami, T and Takizawa, S and Fujimaki, A and Murata, J and Oida, Y and Hozumi, I and Kitaichi, K and Inden, M}, title = {Neuroprotective effects of activated fibroblast growth factor receptor 1 via the suppression of p53 accumulation against poly-PR-mediated toxicity.}, journal = {Biochemical and biophysical research communications}, volume = {743}, number = {}, pages = {151181}, doi = {10.1016/j.bbrc.2024.151181}, pmid = {39693933}, issn = {1090-2104}, mesh = {*Tumor Suppressor Protein p53/metabolism/genetics ; *Receptor, Fibroblast Growth Factor, Type 1/metabolism/genetics/antagonists & inhibitors ; Animals ; Mice ; *Neuroprotective Agents/pharmacology ; Cell Line ; Proto-Oncogene Proteins c-mdm2/metabolism/genetics ; Cell Survival/drug effects ; Motor Neurons/metabolism/drug effects ; Humans ; }, abstract = {A GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene is a major causative factor in amyotrophic lateral sclerosis (ALS). This aberrant HRE results in the generation of five distinct dipeptide repeat proteins (DPRs). Among the DPRs, poly-PR accumulates in the nucleus and exhibits particularly strong toxicity to motor and cortical neurons. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. Nevertheless, there has been no previous report of its neuroprotective effects against poly-PR toxicity. The objective of this study was to investigate the neuroprotective effects of FGFR1 activation in poly-PR-expressing NSC34 motor neuron-like cells. RT-qPCR analysis in NSC34 cells showed that Fgfr1 was the most highly expressed member of the Fgfr family in NSC34 cells. The activation of FGFR1 by FGF2, a common ligand for all FGFRs, exerted neuroprotective effects against the toxicity of poly-PR. Additionally, FGFR1 activation was observed to enhance cell viability through the PI3K-AKT pathway, while the contribution of the MEK-ERK pathway was found to be limited. Furthermore, FGFR1 activation suppressed the accumulation of p53 protein and promoted its degradation through increased murine double minute 2 (MDM2), an E3 ubiquitin ligase that targets p53. The neuroprotective effects were attenuated by PD173074, a selective FGFR1 inhibitor or Nutlin-3a, an inhibitor of the p53-MDM2 interaction. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity. Consequently, this study suggests the potential utility of FGFR1 activation as a therapeutic strategy for ALS.}, } @article {pmid39694468, year = {2025}, author = {Cornell, PY and Gadkari, G and Hua, CL and Smith, L and Johnson, A and Schwartz, L and Rahman, M and Thomas, KS}, title = {Risk of Hospitalization Among Assisted Living Residents Dually Enrolled in Medicare and Medicaid.}, journal = {Journal of the American Medical Directors Association}, volume = {26}, number = {2}, pages = {105421}, doi = {10.1016/j.jamda.2024.105421}, pmid = {39694468}, issn = {1538-9375}, mesh = {Humans ; United States ; *Hospitalization/statistics & numerical data ; *Assisted Living Facilities ; Retrospective Studies ; Male ; Female ; Aged ; *Medicare/statistics & numerical data ; *Medicaid/statistics & numerical data ; Aged, 80 and over ; }, abstract = {OBJECTIVES: To examine how risk of hospitalization among assisted living (AL) residents differs by dual enrollment in Medicare and Medicaid and by the percent of dually enrolled individuals in an AL community.

DESIGN: Retrospective cohort study.

SETTING AND PARTICIPANTS: We used Medicare data from 2008 to 2018 and a national directory of licensed AL communities to identify Medicare beneficiaries with a change in their ZIP+4 code suggesting a new residence in an AL.

METHODS: We estimated linear regression models of hospitalization onto interactions of residents' dual enrollment status and categories of the AL community's percentage of dually enrolled residents. In the models, we adjusted for person-level clinical and demographic characteristics, year-fixed effects, and fixed effects for the AL residents' prior ZIP code.

RESULTS: Among 620,542 Medicare beneficiaries who moved to an AL community, the 1-year risk of hospitalization was higher for dually enrolled residents compared with Medicare-only residents. In adjusted models, dually enrolled residents in high-dual AL communities (>50% dually enrolled) had an 7.4% higher risk of hospital admission compared with dually enrolled residents in low-dual AL communities. Medicare-only beneficiaries in high-dual AL communities had a 9.4% higher risk of hospitalization than Medicare-only beneficiaries in low-dual ALs.

CONCLUSIONS AND IMPLICATIONS: The proportion of residents in an AL community who were dually enrolled was associated with residents' risk of hospitalization, regardless of their dual enrollment status. Additional research is needed to understand whether differences observed in residents' risk of hospitalization are due to differences in the types of services provided, unmeasured resident acuity, or the quality of care delivered in these settings.}, } @article {pmid39694549, year = {2024}, author = {Ma, YL and Qiu, T and Xu, XL and Wang, LX and Zhuang, PY}, title = {[Analysis of clinical characteristics of amyotrophic lateral sclerosis patients initially diagnosed with abnormal laryngeal function].}, journal = {Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery}, volume = {59}, number = {12}, pages = {1293-1298}, doi = {10.3760/cma.j.cn115330-20240630-00388}, pmid = {39694549}, issn = {1673-0860}, support = {82271155//National Natural Science Foundation of China/ ; 2020J011212//Fujian Provincial Natural Science Foundation/ ; }, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Adult ; Larynx/physiopathology ; }, abstract = {Objective: To study the laryngeal functional characteristics of patients with amyotrophic lateral sclerosis (ALS)disease diagnosed at the voice clinic. Methods: A retrospective analysis(case series study) was conducted on the laryngeal functional characteristics of 7 patients [2 males, 5 females, age ranged from 43 to 76(60.85±13.18)]with motor neuron disease who visited the voice clinic and were ultimately diagnosed by neurologists. The data included laryngostroboscopy, fiberoptic endoscopic examination of swallowing(FEES), acoustic analysis and laryngeal electromyography(LEMG). Descriptive methods were used for analysis. Results: ①There were 2 males and 5 females, with an average age of (60.85±13.18) years. They had previously visited the otolaryngology department more than twice, visit frequency with an average of 3.57 and an average diagnosis time of 12.28 months. The main complaints of the patient at the time of treatment were voice change, dysphagia or vocal fatigue. ②LEMG: Among 7 cases, 4 cases demonstrated neurogenic damage, all of which were bilateral, and 3 cases showed normal findings on examination. Spontaneous potentials (SP) were present in three cases for more than 6 months, with the longest duration being 24 months. Three cases exhibited the coexistence of spontaneous potential and reinnervated motor unit potentials (MUPs), and two cases showed bundle tremor potential.③Laryngostroboscopy revealed bilateral vocal fold asymmetry and glottic insufficiency in 7 cases, and decreased vocal cord movement in 4 cases, and vocal cord atrophy in 5 cases. FEES showed that 7 patients presented with mild to severe swallowing dysfunction, 3 cases had soft palate insufficiency and mild to severe food residues in the epiglottic valley and pyriform fossa. 1 case showed leakage and 1 case showed aspiration. Conclusions: Patients presenting with initial symptoms of abnormal laryngeal function should be vigilant for the possibility of motor neuron disease, especially when laryngostroboscopy reveals abnormal vocal fold movement and swallowing dysfunction. LEMG examination reveals bilateral neurogenic damage, prolonged spontaneous potential, coexistence of spontaneous potential and reinnervated MUPs, and the appearance of bundle tremor potential, which is beneficial for early detection of motor neuron disease.}, } @article {pmid39696212, year = {2024}, author = {Giusti, A and Pukrittayakamee, P and Wannarit, K and Thongchot, L and Janwanishstaporn, S and Nkhoma, K and Venkatapuram, S and Harding, R}, title = {How to deliver person-centred care for people living with heart failure: a multi stakeholder interview study with patients, caregivers and healthcare professionals in Thailand.}, journal = {BMC health services research}, volume = {24}, number = {1}, pages = {1570}, pmid = {39696212}, issn = {1472-6963}, support = {GHRU 16/136/54//National Institute of Health Research (NIHR) Global Health Research Unit on Health System Strengthening in Sub-Saharan Africa, King's College London/ ; GA-00937//Funds for Graduate Women (FfGW)/ ; }, mesh = {Humans ; *Heart Failure/therapy/psychology ; Thailand ; *Caregivers/psychology ; Male ; *Patient-Centered Care ; Cross-Sectional Studies ; Female ; Middle Aged ; *Qualitative Research ; *Health Personnel/psychology ; Aged ; Adult ; Interviews as Topic ; }, abstract = {CONTEXT: Heart failure has high, growing global prevalence, morbidity and mortality, and is a leading cause of death with serious health-related suffering in low- and middle-income countries. Person-centred care (PCC) is a critical component of high-quality healthcare and is particularly vital in the context of a serious illness such as heart failure. However, there are limited data exploring PCC in this population in low- and middle-income settings.

AIM: The aim of this study was to explore how clinical services could respond to the PCC needs of individuals living with heart failure in Thailand, with potential for adaptation in other settings. The specific objectives were (i) to understand the experiences and needs of persons living with heart failure, their caregivers and HCPs; (ii) to explore specific practical actions that can help deliver PCC for heart failure patients in this setting.

METHODS: Cross-sectional qualitative study. In depth, semi-structured interviews were conducted in Thailand with heart failure patients (n = 14), their caregivers (n = 10) and healthcare professionals (n = 12). Framework analysis was conducted with deductive coding to populate an a priori coding frame based on Santana et al's PCC model (2018) and Giusti et al's systematic review (2020), with further inductive coding of novel findings to expand the frame. The study is reported in accordance with the consolidated criteria for reporting qualitative research guidelines (COREQ).

RESULTS: The findings reveal specific practice actions that deliver PCC for persons living with heart failure in Thailand, such as (i) compassionate communication by healthcare professionals; (ii) effective teamwork amongst multidisciplinary healthcare professionals; (iii) proactive responses to physical, psychosocial, relational and information needs of patients and caregivers; (iv) engaging patients and families in symptom management; (v) providing opportunities for patients to be cared for in the community; and (vi) responding to the social determinants of health, illness and healthcare access.

CONCLUSION: Person-centred healthcare systems must aim to address the social determinants of illness and place focus on community- and home-based care. Heart failure patients and caregivers must be supported to self-manage, including how to recognise symptoms and take appropriate action. Delivering PCC in such a way has the potential to improve outcomes for patients, enhance patients' sense of agency and experiences of care, improve health equity, and reduce hospital admissions, relieving pressure on the hospital system and reducing overall costs of care.}, } @article {pmid39696694, year = {2024}, author = {El-Khatib, SM and Vagadia, AR and Le, ACD and Baulch, JE and Ng, DQ and Du, M and Johnston, KG and Tan, Z and Xu, X and Chan, A and Acharya, MM}, title = {BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {190}, pmid = {39696694}, issn = {2051-5960}, support = {R01 CA251110/CA/NCI NIH HHS/United States ; R01 CA276212/CA/NCI NIH HHS/United States ; R01 CA262213/CA/NCI NIH HHS/United States ; P30CA062203//National Institutes of Health (UC Irvine Comprehensive Cancer Center)/ ; P30 CA062203/CA/NCI NIH HHS/United States ; UL1TR001414//National Institutes of Health (UC Irvine and National Center for Advancing Translational Sciences, NCATS)/ ; UL1 TR001414/TR/NCATS NIH HHS/United States ; R01CA276212/NH/NIH HHS/United States ; }, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; *Cognitive Dysfunction/etiology/metabolism ; *Cranial Irradiation/adverse effects ; Mice ; Male ; Mice, Inbred C57BL ; Neuroprotective Agents/pharmacology ; Neurodegenerative Diseases/radiotherapy ; Hippocampus/metabolism/radiation effects/drug effects ; Female ; }, abstract = {Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo. In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT + Vehicle with the RT + RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and mature neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.}, } @article {pmid39697444, year = {2024}, author = {He, SY and Cai, WC and Su, WM and Duan, QQ and Jiang, Z and Yin, KF and Gu, XJ and Chen, YP and Cao, B}, title = {Quantifying the split-elbow sign: a comprehensive study in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1499668}, pmid = {39697444}, issn = {1664-2295}, abstract = {PURPOSE: The split-elbow sign (SES), characterized by preferential dysfunction of the biceps brachii compared to the triceps, is a clinical feature observed in amyotrophic lateral sclerosis (ALS). However, the quantified SES index has not been extensively investigated, and its role in diagnosing ALS remains unknown. Therefore, this study aimed to investigate the split-elbow index (SEI) derived from compound muscle action potential (CMAP), motor unit number index (MUNIX), and echo intensity (EI) in ALS.

METHODS: A cohort comprising 70 individuals diagnosed with ALS, along with 41 disease controls and 40 healthy controls, was recruited for the study. The SEI was calculated by dividing the recorded values of CMAP, MUNIX, and EI obtained over the biceps brachii by the corresponding value measured in the triceps, resulting in SEICMAP, SEIMUNIX, and SEIEI, respectively. Receiver operating characteristic (ROC) curves of the three methods were used for comparison. Statistical analyses were performed using SPSS V.26.0 and R software.

RESULTS: Both SEICMAP and SEIMUNIX exhibited significant reductions in ALS patients compared to that in controls (PSEICMAp  < 0.0001, PSEIMUNIX < 0.0001), while SEIEI showed an elevation (P < 0.0001). Furthermore, there was a notable decrease in SEIMUNIX values as the disease progressed (p < 0.001). Moreover, ROC for SEIMUNIX exhibited superior diagnostic performance (AUC = 0.846), and a comprehensive diagnostic approach combining SEICMAP, SEIMUNIX, and SEIEI resulted in AUC (0.90) on the ROC curve.

CONCLUSION: Our study suggested that SES has emerged as a significant clinical characteristic in ALS and indicated the potential of SES indicators as biomarkers for both diagnosis and assessment of disease progression in ALS.}, } @article {pmid39697625, year = {2024}, author = {Zhao, X and Huang, S}, title = {Plasma extracellular vesicle: a novel biomarker for neurodegenerative disease diagnosis.}, journal = {Extracellular vesicles and circulating nucleic acids}, volume = {5}, number = {3}, pages = {569-573}, pmid = {39697625}, issn = {2767-6641}, abstract = {Extracellular vesicles (EVs) are membrane-bound structures that carry proteins, lipids, RNA, and DNA, playing key roles in cell communication and material transport. Recent research highlights their potential as disease biomarkers due to their stability in bodily fluids. This study explores using tau and TDP-43 proteins in plasma EVs as diagnostic biomarkers for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Analyzing plasma EVs from clinical cohorts, the study found that the 3R/4R tau ratio and TDP-43 levels effectively differentiate between diagnostic groups with high accuracy. Notably, plasma EV biomarkers demonstrate higher diagnostic accuracy and stability compared to direct plasma testing, providing new insights and approaches for future research and clinical practice. Further research is needed to validate these biomarkers in diverse populations and to establish standardized protocols. Future studies should continue to explore the potential of EV biomarkers in a broader range of neurodegenerative diseases and delve deeper into the mechanisms of EV secretion and sorting to enhance their diagnostic utility.}, } @article {pmid39698283, year = {2024}, author = {Kos, JA and Langiu, M and Hellyer, SD and Gregory, KJ}, title = {Pharmacology, Signaling and Therapeutic Potential of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {12}, pages = {3671-3690}, pmid = {39698283}, issn = {2575-9108}, abstract = {Metabotropic glutamate receptors are a family of eight class C G protein-coupled receptors regulating higher order brain functions including cognition and motion. Metabotropic glutamate receptors have thus been heavily investigated as potential drug targets for treating neurological disorders. Drug discovery efforts directed toward metabotropic glutamate receptor subtype 5 (mGlu5) have been particularly fruitful, with a wealth of drug candidates and pharmacological tools identified. mGlu5 negative allosteric modulators (NAMs) are promising novel therapeutics for developmental, neuropsychiatric and neurodegenerative disorders (e.g., Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, autism spectrum disorders, substance use disorders, stroke, anxiety and depression) and show promise in ameliorating adverse effects induced by other medications (e.g., L-dopa induced dyskinesia in Parkinson's Disease). However, despite preclinical success, mGlu5 NAMs are yet to reach the market due to poor safety and efficacy profiles in clinical trials. Herein, we review the physiology and signal transduction of mGlu5. We provide a comprehensive critique of therapeutic options with respect to mGlu5 inhibitors, spanning from orthosteric antagonists to NAMs. Finally, we address the challenges associated with drug development and highlight future directions to guide rational drug discovery of safe and effective novel therapeutics.}, } @article {pmid39700696, year = {2025}, author = {Ghaderi, S and Mohammadi, S and Fatehi, F}, title = {Current evidence of arterial spin labeling in amyotrophic lateral sclerosis: A systematic review.}, journal = {Clinical neurology and neurosurgery}, volume = {249}, number = {}, pages = {108691}, doi = {10.1016/j.clineuro.2024.108691}, pmid = {39700696}, issn = {1872-6968}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; *Spin Labels ; *Cerebrovascular Circulation/physiology ; *Brain/diagnostic imaging/blood supply ; Magnetic Resonance Imaging/methods ; }, abstract = {OBJECTIVE: This study aimed to evaluate the utility of arterial spin labeling (ASL) in assessing cerebral blood flow (CBF) changes in amyotrophic lateral sclerosis (ALS), and its potential as a biomarker for early diagnosis.

METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies that employed ASL to compare CBF between ALS patients and healthy controls were included.

RESULTS: Seven studies were included. A consistent finding across these studies was hypoperfusion in both the motor and non-motor regions, particularly in the frontotemporal cortex. Hypoperfusion in motor regions was correlated with functional impairment and was observed prior to structural changes, suggesting its potential as an early biomarker. There is limited evidence to suggest that monitoring changes in CBF patterns in the brain. Besides, limited findings showed initial hyperperfusion in regions not yet involved in the pathological process, and progressing hypoperfusion in regions with increasing pathological burden.

CONCLUSIONS: This review highlights the potential of ASL as a valuable tool for understanding the neurovascular dysfunction in ALS. Further research is required to validate its clinical utility for diagnosing ALS and monitoring disease progression.}, } @article {pmid39701395, year = {2025}, author = {Force, E and Alvarez, C and Fuentes, A and Maria, A and Bozzolan, F and Debernard, S}, title = {Diet influence on male sexual maturation through interplay between insulin signaling and juvenile hormone in insects.}, journal = {Insect biochemistry and molecular biology}, volume = {177}, number = {}, pages = {104252}, doi = {10.1016/j.ibmb.2024.104252}, pmid = {39701395}, issn = {1879-0240}, mesh = {Animals ; Male ; *Sexual Maturation ; *Insulin/metabolism ; *Juvenile Hormones/metabolism ; Signal Transduction ; *Moths/growth & development/metabolism/physiology/genetics ; Diet ; Receptor, Insulin/metabolism ; Female ; }, abstract = {In animals, sexual maturation coincides with the development of sexual behaviors and reproductive system. These developmental events are influenced by diet and governed by endocrine signals. Here, for the first time in insects, we explored functional links between nutrition and juvenile hormone (JH) in the male reproductive physiology through the insulin signaling pathway (ISP) acting as a transducer of nutritional signals. We turned to the male moth Agrotis ipsilon for which sexual maturation, including accessory sex glands (ASGs) development concomitantly with antennal lobes (ALs) maturation for female sex pheromone processing and display of sexual behavior, is known to be JH- and diet-dependent. Indeed, a diet rich in sugars with sodium was previously shown to accelerate sexual maturation, which was achieved from the third day of adult life. In this study, we demonstrated that such a diet raised i) the expression of JH signaling actors (Methoprene-tolerant, Taiman, and Krüppel homolog 1) in ALs and ASGs, ii) the biosynthesis and circulating levels of JH, and iii) the expression of both insulin receptor (InR) and insulin-like peptides (ILPs) in corpora allata (CAs) and brain respectively. Insulin injection raised JH biosynthesis following increased HMG-CoA reductase expression in CAs; opposite effects were induced in InR-deficient males. Thus, we highlighted that promoting effects of a diet composed of sugars with sodium on male sexual maturation results from an early induction of ISP causing an increase in JH biosynthesis followed by a potentiation of JH actions on the development of ASGs and ALs in A. ipsilon.}, } @article {pmid39701414, year = {2025}, author = {Tantoco, AM and Peterson, R and Corbin, B and Coyne, F and Herbst, B and Hunt, S and Levoy, E and Luttrell, H and Shanske, S and Sanyal, S and Dwyer-Matzky, K and Jenkins, AM}, title = {Pediatric to Adult Care Transition in the Hospital Context (PATCH) Tool: A Novel Tool to Assess Pediatric Institutional Guidelines for Inpatient Care of Adults.}, journal = {Academic pediatrics}, volume = {25}, number = {3}, pages = {102625}, doi = {10.1016/j.acap.2024.102625}, pmid = {39701414}, issn = {1876-2867}, mesh = {Humans ; *Transition to Adult Care/standards ; Adult ; *Hospitals, Pediatric ; *Practice Guidelines as Topic ; Child ; Chronic Disease/therapy ; Reproducibility of Results ; Adolescent ; Inpatients ; }, abstract = {OBJECTIVE: The growing number of adults with childhood onset chronic conditions (COCC) is reflected in the increase of adult-aged admissions to pediatric institutions. Despite national bodies advising pediatric institutions to have a pediatric to adult health care transition (HCT) policy, little guidance is available on if or how to include inpatient care. We sought to create a framework-based Pediatric to Adult Transitional Care in the Hospital Context (PATCH) tool to assess how inpatient care of adults is addressed in pediatric institutional guidelines or policies (hereafter guidelines) as a first step towards informing future PATCH guideline development.

METHODS: We used convenience and snowball sampling to obtain 11 pediatric institutional guidelines. Combining the GotTransition core elements with Coller et al's inpatient transition conceptual model through iterative consensus building, we developed the PATCH tool. Interrater reliability was assessed by using mean percent agreement among raters. A three-phase content validity process utilizing existing guidelines refined the finalized tool.

RESULTS: The PATCH tool included 42 items within nine domains. There was a high degree of agreeability among reviewers, and qualitative analysis revealed no missing items. Twenty-five (59%) of our 42 PATCH tool items were present in at least one of the reviewed guidelines, with age being present in all.

CONCLUSIONS: We developed the PATCH tool as a guide for pediatric institutions regarding the care of adolescent and adult patients. The PATCH tool, embedded in multidisciplinary stakeholder discussion and patient- and system-specific knowledge, may help institutions incorporate HCT into processes for adolescent and adult patients with COCCs.}, } @article {pmid39702138, year = {2024}, author = {Chen, C and Meng, J and Cheng, K and Kang, C and Zhou, L and Guo, H and Zhu, X}, title = {Spatial and morphologic features of lenses with different axial lengths in cataract patients: a swept-source optical coherence tomography-based study.}, journal = {BMC ophthalmology}, volume = {24}, number = {1}, pages = {542}, pmid = {39702138}, issn = {1471-2415}, support = {82122017, 82271069, 81870642, 82371040, 81970780, 81470613 and 81670835//National Natural Science Foundation of China/ ; 23Y11909800 and 21S31904900//Science and Technology Innovation Action Plan of Shanghai Science and Technology Commission/ ; SHDC12020111//Clinical Research Plan of Shanghai Shenkang Hospital Development Center/ ; shslczdzk01901//Shanghai Municipal Key Clinical Specialty Program/ ; }, mesh = {Humans ; *Tomography, Optical Coherence/methods ; Female ; Male ; *Cataract/pathology ; *Axial Length, Eye/pathology/diagnostic imaging ; Aged ; Middle Aged ; *Lens, Crystalline/diagnostic imaging/pathology ; Visual Acuity/physiology ; Myopia/physiopathology ; Retrospective Studies ; Aged, 80 and over ; Cataract Extraction ; }, abstract = {BACKGROUND: To investigate the spatial and morphologic features of lenses with different axial length (ALs) in cataract patients using swept-source optical coherence tomography (SS-OCT).

METHODS: Totally 105 eyes of 105 patients scheduled to have cataract surgery were included. Eyes were divided into the control (AL < 24.5 mm), moderate myopia (MM, 24.5 ≤ AL < 26 mm) and high myopia (HM, AL ≥ 26 mm) groups. Spatial features including lens vault (LV) and iris-to-lens distance (ILD), and morphologic features including radii of curvature of anterior and posterior surface (Ra, Rp), lens diameter (LD) and lens thickness (LT) were measured in eight directions by SS-OCT.

RESULTS: Spatially, the HM group had larger LV and ILD than the control group (both P < .05). LV and ILD were negatively correlated with AL, respectively (LV: r = -.484, P < .0001; ILD: r = -.656, P < .0001). Morphologically, both MM and HM groups had greater Ra and Rp than the control group. Ra was positively correlated with AL (r = .622, P < .0001), while the relationship between Rp and AL was non-linear. Moreover, the MM and HM groups had larger LD than the control group (both P < .001). Anterior LT was thinner in the HM than in the MM group (P = .026), while posterior LT between these two groups was similar. When compared in eight directions, similar trends were seen in Ra, Rp and LD, and the HM group showed a greater difference in Ra between horizontal and vertical directions.

CONCLUSIONS: This SS-OCT-based study showed that longer axial length is associated with a flatter lens, which was mainly attributed to the increase of Ra and LD. Longitudinal studies would be necessary to establish a causal relationship and temporal progression.}, } @article {pmid39703094, year = {2025}, author = {De Decker, M and Zelina, P and Moens, TG and Beckers, J and Contardo, M and Dittlau, KS and Van Schoor, E and Ronisz, A and Eggermont, K and Moisse, M and Chandran, S and Veldink, JH and Thal, DR and Van Den Bosch, L and Pasterkamp, RJ and Van Damme, P}, title = {C21ORF2 mutations point towards primary cilia dysfunction in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {3}, pages = {803-816}, pmid = {39703094}, issn = {1460-2156}, support = {C1-C14-17-107//KU Leuven/ ; //Opening the Future Fund (KU Leuven)/ ; 150031//Agency for Innovation by Science and Technology/ ; //ALS Liga België/ ; //National Lottery of Belgium/ ; //European E-Rare-3 project INTEGRALS/ ; //European E-Rare-3 project MAXOMOD/ ; //Stichting ALS Nederland/ ; //Vlaanderen/ ; 772376/ERC_/European Research Council/International ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Cilia/pathology/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; *Mutation/genetics ; Animals ; Female ; Neuromuscular Junction/pathology ; Male ; *Proteins/genetics/metabolism ; }, abstract = {Progressive loss of motor neurons is the hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain incompletely understood. In this study, we investigate the effects of C21ORF2 mutations, a gene recently linked to ALS, and find that primary cilia are dysfunctional. Human patient-derived mutant C21ORF2 motor neurons have a reduced ciliary frequency and length. We report that C21ORF2 is located at the basal body of the primary cilium, and mutations associated with ALS alter this localization. Furthermore, we show that a reduction of C21ORF2 levels in cell lines and motor neurons is sufficient to cause fewer primary cilia and reduced cilial length. This ciliary dysfunction leads to defective downstream sonic hedgehog signalling and reduces the expression of cellular retinoic acid binding protein 1 (CRABP1), a protein involved in motor neuron maintenance and survival. In a compartmentalized co-culture system of motor neurons and muscle cells, these ciliary defects were associated with a reduced ability of neuromuscular junction formation. Interestingly, these cilia defects are seemingly not restricted to C21ORF2 ALS, as we also observed perturbed primary cilia in cultured motor neurons and post-mortem motor cortex from patients with the most common genetic subtype of ALS caused by repeat expansions in the C9ORF72 gene. Finally, overexpression of C21ORF2 in mutant C21ORF2 motor neurons rescued the ciliary frequency and length, CRAPBP1 expression and neuromuscular junction formation, confirming the importance of primary cilia for motor neuron function. These results point towards primary cilia dysfunction contributing to motor neuron degeneration in ALS and open new avenues for further research and interventions for this as yet untreatable disease.}, } @article {pmid39703273, year = {2024}, author = {Solano, J and Eni, G and Viswanath, A and Enany, B}, title = {Successful Rescue of Ventricular Fibrillation Electrical Storm Secondary to Acute Myocardial Infarction in a Patient Presenting to a District General Hospital: A Case Report.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e73959}, pmid = {39703273}, issn = {2168-8184}, abstract = {Ventricular arrhythmia is a critical and challenging cardiovascular complication of myocardial infarction (MI). An electrical storm (ES), characterised by three or more episodes of sustained ventricular arrhythmia within 24 hours, poses a significant life-threatening risk. Standard management includes advanced life support (ALS) protocols and specialised pharmacological interventions. We present the case of a 43-year-old female who presented to the emergency department (ED) following an out-of-hospital ventricular fibrillation (OOHVF) arrest, with the return of spontaneous circulation (ROSC) achieved after multiple defibrillation shocks. Electrocardiography (ECG) revealed anterior ST-segment elevation MI (STEMI) involving the left anterior descending (LAD) artery. During her ED stay, she experienced recurrent ventricular fibrillation (VF) arrests requiring repeated defibrillation, adrenaline, amiodarone, and thrombolysis with alteplase. She was subsequently intubated and transferred to a primary percutaneous coronary intervention (PPCI) centre with intensive care support. Angiography confirmed a 100% occlusion of the LAD, which was successfully treated with stenting. The patient was admitted to the intensive care unit (ICU) and later discharged with full neurological recovery, on secondary prevention and heart failure therapy, with follow-up planned. This case underscores the complexity of managing electrical storms in MI, particularly in non-PPCI centres. It emphasises the importance of thrombolysis as an early reperfusion strategy in STEMI, especially when PPCI is not immediately available.}, } @article {pmid39703459, year = {2024}, author = {Oliveira, D and Nishimura, AL}, title = {Editorial: Mechanisms of neurodegeneration in amyotrophic lateral sclerosis and related disorders.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1531449}, doi = {10.3389/fncel.2024.1531449}, pmid = {39703459}, issn = {1662-5102}, } @article {pmid39703667, year = {2024}, author = {Lewis, RD and Keilholz, AN and Smith, CL and Burd, EA and Nichols, NL}, title = {Spinal TNF-α receptor 1 is differentially required for phrenic long-term facilitation (pLTF) over the course of motor neuron death in adult rats.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1488951}, pmid = {39703667}, issn = {1664-042X}, support = {T32 OD011126/OD/NIH HHS/United States ; }, abstract = {INTRODUCTION: Intrapleural injections of cholera toxin B conjugated to saporin (CTB-SAP) result in selective respiratory (e.g., phrenic) motor neuron death and mimics aspects of motor neuron disease [(e.g., amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA)], such as breathing deficits. This rodent model allows us to study the impact motor neuron death has on the output of surviving phrenic motor neurons as well as the compensatory mechanisms that are recruited. Microglial density in the phrenic motor nucleus as well as cervical gene expression of markers associated with inflammation (e.g., tumor necrosis factor α; TNF-α) are increased following CTB-SAP-induced phrenic motor neuron death, and ketoprofen (nonsteroidal anti-inflammatory drug) delivery attenuated phrenic long-term facilitation (pLTF) in 7 day (d) CTB-SAP rats but enhanced pLTF in 28d CTB-SAP rats.

METHODS: Here, we worked to determine the impact of TNF-α in the phrenic motor nucleus by: 1) quantifying TNFR1 (a high affinity transmembrane receptor for TNF-α) expression; 2) investigating astrocytes (glial cells known to release TNF-α) by performing a morphological analysis in the phrenic motor nucleus; and 3) determining whether acute TNFR1 inhibition differentially affects phrenic plasticity over the course of CTB-SAP-induced motor neuron loss by delivering an inhibitor for TNF-α receptor 1 (sTNFR1i) in 7d and 28d male CTB-SAP and control rats.

RESULTS: Results revealed that TNFR1 expression was increased on phrenic motor neurons of 28d CTB-SAP rats (p < 0.05), and that astrocytes were increased and exhibited reactive morphology (consistent with an activated phenotype; p < 0.05) in the phrenic motor nucleus of CTB-SAP rats. Additionally, we found that pLTF was attenuated in 7d CTB-SAP rats but enhanced in 28d CTB-SAP rats (p < 0.05) following intrathecal sTNFR1i delivery.

CONCLUSION: This work suggests that we could harness TNFR1 as a potential therapeutic agent in CTB-SAP rats and patients with respiratory motor neuron disease by increasing compensatory plasticity in surviving neurons to improve phrenic motor neuron function and breathing as well as quality of life. Future studies will focus on microglial and astrocytic cytokine release, the role they play in the differential mechanisms of pLTF utilized by 7d and 28d CTB-SAP rats, and potential therapies that target them.}, } @article {pmid39705260, year = {2024}, author = {Lima, TBWE and Fonseca, JDMD and Silva, AAMD and Vieira, RGDS and Montemezzo, D and Otto-Yáñez, M and Torres-Castro, R and Júnior, METD and Resqueti, VR and Fregonezi, GAF}, title = {Methods to normalize surface electromyography in respiratory muscles: Is it similar between amyotrophic lateral sclerosis and healthy people?.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0315846}, pmid = {39705260}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Electromyography/methods ; Male ; Female ; *Respiratory Muscles/physiopathology ; Middle Aged ; Adult ; Cross-Sectional Studies ; Aged ; Case-Control Studies ; Isometric Contraction/physiology ; }, abstract = {The normalization process is important to determine the best approach for normalizing electromyographic signals from respiratory muscles in healthy subjects and those with ALS. The aim of this study is to compare different methods of normalizing the sEMG signal of respiratory muscles in both healthy subjects and those with Amyotrophic Lateral Sclerosis (ALS). This cross-sectional study was conducted in 67 subjects (50 healthy and 17 with ALS). The electrical activity of the sternocleidomastoid (SCM), scalene (ESC), diaphragm (DIA), parasternal (PS), external intercostal (EI), external oblique (EO), and rectus abdominal (RA) muscles were analyzed during maximal inspiratory pressure maneuvers (MIP), maximal nasal inspiratory pressure (SNIP), maximal expiratory pressure (MEP), and maximal voluntary isometric contraction of SCM and ESC (MVICSCM/ESC) and RA (MVICRA) using surface electromyography (sEMG). In the healthy group, inspiratory and expiratory muscles displayed higher electrical activity during MVICSCM/ESC and MIVCRA maneuvers, respectively (p<0.05). In the ALS group, inspiratory muscle activity was higher during the SNIP maneuver, while expiratory muscles showed higher activity during MVICRA (p<0.05). Based on the findings, it can be concluded that the MVIC resulted in greater inspiratory muscle activity, being the ideal method of normalization for inspiratory and expiratory muscles in healthy subjects. In ALS patients, the SNIP maneuver resulted in greater inspiratory muscle activity, while MVIC resulted in greater muscle activity in expiratory muscles.}, } @article {pmid39705326, year = {2025}, author = {}, title = {Correction to Supporting Information for Le et al., Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {2}, pages = {e2424914121}, doi = {10.1073/pnas.2424914121}, pmid = {39705326}, issn = {1091-6490}, } @article {pmid39705453, year = {2024}, author = {Jeong, J and Song, KJ and Lee, JC and Shin, SD and Kim, YJ}, title = {Optimal wearable camera mount locations for medical supervision during simulated out-of-hospital cardiopulmonary resuscitation.}, journal = {Medicine}, volume = {103}, number = {51}, pages = {e40973}, pmid = {39705453}, issn = {1536-5964}, support = {2020R1F1A1076561//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Cardiopulmonary Resuscitation/instrumentation/methods ; Prospective Studies ; *Video Recording ; *Out-of-Hospital Cardiac Arrest/therapy ; *Wearable Electronic Devices ; Male ; Female ; Emergency Medical Technicians/education ; Emergency Medical Services/methods ; Adult ; Simulation Training/methods ; }, abstract = {The quality of the visual information transmitted from a scene is crucial for effective medical supervision in prehospital settings. This study investigated the influence of wearable camera mount locations on visibility during simulated out-of-hospital cardiopulmonary resuscitation. A prospective, observational, non-randomized simulation study was conducted to replicate a cardiac arrest scenario adhering to an advanced life support (ALS) protocol. Seven advanced emergency medical technicians (AEMTs) participated, and 5 camera mount locations were tested: the sternum, forehead, lateral side of the eyelid, mid-nasal, and glabella. Video recordings were captured from the Airway, Intravenous (IV), and Leading providers. Five experienced medical directors independently evaluated visibility scores (1-5) for each procedure with optimal visibility defined as a score of 4 to 5. Glabella mount demonstrated the highest median visibility score and interquartile range (5 [4-5]) and proportion of optimal visibility (77.5%) for most procedures across provider positions. Mixed models revealed significant estimates for the lateral side of the eyelid, mid-nasal, and glabella mounts compared to the sternum, with glabella having the largest effect size (estimate = 1.62). Generalized linear mixed models showed that the glabella mount had the highest odds ratio (OR = 8.07, 95% confidence interval [CI]: 3.01-21.6) to achieve optimal visibility. Wearable camera mount location significantly affected visibility during simulated resuscitation. Mounting cameras closer to eye level provided the most accurate visual data. Further research using objective measures, such as artificial intelligence, and evaluating the visibility of wearable cameras in real-world situations is warranted to optimize simulation-based training for prehospital care.}, } @article {pmid39705668, year = {2024}, author = {Khandia, R and Gurjar, P and Priyanka, and Romashchenko, V and Al-Hussain, SA and Zaki, MEA}, title = {Recent advances in stem cell therapy: efficacy, ethics, safety concerns, and future directions focusing on neurodegenerative disorders - a review.}, journal = {International journal of surgery (London, England)}, volume = {110}, number = {10}, pages = {6367-6381}, pmid = {39705668}, issn = {1743-9159}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; }, abstract = {Neurodegeneration refers to the gradual loss of neurons and extensive changes in glial cells like tau inclusions in astrocytes and oligodendrocytes, α-synuclein inclusions in oligodendrocytes and SOD1 aggregates in astrocytes along with deterioration in the motor, cognition, learning, and behavior. Common neurodegenerative disorders are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxia (SCA), and supranuclear palsy. There is a lack of effective treatment for neurodegenerative diseases, and scientists are putting their efforts into developing therapies against them. Stem cell therapy has emerged as a hope for neurodegenerative disorders since it is not only the damaged neurons that might be replaced, but other neuromodulators and neuroprotectors are secreted. Stem cell terminal differentiation before implantation ensures the implantation of correct cells and molecular markers like carbonic anhydrase II, CNPase (2',3'-cyclic nucleotide 3'-phosphohydrolase), myelin basic protein (MBP), and myelin oligodendrocyte glycoprotein (MOG) elucidate the differentiation. Secretion of various growth factors like epidermal growth factor (EGF), keratinocyte growth factor (KGF), vascular endothelial growth factor-α (VEGF-α), transforming growth factor (TGF), and macrophage inflammatory protein (MIP) supports cell survival, cell proliferation, blood vessel formation, axon regeneration, and neuroglial functional connection formation at the site of degeneration. Adverse effects of stem cell therapy, like teratogenicity and differentiation in different cells other than the desired one under the influence of microenvironment, are a few key concerns. Post-transplantation improved synaptic plasticity, apoptosis inhibition, and reduction in tau-phosphorylation and amyloid beta (Aβ) production has been observed in Alzheimer's patients. A large number of experimental, preclinical, and clinical studies have been conducted, and encouraging results have been obtained. The present review exhaustively discusses various kinds of stem cells, their usage in treating neurodegenerative disorders, limitations and challenges, and ethical issues related to stem cell therapy.}, } @article {pmid39706179, year = {2025}, author = {Setsu, S and Morimoto, S and Nakamura, S and Ozawa, F and Utami, KH and Nishiyama, A and Suzuki, N and Aoki, M and Takeshita, Y and Tomari, Y and Okano, H}, title = {Swift induction of human spinal lower motor neurons and robust ALS cell screening via single-cell imaging.}, journal = {Stem cell reports}, volume = {20}, number = {1}, pages = {102377}, pmid = {39706179}, issn = {2213-6711}, mesh = {Humans ; *Motor Neurons/metabolism/cytology ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Single-Cell Analysis/methods ; Cell Differentiation ; *Spinal Cord/cytology ; Time-Lapse Imaging ; Cells, Cultured ; }, abstract = {This study introduces a novel method for rapidly and efficiently inducing human spinal lower motor neurons (LMNs) from induced pluripotent stem cells (iPSCs) to eventually elucidate the pathomechanisms of amyotrophic lateral sclerosis (ALS) and facilitate drug screening. Previous methods were limited by low induction efficiency, poor LMN purity, or labor-intensive induction and evaluation processes. Our protocol overcomes these challenges, achieving around 80% induction efficiency within just two weeks by combining a small molecule-based approach with transcription factor transduction. Moreover, to exclude non-LMN cells from the analysis, we utilized time-lapse microscopy and machine learning to analyze the morphology and viability of iPSC-derived LMNs on a single-cell basis, establishing an effective pathophysiological evaluation system. This rapid, efficient, and streamlined protocol, along with our single-cell-based evaluation method, enables large-scale analysis and drug screening using iPSC-derived motor neurons.}, } @article {pmid39706377, year = {2025}, author = {Rush, CL and Lyons, C and Gittle, J and Seward, M and Scalia, J and Ho, D and Babu, S and Garret, MA and Brizzi, K and Berry, JD and Fava, M and Lindenberger, E and Vranceanu, AM and , }, title = {Clinician Perspectives Highlight the Need for Early Dyadic Coping Skills for People Living With Amyotrophic Lateral Sclerosis.}, journal = {Journal of pain and symptom management}, volume = {69}, number = {3}, pages = {236-242.e4}, doi = {10.1016/j.jpainsymman.2024.12.010}, pmid = {39706377}, issn = {1873-6513}, support = {K24 AT011760/AT/NCCIH NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Adaptation, Psychological ; Female ; Male ; Focus Groups ; *Caregivers/psychology ; Middle Aged ; *Attitude of Health Personnel ; Adult ; Psychological Distress ; Coping Skills ; }, abstract = {CONTEXT: A diagnosis of ALS can be challenging, and many people find ways to adapt. At the same time, emotional distress can arise early after an ALS diagnosis even when high quality multidisciplinary care is provided. When emotional distress occurs, it can become chronic over time, and can affect both the person living with ALS and their care-partner (together called a dyad).

OBJECTIVES: We set out to understand ALS multidisciplinary clinicians' perception of the challenges experienced by people with ALS and care-partners who experience emotional distress after diagnosis and potential benefits of a coping skills program to help these patients and their care-partners, Resilient Together-ALS (RT-ALS).

METHODS: We conducted semi-structured focus groups and individual interviews with 17 clinicians at the Sean M. Healey & AMG Center for ALS at MGH (N = 2 focus groups and five interviews) to elicit feedback on four domains: 1) Psychosocial Needs of ALS Dyads seen in the clinic; 2) Clinic Flow and Referral System to RT-ALS; 3) Clinic Partnership Approach in Support of RT-ALS; 4) RT-ALS Program Content and Manual Format. We conducted rapid data analyses for a time-efficient hybrid inductive-deductive thematic approach.

RESULTS: Clinicians noted that dyadic distress (distress experienced by both patient and their care-partner individually and as a unit), though not universal, is often present early after diagnosis. The response to the proposed program content (dyadic and individual coping skills) and structure (6 weekly virtual sessions delivered within about 2 months after diagnosis) was positive. Multidisciplinary clinicians emphasized the importance of a skills-based program for dyads experiencing elevated early emotional distress for which referral can be easily integrated within clinic flow so as not to not increase provider and dyad burden.

CONCLUSION: RT-ALS program content and structure is acceptable to clinicians. It is imperative to next seek further input from dyads about whether this type of program would be of interest and if yes, to pilot and refine the program for feasibility testing and then efficacy.}, } @article {pmid39706627, year = {2025}, author = {Andersen, PM and Benatar, M}, title = {Patrikios syndrome and SOD1 ALS.}, journal = {The Lancet. Neurology}, volume = {24}, number = {1}, pages = {27}, doi = {10.1016/S1474-4422(24)00491-5}, pmid = {39706627}, issn = {1474-4465}, } @article {pmid39706636, year = {2025}, author = {Benatar, M and Robertson, J and Andersen, PM}, title = {Amyotrophic lateral sclerosis caused by SOD1 variants: from genetic discovery to disease prevention.}, journal = {The Lancet. Neurology}, volume = {24}, number = {1}, pages = {77-86}, doi = {10.1016/S1474-4422(24)00479-4}, pmid = {39706636}, issn = {1474-4465}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/prevention & control ; Disease Models, Animal ; Genetic Therapy/methods ; *Superoxide Dismutase-1/genetics ; }, abstract = {Pathogenic variants in the superoxide dismutase 1 (SOD1) gene were the first identified genetic cause of amyotrophic lateral sclerosis (ALS), in 1993. This discovery enabled the development of transgenic rodent models for studying the biology of SOD1 ALS. The understanding that SOD1 ALS is driven by a toxic gain-of-function mutation has led to therapeutic strategies that aim to lower concentrations of SOD1 protein, an endeavour that has been complicated by the phenotypic heterogeneity of SOD1 ALS. The successful development of genetically targeted therapies to reduce SOD1 expression, together with a better understanding of pre-symptomatic disease and the discovery of neurofilament light protein as a susceptibility/risk biomarker that predicts phenoconversion, has ushered in a new era of trials that aim to prevent clinically manifest SOD1 ALS. The 30-year journey from gene discovery to gene therapy has not only uncovered the pathophysiology of SOD1 ALS, but has also facilitated the development of biomarkers that should aid therapy development for all forms of ALS.}, } @article {pmid39707523, year = {2024}, author = {Straczkiewicz, M and Burke, KM and Calcagno, N and Premasiri, A and Vieira, FG and Onnela, JP and Berry, JD}, title = {Free-living monitoring of ALS progression in upper limbs using wearable accelerometers.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {223}, pmid = {39707523}, issn = {1743-0003}, support = {U01 HL145386/HL/NHLBI NIH HHS/United States ; R37 MH119194/MH/NIMH NIH HHS/United States ; }, mesh = {*Upper Extremity/physiopathology ; Disease Progression ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Monitoring, Ambulatory/instrumentation/methods ; Accelerometry/instrumentation/methods ; *Wearable Electronic Devices ; *Motor Activity/physiology ; Sensitivity and Specificity ; Humans ; Male ; Female ; Young Adult ; Adult ; Middle Aged ; Aged ; Self Report ; }, abstract = {BACKGROUND: Wearable technology offers objective and remote quantification of disease progression in neurological diseases such as amyotrophic lateral sclerosis (ALS). Large population studies are needed to determine generalization and reproducibility of findings from pilot studies.

METHODS: A large cohort of patients with ALS (N = 202) wore wearable accelerometers on their dominant and non-dominant wrists for a week every two to four weeks and self-entered the ALS Functional Rating Scale-Revised (ALSFRS-RSE) in similar time intervals. Wearable device data were processed to quantify digital biomarkers on four upper limb movements: flexion, extension, supination, and pronation using previously developed and validated open-source methodology. In this study, we determined the association between digital biomarkers and disease progression, studied the impact of study design in terms of required sensor wear-time and sensor position, and determined the impact of self-reported disease onset location on upper limb movements.

RESULTS: The main investigation considered data from a sensor placed on the non-dominant wrist. Participants with higher ALSFRS-RSE scores performed more frequent and faster upper limb movements compared to participants with more advanced disease status. Digital biomarkers exhibited statistically significant change over time while their rate of change was more profound compared to survey responses. Using data from the dominant wrist and changing data inclusion criteria did not alter our findings. ALS disease onset location significantly impacted use of upper limbs. Results presented here were comparable to an earlier study on twenty patients with ALS.

DISCUSSION: Digital health technologies provide sensitive and objective means to quantify ALS disease progression. Interpretable approaches, such as the one used in this paper, can improve patient evaluation and hasten therapeutic development.}, } @article {pmid39708835, year = {2025}, author = {Davalos, L and Kushlaf, H}, title = {Advances in Disease-Modifying Therapeutics for Chronic Neuromuscular Disorders.}, journal = {Seminars in respiratory and critical care medicine}, volume = {46}, number = {3}, pages = {250-258}, doi = {10.1055/a-2463-3385}, pmid = {39708835}, issn = {1098-9048}, mesh = {Humans ; *Neuromuscular Diseases/drug therapy/physiopathology/therapy ; Chronic Disease ; Myasthenia Gravis/drug therapy ; }, abstract = {Neuromuscular disorders can cause respiratory impairment by affecting the muscle fibers, neuromuscular junction, or innervation of respiratory muscles, leading to significant morbidity and mortality. Over the past few years, new disease-modifying therapies have been developed and made available for treating different neuromuscular disorders. Some of these therapies have remarkable effectiveness, resulting in the prevention and reduction of respiratory complications. For myasthenia gravis (MG), efgartigimod, ravulizumab, rozanolixizumab, and zilucoplan have been Food and Drug Administration (FDA)-approved for the treatment of acetylcholine receptor (AChR) antibody-positive generalized MG in the past 2 years. Rozanolixiumab is also approved for treating MG caused by muscle-specific tyrosine kinase (MuSK) antibodies. The new MG therapeutics target the complement system or block the neonatal fragment crystallizable (Fc) receptors (FcRn), leading to significant clinical improvement. For spinal muscular atrophy (SMA), nusinersen (intrathecal route) and risdiplam (oral route) modify the splicing of the SMN2 gene, increasing the production of normal survival motor neuron (SMN) protein. Onasemnogene abeparvovec is a gene replacement therapy that encodes a functional SMN protein. All SMA medications, particularly onasemnogene abeparvovec, have led to clinically meaningful improvement. For late-onset Pompe disease (LOPD), avalglucosidase alfa has shown a greater improvement in respiratory function, ambulation, and functional outcomes in comparison to alglucosidase alfa, and cipaglucosidase alfa combined with miglustat has shown improvement in respiratory and motor function in a cohort of enzyme replacement therapy-experienced LOPD patients. Amyotrophic lateral sclerosis (ALS) remains a challenge. The two most recent FDA-approved medications, namely sodium phenylbutyrate and tofersen, may slow down the disease by a few months in a selected population but do not stop the progression of the disease.}, } @article {pmid39709457, year = {2024}, author = {Keeley, O and Mendoza, E and Menon, D and Coyne, AN}, title = {CHMP2B promotes CHMP7 mediated nuclear pore complex injury in sporadic ALS.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {199}, pmid = {39709457}, issn = {2051-5960}, support = {R00 NS123242/NS/NINDS NIH HHS/United States ; R01 NS132836/NS/NINDS NIH HHS/United States ; R00NS123242//National Institute of Aging/ ; R01NS132836/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Nuclear Pore/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Endosomal Sorting Complexes Required for Transport/metabolism/genetics ; Neurons/metabolism/pathology ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Alterations to the composition and function of neuronal nuclear pore complexes (NPCs) have been documented in multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Moreover, recent work has suggested that injury to the NPC can at least in part contribute to TDP-43 loss of function and mislocalization, a pathological hallmark of ALS and related neurodegenerative diseases. Collectively, these studies highlight a role for disruptions in NPC homeostasis and surveillance as a significant pathophysiologic event in neurodegeneration. The ESCRT-III nuclear surveillance pathway plays a critical role in the surveillance and maintenance of NPCs and the surrounding nuclear environment. Importantly, pathologic alterations to this pathway and its protein constituents have been implicated in neurodegenerative diseases such as ALS. However, the mechanism by which this pathway contributes to disease associated alterations in the NPC remains unknown. Here we use an induced pluripotent stem cell (iPSC) derived neuron (iPSN) model of sALS to demonstrate that CHMP7/ESCRT-III nuclear maintenance/surveillance is overactivated in sALS neurons. This overactivation is dependent upon the ESCRT-III protein CHMP2B and sustained CHMP2B dependent "activation" is sufficient to contribute to pathologic CHMP7 nuclear accumulation and POM121 reduction. Importantly, partial knockdown of CHMP2B was sufficient to alleviate NPC injury and downstream TDP-43 dysfunction in sALS neurons thereby highlighting CHMP2B as a potential therapeutic target in disease.}, } @article {pmid39709476, year = {2024}, author = {Udine, E and Finch, NA and DeJesus-Hernandez, M and Jackson, JL and Baker, MC and Saravanaperumal, SA and Wieben, E and Ebbert, MTW and Shah, J and Petrucelli, L and Rademakers, R and Oskarsson, B and van Blitterswijk, M}, title = {Targeted long-read sequencing to quantify methylation of the C9orf72 repeat expansion.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {99}, pmid = {39709476}, issn = {1750-1326}, support = {P30 AG072946/AG/NIA NIH HHS/United States ; ALS Association//ALS Association/ ; R21 NS099631/NS/NINDS NIH HHS/United States ; Muscular Dystrophy Association//Muscular Dystrophy Association/ ; P01 NS084974/NS/NINDS NIH HHS/United States ; Robert Packard Center for ALS Research, Johns Hopkins University//Robert Packard Center for ALS Research, Johns Hopkins University/ ; RF1 NS123052/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *DNA Repeat Expansion/genetics ; *DNA Methylation/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; Aged ; Frontotemporal Dementia/genetics ; Sequence Analysis, DNA/methods ; }, abstract = {BACKGROUND: The gene C9orf72 harbors a non-coding hexanucleotide repeat expansion known to cause amyotrophic lateral sclerosis and frontotemporal dementia. While previous studies have estimated the length of this repeat expansion in multiple tissues, technological limitations have impeded researchers from exploring additional features, such as methylation levels.

METHODS: We aimed to characterize C9orf72 repeat expansions using a targeted, amplification-free long-read sequencing method. Our primary goal was to determine the presence and subsequent quantification of observed methylation in the C9orf72 repeat expansion. In addition, we measured the repeat length and purity of the expansion. To do this, we sequenced DNA extracted from blood for 27 individuals with an expanded C9orf72 repeat.

RESULTS: For these individuals, we obtained a total of 7,765 on-target reads, including 1,612 fully covering the expanded allele. Our in-depth analysis revealed that the expansion itself is methylated, with great variability in total methylation levels observed, as represented by the proportion of methylated CpGs (13 to 66%). Interestingly, we demonstrated that the expanded allele is more highly methylated than the wild-type allele (P-Value = 2.76E-05) and that increased methylation levels are observed in longer repeat expansions (P-Value = 1.18E-04). Furthermore, methylation levels correlate with age at collection (P-Value = 3.25E-04) as well as age at disease onset (P-Value = 0.020). Additionally, we detected repeat lengths up to 4,088 repeats (~ 25 kb) and found that the expansion contains few interruptions in the blood.

CONCLUSIONS: Taken together, our study demonstrates robust ability to quantify methylation of the expanded C9orf72 repeat, capturing differences between individuals harboring this expansion and revealing clinical associations.}, } @article {pmid39709547, year = {2025}, author = {Bakshi, B and Yerraguntla, S and Armon, C and Barkhaus, P and Bertorini, T and Bowser, R and Breevoort, S and Bromberg, M and Brown, A and Carter, GT and Chang, V and Crayle, J and Fullam, T and Greene, M and Heiman-Patterson, T and Jackson, C and Jhooty, S and Mallon, E and Cadavid, JM and Mcdermott, CJ and Pattee, G and Pierce, K and Ratner, D and Sun, Y and Wang, O and Wicks, P and Wiedau, M and Bedlack, R}, title = {ALSUntangled #77: Psilocybin.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {385-388}, doi = {10.1080/21678421.2024.2441274}, pmid = {39709547}, issn = {2167-9223}, mesh = {*Psilocybin/therapeutic use/pharmacology ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Hallucinogens/therapeutic use/pharmacology ; Animals ; }, abstract = {ALSUntangled reviews alternate and off-label treatments prompted by patient interest. Here, we review psilocybin, a chemical derived from mushrooms and belonging in the category of drugs known as psychedelics. Psilocybin has plausible mechanisms for slowing ALS progression because of its ability to cross the blood brain barrier and effect neurogenesis and inflammation. Currently, there are no pre-clinical ALS models, case reports, or trials for psilocybin and ALS in the context of disease modifying therapy. Depending on dosing, there can be a high risk of psychological side effects including hallucinations and physical harm. Based on the above information, we do not currently support the use of psilocybin as a means to slow ALS progression.}, } @article {pmid39711523, year = {2024}, author = {Thompson, EG and Spead, O and Akerman, SC and Curcio, C and Zaepfel, BL and Kent, ER and Philips, T and Vijayakumar, BG and Zacco, A and Zhou, W and Nagappan, G and Rothstein, JD}, title = {A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV- C9ORF72 (G 4 C 2) 66 mouse model.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39711523}, issn = {2693-5015}, support = {F32 NS120940/NS/NINDS NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {The G4C2 hexanucleotide repeat expansion in C9ORF72is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. The model displays key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis. However, the AAV-(G4C2)66 mouse model in this study has marginal neurodegeneration with negligible neuronal loss, or clinical deficits. Human C9orf72 is typically associated with altered TAR DNA-binding protein (TDP-43) function, yet studies of this rodent model revealed no significant evidence of TDP-43 dysfunction. While our findings indicate and support that this is a highly valuable robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease- associated TDP-43 dysfunction or clinical impairment. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.}, } @article {pmid39712644, year = {2024}, author = {Yusuf, IO and Camille, W and Thompson, PR and Xu, Z}, title = {Protein Citrullination in Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases.}, journal = {Journal of experimental neurology}, volume = {5}, number = {4}, pages = {183-191}, pmid = {39712644}, issn = {2692-2819}, support = {R01 NS118145/NS/NINDS NIH HHS/United States ; R35 GM118112/GM/NIGMS NIH HHS/United States ; }, abstract = {Protein citrullination (PC) is a posttranslational modification (PTM) that converts a peptidyl arginine into a peptidyl citrulline. Aberrant PC is a hallmark of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, prion disease, and multiple sclerosis. Common among these diseases is a dramatic increase of PC in reactive astrocytes. Some citrullinated proteins have been identified. The most prominent are astrocytic cytoskeletal proteins such as GFAP and vimentin, and myelin protein MBP. Recent investigation in ALS has revealed new changes, including a decreased PC in neurons and an association of PC with myelin protein aggregates. These findings suggest that PC contributes to protein aggregation, neuronal dysfunction, neuroinflammation, and axonal degeneration. However, how PC impact neurodegeneration remains to be understood. Further studies are needed to understand a range of questions, from how PC modulates individual protein functions to its impact on diseases. Because of the PC's robust changes in neurodegenerative diseases, there are also prospects that this PTM may be harnessed as biomarkers, and modulation of this PTM may be an avenue for therapy. In this review, we summarize the current understanding of PC in ALS and other neurodegenerative diseases, the investigative methods for PC, and PC's potential as a biomarker and a therapeutic target.}, } @article {pmid39713159, year = {2024}, author = {Wang, YB and Jin, CZ}, title = {Roles of traditional Chinese medicine extracts in hyperuricemia and gout treatment: Mechanisms and clinical applications.}, journal = {World journal of gastroenterology}, volume = {30}, number = {47}, pages = {5076-5080}, pmid = {39713159}, issn = {2219-2840}, mesh = {*Hyperuricemia/drug therapy/blood ; Humans ; *Gout/drug therapy ; *Gastrointestinal Microbiome/drug effects ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Medicine, Chinese Traditional/methods ; *Uric Acid/blood/metabolism ; Gout Suppressants/therapeutic use ; Animals ; }, abstract = {In this manuscript, we comment on the article by Liu et al published in the recent issue of the journal. Hyperuricemia (HUA) has become the second most common metabolic disease after type 2 diabetes mellitus and is the most important risk factor for gout. This discussion focuses on the targets and clinical application value of traditional Chinese medicine (TCM) extracts in the treatment of HUA and gout, emphasizing the role of gut microbiota. Liu et al's study demonstrated that Poecilobdella manillensis protein extract alleviated HUA through multiple mechanisms, including inhibition of uric acid (UA) reabsorption, promotion of UA excretion, repair of intestinal barrier function, and regulation of gut microbiota and metabolome. Unlike the commonly used urate-lowering drugs such as allopurinol and febuxostat, which have clear and single targets, many TCMs have multi-target effects. However, the active components and mechanisms of TCMs are not fully understood, limiting their clinical application in the treatment of HUA and gout. Additionally, the role of gut microbiota in UA metabolic homeostasis needs to be further explored.}, } @article {pmid39714593, year = {2025}, author = {Eldeeb, MA and Hohman, G and Shahid, M}, title = {Novel Approaches in Targeting Cell Surface and Secreted Proteins for Lysosomal Degradation.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {26}, number = {7}, pages = {e202400887}, doi = {10.1002/cbic.202400887}, pmid = {39714593}, issn = {1439-7633}, mesh = {*Lysosomes/metabolism ; Humans ; Proteolysis ; *Membrane Proteins/metabolism ; Animals ; Proteasome Endopeptidase Complex/metabolism ; Autophagy ; *Proteins/metabolism ; }, abstract = {Protein degradation is pivotal for all biochemical aspects of cellular function. In mammalian cells, protein degradation is mediated mainly by the ubiquitin proteasome system (UPS) and the autophagic-lysosomal system (ALS). Over the last two decades, different types of targeted protein degradation approaches have been developed including proteolysis targeting chimeras (PROTACs) and lysosome targeting chimeras (LYTACs), which employ the UPS to degrade intracellular proteins and the ALS to degrade extracellular and membrane proteins respectively. Nevertheless, Current targeted membrane protein degradation approaches face some inherent challenges including limited target protein degradation efficacy and cell type specific applicability. Herein, we highlight some recent developments of novel targeted membrane protein degradation modalities that exhibit wide-applicability and high protein degradation efficiency. These novel membrane protein degraders hold tremendous promise as new pharmacological and biochemical tools in targeting membrane and secretory proteins for lysosomal degradation.}, } @article {pmid39715090, year = {2025}, author = {Huggon, L and Clayton, EL}, title = {Beginning from the end: the presynaptic terminal as a pathomechanism hub in frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3217-3218}, pmid = {39715090}, issn = {1673-5374}, } @article {pmid39715100, year = {2025}, author = {Wu, Y and Tian, X and Ma, J and Lin, Y and Ye, J and Wang, Y and Lu, J and Yin, W}, title = {Label-free discrimination analysis of breast cancer tumor and adjacent tissues of patients after neoadjuvant treatment using Raman spectroscopy: a diagnostic study.}, journal = {International journal of surgery (London, England)}, volume = {111}, number = {2}, pages = {1788-1800}, doi = {10.1097/JS9.0000000000002201}, pmid = {39715100}, issn = {1743-9159}, mesh = {Humans ; *Spectrum Analysis, Raman/methods ; *Breast Neoplasms/therapy/pathology/diagnosis/surgery ; Female ; *Neoadjuvant Therapy ; Middle Aged ; Adult ; Mastectomy, Segmental ; Aged ; }, abstract = {BACKGROUND AND OBJECTIVE: Breast-conserving surgery (BCS) plays a crucial role in breast cancer treatment, with a primary focus on ensuring cancer-free surgical margins, particularly for patients undergoing neoadjuvant treatment. After neoadjuvant treatment, tumor regression can complicate the differentiation between breast cancer tumor and adjacent tissues. Raman spectroscopy, as a rapid and non-invasive optical technique, offers the advantage of providing detailed biochemical information and molecular signatures of internal molecular components in tissue samples. Despite its potential, there is currently no research on using label-free Raman spectroscopy to distinguish between breast cancer tumors and adjacent tissues after neoadjuvant treatment. This study intends to distinguish between tumor and adjacent tissues after neoadjuvant treatment in breast cancer through label-free Raman spectroscopy.

METHODS: In this study, the intraoperative frozen samples of breast cancer tumor and adjacent tissue were collected from patients who underwent neoadjuvant treatment during surgery. The samples were examined using Raman confocal microscopy, and Raman spectra were collected by LabSpec6 software. Spectra were preprocessed by Savitz-Golay filter, adaptive iterative reweighted penalized least squares and MinMax normalization method. The differences in Raman spectra between breast cancer tumor and adjacent tissues after neoadjuvant treatment were analyzed by Wilcoxon rank-sum test, with a Bonferroni correction for multiple comparisons. Based on the support vector machine (SVM) method in machine learning, a predictive model for classification was established in the total group and subgroups of different hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) status and Ki-67 expression level. The independent test set was used to evaluate the performance of the model, and the area under curve (AUC) of the receiver operating characteristic (ROC) curve, sensitivity, specificity and accuracy of different models were obtained.

RESULT: This study comprised 4260 Raman spectra of breast cancer tumor and adjacent frozen tissue samples from 142 breast cancer patients treated with neoadjuvant treatment. The Raman peaks associated with nucleotides and their metabolites in the Raman spectra of breast cancer tumor tissues were higher in intensities than those of adjacent tissues after neoadjuvant therapy (676 cm -1 : Bonferroni adjusted P < 0.0001; 724 cm -1 : P < 0.0001; 754 cm -1 : P < 0.0001), and the Raman peaks from amide III bands were more intense (1271 cm -1 : P < 0.01). Multivariate curve resolution-alternating least squares (MCR-ALS) decomposition of Raman spectra revealed reduced lipid content and increased collagen and nucleic acid content in breast cancer tumor tissues compared to adjacent tissues following neoadjuvant therapy. The predictive model based on the Raman spectral signature of breast cancer tumor and adjacent tissues after neoadjuvant treatment achieved an AUC of 0.98, with accuracy, sensitivity, and specificity values of 0.89, 0.97, and 0.83, respectively. The AUC of subgroup analysis according to different status of molecular pathological biomarkers was stably around 99%.

CONCLUSION: This study demonstrated that label-free Raman spectroscopy can differentiate tumor and adjacent tissues of breast cancer patients treated with neoadjuvant therapy thorough getting the panoramic perspective of the biochemical compounds for the first time. Our study provided a novel technique for determining the margin status in BCS in breast cancer following neoadjuvant treatment rapidly and precisely.}, } @article {pmid39715603, year = {2025}, author = {Dibling, M and Ortholand, J and Salachas, F and Hesters, A and Tezenas du Montcel, S}, title = {Care Pathway Heterogeneity in Amyotrophic Lateral Sclerosis: Effects of Gender, Age, and Onset.}, journal = {Neuroepidemiology}, volume = {59}, number = {6}, pages = {663-676}, doi = {10.1159/000542300}, pmid = {39715603}, issn = {1423-0208}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology ; Male ; Female ; Aged ; Middle Aged ; Retrospective Studies ; Age of Onset ; Registries ; Sex Factors ; Age Factors ; Aged, 80 and over ; France/epidemiology ; *Critical Pathways ; Cohort Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron degeneration resulting in loss of muscle function. Care management is restricted to symptomatic and palliative strategies, while clinical manifestations are heterogeneous. However, assessing the timing and benefits of ALS major clinical interventions remains challenging, with varying and nonspecific time-to-events estimates reported in the literature. Consequently, we proposed a retrospective cohort study leveraging healthcare system data to investigate ALS patients care pathway stratified by gender, age class, and onset site to describe strategies diversity and temporality.

METHODS: We developed an algorithm to identify incident ALS patients in the French hospitalization registry and assessed its quality through comparison with literature. We described 7 states, encompassing patient status regarding clinical intervention history, considered 15 transitions, and stratified the analysis depending on 12 different patient profiles, defined according to gender, the presence of symptoms indicative of disease onset site, and age class, to model profile-specific care pathway trajectories. Alongside analysis of median time before transition, we compared acceleration factors resulting from accelerated failure time and time-inhomogeneous models.

RESULTS: We identified 21,153 incident patients with ALS between 2013 and 2022 with a mean age of 67.7±13.1 years at time of in-registry detection, male/female and spinal/bulbar ratios of 1.2 and 1.9, respectively. Noninvasive ventilation (NIV), gastrostomy, tracheostomy, or death at hospital were recorded for 55.24% of the study population. We identified significant variations in utilization based on gender, age class, and onset site. Notably, older age and bulbar onset site accelerated gastrostomy use and spinal onset site was associated with delayed NIV initiation while tracheostomy, mainly considered for younger patients (<64 years), is rarely indicated in ALS care management. Alongside investigation of time-to-event speed, we report extensively the patient profile-specific estimated median delay before clinical event start.

CONCLUSION: Leveraging real-world data from hospital registries provides a large sample size to investigate low prevalence diseases. In conjunction with multistate models, such data enable a comprehensive analysis of care pathways, which revealed variations in ALS management strategies based on patient profiles. By identifying these disparities, our study contributes to enhancing the foreseeability of support strategies for ALS patients.}, } @article {pmid39717315, year = {2024}, author = {Alhayali, M}, title = {Concomitant Amyotrophic Lateral Sclerosis and Rheumatoid Arthritis: A Case Report.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e74301}, pmid = {39717315}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motor neuron disease that leads to a gradual loss of motor neurons manifesting as progressive weakness, dysarthria, and respiratory decline, with a relatively short life expectancy. Rheumatoid arthritis (RA) is an autoimmune disorder characterized by polyarthritis and affects multiple systems. Motor neuron involvement is rare in rheumatoid arthritis. Here, we report a unique case of a patient with an established diagnosis of ALS who later developed seropositive RA. A 58-year-old male from Baghdad presented to our center with polyarticular joint pain, stiffness, and swelling for about four months, the patient had a history of progressive neurological deficits. The final diagnosis was seropositive rheumatoid arthritis with concomitant amyotrophic lateral sclerosis. While the patient's joint symptoms responded well to methotrexate and prednisolone, he continued to experience a neurological decline. This is one of the few reported cases of concurrent ALS and RA, highlighting the complexity of managing overlapping neurodegenerative and autoimmune conditions.}, } @article {pmid39717968, year = {2024}, author = {Vergini, DE and Hadjipavlou-Litina, D}, title = {"A patent review on arachidonic acid lipoxygenase (LOX) inhibitors for the treatment of neurodegenerative diseases (2018-present)".}, journal = {Expert opinion on therapeutic patents}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/13543776.2024.2447067}, pmid = {39717968}, issn = {1744-7674}, abstract = {INTRODUCTION: Neuroinflammation is correlated to neurodegenerative diseases like Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Huntington Disease (HD), and Parkinson's disease (PD). A lot of recent research and patents are focused on the design and synthesis of arachidonic acid lipoxygenase (ALOX) inhibitors for the treatment of neurodegenerative diseases.

AREAS COVERED: The survey covers natural products, synthesis, hybrids, and assessments of biological effects in biological studies as ALOX inhibitors. A survey of patent publications from 2018 to present, taken from Google Scholar, Espanet, Web of Science, Drugbank, Scopus, or PubMed is analyzed.

EXPERT OPINION: The authors suggest that (i) numerous areas of biology-pharmacology need to be considered: selectivity, in vivo studies, toxicity, bioavailability, and drug-likeness, the mechanism of action in different animals and humans, evaluation of more efficient and selective biological tests; (ii) synthetic method outbalance in the discovery and production of ALOX inhibitors with greater selectivity. Several ALOX inhibitors show promising results for the treatment of neurological disorders. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action and their bioavailability are well defined can be used as lead compounds for the treatment of neurodegenerative diseases.}, } @article {pmid39718201, year = {2025}, author = {}, title = {Correction to "Access for ALL in ALS: A Large-Scale, Inclusive, Collaborative Consortium to Unlock the Molecular and Genetic Mechanisms of Amyotrophic Lateral Sclerosis" J. D. Berry , S. Paganoni , M. B. Harms , et al., "Access for ALL in ALS: A Large-Scale, Inclusive, Collaborative Consortium to Unlock the Molecular and Genetic Mechanisms of Amyotrophic Lateral Sclerosis," Muscle & Nerve 70, no. 6 (2024): 1140-1150, https://doi.org/10.1002/mus.28244.}, journal = {Muscle & nerve}, volume = {71}, number = {2}, pages = {280}, doi = {10.1002/mus.28317}, pmid = {39718201}, issn = {1097-4598}, } @article {pmid39718871, year = {2025}, author = {Jiang, W and Hua, L and Chakraborty, S}, title = {Degenerate phase-matching for multi-wavelength nonlinear mixing in aperiodic lattice lasers.}, journal = {Optics letters}, volume = {50}, number = {1}, pages = {133-136}, doi = {10.1364/OL.544664}, pmid = {39718871}, issn = {1539-4794}, abstract = {Holographically designed aperiodic lattices (ALs) have proven to be an exciting engineering technique for achieving electrically switchable single- or multi-frequency emissions in terahertz (THz) semiconductor lasers. Here, we employ the nonlinear transfer matrix modeling method to investigate multi-wavelength nonlinear (sum- or difference-) frequency generation within an integrated THz (idler) laser cavity that also supports optical (pump and signal) waves. The laser cavity includes an aperiodic lattice, which engineers the idler photon lifetimes and effective refractive indices. The key findings are the following: (i) the nonlinear conversion efficiency reveals resonant enhancement at those idler frequencies where the photon lifetime is high; (ii) the resonant phase-matching (PM) process between the pump and idler waves has a one-to-one link with the engineered effective index dispersion; and (iii) in the absence of any other dispersion, the lowest threshold, multi-wavelength defect modes of the aperiodic lattice laser have degenerate phase-matched pump frequencies. This set of results will potentially have a significant impact on the wavelength multiplexing in electronically switchable THz-over-fiber communication systems [U.S. patent application 20,150,248,047A1 (3 September 2015)].}, } @article {pmid39718981, year = {2025}, author = {Chen, JQA and McNamara, NB and Engelenburg, HJ and Jongejan, A and Wever, DD and Hopman, K and van Rixel, E and Nijhuis, PJH and de Winter, F and Moerland, PD and Smolders, J and Verhaagen, J and Hamann, J and Huitinga, I}, title = {Distinct transcriptional changes distinguish efficient and poor remyelination in multiple sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {6}, pages = {2201-2217}, pmid = {39718981}, issn = {1460-2156}, support = {project 0-TI-01//Start2Cure Foundation/ ; }, mesh = {Humans ; *Remyelination/genetics/physiology ; *Multiple Sclerosis/genetics/pathology/metabolism ; Male ; Female ; Middle Aged ; Adult ; Microglia/pathology/metabolism ; Macrophages/metabolism/pathology ; Aged ; Cohort Studies ; Brain/pathology/metabolism ; }, abstract = {Multiple sclerosis (MS) is a highly heterogeneous disease, with varying remyelination potential across individuals and between lesions. However, the molecular mechanisms underlying the potential to remyelinate remain poorly understood. In this study, we aimed to take advantage of the intrinsic heterogeneity in remyelinating capacity between MS donors and lesions to uncover known and novel pro-remyelinating molecules for MS therapies. To elucidate distinct molecular signatures underlying the potential to remyelinate, we stratified MS donors from the Netherlands Brain Bank cohort (n = 239), based on proportions of remyelinated lesions (RLs), into efficiently remyelinating donors (ERDs; n = 21) and poorly remyelinating donors (PRDs; n = 19). We performed bulk RNA sequencing of RLs, active lesions with ramified and amoeboid microglia/macrophage morphology (ALs non-foamy), active lesions with foamy microglia/macrophage morphology (ALs foamy) and normal-appearing white matter (NAWM) from ERDs and PRDs. We found that ALs non-foamy were positively correlated with remyelination, whereas ALs foamy were not, indicating a role for microglia/macrophage state in influencing remyelination potential. Bioinformatics analyses were performed to identify key pathways and molecules implicated in the remyelination process. We found distinct differences between the donors with differing remyelination potential in comparable MS lesion types. The RLs and ALs non-foamy of ERDs versus PRDs showed upregulation of the epithelial-mesenchymal transition pathway, whereas in ALs foamy of PRDs, inflammation and damage-associated pathways (i.e. MTORC1 signalling, TNF signalling and oxidative phosphorylation) were upregulated in comparison to ALs foamy of ERDs, suggesting that these latter pathways might counteract remyelination. We found genes significantly upregulated in RLs and/or ALs non-foamy of ERDs that have previously been associated with remyelination, including CXCL12, EGF, HGF, IGF2, IL10, PDGFB, PPARG and TREM2, illustrating the strength of our donor and lesion stratification. TGFB1, TGFB2, EGF and IGF1 were determined to be key upstream regulators of genes upregulated in RLs and ALs non-foamy of ERDs. We also identified potential novel pro-remyelinating molecules, such as BTC, GDF10, GDF15, CCN1, CCN4, FGF5, FGF10 and INHBB. Our study identified both known and novel genes associated with efficient remyelination that might facilitate the development of therapeutic strategies to promote tissue repair and clinical recovery in MS.}, } @article {pmid39719207, year = {2025}, author = {Jirström, E and Matveeva, A and Baindoor, S and Donovan, P and Ma, Q and Morrissey, EP and Arijs, I and Boeckx, B and Lambrechts, D and Garcia-Munoz, A and Dillon, ET and Wynne, K and Ying, Z and Matallanas, D and Hogg, MC and Prehn, JHM}, title = {Effects of ALS-associated 5'tiRNA[Gly-GCC] on the transcriptomic and proteomic profile of primary neurons in vitro.}, journal = {Experimental neurology}, volume = {385}, number = {}, pages = {115128}, doi = {10.1016/j.expneurol.2024.115128}, pmid = {39719207}, issn = {1090-2430}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Neurons/metabolism ; Cells, Cultured ; *Transcriptome/genetics ; Proteomics ; Mice, Transgenic ; Mice, Inbred C57BL ; Ribonuclease, Pancreatic/genetics ; Humans ; Disease Models, Animal ; *Proteome/metabolism ; }, abstract = {tRNA-derived stress-induced RNAs (tiRNAs) are a new class of small non-coding RNA that have emerged as important regulators of cellular stress responses. tiRNAs are derived from specific tRNA cleavage by the stress-induced ribonuclease angiogenin (ANG). Loss-of-function mutations in the ANG gene are linked to amyotrophic lateral sclerosis (ALS), and elevated levels of specific tiRNAs were recently identified in ALS patient serum samples. However, the biological role of tiRNA production in neuronal stress responses and neurodegeneration remains largely unknown. Here, we investigated the genome-wide regulation of neuronal stress responses by a specific tiRNA, 5'tiRNA[Gly-GCC], which we found to be upregulated in primary neurons exposed to ALS-relevant stresses and in the spinal cord of three ALS mouse models. Whole-transcript RNA sequencing and label-free mass spectrometry on primary neurons transfected with a synthetic mimic of 5'tiRNA[Gly-GCC] revealed predominantly downregulated RNA and protein levels, with more pronounced changes in the proteome. Over half of the downregulated mRNAs contained predicted 5'tiRNA[Gly-GCC] binding sites, indicating that this tiRNA may silence target genes via complementary binding. On the proteome level, we observed reduction in proteins involved in translation initiation and ribosome assembly, pointing to inhibitory effects on translation. Together, these findings suggest that 5'tiRNA[Gly-GCC] is an ALS-associated tiRNA that functions to fine-tune gene expression and supress protein synthesis as part of an ANG-induced neuronal stress response.}, } @article {pmid39719601, year = {2024}, author = {Kelani, KM and Hegazy, MA and Hassan, AM and Nadim, AH}, title = {Ecological multivariate assisted spectrophotometric methods for determination of antipyrine and benzocaine HCl in presence of antipyrine official impurity and benzocaine HCl degradant: toward greenness and whiteness.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {250}, pmid = {39719601}, issn = {2661-801X}, abstract = {A simple and green chemometrics-assisted spectrophotometric technique has beendeveloped and validated for the determination of antipyrine (ANT) and benzocaine HCl (BEN) along with the official impurity of ANT, antipyrine impurity A (ANT imp-A), and the degradation product of BEN, p-amino benzoic acid (PABA), in their quaternary mixture. Three models were developed and compared: partial least squares (PLS), artificial neural networks (ANN), and multivariate curve resolution-alternating least squares (MCR-ALS) where the four studied drugs were successfully quantified. The quantitative determination of the studied drugs was assessed using percentage recoveries, standard errors of prediction, and root mean square errors of prediction. The ANN model demonstrated the lowest error and the best correlation making it the most accurate method for analysis. The models were constructed in the ranges of 5.0-9.0 µg mL[-1] for ANT, 1.0-5.0 µg mL[-1] for BEN, 0.5-2.5 µg mL[-1] for ANT imp-A, and 0.25-1.25 µg mL[-1] for PABA. The established models successfully determined ANT, BEN, ANT imp-A, and PABA with detection limits of 0.312, 0.178, 0.093, and 0.042 µg mL[-1] for PLS, 0.185, 0.085, 0.001, and 0.034 µg mL[-1] for ANN; and 0.473, 0.240, 0.073, and 0.069 µg mL[-1] for MCR-ALS, respectively. The greenness and the whiteness of the proposed method were assessed using two green evaluating approaches: analytical Eco-scale, and AGREE, along with one white analytical chemistry evaluating tool, RGB. The three proposed models were successfully applied for determination of ANT and BEN in their pharmaceutically co-formulated dosage forms. They are also recommended for stability assays and purity testing of these drugs in quality control laboratories.}, } @article {pmid39719859, year = {2025}, author = {Koumasopoulos, E and Stanitsa, E and Angelopoulou, E and Koros, C and Barbarousi, V and Velonakis, G and Michaletou, C and Alevetsovitis, SK and Constantinides, VC and Kyrozis, A and Stefanis, L and Kroupis, C and Papageorgiou, SG}, title = {Heterozygous p62/SQSTM1 mutation and right temporal variant of frontotemporal dementia: Α case report.}, journal = {Neurocase}, volume = {31}, number = {2}, pages = {70-73}, doi = {10.1080/13554794.2024.2446315}, pmid = {39719859}, issn = {1465-3656}, mesh = {Female ; Humans ; *Frontotemporal Dementia/genetics/pathology ; Heterozygote ; Mutation ; *Sequestosome-1 Protein/genetics ; Aged ; }, abstract = {Mutations in sequestosome 1 (SQSTM1) gene have been associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia - ALS (FTD-ALS), and very recently, progressive supranuclear palsy (PSP), paget disease of bone (PDB), distal myopathy with rimmed vacuoles (DMRV), and neurodegenerative disorders in childhood. We present a case of right temporal variant of FTD (rtvFTD) with heterozygous mutation (c.823_824del(p.Ser275Phefs *17)) in SQSTM1 gene.}, } @article {pmid39720419, year = {2024}, author = {Haikal, C and Weissert, R}, title = {Editorial: Aging, peripheral inflammation, and neurodegeneration.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1529026}, pmid = {39720419}, issn = {1663-4365}, } @article {pmid39720511, year = {2024}, author = {Terao, SI and Nosaki, Y and Murao, A and Torii, R and Ogawa, N and Miura, N and Sasaki, Y and Sobue, G}, title = {Onset of age, site and respiratory symptoms are strongly associated with respiratory decline in sporadic amyotrophic lateral sclerosis: a long-term longitudinal study.}, journal = {BMJ neurology open}, volume = {6}, number = {2}, pages = {e000829}, pmid = {39720511}, issn = {2632-6140}, abstract = {OBJECTIVE: The objective of this study is to identify factors influencing progression of respiratory decline from the onset of neurological symptoms to respiratory failure in patients with amyotrophic lateral sclerosis (ALS).

METHODS: In 100 patients with sporadic ALS, %vital capacity (%VC) was continuously measured from the first visit to the respiratory endpoint (REP). Cox proportional hazards model identified factors influencing the duration from onset of ALS to REP (Onset-REP). We performed Kaplan-Meier survival curve analysis for onset-REP according to identified factors.

RESULTS: Onset sites were the upper limb (U-ALS), lower limb (L-ALS), bulbar paralysis (B-ALS) and respiratory paralysis (R-ALS) in 37, 19, 32 and 12 patients, respectively. Duration from the onset of ALS to the onset of respiratory symptoms (Onset-Rp) and REP (Onset-REP) was 16.1 (SD 12.1) and 24.9 months (SD 14.6), respectively. Multivariate analysis revealed that age at onset, site of onset, Onset-Rp and %VC decline rate significantly influenced Onset-REP duration. Elderly patients had a significantly shorter Onset-REP duration. Onset-REP duration did not significantly differ between patients with U-ALS and L-ALS, but was longer in these patients than in those with B-ALS and R-ALS. Onset-REP duration was positively associated with Onset-Rp duration. The average monthly %VC decline rate was -5.6% (SD 3.3). Age at onset, onset site and Onset-Rp duration significantly influenced the %VC decline rate.

CONCLUSIONS: Our findings revealed strong and independent patient-specific factors that influence the Onset-REP duration and the %VC decline rate in patients with ALS. These could inform future clinical trials and interventions considering the respiratory function and natural history of patients with ALS.}, } @article {pmid39721808, year = {2024}, author = {Almukhlifi, Y and Crowfoot, G and Hutton, A}, title = {Barriers and Facilitators Toward Disaster Knowledge, Skills, and Preparedness among Emergency Medical Services in Saudi Arabia.}, journal = {Prehospital and disaster medicine}, volume = {39}, number = {6}, pages = {395-401}, doi = {10.1017/S1049023X24000670}, pmid = {39721808}, issn = {1945-1938}, mesh = {Humans ; Saudi Arabia ; Male ; Female ; Adult ; *Emergency Medical Services ; Interviews as Topic ; Qualitative Research ; *Disaster Planning ; *Health Knowledge, Attitudes, Practice ; Middle Aged ; }, abstract = {INTRODUCTION: Disasters pose significant challenges globally, affecting millions of people annually. In Saudi Arabia, floods constitute a prevalent natural disaster, underscoring the necessity for effective disaster preparedness among Emergency Medical Services (EMS) workers. Despite their critical role in disaster response, research on disaster preparedness among EMS workers in Saudi Arabia is limited.

STUDY OBJECTIVE/METHODS: The study aimed to explore the disaster preparedness among EMS workers in Saudi Arabia. This study applied an explanatory sequential mixed-methods design to explore disaster preparedness among EMS workers in Saudi Arabia, focusing on the qualitative phase. Semi-structured interviews were conducted with 15 EMS workers from National Guard Health Affairs (NGHA) and Ministry of Health (MOH) facilities in Riyadh, Dammam, and Jeddah. Thematic analysis was conducted following Braun and Clarke's six-step process, ensuring data rigor through Schwandt, et al's criteria for trustworthiness.

FINDINGS: The demographic characteristics of participants revealed a predominantly young, male workforce with varying levels of experience and educational backgrounds. Thematic analysis identified three key themes: (1) Newly/developed profession, highlighting the challenges faced by young EMS workers in acquiring disaster preparedness; (2) Access to opportunities and workplace resources (government versus military), indicating discrepancies in disaster preparedness support between government and military hospitals; and (3) Workplace policies and procedures, highlighting the need for clearer disaster policies, training opportunities, and role clarity among EMS workers.

CONCLUSION: The study underscores the importance of addressing the unique challenges faced by EMS workers in Saudi Arabia to enhance disaster preparedness. Recommendations include targeted support for young EMS professionals, standardization of disaster training across health care facilities, and improved communication of disaster policies and procedures. These findings have implications for policy and practice in disaster management and EMS training in Saudi Arabia.}, } @article {pmid39722074, year = {2024}, author = {Thompson, EG and Spead, O and Akerman, SC and Curcio, C and Zaepfel, BL and Kent, ER and Philips, T and Vijayakumar, BG and Zacco, A and Zhou, W and Nagappan, G and Rothstein, JD}, title = {A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G4C2)66 mouse model.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {203}, pmid = {39722074}, issn = {2051-5960}, support = {R35 NS132179/NS/NINDS NIH HHS/United States ; R01 5R35NS132179/NS/NINDS NIH HHS/United States ; F32 NS120940/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *C9orf72 Protein/genetics ; *Disease Models, Animal ; *DNA-Binding Proteins/genetics/metabolism ; *DNA Repeat Expansion/genetics ; Mice ; *Mice, Transgenic ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Dependovirus/genetics ; Humans ; Male ; Behavior, Animal/physiology ; Mice, Inbred C57BL ; }, abstract = {The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. The model displays key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis. However, the AAV-(G4C2)66 mouse model in this study has marginal neurodegeneration with negligible neuronal loss, or clinical deficits. Human C9orf72 is typically associated with altered TAR DNA-binding protein (TDP-43) function, yet studies of this rodent model revealed no significant evidence of TDP-43 dysfunction. While our findings indicate and support that this is a highly valuable robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease- associated TDP-43 dysfunction or clinical impairment. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.}, } @article {pmid39722149, year = {2025}, author = {Simão, S and Naumann, LL and de Carvalho, M and Santos, MO and Martins, IP}, title = {Adaptation and Validation of Version B of the Edinburgh Cognitive and Behavioural ALS Screen for the Portuguese Population.}, journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists}, volume = {40}, number = {3}, pages = {553-564}, doi = {10.1093/arclin/acae118}, pmid = {39722149}, issn = {1873-5843}, support = {GA101017598//European Union's Horizon 2020/ ; }, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/psychology ; Middle Aged ; Psychometrics ; Reproducibility of Results ; Portugal ; Aged ; *Neuropsychological Tests/standards ; Adult ; *Cognitive Dysfunction/diagnosis/etiology ; *Cognition Disorders/diagnosis/etiology ; }, abstract = {OBJECTIVE: This study aims to adapt and provide psychometric support for the validation of version B of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) for the Portuguese population, addressing the need for consistent cognitive evaluations in amyotrophic lateral sclerosis (ALS). A second culturally adapted ECAS screen facilitates the accurate characterization of ALS progression, mitigates learning effects, and supports tailored care management.

METHODS: The adaptation process included forward-backward translation, cultural adaptation, and cognitive debriefing on a prospective sample of 193 ALS patients and 106 controls. A multiple regression analysis identified predictors relevant for establishing ECAS cut-off scores. Psychometric evaluations, including reliability assessments and tests of convergent, construct, and criterion validity, were conducted. Additionally, version A's psychometric properties were reevaluated with complementary analyses and a larger sample.

RESULTS: Version B demonstrated good internal consistency with Cronbach's alpha of 0.802, comparable to the previously established version A. Moderate inter-item correlations further supported reliability, reflecting internal coherence. Equivalence testing between the Portuguese versions supported convergent validity, confirming version B's alignment with version A's theoretical framework. Exploratory factor analysis provided preliminary support for construct validity, and receiver operating characteristic analyses established cut-off values for both versions, revealing moderate sensitivity with a tendency toward false negatives, and higher specificity.

CONCLUSIONS: This study provided evidence for the cultural suitability, reliability, and validity of the Portuguese ECAS B. As evidence supports the equivalence of the Portuguese ECAS versions, they can be used for flexible screenings and applied with the calculated cut-off values to enhance diagnostic accuracy.}, } @article {pmid39722495, year = {2025}, author = {García-Ramírez, Y and Cayuela-Fuentes, JM and Mira-Escolano, MP and Maceda-Roldán, LA and Mikulasova, E and Oliva-López, C and Sánchez-Escámez, A and Ciller-Montoya, P and Palomar-Rodríguez, JA}, title = {Characterization, epidemiology, and factors associated with evolution and survival in patients with amyotrophic lateral sclerosis in southeastern Spain, 2008-2021: a population-based study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {268-280}, doi = {10.1080/21678421.2024.2439454}, pmid = {39722495}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/mortality/diagnosis ; Spain/epidemiology ; Male ; Female ; Aged ; Middle Aged ; Aged, 80 and over ; Prevalence ; Incidence ; Adult ; Disease Progression ; }, abstract = {OBJECTIVE: To describe the epidemiology, characteristics, and factors associated with the evolution and survival in patients with amyotrophic lateral sclerosis (ALS) in a region of southeastern Spain.

METHODS: An observational study was carried out in people with a diagnosis of ALS in the period 2008-2021 who were registered in the Information System of Rare Diseases of the Region of Murcia (SIER). We calculated crude and standardized incidence rate (SIR) using European Standard Population of 2013 and point prevalence. The Kaplan-Meier method and the log-rank test were used to estimate and compare survival curves.

RESULTS: We identified 374 cases. The mean age at diagnosis was 66.5 ± 11.7 and 50.3% persons were spinal onset. Mean time from the onset of symptoms to diagnosis was 0.9 ± 1.0 years. The global SIR was 1.95/100,000 person-years (95%CI: 1.77-2.12), which was higher in men (ratio 1.34), and the point prevalence in 2021 was 4.57 per 100,000 (95% CI: 4.46-4.68). There were 297 deaths with a mean age of 69.8 ± 10.8. The median survival from clinical onset was 2 years (95%CI: 1.0-3.0). Factors associated with lower survival were bulbar onset (p < 0.001), older age at the onset of symptoms (p < 0.001), and the absence of riluzole treatment (p = 0.003).

CONCLUSIONS: This study is one of few to evaluate the epidemiological, characteristics, and prognostic factors of ALS in Spain, with findings similar to previous population studies. The use of population-based registries offers reliable information on the magnitude, or evolution in these patients.}, } @article {pmid39722698, year = {2024}, author = {Jiao, L and Yang, J and Wang, W and Liu, X and Fu, Y and Fan, D}, title = {sTREM2 cerebrospinal fluid levels are a potential biomarker in amyotrophic lateral sclerosis and associate with UMN burden.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1515252}, pmid = {39722698}, issn = {1664-2295}, abstract = {OBJECTIVES: The aims of this study were to investigate whether CSF sTREM2 may be a potential marker of disease monitoring for amyotrophic lateral sclerosis (ALS).

METHODS: We investigated whether CSF sTREM2 levels are altered in ALS patients and are correlated with upper motor neuron (UMN) burden and disease progression.

RESULTS: CSF sTREM2 was greater in the ALS patients than in the controls (p = 0.002). Elevated CSF sTREM2 was associated with the UMN score (r = 0.38, p = 0.009), ΔFS (r = 0.30, p = 0.04) and serum NFL (lg) (r = 0.35, p = 0.015). As the motor band sign (MBS) score increased, the CSF sTREM2 level increased (p-trend = 0.014). Furthermore, the correlations became stronger (UMN score (r = 0.50, p = 0.01) ΔFRS (r = 0.52, p = 0.008) and serum NFL (lg) (r = 0.55, p = 0.004) when estimated only among patients with a disease duration >12 months.

CONCLUSION: We found that CSF sTREM2 is elevated in ALS patients and may be a novel marker, probably reflecting upper motor unit severity and prognosis.}, } @article {pmid39724103, year = {2024}, author = {Garcia-Toscano, L and Currey, HN and Hincks, JC and Stair, JG and Lehrbach, NJ and Liachko, NF}, title = {Decreased Hsp90 activity protects against TDP-43 neurotoxicity in a C. elegans model of amyotrophic lateral sclerosis.}, journal = {PLoS genetics}, volume = {20}, number = {12}, pages = {e1011518}, pmid = {39724103}, issn = {1553-7404}, support = {P40 OD010440/OD/NIH HHS/United States ; R01 AG066729/AG/NIA NIH HHS/United States ; I01 BX005762/BX/BLRD VA/United States ; I01 BX004044/BX/BLRD VA/United States ; R35 GM142728/GM/NIGMS NIH HHS/United States ; P30 DK017047/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *HSP90 Heat-Shock Proteins/metabolism/genetics ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Humans ; Phosphorylation ; Mutation ; Heat-Shock Response/genetics ; TDP-43 Proteinopathies/genetics/metabolism ; }, abstract = {Neuronal inclusions of hyperphosphorylated TDP-43 are hallmarks of disease for most patients with amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene coding for TDP-43, can cause some cases of familial inherited ALS (fALS), indicating dysfunction of TDP-43 drives disease. Aggregated, phosphorylated TDP-43 may contribute to disease phenotypes; alternatively, TDP-43 aggregation may be a protective cellular response sequestering toxic protein away from the rest of the cell. The heat shock responsive chaperone Hsp90 has been shown to interact with TDP-43 and stabilize its normal conformation; however, it is not known whether this interaction contributes to neurotoxicity in vivo. Using a C. elegans model of fALS mutant TDP-43 proteinopathy, we find that loss of function of HSP-90 protects against TDP-43 neurotoxicity and subsequent neurodegeneration in adult animals. This protection is accompanied by a decrease in both total and phosphorylated TDP-43 protein. We also find that hsp-90 mutation or inhibition upregulates key stress responsive heat shock pathway gene expression, including hsp-70 and hsp-16.1, and we demonstrate that normal levels of hsp-16.1 are required for hsp-90 mutation effects on TDP-43. We also observe that the neuroprotective effect due to HSP-90 dysfunction does not involve direct regulation of proteasome activity in C. elegans. Our data demonstrate for the first time that Hsp90 chaperone activity contributes to adverse outcomes in TDP-43 proteinopathies in vivo using a whole animal model of ALS.}, } @article {pmid39725771, year = {2024}, author = {Pagliari, E and Taiana, M and Manzini, P and Sali, L and Quetti, L and Bertolasi, L and Oldoni, S and Melzi, V and Comi, G and Corti, S and Nizzardo, M and Rizzo, F}, title = {Targeting STMN2 for neuroprotection and neuromuscular recovery in Spinal Muscular Atrophy: evidence from in vitro and in vivo SMA models.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {82}, number = {1}, pages = {29}, pmid = {39725771}, issn = {1420-9071}, support = {Craiplo Grant 2020-3623//Fondazione Cariplo/ ; 22739//SMA Europe Grant/ ; }, mesh = {Animals ; *Stathmin/metabolism/genetics ; *Muscular Atrophy, Spinal/therapy/genetics/pathology/metabolism ; Humans ; Mice ; *Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/cytology ; Neuromuscular Junction/metabolism/pathology ; Neuroprotection ; Dependovirus/genetics ; Genetic Therapy/methods ; }, abstract = {The development of ground-breaking Survival Motor Neuron (SMN) replacement strategies has revolutionized the field of Spinal Muscular Atrophy (SMA) research. However, the limitations of these therapies have now become evident, highlighting the need for the development of complementary targets beyond SMN replacement. To address these challenges, here we explored, in in vitro and in vivo disease models, Stathmin-2 (STMN2), a neuronal microtubule regulator implicated in neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), as a novel SMN-independent target for SMA therapy. Our findings revealed that STMN2 overexpression effectively restored axonal growth and outgrowth defects in induced pluripotent stem cell-(iPSC)-derived motor neurons (MNs) from SMA patients. Intracerebroventricular administration of adeno-associated virus serotype 9 (AAV9) carrying Stmn2 cDNA significantly ameliorated survival rates, motor functions, muscular and neuromuscular junction pathological features in SMA mice, mirrored by in vitro outcomes. Overall, this pioneering study not only provides insight into the therapeutic potential of STMN2 in SMA, but also suggests its broader applications for MN diseases, marking a substantial step forward in addressing the multifaceted challenges of neurological diseases treatment.}, } @article {pmid39726289, year = {2025}, author = {Kollstrøm, AM and Christiansen, N and Sandvig, A and Sandvig, I}, title = {Dysregulation of synaptic transcripts underlies network abnormalities in ALS patient-derived motor neurons.}, journal = {American journal of physiology. Cell physiology}, volume = {328}, number = {3}, pages = {C1029-C1044}, doi = {10.1152/ajpcell.00725.2024}, pmid = {39726289}, issn = {1522-1563}, support = {//Alf Harborgs fund/ ; //Olav Thon Stiftelsen (Olav Thon Foundation)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/physiopathology ; *Motor Neurons/metabolism/pathology ; Humans ; *Synapses/metabolism/genetics/pathology ; C9orf72 Protein/genetics/metabolism ; *Nerve Net/metabolism/pathology/physiopathology ; Mutation ; Action Potentials ; Neuronal Outgrowth ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by dysfunction and loss of upper and lower motor neurons. Several studies have identified structural and functional alterations in the motor neurons before the manifestation of symptoms, yet the underlying cause of such alterations and how they contribute to the progressive degeneration of affected motor neuron networks remain unclear. Importantly, the short- and long-term spatiotemporal dynamics of neuronal network activity make it challenging to discern how ALS-related network reconfigurations emerge and evolve. To address this, we systematically monitored the structural and functional dynamics of motor neuron networks with a confirmed endogenous C9orf72 mutation. We show that ALS patient-derived motor neurons display time-dependent neural network dysfunction, specifically reduced firing rate and spike amplitude, impaired bursting, but higher overall synchrony in network activity. These changes coincided with altered neurite outgrowth and branching within the networks. Moreover, transcriptional analyses revealed dysregulation of molecular pathways involved in synaptic development and maintenance, neurite outgrowth, and cell adhesion, suggesting impaired synaptic stabilization. This study identifies early synaptic dysfunction as a contributing mechanism resulting in network-wide structural and functional compensation, which may over time render the networks vulnerable to neurodegeneration.NEW & NOTEWORTHY RNA-sequencing of ALS patient-derived motor neurons revealed altered expression of genes involved in cell adhesion, neurite outgrowth, synaptic development and maintenance, and synaptic plasticity. These alterations were accompanied by time-dependent structural impairments and disrupted neuronal activity, suggesting that early synaptic changes and network-wide structural and functional compensations contribute to motor neuron vulnerability in ALS.}, } @article {pmid39727843, year = {2024}, author = {An, J and Gopalakrishnan, L and Ortega, V and Saul, J and Kadali, R and Bowser, R}, title = {Development of a Sensitive and Reliable Meso Scale Discovery-Based Electrochemiluminescence Immunoassay to Quantify TDP-43 in Human Biofluids.}, journal = {Biosensors}, volume = {14}, number = {12}, pages = {}, pmid = {39727843}, issn = {2079-6374}, support = {Development of TDP-43 Immunoassays//Target ALS/ ; }, mesh = {Humans ; Immunoassay ; *DNA-Binding Proteins/metabolism ; Amyotrophic Lateral Sclerosis/diagnosis ; Luminescent Measurements ; Biomarkers/blood ; Reproducibility of Results ; Electrochemical Techniques ; Biosensing Techniques ; Limit of Detection ; }, abstract = {Transactive response DNA-binding protein of 43 kDa (TDP-43) is a major component of pathological inclusions in various neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The detection of TDP-43 in biofluids is crucial for the development of diagnostic and prognostic indicators of disease and therapeutic development for TDP-43-related proteinopathies. Despite its potential as a biomarker for numerous neurological disorders, the lack of a sensitive and reproducible TDP-43 assay hinders progress in TDP-43-based therapy development, underscoring the need for an effective and standardized method for accurate quantification. Addressing the limitations of sensitivity and reproducibility in existing assays, in this study, we developed and validated a highly sensitive electrochemiluminescence immunoassay on the Meso Scale Discovery platform. The assay demonstrated the detection of full-length TDP-43 in human biofluids with a limit of detection of 4pg/mL, a working range of 4-20,000 pg/mL, and a total assay time of 16 h. In this study, we developed and validated a sensitive immunoassay for the detection of full-length TDP-43 in human biofluids using the Meso Scale Discovery platform. We used this immunoassay to quantify TDP-43 levels in the plasma and serum of healthy controls and ALS patients. Our results indicate a reduction in full-length TDP-43 in the blood of ALS patients compared to healthy controls.}, } @article {pmid39728018, year = {2024}, author = {Jeyarajan, S and Ranjith, S and Veerapandian, R and Natarajaseenivasan, K and Chidambaram, P and Kumarasamy, A}, title = {Antibiofilm Activity of Epinecidin-1 and Its Variants Against Drug-Resistant Candida krusei and Candida tropicalis Isolates from Vaginal Candidiasis Patients.}, journal = {Infectious disease reports}, volume = {16}, number = {6}, pages = {1214-1229}, pmid = {39728018}, issn = {2036-7430}, support = {BT/PR2071/BBE/117/241/2016//Department of Biotechnology, India/ ; 311/RUSA(2.0)/2018//RUSA 2.0 Biological Sciences/ ; 01706/P6/2021//Tamil Nadu State Council for Higher Education (TANSCHE)/ ; ICMR-NET- 61754/2010//Indian Council of Medical Research/ ; }, abstract = {Background/Objective: Indwelling intrauterine contraceptive devices (IUDs) have surfaces that facilitate the attachment of Candida spp., creating a suitable environment for biofilm formation. Due to this, vulvovaginal candidiasis (VVC) is frequently linked to IUD usage, necessitating the prompt removal of these devices for effective treatment. In this study, we evaluated the susceptibility of antimicrobial peptides in vitro against biofilm forming, Amphotericin B (MIC50 > 2 mg L[-1]) resistant Candida krusei and Candida tropicalis isolated from IUD users who had signs of vaginal candidiasis (hemorrhage, pelvic pain, inflammation, itching, and vaginal discharge). Three antimicrobial peptides, namely, epinecidin-1 (epi-1) and its two variants, namely, variant-1 (Var-1) and variant-2 (Var-2), which were reported to have enhanced antibacterial activity were tested against IUD isolates (C. krusei and C. tropicalis) with pathogenic form of Candida albicans as control. Variants of epi-1, namely, Var-1 and Var-2 were created by substituting lysine in the place of histidine and alanine. Methods: The antimicrobial activity was measured using the microbroth dilution method to determine the minimum inhibitory concentration (MIC) of peptides against C. albicans, C. krusei and C. tropicalis. The MIC of each peptide was used for biofilm assay by Crystal violet staining, Scanning Electron Microscopy, and Reactive Oxygen Species (ROS) assay. To find the possible mechanism of anti-biofilm activity by the peptides, their ability to interact with Candida spp. cell membrane proteins such as Exo-β-(1,3)-Glucanase, Secreted Aspartic Proteinase (Sap) 1, and N-terminal Domain Adhesin: Als 9-2 were determined through PatchDock. Results: The MIC values of peptides: epi-1, var-1 and var-2 against C. albicans are 128 μg mL[-1], 64 μg mL[-1] and 32 μg mL[-1], C. tropicalis are 256 μg mL[-1], 64 μg mL[-1,] and 32 μg mL[-1] and C. krusei are 128 µg mL[-1], 128 µg mL[-1] and 64 µg mL[-1], respectively. Both the variants outperformed epi-1. Specifically for tested Candida spp., var-1 showed two- to four-fold enhancements and var-2 showed two- to eight-fold enhancements compared to epi-1. Electron microscopy confirmed that the mechanism of action involves pore formation thus inducing reactive oxygen species in Candida spp. cell membrane. Computational analysis showed that the peptides have a high tendency to interact with Candida spp. cell membrane proteins such as Exo-β-(1,3)-Glucanase, Secreted Aspartic Proteinase (Sap) 1, and N-terminal Domain Adhesin: Als 9-2, thereby preventing biofilm formation. Conclusions: The in vitro evidence supports the potential use of epi-1 and its variants to be used as an anti-biofilm agent to coat IUDs in the future for therapeutic purposes.}, } @article {pmid39728753, year = {2024}, author = {Boziki, M and Theotokis, P and Kesidou, E and Nella, M and Bakirtzis, C and Karafoulidou, E and Tzitiridou-Chatzopoulou, M and Doulberis, M and Kazakos, E and Deretzi, G and Grigoriadis, N and Kountouras, J}, title = {Impact of Mast Cell Activation on Neurodegeneration: A Potential Role for Gut-Brain Axis and Helicobacter pylori Infection.}, journal = {Neurology international}, volume = {16}, number = {6}, pages = {1750-1778}, pmid = {39728753}, issn = {2035-8385}, abstract = {BACKGROUND: The innate immune response aims to prevent pathogens from entering the organism and/or to facilitate pathogen clearance. Innate immune cells, such as macrophages, mast cells (MCs), natural killer cells and neutrophils, bear pattern recognition receptors and are thus able to recognize common molecular patterns, such as pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), the later occurring in the context of neuroinflammation. An inflammatory component in the pathology of otherwise "primary cerebrovascular and neurodegenerative" disease has recently been recognized and targeted as a means of therapeutic intervention. Activated MCs are multifunctional effector cells generated from hematopoietic stem cells that, together with dendritic cells, represent first-line immune defense mechanisms against pathogens and/or tissue destruction.

METHODS: This review aims to summarize evidence of MC implication in the pathogenesis of neurodegenerative diseases, namely, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis.

RESULTS: In view of recent evidence that the gut-brain axis may be implicated in the pathogenesis of neurodegenerative diseases and the characterization of the neuroinflammatory component in the pathology of these diseases, this review also focuses on MCs as potential mediators in the gut-brain axis bi-directional communication and the possible role of Helicobacter pylori, a gastric pathogen known to alter the gut-brain axis homeostasis towards local and systemic pro-inflammatory responses.

CONCLUSION: As MCs and Helicobacter pylori infection may offer targets of intervention with potential therapeutic implications for neurodegenerative disease, more clinical and translational evidence is needed to elucidate this field.}, } @article {pmid39728809, year = {2024}, author = {Al Haffar, M and Fajloun, Z and Azar, S and Sabatier, JM and Abi Khattar, Z}, title = {Lesser-Known Cyanotoxins: A Comprehensive Review of Their Health and Environmental Impacts.}, journal = {Toxins}, volume = {16}, number = {12}, pages = {}, pmid = {39728809}, issn = {2072-6651}, mesh = {Humans ; *Cyanobacteria/metabolism ; *Bacterial Toxins/toxicity ; Animals ; Harmful Algal Bloom ; Cyanobacteria Toxins ; Microcystins/toxicity ; }, abstract = {Cyanobacteria, also known as blue-green algae, are a diverse phylum of photosynthetic, Gram-negative bacteria and one of the largest microbial taxa. These organisms produce cyanotoxins, which are secondary metabolites that can have significant impacts on both human health and the environment. While toxins like Microcystins and Cylindrospermopsins are well-documented and have been extensively studied, other cyanotoxins, including those produced by Lyngbya and Nostoc, remain underexplored. These lesser-known toxins can cause various health issues in humans, including neurotoxicity, hepatotoxicity, and dermatotoxicity, each through distinct mechanisms. Moreover, recent studies have shown that cyanobacteria can be aerosolized and transmitted through the air over long distances, providing an additional route for human exposure to their harmful effects. However, it remains an area that requires much more investigation to accurately assess the health risks and develop appropriate public health guidelines. In addition to direct exposure to toxins, cyanobacteria can lead to harmful algal blooms, which pose further risks to human and wildlife health, and are a global concern. There is limited knowledge about these lesser-known cyanotoxins, highlighting the need for further research to understand their clinical manifestations and improve society's preparedness for the associated health risks. This work aims to review the existing literature on these underexplored cyanotoxins, which are associated with human intoxication, elucidate their clinical relevance, address significant challenges in cyanobacterial research, and provide guidance on mitigating their adverse effects.}, } @article {pmid39729643, year = {2024}, author = {Meiling, JB and Caress, JB and Cartwright, MS}, title = {Ultra High-Frequency Ultrasound of Median Nerve Fascicles at the Wrist in Amyotrophic Lateral Sclerosis: An Exploratory Study.}, journal = {Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society}, volume = {42}, number = {5}, pages = {466-469}, doi = {10.1097/WNP.0000000000001136}, pmid = {39729643}, issn = {1537-1603}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; Male ; *Median Nerve/diagnostic imaging ; Female ; Middle Aged ; Ultrasonography/methods ; *Wrist/diagnostic imaging/innervation ; Aged ; Adult ; }, abstract = {PURPOSE: High-frequency ultrasound (HFUS) of muscle and nerve has the potential to be a reliable, responsive, and informative biomarker of disease progression for individuals with amyotrophic lateral sclerosis (ALS). High-frequency ultrasound is not able to visualize median nerve fascicles to the same extent as ultra-high-frequency ultrasound (UHFUS). Evaluating the number and size of fascicles within a nerve may facilitate a better understanding of nerve diseases. This exploratory study aims to image median nerve fascicles at the wrist in individuals with ALS using UHFUS and compare these findings with those from previously observed controls.

METHODS: Fifteen individuals with ALS underwent sonographic examination of the median nerves on each upper limb using UHFUS with a 48-MHz linear array transducer. Fascicle count and density in each examined nerve were determined by a single rater. Demographic and sonographic data from 20 previously studied controls were compared.

RESULTS: In individuals with ALS, the average fascicle number was 22.4 (SD 5.2) and average fascicle density 1.7 (SD 0.5). There was no significant difference in fascicle counts between individuals with ALS and controls.

CONCLUSIONS: Fascicular quantification using UHFUS is possible in individuals with ALS. Given the lack of appreciable difference between fascicle counts in individuals with ALS and controls, UHFUS of the median nerve at the wrist may not be a responsive biomarker for ALS disease progression.}, } @article {pmid39730482, year = {2024}, author = {Mitsi, E and Votsi, C and Koutsou, P and Georghiou, A and Christodoulou, CC and Kleopa, K and Zamba-Papanicolaou, E and Christodoulou, K and Nicolaou, P}, title = {Genetic epidemiology of amyotrophic lateral sclerosis in Cyprus: a population-based study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {30781}, pmid = {39730482}, issn = {2045-2322}, support = {73234//Telethon Cyprus/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Cyprus/epidemiology ; Female ; Middle Aged ; Aged ; *C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Genetic Predisposition to Disease ; Molecular Epidemiology ; DNA-Binding Proteins/genetics ; Adult ; RNA-Binding Protein FUS/genetics ; High-Throughput Nucleotide Sequencing ; Mutation ; Cohort Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disease of motor neurons, presenting with relentlessly progressive muscle atrophy and weakness. More than fifty genes carrying causative or disease-modifying variants have been identified since the 1990s, when the first ALS-associated variant in the gene SOD1 was discovered. The most commonly mutated ALS genes in the European populations include the C9orf72, SOD1, TARDBP and FUS. Understanding the genetic causes of ALS within a population is becoming more significant, especially in light of the possible development of personalized medicine. Here, we provide clinical and genetic data on familial and sporadic ALS patients in a Greek-Cypriot population-based cohort. Eighty-nine ALS patients, including 21 familial ALS (fALS) (23.6%) and 68 sporadic ALS (sALS) (76.4%), provided the cohort for variant screening of the most common ALS-associated genes. Moreover, next-generation sequencing (NGS) was also performed to identify rare ALS variants, and in silico prediction tools were applied to predict the downstream effect of the variants detected in our study. The pathogenic hexanucleotide G4C2 repeat expansion in C9orf72 was the predominant genetic cause (22.47%) of ALS in our population, while variants in six additional ALS-associated genes were identified, including ALS2, TARDBP, FIG4, TBK1, GLT8D1, and BICD2.}, } @article {pmid39731185, year = {2024}, author = {Itou, T and Fujita, K and Okuzono, Y and Warude, D and Miyakawa, S and Mihara, Y and Matsui, N and Morino, H and Kikukawa, Y and Izumi, Y}, title = {Th17 and effector CD8 T cells relate to disease progression in amyotrophic lateral sclerosis: a case control study.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {331}, pmid = {39731185}, issn = {1742-2094}, support = {NA//Takeda Pharmaceutical Company/ ; JPMH23FC1008//Ministry of Health, Labour and Welfare/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/pathology ; Humans ; *Disease Progression ; Female ; *CD8-Positive T-Lymphocytes/immunology ; Middle Aged ; Male ; *Th17 Cells/immunology/metabolism ; Case-Control Studies ; Aged ; Adult ; }, abstract = {The immune system has garnered attention due to its association with disease progression in amyotrophic lateral sclerosis (ALS). However, the role of peripheral immune cells in this context remains controversial. Here, we conducted single-cell RNA-sequencing of peripheral blood mononuclear cells to comprehensively profile immune cells concerning the rate of disease progression in patients with ALS. Our analysis revealed increased frequencies of T helper 17 cells (Th17) relative to regulatory T cells, effector CD8 T cells relative to naïve CD8 T cells, and CD16[high]CD56[low] mature natural killer cells relative to CD16[low]CD56[high] naïve natural killer cells in patients with rapidly progressive ALS. Additionally, we employed serum proteomics through a proximity extension assay combined with next-generation sequencing to identify inflammation-related proteins associated with rapid disease progression. Among these proteins, interleukin-17 A correlated with the frequency of Th17, while killer cell lectin-like receptor D1 (CD94) correlated with the frequency of effector CD8 T cells. These findings further support the active roles played by these specific immune cell types in the progression of ALS.}, } @article {pmid39731449, year = {2025}, author = {Fabbrizio, P and Baindoor, S and Margotta, C and Su, J and Morrissey, EP and Woods, I and Hogg, MC and Vianello, S and Venø, MT and Kjems, J and Sorarù, G and Bendotti, C and Prehn, JHM and Nardo, G}, title = {Protective role of Angiogenin in muscle regeneration in amyotrophic lateral sclerosis: Diagnostic and therapeutic implications.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {35}, number = {4}, pages = {e13328}, pmid = {39731449}, issn = {1750-3639}, support = {CUP E48I20000000007//Regione Lombardia/ ; //EU Joint Programme-Neurodegenerative Disease Research/ ; SG-2018-12366226//Ministero della Salute, Italy/ ; MUSALS-AChR//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; 18/CRT/6214//Science Foundation Ireland CRT in Genomics Data Science/ ; 17/JPND/3455/SFI_/Science Foundation Ireland/Ireland ; 20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; 21/RC/10294_P2/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology/diagnosis ; *Ribonuclease, Pancreatic/metabolism ; Animals ; Humans ; *Muscle, Skeletal/metabolism/pathology ; Mice ; *Regeneration/physiology ; Mice, Transgenic ; Male ; Female ; Disease Models, Animal ; Middle Aged ; Aged ; Muscle Development/physiology ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease with no effective treatments, in part caused by variations in progression and the absence of biomarkers. Mice carrying the SOD1G93A transgene with different genetic backgrounds show variable disease rates, reflecting the diversity of patients. While extensive research has been done on the involvement of the central nervous system, the role of skeletal muscle remains underexplored. We examined the impact of angiogenin, including its RNase activity, in skeletal muscles of ALS mouse models and in biopsies from ALS patients. Elevated levels of angiogenin were found in slowly progressing mice but not in rapidly progressing mice, correlating with increased muscle regeneration and vascularisation. In patients, higher levels of angiogenin in skeletal muscles correlated with milder disease. Mechanistically, angiogenin promotes muscle regeneration and vascularisation through satellite cell-endothelial interactions during myogenesis and angiogenesis. Furthermore, specific angiogenin-derived tiRNAs were upregulated in slowly progressing mice, suggesting their role in mediating the effects of angiogenin. These findings highlight angiogenin and its tiRNAs as potential prognostic markers and therapeutic targets for ALS, offering avenues for patient stratification and interventions to mitigate disease progression by promoting muscle regeneration.}, } @article {pmid39735081, year = {2024}, author = {Dost, W and Rasully, MQ and Zaman, MN and Dost, W and Ali, W and Ayobi, SA and Dost, R and Niazi, J and Bakht, K and Iqbal, A and Bokhari, SFH}, title = {Predictive Biomarkers for the Early Detection of Anastomotic Leaks in Colorectal Surgeries: A Systematic Review.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e74616}, pmid = {39735081}, issn = {2168-8184}, abstract = {Anastomotic leaks (ALs) remain a serious postoperative complication in colorectal surgery, often resulting in significant morbidity, prolonged hospitalization, and increased mortality risk. This systematic review aims to evaluate the role of predictive biomarkers in the early detection of ALs, focusing on their diagnostic accuracy and clinical utility. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive literature search was conducted across MEDLINE, Scopus, CENTRAL, and Web of Science, identifying studies that examined biomarkers such as C-reactive protein (CRP), procalcitonin (PCT), and white blood cell (WBC) count in the context of AL. A total of 20 studies met the inclusion criteria, with sample sizes ranging from 59 to 2,655 patients undergoing colorectal surgeries with primary anastomosis. CRP emerged as the most widely studied and reliable biomarker, with studies suggesting that elevated CRP levels, particularly on postoperative days 3-4, can effectively indicate AL risk, showing high negative predictive value. PCT has also shown promise as a complementary biomarker, offering enhanced specificity for infectious complications. Although WBC count alone was a limited predictor, it may add diagnostic value when used with other markers. In addition, innovative biomarkers, such as inflammatory indices in peritoneal fluid, demonstrated potential for further improving AL detection accuracy.}, } @article {pmid39735276, year = {2024}, author = {Moyana, TN}, title = {Small cell lung carcinoma metastatic to the stomach: Commonly overlooked, limited treatment options.}, journal = {World journal of gastroenterology}, volume = {30}, number = {48}, pages = {5198-5204}, pmid = {39735276}, issn = {2219-2840}, mesh = {Humans ; *Small Cell Lung Carcinoma/therapy/secondary/pathology/diagnostic imaging ; *Stomach Neoplasms/pathology/therapy/diagnostic imaging ; *Lung Neoplasms/secondary/therapy/pathology/diagnostic imaging ; Prognosis ; Biomarkers, Tumor/analysis/metabolism ; Positron Emission Tomography Computed Tomography/methods ; Immune Checkpoint Inhibitors/therapeutic use ; Immunohistochemistry ; }, abstract = {Small cell lung carcinoma metastatic to the stomach, whether synchronous or metachronous, is a rare phenomenon accounting for < 0.5% of lung cancers. Hence it can be overlooked by clinicians resulting in delayed diagnosis. This manuscript comments on Yang et al's article which reported 3 such cases. The main diagnostic features are based on routine morphology comprised of small cells with hyperchromatic nuclei, scant cytoplasm, brisk mitoses and necrosis. This can be supplemented by immunohistochemistry demonstrating positivity for cytokeratin, thyroid transcription factor-1 and neuroendocrine markers as well as a high Ki-67 labelling index. Imaging modalities such as positron emission tomography/contrast computed tomography help to confirm lung origin and rule out the possibility of extra-pulmonary small cell carcinoma. The predominant mechanism of spread is most likely hematogeneous. Prognosis is generally poor since this represents stage 4 disease but survival can be improved by chemo/radiotherapy and palliative surgery in select cases. Though outcomes have not changed much in the last several decades, the recent Food and Drug Administration approval of immune checkpoint inhibitors was a significant milestone as was the delineation of small cell lung carcinoma molecular subtypes. Liquid biopsies are increasingly being used for biomarker studies in clinical trials to assess treatment response and prognosis.}, } @article {pmid39736783, year = {2024}, author = {Zeng, J and Luo, C and Jiang, Y and Hu, T and Lin, B and Xie, Y and Lan, J and Miao, J}, title = {Decoding TDP-43: the molecular chameleon of neurodegenerative diseases.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {205}, pmid = {39736783}, issn = {2051-5960}, support = {YNXM2024062//High-quality development project of public hospitals in Baoan District, Shenzhen/ ; YNXM2024015//High-quality development project of public hospitals in Baoan District, Shenzhen/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics/pathology ; Animals ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) has emerged as a critical player in neurodegenerative disorders, with its dysfunction implicated in a wide spectrum of diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer's disease (AD). This comprehensive review explores the multifaceted roles of TDP-43 in both physiological and pathological contexts. We delve into TDP-43's crucial functions in RNA metabolism, including splicing regulation, mRNA stability, and miRNA biogenesis. Particular emphasis is placed on recent discoveries regarding TDP-43's involvement in DNA interactions and chromatin dynamics, highlighting its broader impact on gene expression and genome stability. The review also examines the complex pathogenesis of TDP-43-related disorders, discussing the protein's propensity for aggregation, its effects on mitochondrial function, and its non-cell autonomous impacts on glial cells. We provide an in-depth analysis of TDP-43 pathology across various neurodegenerative conditions, from well-established associations in ALS and FTLD to emerging roles in diseases such as Huntington's disease and Niemann-Pick C disease. The potential of TDP-43 as a therapeutic target is explored, with a focus on recent developments in targeting cryptic exon inclusion and other TDP-43-mediated processes. This review synthesizes current knowledge on TDP-43 biology and pathology, offering insights into the protein's central role in neurodegeneration and highlighting promising avenues for future research and therapeutic interventions.}, } @article {pmid39736981, year = {2024}, author = {Zhang, Y and Li, N and Ge, Z and Li, F}, title = {Blood component therapy for dry eye disease: a systematic review and network meta-analysis.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1500160}, pmid = {39736981}, issn = {2296-858X}, abstract = {OBJECTIVE: Blood component therapy has shown promising potential as an emerging treatment for dry eye disease; however, it remains unclear which specific blood component is the most effective. This study aims to compare the efficacy of different blood components in the treatment of dry eye disease through a network meta-analysis, with the goal of providing the latest and most reliable evidence for clinical practice.

METHODS: We conducted a systematic search of the PubMed, Web of Science, Cochrane, Embase, and Scopus databases, with the search concluding on June 1, 2024. Two independent researchers performed literature screening, data extraction, and quality assessment.

RESULTS: A total of 16 randomized controlled trials (RCTs) involving 898 patients with dry eye disease were included. Six different blood components were utilized in treating dry eye disease, with platelet-rich plasma (PRP) being the most widely used. The results of the network meta-analysis indicated that platelet-rich plasma eye drops (PRPD) significantly outperformed artificial tears (AT) in improving the corneal fluorescein staining score (CFSS), while autologous serum (ALS) and umbilical cord serum (UCS) also demonstrated significantly better effects than AT in enhancing tear break-up time (TBUT). Additionally, ALS, PRP injection (PRPI), and PRPD showed significantly superior outcomes compared to AT in improving the ocular surface disease index (OSDI). However, no statistically significant differences were found among the various treatment modalities regarding their effects on Schirmer's I value, CFSS, TBUT, and OSDI. SUCRA analysis predicted that UCS was the most effective in improving Schirmer's I value and TBUT, while PRP excelled in enhancing CFSS and OSDI. Limitations such as publication bias and issues related to randomization, allocation concealment, and blinding may affect the reliability of the current findings.

CONCLUSION: Blood component therapy can significantly improve the pathological damage and ocular surface health in patients with dry eye disease. For those with aqueous-deficient dry eye, UCS may represent the optimal treatment option. In contrast, for patients with more severe corneal epithelial damage, PRP may offer a more effective therapeutic approach.

https://www.crd.york.ac.uk/PROSPERO/, CRD42024534091.}, } @article {pmid39737526, year = {2025}, author = {Nakaya, T}, title = {Release of FUS into the extracellular space is regulated by its amino-terminal prion-like domain.}, journal = {FEBS letters}, volume = {599}, number = {7}, pages = {1046-1054}, doi = {10.1002/1873-3468.15086}, pmid = {39737526}, issn = {1873-3468}, support = {22K07374//Japan Society for the Promotion of Science/ ; }, mesh = {*RNA-Binding Protein FUS/metabolism/chemistry/genetics ; Animals ; Humans ; Mice ; Protein Domains ; *Extracellular Space/metabolism ; *Neurons/metabolism ; *Prions/metabolism/chemistry ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Fused in sarcoma (FUS) is a causative factor of amyotrophic lateral sclerosis (ALS) and is believed to propagate pathologically by transmission from cell to cell. However, the mechanism underlying FUS release from cells, which is a critical step for the propagation system, remains poorly understood. This study conducted an analysis of the release of human and mouse FUS from neurons, revealing that human FUS is significantly released into the media compared to its mouse counterpart. Further study using chimeric FUS proteins identified the amino-terminal region of human FUS as essential for its release. These findings indicate that human FUS is released directly from neurons and underscore the novel functional role of its amino-terminal region in this process.}, } @article {pmid39737769, year = {2025}, author = {Akyuz, E and Aslan, FS and Hekimoglu, A and Yilmaz, BN}, title = {Insights Into Retinal Pathologies in Neurological Disorders: A Focus on Parkinson's Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Alzheimer's Disease.}, journal = {Journal of neuroscience research}, volume = {103}, number = {1}, pages = {e70006}, doi = {10.1002/jnr.70006}, pmid = {39737769}, issn = {1097-4547}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/pathology ; *Parkinson Disease/diagnosis/diagnostic imaging/pathology ; *Multiple Sclerosis/pathology/diagnosis/diagnostic imaging ; *Alzheimer Disease/pathology/diagnosis ; *Retina/pathology/diagnostic imaging ; Tomography, Optical Coherence/methods ; Retinal Diseases/diagnosis/pathology/etiology ; Animals ; }, abstract = {Neurological diseases are central nervous system (CNS) disorders affecting the whole body. Early diagnosis of the diseases is difficult due to the lack of disease-specific tests. Adding new biomarkers external to the CNS facilitates the diagnosis of neurological diseases. In this respect, the retina has a common embryologic origin with the CNS. Retinal imaging technologies including optical coherence tomography (OCT) can be used in the understanding and processual monitoring of neurological diseases. Retinal imaging has been recently recognized as a potential source of biomarkers for neurological diseases, increasing the number of studies in this direction. In this review, the association of retinal abnormalities with Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD) is explained. Structural and functional abnormalities in retina as a predictive marker may facilitate early diagnosis of diseases. Although not all retinal abnormalities are predictive of neurologic diseases, changes in the retinal layers including retinal pigment epithelium and plexiform layers should suggest the risk of PD, MS, ALS, and AD.}, } @article {pmid39737952, year = {2024}, author = {Alecki, C and Rizwan, J and Le, P and Jacob-Tomas, S and Comaduran, MF and Verbrugghe, M and Xu, JMS and Minotti, S and Lynch, J and Biswas, J and Wu, T and Durham, HD and Yeo, GW and Vera, M}, title = {Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10796}, pmid = {39737952}, issn = {2041-1723}, support = {RF1 MH126719/MH/NIMH NIH HHS/United States ; 300232//Fonds de Recherche du Québec - Santé (Fonds de la recherche en sante du Quebec)/ ; MH126719//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; HG009889//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U24 HG009889/HG/NHGRI NIH HHS/United States ; R01 HG004659/HG/NHGRI NIH HHS/United States ; HG011864//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; PJT-186141//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; HG004659//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; Hudson Translational Team Grant//ALS Society of Canada (ALS Canada)/ ; R01 HG011864/HG/NHGRI NIH HHS/United States ; R01 NS103172/NS/NINDS NIH HHS/United States ; 2022-ALS Discovery Grant//ALS Society of Canada (ALS Canada)/ ; P30 CA008748/CA/NCI NIH HHS/United States ; U41 HG009889/HG/NHGRI NIH HHS/United States ; }, mesh = {*Dendrites/metabolism ; *Proteostasis ; Animals ; Humans ; Mice ; *RNA-Binding Protein FUS/metabolism/genetics ; *RNA, Messenger/metabolism/genetics ; *Motor Neurons/metabolism ; *HSC70 Heat-Shock Proteins/metabolism/genetics ; *Hippocampus/metabolism/cytology ; Spinal Cord/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Protein Biosynthesis ; Molecular Chaperones/metabolism/genetics ; HSP70 Heat-Shock Proteins/metabolism/genetics ; Microtubules/metabolism ; }, abstract = {Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discover that hippocampal and spinal cord motor neurons of mouse and human origin localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress. The most abundant dendritic chaperone mRNA encodes a constitutive heat shock protein 70 family member (HSPA8). Proteotoxic stress also enhances HSPA8 mRNA translation efficiency in dendrites. Stress-mediated HSPA8 mRNA localization to the dendrites is impaired by depleting fused in sarcoma-an amyotrophic lateral sclerosis-related protein-in cultured spinal cord mouse motor neurons or by expressing a pathogenic variant of heterogenous nuclear ribonucleoprotein A2/B1 in neurons derived from human induced pluripotent stem cells. These results reveal a neuronal stress response in which RNA-binding proteins increase the dendritic localization of HSPA8 mRNA to maintain proteostasis and prevent neurodegeneration.}, } @article {pmid39738171, year = {2024}, author = {Jeon, P and Ham, HJ and Choi, H and Park, S and Jang, JW and Park, SW and Cho, DH and Lee, HJ and Song, HK and Komatsu, M and Han, D and Jang, DJ and Lee, JA}, title = {NS1 binding protein regulates stress granule dynamics and clearance by inhibiting p62 ubiquitination.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10925}, pmid = {39738171}, issn = {2041-1723}, support = {2020M3E5D9079911//National Research Foundation of Korea (NRF)/ ; 2023R1A2C2008092//National Research Foundation of Korea (NRF)/ ; 2023R1A2C2008092//National Research Foundation of Korea (NRF)/ ; RS-2023-00218515//National Research Foundation of Korea (NRF)/ ; JP19H05706//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP21H004771//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K20044//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 24H00060//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP22gm1410004h0003//Japan Agency for Medical Research and Development (AMED)/ ; }, mesh = {Humans ; *Ubiquitination ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Stress Granules/metabolism ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Sequestosome-1 Protein/metabolism/genetics ; Microtubule-Associated Proteins/metabolism/genetics ; Neurons/metabolism ; HEK293 Cells ; Oxidative Stress ; HeLa Cells ; Autophagy ; Viral Nonstructural Proteins/metabolism/genetics ; Protein Binding ; Cytoplasmic Granules/metabolism ; Apoptosis Regulatory Proteins ; }, abstract = {The NS1 binding protein, known for interacting with the influenza A virus protein, is involved in RNA processing, cancer, and nerve cell growth regulation. However, its role in stress response independent of viral infections remains unclear. This study investigates NS1 binding protein's function in regulating stress granules during oxidative stress through interactions with GABARAP subfamily proteins. We find that NS1 binding protein localizes to stress granules, interacting with core components, GABARAP proteins, and p62, a protein involved in autophagy. In cells lacking NS1 binding protein, stress granule dynamics are altered, and p62 ubiquitination is increased, suggesting impaired stress granule degradation. Overexpression of NS1 binding protein reduces p62 ubiquitination. In amyotrophic lateral sclerosis patient-derived neurons, reduced NS1 binding protein and p62 disrupt stress granule morphology. These findings identify NS1 binding protein as a negative regulator of p62 ubiquitination and a facilitator of GABARAP recruitment to stress granules, implicating it in stress granule regulation and amyotrophic lateral sclerosis pathogenesis.}, } @article {pmid39739450, year = {2025}, author = {Aiello, EN and Poletti, B and Consonni, M and Iazzolino, B and Torre, S and Faltracco, V and Telesca, A and Palumbo, F and Curti, B and De Luca, G and Bella, ED and Bersano, E and Riva, N and Verde, F and Messina, S and Doretti, A and Maranzano, A and Morelli, C and Calvo, A and Silani, V and Lauria, G and Chiò, A and Ticozzi, N}, title = {Education moderates the association between motor involvement and executive status in ALS.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70027}, pmid = {39739450}, issn = {1468-1331}, support = {//BIBLIOSAN/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; Male ; Female ; *Executive Function/physiology ; Middle Aged ; *Educational Status ; Aged ; *Cognitive Reserve/physiology ; Neuropsychological Tests ; Cohort Studies ; }, abstract = {BACKGROUND: This study aimed to determine whether educational attainment-a common proxy of cognitive reserve (CR)-influences the association between motor and cognitive/behavioural outcomes in a large cohort of ALS patients without dementia.

METHODS: N = 726 ALS patients without FTD were assessed for motor (ALSFRS-R), cognitive (Edinburgh Cognitive and Behavioural ALS Screen, ECAS) and behavioural outcomes (ECAS-Carer Interview, ECAS-CI). CR was operationalized via educational attainment (in years). Moderation models were run on each subscale of the cognitive section of the ECAS and on the ECAS-CI by addressing ALSFRS-R as the predictor and education as the moderator.

RESULTS: Education was associated with both the ALSFRS-R and all the cognitive subscales of the ECAS, while not with the ECAS-CI. As to moderation models, a significant Education*ALSFRS-R interaction was detected solely with regard to the ECAS-Executive-with its simple slope-based decomposition revealing that higher ALSFRS-R scores were associated with higher scores on the ECAS-Executive for patients with low (p < 0.001) and average (p = 0.007), while not high, levels of education.

DISCUSSION: Education seems to moderate the association between motor involvement and executive status in ALS patients without dementia, thus possibly exerting a protective role towards both motor function and cognition in this population.}, } @article {pmid39739500, year = {2025}, author = {Saiduzzaman, M and Roy, S and Bhattacharjee, M}, title = {Young Patient with Amyotrophic Lateral Sclerosis Following Suicidal Organophosphorus Compounds Poisoning: A Case Report.}, journal = {Mymensingh medical journal : MMJ}, volume = {34}, number = {1}, pages = {272-275}, pmid = {39739500}, issn = {2408-8757}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Organophosphate Poisoning/complications/therapy/etiology ; Suicide, Attempted ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving both upper and lower motor neurons. Its underlying etiology is not well established. But certain risk factors including genetic predilection and exposure to certain environmental toxins like Organophosphorus Compounds (OPC) have been postulated. Here we describe a young male patient presented with progressive weakness of all four limbs immediately following survival from OPC ingestion as a suicidal attempt. He also had slurred, indistinct speech without swallowing difficulty and sensory findings. Neurological examination findings are having mixed upper and lower motor neuron signs. EMG (Electromyography) shows features of denervation and reinnervation suggestive of ALS. ALS following single exposure to OPC is a relatively rare finding. Supportive treatments including physiotherapy and psychotherapy were given. This case may strengthen the etiological link between OPC and ALS.}, } @article {pmid39739690, year = {2024}, author = {Tian, Y and Heinsinger, N and Hu, Y and Lim, UM and Wang, Y and Fernandis, AZ and Parmentier-Batteur, S and Klein, B and Uslaner, JM and Smith, SM}, title = {Deciphering the interactome of Ataxin-2 and TDP-43 in iPSC-derived neurons for potential ALS targets.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0308428}, pmid = {39739690}, issn = {1932-6203}, mesh = {*Induced Pluripotent Stem Cells/metabolism ; *Ataxin-2/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Neurons/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Protein Binding ; }, abstract = {Ataxin-2 is a protein containing a polyQ extension and intermediate length of polyQ extensions increases the risk of Amyotrophic Lateral Sclerosis (ALS). Down-regulation of Ataxin-2 has been shown to mitigate TDP-43 proteinopathy in ALS models. To identify alternative therapeutic targets that can mitigate TDP-43 toxicity, we examined the interaction between Ataxin-2 and TDP-43. Co-immunoprecipitation demonstrated that Ataxin-2 and TDP-43 interact, that their interaction is mediated through the RNA recognition motif (RRM) of TDP-43, and knocking down Ataxin-2 or mutating the RRM domains rescued TDP-43 toxicity in an iPSC-derived neuronal model with TDP-43 overexpression. To decipher the Ataxin-2 and TDP-43 interactome, we used co-immunoprecipitation followed by mass spectrometry to identify proteins that interacted with Ataxin-2 and TDP-43 under conditions of endogenous or overexpressed TDP-43 in iPSC-derived neurons. Multiple interactome proteins were differentially regulated by TDP-43 overexpression and toxicity, including those involved in RNA regulation, cell survival, cytoskeleton reorganization, protein modification, and diseases. Interestingly, the RNA-binding protein (RBP), TAF15 which has been implicated in ALS was identified as a strong binder of Ataxin-2 in the condition of TDP-43 overexpression. Together, this study provides a comprehensive annotation of the Ataxin-2 and TDP-43 interactome and identifies potential therapeutic pathways and targets that could be modulated to alleviate Ataxin-2 and TDP-43 interaction-induced toxicity in ALS.}, } @article {pmid39740575, year = {2025}, author = {Fortuna, A and Sorarù, G}, title = {Cervical lower motor neuron syndromes: A diagnostic challenge.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123357}, doi = {10.1016/j.jns.2024.123357}, pmid = {39740575}, issn = {1878-5883}, mesh = {Humans ; *Motor Neuron Disease/diagnosis/physiopathology/diagnostic imaging ; Magnetic Resonance Imaging/methods ; }, abstract = {Cervical lower motor neuron (LMN) syndromes, also known as brachial paresis, are characterized by muscle atrophy, weakness, and decreased reflexes in the upper limbs, devoid of sensory symptoms. These syndromes can stem from various factors, including degenerative conditions, immune-mediated diseases, infections, toxic exposures, metabolic disorders, and vascular anomalies.[1] Clinical presentations vary, with motor neuron involvement potentially limited to the cervical area or extending to other regions, affecting prognosis. Misdiagnosis is a significant issue, particularly in lower motor neuron presentations, with an error rate nearing 20 %.[2] This review proposes a classification system based on magnetic resonance imaging (MRI) findings, the onset timing of symptoms (acute, subacute, or chronic), the symmetry and distribution of atrophy, and the etiology (sporadic or hereditary). Acute conditions may include spinal ischemia,[3] whereas subacute or chronic forms can manifest as symmetric (e.g., cervical spondylogenic myelopathy)[4] or asymmetric (e.g., Hirayama disease)[5] presentations. Neurophysiological assessments and cervical MRI are crucial for accurate diagnosis, as they reveal patterns that provide lesion localization and additional clues to the underlying cause. A systematic diagnostic approach is essential for navigating the complexities of these syndromes.}, } @article {pmid39740768, year = {2025}, author = {Jiang, Y and Fan, W and Li, Y and Xue, H}, title = {Genetic Insights Into the Role of Cathepsins in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis: Evidence From Mendelian Randomization Study.}, journal = {Brain and behavior}, volume = {15}, number = {1}, pages = {e70207}, pmid = {39740768}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Mendelian Randomization Analysis ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; *Cathepsins/genetics ; *Genome-Wide Association Study ; Cathepsin B/genetics/metabolism ; Cathepsin H/genetics ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Previous studies have confirmed the significant role of cathepsins in the development of neurodegenerative diseases. We aimed to determine whether genetically predicted 10 cathepsins may have a causal effect on Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

METHODS: We conducted a two-sample bidirectional Mendelian randomization (MR) study using publicly available data from genome-wide association study (GWAS) to assess the causal associations between 10 cathepsins and three neurodegenerative diseases, including AD, PD, and ALS. We employed the following methods, including inverse variance weighting (IVW), MR-Egger, and weighted median (WM). The results were further validated using sensitivity analysis.

RESULTS: The forward MR analysis results indicate that elevated cathepsin H levels increase the risk of AD (p = 0.005, odds ratio [OR] = 1.040, 95% confidence interval [CI] = 1.011-1.069), elevated cathepsin B levels decrease the risk of PD (p < 0.001, OR = 0.890, 95% CI = 0.831-0.954), and no significant association was found between cathepsin levels and ALS. Reverse MR analysis suggests that there is no causal association between 10 cathepsins and three neurodegenerative diseases.

CONCLUSION: Our study provides new genetic insights into the role of cathepsin H in AD and cathepsin B in PD. However, our findings need to be further validated in a wider population, and future research should explore the potential mechanisms of cathepsins in these diseases in order to provide a basis for the development of new therapeutic strategies.}, } @article {pmid39741002, year = {2024}, author = {Lembo, A and Schiavetti, I and Serafino, M and Caputo, R and Nucci, P}, title = {Comparison of the performance of myopia control in European children and adolescents with defocus incorporated multiple segments (DIMS) and highly aspherical lenslets (HAL) spectacles.}, journal = {BMJ paediatrics open}, volume = {8}, number = {1}, pages = {}, pmid = {39741002}, issn = {2399-9772}, mesh = {Humans ; *Eyeglasses ; Adolescent ; Child ; Male ; Female ; Retrospective Studies ; *Myopia/therapy/epidemiology/physiopathology/prevention & control ; *Refraction, Ocular/physiology ; Disease Progression ; Europe/epidemiology ; Equipment Design ; Visual Acuity/physiology ; }, abstract = {PURPOSE: A performance comparison of two myopia control spectacle lens designs, defocus incorporated multiple segments (DIMS) and highly aspherical lenslets (HAL), at slowing myopia progression in a European child/adolescent population. Previous research directly comparing these designs has been limited to Chinese participants and 1-year follow-up. The prevalence of myopia in European child/adolescent has been estimated at 22.60%.

METHODS: Retrospective cohort study of individuals (6-17 years) with myopia progression. Participants wore DIMS (Hoya MiyoSmart) or HAL (Essilor Stellest) spectacles for a minimum of 2 years. Axial length (AL) and cycloplegic autorefraction (spherical equivalent refraction (SER)) were measured at baseline and 1 and 2 years.

RESULTS: Mean 1-year SER changes for DIMS were -0.34D (±0.46 SD) and HAL -0.30D (±0.30); 2-year changes for DIMS were -0.50D (±0.64 SD) and HAL -0.63D (±0.56). Mean 1-year AL increases for DIMS were 0.19 mm (±0.56) and HAL 0.15 mm (±0.47); 2-year increases for DIMS were 0.29 mm (±0.63) and HAL 0.32 mm (±0.72). For equivalence margins of 0.25D and 0.50D for SER at 1 and 2 years, respectively, and similarly 0.20 mm and 0.30 mm margins for AL, DIMS and HAL lenses were equivalent apart from AL at 1 year where the 0.21 mm 95% CI upper limit just exceeded 0.20 mm. At both 1 and 2 years, none of the differences in mean SERs or ALs between DIMS and HAL were clinically or statistically significant (p≥0.05 Mann-Whitney U test). Using linear mixed model analysis, the interaction between lens type and time did not significantly affect SER or AL at 1- or 2-year follow-up (p≥0.05). 38.4% of children/adolescents with DIMS had no SER progression at 2 years, compared with 21.9% with HAL (p=0.047).

CONCLUSION: In a European population, DIMS and HAL lenses are essentially equivalent in their ability to reduce myopia progression and AL elongation over a 2-year follow-up period.}, } @article {pmid39741274, year = {2024}, author = {Mandeville, R and Sedghamiz, H and Mansfield, P and Sheean, G and Studer, C and Cordice, D and Ghanbari, G and Malhotra, A and Nemati, S and Koola, J}, title = {Deep learning enhanced transmembranous electromyography in the diagnosis of sleep apnea.}, journal = {BMC neuroscience}, volume = {25}, number = {1}, pages = {80}, pmid = {39741274}, issn = {1471-2202}, support = {R01 HL157985/HL/NHLBI NIH HHS/United States ; T15 LM011271/LM/NLM NIH HHS/United States ; R01 HL166485/HL/NHLBI NIH HHS/United States ; R01 AG063925/AG/NIA NIH HHS/United States ; R01 HL154926/HL/NHLBI NIH HHS/United States ; R01 HL148436/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Deep Learning ; *Electromyography/methods ; Male ; Middle Aged ; Female ; Adult ; Sleep Apnea, Obstructive/diagnosis/physiopathology ; Polysomnography/methods ; Aged ; Sleep Apnea Syndromes/diagnosis/physiopathology ; }, abstract = {Obstructive sleep apnea (OSA) is widespread, under-recognized, and under-treated, impacting the health and quality of life for millions. The current gold standard for sleep apnea testing is based on the in-lab sleep study, which is costly, cumbersome, not readily available and represents a well-known roadblock to managing this huge societal burden. Assessment of neuromuscular function involved in the upper airway using electromyography (EMG) has shown potential to characterize and diagnose sleep apnea, while the development of transmembranous electromyography (tmEMG), a painless surface probe, has made this opportunity practical and highly feasible. However, experience and ability to interpret electrical signals from the upper airway are scarce, and much of the pertinent information within the signal is likely difficult to detect visually. To overcome this issue, we explored the use of transformers, a deep learning (DL) model architecture with attention mechanisms, to model tmEMG data and distinguish between electromyographic signals from a cohort of control, neurogenic, and sleep apnea patients. Our approach involved three strategies to train a generalizable model on a relatively small dataset including, (1) transfer learning using an audio spectral transformer (AST), (2) the use of 6,000 simulated EMG recordings, converted to spectrograms and using standard backpropagation for fine-tuning, and (3) application of regularization to prevent overfitting and enhance generalizability. This DL approach was tested using 177 transoral EMG recordings from a prior study's database that included six healthy controls, five moderate to severe OSA patients, and five amyotrophic lateral sclerosis (ALS) patients with evidence of bulbar involvement (neurogenic injury). Sensitivity and specificity for classifying neurogenic cases from controls were 98% and 73%, respectively, while classifying OSA from controls were 88% and 64%, respectively. Notably, by averaging the predicted probabilities of each segment for individual patients, the model correctly classified up to 82% of control and OSA patients. These results not only suggest a potential to diagnose OSA patients accurately, but also to identify OSA endotypes that involve neuromuscular pathology, which has major implications for clinical management, patient outcomes, and research.}, } @article {pmid39742161, year = {2024}, author = {Mashimo, S and Matsuoka, A and Tanese, K and Kano, O and Ishiko, A}, title = {Idiopathic Multiple Localized Lipoatrophy Mimicking Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e74887}, pmid = {39742161}, issn = {2168-8184}, abstract = {Localized lipoatrophy is a rare condition characterized by the localized loss of subcutaneous adipose tissue. It may occur idiopathically without specific triggers. The pathogenesis of idiopathic localized lipoatrophy remains largely unknown. We present the case of a 53-year-old Japanese woman with multiple localized lipoatrophy who exhibited upper motor neuron signs clinically and panniculitis histologically. She was initially suspected to have amyotrophic lateral sclerosis due to progressive left limb volume loss. Histologically, the lesions showed adipocyte destruction accompanied by predominant plasma infiltration.}, } @article {pmid39743032, year = {2025}, author = {Li, Y and Zhang, W and Zhang, Q and Li, Y and Xin, C and Tu, R and Yan, H}, title = {Oxidative stress of mitophagy in neurodegenerative diseases: Mechanism and potential therapeutic targets.}, journal = {Archives of biochemistry and biophysics}, volume = {764}, number = {}, pages = {110283}, doi = {10.1016/j.abb.2024.110283}, pmid = {39743032}, issn = {1096-0384}, mesh = {Humans ; *Mitophagy/drug effects ; *Oxidative Stress/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; Animals ; Antioxidants/therapeutic use/pharmacology ; Mitochondria/metabolism/pathology ; }, abstract = {Neurodegenerative diseases are now significant chronic progressive neurological conditions that affect individuals' physical health. Oxidative stress is crucial in the development of these diseases. Among the various neurodegenerative diseases, mitochondrial damage has become a major factor in oxidative stress and disease advancement. During this process, oxidative stress and mitophagy plays an important role. In this paper, we introduced the role of mitophagy and oxidative stress in detail, and expounded the relationship between them. In addition, we summarized the pathogenesis of some neurodegenerative diseases and the mechanism of three antioxidants. The former includes AD, PD, HD and ALS, while the latter includes carnosine, adiponectin and resveratrol. Provide goals and directions for further research and treatment of neurodegenerative diseases. This review summarizes the impact of oxidative stress on neurodegenerative diseases by regulating mitophagy, provides a deeper understanding of their pathological mechanisms, and suggests potential new therapeutic targets.}, } @article {pmid39743215, year = {2025}, author = {Chiu, Y and Xia, S and Qiao, H and Zhao, Z}, title = {Genetically Engineered Mouse Models for Alzheimer Disease and Frontotemporal Dementia: New Insights from Single-Cell and Spatial Transcriptomics.}, journal = {The American journal of pathology}, volume = {195}, number = {11}, pages = {2118-2130}, pmid = {39743215}, issn = {1525-2191}, support = {R21 AG066090/AG/NIA NIH HHS/United States ; R01 NS122060/NS/NINDS NIH HHS/United States ; RF1 NS135617/NS/NINDS NIH HHS/United States ; R56 AG082361/AG/NIA NIH HHS/United States ; R61 NS137365/NS/NINDS NIH HHS/United States ; RF1 NS122060/NS/NINDS NIH HHS/United States ; R01 AG089640/AG/NIA NIH HHS/United States ; R01 NS110687/NS/NINDS NIH HHS/United States ; R01 AG089756/AG/NIA NIH HHS/United States ; R01 AG061288/AG/NIA NIH HHS/United States ; R21 AG085559/AG/NIA NIH HHS/United States ; R03 AG063287/AG/NIA NIH HHS/United States ; }, abstract = {Neurodegenerative diseases, including Alzheimer disease, frontotemporal dementia, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis, are often casually linked to protein aggregation and inclusion. As the origins of those proteinopathies have been biochemically traced and genetically mapped, genetically engineered animal models carrying the specific mutations or variants are widely used for investigating the etiology of these diseases, as well as for testing potential therapeutics. This article focuses on the mouse models of Alzheimer disease and closely related frontotemporal dementia, particularly the ones that have provided most valuable knowledge, or are in a trajectory of doing so. More importantly, some of the major findings from these models are summarized, based on the recent single-cell transcriptomics, multiomics, and spatial transcriptomics studies. While no model is perfect, it is hoped that the new insights from these models and the practical use of these models will continue to help to establish a path forward.}, } @article {pmid39743298, year = {2024}, author = {Wang, L and Liu, H and Li, L}, title = {Autophagy receptor-inspired chimeras: a novel approach to facilitate the removal of protein aggregates and organelle by autophagy degradation.}, journal = {Journal of Zhejiang University. Science. B}, volume = {25}, number = {12}, pages = {1115-1119}, pmid = {39743298}, issn = {1862-1783}, support = {81970431//the National Natural Science Foundation of China/ ; 2023JJ50136//the Hunan Provincial Natural Science Foundation of China/ ; }, mesh = {*Autophagy ; Humans ; *Neurodegenerative Diseases/metabolism ; *Protein Aggregates ; Animals ; Organelles/metabolism ; Alzheimer Disease/metabolism ; Neurons/metabolism ; Huntington Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Neurodegenerative diseases (NDDs), mainly including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD), are sporadic and rare genetic disorders of the central nervous system. A key feature of these conditions is the slow accumulation of misfolded protein deposits in brain neurons, the excessive aggregation of which leads to neurotoxicity and further disorders of the nervous system.}, } @article {pmid39743546, year = {2025}, author = {Faller, KME and Chaytow, H and Gillingwater, TH}, title = {Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {2}, pages = {86-102}, pmid = {39743546}, issn = {1759-4766}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy ; }, abstract = {The motor neuron disease amyotrophic lateral sclerosis (ALS) is a devastating condition with limited treatment options. The past few years have witnessed a ramping up of translational ALS research, offering the prospect of disease-modifying therapies. Although breakthroughs using gene-targeted approaches have shown potential to treat patients with specific disease-causing mutations, the applicability of such therapies remains restricted to a minority of individuals. Therapies targeting more general mechanisms that underlie motor neuron pathology in ALS are therefore of considerable interest. ALS pathology is associated with disruption to a complex array of key cellular pathways, including RNA processing, proteostasis, metabolism and inflammation. This Review details attempts to restore cellular homeostasis by targeting these pathways in order to develop effective, broadly-applicable ALS therapeutics.}, } @article {pmid39743746, year = {2025}, author = {Wang, Z and Wang, X and Li, P and Xia, H and Yang, X}, title = {Genetic associations between immune-related plasma proteins and neurodegenerative diseases.}, journal = {Neurological research}, volume = {47}, number = {2}, pages = {129-138}, doi = {10.1080/01616412.2024.2448745}, pmid = {39743746}, issn = {1743-1328}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/immunology/blood ; *Blood Proteins/genetics/immunology ; Genome-Wide Association Study ; *Genetic Predisposition to Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics/immunology ; Parkinson Disease/genetics/immunology ; }, abstract = {BACKGROUND: Immune dysregulation is commonly associated with neurodegenerative diseases (NDs), yet the underlying causes and mechanisms still require further investigation.

OBJECTIVE: This study investigates the correlation between immune-related plasma proteins and the risk of NDs by integrating genome-wide association study (GWAS) data for Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) with plasma proteome analysis.

METHODS: By analyzing GWAS data for 4907 immune-related plasma proteins, this research evaluates the direct impact of plasma proteins on the risk of four NDs: AD, PD, ALS, and MS. Additionally, the study conducts an analysis of protein expression levels using single-cell RNA sequencing data.

RESULTS: We have identified plasma proteins that are closely associated with the risk of NDs. Using stringent criteria, we identified 88 proteins associated with AD, 115 with PD, 100 with ALS, and 87 with MS. Additionally, single-cell sequencing analyzed the protein expression and its distribution within different cell types in the brain.

CONCLUSIONS: Our research has demonstrated that plasma proteins may contribute to the risk of NDs, and it has also provided concrete evidence linking genetic susceptibility for these diseases to immune mechanisms. Furthermore, we found that specific proteins influence genetic variations linked to NDs risk via plasma-mediated regulation, emphasizing the importance of interactions between the brain and circulatory system.}, } @article {pmid39744204, year = {2024}, author = {Morales-Galicia, AE and Ramírez-Mejía, MM and Ponciano-Rodriguez, G and Méndez-Sánchez, N}, title = {Revolutionizing the understanding of liver disease: Metabolism, function and future.}, journal = {World journal of hepatology}, volume = {16}, number = {12}, pages = {1365-1370}, pmid = {39744204}, issn = {1948-5182}, abstract = {The intersection between metabolic-associated steatotic liver disease (MASLD) and chronic hepatitis B virus (HBV) infection is an emerging area of research with significant implications for public health and clinical practice. Wang et al's study highlights the complexities of managing patients with concurrent MASLD and HBV. The findings revealed that patients with concurrent MASLD-HBV exhibited more severe liver inflammation and fibrosis, whereas those with HBV alone presented a better lipid profile. The growing recognition of metabolic dysfunction in liver disease, reflected in the shift from nonalcoholic liver disease to MASLD, demands updates to clinical guidelines, particularly for patients with dual etiologies. Understanding the biological interactions between MASLD and HBV could lead to novel therapeutic approaches, emphasizing the need for personalized treatment strategies. The coexistence of MASLD and HBV presents therapeutic challenges, particularly in managing advanced fibrosis and cirrhosis, which are more likely in these patients. The aim of this editorial is to analyze the interaction between MASLD and HBV, highlight the pathophysiological mechanisms that exacerbate liver disease when both conditions coexist, and discuss the clinical implications of the findings of Wang et al.}, } @article {pmid39745174, year = {2025}, author = {Antonelli, S and Castañeda, FN and Olivieri, AC and Carabajal, MD and Pellegrino Vidal, RB}, title = {Novel Data Fusion Strategy for Second-Order Data: Multivariate Curve Resolution for the Determination of Pharmaceuticals by Means of Fluorimetric Measurements.}, journal = {Analytical chemistry}, volume = {97}, number = {1}, pages = {962-968}, doi = {10.1021/acs.analchem.4c05725}, pmid = {39745174}, issn = {1520-6882}, mesh = {*Fluorometry/methods ; Multivariate Analysis ; Least-Squares Analysis ; Pharmaceutical Preparations/analysis ; *Water Pollutants, Chemical/analysis ; }, abstract = {A new strategy is proposed for second-order data fusion based on the simultaneous modeling of two data sets using the multivariate curve resolution-alternating least-squares (MCR-ALS) model, applying a new constraint during the ALS stage, called "Proportionality of Scores". This approach allows for the fusion of data from different sources, without requiring common dimensionality, and enables the application of specific constraints to each data set. This strategy was applied to the determination of five pharmaceutical contaminants (naproxen, danofloxacin, ofloxacin, sarafloxacin, and enoxacin) in environmental water samples, by fusing two sets of excitation-emission fluorescence matrices, measured before and after photochemical derivatization. The predictive performance of the fused model was compared to individual PARAFAC models built for each fluorescence data set, showing that data fusion significantly increases precision and accuracy, as indicated by the elliptical joint confidence region test. Data fusion allowed improvement of relative errors of prediction, from 13-32% to 8-15% in validation samples and from 25-121% to 13-20% in real samples. The advantages of data fusion were evident in both cases, particularly in instances of substantial signal overlap between analytes or the presence of uncalibrated interferents with similar profiles, as demonstrated by the superior predictive capacity achieved through the proposed strategy.}, } @article {pmid39747563, year = {2025}, author = {Adim, H and Fahmideh, L and Fakheri, BA and Zarrini, HN and Sasanfar, H}, title = {iTRAQ-based quantitative proteomic analysis of herbicide stress in Avena ludoviciana Durieu.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {577}, pmid = {39747563}, issn = {2045-2322}, mesh = {*Herbicides/pharmacology/toxicity ; *Avena/drug effects/genetics/metabolism ; *Proteomics/methods ; *Herbicide Resistance/genetics ; *Plant Proteins/metabolism/genetics ; Gene Expression Regulation, Plant/drug effects ; Stress, Physiological/drug effects ; Acetyl-CoA Carboxylase/metabolism/genetics ; }, abstract = {Winter wild oat (Avena sterilis subsp. ludoviciana (Durieu) Gillet & Magne) has been considered the most common and troublesome weed in wheat fields of Iran. The widespread and continuous use of herbicides has led to the emergence and development of resistant biotypes in A. ludoviciana, making it one of the most important herbicide-resistant weeds within field crops. Considering the importance of understanding the mechanisms underlying resistance to herbicides and identifying key proteins involved in the response to Acetyl-coenzyme A carboxylase (ACCase) and Acetolactate synthase (ALS) inhibitor herbicides in A. ludoviciana. This study aimed to identify the proteins involved in herbicide resistance in A. ludoviciana using the Isobaric Tags for Relative and Absolute Quantification (iTRAQ) technique. In this study, a total of 18,313 peptides were identified with ≤ 0.01 FDR, which could be classified into 484 protein groups. Additionally, 138 differentially expressed proteins (DEPs) were identified in the resistant biotype (R), while 93 DEPs were identified in the susceptible biotype (S). Gene Ontology (GO) analysis revealed that these DEPs mainly consisted of proteins related to photosynthesis, respiration, amino acid synthesis and translation, secondary metabolite biosynthesis, defense proteins, and detoxification. Furthermore, enrichment pathway analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that the most important pathways included metabolic pathways, carbohydrate metabolism, secondary metabolites, amino acid synthesis, and photosynthesis. The function of DEPs indicated that some proteins, such as cytochrome P450, play a direct role in herbicide detoxification. Overall, the results of this study demonstrated the complex response of the resistant biotype to herbicides and its ability to increase antioxidant capacity through up-regulated detoxification proteins, particularly cytochrome P450 (Q6YSB4), and defense proteins, particularly superoxide dismutase (Q0DRV6) and polyamine oxidase (Q7XR46). In the resistant A. ludoviciana populations, in addition to the activation of enzymatic and non-enzymatic defense systems, other strategies such as reduced photosynthesis and respiration, increased transcription and translation activity, enhanced lipid metabolism, regulation of cellular processes and homeostasis, and up-regulation of proteins associated with signaling and ion channels play a role in resistance to herbicide. Overall these findings provide new insights into the role of different proteins in resistance to herbicides and contribute to a comprehensive understanding of herbicide resistance in A. ludoviciana.}, } @article {pmid39747573, year = {2025}, author = {Kim, KM and Girdhar, A and Cicardi, ME and Kankate, V and Hayashi, M and Yang, R and Carey, JL and Fare, CM and Shorter, J and Cingolani, G and Trotti, D and Guo, L}, title = {NLS-binding deficient Kapβ2 reduces neurotoxicity via selective interaction with C9orf72-ALS/FTD dipeptide repeats.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {2}, pmid = {39747573}, issn = {2399-3642}, support = {R35GM138109//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; F31 NS111870/NS/NINDS NIH HHS/United States ; R21 NS128396/NS/NINDS NIH HHS/United States ; 628389//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; R01 NS121143/NS/NINDS NIH HHS/United States ; F31NS111870//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35 GM140733/GM/NIGMS NIH HHS/United States ; R35GM140733//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; RF1NS121143//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21-NS090912//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS128396//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01GM099836//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R21 NS090912/NS/NINDS NIH HHS/United States ; RF1 NS121143/NS/NINDS NIH HHS/United States ; T32GM008275//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 GM099836/GM/NIGMS NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; T32 GM008275/GM/NIGMS NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Frontotemporal Dementia/metabolism/genetics ; *Dipeptides/metabolism ; beta Karyopherins/metabolism/genetics ; RNA-Binding Protein FUS/metabolism/genetics ; Protein Binding ; HEK293 Cells ; }, abstract = {Arginine-rich dipeptide repeat proteins (R-DPRs) are highly toxic proteins found in patients with C9orf72-linked amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). R-DPRs can cause toxicity by disrupting the natural phase behavior of RNA-binding proteins (RBPs). Mitigating this abnormal phase behavior is, therefore, crucial to reduce R-DPR-induced toxicity. Here, we use FUS as a model RBP to investigate the mechanism of R-DPR-induced aberrant RBP phase transition. We find that this phase transition can be mitigated by Kapβ2. However, as a nuclear import receptor and phase modifier for PY-NLS-containing RBPs, the function of WT Kapβ2 could lead to undesired interaction with its native substrates when used as therapeutics for C9-ALS/FTD. To address this issue, it is crucial to devise effective strategies that allow Kapβ2 to selectively target its binding to the R-DPRs, instead of the RBPs. We show that NLS-binding deficient Kapβ2W460A:W730A can indeed selectively interact with R-DPRs in FUS assembly without affecting normal FUS phase separation. Importantly, Kapβ2W460A:W730A prevents enrichment of poly(GR) in stress granules and mitigates R-DPR neurotoxicity. Thus, NLS-binding deficient Kapβ2 may be implemented as a potential therapeutic for C9-ALS/FTD.}, } @article {pmid39747792, year = {2025}, author = {Lee, J and Kouznetsova, VL and Kesari, S and Tsigelny, I}, title = {Selective diagnostics of Amyotrophic Lateral Sclerosis, Alzheimer's and Parkinson's Diseases with machine learning and miRNA.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {79}, pmid = {39747792}, issn = {1573-7365}, mesh = {*MicroRNAs/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/metabolism ; *Machine Learning ; *Alzheimer Disease/diagnosis/genetics/metabolism ; *Parkinson Disease/diagnosis/genetics/metabolism ; *Biomarkers ; }, abstract = {The diagnosis of neurological diseases can be expensive, invasive, and inaccurate, as it is often difficult to distinguish between different types of diseases with similar motor symptoms. However, the dysregulation of miRNAs can be used to create a robust machine-learning model for a reliable diagnosis of neurological diseases. We used miRNA sequence descriptors and gene target data to create machine-learning models that can be used as diagnostic tools. The top-performing machine-learning models, trained on filtered miRNA datasets for Amyotrophic Lateral Sclerosis, Alzheimer's and Parkinson's Diseases of this research yielded 94, 97, and 96, percent accuracies, respectively. Analysis of dysregulated miRNA in neurological diseases elucidated novel biomarkers that could be used to diagnose and distinguish between the diseases. Machine-learning models developed using sequence and gene target descriptors of miRNA biomarkers can achieve favorable accuracies for disease classification and attain a robust discerning capability of neurological diseases.}, } @article {pmid39748214, year = {2025}, author = {Brown, G and Jesus, S and Leboffe, E and Esch, A and Newport, K}, title = {Advance Care Planning Billing Codes Associated With Decreased Healthcare Utilization in Neurological Disease.}, journal = {Journal of healthcare management / American College of Healthcare Executives}, volume = {70}, number = {1}, pages = {58-73}, pmid = {39748214}, issn = {1096-9012}, mesh = {Humans ; Aged ; Male ; Female ; *Advance Care Planning/statistics & numerical data ; United States ; *Nervous System Diseases/therapy ; Aged, 80 and over ; *Patient Acceptance of Health Care/statistics & numerical data ; Cohort Studies ; }, abstract = {GOALS: Advance care planning (ACP) procedure codes have been established to reimburse meaningful care goal discussions; however, the utilization frequency of these codes in neurological disease is unknown. The objective of this study is to identify the association between ACP codes and healthcare utilization in chronic neurodegenerative diseases.

METHODS: This is a multicenter cohort study using real-world electronic health data. Using the TriNetX database, we collected electronic health data from 92 institutions in the United States. We included patients aged 65 and older who had been diagnosed with one of four neurological diseases: Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis (ALS). Patients with congestive heart failure were included as a reference. From the 64,683,009 total patients in the database, 877,138 had Alzheimer's disease, 544,610 had Parkinson's disease, 208,341 had multiple sclerosis, 9,944 had amyotrophic lateral sclerosis, and 1,500,186 had congestive heart failure. For each disease, we compared hospitalizations and emergency department (ED) visits over a two-year period between patients with and without ACP codes documented. Then, in patients with ACP, we investigated the rates of hospitalizations and ED visits over the two years before ACP and two years after ACP to understand the impact of ACP on the healthcare utilization trend. All patients had records for at least two years after index.

PRINCIPAL FINDINGS: The rate of ACP code documentation ranged from 1.8% of multiple sclerosis patients to 3.6% of Alzheimer's disease patients. After matching for demographic and health variables, usage of ACP codes was associated with significantly fewer hospitalizations for Alzheimer's disease patients. Across all diseases, there was a 20% to 30% decrease in ED visits, which was significant. Furthermore, there was a significant change in the trend of hospitalizations and ED visits for patients after ACP documentation. Patients went from increasing utilization before ACP documentation to decreasing utilization after documentation.

PRACTICAL APPLICATIONS: ACP billing codes are used infrequently in neurological disease, which may indicate that reimbursement alone is not sufficient to drive code usage. Usage of ACP billing codes was associated with decreased healthcare utilization, particularly in terms of ED visits. Beyond the primary objective of providing goal-concordant care, ACP may impact the economic burden of chronic neurodegenerative disease, which has high costs of care in our aging society. There may be particular benefits with Alzheimer's disease, which had an impact on both hospitalizations and ED visits and is the most prevalent neurodegenerative disease. Future work is needed to better understand the best implementation strategy for ACP in a multifaceted approach that emphasizes patient care preferences for their illness.}, } @article {pmid39748816, year = {2024}, author = {Li, Z and Liu, X and Zhang, H and Li, P and Yao, F}, title = {Improving resistance to lepidopteran pests and herbicide using Sanming dominant genic male sterile rice (Oryza sativa L.).}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1525620}, pmid = {39748816}, issn = {1664-462X}, abstract = {In order to improve both resistance to lepidopteran pests and resistance to the herbicide imazethapyr in mainstay japonica varieties of the Huang-Huai rice region, Sanming dominant genic male sterile (S-DGMS) rice was used as a platform to facilitate the pyramiding of functional genes and the replacement of the genomic background. Twelve novel lines were developed, each carrying a crystal toxin gene conferring resistance to lepidopteran pests and the ALS[627N] allele conferring resistance to herbicide imazethapyr in the background of a mainstay japonica variety. The genomic background of the 12 novel lines was examined using 48 specified molecular markers, and each line carried less than two polymorphic markers relative to the corresponding mainstay variety. All 12 lines displayed high resistance to lepidopteran pests and the herbicide imazethapyr. The major agronomic traits of the 12 lines showed no difference relative to the responding mainstay variety when sprayed with pesticide. The popularization of the 12 japonica lines could reduce the use of pesticides and provide highly efficient control of weeds and weedy rice in the future, thus promoting the development of japonica rice production. Therefore, S-DGMS rice could be a powerful tool for the genetic improvement of target traits in rice.}, } @article {pmid39748876, year = {2025}, author = {Salter, S and Salter, E and Kim, AJ and Liu, AK}, title = {Rising Voltage-Gated Potassium Channel Antibody Level as a Possible Disease Progression Marker for Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Cureus}, volume = {17}, number = {1}, pages = {e76760}, pmid = {39748876}, issn = {2168-8184}, abstract = {A subset of amyotrophic lateral sclerosis (ALS) patients tests positive for antibodies commonly associated with autoimmune neurological diseases, including voltage-gated potassium channel (VGKC)-complex antibodies. Although an autoimmune basis for ALS remains speculative, and immunomodulatory therapies have shown minimal benefit as of yet, isolated cases suggest that VGKC-complex antibodies may be relevant to disease type and progression. In this report, we present a case of ALS in which increasing VGKC-complex antibody levels correlated with clinical decline, raising the question of whether such antibodies could serve as biomarkers of progression in VGKC-complex antibody-positive ALS patients. To date, no published studies have systematically evaluated changes in VGKC-complex antibody levels in ALS patients over time. Our findings suggest that tracking VGKC-complex antibodies in ALS may offer insights into disease progression and prompt further investigation into their potential role as prognostic biomarkers, especially in certain subtypes of the disease.}, } @article {pmid39749172, year = {2024}, author = {Chauhan, A and Begum, J and Lavanya, KM and Gupta, A and Ghosh, S and Kulkarni, S}, title = {Experiential Learning of Active Learning Strategies in Mentor Learner Web-based Discussions: A Perceptions Study.}, journal = {International journal of applied & basic medical research}, volume = {14}, number = {4}, pages = {258-265}, pmid = {39749172}, issn = {2229-516X}, abstract = {BACKGROUND: Active learning strategies (ALSs) in medical education are valued for their effectiveness but face adoption challenges among educators, underscoring the need for a deeper understanding of their implementation and impact.

AIM: The aim of the study was to investigate the perceptions of medical educators regarding the effectiveness and challenges of ALS through mentor-learner (ML) web-based discussions.

SETTINGS AND DESIGN: The retrospective cross-sectional study analyzed data from 32 medical educators enrolled in the Foundation for Advancement of International Medical Education Research course at Christian Medical College, Ludhiana. It utilized a mixed-method approach, gathering both quantitative and qualitative data through ML web discussions.

MATERIALS AND METHODS: The study used a "dual-method" approach, combining traditional online discussions with a "role-reversal" method on an ML web platform, promoting experiential learning. Participant responses on ALS implementation tasks were collected and analyzed within these discussions.

RESULTS: Participants shared various ALS for collaborative learning (20), classroom engagement (26), assessing prior knowledge (12), and note-taking during lectures (10). Further, among the 11 ALS examined, the ease of implementation varied significantly among participants (P < 0.0001). Challenges in ALS implementation included inadequate faculty training (91%), motivation (84%), resource constraints (81%), student (75%), and administrative resistance (69%). Four themes emerged as recommendations for effective ALS implementation: empowering educators, engaging students, streamlining support systems, and monitoring impact.

CONCLUSION: The study highlights a mixed perspective of medical educators on ALS. Although ALS was perceived as effective in fostering critical thinking and developing collaborative learning among students, various challenges, such as a lack of skilled faculty and resources, necessitated robust faculty development initiatives.}, } @article {pmid39749668, year = {2025}, author = {Mehta, P and Raymond, J and Nair, T and Han, M and Berry, J and Punjani, R and Larson, T and Mohidul, S and Horton, DK}, title = {Amyotrophic lateral sclerosis estimated prevalence cases from 2022 to 2030, data from the national ALS Registry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {290-295}, doi = {10.1080/21678421.2024.2447919}, pmid = {39749668}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; *Registries ; Male ; Female ; Prevalence ; Aged ; Middle Aged ; United States/epidemiology ; Adult ; Aged, 80 and over ; Retrospective Studies ; Young Adult ; Adolescent ; }, abstract = {Objective: To estimate the projected number of ALS cases in the United States from 2022 to 2030. Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with no known cure. Because ALS is not a notifiable disease in the United States, the accurate ascertainment of prevalent ALS cases continues to be a challenge. To overcome this, the National ALS Registry (Registry) uses novel methods to estimate newly diagnosed and existing cases in the United States. Methods: We estimated ALS prevalence retrospectively from 2022 to 2024 and prospectively from 2025 to 2030 using prevalence obtained through previous CRC analyses on 2018 Registry data (the most current data available) to generate projected observed, missing, and total cases. Projected prevalent cases were then stratified by age, race, and sex. Results: The number of estimated ALS cases in 2022 was 32,893. By 2030, projected cases increase more than 10%, to 36,308. The largest increase occurs for the population ages 66 years and older, with a 25% increase (from 16,349 cases in 2022 to 20,438 cases in 2030). The projected number of cases classified as "other race" will increase by 15% (from 2,473 cases in 2022 to 2,854 cases in 2030). Conclusions: These estimates of projected ALS cases reflect anticipated changes in the underlying demographics of the United States. Our projections are likely an underestimation because emerging therapeutics and improved healthcare will improve survivability in this vulnerable population. These results should inform policy to more efficiently allocate resources for ALS patients and programs.}, } @article {pmid39749674, year = {2025}, author = {Tankéré, P and Cascarano, E and Saint Raymond, C and Mallaret, M and Toribio Ruiz, C and Herquelot, E and Denis, H and Cals Maurette, M and Tamisier, R and Pépin, JL}, title = {Care trajectories and adherence to respiratory management recommendations in persons living with amyotrophic lateral sclerosis: a ten-year cohort study in a French tertiary university centre.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {259-267}, doi = {10.1080/21678421.2024.2447911}, pmid = {39749674}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/mortality/epidemiology/complications ; Male ; Female ; Middle Aged ; Aged ; Tertiary Care Centers ; France/epidemiology ; *Noninvasive Ventilation/methods ; Cohort Studies ; *Respiratory Insufficiency/therapy/etiology ; Prospective Studies ; }, abstract = {Objective: This study determined real-life care trajectories before and after initiation of noninvasive ventilation (NIV) in patients with amyotrophic lateral sclerosis (ALS). Caregiver adherence to respiratory management recommendations and the associated survival rate of people with ALS were also assessed. Methods: Data were obtained from a tertiary center prospective ALS database that included 10 years of follow-up data for people with ALS. Results are presented numerically and with graphical time sequence analysis through K clustering (TAK) representation. Kaplan Meier and Cox models were used to determine survival and associated prognostic factors. Results: 109 patients with ALS patients were included; median [interquartile range] follow-up was 25.0 months [15.3-43.3]. During study timeframe patients had a median of 4.0 [2.0-6.0] clinical visits; death occurred in 54.1%. Median time between clinical visits was 3.9 [2.8-6.5] months, between arterial blood gases was 4.3 months [3.0-6.6], between spirometry testing was 5.8 months [4.1-8.2], and between nocturnal oximetry was 4.4 months [3.0-7.8]. Visualization of care trajectories TAK show marked heterogeneity in survival, time to NIV initiation, and time from NIV initiation to death. Mortality was correlated with NIV initiation and arterial carbon dioxide pressure increase. Conclusions: The current framework in ALS guidelines should be adapted to the ALS disease stage and individual patient characteristics. Understanding how subgroups of patients with ALS use healthcare services over time could help to highlight fragility areas and priorities in the allocation of care resources and implementation of best practices.}, } @article {pmid39749679, year = {2025}, author = {Young, CA and Chaouch, A and Mcdermott, CJ and Al-Chalabi, A and Chhetri, SK and Bidder, C and Edmonds, E and Ellis, C and Annadale, J and Wilde, L and Sharrack, B and Malaspina, A and Leach, O and Mills, R and Tennant, A}, title = {Determinants and progression of stigma in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {192-202}, pmid = {39749679}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis/epidemiology ; Male ; Female ; Middle Aged ; *Social Stigma ; Aged ; Disease Progression ; Self Concept ; Quality of Life/psychology ; Adult ; Fatigue/psychology ; *Motor Neuron Disease/psychology ; }, abstract = {Objective: Stigma in amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) may be felt or enacted; felt stigma covers feeling devalued by the illness, whereas enacted stigma refers to being treated differently because of it. Stigma in ALS/MND has been shown to increase social withdrawal, worsen quality of life, and reduce use of assistive devices, so we explored prevalence and factors influencing stigma. Methods: Participants in the Trajectories of Outcome in Neurological Conditions-ALS study completed scales measuring stigma, fatigue, spasticity, functioning, mood, worry, self-esteem, and perceived health, as well as demographic information and symptoms like head drop or emotional lability. Following transformation to interval-scale estimates, data were analyzed by regression, structural equation modeling, and trajectory models. Results: Stigma was experienced by 83.5% of 1059 respondents. Worry, disease severity (King's stage ≥ 3), emotional lability, fatigue, spasticity, and bulbar onset increase stigma. In contrast, increasing age, living with spouse/partner, and greater self-esteem were associated with reduced stigma. Trajectory analysis over 30 months (N = 1049) showed three groups, the largest (70.2%) had high levels of stigma which significantly increased during follow-up. In a recently diagnosed subset of 347 participants, stigma was experienced early in the disease course (<7 months after diagnosis), and for 77.2% stigma significantly increased over time. Conclusions: Both felt and enacted stigma are frequently perceived by people living with ALS/MND. Younger people and those with bulbar onset, emotional lability, worry, fatigue, and spasticity, or at more advanced clinical stages, are at greater risk.}, } @article {pmid39751824, year = {2025}, author = {Sghaier, I and Kacem, I and Ratti, A and Takout, K and Abida, Y and Peverelli, S and Ticozzi, N and Gargouri-Berrachid, A and Silani, V and Gouider, R}, title = {Impact of APOE and MAPT genetic profile on the cognitive functions among Amyotrophic Lateral Sclerosis Tunisian patients.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {4}, pages = {609-618}, pmid = {39751824}, issn = {1435-1463}, mesh = {Humans ; Tunisia ; *Amyotrophic Lateral Sclerosis/genetics/complications/psychology ; Male ; Female ; *tau Proteins/genetics ; Middle Aged ; Aged ; *Apolipoproteins E/genetics ; Adult ; *Cognitive Dysfunction/genetics/etiology ; Genotype ; }, abstract = {Amyotrophic Lateral Sclerosis(ALS) has traditionally been managed as a neuromuscular disorder. However, recent evidence suggests involvement of non-motor domains. This study aims to evaluate the impact of APOE and MAPT genotypes on the cognitive features of ALS. We included confirmed ALS cases from the Neurology department at Razi University Hospital, Tunisia. APOE and MAPT screening were conducted with Sanger sequencing validation, and preliminary screening for four main ALS genes was performed. Clinical phenotypes and genotypes were analyzed using appropriate tests, with healthy controls (HC) representing the Tunisian population. Two-hundred-seventy ALS patients were included, stratified as 213 spinal cases,49 with bulbar onset and 8 patients with generalized form with 140 HC. Regarding APOE, we reported high frequency of ALS cases carrier of APOE-ε4 isoform compared to controls(p < 0.0001).We found a significant association between APOE-ɛ4 and ALS onset site (p = 0.05,r = 0.33),with higher frequencies in bulbar onset patients. Cognitive signs were more frequent in ɛ4 carriers (r = 0.43,p < 0.01),and a significant link was observed between dysexecutive functions and the APOE risk allele (p = 0.0495).Concerning the MAPT haplotypes, we reported high frequency of ALS cases carrier of MAPT H1-haplotype HC (94.45% and 72.14% respectively, p < 0.001).Among ALS cases,MAPT-H1 showed a stronger positive correlation with the presence of oculomotor signs(p = 0.05,r = 0.28).As well as significant positive association between cognitive impairments(p = 0.039,r = 0.59). Our findings emphasize the correlation between APOE and MAPT genotypes and the cognitive features in our ALS patients. We also observed other interesting, though weak, significant correlations (with coefficients not exceeding 0.20),which require further validation in a larger cohort to confirm our results.}, } @article {pmid39752797, year = {2025}, author = {Ju, W and Min, YG and Kim, JS and Ryu, S and Ahn, SW and Hong, YH and Choi, SJ and Sung, JJ}, title = {Clinical features of FOSMN syndrome in Korea: A comparative analysis with bulbar-onset amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {469}, number = {}, pages = {123372}, doi = {10.1016/j.jns.2024.123372}, pmid = {39752797}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/physiopathology/therapy ; Male ; Female ; Middle Aged ; Republic of Korea/epidemiology ; Aged ; Adult ; *Facial Nerve Diseases/epidemiology/diagnosis/physiopathology/therapy ; Age of Onset ; Cohort Studies ; Disease Progression ; }, abstract = {Facial onset sensory and motor neuronopathy (FOSMN) syndrome is a rare neurodegenerative disorder initially characterized by facial sensory deficits, which later progress to motor deficits in a rostral-caudal distribution. This study investigated the prevalence, clinical features, and prognosis of FOSMN syndrome and compared these aspects with those of bulbar-onset amyotrophic lateral sclerosis (ALS) within a single institutional cohort of motor neuron diseases. We identified four patients with FOSMN syndrome who had been misclassified as having bulbar-onset ALS, representing approximately 2 % of such ALS cases. The median age of onset for FOSMN syndrome was similar to that of bulbar-onset ALS. However, patients with FOSMN syndrome were often diagnosed at more advanced stages and had lower ALS Functional Rating Scale-revised (ALSFRS-R) scores. Despite the slower progression of FOSMN syndrome, therapeutic interventions such as gastrostomy or non-invasive ventilation were frequently required. In conclusion, this study provides detailed clinical profiles of patients with FOSMN syndrome and deepens our understanding of a heterogeneous group of neurodegenerative disorders.}, } @article {pmid39753182, year = {2025}, author = {Swarup, G and Medchalmi, S and Ramachandran, G and Sayyad, Z}, title = {Molecular aspects of cytoprotection by Optineurin during stress and disease.}, journal = {Biochimica et biophysica acta. Molecular cell research}, volume = {1872}, number = {3}, pages = {119895}, doi = {10.1016/j.bbamcr.2024.119895}, pmid = {39753182}, issn = {1879-2596}, mesh = {Humans ; Membrane Transport Proteins ; Cell Cycle Proteins ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Transcription Factor TFIIIA/genetics/metabolism ; *Cytoprotection ; Endoplasmic Reticulum Stress ; Signal Transduction ; Oxidative Stress ; Autophagy ; *Glaucoma/genetics/metabolism/pathology ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; }, abstract = {Optineurin/OPTN is an adapter protein that plays a crucial role in mediating many cellular functions, including autophagy, vesicle trafficking, and various signalling pathways. Mutations of OPTN are linked with neurodegenerative disorders, glaucoma, and amyotrophic lateral sclerosis (ALS). Recent work has shown that OPTN provides cytoprotection from many types of stress, including oxidative stress, endoplasmic reticulum stress, protein homeostasis stress, tumour necrosis factor α, and microbial infection. Here, we discuss the mechanisms involved in cytoprotective functions of OPTN, which possibly depend on its ability to modulate various stress-induced signalling pathways. ALS- and glaucoma-causing mutants of OPTN are altered in this regulation, which may affect cell survival, particularly under various stress conditions. We suggest that OPTN deficiency created by mutations may cooperate with stress-induced signalling to enhance or cause neurodegeneration. Other functions of OPTN, such as neurotrophin secretion and vesicle trafficking, may also contribute to cytoprotection.}, } @article {pmid39753538, year = {2025}, author = {Larrea, D and Tamucci, KA and Kabra, K and Velasco, KR and Yun, TD and Pera, M and Montesinos, J and Agrawal, RR and Paradas, C and Smerdon, JW and Lowry, ER and Stepanova, A and Yoval-Sanchez, B and Galkin, A and Wichterle, H and Area-Gomez, E}, title = {Altered mitochondria-associated ER membrane (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS).}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {379}, pmid = {39753538}, issn = {2041-1723}, support = {R21 NS125466/NS/NINDS NIH HHS/United States ; 27302C0028/ES/NIEHS NIH HHS/United States ; R01 NS131322/NS/NINDS NIH HHS/United States ; R01 AG056387/AG/NIA NIH HHS/United States ; F31 NS095571/NS/NINDS NIH HHS/United States ; S10 OD030335/OD/NIH HHS/United States ; T32 DK007647/DK/NIDDK NIH HHS/United States ; R01 NS112381/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Endoplasmic Reticulum/metabolism ; *Mitochondria/metabolism ; Humans ; Animals ; Spinal Cord/metabolism ; Mice ; Glucose/metabolism ; Fatty Acids/metabolism ; Male ; Energy Metabolism ; Pyruvic Acid/metabolism ; Intracellular Membranes/metabolism ; Electron Transport Complex I/metabolism/genetics ; Brain/metabolism ; Mitochondria Associated Membranes ; }, abstract = {Mitochondrial function is modulated by its interaction with the endoplasmic reticulum (ER). Recent research indicates that these contacts are disrupted in familial models of amyotrophic lateral sclerosis (ALS). We report here that this impairment in the crosstalk between mitochondria and the ER impedes the use of glucose-derived pyruvate as mitochondrial fuel, causing a shift to fatty acids to sustain energy production. Over time, this deficiency alters mitochondrial electron flow and the active/dormant status of complex I in spinal cord tissues, but not in the brain. These findings suggest mitochondria-associated ER membranes (MAM domains) play a crucial role in regulating cellular glucose metabolism and that MAM dysfunction may underlie the bioenergetic deficits observed in ALS.}, } @article {pmid39753643, year = {2025}, author = {Mravinacová, S and Bergström, S and Olofsson, J and de San José, NG and Anderl-Straub, S and Diehl-Schmid, J and Fassbender, K and Fliessbach, K and Jahn, H and Kornhuber, J and Landwehrmeyer, GB and Lauer, M and Levin, J and Ludolph, AC and Prudlo, J and Schneider, A and Schroeter, ML and Wiltfang, J and Steinacker, P and , and Otto, M and Nilsson, P and Månberg, A}, title = {Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {668}, pmid = {39753643}, issn = {2045-2322}, mesh = {Humans ; *Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; *Biomarkers/cerebrospinal fluid ; Male ; Female ; Aged ; Middle Aged ; Brain/metabolism/pathology ; Alzheimer Disease/cerebrospinal fluid/diagnosis ; Cerebrospinal Fluid Proteins/analysis ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; }, abstract = {Accurate diagnosis and monitoring of neurodegenerative diseases require reliable biomarkers. Cerebrospinal fluid (CSF) proteins are promising candidates for reflecting brain pathology; however, their diagnostic utility may be compromised by natural variability between individuals, weakening their association with disease. Here, we measured the levels of 69 pre-selected proteins in cerebrospinal fluid using antibody-based suspension bead array technology in a multi-disease cohort of 499 individuals with neurodegenerative disorders including Alzheimer's disease (AD), behavioral variant frontotemporal dementia, primary progressive aphasias, amyotrophic lateral sclerosis (ALS), corticobasal syndrome, primary supranuclear palsy, along with healthy controls. We identify significant inter-individual variability in overall CSF levels of brain-derived proteins, which could not be attributed to specific disease associations. Using linear modelling, we show that adjusting for median CSF levels of brain-derived proteins increases the diagnostic accuracy of proteins previously identified as altered in CSF in the context of neurodegenerative disorders. We further demonstrate a simplified approach for the adjustment using pairs of correlated proteins with opposite alteration in the diseases. With this approach, the proteins adjust for each other and further increase the biomarker performance through additive effect. When comparing the diseases, two proteins-neurofilament medium and myelin basic protein-showed increased levels in ALS compared to other diseases, and neurogranin showed a specific increase in AD. Several other proteins showed similar trends across the studied diseases, indicating that these proteins likely reflect shared processes related to neurodegeneration. Overall, our findings suggest that accounting for inter-individual variability is crucial in future studies to improve the identification and performance of relevant biomarkers. Importantly, we highlight the need for multi-disease studies to identify disease-specific biomarkers.}, } @article {pmid39753665, year = {2025}, author = {Quintanilla, CA and Fitzgerald, Z and Kashow, O and Radojicic, MS and Ulupinar, E and Bitlis, D and Genc, B and Andjus, P and van Drongelen, W and Ozdinler, PH}, title = {High-density multielectrode arrays bring cellular resolution to neuronal activity and network analyses of corticospinal motor neurons.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {732}, pmid = {39753665}, issn = {2045-2322}, support = {778405 "AUTOIGG"//EU H2020 MSCA RISE/ ; R01 AG061708/AG/NIA NIH HHS/United States ; 4242 "NIMOCHIP"//Science Fund of the Republic of Serbia/ ; R01AG061708-03/NH/NIH HHS/United States ; 5T32NS041234-18/NH/NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/physiology ; Mice ; *Microelectrodes ; Motor Cortex/physiology ; Pyramidal Tracts/physiology ; Nerve Net/physiology ; Mice, Transgenic ; }, abstract = {Corticospinal motor neurons (CSMN), located in the motor cortex of the brain, are one of the key components of the motor neuron circuitry. They are in part responsible for the initiation and modulation of voluntary movement, and their degeneration is the hallmark for numerous diseases, such as amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia, and primary lateral sclerosis. Cortical hyperexcitation followed by in-excitability suggests the early involvement of cortical dysfunction in ALS pathology. However, a high-spatiotemporal resolution on our understanding of their functional health and connectivity is lacking. Here, we combine optical imaging with high-density microelectrode array (HD-MEA) system enabling single cell resolution and utilize UCHL1-eGFP mice to bring cell-type specificity to our understanding of the electrophysiological features of healthy CSMN, as they mature and form network connections with other cortical neurons, in vitro. This novel approach lays the foundation for future cell-type specific analyses of CSMN that are diseased due to different underlying causes with cellular precision, and it will allow the assessment of their functional response to compound treatment, especially for drug discovery efforts in upper motor neuron diseases.}, } @article {pmid39753993, year = {2025}, author = {Cheng, L and Liu, Z and Shen, C and Xiong, Y and Shin, SY and Hwang, Y and Yang, SB and Chen, Z and Zhang, X}, title = {A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {1}, pages = {e70208}, pmid = {39753993}, issn = {1755-5949}, support = {20224BAB216045//Youth Foundation of Natural Science Foundation of Jiangxi Province/ ; GJJ211812//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; GJJ211813//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; 202131084//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; 202211982//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; RZYB202201//Research project of Cognitive Science and Transdisciplinary Studies Center of Jiangxi Province/ ; 20224BAB206040//Provincial Natural Science Foundation of Jiangxi Province/ ; 202411843024//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; S202411843050//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; 2022B1010//Administration of Traditional Chinese Medicine of Jiangxi Province/ ; }, mesh = {*Adenosine Deaminase/genetics/metabolism ; Humans ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; *Central Nervous System Diseases/genetics/metabolism/therapy ; RNA Editing ; }, abstract = {BACKGROUND: Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double-stranded RNA (dsRNA) molecules into inosine in a process known as A-to-I RNA editing. ADAR1 regulates gene expression output by interacting with RNA and other proteins; plays important roles in development, including growth; and is linked to innate immunity, tumors, and central nervous system (CNS) diseases.

RESULTS: In recent years, the role of ADAR1 in tumors has been widely discussed, but its role in CNS diseases has not been reviewed. It is worth noting that recent studies have shown ADAR1 has great potential in the treatment of neurodegenerative diseases, but the mechanisms are still unclear. Therefore, it is necessary to elaborate on the role of ADAR1 in CNS diseases.

CONCLUSIONS: Here, we focus on the effects and mechanisms of ADAR1 on CNS diseases such as Aicardi-AicardiGoutières syndrome, Alzheimer's disease, Parkinson's disease, glioblastoma, epilepsy, amyotrophic lateral sclerosis, and autism. We also evaluate the impact of ADAR1-based treatment strategies on these diseases, with a particular focus on the development and treatment strategies of new technologies such as microRNAs, nanotechnology, gene editing, and stem cell therapy. We hope to provide new directions and insights for the future development of ADAR1 gene editing technology in brain science and the treatment of CNS diseases.}, } @article {pmid39755715, year = {2025}, author = {Liu, Q and Sun, Y and He, B and Chen, H and Wang, L and Wang, G and Zhang, K and Zhao, X and Zhang, X and Shen, D and Zhang, X and Cui, L}, title = {Gain-of-function ANXA11 mutation cause late-onset ALS with aberrant protein aggregation, neuroinflammation and autophagy impairment.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {2}, pmid = {39755715}, issn = {2051-5960}, support = {2021-I2M-1-034//the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences/ ; 2021-I2M-1-034//the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences/ ; 2022YFC2703904//National Key Research and Development Program/ ; 2022YFC2703900//National Key Research and Development Program/ ; 2022-PUMCH-B-017//National High Level Hospital Clinical Research Funding/ ; 81971293//National Natural Science Foundation of China/ ; 82201562//National Natural Science Foundation of China/ ; XDB39040000//Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; }, mesh = {Animals ; *Autophagy/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mice ; Humans ; Male ; *Gain of Function Mutation ; Neuroinflammatory Diseases/pathology/genetics/metabolism ; Female ; Annexins/genetics/metabolism ; Mice, Transgenic ; Protein Aggregation, Pathological/genetics/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Middle Aged ; Age of Onset ; Protein Aggregates ; RNA-Binding Proteins/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {Mutations in the ANXA11 gene, encoding an RNA-binding protein, have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but the underlying in vivo mechanisms remain unclear. This study examines the clinical features of ALS patients harboring the ANXA11 hotspot mutation p.P36R, characterized by late-onset motor neuron disease and occasional multi-system involvement. To elucidate the pathogenesis, we developed a knock-in mouse model carrying the p.P36R mutation. In both heterozygous and homozygous mutant mice, ANXA11 protein levels were comparable to those in wild-type. Both groups exhibited late-onset motor dysfunction at approximately 10 months of age, with similar survival rates to wild-type (> 24 months) and no signs of dementia. Pathological analysis revealed early abnormal aggregates in spinal cord motor neurons, cortical neurons, and muscle cells of homozygous mice. From 2 months of age, we observed mislocalized ANXA11 aggregates, SQSTM1/p62-positive inclusions, and cytoplasmic TDP-43 mislocalization, which intensified with disease progression. Importantly, mutant ANXA11 co-aggregated with TDP-43 and SQSTM1/p62-positive inclusions. Electron microscopy of the gastrocnemius muscle uncovered myofibrillar abnormalities, including sarcomeric disorganization, Z-disc dissolution, and subsarcolemmal electron-dense structures within autophagic vacuoles. Autophagic flux, initially intact at 2 months, was impaired by 9 months, as evidenced by decreased Beclin-1 and LC3BII/I levels and increased SQSTM1/p62 expression, coinciding with mTORC1 hyperactivation. Significant motor neuron loss and neuroinflammation were detected by 9 months, with marked muscle dystrophy apparent by 12 months compared to wild-type controls. These findings implicate the gain-of-function ANXA11 mutation drives late-onset motor neuron disease by early presymptomatic proteinopathy, progressive neuronal degeneration, neuroinflammation, and autophagic dysfunction.}, } @article {pmid39756021, year = {2025}, author = {Akaree, N and Secco, V and Levy-Adam, F and Younis, A and Carra, S and Shalgi, R}, title = {Regulation of physiological and pathological condensates by molecular chaperones.}, journal = {The FEBS journal}, volume = {292}, number = {13}, pages = {3271-3297}, pmid = {39756021}, issn = {1742-4658}, support = {//AriSLA/ ; //Giovanni Armenise Harvard Foundation/ ; HT94252310319//Congressionally Directed Medical Research Programs/ ; AHA-MCA 2022//AriAlzh/ ; //Rappaport Family Institute for Research in Medical Sciences/ ; //Prince Center for Neurodegenerative Disorders of the Brain/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Stress Granules/metabolism/pathology/genetics ; *Molecular Chaperones/metabolism/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; RNA-Binding Protein FUS/genetics/metabolism ; Animals ; *Biomolecular Condensates/metabolism/genetics ; DNA-Binding Proteins/genetics/metabolism ; *Protein Aggregation, Pathological/genetics/metabolism/pathology ; Heterogeneous Nuclear Ribonucleoprotein A1/genetics/metabolism ; }, abstract = {Biomolecular condensates are dynamic membraneless compartments that regulate a myriad of cellular functions. A particular type of physiological condensate called stress granules (SGs) has gained increasing interest due to its role in the cellular stress response and various diseases. SGs, composed of several hundred RNA-binding proteins, form transiently in response to stress to protect mRNAs from translation and disassemble when the stress subsides. Interestingly, SGs contain several aggregation-prone proteins, such as TDP-43, FUS, hnRNPA1, and others, which are typically found in pathological inclusions seen in autopsy tissues from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. Moreover, mutations in these genes lead to the familial form of ALS and FTD. This has led researchers to propose that pathological aggregation is seeded by aberrant SGs: SGs that fail to properly disassemble, lose their dynamic properties, and become pathological condensates which finally 'mature' into aggregates. Here, we discuss the evidence supporting this model for various ALS/FTD-associated proteins. We further continue to focus on molecular chaperone-mediated regulation of ALS/FTD-associated physiological condensates on one hand, and pathological condensates on the other. In addition to SGs, we review ALS/FTD-relevant nuclear condensates, namely paraspeckles, anisosomes, and nucleolar amyloid bodies, and discuss their emerging regulation by chaperones. As the majority of chaperoning mechanisms regulate physiological condensate disassembly, we highlight parallel themes of physiological and pathological condensation regulation across different chaperone families, underscoring the potential for early disease intervention.}, } @article {pmid39756374, year = {2025}, author = {Loap, P and Loap, P and Kirova, Y}, title = {Initial Characterization and Outcome Assessment of Anal Lymphomas in a Large-Size Contemporary Cohort: A Population-Based SEER Database Study (2000-2022).}, journal = {Acta haematologica}, volume = {148}, number = {6}, pages = {610-617}, doi = {10.1159/000541595}, pmid = {39756374}, issn = {1421-9662}, mesh = {Humans ; Male ; Female ; SEER Program ; Middle Aged ; *Anus Neoplasms/therapy/epidemiology/mortality/diagnosis ; Aged ; Retrospective Studies ; Adult ; Aged, 80 and over ; *Lymphoma/therapy/epidemiology/mortality/diagnosis ; Young Adult ; Survival Rate ; United States/epidemiology ; }, abstract = {INTRODUCTION: Anal lymphoma (AL) is a rare presentation of extranodal lymphomas, characterized by occurrence in the anal area and largely understudied due to its infrequency. This study aimed to address gaps in knowledge about AL's demographic and clinical profiles, treatments, and survival outcomes, leveraging data from the SEER program.

METHODS: We conducted a retrospective analysis of 79 AL cases identified in the SEER database from 2000 to 2022; 36 stage I AL cases were identified and defined as localized primary anal lymphoma (L-PAL). Data on demographics, tumor specifics, treatment modalities, and survival were analyzed using the Kaplan-Meier method and Cox proportional hazards models.

RESULTS: The majority of AL cases were diffuse large B-cell lymphoma (70.9%). Other notable subtypes included anaplastic T-cell lymphoma, marginal zone lymphoma, B-cell non-Hodgkin lymphoma, Burkitt lymphoma/leukemia (each accounting for 6.3%), followed by follicular lymphoma and mantle-cell lymphoma (each at 1.3%). AL primarily affected younger males (median age 50), with a significant majority being Caucasian. Initial stages (I and II) were more commonly observed, and treatments varied, with chemotherapy being most prevalent (67.1%), followed by radiation (30.4%) and surgery (30.4%). The 5- and 10-year overall survival (OS) rates were 59.4% and 44.1%, respectively, while the corresponding cancer-specific survival (CSS) rates were 67.9% and 58.0%, respectively. Age was a significant prognostic factor for OS but not for CSS. Radiotherapy tended to improve CSS in the AL population.

CONCLUSION: This research corresponds to the first in-depth analysis of AL, highlighting its distinct demographic patterns, clinical features, and responses to various treatments, distinguishing it from other types of anal cancers. Our results underscore the importance of developing specialized diagnostic and treatment strategies. To enhance our understanding and management of this uncommon form of lymphoma, future studies should aim for broader and more collaborative international research efforts.}, } @article {pmid39759457, year = {2024}, author = {Ahmad, SR and Zeyaullah, M and Khan, MS and AlShahrani, AM and Altijani, AAG and Ali, H and Dawria, A and Mohieldin, A and Alam, MS and Mohamed, AOA}, title = {Pharmacogenomics for neurodegenerative disorders - a focused review.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1478964}, pmid = {39759457}, issn = {1663-9812}, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by the progressive degeneration of neuronal structure and function, leading to severe cognitive and motor impairments. These conditions present significant challenges to healthcare systems, and traditional treatments often fail to account for genetic variability among patients, resulting in inconsistent therapeutic outcomes. Pharmacogenomics aims to tailor medical treatments based on an individual's genetic profile, thereby improving therapeutic efficacy and reducing adverse effects. This focused review explores the genetic factors influencing drug responses in neurodegenerative diseases and the potential of pharmacogenomics to revolutionize their treatment. Key genetic markers, such as the APOE ε4 allele in AD and the CYP2D6 polymorphisms in PD, are highlighted for their roles in modulating drug efficacy. Additionally, advancements in pharmacogenomic tools, including genome-wide association studies (GWAS), next-generation sequencing (NGS), and CRISPR-Cas9, are discussed for their contributions to personalized medicine. The application of pharmacogenomics in clinical practice and its prospects, including ethical and data integration challenges, are also examined.}, } @article {pmid39759580, year = {2025}, author = {Chourpiliadis, C and Lovik, A and Seitz, C and Hu, Y and Wu, J and Ljungman, P and Press, R and Samuelsson, K and Ingre, C and Fang, F}, title = {Association between cardiometabolic diseases and the risk and progression of motor neuron diseases in Sweden: a population-based case-control study.}, journal = {The Lancet regional health. Europe}, volume = {49}, number = {}, pages = {101173}, pmid = {39759580}, issn = {2666-7762}, support = {R01 TS000324/TS/ATSDR CDC HHS/United States ; }, abstract = {BACKGROUND: The evidence on the link between cardiometabolic diseases (CMDs) and motor neuron diseases (MNDs) remains inconsistent. We aimed to determine whether there is an association of CMDs, namely, any cardiovascular disease, cardiac arrhythmia, heart failure, thromboembolic disease, hypertension, cerebrovascular disease, ischemic heart disease, diabetes mellitus type 2, and hypercholesterolemia with the risk and progression of MNDs.

METHODS: We included 1463 MND patients (amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive spinal muscular atrophy (PSMA), and unspecified MND) diagnosed from January 1, 2015, to July 1, 2023, in Sweden according to the Swedish Motor Neuron Disease Quality Registry (i.e., cases), up to 5 MND-free population controls per case (N = 7311) who were individually matched to the cases on age and sex, and the full siblings (N = 2002) and spouses (N = 1220) of MND patients (i.e., relative controls). Conditional logistic regression models were used to estimate the risk of MND diagnosis in relation to previous CMDs, through comparing MND patients to population controls or relative controls. MND patients were followed from diagnosis to assess the role of pre-diagnostic CMDs on disease progression. A joint longitudinal-survival model was used to estimate risk of mortality (or use of invasive ventilation) in relation to CMDs after taking into account the longitudinal changes of ALS functional rating scale-revised (ALSFRS-R) in the time-to-event analysis. Hierarchical clustering with the Ward's linkage and a dissimilarity matrix created by Gower's method was used to identify clusters of MND patients with distinct phenotypes.

FINDINGS: Among the CMDs studied, a history of diabetes mellitus type 2 (OR 0.75; 95% CI 0.62, 0.93) or hypercholesterolemia (OR 0.82; 95% CI 0.71, 0.94) more than one year before diagnosis was associated with a lower risk for MNDs. The associations persisted for more than five years before MND diagnosis. MND patients with a history of any cardiovascular disease (HR 1.43; 95% CI 1.13, 1.81), arrhythmia (HR 1.42; 95% CI 1.04, 1.93), heart failure (HR 1.79; 95% CI 1.02, 3.14), hypertension (HR 1.41; 95% CI 1.12, 1.77), or hypercholesterolemia (HR 1.28; 95% CI 1.01, 1.62) had an increased mortality risk, compared to others, after taking into consideration the longitudinal changes in ALSFRS-R. Cluster analysis identified two clusters of MND patients, where one cluster demonstrated higher age, worse functional status, and higher prevalence of CMDs at the time of diagnosis as well as a higher mortality and faster functional decline during follow-up, compared to the ones included in the other cluster.

INTERPRETATION: Diabetes mellitus type 2 and hypercholesterolemia were associated with a lower future risk of MND. On the other hand, most of the CMDs were indicative of a poor disease progression after an MND diagnosis.

FUNDING: European Research Council, US Center for Disease Control and Prevention, Swedish Research Council.}, } @article {pmid39761853, year = {2025}, author = {Weeks, AT and Bird, AJ}, title = {Regulation of sod1 mRNA and protein abundance by zinc in fission yeast is dependent on the CCR4-NOT complex.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {2}, pages = {108156}, pmid = {39761853}, issn = {1083-351X}, support = {R01 GM105695/GM/NIGMS NIH HHS/United States ; }, mesh = {*Schizosaccharomyces/genetics/metabolism/enzymology ; *Schizosaccharomyces pombe Proteins/metabolism/genetics ; *Zinc/metabolism/pharmacology ; *RNA, Messenger/genetics/metabolism/biosynthesis ; Superoxide Dismutase-1 ; *Gene Expression Regulation, Fungal/drug effects ; *Superoxide Dismutase/genetics/metabolism/biosynthesis ; *Ribonucleases/metabolism/genetics ; }, abstract = {Zinc is an essential micronutrient that serves as a cofactor in a wide variety of enzymes, including Cu-Zn Superoxide Dismutase 1 (Sod1). We have discovered in Schizosaccharomyces pombe that Sod1 mRNA and protein levels are regulated in response to cellular zinc availability. We demonstrate that lower levels of sod1 mRNA and protein accumulate under low zinc conditions and that this regulation does not require the sod1 promoter or known factors that regulate the transcription of sod1 in response to zinc and other environmental stresses. Further analyses using yeast deletion strains and an inactive allele of Caf1 revealed that the reduced accumulation of sod1 mRNA and protein under low zinc conditions depends on the Caf1 and Ccr4 deadenylases of the CCR4-NOT complex. We also found that Caf1 and Ccr4 are both required for growth under zinc-limiting conditions. To gain additional mechanistic insight we used immunoblot analysis to map the regions required for the regulation of the Sod1 protein by zinc. We found that the sod1 ORF and 3'UTR are both necessary and sufficient for the zinc-dependent changes in Sod1 protein abundance. Our studies reveal a novel mechanism of altering mRNA and protein abundance in response to zinc status, which depends on the CCR4-NOT complex.}, } @article {pmid39762711, year = {2025}, author = {Apostolo, D and Ferreira, LL and D'Onghia, D and Vincenzi, F and Vercellino, N and Perazzi, M and Pirisi, M and Cantello, R and Minisini, R and Mazzini, L and Bellan, M and De Marchi, F}, title = {Lower Circulating Gas6 Levels Are Associated with Bulbar Phenotype and Faster Disease Progression in Amyotrophic Lateral Sclerosis Patients.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {6273-6282}, pmid = {39762711}, issn = {1559-1182}, support = {2021-1541//Fondazione Cariplo/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/pathology ; *Disease Progression ; Male ; Female ; Middle Aged ; Phenotype ; *Intercellular Signaling Peptides and Proteins/blood ; Aged ; Biomarkers/blood ; Prospective Studies ; Growth Arrest-Specific Protein 6 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily affects the motor neurons in the brain and spinal cord. While the exact cause of ALS is not fully understood, a combination of genetic and environmental factors is believed to contribute to its development. Growth arrest-specific 6 (Gas6), a vitamin K-dependent protein, has been recognized to enhance oligodendrocytes and neurons' survival and is associated with different kinds of (neuro)inflammatory conditions. Therefore, we aimed to determine a possible implication of Gas6 in ALS phenotype and progression by evaluating the value of circulating Gas6 and its soluble receptors (sAxl, sMer, sTyro-3) in ALS patients. We conducted a prospective observational study including 65 ALS patients and measured the circulating serum levels of Gas6, sAxl, sMer, soluble Tyro-3 (sTyro-3), and neurofilaments (NfLs). In our ALS cohort, lower serum levels of Gas6 and concomitantly higher levels of NfLs were associated with a more aggressive disease, expressed with bulbar phenotype (p-value for Gas6 = 0.03) and faster progression (p-value for Gas6 = 0.03). Also, serum Gas6 was able to distinguish (area under the curve, cut-off 13.70 ng/mL, sensitivity 69.57%, specificity 72.72%) between fast and slow progressors. Due to its neuroprotective properties, our data suggest that Gas6 could be an intriguing biomarker in ALS patients.}, } @article {pmid39762986, year = {2025}, author = {Berlowitz, DJ and Rowe, D and Howard, ME and Piper, A and Graco, M and Braat, S and Singh, B and Souza, TV and Lannin, N and McLean, A and Sawyer, A and Carey, KA and Ahamed, Y and , }, title = {Polysomnographic titration of non-invasive ventilation in motor neurone disease (3TLA): study protocol for a randomised controlled trial.}, journal = {Trials}, volume = {26}, number = {1}, pages = {10}, pmid = {39762986}, issn = {1745-6215}, mesh = {Humans ; *Noninvasive Ventilation/methods/adverse effects/instrumentation ; *Motor Neuron Disease/therapy/physiopathology ; *Polysomnography ; *Randomized Controlled Trials as Topic ; Treatment Outcome ; Australia ; Multicenter Studies as Topic ; Time Factors ; Sleep ; Respiratory Insufficiency/therapy/physiopathology ; Quality of Life ; }, abstract = {BACKGROUND: Non-invasive ventilation (NIV) uses positive pressure to assist people with respiratory muscle weakness or severe respiratory compromise to breathe. Most people use this treatment during sleep when breathing is most susceptible to instability. The benefits of using NIV in motor neurone disease (MND) are well-established. However, uptake and usage are low (~ 19%) and there is no consensus on how to best implement NIV in MND in Australia. Consequently, clinical practice models are highly variable. Our team has recently provided evidence that specific and individualised NIV titration using a sleep study (polysomnography; PSG) leads to better outcomes in people with MND. However, for this clinical practice model to result in sustained benefits, evidence of effectiveness across multiple sites, as well as culture and practice change, must occur.

METHODS: A two-arm, assessor-blinded, individual participant randomised controlled trial in MND care centres across Australia will be undertaken. Two-hundred and forty-four participants will be randomised (1:1) to either the intervention group (PSG-assisted commencement of NIV settings; PSG) or a control group (sham PSG). Participants will be asked to use their NIV device for 7 weeks and will then return for follow-up assessments. Respiratory, sleep and patient-reported outcome measures will be collected at baseline and follow-up. The primary aim is to determine if the proportion of participants using NIV for > 4 h/day during the intervention period is higher in the PSG than the control group. A process evaluation, health economic evaluation and 12-month cohort follow-up will be undertaken and reported separately.

DISCUSSION: The results of this trial will demonstrate the effects of PSG-assisted titration of NIV on usage of NIV in people with MND. We hypothesise that the PSG intervention will improve synchrony between the user and the machine, which will lead to greater NIV usage compared to the control group.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05136222. Registered on November 25, 2021.}, } @article {pmid39763885, year = {2024}, author = {Shelest, O and Tindel, I and Lauzon, M and Dawson, A and Ho, R}, title = {Delineating sex-dependent and anatomic decline of motor functions in the SOD1G93A mouse model of amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763885}, issn = {2692-8205}, support = {R00 AG056678/AG/NIA NIH HHS/United States ; }, abstract = {The transgenic SOD1G93A mouse model is the most widely used animal model of amyotrophic lateral sclerosis (ALS), a fatal disease of motor neuron degeneration. While genetic background influences onset and progression variability of motor dysfunction, the C57BL/6 background most reliably exhibits robust ALS phenotypes; thus, it is the most widely used strain in mechanistic studies. In this model, paresis begins in the hindlimbs and spreads rostrally to the forelimbs. Males experience earlier onset, greater disease severity, and shorter survival than females. However, the influence of sex on patterns of declining motor function between forelimbs and hindlimbs as well as among distinct, spinal-innervated muscle groups within each limb are not fully understood. To provide a higher resolution framework of degenerating motor function across the body, we conducted more comprehensive, limb-dependent and independent measures of motor decline over the course of disease. Subsequently, we compared the timing and intensity of these features across sex, and we consider to what extent these patterns are conserved in clinical observations from human ALS patients. We found male mice experienced earlier and less localized onset than females. We also report distinct motor features decline at different rates between sexes. Finally, mice showed differences in correlation between the decline of left- and right-side measures of the hindlimb. Consequently, our findings reinforce and refine the utility of the SOD1 mouse in modeling more highly resolved, sex-specific differences in ALS patient motor behavior. This may better guide preclinical studies in stratifying patients by sex and anatomical site of onset.}, } @article {pmid39764140, year = {2024}, author = {Akif, A and My Nguyen, TT and Liu, L and Xu, X and Kulkarni, A and Jiang, J and Zhang, Y and Hao, J}, title = {Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39764140}, issn = {2693-5015}, support = {R01 NS105787/NS/NINDS NIH HHS/United States ; R21 NS133895/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD.

METHODS: In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50[th] day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-4 (IL-4) in the blood were measured using ELISA.

RESULTS: AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-α and IL-1β levels, while increasing the anti-inflammatory IL-4 level in the blood.

CONCLUSIONS: The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.}, } @article {pmid39765493, year = {2024}, author = {Zhang, T and Xu, Q and Zhou, B and Xiao, J and Zheng, S and Li, J and Lv, Q and Zhang, Y and Wang, R and Su, R and Wang, Z}, title = {Development and Validation of a 5K Liquid Chip for Identifying Cashmere Goat Populations in Inner Mongolia Autonomous Region.}, journal = {Animals : an open access journal from MDPI}, volume = {14}, number = {24}, pages = {}, pmid = {39765493}, issn = {2076-2615}, support = {2022YFE0113300，2022YFD1300201,2022YFD1300204//National Key Research and Development Program/ ; BR220112//Project for Enhancing Young Teacher's Research Ability/ ; NJYT22038//Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region/ ; 2023ZD0405102//Project for 2030 Science and Technology Innovation Major/ ; NMGIRT2322//Program for Inner Mongolia Autonomous Region Higher Education Innovation Team Development/ ; }, abstract = {(1) Background: Cashmere goats, as one of the characteristic species, are rich in genetic resources. Protecting and rationally utilizing these genetic resources is of great significance for the genetic improvement of cashmere goats. (2) Methods: In this study, tissue samples were collected from Inner Mongolia white cashmere goats, which included the Arbas type (ARBS); Erlangshan type (ELS); Alashan type (ALS), Hanshan white cashmere goats (HS), and Ujimqin white cashmere goats (WZMQ). Genomic DNA was extracted and subjected to high-depth genome resequencing. GenoBait technology was used for probe design and site optimization, followed by the synthesis of a low-density liquid phase chip. Finally, a total of 281 individuals from five cashmere goat populations in the Inner Mongolia Autonomous Region were randomly selected to verify the chip. (3) Results: The results showed that a total of 5002 SNP sites were finally screened and retained for the synthesis of the low-density liquid chip for identifying cashmere goats in Inner Mongolia Autonomous Region. Principal component analysis and phylogenetic tree construction indicated that the ARBS, ELS, and ALS populations were clustered into one category. (4) Conclusions: This chip can accurately identify the three breeds: Inner Mongolia white cashmere goats, Hanshan white cashmere goats, and Ujimqin white cashmere goats.}, } @article {pmid39766276, year = {2024}, author = {Wysoczański, B and Świątek, M and Wójcik-Gładysz, A}, title = {Organ-on-a-Chip Models-New Possibilities in Experimental Science and Disease Modeling.}, journal = {Biomolecules}, volume = {14}, number = {12}, pages = {}, pmid = {39766276}, issn = {2218-273X}, mesh = {*Lab-On-A-Chip Devices ; Humans ; Animals ; Models, Biological ; Liver/metabolism/cytology ; Cell Culture Techniques/methods ; Microphysiological Systems ; }, abstract = {'Organ-on-a-chip' technology is a promising and rapidly evolving model in biological research. This innovative microfluidic cell culture device was created using a microchip with continuously perfused chambers, populated by living cells arranged to replicate physiological processes at the tissue and organ levels. By consolidating multicellular structures, tissue-tissue interfaces, and physicochemical microenvironments, these microchips can replicate key organ functions. They also enable the high-resolution, real-time imaging and analysis of the biochemical, genetic, and metabolic activities of living cells in the functional tissue and organ contexts. This technology can accelerate research into tissue development, organ physiology and disease etiology, therapeutic approaches, and drug testing. It enables the replication of entire organ functions (e.g., liver-on-a-chip, hypothalamus-pituitary-on-a-chip) or the creation of disease models (e.g., amyotrophic lateral sclerosis-on-a-chip, Parkinson's disease-on-a-chip) using specialized microchips and combining them into an integrated functional system. This technology allows for a significant reduction in the number of animals used in experiments, high reproducibility of results, and the possibility of simultaneous use of multiple cell types in a single model. However, its application requires specialized equipment, advanced expertise, and currently incurs high costs. Additionally, achieving the level of standardization needed for commercialization remains a challenge at this stage of development.}, } @article {pmid39766450, year = {2024}, author = {Donaghy, R and Pioro, EP}, title = {Neurophysiologic Innovations in ALS: Enhancing Diagnosis, Monitoring, and Treatment Evaluation.}, journal = {Brain sciences}, volume = {14}, number = {12}, pages = {}, pmid = {39766450}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease of both upper motor neurons (UMNs) and lower motor neurons (LMNs) leading invariably to decline in motor function. The clinical exam is foundational to the diagnosis of the disease, and ordinal severity scales are used to track its progression. However, the lack of objective biomarkers of disease classification and progression delay clinical trial enrollment, muddle inclusion criteria, and limit accurate assessment of drug efficacy. Ultimately, biomarker evidence of therapeutic target engagement will support, and perhaps supplant, more traditional clinical trial outcome measures. Electrophysiology tools including nerve conduction study and electromyography (EMG) have already been established as diagnostic biomarkers of LMN degeneration in ALS. Additional understanding of the motor manifestations of disease is provided by motor unit number estimation, electrical impedance myography, and single-fiber EMG techniques. Dysfunction of UMN and non-motor brain areas is being increasingly assessed with transcranial magnetic stimulation, high-density electroencephalography, and magnetoencephalography; less common autonomic and sensory nervous system dysfunction in ALS can also be characterized. Although most of these techniques are used to explore the underlying disease mechanisms of ALS in research settings, they have the potential on a broader scale to noninvasively identify disease subtypes, predict progression rates, and assess physiologic engagement of experimental therapies.}, } @article {pmid39766833, year = {2024}, author = {Bisogni, G and Conte, A and Costantino, U and Lattante, S and Bernardo, D and Lucioli, G and Patanella, AK and Cimbolli, P and Del Giudice, E and Vettor, F and Marangi, G and Doronzio, PN and Zollino, M and Sabatelli, M}, title = {Exploring the Role of CCNF Variants in Italian ALS Patients.}, journal = {Genes}, volume = {15}, number = {12}, pages = {}, pmid = {39766833}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Italy ; Middle Aged ; Aged ; Mutation, Missense ; Cyclins/genetics ; Frontotemporal Dementia/genetics/pathology ; Genetic Association Studies ; High-Throughput Nucleotide Sequencing ; Phenotype ; Adult ; Genetic Predisposition to Disease ; }, abstract = {Objectives: Variants in Cyclin F (CCNF) have been associated to amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) in a group of cases. The objectives of this study were to determine the contribution of CCNF in a large cohort of Italian ALS patients, to look for genotype-phenotype correlation of the mutations and to evaluate the CCNF-associated clinical features. Methods: We applied next-generation sequencing technologies on 971 unrelated Italian ALS patients and we filtered results to look for variants in CCNF gene. Results: We identified 13 rare missense variants in 16 index cases (2 familial and 14 sporadic), with a cumulative mutational frequency of 1.6%. The most prevalent variant was p.Phe197Leu, found in three patients. The clinical presentation was heterogeneous, with a classic phenotype in eight patients, upper motor neuron dominant (UMN-D) phenotype in four patients, and flail arm in four patients. Clinical evaluation for cognitive impairment was performed in 13 patients using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) test, demonstrating that almost half of the patients (n = 6) had variable degrees of frontal dysfunction. Discussion: In our cohort, we observed CCNF variants in 1.6% of patients (16/971), a percentage similar to that found in other series. Clinical presentation is heterogeneous, but CCNF variants are significantly associated to cognitive impairment. Conclusions: Our study expands the CCNF genetic variant spectrum in a large cohort of Italian ALS patients. Further studies are needed to assess genotype-phenotype associations of CCNF variants and to specify the role of each variant, which are quite common, especially in sALS patients.}, } @article {pmid39767639, year = {2024}, author = {Wan, M and Zhang, L and Huo, J and Fu, Y and Huang, T and Fan, D}, title = {Genetic Variation in Targets of Antidiabetic Drugs and Amyotrophic Lateral Sclerosis Risk.}, journal = {Biomedicines}, volume = {12}, number = {12}, pages = {}, pmid = {39767639}, issn = {2227-9059}, support = {82101490, and 82071426//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Previous studies have suggested that antidiabetic drug use may be associated with amyotrophic lateral sclerosis. However, these studies are limited by many confounding and reverse causality biases. We aimed to determine whether antidiabetic drug use has causal effects on ALS.

METHODS: Drug-target Mendelian randomization analysis was conducted to evaluate the association between genetic variation in the targets of antidiabetic drugs and ALS risk. The antidiabetic drugs included sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin/insulin analogues, metformin, and SGLT2 inhibitors. Summary statistics for ALS were retrieved from previous genome-wide association studies comprising 27,205 ALS patients and 55,058 controls. The instrumental variables for these drugs are from previous published articles.

RESULTS: Genetic variation in SGLT2 inhibition targets was associated with lower risk of ALS (odds ratio [OR] = 0.32, 95% CI = 0.14-0.74; p = 0.008). We did not find that genetic variation in metformin targets was associated with ALS (OR = 1.61, 95% CI = 0.94-2.73; p = 0.081). Nevertheless, mitochondrial complex I, a target of metformin, was associated with a higher risk of ALS (OR = 1.83, 95% CI = 1.01-3.32; p = 0.047). The analysis showed that genetic variation in sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin or insulin analogues targets was not associated with ALS (all p > 0.05).

CONCLUSIONS: The complex interaction between hypoglycemic, antioxidation, and anti-inflammatory effects may account for the different results across antidiabetic drug types. These findings provide key evidence to guide the use of antidiabetic drugs and will help to identify novel therapeutic targets in ALS.}, } @article {pmid39768167, year = {2024}, author = {Chen, X and Lv, S and Liu, J and Guan, Y and Xu, C and Ma, X and Li, M and Bai, X and Liu, K and Zhang, H and Yan, Q and Zhou, F and Chen, Y}, title = {Exploring the Role of Axons in ALS from Multiple Perspectives.}, journal = {Cells}, volume = {13}, number = {24}, pages = {}, pmid = {39768167}, issn = {2073-4409}, support = {82271483//The National Natural Science Foundation of China/ ; ZR2024MH112; ZR2024QH628//Shandong Province Natural Science Foundation of China/ ; 2023YX036; 2022YX043//Weifang Science and Technology Development Plan Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Axons/pathology/metabolism ; Animals ; Axonal Transport ; Motor Neurons/pathology ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS), commonly known as motor neuron disease, is a neurodegenerative disorder characterized by the progressive degeneration of both upper and lower motor neurons. This pathological process results in muscle weakness and can culminate in paralysis. To date, the precise etiology of ALS remains unclear. However, a burgeoning body of research indicates that axonal dysfunction is a pivotal element in the pathogenesis of ALS and significantly influences the progression of disease. Dysfunction of axons in ALS can result in impediments to nerve impulse transmission, leading to motor impairment, muscle atrophy, and other associated complications that severely compromise patients' quality of life and survival prognosis. In this review, we concentrate on several key areas: the ultrastructure of axons, the mechanisms of axonal degeneration in ALS, the impact of impaired axonal transport on disease progression in ALS, and the potential for axonal regeneration within the central nervous system (CNS). Our objective is to achieve a more holistic and profound understanding of the multifaceted role that axons play in ALS, thereby offering a more intricate and refined perspective on targeted axonal therapeutic interventions.}, } @article {pmid39768371, year = {2024}, author = {Orlova, A and Malygin, Y and Gofman, A and Sotulenko, S and Gandalian, V and Kartashov, I and Brylev, L and Bolevich, S and Nikolic Turnic, T and Jakovljevic, V}, title = {Survival Prognostic Factors of Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {12}, pages = {}, pmid = {39768371}, issn = {2075-1729}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis is a neurodegenerative disease with high rates of disability and mortality. Non-invasive ventilation (NIV) is an effective method of treating patients, increasing life expectancy, but currently, predictors available to determine the best outcome of therapy in this category of patients are unknown. This systematic review aimed to determine the impact of prognostic factors on benefits from NIV application compared with non-NIV tools of treatment (invasive ventilation and standard care) in case of survival of ALS patients.

METHOD: We systematically sought relevant longitudinal cohort and case-control studies published in PubMed, CINAHL/EMBASE, Cochrane library, and Scopus.

RESULTS: We included seven prospective studies, published in 2010-2020, in the analysis. According to the evidence base available to date, NIV favors survival compared to non-NIV in patients with bulbar onset ALS. We obtained conflicting data on the significance of spinal onset and bulbar function. Survival depending on patient age, and also for spinal, cervical, and flail limb phenotypes during NIV therapy has not been sufficiently studied and needs further investigation.

CONCLUSIONS: The studies analyzed in this review allow us to state with confidence that NIV is effective in bulbar onset ALS, taking into account recommendations for duration of ventilation and the use of the full range of symptomatic therapy, including mechanically assisted coughing. The effectiveness of NIV on severe bulbar symptoms requires further research.}, } @article {pmid39769187, year = {2024}, author = {O'Day, DH}, title = {The Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769187}, issn = {1422-0067}, mesh = {Animals ; Humans ; alpha-Synuclein/metabolism ; Alzheimer Disease/metabolism/pathology/drug therapy/therapy ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Calmodulin/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; Parkinson Disease/metabolism/pathology/therapy ; Protein Glutamine gamma Glutamyltransferase 2 ; RNA-Binding Protein FUS/metabolism/genetics ; tau Proteins/metabolism ; Transglutaminases/metabolism ; Huntingtin Protein ; Superoxide Dismutase-1 ; }, abstract = {The predominant neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are rarely pure diseases but, instead, show a diversity of mixed pathologies. At some level, all of them share a combination of one or more different toxic biomarker proteins: amyloid beta (Aβ), phosphorylated Tau (pTau), alpha-synuclein (αSyn), mutant huntingtin (mHtt), fused in sarcoma, superoxide dismutase 1, and TAR DNA-binding protein 43. These toxic proteins share some common attributes, making them potentially universal and simultaneous targets for therapeutic intervention. First, they all form toxic aggregates prior to taking on their final forms as contributors to plaques, neurofibrillary tangles, Lewy bodies, and other protein deposits. Second, the primary enzyme that directs their aggregation is transglutaminase 2 (TGM2), a brain-localized enzyme involved in neurodegeneration. Third, TGM2 binds to calmodulin, a regulatory event that can increase the activity of this enzyme threefold. Fourth, the most common mixed pathology toxic biomarkers (Aβ, pTau, αSyn, nHtt) also bind calmodulin, which can affect their ability to aggregate. This review examines the potential therapeutic routes opened up by this knowledge. The end goal reveals multiple opportunities that are immediately available for universal therapeutic treatment of the most devastating neurodegenerative diseases facing humankind.}, } @article {pmid39769209, year = {2024}, author = {Xing, C and Chen, H and Bi, W and Lei, T and Hang, Z and Du, H}, title = {Targeting 5-HT Is a Potential Therapeutic Strategy for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769209}, issn = {1422-0067}, support = {32300682//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Serotonin/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; Alzheimer Disease/metabolism/drug therapy ; Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Parkinson Disease/metabolism/drug therapy ; Receptors, Serotonin/metabolism ; }, abstract = {There is increasing interest in the potential therapeutic role of 5-HT (serotonin) in the treatment of neurodegenerative diseases, which are characterized by the progressive degeneration and death of nerve cells. 5-HT is a vital neurotransmitter that plays a central role in regulating mood, cognition, and various physiological processes in the body. Disruptions in the 5-HT system have been linked to several neurological and psychiatric disorders, making it an attractive target for therapeutic intervention. Although the exact causes of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are not fully understood, researchers believe that regulating the 5-HT system could help alleviate symptoms and potentially slow the progression of these diseases. Here, we delve into the potential of harnessing 5-HT as a therapeutic target for the treatment of neurodegenerative diseases. It is important to note that the current clinical drugs targeting 5-HT are still limited in the treatment of these complex diseases. Therefore, further research and clinical trials are needed to evaluate the feasibility and effectiveness of its clinical application.}, } @article {pmid39769213, year = {2024}, author = {Gu, A and Zhang, Y and He, J and Zhao, M and Ding, L and Liu, W and Xiao, J and Huang, J and Liu, M and Liu, X}, title = {Chronic Oxidative Stress and Stress Granule Formation in UBQLN2 ALS Neurons: Insights into Neuronal Degeneration and Potential Therapeutic Targets.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769213}, issn = {1422-0067}, support = {2016YFC0905100//National Key Research and Development Program of China/ ; 2021JJ30801//Natural Science Foundation of Hunan Province, China/ ; kq2202077//Natural Science Foundation of Changsha, China/ ; 1053320222758//Fundamental Research Funds for the Central Universities of Central South University/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Autophagy-Related Proteins/metabolism/genetics ; *Oxidative Stress ; *Motor Neurons/metabolism/pathology ; Adaptor Proteins, Signal Transducing/metabolism/genetics ; Stress Granules/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Autophagy ; Cell Cycle Proteins/metabolism/genetics ; Nerve Degeneration/pathology/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Sodium Compounds/pharmacology ; }, abstract = {The pathogenesis of neurodegenerative diseases results from the interplay between genetic and environmental factors. Aging and chronic oxidative stress are critical contributors to neurodegeneration. UBQLN2, a ubiquitin-related protein, aids in protein degradation and protects against oxidative stress. In ALS neurons harboring UBQLN2 mutations, oxidative stress accelerates pathological changes, yet the precise mechanisms remain unclear. Using induced motor neurons (iMNs) derived from UBQLN2 P497H iPSCs, we observed ALS-like phenotypes, including TDP-43 mislocalization, increased cell death, and reduced viability. Sodium arsenite (SA)-induced oxidative stress triggered stress granule formation, while autophagy dysfunction exacerbated neuronal degeneration. CHX and bosutinib treatments reduced ubiquitinated protein accumulation and alleviated degeneration, highlighting potential therapeutic pathways. These findings emphasize the role of chronic oxidative stress and stress granule formation in UBQLN2 ALS, offering insights into novel therapeutic targets.}, } @article {pmid39769215, year = {2024}, author = {Wei, Z and Iyer, MR and Zhao, B and Deng, J and Mitchell, CS}, title = {Artificial Intelligence-Assisted Comparative Analysis of the Overlapping Molecular Pathophysiology of Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769215}, issn = {1422-0067}, support = {R56 AG056169/AG/NIA NIH HHS/United States ; R01 AG056169/AG/NIA NIH HHS/United States ; R35GM152245/NH/NIH HHS/United States ; U19-AG056169/NH/NIH HHS/United States ; 1944247//National Science Foundation/ ; 253558//Chan Zuckerberg Initiative/ ; R35 GM152245/GM/NIGMS NIH HHS/United States ; U19 AG065169/AG/NIA NIH HHS/United States ; R01 AG070937/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology ; *Alzheimer Disease/metabolism/genetics/physiopathology/pathology ; *Artificial Intelligence ; Algorithms ; }, abstract = {The overlapping molecular pathophysiology of Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD) was analyzed using relationships from a knowledge graph of 33+ million biomedical journal articles. The unsupervised learning rank aggregation algorithm from SemNet 2.0 compared the most important amino acid, peptide, and protein (AAPP) nodes connected to AD, ALS, or FTD. FTD shared 99.9% of its nodes with ALS and AD; AD shared 64.2% of its nodes with FTD and ALS; and ALS shared 68.3% of its nodes with AD and FTD. The results were validated and mapped to functional biological processes using supervised human supervision and an external large language model. The overall percentages of mapped intersecting biological processes were as follows: inflammation and immune response, 19%; synapse and neurotransmission, 19%; cell cycle, 15%; protein aggregation, 12%; membrane regulation, 11%; stress response and regulation, 9%; and gene regulation, 4%. Once normalized for node count, biological mappings for cell cycle regulation and stress response were more prominent in the intersection of AD and FTD. Protein aggregation, gene regulation, and energetics were more prominent in the intersection of ALS and FTD. Synapse and neurotransmission, membrane regulation, and inflammation and immune response were greater at the intersection of AD and ALS. Given the extensive molecular pathophysiology overlap, small differences in regulation, genetic, or environmental factors likely shape the underlying expressed disease phenotype. The results help prioritize testable hypotheses for future clinical or experimental research.}, } @article {pmid39770252, year = {2024}, author = {Guo, H and Yao, J and Chen, S and Qian, C and Pan, X and Yin, K and Zhu, H and Gao, X and Wang, S and Sun, L}, title = {Enhancing Resistive Switching in AlN-Based Memristors Through Oxidative Al2O3 Layer Formation: A Study on Preparation Techniques and Performance Impact.}, journal = {Micromachines}, volume = {15}, number = {12}, pages = {}, pmid = {39770252}, issn = {2072-666X}, support = {11874105//National Natural Science Foundation of China/ ; }, abstract = {Aluminum nitride (AlN) with a wide band gap (approximately 6.2 eV) has attractive characteristics, including high thermal conductivity, a high dielectric constant, and good insulating properties, which are suitable for the field of resistive random access memory. AlN thin films were deposited on ITO substrate using the radio-frequency magnetron sputtering technique. Al's and Au's top electrodes were deposited on AlN thin films to make a Au/Al/AlN/ITO sandwich structure memristor. The effects of the Al2O3 film on the on/off window and voltage characteristics of the device were investigated. The deposition time and nitrogen content in the sputtering atmosphere were changed to adjust the thickness and composition of AlN films, respectively. The possible mechanism of resistive switching was examined via analyses of the electrical resistive switching characteristics, forming voltage, and switching ratio.}, } @article {pmid39770989, year = {2024}, author = {Pekdemir, B and Raposo, A and Saraiva, A and Lima, MJ and Alsharari, ZD and BinMowyna, MN and Karav, S}, title = {Mechanisms and Potential Benefits of Neuroprotective Agents in Neurological Health.}, journal = {Nutrients}, volume = {16}, number = {24}, pages = {}, pmid = {39770989}, issn = {2072-6643}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; Brain/drug effects/metabolism ; Animals ; Flavonoids/pharmacology/therapeutic use ; Apoptosis/drug effects ; Antioxidants/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {The brain contains many interconnected and complex cellular and molecular mechanisms. Injury to the brain causes permanent dysfunctions in these mechanisms. So, it continues to be an area where surgical intervention cannot be performed except for the removal of tumors and the repair of some aneurysms. Some agents that can cross the blood-brain barrier and reach neurons show neuroprotective effects in the brain due to their anti-apoptotic, anti-inflammatory and antioxidant properties. In particular, some agents act by reducing or modulating the accumulation of protein aggregates in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and prion disease) caused by protein accumulation. Substrate accumulation causes increased oxidative stress and stimulates the brain's immune cells, microglia, and astrocytes, to secrete proinflammatory cytokines. Long-term or chronic neuroinflammatory response triggers apoptosis. Brain damage is observed with neuronal apoptosis and brain functions are impaired. This situation negatively affects processes such as motor movements, memory, perception, and learning. Neuroprotective agents prevent apoptosis by modulating molecules that play a role in apoptosis. In addition, they can improve impaired brain functions by supporting neuroplasticity and neurogenesis. Due to the important roles that these agents play in central nervous system damage or neurodegenerative diseases, it is important to elucidate many mechanisms. This review provides an overview of the mechanisms of flavonoids, which constitute a large part of the agents with neuroprotective effects, as well as vitamins, neurotransmitters, hormones, amino acids, and their derivatives. It is thought that understanding these mechanisms will enable the development of new therapeutic agents and different treatment strategies.}, } @article {pmid39771101, year = {2024}, author = {Chetverikova, D and Bakaeva, M and Starikov, S and Kendjieva, A and Chetverikov, S}, title = {The Influence of Plant Growth-Stimulating Bacteria on the Glutathione-S-Transferase Activity and the Toxic Effect of the Herbicide Metsulfuron-Methyl in Wheat and Canola Plants.}, journal = {Toxics}, volume = {12}, number = {12}, pages = {}, pmid = {39771101}, issn = {2305-6304}, support = {23-26-00097//Russian Science Foundation/ ; }, abstract = {The ability of some rhizosphere bacteria to mitigate herbicidal stress in cultivated plants may be useful in agriculture and bioremediation. There is poor understanding of how bacteria directly or through herbicide degradation affect the biochemical processes in plants exposed to sulfonylurea herbicides. In this study, treatment with a combination of herbicide metsulfuron-methyl (MSM) and bacteria (Pseudomonas protegens DA1.2 or P. chlororaphis 4CH) of wheat (Triticum aestivum L.) and canola (Brassica napus L.) plants was carried out. Activity of glutathione-S-transferase (GST), an important enzyme for the herbicide detoxification, and acetolactate synthase (ALS), a target for MSM in plants, was measured by spectrophotometric assays. MSM residues were analyzed using the HPLC-MS. Then, 24 h after bacterial treatment, GST activity increased by 75-91% in wheat and by 38-94% in canola. On the 30th day, a decrease in MSM in the soil associated with bacterial treatment was 54.6-79.7%. An increase in GST activity and acceleration of MSM degradation were accompanied by a decrease in inhibition of the ALS enzyme in plants, which indicated a mitigation of the toxic effect. The results obtained are evidence that rhizospheric bacteria can have beneficial effects on plants exposed to MSM due to the combination of abilities to directly affect detoxification enzymes in plants and degrade MSM in the soil.}, } @article {pmid39772789, year = {2025}, author = {Stolwyk, K and Lee, I}, title = {Rapid progression of amyotrophic lateral sclerosis after initiation of GLP-1 agonist: a case report.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {382-384}, pmid = {39772789}, issn = {2167-9223}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; }, } @article {pmid39774976, year = {2025}, author = {Naito, H and Nakamori, M and Toko, M and Hayashi, Y and Tazuma, T and Watanabe, T and Ishihara, K and Tachiyama, K and Yamazaki, Y and Maruyama, H}, title = {A single-center, single-arm, prospective, open-label, and comparative trial to evaluate the safety and tolerability profile of a 90-day oral L-arginine hydrochloride intervention for patients with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1120}, pmid = {39774976}, issn = {2045-2322}, support = {23K16642//Japan Society for the Promotion of Science/ ; NA//ALS Foundation, Japan ALS Association/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Administration, Oral ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Arginine/administration & dosage/adverse effects/therapeutic use ; Nutritional Status ; Prospective Studies ; Treatment Outcome ; }, abstract = {Weight loss, a key indicator of malnutrition in amyotrophic lateral sclerosis (ALS) patients, negatively impacts patient prognosis. However, effective nutritional interventions have not been adequately established. Research in ALS model mice has shown that L-arginine can prolong survival; however, no human intervention studies have been conducted. We conducted a single-center, single-arm, prospective, open-label, and comparative trial to assess the safety and tolerability of L-arginine hydrochloride in ALS patients. ALS patients were administered 15 g/day L-arginine hydrochloride for 90 days. The primary outcome of safety was evaluated on days 45 and 90. The secondary outcome of efficacy was evaluated by measuring nutritional status, ALS Functional Rating Scale (ALSFRS) scores, and the occurrence of events such as the initiation of tracheostomy positive pressure ventilation (TPPV) and death. The study included 20 patients (40% female; mean age, 62.0 ± 6.9 years; median disease duration, 1.9 years). Six participants (30%) experienced treatment-emergent adverse events (TEAEs), including elevated creatine kinase levels, liver function test abnormalities, glucose tolerance issues, hyperammonemia, anorexia, dysgeusia, and vasculitis. No serious TEAEs were associated with L-arginine hydrochloride. Over the course of three months, the average changes in body weight, body mass index, and the ALSFRS score were - 0.37 kg, -1.1 kg/m[2], and - 1.7 points, respectively. There were no events requiring TPPV initiation or deaths. This study demonstrated that the oral administration of L-arginine hydrochloride over three months was well tolerated by ALS patients, with no serious TEAEs or deaths attributed to the study drug.Trial Registration number: Japan Registry of Clinical Trials (jRCTs061230001), first registered 11/04/2023.}, } @article {pmid39775401, year = {2025}, author = {Grassi, M and Tarantino, B}, title = {SEMdag: Fast learning of Directed Acyclic Graphs via node or layer ordering.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0317283}, pmid = {39775401}, issn = {1932-6203}, mesh = {Humans ; *Algorithms ; *COVID-19 ; SARS-CoV-2 ; Breast Neoplasms ; Software ; }, abstract = {A Directed Acyclic Graph (DAG) offers an easy approach to define causal structures among gathered nodes: causal linkages are represented by arrows between the variables, leading from cause to effect. Recently, industry and academics have paid close attention to DAG structure learning from observable data, and many techniques have been put out to address the problem. We provide a two-step approach, named SEMdag(), that can be used to quickly learn high-dimensional linear SEMs. It is included in the R package SEMgraph and employs a two-stage order-based search using previous knowledge (Knowledge-based, KB) or data-driven method (Bottom-up, BU), under the premise that a linear SEM with equal variance error terms is assumed. We evaluated our framework's for finding plausible DAGs against six well-known causal discovery techniques (ARGES, GES, PC, LiNGAM, CAM, NOTEARS). We conducted a series of experiments using observed expression (or RNA-seq) data, taking into account a pair of training and testing datasets for four distinct diseases: Amyotrophic Lateral Sclerosis (ALS), Breast cancer (BRCA), Coronavirus disease (COVID-19) and ST-elevation myocardial infarction (STEMI). The results show that the SEMdag() procedure can recover a graph structure with good disease prediction performance evaluated by a conventional supervised learning algorithm (RF): in the scenario where the initial graph is sparse, the BU approach may be a better choice than the KB one; in the case where the graph is denser, both BU an KB report high performance, with highest score for KB approach based on topological layers. Besides its superior disease predictive performance compared to previous research, SEMdag() offers the user the flexibility to define distinct structure learning algorithms and can handle high dimensional issues with less computing load. SEMdag() function is implemented in the R package SEMgraph, easily available at https://CRAN.R-project.org/package=SEMgraph.}, } @article {pmid39775908, year = {2025}, author = {de Vries, E and Hagbohm, C and Ouellette, R and Granberg, T}, title = {Clinical 7 Tesla magnetic resonance imaging: Impact and patient value in neurological disorders.}, journal = {Journal of internal medicine}, volume = {297}, number = {3}, pages = {244-261}, pmid = {39775908}, issn = {1365-2796}, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Nervous System Diseases/diagnostic imaging ; Amyotrophic Lateral Sclerosis/diagnostic imaging ; }, abstract = {Magnetic resonance imaging (MRI) is a cornerstone of non-invasive diagnostics and treatment monitoring, particularly for diseases of the central nervous system. Although 1.5- and 3 Tesla (T) field strengths remain the clinical standard, the advent of 7 T MRI represents a transformative step forward, offering superior spatial resolution, contrast, and sensitivity for visualizing neuroanatomy, metabolism, and function. Recent innovations, including parallel transmission and deep learning-based reconstruction, have resolved many prior technical challenges of 7 T MRI, enabling its routine clinical use. This review examines the diagnostic impact, patient value, and practical considerations of 7 T MRI, emphasizing its role in facilitating earlier diagnoses and improving care in conditions, such as amyotrophic lateral sclerosis (ALS), epilepsy, multiple sclerosis (MS), dementia, parkinsonism, tumors, and vascular diseases. Based on insights from over 1200 clinical scans with a second-generation 7 T system, the review highlights disease-specific biomarkers such as the motor band sign in ALS and the new diagnostic markers in MS, the central vein sign, and paramagnetic rim lesions. The unparalleled ability of 7 T MRI to study neurological diseases ex vivo at ultra-high resolution is also explored, offering new opportunities to understand pathophysiology and identify novel treatment targets. Additionally, the review provides a clinical perspective on patient handling and safety considerations, addressing challenges and practicalities associated with clinical 7 T MRI. By bridging research and clinical practice, 7 T MRI has the potential to redefine neuroimaging and advance the understanding and management of complex neurological disorders.}, } @article {pmid39776251, year = {2025}, author = {Öijerstedt, L and Foucher, J and Lovik, A and Yazdani, S and Juto, A and Kläppe, U and Fang, F and Ingre, C}, title = {Correction: Repeated cognitive assessments show stable function over time in patients with ALS.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {104}, doi = {10.1007/s00415-024-12833-z}, pmid = {39776251}, issn = {1432-1459}, } @article {pmid39776752, year = {2024}, author = {Schwamburger, J and Brock, K and Cooper, R}, title = {The effect of GV-58, a calcium channel modifier, on synaptic transmission at the larval Drosophila and crayfish neuromuscular junctions.}, journal = {microPublication biology}, volume = {2024}, number = {}, pages = {}, pmid = {39776752}, issn = {2578-9430}, abstract = {GV-58 is known to increase the opening time of the mammalian P-type calcium channel in presynaptic motor nerve terminals. GV-58 is suggested as a therapeutic agent for dampening the symptoms of amyotrophic lateral sclerosis. To further understand the mechanisms of GV-58 actions, the Drosophila and crayfish neuromuscular junctions were used as models. Their presynaptic calcium channels are a P-type based on pharmacology profiles. However, exposure of GV-58 (1mM) did not produce any consistent alteration in synaptic transmission in these two preparations. It is possible that the molecular structure of the P-type channels is different in the Drosophila and crayfish.}, } @article {pmid39777244, year = {2025}, author = {Moura, FA and Siqueira, AIAN}, title = {Gut-liver axis in sepsis-associated liver injury: Epidemiology, challenges and clinical practice.}, journal = {World journal of gastroenterology}, volume = {31}, number = {1}, pages = {99987}, pmid = {39777244}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Sepsis/complications/epidemiology ; *Dysbiosis ; *Liver/metabolism/pathology ; Animals ; *Oxidative Stress ; Bacterial Translocation ; Liver Diseases/epidemiology/microbiology ; Critical Illness ; Intensive Care Units/statistics & numerical data ; Anti-Bacterial Agents/therapeutic use ; }, abstract = {Although the liver has a remarkable regenerative capacity, sepsis-associated liver injury (SLI) is a complication often seen in intensive care units. Due to its role in immune and inflammatory regulation, the liver is particularly vulnerable during severe infections. Understanding the global prevalence, causes, and management of SLI is essential to improve outcomes and reduce healthcare costs. This paper aims to explore these factors, with an emphasis on identifying effective strategies for clinical management. Zhang et al's bibliometric analysis of 787 publications (745 original articles and 42 reviews, mostly in animal models) from 2000 to 2023 highlights the growing interest in SLI, focusing on oxidative stress, gut microbiota, and inflammatory processes. Key components such as nuclear factor-kappa B and the NOD-like receptor thermal protein domain associated protein 3 inflammasome pathway, along with their links to gut microbiota imbalance and oxidative stress, are crucial for understanding SLI pathogenesis. The gut-liver axis, particularly the role of intestinal permeability and bacterial translocation in liver inflammation, is emphasized. In this context, bacterial translocation is especially relevant for critically ill patients, as it can exacerbate liver inflammation. The findings underscore the need for integrated care in intensive care units, prioritizing gut health and careful antibiotic use to prevent dysbiosis. Despite extensive research, there remains a lack of clinical trials to validate therapeutic approaches. The abundance of experimental studies highlights potential therapeutic targets, stressing the need for high-quality randomized clinical trials to translate these findings into clinical practice.}, } @article {pmid39778572, year = {2025}, author = {Je, Y and Park, YE and Shin, YB}, title = {Differentiating Inclusion Body Myositis From Amyotrophic Lateral Sclerosis Based on the Features of Dysphagia: Insights From a Patient With Rapidly Progressive Dysphagia.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {21}, number = {1}, pages = {83-85}, pmid = {39778572}, issn = {1738-6586}, support = {/PNUH/Pusan National University Hospital/Korea ; }, } @article {pmid39778593, year = {2025}, author = {Chen, Q and Chen, G and Wang, Q}, title = {Application of Network Pharmacology in the Treatment of Neurodegenerative Diseases with Traditional Chinese Medicine.}, journal = {Planta medica}, volume = {91}, number = {5}, pages = {226-237}, pmid = {39778593}, issn = {1439-0221}, support = {2023AFB677//the Natural Science Foundation of Hubei Province/ ; 2024AFB578//the Natural Science Foundation of Hubei Province/ ; 2023LYYYGZRP0003//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; 2023LYYYSZRP0001//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; }, mesh = {Humans ; *Medicine, Chinese Traditional/methods ; *Neurodegenerative Diseases/drug therapy ; *Network Pharmacology/methods ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; }, abstract = {In recent years, the incidence of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, has exhibited a steadily rising trend, which has posed a major challenge to the global public health. Traditional Chinese medicine, with its multicomponent and multitarget characteristics, offers a promising approach to treating neurodegenerative diseases. However, comprehensively elucidating the complex mechanisms underlying traditional Chinese medicine formulations remains challenging. As an emerging systems biology method, network pharmacology has provided a vital tool for revealing the multitarget mechanisms of traditional Chinese medicine through high-throughput technologies, molecular docking, and network analysis. This paper reviews the advancements in the application of network pharmacology in treating neurodegenerative diseases using traditional Chinese medicine, analyzes the current status of relevant databases and technological methods, discusses the limitations, and proposes future directions to promote the modernization of traditional Chinese medicine and the development of precision medicine.}, } @article {pmid39778605, year = {2025}, author = {Urano, Y and Iwagaki, A and Takeishi, A and Uchiyama, N and Noguchi, N}, title = {Downregulation of the SREBP pathways and disruption of redox status by 25-hydroxycholesterol predispose cells to ferroptosis.}, journal = {Free radical biology & medicine}, volume = {228}, number = {}, pages = {319-328}, doi = {10.1016/j.freeradbiomed.2025.01.010}, pmid = {39778605}, issn = {1873-4596}, mesh = {*Ferroptosis/drug effects ; *Hydroxycholesterols/pharmacology/metabolism ; Animals ; Mice ; Oxidation-Reduction ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics/metabolism ; Signal Transduction ; *Schwann Cells/metabolism/drug effects/pathology ; Cell Line ; Down-Regulation ; Steroid Hydroxylases/genetics/metabolism ; *Sterol Regulatory Element Binding Proteins/metabolism/genetics ; Humans ; }, abstract = {Enzymatically formed side-chain oxysterols function as signaling molecules regulating cholesterol homeostasis and act as intermediates in the biosynthesis of bile acids. In addition to these physiological functions, an imbalance in oxysterol homeostasis has been implicated in pathophysiology. Cholesterol 25-hydroxylase (CH25H) and its product 25-hydroxycholesterol (25-OHC), also formed by autoxidation, are associated with amyotrophic lateral sclerosis. However, the effects of 25-OHC on cell viability in glial cells remain unclear. This study demonstrates that 25-OHC induces ferroptosis, an iron-dependent programmed cell death, in mouse Schwann IMS32 cells. Mechanistically, 25-OHC suppressed the expression of selenoprotein glutathione peroxidase 4 (GPX4) at both the transcriptional and translational levels by inhibiting the processing of sterol regulatory element-binding proteins (SREBPs). In addition, 25-OHC upregulated the expression of NADH-cytochrome b5 reductase 1 (CYB5R1) and NADPH-cytochrome P450 reductase (POR), enzymes that promote lipid peroxidation. We further found that 25-OHC increases the expression of glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) and decreases glutathione levels. Importantly, non-cytotoxic concentrations of 25-OHC enhanced cellular sensitivity to ferroptosis inducers by downregulating GPX4 expression. These findings reveal a multifaceted approach whereby 25-OHC induces ferroptosis through SREBP pathway suppression and redox imbalance in mouse Schwann IMS32 cells.}, } @article {pmid39778888, year = {2025}, author = {Etxebeste-Mitxeltorena, M and Flores-Romero, H and Ramos-Inza, S and Masiá, E and Nenchova, M and Montesinos, J and Martinez-Gonzalez, L and Porras, G and Orzáez, M and Vicent, MJ and Gil, C and Area-Gomez, E and Garcia-Saez, AJ and Martinez, A}, title = {Modulation of Mitochondria-Endoplasmic Reticulum Contacts (MERCs) by Small Molecules as a New Strategy for Restoring Lipid Metabolism in an Amyotrophic Lateral Sclerosis Model.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {2}, pages = {1179-1194}, pmid = {39778888}, issn = {1520-4804}, support = {/ERC_/European Research Council/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; *Endoplasmic Reticulum/metabolism/drug effects ; *Mitochondria/metabolism/drug effects ; *Lipid Metabolism/drug effects ; *Small Molecule Libraries/pharmacology/chemistry ; Cholesterol/metabolism ; HCT116 Cells ; Mitochondria Associated Membranes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without effective treatment. The progressive motoneuron death in ALS is associated with alterations in lipid metabolism. As its regulation occurs in mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), modulation of mitochondria-ER contacts (MERCs) is emerging as a crucial factor in MAM formation and lipid metabolism control. Using the MERLIN biosensor in a high-throughput screening within the EU-OPENSCREEN ERIC, we discovered small molecules that increase MERCs in HCT116 cells, enhancing their ability to uptake cholesterol. We demonstrated that cholesterol trafficking is decreased in an ALS patient-derived cell model, and this trafficking is restored after treatment with the discovered MERC modulator 24. Electron microscopy revealed that treatment with compound 24 increases MERCs, promotes lipid droplet formation, and restores mitochondrial cristae. Overall, the brain-permeable MERC modulator, compound 24, may serve as a valuable pharmacological tool for studying MAM function and holds potential for in vivo studies in ALS and other MAM dysfunction diseases.}, } @article {pmid39779313, year = {2025}, author = {Xiao, Y and Tan, Y and Li, C and Wei, Q and Jiang, Q and Wang, S and Yang, T and Lin, J and Zhang, L and Shang, H}, title = {Genetic and clinical analysis of OPTN in amyotrophic lateral sclerosis.}, journal = {Journal of medical genetics}, volume = {62}, number = {4}, pages = {242-248}, doi = {10.1136/jmg-2024-109978}, pmid = {39779313}, issn = {1468-6244}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Asian People/genetics ; *Cell Cycle Proteins/genetics ; Genetic Association Studies ; *Genetic Predisposition to Disease ; Genotype ; *Membrane Transport Proteins/genetics ; Mutation ; Phenotype ; *Transcription Factor TFIIIA/genetics ; White People/genetics ; Cohort Studies ; }, abstract = {BACKGROUND: Considerable heterogeneity in genotypes and phenotypes has been observed among patients with amyotrophic lateral sclerosis (ALS) harbouring optineurin gene (OPTN) mutations, as reported in prior studies. The study aimed to elucidate the correlation between OPTN genotypes and phenotypes.

METHODS: OPTN gene variants were screened within a substantial Chinese cohort of patients with ALS, encompassing LoF and rare missense variants. Additionally, a systematic literature review was conducted to compile the spectrum of OPTN mutations and explore the relationship between the genotype and phenotype of patients with ALS with OPTN.

RESULTS: A total of 33 unrelated patients with ALS with 24 rare OPTN variants, including 17 novel variants, were identified in 2279 patients with ALS. Among 24 variants in our cohort and 106 variants in previous studies, only 33.3% and 35.8% were pathogenic/likely pathogenic variants. Moreover, the frequency of OPTN variants in the Asian ALS population was higher (1.08%) than that of the Caucasian population (0.55%). For the phenotype of patients with ALS carrying OPTN variants, we found that patients with pathogenic/likely pathogenic variants had the highest baseline progression rate and the shortest survival time among groups in our cohort.

CONCLUSION: Our study contributed to a broader understanding of the genotype and phenotype spectrum of patients with ALS carrying OPTN variants. Further investigations are warranted to definitively establish the genotype-phenotype associations.}, } @article {pmid39779681, year = {2025}, author = {McCallister, TX and Lim, CKW and Singh, M and Zhang, S and Ahsan, NS and Terpstra, WM and Xiong, AY and Zeballos C, MA and Powell, JE and Drnevich, J and Kang, Y and Gaj, T}, title = {A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {460}, pmid = {39779681}, issn = {2041-1723}, support = {1R01NS123556-01A1//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 1U01NS122102-01A1//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 5R01GM141296//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; MDA602798//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; R01 GM141296/GM/NIGMS NIH HHS/United States ; 20-IIP-516//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; T32 EB019944/EB/NIBIB NIH HHS/United States ; U01 NS122102/NS/NINDS NIH HHS/United States ; R01 NS123556/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *CRISPR-Cas Systems ; Humans ; Animals ; DNA Repeat Expansion/genetics ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Mice ; }, abstract = {An abnormal expansion of a GGGGCC (G4C2) hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we develop here a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the G4C2 repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci, reduced the production of a dipeptide repeat protein, and reversed transcriptional deficits. This high-fidelity system possessed improved transcriptome-wide specificity compared to its native form and mediated targeting in motor neuron-like cells derived from a patient with ALS. These results lay the foundation for the implementation of RNA-targeting CRISPR technologies for C9ORF72-linked ALS/FTD.}, } @article {pmid39779704, year = {2025}, author = {Kempthorne, L and Vaizoglu, D and Cammack, AJ and Carcolé, M and Roberts, MJ and Mikheenko, A and Fisher, A and Suklai, P and Muralidharan, B and Kroll, F and Moens, TG and Yshii, L and Verschoren, S and Hölbling, BV and Moreira, FC and Katona, E and Coneys, R and de Oliveira, P and Zhang, YJ and Jansen, K and Daughrity, LM and McGown, A and Ramesh, TM and Van Den Bosch, L and Lignani, G and Rahim, AA and Coyne, AN and Petrucelli, L and Rihel, J and Isaacs, AM}, title = {Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivo.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {459}, pmid = {39779704}, issn = {2041-1723}, support = {/WT_/Wellcome Trust/United Kingdom ; 217150/Z/19/Z//Wellcome Trust (Wellcome)/ ; 648716 - C9ND//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Humans ; *Frontotemporal Dementia/genetics/metabolism ; Animals ; *CRISPR-Cas Systems ; *RNA, Antisense/genetics ; Mice ; HEK293 Cells ; *Induced Pluripotent Stem Cells/metabolism ; DNA Repeat Expansion/genetics ; Disease Models, Animal ; Neurons/metabolism ; Genetic Therapy/methods ; }, abstract = {The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is an intronic G4C2 repeat expansion in C9orf72. The repeats undergo bidirectional transcription to produce sense and antisense repeat RNA species, which are translated into dipeptide repeat proteins (DPRs). As toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs, targeting both strands may provide the most effective therapeutic strategy. CRISPR-Cas13 systems mature their own guide arrays, allowing targeting of multiple RNA species from a single construct. We show CRISPR-Cas13d variant CasRx effectively reduces overexpressed C9orf72 sense and antisense repeat transcripts and DPRs in HEK cells. In C9orf72 patient-derived iPSC-neuron lines, CRISPR-CasRx reduces endogenous sense and antisense repeat RNAs and DPRs and protects against glutamate-induced excitotoxicity. AAV delivery of CRISPR-CasRx to two distinct C9orf72 repeat mouse models significantly reduced both sense and antisense repeat-containing transcripts. This highlights the potential of RNA-targeting CRISPR systems as therapeutics for C9orf72 ALS/FTD.}, } @article {pmid39779800, year = {2025}, author = {Regondi, S and Donvito, G and Frontoni, E and Kostovic, M and Minazzi, F and Bratières, S and Filosto, M and Pugliese, R}, title = {Artificial intelligence empowered voice generation for amyotrophic lateral sclerosis patients.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1361}, pmid = {39779800}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/therapy/complications/psychology ; Humans ; *Artificial Intelligence ; *Voice ; Female ; Male ; Middle Aged ; *Quality of Life ; Aged ; Communication Devices for People with Disabilities ; Speech/physiology ; Adult ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that can result in a progressive loss of speech due to bulbar dysfunction, which can have significant negative impact on the patient's mental well-being. Alternative Augmentative Communication (AAC) strategies based on synthetic voices have been shown to assist patients in maintaining communication and improving their Quality of Life (QoL). However, such synthetic voices are often perceived as impersonal and fail to capture the unique voice and identity of the patient. To tackle this issue, combining voice banking (VB) and artificial intelligence (AI) has emerged as a more natural communication strategy, enabling individuals to preserve their voice for use with AAC devices as needed. This involves recording speech samples to generate a synthetic voice closely resembling the individual's own. Despite the increasing interest in VB, there's a lack of clear strategies for its effective implementation in rapidly progressing diseases like ALS. Additionally, the perceptual quality of VB on patients with preserved speech, especially when offered early in the disease, remains poorly understood. In light of these challenges, this study aims to assess the effectiveness and the perceptual impact of AI-generated voices on ALS patients with preserved speech, utilizing a personalized voice synthesis system based on machine learning. The AI-generated patient-specific voice is achieved through voice recording, followed by fine-tuning using a Generative Adversarial Network for Efficient and High Fidelity Speech Synthesis (HiFi-GAN), resulting in a model capable of producing speech highly similar to the patient's own voice, with exceptional expressive and audio quality. By addressing these aspects, this study intends to offer valuable insights into the potential benefits and challenges of combining VB with AI voices to enhance communication support for ALS patients.}, } @article {pmid39783194, year = {2025}, author = {Smith, SE and McCoy-Gross, K and Malcolm, A and Oranski, J and Markway, JW and Miller, TM and Bucelli, RC}, title = {Tofersen treatment leads to sustained stabilization of disease in SOD1 ALS in a "real-world" setting.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {2}, pages = {311-319}, pmid = {39783194}, issn = {2328-9503}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Male ; Middle Aged ; Female ; *Superoxide Dismutase-1/genetics ; Aged ; Neurofilament Proteins/blood/cerebrospinal fluid ; Adult ; Disease Progression ; *Outcome Assessment, Health Care ; }, abstract = {OBJECTIVE: Patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1 ALS) treated with tofersen have shown slowing of disease progression, and disease stabilization with recovery of function in some patients. We report our clinical experience with treating patients with SOD1 ALS and the effects of tofersen on outcome measures.

METHODS: This was a single-center observational study of patients with SOD1 ALS receiving treatment with tofersen. The effects of tofersen treatment on neurofilament levels, muscle strength, and clinical outcome measures were assessed. Several patients had outpatient neuromuscular rehabilitation in addition to tofersen treatment and we report changes in functional outcomes.

RESULTS: Seven SOD1 ALS patients received treatment at our institution. All patients showed robust and sustained declines in serum NfL and CSF pNFH (mean change serum NfL: -57.9%; mean change CSF pNFH: -67.6%). There was apparent disease stabilization as assessed by the ALSFRS-R total score, mean change 1.1 (SD = 0.7). There was notable improvement in functional independence measured by the FIM motor score, mean change 5.13 points (SD = 3.85).

INTERPRETATION: This study provides evidence that tofersen treatment in SOD1 ALS can lead to meaningful preservation of function and suggestions of sustained improvement in neurologic function in some patients, and strongly supports the role of neurofilaments as therapeutic biomarkers.}, } @article {pmid39783196, year = {2025}, author = {Lee, I and Mitsumoto, H and Lee, S and Kasarskis, E and Rosenbaum, M and Factor-Litvak, P and Nieves, JW}, title = {Interaction between riluzole treatment and dietary glycemic index in the disease progression of amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {3}, pages = {491-498}, pmid = {39783196}, issn = {2328-9503}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; K23NS131586/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Cohort Studies ; *Disease Progression ; *Glycemic Index/physiology ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Riluzole/pharmacology/administration & dosage ; }, abstract = {OBJECTIVE: We examined whether riluzole treatment modifies the associations between the dietary glycemic index (GI) and load (GL) and disease progression in amyotrophic lateral sclerosis (ALS).

METHODS: Sporadic ALS patients in the Multicenter Cohort Study of Oxidative Stress who completed a baseline food frequency questionnaire were included (n = 304). Interactions between baseline riluzole treatment and GI/GL on functional decline and tracheostomy-free survival were examined using linear regression and Cox proportional hazard models adjusted for covariates. Age, sex, disease duration, diagnostic certainty, body mass index, bulbar onset, revised ALS functional rating scale (ALSFRS-r) total score, and forced vital capacity, from baseline were included as covariates.

RESULTS: Baseline higher GI and GL were associated with less decline of ALSFRS-r total score at 3-month follow-up in the riluzole treatment group (RTG) but not in the no-riluzole group (NRG). When quartile groups were used, GI second [β = -1.9, 95% CI (-4.1, -0.2), p = 0.07], third [β = -3.0, 95% CI (-5.1, -0.8), p < 0.01] and fourth [β = -2.2, 95% CI (-4.3, -0.01), p < 0.05] quartile groups were associated with less ALSFRS-r decline at 3-months compared to the first quartile group (GI < 47.2) among the RTG. Similarly, GL fourth quartile group (GL > 109.5) was associated with less ALSFRS-r decline at 3 months compared to the first quartile group [β = -2.6, 95% CI (-4.7, -0.5), p < 0.05] among the RTG. In NRG, no statistically significant differences in ALSFRS-r decline were found among GI/GL quartile groups.

INTERPRETATION: High dietary GI and GL are associated with a slower functional decline only among ALS patients taking riluzole.}, } @article {pmid39786151, year = {2025}, author = {Harrison, J and Bhardwaj, A and Houck, O and Sather, K and Sekiya, A and Knack, S and Saarunya Clarke, G and Puskarich, MA and Tignanelli, C and Rogers, L and Marmor, S and Beilman, G}, title = {Emergency medical services level of training is associated with mortality in trauma patients: A combined prehospital and in hospital database analysis.}, journal = {The journal of trauma and acute care surgery}, volume = {98}, number = {3}, pages = {402-409}, pmid = {39786151}, issn = {2163-0763}, mesh = {Humans ; Male ; Female ; *Wounds and Injuries/mortality/therapy ; Middle Aged ; Adult ; Aged ; *Emergency Medical Services/statistics & numerical data ; Adolescent ; Trauma Centers/statistics & numerical data ; Aged, 80 and over ; Databases, Factual ; Young Adult ; Propensity Score ; Retrospective Studies ; Hospital Mortality ; }, abstract = {BACKGROUND: There is conflicting evidence regarding emergency medical service (EMS) provider level of training and outcomes in trauma. We hypothesized that advanced life support (ALS) provider transport is associated with lower mortality compared with basic life support transport.

METHODS: We performed secondary analysis of a combined prehospital and in-hospital database of trauma patients utilizing ESO electronic medical records from 2018 to 2022. We included encounters with patients aged 15 years to 100 years transported by ground to a Level I or II trauma center with trauma-specific ICD-10-CM codes. Patients dead upon EMS arrival and transfers were excluded. We matched patients using 1:1 nearest neighbor propensity scores based on demographic, injury, and EMS characteristics, prehospital vitals, and trauma center designation. The exposure variable was EMS level of training and outcome was mortality. We conducted subgroup analyses on predefined cohorts (age > 50 years, mechanism of injury, prehospital EMS time > 30 minutes).

RESULTS: We identified 30,735 ALS and 1,758 basic life support encounters, representing 1,154 pairs following propensity matching. Mortality was lower among patients transported by ALS providers (odds ratio [OR], 0.40; 95% confidence interval [CI], 0.18-0.88; p = 0.023). Mortality was also lower in the subgroups of patients aged > 50 years (OR, 0.35; 95% CI, 0.13-0.98; p = 0.046), and in patients with mechanisms of injury excluding falls (OR, 0.35; 95% CI, 0.13-0.98; p = 0.047). In those with prolonged prehospital time, the association approached significance (OR, 0.30; 95% CI, 0.08-1.08; p = 0.067). In those with mechanisms of injury of fall, the association was not significant.

CONCLUSION: In this retrospective, propensity matched cohort study using a national sample of trauma patients, attendance by ALS providers was associated with reduced mortality. This was observed in the entire cohort, in those aged > 50 years, and those with a higher-risk mechanism of injury. It approached significance in those with prolonged prehospital time.

LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.}, } @article {pmid39786321, year = {2025}, author = {Kim, K and Kim, S and Katana, M and Terentyev, D and Radwański, PB and Munger, MA}, title = {Riluzole is associated with reduced risk of heart failure.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70033}, pmid = {39786321}, issn = {1468-1331}, support = {R01HL14488/HL/NHLBI NIH HHS/United States ; R01 NS121234/NS/NINDS NIH HHS/United States ; R01 HL142588/HL/NHLBI NIH HHS/United States ; R01 HL166604/HL/NHLBI NIH HHS/United States ; R01 HL155378/HL/NHLBI NIH HHS/United States ; R01HL166604/HL/NHLBI NIH HHS/United States ; R01HL155378/HL/NHLBI NIH HHS/United States ; }, mesh = {*Riluzole/therapeutic use ; Humans ; *Heart Failure/epidemiology/drug therapy ; Male ; Female ; Aged ; Middle Aged ; Incidence ; Amyotrophic Lateral Sclerosis/epidemiology/drug therapy ; Aged, 80 and over ; Cohort Studies ; United States/epidemiology ; }, abstract = {BACKGROUND: Reduction of intracellular Na[+] accumulation through late Na[+] current inhibition has been recognized as a target for cardiac Ca[2+] handling which underlies myocardial contractility and relaxation in heart failure (HF). Riluzole, an Na[+] channel blocker with enhancement of Ca[2+]-activated K[+] channel function, used for management of amyotrophic lateral sclerosis (ALS), is effective in suppressing Ca[2+] leak and therefore may improve cardiac function.

OBJECTIVES: The study aim was to investigate whether riluzole lowers HF incidence.

METHODS: Rates of HF incident were compared using a commercial insurance and Medicare supplement claims databases. Patients with a filled riluzole prescription (treatment) between 06/2009 and 12/2019 were compared to those with no-riluzole (control). We excluded HF patients during the 180-day baseline period. Study endpoint was the first HF diagnosis from the index riluzole prescription or ALS diagnosis. HF onset was compared between the propensity score matched treatment and control cohorts.

RESULTS: The matched cohort consisted of 4060 pairs of riluzole/control patients. The 24-month cumulative incidence of HF onset for riluzole versus control patients was 4.96% versus 7.27%, calculating hazard ratio (HR) [95% CI, p-value] of 0.55 [0.40-0.76, p < 0.01]. The HR estimates favoring riluzole over the ALS control were consistent across the 3 months to 2-year follow-up. The clinically and statistically significant effect on HF onset was driven by the lower rate of HFrEF with the 2-year HR [95% CI] of 0.46 [0.21-0.99].

CONCLUSIONS: Riluzole is associated with a lower rate of HF onset, suggesting a potential prevention strategy for early management.}, } @article {pmid39786727, year = {2025}, author = {Midgley, SD and Bariami, S and Habgood, M and Mackey, M}, title = {Adaptive Lambda Scheduling: A Method for Computational Efficiency in Free Energy Perturbation Simulations.}, journal = {Journal of chemical information and modeling}, volume = {65}, number = {2}, pages = {512-516}, pmid = {39786727}, issn = {1549-960X}, mesh = {Thermodynamics ; Ligands ; *Proteins/chemistry/metabolism ; Protein Binding ; }, abstract = {Recent increases in the availability of computational power have improved the accessibility of ligand-protein relative binding free energy (RBFE) calculations; however, these calculations remain resource-intensive, which can limit their practical application. RBFE calculations typically use a set of thermodynamic intermediates mediated by the transformation coordinate λ. Optimizing λ offers a way to tune the computational efforts required for a given RBFE calculation. Here, we present Adaptive Lambda Scheduling (ALS), a streamlined approach for on-the-fly bespoke λ scheduling. We show it can achieve substantial reductions in computational cost while retaining predictive performance.}, } @article {pmid39786806, year = {2025}, author = {Yang, S and Song, J and Deng, M and Cheng, S}, title = {Identification of Drug-Targetable Genes for Eczema and Dermatitis Using Integrated Genomic and Proteomic Approaches.}, journal = {Dermatitis : contact, atopic, occupational, drug}, volume = {36}, number = {4}, pages = {369-381}, doi = {10.1089/derm.2024.0429}, pmid = {39786806}, issn = {2162-5220}, mesh = {Humans ; *Eczema/genetics/drug therapy ; Proteomics ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; Quantitative Trait Loci ; Mendelian Randomization Analysis ; Genomics ; *Dermatitis/genetics/drug therapy ; }, abstract = {Background: Eczema and dermatitis are common inflammatory skin conditions with significant morbidity. Identifying drug-targetable genes can facilitate the development of effective treatments. Methods: This study analyzed data obtained by meta-analysis of 2 genome-wide association studies on eczema/dermatitis (57,311 cases and 896,779 controls, European ancestry). We identified drug-targetable genes from the Drug-Gene Interaction Database and Finan et al's findings. Cis-expression quantitative trait loci (eQTL) data from human blood and skin tissues were used for Mendelian randomization (MR) analysis. Bayesian colocalization, proteomic MR, and meta-analysis validated the causal relationships. Finally, protein-protein interactions (PPIs) and correlation analysis of potential drug targets and cytokines were performed. Results: We identified 2532 drug-targetable genes; 3378 Single Nucleotide Polymorphism (SNPs) were associated with 1531 genes in blood cis-eQTLs, 664 SNPs with 667 genes in sun-exposed skin eQTLs, and 572 SNPs with 574 genes in nonsun-exposed skin eQTLs. Five genes (SLC22A5, NOTCH4, AGER, HLA-DRB5, and EHMT2) showed causal relationships with eczema/dermatitis across multiple datasets. Single-variable and multi-variable Mendelian randomization (SMR) and multi-SNP SMR analysis identified 8 genes (PIK3R4, DHODH, CXCR2, Interleukin (IL)18, LGALS9, RPS6KB2, SLC22A5, and AGER) across all tissues. Functional Summary Information for Variants in the Online Network (FUSION) analysis confirmed associations for SLC22A5 and AGER. Bayesian colocalization indicated AGER (PPH4: 0.95) as a shared causal variant. Proteomic MR and meta-analysis showed that increased AGER protein levels were associated with a lower risk of eczema or dermatitis (odds ratio: 0.995, 95% confidence interval: 0.997-0.993, P = 0.0002). A PPI network revealed interactions of AGER with NOTCH4 and multiple cytokines, whereas SLC22A5 showed no cytokine interactions. Conclusions: This study identified potential drug-targetable genes, with AGER showing strong potential as a target for reducing eczema/dermatitis risk. These findings provide a basis for developing targeted therapies.}, } @article {pmid39788313, year = {2025}, author = {Cassina, P and Miquel, E and Martínez-Palma, L and Cassina, A}, title = {Mitochondria and astrocyte reactivity: Key mechanism behind neuronal injury.}, journal = {Neuroscience}, volume = {567}, number = {}, pages = {227-234}, doi = {10.1016/j.neuroscience.2024.12.058}, pmid = {39788313}, issn = {1873-7544}, mesh = {Animals ; Humans ; *Astrocytes/metabolism/pathology ; *Mitochondria/metabolism ; *Neurons/metabolism/pathology ; }, abstract = {In this special issue to celebrate the 30th anniversary of the Uruguayan Society for Neuroscience (SNU), we find it pertinent to highlight that research on glial cells in Uruguay began almost alongside the history of SNU and contributed to the understanding of neuron-glia interactions within the international scientific community. Glial cells, particularly astrocytes, traditionally regarded as supportive components in the central nervous system (CNS), undergo notable morphological and functional alterations in response to neuronal damage, a phenomenon referred to as glial reactivity. Among the myriad functions of astrocytes, metabolic support holds significant relevance for neuronal function, given the high energy demand of the nervous system. Although astrocytes are typically considered to exhibit low mitochondrial respiratory chain activity, they possess a noteworthy mitochondrial network. Interestingly, both the morphology and activity of these organelles change following glial reactivity. Despite receiving less attention compared to studies on neuronal mitochondria, recent studies indicate that mitochondria play a crucial role in driving the transition of astrocytes from a quiescent to a reactive state in various neurological disorders. Notably, stimulating mitochondria in astrocytes has been shown to reduce damage associated with the neurodegenerative disease amyotrophic lateral sclerosis. Here, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage. In this review, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage.}, } @article {pmid39789167, year = {2025}, author = {Kassubek, J and Roselli, F and Witzel, S and Dorst, J and Ludolph, AC and Rasche, V and Vernikouskaya, I and Müller, HP}, title = {Hypothalamic atrophy in primary lateral sclerosis, assessed by convolutional neural network-based automatic segmentation.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1551}, pmid = {39789167}, issn = {2045-2322}, mesh = {Humans ; Female ; Male ; *Hypothalamus/pathology/diagnostic imaging ; Middle Aged ; *Neural Networks, Computer ; *Magnetic Resonance Imaging/methods ; *Atrophy/pathology ; Aged ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging ; Adult ; Motor Neuron Disease/pathology/diagnostic imaging ; Image Processing, Computer-Assisted/methods ; Case-Control Studies ; }, abstract = {Primary lateral sclerosis (PLS) is a motor neuron disease (MND) which mainly affects upper motor neurons. Within the MND spectrum, PLS is much more slowly progressive than amyotrophic laterals sclerosis (ALS). `Classical` ALS is characterized by catabolism and abnormal energy metabolism preceding onset of motor symptoms, and previous studies indicated that the disease progression of ALS involves hypothalamic atrophy. Very limited weight loss is observed in patients with PLS, which raises the question of whether there are also less hypothalamic alterations. The purpose of this study was to quantitatively investigate the hypothalamic volume in a group of PLS patients and to compare it with ALS and controls. Recently, we have introduced automatic hypothalamic quantification method based on the use of convolutional neural network (CNN) to reduce human variability and enhance analysis robustness. This CNN of U-Net architecture was applied for automatic segmentation of the hypothalamus and intracranial volume (ICV) to allow adjustments of the hypothalamic volume between subjects with different head sizes respectively. Automatic segmentation and volumetric analysis were performed in high resolution T1 weighted MRI volumes (acquired on a 1.5 T MRI scanner) of 46 PLS patients in comparison to 107 healthy controls and 411 `classical` ALS patients, respectively. Significant hypothalamic volume reduction was observed in PLS (818 ± 73 mm[3]) when compared to controls (852 ± 77 mm[3]); significant hypothalamic volume reduction was also confirmed in ALS (823 ± 84 mm[3]), in support of previous studies. No significant differences were found in normalized hypothalamic volumes between ALS patients and PLS patients at the group level. This unbiased CNN-based hypothalamus volume quantification study demonstrated similarly reduced hypothalamus volume in PLS and ALS patients, despite the clinical phenotypic differences.}, } @article {pmid39791335, year = {2025}, author = {Dogan, EO and Simonini, SR and Bouley, J and Weiss, A and Brown, RH and Henninger, N}, title = {Genetic Ablation of Sarm1 Mitigates Disease Acceleration after Traumatic Brain Injury in the SOD1[G93A] Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {97}, number = {5}, pages = {963-975}, pmid = {39791335}, issn = {1531-8249}, support = {R21 NS131756/NS/NINDS NIH HHS/United States ; NS131756/NS/NINDS NIH HHS/United States ; //Moloney Fellowship/ ; //Angel Fund for ALS Research/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Mice ; Mice, Transgenic ; *Armadillo Domain Proteins/genetics/deficiency ; Disease Models, Animal ; *Cytoskeletal Proteins/genetics/deficiency ; *Superoxide Dismutase-1/genetics ; Male ; *Brain Injuries, Traumatic/genetics/complications/pathology ; Female ; Mice, Knockout ; Disease Progression ; }, abstract = {OBJECTIVE: Approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Epidemiological data have identified traumatic brain injury (TBI) as an exogenous risk factor for ALS; however, the mechanisms by which TBI may worsen SOD1 ALS remain largely undefined.

METHODS: We sought to determine whether repetitive TBI (rTBI) accelerates disease onset and progression in the transgenic SOD1[G93A] mouse ALS model, and whether loss of the primary regulator of axonal degeneration sterile alpha and TIR motif containing 1 (Sarm1) mitigates the histological and behavioral pathophysiology. We subjected wild-type (n = 23), Sarm1 knockout (KO; n = 17), SOD1[G93A] (n = 19), and SOD1[G93A]xSarm1[KO] (n = 26) mice of both sexes to rTBI or sham surgery at age 64 days (62-68 days). Body weight and ALS-deficit score were serially assessed up to 17 weeks after surgery and histopathology assessed in layer V of the primary motor cortex at the study end point.

RESULTS: In sham injured SOD1[G93A] mice, genetic ablation of Sarm1 did not attenuate axonal loss, improve neurological deficits, or survival. The rTBI accelerated onset of G93A-SOD1 ALS, as indicated by accentuated body weight loss, earlier onset of hindlimb tremor, and shortened survival. The rTBI also triggered TDP-43 mislocalization, enhanced axonal and neuronal loss, microgliosis, and astrocytosis. Loss of Sarm1 significantly diminished the impact of rTBI on disease progression and rescued rTBI-associated neuropathology.

INTERPRETATION: SARM1-mediated axonal death pathway promotes pathogenesis after TBI in SOD1[G93A] mice suggesting that anti-SARM1 therapeutics are a viable approach to preserve neurological function in injury-accelerated G93A-SOD1 ALS. ANN NEUROL 2025;97:963-975.}, } @article {pmid39791705, year = {2024}, author = {Sun, D and Amiri, M and Meng, Q and Unnithan, RR and French, C}, title = {Calcium Signalling in Neurological Disorders, with Insights from Miniature Fluorescence Microscopy.}, journal = {Cells}, volume = {14}, number = {1}, pages = {}, pmid = {39791705}, issn = {2073-4409}, support = {DP170100363//Australian Research Council under Discovery Project/ ; }, mesh = {*Calcium Signaling ; Humans ; *Nervous System Diseases/metabolism/pathology ; Animals ; *Microscopy, Fluorescence/methods ; Calcium/metabolism ; Neurons/metabolism ; }, abstract = {Neurological disorders (NDs), such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and schizophrenia, represent a complex and multifaceted health challenge that affects millions of people around the world. Growing evidence suggests that disrupted neuronal calcium signalling contributes to the pathophysiology of NDs. Additionally, calcium functions as a ubiquitous second messenger involved in diverse cellular processes, from synaptic activity to intercellular communication, making it a potential therapeutic target. Recently, the development of the miniature fluorescence microscope (miniscope) enabled simultaneous recording of the spatiotemporal calcium activity from large neuronal ensembles in unrestrained animals, providing a novel method for studying NDs. In this review, we discuss the abnormalities observed in calcium signalling and its potential as a therapeutic target for NDs. Additionally, we highlight recent studies that utilise miniscope technology to investigate the alterations in calcium dynamics associated with NDs.}, } @article {pmid39791748, year = {2025}, author = {Moss, KR and Saxena, S}, title = {Schwann Cells in Neuromuscular Disorders: A Spotlight on Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {14}, number = {1}, pages = {}, pmid = {39791748}, issn = {2073-4409}, support = {K22 NS125057/NS/NINDS NIH HHS/United States ; }, mesh = {*Schwann Cells/pathology/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Humans ; Animals ; Neuromuscular Diseases/pathology ; Motor Neurons/pathology/metabolism ; Charcot-Marie-Tooth Disease/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease primarily affecting motor neurons, leading to progressive muscle atrophy and paralysis. This review explores the role of Schwann cells in ALS pathogenesis, highlighting their influence on disease progression through mechanisms involving demyelination, neuroinflammation, and impaired synaptic function. While Schwann cells have been traditionally viewed as peripheral supportive cells, especially in motor neuron disease, recent evidence indicates that they play a significant role in ALS by impacting motor neuron survival and plasticity, influencing inflammatory responses, and altering myelination processes. Furthermore, advancements in understanding Schwann cell pathology in ALS combined with lessons learned from studying Charcot-Marie-Tooth disease Type 1 (CMT1) suggest potential therapeutic strategies targeting these cells may support nerve repair and slow disease progression. Overall, this review aims to provide comprehensive insights into Schwann cell classification, physiology, and function, underscoring the critical pathological contributions of Schwann cells in ALS and suggests new avenues for targeted therapeutic interventions aimed at modulating Schwann cell function in ALS.}, } @article {pmid39791815, year = {2025}, author = {Rossi, A and Cuccioloni, M and Pellegrino, F and Giovannetti, R and Alladio, E}, title = {Discriminating Analysis of Metal Ions via Multivariate Curve Resolution-Alternating Least Squares Applied to Silver Nanoparticle Sensor.}, journal = {Nanomaterials (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {39791815}, issn = {2079-4991}, abstract = {Heavy metals are life-threatening pollutions because of their great toxicity, long-term persistence in nature and their bioaccumulation in living organisms. In this work, we performed multivariate curve resolution-alternating least squares analysis of UV-Vis raw spectra received by a colorimetric sensor constructed on mercaptoundecanoic acid functionalized silver nanoparticles (AgNPs@11MUA) to detect Cd[2+], Cu[2+], Mn[2+], Ni[2+], and Zn[2+] in water. This combined approach allowed the rapid identification and quantification of multiple heavy metals and showed adequate sensitivity and selectivity, thus representing a promising analytical and computational method for both laboratory and field applications such as environmental safety and public health monitoring.}, } @article {pmid39792201, year = {2025}, author = {Fu, Z and Feng, B and Akogo, HY and Ma, J and Liu, Y and Quan, H and Zhang, X and Hou, Y and Zhang, X and Ma, J and Cui, H}, title = {Amyotrophic Lateral Sclerosis and Parkinson's Disease: Brain Tissue Transcriptome Analysis Reveals Interactions.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {6383-6396}, pmid = {39792201}, issn = {1559-1182}, support = {81801278//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Parkinson Disease/genetics/metabolism ; *Brain/metabolism/pathology ; *Gene Expression Profiling/methods ; *Transcriptome/genetics ; Gene Regulatory Networks ; Protein Interaction Maps/genetics ; MicroRNAs/genetics/metabolism ; }, abstract = {This study utilises amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) human brain samples from the GEO database and employs differential expression gene (DEG) analysis to identify genes that are pivotal in both neurodegenerative diseases. Through in depth GO and KEGG enrichment analyses, we elucidated the biological functions and potential pathways associated with these DEGs. Furthermore, by constructing protein‒protein interaction networks, we highlight the significance of shared DEGs in both cellular physiology and disease contexts. Analysis of drug‒gene associations revealed potential therapeutic compounds linked to ALS and PD treatment. Additionally, we explored the interactions between transcription factors, miRNAs, and common DEGs, revealing aspects of gene regulatory networks. This study provides insights into the molecular mechanisms of ALS and PD, offering valuable contributions to ongoing research and potential therapeutic avenues.}, } @article {pmid39792557, year = {2025}, author = {Dykstra, MM and Weskamp, K and Gómez, NB and Waksmacki, J and Tank, E and Glineburg, MR and Snyder, A and Pinarbasi, E and Bekier, M and Li, X and Miller, MR and Bai, J and Shahzad, S and Nedumaran, N and Wieland, C and Stewart, C and Willey, S and Grotewold, N and McBride, J and Moran, JJ and Suryakumar, AV and Lucas, M and Tessier, PM and Ward, M and Todd, PK and Barmada, SJ}, title = {TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115113}, pmid = {39792557}, issn = {2211-1247}, support = {I01 BX004842/BX/BLRD VA/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; F31 NS134123/NS/NINDS NIH HHS/United States ; R35 GM136300/GM/NIGMS NIH HHS/United States ; F31 NS115257/NS/NINDS NIH HHS/United States ; T32 GM145470/GM/NIGMS NIH HHS/United States ; T32 GM007863/GM/NIGMS NIH HHS/United States ; K08 NS072233/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Protein Isoforms/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Nonsense Mediated mRNA Decay ; Animals ; *Homeostasis ; HEK293 Cells ; *Transcription, Genetic ; *Protein Processing, Post-Translational ; Mice ; }, abstract = {The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a by-product of TDP43 autoregulation and cleared by nonsense-mediated RNA decay (NMD). sTDP43-encoding transcripts that escape NMD are rapidly degraded post-translationally via the proteasome and macroautophagy. Circumventing these regulatory mechanisms by overexpressing sTDP43 results in neurodegeneration via N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA-binding-dependent gain-of-function toxicity. Collectively, these studies highlight endogenous mechanisms that tightly regulate sTDP43 expression and underscore the consequences of aberrant sTDP43 accumulation in disease.}, } @article {pmid39792652, year = {2026}, author = {Mercadante, S and Petronaci, P and Lo Cascio, A}, title = {Living Will and Advance Care Planning in Patients With Amyotrophic Lateral Sclerosis Admitted to Specialistic Home Palliative Care.}, journal = {The American journal of hospice & palliative care}, volume = {43}, number = {2}, pages = {139-143}, doi = {10.1177/10499091241312906}, pmid = {39792652}, issn = {1938-2715}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; *Palliative Care/organization & administration/legislation & jurisprudence ; Male ; *Advance Care Planning/organization & administration/legislation & jurisprudence/statistics & numerical data ; Female ; Aged ; Italy ; Middle Aged ; *Home Care Services/organization & administration ; Prospective Studies ; Aged, 80 and over ; Adult ; }, abstract = {Objectives: In Italy a recent law was approved for providing patients' wishes regarding end of life issues, commonly referred internationally to as "living wills", (Dichiarazione anticipata di trattamento, DAT). Regardless of this official document, advance care planning (ACP) is often used in a palliative care setting to share the treatments to start, to continue, to withdraw, thus preventing the stress on an acute decision. The aim of this study was to assess DAT and ACP in patients with amyotropic lateral sclerosis admitted to home palliative care. Methods: Patients consecutively admitted to speciliazed home palliative care were prospectively assessed. The presence of DAT or ACP was recorded. Results: Sixty-eight patients were enrolled in the period taken into consideration. No patient had drown up DAT, and only one patient provided his ACP prior to home palliative care admission. Along the course of home palliative care care assistance, 30.9% of patients provided their ACP. Discussion: In Italy DAT resulted scarcely widespread, despite an existing law, as no patient officially provided their indication on end of life issues. In addition, ACP was given only after starting specialized home palliative care in less than 1/3 of patients. Home palliative care seems to be a fundamental resource for improving communication and soliciting expression of patients' wishes regarding end of life issues.}, } @article {pmid39793633, year = {2025}, author = {Baker, RS and Wang, JT and Rouatbi, N and Lu, Y and Al-Adhami, T and Asker, D and Rahman, KM and Al-Chalabi, A and Forbes, B and Bansal, S and Al-Jamal, KT}, title = {Brain distribution study of [[14]C]-Riluzole following intranasal administration in mice.}, journal = {International journal of pharmaceutics}, volume = {670}, number = {}, pages = {125195}, doi = {10.1016/j.ijpharm.2025.125195}, pmid = {39793633}, issn = {1873-3476}, mesh = {Animals ; Administration, Intranasal ; *Brain/metabolism ; Male ; Mice ; *Riluzole/administration & dosage/pharmacokinetics ; Tissue Distribution ; Tetrahydroisoquinolines/pharmacology/administration & dosage ; Acridines/pharmacology/administration & dosage ; Carbon Radioisotopes ; Biological Availability ; Blood-Brain Barrier/metabolism ; *Neuroprotective Agents/pharmacokinetics/administration & dosage ; }, abstract = {Amyotrophic lateral sclerosis (ALS) presents a substantial challenge due to its complex nature, limited effective treatment options, and modest benefits from current therapies in slowing disease progression. This study explores the potential of intranasal (IN) delivery to enhance the CNS delivery of riluzole (RLZ), a standard ALS treatment which is subject to blood-brain barrier efflux mechanisms. Additionally, the impact of elacridar (ELC), an efflux pump inhibitor, on IN RLZ CNS bioavailability was examined. To quantify RLZ in vivo in mice, [[14]C]-RLZ was synthesised using an optimised one-pot method. [[14]C]-RLZ yield was 21.3 ± 3.4 %, measured by High Performance Liquid Chromatography (HPLC), with a specific activity of 40.4 ± 3.9 µCi/mg measured by HPLC and liquid scintillation counting. RLZ synthesis was verified using proton nuclear magnetic resonance ([1]H NMR), and liquid chromatography-mass spectrometry. IN RLZ (5 mg/kg) produced double the maximum brain levels (1.11 ± 0.34 % Injected Dose (ID)/brain) at 30 min as oral RLZ (5 mg/kg). The uptake of RLZ in the liver was reduced by half for intranasal administration compared to oral administration. Intravenous ELC (5 mg/kg) substantially increased brain levels of IN RLZ to 3.52 ± 0.62 % ID/g brain at 60 min post-administration, compared to 1.87 ± 0.33 % ID/g brain in the absence of the efflux pump inhibitor. However, increased concentrations were also observed in the liver and blood. These results indicate that intranasal delivery of RLZ enhances brain targeting and reduces liver accumulation compared to the oral route. Brain uptake of IN RLZ was enhanced further by ELC, although not selectively as accumulation in the liver or blood was also observed. Further metabolic research using Chromatography-Mass spectrometry (LC-MS) or NMR along with excretion studies are warranted for a more comprehensive understanding of the pharmacokinetics of IN RLZ and IN RLZ/ELC. Additionally, employing suitable ALS animal models is crucial for understanding RLZ's effects on disease progression, mechanism of action, efficacy, and potential side effects to aid further development.}, } @article {pmid39794401, year = {2025}, author = {Cheng, J and Wu, BT and Liu, HP and Lin, WY}, title = {Machine learning identified novel players in lipid metabolism, endosomal trafficking, and iron metabolism of the ALS spinal cord.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1564}, pmid = {39794401}, issn = {2045-2322}, support = {CMU110-MF-92//China Medical University, Taiwan/ ; CMU112-MF-62//China Medical University, Taiwan/ ; MOST 111-2314-B-039-017-MY3//National Science and Technology Council of Taiwan/ ; DMR-112-125//China Medical University Hospital, Taiwan/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; *Iron/metabolism ; *Machine Learning ; *Lipid Metabolism/genetics ; *Spinal Cord/metabolism/pathology ; *Endosomes/metabolism ; Mitochondria/metabolism ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Although genes causing familial cases have been identified, those of sporadic ALS, which occupies the majority of patients, are still elusive. In this study, we adopted machine learning to build binary classifiers based on the New York Genome Center (NYGC) ALS Consortium's RNA-seq data of the postmortem spinal cord of ALS and non-neurological disease control. The accuracy of the classifiers was greater than 83% and 77% for the training set and the unseen test set, respectively. The classifiers contained 114 genes. Among them, 41 genes have been reported in previous ALS studies, and others are novel in this field. These genes are involved in mitochondrial respiration, lipid metabolism, endosomal trafficking, and iron metabolism, which may promote the progression of ALS pathology.}, } @article {pmid39794859, year = {2025}, author = {Niccolai, E and Di Gloria, L and Trolese, MC and Fabbrizio, P and Baldi, S and Nannini, G and Margotta, C and Nastasi, C and Ramazzotti, M and Bartolucci, G and Bendotti, C and Nardo, G and Amedei, A}, title = {Correction: Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1G93A mice.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {5}, pmid = {39794859}, issn = {2051-5960}, } @article {pmid39795334, year = {2024}, author = {Bhattacharya, S and Sen, MK and Hamouzová, K and Košnarová, P and Bharati, R and Menendez, J and Soukup, J}, title = {Pyroxsulam Resistance in Apera spica-venti: An Emerging Challenge in Crop Protection.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, pmid = {39795334}, issn = {2223-7747}, support = {QL24010167//National Agency for Agricultural Research (NAZV)/ ; }, abstract = {Apera spica-venti, a prevalent weed in Czech winter wheat fields, has developed resistance to ALS-inhibiting herbicides due to their frequent use. This study reports a biotype of A. spica-venti resistant to pyroxsulam, with cross and multiple resistance to iodosulfuron, propoxycarbazone, pinoxaden, and chlortoluron. Dose-response experiments revealed high resistance of both R1 and R2 biotypes to pyroxsulam, with resistance factors (RF) of 6.69 and 141.65, respectively. Pre-treatment with malathion reduced RF by 2.40× and 1.25× in R1 and R2, indicating the potential involvement of cytochrome P450 (CytP450). NBD-Cl pre-treatment decreased RF only in R2, suggesting possible GST involvement. Gene analysis revealed no mutations (at previously reported sites) or overexpression in the acetolactate synthase (ALS) gene. However, a significant difference in ALS enzyme activity between resistant and susceptible biotypes points to target-site resistance mechanisms. Studies with [14]C-labeled pyroxsulam showed that reduced absorption and translocation were not likely resistance mechanisms. In summary, herbicide resistance in A. spica-venti appears to result from multiple mechanisms. Possible causes include target-site resistance from an unidentified ALS mutation (within coding or regulatory regions). Enhanced herbicide metabolism via CytP450s and GSTs is also a contributing factor. Further experimental validation is needed to confirm these mechanisms and fully understand the resistance. This evolution underscores the adaptive capacity of weed populations under herbicide pressure, emphasizing the need for alternative control strategies.}, } @article {pmid39796536, year = {2024}, author = {Cuffaro, F and Lamminpää, I and Niccolai, E and Amedei, A}, title = {Nutritional and Microbiota-Based Approaches in Amyotrophic Lateral Sclerosis: From Prevention to Treatment.}, journal = {Nutrients}, volume = {17}, number = {1}, pages = {}, pmid = {39796536}, issn = {2072-6643}, support = {PNRR-MAD-2022-12375798//Ministero della Salute/ ; PE0000006//Ministry of University and Research (MUR)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/prevention & control/therapy/microbiology/diet therapy ; Humans ; *Gastrointestinal Microbiome/physiology ; Probiotics ; Dysbiosis ; Prebiotics/administration & dosage ; Fecal Microbiota Transplantation ; Oxidative Stress ; Fatty Acids, Omega-3/administration & dosage ; }, abstract = {Metabolic alterations, including hypermetabolism, lipid imbalances, and glucose dysregulation, are pivotal contributors to the onset and progression of Amyotrophic Lateral Sclerosis (ALS). These changes exacerbate systemic energy deficits, heighten oxidative stress, and fuel neuroinflammation. Simultaneously, gastrointestinal dysfunction and gut microbiota (GM) dysbiosis intensify disease pathology by driving immune dysregulation, compromising the intestinal barrier, and altering gut-brain axis (GBA) signaling, and lastly advancing neurodegeneration. Therapeutic and preventive strategies focused on nutrition offer promising opportunities to address these interconnected pathophysiological mechanisms. Diets enriched with antioxidants, omega-3 fatty acids, and anti-inflammatory compounds-such as the Mediterranean diet-have shown potential in reducing oxidative stress and systemic inflammation. Additionally, microbiota-targeted approaches, including probiotics, prebiotics, postbiotics, and fecal microbiota transplantation, are emerging as innovative tools to restore microbial balance, strengthen gut integrity, and optimize GBA function. This review highlights the critical need for personalized strategies integrating immunonutrition and microbiota modulation to slow ALS progression, improve quality of life, and develop preventive measures for neurodegenerative and neuroinflammatory diseases. Future research should prioritize comprehensive dietary and microbiota-based interventions to uncover their therapeutic potential and establish evidence-based guidelines for managing ALS and related disorders.}, } @article {pmid39797438, year = {2025}, author = {Zeng, Y and Liu, M and Qian, H and Zhao, H and Fang, Y and Yu, Q and Bai, L and Pan, L}, title = {Investigating non-target site resistance to pyroxsulam in a glyphosate-resistant Lolium rigidum population.}, journal = {Pest management science}, volume = {81}, number = {6}, pages = {2751-2758}, doi = {10.1002/ps.8636}, pmid = {39797438}, issn = {1526-4998}, support = {//the National Key RandD Program of China (no. 2023YFD1401100)/ ; //National Natural Science Foundation of China (32372568 and 32130091)/ ; //Young Elite Scientists Sponsorship Program by CAST (2021QNRC001)/ ; //Earmarked Fund for China Agriculture Research System (CARS-16-E19)/ ; //Postgraduate Scientific Research Innovation Project of Hunan Province (QL20230088)/ ; //Scientific Research Fund of Hunan Provincial Education Department (23B0225)/ ; //National Natural Science Foundation of China (U23A20174)/ ; //Australian Grains and Research Development and Corporation (GRDC)/ ; }, mesh = {*Herbicide Resistance/genetics ; Glyphosate ; *Herbicides/pharmacology ; *Glycine/analogs & derivatives/pharmacology ; *Lolium/drug effects/genetics ; Acetolactate Synthase/antagonists & inhibitors/metabolism/genetics ; Acetyl-CoA Carboxylase/antagonists & inhibitors ; Plant Proteins/genetics/metabolism ; Isoxazoles ; Tetrazoles ; }, abstract = {BACKGROUND: Resistance to multiple herbicides is common in Lolium rigidum. Here, resistance to acetolactate synthase (ALS)- and susceptibility to acetyl-CoA carboxylase (ACCase)-inhibiting herbicides was confirmed in a glyphosate-resistant L. rigidum population (NLR70) from Australia and the mechanisms of pyroxsulam resistance were examined.

RESULTS: No ALS target-site mutations nor gene overexpression were detected. Cytochrome P450 monooxygenase (P450) and glutathione S-transferase (GST) inhibitors (indicators of some certain P450s or GSTs) did not significantly affect the resistance to pyroxsulam. Nevertheless, HPLC analysis showed that plants of the NLR70 population metabolized pyroxsulam faster than plants of the herbicide-susceptible population (SVLR1). RNA sequencing analysis and RT-qPCR validation confirmed that four P450s (CYP709B2, CYP72A14, CYP89A2, CYP94B3), one GT (UGT79), and one ABC transporter (ABCG41) genes were constitutively upregulated in NLR70 plants.

CONCLUSION: This study demonstrates that the glyphosate-resistant L. rigidum population (NLR70) also exhibits resistance to pyroxsulam and identifies six candidate genes associated with non-target site resistance to pyroxsulam. © 2025 Society of Chemical Industry.}, } @article {pmid39798254, year = {2025}, author = {Cao, S and Fu, X and Li, W and Wang, P and Li, C and Shang, H}, title = {Protective role of apolipoprotein A and B in Parkinson's disease: A prospective study from UK Biobank.}, journal = {Parkinsonism & related disorders}, volume = {132}, number = {}, pages = {107266}, doi = {10.1016/j.parkreldis.2025.107266}, pmid = {39798254}, issn = {1873-5126}, mesh = {Humans ; Male ; *Parkinson Disease/blood/epidemiology ; Female ; United Kingdom/epidemiology ; Aged ; Middle Aged ; Prospective Studies ; Biological Specimen Banks ; *Apolipoproteins A/blood ; *Apolipoprotein B-100/blood ; *Apolipoproteins B/blood ; UK Biobank ; }, abstract = {INTRODUCTION: Evidence have indicated relation between apolipoproteins and neurodegenerative disorders (NDDs). However, previous studies have produced inconsistent results, and a comprehensive analysis of apolipoproteins in NDDs is currently lacking.

METHODS: Using Cox proportional hazards regression analysis based on data from UK Biobank, we examined the association between baseline serum levels of apolipoprotein A (ApoA) and apolipoprotein B (ApoB) and risk of Parkinson's disease (PD), Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and multiple sclerosis.

RESULTS: Elevated baseline levels of serum ApoA (HR = 0.84, 95 % CI: 0.71-0.99, P = 0.047) and ApoB (HR = 0.67, 95 % CI: 0.57-0.78, P = 3.18E-07) were associated with a reduced risk of incident PD. Subgroup analyses suggested the protective effect of serum ApoA was more significant for older participants and those with lower alcohol consumption, while higher serum ApoB was a more significant protective factor in males and those without stroke. No significant associations were found between apolipoproteins and other NDDs.

CONCLUSION: Increased baseline levels of serum ApoA and ApoB are linked to a lower risk of PD. These findings enhance understanding of the role of apolipoproteins in PD, and have implications for the development of therapeutic strategies in clinical trials.}, } @article {pmid39798853, year = {2025}, author = {Guan, D and Liang, C and Zheng, D and Liu, S and Luo, J and Cai, Z and Zhang, H and Chen, J}, title = {The role of mitochondrial remodeling in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {183}, number = {}, pages = {105927}, doi = {10.1016/j.neuint.2024.105927}, pmid = {39798853}, issn = {1872-9754}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Energy Metabolism/physiology ; *Mitochondrial Dynamics/physiology ; }, abstract = {Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.}, } @article {pmid39798947, year = {2026}, author = {Sorice, V and Ekumah, ND}, title = {Exploring the psychosocial dimensions and impacts of infertility in Africa: a commentary on Roomaney et al's scoping review of current evidence.}, journal = {Evidence-based nursing}, volume = {29}, number = {2}, pages = {111-112}, pmid = {39798947}, issn = {1468-9618}, } @article {pmid39799044, year = {2025}, author = {Bracca, V and Premi, E and Cotelli, MS and Micheli, A and Altomare, D and Cantoni, V and Gasparotti, R and Borroni, B}, title = {Loss of Insight in Syndromes Associated with Frontotemporal Lobar Degeneration: Clinical and Imaging Features.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {33}, number = {4}, pages = {450-462}, doi = {10.1016/j.jagp.2024.12.005}, pmid = {39799044}, issn = {1545-7214}, mesh = {Humans ; Male ; Female ; Aged ; *Frontotemporal Lobar Degeneration/diagnostic imaging/pathology/psychology/physiopathology/complications ; Magnetic Resonance Imaging ; Longitudinal Studies ; Retrospective Studies ; Middle Aged ; *Aphasia, Primary Progressive/diagnostic imaging/physiopathology/pathology ; *Brain/diagnostic imaging/pathology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; Atrophy ; }, abstract = {OBJECTIVES: The present study aims to assess the prevalence, associated clinical symptoms, longitudinal changes, and imaging correlates of Loss of Insight (LOI), which is still unexplored in syndromes associated with Frontotemporal Lobar Degeneration (FTLD).

DESIGN: Retrospective longitudinal cohort study, from Oct 2009 to Feb 2023.

SETTING: Tertiary Frontotemporal Dementia research clinic.

PARTICIPANTS: A sample of 712 FTLD patients, 331 of whom had follow-up evaluation.

MEASUREMENTS: LOI was assessed by interview with the primary caregiver. Univariate and multiple logistic regression and linear mixed models were used to estimate predictors and longitudinal changes over time associated with LOI. Voxel-based morphometry and structural covariance analyses of brain structural MRI images were implemented in Statistical Parametric Mapping.

RESULTS: LOI was reported in 45% of patients (321/712, 95%CI = 41-49), with progressively increased prevalence from prodromal to severe dementia stages. LOI was more prevalent in the behavioural variant FTD, in the semantic variant of Primary Progressive Aphasia (svPPA) and FTD with Amyotrophic Lateral Sclerosis than in other phenotypes (all p-values<0.001). LOI severity increased over time only in patients with svPPA (β = +0.59, p <0.001) and clustered with other behavioral symptoms (all p-values <0.05). Finally, LOI was significantly associated with greater atrophy in the right medial orbital gyrus (p <0.001 uncorrected). Structural covariance analysis demonstrated loss of negative correlation between right medial orbital gyrus and regions belonging to the Default Mode Network (DMN), such as the left precuneus and the left angular gyrus (p ≤0.05 family-wise error-corrected) in FTLD patients with LOI.

CONCLUSIONS: A better comprehension of LOI mechanisms could lead to more effective interventions and healthcare policies.}, } @article {pmid39799324, year = {2025}, author = {Freiha, J and Grand, E and Marshall, B and Arunchalam, R and Pinto, A and Osman, C}, title = {Amyotrophic lateral sclerosis in a patient with chronic lymphocytic leukaemia and drug related sarcoid-like reaction.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {16}, pmid = {39799324}, issn = {1471-2377}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/chemically induced ; Middle Aged ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/complications ; *Sarcoidosis/chemically induced/diagnosis/complications ; Rituximab/adverse effects ; Sulfonamides/adverse effects ; }, abstract = {Sarcoid-like reaction is an immunological reaction that can affect lymph nodes and organs but does not meet the diagnostic criteria for systemic sarcoidosis. Anti-CD20 auto-antibodies have been reported to be responsible for such reactions. There are several reported associations between Chronic lymphocytic leukaemia (CLL), Amyotrophic lateral sclerosis (ALS) and Sarcoid-like reactions (SLR). We report a case of ALS developing in a patient with treated CLL and drug related SLR one day after exposure to Venetoclax and Rituximab. A 60-year-old male presented with lower limb rash, left leg weakness followed by bulbar symptoms which progressed over 12-months. Workup demonstrated a Cerebrospinal fluid (CSF) pleocytosis and inguinal lymphadenopathy. Skin and inguinal lymph node biopsies showed non-necrotising granulomata. Electromyography met diagnostic criteria for ALS. He was treated for presumed neurosarcoidosis mimicking ALS. Despite prednisolone and infliximab treatment, the motor symptoms rapidly progressed; Hence, we made a clinical diagnosis of ALS. We discuss the diagnostic and treatment challenges of this case.}, } @article {pmid39799393, year = {2025}, author = {Valenzuela, V and Becerra, D and Astorga, JI and Fuentealba, M and Diaz, G and Bargsted, L and Chacón, C and Martinez, A and Gozalvo, R and Jackson, K and Morales, V and Heras, ML and Tamburini, G and Petrucelli, L and Sardi, SP and Plate, L and Hetz, C}, title = {Artificial enforcement of the unfolded protein response reduces disease features in multiple preclinical models of ALS/FTD.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {3}, pages = {1226-1245}, pmid = {39799393}, issn = {1525-0024}, mesh = {Animals ; *Unfolded Protein Response/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology ; Disease Models, Animal ; Mice ; *Frontotemporal Dementia/metabolism/genetics/therapy/pathology ; *X-Box Binding Protein 1/genetics/metabolism ; Humans ; Dependovirus/genetics ; Endoplasmic Reticulum Stress/genetics ; Mice, Transgenic ; Genetic Vectors/administration & dosage/genetics ; Superoxide Dismutase-1/genetics ; Genetic Therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a spectrum of diseases that share several causative genes, resulting in a combinatory of motor and cognitive symptoms and abnormal protein aggregation. Multiple unbiased studies have revealed that proteostasis impairment at the level of the endoplasmic reticulum (ER) is a transversal pathogenic feature of ALS/FTD. The transcription factor XBP1s is a master regulator of the unfolded protein response (UPR), the main adaptive pathway to cope with ER stress. Here, we provide evidence of suboptimal activation of the UPR in ALS/FTD models under experimental ER stress. To artificially engage the UPR, we intracerebroventricularly administrated adeno-associated viruses (AAVs) to express the active form of XBP1 (XBP1s) in the nervous system of ALS/FTD models. XBP1s expression improved motor performance and extended lifespan of mutant SOD1 mice, associated with reduced protein aggregation. AAV-XBP1s administration also attenuated disease progression in models of TDP-43 and C9orf72 pathogenesis. Proteomic profiling of spinal cord tissue revealed that XBP1s overexpression improved proteostasis and modulated the expression of a cluster of synaptic and cell morphology proteins. Our results suggest that strategies to improve ER proteostasis may serve as a pan-therapeutic strategy to treat ALS/FTD.}, } @article {pmid39799559, year = {2025}, author = {Üremiş, N and Üremiş, MM}, title = {Oxidative/Nitrosative Stress, Apoptosis, and Redox Signaling: Key Players in Neurodegenerative Diseases.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {1}, pages = {e70133}, pmid = {39799559}, issn = {1099-0461}, support = {//This research was supported by the Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (grant number: TUB1)./ ; }, mesh = {Humans ; *Apoptosis ; *Oxidative Stress ; *Neurodegenerative Diseases/metabolism/pathology ; *Nitrosative Stress ; Animals ; *Signal Transduction ; Oxidation-Reduction ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases are significant health concerns that have a profound impact on the quality and duration of life for millions of individuals. These diseases are characterized by pathological changes in various brain regions, specific genetic mutations associated with the disease, deposits of abnormal proteins, and the degeneration of neurological cells. As neurodegenerative disorders vary in their epidemiological characteristics and vulnerability of neurons, treatment of these diseases is usually aimed at slowing disease progression. The heterogeneity of genetic and environmental factors involved in the process of neurodegeneration makes current treatment methods inadequate. However, the existence of common molecular mechanisms in the pathogenesis of these diseases may allow the development of new targeted therapeutic strategies. Oxidative and nitrosative stress damages membrane components by accumulating ROS and RNS and disrupting redox balance. This process results in the induction of apoptosis, which is important in the pathogenesis of neurodegenerative diseases through oxidative stress. Studies conducted using postmortem human samples, animal models, and cell cultures have demonstrated that oxidative stress, nitrosative stress, and apoptosis are crucial factors in the development of diseases such as Alzheimer's, Parkinson's, Multiple Sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. The excessive production of reactive oxygen and nitrogen species, elevated levels of free radicals, heightened mitochondrial stress, disturbances in energy metabolism, and the oxidation and nitrosylation of cellular macromolecules are recognized as triggers for neuronal cell death. Challenges in managing and treating neurodegenerative diseases require a better understanding of this field at the molecular level. Therefore, this review elaborates on the molecular mechanisms by which oxidative and nitrosative stress are involved in neuronal apoptosis.}, } @article {pmid39801319, year = {2025}, author = {Oliveira Santos, M and Domingues, S and Simão, S and Gromicho, M and Alves, I and de Carvalho, M}, title = {The Role of Gastrostomy and Noninvasive Ventilation in Primary Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {71}, number = {3}, pages = {450-456}, doi = {10.1002/mus.28346}, pmid = {39801319}, issn = {1097-4598}, mesh = {Humans ; *Gastrostomy/methods ; *Noninvasive Ventilation/methods ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; *Respiratory Insufficiency/therapy/etiology ; *Deglutition Disorders/etiology/therapy ; Adult ; *Motor Neuron Disease/therapy/complications ; }, abstract = {INTRODUCTION/AIMS: Literature on the role of gastrostomy and noninvasive ventilation (NIV) in primary lateral sclerosis (PLS) is limited. We aim to investigate whether PLS patients develop dysphagia requiring feeding tubes or respiratory failure necessitating NIV.

METHODS: We conducted a retrospective study of PLS patients with a definite diagnosis followed at our center (1994-2024). Patients with marked dysphagia (score < 3 on Question 3 of the ALSFRS-R) received a recommendation for gastrostomy and were divided into two groups: G1/G2 (accepted/declined gastrostomy). We investigated NIV indications due to respiratory failure and compared these patients (G3) to those without respiratory impairment (G4). Demographic, clinical, and neurophysiological data were collected and compared.

RESULTS: Forty-eight patients had a definite diagnosis of PLS. Gastrostomy was recommended to 18 (37.5%), yet only 7 patients (38.9%-G1) consented. The median time to gastrostomy was 77 months. Total survival and survival post-gastrostomy recommendation were not different between G1 and G2. Six PLS patients (12.5%-G3) developed respiratory failure and initiated NIV (median of 63 months). At 63 months, G3 had significantly lower median forced vital capacity (65% vs. 99%; p < 0.001) and phrenic nerve amplitude (0.43 vs. 0.75 mV; p = 0.039), but a greater ALSFRS-R slope (0.34 vs. 0.14; p = 0.046) and shorter survival (35 vs. 94.9 months; p = 0.009) compared to G4.

DISCUSSION: Dysphagia requiring gastrostomy was common in our PLS cohort, but survival after gastrostomy recommendation did not differ between groups. Patients who developed respiratory impairment may represent a distinct group with faster disease progression and shorter survival. Our findings may contribute to a deeper understanding and improved management of PLS.}, } @article {pmid39801516, year = {2024}, author = {Kamiyama, D and Nishida, Y and Kamiyama, R and Sego, A and Vining, G and Bui, K and Fitch, M and Do, H and Avraham, O and Chihara, T}, title = {The VAPB Axis Precisely Coordinates the Timing of Motoneuron Dendritogenesis in Neural Map Development.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39801516}, issn = {2693-5015}, support = {P40 OD018537/OD/NIH HHS/United States ; R01 NS107558/NS/NINDS NIH HHS/United States ; }, abstract = {In Drosophila motoneurons, spatiotemporal dendritic patterns are established in the ventral nerve cord. While many guidance cues have been identified, the mechanisms of temporal regulation remain unknown. Previously, we identified the actin modulator Cdc42 GTPase as a key factor in this process. In this report, we further identify the upstream factors that activate Cdc42. Using single-cell genetics, FRET-based imaging, and biochemical techniques, we demonstrate that the guanine nucleotide exchange factor Vav is anchored to the plasma membrane via the Eph receptor tyrosine kinase, enabling Cdc42 activation. VAMP-associated protein 33 (Vap33), an Eph ligand supplied non-cell-autonomously, may induce Eph autophosphorylation, initiating downstream signaling. Traditionally known as an ER-resident protein, Vap33 is secreted extracellularly at the onset of Cdc42 activation, acting as a temporal cue. In humans, VAPB-the ortholog of Vap33-is similarly secreted in the spinal cord, and its dysregulation leads to amyotrophic lateral sclerosis type 8 (ALS8) and spinal muscular atrophy (SMA). Our findings provide a framework linking VAPB signaling to motor circuitry formation in both health and disease.}, } @article {pmid39801778, year = {2025}, author = {Ngo, HM and Khatib, T and Thai, MT and Kahveci, T}, title = {QOMIC: quantum optimization for motif identification.}, journal = {Bioinformatics advances}, volume = {5}, number = {1}, pages = {vbae208}, pmid = {39801778}, issn = {2635-0041}, abstract = {MOTIVATION: Network motif identification (MI) problem aims to find topological patterns in biological networks. Identifying disjoint motifs is a computationally challenging problem using classical computers. Quantum computers enable solving high complexity problems which do not scale using classical computers. In this article, we develop the first quantum solution, called QOMIC (Quantum Optimization for Motif IdentifiCation), to the MI problem. QOMIC transforms the MI problem using a integer model, which serves as the foundation to develop our quantum solution. We develop and implement the quantum circuit to find motif locations in the given network using this model.

RESULTS: Our experiments demonstrate that QOMIC outperforms the existing solutions developed for the classical computer, in term of motif counts. We also observe that QOMIC can efficiently find motifs in human regulatory networks associated with five neurodegenerative diseases: Alzheimer's, Parkinson's, Huntington's, Amyotrophic Lateral Sclerosis, and Motor Neurone Disease.

Our implementation can be found in https://github.com/ngominhhoang/Quantum-Motif-Identification.git.}, } @article {pmid39801792, year = {2024}, author = {Ansari, U and Wen, J and Syed, B and Nadora, D and Sedighi, R and Nadora, D and Chen, V and Lui, F}, title = {Analyzing the potential of neuronal pentraxin 2 as a biomarker in neurological disorders: A literature review.}, journal = {AIMS neuroscience}, volume = {11}, number = {4}, pages = {505-519}, pmid = {39801792}, issn = {2373-7972}, abstract = {Neuronal pentraxin 2 (NP2) plays a significant role in synaptic plasticity, neuronal survival, and excitatory synapse regulation. Emerging research suggests that NP2 is implicated in the pathogenesis of various neurological disorders, including neurodegenerative diseases, neuropsychiatric disorders, and neuropathies. This literature review extensively analyzes NP2's role in these conditions, thereby highlighting its contributions to synaptic dysfunction, neuroinflammation, and neurotoxic protein aggregation. In Alzheimer's and Parkinson's diseases, NP2 is linked to amyloid-beta aggregation and dopaminergic neuron degeneration, respectively. Additionally, altered NP2 expression is observed in schizophrenia and bipolar disorder, thus suggesting its involvement in synaptic dysfunction and neurotransmitter imbalance. In neuropathic pain and epilepsy, NP2 modulates the synaptic plasticity and inflammatory responses, with altered levels correlating with disease severity. Furthermore, NP2's involvement in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) emphasizes its broad impact on neuronal health. Understanding NP2's multifaceted roles may reveal novel therapeutic targets and improve the clinical outcomes for these neurological disorders. Though the precise role of NP2 remains uncertain, its clinical potential and initial findings justify further investigations into neuronal pentraxins and other related neuroproteins.}, } @article {pmid39801873, year = {2025}, author = {Kumar, AJ and Sathiyaseelan, N and Vinodh, JB and Vignesh, A and Rathi, NK}, title = {Recent Advances in Managing Ankylosing Spondylitis with Andersson Lesion: A Clinical Overview and Case Report.}, journal = {Journal of orthopaedic case reports}, volume = {15}, number = {1}, pages = {21-25}, pmid = {39801873}, issn = {2250-0685}, abstract = {INTRODUCTION: Ankylosing spondylitis (AS) is a chronic inflammatory disorder that primarily affects the spine and sacroiliac joints, leading to pain, stiffness, and progressive thoracolumbar kyphotic deformity. A key complication in advanced AS is the development of Andersson lesions (AL), degenerative vertebral lesions resulting from the disease's progression. These lesions can cause significant mechanical pain, often mistaken for the chronic discomfort associated with AS. The exact cause of AL remains unclear, with hypotheses ranging from spinal stress fractures to delays in the ankylosing process. Understanding AL's pathophysiology is essential for timely diagnosis and effective management.

CASE REPORT: A 52-year-old male presented with a 20-year history of diffuse abdominal pain, later developing insidious lower back pain over the past 2 months. The pain was aggravated by walking and prolonged standing. Physical examination revealed tenderness in the D11 region of the spine, with limited chest expansion and positive findings on the modified Schober's test. Radiographic studies showed irregularities and erosions at the D11-D12 vertebral levels, and magnetic resonance imaging confirmed the presence of an AL associated with asymmetrical bilateral sacroiliitis. The patient tested positive for human leukocyte antigen-B27, supporting a diagnosis of AS with an AL. Medical management, including methotrexate, sulfasalazine, non-steroidal anti-inflammatory drugs, and corticosteroids, led to significant pain reduction and improved mobility. The patient's condition remained stable with continued treatment over a 2-year follow-up period.

CONCLUSION: AL s are chronic, often overlooked complications of AS that can lead to spinal instability and neurological deficits if untreated. Early recognition and management are critical to preventing progressive kyphotic deformities and associated complications. While conservative treatment remains the cornerstone for managing AL, surgical intervention may be required in cases of severe pain, deformity, or neurological involvement. Understanding AL's presentation and treatment options is vital for improving patient outcomes in AS.}, } @article {pmid39802934, year = {2025}, author = {Ogonah, MGT and Botchway, S and Yu, R and Schofield, PW and Fazel, S}, title = {An umbrella review of health outcomes following traumatic brain injury.}, journal = {Nature. Mental health}, volume = {3}, number = {1}, pages = {83-91}, pmid = {39802934}, issn = {2731-6076}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {While numerous reviews have assessed the association between traumatic brain injury (TBI) and various mental and physical health outcomes, a comprehensive evaluation of the scope, validity, and quality of evidence is lacking. Here we present an umbrella review of a wide range of health outcomes following TBI and outline outcome risks across subpopulations. On 17 May 2023, we searched Embase, Medline, Global Health, PsycINFO, and Cochrane Database of Systematic Reviews for systematic reviews and meta-analyses. We compared risk ratios across different outcomes for risks compared with people without TBI and examined study quality, including heterogeneity, publication bias, and prediction intervals. The study was registered with PROSPERO (CRD42023432255). We identified 24 systematic reviews and meta-analyses covering 24 health outcomes in 31,397,958 participants. The current evidence base indicates an increased risk of multiple mental and physical health outcomes, including psychotic disorders, attention-deficit/hyperactivity disorder, suicide, and depression. Three outcomes-dementia, violence perpetration, and amyotrophic lateral sclerosis-had meta-analytical evidence of at least moderate quality, which suggest targets for more personalized assessment. Health-care services should review how to prevent adverse long-term outcomes in TBI.}, } @article {pmid39803328, year = {2025}, author = {Niu, T and Wang, P and Zhou, X and Liu, T and Liu, Q and Li, R and Yang, H and Dong, H and Liu, Y}, title = {An overlap-weighted analysis on the association of constipation symptoms with disease progression and survival in amyotrophic lateral sclerosis: a nested case-control study.}, journal = {Therapeutic advances in neurological disorders}, volume = {18}, number = {}, pages = {17562864241309811}, pmid = {39803328}, issn = {1756-2856}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and rare neurodegenerative disease. Therefore, evaluating the risk factors affecting the survival of patients with ALS is crucial. Constipation, a common but overlooked symptom of ALS, can be effectively managed. It is currently unknown whether constipation contributes to the progression and survival of ALS.

OBJECTIVES: This study aimed to investigate the association between constipation and ALS development and survival using a novel overlap-weighted (OW) method to enhance the robustness and reliability of results.

DESIGN: This prospective matching nested case-control (NCC) study was conducted within an ongoing ALS cohort at the Second Hospital of Hebei Medical University. Baseline data were collected from patients meeting the inclusion and exclusion criteria, with constipation as the exposure factor. A 9-month follow-up was conducted, with death as the endpoint event.

METHODS: We primarily used the OW method in NCC studies to examine the association between constipation and ALS development and survival. Weighted Cox proportional hazards model was used to assess risk factors associated with overall survival. Survival differences between the two groups were analyzed using Kaplan-Meier's plots and log-rank tests. Finally, the bioinformatic analysis explored common pathways between ALS and constipation.

RESULTS: Among the 190 patients included, the prevalence of constipation was 50%. Patients with ALS constipation exhibited faster disease progression (p < 0.001), with a positive correlation between constipation severity and progression rate (r = 0.356, p < 0.001). The constipation group had poorer survival before and after OW (log-rank test, p < 0.0001). In the Cox proportional hazards model of 114 patients, constipation was a risk factor for ALS both before (hazard ratio (HR) = 5.840, 95% confidence interval (CI) = 1.504-22.675, p = 0.011) and after (HR = 5.271, 95% CI = 1.241-22.379, p = 0.024) OW.

CONCLUSION: Constipation in individuals with ALS is associated with faster disease progression and reduced survival rates, potentially through the peroxisome proliferator-activated receptor pathway.}, } @article {pmid39804470, year = {2025}, author = {Edgar, S and Zulhairy-Liong, NA and Ellis, M and Trivedi, S and Zhu, D and Odongo, JO and Goh, KJ and Capelle, DP and Shahrizaila, N and Kennerson, ML and Ahmad-Annuar, A}, title = {ATXN2 polyglutamine intermediate repeats length expansions in Malaysian patients with amyotrophic lateral sclerosis (ALS).}, journal = {Neurogenetics}, volume = {26}, number = {1}, pages = {19}, pmid = {39804470}, issn = {1364-6753}, support = {FRGS/1/2018/SKK08/UM/01/1//Malaysian Ministry of Education Fundamental Research Grant Scheme/ ; IF091-2022//ALS Association Seed Grant/ ; IF095-2023//ALS Association Seed Grant/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; *Ataxin-2/genetics ; Genetic Predisposition to Disease ; Malaysia ; *Peptides/genetics ; *Trinucleotide Repeat Expansion/genetics ; Southeast Asian People/genetics ; }, abstract = {Intermediate CAG repeats from 29 to 33 in the ATXN2 gene contributes to the risk of amyotrophic lateral sclerosis (ALS) in European and Asian populations. In this study, 148 ALS patients of multiethnic descent: Chinese (56.1%), Malay (24.3%), Indian (12.8%), others (6.8%) and 100 neurologically normal controls were screened for the ATXN2 CAG repeat expansion. The most common repeat length in both the controls and patients was 22. No familial ALS patients were positive for the intermediate repeat sizes (29-33), while four sporadic patients (2.8%) were positive, with one harbouring a rare ATXN2 homozygous 32 repeat expansion, and a likely pathogenic variant in SPAST. All four patients had limb-onset ALS. Despite representing the smallest ethnic group in our patient cohort, three of the four patients with intermediate repeat sizes were of Indian ancestry. This study, which is the first in Malaysia and Southeast Asia, shows that ATXN2 intermediate risk expansions are relevant to ALS in these populations and will help to inform future genetic testing strategies in the clinic.}, } @article {pmid39804774, year = {2025}, author = {Agnihotri, D and Lee, CC and Lu, PC and He, RY and Huang, YA and Kuo, HC and Huang, JJ}, title = {C9ORF72 poly-PR induces TDP-43 nuclear condensation via NEAT1 and is modulated by HSP70 activity.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115173}, doi = {10.1016/j.celrep.2024.115173}, pmid = {39804774}, issn = {2211-1247}, mesh = {Humans ; *HSP70 Heat-Shock Proteins/metabolism ; *C9orf72 Protein/metabolism/genetics ; *DNA-Binding Proteins/metabolism ; *Cell Nucleus/metabolism ; *RNA, Long Noncoding/metabolism/genetics ; *Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; }, abstract = {The toxicity of C9ORF72-encoded polyproline-arginine (poly-PR) dipeptide is associated with its ability to disrupt the liquid-liquid phase separation of intrinsically disordered proteins participating in the formation of membraneless organelles, such as the nucleolus and paraspeckles. Amyotrophic lateral sclerosis (ALS)-related TAR DNA-binding protein 43 (TDP-43) also undergoes phase separation to form nuclear condensates (NCs) in response to stress. However, whether poly-PR alters the nuclear condensation of TDP-43 in ALS remains unclear. In this study, we find that the poly-PR dipeptide enhances the formation of TDP-43 NCs with decreased fluidity. While the non-coding RNA, nuclear-enriched abundant transcript 1 (NEAT1), is essential for the formation of TDP-43 NCs, heat shock protein 70 (HSP70) chaperone maintains their fluidity. Under prolonged poly-PR stress, HSP70 delocalizes from TDP-43 NCs, leading to the oligomerization of TDP-43 within these condensates. This phenomenon is accompanied with TDP-43 mislocalization and increasing cytotoxicity. Our study demonstrates the role of NEAT1 and HSP70 in the aberrant phase transition of TDP-43 NCs under poly-PR stress.}, } @article {pmid39805247, year = {2025}, author = {Uzunçakmak-Uyanık, H and Yıldız, FG and Tan, E and Temuçin, ÇM}, title = {Thoracic paraspinal muscle concentric needle electrode jitter analysis in electrophysiological diagnosis of ALS.}, journal = {Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology}, volume = {81}, number = {}, pages = {102975}, doi = {10.1016/j.jelekin.2025.102975}, pmid = {39805247}, issn = {1873-5711}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; *Electromyography/instrumentation/methods ; Middle Aged ; *Paraspinal Muscles/physiopathology ; Needles ; Electrodes ; Reproducibility of Results ; Aged ; *Muscle Contraction ; Sensitivity and Specificity ; Adult ; }, abstract = {OBJECTIVES: Jitter analysis with concentric needle electrode of the thoracic 9 (T9) paraspinal muscle (PM), where the needle EMG examination at rest is difficult, was performed in both amyotrophic lateral sclerosis (ALS) patients and the controls.

METHODS: For the T9 PM, both upper limit for mean and individual mean consecutive difference (MCD) values and spike numbers were calculated according to jitter values of pairs from controls. In addition to the descriptive statistics, differences between two groups and T9 PM needle EMG and jitter analysis findings of patients were compared (p = 0.05).

RESULTS: Mean MCD median values of T9 PM were 62.8 and 26.2 µs in patient and controls respectively. Upper limit of mean and individual MCDs for the T9 PM were determined as 36.95 μs, 57.95 μs respectively. The differences between controls and patients in terms of all jitter analysis parametres (p < 0.001) and the comparison of patients' T9 PM needle EMG and jitter analysis findings grading were statistically significant (p = 0.029).

CONCLUSION: The T9 PM jitter analysis performed during routine EMG can be used to support the electrophysiological diagnosis of ALS in challenging cases and may contribute to minimizing the number of muscles examined. Furthermore, our study contributed to the T9 PM reference values for jitter analysis.}, } @article {pmid39806490, year = {2025}, author = {Shen, Y and Zhang, X and Liu, S and Xin, L and Xuan, W and Zhuang, C and Chen, Y and Chen, B and Zheng, X and Wu, R and Lin, Y}, title = {CEST imaging combined with [1]H-MRS reveal the neuroprotective effects of riluzole by improving neurotransmitter imbalances in Alzheimer's disease mice.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {20}, pmid = {39806490}, issn = {1758-9193}, support = {240428226498013//Shantou Science and Technology Project/ ; 213769/SNSF_/Swiss National Science Foundation/Switzerland ; 82020108016//National Natural Science Foundation of China/ ; 82071973//National Natural Science Foundation of China/ ; 2023A1515010326//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022ZDZX2020//Key Research Platform and Project of Guangdong University/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/diagnostic imaging ; *Riluzole/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; *Glutamic Acid/metabolism ; *gamma-Aminobutyric Acid/metabolism ; Mice, Transgenic ; *Brain/drug effects/metabolism/diagnostic imaging ; Proton Magnetic Resonance Spectroscopy ; Disease Models, Animal ; Magnetic Resonance Imaging/methods ; Male ; *Neurotransmitter Agents/metabolism ; }, abstract = {BACKGROUND: The imbalance of glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmitter system plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Riluzole is a Glu modulator originally approved for amyotrophic lateral sclerosis that has shown potential neuroprotective effects in various neurodegenerative disorders. However, whether riluzole can improve Glu and GABA homeostasis in AD brain and its related mechanism of action remain unknown. This study utilized chemical exchange saturation transfer (CEST) imaging combined with proton magnetic resonance spectroscopy ([1]H-MRS) to monitor the dynamic changes of Glu and GABA in riluzole-treated AD mice, aiming to evaluate the efficacy and mechanism of riluzole in AD treatment.

METHODS: GluCEST, GABACEST and [1]H-MRS were used to longitudinally monitor Glu and GABA levels in 3xTg AD mice treated with riluzole (12.5 mg/kg/day) or vehicle for 20 weeks. Magnetic resonance measurements were performed at baseline, 6, 12, and 20 weeks post-treatment. Cognitive performance was assessed using the Morris Water Maze (MWM) at baseline, 10, and 20 weeks. At the study endpoint, immunohistochemistry, Nissl staining, and Western blot were used to evaluate the brain pathology, neuronal survival, and protein expression.

RESULTS: GluCEST, GABACEST and [1]H-MRS consistently revealed higher levels of Glu and GABA in the brain of riluzole-treated AD mice compared to untreated controls, which were associated with improvements in spatial learning and memory. The cognitive improvements significantly correlated with the increased GluCEST signals and Glu levels. Immunohistochemistry and Nissl staining demonstrated that riluzole treatment reduced amyloid-beta (Aβ) deposition, tau hyperphosphorylation, GFAP-positive astrocyte activation, and prevented neuronal loss. Moreover, riluzole upregulated the expression of excitatory amino acid transporter 2 (EAAT2), glutamic acid decarboxylase 65/67 (GAD65/67), and glutamine synthetase (GS), suggesting enhanced neurotransmitter metabolism.

CONCLUSIONS: CEST imaging combined with [1]H-MRS demonstrated the effectiveness of riluzole in modulating Glu- and GABA-related changes and improving cognitive function in 3xTg AD mice, potentially through regulating key proteins involved in neurotransmitter metabolism. These findings suggest riluzole as a therapeutic agent for Alzheimer's disease and highlight the utility of multimodal MR imaging in monitoring treatment response and exploring disease mechanisms.}, } @article {pmid39806943, year = {2024}, author = {Lee, K and Kim, SI and Shim, YM and Kim, EE and Yoo, S and Won, JK and Park, SH}, title = {Current Status and Future Perspective of Seoul National University Hospital-Dementia Brain Bank with Concordance of Clinical and Neuropathological Diagnosis.}, journal = {Experimental neurobiology}, volume = {33}, number = {6}, pages = {295-311}, pmid = {39806943}, issn = {1226-2560}, abstract = {This paper introduces the current status of Seoul National University Hospital Dementia Brain Bank (SNUH-DBB), focusing on the concordance rate between clinical diagnoses and postmortem neuropathological diagnoses. We detail SNUH-DBB operations, including protocols for specimen handling, induced pluripotent stem cells (iPSC) and cerebral organoids establishment from postmortem dural fibroblasts, and adult neural progenitor cell cultures. We assessed clinical-neuropathological diagnostic concordance rate. Between 2015 and September 2024, 162 brain specimens were collected via brain donation and autopsy. The median donor age was 73 years (1-94) with a male-to -female ratio of 2:1. The median postmortem interval was 9.5 hours (range: 2.5-65). Common neuropathological diagnoses included pure Lewy body disease (10.6%), Lewy body disease (LBD) with other brain diseases (10.6%), pure Alzheimer's disease-neuropathological change (ADNC) (6.0%), ADNC with other brain diseases (10.7%), vascular brain injury (15.2%), and primary age-related tauopathy (7.3%). APOE genotype distribution was following: ε3/ε3: 62.3%, ε2/ε3: 9.6%, ε2/ε4: 3.4%, ε3/ε4: 24.0%, and ε4/ε4: 0.7%. Concordance rates between pathological and clinical diagnoses were: ADNC/AD at 42.4%; LBD at 59.0%; PSP at 100%; ALS at 85.7%; Huntington's disease 100%. The varying concordance rates across different diseases emphasize the need for improved diagnostic criteria and biomarkers, particularly for AD and LBD. Tissues have been distributed to over 40 national studies. SNUH-DBB provides high-quality brain tissues and cell models for neuroscience research, operating under standardized procedures and international guidelines. It supports translational research in dementia and neurodegenerative diseases, potentially advancing diagnostic and therapeutic strategies.}, } @article {pmid39809899, year = {2025}, author = {Cui, Y and Arnold, FJ and Li, JS and Wu, J and Wang, D and Philippe, J and Colwin, MR and Michels, S and Chen, C and Sallam, T and Thompson, LM and La Spada, AR and Li, W}, title = {Multi-omic quantitative trait loci link tandem repeat size variation to gene regulation in human brain.}, journal = {Nature genetics}, volume = {57}, number = {2}, pages = {369-378}, pmid = {39809899}, issn = {1546-1718}, support = {R01 CA193466/CA/NCI NIH HHS/United States ; R01 CA228140/CA/NCI NIH HHS/United States ; R01 HG007538/HG/NHGRI NIH HHS/United States ; T32 CA009054/CA/NCI NIH HHS/United States ; R35 NS122140/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Quantitative Trait Loci/genetics ; *Brain/metabolism ; *Gene Expression Regulation/genetics ; *Tandem Repeat Sequences/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Phenotype ; Alzheimer Disease/genetics ; Genetic Variation ; Male ; C9orf72 Protein/genetics ; Female ; Multiomics ; }, abstract = {Tandem repeat (TR) size variation is implicated in ~50 neurological disorders, yet its impact on gene regulation in the human brain remains largely unknown. In the present study, we quantified the impact of TR size variation on brain gene regulation across distinct molecular phenotypes, based on 4,412 multi-omics samples from 1,597 donors, including 1,586 newly sequenced ones. We identified ~2.2 million TR molecular quantitative trait loci (TR-xQTLs), linking ~139,000 unique TRs to nearby molecular phenotypes, including many known disease-risk TRs, such as the G2C4 expansion in C9orf72 associated with amyotrophic lateral sclerosis. Fine-mapping revealed ~18,700 TRs as potential causal variants. Our in vitro experiments further confirmed the causal and independent regulatory effects of three TRs. Additional colocalization analysis indicated the potential causal role of TR variation in brain-related phenotypes, highlighted by a 3'-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer's disease.}, } @article {pmid39809929, year = {2025}, author = {Antico, O and Thompson, PW and Hertz, NT and Muqit, MMK and Parton, LE}, title = {Targeting mitophagy in neurodegenerative diseases.}, journal = {Nature reviews. Drug discovery}, volume = {24}, number = {4}, pages = {276-299}, pmid = {39809929}, issn = {1474-1784}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Mitophagy/drug effects/physiology ; *Neurodegenerative Diseases/drug therapy/metabolism/genetics ; Animals ; Mitochondria/drug effects/metabolism ; Protein Kinases ; PTEN-Induced Putative Kinase ; }, abstract = {Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need. Accumulating genetic, molecular and preclinical model-based evidence now supports targeting mitophagy in neurodegenerative diseases. Despite clinical development challenges, small-molecule-based approaches for selective mitophagy enhancement - namely, USP30 inhibitors and PINK1 activators - are entering phase I clinical trials for the first time.}, } @article {pmid39810183, year = {2025}, author = {Harvey, C and Nowak, A and Zhang, S and Moll, T and Weimer, AK and Barcons, AM and Souza, CDS and Ferraiuolo, L and Kenna, K and Zaitlen, N and Caggiano, C and Shaw, PJ and Snyder, MP and Mill, J and Hannon, E and Cooper-Knock, J}, title = {Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons.}, journal = {BMC medical genomics}, volume = {18}, number = {1}, pages = {10}, pmid = {39810183}, issn = {1755-8794}, support = {CEGS 5P50HG00773504//NIH (USA)/ ; 899-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; NF-SI-0617-10077//National Institute for Health and Care Research/ ; /WT_/Wellcome Trust/United Kingdom ; IS-BRC-1215-20017//NIHR Sheffield Biomedical Research Centre/ ; 216596/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; P50 HL083800/HL/NHLBI NIH HHS/United States ; R01 HL101388/HL/NHLBI NIH HHS/United States ; R01 HL122939/HL/NHLBI NIH HHS/United States ; S10 OD025212/OD/NIH HHS/United States ; P30 DK116074/DK/NIDDK NIH HHS/United States ; UM1 HG009442/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/cerebrospinal fluid ; *Motor Neurons/metabolism/pathology ; *Biomarkers/metabolism/cerebrospinal fluid/blood ; *DNA Methylation ; Cell-Free Nucleic Acids/cerebrospinal fluid/blood ; Induced Pluripotent Stem Cells/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity to develop a sensitive and specific biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we have performed whole genome bisulfite sequencing (WGBS) of iPSC-derived MN from neurologically normal individuals. By comparing MN methylation with an atlas of tissue methylation we have derived a MN-specific signature of hypomethylated genomic regions, which accords with genes important for MN function. Through simulation we have optimised the selection of regions for biomarker detection in plasma and CSF cell-free DNA (cfDNA). However, we show that MN-derived DNA is not detectable via WGBS in plasma cfDNA. In support of our experimental finding, we show theoretically that the relative sparsity of lower MN sets a limit on the proportion of plasma cfDNA derived from MN which is below the threshold for detection via WGBS. Our findings are important for the ongoing development of ALS biomarkers. The MN-specific hypomethylated genomic regions we have derived could be usefully combined with more sensitive detection methods and perhaps with study of CSF instead of plasma. Indeed we demonstrate that neuronal-derived DNA is detectable in CSF. Our work is relevant for all diseases featuring death of rare cell-types.}, } @article {pmid39810199, year = {2025}, author = {Eck, RJ and Valdmanis, PN and Liachko, NF and Kraemer, BC}, title = {Alternative 3' UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD.}, journal = {Molecular brain}, volume = {18}, number = {1}, pages = {1}, pmid = {39810199}, issn = {1756-6606}, support = {R21 AG082032/AG/NIA NIH HHS/United States ; RF1 AG078374/AG/NIA NIH HHS/United States ; F99AG088436/NH/NIH HHS/United States ; R01 AG066729/AG/NIA NIH HHS/United States ; IK6 BX006467/BX/BLRD VA/United States ; R01 NS122766/NS/NINDS NIH HHS/United States ; F99 AG088436/AG/NIA NIH HHS/United States ; I01 BX005762/BX/BLRD VA/United States ; IK6BX006467//U.S. Department of Veterans Affairs/ ; P30 AG066509/AG/NIA NIH HHS/United States ; R21AG082032/NH/NIH HHS/United States ; R01AG066729/NH/NIH HHS/United States ; RF1AG078374/NH/NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; *Polyadenylation/genetics ; Disease Models, Animal ; *3' Untranslated Regions/genetics ; *Frontotemporal Lobar Degeneration/genetics ; Mice ; Humans ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Recent research has highlighted widespread dysregulation of alternative polyadenylation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Here, we identify significant disruptions to 3` UTR polyadenylation in the ALS/FTLD-TDP mouse model rNLS8 that correlate with changes in gene expression and protein levels through the re-analysis of published RNA sequencing and proteomic data. A subset of these changes are shared with TDP-43 knock-down mice suggesting depletion of endogenous mouse TDP-43 is a contributor to polyadenylation dysfunction in rNLS8 mice. Some conservation exists between alternative polyadenylation in rNLS8 mice and human disease models including in disease relevant genes and biological pathways. Together, these findings support both TDP-43 loss and toxic gain-of-function phenotypes as contributors to the neurodegeneration in rNLS8 mice, nominating its continued utility as a preclinical model for investigating mechanisms of neurodegeneration in ALS/FTLD-TDP.}, } @article {pmid39811452, year = {2024}, author = {Li, R and Bao, T and Li, B and Xia, P and Zhang, T and Zhang, H and Huang, F}, title = {Effectiveness and safety of traditional Chinese therapies intreating patients with amyotrophic lateral sclerosis: a protocol for systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1519513}, pmid = {39811452}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a chronic, progressive disease that affects both upper and lower motor neurons. Some physicians have used traditional Chinese therapies (TCT) to treat ALS. However, there has been no systematic review or meta-analysis to evaluate the effectiveness and safety of TCT interventions. This review aims to analyze the effects of TCT interventions for patients with amyotrophic lateral sclerosis.

METHODS AND ANALYSIS: This study will include randomized, non-randomized, and quasi-experimental clinical trials, with participants being any age Amyotrophic Lateral Sclerosis (ALS) patients who have undergone TCT treatment. Two researchers will independently search databases including CENTRAL, PubMed, PEDro, EMBASE, CNKI, CBM, and SPORTDiscus, without restrictions on language or publication date. These researchers will independently screen titles and abstracts and extract data from the included studies. If deemed suitable for meta-analysis, data synthesis will be conducted using Review Manager V.5.3 software; any discrepancies will be resolved by a third researcher. The meta-analysis will compare the effects of TCT with placebo or other interventions. The main endpoint evaluated was the decrease in the overall score of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; scoring from 0 to 48, where higher scores denote greater functionality) over a period of 24 weeks. Additional endpoints included the reduction rates in isometric muscle power, levels of phosphorylated axonal neurofilament H subunits in plasma, and slow vital capacity measurements. Furthermore, the study monitored the duration until occurrence of death, tracheostomy, or the need for long-term ventilation, as well as the time until death, tracheostomy, long-term ventilation, or hospital admission.

ETHICS AND DISSEMINATION: Throughout the entire process of this systematic review, no personal information was used, hence ethical review is not required. The results of this meta-analysis will be disseminated through publication in peer-reviewed journals and/or conference presentations.}, } @article {pmid39812044, year = {2025}, author = {Liu, B and Chen, L and Chen, H and Pan, J and Yu, C}, title = {Bioinformatics Analysis Reveals Microrchidia Family Genes as the Prognostic and Therapeutic Markers for Colorectal Cancer.}, journal = {Endocrine, metabolic & immune disorders drug targets}, volume = {25}, number = {15}, pages = {1240-1261}, pmid = {39812044}, issn = {2212-3873}, support = {2024KY1801//Health and Family planning Commission of Zhejiang Province/ ; 2024ZL1248//Traditional Chinese Medicine Science and Technology Plan Project of Zhejiang Province/ ; 23ywa30, 23ywb50//Taizhou Science and Technology Bureau in Zhejiang Province/ ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/diagnosis/therapy/metabolism/pathology ; Prognosis ; *Biomarkers, Tumor/genetics/metabolism ; *Computational Biology/methods ; Gene Expression Regulation, Neoplastic ; Tumor Microenvironment/genetics ; Female ; Male ; }, abstract = {AIM: The aim of this study is to examine the role of the microrchidia (MORC) family, a group of chromatin remodeling proteins, as the therapeutic and prognostic markers for colorectal cancer (CRC).

BACKGROUND: MORC protein family genes are a highly conserved nucleoprotein superfamily whose members share a common domain but have distinct biological functions. Previous studies have analyzed the roles of MORCs as epigenetic regulators and chromatin remodulators; however, the involvement of MORCs in the development and pathogenesis of CRC was less examined.

OBJECTIVE: The current work examined the role of the MORCs as the therapeutic and prognostic markers for CRC.

METHODS: The expressions and prognostic significance of MORC family genes in CRC were explored. The role of these genes in tumor immunity was comprehensively analyzed in terms of their functions in immune cell infiltration, tumor microenvironment (TME), and their interaction with immune regulatory genes such as immunosuppressive genes, immune checkpoints and immunostimulatory genes. The relations between MORC family genes, tumor mutation burden (TMB), DNA, mismatch repair (MMR), RNA methylation, microsatellite instability (MSI), and drug sensitivity were investigated using the R statistical software. The expressions of MORC4 in 150 CRC tissues and 60 paracancer tissues were detected by immunohistochemical method. CRC cell proliferation, migration, and invasion were measured by cell counting kit-8 (CCK-8), scratch assay, and transwell cell invasion assay.

RESULTS: The expressions of MORC2 and MORC4 were significantly upregulated, whereas those of MORC1 and MORC3 were noticeably downregulated in CRC in comparison to their expressions in normal colorectal mucosal tissues. Patients with high-expressed MORC2 showed a more unfavorable prognosis than those with a low MORC2 level. Functional annotation analysis identified 100 MORC family genes with the most significant negative or positive correlations to diabetic cardiomyopathy, amyotrophic lateral sclerosis, oxidative phosphorylation, Huntington's disease, thermogenesis, Parkinson's disease, olfactory transduction, Alzheimer's disease, prion disease. MORC3 expression was positively correlated with Stromal score, Immune score and ESTIMATE score, while MORC2 expression was negatively related to the three scores in CRC, these correlations were not statistically significant. Additionally, the MORC family genes were significantly positively correlated with tumor-infiltrating immune cells such as T helper cells and exhibited close relations to some immunosuppressive genes such as CXCR4 and PVR, immunostimulatory genes such as TGFBR1, KDR, and CD160 as well as some immune checkpoint genes. It was found that the expressions of some members of MORC family genes were positively correlated with DNA methylation, MSI, TMB, MMRs, and drug sensitivity in CRC and that the mRNA and protein levels of MORC4 were remarkably upregulated in CRC tissues than in adjacent normal tissues (P<0.05). In the MORC4 knockdown group, DLD-1 cell proliferation was more inhibited than in the negative control (NC) and siRNA groups (P<0.05). Furthermore, the migratory capacity of DLD-1 cells and the number of cells crossing the basement membrane in the MORC4 knockdown group were reduced compared to the NC and siRNA groups (all P<0.05).

CONCLUSION: The expressions of MORC family genes were significantly different in CRC samples, which was related to the immune cell infiltration and prognosis of CRC. Thus, the MORC family genes were considered as markers for indicating the clinical immunotherapy and prognostic outcome of CRC.}, } @article {pmid39812841, year = {2025}, author = {Didcote, L and Vitoratou, S and Al-Chalabi, A and Goldstein, LH}, title = {Predicting ALS informant distress from cognitive and behavioural change in people with ALS.}, journal = {Journal of neurology}, volume = {272}, number = {2}, pages = {144}, pmid = {39812841}, issn = {1432-1459}, support = {Goldstein/Oct17/892-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; Middle Aged ; Aged ; *Cognitive Dysfunction/psychology/etiology/diagnosis ; *Caregivers/psychology ; Adult ; *Psychological Distress ; *Stress, Psychological/psychology/diagnosis/etiology ; Depression/psychology ; COVID-19 ; }, abstract = {BACKGROUND: The cognitive and behavioural changes that occur in around 50% of people with amyotrophic lateral sclerosis (ALS) may significantly affect people around them, contributing to heightened burden, anxiety, and depression. Despite existing evidence linking behavioural impairment to caregiver distress, the role of cognitive impairment remains less clear, with mixed findings on its impact.

METHODS: This study assessed the influence of cognitive and behavioural impairments in people with ALS on the distress of their nominated informants. The data were collected face-to-face and remotely due to the COVID-19 pandemic. The cognitive and behavioural impairments were measured using established screening tools. Informants' distress was evaluated through composite measures of burden, anxiety, and depression. Regression analyses were employed to determine the predictive value of cognitive and behavioural impairment on informant distress.

RESULTS: A total of 98 ALS patients and 84 informants participated. Behavioural impairment predicted informant distress across various tools. In contrast, cognitive impairment was a less consistent predictor of informant distress across screening measures and did not significantly interact with behavioural impairment in predicting distress. Administration mode did not affect predictive relationships.

CONCLUSIONS: Behavioural impairment in ALS significantly predicts informant distress, with varying predictive power across different screening tools. Cognitive impairment also affects informant distress, but its impact is less substantial compared to behavioural factors. The interaction between cognitive and behavioural impairments did not significantly predict informant distress.}, } @article {pmid39813072, year = {2025}, author = {Raines, C and Mefferd, A}, title = {Disease-Specific Speech Movement Characteristics of the Tongue and Jaw.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {68}, number = {7S}, pages = {3544-3557}, pmid = {39813072}, issn = {1558-9102}, support = {R01 DC019648/DC/NIDCD NIH HHS/United States ; R03 DC015075/DC/NIDCD NIH HHS/United States ; T32 DC020141/DC/NIDCD NIH HHS/United States ; UL1 TR002243/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Tongue/physiopathology ; *Dysarthria/physiopathology/etiology ; Male ; Female ; *Jaw/physiopathology ; Middle Aged ; Aged ; Biomechanical Phenomena ; *Speech/physiology ; Parkinson Disease/physiopathology/complications ; Movement/physiology ; Multiple Sclerosis/physiopathology/complications ; Adult ; Huntington Disease/physiopathology/complications ; Amyotrophic Lateral Sclerosis/physiopathology/complications ; Range of Motion, Articular/physiology ; Speech Production Measurement ; }, abstract = {PURPOSE: To advance our understanding of disease-specific articulatory impairment patterns in speakers with dysarthria, this study investigated the articulatory performance of the tongue and jaw in speakers with differing neurological diseases (Parkinson's disease [PD], amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease).

METHOD: Fifty-seven speakers with dysarthria and 30 controls produced the sentence "Buy Kaia a kite" five times. A three-dimensional electromagnetic articulography was used to record the articulatory movements of the posterior tongue and jaw. Sentence-length kinematic measures (e.g., duration, tongue range of motion [ROM], jaw ROM, tongue speed, jaw speed) were extracted.

RESULTS: Results revealed significant group effects for the duration, jaw ROM, and tongue speed but not for tongue ROM. Post hoc pairwise comparisons revealed more significant between-groups differences for duration and jaw ROM than for tongue speed. Statistically significant findings between clinical groups were predominantly driven by the difference between speakers with PD and speakers of other clinical groups.

CONCLUSIONS: Reduced jaw ROM and trends toward reduced tongue ROM confirm hypokinesia as a distinguishing motor feature of speakers with PD. However, deviancies in speed or movement duration did not emerge as a distinguishing motor feature for any of the four studied clinical groups. Nevertheless, movement duration, but not movement speed, may be useful to index dysarthria severity.}, } @article {pmid39813104, year = {2025}, author = {Corti, S and Hedlund, E}, title = {Intrinsic neuronal resilience as a tool for therapeutic discovery.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {4}, pages = {1058-1061}, pmid = {39813104}, issn = {1460-2156}, support = {RF-2018-12366357//MoH/ ; //Ricerca Corrente 2024/ ; 2020-01049//The Swedish Research Council/ ; //Radala Foundation for ALS Research/ ; FO2023-0346//The Swedish Brain Foundation/ ; //Olov Thon's Foundation/ ; 233021//Åhlen Foundation/ ; //Ollie & Elof Ericssons Foundation to E.H./ ; }, abstract = {Corti and Hedlund argue that understanding the molecular underpinnings of neuronal resilience and vulnerability to neurodegenerative diseases such as ALS is key to identifying new therapeutic targets.}, } @article {pmid39814005, year = {2025}, author = {Teive, HAG and Coutinho, L and Cardoso, FEC and Tsuji, S}, title = {Neurology pioneers in Japan.}, journal = {Arquivos de neuro-psiquiatria}, volume = {83}, number = {1}, pages = {1-3}, pmid = {39814005}, issn = {1678-4227}, mesh = {Japan ; *Neurology/history ; Bulbar Palsy, Progressive/history ; Amyotrophic Lateral Sclerosis/history ; Textbooks as Topic/history ; *Neurologists/history ; Humans ; Male ; History, 19th Century ; History, 20th Century ; }, abstract = {The pioneers of neurology in Japan were professors Hiroshi Kawahara and Kinnosuke Miura. Kawahara published the first description of progressive bulbar palsy and wrote the first neurology textbook in Japan. Miura, on the other hand, published studies about amyotrophic lateral sclerosis, in addition to participating in the founding of the Japanese Society of Neurology. The influence of European neurology, particularly French and German, in the figures of Professor Jean-Martin Charcot and Professor Erwin Bälz, was fundamental in the consolidation of neurology in Japan.}, } @article {pmid39816195, year = {2025}, author = {Yildiz, O and Hunt, GP and Schroth, J and Dhillon, G and Spargo, TP and Al-Chalabi, A and Koks, S and Turner, MR and Shaw, PJ and Henson, SM and Iacoangeli, A and Malaspina, A}, title = {Lipid-mediated resolution of inflammation and survival in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcae402}, pmid = {39816195}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Neuroinflammation impacts on the progression of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Specialized pro-resolving mediators trigger the resolution of inflammation. We investigate the specialized pro-resolving mediator blood profile and their receptors' expression in peripheral blood mononuclear cells in relation to survival in ALS. People living with ALS (pwALS) were stratified based on bulbar versus limb onset and on key progression metrics using a latent class model, to separate faster progressing from slower progressing ALS. Specialized pro-resolving mediator blood concentrations were measured at baseline and in one additional visit in 20 pwALS and 10 non-neurological controls (Cohort 1). Flow cytometry was used to study the GPR32 and GPR18 resolvin receptors' expression in peripheral blood mononuclear cells from 40 pwALS and 20 non-neurological controls (Cohort 2) at baseline and in two additional visits in 17 pwALS. Survival analysis was performed using Cox proportional hazards models, including known clinical predictors and GPR32 and GPR18 mononuclear cell expression. Differential expression and linear discriminant analyses showed that plasma resolvins were able to distinguish phenotypic variants of ALS from non-neurological controls. RvE3 was elevated in blood from pwALS, whilst RvD1, RvE3, RvT4 and RvD1n-3 DPA were upregulated in A-S and RvD2 in A-F. Compared to non-neurological controls, GPR32 was upregulated in monocytes expressing the active inflammation-suppressing CD11b[+] integrin from fast-progressing pwALS, including those with bulbar onset disease (P < 0.0024), whilst GPR32 and GPR18 were downregulated in most B and T cell subtypes. Only GPR18 was upregulated in naïve double positive Tregs, memory cytotoxic Tregs, senescent late memory B cells and late senescent CD8[+] T cells from pwALS compared to non-neurological controls (P < 0.0431). Higher GPR32 and GPR18 median expression in blood mononuclear cells was associated with longer survival, with GPR32 expression in classical monocytes (hazard ratio: 0.11, P = 0.003) and unswitched memory B cells (hazard ratio: 0.44, P = 0.008) showing the most significant association, along with known clinical predictors. Low levels of resolvins and downregulation of their membrane receptors in blood mononuclear cells are linked to a faster progression of ALS. Higher mononuclear cell expression of resolvin receptors is a predictor of longer survival. These findings suggest a lipid-mediated neuroprotective response that could be harnessed to develop novel therapeutic strategies and biomarkers for ALS.}, } @article {pmid39816800, year = {2025}, author = {Shokr, MM and Badawi, GA and Elshazly, SM and Zaki, HF and Mohamed, AF}, title = {Sigma 1 Receptor and Its Pivotal Role in Neurological Disorders.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {1}, pages = {47-65}, pmid = {39816800}, issn = {2575-9108}, abstract = {Sigma 1 receptor (S1R) is a multifunctional, ligand-activated protein located in the membranes of the endoplasmic reticulum (ER). It mediates a variety of neurological disorders, including epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease. The wide neuroprotective effects of S1R agonists are achieved by a variety of pro-survival and antiapoptotic S1R-mediated signaling functions. Nonetheless, relatively little is known about the specific molecular mechanisms underlying S1R activity. Many studies on S1R protein have highlighted the importance of maintaining normal cellular homeostasis through its control of calcium and lipid exchange between the ER and mitochondria, ER-stress response, and many other mechanisms. In this review, we will discuss S1R different cellular localization and explain S1R-associated biological activity, such as its localization in the ER-plasma membrane and Mitochondrion-Associated ER Membrane interfaces. While outlining the cellular mechanisms and important binding partners involved in these processes, we also explained how the dysregulation of these pathways contributes to neurodegenerative disorders.}, } @article {pmid39817131, year = {2025}, author = {Lampridis, S}, title = {Unraveling the landscape of pediatric pancreatic tumors: Insights from Japan.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {1}, pages = {101477}, pmid = {39817131}, issn = {1948-5204}, abstract = {Pediatric pancreatic tumors, though rare, pose significant diagnostic and management challenges. The recent, 22-year nationwide survey on pediatric pancreatic tumors in Japan by Makita et al offers valuable insights into this uncommon entity, revealing striking geographical variations and questioning current treatment paradigms. This editorial commentary analyzes the study's key findings, including the predominance of solid pseudopapillary neoplasms and their younger age of onset, which contrast sharply with Western data. It explores the implications for clinical practice and research, emphasizing the need for population-specific approaches to diagnosis and treatment. The revealed limited institutional experience and surgical management patterns prompt a reevaluation of optimal care delivery for these complex cases, suggesting benefits of centralizing healthcare services. Furthermore, the commentary advocates for international collaborative studies to elucidate the genetic, environmental, and lifestyle factors influencing the development and progression of pediatric pancreatic tumors across diverse populations. It also outlines future directions, calling for advancements in precision medicine and innovative care delivery models to improve global patient outcomes. Unraveling Makita et al's findings within the broader landscape of pediatric oncology can stimulate further research and clinical advancements in managing pancreatic and other rare tumors in children.}, } @article {pmid39817143, year = {2025}, author = {Chew, FY and Tsai, CH and Chang, KH and Chang, YK and Chou, RH and Liu, YJ}, title = {Exosomes as promising frontier approaches in future cancer therapy.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {1}, pages = {100713}, pmid = {39817143}, issn = {1948-5204}, abstract = {In this editorial, we will discuss the article by Tang et al published in the recent issue of the World Journal of Gastrointestinal Oncology. They explored an innovative approach to enhancing gemcitabine (GEM) delivery and efficacy using human bone marrow mesenchymal stem cells (HU-BMSCs)-derived exosomes. The manufacture of GEM-loaded HU-BMSCs-derived exosomes (Exo-GEM) has been optimized. The Tang et al's study demonstrated that Exo-GEM exhibits enhanced cytotoxicity and apoptosis-inducing effects compared to free GEM, highlighting the potential of exosome-based drug delivery systems as a more effective and targeted approach to chemotherapy in pancreatic cancer. Additional in vivo studies are required to confirm the safety and effectiveness of Exo-GEM before it can be considered for clinical use.}, } @article {pmid39817215, year = {2025}, author = {Liu, SQ and Wang, D and Tang, CC}, title = {Association between age at diagnosis of diabetes and ocular disease: Insights from a recent article.}, journal = {World journal of diabetes}, volume = {16}, number = {1}, pages = {94846}, pmid = {39817215}, issn = {1948-9358}, abstract = {In this article, we discuss Ye et al's recent article on the association between age at diabetes diagnosis and subsequent risk of age-related ocular diseases. The study, which utilized United Kingdom Biobank data, highlighted a strong link between early diabetes onset and major eye conditions, such as cataracts, glaucoma, age-related macular degeneration, and vision loss, independent of glycemic control and disease duration. This finding challenges the previous belief that diabetic eye disease primarily correlates with hyperglycemia. As lifestyles evolve and the age of diabetes diagnosis decreases, understanding this relationship may reveal the complex pathogenesis underlying diabetes-related complications. This editorial summarizes potential mechanisms connecting the age of diabetes onset with four types of ocular diseases, emphasizing the significance of early diagnosis.}, } @article {pmid39817235, year = {2024}, author = {Cicardi, ME and Trotti, D}, title = {C9orf72 role in myeloid cells: new perspectives in the investigation of the neuro-immune crosstalk in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Annals of translational medicine}, volume = {12}, number = {6}, pages = {120}, pmid = {39817235}, issn = {2305-5839}, } @article {pmid39817908, year = {2025}, author = {Aikio, M and Odeh, HM and Wobst, HJ and Lee, BL and Chan, Ú and Mauna, JC and Mack, KL and Class, B and Ollerhead, TA and Ford, AF and Barbieri, EM and Cupo, RR and Drake, LE and Smalley, JL and Lin, YT and Lam, S and Thomas, R and Castello, N and Baral, A and Beyer, JN and Najar, MA and Dunlop, J and Gitler, AD and Javaherian, A and Kaye, JA and Burslem, GM and Brown, DG and Donnelly, CJ and Finkbeiner, S and Moss, SJ and Brandon, NJ and Shorter, J}, title = {Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115205}, pmid = {39817908}, issn = {2211-1247}, support = {K99 AG075242/AG/NIA NIH HHS/United States ; T32 AG000255/AG/NIA NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; R35 GM142505/GM/NIGMS NIH HHS/United States ; F32 NS108598/NS/NINDS NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; R01 LM013617/LM/NLM NIH HHS/United States ; F31 AG060672/AG/NIA NIH HHS/United States ; T32 GM008275/GM/NIGMS NIH HHS/United States ; F31 NS087676/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Phosphorylation ; *Protein-Arginine N-Methyltransferases/metabolism ; Methylation ; *DNA-Binding Proteins/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Mitogen-Activated Protein Kinase 14/metabolism ; *Arginine/metabolism ; *TDP-43 Proteinopathies/metabolism/pathology ; Motor Neurons/metabolism/pathology ; *Repressor Proteins/metabolism ; HEK293 Cells ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we show that p38α MAPK inhibition reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. Remarkably, p38α MAPK inhibition mitigates aberrant TDP-43 phenotypes in diverse ALS patient-derived motor neurons. p38α MAPK phosphorylates TDP-43 at pathological S409/S410 and S292, which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we establish that PRMT1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. Notably, R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote PRMT1-mediated R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.}, } @article {pmid39818026, year = {2025}, author = {Choi, Y and Jung, HJ and Jung, HK and Jeong, E and Kim, S and Kim, JY and Lee, EJ and Lim, YM and Kim, H}, title = {In vivo imaging markers of glymphatic dysfunction in amyotrophic lateral sclerosis: Analysis of ALPS index and choroid plexus volume.}, journal = {Journal of the neurological sciences}, volume = {469}, number = {}, pages = {123393}, doi = {10.1016/j.jns.2025.123393}, pmid = {39818026}, issn = {1878-5883}, mesh = {*Glymphatic System/diagnostic imaging/pathology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Choroid Plexus/diagnostic imaging ; Organ Size ; *Biomarkers/analysis ; Humans ; Male ; Female ; Middle Aged ; Aged ; Sensitivity and Specificity ; Diffusion Tensor Imaging ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: The glymphatic system, essential for brain waste clearance, has been implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Emerging imaging markers, such as the analysis along the perivascular space (ALPS) index and choroid plexus volume (CPV), may provide insights into glymphatic function, but their relevance to ALS remains unclear.

OBJECTIVE: To assess glymphatic dysfunction in ALS patients using the ALPS index and CPV.

METHODS: In this prospective single-center study, we analyzed 51 ALS patients and 51 age- and sex-matched healthy controls (HC). The ALPS index was calculated using diffusion tensor imaging, and 3D T1-weighted MRI was used for automated estimation of CPV and its fraction (CPV/total intracranial volume). Diagnostic performance was assessed using area under the receiver operating curve (AUC). Correlations between imaging markers and clinical parameters were also examined.

RESULTS: ALS patients had a significantly lower ALPS index (ALS: 1.45 ± 0.15; HC: 1.55 ± 0.16; p = 0.002) and higher CPV fraction (ALS: 0.12 ± 0.04 %; HC: 0.10 ± 0.02 %; p < 0.001). The ALPS index and CPV fraction had AUCs of 0.70 and 0.72, respectively. A significant inverse correlation was observed between the ALPS index and CPV fraction (r = -0.31, p = 0.002). Both markers correlated with aging but not with clinical disability or progression rate.

CONCLUSION: This study identifies glymphatic dysfunction in ALS, as evidenced by changes in the ALPS index and CPV. Larger studies are warranted to validate these findings and assess their potential as biomarkers for ALS.}, } @article {pmid39819257, year = {2025}, author = {Barton, M and Roman, A and Spencer, K and Cheng, L and Baylor, C}, title = {Examining the perspectives of augmentative and alternative communication (AAC) specialists on conducting AAC evaluations with people with amyotrophic lateral sclerosis via telehealth.}, journal = {Augmentative and alternative communication (Baltimore, Md. : 1985)}, volume = {41}, number = {2}, pages = {169-182}, doi = {10.1080/07434618.2024.2443669}, pmid = {39819257}, issn = {1477-3848}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/complications ; *Communication Devices for People with Disabilities ; *Telemedicine ; *Speech-Language Pathology ; Male ; Female ; COVID-19 ; Middle Aged ; *Attitude of Health Personnel ; Adult ; *Communication Disorders/rehabilitation/diagnosis ; }, abstract = {The purpose of this study was to explore what speech-language pathologists (SLPs) who are AAC specialists see as advantages and disadvantages of providing AAC services via telehealth, how well tele-AAC assessments align with guidelines for in-person assessments, and how SLPs' perspectives of tele-AAC services changed post-COVID. Fifteen SLPs who are AAC specialists and experienced working with people with amyotrophic lateral sclerosis watched videos of speech generating device (SGD) assessments conducted via telehealth for eight people with amyotrophic lateral sclerosis. Using a checklist based on the AAC Clinical Assessment Project (AAC-CAP), the SLPs rated how comparable remote assessment was to in-person assessment, and described advantages and challenges. Across checklist elements, most participants rated AAC assessment via telemedicine as "same/comparable" to in-person assessment. The most common advantages of tele-AAC assessment were that tele-AAC was more functional, increased care partner availability, and increased clients' comfort at home. The most common challenges were technical difficulties and a limited comprehensive assessment due to the remote modality. Tele-AAC should be considered a viable assessment option as it may increase equitable access to care for more people with amyotrophic lateral sclerosis. Tools such as the AAC-CAP may help generalist SLPs increase their comfort and proficiency providing AAC services.}, } @article {pmid39819742, year = {2025}, author = {Xu, B and Lei, X and Yang, Y and Yu, J and Chen, J and Xu, Z and Ye, K and Zhang, J}, title = {Peripheral proteinopathy in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {2}, pmid = {39819742}, issn = {2047-9158}, support = {82020108012//National Natural Science Foundation of China/ ; 82371250//National Natural Science Foundation of China/ ; LY24H090006//Natural Science Foundation of Zhejiang Province/ ; LZ23H090002//Natural Science Foundation of Zhejiang Province/ ; 2024C03098//Key Research and Development Program of Zhejiang Province/ ; 2024SSYS0018//Key Research and Development Program of Zhejiang Province/ ; ZR2022QH177//Natural Science Foundation of Shandong Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; }, abstract = {Proteinopathies in neurology typically refer to pathological changes in proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and multiple system atrophy, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal dementia. Interestingly, these proteins are also commonly found in peripheral tissues, raising important questions about their roles in neurological disorders. Multiple studies have shown that peripherally derived pathological proteins not only travel to the brain through various routes, aggravating brain pathology, but also contribute significantly to peripheral dysfunction, highlighting their crucial impact on neurological diseases. Investigating how these peripherally derived proteins influence the progression of neurological disorders could open new horizons for achieving early diagnosis and treatment. This review summarizes the distribution, transportation pathways, and pathogenic mechanisms of several neurodegenerative disease-related pathological proteins in the periphery, proposing that targeting these peripheral pathological proteins could be a promising strategy for preventing and managing neurological diseases.}, } @article {pmid39819841, year = {2025}, author = {Cintora-Sanz, AM and Horrillo-García, C and Quesada-Cubo, V and Pérez-Alonso, AM and Gutiérrez-Misis, A}, title = {Prevalence and Economic Impact of Acute Respiratory Failure in the Prehospital Emergency Medical Service of the Madrid Community: Retrospective Cohort Study.}, journal = {JMIR public health and surveillance}, volume = {11}, number = {}, pages = {e66179}, pmid = {39819841}, issn = {2369-2960}, mesh = {Humans ; Retrospective Studies ; *Emergency Medical Services/economics/statistics & numerical data ; Spain/epidemiology ; *Respiratory Insufficiency/epidemiology/economics/therapy ; Prevalence ; Male ; Female ; Aged ; COVID-19/epidemiology ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/epidemiology ; Aged, 80 and over ; Acute Disease ; Health Care Costs/statistics & numerical data ; }, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), and acute pulmonary edema (APE) are serious illnesses that often require acute care from prehospital emergency medical services (EMSs). These respiratory diseases that cause acute respiratory failure (ARF) are one of the main reasons for hospitalization and death, generating high health care costs. The prevalence of the main respiratory diseases treated in a prehospital environment in the prepandemic period and during the COVID-19 pandemic in Spain is unknown. The Madrid Community EMS is a public service that serves all types of populations and represents an epidemiological reference for supporting a population of 6.4 million inhabitants. The high volume of patients treated by Madrid's medical advanced life supports (ALSs) allows us to analyze this little-studied problem.

OBJECTIVES: Our goal was to lay the groundwork for comprehensive data collection and surveillance of respiratory failure, with an emphasis on the most prevalent diseases that cause it, an aspect that has been largely overlooked in previous initiatives. By achieving these objectives, we hope to inform efforts to address respiratory failure and establish a standardized methodology and framework that can facilitate expansion to a continuous community-wide registry in Madrid, driving advances in emergency care and care practices in these pathologies. The aim of this retrospective observational study was to determine the pathologies that have mainly caused respiratory failure in patients and required medicalized ALS and to evaluate the cost of care for these pathologies collected through this pilot registry.

METHODS: A multicenter descriptive study was carried out in the Madrid Community EMS. The anonymized medical records of patients treated with medical ALS, who received any of the following medical diagnoses, were extracted: ARF not related to chronic respiratory disease, ARF in chronic respiratory failure, exacerbations of COPD, APE, CHF, and bronchospasm (not from asthma or COPD). The prevalence of each pathology, its evolution from 2014 to 2020, and the economic impact of the Medical ALSs were calculated.

RESULTS: The study included 96,221 patients. The most common pathology was exacerbation of COPD, with a prevalence of 0.07% in 2014; it decreased to 0.03% in 2020. CHF followed at 0.06% in 2014 and 0.03% in 2020. APE had a prevalence of 0.01% in 2014, decreasing to 0.005% in 2020 with the pandemic. The greatest economic impact was on exacerbation of COPD in 2015, with an annual cost of €2,726,893 (which equals to US $2,864,628).

CONCLUSIONS: COPD exacerbations had the higher prevalence in the Madrid region among the respiratory diseases studied. With the COVID-19 pandemic, the prevalence and costs of almost all these diseases decreased, except for ARF not related to chronic disease. The cost of these pathologies over 5 years was €58,791,031 (US $61,832,879).}, } @article {pmid39819944, year = {2025}, author = {Kristensen, RK and Andersen, PT and Bilenberg, N and Milling, ED and Dalgaard Guldager, J}, title = {Mapping the landscape and evidence of cross-sectoral collaboration models targeting individuals referred for assessment of attention-deficit hyperactivity disorder or autism spectrum disorder: protocol for a scoping review.}, journal = {BMJ open}, volume = {15}, number = {1}, pages = {e088850}, pmid = {39819944}, issn = {2044-6055}, mesh = {Humans ; Scoping Reviews as Topic ; *Autism Spectrum Disorder/diagnosis/therapy ; *Attention Deficit Disorder with Hyperactivity/diagnosis/therapy ; Research Design ; *Referral and Consultation ; }, abstract = {INTRODUCTION: Neurodevelopmental disorders, notably attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), present substantial challenges in mental health. Individuals referred for assessment in a psychiatric unit experience complex needs. This implies that their needs necessitate coordination across multiple sectors. Cross-sectoral collaboration models have emerged as essential strategies for addressing the complexities of these disorders. However, evidence of their existence, implementation and success remains limited. This protocol aims to outline a scoping review where we will explore existing collaboration models, evaluate their implementation and gain an understanding of how cross-sectoral collaboration models can be developed to ultimately benefit individuals referred for assessment of ADHD or ASD.

METHODS AND ANALYSIS: This proposed scoping review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. A comprehensive search will be conducted across PubMed, CINAHL, Embase, PsycINFO and Google Scholar, as well as grey literature sources, between 1 December 2024 and 1 January 2025. Inclusion criteria will encompass studies focusing on cross-sectoral collaboration for individuals referred for assessment of ADHD or ASD, published in English, Danish, Norwegian or Swedish. The search will use a three-block search string, with iterative refinement guided by familiarity with the evidence base. Data extraction will involve study characteristics and implementation details, using the Consolidated Framework for Implementation Research in combination with Proctor et al's implementation outcomes framework. Results will be synthesised into descriptive tables, providing a comprehensive mapping of existing models and emphasising implementation feasibility.

ETHICS AND DISSEMINATION: Ethical approval is not required for this protocol since it involves the review of existing literature without the involvement of human participants or personal data. Findings will be disseminated at national and international conferences and will be integrated into future efforts to develop cross-sectoral collaboration models in Denmark.}, } @article {pmid39820267, year = {2025}, author = {Martinez-Thompson, JM and Mazurek, KA and Parra-Cantu, C and Naddaf, E and Gogineni, V and Botha, H and Jones, DT and Laughlin, RS and Barnard, L and Staff, NP}, title = {Artificial intelligence models using F-wave responses predict amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {7}, pages = {2320-2330}, pmid = {39820267}, issn = {1460-2156}, support = {UL1 TR002377/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Artificial Intelligence ; Retrospective Studies ; *Neural Conduction/physiology ; Adult ; }, abstract = {Nerve conduction F-wave studies contain crucial information about subclinical motor dysfunction that can be used to diagnose patients with amyotrophic lateral sclerosis (ALS). However, F-wave responses are highly variable in morphology, making waveform interpretation challenging. Artificial intelligence techniques can extract time-frequency features to provide new insights into ALS diagnosis and prognosis. A retrospective analysis was performed on F-wave responses from 46 802 patients. Discrete wavelet transforms were applied to time-series waveform responses after stimulating ulnar, median, fibular and tibial nerves. Wavelet coefficient statistics, onset age, sex and body mass index were features for training a Gradient Boosting Machine model on 40 095 patients (5329 diagnosed with motor neuron disease). Model performance was tested on responses from 689 ALS patients meeting Gold Coast criteria and 689 age- and sex-matched controls. An exploratory analysis examined model performance on cohorts of patients with inclusion body myositis, cervical radiculopathy, lumbar radiculopathy or peripheral neuropathy, which can mimic ALS symptoms. Factors affecting survival were estimated through Cox proportional hazards regression. The model trained using wavelet features on the full waveform had 90% recall, 87% precision and 88% accuracy. Similar model performance was measured using features from only the M-wave or F-wave. Classification probabilities for ALS patients were statistically different from the diagnoses mimicking ALS symptoms (P < 0.001, ANOVA, Tukey's post hoc test). Higher model classification probabilities of ALS, older age at onset, and family history of ALS alone or with frontotemporal dementia were factors decreasing survival. Longer diagnostic delay and upper limb onset site were factors increasing survival. Model scores two standard deviations below the mean had 4 months increased survival (two standard deviations below had 3 months decreased survival). Artificial intelligence techniques extracted important information from F-wave responses to estimate a patient's likelihood of ALS and their survival risks. Although the model can make predictions at a specific decision threshold as presented here, the true strength of such a model lies in its ability to provide probabilities about whether a patient is likely to have ALS in comparison to other mimicking diagnoses, such as inclusion body myositis, cervical or lumbar radiculopathy or peripheral neuropathy. These probabilities provide clinicians with additional information that they can use to make the final diagnosis with greater confidence and precision. Integrating such a model into the clinical workflow could help clinicians to diagnose ALS sooner and manage treatment based on estimated survival, which might improve outcomes and the quality of life of patients.}, } @article {pmid39820861, year = {2025}, author = {van Zundert, B and Montecino, M}, title = {Epigenetics in Neurodegenerative Diseases.}, journal = {Sub-cellular biochemistry}, volume = {108}, number = {}, pages = {73-109}, pmid = {39820861}, issn = {0306-0225}, mesh = {Humans ; *Epigenesis, Genetic ; Animals ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *DNA Methylation ; *Alzheimer Disease/genetics/pathology/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Frontotemporal Dementia/genetics/pathology/metabolism ; }, abstract = {Healthy brain functioning requires a continuous fine-tuning of gene expression, involving changes in the epigenetic landscape and 3D chromatin organization. Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are three multifactorial neurodegenerative diseases (NDDs) that are partially explained by genetics (gene mutations and genetic risk factors) and influenced by non-genetic factors (i.e., aging, lifestyle, and environmental conditions). Examining comprehensive studies of global and locus-specific (epi)genomic and transcriptomic alterations in human and mouse brain samples at the cell-type resolution has uncovered important phenomena associated with AD. First, DNA methylation and histone marks at promoters contribute to transcriptional dysregulation of genes that are directly implicated in AD pathogenesis (i.e., APP), neuroplasticity and cognition (i.e., PSD95), and microglial activation (i.e., TREM2). Second, the presence of AD genetic risk variants in cell-type-specific distal enhancers (i.e., BIN1 in microglia) alters transcription, presumably by disrupting associated enhancer-promoter interactions and chromatin looping. Third, epigenomic erosion is associated with widespread transcriptional disruption and cell identity loss. And fourth, aging, high cholesterol, air pollution, and pesticides have emerged as potential drivers of AD by inducing locus-specific and global epigenetic modifications that impact key AD-related pathways. Epigenetic studies in ALS/FTD also provide evidence that genetic and non-genetic factors alter gene expression profiles in neurons and astrocytes through aberrant epigenetic mechanisms. We additionally overview the recent development of potential new therapeutic strategies involving (epi)genetic editing and the use of small chromatin-modifying molecules (epidrugs).}, } @article {pmid39820998, year = {2025}, author = {Hamad, AA and Alkhawaldeh, IM and Nashwan, AJ and Meshref, M and Imam, Y}, title = {Tofersen for SOD1 amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {5}, pages = {1977-1985}, pmid = {39820998}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Superoxide Dismutase-1/genetics ; *Oligonucleotides/therapeutic use/pharmacology ; *Oligonucleotides, Antisense/therapeutic use/pharmacology ; }, abstract = {OBJECTIVE: Tofersen, an antisense oligonucleotide, has recently received FDA and EMA approval for treating amyotrophic lateral sclerosis (ALS) in adults with SOD1 gene mutations. This systematic review and meta-analysis synthesized evidence on tofersen's safety and efficacy in patients with SOD1-related ALS.

METHODS: A comprehensive search of three databases was conducted from inception through October 2024. Eligible studies included clinical trials, observational studies, and case studies. Meta-analyses were conducted using a random-effects model in RevMan.

RESULTS: Twelve studies involving 195 patients treated with tofersen met the inclusion criteria, comprising two randomized controlled trials (RCTs), five cohort studies, one case series, and four case reports. Tofersen demonstrated promising effects, notably reducing SOD1 levels in cerebrospinal fluid and neurofilament light chain (NfL) in plasma, a biomarker strongly correlated with ALS progression and survival. Meta-analysis of RCTs showed a significantly lower rate of decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores from baseline in the tofersen group compared to placebo (SMD = 0.44, 95% CI [0.05 to 0.83], P = 0.03) and a significant reduction in the decline of predicted Slow Vital Capacity (P = 0.005). In a pre-post meta-analysis of five studies, a significant decrease in ALS progression rate (ALSFRS-R decline rate) was observed (MD = -0.28, 95% CI [-0.40 to -0.15], P < 0.0001). Reported adverse events were consistent with ALS progression or procedural effects.

CONCLUSION: Current evidence suggests that tofersen effectively reduces SOD1 and NfL levels and slow disease progression in SOD1 ALS, showing promise as a targeted therapeutic option.}, } @article {pmid39821843, year = {2025}, author = {Zhang, J and Guo, R and Zhou, Z and Fu, Z and Akogo, HY and Li, Y and Zhang, X and Wang, N and Liu, Y and Li, H and Feng, B and Cui, H and Ma, J}, title = {Neural Stem/Progenitor Cell Therapy in Patients and Animals with Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-analysis.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {6521-6536}, pmid = {39821843}, issn = {1559-1182}, support = {81801278//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/physiopathology ; Animals ; Humans ; *Neural Stem Cells/transplantation/cytology ; *Stem Cell Transplantation/methods ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative malady that causes progressive degeneration and loss of motor neuron function in the brain and spinal cord, eventually resulting in muscular atrophy, paralysis, and death. Neural stem/progenitor cell (NSPC) transplantation can improve bodily function in animals and delay disease progression in patients with ALS. This paper summarizes and analyzes the efficacy and safety of neural stem/progenitor cell (NSPC) transplantation as a treatment for ALS, aiming to improve function and delay disease progression in patients. We present a summary of the pathogenic mechanism and causative genes associated with ALS and describe the mechanism and efficacy of NSPC treatment for ALS. We comprehensively searched for relevant English-language articles published between January 1, 2000 and October 1, 2023, across the following five medical databases: PubMed, EMBASE, OVID, Web of Science, and the Cochrane Library. We examined experimental indices of physical function in animals and patients who underwent stem cell transplantation. All statistical analyses were performed via Review Manager 5.4. The study comprised a total of 16 investigations, including 5 clinical studies and 11 animal studies and involving 66 patients and 203 animals. The meta-analysis revealed that the administration of NSPCs appeared to yield positive outcomes in clinical patients, as assessed by the ALS functional rating scale and forced vital capacity. Furthermore, improvements following cell injection were observed in the rotarod test results, the Basso-Beattie-Bresnahan Locomotor Rating Scale score, weight, and survival time. Our meta-analysis, which was grounded in randomized controlled trials, revealed that the transplantation of neural stem/progenitor cells (NSPCs), has potential effects on ALS patients, enhancing the physical function of animals and mitigating degenerative effects in individuals. These underscored the promise of NSPC therapy as a viable treatment option. We report that the transplantation of neural stem/progenitor cells (NSPCs) is promising for enhancing bodily function and slowing the progression of ALS in affected patients. In this review, we summarize the treatment of ALS with NSPCs, evaluating both its efficacy and safety. Through database searches, we identified 16 studies involving 66 patients and 203 animals and analyzed the experimental indices of physical function following stem cell transplantation. The meta-analysis results indicated a positive impact of NSPCs on the clinical conditions of patients and the behavior of animals. A meta-analysis of randomized controlled trials further supported the conclusion that NSPC transplantation has a beneficial effect on improving physical function and mitigating degeneration in ALS patients.}, } @article {pmid39822067, year = {2025}, author = {Zhu, Y and Verkhratsky, A and Chen, H and Yi, C}, title = {Understanding glucose metabolism and insulin action at the blood-brain barrier: Implications for brain health and neurodegenerative diseases.}, journal = {Acta physiologica (Oxford, England)}, volume = {241}, number = {2}, pages = {e14283}, pmid = {39822067}, issn = {1748-1716}, support = {RCJC20231211090018040//Shenzhen Fundamental Research Program/ ; ZDSYS20220606100801003//Shenzhen Fundamental Research Program/ ; 2022B1515020012//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 32170980//National Natural Science Foundation of China/ ; }, mesh = {*Blood-Brain Barrier/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism ; Animals ; *Insulin/metabolism ; *Glucose/metabolism ; *Brain/metabolism ; }, abstract = {The blood-brain barrier (BBB) is a highly selective, semipermeable barrier critical for maintaining brain homeostasis. The BBB regulates the transport of essential nutrients, hormones, and signaling molecules between the bloodstream and the central nervous system (CNS), while simultaneously protecting the brain from potentially harmful substances and pathogens. This selective permeability ensures that the brain is nourished and shielded from toxins. An exception to this are brain regions, such as the hypothalamus and circumventricular organs, which are irrigated by fenestrated capillaries, allowing rapid and direct response to various blood components. We overview the metabolic functions of the BBB, with an emphasis on the impact of altered glucose metabolism and insulin signaling on BBB in the pathogenesis of neurodegenerative diseases. Notably, endothelial cells constituting the BBB exhibit distinct metabolic characteristics, primarily generating ATP through aerobic glycolysis. This occurs despite their direct exposure to the abundant oxygen in the bloodstream, which typically supports oxidative phosphorylation. The effects of insulin on astrocytes, which form the glial limitans component of the BBB, show a marked sexual dimorphism. BBB nutrient sensing in the hypothalamus, along with insulin signaling, regulates systemic metabolism. Insulin modifies BBB permeability by regulating the expression of tight junction proteins, angiogenesis, and vascular remodeling, as well as modulating blood flow in the brain. The disruptions in glucose and insulin signaling are particularly evident in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, where BBB breakdown accelerates cognitive decline. This review highlights the critical role of normal glucose metabolism and insulin signaling in maintaining BBB functionality and investigates how disruptions in these pathways contribute to the onset and progression of neurodegenerative diseases.}, } @article {pmid39823433, year = {2025}, author = {Tindale, A and Cretu, I and Gomez, N and Haynes, R and Meng, H and Mason, MJ and Francis, DP}, title = {Central venous pressure as a method of optimising atrio-ventricular delay after cardiac surgery.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0310905}, pmid = {39823433}, issn = {1932-6203}, support = {FS/19/73/34690/BHF_/British Heart Foundation/United Kingdom ; }, mesh = {Humans ; *Central Venous Pressure/physiology ; Male ; Female ; Aged ; *Cardiac Surgical Procedures ; Middle Aged ; *Heart Ventricles/physiopathology ; Pacemaker, Artificial ; *Heart Atria/physiopathology ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Haemodynamic atrioventricular delay (AVD) optimisation has primarily focussed on signals that are not easy to acquire from a pacing system itself, such as invasive left ventricular catheterisation or arterial blood pressure (ABP). In this study, standard clinical central venous pressure (CVP) signals are tested as a potential alternative.

METHODS: Sixteen patients with a temporary pacemaker after cardiac surgery were studied. AV delay optimisation was performed by alternating between a reference AVD of 120ms and tested settings ranging from 40 to 280ms, with 8 replicates for each setting. Alongside (a) the raw data, three methods of correcting for respiration were tested: (b) limiting analysis to a respiratory cycle, (c) asymmetric least squares (ALS) and (d) discrete wavelet transform (DWT). The utility of a quality control step was tested.

RESULTS: CVP signals were a mirror image of the systolic ABP signals: The four R values were -0.674, -0.692, -0.631, -0.671 respectively (all p<0.001). With quality control, the mirror image was best for DWT (R = -0.76, p<0.001), with the CVP and ABP optima agreeing well (R = 0.78, p<0.001). The automated quality control signal correctly predicted the gap between the AVD optima calculated from ABP and CVP (R = 0.8, p<0.001).

CONCLUSIONS: Central venous pressure signals could be used to optimise AVD, because they have a reliable inverse relationship with ABP when pacemaker settings undergo protocolised testing. However, protocols need careful design to circumvent spontaneous biological variability.}, } @article {pmid39823474, year = {2025}, author = {Zhang, Y and He, L and Gundelach, J and Ge, A and Edlund, H and Norlin, S and Bram, RJ}, title = {Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.}, journal = {PLoS genetics}, volume = {21}, number = {1}, pages = {e1011547}, pmid = {39823474}, issn = {1553-7404}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Endoplasmic Reticulum/metabolism/genetics ; Mice, Transgenic ; *Motor Neurons/metabolism/pathology ; Neuromuscular Junction/metabolism ; Protein Transport ; Spinal Cord/metabolism/pathology ; *Adaptor Proteins, Signal Transducing/genetics ; }, abstract = {Motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and progressive bulbar palsy, involve loss of muscle control resulting from death of motor neurons. Although the exact pathogenesis of these syndromes remains elusive, many are caused by genetically inherited mutations. Thus, it is valuable to identify additional genes that can impact motor neuron survival and function. In this report, we describe mice that express globally reduced levels of calcium-modulating cyclophilin ligand (CAML) protein. CAML is an essential component in the transmembrane domain recognition complex (TRC) pathway, responsible for inserting C-terminal tail anchored (TA) proteins into the endoplasmic reticulum membrane. The primary phenotype observed in these mice was rapid development of hind limb weakness and paralysis. Spinal cord sections revealed a loss of motor neuron cell bodies. Targeting CAML loss specifically to neurons using SLICK-H-Cre or synapsin-Cre transgenic mice yielded similar phenotypes, indicating that CAML plays a cell autonomous role in this process. We found that intracellular trafficking was perturbed in cells depleted of CAML, with aberrant release of procathepsin D and defective retention of CD222 within the trans-Golgi network, as well as reduced levels and mislocalization of syntaxin 5 (Stx5). Dysfunctional lysosomes and abnormal protein glycosylation were also revealed in CAML deficient cells, further indicating a defect in Golgi trafficking. In addition, we observed an identical phenotype in mice lacking ASNA1 in neurons, suggesting that CAML's role in sustaining muscle function is related to its involvement in the TRC pathway. Together, these findings implicate motor neuron survival as a key role for the TA protein insertion machinery in mice, which may shed light on the pathogenesis of neuromuscular disease in humans.}, } @article {pmid39824655, year = {2025}, author = {Jia, M and Li, P and Yan, Y and Liu, X and Gao, L and Zhu, G and Chen, Z}, title = {Antimicrobial susceptibility and genomic characterization of Vibrio cholerae non-O1/non-O139 isolated from clinical and environmental samples in Jiaxing City, China.}, journal = {FEMS microbiology letters}, volume = {372}, number = {}, pages = {}, doi = {10.1093/femsle/fnaf009}, pmid = {39824655}, issn = {1574-6968}, support = {2024KY1697//Medical Science and Technology Project of Zhejiang Province/ ; 2023AY31028//Science and Technology Bureau of Jiaxing City/ ; }, mesh = {China ; Humans ; *Anti-Bacterial Agents/pharmacology ; Microbial Sensitivity Tests ; Multilocus Sequence Typing ; *Vibrio cholerae non-O1/genetics/drug effects/isolation & purification/pathogenicity/classification ; Drug Resistance, Bacterial/genetics ; Virulence/genetics ; Environmental Microbiology ; Virulence Factors/genetics ; Genome, Bacterial ; Genetic Variation ; }, abstract = {Non-O1/non-O139 (NOVC) strains inhabit aquatic environments and sporadically induce human illnesses. This study involved the virulence and antimicrobial genetic characterization of 176 NOVC strains, comprising 25 from clinical samples and 151 from environmental sources, collected between 2021 and 2023. The antimicrobial susceptibility of the examined NOVC population was predominantly high, exhibiting only poor susceptibility to colistin, with 89.2% resistance. The examination of virulence genes revealed that the majority of strains were positive for glucose metabolism (als gene) (169/176, 96.0%). Through multilocus sequence typing, the 176 NOVC strains were categorised into 121 sequence types, 79 of which were novel. NOVC strains demonstrate significant genetic variability and frequently engage in recombination. This work offers genetic characterization of the pathogenicity and antimicrobial resistance of a NOVC community. Our findings offer insights that may aid in the development of preventative and treatment methods for this pathogen.}, } @article {pmid39824736, year = {2025}, author = {Chow, G and Scher, M and Krisciunas, GP and Tracy, LF}, title = {Comprehensive Review of Multilingual Patient-Reported Outcome Measures for Dysphonia.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2025.01.005}, pmid = {39824736}, issn = {1873-4588}, abstract = {INTRODUCTION: Patient-reported outcome measures (PROMs) represent an important part of a comprehensive voice assessment for clinical care and research. Access to multilingual PROMs enables inclusion of information from diverse patient populations. This review compares available translated and validated PROMs for adult dysphonia.

METHODS: A comprehensive review of Cochrane Library, PubMed, and OnBase was performed for PROMs evaluating adult dysphonia in all languages. References were additionally queried. PROM development process, available languages, and study group demographics were compared between PROMs available in at least one language other than English. Cultural validation for each PROM was assessed against Beaton et al's six-stage cross-cultural adaptation guidelines.

RESULTS: Of 21 PROMs assessing adult dysphonia, 13 (62%) were available in one or more language other than English, and nine (43%) were available in seven or more. Voice Handicap Index (VHI) and VHI-10 were the most widely available translated questionnaires (n = 29, n = 15) followed by Vocal Fatigue Index (VFI), Singing-VHI (S-VHI), and Voice-Related Quality of Life (V-RQOL) (n = 11). Identified questionnaires were available in English (n = 21), Persian (n = 9), Kannada (n = 8), and Turkish (n = 7) as the most common languages. Females averaged 60% (range 13%-81%) of dysphonic subject groups and 59% of non-dysphonic subject groups (range 20%-88%). Of the 113 articles that reported cultural validation techniques, 16 (14%) adequately fulfilled the cross-cultural adaptation guidelines used.

CONCLUSION: Multilingual PROMs for dysphonia are widely available, but linguistic representation varied. VHI, VFI, S-VHI, and V-RQOL are the most widely translated. The most represented languages were Persian, Kannada, and Turkish. Few studies adequately followed cross-cultural adaptation standards. Efforts to translate and validate questionnaires into different languages may allow more diverse assessment and comparison of larger populations with dysphonia. This review identifies translated PROMs for dysphonia and analyzes their level of cultural validation for future use.}, } @article {pmid39824815, year = {2025}, author = {Leau, C and Wang, Y and Gervillié-Mouravieff, C and Boles, ST and Zhang, XH and Coudray, S and Boussard-Plédel, C and Tarascon, JM}, title = {Tracking solid electrolyte interphase dynamics using operando fibre-optic infra-red spectroscopy and multivariate curve regression.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {757}, pmid = {39824815}, issn = {2041-1723}, abstract = {As batteries drive the transition to electrified transportation and energy systems, ensuring their quality, reliability, lifetime, and safety is crucial. While the solid electrolyte interphase (SEI) is known to govern these performance characteristics, its dynamic nature makes understanding its nucleation, growth, and composition an ambitious, yet elusive aspiration. This work employs chalcogenide fibres embedded in negative electrode materials for operando Infra-red Fibre-optic Evanescent Wave Spectroscopy (IR-FEWS), combined with Multivariate Curve Resolution by Alternating Least Squares (MCR-ALS) algorithms for spectra analysis. By establishing molecular fingerprints that can be used to identify reaction products, IR-FEWS combined with MCR-ALS enables improved understanding of SEI evolution during cell formation with notable differences stemming from electrolyte or anode material. For example, despite operating at an elevated potential, lithium titanate's SEI has intrinsic instability, evidenced by continued carbonate formation. This approach leads the hunt for the SEI down a new path, giving empirical formulations theoretical roots.}, } @article {pmid39825381, year = {2025}, author = {Gupta, R and Bhandari, M and Grover, A and Al-Shehari, T and Kadrie, M and Alfakih, T and Alsalman, H}, title = {Correction: Predictive modeling of ALS progression: an XGBoost approach using clinical features.}, journal = {BioData mining}, volume = {18}, number = {1}, pages = {5}, pmid = {39825381}, issn = {1756-0381}, } @article {pmid39827337, year = {2025}, author = {Mwale, PF and Hsieh, CT and Yen, TL and Jan, JS and Taliyan, R and Yang, CH and Yang, WB}, title = {Chitinase-3-like-1: a multifaceted player in neuroinflammation and degenerative pathologies with therapeutic implications.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {7}, pmid = {39827337}, issn = {1750-1326}, support = {NSTC 112-2320-B-038 -018 -MY3//National Science and Technology Council/ ; CGH-MR-A11315//Cathay General Hospital/ ; CGH-MR-A11314//Cathay General Hospital/ ; }, mesh = {Humans ; *Chitinase-3-Like Protein 1/metabolism ; *Neuroinflammatory Diseases/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Biomarkers/metabolism ; Inflammation/metabolism ; }, abstract = {Chitinase-3-like-1 (CHI3L1) is an evolutionarily conserved protein involved in key biological processes, including tissue remodeling, angiogenesis, and neuroinflammation. It has emerged as a significant player in various neurodegenerative diseases and brain disorders. Elevated CHI3L1 levels have been observed in neurological conditions such as traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD), multiple sclerosis (MS), Neuromyelitis optica (NMO), HIV-associated dementia (HAD), Cerebral ischemic stroke (CIS), and brain tumors. This review explores the role of CHI3L1 in the pathogenesis of these disorders, with a focus on its contributions to neuroinflammation, immune cell infiltration, and neuronal degeneration. As a key regulator of neuroinflammation, CHI3L1 modulates microglia and astrocyte activity, driving the release of proinflammatory cytokines that exacerbate disease progression. In addition to its role in disease pathology, CHI3L1 has emerged as a promising biomarker for the diagnosis and monitoring of brain disorders. Elevated cerebrospinal fluid (CSF) levels of CHI3L1 have been linked to disease severity and cognitive decline, particularly in AD and MS, highlighting its potential for clinical diagnostics. Furthermore, therapeutic strategies targeting CHI3L1, such as small-molecule inhibitors and neutralizing antibodies, have shown promise in preclinical studies, demonstrating reduced neuroinflammation, amyloid plaque accumulation, and improved neuronal survival. Despite its therapeutic potential, challenges remain in developing selective and safe CHI3L1-targeted therapies, particularly in ensuring effective delivery across the blood-brain barrier and mitigating off-target effects. This review addresses the complexities of targeting CHI3L1, highlights its potential in precision medicine, and outlines future research directions aimed at unlocking its full therapeutic potential in treating neurodegenerative diseases and brain pathologies.}, } @article {pmid39827940, year = {2025}, author = {Jinno, J and Abdelhamid, RF and Morita, J and Saga, R and Yamasaki, Y and Kadowaki, A and Ogawa, K and Kimura, Y and Ikenaka, K and Beck, G and Baba, K and Nagai, Y and Kasahara, E and Sekiyama, A and Hirayama, T and Hozumi, I and Hasegawa, T and Araki, T and Mochizuki, H and Nagano, S}, title = {TDP-43 transports ferritin heavy chain mRNA to regulate oxidative stress in neuronal axons.}, journal = {Neurochemistry international}, volume = {184}, number = {}, pages = {105934}, doi = {10.1016/j.neuint.2025.105934}, pmid = {39827940}, issn = {1872-9754}, mesh = {*Oxidative Stress/physiology ; *RNA, Messenger/metabolism/genetics ; *Apoferritins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Axons/metabolism ; Animals ; Humans ; *Neurons/metabolism ; *Ferritins/metabolism/genetics ; Iron/metabolism ; Oxidoreductases ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the mislocalization and abnormal deposition of TAR DNA-binding protein 43 (TDP-43). This protein plays important roles in RNA metabolism and transport in motor neurons and glial cells. In addition, abnormal iron accumulation and oxidative stress are observed in the brain and spinal cord of patients with ALS exhibiting TDP-43 pathology and in animal models of ALS. We have previously demonstrated that TDP-43 downregulation significantly affects the expression of ferritin heavy chain (Fth1) mRNA in the axonal regions of neurons. Nevertheless, the mechanisms by which TDP-43 contributes to oxidative stress and iron accumulation in the central nervous system remain elusive. In this study, we aimed to investigate whether Fth1 mRNA is a target transported to the axon by TDP-43 using biophysical and biochemical analyses. Our results revealed Fth1 mRNA as a target mRNA transported to axons by TDP-43. Moreover, we demonstrated that TDP-43 regulates iron homeostasis and oxidative stress in neurons via Fth1 mRNA transport to the axons, possibly followed by a local translation of the ferritin heavy chain in the axons. This study suggests that TDP-43 plays an important role in preventing iron-mediated oxidative stress in neurons, with its loss contributing to ALS pathogenesis.}, } @article {pmid39828018, year = {2025}, author = {Sharma, D and Singh, V and Kumar, A and Singh, TG}, title = {Genistein: A promising ally in combating neurodegenerative disorders.}, journal = {European journal of pharmacology}, volume = {991}, number = {}, pages = {177273}, doi = {10.1016/j.ejphar.2025.177273}, pmid = {39828018}, issn = {1879-0712}, mesh = {*Genistein/therapeutic use/pharmacology ; Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative disorders arise when nerve cells in the brain or peripheral nervous system gradually lose functions and eventually die. Although certain therapies may alleviate some of the physical and mental symptoms associated with neurodegenerative disorders, hence slowing their progression, but no sure-shot treatment is currently available. It was shown that the rise in life expectancy and the number of elderly people in the community led to an increasing trend in the incidence and prevalence of neurodegenerative disease. Phytomolecules are demonstrating their effectiveness in combating, regression, and delaying various diseases. Genistein is one of soy isoflavone with antioxidant, anti-inflammatory, and estrogenic effects. Researchers demonstrated that Genistein treatment significantly reduced hyperglycemia, improved cognitive performance by modulating acetylcholinesterase activity and oxidative stress, and alleviated neuroinflammatory conditions in mice. This paper evaluates (in vivo and in vitro) various molecular targets of isoflavones and their ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. In this review, we aim to provide an overview of the role that genistein plays in delaying the development of neurodegenerative disorders.}, } @article {pmid39828029, year = {2025}, author = {Fantini, J and Azzaz, F and Di Scala, C and Aulas, A and Chahinian, H and Yahi, N}, title = {Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow.}, journal = {Pharmacology & therapeutics}, volume = {267}, number = {}, pages = {108797}, doi = {10.1016/j.pharmthera.2025.108797}, pmid = {39828029}, issn = {1879-016X}, mesh = {*Intrinsically Disordered Proteins/chemistry/metabolism/antagonists & inhibitors ; Humans ; *Drug Discovery/methods ; *Peptides/therapeutic use/chemistry/pharmacology ; Protein Conformation ; Animals ; Drug Design ; }, abstract = {The traditional model of protein structure determined by the amino acid sequence is today seriously challenged by the fact that approximately half of the human proteome is made up of proteins that do not have a stable 3D structure, either partially or in totality. These proteins, called intrinsically disordered proteins (IDPs), are involved in numerous physiological functions and are associated with severe pathologies, e.g. Alzheimer, Parkinson, Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), and type 2 diabetes. Targeting these proteins is challenging for two reasons: i) we need to preserve their physiological functions, and ii) drug design by molecular docking is not possible due to the lack of reliable starting conditions. Faced with this challenge, the solutions proposed by artificial intelligence (AI) such as AlphaFold are clearly unsuitable. Instead, we suggest an innovative approach consisting of mimicking, in short synthetic peptides, the conformational flexibility of IDPs. These peptides, which we call adaptive peptides, are derived from the domains of IDPs that become structured after interacting with a ligand. Adaptive peptides are designed with the aim of selectively antagonizing the harmful effects of IDPs, without targeting them directly but through selected ligands, without affecting their physiological properties. This "target the target, not the arrow" strategy is promised to open a new route to drug discovery for currently undruggable proteins.}, } @article {pmid39828328, year = {2025}, author = {Yorimoto, K and Ariake, Y and Kawaguchi, T and Hara, T}, title = {Long-term lung volume recruitment therapy maintains ventilator weaning in a patient with ALS following tracheostomy.}, journal = {BMJ case reports}, volume = {18}, number = {1}, pages = {}, doi = {10.1136/bcr-2024-262945}, pmid = {39828328}, issn = {1757-790X}, mesh = {Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/therapy/complications/physiopathology ; *Respiratory Therapy/methods ; *Tracheostomy ; Treatment Outcome ; *Ventilator Weaning/methods ; Vital Capacity ; }, abstract = {We report a case of amyotrophic lateral sclerosis (ALS) in a patient in their 50s, presenting with spastic paraparesis and bulbar palsy, treated with lung volume recruitment therapy (LVRT). From early stage in the disease, vital capacity (VC), lung insufflation capacity (LIC) and ALS Functional Rating Scale-Revised scores were regularly measured, and LVRT was continuously performed at home. After 10 years, the patient had complete limb function loss and required nutritional management via gastrostomy and full assistance with daily activities. Despite this, the gap between VC and LIC remained approximately 2000 mL, and the patient was not ventilator-dependent during the day after tracheostomy. Chest CT showed improvement in lower lobe atelectasis due to LVRT. Typically, respiratory physiotherapy is challenging in patients with bulbar palsy or post-tracheostomy, but in this case, LVRT successfully maintained lung mobility. Early LVRT implementation may improve ALS patients' survival prognosis and warrants further exploration.}, } @article {pmid39829311, year = {2025}, author = {Falanga, AP and Piccialli, I and Greco, F and D'Errico, S and Nolli, MG and Borbone, N and Oliviero, G and Roviello, GN}, title = {Nanostructural Modulation of G-Quadruplex DNA in Neurodegeneration: Orotate Interaction Revealed Through Experimental and Computational Approaches.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16296}, pmid = {39829311}, issn = {1471-4159}, support = {IR0000010 "ELIXIRxNextGenIT"//European Commission/ ; PNRRMUR-M4C2-I//European Commission/ ; FOE 2020-ISBE-IT Joint Research Unit//Ministero dell'Università e della Ricerca/ ; }, mesh = {*G-Quadruplexes/drug effects ; Humans ; *DNA/chemistry/metabolism ; Molecular Docking Simulation/methods ; *Neurodegenerative Diseases/metabolism/genetics ; *Nanostructures/chemistry ; }, abstract = {The natural compound orotic acid and its anionic form, orotate, play a pivotal role in various biological processes, serving as essential intermediates in pyrimidine de novo synthesis, with demonstrated connections to dietary, supplement, and neurodrug applications. A novel perspective on biomolecular aggregation at the nanoscale, particularly pertinent to neurodegeneration, challenges the established paradigm positing that peptide (amyloid beta) and protein (tau) aggregation mainly govern the molecular events underlying prevalent neuropathologies. Emerging biological evidence indicates a notable role for G-quadruplex (G4) DNA aggregation in neurodegenerative processes affecting neuronal cells, particularly in the presence of extended (G4C2)n repeats in nuclear DNA sequences. Our study concerns d[(GGGGCC)3GGGG], a G4-forming DNA model featuring G4C2 repeats that is in correlation with neurodegeneration. Through different investigations utilizing spectroscopic techniques (CD, UV, and thermal denaturations), PAGE electrophoresis, and molecular docking, the study explores the influence of orotate on the aggregation of this neurodegeneration-associated DNA. A computational approach was employed to construct an in silico model of the DNA aggregate, which involved the docking of multiple G4 units and subsequent integration of the ligand into both the DNA monomer and its in silico aggregated model. The convergence of computational analyses and empirical data collectively supports the hypothesis that orotate possesses the capability to modulate the aggregation of neurodegeneration-related DNA. Notably, the findings suggest the potential utility of orotate as a neurodrug, especially for the therapy of amyotrophic lateral sclerosis (ALS) and Frontotemporal Dementia (FTD), with its current status as a dietary supplement indicating minimal safety concerns. Additionally, orotate demonstrated a slight increase in mitochondrial dehydrogenase activity as assessed by the MTT assay, which is beneficial for a neurodrug as it suggests a potential role in enhancing mitochondrial function and supporting neuronal health.}, } @article {pmid39829368, year = {2025}, author = {Bedlack, R}, title = {Stitching strength: things I've learned about hope and how I am trying to weave them into my in ALS practice.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {189-191}, doi = {10.1080/21678421.2025.2454903}, pmid = {39829368}, issn = {2167-9223}, } @article {pmid39829394, year = {2025}, author = {Buddenhagen, CE and Ngow, Z and Wynne-Jones, B and Rolston, MP}, title = {Resistance to the herbicides haloxyfop and iodosulfuron is common in commercial ryegrass (Lolium) seed lines.}, journal = {Pest management science}, volume = {81}, number = {6}, pages = {2990-2996}, pmid = {39829394}, issn = {1526-4998}, support = {//AgResearch Ltd via its contribution to the Better Border Biosecurity (B3) research collaboration, www.b3nz.org/ ; }, mesh = {*Lolium/drug effects/genetics/growth & development ; *Herbicides/pharmacology ; *Herbicide Resistance/genetics ; Seeds/drug effects/genetics/growth & development ; *Sulfonylurea Compounds/pharmacology ; *Halogenated Diphenyl Ethers/pharmacology ; *Sulfonamides/pharmacology ; New Zealand ; Glycine/analogs & derivatives/pharmacology ; Pyridines ; }, abstract = {BACKGROUND: Ryegrass (Lolium spp.) is a key forage providing a $14 billion contribution to New Zealand's gross domestic product (GDP). However, ryegrass can also act as a weed and evolve resistance to herbicides used for its control. Farmers suspected that imported seed might contribute to resistance issues. Herbicide resistance frequencies were investigated in commercial ryegrass seed lines intended for multiplication in New Zealand. Samples from 56 basic seed lots and 52 unique cultivars sourced from regions including New Zealand, United States, Europe and Japan were planted in field trials. Seedlings were then sprayed with three common herbicides: glyphosate, iodosulfuron, and haloxyfop. Surviving plants were retested to confirm resistance.

RESULTS: Resistance to haloxyfop and or iodosulfuron was detected in 79% of seed lines. However, frequencies were not significantly higher in imported lines (from United States and Europe) compared with New Zealand lines. Resistance was detected at frequencies between 0.00112% and 10% for haloxyfop and between 0.00212% and 14.28% for iodosulfuron Resistance to glyphosate was not found. There was no significant difference between the resistance detected in seed samples sourced from different seed companies.

CONCLUSIONS: It was found that 63% of resistant lines had resistance frequencies rarer than 0.1%, but this is potentially problematic considering typical sowing rates. Imported versus domestic seed sources were not significantly different; they pose similar levels of resistance risk to farmers. Lolium multiflorum had a higher resistance frequency compared to Lolium perenne (although only six L. multiflorum lots were evaluated). Breeders should screen progeny of early crosses for herbicide resistance. © 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid39831022, year = {2025}, author = {Okpete, UE and Byeon, H}, title = {Brain-derived neurotrophic factor alterations and cognitive decline in schizophrenia: Implications for early intervention.}, journal = {World journal of psychiatry}, volume = {15}, number = {1}, pages = {102131}, pmid = {39831022}, issn = {2220-3206}, abstract = {This manuscript explores the recent study by Cui et al which assessed the interplay between inflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels in first-episode schizophrenia patients. The study revealed that higher levels of interleukin-6 and tumor necrosis factor-α correlated with reduced BDNF levels and poorer cognitive performance. Schizophrenia is a severe psychiatric disorder impacting approximately 1% of the global population, characterized by positive symptoms (hallucinations and delusions), negative symptoms (diminished motivation and cognitive impairments) and disorganized thoughts and behaviors. Emerging research highlights the role of BDNF as a potential biomarker for early diagnosis and therapeutic targeting. The findings from Cui et al's study suggest that targeting neuroinflammation and enhancing BDNF levels may improve cognitive outcomes. Effective treatment approaches involve a combination of pharmacological and non-pharmacological interventions tailored to individual patient needs. Hence, monitoring cognitive and neuroinflammatory markers is essential for improving patient outcomes and quality of life. Consequently, this manuscript highlights the need for an integrated approach to schizophrenia management, considering both clinical symptoms and underlying neurobiological changes.}, } @article {pmid39831374, year = {2025}, author = {Risi, B and Imarisio, A and Cuconato, G and Padovani, A and Valente, EM and Filosto, M}, title = {Mitochondrial DNA (mtDNA) as fluid biomarker in neurodegenerative disorders: A systematic review.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70014}, pmid = {39831374}, issn = {1468-1331}, mesh = {Humans ; Alzheimer Disease/cerebrospinal fluid/blood ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood ; Biomarkers/cerebrospinal fluid/blood ; *DNA, Mitochondrial/cerebrospinal fluid/blood ; *Neurodegenerative Diseases/cerebrospinal fluid/blood/genetics/diagnosis ; Parkinson Disease/cerebrospinal fluid/blood ; }, abstract = {BACKGROUND: Several studies evaluated peripheral and cerebrospinal fluid (CSF) mtDNA as a putative biomarker in neurodegenerative diseases, often yielding inconsistent findings. We systematically reviewed the current evidence assessing blood and CSF mtDNA levels and variant burden in Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Multiple sclerosis (MS) was also included as a paradigm of chronic neuroinflammation-driven neurodegeneration.

METHODS: Medline, Embase, Scopus and Web of Science were searched for articles published from inception until October 2023. Studies focused on mtDNA haplogroups or hereditary pathogenic variants were excluded. Critical appraisal was performed using the Quality Assessment for Diagnostic Accuracy Studies criteria.

RESULTS: Fifty-nine original studies met our a priori-defined inclusion criteria. The majority of CSF-focused studies showed (i) decreased mtDNA levels in PD and AD; (ii) increased levels in MS compared to controls. No studies evaluated CSF mtDNA in ALS. Results focused on blood cell-free and intracellular mtDNA were contradictory, even within studies evaluating the same disease. This poor reproducibility is likely due to the lack of consideration of the many factors known to affect mtDNA levels. mtDNA damage and methylation levels were increased and reduced in patients compared to controls, respectively. A few studies investigated the correlation between mtDNA and disease severity, with conflicting results.

CONCLUSIONS: Additional well-designed studies are needed to evaluate CSF and blood mtDNA profiles as putative biomarkers in neurodegenerative diseases. The identification of "mitochondrial subtypes" of disease may enable novel precision medicine strategies to counteract neurodegeneration.}, } @article {pmid39831399, year = {2025}, author = {Wang, F and Jing, Z and Wang, Q and Li, M and Lu, B and Huo, A and Zhao, C and Zhou, H and Liang, W and Hu, W and Fu, X}, title = {Bidirectional Mendelian Randomization Analysis of the Association Between Mitochondrial Proteins and Neurodegenerative Diseases.}, journal = {Brain and behavior}, volume = {15}, number = {1}, pages = {e70283}, pmid = {39831399}, issn = {2162-3279}, support = {82303029//National Natural Science Foundation of China/ ; 2024YLZDJH027//the Zhengzhou Science and Technology Innovation Project for Healthcare/ ; YXKC2022020//Health Commission of Henan Province/ ; 232102311134//Science and Technology Department of Henan Province/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis/methods ; *Neurodegenerative Diseases/genetics/metabolism ; *Mitochondrial Proteins/genetics/metabolism ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; }, abstract = {BACKGROUND: Neurodegenerative diseases involve progressive neuronal dysfunction and cognitive decline, posing substantial global challenges. Although the precise causes remain unclear, several studies highlight the role of protein metabolism abnormalities in disease development. This study investigates the causal links between variations in mitochondrial protein genes and neurodegenerative diseases, aiming to elucidate their potential contributions to disease progression and identify novel therapeutic strategies.

METHODS: Herein, we utilized data from genome-wide association studies (GWAS) on mitochondrial proteins and neurodegenerative diseases. Bidirectional Mendelian randomization (MR), employing instrumental variables (IVs), was used to assess causal relationships. The primary method for estimating causal effects was the inverse variance-weighted (IVW) method, supplemented by additional MR approaches.

RESULTS: Bidirectional MR revealed significant associations between mitochondrial protein gene variants and neurodegenerative diseases. Specifically, associations were found with Alzheimer's disease (AD) (three proteins), Parkinson's disease (PD) (four proteins), amyotrophic lateral sclerosis (ALS) (six proteins), multiple sclerosis (two proteins), and dementia with Lewy bodies (four proteins). Conversely, analyses indicated significant associations of neurodegenerative diseases with mitochondrial protein gene variants, notably with AD, dementia with Lewy bodies, and multiple sclerosis, affecting multiple mitochondrial protein levels. Bidirectional causality was observed between dementia with Lewy bodies and C21orf33.

CONCLUSIONS: Using MR, we identified significant links between mitochondrial protein gene mutations and the risk of neurodegenerative diseases. These results highlight reciprocal relationships where certain neurodegenerative diseases influence mitochondrial protein expression levels. These findings underscore the pivotal role of mitochondrial proteins in neurodegenerative diseases, offering critical insights into disease mechanisms and potential therapeutic avenues.}, } @article {pmid39831450, year = {2025}, author = {Hoehne, SN and Cary, JA and Bailey, LN and Davidow, EB and Martin, LG and DeJong, TL}, title = {An exploratory study on the effect of rescuer team size on basic and advanced life support technical skills in a high-fidelity simulation of canine cardiopulmonary arrest.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {35}, number = {1}, pages = {9-18}, pmid = {39831450}, issn = {1476-4431}, support = {//Converse Fund, Washington State University College of Veterinary Medicine 2021-2022 CVM Intramural Research Grants/ ; }, mesh = {Animals ; Dogs ; *Cardiopulmonary Resuscitation/veterinary ; *Heart Arrest/veterinary/therapy ; Prospective Studies ; *Dog Diseases/therapy ; Clinical Competence ; *Advanced Cardiac Life Support/veterinary ; Humans ; }, abstract = {OBJECTIVE: To evaluate the effect of rescuer team size on objective skill measures of basic life support (BLS) and advanced life support (ALS) using high-fidelity canine CPR simulation.

DESIGN: Prospective, experimental study.

SETTING: Veterinary clinical simulation center.

SUBJECTS: Forty-eight Reassessment Campaign on Veterinary Resuscitation CPR-certified veterinary students.

MEASUREMENTS AND MAIN RESULTS: Five groups of participants each conducted 3 CPR simulations in configurations of 4, 6, and 8 rescuers. Simulations represented a shock patient declining into asystole, followed by ventricular fibrillation and return of spontaneous circulation. Resuscitation efforts were video-recorded to evaluate BLS and ALS tasks. Mean (±SD) was derived and data were compared among team sizes using ANOVA and Tukey's post hoc analysis. Significance was set at P < 0.05. Among teams of 4, 6, and 8 rescuers, time to first chest compression (13 s [±6], 9 s [±2], 8 s [±4]; P = 0.24) and positive-pressure breath (101 s [±37], 56 s [±15], 67 s [±24]; P = 0.05) were not significantly different. Chest compression (100/min [±5], 108/min [±6], 107/min [±6]; P = 0.12) and ventilatory rates (9/min [±1], respectively, P = 0.52) were not significantly different. Time without chest compressions/total length of CPR was not significantly different (72 s [±16], 61 s [±16], 54 s [±8]; P = 0.15). Capnography and ECG monitoring were used by all teams. Time to first vasopressor administration was significantly different among team sizes (268 s [±70], 164 s [±65], 174 s [±34]; P = 0.04), with vasopressors being most quickly administered by teams of 6 rescuers. Time to electrical defibrillation was not significantly different (486 s [±45], 424 s [±22], 488 s [±181]; P = 0.57). Incorrect ALS interventions occurred in 60%, 0%, and 40% of CPR events in 4, 6, and 8 rescuer teams, respectively.

CONCLUSIONS: Although the achievement of BLS tasks was comparable in teams of 4 rescuers, teams of 6 rescuers may be preferable based on differences in the rate of guideline-incompliant treatments and ALS task efficiency. Teams of 8 rescuers were neither more efficient nor more accurate at conducting BLS and ALS tasks.}, } @article {pmid39832811, year = {2025}, author = {Ghaderi, S and Mohammadi, S and Ahmadzadeh, AM and Darmiani, K and Arab Bafrani, M and Jashirenezhad, N and Helfi, M and Alibabaei, S and Azadi, S and Heidary, S and Fatehi, F}, title = {Thalamic Magnetic Susceptibility (χ) Alterations in Neurodegenerative Diseases: A Systematic Review and Meta-Analysis of Quantitative Susceptibility Mapping Studies.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {62}, number = {1}, pages = {271-294}, doi = {10.1002/jmri.29698}, pmid = {39832811}, issn = {1522-2586}, mesh = {Humans ; *Brain Mapping/methods ; Iron/metabolism ; *Magnetic Resonance Imaging/methods ; *Neurodegenerative Diseases/diagnostic imaging ; *Thalamus/diagnostic imaging ; }, abstract = {BACKGROUND: Quantitative Susceptibility Mapping (QSM) provides a non-invasive post-processing method to investigate alterations in magnetic susceptibility (χ), reflecting iron content within brain regions implicated in neurodegenerative diseases (NDDs).

PURPOSE: To investigate alterations in thalamic χ in patients with NDDs using QSM.

STUDY TYPE: Systematic review and meta-analysis.

POPULATION: A total of 696 patients with NDDs and 760 healthy controls (HCs) were included in 27 studies.

FIELD STRENGTH/SEQUENCE: Three-dimensional multi-echo gradient echo sequence for QSM at mostly 3 Tesla.

ASSESSMENT: Studies reporting QSM values in the thalamus of patients with NDDs were included. Following PRISMA 2020, we searched the four major databases including PubMed, Scopus, Web of Science, and Embase for peer-reviewed studies published until October 2024.

STATISTICAL TESTS: Meta-analysis was conducted using a random-effects model to calculate the standardized mean difference (SMD) between patients and HCs.

RESULTS: The pooled SMD indicated a significant increase in thalamic χ in NDDs compared to HCs (SMD = 0.42, 95% CI: 0.05-0.79; k = 27). Notably, amyotrophic lateral sclerosis patients showed a significant increase in thalamic χ (1.09, 95% CI: 0.65-1.53, k = 2) compared to HCs. Subgroup analyses revealed significant χ alterations in younger patients (mean age ≤ 62 years; 0.56, 95% CI: 0.10-1.02, k = 11) and studies using greater coil channels (coil channels > 16; 0.64, 95% CI: 0.28-1.00, k = 9). Publication bias was not detected and quality assessment indicated that studies with a lower risk of bias presented more reliable findings (0.75, 95% CI: 0.32-1.18, k = 9). Disease type was the primary driver of heterogeneity, while other factors, such as coil type and geographic location, also contributed to variability.

DATA CONCLUSION: Our findings support the potential of QSM for investigating thalamic involvement in NDDs. Future research should focus on disease-specific patterns, thalamic-specific nucleus analysis, and temporal evolution.

PLAIN LANGUAGE SUMMARY: Our research investigated changes in iron levels within the thalamus, a brain region crucial for motor and cognitive functions, in patients with various neurodegenerative diseases (NDDs). The study utilized a specific magnetic resonance imaging technique called Quantitative Susceptibility Mapping (QSM) to measure iron content. It identified a significant increase in thalamic iron levels in NDD patients compared to healthy individuals. This increase was particularly prominent in patients with Amyotrophic Lateral Sclerosis, younger individuals, and studies employing advanced imaging equipment.

LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.}, } @article {pmid39833708, year = {2025}, author = {Bidarolli, M and Das, B and Rawat, VS and Manocha, S and Sony, HT and Agnihotri, A and Gupta, M and Agera, F}, title = {Polypharmacy and anticholinergic burden scales in older adults: a cross-sectional study among psychiatric outpatients in a tertiary care hospital.}, journal = {BMC geriatrics}, volume = {25}, number = {1}, pages = {43}, pmid = {39833708}, issn = {1471-2318}, mesh = {Humans ; Male ; Cross-Sectional Studies ; Female ; *Polypharmacy ; Aged ; *Cholinergic Antagonists/adverse effects/therapeutic use ; Middle Aged ; Tertiary Care Centers ; *Mental Disorders/drug therapy/epidemiology ; India/epidemiology ; Outpatients/psychology ; Aged, 80 and over ; *Psychotropic Drugs/adverse effects/therapeutic use ; }, abstract = {INTRODUCTION: Mental disorders are prevalent among older adults, often leading to the use of multiple medications, many with anticholinergic properties. Polypharmacy, common in this population, is a major contributor to anticholinergic burden, which is linked to cognitive and physical decline. This study investigates the relationship between polypharmacy and anticholinergic burden across seven anticholinergic burden scales in elderly patients attending the psychiatric outpatient.

METHODS: Study was conducted at a psychiatry outpatient clinic at All India Institute of Medical Sciences, Rishikesh, India, from December 2021 to March 2023. Elderly patients (aged ≥ 60 years) who were on at least one psychotropic medication and had a primary working diagnosis of psychiatric illness were included. All psychotropic medications, including antidepressants, antipsychotics, mood stabilizers, and hypnotics, were evaluated. Anticholinergic burden scales were calculated by the respective tools. Univariate analysis was adopted to determine the factors that may affect polypharmacy.

RESULTS: Study included 1165 elderly patients aged ≥ 60 years. The prevalence of polypharmacy was 20.43% (n = 238). Clonazepam (n = 364, 17.28%), escitalopram (n = 197, 9.35%), metformin (n = 165, 7.83%), sertraline (n = 141, 6.69%), mirtazapine (n = 129, 6.12%), and lorazepam (n = 110, 5.22%) were among the most frequently prescribed anticholinergic drugs. Univariate analysis demonstrated that all anticholinergic risk assessment scales were closely correlated with polypharmacy, with the strongest association observed for the Anticholinergic Load Scale (ALS) (Odds Ratio = 4.3; p < 0.001). Polypharmacy was also positively associated with adverse drug reactions (Odds Ratio = 1.81; 95% Confidence Interval = 1.27-2.56).

CONCLUSION: The anticholinergic burden in this cohort of elderly psychiatry patients was high, with 95.1% (n = 1108) experiencing a significant burden. Adverse drug events and anticholinergic burden scales were positively associated with polypharmacy, with a stronger correlation between polypharmacy and ALS scores than with other anticholinergic burden scales in older adults.}, } @article {pmid39834142, year = {2025}, author = {Stikvoort García, DJL and van den Berg, LH and Sleutjes, BTHM and Goedee, HS}, title = {Diagnostic Accuracy of Median Nerve Cross-Sectional Area in Suspected Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {71}, number = {4}, pages = {680-684}, pmid = {39834142}, issn = {1097-4598}, support = {//Stichting ALS Nederland/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Median Nerve/diagnostic imaging/pathology ; Aged ; Prospective Studies ; Ultrasonography ; Adult ; ROC Curve ; Retrospective Studies ; }, abstract = {INTRODUCTION/AIMS: Reduced nerve sizes obtained by nerve ultrasound (NUS) have been proposed as a potential diagnostic marker for amyotrophic lateral sclerosis (ALS). However, prospective studies evaluating patients with suspected ALS are currently lacking. We, therefore, evaluated the diagnostic accuracy of a standardized NUS protocol in a large sample of suspected ALS patients.

METHODS: We prospectively recruited 193 patients with suspected ALS, all of whom underwent the relevant ancillary tests. They also underwent a standardized NUS protocol, evaluating median nerve cross-sectional area (CSA) at upper arm, forearm and wrist. Additionally, we selected, retrospectively, a random sample of incident patients with multifocal motor neuropathy (MMN, n = 42). We determined diagnostic accuracy using receiver operating characteristic (ROC) analysis.

RESULTS: Ultimately, 143/193 patients received a final diagnosis of ALS, at a median disease duration of 10 months. Fifty patients were classified as non-ALS. Diagnostic yield of NUS to distinguish between patients with and without ALS was low (highest area under the curve (AUC) at the wrist: 0.57). In contrast, abnormal nerve sizes accurately discriminated MMN from patients with ALS, with AUCs ranging from 0.65 at the wrist to 0.86 at the upper arm.

DISCUSSION: Our study shows that reductions in nerve size are unlikely to have diagnostic utility during routine evaluation of suspected patients with ALS. However, when the differential diagnosis includes both ALS and MMN, median nerve size demonstrates high diagnostic accuracy.}, } @article {pmid39834320, year = {2025}, author = {Lero, CM and Park, S and Mroz, EL}, title = {Mapping the evidence of self-compassion in caregiver wellbeing for caregivers of persons with neurodegenerative disease: A scoping review.}, journal = {Palliative & supportive care}, volume = {23}, number = {}, pages = {e38}, pmid = {39834320}, issn = {1478-9523}, support = {T32 AG019134/AG/NIA NIH HHS/United States ; T32 MH019960/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Caregivers/psychology ; *Empathy ; *Neurodegenerative Diseases/psychology/complications ; }, abstract = {OBJECTIVES: Caregivers of those with neurodegenerative disease (ND) manage complex symptoms which impact their wellbeing. Self-compassion can promote maintenance of wellbeing during challenging experiences, including caregiving. Little guidance exists for observationally studying self-compassion or targeted interventions for this population. Our objective was to complete a scoping review of research describing self-compassion in the context of caregiver wellbeing of caregivers of those living with ND.

METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-analysis extension for Scoping Reviews (PRISMA-ScR) guidelines, 3 online databases identified 350 peer-reviewed articles, 18 of which were included in this study. Eligibility included being written in English, targeting caregivers of those living with ND, and examination of self-compassion. Articles were organized by the incorporation or characterization of self-compassion in the study design.

RESULTS: Alzheimer's disease predominated study samples of care recipients. Across study types self-compassion appeared as a theoretical concept, emerging theme, variable associated with other outcomes, and main outcome variable. Self-compassion is frequently measured using the Self-Compassion Scale, full or short form .

SIGNIFICANCE OF RESULTS: The study of self-compassion with caregivers of individuals living with ND is growing. Current literature is somewhat unfocussed, leading to gaps in understanding conceptualization to achieve maximum intervention benefits. Clarifying the role of self-compassion in caregiver wellbeing will provide a lens through which non-pharmacologic, psychotherapeutic, and behavioral intervention development may be framed to reduce negative psychological outcomes. The most frequently represented ND is Alzheimer's disease or other dementia, obscuring other NDs like amyotrophic lateral sclerosis, Parkinson's disease, and others.}, } @article {pmid39834554, year = {2025}, author = {Sarallah, R and Jahani, S and Soltani Khaboushan, A and Moaveni, AK and Amiri, M and Majidi Zolbin, M}, title = {The role of CXCL12/CXCR4/CXCR7 axis in cognitive impairment associated with neurodegenerative diseases.}, journal = {Brain, behavior, & immunity - health}, volume = {43}, number = {}, pages = {100932}, pmid = {39834554}, issn = {2666-3546}, abstract = {Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal loss and cognitive impairment (CI). The: Cysteine-X-cysteine chemokine ligand 12(CXCL12)/CXC chemokine receptor type 4 (CXCR4)/CXC chemokine receptor type 7 (CXCR7) axis has emerged as a critical molecular pathway in the development of CI in these disorders. This review explores the role of this axis in the pathogenesis of CI across these neurodegenerative diseases, synthesizing current evidence and its implications for targeted therapies. In AD, dysregulation of this axis contributes to amyloid-β accumulation and tau hyperphosphorylation, leading to synaptic dysfunction and cognitive decline. PD studies reveal that CXCL12/CXCR4 signaling influences dopaminergic neuron survival and microglial activation, affecting cognitive function. In MS, the axis modulates neuroinflammation and demyelination processes, impacting cognitive performance. ALS research indicates that the CXCL12/CXCR4/CXCR7 pathway is involved in motor neuron degeneration and associated cognitive deficits. Across these diseases, the axis influences neuroinflammation, synaptic plasticity, and neuronal survival through various signaling cascades, including PI3K/AKT, MAPK, and JAK/STAT pathways. Emerging evidence suggests that modulating this axis could provide neuroprotective effects and potentially alleviate cognitive symptoms. This review highlights the potential of the CXCL12/CXCR4/CXCR7 axis as a therapeutic target for addressing CI in neurodegenerative diseases. It also underscores the need for further research to fully elucidate its role and develop effective interventions, potentially leading to improved clinical management strategies for these devastating disorders.}, } @article {pmid39834841, year = {2024}, author = {Coutinho, KMD and Fernandes, F and Medeiros, KC and Coutinho, KD and Dias, AP and Valentim, RAM and Leite-Lais, L and Lima, KC}, title = {Data Report: Educational pathway addressing food and nutrition in amyotrophic lateral sclerosis on the AVASUS platform.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1476293}, pmid = {39834841}, issn = {2673-253X}, } @article {pmid39835009, year = {2024}, author = {Frolov, A and D'sa, E and Henderson, C and Guzman, MA and Hayat, G and Martin, JR}, title = {Complex Genetic Framework in Familial Amyotrophic Lateral Sclerosis With a C9ORF72 Mutation: A Case Report.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e76027}, pmid = {39835009}, issn = {2168-8184}, abstract = {A significantly diverse clinical presentation of amyotrophic lateral sclerosis (ALS), even in its best-studied familial form, continues to hinder current efforts to develop effective disease-modifying drugs for the cure of this rapidly progressive, fatal neuromuscular disease. We have previously shown that clinical heterogeneity of sporadic ALS (sALS) could be explained, at least in part, by its polygenic nature as well as by the presence of mutated genes linked to non-ALS neurological diseases and genes known to mediate ALS-related pathologies. We hypothesized that a similar genetic framework could also be present in patients with familial ALS (fALS). To test this hypothesis, we conducted post-mortem genetic screening of an individual with fALS and a mutation in the C9ORF72 gene. C9ORF72 mutations are highly penetrant and are present in the majority of fALS patients. Genetic screening by whole exome sequencing (WES) on the next generation sequencing (NGS) Illumina platform (San Diego, CA, USA) followed by examination of the respective rare (minor allele frequency (MAF) ≤ 0.01) pathological/deleterious genetic variants yielded results consistent with our hypothesis of the presence of a complex genetic framework in fALS. Additional members of this genetic framework were identified when the low-frequency (0.01 < MAF < 0.05) pathological/deleterious genetic variants were analyzed with the low-frequency biallelic AHNAK2, GLI3, PTIRM1, and ZNF254 variants, warranting a closer look at their potentially important role in fALS as C9ORF72 genetic modifiers as well as their link to both neuromuscular disorders/ALS and cancer. Therefore, in addition to the current genetic screening using a standard panel of ALS-related genes, a supplementary screening by WES could be very beneficial for the development of personalized treatment of ALS patients as well as in search of the respective efficient disease-modifying drugs.}, } @article {pmid39835561, year = {2025}, author = {Rai, A and Shukla, S and Gupta, RK and Mishra, A}, title = {ALS: A Silent Slayer of Motor Neurons. Traditional Chinese Herbal Medicine as an Effective Therapy.}, journal = {Current pharmaceutical design}, volume = {31}, number = {17}, pages = {1328-1346}, pmid = {39835561}, issn = {1873-4286}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Motor Neurons/drug effects/pathology ; *Medicine, Chinese Traditional ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disease characterized by motor symptoms, and cognitive impairment. The complexity in treating ALS arises from genetic and environmental factors, contributing to the gradual decline of lower and upper motor neurons. The anticipated pharmaceutical market valuation for ALS is projected to reach $1,038.94 million by 2032. This projection underscores the escalating impact of ALS on global healthcare systems. ALS prevalence is expected to surge to 376,674 cases by 2040. In 2022, India ranked among the top 3 Asian-Pacific nations, while North America dominated the global ALS market. Ongoing investigations explore the potential of neuroprotective drugs like riluzole and edaravone in ALS treatment. Recently approved drugs, Relyvrio (sodium phenylbutyrate and taurursodiol) and Tofersen (Qalsody) have completed the trials, and others are currently undergoing extensive clinical trials. Continuous research and exploration of therapeutic avenues, including gene therapy and neuroprotective treatments, are imperative to address the challenges posed by ALS and other neurodegenerative diseases. Traditional Chinese medicine (TCM) approaches and clinical trials are being explored for treating ALS symptoms, targeting neuroinflammation, oxidative damage, and muscle weakness, showcasing the potential benefits of integrating traditional and modern approaches in ALS management.}, } @article {pmid39836043, year = {2025}, author = {Berry, JD and Hagan, M and Zhang, J and Liu, Y and Ciepielewska, M}, title = {Longer disease progression milestone-free time in people with amyotrophic lateral sclerosis treated versus not treated with intravenous edaravone: results from an administrative claims analysis.}, journal = {Journal of comparative effectiveness research}, volume = {14}, number = {2}, pages = {e240007}, pmid = {39836043}, issn = {2042-6313}, mesh = {Humans ; *Edaravone/administration & dosage/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Retrospective Studies ; Middle Aged ; Disease Progression ; Aged ; Administration, Intravenous ; *Free Radical Scavengers/therapeutic use/administration & dosage ; }, abstract = {Aim: To estimate time-to-progression milestones in people with amyotrophic lateral sclerosis (PALS) treated versus not treated with intravenous (IV) edaravone (Radicava[®] IV, Mitsubishi Tanabe Pharma America [MTPA], hereafter "IV edaravone") in a real-world setting. Background: IV edaravone is US FDA approved for the treatment of ALS and was shown in clinical trials to slow the rate of physical functional decline. Patients & methods: This retrospective observational analysis included PALS continuously enrolled in Optum's Clinformatics[®] Data Mart between 8 August 2017 and 31 December 2021. Cases treated with IV edaravone and controls not treated with IV edaravone were propensity score matched for: age, sex, race, US region of residence, pre-index disease duration, insurance, riluzole prescription; and pre-index claims for cardiovascular disease, artificial nutrition/gastrostomy tube, noninvasive ventilation and all-cause hospitalization. The index date was the first IV edaravone claim for cases; for controls, the index date was randomly assigned after IV edaravone market availability. Restricted mean time lost was calculated for the following disease progression milestones: new use of canes/walkers/wheelchairs, artificial nutrition, noninvasive ventilation, invasive ventilation, speech-generating devices and hospice. Results: Cases (n = 395) were matched to controls (n = 395). Cases had less restricted mean time lost, indicating longer disease progression milestone-free time, for all disease progression milestones. From 0 to 24 months post index, more cases (n = 129) than controls (n = 103) reported no milestones and more controls (n = 232) than cases (n = 131) reported deaths. Conclusion: In a US-based real-world setting, IV edaravone-treated PALS had a longer time to disease progression milestone events and fewer deaths in 2 years compared with PALS not treated with IV edaravone.}, } @article {pmid39836386, year = {2025}, author = {Babu, S and Sharfstein, JM and Feldman, EL}, title = {Reimagining Care and Research for Amyotrophic Lateral Sclerosis.}, journal = {JAMA neurology}, volume = {82}, number = {6}, pages = {535-536}, doi = {10.1001/jamaneurol.2024.4757}, pmid = {39836386}, issn = {2168-6157}, } @article {pmid39837305, year = {2025}, author = {Tan, Y and Yang, T and Cheng, Y and Zhang, S and Xiao, Y and Liu, J and Shang, H}, title = {Association between Psychiatric Disorders and Amyotrophic Lateral Sclerosis: A Prospective Cohort Study from the UK Biobank.}, journal = {Neuroepidemiology}, volume = {59}, number = {6}, pages = {701-713}, doi = {10.1159/000543473}, pmid = {39837305}, issn = {1423-0208}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/psychology ; Male ; Female ; United Kingdom/epidemiology ; Prospective Studies ; Middle Aged ; Aged ; Risk Factors ; Biological Specimen Banks ; *Mental Disorders/epidemiology ; Adult ; Schizophrenia/epidemiology ; Cohort Studies ; Proportional Hazards Models ; UK Biobank ; }, abstract = {INTRODUCTION: Psychiatric disorders have been reported to be associated with amyotrophic lateral sclerosis (ALS). However, evidence for the association remains inconsistent, and it is unclear whether specific categories of psychiatric disorders constitute risk factors for ALS. The study aimed to investigate the association between different categories of psychiatric disorders and the risk of ALS.

METHODS: We utilized data from the UK Biobank to conduct a population-based prospective cohort study. Cox proportional hazards models were employed to evaluate the association between a history of various psychiatric disorders including schizophrenia, bipolar disorder, depression, anxiety, stress-related disorders, and the risk of ALS. Analyses were adjusted for covariates including sociodemographic factors, lifestyle factors, and medical history.

RESULTS: Among the 484,065 participants initially included, 558 participants were diagnosed with ALS during a median follow-up of 13.63 years. With complete adjustment, previous schizophrenia (hazard ratio [HR] 6.32; 95% confidence interval [CI]: 2.60-15.36; p < 0.001) and depression (HR 1.37; 95% CI: 1.03-1.81; p = 0.03) were found to be significantly associated with ALS.

CONCLUSION: This large prospective cohort study indicated the association between schizophrenia, depression, and a higher risk of subsequent ALS. These findings suggest potential implications for early process of global neurodegeneration in ALS, underlining the need for further research to explore the underlying mechanisms.}, } @article {pmid39837582, year = {2025}, author = {Brubacher, LJ and Yellappa, V and Lestari, BW and Heitkamp, P and Aguilera Vasquez, N and Sassi, A and Olusola-Faleye, B and Thapa, P and Shyam Klinton, J and Sheokand, S and Pai, M and Oga-Omenka, C}, title = {Health and tuberculosis systems resilience, the role of the private sector and pandemic preparedness: insights from a cross-country qualitative study with policy-makers in India, Indonesia and Nigeria.}, journal = {BMJ global health}, volume = {10}, number = {1}, pages = {}, pmid = {39837582}, issn = {2059-7908}, support = {INV-022420/GATES/Gates Foundation/United States ; }, mesh = {Humans ; *COVID-19/epidemiology ; Indonesia/epidemiology ; *Tuberculosis/therapy/epidemiology ; India/epidemiology ; Nigeria/epidemiology ; Qualitative Research ; *Private Sector/organization & administration ; *Delivery of Health Care/organization & administration ; Pandemics ; *Administrative Personnel/psychology ; Health Policy ; SARS-CoV-2 ; Pandemic Preparedness ; }, abstract = {INTRODUCTION: The COVID-19 pandemic was an unprecedented challenge to health systems worldwide and had a severe impact on tuberculosis (TB) case notifications and service delivery. India, Indonesia and Nigeria are high TB-burden countries where the majority of initial care-seeking happens in the private health sector. The objectives of this study were to (1) explore policy-makers' perspectives on the impact of the COVID-19 pandemic on private sector TB service delivery in India, Indonesia and Nigeria and (2) identify cross-cutting insights for pandemic preparedness with respect to TB service delivery.

METHODS: From May to November 2021, 33 interviews were conducted with key policy-makers involved in health service administration, TB service delivery and/or the COVID-19 response in India, Indonesia and Nigeria (n=11 in each country). Interviews focused on the impact of COVID-19 on TB services and lessons learnt for pandemic preparedness with respect to TB in each study context. Data were analysed thematically using a hybrid inductive-deductive approach, informed by Haldane et al's Determinants of Health Systems Resilience Framework.

RESULTS: Policy-makers highlighted the crucial role of intersectoral collaboration, effective governance, innovative financing strategies, health workforce reallocation and technological advancements such as virtual consultations and mHealth in strengthening TB service delivery amid the COVID-19 pandemic. India relied on patient-provider support agencies to implement a joint strategy for TB care across sectors and states. Indonesia engaged networks of private provider professional associations to facilitate coordination of the COVID-19 response. Nigeria implemented a pandemic policy for public-private referral for the continuity of TB care.

CONCLUSIONS: Countries implemented varied measures to support TB service delivery during the COVID-19 pandemic. This study presents insights from three countries (India, Indonesia and Nigeria) that together offer a 'menu' of possibilities for supporting pandemic preparedness with respect to TB care vis-à-vis strengthening health systems resilience.}, } @article {pmid39838017, year = {2025}, author = {McCaig, CD}, title = {Neurological Diseases can be Regulated by Phase Separation.}, journal = {Reviews of physiology, biochemistry and pharmacology}, volume = {187}, number = {}, pages = {273-338}, pmid = {39838017}, issn = {0303-4240}, mesh = {Humans ; Animals ; *Nervous System Diseases/physiopathology/metabolism ; Superoxide Dismutase/metabolism ; Motor Neuron Disease/physiopathology/metabolism ; Protein Aggregation, Pathological ; Phase Separation ; }, abstract = {Several neurological diseases arise from abnormal protein aggregation within neurones and this is closely regulated by phase separation. One such is motor neurone disease and aberrant aggregation of superoxide dismutase. Again these events are regulated by electrical forces that are examined.}, } @article {pmid39838446, year = {2025}, author = {Ou, K and Jia, Q and Li, D and Li, S and Li, XJ and Yin, P}, title = {Application of antisense oligonucleotide drugs in amyotrophic lateral sclerosis and Huntington's disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {4}, pmid = {39838446}, issn = {2047-9158}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/therapy ; Humans ; *Huntington Disease/drug therapy/genetics/therapy ; *Oligonucleotides, Antisense/therapeutic use ; Animals ; *Genetic Therapy/methods ; *Neuroprotective Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are diverse in clinical presentation and are caused by complex and multiple factors, including genetic mutations and environmental factors. Numerous therapeutic approaches have been developed based on the genetic causes and potential mechanisms of ALS and HD. Currently, available treatments for various neurodegenerative diseases can alleviate symptoms but do not provide a definitive cure. Gene therapy, which aims to modify or express specific proteins for neuroprotection or correction, is considered a powerful tool in managing neurodegenerative conditions. To date, antisense oligonucleotide (ASO) drugs targeting the pathological genes associated with ALS and HD have shown promising results in numerous animal studies and several clinical trials. This review provides a comprehensive overview of the development, mechanisms of action, limitations, and clinical applications of ASO drugs in neurodegenerative diseases, with a specific focus on ALS and HD therapeutic strategies.}, } @article {pmid39838927, year = {2025}, author = {Wang, Z and Sun, Y and Bai, Z and Li, M and Kong, D and Wu, G}, title = {Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Causal Genes for Neurodegenerative Diseases.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {40}, number = {4}, pages = {693-703}, doi = {10.1002/mds.30123}, pmid = {39838927}, issn = {1531-8257}, support = {SDQLQN2021-01//Qilu Young Scholars Program of Shandong University/ ; 202306352//Taishan Scholar Foundation of Shandong Province/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics ; *Mitochondria/genetics/metabolism ; *Genetic Predisposition to Disease/genetics ; Quantitative Trait Loci/genetics ; }, abstract = {BACKGROUND: Mitochondrial dysfunction is increasingly recognized as a key factor in neurodegenerative diseases (NDDs), underscoring the therapeutic potential of targeting mitochondria-related genes. This study aimed to identify novel biomarkers and drug targets for these diseases through a comprehensive analysis that integrated genome-wide Mendelian randomization (MR) with genes associated with mitochondrial function.

METHODS: Using existing publicly available genome-wide association studies (GWAS) summary statistics and comprehensive data on 1136 mitochondria-related genes, we initially identified a subset of genes related to mitochondrial function that exhibited significant associations with NDDs. We then conducted colocalization and summary-data-based Mendelian randomization (SMR) analyses using expression quantitative trait loci (eQTL) to validate the causal role of these candidate genes. Additionally, we assessed the druggability of the encoded proteins to prioritize potential therapeutic targets for further exploration.

RESULTS: Genetically predicted levels of 10 genes were found to be significantly associated with the risk of NDDs. Elevated DMPK and LACTB2 levels were associated with increased Alzheimer's disease risk. Higher expression of NDUFAF2, BCKDK, and MALSU1, along with lower TTC19, raised Parkinson's disease risk. Higher ACLY levels were associated with both amyotrophic lateral sclerosis and multiple sclerosis (MS) risks, while decreased MCL1, TOP3A, and VWA8 levels raised MS risk. These genes primarily impact mitochondrial function and energy metabolism. Notably, several druggable protein targets identified are being explored for potential NDDs treatment.

CONCLUSIONS: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in NDDs. Additionally, this study identified candidate genes that could serve as potential pharmacological targets for the prevention and treatment of NDDs. © 2025 International Parkinson and Movement Disorder Society.}, } @article {pmid39838960, year = {2025}, author = {Min, SM and Bashore, FM and Smith, JL and Havener, TM and Howell, S and Li, H and Couñago, RM and Popov, KI and Axtman, AD}, title = {Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {3}, pages = {3282-3308}, pmid = {39838960}, issn = {1520-4804}, support = {S10 OD032476/OD/NIH HHS/United States ; }, mesh = {Humans ; *Phosphoinositide-3 Kinase Inhibitors/pharmacology/chemistry/chemical synthesis/pharmacokinetics ; Animals ; Phosphatidylinositol 3-Kinases/metabolism ; Mice ; Morpholines/chemistry/pharmacokinetics/pharmacology/chemical synthesis ; Structure-Activity Relationship ; Crohn Disease/drug therapy ; COVID-19 Drug Treatment ; Molecular Probes/chemistry/pharmacokinetics ; Hydrazones ; Pyrimidines ; }, abstract = {We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency and demonstrated in vivo stability. Use of an in-cell, kinome-wide selectivity panel allowed for confirmation of excellent in-cell selectivity of our lead compound, 40, and another promising analogue, 46. Evaluation of the pharmacokinetic (PK) profiles of these two compounds revealed that both are well tolerated systemically and orally bioavailable. Coupled with its subnanomolar cellular potency and impressive selectivity in cells, the long half-life of 40 makes it an ideal candidate for the evaluation of the consequences of PIKfyve inhibition in vivo. PIKfyve inhibition has been investigated clinically for indications including rheumatoid arthritis, Crohn's disease, COVID-19, and ALS using a single compound (apilimod), supporting the development of orthogonal PIKfyve inhibitors with in vivo stability.}, } @article {pmid39839311, year = {2024}, author = {Zhang, J and Li, Y and Shi, Q}, title = {Decremental response in patients with amyotrophic lateral sclerosis during repetitive nerve stimulation and its relationships with impaired homeostasis.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1502025}, pmid = {39839311}, issn = {1663-4365}, abstract = {BACKGROUND: Previous studies have suggested that neuromuscular junction (NMJ) denervation plays a critical role in amyotrophic lateral sclerosis (ALS). Repetitive nerve stimulation (RNS) has been used as a technique to test neuromuscular transmission, but the sensitivity and stability of its parameters have not been investigated in patients with ALS. In addition, the impact of impaired homeostasis on NMJ stability in patients with ALS remains unclear.

METHODS: A total of 421 patients with ALS were enrolled. Data on their clinical, biochemical and electrophysiological indicators were divided into a training set (collected from June 2019 to June 2022) and a test set (collected from July 2022 to June 2023). The coefficient of variation (CV) was used to assess the extent of variability. Stepwise regression was used in independent variable selection and model building.

RESULTS: In patients with ALS, area decrement had a higher rate of abnormal result and a lower CV than amplitude decrement. No significant difference in the rate of abnormal decrement was found when the first compound muscle action potential (CMAP) was compared with either the fourth or fifth one. Moreover, multivariate regression analysis suggests high-density lipoprotein cholesterol (HDL-C) had the greatest impact on decremental response, followed by serum uric acid (UA) and forced vital capacity (FVC). Females had a larger range of area decrement than males.

CONCLUSION: During RNS test, assessing area decrement significantly enhances our ability to detect the impairment of neuromuscular transmission in patients with ALS. Independent factors contributing to decremental response need to be considered in drug development and clinical trials targeting NMJ in patients with ALS.}, } @article {pmid39839897, year = {2025}, author = {Jiang, QR and Zeng, DW}, title = {Gut microbiota shifts in hepatitis B-related portal hypertension after transjugular intrahepatic portosystemic shunt: Mechanistic and clinical implications.}, journal = {World journal of gastroenterology}, volume = {31}, number = {3}, pages = {100752}, pmid = {39839897}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Hypertension, Portal/microbiology/surgery/virology/etiology ; *Portasystemic Shunt, Transjugular Intrahepatic/adverse effects ; *Hepatic Encephalopathy/microbiology/etiology/diagnosis ; *Liver Cirrhosis/virology/microbiology/surgery ; Hepatitis B virus/pathogenicity ; *Hepatitis B/complications ; Dysbiosis ; }, abstract = {In this article, we provide commentary on the recent article by Zhao et al. We focus on the shifts in the gut microbiota of patients with hepatitis B virus (HBV)-associated cirrhosis/portal hypertension (PH) following transjugular intrahepatic portosystemic shunt (TIPS) and the implications for understanding the mechanisms, diagnosis, and treatment. By comparing the gut microbiota composition and dynamic changes before and after TIPS in patients with and without hepatic encephalopathy, the authors found an increase in non-probiotic bacteria in those who developed hepatic encephalopathy post-TIPS, with Morganella species present only in the hepatic encephalopathy group. The gut microbiota changes post-TIPS among patients without the occurrence of hepatic encephalopathy suggest potential therapeutic benefits through prophylactic microbiome therapies. Furthermore, the specific gut microbiota alterations may hold promise to predict the risk of hepatic encephalopathy in individuals undergoing TIPS for HBV-related PH. Despite these promising findings, future studies are needed to address limitations, including a small sample size, a relatively short evaluation period for gut microbiota alterations, the absence of data on dynamic alterations in gut microbiota post-TIPS and their correlation with blood ammonia levels, and the lack of validation in animal models. In conclusion, Zhao et al's study has shed new light on the link of gut microbiota with post-TIPS hepatic encephalopathy, potentially through the intricate gut-liver axis, and has important clinical implications for improving the management of patients with HBV-related PH.}, } @article {pmid39839899, year = {2025}, author = {Goyal, MK and Goyal, O}, title = {Can Emax and platelet count truly differentiate between benign and malignant liver lesions?.}, journal = {World journal of gastroenterology}, volume = {31}, number = {3}, pages = {98758}, pmid = {39839899}, issn = {2219-2840}, mesh = {Humans ; *Liver Neoplasms/blood/diagnosis/pathology ; Platelet Count ; Diagnosis, Differential ; *Carcinoma, Hepatocellular/blood/diagnosis/pathology ; Nomograms ; *Liver/pathology ; Liver Cirrhosis/blood/diagnosis ; Predictive Value of Tests ; }, abstract = {This letter critically evaluates Jiang et al's article on the differentiation of benign and malignant liver lesions using Emax and platelet count. Despite notable findings, significant methodological and interpretative limitations are identified. The study lacks detailed assay conditions for Emax measurement, employs inadequate statistical methods without robust multivariate analysis, and does not provide clinically relevant threshold values. The nomogram's reliance on Emax as a major diagnostic contributor is questionable due to attenuation in hepatocellular carcinoma patients with cirrhosis. Moreover, the study's limitations, such as selection bias and confounding factors, are not adequately addressed. Future research should adopt more rigorous methodologies, including prospective studies with larger cohorts and standardized protocols for biomarker measurement, to enhance validity and clinical applicability.}, } @article {pmid39840015, year = {2024}, author = {Yang, J and Li, W and Tian, M and Zhang, L and Du, F and Li, X and Liu, Q and Li, R and Li, Z and Dong, H and Liu, Y}, title = {Cortical thickness correlated with peripheral inflammatory cytokines in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1514554}, pmid = {39840015}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare, devastating neurodegenerative disease that affects upper and lower motor neurons, resulting in muscle atrophy, spasticity, hyperreflexia, and paralysis. Inflammation plays an important role in the development of ALS, and associated with rapid disease progression. Current observational studies indicate the thinning of cortical thickness in patients with ALS is associated with rapid disease progression and cognitive changes. However, the effects of inflammatory cytokines on cortical thickness in patients with ALS are unclear. Here, we investigated the relationship between inflammatory cytokines and cortical thickness in patients with ALS.

METHODS: We evaluated 51 patients with ALS for inflammatory cytokines including interleukin (IL)-4, interferon (IFN)-α, IL-1β, IL-2, IL-5, IL-12, tumor necrosis factor (TNF)-α, IL-6, IL-10, IL-8, IL-17, and IFN-γ and analyzed the correlation between these indicators and the ALS functional rating scale-revised (ALSFRS-R) score or disease progression rate (ΔFS score). Twenty-six patients with ALS and 26 controls were studied using whole-cortex analysis, and post-hoc analyses were performed to examine the correlation between brain cortical thickness and ALSFRS-R or ΔFS scores.

RESULTS: IL-4, IFN-α, IL-1β, and IL-2 levels were significantly correlated with ALSFRS-R scores, and the IL-2 level was significantly correlated with ΔFS scores. After controlling for age and sex, the ALS group had thinner cortexes in multiple clusters across the brain than the control group. Further analyses revealed that cortical thickness in the right superior temporal and lingual gyrus regions was inversely correlated with ΔFS scores. There was a significant positive correlation between the clusters in the right lingual cortex and IL-2 level.

CONCLUSION: These results suggest cortical thickness was reduced in patients with ALS in motor and non-motor cortical areas. Inflammatory factors (especially IL-2) were correlated with cortical thickness, and both were related to the disease progression rate, suggesting IL-2 plays an important role in ALS.}, } @article {pmid39840019, year = {2024}, author = {De Cleene, N and Schwarzová, K and Labrecque, S and Cerejo, C and Djamshidian, A and Seppi, K and Heim, B}, title = {Olfactory dysfunction as potential biomarker in neurodegenerative diseases: a narrative review.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1505029}, pmid = {39840019}, issn = {1662-4548}, abstract = {Neurodegenerative diseases represent a group of disorders characterized by progressive degeneration of neurons in the central nervous system, leading to a range of cognitive, motor, and sensory impairments. In recent years, there has been growing interest in the association between neurodegenerative diseases and olfactory dysfunction (OD). Characterized by a decline in the ability to detect or identify odors, OD has been observed in various conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). This phenomenon often precedes the onset of other clinical symptoms, suggesting its potential utility as an early marker or prodromal symptom of neurodegenerative diseases. This review provides a vast literature overview on the current knowledge of OD in PD, AD, ALS, and HD in order to evaluate its potential as a biomarker, particularly in the early and prodromal stages of these diseases. We summarize the most common methods used to measure olfactory function and delve into neuropathological correlations and the alterations in neurotransmitter systems associated with OD in those neurodegenerative diseases, including differences in genetic variants if applicable, and cater to current pitfalls and shortcomings in the research.}, } @article {pmid39840885, year = {2025}, author = {McKinnon, S and Qiang, Z and Keerie, A and Wells, T and Shaw, PJ and Alix, JJP and Mead, RJ}, title = {Maximizing the translational potential of neurophysiology in amyotrophic lateral sclerosis: a study on compound muscle action potentials.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {322-330}, doi = {10.1080/21678421.2024.2448540}, pmid = {39840885}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/genetics ; Animals ; Humans ; *Action Potentials/physiology ; *Muscle, Skeletal/physiopathology ; Mice ; Disease Models, Animal ; Mice, Transgenic ; Male ; Female ; *Translational Research, Biomedical ; Middle Aged ; Motor Neurons/physiology ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase/genetics ; Aged ; *Neurophysiology ; }, abstract = {Mouse models of amyotrophic lateral sclerosis (ALS) enable testing of novel therapeutic interventions. However, treatments that have extended survival in mice have often failed to translate into human benefit in clinical trials. Compound muscle action potentials (CMAPs) are a simple neurophysiological test that measures the summation of muscle fiber depolarization in response to maximal stimulation of the innervating nerve. CMAPs can be measured in both mice and humans and decline with motor axon loss in ALS, making them a potential translational read-out of disease progression. We assessed the translational potential of CMAPs and ascertained time points when human and mouse data aligned most closely. We extracted data from 18 human studies and compared with results generated from SOD1[G93A] and control mice at different ages across different muscles. The relative CMAP amplitude difference between SOD1[G93A] and control mice in tibialis anterior (TA) and gastrocnemius muscles at 70 days of age was most similar to the relative difference between baseline ALS patient CMAP measurements and healthy controls in the abductor pollicis brevis (APB) muscle. We also found that the relative decline in SOD1[G93A] TA CMAP amplitude between 70 and 140 days was similar to that observed in 12 month human longitudinal studies in APB. Our findings suggest CMAP amplitudes can provide a "translational window", from which to make comparisons between the SOD1[G93A] model and human ALS patients. CMAPs are easy to perform and can help determine the most clinically relevant starting/end points for preclinical studies and provide a basis for predicting potential clinical effect sizes.}, } @article {pmid39840922, year = {2025}, author = {Saucier, D and Bélanger, M and Liu, Z and Lavigne, E and O'Connell, C}, title = {Associations between water exposure and the development of amyotrophic lateral sclerosis: a matched case-control study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {281-289}, doi = {10.1080/21678421.2025.2453450}, pmid = {39840922}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/etiology/diagnosis ; Female ; Male ; Case-Control Studies ; Middle Aged ; Aged ; *Environmental Exposure/adverse effects ; }, abstract = {OBJECTIVE: Previous studies have hinted at an association between water exposure and the development of ALS. However, proximity measures to these water sources have been limited to questionnaires or large buffers due to a lack of fine geospatial measures. They also do not distinguish the various classes of hydrographic features. Thus, we created a robust database to investigate the association between proximity to water bodies at place of residence and the development of ALS.

METHODS: A matched (sex and year of birth) case-control study was conducted in New Brunswick, Canada from January 2003 to February 2021. Study population included 304 ALS patients and 1207 controls with their historical postal codes linked to spatial proximity datasets and air pollution index indicators (proxy measures for contamination by run-off).

RESULTS: Odds of ALS were not significantly associated with proximity to water bodies, even within a 250 m buffer from place of residence (Oceans: 1.10, 0.60-2.00 [95% CI], Reservoirs/Ponds/Lakes: 1.24, 0.47-3.30 [95% CI]). As for interaction models investigating proximity to potentially contaminated water bodies, none of the final fitted models observed an association between proximity to water bodies with indicators of potential run-off sources and the development of ALS.

CONCLUSIONS: No significant association between proximity to water bodies at place of residence and the development of ALS were observed in the current study. Future studies should consider taking direct measurements of water quality or utilize geomaps of spraying activities and cyanobacteria blooms alongside proximity measures. Household water quality is another avenue to explore, particularly well water use.}, } @article {pmid39841625, year = {2025}, author = {Hoengenaert, L and Anders, C and Van Doorsselaere, J and Vanholme, R and Boerjan, W}, title = {Transgene-free genome editing in poplar.}, journal = {The New phytologist}, volume = {247}, number = {1}, pages = {224-232}, doi = {10.1111/nph.20415}, pmid = {39841625}, issn = {1469-8137}, support = {//Universiteit Gent/ ; G011620N//Fonds Wetenschappelijk Onderzoek/ ; //Energy Transition Fund/ ; //Advanced ERC grant POPMET/ ; }, mesh = {*Populus/genetics ; *Gene Editing/methods ; *Transgenes/genetics ; *Genome, Plant/genetics ; Plants, Genetically Modified ; DNA, Bacterial/genetics ; }, abstract = {Precise gene-editing methods are valuable tools to enhance genetic traits. Gene editing is commonly achieved via stable integration of a gene-editing cassette in the plant's genome. However, this technique is unfavorable for field applications, especially in vegetatively propagated plants, such as many commercial tree species, where the gene-editing cassette cannot be segregated away without breaking the genetic constitution of the elite variety. Here, we describe an efficient method for generating gene-edited Populus tremula × P. alba (poplar) trees without incorporating foreign DNA into its genome. Using Agrobacterium tumefaciens, we expressed a base-editing construct targeting CCoAOMT1 along with the ALS genes for positive selection on a chlorsulfuron-containing medium. About 50% of the regenerated shoots were derived from transient transformation and were free of T-DNA. Overall, 7% of the chlorsulfuron-resistant shoots were T-DNA free, edited in the CCoAOMT1 gene and nonchimeric. Long-read whole-genome sequencing confirmed the absence of any foreign DNA in the tested gene-edited lines. Additionally, we evaluated the CodA gene as a negative selection marker to eliminate lines that stably incorporated the T-DNA into their genome. Although the latter negative selection is not essential for selecting transgene-free, gene-edited Populus tremula × P. alba shoots, it may prove valuable for other genotypes or varieties.}, } @article {pmid39841674, year = {2025}, author = {Grapperon, AM and El Mendili, MM and Maarouf, A and Ranjeva, JP and Guye, M and Verschueren, A and Attarian, S and Zaaraoui, W}, title = {In vivo mapping of sodium homeostasis disturbances in individual ALS patients: A brain 23Na MRI study.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0316916}, pmid = {39841674}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging/pathology ; Male ; Female ; *Magnetic Resonance Imaging/methods ; Middle Aged ; *Homeostasis ; *Sodium/metabolism ; *Brain/metabolism/diagnostic imaging ; Aged ; Adult ; Sodium Isotopes ; Brain Mapping ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by significant heterogeneity among patients. 23Na MRI maps abnormal sodium homeostasis that reflects metabolic alterations and energetic failure contributing to the neurodegenerative process. In this study, we investigated disease severity at the individual level in ALS patients using brain 23Na MRI.

METHODS: 1H and 23Na brain MRI were collected prospectively from 28 ALS patients. Individual map of abnormal total sodium concentration (TSC) was computed using voxel-based statistical mapping for each patient compared to a local database of 62 healthy controls. Clinical data included the revised ALS functional rating scale (ALSFRS-R), ALSFRS-R slope, ALSFRS-R at 6-month and survival time.

RESULTS: Individual maps quantifying voxels with TSC increase evidenced a high heterogeneity between patients consistent with clinical presentation. The main areas involved were the corticospinal tracts. Half of patients showed abnormal TSC increase within more than 1% of whole brain voxels. Patients with TSC increase had worse clinical severity: higher ALSFRS-R slope (p = 0.02), lower ALSFRS-R at 6-month (p = 0.04), and shorter survival (p = 0.04). ALS patients with limited TSC increase had slower progression of disability or predominant lower motor neuron phenotype or shorter disease duration.

DISCUSSION: This study mapping sodium homeostasis disturbances at the individual level in ALS patients through 23Na MRI evidenced heterogeneity of TSC increase among patients associated with clinical presentation and disease severity. These findings suggest that TSC increase detected at the individual level by 23Na MRI may be a useful marker of the clinical heterogeneity of ALS patients, a factor that is likely to greatly influence the results of therapeutic trials.}, } @article {pmid39842380, year = {2025}, author = {Faltracco, V and Pain, D and Dalla Bella, E and Riva, N and Telesca, A and Soldini, E and Gandini, G and Radici, A and Poletti, B and Lauria, G and Consonni, M}, title = {Mood disorders in patients with motor neuron disease and frontotemporal symptoms: Validation of the Hospital Anxiety and Depression Scale for use in motor neuron disease.}, journal = {Journal of the neurological sciences}, volume = {469}, number = {}, pages = {123378}, doi = {10.1016/j.jns.2024.123378}, pmid = {39842380}, issn = {1878-5883}, mesh = {Humans ; Female ; Male ; *Motor Neuron Disease/psychology/complications ; Middle Aged ; *Mood Disorders/diagnosis/etiology/psychology/complications ; Aged ; *Psychiatric Status Rating Scales/standards ; *Anxiety/diagnosis/etiology ; Reproducibility of Results ; *Depression/diagnosis/etiology ; Adult ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a heterogeneous neurodegenerative disorder, with nearly 50 % of patients exhibiting cognitive and behavioral symptoms in addition to motor decline. Anxiety and depression, though frequently observed in this population, have been understudied in relation to motor and extra-motor profiles.

OBJECTIVES: Our study addresses this gap by validating the Hospital Anxiety and Depression Scale for Motor Neuron Disease (HADS-MND) and investigating the interplay between mood, clincial, and frontotemporal symptoms in a large sample of MND patients.

METHODS: A total of 249 MND patients underwent clinical, genetic, and neuropsychological assessments. The validity, reliability, sensitivity, and specificity of the HADS-MND global score and subscores were explored. Correlation analyses and group comparisons tested the link between mood, motor and extra-motor profiles.

RESULTS: The bidirectional structure of the HADS-MND was confirmed, but receiver operating characteristics analysis suggests caution for clinical use of the anxiety and depression subscales. The global HADS-MND score is recommended as a measure of psychological distress, with a cut-off point of 10 detecting 38 % of patients with altered scores. Moderate symptoms of anxiety and depression were present in 14 % and 11 % of cases, respectively. Depressive mood was higher in women, patients with frontotemporal symptoms, and severe motor-functional disabilities. Depressive and/or anxiety symptoms were linked to loneliness, behavioral changes, emotional dysregulation, and poor quality of life. Cognitive efficiency was not associated with mood.

CONCLUSION: Mood disorders appeared independent of cognitive profiles but related to behavioral changes. This is particularly relevant for clinicians discussing end-of-life decisions with patients.}, } @article {pmid39843865, year = {2025}, author = {Calancie, B and Alexeeva, N}, title = {Revisiting motor unit recruitment to TMS in amyotrophic lateral sclerosis: cortical inhibition is retained during voluntary contractions.}, journal = {Experimental brain research}, volume = {243}, number = {2}, pages = {51}, pmid = {39843865}, issn = {1432-1106}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology ; *Transcranial Magnetic Stimulation/methods ; Male ; Female ; Middle Aged ; *Recruitment, Neurophysiological/physiology ; Electromyography ; *Muscle Contraction/physiology ; Aged ; Muscle, Skeletal/physiopathology ; *Neural Inhibition/physiology ; *Motor Cortex/physiopathology ; Evoked Potentials, Motor/physiology ; Adult ; *Motor Neurons/physiology ; }, abstract = {Transcranial magnetic stimulation (TMS) has been used for many years to study the pathophysiology of amyotrophic lateral sclerosis (ALS). Based on single- or dual-pulse TMS and EMG and/or single motor unit (MU) recordings, many groups have described a loss of central inhibition as an early marker of ALS dysfunction, reflecting a state of cortical 'hyperexcitability'. This conclusion is not without its detractors, however, leading us to reexamine this issue using 4-pulse TMS, shown previously to be more effective for testing central motor pathway functional integrity. A total of 221 motor units were tested in 13 subjects (6 controls; 7 with ALS) across a total of 798 unique TMS conditions. MUs were studied from hand muscles (usually first dorsal interosseus) and from tibialis anterior (TA). Subjects were required to recruit a MU to fire rhythmically, during which time 4-pulse trains of TMS were delivered. A given motor unit's recruitment was examined for different stimulus intensities and interpulse intervals (IPI). All motor units from control subjects showed short latency excitation to TMS, and short latency inhibition for TMS pulses of slightly weaker intensity (i.e. the threshold for inhibition was lower than that for excitation). The same was largely true for MUs studied in subjects with ALS, with the primary difference between control and ALS subjects being the need for stronger stimulus intensities to effect recruitment in subjects with ALS. We saw no evidence for a loss or reduction of inhibition of central motor output in persons with ALS, at least when tested during voluntary contractions.}, } @article {pmid39844762, year = {2025}, author = {Theuriet, J and Bernard, E and Guy, N and Taithe, F and Even, C and Maisonobe, T and Sangaré, A and Lardeux, P and Tilikete, CF and Couratier, P and Lenglet, T and Pegat, A}, title = {Electrophysiological Abnormalities in Finger Extension Weakness and DOwnbeat Nystagmus Motor Neuron Disease: Three New Patients and Review of the Literature.}, journal = {Muscle & nerve}, volume = {71}, number = {4}, pages = {644-650}, pmid = {39844762}, issn = {1097-4598}, mesh = {Humans ; *Motor Neuron Disease/physiopathology/complications/diagnosis ; Male ; Electromyography ; *Nystagmus, Pathologic/physiopathology/complications/diagnosis ; Female ; Middle Aged ; *Fingers/physiopathology ; *Muscle Weakness/physiopathology/etiology/diagnosis ; Adult ; Neural Conduction/physiology ; Action Potentials/physiology ; Muscle, Skeletal/physiopathology ; }, abstract = {INTRODUCTION/AIMS: Finger Extension Weakness and DOwnbeat Nystagmus Motor Neuron Disease (FEWDON-MND) is characterized by motor weakness predominantly affecting finger extension, accompanied by downbeat nystagmus. To date, only 11 patients have been reported. The present study adds a further three and aims to provide a more detailed description of the electrodiagnostic features of these patients.

METHODS: We present the clinical and electrophysiological features of three French patients from specialized motor neuron centers and review the electrophysiological findings of previously reported patients.

RESULTS: These three patients presented with pure motor weakness affecting finger extension and downbeat nystagmus. They exhibited a slowly progressive disease course without respiratory involvement. Nerve conduction studies showed decreased compound muscle action potential amplitudes in the extensor indicis muscles. Abnormal spontaneous activity on needle electromyography (EMG) was rare in two patients, absent in one, and otherwise limited to weak muscles. Additionally, chronic motor axon loss features suggestive of motor neuronopathy were seen in our patients. Importantly, they were also detected in distant asymptomatic muscles.

DISCUSSION: The three patients reported here confirm the typical phenotype of FEWDON-MND, characterized by slowly progressive distal motor weakness initially affecting finger extension, associated with downbeat nystagmus. Although chronic motor axon loss features have been found in all reported patients, our three patients show that active denervation can be absent or rare. Thus, finger drop and diffuse chronic neurogenic changes on EMG should lead clinicians to look for downbeat nystagmus and to consider FEWDON-MND.}, } @article {pmid39844875, year = {2024}, author = {Kõks, S and Rallmann, K and Muldmaa, M and Price, J and Pfaff, AL and Taba, P}, title = {Whole blood transcriptome profile identifies motor neurone disease RNA biomarker signatures.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {249}, number = {}, pages = {10401}, pmid = {39844875}, issn = {1535-3699}, mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Transcriptome/genetics ; Middle Aged ; *Motor Neuron Disease/genetics/blood ; *Gene Expression Profiling ; Aged ; *RNA/blood/genetics ; Case-Control Studies ; Adult ; }, abstract = {Blood-based biomarkers for motor neuron disease are needed for better diagnosis, progression prediction, and clinical trial monitoring. We used whole blood-derived total RNA and performed whole transcriptome analysis to compare the gene expression profiles in (motor neurone disease) MND patients to the control subjects. We compared 42 MND patients to 42 aged and sex-matched healthy controls and described the whole transcriptome profile characteristic for MND. In addition to the formal differential analysis, we performed functional annotation of the genomics data and identified the molecular pathways that are differentially regulated in MND patients. We identified 12,972 genes differentially expressed in the blood of MND patients compared to age and sex-matched controls. Functional genomic annotation identified activation of the pathways related to neurodegeneration, RNA transcription, RNA splicing and extracellular matrix reorganisation. Blood-based whole transcriptomic analysis can reliably differentiate MND patients from controls and can provide useful information for the clinical management of the disease and clinical trials.}, } @article {pmid39844967, year = {2025}, author = {de Melo, R and Alcantara, L and Sarmet, M and Sheers, NL and Berlowitz, DJ and Maldaner, V}, title = {Use of Lung Volume Recruitment Technique in Patients With Chronic Respiratory Disease Among Brazilian Health Professionals.}, journal = {Pulmonary medicine}, volume = {2025}, number = {}, pages = {4073171}, pmid = {39844967}, issn = {2090-1844}, mesh = {Humans ; Brazil ; Cross-Sectional Studies ; Male ; Female ; Adult ; *Respiratory Therapy/methods ; *Health Personnel/statistics & numerical data ; Chronic Disease ; *Allied Health Personnel/statistics & numerical data ; Surveys and Questionnaires ; }, abstract = {Background: Lung volume recruitment (LVR) is a stacked-breath assisted inflation technique in which consecutive insufflations are delivered, without exhaling in between, until the maximum tolerable inflation capacity is reached. Although LVR is recommended in some neuromuscular disease guidelines, there is little information detailing when and how allied health professionals (AHPs) prescribe LVR. Objective: This study is aimed at describing the use of LVR in practice across Brazil. Methods: A cross-sectional e-survey (Sep-Nov 2023) explored LVR practices among qualified clinical or home care AHPs in Brazil. It gathered participant data on geographical region, profession, and experience. It delved into LVR specifics: clinical population and indications for use, prescription (frequency, dosage, and interfaces), related side effects, outcomes assessed, and combined therapies. Results were presented descriptively. Results: One hundred two surveys (74 physical therapists (PTs) and 28 speech and language pathologists (SLPs)) from diverse locations were collected. LVR was predominantly prescribed for adults (57%), with the most common diagnosis being amyotrophic lateral sclerosis (84%). Changes in peak cough flow and vital capacity were the most common reasons for LVR prescription. Maximal insufflation capacity was reportedly measured by 58% of PTs and 22% of SLPs. Chest wall soreness and discomfort were the most common side effects, and many respondents did not provide warnings about potential side effects (42% PTs and 50% SLPs). The study highlighted common use of other respiratory therapy devices alongside LVR. Conclusion: LVR is available in routine clinical and home care settings in Brazil. There is a lack of standardization regarding indications, prescription, and outcome measures among PTs and SLPs in Brazil. Clear recommendations and guidelines are needed to standardize these parameters, enabling more objective data and facilitating comparisons between centers.}, } @article {pmid39845577, year = {2025}, author = {Ludolph, A and Wiesenfarth, M}, title = {Tofersen and other antisense oligonucleotides in ALS.}, journal = {Therapeutic advances in neurological disorders}, volume = {18}, number = {}, pages = {17562864251313915}, pmid = {39845577}, issn = {1756-2856}, abstract = {The advent of antisense oligonucleotide (ASO) therapies in neurodegenerative disorders is associated with enormous hope. Nusinersen treatment was a breakthrough intervention in the recessive disease spinal muscular atrophy, and superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS) seems to be the paradigm disease in dominant degenerative diseases. The results of treatment with the ASO tofersen in SOD1-ALS show that the drug has a convincing beneficial effect on ALS caused by SOD1 mutations, that preclinical studies in rodents predicted the therapeutic effect in the human disease, and that clinical efficacy is associated with a specific sequence of effects of the drug on mechanistic and degenerative biomarkers and, subsequently, functional outcomes such as weight stabilization and ALSFRS-R. Therefore, the enthusiasm seems to be justified; but this should be followed by an attempt to obtain further insights with the goal to improve this therapy. In particular, the following issues are only partially resolved: Which mechanisms are responsible for the clinical effect following the downregulation of SOD1 protein by ASOs? Is long-term downregulation of SOD1 function associated with side effects? Is there an autoimmune response caused by this and other ASO? Is prevention of SOD1-associated ALS possible?}, } @article {pmid39845951, year = {2024}, author = {Zucchi, E and Banchelli, F and Simonini, C and De Biasi, S and Martinelli, I and Gianferrari, G and Lo Tartaro, D and Cossarizza, A and D'Amico, R and Mandrioli, J}, title = {Tregs levels and phenotype modifications during Amyotrophic Lateral Sclerosis course.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1508974}, pmid = {39845951}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/diagnosis ; Male ; Female ; Middle Aged ; *T-Lymphocytes, Regulatory/immunology/metabolism ; Disease Progression ; Aged ; Phenotype ; Biomarkers ; Immunophenotyping ; Adult ; }, abstract = {INTRODUCTION: T regulatory cells (Tregs) inversely correlate with disease progression in Amyotrophic Lateral Sclerosis (ALS) and fast-progressing ALS patients have been reported to exhibit dysfunctional, as well as reduced, levels of Tregs. This study aimed to evaluate the longitudinal changes in Tregs among ALS patients, considering potential clinical and biological modifiers of their percentages and concentrations. Additionally, we explored whether measures of ALS progression, such as the decline over time in the revised ALS Functional Rating Scale (ALSFRS-r) or forced vital capacity (FVC) correlated Treg levels and whether Treg phenotype varied during the course of ALS.

METHODS: Total Tregs (detected by CD3, CD4, FoxP3, CD25, and CD127) were quantified at five time points over 54 weeks in 21 patients in the placebo arm of the RAP-ALS trial; next they were characterized for the expression of surface markers including CD38, CD39, CXCR3, and PD1. Repeated measures mixed models were used to analyze the longitudinal course of Tregs, considering potential associations with other clinical and laboratory characteristics. Correlations between ALSFRS-r or FVC and Tregs over time were similarly investigated.

RESULTS: Our study showed that Treg levels did not change significantly on average during the observation period in our ALS cohort. However, PD1+Tregs decreased and CD39+Tregs increased over time. Male sex and cholesterol levels were associated with increasing Tregs (%) over time, while monocytes positively affected Treg concentrations. Treg concentrations showed a modesty association with FVC decline but were not associated with ALSFRS-r decline.

DISCUSSION: Treg levels remained stable during the ALS observation period and were not significantly associated with ALSFRS-r variations, suggesting that Treg numbers alone may have limited utility as a pharmaco-dynamic biomarker for ALS trials. However the observed changes in Treg phenotypes, such as the decrease in PD1+Tregs, indicate that phenotypic variations may warrant further investigation for their potential role in ALS progression and therapeutic targeting.}, } @article {pmid39849126, year = {2025}, author = {Gupta, S and Kishore, A and Rishi, V and Aggarwal, A}, title = {Mitochondria and its epigenetic dynamics: Insight into synaptic regulation and synaptopathies.}, journal = {Functional & integrative genomics}, volume = {25}, number = {1}, pages = {26}, pmid = {39849126}, issn = {1438-7948}, mesh = {Humans ; *Mitochondria/metabolism/genetics ; *Epigenesis, Genetic ; *Synapses/metabolism/genetics/pathology ; *Mitochondrial Dynamics/genetics ; Animals ; Synaptic Transmission ; Calcium/metabolism ; }, abstract = {Mitochondria, the cellular powerhouses, are pivotal to neuronal function and health, particularly through their role in regulating synaptic structure and function. Spine reprogramming, which underlies synapse development, depends heavily on mitochondrial dynamics-such as biogenesis, fission, fusion, and mitophagy as well as functions including ATP production, calcium (Ca[2+]) regulation, and retrograde signaling. Mitochondria supply the energy necessary for assisting synapse development and plasticity, while also regulating intracellular Ca[2+] homeostasis to prevent excitotoxicity and support synaptic neurotransmission. Additionally, the dynamic processes of mitochondria ensure mitochondrial quality and adaptability, which are essential for maintaining effective synaptic activity. Emerging evidence highlights the significant role of epigenetic modifications in regulating mitochondrial dynamics and function. Epigenetic changes influence gene expression, which in turn affects mitochondrial activity, ensuring coordinated responses necessary for synapse development. Furthermore, metabolic changes within mitochondria can impact the epigenetic machinery, thereby modulating gene expression patterns that support synaptic integrity. Altered epigenetic regulation affecting mitochondrial dynamics and functions is linked to several neurological disorders, including Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases, emphasizing its crucial function. The review delves into the molecular machinery involved in mitochondrial dynamics, ATP and Ca[2+] regulation, highlighting the role of key proteins that facilitate the processes. Additionally, it also shed light on the emerging epigenetic factors influencing these regulations. It provides a thorough summary on the current understanding of the role of mitochondria in synapse development and emphasizes the importance of both molecular and epigenetic mechanisms in maintaining synaptic integrity.}, } @article {pmid39849490, year = {2025}, author = {Álvarez-Sánchez, E and Carbayo, Á and Valle-Tamayo, N and Muñoz, L and Aumatell, J and Torres, S and Rubio-Guerra, S and García-Castro, J and Selma-González, J and Alcolea, D and Turon-Sans, J and Lleó, A and Illán-Gala, I and Fortea, J and Rojas-García, R and Dols-Icardo, O}, title = {Single-cell RNA sequencing highlights the role of distinct natural killer subsets in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {15}, pmid = {39849490}, issn = {1742-2094}, support = {PI21/00791//Instituto de Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; AARF-22-924456/ALZ/Alzheimer's Association/United States ; R01 AG056850/NH/NIH HHS/United States ; Por un mundo sin ELA//Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica/ ; INT21/00073//Instituto de Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; PI19/01543//Instituto de Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; PDC-2023-51; #202307//Fondation Jérôme Lejeune/ ; RF1 AG056850/AG/NIA NIH HHS/United States ; AACSF-21-850193/ALZ/Alzheimer's Association/United States ; FI22/00077//Instituto de Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; GBHI ALZ UK-21-720973//Global Brain Health Institute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/genetics/blood/pathology ; Male ; Female ; *Killer Cells, Natural/metabolism/immunology ; Middle Aged ; *Sequence Analysis, RNA/methods ; Aged ; *Single-Cell Analysis/methods ; Leukocytes, Mononuclear/metabolism ; Adult ; }, abstract = {BACKGROUND: Neuroinflammation plays a major role in amyotrophic lateral sclerosis (ALS), and cumulative evidence suggests that systemic inflammation and the infiltration of immune cells into the brain contribute to this process. However, no study has investigated the role of peripheral blood immune cells in ALS pathophysiology using single-cell RNA sequencing (scRNAseq).

METHODS: We aimed to characterize immune cells from blood and identify ALS-related immune alterations at single-cell resolution. For this purpose, peripheral blood mononuclear cells (PBMC) were isolated from 14 ALS patients and 14 cognitively unimpaired healthy individuals (HC), matched by age and gender, and cryopreserved until library preparation and scRNAseq. We analyzed differences in the proportions of PBMC, gene expression, and cell-cell communication patterns between ALS patients and HC, as well as their association with plasma neurofilament light (NfL) concentrations, a surrogate biomarker for neurodegeneration. Flow cytometry was used to validate alterations in cell type proportions.

RESULTS: We identified the expansion of CD56[dim] natural killer (NK) cells in ALS (fold change = 2; adj. p-value = 0.0051), mainly driven by a specific subpopulation, NK_2 cells (fold change = 3.12; adj. p-value = 0.0001), which represent a mature and cytotoxic CD56[dim] NK subset. Our results revealed extensive gene expression alterations in NK_2 cells, pointing towards the activation of immune response (adj. p-value = 9.2 × 10[- 11]) and the regulation of lymphocyte proliferation (adj. p-value = 6.46 × 10[- 6]). We also identified gene expression changes in other immune cells, such as classical monocytes, and distinct CD8 + effector memory T cells which suggested enhanced antigen presentation via major histocompatibility class-II (adj. p-value = 1.23 × 10[- 8]) in ALS. The inference of cell-cell communication patterns demonstrated that the interaction between HLA-E and CD94:NKG2C from different lymphocytes to NK_2 cells is unique to ALS blood compared to HC. Finally, regression analysis revealed that the proportion of CD56[bright] NK cells along with the ALSFRS-r, disease duration, and gender, explained up to 76.4% of the variance in plasma NfL levels.

CONCLUSION: Our results reveal a signature of relevant changes occurring in peripheral blood immune cells in ALS and underscore alterations in the proportion, gene expression, and signaling patterns of a cytotoxic and terminally differentiated CD56[dim] NK subpopulation (NK_2), as well as a possible role of CD56[bright] NK cells in neurodegeneration.}, } @article {pmid39850989, year = {2025}, author = {Matsuda, C and Nakayama, Y and Haraguchi, M and Morishima, R and Itagaki, Y and Bokuda, K and Kimura, H and Takahashi, K and Shimizu, T}, title = {Patients' choices regarding ventilatory support affect opioid use in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {409-416}, doi = {10.1080/21678421.2025.2453463}, pmid = {39850989}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Male ; Female ; *Analgesics, Opioid/therapeutic use ; Middle Aged ; Retrospective Studies ; Aged ; *Respiration, Artificial/methods ; Noninvasive Ventilation ; Adult ; Respiratory Insufficiency/therapy/etiology ; *Choice Behavior ; }, abstract = {OBJECTIVE: To investigate the impact of different ventilatory support options on opioid use among patients with amyotrophic lateral sclerosis (ALS).

METHODS: We retrospectively reviewed 889 consecutive patients with ALS and enrolled 399 eligible patients. All patients were followed until death or tracheostomy. Clinical characteristics of patients and the timing of initial opioid administration were evaluated. Patients were categorized into four subgroups: (1) 160 patients who never used a ventilator, (2) 120 patients who used only noninvasive ventilation (NIV), (3) 61 patients who transitioned from NIV to tracheostomy and invasive ventilation (TIV), and (4) 58 patients who underwent TIV without prior NIV. We compared the prevalence of opioid use across these groups and assessed its relationship with ventilatory support options using multivariate logistic analysis.

RESULTS: A total of 130 patients (32.6%) used opioids. The number of patients who used opioids in each group was as follows: 55 (34.4%) in Group 1, 69 (57.5%) in Group 2, 5 (8.2%) in Group 3, and 1 (1.7%) in Group 4 (p < 0.0001). Multivariate logistic analysis revealed that, compared to Group 1, the use of NIV only was positively associated with opioid use (p = 0.002). In contrast, transitioning from NIV to TIV (Group 3) and using TIV only (Group 4) were negatively associated with opioid use (p = 0.0001 and 0.001, respectively).

CONCLUSIONS: The choice of ventilatory support significantly influences opioid use in patients with ALS. Patients who opted against TIV required opioids to relieve distress more commonly than those who chose TIV.}, } @article {pmid39851451, year = {2025}, author = {Milligan, C and Cowley, DO and Stewart, W and Curry, AM and Forbes, E and Rector, B and Hastie, A and Liu, L and Hawkins, GA}, title = {Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models.}, journal = {Brain sciences}, volume = {15}, number = {1}, pages = {}, pmid = {39851451}, issn = {2076-3425}, support = {R03 AI137866/AI/NIAID NIH HHS/United States ; Hope for Tomorrow ALS Fund//Wake Forest University School of Medicine/ ; TAB Williams Endowment//Wake Forest University School of Medicine/ ; 1R03AI137866-21A1/NH/NIH HHS/United States ; DoD W81XWH1810377//US Department of the Army/ ; Neuroscience Clinical Trial and Innovation Center//Wake Forest University School of Medicine/ ; }, abstract = {Background/Objectives: Charcot first described ALS in 1869, but the specific mechanisms that mediate the disease pathology are still not clear. Intense research efforts have provided insight into unique neuroanatomical regions, specific neuronal populations and genetic associations for ALS and other neurodegenerative diseases; however, the experimental results also suggest a convergence of these events to common toxic pathways. We propose that common toxic pathways can be therapeutically targeted, and this intervention will be effective in slowing progression and improving patient quality of life. Here, we focus on understanding the role of IL6 trans-signaling in ALS disease processes. Methods: We leveraged unique mouse models of IL6 trans-signaling that we developed that recapitulate the production of active sIL6R in a genotypic and quantitative fashion observed in humans. Given that the SOD1 transgenic mouse is one of the most highly studied and characterized models of ALS, we bred SOD1[G93A] mice with IL6R trans-signaling mice to determine how enhanced trans-signaling influenced symptom onset and pathological processes, including neuromuscular junction (NMJ) denervation, glial activation and motoneuron (MN) survival. Results: The results indicate that in animals with enhanced trans-signaling, symptom onset and pathological processes were accelerated, suggesting a role in disease modification. Administration of an IL6R functional blocking antibody failed to alter accelerated symptom onset and disease progression. Conclusions: Future work to investigate the site-specific influence of enhanced IL6 trans-signaling and the tissue-specific bioavailability of potential therapeutics will be necessary to identify targets for precise therapeutic interventions that may limit disease progression in the 60% of ALS patients who inherit the common Il6R Asp[358]Ala variant.}, } @article {pmid39852477, year = {2025}, author = {Bennett, SA and Cobos, SN and Fisher, RMA and Son, E and Frederic, R and Segal, R and Yousuf, H and Chan, K and Dansu, DK and Torrente, MP}, title = {Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {39852477}, issn = {2309-608X}, support = {S10 OD010582/OD/NIH HHS/United States ; R35 NS111604/NS/NINDS NIH HHS/United States ; K22NS09131401//NIH NINDS/ ; R35NS111604//NIH NINDS/ ; R15NS125394//NIH NINDS/ ; N/A//Brooklyn College, CUNY/ ; N/A//The Graduate Center, CUNY/ ; K12 GM102778/GM/NIGMS NIH HHS/United States ; K22 NS091314/NS/NINDS NIH HHS/United States ; R15 NS125394/NS/NINDS NIH HHS/United States ; R15NS125394-01S1//NIH NINDS/ ; K12GM102778//NIH NIGMS/ ; 1S01OD010582-01A1/GF/NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative disorders sharing pathological and genetic features, including mutations in the FUS gene. FUS is an RNA-binding protein that mislocalizes to the cytoplasm and aggregates in ALS/FTD. In a yeast model, FUS proteinopathy is connected to changes in the epigenome, including reductions in the levels of H3S10ph, H3K14ac, and H3K56ac. Exploiting the same model, we reveal novel connections between FUS aggregation and epigenetic dysregulation. We show that the histone-modifying enzymes Ipl1 and Rtt109-responsible for installing H3S10ph and H3K56ac-are excluded from the nucleus in the context of FUS proteinopathy. Furthermore, we found that Ipl1 colocalizes with FUS, but does not bind it directly. We identified Nop1 and Rrp5, a histone methyltransferase and rRNA biogenesis protein, respectively, as FUS binding partners involved in the growth suppression phenotype connected to FUS proteinopathy. We propose that the nuclear exclusion of Ipl1 through indirect interaction with FUS drives the dysregulation of H3S10ph as well as H3K14ac via crosstalk. We found that the knockdown of Nop1 interferes with these processes. In a parallel mechanism, Rtt109 mislocalization results in reduced levels of H3K56ac. Our results highlight the contribution of epigenetic mechanisms to ALS/FTD and identify novel targets for possible therapeutic intervention.}, } @article {pmid39852553, year = {2025}, author = {Tang, X and Chen, Y and Ren, Y and Yang, W and Yu, W and Zhou, Y and Guo, J and Hu, J and Chen, X and Gu, Y and Wang, C and Dong, Y and Yang, H and Sato, C and He, J and Fan, D and You, L and Zinman, L and Rogaeva, E and Chen, Y and Zhang, M}, title = {Deep learning analyses of splicing variants identify the link of PCP4 with amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {7}, pages = {2331-2347}, doi = {10.1093/brain/awaf025}, pmid = {39852553}, issn = {1460-2156}, support = {//National Natural Science Foundation of China/ ; //Shanghai Municipal Natural Science Foundation/ ; //Fundamental Research Funds for the Central Universities/ ; //Brain Science and Brain-Inspired Intelligence Technology/ ; //Ministry of Science and Technology/ ; //G. Harry Sheppard Memorial Research Fund/ ; //Canadian Consortium on Neurodegeneration in Aging/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Deep Learning ; *RNA Splicing/genetics ; *Nerve Tissue Proteins/genetics ; Introns ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with most sporadic cases lacking clear genetic causes. Abnormal pre-mRNA splicing is a fundamental mechanism in neurodegenerative diseases. For example, TAR DNA-binding protein 43 (TDP-43) loss of function causes widespread RNA mis-splicing events in ALS. Additionally, splicing mutations are major contributors to neurological disorders. However, the role of intronic variants driving RNA mis-splicing in ALS remains poorly understood. To address this, we developed Spliformer to predict RNA splicing. Spliformer is a transformer-based deep learning model trained and tested on splicing events from the GENCODE database, in addition to RNA-sequencing data from blood and CNS tissues. We benchmarked Spliformer against SpliceAI and Pangolin using testing datasets and paired whole-genome sequencing with RNA-sequencing data. We also developed the Spliformer-motif model to identify splicing regulatory motifs. We analysed the Clinvar dataset to identify the link of splicing variants with disease pathogenicity. Additionally, we analysed whole-genome sequencing data of ALS patients and controls to identify common intronic splicing variants linked to ALS risk or disease phenotypes. We also profiled rare intronic splicing variants in ALS patients to identify known or novel ALS-associated genes. Minigene assays were used to validate candidate splicing variants. Finally, we measured spine density in neurons with a specific gene knockdown or those expressing a TDP-43 disease-causing mutant. Spliformer accurately predicts the possibilities of a nucleotide within a pre-mRNA sequence being a splice donor, acceptor or neither. Spliformer outperformed SpliceAI and Pangolin in both speed and accuracy in tested splicing events and/or paired whole-genome sequencing/RNA-sequencing data. Spliformer-motif successfully identified canonical and novel splicing regulatory motifs. In the Clinvar dataset, splicing variants are highly related to disease pathogenicity. Genome-wide analyses of common intronic splicing variants nominated one variant linked to ALS progression. Deep learning analyses of whole-genome sequencing data from 1370 ALS patients revealed rare splicing variants in reported ALS genes (such as PTPRN2 and CFAP410, validated through minigene assays and RNA sequencing) and TDP-43 loss-of-function-related RNA mis-splicing genes (such as PTPRD). Further genetic analysis and minigene assays nominated PCP4 and TMEM63A as ALS-associated genes. Functional assays demonstrated that PCP4 is crucial for maintaining spine density and can rescue spine loss in neurons expressing a disease-causing TDP-43 mutant. In summary, we developed Spliformer and Spliformer-motif, which accurately predict and interpret pre-mRNA splicing. Our findings highlight an intronic genetic mechanism driving RNA mis-splicing in ALS and nominate PCP4 as an ALS-associated gene.}, } @article {pmid39853150, year = {2025}, author = {Shune, S and Gray, LT and Perry, S and Kosty, D and Namasivayam-MacDonald, A}, title = {Validation of the Caregiver Analysis of Reported Experiences with Swallowing Disorders (CARES) Screening Tool for Neurodegenerative Disease.}, journal = {American journal of speech-language pathology}, volume = {34}, number = {2}, pages = {633-645}, doi = {10.1044/2024_AJSLP-24-00253}, pmid = {39853150}, issn = {1558-9110}, mesh = {Humans ; *Deglutition Disorders/diagnosis/etiology/physiopathology/psychology ; Male ; Female ; *Caregivers/psychology ; Aged ; Reproducibility of Results ; Middle Aged ; *Neurodegenerative Diseases/complications/diagnosis ; Amyotrophic Lateral Sclerosis/diagnosis/complications ; Surveys and Questionnaires ; Cost of Illness ; *Deglutition ; *Parkinson Disease/complications/diagnosis ; Aged, 80 and over ; Adult ; Dementia ; ROC Curve ; }, abstract = {PURPOSE: Swallowing difficulties have a substantial impact on the burden experienced by care partners of individuals with neurodegenerative disease. Given this, there is a clear need to easily identify and quantify the unique aspects of swallowing-related burden. The purpose of this study was to establish the validity and reliability of the Caregiver Analysis of Reported Experiences with Swallowing Disorders (CARES) screening tool in care partners of individuals with neurodegenerative disease.

METHOD: Survey data were collected from an international sample of 212 individuals caring for family members with amyotrophic lateral sclerosis (n = 49), dementia (n = 110), or Parkinson's disease (n = 53). Respondents completed the CARES, Eating Assessment Tool-10, International Dysphagia Diet Standardisation Initiative-Functional Diet Scale, and Zarit Burden Interview. Reliability and validity of the CARES were evaluated via internal consistency alpha coefficients, Spearman's rho correlations, and logistic regression analyses with receiver operating characteristic (ROC) curves.

RESULTS: CARES scores demonstrated excellent internal consistency (α = .90-.95) and high test-retest reliability (r = .86-.91). The CARES was found to be valid, as increased swallowing-related burden was associated with increased severity of swallowing difficulties (r = .79 to .84), diet restrictiveness (r = -.50 to -.54), and general caregiver burden (r = .36 to .40). The CARES had excellent discrimination between care partners with and without self-reported swallowing-related burden, with a score of ≥ 4 suggesting a heightened risk of experiencing this burden.

CONCLUSIONS: Results establish the CARES as a valid and reliable screening tool that can detect burden related to swallowing difficulties among care partners of individuals living with neurodegenerative disease (score ≥ 4). Clinical implementation of the CARES requires the concerted efforts of the larger multidisciplinary team who can collaboratively identify the presence of burden and target the multifaceted sources of burden that a care partner may be experiencing.}, } @article {pmid39854095, year = {2025}, author = {Hansen, G and Shaw, A and Bolt, K and Verity, R and Nataraj, RT and Schellenberg, KL}, title = {Thoracic Electric Impedance Tomography Detects Lung Volume Changes in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {71}, number = {4}, pages = {552-557}, pmid = {39854095}, issn = {1097-4598}, support = {//ALS Society of Saskatchewan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; Middle Aged ; *Electric Impedance ; Aged ; Vital Capacity/physiology ; *Tomography/methods ; *Lung/physiopathology/diagnostic imaging ; Spirometry ; Lung Volume Measurements/methods ; Adult ; Supine Position ; }, abstract = {INTRODUCTION/AIMS: Spirometry is the conventional means to measure lung function in amyotrophic lateral sclerosis (ALS), but is dependent on patient effort and bulbar strength. We aimed to use electric impedance tomography (EIT), an emerging non-invasive imaging modality, to measure dynamic lung volume changes.

METHODS: Twenty-one patients with ALS underwent sitting and supine spirometry for forced vital capacity (FVC), and sitting and supine EIT. There were 13 patients in the high FVC group (FVC ≥ 80% predicted) and 8 in the low FVC group (FVC < 80% predicted). Additional demographic and clinical data were collected from clinical records.

RESULTS: Only the low FVC group had significant loss of lung volumes in the supine position (R [2] = 0.89 and p < 0.001). The supine volume loss measurement at 10 min correlated with sitting (r [2] = 0.47) and supine FVC (r [2] = 0.36), maximum inspiratory (r [2] = -0.44) and expiratory pressures (r [2] = 0.36) (MIP and MEP), and the ALS Functional Rating Scale-Revised (ALSFRS-R) dyspnea subscore (r [2] = 0.36).

DISCUSSION: EIT is an emerging alternative to existing measures of lung function in ALS, but without need for patient effort or bulbar strength. Significant losses in lung volume are seen on supine compared to upright position in patients with respiratory dysfunction. Further study is needed to determine relationships to existing clinical measures.}, } @article {pmid39854930, year = {2025}, author = {Drouet, C and Priou, P and Gagnadoux, F and Trzepizur, W}, title = {Constraints to the initiation of home non-invasive ventilation and short-term efficacy in different diagnostic groups (as a prelude to an ambulatory shift).}, journal = {Respiratory medicine and research}, volume = {87}, number = {}, pages = {101154}, doi = {10.1016/j.resmer.2025.101154}, pmid = {39854930}, issn = {2590-0412}, mesh = {Humans ; *Noninvasive Ventilation/methods/statistics & numerical data ; Retrospective Studies ; Male ; Female ; Aged ; Middle Aged ; Cross-Sectional Studies ; *Respiratory Insufficiency/therapy/etiology ; Longitudinal Studies ; Pulmonary Disease, Chronic Obstructive/complications/therapy ; Treatment Outcome ; *Home Care Services ; Obesity Hypoventilation Syndrome/complications ; Amyotrophic Lateral Sclerosis/complications ; *Ambulatory Care ; }, abstract = {INTRODUCTION: Non-invasive ventilation (NIV) is the reference treatment for chronic respiratory failure (CRF) due to impairment of the ventilatory system. Home initiation is increasingly practiced. To better support this ambulatory shift, we aimed to assess the implementation constraints and short-term efficacy according to different aetiologies of CRF.

METHODS: This retrospective study with cross-sectional and longitudinal analysis included patients initiated with NIV at Angers University Hospital. Patients were separated according to the following aetiologies: obesity hypoventilation syndrome (OHS), chronic obstruction pulmonary disease (COPD), amyotrophic lateral sclerosis (ALS), myopathy and chest wall disease. Implementation constraints were assessed by analysing the variability of NIV settings, the number of masks tried and the duration of hospitalisation. NIV effectiveness was assessed by measuring residual PaCO2 (arterial pressure in CO2), apnoea hypopnea index (AHIflow) and tidal volume (VT) (as displayed by the NIV software).

RESULTS: Between October 2020 and May 2022, 102 patients were started with NIV, including a majority of ALS patients. We found a moderate variability in NIV settings (pressure, slope, triggers, etc.) within the different etiological groups, particularly in ALS. On the other hand, ALS patients required more interface trials than other groups and often had unmet efficacy criteria at hospital discharge. Interestingly, longitudinal follow-up showed a progressive improvement in efficacy criteria, particularly in patients who were initially inadequately ventilated.

CONCLUSION: Each aetiological group has specific constraints in the initiation of NIV that should be considered when initiating NIV in the outpatient setting.}, } @article {pmid39855275, year = {2025}, author = {Zhang, W and Zhang, L and Fu, S and Yan, R and Zhang, X and Song, J and Lu, Y}, title = {Roles of NLRC4 inflammasome in neurological disorders: Mechanisms, implications, and therapeutic potential.}, journal = {Pharmacology & therapeutics}, volume = {267}, number = {}, pages = {108803}, doi = {10.1016/j.pharmthera.2025.108803}, pmid = {39855275}, issn = {1879-016X}, mesh = {Humans ; *Inflammasomes/metabolism/immunology ; Animals ; *Calcium-Binding Proteins/metabolism ; *Nervous System Diseases/drug therapy/immunology/metabolism ; *CARD Signaling Adaptor Proteins/metabolism ; *Apoptosis Regulatory Proteins/metabolism ; Neurodegenerative Diseases/drug therapy/immunology ; }, abstract = {The nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 4 (NLRC4) inflammasome, a vital component of the innate immune system, is known for defending against bacterial infections. However, recent insights have revealed its significant impact on neurological disorders. This comprehensive review discussed the mechanisms underlying the activation and regulation of the NLRC4 inflammasome, highlighting the complexity of its response to cellular stress and damage signals. The biological functions of NLRC4 were explored, particularly its influence on cytokine production and the induction of pyroptosis, a form of inflammatory cell death. This review further emphasized the role of the NLRC4 inflammasome in brain injuries and neurodegenerative disorders. In the realm of brain injuries such as stroke and traumatic brain injury, as well as in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, the NLRC4 inflammasome played a pivotal role in modulating neuroinflammatory responses, which was crucial for understanding the progression and potential therapeutic targeting of these conditions. The emerging role of NLRC4 in psychiatric disorders and its potential impact on glioma progression were also examined. Additionally, this review presented a thorough summary of the latest research on inhibitors that impeded the assembly and activation of the NLRC4 inflammasome, pointing to new therapeutic possibilities in neurological disorders. In conclusion, by integrating current knowledge on the activation and regulation of NLRC4 with its biological functions and clinical implications, this article underscored the importance of NLRC4 inflammasome in neurological pathologies, which opened new possibilities for the treatment of challenging neurological conditions.}, } @article {pmid39857328, year = {2025}, author = {Stoccoro, A}, title = {Epigenetic Mechanisms Underlying Sex Differences in Neurodegenerative Diseases.}, journal = {Biology}, volume = {14}, number = {1}, pages = {}, pmid = {39857328}, issn = {2079-7737}, support = {GR-2021-12374436//Italian Ministry of Health, Ricerca Finalizzata/ ; }, abstract = {Neurodegenerative diseases are characterized by profound differences between females and males in terms of incidence, clinical presentation, and disease progression. Furthermore, there is evidence suggesting that differences in sensitivity to medical treatments may exist between the two sexes. Although the role of sex hormones and sex chromosomes in driving differential susceptibility to these diseases is well-established, the molecular alterations underlying these differences remain poorly understood. Epigenetic mechanisms, including DNA methylation, histone tail modifications, and the activity of non-coding RNAs, are strongly implicated in the pathogenesis of neurodegenerative diseases. While it is known that epigenetic mechanisms play a crucial role in sexual differentiation and that distinct epigenetic patterns characterize females and males, sex-specific epigenetic patterns have been largely overlooked in studies aiming to identify epigenetic alterations associated with neurodegenerative diseases. This review aims to provide an overview of sex differences in epigenetic mechanisms, the role of sex-specific epigenetic processes in the central nervous system, and the main evidence of sex-specific epigenetic alterations in three neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Understanding the sex-related differences of these diseases is essential for developing personalized treatments and interventions that account for the unique epigenetic landscapes of each sex.}, } @article {pmid39857620, year = {2024}, author = {Frawley, L and Taylor, NT and Sivills, O and McPhillamy, E and To, TD and Wu, Y and Chin, BY and Wong, CY}, title = {Stem Cell Therapy for the Treatment of Amyotrophic Lateral Sclerosis: Comparison of the Efficacy of Mesenchymal Stem Cells, Neural Stem Cells, and Induced Pluripotent Stem Cells.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857620}, issn = {2227-9059}, support = {Australian Government New Colombo Plan (NCP) scheme//Australian Government New Colombo Plan (NCP) scheme/ ; }, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a debilitating, incurable neurodegenerative disorder characterised by motor neuron death in the spinal cord, brainstem, and motor cortex. With an incidence rate of about 4.42 cases per 100,000 people annually, ALS severely impacts motor function and quality of life, causing progressive muscle atrophy, spasticity, paralysis, and eventually death. The cause of ALS is largely unknown, with 90% of cases being sporadic and 10% familial. Current research targets molecular mechanisms of inflammation, excitotoxicity, aggregation-prone proteins, and proteinopathy.

METHODS: This review evaluates the efficacy of three stem cell types in ALS treatment: mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs).

RESULTS: MSCs, derived from various tissues, show neuroprotective and regenerative qualities, with clinical trials suggesting potential benefits but limited by small sample sizes and non-randomised designs. NSCs, isolated from the fetal spinal cord or brain, demonstrate promise in animal models but face functional integration and ethical challenges. iPSCs, created by reprogramming patient-specific somatic cells, offer a novel approach by potentially replacing or supporting neurons. iPSC therapy addresses ethical issues related to embryonic stem cells but encounters challenges regarding genotoxicity and epigenetic irregularities, somatic cell sources, privacy concerns, the need for extensive clinical trials, and high reprogramming costs.

CONCLUSIONS: This research is significant for advancing ALS treatment beyond symptomatic relief and modest survival extensions to actively modifying disease progression and improving patient outcomes. Successful stem cell therapies could lead to new ALS treatments, slowing motor function loss and reducing symptom severity.}, } @article {pmid39857633, year = {2024}, author = {Zhang, G and Cao, W and Wang, Z and Xia, K and Deng, B and Fan, D}, title = {Associations of Abnormal Sleep Duration and Chronotype with Higher Risk of Incident Amyotrophic Lateral Sclerosis: A UK Biobank Prospective Cohort Study.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857633}, issn = {2227-9059}, support = {82301601 81873784 82071426//National Natural Science Foundation of China/ ; }, abstract = {Background: The occurrence of sleep disturbances in amyotrophic lateral sclerosis (ALS) patients is widely reported. However, there is still a lack of reliable evidence of a relationship between sleep disturbances and the risk of developing ALS. The aim of this study was to prospectively investigate the longitudinal associations between sleep traits and the risk of incident ALS. Methods: We included information from 409,045 individuals from the prospective cohort of the UK Biobank. Sleep traits at baseline were measured using a standardized questionnaire. All sleep traits were analyzed in relation to the subsequent incidence of ALS using Cox proportional hazards models. Results: Multivariate analysis showed that 6-7 h of sleep was related to the lowest risk for ALS. A long sleep duration (≥8 h) was associated with an increased risk of ALS incidence (HR: 1.31, 95% CI: 1.07-1.61; p = 0.009). A short sleep duration (<6 h) was associated with an increased risk of ALS incidence (HR: 1.91, 95% CI: 1.10-3.30, p = 0.021) in females. In participants aged ≥65 years, eveningness was associated with increased ALS risk (HR: 1.32, 95% CI: 1.08-1.61; p = 0.006). Conclusion: Our results hint at a sleep duration that is too short or too long, and certain chronotypes might be related to the risk of developing ALS. Despite the limitations imposed by the study design and the subjectivity of sleep information, our findings suggest that sleep disturbances may influence the risk of developing ALS.}, } @article {pmid39857761, year = {2025}, author = {Sun, C and Chen, Y and Xu, L and Wang, W and Zhang, N and Fournier, CN and Li, N and Fan, D}, title = {Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale as a Novel Tool to Measure Disease Progression.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857761}, issn = {2227-9059}, support = {82001347//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; 81701067//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; }, abstract = {Background: A valuable outcome measure to monitor amyotrophic lateral sclerosis (ALS) disease progression is crucial in clinical trials. Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) is a novel questionnaire assessing ALS disability. Currently, there are no studies on the relationship between ROADS and ALS survival. This study explored the value of Chinese ROADS as a novel tool for measuring disease progression and the correlation between ROADS and ALS survival. Methods: A total of 170 ALS participants were included in this study. Clinical characteristics and baseline ROADS, ΔROADS, ALSFRS-R, and ΔFRS of patients were collected. Participants were followed for 18 months to assess time to tracheostomy and survival. Scales were collected every 3 to 6 months. We evaluated the association of baseline ROADS and ΔROADS with survival using Cox regression analyses. Linear mixed effects models were used to assess changes over time in ROADS and ALSFRS-R. Results: Multivariate Cox models confirmed that baseline ROADS positively correlated with ALS survival (HR = 0.95, p < 0.001), while baseline ΔROADS negatively correlated with survival (HR = 1.26, p < 0.001). Additionally, linear mixed effects models suggested that ROADS, similar to ALSFRS-R, declined significantly over time, but there was no significant difference between these two. Conclusions: Our study indicates that Chinese ROADS is strongly related to ALS survival. Changes in ROADS with disease progression are similar to those in ALSFRS-R. These findings support Chinese ROADS as a reliable outcome measure for clinical trials, potentially enhancing the dimension of evaluating treatment effectiveness in ALS trials.}, } @article {pmid39858428, year = {2024}, author = {Argueti-Ostrovsky, S and Barel, S and Kahn, J and Israelson, A}, title = {VDAC1: A Key Player in the Mitochondrial Landscape of Neurodegeneration.}, journal = {Biomolecules}, volume = {15}, number = {1}, pages = {}, pmid = {39858428}, issn = {2218-273X}, support = {#284/19 and #485/24//Israel Science Foundation/ ; }, mesh = {Humans ; *Voltage-Dependent Anion Channel 1/metabolism/genetics ; *Mitochondria/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; alpha-Synuclein/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; Superoxide Dismutase-1/metabolism/genetics ; Oxidative Stress ; }, abstract = {Voltage-Dependent Anion Channel 1 (VDAC1) is a mitochondrial outer membrane protein that plays a crucial role in regulating cellular energy metabolism and apoptosis by mediating the exchange of ions and metabolites between mitochondria and the cytosol. Mitochondrial dysfunction and oxidative stress are central features of neurodegenerative diseases. The pivotal functions of VDAC1 in controlling mitochondrial membrane permeability, regulating calcium balance, and facilitating programmed cell death pathways, position it as a key determinant in the delicate balance between neuronal viability and degeneration. Accordingly, increasing evidence suggests that VDAC1 is implicated in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and others. This review summarizes the current findings on the contribution of VDAC1 to neurodegeneration, focusing on its interactions with disease-specific proteins, such as amyloid-β, α-synuclein, and mutant SOD1. By unraveling the complex involvement of VDAC1 in neurodegenerative processes, this review highlights potential avenues for future research and drug development aimed at alleviating mitochondrial-related neurodegeneration.}, } @article {pmid39859258, year = {2025}, author = {Szablewski, L}, title = {Associations Between Diabetes Mellitus and Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {2}, pages = {}, pmid = {39859258}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/etiology/complications/pathology ; *Diabetes Mellitus, Type 2/complications/metabolism ; Oxidative Stress ; Animals ; Parkinson Disease ; Huntington Disease ; *Diabetes Mellitus, Type 1/complications/metabolism ; Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis ; *Diabetes Mellitus/metabolism ; }, abstract = {Diabetes mellitus (DM) and neurodegenerative diseases/disturbances are worldwide health problems. The most common chronic conditions diagnosed in persons 60 years and older are type 2 diabetes mellitus (T2DM) and cognitive impairment. It was found that diabetes mellitus is a major risk for cognitive decline, dementia, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Different mechanisms of associations between these diseases and diabetes mellitus have been suggested. For example, it is postulated that an impaired intracellular insulin signaling pathway, together with hyperglycemia and hyperinsulinemia, may cause pathological changes, such as dysfunction of the mitochondria, oxidative stress inflammatory responses, etc. The association between diabetes mellitus and neurodegenerative diseases, as well as the mechanisms of these associations, needs further investigation. The aim of this review is to describe the associations between diabetes mellitus, especially type 1 (T1DM) and type 2 diabetes mellitus, and selected neurodegenerative diseases, i.e., Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Suggested mechanisms of these associations are also described.}, } @article {pmid39859339, year = {2025}, author = {Yashooa, RK and Duranti, E and Conconi, D and Lavitrano, M and Mustafa, SA and Villa, C}, title = {Mitochondrial microRNAs: Key Drivers in Unraveling Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {2}, pages = {}, pmid = {39859339}, issn = {1422-0067}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Mitochondria/genetics/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Animals ; Gene Expression Regulation ; Parkinson Disease/genetics/metabolism ; DNA, Mitochondrial/genetics ; }, abstract = {MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) crucial for regulating gene expression at the post-transcriptional level. Recent evidence has shown that miRNAs are also found in mitochondria, organelles that produce energy in the cell. These mitochondrial miRNAs, also known as mitomiRs, are essential for regulating mitochondrial function and metabolism. MitomiRs can originate from the nucleus, following traditional miRNA biogenesis pathways, or potentially from mitochondrial DNA, allowing them to directly affect gene expression and cellular energy dynamics within the mitochondrion. While miRNAs have been extensively investigated, the function and involvement of mitomiRs in the development of neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis remain to be elucidated. This review aims to discuss findings on the role of mitomiRs in such diseases and their potential as therapeutic targets, as well as to highlight future research directions.}, } @article {pmid39860557, year = {2025}, author = {Chmiel, J and Stępień-Słodkowska, M}, title = {Resting-State EEG Oscillations in Amyotrophic Lateral Sclerosis (ALS): Toward Mechanistic Insights and Clinical Markers.}, journal = {Journal of clinical medicine}, volume = {14}, number = {2}, pages = {}, pmid = {39860557}, issn = {2077-0383}, abstract = {Introduction: Amyotrophic lateral sclerosis (ALS) is a complex, progressive neurodegenerative disorder characterized by the degeneration of motor neurons in the brain, brainstem, and spinal cord. Several neuroimaging techniques can help reveal the pathophysiology of ALS. One of these is the electroencephalogram (EEG), a noninvasive and relatively inexpensive tool for examining electrical activity of the brain with excellent temporal precision. Methods: This mechanistic review examines the pattern of resting-state EEG activity. With a focus on publications published between January 1995 and October 2024, we carried out a comprehensive search in October 2024 across a number of databases, including PubMed/Medline, Research Gate, Google Scholar, and Cochrane. Results: The literature search yielded 17 studies included in this review. The studies varied significantly in their methodology and patient characteristics. Despite this, a common biomarker typical of ALS was found-reduced alpha power. Regarding other oscillations, the findings are less consistent and sometimes contradictory. As this is a mechanistic review, three possible explanations for this biomarker are provided. The main and most important one is increased cortical excitability. In addition, due to the limitations of the studies, recommendations for future research on this topic are outlined to enable a further and better understanding of EEG patterns in ALS. Conclusions: Most studies included in this review showed alpha power deficits in ALS patients, reflecting pathological hyperexcitability of the cerebral cortex. Future studies should address the methodological limitations identified in this review, including small sample sizes, inconsistent frequency-band definitions, and insufficient functional outcome measures, to solidify and extend current findings.}, } @article {pmid39861520, year = {2025}, author = {Tripolskaja, L and Kazlauskaite-Jadzevice, A and Razukas, A and Baksiene, E}, title = {Perennial Grasses on Stony Sandy Loam Arenosol: Summary of Results of Long-Term Experiment in Northern Europe Region (1995-2024).}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {2}, pages = {}, pmid = {39861520}, issn = {2223-7747}, support = {"Improvement of the preparation of highly skilled professionals for development of science-intensive economic entities-NKPDOKT" (project code No: VP1-3.1-ŠMM-01-V-03-001)//Lietuvos mokslų taryba/ ; }, abstract = {Grasses can sustain soil functions despite nutrient depletion, which can have serious consequences for soil processes and ecosystem services. This paper summarizes the results of the long-term experiment (1995-2024) carried out in Arenosol within a temperate climate zone, focusing on the productivity of natural and managed grasslands; their succession changes over time, and so do the effects on soil chemical properties, and soil organic carbon (SOC) sequestration. The results indicated that two land uses-abandoned land (AL) and grassland fertilized with mineral fertilizers (MGf)-can be effectively applied to prevent Arenosol soil degradation. SOC accumulation occurs more rapidly in AL soils, and their chemical properties show less change over time. The ability of grasses to sequester SOC is better reflected by SOC stocks across the Ah horizon, where thickness varies over long-term grassland use. Significant changes in soil properties were observed more than 20 years after converting arable to herbaceous land use. While MGf has the highest biomass productivity, the use of fertilizers leads to soil acidification. The biomass productivity of AL and MGf increased with longer grassland use; however, in MG, productivity decreased without fertilizers, reaching AL's productivity levels after 20 years. As the age of AL increased, plant biodiversity decreased, and drought-resistant plants began to spread.}, } @article {pmid39862877, year = {2025}, author = {Feldman, EL and Sattler, R and Kiernan, MC and Goutman, SA and Chiò, A and Al-Chalabi, A}, title = {Transforming amyotrophic lateral sclerosis into a liveable disease.}, journal = {The Lancet. Neurology}, volume = {24}, number = {2}, pages = {100-101}, doi = {10.1016/S1474-4422(24)00523-4}, pmid = {39862877}, issn = {1474-4465}, } @article {pmid39862884, year = {2025}, author = {Moens, TG and Da Cruz, S and Neumann, M and Shelkovnikova, TA and Shneider, NA and Van Den Bosch, L}, title = {Amyotrophic lateral sclerosis caused by FUS mutations: advances with broad implications.}, journal = {The Lancet. Neurology}, volume = {24}, number = {2}, pages = {166-178}, doi = {10.1016/S1474-4422(24)00517-9}, pmid = {39862884}, issn = {1474-4465}, support = {SHELKOVNIKOVA/OCT17/968-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology ; *RNA-Binding Protein FUS/genetics ; *Mutation/genetics ; Animals ; }, abstract = {Autosomal dominant mutations in the gene encoding the DNA and RNA binding protein FUS are a cause of amyotrophic lateral sclerosis (ALS), and about 0·3-0·9% of patients with ALS are FUS mutation carriers. FUS-mutation-associated ALS (FUS-ALS) is characterised by early onset and rapid progression, compared with other forms of ALS. However, different pathogenic mutations in FUS can result in markedly different age at symptom onset and rate of disease progression. Most FUS mutations disrupt its nuclear localisation, leading to its cytoplasmic accumulation in the CNS. FUS also forms inclusions in around 5% of patients with the related neurodegenerative condition frontotemporal dementia. However, there are key differences between the two diseases at the genetic and neuropathological level, which suggest distinct pathogenic processes. Experimental models have uncovered potential pathogenic mechanisms in FUS-ALS and informed therapeutic strategies that are currently in development, including the silencing of FUS expression using an intrathecally administered antisense oligonucleotide.}, } @article {pmid39863029, year = {2025}, author = {Liu, X and Li, T and Tu, X and Xu, M and Wang, J}, title = {Mitochondrial fission and fusion in neurodegenerative diseases:Ca[2+] signalling.}, journal = {Molecular and cellular neurosciences}, volume = {132}, number = {}, pages = {103992}, doi = {10.1016/j.mcn.2025.103992}, pmid = {39863029}, issn = {1095-9327}, mesh = {Humans ; *Mitochondrial Dynamics/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; *Calcium Signaling ; Animals ; *Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; }, abstract = {Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive loss of neuronal structure and function. The pathogenesis is intricate and involves a network of interactions among multiple causes and systems. Mitochondria and Ca[2+] signaling have long been considered to play important roles in the development of various NDs. Mitochondrial fission and fusion dynamics are important processes of mitochondrial quality control, ensuring the stability of mitochondrial structure and function. Mitochondrial fission and fusion imbalance and Ca[2+] signaling disorders can aggravate the disease progression of NDs. In this review, we explore the relationship between mitochondrial dynamics and Ca[2+] signaling in AD, PD, ALS, and HD, focusing on the roles of key regulatory proteins (Drp1, Fis1, Mfn1/2, and Opa1) and the association structures between mitochondria and the endoplasmic reticulum (MERCs/MAMs). We provide a detailed analysis of their involvement in the pathogenesis of these four NDs. By integrating these mechanisms, we aim to clarify their contributions to disease progression and offer insights into the development of therapeutic strategies that target mitochondrial dynamics and Ca[2+] signaling. We also examine the progress in drug research targeting these pathways, highlighting their potential as therapeutic targets in the treatment of NDs.}, } @article {pmid39863163, year = {2025}, author = {Kearney, CA and Needle, CD and Brinks, AL and Gutierrez, D and Lo Sicco, KI}, title = {Response to Sood et al's "Systemic Janus kinase inhibitor treatment for vitiligo: An evidence-based review".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {5}, pages = {e155-e156}, doi = {10.1016/j.jaad.2025.01.059}, pmid = {39863163}, issn = {1097-6787}, } @article {pmid39863573, year = {2025}, author = {Ting, HC and Guo, YT and Su, HL and Chen, YS and Lin, SZ and Harn, HJ and Chang, CY}, title = {Rapid iPSC-derived neuromuscular junction model uncovers motor neuron dominance in amyotrophic lateral sclerosis cytopathy.}, journal = {Cell death discovery}, volume = {11}, number = {1}, pages = {23}, pmid = {39863573}, issn = {2058-7716}, abstract = {The neuromuscular junction (NMJ) is essential for transmitting signals from motor neurons (MNs) to skeletal muscles (SKMs), and its dysfunction can lead to severe motor disorders. However, our understanding of the NMJ is limited by the absence of accurate human models. Although human induced pluripotent stem cell (iPSC)-derived models have advanced NMJ research, their application is constrained by challenges such as limited differentiation efficiency, lengthy generation times, and cryopreservation difficulties. To overcome these limitations, we developed a rapid human NMJ model using cryopreserved MNs and SKMs derived from iPSCs. Within 12 days of coculture, we successfully recreated NMJ-specific connectivity that closely mirrors in vivo synapse formation. Using this model, we investigated amyotrophic lateral sclerosis (ALS) and replicated ALS-specific NMJ cytopathies with SOD1 mutant and corrected isogenic iPSC lines. Quantitative analysis of 3D confocal microscopy images revealed a critical role of MNs in initiating ALS-related NMJ cytopathies, characterized by alterations in the volume, number, intensity, and distribution of acetylcholine receptors, ultimately leading to impaired muscle contractions. Our rapid and precise in vitro NMJ model offers significant potential for advancing research on NMJ physiology and pathology, as well as for developing treatments for NMJ-related diseases.}, } @article {pmid39865616, year = {2025}, author = {Dong, S and Liu, X and Zhou, Y and Li, J and Qi, Z and Wang, Z and Yang, W and Chen, X}, title = {Prognostic Value of Cerebrospinal Fluid and Serum Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: A Correlation Study.}, journal = {Brain and behavior}, volume = {15}, number = {1}, pages = {e70256}, pmid = {39865616}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/diagnosis ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Male ; Female ; Middle Aged ; Prognosis ; Aged ; Biomarkers/blood/cerebrospinal fluid ; Disease Progression ; Adult ; }, abstract = {BACKGROUND: The diagnostic and prognostic values of serum neurofilament light chain (sNfL), in comparison to cerebrospinal fluid (CSF) neurofilament light chain (cNfL), and other clinical parameters in amyotrophic lateral sclerosis (ALS) at the time of diagnosis remain elusive.

METHODS: We examine paired serum and CSF samples from 80 ALS patients and 21 control subjects, all obtained at the time of diagnosis. Additional serum samples were collected from 51 other ALS patients. NfL concentrations were quantified using the single molecule array (Simoa) technique.

RESULTS: Our findings demonstrate a robust correlation between NfL levels in matched CSF and serum samples. Notably, both sNfL (p < 0.0001) and cNfL (p < 0.0001) exhibited significantly elevated levels in ALS patients compared to controls. Furthermore, baseline sNfL concentrations, as well as cNfL levels, emerged as predictive indicators of subsequent disease progression rate (sNfL: p < 0.0001, cNfL: p = 0.0005) and overall survival (sNfL: p = 0.0073, cNfL: p = 0.0044). Employing a Cox regression model, we identified baseline sNfL level (HR = 1.01, p = 0.013), and diagnostic delay (HR = 0.94, p = 0.003) as independent prognostic factors for mortality. Furthermore, we constructed a nomogram model that incorporates both sNfL and pertinent clinical variables, which substantially enhances the accuracy of predicting disease outcomes (Concordance Index, 0.808).

CONCLUSION: Our study underscores the robust correlation between sNfL and cNfL in ALS patients and establishes baseline sNfL as a potent and independent prognostic marker for mortality.}, } @article {pmid39865792, year = {2025}, author = {Murakami, E and Shibata, T and Tomemori, M and Kawai, G and Nakatani, K}, title = {The role of spatial arrangement of aromatic rings on the binding of N,N'-diheteroaryl guanidine ligands to the G2C4/G2C4 motif DNA.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {27}, number = {6}, pages = {3341-3350}, doi = {10.1039/d4cp03213f}, pmid = {39865792}, issn = {1463-9084}, mesh = {*DNA/chemistry/metabolism ; Ligands ; Surface Plasmon Resonance ; *Guanidine/chemistry/analogs & derivatives ; Circular Dichroism ; Hydrogen Bonding ; Humans ; }, abstract = {Non-canonical DNA structures formed by aberrantly expanded repeat DNA are implicated in promoting repeat instability and the onset of repeat expansion diseases. Small molecules that target these disease-causing repeat DNAs hold promise as therapeutic agents for such diseases. Specifically, 1,3-di(quinolin-2-yl)guanidine (DQG) has been identified to bind to the disease-causing GGCCCC (G2C4) repeat DNA associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In this study, we investigate the structure-binding relationships between DQG analogs and double-stranded DNA (dsDNA) containing a G2C4/G2C4 unit. Our findings, derived from UV melting temperature, circular dichroism spectra, and surface plasmon resonance (SPR) analyses of DQG analogs, highlight the crucial role of the spatial arrangements of aromatic rings in binding to the G2C4/G2C4 unit. Among the tested DQG analogs, N,N'-di(quinazolin-2-yl)guanidine (DQzG) stands out for its ability to form seven planar conformers. These conformers enable ADD-DAA hydrogen bonding with cytosine and multiple spatial arrangements of aromatic rings, including those resembling DQG. Our binding analyses revealed that DQzG exhibits the highest affinity binding for the G2C4/G2C4 unit. NMR analysis of the DQzG-bound G2C4/G2C4-dsDNA further suggested that DQzG binds to the G2C4/G2C4 unit via hydrogen bonding. Moreover, SPR analysis demonstrated that DQzG binds more strongly to G2C4 repeat DNA compared to DQG. These results position DQzG as a promising lead compound for targeting the G2C4 repeat, offering potential therapeutic avenues for the treatment of ALS/FTD and other repeat expansion diseases.}, } @article {pmid39866212, year = {2025}, author = {Wang, W and Cooper, C}, title = {Metabolic dysfunction-associated steatotic liver disease and type 2 diabetes: A dual threat to cardiac dysfunction progression.}, journal = {World journal of cardiology}, volume = {17}, number = {1}, pages = {102467}, pmid = {39866212}, issn = {1949-8462}, abstract = {Metabolic dysfunction-associated steatotic liver disease (MASLD), particularly in patients with type 2 diabetes mellitus (T2DM), is increasingly recognized as a multi-system disease that affects both hepatic and cardiovascular health. This study explores the association between MASLD-related liver fibrosis and cardiac dysfunction, focusing on how liver fibrosis contributes to cardiac remodeling and dysfunction. Cernea et al's research highlights the strong correlation between liver fibrosis and changes in left ventricular mass, left atrial dimensions, and systolic and diastolic function in diabetic patients. Notably, the study suggests a protective role of sex-hormone binding protein against cardiac remodeling. These findings underline the importance of early detection of liver fibrosis using non-invasive markers like fibrosis-4 index and nonalcoholic fatty liver disease fibrosis scores, which may offer dual protection for both liver and heart health in T2DM patients. Moreover, this study calls for further research into the shared pathogenic mechanisms, including inflammation and fibrosis pathways, between the liver and heart. It advocates for the integration of liver fibrosis screening into cardiovascular risk management, urging clinicians to adopt a more holistic approach in treating patients with MASLD and T2DM. The research has broad implications for preventing cardiovascular complications and improving outcomes in this high-risk population.}, } @article {pmid39867453, year = {2024}, author = {Rong, P and Heidrick, L and Pattee, G}, title = {A novel muscle network approach for objective assessment and profiling of bulbar involvement in ALS.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1491997}, pmid = {39867453}, issn = {1662-4548}, abstract = {INTRODUCTION: As a hallmark feature of amyotrophic lateral sclerosis (ALS), bulbar involvement significantly impacts psychosocial, emotional, and physical health. A validated objective marker is however lacking to characterize and phenotype bulbar involvement, positing a major barrier to early detection, progress monitoring, and tailored care. This study aimed to bridge this gap by constructing a multiplex functional mandibular muscle network to provide a novel objective measurement tool of bulbar involvement.

METHODS: A noninvasive electrophysiological technique-surface electromyography-was combined with graph network analysis to extract 48 features measuring the regulatory mechanisms, connectivity, integration, segregation, assortativity, and lateralization of the functional muscle network during a speech task. These features were clustered into 10 interpretable latent factors. To evaluate the utility of the muscle network as a bulbar measurement tool, a heterogenous ALS cohort, consisting of eight individuals with overt clinical bulbar symptoms and seven without, along with 10 neurologically healthy controls, was employed to train and validate statistical and machine learning algorithms to assess the disease effects on the network features and the relation of the network performance to the current clinical diagnostic standard and behavioral patterns of bulbar involvement.

RESULTS: Significant disease effects were found on most network features. The most robust effects were manifested by reduced and more variable myoelectric activities, and reduced functional connectivity and integration of the muscle network. The 10 latent factors (1) demonstrated acceptably high efficacy for detecting bulbar neuromuscular changes across all clinically confirmed symptomatic cases and clinically silent prodromal cases (area under the curve = 0.89-0.91; F1 score = 0.85-0.87; precision = 0.84-0.86; recall = 0.87-0.88); and (2) selectively correlated with clinically meaningful behavioral patterns (conditional R [2] = 0.45-0.81).

CONCLUSION: The functional muscle network shows promise for an objective quantifiable measurement tool to improve early detection and profiling of bulbar involvement across the prodromal and symptomatic stages. This tool has various strengths, including the use of a clinically readily available noninvasive instrument, fully automated data processing and analytics, and generation of interpretable objective outcome measures (i.e., latent factors), together rendering it highly scalable in routine clinical practice for assessing and monitoring of bulbar involvement.}, } @article {pmid39868844, year = {2025}, author = {Elyaman, W and Stern, LJ and Jiang, N and Dressman, D and Bradley, P and Klatzmann, D and Bradshaw, EM and Farber, DL and Kent, SC and Chizari, S and Funk, K and Devanand, D and Thakur, KT and Raj, T and Dalahmah, OA and Sarkis, RA and Weiner, HL and Shneider, NA and Przedborski, S}, title = {Exploring the role of T cells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14548}, pmid = {39868844}, issn = {1552-5279}, support = {T32 AI148099/AI/NIAID NIH HHS/United States ; P01 AI106697/AI/NIAID NIH HHS/United States ; R01AI137198/NH/NIH HHS/United States ; R13 AG090018/AG/NIA NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; R01 AG076018/AG/NIA NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; T32AI148099-4/NH/NIH HHS/United States ; AI106697/NH/NIH HHS/United States ; R01 AG055422/AG/NIA NIH HHS/United States ; R01AG067581/NH/NIH HHS/United States ; R13AG090018-01/NH/NIH HHS/United States ; R01AG076018/NH/NIH HHS/United States ; AG R01AG055422/NH/NIH HHS/United States ; R35GM141457/NH/NIH HHS/United States ; R01 AI137198/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/immunology/therapy ; *Brain/immunology ; Immunotherapy ; *Neurodegenerative Diseases/immunology/therapy ; *T-Lymphocytes/immunology ; }, abstract = {This proceedings article summarizes the inaugural "T Cells in the Brain" symposium held at Columbia University. Experts gathered to explore the role of T cells in neurodegenerative diseases. Key topics included characterization of antigen-specific immune responses, T cell receptor (TCR) repertoire, microbial etiology in Alzheimer's disease (AD), and microglia-T cell crosstalk, with a focus on how T cells affect neuroinflammation and AD biomarkers like amyloid beta and tau. The symposium also examined immunotherapies for AD, including the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, and two clinical trials leveraging regulatory T cell approaches for multiple sclerosis and amyotrophic lateral sclerosis therapy. Additionally, single-cell RNA/TCR sequencing of T cells and other immune cells provided insights into immune dynamics in neurodegenerative diseases. This article highlights key findings from the symposium and outlines future research directions to further understand the role of T cells in neurodegeneration, offering innovative therapeutic approaches for AD and other neurodegenerative diseases. HIGHLIGHTS: Researchers gathered to discuss approaches to study T cells in brain disorders. New technologies allow high-throughput screening of antigen-specific T cells. Microbial infections can precede several serious and chronic neurological diseases. Central and peripheral T cell responses shape neurological disease pathology. Immunotherapy can induce regulatory T cell responses in neuroinflammatory disorders.}, } @article {pmid39870443, year = {2025}, author = {Zhang, Q and Walkley, CR}, title = {Mouse models for understanding physiological functions of ADARs.}, journal = {Methods in enzymology}, volume = {710}, number = {}, pages = {153-185}, doi = {10.1016/bs.mie.2024.11.024}, pmid = {39870443}, issn = {1557-7988}, support = {GNT1183553//National Health and Medical Research Council Australia (NHMRC)/ ; }, mesh = {Animals ; *Adenosine Deaminase/genetics/metabolism ; Mice ; Humans ; *Disease Models, Animal ; RNA Editing ; Adenosine/metabolism/genetics ; Autoimmune Diseases of the Nervous System/genetics ; *RNA-Binding Proteins/genetics/metabolism ; Nervous System Malformations/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Mutation ; }, abstract = {Adenosine-to-inosine (A-to-I) editing, is a highly prevalent posttranscriptional modification of RNA, mediated by the adenosine deaminases acting on RNA (ADAR) proteins. Mammalian transcriptomes contain tens of thousands to millions of A-to-I editing events. Mutations in ADAR can result in rare autoinflammatory disorders such as Aicardi-Goutières syndrome (AGS) through to irreversible conditions such as motor neuron disease, amyotrophic lateral sclerosis (ALS). Mouse models have played an important role in our current understanding of the physiology of ADAR proteins. With the advancement of genetic engineering technologies, a number of new mouse models have been recently generated, each providing additional insight into ADAR function. This review highlights both past and current mouse models, exploring the methodologies used in their generation, their respective discoveries, and the significance of these findings in relation to human ADAR physiology.}, } @article {pmid39870504, year = {2025}, author = {Wilson, C and Giaquinto, L and Santoro, M and Di Tullio, G and Morra, V and Kukulski, W and Venditti, R and Navone, F and Borgese, N and De Matteis, MA}, title = {A role for mitochondria-ER crosstalk in amyotrophic lateral sclerosis 8 pathogenesis.}, journal = {Life science alliance}, volume = {8}, number = {4}, pages = {}, pmid = {39870504}, issn = {2575-1077}, support = {MC_UP_1201/8//Medical Research Council / United Kingdom Research and Innovation/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Mitochondria/metabolism ; Humans ; *Endoplasmic Reticulum/metabolism ; Motor Neurons/metabolism/pathology ; Vesicular Transport Proteins/genetics/metabolism ; Mutation ; Saccharomyces cerevisiae/metabolism/genetics ; Animals ; Protein Aggregation, Pathological ; }, abstract = {Protein aggregates in motoneurons, a pathological hallmark of amyotrophic lateral sclerosis, have been suggested to play a key pathogenetic role. ALS8, characterized by ER-associated inclusions, is caused by a heterozygous mutation in VAPB, which acts at multiple membrane contact sites between the ER and almost all other organelles. The link between protein aggregation and cellular dysfunction is unclear. A yeast model, expressing human mutant and WT-VAPB under the control of the orthologous yeast promoter in haploid and diploid cells, was developed to mimic the disease situation. Inclusion formation was found to be a developmentally regulated process linked to mitochondrial damage that could be attenuated by reducing ER-mitochondrial contacts. The co-expression of the WT protein retarded P56S-VAPB inclusion formation. Importantly, we validated these results in mammalian motoneuron cells. Our findings indicate that (age-related) damage to mitochondria influences the propensity of the mutant VAPB to form aggregates via ER-mitochondrial contacts, initiating a series of events leading to disease progression.}, } @article {pmid39871559, year = {2025}, author = {Rani, S and Tuteja, M}, title = {Chaperones as Potential Pharmacological Targets for Treating Protein Aggregation Illness.}, journal = {Current protein & peptide science}, volume = {26}, number = {6}, pages = {451-466}, pmid = {39871559}, issn = {1875-5550}, mesh = {Humans ; *Molecular Chaperones/metabolism ; Animals ; Protein Folding/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy ; Heat-Shock Proteins/metabolism ; *Protein Aggregation, Pathological/drug therapy/metabolism ; Protein Aggregates/drug effects ; Molecular Targeted Therapy ; *Proteostasis Deficiencies/drug therapy/metabolism ; }, abstract = {The three-dimensional structure of proteins, achieved through the folding of the nascent polypeptide chain in vivo, is largely facilitated by molecular chaperones, which are crucial for determining protein functionality. In addition to aiding in the folding process, chaperones target misfolded proteins for degradation, acting as a quality control system within the cell. Defective protein folding has been implicated in a wide range of clinical conditions, including neurodegenerative and metabolic disorders. It is now well understood that the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Creutzfeldt-Jakob disease shares a common mechanism: the accumulation of misfolded proteins, which aggregate and become toxic to cells. Among the family of molecular chaperones, Heat Shock Proteins (HSPs) are highly expressed in response to cellular stress and play a pivotal role in preventing protein aggregation. Specific chaperones, particularly HSPs, are now recognized as critical in halting the accumulation and aggregation of misfolded proteins in these conditions. Consequently, these chaperones are increasingly considered promising pharmacological targets for the treatment of protein aggregation-related diseases. This review highlights research exploring the potential roles of specific molecular chaperones in disorders characterized by the accumulation of misfolded proteins.}, } @article {pmid39871563, year = {2025}, author = {Guo, J and Liu, XY and Yang, SS and Li, Q and Duan, Y and Zhu, SS and Zhou, K and Yan, YZ and Zeng, P}, title = {Roles of C/EBPβ/AEP in Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {25}, number = {20}, pages = {2440-2452}, pmid = {39871563}, issn = {1873-4294}, support = {82301506//National Natural Science Foundation of China/ ; 220XQD090//Research Foundation of Scientific Research Program of University of South China/ ; 2023JJ40560//Provincial Natural Science Foundation of Hunan/ ; S202410555234, S202410555259, S202410555262//Science and Technology Innovation Project for College Students/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; *CCAAT-Enhancer-Binding Protein-beta/metabolism/antagonists & inhibitors/chemistry ; Animals ; Small Molecule Libraries/chemistry/pharmacology ; }, abstract = {In recent years, an increasing number of studies have shown that increased activation of aspartic endopeptidases (AEPs) is a common symptom in neurodegenerative diseases (NDDs). AEP cleaves amyloid precursor protein (APP), tau (microtubule-associated protein tau), α- synuclein (α-syn), SET (a 39-KDa phosphoprotein widely expressed in various tissues and localizes predominantly in the nucleus), and TAR DNA-binding protein 43 (TDP-43), and promotes their aggregation, contributing to Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) pathogenesis. Abundant evidence supports the notion that CCAAT/enhancer-binding protein β (C/EBPβ)/AEP may play an important role in NDDs. Developing its small molecule inhibitors is a promising treatment of NDDs. However, current research suggests that the pathophysiological mechanism of the C/EBPβ/AEP pathway is very complex in NDDs. This review summarizes the structure of C/EBPβ and AEP, their major physiological functions, potential pathogenesis, their small molecule inhibitors, and how C/EBPβ/AEP offers a novel pathway for the treatment of NDDs.}, } @article {pmid39871987, year = {2024}, author = {Ribichini, E and Pallotta, N and Badiali, D and Carlucci, M and Ceccanti, M and Cambieri, C and Libonati, L and Corazziari, ES and Ruoppolo, G and Inghilleri, M}, title = {Assessment of upper GI motor activity and GI symptoms in patients with amyotrophic lateral sclerosis: an observational study.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1509917}, pmid = {39871987}, issn = {1664-2295}, abstract = {BACKGROUND/AIMS: Oro-pharyngeal dysfunction has been reported in Amyotrophic Lateral Sclerosis (ALS). We aimed to assess ALS patients upper gastrointestinal (GI) motor activity and GI symptoms according to bulbar and spinal onset and severity of ALS.

METHODS: ALS bulbar (B) and spinal (S) patients with ALS Functional Rating Scale (ALSFRS-r) ≥35, bulbar sub-score ≥10, and Forced Vital Capacity (FVC) >50%, underwent to: Fiberoptic Endoscopic Evaluation of Swallowing (FEES); esophageal manometry; gastric emptying; Rome symptom questionnaire. Medical Research Council Scale for Muscle Strength (MRC) was performed for the upper and lower limbs. Mann-Whitney's U, Fisher's ranks test, Pearson's test was used.

RESULTS: Thirteen ALS patients were included (6 F; mean age 61.2 ± 13.7 years, range: 37-87), 5 with B and 8 with S onset (ALSFRS-R score 39.5 ± 4.9, MRC score 128.6 ± 23.3, disease duration 22.8 ± 17.9 months). FEES detected a high dysphagia score in 5 patients with no difference between S and B phenotype. Lower esophageal sphincter pressure was normal in all patients. Esophageal dysmotility was observed in three S and two B onset patients. Upper esophageal sphincter (UES) pressure was higher in all ALS patients. UES spasms and delayed gastric emptying were detected in two B and one S and in two B and four S patients, respectively. There was no correlation between esophagogastric motor abnormalities and clinical characteristics of ALS, nor GI symptoms.

CONCLUSIONS: The presence of UES spasm and the delayed gastric emptying in a subgroup of ALS patients may suggest the role of ANS dysfunction in ALS.}, } @article {pmid39872677, year = {2025}, author = {Pulst, SM}, title = {Spinocerebellar Ataxia Type 2: A Review and Personal Perspective.}, journal = {Neurology. Genetics}, volume = {11}, number = {1}, pages = {e200225}, pmid = {39872677}, issn = {2376-7839}, support = {R35 NS127253/NS/NINDS NIH HHS/United States ; }, abstract = {Spinocerebellar ataxias (SCAs) are dominantly inherited diseases that lead to neurodegeneration in the cerebellum and other parts of the nervous system. This review examines the progress that has been made in SCA2 from its initial clinical description to discovery of DNA CAG-repeat expansions in the ATXN2 gene. ATXN2 repeat alleles cover the range from recessive and dominant mendelian alleles to risk alleles for amyotrophic lateral sclerosis. We review studies aimed at defining the normal function of ATXN2 and mutant ATXN2 using cellular and mouse models. Progress in testing small compounds and antisense oligonucleotides in preclinical studies is described as well including our recent focus on staufen-1 (STAU1) and mRNA metabolism and control of autophagy.}, } @article {pmid39872952, year = {2023}, author = {Wang, J and Zhou, XF and Wang, YJ}, title = {Continuous antioxidant drug exposure: a bridge from ideal world to real world of therapy for amyotrophic lateral sclerosis.}, journal = {Life medicine}, volume = {2}, number = {1}, pages = {lnac042}, pmid = {39872952}, issn = {2755-1733}, } @article {pmid39874287, year = {2025}, author = {Baek, Y and Kim, H and Lee, D and Kim, D and Jo, E and Roh, SH and Ha, NC}, title = {Structural insights into the role of reduced cysteine residues in SOD1 amyloid filament formation.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {5}, pages = {e2408582122}, pmid = {39874287}, issn = {1091-6490}, support = {RS-2021-IP321036//Ministry of Agriculture, Food and Rural Affairs (MAFRA)/ ; RS-2024-00344154//Ministry of Science and ICT, South Korea (MSIT)/ ; RS-2023-00245941//National Research Foundation of Korea (NRF)/ ; 2021M3A9I4021220//Ministry of Science and ICT, South Korea (MSIT)/ ; }, mesh = {*Superoxide Dismutase-1/chemistry/genetics/metabolism ; *Cysteine/chemistry/metabolism/genetics ; *Amyloid/chemistry/metabolism/genetics/ultrastructure ; Humans ; Amyotrophic Lateral Sclerosis/genetics ; Cryoelectron Microscopy ; Mutation ; }, abstract = {The formation of superoxide dismutase 1 (SOD1) filaments has been implicated in amyotrophic lateral sclerosis (ALS). Although the disulfide bond formed between Cys57 and Cys146 in the active state has been well studied, the role of the reduced cysteine residues, Cys6 and Cys111, in SOD1 filament formation remains unclear. In this study, we investigated the role of reduced cysteine residues by determining and comparing cryoelectron microscopy (cryo-EM) structures of wild-type (WT) and C6A/C111A SOD1 filaments under thiol-based reducing and metal-depriving conditions, starting with protein samples possessing enzymatic activity. The C6A/C111A mutant SOD1 formed filaments more rapidly than the WT protein. The mutant structure had a unique paired-protofilament arrangement, with a smaller filament core than that of the single-protofilament structure observed in WT SOD1. Although the single-protofilament form developed more slowly, cross-seeding experiments demonstrated the predominance of single-protofilament morphology over paired protofilaments, regardless of the presence of the Cys6 and Cys111 mutations. These findings highlight the importance of the number of amino acid residues within the filament core in determining the energy requirements for assembly. Our study provides insights into ALS pathogenesis by elucidating the initiation and propagation of filament formation, which potentially leads to deleterious amyloid filaments.}, } @article {pmid39875548, year = {2025}, author = {Rabhi, C and Babault, N and Martin, C and Desforges, B and Maucuer, A and Joshi, V and Pankivskyi, S and Feng, Y and Bollot, G and Rattenbach, R and Pastré, D and Bouhss, A}, title = {TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {136}, pmid = {39875548}, issn = {2399-3642}, support = {ANR-24-CE44-3867-01-SUFATOP//Agence Nationale de la Recherche (French National Research Agency)/ ; CIFRE Grant//Association Nationale de la Recherche et de la Technologie (National Association for Research and Technology)/ ; }, mesh = {Phosphorylation ; Humans ; *Cytoplasm/metabolism ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; *Cell Nucleus/metabolism ; RNA, Messenger/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), in which TDP-43, a nuclear RNA-binding protein, forms cytoplasmic inclusions. Here, we have developed a robust and automated method to assess protein self-assembly in the cytoplasm using microtubules as nanoplatforms. Importantly, we have analyzed specifically the self-assembly of full-length TDP-43 and its mRNA binding that are regulated by the phosphorylation of its self-adhesive C-terminus, which is the recipient of many pathological mutations. We show that C-terminus phosphorylation prevents the recruitment of TDP-43 in mRNA-rich stress granules only under acute stress conditions because of a low affinity for mRNA but not under mild stress conditions. In addition, the self-assembly of the C-terminus is negatively regulated by phosphorylation in the cytoplasm which in turn promotes TDP-43 nuclear import. We anticipate that reducing TDP-43 C-terminus self-assembly in the cytoplasm may be an interesting strategy to reverse TDP-43 nuclear depletion in neurodegenerative diseases.}, } @article {pmid39875596, year = {2025}, author = {Tomar, VR and Sharma, S and Siddhanta, S and Deep, S}, title = {Biophysical and spectroscopical insights into structural modulation of species in the aggregation pathway of superoxide dismutase 1.}, journal = {Communications chemistry}, volume = {8}, number = {1}, pages = {22}, pmid = {39875596}, issn = {2399-3669}, support = {CRG/2020/002091//DST | Science and Engineering Research Board (SERB)/ ; }, abstract = {Superoxide dismutase 1 (SOD1) aggregation is implicated in the development of Amyotrophic Lateral Sclerosis (ALS). Despite knowledge of the role of SOD1 aggregation, the mechanistic understanding remains elusive. Our investigation aimed to unravel the complex steps involved in SOD1 aggregation associated with ALS. Therefore, we probed the aggregation using ThT fluorescence, size-exclusion chromatography, and surface-enhanced Raman spectroscopy (SERS). The removal of metal ions and disulfide bonds resulted in the dimers rapidly first converting to an extended monomers then coming together slowly to form non-native dimers. The rapid onset of oligomerization happens above critical non-native dimer concentration. Structural features of oligomer was obtained through SERS. The kinetic data supported a fragmentation-dominant mechanism for the fibril formation. Quercetin acts as inhibitor by delaying the formation of non-native dimer and soluble oligomers by decreasing the elongation rate. Thus, results provide significant insights into the critical steps in oligomer formation and their structure.}, } @article {pmid39876814, year = {2025}, author = {Papadopoulou, M and Stefanou, MI and Fanouraki, S and Moschovos, C and Bakola, E and Salakou, S and Zouvelou, V and Papadimas, GK and Tsivgoulis, G}, title = {Motor neuron diseases are not exclusively motor; the SSR paradigm.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {399-408}, doi = {10.1080/21678421.2025.2458694}, pmid = {39876814}, issn = {2167-9223}, mesh = {Humans ; *Motor Neuron Disease/physiopathology/diagnosis/complications ; *Galvanic Skin Response/physiology ; *Autonomic Nervous System Diseases/diagnosis/physiopathology/etiology ; }, abstract = {Motor Neuron Diseases (MNDs), familial and sporadic, are progressive neurodegenerative disorders that, for an extended period in the past, were considered purely motor disorders. During the course of the disease, however, some patients exhibit concomitant non-motor signs; thus, MNDs are currently perceived as multisystem disorders. Assessment of non-motor symptoms is usually performed clinically, although laboratory tests can also be routinely used to objectively evaluate these symptoms. Sympathetic Skin Response (SSR) is an example of a neurophysiological test that has been used in cases of Amyotrophic Lateral Sclerosis, Spinal Muscular Atrophy, and Monomelic Atrophy, mostly to assess Autonomic Nervous System (ANS) disorders. Dysautonomia affects quality of life and life expectancy, as it is involved in cardiovascular events and incidents of sudden death. SSR abnormalities are present even in subclinical involvement of the ANS in MNDs. In this review, we present published research examining SSR findings in various MNDs, and discuss the correlation of SSR findings with clinical symptoms and disease severity, as well as the potential sources of abnormal findings. The aim of this study is to raise clinician awareness of autonomic dysfunction in MNDs and present the benefits of SSR examination in patient care.}, } @article {pmid39877010, year = {2024}, author = {Stavrovskaya, AV and Voronkov, DN and Pavlova, AK and Olshanskiy, AS and Belugin, BV and Ivanova, MV and Zakharova, MN and Illarioshkin, SN}, title = {Intraventricular Administration of Exosomes from Patients with Amyotrophic Lateral Sclerosis Provokes Motor Neuron Disease in Mice.}, journal = {Acta naturae}, volume = {16}, number = {4}, pages = {73-80}, pmid = {39877010}, issn = {2075-8251}, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe disease of the central nervous system (CNS) characterized by motor neuron damage leading to death from respiratory failure. The neurodegenerative process in ALS is characterized by an accumulation of aberrant proteins (TDP-43, SOD1, etc.) in CNS cells. The trans-synaptic transmission of these proteins via exosomes may be one of the mechanisms through which the pathology progresses. The aim of this work was to study the effect of an intraventricular injection of exosomes obtained from the cerebrospinal fluid (CSF) of ALS patients on the motor activity and CNS pathomorphology of mice. The exosomes were obtained from two ALS patients and a healthy donor. Exosome suspensions at high and low concentrations were injected into the lateral brain ventricles of male BALB/c mice (n = 45). Motor activity and physiological parameters were evaluated twice a month; morphological examination of the spinal cord was performed 14 months after the start of the experiment. Nine months after administration of exosomes from the ALS patients, the animals started exhibiting a pathological motor phenotype; i.e., altered locomotion with paresis of hind limbs, coordination impairment, and increasing episodes of immobility. The motor symptoms accelerated after administration of a higher concentration of exosomes. The experimental group showed a significant decrease in motor neuron density in the ventral horns of the spinal cord, a significant increase in the number of microglial cells, and microglia activation. The TDP43 protein in the control animals was localized in the nuclei of motor neurons. TDP43 mislocation with its accumulation in the cytoplasm was observed in the experimental group. Thus, the triggering effect of the exosomal proteins derived from the CSF of ALS patients in the development of a motor neuron pathology in the experimental animals was established. This confirms the pathogenetic role of exosomes in neurodegenerative progression and makes it possible to identify a new target for ALS therapy.}, } @article {pmid39877726, year = {2025}, author = {Fournier, CN and Levine, M and Simmons, K and García-Santibáñez, RC and Rowland, A and Quinn, CC and Ho, DT and Bedlack, RS and Glass, JD}, title = {ALS Motor Observational Telemedicine Objective Rasch-Built Assessment: A Quantitative Scale for the Era of Teleneurology.}, journal = {Neurology. Clinical practice}, volume = {15}, number = {2}, pages = {e200432}, pmid = {39877726}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: Telemedicine has become a mainstay of ALS clinical care, but there is currently no standardized approach for assessing and tracking changes to the neurologic examination in this format. The goal of this study was to create a standardized telemedicine-based motor examination scale to objectively and reliably track ALS progression and use Rasch methodology to validate the scale and improve its psychometric properties.

METHODS: A draft telemedicine examination scale with 25 items assessing movement in the bulbar muscles, neck, trunk, and extremities was created by an ALS expert panel, incorporating input from patient advisors. This prospective, observational study was approved by the Emory IRB, and participants provided informed consent. Adults with a diagnosis of ALS who were able to undergo a video telemedicine evaluation by an Emory clinician were eligible for participation. Rasch analyses were performed to determine the final item responses and optimize the scoring structure. Test-retest reliability was assessed in a subset of participants through 2 separate examinations by 2 different examiners within a 7-day period. Construct validity was assessed by calculating correlations with simultaneously administered Rasch-built Overall ALS Disability Scale (ROADS) and revised ALS Functional Rating Scale (ALSFRS-R).

RESULTS: The ALS Motor Observational Telemedicine Objective Rasch-built assessment was administered to a total of 258 PALS representing the full spectrum of a typical ALS clinic population. After performing Rasch analyses, 3 items were removed and item response categories were consolidated for 8 items. The final 22-item ALS MOTOR scale conformed to Rasch model criteria. The inter-rater reliability was 95%. The ALS MOTOR had a 0.78 (95% CI 0.72-0.83) correlation with ALSFRS-R and 0.81 (95% CI 0.76-0.85) correlation with ROADS.

DISCUSSION: The ALS MOTOR is a novel, accessible tool for remotely and objectively tracking ALS progression for both clinical care and research studies. Use of Rasch methodology for scale validation allowed for optimization of scale psychometric properties, which is particularly important when using the sum score as an overall outcome measure. Longitudinal and external validation studies are ongoing.}, } @article {pmid39879320, year = {2025}, author = {Guillot, SJ and Lang, C and Simonot, M and Beckett, D and Lulé, D and Balz, LT and Knehr, A and Stuart-Lopez, G and Vercruysse, P and Dieterlé, S and Weydt, P and Dorst, J and Kandler, K and Kassubek, J and Wassermann, L and Rouaux, C and Arthaud, S and Da Cruz, S and Luppi, PH and Roselli, F and Ludolph, AC and Dupuis, L and Bolborea, M}, title = {Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models.}, journal = {Science translational medicine}, volume = {17}, number = {783}, pages = {eadm7580}, doi = {10.1126/scitranslmed.adm7580}, pmid = {39879320}, issn = {1946-6242}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/drug therapy ; Disease Models, Animal ; Humans ; *Orexins/antagonists & inhibitors/metabolism ; Mice ; *Sleep/drug effects ; Male ; *Orexin Receptor Antagonists/therapeutic use/pharmacology ; Female ; Melanins/pharmacology/therapeutic use ; Pituitary Hormones/pharmacology/therapeutic use ; Hypothalamic Hormones/pharmacology/therapeutic use/administration & dosage ; Motor Neurons/pathology/drug effects ; Wakefulness/drug effects ; Mice, Transgenic ; Middle Aged ; *Sleep Wake Disorders/drug therapy/complications/physiopathology ; Polysomnography ; }, abstract = {Sleep alterations have been described in several neurodegenerative diseases yet are currently poorly characterized in amyotrophic lateral sclerosis (ALS). This study investigates sleep macroarchitecture and related hypothalamic signaling disruptions in ALS. Using polysomnography, we found that both patients with ALS as well as asymptomatic C9ORF72 and SOD1 mutation carriers exhibited increased wakefulness and reduced non-rapid eye movement sleep. Increased wakefulness correlated with diminished cognitive performance in both clinical cohorts. Similar changes in sleep macroarchitecture were observed in three ALS mouse models (Sod1[G86R], Fus[ΔNLS/+], and TDP43[Q331K]). A single oral administration of a dual-orexin receptor antagonist or intracerebroventricular delivery of melanin-concentrating hormone (MCH) through an osmotic pump over 15 days partially normalized sleep patterns in mouse models. MCH treatment did not extend the survival of Sod1[G86R] mice but did decrease the loss of lumbar motor neurons. These findings suggest MCH and orexin signaling as potential targets to treat sleep alterations that arise in early stages of the disease.}, } @article {pmid39879575, year = {2025}, author = {Jang, DG and Kind, AJ and Patterson, A and Pedde, M and Powell, WR and Feldman, EL and Goutman, SA}, title = {Impact of the Adverse Social Exposome on Survival in Individuals With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {104}, number = {4}, pages = {e213362}, pmid = {39879575}, issn = {1526-632X}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 AG070883/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/psychology ; Female ; Male ; Aged ; Retrospective Studies ; Middle Aged ; Aged, 80 and over ; *Exposome ; Michigan/epidemiology ; }, abstract = {BACKGROUND AND OBJECTIVES: An adverse social exposome negatively affects many diseases, but its association with amyotrophic lateral sclerosis (ALS) survival is unknown. This study examined the association between the social exposome measure Area Deprivation Index (ADI) and ALS survival.

METHODS: This is a retrospective analysis of patients with ALS at the University of Michigan Pranger ALS Clinic diagnosed after January 1, 2012. Extracted data included age, sex, race, residential address, disease characteristics, and survival. National ADI ranking was assigned to each patient's geocoded address. Accelerated failure time survival analysis determined association between the ADI group and survival with adjustment for clinicodemographic covariates.

RESULTS: 1,085 patients (median age at diagnosis, 72 years; 45% female) met inclusion criteria. The highest ADI decile (most disadvantaged neighborhood group) was associated with 37.0% shorter survival time (95% CI -50.4% to -20.1%). Results were similar when grouping patients by ADI ranking (as opposed to decile) or including only those with a classical ALS phenotype.

DISCUSSION: Exposure to adverse social exposome, as measured by ADI, associates with poorer ALS survival. Because this is a single-center study, replication in other cohorts is encouraged. Further research is needed to understand the underlying mechanisms, which could influence ALS clinical care.}, } @article {pmid39879721, year = {2025}, author = {Derevyanko, A and Tao, T and Allen, NJ}, title = {Common alterations to astrocytes across neurodegenerative disorders.}, journal = {Current opinion in neurobiology}, volume = {90}, number = {}, pages = {102970}, doi = {10.1016/j.conb.2025.102970}, pmid = {39879721}, issn = {1873-6882}, mesh = {Humans ; *Astrocytes/metabolism/pathology/immunology ; *Neurodegenerative Diseases/pathology/metabolism/immunology ; Animals ; *Brain/pathology/metabolism ; }, abstract = {Astrocytes perform multiple functions in the nervous system, many of which are altered in neurodegenerative disorders. In this review, we explore shared astrocytic alterations across neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobe degeneration. Assessing recent datasets of single-nucleus RNA-sequencing of human brains, a theme emerges of common alterations in astrocyte state across disorders including in neuroinflammation, synaptic organization, metabolic support, and the cellular stress response. Immune pathways are upregulated by astrocytes across disorders and may exacerbate neurodegeneration. Dysregulated expression of synaptogenic factors could contribute to synaptic loss, while compromised metabolic support affects neuronal homeostasis. On the other hand, upregulated responses to cellular stress may represent a protective response of astrocytes and thus mitigate pathology. Understanding these shared responses offers insights into disease progression and provides potential therapeutic targets for various neurodegenerative disorders.}, } @article {pmid39880202, year = {2025}, author = {Xu, F and Liu, H and Yin, Z and Xing, X and Chen, X}, title = {Associations of dietary factors with amyotrophic lateral sclerosis: A Mendelian randomization study.}, journal = {Clinical nutrition ESPEN}, volume = {66}, number = {}, pages = {226-235}, doi = {10.1016/j.clnesp.2025.01.042}, pmid = {39880202}, issn = {2405-4577}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/prevention & control/epidemiology ; Humans ; *Mendelian Randomization Analysis ; *Diet ; Genome-Wide Association Study ; Fruit ; Vegetables ; Risk Factors ; *Feeding Behavior ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: An inconsistent yet notable relationship between dietary habits and the risk of amyotrophic lateral sclerosis (ALS) has been previously established, with the causative nature of this relationship remaining uncertain. This study aims to explore the causal connections at a genetic level.

METHODS: A two-sample Mendelian Randomization (MR) based analysis was conducted utilizing a comprehensive, publicly assessable Genome-wide association study (GWAS) database. Fourteen dietary variables were examined as potential exposure factors, and the ALS outcome data was statistically analyzed. The inverse-variance weighted (IVW) approach was used as the primary analytical method, supplemented by sensitivity analyses to assess the reliability of our findings.

RESULTS: Our analysis identified significant protective effects against ALS from increased intake of water (fixed-effects IVW: OR = 0.700, 95 % CI: 0.524-0.935, P = 0.016), fresh fruit (random-effects IVW: OR = 0.561, 95 % CI: 0.361-0.871, P = 0.010), and cooked vegetable (fixed-effects IVW: OR = 0.200, 95 % CI: 0.090-0.445, P = 0.000). No significant associations were found for the other 11 dietary factors examined.

CONCLUSION: The study highlights the protective association of cooked vegetables and fresh fruit intake with ALS risk reduction. Additionally, an intriguing association between water intake and ALS was observed, warranting further investigation to elucidate the underlying mechanisms.}, } @article {pmid39880289, year = {2025}, author = {Chen, SJ and Li, QY and Zhou, J and Wu, Q and Zhang, Y and Zhang, QQ and Hu, H and Xu, XQ and Wu, FY and Niu, Q}, title = {Differed brain spontaneous neural activity between limb-onset and bulbar-onset amyotrophic lateral sclerosis patients.}, journal = {Brain research bulletin}, volume = {221}, number = {}, pages = {111229}, doi = {10.1016/j.brainresbull.2025.111229}, pmid = {39880289}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; Middle Aged ; Magnetic Resonance Imaging/methods ; *Brain/physiopathology/diagnostic imaging ; Aged ; Adult ; Brain Mapping/methods ; Support Vector Machine ; }, abstract = {PURPOSE: To investigate the differences in brain spontaneous neural activity between limb-onset and bulbar-onset amyotrophic lateral sclerosis (ALS-L and ALS-B, respectively) patients using resting-state functional MRI (rs-fMRI) with amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo).

MATERIALS AND METHODS: The rs-fMRI data were collected from 41 ALS patients (11 ALS-B and 30 ALS-L) and 25 healthy controls (HC). ALFF and ReHo values were calculated, and group differences were assessed using one-way ANCOVA and two-sample t-tests. Correlation analyses with clinical measures were conducted. Support vector machine (SVM) analysis was performed to distinguish ALS subtypes.

RESULTS: Compared with ALS-L, ALS-B showed increased ALFF values in the right gyrus rectus/ orbital part of right middle frontal gyrus, orbital part of left middle frontal gyrus and left dorsolateral superior frontal gyrus/ left medial superior frontal gyrus and decreased ALFF values in the left superior occipital gyrus (FDR-corrected, P < 0.05). Both ALS subtypes demonstrated distinct ALFF alterations compared to HC. Differences in ReHo values were only found between ALS-B and HC. Correlation analyses revealed associations between ALFF in specific brain regions and ALS clinical scores. SVM analysis achieved an accuracy of 90.2 %, with an AUC of 0.909 in differentiating ALS-B and ALS-L.

CONCLUSION: ALS-B and ALS-L patients had distinct alterations in brain spontaneous neural activity, which could serve as potential biomarkers for accurately distinguishing these two subtypes. Our findings offer a new insight into the neural mechanism of ALS, underscoring the importance of personalized diagnostic approaches for this complex neurological disorder.}, } @article {pmid39880333, year = {2025}, author = {Izrael, M and Chebath, J and Molakandov, K and Revel, M}, title = {Clinical perspective on pluripotent stem cells derived cell therapies for the treatment of neurodegenerative diseases.}, journal = {Advanced drug delivery reviews}, volume = {218}, number = {}, pages = {115525}, doi = {10.1016/j.addr.2025.115525}, pmid = {39880333}, issn = {1872-8294}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Pluripotent Stem Cells/transplantation/cytology ; Animals ; *Cell- and Tissue-Based Therapy/methods ; *Stem Cell Transplantation/methods ; Clinical Trials as Topic ; }, abstract = {Self-renewal capacity and potential to differentiate into almost any cell type of the human body makes pluripotent stem cells a valuable starting material for manufacturing of clinical grade cell therapies. Neurodegenerative diseases are characterized by gradual loss of structure or function of neurons, often leading to neuronal death. This results in gradual decline of cognitive, motor, and physiological functions due to the degeneration of the central nervous systems. Over the past two decades, comprehensive preclinical efficacy (proof-of-concept) and safety studies have led to the initiation of First-in-Human phase I-II clinical trials for a range of neurodegenerative diseases. In this review, we explore the fundamentals and challenges of neural-cell therapies derived from pluripotent stem cells for treating neurodegenerative diseases. Additionally, we highlight key preclinical investigations that paved the way for regulatory approvals of these trials. Furthermore, we provide an overview on progress and status of clinical trials done so far in treating neurodegenerative diseases such as spinal cord injury (SCI), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), as well as advances in retina diseases such as Stargardt disease (a.k.a fundus flavimaculatus), retinitis pigmentosa (RP) and age-related macular degeneration (AMD). These trials will pave the way for the development of new cell-based therapies targeting additional neurological conditions, including Alzheimer's disease and epilepsy.}, } @article {pmid39880678, year = {2025}, author = {Kozlowski, MM and Strickland, A and Benitez, AM and Schmidt, RE and Bloom, AJ and Milbrandt, J and DiAntonio, A}, title = {Pmp2+ Schwann Cells Maintain the Survival of Large-Caliber Motor Axons.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {45}, number = {13}, pages = {}, pmid = {39880678}, issn = {1529-2401}, support = {R01 NS105645/NS/NINDS NIH HHS/United States ; R37 NS065053/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Schwann Cells/metabolism/physiology/ultrastructure ; Mice ; *Axons/physiology/ultrastructure/metabolism ; Female ; Male ; *Motor Neurons/physiology/ultrastructure/metabolism ; Cell Survival/physiology ; Mice, Transgenic ; *Myelin Proteins/metabolism/genetics ; Mice, Inbred C57BL ; Tamoxifen/pharmacology ; }, abstract = {Neurodegenerative diseases of both the central and peripheral nervous system are characterized by selective neuronal vulnerability, i.e., pathology that affects particular types of neurons. While much of this cell type selectivity may be driven by intrinsic differences among the neuron subpopulations, neuron-extrinsic mechanisms such as the selective malfunction of glial support cells may also play a role. Recently, we identified a population of Schwann cells (SCs) expressing Adamtsl1, Cldn14, and Pmp2 (a.k.a. PMP2+ SCs) that preferentially myelinate large-caliber motor axons. PMP2+ SCs are decreased in both amyotrophic lateral sclerosis (ALS) model mice and ALS patient nerves. Thus, PMP2+ SC dysfunction could contribute to motor-selective neuropathies. We engineered a tamoxifen-inducible Pmp2-CreERT2 mouse and expressed diphtheria toxin in PMP2+ SCs to assess the consequences of ablating this SC subtype in male and female mice. Loss of PMP2+ SCs led to significant loss of large-caliber motor axons with concomitant behavioral, electrophysiological, and ultrastructural defects. Subsequent withdrawal of tamoxifen restored both PMP2+ SCs and large-caliber motor axons and improved behavioral and electrophysiological readouts. Together, our findings highlight that the survival of large-caliber motor axons relies on PMP2+ SCs, demonstrating that malfunction of a specific SC subtype can lead to selective neuronal vulnerability.}, } @article {pmid39881481, year = {2025}, author = {Steenland, K and Tan, Y and Mullins, SM and Kidd, TE and Gong, Q and Lah, JJ}, title = {Survival of Patients at a Neurology Clinic: No Improvement Over 12 Years.}, journal = {Alzheimer disease and associated disorders}, volume = {39}, number = {1}, pages = {28-32}, doi = {10.1097/WAD.0000000000000658}, pmid = {39881481}, issn = {1546-4156}, mesh = {Humans ; Female ; Male ; Aged ; *Neurodegenerative Diseases/mortality ; Middle Aged ; Neurology ; Aged, 80 and over ; Dementia/mortality ; Neuropsychological Tests ; Cognitive Dysfunction/mortality ; }, abstract = {INTRODUCTION: We previously followed Emory patients with neurodegenerative disease from 1993 to 2006. Here, we follow survivor and new patients for 2007 to 2018.

METHODS: We studied mortality from 10 different diagnostic groups among 4322 research volunteers, and compared mortality rates to controls with normal cognition, using Cox regression. We assessed mortality through the National Death Index, controlling for sex, education, race, comorbidities, and age. Supplemental analyses considered APOE and cognitive test scores.

RESULTS: Fifty-nine percent of patients died during follow-up. Mortality rate ratios, compared with controls (n=641) in descending order were 12.54, 6.61, 4.77, 4.92, 3.36, 2.25, 2.21 1.71, 1.39, and 1.17 for diagnostic groups ALS, (n=571), FTD (n=197), LBD (n=134), PD (n=584), AD (n=1118), MCI/dementia (n=82), dementia not specified (n=165), PD symptoms (n=256), vascular dementia (n=234), and MCI (n=340), respectively. Women, non-whites, those with higher education, with no comorbidities, and lower ages had lower mortality rates for most diagnostic groups. Mortality rates were higher in the presence of APOE4 variants for several diagnostic groups. Lower MMSEs predicted worse survival for most diseases. Overall, 41% of patients survived during 12 years of follow-up, compared with an expected 75% in the US population.

CONCLUSION: Survival times for different diagnostic groups have changed little over several decades.}, } @article {pmid39882298, year = {2024}, author = {Johnsen, JT and Rafaela Lima do Vale, M and Bhangaonkar, R and Nyaga, W and Ayyad, S and Ray, S}, title = {COVID-19's impact on food environment in the Indian states of Telangana, Maharashtra, West Bengal, Tamil Nadu and Punjab: a descriptive qualitative study to build further research in India's food environment resilience building.}, journal = {BMJ nutrition, prevention & health}, volume = {7}, number = {2}, pages = {e000844}, pmid = {39882298}, issn = {2516-5542}, abstract = {BACKGROUND AND AIM: Globally, COVID-19 has had a profound impact on food and nutrition security. This paper aims to gather the perspective from Transforming India's Green Revolution by Research and Empowerment for Sustainable food Supplies (TIGR2ESS) Flagship Project 6 (FP-6) team on the impact of COVID-19 on the food systems in India. The responses collected will be used for further research projects after TIGR2ESS ends in March 2022.

METHOD: Members of the TIGR2ESS FP-6 team in India were invited to complete an online open-ended questionnaire with 21 questions exploring the impact of the COVID-19 pandemic on food systems and environments in India. The questionnaire and data analysis were guided by the food environment framework developed by Turner et al and the adaptations proposed by the United Nations System Standing Committee on Nutrition. Discussions and organisation of codes under the respective themes and subthemes were held online using the virtual platform Miro. 35 individual codes and 65 subcodes were agreed on. Responses were collated and analysed using the template with support from NVivo software and synthesised the relevant themes under Turner et al's framework.

RESULTS: The organisation representatives from TIGR2ESS FP-6 (n=16) captured the perceived impact of the COVID-19 on food systems and the environment from the Indian states of Maharashtra, Punjab, Tamil Nadu, Telangana and West Bengal. Negative disruptions were caused by the COVID-19 restrictions across all the themes affecting food actors and consumers. Myths and misconception on dietary intake were reported across the state affecting especially the consumption of poultry. Positive aspects such as home cooking and awareness around healthy food emerged.

CONCLUSION: Potential research areas were identified and involve the effects of supply chain resilience buidling, farmers selling their produce directly to consumer and the revival of local and traditional food's impact on diets, understanding the harm for consumers by implementing restrictions, how indigenous and local food may impact peoples' diets, how to build on the encouragement of healthy home cooking during the pandemic, investigate the negative and positive effects of digital environments during the pandemic and dispelling myths and misconception while advocating for healthy diets.}, } @article {pmid39882923, year = {2025}, author = {Koltsova, E and Smotraiev, R and Nehrii, A and Zhekeev, M and Ratnaweera, H}, title = {Mechanisms for removing phosphorus species through sequential coagulation using inorganic coagulants and organic polymers.}, journal = {Water science and technology : a journal of the International Association on Water Pollution Research}, volume = {91}, number = {2}, pages = {202-218}, pmid = {39882923}, issn = {0273-1223}, mesh = {*Phosphorus/chemistry/isolation & purification ; *Polymers/chemistry ; *Water Pollutants, Chemical/chemistry/isolation & purification ; Alum Compounds/chemistry ; *Waste Disposal, Fluid/methods ; *Water Purification/methods ; Flocculation ; Phosphates/chemistry ; }, abstract = {The need for stringent phosphorus removal from domestic wastewater is increasing to mitigate eutrophication, while efficient phosphate reuse is critical due to the global phosphate crisis. Combining aluminum sulfate (ALS) with high molecular weight organic polymers achieved 95-99% removal of particles, turbidity, and phosphates, reducing ALS usage by 40%. We propose mechanisms to explain the enhanced treatment efficiency. Particle and turbidity removal is more influenced by polymer charge density than molecular weight, while orthophosphate (OP) removal is linked to a change in zeta potential from negative to positive, allowing additional OP binding through complex formation with hydrolysis products and polymers. Enhanced phospholipid (PL) removal likely results from adsorption and neutralization of micelle PL charges by intermediate positively charged aluminum hydroxyphosphate ions. Higher PL removal with low ALS doses is attributed to a two-stage dosing process that optimizes coagulant and polymer dosages. The combined removal of OP and PL improves phosphorus bioavailability, increasing the sludge's fertilizer value.}, } @article {pmid39883903, year = {2025}, author = {Fournier, CN and Quinn, CC}, title = {The Amyotrophic Lateral Sclerosis Multidisciplinary Clinic: Broke but Not Broken.}, journal = {Neurology}, volume = {104}, number = {4}, pages = {e210189}, doi = {10.1212/WNL.0000000000210189}, pmid = {39883903}, issn = {1526-632X}, } @article {pmid39883905, year = {2025}, author = {Hollin, IL and Giler, G and Heiman-Patterson, TD and , }, title = {Health Care Delivery and Financial Considerations in Amyotrophic Lateral Sclerosis Clinics: A Survey of Clinic Directors.}, journal = {Neurology}, volume = {104}, number = {4}, pages = {e210015}, pmid = {39883905}, issn = {1526-632X}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/economics ; Humans ; *Delivery of Health Care/economics ; Surveys and Questionnaires ; United States ; *Ambulatory Care Facilities/economics ; }, abstract = {BACKGROUND AND OBJECTIVES: Clinical care for people living with amyotrophic lateral sclerosis (PLWALS) is directed at slowing disease progression and symptom management. The American Academy of Neurology recommends a multidisciplinary approach to providing ALS health care because observational studies show that multidisciplinary clinics (MDCs) extend survival and improve quality of life. However, providing multidisciplinary care is a challenging financial proposition. To understand how MDCs are financed, we surveyed ALS MDCs across the Northeast ALS Consortium network in the United States.

METHODS: We surveyed clinic directors in the Northeast ALS Consortium, a group of institutions equipped to provide ALS care and perform research and clinical trials in ALS. Respondents (n = 61; response rate = 49.6%) provided information regarding their care model, services, funding sources, and financial solvency between December 2020 and August 2021.

RESULTS: In 74% (n = 45) of clinics, PLWALS were seen by the entire multidisciplinary team, and in 26% (n = 16) of clinics, PLWALS were seen by the physician and triaged according to needs. In 79% (n = 48) of clinics, visit duration was ≥3 hours, and on average, 8.4 services were available, compared with 6.8 in clinics lasting <3 hours. Most of the MDCs offer occupational (97%; n = 59), speech (97%; n = 59), and physical (95%; n = 58) therapies on site. The most common source of financial support was third-party nonprofits/philanthropy (92%; n = 56). Fifty-nine percent (n = 36) of clinics received financial support from their parent organizations (e.g., universities). Only 17% (n = 10) of clinics reported no deficit, and all clinics used multiple income sources.

DISCUSSION: These findings reconfirm the range of services available to PLWALS and highlight the financial challenges facing ALS MDCs. The main limitation is that recruitment was through the NEALS network which primarily includes MDCs, so we were not able to compare with non-MDCs. Since not all centers responded, there may be other differences in the characteristics of the centers that did respond and those that did not leading to some bias. Future work should support the goal of reducing reliance on funding from nonprofits and increase reimbursement from payers, so health care providers can provide high-quality ALS care and cover costs.}, } @article {pmid39884579, year = {2025}, author = {Liu, WW and Wei, JC}, title = {Response to Vera et al's "Interleukin-23 inhibition associates with lower incidence of cardiovascular risk factor type diseases compared to biologic naïve patients with psoriasis: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {5}, pages = {e157-e158}, doi = {10.1016/j.jaad.2024.12.044}, pmid = {39884579}, issn = {1097-6787}, } @article {pmid39884586, year = {2025}, author = {Ye, L and Dittlau, KS and Sicart, A and Janky, R and Van Damme, P and Van Den Bosch, L}, title = {Sporadic ALS hiPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways.}, journal = {Neurobiology of disease}, volume = {206}, number = {}, pages = {106815}, doi = {10.1016/j.nbd.2025.106815}, pmid = {39884586}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Induced Pluripotent Stem Cells/pathology/metabolism ; *Motor Neurons/pathology/metabolism ; *Axon Guidance/physiology ; *Axons/pathology/metabolism ; Axonal Transport/physiology ; Female ; Male ; Neuromuscular Junction/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and progressive loss of motor neurons, leading to gradual paralysis and death within 2 to 5 years after diagnosis. The exact underlying pathogenic mechanism(s) remain elusive. This is particularly the case for sporadic ALS (sALS), representing 90 % of cases, as modelling a sporadic disease is extremely difficult. We used human induced pluripotent stem cell (hiPSC)-derived motor neurons from sALS patients to investigate early disease mechanisms. The earliest phenotype that we observed were profound axonal defects including impaired axonal transport, defective axonal outgrowth and a reduced formation of neuromuscular junctions. Transcriptomic profiling revealed significant dysregulation in axon guidance pathways, with upregulation of specific axonal regeneration-inhibiting genes, such as EphA4 and DCC in sALS motor neurons. Our findings suggest that dysregulation of axon guidance pathways contributes to axonal defects and that this could play a crucial role in the pathogenesis of sALS.}, } @article {pmid39885728, year = {2025}, author = {Gondim, F and Fernandes, JMA}, title = {Another family with ALS and homozygosity for p.Val120Leu (c.358G > C) mutation of SOD1.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {597-598}, doi = {10.1080/21678421.2025.2457973}, pmid = {39885728}, issn = {2167-9223}, } @article {pmid39885830, year = {2025}, author = {Marthinsen, A and Gaweł, BA and Warden, GK and Górska-Ratusznik, A and Gaweł, K and Di Sabatino, M and Hallam, B}, title = {Al doped silica glass: investigation of structural response and defect interactions based on crystalline models.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {27}, number = {7}, pages = {3803-3809}, doi = {10.1039/d4cp04581e}, pmid = {39885830}, issn = {1463-9084}, abstract = {High purity quartz glass is an important material in high-tech industries like semiconductors and photovoltaics due to, among other properties, its good mechanical performance at high temperatures. Small amounts of Al in silica glass (in the range between 20 ppm and 100 ppm) have previously been shown to increase the viscosity of the SiO2 glass. The underlying mechanism for this increase is, however, not well understood. In this paper we report on the local structural and electronic effects of the presence of Al in the SiO2 structure by density functional theory (DFT). Comparing the quartz and cristobalite polymorphs, we found that the driving force for Al substitution is larger in the denser quartz structure compared to cristobalite, and that oxygen vacancy (Vo) formation is most stabilized in the nearest neighbour position relative to Al in both polymorphs. Al was not found to inherently strengthen the SiO2 network in the two crystalline polymorphs considered. However, our results suggest that Al preferentially substitutes Si in denser ring configurations, which combined with local Vo formation could lead to locally favourable SiO2 network reconstructions in SiO2 glasses (likely towards 6-membered rings), which could propagate causing an increase in the viscosity. Furthermore, we show that the presence of Al can lower the stability of OH groups due to increased electrostatic interactions between the substitutional Al and H2O which may also be a contributing factor in the increased viscosity of Al doped SiO2 glass. The modelling results are in line with the experimental fluorescence and FT-IR spectroscopy data confirming that the presence of Al in the glass causes formation of oxygen vacancies and correlates with a lower fictive temperature which typically corresponds to a larger average Si-O-Si angle in the glass structure. Our results suggest that Al's contribution to high glass viscosity is not solely due to the substitution of Si atoms by Al atoms in the glass structure but rather due to structural changes of the silica network the substitution causes.}, } @article {pmid39886777, year = {2025}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Farkhad, NK and Khodadoust, MA and Ganjali, R and Tavakol-Afshari, J}, title = {WITHDRAWN: Evaluation of Safety and Efficacy of Repeated Mesenchymal Stem Cell Transplantation in Patients with Amyotrophic Lateral Sclerosis (ALS) by Investigating Patient’s Specific microRNAs as Novel Biomarkers: A Clinical Trial Study.}, journal = {Current stem cell research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.2174/011574888X330199250106081717}, pmid = {39886777}, issn = {2212-3946}, abstract = {UNLABELLED: Since the authors are not responding to the editor’s requests to fulfill the editorial requirement, therefore, the article has been withdrawn from the journal Current Stem Cell Research & Therapy. The Publisher apologizes to the readers of the journal for any inconvenience this may have caused. The Bentham editorial policy on article withdrawal can be found at https://benthamscience.com/pages/editorial-policies-main

BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.}, } @article {pmid39887552, year = {2025}, author = {Dopler, MB and Abeer, MI and Arezoumandan, S and Cox, K and Petersen, TL and Daniel, EH and Cannon, CL and Bautista, A and Blancher, KD and Bland, AM and Bond, KJ and Davis, DA and Francois, JM and McCray, EJ and Morgan, JM and Pulliam, JL and Robinson, ZA and Taylor, MJ and Dowell, JA and Cairns, NJ and Gitcho, MA}, title = {A cellular model of TDP-43 induces phosphorylated TDP-43 aggregation with distinct changes in solubility and autophagy dysregulation.}, journal = {The FEBS journal}, volume = {292}, number = {18}, pages = {4870-4897}, pmid = {39887552}, issn = {1742-4658}, support = {52008702//HHMI/ ; T32 GM144895/GM/NIGMS NIH HHS/United States ; 2023004//National Science Foundation/ ; P30 GM145765/GM/NIGMS NIH HHS/United States ; P20GM103446/GM/NIGMS NIH HHS/United States ; P20 GM103446/GM/NIGMS NIH HHS/United States ; 0823//The Paul H. Boerger Fund of the Delaware Community Foundation/ ; R25 NS095371/NS/NINDS NIH HHS/United States ; P20 GM103653/GM/NIGMS NIH HHS/United States ; R25 GM122722/GM/NIGMS NIH HHS/United States ; P20GM103653/GM/NIGMS NIH HHS/United States ; T32GM144895-03/GM/NIGMS NIH HHS/United States ; }, mesh = {*Autophagy ; Solubility ; *DNA-Binding Proteins/genetics/metabolism ; Cell Line ; Humans ; Cytoplasm/metabolism ; Cell Nucleus/metabolism ; Mutation ; Glycolysis ; Phosphorylation ; alpha Karyopherins/genetics/metabolism ; HSP70 Heat-Shock Proteins/genetics/metabolism ; Protein Disulfide-Isomerases/genetics/metabolism ; Proteomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that affects neurons in the brain and spinal cord, causing loss of muscle control, and eventually leads to death. Phosphorylated transactive response DNA binding protein-43 (TDP-43) is the major pathological protein in both sporadic and familial ALS, forming cytoplasmic aggregates in over 95% of cases. Of the 10-15% of ALS cases that are familial, mutations in TDP-43 represent about 5% of those with a family history. We have developed an in vitro overexpression model by introducing three familial ALS mutations (A315T, M337V, and S379P) in the TDP-43 (TARDBP) gene which we define as 3X-TDP-43. This overexpression model TDP-43 shows deficits in autophagy flux and colocalization of TDP-43 with stress granules. We also observe a progressive shift of TDP-43 to the cytoplasm in this model. This overexpression model shows a reduction in solubility of phosphorylated TDP-43 from RIPA to urea soluble. Four glycolytic enzymes, phosphoglycerate kinase one (PGK1), aldolase A (ALDOA), enolase 1 (ENO1), and pyruvate dehydrogenase kinase 1 (PDK1) show significant time-dependent decreases in 3X-TDP-43 expressing cells. Shotgun proteomic analysis shows global changes in the importin subunit alpha-1 (KPNA2), heat shock 70 kDa protein 1A (HSPA1A), and protein disulfide-isomerase A3 (PDIA3) expression levels and coimmunoprecipitation reveals that these proteins complex with TDP-43. Overall, these results suggest that the 3X-TDP-43 model may provide new insights into pathophysiology and an avenue for drug screening in vitro for those suffering from ALS and related TDP-43 proteinopathies.}, } @article {pmid39889424, year = {2025}, author = {Pascual, A and May, PB and Cárdenas-Martínez, A and Guerra-Hernández, J and Hunka, N and Bruening, JM and Healey, SP and Armston, JD and Dubayah, RO}, title = {Calibration of GEDI footprint aboveground biomass models in Mediterranean forests with NFI plots: A comparison of approaches.}, journal = {Journal of environmental management}, volume = {375}, number = {}, pages = {124313}, doi = {10.1016/j.jenvman.2025.124313}, pmid = {39889424}, issn = {1095-8630}, mesh = {*Biomass ; *Forests ; Calibration ; Ecosystem ; Spain ; Models, Theoretical ; }, abstract = {Observations from the NASA Global Ecosystem Dynamics Investigation (GEDI) provide global information on forest structure and biomass. Footprint-level predictions of aboveground biomass density (AGBD) in the GEDI mission are based on training data sourced from sparsely distributed field plots coincident with airborne laser scanning surveys. National Forest Inventories (NFI) are rarely used to calibrate GEDI footprint biomass models because their sampling and positional accuracy prevent accurate colocation with GEDI or ALS. This omission can limit the harmonization of jurisdictional biomass estimates from NFI's and GEDI; however, there are methods available to improve the colocation of NFI plots with GEDI footprints. Focusing on Mediterranean forests in Spain, we compared different approaches to the collocation of NFI and GEDI data: (i) simulated waveforms from ALS; (ii) nearest-neighbor on-orbit GEDI waveforms; and (iii) imputed GEDI waveforms imputed to NFI plot locations using a novel geostatistical method. These methods are potential solutions to improve the local performance of biomass models and address potential local systematic deviations between GEDI and NFI estimates. We assess the advantages and limitations of these methods to locally calibrate GEDI biomass models and quantify the impact of geolocation errors in reference NFI plot data. The new biomass models from each method were used to predict footprint level AGBD, which were then gridded for a province in the North-West of Spain. It was found that the imputation approach is not sensitive to common errors in NFI plot geolocation, but it can outperform ALS-based simulation in some cases, highlighting the benefit of information from multiple GEDI footprints proximate to NFI plots for improving biomass predictions. This research provides users with benchmark of available techniques to locally-calibrate GEDI footprint biomass models.}, } @article {pmid39889542, year = {2025}, author = {Albrecht, F and Kvist, A and Franzén, E}, title = {Resting-state functional near-infrared spectroscopy in neurodegenerative diseases - A systematic review.}, journal = {NeuroImage. Clinical}, volume = {45}, number = {}, pages = {103733}, pmid = {39889542}, issn = {2213-1582}, mesh = {Humans ; Spectroscopy, Near-Infrared/methods ; *Neurodegenerative Diseases/diagnostic imaging/physiopathology ; *Brain/diagnostic imaging/physiopathology ; Rest/physiology ; *Functional Neuroimaging/methods ; }, abstract = {OBJECTIVE: To systematically review and summarize alterations found in resting-state activity as measured via functional near-infrared spectroscopy (fNIRS) in neurodegenerative diseases.

BACKGROUND: fNIRS is a novel and emerging neuroimaging method suitable for a variety of study designs. Resting-state is the measure of brain activity in the absence of a task, which has been investigated for yielding information about neurodegenerative diseases, mainly using magnetic resonance imaging. We aimed to systematically review the usage of resting-state fNIRS (rsfNIRS) in neurodegenerative diseases.

INCLUSION CRITERIA: Studies investigating people diagnosed with a neurodegenerative disease and resting-state activity obtained with fNIRS using at least two channels.

METHODS: We searched three databases for publications. After the screening, 16 studies were included in the systematic review. The quality of the studies was assessed, and data were extracted. Data were qualitatively synthesized and in the case of at least 10 similar studies, a meta-analysis was planned.

RESULTS: Most studies investigated Mild cognitive impairment (50%), followed by Alzheimer's disease (25%). Other neurodegenerative diseases encompassed Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis. All studies reported oxygenated hemoglobin. Still, studies were heterogeneous in terms of study design, measurement duration, fNIRS device, montage, pre-processing, and analyses. A meta-analysis was not considered possible due to this heterogeneity.

CONCLUSION: rsfNIRS shows promise in neurodegenerative disease, as most studies have observed resting-state alterations when compared to healthy controls. However, inconsistencies across studies limit data comparison and meta-analysis. Hence, we strongly advocate the application of fNIRS reporting guidelines and the establishment of rsfNIRS-specific guidelines. This will ensure reliable and comparable results in future research.}, } @article {pmid39889925, year = {2025}, author = {Bian, Y and Fukui, Y and Ota-Elliott, RS and Hu, X and Sun, H and Bian, Z and Zhai, Y and Yu, H and Hu, X and An, H and Liu, H and Morihara, R and Ishiura, H and Yamashita, T}, title = {The potential mechanism maintaining transactive response DNA binding protein 43 kDa in the mouse stroke model.}, journal = {Neuroscience research}, volume = {213}, number = {}, pages = {128-137}, doi = {10.1016/j.neures.2025.01.006}, pmid = {39889925}, issn = {1872-8111}, mesh = {Animals ; Male ; Mice, Inbred C57BL ; *DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Histone Deacetylase 6/metabolism ; Mice ; Infarction, Middle Cerebral Artery/metabolism/pathology ; *Stroke/metabolism/pathology ; *Brain/metabolism/pathology ; DNA Helicases/metabolism ; RNA Recognition Motif Proteins/metabolism ; }, abstract = {The disruption of transactive response DNA binding protein 43 kDa (TDP-43) shuttling leads to the depletion of nuclear localization and the cytoplasmic accumulation of TDP-43. We aimed to evaluate the mechanism underlying the behavior of TDP-43 in ischemic stroke. Adult male C57BL/6 J mice were subjected to 30 or 60 min of transient middle cerebral artery occlusion (tMCAO), and examined at 1, 6, and 24 h post reperfusion. Immunostaining was used to evaluate the expression of TDP-43, G3BP1, HDAC6, and RAD23B. The total and cytoplasmic number of TDP-43-positive cells increased compared with sham operation group and peaked at 6 h post reperfusion after tMCAO. The elevated expression of G3BP1 protein peaked at 6 h after reperfusion and decreased at 24 h after reperfusion in ischemic mice brains. We also observed an increase of expression level of HDAC6 and the number of RAD23B-positive cells increased after tMCAO. RAD23B was colocalized with TDP-43 24 h after tMCAO. We proposed that the formation of stress granules might be involved in the mislocalization of TDP-43, based on an evaluation of G3BP1 and HDAC6. Subsequently, RAD23B, may also contribute to the downstream degradation of mislocalized TDP-43 in mice tMCAO model.}, } @article {pmid39891231, year = {2025}, author = {Rakab, MS and Zaid, AB and Hamadein, MA and Hamadein, SA and Ashour, MAE and El-Shamia, AS and Mostafa, DA and Rateb, RM and Elashry, MA and El-Badawy, MM and Shaheen, RSB}, title = {Assessment of ABCDE approach knowledge among residents and interns in multiple Egyptian hospitals, a cross-sectional study.}, journal = {BMC medical education}, volume = {25}, number = {1}, pages = {164}, pmid = {39891231}, issn = {1472-6920}, mesh = {Humans ; *Internship and Residency ; Egypt ; Cross-Sectional Studies ; Male ; Female ; Adult ; *Clinical Competence ; Surveys and Questionnaires ; *Health Knowledge, Attitudes, Practice ; }, abstract = {BACKGROUND: The Airway, Breathing, Circulation, Disability, and Exposure (ABCDE) approach is crucial in emergency care, but there may be variability in adherence among healthcare professionals. Inconsistent application of this approach may lead to variations in patient care quality and outcomes. Identifying the factors influencing adherence can help improve training to ensure more effective application across emergency settings. This study explores the theoretical knowledge of the ABCDE approach among Egyptian resident doctors and medical interns.

METHODS: An online survey was conducted in Egypt targeting resident doctors and medical interns. Statistical analyses were performed using SPSS 26 and Excel, descriptive statistics and association tests were used to measure the relationship between knowledge and demographic factors.

RESULTS: The study included 422 medical residents and interns, with most in university hospitals. The average knowledge score of 59.1% exposed specific gaps in understanding, emphasizing deficiencies in 12 questions answered by less than 50%. Notably, 49.5% acquired ABCDE knowledge from medical school, while 28.2% had ALS/BLS courses. Encouragingly, 91.2% expressed willingness for life support training. Statistical analyses unveiled significant associations between knowledge scores and both medical practice settings and sources of ABCDE knowledge. Surgeons exhibited the lowest knowledge scores among participants, emphasizing the need for tailored interventions across specialties.

CONCLUSION: This study addresses a critical gap in ABCDE approach knowledge among Egyptian resident doctors and medical interns. The study points to the need for focused education, especially for surgeons, to improve emergency care skills and patient outcomes through continued training.}, } @article {pmid39891383, year = {2025}, author = {Chen, M and Cui, H and Zhang, X and Ma, S and Guo, J and Liu, Z and Gu, D and Fan, Y}, title = {Super-Enhancer Protects Cells From Toxicity of C9orf72 Poly(proline-arginine) by Inducing the Expression of KPNA2/KPNB1.}, journal = {Cell biochemistry and function}, volume = {43}, number = {2}, pages = {e70053}, doi = {10.1002/cbf.70053}, pmid = {39891383}, issn = {1099-0844}, support = {//This work was supported by the National Natural Science Foundation of China (31970616, 82070505) and Jiangsu Provincial Natural Science Foundation (BK20211330)./ ; }, mesh = {Humans ; *alpha Karyopherins/genetics/metabolism ; *C9orf72 Protein/metabolism/genetics ; Cell Nucleus/metabolism ; Triazoles/pharmacology ; Cell Death/drug effects ; Azepines ; }, abstract = {Hexanucleotide repeat expansions in C9orf72 are the most common genetic mutation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Dipeptide repeat (DPR) proteins, such as poly(proline-arginine) (polyPR) generated from G4C2 repeat expansions, have been shown to be highly toxic. In this study, PR20 was labeled with fluorescein isothiocyanate (FITC) to track its cellular localization. Several cell lines demonstrated survival under PR20 treatment by sequestering PR20 in the cytoplasm. Treatment with JQ-1 or Ivermectin (Iver) translocated PR20 into the nucleus, leading to cell death. Mechanistically, KPNA2/KPNB1 interacted with PR20 in the cytoplasm and hindered PR20 from entering the cell nucleus. Genetic silencing of KPNA2/KPNB1 converted PR20-resistant cells into PR20-sensitive cells. Treatment with JQ1 significantly reduced the protein levels of KPNA2/KPNB1, allowing PR20 to enter the nucleus. Overexpression of KPNA2 or KPNB1 effectively blocked cell death induced by co-treatment with JQ-1 and PR20. Our results indicate that super-enhancers shield cells from PR20 toxicity by upregulating the expression of KPNA2/KPNB1.}, } @article {pmid39891470, year = {2025}, author = {Iazzolino, B and Palumbo, F and Moglia, C and Manera, U and Grassano, M and Matteoni, E and Cabras, S and Brunetti, M and Vasta, R and Pagani, M and Mora, G and Canosa, A and Calvo, A and Chiò, A}, title = {Frequency and Early Predictors of Cognitive Deterioration in Amyotrophic Lateral Sclerosis: A Longitudinal Population-Based Study.}, journal = {Annals of neurology}, volume = {97}, number = {6}, pages = {1122-1133}, pmid = {39891470}, issn = {1531-8249}, support = {ALS-Care//EU Joint Programme - Neurodegenerative Disease Research/ ; Brain-Mend//EU Joint Programme - Neurodegenerative Disease Research/ ; 101017598//HORIZON EUROPE Health/ ; RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca (Department of Excellence)/ ; 20228N7573//Ministero dell'Università e della Ricerca (Department of Excellence)/ ; 259867//FP7 Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/complications/genetics/psychology ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; Disease Progression ; *Cognitive Dysfunction/etiology/diagnostic imaging/epidemiology ; Neuropsychological Tests ; Positron-Emission Tomography ; Adult ; }, abstract = {OBJECTIVE: The objective is to evaluate cognitive and behavioral progression and identify early predictors of these changes in a cohort of amyotrophic lateral sclerosis (ALS) patients.

METHODS: A total of 161 ALS patients were tested at diagnosis (T0), and 107 were re-tested after 1 year (T1) using cognitive/behavioral tests. All patients underwent whole-genome sequencing, and 46 patients (ALS-normal cognition [CN]) underwent [18F]Fluorodeoxyglucose positron emission tomography.

RESULTS: Of the 161 patients, 107 were re-rested at T1; non-retested patients included 10 with frontotemporal dementia and 44 who were either non-testable or deceased. At T0, 67 patients (62.6%) were classified as ALS-CN, whereas 40 (38.4%) showed some degree of cognitive/behavioral impairment. Eighteen ALS-CN patients (26.9%) experienced cognitive decline at T1. Phenoconverters had lower baseline scores in letter fluency (Letter Fluency Test [FAS]) (p < 0.001), Edinburgh Cognitive and Behavioral ALS Screen (ECAS) verbal fluency score (p = 0.017). Both tests were independently predictive of phenoconversion in binary logistic regression models, with optimal cut-off scores of 28.75 and 14.2, with good sensitivity and specificity. Other predictors included older age, lower education, and ALS-related genetic variants. Phenoconverters were hypometabolic in the left temporal lobe. Thirteen (32.5%) of the 40 patients with cognitive impairment at T0 worsened by T1, with FAS (p = 0.02) and the ECAS verbal fluency score (p = 0.023) predicting further decline.

INTERPRETATION: Approximately 30% of ALS patients experienced cognitive/behavioral decline within the first year after diagnosis. FAS and ECAS verbal fluency were predictive of cognitive phenoconversion. Our findings highlight the importance of early detection of at-risk individuals and the need for longitudinal cognitive assessments to monitor disease progression. ANN NEUROL 2025;97:1122-1133.}, } @article {pmid39893047, year = {2025}, author = {Zhu, A and Hu, JC}, title = {Reply to Alireza Ghoreifi, Jaffar Hussain, Wei Phin Tan, et al's Letter to the Editor re: Alec Zhu, Mary O. Strasser, Timothy D. McClure, et al. Comparative Effectiveness of Partial Gland Cryoablation Versus Robotic Radical Prostatectomy for Cancer Control. Eur Urol Focus 2024;10:843-50.}, journal = {European urology focus}, volume = {11}, number = {3}, pages = {535-536}, doi = {10.1016/j.euf.2025.01.013}, pmid = {39893047}, issn = {2405-4569}, } @article {pmid39893487, year = {2025}, author = {Pilotto, F and Smeele, PH and Scheidegger, O and Diab, R and Schobesberger, M and Sierra-Delgado, JA and Saxena, S}, title = {Kaempferol enhances ER-mitochondria coupling and protects motor neurons from mitochondrial dysfunction and ER stress in C9ORF72-ALS.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {21}, pmid = {39893487}, issn = {2051-5960}, support = {725825//European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program/ ; }, mesh = {Animals ; *Endoplasmic Reticulum Stress/drug effects/physiology ; *Kaempferols/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/pathology/genetics/drug therapy/metabolism ; *Mitochondria/drug effects/metabolism/pathology ; Humans ; C9orf72 Protein/genetics/metabolism ; *Motor Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; Mice ; *Endoplasmic Reticulum/drug effects/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Male ; Mice, Inbred C57BL ; Rats ; }, abstract = {Repeat expansions in the C9ORF72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Considerable progress has been made in identifying C9ORF72-mediated disease and resolving its underlying etiopathogenesis. The contributions of intrinsic mitochondrial deficits as well as chronic endoplasmic reticulum stress to the development of the C9ORF72-linked pathology are well established. Nevertheless, to date, no cure or effective therapy is available, and thus attempts to find a potential drug target, have received increasing attention. Here, we investigated the mode of action and therapeutic effect of a naturally occurring dietary flavanol, kaempferol in preclinical rodent and human models of C9ORF72-ALS. Notably, kaempferol treatment of C9ORF72-ALS human patient-derived motor neurons/neurons, resolved mitochondrial deficits, promoted resiliency against severe ER stress, and conferred neuroprotection. Treatment of symptomatic C9ORF72 mice with kaempferol, normalized mitochondrial calcium uptake, restored mitochondria function, and diminished ER stress. Importantly, in vivo, chronic kaempferol administration ameliorated pathological motor dysfunction and inhibited motor neuron degeneration, highlighting the translational potential of kaempferol. Lastly, in silico modelling identified a novel kaempferol target and mechanistically the neuroprotective mechanism of kaempferol is through the iP3R-VDAC1 pathway via the modulation of GRP75 expression. Thus, kaempferol holds great promise for treating neurodegenerative diseases where both mitochondrial and ER dysfunction are causally linked to the pathophysiology.}, } @article {pmid39894369, year = {2025}, author = {Jairath, N and Manduca, S and Que, SKT}, title = {Response to Wang et al's limitations and risks of custom GPTs in dermatology. Comment on "ReconGPT: A novel artificial intelligence tool and its potential use in post-Mohs reconstructive decision-making".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {5}, pages = {e163}, doi = {10.1016/j.jaad.2025.01.072}, pmid = {39894369}, issn = {1097-6787}, } @article {pmid39894561, year = {2025}, author = {Ito, T and Ohuchi, K and Kurita, H and Murakami, T and Takizawa, S and Fujimaki, A and Murata, J and Oida, Y and Hozumi, I and Kitaichi, K and Inden, M}, title = {Activated Fibroblast Growth Factor Receptor 1 Mitigated Poly-PR-Induced Oxidative Stress and Protein Translational Impairment.}, journal = {Biological & pharmaceutical bulletin}, volume = {48}, number = {2}, pages = {93-100}, doi = {10.1248/bpb.b24-00794}, pmid = {39894561}, issn = {1347-5215}, mesh = {*Oxidative Stress/drug effects ; Animals ; *Receptor, Fibroblast Growth Factor, Type 1/metabolism/genetics ; NF-E2-Related Factor 2/metabolism/genetics ; Mice ; Protein Biosynthesis/drug effects ; Cell Line ; Motor Neurons/metabolism/drug effects ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron cell death. A GGGGCC hexanucleotide repeat expansion (HRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is a major causative factor in ALS. This abnormal HRE triggers five types of dipeptide repeat protein (DPR), each composed of two alternating amino acid expressions. Among the DPRs, arginine-rich Poly-PR localizes predominantly to the nucleus, exerting particularly strong toxicity on motor and cortical neurons. Several mechanisms have been proposed for poly-PR-induced neurotoxicity. In this study, poly-PR-expressing NSC34 motor neuron-like cells showed an increase in oxidative stress. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. However, its neuroprotective effects against DPR-induced toxicity have not been previously reported. Here, we demonstrated that FGFR1 activation reduced oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (NRF2) expression. Furthermore, we propose that the increase in NRF2 through FGFR1 activation may result from the alleviation of protein translation impairment. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity and may represent a potential therapeutic strategy for ALS.}, } @article {pmid39894843, year = {2025}, author = {Chen, L and Shen, Q and Liu, Y and Zhang, Y and Sun, L and Ma, X and Song, N and Xie, J}, title = {Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.}, journal = {Signal transduction and targeted therapy}, volume = {10}, number = {1}, pages = {31}, pmid = {39894843}, issn = {2059-3635}, support = {32471049//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32170984//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32200802//National Natural Science Foundation of China (National Science Foundation of China)/ ; ZR2020YQ23//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; ZR2024MC153//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; }, mesh = {Humans ; *Iron/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology/genetics ; *Homeostasis ; Zinc/metabolism ; Copper/metabolism ; Animals ; Parkinson Disease/metabolism/genetics/drug therapy/pathology ; Alzheimer Disease/metabolism/genetics/drug therapy/pathology ; Manganese/metabolism ; Oxidative Stress ; Chelating Agents/therapeutic use ; }, abstract = {As essential micronutrients, metal ions such as iron, manganese, copper, and zinc, are required for a wide range of physiological processes in the brain. However, an imbalance in metal ions, whether excessive or insufficient, is detrimental and can contribute to neuronal death through oxidative stress, ferroptosis, cuproptosis, cell senescence, or neuroinflammation. These processes have been found to be involved in the pathological mechanisms of neurodegenerative diseases. In this review, the research history and milestone events of studying metal ions, including iron, manganese, copper, and zinc in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), will be introduced. Then, the upstream regulators, downstream effector, and crosstalk of mental ions under both physiologic and pathologic conditions will be summarized. Finally, the therapeutic effects of metal ion chelators, such as clioquinol, quercetin, curcumin, coumarin, and their derivatives for the treatment of neurodegenerative diseases will be discussed. Additionally, the promising results and limitations observed in clinical trials of these metal ion chelators will also be addressed. This review will not only provide a comprehensive understanding of the role of metal ions in disease development but also offer perspectives on their modulation for the prevention or treatment of neurodegenerative diseases.}, } @article {pmid39896335, year = {2025}, author = {Eckardt, A and Marble, C and Fern, B and Moritz, H and Kotula, C and Ke, J and Rebancos, C and Robertson, S and Nishimune, H and Suzuki, M}, title = {Muscle-specific Bet1L knockdown induces neuromuscular denervation, motor neuron degeneration, and motor dysfunction in a rat model of familial ALS.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1527181}, pmid = {39896335}, issn = {1662-4548}, support = {R01 AR077191/AR/NIAMS NIH HHS/United States ; R01 NS091540/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by specific loss of motor neurons in the spinal cord and brain stem. Although ALS has historically been characterized as a motor neuron disease, there is evidence that motor neurons degenerate in a retrograde manner, beginning in the periphery at the neuromuscular junctions (NMJs) and skeletal muscle. We recently reported a vesicle trafficking protein Bet1L (Bet1 Golgi Vesicular Membrane Trafficking Protein Like) as a new molecule possibly linked to NMJ degeneration in ALS. In this study, we tested the hypothesis that Bet1L gene silencing in skeletal muscle could influence NMJ integrity, motor neuron function, and survival in a rat model of familial ALS (SOD1[G93A] transgenic). Small interfering RNA (siRNA) targeting the Bet1L gene was injected on a weekly basis into the hindlimb muscle of pre-symptomatic ALS and wild-type (WT) rats. After 3 weeks, intramuscular Bet1L siRNA injection significantly increased the number of denervated NMJs in the injected muscle. Bet1L knockdown decreased motor neuron size in the lumbar spinal cord, which innervated the siRNA-injected hindlimb. Impaired motor function was identified in the hindlimbs of Bet1L siRNA-injected rats. Notably, the effects of Bet1L knockdown on NMJ and motor neuron degeneration were more significant in ALS rats when compared to WT rats. Together, Bet1L knockdown induces denervation of NMJs, but also this knockdown accelerates the disease progression in ALS. Our results provide new evidence to support the potential roles of Bet1L as a key molecule in NMJ maintenance and ALS pathogenesis.}, } @article {pmid39897290, year = {2025}, author = {McBenedict, B and Hauwanga, WN and Nezam, U and Ko Oo, A and Eapi, S and Pradhan, S and Dang, NB and Cher, PW and Orsini, MA and Lima Pessôa, B}, title = {Amyotrophic Lateral Sclerosis (ALS) Type 8: A Narrative Review.}, journal = {Cureus}, volume = {17}, number = {1}, pages = {e76717}, pmid = {39897290}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis type 8 (ALS8) is a rare familial subtype of ALS caused by mutations in the vesicle-associated membrane protein-associated protein B (VAPB) gene, particularly the p.P56S mutation. It is distinguished by slower disease progression and an earlier onset compared to sporadic ALS forms, along with unique clinical features such as severe cramping, fasciculations, postural tremors, and cognitive and behavioral impairments. Although current pharmacological options, such as riluzole, edaravone, and sodium phenylbutyrate/taurursodiol, provide modest benefits, they fail to address the underlying genetic mechanisms of ALS8. Emerging gene therapies, RNA-based interventions, and stem cell approaches hold promise for precision-targeted treatments but face challenges in clinical application. Symptom management strategies, including respiratory, nutritional, and psychological support, are crucial for improving patient outcomes and quality of life. Despite significant progress in understanding the genetic and molecular pathogenesis of ALS8, its rarity, phenotypic variability, and limited clinical data pose challenges to therapeutic advancements. This narrative review highlights current therapeutic strategies, the unique clinical trajectory of ALS8, and potential pathways for innovative, subtype-specific interventions, emphasizing the need for multidisciplinary and targeted approaches to optimize care for this distinct ALS subtype.}, } @article {pmid39897942, year = {2025}, author = {Quarracino, C and Capani, F and Otero-Losada, M and Rodríguez, GE and Pérez-Lloret, S}, title = {Frequency of orthostatic hypotension in the Pooled Resource Open-Access ALS Clinical Trials database.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1512357}, pmid = {39897942}, issn = {1664-2295}, abstract = {PURPOSE: To explore the frequency of orthostatic hypotension (OH) in a large sample of amyotrophic lateral sclerosis patients (ALS).

METHODS: From the PRO-ACT database, data of 1,240 ALS patients were analyzed, focusing on blood pressure and heart rate before and after standing. OH was defined as a drop in systolic/diastolic blood pressure > 20/10 mm Hg within 3 min of standing. Neurogenic OH was diagnosed when the heart rate increase was below 15 bpm in patients not taking medications that could affect this response.

RESULTS: At baseline, 138 (11.1%) patients showed OH, 76.1% of whom had neurogenic OH. At follow-up, 163 patients (13.1%) had OH, 71.2% with neurogenic OH. Only 22.5% of the patients with OH at baseline had OH at follow-up.

CONCLUSION: In a large sample of ALS patients, OH occurred in 11-13%, pointing to a subgroup that might require special care to avoid related complications.}, } @article {pmid39898446, year = {2025}, author = {Boddy, SL and Simpson, RM and Walters, SJ and Bamford, H and Walsh, T and McDermott, CJ and , }, title = {Estimating the minimum important difference in the ALSFRS-R-instrument in people living with MND.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {249-258}, pmid = {39898446}, issn = {2167-9223}, support = {MCRGS-07-16-13/MCCC_/Marie Curie/United Kingdom ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; *Quality of Life/psychology ; Severity of Illness Index ; *Minimal Clinically Important Difference ; Adult ; }, abstract = {Objective: The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is a commonly used outcome measure in clinical trials for motor neuron disease (MND) therapies. As such, understanding how differences in scores relate to patient perception of their disease status is important when interpreting ALSFRS-R data. Our study sought to estimate the minimal important difference (MID) for the ALSFRS-R, the smallest difference in scores at which patients perceive a change in their quality of life. Methods: Data were collected as part of a longitudinal, observational saliva management study, ProSec3. These included both the ALSFRS-R and a global rating of change question (GRoC), which asked participants to rate how their disease had progressed since the previous visit. Anchor-based and distribution-based methods have been used to estimate the MID of the ALSFRS-R. The MID was estimated using two methods of calculating the total ALSFRS-R score, the original summation scale method and the recently proposed interval scale method. Results: A total of 145 people with MND had longitudinal ALSFRS-R and GRoC data. Different methods estimated the ALSFRS-R MID to be in the range of 2.02-5.43 for the summation scale and 1.23-3.31 for the interval scale method over a 3-month period, the time between study visits. Using anchor-based methods our MID estimates for the ALSFRS-R are 3.8 points and 2 points, respectively. Conclusions: The results of this study can guide clinicians and researchers in the interpretation of ALSFRS-R data. However, further studies are required to more precisely estimate the ALSFRS-R MID.}, } @article {pmid39899435, year = {2025}, author = {Blake, J and Peryer, G and Dance, R and Parke, S and Aryankhesal, A and Farquhar, M}, title = {How can healthcare professionals work with families to address misaligned expectations of recovery in brain injury rehabilitation? A scoping review.}, journal = {Brain injury}, volume = {39}, number = {7}, pages = {551-564}, doi = {10.1080/02699052.2025.2450603}, pmid = {39899435}, issn = {1362-301X}, mesh = {Humans ; *Brain Injuries/rehabilitation/psychology ; *Health Personnel/psychology ; *Family/psychology ; *Professional-Family Relations ; Recovery of Function ; }, abstract = {INTRODUCTION: Most survivors of severe acquired brain injuries will have significant long-term disability. During inpatient rehabilitation, families often have expectations of recovery that do not match healthcare professional opinion. This impacts on patient care, service processes, professional-family relations, and wellbeing. This review aimed to understand how family expectations are managed in this setting, and to explore potential areas of improvement.

METHOD: A scoping review was conducted by searching CINAHL, Medline, EMBASE and Web of Science. Krieger et al's 'Conceptual Building Blocks' provided a framework to analyze the data using a 'best fit' framework synthesis approach.

RESULTS: Twenty-one papers were included in the review. Six sub-themes within three overarching themes were generated, which explored recommendations for effective expectation management. The sub-themes within the 'staff behaviors' theme were 'appropriate information provision,' 'open communication' and 'prioritize family.' Sub-themes within 'system behaviors' were 'cultural change' and 'increased resource.' 'Rehabilitation as a shared process' was the third theme.

DISCUSSION: Misaligned expectations of recovery appear to reflect a range of unmet family needs related to their position within the healthcare hierarchy, professional-family communication, and their involvement in rehabilitation processes. Early identification of family and healthcare professional expectations alongside regular review may prevent misunderstanding and conflict.}, } @article {pmid39900510, year = {2025}, author = {van Altena, EJE and Jansen, BHE and Vis, AN}, title = {Reply to Ignacio Puche-Sanz, Ugo Giovanni Falagario, Giorgio Gandaglia, et al's Letter to the Editor re: Evelien J.E. van Altena, Bernard H.E. Jansen, Marieke L. Korbee, et al. Prostate-specific Membrane Antigen Positron Emission Tomography Before Reaching the Phoenix Criteria for Biochemical Recurrence of Prostate Cancer After Radiotherapy: Earlier Detection of Recurrences. Eur Urol Oncol. In press. https://doi.org/10.1016/j.euo.2024.09.015.}, journal = {European urology oncology}, volume = {8}, number = {3}, pages = {854-855}, doi = {10.1016/j.euo.2025.01.011}, pmid = {39900510}, issn = {2588-9311}, } @article {pmid39901378, year = {2025}, author = {San Gil, R and Walker, AK}, title = {Unlocking Disease-Modifying Treatments for TDP-43-Mediated Neurodegeneration.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {47}, number = {4}, pages = {e202400257}, pmid = {39901378}, issn = {1521-1878}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics/therapy ; *DNA-Binding Proteins/metabolism/genetics ; *Frontotemporal Dementia/metabolism/pathology/genetics/therapy ; Animals ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Neurons degenerate in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing progressive and inevitably fatal neurological decline. The best therapeutic strategies target underlying disease mediators, but after decades of intensive research, the causes of these neurodegenerative diseases remain elusive. Recently, coordinated activities of large consortia, increasing open access to large datasets, new methods such as cryo-transmission electron microscopy, and advancements in high-resolution omics technologies have offered new insights into the biology of disease that bring us closer to understanding mechanisms of neurodegeneration. In particular, improved understanding of the roles of the key pathological protein TAR DNA binding protein 43 (TDP-43) in disease has revealed intriguing new opportunities that provide hope for better diagnostic tools and effective treatments for ALS and FTD.}, } @article {pmid39901566, year = {2025}, author = {Park, NY and Heo, Y and Yang, JW and Yoo, JM and Jang, HJ and Jo, JH and Park, SJ and Lin, Y and Choi, J and Jeon, H and Cha, SJ and Bae, G and Kim, D and Kim, J and Zeno, W and Park, JB and Isozumi, N and Saio, T and Kim, SH and Lee, H and Hong, BH and Nahm, M and Lee, YH and Hong, YB}, title = {Graphene Quantum Dots Attenuate TDP-43 Proteinopathy in Amyotrophic Lateral Sclerosis.}, journal = {ACS nano}, volume = {19}, number = {9}, pages = {8692-8710}, pmid = {39901566}, issn = {1936-086X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; *Graphite/chemistry/pharmacology ; Animals ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; Humans ; Mice ; *Quantum Dots/chemistry ; Mice, Transgenic ; Disease Models, Animal ; *TDP-43 Proteinopathies/drug therapy/metabolism ; Motor Neurons/metabolism/drug effects ; }, abstract = {Aberrant phase separation- and stress granule (SG)-mediated cytosolic aggregation of TDP-43 in motor neurons is the hallmark of amyotrophic lateral sclerosis (ALS). In this study, we found that graphene quantum dots (GQDs) potentially modulate TDP-43 aggregation during SG dynamics and phase separation. The intrinsically disordered region in the C-terminus of TDP-43 exhibited amyloid fibril formation; however, GQDs inhibited the formation of amyloid fibrils through direct intermolecular interactions with TDP-43. These effects were accompanied by attenuation of the ALS phenotype in animal models. Additionally, GQDs delayed the onset and survival of TDP-43 transgenic mouse models by enhancing motor neuron survival, reducing glial activation, and reducing the cytosolic aggregation of TDP-43 in motor neurons. In this research, we demonstrated the efficacy of GQDs on the SG-mediated aggregation of TDP-43 and the binding property of GQDs with TDP-43. Additionally, we demonstrated the clinical feasibility of GQDs using several animal models and other types of ALS caused by FUS and C9orf72. Therefore, GQDs could offer a new therapeutic approach for proteinopathy-associated ALS.}, } @article {pmid39901730, year = {2025}, author = {Wu, W and Wang, X and Xu, Y and Ma, C and Qian, X and Qiu, W}, title = {Neuropathological comorbidity, genetics and cognition in a Chinese community-based autopsy cohort.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {7}, pages = {2481-2492}, pmid = {39901730}, issn = {1460-2156}, support = {2021-1-I2M-025//CAMS Innovation Fund for Medical Sciences (CIFMS)/ ; 2021ZD0201100//STI 2030-Major Project/ ; 3332023040//Fundamental Research Funds for the Central Universities/ ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Asian People/genetics ; Autopsy ; *Brain/pathology ; China/epidemiology ; *Cognition/physiology ; Cohort Studies ; Comorbidity ; *Neurodegenerative Diseases/genetics/pathology/epidemiology ; }, abstract = {Neurodegenerative comorbidities are common and critical, yet data specific to the Chinese population remains limited. In this study, we aimed to investigate the prevalence and associations of neuropathological changes and comorbidities and their correlation with genetics and cognition in a community-dwelling autopsy cohort in China. Datasets of 610 participants were obtained from the National Human Brain Bank for Development and Function at the Chinese Academy of Medical Sciences/Peking Union Medical College. Neuropathological changes analysed included: Alzheimer's disease neuropathological change (ADNC; n = 331); α-synucleinopathies (n = 124), including 120 Lewy body disease (LBD) and 4 multiple system atrophy; limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC; n = 341); primary age-related tauopathy (PART; n = 231); argyrophilic grain disease (n = 107); age-related tau astrogliopathy (n = 144); cerebral amyloid angiopathy (n = 183); and hippocampal sclerosis (n = 46). Frontotemporal lobar degeneration, amyotrophic lateral sclerosis and amygdala-predominant LBD were rare. Descriptive statistics and logistic regression models were used to assess the neuropathological associations. Increased age at death was correlated with increased severity in ADNC, LBD and LATE-NC and with a higher number of comorbidities. APOE ε4 allele frequency in the present autopsy cohort was 13.63%. The presence of the APOE ε4 allele was linked to an advanced ADNC stage and increased comorbidities. The co-pathology prevalence varied by pathologies, with notable increases in specific subgroups: within the ADNC subgroups, LBD, LATE-NC, cerebral amyloid angiopathy and hippocampal sclerosis were more frequent in advanced stages; in the LATE-NC subgroups, ADNC, cerebral amyloid angiopathy and age-related tau astrogliopathy increased, and PART decreased in higher LATE-NC stages. PART cases presented the highest proportion of pure pathology (37.2%) compared with the other groups. Advanced ADNC stages were significantly associated with higher LATE-NC stages, and vice versa. Neocortical LBD was correlated with elevated ADNC levels, and higher LATE-NC stages were associated with worsening LBD pathology. High-level ADNC, neocortical LBD and stage 3 of LATE-NC were identified as independent predictors of severe cognition status. Our study suggests that older age at death and APOE ε4 presence are the risk factors for neuropathological comorbidities in Chinese people. The findings underscore the importance of considering comorbid neurological diagnoses and therapies in clinical practice.}, } @article {pmid39902127, year = {2024}, author = {Ma, J and Wang, H and Gui, Z and Yang, Y}, title = {Unveiling the role of SYNGR4 in breast cancer development: a novel target for immunotherapy.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1490073}, pmid = {39902127}, issn = {2234-943X}, abstract = {INTRODUCTION: SYNGR4 is considered to be one of the causative genes for amyotrophic lateral sclerosis, but its role in breast cancer development has not been revealed.

METHODS: The expression of SYNGR4 in a variety of malignancies including breast cancer was analyzed using Genotype Tissue Expression (GTEx) and the Cancer Genome Atlas (TCGA) databases and verified by specimens collected from our center. The effect of SYNGR4 on breast cancer prognosis was analyzed using bioinformatics and possible pathways by which this molecule affects breast cancer prognosis were explored. The effect of SYNGR4 on immune infiltration of breast cancer was analyzed using GSVA, and the effects of SYNGR4 on breast cancer proliferation, migration, and tumor-associated macrophage polarization in cancer foci were verified by cellular and animal experiments, respectively.

RESULTS: SYNGR4 is highly expressed in a variety of malignant tumors, including breast cancer, and affects the prognosis of breast cancer patients. This may be a volatile effect through Organelle fission, chromosome segregation, nuclear division, etc. SYNGR4 overexpression affects breast cancer proliferation, migration, and tumor immune infiltration, and promotes breast cancer tumor-associated macrophage polarization toward M2.

DISCUSSION: SYNGR4 overexpression can affect the prognosis of breast cancer patients by promoting M2 polarization of tumor-associated macrophages in breast cancer, and this molecule may be a novel target for breast cancer immunotherapy.}, } @article {pmid39902522, year = {2025}, author = {Yu, WQ and Zhao, LX and Bian, Y and Zhang, PX and Jia, L and Zhao, DM and Fu, Y and Ye, F}, title = {Pharmacophore Recombination Design, Synthesis, and Bioactivity of Ester-Substituted Pyrazole Purine Derivatives as Herbicide Safeners.}, journal = {Journal of agricultural and food chemistry}, volume = {73}, number = {6}, pages = {3341-3352}, doi = {10.1021/acs.jafc.4c07027}, pmid = {39902522}, issn = {1520-5118}, mesh = {*Herbicides/chemistry/pharmacology/chemical synthesis ; *Pyrazoles/chemistry/pharmacology/chemical synthesis ; *Purines/chemistry/pharmacology/chemical synthesis ; Molecular Docking Simulation ; Drug Design ; Acetolactate Synthase/chemistry/antagonists & inhibitors/metabolism ; Triticum/drug effects ; Plant Proteins/chemistry/antagonists & inhibitors/metabolism ; Molecular Structure ; Structure-Activity Relationship ; Esters/chemistry ; Enzyme Inhibitors/chemistry/pharmacology/chemical synthesis ; Plant Weeds/drug effects ; Molecular Dynamics Simulation ; Sulfonylurea Compounds/chemistry ; Pharmacophore ; }, abstract = {Mesosulfuron-methyl, an acetolactate synthase (ALS) inhibitor primarily applied to wheat and rye, can injure or even kill wheat crops. Herbicide safeners can improve the herbicide resistance of crops without reducing the herbicidal effect on targeted weed species. Herein, we present a series of pyrazole purine derivatives with the primary structure of the natural product cytokinin and commercialized safener mefenpyridyl, designed using the pharmacophore recombination method. The title compounds were synthesized and characterized using infrared spectroscopy, [1]H and [13]C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. A bioactivity assay proved that most of the target compounds can reduce the wheat phytotoxicity of mesosulfuron-methyl. Measurements of chlorophyll and glutathione contents, along with other enzyme activity assays, confirmed that compounds I-15 and I-13 exhibit higher safety activities compared with the mefenpyr-diethyl safener. Molecular structure comparisons demonstrated that I-15 is more readily absorbed and disseminated through the crop than the commercialized safener mefenpyr-diethyl. Molecular docking models and molecular dynamics simulations elucidated the protective mechanism of safeners; specifically, compound I-15 competitively binds to the ALS active site with mesosulfuron-methyl. The current study reveals the potential of pyrazole purine derivatives in the future discovery of novel herbicide safeners.}, } @article {pmid39902643, year = {2025}, author = {Abad-Yang, N and Raguseo, F and Di Michele, L and Patani, R and Di Antonio, M}, title = {The potential of multimolecular G-quadruplex structures for targeted treatment of Amyotrophic Lateral Sclerosis.}, journal = {Expert opinion on therapeutic targets}, volume = {29}, number = {1-2}, pages = {1-4}, doi = {10.1080/14728222.2025.2463361}, pmid = {39902643}, issn = {1744-7631}, } @article {pmid39904421, year = {2025}, author = {Dragoni, F and Garofalo, M and Di Gerlando, R and Rizzo, B and Bordoni, M and Scarian, E and Viola, C and Bettoni, V and Fiamingo, G and Tornabene, D and Scanu, L and Pansarasa, O and Diamanti, L and Gagliardi, S}, title = {Whole transcriptome analysis of unmutated sporadic ALS patients' peripheral blood reveals phenotype-specific gene expression signature.}, journal = {Neurobiology of disease}, volume = {206}, number = {}, pages = {106823}, doi = {10.1016/j.nbd.2025.106823}, pmid = {39904421}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood ; Male ; Female ; Middle Aged ; Phenotype ; Aged ; *Gene Expression Profiling/methods ; *Transcriptome ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult neurodegenerative disorder. According to clinical criteria, ALS patients can be classified into eight subgroups: classic, bulbar, pyramidal, pure lower motor neuron, flail arm, pure upper motor neuron, flail leg, and respiratory. There are no well-established molecular biomarkers for early diagnosis, prognosis, and progression monitoring of this fatal disease. Classification based on clinical phenotypes could be associated with peculiar gene expression patterns shaped during lifespan, allowing the identification of specific sporadic ALS (sALS) subtypes with less heterogeneous clinical and biological features. Our objective was to define a phenotype-specific transcriptomic signature of distinct ALS phenotypes, and lay the foundation for biomarkers development. We characterized 48 sALS patients by clinical and paraclinical parameters, and subdivided them in "Classic" (n = 12), "Bulbar" (n = 10), "Flail Arm" (n = 7), "Flail Leg" (n = 10) and "Pyramidal" (n = 9) phenotypes. RNAs extracted from patients' PBMCs and 19 controls were sequenced. Our analysis allowed the visualization of gene expression differential clusters between patients and controls. Interestingly, only one gene (Y3_RNA, a misc_RNA component of the Ro60 ribonucleoprotein involved in cellular response to interferon-alpha) was upregulated at different levels across all phenotypes, whereas other genes appeared phenotype-specific. The work proposed stress the innovative view of ALS as a multi-systemic disorder rather than a pure motor neuron-associated and 'neurocentric' pathology. The possibility to cluster ALS patients based on their molecular signature pave the way for future personalized clinical trials and early diagnosis.}, } @article {pmid39905402, year = {2025}, author = {Li, J and Guo, S and Sun, Q and An, N and Lin, J and Fei, Q}, title = {Bioinformatics screening and clinical validation of CircRNA and related miRNA in male osteoporosis.}, journal = {BMC musculoskeletal disorders}, volume = {26}, number = {1}, pages = {117}, pmid = {39905402}, issn = {1471-2474}, mesh = {Humans ; Male ; *RNA, Circular/genetics/blood ; *Osteoporosis/genetics/blood/diagnosis ; *MicroRNAs/genetics/blood ; *Computational Biology/methods ; Gene Regulatory Networks ; Middle Aged ; Gene Expression Profiling ; Aged ; RNA, Messenger/genetics ; Biomarkers/blood ; }, abstract = {BACKGROUND: The pathogenesis of male osteoporosis (MOP) remains unclear, with the role of genetic factors attracting the attention of researchers. In the present study, we aimed to investigate critical circRNA biomarkers associated with male osteoporosis.

METHODS: RNA-sequencing was performed to investigate the circRNA expression profiles between 3 men with osteoporosis and 3 with normal mass density. Then, shared mRNAs between host genes acquired in this present study and mRNAs acquired in previous study were identified to screen vital circRNAs associated with male osteoporosis. PPI networks of shared mRNAs were constructed and the hub genes in the PPI networks were identified with CytoHubba, a plugin in Cytoscape software (3.10.1). Finally, a ceRNA network of four circRNAs derived from three hub genes was constructed. Validation experiments were performed on selected circRNAs and related miRNAs in this ceRNA network using peripheral blood clinical samples.

RESULTS: In total, 657 circRNAs were detected in male osteoporosis. The shared mRNAs were significantly enriched in the metabolic pathways, RNA transport, Ubiquitin mediated proteolysis and Amyotrophic lateral sclerosis. Then, three genes, including SETD2, ATM and XPO1, were identified as hub genes with four algorithms. Ultimately, the ceRNA network, involving 4 circRNAs, 40 miRNAs, and 592 mRNAs, was obtained. Using 35 clinical samples, three potential circRNAs and three miRNAs associated with male osteoporosis were selected for validation. It was ultimately found that three miRNAs were upregulated in MOP, while hsa-circ-9130, novel_circ_0014940 and hsa-circ-0054894 were upregulated, hsa-circ-2484 and novel_circ_0033084 were downregulated in patients with MOP.

CONCLUSION: We emphasized the roles of several significantly up- and down-regulated circRNAs and four circRNAs derived from three hub genes in male osteoporosis. Differences in expression were confirmed for three miRNAs and five circRNAs in the ceRNA network among patients with male osteoporosis.}, } @article {pmid39906330, year = {2024}, author = {Hruška, J and Bachmann, P and Odei, SA}, title = {Enhancing ALS disease management: exploring integrated user value through online communities evidence.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1393261}, pmid = {39906330}, issn = {1664-2295}, abstract = {INTRODUCTION: Assistive technologies (ATs) offer significant potential to improve the quality of life for individuals with Amyotrophic Lateral Sclerosis (ALS). This study explores the concept of integrated user value (IUV), focusing on five key aspects: quality, user experience, cost-effectiveness, safety, and accessibility. Understanding IUV is crucial for enhancing the development and deployment of ATs in ALS disease management.

METHODS: A systematic search approach was utilized to collect data from Facebook ALS support groups, comprising posts from individuals with ALS and their caregivers. Using a predefined set of keywords, 416 posts were analyzed. The posts were categorized based on the five aspects of IUV, and an in-depth content analysis was conducted to explore patterns, challenges, and experiences associated with AT usage.

RESULTS: The analysis revealed significant challenges across all aspects of IUV. Quality and user experience were interlinked, with users frequently citing inadequate designs and unmet customization needs. Cost-effectiveness was a key concern, with high costs and limited insurance coverage contributing to financial strain. Accessibility issues, including delays in acquiring devices and insufficient public facilities, further highlighted systemic challenges. Safety concerns emphasized the need for personalized and intuitive AT designs.

DISCUSSION: The findings underscore the importance of a holistic approach to AT development, integrating all five aspects of IUV. Recommendations include enhancing product quality, ensuring affordability, prioritizing user-centered design, and addressing accessibility gaps. Collaboration between AT designers, healthcare providers, and policymakers is essential to optimize AT value and improve the quality of life for individuals with ALS and their caregivers.}, } @article {pmid39907139, year = {2025}, author = {Matera, AG}, title = {Chaperone dysfunction in motor neuron disease: new insights from studies of the SMN complex.}, journal = {Genetics}, volume = {229}, number = {3}, pages = {}, pmid = {39907139}, issn = {1943-2631}, support = {R35 GM136435/GM/NIGMS NIH HHS/United States ; //USA National Institutes of Health/ ; }, mesh = {Humans ; Muscular Atrophy, Spinal/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; *SMN Complex Proteins/metabolism/genetics ; *Molecular Chaperones/metabolism/genetics ; Animals ; *Motor Neuron Disease/genetics/metabolism ; Motor Neurons/metabolism ; }, abstract = {Spinal muscular atrophy and amyotrophic lateral sclerosis are devastating neurodegenerative diseases characterized by motor neuron loss. Although these 2 disorders have distinct genetic origins, recent studies suggest that they share common etiological mechanisms rooted in proteostatic dysfunction. At the heart of this emerging understanding is the survival motor neuron (SMN) complex.}, } @article {pmid39907297, year = {2024}, author = {Čižek Sajko, M and Suklan, J and Osmanović, D and Peterlin, B}, title = {Translational Research on Polygenic Risk Scores in Common Neurodegenerative Diseases - A Scoping Review Protocol.}, journal = {Acta medica academica}, volume = {53}, number = {3}, pages = {303-308}, pmid = {39907297}, issn = {1840-2879}, mesh = {Humans ; Alzheimer Disease/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics ; Genetic Predisposition to Disease ; *Genetic Risk Score ; *Multifactorial Inheritance ; Multiple Sclerosis/genetics ; *Neurodegenerative Diseases/genetics ; Parkinson Disease/genetics/diagnosis ; Research Design ; Risk Assessment ; Risk Factors ; Scoping Reviews as Topic ; *Translational Research, Biomedical ; }, abstract = {OBJECTIVE: The purpose of this protocol is to clearly describe the process for the scoping review we plan to conduct on the topic of polygenic risk scores (PRS) in common neurodegenerative diseases. We will present the review's objective, the strategy for evidence search, the data extraction and analysis procedure, and how the results will be presented.

METHODS: The inclusion criteria for the planned scoping review will focus on evidence sources that involve PRS applied to neurogenerative diseases such as Multiple sclerosis, Parkinson's disease, Alzheimer's disease, and Amyotrophic lateral sclerosis in any phase of translational research, from early development to clinical implementation. This includes its use in risk prediction, early diagnosis, prognosis, and treatment decision-making. The research questions were created based on the population, context, and concept framework. We will consider both peer-reviewed papers and grey literature published in English or German for inclusion. Two independent reviewers will search for information.

CONCLUISON: The findings from the scoping review will be presented descriptively and summarized according to the research questions to illustrate the current status of translational research on PRS in common neurodegenerative diseases.}, } @article {pmid39908264, year = {2025}, author = {Hobert, MA and Helle, N and Siebert, C and Eisenhauer, A and Gledhill, M and Maetzler, W}, title = {Exploiting the Fractionation of Stable Isotopes in Biochemical Processes for Medical Diagnosis: A Narrative Review.}, journal = {Aging and disease}, volume = {17}, number = {1}, pages = {274-285}, pmid = {39908264}, issn = {2152-5250}, mesh = {Humans ; *Isotopes/analysis ; Biomarkers/analysis ; Hemochromatosis/diagnosis ; }, abstract = {Analysis of isotope distributions plays a crucial role in medical diagnostics. While radioactive and radiogenic isotopes - those that undergo or result from radioactive decay - are widely used, stable isotopes are less commonly applied despite their significant diagnostic potential. For example, calcium isotope ratio analysis is already commercially utilized for calcium loss and the early diagnosis of osteoporosis. Additionally, analyses of iron, copper, and zinc isotope ratios have been explored in various conditions, including hemochromatosis, Wilson's disease, cancer, Alzheimer's disease, and amyotrophic lateral sclerosis. Altered isotope ratios in these diseases are thought to reflect pathophysiologically relevant processes, making them promising biomarkers. This review provides a comprehensive overview of the current and potential applications of stable isotope analysis in medicine.}, } @article {pmid39908735, year = {2025}, author = {Ghannam, IAY and Hassan, RM and Abdel-Maksoud, MS}, title = {Peroxisome proliferator-activated receptors (PPARs) agonists as promising neurotherapeutics.}, journal = {Bioorganic chemistry}, volume = {156}, number = {}, pages = {108226}, doi = {10.1016/j.bioorg.2025.108226}, pmid = {39908735}, issn = {1090-2120}, mesh = {Humans ; *Peroxisome Proliferator-Activated Receptors/agonists/metabolism ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis/therapeutic use ; Molecular Structure ; }, abstract = {Neurodegenerative disorders are characterized by a continuous neurons loss resulting in a wide range of pathogenesis affecting the motor impairment. Several strategies are outlined for therapeutics of synthetic and natural PPARs agonists in some neurological disorders; Parkinson's disease (PD), Alzheimer's disease (AD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The aim of this review is to provide a recent update of the previously reported studies, and reviews dealing with the medicinal chemistry of PPARs and their agonists, and to highlight the outstanding advances in the development of both synthetic compounds including; PPARα agonists (fibrates), PPARγ agonists (thiazolidindiones), and PPARβ/δ agonists either as sole or dual acting PPAR full or pan agonists, in addition to the natural phytochemicals; acids, cannabinoids, and flavonoids for their different neuroprotection effects in the previously mentioned neurodegenerative disorders (PD, AD, MS, ALS, and HD). Moreover, this review reports the diverse pre-clinical and clinical studies of PPARs agonists in the neurodegenerative diseases via cellular, and animal models and human.}, } @article {pmid39908935, year = {2025}, author = {Lu, T and Li, J and Xiao, E and Zhong, H and Deng, J and Ma, L and Ning, Z and Xiao, T}, title = {Assemblage of root-associated microbiome contributes to disparate performance of two rice genotypes under aluminum stress.}, journal = {Plant physiology and biochemistry : PPB}, volume = {220}, number = {}, pages = {109539}, doi = {10.1016/j.plaphy.2025.109539}, pmid = {39908935}, issn = {1873-2690}, mesh = {*Oryza/genetics/microbiology/drug effects/growth & development ; *Aluminum/toxicity ; *Plant Roots/microbiology/drug effects/genetics ; *Microbiota/drug effects/genetics ; Genotype ; *Stress, Physiological/drug effects/genetics ; Rhizosphere ; Soil Microbiology ; }, abstract = {Aluminum (Al) toxicity severely inhibits rice growth under acidic soils, posing a significant threat to food security. The assemblies of root-associated microbiomes throughout the lifecycle of rice are hypothesized to furnish a resilient reservoir of ecological functions for rice growth performance under Al stresses. However, the mechanisms that drive the assembly of root-associated microbiomes of rice are largely unknown. In this study, we chose two rice genotypes (including aluminum-tolerant (Al-T) and aluminum-sensitive (Al-S)) as model plants to investigate the microbial assemblage of root-associated microbiome and their potential roles on the plant growth performance under Al stress. The microbial community diversity (Shannon) and evenness (Chao1) in the endosphere of the Al-T genotype gradually decreased, converging towards levels observed in the Al-S genotype. In addition, the rhizosphere and endosphere microbiomes of Al-T genotype are primarily influenced by deterministic processes, while those of Al-S genotype are more influenced by stochastic processes. Compared to Al-S genotype, Al-T genotype exhibited higher complexity and stability in its rhizosphere and endosphere microbiomes, while the rhizoplane microbiome showed the opposite trend. In the rhizosphere microbiome of the Al-T genotype, we identified Gallionellales, Rhodobacterales, and Rhizobiales as keystone taxa. Their abundance was closely associated with microbial functions, including indole-3-acetic acid (IAA) synthesis, phosphorus solubilization, glutathione (GSH) metabolism, and 1-aminocyclopropane-1-carboxylate (ACC) metabolism. In the Al-S genotype, the keystone taxa included Actinomycetales and Burkholderiales. This study offers new insights into plant adaptation to abiotic stress and underscores the significance of the assemblage of root-associated microbiome in this process.}, } @article {pmid39910275, year = {2025}, author = {Peters, TL and Qiu, W and Yang, H and Huang, W and Hu, Y and Zou, Z and Ye, W}, title = {Associations of cachexia and frailty with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {4437}, pmid = {39910275}, issn = {2045-2322}, support = {2024XH028//Postdoctoral Fund project of Fujian Medical University Union Hospital/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications/physiopathology/etiology ; *Cachexia/complications/epidemiology ; Male ; Female ; *Frailty/complications/physiopathology ; Middle Aged ; Aged ; Prospective Studies ; United Kingdom/epidemiology ; Risk Factors ; Body Mass Index ; Hand Strength ; }, abstract = {In the present study, we investigated the associations of cachexia (loss of muscle, weight and fat) and frailty (loss of weight and muscle) status with the risk of developing amyotrophic lateral sclerosis, because these specific terms are rarely used in this research area. In this prospective study, we extracted cachexia and frailty status from the UK Biobank cohort to study the associations of these conditions (as determined via international classification of disease-10 codes) with amyotrophic lateral sclerosis. There was a greater risk of developing amyotrophic lateral sclerosis among individuals with cachexia and frailty status after adjusting for age, sex, income (pounds), body mass index, UK Biobank centers and smoking status. Among individuals with frailty status: a grip strength of < 21 kg, a slow walking speed, and exhaustion (more than half the days or nearly every day) increase the risk of developing amyotrophic lateral sclerosis. We believe that studying cachexia and frailty status can be used to help define and treat amyotrophic lateral sclerosis.}, } @article {pmid39910617, year = {2025}, author = {Mai, YD and Zhang, Q and Fung, CL and Leung, SO and Chong, CH}, title = {CD22 modulation alleviates amyloid β-induced neuroinflammation.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {32}, pmid = {39910617}, issn = {1742-2094}, mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; Mice ; Mice, Transgenic ; *Neuroinflammatory Diseases/metabolism/chemically induced/drug therapy ; *Sialic Acid Binding Ig-like Lectin 2/metabolism/genetics ; Humans ; Microglia/metabolism/drug effects ; Mice, Inbred C57BL ; Male ; }, abstract = {Neuroinflammation is a crucial driver of multiple neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Yet, therapeutic targets for neurodegenerative diseases based on neuroinflammation still warrant investigation. CD22 has been implicated in neuroinflammatory diseases, namely AD. Specifically, plasma soluble CD22 (sCD22) level is upregulated in patients with AD. Direct experimental evidence for the role of CD22 in neuroinflammation is needed, as is a better understanding of its impact on microglia activation and therapeutic potential. Here we reported that sCD22 promotes neuroinflammation both in vivo and in vitro. sCD22 activated microglia via both p38 and ERK1/2 signaling pathway for the secretion of TNFα, IL-6 and CCL3. Moreover, sCD22 activated microglia via sialic acid binding domain and 2,6 linked sialic acid glycan on sCD22. The pivotal therapeutic potential of targeting CD22 was demonstrated in Amyloid β (Aβ) induced-neuroinflammation in hCD22 transgenic mice. Suciraslimab improved working memory and resolved neuroinflammation in vivo. Further, membrane CD22 inhibited Amyloid β (Aβ) induced-NFκB signaling pathway and mechanistic study delineated that suciraslimab suppressed Aβ-induced IL-1β secretion in human microglia and PBMC. Suciraslimab also suppressed IL-12 and IL-23 secretion in human PBMC. Moreover, suciraslimab reduced the surface expression of α4 integrin on B cells. Intriguingly, we discovered that CD22 interact with Aβ and suciraslimab enhanced internalization of CD22-Aβ complex in microglia. Our data highlights the importance of sCD22 in driving neuroinflammation and the dual mechanism of targeting CD22 to resolve Aβ-induced inflammation and promote Aβ phagocytosis.}, } @article {pmid39910638, year = {2025}, author = {Möhwald, LM and Maier, A and Grehl, T and Weyen, U and Weydt, P and Günther, R and Lingor, P and Göricke, B and Petri, S and Grosskreutz, J and Boentert, M and Cordts, I and Weishaupt, JH and Dorst, J and Münch, C and Meyer, T and Baum, P}, title = {Shared prognostic information in amyotrophic lateral sclerosis - systematic assessment of the patients' perception of neurofilament light chain and the ALS functional rating scale.}, journal = {Neurological research and practice}, volume = {7}, number = {1}, pages = {6}, pmid = {39910638}, issn = {2524-3489}, support = {Open Access Publishing Fund of Leipzig University ("Read & Publish" contract with Springer Nature)//Open Access Publishing Fund of Leipzig University ("Read & Publish" contract with Springer Nature)/ ; }, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS), neurofilament light chain (NfL) was introduced as a prognostic biomarker. More recently, NfL values can be shared on the patient's ALS app. Also, the ALS functional rating scale (ALSFRS-R) is an established patient-reported assessment of disease progression. The scale can be obtained during clinic visits or remotely. However, few systematic data are available on the patients' perception of prognostic information about NfL and ALSFRS-R and the remote sharing of these data.

METHODS: In a multicenter study, 149 ALS patients were assessed for their perception of shared information about NfL and ALSFRS-R using an investigator-designed survey and established questionnaires. The recommendation of NfL and ALSFRS-R to fellow patients was assessed using the Net Promoter Score (NPS). Burden by shared information was investigated in two distinct settings: (1) clinic information when receiving results on NfL and/or ALSFRS-R during clinic visits and (2) remote information about NfL values and self-rating of the ALSFRS-R via the ALS app. General anxiety was measured by the Fear of Progression Questionnaire - Short Form (FoP-Q-SF).

RESULTS: Information about NfL and ALSFRS-R, respectively (n = 149), were regarded as relevant for patients themselves (75.2% and 77.2%) and for research (98% and 96%). The NPS showed a high recommendation rate for NfL (+ 21) and ALSFRS-R (+ 26). Only a minority of patients perceived shared information about NfL as burdensome, with a lower burden in the clinic setting (n = 1, 4.2%) than in the remote setting (n = 8, 12%; p = 0.015). Remote digital assessment of the ALSFRS-R was well received, with a reported burden in 9.8% (n = 9) of the participants. The FoP-Q-SF revealed fear of progression in 40% of the respondents (n = 60).

CONCLUSIONS: This study underscored the relevance of information about NfL and ALSFRS-R from the patient's perspective. Furthermore, patients proved to appreciate the relevance of this data for ALS research. Sharing information about NfL or ALSFRS-R was rarely perceived as burdensome even in a remote setting using the ALS app. These findings pave the way for further development of the patient-centered approach to sharing prognostic information in ALS.}, } @article {pmid39910731, year = {2025}, author = {Singh, S and Khan, S and Khan, S and Ansari, O and Malhotra, N and Shukla, SK and Narang, J}, title = {Muscle Matters: Transforming Amyotrophic Lateral Sclerosis Diagnostics with Next-Gen Biosensors and Smart Detection.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {4}, pages = {563-587}, doi = {10.1021/acschemneuro.4c00664}, pmid = {39910731}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/genetics ; Humans ; *Biosensing Techniques/methods ; Biomarkers ; Electromyography/methods ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily targets the motor system, causing patients' speech and swallowing ability to rapidly deteriorate. Although ALS is usually classified into familial and sporadic forms, diagnosing it can be extremely difficult due to the absence of definitive biomarkers, often resulting in delays in diagnosis. Current diagnostic practices rely heavily on clinical assessments that indicate damage to both upper motor neurons (UMNs) and lower motor neurons (LMNs). This includes comprehensive physical examinations, electromyography (EMG) to assess neuromuscular function, and the exclusion of other similar conditions such as cervical spondylotic myelopathy, multifocal motor neuropathy, and Kennedy's disease through appropriate diagnostic procedures. The urgent need for specific biomarkers is critical for timely diagnosis and therapeutic advancements in ALS management. While many recent developments in research have not yet translated into direct patient benefits, the recognition of ALS as a complex disease is beginning to influence clinical practice significantly. Optimal management strategies emphasize on symptom control and improving the quality of life for patients within a holistic healthcare framework. This review provides a comprehensive overview of ALS, delving into its pathophysiology, clinical symptoms, and the latest advancements in detection methods that utilize traditional approaches, innovative biosensors, and smart diagnostic technologies. It discusses various treatment options available for ALS while exploring future developments that may enhance patient screening and improve clinical outcomes. By integrating assessments into the underlying mechanisms of the disease with cutting-edge diagnostic approaches, this review aims to contribute meaningfully to ongoing efforts to optimize ALS management and therapeutic strategies, ultimately improving patient care and outcomes.}, } @article {pmid39913612, year = {2025}, author = {Thomas, EV and Han, C and Kim, WJ and Asress, S and Li, Y and Taylor, JA and Gearing, M and Fournier, CN and McEachin, ZT and Seyfried, NT and Glass, JD}, title = {ALS plasma biomarkers reveal neurofilament and pTau correlate with disease onset and progression.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {4}, pages = {714-723}, pmid = {39913612}, issn = {2328-9503}, support = {P01 NS084974/NS/NINDS NIH HHS/United States ; 5P01NS084974/CL/CLC NIH HHS/United States ; //American Academy of Neurology/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/genetics ; *tau Proteins/blood ; Biomarkers/blood ; *Neurofilament Proteins/blood ; Female ; Male ; Middle Aged ; Disease Progression ; Adult ; Aged ; Pilot Projects ; Phosphorylation ; C9orf72 Protein/genetics ; }, abstract = {OBJECTIVE: We performed a pilot screen to assess the utility of the NULISA™ (Nucleic-acid-Linked Immuno-Sandwich Assay) platform in the identification of amyotrophic lateral sclerosis (ALS) biomarkers.

METHODS: Plasma from 86 individuals (48 ALS, 18 asymptomatic C9orf72 repeat expansion carriers (AsymC9), and 20 healthy controls) was analyzed via a multiplexed NULISA™ assay that includes 120 neurodegeneration-associated proteins. Statistical analysis of NULISA™ results was performed to identify proteins differentially expressed in plasma and their correlation with disease-associated parameters.

RESULTS: ALS plasma showed elevation of the established biomarkers, neurofilament light chain (NEFL) and neurofilament heavy chain (NEFH). Compared to controls and AsymC9, microtubule-associated protein tau (MAPT), phosphorylated tau 181 (pTau181), phosphorylated tau 217 (pTau217), phosphorylated tau 231 (pTau231), and phosphorylated TDP-43 (pTDP-43) were elevated in ALS. NEFL levels positively correlated with pTau181, pTau217, pTau231, and pTDP-43. MAPT and pTDP-43 were also correlated with pTau181, pTau217 and pTau231. Elevated pTau was negatively correlated with survival and ALSFRS-R. Spinal onset ALS was associated with higher pTau181, pTau217, and pTau231.

INTERPRETATION: We confirm previous reports showing elevated pTau181 in ALS plasma and show elevation of other phosphorylated tau forms, pTau217 and pTau231, typically observed in Alzheimer's disease. We provide preliminary data showing the detection and elevation of pTDP-43-409/410 in a subset of ALS samples compared to healthy controls. Neurofilament and tau levels are highly correlated suggesting their elevation may reflect a common pathology and disease state. Total and phosphorylated tau are correlated with multiple disease measures, such as ALS duration, ALSFRS-R, and site of onset.}, } @article {pmid39914221, year = {2025}, author = {Gusain, S and Mishra, CB and Yadav, K and Sharma, M and Saluja, D and Tiwari, M}, title = {Development of carbazole-based molecules for inhibition of mutant hSOD1 protein aggregation in Amyotrophic Lateral Sclerosis.}, journal = {Bioorganic & medicinal chemistry}, volume = {120}, number = {}, pages = {118091}, doi = {10.1016/j.bmc.2025.118091}, pmid = {39914221}, issn = {1464-3391}, mesh = {*Carbazoles/chemistry/pharmacology/chemical synthesis ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Humans ; *Superoxide Dismutase-1/metabolism/genetics/chemistry/antagonists & inhibitors ; *Protein Aggregates/drug effects ; Mutation ; Animals ; Apoptosis/drug effects ; Mice ; Molecular Structure ; Structure-Activity Relationship ; Dose-Response Relationship, Drug ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the loss of upper and lower motor neurons. Cu/Zn superoxide dismutase (SOD1) is one of the genes associated with the familial form of the disease (fALS). The mechanism of neuron degeneration by SOD1 is not clear, it is hypothesised that there is a toxic gain of function in the protein which leads to the downstream effects. In the present study, carbazole-based molecules have been rationally designed and synthesised as potential inhibitors of mutant hSOD1 protein aggregation. SG-9 and SG-10 prevented the aggregation of all three purified mutant hSOD1 proteins. Transmission electron microscopy and dynamic light scattering experiments also revealed that co-incubation of SG-9 and SG-10 with mutant hSOD1 protein resulted in smaller and slender fibril forming. Molecules SG-9 and SG-10 did not display toxicity and prevented Neuro-2a cells expressing hSOD1 G85R protein from its associated cytotoxicity. SG-9 and SG-10 were also able to prevent the transfected cells from apoptosis and were also able to reduce ROS levels associated with hSOD1 G85R protein aggregation significantly. Therefore, novel carbazole derivatives SG-9 and SG-10 proved to be effective inhibitors of mutant hSOD1 protein aggregation and can be further utilised as lead molecules for the amelioration of mutant hSOD1 aggregation-associated ALS.}, } @article {pmid39914266, year = {2025}, author = {Wei, D and Freydenzon, A and Guinebretiere, O and Zaidi, K and Yang, F and Ye, W and Hammar, N and Modig, K and Wray, NR and Feychting, M and Hamieh, N and Ventelou, B and Lekens, B and Gantzer, L and Durrleman, S and McRae, A and Couvy-Duchesne, B and Fang, F and Nedelec, T and , }, title = {Ten years preceding a diagnosis of neurodegenerative disease in Europe and Australia: medication use, health conditions, and biomarkers associated with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {113}, number = {}, pages = {105585}, pmid = {39914266}, issn = {2352-3964}, mesh = {Humans ; *Biomarkers/blood ; Aged ; Male ; Female ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; *Alzheimer Disease/epidemiology/diagnosis ; Europe/epidemiology ; *Parkinson Disease/epidemiology/diagnosis ; Australia/epidemiology ; Aged, 80 and over ; Case-Control Studies ; *Neurodegenerative Diseases/epidemiology/diagnosis ; Risk Factors ; }, abstract = {BACKGROUND: Many studies have investigated early predictors for Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, evidence is sparse regarding specific and common predictors for these diseases. We aimed to identify medication use, health conditions, and blood biomarkers that might be associated with the risk of AD, PD, and ALS ten years later.

METHODS: We conducted population-based nested case-control studies of AD, PD, and ALS using electronic medical records in Europe (France, the UK, and Sweden) and Australia. We retrieved data on medication use, diagnosed health conditions, and measured blood biomarkers from electronic medical records or biomedical cohorts. Conditional logistic regression models and meta-analysis were applied to assess the associations between these factors and the risk of receiving a diagnosis of AD, PD, or ALS.

FINDINGS: We included a total of 149,642 AD cases (mean age: 79.1-81.2 years), 252,696 PD cases (73.2-75.9 years), and 27,533 ALS cases (64.4-69.6 years). The prescription of psychoanaleptics and nasal preparations was consistently associated with an increased risk of AD, PD, and ALS 5-10 years later. Constipation and use of related medications were associated with an increased risk of AD and PD, while diabetes and use of antidiabetics were associated with a reduced risk of ALS. A higher level of triglycerides was associated with a lower risk of AD, whereas a higher level of Apolipoprotein B was associated with a lower risk of PD, 5-10 years later.

INTERPRETATION: Psychoanaleptics and nasal preparations may serve as common predictors for diagnosis of AD, PD, and ALS 5-10 years later. Conversely, the increased prevalence of constipation is specific to AD and PD, while the decreased prevalence of diabetes and use of antidiabetics is specific to ALS.

FUNDING: EU Joint Programme-Neurodegenerative Disease Research.}, } @article {pmid39914774, year = {2025}, author = {Zamani, A and Walker, AK and Wright, DK}, title = {Glymphatic dysfunction and neurodegeneration in ALS: Longitudinal insights from rNLS8 TDP-43 mice.}, journal = {Neurobiology of disease}, volume = {206}, number = {}, pages = {106832}, doi = {10.1016/j.nbd.2025.106832}, pmid = {39914774}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/diagnostic imaging/genetics/physiopathology ; *Glymphatic System/metabolism/diagnostic imaging/pathology/physiopathology ; *DNA-Binding Proteins/genetics/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Magnetic Resonance Imaging ; Humans ; Male ; Aquaporin 4/metabolism ; *Brain/metabolism/pathology/diagnostic imaging ; }, abstract = {Dysfunctional Tar DNA binding protein-43 (TDP-43) is found in approximately 95 % of all people with amyotrophic lateral sclerosis (ALS). Recent evidence suggests that the glymphatic system, which clears the brain of waste proteins, is impaired in ALS and may contribute to the accumulation of TDP-43. This study extends this work to investigate how glymphatic function changes over time in the rNLS8 doxycycline (Dox)-dependent TDP-43 mouse model of ALS. Motor function, advanced MRI biomarkers of neurodegeneration, and cortical glymphatic pathway gene expression were assessed together with dynamic contrast-enhanced MRI (DCE-MRI) assessment of glymphatic function at 0-, 3-, 7-, and 21-days after removing mice from Dox feed to initiate cytoplasmic human TDP-43 expression. A trend toward increased glymphatic influx was observed at 3-days post-Dox, together with MRI evidence of brain changes that occurred in the absence of hind-limb clasping and motor impairment. Glymphatic flow is facilitated by aquaporin-4 (AQP4) water channels polarized to astrocytic end feet. We found that while glymphatic function normalized to control levels at 7-days post-Dox, AQP4 expression in the cortex was significantly decreased. After 3-weeks of human TDP-43 expression, glymphatic dysfunction, weight loss, neurodegeneration, motor impairments and astrogliosis were observed. Our findings highlight early glymphatic dysfunction in ALS, suggesting its potential as a therapeutic target.}, } @article {pmid39915090, year = {2025}, author = {Noh, MY and Kwon, MS and Oh, KW and Nahm, M and Park, J and Jin, HK and Bae, JS and Son, B and Kim, SH}, title = {miRNA-214 to predict progression and survival in ALS.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {7}, pages = {716-720}, pmid = {39915090}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/mortality/blood ; *MicroRNAs/blood ; Disease Progression ; Male ; Female ; Middle Aged ; Aged ; Biomarkers/blood ; Neurofilament Proteins/blood ; Prognosis ; Adaptor Proteins, Signal Transducing/genetics ; Cohort Studies ; Cytokines/cerebrospinal fluid ; Adult ; Microglia/metabolism ; }, abstract = {BACKGROUND: Reliable biomarkers are essential for predicting the progression speed and prognosis of patients with amyotrophic lateral sclerosis (ALS). We previously identified NCK-associated protein 1 (NCKAP1) as a critical factor in the defective phagocytosis observed in induced microglia-like cells (iMGs) from patients with rapidly progressive sporadic ALS. This study explored the roles of microRNA (miRNA)-214, which targets the NCKAP1 gene, in the progression of ALS.

METHODS: The discovery cohort (n=29) was used to identify miR-214 targeting NCKAP1 genes. The validation cohort (n=132) was used to determine the clinical usability of miR-214 for predicting disease progression speed and survival time.

RESULTS: In the discovery cohort, miR-214 levels were increased in plasma and iMGs from rapidly progressive ALS participants. This finding was validated in another cohort of 132 ALS participants and 30 age-matched healthy volunteers. Plasma miR-214 levels correlated with disease progression, severity and survival, distinguishing between rapidly progressive and slowly progressive ALS. In addition, miR-214 levels also correlated with plasma neurofilament light chain (NfL) and cerebrospinal fluid inflammatory cytokines, showing specific associations with increased NfL and monocyte chemoattractant protein 1 (MCP-1). Survival prediction accuracy improved when miR-214 levels were considered with NfL or MCP-1 levels.

CONCLUSIONS: Plasma miRNA-214 could serve as a novel biomarker for predicting the progression and prognosis of ALS.}, } @article {pmid39916336, year = {2025}, author = {Calvi, F and Fortuna, A and Bello, L and Anglani, M and Cecchin, D and Sabbatini, D and Andrigo, C and Ferullo, M and Ruggero, S and Falda, M and Pegoraro, E and Sorarù, G}, title = {MEPs and MRI Motor Band Sign as Potential Complementary Markers of Upper Motor Neuron Involvement in Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {32}, number = {2}, pages = {e70055}, pmid = {39916336}, issn = {1468-1331}, support = {//EuroBiobank/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/pathology/diagnostic imaging ; Male ; Female ; Middle Aged ; *Magnetic Resonance Imaging ; *Evoked Potentials, Motor/physiology ; Aged ; Retrospective Studies ; *Motor Neurons/pathology/physiology ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of both upper and lower motor neurons (UMNs and LMNs). Recognizing the involvement of UMNs is challenging because of the absence of reliable biomarkers beyond clinical evaluation.

AIM: To identify a reliable marker of UMN damage in a cohort of patients with ALS referring to the Motor Neuron Disease Clinic of the University Hospital of Padova.

METHODS: We retrospectively evaluated the clinical records of 79 patients with ALS and compared the results of various investigations, including the motor-evoked potentials (MEPs), positron emission tomography-magnetic resonance imaging (MRI) and light neurofilaments (NfLs), with the degree of UMN clinical involvement, as assessed by the Penn Upper Motor Neuron Score (PUMNS).

RESULTS: MEPs, considering the central motor conduction time (CMCT) values in both the upper and lower limbs, showed a significant correlation with the relative PUMNS subscores (p = 0.01, ρ = 0.4; and p = 0.005, ρ = 0.45, respectively). Additionally, there was a positive correlation between NfLs and PUMNS values (p = 0.04, ρ = 0.33). The presence of the motor band sign on MRI was associated with higher PUMNS values. Receiver operating characteristic analysis revealed that PUMNS accurately predicted abnormalities in CMCT values (specificity 86%, sensitivity 62%) and the presence of the motor band sign (specificity 58%, sensitivity 80%).

INTERPRETATION: In our cohort of patients with ALS, CMCT values proved to be the most reliable test for assessing UMN involvement, albeit the presence of the motor band sign on MRI showed higher sensitivity.}, } @article {pmid39916853, year = {2025}, author = {Rosina, M and Scaricamazza, S and Riggio, F and Fenili, G and Giannessi, F and Matteocci, A and Nesci, V and Salvatori, I and Angelini, DF and Aquilano, K and Chiurchiù, V and Lettieri Barbato, D and Mercuri, NB and Valle, C and Ferri, A}, title = {Brown Adipose Tissue undergoes pathological perturbations and shapes C2C12 myoblast homeostasis in the SOD1-G93A mouse model of Amyotrophic Lateral Sclerosis.}, journal = {Heliyon}, volume = {11}, number = {3}, pages = {e41801}, pmid = {39916853}, issn = {2405-8440}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons. The contribution of peripheral organs remains incompletely understood. We focused our attention on brown adipose tissue (BAT) and its secreted extracellular vesicles (EVs) given their role in regulating systemic energy balance. In this study, we employed a multi-omics approach, including RNA sequencing (GEO identifier GSE273052) and proteomics (ProteomeXchange identifier PXD054147), to investigate the alterations in BAT and its EVs in the SOD1-G93A mouse model of ALS. Our results revealed consistent changes in the proteomic and transcriptomic profiles of BAT from SOD1-G93A mice, highlighting alterations such as mitochondrial dysfunction and impaired differentiation capacity. Specifically, primary brown adipocytes (PBAs) from SOD1-G93A mice exhibited differentiation impairment, respiratory defects, and alterations in mitochondrial dynamics. Furthermore, the BAT-derived EVs from SOD1-G93A mice displayed distinct changes in size distribution and cargo content. In parallel, such EVs negatively impacted the differentiation and homeostasis of C2C12 murine myoblasts, as well as induced atrophy in C2C12-derived myotubes. These findings suggest that BAT undergoes pathological perturbations in ALS mouse model and could impact on skeletal muscle homeostasis through the secretion of dysfunctional EVs.}, } @article {pmid39916983, year = {2024}, author = {González Bolívar, S and Ayoubi, R and Alende, C and Fothouhi, M and Shlaifer, I and McPherson, PS and Laflamme, C and , and , }, title = {A guide to selecting high-performing antibodies for VAPB (UniProt ID: O95292) for use in western blot, immunoprecipitation, and immunofluorescence.}, journal = {F1000Research}, volume = {13}, number = {}, pages = {1559}, pmid = {39916983}, issn = {2046-1402}, mesh = {Humans ; *Immunoprecipitation/methods ; *Blotting, Western/methods ; *Fluorescent Antibody Technique/methods ; *Antibodies/immunology ; *Vesicular Transport Proteins/immunology/genetics/metabolism ; }, abstract = {VAPB is an adaptor protein known for its role as an anchor for other proteins at the endoplasmic reticulum. A mutant form of VAPB has been linked to amyotrophic lateral sclerosis and the underlying mechanisms resulting from this defect are studied by researchers in this area to uncover its implication in the disease. Here we have characterized six VAPB commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.}, } @article {pmid39917359, year = {2025}, author = {Ahmadi Marzaleh, M and Bastani, P and Raeyat Mohtashami, A and Farhadi, P and Ghanbari, S and Ravangard, R}, title = {Predicting Factors Affecting the Behavior of Healthcare Employees in the Use of Personal Protective Equipment During Epidemics Based on Godin et al's Model: A Study in Iran.}, journal = {Health services insights}, volume = {18}, number = {}, pages = {11786329251316668}, pmid = {39917359}, issn = {1178-6329}, abstract = {BACKGROUND: Protecting healthcare employees and preventing infection transmission are paramount concerns during epidemics. Predicting healthcare employees' behavior regarding the use of personal protective equipment (PPE) and identifying the related effective factors can guide educational and administrative strategies and enable timely interventions during outbreaks. This study aimed to predict factors affecting the healthcare employees' behavior in the use of PPE at Shiraz University of Medical Sciences in Iran, based on Godin et al's model.

METHODS: This was a cross-sectional and descriptive-analytical study. After reviewing the related articles and interviewing the experts and based on the model of Godin et al. (2008), a questionnaire was developed, validated, and tested for reliability using face and content validity as well as Cronbach's alpha. Collected data were analyzed using SPSS v.21 and modeled by Structural Equation Modeling (SEM) via SPSS v.21 and Smart PLS v.3 software.

RESULTS: The questionnaire was valid (CVI = 86.42, CVR = 81.71) and reliable (α = .85). The model exhibited appropriate measurement, structural, and overall fit. Beliefs about consequences, social influences, habits/past behavior, role and identity, characteristics of employees, moral norms, and beliefs about capabilities indirectly and significantly influenced behavior (P < .001). Additionally, beliefs about capabilities (P < .001), habits/past behavior (P = .001), and intention (P = .001) directly and significantly influenced PPE use behavior during epidemics.

CONCLUSION: The results emphasized the necessity of targeted interventions based on the studied model constructs within healthcare organizations. By promoting positive beliefs about PPE effectiveness and encouraging appropriate intentions and behaviors, healthcare organizations can significantly improve employee's adherence to PPE use during pandemics.}, } @article {pmid39918735, year = {2025}, author = {Wentzel, A and Smith, W and Jansen van Vuren, E and Kruger, R and Breet, Y and Wonkam-Tingang, E and Hanchard, NA and Chung, ST}, title = {Allostatic load and cardiometabolic health in a young adult South African population: the African-PREDICT study.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {328}, number = {3}, pages = {H581-H593}, doi = {10.1152/ajpheart.00845.2024}, pmid = {39918735}, issn = {1522-1539}, support = {//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; //South African Medical Research Council (SAMRC)/ ; //South African National Research Foundation (SA-NRF)/ ; //Newton Fund (NF)/ ; //Pfizer (South Africa)/ ; //Boeringer-Ingelheim (South Africa)/ ; //Norvatis (South Africa)/ ; //MediClinic Hospital Group (South Africa)/ ; //Roche Holding | Roche Diagnostics (Roche Diagnostics Corporation)/ ; }, mesh = {Humans ; *Allostasis ; Male ; Female ; South Africa/epidemiology ; Adult ; Young Adult ; Prospective Studies ; Cardiometabolic Risk Factors ; *Hypertension/physiopathology/epidemiology/diagnosis/blood ; *Cardiovascular Diseases/physiopathology/epidemiology/diagnosis/blood ; Biomarkers/blood ; Age Factors ; Risk Assessment ; *Prediabetic State/epidemiology/physiopathology/diagnosis/blood ; Blood Pressure ; *Stress, Psychological/physiopathology/epidemiology/diagnosis/blood ; Inflammation Mediators/blood ; }, abstract = {Sustained stress, assessed as a high allostatic load score (ALS), is an independent cardiovascular disease (CVD) risk factor in older adults but its associations in young people are undefined. Since neurological maturation impacts stress adaptation and CVD risk, we assessed the relationship of ALS with CVD profile by using a tiered approach stratified by age [emerging adults (EA) aged 20-24 yr vs. young adults (YA) aged 25-30 yr] and ALS (high vs. low). In 1,054 healthy participants of the African Prospective Study on Early Detection and Identification of Cardiovascular Disease and Hypertension (African-PREDICT), we determined: 1) ALS in EA versus YA; 2) the relationship between ALS and cardiovascular (CV) health, and 3) the odds of high ALS > 4 to identify masked hypertension (HT) and prediabetes as cardiometabolic outcomes. A nine-component, four-domain ALS was compiled: neuroendocrine [dehydroepiandrosterone (DHEA), cortisol], inflammatory [interleukin-6 (IL-6), C-reactive protein (CRP)], cardiovascular [systolic blood pressure (SBP) and diastolic blood pressure (DBP)], and metabolic [total cholesterol, high density lipoprotein cholesterol (HDL-cholesterol), body mass index (BMI)]. Retinal vessel caliber, pulse wave velocity (PWV), and cardiac structure and function were assessed. Median ALS was 3 (range: 1-9). A high-ALS > 4 was more common in YA versus EA (47 vs. 35%, P = 0.032). Higher ALS associated with narrower retinal arteries (P < 0.01), greater PWV (P ≤ 0.01), lower diastolic function (P < 0.01), and left ventricular (LV) function (P < 0.01). High-ALS increased the odds of having masked hypertension, prediabetes, narrower retinal arteries, higher LV mass, poorer diastolic and ventricular functions (all P ≤ 0.01), in EA and YA independent of traditional CVD risk factors. The composite ALS identified early-stress dysregulation in cardiometabolic health and higher odds for masked hypertension and prediabetes in young adults. Cumulative stress may be a modifiable, independent cardiometabolic risk factor in younger populations that needs further investigation.NEW & NOTEWORTHY This is the first study to assess the effect of stress, as a composite allostatic load score, on micro-, macrovascular, and central cardiac features in healthy emerging and young adults, independent of traditional cardiovascular risk markers. It exemplifies independent stress-induced changes throughout the cardiovascular tree, which may increase the risk of cardiometabolic complications, masked hypertension, and prediabetes. Sustained stress may be a key etiological factor in cardiometabolic disease development in a young population.}, } @article {pmid39920055, year = {2025}, author = {Ramsden, V and McInnes, E and Wilson, P and Babl, FE and Kuhn, L and Cowie, J and Campbell, P and Middleton, S and Wilson, C and Straiton, N and Tavender, E}, title = {Sustainability of healthcare system improvements, programmes and interventions in acute care settings: protocol for a mixed methods systematic review.}, journal = {BMJ open}, volume = {15}, number = {2}, pages = {e094174}, pmid = {39920055}, issn = {2044-6055}, mesh = {Humans ; Systematic Reviews as Topic ; *Delivery of Health Care/standards/organization & administration ; *Quality Improvement ; Research Design ; Program Evaluation ; }, abstract = {INTRODUCTION: Sustaining evidence-based care is challenging in all clinical settings. Acute care settings have a unique set of contextual factors that may impact sustainability (eg, fast-paced, regular staff turnover). Much of the previous research explores sustainability across undifferentiated healthcare settings making it difficult to determine factors that influence sustainability in acute care settings. The aim of this review is to identify facilitators and barriers that influence the delivery of sustained healthcare interventions (eg, integration of clinical guidelines) within adult and paediatric hospital-based acute care settings.

METHODS AND ANALYSIS: A mixed methods systematic review updating Cowie et al's (which included studies from 2008 to 2017) previously published systematic review will be conducted. The following databases will be searched: Medline, Embase, Cochrane Database of Systematic Reviews, CINAHL and Allied and Complementary Medicine (AMED), from November 2017 to the present for studies published in English. Relevant reference lists of included studies will be manually searched. Empirical quantitative and qualitative studies that report the sustainability of an intervention or programme in acute care settings using a theoretical framework(s), model(s) or theory(ies) to explore facilitators and barriers, will be included. Studies will be exported into Covidence (Melbourne) and pairs of reviewers will independently screen abstracts and full-text studies. The discussion will be used to resolve any disagreements and a third coauthor enlisted should a consensus not be reached. Two independent coauthors will extract key study characteristics and assess each study's quality. Data will be extracted using Covidence (Melbourne). Evidence tables will be used to present descriptive data. Facilitators and barriers will be mapped to the Consolidated Framework for Sustainability Constructs in Healthcare and a narrative approach will be used to present key findings.

ETHICS AND DISSEMINATION: No primary data will be collected so formal ethical approval is not required. Findings will be disseminated through peer-reviewed publications, presented at international conferences and on social media.

PROSPERO REGISTRATION NUMBER: PROSPERO CRD42024547535.}, } @article {pmid39920775, year = {2025}, author = {Yousefian-Jazi, A and Kim, S and Chu, J and Choi, SH and Nguyen, PTT and Park, U and Kim, MG and Hwang, H and Lee, K and Kim, Y and Hyeon, SJ and Rhim, H and Ryu, HL and Lim, G and Stein, TD and Lim, K and Ryu, H and Lee, J}, title = {Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {16}, pmid = {39920775}, issn = {1750-1326}, support = {R01NS109537//NIH R01/ ; 2E30954//KIST Grant/ ; HU23C0217//Korea Dementia Research Project Grant/ ; 2022R1A2C3013138//National Research Foundation/ ; R01 NS109537/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Mitochondria/metabolism/genetics/pathology ; Mice ; *MEF2 Transcription Factors/genetics ; Humans ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Mutation/genetics ; HEK293 Cells ; Disease Models, Animal ; Enhancer Elements, Genetic/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, leading to progressive paralysis. Both genetic alterations and epigenetic modifications contribute to neuronal dysfunction in the pathogenesis of ALS. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear.

METHODS: Convolutional neural network was used to identify an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element. To examine the alteration of MEF2C transcription by the SNP, we generated HEK293T cells carrying the major or minor allele by CRISPR-Cas9. To verify the role of MEF2C-knockdown (MEF2C-KD) in mice, we developed AAV expressing shRNA for MEF2C based on AAV-U6 promoter vector. Neuropathological alterations of MEF2C-KD mice with mitochondrial dysfunction and motor neuronal damage were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through longitudinal study by tail suspension, inverted grid test and automated gait analysis.

RESULTS: Here, we show that enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits.

CONCLUSIONS: Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.}, } @article {pmid39921200, year = {2025}, author = {Shiozumi, T and Matsuyama, T and Nishioka, N and Kiguchi, T and Kitamura, T and Ohta, B and Iwami, T}, title = {Evaluation of interventions in prehospital and in-hospital settings and outcomes for out-of-hospital cardiac arrest patients meeting the termination of resuscitation rule in Japan: A nationwide database study (The JAAM-OHCA Registry).}, journal = {Resuscitation}, volume = {208}, number = {}, pages = {110530}, doi = {10.1016/j.resuscitation.2025.110530}, pmid = {39921200}, issn = {1873-1570}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Japan/epidemiology ; Male ; Female ; Retrospective Studies ; Registries ; *Emergency Medical Services/statistics & numerical data/methods ; Aged ; *Cardiopulmonary Resuscitation/methods/statistics & numerical data ; Middle Aged ; Airway Management/statistics & numerical data ; Databases, Factual ; Epinephrine/administration & dosage ; Aged, 80 and over ; Advanced Cardiac Life Support/statistics & numerical data ; }, abstract = {BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a global health burden with low survival rates. The termination of resuscitation (TOR) rule, widely adopted internationally, aims to preserve dignity, optimize resources, and protect healthcare providers. However, prehospital TOR is not implemented in Japan, presenting legal and practical challenges. This study analyzes temporal trends in prehospital and in-hospital interventions for OHCA patients with poor predicted outcomes.

METHODS: This retrospective study analyzed data from the Japanese Association for Acute Medicine Out-of-Hospital Cardiac Arrest (JAAM-OHCA) registry (June 2014-December 2021). Adult OHCA patients with medical causes were included if they fulfilled all the advanced life support (ALS) TOR rule criteria: unwitnessed arrest, no return of spontaneous circulation, no bystander-initiated cardiopulmonary resuscitation, and no automated external defibrillator use or defibrillation. Prehospital and in-hospital interventions were evaluated.

RESULTS: Among 11,334 patients meeting the inclusion criteria, 2,447 received all three ALS interventions (advanced airway management, intravenous access, and epinephrine administration). Over time, in-hospital interventions, including endotracheal intubation (56%) and epinephrine administration (82%), decreased, while advanced therapies, including coronary angiography, extracorporeal membrane oxygenation, and targeted temperature management, remained rare (<1%). The median time to TOR after hospital arrival shortened to 18 min. In contrast, prehospital epinephrine administration increased, while advanced airway management and intravenous access decreased.

CONCLUSIONS: OHCA patients who met TOR rule showed a decrease in in-hospital interventions. Further efforts are warranted to avoid futile medical treatments and promote patient-centered care.}, } @article {pmid39922366, year = {2025}, author = {Kopalli, SR and Behl, T and Kyada, A and Rekha, MM and Kundlas, M and Rani, P and Nathiya, D and Satyam Naidu, K and Gulati, M and Bhise, M and Gupta, P and Wal, P and Fareed, M and Ramniwas, S and Koppula, S and Gasmi, A}, title = {Synaptic plasticity and neuroprotection: The molecular impact of flavonoids on neurodegenerative disease progression.}, journal = {Neuroscience}, volume = {569}, number = {}, pages = {161-183}, doi = {10.1016/j.neuroscience.2025.02.007}, pmid = {39922366}, issn = {1873-7544}, mesh = {Humans ; *Neuronal Plasticity/drug effects/physiology ; *Flavonoids/pharmacology/therapeutic use ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neuroprotection/drug effects/physiology ; Signal Transduction/drug effects ; Disease Progression ; }, abstract = {Flavonoids are a broad family of polyphenolic chemicals that are present in a wide variety of fruits, vegetables, and medicinal plants. Because of their neuroprotective qualities, flavonoids have attracted a lot of interest. The potential of flavonoids to control synaptic plasticity-a crucial process underlying memory, learning, and cognitive function-is becoming more and more clear. Dysregulation of synaptic plasticity is a feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (0.4 %), Parkinson's (1-2 %), Alzheimer's (5-7 %), and Huntington's ((0.2 %)). This review discusses the molecular mechanisms via which flavonoids influence synaptic plasticity as well as their therapeutic potential in neurodegenerative diseases. Flavonoids modulate key signaling pathways such as MAPK/ERK and PI3K/Akt/mTOR to support neuroprotection, synaptic plasticity, and neuronal health, while also influencing neurotrophic factors (BDNF, NGF) and their receptors (TrkB, TrkA). They regulate neurotransmitter receptors like GABA, AMPA, and NMDA to balance excitatory and inhibitory transmission, and exert antioxidant effects via the Nrf2-ARE pathway and anti-inflammatory actions by inhibiting NF-κB signaling, highlighting their potential for treating neurodegenerative diseases. These varied reactions support the preservation of synapse function and neuronal integrity in the face of neurodegenerative insults. Flavonoids can reduce the symptoms of neurodegeneration, prevent synaptic loss, and enhance cognitive function, according to experimental studies. However, there are still obstacles to using these findings in clinical settings, such as limited bioavailability and the need for consistent dose. The focus of future research should be on improving flavonoid delivery systems and combining them with conventional medications.}, } @article {pmid39922547, year = {2025}, author = {Rossi, S and Milani, M and Della Valle, I and Apolloni, S}, title = {Transcriptomic profiling of symptomatic and end-stage SOD1-G93A transgenic mice reveals extracellular matrix components as key players in ALS pathogenesis.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1871}, number = {4}, pages = {167707}, doi = {10.1016/j.bbadis.2025.167707}, pmid = {39922547}, issn = {1879-260X}, } @article {pmid39923073, year = {2025}, author = {Wang, Z and Yin, Z and Sun, G and Zhang, D and Zhang, J}, title = {Genetic evidence for the liver-brain axis: lipid metabolism and neurodegenerative disease risk.}, journal = {Lipids in health and disease}, volume = {24}, number = {1}, pages = {41}, pmid = {39923073}, issn = {1476-511X}, mesh = {Humans ; *Lipid Metabolism/genetics ; Genome-Wide Association Study ; *Liver/metabolism/pathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Brain/metabolism/pathology ; Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Parkinson Disease/genetics/metabolism/pathology ; Cholesterol, LDL/blood/genetics ; Alzheimer Disease/genetics/pathology/metabolism ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Risk Factors ; Multiple Sclerosis/genetics/metabolism/pathology ; Male ; Female ; Cholesterol/blood ; }, abstract = {BACKGROUND: The liver‒brain axis is critical in neurodegenerative diseases (NDs), with lipid metabolism influencing neuroinflammation and microglial function. A systematic investigation of the genetic relationship between lipid metabolism abnormalities and ND, namely, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), is lacking. To assess potential causal links between ND and six lipid parameters, two-sample Mendelian randomization (MR) was used.

METHODS: Large-scale European ancestry GWAS data for lipid parameters and ND (AD, ALS, PD, and MS) were used. Genetic variants demonstrating significant correlations (P < 5 × 10[-8]) with lipid metabolism parameters were identified and employed as instrumental variables (IVs) after proper validation. The research incorporated UK Biobank genomic data to examine associations between genetic variants and lipid metabolism parameters. The analysis included primary MR, sensitivity analyses, and multivariable MR, which considered potential mediators.

RESULTS: MR via the inverse-variance weighted method revealed causal effects of cholesterol (CHOL, OR = 1.10, 95% CI: 1.03-1.18, P = 4.23 × 10⁻[3]) and low-density lipoprotein cholesterol (LDLC, OR = 1.10, 95% CI: 1.03-1.17, P = 3.28 × 10⁻[3]) on the risk of ALS, which were validated across multiple methods. Potential correlations were observed between ApoB and ALS and inversely correlated with AD, whereas no significant associations were found for PD or MS. CHOL and LDLC associations with ALS demonstrated no significant heterogeneity or pleiotropy, supporting their reliability.

CONCLUSIONS: Higher CHOL and LDLC levels were associated with increased ALS risk, suggesting a potential causal link, and supporting the liver‒brain axis hypothesis in ND. Current genetic evidence does not support a significant role for lipid metabolism in PD and MS etiology, suggesting the relationship between lipid metabolism and other NDs may be more complex and warrants further investigation.}, } @article {pmid39924298, year = {2025}, author = {Malouin-Lachance, A and Capolupo, J and Laplante, C and Hudon, A}, title = {Does the Digital Therapeutic Alliance Exist? Integrative Review.}, journal = {JMIR mental health}, volume = {12}, number = {}, pages = {e69294}, pmid = {39924298}, issn = {2368-7959}, mesh = {Humans ; *Digital Health ; *Mental Disorders/therapy ; *Artificial Intelligence ; *Psychotherapy/methods ; *Therapeutic Alliance ; }, abstract = {BACKGROUND: Mental health disorders significantly impact global populations, prompting the rise of digital mental health interventions, such as artificial intelligence (AI)-powered chatbots, to address gaps in access to care. This review explores the potential for a "digital therapeutic alliance (DTA)," emphasizing empathy, engagement, and alignment with traditional therapeutic principles to enhance user outcomes.

OBJECTIVE: The primary objective of this review was to identify key concepts underlying the DTA in AI-driven psychotherapeutic interventions for mental health. The secondary objective was to propose an initial definition of the DTA based on these identified concepts.

METHODS: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) for scoping reviews and Tavares de Souza's integrative review methodology were followed, encompassing systematic literature searches in Medline, Web of Science, PsycNet, and Google Scholar. Data from eligible studies were extracted and analyzed using Horvath et al's conceptual framework on a therapeutic alliance, focusing on goal alignment, task agreement, and the therapeutic bond, with quality assessed using the Newcastle-Ottawa Scale and Cochrane Risk of Bias Tool.

RESULTS: A total of 28 studies were identified from an initial pool of 1294 articles after excluding duplicates and ineligible studies. These studies informed the development of a conceptual framework for a DTA, encompassing key elements such as goal alignment, task agreement, therapeutic bond, user engagement, and the facilitators and barriers affecting therapeutic outcomes. The interventions primarily focused on AI-powered chatbots, digital psychotherapy, and other digital tools.

CONCLUSIONS: The findings of this integrative review provide a foundational framework for the concept of a DTA and report its potential to replicate key therapeutic mechanisms such as empathy, trust, and collaboration in AI-driven psychotherapeutic tools. While the DTA shows promise in enhancing accessibility and engagement in mental health care, further research and innovation are needed to address challenges such as personalization, ethical concerns, and long-term impact.}, } @article {pmid39926223, year = {2025}, author = {Moore, S and Donlon, NE}, title = {Improving gastrointestinal scoring systems for predicting short-term mortality in critically ill patients.}, journal = {World journal of gastroenterology}, volume = {31}, number = {5}, pages = {102622}, pmid = {39926223}, issn = {2219-2840}, mesh = {Humans ; *Critical Illness/mortality ; *Gastrointestinal Diseases/mortality/diagnosis ; Intensive Care Units/statistics & numerical data ; Retrospective Studies ; Severity of Illness Index ; Prognosis ; Hospital Mortality ; Predictive Value of Tests ; Risk Assessment/methods ; }, abstract = {Shen et al's retrospective study aims to compare the utility of two separate scoring systems for predicting mortality attributable to gastrointestinal (GI) injury in critically ill patients [the GI Dysfunction Score (GIDS) and the Acute Gastrointestinal Injury (AGI) grade]. The authors note that this study is the first proposal that suggests an equivalence between the ability of both scores to predict mortality at 28 days from intensive care unit (ICU) admission. Shen et al retrospectively analysed an ICU cohort of patients utilising two physicians administering both the AGI grade and GIDS score, using electronic healthcare records and ICU flowsheets. Where these physicians disagreed about the scores, the final decision as to the scores was made by an associate chief physician, or chief physician. We note that the primary reason for the development of GIDS was to create a clear score for GI dysfunction, with minimal subjectivity or inter-operator variability. The subjectivity inherent to the older AGI grading system is what ultimately led to the development of GIDS in 2021. By ensuring consensus between physicians administering the AGI, Shen et al have controlled for one of this grading systems biggest issues. We have concerns, however, that this does not represent the real-world challenges associated with applying the AGI compared to the newer GIDS, and wonder if this arbitration process had not been instituted, would the two scoring systems remain equivalent in terms of predicted mortality?}, } @article {pmid39927436, year = {2025}, author = {}, title = {Novel Biomarkers of FTD-ALS.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {31}, number = {1}, pages = {6}, doi = {10.1177/10738584241308752}, pmid = {39927436}, issn = {1089-4098}, } @article {pmid39928236, year = {2025}, author = {Kaspute, G and Ramanavicius, A and Prentice, U}, title = {Natural drug delivery systems for the treatment of neurodegenerative diseases.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {217}, pmid = {39928236}, issn = {1573-4978}, support = {S-MIP-24-111//Research Council of Lithuania (LMTLT)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; *Biological Products/therapeutic use/administration & dosage ; Nanoparticles/chemistry ; Liposomes ; Anti-Inflammatory Agents ; Biological Availability ; }, abstract = {Today, herbal drugs are prominent in the pharmaceutical industry due to their well-known therapeutic and side effects. Plant-based compounds often face limitations such as poor solubility, low bioavailability, and instability in physiological environments, restricting their therapeutic efficacy and delivery. Nanotechnology-based solutions, including nanoparticle formulations and advanced delivery systems like liposomes and transfersomes, address these issues by enhancing solubility, stability, bioavailability, and targeted delivery, thereby optimizing the therapeutic potential of phytoactive compounds. Neuroinflammation can be a cause of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, or amyotrophic lateral sclerosis. Consequently, there is a need for the optimal delivery of a pharmacological anti-inflammatory agents to the CNS. Thus, the non-invasive administration of a stable compound at a therapeutic concentration is needed to assure molecule crossing through the blood-brain barrier. Natural resources have more structural diversity and novelty than synthetic compounds, e.g. plant-derived drug products have higher molecular weights, incorporate more oxygen atoms, and are more complex. As a result, plant-derived products have unique features which can be used to effectively modulate neuroinflammation. Therefore, this review aims to identify herbal molecules capable of targeting neuroinflammation and present novel strategies for their efficient delivery.}, } @article {pmid39928509, year = {2025}, author = {Scafide, KN and Arundel, L and Assas, G and King, EL}, title = {Pressure injury detection using alternate light: a proof-of-concept study.}, journal = {Journal of wound care}, volume = {34}, number = {Sup2}, pages = {S17-S23}, doi = {10.12968/jowc.2023.0304}, pmid = {39928509}, issn = {0969-0700}, mesh = {Humans ; *Pressure Ulcer/diagnosis ; Male ; Female ; Proof of Concept Study ; Middle Aged ; Aged ; *Light ; Adult ; Skin Pigmentation ; Aged, 80 and over ; }, abstract = {OBJECTIVE: Identification of early-stage pressure injuries (PIs) during visual skin assessment may be subjective and unreliable. An alternate light source (ALS) has been shown to increase the probability of detecting evidence of bruises on individuals with darker skin tones. Bruises and early-stage PIs are often difficult to identify, especially in those with darker skin tones, where melanin concentration is high. Given the effect skin pigmentation has on detecting both types of cutaneous injuries, this proof-of-concept study aimed to describe the characteristics of Stage 1 PIs and deep tissue PIs as viewed under an ALS.

METHOD: Eligible participants were first examined by a certified wound ostomy continence nurse using environmentally available white light. A blinded second examiner then evaluated the size of the potential tissue impairment using violet (406nm) and blue (448nm) ALS viewed through yellow and orange goggles, respectively. Portable ultrasound was used to confirm tissue involvement. Data were summarised using descriptive statistics.

RESULTS: The study included 10 participants (40% of whom were from minority racial/ethnic groups) with a mean Braden Scale score of 11.1. The majority of PIs (80%) involved deep tissue and were located on lower extremities (60%). The median PI size was larger by 17.5cm[2] and 13.7cm[2], respectively, using ALS compared with white light when viewed under violet and blue wavelengths. Ultrasound data were limited to non-extremity regions (n=3 participants) with hypoechoic areas noted as being 10-13mm in thickness and up to 16.7mm deep.

CONCLUSION: Evidence of tissue damage that extended beyond that visualised under white light was noted with ALS. Usefulness of ultrasound was limited over bony prominences where there was too little subcutaneous tissue. Further research is warranted to investigate the potential application of ALS for the early detection of PIs.}, } @article {pmid39929112, year = {2025}, author = {Zhao, H and Liu, L and Zeng, Y and Nie, X and Wang, J and Bai, L and Pan, L}, title = {Identification of metabolic enzyme genes linked to mesosulfuron-methyl resistance in Bromus japonicus.}, journal = {Plant physiology and biochemistry : PPB}, volume = {221}, number = {}, pages = {109609}, doi = {10.1016/j.plaphy.2025.109609}, pmid = {39929112}, issn = {1873-2690}, mesh = {*Sulfonylurea Compounds/pharmacology ; *Herbicide Resistance/genetics ; Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Herbicides/pharmacology ; *Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; *Genes, Plant ; Cytochrome P-450 Enzyme System/genetics/metabolism ; }, abstract = {Bromus japonicus is a very troublesome weed in major winter wheat fields in China and substantially reduces wheat yield. Resistance to acetolactate synthase (ALS)-inhibiting herbicides in B. japonicus has become increasingly prevalent in recent years. While the mechanism of target site resistance (TSR) to ALS-inhibiting herbicides in B. japonicus has been well elucidated, the understanding of non-target site resistance (NTSR) remains limited. In this study, we identified a B. japonicus population (BJ-NTSR-1) which has developed resistance to mesosulfuron-methyl. Compared to the mesosulfuron-methyl-susceptible population (BJ-S), the resistance level of BJ-NTSR-1 was found to be 22.56 times higher. Based on the results of ALS gene sequencing and relative expression analyses, TSR was not detected in the BJ-NTSR-1 population. Additionally, pretreatment with cytochrome P450 (CYP450) and glutathione S-transferase (GST) inhibitors did not reverse the resistance to mesosulfuron-methyl in BJ-NTSR-1 population. RNA-seq and RT-qPCR analyses revealed that, three uridine 5'-diphospho-glucosyl transferase (UGT) genes (UGT76F1, UGT88F5, and UGT85A1), four ATP-binding cassette (ABC) transporter genes (ABCB19s, ABCG1, and ABCB21), and three CYP450 genes (CYP71C1, CYP71C2, and CYP72A15) are significantly upregulated in the BJ-NTSR-1 population. Among these genes, the overexpression of ABCG1 enhanced yeast resistance to mesosulfuron-methyl. These genes are likely involved in mediating NTSR to mesosulfuron-methyl in the BJ-NTSR-1 population. This study presents the first global report that CYP450, UGT, and ABC transporter genes may collectively mediate NTSR to ALS-inhibiting herbicides in Brome species.}, } @article {pmid39929580, year = {2025}, author = {Matheoudakis, K and O'Connor, JJ}, title = {Modulatory and protective effects of prolyl hydroxylase domain inhibitors in the central nervous system.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {102}, number = {}, pages = {211-235}, doi = {10.1016/bs.apha.2024.10.006}, pmid = {39929580}, issn = {1557-8925}, mesh = {Humans ; Animals ; *Prolyl-Hydroxylase Inhibitors/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Central Nervous System/drug effects/metabolism ; }, abstract = {Oxygen is essential for all mammalian species, with complex organs such as the brain requiring a large and steady supply to function. During times of low or inadequate oxygen supply (hypoxia), adaptation is required in order to continue to function. Hypoxia inducible factors (HIF) are transcription factors which are activated during hypoxia and upregulate protective genes. Normally, when oxygen levels are sufficient (normoxia) HIFs are degraded by oxygen sensing prolyl hydroxylase domain proteins (PHD), but during hypoxia PHDs no longer exert influence on HIFs allowing their activation. Given that PHDs regulate the activity of HIFs, their pharmacological inhibition through PHD inhibitors (PHDIs) is believed to be the basis of their neuroprotective benefits. This review discusses some of the potential therapeutic benefits of PHDIs in a number of neurological disorders which see hypoxia as a major pathophysiological mechanism. These include stroke, Parkinson's disease, and amyotrophic lateral sclerosis. We also explore the potential neuroprotective benefits and limitations of PHDIs in a variety of disorders in the central nervous system (CNS). Additionally, the activation of HIFs by PHDIs can have modulatory effects on CNS functions such as neurotransmission and synaptic plasticity, mechanisms critical to cognitive processes such as learning and memory.}, } @article {pmid39929585, year = {2025}, author = {Huang, M and Stremlau, M and Zavras, J and Zivko, C and Thomas, AG and Pietri, P and Machairaki, V and Slusher, BS}, title = {Neutral sphingomyelinase 2: A promising drug target for CNS disease.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {102}, number = {}, pages = {65-101}, pmid = {39929585}, issn = {1557-8925}, support = {P30 MH075673/MH/NIMH NIH HHS/United States ; R01 AG063831/AG/NIA NIH HHS/United States ; R01 AG084728/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Sphingomyelin Phosphodiesterase/metabolism/antagonists & inhibitors ; Animals ; *Central Nervous System Diseases/drug therapy/enzymology/metabolism ; *Enzyme Inhibitors/pharmacology/therapeutic use ; }, abstract = {Neutral sphingomyelinase 2 (nSMase2), encoded by the SMPD3 gene, is a pivotal enzyme in sphingolipid metabolism, hydrolyzing sphingomyelin to produce ceramide, a bioactive lipid involved in apoptosis, inflammation, membrane structure, and extracellular vesicle (EV) biogenesis. nSMase2 is abundantly expressed in the central nervous system (CNS), particularly in neurons, and its dysregulation is implicated in pathologies such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), prion diseases, and neuroviral diseases. In this review, we discuss the critical role of nSMase2 in the CNS and its involvement in neurological as well as non-neurological diseases. We explore the enzyme's functions in sphingolipid metabolism, its regulatory mechanisms, and the implications of its dysregulation in disease pathogenesis. The chapter highlights the therapeutic potential of pharmacologically targeting nSMase2 with small molecule inhibitors and emphasizes the need for further research to optimize inhibitor specificity and efficacy for clinical applications. By understanding the multifaceted roles of nSMase2, we aim to provide insights into novel therapeutic strategies for treating complex diseases associated with its dysregulation.}, } @article {pmid39929612, year = {2025}, author = {Chen, BL and Lu, JZ and Zhou, XM and Wen, XD and Jiang, YJ and Luo, N}, title = {[Mechanism of Daotan Xixin Decoction in treating APP/PS1 mice based on high-throughput sequencing technology and bioinformatics analysis].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {2}, pages = {301-313}, doi = {10.19540/j.cnki.cjcmm.20241011.401}, pmid = {39929612}, issn = {1001-5302}, mesh = {Animals ; *Drugs, Chinese Herbal/administration & dosage ; Mice ; Male ; *Alzheimer Disease/drug therapy/genetics/metabolism ; Computational Biology ; Mice, Inbred C57BL ; High-Throughput Nucleotide Sequencing ; *Amyloid beta-Protein Precursor/genetics/metabolism ; Hippocampus/drug effects/metabolism ; Mice, Transgenic ; *Presenilin-1/genetics/metabolism ; Humans ; Memory/drug effects ; Maze Learning/drug effects ; Amyloid beta-Peptides/metabolism/genetics ; Disease Models, Animal ; }, abstract = {This study aims to investigate the therapeutic effect and mechanism of Daotan Xixin Decoction on APP/PS1 mice. Twelve APP/PS1 male mice were randomized into four groups: APP/PS1 and low-, medium-, and high-dose Daotan Xixin Decoction. Three C57BL/6 wild-type mice were used as the control group. The learning and memory abilities of mice in each group were examined by the Morris water maze test. The pathological changes of hippocampal nerve cells were observed by hematoxylin-eosin staining and Nissl staining. Immunohistochemistry was employed to detect the expression of β-amyloid(Aβ)_(1-42) in the hippocampal tissue. The high-dose Daotan Xixin Decoction group with significant therapeutic effects and the model group were selected for high-throughput sequencing. The differentially expressed gene(DEG) analysis, Gene Ontology(GO) analysis, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and Gene Set Variation Analysis(GSVA) were performed on the sequencing results. RT-qPCR and Western blot were conducted to determine the mRNA and protein levels, respectively, of some DEGs. Compared with the APP/PS1 group, Daotan Xixin Decoction at different doses significantly improved the learning and memory abilities of APP/PS1 mice, ameliorated the neuropathological damage in the CA1 region of the hippocampus, increased the number of neurons, and decreased the deposition of Aβ_(1-42) in the brain. A total of 1 240 DEGs were screened out, including 634 genes with up-regulated expression and 606 genes with down-regulated expression. The GO analysis predicted the biological processes including RNA splicing and protein folding, the cellular components including spliceosome complexes and nuclear spots, and the molecular functions including unfolded protein binding and heat shock protein binding. The KEGG pathway enrichment analysis revealed the involvement of neurodegenerative disease pathways, amyotrophic lateral sclerosis, and splicing complexes. Further GSVA pathway enrichment analysis showed that the down-regulated pathways involved nuclear factor-κB(NF-κB)-mediated tumor necrosis factor-α(TNF-α) signaling pathway, UV response, and unfolded protein response, while the up-regulated pathways involved the Wnt/β-catenin signaling pathway. The results of RT-qPCR and Western blot showed that compared with the APP/PS1 group, Daotan Xixin Decoction at different doses down-regulated the mRNA and protein levels of signal transducer and activator of transcription 3(STAT3), NF-κB, and interleukin-6(IL-6) in the hippocampus. In conclusion, Daotan Xixin Decoction can improve the learning and memory abilities of APP/PS1 mice by regulating the STAT3/NF-κB/IL-6 signaling pathway.}, } @article {pmid39930680, year = {2025}, author = {Guzanova, EV and Sorokina, TA and Zorkova, AV}, title = {[Nutritional care for patients with neurodegenerative diseases in the outpatient practice of a neurologist].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {125}, number = {1}, pages = {76-83}, doi = {10.17116/jnevro202512501176}, pmid = {39930680}, issn = {1997-7298}, mesh = {Humans ; *Ambulatory Care ; *Amyotrophic Lateral Sclerosis/complications ; *Dehydration/etiology/diagnosis/therapy ; Enteral Nutrition ; *Malnutrition/etiology/diagnosis/therapy ; *Neurodegenerative Diseases/complications ; Neurologists ; }, abstract = {Nutrition is a basic factor of health and well-being of people, affecting the quality and duration of life. Meanwhile, patients with neurodegenerative diseases of the central nervous system are particularly at risk of malnutrition and dehydration with serious health consequences. The article presents an analysis of the main causes of malnutrition in patients with neurodegenerative diseases, and considers a clinical case of including additional nutritional support in the comprehensive management of a patient with amyotrophic lateral sclerosis. The importance of screening elderly patients for the risks of malnutrition and dehydration during an outpatient medical appointment and including appropriate additional diagnostic and therapeutic (additional enteral nutrition and fluid regimen) measures in the work of an outpatient neurologist is emphasized.}, } @article {pmid39931973, year = {2025}, author = {Xu, C and Diemant, T and Zhang, S and Liu, X and Passerini, S}, title = {Enhanced Cathode-Electrolyte Interphase for Prolonged Cycling Stability of Aluminum-Selenium Batteries Using Locally Concentrated Ionic Liquid Electrolytes.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {64}, number = {17}, pages = {e202500041}, pmid = {39931973}, issn = {1521-3773}, support = {//China Sponsorship Council/ ; //China Scholarship Council/ ; //Helmholtz Association/ ; Start-up Research Fund of Southeast University4003002418//Start-up Research Fund of Southeast University/ ; }, abstract = {Al-Se batteries (ASeBs) with high theoretical specific capacity and discharge voltage are promising energy storage devices. However, the detrimental shuttle effect occurring in conventional ionic liquid electrolytes (ILEs) challenges their development. Herein, a thicker cathode/electrolyte interphase (CEI) is constructed via employing locally concentrated IL electrolytes (LCILEs) to overcome these issues. It is demonstrated that LCILEs facilitate the incorporation of Emim[+] into the electrode/electrolyte interphases, and, meanwhile, more Al-Cl species deposits are observed in the CEI. The formed CEI effectively prevents the dissolution of poly-selenides, inhibiting their related parasitic reactions. These result in ASeBs, employing the LCILE, to deliver a specific discharge capacity of 218 mAh g[-1] at 0.5 A g[-1] after 100 cycles at 20 °C, while the cell using the neat ILE only maintains 38 mAh g[-1] under the same conditions. Moreover, an Al-S cell operated in LCILEs reaches 578 mAh g[-1] at 0.1 A g[-1] after 150 cycles, which is also significantly better than 317 mAh g[-1] in the neat ILE. This study provides an LCILE-based strategy to reinforce the CEI in order to suppress the shuttle effect, realizing Al-chalcogen batteries with better performance.}, } @article {pmid39932195, year = {2025}, author = {Ruggieri, V and Scaricamazza, S and Bracaglia, A and D'Ercole, C and Parisi, C and D'Angelo, P and Proietti, D and Cappelletti, C and Macone, A and Lozanoska-Ochser, B and Bouchè, M and Latella, L and Valle, C and Ferri, A and Giordani, L and Madaro, L}, title = {Polyamine metabolism dysregulation contributes to muscle fiber vulnerability in ALS.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115123}, doi = {10.1016/j.celrep.2024.115123}, pmid = {39932195}, issn = {2211-1247}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Polyamines/metabolism ; *Muscle Fibers, Skeletal/metabolism/pathology ; Mice ; Superoxide Dismutase-1/metabolism/genetics ; Mice, Transgenic ; Disease Models, Animal ; Humans ; Motor Neurons/metabolism/pathology ; Muscle, Skeletal/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing progressive paralysis due to motor neuron degeneration with no curative therapy despite extensive biomedical research. One of the primary targets of ALS is skeletal muscle, which undergoes profound functional changes as the disease progresses. To better understand how altered innervation interferes with muscle homeostasis during disease progression, we generated a spatial transcriptomics dataset of skeletal muscle in the SOD1[G93A] mouse model of ALS. Using this strategy, we identified polyamine metabolism as one of the main altered pathways in affected muscle fibers. By establishing a correlation between the vulnerability of muscle fibers and the dysregulation of this metabolic pathway, we show that disrupting polyamine homeostasis causes impairments similar to those seen in ALS muscle. Finally, we show that restoration of polyamine homeostasis rescues the muscle phenotype in SOD1[G93A] mice, opening new perspectives for the treatment of ALS.}, } @article {pmid39932579, year = {2025}, author = {Ando, M and Higuchi, Y and Yuan, JH and Yoshimura, A and Yano, C and Hobara, T and Kojima, F and Hiramatsu, Y and Nozuma, S and Nakamura, T and Sakiyama, Y and Hashiguchi, A and Okamoto, Y and Matsushige, T and Mitsui, J and Tsuji, S and Takashima, H}, title = {SOD1-related inherited peripheral neuropathies in a Japanese cohort: genetic variants and clinical insights.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {191}, pmid = {39932579}, issn = {1432-1459}, support = {2016100002B//Ministry of Health, Labour and Welfare/ ; 201442014A//Agency for Medical Research and Development/ ; 201442071A//Agency for Medical Research and Development/ ; 18H02742//JSPS KAKENHI/ ; 20K16604//JSPS KAKENHI/ ; 21K15702//JSPS KAKENHI/ ; 21H02842//JSPS KAKENHI/ ; 22K15713//JSPS KAKENHI/ ; 22K07495//JSPS KAKENHI/ ; 22K07519//JSPS KAKENHI/ ; 23K06931//JSPS KAKENHI/ ; }, mesh = {Humans ; Male ; Female ; *Superoxide Dismutase-1/genetics ; Middle Aged ; Adult ; Japan ; *Peripheral Nervous System Diseases/genetics/physiopathology/diagnosis ; Aged ; Cohort Studies ; Young Adult ; East Asian People ; }, abstract = {BACKGROUND: Inherited peripheral neuropathies (IPNs) encompass a wide range of disorders affecting the peripheral nervous system, often with complex genetic causes and frequent underdiagnosis. The variants in the superoxide dismutase 1 (SOD1) gene, primarily linked to amyotrophic lateral sclerosis (ALS), have also been associated with peripheral neuropathy. The recent approval of Tofersen, targeting SOD1-related ALS, highlights the importance of precise genetic diagnosis. This study explores the clinical and genetic profiles of SOD1-related IPNs (SOD1-IPN) in a nationwide Japanese IPN cohort.

METHODS: Clinical and genetic data were assessed from 1483 Japanese patients with IPN, with a focus on those harboring SOD1 pathogenic variants. The clinical evaluations included age of onset, gender, muscle weakness patterns, sensory disturbances, reflex responses, and electrophysiological findings.

RESULTS: Seventeen patients with SOD1 pathogenic variants were identified, reinforcing SOD1's role in IPN. The average onset age was 47, with a slight male predominance. Distal muscle weakness was noted in 9 of 13 patients, and asymmetric muscle weakness and atrophy in 10 of 14 cases. Mild sensory disturbances were observed in eight patients, with some showing hyperreflexia and abnormal reflexes. Electrophysiology predominantly indicated a length-dependent, motor-dominant axonal neuropathy.

CONCLUSION: This study reveals the clinical variability and likely underdiagnosis of SOD1-IPN, supporting the integration of SOD1 screening in IPN genetic testing, especially for patients with asymmetric, length-dependent axonal neuropathy evident in clinical and electrophysiological assessments.}, } @article {pmid39933302, year = {2025}, author = {Li, H and Qiao, Z and Xiao, X and Cao, X and Li, Z and Liu, M and Jiao, Q and Chen, X and Du, X and Jiang, H}, title = {G protein-coupled receptors: A golden key to the treasure-trove of neurodegenerative diseases.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {46}, number = {}, pages = {155-168}, doi = {10.1016/j.clnu.2025.01.032}, pmid = {39933302}, issn = {1532-1983}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Receptors, G-Protein-Coupled/metabolism ; Signal Transduction ; Animals ; }, abstract = {G protein-coupled receptors (GPCRs) are a class of transmembrane proteins that distribute in various organs extensively. They can regulate physiological functions such as perception, neurotransmission and endocrinology through the synergies of signaling pathways. At present, Food and Drug Administration (FDA) have approved more than 500 drugs targeting GPCRs to treat a variety of conditions, including neurological diseases, gastrointestinal diseases and tumors. Conformational diversity and dynamic changes make GPCRs a star target for the treatment of neurodegenerative diseases. Moreover, GPCRs can also open biased signaling pathways for G protein and β-arrestin, which has unique functional selectivity and the possibility of overcoming side effects. Some studies believe that biased drugs will be the mainstream direction of drug innovation in the future. To disclose the essential role and research process of GPCRs in neurodegenerative diseases, we firstly reviewed several pivotal GPCRs and their mediated signaling pathways in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Then we focused on the biased signaling pathway of GPCRs in these diseases. Finally, we updated the GPCR drugs under research for the treatment of neurodegenerative diseases in the clinical trials or approval. This review could provide valuable targets for precision therapy to cope with the dysfunction of neurodegenerative diseases in the future.}, } @article {pmid39933303, year = {2025}, author = {Zeng, JY and Huang, HW and Zhuang, SP and Wu, Y and Chen, S and Zou, ZY and Chen, HJ}, title = {Soma and neurite density imaging detects brain microstructural impairments in amyotrophic lateral sclerosis.}, journal = {European journal of radiology}, volume = {184}, number = {}, pages = {111981}, doi = {10.1016/j.ejrad.2025.111981}, pmid = {39933303}, issn = {1872-7727}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging ; Male ; Female ; Middle Aged ; *Neurites/pathology ; *Diffusion Tensor Imaging/methods ; *Brain/pathology ; Aged ; Adult ; Sensitivity and Specificity ; *Diffusion Magnetic Resonance Imaging/methods ; Reproducibility of Results ; *Image Interpretation, Computer-Assisted/methods ; }, abstract = {OBJECTIVE: To investigate whole-brain microstructural changes in amyotrophic lateral sclerosis (ALS) using soma and neurite density imaging (SANDI), a novel multicompartment model of diffusion-weighted imaging that estimates apparent soma and neurite density.

METHODS: This study consists of 41 healthy controls and 43 patients with ALS, whose diffusion-weighted data were acquired. The SANDI-derived (including signal fractions of soma (fsoma), neurite (fneurite), and extra-cellular space (fextra)) and diffusion tensor imaging (DTI)-derived metrics were obtained. Voxel-based analyses were performed to evaluate intergroup differences and the correlation of SANDI and DTI metrics with clinical parameters.

RESULTS: In ALS patients, fneurite reduction involved both gray matter (primarily the bilateral precentral gyri, supplementary motor area, medial frontal gyrus, anterior cingulate cortex, inferior frontal gyrus, orbital gyrus, paracentral lobule, postcentral gyrus, middle cingulate cortex, hippocampus and parahippocampal gyrus, and insula, and left anterior parts of the temporal lobe) and white matter (primarily the bilateral corticospinal tract, body of corpus callosum, and brainstem) (P <0.05 after false discovery rate correction). The fextra increment showed a similar spatial distribution in ALS patients. Interestingly, the decreased fsoma in ALS primarily located in gray matter; while, the increased fsoma primarily involved white matter. The spatial distribution of fneurite/fextra/fsoma changes was larger than that detected by conventional DTI metrics, and the fneurite/fextra/fsoma were correlated with disease severity.

CONCLUSIONS: SANDI may serve as a clinically relevant model, superior to conventional DTI, for characterizing microstructural impairments such as neurite degeneration and soma alteration in ALS.}, } @article {pmid39933343, year = {2025}, author = {Hatamli, K and Eritja, R and Giménez, E and Benavente, F and Gargallo, R}, title = {Resolution of complex mixtures of duplex and antiparallel triplex DNA structures by capillary electrophoresis and multivariate analysis.}, journal = {Talanta}, volume = {288}, number = {}, pages = {127616}, doi = {10.1016/j.talanta.2025.127616}, pmid = {39933343}, issn = {1873-3573}, mesh = {Electrophoresis, Capillary/methods ; *DNA/chemistry/analysis ; Multivariate Analysis ; Nucleic Acid Conformation ; Spectrophotometry, Ultraviolet ; Least-Squares Analysis ; }, abstract = {Triplex DNA structures, which are formed by the addition of an extra strand to a target B-DNA duplex, have attracted increasing interest due to their analytical and therapeutic applications. These structures are classified into parallel and antiparallel, depending on the orientation of the Triplex-Forming Oligonucleotide (TFO) relative to the B-DNA duplex. Whereas the formation of parallel triplexes is easily detected by monitoring spectral changes in the UV region, the formation of antiparallel triplexes produces small or even no spectral variations, which makes their detection difficult and uncertain. In this study, we propose the use of capillary electrophoresis with ultraviolet absorption spectrophotometric (CE-UV) detection combined with the multivariate curve resolution-alternating least squares (MCR-ALS) chemometric method to analyse mixtures of DNA sequences capable of forming mixtures of B-DNA duplex and triplex antiparallel structures. Rapid and reproducible CE-UV analysis in hydroxypropylcellulose (HPC)-coated capillaries are done in a pH 7.4 buffer containing Mg(II) for the stabilization of the intermolecular species. Spectra measured from 220 to 300 nm along the CE-UV analysis of individual DNA strands and of their mixtures at different ratios are merged into an augmented data matrix. This is later analyzed with MCR-ALS to deconvolute characteristic pure spectra and electropherograms for each one of the CE-UV analysis considered. This procedure has allowed the resolution and detection of DNA species present in mixtures of DNA strands capable of forming duplexes, as well as antiparallel triplex structures.}, } @article {pmid39933412, year = {2025}, author = {Noli, B and Borghero, G and Mascia, MM and Hkir, M and Puligheddu, M and Cocco, C}, title = {NERP-1 modifications in amyotrophic lateral sclerosis.}, journal = {Tissue & cell}, volume = {93}, number = {}, pages = {102780}, doi = {10.1016/j.tice.2025.102780}, pmid = {39933412}, issn = {1532-3072}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/pathology/metabolism ; Female ; Male ; Middle Aged ; Motor Neurons/metabolism/pathology ; Aged ; Oxidative Stress ; Adult ; *Neuropeptides/blood ; Cell Line ; Nerve Growth Factors ; }, abstract = {VGF peptides, such as NERPs (neuroendocrine regulatory peptides 1 and 2), are derived from amino acids 282-306 and 313-350, respectively, of the human proVGF, which is produced in spinal cord motor neurons. Although certain VGF-derived peptides are changed in ALS, less is known about NERPs. Possible modulations of NERPs and additional VGF peptides (NAPP and TPGH) were investigated using specific antibodies through competitive ELISA in the plasma of ALS patients (at both the initial and advanced phases; n = 46 each vs. 46 controls). As additional controls, naïve PD patients were also enrolled (n = 19 vs. 18 controls) while the potential VGF peptide role in oxidative stress was investigated using a motoneuron-like cell line (NSC34) stressed with sodium arsenate (SA). Western blot (WB) and sephadex chromatography (SC) were used to identify the molecular weight (MW) forms recognized by the VGF antibodies. Exclusively NERP-1 immunoreactivity was changed (elevated) in all plasma samples of ALS patients (compared to controls). Therefore, the NERP-1 antibody was the sole antibody used in ELISA with PD samples and NSC-34 cells. No alterations were seen in PD samples (vs. controls) while NERP-1 immunoreactivity decreased within SA-treated cells but increased in their culture medium. The viability test performed by adding NERP-1 to the stressed cells showed no protective effect. Using WB and SC, we revealed NERP-1 antibody reactivity against various MW forms, including those compatible with the NERP-1 peptide and/or proVGF. NERP-1 is suggested as a possible ALS blood biomarker.}, } @article {pmid39933444, year = {2025}, author = {Rob, M and Yousef, M and Lakshmanan, AP and Mahboob, A and Terranegra, A and Chaari, A}, title = {Microbial signatures and therapeutic strategies in neurodegenerative diseases.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {184}, number = {}, pages = {117905}, doi = {10.1016/j.biopha.2025.117905}, pmid = {39933444}, issn = {1950-6007}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/microbiology/therapy/metabolism ; Animals ; Dysbiosis ; Probiotics/therapeutic use ; Fecal Microbiota Transplantation ; Metabolome ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), arise from complex interactions between genetic factors, environmental exposures, and aging. Additionally, gut dysbiosis has been linked to systemic inflammation and neurodegeneration. Advances in microbiome and metabolome profiling techniques have provided deeper insights into how alterations in gut microbiota and dietary patterns affect metabolic pathways and contribute to the progression of NDs. This review explores the profiles of gut microbiome and metabolome derived biomarkers and their roles in NDs. Across phyla, families, and genera, we identified 55 microbial alterations in PD, 24 in AD, 4 in ALS, and 17 in MS. Some notable results include an increase in Akkermansia in PD, AD, and MS and a decrease in short-chain fatty acids (SCFAs) in PD and AD. We examined the effects of probiotics, prebiotics, fecal microbiota transplants (FMT), sleep, exercise, and diet on the microbiota, all of which contributed to delayed onset and alleviation of symptoms. Further, artificial intelligence (AI) and machine learning (ML) algorithms applied to omics data have been crucial in identifying novel therapeutic targets, diagnosing and predicting prognosis, and enabling personalized medicine using microbiota-modulating therapies in NDs patients.}, } @article {pmid39935503, year = {2025}, author = {Tsuruta, M and Shil, S and Taniguchi, S and Kawauchi, K and Miyoshi, D}, title = {The role of cytosine methylation in regulating the topology and liquid-liquid phase separation of DNA G-quadruplexes.}, journal = {Chemical science}, volume = {16}, number = {10}, pages = {4213-4225}, pmid = {39935503}, issn = {2041-6520}, abstract = {Aberrant expansion of GGGGCC DNA repeats that form G-quadruplexes (G4) is the main cause of amyotrophic lateral sclerosis (ALS). Expanded GGGGCC repeats induce liquid-liquid phase separation (LLPS) through their interaction with cellular proteins. Furthermore, GGGGCC expansion induces cytosine methylation (mC). Previous studies have shown that even slight chemical modifications of RNAs and proteins can drastically affect their LLPS ability, yet the relationship between LLPS and epigenetic DNA modifications like mC remains unexplored. As a model system, we investigated the effects of mC on LLPS induced by GGGGCC repeat DNAs and show for the first time that mC suppresses LLPS by altering the topology of G4 from being parallel to antiparallel.}, } @article {pmid39936179, year = {2025}, author = {Morrison, AH and Jimenez, JV and Hsu, JY and Elman, L and Choi, PJ and Ackrivo, J}, title = {Identifying Daytime Hypercapnia Using Transcutaneous Carbon Dioxide Monitoring in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {71}, number = {4}, pages = {611-619}, pmid = {39936179}, issn = {1097-4598}, support = {K23 HL151879/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Hypercapnia/diagnosis/etiology/epidemiology ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; *Carbon Dioxide/blood ; *Blood Gas Monitoring, Transcutaneous/methods ; Respiratory Function Tests ; Vital Capacity ; Adult ; }, abstract = {INTRODUCTION/AIMS: Respiratory failure from hypoventilation is the most common cause of death in amyotrophic lateral sclerosis (ALS). However, ALS care rarely assesses hypercapnia, a physiologic measure of hypoventilation. We investigated the prevalence and clinical significance of daytime hypercapnia measured by transcutaneous carbon dioxide (tcCO2) monitoring in patients with ALS.

METHODS: This retrospective study included patients seen at two ALS clinics in the United States between 2012 and 2024 who had tcCO2 measured concurrently with pulmonary function tests (PFTs), which included forced vital capacity (FVC) and, at one site, maximum inspiratory pressure (MIP). We assessed the prevalence of hypercapnia (tcCO2 > 45 mmHg), the sensitivity and specificity of patient symptoms and PFTs for hypercapnia, and the relationship between hypercapnia and survival.

RESULTS: Daytime hypercapnia was present in 33/328 (10%) patients at baseline. Hypercapnia was associated with an increased rate of death (aHR 2.1, 95% CI 1.4-3.3). Orthopnea or dyspnea was 70% sensitive for hypercapnia (95% CI 51%-84%). Absolute value of MIP (|MIP|) < 60 cmH2O was 95% sensitive (95% CI 74%-100%) and 22% specific (95% CI 16%-30%), FVC < 50% predicted was 33% sensitive (95% CI 18%-52%) and 82% specific (95% CI 78%-87%), and FVC < 80% predicted was 85% sensitive (95% CI 68%-95%) and 31% specific (95% CI 26%-36%) for hypercapnia.

DISCUSSION: TcCO2 monitoring identified strengths and weaknesses of PFTs in identifying hypercapnia in ALS. We found high sensitivity of |MIP| < 60 cmH2O and FVC < 80% predicted and high specificity of FVC < 50% predicted. Prospective studies should investigate the optimal clinical role for tcCO2.}, } @article {pmid39936211, year = {2025}, author = {Naveed, A and Usmani, WA and Vandara, MP and Karmani, VK}, title = {Tofersen for Amyotrophic Lateral Sclerosis: A Step Forward or Another False Hope?.}, journal = {Journal of the College of Physicians and Surgeons--Pakistan : JCPSP}, volume = {35}, number = {2}, pages = {259-260}, doi = {10.29271/jcpsp.2025.02.259}, pmid = {39936211}, issn = {1681-7168}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Treatment Outcome ; }, } @article {pmid39936266, year = {2025}, author = {Denton, TT and Carter, GT and Goddard, M and Weiss, J and Weeks, DL and Weydt, P and Russo, EB and Weiss, MD}, title = {Amyotrophic Lateral Sclerosis, the Endocannabinoid System, and Exogenous Cannabinoids: Current State and Clinical Implications.}, journal = {Muscle & nerve}, volume = {72}, number = {1}, pages = {7-14}, doi = {10.1002/mus.28359}, pmid = {39936266}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; Animals ; *Cannabinoids/therapeutic use/pharmacology ; *Endocannabinoids/metabolism/therapeutic use ; Mice ; }, abstract = {A unifying mechanistic cause for amyotrophic lateral sclerosis (ALS) remains uncertain. Multiple pathophysiological processes appear to occur simultaneously. Cannabinoids, including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), and others found in cannabis, and cannabis extracts (CEs), appear to have activity in these pathogenic pathways, which have led to increasing interest in cannabinoids as therapeutic agents for ALS. The use of cannabinoids as a treatment strategy is substantiated by preclinical evidence suggesting a role for the endocannabinoid system (ECS) in ALS and other neurodegenerative disorders. Preclinical data indicate that cannabis and CEs have powerful antioxidative, anti-inflammatory, and neuroprotective effects in the SOD1 [G93A] mouse model of ALS. The use of CEs in SOD1 [G93A] murine models has been shown to prolong neuronal cell survival, which leads to delayed onset of the disease state, and slows progression of the disease. Although research in humans remains limited, a few studies suggest that cannabis and CBD, in humans, provide benefits for both motor symptoms, including rigidity, cramps, and fasciculations, and non-motor symptoms including sleep quality, pain, emotional state, quality of life, and depression. There remains a need for further, well-designed clinical trials to validate further the use of an individual cannabinoid, or a combination of cannabinoids, as a disease-modifying therapy for ALS.}, } @article {pmid39936380, year = {2025}, author = {Lero, CM and Yang, A and Everett, E and Pitzer, KA and McCoy Gross, K and Washington, KT}, title = {Associations Between End-Stage ALS Care and Specialty Palliative Care: A Hypothesis-Generating Study.}, journal = {Muscle & nerve}, volume = {71}, number = {4}, pages = {632-638}, pmid = {39936380}, issn = {1097-4598}, support = {T32 MH019960/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Female ; Male ; *Palliative Care/methods ; Middle Aged ; Aged ; *Terminal Care ; Electronic Health Records ; Aged, 80 and over ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) care is typically delivered via a multidisciplinary approach that may include specialty palliative care (SPC). Opportunities for SPC to enhance ALS care have been identified; however, investigation of these proposed benefits is scant. In this exploratory study, investigators examined associations between receipt of SPC and variables particularly relevant to end-stage ALS.

METHODS: Researchers reviewed electronic health records for all patients with ALS who received standard ALS care from one Midwestern US academic medical center and died between January 1, 2020, and June 30, 2022 (N = 156). Receipt of SPC, duration of illness, hospice enrollment and length of service, report of a healthcare proxy, documentation of a healthcare proxy, participation in goals of care conversations, and location of death were examined.

RESULTS: Patients who received SPC (59%), had lower mean forced vital capacity (FVC) (p < 0.05), and more often used respiratory support (p < 0.001), participated in goals of care conversations (p < 0.001), reported a healthcare proxy (p < 0.01), and enrolled in hospice (p < 0.001) than patients who received standard care alone. No differences between groups were found in duration of illness (mean = 51.7 months), use of assistive feeding, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores (mean = 32.1), documentation of a healthcare proxy, length of hospice stay (mean = 47.3 days), or location of death.

DISCUSSION: Clinical characteristics and end-of-life outcome differences between groups support further investigation of the proposed benefits of SPC regarding hospice enrollment, report of healthcare proxies, and documented goals of care conversations.}, } @article {pmid39936815, year = {2025}, author = {Mendes, RA and Lima, ILB and Dourado Júnior, MET and Gonçalves, MJ}, title = {Is there a decline in speech and swallowing in Amyotrophic Lateral Sclerosis over ten years?.}, journal = {CoDAS}, volume = {37}, number = {2}, pages = {e20240159}, pmid = {39936815}, issn = {2317-1782}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Male ; *Deglutition Disorders/etiology/physiopathology ; Female ; Retrospective Studies ; Middle Aged ; Longitudinal Studies ; Aged ; Disease Progression ; Dysarthria/etiology/physiopathology ; *Speech Disorders/etiology/physiopathology ; Adult ; Deglutition/physiology ; Time Factors ; Aged, 80 and over ; }, abstract = {PURPOSE: To analyze the evolution of speech and swallowing decline in patients with amyotrophic lateral sclerosis (ALS) over a ten-year period.

METHODS: A retrospective and longitudinal cohort study. Data were collected using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) from 101 medical records of ALS patients treated at the multidisciplinary neuromuscular diseases clinic of a University Hospital over a ten-year period. The data were statistically analyzed, adopting a significance level of p<0.05.

RESULTS: The analysis of the studied functions indicated that speech, swallowing, and salivation are altered over ten years in ALS. There are differences in patterns between the variables sex and disease type concerning symptoms related to dysarthria and dysphagia in these individuals, which may indicate the rate of progression over a given time interval.

CONCLUSION: There is a decline in speech and swallowing over ten years in ALS. The bulbar type leads to a faster decline in the studied functions than the spinal type.}, } @article {pmid39936986, year = {2025}, author = {Ramírez, OA and Hellwig, A and Zhang, Z and Bading, H}, title = {Pharmacological Targeting of the NMDAR/TRPM4 Death Signaling Complex with a TwinF Interface Inhibitor Prevents Excitotoxicity-Associated Dendritic Blebbing and Organelle Damage.}, journal = {Cells}, volume = {14}, number = {3}, pages = {}, pmid = {39936986}, issn = {2073-4409}, mesh = {*TRPM Cation Channels/metabolism ; *Receptors, N-Methyl-D-Aspartate/metabolism ; *Dendrites/drug effects/metabolism/pathology/ultrastructure ; Animals ; Mitochondria/metabolism/drug effects ; Endoplasmic Reticulum/metabolism/drug effects ; Humans ; Signal Transduction/drug effects ; *Organelles/drug effects/metabolism/pathology ; Mice ; Glutamic Acid ; Calcium/metabolism ; Neurons/metabolism/drug effects ; }, abstract = {Focal swellings of dendrites ("dendritic blebbing") together with structural damage of mitochondria and the endoplasmic reticulum (ER) are morphological hallmarks of glutamate neurotoxicity, also known as excitotoxicity. These pathological alterations are generally thought to be caused by the so-called "overactivation" of N-methyl-D-aspartate receptors (NMDARs). Here, we demonstrate that the activation of extrasynaptic NMDARs, specifically when forming a protein-protein complex with TRPM4, drives these pathological traits. In contrast, strong activation of synaptic NMDARs fails to induce cell damage despite evoking plateau-type calcium signals that are comparable to those generated by activation of the NMDAR/TRPM4 complex, indicating that high intracellular calcium levels per se are not toxic to neurons. Using confocal laser scanning microscopy and transmission electron microscopy, we show that disrupting the NMDAR/TRPM4 complex using the recently discovered small-molecule TwinF interface inhibitor FP802 inhibits the NMDA-induced neurotoxicity-associated dendritic blebbing and structural damage to mitochondria and the ER. It also prevents, at least in part, the disruption of ER-mitochondria contact sites. These findings establish the NMDAR/TRPM4 complex as the trigger for the structural damage of dendrites and intracellular organelles associated with excitotoxicity. They also suggest that activation of the NMDAR/TRPM4 complex, in addition to inducing high-amplitude, plateau-type calcium signals, generates a second signal required for glutamate neurotoxicity ("two-hit hypothesis"). As structural damage to organelles, particularly mitochondria, is a common feature of many human neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis (ALS), TwinF interface inhibitors have the potential to provide neuroprotection across a broad spectrum of these diseases.}, } @article {pmid39937422, year = {2025}, author = {Grassano, M and Chiò, A}, title = {microRNA in ALS: finally ready for prime time?.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {4}, pages = {1463-1464}, pmid = {39937422}, issn = {1590-3478}, } @article {pmid39938752, year = {2025}, author = {Zhu, Y and Tian, M and Lu, S and Qin, Y and Zhao, T and Shi, H and Li, Z and Qin, D}, title = {The antioxidant role of aromatic plant extracts in managing neurodegenerative diseases: A comprehensive review.}, journal = {Brain research bulletin}, volume = {222}, number = {}, pages = {111253}, doi = {10.1016/j.brainresbull.2025.111253}, pmid = {39938752}, issn = {1873-2747}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Antioxidants/pharmacology/therapeutic use ; *Plant Extracts/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Animals ; Polyphenols/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative diseases (NDDs) are a class of cognitive and motor disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), and others. They are caused by lesions in cells and tissues of the central nervous system, resulting in corresponding dysfunctions and consequent decline in cognitive and motor functions. Neural tissues are extremely vulnerable to oxidative stress, which plays critical biological roles in NDDs. Aromatic compounds are found extensively in natural plants and have substantial effects of anti-oxidative stress damage, which not only have a wide range of research applications in cosmetics, foods, etc., but are also frequently utilized in the treatment of various central nervous system diseases. This review summarizes the relevant oxidative stress mechanisms in NDDs (AD, PD, HD, and ALS) and reviews aromatic compounds such as polyphenols, terpenoids, and flavonoids that can be used in the management of neurodegenerative diseases, as well as their specific mechanisms of antioxidant action. This review will serve as a reference for future experimental studies on neurodegenerative illnesses while also offering fresh insights into clinical therapy.}, } @article {pmid39938954, year = {2025}, author = {Flügel, V and Hering, T and Dadaczynski, K}, title = {Development and validation of a questionnaire on parental health literacy in the context of promoting healthy lifestyles during childhood: a study protocol.}, journal = {BMJ open}, volume = {15}, number = {2}, pages = {e088037}, pmid = {39938954}, issn = {2044-6055}, mesh = {Humans ; *Health Literacy ; *Parents/education ; Surveys and Questionnaires/standards ; Child ; Child, Preschool ; *Health Promotion ; *Healthy Lifestyle ; Reproducibility of Results ; Female ; Research Design ; Male ; }, abstract = {INTRODUCTION: Becoming a parent presents profound changes and numerous challenges, notably the necessity for reliable information regarding their child's health. Given the overabundance of information available today, it is important for parents to acquire the skills necessary to find, understand, evaluate and apply health information. Research demonstrates that this ability, known as parental health literacy (PHL), is crucial for developing and maintaining a healthy lifestyle during childhood. However, there is currently no reliable instrument for measuring PHL in the field of prevention and health promotion. This paper presents the development and validation of a new questionnaire designed to assess parents' ability to process health-related information to support the healthy development of their children aged 3-6 years.

METHODS AND ANALYSIS: The development of the item pool is based on Sørensen et al's conceptualisation of general health literacy (finding, understanding, evaluating and applying health information). Empirical findings suggest that communication with healthcare providers and the social network represents another important skill area for parents and is therefore included as an additional subscale. The questionnaire will be developed in four stages, including a literature search and analysis, expert consultations via Delphi study, cognitive interviews with parents and a validation study. The validation study uses exploratory (EFA) and confirmatory factor analysis (CFA) for construct validity, first identifying test dimensions through EFA, then confirming these dimensions with CFA to ensure the factor structure aligns with theoretical expectations. This methodology, alongside reliability and correlational analyses, seeks to assess the questionnaire's validity and reliability, expecting strong correlations with existing related constructs.

ETHICS AND DISSEMINATION: Ethical approval was obtained from the Ethics Committee of Fulda University of Applied Sciences. All participants receive a consent form together with the study information, in which they give their written consent to the storage, processing and linking of all data collected. The results of the study will be presented at national and international conferences and published in specialist journals.

TRIAL REGISTRATION NUMBER: DRKS00033482.}, } @article {pmid39939579, year = {2025}, author = {Zhou, T and Solis, NV and Marshall, M and Yao, Q and Pearlman, E and Filler, SG and Liu, H}, title = {Fungal Als proteins hijack host death effector domains to promote inflammasome signaling.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1562}, pmid = {39939579}, issn = {2041-1723}, support = {R01 EY036478/EY/NEI NIH HHS/United States ; R01 GM117111/GM/NIGMS NIH HHS/United States ; R01EY036478//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; R01GM117111//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {Humans ; *Inflammasomes/metabolism/immunology ; Animals ; Mice ; Caspase 8/metabolism ; Signal Transduction ; Interleukin-1beta/metabolism ; Jurkat Cells ; *Fungal Proteins/metabolism/genetics/immunology ; Fas-Associated Death Domain Protein/metabolism ; CARD Signaling Adaptor Proteins/metabolism ; *Candida albicans/metabolism/immunology ; Macrophages/metabolism/immunology ; Mice, Inbred C57BL ; Apoptosis ; Colitis ; }, abstract = {High-damaging Candida albicans strains tend to form hyphae and exacerbate intestinal inflammation in ulcerative colitis patients through IL-1β-dependent mechanisms. Fungal agglutinin-like sequence (Als) proteins worsen DSS-induced colitis in mouse models. FADD and caspase-8 are important regulators of gut homeostasis and inflammation. However, whether they link directly to fungal proteins is not fully understood. Here, we report that Als proteins induce IL-1β release in immune cells. We show that hyphal Als3 is internalized in macrophages and interacts with caspase-8 and the inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC). Caspase-8 is essential for Als3-mediated ASC oligomerization and IL-1β processing. In non-immune cells, Als3 is associated with cell death core components FADD and caspase-8. N-terminal Als3 (N-Als3) expressed in Jurkat cells partially inhibits apoptosis. Mechanistically, N-Als3 promotes oligomerization of FADD and caspase-8 through their death effector domains (DEDs). N-Als3 variants with a mutation in the peptide-binding cavity or amyloid-forming region are impaired in DED oligomerization. Together, these results demonstrate that DEDs are intracellular sensors of Als3. This study identifies additional potential targets to control hypha-induced inflammation.}, } @article {pmid39940644, year = {2025}, author = {Lee, AJB and Bi, S and Ridgeway, E and Al-Hussaini, I and Deshpande, S and Krueger, A and Khatri, A and Tsui, D and Deng, J and Mitchell, CS}, title = {Restoring Homeostasis: Treating Amyotrophic Lateral Sclerosis by Resolving Dynamic Regulatory Instability.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940644}, issn = {1422-0067}, support = {P30 AG066511/AG/NIA NIH HHS/United States ; R35GM152245/NH/NIH HHS/United States ; 1944247//National Science Foundation/ ; 253558//Chan Zuckerberg Initiative/ ; R35 GM152245/GM/NIGMS NIH HHS/United States ; T32 EB025816/EB/NIBIB NIH HHS/United States ; U19 AG065169/AG/NIA NIH HHS/United States ; R01 AG070937/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/therapy/genetics/pathology/drug therapy/physiopathology ; Animals ; *Homeostasis ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase-1/genetics/metabolism ; Humans ; Disease Progression ; Computer Simulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has an interactive, multifactorial etiology that makes treatment success elusive. This study evaluates how regulatory dynamics impact disease progression and treatment. Computational models of wild-type (WT) and transgenic SOD1-G93A mouse physiology dynamics were built using the first-principles-based first-order feedback framework of dynamic meta-analysis with parameter optimization. Two in silico models were developed: a WT mouse model to simulate normal homeostasis and a SOD1-G93A ALS model to simulate ALS pathology dynamics and their response to in silico treatments. The model simulates functional molecular mechanisms for apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, and proteomics using curated data from published SOD1-G93A mouse experiments. Temporal disease progression measures (rotarod, grip strength, body weight) were used for validation. Results illustrate that untreated SOD1-G93A ALS dynamics cannot maintain homeostasis due to a mathematical oscillating instability as determined by eigenvalue analysis. The onset and magnitude of homeostatic instability corresponded to disease onset and progression. Oscillations were associated with high feedback gain due to hypervigilant regulation. Multiple combination treatments stabilized the SOD1-G93A ALS mouse dynamics to near-normal WT homeostasis. However, treatment timing and effect size were critical to stabilization corresponding to therapeutic success. The dynamics-based approach redefines therapeutic strategies by emphasizing the restoration of homeostasis through precisely timed and stabilizing combination therapies, presenting a promising framework for application to other multifactorial neurodegenerative diseases.}, } @article {pmid39940966, year = {2025}, author = {Jamerlan, AM and Shim, KH and Sharma, N and An, SSA}, title = {Multimer Detection System: A Universal Assay System for Differentiating Protein Oligomers from Monomers.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940966}, issn = {1422-0067}, support = {RS-2023-00251396//National Research Foundation of Korea/ ; 2021R1A6A1A03038996//National Research Foundation of Korea/ ; }, mesh = {Humans ; alpha-Synuclein/metabolism ; *Protein Multimerization ; *Neurodegenerative Diseases/metabolism ; Protein Aggregates ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; *Protein Aggregation, Pathological/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer's disease (AD); α-synuclein in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington's disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics.}, } @article {pmid39941012, year = {2025}, author = {Sonkodi, B}, title = {PIEZO2 Proton Affinity and Availability May Also Regulate Mechanical Pain Sensitivity, Drive Central Sensitization and Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39941012}, issn = {1422-0067}, mesh = {Humans ; *Ion Channels/metabolism/genetics ; Animals ; *Protons ; *Pain/metabolism ; Motor Neurons/metabolism ; *Central Nervous System Sensitization ; *Neurodegenerative Diseases/metabolism ; }, abstract = {The current opinion manuscript posits that not only Piezo2 voltage block, but also proton affinity and availability in relation to Piezo2, a mechanically gated ion channel, may count in the mediation of pain and its sensitivity. Moreover, this paper argues that autonomously acquired Piezo2 channelopathy on somatosensory terminals is likely the initiating peripheral impaired input source that drives the central sensitization of spinal nociceptive neurons on the chronic path as being the autonomous pain generator. In parallel, impaired proprioception and the resultant progressive deficit in neuromuscular junctions of motoneurons might be initiated on the chronic path by the impairment of the proton-based ultrafast proprioceptive feedback to motoneurons due to disconnection through vesicular glutamate transporter 1. The irreversible form of this autonomously acquired Piezo2 ion channel microdamage, in association with genetic predisposition and/or environmental risk factors, is suggested to lead to progressive motoneuron death in addition to loss of pain sensation in amyotrophic lateral sclerosis. Furthermore, the impairment of the proton-based ultrafast long-range oscillatory synchronization to the hippocampus through vesicular glutamate transporter 2 may gain further importance in pain modulation and formation on the chronic path. Overall, this novel, unaccounted Piezo2-initiated protonic extrafast signaling, including both the protonic ultrafast proprioceptive and the rapid nociceptive ones, within the nervous system seems to be essential in order to maintain life. Hence, its microdamage promotes neurodegeneration and accelerates aging, while the complete loss of it is incompatible with life sustainment, as is proposed in amyotrophic lateral sclerosis.}, } @article {pmid39941101, year = {2025}, author = {Orywal, K and Socha, K and Iwaniuk, P and Kaczyński, P and Farhan, JA and Zoń, W and Łozowicka, B and Perkowski, M and Mroczko, B}, title = {Vitamins in the Prevention and Support Therapy of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39941101}, issn = {1422-0067}, support = {NdS/551580/2022/2022//Polish Ministry of Education and Science/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/prevention & control/drug therapy ; *Vitamins/therapeutic use/pharmacology ; Animals ; Parkinson Disease/prevention & control ; Dietary Supplements ; Neuroprotective Agents/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), which are a consequence of the progressive loss of neuronal function and structure, cause significant cognitive impairment. The incidence of these diseases in the world's population is constantly increasing as a result of an aging population. Although genetic and environmental factors are most often mentioned as the pathogenetic factors of these diseases, increasing evidence points to the important role of proper nutrition in the prevention and support of the treatment of these disorders. A healthy, balanced diet can mitigate the risks associated with the risk factors mentioned above and slow the progression of the disease by reducing oxidative stress and inflammation. Vitamins B, D, E, C, K, and A have been shown to support cognitive functions and protect the nervous system. This review demonstrates the importance of vitamins in preventing and supporting the therapy of neurodegenerative diseases. Information regarding the health-promoting properties of these vitamins must be effectively communicated to consumers seeking to protect their health, particularly in the context of neurodegenerative diseases. Consequently, this review also examines the authorized health claims under EU food law related to these vitamins, assessing their role in promoting awareness of the vitamins' potential benefits for neuroprotection and the management of neurodegenerative diseases.}, } @article {pmid39942481, year = {2025}, author = {Kavanaugh, MS and Zawadzki, MJ and Johnson, KT and Boville, MR}, title = {Moments of Care: Perceptions of Young Carers and Day-to-Day Well-Being.}, journal = {Healthcare (Basel, Switzerland)}, volume = {13}, number = {3}, pages = {}, pmid = {39942481}, issn = {2227-9032}, abstract = {Background/Objectives: Over 5 million youth under the age of 19 provide daily, hands-on care to an ill or injured family member across the United States. Yet how these young carers perceive the care they deliver in the moment, and how these perceptions relate to well-being, is unexplored, particularly in complex neurological conditions. This paper presents initial data on young carers for a family member with amyotrophic lateral sclerosis (ALS). Methods: Ecological momentary assessment (EMA) was used to measure perceptions of care in the moments of care and the cognitive and emotional states of the young carers during those moments. Young carers (n = 15) aged 10-19 were followed for seven days, completing assessments three times per day, which provided 260 total measurements. Young carers reported frequently engaging in caregiving (~39% of assessments). Results: The results indicated that it was not simply performing a caregiving task that related to outcomes, but rather how caregiving moments were perceived that mattered. Caregiving moments perceived as more fulfilling resulted in young carers feeling less discontent and more focused, whereas caregiving moments perceived as lacking resources predicted more discontent and distress. Exploratory analyses highlighted the potential for burden for young carers. They reported high levels of worry when they were not around the care recipient, with this worry predicting feeling more discontent and distressed. Conclusions: Young carers are deeply involved in care and perceive care differently across moments, both positive and negative. These initial data can be used to develop targeting support programs in the moment of care, potentially lessening the negative impacts of care.}, } @article {pmid39942798, year = {2025}, author = {Długosz, A and Błaszak, B and Czarnecki, D and Szulc, J}, title = {Mechanism of Action and Therapeutic Potential of Xanthohumol in Prevention of Selected Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {3}, pages = {}, pmid = {39942798}, issn = {1420-3049}, mesh = {*Propiophenones/pharmacology/therapeutic use/chemistry ; *Flavonoids/pharmacology/therapeutic use/chemistry ; Humans ; *Neurodegenerative Diseases/drug therapy/prevention & control/metabolism ; Animals ; Antioxidants/pharmacology/therapeutic use/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Parkinson Disease/drug therapy ; Alzheimer Disease/drug therapy/metabolism ; Humulus/chemistry ; }, abstract = {Xanthohumol (XN), a bioactive plant flavonoid, is an antioxidant, and as such, it exhibits numerous beneficial properties, including anti-inflammatory, antimicrobial, and antioxidative effects. The main dietary source of XN is beer, where it is introduced through hops. Although the concentration of XN in beer is low, the large quantities of hop-related post-production waste present an opportunity to extract XN residues for technological or pharmaceutical purposes. The presented study focuses on the role of XN in the prevention of neurodegenerative diseases, analyzing its effect at a molecular level and including its signal transduction and metabolism. The paper brings up XN's mechanism of action, potential effects, and experimental and clinical studies on Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Additionally, challenges and future research directions on XN, including its bioavailability, safety, and tolerance, have been discussed.}, } @article {pmid39944085, year = {2025}, author = {Sakurai, H and Suzuki, M and Asakura, A}, title = {Editorial: Induced pluripotent stem cells (iPSCs) for skeletal muscle diseases.}, journal = {Frontiers in cell and developmental biology}, volume = {13}, number = {}, pages = {1556403}, pmid = {39944085}, issn = {2296-634X}, support = {R01 AR077191/AR/NIAMS NIH HHS/United States ; }, } @article {pmid39944166, year = {2025}, author = {Islam, S and Noorani, A and Sun, Y and Michikawa, M and Zou, K}, title = {Multi-functional role of apolipoprotein E in neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1535280}, pmid = {39944166}, issn = {1663-4365}, abstract = {Genetic diversity in the apolipoprotein E (ApoE) gene has been identified as the major susceptibility genetic risk factor for sporadic Alzheimer's disease (SAD). Specifically, the ApoEε4 allele is a significant risk factor for SAD, while ApoEε2 allele provides protection compared to the more common ApoEε3 allele. This review discusses the role of the ApoE in AD and other neurodegenerative disorders. ApoE, a cholesterol transport protein, influences several pathways involved in neurodegeneration, particularly in AD. Beyond its established role in amyloid β-protein (Aβ) metabolism and deposition, ApoE also impacts tau pathology, neurodegeneration, and the microglial response to AD. The review aims to provide an updated overview of ApoE's diverse roles, emphasizing its involvement in Aβ clearance through ApoE receptors. It also covers ApoE's influence in other neurodegenerative diseases like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Huntington's disease (HD), vascular dementia (VD), and multiple sclerosis (MS). New research highlights the interaction between ApoE and presenilin (PS), suggesting connections between familial AD (FAD) and SAD. The review also explores protective effects of ApoE mutations against AD and ApoE4-induced tauopathy, neurodegeneration, and neuroinflammation. The insights from this comprehensive update could indeed lead to new therapeutic strategies for neurodegenerative diseases.}, } @article {pmid39944773, year = {2025}, author = {Cheng, R and Dimitriou, D and Yao, G and Li, X and Lv, X and Yang, Y and Ying, H and Wang, Z and Tsai, TY}, title = {Outperformance of Combined Artificial Anterolateral Ligament and ACL Reconstruction Compared With Isolated Artificial ACL Reconstruction in Knees With Anterolateral Structure and ACL Deficiency: A Biomechanical Analysis.}, journal = {Orthopaedic journal of sports medicine}, volume = {13}, number = {2}, pages = {23259671241309270}, pmid = {39944773}, issn = {2325-9671}, abstract = {BACKGROUND: Despite the promising clinical outcomes of artificial polyethylene terephthalate (PET) ligaments in isolated anterior cruciate ligament reconstruction (ACLR), their biomechanical performance after combined anterolateral ligament reconstruction (ALLR)/ACLR in anterolateral structure (ALS)/anterior cruciate ligament (ACL)-deficient knees has not been investigated.

PURPOSE/HYPOTHESIS: The purpose of this study was to compare biomechanical performance in cadaveric knees between combined artificial ALLR/ACLR and isolated artificial ACLR using PET ligaments. It was hypothesized that combined artificial ALLR/ACLR would restore native knee stability and outperform isolated artificial ACLR in ALS/ACL-deficient knees.

STUDY DESIGN: Controlled laboratory study.

METHODS: Eight fresh-frozen cadaveric knees were tested using a robotic manipulator. Each knee was tested in 4 states: (1) ALS/ACL intact, (2) ALS/ACL deficient, (3) ACLR, and (4) ALLR/ACLR. The anterior tibial translation (ATT) and tibial internal rotation (IR) in each knee condition were measured under 3 loads: (1) 89 N of anterior tibial loading, (2) 5 N·m of IR torque, and (3) simulated pivot shift (combined 5 N·m of IR torque and 7 N·m of valgus load).

RESULTS: During 89 N of anterior tibial loading, there were no significant differences in ATT between the isolated ACLR and ALLR/ACLR knees. During 5 N·m of IR torque, the mean tibial IR at 45° of flexion was significantly higher in the ACLR knees (32.49°± 7.96°) than in the ALLR/ACLR knees (21.78°± 3.03°) (P < .05). During the simulated pivot shift, the mean ATT and tibial IR at 30° and 45° of flexion were significantly higher in the ACLR knees (ATT: 5.09 ± 2.74 mm at 30°, 5.43 ± 2.79 mm at 45°; IR: 30.08°± 7.31° at 30°, 32.55°± 6.48° at 45°) than in the ALLR/ACLR knees (ATT: 1.93 ± 2.71 mm at 30°, 1.17 ± 2.26 mm at 45°; IR: 22.12°± 4.05° at 30°, 22.18°± 3.37° at 45°) (P < .05).

CONCLUSION: Combined artificial ALLR/ACLR restored native knee stability across multiple flexion angles and outperformed isolated artificial ACLR in ALS/ACL-deficient knees, particularly with respect to ATT and tibial IR during the pivot-shift test.

CLINICAL RELEVANCE: The indications of the artificial PET ligament may be expanded to include combined ALLR/ACLR to restore knee stability better than isolated artificial ACLR in ALS/ACL-deficient knees.}, } @article {pmid39945358, year = {2025}, author = {Badger, SE and Coldicott, I and Kyrgiou-Balli, E and Higginbottom, A and Moutin, C and Mohd Imran, K and Day, JC and Cooper-Knock, J and Mead, RJ and Alix, JJP}, title = {A bacterial artificial chromosome mouse model of amyotrophic lateral sclerosis manifests 'space cadet syndrome' on two FVB backgrounds.}, journal = {Disease models & mechanisms}, volume = {18}, number = {2}, pages = {}, pmid = {39945358}, issn = {1754-8411}, support = {Alix/Apr19/871-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; //University of Sheffield/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/pathology ; Disease Models, Animal ; *Chromosomes, Artificial, Bacterial/genetics ; Mice, Transgenic ; C9orf72 Protein/metabolism ; *Frontotemporal Dementia/genetics/physiopathology/pathology ; Phenotype ; *Genetic Background ; Mice ; Seizures/complications/pathology/physiopathology ; }, abstract = {C9orf72-related amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) has proven difficult to model in mice. Liu et al. (2016) reported a bacterial artificial chromosome (BAC) transgenic mouse displaying behavioural, motor and pathological abnormalities. This was followed by multiple laboratories independently refuting and confirming phenotypes. A proposed explanation centred on the use of different FVB background lines (from The Jackson Laboratory and Janvier Labs). We studied C9orf72 BAC mice on both backgrounds and found significantly elevated levels of dipeptide repeat proteins, but no evidence of a transgene-associated phenotype. We observed seizures and a gradual decline in functional performance in transgenic and non-transgenic mice, irrespective of genetic background. The phenotype was in keeping with the so-called 'space cadet syndrome'. Our findings indicate that the differences previously reported are not due to C9orf72 status and highlight the importance of using genetic backgrounds that do not confound interpretation of neurodegenerative phenotypes.}, } @article {pmid39946043, year = {2025}, author = {Patnana, DP and Kanikaram, SP and Kumar, P and Cheerala, VSK and Sivaramakrishnan, V and Tripathi, P and Chandra, BP}, title = {Simultaneous determination of polycyclic aromatic hydrocarbons, their derivatives, and phthalic acid esters bound to ambient PM2.5 during pre-summer season in Bengaluru, India, and potential effect on protein aggregation diseases.}, journal = {Environmental science and pollution research international}, volume = {32}, number = {29}, pages = {17393-17406}, pmid = {39946043}, issn = {1614-7499}, mesh = {*Polycyclic Aromatic Hydrocarbons/analysis ; *Particulate Matter ; India ; *Phthalic Acids/analysis ; Air Pollutants/analysis ; Esters ; Environmental Monitoring ; Seasons ; Humans ; Tandem Mass Spectrometry ; }, abstract = {Air pollution pertaining to particulate matter (PM) is a major issue in most of the metropolitan cities across the world. Inhalation exposure to organic species like polycyclic aromatic hydrocarbons (PAHs), derivatives of PAHs (oxygenated and nitrated PAHs), and phthalic acid esters (PAEs) bound to PM is of major concern owing to its carcinogenic, mutagenic, and endocrine disrupting nature. In this study for the first time, we report a total of 22 aromatic organic species which include PAHs, derivatives of PAHs, and PAEs using an optimized high-performance liquid chromatography coupled to the tandem mass spectrometer (HPLC-MS/MS) method. Further, this optimized method was used to carry out the measurements of the 22 targeted organic constituents bound to the ambient fine particulate matter (PM2.5) collected in Bengaluru, a metropolitan city in India as a part of a pilot study during the pre-summer season. Among the reported compounds, benzo[b]fluoranthene (3.82 ng m[-3]), 9-nitroanthracene (10.47 ng m[-3]), and diethyl phthalate (5.38 ng m[-3]) are the most abundant PAHs, the derivatives of PAHs, and PAEs, respectively. Determined diagnostic ratios of PAHs have shown that the sampling site is majorly influenced by traffic emissions. Benzo[a]pyrene, a Group 1 carcinogen has occasionally exceeded the limits set by National Ambient Air Quality Standards (NAAQs), India during the sampling period. Further, a preliminary study was performed using a yeast model of amyotrophic lateral sclerosis (ALS) expressing transactive response DNA binding protein 43 (TDP43) and we demonstrated that commonly reported organics such as PAHs and PAEs bound to PM2.5 have induced significantly elevated aggregation in wild type TDP43. Preliminary results of this study indicate that there is a need for further detailed health risk assessment due to inhalation exposure of organic constituents bound to the ambient PM in Bengaluru.}, } @article {pmid39946662, year = {2025}, author = {Cordts, I and Fuetterer, C and Wachinger, A and von Heynitz, R and Kessler, T and Freigang, M and Quinten, AL and Bjelica, B and Brakemeier, S and Hobbiebrunken, E and Hagenacker, T and Petri, S and Koch, JC and Hahn, A and Lingor, P and Deschauer, M and Günther, R and Weiler, M and Haller, B and Feneberg, E}, title = {Long-Term Dynamics of CSF and Serum Neurofilament Light Chain in Adult Patients With 5q Spinal Muscular Atrophy Treated With Nusinersen.}, journal = {Neurology}, volume = {104}, number = {5}, pages = {e213371}, pmid = {39946662}, issn = {1526-632X}, mesh = {Humans ; Female ; Male ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Adult ; Retrospective Studies ; *Oligonucleotides/therapeutic use ; Middle Aged ; *Muscular Atrophy, Spinal/drug therapy/cerebrospinal fluid/blood ; Biomarkers/cerebrospinal fluid/blood ; Young Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: The availability of disease-modifying therapies for 5q-associated spinal muscular atrophy (SMA) has heightened the need to identify suitable biomarkers. This study investigates neurofilament light chain (NfL) concentrations during long-term nusinersen treatment in adult SMA.

METHODS: In a retrospective study of prospectively collected data, NfL concentrations in the CSF (cNfL) and serum (sNfL) were measured in patients with SMA from 8 German centers and in neurologic controls using a single-molecule array (Simoa) assay. NfL concentrations and clinical characteristics, including the clinical scores Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), were analyzed for defined treatment intervals (T1-T4 [loading phase until 4 months], T5-T8 [until 23 months], T9-T12 [until 37 months], and T13-T19 [until 60 months]). Linear mixed models with a random intercept were used to assess the changes in NfL levels during treatment, considering time and covariates as fixed effects.

RESULTS: One hundred thirteen adult patients with SMA (median age 35, 46% female), with a treatment duration of maximum 60 months, and 52 controls were included. At baseline, NfL concentrations were significantly higher in SMA {cNfL median, 585 (interquartile range [IQR] 428-787) pg/mL; sNfL, 11 (IQR 8-14) pg/mL} than in controls (cNfL, 420 [IQR 323-662] pg/mL; sNfL, 8 [IQR 6-12] pg/mL) (cNfL, p = 0.021; sNfL, p = 0.030). Median differences for all clinical scores were the highest for T5-T8 compared with the loading phase (Δ HFMSE, 0.6 [IQR 0.1-1.4], p = 0.017; Δ RULM, 0.9 [IQR 0.4-1.3], p < 0.001; Δ ALSFRS-R, 0.7 [IQR 0.4-1.0], p < 0.001), but not for subsequent intervals. Longitudinal analysis revealed a significant decrease of NfL concentrations during each treatment interval compared with the loading phase (p < 0.05, respectively) except for sNfL in T13-T19. Even among patients with no measurable clinical improvement (Δ HFMSE ≤ 0), more than 50% showed declining cNfL and sNfL levels up to T13-T19.

DISCUSSION: NfL decreased during nusinersen treatment, suggesting its potential as a pharmacodynamic response marker in adult SMA. However, in patients without detectable clinical improvement, our study cannot determine whether they represent a more sensitive outcome measure or are not clinically meaningful.}, } @article {pmid39947099, year = {2025}, author = {Tan, HHG and Nitert, AD and van Veenhuijzen, K and Dukic, S and van Zandvoort, MJE and Hendrikse, J and van Es, MA and Veldink, JH and Westeneng, HJ and van den Berg, LH}, title = {Neuroimaging correlates of domain-specific cognitive deficits in amyotrophic lateral sclerosis.}, journal = {NeuroImage. Clinical}, volume = {45}, number = {}, pages = {103749}, pmid = {39947099}, issn = {2213-1582}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/pathology/physiopathology/psychology ; Male ; Female ; Middle Aged ; Magnetic Resonance Imaging/methods ; Aged ; *Cognitive Dysfunction/diagnostic imaging/etiology/physiopathology/pathology ; *Neuroimaging/methods ; Gray Matter/diagnostic imaging/pathology ; White Matter/diagnostic imaging/pathology ; Adult ; *Brain/diagnostic imaging/pathology ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with frequent extra-motor involvement. In the present study, we investigated whether specific cognitive and behavioral deficits in ALS correlate with distinct extra-motor neurodegeneration patterns on brain MRI.

METHODS: We performed multimodal brain MRI and Edinburgh cognitive and behavioral ALS screen (ECAS) in 293 patients and 237 controls. Follow-up data were acquired from 171 patients with a median duration of 7.9 months. Domain-level cognitive scores from the ECAS were compared with grey and white matter MRI parameters. Interaction analyses between patients and controls were performed to explore whether correlates were specific to ALS, rather than related to normal aging. Follow-up data were used to assess changes of domain-associated brain structures over time.

RESULTS: Language impairment was significantly associated with (left predominant) frontal, temporal, parietal and subcortical grey matter neurodegeneration. Letter fluency with widespread cortical and subcortical grey matter involvement. Memory dysfunction with hippocampal and medial-temporal atrophy. Executive impairment was exclusively correlated with widespread white matter impairment. Visuospatial scores did not correlate with MRI parameters. Interaction analyses between patients and controls showed that most ECAS-MRI correlations were stronger in ALS than in controls (75.7% significant in grey matter, 52.7% in white matter). Longitudinal analyses showed that all grey matter structures associated with cognitive domains worsened over time while, for this study population, ECAS domain scores did not decline significantly.

CONCLUSIONS: MRI can capture the heterogeneity of cognitive and behavioral involvement in ALS and provides a useful longitudinal biomarker for progression of extra-motor neurodegeneration.}, } @article {pmid39947279, year = {2025}, author = {Gelbenegger, G and Cheskes, S and Jilma, B and Zeitlinger, M and Lin, S and Drennan, IR and Jorda, A}, title = {Amiodarone dose in patients with shockable out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {209}, number = {}, pages = {110534}, doi = {10.1016/j.resuscitation.2025.110534}, pmid = {39947279}, issn = {1873-1570}, mesh = {Humans ; *Amiodarone/administration & dosage ; *Out-of-Hospital Cardiac Arrest/therapy/mortality/drug therapy ; Male ; Female ; *Anti-Arrhythmia Agents/administration & dosage ; Aged ; Middle Aged ; *Cardiopulmonary Resuscitation/methods ; Registries ; *Electric Countershock/methods ; Dose-Response Relationship, Drug ; Treatment Outcome ; }, abstract = {BACKGROUND: Amiodarone is used in shockable out-of-hospital cardiac arrest (OHCA), but the ideal dose is unknown.

METHODS: This was an analysis from the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry (2011-2015). Patients with shockable OHCA who received 5 or more defibrillation attempts and treatment with 300 or 450 mg of amiodarone were included. Outcomes were ROSC at ED arrival, survival at hospital discharge, and favorable neurologic function at discharge. Group-differences were adjusted for using inverse probability weighting and a multiple logistic regression model.

RESULTS: The present study included 910 patients; 426 received amiodarone 300 mg and 484 received amiodarone 450 mg. The amiodarone 300 mg group had a higher estimated probability of ROSC at ED arrival as compared with the amiodarone 450 mg group (30.8% [95% CI, 26.6-35.1] vs 24.2% [95% CI, 20.5-27.9], respectively; adjusted probability difference, 6.6% (0.9-12.3), p = 0.0234). The group differences in survival at hospital discharge (21.3% [95% CI, 17.2-25.4] vs 18.0% [95% CI, 14.6-21.5]; adjusted probability difference, 3.3% [-2.3-8.8]) and favorable neurologic outcome at discharge (16.5% [95% CI, 12.9-20.2] vs 12.7% [95% CI, 9.5-16.0]; adjusted probability difference, 3.8% [95% CI, -1.2-8.7]) did not reach statistical significance.

CONCLUSION: In patients with shockable OHCA who received 5 or more defibrillation attempts, a dose of amiodarone 300 mg was associated with a similar survival compared with a total dose of amiodarone 450 mg. Further study is needed to evaluate the need for a second administration of amiodarone in patients with shockable OHCA.}, } @article {pmid39947630, year = {2025}, author = {Moreno-Martinez, L and Gaja-Capdevila, N and Mosqueira-Martín, L and Herrando-Grabulosa, M and Rodriguez-Gomez, L and Gonzalez-Imaz, K and Calvo, AC and Sagartzazu-Aizpurua, M and Moreno-García, L and Fuentes, JM and Acevedo-Arozena, A and Aizpurua, JM and Miranda, JI and López de Munain, A and Vallejo-Illarramendi, A and Navarro, X and Osta, R and Gil-Bea, FJ}, title = {Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1[G93A] amyotrophic lateral sclerosis (ALS) mice.}, journal = {British journal of pharmacology}, volume = {182}, number = {11}, pages = {2466-2486}, doi = {10.1111/bph.17448}, pmid = {39947630}, issn = {1476-5381}, support = {PID2022-140354OB-I00//Agencia Estatal de Investigación/ ; PID2020-119780RB-100//Agencia Estatal de Investigación/ ; IKERBASQUE/PP/2022/003//Ikerbasque, Basque Foundation for Science/ ; PIF19/184//Euskal Herriko Unibertsitatea/ ; PI2020/08-1//CIBER-CALS/ ; CB06/05/1105//Instituto de Salud Carlos III of Spain/ ; CB06/05/0041//Instituto de Salud Carlos III of Spain/ ; BIO19/ROCHE/017/BD//Roche Stop Fuga de Cerebros/ ; IT1732-22//Basque Government/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology/genetics ; Ligands ; Mice ; *Superoxide Dismutase-1/genetics ; Mice, Transgenic ; *Tacrolimus Binding Protein 1A/metabolism ; Disease Models, Animal ; Humans ; Male ; Motor Neurons/drug effects ; Ryanodine Receptor Calcium Release Channel/metabolism ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. ALS pathogenesis involves intricate processes within motor neurons, characterized by dysregulated Ca[2+] influx and buffering in early ALS-affected motor neurones. This study proposes the modulation of ryanodine receptors (RyRs), key mediators of intracellular Ca[2+], as a therapeutic target.

EXPERIMENTAL APPROACH: A novel class of novel FKBP12 ligands that show activity as cytosolic calcium modulators through stabilizing RyR channel activity, were tested in the superoxide dismutase 1 (SOD1)[G93A] mouse model of ALS. Different outcomes were used to assess treatment efficacy, including electrophysiology, histopathology, neuromuscular function and survival.

KEY RESULTS: Among the novel FKBP12 ligands, MP-010 was chosen for its central nervous system availability and favourable in vitro pharmaco-toxicological profile. Chronic administration of MP-010 to SOD1[G93A] mice produced preservation of motor nerve conduction, with the 61-mg·kg[-1] dose significantly delaying the onset of motor impairment. This was accompanied by improved motor coordination, increased innervated endplates and significant preservation of motor neurones in the spinal cord of treated mice. Notably, MP-010 treatment significantly extended lifespan by an average of 10 days compared to vehicle.

CONCLUSIONS AND IMPLICATIONS: FKBP12 ligands, particularly MP-010, exhibit promising neuroprotective effects in ALS, highlighting their potential as novel therapeutic agents. Further investigations into the molecular mechanisms and clinical translatability of these compounds are needed for their application in ALS treatment.}, } @article {pmid39947885, year = {2025}, author = {Iacoangeli, A and Dilliott, AA and Al Khleifat, A and Andersen, PM and Başak, NA and Cooper-Knock, J and Corcia, P and Couratier, P and deCarvalho, M and Drory, VE and Glass, JD and Gotkine, M and Lerner, YM and Hardiman, O and Landers, JE and McLaughlin, RL and Pardina, JSM and Morrison, K and Pinto, S and Povedano, M and Shaw, CE and Shaw, PJ and Silani, V and Ticozzi, N and van Damme, P and van den Berg, LH and Vourc'h, P and Weber, M and Veldink, JH and , and Dobson, R and Rouleau, GA and Al-Chalabi, A and Farhan, SMK}, title = {Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {10}, pages = {928-936}, pmid = {39947885}, issn = {1468-330X}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Genetic Testing ; Case-Control Studies ; *Genetic Counseling ; Male ; Female ; Genetic Predisposition to Disease/genetics ; Middle Aged ; Aged ; Adult ; }, abstract = {BACKGROUND: Despite several studies suggesting a potential oligogenic risk model in amyotrophic lateral sclerosis (ALS), case-control statistical evidence implicating oligogenicity with disease risk or clinical outcomes is limited. Considering its direct clinical and therapeutic implications, we aim to perform a large-scale robust investigation of oligogenicity in ALS risk and in the disease clinical course.

METHODS: We leveraged Project MinE genome sequencing datasets (6711 cases and 2391 controls) to identify associations between oligogenicity in known ALS genes and disease risk, as well as clinical outcomes.

RESULTS: In both the discovery and replication cohorts, we observed that the risk imparted from carrying multiple ALS rare variants was significantly greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, did not follow the same pattern.

CONCLUSIONS: Our findings represent the first large-scale, case-control assessment of oligogenicity in ALS and show that oligogenic events involving known ALS risk genes are relevant for disease risk in ~6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring to use comprehensive gene panels even when a pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need for a complete genetic profile for the correct choice of therapy in all ALS patients.}, } @article {pmid39948244, year = {2025}, author = {Picard, F and Nonaka, T and Belotti, E and Osseni, A and Errazuriz-Cerda, E and Jost-Mousseau, C and Bernard, E and Conjard-Duplany, A and Bohl, D and Hasegawa, M and Raoul, C and Galli, T and Schaeffer, L and Leblanc, P}, title = {Enhanced secretion of the amyotrophic lateral sclerosis ALS-associated misfolded TDP-43 mediated by the ER-ubiquitin specific peptidase USP19.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {82}, number = {1}, pages = {76}, pmid = {39948244}, issn = {1420-9071}, support = {MyoNeurALP strategic grants//AFM-Téléthon/ ; SPREADALS//Agence Nationale de la Recherche/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Endoplasmic Reticulum/metabolism ; *DNA-Binding Proteins/metabolism/chemistry/genetics ; Protein Folding ; *Endopeptidases/metabolism/genetics ; HEK293 Cells ; rab GTP-Binding Proteins/metabolism ; HeLa Cells ; }, abstract = {Proteinopathies, such as amyotrophic lateral sclerosis (ALS), are marked by the accumulation of misfolded proteins that disrupt cellular processes. Eukaryotic cells have developed protein quality control systems to eliminate these aberrant proteins, but these systems often fail to differentiate between normal and misfolded proteins. In ALS, pathological inclusions primarily composed of misfolded TDP-43 are a hallmark of the disease. Recently, a novel unconventional secretion process called misfolding-associated protein secretion (MAPS) has been discovered to selectively export misfolded proteins. USP19, an Endoplasmic Reticulum-associated ubiquitin peptidase, plays a crucial role in this process. In this study, we investigated the impact of ER-anchored USP19 on the secretion of misfolded TDP-43. Here we found that USP19 overexpression significantly promotes the secretion of soluble and aggregated misfolded TDP-43, requiring both ER anchoring and ubiquitin peptidase activity. Characterization of the cellular and molecular mechanisms involved in this process highlighted the importance of early autophagosomal and late endosomal/amphisomal compartments, while lysosomes did not play a key role. By using dominant-negative mutants and small interfering RNAs, we identified that USP19-mediated secretion of misfolded TDP-43 is modulated by key factors involved in cellular trafficking and secretion pathways, such as ATG7, the ESCRT-O HGS/HRS, the Rab GTPases RAB11A, RAB8A, and RAB27A, and the v-SNARE VAMP7. We also confirmed the crucial role of the DNAJC5/CSPα cochaperone. Overall, this study provides new insights into how cells manage the secretion of misfolded TDP-43 proteins and potentially opens new avenues for therapeutic interventions in ALS and related disorders.}, } @article {pmid39949668, year = {2025}, author = {Xu, J and Yu, Y and Wang, Y and Zhang, S and Liu, E and Wang, W and Zhu, C and Li, J}, title = {Postoperative Axial Length Prediction Model in Children With Congenital Cataract and Intraocular Lens Implantation.}, journal = {Journal of ophthalmology}, volume = {2025}, number = {}, pages = {9948890}, pmid = {39949668}, issn = {2090-004X}, abstract = {Purpose: To develop a prediction model for postoperative axial length (AL) in Asian children with congenital cataracts undergoing primary/secondary intraocular lens (IOL) implantation. Design: Retrospective observational study. Methods: Data were collected from children who underwent cataract surgery for congenital cataracts at the Eye Hospital of Wenzhou Medical University between 2006 and 2020. All participants completed preoperative and at least 1-year of postoperative follow-up. SPSS 26.0 software was used to analyze the variable factors affecting AL growth and the interactions among these factors. A generalized estimating equation (GEE) was employed to assess the correlation between the AL and related univariates over time. The univariate model was applied to build a multivariate model to predict the postoperative AL. Two validation sets were used to verify the accuracy of the formula. Results: The study involved 86 children, accounting for 148 eyes. The median age at the time of surgery was 3.00 years, with a median age of 9.50 years at the final follow-up visit. The median duration of follow-up was 5.00 years. The preoperative and final follow-up mean ALs were 21.79 ± 1.77 and 23.36 ± 1.90 mm, respectively. Taking the predicted AL (Y) as the dependent variable and the age at surgery (X 1), age at review (X 2), and preoperative AL (X 3) as the independent variables, the prediction model was established as Y = 0.20 - 0.473 × X 1 + 0.446 × X 2 + 0.993 × X 3 - 0.014 × (X 2 - X 1)∗X 2. Conclusions: This model predicts AL growth in children following congenital cataract surgery and IOL implantation, helping ophthalmologists select appropriate IOL power.}, } @article {pmid39950184, year = {2025}, author = {Høj, A and Holm-Yildiz, S and Krag, T and Dejanovic, D and van Overeem Hansen, T and Dunø, M and Ørngreen, MC and Vissing, J and Løkken, N}, title = {2-[[18]F] FDG PET/CT in Rapid Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Case Report.}, journal = {JIMD reports}, volume = {66}, number = {2}, pages = {e12469}, pmid = {39950184}, issn = {2192-8304}, abstract = {Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn metabolic myopathy affecting fat and protein metabolism. Patients with late-onset MADD typically present with exercise intolerance and muscle weakness. We present a patient with an acute, very late-onset symptom debut at 52 years of age. Over 5 months, the patient deteriorated from asymptomatic to almost complete loss of ambulation. He had a substantial weight loss, head-drop, progressive proximal limb and chewing weakness. Due to the rapid progression, amyotrophic lateral sclerosis, myositis, myasthenia gravis and a paraneoplastic syndrome in relation to underlying malignancy were considered first. A 2-[[18]F] FDG PET/CT scan was performed to exclude a paraneoplastic syndrome. The scan revealed diffuse and symmetric, pathologically high 2-[[18]F] FDG-uptake in the patient's neck, shoulder, and paravertebral muscles, which was later suggested as a sign of a metabolic myopathy. Muscle biopsy (Oil Red O staining) and acylcarnitine profile (elevated C5-C18 acylcarnitines) findings suggested MADD, which was confirmed by genetic analysis showing biallelic variants in the ETFDH gene (c.1763A>G, p.(His588Arg); c.897G>A, p.(Leu299=)). After 1 month of dietary intervention and daily diet supplements (riboflavin 400 mg TID, levocarnitine 1 g TID, Q10 150 mg qD in two doses), the patient had almost recovered to his habitual level. A posttreatment muscle biopsy showed less disrupted ultrastructure of the myofibers. We learned from this case of rapid and late-onset MADD that 2-[[18]F] FDG PET/CT, with diffuse and symmetric 2-[[18]F] FDG-uptake in skeletal muscle, can be valuable in clarifying this rare diagnosis.}, } @article {pmid39952329, year = {2025}, author = {Ji, Y and Jiang, Q and Chen, B and Chen, X and Li, A and Shen, D and Shen, Y and Liu, H and Qian, X and Yao, X and Sun, H}, title = {Endoplasmic reticulum stress and unfolded protein response: Roles in skeletal muscle atrophy.}, journal = {Biochemical pharmacology}, volume = {234}, number = {}, pages = {116799}, doi = {10.1016/j.bcp.2025.116799}, pmid = {39952329}, issn = {1873-2968}, mesh = {*Unfolded Protein Response/physiology/drug effects ; Humans ; *Endoplasmic Reticulum Stress/physiology/drug effects ; *Muscular Atrophy/metabolism/pathology ; Animals ; *Muscle, Skeletal/metabolism/pathology/drug effects ; }, abstract = {Skeletal muscle atrophy is commonly present in various pathological states, posing a huge burden on society and patients. Increased protein hydrolysis, decreased protein synthesis, inflammatory response, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are all important molecular mechanisms involved in the occurrence and development of skeletal muscle atrophy. The potential mechanisms of ERS and UPR in skeletal muscle atrophy are extremely complex and have not yet been fully elucidated. This article elucidates the molecular mechanisms of ERS and UPR, and discusses their effects on different types of muscle atrophy (muscle atrophy caused by disuse, cachexia, chronic kidney disease (CKD), diabetes mellitus (DM), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), aging, sarcopenia, obesity, and starvation), and explores the preventive and therapeutic strategies targeting ERS and UPR in skeletal muscle atrophy, including inhibitor therapy and drug therapy. This review aims to emphasize the importance of endoplasmic reticulum (ER) in maintaining skeletal muscle homeostasis, which helps us further understand the molecular mechanisms of skeletal muscle atrophy and provides new ideas and insights for the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy.}, } @article {pmid39952435, year = {2025}, author = {Truel, JS and Novice, M and Shapiro, J and Lo Sicco, KI}, title = {Response to Folliat et al's "Characteristics of pruritus in lichen planopilaris and frontal fibrosing alopecia: A cohort study in a French hospital".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {6}, pages = {e195}, doi = {10.1016/j.jaad.2024.11.084}, pmid = {39952435}, issn = {1097-6787}, } @article {pmid39953725, year = {2025}, author = {Nishida, K and Sakashita, K and Futamura, N}, title = {Decision-making trends in therapeutic interventions for multiple system atrophy: a 24-year retrospective study.}, journal = {Movement disorders clinical practice}, volume = {12}, number = {6}, pages = {823-827}, pmid = {39953725}, issn = {2330-1619}, support = {JPMH23FC1010//the Ministry of Health, Labour and Welfare, Japan/ ; }, mesh = {Humans ; *Multiple System Atrophy/therapy ; Retrospective Studies ; Male ; Female ; Middle Aged ; *Tracheostomy/trends ; Aged ; Enteral Nutrition/trends ; Japan ; Adult ; *Respiration, Artificial/trends ; *Clinical Decision-Making ; Age Factors ; }, abstract = {BACKGROUND: Managing multiple system atrophy (MSA) is challenging. While invasive interventions for amyotrophic lateral sclerosis are well-studied, those for MSA remain less explored.

OBJECTIVES: To explore factors influencing treatment choices and trends in advanced-stage MSA.

METHODS: A retrospective cohort study analyzed 128 MSA patients at Hyogo Chuo National Hospital, Japan, from 2000 to 2024, focusing on treatment period and age at onset.

RESULTS: Tracheostomy invasive ventilation (TIV) decreased after 2014 (26.9% vs. 9.2%; P = 0.023). TIV-treated patients remained similarly young before and after 2014 (age at onset 52.7 vs. 54.5 years; P = 0.659) and tracheostomy was chosen by younger patients after 2014 (58.3 vs. 51.5 years; P < 0.001). Conversely, enteral nutrition increased in older patients (57.4 vs. 62.9 years; P = 0.011).

CONCLUSIONS: In Japanese MSA, preferences for invasive treatments shifted, with younger patients favoring TIV and tracheostomy, while older patients preferred less invasive options, emphasizing personalized care.}, } @article {pmid39954028, year = {2025}, author = {Al Ojaimi, Y and Vallet, N and Dangoumau, A and Lanznaster, D and Bruno, C and Lefevre, A and Osman, S and Dupuy, C and Emond, P and Vourc'h, P and Corcia, P and Krupova, Z and Veyrat-Durebex, C and Blasco, H}, title = {Metabolomic and Proteomic Profiling of Serum-Derived Extracellular Vesicles from Early-Stage Amyotrophic Lateral Sclerosis Patients.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {1}, pages = {21}, pmid = {39954028}, issn = {1559-1166}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; Male ; Female ; Middle Aged ; *Extracellular Vesicles/metabolism ; Aged ; Biomarkers/blood ; *Proteome/metabolism ; *Metabolome ; Adult ; }, abstract = {The identification of reliable biomarkers for amyotrophic lateral sclerosis (ALS) is an unmet medical need for the development of diagnostic and therapeutic strategies. Brain-derived extracellular vesicles (EVs) have been described in peripheral blood serum and used as a direct readout of the status of the central nervous system. Here, we aimed to explore exosome-enriched EVs (referred to simply as EVs) from ALS patients via omics analysis at an early disease stage. Serum EVs were obtained from 9 healthy controls and 9 ALS patients. After EV purification, proteomic (LC‒MS/MS followed by TimsTOF Pro Mass Spectrometry) and metabolomic (Q Exactive mass spectrometer) analyses were performed. No differences in the size or concentration of EVs were observed between the controls and ALS patients. Proteomic analysis revealed 45 proteins differentially expressed in the EVs of ALS patients compared with those of controls. Metabolomic analysis revealed several distinctly represented metabolites involved in the citrate cycle and complex lipid metabolism between patients and controls. Interomics correlation analysis revealed 2 modules that were strongly associated with ALS and included several lipid metabolism-related proteins and metabolites. This study is the first to evaluate EVs by integrated proteomics and metabolomics in early-stage ALS patients, highlighting the technological progress in global inter-omics explorations of small biological samples. The differences observed in the levels of several exosomal proteins and metabolites, including phospholipids, could be used to identify serum biomarkers and novel players involved in ALS pathogenesis.}, } @article {pmid39954119, year = {2025}, author = {Jacobsen, AB and Fanella, G and de Carvalho, M and Koltzenburg, M and Oliveira Santos, M and Cengiz, B and Blicher, J and Obál, I and Heintzelmann, MB and Nix, W and Camdessanché, JP and Fuglsang-Frederiksen, A and Tankisi, H}, title = {Variability of the Penn upper motor neuron score in amyotrophic lateral sclerosis: need for a revised score.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {208}, pmid = {39954119}, issn = {1432-1459}, support = {R346-2020-1946//Lundbeck Foundation/ ; R392-2022-699//Lundbeck Foundation/ ; J.nr.23-2B-12533//Aage og Johanne Louis-Hansens Fond/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Aged ; Reproducibility of Results ; Middle Aged ; *Severity of Illness Index ; *Motor Neurons/pathology ; Aged, 80 and over ; Observer Variation ; }, abstract = {There is a need for a consensus on a clinical scale for evaluating upper motor neuron (UMN) burden in amyotrophic lateral sclerosis (ALS) to improve consistency in clinical diagnosis, research and monitoring of disease progression. The Penn upper motor neuron score (PUMNS) is the most commonly published scale, however, the reliability of the scale has only been evaluated in a single study involving two raters. The objective of this study was to evaluate the inter-rater reliability of the PUMNS in ALS patients among multiple raters, and to discuss an updated UMN score including the signs with the highest inter-rater reliability. This study included seven ALS patients (mean age: 71 ± 11.5, six males, one female). Each patient was evaluated with the PUMNS by eight raters from different centers blinded to previous observations. The intra-class correlation coefficient (ICC) was calculated to assess the inter-rater reliability of the total PUMNS. The inter-rater reliability of the binary subscores was assessed with Gwet's AC1 coefficient. The inter-rater agreement for the total PUMNS yielded an ICC of 0.81 (95% CI 0.56;0.96). Items with the highest inter-rater reliability included Hoffman's sign, Babinski's sign, clonus and deep tendon reflexes, while the facial reflex (Gwet's AC1 -0.038 (95% CI -0.25,0.18)) and crossed adduction (0.18 (95% CI (-0.32,0.67)) had the lowest inter-rater reliability. In conclusion, PUMNS demonstrated good inter-rater reliability overall, while some of the subscores had poor inter-rater reliability. Based on this, we call for an updated UMN score to enhance diagnostic accuracy and research consistency in ALS.}, } @article {pmid39954573, year = {2025}, author = {Kiernan, MC and Timmins, HC}, title = {Utility of the Gold Coast criteria for amyotrophic lateral sclerosis: Experience with fast progressors.}, journal = {Journal of the neurological sciences}, volume = {470}, number = {}, pages = {123417}, doi = {10.1016/j.jns.2025.123417}, pmid = {39954573}, issn = {1878-5883}, } @article {pmid39954710, year = {2025}, author = {Nadeem, ZA and Ahmed, S}, title = {Amyotrophic lateral sclerosis and lovastatin: a promising treatment perspective.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {595-596}, doi = {10.1080/21678421.2025.2463943}, pmid = {39954710}, issn = {2167-9223}, } @article {pmid39954940, year = {2025}, author = {Satao, KS and Doshi, GM}, title = {Intercellular communication via exosomes: A new paradigm in the pathophysiology of neurodegenerative disorders.}, journal = {Life sciences}, volume = {365}, number = {}, pages = {123468}, doi = {10.1016/j.lfs.2025.123468}, pmid = {39954940}, issn = {1879-0631}, mesh = {Humans ; *Exosomes/metabolism/physiology ; *Neurodegenerative Diseases/physiopathology/metabolism/pathology ; *Cell Communication/physiology ; Animals ; }, abstract = {Neurodegenerative disorders are one of the leading causes of death and disability and pose a great economic burden on healthcare systems. Generally, these neurodegenerative disorders have a progressive deterioration in neural function and structure, and deposition of misfolded proteins commonly occurs, such as amyloid-β in AD and α-synuclein in PD. However, there exists a special class of exosomes, which acts like a transmitter and enhances communication between cells. The present review discusses the significant role of exosomes in neurodegenerative diseases, with a focus on Amyotrophic lateral Sclerosis (ALS), AD, PD, and Huntington's disease (HD). In this review, the biogenesis of exosomes is discussed from multivesicular bodies and onwards to their release into the extracellular environment. The present review focuses on recent data concerning the possible use of modified exosomes as ND therapy. Indeed, future work is needed to explain the processes driving exosome biogenesis and cargo selection, while opening new routes by the use of exosome-based therapeutics in neurodegenerative disease diagnosis and treatment.}, } @article {pmid39954969, year = {2025}, author = {Utami, KH and Morimoto, S and Mitsukura, Y and Okano, H}, title = {The roles of intrinsically disordered proteins in neurodegeneration.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1869}, number = {4}, pages = {130772}, doi = {10.1016/j.bbagen.2025.130772}, pmid = {39954969}, issn = {1872-8006}, mesh = {Humans ; *Intrinsically Disordered Proteins/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Proteostasis ; Autophagy ; alpha-Synuclein/metabolism ; Proteasome Endopeptidase Complex/metabolism ; }, abstract = {Neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease share a common pathological hallmark: the accumulation of misfolded proteins, particularly involving intrinsically disordered proteins (IDPs) like TDP-43, FUS, Tau, α-synuclein, and Huntingtin. These proteins undergo pathological aggregation, forming toxic inclusions that disrupt cellular function. The dysregulation of proteostasis mechanisms, including the ubiquitin-proteasome system (UPS), ubiquitin-independent proteasome system (UIPS), autophagy, and molecular chaperones, exacerbates these proteinopathies by failing to clear misfolded proteins effectively. Emerging therapeutic strategies aim to restore proteostasis through proteasome activators, autophagy enhancers, and chaperone-based interventions to prevent the toxic accumulation of IDPs. Additionally, understanding liquid-liquid phase separation (LLPS) and its role in stress granule dynamics offers novel insights into how aberrant phase transitions contribute to neurodegeneration. By targeting the molecular pathways involved in IDP aggregation and proteostasis regulation, and better understanding the specificity of each component, research in this area will pave the way for innovative therapeutic approaches to combat these neurodegenerative diseases. This review discusses the molecular mechanisms underpinning IDP pathology, highlights recent advancements in drug discovery, and explores the potential of targeting proteostasis machinery to develop effective therapies.}, } @article {pmid39955058, year = {2025}, author = {Paul, S and Dansithong, W and Figueroa, KP and Gandelman, M and Hivare, P and Scoles, DR and Pulst, SM}, title = {Staufen2 dysregulation in neurodegenerative disease.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {3}, pages = {108316}, pmid = {39955058}, issn = {1083-351X}, support = {R37 NS033123/NS/NINDS NIH HHS/United States ; R56 NS033123/NS/NINDS NIH HHS/United States ; R35 NS127253/NS/NINDS NIH HHS/United States ; R21 NS128630/NS/NINDS NIH HHS/United States ; R21 NS127028/NS/NINDS NIH HHS/United States ; R01 NS137233/NS/NINDS NIH HHS/United States ; R01 NS097903/NS/NINDS NIH HHS/United States ; U01 NS103883/NS/NINDS NIH HHS/United States ; R33 NS124965/NS/NINDS NIH HHS/United States ; R61 NS124965/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Animals ; MicroRNAs/genetics/metabolism ; *RNA-Binding Proteins/genetics/metabolism ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; HEK293 Cells ; TOR Serine-Threonine Kinases/metabolism/genetics ; Frontotemporal Dementia/metabolism/genetics/pathology ; Spinocerebellar Ataxias/metabolism/genetics/pathology ; 3' Untranslated Regions ; *Neurodegenerative Diseases/metabolism/genetics ; *Cytoskeletal Proteins/genetics/metabolism ; Disease Models, Animal ; Stress Granules/metabolism/genetics ; }, abstract = {Staufen2 (STAU2) is an RNA-binding protein that controls mRNA trafficking and expression. Previously, we showed that its paralog, Staufen1 (STAU1), was overabundant in cellular and mouse models of neurodegenerative diseases and amyotrophic lateral sclerosis (ALS) patient spinal cord. Here, we investigated features of STAU2 that might parallel STAU1. STAU2 protein, but not mRNA, was overabundant in spinocerebellar ataxia type 2 (SCA2), ALS/frontotemporal dementia patient fibroblasts, ALS patient spinal cord tissues, and in central nervous system tissues from SCA2 and ALS animal models. Exogenous expression of STAU2 in human embryonic kidney 293 cells activated mechanistic target of rapamycin (mTOR) and stress granule formation. Targeting STAU2 by RNAi normalized mTOR in SCA2 and C9ORF72 cellular models. The microRNA miR-217, previously identified as downregulated in SCA2 mice, targets the STAU2 3'-UTR. We now demonstrate that exogenous expression of miR-217 significantly reduced STAU2 and mTOR levels in cellular models of neurodegenerative disease. These results suggest a functional link between STAU2 and mTOR signaling and identify a major role for miR-217 that could be exploited in therapeutic development.}, } @article {pmid39956001, year = {2025}, author = {Romero-Gavilán, F and Cerqueira, A and García-Arnáez, I and Scalschi, L and Vicedo, B and Azkargorta, M and Elortza, F and Izquierdo, R and Gurruchaga, M and Goñi, I and Suay, J}, title = {Proteomic evaluation of borosilicate hybrid sol-gel coatings with osteogenic, immunomodulatory and antibacterial properties.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {250}, number = {}, pages = {114561}, doi = {10.1016/j.colsurfb.2025.114561}, pmid = {39956001}, issn = {1873-4367}, mesh = {Humans ; Staphylococcus aureus/drug effects ; *Proteomics ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Osteogenesis/drug effects ; Escherichia coli/drug effects ; *Coated Materials, Biocompatible/pharmacology/chemistry ; *Silicates/chemistry/pharmacology ; Osteoblasts/drug effects/cytology/metabolism ; Gels/chemistry ; *Immunologic Factors/pharmacology/chemistry ; Microbial Sensitivity Tests ; Surface Properties ; }, abstract = {Silica hybrid sol-gel coatings represent an interesting approach to bioactivate dental implants. Boron is known for its osteogenic, angiogenic and antibacterial functions in biomedical applications. This study describes the synthesis of a novel borosilicate hybrid sol-gel coating using a mixture of methyltrimethoxysilane, tetraethyl orthosilicate and trimethyl borate (TMB). Coatings with different amounts of boron were obtained, and their physiochemical properties were examined; in vitro tests with human osteoblasts and macrophages (THP-1) were carried out. The effects of these materials on bacteria viability were evaluated using Escherichia coli and Staphylococcus aureus. The human serum proteins adsorbed onto the coatings were analysed employing proteomic techniques. To synthesise the new materials, the appropriate sol-gel reactions were developed; boron was integrated into the silica network, and well-adhering coatings were obtained. These borosilicate coatings were non-cytotoxic, displayed osteogenic potential, and upregulated adsorption of proteins related to bone regeneration (IGF2, ALS and APOE). Boron upregulated the expression of TNF-α, INFg and TGF-β and increased the TNF-α and TGF-β cytokine production in THP-1. Moreover, the addition of boron caused downregulation of NOX2 expression. Proteomic analysis revealed that boron-doping reduced the adsorption of immunoglobulins and complement system proteins. It also caused an increase in the levels of apolipoproteins, antioxidant proteins and serum amyloid A proteins, which was in agreement with in vitro results. The coatings with 10 and 20 % TMB displayed antibacterial effect against S. aureus. The results of this study will enhance our comprehension of interactions between boron-containing biomaterials and biological systems.}, } @article {pmid39956201, year = {2025}, author = {Potestio, L and Martora, F and Megna, M}, title = {Response to Sood et al's "Real-world experience of bimekizumab for plaque psoriasis in adult patients with prior exposure to interleukin-17 inhibitors: A 16-week multicenter retrospective review".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {6}, pages = {e189-e190}, doi = {10.1016/j.jaad.2024.10.129}, pmid = {39956201}, issn = {1097-6787}, } @article {pmid39956874, year = {2025}, author = {Demaegd, KC and Kernan, A and Cooper-Knock, J and van Vugt, JJFA and Harvey, C and Moll, T and O'Brien, D and Gornall, S and Drury, L and Farhan, SMK and Dion, PA and Rouleau, GA and Western, A and Parsons, PJ and Mclean, B and Benatar, M and van den Berg, LH and Van Damme, P and Willem Dankbaar, J and Hendrikse, J and Koole, W and de Bie, C and Hobson, E and Veldink, JH and van de Warrenburg, B and Pasterkamp, RJ and van Rheenen, W and Kirby, J and Shaw, PJ and van Es, MA}, title = {An observational study of pleiotropy and penetrance of amyotrophic lateral sclerosis associated with CAG-repeat expansion of ATXN2.}, journal = {European journal of human genetics : EJHG}, volume = {33}, number = {9}, pages = {1106-1112}, pmid = {39956874}, issn = {1476-5438}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; 899-792//Motor Neurone Disease Association (MNDA)/ ; /WT_/Wellcome Trust/United Kingdom ; 972-797//Motor Neurone Disease Association (MNDA)/ ; 974-797//Motor Neurone Disease Association (MNDA)/ ; 216596/Z/19/Z//Wellcome Trust (Wellcome)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Ataxin-2/genetics ; Male ; Female ; Middle Aged ; *Trinucleotide Repeat Expansion ; *Penetrance ; Aged ; Adult ; *Genetic Pleiotropy ; Pedigree ; Phenotype ; Spinocerebellar Ataxias/genetics ; }, abstract = {Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are both associated with a CAG-repeat expansion in ATXN2 and with TDP-43-positive neuronal cytoplasmic inclusions. The two disorders have been viewed as distinct entities, where an intermediate length expansion of 31-33 CAG-repeats is associated with sporadic ALS and a full length expansion of ≥34 CAG-repeats is associated with SCA2. We report the clinical phenotype of ATXN2-positive patients and their relatives, identified in three specialist ALS clinics, which force a reconsideration of this dichotomy. We also report the frequency of ATXN2 expansions in two large cohorts of ALS patients and in a population-matched cohort of controls. We report ten cases of familial ALS in which disease is associated with either an intermediate or a full-length ATXN2 CAG-repeat expansion. Pedigrees and patients feature additional phenotypes including parkinsonism, dementia and essential tremor (ET). We conclude that CAG-repeat expansions in ATXN2 exhibit pleiotropy and are associated with a disease spectrum that includes ALS, SCA2, and parkinsonism; to recognise this complexity we propose the new term 'ATXN2-related neurodegeneration'. We also observed sporadic ALS associated with full-length expansions. We conclude that ATXN2 CAG-repeat expansions, irrespective of length, should be considered a risk factor for ALS. Interrupted CAG-repeats were associated with an ALS phenotype in our data but we also identified ALS cases with uninterrupted expansions. Our findings have relevance for researchers, patients and families linked to CAG-repeat expansions in ATXN2.}, } @article {pmid39957101, year = {2025}, author = {Kikuchi, K and Yamazaki, Y and Kanekura, K and Hayamizu, Y}, title = {Graphene Biosensor Differentiating Sensitive Interactions between Ribonucleic Acid and Dipeptide Repeats in Liquid-Liquid Phase Separation.}, journal = {ACS applied materials & interfaces}, volume = {17}, number = {8}, pages = {12765-12771}, pmid = {39957101}, issn = {1944-8252}, mesh = {*Dipeptides/chemistry ; *Biosensing Techniques/methods ; *Graphite/chemistry ; *RNA/chemistry ; Humans ; C9orf72 Protein/genetics/chemistry ; Phase Separation ; }, abstract = {Liquid-Liquid Phase Separation (LLPS) plays a crucial role in cell biology and is closely associated with neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Recent studies connect mutations in the C9ORF72 gene to the production of arginine-rich dipeptide repeat proteins (R-DPRs), such as poly(PR) and poly(GR). These R-DPRs disrupt LLPS in membrane-less organelles (MLOs) and contribute to disease pathology. While traditional analysis techniques like nuclear magnetic resonance (NMR), fluorescence recovery after photobleaching (FRAP), and Förster resonance energy transfer (FRET) provide insights into LLPS's role in these diseases, their ability is limited in detecting weak intermolecular interactions within LLPS droplets. This study employs graphene field-effect transistors (GFETs) for their superior sensitivity in detecting these molecular interactions. We immobilized RNA (poly-A) on GFETs and measured the electrical conductivity of GFETs to characterize shifts in the voltage of the charge neutral point in GFETs, allowing for the detection of dipeptide repeat peptides, such as (PR)12, (GR)12, and R12. Our results show that interactions between peptides and RNA require a specific peptide concentration threshold and vary between peptide types. Notably, the minimal conductivity shift suggests that peptides containing proline residues exhibit a nonuniform spatial distribution during interactions with RNA on graphene surfaces. This finding indicates that peptide rigidity induced by prolines plays a vital role in these molecular interactions and their multivalent contacts with RNA, which agrees with findings reported in other recent works. The capability of GFETs to detect these interactions at nanomolar concentrations marks a significant advancement in sensitivity over existing methods. This research sheds light on the mechanisms of LLPS involving R-DPRs and opens avenues for further understanding of related neurodegenerative diseases.}, } @article {pmid39957655, year = {2025}, author = {Mombaur, B and Dias, K}, title = {Patient Navigation in Amyotrophic Lateral Sclerosis (ALS): A Potential Approach to Timely Diagnosis.}, journal = {Journal of health care for the poor and underserved}, volume = {36}, number = {1}, pages = {361-374}, doi = {10.1353/hpu.2025.a951602}, pmid = {39957655}, issn = {1548-6869}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Patient Navigation/organization & administration ; Healthcare Disparities ; }, abstract = {Amyotrophic lateral sclerosis (ALS) poses challenges for timely diagnosis due to its protean early manifestations and lack of definitive tests. This article explores how patient navigation interventions can expedite diagnosis, particularly for underserved patients who face disproportionately longer delays. Patient navigation has proven effective in reducing disparities in various diseases by providing guidance and support to patients and caregivers. It enhances awareness, facilitates communication with health care providers, and streamlines diagnosis. Drawing from literature on patient navigation in other diseases, this article proposes tailored adaptations for ALS diagnosis and addresses potential implementation barriers and strategies to overcome them. Integrating patient navigation into the ALS diagnostic pathway holds promise for improving efficiency, optimizing outcomes, and reducing health care disparities among underserved populations.}, } @article {pmid39958442, year = {2025}, author = {Ozbey, D and Saribas, S and Kocazeybek, B}, title = {Gut microbiota in Crohn's disease pathogenesis.}, journal = {World journal of gastroenterology}, volume = {31}, number = {6}, pages = {101266}, pmid = {39958442}, issn = {2219-2840}, mesh = {Humans ; Colon/microbiology/pathology/immunology ; *Crohn Disease/therapy/microbiology/immunology/pathology ; Dysbiosis/therapy ; *Fecal Microbiota Transplantation/methods ; *Gastrointestinal Microbiome/immunology ; Ileum/microbiology/pathology/immunology ; Intestinal Mucosa/microbiology/pathology/immunology ; Treatment Outcome ; }, abstract = {Inflammatory bowel diseases (IBDs) are classified into two distinct types based on the area and severity of inflammation: Crohn's disease (CD) and ulcerative colitis. In CD, gut bacteria can infiltrate mesenteric fat, causing expansion known as creeping fat, which may limit bacterial spread and inflammation but can promote fibrosis. The gut bacteria composition varies depending on whether the colon or ileum is affected. Fecal microbiota transplantation (FMT) transfers feces from a healthy donor to restore gut microbiota balance, often used in IBD patients to reduce inflammation and promote mucosal repair. The use of FMT for CD remains uncertain, with insufficient evidence to fully endorse it as a definitive treatment. While some studies suggest it may improve symptoms, questions about the duration of these improvements and the need for repeated treatments persist. There is a pressing need for methods that provide long-term benefits, as highlighted by Wu et al's research.}, } @article {pmid39958549, year = {2025}, author = {Zhang, Y}, title = {Enhancing rectal cancer liver metastasis prediction: Magnetic resonance imaging-based radiomics, bias mitigation, and regulatory considerations.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {2}, pages = {102151}, pmid = {39958549}, issn = {1948-5204}, abstract = {In this article, we comment on the article by Long et al published in the recent issue of the World Journal of Gastrointestinal Oncology. Rectal cancer patients are at risk for developing metachronous liver metastasis (MLM), yet early prediction remains challenging due to variations in tumor heterogeneity and the limitations of traditional diagnostic methods. Therefore, there is an urgent need for non-invasive techniques to improve patient outcomes. Long et al's study introduces an innovative magnetic resonance imaging (MRI)-based radiomics model that integrates high-throughput imaging data with clinical variables to predict MLM. The study employed a 7:3 split to generate training and validation datasets. The MLM prediction model was constructed using the training set and subsequently validated on the validation set using area under the curve (AUC) and dollar-cost averaging metrics to assess performance, robustness, and generalizability. By employing advanced algorithms, the model provides a non-invasive solution to assess tumor heterogeneity for better metastasis prediction, enabling early intervention and personalized treatment planning. However, variations in MRI parameters, such as differences in scanning resolutions and protocols across facilities, patient heterogeneity (e.g., age, comorbidities), and external factors like carcinoembryonic antigen levels introduce biases. Additionally, confounding factors such as diagnostic staging methods and patient comorbidities require further validation and adjustment to ensure accuracy and generalizability. With evolving Food and Drug Administration regulations on machine learning models in healthcare, compliance and careful consideration of these regulatory requirements are essential to ensuring safe and effective implementation of this approach in clinical practice. In the future, clinicians may be able to utilize data-driven, patient-centric artificial intelligence (AI)-enhanced imaging tools integrated with clinical data, which would help improve early detection of MLM and optimize personalized treatment strategies. Combining radiomics, genomics, histological data, and demographic information can significantly enhance the accuracy and precision of predictive models.}, } @article {pmid39958595, year = {2025}, author = {Arnold, WD and Majithia, K}, title = {Triumphs, Trials, and Future Considerations in Genetic Therapies for Hereditary Neuromuscular Diseases.}, journal = {Missouri medicine}, volume = {122}, number = {1}, pages = {46-52}, pmid = {39958595}, issn = {0026-6620}, mesh = {Humans ; *Genetic Therapy/methods/trends ; *Neuromuscular Diseases/therapy/genetics ; Muscular Dystrophy, Duchenne/therapy/genetics ; Amyotrophic Lateral Sclerosis/therapy/genetics ; Muscular Atrophy, Spinal/therapy/genetics ; Precision Medicine/methods ; }, abstract = {Neuromuscular diseases include conditions that affect the spinal motor neurons, peripheral nerves, neuromuscular junctions, and muscles, and they can result from acquired and inherited causes. The number of genetic therapies targeting the inherited causes of neuromuscular diseases has surged in the last decade. This review aims to highlight the current state of genetic therapies within the framework of precision medicine, focusing on the achievements and the gaps that remain. A major emphasis is on spinal muscular atrophy, Duchenne muscular dystrophy, and amyotrophic lateral sclerosis, as these neuromuscular diseases have seen tremendous recent advancements. We will also discuss the future considerations necessary to accelerate the development of next-generation genetic therapies and enhance therapeutic outcomes for patients with neuromuscular diseases.}, } @article {pmid39959987, year = {2025}, author = {Lee, D and Shin, Y and Roh, JS and Ahn, J and Jeoong, S and Shin, SS and Yoon, M}, title = {RETRACTED: Lee et al. Lemon Balm Extract ALS-L1023 Regulates Obesity and Improves Insulin Sensitivity via Activation of Hepatic PPARα in High-Fat Diet-Fed Obese C57BL/6J Mice. Int. J. Mol. Sci. 2020, 21, 4256.}, journal = {International journal of molecular sciences}, volume = {26}, number = {4}, pages = {}, pmid = {39959987}, issn = {1422-0067}, abstract = {The journal retracts the article titled "Lemon Balm Extract ALS-L1023 Regulates Obesity and Improves Insulin Sensitivity via Activation of Hepatic PPARα in High-Fat Diet-Fed Obese C57BL/6J Mice" [...].}, } @article {pmid39960672, year = {2025}, author = {Paganoni, S and Fournier, CN and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Ajroud-Driss, S and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Shefner, JM and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and Dagostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Heiman-Patterson, T and Caress, JB and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Harvey, B and Patel, S and Mahoney, P and Duda, PW and Cudkowicz, ME and , }, title = {Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2459058}, pmid = {39960672}, issn = {2574-3805}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Double-Blind Method ; Aged ; Treatment Outcome ; }, abstract = {IMPORTANCE: The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression.

OBJECTIVE: To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS.

Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens.

INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing.

MAIN OUTCOMES AND MEASURES: The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164).

RESULTS: Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04297683.}, } @article {pmid39960747, year = {2025}, author = {Turnbull, J}, title = {Platform Trials in ALS.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2025.0100}, pmid = {39960747}, issn = {1538-3598}, } @article {pmid39961396, year = {2025}, author = {Ferraro, PM and Mollar, E and Melissari, L and Buscema, M and Bagnoli, E and Cabona, C and Gemelli, C and Vignolo, M and Maranzana, C and Marogna, M and Ferrera, L and Beronio, A and De Michelis, C and Bergamaschi, V and Bragadin, MM and Brichetto, G and Braido, F and Rao, F}, title = {Longitudinal respiratory trajectories in motor neuron disease phenotypes: Multiparametric characterization and clinical management.}, journal = {Respiratory medicine}, volume = {239}, number = {}, pages = {108003}, doi = {10.1016/j.rmed.2025.108003}, pmid = {39961396}, issn = {1532-3064}, mesh = {Humans ; Male ; Female ; Phenotype ; Middle Aged ; *Motor Neuron Disease/physiopathology/complications/therapy ; Respiratory Function Tests/methods ; Aged ; Longitudinal Studies ; Noninvasive Ventilation/methods ; Spirometry ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Blood Gas Analysis ; }, abstract = {BACKGROUND: Motor neuron diseases (MNDs) encompass amyotrophic lateral sclerosis (ALS), pure/predominant upper (pUMN) and lower motor neuron (pLMN) phenotypes. However respiratory studies have mainly focused on bulbar (B-ALS) and spinal (S-ALS) onset ALS, while little is known in other MNDs. In this study we therefore aimed at characterizing baseline and longitudinal patterns of respiratory involvement and their clinical management in MND patients stratified by their clinical phenotype.

METHODS: Serial pulmonary function tests (PFTs) (spirometry, arterial blood gas analysis, overnight pulse oximetry and peak cough expiratory flow) records of the MND patients hospitalized between 2020 and 2024 were reviewed. Using longitudinal examinations, deltas of variation in respiratory measures were generated and frequency and timings of non-invasive ventilation (NIV) adaptation were evaluated. Data were compared between phenotypes using the Kruskal-Wallis test with Bonferroni adjustment.

RESULTS: 42 S-ALS, 105 B-ALS, 42 pLMN and 31 pUMN patients were included. Both at baseline and longitudinally, B-ALS showed the worst respiratory parameters, followed by pLMN, S-ALS and pUMN. NIV adaptation was equally frequent between groups, but earlier in B-ALS compared to pUMN (p = 0.01). At baseline, B-ALS showed worse spirometry and PCEF only, but compared to all the other phenotypes (p from <0.0001 to 0.03). Longitudinally, they conversely exhibited more severe decline in all PFTs, but only relative to pUMN (p from 0.0009 to 0.04), with deltas of variation comparable to the ones observed in S-ALS and pLMN. Among NIV users, more severe PCEF and spirometry impairment further emerged in S-ALS compared to pUMN (p from 0.01 to 0.04).

CONCLUSIONS: We evidenced convergent trajectories of respiratory decline across B-ALS, S-ALS and pLMN, highlighting the utility of multimodal assessments for tracking progressing respiratory disturbances. These findings have potential to accelerate earlier and more tailored respiratory management across diverse MND phenotypes.}, } @article {pmid39961464, year = {2025}, author = {Soumya, BS and Gamit, N and Patil, M and Shreenidhi, VP and Dharmarajan, A and Warrier, S}, title = {Modeling amyotrophic lateral sclerosis with amniotic membrane-derived mesenchymal stem cells: A novel approach for disease modeling.}, journal = {Experimental cell research}, volume = {446}, number = {1}, pages = {114449}, doi = {10.1016/j.yexcr.2025.114449}, pmid = {39961464}, issn = {1090-2422}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Mesenchymal Stem Cells/cytology/metabolism/pathology ; Humans ; *Amnion/cytology ; Cell Differentiation ; Motor Neurons/metabolism/pathology ; Superoxide Dismutase-1/genetics ; Animals ; Superoxide Dismutase/genetics/metabolism ; Cells, Cultured ; Disease Models, Animal ; }, abstract = {Advancement of therapeutics for neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) has been predominantly hampered by the dearth of relevant disease models. Despite numerous animal models, significant challenges remain in correlating these with human disease complexities. In this study, the ALS model was created using amniotic membrane-derived mesenchymal stem cells (AM-MSCs) which were differentiated into motor neurons (MN) with specific MN induction media and transiently transfected with mutated human SOD1 G93A plasmid to induce ALS-like condition. Characterization included gene expression analysis, immunocytochemistry, flow cytometry, and Western blot. Functional assays assessed the extent of degeneration and model efficiency. AM-MSCs demonstrated multipotency and were positive for MSC markers. Upon differentiation, the expression of MN markers like MNX1, Olig2, and ChAT were found to be elevated. SOD1 G93A overexpression, downregulated MN markers, upregulated NURR1 gene, reduced acetylcholine (ACh), reduced glutathione, and elevated oxidative stress markers. This robust in-vitro ALS model derived from AM-MSCs offers an alternative to animal models to provide an efficient and cost-effective platform to conduct rapid drug screening.}, } @article {pmid39961673, year = {2025}, author = {Aryapadi, V and Trivedi, J}, title = {Atypical presentation of amyotrophic lateral sclerosis with SOD1-H47R mutation.}, journal = {BMJ case reports}, volume = {18}, number = {2}, pages = {}, doi = {10.1136/bcr-2024-263293}, pmid = {39961673}, issn = {1757-790X}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/physiopathology ; Mutation ; *Superoxide Dismutase/genetics ; *Superoxide Dismutase-1/genetics ; }, abstract = {Traditionally, amyotrophic lateral sclerosis (ALS) is recognised as a fatal neurodegenerative disease that typically emerges in the later decades of life, with a life expectancy of 2-5 years after symptom onset. We now understand that ALS exhibits a wide phenotypic clinical spectrum, significantly influenced by genetic factors. Here, we describe a patient with familial ALS carrying a heterozygous pathogenic H47R mutation of the superoxide dismutase 1 (SOD1) gene. His clinical presentation is atypical, with a slow progressive course, lower extremity weakness, and sparing of bulbar and respiratory function, consistent with the flail leg variant of ALS. The objective of this report is to increase awareness of atypical presentations of ALS and the diagnostic challenges they pose to clinicians. In addition to a description of the clinical case, we briefly discuss the new role of gene therapy in the treatment of familial ALS with SOD1 mutations.}, } @article {pmid39961705, year = {2025}, author = {Shah, NM and Kaltsakas, G and Madden-Scott, S and Apps, C and Sheridan, S and Ramsay, M and Srivastava, S and Suh, ES and D'Cruz, R and Mackie, M and Weston, N and Hart, N and Murphy, P}, title = {Mechanical insufflation-exsufflation use in neuromuscular disease: a single centre cohort study.}, journal = {BMJ open respiratory research}, volume = {12}, number = {1}, pages = {}, pmid = {39961705}, issn = {2052-4439}, mesh = {Humans ; Middle Aged ; *Insufflation/methods ; Male ; Female ; Retrospective Studies ; *Neuromuscular Diseases/therapy/mortality ; Adult ; Aged ; *Respiratory Therapy/methods ; }, abstract = {INTRODUCTION: Mechanical insufflation-exsufflation (MIE) is a commonly used therapy to augment secretion clearance in individuals with neuromuscular disease. There are no clear evidence-based guidelines on the settings that should be used in different diagnostic groups and how they should be titrated. We report on the settings used in the largest cohort of individuals using domiciliary MIE in the literature.

METHODS: A retrospective observational study reporting on all individuals initiated on MIE for long-term domiciliary use at our centre, 2013-2019.

RESULTS: This study reports on 359 adults established on domiciliary MIE. The most common diagnostic groups were congenital neuromuscular disease (26%), spinal cord injury (23%) and amyotrophic lateral sclerosis (23%). Median age at initiation was 55 years. Median (IQR) insufflation pressure was 35 (30-40) cm H2O and exsufflation pressure was 45 (40-50) cm H2O. Inspiratory time was 2.5 (2.3-2.8) s, expiratory time was 2.7 (2.3-2.8) s, and pause between expiration and inspiration was 2.0 (1.2-2.0) s. Median (IQR) survival following the initiation of MIE was 66 (54-78) months. Increasing age and amyotrophic lateral sclerosis were significantly associated with shorter life expectancy, while the delivery of MIE via oronasal interface compared with tracheostomy was associated with longer life expectancy.

CONCLUSION: This is the largest reported cohort of adults using domiciliary MIE. The most common groups using MIE were congenital neuromuscular disease, spinal cord injury patients and amyotrophic lateral sclerosis. The range of prescribed settings is narrow, reflecting the limited evidence base in this field and the need to better understand optimal targets for titration of different MIE settings.}, } @article {pmid39962623, year = {2025}, author = {Caratelli, S and De Paolis, F and Silvestris, DA and Baldari, S and Salvatori, I and Tullo, A and Lanzilli, G and Gurtner, A and Ferri, A and Valle, C and Padovani, S and Cesarini, V and Sconocchia, T and Cifaldi, L and Arriga, R and Spagnoli, GC and Ferrone, S and Venditti, A and Rossi, P and Pesole, G and Toietta, G and Sconocchia, G}, title = {The CD64/CD28/CD3ζ chimeric receptor reprograms T-cell metabolism and promotes T-cell persistence and immune functions while triggering antibody-independent and antibody-dependent cytotoxicity.}, journal = {Experimental hematology & oncology}, volume = {14}, number = {1}, pages = {17}, pmid = {39962623}, issn = {2162-3619}, support = {TITAN 2021- ARS01_00906//European Union, European Fund for Regional Development/ ; TITAN 2021- ARS01_00906//European Union, European Fund for Regional Development/ ; Investigator Grants 2020-24440//Italian Association for Cancer Research (AIRC) Foundation/ ; }, abstract = {BACKGROUND: Recent studies have shown that CD32/CD8a/CD28/CD3ζ chimeric receptor cells directly kill breast cancer cells, suggesting the existence of cell surface myeloid FcγR alternative ligands (ALs). Here, we investigated the metabolism, ALs, cytotoxicity, and immunoregulatory functions of CD64/CD28/CD3ζ in colorectal cancer (CRC) and squamous cell carcinoma of the head and neck.

METHODS: The CD64/CD28/CD3ζ -SFG retroviral vector was used to produce viruses for T-cell transduction. T-cell expansion and differentiation were monitored via flow cytometry. Gene expression was assessed by RNA-seq. Bioenergetics were documented on a Seahorse extracellular flux analyzer. CD64/CD28/CD3ζ polarization was identified via confocal microscopy. Cytotoxicity was determined by MTT assay and bioluminescent imaging, and flow cytometry. Tridimensional antitumor activity of CD64/CD28/CD3ζ T cells was achieved by utilizing HCT116-GFP 3D spheroids via the IncuCyte S3 Live-Cell Analysis system. The intraperitoneal distribution and antitumor activity of NIR-CD64/CD28/CD3ζ and NIR-nontransduced T cells were investigated in CB17-SCID mice bearing subcutaneous FaDu Luc + cells by bioluminescent and fluorescent imaging. IFNγ was assessed by ELISA.

RESULTS: Compared to CD16/CD8a/CD28/CD3ζ T cells, CD32/CD8a/CD28/CD3ζ T cells, and non-transduced T cells, CD64/CD28/CD3ζ T cells exhibited the highest levels of cell expansion and persistence capacity. A total of 235 genes linked to cell division and 52 genes related to glycolysis were overexpressed. The glycolytic phenotype was confirmed by functional in vitro studies accompanied by preferential T-cell effector memory differentiation. Interestingly, oxamic acid was found to inhibit CD64-CR T cell proliferation, indicating the involvement of lactate. Upon CD64/CD28/CD3ζ T-cell conjugation with CRC cells, CD64/CD28/CD3ζ cells polarize at immunological synapses, leading to CRC cell death. CD64/CD28/CD3ζ T cells kill SCCHN cells, and in combination with the anti-B7-H3 mAb (376.96) or anti-EGFR mAb, these cells trigger antibody-dependent cellular cytotoxicity (ADCC) in vitro under 2D and 3D conditions. The 376.96 mAb combined with CD64/CD28/CD3ζ T cells had anti-SCCHN activity in vivo. In addition, they induce the upregulation of PD-L1 and HLA-DR expression in cancer cells via IFNγ. PD-L1 positive SCCHN cells in combination with anti-PD-L1 mAb and CD64-CR T cells were killed by ADCC, which enhanced direct cytotoxicity. These findings indicate that the glycolytic phenotype is involved in CD64-CR T cell proliferation/expansion. These cells mediate long-lasting HLA-independent cytotoxicity and ADCC in CRC and SCCHN cells.

CONCLUSIONS: CD64/CD28/CD3ζ T cells could significantly impact the rational design of personalized studies to treat CRC and SCCHN and the identification of novel FcγR ALs in cancer and healthy cells.}, } @article {pmid39962920, year = {2025}, author = {}, title = {Correction to "Early Nuclear Phenotypes and Reactive Transformation in Human iPSC-Derived Astrocytes From ALS Patients With SOD1 Mutations".}, journal = {Glia}, volume = {73}, number = {5}, pages = {1107}, doi = {10.1002/glia.70003}, pmid = {39962920}, issn = {1098-1136}, } @article {pmid39963928, year = {2025}, author = {Lomas, C and Dubey, RC and Perez-Alvarez, G and Lopez Hernandez, Y and Atmar, A and Arias, AY and Vashist, A and Aggarwal, S and Manickam, P and Lakshmana, MK and Vashist, A}, title = {Recent advances in nanotherapeutics for HIV-associated neurocognitive disorders and substance use disorders.}, journal = {Nanomedicine (London, England)}, volume = {20}, number = {6}, pages = {603-619}, pmid = {39963928}, issn = {1748-6963}, support = {R01 DA049657/DA/NIDA NIH HHS/United States ; R01 DA052271/DA/NIDA NIH HHS/United States ; R03 AG087475/AG/NIA NIH HHS/United States ; U01 ES033265/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Substance-Related Disorders/drug therapy/therapy ; Blood-Brain Barrier/metabolism ; *Nanomedicine/methods ; *HIV Infections/complications/drug therapy ; *Nanoparticles/chemistry/therapeutic use ; Animals ; *Neurocognitive Disorders/drug therapy ; *AIDS Dementia Complex/drug therapy ; }, abstract = {Substance use disorders (SUD) and HIV-associated neurocognitive disorders (HAND) work synergistically as a significant cause of cognitive decline in adults and adolescents globally. Current therapies continue to be limited due to difficulties crossing the blood-brain barrier (BBB) leading to limited precision and effectiveness, neurotoxicity, and lack of co-treatment options for both HAND and SUD. Nanoparticle-based therapeutics have several advantages over conventional therapies including more precise targeting, the ability to cross the BBB, and high biocompatibility which decreases toxicity and optimizes sustainability. These advantages extend to other neurological disorders such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). This review summarizes recent advances in nanotechnology for application to HAND, SUD, and co-treatment, as well as other neurological disorders. This review also highlights the potential challenges these therapies face in clinical translation and long-term safety.}, } @article {pmid39965330, year = {2025}, author = {Petro, TM and Esmael, A and Pattee, GL and Al-Sarmi, F and Chiodo, F and Agarkova, IV and Dunigan, DD and Van Etten, JL}, title = {Expression of human superoxide dismutase (SOD) 1 G93A and chlorovirus ATCV-1 SOD increases the response of macrophages to inflammatory stimulants, including ATCV-1 major capsid protein glycans.}, journal = {Immunobiology}, volume = {230}, number = {2}, pages = {152881}, doi = {10.1016/j.imbio.2025.152881}, pmid = {39965330}, issn = {1878-3279}, mesh = {Animals ; Humans ; *Macrophages/immunology/metabolism ; Mice ; *Superoxide Dismutase-1/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/immunology/genetics ; *Capsid Proteins/immunology/metabolism ; Cytokines/metabolism ; RAW 264.7 Cells ; Female ; Inflammation Mediators/metabolism ; Male ; }, abstract = {One cause of familial Amyotrophic Lateral Sclerosis (ALS) is a mutation in Super Oxide Dismutase 1 (SOD1) whereby amino acid 93 is alanine instead of glycine (SOD1-G93A). Transgenic mice expressing human SOD1-G93A pathogenic variant develop motor neuron disease (MND), similar to ALS. Humans with ALS and SOD1-G93A mice have elevated production of inflammatory cytokines, such as IL-6, which may promote MND. We previously showed that infection with the Chlorovirus Acanthocystis turfacea chlorella virus 1 (ATCV-1), which encodes a SOD1, accelerates onset of MND in these mice and induces macrophages to produce high levels of IL-6. We confirm here that ALS patients compared with healthy controls have significantly elevated levels of plasma IL-6 and Interferon-gamma (IFN-γ), but not IL-17. To determine if expression of ATCV-1 SOD1 or SOD1-G93A in mouse macrophages elevates expression of inflammatory cytokines, we transfected the RAW264.7 mouse macrophage cell line with plasmids encoding ATCV-1 SOD1, wild-type human SOD1, SOD1-G93A, or an empty vector. RAW264.7 cells stably expressing wtSOD1 or G93A-SOD1 were stimulated with poly I:C and Interferon-gamma, alone, or in combination to induce inflammatory factors, such as IL-6 and Nitric Oxide (NO), anti-inflammatory factors, such as IL-10, or activation of Interferon Stimulated Response Elements (ISRE) promoters. After stimulation, production of IL-6 and NO, but not IL-10 or ISRE promoter activity was significantly higher in RAW264.7 cells expressing SOD1-G93A compared with wt SOD1. Moreover, RAW264.7 cells expressing SOD1-G93A compared with wt SOD1 produced higher levels of IL-6 and NO in response to ATCV-1 glycoproteins. Finally, transfection of plasmid encoding ATCV-1 SOD1 into RAW264.7 cells significantly increased expression of inflammatory factors in responses to poly I:C and IFN-γ, primarily in an Interferon regulatory factor 3 (IRF3) dependent fashion. These data clearly show that expression of G93A-SOD1 or ATCV-1 SOD1 in macrophages significantly elevates expression of inflammatory factors following stimulations that mimic virus infection, viral components, or T cell cytokines, thereby suggesting one mechanism by which atypical SOD1 in macrophages can contribute to ALS-MND.}, } @article {pmid39965449, year = {2025}, author = {Awasthi, S and Tiwari, PC and Awasthi, S and Dwivedi, A and Srivastava, S}, title = {Mechanistic role of proteins and peptides in Management of Neurodegenerative Disorders.}, journal = {Neuropeptides}, volume = {110}, number = {}, pages = {102505}, doi = {10.1016/j.npep.2025.102505}, pmid = {39965449}, issn = {1532-2785}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Peptides/therapeutic use/metabolism ; Animals ; *Proteins/therapeutic use/metabolism ; }, abstract = {Proteins and peptides have emerged as significant contributors in the management of neurodegenerative disorders due to their diverse biological functions. These biomolecules influence various cellular processes, including cellular repair, inflammation reduction, and neuronal survival, which are crucial for mitigating the effects of diseases such as Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS). By interacting with specific cellular receptors, proteins and peptides like neurotrophic factors, cytokines, and enzyme inhibitors promote neurogenesis, reduce oxidative stress, and enhance synaptic plasticity. Nevertheless, till certain limitations and challenges do exist to deliver these fragile therapeutic bioactives. Moreover, targeted delivery systems, such as nanoparticles and biomolecular carriers, are being developed to improve the bioavailability and specificity of these protein-based therapeutics, ensuring efficient crossing of the blood-brain barrier. This review explores the mechanistic pathways through which these biomolecules act, emphasizing their potential to modify disease progression and improve the quality of life in patients with neurodegenerative conditions. Overall, proteins and peptides are not only seen as promising therapeutic agents but also as foundational tools in advancing personalized medicine in the field of neurodegenerative disorders.}, } @article {pmid39967643, year = {2025}, author = {Abdel-Magid, AF}, title = {Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors as Potential Treatment for Several Inflammatory and Neurodegenerative Diseases.}, journal = {ACS medicinal chemistry letters}, volume = {16}, number = {2}, pages = {204-206}, pmid = {39967643}, issn = {1948-5875}, abstract = {The invention in this patent application relates to 2-amino-[1,2,4]triazolo[1,5-a]pyridin derivatives represented generally herein as formula 1. These compounds have activities as receptor-interacting protein kinase 1 (RIPK1) inhibitors and may potentially provide treatment and/or prophylaxis of inflammatory and neurodegenerative diseases associated with aberrant RIPK1 activity such as ulcerative colitis, Crohn's disease, psoriasis, NASH, heart failure, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease.}, } @article {pmid39968231, year = {2025}, author = {Nagadi, E and Muryani, A and Adang, RAF}, title = {Integrated Endodontic and Restorative Management of C-Shaped Canals with Severe Coronal Loss in Mandibular Second Molar: A Case Report.}, journal = {Clinical, cosmetic and investigational dentistry}, volume = {17}, number = {}, pages = {121-134}, pmid = {39968231}, issn = {1179-1357}, abstract = {This case report describes the endodontic treatment of a lower right second molar with a C-shaped root canal in a 49-year-old woman exhibiting severe loss of coronal structure. Clinical examination revealed a cavity with temporary filling on tooth 47, which tested negative to cold stimuli but was positive to percussion and bite tests. Cone beam computed tomography (CBCT) scan revealed a C-shaped canal morphology with associated periapical radiolucency, graded as CBCT-PAI score 4. The canal was classified as C3 subdivision III (Melton et al), C3 type II (Fan et al), and [2]47 M[2-2]D[2-1] (Ahmed et al's). A non-surgical endodontic procedure was performed using metallurgically gold heat-treated files, passive ultrasonic irrigation, and warm hydraulic condensation obturation. Post-endodontic restoration included a post and core build-up with the wallpapering technique and a zirconia overlay. This case highlights the importance of CBCT imaging for diagnosis and treatment planning, careful selection of endodontic instruments and technique, and the use of advanced restoration methods to improve the outcome of challenging C-shaped canal treatments with extensive cavity involvement.}, } @article {pmid39969486, year = {2025}, author = {Alder, J and Chukwuma, C and Farragher, T and Holden Smith, S and Morris, R and Ealing, J and Hamdalla, H and Bentley, A and Bokhari, S and Freeman, D and Al-Chalabi, A and Rog, D and Das, J and Chaouch, A}, title = {Impact of relative deprivation and ethnicity on the incidence rate of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {558-565}, doi = {10.1080/21678421.2025.2465609}, pmid = {39969486}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/ethnology ; Male ; Female ; Incidence ; Middle Aged ; Aged ; *Ethnicity/statistics & numerical data ; England/epidemiology ; Adult ; Cohort Studies ; *Social Deprivation ; Risk Factors ; White People ; Aged, 80 and over ; }, abstract = {Objective: This study assessed a sizable cohort of patients with amyotrophic lateral sclerosis (ALS) in a relatively deprived and ethnically diverse area in the northwest of England. We aimed to evaluate the interaction of relative deprivation and ethnicity with the incidence of ALS. Methods: Six hundred and ninety-three adults from Greater Manchester who were diagnosed with ALS between 1 January 2011 and 31 December 2021 were included in this study. Data were collected from electronic patient records. Relative deprivation was estimated using the Index of Multiple Deprivation 2019 and patients were divided into quartiles of deprivation in England. Ethnicity was sub-grouped into White, Southeast Asian, Black, and Other. Poisson's regression analysis was used to calculate the incidence rate and its interactions with deprivation and ethnicity. Results: 55.4% of patients were male, 95.4% were White, 57.4% were in the two most deprived quartiles, and 87.2% had died by the end of the observation period. The crude incidence rate was 2.21 cases per 100,000 (95% CI 2.00-2.40) per year. There was no difference in the adjusted incidence rates among the quartiles of deprivation, even when considering ethnicity as a confounding variable. The risk of ALS in the White population was 2.08 (95% CI 1.47-3.04) times greater than that in the non-White population. Conclusion: In our cohort, relative deprivation was not an independent risk factor for ALS. A stronger association between White ethnicity and ALS was noted. The reason for this association remains unclear, highlighting the need for more research in this field.}, } @article {pmid39969638, year = {2025}, author = {Almgren, H and Mahoney, CJ and Huynh, W and D'Souza, A and Berte, S and Lv, J and Wang, C and Kiernan, MC and Calamante, F and Tu, S}, title = {Quantifying neurodegeneration within subdivisions of core motor pathways in amyotrophic lateral sclerosis using diffusion MRI.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {215}, pmid = {39969638}, issn = {1432-1459}, support = {APP2029871//NHMRC/ ; 1156093//NHMRC Practitioner Fellowship/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Pyramidal Tracts/diagnostic imaging/pathology ; *Corpus Callosum/diagnostic imaging/pathology ; Aged ; *Diffusion Magnetic Resonance Imaging/methods ; *White Matter/diagnostic imaging/pathology ; Adult ; Disease Progression ; Diffusion Tensor Imaging ; }, abstract = {BACKGROUND: Diffusion MRI is sensitive to white matter changes in amyotrophic lateral sclerosis (ALS). The current study aimed to establish disease profiles across core motor pathways, and their relevance to clinical progression in ALS.

METHODS: Sixty-five participants (ALS = 47; Control = 18) were recruited for the study. White matter integrity of motor, somatosensory, and premotor subdivisions within the corticospinal tract and corpus callosum were quantified by fibre density, fibre-bundle cross-section, structural connectivity, and fractional anisotropy. Analyses focused on identifying diffusion metrics and tract profiles sensitive to ALS pathology, and their association with clinical progression.

RESULTS: Reduced fibre density of the motor subdivision of the corpus callosum (CC) and corticospinal tract (CST) demonstrated best performance in classifying ALS from controls (area-under-curve: CCmotor = 0.81, CSTmotor = 0.76). Significant reductions in fibre density (CCmotor: p < 0.001; CSTmotor: p = 0.016), and structural connectivity (CCmotor: p = 0.008; CSTsomatosensory: p = 0.012) indicated presence of ALS pathology. Reduced fibre density & cross-section significantly correlated with severity of functional impairment (ALSFRS-R; CCmotor: r = 0.52, p = 0.019; CSTmotor: r = 0.59, p = 0.016). The largest effect sizes were generally found for motor and somatosensory subdivisions across both major white matter bundles.

CONCLUSION: Current findings suggest that ALS does not uniformly impact the corticospinal tract and corpus callosum. There is a preferential disease profile of neurodegeneration mainly impacting primary motor fibres. Microstructural white matter abnormality indicated presence of ALS pathology while macrostructural white matter abnormality was associated with severity of functional impairment. Quantification of white matter abnormality in corticospinal tract and callosal subdivisions holds translational potential as an imaging biomarker for neurodegeneration in ALS.}, } @article {pmid39969664, year = {2025}, author = {Irdianto, SA and Dwiranti, A and Bowolaksono, A}, title = {Extrachromosomal circular DNA: a double-edged sword in cancer progression and age-related diseases.}, journal = {Human cell}, volume = {38}, number = {2}, pages = {58}, pmid = {39969664}, issn = {1749-0774}, support = {NKB-888/UN2.RST/HKP.05.00/2024//Kementerian Riset Teknologi Dan Pendidikan Tinggi Republik Indonesia/ ; }, mesh = {Humans ; *Neoplasms/genetics/therapy/pathology ; *DNA, Circular/genetics/physiology ; Disease Progression ; *Diabetes Mellitus, Type 2/genetics ; *Aging/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Werner Syndrome/genetics ; Genomic Instability/genetics ; }, abstract = {Extrachromosomal circular DNA (eccDNA) is a fascinating form of genetic material found outside the usual chromosomal DNA in eukaryotic cells, including humans. Since its discovery in the 1960s, eccDNA has been linked to critical roles in cancer progression and age-related diseases. This review thoroughly explores eccDNA, covering its types, how it forms, and its significant impact on diseases, particularly cancer. EccDNA, especially in its extrachromosomal DNA (ecDNA) form, contributes to the genetic diversity of tumour cells, helping them evolve quickly and resist treatments. Beyond cancer, eccDNA is also connected to age-related conditions like Werner syndrome, amyotrophic lateral sclerosis (ALS), and type 2 diabetes mellitus (T2DM), where it may affect genomic stability and disease development. The potential of eccDNA as a biomarker for predicting disease outcomes and as a target for new treatments is also highlighted. This review aims to deepen our understanding of eccDNA and inspire further research into its roles in human health and disease, paving the way for innovative diagnostic and therapeutic approaches.}, } @article {pmid39969750, year = {2025}, author = {de Alcântara, C and Cruzeiro, MM and França, MC and Alencar, MA and de Araújo, CM and Camargos, ST and de Souza, LC}, title = {Cognitive and behavioral follow-up of patients with amyotrophic lateral sclerosis type 8.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {5}, pages = {2167-2170}, pmid = {39969750}, issn = {1590-3478}, support = {APQ-02980-17//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; Bolsa de Produtividade//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/psychology/physiopathology/genetics ; Female ; Middle Aged ; Neuropsychological Tests ; Disease Progression ; Aged ; Follow-Up Studies ; Adult ; *Cognitive Dysfunction/etiology/physiopathology ; Longitudinal Studies ; }, abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic Lateral Sclerosis type 8 (ALS8) is a familial motor neuron disease caused by the VAPB p.P56S mutation. There is a lack of longitudinal studies to elucidate the cognitive and behavioral progression of this disease. We aimed to investigate the progression of cognitive performance and behavioral symptoms of ALS8 patients over time.

METHODS: The cohort was composed of 23 ALS8 patients (12 men). They underwent neuropsychological assessments in two periods of time, ranging from 24 to 48 months (mean follow-up: 33 ± 10).

RESULTS: There was mild motor and functional decline during the follow-up. There were no significant differences between the first and the second evaluation on tests of verbal fluency, executive functions, episodic memory, and facial emotion recognition. There was a decline in the Language subdomain from the Addenbrooke's Cognitive Examination-revised. Behavioural measures indicated decreasing stereotypic behaviours. Anxiety and depression symptoms remained stable. No patient developed dementia.

CONCLUSION: Cognitive decline parallels motor degeneration in ALS8, with a slow pattern of progression.}, } @article {pmid39969752, year = {2025}, author = {Liao, D and Zhang, Y and Li, S and Tang, H and Bai, X}, title = {miRNAs in neurodegenerative diseases: from target screening to precision therapy.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {6}, pages = {2393-2399}, pmid = {39969752}, issn = {1590-3478}, support = {NO.2022-CXTD-05//Sichuan Province Science and Technology Support Program/ ; }, mesh = {Humans ; *MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/therapy/genetics/diagnosis/metabolism ; Animals ; *Precision Medicine/methods ; }, abstract = {miRNAs are critical for different disease development processes, including cell growth, signaling, apoptosis, cancer and neurodegenerative diseases. It has been shown that altered miRNA levels are associated with reactive oxygen species (ROS) formation and mitochondrial dysfunction. While mitochondrial dysfunction and ROS formation occur in many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, amyotrophic lateral sclerosis, miRNAs have the potential to be diagnostic biomarkers and therapeutic targets with a high degree of specificity, which is highly relevant in neurodegenerative pathologies.This paper gives a general summary of the current expression of miRNAs in neurodegenerative diseases, including miRNAs up-regulated or down-regulated in a variety of diseases, as well as the associated factors of influence. miRNAs are more like a double-edged sword, their multi-targeted role has brought light to many diseases for which there are currently no clear therapeutic options, but at the same time, their low specificity and possible side effects on the whole body should not be ignored, therefore However, at the same time, its low specificity and possible side effects on the whole body should not be ignored, therefore, more attention should be paid to the development of miRNA therapy in terms of its high efficiency, the use of carriers, and the clarification of side effects.}, } @article {pmid39971210, year = {2025}, author = {Brandstötter, C and Büssing, A and Eham, M and Littger, B and Lorenzl, S and Memmel, M and Paal, P and Bublitz, SK}, title = {Assessment of the Spiritual Needs of People With Amyotrophic Lateral Sclerosis and Their Caregivers.}, journal = {Journal of pain and symptom management}, volume = {69}, number = {5}, pages = {507-514}, doi = {10.1016/j.jpainsymman.2025.02.012}, pmid = {39971210}, issn = {1873-6513}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Caregivers/psychology ; Male ; Female ; Middle Aged ; *Spirituality ; Aged ; Surveys and Questionnaires ; Germany ; *Needs Assessment ; Longitudinal Studies ; Pilot Projects ; Adult ; }, abstract = {CONTEXT: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disorder which poses multidimensional burden to patients and caregivers.

OBJECTIVES: This study aimed to investigate spiritual needs in people with Amyotrophic Lateral Sclerosis (pALS) and their closest caregivers, and to identify factors which may contribute to these needs.

METHODS: Spiritual needs were assessed based on the Spiritual Needs Questionnaire (SpNQ) as part of a longitudinal cohort study in pALS and their closest caregivers who were included in a multiprofessional pilot project for ALS in Southern Germany with a focus on neuropalliative care.

RESULTS: About 61 pALS and 52 caregivers were assessed for their spiritual needs. We show that both pALS and their caregivers maintain stable and distinct spiritual needs over time, irrespective of age, gender, care setting, or perceived level of loneliness. While pALS emphasize generativity and inner peace needs, caregivers primarily focus on finding inner peace, which they value even more than pALS.

CONCLUSIONS: Both pALS and their caregivers have strong unmet spiritual, and particularly nonreligious needs, which should be regularly assessed by the interprofessional team. Documenting these needs is the initial step in the spiritual care process, which requires a collaborative response from the interprofessional team. All healthcare professionals involved in ALS care should be attuned to the potential for unmet spiritual needs in patients and their caregivers. Early identification of these needs can facilitate the initiation of appropriate support processes.}, } @article {pmid39971247, year = {2025}, author = {Zhang, H and Sun, Y}, title = {Response to Chen et al's "Incorporating regional variability and demographic insights into melanoma public health strategies".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {6}, pages = {e207}, doi = {10.1016/j.jaad.2025.02.029}, pmid = {39971247}, issn = {1097-6787}, } @article {pmid39971261, year = {2025}, author = {Álvarez-Aznar, A and Desai, M and Orlich, MM and Vázquez-Liébanas, E and Adams, RH and Brakebusch, C and Gaengel, K}, title = {Cdc42 is crucial for mural cell migration, proliferation and patterning of the retinal vasculature.}, journal = {Vascular pharmacology}, volume = {159}, number = {}, pages = {107472}, doi = {10.1016/j.vph.2025.107472}, pmid = {39971261}, issn = {1879-3649}, mesh = {Animals ; *Cell Movement ; *Pericytes/pathology/enzymology/metabolism ; *cdc42 GTP-Binding Protein/genetics/metabolism/deficiency ; *Cell Proliferation ; *Retinal Vessels/pathology/metabolism/growth & development ; *Myocytes, Smooth Muscle/pathology/metabolism/enzymology ; Mice, Knockout ; *Retinal Neovascularization/pathology/genetics/enzymology/metabolism/physiopathology ; *Neovascularization, Physiologic ; Signal Transduction ; Mice, Inbred C57BL ; Mice ; Muscle, Smooth, Vascular ; }, abstract = {AIMS: Mural cells constitute the outer lining of blood vessels and are essential for vascular development and function. Mural cell loss or malfunction has been associated with numerous diseases including diabetic retinopathy, stroke and amyotrophic lateral sclerosis. In this work, we investigate the role of CDC42 in mural cells in vivo, using the developing mouse retina as a model.

METHODS: In this study, we generated a mouse model for Cdc42 deletion in mural cells by crossing Pdgfrb-CreER[T2] mice with Cdc42flox/flox mice. This model (Cdc42[iΔMC]) allowed us to investigate the role of CDC42 in pericytes and smooth muscle cells in the developing and adult retinal vasculature.

RESULTS: We find that, during postnatal development, CDC42 is required in both, pericytes and smooth muscle cells to maintain proper cell morphology, mural cell coverage and distribution. During retinal angiogenesis, Cdc42-depleted pericytes lag behind the sprouting front and exhibit decreased proliferation. Consequently, capillaries at the sprouting front remain pericyte deprived, become dilated and are prone to increased vascular leakage. In addition, arteries and arterioles deviate from their normal growth directions and trajectory. While in the adult retina, mural cell coverage normalizes and pericytes adopt a normal morphology, smooth muscle cell morphologies remain abnormal and arteriolar branching angles are markedly reduced.

CONCLUSIONS: Our findings demonstrate that CDC42 is required for mural cell migration and proliferation and suggest that mural cells are essential for normal morphogenesis and patterning of the developing retinal vasculature.}, } @article {pmid39971904, year = {2025}, author = {Hossain, MA and Brahme, RR and Miller, BC and Amin, J and de Barros, M and Schneider, JL and Auclair, JR and Mattos, C and Wang, Q and Agar, NYR and Greenblatt, DJ and Manetsch, R and Agar, JN}, title = {Mass spectrometry methods and mathematical PK/PD model for decision tree-guided covalent drug development.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1777}, pmid = {39971904}, issn = {2041-1723}, support = {R01 NS065263/NS/NINDS NIH HHS/United States ; R01NS065263//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 18-IIA-420//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; }, mesh = {Humans ; *Decision Trees ; *Mass Spectrometry/methods ; *Drug Development/methods ; Models, Biological ; Drug Discovery/methods ; }, abstract = {Covalent drug discovery efforts are growing rapidly but have major unaddressed limitations. These include high false positive rates during hit-to-lead identification; the inherent uncoupling of covalent drug concentration and effect [i.e., uncoupling of pharmacokinetics (PK) and pharmacodynamics (PD)]; and a lack of bioanalytical and modeling methods for determining PK and PD parameters. We present a covalent drug discovery workflow that addresses these limitations. Our bioanalytical methods are based upon a mass spectrometry (MS) assay that can measure the percentage of drug-target protein conjugation (% target engagement) in biological matrices. Further we develop an intact protein PK/PD model (iPK/PD) that outputs PK parameters (absorption and distribution) as well as PD parameters (mechanism of action, protein metabolic half-lives, dose, regimen, effect) based on time-dependent target engagement data. Notably, the iPK/PD model is applicable to any measurement (e.g., bottom-up MS and other drug binding studies) that yields % of target engaged. A Decision Tree is presented to guide researchers through the covalent drug development process. Our bioanalytical methods and the Decision Tree are applied to two approved drugs (ibrutinib and sotorasib); the most common plasma off-target, human serum albumin; three protein targets (KRAS, BTK, SOD1), and to a promising SOD1-targeting ALS drug candidates.}, } @article {pmid39973136, year = {2025}, author = {Deng, FY and Zhu, GL and Ou, KL and Zhu, LH and Jia, QQ and Wang, X and Guo, MW and Li, B and Li, SH and Li, XJ and Yin, P}, title = {Ribosome-associated pathological TDP-43 alters the expression of multiple mRNAs in the monkey brain.}, journal = {Zoological research}, volume = {46}, number = {2}, pages = {263-276}, pmid = {39973136}, issn = {2095-8137}, mesh = {Animals ; *RNA, Messenger/metabolism/genetics ; *Macaca fascicularis/metabolism ; *Brain/metabolism ; *Ribosomes/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *Gene Expression Regulation/physiology ; }, abstract = {Cytoplasmic accumulation of TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. While current studies have primarily focused on gene regulation mediated by full-length nuclear TDP-43, the potential effects of cytoplasmic TDP-43 fragments remain less explored. Our previous findings demonstrated that primate-specific cleavage of TDP-43 contributes to its cytoplasmic localization, prompting further investigation into its pathological effects. In the cynomolgus monkey brain, we observed that mutant or truncated TDP-43 was transported onto the ribosome organelle. Ribosome-associated transcriptomic analysis revealed dysregulation of apoptosis- and lysosome-related genes, indicating that cytoplasmic TDP-43 induces neurotoxicity by binding to ribosomes and disrupting mRNA expression. These findings provide mechanistic insights into the gain-of-function effects of pathological TDP-43.}, } @article {pmid39973992, year = {2025}, author = {Nassan, M and Ayala, IA and Sloan, J and Bonfitto, A and Stark, B and Song, S and Naymik, M and Geula, C and Gefen, T and Barbieri, E and Piras, IS and Mesulam, MM and Huentelman, MJ}, title = {The genetics of TDP43-Type-C neurodegeneration: a whole genome sequencing study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.01.25.25320561}, pmid = {39973992}, abstract = {Frontotemporal lobar degeneration-TDP Type C (TDP-C) is a unique neurodegenerative disease that starts by attacking the anterior temporal lobe leading to language and/or behavioral syndromes. Current literature on the genetic associations of TDP-C, which we have reviewed here, is uneven and lacks a discernible corpus of robust findings. In our study, we completed genome wide hypothesis-free analyses utilizing artificial Intelligence (AI) to identify rare and common variants associated with TDP-C. We then investigated ANXA11 and TARDBP in a hypothesis-driven analysis, since it was recently shown that TDP-43 and Annexin A11 co-aggregate in all TDP-C cases. 1) Whole genome sequencing was completed to identify pathogenic rare variants prioritized with Illumina's AI-based Emedgene software on 37 confirmed or probable TDP-C cases from the Northwestern-University Cohort. 2) A genome wide association study was then completed to identify common variants associated with TDP-C cases vs 290 controls. 3) Next, common and rare variants in TARDBP, and ANXA11 were investigated in TDP-C vs controls. These analyses identified novel genetic associations between FIG4 , UBQLN2 , INPP5A , and ANXA11 with TDP-C. Of these FIG4, UBQLN2 and ANXA11 have been associated previously with Amyotrophic lateral sclerosis (ALS). To further assess the observed potential genetic overlap between ALS and TDP-C, we leveraged Mendelian randomization (MR) to assess if the ALS genetic load is associated with TDP-C risk, and found evidence supporting this association. The genetic association of ANXA11 with TDP-C is particularly interesting in view of the recently discovered role of Annexin A11 in forming heterodimers with TDP-43 in all abnormal precipitates, a feature not found in TDP-A or TDP-B, which have no similar predilection for the anterior temporal lobe. In addition to the observed overlap between ALS genetics/ genetic load and TDP-C, it is worth mentioning that FIG4, INPP5A and ANXA11 have been implicated in the inositol metabolism pathway, a feature that remains to be elucidated mechanistically. Our TDP-C genetic literature review identified a surprising paucity of neuropathologically confirmed cases in published investigations. Nonetheless, the literature offers support for some of our findings and reemphasizes the absence of dominant or major pathogenic genes for TDP-C, another feature that sets this neuropathologic entity apart from TDP-A and TDP-B.}, } @article {pmid39975241, year = {2025}, author = {Ghaffari, LT and Welebob, E and Boehringer, A and Cyliax, K and Pasinelli, P and Trotti, D and Haeusler, AR}, title = {Neuronal Activity-Dependent Gene Dysregulation in C9orf72 i[3]Neuronal Models of ALS/FTD Pathogenesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975241}, issn = {2692-8205}, support = {R01 NS109150/NS/NINDS NIH HHS/United States ; R01 NS114128/NS/NINDS NIH HHS/United States ; RF1 NS114128/NS/NINDS NIH HHS/United States ; }, abstract = {The GGGGCC nucleotide repeat expansion (NRE) mutation in the C9orf72 (C9) gene is the most common cause of ALS and FTD. Neuronal activity plays an essential role in shaping biological processes within both healthy and neurodegenerative disease scenarios. Here, we show that at baseline conditions, C9-NRE iPSC-cortical neurons display aberrations in several pathways, including synaptic signaling and transcriptional machinery, potentially priming diseased neurons for an altered response to neuronal stimulation. Indeed, exposure to two pathophysiologically relevant stimulation modes, prolonged membrane depolarization, or a blockade of K[+] channels, followed by RNA sequencing, induces a temporally divergent activity-dependent transcriptome of C9-NRE cortical neurons compared to healthy controls. This study provides new insights into how neuronal activity influences the ALS/FTD-associated transcriptome, offering a dataset that enables further exploration of pathways necessary for conferring neuronal resilience or degeneration.}, } @article {pmid39975323, year = {2025}, author = {Bekier, ME and Pinarbasi, E and Mesojedec, JJ and Ghaffari, L and de Majo, M and Ullian, E and Koontz, M and Coleman, S and Li, X and Tank, EMH and Waksmacki, J and Barmada, S}, title = {Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975323}, issn = {2692-8205}, support = {UL1 TR000433/TR/NCATS NIH HHS/United States ; R44 NS124457/NS/NINDS NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; }, abstract = {Cytoplasmic TDP43 mislocalization and aggregation are pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the initial cellular insults that lead to TDP43 mislocalization remain unclear. In this study, we demonstrate that Nemo-like kinase (NLK)-a proline-directed serine/threonine kinase-promotes the mislocalization of TDP43 and other RNA-binding proteins by disrupting nuclear import. NLK levels are selectively elevated in neurons exhibiting TDP43 mislocalization in ALS patient tissues, while genetic reduction of NLK reduces toxicity in human neuron models of ALS. Our findings suggest that NLK is a promising therapeutic target for neurodegenerative diseases.}, } @article {pmid39975337, year = {2025}, author = {Zinn, KM and McLaren, MW and Imai, MT and Jayaram, MM and Rothstein, JD and Elrick, MJ}, title = {Enterovirus D68 2A protease causes nuclear pore complex dysfunction and motor neuron toxicity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.01.23.632178}, pmid = {39975337}, issn = {2692-8205}, support = {K08 NS124989/NS/NINDS NIH HHS/United States ; R01 NS143998/NS/NINDS NIH HHS/United States ; }, abstract = {The picornavirus Enterovirus D68 (EV-D68) is an important pathogen associated with acute flaccid myelitis (AFM). The pathogenesis of AFM involves infection of spinal motor neurons and motor neuron death, however the mechanisms linking EV-D68 infection to selective neurotoxicity are not well understood. Dysfunction of the nuclear pore complex (NPC) has been implicated in motor neuron injury in neurodegenerative diseases such as amyotrophic lateral sclerosis, and the NPC is also modified by picornavirus proteases during the course of infection. We therefore sought to determine the impact of EV-D68 proteases on NPC composition and function and their role in motor neuron toxicity. We demonstrate widespread disruption of NPC composition by EV-D68 2A and 3C proteases via the direct cleavage of a relatively small number of nucleoporins, notably Nup98 and POM121 by 2A [pro] . Using reporter systems, we demonstrate that 2A [pro] inhibits nuclear import and export of protein cargoes and also disrupts the permeability barrier of the NPC, while having no apparent effect on RNA export. We further show that 2A [pro] is toxic to induced pluripotent stem cell derived motor neurons by demonstrating a rescue of toxicity with 2A [pro] inhibitor telaprevir at concentrations that are insufficient to inhibit viral replication. This study expands our understanding of EV-D68 neuropathogenesis and provides a rationale for targeting the NPC or 2A [pro] therapeutically in AFM.}, } @article {pmid39976178, year = {2025}, author = {Canosa, A and Manera, U and Vasta, R and Zocco, G and Di Pede, F and Cabras, S and De Mattei, F and Palumbo, F and Iazzolino, B and Minerva, E and Sbaiz, L and Brunetti, M and Gallone, S and Grassano, M and Matteoni, E and Polverari, G and Fuda, G and Casale, F and Salamone, P and De Marco, G and Marchese, G and Moglia, C and Calvo, A and Pagani, M and Chiò, A}, title = {Brain Metabolic Features of FUS-ALS: A 2-[[18]F]FDG-PET Study.}, journal = {Annals of neurology}, volume = {97}, number = {6}, pages = {1134-1143}, pmid = {39976178}, issn = {1531-8249}, support = {//A.S.D. Polisportiva U.I.C.I Torino Onlus (Oltre la Vista, Oltre la SLA)/ ; PRIN 2017//Ministero dell'Università e della Ricerca/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; //Fondation Thierry Latran (INSPIRED)/ ; RF-2016- 02362405//Ministero della Salute (The Italian Ministry of Health [Ricerca Sanitaria Finalizzata])/ ; 259867//European Commission's Health Seventh Framework Programme (FP7/2007-2013)/ ; GA101017598//Horizon 2020 Framework Programme (BRAINTEASER [Bringing Artificial Intelligence Home for a Better Care of Amyotrophic Lateral Sclerosis and Multiple Sclerosis])/ ; 101137074//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; Male ; Female ; Positron-Emission Tomography/methods ; Middle Aged ; Fluorodeoxyglucose F18 ; Aged ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging/genetics ; *Brain/metabolism/diagnostic imaging ; *RNA-Binding Protein FUS/genetics/metabolism ; Adult ; Radiopharmaceuticals ; }, abstract = {OBJECTIVE: We aimed at evaluating the brain metabolic features of fused in sarcoma amyotrophic lateral sclerosis (FUS-ALS) compared with sporadic ALS (sALS), using 2-[fluorine-18] fluoro-2-deoxy-D-glucose positron emission tomography (2-[[18]F]FDG-PET).

METHODS: We employed the 2-sample t-test model of SPM12, implemented in MATLAB, to compare 12 FUS-ALS cases with 40 healthy controls (HC) and 48 sALS, randomly collected from the series of patients who underwent brain 2-[[18]F]FDG-PET at the ALS Center of Turin (Italy) at diagnosis from 2009 to 2019. In the comparisons between cases and HC, we included age at PET and sex as covariates. Because FUS-ALS usually shows early onset in spinal regions, in the comparison between FUS-ALS and sALS, we included singularly the following covariates in a second step, to evaluate the determinants of eventual metabolic differences: age at PET, sex, and onset (spinal/bulbar).

RESULTS: sALS patients showed significant relative hypometabolism in bilateral fronto-temporo-occipital cortex and right insula as compared with FUS-ALS. After adjusting for age, the relative hypometabolism remained in the bilateral precentral gyrus and in the right middle and inferior temporal gyrus. As compared with HC, FUS patients displayed a significant relative hypermetabolism in the pontobulbar region and right cerebellar tonsil, dentate nucleus, and uvula, while sALS showed relative hypometabolism in bilateral frontal and occipital cortices and in left temporal and parietal regions.

INTERPRETATION: Patients with FUS-ALS show relative preservation of motor cortex metabolism compared with those with sALS, possibly reflecting the prevalence of lower motor neuron impairment in their phenotype. Prospective studies are necessary to investigate the possible role of 2-[[18]F]FDG-PET as a biomarker to track disease spreading in clinical trials. ANN NEUROL 2025;97:1134-1143.}, } @article {pmid39976261, year = {2025}, author = {Menendez-Gonzalez, M}, title = {Implementing a tridimensional diagnostic framework for personalized medicine in neurodegenerative diseases.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14591}, pmid = {39976261}, issn = {1552-5279}, support = {PI21/00467//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/diagnosis/genetics ; Biomarkers ; Neuroimaging ; }, abstract = {Neurodegenerative diseases (NDDs) pose a significant challenge in modern medicine due to their clinical heterogeneity, multifactorial etiologies, and frequent co-pathologies. Traditional diagnostic systems, based on clinical symptoms and post mortem findings, are limited in capturing the complex interactions among genetic, molecular, and neuroanatomical factors. This manuscript introduces a novel tridimensional diagnostic framework that integrates these factors across three key axes: etiology (genetic and environmental influences), molecular markers (primary and secondary biomarkers), and neuroanatomoclinical correlations. Through case studies, we demonstrate the framework's ability to synthesize incomplete datasets, stratify patients, and guide precision medicine. By incorporating omics technologies, neuroimaging, and AI-driven probabilistic modeling, the framework enhances diagnostic accuracy and clinical relevance. This approach may contribute to overcoming the limitations of traditional nosologies, offering a scalable and adaptable tool for both clinical practice and research and advancing the field of precision medicine in NDD management. HIGHLIGHTS: Tridimensional diagnostic system: We propose a new framework that incorporates three axes - etiology, molecular markers, and neuroanatomical-clinical correlations - to enhance diagnostic accuracy for NDDs. Personalized medicine: The tridimensional system enables the integration of genetic, molecular, and clinical data, allowing for highly personalized treatment strategies tailored to individual patients. Proteinopathies as key biomarkers: This diagnostic system emphasizes the use of primary proteinopathies (amyloid, tau, synuclein) and secondary biomarkers (eg, NfL, GFAP) to monitor disease progression and treatment efficacy. Addressing clinical heterogeneity: The framework accommodates the complexity and heterogeneity of NDDs, offering an adaptable diagnostic approach for classical conditions like Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and ALS. Case studies and real-world application: Practical case studies illustrate how this system can be implemented in clinical practice, enabling the combination of DMTs with symptomatic treatments.}, } @article {pmid39976286, year = {2025}, author = {Guo, K and Savelieff, MG and Jang, DG and Teener, SJ and Zhao, L and Hur, J and Goutman, SA and Feldman, EL}, title = {Longitudinal Metabolomics in Amyotrophic Lateral Sclerosis Implicates Impaired Lipid Metabolism.}, journal = {Annals of neurology}, volume = {98}, number = {1}, pages = {19-34}, pmid = {39976286}, issn = {1531-8249}, support = {UL1 TR000433/TR/NCATS NIH HHS/United States ; //the Scott L. Pranger ALS Clinic Fund/ ; //the Peter R. Clark Fund for ALS Research/ ; //the Dr. Randall Whitcomb Fund for ALS Genetics/ ; K23 ES027221/ES/NIEHS NIH HHS/United States ; //the Coleman Therapeutic Discovery Fund/ ; R01ES030049/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; UL1TR002240//National Center for Advancing Translational Sciences at the National Institutes of Health/ ; R01TS000289/CC/CDC HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; K23ES027221/ES/NIEHS NIH HHS/United States ; R01NS127188/NS/NINDS NIH HHS/United States ; R01 TS000289/TS/ATSDR CDC HHS/United States ; UL1TR000433//Michigan Institute for Clinical and Health Research/ ; //the Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund/ ; UL1 TR002240/TR/NCATS NIH HHS/United States ; //the Sinai Medical Staff Foundation/ ; //the A. Alfred Taubman Medical Research Institute/ ; //the NeuroNetwork for Emerging Therapies, University of Michigan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Male ; *Metabolomics ; Female ; *Lipid Metabolism/physiology ; Middle Aged ; Longitudinal Studies ; Aged ; Spinal Cord/metabolism ; Disease Progression ; Motor Cortex/metabolism ; *Metabolome ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by altered metabolome and energy homeostasis, manifesting with body mass index changes and hypermetabolism-both prognostic of disease progression and survival. The cross-sectional ALS metabolome has been characterized, but longitudinal correlations to functional decline are lacking.

METHODS: We longitudinally evaluated metabolomes from ALS plasma and terminal postmortem spinal cord and brain motor cortex tissue. We constructed 3 plasma models. A linear mixed effects model correlated all metabolite levels across all timepoints to their corresponding functional scores. An interaction model predicted a longitudinal change in function from baseline metabolites, whereas a progression model identified metabolites linked to a 20% or 50% drop in function. In postmortem samples, differential metabolites in onset versus second spinal cord segments served as a surrogate of disease progression. Mendelian randomization assessed potential causality from metabolites.

RESULTS: In plasma, all models primarily selected lipid metabolites and sub-pathways, in addition to amino acids, xenobiotics, and various less frequently selected pathways. Among lipids, fatty acids and sphingomyelins were predominant, along with plasmalogens, phosphatidylcholines, and lysophospholipids. Sex interaction findings were nominal. In the spinal cord, sphingomyelin and long-chain saturated and monounsaturated fatty acids were more abundant in the onset segment tissue, whereas phosphatidylcholines and phosphatidylethanolamines were less abundant. Mendelian randomization suggested that impaired carnitine and short chain acylcarnitine metabolism may be genetically determined in ALS, along with various antioxidant derivatives.

INTERPRETATION: Our findings suggest metabolomic changes primarily involving different lipid classes and carnitine metabolism may underscore ALS severity and progression. ANN NEUROL 2025;98:19-34.}, } @article {pmid39977838, year = {2025}, author = {Chang, JH and Tschannen, D}, title = {An Integrative Review of Quality Improvement Competence and Engagement Among Frontline Nurses.}, journal = {Journal of nursing care quality}, volume = {40}, number = {2}, pages = {173-180}, pmid = {39977838}, issn = {1550-5065}, mesh = {Humans ; *Quality Improvement ; *Clinical Competence/standards ; Leadership ; *Nursing Staff, Hospital ; }, abstract = {BACKGROUND: Nurses providing direct care have firsthand knowledge of gaps in practice and thus must actively engage in quality improvement (QI) to enhance patient outcomes.

PURPOSE: This integrative review evaluated QI competence and engagement among frontline nurses.

METHODS: Using Souza et al's 6-step framework, literature on QI engagement and competence was synthesized using a rigorous search strategy and quality assessment.

RESULTS: Sixteen studies revealed generally low QI engagement and competence. Factors such as education, experience, and role influenced engagement, with higher levels of education and experience linked to higher QI involvement. Nurse leaders had higher engagement, underscoring the need for strong leadership in creating a culture of improvement.

CONCLUSIONS: Successful and sustainable QI programs and supportive environments enhance QI engagement and competence among frontline nurses.}, } @article {pmid39978484, year = {2025}, author = {Hülsmeier, AJ}, title = {Glycosphingolipids in neurodegeneration - Molecular mechanisms, cellular roles, and therapeutic perspectives.}, journal = {Neurobiology of disease}, volume = {207}, number = {}, pages = {106851}, doi = {10.1016/j.nbd.2025.106851}, pmid = {39978484}, issn = {1095-953X}, mesh = {Humans ; *Glycosphingolipids/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; Animals ; }, abstract = {Neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuronal loss and pose significant global health challenges. Glycosphingolipids (GSLs), critical components of neuronal membranes, regulate signal transduction, membrane organization, neuroinflammation, and lipid raft functionality. This review explores GSL roles in neural development, differentiation, and neurogenesis, along with their dysregulation in neurodegenerative diseases. Aberrations in GSL metabolism drive key pathological features such as protein aggregation, neuroinflammation, and impaired signaling. Specific GSLs, such as GM1, GD3, and GM3, influence amyloid-beta aggregation in AD, α-synuclein stability in PD, and mutant huntingtin toxicity in HD. Therapeutic strategies targeting GSL metabolism, such as GM1 supplementation and enzyme modulation, have demonstrated potential to mitigate disease progression. Further studies using advanced lipidomics and glycomics may support biomarker identification and therapeutic advancements. This work aims to highlight the translational potential of GSL research for diagnosing and managing devastating neurodegenerative conditions.}, } @article {pmid39979261, year = {2025}, author = {Liu, D and Webber, HC and Bian, F and Xu, Y and Prakash, M and Feng, X and Yang, M and Yang, H and You, IJ and Li, L and Liu, L and Liu, P and Huang, H and Chang, CY and Liu, L and Shah, SH and La Torre, A and Welsbie, DS and Sun, Y and Duan, X and Goldberg, JL and Braun, M and Lansky, Z and Hu, Y}, title = {Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1789}, pmid = {39979261}, issn = {2041-1723}, support = {R01 EY034353/EY/NEI NIH HHS/United States ; P30 EY026877/EY/NEI NIH HHS/United States ; 1F32EY029567//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; EY026877//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; EY034353//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; S10 OD025091/OD/NIH HHS/United States ; R01 EY032518/EY/NEI NIH HHS/United States ; EY032518//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; R01 EY023295/EY/NEI NIH HHS/United States ; EY023295//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; F32 EY029567/EY/NEI NIH HHS/United States ; R01 EY032159/EY/NEI NIH HHS/United States ; R01 EY024932/EY/NEI NIH HHS/United States ; EY024932//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; R01 EY025295/EY/NEI NIH HHS/United States ; S10 OD030452/OD/NIH HHS/United States ; }, mesh = {Animals ; *Mitochondria/metabolism ; *Axons/metabolism/physiology ; Membrane Transport Proteins/metabolism ; Retinal Ganglion Cells/metabolism/pathology ; Cell Cycle Proteins ; Mice ; Humans ; Microtubules/metabolism ; *Nerve Regeneration/physiology ; *Neuroprotection ; Optic Nerve/metabolism/pathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Transcription Factor TFIIIA/metabolism/genetics ; Disease Models, Animal ; Axonal Transport ; Low Tension Glaucoma/genetics/metabolism/pathology ; Motor Neurons/metabolism ; Mice, Inbred C57BL ; Male ; }, abstract = {Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We find that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a decrease of axonal mitochondria in mice. We discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Furthermore, overexpressing OPTN/TRAK1/KIF5B prevents not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes robust ON regeneration. Therefore, in addition to generating animal models for NTG and ALS, our results establish OPTN as a facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.}, } @article {pmid39980027, year = {2025}, author = {Jin, Y and Conneely, KN and Ma, W and Naviaux, RK and Siddique, T and Allen, EG and Guingrich, S and Pascuzzi, RM and Jin, P}, title = {Whole-genome bisulfite sequencing of cell-free DNA unveils age-dependent and ALS-associated methylation alterations.}, journal = {Cell & bioscience}, volume = {15}, number = {1}, pages = {26}, pmid = {39980027}, issn = {2045-3701}, support = {P50 HD104458/HD/NICHD NIH HHS/United States ; R35 NS111602/NS/NINDS NIH HHS/United States ; NS111602/NS/NINDS NIH HHS/United States ; HD104458//National Institute of Child Health and Human Development/ ; }, abstract = {BACKGROUND: Cell-free DNA (cfDNA) in plasma carries epigenetic signatures specific to tissue or cell of origin. Aberrant methylation patterns in circulating cfDNA have emerged as valuable tools for noninvasive cancer detection, prenatal diagnostics, and organ transplant assessment. Such epigenetic changes also hold significant promise for the diagnosis of neurodegenerative diseases, which often progresses slowly and has a lengthy asymptomatic period. However, genome-wide cfDNA methylation changes in neurodegenerative diseases remain poorly understood.

RESULTS: We used whole-genome bisulfite sequencing (WGBS) to profile age-dependent and ALS-associated methylation signatures in cfDNA from 30 individuals, including young and middle-aged controls, as well as ALS patients with matched controls. We identified 5,223 age-related differentially methylated loci (DMLs) (FDR < 0.05), with 51.6% showing hypomethylation in older individuals. Our results significantly overlapped with age-associated CpGs identified in a large blood-based epigenome-wide association study (EWAS). Comparing ALS patients to controls, we detected 1,045 differentially methylated regions (DMRs) in gene bodies, promoters, and intergenic regions. Notably, these DMRs were linked to key ALS-associated pathways, including endocytosis and cell adhesion. Integration with spinal cord transcriptomics revealed that 31% of DMR-associated genes exhibited differential expression in ALS patients compared to controls, with over 20 genes significantly correlating with disease duration. Furthermore, comparison with published single-nucleus RNA sequencing (snRNA-Seq) data of ALS demonstrated that cfDNA methylation changes reflects cell-type-specific gene dysregulation in the brain of ALS patients, particularly in excitatory neurons and astrocytes. Deconvolution of cfDNA methylation profiles suggested altered proportions of immune and liver-derived cfDNA in ALS patients.

CONCLUSIONS: cfDNA methylation is a powerful tool for assessing age-related changes and ALS-specific molecular dysregulation by revealing perturbed locus, genes, and the proportional contributions of different tissues/cells to the plasma. This technique holds promise for clinical application in biomarker discovery across a broad spectrum of neurodegenerative disorders.}, } @article {pmid39980944, year = {2025}, author = {Ji, J}, title = {To the Editor: In Response to Park et al's Perspective on the Resignation of South Korean Residents: A Medical Student View.}, journal = {Journal of graduate medical education}, volume = {17}, number = {1}, pages = {113-114}, pmid = {39980944}, issn = {1949-8357}, } @article {pmid39981199, year = {2025}, author = {Kiernan, MC}, title = {Recent developments in consensus diagnostic criteria for amyotrophic lateral sclerosis.}, journal = {eNeurologicalSci}, volume = {38}, number = {}, pages = {100559}, pmid = {39981199}, issn = {2405-6502}, } @article {pmid39981400, year = {2025}, author = {Yang, EJ and Lee, SH}, title = {Herbal Medicine Extracts Improve Motor Function by Anti-Inflammatory Activity in hSOD1[G93A] Animal Model.}, journal = {Mediators of inflammation}, volume = {2025}, number = {}, pages = {1999953}, pmid = {39981400}, issn = {1466-1861}, mesh = {Animals ; Mice ; Mice, Transgenic ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Disease Models, Animal ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Plant Extracts/therapeutic use/pharmacology ; Muscle, Skeletal/drug effects/metabolism ; Motor Neurons/drug effects/metabolism ; Oxidative Stress/drug effects ; *Herbal Medicine ; Male ; Superoxide Dismutase-1/metabolism/genetics ; Spinal Cord/drug effects/metabolism ; Inflammation/drug therapy ; Paeonia/chemistry ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multicomplex neurodegenerative disorder characterized by motor neuron death, muscle atrophy, and respiratory failure. Owing to its multicomplex mechanisms and multifactorial nature in the skeletal muscle and spinal cord (SC), no effective therapy has been developed. However, herbal medicines, known for their multitarget properties, have demonstrated promising efficacy with limited side effects in treating various diseases. Specifically, Paeonia lactiflora Pallas has been demonstrated to exhibit analgesic, antidepressant, anti-inflammatory, and neuroprotective effects. However, the pharmacological mechanisms underlying the beneficial effects of P. lactiflora in hSOD1[G93A] animal models remain unexplored. Therefore, this study was conducted to investigate the multitarget effects of P. lactiflora in hSOD1[G93A] transgenic mice, an ALS model. Footprint tests, western blot assays, and immunohistochemical analysis were used to assess the effect of P. lactiflora on the tibia anterior (TA), gastrocnemius (GC), and SC. The results revealed that P. lactiflora augmented motor function and decreased motor neuron loss in hSOD1[G93A] mice. Furthermore, P. lactiflora significantly lowered the expression of proteins associated with inflammation and oxidative stress in the skeletal muscle (TA and GC) and SC. P. lactiflora also regulated autophagy function by reducing the levels of key markers, such as P62/sequestosome 1 (SQSTM1), microtubule-associated proteins 1A/1B light chain 3B, and SMAD family member 2, in the muscle and SC. Overall, P. lactiflora treatment improved motor function, prevented motor neuron death, and exhibited anti-inflammatory and antioxidative effects in the skeletal muscle and SC of ALS mouse models. These results suggest that P. lactiflora could serve as a promising multitarget therapeutic agent for systemic and multipathological diseases.}, } @article {pmid39982214, year = {2026}, author = {Peng, T and Hu, N and Huang, L and Kang, Y and Yan, Y and Zhang, H and Wan, D and Jin, X and Yang, Y}, title = {Safety of edaravone in real-world use: analysis based on FDA adverse event reporting system.}, journal = {Expert opinion on drug safety}, volume = {25}, number = {7}, pages = {1299-1307}, doi = {10.1080/14740338.2025.2470874}, pmid = {39982214}, issn = {1744-764X}, mesh = {*Edaravone/adverse effects/administration & dosage ; Humans ; *Adverse Drug Reaction Reporting Systems/statistics & numerical data ; United States Food and Drug Administration ; United States ; Amyotrophic Lateral Sclerosis/drug therapy ; *Free Radical Scavengers/adverse effects/administration & dosage ; Databases, Factual ; Time Factors ; Bayes Theorem ; Algorithms ; }, abstract = {BACKGROUND: Edaravone is a novel free radical scavenger utilized to treat amyotrophic lateral sclerosis (ALS). However, long-term safety data remain limited.

RESEARCH DESIGN AND METHODS: Adverse event reports related to edaravone from the second quarter of 2017 to the second quarter of 2024 were extracted from the US Food and Drug Administration (FDA) Adverse Event Reporting System database (FAERS). Disproportionality analysis was conducted utilizing the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms.

RESULTS: A total of 3,149 adverse event reports related to edaravone were analyzed. The most common adverse reactions included systemic disorders and administration site reactions, nervous system disorders, respiratory system disorders, and surgical and medical procedures. New adverse reaction signals included disseminated intravascular coagulation, gastric fistula, sputum retention, excessive salivation, fractures, elevated cystatin C. The median onset time for adverse events was 43 days (interquartile range: 7-173 days).

CONCLUSION: This study confirmed previously reported adverse events and identified several new ones associated with edaravone. These findings provide valuable insights for optimizing ALS patient management and highlight the need for further research into the mechanisms of these adverse reactions.}, } @article {pmid39982687, year = {2025}, author = {Loher, P and Londin, E and Ilieva, H and Pasinelli, P and Rigoutsos, I}, title = {Re-Analyses of Samples From Amyotrophic Lateral Sclerosis Patients and Controls Identify Many Novel Small RNAs With Diagnostic And Prognostic Potential.}, journal = {Molecular neurobiology}, volume = {62}, number = {7}, pages = {8135-8149}, pmid = {39982687}, issn = {1559-1182}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood ; Prognosis ; Male ; Female ; Case-Control Studies ; Middle Aged ; *MicroRNAs/genetics/blood ; Biomarkers/blood ; RNA, Ribosomal/genetics/blood ; Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease for which accurate diagnostic and prognostic biomarkers are needed. Toward this goal, we reanalyzed two published collections of datasets generated from the plasma and serum of ALS patients and controls. We profiled these datasets for isoforms of microRNAs (miRNAs) known as isomiRs, transfer RNA-derived fragments (tRFs), and ribosomal RNA-derived fragments (rRFs), placing all remaining reads into a group labeled "not-itrs." We found that plasma and serum are rich in isomiRs (canonical, non-canonical, and non-templated), tRFs, rRFs, and members of an emerging class of small RNAs known as Y RNA-derived fragments (yRFs). In both analyzed collections, we found many isomiRs, tRFs, rRFs, and yRFs that are differentially abundant between patients and controls. We also performed a survival analysis that considered Riluzole treatment status, demographics (age at onset, age at enrollment, sex), and disease characteristics (ALSFRS, rD50, onset type) and found many of the differentially abundant small RNAs to be associated with survival time, with some of these associations being independent of Riluzole treatment. Unexpectedly, many not-itrs that did not map to the human genome mapped exactly to sequences from the SILVA database of ribosomal DNAs (rDNAs). Not-itrs from the plasma datasets mapped primarily to rDNAs from the order of Burkholderiales, and several of them were associated with patient survival. Not-itrs from the serum datasets also showed support for rDNA from Burkholderiales but a stronger support for rDNAs from the fungi group of the Nucletmycea taxon. The findings suggest that many previously unexplored small non-coding RNAs, including human isomiRs, tRFs, rRFs, and yRFs, could potentially serve as novel diagnostic and prognostic biomarkers for ALS.}, } @article {pmid39982984, year = {2025}, author = {Verde, EM and Antoniani, F and Mediani, L and Secco, V and Crotti, S and Ferrara, MC and Vinet, J and Sergeeva, A and Yan, X and Hoege, C and Stuani, C and Paron, F and Kao, TT and Shrivastava, R and Polanowska, J and Bailly, A and Rosa, A and Aronica, E and Goswami, A and Shneider, N and Hyman, AA and Buratti, E and Xirodimas, D and Franzmann, TM and Alberti, S and Carra, S}, title = {SUMO2/3 conjugation of TDP-43 protects against aggregation.}, journal = {Science advances}, volume = {11}, number = {8}, pages = {eadq2475}, pmid = {39982984}, issn = {2375-2548}, mesh = {Humans ; *Small Ubiquitin-Related Modifier Proteins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/chemistry/genetics ; *Protein Aggregates ; Protein Inhibitors of Activated STAT/metabolism/genetics ; *Ubiquitins/metabolism/genetics ; Oxidative Stress ; Sumoylation ; Stress Granules/metabolism ; *Protein Aggregation, Pathological/metabolism ; Protein Binding ; Poly-ADP-Ribose Binding Proteins ; }, abstract = {Cytosolic aggregation of the RNA binding protein TDP-43 (transactive response DNA-binding protein 43) is a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. Here, we report that during oxidative stress, TDP-43 becomes SUMO2/3-ylated by the SUMO E3 ligase protein PIAS4 (protein inhibitor of activated STAT 4) and enriches in cytoplasmic stress granules (SGs). Upon pharmacological inhibition of TDP-43 SUMO2/3-ylation or PIAS4 depletion, TDP-43 enrichment in SGs is accompanied by irreversible aggregation. In cells that are unable to assemble SGs, SUMO2/3-ylation of TDP-43 is strongly impaired, supporting the notion that SGs are compartments that promote TDP-43 SUMO2/3-ylation during oxidative stress. Binding of TDP-43 to UG-rich RNA antagonizes PIAS4-mediated SUMO2/3-ylation, while RNA dissociation promotes TDP-43 SUMO2/3-ylation. We conclude that SUMO2/3 protein conjugation is a cellular mechanism to stabilize cytosolic RNA-free TDP-43 against aggregation.}, } @article {pmid39984353, year = {2025}, author = {Comini, L and Di Pietro, DA and Olivares, A and Bertella, E and Vitacca, M}, title = {Gut dysbiosis and leaky gut syndrome in moderately impaired amyotrophic lateral sclerosis patients.}, journal = {European journal of internal medicine}, volume = {136}, number = {}, pages = {150-152}, doi = {10.1016/j.ejim.2025.02.019}, pmid = {39984353}, issn = {1879-0828}, } @article {pmid39985110, year = {2025}, author = {Swanson, MEV and Mrkela, M and Turner, C and Curtis, MA and Faull, RLM and Walker, AK and Scotter, EL}, title = {Neuronal TDP-43 aggregation drives changes in microglial morphology prior to immunophenotype in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {39}, pmid = {39985110}, issn = {2051-5960}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Microglia/pathology/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; Humans ; Male ; Female ; Mice ; Middle Aged ; Aged ; Mice, Transgenic ; Immunophenotyping ; Disease Models, Animal ; Antigens, CD/metabolism ; *Motor Cortex/pathology/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; Calcium-Binding Proteins/metabolism ; Microfilament Proteins/metabolism ; Aged, 80 and over ; }, abstract = {Microglia are the innate immune cells of the brain with the capacity to react to damage or disease. Microglial reactions can be characterised in post-mortem tissues by assessing their pattern of protein expression, or immunophenotypes, and cell morphologies. We recently demonstrated that microglia have a phagocytic immunophenotype in early-stage ALS but transition to a dysfunctional immunophenotype by end stage, and that these states are driven by TAR DNA-binding protein 43 (TDP-43) aggregation in the human brain. However, it remains unclear how microglial morphologies are changed in ALS. Here we examine the relationship between microglial immunophenotypes and morphologies, and TDP-43 pathology in motor cortex tissue from people with ALS and from a TDP-43-driven ALS mouse model. Post-mortem human brain tissue from 10 control and 10 ALS cases was analysed alongside brain tissue from the bigenic NEFH-tTA/tetO-hTDP-43∆NLS (rNLS) mouse model of ALS at distinct disease stages. Sections were immunohistochemically labelled for microglial markers (HLA-DR, CD68, and Iba1) and phosphorylated TDP-43 (pTDP-43). Single-cell microglial HLA-DR, CD68, and Iba1 average intensities, and morphological features (cell body area, process number, total outgrowth, and branch number) were measured using custom image analysis pipelines. In human ALS motor cortex, we identified a significant change in microglial morphologies from ramified to hypertrophic, which was associated with increased Iba1 and CD68 levels. In the rNLS mouse motor cortex, the microglial morphologies changed from ramified to hypertrophic and increased Iba1 levels occurred in parallel with pTDP-43 aggregation, prior to increases in CD68 levels. Overall, the evidence presented in this study demonstrates that microglia change their morphologies prior to immunophenotype changes. These morphological changes may prime microglia near neurons with pTDP-43 aggregation for phagocytosis, in turn triggering immunophenotype changes; first, to a phagocytic state then to a dysfunctional one.}, } @article {pmid39985291, year = {2025}, author = {Steinfurth, L and Grehl, T and Weyen, U and Kettemann, D and Steinbach, R and Rödiger, A and Grosskreutz, J and Petri, S and Boentert, M and Weydt, P and Bernsen, S and Walter, B and GüNTHER, R and Lingor, P and Koch, JC and Baum, P and Weishaupt, JH and Dorst, J and Koc, Y and Cordts, I and Vidovic, M and Norden, J and Schumann, P and Körtvélyessy, P and Spittel, S and Münch, C and Maier, A and Meyer, T}, title = {Self-assessment of amyotrophic lateral sclerosis functional rating scale on the patient's smartphone proves to be non-inferior to clinic data capture.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {495-506}, doi = {10.1080/21678421.2025.2468404}, pmid = {39985291}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology/physiopathology ; Male ; *Smartphone ; Female ; Middle Aged ; Aged ; *Mobile Applications ; *Self-Assessment ; Disease Progression ; Severity of Illness Index ; Cohort Studies ; }, abstract = {OBJECTIVE: To investigate self-assessment of the amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) using the patient's smartphone and to analyze non-inferiority to clinic assessment.

METHODS: In an observational study, ALSFRS-R data being remotely collected on a mobile application (App-ALSFRS-R) were compared to ALSFRS-R captured during clinic visits (clinic-ALSFRS-R). ALS progression rate (ALSPR)-as calculated by the monthly decline of ALSFRS-R-and its intrasubject variability (ALSPR-ISV) between ratings were used to compare both cohorts. To investigate non-inferiority of App-ALSFRS-R data, a non-inferiority margin was determined.

RESULTS: A total of 691 ALS patients using the ALS-App and 1895 patients with clinic assessments were included. Clinical characteristics for the App-ALSFRS-R and clinic-ALSFRS-R cohorts were as follows: Mean age 60.45 (SD 10.43) and 63.69 (SD 11.30) years (p < 0.001), disease duration 38.7 (SD 37.68) and 56.75 (SD 54.34) months (p < 0.001) and ALSPR 0.72 and 0.59 (p < 0.001), respectively. A paired sample analysis of ALSPR-ISV was applicable for 398 patients with clinic as well as app assessments and did not show a significant difference (IQR 0.12 [CI 0.11, 0.14] vs 0.12 [CI 0.11, 0.14], p = 0.24; Cohen's d = 0.06). CI of IQR for App-ALSFRS-R was below the predefined non-inferiority margin of 0.15 IQR, demonstrating non-inferiority.

CONCLUSIONS: Patients using a mobile application for remote digital self-assessment of the ALSFRS-R revealed younger age, earlier disease course, and faster ALS progression. The finding of non-inferiority of App-ALSFRS-R assessments underscores, that data collection using the ALS-App on the patient's smartphone can serve as additional source of ALSFRS-R in ALS research and clinical practice.}, } @article {pmid39985309, year = {2025}, author = {Lajoie, I and , and Kalra, S and Dadar, M}, title = {Regional Cerebral Atrophy Contributes to Personalized Survival Prediction in Amyotrophic Lateral Sclerosis: A Multicentre, Machine Learning, Deformation-Based Morphometry Study.}, journal = {Annals of neurology}, volume = {97}, number = {6}, pages = {1144-1157}, pmid = {39985309}, issn = {1531-8249}, support = {//Fondation Brain Canada/ ; //ALS Society of Canada/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnostic imaging/pathology ; Male ; Female ; Atrophy/pathology ; Middle Aged ; Magnetic Resonance Imaging/methods ; Aged ; *Machine Learning ; Gray Matter/diagnostic imaging/pathology ; *Brain/pathology/diagnostic imaging ; White Matter/diagnostic imaging/pathology ; Disease Progression ; }, abstract = {OBJECTIVE: Accurate personalized survival prediction in amyotrophic lateral sclerosis is essential for effective patient care planning. This study investigates whether grey and white matter changes measured by magnetic resonance imaging can improve individual survival predictions.

METHODS: We analyzed data from 178 patients with amyotrophic lateral sclerosis and 166 healthy controls in the Canadian Amyotrophic Lateral Sclerosis Neuroimaging Consortium study. A voxel-wise linear mixed-effects model assessed disease-related and survival-related atrophy detected through deformation-based morphometry, controlling for age, sex, and scanner variations. Additional linear mixed-effects models explored associations between regional imaging and clinical measurements, and their associations with time to the composite outcome of death, tracheostomy, or permanent assisted ventilation. We evaluated whether incorporating imaging features alongside clinical data could improve the performance of an individual survival distribution model.

RESULTS: Deformation-based morphometry uncovered distinct voxel-wise atrophy patterns linked to disease progression and survival, with many of these regional atrophies significantly associated with clinical manifestations of the disease. By integrating regional imaging features with clinical data, we observed a substantial enhancement in the performance of survival models across key metrics. Our analysis identified specific brain regions, such as the corpus callosum, rostral middle frontal gyrus, and thalamus, where atrophy predicted an increased risk of mortality.

INTERPRETATION: This study suggests that brain atrophy patterns measured by deformation-based morphometry provide valuable insights beyond clinical assessments for prognosis. It offers a more comprehensive approach to prognosis and highlights brain regions involved in disease progression and survival, potentially leading to a better understanding of amyotrophic lateral sclerosis. ANN NEUROL 2025;97:1144-1157.}, } @article {pmid39985812, year = {2025}, author = {Filippi, M and Ghirelli, A and Spinelli, EG and Agosta, F}, title = {A comprehensive update on neuroimaging endpoints in amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {4}, pages = {397-413}, doi = {10.1080/14737175.2025.2470324}, pmid = {39985812}, issn = {1744-8360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/therapy ; *Neuroimaging/methods ; Magnetic Resonance Imaging/methods ; Positron-Emission Tomography/methods ; Disease Progression ; Biomarkers ; }, abstract = {INTRODUCTION: There are currently few treatments approved for amyotrophic lateral sclerosis (ALS). Additionally, there remains a significant unmet need for reliable, standardized biomarkers to assess endpoints in clinical trials. Magnetic resonance imaging (MRI)- and positron emission tomography (PET)-derived metrics could help in patient selection and stratification, shortening trial duration and reducing costs.

AREAS COVERED: This review focuses on the potential use of neuroimaging endpoints in the context of ALS therapeutic trials, providing insights on structural and functional neuroimaging, plexus and muscle alterations, glial involvement and neuroinflammation, envisioning how these surrogates of disease progression could be implemented in clinical trials. A PubMed search covering the past 15 years was performed.

EXPERT OPINION: Neuroimaging is essential in understanding ALS pathophysiology, aiding in disease progression tracking and evaluating therapeutic interventions. High costs, limited accessibility, lack of standardization, and patient tolerability limit their use in routine ALS care. Addressing these obstacles is essential for fully harnessing neuroimaging potential in improving diagnostics and treatment in ALS.}, } @article {pmid39985864, year = {2025}, author = {Wilk, LS and Hoveling, RJM and van Velthoven, MFAM and Nijs, HGT and Aalders, MCG}, title = {Optimizing the detection and characterization of bruises using multispectral imaging.}, journal = {Journal of forensic and legal medicine}, volume = {111}, number = {}, pages = {102811}, doi = {10.1016/j.jflm.2025.102811}, pmid = {39985864}, issn = {1878-7487}, mesh = {Humans ; *Contusions/pathology/diagnostic imaging ; Algorithms ; Photography ; *Hematoma/diagnostic imaging/pathology ; }, abstract = {The detection and visualization of sub-dermal hematoma (bruises) plays a key role in suspected physical abuse cases, as it aids in the evaluation of both victim and suspect statements. Current methods rely on visual inspection, frequently aided by alternate light sources (ALS). Ideally, ALS increase visual contrast by exploiting differences in light absorption (due to the formation and clearance of chromophores within the bruise). However, in practice the achievable contrast is often limited by light-scattering: the short-wavelength region of the spectrum (comprising most of the chromophore-specific absorption peaks), is also strongly scattered by the dermal tissue. This, in turn, limits achievable penetration depths, effectively obscuring deep-lying bruises. ALS-based contrast enhancement is further complicated by bruise healing; diffusion and enzymatic activity alter the chromophore concentrations as well as their 3D-distribution within the tissue. To overcome these critical limitations, we employ a multi-spectral camera (8 wavelengths simultaneously) in conjunction with both observer-based scoring and a contrast-quantification algorithm to determine the optimal wavelength for the detection and characterization of bruises over time. We show that (i) bruise contrast significantly increases at 480 nm, 620 nm and 850 nm and (ii) the wavelength achieving optimal contrast gradually changes from 850 nm to 578 nm-480 nm as the bruise heals.}, } @article {pmid39986312, year = {2025}, author = {Mizielinska, S and Hautbergue, GM and Gendron, TF and van Blitterswijk, M and Hardiman, O and Ravits, J and Isaacs, AM and Rademakers, R}, title = {Amyotrophic lateral sclerosis caused by hexanucleotide repeat expansions in C9orf72: from genetics to therapeutics.}, journal = {The Lancet. Neurology}, volume = {24}, number = {3}, pages = {261-274}, pmid = {39986312}, issn = {1474-4465}, support = {U19 AG063911/AG/NIA NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; UG3 NS103870/NS/NINDS NIH HHS/United States ; RF1 NS123052/NS/NINDS NIH HHS/United States ; R01 NS117461/NS/NINDS NIH HHS/United States ; R01 NS121125/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/diagnosis ; C9orf72 Protein/genetics ; *DNA Repeat Expansion/genetics ; }, abstract = {GGGGCC repeat expansions in C9orf72 are a common genetic cause of amyotrophic lateral sclerosis in people of European ancestry; however, substantial variability in the penetrance of the mutation, age at disease onset, and clinical presentation can complicate diagnosis and prognosis. The repeat expansion is bidirectionally transcribed in the sense and antisense directions into repetitive RNAs and translated into dipeptide repeat proteins, and both accumulate in the cortex, cerebellum, and the spinal cord. Furthermore, neuropathological aggregates of phosphorylated TDP-43 are observed in motor cortex and other cortical regions, and in the spinal cord of patients at autopsy. C9orf72 repeat expansions can also cause frontotemporal dementia. The GGGGCC repeat induces a complex interplay of loss-of-function and gain-of-function pathological mechanisms. Clinical trials using antisense oligonucleotides to target the GGGGCC repeat RNA have not been successful, potentially because they only target a single gain-of-function mechanism. Novel therapeutic approaches targeting the DNA repeat expansion, multiple repeat-derived RNA species, or downstream targets of TDP-43 dysfunction are, however, on the horizon, together with the development of diagnostic and prognostic biomarkers.}, } @article {pmid39987111, year = {2025}, author = {Zeng, L and Yang, F and Xu, D and Zhou, J and Qiao, G and Wu, M and Li, C and Yu, Y and Qiu, Y and Liu, J}, title = {Actual needs of patients with amyotrophic lateral sclerosis: a qualitative study from Wuhan, China.}, journal = {BMC palliative care}, volume = {24}, number = {1}, pages = {50}, pmid = {39987111}, issn = {1472-684X}, support = {2023AFD160//Hubei Provincial Natural Science Foundation and Traditional Chinese Medicine Innovation and Development Joint/ ; 2024AFD279//Department of Science and Technology, Hubei Province, China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/complications ; China ; Qualitative Research ; Male ; Female ; Middle Aged ; Aged ; Adult ; Quality of Life/psychology ; *Health Services Needs and Demand ; *Needs Assessment ; Medicine, Chinese Traditional/methods ; Interviews as Topic/methods ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disorder that significantly impacts individuals and families. Previous research on ALS has predominantly focused on its pathophysiology, genetic factors, and potential therapeutic interventions. While these aspects are essential for understanding and treating the disease, there has been a growing recognition of the importance of studying patients' actual needs. Understanding these needs is vital for developing patient-centered care models that can enhance the well-being of ALS patients. However, existing studies on patients' needs are often limited in scope. Many are conducted in Western countries, and the results may not be directly applicable to patients in other cultural and socioeconomic contexts. China, with its large population and diverse cultural, economic, and healthcare landscapes, presents a unique setting for studying ALS patients' needs. At the same time, traditional Chinese medicine (TCM) practices are deeply ingrained in their healthcare system and may affect the way people with ALS seek treatment and manage their condition. Therefore, these differences may lead to differences in the actual needs of ALS patients in China. In conclusion, this qualitative study on the actual needs of ALS patients in China aims to bridge the gap in the existing research. By exploring these needs, it can provide valuable insights for healthcare providers, policymakers, and researchers, ultimately contributing to the improvement of care and quality of life for ALS patients in China.

METHOD: We carried out a qualitative study using an empirical phenomenological approach. Individual in-depth interviews were performed among 22 people with ALS from the motor neuron disease rehabilitation center of a tertiary Chinese medicine hospital in China, and the interview content was analyzed qualitatively. Interview recordings were converted to text content by NVivo 11.0 software and analyzed using Colaizzi's phenomenological method.

RESULT: Three main themes were identified in this study: (1) Demand for healthcare services, (2) Emotional requirements, (3) Functional requirements. In addition, 8 sub-themes were extracted as the actual needs of ALS patients.

CONCLUSION: This study is based on the real experience of ALS patients after diagnosis, and a deep understanding of these experiences can explore the actual needs of patients from many aspects and give reasonable advice and help. Given the particularity of the disease and the uncertainty of treatment, patients will have practical needs for relevant medical support, emotional requirements, physical functions, and other aspects during the period of illness, and the corresponding support is an effective measure to reduce the burden on patients.}, } @article {pmid39987285, year = {2025}, author = {Fang, M and Zhou, Y and He, K and Lu, Y and Tao, F and Huang, H}, title = {Glucose Metabolic Reprogramming in Microglia: Implications for Neurodegenerative Diseases and Targeted Therapy.}, journal = {Molecular neurobiology}, volume = {62}, number = {7}, pages = {8204-8221}, pmid = {39987285}, issn = {1559-1182}, support = {82204651//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Microglia/metabolism/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology/therapy ; *Glucose/metabolism ; Animals ; *Molecular Targeted Therapy ; Glycolysis ; Metabolic Reprogramming ; }, abstract = {As intrinsic immune cells in the central nervous system, microglia play a crucial role in maintaining brain homeostasis. Microglia can transition from homeostasis to various responsive states in reaction to different external stimuli, undergoing corresponding alterations in glucose metabolism. In neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), microglial glucose metabolic reprogramming is widespread. This reprogramming leads to changes in microglial function, exacerbating neuroinflammation and the accumulation of pathological products, thereby driving the progression of neurodegeneration. This review summarizes the specific alterations in glucose metabolism within microglia in AD, PD, ALS, and MS, as well as the corresponding treatments aimed at reprogramming glucose metabolism. Compounds that inhibit key glycolytic enzymes like hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2), or activate regulators of energy metabolism such as AMP-activated protein kinase (AMPK), have shown significant potential in the treatment of various neurodegenerative diseases. However, current research faces numerous challenges, including side effects and blood-brain barrier (BBB) penetration of compounds. Screening relevant drugs from natural products, especially flavonoids, is a reliable approach. On the one hand, longtime herbal medical practices provide a certain degree of assurance regarding clinical safety, and their chemical properties contribute to effective BBB permeability. On the other hand, the concurrent anti-tumor and anti-neuroinflammatory activities of flavonoids suggest that regulation of glucose metabolism reprogramming might be a potential common mechanism of action. Notably, considering the dynamic nature of microglial metabolism, there is an urgent need to develop technologies for real-time monitoring of glucose metabolism processes, which would significantly advance research in this field.}, } @article {pmid39987392, year = {2025}, author = {Liu, Y and Xiang, J and Gong, H and Yu, T and Gao, M and Huang, Y}, title = {The Regulation of TDP-43 Structure and Phase Transitions: A Review.}, journal = {The protein journal}, volume = {44}, number = {2}, pages = {113-132}, pmid = {39987392}, issn = {1875-8355}, support = {22477022//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; Phase Transition ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Frontotemporal Dementia/metabolism/genetics/pathology ; Animals ; Protein Processing, Post-Translational ; }, abstract = {The transactive response DNA binding protein 43 (TDP-43) is an RNA/DNA-binding protein that is involved in a number of cellular functions, including RNA processing and alternative splicing, RNA transport and translation, and stress granule assembly. It has attracted significant attention for being the primary component of cytoplasmic inclusions in patients with amyotrophic lateral sclerosis or frontotemporal dementia. Mounting evidence suggests that both cytoplasmic aggregation of TDP-43 and loss of nuclear TDP-43 function contribute to TDP-43 pathology. Furthermore, recent studies have demonstrated that TDP-43 is an important component of many constitutive or stress-induced biomolecular condensates. Dysregulation or liquid-to-gel transition of TDP-43 condensates can lead to alterations in TDP-43 function and the formation of TDP-43 amyloid fibrils. In this review, we summarize recent research progress on the structural characterization of TDP-43 and the TDP-43 phase transition. In particular, the roles that disease-associated genetic mutations, post-translational modifications, and extrinsic stressors play in the transitions among TDP-43 monomers, liquid condensates, solid condensates, and fibrils are discussed. Finally, we discuss the effectiveness of available regulators of TDP-43 phase separation and aggregation. Understanding the underlying mechanisms that drive the pathological transformation of TDP-43 could help develop therapeutic strategies for TDP-43 pathology.}, } @article {pmid39987720, year = {2025}, author = {Ohnari, K and Mafune, K and Adachi, H}, title = {Usefulness of the Gold Coast criteria in diagnosing fast-progressing amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {471}, number = {}, pages = {123418}, doi = {10.1016/j.jns.2025.123418}, pmid = {39987720}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Disease Progression ; Retrospective Studies ; Aged ; Electromyography ; Sensitivity and Specificity ; Adult ; }, abstract = {The Gold Coast criteria are reportedly more sensitive for diagnosing amyotrophic lateral sclerosis (ALS) than the previously used criteria; however, the sensitivity of these sets of criteria among groups classified according to their prognosis has not been compared. In this study, we examined the difference in the sensitivity for ALS diagnosis among these criteria, especially in patients with fast-progression ALS. We enrolled 95 patients diagnosed with ALS and retrospectively classified them into three groups based on the interval between disease onset and death or tracheostomy. We retrospectively examined the number of patients meeting the Gold Coast, Awaji, or revised El Escorial criteria (rEEC) (definite/probable/possible) at initial clinical examination and electromyography and compared the rates of diagnosis according to each set of criteria among the three groups. The sensitivity of the Gold Coast criteria was significantly higher than that of the Awaji and rEEC criteria (sensitivity, 92.6 % vs. 71.8 % vs. 71.7 %, p < 0.001). The sensitivity of the Gold Coast criteria in patients with fast progression (n = 30) was significantly higher than that of the Awaji and rEEC criteria (sensitivity, 100 % vs. 73.3 % vs. 73.3 %, p = 0.001). Most patients diagnosed only based on the Gold Coast criteria had lower motor signs. Hence, the Gold Coast criteria are particularly useful for diagnosing fast-progression ALS.}, } @article {pmid39989203, year = {2025}, author = {Wu, J and Sun, C and Xu, Y and Fan, D and Ye, S}, title = {The contralateral co-movement test in a Chinese population with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {426-435}, doi = {10.1080/21678421.2025.2467959}, pmid = {39989203}, issn = {2167-9223}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; China ; *Functional Laterality/physiology ; Movement/physiology ; Prospective Studies ; East Asian People ; }, abstract = {INTRODUCTION: Mirror movements (MMs) are often overlooked in patients with amyotrophic lateral sclerosis (ALS). Although the contralateral co-movement (COMO) test can be used to evaluate MMs in patients with ALS, it lacks a systematic evaluation. The aim of this study was to validate the effectiveness of the Chinese version of the COMO test in a Chinese ALS population.

METHODS: We prospectively enrolled 173 patients with ALS as the disease group and 28 healthy individuals as controls. All participants were evaluated using the Chinese version of the COMO test. Univariate analysis and multiple linear regression were used to compare differences between groups. Subgroup analysis of the COMO scores was performed based on different disease characteristics.

RESULTS: The COMO score in the ALS group was significantly greater (5.00% [1.67-10.00]) than that in the healthy control group (1.67% [0.00-3.33]). After adjusting for confounders, this difference remained significant. Multivariate linear analysis suggested that the upper motor neuron (UMN) score independently predicted the COMO score (P < 0.001). The COMO score was not affected by different onset regions or lateralizations. Propensity score matching revealed no significant difference in COMO scores between uninvolved limb segments and the corresponding limb segments in other patients. The Cronbach's α of the Chinese COMO test was 0.621.

CONCLUSION: The Chinese COMO test can serve as a potential tool for assessing MMs in Chinese patients with ALS. The UMN score is a factor influencing the COMO score. The COMO test can provide objective evidence for ALS characteristics and the severity of UMN damage.}, } @article {pmid39989811, year = {2025}, author = {Marzi, I and Pieraccini, G and Bemporad, F and Chiti, F}, title = {Detection of an Intermediate in the Unfolding Process of the N-Terminal Domain of TDP-43.}, journal = {ACS omega}, volume = {10}, number = {6}, pages = {5616-5633}, pmid = {39989811}, issn = {2470-1343}, abstract = {TAR DNA-binding protein 43 (TDP-43) is a nuclear protein accumulating in intraneuronal cytoplasmic inclusions associated with amyotrophic lateral sclerosis, frontotemporal lobar degeneration with tau-negative/ubiquitin-positive inclusions, and limbic-predominant age-related TDP-43 encephalopathy. Oligomerization of full-length TDP-43, driven by its N-terminal domain (NTD), is essential for its function, but aberrant self-assembly also promotes liquid-liquid phase separation and formation of solid inclusions. Building on recent all-atom molecular dynamics simulations and using various biophysical approaches, we identified a partially unfolded state accumulating during unfolding of TDP-43 NTD, before the major energy barrier of unfolding is crossed. Intrinsic fluorescence spectroscopy coupled to a stopped-flow device at high urea concentration reveals that the intermediate state has a fluorescence emission distinct from those of the native and unfolded states and forms within the 14 ms dead time. Conventional fluorescence spectroscopy shows it still accumulates at moderate urea concentration. Circular dichroism and H/D exchange results show a species with an intermediate content of secondary structure and a distorted β-sheet, whereas SYPRO orange fluorescence indicates an open conformation with more exposed hydrophobic regions compared to the native state. Importantly, this intermediate is observed even at low protein concentration, when TDP-43 NTD is largely monomeric, indicating that its formation is independent of the initial TDP-43 NTD oligomeric state. Dynamic light scattering at high protein concentration shows that the intermediate is a partially folded dimer. The intermediate forms upon chemical denaturation and does not occur under thermal unfolding. Overall, the findings highlight the presence of one more partially folded state for TDP-43 NTD, underlining its high structural plasticity and suggesting that its distinct unfolding pathway may play a critical role in both its functional and pathological behaviors.}, } @article {pmid39989851, year = {2025}, author = {Rea, D and Tham, C and Tham, TC}, title = {Endoscopic calabash technique for gastric mesenchymal tumours: A low hanging fruit or a novel endoscopic technique?.}, journal = {World journal of gastrointestinal endoscopy}, volume = {17}, number = {2}, pages = {101676}, pmid = {39989851}, issn = {1948-5190}, abstract = {The term subepithelial lesions encompasses a wide array of pathology of which numerous benign and malignant pathologies are grouped. A subset of these lesions are termed gastric mesenchymal tumours of which some have innate malignant potential. Currently there is various guidance on the recommended approach to the investigation and management of these lesions and there exists multiple methods of resection. Lin et al have developed and proposed a new method of resection of these gastric mesenchymal tumours within the field of endoscopy, a procedure they have termed endoscopic calabash ligation and resection. This editorial aims to outlay the current landscape for gastric mesenchymal tumours with regards to the various guidelines and resection techniques while comparing Lin et al's new technique to those that are already established in the field of endoscopy. Advancements in endoscopy that maintain or improve patient outcomes compared to the gold standard approach are exciting developments. Lin et al's study suggests that their technique is comparable in regard to patient outcomes while simultaneously being more efficient in its use of hospital resources including procedural time. Whilst the data and analysis proposed in the study is promising, there are areas that need to be addressed before advocating the procedure for widespread use. However, with further studies and analysis this may be foreseeable in the future.}, } @article {pmid39990107, year = {2025}, author = {Zhao, S and Chen, R and An, Y and Zhang, Y and Ma, C and Gao, Y and Lu, Y and Yang, F and Bai, X and Zhang, J}, title = {Optineurin overexpression ameliorates neurodegeneration through regulating neuroinflammation and mitochondrial quality in a murine model of amyotrophic lateral sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1522073}, pmid = {39990107}, issn = {1663-4365}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neurons (MNs). Genetic mutations in Optineurin (OPTN) and Superoxide Dismutase 1 (SOD1) have been identified as causal factors for ALS. OPTN immunopositive inclusions have been confirmed in the cases of ALS with SOD1 mutations. However, the role of the OPTN gene in ALS caused by SOD1 mutations is ambiguous.

METHODS: The murine Optn lentivirus and empty vector lentivirus were injected into SOD1 [G93A] mice after discovering variations in Optn expression over time. The phenotype onset date, life span, locomotor activity, and pathological changes in the spinal cord were determined and recorded subsequently. In addition, the influences on cellular apoptosis, mitochondrial dynamics, mitophagy, and neuroinflammation were further investigated.

RESULTS: Optn expression was increased in the spinal cord of SOD1 [G93A] mice at the pre-symptomatic phase, but decreased after disease onset. Optn overexpression led to a 9.7% delay in the onset of disease and improved motor performance in SOD1 [G93A] mice. Optn overexpression also ameliorated the MNs loss by 46.8%. Moreover, all these ameliorating effects induced by Optn overexpression might be due to the inhibition of cellular apoptosis, improvement of mitochondrial quality, regulation of mitochondrial dynamics, promotion of mitophagy, and anti-inflammatory properties.

CONCLUSION: Our data demonstrate that Optn overexpression protects MNs, inhibites cellular apoptosis, improves mitochondrial quality and regulates neuroinflamation in SOD1 [G93A] mice at the pre-symptomatic stage.}, } @article {pmid39990425, year = {2025}, author = {Chakraborty, A and Mitra, J and Malojirao, VH and Kodavati, M and Mandal, SM and Gill, SK and Sreenivasmurthy, SG and Vasquez, V and Mankevich, M and Bosch, LVD and Garruto, RM and Robey, IF and Krishnan, B and Ghosh, G and Hegde, M and Hazra, T}, title = {Fructose-2,6-bisphosphate restores TDP-43 pathology-driven genome repair deficiency in motor neuron diseases.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.13.623464}, pmid = {39990425}, issn = {2692-8205}, abstract = {TAR DNA-binding protein 43 (TDP-43) proteinopathy plays a critical role in neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). In our recent discovery, we identified that TDP-43 plays an essential role in DNA double-strand break (DSB) repair via the non-homologous end joining (NHEJ) pathway. Here, we found persistent DNA damage in the brains of ALS/FTD patients, primarily in the transcribed regions of the genome. We further investigated the underlying mechanism and found that polynucleotide kinase 3'-phosphatase (PNKP) activity was severely impaired in the nuclear extracts of both patient brains and TDP-43-depleted cells. PNKP is a key player in DSB repair within the transcribed genome, where its 3'-P termini processing activity is crucial for preventing persistent DNA damage and neuronal death. The inactivation of PNKP in ALS/FTD was due to reduced levels of its interacting partner, phosphofructo-2-kinase fructose 2,6 bisphosphatase (PFKFB3), and its biosynthetic product, fructose-2,6-bisphosphate (F2,6BP), an allosteric modulator of glycolysis. Recent work from our group has shown that F2,6BP acts as a positive modulator of PNKP activity in vivo. Notably, exogenous supplementation with F2,6BP restored PNKP activity in nuclear extracts from ALS/FTD brain samples and patient-derived induced pluripotent stem (iPS) cells harboring pathological mutations. Furthermore, we demonstrate that supplementation of F2,6BP restores genome integrity and partially rescues motor phenotype in a Drosophila model of ALS. Our findings underscore the possibility of exploring the therapeutic potential of F2,6BP or its analogs in TDP-43 pathology-associated motor neuron diseases.}, } @article {pmid39991082, year = {2025}, author = {Chen, G and Cao, Y and Du, X and Cui, J and Zeng, X and Yang, H and Ren, Z and Xu, K}, title = {The Clinical Research Landscape of Intracranial Nicardipine for Aneurysmal Subarachnoid Hemorrhage: Insights From Bibliometric Analysis.}, journal = {Drug design, development and therapy}, volume = {19}, number = {}, pages = {1129-1146}, pmid = {39991082}, issn = {1177-8881}, mesh = {*Nicardipine/administration & dosage/therapeutic use ; *Subarachnoid Hemorrhage/drug therapy ; Humans ; *Bibliometrics ; }, abstract = {BACKGROUND: The 2023 American Heart Association/American Stroke Association guideline and Wessels et al's 2024 randomized controlled trial highlight the potential benefits of intracranial nicardipine for aneurysmal subarachnoid hemorrhage (aSAH). This study aims to systematically identify the publication trends and research hotspots in this field through bibliometric analysis.

METHODS: Relevant publications were sourced from the Web of Science Core Collection (WoSCC). Bibliometric and visualization analyses were conducted using the online tools of the WoSCC database and CiteSpace 6.2.R6.

RESULTS: Analysis of 28 articles published by 158 researchers from 55 institutions across 8 countries revealed an intermittent small-scale growth in annual publication volume from 1994 to 2024, with a continuous rise in annual citation volume since 2005, indicating growing interest in the field. Japan, Germany, and the United States of America (USA) were the most prolific and influential countries. Institutions such as Tokyo Women's Medical University showed particularly significant contributions. Kasuya Hidetoshi was the most prolific author. There was little global collaboration among countries, institutions, and authors, with distinct regional research characteristics: Japan and Germany focused on intracranial implants, while the USA concentrated on intrathecal injections. Major publishing and co-cited journals included Neurocritical Care, Acta Neurochirurgica, Journal of Neurosurgery, and Stroke. Popular keywords in 2024 included "preventing cerebral vasospasm", "delayed cerebral ischemia", "outcome events", and "clinical trials", revealing current research hotspots.

CONCLUSION: This study maps the global clinical research landscape of intracranial application of nicardipine for aSAH from 1994 to 2024, providing valuable references and guidance for future research.}, } @article {pmid39992655, year = {2025}, author = {Liu, X and Shang, H and Wei, Q and Yao, X and Lian, L and Dang, J and Jia, R and Wu, Z and Li, H and Niu, Q and Cheng, X and Zou, Z and Chen, S and Zhang, M and Liu, Y and Liu, Y and Liu, Q and Huang, X and Wang, H and Feng, H and Wang, S and Fan, D and , }, title = {Tetramethylpyrazine Nitrone in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2461055}, pmid = {39992655}, issn = {2574-3805}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Pyrazines/therapeutic use/administration & dosage ; Male ; Female ; Middle Aged ; Aged ; Double-Blind Method ; China ; Treatment Outcome ; }, abstract = {IMPORTANCE: Tetramethylpyrazine nitrone has exhibited promising results in improving motor dysfunction in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).

OBJECTIVE: To evaluate the safety and efficacy of orally administered tetramethylpyrazine nitrone in patients with ALS.

This phase 2, multicenter, double-masked, placebo-controlled, randomized clinical trial was conducted from December 24, 2020, through July 14, 2023, in 11 centers in China, with a 180-day follow-up. Patients aged 45 to 70 years, with ALS onset within 2 years, ALS Functional Rating Scale-Revised (ALSFRS-R) scores of at least 2 points on each item, and forced vital capacity (FVC) of at least 80% were included. Patients experienced a 1- to 4-point decrease in ALSFRS-R score during a 3-month screening period.

INTERVENTIONS: Patients were randomly assigned 1:1:1 to receive low-dose tetramethylpyrazine nitrone (600 mg twice daily), high-dose tetramethylpyrazine nitrone (1200 mg twice daily), or placebo (twice daily) for 180 days.

MAIN OUTCOMES AND MEASURES: The primary outcome was change in ALSFRS-R score (range of 0-48, with lower scores indicating worse function) from baseline to 180 days. The secondary outcomes were changes in FVC, grip strength, ALS Assessment Questionnaire-40 (ALSAQ-40) score, and end point events. Safety outcomes included adverse events.

RESULTS: A total of 155 patients (mean [SD] age, 55.0 [6.5] years; 115 men [74.2%]) were randomized (51 [32.9%] to the low-dose tetramethylpyrazine nitrone group, 52 [33.6%] to the high-dose tetramethylpyrazine nitrone group, and 52 [33.6%] to the placebo group). No significant differences were observed in ALSFRS-R score changes between low-dose tetramethylpyrazine nitrone (least squares [LS] mean difference, -0.89 points; 95% CI -3.25 to 1.48 points) and high-dose tetramethylpyrazine nitrone (LS mean difference, -0.20 points; 95% CI -2.48 to 2.07 points) compared with placebo. High-dose tetramethylpyrazine nitrone showed a significantly slower decline in grip strength at day 180 (LS mean difference, 2.46 kg; 95% CI, 0.15-4.76 kg). In a subgroup of patients younger than 65 years with slower disease progression, tetramethylpyrazine nitrone significantly attenuated the decline in grip strength (LS mean difference, 3.63 kg; 95% CI, 0.84-6.41 kg), bulbar scores (LS mean difference, 0.66 points; 95% CI, 0.03-1.29 points), and respiratory scores (LS mean difference, 0.54 points; 95% CI, 0.03-1.06 points). Adverse events were mostly mild or moderate, with no severe treatment-related adverse events or deaths.

CONCLUSIONS AND RELEVANCE: This randomized clinical trial demonstrates that tetramethylpyrazine nitrone is safe and well-tolerated in patients with ALS. There was no difference in the primary end point across the low-dose, high-dose, and placebo groups, with significant benefits in a subgroup of younger patients with slower disease progression.

TRIAL REGISTRATION: ChiCTR Identifier: ChiCTR2000039689.}, } @article {pmid39992908, year = {2025}, author = {Nemeth, T and Zarnocki, A and Ladanyi, A and Papp, C and Ayaydin, F and Szebeni, GJ and Gacser, A}, title = {PCR-based CRISPR/Cas9 system for fluorescent tagging: A tool for studying Candida parapsilosis virulence.}, journal = {PloS one}, volume = {20}, number = {2}, pages = {e0312948}, pmid = {39992908}, issn = {1932-6203}, mesh = {*CRISPR-Cas Systems/genetics ; *Candida parapsilosis/pathogenicity/genetics/isolation & purification ; Animals ; Mice ; Virulence/genetics ; *Polymerase Chain Reaction/methods ; Macrophages/microbiology ; Humans ; Candidiasis/microbiology ; Cell Line ; }, abstract = {Candida parapsilosis is persistent in a hospital environment hence it is often associated with nosocomial infections especially amongst low-birth weight neonates. Genetic modification is therefore important to characterise the physiological and virulence related properties of this fungus. A PCR-based CRISPR/Cas9 system has been adopted to facilitate the generation of fluorescent tagged prototroph isolates. We examined a total of eight fluorescent protein coding genes, out of which three were found to be applicable for simultaneous utilisation. We investigated three clinical isolates of C. parapsilosis in terms of their adherence to silicone and their uptake by J774.2 murine macrophages in competition assays. Interestingly, we found significant differences between them in both experiments where GA1 isolate was significantly less resistant to macrophage uptake and CDC317 was significantly more adherent to silicone material. In silico analysis of the agglutinin-like sequences (Als) exposed remarkable diversity in this protein family and additionally, the thorough analysis of the ALS genes revealed evidence of formation of a new gene by intrachromosomal recombination in the GA1 isolate. Finally, we provide a step by step protocol for the application of the PCR-based CRISPR/Cas9 system for fluorescently labelling C. parapsilosis isolates.}, } @article {pmid39993604, year = {2025}, author = {Huertas, A and Moghanaki, D and Siva, S}, title = {Comment on Wu et al's article on toxicity in patients receiving radiotherapy for ultracentral stage I non-small cell lung cancer.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {206}, number = {}, pages = {110805}, doi = {10.1016/j.radonc.2025.110805}, pmid = {39993604}, issn = {1879-0887}, } @article {pmid39993605, year = {2025}, author = {David Wu, CH and Whelan, TJ and Swaminath, A}, title = {Response to: Comment on Wu et al's article on toxicity in patients receiving radiotherapy for ultracentral stage I non-small cell lung cancer.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {206}, number = {}, pages = {110804}, doi = {10.1016/j.radonc.2025.110804}, pmid = {39993605}, issn = {1879-0887}, } @article {pmid39994160, year = {2025}, author = {Dubey, PR and Kaur, G and Shukla, R}, title = {Nano-mediated Management of Metal Toxicity-induced Neurodegeneration: A Critical Review.}, journal = {Molecular neurobiology}, volume = {62}, number = {7}, pages = {8400-8419}, pmid = {39994160}, issn = {1559-1182}, mesh = {Humans ; Animals ; *Neurodegenerative Diseases/chemically induced/therapy ; *Metals, Heavy/toxicity ; *Nanotechnology/methods ; *Nanoparticles/therapeutic use ; Oxidative Stress/drug effects ; Drug Delivery Systems/methods ; }, abstract = {Heavy metals, omnipresent in the environment, though imperative in trace quantities for human physiology, become a serious health hazard due to their toxicity. Copper, arsenic, lead, iron, and mercury are some examples of the heavy metals responsible for oxidative stress, which is one of the primary factors behind neurodegenerative diseases like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Neurodegeneration is caused by toxicity due to environmental exposure to these toxic substances or genetic variation. Conventional therapies, relying on chelation and antioxidants, suffer from the broader perspective of metal removal in a non-selective manner and poor targeting of the brain. In this respect, treatments based on nanotechnology that employ nanoparticles such as dendrimers, micelles, and liposomes constitute a promising interest in enhancing drug delivery with minimal neurotoxicity. The present review outlines the heavy metals responsible for neurodegenerative diseases, their pathophysiology, management strategies available at present, and the scope of nanotechnology intervention in overcoming shortcomings of conventional therapies. The genetic influence of heavy metals on neurological health is also part of this article.}, } @article {pmid39994742, year = {2025}, author = {Djukic, S and Zhao, Z and Jørgensen, LMH and Bak, AN and Jensen, DB and Meehan, CF}, title = {TDP-43 pathology is sufficient to drive axon initial segment plasticity and hyperexcitability of spinal motoneurones in vivo in the TDP43-ΔNLS model of Amyotrophic Lateral Sclerosis.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {42}, pmid = {39994742}, issn = {2051-5960}, support = {R370-2021-1109//The Lundbeck Foundation/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics/physiopathology/metabolism ; *Motor Neurons/pathology/physiology ; Disease Models, Animal ; *DNA-Binding Proteins/genetics/metabolism ; *Spinal Cord/pathology/physiopathology ; Mice, Transgenic ; *Neuronal Plasticity/physiology ; Mice ; *Axon Initial Segment/pathology/physiology ; Action Potentials/physiology ; Male ; Humans ; *Axons/pathology ; }, abstract = {A hyperexcitability of the motor system is consistently observed in Amyotrophic Lateral Sclerosis (ALS) and has been implicated in the disease pathogenesis. What drives this hyperexcitability in the vast majority of patients is unknown. This is important to know as existing treatments simply reduce all neuronal excitability and fail to distinguish between pathological changes and important homeostatic changes. Understanding what drives the initial pathological changes could therefore provide better treatments. One challenge is that patients represent a heterogeneous population and the vast majority of cases are sporadic. One pathological feature that almost all (~97%) cases (familial and sporadic) have in common are cytoplasmic aggregates of the protein TDP-43 which is normally located in the nucleus. In our experiments we investigated whether this pathology was sufficient to increase neuronal excitability and the mechanisms by which this occurs. We used the TDP-43(ΔNLS) mouse model which successfully recapitulates this pathology in a controllable way. We used in vivo intracellular recordings in this model to demonstrate that TDP-43 pathology is sufficient to drive a severe hyper-excitability of spinal motoneurones. Reductions in soma size and a lengthening and constriction of axon initial segments were observed, which would contribute to enhanced excitability. Resuppression of the transgene resulted in a return to normal excitability parameters by 6-8 weeks. We therefore conclude that TDP-43 pathology itself is sufficient to drive a severe but reversible hyperexcitability of spinal motoneurones.}, } @article {pmid39995075, year = {2025}, author = {Manco, C and Righi, D and Primiano, G and Romano, A and Luigetti, M and Leonardi, L and De Stefano, N and Plantone, D}, title = {Peripherin, A New Promising Biomarker in Neurological Disorders.}, journal = {The European journal of neuroscience}, volume = {61}, number = {4}, pages = {e70030}, pmid = {39995075}, issn = {1460-9568}, mesh = {Humans ; *Peripherins/metabolism/genetics/blood ; Biomarkers/metabolism/blood ; Animals ; *Nervous System Diseases/metabolism/diagnosis ; }, abstract = {Peripherin is a class III intermediate filament protein that has recently gained attention as a potential biomarker for axonal damage in the peripheral nervous system. This review examines peripherin gene expression, protein structure, and its functions in both healthy and diseased states. Peripherin is predominantly expressed in the peripheral nervous system, especially in motor and sensory neurons, and plays a critical role in neurite growth, stability, and axonal transport during myelination. Its expression is regulated by various cytokines and undergoes several post-transcriptional modifications. Peripherin interacts with multiple proteins, including neurofilaments and kinases, influencing cytoskeletal dynamics and neuronal functions. The review also explores peripherin involvement in several neurological disorders, such as Amyotrophic Lateral Sclerosis, where its abnormal expression and aggregation contribute to disease pathology. Additionally, peripherin has been linked to polyneuropathies, traumatic axonal injury, and diabetic neuropathy, suggesting its broader relevance as a biomarker in these conditions. The potential of peripherin as a biomarker is further supported by recent studies using ultrasensitive detection methods, which have identified elevated peripherin levels in the serum of patients with neurological diseases. Despite the promising findings, the application of peripherin as a biomarker in clinical settings remains limited, primarily due to challenges in its detection and the need for further validation in diverse patient populations. Future research directions include the development of more sensitive assays and the exploration of peripherin's role in non-neuronal tissues, which may expand its diagnostic and therapeutic potential.}, } @article {pmid39995102, year = {2025}, author = {Perdikakis, M and Papadimitrakis, D and Floros, N and Tzavellas, E and Piperi, C and Gargalionis, AN and Papavassiliou, AG}, title = {Diagnostic role of circulating cell-free DNA in schizophrenia and neuro-degenerative disorders.}, journal = {Biomarkers in medicine}, volume = {19}, number = {5}, pages = {165-176}, pmid = {39995102}, issn = {1752-0371}, mesh = {Humans ; *Cell-Free Nucleic Acids/blood ; *Schizophrenia/diagnosis/blood/genetics ; *Neurodegenerative Diseases/diagnosis/blood/genetics ; Biomarkers/blood ; }, abstract = {Over the past few years, circulating cell-free DNA (cfDNA) research has grown exponentially. Several studies have associated the release of cfDNA in the bloodstream, cerebrospinal fluid, and other body fluids with increased apoptosis and cell death. Therefore, their possible use as biomarkers for cancer and other diseases has emerged. The diagnosis of pathological entities such as schizophrenia and neurodegenerative diseases involves many challenges and requires ruling out conditions with similar symptoms. In this context, cfDNA could serve as a valuable diagnostic biomarker. This study encompasses the recent bibliography and research regarding the utilization of circulating cfDNA for diagnostic purposes in schizophrenia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. This minimally invasive method has provided important evidence regarding the diagnosis of the aforementioned diseases although further research is necessary.}, } @article {pmid39995125, year = {2025}, author = {Kalinin, AP and Zubkova, ES and Menshikov, MY and Parfyonova, YV}, title = {ISR Modulators in Neurological Diseases.}, journal = {Current neuropharmacology}, volume = {23}, number = {10}, pages = {1184-1214}, pmid = {39995125}, issn = {1875-6190}, support = {23-15-00539//Russian Science Foundation, RSF/ ; }, mesh = {Humans ; *Nervous System Diseases/metabolism/drug therapy ; Animals ; *Signal Transduction/drug effects/physiology ; *Stress, Physiological/physiology/drug effects ; }, abstract = {The dysfunction of different cells lies in the pathogenesis of neurological diseases and is usually associated with cellular stress. Various stressors trigger the integrated stress response (ISR) signaling, whose highly conserved mechanism is primarily aimed at protecting a stress-exposed cell to cope as safely as possible with such stressful conditions. On the contrary, if a cell is unable to cope with excessive stress, the ISR can induce apoptosis. The ISR mechanism, whose main stage is the inhibition of translation machinery in favor of the synthesis of specific proteins, including the transcription factors ATF3, ATF4, CEBPA, and CEBPB, which function only as dimers and determine the uniqueness of the ISR response in each individual case, thus ensures different outcomes of the ISR. Inhibition of global protein synthesis is achieved through phosphorylation of eIF2α by PERK, HRI, PKR, or GCN2. To date, a number of compounds have been developed that modulate the ISR, including activators and inhibitors of the abovementioned ISR kinases as well as modulators of p-eIF2α dephosphorylation. They target different ISR stages, allowing a broad ISR modulation strategy. At the same time, there are no drugs that are both exceptionally safe and effective for the treatment of several neurological diseases, so there is an urgent need for new approaches to the treatment of these disorders. In this review, we represent ISR signaling as an important participant in the pathogenesis of neurological diseases. We also describe how various ISR modulators may become a part of future therapies for these diseases.}, } @article {pmid39995927, year = {2025}, author = {McDonald, TS and Cui, CS and Lerskiatiphanich, T and Marallag, J and Lee, JD}, title = {Metabolic rate and insulin-independent glucose uptake increase in a TDP-43[Q331K] mouse model of amyotrophic lateral sclerosis.}, journal = {Heliyon}, volume = {11}, number = {3}, pages = {e42482}, pmid = {39995927}, issn = {2405-8440}, abstract = {Impaired glucose regulation is increasingly recognised in amyotrophic lateral sclerosis (ALS), yet the precise mechanisms remain unclear. Here, we investigated energy balance and glucose control in TAR DNA-binding protein 43 (TDP-43)[Q331K] mice, a model of ALS, at both the early and late symptomatic stages of disease. Mutant TDP-43[Q331K] mice and non-transgenic controls underwent indirect calorimetry, as well as intraperitoneal glucose, insulin, and glucagon tolerance testing. We also examined plasma hormone levels and quantified α- and β-cell areas in pancreatic islets. Throughout disease progression, TDP-43[Q331K] mice exhibited elevated metabolic rates, with a transient increase in food intake at the early stages. At the later stages of disease, heightened glucose uptake was observed despite unchanged insulin secretion or tolerance, indicating mechanisms independent of insulin. Notably, TDP-43[Q331K] mice maintained fasting blood glucose levels even when circulating glucagon levels were reduced, suggesting that alternative pathways contribute to preserving euglycemia. These findings reveal a distinct metabolic profile in TDP-43[Q331K] mice, underscoring the complexity of glucose dyshomeostasis in ALS.}, } @article {pmid39996130, year = {2025}, author = {Dilliott, AA and Costanzo, MC and Bandres-Ciga, S and Blauwendraat, C and Casey, B and Hoang, Q and Iwaki, H and Jang, D and Kim, JJ and Leonard, HL and Levine, KS and Makarious, M and Nguyen, TT and Rouleau, GA and Singleton, AB and Smadbeck, P and Solle, J and Vitale, D and Nalls, M and Flannick, J and Burtt, NP and Farhan, SMK}, title = {The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.}, journal = {Neurology. Genetics}, volume = {11}, number = {2}, pages = {e200246}, pmid = {39996130}, issn = {2376-7839}, support = {U24 HG011453/HG/NHGRI NIH HHS/United States ; }, abstract = {Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathologic mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across 10 different phenotypic groups, including neurologic conditions such as Alzheimer disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively use the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for patients with neurodegenerative disease.}, } @article {pmid39996599, year = {2025}, author = {Chowdhury, RN and Azam, MA and Azam, SA and Lana, S and Culver, EN and Garruto, RM and Wander, K}, title = {Elevated Serum MCP-2 and TARC Associated With Increased Risk of Death in Guamanian ALS Patients.}, journal = {European journal of neurology}, volume = {32}, number = {3}, pages = {e70088}, pmid = {39996599}, issn = {1468-1331}, support = {//Sigma Xia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/blood ; Male ; Female ; Middle Aged ; *Chemokine CCL2/blood ; Aged ; Adult ; *Chemokine CCL20/blood ; Guam/epidemiology ; }, abstract = {BACKGROUND: This study explores the relationship between inflammation and longevity in a high-incidence focus of amyotrophic lateral sclerosis (ALS) in post-WWII Guam. Characteristics of this focus include the sudden appearance of the disease in high numbers and the unusually long lifespan (without medical interventions) seen in some cases. We used bio-banked specimens to evaluate the relationship between serum immunoregulators and survival time.

METHODS: We evaluated sera from 69 Guam ALS cases collected within 2 years of symptom onset by NIH researchers from 1950 to 1983 for 11 immunoregulators via ELISA (CRP, eotaxin-1, RANTES, IL-6, IL-8, IL-10, IFN-γ, IP-10, MCP-1, MCP-2 and TARC). Factor analysis identified two factors responsible for ~68% of the variation in the data. We estimated Cox proportional hazards models to identify immunoregulators associated with time to death.

RESULTS: Each 10-unit increase in factor 2 cytokines (MCP-2 and TARC) was associated with a 38% increase in the risk of death (HR: 1.38; 95% CI: 1.19, 1.65; p: 0.00).

DISCUSSION: Like sporadic ALS cases worldwide, inflammation is associated with a shortened lifespan in Guamanian ALS; more specifically, our findings suggest serum levels of MCP-2 and TARC at onset may predict disease duration. Further investigation is needed to determine the role of these immunoregulators in disease prognosis and as targets for diagnostic and therapeutic interventions.}, } @article {pmid39996723, year = {2025}, author = {Deecke, L and Ohlei, O and Goldeck, D and Homann, J and Toepfer, S and Demuth, I and Bertram, L and Pawelec, G and Lill, CM}, title = {Peripheral Immune Profiles in Individuals at Genetic Risk of Amyotrophic Lateral Sclerosis and Alzheimer's Disease.}, journal = {Cells}, volume = {14}, number = {4}, pages = {}, pmid = {39996723}, issn = {2073-4409}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; LI 2654/4-1//German Research Foundation/ ; #16SV5536K, #16SV5537, #16SV5538, #16SV5837, #01UW0808,01GL1716A, and 01GL1716B//Bundesministerium für Bildung und Forschung/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/immunology ; *Alzheimer Disease/genetics/immunology ; Female ; Male ; *Genetic Predisposition to Disease ; Aged ; Middle Aged ; Genome-Wide Association Study ; Risk Factors ; Polymorphism, Single Nucleotide/genetics ; Aged, 80 and over ; }, abstract = {The immune system plays a crucial role in the pathogenesis of neurodegenerative diseases. Here, we explored whether blood immune cell profiles are already altered in healthy individuals with a genetic predisposition to amyotrophic lateral sclerosis (ALS) or Alzheimer's disease (AD). Using multicolor flow cytometry, we analyzed 92 immune cell phenotypes in the blood of 448 healthy participants from the Berlin Aging Study II. We calculated polygenic risk scores (PGSs) using genome-wide significant SNPs from recent large genome-wide association studies on ALS and AD. Linear regression analyses were then performed of the immune cell types on the PGSs in both the overall sample and a subgroup of older participants (>60 years). While we did not find any significant associations between immune cell subtypes and ALS and AD PGSs when controlling for the false discovery rate (FDR = 0.05), we observed several nominally significant results (p < 0.05) with consistent effect directions across strata. The strongest association was observed with CD57+ CD8+ early-memory T cells and ALS risk (p = 0.006). Other immune cell subtypes associated with ALS risk included PD-1+ CD8+ and CD57+ CD4+ early-memory T cells, non-classical monocytes, and myeloid dendritic cells. For AD, naïve CD57+ CD8+ T cells and mature NKG2A+ natural killer cells showed nominally significant associations. We did not observe major immune cell changes in individuals at high genetic risk of ALS or AD, suggesting they may arise later in disease progression. Additional studies are required to validate our nominally significant findings.}, } @article {pmid39996748, year = {2025}, author = {Yang, HM}, title = {Mitochondrial Dysfunction in Neurodegenerative Diseases.}, journal = {Cells}, volume = {14}, number = {4}, pages = {}, pmid = {39996748}, issn = {2073-4409}, support = {2020R1A2C1011311//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Oxidative Stress ; Mitophagy ; Reactive Oxygen Species/metabolism ; }, abstract = {Mitochondrial dysfunction represents a pivotal characteristic of numerous neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These conditions, distinguished by unique clinical and pathological features, exhibit shared pathways leading to neuronal damage, all of which are closely associated with mitochondrial dysfunction. The high metabolic requirements of neurons make even minor mitochondrial deficiencies highly impactful, driving oxidative stress, energy deficits, and aberrant protein processing. Growing evidence from genetic, biochemical, and cellular investigations associates impaired electron transport chain activity and disrupted quality-control mechanisms, such as mitophagy, with the initial phases of disease progression. Furthermore, the overproduction of reactive oxygen species and persistent neuroinflammation can establish feedforward cycles that exacerbate neuronal deterioration. Recent clinical research has increasingly focused on interventions aimed at enhancing mitochondrial resilience-through antioxidants, small molecules that modulate the balance of mitochondrial fusion and fission, or gene-based therapeutic strategies. Concurrently, initiatives to identify dependable mitochondrial biomarkers seek to detect pathological changes prior to the manifestation of overt symptoms. By integrating the current body of knowledge, this review emphasizes the critical role of preserving mitochondrial homeostasis as a viable therapeutic approach. It also addresses the complexities of translating these findings into clinical practice and underscores the potential of innovative strategies designed to delay or potentially halt neurodegenerative processes.}, } @article {pmid39997929, year = {2025}, author = {Newell, ME and Aravindan, A and Babbrah, A and Halden, RU}, title = {Epigenetic Biomarkers Driven by Environmental Toxins Associated with Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis in the United States: A Systematic Review.}, journal = {Toxics}, volume = {13}, number = {2}, pages = {}, pmid = {39997929}, issn = {2305-6304}, support = {GF000000002135//Glen Swette Memorial Fund/ ; }, abstract = {Environmental toxins and epigenetic changes have been linked to neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS). This paper aimed to (i) identify environmental toxins associated with AD, PD, and ALS, (ii) locate potential industrial sources of toxins in the United States (U.S.), and (iii) assess epigenetic changes driven by exposure to toxins reported by patients. Environmental factors and epigenetic biomarkers of neurodegeneration were compiled from 69 studies in the literature using Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) and geographic information system approaches. Some 127 environmental toxins have been associated or putatively associated with AD, PD, or ALS, with four toxic metals (As, Cd, Mn, and Hg) common to all three of these neurodegenerative diseases. Environmental toxins associated with epigenetic changes (e.g., DNA methylation) in patients include air pollutants, metals, and organic chemicals (e.g., pesticides, mycotoxins, and cyanotoxins). Geographic analysis showed that study locations (e.g., U.S., Europe, and East Asia) were selected by researchers based on convenience of access rather than exposure risk and disease prevalence. We conclude that several toxins and epigenetic markers shared among neurodegenerative diseases could serve as attractive future targets guiding environmental quality improvements and aiding in early disease detection.}, } @article {pmid39998031, year = {2025}, author = {Burke, KM and Shea, C and Arulanandam, V and Sullivan, S and Ellrodt, AS and MacAdam, C and Carney, K and Casagrande, G and Christiansen, E and Paganoni, S}, title = {Cervical Collar Satisfaction and Functional Impact in Amyotrophic Lateral Sclerosis: A Survey Study.}, journal = {American journal of physical medicine & rehabilitation}, volume = {104}, number = {9}, pages = {809-813}, doi = {10.1097/PHM.0000000000002716}, pmid = {39998031}, issn = {1537-7385}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/complications/physiopathology ; Female ; Male ; Middle Aged ; *Patient Satisfaction ; Aged ; Activities of Daily Living ; *Neck Pain/etiology/rehabilitation ; Cervical Vertebrae ; Quality of Life ; Adult ; Surveys and Questionnaires ; *Muscle Weakness/etiology/rehabilitation ; *Braces ; }, abstract = {OBJECTIVES: Many people with amyotrophic lateral sclerosis develop cervical muscle weakness, often managed with cervical collars. Finding supportive and comfortable collars can be challenging. This study aimed to evaluate satisfaction with various collars and their impact on activities of daily living.

DESIGN: This electronic survey study collected demographic information, clinical status, and participant experiences with commonly used cervical collars.

RESULTS: Thirty-four participants (33 with amyotrophic lateral sclerosis, 1 with primary lateral sclerosis) completed the survey, with 79% reporting neck weakness and 38% experiencing neck pain. Among those who tried cervical collars (65%), many had tried multiple options. The mean satisfaction across all collar types was 5.03 (SD = 2.92) out of 10.

CONCLUSIONS: These findings suggest current collars do not fully meet the needs of people living with amyotrophic lateral sclerosis, emphasizing the importance of improved treatment options. Future research should explore innovative technologies to improve cervical support, function, and quality of life.}, } @article {pmid39998694, year = {2025}, author = {Paramasivan, NK and Sarker, P and Zekeridou, A and Staff, NP and Klein, CJ and McKeon, A and Pittock, SJ and Dubey, D}, title = {Upper motor neuron-predominant motor neuron disease: a novel immunotherapy-responsive association of GAD65 autoimmunity.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {230}, pmid = {39998694}, issn = {1432-1459}, support = {R01 NS126227/NS/NINDS NIH HHS/United States ; U01 NS120901/NS/NINDS NIH HHS/United States ; MN OHE#15//Minnesota Office of Higher Education/ ; }, mesh = {Humans ; Male ; *Glutamate Decarboxylase/immunology ; Female ; Middle Aged ; Aged ; Retrospective Studies ; *Motor Neuron Disease/immunology/therapy/blood/physiopathology ; *Immunotherapy/methods ; *Autoantibodies/blood/cerebrospinal fluid ; *Autoimmunity ; Adult ; }, abstract = {BACKGROUND: Autoimmune disorders can present as motor neuronopathies and need to be excluded prior to the diagnosis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the clinical phenotypes of patients with motor neuron disease (MND) in the context of high-titer serum/CSF GAD65 antibodies (radioimmunoassay).

METHODS: A retrospective review of all Mayo patients (between 1/1/2003 and 12/31/2023) with motor neuronopathy and co-existing high-titer GAD65 antibodies (≥ 20 nmol/L in serum [equivalent to > 10,000 IU, ELISA] or detection in CSF) was performed. Clinical phenotypes and outcomes were compared with ALS patients diagnosed in the last 5 years (1/1/2019-12/31/2023) who tested negative for GAD65 IgG.

RESULTS: We identified 12 patients with high-titer GAD65 IgG and motor neuronopathy, who often had lower back spasms, history of an exaggerated startle response with immunotherapy responsiveness as compared to ALS patients. On further analysis, a subgroup of these patients with neurogenic changes on EMG, had an upper motor neuron (UMN) predominant syndrome (58%), with history of exaggerated startle (57%), lower back spasms (43%), tandem gait impairment (86%) and UMN bladder symptoms (71%) that were significantly different from the ALS controls. The UMN predominant GAD65 MN responded favorably to immunotherapy with stable electromyography; significantly lesser worsening in mRS and mortality on long-term follow-up.

DISCUSSION: An upper motor neuron predominant motor neuronopathy is a distinct manifestation of GAD65 autoimmunity. Co-existing symptoms like exaggerated startle response, lower back spasms, impaired tandem gait, and UMN bladder signs might warrant consideration of an immunotherapy trial, which could yield favorable results.}, } @article {pmid39998997, year = {2025}, author = {García-Casanova, PH and Vázquez-Costa, JF}, title = {Advances in the early diagnosis of amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {4}, pages = {415-425}, doi = {10.1080/14737175.2025.2471556}, pmid = {39998997}, issn = {1744-8360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Early Diagnosis ; Biomarkers ; Disease Progression ; Delayed Diagnosis ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Despite rapid disease progression, diagnostic delay of 10-16 months persists, influenced by disease-specific factors and healthcare systems. Reducing it is crucial for early intervention, multidisciplinary care planning, and patient participation in clinical trials.

AREAS COVERED: The authors review relevant studies identified through PubMed from 1990 to 2024. The article explores factors contributing to diagnostic delay, the importance of early diagnosis, and strategies for improvement, including the role of diagnostic criteria and biomarkers.

EXPERT OPINION: Diagnosis of ALS remains clinical, with clinical expertise as the main modifiable factor in the diagnostic delay. Some biomarkers may be useful to speed up diagnosis at an earlier stage of the disease and in patients with atypical presentations or co-morbidities. However, the use of biomarkers for ALS diagnosis in clinical practice is far from being established and poses considerable challenges, including the lack of disease-specific biomarkers and the potential for delayed results. Until disease-specific biomarkers become available, early referral to ALS specialists, together with physician education programs, will remain the main tools to reduce diagnostic delay in the next years.}, } @article {pmid39999167, year = {2025}, author = {Wang, HV and Xiang, JF and Yuan, C and Veire, AM and Gendron, TF and Murray, ME and Tansey, MG and Hu, J and Gearing, M and Glass, JD and Jin, P and Corces, VG and McEachin, ZT}, title = {pTDP-43 levels correlate with cell type-specific molecular alterations in the prefrontal cortex of C9orf72 ALS/FTD patients.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {9}, pages = {e2419818122}, pmid = {39999167}, issn = {1091-6490}, support = {F32 ES031827/ES/NIEHS NIH HHS/United States ; RM1 HG008935/HG/NHGRI NIH HHS/United States ; U01 MH116441/MH/NIMH NIH HHS/United States ; R35 NS111602/NS/NINDS NIH HHS/United States ; R35 GM139408/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *C9orf72 Protein/genetics/metabolism ; *Prefrontal Cortex/metabolism/pathology ; *Frontotemporal Dementia/metabolism/genetics/pathology ; Male ; *DNA-Binding Proteins/metabolism/genetics ; Female ; Middle Aged ; Microglia/metabolism/pathology ; Aged ; Phosphorylation ; Neurons/metabolism/pathology ; }, abstract = {Repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place in the dorsolateral frontal cortex of patients with C9orf72 ALS/FTD, we compared healthy controls with C9orf72 ALS/FTD donor samples staged based on the levels of cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark of disease progression. We identified distinct molecular changes in different cell types that take place during FTD development. Loss of neurosurveillance microglia and activation of the complement cascade take place early, when pTDP-43 aggregates are absent or very low, and become more pronounced in late stages, suggesting an initial involvement of microglia in disease progression. Reduction of layer 2-3 cortical projection neurons with high expression of CUX2/LAMP5 also occurs early, and the reduction becomes more pronounced as pTDP-43 accumulates. Several unique features were observed only in samples with high levels of pTDP-43, including global alteration of chromatin accessibility in oligodendrocytes, microglia, and astrocytes; higher ratios of premature oligodendrocytes; increased levels of the noncoding RNA NEAT1 in astrocytes and neurons, and higher amount of phosphorylated ribosomal protein S6. Our findings reveal progressive functional changes in major cell types found in the prefrontal cortex of C9orf72 ALS/FTD patients that shed light on the mechanisms underlying the pathology of this disease.}, } @article {pmid39999835, year = {2025}, author = {Saxena, S and Liebscher, S}, title = {Boosting the X factor: Increasing XBP1s-mediated ER stress signaling protects motor neurons in ALS/FTD.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {3}, pages = {844-846}, pmid = {39999835}, issn = {1525-0024}, } @article {pmid40000618, year = {2025}, author = {Ru, Q and Li, Y and Zhang, X and Chen, L and Wu, Y and Min, J and Wang, F}, title = {Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects.}, journal = {Bone research}, volume = {13}, number = {1}, pages = {27}, pmid = {40000618}, issn = {2095-4700}, support = {82071970//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82072506//National Natural Science Foundation of China (National Science Foundation of China)/ ; 31970689//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32330047//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024AFB971//Natural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation)/ ; }, mesh = {Humans ; *Ferroptosis/physiology ; *Iron/metabolism ; *Homeostasis ; *Muscular Diseases/metabolism/pathology/therapy ; Animals ; Muscle, Skeletal/metabolism ; }, abstract = {The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.}, } @article {pmid40000803, year = {2025}, author = {Giblin, A and Cammack, AJ and Blomberg, N and Anoar, S and Mikheenko, A and Carcolé, M and Atilano, ML and Hull, A and Shen, D and Wei, X and Coneys, R and Zhou, L and Mohammed, Y and Olivier-Jimenez, D and Wang, LY and Kinghorn, KJ and Niccoli, T and Coyne, AN and van der Kant, R and Lashley, T and Giera, M and Partridge, L and Isaacs, AM}, title = {Neuronal polyunsaturated fatty acids are protective in ALS/FTD.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {737-747}, pmid = {40000803}, issn = {1546-1726}, support = {K99 NS123242/NS/NINDS NIH HHS/United States ; R01 NS132836/NS/NINDS NIH HHS/United States ; NS123242//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS132836//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R00 NS123242/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Fatty Acids, Unsaturated/metabolism ; Humans ; *Frontotemporal Dementia/metabolism/genetics/pathology ; *Neurons/metabolism ; C9orf72 Protein/genetics ; Induced Pluripotent Stem Cells/metabolism ; Drosophila ; Disease Models, Animal ; Fatty Acid Desaturases/metabolism/genetics ; Animals, Genetically Modified ; Male ; Brain/metabolism ; }, abstract = {Here we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in a Drosophila model of C9orf72 repeat expansion, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), and in human postmortem ALS spinal cord. We performed lipidomics on C9 ALS/FTD Drosophila, induced pluripotent stem (iPS) cell neurons and postmortem FTD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). Feeding C9 ALS/FTD flies PUFAs yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of C9 ALS/FTD flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor-induced neuronal death in iPS cell neurons of patients with both C9 and TDP-43 ALS/FTD. These data implicate neuronal fatty acid saturation in the pathogenesis of ALS/FTD and suggest that interventions to increase neuronal PUFA levels may be beneficial.}, } @article {pmid40001370, year = {2025}, author = {Silva Ortíz, YL and de Sousa, TC and Kruklis, NE and Galeano García, P and Brango-Vanegas, J and Soller Ramada, MH and Franco, OL}, title = {The Role of Amphibian AMPs Against Oxidative Stress and Related Diseases.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {14}, number = {2}, pages = {}, pmid = {40001370}, issn = {2079-6382}, abstract = {Amphibians use their skin as an effective defense mechanism against predators and microorganisms. Specialized glands produce antimicrobial peptides (AMPs) that possess antioxidant properties, effectively reducing reactive oxygen species (ROS) levels. These peptides are promising candidates for treating diseases associated with oxidative stress (OS) and redox imbalance, including neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), as well as age-related conditions, like cardiovascular diseases and cancer. This review highlights the multifaceted roles of AMPs and antioxidant peptides (AOPs) in amphibians, emphasizing their protective capabilities against oxidative damage. They scavenge ROS, activate antioxidant enzyme systems, and inhibit cellular damage. AOPs often share structural characteristics with AMPs, suggesting a potential evolutionary connection and similar biosynthetic pathways. Peptides such as brevinin-1FL and Cath-KP demonstrate neuroprotective effects, indicating their therapeutic potential in managing oxidative stress-related diseases. The antioxidant properties of amphibian-derived peptides pave the way for novel therapeutic developments. However, a deeper understanding of the molecular mechanisms underlying these peptides and their interactions with oxidative stress is essential to addressing ROS-related diseases and advancing therapeutic strategies in clinical practice.}, } @article {pmid40001529, year = {2025}, author = {Onu, CJ and Adu, M and Chakkour, M and Kumar, V and Greenberg, ML}, title = {Inositol Phosphates and Synthesizing Enzymes: Implications in Neurodegenerative Disorders.}, journal = {Biomolecules}, volume = {15}, number = {2}, pages = {}, pmid = {40001529}, issn = {2218-273X}, support = {R01 GM125082/GM/NIGMS NIH HHS/United States ; R35 GM149271/GM/NIGMS NIH HHS/United States ; GM149271/GF/NIH HHS/United States ; GM125082/GF/NIH HHS/United States ; }, mesh = {Humans ; *Inositol Phosphates/metabolism ; *Neurodegenerative Diseases/metabolism/enzymology ; Animals ; Inositol/metabolism ; Signal Transduction ; }, abstract = {Inositol is a vital sugar molecule involved in numerous signaling pathways required for cellular homeostasis and cell survival. Myo-inositol and its phospho-derivatives, inositol phosphates (IPs), are the most prevalent forms of inositol found in living cells. They are involved in regulating ion channels, metabolic flux, stress response, and other key biological processes. While emerging research has highlighted the significant roles of inositol phosphates in immunity, cancer, and metabolic diseases, there is a lack of comprehensive reviews on their roles in psychiatric and neurological disorders. This review aims to fill that gap by analyzing the existing literature on the importance of inositol phosphates in severe psychiatric and neurological conditions such as Parkinson's disease, Alzheimer's disease, bipolar disorder, amyotrophic lateral sclerosis, schizophrenia, and Huntington's disease, underscoring the potential to pave the way for new treatment regimens for these debilitating disorders targeting inositol pathways.}, } @article {pmid40001624, year = {2025}, author = {Ma, B and Ren, J and Qian, X}, title = {Study on the Polarization of Astrocytes in the Optic Nerve Head of Rats Under High Intraocular Pressure: In Vitro.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {}, pmid = {40001624}, issn = {2306-5354}, support = {12472309 12072210//National Natural Science Foundation of China/ ; }, abstract = {Astrocytes, the most common glial cells in the optic nerve head (ONH), provide support and nutrition to retinal ganglion cells. This study aims to investigate the polarization types of astrocytes in the ONH of rats under high intraocular pressure (IOP) and explore signaling pathways potentially associated with different types of polarized astrocytes. The rat models with chronic high IOP were established. High IOP lasted for 2, 4, 6, and 8 weeks. Astrocytes were extracted from the ONH of rats using the tissue block cultivation method. Western blot was used to detect the expression of proteins associated with astrocyte polarization. Proteomics was employed to identify differential proteins associated with astrocyte polarization. Astrocytes polarized into A2 astrocytes after 2, 4, 6, and 8 weeks of high IOP, while polarization into A1 astrocytes began only after 8 weeks of high IOP. The differential proteins associated with A1 astrocyte polarization are primarily enriched in pathways of neurodegeneration with respect to multiple diseases, while the differential proteins associated with A2 astrocyte polarization are primarily enriched in pathways of spliceosome in amyotrophic lateral sclerosis. Our findings could provide a better understanding of the role of ONH astrocytes in the pathogenesis of glaucoma and offer new perspectives for glaucoma treatment.}, } @article {pmid40002444, year = {2025}, author = {Okoh, C and Mayall, L and Makin, SM and Chen, C and Zarotti, N}, title = {Non-Pharmacological Interventions for Caregivers of People with Motor Neurone Disease: A Scoping Review of Psychosocial Outcomes.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002444}, issn = {2076-3425}, abstract = {Objective: Caregivers of individuals with motor neurone disease (MND) face a wide range of psychosocial difficulties. To address these, non-pharmacological interventions have been trialled, showing promising results. However, no clear characterisation of the breadth of psychosocial constructs examined by the interventions is currently available, resulting in the lack of a core outcome set (COS). The present review explored the types of psychosocial outcomes investigated in studies that adopted non-pharmacological interventions with caregivers of people with MND. Methods: A scoping review was conducted across four major databases (Academic Search Ultimate, CINAHL, PsycINFO, and MEDLINE) from inception to the 1 March 2024. Results: From an initial return of 4802 citations, 10 were considered eligible for inclusion. A total of 10 main psychosocial outcomes were identified: anxiety and depression, psychological distress, resilience, caregiver burden, caregiver preparedness, self-efficacy, quality of life, spiritual wellbeing, and mindfulness. Conclusions: Caregiver burden and symptoms of anxiety and depression represent pivotal outcomes, but caution is advised with regard to caregiver burden's potential multidimensional structure. Psychological distress and quality of life are also commonly investigated, but clearer consensus is needed on their conceptualisation. There is a paucity of studies characterising important psychosocial outcomes such as resilience, problem-solving, self-efficacy, and mindfulness, while no investigations are available for relevant outcomes such as coping, isolation, and loneliness. Further research is warranted to address these gaps to improve our insight into non-pharmacological support for MND caregivers and ultimately lead to the development of a core psychosocial outcome set in this population.}, } @article {pmid40002468, year = {2025}, author = {Dawoody Nejad, L and Pioro, EP}, title = {Modeling ALS with Patient-Derived iPSCs: Recent Advances and Future Potentials.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002468}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a terminal complex neurodegenerative disease, with 10-15% of cases being familial and the majority being sporadic with no known cause. There are no animal models for the 85-90% of sporadic ALS cases. More creative, sophisticated models of ALS disease are required to unravel the mysteries of this complicated disease. While ALS patients urgently require new medications and treatments, suitable preclinical in vitro models for drug screening are lacking. Therefore, human-derived induced pluripotent stem cell (hiPSC) technology offers the opportunity to model diverse and unreachable cell types in a culture dish. In this review, we focus on recent hiPSC-derived ALS neuronal and non-neuronal models to examine the research progress of current ALS 2D monocultures, co-cultures, and more complex 3D-model organoids. Despite the challenges inherent to hiPSC-based models, their application to preclinical drug studies is enormous.}, } @article {pmid40002476, year = {2025}, author = {Raymond, J and Howard, IM and Berry, J and Larson, T and Horton, DK and Mehta, P}, title = {Head Injury and Amyotrophic Lateral Sclerosis: Population-Based Study from the National ALS Registry.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002476}, issn = {2076-3425}, support = {n/a/CC/CDC HHS/United States ; }, abstract = {Background/Objectives: To examine if head injury (HI) is associated with age at ALS diagnosis in the United States. Methods: In this cross-sectional populationf-based analysis, we identified patients with ALS who were registered from 2015 to 2023 who completed the Registry's head trauma survey module. The association between HI and age at ALS diagnosis was assessed using multivariate analysis. Results: Of the 3424 respondents, 56.6% had experienced a HI. The adjusted odds ratio (aOR) for an ALS diagnosis before age 60 years for patients with a HI was 1.24 (95% CI, 1.07-1.45). One or two HIs had an aOR of 1.15 (95% CI, 0.97-1.36), and five or more HIs had an aOR of 1.58 (95% CI, 1.19-2.09). HI before age 18 years yielded an aOR of 2.03 (95% CI, 1.53-2.70) as well as HI between the ages of 18 and 30 years (aOR = 1.48, 95% CI: 1.06-2.06)). When narrowing the analysis to patients with HI before age 18 compared with patients with no HI, we found an association with HI that led to an emergency department or hospital visit (aOR = 1.50 (95% CI: 1.21-1.86)). Conclusions: In this cross-sectional analysis of ALS patients, HIs occurring in childhood and early adulthood and the number of HIs increased the odds of being diagnosed before age 60 years. These results suggest that HI continues to be a risk factor for ALS and could be associated with a younger age of diagnosis.}, } @article {pmid40002527, year = {2025}, author = {Eisen, A and Kiernan, MC}, title = {The Neonatal Microbiome: Implications for Amyotrophic Lateral Sclerosis and Other Neurodegenerations.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002527}, issn = {2076-3425}, abstract = {Most brain development occurs in the "first 1000 days", a critical period from conception to a child's second birthday. Critical brain processes that occur during this time include synaptogenesis, myelination, neural pruning, and the formation of functioning neuronal circuits. Perturbations during the first 1000 days likely contribute to later-life neurodegenerative disease, including sporadic amyotrophic lateral sclerosis (ALS). Neurodevelopment is determined by many events, including the maturation and colonization of the infant microbiome and its metabolites, specifically neurotransmitters, immune modulators, vitamins, and short-chain fatty acids. Successful microbiome maturation and gut-brain axis function depend on maternal factors (stress and exposure to toxins during pregnancy), mode of delivery, quality of the postnatal environment, diet after weaning from breast milk, and nutritional deficiencies. While the neonatal microbiome is highly plastic, it remains prone to dysbiosis which, once established, may persist into adulthood, thereby inducing the development of chronic inflammation and abnormal excitatory/inhibitory balance, resulting in neural excitation. Both are recognized as key pathophysiological processes in the development of ALS.}, } @article {pmid40002740, year = {2025}, author = {Meng, K and Jia, H and Hou, X and Zhu, Z and Lu, Y and Feng, Y and Feng, J and Xia, Y and Tan, R and Cui, F and Yuan, J}, title = {Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.}, journal = {Biomedicines}, volume = {13}, number = {2}, pages = {}, pmid = {40002740}, issn = {2227-9059}, support = {600791001//the Research Start-up Fund of Jining Medical University/ ; JYHL2021MS13//Research Fund for Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University/ ; 81700055//the National Natural Science Foundation of China/ ; Grant No. D2016021//Outstanding Talent Research Funding of Xuzhou Medical University/ ; BK20160229//Natural Science Foundation of Jiangsu Province/ ; tsqn201909147//Taishan Scholars Program of Shandong Province/ ; G2Y-kJS-SD-2023-097//Co-construction of Science and Technology Projects by the Science and Technology Department of the State Administration of Traditional Chinese Medicine/ ; }, abstract = {Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role in cell signaling, immune response, and metabolic regulation. For example, mitochondrial dysfunction is closely associated with the onset and progression of a variety of diseases, including ND, cardiovascular diseases, diabetes, and cancer. The dysfunction of energy metabolism, imbalance of mitochondrial dynamics, or abnormal mitophagy can lead to the imbalance of mitochondrial homeostasis, which can induce pathological reactions such as oxidative stress, apoptosis, and inflammation, damage the nervous system, and participate in the occurrence and development of degenerative nervous system diseases such as AD, PD, and ALS. In this paper, the latest research progress of this subject is detailed. The mechanisms of oxidative stress, mitochondrial homeostasis, and mitophagy-mediated ND are reviewed from the perspectives of β-amyloid (Aβ) accumulation, dopamine neuron damage, and superoxide dismutase 1 (SOD1) mutation. Based on the mechanism research, new ideas and methods for the treatment and prevention of ND are proposed.}, } @article {pmid40004056, year = {2025}, author = {Yan, B and Suen, MC and Xu, N and Lu, C and Liu, C and Zhu, G}, title = {G-Quadruplex Structures Formed by Human Telomere and C9orf72 GGGGCC Repeats.}, journal = {International journal of molecular sciences}, volume = {26}, number = {4}, pages = {}, pmid = {40004056}, issn = {1422-0067}, support = {32071188//National Scientific Foundation of China/ ; 16101120, 161011121, AoE/M-403-16, AoE/M-401/20//Research Grants Council of the Hong Kong Special Administrative Region, China/ ; BGF.2023.019//Hong Kong University of Science and Technology, China/ ; 2021A1515220104//Guangdong Basic and Applied Basic Research Foundation, China/ ; 32301012//Young Scientists Fund of the National Natural Science Foundation of China/ ; }, mesh = {Humans ; *G-Quadruplexes ; *Telomere/genetics/chemistry ; *C9orf72 Protein/genetics/chemistry ; Amyotrophic Lateral Sclerosis/genetics ; *DNA Repeat Expansion ; Frontotemporal Dementia/genetics ; }, abstract = {G-quadruplexes (G4s) are unique nucleic acid structures composed of guanine-rich (G-rich) sequences that can form diverse topologies based on the arrangement of their four strands. G4s have attracted attention for their potential roles in various biological processes and human diseases. In this review, we focus on the G4 structures formed by human telomeric sequences, (GGGTTA)n, and the hexanucleotide repeat expansion, (GGGGCC)n, in the first intron region of the chromosome 9 open reading frame 72 (C9orf72) gene, highlighting their structural diversity and biological significance. Human telomeric G4s play crucial roles in telomere retention and gene regulation. In particular, we provide an in-depth summary of known telomeric G4s and focus on our recently discovered chair-type conformation, which exhibits distinct folding patterns. The chair-type G4s represent a novel folding pattern with unique characteristics, expanding our knowledge of telomeric G4 structural diversity and potential biological functions. Specifically, we emphasize the G4s formed by the (GGGGCC)n sequence of the C9orf72 gene, which represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The thorough structural analysis in this review advances our comprehension of the disease mechanism and provides valuable insights into developing targeted therapeutic strategies in ALS/FTD.}, } @article {pmid40004464, year = {2025}, author = {Liu, Z and Song, SY}, title = {Genomic and Transcriptomic Approaches Advance the Diagnosis and Prognosis of Neurodegenerative Diseases.}, journal = {Genes}, volume = {16}, number = {2}, pages = {}, pmid = {40004464}, issn = {2073-4425}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/diagnosis ; Prognosis ; *Transcriptome/genetics ; *Genomics/methods ; Genome-Wide Association Study ; Gene Expression Profiling/methods ; Parkinson Disease/genetics/diagnosis ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a growing societal challenge due to their irreversible progression and significant impact on patients, caregivers, and healthcare systems. Despite advances in clinical and imaging-based diagnostics, these diseases are often detected at advanced stages, limiting the effectiveness of therapeutic interventions. Recent breakthroughs in genomic and transcriptomic technologies, including whole-genome sequencing, single-cell RNA sequencing (scRNA-seq), and CRISPR-based screens, have revolutionized the field, offering new avenues for early diagnosis and personalized prognosis. Genomic approaches have elucidated disease-specific genetic risk factors and molecular pathways, while transcriptomic studies have identified stage-specific biomarkers that correlate with disease progression and severity. Furthermore, genome-wide association studies (GWAS), polygenic risk scores (PRS), and spatial transcriptomics are enabling the stratification of patients based on their risk profiles and prognostic trajectories. Advances in functional genomics have uncovered actionable targets, such as ATXN2 in ALS and TREM2 in AD, paving the way for tailored therapeutic strategies. Despite these achievements, challenges remain in translating genomic discoveries into clinical practice due to disease heterogeneity and the complexity of neurodegenerative pathophysiology. Future integration of genetic technologies holds promise for transforming diagnostic and prognostic paradigms, offering hope for improved patient outcomes and precision medicine approaches.}, } @article {pmid40006784, year = {2025}, author = {Ji, M and Yu, H and Cui, H and Chen, J and Yu, J and Li, X}, title = {A New Pro-197-Ile Mutation in Amaranthus palmeri Associated with Acetolactate Synthase-Inhibiting Herbicide Resistance.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, pmid = {40006784}, issn = {2223-7747}, support = {CARS25//China Agriculture Research System/ ; }, abstract = {Palmer amaranth (Amaranthus palmeri S. Watson), native to North America, is one of the most prominent invasive weed species on agricultural land. Acetolactate synthase (ALS)-resistant A. palmeri (Amaranthus palmeri) is widespread, while the research focus on resistance pattern and molecular basis of A. palmeri to imazethapyr is seldom documented in China. An A. palmeri population that survived the recommended rate of imazethapyr was collected in Shandong Province, China. The resistant mechanism and pattern of A. palmeri to imazethapyr was investigated. Dose-response assay showed that the resistant (R) population displayed a high resistance level (292.5-fold) to imazethapyr compared with the susceptible (S) population. Sequence analysis of the ALS gene revealed that nucleotide mutations resulted in three resistance-conferring amino acid substitutions, Pro-197-Ile, Trp-574-Leu, and Ser-653-Asp, in the individual plants of the R population. An in vitro enzyme assay indicated that the ALS was relatively unsusceptible to imazethapyr in the R population, showing a resistance index of 88.6-fold. ALS gene expression and copy number did not confer resistance to imazethapyr in the R population. Pro-197-Ile is the first reported amino acid substitution conferring ALS resistance to A. palmeri. This is the first case of an imazethapyr-resistant A. palmeri biotype in China.}, } @article {pmid40006958, year = {2025}, author = {Mielcarska, MB and Rouse, BT}, title = {Viruses and the Brain-A Relationship Prone to Trouble.}, journal = {Viruses}, volume = {17}, number = {2}, pages = {}, pmid = {40006958}, issn = {1999-4915}, mesh = {Humans ; *Brain/virology ; *Viruses/pathogenicity ; Animals ; *Virus Diseases/virology/complications ; Neurodegenerative Diseases/virology ; Antiviral Agents/therapeutic use ; *Central Nervous System Viral Diseases/virology ; }, abstract = {Neurological disorders, some of which are associated with viral infections, are growing due to the aging and expanding population. Despite strong defenses of the central nervous system, some viruses have evolved ways to breach them, which often result in dire consequences. In this review, we recount the various ways by which different viruses can enter the CNS, and we describe the consequences of such invasions. Consequences may manifest as acute disease, such as encephalitis, meningitis, or result in long-term effects, such as neuromuscular dysfunction, as occurs in poliomyelitis. We discuss evidence for viral involvement in the causation of well-known chronic neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, as well as vascular dementia in the elderly. We also describe the approaches currently available to control a few of the neural viral infections. These include antivirals that are effective against human immunodeficiency virus and herpes simplex virus, as well as vaccines valuable for controlling rabies virus, poliomyelitis virus, and some flavivirus infections. There is an urgent need to better understand, at a molecular level, how viruses contribute to acute and, especially, chronic neurological diseases and to develop more precise and effective vaccines and therapies.}, } @article {pmid40007904, year = {2025}, author = {Esteruelas, G and Ettcheto, M and Haro, I and Herrando-Grabulosa, M and Gaja-Capdevila, N and Gomara, MJ and Navarro, X and Espina, M and Souto, EB and Camins, A and García, ML and Sánchez-López, E}, title = {Novel Tissue-Specific Multifunctionalized Nanotechnological Platform Encapsulating Riluzole Against Motor Neuron Diseases.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {2273-2288}, pmid = {40007904}, issn = {1178-2013}, mesh = {*Riluzole/administration & dosage/pharmacokinetics/chemistry ; Animals ; *Nanoparticles/chemistry ; *Neuroprotective Agents/administration & dosage/pharmacokinetics/chemistry ; *Motor Neuron Disease/drug therapy ; Humans ; Motor Neurons/drug effects/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy ; Drug Carriers/chemistry ; Mice ; Polyethylene Glycols/chemistry ; Drug Delivery Systems/methods ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Blood-Brain Barrier/metabolism ; }, abstract = {BACKGROUND: Motor neuron diseases are neurological disorders characterized by progressive degeneration of upper and/or lower motor neurons. Amyotrophic Lateral Sclerosis (ALS) is the most common form of motor neuron diseases, where patients suffer progressive paralysis, muscle atrophy and finally death. Despite ALS severity, no treatment is safe and fully effective. In this area, Riluzole was the first drug approved and it constitutes the gold-standard for this pathology. However, to obtain suitable therapeutic efficacy, Riluzole requires high doses that are associated with severe adverse effects in other tissues. To attain Riluzole therapeutic efficacy avoiding other organs side-effects, new therapeutic strategies to enhance the delivery of Riluzole specifically to motor neurons constitute an unmet medical need. In this area, we have developed a novel multifunctional nanostructurated carrier to selectively deliver Riluzole to motor neurons.

RESULTS: This work develops and characterizes at in vitro and in vivo levels a tissue-targeted formulation of peptide and PEG-labelled PLGA nanoparticles encapsulating Riluzole. For this purpose, pVEC, a cell penetrating peptide able to increase transport through the blood-brain barrier, was attached to the nanoparticles surface. The multifunctionalized nanoparticles show suitable characteristics for the release of Riluzole in the central nervous system and were detected in motor neurons within 1 h after administration while significantly reducing the concentration of Riluzole in non-therapeutic organs responsible of side effects.

CONCLUSION: A novel drug delivery system has been developed and characterized, demonstrating enhanced CNS biodistribution of riluzole, which shows promise as efficient therapeutic tool for motor neuron diseases, including amyotrophic lateral sclerosis.}, } @article {pmid40008198, year = {2025}, author = {Garetto, B and Cao, N and Finelli, V and Aunan, E and Signorile, M and Olsbye, U and Bordiga, S and Nova, A and Borfecchia, E}, title = {Pinpointing Cu-Coordination Motifs in Bio-Inspired MOFs by Combining DFT-Assisted XAS Analysis and Multivariate Curve Resolution.}, journal = {The journal of physical chemistry. C, Nanomaterials and interfaces}, volume = {129}, number = {7}, pages = {3570-3582}, pmid = {40008198}, issn = {1932-7447}, abstract = {In recent years, X-ray absorption spectroscopy (XAS) has emerged as an essential technique for investigating the structure and composition of heterogeneous catalysts, providing valuable insights into the nature of active sites within these systems. However, the average nature of the XAS signal, inherently merged over all the absorber-containing species forming during in situ/operando experiments, often complicates the interpretation of the data. Nonetheless, advanced analysis methods have been developed to address this problem. In particular, herein we employed in situ XAS spectroscopy together with multivariate curve resolution-alternating least squares (MCR-ALS) and wavelet transform (WT) analysis to monitor the evolution of distinct Cu species in histidine-modified Cu-UiO-66 MOFs and to obtain detailed structural insights about the Cu sites. A novel approach adopted in this work was the application of density functional theory (DFT)-assisted extended X-ray absorption fine structure (EXAFS) fitting to quantitatively refine the local structure of the MCR-derived pure Cu species. This approach revealed the preferential redox activity of Cu[II] ions coordinated within the defective Zr clusters of the MOF, compared to Cu[II] ions bound to both the histidine molecule and the defective site during a standard redox reaction protocol.}, } @article {pmid40008320, year = {2025}, author = {Wulterkens, D and Coumou, F and Slagt, C and Waalewijn, RA and Mommers, L}, title = {Defibrillation pad placement accuracy among Advanced Life Support instructors: A manikin-based observational study examining experience, self-evaluation, and actual performance.}, journal = {Resuscitation plus}, volume = {22}, number = {}, pages = {100886}, pmid = {40008320}, issn = {2666-5204}, abstract = {BACKGROUND: Ventricular fibrillation is common in patients with out-of-hospital cardiac arrest. Early and effective defibrillation is important for their survival. Effective defibrillation depends highly on correct positioning of the defibrillation pads. Teaching this correctly by ALS instructors is therefore crucial.

METHODS: Fifty certified advanced life support instructors were recruited from a large training institute. Participants were asked to place defibrillation pads on an anatomically and real-weight (90 kg) manikin. Primary outcome was the placement of defibrillation pads placed in the sternal-apical and anterior-posterior positions. Secondary outcomes were performance self-assessment, defibrillation experience, self-perceived competence and self-efficacy in teaching defibrillation. These measures were evaluated using an 11-point Likert scale.

RESULTS: A total of 31 medical doctors and 19 registered nurses were enrolled in this study. Defibrillation pads were placed (mean ± SD) 42 ± 21 mm, 38 ± 23 mm, 35 ± 19 mm and 61 ± 48 mm from the reference point for the sternal, apical, anterior and posterior pads respectively, resulting in a respectively correct placement of 18%, 20%, 32% and 28%. The average number of correctly applied pads per instructor was 0.98 ± 0.74 out of four.Self-assessment of defibrillation pads placed by the participants were 8.56 ± 1.33 and 7.88 ± 1.64 for the sternal-apical and anterior-posterior positions respectively. Personal defibrillation experience showed that the majority had applied over 20 standard defibrillations. Experience with anterior-posterior pad placement was less and experience with bi-axillary and double sequential external defibrillation positions were absent in most participants. Self-perceived competence for the sternal-apical, anterior-posterior, bi-axillary and dual external synchronized positions were 8.68 ± 1.06, 8.08 ± 1.37, 5.57 ± 2.95 and 5.11 ± 2.67 respectively. Self-efficacy score for teaching defibrillation was 8.59 ± 0.81. No association was found between the number of correctly applied pads and any of the participants' variables.

CONCLUSION: This study corroborates and expands upon existing knowledge regarding the challenges of defibrillator pad placement, revealing substantial variation in placement accuracy among instructors. Our novel analysis of pad angles and anterior-posterior analysis demonstrates that a significant portion of pads are incorrectly placed. These findings highlight the need for standardized approaches and improved training methodologies in defibrillator pad placement.}, } @article {pmid40008327, year = {2025}, author = {van Eijk, RPA and Steyn, FJ and Janse van Mantgem, MR and Schmidt, A and Meyjes, M and Allen, S and Daygon, DV and Loeffler, JP and Al-Chalabi, A and van den Berg, LH and Henderson, RD and Ngo, ST}, title = {An open-label Phase 2a study to assess the safety and tolerability of trimetazidine in patients with amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcaf063}, pmid = {40008327}, issn = {2632-1297}, abstract = {Metabolic imbalance is associated with amyotrophic lateral sclerosis progression. Impaired glucose oxidation and increased reliance on fatty acid oxidation contribute to reduced metabolic flexibility and faster disease progression in amyotrophic lateral sclerosis. We sought to evaluate the safety and tolerability, and explore the pharmacodynamic response of trimetazidine, a partial fatty acid oxidation inhibitor, on oxidative stress markers and energy expenditure in amyotrophic lateral sclerosis. The study was conducted between June 29, 2021 and May 24, 2023. People living with amyotrophic lateral sclerosis, recruited in Australia and the Netherlands, received open-label oral trimetazidine for 12 weeks after an initial 4-week lead-in period. The primary outcome measures were safety and tolerability, as well as the change from baseline in oxidative stress markers malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Secondary outcome measures were change from baseline in energy expenditure, amyotrophic lateral sclerosis functional rating scale-revised, and slow vital capacity (SVC). Linear mixed effects were used to estimate the mean difference in MDA and 8-OHdG between the on- and off-treatment periods. This trial is registered under ClinicalTrial.gov National Clinical Trial (NCT) number NCT04788745 and European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2020-005018-17. Twenty-one participants received trimetazidine; 19 (90%) completed the treatment period. Trimetazidine was well tolerated; there were 57 adverse events reported, of which 7 (11%) were deemed potentially drug-related, including hot flushes (2), nausea (2), paraesthesia (2) and fatigue (1). MDA was numerically lower during treatment [-0.29 uM; 95% confidence interval (CI) -0.90 to 0.33, P = 0.36]; 8-OHdG was significantly lower during treatment (-0.12 nM; 95% CI -0.23 to -0.01, P = 0.0245). The decrease in oxidative stress markers was accompanied by a reduction in resting energy expenditure (95 kcal, 95% CI 36.8-154, P = 0.0014). The absence of a placebo group prevented the interpretation of the clinical parameters. Oral trimetazidine was safe and well tolerated among patients with amyotrophic lateral sclerosis. This, combined with the significant reduction in markers of oxidative stress and resting energy expenditure, warrants a larger double-blind placebo-controlled efficacy study.}, } @article {pmid40008462, year = {2025}, author = {Huertas-Alonso, AJ and González-Serrano, DJ and Salgado-Ramos, M and Hadidi, M and Sánchez-Verdú, P and Cabañas, B and Chuck, CJ and Clark, JH and Moreno, A}, title = {Sustainable Microwave-Assisted Synthesis of Medium- and Long-Chain Alkyl Levulinates from Biomass-Derived Levulinic Acid.}, journal = {ChemSusChem}, volume = {18}, number = {10}, pages = {e202402508}, pmid = {40008462}, issn = {1864-564X}, support = {SBPLY/17/180501/000522//Junta de Comunidades de Castilla-La Mancha/ ; RTI2018-099503-B-I00//Ministerio de Ciencia, Innovación y Universidades/ ; }, abstract = {Alkyl levulinates (ALs) represent a family of bio-compounds derived from levulinic acid (LA), a platform chemical obtained from lignocellulosic biomass. Medium- and long-chain ALs (pentyl levulinate or longer) have shown potential as biofuel and fuel additives due to their relatively low oxygen content and resemblance to biodiesel. This study reports a fast and environmentally friendly method for synthesizing ALs via microwave (MW)-assisted LA esterification, laying emphasis on medium- and long-chain ALs. By combining p-toluenesulfonic acid (5 wt % loading) as catalyst and MW radiation as heating source for a short time (5 minutes), excellent yields of ALs (≥89 mol %) were achieved for a wide range of primary and secondary alcohols (2-10 carbons), overcoming the expected lower reactivity of long chain alcohols. Additionally, formation of undesired side products, such as dialkyl ethers or LA aldol condensation products, was significantly minimized. The feasibility of recovering the unreacted alcohol was successfully proved by simple distillation (88 wt % recovery). The green chemistry metrics assessment proved that this approach aligns with the green chemistry principles and the United Nations Sustainable Development Goals, offering a more sustainable pathway for biofuel and fuel additive production.}, } @article {pmid40009238, year = {2025}, author = {Ruffo, P and Traynor, BJ and Conforti, FL}, title = {Advancements in genetic research and RNA therapy strategies for amyotrophic lateral sclerosis (ALS): current progress and future prospects.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {233}, pmid = {40009238}, issn = {1432-1459}, support = {ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Genetic Therapy/methods/trends ; Animals ; }, abstract = {This review explores the intricate landscape of neurodegenerative disease research, focusing on Amyotrophic Lateral Sclerosis (ALS) and the intersection of genetics and RNA biology to investigate the causative pathogenetic basis of this fatal disease. ALS is a severe neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness and paralysis. Despite significant research advances, the exact cause of ALS remains largely unknown. Thanks to the application of next-generation sequencing (NGS) approaches, it was possible to highlight the fundamental role of rare variants with large effect sizes and involvement of portions of non-coding RNA, providing valuable information on risk prediction, diagnosis, and treatment of age-related diseases, such as ALS. Genetic research has provided valuable insights into the pathophysiology of ALS, leading to the development of targeted therapies such as antisense oligonucleotides (ASOs). Regulatory agencies in several countries are evaluating the commercialization of Qalsody (Tofersen) for SOD1-associated ALS, highlighting the potential of gene-targeted therapies. Furthermore, the emerging significance of microRNAs (miRNAs) and long RNAs are of great interest. MiRNAs have emerged as promising biomarkers for diagnosing ALS and monitoring disease progression. Understanding the role of lncRNAs in the pathogenesis of ALS opens new avenues for therapeutic intervention. However, challenges remain in delivering RNA-based therapeutics to the central nervous system. Advances in genetic screening and personalized medicine hold promise for improving the management of ALS. Ongoing clinical trials use genomic approaches for patient stratification and drug targeting. Further research into the role of non-coding RNAs in the pathogenesis of ALS and their potential as therapeutic targets is crucial to the development of effective treatments for this devastating disease.}, } @article {pmid40009412, year = {2025}, author = {Finsterer, J}, title = {Before Trapezius RNS Can Be Recommended as an Additional Tool for the Diagnosis of ALS, Well-Powered Prospective Studies Are Required.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {3}, pages = {114-115}, doi = {10.1097/CND.0000000000000515}, pmid = {40009412}, issn = {1537-1611}, } @article {pmid40009414, year = {2025}, author = {Hamad, AA}, title = {Tofersen for Amyotrophic Lateral Sclerosis: Genetic Treatment With Precision Medicine: The Future of ALS Treatment.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {3}, pages = {117-119}, doi = {10.1097/CND.0000000000000517}, pmid = {40009414}, issn = {1537-1611}, } @article {pmid40009417, year = {2025}, author = {Oliveira Santos, M and Pinto, S and Silveira, F and Gromicho, M and Alves, I and Castro, J and Castro, I and de Carvalho, M}, title = {Amyotrophic Lateral Sclerosis Associated With Severe Sensory Neuronopathy: Case Series.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {3}, pages = {133-139}, doi = {10.1097/CND.0000000000000520}, pmid = {40009417}, issn = {1537-1611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Middle Aged ; Female ; Aged ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system. However, an association with sensory neuronopathy has been scarcely described. We described 3 unrelated patients (2 males) with sporadic spinal-onset ALS and sensory neuronopathy. Mean onset age was 63.7 years and mean Revised Amyotrophic Lateral Sclerosis Functional Rating Scale at diagnosis was 42. Sensory disturbances emerged before or overlap with motor symptoms in the same onset region and followed the same pattern of lower motor neuron involvement over disease progression. Two patients have also bilateral trigeminal sensory fibers affection. None had cognitive abnormalities. Genetic testing for the most common ALS-associated genes was unrevealing. Mean disease duration and ALS functional rating scale-revised at last visit was 47 months and 27, respectively. One patient is still alive, dependent on nocturnal noninvasive ventilation. Motor neuron disease is now considered a multisystem neurodegenerative disorder, and sensory neuronopathy, although very rare, should not be neglected as a possible part of the disease spectrum.}, } @article {pmid40009787, year = {2025}, author = {Mondesert, E and Delaby, C and De La Cruz, E and Kuhle, J and Benkert, P and Pradeilles, N and Duchiron, M and Morchikh, M and Camu, W and Cristol, JP and Hirtz, C and Esselin, F and Lehmann, S}, title = {Comparative Performances of 4 Serum NfL Assays, pTau181, and GFAP in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {104}, number = {6}, pages = {e213400}, pmid = {40009787}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/mortality ; Female ; Male ; *Neurofilament Proteins/blood ; Aged ; *tau Proteins/blood ; Middle Aged ; *Glial Fibrillary Acidic Protein/blood ; Biomarkers/blood ; Cohort Studies ; Prognosis ; Phosphorylation ; }, abstract = {BACKGROUND AND OBJECTIVES: Selecting the most appropriate blood tests is crucial for the management of patients with amyotrophic lateral sclerosis (ALS). This study evaluates the diagnostic and prognostic performance of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau 181 (pTau181) biomarkers in ALS to establish their clinical relevance and cutoff values.

METHODS: In a cohort of patients from the ALS center in Montpellier, we conducted a head-to-head comparison of 4 different technologies and 3 distinct serum analytes: NfL was tested using the ultrasensitive Simoa and the microfluidic Ella platforms, along with 2 assays recently set up on clinical-grade platforms: Lumipulse and Elecsys. We also used Elecsys to assess serum GFAP and pTau181.

RESULTS: Our cohort included 139 patients with ALS and 70 non-ALS patients, with a mean age of 66.1 ± 11.4 years and 47.4% of women. The mean follow-up was 42 ± 26.3 months for patients with ALS and 141.6 ± 106.3 months for non-ALS patients, with a mortality rate of 85.5% vs 7.7%. There was a high correlation between all methods tested for serum NfL quantification (R[2] = 0.939 to 0.963). The area under the curve (AUC) for ALS diagnosis was 0.889 (0.827-0.932) for NfL Simoa, 0.906 (0.847-0.944) for Ella, 0.912 (0.853-0.948) for Lumipulse, and 0.910 (0.851-0.946) for Elecsys. Serum pTau181 and GFAP showed poor diagnostic performance with AUCs of 0.565 (0.472-0.649) and 0.546 (0.461-0.636), respectively. Kaplan-Meier survival analysis revealed significant hazard ratios (4.4-5.4) for blood NfL. Patients with ALS had a 40%-50% chance of surviving 50 weeks below the prognostic cutoff values while survival rates dropped to near zero above. NfL and GFAP levels were associated with age and body mass index, considered confounding factors. pTau181 levels varied significantly in patients with ALS depending on the site of onset.

DISCUSSION: This study demonstrates the consistent performance of 4 immunoassays for serum NfL quantification in ALS. NfL showed high diagnostic and prognostic accuracy, making it suitable for individual assessment, unlike GFAP or pTau181. We propose diagnostic and prognostic cutoff values for serum NfL, providing a basis for wider implementation, especially with the clinically accredited Lumipulse and Elecsys platforms, which are becoming standard practice.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that serum NfL levels are useful in identifying over 80% of patients with ALS and predicting survival in patients with ALS compared with pTau181 and GFAP levels.}, } @article {pmid40009859, year = {2025}, author = {Chung, J and Lim, F}, title = {Effect of Nurse Residency Programs on New Graduate Nurses Entering the Critical Care Setting: An Integrative Review.}, journal = {Critical care nursing quarterly}, volume = {48}, number = {2}, pages = {120-142}, pmid = {40009859}, issn = {1550-5111}, mesh = {Humans ; *Clinical Competence ; Preceptorship ; *Critical Care Nursing/education ; *Internship, Nonmedical ; *Critical Care ; }, abstract = {The transition period from undergraduate nursing education to professional practice is a time of uncertainty and great difficulty for new graduate nurses (NGNs). Nurse residency programs (NRPs) provide structured education, simulation-based learning, and preceptorship to ease the transition. Although its effect on improving retention of NGNs is well established in the literature, the effect on clinical competency has not been documented as well. The purpose of this integrative review is to appraise the available literature and synthesize the evidence that demonstrates the effect of NRPs on clinical competency of NGNs entering the critical care setting. Inclusion criteria were quantitative and qualitative studies, peer-reviewed studies published after 2004 and in English, identified through a systematic literature search using the CINAHL database. Critical appraisal of the articles was completed using Law et al's Critical Review Form. Eight articles (4 quantitative, 3 mixed method, and 1 qualitative study) met the inclusion criteria. The themes identified were common tools used to assess the efficacy of NRPs, improved clinical competency of NGNs, improved self-confidence, improved retention rates, and peer support among NGNs. Implications for nursing education and practice include applying evidence-based NRPs, incorporating simulation, enhancing sustainability, and reducing NRP variability through accreditation.}, } @article {pmid40010009, year = {2025}, author = {Mikuriya, S and Takegawa-Araki, T and Tamura, M}, title = {Edaravone mitigates TDP-43 mislocalization in human amyotrophic lateral sclerosis neurons with potential implication of the SIRT1-XBP1 pathway.}, journal = {Free radical biology & medicine}, volume = {230}, number = {}, pages = {283-293}, doi = {10.1016/j.freeradbiomed.2025.01.012}, pmid = {40010009}, issn = {1873-4596}, mesh = {*Edaravone/pharmacology ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *X-Box Binding Protein 1/genetics/metabolism ; *Motor Neurons/drug effects/metabolism/pathology ; Induced Pluripotent Stem Cells/drug effects/metabolism ; *Sirtuin 1/metabolism/genetics ; Endoplasmic Reticulum Stress/drug effects ; Signal Transduction/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss along with pathological mislocalization of TAR DNA-binding protein 43 (TDP-43), a protein implicated in RNA metabolism. Although edaravone, a free-radical scavenger, has been approved for ALS treatment, its precise mechanism of action is not fully understood, particularly in relation to TDP-43 pathology. Here, we investigated the effects of edaravone on induced pluripotent stem cell (iPSC)-derived motor neurons in a patient with ALS harboring a TDP-43 mutation. Our results demonstrated that edaravone significantly attenuated neurodegeneration, as evidenced by neurite preservation, neuronal cell death reduction, and correction of aberrant cytoplasmic localization of TDP-43. These neuroprotective effects were not observed with vitamin C, indicating a unique mechanism of action for edaravone, distinct from its antioxidative properties. RNA sequencing revealed that edaravone rapidly modulated gene expression, including protein quality control pathway, such as the ubiquitin-proteasome system. Further analysis identified X-box binding protein (XBP1), a key regulator of the endoplasmic reticulum stress response, as a critical factor in the therapeutic effects of edaravone. This study suggests that edaravone may offer a multifaceted therapeutic approach for ALS by targeting oxidative stress and TDP-43 mislocalization through distinct molecular pathways.}, } @article {pmid40011434, year = {2025}, author = {Gao, G and Shi, Y and Deng, HX and Krainc, D}, title = {Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1982}, pmid = {40011434}, issn = {2041-1723}, support = {R21 NS114765/NS/NINDS NIH HHS/United States ; NS114765//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS099623/NS/NINDS NIH HHS/United States ; R35 NS122257/NS/NINDS NIH HHS/United States ; NS122257//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS099623//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *Mitochondria/metabolism/enzymology ; *Ketoglutarate Dehydrogenase Complex/metabolism/genetics ; Humans ; *Lipid Peroxidation/drug effects ; *Parkinson Disease/metabolism/genetics/pathology ; Male ; Mice ; Disease Models, Animal ; alpha-Synuclein/metabolism ; Dopaminergic Neurons/metabolism/drug effects ; *Transcription Factors/genetics/metabolism ; Mice, Knockout ; Thioctic Acid/pharmacology ; DNA-Binding Proteins/metabolism/genetics ; Brain/metabolism ; *Mitochondrial Proteins/metabolism/genetics ; Ketoglutaric Acids/metabolism ; Mice, Inbred C57BL ; }, abstract = {Dysregulation of mitochondrial function has been implicated in Parkinson's disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human dopaminergic neurons. This deficiency of KGDH led to elevated α-ketoglutarate and increased lipid peroxidation. Treatment of CHCHD2-deficient dopaminergic neurons with lipoic acid, a KGDH cofactor and antioxidant agent, resulted in decreased levels of lipid peroxidation and phosphorylated α-synuclein. CHCHD10, a close homolog of CHCHD2 that is primarily linked to amyotrophic lateral sclerosis/frontotemporal dementia, did not affect the KGDH pathway or lipid peroxidation. Together, these results identify KGDH metabolic pathway as a targetable mitochondrial mechanism for correction of increased lipid peroxidation and α-synuclein in Parkinson's disease.}, } @article {pmid40011708, year = {2025}, author = {Yang, C and Lee, GB and Hao, L and Hu, F}, title = {TMEM106B deficiency leads to alterations in lipid metabolism and obesity in the TDP-43[Q331K] knock-in mouse model.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {315}, pmid = {40011708}, issn = {2399-3642}, support = {R01 NS088448/NS/NINDS NIH HHS/United States ; R21 AG078741/AG/NIA NIH HHS/United States ; R01NS088448//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS121608/NS/NINDS NIH HHS/United States ; R21AG078741//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01NS121608//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *Lipid Metabolism/genetics ; Mice ; *Membrane Proteins/genetics/deficiency/metabolism ; *Obesity/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Disease Models, Animal ; Gene Knock-In Techniques ; *Nerve Tissue Proteins/genetics/deficiency/metabolism ; Male ; Liver/metabolism ; Mice, Knockout ; *TDP-43 Proteinopathies/genetics/metabolism ; }, abstract = {The TMEM106B gene, encoding a lysosomal membrane protein, is closely linked with brain aging and neurodegeneration. TMEM106B has been identified as a risk factor for several neurodegenerative diseases characterized by aggregation of the RNA-binding protein TDP-43, including frontotemporal lobar degeneration (FTLD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). To investigate the role of TMEM106B in TDP-43 proteinopathy, we ablated TMEM106B in the TDP-43[Q331K] knock-in mouse line, which expresses an ALS-linked TDP-43 mutation at endogenous levels. We found that TMEM106B deficiency leads to glial activation, Purkinje cell loss, and behavioral deficits in TDP-43[Q331K] mice without inducing typical TDP-43 pathology. Interestingly, ablation of TMEM106B results in significant body weight gain, increased fat deposition, and hepatic triglyceride (TG) accumulation in TDP-43[Q331K] mice. In addition, lipidomic and transcriptome analysis shows a profound alteration in lipid metabolism in the liver of TDP-43[Q331K]Tmem106b[-/-] mice. Our studies reveal a novel function of TMEM106B and TDP-43 in lipid metabolism and provide new insights into their roles in neurodegeneration.}, } @article {pmid40011745, year = {2025}, author = {Rödström, KEJ and Eymsh, B and Proks, P and Hayre, MS and Cordeiro, S and Mendez-Otalvaro, E and Madry, C and Rowland, A and Kopec, W and Newstead, S and Baukrowitz, T and Schewe, M and Tucker, SJ}, title = {Cryo-EM structure of the human THIK-1 K2P K[+] channel reveals a lower Y gate regulated by lipids and anesthetics.}, journal = {Nature structural & molecular biology}, volume = {32}, number = {7}, pages = {1167-1174}, pmid = {40011745}, issn = {1545-9985}, support = {102161/WT_/Wellcome Trust/United Kingdom ; 215519/WT_/Wellcome Trust/United Kingdom ; MR/W017741/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; Cryoelectron Microscopy ; *Potassium Channels, Tandem Pore Domain/chemistry/metabolism/ultrastructure/genetics ; Halothane/pharmacology/chemistry ; Models, Molecular ; Binding Sites ; Ion Channel Gating/drug effects ; *Anesthetics/pharmacology ; Protein Conformation ; }, abstract = {THIK-1 (KCNK13) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K[+] channel implicated in microglial activation and neuroinflammation, and a current target for the treatment of neurodegenerative disorders, for example Alzheimer's disease and amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little is known about the structural and functional properties of THIK-1. Here we present a 3.16-Å-resolution cryo-EM structure of human THIK-1 that reveals several distinct features, in particular, a tyrosine in M4 that contributes to a lower 'Y gate' that opens upon activation by physiologically relevant G-protein-coupled receptor and lipid signaling pathways. We demonstrate that linoleic acid bound within a modulatory pocket adjacent to the filter influences channel activity, and that halothane inhibition involves a binding site within the inner cavity, both resulting in conformational changes to the Y gate. Finally, the extracellular cap domain contains positively charged residues that line the ion exit pathway and contribute to the distinct biophysical properties of this channel. Overall, our results provide structural insights into THIK-1 function and identify distinct regulatory sites that expand its potential as a drug target for the modulation of microglial function.}, } @article {pmid40012174, year = {2025}, author = {Rajamanickam, G and Hu, Z and Liao, P}, title = {Targeting the TRPM4 Channel for Neurologic Diseases: Opportunity and Challenge.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {31}, number = {5}, pages = {464-482}, doi = {10.1177/10738584251318979}, pmid = {40012174}, issn = {1089-4098}, mesh = {*TRPM Cation Channels/metabolism/antagonists & inhibitors ; Humans ; *Nervous System Diseases/metabolism/drug therapy ; Animals ; }, abstract = {As a monovalent cation channel, the transient receptor potential melastatin 4 (TRPM4) channel is a unique member of the transient receptor potential family. Abnormal TRPM4 activity has been identified in various neurologic disorders, such as stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, amyotrophic lateral sclerosis, pathologic pain, and epilepsy. Following brain hypoxia/ischemia and inflammation, TRPM4 up-regulation and enhanced activity contribute to the cell death of neurons, vascular endothelial cells, and astrocytes. Enhanced ionic influx via TRPM4 leads to cell volume increase and oncosis. Depolarization of membrane potential following TRPM4 activation and interaction between TRPM4 and N-methyl-d-aspartate receptors exacerbate excitotoxicity during hypoxia. Importantly, TRPM4 expression and activity remain low in healthy neurons, making it an ideal drug target. Current approaches to inhibit or modulate the TRPM4 channel have various limitations that hamper the interpretation of TRPM4 physiology in the nervous system and potentially hinder their translation into therapy. In this review, we discuss the pathophysiologic roles of TRPM4 and the different inhibitors that modulate TRPM4 activity for potential treatment of neurologic diseases.}, } @article {pmid40012394, year = {2025}, author = {Kumar, P and Kumar, A and Keerthipriya, M and H, C and Nalini, A and Vengalil, S and Sitani, K and Nagaraj, C and Dey, S and Debnath, M and K, V and Sathyaprabha, TN}, title = {A New Approach to Synthesize Carbon-11-PBR28 and its Clinical Validation in ALS Patients.}, journal = {Current radiopharmaceuticals}, volume = {18}, number = {3}, pages = {216-223}, pmid = {40012394}, issn = {1874-4729}, support = {5/4-5/184/Neuro/CAR-Phase-II/2018-NCD-I//Indian Council of Medical Research (ICMR)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging ; Humans ; *Carbon Radioisotopes/chemistry ; *Radiopharmaceuticals/chemical synthesis ; Positron-Emission Tomography/methods ; Male ; Middle Aged ; Female ; Magnetic Resonance Imaging ; Aged ; Receptors, GABA/metabolism ; Chromatography, High Pressure Liquid ; *Pyridines/chemical synthesis ; }, abstract = {INTRODUCTION: Many studies have reported translocator protein (TSPO) overexpression in various neurological disorders. Carbon-11[[11]C]PBR28 is a widely used TSPO Positron Emission Tomography (PET) radiopharmaceutical. We compared HPLC-based purification with cartridge-based purification and performed PET-MR imaging in ALS patients.

METHODS: [[11]C]PBR28 was synthesized using both an HPLC-based and cartridge-based purification technique on the FX2C chemistry module. We injected 350 ± 20 MBq of the [[11]C]PBR28 intravenously into the patients diagnosed with amyotrophic lateral syndrome (ALS) limb onset (n =3) and bulbar (n =3). Simultaneous PET-MR dynamic imaging was then performed.

RESULTS: The radiochemical purity exceeded 95% with both methods. Using the HPLC-based method, the radiochemical yield was 11.8 ± 3.3%, molar activity was 253 ± 20.9 GBq/μmol, and the total synthesis time of 25 ± 2 minutes. In contrast, the cartridge-based method yielded a radiochemical yield of 53.0 ± 3.6%, a molar activity of 885 ± 17.7 GBq/μmol, and a total synthesis time of 12 ± 2 minutes. In imaging results, higher activity was observed in the precentral gyrus and cerebellum at 2.5 ± 0.5 minutes in bulbar-onset ALS cases, with a standardized uptake value (SUV) of 2.3 ± 0.3. In contrast, limb-onset ALS cases showed the highest uptake at 0.5 ± 0.2 minutes, with an SUV of 1.5 ± 0.2.

DISCUSSION: The difference in SUV in bulbar and limb onset may be due to pathological changes.

CONCLUSION: The cartridge-based purification method provided higher radiochemical yield and molar activity as compared to the HPLC purification method.}, } @article {pmid40012679, year = {2025}, author = {Glashutter, M and Wijesinghe, P and Matsubara, JA}, title = {TDP-43 as a potential retinal biomarker for neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1533045}, pmid = {40012679}, issn = {1662-4548}, abstract = {TDP-43 proteinopathies are a spectrum of neurodegenerative diseases (NDDs) characterized by the pathological cytoplasmic aggregation of the TDP-43 protein. These include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and others. TDP-43 in the eye shows promise as a biomarker for these NDDs. Several studies have identified cytoplasmic TDP-43 inclusions in retinal layers of donors with ALS, FTLD, AD, CTE, and other conditions using immunohistochemistry. Our findings suggest that pathological aggregates of TDP-43 in the human retina are most prevalent in FTLD-TDP, ALS, and CTE, suggesting these diseases may provide the most reliable context for studying the potential of TDP-43 as a retinal biomarker. Animal model studies have been pivotal in exploring TDP-43's roles in the retina, including its nuclear and cytoplasmic localization, RNA binding properties, and interactions with other proteins. Despite these advances, more research is needed to develop therapeutic strategies. A major limitation of human autopsy studies is the lack of corresponding brain pathology assessments to confirm TDP-43 proteinopathy diagnosis and staging. Other limitations include small sample sizes, lack of antemortem eye pathology and clinical histories, and limited comparisons across multiple NDDs. Future directions for the TDP-43 as a retinal biomarker for NDDs include retinal tracers, hyperspectral imaging, oculomics, and machine learning development.}, } @article {pmid40012862, year = {2024}, author = {Tang, MB and Liu, YX and Hu, ZW and Luo, HY and Zhang, S and Shi, CH and Xu, YM}, title = {Study insights in the role of PGC-1α in neurological diseases: mechanisms and therapeutic potential.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1454735}, pmid = {40012862}, issn = {1663-4365}, abstract = {Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which is highly expressed in the central nervous system, is known to be involved in the regulation of mitochondrial biosynthesis, metabolic regulation, neuroinflammation, autophagy, and oxidative stress. This knowledge indicates a potential role of PGC-1α in a wide range of functions associated with neurological diseases. There is emerging evidence indicating a protective role of PGC-1α in the pathogenesis of several neurological diseases. As such, a deeper and broader understanding of PGC-1α and its role in neurological diseases is urgently needed. The present review provides a relatively complete overview of the current knowledge on PGC-1α, including its functions in different types of neurons, basic structural characteristics, and its interacting transcription factors. Furthermore, we present the role of PGC-1α in the pathogenesis of various neurological diseases, such as intracerebral hemorrhage, ischemic stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and other PolyQ diseases. Importantly, we discuss some compounds or drug-targeting strategies that have been studied to ameliorate the pathology of these neurological diseases and introduce the possible mechanistic pathways. Based on the available studies, we propose that targeting PGC-1α could serve as a promising novel therapeutic strategy for one or more neurological diseases.}, } @article {pmid40012994, year = {2025}, author = {Sabetta, E and Ferrari, D and Massimo, L and Kõks, S}, title = {Tandem repeat expansions and copy number variations as risk factors and diagnostic tools for amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1522445}, pmid = {40012994}, issn = {1664-2295}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder leading to upper and lower motoneurons degeneration. Although several mechanisms potentially involved in disease development have been identified, its pathogenesis is not fully understood. From the patient side, ALS diagnosis, still based on clinical criteria, can be difficult and may take up to 1 year. More than 30 genes have been associated to genetically inherited ALS, among which four (C9ORF72, SOD1, TARDBP and FUS) would explain around 60-70% of cases. However, familial ALS represents only 5-10% of ALS cases while the remaining are sporadic, with genetics explaining 6-10% of such cases only. In this context, short tandem repeats (STRs) expansions, have recently been found in clinically diagnosed ALS patients. In this review, we discuss the recent discoveries on ALS associated STRs and their potential as biomarkers as well as prognosis and therapy targets.}, } @article {pmid40013906, year = {2025}, author = {Howard, J and Bekker, HL and McDermott, CJ and McNeill, A}, title = {Exploring the needs and preferences of people with amyotrophic lateral sclerosis (ALS) when making genomic testing decisions: an interview study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {436-443}, doi = {10.1080/21678421.2025.2469727}, pmid = {40013906}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology/diagnosis ; Male ; Female ; Middle Aged ; *Genetic Testing/methods ; Aged ; *Decision Making ; *Patient Preference/psychology ; Adult ; Whole Genome Sequencing ; Interviews as Topic ; Genetic Counseling/psychology ; United Kingdom ; }, abstract = {Objective: Whole Genome Sequencing (WGS) for amyotrophic lateral sclerosis (ALS) (also known as motor neuron disease, MND) raises multiple considerations and has a range of implications for individuals and their family. However, it is unclear what needs people with ALS have when making genomic testing decisions. This study explores the experiences, needs and preferences of these individuals when considering WGS and going through the process. Methods: A semi-structured interview study was carried out with 14 people with ALS from across the UK who had, or were considering, WGS. Participants were recruited from a local ALS care center and MND Association/MND Scotland channels. Data were analyzed using framework analysis. Results: Findings indicate variation in (a) how WGS and access to pretest genetic counseling is provided, (b) the perceived adequacy of information to support decision-making and prepare people with ALS for their test result and its consequences, and (c) preferences for making decisions with family and health professionals that best meets their clinical and life needs along the care pathway. Conclusions: There is an urgent need for people with ALS to have relevant, accurate and accessible information that supports proactively their decision-making around WGS, particularly in the context of genetically-targeted treatments and clinical trials. These findings will contribute to the development of a shared decision-making intervention supporting people with ALS to make genomic testing decisions with their family and neurology services.}, } @article {pmid40014834, year = {2025}, author = {Gusovsky Chevalier, AV and Lin, CC and Kerber, K and Reynolds, EL and Callaghan, BC and Burke, JF}, title = {Cost Trends of New-To-Market Neurologic Medications: An Insurance Claims Database Analysis.}, journal = {Neurology}, volume = {104}, number = {6}, pages = {e213428}, pmid = {40014834}, issn = {1526-632X}, support = {T32 HS029590/HS/AHRQ HHS/United States ; }, mesh = {Humans ; Male ; Female ; Databases, Factual ; United States ; *Nervous System Diseases/drug therapy/economics ; Middle Aged ; Aged ; Adult ; *Drug Costs/trends ; Migraine Disorders/drug therapy/economics ; Insurance Claim Review ; Young Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: Costs for neurologic medications have increased considerably in recent years. Since 2014, more than 30 neurologic medications have been approved by the US Food and Drug Administration (FDA) for neurologic conditions. This study aims to characterize recent trends in annual costs and aggregate spending from 2012 to 2021 for new-to-market (NTM) medications for 9 neurologic conditions.

METHODS: We used the Merative MarketScan commercial and Medicare supplemental databases to observe patients seen by a neurologist with neurologic diseases with newly FDA-approved medications from 2014 to 2021: amyotrophic lateral sclerosis (ALS), transthyretin amyloidosis (ATTR), Duchenne muscular dystrophy (DMD), Huntington disease (HD), myasthenia gravis (MG), migraine, orthostatic hypotension (OH), tardive dyskinesia (TD), and spinal muscular atrophy (SMA). Patients were included if they had ≥1 disease-related prescription medication fill from 2012 to 2021. NTM (medications approved from 2014 to 2021) and older evidence-based guideline-supported medications were observed annually. Outcomes examined were annual and aggregate out-of-pocket (OOP) and total medication costs.

RESULTS: We identified 2,687 unique individuals with ALS, 38 with ATTR, 69 with DMD, 884 with HD, 9,984 with MG, 441,099 with migraine, 4,723 with OH, 1,266 with TD, and 17 with SMA. The youngest population was DMD (mean = 25 years [SD = 7]), and the oldest was TD (mean = 66 years [SD = 14]). For DMD, the population was 99% male and for migraine, the population was 84% female, and the other conditions had more relatively even sex divides. Collectively, migraine medications had the largest increase in aggregate costs (1993%) and had a substantial increase in OOP costs on average by 234% ($86-$288). Eculizumab for MG was an extreme outlier, with OOP costs increasing by 4,099% ($413-$17,359) and aggregate OOP costs by 7,005% ($5,375-$381,894). OOP costs of edaravone ($304-$5,707) and deutetrabenazine ($670-$7,170) sharply increased by 1,775% and 971%, respectively.

DISCUSSION: NTM medications for neurologic conditions have substantial and increasing individual and societal costs, which was not observed for older generic medications. These data suggest a need for policies to limit the financial burden of NTM medications on patients with neurologic conditions.}, } @article {pmid40015643, year = {2025}, author = {Hasumi, M and Ito, H and Machida, K and Niwa, T and Taminato, T and Nagai, Y and Imataka, H and Taguchi, H}, title = {Dissecting the mechanism of NOP56 GGCCUG repeat-associated non-AUG translation using cell-free translation systems.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {4}, pages = {108360}, pmid = {40015643}, issn = {1083-351X}, mesh = {Humans ; Cell-Free System ; *Protein Biosynthesis ; *Nuclear Proteins/genetics/metabolism ; Introns ; Spinocerebellar Ataxias/genetics/metabolism ; Codon, Initiator/genetics ; *RNA, Small Nucleolar/genetics/metabolism ; *Trinucleotide Repeat Expansion ; }, abstract = {The repeat expansion in the human genome contributes to neurodegenerative disorders such as spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis. Transcripts with repeat expansions undergo noncanonical translation called repeat-associated non-AUG (RAN) translation. The NOP56 gene, implicated in SCA36, contains a GGCCTG repeat in its first intron. In tissues of patients with SCA36, poly (Gly-Pro) and poly (Pro-Arg) peptides, likely produced through NOP56 RAN translation in (NOP56-RAN), have been detected. However, the detailed mechanism underlying NOP56-RAN remains unclear. To address this, we used cell-free translation systems to investigate the mechanism of NOP56-RAN and identified the following features. (i) Translation occurs in all reading frames of the sense strand of NOP56 intron 1. (ii) Translation is initiated in a 5' cap-dependent manner from near-cognate start codons upstream of the GGCCUG repeat in each frame. (iii) Longer GGCCUG repeats enhance NOP56-RAN. (iv) A frameshift occurs within the GGCCUG repeat. These findings provide insights into the similarities between NOP56-RAN and other types of RAN translation.}, } @article {pmid40015855, year = {2025}, author = {Xu, Y and Xu, F and Li, Y and Wang, X and Han, Y and Zheng, M}, title = {Effects of Pro197 resistance mutations occurring in different acetolactate synthase (ALS) isozymes on Descurainia sophia L. resistance to tribenuron-methyl.}, journal = {Pesticide biochemistry and physiology}, volume = {208}, number = {}, pages = {106263}, doi = {10.1016/j.pestbp.2024.106263}, pmid = {40015855}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Arylsulfonates/pharmacology ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Mutation ; Isoenzymes/genetics/metabolism ; *Plant Proteins/genetics/metabolism ; }, abstract = {Descurainia sophia L. is one of the most problematic broad-leaf weed infesting winter wheat in China, and have evolved resistance to acetolactate synthase (ALS)-inhibiting herbicide of tribenuron-methyl. At least four ALS isozymes (ALS1 ∼ ALS4) exist in D. sophia, but these four ALS isozymes are not present in all D. sophia. In addition, amino acid mutations in ALS are mainly responsible for D. sophia resistance to tribenuron-methyl. In this study, D. sophia populations carrying homozygous mutation of Pro197Ser/Thr/Leu/Ala/His in ALS1 or in ALS2 were purified, respectively. Resistant D. sophia populations carrying mutant ALS exhibited 17 ∼ 694 folds resistance to tribenuorn-methyl. In addition, tribenuron-methyl resistance in D. sophia carrying ALS1 mutation was about 2.3 ∼ 11.4 folds higher than D. sophia with the same mutation in ALS2. The reduced binding affinity of ALS to tribenuron-methyl was mainly responsible for D. sophia resistance to tribenuron-methyl. However, the increase in resistance of D. sophia was not linear with the decrease of binding affinity of ALS to tribenuron-methyl. These results indicate that the effects of resistance mutations on ALS1 and ALS2 isozymes are not the same, and the ALS1 and ALS2 function differently in resistance evolution of D. sophia to tribenuron-methyl.}, } @article {pmid40015858, year = {2025}, author = {Vijayarajan, VBA and Torra, J and Runge, F and de Jong, H and van de Belt, J and Hennessy, M and Forristal, PD}, title = {Confirmation and characterisation of ALS inhibitor resistant Poa trivialis from Ireland.}, journal = {Pesticide biochemistry and physiology}, volume = {208}, number = {}, pages = {106266}, doi = {10.1016/j.pestbp.2024.106266}, pmid = {40015858}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/antagonists & inhibitors/genetics ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Ireland ; Sulfonylurea Compounds/pharmacology ; Sulfonamides/pharmacology ; Mutation ; Plant Proteins/genetics/antagonists & inhibitors/metabolism ; *Enzyme Inhibitors/pharmacology ; Plant Weeds/drug effects/genetics ; }, abstract = {Relying on one broad-spectrum product to control grass weeds has resulted in cases of resistance to acetolactate synthase (ALS) inhibitors in species that were not the primary target such as Poa trivialis (POATR), in wheat fields in Ireland. In this study, we have characterised ALS inhibitor resistance in two populations of POATR-R, suspected of being resistant, to (i) sulfonylurea (SUs)-mesosulfuron + iodosulfuron (the selecting agent), (ii) SU + sulfonylamino‑carbonyl-triazolinone (SCT)-mesosulfuron + propoxycarbazone, and (iii) triazolopyrimidine (TP)-pyroxsulam ALS chemistries. Resistant POATR-R populations showed ALS inhibitor cross-resistance associated with target-site resistance (TSR) mutations. Combined mutations (Pro-197 and Trp-574) were found in POATR-R plants; Trp-574-Leu in POATR-R1 conferring greater SUs, SU + SCT and TP (resistance index, RI >214) resistance, while Pro-197-Thr in POATR-R2 (RI >37) was associated with less resistance. The high levels of ALS inhibitor cross-resistance in POATR-R populations caused by TSR mutations are consistent with the ploidy status, as cytogenetic tests revealed that both the R and S populations were diploid (2n = 2× = 14). Cytochrome P450 inhibitor assays did not detect metabolism-based ALS resistance in POATR-R. Alternative herbicide modes of action, including acetyl-CoA carboxylase (pinoxaden, fenoxaprop, propaquizafop, cycloxydim or clethodim) and 5-enolpyruvylshikimate-3-phosphate synthase (glyphosate) inhibitors applied at the recommended label rate were highly effective on these resistant populations. Residual herbicides and cultural methods, as well as the judicious use of alternative in-crop herbicide options, should be prioritized as sustainable options for managing these ALS-resistant populations. This is first worldwide characterisation of resistance mechanisms in P. trivialis to ALS inhibitor chemistries.}, } @article {pmid40016300, year = {2025}, author = {Xia, Y and Gregory, JM and Waldron, FM and Spence, H and Vallejo, M}, title = {Improving ALS detection and cognitive impairment stratification with attention-enhanced deep learning models.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {7045}, pmid = {40016300}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/diagnostic imaging/complications ; *Deep Learning ; *Cognitive Dysfunction/diagnosis/diagnostic imaging ; Male ; Female ; Middle Aged ; Aged ; *Attention ; Neuroimaging/methods ; Brain/diagnostic imaging/pathology ; Neural Networks, Computer ; Frontotemporal Dementia/diagnosis ; Early Diagnosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease marked by motor deterioration and cognitive decline. Early diagnosis is challenging due to the complexity of sporadic ALS and the lack of a defined risk population. In this study, we developed Miniset-DenseSENet, a convolutional neural network combining DenseNet121 with a Squeeze-and-Excitation attention mechanism, using 190 autopsy brain images from the Gregory Laboratory at the University of Aberdeen. The model distinguishes controls, ALS patients with no cognitive impairment, and ALS patients with cognitive impairment (ALS-frontotemporal dementia) with 97.37% accuracy, addressing a significant challenge in overlapping neurodegenerative disorders involving TDP-43 proteinopathy. Miniset-DenseSENet outperformed other transfer learning models, achieving a sensitivity of 1 and specificity of 0.95. These findings suggest that integrating transfer learning and attention mechanisms into neuroimaging can enhance diagnostic accuracy, enabling earlier ALS detection and improving patient stratification. This model has the potential to guide clinical decisions and support personalied therapeutic strategies.}, } @article {pmid40017137, year = {2025}, author = {Lovett, A and Chary, S and Babu, S and Bruneteau, G and Glass, JD and Karlsborg, M and Ladha, S and Mayl, K and McDermott, C and Bucelli, RC and Chiò, A and Ferguson, TA and Cochrane, T and Fradette, S and Smirnakis, K and Inra, J and Malek, S and Fanning, L}, title = {Serious Neurologic Adverse Events in Tofersen Clinical Trials for Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {71}, number = {6}, pages = {1006-1015}, pmid = {40017137}, issn = {1097-4598}, support = {//Biogen/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Middle Aged ; Male ; Female ; *Oligonucleotides/adverse effects/therapeutic use ; Adult ; Aged ; Superoxide Dismutase-1/genetics ; Myelitis/chemically induced ; Papilledema/chemically induced ; }, abstract = {INTRODUCTION/AIMS: Tofersen is approved for the treatment of amyotrophic lateral sclerosis (ALS) due to superoxide dismutase 1 mutations (SOD1-ALS). Here we report serious neurologic adverse events (AEs) that occurred in the tofersen clinical trials in people with SOD1-ALS.

METHODS: Serious neurologic AEs of myelitis, radiculitis, aseptic meningitis, and papilledema reported in the tofersen clinical trials are described. Serious AEs were defined according to International Conference for Harmonization guidelines, and neurologic AEs in clinical trials were diagnosed by investigators based on symptoms, clinical examination findings, and diagnostic workup.

RESULTS: Ten participants (approximately 7% of tofersen 100-mg-treated trial participants) experienced a total of 12 serious neurologic AEs-4 of myelitis, 2 of radiculitis, 2 of aseptic meningitis, and 4 of intracranial hypertension (ICH) and/or papilledema. All events but one resolved either spontaneously, with dosing interruption/modification, or with concomitant therapies. One event was ongoing but improved as of December 2022. While 3 events led to tofersen treatment discontinuation, all other participants were able to remain on treatment. No event was life-threatening or fatal.

DISCUSSION: Some antisense oligonucleotides (ASOs) have been described as having pro-inflammatory properties. Aseptic meningitis has been reported with nusinersen; however, myelitis, radiculitis, increased intracranial pressure, and papilledema have not been reported with ASO treatment. These neurologic AEs should be considered when assessing the overall benefit/risk of tofersen treatment for SOD1-ALS. Safety data from the open-label extension and expanded access program will continue to characterize these events and further inform the safety profile of tofersen in SOD1-ALS.}, } @article {pmid40017539, year = {2025}, author = {Mengistu, DY and Terribili, M and Pellacani, C and Ciapponi, L and Marzullo, M}, title = {Epigenetic regulation of TDP-43: potential implications for amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular medicine}, volume = {5}, number = {}, pages = {1530719}, pmid = {40017539}, issn = {2674-0095}, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the progressive degeneration of motor neurons. One of the key pathogenic factors implicated in ALS is TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the TARDBP gene. Under normal physiological conditions, TDP-43 predominantly resides in the nucleus, where it plays a critical role in regulating gene expression, alternative splicing, RNA transport, and stability. In ALS, TDP-43 undergoes pathological mislocalization from the nucleus to the cytoplasm, disrupting its normal function and contributing to disease progression. The nuclear loss of TDP-43 leads to widespread dysregulation of RNA metabolism. Moreover, mislocalized TDP-43 aggregates in the cytoplasm, acquires toxic properties that sequester essential RNA molecules and proteins. Importantly, deviations in TDP-43 levels, whether excessive or reduced, can lead to cellular dysfunction, and contribute to disease progression, highlighting the delicate balance required for neuronal health. Emerging evidence suggests that epigenetic mechanisms may play a crucial role in regulating TARDBP expression and, consequently, TDP-43 cellular levels. Epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNAs are increasingly recognized as modulators of gene expression and cellular function in neurodegenerative diseases, including ALS. Dysregulation of these processes could contribute to aberrant TARDBP expression, amplifying TDP-43-associated pathologies. This review explores and summarizes the recent findings on how specific epigenetic modifications influence TDP-43 expression and discusses their possible implications for disease progression.}, } @article {pmid40017821, year = {2025}, author = {Dierksen, F and Geibel, JS and Albrecht, J and Hofer, S and Dechent, P and Hesse, AC and Frahm, J and Bähr, M and Koch, JC and Liman, J and Maier, IL}, title = {T1-relaxation times along the corticospinal tract as a diagnostic marker in patients with amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroimaging}, volume = {4}, number = {}, pages = {1549727}, pmid = {40017821}, issn = {2813-1193}, abstract = {BACKGROUND AND PURPOSE: In the differential diagnostic workup of amyotrophic lateral sclerosis (ALS), magnetic resonance imaging (MRI) is primarily used to rule out significant differential diagnoses. So far, whole-brain T1-mapping has not been assessed as a diagnostic tool in this patient population.

METHODS: We investigated the diagnostic potential of a novel T1-mapping method based on real-time MRI with 0.5 mm in-plane resolution and 4s acquisition time per slice. The study included patients aged 18 to 90 years who met the revised El Escorial criteria for at least possible ALS. T1-relaxation times were measured along the corticospinal tract in predefined regions of interest.

RESULTS: Twenty-nine ALS-patients and 43 control group patients (CG) were included in the study. Median ALS Functional Rating Scale revised (ALSFRS-R) was 37 (IQR, 35-44) points and the mean duration from symptom onset to MRI was 21 ± 17 (SD) months. ALS patients showed significantly higher T1-relaxation times in all ROIs compared to CG with mean differences in the hand knob of 50 ms (p < 0.001), corona radiata 24 ms (p = 0.034), internal capsule 27 ms (p = 0.002) and midbrain peduncles 48 ms (p < 0.001). There was a consistent negative correlation between the ALSFRS-R and T1-relaxation times in all ROIs.

CONCLUSIONS: T1-relaxation times along the corticospinal tract are significantly elevated in ALS patients compared to CG and associated with lower ALSFRS-R. These results imply the analysis of T1-relaxation times as a promising diagnostic tool that can distinguish ALS patients from the control group. Ongoing longitudinal studies may provide deeper insights into disease progression and the effects of therapeutic interventions.}, } @article {pmid40019378, year = {2025}, author = {Li, X and Jin, S and Wang, D and Wu, Y and Tang, X and Liu, Y and Yao, T and Han, S and Sun, L and Wang, Y and Hou, SX}, title = {Accumulation of Damaging Lipids in the Arf1-Ablated Neurons Promotes Neurodegeneration through Releasing mtDNA and Activating Inflammatory Pathways in Microglia.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {16}, pages = {e2414260}, pmid = {40019378}, issn = {2198-3844}, support = {2023YFA1800202//National Key Research and Development Program of China/ ; 82450108//National Natural Science Foundation of China/ ; 82203511//National Natural Science Foundation of China/ ; 82472817//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *DNA, Mitochondrial/metabolism/genetics ; *Neurons/metabolism ; *Microglia/metabolism ; Mice ; *ADP-Ribosylation Factor 1/genetics/metabolism ; Mice, Knockout ; *Lipid Metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics ; Mitochondria/metabolism ; Endoplasmic Reticulum Stress ; Autophagy ; *Inflammation/metabolism ; }, abstract = {Lipid metabolism disorders in both neurons and glial cells have been found in neurodegenerative (ND) patients and animal models. However, the pathological connection between lipid droplets and NDs remains poorly understood. The recent work has highlighted the utility of a neuron-specific Arf1-knockout mouse model and corresponding cells for elucidating the nexus between lipid metabolism disorders and amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). In this study, it is found that Arf1 deficiency first induced surplus fatty acid synthesis through the AKT-mTORC1-SREBP1-FASN axis, which further triggered endoplasmic reticulum (ER)-mitochondrial stress cascade via calcium flux. The organelle stress cascade further caused mitochondrial DNA (mtDNA) to be released into cytoplasm. Concurrently, the FASN-driven fatty acid synthesis in the Arf1-deficient neurons might also induce accumulation of sphingolipids in lysosomes that caused dysfunction of autophagy and lysosomes, which further promoted lysosomal stress and mitochondria-derived extracellular vesicles (MDEVs) release. The released MDEVs carried mtDNA into microglia to activate the inflammatory pathways and neurodegeneration. The studies on neuronal lipid droplets (LDs) and recent studies of microglial LDs suggest a unified pathological function of LDs in NDs: activating the inflammatory pathways in microglia. This finding potentially provides new therapeutic strategies for NDs.}, } @article {pmid40019589, year = {2025}, author = {Shaw, SK and Sravani, N and Sharma, A and Anand, J}, title = {Assessment of probable zones of agricultural land suitability based on MCDM, probabilistic, and data-driven approach in Krishna District, India.}, journal = {Environmental monitoring and assessment}, volume = {197}, number = {3}, pages = {339}, pmid = {40019589}, issn = {1573-2959}, mesh = {*Agriculture/statistics & numerical data ; Conservation of Natural Resources/methods ; Decision Making ; *Decision Support Techniques ; Ecosystem ; Geographic Information Systems ; India ; Meteorological Concepts ; Remote Sensing Technology ; }, abstract = {Agricultural land evaluation is essential for crop cultivation for fostering a sustainable and productive agricultural system. To address this issue, this current study implements geographic information system (GIS)-based analytical hierarchy process (AHP), frequency ratio (FR), Shannon entropy (SE), and evidential belief function (EBF) models for possible identification of agricultural land in Krishna district, India. Eight thematic layers viz. rainfall, temperature, soil texture, slope, soil moisture index, organic matter content, groundwater level, and land use/land cover (LULC) exhibit their relative contribution toward the agricultural land suitability (ALS) assessment. A total of 56 groundwater wells are considered to prepare well inventory map. Then, 70% (40) and 30% (16) wells are taken to perform accuracy assessment of the proposed methods in training and validation phase respectively by receiver operating characteristics (ROC) curve and Seed Cell Area Index (SCAI) method. Four distinct classes of ALS have been delineated by each model viz. poor, moderate, high, and very high. AHP (79.05%) and SE (89.94%) showcases their effectiveness in delineating highly suitable agricultural land constituting higher area. Whereas EBF and FR model identifies 33.35% and 27% area of this district as moderate to poor ALS respectively. AUC value reveals that AHP (AUC = 0.701) method can be highly convenient in training phase, whereas EBF (AUC = 0.626) model evaluates average predictive strength for ALS assessment in validation phase for this study area. Outcomes of SCAI method demonstrate higher classification accuracy of SE model indicating higher suitability of bivariate approaches in accurate prediction. Results of this research significantly develop useful perception for the sustainable use and management of agricultural land of Krishna district with higher crop production. This will also help the Agricultural and Irrigation department of this district to build applicative plan for effective utilization of agricultural land with optimized use of available water resources.}, } @article {pmid40019593, year = {2025}, author = {Dobroniak, CC and Lesche, V and Olgemöller, U and Beck, P and Lehmann, W and Spering, C}, title = {Surgical strategy for chest wall reconstruction secondary to cardiopulmonary resuscitation versus post-traumatic.}, journal = {European journal of trauma and emergency surgery : official publication of the European Trauma Society}, volume = {51}, number = {1}, pages = {122}, pmid = {40019593}, issn = {1863-9941}, mesh = {Humans ; *Cardiopulmonary Resuscitation/adverse effects ; Male ; *Flail Chest/surgery/etiology ; Female ; Middle Aged ; Retrospective Studies ; *Thoracic Wall/surgery ; *Rib Fractures/surgery ; Sternum/injuries/surgery ; Adult ; *Plastic Surgery Procedures/methods ; *Fracture Fixation, Internal/methods ; Aged ; Length of Stay/statistics & numerical data ; *Thoracic Injuries/surgery ; Germany ; Bone Plates ; Treatment Outcome ; }, abstract = {PURPOSE: In mechanically cardiopulmonary resuscitated (CPR) patients, chest compressions at the level of the 3rd to 5th rib on the sternum result in reproducibly similar injury patterns: parasternal osteochondral dissociation (OCS) on both sides in combination with a sternal fracture with or without an additional serial rib fracture in the anterolateral column (ALS). This injury biomechanically impairs physiological breathing, resulting in an inverse breathing pattern. Trauma patients, on the other hand, often show a mixed pattern depending on the location of the main energy. The aim of the study was to evaluate the surgical technique of chest wall reconstruction (CWR) using transsternal refixation of the 5th rib on both sides in combination with plate osteosynthesis of the sternum and to analyze its success in comparison to the surgical strategy of CWR in the context of a traumatic genesis.

METHOD: Data acquisition was performed using medical records of a Level I Trauma Centre in Germany and compare patients with radiologically or clinically diagnosed flail chest as a result of cardiopulmonary mechanical resuscitation (CPR). The retrospective study included patients in the period 2018-2023 after surgical CWR. The patients were either post-CPR (n = 29; CPR) or trauma patients (n = 36; trauma). The collective was described and analyzed using the digital patient file, as well as data on ICU stay and duration of ventilation or conversion to assisted ventilation modes, reason for chest wall instability, time of surgery, length of stay and mortality. As a long-term follow-up, body plethysmography was analyzed comparatively. Primary endpoints were mean length of stay in ICU, time to surgery, ventilator dependency and mortality rate. Secondary endpoints were time to transfer to rehabilitation, ventilation disorders and long term outcome.

RESULTS: In the period 65 patients (48 m, 17w) were included, 29 of whom had been mechanically resuscitated (CPR), 36 formed to post-traumatic cohort (trauma). The CPR were significantly older (69 vs. 58 years; p-value 0.003). The duration from CPR to surgery was on average significantly longer than trauma to surgery (16.76 vs. 4.11 days). The mean length of stay in ICU were 30 days (trauma) and 45 days for CPR (significantly longer, p-value 0.0008). The mean duration of ventilation was 188 h for trauma and 593 h for CPR. Extubation or conversion to assisted, relevant de-escalating ventilation modes was possible in both groups after a mean of 38 h post-OP. Among the CPR patients, 4 died in hospital (hospital mortality: CPR 20.7% vs. trauma 5.6%), 7 (30%) were transferred to an early clinical rehabilitation and 10 were discharged to home or follow-up treatment. In the case of trauma, 5 (14.7%) were transferred to an early clinical rehabilitation and 20 were discharged to home or follow-up treatment. Bodyplethysmography 6 months after CPR / trauma showed no differences in both collectives with regard to ventilation disorders. Diffusion was prolonged in both groups, presumably due to the healing process of lungs contusion. Both showed no restriction disorders.

CONCLUSION: Chest wall reconstruction, including plate osteosynthesis of the sternum in combination with transsternal fixation of the 5th rib on both sides can largely restore physiological respiratory mechanics immediately after surgery and accelerate the weaning success. In the management of patients after CPR, the initial diagnosis which had indicated resuscitation, is the main focus and can often be an obstacle to extubation. Nevertheless, independent breathing can be accelerated by restoring the biomechanics through early surgical treatment using CWR and saves long-term ICU stays with the potential for further complication and resource consumption. CWR forms the essential basis for early rehabilitation of the underlying cause of resuscitation. Ventilation disorders do not occur after surgical CWR, even during the course of the procedure.}, } @article {pmid40020551, year = {2025}, author = {Tafuri, B and Giugno, A and Nigro, S and Zoccolella, S and Barone, R and Tamburrino, L and Gnoni, V and Urso, D and Rollo, E and De Blasi, R and Logroscino, G}, title = {Radiomic alterations and clinical correlates of hypothalamic nuclei in ALS.}, journal = {Computers in biology and medicine}, volume = {189}, number = {}, pages = {109906}, doi = {10.1016/j.compbiomed.2025.109906}, pmid = {40020551}, issn = {1879-0534}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; Male ; Female ; Middle Aged ; *Hypothalamus/diagnostic imaging ; Aged ; *Magnetic Resonance Imaging ; Retrospective Studies ; Adult ; Body Mass Index ; Radiomics ; }, abstract = {OBJECTIVE: The aim of this study is to analyze hypothalamic changes and clinical/metabolic correlates with a radiomic approach in Amyotrophic Lateral Sclerosis (ALS).

METHODS: We retrospectively identified 54 sporadic ALS patients and 53 matched controls. We compared radiomics features over hypothalamic subunits in T1-weighted. Semi-partial correlation (Spearman's correlation) assessed the relationship between Body Mass Index (BMI) and clinical scores with radiomics features. We considered only moderate correlations (rho>|0.4|).

RESULTS: Compared to HC, individuals with ALS showed significantly higher values of radiomic measures in the left Anterior-Inferior, Posterior and Inferior-Tubular hypothalamic subunits. Similarly, right hypothalamic nuclei reported significant differences in Anterior-Superior, Posterior and Inferior-Tubular nuclei. Two radiomics measures of randomness of the intensities in left Anterior-Inferior subunit showed highly significant correlation with greater BMI values. Higher local homogeneity of the right Inferior-Tubular subunit corresponded to higher ALS Functional Rating Scale-Revised (ALSFRS-r), while finer textures of the left Anterior-Superior subunit were negatively related with disease progression rate.

CONCLUSIONS: These results support the hypothesis that a degenerative process affecting hypothalamus in ALS extends beyond the atrophy process. Intriguingly, the close relationship between the entropy of left Anterior-Inferior nucleus and the higher BMI may further demonstrate the critical role of hypothalamus in eating abnormalities. Furthermore, the inhomogeneity of the right Inferior-Tubular subunit reflects a more severe clinical condition by ALSFRS-R. This work represents a significant advancement in the study of ALS and its association with hypothalamic changes through a novel radiological approach, uncovering new associations between sub-hypothalamic radiomic changes, anthropometric measures, and disease outcomes.}, } @article {pmid40021952, year = {2025}, author = {Hao, Y and Li, Z and Du, X and Xie, Q and Li, D and Lei, S and Guo, Y}, title = {Characterization and chemoproteomic profiling of protein O-GlcNAcylation in SOD1-G93A mouse model.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {31}, number = {1}, pages = {82}, pmid = {40021952}, issn = {1528-3658}, support = {92478109//National Natural Science Foundation of China/ ; 82471451//National Natural Science Foundation of China/ ; ZR2024QB108//Shandong Provincial Natural Science Foundation/ ; 7222082//Beijing Municipal Natural Science Foundation，China/ ; }, mesh = {Animals ; Disease Models, Animal ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Mice ; *Proteomics/methods ; *Acetylglucosamine/metabolism ; Mice, Transgenic ; *Superoxide Dismutase-1/genetics/metabolism ; Spinal Cord/metabolism/pathology ; *Protein Processing, Post-Translational ; Glycosylation ; Humans ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. Protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification has been found to affect the processing of several important proteins implicated in ALS. However, the overall level and cellular localization of O-GlcNAc during ALS progression are incompletely understood, and large-scale profiling of O-GlcNAcylation sites in this context remains unexplored.

METHODS: By using immunostaining analysis and chemoenzymatic labeling-based quantitative chemoproteomics, we assayed O-GlcNAcylation dynamics of lumbar spinal cords from SOD-G93A mice and their non-transgenic (NTG) littermates, the most widely used animal model for studying ALS pathogenesis.

RESULTS: We discovered that the global O-GlcNAcylation was significantly reduced at the disease end stage. Correlatively, a great increase of OGA was observed. Immunohistochemistry and immunofluorescence analysis showed a higher proportion of O-GlcNAc-positive neurons in the NTG group, while O-GlcNAc colocalization with astrocytes/microglia was elevated in SOD1-G93A mice. Moreover, we reported the identification of 568 high-confidence O-GlcNAc sites from end-stage SOD1-G93A and NTG mice. Of the 568 sites, 226-many of which occurred on neuronal function and structure-related proteins-were found to be dynamically regulated.

CONCLUSION: These data provide a valuable resource for dissecting the functional role of O-GlcNAcylation in ALS and shed light on promising therapeutic avenues for ALS. The chemoenzymatic labeling-based chemoproteomic approach is applicable for probing O-GlcNAc dynamics in various pathological processes.}, } @article {pmid40022581, year = {2025}, author = {Galvin, M and Heverin, M and Mac Domhnaill, É and Mcfarlane, R and Meldrum, D and Murray, D and Bolger, A and Connelly, J and Flynn, K and Fox, E and Gibbons, F and Hederman, L and Impey, S and O'Keefe, I and O'Meara, C and McKibben, D and Nicholson, M and Stephens, G and Van Dijk, J and Van Den Berg, L and Hardiman, O}, title = {Challenges and solutions to complex data governance issues in cross-national, cross-sectoral, multidisciplinary real world health research: a descriptive overview.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {1-7}, doi = {10.1080/21678421.2024.2428927}, pmid = {40022581}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology ; *Biomedical Research ; *Precision Medicine ; Europe ; *Data Management ; }, abstract = {Real-world clinical data is generated during clinical engagements. The collection and further processing and mining of clinical information requires consents and navigation of necessary and important data governance processes. PRECISION ALS is an academic industry programme that collects, collates and analyses clinical and para-clinical data from patients with ALS across 10 European sites. The infrastructure of PRECISION ALS represents a complex interplay of the clinical, governance, and technical frameworks. Incorporation of infrastructural and operational measures enables sophisticated cross-national, cross-sectoral and cross disciplinary health research. PRECISION ALS has established a range of domain expertise, technologies, governance and clinical data management practices that can be applied throughout the life cycle of patient data from generation, collation, delivery and secure storage for advanced analytics. PRECISION ALS is designed to move the field of ALS research to a true Precision Medicine based approach toward new and more effective therapeutics.}, } @article {pmid40022663, year = {2025}, author = {Buckett, LE and Holdom, CJ and Howe, SL and McCombe, PA and Henderson, RD and Al-Chalabi, A and Steyn, FJ and Ngo, ST}, title = {Persistent high levels of perceived fatigue are not associated with hypermetabolism in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {485-494}, doi = {10.1080/21678421.2025.2471429}, pmid = {40022663}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/complications/psychology/physiopathology ; Male ; Female ; *Fatigue/etiology/metabolism/diagnosis/psychology ; Middle Aged ; Prospective Studies ; Aged ; Disease Progression ; Severity of Illness Index ; Self Report ; Adult ; }, abstract = {Objective: Fatigue is a common symptom in amyotrophic lateral sclerosis (ALS). Little is known about factors that contribute to fatigue, and whether levels of fatigue change throughout disease course. We aimed to determine associations between self-reported perceived fatigue and metabolic and clinical features of ALS, and perceived fatigue over the course of disease. Methods: This prospective study was conducted between July 2017 and March 2024. Baseline measures of self-reported perceived fatigue, metabolic rate, and clinical measures of disease were assessed in 117 participants with clinically definite or probable ALS. For comparison, fatigue and metabolic rate were collected from 107 control participants. Perceived fatigue was determined using the Fatigue Severity Scale (FSS). Metabolic rate was assessed using indirect calorimetry. Functional capacity and clinical progression were assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R). Results: Baseline levels of perceived fatigue were greater in people living with ALS (plwALS) when compared to controls (5.44 vs. 2.55; p < 0.01). Perceived fatigue was higher in plwALS with lower ALSFRS-R scores and was not associated with measures of metabolism. For most plwALS, perceived fatigue remained high as functional capacity worsened. Conclusion: Our findings confirm higher prevalence of perceived fatigue in plwALS, with persistently high FSS scores reported by most patients during follow-up. High levels of fatigue were not associated with hypermetabolism, suggesting that metabolic rate is unlikely to be a primary contributor. Results highlight a need for further research to identify factors that contribute to fatigue in ALS, and options for improved fatigue management.}, } @article {pmid40024058, year = {2025}, author = {Baumgarten, BR and Freye, CE}, title = {Use of Fisher's Ratio assisted multivariate curve resolution- alternating least squares for discovery-based analysis using ultrahigh pressure liquid chromatography-high resolution mass spectrometry.}, journal = {Journal of chromatography. A}, volume = {1747}, number = {}, pages = {465812}, doi = {10.1016/j.chroma.2025.465812}, pmid = {40024058}, issn = {1873-3778}, mesh = {Chromatography, High Pressure Liquid/methods ; *Mass Spectrometry/methods ; Least-Squares Analysis ; Multivariate Analysis ; Ponds/chemistry ; Pharmaceutical Preparations/analysis/chemistry ; }, abstract = {Non-targeted analysis of complex chemical mixtures can be difficult considering the convoluted nature of the matrix and the potential unknown chemical differences between samples or classes of samples. Ultrahigh pressure liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QTOF) is an ideal technique to probe chemical differences for a wide variety of samples. While UHPLC-QTOF can discover minute chemical differences down to low part per billion (ppb) concentrations with a high degree of confidence, the application of high-resolution mass spectrometry can yield massive amounts of information (∼ 10 gb per sample) that cannot be analyzed manually. Therefore, the application of chemometric techniques is mandatory for the interrogation of complex samples. Fisher's ratio (FR) assisted multivariate curve resolution-alternating least squares (MCR-ALS) was used to the discover and identify the chemical differences between two classes of materials: 1) a pond water matrix and 2) the matrix spiked with a pharmaceutical standard mix containing 17 compounds. Thirteen of the seventeen spiked compounds were discovered using FR analysis, and then five were successfully deconvoluted using MCR-ALS wherein the number of curves chosen were automatically determined using singular value decomposition (SVD). The use of an automated FR assisted MCR-ALS will aid in discovering trace levels of chemical components without the need for the researcher to provide potentially biased input which will aid in non-targeted workflow.}, } @article {pmid40024955, year = {2025}, author = {Masood, S and Almas, MS and Hassan, SSU and Tahira, S and Fiaz, MH and Minhas, UEA and Zafar, HMQ and Masood, M}, title = {Safety and efficacy of arimoclomol in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {7}, pages = {2985-2994}, pmid = {40024955}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Randomized Controlled Trials as Topic ; *Neuroprotective Agents/adverse effects/therapeutic use ; Treatment Outcome ; Hydroxylamines ; }, abstract = {OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) is a debilitating motor neuron disorder characterized by muscle weakness, atrophy, and spasticity. This meta-analysis aims to assess the safety and efficacy of Arimoclomol in patients with ALS.

METHOD: A comprehensive literature search was conducted on 3 databases to discover articles published up to August 2024. Included studies were randomized controlled trials (RCTs). Data was analysed using Review Manager (v5.4). Cochrane Risk of Bias-2 (RoB-2) was adopted to assess the quality of RCTs.

RESULTS: A total of 359 patients were analysed, with 239 individuals in the Arimoclomol group and 120 individuals in the placebo group. The pooled analysis of the primary outcome, change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score from baseline, did not demonstrate a statistically significant difference favoring the Arimoclomol group (MD = 0.4495; 95% CI: -0.39, 1.27; p = 0.30). Similarly, secondary outcomes, including the Combined Assessment of Function and Survival (CAFS) rank score (MD = 1.00; 95% CI: -2.68, 4.67; p = 0.60), increase in transaminases (RR = 1.05; 95% CI: 0.19, 5.70; p = 0.95), mortality rate (RR = 0.86; 95% CI: 0.55, 1.34; p = 0.50), and adverse events (RR = 0.86; 95% CI: 0.55, 1.34; p = 0.50), showed no statistically significant differences between the groups.

CONCLUSION: This study does not conclusively demonstrate that Arimoclomol has beneficial effects on ALS patients' physical functionality but shows promise for safety. Further clinical trials are needed to explore the neuroprotective effects of Arimoclomol in the treatment of ALS.}, } @article {pmid40025162, year = {2025}, author = {Hiew, JY and Lim, YS and Liu, H and Ng, CS}, title = {Integrated transcriptomic profiling reveals a STING-mediated Type II Interferon signature in SOD1-mutant amyotrophic lateral sclerosis models.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {347}, pmid = {40025162}, issn = {2399-3642}, support = {#SED000125//Monash University Malaysia (Monash Malaysia)/ ; #PM010CNI000148//International Brain Research Organization (IBRO)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/immunology ; Animals ; Humans ; Mice ; *Superoxide Dismutase-1/genetics/metabolism ; *Membrane Proteins/metabolism/genetics ; Disease Models, Animal ; Gene Expression Profiling ; *Mutation ; *Transcriptome ; *Interferon-gamma/genetics/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Male ; Female ; STING Protein ; }, abstract = {Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS), particularly in cases with SOD1 mutations. Using integrative transcriptomics, we analyzed gene expression changes in mouse models throughout progression, human induced-pluripotent stem cells (hiPSCs), and post-mortem spinal cord tissue from ALS patients. We identified a conserved upregulation of interferon (IFN) genes and IFN-stimulating genes (ISGs) in both mouse models and human ALS, with a predominance Type I IFNs (IFN-α/β) in mice and Type II IFNs (IFN-γ) in humans. In mouse models, we observed robust and sustained upregulation of Type I and II ISGs, including ATF3, beginning at disease onset stage and persisting throughout disease progression. Single-cell transcriptomics further pinpointed vascular endothelial cells as a major source of ISGs. Furthermore, we found that the STING-TBK1 axis is essential for the induction of Type II ISGs in ALS, as its deletion impaired their expression. Our study uncovers a conserved ISGs signature across ALS models and patients, highlighting the potential role of innate immune activation in ALS pathogenesis. These findings suggest that ISGs may serve as potential biomarkers and therapeutic targets for ALS.}, } @article {pmid40025240, year = {2025}, author = {Maier, A and Kettemann, D and Weyen, U and Grehl, T and Schulte, PC and Steinbach, R and Rödiger, A and Weydt, P and Petri, S and Wolf, J and Grosskreutz, J and Koch, JC and Weishaupt, JH and Rosseau, S and Norden, J and Körtvélyessy, P and Koch, B and Holm, T and Hildebrandt, B and Schumann, P and Walter, B and Riitano, A and Münch, C and Meyer, T and Spittel, S}, title = {Provision, cough efficacy and treatment satisfaction of mechanical insufflation-exsufflation in a large multicenter cohort of patients with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {7360}, pmid = {40025240}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/physiopathology ; *Cough/therapy/etiology ; Male ; Female ; Middle Aged ; *Insufflation/methods ; Aged ; *Patient Satisfaction ; Treatment Outcome ; Longitudinal Studies ; Germany ; Adult ; }, abstract = {In patients with amyotrophic lateral sclerosis (ALS), mechanical insufflation-exsufflation (MI-E) addresses cough deficiency to achieve major therapeutic goals: improving costal muscle and joint function, reducing atelectasis through insufflation, and clearing bronchial secretions via exsufflation. Despite its perceived benefits, there is limited systematic research on MI-E provision, symptom alleviation, or patient satisfaction. The research platform Ambulanzpartner coordinated this longitudinal observational study conducted in 12 German ALS centers from July 2018 to September 2023. Patients were enrolled based on ALS-related cough deficiency requiring MI-E therapy. The study recorded provision, reasons for withholding MI-E, clinical parameters, therapy frequency, subjective cough deficiency, and symptomatic relief. Satisfaction with MI-E therapy was determined by the likelihood of recommendation. Out of 694 ALS patients indicated for MI-E, 527 (75.9%) received the therapy. The primary reason for non-provision was that the patient had died before provision (n = 66 of 167; 39.5%). These patients were significantly more affected as represented by higher progression rates and lower cough peak flows (CPF) at the time of MI-E indication (p < 0.05). Most patients who received MI-E used it daily (n = 290 of 370; 78.4%). Self-assessed cough deficiency correlated with clinical measurements, especially for patients with higher deficits. At follow-up visits, patients reported reduced cough deficiency (p < 0.001). Frequent MI-E use was linked to greater symptom relief and higher likelihood of recommending the therapy. This study highlights the symptomatic and palliative potential of MI-E therapy for ALS patients.}, } @article {pmid40025671, year = {2025}, author = {Wang, Y and Li, C and Yang, Y and Ma, C and Zhao, X and Li, J and Wei, L and Li, Y}, title = {A Surface-Enhanced Raman Spectroscopy Platform Integrating Dual Signal Enhancement and Machine Learning for Rapid Detection of Veterinary Drug Residues in Meat Products.}, journal = {ACS applied materials & interfaces}, volume = {17}, number = {10}, pages = {16202-16212}, doi = {10.1021/acsami.4c21938}, pmid = {40025671}, issn = {1944-8252}, mesh = {*Spectrum Analysis, Raman/methods ; *Machine Learning ; *Veterinary Drugs/analysis ; *Meat Products/analysis ; *Drug Residues/analysis ; Animals ; Metal Nanoparticles/chemistry ; Food Contamination/analysis ; }, abstract = {The detection and quantification of veterinary drug residues in meat remain a significant challenge due to the complex background interference inherent to the meat matrix, which compromises the stability and accuracy of spectroscopic analysis. This study introduces an advanced label-free surface-enhanced Raman spectroscopy (SERS) platform for the precise identification and quantification of veterinary drugs. By employing a dual enhancement strategy involving sodium borohydride activation and calcium ion-deuterium oxide guidance, this platform achieves the efficient capture and signal amplification of drug molecules on highly active nanoparticles. High-quality SERS spectra were obtained for carprofen, doxycycline hydrochloride, chloramphenicol, and penicillin G sodium salt, enabling accurate classification and interference suppression. In addition, the application of machine learning algorithms, including PCA-LDA, heatmap, and decision tree modeling, allows for accurate differentiation of mixed drug samples. Quantitative analyses in meat samples were achieved through Raman intensity ratios and multivariate curve resolution-alternate least-squares (MCR-ALS) analysis, with results showing high consistency with high-performance liquid chromatography (HPLC) measurements. These findings highlight the potential of this SERS-based platform for accurate and rapid detection of multicomponent veterinary drug residues in complex food matrices.}, } @article {pmid40027570, year = {2025}, author = {Giorgio, A and Ciracì, E and De Luca, M and Stella, G and Giorgio, V}, title = {Hepatic abscess and hydatid liver cyst: European infectious disease point of view.}, journal = {World journal of hepatology}, volume = {17}, number = {2}, pages = {103325}, pmid = {40027570}, issn = {1948-5182}, abstract = {This manuscript is based on a recent study by Pillay et al that was published in recently. Liver abscesses can be caused by rare potentially life-threatening infections of either bacterial or parasitic origin. The incidence rate in Europe is lower than in developing countries, but it is a major complication with high morbidity, particularly in immunocompromised patients. They are most frequently caused by Enterobacterales infections, but hypervirulent Klebsiella strains are an emerging problem in Western countries. Amoebiasis has been a public health problem in Europe, primarily imported from other endemic foci. At the same time, this infection is becoming an emerging disease, as the number of infected patients who have not traveled to endemic areas is rising. Treatment options for hydatid liver cyst include chemotherapy, open or laparoscopic surgery, percutaneous treatment (percutaneous aspiration, re-aspiration and injection and its modification) and ''wait and watch'' strategy. Most hydatid liver cyst patients in Pillay et al's study received surgical treatment, but several studies have confirmed the safety and efficacy of percutaneous aspiration, re-aspiration and injection.}, } @article {pmid40027590, year = {2025}, author = {Untalan, LGV and Malanog, JPD and Jamora, RDG}, title = {Evaluating YouTube as a source of information on amyotrophic lateral sclerosis.}, journal = {Digital health}, volume = {11}, number = {}, pages = {20552076251324439}, pmid = {40027590}, issn = {2055-2076}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that leads to progressive motor weakness and eventual death. Recent years have seen an increase in online information on ALS, with the popular video platform YouTube becoming a prominent source. We aimed to evaluate the quality, reliability, actionability, and understandability of ALS videos on YouTube.

METHODS: A search was performed using the keyword "Amyotrophic Lateral Sclerosis" on YouTube. A total of 240 videos were viewed and assessed by two independent raters. Video characteristics such as type of uploader, views, likes, comments, and Video Power Index were also collected.

RESULTS: Videos had moderate to low quality and reliability (Global Quality Scale [GQS] and modified DISCERN [mDISCERN] median 2.5), and poor understandability and actionability (PEMAT total median 8.5). Among the general video characteristics, only length of video showed a significant positive correlation across the tools (with mDISCERN [p < 0.001]; with GQS [p < 0.001]; with PEMAT [p < 0.001]). Videos from physicians (p = 0.024, sig <0.05), other healthcare professionals (p = 0.017, sig <0.05), and educational channels (p = 0.001, sig <0.05) had better quality when compared to others.

CONCLUSION: YouTube videos are a poor source of information for ALS as videos tend to have moderate to low quality and reliability and are poorly understandable and actionable. Longer videos, and videos uploaded by those in the healthcare and educational fields, were found to perform relatively better. Thus, when using YouTube, caution and careful attention to the video characteristics are recommended.}, } @article {pmid40027671, year = {2025}, author = {Woo, E and Tasnim, F and Kawamata, H and Manfredi, G and Konrad, C}, title = {Investigation of mitochondrial phenotypes in motor neurons derived by direct conversion of fibroblasts from familial ALS subjects.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40027671}, issn = {2692-8205}, support = {R01 NS139141/NS/NINDS NIH HHS/United States ; R35 NS122209/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons, leading to fatal muscle paralysis. Familial forms of ALS (fALS) account for approximately 10% of cases and are associated with mutations in numerous genes. Alterations of mitochondrial functions have been proposed to contribute to disease pathogenesis. Here, we employed a direct conversion (DC) technique to generate induced motor neurons (iMN) from skin fibroblasts to investigate mitochondrial phenotypes in a patient-derived disease relevant cell culture system. We converted 7 control fibroblast lines and 17 lines harboring the following fALS mutations, SOD1[A4V], TDP-43[N352S], FUS[R521G], CHCHD10[R15L], and C9orf72 repeat expansion. We developed new machine learning approaches to identify iMN, analyze their mitochondrial function, and follow their fate longitudinally. Mitochondrial and energetic abnormalities were observed, but not all fALS iMN lines exhibited the same alterations. SOD1[A4V], C9orf72, and TDP-43[N352S] iMN had increased mitochondrial membrane potential, while in CHCHD10[R15L] cells membrane potential was decreased. TDP-43[N352S] iMN displayed changes in mitochondrial morphology and increased motility. SOD1[A4V], TDP-43[N352S], and CHCHD10[R15L] iMN had increased oxygen consumption rates and altered extracellular acidification rates, reflecting a hypermetabolic state similar to the one described in sporadic ALS fibroblasts. FUS[R521G] mutants had decreased ATP/ADP ratio, suggesting impaired energy metabolism. We then tested the viability of iMN and found decreases in survival in SOD1[A4V], C9orf72, and FUS[R521G], which were corrected by small molecules that target mitochondrial stress. Together, our findings reinforce the role of mitochondrial dysfunction in ALS and indicate that fibroblast-derived iMN may be useful to study fALS metabolic alterations. Strengths of the DC iMN approach include low cost, speed of transformation, and the preservation of epigenetic modifications. However, further refinement of the fibroblasts DC iMN technique is still needed to improve transformation efficiency, reproducibility, the relatively short lifespan of iMN, and the senescence of the parental fibroblasts.}, } @article {pmid40027730, year = {2025}, author = {Pant, DC and Lone, MA and Parameswaran, J and Ma, F and Dutta, P and Wang, Z and Park, J and Verma, S and Hornemann, T and Jiang, J}, title = {Lack of motor defects and ALS-like neuropathology in heterozygous Sptlc1 Exon 2 deletion mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40027730}, issn = {2692-8205}, support = {R01 AG068247/AG/NIA NIH HHS/United States ; UL1 TR000454/TR/NCATS NIH HHS/United States ; }, abstract = {Mutations in the human SPTLC1 gene have recently been linked to early onset amyotrophic lateral sclerosis (ALS), characterized by global atrophy, motor impairments, and symptoms such as tongue fasciculations. All known ALS-linked SPTLC1 mutations cluster within exon 2 and a specific variant, c.58G>T, results in exon 2 skipping. However, it is unclear how the exon 2 deletion affects SPTLC1 function in vivo and contributes to ALS pathogenesis. Leveraging the high genomic sequence similarity between mouse and human SPTLC1, we created a novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine Sptlc1 locus. While heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely. These findings indicate that Sptlc1 ΔExon2 heterozygous mice do not replicate the disease phenotype but provide valuable insights into SPTLC1 biology and serve as a useful resource for future mechanistic studies.}, } @article {pmid40028680, year = {2025}, author = {Khosravi, S and Amini, E and Emamikhah, M and Alavi, A and Lang, AE and Rohani, M}, title = {Motor Neuron Involvement in Two ATP13A2-Related Families: ALS And HSP-Like Phenotypes.}, journal = {Movement disorders clinical practice}, volume = {12}, number = {6}, pages = {852-857}, pmid = {40028680}, issn = {2330-1619}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Iran ; *Motor Neuron Disease/genetics ; Mutation/genetics ; Pedigree ; Phenotype ; *Proton-Translocating ATPases/genetics ; *Spastic Paraplegia, Hereditary/genetics/physiopathology ; Parkinsonian Disorders ; }, abstract = {BACKGROUND: Mutations in the ATP13A2 gene have been implicated in various neurodegenerative disorders, including Kufor-Rakeb syndrome (KRS), neuronal ceroid lipofuscinosis (NCL), hereditary spastic paraplegia (HSP), and amyotrophic lateral sclerosis (ALS). This report presents two Iranian families with ATP13A2 variants exhibiting atypical features of KRS.

CASES: We highlight four patients from two consanguineous Iranian families with mutations in the ATP13A2 gene presenting with variable features of motor neuron disease as well as juvenile-onset parkinsonism, and cognitive decline. The onset of symptoms ranged from 11 to 29 years, with initial manifestations including gait disturbance, postural instability, and cognitive impairment. As the disease progressed, patients developed a range of neurological signs, such as dystonia, spasticity, and dysarthria.

CONCLUSION: This report expands the phenotypic spectrum of ATP13A2-related disorders, highlighting the potential overlap of symptoms associated with KRS, ALS, and HSP.}, } @article {pmid40029136, year = {2025}, author = {Revi, N and Nandeshwar, M and Harijan, D and Sankaranarayanan, SA and Joshi, M and Prabusankar, G and Rengan, AK}, title = {Acridine Benzimidazolium Derivatives Induced Protective Microglia Polarization and In Silico TDP-43 Interaction─Potential Implications for Amyotrophic Lateral Sclerosis.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {6}, pages = {1103-1116}, doi = {10.1021/acschemneuro.4c00791}, pmid = {40029136}, issn = {1948-7193}, mesh = {*Microglia/drug effects/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Animals ; *DNA-Binding Proteins/metabolism/antagonists & inhibitors ; Humans ; Mice ; *Acridines/pharmacology/chemistry ; *Benzimidazoles/pharmacology/chemistry ; Molecular Docking Simulation ; *Neuroprotective Agents/pharmacology ; Cell Polarity/drug effects ; }, abstract = {Abnormal protein aggregation and associated neuronal-glial cell cytotoxicity lead to a plethora of neurodegenerative disorders. Most of the earlier investigations on understanding neurodegenerative disease progression and cure focused on neuronal damage and restoration potential. With increased evidence on the role of glial cells like microglia and astrocytes in mediating these disorders, more studies are dedicated to understanding the role of inflammatory responses mediated by glial cells and how they lead to neuroinflammation. Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder caused by TDP-43 aggregation that affects motor neurons. Pro-inflammatory microglia are considered to aggravate the disorder condition. In the current study, a previously reported molecule with TDP-43 inhibition, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)imidazol-3-ium) dibromide salt (AIM4), is analyzed for its microglia polarization properties along with two other derivatives, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)benzoimidazol-3-ium) dibromide salt (ABA). The 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl) benzimidazol-3-ium) dibromide salt (ABA) display the increased ability to maintain microglial cells to anti-inflammatory state and TDP-43 binding as compared to 3,3'-(acridine-4,5-diylbis(methylene)) bis(carboxymethyl)imidazolium dibromide salt (AIM4). This was confirmed from total nitrite levels, mitochondria membrane potential analysis, and molecular docking studies. The selected pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) displayed decreased levels, and anti-inflammatory cytokines IL-4 and IL-10 displayed increased levels, however not very significantly, upon treatment with all acridine derivatives. The compounds were investigated on lipopolysaccharides (LPS)-triggered mouse microglial cells and Danio rerio embryos displaying no significant cytotoxicity and physiological changes (cardiac rhythm), respectively. In molecular docking studies, alanine at 315 mutated to glutamate of TDP-43 directly interacts with AIM4. However, π-σ interactions of the aromatic backbone of acridine in ABE and ABA with 313 phenylalanine of TDP-43 along with hydrogen bonds formed between 309, 310 glycine amino acids and imidazolium bromide side chains rendered a stronger binding of these acridine derivatives with the protein potentially inhibiting fibrillation. Conclusion: ABA, ABE, and AIM4 maintain microglia in an anti-inflammatory state. However, more studies are required to understand its interaction with TDP-43 and the mechanism of its anti-inflammatory nature.}, } @article {pmid40029669, year = {2025}, author = {Carroll, E and Scaber, J and Huber, KVM and Brennan, PE and Thompson, AG and Turner, MR and Talbot, K}, title = {Drug repurposing in amyotrophic lateral sclerosis (ALS).}, journal = {Expert opinion on drug discovery}, volume = {20}, number = {4}, pages = {447-464}, pmid = {40029669}, issn = {1746-045X}, mesh = {*Drug Repositioning/methods ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Humans ; Animals ; Drug Discovery/methods ; Translational Research, Biomedical/methods ; }, abstract = {INTRODUCTION: Identifying treatments that can alter the natural history of amyotrophic lateral sclerosis (ALS) is challenging. For years, drug discovery in ALS has relied upon traditional approaches with limited success. Drug repurposing, where clinically approved drugs are reevaluated for other indications, offers an alternative strategy that overcomes some of the challenges associated with de novo drug discovery.

AREAS COVERED: In this review, the authors discuss the challenge of drug discovery in ALS and examine the potential of drug repurposing for the identification of new effective treatments. The authors consider a range of approaches, from screening in experimental models to computational approaches, and outline some general principles for preclinical and clinical research to help bridge the translational gap. Literature was reviewed from original publications, press releases and clinical trials.

EXPERT OPINION: Despite remaining challenges, drug repurposing offers the opportunity to improve therapeutic options for ALS patients. Nevertheless, stringent preclinical research will be necessary to identify the most promising compounds together with innovative experimental medicine studies to bridge the translational gap. The authors further highlight the importance of combining expertise across academia, industry and wider stakeholders, which will be key in the successful delivery of repurposed therapies to the clinic.}, } @article {pmid40029926, year = {2025}, author = {Panda, P and Mohanty, S and Gouda, SR and Baral, TC and Mohanty, A and Nayak, J and Mohapatra, R}, title = {Advanced strategies for enhancing the neuroprotective potential of curcumin: delivery systems and mechanistic insights in neurodegenerative disorders.}, journal = {Nutritional neuroscience}, volume = {28}, number = {9}, pages = {1151-1176}, doi = {10.1080/1028415X.2025.2472773}, pmid = {40029926}, issn = {1476-8305}, mesh = {*Curcumin/administration & dosage/pharmacokinetics/pharmacology/therapeutic use ; Humans ; *Neuroprotective Agents/administration & dosage/pharmacokinetics/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; *Drug Delivery Systems ; Blood-Brain Barrier/metabolism/drug effects ; Biological Availability ; }, abstract = {Background: Curcumin, a polyphenolic compound derived from Curcuma longa, exhibits significant neuroprotective potential due to its diverse pharmacological properties.Objective: This review explores curcumin's role in modulating key pathological mechanisms underlying neurodegenerative disorders such as Alzheimer's, Parkinson's diseases, Amyotrophic Lateral Sclerosis, Huntington's Disease and Prion Disease.Methods: A comprehensive analysis of curcumin's molecular interactions, including its effects on amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal-induced neurotoxicity, was conducted. Additionally, strategies to overcome its low bioavailability and blood-brain barrier (BBB) permeability were evaluated.Results: Curcumin inhibits Aβ aggregation and promotes disaggregation, reducing amyloid plaque formation in Alzheimer's disease. It modulates glial cell activity, attenuating neuroinflammation and fostering a neuroprotective environment. By interacting with tau proteins, curcumin prevents hyperphosphorylation and neurofibrillary tangle formation. As a potent antioxidant, it scavenges reactive oxygen species, mitigating oxidative stress-related neuronal damage. Its metal-chelating properties further diminish neurotoxicity by sequestering iron and copper ions. Despite its limited bioavailability and BBB permeability, curcumin's therapeutic efficacy can be enhanced using nanocarriers such as nanoparticles, liposomes, and micelles, which improve solubility, stability, and brain penetration.Conclusion: Curcumin's multifaceted neuroprotective mechanisms make it a promising candidate for preventing or slowing neurodegenerative disease progression. Advanced drug delivery systems hold potential for overcoming its pharmacokinetic limitations, paving the way for future clinical applications.}, } @article {pmid40030015, year = {2025}, author = {Johnson, EA and Nowar, R and Viola, KL and Huang, W and Zhou, S and Bicca, MA and Zhu, W and Kranz, DL and Klein, WL and Silverman, RB}, title = {Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {10}, pages = {e2402117122}, pmid = {40030015}, issn = {1091-6490}, support = {AG061708//HHS | National Institutes of Health (NIH)/ ; S10 OD032367/OD/NIH HHS/United States ; R56 AG050492/AG/NIA NIH HHS/United States ; R01 AG061708/AG/NIA NIH HHS/United States ; AG050492//HHS | National Institutes of Health (NIH)/ ; }, mesh = {*Amyloid beta-Peptides/metabolism ; Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Neurons/metabolism/drug effects ; Hippocampus/metabolism/drug effects ; Mice ; Autophagy/drug effects ; Protein Aggregation, Pathological/drug therapy/metabolism ; Alzheimer Disease/metabolism/drug therapy ; Lysosomes/metabolism ; Protein Aggregates/drug effects ; }, abstract = {Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., Clin. Transl. Med. 11, e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (AβOs), small peptide aggregates that are instigators of Alzheimer's disease neurodegeneration [M. Tolar et al., Int. J. Mol. Sci. 22, 6355 (2021)]. AβO buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L- and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against AβO buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.}, } @article {pmid40030411, year = {2024}, author = {Mishra, S and Chatterjee, D and Kanekar, N}, title = {Topological Gait Analysis: A New Framework and Its Application to the Study of Human Gait.}, journal = {IEEE journal of biomedical and health informatics}, volume = {28}, number = {12}, pages = {7040-7053}, doi = {10.1109/JBHI.2024.3427700}, pmid = {40030411}, issn = {2168-2208}, mesh = {Humans ; *Gait Analysis/methods ; Adult ; Male ; Female ; Middle Aged ; Parkinson Disease/physiopathology ; *Gait/physiology ; Amyotrophic Lateral Sclerosis/physiopathology ; Aged ; Huntington Disease/physiopathology ; Gait Disorders, Neurologic/physiopathology ; }, abstract = {OBJECTIVE: This study introduces a physiologically driven topological gait analysis (TGA) framework to gain insights into pathological gait.

METHODS: A publicly available gait dataset consisting of four groups: healthy adults, people with Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) was used. The topological properties of the configuration space of three gait parameters were studied by approximating the underlying distribution through a Gaussian kernel-based density estimation technique. Thereafter, sublevel sets of the density estimate were analyzed using cubical persistence homology.

RESULTS: Three new features were constructed: 1. Probability density estimates (PDEs) that characterize the distribution of gait parameters over their configuration space. Healthy adults exhibited a unimodal distribution, while people with neurodegenerative disorders displayed a multi-modal distribution. 2. Persistence entropy plots that summarize changes in the PDEs and characterize the uncertainty in the underlying distribution. Gait of healthy adults was concentrated at higher entropy values as opposed to neurodegenerative gait. 3. A number that captures disease severity trends.

CONCLUSIONS: Topological features in PD and HD indicate a 'bias' to a certain set of gait configurations. This lack of exploration may reflect poor planning of the underlying topology, resulting in outward manifestations of impaired gait. The lower variegations in PDEs in ALS compared to PD and HD suggest that the planning of the topology of gait may occur at higher levels of the neural architecture.

SIGNIFICANCE: TGA offers characterization of gait at a hitherto uncharted level, potentially serving neuromotor markers for early diagnosis and personalized rehabilitation protocols.}, } @article {pmid38889636, year = {2024}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Tavakol-Afshari, J}, title = {MicroRNA (miRNA) as a biomarker for diagnosis, prognosis, and therapeutics molecules in neurodegenerative disease.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {177}, number = {}, pages = {116899}, doi = {10.1016/j.biopha.2024.116899}, pmid = {38889636}, issn = {1950-6007}, mesh = {Humans ; *MicroRNAs/genetics ; *Neurodegenerative Diseases/diagnosis/genetics/therapy ; *Biomarkers/metabolism ; Animals ; Prognosis ; }, abstract = {Neurodegenerative diseases that include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS) that arise due to numerous causes like protein accumulation and autoimmunity characterized by neurologic depletion which lead to incapacity in normal physiological function such as thinking and movement in these patients. Glial cells perform an important role in protective neuronal function; in the case of neuroinflammation, glial cell dysfunction can promote the development of neurodegenerative diseases. miRNA that participates in gene regulation and plays a vital role in many biological processes in the body; in the central nervous system (CNS), it can play an essential part in neural maturation and differentiation. In neurodegenerative diseases, miRNA dysregulation occurs, enhancing the development of these diseases. In this review, we discuss neurodegenerative disease (Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)) and how miRNA is preserved as a diagnostic biomarker or therapeutic agent in these disorders. Finally, we highlight miRNA as therapy.}, } @article {pmid38890465, year = {2024}, author = {Brown, AL and Wilkins, OG and Keuss, MJ and Kargbo-Hill, SE and Zanovello, M and Lee, WC and Bampton, A and Lee, FCY and Masino, L and Qi, YA and Bryce-Smith, S and Gatt, A and Hallegger, M and Fagegaltier, D and Phatnani, H and , and Newcombe, J and Gustavsson, EK and Seddighi, S and Reyes, JF and Coon, SL and Ramos, D and Schiavo, G and Fisher, EMC and Raj, T and Secrier, M and Lashley, T and Ule, J and Buratti, E and Humphrey, J and Ward, ME and Fratta, P}, title = {Author Correction: TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.}, journal = {Nature}, volume = {631}, number = {8020}, pages = {E7}, doi = {10.1038/s41586-024-07577-9}, pmid = {38890465}, issn = {1476-4687}, support = {P30 AG066514/AG/NIA NIH HHS/United States ; }, } @article {pmid38890531, year = {2024}, author = {Chatterjee, M and Özdemir, S and Fritz, C and Möbius, W and Kleineidam, L and Mandelkow, E and Biernat, J and Doğdu, C and Peters, O and Cosma, NC and Wang, X and Schneider, LS and Priller, J and Spruth, E and Kühn, AA and Krause, P and Klockgether, T and Vogt, IR and Kimmich, O and Spottke, A and Hoffmann, DC and Fliessbach, K and Miklitz, C and McCormick, C and Weydt, P and Falkenburger, B and Brandt, M and Guenther, R and Dinter, E and Wiltfang, J and Hansen, N and Bähr, M and Zerr, I and Flöel, A and Nestor, PJ and Düzel, E and Glanz, W and Incesoy, E and Bürger, K and Janowitz, D and Perneczky, R and Rauchmann, BS and Hopfner, F and Wagemann, O and Levin, J and Teipel, S and Kilimann, I and Goerss, D and Prudlo, J and Gasser, T and Brockmann, K and Mengel, D and Zimmermann, M and Synofzik, M and Wilke, C and Selma-González, J and Turon-Sans, J and Santos-Santos, MA and Alcolea, D and Rubio-Guerra, S and Fortea, J and Carbayo, Á and Lleó, A and Rojas-García, R and Illán-Gala, I and Wagner, M and Frommann, I and Roeske, S and Bertram, L and Heneka, MT and Brosseron, F and Ramirez, A and Schmid, M and Beschorner, R and Halle, A and Herms, J and Neumann, M and Barthélemy, NR and Bateman, RJ and Rizzu, P and Heutink, P and Dols-Icardo, O and Höglinger, G and Hermann, A and Schneider, A}, title = {Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS.}, journal = {Nature medicine}, volume = {30}, number = {6}, pages = {1771-1783}, pmid = {38890531}, issn = {1546-170X}, support = {P30 AG066614/AG/NIA NIH HHS/United States ; R01 AG080470/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/pathology/genetics ; *tau Proteins/blood/metabolism ; *Extracellular Vesicles/metabolism ; *Frontotemporal Dementia/blood/diagnosis/genetics/pathology ; *Biomarkers/blood ; *DNA-Binding Proteins/blood/genetics ; Female ; Male ; Aged ; Middle Aged ; Supranuclear Palsy, Progressive/blood/diagnosis ; Protein Isoforms/blood ; }, abstract = {Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.}, } @article {pmid38890532, year = {2024}, author = {}, title = {Molecular pathology markers of FTD and ALS in blood extracellular vesicles.}, journal = {Nature medicine}, volume = {30}, number = {6}, pages = {1545-1546}, pmid = {38890532}, issn = {1546-170X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/pathology ; *Extracellular Vesicles/metabolism/genetics ; *Biomarkers/blood ; *Frontotemporal Dementia/genetics/blood/pathology ; Pathology, Molecular ; }, } @article {pmid38891002, year = {2024}, author = {Genchi, G and Lauria, G and Catalano, A and Carocci, A and Sinicropi, MS}, title = {Neuroprotective Effects of Curcumin in Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {38891002}, issn = {2304-8158}, abstract = {Curcumin, a hydrophobic polyphenol extracted from the rhizome of Curcuma longa, is now considered a candidate drug for the treatment of neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and prion disease, due to its potent anti-inflammatory, antioxidant potential, anticancerous, immunomodulatory, neuroprotective, antiproliferative, and antibacterial activities. Traditionally, curcumin has been used for medicinal and dietary purposes in Asia, India, and China. However, low water solubility, poor stability in the blood, high rate of metabolism, limited bioavailability, and little capability to cross the blood-brain barrier (BBB) have limited the clinical application of curcumin, despite the important pharmacological activities of this drug. A variety of nanocarriers, including liposomes, micelles, dendrimers, cubosome nanoparticles, polymer nanoparticles, and solid lipid nanoparticles have been developed with great success to effectively deliver the active drug to brain cells. Functionalization on the surface of nanoparticles with brain-specific ligands makes them target-specific, which should significantly improve bioavailability and reduce harmful effects. The aim of this review is to summarize the studies on curcumin and/or nanoparticles containing curcumin in the most common neurodegenerative diseases, highlighting the high neuroprotective potential of this nutraceutical.}, } @article {pmid38891021, year = {2024}, author = {Nguyen, L}, title = {Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891021}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/drug therapy ; Animals ; C9orf72 Protein/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a motor neuron disease. In ALS, upper and lower motor neurons in the brain and spinal cord progressively degenerate during the course of the disease, leading to the loss of the voluntary movement of the arms and legs. Since its first description in 1869 by a French neurologist Jean-Martin Charcot, the scientific discoveries on ALS have increased our understanding of ALS genetics, pathology and mechanisms and provided novel therapeutic strategies. The goal of this review article is to provide a comprehensive summary of the recent findings on ALS mechanisms and related therapeutic strategies to the scientific audience. Several highlighted ALS research topics discussed in this article include the 2023 FDA approved drug for SOD1 ALS, the updated C9orf72 GGGGCC repeat-expansion-related mechanisms and therapeutic targets, TDP-43-mediated cryptic splicing and disease markers and diagnostic and therapeutic options offered by these recent discoveries.}, } @article {pmid38891059, year = {2024}, author = {Dashtmian, AR and Darvishi, FB and Arnold, WD}, title = {Chronological and Biological Aging in Amyotrophic Lateral Sclerosis and the Potential of Senolytic Therapies.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891059}, issn = {2073-4409}, support = {1R01AG067758, R01AG078129, and R01AG067758-02S2//national institute of health/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/therapy ; Humans ; *Aging/pathology ; Senotherapeutics/pharmacology/therapeutic use ; Animals ; Cellular Senescence ; Mitochondria/metabolism/pathology ; DNA Damage ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a group of sporadic and genetic neurodegenerative disorders that result in losses of upper and lower motor neurons. Treatment of ALS is limited, and survival is 2-5 years after disease onset. While ALS can occur in younger individuals, the risk significantly increases with advancing age. Notably, both sporadic and genetic forms of ALS share pathophysiological features overlapping hallmarks of aging including genome instability/DNA damage, mitochondrial dysfunction, inflammation, proteostasis, and cellular senescence. This review explores chronological and biological aging in the context of ALS onset and progression. Age-related muscle weakness and motor unit loss mirror aspects of ALS pathology and coincide with peak ALS incidence, suggesting a potential link between aging and disease development. Hallmarks of biological aging, including DNA damage, mitochondrial dysfunction, and cellular senescence, are implicated in both aging and ALS, offering insights into shared mechanisms underlying disease pathogenesis. Furthermore, senescence-associated secretory phenotype and senolytic treatments emerge as promising avenues for ALS intervention, with the potential to mitigate neuroinflammation and modify disease progression.}, } @article {pmid38891099, year = {2024}, author = {Hernan-Godoy, M and Rouaux, C}, title = {From Environment to Gene Expression: Epigenetic Methylations and One-Carbon Metabolism in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891099}, issn = {2073-4409}, support = {ANR-21-CE16-0024//Agence Nationale de la Recherche/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Epigenesis, Genetic ; *DNA Methylation/genetics ; *Carbon/metabolism ; Animals ; }, abstract = {The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute to ALS. Numerous environmental factors are considered, which may add up and synergize throughout an individual's lifetime building its unique exposome. One level of integration between genetic and environmental factors is epigenetics, which results in alterations in gene expression without modification of the genome sequence. Methylation reactions, targeting DNA or histones, represent a large proportion of epigenetic regulations and strongly depend on the availability of methyl donors provided by the ubiquitous one-carbon (1C) metabolism. Thus, understanding the interplay between exposome, 1C metabolism, and epigenetic modifications will likely contribute to elucidating the mechanisms underlying altered gene expression related to ALS and to developing targeted therapeutic interventions. Here, we review evidence for 1C metabolism alterations and epigenetic methylation dysregulations in ALS, with a focus on the impairments reported in neural tissues, and discuss these environmentally driven mechanisms as the consequences of cumulative exposome or late environmental hits, but also as the possible result of early developmental defects.}, } @article {pmid38891112, year = {2024}, author = {Santos, JR and Park, J}, title = {MATR3's Role beyond the Nuclear Matrix: From Gene Regulation to Its Implications in Amyotrophic Lateral Sclerosis and Other Diseases.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891112}, issn = {2073-4409}, support = {n/a//Canada Research Chairs/ ; 202104PJT-462444-NSB-CEAB-275899//CIHR/Canada ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Nuclear Matrix-Associated Proteins/metabolism/genetics ; *Gene Expression Regulation ; *Nuclear Matrix/metabolism ; Animals ; RNA-Binding Proteins/metabolism/genetics ; }, abstract = {Matrin-3 (MATR3) was initially discovered as a component of the nuclear matrix about thirty years ago. Since then, accumulating studies have provided evidence that MATR3 not only plays a structural role in the nucleus, but that it is also an active protein involved in regulating gene expression at multiple levels, including chromatin organization, DNA transcription, RNA metabolism, and protein translation in the nucleus and cytoplasm. Furthermore, MATR3 may play a critical role in various cellular processes, including DNA damage response, cell proliferation, differentiation, and survival. In addition to the revelation of its biological role, recent studies have reported MATR3's involvement in the context of various diseases, including neurodegenerative and neurodevelopmental diseases, as well as cancer. Moreover, sequencing studies of patients revealed a handful of disease-associated mutations in MATR3 linked to amyotrophic lateral sclerosis (ALS), which further elevated the gene's importance as a topic of study. In this review, we synthesize the current knowledge regarding the diverse functions of MATR3 in DNA- and RNA-related processes, as well as its involvement in various diseases, with a particular emphasis on ALS.}, } @article {pmid38891289, year = {2024}, author = {Idziak, R and Waligóra, H and Majchrzak, L and Szulc, P}, title = {Multifunctional Adjuvants Affect Sulfonylureas with Synthetic Auxin Mixture in Weed and Maize Grain Yield.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {38891289}, issn = {2223-7747}, abstract = {A field study in the years 2017-2019 was carried out to evaluate the impact of novel adjuvant formulations on the efficacy of sulfonylurea and synthetic auxin herbicides. Treatments included nicosulfuron + rimsulfuron + dicamba (N+R+D) at full and reduced rates with three multicomponent (TEST-1, TEST-2, TEST-3) as well as standard (MSO, S) adjuvants. In this greenhouse study, Echinochloa crus-galli seeds were planted and treated with N+R+D at 2-3 leaf stages. The water with the desired pH (4, 7, and 9) for the preparation of the spray liquid was prepared by incorporating citric acid or K3PO4 to either lower or raise the pH of the water. Adjuvant TEST-1 added to the spray liquid at pH 4 increased the effectiveness to 68%, TEST-2 to 81%, and TEST-3 to 80%, compared to 73% and 66% with the MSO and S. The efficacy of N+R+D at pH 7 with TEST-1 increased to 83%, TEST-2 to 82%, and TEST-3 to 77%, but with MSO, it increased to 81%, and 71% with S. Adjuvants TEST-1, TEST-2, and TEST-3 in the liquid at pH 9 increased efficacy to 76 and 80%, compared to 79 and 63% with MSO or S adjuvants. N+R+D applied with TEST-1, TEST-2, and TEST-3 provided greater weed control than herbicides with surfactant (S) and similar or even better than with standard methylated seed oil (MSO) adjuvants. Maize grain yield after herbicide-with-tested-adjuvant application was higher than from an untreated check, and comparable to yield from herbicide-with-MSO treatment, but higher than from S treatment.}, } @article {pmid38891774, year = {2024}, author = {Arnold, FJ and Putka, AF and Raychaudhuri, U and Hsu, S and Bedlack, RS and Bennett, CL and La Spada, AR}, title = {Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891774}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Glutamic Acid/metabolism ; Animals ; Motor Neurons/metabolism/pathology ; Aging/metabolism ; Receptors, AMPA/metabolism ; Endoplasmic Reticulum Stress ; Mitochondria/metabolism ; Excitatory Amino Acid Transporter 2/metabolism ; Astrocytes/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies for ALS, particularly for sporadic ALS of unknown and diverse etiologies, we must identify key, convergent mechanisms of disease pathogenesis. This review focuses on the origin and effects of glutamate-mediated excitotoxicity in ALS (the cortical hyperexcitability hypothesis), in which increased glutamatergic signaling causes motor neurons to become hyperexcitable and eventually die. We characterize both primary and secondary contributions to excitotoxicity, referring to processes taking place at the synapse and within the cell, respectively. 'Primary pathways' include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased release of glutamate from the presynaptic terminal, and reduced inhibition by cortical interneurons-all of which have been observed in ALS patients and model systems. 'Secondary pathways' include changes to mitochondrial morphology and function, increased production of reactive oxygen species, and endoplasmic reticulum (ER) stress. By identifying key targets in the excitotoxicity cascade, we emphasize the importance of this pathway in the pathogenesis of ALS and suggest that intervening in this pathway could be effective for developing therapies for this disease.}, } @article {pmid38891791, year = {2024}, author = {Tokuda, E and Sakashita, Y and Tokoro, N and Date, A and Kosuge, Y and Miyasaka, T}, title = {MS785-MS27 Reactive Misfolded/Non-Native Zn-Deficient SOD1 Species Exhibit Cytotoxicity and Adopt Heterozygous Conformations in Motor Neurons.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891791}, issn = {1422-0067}, support = {2022-2025//The Takeda Science Foundation/ ; }, mesh = {Animals ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Motor Neurons/metabolism/pathology ; Mice ; *Zinc/metabolism/deficiency ; *Protein Folding ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Mutation ; Mice, Transgenic ; Heterozygote ; Protein Conformation ; }, abstract = {Misfolding of superoxide dismutase-1 (SOD1) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) with SOD1 mutations. The development of antibodies specific for misfolded SOD1 deepens our understanding of how the protein participates in ALS pathogenesis. Since the term "misfolding" refers to various disordered conformers other than the natively folded one, which misfolded species are recognized by specific antibodies should be determined. Here, we molecularly characterized the recognition by MS785-MS27, an antibody cocktail experimentally confirmed to recognize over 100 ALS-linked SOD1 mutants. Indirect ELISA revealed that the antibody cocktail recognized Zn-deficient wild-type and mutated SOD1 species. It also recognized conformation-disordered wild-type and mutated SOD1 species, such as unfolded and oligomeric forms, but had less affinity for the aggregated form. Antibody-reactive SOD1 exhibited cytotoxicity to a motor neuron cell model, which was blocked by Zn treatment with Zn-deficient SOD1. Immunohistochemistry revealed antibody-reactive SOD1 mainly in spinal motor neurons of SOD1[G93A] mice throughout the disease course, and the distribution after symptomatic stages differed from that of other misfolded SOD1 species. This suggests that misfolded/non-native SOD1 species exist as heterogeneous populations. In conclusion, MS785-MS27 recognizes various conformation-disordered SOD1 species lacking the Zn ion.}, } @article {pmid38891895, year = {2024}, author = {Dabrowska, S and Turano, E and Scambi, I and Virla, F and Nodari, A and Pezzini, F and Galiè, M and Bonetti, B and Mariotti, R}, title = {A Cellular Model of Amyotrophic Lateral Sclerosis to Study the Therapeutic Effects of Extracellular Vesicles from Adipose Mesenchymal Stem Cells on Microglial Activation.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891895}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/metabolism/pathology ; *Extracellular Vesicles/metabolism ; *Microglia/metabolism ; *Mesenchymal Stem Cells/metabolism ; Humans ; *Superoxide Dismutase-1/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Cell Line ; Adipose Tissue/cytology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons (MNs) in the brain and spinal cord, leading to progressive paralysis and death. Increasing evidence indicates that neuroinflammation plays an important role in ALS's pathogenesis and disease progression. Neuroinflammatory responses, primarily driven by activated microglia and astrocytes, and followed by infiltrating peripheral immune cells, contribute to exacerbate/accelerate MN death. In particular, the role of the microglia in ALS remains unclear, partly due to the lack of experimental models that can fully recapitulate the complexity of ALS's pathology. In this study, we developed and characterized a microglial cell line, SIM-A9-expressing human mutant protein Cu[+]/Zn[+] superoxide dismutase_1 (SIM-A9hSOD1(G93A)), as a suitable model in vitro mimicking the microglia activity in ALS. The expression of hSOD1(G93A) in SIM-A9 cells induced a change in their metabolic activity, causing polarization into a pro-inflammatory phenotype and enhancing reactive oxygen species production, which is known to activate cell death processes and apoptosis. Afterward, we used our microglial model as an experimental set-up to investigate the therapeutic action of extracellular vesicles isolated from adipose mesenchymal stem cells (ASC-EVs). ASC-EVs represent a promising therapeutic treatment for ALS due to their neuroprotective and immunomodulatory properties. Here, we demonstrated that treatment with ASC-EVs is able to modulate activated ALS microglia, reducing their metabolic activity and polarizing their phenotype toward an anti-inflammatory one through a mechanism of reduction of reactive oxygen species.}, } @article {pmid38892250, year = {2024}, author = {Cerantonio, A and Citrigno, L and Greco, BM and De Benedittis, S and Passarino, G and Maletta, R and Qualtieri, A and Montesanto, A and Spadafora, P and Cavalcanti, F}, title = {The Role of Mitochondrial Copy Number in Neurodegenerative Diseases: Present Insights and Future Directions.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38892250}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *DNA, Mitochondrial/genetics ; *DNA Copy Number Variations ; *Mitochondria/genetics/metabolism ; Huntington Disease/genetics/pathology ; Animals ; }, abstract = {Neurodegenerative diseases are progressive disorders that affect the central nervous system (CNS) and represent the major cause of premature death in the elderly. One of the possible determinants of neurodegeneration is the change in mitochondrial function and content. Altered levels of mitochondrial DNA copy number (mtDNA-CN) in biological fluids have been reported during both the early stages and progression of the diseases. In patients affected by neurodegenerative diseases, changes in mtDNA-CN levels appear to correlate with mitochondrial dysfunction, cognitive decline, disease progression, and ultimately therapeutic interventions. In this review, we report the main results published up to April 2024, regarding the evaluation of mtDNA-CN levels in blood samples from patients affected by Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). The aim is to show a probable link between mtDNA-CN changes and neurodegenerative disorders. Understanding the causes underlying this association could provide useful information on the molecular mechanisms involved in neurodegeneration and offer the development of new diagnostic approaches and therapeutic interventions.}, } @article {pmid38892814, year = {2024}, author = {Barbato, F and Bombaci, A and Colacicco, G and Bruno, G and Ippolito, D and Pota, V and Dongiovanni, S and Sica, G and Bocchini, G and Valente, T and Scaglione, M and Mainenti, PP and Guarino, S}, title = {Chest Dynamic MRI as Early Biomarker of Respiratory Impairment in Amyotrophic Lateral Sclerosis Patients: A Pilot Study.}, journal = {Journal of clinical medicine}, volume = {13}, number = {11}, pages = {}, pmid = {38892814}, issn = {2077-0383}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neuromuscular progressive disorder characterized by limb and bulbar muscle wasting and weakness. A total of 30% of patients present a bulbar onset, while 70% have a spinal outbreak. Respiratory involvement represents one of the worst prognostic factors, and its early identification is fundamental for the early starting of non-invasive ventilation and for the stratification of patients. Due to the lack of biomarkers of early respiratory impairment, we aimed to evaluate the role of chest dynamic MRI in ALS patients. Methods: We enrolled 15 ALS patients and 11 healthy controls. We assessed the revised ALS functional rating scale, spirometry, and chest dynamic MRI. Data were analyzed by using the Mann-Whitney U test and Cox regression analysis. Results: We observed a statistically significant difference in both respiratory parameters and pulmonary measurements at MRI between ALS patients and healthy controls. Moreover, we found a close relationship between pulmonary measurements at MRI and respiratory parameters, which was statistically significant after multivariate analysis. A sub-group analysis including ALS patients without respiratory symptoms and with normal spirometry values revealed the superiority of chest dynamic MRI measurements in detecting signs of early respiratory impairment. Conclusions: Our data suggest the usefulness of chest dynamic MRI, a fast and economically affordable examination, in the evaluation of early respiratory impairment in ALS patients.}, } @article {pmid38894662, year = {2024}, author = {Jacobsen, AB and Bostock, H and Howells, J and Cengiz, B and Samusyte, G and Koltzenburg, M and Pia, H and Fuglsang-Frederiksen, A and Blicher, J and Obál, I and Andersen, H and Tankisi, H}, title = {Threshold tracking transcranial magnetic stimulation and neurofilament light chain as diagnostic aids in ALS.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {7}, pages = {1887-1896}, pmid = {38894662}, issn = {2328-9503}, support = {//Sundhedsvidenskabelige Fakultet, Aarhus Universitet/ ; R290-2018-751//Lundbeck Foundation/ ; R346-2020-1946//Lundbeck Foundation/ ; //William Demant Fonden/ ; //Familien Hede Nielsens Fond/ ; //Aage og Johanne Louis-Hansens Fond/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Middle Aged ; Male ; Female ; Aged ; *Neurofilament Proteins ; *Transcranial Magnetic Stimulation/methods ; *Biomarkers ; Electromyography ; Evoked Potentials, Motor/physiology ; }, abstract = {OBJECTIVE: There is a need for sensitive biomarkers in amyotrophic lateral sclerosis (ALS), to enable earlier diagnosis and to help assess potential treatments. The main objective of this study was to compare two potential biomarkers, threshold-tracking short-interval cortical inhibition (T-SICI), which has shown promise as a diagnostic aid, and neurofilament light chains (NfL).

METHODS: Ninety-seven patients with ALS (mean age 67.1 ± 11.5 years) and 53 ALS mimics (aged 62.4 ± 12.9) were included. Mean disease duration was 14 months ±14.1. Patients were evaluated with revised ALS functional rating score (ALSFRS-R), Penn upper motor neuron score (UMNS), muscle strength using the Medical Research Council (MRC) score and examined with T-SICI, quantitative electromyography (EMG), and NfL measured in spinal fluid.

RESULTS: NfL increased with increasing UMNS (rho = 0.45, p = 8.2 × 10[-6]) whereas T-SICI at 2.5 ms paradoxically increased toward normal values (rho = 0.53, p = 1.9 × 10[-7]). However, these two measures were uncorrelated. Discrimination between ALS patients and mimics was best for NfL (area under ROC curve 0.842, sensitivity 84.9%, specificity 83.5%), compared with T-SICI (0.675, 39.6%, 91.8%). For the patients with no UMN signs, NfL also discriminated best (0.884, 89.3%, 82.6%), compared with T-SICI (0.811, 71.4%, 82.6%). However, when combining NfL and T-SICI, higher AUCs of 0.854 and 0.922 and specificities of 93.8 and 100 were found when considering all patients and patients with no UMN signs, respectively.

INTERPRETATION: Both T-SICI and NfL correlated with UMN involvement and combined, they provided a strong discrimination between ALS patients and ALS mimics.}, } @article {pmid38894913, year = {2024}, author = {Sabnis, RW and Sabnis, AR}, title = {Novel Compounds as S1P5 Modulators for Treating Neurodegenerative Diseases.}, journal = {ACS medicinal chemistry letters}, volume = {15}, number = {6}, pages = {750-751}, pmid = {38894913}, issn = {1948-5875}, abstract = {Provided herein are novel compounds as S1P5 modulators, pharmaceutical compositions, use of such compounds in treating neurodegenerative diseases, particularly Alzheimer's disease, multiple sclerosis, migraine and amyotrophic lateral sclerosis, and processes for preparing such compounds.}, } @article {pmid38894936, year = {2024}, author = {Brown, SP}, title = {Diagnosis of Cervical Spinal Cord Multiple Sclerosis by a Chiropractic Physician: A Case Report.}, journal = {Cureus}, volume = {16}, number = {6}, pages = {e62618}, pmid = {38894936}, issn = {2168-8184}, abstract = {We present a case report of diagnosis of cervical spine multiple sclerosis by a chiropractic physician. This unique case contributes an account of a challenging differential diagnosis to the literature. A 30-year-old male presented with a three-year history of diffuse left upper extremity motor strength deficits and paresthesia (numbness and tingling). The patient had seen multiple physicians for these symptoms with no diagnosis of multiple sclerosis and no advanced imaging. The differential diagnosis included lower cervical spine nerve root compression or neurological disorders such as amyotrophic lateral sclerosis, cerebral lesion, motor neuropathy, multiple sclerosis, or spinal cord lesion. MRI of the cervical spine with and without IV contrast revealed evidence of spinal cord multiple sclerosis. The patient was referred to a neurologist where the diagnosis of multiple sclerosis was confirmed. A 10-year follow-up showed the patient was controlling his condition with medications and had no disability. This case underscores the importance for physicians to consider neurological conditions and advanced imaging in the presence of diffuse motor strength deficits and paresthesia in the absence of injury, pain, or any other symptoms.}, } @article {pmid38895204, year = {2024}, author = {Maitra, S and Baek, M and Choe, YJ and Kim, NC}, title = {FDA-approved PDE4 inhibitors reduce the dominant toxicity of ALS-FTD-associated CHCHD10 [S59L].}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.04.597429}, pmid = {38895204}, issn = {2692-8205}, abstract = {Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10(CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing C2C10H [S81L] , and human cell models expressing CHCHD10 [S59L] , we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10 [S59L] . Evidences using in vitro/ in vivo genetic and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10 [S59L] -induced diseases. Therefore, we have investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10 [S59L] -induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10 [S59L] -induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H [S81L] . Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10 [S59L] . These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10 [S59L] -induced ALS-FTD and possibly other related diseases.}, } @article {pmid38895337, year = {2024}, author = {Vazquez-Sanchez, S and Tilkin, B and Gasset-Rosa, F and Zhang, S and Piol, D and McAlonis-Downes, M and Artates, J and Govea-Perez, N and Verresen, Y and Guo, L and Cleveland, DW and Shorter, J and Da Cruz, S}, title = {Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.03.593639}, pmid = {38895337}, issn = {2692-8205}, abstract = {RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fu sed in s arcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic FTLD. Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.}, } @article {pmid38895380, year = {2024}, author = {König, LE and Rodriguez, S and Hug, C and Daneshvari, S and Chung, A and Bradshaw, GA and Sahin, A and Zhou, G and Eisert, RJ and Piccioni, F and Das, S and Kalocsay, M and Sokolov, A and Sorger, P and Root, DE and Albers, MW}, title = {TYK2 as a novel therapeutic target in Alzheimer's Disease with TDP-43 inclusions.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38895380}, issn = {2692-8205}, support = {R01 AG058063/AG/NIA NIH HHS/United States ; R01 AG078377/AG/NIA NIH HHS/United States ; U54 CA225088/CA/NCI NIH HHS/United States ; }, abstract = {Neuroinflammation is a pathological feature of many neurodegenerative diseases, including Alzheimer's disease (AD)[1,2] and amyotrophic lateral sclerosis (ALS)[3], raising the possibility of common therapeutic targets. We previously established that cytoplasmic double-stranded RNA (cdsRNA) is spatially coincident with cytoplasmic pTDP-43 inclusions in neurons of patients with C9ORF72-mediated ALS[4]. CdsRNA triggers a type-I interferon (IFN-I)-based innate immune response in human neural cells, resulting in their death[4]. Here, we report that cdsRNA is also spatially coincident with pTDP-43 cytoplasmic inclusions in brain cells of patients with AD pathology and that type-I interferon response genes are significantly upregulated in brain regions affected by AD. We updated our machine-learning pipeline DRIAD-SP (Drug Repurposing In Alzheimer's Disease with Systems Pharmacology) to incorporate cryptic exon (CE) detection as a proxy of pTDP-43 inclusions and demonstrated that the FDA-approved JAK inhibitors baricitinib and ruxolitinib that block interferon signaling show a protective signal only in cortical brain regions expressing multiple CEs. Furthermore, the JAK family member TYK2 was a top hit in a CRISPR screen of cdsRNA-mediated death in differentiated human neural cells. The selective TYK2 inhibitor deucravacitinib, an FDA-approved drug for psoriasis, rescued toxicity elicited by cdsRNA. Finally, we identified CCL2, CXCL10, and IL-6 as candidate predictive biomarkers for cdsRNA-related neurodegenerative diseases. Together, we find parallel neuroinflammatory mechanisms between TDP-43 associated-AD and ALS and nominate TYK2 as a possible disease-modifying target of these incurable neurodegenerative diseases.}, } @article {pmid38895485, year = {2024}, author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M}, title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.06.597745}, pmid = {38895485}, issn = {2692-8205}, abstract = {UNLABELLED: Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.

AUTHOR SUMMARY: This manuscript outlines our project involving the application of AGATHA, an AI-based literature mining tool, to discover drugs with the potential for repurposing in the context of neurocognitive disorders. The primary objective is to identify connections between approved medications and specific health conditions through advanced statistical analysis, including techniques like Partial Least Squares Discriminant Analysis (PLSDA) and unsupervised clustering. The methodology involves grouping scientific terms related to different health conditions and genes, followed by building discrimination models to extract lists of disease-specific genes. These genes are then analyzed through pathway analysis to select candidates for drug repurposing.}, } @article {pmid38895610, year = {2024}, author = {Kaundun, SS and Martin-Sanz, A and Rodríguez, M and Serbanoiu, T and Moreno, J and Mcindoe, E and le Goupil, G}, title = {First case of evolved herbicide resistance in the holoparasite sunflower broomrape, Orobanche cumana Wallr.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1420009}, pmid = {38895610}, issn = {1664-462X}, abstract = {The development and commercialisation of sunflower varieties tolerant to acetolactate synthase (ALS)-inhibiting herbicides some 20 years ago provided farmers with an alternative method for the cost-effective control of Orobanche cumana. In 2020, however, two independent sunflower broomrape populations from Drama (GR-DRA) and Orestiada (GR-ORE), Greece, were reported to be heavily infested with O. cumana after application of the ALS-inhibiting herbicide imazamox. Here we have investigated the race of GR-DRA and GR-ORE and determined the basis of resistance to imazamox in the two Greek O. cumana samples. Using a set of five diagnostic sunflower varieties characterised by different resistant genes with respect to O. cumana infestation, we have clearly established that the GR-ORE and GR-DRA populations belong to the invasive broomrape races G and G+, respectively. Live underground tubercles and emerged shoots were identified at the recommended field rate of imazamox for GR-DRA and GR-ORE but not for two other standard sensitive populations in a whole plant dose response test using two different herbicide-tolerant sunflower hybrids as hosts. Sequencing of the ALS gene identified an alanine 205 to aspartate mutation in all GR-ORE samples. Most GR-DRA tubercles were characterised by a second serine 653 to asparagine ALS mutation whilst a few GR-DRA individuals contained the A205D mutation. Mutations at ALS codons 205 and 653 are known to impact on the binding and efficacy of imazamox and other imidazolinone herbicides. The knowledge generated here will be important for tracking and managing broomrape resistance to ALS-inhibiting herbicides in sunflower growing regions.}, } @article {pmid38895672, year = {2024}, author = {Deng, J and Sun, WT and Gong, K and Wang, LP and Li, FZ}, title = {Internal limiting membrane peeling combined with silicone oil or air tamponade for highly myopic foveoschisis.}, journal = {International journal of ophthalmology}, volume = {17}, number = {6}, pages = {1079-1085}, pmid = {38895672}, issn = {2222-3959}, abstract = {AIM: To compare the efficacy of pars plana vitrectomy (PPV) combined with internal limiting membrane (ILM) and silicone oil or sterile air tamponade for the treatment of myopic foveoschisis (MF) in highly myopic eyes.

METHODS: This retrospective study included 48 myopic eyes of 40 patients with MF and axial lengths (ALs) ranging from 26-32 mm treated between January 2020 and January 2022. All patients were underwent PPV combined with ILM peeling followed by sterile air or silicone oil tamponade and followed up at least 12mo. Based on the features on spectral-domain optical coherence tomography (SD-OCT), the eyes were divided into the MF-only group (Group A, n=15 eyes), MF with central foveal detachment group (Group B, n=20 eyes), and MF with lamellar macular hole group (Group C, n=13 eyes). According to AL, eyes were further divided into three groups: Group D (26.01-28.00 mm, n=12 eyes), Group E (28.01-30.00 mm, n=26 eyes), and Group F (30.01-32.00 mm, n=10 eyes). The best-corrected visual acuity (BCVA), central foveal thickness (CFT), and complications were recorded.

RESULTS: The patients included 16 males and 24 females with the mean age of 56±9.82y. The BCVA and CFT improved in all groups after surgery (P<0.01), while there was no significant difference of the CFT in Group A, B, and C postoperatively (P>0.05). The intergroup differences of BCVA and CFT postoperatively were statistically significant in Group D, E, and F. Twenty eyes were injected with sterile air, and 28 eyes were injected with silicone oil for tamponade based on the AL. However, there was no statistically significant difference among Groups D, E, and F in terms of the results of sterile air or silicone oil tamponade. The mean recovery time was 5.9mo for MF patients subjected to silicone oil tamponade and 7.7mo for patients subjected to sterile air tamponade, and the difference was not statistically significant.

CONCLUSION: PPV and ILM peeling combined with silicone oil or sterile air tamponade can achieve good results for MF in highly myopic eyes with ALs≤32 mm.}, } @article {pmid38896163, year = {2024}, author = {Woodworth, DC and Nguyen, KM and Sordo, L and Scambray, KA and Head, E and Kawas, CH and Corrada, MM and Nelson, PT and Sajjadi, SA}, title = {Comprehensive assessment of TDP-43 neuropathology data in the National Alzheimer's Coordinating Center database.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {103}, pmid = {38896163}, issn = {1432-0533}, support = {P20 AG068053/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P20 AG068077/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; T32AG073088/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; T32 AG073088/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; R01 AG062706/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P20 AG068024/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; RF1 AG082339/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; R01AG062706/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Female ; Aged ; Male ; *Alzheimer Disease/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; *TDP-43 Proteinopathies/pathology ; Aged, 80 and over ; Databases, Factual ; Frontotemporal Lobar Degeneration/pathology/metabolism ; Brain/pathology/metabolism ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Hippocampus/pathology/metabolism ; Middle Aged ; }, abstract = {TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer's Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by FTLD-TDP (83%). Regional TDP-43 pathologic assessment was available for 77% of participants, with hippocampus the most common region. Availability for the TDP-43-related measures increased over time, and was higher in centers with high proportions of participants with clinical FTLD. Part II: In 2142 participants with all TDP-43-related assessments available, 27% of participants had LATE-NC, whereas ALS-TDP or FTLD-TDP (ALS/FTLD-TDP) was present in 9% of participants, and 2% of participants had TDP-43 related to other pathologies ("Other TDP-43"). HS-A was present in 14% of participants, of whom 55% had LATE-NC, 20% ASL/FTLD-TDP, 3% Other TDP-43, and 23% no TDP-43. LATE-NC, ALS/FTLD-TDP, and Other TDP-43, were each associated with higher odds of dementia, HS-A, and hippocampal atrophy, compared to those without TDP-43 pathology. LATE-NC was associated with higher odds for Alzheimer's disease (AD) clinical diagnosis, AD neuropathologic change (ADNC), Lewy bodies, arteriolosclerosis, and cortical atrophy. ALS/FTLD-TDP was associated with higher odds of clinical diagnoses of primary progressive aphasia and behavioral-variant frontotemporal dementia, and cortical/frontotemporal lobar atrophy. When using NACC data for TDP-43-related analyses, researchers should carefully consider the incomplete availability of the different regional TDP-43 assessments, the high frequency of participants with ALS/FTLD-TDP, and the presence of other forms of TDP-43 pathology.}, } @article {pmid38896262, year = {2024}, author = {Shen, D and Yang, X and He, D and Zhang, K and Liu, S and Sun, X and Li, J and Cai, Z and Liu, M and Zhang, X and Liu, Q and Cui, L}, title = {Clinical and genetic characteristics of 1672 cases of amyotrophic lateral sclerosis in China: a single-center retrospective study.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5541-5548}, pmid = {38896262}, issn = {1432-1459}, support = {XDB39040100//Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; 2022-PUMCH-B-017//High-level Hospital Construction Project of Guangdong Provincial People's Hospital/ ; 2022YFC2703904//Key Technologies Research and Development Program/ ; 2021-I2M-1-034//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 81971293//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Middle Aged ; Female ; Adult ; Aged ; Young Adult ; Adolescent ; Aged, 80 and over ; China/epidemiology ; Retrospective Studies ; *C9orf72 Protein/genetics ; Age of Onset ; Mutation ; Phenotype ; Exome Sequencing ; Genotype ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, continuous discoveries of new ALS-causing genes have enhanced the understanding of the genotype-phenotype relationship in ALS, aiding in disease progression prediction and providing a more comprehensive basis for genetic diagnosis.

METHODS: A total of 1672 ALS patients who visited the Neurology Department of Peking Union Medical College Hospital between January 2014 and December 2022 and met the revised El Escorial diagnostic criteria were included. Clinical data were collected, whole exome sequencing and dynamic mutation screening of the C9ORF72 gene were performed, and the clinical phenotypes and genotypes of the patients were analyzed.

RESULTS: The average age of onset for the 1672 ALS patients was 52.6 ± 11.2 years (range 17-85 years), with a median disease duration of 14 months at the time of visit (interquartile range 9-24 months, range 2-204 months). The male to female ratio was 833:839. The patients included 297 (17.8%) with bulbar onset, 198 (11.8%) with flail arm/leg syndrome, 89 (5.3%) with familial ALS, and 52 (3.1%) with concomitant frontotemporal dementia (FTD). Pathogenic variants associated with ALS were detected in 175 patients (10.5% of the cohort), with the most common mutations being SOD1, FUS, and ANXA11. Among patients with familial ALS, 56.2% (50/89) had genetic mutations, compared to 7.9% (125/1583) in sporadic ALS cases. From the perspective of phenotype-genotype correlation, (1) In ALS-FTD patients, the most common genetic mutations were ANXA11 and C9ORF72 repeat expansions. Patients with flail arm/leg syndrome more frequently carried mutations in SOD1, ANXA11, and hnRNPA1; (2) Despite genetic heterogeneity, it was observed that mutations in FUS and NEK1 were more common in males, and patients with FUS mutations had a younger age of onset; mutations in SOD1 and SQSTM1 were more likely to present with lower limb onset.

CONCLUSION: This study provides comprehensive data on the genetic characteristics of ALS patients in China through large-scale clinical data and genetic analysis of 1672 cases. Differences in age of onset, onset site, and clinical phenotype among ALS patients with different genotypes can help clinicians better predict disease progression and provide a basis for precise diagnosis and individualized treatment.}, } @article {pmid38896345, year = {2024}, author = {Robinson, JL and Suh, E and Xu, Y and Hurtig, HI and Elman, L and McMillan, CT and Irwin, DJ and Porta, S and Van Deerlin, VM and Lee, EB}, title = {Annexin A11 aggregation in FTLD-TDP type C and related neurodegenerative disease proteinopathies.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {104}, pmid = {38896345}, issn = {1432-0533}, support = {RF1 AG065341/AG/NIA NIH HHS/United States ; U19 AG062418/AG/NIA NIH HHS/United States ; R01 AG065341/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P01AG066597/AG/NIA NIH HHS/United States ; U19AG062418/AG/NIA NIH HHS/United States ; R01 AG075276/AG/NIA NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; P30AG072979/AG/NIA NIH HHS/United States ; RF1AG065341/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Aged ; *Annexins/genetics/metabolism ; Female ; Male ; *DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Lobar Degeneration/genetics/pathology/metabolism ; Middle Aged ; Aged, 80 and over ; TDP-43 Proteinopathies/pathology/genetics ; Neurodegenerative Diseases/pathology/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Inclusion Bodies/pathology/metabolism ; Brain/pathology/metabolism ; Protein Aggregation, Pathological/pathology/genetics/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11. Annexin A11 aggregation has not been described in sporadic ALS, FTLD-TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare ANXA11 variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD-TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3-6%) of sporadic and genetic forms of FTLD-TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic ANXA11 p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, ANXA11 p.P75S. By immunoblot, FTLD-TDP with annexinopathy and ANXA11 variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to ANXA11 p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.}, } @article {pmid38897956, year = {2025}, author = {Takahashi, R and Furuta, M and Nagashima, K and Ikeda, Y}, title = {Concurrent Amyotrophic Lateral Sclerosis and Huntington's Disease.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {64}, number = {2}, pages = {297-300}, pmid = {38897956}, issn = {1349-7235}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/genetics/diagnosis ; Huntingtin Protein ; *Huntington Disease/complications/genetics/diagnosis ; Trinucleotide Repeat Expansion ; }, abstract = {Huntington's disease (HD) is a dominantly inherited neurological disorder characterized by chorea, psychiatric symptoms, and cognitive decline but typically lacks muscular atrophy and weakness. We herein report a case of genetically confirmed HD showing progressive systemic weakness with findings of upper and lower motor neuron involvement due to amyotrophic lateral sclerosis (ALS). The current patient and the previously reported cases with complications of HD and ALS indicate that cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin gene might have a pathogenic role in causing the two neurological disorders.}, } @article {pmid38898006, year = {2024}, author = {Nógrádi, B and Nógrádi-Halmi, D and Erdélyi-Furka, B and Kádár, Z and Csont, T and Gáspár, R}, title = {Mechanism of motoneuronal and pyramidal cell death in amyotrophic lateral sclerosis and its potential therapeutic modulation.}, journal = {Cell death discovery}, volume = {10}, number = {1}, pages = {291}, pmid = {38898006}, issn = {2058-7716}, support = {BO/00574/22//Magyar Tudományos Akadémia (Hungarian Academy of Sciences)/ ; ÚNKP-23-5 -SZTE-711//Emberi Eroforrások Minisztériuma (Ministry of Human Capacities)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder clinically characterized by muscle atrophy and progressive paralysis. Loss of motoneurons and pyramidal cells is thought to be the center piece of the complex and multifaceted ALS pathology, however, the exact mechanisms laying behind motoneuronal cell death in the spinal cord and motor cortex are still unknown. It was originally proposed that apoptosis plays a fundamental role in motoneuronal demise, nonetheless, later it became clear that other forms of regulated cell death, including necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death, may also contribute to motoneuron loss. Over the past years, multiple studies aimed to improve our understanding of the contributory role of these mechanisms as well as to offer novel targets for potential therapeutic interventions. The pharmacological inhibition of the ferroptotic pathway and the modulation of the autophagic machinery seem to have particularly promising effects, reducing motoneuron loss and slowing disease progression in transgenic models of ALS. Nevertheless, the potential beneficial effects of necroptosis-targeting interventions were mostly disproven in the latest studies. In this review we aim to summarize the current view on regulated cell death mechanisms that lead to motoneuronal and pyramidal cell degeneration in ALS and showcase their applicability as future drug targets.}, } @article {pmid38898231, year = {2024}, author = {Gao, J and Gunasekar, S and Xia, ZJ and Shalin, K and Jiang, C and Chen, H and Lee, D and Lee, S and Pisal, ND and Luo, JN and Griciuc, A and Karp, JM and Tanzi, R and Joshi, N}, title = {Gene therapy for CNS disorders: modalities, delivery and translational challenges.}, journal = {Nature reviews. Neuroscience}, volume = {25}, number = {8}, pages = {553-572}, pmid = {38898231}, issn = {1471-0048}, mesh = {Humans ; *Genetic Therapy/methods/trends ; *Central Nervous System Diseases/therapy/genetics ; Animals ; Translational Research, Biomedical/methods ; Gene Transfer Techniques/trends ; }, abstract = {Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.}, } @article {pmid38898538, year = {2024}, author = {Bravo-Miana, RDC and Arizaga-Echebarria, JK and Otaegui, D}, title = {Central nervous system-derived extracellular vesicles: the next generation of neural circulating biomarkers?.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {32}, pmid = {38898538}, issn = {2047-9158}, support = {PI20/1253//Instituto de Salud Carlos III/ ; KK-2021/00009//Departamento de Desarrollo Económico, Sostenibilidad y Medio Ambiente/ ; ECTRIMS Postdoctoral Research Fellowship 2023//European Committee for Treatment and Research in Multiple Sclerosis/ ; Predoctoral fellowship//Basque Government/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/blood ; *Central Nervous System/metabolism ; *Neurodegenerative Diseases/blood/diagnosis/metabolism ; Animals ; }, abstract = {The central nervous system (CNS) is integrated by glial and neuronal cells, and both release extracellular vesicles (EVs) that participate in CNS homeostasis. EVs could be one of the best candidates to operate as nanosized biological platforms for analysing multidimensional bioactive cargos, which are protected during systemic circulation of EVs. Having a window into the molecular level processes that are happening in the CNS could open a new avenue in CNS research. This raises a particular point of interest: can CNS-derived EVs in blood serve as circulating biomarkers that reflect the pathological status of neurological diseases? L1 cell adhesion molecule (L1CAM) is a widely reported biomarker to identify CNS-derived EVs in peripheral blood. However, it has been demonstrated that L1CAM is also expressed outside the CNS. Given that principal data related to neurodegenerative diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease were obtained using L1CAM-positive EVs, efforts to overcome present challenges related to its specificity are required. In this sense, other surface biomarkers for CNS-derived EVs, such as glutamate aspartate transporter (GLAST) and myelin oligodendrocyte glycoprotein (MOG), among others, have started to be used. Establishing a panel of EV biomarkers to analyse CNS-derived EVs in blood could increase the specificity and sensitivity necessary for these types of studies. This review covers the main evidence related to CNS-derived EVs in cerebrospinal fluid and blood samples of patients with neurological diseases, focusing on the reported biomarkers and the technical possibilities for their isolation. EVs are emerging as a mirror of brain physiopathology, reflecting both localized and systemic changes. Therefore, when the technical hindrances for EV research and clinical applications are overcome, novel disease-specific panels of EV biomarkers would be discovered to facilitate transformation from traditional medicine to personalized medicine.}, } @article {pmid38898687, year = {2024}, author = {Lee, B and Lee, SM and Song, JW and Choi, JW}, title = {Gut Microbiota Metabolite Messengers in Brain Function and Pathology at a View of Cell Type-Based Receptor and Enzyme Reaction.}, journal = {Biomolecules & therapeutics}, volume = {32}, number = {4}, pages = {403-423}, pmid = {38898687}, issn = {1976-9148}, abstract = {The human gastrointestinal (GI) tract houses a diverse microbial community, known as the gut microbiome comprising bacteria, viruses, fungi, and protozoa. The gut microbiome plays a crucial role in maintaining the body's equilibrium and has recently been discovered to influence the functioning of the central nervous system (CNS). The communication between the nervous system and the GI tract occurs through a two-way network called the gut-brain axis. The nervous system and the GI tract can modulate each other through activated neuronal cells, the immune system, and metabolites produced by the gut microbiome. Extensive research both in preclinical and clinical realms, has highlighted the complex relationship between the gut and diseases associated with the CNS, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review aims to delineate receptor and target enzymes linked with gut microbiota metabolites and explore their specific roles within the brain, particularly their impact on CNS-related diseases.}, } @article {pmid38900570, year = {2024}, author = {Privado, J and Sanchis Sanchis, E and Sancho-Cantus, D and Cubero-Plazas, L and Navarro-Illana, E and de la Rubia Ortí, JE}, title = {Prediction of caregiver psychological distress in amyotrophic lateral sclerosis: A cross-sectional study.}, journal = {Rehabilitation psychology}, volume = {69}, number = {4}, pages = {364-374}, doi = {10.1037/rep0000554}, pmid = {38900570}, issn = {1939-1544}, support = {//Catholic University of Valencia San Vicente Mártir/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; *Caregivers/psychology ; Female ; Cross-Sectional Studies ; Middle Aged ; *Psychological Distress ; Aged ; Adult ; Stress, Psychological/psychology/complications ; }, abstract = {PURPOSE/OBJECTIVE: To propose a predictive model for caregivers' psychological distress (including anxiety, depression, and cognitive overload) based on different data gathered from amyotrophic lateral sclerosis (ALS) patients (cognitive level, psychological distress, type of ALS, and sex).

RESEARCH METHOD/DESIGN: A cross-sectional study with a sample of 51 ALS patients and their respective main carers. Various instruments were used such as the Beck Anxiety Inventory, ALS Depression Inventory-12, and the Edinburgh Cognitive and Behavioral ALS Screen, Zarit Burden Interview, Self-Rating Depression Scale, and Self-Rating Anxiety Scale for caregivers.

RESULTS: ALS type, sex, and cognition were predictive variables for caregiver distress, with the main explanatory variable being the distress of the patients themselves. Spinal ALS led to higher psychological distress in caregivers (β = .38), as did male patients with ALS and preserved cognition.

CONCLUSIONS/IMPLICATIONS: The proposed confirmatory model demonstrates that patients' psychological distress is the best predictor of psychological distress in their caregivers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).}, } @article {pmid38900757, year = {2024}, author = {Serian, A and Finsel, J and Ludolph, AC and Uttner, I and Lulé, D}, title = {Screening instruments of cognition: The relation of the mini-mental state examination to the Edinburgh cognitive and behavioural ALS screen in amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0304593}, pmid = {38900757}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology/complications/epidemiology ; Male ; Female ; Middle Aged ; Aged ; *Mental Status and Dementia Tests ; Cognition/physiology ; Cognitive Dysfunction/diagnosis/epidemiology ; Neuropsychological Tests ; Cognition Disorders/diagnosis ; }, abstract = {OBJECTIVE: The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) is an established cognitive screening instrument for patients with amyotrophic lateral sclerosis (ALS). Different from tools like the Mini-Mental State Examination (MMSE), it is adjusted for motor impairment, yet, the latter remains one of the most widely used screening instruments, also in ALS studies. Thus, it is of utmost importance to relate outcome scores of both instruments to allow for comparison in ALS patients. This study reports on the performance of ALS patients in both tests with regard to incidence and degree of cognitive impairment, and the correspondence of both, ECAS and MMSE scores.

METHODS: We examined N = 84 ALS patients with the German versions of the ECAS and the MMSE. Performance in both tests regarding incidence and degree of cognitive impairment, and correspondence of frequency of cognitive impairment according to both tests was examined. The relationship between ECAS and MMSE scores was modelled with a non-linear regression model.

RESULTS: All ALS patients were able to complete the ECAS, 89.3% (N = 75) were capable to complete the MMSE. Prevalence of cognitive impairment was in both tests 22.7%, however agreement was only 52.9%. Despite, regression analyses yielded a strong positive relationship (adjusted R2 = .68) between the ECAS total score and the MMSE total score. Both tests were able to identify all patients with dementia.

CONCLUSION: These results suggest that the MMSE is not ideal for cognitive screening in early-stage ALS patients. However, a rough translation of MMSE scores in ECAS scores is possible to estimate the cognitive performance level of patients, with the ECAS being more discriminative in the lower range of cognitive dysfunction (ECAS score: 80-136), for which the MMSE does not define cognitive impairment (corresponding MMSE score: 27-30).}, } @article {pmid38900989, year = {2024}, author = {Tahedl, M and Tan, EL and Kleinerova, J and Delaney, S and Hengeveld, JC and Doherty, MA and Mclaughlin, RL and Pradat, PF and Raoul, C and Ango, F and Hardiman, O and Chang, KM and Lope, J and Bede, P}, title = {Progressive Cerebrocerebellar Uncoupling in Sporadic and Genetic Forms of Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209623}, doi = {10.1212/WNL.0000000000209623}, pmid = {38900989}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/pathology/physiopathology ; Male ; Female ; Middle Aged ; *Cerebellum/diagnostic imaging/pathology ; Aged ; *C9orf72 Protein/genetics ; Prospective Studies ; Ataxin-2/genetics ; Magnetic Resonance Imaging ; Disease Progression ; Cerebral Cortex/diagnostic imaging/pathology/physiopathology ; Adult ; Longitudinal Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is predominantly associated with motor cortex, corticospinal tract (CST), brainstem, and spinal cord degeneration, and cerebellar involvement is much less well characterized. However, some of the cardinal clinical features of ALS, such as dysarthria, dysphagia, gait impairment, falls, and impaired dexterity, are believed to be exacerbated by coexisting cerebellar pathology. Cerebellar pathology may also contribute to cognitive, behavioral, and pseudobulbar manifestations. Our objective was to systematically assess both intracerebellar pathology and cerebrocerebellar connectivity alterations in a genetically stratified cohort of ALS.

METHODS: A prospective, multimodal neuroimaging study was conducted to evaluate the longitudinal evolution of intracerebellar pathology and cerebrocerebellar connectivity, using structural and functional measures.

RESULTS: A total of 113 healthy controls and 212 genetically stratified individuals with ALS were included: (1) C9orf72 hexanucleotide carriers ("C9POS"), (2) sporadic patients who tested negative for ALS-associated genetic variants, and (3) intermediate-length CAG trinucleotide carriers in ATXN2 ("ATXN2"). Flocculonodular lobule (padj = 0.014, 95% CI -5.06e-5 to -3.98e-6) and crura (padj = 0.031, 95% CI -1.63e-3 to -5.55e-5) volume reductions were detected at baseline in sporadic patients. Cerebellofrontal and cerebelloparietal structural connectivity impairment was observed in both C9POS and sporadic patients at baseline, and both projections deteriorated further over time in sporadic patients (padj = 0.003, t(249) = 3.04 and padj = 0.05, t(249) = 1.93). Functional cerebelloparietal uncoupling was evident in sporadic patients at baseline (padj = 0.004, 95% CI -0.19 to -0.03). ATXN2 patients exhibited decreased cerebello-occipital functional connectivity at baseline (padj = 0.004, 95% CI -0.63 to -0.06), progressive cerebellotemporal functional disconnection (padj = 0.025, t(199) = -2.26), and progressive flocculonodular lobule degeneration (padj = 0.017, t(249) = -2.24). C9POS patients showed progressive ventral dentate atrophy (padj = 0.007, t(249) = -2.75). The CSTs (padj < 0.001, 95% CI 4.89e-5 to 1.14e-4) and transcallosal interhemispheric fibers (padj < 0.001, 95% CI 5.21e-5 to 1.31e-4) were affected at baseline in C9POS and exhibited rapid degeneration over the 4 time points. The rate of decline in CST and corpus callosum integrity was faster than the rate of cerebrocerebellar disconnection (padj = 0.001, t(190) = 6.93).

DISCUSSION: ALS is associated with accruing intracerebellar disease burden as well as progressive corticocerebellar uncoupling. Contrary to previous suggestions, we have not detected evidence of compensatory structural or functional changes in response to supratentorial degeneration. The contribution of cerebellar disease burden to dysarthria, dysphagia, gait impairment, pseudobulbar affect, and cognitive deficits should be carefully considered in clinical assessments, monitoring, and multidisciplinary interventions.}, } @article {pmid38901111, year = {2024}, author = {Pavey, NA and Menon, P and Peterchev, AV and Kiernan, MC and Vucic, S}, title = {Abnormalities of cortical stimulation strength-duration time constant in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {164}, number = {}, pages = {161-167}, pmid = {38901111}, issn = {1872-8952}, support = {R01 MH128422/MH/NIMH NIH HHS/United States ; R01 NS117405/NS/NINDS NIH HHS/United States ; RF1 MH124943/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; *Transcranial Magnetic Stimulation/methods ; Middle Aged ; *Motor Cortex/physiopathology ; Aged ; *Evoked Potentials, Motor/physiology ; Adult ; Motor Neurons/physiology ; }, abstract = {OBJECTIVES: Strength-duration time constant (SDTC) may now be determined for cortical motor neurones, with activity mediated by transient Na[+] conductances. The present study determined whether cortical SDTC is abnormal and linked to the pathogenesis of amyotrophic lateral sclerosis.

METHODS: Cortical SDTC and rheobase were estimated from 17 ALS patients using a controllable pulse parameter transcranial magnetic stimulation (cTMS) device. Resting motor thresholds (RMTs) were determined at pulse widths (PW) of 30, 45, 60, 90 and 120 µs and M-ratio of 0.1, using a figure-of-eight coil applied to the primary motor cortex.

RESULTS: SDTC was significantly reduced in ALS patients (150.58 ± 9.98 µs; controls 205.94 ± 13.7 µs, P < 0.01). The reduced SDTC correlated with a rate of disease progression (Rho = -0.440, P < 0.05), ALS functional rating score (ALSFRS-R) score (Rho = 0.446, P < 0.05), and disease duration (R = 0.428, P < 0.05). The degree of change in SDTC was greater in patients with cognitive abnormalities as manifested by an abnormal total Edinburgh Cognitive ALS Screen score (140.5 ± 28.7 µs, P < 0.001) and ALS-specific subscore (141.7 ± 33.2 µs, P = 0.003).

CONCLUSIONS: Cortical SDTC reduction was associated with a more aggressive ALS phenotype, or with more prominent cognitive impairment.

SIGNIFICANCE: An increase in transient Na[+] conductances may account for the reduction in SDTC, linked to the pathogenesis of ALS.}, } @article {pmid38902525, year = {2024}, author = {Kitamura, A and Fujimoto, A and Kawashima, R and Lyu, Y and Sasaki, K and Hamada, Y and Moriya, K and Kurata, A and Takahashi, K and Brielmann, R and Bott, LC and Morimoto, RI and Kinjo, M}, title = {Hetero-oligomerization of TDP-43 carboxy-terminal fragments with cellular proteins contributes to proteotoxicity.}, journal = {Communications biology}, volume = {7}, number = {1}, pages = {743}, pmid = {38902525}, issn = {2399-3642}, support = {JP22gm6410028//Japan Agency for Medical Research and Development (AMED)/ ; JP22ym0126814//Japan Agency for Medical Research and Development (AMED)/ ; 24H02286//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22H04826//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 16KK0156//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 18K06201//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22H02578//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K19886//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JPMJSP2119//MEXT | Japan Science and Technology Agency (JST)/ ; JPMJFS2101//MEXT | Japan Science and Technology Agency (JST)/ ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry/genetics ; Humans ; Animals ; Protein Multimerization ; Caenorhabditis elegans/metabolism/genetics ; Intrinsically Disordered Proteins/chemistry/metabolism/genetics ; }, abstract = {Carboxy terminal fragments (CTFs) of TDP-43 contain an intrinsically disordered region (IDR) and form cytoplasmic condensates containing amyloid fibrils. Such condensates are toxic and associated with pathogenicity in amyotrophic lateral sclerosis. However, the molecular details of how the domain of TDP-43 CTFs leads to condensation and cytotoxicity remain elusive. Here, we show that truncated RNA/DNA-recognition motif (RRM) at the N-terminus of TDP-43 CTFs leads to the structural transition of the IDR, whereas the IDR itself of TDP-43 CTFs is difficult to assemble even if they are proximate intermolecularly. Hetero-oligomers of TDP-43 CTFs that have recruited other proteins are more toxic than homo-oligomers, implicating loss-of-function of the endogenous proteins by such oligomers is associated with cytotoxicity. Furthermore, such toxicity of TDP-43 CTFs was cell-nonautonomously affected in the nematodes. Therefore, misfolding and oligomeric characteristics of the truncated RRM at the N-terminus of TDP-43 CTFs define their condensation properties and toxicity.}, } @article {pmid38902629, year = {2024}, author = {Takemoto, Y and Ito, D and Komori, S and Kishimoto, Y and Yamada, S and Hashizume, A and Katsuno, M and Nakatochi, M}, title = {Comparing preprocessing strategies for 3D-Gene microarray data of extracellular vesicle-derived miRNAs.}, journal = {BMC bioinformatics}, volume = {25}, number = {1}, pages = {221}, pmid = {38902629}, issn = {1471-2105}, support = {JP21wm0425013//Japan Agency for Medical Research and Development/ ; 23H00420//Japan Society for the Promotion of Science/ ; 16H06277//Japan Society for the Promotion of Science/ ; }, mesh = {*Extracellular Vesicles/metabolism/genetics ; *MicroRNAs/genetics/metabolism ; Humans ; *Oligonucleotide Array Sequence Analysis/methods ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Gene Expression Profiling/methods ; }, abstract = {BACKGROUND: Extracellular vesicle-derived (EV)-miRNAs have potential to serve as biomarkers for the diagnosis of various diseases. miRNA microarrays are widely used to quantify circulating EV-miRNA levels, and the preprocessing of miRNA microarray data is critical for analytical accuracy and reliability. Thus, although microarray data have been used in various studies, the effects of preprocessing have not been studied for Toray's 3D-Gene chip, a widely used measurement method. We aimed to evaluate batch effect, missing value imputation accuracy, and the influence of preprocessing on measured values in 18 different preprocessing pipelines for EV-miRNA microarray data from two cohorts with amyotrophic lateral sclerosis using 3D-Gene technology.

RESULTS: Eighteen different pipelines with different types and orders of missing value completion and normalization were used to preprocess the 3D-Gene microarray EV-miRNA data. Notable results were suppressed in the batch effects in all pipelines using the batch effect correction method ComBat. Furthermore, pipelines utilizing missForest for missing value imputation showed high agreement with measured values. In contrast, imputation using constant values for missing data exhibited low agreement.

CONCLUSIONS: This study highlights the importance of selecting the appropriate preprocessing strategy for EV-miRNA microarray data when using 3D-Gene technology. These findings emphasize the importance of validating preprocessing approaches, particularly in the context of batch effect correction and missing value imputation, for reliably analyzing data in biomarker discovery and disease research.}, } @article {pmid38902734, year = {2024}, author = {Hu, Y and Hruscha, A and Pan, C and Schifferer, M and Schmidt, MK and Nuscher, B and Giera, M and Kostidis, S and Burhan, Ö and van Bebber, F and Edbauer, D and Arzberger, T and Haass, C and Schmid, B}, title = {Mis-localization of endogenous TDP-43 leads to ALS-like early-stage metabolic dysfunction and progressive motor deficits.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {50}, pmid = {38902734}, issn = {1750-1326}, mesh = {Animals ; *Zebrafish ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Zebrafish Proteins/metabolism/genetics ; Animals, Genetically Modified ; Neuromuscular Junction/metabolism/pathology ; }, abstract = {BACKGROUND: The key pathological signature of ALS/ FTLD is the mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm. However, TDP-43 gain of function in the cytoplasm is still poorly understood since TDP-43 animal models recapitulating mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm are missing.

METHODS: CRISPR/Cas9 technology was used to generate a zebrafish line (called CytoTDP), that mis-locates endogenous TDP-43 from the nucleus to the cytoplasm. Phenotypic characterization of motor neurons and the neuromuscular junction was performed by immunostaining, microglia were immunohistochemically localized by whole-mount tissue clearing and muscle ultrastructure was analyzed by scanning electron microscopy. Behavior was investigated by video tracking and quantitative analysis of swimming parameters. RNA sequencing was used to identify mis-regulated pathways with validation by molecular analysis.

RESULTS: CytoTDP fish have early larval phenotypes resembling clinical features of ALS such as progressive motor defects, neurodegeneration and muscle atrophy. Taking advantage of zebrafish's embryonic development that solely relys on yolk usage until 5 days post fertilization, we demonstrated that microglia proliferation and activation in the hypothalamus is independent from food intake. By comparing CytoTDP to a previously generated TDP-43 knockout line, transcriptomic analyses revealed that mis-localization of endogenous TDP-43, rather than TDP-43 nuclear loss of function, leads to early onset metabolic dysfunction.

CONCLUSIONS: The new TDP-43 model mimics the ALS/FTLD hallmark of progressive motor dysfunction. Our results suggest that functional deficits of the hypothalamus, the metabolic regulatory center, might be the primary cause of weight loss in ALS patients. Cytoplasmic gain of function of endogenous TDP-43 leads to metabolic dysfunction in vivo that are reminiscent of early ALS clinical non-motor metabolic alterations. Thus, the CytoTDP zebrafish model offers a unique opportunity to identify mis-regulated targets for therapeutic intervention early in disease progression.}, } @article {pmid38902980, year = {2024}, author = {Dratch, L and Kinnamon, DD and Harrington, EA and Goldman, J and Fong, JC and Jones, T and Uhlmann, WR and Roggenbuck, J}, title = {Response to "assessment of risk of ALS conferred by the GGGGCC hexanucleotide expansion in C9orf72 among first-degree relatives of patients with ALS carrying the repeat expansion".}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {797-799}, doi = {10.1080/21678421.2024.2362854}, pmid = {38902980}, issn = {2167-9223}, } @article {pmid38903116, year = {2024}, author = {Matera, AG and Steiner, RE and Mills, CA and Herring, LE and Garcia, EL}, title = {Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38903116}, issn = {2692-8205}, support = {P30 CA016086/CA/NCI NIH HHS/United States ; R35 GM136435/GM/NIGMS NIH HHS/United States ; }, abstract = {Molecular chaperones and co-chaperones are highly conserved cellular components that perform variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an RNP assembly chaperone and serves as a paradigm for studying how specific small nuclear (sn)RNAs are identified and paired with their client substrate proteins. SMN protein is the eponymous component of a large complex required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs) and localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN forms the oligomeric core of this complex, and missense mutations in its YG box self-interaction domain are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood. Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. Here, we carried out affinity purification mass spectrometry (AP-MS) of SMN using stable fly lines exclusively expressing either wildtype or SMA-causing missense alleles. Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially interacted with SMA-causing alleles of SMN. Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and Drosophila ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.}, } @article {pmid38903475, year = {2024}, author = {Dash, D and Teplansky, K and Ferrari, P and Babajani-Feremi, A and Calley, CS and Heitzman, D and Austin, SG and Wang, J}, title = {Automatic detection of ALS from single-trial MEG signals during speech tasks: a pilot study.}, journal = {Frontiers in psychology}, volume = {15}, number = {}, pages = {1114811}, pmid = {38903475}, issn = {1664-1078}, abstract = {Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, and fast-progressive neurodegenerative disease characterized by the degeneration of motor neurons. ALS patients often experience an initial misdiagnosis or a diagnostic delay due to the current unavailability of an efficient biomarker. Since impaired speech is typical in ALS, we hypothesized that functional differences between healthy and ALS participants during speech tasks can be explained by cortical pattern changes, thereby leading to the identification of a neural biomarker for ALS. In this pilot study, we collected magnetoencephalography (MEG) recordings from three early-diagnosed patients with ALS and three healthy controls during imagined (covert) and overt speech tasks. First, we computed sensor correlations, which showed greater correlations for speakers with ALS than healthy controls. Second, we compared the power of the MEG signals in canonical bands between the two groups, which showed greater dissimilarity in the beta band for ALS participants. Third, we assessed differences in functional connectivity, which showed greater beta band connectivity for ALS than healthy controls. Finally, we performed single-trial classification, which resulted in highest performance with beta band features (∼ 98%). These findings were consistent across trials, phrases, and participants for both imagined and overt speech tasks. Our preliminary results indicate that speech-evoked beta oscillations could be a potential neural biomarker for diagnosing ALS. To our knowledge, this is the first demonstration of the detection of ALS from single-trial neural signals.}, } @article {pmid38903602, year = {2024}, author = {Al-Kuraishy, HM and Jabir, MS and Sulaiman, GM and Mohammed, HA and Al-Gareeb, AI and Albuhadily, AK and Jawad, SF and Swelum, AA and Abomughaid, MM}, title = {The role of statins in amyotrophic lateral sclerosis: protective or not?.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1422912}, pmid = {38903602}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting. ALS is regarded as the third-most frequent neurodegenerative disease, subsequent to Alzheimer's disease (AD) and Parkinson's disease (PD). The World Health Organization (WHO) in 2007 declared that prolonged use of statins may induce development of ALS-like syndrome and may increase ALS risk. Subsequently, different studies have implicated statins in the pathogenesis of ALS. In contrast, results from preclinical and clinical studies highlighted the protective role of statins against ALS neuropathology. Recently, meta-analyses and systematic reviews illustrated no association between long-term use of statins and ALS risk. These findings highlighted controversial points regarding the effects of statins on ALS pathogenesis and risk. The neuroprotective effects of statins against the development and progression of ALS may be mediated by regulating dyslipidemia and inflammatory changes. However, the mechanism for induction of ALS neuropathology by statins may be related to the dysregulation of liver X receptor signaling (LXR) signaling in the motor neurons and reduction of cholesterol, which has a neuroprotective effect against ALS neuropathology. Nevertheless, the exact role of statins on the pathogenesis of ALS was not fully elucidated. Therefore, this narrative review aims to discuss the role of statins in ALS neuropathology.}, } @article {pmid38904729, year = {2024}, author = {Portes E Silva, KR and Nogueira, EM and Jesus Mendes, AL and Pena, ALB and Simões E Silva, AC}, title = {The potential role of renin angiotensin system in acute leukemia: a narrative review.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {775}, pmid = {38904729}, issn = {1573-4978}, support = {304496/2023-5//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {Humans ; *Renin-Angiotensin System/physiology ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism/pathology ; *Angiotensin II/metabolism ; Leukemia, Myeloid, Acute/metabolism/pathology ; Signal Transduction ; Angiotensin I/metabolism ; Neovascularization, Pathologic/metabolism ; Animals ; Peptide Fragments/metabolism ; }, abstract = {Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.}, } @article {pmid38904901, year = {2024}, author = {Aiello, EN and Torre, S and Solca, F and Curti, B and De Luca, G and Gendarini, C and Cocuzza, A and Colombo, E and Maranzano, A and Verde, F and Morelli, C and Messina, S and Doretti, A and Silani, V and Ticozzi, N and Poletti, B}, title = {Ecological validity of performance-based cognitive screeners in amyotrophic lateral sclerosis: preliminary evidence.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {11}, pages = {5319-5325}, pmid = {38904901}, issn = {1590-3478}, support = {Ministero della Salute//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Male ; Female ; Middle Aged ; *Caregivers/psychology ; Aged ; *Neuropsychological Tests/standards ; Reproducibility of Results ; Cognition Disorders/diagnosis/etiology ; Adult ; }, abstract = {BACKGROUND: This study aimed at preliminarily assessing, in a cohort of non-demented amyotrophic lateral sclerosis (ALS) patients, the ecological validity, and more specifically the veridicality, of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and the ALS Cognitive Behavioral Screen (ALS-CBS™), by relating their scores to caregiver-report ratings of cognitive changes.

METHODS: N = 147 patient-caregiver dyads were recruited. Patients were administered the ECAS and ALS-CBS™, whilst caregiver the Caregiver Behavioral Questionnaire (CBQ) and Beaumont Behavioural Inventory (BBI). An Ecological Cognitive Functioning Index (ECFI) was derived from those items of the CBQ and BBI that tap on executive and language changes. Ecological validity was assessed via both correlational and predictive analyses net of caregiver-rated behavioural changes (as assessed by the ECAS-Carer Interview).

RESULTS: The ECFI was associated with the total scores on both the ECAS (p = .014) and ALS-CBS™ (p = .017). When looking at ECAS and ALS-CBS™ subscales, those assessing verbal fluency were selectively associated with the ECFI. The ECFI was higher in patients performing defectively on the ECAS (p = .004) and on the ALS-CBS™ (p = .027).

DISCUSSION: This study suggests that both the ECAS and the ALS-CBS™ represent a valid estimate of non-demented ALS patients' cognitive status in the real world, also highlighting the clinical relevance of cognitive changes reported by caregivers.}, } @article {pmid38905379, year = {2024}, author = {Park, BK and Oh, SI and Kang, M and Seok, HY and Park, JM and Kim, S and Kim, HI and Kim, JA and Park, JS}, title = {Reliability and Validity of the Korean version of the Center for Neurologic Study Bulbar Function Scale (K-CNS-BFS): An observational study.}, journal = {Medicine}, volume = {103}, number = {25}, pages = {e38216}, pmid = {38905379}, issn = {1536-5964}, mesh = {Humans ; Male ; Female ; Republic of Korea ; Middle Aged ; Reproducibility of Results ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; Aged ; *Severity of Illness Index ; Adult ; }, abstract = {Bulbar dysfunction in amyotrophic lateral sclerosis (ALS) significantly affects daily life, leading to weight loss and reduced survival. Methods for evaluating bulbar dysfunction, including videofluoroscopic swallowing studies and the bulbar component of the ALS Functional Rating Scale-Revised (ALSFRS-R), have been employed; however, Korean-specific tools are lacking. The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) comprehensively evaluates bulbar symptoms. This study aimed to develop and validate the Korean version of the CNS-BFS (K-CNS-BFS) to assess bulbar dysfunction in Korean patients with ALS. Twenty-seven patients with ALS were recruited from a tertiary hospital in South Korea based on revised El Escorial criteria. Demographic, clinical, and measurement data were collected. The K-CNS-BFS was evaluated for reliability and validity. Reliability assessment revealed strong internal consistency (Cronbach alpha) for the K-CNS-BFS subscales and total score. Test-retest reliability showed significant correlation. Content validity index was excellent, and convergent validity demonstrated significant correlations between the K-CNS-BFS and relevant measures. Discriminant validity was observed between the K-CNS-BFS and motor/respiratory subscores of the ALSFRS-R. Construct validity demonstrated significant correlations between the K-CNS-BFS subscales and total score. This is the first study to investigate the reliability and validity of the Korean version of the CNS-BFS, which showed consistent and reliable scores that correlated with tests for bulbar or general dysfunction. The K-CNS-BFS effectively measured bulbar dysfunction similar to the original CNS-BFS. The K-CNS-BFS is a reliable and valid tool for assessing bulbar dysfunction in patients with ALS in South Korea.}, } @article {pmid38905382, year = {2024}, author = {Jing, Z and Qi, X and Teng, J}, title = {Dietary factors and risk for amyotrophic lateral sclerosis: A two sample mendelian randomization study.}, journal = {Medicine}, volume = {103}, number = {25}, pages = {e38473}, pmid = {38905382}, issn = {1536-5964}, mesh = {*Mendelian Randomization Analysis/methods ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/etiology ; Humans ; *Diet ; Risk Factors ; Fruit ; Genome-Wide Association Study ; Vegetables ; Coffee/adverse effects ; Meat/adverse effects ; }, abstract = {Correlations between dietary factors and amyotrophic lateral sclerosis (ALS) have been found in previous observational studies. However, no further studies have used Mendelian randomization to further explore the causal relationship between dietary factors and ALS. Clarifying these relationships is a crucial part of developing nutritional recommendations for ALS prevention. The exposure and outcome datasets employed in this study were extracted from the IEU Open GWAS project (https://gwas.mrcieu.ac.uk/). The exposure datasets involved in our Mendelian analyses consisted of meat intake (processed meat intake, poultry intake, beef intake, pork intake, non-oily fish intake, and oily fish intake), staple foods intake (bread intake and cereal intake), vegetable intake (cooked vegetable intake, salad/raw vegetable intake), fruit intake (fresh fruit intake and dried fruit intake), and beverage intake (coffee intake and tea intake). The weighted median, MR-Egger, Inverse Variance Weighted, Simple mode and Weighted mode methods were all utilized. And we applied Inverse Variance Weighted method as the main judgement criterion for Mendelian randomization analysis. Heterogeneity and pleiotropy analyses were conducted to confirm the validity of the outcomes. Genetically predicted that oily fish intake (OR: 0.7648; 95% CI: 0.5905-0.9904; P = .0420), coffee intake (OR: 0.7385; 95% CI: 0.5660-0.9637; P = .0256), and fresh fruit intake (OR: 0.6165; 95% CI: 0.4007-0.9487; P = .0278) were causally associated with a decreased risk of ALS. Negative results (P > .05) were received for all other dietary factors. This study found that oily fish intake, coffee intake and fresh fruit intake reduced the risk of developing ALS. Additionally, other factors were not associated with ALS.}, } @article {pmid38905535, year = {2024}, author = {}, title = {Addendum: Relyvrio withdrawn.}, journal = {The Medical letter on drugs and therapeutics}, volume = {66}, number = {1704}, pages = {96}, doi = {10.58347/tml.2024.1704e}, pmid = {38905535}, issn = {1523-2859}, mesh = {Humans ; Phenylbutyrates ; }, } @article {pmid38906259, year = {2024}, author = {Barbieri, JS}, title = {Response to Veenstra et al's "Benzoyl peroxide use in acne therapy: Evaluating the association with acute myeloid leukemia risk".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e109-e110}, doi = {10.1016/j.jaad.2024.05.090}, pmid = {38906259}, issn = {1097-6787}, mesh = {Humans ; *Acne Vulgaris/drug therapy ; *Leukemia, Myeloid, Acute/drug therapy/chemically induced ; *Benzoyl Peroxide/therapeutic use/adverse effects ; Dermatologic Agents/adverse effects/therapeutic use ; }, } @article {pmid38906263, year = {2024}, author = {Veenstra, J and Ozog, D}, title = {Response to Barbieri, "Response to Veenstra et al's 'benzoyl peroxide use in acne therapy: Evaluating the association with acute myeloid leukemia risk'".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e111-e112}, doi = {10.1016/j.jaad.2024.06.036}, pmid = {38906263}, issn = {1097-6787}, mesh = {Humans ; *Acne Vulgaris/drug therapy ; *Leukemia, Myeloid, Acute/drug therapy/chemically induced ; *Benzoyl Peroxide/therapeutic use/adverse effects ; Dermatologic Agents/adverse effects/therapeutic use ; }, } @article {pmid38906677, year = {2024}, author = {Au, WH and Miller-Fleming, L and Sanchez-Martinez, A and Lee, JA and Twyning, MJ and Prag, HA and Raik, L and Allen, SP and Shaw, PJ and Ferraiuolo, L and Mortiboys, H and Whitworth, AJ}, title = {Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models.}, journal = {Life science alliance}, volume = {7}, number = {9}, pages = {}, pmid = {38906677}, issn = {2575-1077}, support = {/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Oxidative Stress ; *NF-E2-Related Factor 2/metabolism/genetics ; *C9orf72 Protein/genetics/metabolism ; *Mitochondria/metabolism ; Animals ; *Disease Models, Animal ; *Kelch-Like ECH-Associated Protein 1/metabolism/genetics ; Humans ; *Signal Transduction ; *Frontotemporal Dementia/genetics/metabolism ; *Phenotype ; Drosophila Proteins/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Mitophagy/genetics ; Dimethyl Fumarate/pharmacology ; Male ; }, abstract = {Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.}, } @article {pmid38907103, year = {2024}, author = {Limone, F and Mordes, DA and Couto, A and Joseph, BJ and Mitchell, JM and Therrien, M and Ghosh, SD and Meyer, D and Zhang, Y and Goldman, M and Bortolin, L and Cobos, I and Stevens, B and McCarroll, SA and Kadiu, I and Burberry, A and Pietiläinen, O and Eggan, K}, title = {Single-nucleus sequencing reveals enriched expression of genetic risk factors in extratelencephalic neurons sensitive to degeneration in ALS.}, journal = {Nature aging}, volume = {4}, number = {7}, pages = {984-997}, pmid = {38907103}, issn = {2662-8465}, support = {K08 NS104270/NS/NINDS NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; P50 HD105351/HD/NICHD NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *Neurons/metabolism/pathology ; Risk Factors ; Microglia/metabolism/pathology ; Cell Nucleus/metabolism/genetics ; Oligodendroglia/metabolism/pathology ; Male ; Single-Cell Analysis ; Sequence Analysis, RNA ; Female ; Middle Aged ; Nerve Degeneration/genetics/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls. In both patients and unaffected individuals, we found significantly higher expression of ALS risk genes in THY1[+] ETNs, regardless of diagnosis. In patients, this was accompanied by the induction of genes involved in protein homeostasis and stress responses that were significantly induced in a wide collection of ETNs. Examination of oligodendroglial and microglial nuclei revealed patient-specific downregulation of myelinating genes in oligodendrocytes and upregulation of an endolysosomal reactive state in microglia. Our findings suggest that selective vulnerability of extratelencephalic neurons is partly connected to their intrinsic molecular properties sensitizing them to genetics and mechanisms of degeneration.}, } @article {pmid38907861, year = {2024}, author = {Yang, T and Wei, Q and Pang, D and Cheng, Y and Huang, J and Lin, J and Xiao, Y and Jiang, Q and Wang, S and Li, C and Shang, H}, title = {Clinical and genetic characteristics of ALS patients with variants in genes regulating DNA methylation.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5556-5566}, pmid = {38907861}, issn = {1432-1459}, support = {82371430//National Natural Science Foundation of China/ ; 2022ZDZX0023//Sichuan Science and Technology Program/ ; YCXJ-JZ-2022-007//Beijing E-town Coorperation & Development Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *DNA Methylation ; Female ; Male ; Middle Aged ; Aged ; China ; Genetic Predisposition to Disease/genetics ; DNA-Binding Proteins/genetics ; Cohort Studies ; Adult ; Dioxygenases ; Genetic Variation ; }, abstract = {BACKGROUND: Aberrant DNA methylation alterations are implicated in amyotrophic lateral sclerosis (ALS). Nevertheless, the influence of genetic variants in genes regulating DNA methylation on ALS patients is not well understood. Therefore, we aim to provide a comprehensive variant profile of genes related to DNA methylation (DNMT1, DNMT3A, DNMT3B, DNMT3L) and demethylation (TET1, TET2, TET3, TDG) and to investigate the association of these variants with ALS.

METHODS: Variants were screened in a cohort of 2240 ALS patients from Southwest China, using controls from the Genome Aggregation Database (n = 9976) and the China Metabolic Analytics Project (n = 10,588). The over-representation of rare variants and their association with ALS risk were evaluated using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis and Cox regression analysis were employed to explore the relationship between variants and survival.

RESULTS: A total of 210 variants meeting the criteria were identified. Gene-based burden analysis identified a significant increase in ALS risk associated with rare variants in the TET2 gene (OR = 1.95, 95% CI = 1.29-2.88, P = 0.001). Survival analysis demonstrated that patients carrying variants in demethylation-related genes had a higher risk of death compared to those with methylation-related gene variants (HR = 1.29, 95% CI = 1.03-1.86, P = 0.039).

CONCLUSIONS: This study provides a genetic variant profile of genes involved in DNA methylation and demethylation regulation, along with the clinical characteristics of ALS patients carrying these variants. The findings offer genetic evidence implicating disrupted DNA methylation dynamics in ALS.}, } @article {pmid38908137, year = {2024}, author = {Cain, CN and Synovec, RE}, title = {Enhancing gas chromatography-mass spectrometry resolution and pure analyte discovery using intra-chromatogram elution profile matching.}, journal = {Talanta}, volume = {278}, number = {}, pages = {126453}, doi = {10.1016/j.talanta.2024.126453}, pmid = {38908137}, issn = {1873-3573}, abstract = {Chemometric decomposition methods like multivariate curve resolution-alternating least squares (MCR-ALS) are often employed in gas chromatography-mass spectrometry (GC-MS) to improve analyte identification and quantitation. However, these methods can perform poorly for analytes with a low chromatographic resolution (Rs) and a high degree of spectral contamination from noise and background interferences. Thus, we propose a novel computational algorithm, termed mzCompare, to improve analyte identification and quantitation when coupled to MCR-ALS. The mzCompare method utilizes an underlying requirement that the retention time and peak shape between mass channels (m/z) of the same analyte should be similar. By discovering the selective m/z for a given analyte in a chromatogram, a pure elution profile can be generated and used as an equality constraint in MCR-ALS. The performance of the mzCompare methodology is demonstrated with both experimental and simulated chromatograms. Experimentally, unresolved analytes with a Rs as low as 0.05 could be confidently identified with mzCompare assisted MCR-ALS. Furthermore, application of the mzCompare algorithm to a complex aerospace fuel resulted in the discovery of 335 analytes, a 44 % increase compared to conventional peak detection methods. GC-MS simulations of target-interferent analyte pairs demonstrated that the performance of MCR-ALS deteriorated below a Rs of ∼0.25. However, mzCompare assisted MCR-ALS showed excellent identification and acceptable quantitative accuracy at a Rs of ∼0.02. These results show that the mzCompare algorithm can help analysts overcome modeling ambiguities resulting from the chemometric multiplex disadvantage.}, } @article {pmid38908196, year = {2024}, author = {Donders, Z and Skorupska, IJ and Willems, E and Mussen, F and Broeckhoven, JV and Carlier, A and Schepers, M and Vanmierlo, T}, title = {Beyond PDE4 inhibition: A comprehensive review on downstream cAMP signaling in the central nervous system.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {177}, number = {}, pages = {117009}, doi = {10.1016/j.biopha.2024.117009}, pmid = {38908196}, issn = {1950-6007}, mesh = {Humans ; *Cyclic AMP/metabolism ; *Phosphodiesterase 4 Inhibitors/pharmacology ; Animals ; *Central Nervous System/drug effects/metabolism ; *Signal Transduction/drug effects ; *Central Nervous System Diseases/drug therapy/metabolism/enzymology ; *Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; }, abstract = {Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP levels are spatiotemporally regulated by their hydrolyzing enzymes called phosphodiesterases (PDEs). It has been shown that increased cAMP levels in the central nervous system (CNS) promote neuroplasticity, neurotransmission, neuronal survival, and myelination while suppressing neuroinflammation. Thus, elevating cAMP levels through PDE inhibition provides a therapeutic approach for multiple CNS disorders, including multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, and Alzheimer's disease. In particular, inhibition of the cAMP-specific PDE4 subfamily is widely studied because of its high expression in the CNS. So far, the clinical translation of full PDE4 inhibitors has been hampered because of dose-limiting side effects. Hence, focusing on signaling cascades downstream activated upon PDE4 inhibition presents a promising strategy, offering novel and pharmacologically safe targets for treating CNS disorders. Yet, the underlying downstream signaling pathways activated upon PDE(4) inhibition remain partially elusive. This review provides a comprehensive overview of the existing knowledge regarding downstream mediators of cAMP signaling induced by PDE4 inhibition or cAMP stimulators. Furthermore, we highlight existing gaps and future perspectives that may incentivize additional downstream research concerning PDE(4) inhibition, thereby providing novel therapeutic approaches for CNS disorders.}, } @article {pmid38908354, year = {2024}, author = {Kim, K and Choi, D and Shim, H and Lee, CA}, title = {Effects of gamification in advanced life support training for clinical nurses: A cluster randomized controlled trial.}, journal = {Nurse education today}, volume = {140}, number = {}, pages = {106263}, doi = {10.1016/j.nedt.2024.106263}, pmid = {38908354}, issn = {1532-2793}, mesh = {Humans ; Female ; Adult ; Male ; *COVID-19/nursing ; Cardiopulmonary Resuscitation/education ; Clinical Competence/standards ; Advanced Cardiac Life Support/education ; Games, Experimental ; }, abstract = {BACKGROUND: Cardiopulmonary resuscitation training is a mandatory competency, especially for healthcare professionals. However, the spread of COVID-19 caused a sharp decline in the number of participants on advanced life support training, thereby accelerating the diversification of educational methods. Gamification is an increasingly popular method of diversifying instruction, but its effectiveness remains controversial.

AIM: To evaluate the effectiveness of gamification learning in advanced life support training.

DESIGN: A cluster randomized controlled trial.

SETTING: A single advanced life support training center.

PARTICIPANTS: Clinical nurses who are currently practicing in a hospital.

METHODS: A part of the existing advanced life support course was gamified using Kahoot! platform. Conventional learning and gamified learning were each conducted 11 times, and the level of knowledge after training was assessed. The assessment questions were categorized into advanced life support algorithms, teamwork, and cardiac arrest rhythms.

RESULTS: A total of 267 were enrolled in the study, and 148 and 139 learners were assigned to CL and GL, respectively. There was no difference in post-training knowledge related to teamwork, and cardiac arrest rhythms between the conventional learning and gamified learning groups, but knowledge related to the advanced life support algorithm was low in the gamified learning group.

CONCLUSIONS: Even if the learners are the same, advanced life support gamification training can lead to negative outcomes depending on the simplicity or goal of the training content. To improve the effectiveness of the training, various methods of gamification training should be applied depending on the goal and content of the training.}, } @article {pmid38909069, year = {2024}, author = {Ngo, TD and Kieu, HD and Nguyen, MH and Nguyen, TH and Can, VM and Nguyen, BH and Le, TH}, title = {An EEG & eye-tracking dataset of ALS patients & healthy people during eye-tracking-based spelling system usage.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {664}, pmid = {38909069}, issn = {2052-4463}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Brain-Computer Interfaces ; *Electroencephalography ; *Eye-Tracking Technology ; }, abstract = {This research presents a dataset consisting of electroencephalogram and eye tracking recordings obtained from six patients with amyotrophic lateral sclerosis (ALS) in a locked-in state and one hundred seventy healthy individuals. The ALS patients exhibited varying degrees of disease progression, ranging from partial mobility and weakened speech to complete paralysis and loss of speech. Despite these physical impairments, the ALS patients retained good eye function, which allowed them to use a virtual keyboard for communication. Data from ALS patients was recorded multiple times at their homes, while data from healthy individuals was recorded once in a laboratory setting. For each data recording, the experimental design involved nine recording sessions per participant, each corresponding to a common human action or demand. This dataset can serve as a valuable benchmark for several applications, such as improving spelling systems with brain-computer interfaces, investigating motor imagination, exploring motor cortex function, monitoring motor impairment progress in patients undergoing rehabilitation, and studying the effects of ALS on cognitive and motor processes.}, } @article {pmid38909342, year = {2024}, author = {Réginault, T and Wibart, P and Mathis, S and Le Masson, G and Pillet, O and Grassion, L}, title = {Factors associated with survival after early at-home NIV initiation in ALS patients.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5590-5597}, pmid = {38909342}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/mortality/physiopathology ; Male ; Female ; *Noninvasive Ventilation ; Middle Aged ; Retrospective Studies ; Aged ; Respiratory Insufficiency/therapy/mortality/etiology ; Home Care Services ; }, abstract = {BACKGROUND: The initiation of early non-invasive ventilation (NIV) often involves a careful balance between tolerance and effectiveness. In amyotrophic lateral sclerosis (ALS) patients, the establishment of a strategy, including the decision to focus on adhering to a cut-off, setting specific targets, or correcting all events, is crucial.

OBJECTIVE: To identify factors at 1 month after early at-home NIV initiation that are associated with improved survival in ALS patients. We explored the impacts of adherence (ADH), quality of treatment, and NIV parameters at 1 month after early at-home NIV initiation on patient survival.

METHODS: We conducted a retrospective study of 184 ALS patients at the Bordeaux ALS Centre for whom NIV was initiated between September 2017 and June 2021, and we collected data for a minimum period of 2 years after the last patient included. The primary outcome was the risk of death according to baseline characteristics of our population and the NIV parameters and monitoring during the early NIV initiation period. The secondary outcomes were association with NIV ADH during the early NIV initiation period on prognosis, and NIV ADH cut-off for good versus poor prognosis.

RESULTS: Among the 178 ALS patients analysed, we found that quality of NIV treatment and device settings did not significantly influence prognosis. However, low ADH was significantly associated with a higher risk of death. The use of NIV for > 5 h/day during the early NIV initiation period was linked to a decreased risk of death [hazard ratio = 0.4; 95% confidence interval: 0.27-0.9].

CONCLUSION: The use of NIV for > 5 h/day during the early NIV initiation period was associated with increased survival.}, } @article {pmid38909349, year = {2024}, author = {Ketabforoush, A and Faghihi, F and Azedi, F and Ariaei, A and Habibi, MA and Khalili, M and Ashtiani, BH and Joghataei, MT and Arnold, WD}, title = {Sodium Phenylbutyrate and Tauroursodeoxycholic Acid: A Story of Hope Turned to Disappointment in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Clinical drug investigation}, volume = {44}, number = {7}, pages = {495-512}, pmid = {38909349}, issn = {1179-1918}, mesh = {Humans ; *Taurochenodeoxycholic Acid/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; *Phenylbutyrates/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {The absence of a definitive cure for amyotrophic lateral sclerosis (ALS) emphasizes the crucial need to explore new and improved treatment approaches for this fatal, progressive, and disabling neurodegenerative disorder. As at the end of 2023, five treatments - riluzole, edaravone, dextromethorphan hydrobromide + quinidine sulfate (DHQ), tofersen, and sodium phenylbutyrate-tauroursodeoxycholic acid (PB-TUDCA) - were FDA approved for the treatment of patients with ALS. Among them PB-TUDCA has been shown to impact DNA processing impairments, mitochondria dysfunction, endoplasmic reticulum stress, oxidative stress, and pathologic folded protein agglomeration defects, which have been associated with ALS pathophysiology. The Phase 2 CENTAUR trial demonstrated significant impact of PB-TUDCA on the ALS Functional Rating Scale-Revised (ALSFRS-R) risk of death, hospitalization, and the need for tracheostomy or permanent assisted ventilation in patients with ALS based on post hoc analyses. More recently, contrasting with the CENTAUR trial results, results from the Phase 3 PHOENIX trial (NCT05021536) showed no change in ALSFRS-R total score at 48 weeks. Consequently, the sponsor company initiated the process with the US FDA and Health Canada to voluntarily withdraw the marketing authorizations for PB-TUDCA. In the present article, we review ALS pathophysiology, with a focus on PB-TUDCA's proposed mechanisms of action and recent clinical trial results and discuss the implications of conflicting trial data for ALS and other neurological disorders.}, } @article {pmid38909659, year = {2024}, author = {Issa, NT and Bunick, CG}, title = {In response to Reynolds et al's "guidelines of care for the management of acne vulgaris".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e113-e114}, doi = {10.1016/j.jaad.2024.05.091}, pmid = {38909659}, issn = {1097-6787}, mesh = {Humans ; *Acne Vulgaris/therapy/diagnosis/drug therapy ; *Practice Guidelines as Topic ; }, } @article {pmid38911266, year = {2024}, author = {Huang, X and Lee, S and Chen, K and Kawaguchi, R and Wiskow, O and Ghosh, S and Frost, D and Perrault, L and Pandey, R and Klim, JR and Boivin, B and Hermawan, C and Livak, KJ and Geschwind, DH and Wainger, BJ and Eggan, KC and Bean, BP and Woolf, CJ}, title = {Downregulation of the silent potassium channel Kv8.1 increases motor neuron vulnerability in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {3}, pages = {fcae202}, pmid = {38911266}, issn = {2632-1297}, support = {P50 HD105351/HD/NICHD NIH HHS/United States ; R35 NS127216/NS/NINDS NIH HHS/United States ; }, abstract = {While voltage-gated potassium channels have critical roles in controlling neuronal excitability, they also have non-ion-conducting functions. Kv8.1, encoded by the KCNV1 gene, is a 'silent' ion channel subunit whose biological role is complex since Kv8.1 subunits do not form functional homotetramers but assemble with Kv2 to modify its ion channel properties. We profiled changes in ion channel expression in amyotrophic lateral sclerosis patient-derived motor neurons carrying a superoxide dismutase 1(A4V) mutation to identify what drives their hyperexcitability. A major change identified was a substantial reduction of KCNV1/Kv8.1 expression, which was also observed in patient-derived neurons with C9orf72 expansion. We then studied the effect of reducing KCNV1/Kv8.1 expression in healthy motor neurons and found it did not change neuronal firing but increased vulnerability to cell death. A transcriptomic analysis revealed dysregulated metabolism and lipid/protein transport pathways in KCNV1/Kv8.1-deficient motor neurons. The increased neuronal vulnerability produced by the loss of KCNV1/Kv8.1 was rescued by knocking down Kv2.2, suggesting a potential Kv2.2-dependent downstream mechanism in cell death. Our study reveals, therefore, unsuspected and distinct roles of Kv8.1 and Kv2.2 in amyotrophic lateral sclerosis-related neurodegeneration.}, } @article {pmid38913386, year = {2024}, author = {Shamaskin-Garroway, AM and Shamaskin, J}, title = {Slowing Down-A Family's Experience With ALS.}, journal = {JAMA neurology}, volume = {81}, number = {9}, pages = {907-908}, doi = {10.1001/jamaneurol.2024.1922}, pmid = {38913386}, issn = {2168-6157}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Family/psychology ; Male ; Female ; Middle Aged ; }, } @article {pmid38914173, year = {2024}, author = {Tortarolo, M and Re Cecconi, AD and Camporeale, L and Margotta, C and Nardo, G and Pasetto, L and Bonetto, V and Galbiati, M and Crippa, V and Poletti, A and Piccirillo, R and Bendotti, C}, title = {Sunitinib-mediated inhibition of STAT3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of ALS.}, journal = {Neurobiology of disease}, volume = {199}, number = {}, pages = {106576}, doi = {10.1016/j.nbd.2024.106576}, pmid = {38914173}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; *Sunitinib/pharmacology ; *Muscle, Skeletal/drug effects/metabolism/pathology ; *STAT3 Transcription Factor/metabolism/antagonists & inhibitors ; *Mice, Transgenic ; *Indoles/pharmacology ; Mice ; *Disease Models, Animal ; *Spinal Cord/metabolism/drug effects/pathology ; *Mice, Inbred C57BL ; *Pyrroles/pharmacology ; Superoxide Dismutase/metabolism/genetics ; Muscular Atrophy/metabolism/pathology ; Motor Neurons/drug effects/metabolism/pathology ; Disease Progression ; }, abstract = {Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.}, } @article {pmid38914219, year = {2024}, author = {Asahina, R and Takahashi, M and Takano, H and Yao, R and Abe, M and Goshima, Y and Ohshima, T}, title = {The role of CRMP4 in LPS-induced neuroinflammation.}, journal = {Brain research}, volume = {1841}, number = {}, pages = {149094}, doi = {10.1016/j.brainres.2024.149094}, pmid = {38914219}, issn = {1872-6240}, mesh = {Animals ; *Lipopolysaccharides/pharmacology ; *Microglia/metabolism/drug effects ; *Mice, Knockout ; *Nerve Tissue Proteins/metabolism/genetics ; Mice ; *Neuroinflammatory Diseases/metabolism/chemically induced ; Inflammation/metabolism/chemically induced ; Interleukin-10/metabolism ; Substantia Nigra/metabolism/drug effects ; Mice, Inbred C57BL ; Corpus Striatum/metabolism/drug effects ; Male ; Microfilament Proteins/metabolism ; Arginase/metabolism ; }, abstract = {Neuroinflammation has been gaining attention as one of the potential causes of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis in recent years. The suppression of excessive proinflammatory responses is expected to be a target for the treatment and prevention of neurodegenerative diseases. Collapsin response mediator protein 4 (CRMP4) is involved in cytoskeleton-associated axonal guidance in the developing brain. Recently, the involvement of CRMP4 in several pathological conditions, including inflammation induced by lipopolysaccharide (LPS), a widely used inflammatory molecule, has been reported. However, the role of CRMP4 in LPS-induced inflammation in vivo remains largely unknown. In this study, we generated microglia-specific CRMP4 knockout mice for the first time and examined the role of CRMP4 in an LPS-induced brain inflammation model. We found that microglia after LPS injection in substantia nigra was significantly reduced in Crmp4[-/-] mice compared to Crmp4[+/+]mice. The increased expression of IL-10 in striatum samples was downregulated in Crmp4[-/-] mice. A significant reduction in Iba1 expression was also observed in microglia-specific Crmp4 knockout mice compared with that in control mice. In contrast, the expression of IL-10 did not change in these mice, whereas arginase 1 (Arg1) expression was significantly suppressed. These results demonstrate the involvement of CRMP4 in LPS-induced inflammation in vivo, that CRMP4 suppresses microglial proliferation in a cell-autonomous manner.}, } @article {pmid38914784, year = {2024}, author = {Sang, A and Zhuo, S and Bochanis, A and Manautou, JE and Bahal, R and Zhong, XB and Rasmussen, TP}, title = {Mechanisms of Action of the US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs.}, journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy}, volume = {38}, number = {4}, pages = {511-526}, pmid = {38914784}, issn = {1179-190X}, support = {R01 HL147028/HL/NHLBI NIH HHS/United States ; R35 GM140862/GM/NIGMS NIH HHS/United States ; R35GM140862/GM/NIGMS NIH HHS/United States ; R01HL147028/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use/pharmacology ; United States ; *United States Food and Drug Administration ; *Drug Approval ; RNA, Messenger/genetics/metabolism ; Animals ; RNA Splicing/drug effects ; }, abstract = {Antisense oligonucleotides (ASOs) are single stranded nucleic acids that target RNA. The US Food and Drug Administration has approved ASOs for several diseases. ASOs utilize three principal modes of action (MOA). The first MOA is initiated by base-pairing between the ASO and its target mRNA, followed by RNase H-dependent mRNA degradation. The second MOA is triggered by ASOs that occlude splice acceptor sites in pre-mRNAs leading to skipping of a mutation-bearing exon. The third MOA involves ASOs that sterically hinder mRNA function, often inhibiting translation. ASOs contain a variety of modifications to the sugar-phosphate backbone and bases that stabilize the ASO or render them resistant to RNase activity. RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.].}, } @article {pmid38914810, year = {2024}, author = {Manchia, M and Paribello, P and Pinna, M and Steardo, L and Carpiniello, B and Pinna, F and Pisanu, C and Squassina, A and Hajek, T}, title = {Lithium and its effects: does dose matter?.}, journal = {International journal of bipolar disorders}, volume = {12}, number = {1}, pages = {23}, pmid = {38914810}, issn = {2194-7511}, abstract = {BACKGROUND: Decades of clinical research have demonstrated the efficacy of lithium in treating acute episodes (both manic and depressive), as well as in preventing recurrences of bipolar disorder (BD). Specific to lithium is its antisuicidal effect, which appears to extend beyond its mood-stabilizing properties. Lithium's clinical effectiveness is, to some extent, counterbalanced by its safety and tolerability profile. Indeed, monitoring of lithium levels is required by its narrow therapeutic index. There is consensus that adequate serum levels should be above 0.6 mEq/L to achieve clinical effectiveness. However, few data support the choice of this threshold, and increasing evidence suggests that lithium might have clinical and molecular effects at much lower concentrations.

CONTENT: This narrative review is aimed at: (1) reviewing and critically interpreting the clinical evidence supporting the use of the 0.6 mEq/L threshold, (2) reporting a narrative synthesis of the evidence supporting the notion that lithium might be effective in much lower doses. Among these are epidemiological studies of lithium in water, evidence on the antisuicidal, anti-aggressive, and neuroprotective effects, including efficacy in preventing cognitive impairment progression, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS), of lithium; and (3) revieweing biological data supporting clinically viable uses of lithium at low levels with the delineation of a mechanistic hypothesis surrounding its purported mechanism of action. The study selection was based on the authors' preference, reflecting the varied and extensive expertise on the review subject, further enriched with an extensive pearl-growing strategy for relevant reviews and book sections.

CONCLUSIONS: Clinical and molecular effects of lithium are numerous, and its effects also appear to have a certain degree of specificity related to the dose administered. In sum, the clinical effects of lithium are maximal for mood stabilisation at concentrations higher than 0.6 mEq/l. However, lower levels may be sufficient for preventing depressive recurrences in older populations of patients, and microdoses could be effective in decreasing suicide risk, especially in patients with BD. Conversely, lithium's ability to counteract cognitive decline appears to be exerted at subtherapeutic doses, possibly corresponding to its molecular neuroprotective effects. Indeed, lithium may reduce inflammation and induce neuroprotection even at doses several folds lower than those commonly used in clinical settings. Nevertheless, findings surrounding its purported mechanism of action are missing, and more research is needed to investigate the molecular targets of low-dose lithium adequately.}, } @article {pmid38915526, year = {2024}, author = {Mackness, BC and Morgan, BR and Deveau, LM and Kathuria, SV and Zitzewitz, JA and Massi, F}, title = {A hydrophobic core stabilizes the residual structure in the RRM2 intermediate state of the ALS-linked protein TDP-43.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.12.598648}, pmid = {38915526}, issn = {2692-8205}, abstract = {Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43, using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.}, } @article {pmid38915767, year = {2024}, author = {Ambrosini, A and Dalla Bella, E and Ravasi, M and Melazzini, M and Lauria, G}, title = {New clinical insight in amyotrophic lateral sclerosis and innovative clinical development from the non-profit repurposing trial of the old drug guanabenz.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1407912}, pmid = {38915767}, issn = {2296-858X}, abstract = {Drug repurposing is considered a valid approach to accelerate therapeutic solutions for rare diseases. However, it is not as widely applied as it could be, due to several barriers that discourage both industry and academic institutions from pursuing this path. Herein we present the case of an academic multicentre study that considered the repurposing of the old drug guanabenz as a therapeutic strategy in amyotrophic lateral sclerosis. The difficulties encountered are discussed as an example of the barriers that academics involved in this type of study may face. Although further development of the drug for this target population was hampered for several reasons, the study was successful in many ways. Firstly, because the hypothesis tested was confirmed in a sub-population, leading to alternative innovative solutions that are now under clinical investigation. In addition, the study was informative and provided new insights into the disease, which are now giving new impetus to laboratory research. The message from this example is that even a repurposing study with an old product has the potential to generate innovation and interest from industry partners, provided it is based on a sound rationale, the study design is adequate to ensure meaningful results, and the investigators keep the full clinical development picture in mind.}, } @article {pmid38915796, year = {2024}, author = {Thonhoff, JR and Beers, DR and Zhao, W and Faridar, A and Thome, A and Wen, S and Zhang, A and Wang, J and Appel, SH}, title = {A phase 1 proof-of-concept study evaluating safety, tolerability, and biological marker responses with combination therapy of CTLA4-Ig and interleukin-2 in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1415106}, pmid = {38915796}, issn = {1664-2295}, abstract = {OBJECTIVE: To determine whether a combination therapy with abatacept (CTLA4-Ig) and interleukin-2 (IL-2) is safe and suppresses markers of oxidative stress, inflammation, and degeneration in ALS.

METHODS: In this open-label study, four participants with ALS received subcutaneous injections of low dose IL-2 (1 × 10[6] IU/injection/day) for 5 consecutive days every 2 weeks and one subcutaneous injection of CTLA4-Ig (125 mg/mL/injection) every 2 weeks coinciding with the first IL-2 injection of each treatment cycle. Participants received a total of 24 treatment cycles during the first 48 weeks in this 56-week study. They were closely monitored for treatment-emergent adverse events (TEAEs) and disease progression with the ALSFRS-R. Phenotypic changes within T cell populations and serum biological markers of oxidative stress [4-hydroxynonenal (4-HNE) and oxidized-LDL (ox-LDL)], inflammation (IL-18), and structural neuronal degeneration [neurofilament light chain (Nf-L)] were assessed longitudinally.

RESULTS: CTLA4-Ig/IL-2 therapy was safe and well-tolerated in all four participants over the 56-week study. During the first 24 weeks, the average rate of change in the ALSFRS-R was +0.04 points/month. Over the 48-week treatment period, the average rate of change was -0.13 points/month with one participant improving by 0.9 points/month while the other three participants experienced an average decrease of -0.47 points/month, which is slower than the average - 1.1 points/month prior to initiation of therapy. Treg suppressive function and numbers increased during treatment. Responses in the biological markers during the first 16 weeks coincided with minimal clinical progression. Mean levels of 4-HNE decreased by 30%, ox-LDL decreased by 19%, IL-18 decreased by 23%, and Nf-L remained the same, on average, in all four participants. Oxidized-LDL levels decreased in all four participants, 4-HNE and IL-18 levels decreased in three out of four participants, and Nf-L decreased in two out of four participants.

CONCLUSION: The combination therapy of CTLA4-Ig and IL-2 in ALS is safe and well-tolerated with promising results of clinical efficacy and suppression of biomarkers of oxidative stress, neuroinflammation and neuronal degeneration. In this open-label study, the efficacy as measured by the ALSFRS-R and corresponding biomarkers suggests the therapeutic potential of this treatment and warrants further study in a phase 2 double-blind, placebo-controlled trial.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT06307301.}, } @article {pmid38916676, year = {2024}, author = {Schaub, A and Erdmann, H and Scholz, V and Timmer, M and Cordts, I and Günther, R and Reilich, P and Abicht, A and Schöberl, F}, title = {Analysis and occurrence of biallelic pathogenic repeat expansions in RFC1 in a German cohort of patients with a main clinical phenotype of motor neuron disease.}, journal = {Journal of neurology}, volume = {271}, number = {9}, pages = {5804-5812}, pmid = {38916676}, issn = {1432-1459}, mesh = {Humans ; *Motor Neuron Disease/genetics ; *Phenotype ; *Replication Protein C/genetics ; Male ; Female ; Cohort Studies ; Germany ; *DNA Repeat Expansion ; Middle Aged ; Aged ; Adult ; }, abstract = {Biallelic pathogenic repeat expansions in RFC1 were recently identified as molecular origin of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) as well as of one of the most common causes of adult-onset ataxia. In the meantime, the phenotypic spectrum has expanded massively and now includes mimics of multiple system atrophy or parkinsonism. After identifying a patient with a clinical diagnosis of amyotrophic lateral sclerosis (ALS) as a carrier of biallelic pathogenic repeat expansions in RFC1, we studied a cohort of 106 additional patients with a clinical main phenotype of motor neuron disease (MND) to analyze whether such repeat expansions are more common in MND patients. Indeed, two additional MND patients (one also with ALS and one with primary lateral sclerosis/PLS) have been identified as carrier of biallelic pathogenic repeat expansions in RFC1 in the absence of another genetic alteration explaining the phenotype, suggesting motor neuron disease as another extreme phenotype of RFC1 spectrum disorder. Therefore, MND might belong to the expanding phenotypic spectrum of pathogenic RFC1 repeat expansions, particularly in those MND patients with additional features such as sensory and/or autonomic neuropathy, vestibular deficits, or cerebellar signs. By systematically analyzing the RFC1 repeat array using Oxford nanopore technology long-read sequencing, our study highlights the high intra- and interallelic heterogeneity of this locus and allows the identification of the novel repeat motif 'ACAAG'.}, } @article {pmid38916909, year = {2024}, author = {Honda, H and Sadashima, S and Yoshimura, M and Sakurada, N and Koyama, S and Yagita, K and Hamasaki, H and Noguchi, H and Arahata, H and Sasagasako, N}, title = {Altered expression of human myxovirus resistance protein A in amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {9}, pages = {745-751}, doi = {10.1093/jnen/nlae052}, pmid = {38916909}, issn = {1554-6578}, mesh = {Humans ; *Myxovirus Resistance Proteins/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Female ; Male ; Middle Aged ; Aged ; *Spinal Cord/metabolism/pathology ; Adult ; Aged, 80 and over ; Anterior Horn Cells/pathology/metabolism ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. The etiology of sporadic ALS (sALS) has not yet been clarified. An increasing body of evidence suggests the involvement of viral infections and interferons (IFNs). Human myxovirus resistance protein A (MxA) is an IFN-induced dynamin-like GTPase that acts as a potent antiviral factor. This study examined MxA expression in ALS patient spinal cords using immunohistochemistry. Thirty-two cases of sALS (pathologically proven ALS-TDP), 10 non-ALS, other neurological disease control cases were examined. In most ALS cases, MxA cytoplasmic condensates were observed in the remaining spinal anterior horn neurons. The ALS group had a significantly higher rate of MxA-highly expressing neurons than the non-ALS group. Colocalization of MxA cytoplasmic condensate and transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusions was rarely observed. Because MxA has antiviral activity induced by IFNs, our results suggest that IFNs are involved in the pathogenesis of ALS in spinal cord anterior horn neurons. Our study also suggests that monitoring viral infections and IFN activation in patients with ALS may be critically important.}, } @article {pmid38917317, year = {2024}, author = {LaBarbera, VA and Gill, E and Hill, NS and Sachs, G}, title = {The Louise Wilcox ALS Clinic at Rhode Island Hospital: 25th Anniversary (1999-2024).}, journal = {Rhode Island medical journal (2013)}, volume = {107}, number = {7}, pages = {51-53}, pmid = {38917317}, issn = {2327-2228}, mesh = {Rhode Island ; Humans ; *Amyotrophic Lateral Sclerosis/history ; Anniversaries and Special Events ; }, } @article {pmid38917432, year = {2024}, author = {Atkinson, RAK and Collins, JM and Sreedharan, J and King, AE and Fernandez-Martos, CM}, title = {Alterations to metabolic hormones in amyotrophic lateral sclerosis and frontotemporal dementia postmortem human tissue.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {11}, pages = {907-916}, pmid = {38917432}, issn = {1554-6578}, support = {//"la Caixa" Banking Foundation/ ; PR-HR18-000341b//Fundación Luzón/ ; //Victorian Brain Bank/ ; //The Florey, The Alfred, Victorian Institute of Forensic Medicine/ ; //Coroners Court of Victoria/ ; //Fundación Luzón/ ; //The Alfred, Victorian Institute of Forensic Medicine/ ; //Parkinson's Victoria/ ; //FightMND/ ; //Yulgilbar Foundation/ ; //Ian and Maria Cootes/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Male ; Female ; Aged ; *Frontotemporal Dementia/metabolism/pathology/genetics ; Middle Aged ; *Neuropeptide Y/metabolism ; Receptors, Leptin/metabolism/genetics ; Receptor, Insulin/metabolism ; Aged, 80 and over ; Spinal Cord/metabolism/pathology ; RNA, Messenger/metabolism ; Motor Cortex/metabolism/pathology ; Antigens, CD ; }, abstract = {Metabolic changes are observed in patients with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although regulation of metabolic processes in the CNS is predominantly carried out within the hypothalamus, extra-hypothalamic CNS areas contain metabolic hormone receptors, including those for leptin (LEPR), insulin (INSR), and neuropeptide Y (NPY), indicating that they may play a role in biological processes underlying pathogenic disease processes. The status of these hormones within regions vulnerable in ALS/FTD is not well described. This study sought to determine whether the expression of these hormones and their receptors is altered in pathology-rich regions in cases of human FTD (superior frontal gyrus and insular cortex) and ALS (primary motor cortex and lumbar spinal cord) with TDP-43 pathology compared to matched healthy controls. LEPR mRNA was increased within the superior frontal gyrus of FTD cases and within primary motor cortex and lumbar spinal cord of ALS cases; INSR mRNA was increased in superior frontal gyrus and insular cortex of FTD cases. NPY protein was decreased in primary motor cortex and lumbar spinal cord of ALS cases. Our results demonstrate that metabolic hormones undergo complex alterations in ALS and FTD and suggest that these hormones could play critical roles in the pathogenesis of these diseases.}, } @article {pmid38917863, year = {2024}, author = {Chou, CZ and Everett, EA and McFarlin, J and Ramanathan, U}, title = {End-of-Life and Hospice Care in Neurologic Diseases.}, journal = {Seminars in neurology}, volume = {44}, number = {5}, pages = {523-533}, doi = {10.1055/s-0044-1787809}, pmid = {38917863}, issn = {1098-9021}, mesh = {Humans ; *Nervous System Diseases/therapy ; *Hospice Care ; *Terminal Care/methods ; Advance Care Planning ; }, abstract = {The care of a patient with neurologic disease at end-of-life requires expertise in addressing advance care planning, hospice, symptom management, and caregiver support. Neurologists caring for patients with advanced neurologic disease often identify changes in disease trajectory, functional status, or goals of care that prompt discussions of advance care planning and hospice. Patients nearing end-of-life may develop symptoms such as dyspnea, secretions, delirium, pain, and seizures. Neurologists may be the primary clinicians managing these symptoms, particularly in the hospitalized patient, though they may also lend their expertise to non-neurologists about expected disease trajectories and symptoms in advanced neurologic disease. This article aims to help neurologists guide patients and caregivers through the end-of-life process by focusing on general knowledge that can be applied across diseases as well as specific considerations in severe stroke and traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's disease, and dementia.}, } @article {pmid38918327, year = {2024}, author = {Sharma, V and Sharma, P and Singh, TG}, title = {Mechanistic insights on TLR-4 mediated inflammatory pathway in neurodegenerative diseases.}, journal = {Pharmacological reports : PR}, volume = {76}, number = {4}, pages = {679-692}, pmid = {38918327}, issn = {2299-5684}, mesh = {Humans ; *Toll-Like Receptor 4/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; *Signal Transduction ; NF-kappa B/metabolism ; Inflammation/metabolism/drug therapy ; }, abstract = {Neurodegenerative diseases (NDDs) pose a significant issue in healthcare, needing a thorough knowledge of their complex molecular mechanisms. A diverse set of cell signaling mediators and their interactions play critical roles in neuroinflammation. The release of pro-inflammatory mediators in response to neural dysfunction is detrimental to normal cell survival. Moreover, the important role of nuclear factor-κB (NF-κB) in the central nervous system through Toll-like receptor (TLR) activation has been well established. Therefore, through a comprehensive review of current research and experimentation, this investigation elucidates the interactions between novel pharmacological agents (TLR-4/NF-κB inhibitors) and neurodegeneration encompassing Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis and stroke. Insights garnered from this exploration underscore the potential of TLR-4 as a therapeutic target. Through the revelation of these insights, our aim is to establish a foundation for the development of enhanced and focused therapeutic approaches in the continuous endeavor to combat neurodegeneration. This review thus serves as a roadmap, guiding future research endeavors toward innovative strategies for combatting the complex interplay between TLR-4 signaling and NDDs.}, } @article {pmid38918466, year = {2024}, author = {Bahram Sangani, N and Koetsier, J and Mélius, J and Kutmon, M and Ehrhart, F and Evelo, CT and Curfs, LMG and Reutelingsperger, CP and Eijssen, LMT}, title = {A novel insight into neurological disorders through HDAC6 protein-protein interactions.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {14666}, pmid = {38918466}, issn = {2045-2322}, mesh = {*Histone Deacetylase 6/metabolism/genetics ; Humans ; *Protein Interaction Maps ; Nervous System Diseases/metabolism/genetics ; Alzheimer Disease/metabolism/genetics ; Phosphorylation ; Acetylation ; Parkinson Disease/metabolism/genetics/pathology ; }, abstract = {Due to its involvement in physiological and pathological processes, histone deacetylase 6 (HDAC6) is considered a promising pharmaceutical target for several neurological manifestations. However, the exact regulatory role of HDAC6 in the central nervous system (CNS) is still not fully understood. Hence, using a semi-automated literature screening technique, we systematically collected HDAC6-protein interactions that are experimentally validated and reported in the CNS. The resulting HDAC6 network encompassed 115 HDAC6-protein interactions divided over five subnetworks: (de)acetylation, phosphorylation, protein complexes, regulatory, and aggresome-autophagy subnetworks. In addition, 132 indirect interactions identified through HDAC6 inhibition were collected and categorized. Finally, to display the application of our HDAC6 network, we mapped transcriptomics data of Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis on the network and highlighted that in the case of Alzheimer's disease, alterations predominantly affect the HDAC6 phosphorylation subnetwork, whereas differential expression within the deacetylation subnetwork is observed across all three neurological disorders. In conclusion, the HDAC6 network created in the present study is a novel and valuable resource for the understanding of the HDAC6 regulatory mechanisms, thereby providing a framework for the integration and interpretation of omics data from neurological disorders and pharmacodynamic assessments.}, } @article {pmid38918634, year = {2024}, author = {Zhang, N and Westerhaus, A and Wilson, M and Wang, E and Goff, L and Sockanathan, S}, title = {Physiological regulation of neuronal Wnt activity is essential for TDP-43 localization and function.}, journal = {The EMBO journal}, volume = {43}, number = {16}, pages = {3388-3413}, pmid = {38918634}, issn = {1460-2075}, support = {T32GM007445//HHS | National Institutes of Health (NIH)/ ; T32 GM007445/GM/NIGMS NIH HHS/United States ; F31AG072745//HHS | National Institutes of Health (NIH)/ ; R01 AG068043/AG/NIA NIH HHS/United States ; 5RO1AG068043//HHS | National Institutes of Health (NIH)/ ; F31 AG072745/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; *Wnt Signaling Pathway ; *Neurons/metabolism ; Mice ; *Phosphoric Diester Hydrolases/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Active Transport, Cell Nucleus ; Cell Nucleus/metabolism ; }, abstract = {Nuclear exclusion of the RNA- and DNA-binding protein TDP-43 can induce neurodegeneration in different diseases. Diverse processes have been implicated to influence TDP-43 mislocalization, including disrupted nucleocytoplasmic transport (NCT); however, the physiological pathways that normally ensure TDP-43 nuclear localization are unclear. The six-transmembrane enzyme glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) cleaves the glycosylphosphatidylinositol (GPI) anchor that tethers some proteins to the membrane. Here we show that GDE2 maintains TDP-43 nuclear localization by regulating the dynamics of canonical Wnt signaling. Ablation of GDE2 causes aberrantly sustained Wnt activation in adult neurons, which is sufficient to cause NCT deficits, nuclear pore abnormalities, and TDP-43 nuclear exclusion. Disruption of GDE2 coincides with TDP-43 abnormalities in postmortem tissue from patients with amyotrophic lateral sclerosis (ALS). Further, GDE2 deficits are evident in human neural cell models of ALS, which display erroneous Wnt activation that, when inhibited, increases mRNA levels of genes regulated by TDP-43. Our study identifies GDE2 as a critical physiological regulator of Wnt signaling in adult neurons and highlights Wnt pathway activation as an unappreciated mechanism contributing to nucleocytoplasmic transport and TDP-43 abnormalities in disease.}, } @article {pmid38920626, year = {2024}, author = {Cihankaya, H and Bader, V and Winklhofer, KF and Vorgerd, M and Matschke, J and Stahlke, S and Theiss, C and Matschke, V}, title = {Elevated NLRP3 Inflammasome Activation Is Associated with Motor Neuron Degeneration in ALS.}, journal = {Cells}, volume = {13}, number = {12}, pages = {}, pmid = {38920626}, issn = {2073-4409}, support = {91753179//German Academic Exchange Service/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Motor Neurons/metabolism/pathology ; *Inflammasomes/metabolism ; Mice ; *MicroRNAs/metabolism/genetics ; Spinal Cord/pathology/metabolism ; Disease Models, Animal ; Nerve Degeneration/pathology/metabolism ; Microglia/metabolism/pathology ; Mice, Inbred C57BL ; Caspase 1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration in the central nervous system. Recent research has increasingly linked the activation of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome to ALS pathogenesis. NLRP3 activation triggers Caspase 1 (CASP 1) auto-activation, leading to the cleavage of Gasdermin D (GSDMD) and pore formation on the cellular membrane. This process facilitates cytokine secretion and ultimately results in pyroptotic cell death, highlighting the complex interplay of inflammation and neurodegeneration in ALS. This study aimed to characterize the NLRP3 inflammasome components and their colocalization with cellular markers using the wobbler mouse as an ALS animal model. Firstly, we checked the levels of miR-223-3p because of its association with NLRP3 inflammasome activity. The wobbler mice showed an increased expression of miR-223-3p in the ventral horn, spinal cord, and cerebellum tissues. Next, increased levels of NLRP3, pro-CASP 1, cleaved CASP 1 (c-CASP 1), full-length GSDMD, and cleaved GDSMD revealed NLRP3 inflammasome activation in wobbler spinal cords, but not in the cerebellum. Furthermore, we investigated the colocalization of the aforementioned proteins with neurons, microglia, and astrocyte markers in the spinal cord tissue. Evidently, the wobbler mice displayed microgliosis, astrogliosis, and motor neuron degeneration in this tissue. Additionally, we showed the upregulation of protein levels and the colocalization of NLRP3, c-CASP1, and GSDMD in neurons, as well as in microglia and astrocytes. Overall, this study demonstrated the involvement of NLRP3 inflammasome activation and pyroptotic cell death in the spinal cord tissue of wobbler mice, which could further exacerbate the motor neuron degeneration and neuroinflammation in this ALS mouse model.}, } @article {pmid38920691, year = {2024}, author = {Ilieva, MS}, title = {Non-Coding RNAs in Neurological and Neuropsychiatric Disorders: Unraveling the Hidden Players in Disease Pathogenesis.}, journal = {Cells}, volume = {13}, number = {12}, pages = {}, pmid = {38920691}, issn = {2073-4409}, mesh = {Humans ; *RNA, Untranslated/genetics/metabolism ; *Nervous System Diseases/genetics/metabolism ; *Mental Disorders/genetics/metabolism ; RNA, Circular/genetics/metabolism ; Animals ; RNA, Long Noncoding/genetics/metabolism ; Gene Expression Regulation ; MicroRNAs/genetics/metabolism ; }, abstract = {Neurological and neuropsychiatric disorders pose substantial challenges to public health, necessitating a comprehensive understanding of the molecular mechanisms underlying their pathogenesis. In recent years, the focus has shifted toward the intricate world of non-coding RNAs (ncRNAs), a class of RNA molecules that do not encode proteins but play pivotal roles in gene regulation and cellular processes. This review explores the emerging significance of ncRNAs in the context of neurological and neuropsychiatric disorders, shedding light on their diverse functions and regulatory mechanisms. The dysregulation of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), has been implicated in the pathophysiology of conditions such as Alzheimer's disease, Parkinson's disease, schizophrenia, and mood disorders. This review delves into the specific roles these ncRNAs play in modulating key cellular processes, including synaptic plasticity, neuroinflammation, and apoptosis, providing a nuanced understanding of their impact on disease progression. Furthermore, it discusses the potential diagnostic and therapeutic implications of targeting ncRNAs in neurological and neuropsychiatric disorders. The identification of specific ncRNA signatures holds promise for the development of novel biomarkers for early disease detection, while the manipulation of ncRNA expression offers innovative therapeutic avenues. Challenges and future directions in the field are also considered, highlighting the need for continued research to unravel the complexities of ncRNA-mediated regulatory networks in the context of neurological and neuropsychiatric disorders. This review aims to provide a comprehensive overview of the current state of knowledge and stimulate further exploration into the fascinating realm of ncRNAs in the brain's intricate landscape.}, } @article {pmid38920997, year = {2024}, author = {Nowak, I and Paździor, M and Sarna, R and Madej, M}, title = {Molecular Mechanisms in the Design of Novel Targeted Therapies for Neurodegenerative Diseases.}, journal = {Current issues in molecular biology}, volume = {46}, number = {6}, pages = {5436-5453}, pmid = {38920997}, issn = {1467-3045}, abstract = {Neurodegenerative diseases are a diverse group of diseases characterized by a progressive loss of neurological function due to damage to nerve cells in the central nervous system. In recent years, there has been a worldwide increase in the expanding associated with increasing human life expectancy. Molecular mechanisms control many of the essential life processes of cells, such as replication, transcription, translation, protein synthesis and gene regulation. These are complex interactions that form the basis for understanding numerous processes in the organism and developing new diagnostic and therapeutic approaches. In the context of neurodegenerative diseases, molecular basis refers to changes at the molecular level that cause damage to or degeneration of nerve cells. These may include protein aggregates leading to pathological structures in brain cells, impaired protein transport in nerve cells, mitochondrial dysfunction, inflammatory processes or genetic mutations that impair nerve cell function. New medical therapies are based on these mechanisms and include gene therapies, reduction in inflammation and oxidative stress, and the use of miRNAs and regenerative medicine. The aim of this study was to bring together the current state of knowledge regarding selected neurodegenerative diseases, presenting the underlying molecular mechanisms involved, which could be potential targets for new forms of treatment.}, } @article {pmid38921029, year = {2024}, author = {Carata, E and Muci, M and Di Giulio, S and Di Giulio, T and Mariano, S and Panzarini, E}, title = {The Neuromuscular Disorder Mediated by Extracellular Vesicles in Amyotrophic Lateral Sclerosis.}, journal = {Current issues in molecular biology}, volume = {46}, number = {6}, pages = {5999-6017}, pmid = {38921029}, issn = {1467-3045}, abstract = {Amyotrophic lateral sclerosis (ALS) represents a neurodegenerative disorder characterized by the progressive loss of both upper and lower motor neurons, resulting in muscular atrophy and eventual paralysis. While much research has concentrated on investigating the impact of major mutations associated with ALS on motor neurons and central nervous system (CNS) cells, recent studies have unveiled that ALS pathogenesis extends beyond CNS imbalances, encompassing dysregulation in other tissues such as skeletal muscle. Evidence from animal models and patients supports this broader perspective. Skeletal muscle, once considered solely as an effector organ, is now recognized as possessing significant secretory activity capable of influencing motor neuron survival. However, the precise cellular and molecular mechanisms underlying the detrimental effects observed in muscle and its associated structures in ALS remain poorly understood. Additionally, emerging data suggest that extracellular vesicles (EVs) may play a role in the establishment and function of the neuromuscular junction (NMJ) under both physiological and pathological conditions and in wasting and regeneration of skeletal muscles, particularly in neurodegenerative diseases like ALS. This review aims to explore the key findings about skeletal muscle involvement in ALS, shedding light on the potential underlying mechanisms and contributions of EVs and their possible application for the design of biosensors.}, } @article {pmid38921286, year = {2024}, author = {Katz, L and Gur, A}, title = {Psychosocial Intervention for Family Caregivers of ALS Patients: A Systematic Review.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {12}, pages = {}, pmid = {38921286}, issn = {2227-9032}, abstract = {PROPOSAL: This systematic review aims to comprehensively examine all existing knowledge on psychosocial interventions for family caregivers for ALS patients. Also, the study will present the gaps in knowledge, recommendations for future research, and guidelines for psychosocial interventions that are focused and adapted to the needs of family caregivers of ALS patients.

MATERIALS AND METHODS: The systematic review was conducted according to the PRISMA guidelines and identified studies on psychosocial intervention for family caregivers of ALS patients, using five electronic databases: PsychNET, PubMed, EBSCO, PRIMO, and PROQUEST. Seven articles met the criteria and were included in the review. A thematic analysis was conducted to extract major themes.

RESULTS: Three major themes emerged from the data: (1) Personal benefits; (2) Interpersonal benefits; and (3) Charting challenges and pathways to improve psychosocial interventions.

CONCLUSIONS: Based on the findings, practical guidelines were formulated that focus on the group's composition, the facilitator's role, the contents, the relationships within the group, and the opportunities and limitations of online interventions.}, } @article {pmid38922880, year = {2025}, author = {Goldschmidt-Clermont, PJ and Khan, A and Jimsheleishvili, G and Graham, P and Brooks, A and Silvera, R and Goldschmidt, AJP and Pearse, DD and Dietrich, WD and Levi, AD and Guest, JD}, title = {Treating amyotrophic lateral sclerosis with allogeneic Schwann cell-derived exosomal vesicles: a case report.}, journal = {Neural regeneration research}, volume = {20}, number = {4}, pages = {1207-1216}, pmid = {38922880}, issn = {1673-5374}, abstract = {Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where motor neuron function is progressively lost, Schwann cell function may also be impaired. Recently, important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported. This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles, marking, to our knowledge, the first instance of such treatment. An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis. After initial diagnosis, the patient underwent a combination of generic riluzole, sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis, and taurursodiol. The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function. We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired (senescent) and that exposure of the patient's Schwann cells to allogeneic Schwann cell-derived exosomal vesicles, cultured expanded from a cadaver donor improved their growth capacity in vitro. After a period of observation lasting 10 weeks, during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored, the patient received weekly consecutive infusions of 1.54 × 10 12 (×2), and then consecutive infusions of 7.5 × 10 12 (×6) allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco's phosphate-buffered saline. None of the infusions were associated with adverse events such as infusion reactions (allergic or otherwise) or changes in vital signs. Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend. A more sensitive in-house assay suggested possible inflammasome activation during the disease course. A trend for clinical stabilization was observed during the infusion period. Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles. Initial findings suggest that this approach is safe.}, } @article {pmid38923228, year = {2024}, author = {Koch, T and Fabian, R and Weinhold, L and Koch, FW and Barakat, S and Castro-Gomez, S and Grehl, T and Bernsen, S and Weydt, P}, title = {Cardiac troponin T as a serum biomarker of respiratory impairment in amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {8}, pages = {2063-2072}, pmid = {38923228}, issn = {2328-9503}, support = {//Boris Canessa Foundation/ ; 21060//Alzheimer Forschung Initiative e.V/ ; 2021-1A-12//Hertie Network of Excellence in Clinical Neuroscience/ ; //BONFOR-Forschungskommission der Medizinischen Fakultät Bonn/ ; //Neuro-aCSis Bonn Neuroscience Clinician Scientist Program/ ; EXC2151-390873048//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/physiopathology ; *Troponin T/blood ; Male ; Middle Aged ; Female ; *Biomarkers/blood ; Aged ; Retrospective Studies ; Vital Capacity/physiology ; Respiratory Insufficiency/blood/etiology ; Adult ; Neurofilament Proteins/blood ; }, abstract = {OBJECTIVE: Informative biomarkers are an urgent need in the management of amyotrophic lateral sclerosis. Serum cardiac troponin T is elevated in the majority of amyotrophic lateral sclerosis patients and increases with disease progression. We sought to establish the informative value of cardiac troponin T with regard to respiratory function, a major prognostic factor in amyotrophic lateral sclerosis.

METHODS: In this retrospective observation, we analyzed two independent hospital-based cohorts (d = discovery cohort; v = validation cohort) regarding serum cardiac troponin T (nd = 298; nv = 49), serum neurofilament light chain (nd = 117; nv = 17), and respiratory tests (nd = 93; nv = 49).

RESULTS: Serum cardiac troponin T, in contrast to serum neurofilament levels, was associated with the respiratory domain of the revised amyotrophic lateral sclerosis functional rating scale and with pulmonary function parameters, namely forced vital capacity % (r = -0.45, p = 0.001) and slow vital capacity % (r = -0.50, p = 0.001). Serum cardiac troponin T reliably discriminated benchmarks of slow vital capacity <80% (AUC 0.73, 95% CI 0.62-0.84) and <50% (AUC 0.80, 95% CI 0.68-0.93), forced vital capacity <80% (AUC 0.72, 95% CI 0.61-0.83) and <50% (AUC 0.79, 95% CI 0.67-0.91).

INTERPRETATION: Our findings position cardiac Troponin T as a valuable serum biomarker in amyotrophic lateral sclerosis, complementing neurofilaments and expanding the understanding of underlying physiological mechanisms. In clinical practice, serum cardiac troponin T can flag benchmarks of compromised respiratory function.}, } @article {pmid38923364, year = {2024}, author = {Yang, XD and Gong, B and Chen, W and Chen, JJ and Qian, C and Lu, R and Min, Y and Jiang, T and Li, L and Yu, HQ}, title = {In Situ Quantitative Monitoring of Adsorption from Aqueous Phase by UV-vis Spectroscopy: Implication for Understanding of Heterogeneous Processes.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {11}, number = {32}, pages = {e2402732}, pmid = {38923364}, issn = {2198-3844}, support = {//Program for Changjiang Scholars and Innovative Research Team in University/ ; 51821006//National Natural Science Foundation of China/ ; 52027815//National Natural Science Foundation of China/ ; 52192684//National Natural Science Foundation of China/ ; 22276217//National Natural Science Foundation of China/ ; }, abstract = {The development of in situ techniques to quantitatively characterize the heterogeneous reactions is essential for understanding physicochemical processes in aqueous phase. In this work, a new approach coupling in situ UV-vis spectroscopy with a two-step algorithm strategy is developed to quantitatively monitor heterogeneous reactions in a compact closed-loop incorporation. The algorithm involves the inverse adding-doubling method for light scattering correction and the multivariate curve resolution-alternating least squares (MCR-ALS) method for spectral deconvolution. Innovatively, theoretical spectral simulations are employed to connect MCR-ALS solutions with chemical molecular structural evolution without prior information for reference spectra. As a model case study, the aqueous adsorption kinetics of bisphenol A onto polyamide microparticles are successfully quantified in a one-step UV-vis spectroscopic measurement. The practical applicability of this approach is confirmed by rapidly screening a superior adsorbent from commercial materials for antibiotic wastewater adsorption treatment. The demonstrated capabilities are expected to extend beyond monitoring adsorption systems to other heterogeneous reactions, significantly advancing UV-vis spectroscopic techniques toward practical integration into automated experimental platforms for probing aqueous chemical processes and beyond.}, } @article {pmid38923692, year = {2024}, author = {Snyder, A and Ryan, VH and Hawrot, J and Lawton, S and Ramos, DM and Qi, YA and Johnson, KR and Reed, X and Johnson, NL and Kollasch, AW and Duffy, MF and VandeVrede, L and Cochran, JN and Miller, BL and Toro, C and Bielekova, B and Marks, DS and Yokoyama, JS and Kwan, JY and Cookson, MR and Ward, ME}, title = {An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {20}, number = {8}, pages = {5220-5235}, pmid = {38923692}, issn = {1552-5279}, support = {K01AG049152//NIH National Institute on Aging/ ; 75N95022C00031/DA/NIDA NIH HHS/United States ; K01 AG049152/AG/NIA NIH HHS/United States ; U54NS123985//NIH National Institute of Neurological Disorders and Stroke/ ; ZIAAG000534/AG/NIA NIH HHS/United States ; FI2 GM142475/GM/NIGMS NIH HHS/United States ; U54 NS123985/NS/NINDS NIH HHS/United States ; P30AG062422//NIH National Institute on Aging/ ; 1ZIAAG000539-01//NIH National Institute on Aging/ ; R00 AG068271/AG/NIA NIH HHS/United States ; //Global Brain Health Institute/ ; //NIH Undiagnosed Diseases Program, Undiagnosed Diseases Network/ ; P50 AG023501/AG/NIA NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; R01 AG062588/AG/NIA NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; R00AG068271//NIH National Institute on Aging/ ; P01AG019724//NIH National Institute on Aging/ ; U19 AG079774/AG/NIA NIH HHS/United States ; R01AG057234//NIH National Institute on Aging/ ; FI2GM142475//NIH National Institute of General Medical Sciences/ ; P30 AG062422/AG/NIA NIH HHS/United States ; K23AG073514//NIH National Institute on Aging/ ; P01 AG019724/AG/NIA NIH HHS/United States ; 2016-A-005-SUP//Larry L. Hillblom Foundation/ ; //NIH Office of Intramural Training and Education/ ; R01 AG057234/AG/NIA NIH HHS/United States ; ZIA AG000534/ImNIH/Intramural NIH HHS/United States ; //Chan-Zuckerberg Initiative's Neurodegeneration Challenge Network/ ; ZIA AG000539/ImNIH/Intramural NIH HHS/United States ; //Rainwater Charitable Foundation/ ; //Bluefield Project to Cure Frontotemporal Dementia/ ; //French Foundation/ ; U19AG079774//NIH National Institute on Aging/ ; P50AG023501//NIH National Institute on Aging/ ; //Intramural Research Programs of the National Institute of Neurological Disorders and Stroke/ ; P01AG1972403//NIH National Institute on Aging/ ; //HudsonAlpha Foundation Memory and Mobility Fund/ ; R01AG062588//NIH National Institute on Aging/ ; K23 AG073514/AG/NIA NIH HHS/United States ; //Mary Oakley Foundation/ ; }, mesh = {Humans ; *DNA-Binding Proteins/genetics/metabolism ; *Annexins/genetics ; Male ; Mutation/genetics ; Female ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Neurons/metabolism/pathology ; Frontotemporal Dementia/genetics/pathology ; Middle Aged ; Aged ; }, abstract = {INTRODUCTION: Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization.

METHODS: We described the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S's effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling.

RESULTS: ANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways.

DISCUSSION: This study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity.

HIGHLIGHTS: ANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance.}, } @article {pmid38924023, year = {2024}, author = {Spoden, C and Wenzel, O and Erdmann, A and Neitzke, G and Hirschberg, I}, title = {Coping and end-of-life decision-making in ALS: A qualitative interview study.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0306102}, pmid = {38924023}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Male ; Female ; Middle Aged ; *Adaptation, Psychological ; *Decision Making ; *Terminal Care/psychology ; Aged ; *Qualitative Research ; Adult ; Germany ; Interviews as Topic ; }, abstract = {How do people with amyotrophic lateral sclerosis (PALS) deal with their diagnosis and engage in end-of-life decision-making? What informational or supportive needs do they have for counselling about life-sustaining treatment and end-of-life care? Which correlating conditions and influences relate to these needs and how do they connect to the wish to die or wish to live? We conducted a qualitative interview study with 13 people with ALS in Germany from March 2019 to April 2021. Data collection and analysis followed a grounded theory-based approach and revealed close relationships between coping, informational needs and the preparedness for decision-making. We identified the coping strategies 'avoid thinking about end-of-life' and its counterpart, 'planning ahead to be well-prepared,' and differentiated the latter into the patterns 'withdrawing from life and taking precautions against life-prolongation' and 'searching for a new meaning in life and preparing for life-sustaining treatment'. The approaches are based on individual perceptions, attitudes and motives and can be positively/negatively reinforced by healthcare professionals (HCP), family and other interpersonal networks, but also by disease progression and in reaction to health care services. Type and degree of needs concerning information and counselling differed according to coping strategies. These strategies may vary over time, resulting in different support needs. Our findings signify that deep insight is needed into PALS' coping processes to understand their decision-making about life-sustaining treatment. Healthcare professionals should be sensitive to illness experiences beyond medical aspects and foster coping as a biographical process to better support people with ALS.}, } @article {pmid38924530, year = {2024}, author = {Deutsch, AJ and Elbasiouny, SM}, title = {Dysregulation of persistent inward and outward currents in spinal motoneurons of symptomatic SOD1-G93A mice.}, journal = {The Journal of physiology}, volume = {602}, number = {15}, pages = {3715-3736}, pmid = {38924530}, issn = {1469-7793}, support = {R01 NS131816/NS/NINDS NIH HHS/United States ; R01 NS091836/NS/NINDS NIH HHS/United States ; R01 AG067758/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/physiology ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics/pathology ; Mice ; *Mice, Transgenic ; Spinal Cord/physiology ; Superoxide Dismutase-1/genetics ; Male ; Female ; Mice, Inbred C57BL ; Action Potentials ; }, abstract = {Persistent inward currents (PICs) and persistent outward currents (POCs) regulate the excitability and firing behaviours of spinal motoneurons (MNs). Given their potential role in MN excitability dysfunction in amyotrophic lateral sclerosis (ALS), PICs have been previously studied in superoxide dismutase 1 (SOD1)-G93A mice (the standard animal model of ALS); however, conflicting results have been reported on how the net PIC changes during disease progression. Also, individual PICs and POCs have never been examined before in symptomatic ALS. To fill this gap, we measured the net and individual PIC and POC components of wild-type (WT) and SOD MNs in current clamp and voltage clamp during disease progression (assessed by neuroscores). We show that SOD MNs of symptomatic mice experience a much larger net PIC, relative to WT cells from age-matched littermates. Specifically, the Na[+] and Ca[2+] PICs are larger, whereas the lasting SK-mediated (SKL) POC is smaller than WT (Na[+] PIC is the largest and SKL POC is the smallest components in SOD MNs). We also show that PIC dysregulation is present at symptom onset, is sustained throughout advanced disease stages and is proportional to SOD MN cell size (largest dysregulation is in the largest SOD cells, the most vulnerable in ALS). Additionally, we show that studying disease progression using neuroscores is more accurate than using SOD mouse age, which could lead to misleading statistics and age-based trends. Collectively, this study contributes novel PIC and POC data, reveals ionic mechanisms contributing to the vulnerability differential among MN types/sizes, and provides insights on the roles PIC and POC mechanisms play in MN excitability dysfunction in ALS. KEY POINTS: Individual persistent inward currents (PICs) and persistent outward currents (POCs) have never been examined before in spinal motoneurons (MNs) of symptomatic amyotrophic lateral sclerosis (ALS) mice. Thus, we contribute novel PIC and POC data to the ALS literature. Male SOD MNs of symptomatic mice have elevated net PIC, with larger Na[+] and Ca[2+] PICs but reduced SKL POC vs. wild-type littermates. Na[+] PIC is the largest and SKL POC is the smallest current in SOD cells. The PIC/POC dysregulation is present at symptom onset. PIC dysregulation is sustained throughout advanced disease, and is proportional to SOD MN size (largest dysregulation is in the largest cells, the most vulnerable in ALS). Thus, we reveal ionic mechanisms contributing to the vulnerability differential among MN types/sizes in ALS. Studying disease progression using SOD mice neuroscores is more accurate than using age, which could distort the statistical differences between SOD and WT PIC/POC data and the trends during disease progression.}, } @article {pmid38924627, year = {2024}, author = {Burkitt-Creedon, JM and Boller, M and Fletcher, DJ and Brainard, BM and Buckley, GJ and Epstein, SE and Fausak, ED and Hopper, K and Lane, SL and Rozanski, EA and Wolf, J}, title = {2024 RECOVER Guidelines: Updated treatment recommendations for CPR in dogs and cats.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {34 Suppl 1}, number = {}, pages = {104-123}, doi = {10.1111/vec.13391}, pmid = {38924627}, issn = {1476-4431}, support = {//Boehringer Ingelheim Animal Health/ ; //Zoetis Animal Health/ ; }, mesh = {Dogs ; Animals ; Cats ; *Cardiopulmonary Resuscitation/veterinary/standards/methods ; *Cat Diseases/therapy ; Dog Diseases/therapy ; Heart Arrest/veterinary/therapy ; }, abstract = {OBJECTIVE: After the 2012 Reassessment Campaign on Veterinary Resuscitation (RECOVER) CPR Guidelines, this is an update of evidence-based consensus guidelines for Basic Life Support (BLS), advanced life support (ALS), and periarrest monitoring.

DESIGN: These RECOVER CPR Guidelines were generated using a modified version of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for evidence evaluation and translation of this evidence into clear and actionable clinical instructions. Prioritized clinical questions in the Population, Intervention, Comparator, and Outcome (PICO) format were used as the basis to conduct systematic literature searches by information specialists, to extract information from relevant publications, to assess this evidence for quality, and finally to translate the findings into treatment recommendations. These recommendations were reviewed by the RECOVER writing group and opened for comment by veterinary professionals for 4 weeks.

SETTING: Transdisciplinary, international collaboration in university, specialty, and emergency practice.

RESULTS: A total of 40 worksheets were prepared to evaluate questions across the 3 domains of BLS, ALS and Monitoring, resulting in 90 individual treatment recommendations. High-dose epinephrine is no longer recommended, and atropine, if used, is only administered once. Bag-mask ventilation is prioritized over mouth-to-nose ventilation in nonintubated animals. In addition, an algorithm for initial assessment, an updated CPR algorithm, a rhythm diagnosis tool, and an updated drug dosing table are provided.

CONCLUSIONS: While the majority of the BLS and ALS recommendations remain unchanged, some noteworthy changes were made due to new evidence that emerged over the past 10 years. Indirectness of evidence remains the largest impediment to the certainty of guidelines formulation and underscores an urgent need for more studies in the target species of dogs and cats.}, } @article {pmid38924633, year = {2024}, author = {Wolf, J and Buckley, GJ and Rozanski, EA and Fletcher, DJ and Boller, M and Burkitt-Creedon, JM and Weigand, KA and Crews, M and Fausak, ED and , }, title = {2024 RECOVER Guidelines: Advanced Life Support. Evidence and knowledge gap analysis with treatment recommendations for small animal CPR.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {34 Suppl 1}, number = {}, pages = {44-75}, doi = {10.1111/vec.13389}, pmid = {38924633}, issn = {1476-4431}, support = {//Zoetis Animal Health/ ; //Boehringer Ingelheim Animal Health/ ; }, mesh = {Animals ; Dogs ; Cats ; *Dog Diseases/therapy/drug therapy ; Cardiopulmonary Resuscitation/veterinary/standards ; Cat Diseases/therapy/drug therapy ; Veterinary Medicine/standards ; Heart Arrest/veterinary/therapy ; }, abstract = {OBJECTIVE: To systematically review the evidence and devise clinical recommendations on advanced life support (ALS) in dogs and cats and to identify critical knowledge gaps.

DESIGN: Standardized, systematic evaluation of literature pertinent to ALS following Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Prioritized questions were each reviewed by Evidence Evaluators, and findings were reconciled by ALS Domain Chairs and Reassessment Campaign on Veterinary Resuscitation (RECOVER) Co-Chairs to arrive at treatment recommendations commensurate to quality of evidence, risk:benefit relationship, and clinical feasibility. This process was implemented using an Evidence Profile Worksheet for each question that included an introduction, consensus on science, treatment recommendations, justification for these recommendations, and important knowledge gaps. A draft of these worksheets was distributed to veterinary professionals for comment for 4 weeks prior to finalization.

SETTING: Transdisciplinary, international collaboration in university, specialty, and emergency practice.

RESULTS: Seventeen questions pertaining to vascular access, vasopressors in shockable and nonshockable rhythms, anticholinergics, defibrillation, antiarrhythmics, and adjunct drug therapy as well as open-chest CPR were reviewed. Of the 33 treatment recommendations formulated, 6 recommendations addressed the management of patients with nonshockable arrest rhythms, 10 addressed shockable rhythms, and 6 provided guidance on open-chest CPR. We recommend against high-dose epinephrine even after prolonged CPR and suggest that atropine, when indicated, is used only once. In animals with a shockable rhythm in which initial defibrillation was unsuccessful, we recommend doubling the defibrillator dose once and suggest vasopressin (or epinephrine if vasopressin is not available), esmolol, lidocaine in dogs, and/or amiodarone in cats.

CONCLUSIONS: These updated RECOVER ALS guidelines clarify the approach to refractory shockable rhythms and prolonged CPR. Very low quality of evidence due to absence of clinical data in dogs and cats continues to compromise the certainty with which recommendations can be made.}, } @article {pmid38924713, year = {2024}, author = {Vaage, AM and Meyer, HE and Landgraff, IK and Myrstad, M and Holmøy, T and Nakken, O}, title = {Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209575}, doi = {10.1212/WNL.0000000000209575}, pmid = {38924713}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/physiopathology ; Male ; Female ; Adult ; Middle Aged ; Prospective Studies ; Norway/epidemiology ; *Physical Fitness/physiology ; Risk Factors ; Heart Rate/physiology ; Exercise/physiology ; Cohort Studies ; Proportional Hazards Models ; Motor Activity/physiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Observational studies have demonstrated an increased amyotrophic lateral sclerosis (ALS) risk among professional athletes in various sports. For moderately increased levels of physical activity and fitness, the results are diverging. Through a cohort study, we aimed to assess the relationship between indicators of physical activity and fitness (self-reported physical activity and resting heart rate) and long-term ALS risk.

METHODS: From a large Norwegian cardiovascular health survey (1985-1999), we collected information on self-reported physical activity in leisure time, resting heart rate, and other cardiovascular risk factors. Patients with ALS were identified through health registries covering the whole population. We fitted Cox proportional hazard models to assess the risk of ALS according to levels of self-reported physical activity in 3 categories (1: sedentary; 2: minimum 4 hours per week of walking or cycling; 3: minimum 4 hours per week of recreational sports or hard training), and resting heart rate modeled both on the continuous scale and as quartiles of distribution.

RESULTS: Out of 373,696 study participants (mean 40.9 [SD 1.1] years at inclusion), 504 (41.2% women) developed ALS during a mean follow-up time of 27.2 (SD 5.0) years. Compared with participants with the lowest level of physical activity, the hazard ratio was 0.71 (95% CI 0.53-0.95) for those with the highest level. There were no clear associations between resting heart rate and ALS in the total sample. In men, the hazard ratio of ALS was 0.71 (95% CI 0.53-0.95) for those reporting moderate levels of physical activity and 0.59 (95% CI 0.42-0.84) for those reporting high levels, compared with those reporting low levels. Men with resting heart rate in the lowest quartile had 32% reduced risk of ALS (hazard ratio 0.68, 95% CI 0.49-0.94) compared with those in the second highest quartile. In women, no association was detected between neither self-reported levels of physical activity nor resting heart rate and ALS risk.

DISCUSSION: Indicators of high levels of physical activity and fitness are associated with a reduced risk of ALS more than 30 years later in men, but not in women.}, } @article {pmid38924719, year = {2024}, author = {Shaw, PJ and Cooper-Knock, J}, title = {Physical Activity as a Risk Factor for Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209689}, doi = {10.1212/WNL.0000000000209689}, pmid = {38924719}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Risk Factors ; *Exercise ; }, } @article {pmid38924779, year = {2024}, author = {Bratches, RWR and Cohen, J and Carpenter-Song, E and Mistler, L and Barr, PJ}, title = {The Feasibility and Acceptability of Sharing Video Recordings of Amyotrophic Lateral Sclerosis Clinical Encounters With Patients and Their Caregivers: Pilot Randomized Clinical Trial.}, journal = {JMIR formative research}, volume = {8}, number = {}, pages = {e57519}, pmid = {38924779}, issn = {2561-326X}, support = {T32 HS013852/HS/AHRQ HHS/United States ; }, abstract = {BACKGROUND: Multidisciplinary clinics (MDCs) provide benefits to patients with amyotrophic lateral sclerosis (ALS) and their caregivers, but MDC visits are information-heavy and can last 4 hours, with patients and caregivers meeting with multiple specialists within each MDC visit. There are questions about the effectiveness of current methods of sharing information from MDCs with patients. Video recordings are a promising new method of sharing information that may allow patients and caregivers to revisit the MDC and remind them of clinical recommendations and conversations.

OBJECTIVE: The objective of this trial is to determine the feasibility and acceptability of sharing information through video recordings of ALS MDC visits with patients and caregivers.

METHODS: This study was a randomized, controlled pilot trial with 3 months of follow-up from April 2021 to March 2022 in a rural multidisciplinary neurology clinic. We recruited patients with ALS, their caregivers, and their clinicians. Patients and their caregivers were randomized to either receive their normal after-visit summary (treatment as usual) or to receive their normal after-visit summary and a video recording of their MDC visit (video). Each specialist visit had its own recording and was accessible by patients and caregivers using a secure web-based platform called HealthPAL over a 3-month follow-up period. Primary study outcomes were feasibility and acceptability of the video intervention measured by recruitment rate (target: 70%), percentage of participants watching videos (target: 75%), and the Feasibility of Intervention Measure and Acceptability of Intervention Measure (targets: 3/5). We hypothesized that video recording would be feasible and acceptable to patients and their caregivers.

RESULTS: Of the 30 patients approached, 24 were recruited, while all caregivers (n=21) and clinicians (n=34) approached were recruited. A total of 144 specialist visits were recorded, approximately 12 specialist visits at a median of one MDC visit per patient. Of the recorded patients, 75% (9/12) viewed videos. High median intervention feasibility (4, SD 0.99) and acceptability (4, SD 1.22) of intervention measures were reported by patients and caregivers in the intervention arm. High median intervention feasibility (5, SD 0.21) and acceptability (4.88, SD 0.4) were reported by clinicians. Of the 24 patients, 50% (n=12) did not complete a 3-month follow-up, primarily due to death (n=10).

CONCLUSIONS: Video recording is highly feasible and acceptable for patients, caregivers, and clinicians at a rural ALS clinic. Our level of attrition is a useful benchmark for future studies in MDC populations. Despite high rates of patient death, 1-week assessments highlight the value of recordings for both patients and caregivers.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04719403; https://clinicaltrials.gov/study/NCT04719403.}, } @article {pmid38925110, year = {2024}, author = {Wyse-Sookoo, K and Luo, S and Candrea, D and Schippers, A and Tippett, DC and Wester, B and Fifer, M and Vansteensel, MJ and Ramsey, NF and Crone, NE}, title = {Stability of ECoG high gamma signals during speech and implications for a speech BCI system in an individual with ALS: a year-long longitudinal study.}, journal = {Journal of neural engineering}, volume = {21}, number = {4}, pages = {}, pmid = {38925110}, issn = {1741-2552}, support = {T32 EB003383/EB/NIBIB NIH HHS/United States ; UH3 NS114439/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Brain-Computer Interfaces ; Longitudinal Studies ; *Electrocorticography/methods ; *Speech/physiology ; Male ; Gamma Rhythm/physiology ; Middle Aged ; Female ; Electrodes, Implanted ; }, abstract = {Objective.Speech brain-computer interfaces (BCIs) have the potential to augment communication in individuals with impaired speech due to muscle weakness, for example in amyotrophic lateral sclerosis (ALS) and other neurological disorders. However, to achieve long-term, reliable use of a speech BCI, it is essential for speech-related neural signal changes to be stable over long periods of time. Here we study, for the first time, the stability of speech-related electrocorticographic (ECoG) signals recorded from a chronically implanted ECoG BCI over a 12 month period.Approach.ECoG signals were recorded by an ECoG array implanted over the ventral sensorimotor cortex in a clinical trial participant with ALS. Because ECoG-based speech decoding has most often relied on broadband high gamma (HG) signal changes relative to baseline (non-speech) conditions, we studied longitudinal changes of HG band power at baseline and during speech, and we compared these with residual high frequency noise levels at baseline. Stability was further assessed by longitudinal measurements of signal-to-noise ratio, activation ratio, and peak speech-related HG response magnitude (HG response peaks). Lastly, we analyzed the stability of the event-related HG power changes (HG responses) for individual syllables at each electrode.Main Results.We found that speech-related ECoG signal responses were stable over a range of syllables activating different articulators for the first year after implantation.Significance.Together, our results indicate that ECoG can be a stable recording modality for long-term speech BCI systems for those living with severe paralysis.Clinical Trial Information.ClinicalTrials.gov, registration number NCT03567213.}, } @article {pmid38925911, year = {2024}, author = {De La Cruz, E and Esselin, F and Polge, A and Mouzat, K and Guissart, C}, title = {Most SOD1 mutations are pathogenic, and their identification can lead to early access to treatment.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {12}, pages = {1219-1220}, doi = {10.1136/jnnp-2024-333939}, pmid = {38925911}, issn = {1468-330X}, } @article {pmid38926444, year = {2024}, author = {Bhuyan, P and Chatterjee, K}, title = {Estimating prevalence of post-war health disorders using multiple systems data.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {14763}, pmid = {38926444}, issn = {2045-2322}, support = {Category-I Research Project Grant (No. 3878/RP: PSEISMC-RDA HIVS)//Indian Institute of Management Calcutta/ ; Core Research Grant (No. CRG/2019/003204)//Science and Engineering Research Board (SERB), Department of Science & Technology, Government of India/ ; }, mesh = {Humans ; Prevalence ; *Amyotrophic Lateral Sclerosis/epidemiology ; Veterans/statistics & numerical data ; Algorithms ; Monte Carlo Method ; Gulf War ; }, abstract = {Effective surveillance on the long-term public health impact due to war and terrorist attacks remains limited. Such health issues are commonly under-reported, specifically for a large group of individuals. For this purpose, efficient estimation of the size or undercount of the population under the risk of physical and mental health hazards is of utmost necessity. A novel trivariate Bernoulli model is developed allowing heterogeneity among the individuals and dependence between the sources of information, and an estimation methodology using a Monte Carlo-based EM algorithm is proposed. Simulation results show the superiority of the performance of the proposed method over existing competitors and robustness under model mis-specifications. The method is applied to analyse two real case studies on monitoring amyotrophic lateral sclerosis (ALS) cases for the Gulf War veterans and the 9/11 terrorist attack survivors at the World Trade Center, USA. The average annual cumulative incidence rate for ALS disease increases by 33 % and 16 % for deployed and no-deployed military personnel, respectively, after adjusting the undercount. The number of individuals exposed to the risk of physical and mental health effects due to WTC terrorist attacks increased by 42 % . These results provide interesting insights that can assist in effective decision-making and policy formulation for monitoring the health status of post-war survivors.}, } @article {pmid38927130, year = {2024}, author = {Vilardo, B and De Marchi, F and Raineri, D and Manfredi, M and De Giorgis, V and Bebeti, A and Scotti, L and Kustrimovic, N and Cappellano, G and Mazzini, L and Chiocchetti, A}, title = {Shotgun Proteomics Links Proteoglycan-4[+] Extracellular Vesicles to Cognitive Protection in Amyotrophic Lateral Sclerosis.}, journal = {Biomolecules}, volume = {14}, number = {6}, pages = {}, pmid = {38927130}, issn = {2218-273X}, support = {953121//European Union's Horizon 2020 Research and Innovation Program/ ; FOHN//Ministero dell'Istruzione e del Merito/ ; AGING//Ministero dell'Istruzione e del Merito/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; *Extracellular Vesicles/metabolism ; *Proteomics/methods ; Male ; Middle Aged ; Female ; *Biomarkers/blood/metabolism ; Aged ; Proteoglycans/metabolism ; Cognition ; Case-Control Studies ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder lacking reliable biomarkers for early diagnosis and disease progression monitoring. This study aimed to identify the novel biomarkers in plasmatic extracellular vesicles (EVs) isolated from ALS patients and healthy controls (HCs). A total of 61 ALS patients and 30 age-matched HCs were enrolled in the study and the protein content of circulating EVs was analyzed by shotgun proteomics. The study was divided into a discovery phase (involving 12 ALS and 12 HC patients) and a validation one (involving 49 ALS and 20 HC patients). In the discovery phase, more than 300 proteins were identified, with 32 proteins showing differential regulation in ALS patients compared to HCs. In the validation phase, over 400 proteins were identified, with 20 demonstrating differential regulation in ALS patients compared to HCs. Notably, seven proteins were found to be common to both phases, all of which were significantly upregulated in EVs from ALS patients. Most of them have previously been linked to ALS since they have been detected in the serum or cerebrospinal fluid of ALS patients. Among them, proteoglycan (PRG)-4, also known as lubricin, was of particular interest since it was significantly increased in ALS patients with normal cognitive and motor functions. This study highlights the significance of EVs as a promising avenue for biomarker discovery in ALS. Moreover, it sheds light on the unexpected role of PRG-4 in relation to cognitive status in ALS patients.}, } @article {pmid38927501, year = {2024}, author = {Parvanovova, P and Evinova, A and Grofik, M and Hnilicova, P and Tatarkova, Z and Turcanova-Koprusakova, M}, title = {Mitochondrial Dysfunction in Sporadic Amyotrophic Lateral Sclerosis Patients: Insights from High-Resolution Respirometry.}, journal = {Biomedicines}, volume = {12}, number = {6}, pages = {}, pmid = {38927501}, issn = {2227-9059}, abstract = {Amyotrophic lateral sclerosis is a severe neurodegenerative disease whose exact cause is still unclear. Currently, research attention is turning to the mitochondrion as a critical organelle of energy metabolism. Current knowledge is sufficient to confirm the involvement of the mitochondria in the pathophysiology of the disease, since the mitochondria are involved in many processes in the cell; however, the exact mechanism of involvement is still unclear. We used peripheral blood mononuclear cells isolated from whole fresh blood from patients with amyotrophic lateral sclerosis for measurement and matched an age- and sex-matched set of healthy subjects. The group of patients consisted of patients examined and diagnosed at the neurological clinic of the University Hospital Martin. The set of controls consisted of healthy individuals who were actively searched, and controls were selected on the basis of age and sex. The group consisted of 26 patients with sporadic forms of ALS (13 women, 13 men), diagnosed based on the definitive criteria of El Escorial. The average age of patients was 54 years, and the average age of healthy controls was 56 years. We used a high-resolution O2K respirometry method, Oxygraph-2k, to measure mitochondrial respiration. Basal respiration was lower in patients by 29.48%, pyruvate-stimulated respiration (respiratory chain complex I) was lower by 29.26%, and maximal respiratory capacity was lower by 28.15%. The decrease in succinate-stimulated respiration (respiratory chain complex II) was 26.91%. Our data confirm changes in mitochondrial respiration in ALS patients, manifested by the reduced function of complex I and complex II of the respiratory chain. These defects are severe enough to confirm this disease's hypothesized mitochondrial damage. Therefore, research interest in the future should be directed towards a deeper understanding of the involvement of mitochondria and respiratory complexes in the pathophysiology of the disease. This understanding could develop new biomarkers in diagnostics and subsequent therapeutic interventions.}, } @article {pmid38927616, year = {2024}, author = {Wang, H and Guan, L and Ma, X and Wang, Y and Wang, J and Zhang, P and Deng, M}, title = {Whole-Genome Sequencing Identified a Novel Mutation in the N-Terminal Domain of KIF5A in Chinese Patients with Familial Amyotrophic Lateral Sclerosis.}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, pmid = {38927616}, issn = {2073-4425}, support = {82273915//National Natural Science Foundation of China/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; China ; East Asian People/genetics ; *Kinesins/genetics ; Mutation ; *Mutation, Missense ; Pedigree ; Phenotype ; *Whole Genome Sequencing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive damage to both upper and lower motor neurons. Genetic factors are known to play a crucial role in ALS, as genetic studies not only advance our comprehension of disease mechanisms but also help unravel the complex phenotypes exhibited by patients. To gain further insights into the genetic landscape of ALS in the Chinese population and explore genotype-phenotype correlations among individuals, we conducted whole-genome sequencing to screen genes in 34 Chinese familial ALS (FALS) probands lacking the most common ALS-associated genes. Within this cohort, we identified a rare heterozygous missense mutation in the N-terminal domain of KIF5A (c.86A>G) in one of the probands. This finding is significant as mutations in the KIF5A gene have been implicated in ALS in European cohorts since 2018, predominantly characterized by C-terminal mutations. Analysis of the clinical phenotype within this familial lineage revealed a delayed onset of symptoms, an extended survival duration, and initial manifestations in both upper limbs. These observations underscore the clinical heterogeneity observed in ALS patients harboring KIF5A mutations. In conclusion, our study contributes to the growing body of evidence linking KIF5A to ALS and enhances our understanding of the intricate genetic landscape of this disease.}, } @article {pmid38927671, year = {2024}, author = {Carata, E and Muci, M and Mariano, S and Di Giulio, S and Nigro, A and Romano, A and Panzarini, E}, title = {Extracellular Vesicles from NSC-34 MN-like Cells Transfected with Mutant SOD1 Modulate Inflammatory Status of Raw 264.7 Macrophages.}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, pmid = {38927671}, issn = {2073-4425}, mesh = {Animals ; *Extracellular Vesicles/metabolism/genetics ; Mice ; RAW 264.7 Cells ; *Superoxide Dismutase-1/genetics/metabolism ; *Macrophages/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Motor Neurons/metabolism ; Inflammation/genetics/metabolism/pathology ; Mutation ; Transfection ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease targeting the brain and spinal cord. Non-neuronal cells, including macrophages, may contribute to the disruption of motor neurons (MNs), neuromuscular junction dismantling and clinical signs of ALS. Understanding the modality and the effect of MNs-macrophage communication is pivotal. Here, we focus on extracellular vesicle (EVS)-mediated communication and, in particular, we analyze the response of macrophages. NSC-34 cells transfected with mutant SOD1 (G93A, A4V, G85R, G37R) and differentiated towards MN-like cells, and Raw 264.7 macrophages are the cellular models of the study. mSOD1 NSC-34 cells release a high number of vesicles, both large-lEVs (300 nm diameter) and small-sEVs (90 nm diameter), containing inflammation-modulating molecules, and are efficiently taken up by macrophages. RT-PCR analysis of inflammation mediators demonstrated that the conditioned medium of mSOD1 NSC-34 cells polarizes Raw 264.7 macrophages towards both pro-inflammatory and anti-inflammatory phenotypes. sEVs act on macrophages in a time-dependent manner: an anti-inflammatory response mediated by TGFβ firstly starts (12 h); successively, the response shifts towards a pro-inflammation IL-1β-mediated (48 h). The response of macrophages is strictly dependent on the SOD1 mutation type. The results suggest that EVs impact physiological and behavioral macrophage processes and are of potential relevance to MN degeneration.}, } @article {pmid38927674, year = {2024}, author = {Gotte, G}, title = {Effects of Pathogenic Mutants of the Neuroprotective RNase 5-Angiogenin in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, pmid = {38927674}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; *Ribonuclease, Pancreatic/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; Animals ; Mutation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects the motoneurons. More than 40 genes are related with ALS, and amyloidogenic proteins like SOD1 and/or TDP-43 mutants are directly involved in the onset of ALS through the formation of polymorphic fibrillogenic aggregates. However, efficacious therapeutic approaches are still lacking. Notably, heterozygous missense mutations affecting the gene coding for RNase 5, an enzyme also called angiogenin (ANG), were found to favor ALS onset. This is also true for the less-studied but angiogenic RNase 4. This review reports the substrate targets and illustrates the neuroprotective role of native ANG in the neo-vascularization of motoneurons. Then, it discusses the molecular determinants of many pathogenic ANG mutants, which almost always cause loss of function related to ALS, resulting in failures in angiogenesis and motoneuron protection. In addition, ANG mutations are sometimes combined with variants of other factors, thereby potentiating ALS effects. However, the activity of the native ANG enzyme should be finely balanced, and not excessive, to avoid possible harmful effects. Considering the interplay of these angiogenic RNases in many cellular processes, this review aims to stimulate further investigations to better elucidate the consequences of mutations in ANG and/or RNase 4 genes, in order to achieve early diagnosis and, possibly, successful therapies against ALS.}, } @article {pmid38927681, year = {2024}, author = {Adler, GL and Le, K and Fu, Y and Kim, WS}, title = {Human Endogenous Retroviruses in Neurodegenerative Diseases.}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, pmid = {38927681}, issn = {2073-4425}, mesh = {Humans ; *Endogenous Retroviruses/genetics/pathogenicity ; *Neurodegenerative Diseases/virology/genetics ; Amyotrophic Lateral Sclerosis/virology/genetics ; Animals ; }, abstract = {Human endogenous retroviruses (HERVs) are DNA transposable elements that have integrated into the human genome via an ancestral germline infection. The potential importance of HERVs is underscored by the fact that they comprise approximately 8% of the human genome. HERVs have been implicated in the pathogenesis of neurodegenerative diseases, a group of CNS diseases characterized by a progressive loss of structure and function of neurons, resulting in cell death and multiple physiological dysfunctions. Much evidence indicates that HERVs are initiators or drivers of neurodegenerative processes in multiple sclerosis and amyotrophic lateral sclerosis, and clinical trials have been designed to target HERVs. In recent years, the role of HERVs has been explored in other major neurodegenerative diseases, including frontotemporal dementia, Alzheimer's disease and Parkinson's disease, with some interesting discoveries. This review summarizes and evaluates the past and current research on HERVs in neurodegenerative diseases. It discusses the potential role of HERVs in disease manifestation and neurodegeneration. It critically reviews antiretroviral strategies used in the therapeutic intervention of neurodegenerative diseases.}, } @article {pmid38928553, year = {2024}, author = {Di Martino, P and Marcozzi, V and Bibbò, S and Ghinassi, B and Di Baldassarre, A and Gaggi, G and Di Credico, A}, title = {Unraveling the Epigenetic Landscape: Insights into Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis.}, journal = {Brain sciences}, volume = {14}, number = {6}, pages = {}, pmid = {38928553}, issn = {2076-3425}, support = {MUR-Fondo Promozione e Sviluppo-DM 737/2021, DEFENDANTs, Developmental Neurotoxi-city of Endocrine Disruptors from Plastic Pollutants.//NextGenerationEU "MUR-Fondo Promozione e Sviluppo-DM 737/2021, DEFENDANTs, De-velopmental Neurotoxicity of Endocrine Disruptors from Plastic Pollutants./ ; }, abstract = {Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) are examples of neurodegenerative movement disorders (NMDs), which are defined by a gradual loss of motor function that is frequently accompanied by cognitive decline. Although genetic abnormalities have long been acknowledged as significant factors, new research indicates that epigenetic alterations are crucial for the initiation and development of disease. This review delves into the complex interactions that exist between the pathophysiology of NMDs and epigenetic mechanisms such DNA methylation, histone modifications, and non-coding RNAs. Here, we examine how these epigenetic changes could affect protein aggregation, neuroinflammation, and gene expression patterns, thereby influencing the viability and functionality of neurons. Through the clarification of the epigenetic terrain underpinning neurodegenerative movement disorders, this review seeks to enhance comprehension of the underlying mechanisms of the illness and augment the creation of innovative therapeutic strategies.}, } @article {pmid38928564, year = {2024}, author = {Lin, CY and Vanoverbeke, V and Trent, D and Willey, K and Lee, YS}, title = {The Spatiotemporal Expression of SOCS3 in the Brainstem and Spinal Cord of Amyotrophic Lateral Sclerosis Mice.}, journal = {Brain sciences}, volume = {14}, number = {6}, pages = {}, pmid = {38928564}, issn = {2076-3425}, support = {2022-040//Cleveland Clinic Technology Development Investment Project and Ohio Third Frontier Technology Validation and Start-up Fund/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons from the brain and spinal cord. The excessive neuroinflammation is thought to be a common determinant of ALS. Suppressor of cytokine signaling-3 (SOCS3) is pathologically upregulated after injury/diseases to negatively regulate a broad range of cytokines/chemokines that mediate inflammation; however, the role that SOCS3 plays in ALS pathogenesis has not been explored. Here, we found that SOCS3 protein levels were significantly increased in the brainstem of the superoxide dismutase 1 (SOD1)-G93A ALS mice, which is negatively related to a progressive decline in motor function from the pre-symptomatic to the early symptomatic stage. Moreover, SOCS3 levels in both cervical and lumbar spinal cords of ALS mice were also significantly upregulated at the pre-symptomatic stage and became exacerbated at the early symptomatic stage. Concomitantly, astrocytes and microglia/macrophages were progressively increased and reactivated over time. In contrast, neurons were simultaneously lost in the brainstem and spinal cord examined over the course of disease progression. Collectively, SOCS3 was first found to be upregulated during ALS progression to directly relate to both increased astrogliosis and increased neuronal loss, indicating that SOCS3 could be explored to be as a potential therapeutic target of ALS.}, } @article {pmid38928874, year = {2024}, author = {Szulc, A and Wiśniewska, K and Żabińska, M and Gaffke, L and Szota, M and Olendzka, Z and Węgrzyn, G and Pierzynowska, K}, title = {Effectiveness of Flavonoid-Rich Diet in Alleviating Symptoms of Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {12}, pages = {}, pmid = {38928874}, issn = {2304-8158}, support = {533-0C20-GS0D-24//University of Gdansk/ ; }, abstract = {Over the past decades, there has been a significant increase in the burden of neurological diseases, including neurodegenerative disorders, on a global scale. This is linked to a widespread demographic trend in which developed societies are aging, leading to an increased proportion of elderly individuals and, concurrently, an increase in the number of those afflicted, posing one of the main public health challenges for the coming decades. The complex pathomechanisms of neurodegenerative diseases and resulting varied symptoms, which differ depending on the disease, environment, and lifestyle of the patients, make searching for therapies for this group of disorders a formidable challenge. Currently, most neurodegenerative diseases are considered incurable. An important aspect in the fight against and prevention of neurodegenerative diseases may be broadly understood lifestyle choices, and more specifically, what we will focus on in this review, a diet. One proposal that may help in the fight against the spread of neurodegenerative diseases is a diet rich in flavonoids. Flavonoids are compounds widely found in products considered healthy, such as fruits, vegetables, and herbs. Many studies indicated not only the neuroprotective effects of these compounds but also their ability to reverse changes occurring during the progression of diseases such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis. Here, we present the main groups of flavonoids, discussing their characteristics and mechanisms of action. The most widely described mechanisms point to neuroprotective functions due to strong antioxidant and anti-inflammatory effects, accompanied with their ability to penetrate the blood-brain barrier, as well as the ability to inhibit the formation of protein aggregates. The latter feature, together with promoting removal of the aggregates is especially important in neurodegenerative diseases. We discuss a therapeutic potential of selected flavonoids in the fight against neurodegenerative diseases, based on in vitro studies, and their impact when included in the diet of animals (laboratory research) and humans (population studies). Thus, this review summarizes flavonoids' actions and impacts on neurodegenerative diseases. Therapeutic use of these compounds in the future is potentially possible but depends on overcoming key challenges such as low bioavailability, determining the therapeutic dose, and defining what a flavonoid-rich diet is and determining its potential negative effects. This review also suggests further research directions to address these challenges.}, } @article {pmid38929429, year = {2024}, author = {Hillaert, A and Sanmiguel Serpa, LC and Xu, Y and Hesta, M and Bogaert, S and Vanderperren, K and Pullens, P}, title = {Optimization of Fair Arterial Spin Labeling Magnetic Resonance Imaging (ASL-MRI) for Renal Perfusion Quantification in Dogs: Pilot Study.}, journal = {Animals : an open access journal from MDPI}, volume = {14}, number = {12}, pages = {}, pmid = {38929429}, issn = {2076-2615}, support = {01D27919//Special Research Fund of Ghent University, Belgium/ ; }, abstract = {Arterial spin labeling (ASL) MRI allows non-invasive quantification of renal blood flow (RBF) and shows great potential for renal assessment. To our knowledge, renal ASL-MRI has not previously been performed in dogs. The aim of this pilot study was to determine parameters essential for ALS-MRI-based quantification of RBF in dogs: T1, blood (longitudinal relaxation time), λ (blood tissue partition coefficient) and TI (inversion time). A Beagle was scanned at 3T with a multi-TI ASL sequence, with TIs ranging from 250 to 2500 ms, to determine the optimal TI value. The T1 of blood for dogs was determined by scanning a blood sample with a 2D IR TSE sequence. The water content of the dog's kidney was determined by analyzing kidney samples from four dogs with a moisture analyzer and was subsequently used to calculate λ. The optimal TI and the measured values for T1,blood, and λ were 2000 ms, 1463 ms and 0.91 mL/g, respectively. These optimized parameters for dogs resulted in lower RBF values than those obtained from inline generated RBF maps. In conclusion, this study determined preliminary parameters essential for ALS-MRI-based RBF quantification in dogs. Further research is needed to confirm these values, but it may help guide future research.}, } @article {pmid38929462, year = {2024}, author = {De Marchi, I and Buffone, F and Mauro, A and Bruini, I and Vismara, L}, title = {Manual Therapy of Dysphagia in a Patient with Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {6}, pages = {}, pmid = {38929462}, issn = {1648-9144}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Male ; *Deglutition Disorders/etiology/therapy ; Middle Aged ; Manipulation, Osteopathic/methods ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable rare neurodegenerative condition, with 45% of cases showing the symptom of dysphagia; its clinical signs are atrophy, weakness, and fasciculations of the facial muscles, tongue, and pharynx. Furthermore, dysphagia is the main cause of aspiration pneumonia. The traditional treatment for dysphagia varies based on the patient's difficulty of swallowing. The initial phase consists of dietary consistency adjustments, progressing to alternatives like nasogastric tubes or percutaneous endoscopic gastrostomy (PEG) in advanced stages. Osteopathic manipulative treatment (OMT) is a complementary 'hands-on' approach that has already shown positive results as an add-on therapy in various health conditions. This study is a case report of a man diagnosed with ALS with initial dysphagia, managed with a protocol that extraordinarily included OMT. The patient showed somatic dysfunctions in the mediastinal region, upper cervical region, and occipital area which are all anatomically related to the nervous system, especially the glossopharyngeal reflex. At the end of the rehabilitation protocol, there was a reduction in the swallowing problems measured with Strand Scale and swallowing tests, and the patient reported an improved psycho-physical well-being assessed with the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40). Instead, the neurological function measured with ALSFRS-S remained stable. Although the nature of this study design prevents any causal assumption, the positive results should lead to future randomized controlled trials to assess the effectiveness of OMT as an adjunctive therapeutic proposal to improve the health of ALS patients.}, } @article {pmid38932488, year = {2024}, author = {Spencer, D and Polke, J and Campbell, J and Houlden, H and Radunovic, A}, title = {'Outcomes of genetic testing in the London MND Center: the importance of achieving timely results and correlations to family history'.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {737-742}, doi = {10.1080/21678421.2024.2370808}, pmid = {38932488}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; *Genetic Testing/methods ; London/epidemiology ; Middle Aged ; Aged ; Adult ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Mutation/genetics ; Aged, 80 and over ; Genetic Predisposition to Disease/genetics ; Medical History Taking/methods ; }, abstract = {Background: Despite recognition of the importance of genetic factors in the pathogenesis of MND and the increasing availability of genetic testing, testing practice remains highly variable. With the arrival of gene-targeted therapies there is a growing need to promptly identify actionable genetic results and patient death before receipt of results raises ethical dilemmas and limits access to novel therapies. Objective: To identify pathogenic mutations within a London tertiary MND center and their correlation with family history. To record waiting times for genetic results and deaths prior to receipt of results. Methods: In this series of 100 cases, genetic testing was offered to all patients with an MND diagnosis from the tertiary clinic. Data on demographics, disease progression and a detailed family history were taken. Time to receipt of genetic results and patient deaths prior to this were recorded. Results: Of the 97 patients who accepted testing a genetic cause was identified in 10%, including seven C9orf72 and two positive SOD1 cases. Only three patients with positive genetic findings had a family history of MND, although alternative neurological diagnoses and symptoms in the family were frequently reported. 14% of patients who underwent testing were deceased by the time results were received, including one actionable SOD1 case. Conclusions: Genetic testing should be made available to all patients who receive an MND diagnosis as family history alone is inadequate to identify potential familial cases. Time to receipt of results remains a significant issue due to the limited life expectancy following diagnosis.}, } @article {pmid38932502, year = {2024}, author = {Stegmann, G and Krantsevich, C and Liss, J and Charles, S and Bartlett, M and Shefner, J and Rutkove, S and Kawabata, K and Talkar, T and Berisha, V}, title = {Automated speech analytics in ALS: higher sensitivity of digital articulatory precision over the ALSFRS-R.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {767-775}, pmid = {38932502}, issn = {2167-9223}, support = {R01 DC006859/DC/NIDCD NIH HHS/United States ; R43 DC017625/DC/NIDCD NIH HHS/United States ; 1853247//National Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Male ; Female ; Middle Aged ; Aged ; Speech Disorders/etiology/diagnosis/physiopathology ; Speech/physiology ; Adult ; Speech Production Measurement/methods ; Algorithms ; Severity of Illness Index ; Disease Progression ; }, abstract = {Objective: Although studies have shown that digital measures of speech detected ALS speech impairment and correlated with the ALSFRS-R speech item, no study has yet compared their performance in detecting speech changes. In this study, we compared the performances of the ALSFRS-R speech item and an algorithmic speech measure in detecting clinically important changes in speech. Importantly, the study was part of a FDA submission which received the breakthrough device designation for monitoring ALS; we provide this paper as a roadmap for validating other speech measures for monitoring disease progression. Methods: We obtained ALSFRS-R speech subscores and speech samples from participants with ALS. We computed the minimum detectable change (MDC) of both measures; using clinician-reported listener effort and a perceptual ratings of severity, we calculated the minimal clinically important difference (MCID) of each measure with respect to both sets of clinical ratings. Results: For articulatory precision, the MDC (.85) was lower than both MCID measures (2.74 and 2.28), and for the ALSFRS-R speech item, MDC (.86) was greater than both MCID measures (.82 and .72), indicating that while the articulatory precision measure detected minimal clinically important differences in speech, the ALSFRS-R speech item did not. Conclusion: The results demonstrate that the digital measure of articulatory precision effectively detects clinically important differences in speech ratings, outperforming the ALSFRS-R speech item. Taken together, the results herein suggest that this speech outcome is a clinically meaningful measure of speech change.}, } @article {pmid38933387, year = {2022}, author = {Li, X and Lu, S and Lu, B and Sun, X}, title = {Optogenetic control of GGGGCC repeat-containing RNA phase transition.}, journal = {Fundamental research}, volume = {2}, number = {6}, pages = {843-850}, pmid = {38933387}, issn = {2667-3258}, abstract = {The GGGGCC (G4C2) hexanucleotide repeat expansion in the C9ORF72 gene is a major cause of both hereditary amyotrophic lateral sclerosis and familial frontotemporal dementia. Recent studies have shown that G4C2 hexanucleotide repeat-containing RNA transcripts ((G4C2)n RNA) could go through liquid-liquid phase separation to form RNA foci, which may elicit neurodegeneration. However, the direct causality between these abnormal RNA foci and neuronal toxicity remains to be demonstrated. Here we introduce an optogenetic control system that can induce the assembly and phase separation of (G4C2)n RNA foci with blue light illumination in human cells, by fusing a specific (G4C2)n RNA binding protein as the linker domain to Cry2, a protein that oligomerizes in response to blue light. Our results demonstrate that a higher number of G4C2 repeats have the potential to be induced into more RNA foci in the cells. Both spontaneous and induced RNA foci display liquid-like properties according to FRAP measurements. Computational simulation shows strong consistency with the experimental results and supports the effect of our system to promote the propensity of (G4C2)n RNA towards phase separation. This system can thus be used to investigate whether (G4C2)n RNA foci would disrupt normal cellular processes and lead to pathological phenotypes relevant to repeat expansion disorders.}, } @article {pmid38933502, year = {2024}, author = {Chen, BR and Wu, T and Chen, TH and Wang, Y}, title = {Neuroimmune interactions and their roles in neurodegenerative diseases.}, journal = {Fundamental research}, volume = {4}, number = {2}, pages = {251-261}, pmid = {38933502}, issn = {2667-3258}, abstract = {The nervous system possesses bidirectional, sophisticated and delicate communications with the immune system. These neuroimmune interactions play a vitally important role in the initiation and development of many disorders, especially neurodegenerative diseases. Although scientific advancements have made tremendous progress in this field during the last few years, neuroimmune communications are still far from being elucidated. By organizing recent research, in this review, we discuss the local and intersystem neuroimmune interactions and their roles in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Unveiling these will help us gain a better understanding of the process of interplay inside the body and how the organism maintains homeostasis. It will also facilitate a view of the diseases from a holistic, pluralistic and interconnected perspective, thus providing a basis of developing novel and effective methods to diagnose, intervene and treat diseases.}, } @article {pmid38934222, year = {2024}, author = {Kim, A and Lee, DY and Sung, JJ}, title = {Cdk5 inhibition in the SOD1[G93A] transgenic mouse model of amyotrophic lateral sclerosis suppresses neurodegeneration and extends survival.}, journal = {Journal of neurochemistry}, volume = {168}, number = {9}, pages = {2908-2925}, doi = {10.1111/jnc.16160}, pmid = {38934222}, issn = {1471-4159}, support = {2018R1A5A2025964//National Research Foundation of Korea/ ; 2019M3C7A1031867//National Research Foundation of Korea/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Cells, Cultured ; *Cyclin-Dependent Kinase 5/metabolism/genetics/antagonists & inhibitors ; Disease Models, Animal ; Mice, Transgenic ; Motor Neurons/pathology/metabolism ; Nerve Degeneration/pathology/genetics/metabolism ; Superoxide Dismutase ; *Superoxide Dismutase-1/genetics ; tau Proteins/metabolism/genetics ; }, abstract = {Deregulated cyclin-dependent kinase 5 (Cdk5) activity closely correlates with hyperphosphorylated tau, a common pathology found in neurodegenerative diseases. Previous postmortem studies had revealed increased Cdk5 immunoreactivity in amyotrophic lateral sclerosis (ALS); hence, we investigated the effects of Cdk5 inhibition on ALS model mice and neurons in this study. For the in vitro study, motor neuron cell lines with wild-type superoxide dismutase 1 (SOD1) or SOD1[G93A] and primary neuronal cultures from SOD1[G93A] transgenic (TG) mice or non-TG mice were compared for the expression of proteins involved in tau pathology, neuroinflammation, apoptosis, and neuritic outgrowth by applying Cdk5-small interfering RNA or Cdk5-short hairpin RNA (shRNA). For the in vivo study, SOD1[G93A] mice and non-TG mice were intrathecally injected with adeno-associated virus 9 (AAV9)-scramble (SCR)-shRNA or AAV9-Cdk5-shRNA at the age of 5 weeks. Weight and motor function were measured three times per week from 60 days of age, longevity was evaluated, and the tissues were collected from 90-day-old or 120-day-old mice. Neurons with SOD1[G93A] showed increased phosphorylated tau, attenuated neuritic growth, mislocalization of SOD1, and enhanced neuroinflammation and apoptosis, all of which were reversed by Cdk5 inhibition. Weights did not show significant differences among non-TG and SOD1[G93A] mice with or without Cdk5 silencing. SOD1[G93A] mice treated with AAV9-Cdk5-shRNA showed significantly delayed disease onset, delayed rotarod failure, and prolonged survival compared with those treated with AAV9-SCR-shRNA. The brain and spinal cord of SOD1[G93A] mice intrathecally injected with AAV9-Cdk5-shRNA exhibited suppressed tau pathology, neuroinflammation, apoptosis, and an increased number of motor neurons compared to those of SOD1[G93A] mice injected with AAV9-SCR-shRNA. Cdk5 inhibition could be an important mechanism in the development of a new therapeutic strategy for ALS.}, } @article {pmid38934400, year = {2025}, author = {Chen, Y and Wei, Y and Liu, J and Zhu, T and Zhou, C and Zhang, D}, title = {Spatial transcriptomics combined with single-nucleus RNA sequencing reveals glial cell heterogeneity in the human spinal cord.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3302-3316}, pmid = {38934400}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202511000-00032/figure1/v/2024-12-20T164640Z/r/image-tiff Glial cells play crucial roles in regulating physiological and pathological functions, including sensation, the response to infection and acute injury, and chronic neurodegenerative disorders. Glial cells include astrocytes, microglia, and oligodendrocytes in the central nervous system, and satellite glial cells and Schwann cells in the peripheral nervous system. Despite the greater understanding of glial cell types and functional heterogeneity achieved through single-cell and single-nucleus RNA sequencing in animal models, few studies have investigated the transcriptomic profiles of glial cells in the human spinal cord. Here, we used high-throughput single-nucleus RNA sequencing and spatial transcriptomics to map the cellular and molecular heterogeneity of astrocytes, microglia, and oligodendrocytes in the human spinal cord. To explore the conservation and divergence across species, we compared these findings with those from mice. In the human spinal cord, astrocytes, microglia, and oligodendrocytes were each divided into six distinct transcriptomic subclusters. In the mouse spinal cord, astrocytes, microglia, and oligodendrocytes were divided into five, four, and five distinct transcriptomic subclusters, respectively. The comparative results revealed substantial heterogeneity in all glial cell types between humans and mice. Additionally, we detected sex differences in gene expression in human spinal cord glial cells. Specifically, in all astrocyte subtypes, the levels of NEAT1 and CHI3L1 were higher in males than in females, whereas the levels of CST3 were lower in males than in females. In all microglial subtypes, all differentially expressed genes were located on the sex chromosomes. In addition to sex-specific gene differences, the levels of MT-ND4 , MT2A , MT-ATP6 , MT-CO3 , MT-ND2 , MT-ND3 , and MT-CO2 in all spinal cord oligodendrocyte subtypes were higher in females than in males. Collectively, the present dataset extensively characterizes glial cell heterogeneity and offers a valuable resource for exploring the cellular basis of spinal cord-related illnesses, including chronic pain, amyotrophic lateral sclerosis, and multiple sclerosis.}, } @article {pmid38934512, year = {2024}, author = {Zhang, J and Cao, W and Xie, J and Pang, C and Gao, L and Zhu, L and Li, Y and Yu, H and Du, L and Fan, D and Deng, B}, title = {Metabolic Syndrome and Risk of Amyotrophic Lateral Sclerosis: Insights from a Large-Scale Prospective Study.}, journal = {Annals of neurology}, volume = {96}, number = {4}, pages = {788-801}, doi = {10.1002/ana.27019}, pmid = {38934512}, issn = {1531-8249}, support = {12101460//National Natural Science Foundation of China/ ; 81901273//National Natural Science Foundation of China/ ; LQ21H090018//Natural Science Foundation of Zhejiang Province/ ; LQ22A010005//Natural Science Foundation of Zhejiang Province/ ; LQ22H020003//Natural Science Foundation of Zhejiang Province/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; KY2024-R054//Ethical Decision Committee of the Research Administration at First Affiliated Hospital of Wenzhou Medical University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Male ; Female ; *Metabolic Syndrome/epidemiology ; Middle Aged ; Prospective Studies ; Aged ; Risk Factors ; Adult ; United Kingdom/epidemiology ; Body Mass Index ; Hypertension/epidemiology/complications ; }, abstract = {OBJECTIVE: Although metabolic abnormalities are implicated in the etiology of neurodegenerative diseases, their role in the development of amyotrophic lateral sclerosis (ALS) remains a subject of controversy. We aimed to identify the association between metabolic syndrome (MetS) and the risk of ALS.

METHODS: This study included 395,987 participants from the UK Biobank to investigate the relationship between MetS and ALS. Cox regression model was used to estimate hazard ratios (HR). Stratified analyses were performed based on gender, body mass index (BMI), smoking status, and education level. Mediation analysis was conducted to explore potential mechanisms.

RESULTS: In this study, a total of 539 cases of ALS were recorded after a median follow-up of 13.7 years. Patients with MetS (defined harmonized) had a higher risk of developing ALS after adjusting for confounding factors (HR: 1.50, 95% CI: 1.19-1.89). Specifically, hypertension and high triglycerides were linked to a higher risk of ALS (HR: 1.53, 95% CI: 1.19-1.95; HR: 1.31, 95% CI: 1.06-1.61, respectively). Moreover, the quantity of metabolic abnormalities showed significant results. Stratified analysis revealed that these associations are particularly significant in individuals with a BMI <25. These findings remained stable after sensitivity analysis. Notably, mediation analysis identified potential metabolites and metabolomic mediators, including alkaline phosphatase, cystatin C, γ-glutamyl transferase, saturated fatty acids to total fatty acids percentage, and omega-6 fatty acids to omega-3 fatty acids ratio.

INTERPRETATION: MetS exhibits a robust association with an increased susceptibility to ALS, particularly in individuals with a lower BMI. Furthermore, metabolites and metabolomics, as potential mediators, provide invaluable insights into the intricate biological mechanisms. ANN NEUROL 2024;96:788-801.}, } @article {pmid38934637, year = {2025}, author = {Tankus, A and Stern, E and Klein, G and Kaptzon, N and Nash, L and Marziano, T and Shamia, O and Gurevitch, G and Bergman, L and Goldstein, L and Fahoum, F and Strauss, I}, title = {A Speech Neuroprosthesis in the Frontal Lobe and Hippocampus: Decoding High-Frequency Activity into Phonemes.}, journal = {Neurosurgery}, volume = {96}, number = {2}, pages = {356-364}, doi = {10.1227/neu.0000000000003068}, pmid = {38934637}, issn = {1524-4040}, support = {17630//Ministry of Science and Technology, Israel/ ; }, mesh = {Humans ; Male ; Adult ; *Hippocampus/physiology ; *Speech/physiology ; *Frontal Lobe/physiology ; Electrodes, Implanted ; *Phonetics ; *Brain-Computer Interfaces ; *Neural Prostheses ; }, abstract = {BACKGROUND AND OBJECTIVES: Loss of speech due to injury or disease is devastating. Here, we report a novel speech neuroprosthesis that artificially articulates building blocks of speech based on high-frequency activity in brain areas never harnessed for a neuroprosthesis before: anterior cingulate and orbitofrontal cortices, and hippocampus.

METHODS: A 37-year-old male neurosurgical epilepsy patient with intact speech, implanted with depth electrodes for clinical reasons only, silently controlled the neuroprosthesis almost immediately and in a natural way to voluntarily produce 2 vowel sounds.

RESULTS: During the first set of trials, the participant made the neuroprosthesis produce the different vowel sounds artificially with 85% accuracy. In the following trials, performance improved consistently, which may be attributed to neuroplasticity. We show that a neuroprosthesis trained on overt speech data may be controlled silently.

CONCLUSION: This may open the way for a novel strategy of neuroprosthesis implantation at earlier disease stages (eg, amyotrophic lateral sclerosis), while speech is intact, for improved training that still allows silent control at later stages. The results demonstrate clinical feasibility of direct decoding of high-frequency activity that includes spiking activity in the aforementioned areas for silent production of phonemes that may serve as a part of a neuroprosthesis for replacing lost speech control pathways.}, } @article {pmid38935506, year = {2024}, author = {Halim, DO and Krishnan, G and Hass, EP and Lee, S and Verma, M and Almeida, S and Gu, Y and Kwon, DY and Fazzio, TG and Gao, FB}, title = {The exocyst subunit EXOC2 regulates the toxicity of expanded GGGGCC repeats in C9ORF72-ALS/FTD.}, journal = {Cell reports}, volume = {43}, number = {7}, pages = {114375}, pmid = {38935506}, issn = {2211-1247}, support = {RF1 NS101986/NS/NINDS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; R01 HD104971/HD/NICHD NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; R21 NS112766/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *DNA Repeat Expansion/genetics ; Motor Neurons/metabolism/pathology ; }, abstract = {GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this genetic mutation leads to neurodegeneration remains largely unknown. Using CRISPR-Cas9 technology, we deleted EXOC2, which encodes an essential exocyst subunit, in induced pluripotent stem cells (iPSCs) derived from C9ORF72-ALS/FTD patients. These cells are viable owing to the presence of truncated EXOC2, suggesting that exocyst function is partially maintained. Several disease-relevant cellular phenotypes in C9ORF72 iPSC-derived motor neurons are rescued due to, surprisingly, the decreased levels of dipeptide repeat (DPR) proteins and expanded G4C2 repeats-containing RNA. The treatment of fully differentiated C9ORF72 neurons with EXOC2 antisense oligonucleotides also decreases expanded G4C2 repeats-containing RNA and partially rescued disease phenotypes. These results indicate that EXOC2 directly or indirectly regulates the level of G4C2 repeats-containing RNA, making it a potential therapeutic target in C9ORF72-ALS/FTD.}, } @article {pmid38936435, year = {2024}, author = {Tondo, G and Mazzini, L and Caminiti, SP and Gallo, C and Matheoud, R and Comi, C and Sacchetti, GM and Perani, D and De Marchi, F}, title = {Coupling motor evoked potentials and brain [[18]F]FDG-PET in Amyotrophic Lateral Sclerosis: preliminary findings on disease severity.}, journal = {Neurobiology of disease}, volume = {199}, number = {}, pages = {106579}, doi = {10.1016/j.nbd.2024.106579}, pmid = {38936435}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/physiopathology ; Male ; Female ; Middle Aged ; *Fluorodeoxyglucose F18 ; *Positron-Emission Tomography/methods ; *Transcranial Magnetic Stimulation/methods ; Aged ; Retrospective Studies ; *Brain/diagnostic imaging/metabolism/physiopathology ; *Evoked Potentials, Motor/physiology ; Adult ; Severity of Illness Index ; }, abstract = {BACKGROUND: The diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical, supported by the electromyographic examination to reveal signs of lower motor neuron damage. Identifying reliable markers of upper motor neuron (UMN) involvement is challenging. On this regard, the role of transcranial magnetic stimulation-induced motor-evoked potentials (TMS-MEPs), and its relationship with UMN burden, is still under investigation.

OBJECTIVE: To evaluate the ability of TMS-MEPs in delineating the neurophysiological UMN damage, and to determine the relationship between TMS-MEPs and [[18]F]FDG-PET measures of neural dysfunction.

METHODS: We retrospectively selected 13 ALS patients who underwent, during the diagnostic process, the TMS-MEPs and [[18]F]FDG-PET scans. Demographic and clinical data were collected. For the MEP evaluation, we considered normal MEP, absent MEP, or significantly increased central-motor-conduction-time. For [[18]F]FDG-PET, we conducted voxel-wise analyses, both at single-subject and group levels, exploring hypometabolism and hypermetabolism patterns in comparison with a large dataset of healthy controls (HC).

RESULTS: Based on TMS-MEPs, we identified 4/13 patients with normal MEP in all limbs (GROUP-NO), while 9/13 had an abnormal MEP in at least one limb (GROUP-AB). Despite the [[18]F]FDG-PET single-subject analysis revealed heterogenous expression of regional hypo- and hyper-metabolism patterns in the patients, the group-level analysis revealed a common hypometabolism, involving the precentral gyrus and the supplementary motor area, the paracentral lobule and the anterior cingulate cortex in the GROUP-AB. Moreover, exclusively for the GROUP-AB compared with HC, a relative hypermetabolism was observed in the right cerebellum, right inferior and middle temporal gyrus. The GROUP-NO showed no specific cluster of hypo- and hyper-metabolism compared to HC.

CONCLUSION: This study showed altered brain metabolism only in the ALS group with abnormal MEPs, suggesting an association between the two biomarkers in defining the UMN damage.}, } @article {pmid38937912, year = {2024}, author = {Verde, F and Licaj, S and Soranna, D and Ticozzi, N and Silani, V and Zambon, A}, title = {Cerebrospinal fluid and blood neurofilament light chain levels in amyotrophic lateral sclerosis and frontotemporal degeneration: A meta-analysis.}, journal = {European journal of neurology}, volume = {31}, number = {9}, pages = {e16371}, pmid = {38937912}, issn = {1468-1331}, support = {//Ministero della Salute/ ; //BIBLIOSAN/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood ; Humans ; *Neurofilament Proteins/blood/cerebrospinal fluid ; *Frontotemporal Lobar Degeneration/blood/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid/blood ; Frontotemporal Dementia/cerebrospinal fluid/blood ; }, abstract = {BACKGROUND AND PURPOSE: Neurofilament light chain (NFL) has been shown to be increased in amyotrophic lateral sclerosis (ALS) and, to a lesser extent, in frontotemporal dementia (FTD). A meta-analysis of NFL in ALS and FTD was performed.

METHODS: Available studies comparing cerebrospinal fluid and blood NFL levels in ALS versus neurologically healthy controls (NHCs), other neurological diseases (ONDs) and ALS mimics, as well as in FTD and related entities (behavioural variant of FTD and frontotemporal lobar degeneration syndromes) versus NHCs, ONDs and other dementias were evaluated.

RESULTS: In ALS, both cerebrospinal fluid and blood levels of NFL were higher compared to other categories. In FTD, behavioural variant of FTD and frontotemporal lobar degeneration syndromes, NFL levels were consistently higher compared to NHCs; however, several comparisons with ONDs and other dementias did not demonstrate significant differences.

DISCUSSION: Amyotrophic lateral sclerosis is characterized by higher NFL levels compared to most other conditions. In contrast, NFL is not as good at discriminating FTD from other dementias.}, } @article {pmid38939546, year = {2024}, author = {Kararia, N and Kararia, V and Sharma, D and Gupta, S and Chaturvedi, S and Chaturvedi, Y}, title = {Comparative evaluation of the accuracy of two electronic apex locators in detecting simulated incomplete vertical root fractures: An in vitro stereomicroscopic study.}, journal = {Journal of conservative dentistry and endodontics}, volume = {27}, number = {5}, pages = {540-544}, pmid = {38939546}, issn = {2950-4708}, abstract = {AIM: The aim of this study was to compare the accuracy of two different electronic apex locators (EALs) in detecting simulated incomplete vertical root fractures (VRFs).

MATERIALS AND METHODS: Thirty freshly extracted single-rooted teeth were randomly divided into three groups of 10 teeth each labeled as Groups A, B, and C. Incomplete VRFs were simulated in the coronal, middle, and apical one-third of the roots for Groups A, B, and C, respectively. The teeth were embedded in alginate mold and fracture location was determined with Root ZX and Propex EALs for each sample and each group. To calculate the actual length (AL), each sample was sectioned at the upper level of the vertical fracture, and the length was measured by setting the stopper of the #10 K file under a stereomicroscope at ×30 magnification. The electronic lengths and ALs were compared using computer software, and the results were analyzed using SPSS 28.0 at a 95% confidence level.

RESULTS: No significant differences were seen in the accuracy of the two EALs when compared with ALs. Root ZX showed significantly longer measurements than ALs in groups B and C.

CONCLUSION: The tested EALs showed low accuracy (20%) in detecting simulated incomplete VRFs with a tendency for longer measurements compared to ALs.}, } @article {pmid38939990, year = {2024}, author = {Song, XY and Fan, CX and Rahman, AU and Choudhary, MI and Wang, XP}, title = {Neuro-regeneration or Repair: Cell Therapy of Neurological Disorders as A Way Forward.}, journal = {Current neuropharmacology}, volume = {22}, number = {14}, pages = {2272-2283}, pmid = {38939990}, issn = {1875-6190}, mesh = {Humans ; *Nervous System Diseases/therapy ; Animals ; *Cell- and Tissue-Based Therapy/methods ; Nerve Regeneration/physiology ; Stem Cell Transplantation/methods ; }, abstract = {The human central nervous system (CNS) has a limited capacity for regeneration and repair, as many other organs do. Partly as a result, neurological diseases are the leading cause of medical burden globally. Most neurological disorders cannot be cured, and primary treatments focus on managing their symptoms and slowing down their progression. Cell therapy for neurological disorders offers several therapeutic potentials and provides hope for many patients. Here we provide a general overview of cell therapy in neurological disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), stroke and traumatic brain injury (TBI), involving many forms of stem cells, including embryonic stem cells and induced pluripotent stem cells. We also address the current concerns and perspectives for the future. Most studies for cell therapy in neurological diseases are in the pre-clinical stage, and there is still a great need for further research to translate neural replacement and regenerative therapies into clinical settings.}, } @article {pmid38940407, year = {2024}, author = {Xu, A and Liu, T and Liu, D and Li, W and Huang, H and Wang, S and Xu, L and Liu, X and Jiang, S and Chen, Y and Sun, M and Luo, Q and Ding, T and Yao, T}, title = {Edge-Rich Pt-O-Ce Sites in CeO2 Supported Patchy Atomic-Layer Pt Enable a Non-CO Pathway for Efficient Methanol Oxidation.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {40}, pages = {e202410545}, doi = {10.1002/anie.202410545}, pmid = {38940407}, issn = {1521-3773}, support = {12025505//the National Natural Science Foundation of China/ ; 22179125//the National Natural Science Foundation of China/ ; 12205304//the National Natural Science Foundation of China/ ; KY9990000214//USTC research startup funds/ ; 2021YFA1600800//the National Key R&D Program of China/ ; XDB0450200//the Strategic Priority Research Program of the Chinese Academy of Sciences/ ; GXXT-2020-053//the University of China Innovation Program of Anhui Province/ ; 2022458//the Youth Innovation Promotion Association CAS/ ; 2021TQ0319//the Fellowship of China Postdoctoral Science Foundation/ ; BX20240350//the Fellowship of China Postdoctoral Science Foundation/ ; WK2060000038//the Fundamental Research Funds for the Central Universities/ ; WK2310000113//the Fundamental Research Funds for the Central Universities/ ; }, abstract = {Rational design of efficient methanol oxidation reaction (MOR) catalyst that undergo non-CO pathway is essential to resolve the long-standing poisoning issue. However, it remains a huge challenge due to the rather difficulty in maximizing the non-CO pathway by the selective coupling between the key *CHO and *OH intermediates. Here, we report a high-performance electrocatalyst of patchy atomic-layer Pt epitaxial growth on CeO2 nanocube (Pt ALs/CeO2) with maximum electronic metal-support interaction for enhancing the coupling selectively. The small-size monolayer material achieves an optimal geometrical distance between edge Pt-O-Ce sites and *OH absorbed on CeO2, which well restrains the dehydrogenation of *CHO, resulting in the non-CO pathway. Meanwhile, the *CHO/*CO intermediate generated at inner Pt-O-Ce sites can migrate to edge, inducing the subsequent coupling reaction, thus avoiding poisoning while promoting reaction efficiency. Consequently, Pt ALs/CeO2 exhibits exceptionally catalytic stability with negligible degradation even under 1000 s pure CO poisoning operation and high mass activity (14.87 A/mgPt), enabling it one of the best-performing alkali-stable MOR catalysts.}, } @article {pmid38941189, year = {2024}, author = {Huang, WP and Ellis, BCS and Hodgson, RE and Sanchez Avila, A and Kumar, V and Rayment, J and Moll, T and Shelkovnikova, TA}, title = {Stress-induced TDP-43 nuclear condensation causes splicing loss of function and STMN2 depletion.}, journal = {Cell reports}, volume = {43}, number = {7}, pages = {114421}, doi = {10.1016/j.celrep.2024.114421}, pmid = {38941189}, issn = {2211-1247}, support = {MR/W028522/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *RNA Splicing/genetics ; *Cell Nucleus/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Stress, Physiological ; Animals ; Mice ; }, abstract = {TDP-43 protein is dysregulated in several neurodegenerative diseases, which often have a multifactorial nature and may have extrinsic stressors as a "second hit." TDP-43 undergoes reversible nuclear condensation in stressed cells including neurons. Here, we demonstrate that stress-inducible nuclear TDP-43 condensates are RNA-depleted, non-liquid assemblies distinct from the known nuclear bodies. Their formation requires TDP-43 oligomerization and ATP and is inhibited by RNA. Using a confocal nanoscanning assay, we find that amyotrophic lateral sclerosis (ALS)-linked mutations alter stress-induced TDP-43 condensation by changing its affinity to liquid-like ribonucleoprotein assemblies. Stress-induced nuclear condensation transiently inactivates TDP-43, leading to loss of interaction with its protein binding partners and loss of function in splicing. Splicing changes are especially prominent and persisting for STMN2 RNA, and STMN2 protein becomes rapidly depleted early during stress. Our results point to early pathological changes to TDP-43 in the nucleus and support therapeutic modulation of stress response in ALS.}, } @article {pmid38942541, year = {2024}, author = {Shukla, H and John, D and Banerjee, S and Tiwari, AK}, title = {Drug repurposing for neurodegenerative diseases.}, journal = {Progress in molecular biology and translational science}, volume = {207}, number = {}, pages = {249-319}, doi = {10.1016/bs.pmbts.2024.03.035}, pmid = {38942541}, issn = {1878-0814}, mesh = {Humans ; *Drug Repositioning ; *Neurodegenerative Diseases/drug therapy ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) are neuronal problems that include the brain and spinal cord and result in loss of sensory and motor dysfunction. Common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS) etc. The occurrence of these diseases increases with age and is one of the challenging problems among elderly people. Though, several scientific research has demonstrated the key pathologies associated with NDDs still the underlying mechanisms and molecular details are not well understood and need to be explored and this poses a lack of effective treatments for NDDs. Several lines of evidence have shown that NDDs have a high prevalence and affect more than a billion individuals globally but still, researchers need to work forward in identifying the best therapeutic target for NDDs. Thus, several researchers are working in the directions to find potential therapeutic targets to alter the disease pathology and treat the diseases. Several steps have been taken to identify the early detection of the disease and drug repurposing for effective treatment of NDDs. Moreover, it is logical that current medications are being evaluated for their efficacy in treating such disorders; therefore, drug repurposing would be an efficient, safe, and cost-effective way in finding out better medication. In the current manuscript we discussed the utilization of drugs that have been repurposed for the treatment of AD, PD, HD, MS, and ALS.}, } @article {pmid38943019, year = {2024}, author = {He, S and He, XX and Yang, HQ and Zhang, JW and Chen, S}, title = {Two new cases with the UBQLN2 gene mutation in Han Chinese.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {10}, pages = {5047-5051}, pmid = {38943019}, issn = {1590-3478}, mesh = {Humans ; Female ; Male ; *Autophagy-Related Proteins/genetics ; Middle Aged ; *Mutation ; Young Adult ; Amyotrophic Lateral Sclerosis/genetics ; Adaptor Proteins, Signal Transducing/genetics ; China ; Adult ; Pedigree ; East Asian People ; }, abstract = {Variations in the UBQLN2 gene are associated with a group of diseases with X-linked dominant inheritance and clinical phenotypes of amyotrophic lateral sclerosis (ALS) and/or frontal temporal lobe dementia (FTD). Cases with UBQLN2 variations have been rarely reported worldwide. The reported cases exhibit strong clinical heterogeneity. Here, we report two adult-onset cases with UBQLN2 variations in Han Chinese. Whole exome sequencing revealed the hemizygous P506S (c.1516C > T) and the heterozygous P509S variation (c.1525C > T), both of which were located within the hotspot mutation region. The patient with the P506S variation was a 24-year-old male. The clinical feature was spastic paraplegia without lower motor neuron damage. The patient's mother was an asymptomatic heterozygote carrier with skewed X-chromosome inactivation. The patient with the P509S variation was a 63-year-old female. Clinical features included ALS and parkinsonism. [18]F-fluorodopa PET-CT revealed presynaptic dopaminergic deficits in bilateral posterior putamen. These cases further highlight the clinical heterogeneity of UBQLN2 cases.}, } @article {pmid38943180, year = {2024}, author = {Wiesner, D and Feldengut, S and Woelfle, S and Boeckers, TM and Ludolph, AC and Roselli, F and Del Tredici, K}, title = {Neuropeptide FF (NPFF)-positive nerve cells of the human cerebral cortex and white matter in controls, selected neurodegenerative diseases, and schizophrenia.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {108}, pmid = {38943180}, issn = {2051-5960}, support = {446067541//Deutsche Forschungsgemeinschaft/ ; 443642953//Deutsche Forschungsgemeinschaft/ ; 431995586//Deutsche Forschungsgemeinschaft/ ; 251293561//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *White Matter/pathology/metabolism ; Male ; *Schizophrenia/pathology/metabolism ; Female ; *Cerebral Cortex/pathology/metabolism ; Aged ; Middle Aged ; *Neurodegenerative Diseases/pathology/metabolism ; Aged, 80 and over ; Oligopeptides ; Adult ; Neurons/pathology/metabolism ; }, abstract = {We quantified and determined for the first time the distribution pattern of the neuropeptide NPFF in the human cerebral cortex and subjacent white matter. To do so, we studied n = 9 cases without neurological disorders and n = 22 cases with neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (ALS, n = 8), Alzheimer's disease (AD, n = 8), Pick's disease (PiD, n = 3), and schizophrenia (n = 3). NPFF-immunopositive cells were located chiefly, but not exclusively, in the superficial white matter and constituted there a subpopulation of white matter interstitial cells (WMIC): Pyramidal-like and multipolar somata predominated in the gyral crowns, whereas bipolar and ovoid somata predominated in the cortex surrounding the sulci. Their sparsely ramified axons were unmyelinated and exhibited NPFF-positive bead-like varicosities. We found significantly fewer NPFF-immunopositive cells in the gray matter of the frontal, cingulate, and superior temporal gyri of both sporadic ALS and late-stage AD patients than in controls, and significantly fewer NPFF-positive cells in the subjacent as well as deep white matter of the frontal gyrus of these patients compared to controls. Notably, the number of NPFF-positive cells was also significantly lower in the hippocampal formation in AD compared to controls. In PiD, NPFF-positive cells were present in significantly lower numbers in the gray and white matter of the cingulate and frontal gyrii in comparison to controls. In schizophrenic patients, lower wNPFF cell counts in the neocortex were significant and global (cingulate, frontal, superior temporal gyrus, medial, and inferior gyri). The precise functions of NPFF-positive cells and their relationship to the superficial corticocortical white matter U-fibers are currently unknown. Here, NPFF immunohistochemistry and expression characterize a previously unrecognized population of cells in the human brain, thereby providing a new entry-point for investigating their physiological and pathophysiological roles.}, } @article {pmid38944367, year = {2024}, author = {Wankhede, NL and Rajendra Kopalli, S and Dhokne, MD and Badnag, DJ and Chandurkar, PA and Mangrulkar, SV and Shende, PV and Taksande, BG and Upaganlawar, AB and Umekar, MJ and Koppula, S and Kale, MB}, title = {Decoding mitochondrial quality control mechanisms: Identifying treatment targets for enhanced cellular health.}, journal = {Mitochondrion}, volume = {78}, number = {}, pages = {101926}, doi = {10.1016/j.mito.2024.101926}, pmid = {38944367}, issn = {1872-8278}, mesh = {Humans ; *Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; Animals ; }, abstract = {Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein homeostasis, and coordinating apoptosis response. The vitality of cells, therefore, hinges on the optimal functioning of these dynamic organelles. Mitochondrial Quality Control Mechanisms (MQCM) play a pivotal role in ensuring the integrity and functionality of mitochondria. Perturbations in these mechanisms have been closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Compelling evidence suggests that targeting specific pathways within the MQCM could potentially offer a therapeutic avenue for rescuing mitochondrial integrity and mitigating the progression of neurodegenerative diseases. The intricate interplay of cellular stress, protein misfolding, and impaired quality control mechanisms provides a nuanced understanding of the underlying pathology. Consequently, unravelling the specific MQCM dysregulation in neurodegenerative disorders becomes paramount for developing targeted therapeutic strategies. This review delves into the impaired MQCM pathways implicated in neurodegenerative disorders and explores emerging therapeutic interventions. By shedding light on pharmaceutical and genetic manipulations aimed at restoring MQCM efficiency, the discussion aims to provide insights into novel strategies for ameliorating the progression of neurodegenerative diseases. Understanding and addressing mitochondrial quality control mechanisms not only underscore their significance in cellular health but also offer a promising frontier for advancing therapeutic approaches in the realm of neurodegenerative disorders.}, } @article {pmid38946579, year = {2024}, author = {Trucco, AP and Backhouse, T and Mioshi, E}, title = {Describing and assessing behavioural symptoms in amyotrophic lateral sclerosis with and without frontotemporal dementia: a scoping review.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {603-610}, pmid = {38946579}, issn = {1473-6551}, mesh = {Humans ; *Frontotemporal Dementia/psychology/physiopathology/diagnosis ; *Amyotrophic Lateral Sclerosis/psychology/complications/diagnosis ; Behavioral Symptoms/etiology/diagnosis ; }, abstract = {PURPOSE OF REVIEW: Alongside motor and cognitive symptoms, amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal dementia (ALSFTD) present with behavioural symptoms, which can be challenging for all affected by the disease. A scoping review of studies published between 2011 and 2024 was conducted to present the breadth of behavioural symptoms in ALS and ALSFTD, explore how they are described and assessed, and identify patterns in the literature.

FINDINGS: This scoping review identified 3939 articles, with 111/3939 meeting eligibility criteria. Most studies were from Australia (23.22%), Italy (16.94%) and the UK (14.29%); 75.67% were cross-sectional. Sample size ranged from 1 to 1013, as case studies were included. Overall mean age (100/111 studies) was 61.32 (SD = 4.15). Proportion of male patients (reported 102/111 studies) was 61.49%; mean disease duration (reported in 86/111 records) was 32.63 months (SD = 24.72). Papers described a broad range of behavioural symptoms (465 examples), which were thematically collated into seven categories: disinhibition (27.74%), apathy (25.16%), perseverative/compulsive behaviours (17.42%), hyperorality (10.53%), loss of sympathy or empathy (8.6%), psychotic symptoms (7.74%), and loss of insight about disease and changes (2.8%). Most studies (78.37%) used validated behavioural assessments that elicited carer's perspectives.

SUMMARY: Despite extensive evidence of behavioural symptoms in ALS, implementation of assessments and management of behavioural symptoms in clinical care remain limited. Clinicians must assess behavioural symptoms, as these can negatively affect disease prognosis, patient treatment engagement and increase family distress. Measures capturing carers' perspectives through interviews are ideal as they can reveal anosognosia, lack of sympathy and lack of empathy.}, } @article {pmid38946834, year = {2024}, author = {Taherifard, E and Saeed, A}, title = {Predicting liver function after hemihepatectomy in patients with hepatocellular carcinoma using different modalities.}, journal = {World journal of clinical oncology}, volume = {15}, number = {6}, pages = {783-785}, pmid = {38946834}, issn = {2218-4333}, abstract = {In response to Dr. Yue et al's study on prognostic factors for post-hemihepatectomy outcomes in hepatocellular carcinoma (HCC) patients, this critical review identifies methodological limitations and proposes enhancements for future research. While the study identifies liver stiffness measure and standard residual liver volume as potential predictors, concerns regarding small sample size, reliance on biochemical markers for safety assessment, and inadequate adjustment for confounding variables are raised. Recommendations for rigorous methodology, including robust statistical analysis, consideration of confounding factors, and selection of outcome measures with clinical components, are proposed to strengthen prognostic assessments. Furthermore, validation of novel evaluation models is crucial for enhancing clinical applicability and advancing understanding of postoperative outcomes in patients with HCC undergoing hemihepatectomy.}, } @article {pmid38948094, year = {2024}, author = {Haider, KH}, title = {Priming mesenchymal stem cells to develop "super stem cells".}, journal = {World journal of stem cells}, volume = {16}, number = {6}, pages = {623-640}, pmid = {38948094}, issn = {1948-0210}, abstract = {The stem cell pre-treatment approaches at cellular and sub-cellular levels encompass physical manipulation of stem cells to growth factor treatment, genetic manipulation, and chemical and pharmacological treatment, each strategy having advantages and limitations. Most of these pre-treatment protocols are non-combinative. This editorial is a continuum of Li et al's published article and Wan et al's editorial focusing on the significance of pre-treatment strategies to enhance their stemness, immunoregulatory, and immunosuppressive properties. They have elaborated on the intricacies of the combinative pre-treatment protocol using pro-inflammatory cytokines and hypoxia. Applying a well-defined multi-pronged combinatorial strategy of mesenchymal stem cells (MSCs), pre-treatment based on the mechanistic understanding is expected to develop "Super MSCs", which will create a transformative shift in MSC-based therapies in clinical settings, potentially revolutionizing the field. Once optimized, the standardized protocols may be used with slight modifications to pre-treat different stem cells to develop "super stem cells" with augmented stemness, functionality, and reparability for diverse clinical applications with better outcomes.}, } @article {pmid38951089, year = {2024}, author = {Zhang, JH and Chen, ZH and Ling, L and Cheng, HM and Zhang, Y and Zhao, JR and Huang, XS}, title = {[Analysis of the characteristics of patients with amyotrophic lateral sclerosis with neuromuscular junction dysfunction prior to motor neuron degeneration].}, journal = {Zhonghua nei ke za zhi}, volume = {63}, number = {7}, pages = {660-665}, doi = {10.3760/cma.j.cn112138-20230811-00049}, pmid = {38951089}, issn = {0578-1426}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Electromyography ; *Motor Neurons/physiology ; Neuromuscular Junction/physiopathology ; Electric Stimulation ; Accessory Nerve/physiopathology ; Male ; Female ; Middle Aged ; }, abstract = {Objective: To investigate the clinical and electrophysiological characteristics of patients with amyotrophic lateral sclerosis (ALS) with positive repetitive nerve stimulation (RNS) test results on the accessory nerve and negative needle electromyography (EMG) test results on the sternocleidomastoid with the goal to enrich the knowledge of disease progression in patients with ALS. Methods: The clinical data of 612 patients diagnosed with ALS at the Neurology Department of the First Medical Center, Chinese PLA General Hospital from June 2016 to August 2022 were collected. In total, 267 cases had undergone EMG tests on the sternocleidomastoid following a positive 3 Hz RNS test result on the accessory nerve, who were selected as the study subjects. The differences in clinical indicators were compared between RNS (+)/EMG (-) group and RNS (+)/EMG (+) group. A binomial distribution model with multiple variables was built to quantitatively analyze the major factors and their effects. Results: At the initial visit, 15.8% of patients with ALS were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid, accounting for 36.3% of RNS (+) patients. The decremental range of the 3 Hz RNS test delivered to the accessory nerve in these patients [-14% (-19%, -12%)] was lower than that in patients with RNS (+)/EMG (+) [-17% (-23%, -13%)] (P<0.05), while the ratio of upper limb onset (64.9%) and non-definite diagnosis (28.9%) were higher [54.7% and 13.5% for patients with RNS (+)/EMG (+), P<0.05]. Furthermore, the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score [40 (37, 42)], body mass index (BMI) [23.8 (22.0, 25.4) kg/m[2]] and forced vital capacity (FVC) [92.8% (76.6%, 103.8%)] were higher in patients with RNS(+)/EMG(+) (P<0.05). The multivariate model suggested that, in patients with RNS (+)/EMG (-), the ratio of upper limb onset to lower limb onset was 1.04, while that of upper limb onset to bulbar onset was 2.02, and that of lower limb onset to bulbar onset was 1.94. The ratio of non-definite ALS to definite ALS was 1.13. The ALSFRS-R score, BMI, and FVC had a protective contribution to the electrophysiological function of the motor neurons. The ratio of the effect size of the ALSFRS-R or BMI to that of FVC was 3.37 and 1.14, respectively. Conclusions: Patients with ALS that were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid had a smaller decremental range of the compound muscle action potential amplitude, and a higher proportion of upper limb onset and non-definite ALS. A higher ALSFRS-R score, BMI, and FVC have a protective effect to the electrophysiological function of motor neurons. The effect size of the ALSFRS-R score is the largest, followed by BMI and FVC.}, } @article {pmid38951432, year = {2024}, author = {Didcote, L and Vitoratou, S and Al-Chalabi, A and Goldstein, LH}, title = {Comparison of in-person vs. remote administration of cognitive screening tools for people with ALS.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {11}, pages = {5309-5317}, pmid = {38951432}, issn = {1590-3478}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; Goldstein/Oct17/892-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Middle Aged ; Aged ; *Neuropsychological Tests ; Videoconferencing ; Cognition Disorders/diagnosis/etiology ; Cognitive Dysfunction/diagnosis/etiology ; }, abstract = {OBJECTIVE: This study investigated whether cognitive screening tools used for people with amyotrophic lateral sclerosis (pwALS) are affected by the screen being administered face-to-face or remotely online. It also investigated whether demographic variables predicted total cognitive screen scores.

METHODS: The cognitive component of the Edinburgh Cognitive and Behavioural ALS Screen (ECASc), the cognitive component of the ALS Cognitive Behavioural Screen (ALS-CBSc), and the Mini Addenbrooke's Cognitive Examination (Mini-ACE) were administered to 41 pwALS and 41 controls face-to-face. Versions of the cognitive screens designed to be administered remotely were administered to 57 pwALS and 44 controls via videoconferencing methods. Backwards stepwise linear regressions were conducted to assess whether total scores on the ECASc, ALS-CBSc, and Mini-ACE scores were predicted by administration mode (face-to-face or remote) or demographic variables.

RESULTS: Mode of administration significantly affected scores on the ECASc and ALS-CBSc; remote administration was associated with better total scores. Administration mode did not significantly affect Mini-ACE scores. All cognitive screens were significantly affected by IQ scores; higher IQ scores predicted better screening tool scores. Only ECASc scores were significantly affected by age, with older age predicting poorer scores. Being female was associated with better Mini-ACE scores; sex did not predict ECASc and ALS-CBSc scores.

CONCLUSIONS: Our results suggest that videoconferencing versions of the ECASc and ALS-CBSc may function differently to the original, face-to-face versions. There are advantages to using remote versions of cognitive screening tools but clinicians and researchers who use them should consider that they may not yield equivalent scores.}, } @article {pmid38951798, year = {2024}, author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and , and Aitman, TJ and Santoyo-Lopez, J and , and Mitsumoto, H and , and , and , and Goldstein, DB and Harms, MB}, title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.}, journal = {BMC genomics}, volume = {25}, number = {1}, pages = {651}, pmid = {38951798}, issn = {1471-2164}, support = {P01 AG007232/AG/NIA NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; T32 HL144442/HL/NHLBI NIH HHS/United States ; }, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; Ethnicity/genetics ; Genetic Predisposition to Disease ; Genetic Variation ; European People ; East Asian People ; African People ; Hispanic or Latino ; Middle Eastern People ; South Asian People ; Receptors, Peptide ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.

METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.

RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10[-39]; OR = 4.73, p = 2 × 10[-10]; OR = 2.3, p = 7.49 × 10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10[-7]), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10[-6]).

CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.}, } @article {pmid38953009, year = {2024}, author = {Rostás, R and Fekete, I and Horváth, L and Márton, S and Fekete, K}, title = {Correlation of single-fiber electromyography studies and functional status in patients with amyotrophic lateral sclerosis.}, journal = {Open medicine (Warsaw, Poland)}, volume = {19}, number = {1}, pages = {20240990}, pmid = {38953009}, issn = {2391-5463}, abstract = {OBJECTIVE: Our aim was to examine the significance of single-fiber electromyography (SFEMG) in patients diagnosed with amyotrophic lateral sclerosis (ALS) and determine the best correlating parameter with SFEMG parameters and clinical scales across different muscles including facial muscles.

METHODS: SFEMG examinations were conducted on the extensor digitorum (ED), frontalis, and orbicularis oculi muscles. Mean jitter, percentage of increased jitter, fiber density (FD), and impulse blocking percentage were compared to reference values and functional scales.

RESULTS: Significant differences (p < 0.001) were observed between the patients' SFEMG results and reference values in all muscles. Significant correlations were found between SFEMG parameters and clinical scales, particularly when considering both FD and jitter. A notable value of the ALS Functional Rating Scale Revised (ALSFRS-R) was detected in all muscles: 31 points in the ED muscle, 30 in the orbicularis oculi muscle, and 31 in the frontalis muscle. Below this ALSFRS-R threshold, the percentage of increased jitter was higher, while FD remained relatively low.

CONCLUSION: SFEMG examination emerges as a valuable tool for better understanding ALS and holds potential for assessing prognosis. Combined jitter and FD analysis showed the strongest correlation with clinical scales. In addition to the ED muscle, the orbicularis oculi muscle may be important in the assessment.}, } @article {pmid38954254, year = {2025}, author = {Wang, Y and Wang, Y and Yin, H and Xiao, Z and Ren, Z and Ma, X and Zhang, J and Fu, X and Zhang, F and Zeng, L}, title = {BI1 Activates Autophagy and Mediates TDP43 to Regulate ALS Pathogenesis.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {988-1030}, pmid = {38954254}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Autophagy/physiology ; Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; Humans ; Mitochondria/metabolism ; Apoptosis Regulatory Proteins/metabolism ; Apoptosis ; Mice ; Neuromuscular Junction/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disease in adults. Currently, there are no known drugs or clinical approaches that have demonstrated efficacy in treating ALS. Mitochondrial function and autophagy have been identified as crucial mechanisms in the development of ALS. While Bax inhibitor 1 (BI1) has been implicated in neurodegenerative diseases, its exact mechanism remains unknown. This study investigates the therapeutic impact of BI1 overexpression on ALS both in vivo and in vitro, revealing its ability to mitigate SOD1[G93A]-induced apoptosis, nuclear damage, mitochondrial dysfunction, and axonal degeneration of motor neurons. At the same time, BI1 prolongs onset time and lifespan of ALS mice, improves motor function, and alleviates neuronal damage, muscle damage, neuromuscular junction damage among other aspects. The findings indicate that BI1 can inhibit pathological TDP43 morphology and initially stimulate autophagy through interaction with TDP43. This study establishes a solid theoretical foundation for understanding the regulation of autophagy by BI1 and TDP43 while shedding light on the pathogenesis of ALS through their interaction - offering new concepts and targets for clinical implementation and drug development.}, } @article {pmid38954274, year = {2024}, author = {Faltracco, V and Poletti, B and Aiello, EN and Telesca, A and Bella, ED and Bersano, E and Silani, V and Ticozzi, N and Lauria, G and Consonni, M}, title = {Emotional awareness in patients with amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {10}, pages = {5043-5046}, pmid = {38954274}, issn = {1590-3478}, support = {2015-0023//Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia/ ; 1157625//Fondo Europeo di Sviluppo Regionale, Regione Lombardia (POR FESR 2014-2020)/ ; RRC//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; *Affective Symptoms/etiology/physiopathology ; Middle Aged ; Aged ; Emotions/physiology ; Awareness/physiology ; Neuropsychological Tests ; Cohort Studies ; }, abstract = {INTRODUCTION: It has been recently acknowledged that deficits in experiencing and processing one's own emotions, also termed alexithymia, may possibly feature the frontotemporal-spectrum disorders. This study aims to determine whether alexithymia could be included within the frontotemporal syndromes of amyotrophic lateral sclerosis (ALS).

METHODS: Alexithymic traits were estimated in a cohort of 68 non-demented ALS patients with the 20-item Toronto Alexithymia Scale (TAS-20). Patients were assessed for the identification of motor-phenotypes and frontotemporal syndromes based on current classification criteria. Spearman's coefficients explored the correlates of TAS-20 measures with motor-functional profiles, global cognitive, social-cognitive (emotion recognition and empathy) and behavioral status.

RESULTS: Abnormal TAS-20 scores were found in 13% of patients, and their distribution did not vary within motor and frontotemporal phenotypes. Significant associations were detected between TAS-20 and executive (p ≤ .011), memory (p = .006), state-anxiety (p ≤ .013) and depression measures (p ≤ .010). By contrast, TAS-20 scores were unrelated to social-cognitive performances, dysexecutive and apathetic profiles. Disease duration was the only motor-functional feature being related to the TAS-20 (p ≤ .008).

CONCLUSIONS: Alexithymia of potential clinical relevance occur in a minority of ALS patients, and its neuropsychological correlates mostly resemble those featuring the general population. Hence, it is unlikely that alexithymia is a specific feature of frontotemporal-spectrum characterizing ALS, rather it could be an expression of psychogenic factors as a reaction to the disease.}, } @article {pmid38955238, year = {2024}, author = {Wang, M and Tang, Z}, title = {No causal relationship between serum urate and neurodegenerative diseases: A Mendelian randomization study.}, journal = {Experimental gerontology}, volume = {194}, number = {}, pages = {112503}, doi = {10.1016/j.exger.2024.112503}, pmid = {38955238}, issn = {1873-6815}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Uric Acid/blood ; *Neurodegenerative Diseases/genetics/blood ; *Amyotrophic Lateral Sclerosis/genetics/blood ; *Genome-Wide Association Study ; Parkinson Disease/genetics/blood ; Multiple Sclerosis/genetics/blood ; Alzheimer Disease/genetics/blood ; Polymorphism, Single Nucleotide ; Causality ; }, abstract = {OBJECTIVE: Observational studies have shown that increased serum urate is associated with a lower risk of neurodegenerative diseases (NDs), but the causality remains unclear. We employed a two-sample Mendelian randomization (MR) approach to assess the causal relationship between serum urate and four common subtypes of NDs, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS).

METHODS: Serum urate data came from the CKDGen Consortium. GWAS data for PD, AD, ALS, and MS were obtained from four databases in the primary analysis and then acquired statistics from the FinnGen consortium for replication and meta-analysis. Inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods were applied in the MR analyses. Pleiotropic effects, heterogeneity, and leave-one-out analyses were evaluated to validate the results.

RESULTS: There was no evidence for the effect of serum urate on PD (OR: 1.00, 95 % CI: 0.90-1.11, P = 0.97), AD (OR: 1.02, 95 % CI: 1.00-1.04, P = 0.06), ALS (OR: 1.05, 95 % CI: 0.97-1.13, P = 0.22), and MS (OR: 1.01, 95 % CI: 0.89-1.14, P = 0.90) risk when combined with the FinnGen consortium, neither was any evidence of pleiotropy detected between the instrumental variables (IVs).

CONCLUSION: The MR analysis suggested that serum urate may not be causally associated with a risk of PD, AD, ALS, and MS.}, } @article {pmid38956107, year = {2024}, author = {Opie-Martin, S and Iacoangeli, A and Topp, SD and Abel, O and Mayl, K and Mehta, PR and Shatunov, A and Fogh, I and Bowles, H and Limbachiya, N and Spargo, TP and Al-Khleifat, A and Williams, KL and Jockel-Balsarotti, J and Bali, T and Self, W and Henden, L and Nicholson, GA and Ticozzi, N and McKenna-Yasek, D and Tang, L and Shaw, PJ and Chio, A and Ludolph, A and Weishaupt, JH and Landers, JE and Glass, JD and Mora, JS and Robberecht, W and Damme, PV and McLaughlin, R and Hardiman, O and van den Berg, L and Veldink, JH and Corcia, P and Stevic, Z and Siddique, N and Silani, V and Blair, IP and Fan, DS and Esselin, F and de la Cruz, E and Camu, W and Basak, NA and Siddique, T and Miller, T and Brown, RH and Al-Chalabi, A and Shaw, CE}, title = {Author Correction: The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5560}, doi = {10.1038/s41467-024-49938-y}, pmid = {38956107}, issn = {2041-1723}, } @article {pmid38956470, year = {2024}, author = {Cai, H and Jiang, H and Xie, D and Lai, Z and Wu, J and Chen, M and Yang, Z and Xu, R and Zeng, S and Ma, H}, title = {Enhancing image quality in computed tomography angiography follow-ups after endovascular aneurysm repair: a comparative study of reconstruction techniques.}, journal = {BMC medical imaging}, volume = {24}, number = {1}, pages = {162}, pmid = {38956470}, issn = {1471-2342}, support = {82202217//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Retrospective Studies ; Female ; *Computed Tomography Angiography/methods ; Aged ; Male ; *Endovascular Procedures/methods ; *Artifacts ; Middle Aged ; Aortic Aneurysm, Abdominal/surgery/diagnostic imaging ; Deep Learning ; Radiographic Image Interpretation, Computer-Assisted/methods ; Stents ; Endovascular Aneurysm Repair ; }, abstract = {BACKGROUND: The image quality of computed tomography angiography (CTA) images following endovascular aneurysm repair (EVAR) is not satisfactory, since artifacts resulting from metallic implants obstruct the clear depiction of stent and isolation lumens, and also adjacent soft tissues. However, current techniques to reduce these artifacts still need further advancements due to higher radiation doses, longer processing times and so on. Thus, the aim of this study is to assess the impact of utilizing Single-Energy Metal Artifact Reduction (SEMAR) alongside a novel deep learning image reconstruction technique, known as the Advanced Intelligent Clear-IQ Engine (AiCE), on image quality of CTA follow-ups conducted after EVAR.

MATERIALS: This retrospective study included 47 patients (mean age ± standard deviation: 68.6 ± 7.8 years; 37 males) who underwent CTA examinations following EVAR. Images were reconstructed using four different methods: hybrid iterative reconstruction (HIR), AiCE, the combination of HIR and SEMAR (HIR + SEMAR), and the combination of AiCE and SEMAR (AiCE + SEMAR). Two radiologists, blinded to the reconstruction techniques, independently evaluated the images. Quantitative assessments included measurements of image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), the longest length of artifacts (AL), and artifact index (AI). These parameters were subsequently compared across different reconstruction methods.

RESULTS: The subjective results indicated that AiCE + SEMAR performed the best in terms of image quality. The mean image noise intensity was significantly lower in the AiCE + SEMAR group (25.35 ± 6.51 HU) than in the HIR (47.77 ± 8.76 HU), AiCE (42.93 ± 10.61 HU), and HIR + SEMAR (30.34 ± 4.87 HU) groups (p < 0.001). Additionally, AiCE + SEMAR exhibited the highest SNRs and CNRs, as well as the lowest AIs and ALs. Importantly, endoleaks and thrombi were most clearly visualized using AiCE + SEMAR.

CONCLUSIONS: In comparison to other reconstruction methods, the combination of AiCE + SEMAR demonstrates superior image quality, thereby enhancing the detection capabilities and diagnostic confidence of potential complications such as early minor endleaks and thrombi following EVAR. This improvement in image quality could lead to more accurate diagnoses and better patient outcomes.}, } @article {pmid38956726, year = {2024}, author = {Ye, S and Chen, L and Murphy, D and Wu, J and Zhang, H and Liu, H and Zou, B and Hou, G and Zhang, N and Yin, T and Smith, RA and Fan, D}, title = {Validation of the Center for Neurologic Study Bulbar Function Scale-Chinese version in a population with amyotrophic lateral sclerosis.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {246}, pmid = {38956726}, issn = {1750-1172}, support = {82001350//National Natural Science Foundation of China/ ; 81873784//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; YCXJ-JZ-2022-007//Beijing E-Town Cooperation & Development Foundation/ ; YJXJ-JZ-2021-0014//Beijing E-Town Cooperation & Development Foundation/ ; DL2019002//PUTH Cohort Construction Project/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology ; }, abstract = {OBJECTIVE: The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) was specifically designed as a self-reported measure of bulbar function. The purpose of this research was to validate the Chinese translation of the CNS-BFSC as an effective measurement for the Chinese population with ALS.

METHODS: A total of 111 ALS patients were included in this study. The CNS-BFSC score, three bulbar function items from the ALSFRS-R, and visual analog scale (VAS) score for speech, swallowing and salivation were assessed in the present study. Forty-six ALS patients were retested on the same scale 5-10 days after the first evaluation.

RESULTS: The CNS-BFSC sialorrhea, speech and swallowing subscores were separately correlated with the VAS subscores (p < 0.001). The CNS-BFSC total score and sialorrhea and speech scores were significantly correlated with the ALSFRS-R bulbar subscore (p < 0.001). The CNS-BFSC total score and ALSFRS-R bulbar subscale score were highly predictive of a clinician diagnosis of impaired bulbar function (area under the receiver operating characteristic curve, 0.947 and 0.911, respectively; p < 0.001). A cutoff value for the CNS-BFSC total score was selected by maximizing Youden's index; this cutoff score was 33, with 86.4% sensitivity and 93.3% specificity. The CNS-BFSC total score and the sialorrhea, speech and swallowing subscores had good-retest reliability (p > 0.05). The Cronbach's α of the CNS-BFSC was 0.972.

CONCLUSION: The Chinese version of the CNS-BFSC has acceptable efficacy and reliability for the assessment of bulbar dysfunction in ALS patients.}, } @article {pmid38957123, year = {2025}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Mohammadi, S and Batouli, SAH}, title = {Quantitative susceptibility mapping in amyotrophic lateral sclerosis: automatic quantification of the magnetic susceptibility in the subcortical nuclei.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {73-84}, doi = {10.1080/21678421.2024.2372648}, pmid = {38957123}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Male ; Female ; Middle Aged ; *Magnetic Resonance Imaging/methods ; Adult ; *Brain Mapping/methods ; Subthalamic Nucleus/diagnostic imaging ; Aged ; }, abstract = {OBJECTIVE: Previous studies have suggested a link between dysregulation of cortical iron levels and neuronal loss in amyotrophic lateral sclerosis (ALS) patients. However, few studies have reported differences in quantitative susceptibility mapping (QSM) values in subcortical nuclei between patients with ALS and healthy controls (HCs).

METHODS: MRI was performed using a 3 Tesla Prisma scanner (64-channel head coil), including 3D T1-MPRAGE and multi-echo 3D GRE for QSM reconstruction. Automated QSM segmentation was used to measure susceptibility values in the subcortical nuclei, which were compared between the groups. Correlations with clinical scales were analyzed. Group comparisons were performed using independent t-tests, with p < 0.05 considered significant. Correlations were assessed using Pearson's correlation, with p < 0.05 considered significant. Cohen's d was reported to compare the standardized mean difference (SMD) of QSM.

RESULTS: Twelve patients with limb-onset ALS (mean age 48.7 years, 75% male) and 13 age-, sex-, and handedness-matched HCs (mean age 44.6 years, 69% male) were included. Compared to HCs, ALS patients demonstrated significantly lower susceptibility in the left caudate nucleus (CN) (SMD = -0.845), right CN (SMD = -0.851), whole CN (SMD = -1.016), and left subthalamic nucleus (STN) (SMD = -1.000). Susceptibility in the left putamen (SMD = -0.857), left thalamus (SMD = -1.081), and whole thalamus (SMD = -0.968) was significantly higher in the patients. The susceptibility of the substantia nigra (SN), CN, and pulvinar was positively correlated with disease duration.

CONCLUSIONS: QSM detects abnormal iron accumulation patterns in the subcortical gray matter of ALS patients, which correlates with disease characteristics, supporting its potential as a neuroimaging biomarker.}, } @article {pmid38958573, year = {2024}, author = {Tu, S and Vucic, S and Kiernan, MC}, title = {Pathological insights derived from neuroimaging in amyotrophic lateral sclerosis: emerging clinical applications.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {577-584}, doi = {10.1097/WCO.0000000000001295}, pmid = {38958573}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Humans ; *Neuroimaging/methods ; Brain/diagnostic imaging/pathology ; }, abstract = {PURPOSE OF REVIEW: Neuroimaging has been instrumental in shaping current understanding of the pathoanatomical signature of amyotrophic lateral sclerosis (ALS) across clinically well defined patient cohorts. The potential utility of imaging as an objective disease marker, however, remains poorly defined.

RECENT FINDINGS: Increasingly advanced quantitative and computational imaging studies have highlighted emerging clinical applications for neuroimaging as a complementary clinical modality for diagnosis, monitoring, and modelling disease propagation. Multimodal neuroimaging has demonstrated novel approaches for capturing primary motor disease. Extra-motor subcortical dysfunction is increasingly recognized as key modulators of disease propagation.

SUMMARY: The neural signature of cortical and subcortical dysfunction in ALS has been well defined at the population level. Objective metrics of focal primary motor dysfunction are increasingly sensitive and translatable to the individual patient level. Integrity of extra-motor subcortical abnormalities are recognized to represent critical pathways of the ALS disease 'connectome', predicting pathological spread. Neuroimaging plays a pivotal role in capturing upper motor neuron pathology in ALS. Their potential clinical role as objective disease markers for disease classification, longitudinal monitoring, and prognosis in ALS have become increasingly well defined.}, } @article {pmid38958608, year = {2024}, author = {Lang, R and Hodgson, RE and Shelkovnikova, TA}, title = {TDP-43 in nuclear condensates: where, how, and why.}, journal = {Biochemical Society transactions}, volume = {52}, number = {4}, pages = {1809-1825}, pmid = {38958608}, issn = {1470-8752}, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *Cell Nucleus/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Biomolecular Condensates/metabolism ; Animals ; Neurodegenerative Diseases/metabolism ; }, abstract = {TDP-43 is an abundant and ubiquitously expressed nuclear protein that becomes dysfunctional in a spectrum of neurodegenerative diseases. TDP-43's ability to phase separate and form/enter biomolecular condensates of varying size and composition is critical for its functionality. Despite the high density of phase-separated assemblies in the nucleus and the nuclear abundance of TDP-43, our understanding of the condensate-TDP-43 relationship in this cellular compartment is only emerging. Recent studies have also suggested that misregulation of nuclear TDP-43 condensation is an early event in the neurodegenerative disease amyotrophic lateral sclerosis. This review aims to draw attention to the nuclear facet of functional and aberrant TDP-43 condensation. We will summarise the current knowledge on how TDP-43 containing nuclear condensates form and function and how their homeostasis is affected in disease.}, } @article {pmid38960099, year = {2024}, author = {Bhandari, UR and Danish, SM and Ahmad, S and Ikram, M and Nadaf, A and Hasan, N and Kesharwani, P and Ahmad, FJ}, title = {New opportunities for antioxidants in amelioration of neurodegenerative diseases.}, journal = {Mechanisms of ageing and development}, volume = {221}, number = {}, pages = {111961}, doi = {10.1016/j.mad.2024.111961}, pmid = {38960099}, issn = {1872-6216}, mesh = {Humans ; *Antioxidants/pharmacology/therapeutic use ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Oxidative Stress/drug effects ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {This comprehensive review elucidates the critical role of antioxidants to mitigate oxidative stress, a common denominator in an array of neurodegenerative disorders. Oxidative stress-induced damage has been linked to the development of diseases such as Alzheimer's, Parkinson's, Huntington's disease and amyotrophic lateral sclerosis. This article examines a wide range of scientific literature and methodically delineates the several methods by which antioxidants exercise their neuroprotective benefits. It also explores into the complex relationship between oxidative stress and neuroinflammation, focusing on how antioxidants can alter signaling pathways and transcription factors to slow neurodegenerative processes. Key antioxidants, such as vitamins C and E, glutathione, and polyphenolic compounds, are tested for their ability to combat reactive oxygen and nitrogen species. The dual character of antioxidants, which operate as both direct free radical scavengers and regulators of cellular redox homeostasis, is investigated in terms of therapeutic potential. Furthermore, the study focuses on new antioxidant-based therapy techniques and their mechanisms including Nrf-2, PCG1α, Thioredoxin etc., which range from dietary interventions to targeted antioxidant molecules. Insights into ongoing clinical studies evaluating antioxidant therapies in neurodegenerative illnesses offer an insight into the translational potential of antioxidant research. Finally, this review summarizes our present understanding of antioxidant processes in neurodegenerative illnesses, providing important possibilities for future study and treatment development.}, } @article {pmid38960473, year = {2024}, author = {R, HC and Datta, A and S, UK and Zayed, H and D, TK and C, GPD}, title = {Decoding genetic and pathophysiological mechanisms in amyotrophic lateral sclerosis and primary lateral sclerosis: A comparative study of differentially expressed genes and implicated pathways in motor neuron disorders.}, journal = {Advances in protein chemistry and structural biology}, volume = {141}, number = {}, pages = {177-201}, doi = {10.1016/bs.apcsb.2023.12.008}, pmid = {38960473}, issn = {1876-1631}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Gene Expression Profiling ; Motor Neuron Disease/genetics/metabolism ; }, abstract = {Motor Neuron Disorders (MNDs), characterized by the degradation and loss of function of motor neurons, are recognized as fatal conditions with limited treatment options and no known cure. The present study aimed to identify the pathophysiological functions and affected genes in patients with MNDs, specifically Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS). The GSE56808 dataset comprised three sample groups: six patients diagnosed with ALS (GSM1369650, GSM1369652, GSM1369654, GSM1369656, GSM1369657, GSM1369658), five patients diagnosed with PLS (GSM1369648, GSM1369649, GSM1369653, GSM1369655, GSM1369659), and six normal controls (GSM1369642, GSM1369643, GSM1369644, GSM1369645, GSM1369646, and GSM1369647). The application of computational analysis of microarray gene expression profiles enabled us to identify 346 significantly differentially expressed genes (DEGs), 169 genes for the ALS sample study, and 177 genes for the PLS sample study. Enrichment was carried out using MCODE, a Cytoscape plugin. Functional annotation of DEGs was carried out via ClueGO/CluePedia (v2.5.9) and further validated via the DAVID database. NRP2, SEMA3D, ROBO3 and, CACNB1, CACNG2 genes were identified as the gene of interest for ALS and PLS sample groups, respectively. Axonal guidance (GO:0007411) and calcium ion transmembrane transport (GO:0070588) were identified to be some of the significantly dysregulated gene ontology (GO) terms, with arrhythmogenic right ventricular cardiomyopathy (KEGG:05412) to be the top relevant KEGG pathway which is affected in MND patients. ROBO3 gene was observed to have distinctive roles in ALS and PLS-affected patients, hinting towards the differential progression of ALS from PLS. The insights derived from our comprehensive analysis accentuate the distinct variances in the underlying molecular pathogenesis of ALS and PLS. Further research should investigate the mechanistic roles of the identified DEGs and molecular pathways, leading to potential targeted therapies for ALS and PLS.}, } @article {pmid38960585, year = {2025}, author = {Dols-Icardo, O and Carbayo, Á and Jericó, I and Blasco-Martínez, O and Álvarez-Sánchez, E and López Pérez, MA and Bernal, S and Rodríguez-Santiago, B and Cusco, I and Turon-Sans, J and Cabezas-Torres, M and Caballero-Ávila, M and Vesperinas, A and Llansó, L and Pagola-Lorz, I and Torné, L and Valle-Tamayo, N and Muñoz, L and Rubio-Guerra, S and Illán-Gala, I and Cortés-Vicente, E and Gelpi, E and Rojas-García, R}, title = {Identification of a pathogenic mutation in ARPP21 in patients with amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {2}, pages = {132-139}, pmid = {38960585}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Female ; Middle Aged ; Spain/epidemiology ; Aged ; *Phosphoproteins/genetics ; *Mutation, Missense/genetics ; Adult ; Pedigree ; Genetic Predisposition to Disease ; Whole Genome Sequencing ; }, abstract = {BACKGROUND AND OBJECTIVE: Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing.

METHODS: We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region.

RESULTS: We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes.

CONCLUSIONS: While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.}, } @article {pmid38961496, year = {2024}, author = {Linse, K and Weber, C and Reilich, P and Schöberl, F and Boentert, M and Petri, S and Rödiger, A and Posa, A and Otto, M and Wolf, J and Zeller, D and Brunkhorst, R and Koch, J and Hermann, A and Großkreutz, J and Schröter, C and Groß, M and Lingor, P and Machetanz, G and Semmler, L and Dorst, J and Lulé, D and Ludolph, A and Meyer, T and Maier, A and Metelmann, M and Regensburger, M and Winkler, J and Schrank, B and Kohl, Z and Hagenacker, T and Brakemeier, S and Weyen, U and Weiler, M and Lorenzl, S and Bublitz, S and Weydt, P and Grehl, T and Kotterba, S and Lapp, HS and Freigang, M and Vidovic, M and Aust, E and Günther, R}, title = {Patients' and caregivers' perception of multidimensional and palliative care in amyotrophic lateral sclerosis - protocol of a German multicentre study.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {34}, pmid = {38961496}, issn = {2524-3489}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal condition that leads to a progressive loss of physical functioning, which results in a high psychosocial burden and organizational challenges related to medical care. Multidimensional and multiprofessional care is advised to meet the complex needs of patients and their families. Many healthcare systems, including Germany, may not be able to meet these needs because non-medical services such as psychological support or social counselling are not regularly included in the care of patients with ALS (pwALS). Specialised neuropalliative care is not routinely implemented nor widely available. Caregivers of pwALS are also highly burdened, but there is still a lack of support services for them.

METHODS: This project aims to assess the perceptions and satisfaction with ALS care in Germany in pwALS and their caregivers. This will be achieved by means of a cross-sectional, multicentre survey. The examination will assess, to which extend the patients' needs in the six domains of physical, psychological, social, spiritual, practical and informational are being met by current care structures. This assessment will be linked to mental well-being, subjective quality of life, attitudes toward life-sustaining measures and physician-assisted suicide, and caregiver burden. The study aims to recruit 500 participants from nationwide ALS centres in order to draw comprehensive conclusions for Germany. A total of 29 centres, mostly acquired via the clinical and scientific German Network for Motor Neuron Diseases (MND-NET), will take part in the project, 25 of which have already started recruitment.

PERSPECTIVE: It is intended to provide data-based starting points on how current practice of care in Germany is perceived pwALS and their caregivers and how it can be improved according to their needs. Planning and initiation of the study has been completed.

TRIAL REGISTRATION: The study is registered at ClinicalTrails.gov; NCT06418646.}, } @article {pmid38963079, year = {2024}, author = {Naruse, H and Iseki, C and Mitsui, J and Miki, J and Nagasawa, H and Kurokawa, K and Kobayashi, R and Sato, H and Goto, J and Satake, W and Ishiura, H and Tsuji, S and Ohta, Y and Toda, T}, title = {A novel TBK1 loss-of-function variant associated with ALS and parkinsonism phenotypes.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {791-794}, doi = {10.1080/21678421.2024.2374374}, pmid = {38963079}, issn = {2167-9223}, mesh = {Humans ; *Protein Serine-Threonine Kinases/genetics ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Parkinsonian Disorders/genetics ; Male ; Female ; Middle Aged ; *Phenotype ; Loss of Function Mutation/genetics ; Pedigree ; Aged ; Adult ; }, abstract = {Loss-of-function (LoF) variants in the TANK binding kinase 1 (TBK1) gene are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we present the first familial cases of ALS and parkinsonism associated with a novel TBK1 variant. We describe two siblings: one diagnosed with classical ALS and the other with a unique syndrome overlapping ALS and parkinsonism. Comprehensive clinical and imaging evaluations supported these diagnoses. Genetic analysis through whole-genome sequencing revealed a previously unknown heterozygous splice site variant in TBK1. Functional assessments demonstrated that this splice site variant leads to abnormal splicing and subsequent degradation of the mutated TBK1 allele by nonsense-mediated decay, confirming its pathogenic impact. Our findings suggest a broader involvement of TBK1 in neurodegenerative diseases and underscore the need for further research into TBK1's role, advocating for screening for TBK1 variants in similar familial cases.}, } @article {pmid38963090, year = {2024}, author = {Pearson, K and Dobak, S}, title = {Current practices in the nutrition management of people with amyotrophic lateral sclerosis (ALS): a survey of U.S. ALS care teams.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {653-660}, doi = {10.1080/21678421.2024.2374382}, pmid = {38963090}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy ; Cross-Sectional Studies ; United States/epidemiology ; Male ; Patient Care Team ; Female ; Surveys and Questionnaires ; Nutrition Therapy/methods ; Nutritionists/statistics & numerical data ; }, abstract = {OBJECTIVE: To assess current practices of U.S. professionals providing outpatient ALS nutrition care.

METHODS: A cross-sectional survey assessing nutrition care practices was distributed in February/March 2023 through electronic mailing lists of relevant professional organizations.

RESULTS: Of the 87 professionals completing the survey, 85.1% were registered dietitians and 50.6% had five or fewer years of experience in ALS care. Many (44.2%) professionals reported receiving no training on the nutrition care of people with ALS (PALS), and 40.2% reported having no other ALS dietitians in their close network. Methods utilized to estimate calorie and protein requirements in PALS varied widely. Although 95.4% of respondents reported that their clinic's dietitian participates in feeding tube discussions, many practitioners may be waiting until ALS symptoms negatively impact PALS' breathing, eating, swallowing, or weight to begin discussing feeding tubes. Additionally, few professionals reported institutional practices conducive for refeeding syndrome prevention or monitoring.

CONCLUSIONS: Many professionals providing outpatient nutrition care to PALS possess limited experience, received insufficient training, and are not connected to other ALS dietitians. Specific nutrition care practices, including nutrient need estimation, vary widely among health professionals. Practices surrounding feeding tube discussions and refeeding syndrome may be suboptimal at many institutions. These findings highlight the need for initiatives that educate and connect practitioners providing nutrition care to PALS.}, } @article {pmid38963135, year = {2024}, author = {Turano, E and Virla, F and Scambi, I and Dabrowska, S and Bankole, O and Mariotti, R}, title = {Adipose mesenchymal stem cells-derived extracellular vesicles exert their preferential action in damaged central sites of SOD1 mice rather than peripherally.}, journal = {European journal of histochemistry : EJH}, volume = {68}, number = {3}, pages = {}, pmid = {38963135}, issn = {2038-8306}, mesh = {Animals ; *Extracellular Vesicles/metabolism ; *Mesenchymal Stem Cells/metabolism ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/therapy/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Adipose Tissue/metabolism ; Motor Neurons/metabolism ; Neuromuscular Junction/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving motor neuron (MN) loss in the motor cortex, brainstem and spinal cord leading to progressive paralysis and death. Due to the pathogenetic complexity, there are no effective therapies available. In this context the use of mesenchymal stem cells and their vesicular counterpart is an emerging therapeutic strategy to counteract neurodegeneration. The extracellular vesicles derived from adipose stem cells (ASC-EVs) recapitulate and ameliorate the neuroprotective effect of stem cells and, thanks to their small dimensions, makes their use suitable to develop novel therapeutic approaches for neurodegenerative diseases as ALS. Here we investigate a therapeutic regimen of ASC-EVs injection in SOD1(G93A) mice, the most widely used murine model of ALS. Repeated intranasal administrations of high doses of ASC-EVs were able to ameliorate motor performance of injected SOD1(G93A) mice at the early stage of the disease and produce a significant improvement at the end-stage in the lumbar MNs rescue. Moreover, ASC-EVs preserve the structure of neuromuscular junction without counteracting the muscle atrophy. The results indicate that the intranasal ASC-EVs administration acts in central nervous system sites rather than at peripheral level in SOD1(G93A) mice. These considerations allow us to identify future applications of ASC-EVs that involve different targets simultaneously to maximize the clinical and neuropathological outcomes in ALS in vivo models.}, } @article {pmid38963497, year = {2024}, author = {Yu, G and Bai, Y and Zhang, ZY}, title = {Valosin-Containing Protein (VCP)/p97 Oligomerization.}, journal = {Sub-cellular biochemistry}, volume = {104}, number = {}, pages = {485-501}, pmid = {38963497}, issn = {0306-0225}, support = {R01 CA069202/CA/NCI NIH HHS/United States ; }, mesh = {*Valosin Containing Protein/metabolism/genetics/chemistry ; Humans ; Protein Multimerization ; Animals ; Mutation ; Frontotemporal Dementia/genetics/metabolism ; Adenosine Triphosphatases/metabolism/genetics/chemistry ; Osteitis Deformans/genetics/metabolism ; Cell Cycle Proteins/metabolism/genetics/chemistry ; Myositis, Inclusion Body/genetics/metabolism ; Muscular Dystrophies, Limb-Girdle ; }, abstract = {Valosin-containing protein (VCP), also known as p97, is an evolutionarily conserved AAA+ ATPase essential for cellular homeostasis. Cooperating with different sets of cofactors, VCP is involved in multiple cellular processes through either the ubiquitin-proteasome system (UPS) or the autophagy/lysosomal route. Pathogenic mutations frequently found at the interface between the NTD domain and D1 ATPase domain have been shown to cause malfunction of VCP, leading to degenerative disorders including the inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS), and cancers. Therefore, VCP has been considered as a potential therapeutic target for neurodegeneration and cancer. Most of previous studies found VCP predominantly exists and functions as a hexamer, which unfolds and extracts ubiquitinated substrates from protein complexes for degradation. However, recent studies have characterized a new VCP dodecameric state and revealed a controlling mechanism of VCP oligomeric states mediated by the D2 domain nucleotide occupancy. Here, we summarize our recent knowledge on VCP oligomerization, regulation, and potential implications of VCP in cellular function and pathogenic progression.}, } @article {pmid38963716, year = {2024}, author = {Lima, PLGSB and Couto, EM and Nóbrega, PR}, title = {Response letter to: a homozygous p.Val120Leu (c.358G > C) SOD1 mutation led to slowly progressive amyotrophic lateral sclerosis in a Brazilian family.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {803-804}, doi = {10.1080/21678421.2024.2374372}, pmid = {38963716}, issn = {2167-9223}, } @article {pmid38964584, year = {2024}, author = {Peters, S and Bouma, F and Hoek, G and Janssen, N and Vermeulen, R}, title = {Air pollution exposure and mortality from neurodegenerative diseases in the Netherlands: A population-based cohort study.}, journal = {Environmental research}, volume = {259}, number = {}, pages = {119552}, doi = {10.1016/j.envres.2024.119552}, pmid = {38964584}, issn = {1096-0953}, mesh = {Humans ; Netherlands/epidemiology ; *Air Pollution/adverse effects/analysis ; Male ; *Air Pollutants/analysis/adverse effects ; *Neurodegenerative Diseases/mortality/chemically induced/epidemiology ; Middle Aged ; Female ; Cohort Studies ; *Environmental Exposure/adverse effects ; Aged ; *Particulate Matter/analysis/adverse effects ; Adult ; }, abstract = {BACKGROUND: Long-term exposure to ambient air pollution has been linked with all-cause mortality and cardiovascular and respiratory diseases. Suggestive associations between ambient air pollutants and neurodegeneration have also been reported, but due to the small effect and relatively rare outcomes evidence is yet inconclusive. Our aim was to investigate the associations between long-term air pollution exposure and mortality from neurodegenerative diseases.

METHODS: A Dutch national cohort of 10.8 million adults aged ≥30 years was followed from 2013 until 2019. Annual average concentrations of air pollutants (ultra-fine particles (UFP), nitrogen dioxide (NO2), fine particles (PM2.5 and PM10) and elemental carbon (EC)) were estimated at the home address at baseline, using land-use regression models. The outcome variables were mortality due to amyotrophic lateral sclerosis (ALS), Parkinson's disease, non-vascular dementia, Alzheimer's disease, and multiple sclerosis (MS). Hazard ratios (HR) were estimated using Cox models, adjusting for individual and area-level socio-economic status covariates.

RESULTS: We had a follow-up of 71 million person-years. The adjusted HRs for non-vascular dementia were significantly increased for NO2 (1.03; 95% confidence interval (CI) 1.02-1.05) and PM2.5 (1.02; 95%CI 1.01-1.03) per interquartile range (IQR; 6.52 and 1.47 μg/m[3], respectively). The association with PM2.5 was also positive for ALS (1.02; 95%CI 0.97-1.07). These associations remained positive in sensitivity analyses and two-pollutant models. UFP was not associated with any outcome. No association with air pollution was found for Parkinson's disease and MS. Inverse associations were found for Alzheimer's disease.

CONCLUSION: Our findings, using a cohort of more than 10 million people, provide further support for associations between long-term exposure to air pollutants (PM2.5 and particularly NO2) and mortality of non-vascular dementia. No associations were found for Parkinson and MS and an inverse association was observed for Alzheimer's disease.}, } @article {pmid38965379, year = {2024}, author = {Jacob, SM and Lee, S and Kim, SH and Sharkey, KA and Pfeffer, G and Nguyen, MD}, title = {Brain-body mechanisms contribute to sexual dimorphism in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {8}, pages = {475-494}, pmid = {38965379}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/epidemiology/metabolism ; *Sex Characteristics ; Male ; Female ; Animals ; Brain/metabolism/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of human motor neuron disease. It is characterized by the progressive degeneration of upper and lower motor neurons, leading to generalized motor weakness and, ultimately, respiratory paralysis and death within 3-5 years. The disease is shaped by genetics, age, sex and environmental stressors, but no cure or routine biomarkers exist for the disease. Male individuals have a higher propensity to develop ALS, and a different manifestation of the disease phenotype, than female individuals. However, the mechanisms underlying these sex differences remain a mystery. In this Review, we summarize the epidemiology of ALS, examine the sexually dimorphic presentation of the disease and highlight the genetic variants and molecular pathways that might contribute to sex differences in humans and animal models of ALS. We advance the idea that sexual dimorphism in ALS arises from the interactions between the CNS and peripheral organs, involving vascular, metabolic, endocrine, musculoskeletal and immune systems, which are strikingly different between male and female individuals. Finally, we review the response to treatments in ALS and discuss the potential to implement future personalized therapeutic strategies for the disease.}, } @article {pmid38965709, year = {2024}, author = {Arends, S and Drenthen, J and de Koning, L and van den Bergh, P and Hadden, RDM and Kuwabara, S and Reisin, RC and Shahrizaila, N and Ajroud-Driss, S and Antonini, G and Attarian, S and Balducci, C and Bertorini, T and Brannagan, TH and Cavaletti, G and Chao, CC and Chavada, G and Dillmann, KU and Dimachkie, MM and Galassi, G and Gutiérrez-Gutiérrez, G and Harbo, T and Islam, B and Islam, Z and Katzberg, H and Kusunoki, S and Manganelli, F and Miller, JAL and Pardo, J and Pereon, Y and Rajabally, YA and Sindrup, S and Stettner, M and Uncini, A and Verhamme, C and Vytopil, M and Waheed, W and Jacobs, BC and Cornblath, DR and , }, title = {Electrodiagnostic subtyping in Guillain-Barré syndrome patients in the International Guillain-Barré Outcome Study.}, journal = {European journal of neurology}, volume = {31}, number = {9}, pages = {e16335}, pmid = {38965709}, issn = {1468-1331}, mesh = {Humans ; *Guillain-Barre Syndrome/diagnosis/classification/physiopathology ; *Neural Conduction/physiology ; *Electrodiagnosis/methods ; Male ; Female ; Middle Aged ; Adult ; Amyotrophic Lateral Sclerosis/diagnosis/classification/physiopathology ; Aged ; Cohort Studies ; }, abstract = {BACKGROUND AND PURPOSE: Various electrodiagnostic criteria have been developed in Guillain-Barré syndrome (GBS). Their performance in a broad representation of GBS patients has not been evaluated. Motor conduction data from the International GBS Outcome Study (IGOS) cohort were used to compare two widely used criterion sets and relate these to diagnostic amyotrophic lateral sclerosis criteria.

METHODS: From the first 1500 patients in IGOS, nerve conduction studies from 1137 (75.8%) were available for the current study. These patients were classified according to nerve conduction studies criteria proposed by Hadden and Rajabally.

RESULTS: Of the 1137 studies, 68.3% (N = 777) were classified identically according to criteria by Hadden and Rajabally: 111 (9.8%) axonal, 366 (32.2%) demyelinating, 195 (17.2%) equivocal, 35 (3.1%) inexcitable and 70 (6.2%) normal. Thus, 360 studies (31.7%) were classified differently. The areas of differences were as follows: 155 studies (13.6%) classified as demyelinating by Hadden and axonal by Rajabally; 122 studies (10.7%) classified as demyelinating by Hadden and equivocal by Rajabally; and 75 studies (6.6%) classified as equivocal by Hadden and axonal by Rajabally. Due to more strictly defined cutoffs fewer patients fulfilled demyelinating criteria by Rajabally than by Hadden, making more patients eligible for axonal or equivocal classification by Rajabally. In 234 (68.6%) axonal studies by Rajabally the revised El Escorial (amyotrophic lateral sclerosis) criteria were fulfilled; in axonal cases by Hadden this was 1.8%.

CONCLUSIONS AND DISCUSSION: This study shows that electrodiagnosis in GBS is dependent on the criterion set utilized, both of which are based on expert opinion. Reappraisal of electrodiagnostic subtyping in GBS is warranted.}, } @article {pmid38966427, year = {2024}, author = {Couturier, N and Hörner, SJ and Nürnberg, E and Joazeiro, C and Hafner, M and Rudolf, R}, title = {Aberrant evoked calcium signaling and nAChR cluster morphology in a SOD1 D90A hiPSC-derived neuromuscular model.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1429759}, pmid = {38966427}, issn = {2296-634X}, abstract = {Familial amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is due to mutations in one of several target genes, including SOD1. So far, clinical records, rodent studies, and in vitro models have yielded arguments for either a primary motor neuron disease, or a pleiotropic pathogenesis of ALS. While mouse models lack the human origin, in vitro models using human induced pluripotent stem cells (hiPSC) have been recently developed for addressing ALS pathogenesis. In spite of improvements regarding the generation of muscle cells from hiPSC, the degree of maturation of muscle cells resulting from these protocols has remained limited. To fill these shortcomings, we here present a new protocol for an enhanced myotube differentiation from hiPSC with the option of further maturation upon coculture with hiPSC-derived motor neurons. The described model is the first to yield a combination of key myogenic maturation features that are consistent sarcomeric organization in association with complex nAChR clusters in myotubes derived from control hiPSC. In this model, myotubes derived from hiPSC carrying the SOD1 D90A mutation had reduced expression of myogenic markers, lack of sarcomeres, morphologically different nAChR clusters, and an altered nAChR-dependent Ca[2+] response compared to control myotubes. Notably, trophic support provided by control hiPSC-derived motor neurons reduced nAChR cluster differences between control and SOD1 D90A myotubes. In summary, a novel hiPSC-derived neuromuscular model yields evidence for both muscle-intrinsic and nerve-dependent aspects of neuromuscular dysfunction in SOD1-based ALS.}, } @article {pmid38966655, year = {2024}, author = {Saito, S and Ikeguchi, R and Kitagawa, K}, title = {Chronic cerebrospinal fluid leak can cause amyotrophic lateral sclerosis mimic.}, journal = {Journal of general and family medicine}, volume = {25}, number = {4}, pages = {237-238}, pmid = {38966655}, issn = {2189-7948}, abstract = {Chronic cerebrospinal fluid leak with spinal cord compression can mimic the symptoms of ALS, with a snake-eyes appearance on MRI.}, } @article {pmid38966756, year = {2024}, author = {Garg, V and Geurten, BRH}, title = {Diving deep: zebrafish models in motor neuron degeneration research.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1424025}, pmid = {38966756}, issn = {1662-4548}, abstract = {In the dynamic landscape of biomedical science, the pursuit of effective treatments for motor neuron disorders like hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA) remains a key priority. Central to this endeavor is the development of robust animal models, with the zebrafish emerging as a prime candidate. Exhibiting embryonic transparency, a swift life cycle, and significant genetic and neuroanatomical congruencies with humans, zebrafish offer substantial potential for research. Despite the difference in locomotion-zebrafish undulate while humans use limbs, the zebrafish presents relevant phenotypic parallels to human motor control disorders, providing valuable insights into neurodegenerative diseases. This review explores the zebrafish's inherent traits and how they facilitate profound insights into the complex behavioral and cellular phenotypes associated with these disorders. Furthermore, we examine recent advancements in high-throughput drug screening using the zebrafish model, a promising avenue for identifying therapeutically potent compounds.}, } @article {pmid38967083, year = {2024}, author = {Nijs, M and Van Damme, P}, title = {The genetics of amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {560-569}, pmid = {38967083}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *C9orf72 Protein/genetics ; *Genetic Predisposition to Disease/genetics ; *RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase/genetics ; Proteins/genetics ; DNA-Binding Proteins/genetics ; Genetic Testing ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) has a strong genetic basis, but the genetic landscape of ALS appears to be complex. The purpose of this article is to review recent developments in the genetics of ALS.

RECENT FINDINGS: Large-scale genetic studies have uncovered more than 40 genes contributing to ALS susceptibility. Both rare variants with variable effect size and more common variants with small effect size have been identified. The most common ALS genes are C9orf72 , SOD1 , TARDBP and FUS . Some of the causative genes of ALS are shared with frontotemporal dementia, confirming the molecular link between both diseases. Access to diagnostic gene testing for ALS has to improve, as effective gene silencing therapies for some genetic subtypes of ALS are emerging, but there is no consensus about which genes to test for.

SUMMARY: Our knowledge about the genetic basis of ALS has improved and the first effective gene silencing therapies for specific genetic subtypes of ALS are underway. These therapeutic advances underline the need for better access to gene testing for people with ALS. Further research is needed to further map the genetic heterogeneity of ALS and to establish the best strategy for gene testing in a clinical setting.}, } @article {pmid38967302, year = {2024}, author = {Sîrbulescu, RF and Nicholson, K and Kawai, K and Hilton, OM and Sobell, D and Jin, G and Verrill, DE and Dwyer, LJ and Xiong, Y and Bachanová, P and Kim, SE and Gallup, S and Gelevski, D and Daley, H and Hernandez Rodriguez, DE and Negre, H and Sturtevant, O and Nikiforow, S and Ritz, J and Chen, YB and Reeves, PM and Sluder, AE and Berry, JD and Sadri-Vakili, G and Cudkowicz, M and Poznansky, MC}, title = {Allogeneic B cell immunomodulatory therapy in amyotrophic lateral sclerosis.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {38}, number = {13}, pages = {e23796}, doi = {10.1096/fj.202302659R}, pmid = {38967302}, issn = {1530-6860}, support = {//Ward Family Foundation/ ; //Vaccine and Immunotherapy Center Innovation Fund/ ; //Vaccine and Immunotherapy Center Education Fund/ ; //Sean M. Healey and AMG Center for ALS/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/immunology ; Animals ; Mice ; Humans ; *B-Lymphocytes/immunology ; Disease Models, Animal ; Mice, Transgenic ; Male ; Female ; Mice, Inbred C57BL ; Immunomodulation ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease. Immune system dysregulation plays an essential role in ALS onset and progression. Our preclinical studies have shown that the administration of exogenous allogeneic B cells improves outcomes in murine models of skin and brain injury through a process termed pligodraxis, in which B cells adopt an immunoregulatory and neuroprotective phenotype in an injured environment. Here, we investigated the effects of B-cell therapy in the SOD1[G93A] mouse preclinical model of ALS and in a person living with ALS. Purified splenic mature naïve B cells from haploidentical donor mice were administered intravenously in SOD1[G93A] mice for a total of 10 weekly doses. For the clinical study in a person with advanced ALS, IgA gammopathy of unclear significance, and B lymphopenia, CD19[+] B cells were positively selected from a healthy haploidentical donor and infused intravenously twice, at a 60-day interval. Repeated intravenous B-cell administration was safe and significantly delayed disease onset, extended survival, reduced cellular apoptosis, and decreased astrogliosis in SOD1[G93A] mice. Repeated B-cell infusion in a person with ALS was safe and did not appear to generate a clinically evident inflammatory response. An improvement of 5 points on the ALSFRS-R scale was observed after the first infusion. Levels of inflammatory markers showed persistent reduction post-infusion. This represents a first demonstration of the efficacy of haploidentical B-cell infusion in the SOD1[G93A] mouse and the safety and feasibility of using purified haploidentical B lymphocytes as a cell-based therapeutic strategy for a person with ALS.}, } @article {pmid38967638, year = {2024}, author = {Garau, J and Garofalo, M and Dragoni, F and Scarian, E and Di Gerlando, R and Diamanti, L and Zucca, S and Bordoni, M and Pansarasa, O and Gagliardi, S}, title = {RNA expression profiling in lymphoblastoid cell lines from mutated and non-mutated amyotrophic lateral sclerosis patients.}, journal = {The journal of gene medicine}, volume = {26}, number = {7}, pages = {e3711}, doi = {10.1002/jgm.3711}, pmid = {38967638}, issn = {1521-2254}, support = {//Ministero della Salute/ ; //Italian Agency for Research on ALS-ARiSLA/ ; //Italian Ministry of Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Gene Expression Profiling ; *Mutation ; *Transcriptome ; Female ; Male ; Middle Aged ; C9orf72 Protein/genetics/metabolism ; Leukocytes, Mononuclear/metabolism ; Superoxide Dismutase-1/genetics ; Cell Line ; Aged ; Gene Expression Regulation ; DNA-Binding Proteins ; RNA-Binding Protein FUS ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of upper and lower motor neurons with an unknown etiology. The difficulty of recovering biological material from patients led to employ lymphoblastoid cell lines (LCLs) as a model for ALS because many pathways, typically located in neurons, are also activated in these cells.

METHODS: To investigate the expression of coding and long non-coding RNAs in LCLs, a transcriptomic profiling of sporadic ALS (SALS) and mutated patients (FUS, TARDBP, C9ORF72 and SOD1) and matched controls was realized. Thus, differentially expressed genes (DEGs) were investigated among the different subgroups of patients. Peripheral blood mononuclear cells (PBMCs) were isolated and immortalized into LCLs via Epstein-Barr virus infection; RNA was extracted, and RNA-sequencing analysis was performed.

RESULTS: Gene expression profiles of LCLs were genetic-background-specific; indeed, only 12 genes were commonly deregulated in all groups. Nonetheless, pathways enriched by DEGs in each group were also compared, and a total of 89 Kyoto Encyclopedia of Genes and Genomes (KEGG) terms were shared among all patients. Eventually, the similarity of affected pathways was also assessed when our data were matched with a transcriptomic profile realized in the PBMCs of the same patients.

CONCLUSIONS: We conclude that LCLs are a good model for the study of RNA deregulation in ALS.}, } @article {pmid38967655, year = {2024}, author = {Müller, P and Draguhn, A and Egorov, AV}, title = {Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {476}, number = {10}, pages = {1445-1473}, pmid = {38967655}, issn = {1432-2013}, support = {HE8155/1-2//Deutsche Forschungsgemeinschaft/ ; EG134/2-1//Deutsche Forschungsgemeinschaft/ ; Treat-ION01GM1907A//Bundesministerium für Bildung und Forschung/ ; College for Clinician Scientists//Else Kröner-Fresenius-Stiftung/ ; }, mesh = {Humans ; Animals ; *Neurons/metabolism/drug effects/physiology ; Sodium Channel Blockers/pharmacology ; Sodium Channels/metabolism/drug effects ; }, abstract = {Persistent sodium current (INaP) is an important activity-dependent regulator of neuronal excitability. It is involved in a variety of physiological and pathological processes, including pacemaking, prolongation of sensory potentials, neuronal injury, chronic pain and diseases such as epilepsy and amyotrophic lateral sclerosis. Despite its importance, neither the molecular basis nor the regulation of INaP are sufficiently understood. Of particular significance is a solid knowledge and widely accepted consensus about pharmacological tools for analysing the function of INaP and for developing new therapeutic strategies. However, the literature on INaP is heterogeneous, with varying definitions and methodologies used across studies. To address these issues, we provide a systematic review of the current state of knowledge on INaP, with focus on mechanisms and effects of this current in the central nervous system. We provide an overview of the specificity and efficacy of the most widely used INaP blockers: amiodarone, cannabidiol, carbamazepine, cenobamate, eslicarbazepine, ethosuximide, gabapentin, GS967, lacosamide, lamotrigine, lidocaine, NBI-921352, oxcarbazepine, phenytoine, PRAX-562, propofol, ranolazine, riluzole, rufinamide, topiramate, valproaic acid and zonisamide. We conclude that there is strong variance in the pharmacological effects of these drugs, and in the available information. At present, GS967 and riluzole can be regarded bona fide INaP blockers, while phenytoin and lacosamide are blockers that only act on the slowly inactivating component of sodium currents.}, } @article {pmid38967881, year = {2024}, author = {Rojas-López, JC and Estrada-Gualdron, PI and Ramírez-Guerrero, S and Velásquez-Cárdenas, MJ and Redondo-Escobar, J and Vargas-Arenas, S and Palacios-Sánchez, L and Palacios-Espinosa, X}, title = {Efficacy of pain management strategies in adults with Amyotrophic Lateral Sclerosis (ALS): A Systematic Review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {12}, pages = {5591-5604}, pmid = {38967881}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Pain Management/methods ; Adult ; Pain/etiology/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness. Presence of pain in ALS patients is heterogeneously reported in studies, and mostly underrepresented in symptom scales. The aim of this study is to evaluate the efficacy of pharmacological and non-pharmacological therapeutic modalities for pain management in patients with ALS. A systematic review was conducted in four databases; PubMed, Scopus, Clinicaltrials.gov, and Cochrane-Ovid. Five randomized controlled clinical trials were included regarding pharmacological and non-pharmacological pain management interventions in adult patients with confirmed diagnosis of ALS in whom pain was objectively evaluated. Risk of bias assessment was evaluated using the RoB2.0 tool. Eligible studies were reported as a descriptive analysis. This systematic review was registered with PROSPERO ID: CRD42024495009. Five clinical trials regarding pain management strategies in ALS were eligible for analysis. Two out of five were non-pharmacological approaches whilst the remaining three provided pharmacological therapies. Of these, Mexiletine was efficient in terms of pain relief, particularly between 600 and 900 mg per day, whereas Mecasin showed no pain relief at both, high and low doses. Non-pharmacological therapies, such as exercise and osteopathic manual treatment also lacked efficacy in regard to pain management. Clinical trials focusing on pain management strategies for ALS patients are limited. Medical professionals, understandably focused on immediate life-threatening aspects, may inadvertently sideline the nuanced and intricate dimension of pain experienced by patients with ALS.}, } @article {pmid38968328, year = {2024}, author = {Gowrishankar, S and Smith, ME and Creber, N and Muzaffar, J and Borsetto, D}, title = {Immunosuppression in stem cell clinical trials of neural and retinal cell types: A systematic review.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0304073}, pmid = {38968328}, issn = {1932-6203}, mesh = {Humans ; *Stem Cell Transplantation/methods ; *Immunosuppression Therapy/methods ; Retina/immunology ; Immunosuppressive Agents/therapeutic use ; Clinical Trials as Topic ; }, abstract = {BACKGROUND: Pharmacologic immunosuppression regimes are commonly employed in stem cell clinical trials to mitigate host immune rejection and promote survival and viability of transplanted cells. Immunosuppression and cell survival has been extensively studied in retinal and spinal tissues. The applicability of stem cell therapy is rapidly expanding to other sensory organs such as the ear and hearing. As regenerative therapy is directed to new areas, a greater understanding of immunosuppression strategies and their efficacy is required to facilitate translation to organ-specific biologic microenvironments.

OBJECTIVE: This systematic review appraises the current literature regarding immunosuppression strategies employed in stem cell trials of retinal and neural cells.

METHODS: This systematic review was performed in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria included studies presenting data on neural or retinal cells as part of an in-human clinical trial that detailed the immunosuppression regime used. Exclusion criteria included non-English language studies, animal studies, review articles, case reports, editorials, and letters. The databases Medline, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to February 2024. Risk of bias was evaluated using the ROBINS-I tool.

RESULTS: Eighteen articles fit the inclusion criteria. Nine articles concerned retinal cells, 5 concerned spinal cord injury, and 4 concerned amyotrophic lateral sclerosis. A multi-drug and short-term immunosuppression regime were commonly employed in the identified studies. Detected immune responses in treated patients were rare. Common immunosuppression paradigms included tacrolimus, mycophenolate mofetil and tapering doses of steroids. Local immunosuppression with steroids was employed in some studies concerning retinal diseases.

DISCUSSION: A short-term course of systemic immunosuppression seemed efficacious for most included studies, with some showing grafted cells viable months to years after immunosuppression had stopped. Longer-term follow-up is required to see if this remains the case. Side effects related to immunosuppression were uncommon.}, } @article {pmid38969143, year = {2024}, author = {Jha, SK and Nelson, VK and Suryadevara, PR and Panda, SP and Pullaiah, CP and Nuli, MV and Kamal, M and Imran, M and Ausali, S and Abomughaid, MM and Srivastava, R and Deka, R and Pritam, P and Gupta, N and Shyam, H and Singh, IK and Pandey, BW and Dewanjee, S and Jha, NK and Jafari, SM}, title = {Cannabidiol and neurodegeneration: From molecular mechanisms to clinical benefits.}, journal = {Ageing research reviews}, volume = {100}, number = {}, pages = {102386}, doi = {10.1016/j.arr.2024.102386}, pmid = {38969143}, issn = {1872-9649}, mesh = {Humans ; *Cannabidiol/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce psycho-motor malfunctions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-β, huntingtin, and tau, and accumulation of the associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation. Cannabidiol (CBD) is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo. CBD has gained attention as a promising drug candidate for the management of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as the clinical applications of CBD in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.}, } @article {pmid38970158, year = {2024}, author = {Li, Z and Wen, J and Wu, W and Dai, Z and Liang, X and Zhang, N and Cheng, Q and Zhang, H}, title = {Causal relationship and shared genes between air pollutants and amyotrophic lateral sclerosis: A large-scale genetic analysis.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {7}, pages = {e14812}, pmid = {38970158}, issn = {1755-5949}, support = {2023CQBSHTB3095//Chongqing Postdoctoral Research Special Funding Project/ ; CSTB2023NSCQBHX0002//Chongqing Postdoctoral Science Foundation/ ; 2023MD734131//China Postdoctoral Science Foundation/ ; 2023RC3074//Hunan Youth Science and Technology Talent Project/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Polymorphism, Single Nucleotide/genetics ; *Genome-Wide Association Study ; *Air Pollutants/adverse effects/toxicity ; *Mendelian Randomization Analysis ; Genetic Predisposition to Disease/genetics ; Particulate Matter/adverse effects ; }, abstract = {OBJECTIVE: Air pollutants have been reported to have a potential relationship with amyotrophic lateral sclerosis (ALS). The causality and underlying mechanism remained unknown despite several existing observational studies. We aimed to investigate the potential causality between air pollutants (PM2.5, NOX, and NO2) and the risk of ALS and elucidate the underlying mechanisms associated with this relationship.

METHODS: The data utilized in our study were obtained from publicly available genome-wide association study data sets, in which single nucleotide polymorphisms (SNPs) were employed as the instrumental variantswith three principles. Two-sample Mendelian randomization and transcriptome-wide association (TWAS) analyses were conducted to evaluate the effects of air pollutants on ALS and identify genes associated with both pollutants and ALS, followed by regulatory network prediction.

RESULTS: We observed that exposure to a high level of PM2.5 (OR: 2.40 [95% CI: 1.26-4.57], p = 7.46E-3) and NOx (OR: 2.35 [95% CI: 1.32-4.17], p = 3.65E-3) genetically increased the incidence of ALS in MR analysis, while the effects of NO2 showed a similar trend but without sufficient significance. In the TWAS analysis, TMEM175 and USP35 turned out to be the genes shared between PM2.5 and ALS in the same direction.

CONCLUSION: Higher exposure to PM2.5 and NOX might causally increase the risk of ALS. Avoiding exposure to air pollutants and air cleaning might be necessary for ALS prevention.}, } @article {pmid38970668, year = {2024}, author = {Ludolph, AC and Dietrich, J and Dreyhaupt, J and Kassubek, J and Del Tredici, K and Rosenbohm, A}, title = {Clinical spreading of muscle weakness in amyotrophic lateral sclerosis (ALS): a study in 910 patients.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5357-5367}, pmid = {38970668}, issn = {1432-1459}, support = {LU 336/15-1//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; *Muscle Weakness/physiopathology/etiology/pathology ; Disease Progression ; Cohort Studies ; Adult ; Germany/epidemiology ; }, abstract = {BACKGROUND: Neuroanatomical staging of sporadic amyotrophic lateral sclerosis (ALS) indicates that neurodegeneration may spread corticofugally.

METHODS: We conducted an observational study to define the initial sites of disease onset and the clinical progression ('spreading patterns') of motor deficits in a cohort of 910 ALS patients in Germany.

RESULTS: Mean age of ALS onset was 59.0 ± 12.6 years for males and 61.2 ± 10.5 years for females, the mean ALSFRS-R was 35.1 ± 9.2, and 7.7% of the cohort reported a family history. Onset of motor symptoms was bulbar/upper limb in 26.8%/35.9%, the right arm initially being slightly more often affected than the left (18.5% vs.16.3%). Testing on concordance of handedness and onset in the dominant arm did not reach significance. Lower limb onset was observed in 37.3%. Unilateral limb onset patients reported horizontal spreading about three times more often than vertical spreading. 71/244 bulbar onset patients reported spreading pattern to the legs, and 17/339 lumbar onset patients reported spreading secondarily to the bulbar region.

DISCUSSION: Our results indicate that, although the phenotype of so-called 'spinal' or 'intraspinal' spreading predominated, we also observed an additional clinical spreading pattern: 29.1% of patients with bulbar onset experienced spreading clinically to the legs (vice versa in 5.0% of lumbar onset patients). For obvious neuroanatomical reasons, this pattern hardly can be explained solely by a 'spinal' or an 'intraspinal' pattern of spreading. Instead, these findings complement insights from previous clinical and clinicopathological studies supporting a cortical initiation of ALS.}, } @article {pmid38971043, year = {2024}, author = {Malmström, N and Öhlén, J and Jakobsson Larsson, B and Nilsson, S and Nygren, I and M Andersen, P and Ozanne, A}, title = {Adolescents' challenging and grief-filled transitions when living with a parent with ALS: A qualitative interpretive study.}, journal = {Social science & medicine (1982)}, volume = {354}, number = {}, pages = {117063}, doi = {10.1016/j.socscimed.2024.117063}, pmid = {38971043}, issn = {1873-5347}, mesh = {Humans ; *Qualitative Research ; *Amyotrophic Lateral Sclerosis/psychology ; Sweden ; *Grief ; Female ; Male ; Adolescent ; Adult ; Adaptation, Psychological ; Child ; Young Adult ; Parents/psychology ; Parent-Child Relations ; }, abstract = {OBJECTIVE: The study aimed to explore the meaning for adolescents of living with a parent with amyotrophic lateral sclerosis (ALS).

METHODS: The design is qualitative. Interviews were conducted between December 2020 and April 2022 with 11 adolescents (8-25 y), living in households with a parent with ALS in Sweden. The analysis was phenomenologically hermeneutical.

RESULTS: The adolescents were in a difficult and exposed situation, especially if the parent had a severe disability and assistant care providers were in the home. Witnessing the gradual loss of the parent in an indefinite battle against time, while still needing them, elicited grief-filled and hard-to-manage emotions. Everyday life was turned upside down, resulting in greater responsibility for the adolescents, not only in helping with household chores and assisting the ill parent, but also in emotionally protecting both parents. It forced the adolescents to mature faster and put their own life on hold, triggering experiences of being limited. This, together with changing family roles yet being more attached to home, reinforced the imbalance in the adolescents' lives. The interpreted whole of the adolescents' narratives revealed that living with a parent with ALS meant a challenging and grieving transition during an already transition-filled adolescence, which left the adolescents struggling to keep a foothold on a life torn apart.

CONCLUSION: The unbalanced life situation may hinder the adolescents' identity formation and emancipation, which are developmentally important for managing a healthy and independent adulthood. The results emphasize the importance of early targeted support to reach this vulnerable group in order to secure their health.}, } @article {pmid38971939, year = {2024}, author = {Gomez, D and Selvaraj, MG and Casas, J and Mathiyazhagan, K and Rodriguez, M and Assefa, T and Mlaki, A and Nyakunga, G and Kato, F and Mukankusi, C and Girma, E and Mosquera, G and Arredondo, V and Espitia, E}, title = {Advancing common bean (Phaseolus vulgaris L.) disease detection with YOLO driven deep learning to enhance agricultural AI.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {15596}, pmid = {38971939}, issn = {2045-2322}, mesh = {*Phaseolus/virology/microbiology ; *Deep Learning ; *Plant Diseases/virology/microbiology ; Agriculture/methods ; Plant Leaves/virology/microbiology ; Africa ; Colombia ; }, abstract = {Common beans (CB), a vital source for high protein content, plays a crucial role in ensuring both nutrition and economic stability in diverse communities, particularly in Africa and Latin America. However, CB cultivation poses a significant threat to diseases that can drastically reduce yield and quality. Detecting these diseases solely based on visual symptoms is challenging, due to the variability across different pathogens and similar symptoms caused by distinct pathogens, further complicating the detection process. Traditional methods relying solely on farmers' ability to detect diseases is inadequate, and while engaging expert pathologists and advanced laboratories is necessary, it can also be resource intensive. To address this challenge, we present a AI-driven system for rapid and cost-effective CB disease detection, leveraging state-of-the-art deep learning and object detection technologies. We utilized an extensive image dataset collected from disease hotspots in Africa and Colombia, focusing on five major diseases: Angular Leaf Spot (ALS), Common Bacterial Blight (CBB), Common Bean Mosaic Virus (CBMV), Bean Rust, and Anthracnose, covering both leaf and pod samples in real-field settings. However, pod images are only available for Angular Leaf Spot disease. The study employed data augmentation techniques and annotation at both whole and micro levels for comprehensive analysis. To train the model, we utilized three advanced YOLO architectures: YOLOv7, YOLOv8, and YOLO-NAS. Particularly for whole leaf annotations, the YOLO-NAS model achieves the highest mAP value of up to 97.9% and a recall of 98.8%, indicating superior detection accuracy. In contrast, for whole pod disease detection, YOLOv7 and YOLOv8 outperformed YOLO-NAS, with mAP values exceeding 95% and 93% recall. However, micro annotation consistently yields lower performance than whole annotation across all disease classes and plant parts, as examined by all YOLO models, highlighting an unexpected discrepancy in detection accuracy. Furthermore, we successfully deployed YOLO-NAS annotation models into an Android app, validating their effectiveness on unseen data from disease hotspots with high classification accuracy (90%). This accomplishment showcases the integration of deep learning into our production pipeline, a process known as DLOps. This innovative approach significantly reduces diagnosis time, enabling farmers to take prompt management interventions. The potential benefits extend beyond rapid diagnosis serving as an early warning system to enhance common bean productivity and quality.}, } @article {pmid38972199, year = {2024}, author = {Rosén, C and Mitre, B and Nellgård, B and Axelsson, M and Constantinescu, R and Andersen, PM and Dalla, K and Blennow, K and Nilsson, G and Zetterberg, H and Rosén, H}, title = {High levels of neurofilament light and YKL-40 in cerebrospinal fluid are related to poor outcome in ALS.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123112}, doi = {10.1016/j.jns.2024.123112}, pmid = {38972199}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/blood ; *Chitinase-3-Like Protein 1/cerebrospinal fluid/blood ; Female ; Male ; *Neurofilament Proteins/cerebrospinal fluid ; Middle Aged ; Aged ; *Biomarkers/cerebrospinal fluid ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Disease Progression ; Adult ; Membrane Glycoproteins ; Receptors, Immunologic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and β, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls. ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPβ and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS.}, } @article {pmid38972779, year = {2024}, author = {Pelaez, MC and Fiore, F and Larochelle, N and Dabbaghizadeh, A and Comaduran, MF and Arbour, D and Minotti, S and Marcadet, L and Semaan, M and Robitaille, R and Nalbantoglu, JN and Sephton, CF and Durham, HD}, title = {Reversal of cognitive deficits in FUS[R521G] amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {5}, pages = {e00388}, pmid = {38972779}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Mice ; *Mice, Transgenic ; Heat-Shock Proteins/genetics/metabolism ; Hydroxylamines/pharmacology/therapeutic use ; Cognitive Dysfunction/drug therapy/metabolism ; Disease Models, Animal ; Spinal Cord/drug effects/metabolism ; Humans ; Mice, Inbred C57BL ; }, abstract = {Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUS[R521G] or SOD1[G93A] to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUS[R521G] mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1[G93A] mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.}, } @article {pmid38973130, year = {2025}, author = {Corcia, P and Guy, N and Pradat, PF and Soriani, MH and Verschueren, A and Couratier, P}, title = {Treatment continuity of amyotrophic lateral sclerosis with available riluzole formulations: state of the art and current challenges in a 'real-world' setting.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {15-21}, doi = {10.1080/21678421.2024.2375330}, pmid = {38973130}, issn = {2167-9223}, mesh = {*Riluzole/therapeutic use/administration & dosage ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; *Neuroprotective Agents/administration & dosage/therapeutic use ; Deglutition Disorders/drug therapy/etiology ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare multisystem neurodegenerative disease leading to death due to respiratory failure. Riluzole was the first disease modifying treatment approved in ALS. Randomized clinical trials showed a significant benefit of riluzole on survival in the months following randomization, with a good safety profile. 'Real-world' studies suggested that the survival benefit of riluzole is substantially greater, with an extended survival ranging between 6 and 19 months. The main limiting associated adverse effects of riluzole are non-severe gastrointestinal complications and an elevation of liver enzymes, observed in 10% of patients. While different classes of drugs have been approved in some countries, riluzole remains the gold standard of therapy. Dysphagia induced by ALS is a major challenge for food intake and riluzole administration. Tablet crushing is associated with a loss of drug intake and a risk of powder aspiration, which jeopardizes the benefits of riluzole. Riluzole oral suspension (ROS) and oral film (ROF) allow riluzole intake in patients with dysphagia. Both formulations are bioequivalent to riluzole tablets with a good safety profile albeit transient oral hypoaesthesia. In case of severe dysphagia, ROS can be used with percutaneous endoscopic gastrostomy. ROF, the last approved formulation, requires low swallowing capacities and may contribute to maintain the efficacy of riluzole when tablets are inadequate according to patient's status and/or preferences. To optimize treatment continuity in newly diagnosed patients, the expected psychological impact of formulation switching that may be perceived as the sign of disease progression should be anticipated.}, } @article {pmid38974930, year = {2024}, author = {Aziz, S and Barratt, J and Wilson-Baig, N and Lachowycz, K and Major, R and Barnard, EBG and Rees, P}, title = {A protocol for the ERICA-ARREST feasibility study of Emergency Resuscitative Endovascular Balloon occlusion of the Aorta in Out-of-Hospital Cardiac Arrest.}, journal = {Resuscitation plus}, volume = {19}, number = {}, pages = {100688}, pmid = {38974930}, issn = {2666-5204}, abstract = {BACKGROUND: Fewer than one in ten out-of-hospital cardiac arrest (OHCA) patients survive to hospital discharge in the UK. For prehospital teams to improve outcomes in patients who remain in refractory OHCA despite advanced life support (ALS); novel strategies that increase the likelihood of return of spontaneous circulation, whilst preserving cerebral circulation, should be investigated. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) has been shown to improve coronary and cerebral perfusion during cardiopulmonary resuscitation. Early, prehospital initiation of REBOA may improve outcomes in patients who do not respond to standard ALS. However, there are significant clinical, technical, and logistical challenges with rapidly delivering prehospital REBOA in OHCA; and the feasibility of delivering this intervention in the UK urban-rural setting has not been evaluated.

METHODS: The Emergency Resuscitative Endovascular Balloon Occlusion of the Aorta in Out-of-Hospital Cardiac Arrest (ERICA-ARREST) study is a prospective, single-arm, interventional feasibility study. The trial will enrol 20 adult patients with non-traumatic OHCA. The primary objective is to assess the feasibility of performing Zone I (supra-coeliac) aortic occlusion in patients who remain in OHCA despite standard ALS in the UK prehospital setting. The trial's secondary objectives are to describe the hemodynamic and physiological responses to aortic occlusion; to report key time intervals; and to document adverse events when performing REBOA in this context.

DISCUSSION: Using compressed geography, and targeted dispatch, alongside a well-established femoral arterial access programme, the ERICA-ARREST study will assess the feasibility of deploying REBOA in OHCA in a mixed UK urban and rural setting.Trial registration.ClinicalTrials.gov (NCT06071910), registration date October 10, 2023, https://classic.clinicaltrials.gov/ct2/show/NCT06071910.}, } @article {pmid38975145, year = {2024}, author = {Zhang, J and Xie, D and Jiao, D and Zhou, S and Liu, S and Ju, Z and Hu, L and Qi, L and Yao, C and Zhao, C}, title = {From inflammatory signaling to neuronal damage: Exploring NLR inflammasomes in ageing neurological disorders.}, journal = {Heliyon}, volume = {10}, number = {12}, pages = {e32688}, pmid = {38975145}, issn = {2405-8440}, abstract = {The persistence of neuronal degeneration and damage is a major obstacle in ageing medicine. Nucleotide-binding oligomerization domain (NOD)-like receptors detect environmental stressors and trigger the maturation and secretion of pro-inflammatory cytokines that can cause neuronal damage and accelerate cell death. NLR (NOD-like receptors) inflammasomes are protein complexes that contain NOD-like receptors. Studying the role of NLR inflammasomes in ageing-related neurological disorders can provide valuable insights into the mechanisms of neurodegeneration. This includes investigating their activation of inflammasomes, transcription, and capacity to promote or inhibit inflammatory signaling, as well as exploring strategies to regulate NLR inflammasomes levels. This review summarizes the use of NLR inflammasomes in guiding neuronal degeneration and injury during the ageing process, covering several neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and peripheral neuropathies. To improve the quality of life and slow the progression of neurological damage, NLR-based treatment strategies, including inhibitor-related therapies and physical therapy, are presented. Additionally, important connections between age-related neurological disorders and NLR inflammasomes are highlighted to guide future research and facilitate the development of new treatment options.}, } @article {pmid38975625, year = {2024}, author = {Berkman, O and Raveh, E and Harpaz, E and Kreitman, R and Ben-Ami, E and Nechushtan, E and Birman, N and Drory, VE}, title = {Changes in saccadic intrusions over time as an objective biomarker to follow ALS disease progression.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {760-766}, doi = {10.1080/21678421.2024.2376732}, pmid = {38975625}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Disease Progression ; Female ; Middle Aged ; Male ; Aged ; *Saccades/physiology ; Ocular Motility Disorders/etiology/diagnosis/physiopathology ; Biomarkers ; }, abstract = {Objective: Saccadic Intrusions (SIs) are abnormal eye movements during gaze fixation. Studies have indicated the clinical relevance of SIs, especially of square wave jerks (SWJ) in ALS. We used a software-based platform to extract SIs as a part of an interventional drug trial. The objective was to examine SIs' change over time as a potential biomarker of ALS disease progression. Methods: 28 ALS patients (61.95 ± 8.6 years) were assessed with the revised ALS Functional Rating Scale (ALSFRS-R) and with an oculometric test. Changes of SIs over time and correlations with ALSFRS-R and its bulbar subscale were calculated. A power calculation was conducted to understand the practical implications of results. Results: A significant increase of SWJ over trial duration was observed, with an increase in frequency (mean rise of 0.14 ± 0.28, p < 0.01), amplitude (0.001 ± 0.0016 degrees, p < 0.005), overall duration of SWJ (0.13 ± 0.25, in %, p < 0.01), and in their relative part out of all intrusions (0.18 ± 0.32, in %, p < 0.005). Negative correlations were found with the bulbar subscale (R=-0.43, -0.41, -0.39 and -0.47, respectively, p < 0.001). The required sample size for observing a 40% reduction in bulbar aspects when using the oculometric test (α = 0.05 and β = 0.8), was found to be 150 patients per arm, compared with 200 patients using the bulbar subscale. Conclusions: Evaluation of saccadic intrusions during fixation was able to detect disease progression over time, correlated with ALSFRS-R bulbar subscale. Eye movements can potentially serve as an objective biomarker in ALS clinical trials and reduce the required sample size to show clinical effect of therapies.}, } @article {pmid38976599, year = {2024}, author = {Xu, Z and Xu, R}, title = {Current potential diagnostic biomarkers of amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {8}, pages = {917-931}, pmid = {38976599}, issn = {2191-0200}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Humans ; *Biomarkers/metabolism ; Oxidative Stress/physiology ; Proteomics/methods ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) currently lacks the useful diagnostic biomarkers. The current diagnosis of ALS is mainly depended on the clinical manifestations, which contributes to the diagnostic delay and be difficult to make the accurate diagnosis at the early stage of ALS, and hinders the clinical early therapeutics. The more and more pathogenesis of ALS are found at the last 30 years, including excitotoxicity, the oxidative stress, the mitochondrial dysfunction, neuroinflammation, the altered energy metabolism, the RNA misprocessing and the most recent neuroimaging findings. The findings of these pathogenesis bring the new clues for searching the diagnostic biomarkers of ALS. At present, a large number of relevant studies about the diagnostic biomarkers are underway. The ALS pathogenesis related to the diagnostic biomarkers might lessen the diagnostic reliance on the clinical manifestations. Among them, the cortical altered signatures of ALS patients derived from both structural and functional magnetic resonance imaging and the emerging proteomic biomarkers of neuronal loss and glial activation in the cerebrospinal fluid as well as the potential biomarkers in blood, serum, urine, and saliva are leading a new phase of biomarkers. Here, we reviewed these current potential diagnostic biomarkers of ALS.}, } @article {pmid38977656, year = {2025}, author = {Han, M and Raymond, J and Larson, TC and Mehta, P and Horton, DK}, title = {Comparison of Demographics: National Amyotrophic Lateral Sclerosis Registry and Clinical Trials Data.}, journal = {Journal of racial and ethnic health disparities}, volume = {12}, number = {4}, pages = {2270-2278}, pmid = {38977656}, issn = {2196-8837}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/ethnology/epidemiology/therapy ; *Registries/statistics & numerical data ; Middle Aged ; Male ; Female ; Aged ; *Clinical Trials as Topic/statistics & numerical data ; Adult ; United States/epidemiology ; Databases, Factual ; Demography ; }, abstract = {OBJECTIVE: To characterize the participant demographics in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database compared with the web-portal National Amyotrophic Lateral Sclerosis (ALS) Registry (the Registry).

METHODS: Demographics and ALS symptom information were compared between the self-reported registrant data in the Registry web portal (2010-2021) and the latest available PRO-ACT data (updated August 2022), which is a collection of clinical trials data.

RESULTS: Greater percentages of younger (≤ 59 years old) but smaller percentages of older (60 + years old) participants were represented in PRO-ACT compared to Registry. Enrollment for minority race groups was greater in the Registry portal data, but race information was largely missing/unknown in PRO-ACT database. Median age at the time of diagnosis and age at the time of symptom onset were significantly higher for Registry enrollees compared to the participants of PRO-ACT. Symptom onset sites were similarly reported, but duration between self-noted symptom onset and diagnosis was slight, but significantly longer for the Registry enrollees (11 vs. 9 months). Hispanic were as likely as non-Hispanic to participate in research studies, based on the Registry data.

CONCLUSION: There was a notable difference in the age distribution and minority representation of enrollees between the PRO-ACT and Registry study populations. Age distribution in the PRO-ACT database skewed to a younger and less diverse cohort. Despite the clinical heterogeneity and complex disease mechanism of ALS, identifying the underrepresented demographic niche in the PRO-ACT and Registry study populations can help improve patient participation and criteria for patient selection to enhance generalizability.}, } @article {pmid38977678, year = {2024}, author = {M Amaral, D and Soares, DF and Gromicho, M and de Carvalho, M and Madeira, SC and Tomás, P and Aidos, H}, title = {Temporal stratification of amyotrophic lateral sclerosis patients using disease progression patterns.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5717}, pmid = {38977678}, issn = {2041-1723}, support = {101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; 101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; 101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; 101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Humans ; *Disease Progression ; Male ; Cluster Analysis ; Female ; Middle Aged ; Aged ; }, abstract = {Identifying groups of patients with similar disease progression patterns is key to understand disease heterogeneity, guide clinical decisions and improve patient care. In this paper, we propose a data-driven temporal stratification approach, ClusTric, combining triclustering and hierarchical clustering. The proposed approach enables the discovery of complex disease progression patterns not found by univariate temporal analyses. As a case study, we use Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease with a non-linear and heterogeneous disease progression. In this context, we applied ClusTric to stratify a hospital-based population (Lisbon ALS Clinic dataset) and validate it in a clinical trial population. The results unravelled four clinically relevant disease progression groups: slow progressors, moderate bulbar and spinal progressors, and fast progressors. We compared ClusTric with a state-of-the-art method, showing its effectiveness in capturing the heterogeneity of ALS disease progression in a lower number of clinically relevant progression groups.}, } @article {pmid38978024, year = {2024}, author = {Endalamaw, A and Gilks, CF and Ambaw, F and Shiferaw, WS and Assefa, Y}, title = {Explaining inequity in knowledge, attitude, and services related to HIV/AIDS: a systematic review.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {1815}, pmid = {38978024}, issn = {1471-2458}, mesh = {Humans ; *HIV Infections/psychology ; *Health Knowledge, Attitudes, Practice ; Healthcare Disparities ; }, abstract = {BACKGROUND: Equitable service provision and coverage are important responses to end the threat of the HIV/AIDS pandemic. Understanding inequity supports policies and programmes to deliver tailored interventions. There is continuous evidence generation on inequity in HIV/AIDS services. However, there was a lack of evidence on the global picture of inequity in behavioural and biomedical services related to HIV/AIDS. This systematic review assessed inequities in knowledge, attitude, HIV testing, and ART coverage across individual-level social groups and multiple (dis)advantage categories.

METHODS: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline, with a PROSPERO registration number CRD42024521247. The risk of bias was assessed by using Hoy et al's and Joanna Brigg's quality appraisal checklists for cross-sectional quantitative and qualitative studies, respectively. The search date was from inception to the final database search date (May 29, 2023). The included articles were either quantitative or qualitative studies. We used mixed-methods approach to analyse the data from the review articles. Quantitative descriptive analysis was conducted to estimate frequency of articles published from different countries around the world. Qualitative content analysis of the findings from the original studies was conducted using the PROGRESS plus framework which stands for: place of residence, occupation or employment status, gender, religion, education status, socioeconomic status, and social capital.

RESULTS: Out of 6,029 articles that were accessed and screened, only 72 articles met the inclusion criteria. More articles on HIV-related equity in knowledge, attitude, testing, and ART were published in developed countries than in developing countries. Individuals from higher-income households had better knowledge about HIV/AIDS. Unfavourable attitudes towards people living with HIV and HIV/AIDS-associated stigma were common among women. HIV/AIDS service coverage (HIV testing or ART coverage) was higher among richer and urban residents. HIV/AIDS-associated stigma and lower levels of knowledge about HIV/AIDS were observed among multiple disadvantageous groups due to the intersection of two or more identities.

CONCLUSIONS: The current review revealed that there have been disparities in HIV/AIDS services between social classes. Ending service disparity towards the global threat of HIV/AIDS demands tailored interventions based on socially disadvantaged groups (e.g., poor, rural dwellers, and women) and intersectional determinants. There is a need to understand the deep-rooted causes of inequity and the challenges that an equity-oriented system faces over time. More studies on inequity are needed, including intersectional inequity, which has been rarely studied in developing countries.}, } @article {pmid38978196, year = {2024}, author = {Huang, X and Wu, J and Zhang, N and Teng, J and Yang, Q and Zhang, Y and Yin, T and Zhou, W and Fan, D and Ye, S}, title = {Smell loss is associated with cognitive impairment in amyotrophic lateral sclerosis patients.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {7}, pages = {e14851}, pmid = {38978196}, issn = {1755-5949}, support = {82001350//National Natural Science Foundation of China/ ; 2021ZD0204200//STI2030-Major Projects/ ; JCTD-2021-06//The Chinese Academy of Sciences Grants/ ; YCXJ-JZ-2022-007//Beijing E-Town Cooperation & Development Foundation/ ; YJXJ-JZ-2021-0014//Beijing E-Town Cooperation & Development Foundation/ ; DL2019002//PUTH Cohort Construction Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology/epidemiology ; Male ; Female ; Middle Aged ; *Cognitive Dysfunction/epidemiology/etiology ; Aged ; *Olfaction Disorders/etiology/epidemiology ; Adult ; }, abstract = {BACKGROUND: Smell loss significantly impacts the quality of life in patients. However, there is limited research on smell loss in individuals with amyotrophic lateral sclerosis (ALS), and the correlation between smell loss and cognitive impairment is unclear. This study aimed to investigate the correlation between smell loss and cognition impairment in ALS patients.

METHODS: The study included 216 ALS patients. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and smell identification test specifically for the Chinese population (CSIT) were administered to evaluate participants' cognitive and olfactory function, respectively.

RESULTS: After covarying for age, sex, BMI, education level, degree of hunger, dietary bias, eagerness for food, stress, smoking status, alcohol consumption, and upper respiratory tract infection (URTI) or rhinitis, CSIT scores were significantly correlated with ECAS scores (r = 0.162, p = 0.028), especially the ALS-specific scores (r = 0.158, p = 0.031). Even after excluding patients with URTI or rhinitis, the results were similar. CSIT scores were significantly correlated with ECAS scores (r = 0.224, p = 0.011), especially the ALS-specific scores (r = 0.205, p = 0.019).

CONCLUSION: In patients with ALS, smell loss is significantly correlated with cognitive impairment, particularly frontotemporal dysfunction. Cognitive dysfunction may lead to worse olfactory performance in ALS patients.}, } @article {pmid38978682, year = {2024}, author = {Neumann, M and Kothare, H and Ramanarayanan, V}, title = {Multimodal Speech Biomarkers for Remote Monitoring of ALS Disease Progression.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38978682}, support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that severely impacts affected persons' speech and motor functions, yet early detection and tracking of disease progression remain challenging. The current gold standard for monitoring ALS progression, the ALS functional rating scale - revised (ALSFRS-R), is based on subjective ratings of symptom severity, and may not capture subtle but clinically meaningful changes due to a lack of granularity. Multimodal speech measures which can be automatically collected from patients in a remote fashion allow us to bridge this gap because they are continuous-valued and therefore, potentially more granular at capturing disease progression. Here we investigate the responsiveness and sensitivity of multimodal speech measures in persons with ALS (pALS) collected via a remote patient monitoring platform in an effort to quantify how long it takes to detect a clinically-meaningful change associated with disease progression. We recorded audio and video from 278 participants and automatically extracted multimodal speech biomarkers (acoustic, orofacial, linguistic) from the data. We find that the timing alignment of pALS speech relative to a canonical elicitation of the same prompt and the number of words used to describe a picture are the most responsive measures at detecting such change in both pALS with bulbar (n = 36) and non-bulbar onset (n = 107). Interestingly, the responsiveness of these measures is stable even at small sample sizes. We further found that certain speech measures are sensitive enough to track bulbar decline even when there is no patient-reported clinical change, i.e. the ALSFRS-R speech score remains unchanged at 3 out of a total possible score of 4. The findings of this study have the potential to facilitate improved, accelerated and cost-effective clinical trials and care.}, } @article {pmid38979013, year = {2024}, author = {Shi, W and Ding, R and Chen, Y and Ji, F and Ji, J and Ma, W and Jin, J}, title = {The HRD1-SEL1L ubiquitin ligase regulates stress granule homeostasis in couple with distinctive signaling branches of ER stress.}, journal = {iScience}, volume = {27}, number = {7}, pages = {110196}, pmid = {38979013}, issn = {2589-0042}, abstract = {Stress granules (SGs) are membrane-less cellular compartments which are dynamically assembled via biomolecular condensation mechanism when eukaryotic cells encounter environmental stresses. SGs are important for gene expression and cell fate regulation. Dysregulation of SG homeostasis has been linked to human neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we report that the HRD1-SEL1L ubiquitin ligase complex specifically regulates the homeostasis of heat shock-induced SGs through the ubiquitin-proteasome system (UPS) and the UPS-associated ATPase p97. Mechanistically, the HRD1-SEL1L complex mediates SG homeostasis through the BiP-coupled PERK-eIF2α signaling axis of endoplasmic reticulum (ER) stress, thereby coordinating the unfolded protein response (UPR) with SG dynamics. Furthermore, we show that the distinctive branches of ER stress play differential roles in SG homeostasis. Our study indicates that the UPS and the UPR together via the HRD1-SEL1L ubiquitin ligase to maintain SG homeostasis in a stressor-dependent manner.}, } @article {pmid38979232, year = {2024}, author = {Keuss, MJ and Harley, P and Ryadnov, E and Jackson, RE and Zanovello, M and Wilkins, OG and Barattucci, S and Mehta, PR and Oliveira, MG and Parkes, JE and Sinha, A and Correa-Sánchez, AF and Oliver, PL and Fisher, EMC and Schiavo, G and Shah, M and Burrone, J and Fratta, P}, title = {Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38979232}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, abstract = {TDP-43 loss of function induces multiple splicing changes, including a cryptic exon in the amyotrophic lateral sclerosis and fronto-temporal lobar degeneration risk gene UNC13A, leading to nonsense-mediated decay of UNC13A transcripts and loss of protein. UNC13A is an active zone protein with an integral role in coordinating pre-synaptic function. Here, we show TDP-43 depletion induces a severe reduction in synaptic transmission, leading to an asynchronous pattern of network activity. We demonstrate that these deficits are largely driven by a single cryptic exon in UNC13A. Antisense oligonucleotides targeting the UNC13A cryptic exon robustly rescue UNC13A protein levels and restore normal synaptic function, providing a potential new therapeutic approach for ALS and other TDP-43-related disorders.}, } @article {pmid38979270, year = {2024}, author = {Baghel, MS and Burns, GD and Tsapatsis, M and Mallika, AP and Cruz, ALF and Cao, T and Chen, XK and Rosa, I and Marx, SR and Ye, Y and Sun, S and Li, T and Wong, PC}, title = {Depletion of TDP-43 exacerbates tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-mediated endoproteolysis of tau in a mouse model of Multiple Etiology Dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38979270}, issn = {2692-8205}, support = {R61 NS115161/NS/NINDS NIH HHS/United States ; F31 NS135935/NS/NINDS NIH HHS/United States ; R33 NS115161/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; R01 AG078948/AG/NIA NIH HHS/United States ; R01 NS095969/NS/NINDS NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; }, abstract = {TDP-43 proteinopathy, initially disclosed in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, termed multiple etiology dementias (MEDs), including Alzheimer's Disease (AD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration and steeper cognitive decline, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. The loss of TDP-43 splicing repression that occurs in presymptomatic ALS-FTD individuals suggests that such early loss could facilitate the pathological conversion of tau to accelerate neuron loss. Here, we report that the loss of TDP-43 repression of cryptic exons in forebrain neurons (CaMKII-CreER;Tardbp [f/f] mice) is necessary to exacerbate tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-dependent cleavage of endogenous tau to promote tauopathy. Corroborating this finding within the human context, we demonstrate that loss of TDP-43 function in iPSC-derived cortical neurons promotes early cryptic exon inclusion and subsequent caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER;Tardbp [f/f] mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed positively correlates with levels of caspase 3-cleaved tau. Importantly, we found that the vulnerability of hippocampal neurons to TDP-43 depletion is dependent on the amount of caspase 3-cleaved tau: from most vulnerable neurons in the CA2/3, followed by those in the dentate gyrus, to the least in CA1. Taken together, our findings strongly support the view that TDP-43 loss-of-function exacerbates tauopathy-dependent brain atrophy by increasing the sensitivity of vulnerable neurons to caspase 3-mediated endoproteolysis of tau, resulting in a greater degree of neurodegeneration in human disorders with co-pathologies of tau and TDP-43. Our work thus discloses novel mechanistic insights and therapeutic targets for human tauopathies harboring co-pathology of TDP-43 and provides a new MED model for testing therapeutic strategies.}, } @article {pmid38979278, year = {2024}, author = {Arseni, D and Nonaka, T and Jacobsen, MH and Murzin, AG and Cracco, L and Peak-Chew, SY and Garringer, HJ and Kawakami, I and Suzuki, H and Onaya, M and Saito, Y and Murayama, S and Geula, C and Vidal, R and Newell, KL and Mesulam, M and Ghetti, B and Hasegawa, M and Ryskeldi-Falcon, B}, title = {Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.25.600403}, pmid = {38979278}, issn = {2692-8205}, support = {P30 AG013854/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; }, abstract = {Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system [1] . Human genetic studies established a causal role for protein assembly in neurodegeneration [2] . However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in electron cryo-microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains [1] . All diseases studied to date have been characterised by the self-assembly of a single intracellular protein in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) Types A and B [3,4] . Here, we used cryo-EM to determine filament structures from the brains of individuals with FTLD-TDP Type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/284-N345 and ANXA11 residues L39-L74 from their respective low-complexity domains (LCDs). Regions of TDP-43 and ANXA11 previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as a ∼22 kDa N-terminal fragment (NTF) lacking the annexin core domain. Immunohistochemistry of brain sections confirmed the co-localisation of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP Type C. This work establishes a central role for ANXA11 in FTLD-TDP Type C. The unprecedented formation of heteromeric amyloid filaments in human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.}, } @article {pmid38979291, year = {2024}, author = {Weiss, A and Gilbert, JW and Flores, IVR and Belgrad, J and Ferguson, C and Dogan, EO and Wightman, N and Mocarski, K and Echeverria, D and Summers, A and Bramato, B and McHugh, N and Furgal, R and Yamada, N and Cooper, D and Monopoli, K and Godinho, BMDC and Hassler, MR and Yamada, K and Greer, P and Henninger, N and Brown, RH and Khvorova, A}, title = {RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38979291}, issn = {2692-8205}, support = {T32 AI095213/AI/NIAID NIH HHS/United States ; R01 NS111990/NS/NINDS NIH HHS/United States ; S10 OD020012/OD/NIH HHS/United States ; R21 NR020231/NR/NINR NIH HHS/United States ; R21 NS131756/NS/NINDS NIH HHS/United States ; R01 NS104022/NS/NINDS NIH HHS/United States ; R35 GM131839/GM/NIGMS NIH HHS/United States ; U24 NS113844/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene lowering a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo. With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo. Administered intraventricularly, di-siRNA[SOD1] extended survival in SOD1-G93A ALS mice, surpassing survival previously seen in these mice by ASO modalities, slowed disease progression, and prevented ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders.}, } @article {pmid38979791, year = {2024}, author = {Stabellini, N and Cullen, J and Bittencourt, MS and Moore, JX and Sutton, A and Nain, P and Hamerschlak, N and Weintraub, NL and Dent, S and Tsai, MH and Banerjee, A and Ghosh, AK and Sadler, D and Coughlin, SS and Barac, A and Shanahan, J and Montero, AJ and Guha, A}, title = {Allostatic Load/Chronic Stress and Cardiovascular Outcomes in Patients Diagnosed With Breast, Lung, or Colorectal Cancer.}, journal = {Journal of the American Heart Association}, volume = {13}, number = {14}, pages = {e033295}, pmid = {38979791}, issn = {2047-9980}, mesh = {Humans ; Female ; *Colorectal Neoplasms/epidemiology ; *Breast Neoplasms/epidemiology ; *Lung Neoplasms/epidemiology/diagnosis ; Middle Aged ; Male ; Retrospective Studies ; Aged ; *Cardiovascular Diseases/epidemiology ; *Allostasis/physiology ; Risk Assessment ; Risk Factors ; Stress, Psychological/complications ; }, abstract = {BACKGROUND: Cardiovascular disease and cancer share a common risk factor: chronic stress/allostatic load (AL). A 1-point increase in AL is linked to up to a 30% higher risk of major cardiac events (MACE) in patients with prostate cancer. However, AL's role in MACE in breast cancer, lung cancer, or colorectal cancer remains unknown.

METHODS AND RESULTS: Patients ≥18 years of age diagnosed with the mentioned 3 cancers of interest (2010-2019) and followed up at a large, hybrid academic-community practice were included in this retrospective cohort study. AL was modeled as an ordinal measure (0-11). Adjusted Fine-Gray competing risks regressions estimated the impact of AL precancer diagnosis on 2-year MACE (a composite of heart failure, ischemic stroke, acute coronary syndrome, and atrial fibrillation). The effect of AL changes over time on MACE was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after cancer diagnosis). Among 16 467 patients, 50.5% had breast cancer, 27.9% had lung cancer, and 21.4% had colorectal cancer. A 1-point elevation in AL before breast cancer diagnosis corresponded to a 10% heightened associated risk of MACE (adjusted hazard ratio, 1.10 [95% CI, 1.06-1.13]). Similar findings were noted in lung cancer (adjusted hazard ratio, 1.16 [95% CI, 1.12-1.20]) and colorectal cancer (adjusted hazard ratio, 1.13 [95% CI, 1.08-1.19]). When considering AL as a time-varying exposure, the peak associated MACE risk occurred with a 1-point AL rise between 6 and 12 months post- breast cancer, lung cancer, and colorectal cancer diagnosis.

CONCLUSIONS: AL warrants investigation as a potential marker in these patients to identify those at elevated cardiovascular risk and intervene accordingly.}, } @article {pmid38981325, year = {2024}, author = {Asghar, H and Tariq, A and Rasool, G and Hayat, A}, title = {Fabrication of a salivary amylase electrochemical sensor based on surface confined MWCNTs/β-cyclodextrin/starch architect for dental caries in clinical samples.}, journal = {Bioelectrochemistry (Amsterdam, Netherlands)}, volume = {160}, number = {}, pages = {108774}, doi = {10.1016/j.bioelechem.2024.108774}, pmid = {38981325}, issn = {1878-562X}, mesh = {*beta-Cyclodextrins/chemistry ; Humans ; *Nanotubes, Carbon/chemistry ; *Biosensing Techniques/methods ; *Starch/chemistry ; *Electrochemical Techniques/methods ; *Dental Caries/diagnosis ; Saliva/chemistry ; Limit of Detection ; Salivary alpha-Amylases/analysis/metabolism ; Electrodes ; }, abstract = {Salivary α-amylase (α-ALS) has drawn attention as a possible bioindicator for dental caries. Herein, combining the synergistic properties of multi-walled carbon nanotubes (MWCNTs), β-cyclodextrin (β-CD) and starch, an electrochemical sensor is constructed employing ferrocene (FCN) as an electrochemical indicator to oversee the progression of the enzymatic catalysis of α-ALS. The method involves a two-step chemical reaction sequence on a screen-printed carbon electrode (SPCE). X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, Field emission scanning electron microscope (FE-SEM), and Dynamic light scattering (DLS) were used to characterize the synthesized material, while Static water Contact angle measurements, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS) were performed to monitor each step of sensor fabrication. The electrochemical sensor permitted to detect α-ALS within the linear range of 0.5-280 U mL[-1], revealing detection (LOD), and quantification (LOQ) values of 0.041 U mL[-1], and 0.159 U mL[-1], respectively. Remarkably, the sensor demonstrated exceptional specificity and selectivity, effectively discriminating against other interfering substances in saliva. Validation of the method involved analyzing α-ALS levels in artificial saliva with an accuracy range of 97 % to 103 %, as well as in real clinical saliva samples across various age groups.}, } @article {pmid38982381, year = {2024}, author = {Mioshi, E and Heal, S and Katangwe-Chigamba, T}, title = {'A lightbulb moment': carers' experiences of behavioural symptoms in motor neurone disease before and after MiNDToolkit.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {238}, pmid = {38982381}, issn = {1471-2377}, support = {934-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; 934-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Caregivers/psychology ; Male ; *Motor Neuron Disease/psychology/therapy ; Female ; Middle Aged ; *Behavioral Symptoms/therapy/etiology ; Aged ; Adult ; Qualitative Research ; }, abstract = {BACKGROUND: To explore carers' experiences of behavioural symptoms in Motor Neurone Disease (MND), before and after using the MiNDToolkit, a novel internet-based psychoeducational intervention to support management of behavioural symptoms (BehSymp) in MND. The study also investigated carers' views and acceptability of MiNDToolkit.

METHODS: A qualitative process evaluation of carers engagement with, and acceptability of, the MiNDToolkit conducted using semi-structured interviews with carers (n = 11). All interviews were audio-recorded, professionally transcribed verbatim and analysed thematically.

RESULTS: Five themes were identified: (1) In the dark: carers' experiences and reactions to BehSymp; (2) Others can see: the role of HCPs in identifying symptoms - and perceived opportunities for carers to receive support; (3) Shedding light: carers implementation and perceived impact of the MiNDToolkit content; (4) Acceptability and carers' engagement with MiNDToolkit; (5) Future implementation. Carers' experience of BehSymp was particularly distressing when symptoms were apparently out of context. MiNDToolkit appeared to support learning that BehSymp were part of MND. Content resonated with carers, who reported learning about the full picture of MND, which led to acceptance and use of newly learned strategies. Engagement with the platform was good, with varied input from HCPs. Greater and nuanced involvement from HCPs seem important to support management of BehSymp. Recommendations for a full-scale trial emerged, including adding a paper booklet to accompany the intervention and creation of new modules on emotional lability, changes in relationships, and transitioning to a care home.

CONCLUSIONS: MiNDToolkit was acceptable to carers overall. Recommended improvements should be actioned in a full-scale trial.}, } @article {pmid38984582, year = {2025}, author = {Jiang, SS and Nie, HB and Hua, S and Xie, M and Xu, RS}, title = {Preliminary Analysis of Potentially Overlapping Differentially Expressed Proteins in Both the Spinal Cord and Brain of SOD1 G93A Mice.}, journal = {Current protein & peptide science}, volume = {26}, number = {1}, pages = {57-75}, pmid = {38984582}, issn = {1875-5550}, support = {30560042, 81160161, 81360198, 82160255//National Natural Science Foundation of China/ ; GJJ13198, GJJ170021//Education Department of Jiangxi Province/ ; [2014]-47, 20142BBG70062, 20171BAB- 215022, 20192BAB205043//Jiangxi provincial department of science and technology/ ; 20181019, 202210002, 202310119//Health and Family Planning Commission of Jiangxi province/ ; [2015] 108//Jiangxi Provincial Department of Science and Technology Gan Po Elite 555 (Jiangxi Finance Elite Education)/ ; }, mesh = {Animals ; *Spinal Cord/metabolism/pathology ; Mice ; *Brain/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Proteomics/methods ; Mice, Transgenic ; Superoxide Dismutase-1/genetics ; *Proteome/metabolism/genetics ; Disease Models, Animal ; Humans ; Gene Ontology ; Computational Biology ; Superoxide Dismutase ; }, abstract = {OBJECTIVE: Proteomic elucidation is an essential step in improving our understanding of the biological properties of proteins in amyotrophic lateral sclerosis (ALS).

METHODS: Preliminary proteomic analysis was performed on the spinal cord and brain of SOD1 G93A (TG) and wild-type (WT) mice using isobaric tags for relative and absolute quantitation.

RESULTS: Partial up- and downregulated proteins showing significant differences between TG and WT mice were identified, of which 105 proteins overlapped with differentially expressed proteins in both the spinal cord and brain of progression mice. Bioinformatic analyses using Gene Ontology, a cluster of orthologous groups, and Kyoto Encyclopedia of Genes and Genomes pathway revealed that the significantly up- and downregulated proteins represented multiple biological functions closely related to ALS, with 105 overlapping differentially expressed proteins in the spinal cord and brain at the progression stage of TG mice closely related to 122 pathways. Differentially expressed proteins involved in a set of molecular functions play essential roles in maintaining neural cell survival.

CONCLUSION: This study provides additional proteomic profiles of TG mice, including potential overlapping proteins in both the spinal cord and brain that participate in pathogenesis, as well as novel insights into the up- and downregulation of proteins involved in the pathogenesis of ALS.}, } @article {pmid38984619, year = {2024}, author = {Olney, N and Weiss, MD}, title = {Real world experience with sodium phenylbutyrate-taurursodiol for ALS: Lessons learned from a failed drug.}, journal = {Muscle & nerve}, volume = {70}, number = {3}, pages = {299-301}, doi = {10.1002/mus.28203}, pmid = {38984619}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Phenylbutyrates/therapeutic use ; Male ; Female ; Middle Aged ; Treatment Failure ; Aged ; }, } @article {pmid38984697, year = {2024}, author = {Hasan, M and Alam, SM and Rahman, HZ and Khan, MAS and Huq, MR}, title = {Autonomic Dysfunction in Amyotrophic Lateral Sclerosis - A Case-Control Study.}, journal = {Acta medica academica}, volume = {53}, number = {1}, pages = {24-34}, pmid = {38984697}, issn = {1840-2879}, mesh = {Case-Control Studies ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Autonomic Nervous System Diseases/epidemiology ; Bangladesh/epidemiology ; Tertiary Care Centers ; Humans ; Male ; Female ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Upper Extremity/physiopathology ; Lower Extremity/physiopathology ; Sympathetic Nervous System ; }, abstract = {INTRODUCTION: This study aimed to explore autonomic nervous system involvement in amyotrophic lateral sclerosis (ALS) patients by evaluating sympathetic skin response (SSR).

MATERIALS AND METHODS: The study included 35 sporadic (ALS) patients (cases), and 35 healthy age and sex-matched participants (controls) aged <60 years. SSR was recorded in the electrophysiology lab of the Neurology Department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Patients with diseases associated with peripheral or autonomic neuropathy were excluded. Prolonged latency (delayed SSR) or an absent response was considered abnormal SSR.

RESULTS: SSR was found to be abnormal in 17 (48.6 %) ALS cases, with an absent response in the upper limbs of six cases (17.1%). Abnormal SSR was more prevalent in the lower limbs, with 33 (94.3%) and 20 (57.1%) cases having a delayed or absent response, respectively. In comparison, SSR was normal in all control participants (P-value <0.05). Abnormal SSR was significantly more common in the lower limbs of ALS cases with bulbar palsy than those without bulbar palsy (P-value=0.04). There was no association of SSR with disease severity and duration.

CONCLUSION: ALS is significantly associated with abnormal SSR, indicating autonomic nervous system involvement. There could also be an association between bulbar palsy and abnormal SSR among ALS patients. Further studies should be carried out to determine the association of abnormal SSR with disease severity, duration, and type.}, } @article {pmid38986433, year = {2025}, author = {Rifai, OM and Waldron, FM and Sleibi, D and O'Shaughnessy, J and Leighton, DJ and Gregory, JM}, title = {Clinicopathological analysis of NEK1 variants in amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {35}, number = {1}, pages = {e13287}, pmid = {38986433}, issn = {1750-3639}, support = {108890/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; R01 NS127186/NS/NINDS NIH HHS/United States ; 1R01NS127186/NS/NINDS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; BB-2022-C4-L2//Target ALS/ ; }, mesh = {Humans ; *NIMA-Related Kinase 1/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Male ; Female ; Middle Aged ; Aged ; DNA-Binding Proteins/genetics/metabolism ; Mutation ; Mutation, Missense ; Adult ; }, abstract = {Many genes have been linked to amyotrophic lateral sclerosis (ALS), including never in mitosis A (NIMA)-related kinase 1 (NEK1), a serine/threonine kinase that plays a key role in several cellular functions, such as DNA damage response and cell cycle regulation. Whole-exome sequencing studies have shown that NEK1 mutations are associated with an increased risk for ALS, where a significant enrichment of NEK1 loss-of-function (LOF) variants were found in individuals with ALS compared to controls. In particular, the p.Arg261His missense variant was associated with significantly increased disease susceptibility. This case series aims to understand the neuropathological phenotypes resulting from NEK1 mutations in ALS. We examined a cohort of three Scottish patients with a mutation in the NEK1 gene and evaluated the distribution and cellular expression of NEK1, as well as the abundance of phosphorylated TDP-43 (pTDP-43) aggregates, in the motor cortex compared to age- and sex-matched control tissue. We show pathological, cytoplasmic TDP-43 aggregates in all three NEK1-ALS cases. NEK1 protein staining revealed no immunoreactivity in two of the NEK1-ALS cases, indicating a LOF and corresponding to a reduction in NEK1 mRNA as detected by in situ hybridisation. However, the p.Arg261His missense mutation resulted in an increase in NEK1 mRNA molecules and abundant NEK1-positive cytoplasmic aggregates, with the same morphologic appearance, and within the same cells as co-occurring TDP-43 aggregates. Here we show the first neuropathological assessment of a series of ALS cases carrying mutations in the NEK1 gene. Specifically, we show that TDP-43 pathology is present in these cases and that potential NEK1 LOF can either be mediated through loss of NEK1 translation or through aggregation of NEK1 protein as in the case with p.Arg261His mutation, a potential novel pathological feature of NEK1-ALS.}, } @article {pmid38987226, year = {2024}, author = {Luo, X and Heydari, A and Renfrey, D and Gardner, Z and He, S and Tang, Y and Weiss, GA and Rogers, ML and Raston, CL}, title = {Sustainability-Driven Accelerated Shear-Mediated Immunoassay for Amyotrophic Lateral Sclerosis Detection.}, journal = {ChemSusChem}, volume = {17}, number = {21}, pages = {e202401008}, doi = {10.1002/cssc.202401008}, pmid = {38987226}, issn = {1864-564X}, support = {DP200101106//Australian Research Council/ ; IC190100034//Australian Research Council/ ; //Flinders Health Seed Foundation/ ; //Australian Nanotechnology Network/ ; //Flinders University Research Investment Fund/ ; //Australian Microscopy and Microanalysis Research Facility/ ; //Australian National Fabrication Facility (ANFF)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Immunoassay/methods ; Limit of Detection ; Biomarkers ; }, abstract = {Healthcare facilities produce millions of tons of waste annually, with a significant portion consisting of diagnostic plasticware. Here, we introduce a new detection platform that completely replaces traditional assay plates with a piece of membrane, offering a much greener and more sustainable alternative. The membrane, integrated within the portable vortex fluidic device (P-VFD), enables rapid detection of a clinically relevant protein biomarker, urinary p75[ECD]. This biomarker is utilized to evaluate the prognosis, disease severity, and progression of amyotrophic lateral sclerosis (ALS). This assay has a limit-of-detection (LOD) of 4.03 pg, which is comparable to the plate-based assay (2.24 pg) and has been optimised through a full factorial design of experiments (DOE) and response surface methodology (RSM). P-VFD has great potential in quantifying p75[ECD] in human biofluids and can significantly reduce the assay time to 5 min compared to the current plate-based p75[ECD] ELISA assay (3 days), with at least a 4.4-fold reduction in the usage of the detection antibody.}, } @article {pmid38987905, year = {2024}, author = {Bergem, AK and Aamotsmo, T}, title = {Navigating parenthood in the face of amyotrophic lateral sclerosis: A qualitative exploration of partner experiences.}, journal = {Scandinavian journal of caring sciences}, volume = {38}, number = {4}, pages = {835-843}, doi = {10.1111/scs.13282}, pmid = {38987905}, issn = {1471-6712}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/psychology ; *Qualitative Research ; Adult ; Norway ; *Adaptation, Psychological ; Middle Aged ; *Parents/psychology ; Aged ; Child ; }, abstract = {INTRODUCTION: Among people diagnosed with Amyotrophic Lateral Sclerosis (ALS), there are parents with children living at home. Children in families experiencing severe illness are exposed to stress and health risks. Since 2010, healthcare personnel in Norway must assess whether patients have children under 18 years of age and make sure the children's needs for support are met. A child's ability to cope with family life affected by a serious illness depends on how the parent without the disease manages the situation. Little is known about how the partner of someone affected by ALS manages being next of kin and a parent simultaneously, and what kind of support they need.

METHODS: During 2021-2022, six semi-structured interviews were conducted with partners to persons with ALS, whom had children living at home. The interviews were transcribed verbatim and analysed through qualitative content analysis.

RESULTS: Three themes with subthemes emerged: (1) Together, yet alone; (a) restricted home life, (b) missing the sharing of responsibilities and tasks as equal parents, and (c) caught between children's and partner's needs; (2) Experience of coping while waiting for death; (a) cherishing the moments, (b) sense of coping and concern, and (c) ensuring to get recharged; and (3) Support in times of need; (a) difficult to ask the network for help and (b) the healthcare system does not see the whole family.

CONCLUSIONS: Our respondents felt alone, caught between the needs of their children and partner, without necessary support from the services, and were left to handle everyday life with all new challenges on their own. Future healthcare services need to consider the challenges faced by families dealing with life-limiting illnesses. A family-focused perspective is needed, so is peer support and interventions that address both emotional and practical aspects of life with an ill partner.}, } @article {pmid38988008, year = {2025}, author = {Murakami, A and Koga, S and Fujioka, S and White, AE and Bieniek, KF and Sekiya, H and DeJesus-Hernandez, M and Finch, NA and van Blitterswijk, M and Nakamura, M and Tsuboi, Y and Murray, ME and Wszolek, ZK and Dickson, DW}, title = {Upper motor neuron-predominant motor neuron disease presenting as atypical parkinsonism: A clinicopathological study.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {35}, number = {1}, pages = {e13286}, pmid = {38988008}, issn = {1750-3639}, support = {P01-AG03949/GF/NIH HHS/United States ; R01-AG062348/GF/NIH HHS/United States ; 1U19AG063911/GF/NIH HHS/United States ; P30-AG062677/GF/NIH HHS/United States ; FAIN: U19AG063911/GF/NIH HHS/United States ; R01-NS121125/GF/NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; RF1-NS123052/GF/NIH HHS/United States ; RF1 NS123052/NS/NINDS NIH HHS/United States ; R01 NS121125/NS/NINDS NIH HHS/United States ; U54 NS100693/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; R01 AG062348/AG/NIA NIH HHS/United States ; U54-NS100693/GF/NIH HHS/United States ; R01 NS123052/NS/NINDS NIH HHS/United States ; RF1 AG062348/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; *Motor Neuron Disease/pathology/diagnosis ; *Parkinsonian Disorders/pathology/diagnosis ; Aged, 80 and over ; Motor Neurons/pathology ; Amyotrophic Lateral Sclerosis/pathology/diagnosis ; Supranuclear Palsy, Progressive/pathology/diagnosis ; DNA-Binding Proteins/metabolism ; Corticobasal Degeneration/pathology/diagnosis ; Diagnosis, Differential ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by upper and lower motor neuron signs. There are, however, cases where upper motor neurons (UMNs) are predominantly affected, leading to clinical presentations of UMN-dominant ALS or primary lateral sclerosis. Furthermore, cases exhibiting an UMN-predominant pattern of motor neuron disease (MND) presenting with corticobasal syndrome (CBS) have been sparsely reported. This study aims to clarify the clinicopathological features of patients with UMN-predominant MND. We reviewed 24 patients with UMN-predominant MND with TDP-43 pathology in the presence or absence of frontotemporal lobar degeneration. Additionally, we reviewed the medical records of patients with pathologically-confirmed corticobasal degeneration (CBD) who received a final clinical diagnosis of CBS (n = 10) and patients with pathologically-confirmed progressive supranuclear palsy (PSP) who received a final clinical diagnosis of PSP syndrome (n = 10). Of 24 UMN-predominant MND patients, 20 had a clinical diagnosis of an atypical parkinsonian disorder, including CBS (n = 11) and PSP syndrome (n = 8). Only two patients had antemortem diagnoses of motor neuron disease. UMN-predominant MND patients with CBS less frequently exhibited apraxia than those with CBD, and they were less likely to meet clinical criteria for possible or probable CBS. Similarly, UMN-predominant MND patients with PSP syndrome less often met clinical criteria for probable PSP than PSP patients with PSP syndrome. Our findings suggest that UMN-predominant MND can mimic atypical parkinsonism, and should be considered in the differential diagnosis of CBS and PSP syndrome, in particular when criteria are not met.}, } @article {pmid38988205, year = {2024}, author = {Arnaldi, P and Casarotto, E and Relucenti, M and Bellese, G and Gagliani, MC and Crippa, V and Castagnola, P and Cortese, K}, title = {A NSC-34 cell line-derived spheroid model: Potential and challenges for in vitro evaluation of neurodegeneration.}, journal = {Microscopy research and technique}, volume = {87}, number = {11}, pages = {2785-2800}, doi = {10.1002/jemt.24651}, pmid = {38988205}, issn = {1097-0029}, support = {PRIN2020PBS5MJ//Ministero dell'Università e della Ricerca/ ; PRIN2022KSJZF5//Ministero dell'Università e della Ricerca/ ; //University of Genoa/ ; 100008-2022-KC-FRA_ANATOMIA//Fondi Ricerca Ateneo/ ; //Italian Ministry of Health (Ricerca Corrente)/ ; }, mesh = {*Spheroids, Cellular/pathology ; Animals ; Mice ; *DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Cell Line ; Motor Neurons/pathology ; Cell Survival ; Neurodegenerative Diseases/pathology ; Cell Culture Techniques/methods ; Spinal Cord/cytology/pathology ; Hydrogels/chemistry ; Humans ; Mitochondria/metabolism ; }, abstract = {Three-dimensional (3D) spheroid models aim to bridge the gap between traditional two-dimensional (2D) cultures and the complex in vivo tissue environment. These models, created by self-clustering cells to mimic a 3D environment with surrounding extracellular framework, provide a valuable research tool. The NSC-34 cell line, generated by fusing mouse spinal cord motor neurons and neuroblastoma cells, is essential for studying neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), where abnormal protein accumulation, such as TAR-DNA-binding protein 43 (TDP-43), occurs in affected nerve cells. However, NSC-34 behavior in a 3D context remains underexplored, and this study represents the first attempt to create a 3D model to determine its suitability for studying pathology. We generated NSC-34 spheroids using a nonadhesive hydrogel-based template and characterized them for 6 days. Light microscopy revealed that NSC-34 cells in 3D maintained high viability, a distinct round shape, and forming stable membrane connections. Scanning electron microscopy identified multiple tunnel-like structures, while ultrastructural analysis highlighted nuclear bending and mitochondria alterations. Using inducible GFP-TDP-43-expressing NSC-34 spheroids, we explored whether 3D structure affected TDP-43 expression, localization, and aggregation. Spheroids displayed nuclear GFP-TDP-43 expression, albeit at a reduced level compared with 2D cultures and generated both TDP-35 fragments and TDP-43 aggregates. This study sheds light on the distinctive behavior of NSC-34 in 3D culture, suggesting caution in the use of the 3D model for ALS or TDP-43 pathologies. Yet, it underscores the spheroids' potential for investigating fundamental cellular mechanisms, cell adaptation in a 3D context, future bioreactor applications, and drug penetration studies. RESEARCH HIGHLIGHTS: 3D spheroid generation: NSC-34 spheroids, developed using a hydrogel-based template, showed high viability and distinct shapes for 6 days. Structural features: advanced microscopy identified tunnel-like structures and nuclear and mitochondrial changes in the spheroids. Protein dynamics: the study observed how 3D structures impact TDP-43 behavior, with altered expression but similar aggregation patterns to 2D cultures. Research implications: this study reveals the unique behavior of NSC-34 in 3D culture, suggests a careful approach to use this model for ALS or TDP-43 pathologies, and highlights its potential in cellular mechanism research and drug testing applications.}, } @article {pmid38988889, year = {2024}, author = {Ansari, U and Alam, M and Nadora, D and Muttalib, Z and Chen, V and Taguinod, I and FitzPatrick, M and Wen, J and Ansari, Z and Lui, F}, title = {Assessing the efficacy of amyotrophic lateral sclerosis drugs in slowing disease progression: A literature review.}, journal = {AIMS neuroscience}, volume = {11}, number = {2}, pages = {166-177}, pmid = {38988889}, issn = {2373-7972}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and intricate neurodegenerative disease that impacts upper and lower motor neurons within the central nervous system, leading to their progressive destruction. Despite extensive research, the pathogenesis of this multifaceted disease remains elusive. The United States Food and Drug Administration (FDA) has granted approval for seven medications designed to address ALS and mitigate its associated symptoms. These FDA-sanctioned treatments are Qalsody, Relyvrio, Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta. In this review, the effects of these seven drugs on ALS based on their mechanism of action, dosing, and clinical presentations are comprehensively summarized. Each medication offers a distinct approach to manage ALS, aiming to alleviate the burdensome symptoms and slow the disease's progression, thereby improving the quality of life for individuals affected by this neurological condition. However, despite these advancements in pharmaceutical interventions, finding a definitive cure for ALS remains a significant challenge. Continuous investigation into ALS pathophysiology and therapeutic avenues remains imperative, necessitating further research collaborations and innovative approaches to unravel the complex mechanisms underlying this debilitating condition.}, } @article {pmid38989463, year = {2024}, author = {Pasternack, N and Doucet-O'Hare, T and Johnson, K and , and Paulsen, O and Nath, A}, title = {Endogenous retroviruses are dysregulated in ALS.}, journal = {iScience}, volume = {27}, number = {7}, pages = {110147}, pmid = {38989463}, issn = {2589-0042}, abstract = {Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease with no cure. Human endogenous retroviruses (HERVs) have been implicated in its pathogenesis but their relevance to ALS is not fully understood. We examined bulk RNA-seq data from almost 2,000 ALS and unaffected control samples derived from the cortex and spinal cord. Using different methods of feature selection, including differential expression analysis and machine learning, we discovered that transcription of HERV-K loci 1q22 and 8p23.1 were significantly upregulated in the spinal cord of individuals with ALS. Additionally, we identified a subset of ALS patients with upregulated HERV-K expression in the cortex and spinal cord. We also found the expression of HERV-K loci 19q11 and 8p23.1 was correlated with protein coding genes previously implicated in ALS and dysregulated in ALS patients in this study. These results clarify the association of HERV-K and ALS and highlight specific genes in the pathobiology of late-stage ALS.}, } @article {pmid38989900, year = {2025}, author = {Marchica, V and Biasetti, L and Barnard, J and Li, S and Nikolaou, N and Frosch, MP and Lucente, DE and Eldaief, M and King, A and Fanto, M and Troakes, C and Houart, C and Smith, BN}, title = {Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissues.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {1}, pages = {276-290}, pmid = {38989900}, issn = {1460-2156}, support = {//MNDA Studentship/ ; P30 AG062421/AG/NIA NIH HHS/United States ; //Van Geest Foundation/ ; //Motor Neurone Disease Association UK/ ; //Project Grants/ ; /MRF/MRF/United Kingdom ; 855-791//Project Grant by the MNDA/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Zebrafish ; *Nuclear Envelope/metabolism/genetics ; *Mutation ; *Annexins/genetics/metabolism ; Lamin Type B/genetics/metabolism ; Frontotemporal Dementia/genetics/pathology ; Male ; Spinal Cord/metabolism/pathology ; }, abstract = {Annexin A11 mutations are a rare cause of amyotrophic lateral sclerosis (ALS), wherein replicated protein variants P36R, G38R, D40G and D40Y are located in a small helix within the long, disordered N-terminus. To elucidate disease mechanisms, we characterized the phenotypes induced by a genetic loss-of-function and by misexpression of G38R and D40G in vivo. Loss of Annexin A11 results in a low-penetrant behavioural phenotype and aberrant axonal morphology in zebrafish homozygous knockout larvae, which is rescued by human wild-type Annexin A11. Both Annexin A11 knockout/down and ALS variants trigger nuclear dysfunction characterized by Lamin B2 mislocalization. The Lamin B2 signature also presented in anterior horn, spinal cord neurons from post-mortem ALS ± frontotemporal dementia patient tissue possessing G38R and D40G protein variants. These findings suggest mutant Annexin A11 acts as a dominant negative, revealing a potential early nucleopathy highlighting nuclear envelope abnormalities preceding behavioural abnormality in animal models.}, } @article {pmid38989937, year = {2025}, author = {Locatelli, M and Farina, C}, title = {Role of copper in central nervous system physiology and pathology.}, journal = {Neural regeneration research}, volume = {20}, number = {4}, pages = {1058-1068}, pmid = {38989937}, issn = {1673-5374}, abstract = {Copper is a transition metal and an essential element for the organism, as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs, including the central nervous system. Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B, Menkes disease and Wilson's disease, respectively, and also in multifactorial neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology, reports about unbalances in copper levels and/or distribution under disease, describes relevant animal models for human disorders where copper metabolism genes are dysregulated, and discusses relevant therapeutic approaches modulating copper availability. Overall, alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.}, } @article {pmid38990842, year = {2024}, author = {Yip, PK and Pizzasegola, C and Gladman, S and Biggio, ML and Marino, M and Jayasinghe, M and Ullah, F and Dyall, SC and Malaspina, A and Bendotti, C and Michael-Titus, A}, title = {Correction: The Omega-3 Fatty Acid Eicosapentaenoic Acid Accelerates Disease Progression in a Model of Amyotrophic Lateral Sclerosis.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0307246}, pmid = {38990842}, issn = {1932-6203}, abstract = {[This corrects the article DOI: 10.1371/journal.pone.0061626.].}, } @article {pmid38990927, year = {2024}, author = {Srinivasan, V and Homer, V and Barton, D and Clutterbuck-James, A and Jenkins, S and Potter, C and Brock, K and Logan, A and Smith, D and Bruce, L and Nagy, Z and Bach, SP}, title = {A low molecular weight dextran sulphate, ILB®, for the treatment of amyotrophic lateral sclerosis (ALS): An open-label, single-arm, single-centre, phase II trial.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0291285}, pmid = {38990927}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Aged ; Prospective Studies ; Treatment Outcome ; Adult ; Neuroprotective Agents/therapeutic use/administration & dosage/adverse effects ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig´s disease, is a rare neurological condition and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics.

PATIENTS AND METHODS: This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB® (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB® administered. EudraCT number. 2018-000668-28.

FINDINGS: Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB® and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB® treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB® injection.

INTERPRETATION: Long-term weekly ILB® injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS.

TRIAL REGISTRATION: EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, "Conditions and Principles which apply to all Clinical Trials" under the header "Principles based on Articles 2 to 5 of the EU GCP Directive" in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as 'ICH GCP'). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician.}, } @article {pmid38991167, year = {2024}, author = {Cave, R}, title = {How People Living With Amyotrophic Lateral Sclerosis Use Personalized Automatic Speech Recognition Technology to Support Communication.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {11}, pages = {4186-4202}, pmid = {38991167}, issn = {1558-9102}, support = {R13 DC003383/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; *Speech Recognition Software ; Male ; Female ; *Dysarthria/etiology/psychology/rehabilitation ; Middle Aged ; Aged ; Communication ; Communication Devices for People with Disabilities ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive, ultimately fatal disease causing progressive muscular weakness. Most people living with ALS (plwALS) experience dysarthria, eventually becoming unable to communicate using natural speech. Many wish to use speech for as long as possible. Personalized automated speech recognition (ASR) model technology, such as Google's Project Relate, is argued to better recognize speech with dysarthria, supporting maintenance of understanding through real-time captioning. The objectives of this study are how plwALS and communication partners use Relate in everyday conversation over a period of up to 12 months and how it may change with any decline in speech over time.

METHOD: This study videoed interactions between three plwALS and communication partners. We assessed ASR caption accuracy and how well they preserved meaning. Conversation analysis was used to identify participants' own organizational practices in the accomplishment of interaction. Thematic analysis was used to understand better the participants' experiences of using ASR captions.

RESULTS: All plwALS reported lower-than-expected ASR accuracy when used in conversation and felt ASR captioning was only useful in certain contexts. All participants liked the concept of live captioning and were hopeful that future improvements to ASR accuracy may support their communication in everyday life.

CONCLUSIONS: Training is needed on best practices for customization and practical use of ASR technology and for the limitations of ASR in conversational settings. Support is needed for those less confident with technology and to reduce misplaced allocation of ownership of captioning errors, risking negative effects on psychological well-being.}, } @article {pmid38991324, year = {2024}, author = {Reis, J and Spencer, PS}, title = {An introduction to environmental neurotoxicology: Lessons from a clinical perspective.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123108}, doi = {10.1016/j.jns.2024.123108}, pmid = {38991324}, issn = {1878-5883}, mesh = {Humans ; *Environmental Exposure/adverse effects ; *Neurotoxicity Syndromes/etiology ; Animals ; }, abstract = {In 1992, the Committee on Neurotoxicology and Models for Assessing Risk of the National Academy of Sciences in Washington DC focused with a scientific perspective on the identification of substances with neurotoxic potential, studies of exposed populations, risk assessment, and biologic markers of disease. This Committee recommended: "all physicians should be trained to take a thorough occupational-exposure history and to be aware of other possible sources of toxic exposure". Although convened after several outbreaks of neurotoxic syndromes, clinical neurological considerations were lacking. After defining keys words, namely Environment, Neurotoxicology and Neurotoxicants, we present some demonstrative cases; e.g., the Epidemic Neuropathy in Cuba, Minamata disease, ALS/PDC on Guam, and the ALS hot spot in the French Alps. Always with a clinical and practical approach, we will then review the milieux that contain and convey potential neurotoxicants, the different exposure routes and the clinical presentations. Drawing lessons from clinical cases, we offer some thoughts concerning the future of Environmental Neurotoxicology (ENT). Pointing notably to the diffuse chemical contamination of ecosystems and living beings, including Homo sapiens, we question the real impact of agents with neurotoxic potential on the human brain, considering the effects, for example, of air pollution, endocrine disruptors and nanoparticles. Concern is expressed over the lack of knowledge of the non-monotonic kinetics of many of these chemicals, the major concern being related to mixtures and low-dose exposures, as well as the delayed appearance in clinical expression of prevalent neurodegenerative diseases.}, } @article {pmid38992244, year = {2024}, author = {Hunt von Herbing, I}, title = {Energetic Costs of Stress in Developing Fishes: Quantifying Allostasis and Allostatic Load.}, journal = {Integrative and comparative biology}, volume = {64}, number = {3}, pages = {1019-1033}, doi = {10.1093/icb/icae094}, pmid = {38992244}, issn = {1557-7023}, support = {GP64231//University of North Texas/ ; }, mesh = {Animals ; *Zebrafish/physiology/growth & development ; *Allostasis/physiology ; *Energy Metabolism ; *Stress, Physiological ; Larva/growth & development/physiology ; Yolk Sac/physiology ; Hypoxia ; }, abstract = {Stress exerts negative effects on fish health through stimulation of the hypothalamic-pituitary-interrenal axis and autonomic nervous system, resulting in heightened neural and neuroendocrine responses. Energetic investment and physiological adaptation are then required to re-establish homeostatic stability or reach a new allostatic state. The cost of the energetic investment is referred to as allostatic load (AL). While determining the sources of stress and assessing their consequences have resulted in estimates of AL, most of this work has been conducted in adult mammals and humans; no ALs exist for developing fish. From a series of experiments on a model species, zebrafish (Danio rerio), whose yolk-sac larvae were exposed to two chronic stressors (high-temperature and hypoxia), ALs were quantified based on biomarkers of ontogenetic changes in growth, morphometrics, and metabolic activities. Results showed that for zebrafish yolk-sac larvae, chronic stress imposed high AL and, thus, high total allostatic energetic costs, (Rt (AL)), because of prolonged energy demand in the face of limited resources (e.g., yolk). Under severe chronic stress, energetic costs were sufficiently large that energy-limited developing fish may not be able to fully compensate, resulting in maladaptive responses from allostatic overload, leading either to death or to novel allostatic states, possibly more resilient to environmental change.}, } @article {pmid38995133, year = {2024}, author = {Bacigalupo, I and Finocchietti, M and Paoletti, O and Bargagli, AM and Brunori, P and Lombardi, N and Sciancalepore, F and Agabiti, N and Kirchmayer, U}, title = {Incidence and prevalence of Amyotrophic Lateral Sclerosis in three Italian Regions: a study based on health administrative databases.}, journal = {Epidemiologia e prevenzione}, volume = {48}, number = {3}, pages = {201-209}, doi = {10.19191/EP24.3.A710.055}, pmid = {38995133}, issn = {1120-9763}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Italy/epidemiology ; Incidence ; Prevalence ; Male ; Aged ; Female ; Retrospective Studies ; Middle Aged ; Adult ; Databases, Factual ; Aged, 80 and over ; Sex Distribution ; Adolescent ; Archives ; Algorithms ; Young Adult ; Age Distribution ; }, abstract = {OBJECTIVES: to estimate Amyotrophic Lateral Sclerosis (ALS) incidence and prevalence in three Italian Regions (Lazio, Tuscany, and Umbria), using health administrative databases.

DESIGN: retrospective population-based study.

SETTING AND PARTICIPANTS: ALS patients residing in Lazio, Umbria, and Tuscany were identified through an algorithm based on three different administrative databases: hospital discharge records, exemptions from health care co-payment, and emergency departments (study period 2014-2019). Crude, age- and gender-specific prevalence were calculated on 31.12.2019 and incidence rates of ALS were standardised by region, year, and gender between 2014-2019. Using a clinical dataset available in the Lazio Region, the proportion of individuals residing in the region correctly identified as ALS cases by the algorithm were calculated.

MAIN OUTCOMES MEASURES: prevalence and incidence rates.

RESULTS: a total of 1,031 ALS patients (>=18 years) were identified: 408 cases in Tuscany, 546 in Lazio, and 77 in Umbria. ALS standardised prevalence (per 100,000) was similar among regions: 12.31 in Tuscany, 11.52 in Lazio, and 9.90 in Umbria. The 5-year crude rates were higher in men, and in people aged 65-79 years. Among 310 patients included in the clinical dataset, 263 (84.8%) were correctly identified by the algorithm based on health administrative databases.

CONCLUSIONS: ALS prevalence and incidence in three Central Italy Regions are rather similar, but slightly higher than those previously reported. This finding is plausible, given that previous results relate to at least ten years ago and evidenced increasing trends. Overall, the results of this paper encourage the use of administrative data to produce occurrence estimates, useful to both epidemiological surveillance and research and healthcare policies.}, } @article {pmid38996643, year = {2024}, author = {Sheehan, Y and Cochrane, A and Treloar, C and Grebely, J and Tedla, N and Lloyd, AR and Lafferty, L}, title = {Understanding hepatitis C virus (HCV) health literacy and educational needs among people in prison to enhance HCV care in prisons.}, journal = {The International journal on drug policy}, volume = {130}, number = {}, pages = {104516}, doi = {10.1016/j.drugpo.2024.104516}, pmid = {38996643}, issn = {1873-4758}, mesh = {Humans ; Male ; *Health Literacy ; *Hepatitis C ; *Prisoners/psychology ; Adult ; Australia ; *Prisons ; Middle Aged ; Health Knowledge, Attitudes, Practice ; Substance Abuse, Intravenous ; }, abstract = {BACKGROUND: Hepatitis C virus (HCV) is a significant concern within prison populations. Provision of HCV testing and treatment for people in prison is expanding and a key component of global elimination efforts. Despite growing service availability, several challenges remain in HCV testing and treatment engagement during incarceration. The PIVOT study demonstrated that a 'one-stop-shop' intervention (point-of-care HCV RNA testing, Fibroscan®, nurse-led clinical assessment, and fast-tracked direct-acting antiviral prescription) enhanced HCV testing and treatment at a reception prison in Australia. Utilising Squier et al's Health Literacy Skills Framework, this analysis aimed to understand HCV health literacy and educational needs among people at a reception prison in Australia.

METHODS: Semi-structured interviews were conducted with twenty-four male PIVOT study participants. Purposive sampling ensured comparable representation of those with: 1) prior HCV testing history (standard pathology / no prior testing), and 2) injecting drug use history (IDU; ever / never).

RESULTS: Varied HCV health literacy levels and educational needs were evident amongst people in prison. Whilst those with multiple incarceration episodes and IDU history (prior knowledge) appeared to have stronger HCV health literacy than those without, substantial gaps in HCV health literacy were evident. Knowledge of HCV transmission risks in prison was high, and most understood the importance of HCV testing and treatment in prison (comprehension), but ability to engage with HCV testing and treatment services, participation in safe injecting behaviours (health-related behaviours), and knowledge of re-infection and re-treatment, within the context of the prison environment, were suboptimal. There was a general desire for increased HCV education in prison.

CONCLUSION: Gaps in HCV health literacy among people in prison were evident, indicating opportunities for improvement. A targeted HCV education program for people in prison, addressing the gaps identified in this analysis, may enhance HCV testing, treatment, and prevention by fostering stronger HCV health literacy among people in prison.}, } @article {pmid38996764, year = {2024}, author = {Montero, AS and Aliouat, I and Ribon, M and Canney, M and Goldwirt, L and Mourah, S and Berriat, F and Lobsiger, CS and Pradat, PF and Salachas, F and Bruneteau, G and Carpentier, A and Boillée, S}, title = {Effect of ultrasound-mediated blood-spinal cord barrier opening on survival and motor function in females in an amyotrophic lateral sclerosis mouse model.}, journal = {EBioMedicine}, volume = {106}, number = {}, pages = {105235}, pmid = {38996764}, issn = {2352-3964}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/therapy ; Female ; *Disease Models, Animal ; Mice ; *Spinal Cord/metabolism ; *Blood-Brain Barrier/metabolism ; *Insulin-Like Growth Factor I/metabolism ; Mice, Transgenic ; Humans ; Motor Neurons/metabolism ; Ultrasonic Waves ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. The limited efficacy of recent therapies in clinical development may be linked to lack of drug penetration to the affected motor neurons due to the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB).

METHODS: In this work, the safety and efficacy of repeated short transient opening of the BSCB by low intensity pulsed ultrasound (US, sonication) was studied in females of an ALS mouse model (B6.Cg-Tg(SOD1∗G93A)1Gur/J). The BSCB was disrupted using a 1 MHz ultrasound transducer coupled to the spinal cord, with and without injection of insulin-like growth factor 1 (IGF1), a neurotrophic factor that has previously shown efficacy in ALS models.

FINDINGS: Results in wild-type (WT) animals demonstrated that the BSCB can be safely disrupted and IGF1 concentrations significantly enhanced after a single session of transient BSCB disruption (176 ± 32 μg/g vs. 0.16 ± 0.008 μg/g, p < 0.0001). Five repeated weekly US sessions performed in female ALS mice demonstrated a survival advantage in mice treated with IGF1 and US (US IGF1) compared to treatment with IGF1 alone (176 vs. 166 days, p = 0.0038). Surprisingly, this survival advantage was also present in mice treated with US alone vs. untreated mice (178.5 vs. 166.5 days, p = 0.0061). Muscle strength did not show difference among the groups. Analysis of glial cell immunoreactivity and microglial transcriptome showing reduced cell proliferation pathways, in addition to lymphocyte infiltration, suggested that the beneficial effect of US or US IGF1 could act through immune cell modulation.

INTERPRETATION: These results show the first step towards a possible beneficial impact of transient BSCB opening for ALS therapy and suggest implication of immune cells.

FUNDING: Fondation pour la Recherche Médicale (FRM). Investissements d'avenirANR-10-IAIHU-06, Société Française de Neurochirurgie (SFNC), Fond d'étude et de Recherche du Corps Medical (FERCM), Aide à la Recherche des Maladies du Cerveau (ARMC), SLA Fondation Recherche (SLAFR), French Ministry for High Education and Research (MENR), Carthera, Laboratoire de Recherche en Technologies Chirurgicales Avancées (LRTCA).}, } @article {pmid38996790, year = {2024}, author = {Alqahtani, A and Alsubai, S and Sha, M and Dutta, AK and Zhang, YD}, title = {Intellectual assessment of amyotrophic lateral sclerosis using deep resemble forward neural network.}, journal = {Neural networks : the official journal of the International Neural Network Society}, volume = {178}, number = {}, pages = {106478}, doi = {10.1016/j.neunet.2024.106478}, pmid = {38996790}, issn = {1879-2782}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/complications ; Humans ; *Neural Networks, Computer ; Deep Learning ; Algorithms ; Reproducibility of Results ; Machine Learning ; }, abstract = {ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disorder causing profound physical disability that severely impairs a patient's life expectancy and quality of life. It also leads to muscular atrophy and progressive weakness of muscles due to insufficient nutrition in the body. At present, there are no disease-modifying therapies to cure ALS, and there is a lack of preventive tools. The general clinical assessments are based on symptom reports, neurophysiological tests, neurological examinations, and neuroimaging. But, these techniques possess various limitations of low reliability, lack of standardized protocols, and lack of sensitivity, especially in the early stages of disease. So, effective methods are required to detect the progression of the disease and minimize the suffering of patients. Extensive studies concentrated on investigating the causes of neurological disease, which creates a barrier to precise identification and classification of genes accompanied with ALS disease. Hence, the proposed system implements a deep RSFFNNCNN (Resemble Single Feed Forward Neural Network-Convolutional Neural Network) algorithm to effectively classify the clinical associations of ALS. It involves the addition of custom weights to the kernel initializer and neutralizer 'k' parameter to each hidden layer in the network. This is done to increase the stability and learning ability of the classifier. Additionally, the comparison of the proposed approach is performed with SFNN (Single Feed NN) and ML (Machine Learning) based algorithms, namely, NB (Naïve Bayes), XGBoost (Extreme Gradient Boosting) and RF (Random Forest), to estimate the efficacy of the proposed model. The reliability of the proposed algorithm is measured by deploying performance metrics such as precision, recall, F1 score, and accuracy.}, } @article {pmid38997630, year = {2024}, author = {Staderini, T and Bigi, A and Lagrève, C and Marzi, I and Bemporad, F and Chiti, F}, title = {Biophysical characterization of the phase separation of TDP-43 devoid of the C-terminal domain.}, journal = {Cellular & molecular biology letters}, volume = {29}, number = {1}, pages = {104}, pmid = {38997630}, issn = {1689-1392}, support = {AriSLA//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; project TDP-43-STRUCT//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; PRIN Project 2020PBS5MJ//Ministero dell'Università e della Ricerca/ ; Fondi di Ateneo 2021//Università degli studi di Firenze/ ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry ; Humans ; *Protein Domains ; Fluorescence Recovery After Photobleaching ; Phase Separation ; }, abstract = {BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP), amyotrophic lateral sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE) are associated with deposition of cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) in neurons. One complexity of this process lies in the ability of TDP-43 to form liquid-phase membraneless organelles in cells. Previous work has shown that the recombinant, purified, prion-like domain (PrLD) forms liquid droplets in vitro, but the behaviour of the complementary fragment is uncertain.

METHODS: We have purified such a construct without the PrLD (PrLD-less TDP-43) and have induced its phase separation using a solution-jump method and an array of biophysical techniques to study the morphology, state of matter and structure of the TDP-43 assemblies.

RESULTS: The fluorescent TMR-labelled protein construct, imaged using confocal fluorescence, formed rapidly (< 1 min) round, homogeneous and 0.5-1.0 µm wide assemblies which then coalesced into larger, yet round, species. When labelled with AlexaFluor488, they initially exhibited fluorescence recovery after photobleaching (FRAP), showing a liquid behaviour distinct from full-length TDP-43 and similar to PrLD. The protein molecules did not undergo major structural changes, as determined with circular dichroism and intrinsic fluorescence spectroscopies. This process had a pH and salt dependence distinct from those of full-length TDP-43 and its PrLD, which can be rationalized on the grounds of electrostatic forces.

CONCLUSIONS: Similarly to PrLD, PrLD-less TDP-43 forms liquid droplets in vitro through liquid-liquid phase separation (LLPS), unlike the full-length protein that rather undergoes liquid-solid phase separation (LSPS). These results offer a rationale of the complex electrostatic forces governing phase separation of full-length TDP-43 and its fragments. On the one hand, PrLD-less TDP-43 has a low pI and oppositively charged domains, and LLPS is inhibited by salts, which attenuate inter-domain electrostatic attractions. On the other hand, PrLD is positively charged due to a high isoionic point (pI) and LLPS is therefore promoted by salts and pH increases as they both reduce electrostatic repulsions. By contrast, full-length TDP-43 undergoes LSPS most favourably at its pI, with positive and negative salt dependences at lower and higher pH, respectively, depending on whether repulsive or attractive forces dominate, respectively.}, } @article {pmid38997636, year = {2024}, author = {Karagianni, K and Dafou, D and Xanthopoulos, K and Sklaviadis, T and Kanata, E}, title = {RNA editing regulates glutamatergic synapses in the frontal cortex of a molecular subtype of Amyotrophic Lateral Sclerosis.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {101}, pmid = {38997636}, issn = {1528-3658}, support = {01146//Hellenic Foundation for Research and Innovation (H.F.R.I.) under the "2nd Call for H.F.R.I. Research Projects to support Post-Doctoral Researchers"/ ; 10829//Hellenic Foundation for Research and Innovation (H.F.R.I.) under the 4th Call for H.F.R.I. PhD Fellowships/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *RNA Editing ; Humans ; *Frontal Lobe/metabolism ; *Synapses/metabolism/genetics ; Transcriptome ; Gene Expression Profiling ; Glutamic Acid/metabolism ; Computational Biology/methods ; Male ; Female ; Gene Expression Regulation ; Middle Aged ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a highly heterogenous neurodegenerative disorder that primarily affects upper and lower motor neurons, affecting additional cell types and brain regions. Underlying molecular mechanisms are still elusive, in part due to disease heterogeneity. Molecular disease subtyping through integrative analyses including RNA editing profiling is a novel approach for identification of molecular networks involved in pathogenesis.

METHODS: We aimed to highlight the role of RNA editing in ALS, focusing on the frontal cortex and the prevalent molecular disease subtype (ALS-Ox), previously determined by transcriptomic profile stratification. We established global RNA editing (editome) and gene expression (transcriptome) profiles in control and ALS-Ox cases, utilizing publicly available RNA-seq data (GSE153960) and an in-house analysis pipeline. Functional annotation and pathway analyses identified molecular processes affected by RNA editing alterations. Pearson correlation analyses assessed RNA editing effects on expression. Similar analyses on additional ALS-Ox and control samples (GSE124439) were performed for verification. Targeted re-sequencing and qRT-PCR analysis targeting CACNA1C, were performed using frontal cortex tissue from ALS and control samples (n = 3 samples/group).

RESULTS: We identified reduced global RNA editing in the frontal cortex of ALS-Ox cases. Differentially edited transcripts are enriched in synapses, particularly in the glutamatergic synapse pathway. Bioinformatic analyses on additional ALS-Ox and control RNA-seq data verified these findings. We identified increased recoding at the Q621R site in the GRIK2 transcript and determined positive correlations between RNA editing and gene expression alterations in ionotropic receptor subunits GRIA2, GRIA3 and the CACNA1C transcript, which encodes the pore forming subunit of a post-synaptic L-type calcium channel. Experimental data verified RNA editing alterations and editing-expression correlation in CACNA1C, highlighting CACNA1C as a target for further study.

CONCLUSIONS: We provide evidence on the involvement of RNA editing in the frontal cortex of an ALS molecular subtype, highlighting a modulatory role mediated though recoding and gene expression regulation on glutamatergic synapse related transcripts. We report RNA editing effects in disease-related transcripts and validated editing alterations in CACNA1C. Our study provides targets for further functional studies that could shed light in underlying disease mechanisms enabling novel therapeutic approaches.}, } @article {pmid38997748, year = {2024}, author = {Kato, C and Ueda, K and Morimoto, S and Takahashi, S and Nakamura, S and Ozawa, F and Ito, D and Daté, Y and Okada, K and Kobayashi, N and Nakahara, J and Okano, H}, title = {Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery.}, journal = {Inflammation and regeneration}, volume = {44}, number = {1}, pages = {32}, pmid = {38997748}, issn = {1880-9693}, support = {JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; }, abstract = {BACKGROUND: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs.

METHODS: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment.

RESULTS: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search.

CONCLUSIONS: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.}, } @article {pmid38999371, year = {2024}, author = {Dell'Anna, G and Fanti, L and Fanizza, J and Barà, R and Barchi, A and Fasulo, E and Elmore, U and Rosati, R and Annese, V and Laterza, L and Fuccio, L and Azzolini, F and Danese, S and Mandarino, FV}, title = {VAC-Stent in the Treatment of Post-Esophagectomy Anastomotic Leaks: A New "Kid on the Block" Who Marries the Best of Old Techniques-A Review.}, journal = {Journal of clinical medicine}, volume = {13}, number = {13}, pages = {}, pmid = {38999371}, issn = {2077-0383}, abstract = {Esophagectomy, while a pivotal treatment for esophageal cancer, is not without adverse events. Among these, anastomotic leak (AL) is the most feared complication, threatening patient lives and incurring significant healthcare costs. The management of AL is complex and lacks standardization. Given the high morbidity and mortality rates associated with redo-surgery, which poses risks for already fragile patients, various endoscopic treatments have been developed over time. Self-expandable metallic stents (SEMSs) were the most widely used treatment until the early 2000s. The mechanism of action of SEMSs includes covering the wall defect, protecting it from secretions, and promoting healing. In 2010, endoscopic vacuum therapy (EVT) emerged as a viable alternative for treating ALs, quickly gaining acceptance in clinical practice. EVT involves placing a dedicated sponge under negative pressure inside or adjacent to the wall defect, aiming to clear the leak and promote granulation tissue formation. More recently, the VAC-Stent entered the scenario of endoscopic treatment of post-esophagectomy ALs. This device combines a fully covered SEMS with an integrated EVT sponge, blending the ability of SEMSs to exclude defects and maintain the patency of the esophageal lumen with the capacity of EVT to aspirate secretions and promote the formation of granulation tissue. Although the literature on this new device is not extensive, early results from the application of VAC-Stent have shown promising outcomes. This review aims to synthesize the preliminary efficacy and safety data on the device, thoroughly analyze its advantages over traditional techniques and disadvantages, explore areas for improvement, and propose future directions.}, } @article {pmid38999592, year = {2024}, author = {Li, Q and Wang, H and Yu, J and Zhang, W and Guo, W and Liu, Y}, title = {Metabolism-Based Herbicide Resistance to Mesosulfuron-methyl and Identification of Candidate Genes in Bromus japonicus.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {13}, pages = {}, pmid = {38999592}, issn = {2223-7747}, support = {23JCQNJC00450//Tianjin Natural Science Foundation/ ; 2021CXGC010811//Key R&D Program of Shandong Province, China/ ; }, abstract = {The evolved resistance of Bromus japonicus Houtt. to ALS-inhibiting herbicides is well established. Previous studies have primarily focused on target-site resistance; however, non-target-site resistance has not been well characterized. This investigation demonstrated that ALS gene sequencing did not detect any previously known resistance mutations in a mesosulfuron-methyl-resistant (MR) population, and notably, treatment with the P450 monooxygenase (P450) inhibitor malathion markedly heightened susceptibility to mesosulfuron-methyl. Utilizing UPLC-MS/MS analysis confirmed elevated mesosulfuron-methyl metabolism in MR plants. The integration of Isoform Sequencing (Iso-Seq) and RNA Sequencing (RNA-Seq) facilitated the identification of candidate genes associated with non-target sites in a subpopulation with two generations of herbicide selection. Through qRT-PCR analysis, 21 differentially expressed genes were characterized, and among these, 10 genes (comprising three P450s, two glutathione S-transferases, one glycosyltransferase, two ATP-binding cassette transporters, one oxidase, and one hydrolase) exhibited constitutive upregulation in resistant plants. Our findings substantiated that increased herbicide metabolism is a driving force behind mesosulfuron-methyl resistance in this B. japonicus population.}, } @article {pmid38999600, year = {2024}, author = {Chakraborty, N and Das, A and Pal, S and Roy, S and Sil, SK and Adak, MK and Hassanzamman, M}, title = {Exploring Aluminum Tolerance Mechanisms in Plants with Reference to Rice and Arabidopsis: A Comprehensive Review of Genetic, Metabolic, and Physiological Adaptations in Acidic Soils.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {13}, pages = {}, pmid = {38999600}, issn = {2223-7747}, abstract = {Aluminum (Al) makes up a third of the Earth's crust and is a widespread toxic contaminant, particularly in acidic soils. It impacts crops at multiple levels, from cellular to whole plant systems. This review delves into Al's reactivity, including its cellular transport, involvement in oxidative redox reactions, and development of specific metabolites, as well as the influence of genes on the production of membrane channels and transporters, alongside its role in triggering senescence. It discusses the involvement of channel proteins in calcium influx, vacuolar proton pumping, the suppression of mitochondrial respiration, and the initiation of programmed cell death. At the cellular nucleus level, the effects of Al on gene regulation through alterations in nucleic acid modifications, such as methylation and histone acetylation, are examined. In addition, this review outlines the pathways of Al-induced metabolic disruption, specifically citric acid metabolism, the regulation of proton excretion, the induction of specific transcription factors, the modulation of Al-responsive proteins, changes in citrate and nucleotide glucose transporters, and overall metal detoxification pathways in tolerant genotypes. It also considers the expression of phenolic oxidases in response to oxidative stress, their regulatory feedback on mitochondrial cytochrome proteins, and their consequences on root development. Ultimately, this review focuses on the selective metabolic pathways that facilitate Al exclusion and tolerance, emphasizing compartmentalization, antioxidative defense mechanisms, and the control of programmed cell death to manage metal toxicity.}, } @article {pmid39000168, year = {2024}, author = {Ciuro, M and Sangiorgio, M and Cacciato, V and Cantone, G and Fichera, C and Salvatorelli, L and Magro, G and Leanza, G and Vecchio, M and Valle, MS and Gulino, R}, title = {Mitigating the Functional Deficit after Neurotoxic Motoneuronal Loss by an Inhibitor of Mitochondrial Fission.}, journal = {International journal of molecular sciences}, volume = {25}, number = {13}, pages = {}, pmid = {39000168}, issn = {1422-0067}, support = {2015MJBEM2_006//the Italian "Ministero dell'Istruzione, dell'Università e della Ricerca"/ ; }, mesh = {Animals ; *Motor Neurons/drug effects/metabolism/pathology ; *Mitochondrial Dynamics/drug effects ; Mice ; *Disease Models, Animal ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; Cholera Toxin/metabolism ; Saporins ; Quinazolinones/pharmacology ; Neuronal Plasticity/drug effects ; Male ; Mitochondria/drug effects/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an extremely complex neurodegenerative disease involving different cell types, but motoneuronal loss represents its main pathological feature. Moreover, compensatory plastic changes taking place in parallel to neurodegeneration are likely to affect the timing of ALS onset and progression and, interestingly, they might represent a promising target for disease-modifying treatments. Therefore, a simplified animal model mimicking motoneuronal loss without the other pathological aspects of ALS has been established by means of intramuscular injection of cholera toxin-B saporin (CTB-Sap), which is a targeted neurotoxin able to kill motoneurons by retrograde suicide transport. Previous studies employing the mouse CTB-Sap model have proven that spontaneous motor recovery is possible after a subtotal removal of a spinal motoneuronal pool. Although these kinds of plastic changes are not enough to counteract the functional effects of the progressive motoneuron degeneration, it would nevertheless represent a promising target for treatments aiming to postpone ALS onset and/or delay disease progression. Herein, the mouse CTB-Sap model has been used to test the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) as a tool to counteract the CTB-Sap toxicity and/or to promote neuroplasticity. The homeostasis of mitochondrial fission/fusion dynamics is indeed important for cell integrity, and it could be affected during neurodegeneration. Lesioned mice were treated with Mdivi-1 and then examined by a series of behavioral test and histological analyses. The results have shown that the drug may be capable of reducing functional deficits after the lesion and promoting synaptic plasticity and neuroprotection, thus representing a putative translational approach for motoneuron disorders.}, } @article {pmid39000336, year = {2024}, author = {Bodai, L and Borosta, R and Ferencz, Á and Kovács, M and Zsindely, N}, title = {The Role of miR-137 in Neurodegenerative Disorders.}, journal = {International journal of molecular sciences}, volume = {25}, number = {13}, pages = {}, pmid = {39000336}, issn = {1422-0067}, support = {OTKA 145898//National Research, Development and Innovation Office [Hungary]/ ; }, mesh = {*MicroRNAs/genetics/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Animals ; Gene Expression Regulation ; }, abstract = {Neurodegenerative diseases affect an increasing part of the population of modern societies, burdening healthcare systems and causing immense suffering at the personal level. The pathogenesis of several of these disorders involves dysregulation of gene expression, which depends on several molecular processes ranging from transcription to protein stability. microRNAs (miRNAs) are short non-coding RNA molecules that modulate gene expression by suppressing the translation of partially complementary mRNAs. miR-137 is a conserved, neuronally enriched miRNA that is implicated in neurodegeneration. Here, we review the current body of knowledge about the role that miR-137 plays in five prominent neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The presented data indicate that, rather than having a general neuroprotective role, miR-137 modulates the pathology of distinct disorders differently.}, } @article {pmid39000814, year = {2024}, author = {Fan, S and Jing, S and Xu, W and Wu, B and Li, M and Jing, H}, title = {Extraction of Moso Bamboo Parameters Based on the Combination of ALS and TLS Point Cloud Data.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {13}, pages = {}, pmid = {39000814}, issn = {1424-8220}, support = {LTGC23C160002//Zhejiang Provincial Natural Science Foundation of China/ ; 2021LFR057//Research Fund of Zhejiang A&F University/ ; 2023LFK141//Research Fund of Zhejiang A&F University/ ; }, mesh = {*Algorithms ; Sasa ; Lasers ; Poaceae ; }, abstract = {Extracting moso bamboo parameters from single-source point cloud data has limitations. In this article, a new approach for extracting moso bamboo parameters using airborne laser scanning (ALS) and terrestrial laser scanning (TLS) point cloud data is proposed. Using the field-surveyed coordinates of plot corner points and the Iterative Closest Point (ICP) algorithm, the ALS and TLS point clouds were aligned. Considering the difference in point distribution of ALS, TLS, and the merged point cloud, individual bamboo plants were segmented from the ALS point cloud using the point cloud segmentation (PCS) algorithm, and individual bamboo plants were segmented from the TLS and the merged point cloud using the comparative shortest-path (CSP) method. The cylinder fitting method was used to estimate the diameter at breast height (DBH) of the segmented bamboo plants. The accuracy was calculated by comparing the bamboo parameter values extracted by the above methods with reference data in three sample plots. The comparison results showed that by using the merged data, the detection rate of moso bamboo plants could reach up to 97.30%; the R[2] of the estimated bamboo height was increased to above 0.96, and the root mean square error (RMSE) decreased from 1.14 m at most to a range of 0.35-0.48 m, while the R[2] of the DBH fit was increased to a range of 0.97-0.99, and the RMSE decreased from 0.004 m at most to a range of 0.001-0.003 m. The accuracy of moso bamboo parameter extraction was significantly improved by using the merged point cloud data.}, } @article {pmid39001793, year = {2024}, author = {Gao, J and Okolo, O and Siedlak, SL and Friedland, RP and Wang, X}, title = {Ferritin is closely associated with microglia in amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {11}, pages = {917-926}, pmid = {39001793}, issn = {1554-6578}, support = {RF1 AG066578/AG/NIA NIH HHS/United States ; RF1 AG056320/AG/NIA NIH HHS/United States ; R01 AG066578/AG/NIA NIH HHS/United States ; HHSN275200900011C/HD/NICHD NIH HHS/United States ; RF1AG066578/NH/NIH HHS/United States ; AARG-22-923849/ALZ/Alzheimer's Association/United States ; //Brain and Tissue Bank for Developmental Disorders/ ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; RF1 AG065342/AG/NIA NIH HHS/United States ; HHSN275200900011C/HD/NICHD NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Microglia/metabolism/pathology ; *Ferritins/metabolism ; Humans ; *Mice, Transgenic ; Animals ; Female ; Male ; Mice ; Middle Aged ; *Spinal Cord/pathology/metabolism ; Aged ; Aged, 80 and over ; DNA-Binding Proteins/metabolism/genetics ; Superoxide Dismutase/metabolism/genetics ; }, abstract = {Iron deposition is a hallmark of amyotrophic lateral sclerosis (ALS) and has been strongly implicated in its pathogenesis. As a byproduct of cellular oxidative stress, iron dysregulation modifies basal levels of the regulatory iron-binding protein ferritin. Examination of thoracic and lumbar spinal cord tissues found increased ferritin immunostaining in white matter axons that corresponded to areas of increased microgliosis in 8 ALS patients versus 8 normal subjects. Gray matter areas containing the motor neurons also demonstrated increased ferritin and microglia in ALS compared to controls but at lower levels than in the white matter. Motor neurons with or without TDP-43 inclusions did not demonstrate either increased ferritin or associated microglial activation. We also observed an association of ferritin with microglia in cerebral cortical tissue samples of ALS cases and in the spinal cord tissues of transgenic mice expressing the SOD1G93A mutation. Elevated ferritin levels were detected in the insoluble fraction from spinal cord tissues of individuals with ALS. These findings suggest that activated microglia and increased ferritin may play significant roles in ALS progression since they are found closely associated in areas of axonal and cortical degeneration.}, } @article {pmid39002563, year = {2024}, author = {Shih, PC and Wei, JCC}, title = {Response to Hasan et al's "Dupilumab therapy for atopic dermatitis is associated with increased risk of cutaneous T cell lymphoma: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {5}, pages = {e137-e138}, doi = {10.1016/j.jaad.2024.06.076}, pmid = {39002563}, issn = {1097-6787}, } @article {pmid39002811, year = {2024}, author = {Huin, V and Blum, D and Delforge, V and Cailliau, E and Djeziri, S and Dujardin, K and Genet, A and Viard, R and Attarian, S and Bruneteau, G and Cassereau, J and Genestet, S and Kaminsky, AL and Soriani, MH and Lefilliatre, M and Couratier, P and Pittion-Vouyovitch, S and Esselin, F and De La Cruz, E and Guy, N and Kolev, I and Corcia, P and Cintas, P and Desnuelle, C and Buée, L and Danel-Brunaud, V and Devos, D and Rolland, AS}, title = {Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition.}, journal = {Neurobiology of disease}, volume = {199}, number = {}, pages = {106603}, doi = {10.1016/j.nbd.2024.106603}, pmid = {39002811}, issn = {1095-953X}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Basic Helix-Loop-Helix Proteins ; *Caffeine ; Central Nervous System Stimulants/therapeutic use ; Cognition/physiology/drug effects ; Cognitive Dysfunction/genetics ; Cytochrome P-450 CYP1A1/genetics ; *Cytochrome P-450 CYP1A2/genetics ; *Disease Progression ; *Polymorphism, Single Nucleotide ; Prospective Studies ; *Receptor, Adenosine A2A/genetics ; Receptors, Aryl Hydrocarbon/genetics ; Riluzole/therapeutic use ; }, abstract = {Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.}, } @article {pmid39003629, year = {2024}, author = {Yao, S and Yin, H and Li, Y and Yang, Q and Yuan, S and Deng, W}, title = {Cytochrome P450 CYP81A104 in Eleusine indica confers resistance to multiherbicide with different modes of action.}, journal = {Pest management science}, volume = {80}, number = {11}, pages = {5791-5798}, doi = {10.1002/ps.8310}, pmid = {39003629}, issn = {1526-4998}, support = {32372569//National Natural Science Foundation of China/ ; 137050535//Qing Lan Project of Yangzhou University/ ; }, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Cytochrome P-450 Enzyme System/genetics/metabolism ; *Eleusine/genetics/drug effects/enzymology ; Acetolactate Synthase/genetics/metabolism ; Plant Proteins/genetics/metabolism ; Arabidopsis/genetics/drug effects/enzymology ; Plant Weeds/drug effects/genetics ; Imidazoles ; }, abstract = {BACKGROUND: Developing herbicide-resistant (HR) crop cultivars is an efficient way to control weeds and minimize crop yield losses. However, widespread and long-term herbicide application has led to the evolution of resistant weeds. Here, we established a resistant (R) E. indica population, collected from imidazolinone-resistant rice cultivar fields.

RESULTS: The R population evolved 4.5-fold resistance to imazamox. Acetolactate synthase (ALS) gene sequencing and ALS activity assays excluded the effect of target-site resistance in this population. P450 inhibitor malathion pretreatment significantly reversed resistance to imazamox. RNA sequencing showed that a P450 gene CYP81A104 was expressed higher in R versus susceptible (S) plants. Arabidopsis overexpressing CYP81A104 showed resistance to ALS inhibitors (imazamox, tribenuron-methyl, penoxsulam and flucarbazone-sodium), PSII inhibitor (bentazone), hydroxyphenyl pyruvate dioxygenase inhibitor (mesotrione) and auxin mimics (MCPA), which was generally consistent with the results presented in the R population.

CONCLUSION: This study confirmed that the CYP81A104 gene endowed resistance to multiherbicides with different modes-of-action. Our findings provide an insight into the molecular characteristics of resistance and contribute to formulating an appropriate strategy for weed management in HR crops. © 2024 Society of Chemical Industry.}, } @article {pmid39004370, year = {2024}, author = {Hajdukiewicz, H and Hajdukiewicz, M and Ruiz-Villanueva, V and Radecki-Pawlik, A and Zawiejska, J}, title = {Exploring historical changes in mountain river hydrodynamics induced by human impact.}, journal = {The Science of the total environment}, volume = {948}, number = {}, pages = {174742}, doi = {10.1016/j.scitotenv.2024.174742}, pmid = {39004370}, issn = {1879-1026}, abstract = {During the 20th-century many mountain rivers in Europe were subjected to intensive human impacts which substantially modified their channel morphology. How these changes affected river hydrodynamics and response to floods remains uncertain. In this work, we perform hydraulic modelling using data from archival aerial photos to explore relations between hydraulic parameters of floods and human-induced channel incision occurring on the Czarny Dunajec River (Polish Carpathians) between 1964 and 2012. Data on vertical position of the channel used for two-dimensional modelling of flood flows were extracted (as Digital Elevation Models DEMs) from archival aerial photos from 1964 and 1983 and ALS (Airborne Laser Skanning)-derived DEM from 2012. Water depth, flow velocity, bed shear stress, and sediment critical diameter were modelled for four flood scenarios (2-year, 5-year, 20-year, and 50-year floods) as well as the extent of flooded area and additionally the grain size of channel sediment was calculated. The values of water depth, flow velocity, bed shear stress and sediment critical diameter increased significantly between 1964 and 1983, especially for 20-year and 50-year floods. Only the flow velocity within the floodplain zone did not increase for the two largest flood scenarios due to the expansion of riparian forest in the second half of the twentieth century. The increase in flow rate was accompanied by a progressive reduction of the extent of flooded area, especially between 1964 and 1983, as well as by increase in mean grain size of channel sediment. Between 1983 and 2012 changes in hydraulic parameters were less pronounced, and coarser and well packed channel sediment dominated on the river bed. Our work demonstrates that reconstruction of past river hydrodynamics, rather than river state at time horizons, can give essential insights into functioning of the river channel and floodplain during the intensification of human impacts after 1950s.}, } @article {pmid39004530, year = {2024}, author = {Vacchiano, V and Di Stasi, V and Bruni, S and Rizzo, G and Liguori, R}, title = {Thoracic paraspinal muscles denervation assessment in amyotrophic lateral sclerosis: Clinical-neurophysiological correlations and prognostic value.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123133}, doi = {10.1016/j.jns.2024.123133}, pmid = {39004530}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Paraspinal Muscles/physiopathology ; Male ; Middle Aged ; Female ; Prognosis ; Aged ; Electromyography/methods ; Muscle Denervation/methods ; Adult ; }, } @article {pmid39005258, year = {2024}, author = {Feringa, FM and Hertog, SJK and Wang, L and Derks, RJE and Kruijff, I and Erlebach, L and Heijneman, J and Miramontes, R and Pömpner, N and Blomberg, N and Olivier-Jimenez, D and Johansen, LE and Cammack, AJ and Giblin, A and Toomey, CE and Rose, IVL and Yuan, H and Ward, M and Isaacs, AM and Kampmann, M and Kronenberg-Versteeg, D and Lashley, T and Thompson, LM and Ori, A and Mohammed, Y and Giera, M and van der Kant, R}, title = {The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005258}, issn = {2692-8205}, support = {P01 NS084974/NS/NINDS NIH HHS/United States ; P30 CA062203/CA/NCI NIH HHS/United States ; T32 NS115706/NS/NINDS NIH HHS/United States ; }, abstract = {Lipid changes in the brain have been implicated in many neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named the Neurolipid Atlas, that we have pre-populated with novel human, mouse and isogenic induced pluripotent stem cell (iPSC)-derived lipidomics data for different brain diseases. We show that iPSC-derived neurons, microglia and astrocytes display distinct lipid profiles that recapitulate in vivo lipotypes. Leveraging multiple datasets, we show that the AD risk gene ApoE4 drives cholesterol ester (CE) accumulation in human astrocytes recapitulating CE accumulation measured in the human AD brain. Multi-omic interrogation of iPSC-derived astrocytes revealed that cholesterol plays a major role in astrocyte interferon-dependent pathways such as the immunoproteasome and major histocompatibility complex (MHC) class I antigen presentation. We show that through enhanced cholesterol esterification ApoE4 suppresses immune activation of astrocytes. Our novel data commons, available at neurolipidatlas.com, provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.}, } @article {pmid39005286, year = {2024}, author = {Krattli, RP and Do, AH and El-Khatib, SM and Alikhani, L and Markarian, M and Vagadia, AR and Usmani, MT and Madan, S and Baulch, JE and Clark, RJ and Woodruff, TM and Tenner, AJ and Acharya, MM}, title = {C5aR1 inhibition alleviates cranial radiation-induced cognitive decline.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.07.02.601806}, pmid = {39005286}, issn = {2692-8205}, abstract = {UNLABELLED: Cranial radiation therapy (RT) for brain cancers leads to an irreversible decline in cognitive function without an available remedy. Radiation-induced cognitive deficits (RICD) are a particularly pressing problem for the survivors of pediatric and low grade glioma (LGG) cancers who often live long post-RT lives. Radiation-induced elevated neuroinflammation and gliosis, triggered by the detrimental CNS complement cascade, lead to excessive synaptic and cognitive loss. Using intact and brain cancer-bearing mouse models, we now show that targeting anaphylatoxin complement C5a receptor (C5aR1) is neuroprotective against RICD. We used a genetic knockout, C5aR1 KO mouse, and a pharmacologic approach, employing the orally active, brain penetrant C5aR1 antagonist PMX205 to reverse RICD. Irradiated C5aR1 KO and WT mice receiving PMX205 showed significant neurocognitive improvements in object recognition memory and memory consolidation tasks. Inhibiting C5a/C5aR1 axis reduced microglial activation, astrogliosis, and synaptic loss in the irradiated brain. Importantly, C5aR1 blockage in two syngeneic, orthotopic glioblastoma-bearing mice protected against RICD without interfering with the therapeutic efficacy of RT to reduce tumor volume in vivo . PMX205 clinical trials with healthy individuals and amyotrophic lateral sclerosis (ALS) patients showed no toxicity, drug-related adverse events, or infections. Thus, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need.

SIGNIFICANCE: Cranial radiotherapy for brain cancers activates CNS complement cascade, leading to cognitive decline. Ablation of the complement C5a/C5aR1 axis alleviates radiation-induced neuroinflammation, synaptic loss, and cognitive dysfunction, providing a novel tractable approach.}, } @article {pmid39005345, year = {2024}, author = {Rizuan, A and Shenoy, J and Mohanty, P and Dos Passos, PMS and Mercado Ortiz, JF and Bai, L and Viswanathan, R and Wang, SH and Johnson, V and Mamede, LD and Ayala, YM and Ghirlando, R and Mittal, J and Fawzi, NL}, title = {Structural details of helix-mediated TDP-43 C-terminal domain multimerization.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005345}, issn = {2692-8205}, support = {R01 NS116176/NS/NINDS NIH HHS/United States ; }, abstract = {The primarily disordered C-terminal domain (CTD) of TAR DNA binding protein-43 (TDP-43), a key nuclear protein in RNA metabolism, forms neuronal inclusions in several neurodegenerative diseases. A conserved region (CR, spanning residues 319-341) in CTD forms transient helix-helix contacts important for its higher-order oligomerization and function that are disrupted by ALS-associated mutations. However, the structural details of CR assembly and the explanation for several ALS-associated variants' impact on phase separation and function remain unclear due to challenges in analyzing the dynamic association of TDP-43 CTD using traditional structural biology approaches. By employing an integrative approach, combining biophysical experiments, biochemical assays, AlphaFold2-Multimer (AF2-Multimer), and atomistic simulations, we generated structural models of helical oligomerization of TDP-43 CR. Using NMR, we first established that the native state of TDP-43 CR under physiological conditions is α-helical. Next, alanine scanning mutagenesis revealed that while hydrophobic residues in the CR are important for CR assembly, phase separation and TDP-43 nuclear retention function, polar residues down regulate these processes. Finally, pairing AF2-Multimer modeling with AAMD simulations indicated that dynamic, oligomeric assemblies of TDP-43 that are stabilized by a methionine-rich core with specific contributions from a tryptophan/leucine pair. In conclusion, our results advance the structural understanding of the mechanisms driving TDP-43 function and provide a window into the initial stages of its conversion into pathogenic aggregates.}, } @article {pmid39005384, year = {2024}, author = {Dykstra, MM and Weskamp, K and Gómez, NB and Waksmacki, J and Tank, E and Glineburg, MR and Snyder, A and Pinarbasi, E and Bekier, M and Li, X and Bai, J and Shahzad, S and Nedumaran, J and Wieland, C and Stewart, C and Willey, S and Grotewold, N and McBride, J and Moran, JJ and Suryakumar, AV and Lucas, M and Tessier, P and Ward, M and Todd, P and Barmada, SJ}, title = {TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005384}, issn = {2692-8205}, support = {F31 NS134123/NS/NINDS NIH HHS/United States ; T32 GM007863/GM/NIGMS NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; F31 NS115257/NS/NINDS NIH HHS/United States ; T32 GM145470/GM/NIGMS NIH HHS/United States ; }, abstract = {The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, highly prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a byproduct of TDP43 autoregulation and cleared by nonsense mediated RNA decay (NMD). The sTDP43-encoding transcripts that escape NMD can lead to toxicity but are rapidly degraded post-translationally. Circumventing these regulatory mechanisms by overexpressing sTDP43 results in neurodegeneration in vitro and in vivo via N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA binding-dependent gain-of-function toxicity. Collectively, these studies highlight endogenous mechanisms that tightly regulate sTDP43 expression and provide insight into the consequences of aberrant sTDP43 accumulation in disease.}, } @article {pmid39005475, year = {2024}, author = {Xie, M and Miller, AS and Pallegar, PN and Umpierre, A and Liang, Y and Wang, N and Zhang, S and Nagaraj, NK and Fogarty, ZC and Ghayal, NB and Oskarsson, B and Zhao, S and Zheng, J and Qi, F and Nguyen, A and Dickson, DW and Wu, LJ}, title = {Rod-shaped microglia interact with neuronal dendrites to regulate cortical excitability in TDP-43 related neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.30.601396}, pmid = {39005475}, issn = {2692-8205}, support = {RF1 AG082314/AG/NIA NIH HHS/United States ; }, abstract = {Motor cortical hyperexcitability is well-documented in the presymptomatic stage of amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying this early dysregulation are not fully understood. Microglia, as the principal immune cells of the central nervous system, have emerged as important players in sensing and regulating neuronal activity. Here we investigated the role of microglia in the motor cortical circuits in a mouse model of TDP-43 neurodegeneration (rNLS8). Utilizing multichannel probe recording and longitudinal in vivo calcium imaging in awake mice, we observed neuronal hyperactivity at the initial stage of disease progression. Spatial and single-cell RNA sequencing revealed that microglia are the primary responders to motor cortical hyperactivity. We further identified a unique subpopulation of microglia, rod-shaped microglia, which are characterized by a distinct morphology and transcriptional profile. Notably, rod-shaped microglia predominantly interact with neuronal dendrites and excitatory synaptic inputs to attenuate motor cortical hyperactivity. The elimination of rod-shaped microglia through TREM2 deficiency increased neuronal hyperactivity, exacerbated motor deficits, and further decreased survival rates of rNLS8 mice. Together, our results suggest that rod-shaped microglia play a neuroprotective role by attenuating cortical hyperexcitability in the mouse model of TDP-43 related neurodegeneration.}, } @article {pmid39006307, year = {2023}, author = {Ayoubi, R and Alshafie, W and Shlaifer, I and Southern, K and McPherson, PS and Laflamme, C and , }, title = {The identification of high-performing antibodies for Sequestosome-1 for use in Western blot, immunoprecipitation and immunofluorescence.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {324}, pmid = {39006307}, issn = {2046-1402}, mesh = {*Sequestosome-1 Protein/immunology/metabolism ; Humans ; *Fluorescent Antibody Technique/methods ; *Immunoprecipitation/methods ; *Blotting, Western ; Antibodies/immunology ; }, abstract = {Sequestosome-1, encoded by the gene SQSTM1, functions as a bridge between ubiquitinated proteins and the proteasome or autophagosome, thereby regulating protein degradation pathways. Loss of Sequestosome-1 is hypothesized to enhance neurodegeneration progression in several diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal disorders (FTD). Sequestosome-1 reproducible research would be facilitated with the availability of well-characterized anti-Sequestosome-1 antibodies. In this study, we characterized seventeen Sequestosome-1 commercial antibodies for Western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.}, } @article {pmid39006715, year = {2024}, author = {Suleiman Khoury, Z and Sohail, F and Wang, J and Mendoza, M and Raake, M and Tahoor Silat, M and Reddy Bathinapatta, M and Sadeghzadegan, A and Meghana, P and Paul, J}, title = {Neuroinflammation: A Critical Factor in Neurodegenerative Disorders.}, journal = {Cureus}, volume = {16}, number = {6}, pages = {e62310}, pmid = {39006715}, issn = {2168-8184}, abstract = {This review offers a comprehensive review of the signals and the paramount role neuroinflammation plays in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The study explores the sophisticated interactions between microglial, astrocytic, and dendritic cells and how neuroinflammation affects long-term neuronal damage and dysfunction. There are specific pathways related to the mentioned inflammatory processes, including Janus kinases/signal transducer and activator of transcriptions, nuclear factor-κB, and mitogen-activated protein kinases pathways. Neuroinflammation is argued to be a double-edged sword, being not only a protective agent that prevents further neuron damage but also the causative factor in more cell injury development. This concept of contrasting inflammation with neuroprotection advocates for the use of therapeutic techniques that seek to modulate neuroinflammatory responses as part of the neurodegeneration treatment. The recent research findings are integrated with the established knowledge to help present a comprehensive image of neuroinflammation's impact on neurodegenerative diseases and its implications for future therapy.}, } @article {pmid39006764, year = {2024}, author = {Yang, C and Liu, G and Chen, X and Le, W}, title = {Cerebellum in Alzheimer's disease and other neurodegenerative diseases: an emerging research frontier.}, journal = {MedComm}, volume = {5}, number = {7}, pages = {e638}, pmid = {39006764}, issn = {2688-2663}, abstract = {The cerebellum is crucial for both motor and nonmotor functions. Alzheimer's disease (AD), alongside other dementias such as vascular dementia (VaD), Lewy body dementia (DLB), and frontotemporal dementia (FTD), as well as other neurodegenerative diseases (NDs) like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias (SCA), are characterized by specific and non-specific neurodegenerations in central nervous system. Previously, the cerebellum's significance in these conditions was underestimated. However, advancing research has elevated its profile as a critical node in disease pathology. We comprehensively review the existing evidence to elucidate the relationship between cerebellum and the aforementioned diseases. Our findings reveal a growing body of research unequivocally establishing a link between the cerebellum and AD, other forms of dementia, and other NDs, supported by clinical evidence, pathological and biochemical profiles, structural and functional neuroimaging data, and electrophysiological findings. By contrasting cerebellar observations with those from the cerebral cortex and hippocampus, we highlight the cerebellum's distinct role in the disease processes. Furthermore, we also explore the emerging therapeutic potential of targeting cerebellum for the treatment of these diseases. This review underscores the importance of the cerebellum in these diseases, offering new insights into the disease mechanisms and novel therapeutic strategies.}, } @article {pmid39006831, year = {2023}, author = {Kothare, H and Neumann, M and Liscombe, J and Green, J and Ramanarayanan, V}, title = {Responsiveness, Sensitivity and Clinical Utility of Timing-Related Speech Biomarkers for Remote Monitoring of ALS Disease Progression.}, journal = {Interspeech}, volume = {2023}, number = {}, pages = {2323-2327}, pmid = {39006831}, issn = {2958-1796}, support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; }, abstract = {In this study, we describe the responsiveness of timing-related measures extracted from read speech in persons with ALS (pALS) collected via a remote patient monitoring platform in an effort to quantify how long it takes to detect a clinically-meaningful change associated with disease progression. We found that the timing alignment of pALS speech relative to a canonical elicitation of the same prompt is the most responsive measure, of the ones considered in this study, at detecting such change in both pALS with bulbar (n = 35) and non-bulbar onset (n = 94). We further evaluated the sensitivity of speech metrics in tracking disease progression in pALS while their ALSFRS-R speech score remained unchanged at 3 out of a total possible score of 4. We observed that timing-related speech metrics showed significant longitudinal changes even after accounting for learning effects. The findings of this study have the potential to inform disease prognosis and functional outcomes of clinical trials.}, } @article {pmid39006832, year = {2023}, author = {Neumann, M and Kothare, H and Ramanarayanan, V}, title = {Combining Multiple Multimodal Speech Features into an Interpretable Index Score for Capturing Disease Progression in Amyotrophic Lateral Sclerosis.}, journal = {Interspeech}, volume = {2023}, number = {}, pages = {2353-2357}, pmid = {39006832}, issn = {2958-1796}, support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; }, abstract = {Multiple speech biomarkers have been shown to carry useful information regarding Amyotrophic Lateral Sclerosis (ALS) pathology. We propose a two-step framework to compute optimal linear combinations (indexes) of these biomarkers that are more discriminative and noise-robust than the individual markers, which is important for clinical care and pharmaceutical trial applications. First, we use a hierarchical clustering based method to select representative speech metrics from a dataset comprising 143 people with ALS and 135 age- and sex-matched healthy controls. Second, we analyze three methods of index computation that optimize linear discriminability, Youden Index, and sparsity of logistic regression model weights, respectively, and evaluate their performance with 5-fold cross validation. We find that the proposed indexes are generally more discriminative of bulbar vs non-bulbar onset in ALS than their individual component metrics as well as an equally-weighted baseline.}, } @article {pmid39007083, year = {2024}, author = {Chidambaram, SB and Anand, N and Varma, SR and Ramamurthy, S and Vichitra, C and Sharma, A and Mahalakshmi, AM and Essa, MM}, title = {Superoxide dismutase and neurological disorders.}, journal = {IBRO neuroscience reports}, volume = {16}, number = {}, pages = {373-394}, pmid = {39007083}, issn = {2667-2421}, abstract = {Superoxide dismutase (SOD) is a common antioxidant enzyme found majorly in living cells. The main physiological role of SOD is detoxification and maintain the redox balance, acts as a first line of defence against Reactive nitrogen species (RNS), Reactive oxygen species (ROS), and other such potentially hazardous molecules. SOD catalyses the conversion of superoxide anion free radicals (O 2 -.) into molecular oxygen (O 2) and hydrogen peroxide (H 2O 2) in the cells. Superoxide dismutases (SODs) are expressed in neurons and glial cells throughout the CNS both intracellularly and extracellularly. Endogenous oxidative stress (OS) linked with enlarged production of reactive oxygen metabolites (ROMs), inflammation, deregulation of redox balance, mitochondrial dysfunction and bioenergetic crisis are found to be prerequisite for neuronal loss in neurological diseases. Clinical and genetic studies indicate a direct correlation between mutations in SOD gene and neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), Parkinson's Disease (PD) and Alzheimer's Disease (AD). Therefore, inhibitors of OS are considered as an optimistic approach to prevent neuronal loss. SOD mimetics like Metalloporphyrin Mn (II)-cyclic polyamines, Nitroxides and Mn (III)- Salen complexes are designed and used as therapeutic extensively in the treatment of neurological disorders. SODs and SOD mimetics are promising future therapeutics in the field of various diseases with OS-mediated pathology.}, } @article {pmid39007446, year = {2024}, author = {Torra, J and Mora, G and Montull, JM and Royo-Esnal, A and Notter, JS and Salas, M}, title = {A 4-year field study monitoring the evolution of Trp574Leu-resistant plants in an Echinochloa crus-galli population under different crop rotation and herbicide programs in maize.}, journal = {Pest management science}, volume = {80}, number = {11}, pages = {5843-5851}, doi = {10.1002/ps.8315}, pmid = {39007446}, issn = {1526-4998}, support = {//Corteva Agriscience/ ; RYC2018-023866-I//Spanish Ministry of Science, Innovation, and Universities/ ; //Spanish State Research Agency/ ; PID2020-113229RB-C42//European Regional Development Fund (ERDF)/ ; }, mesh = {*Echinochloa/drug effects/genetics ; *Zea mays/growth & development ; *Herbicide Resistance ; *Herbicides/pharmacology ; *Weed Control/methods ; *Plant Weeds/drug effects ; *Acetolactate Synthase/antagonists & inhibitors/metabolism ; Agriculture/methods ; }, abstract = {BACKGROUND: A 4-year experiment evaluated the effects of different integrated weed management (IWM) programs on the evolution of a Echinochloa crus-galli population resistant to acetolactate synthase (ALS) inhibitors in a maize cropping system. The programs included the continued use of ALS inhibitors, mixing them with alternative herbicides, or without ALS-inhibitors, in all cases under maize monocrop or a biennial crop rotation.

RESULTS: IWM programs that relied solely on non-ALS-inhibitors usually achieved high control levels across years (> 90%). Additionally, Trp574Leu-resistant plants became prevalent (> 90%) in programs only using ALS inhibitors, while in the rest the frequency of susceptible plants did not substantially decrease below 40%. Regarding the other monitored grass weeds, Digitaria sanguinalis and Panicum dichotomiflorum were effectively controlled in programs using ALS-inhibitors without soybean rotation or in programs without ALS-inhibitors altogether, excepting the program relying on an 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibitor under maize monocrop for the latter species (0%).

CONCLUSION: At the end of the experiment, the only IWM programs that reduced infestation levels were the one without ALS-inhibitors under soybean rotation, and the one with standard pre-emergence treatments. These findings highlight the effectiveness of crop rotation and alternative herbicides both pre- or post-emergence in controlling E. crus-galli. ALS-inhibitors, while challenged by resistance in E. crus-galli, remain valuable tools for managing other grass weed species in maize. It is crucial to adapt IWM strategies for herbicide-resistant E. crus-galli and other grass weed populations to mitigate the further evolution of resistance. © 2024 Corteva Agriscience. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid39007704, year = {2024}, author = {Gandhi, P and Waito, AA and Peladeau-Pigeon, M and Plowman, EK and Steele, CM}, title = {How Do Quantitative Videofluoroscopy Measures Differ Between People With Amyotrophic Lateral Sclerosis and Age-Matched Healthy Adults?.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {8}, pages = {2512-2532}, pmid = {39007704}, issn = {1558-9102}, support = {R01 AG077481/AG/NIA NIH HHS/United States ; R01 DC011020/DC/NIDCD NIH HHS/United States ; R01 NS100859/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/complications ; Male ; Female ; Aged ; Middle Aged ; Fluoroscopy/methods ; *Deglutition Disorders/physiopathology/etiology/diagnostic imaging ; Aged, 80 and over ; Retrospective Studies ; *Deglutition/physiology ; *Video Recording ; Case-Control Studies ; }, abstract = {PURPOSE: Dysphagia is a leading cause of morbidity in people with amyotrophic lateral sclerosis (PwALS). Previous videofluoroscopic swallowing studies (VFSS) in PwALS do not account for the influence of senescence. We aimed to compare swallowing in PwALS and an age- and sex-matched control group using healthy reference data to define typical and atypical values.

METHOD: We conducted retrospective analysis of VFSS data from 19 PwALS (10 male, Mage = 63 years, range: 47-82) compared to control data from a cohort of healthy adults. Participants swallowed 20% w/v liquid barium from thin to extremely thick consistency. Blinded duplicate VFSS analysis using the ASPEKT (Analysis of Swallowing Physiology: Events, Kinematics and Timing) method yielded descriptive statistics for 16 quantitative VFSS parameters by consistency. Mann-Whitney U tests were used to identify significant cohort differences. Additionally, the frequencies of atypical values (in the 25% tails of the reference distribution) were tabulated by cohort and compared using odds ratios.

RESULTS: PwALS showed increased frequencies of multiple swallows per bolus, incomplete laryngeal vestibule closure, and reduced hyoid speed across consistencies. By contrast, similar frequencies of atypical values for pharyngeal constriction and residue in both cohorts suggest that age-related changes may contribute to the presence of these features in PwALS.

CONCLUSIONS: This analysis builds on previous descriptions of swallowing pathophysiology in amyotrophic lateral sclerosis (ALS) by clarifying the extent to which aging may account for some of the atypical findings seen in this patient population. Longitudinal studies are recommended to further differentiate the effects of ALS from age-related changes in swallowing over the course of disease progression.}, } @article {pmid39008617, year = {2024}, author = {Tsitkanou, S and Lindsay, A and Abbott, G and Foletta, V and Walker, AK and Russell, AP and Della Gatta, PA}, title = {Exercise training induces mild skeletal muscle adaptations without altering disease progression in a TDP-43 mouse model.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {137}, number = {3}, pages = {728-745}, doi = {10.1152/japplphysiol.00192.2023}, pmid = {39008617}, issn = {1522-1601}, support = {//Deakin University | Institute for Physical Activity and Nutrition (IPAN)/ ; //Onassis Foundation Greece/ ; //Deakin University, Alfread Deakin PostDoc Fellowship/ ; //Neurological Foundation of New Zealand/ ; 1124005//Australian National Health and Medical Research Council/ ; //Ross Maclean Fellowship/ ; //Bill Guest FightMND Mid-Career Development Fellowship/ ; //Brazil Family Program for Neurology/ ; }, mesh = {Animals ; *Disease Progression ; *Muscle, Skeletal/metabolism/physiopathology ; Mice ; *Physical Conditioning, Animal/physiology/methods ; *Adaptation, Physiological/physiology ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/physiopathology/metabolism/therapy ; Male ; Mice, Transgenic ; }, abstract = {Exercise training is considered a nonpharmacological therapeutic approach for many diseases. Mild-to-moderate endurance exercise training is suggested to improve the mental and physical state of people with amyotrophic lateral sclerosis (ALS). The aim of the present study was to determine the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TAR DNA-binding protein 43 (TDP-43) pathology and motor dysfunction, to perform mild-to-moderate intensity treadmill exercise training and to evaluate the effects of this training on skeletal muscle health and disease progression. Symptomatic rNLS8 mice were able to complete 4 wk of mild-to-moderate treadmill running (30 min at 6-13 m/min, 3 days a week). Exercise training induced an increase in the percentage of type IIA fibers in the tibialis anterior muscle as well as minor adaptations in molecular markers of myogenic, mitochondrial, and neuromuscular junction health in some forelimb and hindlimb muscles. However, this exercise training protocol did not attenuate the loss in motor function or delay disease progression. Alternative exercise regimens need to be investigated to better understand the role exercise training may play in alleviating symptoms of ALS.NEW & NOTEWORTHY This is the first study to investigate the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TDP-43 pathology and motor dysfunction, to perform exercise training. We demonstrate that despite the ALS-reminiscent aggressive disease progression characterizing the rNLS8 mouse model, rNLS8 mice are capable of performing mild-to-moderate endurance treadmill training for at least 3-4 wk. We demonstrate that exercise training induces several minor skeletal muscle adaptations without delaying disease progression in rNLS8 mice.}, } @article {pmid39008674, year = {2024}, author = {Mason, AH and Motta, A and Kratish, Y and Marks, TJ}, title = {Demystifying group-4 polyolefin hydrogenolysis catalysis. Gaseous propane hydrogenolysis mechanism over the same catalysts.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {30}, pages = {e2406133121}, pmid = {39008674}, issn = {1091-6490}, support = {DE-FG02-03ER15457//DOE | Office of Science (SC)/ ; DOE DE-SC0024448//Dow Chemical Company (Dow)/ ; ECCS-2025633//National Science Foundation (NSF)/ ; NNA04CC36G//NASA | Ames Research Center (ARC)/ ; DOE DE-SC0001329//Dow Chemical Company (Dow)/ ; HP10CPXHA1 2023//CINECA HPC/ ; }, abstract = {A kinetic/mechanistic investigation of gaseous propane hydrogenolysis over the single-site heterogeneous polyolefin depolymerization catalysts AlS/ZrNp2 and AlS/HfNp2 (AlS = sulfated alumina, Np = neopentyl), is use to probe intrinsic catalyst properties without the complexities introduced by time- and viscosity-dependent polymer medium effects. In a polymer-free automated plug-flow catalytic reactor, propane hydrogenolysis turnover frequencies approach 3,000 h[-1] at 150 °C. Both catalysts exhibit approximately linear relationships between rate and [H2] at substoichiometric [H2] with rate law orders of 0.66 ± 0.09 and 0.48 ± 0.07 for Hf and Zr, respectively; at higher [H2], the rates approach zero-order in [H2]. Reaction orders in [C3H8] and [catalyst] are essentially zero-order under all conditions, with the former implying rapid, irreversible alkane binding/activation. This rate law, activation parameter, and DFT energy span analysis support a scenario in which [H2] is pivotal in one of two plausible and competing rate-determining transition states-bimolecular metal-alkyl bond hydrogenolysis vs. unimolecular β-alkyl elimination. The Zr and Hf catalyst activation parameters, ΔH[‡] = 16.8 ± 0.2 kcal mol[-1] and 18.2 ± 0.6 kcal mol[-1], respectively, track the relative turnover frequencies, while ΔS[‡] = -19.1 ± 0.8 and -16.7 ± 1.4 cal mol[-1] K[-1], respectively, imply highly organized transition states. These catalysts maintain activity up to 200 °C, while time-on-stream data indicate multiday activities with an extrapolated turnover number ~92,000 at 150 °C for the Zr catalyst. This methodology is attractive for depolymerization catalyst discovery and process optimization.}, } @article {pmid39009032, year = {2025}, author = {Scheithauer, S and Hoffmann, J and Lang, C and Fenz, D and Berens, MM and Köster, AM and Panchyrz, I and Harst, L and Adorjan, K and Apfelbacher, C and Ciesek, S and Denkinger, CM and Drosten, C and Geraedts, M and Hecker, R and Hoffmann, W and Karch, A and Koch, T and Krefting, D and Lieb, K and Meerpohl, JJ and Rehfuess, EA and Skoetz, N and Sopka, S and von Lengerke, T and Wiegand, H and Schmitt, J}, title = {Pandemic Preparedness - A Proposal for a Research Infrastructure and its Functionalities for a Resilient Health Research System.}, journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))}, volume = {87}, number = {S 03}, pages = {S334-S343}, doi = {10.1055/a-2365-9179}, pmid = {39009032}, issn = {1439-4421}, support = {01KX2121//Bundesministerium für Bildung und Forschung/ ; }, mesh = {Germany/epidemiology ; *COVID-19/epidemiology/prevention & control ; Humans ; *Pandemics/prevention & control ; *Health Services Research/organization & administration ; *Biomedical Research/organization & administration ; *Disaster Planning/organization & administration ; SARS-CoV-2 ; Pandemic Preparedness ; }, abstract = {Während einer Pandemie muss Resilienz nicht nur als Eigenschaft des Gesundheitssystems, sondern auch des umgebenden Forschungsumfelds betrachtet werden. Um verlässliche, evidenzbasierte Empfehlungen aus der Universitätsmedizin an die Gesundheitspolitik und die Entscheidungsträger bereitstellen zu können, müssen wissenschaftliche Erkenntnisse schnell, integrativ und multidisziplinär generiert, synthetisiert und kommuniziert werden. Die Resilienz der öffentlichen Gesundheitssysteme und der Gesundheitsforschungssysteme sind somit eng verknüpft. Die Reaktion auf die SARS-CoV-2-Pandemie in Deutschland wurde jedoch durch das Fehlen einer adäquat vernetzten Gesundheitsforschungsinfrastruktur erschwert. Das Netzwerk Universitätsmedizin (NUM) wurde zu Beginn der Pandemie mit dem Ziel gegründet, Deutschland auf zukünftige Pandemien vorzubereiten. Ziel des Projektes "PREparedness and PAndemic REsponse in Deutschland (PREPARED)" ist es, ein ganzheitliches Konzept für eine kooperative, adaptierbare und nachhaltige Gesundheitsforschungsinfrastruktur innerhalb des NUM zu entwickeln und damit einen Beitrag zu einer umfassenden Pandemiebereitschaft zu leisten. Das vorgeschlagene Konzept dieser Infrastruktur vereint vier Kern- und drei Unterstützungsfunktionalitäten in vier verschiedenen Handlungsfeldern. Die Funktionalitäten gewährleisten im Falle zukünftiger Gesundheitskrisen ein effizientes Funktionieren des Gesundheitsforschungssystems und eine rasche Übertragung entsprechender Implikationen in andere Systeme. Die vier Handlungsfelder sind (a) Monitoring und Surveillance, (b) Synthese und Transfer, (c) Koordination und Organisation sowie (d) Kapazitäten und Ressourcen. Die sieben Funktionalitäten umfassen 1) eine Monitoring- und Surveillance-Einheit, 2) eine Pathogenkompetenz-Plattform, 3) Evidenzsynthese und vertrauenswürdige Empfehlungen, 4) eine Einheit zur regionalen Vernetzung und Implementierung, 5) eine Strategische Kommunikationseinheit, 6) Human Resources Management und 7) ein Rapid Reaction & Response (R[3])-Cockpit. Die Governance wird als Kontroll- und Regulierungssystem eingerichtet, wobei agile Management-Methoden in interpandemischen Phasen trainiert werden, um die Reaktionsfähigkeit zu verbessern sowie die Eignung agiler Methoden für die wissenschaftliche Infrastruktur für die Pandemiebereitschaft zu untersuchen. Der Aufbau der PREPARED-Forschungsinfrastruktur muss vor der nächsten Pandemie erfolgen, da Training und regelmäßige Stresstests grundlegende Voraussetzungen für deren Funktionieren sind.During a pandemic, resilience must be considered not only as an attribute of the health care system, but also of the surrounding research environment. To provide reliable evidence-based advice from university medicine to health policy and decision makers, scientific evidence must be generated, synthesized and communicated in a rapid, integrative and multidisciplinary manner. The resilience of public health systems and the health research systems are thus closely linked. However, the response to the SARS-CoV-2 pandemic in Germany was hampered by the lack of an adequate health research infrastructure. The Network University Medicine (NUM) was founded at the beginning of the pandemic with the aim of preparing Germany for future pandemics. The aim of the project "PREparedness and PAndemic REsponse in Deutschland (PREPARED)" is to develop a holistic concept for a cooperative, adaptable and sustainable health research infrastructure within the NUM and thus contribute to pandemic preparedness and rapid response. The proposed concept for a health research infrastructure includes four core and three supporting functionalities in four different fields of action. The functionalities aim to ensure efficient functioning within the health research system and a rapid translation to other systems in future health crises. The four fields of action are (a) monitoring and surveillance, (b) synthesis and transfer, (c) coordination and organization, and (d) capacities and resources. The seven functionalities include 1) a monitoring and surveillance unit, 2) a pathogen competence platform, 3) evidence synthesis and trustworthy recommendations, 4) a regional networking and implementation unit, 5) a strategic communication unit, 6) human resources management, and 7) a rapid reaction and the response (R[3])-cockpit. A governance will be established as a control and regulatory system for all structures and processes, testing agile management in non-pandemic times to improve responsiveness and flexibility and to investigate the suitability of the methods for scientific pandemic preparedness. The establishment of the PREPARED health research infrastructure must take place before the next pandemic, as training and regular stress tests are its fundamental prerequisites.}, } @article {pmid39009447, year = {2024}, author = {Akter, M and Sepehrimanesh, M and Xu, W and Ding, B}, title = {Assembling a Coculture System to Prepare Highly Pure Induced Pluripotent Stem Cell-Derived Neurons at Late Maturation Stages.}, journal = {eNeuro}, volume = {11}, number = {7}, pages = {}, pmid = {39009447}, issn = {2373-2822}, support = {R21 NS112910/NS/NINDS NIH HHS/United States ; R56 NS133252/NS/NINDS NIH HHS/United States ; }, mesh = {*Induced Pluripotent Stem Cells/physiology ; *Coculture Techniques ; Animals ; *Motor Neurons/physiology ; Mice ; *Astrocytes/physiology ; Humans ; Cell Differentiation/physiology ; Cells, Cultured ; Neurogenesis/physiology ; }, abstract = {Generation of human induced pluripotent stem cell (hiPSC)-derived motor neurons (MNs) offers an unprecedented approach to modeling movement disorders such as dystonia and amyotrophic lateral sclerosis. However, achieving survival poses a significant challenge when culturing induced MNs, especially when aiming to reach late maturation stages. Utilizing hiPSC-derived motor neurons and primary mouse astrocytes, we assembled two types of coculture systems: direct coculturing of neurons with astrocytes and indirect coculture using culture inserts that physically separate neurons and astrocytes. Both systems significantly enhance neuron survival. Compared with these two systems, no significant differences in neurodevelopment, maturation, and survival within 3 weeks, allowing to prepare neurons at maturation stages. Using the indirect coculture system, we obtained highly pure MNs at the late mature stage from hiPSCs. Transcriptomic studies of hiPSC-derived MNs showed a typical neurodevelopmental switch in gene expression from the early immature stage to late maturation stages. Mature genes associated with neurodevelopment and synaptogenesis are highly enriched in MNs at late stages, demonstrating that these neurons achieve maturation. This study introduces a novel tool for the preparation of highly pure hiPSC-derived neurons, enabling the determination of neurological disease pathogenesis in neurons at late disease onset stages through biochemical approaches, which typically necessitate highly pure neurons. This advancement is particularly significant in modeling age-related neurodegeneration.}, } @article {pmid39009686, year = {2024}, author = {Neupane, K and Narayan, A and Sen Mojumdar, S and Adhikari, G and Garen, CR and Woodside, MT}, title = {Direct observation of prion-like propagation of protein misfolding templated by pathogenic mutants.}, journal = {Nature chemical biology}, volume = {20}, number = {9}, pages = {1220-1226}, pmid = {39009686}, issn = {1552-4469}, support = {N/A//Gouvernement du Canada | National Research Council Canada (Conseil national de recherches Canada)/ ; RGPIN-2018-04673//Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)/ ; N/A//Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)/ ; PJT-185931//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; N/A//Alberta Innovates | Alberta Innovates - Health Solutions (AIHS)/ ; }, mesh = {*Protein Folding ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; Humans ; *Mutation ; *Prions/metabolism/genetics/chemistry ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Optical Tweezers ; }, abstract = {Many neurodegenerative diseases feature misfolded proteins that propagate via templated conversion of natively folded molecules. However, crucial questions about how such prion-like conversion occurs and what drives it remain unsolved, partly because technical challenges have prevented direct observation of conversion for any protein. We observed prion-like conversion in single molecules of superoxide dismutase-1 (SOD1), whose misfolding is linked to amyotrophic lateral sclerosis. Tethering pathogenic misfolded SOD1 mutants to wild-type molecules held in optical tweezers, we found that the mutants vastly increased misfolding of the wild-type molecule, inducing multiple misfolded isoforms. Crucially, the pattern of misfolding was the same in the mutant and converted wild-type domains and varied when the misfolded mutant was changed, reflecting the templating effect expected for prion-like conversion. Ensemble measurements showed decreased enzymatic activity in tethered heterodimers as conversion progressed, mirroring the single-molecule results. Antibodies sensitive to disease-specific epitopes bound to the converted protein, implying that conversion produced disease-relevant misfolded conformers.}, } @article {pmid39010704, year = {2024}, author = {Liu, J and Shi, X and Shao, Y}, title = {Sodium-glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study.}, journal = {Brain and behavior}, volume = {14}, number = {7}, pages = {e3624}, pmid = {39010704}, issn = {2162-3279}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; *Polymorphism, Single Nucleotide ; *Neurodegenerative Diseases/genetics ; *Glycated Hemoglobin/metabolism ; *Sodium-Glucose Transporter 1/genetics ; Diabetes Mellitus, Type 2/drug therapy/genetics ; Sodium-Glucose Transporter 2/genetics/metabolism ; Parkinson Disease/genetics/drug therapy ; Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Alzheimer Disease/genetics/drug therapy ; Multiple Sclerosis/drug therapy/genetics ; }, abstract = {INTRODUCTION: This study aims to evaluate the effects of sodium-glucose cotransporter 1 inhibitors (SGLT1i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on neurodegenerative disorders and to investigate the role of hemoglobin A1c (HbA1c) levels.

METHODS: Utilizing drug target Mendelian randomization, we employed single nucleotide polymorphisms (SNPs) proximal to the SLC5A1 and SLC5A2 genes to analyze the influence of SGLT1i and SGLT2i on Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), frontotemporal dementia (FTD), Lewy body dementia (LBD), and amyotrophic lateral sclerosis (ALS), with type 2 diabetes (T2D) as a positive control. An additional analysis examined the impact of HbA1c levels on the same disorders.

RESULTS: SGLT1i exhibited a significant association with decreased risk for ALS and MS. Conversely, SGLT2i were linked to an increased risk of AD, PD, and MS. Elevated HbA1c levels, independent of SGLT1 and SGLT2 effects, were associated with an increased risk of PD. Sensitivity analyses supported the robustness of these findings.

CONCLUSION: Our study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.}, } @article {pmid39015316, year = {2024}, author = {Liu, Y and Chen, Y and Gao, M and Luo, J and Wang, Y and Wang, Y and Gao, Y and Yang, L and Wang, J and Wang, N}, title = {Association between glioma and neurodegenerative diseases risk: a two-sample bi-directional Mendelian randomization analysis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1413015}, pmid = {39015316}, issn = {1664-2295}, abstract = {BACKGROUND: Earlier observational studies have demonstrated a correlation between glioma and the risk of neurodegenerative diseases (NDs), but the causality and direction of their associations remain unclear. The objective of this study was to ascertain the causal link between glioma and NDs using Mendelian randomization (MR) methodology.

METHODS: Genome-wide association study (GWAS) data were used in a two-sample bi-directional MR analysis. From the largest meta-analysis GWAS, encompassing 18,169 controls and 12,488 cases, summary statistics data on gliomas was extracted. Summarized statistics for NDs, including Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) were obtained from the GWAS of European ancestry. Inverse variance weighted (IVW) method was elected as the core MR approach with weighted median (WM) method and MR-Egger method as complementary methods. In addition, sensitivity analyses were performed. A Bonferroni correction was used to correct the results.

RESULTS: Genetically predicted glioma had been related to decreased risk of AD. Specifically, for all glioma (IVW: OR = 0.93, 95% CI = 0.90-0.96, p = 4.88 × 10[-6]) and glioblastoma (GBM) (IVW: OR = 0.93, 95% CI = 0.91-0.95, p = 5.11 × 10[-9]). We also found that genetically predicted all glioma has a suggestive causative association with MS (IVW: OR = 0.90, 95% CI = 0.81-1.00, p = 0.045). There was no evidence of causal association between glioma and ALS or PD. According to the results of reverse MR analysis, no discernible causal connection of NDs was found on glioma. Sensitivity analyses validated the robustness of the above associations.

CONCLUSION: We report evidence in support of potential causal associations of different glioma subtypes with AD and MS. More studies are required to uncover the underlying mechanisms of these findings.}, } @article {pmid39015513, year = {2024}, author = {Barahim Bastani, P and Saber Tehrani, AS and Badihian, S and Rieiro, H and Rastall, D and Farrell, N and Parker, M and Otero-Millan, J and Hassoon, A and Newman-Toker, D and Clawson, LL and Uchil, A and Riley, K and Zeiler, SR}, title = {Self-Recording of Eye Movements in Amyotrophic Lateral Sclerosis Patients Using a Smartphone Eye-Tracking App.}, journal = {Digital biomarkers}, volume = {8}, number = {1}, pages = {111-119}, pmid = {39015513}, issn = {2504-110X}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) can affect various eye movements, making eye tracking a potential means for disease monitoring. In this study, we evaluated the feasibility of ALS patients self-recording their eye movements using the "EyePhone," a smartphone eye-tracking application.

METHODS: We prospectively enrolled ten participants and provided them with an iPhone equipped with the EyePhone app and a PowerPoint presentation with step-by-step recording instructions. The goal was for the participants to record their eye movements (saccades and smooth pursuit) without the help of the study team. Afterward, a trained physician administered the same tests using video-oculography (VOG) goggles and asked the participants to complete a questionnaire regarding their self-recording experience.

RESULTS: All participants successfully completed the self-recording process without assistance from the study team. Questionnaire data indicated that participants viewed self-recording with EyePhone favorably, considering it easy and comfortable. Moreover, 70% indicated that they prefer self-recording to being recorded by VOG goggles.

CONCLUSION: With proper instruction, ALS patients can effectively use the EyePhone to record their eye movements, potentially even in a home environment. These results demonstrate the potential for smartphone eye-tracking technology as a viable and self-administered tool for monitoring disease progression in ALS, reducing the need for frequent clinic visits.}, } @article {pmid39017652, year = {2024}, author = {Ranta-Aho, J and Johari, M and Udd, B}, title = {Current advance on distal myopathy genetics.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {515-522}, pmid = {39017652}, issn = {1473-6551}, mesh = {Humans ; *Distal Myopathies/genetics/pathology ; }, abstract = {PURPOSE OF REVIEW: Distal myopathies are a clinically heterogenous group of rare, genetic muscle diseases, that present with weakness in hands and/or feet at onset. Some of these diseases remain accentuated in the distal muscles whereas others may later progress to the proximal muscles. In this review, the latest findings related to genetic and clinical features of distal myopathies are summarized.

RECENT FINDINGS: Variants in SMPX , DNAJB2, and HSPB6 have been identified as a novel cause of late-onset distal myopathy and neuromyopathy. In oculopharyngodistal myopathies, repeat expansions were identified in two novel disease-causing genes, RILPL1 and ABCD3. In multisystem proteinopathies, variants in HNRNPA1 and TARDBP , genes previously associated with amyotrophic lateral sclerosis, have been shown to cause late-onset distal myopathy without ALS. In ACTN2 -related distal myopathy, the first recessive forms of the disease have been described, adding it to the growing list of genes were both dominant and recessive forms of myopathy are present.

SUMMARY: The identification of novel distal myopathy genes and pathogenic variants contribute to our ability to provide a final molecular diagnosis to a larger number of patients and increase our overall understanding of distal myopathy genetics and pathology.}, } @article {pmid39017978, year = {2025}, author = {Vinceti, M and Urbano, T and Filippini, T and Bedin, R and Simonini, C and Sorarù, G and Trojsi, F and Michalke, B and Mandrioli, J}, title = {Changes in Cerebrospinal Fluid Concentrations of Selenium Species Induced by Tofersen Administration in Subjects with Amyotrophic Lateral Sclerosis Carrying SOD1 Gene Mutations.}, journal = {Biological trace element research}, volume = {203}, number = {4}, pages = {2355-2364}, pmid = {39017978}, issn = {1559-0720}, support = {"PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/drug therapy ; *Selenium/cerebrospinal fluid ; Middle Aged ; *Superoxide Dismutase-1/genetics ; Male ; Female ; *Mutation ; Aged ; *Oligonucleotides/administration & dosage ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the brain and spinal cord motor neurons. On 25 April 2023, the drug tofersen, an antisense oligonucleotide, received the US Food and Drug Administration approval for treating ALS in adults carrying mutations of the SOD1 gene. We aimed at assessing whether cerebrospinal fluid concentrations of selenium, an element of both toxicological and nutritional interest possibly involved in disease etiology and progression, are modified by tofersen administration. We determined concentrations of selenium species by anion exchange chromatography hyphenated to inductively coupled plasma-dynamic reaction cell-mass spectrometry and overall selenium by using inductively coupled plasma sector-field mass spectrometry, at baseline and 6 months after active tofersen treatment in ten Italian ALS patients carrying the SOD1 gene mutation. Concentrations of total selenium and many selenium species substantially increased after the intervention, particularly of inorganic (tetravalent and hexavalent) selenium and of the organic species selenomethionine and a compound co-eluting with the selenocystine standard. Overall, these findings suggest that tofersen treatment markedly alters selenium status and probably the redox status within the central nervous system, possibly due to a direct effect on neurons and/or the blood-brain barrier. Further studies are required to investigate the biological and clinical relevance of these findings and how they might relate to the pharmacological effects of the drug and to disease progression.}, } @article {pmid39019135, year = {2024}, author = {Cao, M and Yi, L and Xu, Y and Tian, Y and Li, Z and Bi, Y and Guo, M and Li, Y and Liu, Y and Xu, X and Sun, J and Li, C and Duan, W}, title = {Inhibiting NF-κB inducing kinase improved the motor performance of ALS animal model.}, journal = {Brain research}, volume = {1843}, number = {}, pages = {149124}, doi = {10.1016/j.brainres.2024.149124}, pmid = {39019135}, issn = {1872-6240}, mesh = {Animals ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy ; *Disease Models, Animal ; Mice, Inbred C57BL ; *Mice, Transgenic ; *NF-kappa B/metabolism ; *NF-kappaB-Inducing Kinase ; *Protein Serine-Threonine Kinases/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a typical neurodegenerative disorder typically characterized by inflammation activation. However, the relationship between non-canonical NF-κB (ncNF-κB) pathway activation and ALS progression is not clear.

METHODS: We tested the ncNF-κB pathway in the ALS animal model including hSOD1-G93A transgenic mice and TBK1 deletion mice.We treated age-matched SOD1-G93A mice with B022 (a NIK inhibitor) to investigate the role of NIK in the ALS animal model. We also established a new mice model by crossing SOD1-G93A mice with NIK[+/-] mice to further evaluate the interrelationship between the NIK and the disease progression in ALS animal model.

RESULTS: In this study, we found the ncNF-κB pathway was activated in SOD1-G93A animal model and TBK1 deletion model. Inhibition of NIK activity by small molecule B022 significantly improved the motor performance of the ALS animal model. However, NIK deletion enhanced the mutant SOD1 toxicity by inflammatory infiltration.

CONCLUSION: TBK1 deletion and mutant SOD1 shared the common pathological feature possibly via effects on NIK activation and inhibitor of NIK could be a novel strategy for treating ALS.}, } @article {pmid39019674, year = {2024}, author = {Georges, M and Perez, T and Rabec, C and Jacquin, L and Finet-Monnier, A and Ramos, C and Patout, M and Attali, V and Amador, M and Gonzalez-Bermejo, J and Salachas, F and Morelot-Panzini, C}, title = {[Proposals from a French expert panel for respiratory care in ALS patients].}, journal = {Revue des maladies respiratoires}, volume = {41}, number = {8}, pages = {620-637}, doi = {10.1016/j.rmr.2024.06.006}, pmid = {39019674}, issn = {1776-2588}, mesh = {*Amyotrophic Lateral Sclerosis/complications/therapy ; Humans ; France/epidemiology ; *Noninvasive Ventilation/methods/standards/instrumentation ; *Respiratory Insufficiency/therapy/etiology ; Respiratory Therapy/methods/standards ; Quality of Life ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive diaphragm weakness and deteriorating lung function. Bulbar involvement and cough weakness contribute to respiratory morbidity and mortality. ALS-related respiratory failure significantly affects quality of life and is the leading cause of death. Non-invasive ventilation (NIV), which is the main recognized treatment for alleviating the symptoms of respiratory failure, prolongs survival and improves quality of life. However, the optimal timing for the initiation of NIV is still a matter of debate. NIV is a complex intervention. Multiple factors influence the efficacy of NIV and patient adherence. The aim of this work was to develop practical evidence-based advices to standardize the respiratory care of ALS patients in French tertiary care centres.

METHODS: For each proposal, a French expert panel systematically searched an indexed bibliography and prepared a written literature review that was then shared and discussed. A combined draft was prepared by the chairman for further discussion. All of the proposals were unanimously approved by the expert panel.

RESULTS: The French expert panel updated the criteria for initiating NIV in ALS patients. The most recent criteria were established in 2005. Practical advice for NIV initiation were included and the value of each tool available for NIV monitoring was reviewed. A strategy to optimize NIV parameters was suggested. Revisions were also suggested for the use of mechanically assisted cough devices in ALS patients.

CONCLUSION: Our French expert panel proposes an evidence-based review to update the respiratory care recommendations for ALS patients in daily practice.}, } @article {pmid39020237, year = {2024}, author = {Yuan, ZL and Ren, J and Huang, ML and Qi, YF and Gao, X and Sun, YY and He, YL and Zhu, L and Xue, HD}, title = {A new magnetic resonance imaging-based PUMCH classification system for congenital cervical malformations: devising a standardised diagnosis pathway.}, journal = {Insights into imaging}, volume = {15}, number = {1}, pages = {177}, pmid = {39020237}, issn = {1869-4101}, support = {2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; }, abstract = {OBJECTIVES: To develop an innovative magnetic resonance imaging (MRI)-based PUMCH (Peking Union Medical College Hospital) classification system aimed at standardising the diagnosis of congenital cervical malformations (CCMs) by identifying their distinctive MRI features.

METHODS: Seventy-nine consecutive patients with CCM underwent pre-treatment pelvic MRI; three experienced gynaecological radiologists retrospectively analysed these images. Qualitative assessments included Rock et al's classification; PUMCH classification; haematometra; cervical signal features; ovarian endometriosis; haematosalpinx; and uterine, vaginal, urinary, and musculoskeletal malformations. Quantitative assessments involved the uterine volume, sagittal cervical length, and maximum ovarian cross-sectional area. The surgical treatment types were also recorded. Statistical methods were used to incorporate differences in clinical features and surgical methods into our classification.

RESULTS: Morphologically, CCMs were categorised into three types: type I (53%) was characterised by the presence of a cervix with visible cervical canals; type II (23%) featured an existing cervix with concealed cervical canals; and type III (24%) indicated cervical aplasia, which involves a blind end in the lower part of the uterine corpus. Haematometra was significantly more prevalent in patients with type I CCM than in those with type II (p < 0.001). There were three cervical signal patterns: no signal (27%), no evident layer differentiation (21%), and multi-layer differentiation with haematocele (52%). Most patients (94%) had complete vaginal atresia. Type I CCM patients had a higher likelihood of regaining normal uterovaginal anatomy compared to types II and III.

CONCLUSIONS: Our proposed PUMCH classification system has a high potential for enhancing the efficiency of clinical diagnosis among patients with CCM.

CRITICAL RELEVANCE STATEMENT: The proposed new PUMCH classification promised to elevate the conventional diagnostic trajectory for congenital cervical malformations, offering a valuable framework to refine the selection and planning of surgical interventions, thereby enhancing overall clinical efficacy.

KEY POINTS: Effective classification of congenital cervical malformations is desirable to optimise the diagnostic process. We presented a PUMCH classification of congenital cervical malformations using pelvic MRI. The new classification significantly aids clinical triage for congenital cervical malformations.}, } @article {pmid39022351, year = {2024}, author = {Corvino, A and Caliendo, G and Fiorino, F and Frecentese, F and Valsecchi, V and Lombardi, G and Anzilotti, S and Andreozzi, G and Scognamiglio, A and Sparaco, R and Perissutti, E and Severino, B and Gargiulo, M and Santagada, V and Pignataro, G}, title = {Newly Synthesized Indolylacetic Derivatives Reduce Tumor Necrosis Factor-Mediated Neuroinflammation and Prolong Survival in Amyotrophic Lateral Sclerosis Mice.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {7}, pages = {1996-2005}, pmid = {39022351}, issn = {2575-9108}, abstract = {The debilitating neurodegenerative disease known as amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons (MNs) in the brain, spinal cord, and motor cortex. The ALS neuroinflammatory component is being characterized and includes the overexpression of mediators, such as inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α). Currently, there are no effective treatments for ALS. Indeed, riluzole, an N-methyl-D-aspartate (NMDA) glutamate receptor blocker, and edaravone, a reactive oxygen species (ROS) scavenger, are currently the sole two medications approved for ALS treatment. However, their efficacy in extending life expectancy typically amounts to only a few months. In order to improve the medicaments for the treatment of neurodegenerative diseases, preferably ALS, novel substituted 2-methyl-3-indolylacetic derivatives (compounds II-IV) were developed by combining the essential parts of two small molecules, namely, the opioids containing a 4-piperidinyl ring with indomethacin, previously shown to be efficacious in different experimental models of neuroinflammation. The synthesized compounds were evaluated for their potential capability of slowing down neurodegeneration associated with ALS progression in preclinical models of the disease in vitro and in vivo. Notably, we produced data to demonstrate that the treatment with the newly synthesized compound III: (1) prevented the upregulation of TNF-α observed in BV-2 microglial cells exposed to the toxin lipopolysaccharides (LPS), (2) preserved SHSY-5Y cell survival exposed to β-N-methylamino-l-alanine (L-BMAA) neurotoxin, and (3) mitigated motor symptoms and improved survival rate of SOD1G93A ALS mice. In conclusion, the findings of the present work support the potential of the synthesized indolylacetic derivatives II-IV in ALS treatment. Indeed, in the attempt to realize an association between two active molecules, we assumed that the combination of the indispensable moieties of two small molecules (the opioids containing a 4-piperidinyl ring with the FANS indomethacin) might lead to new medicaments potentially useful for the treatment of amyotrophic lateral sclerosis.}, } @article {pmid39023172, year = {2024}, author = {Zaky, MH and Shoorangiz, R and Poudel, GR and Yang, L and Innes, CRH and Jones, RD}, title = {Conscious but not thinking-Mind-blanks during visuomotor tracking: An fMRI study of endogenous attention lapses.}, journal = {Human brain mapping}, volume = {45}, number = {11}, pages = {e26781}, pmid = {39023172}, issn = {1097-0193}, support = {08-VDV-01 EHB//Marsden Fund, Royal Society of New Zealand/ ; //University of Canterbury/ ; //University of Otago/ ; 236930//Lottery Health Research/ ; }, mesh = {Humans ; Adult ; *Magnetic Resonance Imaging ; Female ; Male ; Young Adult ; *Attention/physiology ; *Psychomotor Performance/physiology ; Middle Aged ; Eye-Tracking Technology ; Thinking/physiology ; Nerve Net/diagnostic imaging/physiopathology/physiology ; Consciousness/physiology ; Visual Perception/physiology ; Motor Activity/physiology ; }, abstract = {Attention lapses (ALs) are complete lapses of responsiveness in which performance is briefly but completely disrupted and during which, as opposed to microsleeps, the eyes remain open. Although the phenomenon of ALs has been investigated by behavioural and physiological means, the underlying cause of an AL has largely remained elusive. This study aimed to investigate the underlying physiological substrates of behaviourally identified endogenous ALs during a continuous visuomotor task, primarily to answer the question: Were the ALs during this task due to extreme mind-wandering or mind-blanks? The data from two studies were combined, resulting in data from 40 healthy non-sleep-deprived subjects (20M/20F; mean age 27.1 years, 20-45). Only 17 of the 40 subjects were used in the analysis due to a need for a minimum of two ALs per subject. Subjects performed a random 2-D continuous visuomotor tracking task for 50 and 20 min in Studies 1 and 2, respectively. Tracking performance, eye-video, and functional magnetic resonance imaging (fMRI) were recorded simultaneously. A human expert visually inspected the tracking performance and eye-video recordings to identify and categorise lapses of responsiveness as microsleeps or ALs. Changes in neural activity during 85 ALs (17 subjects) relative to responsive tracking were estimated by whole-brain voxel-wise fMRI and by haemodynamic response (HR) analysis in regions of interest (ROIs) from seven key networks to reveal the neural signature of ALs. Changes in functional connectivity (FC) within and between the key ROIs were also estimated. Networks explored were the default mode network, dorsal attention network, frontoparietal network, sensorimotor network, salience network, visual network, and working memory network. Voxel-wise analysis revealed a significant increase in blood-oxygen-level-dependent activity in the overlapping dorsal anterior cingulate cortex and supplementary motor area region but no significant decreases in activity; the increased activity is considered to represent a recovery-of-responsiveness process following an AL. This increased activity was also seen in the HR of the corresponding ROI. Importantly, HR analysis revealed no trend of increased activity in the posterior cingulate of the default mode network, which has been repeatedly demonstrated to be a strong biomarker of mind-wandering. FC analysis showed decoupling of external attention, which supports the involuntary nature of ALs, in addition to the neural recovery processes. Other findings were a decrease in HR in the frontoparietal network before the onset of ALs, and a decrease in FC between default mode network and working memory network. These findings converge to our conclusion that the ALs observed during our task were involuntary mind-blanks. This is further supported behaviourally by the short duration of the ALs (mean 1.7 s), which is considered too brief to be instances of extreme mind-wandering. This is the first study to demonstrate that at least the majority of complete losses of responsiveness on a continuous visuomotor task are, if not due to microsleeps, due to involuntary mind-blanks.}, } @article {pmid39023312, year = {2024}, author = {Miceli, M and Cannariato, M and Tortarolo, R and Pallante, L and Zizzi, EA and Deriu, MA}, title = {Conformational Dynamics and Molecular Characterization of Alsin MORN Monomer and Dimeric Assemblies.}, journal = {Proteins}, volume = {92}, number = {11}, pages = {1343-1353}, doi = {10.1002/prot.26728}, pmid = {39023312}, issn = {1097-0134}, support = {GSP 20005_PAsIAHSP007//Fondazione Telethon/ ; //Associazione Help Olly Onlus-Italy/ ; }, mesh = {*Protein Multimerization ; Humans ; Molecular Dynamics Simulation ; Protein Conformation, alpha-Helical ; Protein Stability ; Protein Conformation, beta-Strand ; Protein Domains ; Amino Acid Sequence ; Models, Molecular ; Protein Interaction Domains and Motifs ; Protein Conformation ; Guanine Nucleotide Exchange Factors ; }, abstract = {Despite the ubiquity of membrane occupation recognition nexus (MORN) motifs across diverse species in both eukaryotic and prokaryotic organisms, these protein domains remain poorly characterized. Their significance is underscored in the context of the Alsin protein, implicated in the debilitating condition known as infantile-onset ascending hereditary spastic paralysis (IAHSP). Recent investigations have proposed that mutations within the Alsin MORN domain disrupt proper protein assembly, precluding the formation of the requisite tetrameric configuration essential for the protein's inherent biological activity. However, a comprehensive understanding of the relationship between the biological functions of Alsin and its three-dimensional molecular structure is hindered by the lack of available experimental structures. In this study, we employed and compared several protein structure prediction algorithms to identify a three-dimensional structure for the putative MORN of Alsin. Furthermore, inspired by experimental pieces of evidence from previous studies, we employed the developed models to predict and investigate two homo-dimeric assemblies, characterizing their stability. This study's insights into the three-dimensional structure of the Alsin MORN domain and the stability dynamics of its homo-dimeric assemblies suggest an antiparallel linear configuration stabilized by a noncovalent interaction network.}, } @article {pmid39025824, year = {2024}, author = {Lorenc, T and Khouja, C and Harden, M and Fulbright, H and Thomas, J}, title = {Defensive healthcare practice: systematic review of qualitative evidence.}, journal = {BMJ open}, volume = {14}, number = {7}, pages = {e085673}, pmid = {39025824}, issn = {2044-6055}, mesh = {Humans ; *Qualitative Research ; *Defensive Medicine ; Attitude of Health Personnel ; }, abstract = {OBJECTIVE: To synthesise qualitative evidence on clinicians' views and experiences of defensive practice.

DESIGN: Systematic review of qualitative data.

DATA SOURCES: MEDLINE, Embase, PsycINFO, AMED, Maternity and Infant Care, CINAHL, ASSIA, Sociological Abstracts, Proquest Dissertations & Theses and PROSPERO were searched from 2000 to October 2023.

ELIGIBILITY CRITERIA: We included English-language studies of clinicians which reported qualitative data on the impact of litigation or complaints on clinical practice.

DATA EXTRACTION AND SYNTHESIS: We coded findings data line by line using a grounded theory approach. We assessed quality using Hawker et al's tool and synthesised data thematically.

RESULTS: 17 studies were included. Participants identify a range of clinical decisions which may be defensively motivated, relating to diagnosis and documentation as well as to treatment. Defensive practice often relates to a diffuse sense of risk rather than the direct threat of litigation and may overlap with other motivations, such as perceived pressure from patients or the desire to avoid harm. Defensive practice is seen to be harmful in many ways, but again, these perceptions may gain force from broader narratives of mistrust and disempowerment, as much as from the risk of litigation.

CONCLUSIONS: The idea of defensive practice, as enacted, is more complex than some theoretical accounts suggest and may often function to express broader concerns about the work of clinical care. The qualitative evidence calls into question the view of defensive practice as a key mediator linking litigation risk to inappropriate treatment and excess costs.}, } @article {pmid39026010, year = {2024}, author = {Read, TA and Cisterna, BA and Skruber, K and Ahmadieh, S and Liu, TM and Vitriol, JA and Shi, Y and Black, JB and Butler, MT and Lindamood, HL and Lefebvre, AE and Cherezova, A and Ilatovskaya, DV and Bear, JE and Weintraub, NL and Vitriol, EA}, title = {The actin binding protein profilin 1 localizes inside mitochondria and is critical for their function.}, journal = {EMBO reports}, volume = {25}, number = {8}, pages = {3240-3262}, pmid = {39026010}, issn = {1469-3178}, support = {R35 GM130312/GM/NIGMS NIH HHS/United States ; R35 GM137959/GM/NIGMS NIH HHS/United States ; R35GM137959//Foundation for the National Institutes of Health (FNIH)/ ; }, mesh = {*Profilins/metabolism/genetics ; *Mitochondria/metabolism/genetics ; Humans ; *Actins/metabolism ; Mitophagy/genetics ; Lysosomes/metabolism ; Cytosol/metabolism ; Gene Knockout Techniques ; Autophagosomes/metabolism ; HeLa Cells ; }, abstract = {The monomer-binding protein profilin 1 (PFN1) plays a crucial role in actin polymerization. However, mutations in PFN1 are also linked to hereditary amyotrophic lateral sclerosis, resulting in a broad range of cellular pathologies which cannot be explained by its primary function as a cytosolic actin assembly factor. This implies that there are important, undiscovered roles for PFN1 in cellular physiology. Here we screened knockout cells for novel phenotypes associated with PFN1 loss of function and discovered that mitophagy was significantly upregulated. Indeed, despite successful autophagosome formation, fusion with the lysosome, and activation of additional mitochondrial quality control pathways, PFN1 knockout cells accumulate depolarized, dysmorphic mitochondria with altered metabolic properties. Surprisingly, we also discovered that PFN1 is present inside mitochondria and provide evidence that mitochondrial defects associated with PFN1 loss are not caused by reduced actin polymerization in the cytosol. These findings suggest a previously unrecognized role for PFN1 in maintaining mitochondrial integrity and highlight new pathogenic mechanisms that can result from PFN1 dysregulation.}, } @article {pmid39026758, year = {2025}, author = {Onwunma, J and Binsabaan, S and Allen, SP and Sankaran, B and Wohlever, ML}, title = {ALS mutations disrupt self-association between the Ubiquilin Sti1 hydrophobic groove and internal placeholder sequences.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39026758}, issn = {2692-8205}, support = {P30 GM124169/GM/NIGMS NIH HHS/United States ; R35 GM137904/GM/NIGMS NIH HHS/United States ; }, abstract = {Ubiquilins are molecular chaperones that play multifaceted roles in proteostasis, with point mutations in UBQLN2 leading to altered phase separation properties and Amyotrophic Lateral Sclerosis (ALS). Our mechanistic understanding of this essential process has been hindered by a lack of structural information on the Sti1 domain, which is essential for Ubiquilin chaperone activity and phase separation. Here, we present the first crystal structure of a Ubiquilin family Sti1 domain bound to a transmembrane domain (TMD) and show that ALS mutations disrupt the Sti1-TMD interaction. We then demonstrate that Ubiquilins contain multiple conserved, internal sequences that bind to the Sti1 domain, including the PXX region which is a hotspot for ALS mutations. We propose that these placeholder sequences prevent solvent exposure of the Sti1 hydrophobic groove and contribute to the multivalency that drives Ubiquilin phase separation. Together, this work provides a new paradigm for understanding how Sti1 domains modulate Ubiquilin chaperone activity and phase separation and offer insights into the molecular basis of ALS pathogenesis.}, } @article {pmid39028002, year = {2025}, author = {Mercadante, S and Petronaci, A and Terranova, A and Casuccio, A}, title = {Characteristics of Patients With Amyotrophic Lateral Sclerosis Followed by a Home Palliative Care Team.}, journal = {The American journal of hospice & palliative care}, volume = {42}, number = {5}, pages = {483-488}, doi = {10.1177/10499091241266985}, pmid = {39028002}, issn = {1938-2715}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Male ; *Palliative Care/organization & administration/statistics & numerical data ; Female ; *Home Care Services/organization & administration ; Middle Aged ; Aged ; *Patient Care Team/organization & administration ; Respiration, Artificial/statistics & numerical data ; Advance Directives/statistics & numerical data ; Nutritional Support ; Aged, 80 and over ; Referral and Consultation ; Adult ; Noninvasive Ventilation/statistics & numerical data ; Patient Care Planning/organization & administration ; }, abstract = {BackgroundInformation about patients with amyothrophic lateral sclerosis (ALS) followed at home is limited.ObjectivesTo assess patients's characteristics at admission to a home palliative care program based on a multidisciplinary team, and the temporal course along the trajectory of ALS disease.DesignRetrospective. Setting/subjects: Charts of a consecutive number of ALS patients who were referred to a specialistic home palliative care were reviewed.MeasurementGeneral data, referral, start of home palliative care, use of ventilator support and nutritional support, were recorded. The existence of advance directives and shared care planning was also collected.Results82 patients were examined; 31 patients died before the term of the study and 51 patients were still living. No patient anticipately expressed their will regarding their treatments. However, a certain number of patients shared a care planning with ALS team, generally after starting home care. Most patients did not have ventilatory support at the beginning of home care assistance, but progressively received ventilatory support by NIV or MV, particularly those who were still living. NIV at start of home care was negatively correlated to frontotemporal dementia. (P = 0.015), and directly correlated to referral from hospital and GP (P = 0.031) and awareness of disease (P = 0.034). Gastrostomy at start of home care was positively correlated to referral from hospital (P = 0.046). Gastrostomy during home care was correlated to bulbar SLA (P = 0.017). The use of NIV during home care was positively correlated to shared care planning (P = 0.001).ConclusionThe continuous presence of a multi-specialist team may provide timely intervention, guarantee and trust on the part of the patient and family members.}, } @article {pmid39029959, year = {2024}, author = {}, title = {Erratum: Garbuzova-Davis et al., "Apolipoprotein A1 Enhances Endothelial Cell Survival in an In Vitro Model of ALS".}, journal = {eNeuro}, volume = {11}, number = {7}, pages = {}, doi = {10.1523/ENEURO.0280-24.2024}, pmid = {39029959}, issn = {2373-2822}, } @article {pmid39030042, year = {2024}, author = {Haberkamp, M and Aislaitner, G and Martínez-Lapiscina, EH and Weise, M}, title = {Tofersen for SOD-1-associated amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {23}, number = {8}, pages = {772-773}, doi = {10.1016/S1474-4422(24)00259-X}, pmid = {39030042}, issn = {1474-4465}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Superoxide Dismutase-1/genetics ; }, } @article {pmid39030186, year = {2024}, author = {Dubbioso, R and Spisto, M and Verde, L and Iuzzolino, VV and Senerchia, G and Salvatore, E and De Pietro, G and De Falco, I and Sannino, G}, title = {Voice signals database of ALS patients with different dysarthria severity and healthy controls.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {800}, pmid = {39030186}, issn = {2052-4463}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; *Dysarthria/physiopathology ; Male ; Female ; Voice ; Databases, Factual ; Middle Aged ; Adult ; Aged ; Case-Control Studies ; }, abstract = {This paper describes a new publicly-available database of VOiCe signals acquired in Amyotrophic Lateral Sclerosis (ALS) patients (VOC-ALS) and healthy controls performing different speech tasks. This dataset consists of 1224 voice signals recorded from 153 participants: 51 healthy controls (32 males and 19 females) and 102 ALS patients (65 males and 37 females) with different severity of dysarthria. Each subject's voice was recorded using a smartphone application (Vox4Health) while performing several vocal tasks, including a sustained phonation of the vowels /a/, /e/, /i/, /o/, /u/ and /pa/, /ta/, /ka/ syllable repetition. Basic derived speech metrics such as harmonics-to-noise ratio, mean and standard deviation of fundamental frequency (F0), jitter and shimmer were calculated. The F0 standard deviation of vowels and syllables showed an excellent ability to identify people with ALS and to discriminate the different severity of dysarthria. These data represent the most comprehensive database of voice signals in ALS and form a solid basis for research on the recognition of voice impairment in ALS patients for use in clinical applications.}, } @article {pmid39030200, year = {2024}, author = {Erb, ML and Sipple, K and Levine, N and Chen, X and Moore, DJ}, title = {Adult-onset deletion of ATP13A2 in mice induces progressive nigrostriatal pathway dopaminergic degeneration and lysosomal abnormalities.}, journal = {NPJ Parkinson's disease}, volume = {10}, number = {1}, pages = {133}, pmid = {39030200}, issn = {2373-8057}, support = {PF-FBS-1894//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; PF-FBS-1894//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; }, abstract = {Although most cases of Parkinson's disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of the disease. Recessive loss-of-function mutations in ATP13A2, a lysosomal transmembrane P5B-type ATPase and polyamine exporter, can cause early-onset familial PD. Familial ATP13A2 mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome, hereditary spastic paraplegias, neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis. Despite the severe effects of ATP13A2 mutations in humans, ATP13A2 knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages, making it challenging to study the neuropathological effects of ATP13A2 loss in vivo. Germline deletion of ATP13A2 in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deleted ATP13A2 in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onset ATP13A2 KO also recreates many of the phenotypes observed in aged germline ATP13A2 KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases.}, } @article {pmid39030617, year = {2024}, author = {Chen, T and Dai, Y and Hu, C and Lin, Z and Wang, S and Yang, J and Zeng, L and Li, S and Li, W}, title = {Cellular and molecular mechanisms of the blood-brain barrier dysfunction in neurodegenerative diseases.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {60}, pmid = {39030617}, issn = {2045-8118}, support = {LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; No.X-202102//Scientific Research Foundation of Zhejiang University City College/ ; }, mesh = {*Blood-Brain Barrier/metabolism/physiopathology ; Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; Animals ; }, abstract = {BACKGROUND: Maintaining the structural and functional integrity of the blood-brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases.

MAIN BODY: Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions.

CONCLUSIONS: BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches.}, } @article {pmid39030740, year = {2024}, author = {Jonson, C and Levine, KS and Lake, J and Hertslet, L and Jones, L and Patel, D and Kim, J and Bandres-Ciga, S and Terry, N and Mata, IF and Blauwendraat, C and Singleton, AB and Nalls, MA and Yokoyama, JS and Leonard, HL}, title = {Assessing the lack of diversity in genetics research across neurodegenerative diseases: A systematic review of the GWAS Catalog and literature.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {20}, number = {8}, pages = {5740-5756}, pmid = {39030740}, issn = {1552-5279}, support = {U19AG079774/NS/NINDS NIH HHS/United States ; R01 AG062588/AG/NIA NIH HHS/United States ; ZO1AG000534/HH/HHS/United States ; U19 AG079774/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; 75N95022C00031/NS/NINDS NIH HHS/United States ; //Intramural Research Program/ ; P01AG019724/NS/NINDS NIH HHS/United States ; P30AG062422/NS/NINDS NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; U54NS123985/NS/NINDS NIH HHS/United States ; 75N95022C00031/DA/NIDA NIH HHS/United States ; U54 NS123985/NS/NINDS NIH HHS/United States ; R01AG057234/NS/NINDS NIH HHS/United States ; R01AG062588/NS/NINDS NIH HHS/United States ; //Global Brain Health Institute; and the Mary Oakley Foundation/ ; //Rainwater Charitable Foundation/ ; }, mesh = {Humans ; Genetic Predisposition to Disease/genetics ; *Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics ; White People/genetics ; }, abstract = {The under-representation of non-European cohorts in neurodegenerative disease genome-wide association studies (GWAS) hampers precision medicine efforts. Despite the inherent genetic and phenotypic diversity in these diseases, GWAS research consistently exhibits a disproportionate emphasis on participants of European ancestry. This study reviews GWAS up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. We conducted a systematic review of GWAS results and publications up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. Rigorous article inclusion and quality assessment methods were employed. Of 123 neurodegenerative disease (NDD) GWAS reviewed, 82% predominantly featured European ancestry participants. A single European study identified over 90 risk loci, compared to a total of 50 novel loci in identified in all non-European or multi-ancestry studies. Notably, only six of the loci have been replicated. The significant under-representation of non-European ancestries in NDD GWAS hinders comprehensive genetic understanding. Prioritizing genomic diversity in future research is crucial for advancing NDD therapies and understanding. HIGHLIGHTS: Eighty-two percent of neurodegenerative genome-wide association studies (GWAS) focus on Europeans. Only 6 of 50 novel neurodegenerative disease (NDD) genetic loci have been replicated. Lack of diversity significantly hampers understanding of NDDs. Increasing diversity in NDD genetic research is urgently required. New initiatives are aiming to enhance diversity in NDD research.}, } @article {pmid39031772, year = {2024}, author = {Meyer, T and Schumann, P and Weydt, P and Petri, S and Weishaupt, JH and Weyen, U and Koch, JC and Günther, R and Regensburger, M and Boentert, M and Wiesenfarth, M and Koc, Y and Kolzarek, F and Kettemann, D and Norden, J and Bernsen, S and Elmas, Z and Conrad, J and Valkadinov, I and Vidovic, M and Dorst, J and Ludolph, AC and Hesebeck-Brinckmann, J and Spittel, S and Münch, C and Maier, A and Körtvélyessy, P}, title = {Clinical and patient-reported outcomes and neurofilament response during tofersen treatment in SOD1-related ALS-A multicenter observational study over 18 months.}, journal = {Muscle & nerve}, volume = {70}, number = {3}, pages = {333-345}, doi = {10.1002/mus.28182}, pmid = {39031772}, issn = {1097-4598}, support = {(H4017703513237604)//Boris Canessa ALS Stiftung (Düsseldorf, Germany) and Martin Herrenknecht Fonds for ALS Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Male ; Female ; *Patient Reported Outcome Measures ; Middle Aged ; Aged ; *Superoxide Dismutase-1/genetics ; *Neurofilament Proteins/blood ; Treatment Outcome ; Disease Progression ; Adult ; Oligonucleotides/therapeutic use ; }, abstract = {INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (SOD1-ALS), tofersen received accelerated approval in the United States and is available via expanded access programs (EAP) outside the United States. This multicenter study investigates clinical and patient-reported outcomes (PRO) and serum neurofilament light chain (sNfL) during tofersen treatment in an EAP in Germany.

METHODS: Sixteen SOD1-ALS patients receiving tofersen for at least 6 months were analyzed. The ALS progression rate (ALS-PR), as measured by the monthly change of the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity (SVC), and sNfL were investigated. PRO included the Measure Yourself Medical Outcome Profile (MYMOP2), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and Net Promoter Score (NPS).

RESULTS: Mean tofersen treatment was 11 months (6-18 months). ALS-PR showed a mean change of -0.2 (range 0 to -1.1) and relative reduction by 25%. Seven patients demonstrated increased ALSFRS-R. SVC was stable (mean 88%, range -15% to +28%). sNfL decreased in all patients except one heterozygous D91A-SOD1 mutation carrier (mean change of sNfL -58%, range -91 to +27%, p < .01). MYMOP2 indicated improved symptom severity (n = 10) or yet perception of partial response (n = 6). TSQM-9 showed high global treatment satisfaction (mean 83, SD 16) although the convenience of drug administration was modest (mean 50, SD 27). NPS revealed a very high recommendation rate for tofersen (NPS +80).

DISCUSSION: Data from this EAP supported the clinical and sNfL response to tofersen in SOD1-ALS. PRO suggested a favorable patient perception of tofersen treatment in clinical practice.}, } @article {pmid39032788, year = {2024}, author = {Wu, KJ and Wei, KC}, title = {Response to Hasan et al's "Dupilumab therapy for atopic dermatitis is associated with increased risk of cutaneous T cell lymphoma: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {5}, pages = {e145-e146}, doi = {10.1016/j.jaad.2024.06.091}, pmid = {39032788}, issn = {1097-6787}, } @article {pmid39032803, year = {2024}, author = {He, Q and Zhou, Y and Jin, J and Tian, Q and Li, H and Hou, B and Xie, A}, title = {Association between NEK1 gene polymorphisms and the potential risk of sporadic Parkinson's disease in the Chinese Northern Han population: A case-control study.}, journal = {Neuroscience letters}, volume = {837}, number = {}, pages = {137913}, doi = {10.1016/j.neulet.2024.137913}, pmid = {39032803}, issn = {1872-7972}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Case-Control Studies ; China/epidemiology ; East Asian People/genetics ; Genetic Association Studies ; *Genetic Predisposition to Disease ; Genotype ; *NIMA-Related Kinase 1/genetics ; *Parkinson Disease/genetics ; *Polymorphism, Single Nucleotide ; }, abstract = {OBJECTIVE: Parkinson's disease (PD) has been identified as a genetically influenced disease linked to various genetic loci. Previous studies have suggested that neurodegenerative illnesses, including PD, Alzheimer's disease, and Amyotrophic lateral sclerosis (ALS), may share certain genetic loci. Recently, the NEK1 gene was identified as overlapping between PD and ALS. We therefore wanted to explore the potential association between the NEK1 gene single nucleotide polymorphisms (SNPs) and the clinical features and pathophysiology of sporadic PD in a northern Chinese population.

METHODS: A total of 510 sporadic PD patients and 510 age- and sex-matched healthy controls (HCs) were included in this study. Two SNPs (rs4563461 and rs66509122) of the NEK1 gene were genotyped using polymerase chain reaction (PCR). And we analyzed the association between NEK1 gene polymorphisms and clinical manifestations.

RESULTS: Allele T (C vs. T, P = 0.018) and genotype TT (CC vs. TT: P = 0.021) of rs66509122 among PD group and HCs were significantly different. In addition, we discovered that the rs66509122 genotype TT was associated with depression in early-onset PD (EOPD) (P = 0.031) and diabetes in female PD (P = 0.032). Unfortunately, no distinct correlation of rs4563461 polymorphisms with sporadic PD susceptibility was found in either the overall group (C vs. T, P = 0.086) or other subgroups. However, the T allele of rs4563461 was significantly correlated with sleep disorders in the PD group, especially in the late-onset PD (LOPD) group and male PD group.

CONCLUSION: This study found that the NEK1 rs66509122 polymorphism was associated with a lower risk of sporadic PD, while T allele of rs66509122 may be a protective factor for PD. The NEK1 rs4563461 and rs66509122 polymorphisms both showed correlations with some non-motor symptoms in sporadic PD patients. Further research with a larger sample and varied ethnic groups is needed to investigate the role of NEK1 gene polymorphisms in the pathophysiology of PD.}, } @article {pmid39033904, year = {2024}, author = {Lu, XY and Li, MQ and Li, YT and Yao, JY and Zhang, LX and Zeng, ZH and Yu-Liu, and Chen, ZR and Li, CQ and Zhou, XF and Li, F}, title = {Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder.}, journal = {Neuropharmacology}, volume = {258}, number = {}, pages = {110089}, doi = {10.1016/j.neuropharm.2024.110089}, pmid = {39033904}, issn = {1873-7064}, mesh = {Animals ; *Valproic Acid/pharmacology/administration & dosage ; *Edaravone/pharmacology ; *Autism Spectrum Disorder/drug therapy/chemically induced ; *Disease Models, Animal ; Female ; *Oxidative Stress/drug effects ; Male ; Administration, Oral ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Brain/drug effects/metabolism/pathology ; Prenatal Exposure Delayed Effects/chemically induced ; Free Radical Scavengers/pharmacology/administration & dosage/therapeutic use ; Dose-Response Relationship, Drug ; Stereotyped Behavior/drug effects ; Behavior, Animal/drug effects ; Social Interaction/drug effects ; }, abstract = {Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.}, } @article {pmid39037015, year = {2024}, author = {Timmins, HC and Thompson, AE and Kiernan, MC}, title = {Diagnostic criteria for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {570-576}, doi = {10.1097/WCO.0000000000001302}, pmid = {39037015}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Humans ; *Biomarkers/analysis ; }, abstract = {PURPOSE OF REVIEW: The present review will discuss the evolution of diagnostic criteria for amyotrophic lateral sclerosis (ALS) and biomarker considerations.

RECENT FINDINGS: To address the limitations of existing ALS diagnostic criteria, a consortium of key stakeholders developed the Gold Coast consensus criteria (GCC). The GCC has similar or greater sensitivity compared with the revised El Escorial (rEEC) and Awaji criteria (AC), particularly for atypical phenotypes, maintained across disease duration, severity, and site of onset. In addition to improving diagnostic sensitivity, using the GCC in clinical trials may promote an increased enrolment of up to 50% of ALS patients who do not currently meet the full diagnostic eligibility requirements of the rEEC. Future inclusion of genetic biomarkers may mitigate some limitations of the GCC, to further improve diagnostic utility. In advance of such a process, validation of these biomarkers will be required before inclusion as additional criteria.

SUMMARY: The GCC are simpler to use than previous consensus criteria, with demonstrated greater sensitivity and, enabling an earlier and more definitive ALS diagnosis, thereby facilitating wider enrolment into clinical trials. Broader implementation of the GCC in clinical trial settings is currently underway, globally.}, } @article {pmid39037980, year = {2024}, author = {Souza, AA and da Silva, ST and Macedo, LRD and Aires, DN and Pondofe, KM and Melo, LP and Valentim, RAM and Ribeiro, TS}, title = {Physical therapy for muscle strengthening in individuals with amyotrophic lateral sclerosis: A protocol for a systematic review and meta-analysis.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0307470}, pmid = {39037980}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Muscle Strength ; *Systematic Reviews as Topic ; *Meta-Analysis as Topic ; Physical Therapy Modalities ; Female ; Male ; }, abstract = {INTRODUCTION: People with Amyotrophic Lateral Sclerosis (ALS) can present initially muscle weakness, which is a debilitating symptom that may be improved by engaging in muscle strengthening activities. Currently, the effects of motor interventions for muscle strengthening in people with ALS are unclear. This review intends to analyze the effects of motor interventions for muscle strengthening in individuals with ALS.

METHODS AND ANALYSIS: Randomized, non-randomized, and quasi-experimental clinical trials assessing individuals with ALS of both sexes, aged 18 years or older, who have received motor interventions for muscle strengthening considering all practices that can lead to increased strength, endurance, power and muscular hypertrophy will be included. No restriction on language, location, or publication date will be applied. MEDLINE, EMBASE, Cochrane Library (CENTRAL), SPORTDiscus, and Physiotherapy Evidence Database (PEDro) databases will be searched. The US National Institutes of Health Ongoing, ClinicalTrials.gov, and the reference lists of included studies will also be searched. Two reviewers will independently screen titles and abstracts and extract data from included studies. The methodological quality of the included studies will be assessed by the PEDro scale and the certainty of the evidence by the GRADE approach. Disagreements will be resolved by a third researcher. Findings will be presented in text and table formats. A meta-analysis will compare the effects of motor interventions for muscle strengthening versus placebo or other interventions.}, } @article {pmid39038319, year = {2024}, author = {Zhao, T and Huang, J and Chi, W}, title = {The Diagnostic Advantages of MRI in Cerebral Infarction: Multi-Sequence Imaging and Improved Sensitivity in Early Detection.}, journal = {Alternative therapies in health and medicine}, volume = {}, number = {}, pages = {}, pmid = {39038319}, issn = {1078-6791}, abstract = {OBJECTIVE: The study aimed to investigate the diagnostic value of computed tomography (CT) and magnetic resonance imaging (MRI) in cerebral infarction (CI) in cerebrovascular diseases.

METHOD: 100 patients with acute ischemic cerebral infarction (AICI) were divided into a CT group and an MRI group. The diagnostic efficacy of the two diagnostic methods for CI was compared and analyzed.

RESULTS: Only 6 patients with acute early stage (AES) CI and 30 patients with acute late stage (ALS) CI were detected by CT, which was significantly less than those detected by MRI (P < .05); 5 patients with <5 mm infarction were detected by CT in ALS and 10 patients with 5-15 mm infarction were detected by CT in ALS, which were significantly less than those detected by MRI (P < .05); 3 patients were diagnosed with cerebral sulcus, fissure, and shallow and disappeared brain cistern, 4 patients with local gyrus swelling, and 31 patients with significant swelling by CT examination, which was significantly less than those detected by MRI (P < .05); the infarct area ratio measured by CT/ diffusion weighted imaging (DWI) was significantly lower than that measured by fluid attenuated inversion recovery (FLAIR)/DWI (P < .05); the diagnostic specificity (Sp), sensitivity (Se), Youden index, positive predictive value (PV), and negative PV of MRI were 0.82, 0.79, 0.58, 0.7, and 0.88, respectively, which were significantly better than those of CT (P < .05).

CONCLUSION: CT is not a sensitive technique for the diagnosis of early CI. Compared to CT, MRI has the characteristics of multi-sequence and multi-parameter imaging, is more sensitive to infarction within 2 hours after onset, and can more clearly and accurately diagnose CI.}, } @article {pmid39039102, year = {2024}, author = {Acien, A and Calcagno, N and Burke, KM and Mondesire-Crump, I and Holmes, AA and Mruthik, S and Goldy, B and Syrotenko, JE and Scheier, Z and Iyer, A and Clark, A and Keegan, M and Ushirogawa, Y and Kato, A and Yasuda, T and Lahav, A and Iwasaki, S and Pascarella, M and Johnson, SA and Arroyo-Gallego, T and Berry, JD}, title = {A novel digital tool for detection and monitoring of amyotrophic lateral sclerosis motor impairment and progression via keystroke dynamics.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {16851}, pmid = {39039102}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; *Disease Progression ; Female ; Male ; Middle Aged ; Aged ; *Smartphone ; Machine Learning ; Case-Control Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition leading to progressive muscle weakness, atrophy, and ultimately death. Traditional ALS clinical evaluations often depend on subjective metrics, making accurate disease detection and monitoring disease trajectory challenging. To address these limitations, we developed the nQiALS toolkit, a machine learning-powered system that leverages smartphone typing dynamics to detect and track motor impairment in people with ALS. The study included 63 ALS patients and 30 age- and sex-matched healthy controls. We introduce the three core components of this toolkit: the nQiALS-Detection, which differentiated ALS from healthy typing patterns with an AUC of 0.89; the nQiALS-Progression, which separated slow and fast progression at specific thresholds with AUCs ranging between 0.65 and 0.8; and the nQiALS-Fine Motor, which identified subtle progression in fine motor dysfunction, suggesting earlier prediction than the state-of-the-art assessment. Together, these tools represent an innovative approach to ALS assessment, offering a complementary, objective metric to traditional clinical methods and which may reshape our understanding and monitoring of ALS progression.}, } @article {pmid39039135, year = {2024}, author = {Tahir, M and Yude, B and Mehmood, T and Bashir, S and Zhenping, Y and Awais, M}, title = {Classification of LAMOST spectra of B-type and hot subdwarf stars using kernel support vector machine.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {16815}, pmid = {39039135}, issn = {2045-2322}, abstract = {Machine learning has emerged as a leading field in artificial intelligence, demonstrating expert-level performance in various domains. Astronomy has benefited from machine learning techniques, particularly in classifying and identifying stars based on their features. This study focuses on the spectra-based classification of 11,408 B-type and 2422 hot subdwarf stars. The study employs baseline correction using Asymmetric Least Squares (ALS) to enhance classification accuracy. It applies the Pan-Core concept to identify 500 unique patterns or ranges for both types of stars. These patterns are the foundation for creating Support Vector Machine (SVM) models, including the linear (L-SVM), polynomial (P-SVM), and radial basis (R-SVM) kernels. Parameter tuning for the SVM models is achieved through cross-validation. Evaluation of the SVM models on test data reveals that the linear kernel SVM achieves the highest accuracy (87.0%), surpassing the polynomial kernel SVM (84.1%) and radial kernel SVM (80.1%). The average calibrated accuracy falls within the range of 90-95%. These results demonstrate the potential of using spectrum-based classification to aid astronomers in improving and expanding their understanding of stars, with a specific focus on the identification of hot subdwarf stars. This study presents a valuable investigation for astronomers, as it enables the classification of stars based on their spectra, leveraging machine learning techniques to enhance their knowledge and insights in astronomy.}, } @article {pmid39039445, year = {2024}, author = {Jonsdottir, G and Haraldsdottir, E and Vilhjalmsson, R and Sigurdardottir, V and Hjaltason, H and Klinke, ME and Tryggvadottir, GB and Jonsdottir, H}, title = {Transition to end-of-life care in patients with neurological diseases in an acute hospital ward.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {253}, pmid = {39039445}, issn = {1471-2377}, support = {71545//The Icelandic Nurses´ Association/ ; }, mesh = {Humans ; Male ; *Terminal Care/methods/statistics & numerical data ; Female ; Aged ; Middle Aged ; Retrospective Studies ; *Nervous System Diseases/therapy/diagnosis/epidemiology ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/therapy/diagnosis/mortality ; }, abstract = {BACKGROUND: Transitioning to end-of-life care and thereby changing the focus of treatment directives from life-sustaining treatment to comfort care is important for neurological patients in advanced stages. Late transition to end-of-life care for neurological patients has been described previously.

OBJECTIVE: To investigate whether previous treatment directives, primary medical diagnoses, and demographic factors predict the transition to end-of-life care and time to eventual death in patients with neurological diseases in an acute hospital setting.

METHOD: All consecutive health records of patients diagnosed with stroke, amyotrophic lateral sclerosis (ALS), and Parkinson's disease or other extrapyramidal diseases (PDoed), who died in an acute neurological ward between January 2011 and August 2020 were retrieved retrospectively. Descriptive statistics and multivariate Cox regression were used to examine the timing of treatment directives and death in relation to medical diagnosis, age, gender, and marital status.

RESULTS: A total of 271 records were involved in the analysis. Patients in all diagnostic categories had a treatment directive for end-of-life care, with patients with haemorrhagic stroke having the highest (92%) and patients with PDoed the lowest (73%) proportion. Cox regression identified that the likelihood of end-of-life care decision-making was related to advancing age (HR = 1.02, 95% CI: 1.007-1.039, P = 0.005), ischaemic stroke (HR = 1.64, 95% CI: 1.034-2.618, P = 0.036) and haemorrhagic stroke (HR = 2.04, 95% CI: 1.219-3.423, P = 0.007) diagnoses. End-of-life care decision occurred from four to twenty-two days after hospital admission. The time from end-of-life care decision to death was a median of two days. Treatment directives, demographic factors, and diagnostic categories did not increase the likelihood of death following an end-of-life care decision.

CONCLUSIONS: Results show not only that neurological patients transit late to end-of-life care but that the timeframe of the decision differs between patients with acute neurological diseases and those with progressive neurological diseases, highlighting the particular significance of the short timeframe of patients with the progressive neurological diseases ALS and PDoed. Different trajectories of patients with neurological diseases at end-of-life should be further explored and clinical guidelines expanded to embrace the high diversity in neurological patients.}, } @article {pmid39042693, year = {2024}, author = {Celona, B and Salomonsson, SE and Wu, H and Dang, B and Kratochvil, HT and Clelland, CD and DeGrado, WF and Black, BL}, title = {Zfp106 binds to G-quadruplex RNAs and inhibits RAN translation and formation of RNA foci caused by G4C2 repeats.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {31}, pages = {e2220020121}, pmid = {39042693}, issn = {1091-6490}, support = {U01NS134062//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; HL146366//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; GM122603//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; K08 NS112330/NS/NINDS NIH HHS/United States ; U19 NS132303/NS/NINDS NIH HHS/United States ; R01 DK119621/DK/NIDDK NIH HHS/United States ; DK119621//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; NS126499//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35 GM122603/GM/NIGMS NIH HHS/United States ; R01 NS126499/NS/NINDS NIH HHS/United States ; U01 NS134062/NS/NINDS NIH HHS/United States ; P01 HL146366/HL/NHLBI NIH HHS/United States ; AL210129//U.S. Department of Defense (DOD)/ ; U19NS132303//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; K99 GM138753/GM/NIGMS NIH HHS/United States ; K99GM138753//HHS | National Institutes of Health (NIH)/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *C9orf72 Protein/genetics/metabolism ; DNA Repeat Expansion ; Frontotemporal Dementia/genetics/metabolism ; *G-Quadruplexes ; Nerve Tissue Proteins/metabolism/genetics ; Protein Binding ; Protein Biosynthesis ; *RNA/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Adaptor Proteins, Signal Transducing ; }, abstract = {Expansion of intronic GGGGCC repeats in the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Transcription of the expanded repeats results in the formation of RNA-containing nuclear foci and altered RNA metabolism. In addition, repeat-associated non-AUG (RAN) translation of the expanded GGGGCC-repeat sequence results in the production of highly toxic dipeptide-repeat (DPR) proteins. GGGGCC repeat-containing transcripts form G-quadruplexes, which are associated with formation of RNA foci and RAN translation. Zfp106, an RNA-binding protein essential for motor neuron survival in mice, suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Here, we show that Zfp106 inhibits formation of RNA foci and significantly reduces RAN translation caused by GGGGCC repeats in cultured mammalian cells, and we demonstrate that Zfp106 coexpression reduces the levels of DPRs in C9orf72 patient-derived cells. Further, we show that Zfp106 binds to RNA G-quadruplexes and causes a conformational change in the G-quadruplex structure formed by GGGGCC repeats. Together, these data demonstrate that Zfp106 suppresses the formation of RNA foci and DPRs caused by GGGGCC repeats and suggest that the G-quadruplex RNA-binding function of Zfp106 contributes to its suppression of GGGGCC repeat-mediated cytotoxicity.}, } @article {pmid39042810, year = {2024}, author = {Haridevamuthu, B and Sathishkumar, K}, title = {Comment on Tsioti et al's "Systemic Lipopolysaccharide Exposure Exacerbates Choroidal Neovascularization in Mice".}, journal = {Ocular immunology and inflammation}, volume = {32}, number = {10}, pages = {2614-2615}, doi = {10.1080/09273948.2024.2377732}, pmid = {39042810}, issn = {1744-5078}, mesh = {*Choroidal Neovascularization/drug therapy ; Animals ; *Lipopolysaccharides ; Mice ; *Disease Models, Animal ; Macrophages/drug effects ; Fluorescein Angiography ; }, abstract = {The study "Systemic Lipopolysaccharide Exposure Exacerbates Choroidal Neovascularization in Mice" by Tsioti et al. explores the impact of systemic lipopolysaccharide (LPS) on choroidal neovascularization (CNV) progression. The findings reveal systemic LPS exposure significantly enhances fluorescein leakage, driven by increased pro-inflammatory monocyte-derived macrophages and microglia activation. The study underscores the importance of managing systemic inflammation to mitigate CNV progression, suggesting potential therapeutic strategies targeting CSF1R inhibition and Müller cell modulation. Future research should focus on elucidating the molecular pathways involved in LPS-induced CNV exacerbation and translating these findings into clinical interventions.}, } @article {pmid39044305, year = {2024}, author = {Chen, HH and Yeo, HT and Huang, YH and Tsai, LK and Lai, HJ and Tsao, YP and Chen, SL}, title = {AAV-NRIP gene therapy ameliorates motor neuron degeneration and muscle atrophy in ALS model mice.}, journal = {Skeletal muscle}, volume = {14}, number = {1}, pages = {17}, pmid = {39044305}, issn = {2044-5040}, support = {NSTC 112-2320-B-002-004//National Science and Technology Council/ ; NSTC 112-2320-B-002-004//National Science and Technology Council/ ; 10R891903//National Taiwan University/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/pathology ; *Genetic Therapy/methods ; *Muscular Atrophy/genetics/therapy/metabolism/pathology ; *Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; *Dependovirus/genetics ; Mice ; Humans ; Muscle, Skeletal/metabolism/pathology ; Neuromuscular Junction/metabolism/pathology ; Genetic Vectors/administration & dosage ; Nerve Degeneration/genetics/therapy ; Male ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving as a calcium sensor for muscle contraction and maintaining sarcomere integrity. Additionally, NRIP binds with the acetylcholine receptor (AChR) for NMJ stabilization. Loss of NRIP in muscles results in progressive motor neuron degeneration with abnormal NMJ architecture, resembling ALS phenotypes. Therefore, we hypothesize that NRIP could be a therapeutic factor for ALS.

METHODS: We used SOD1 G93A mice, expressing human SOD1 with the ALS-linked G93A mutation, as an ALS model. An adeno-associated virus vector encoding the human NRIP gene (AAV-NRIP) was generated and injected into the muscles of SOD1 G93A mice at 60 days of age, before disease onset. Pathological and behavioral changes were measured to evaluate the therapeutic effects of AAV-NRIP on the disease progression of SOD1 G93A mice.

RESULTS: SOD1 G93A mice exhibited lower NRIP expression than wild-type mice in both the spinal cord and skeletal muscle tissues. Forced NRIP expression through AAV-NRIP intramuscular injection was observed in skeletal muscles and retrogradely transduced into the spinal cord. AAV-NRIP gene therapy enhanced movement distance and rearing frequencies in SOD1 G93A mice. Moreover, AAV-NRIP increased myofiber size and slow myosin expression, ameliorated NMJ degeneration and axon terminal denervation at NMJ, and increased the number of α-motor neurons (α-MNs) and compound muscle action potential (CMAP) in SOD1 G93A mice.

CONCLUSIONS: AAV-NRIP gene therapy ameliorates muscle atrophy, motor neuron degeneration, and axon terminal denervation at NMJ, leading to increased NMJ transmission and improved motor functions in SOD1 G93A mice. Collectively, AAV-NRIP could be a potential therapeutic drug for ALS.}, } @article {pmid39044379, year = {2024}, author = {Goutman, SA and Goyal, NA and Payne, K and Paisán-Ruiz, C and Kupelian, V and Kang, ML and Mitchell, AA and Fecteau, TE}, title = {ALS Identified: two-year findings from a sponsored ALS genetic testing program.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {8}, pages = {2201-2211}, pmid = {39044379}, issn = {2328-9503}, support = {//Biogen (Cambridge, MA, USA)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Male ; *Genetic Testing ; Female ; Middle Aged ; Aged ; Adult ; United States ; }, abstract = {OBJECTIVE: To report initial results from the Amyotrophic Lateral Sclerosis (ALS) Identified genetic testing (GT) program on characteristics of individuals tested and frequency of reported disease-causing variants.

METHODS: ALS Identified used the Invitae Amyotrophic Lateral Sclerosis panel (Invitae, San Francisco, CA, USA) to assay 22 ALS-associated genes. Sponsored by Biogen (Cambridge, MA, USA), the program was launched in June 2021 and was available at no charge to individuals ≥18 years in the United States and Puerto Rico with an ALS diagnosis or a known family history of ALS. Deidentified data were available to Biogen.

RESULTS: As of 26 October 2023, 998 healthcare professionals ordered the panel at 681 unique care sites. Of 8054 individuals examined, 7483 (92.9%) were reported to have a clinical diagnosis of ALS, while 571 (7.1%) were asymptomatic relatives. Of the individuals with a clinical ALS diagnosis, 57.7% were male (n = 4319) and 42.3% female (n = 3164). Mean (SD) age at diagnosis is 62 (13) years. Out of the 7483 clinically diagnosed individuals, 1810 (24.2%) showed genetic variations in ALS-associated genes. Among these, 865 individuals (47.8%) carried pathogenic variants, and 44 (2.4%) had likely pathogenic variants, totaling 12.1% of the clinically diagnosed population.

INTERPRETATION: Since 2021 there has been robust uptake and sustained use of the ALS Identified program, one of the largest samples of people with ALS to date across the United States, demonstrating the interest and need for genetic ALS testing.}, } @article {pmid39044591, year = {2024}, author = {Wang, J and Feng, L and Zhang, Y and Xu, P}, title = {[Establishment of a stable THP-1 cell line expressing PSMB9-eGFP-His protein and detection of immunoproteasome activity].}, journal = {Sheng wu gong cheng xue bao = Chinese journal of biotechnology}, volume = {40}, number = {7}, pages = {2282-2293}, doi = {10.13345/j.cjb.240124}, pmid = {39044591}, issn = {1872-2075}, mesh = {Humans ; *Proteasome Endopeptidase Complex/genetics/metabolism ; *Green Fluorescent Proteins/genetics/metabolism ; THP-1 Cells ; Lentivirus/genetics ; Recombinant Fusion Proteins/genetics ; Cysteine Endopeptidases/genetics/metabolism ; }, abstract = {The ubiquitin/proteasome system (UPS) plays a crucial role in maintaining cellular protein homeostasis. The catalytic activity of proteasome in the UPS is regulated by β1 (PSMB6), β2 (PSMB7), and β5 (PSMB5) subunits. Interferon (IFN)-γ, tumor necrosis factor (TNF)-α, inflammation, and oxidative stress can induce the replacement of β1, β2, and β5 with their respective immuno-subunits β1i (PSMB9), β2i (PSMB10), and β5i (PSMB8), which can be assembled into the immunoproteasome. Compared with the standard proteasome, the immunoproteasome exerts enhanced regulatory effects on immune responses, such as processing and presenting MHC class Ⅰ antigens, production of pro-inflammatory cytokines, and T cell differentiation and proliferation. Abnormal aggregation of immunoproteasomes can cause neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. To explore the function of PSMB9 after bacterial infection, we constructed a lentivirus plasmid overexpressing PSMB9-eGFP-His and transfected the plasmid into HEK293T cells for packaging by using a triple-plasmid system in this study. After screening with puromycin, we obtained a stable human leukemia monocytic THP-1 cell line expressing the fusion protein of PSMB9. Western blotting (WB) and fluorescence microscopy verified the expression of the fusion protein in the stable THP-1 cells. Quantitative PCR (qPCR) was employed to measure the copies of PSMB9-eGFP in THP-1 cells. Immunofluorescence results found that eGFP-His did not affect the subcellular localization of PSMB9. The purification with nickel affinity chromatography confirmed that the fusion protein could be assembled into the 20S immunoproteasome and exhibited cleaving activity for fluorescent peptide substrates. These results indicated that the PSMB9-eGFP fusion gene was integrated into the chromosome, and could be stably expressed in the constructed THP-1 cell line. This cell line can be utilized for the research on subcellular localization, dynamic expression, and activity of PSMB9 in live cells at different infection conditions and disease stages. It also provides a model for the stable cell lines construction of other immunoproteasome subunits PSMB8 and PSMB10.}, } @article {pmid39045865, year = {2024}, author = {Sanpei, Y and Yasuda, K and Takahashi, Y and Hanazono, A and Sugawara, M and Iijima, K}, title = {Evaluation of the applicability of weak shoulder and arm sparing signs in amyotrophic lateral sclerosis by multiple neurologists and neurology residents: A single-center study.}, journal = {Muscle & nerve}, volume = {70}, number = {4}, pages = {761-765}, doi = {10.1002/mus.28216}, pmid = {39045865}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Shoulder/physiopathology ; Retrospective Studies ; *Arm/physiopathology ; *Neurologists ; *Muscle Weakness/diagnosis/physiopathology ; Internship and Residency ; Neurology/education ; Muscle, Skeletal/physiopathology ; Adult ; Sensitivity and Specificity ; Aged, 80 and over ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) exhibits selective muscle weakness. The weak shoulder and arm sparing signs, assessed by a single experienced neurologist, have been reported to be superior to previous signs in sensitivity and specificity. However, it is unknown whether the same results are observed when assessed by multiple neurologists.

METHODS: Subjects were retrospectively identified from our department's inpatient database from 2014 to 2023. Medical Research Council (MRC) scores of the deltoid (Del), biceps brachii (BB), triceps brachii (TB), and first dorsal interosseous (FDI) muscles were evaluated. The weak shoulder sign was defined as positive when Del was weaker than BB and TB. The arm sparing sign was defined as positive when both Del and FDI were weaker than BB and TB. Sensitivity was analyzed in all ALS patients and in subgroups based on the region of symptom onset, presence or absence of upper motor neuron (UMN) signs, and the Japanese ALS Severity Classification.

RESULTS: Seventy-one patients with ALS were identified. Eight neurologists and three neurology residents evaluated each patient's MRC scores. The weak shoulder and arm sparing signs were observed in 72% and 48% of patients, respectively, with no significant difference in sensitivity across patient subgroups.

DISCUSSION: The weak shoulder and arm sparing signs showed high and moderate sensitivity, respectively, consistent with a previous report, even when evaluated by multiple examiners. This expands the clinical utility and increases the reliability of these signs, potentially contributing to accurate ALS diagnosis when combined with other clinical features and objective assessments.}, } @article {pmid39046818, year = {2024}, author = {Brink, V and Kirkbride, J}, title = {Reply to Zhou et al's "Refining Psychosis Research: Insights on Cannabis Use and Data Accuracy".}, journal = {Schizophrenia bulletin}, volume = {50}, number = {5}, pages = {965-967}, pmid = {39046818}, issn = {1745-1701}, support = {//European Community's Seventh Framework/ ; 2012/0417-0//São Paulo Research Foundation/ ; MD-PhD 18-41//University Medical Centre Groningen/ ; //National Institute for Health and Care Research/ ; //University College London Hospitals NHS Foundation Trust/ ; //UK Research and Innovation/ ; MR/W030608/1//Clinical Academic Research Partnership/ ; }, mesh = {Humans ; *Psychotic Disorders ; Data Accuracy ; Biomedical Research/standards ; Marijuana Use/epidemiology ; Marijuana Abuse/epidemiology ; }, } @article {pmid39047759, year = {2024}, author = {Schmid, G and Schneeweiss, P and Hirtl, R and Jhala, T and Samaras, T}, title = {Numerical assessment of induced electric fields in a worker's hand with commonly used metallic implants under exposure to low frequency magnetic fields.}, journal = {Journal of radiological protection : official journal of the Society for Radiological Protection}, volume = {44}, number = {3}, pages = {}, doi = {10.1088/1361-6498/ad66dc}, pmid = {39047759}, issn = {1361-6498}, mesh = {Humans ; *Occupational Exposure/analysis ; *Hand ; *Electromagnetic Fields ; Metals ; Magnetic Fields ; Prostheses and Implants ; Bone Screws ; Bone Plates ; }, abstract = {The European Union's Workers' Directive 2013/35/EU on the minimum health and safety requirements regarding the exposure of workers to electromagnetic fields specifies action levels (ALs) for external electric and magnetic fields, which should protect against induced tissue-internal electric field strengthEiabove the exposure limit values, the latter being defined in order to prevent tissue stimulation at low frequencies. However, although 2013/35/EU explicitly calls for the protection of 'workers at particular risk' (including workers with metallic implants), the AL specified in the Directive have been derived under the assumption that there are no metallic parts present inside the body. Therefore, in the present work, we analysed the situation of a worker's hand and forearm bearing metallic implants (Herbert screw and volar radius plate) used for osteosynthesis after the most common bone fractures of the hand/forearm, exposed to low frequency magnetic fields. The uniform exposure of the whole hand and forearm as well as the exposure to a specific and widely used device, a deactivator for single-use labels of acousto-magnetic electronic article surveillance systems, were considered based on numerical computations using a high-resolution anatomical hand and forearm model. The results obtained indicated that the maximum induced electric field strength averaged in a volume of 2 mm × 2 mm × 2 mm cube was higher in the presence of the metallic implants by a factor of up to 4.2 for bone tissue and 2.3 for soft tissue compared with the case without an implant. Hence, it is obvious that the local induced electric field strengths may be substantially increased by the implants. The extent of this increase, however, is highly dependent on the implant's position inside the body, the implant's geometry, and the field distribution and orientation with respect to the anatomical structure and the implant.}, } @article {pmid39050003, year = {2024}, author = {Özaydin Aksun, Z and Erdoğan, S and Kalkanci, A and Şahin, EA and Çuhadar, T and Şener, HÖ}, title = {Is gut microbiota of patients with ALS different from that of healthy individuals?.}, journal = {Turkish journal of medical sciences}, volume = {54}, number = {3}, pages = {579-587}, pmid = {39050003}, issn = {1303-6165}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/microbiology ; *Gastrointestinal Microbiome/genetics/physiology ; Female ; Male ; Middle Aged ; Adult ; Feces/microbiology ; RNA, Ribosomal, 16S/analysis/genetics ; Aged ; Case-Control Studies ; }, abstract = {BACKGROUND/AIM: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Several studies have shown that alterations of microbiota increase the risk of neurodegenerative disorders. We aimed to reveal whether there is a difference in the gut microbiota of patients with ALS.

MATERIALS AND METHODS: The participants are divided into three groups. Group 1 comprised patients with ALS. Healthy family members living in the same house of the patients formed Group 2. Lastly, sex- and age-matched healthy people were included in Group 3. Fecal samples were collected in 15-mL falcon tubes and stored at -80 °C. Genomic DNA isolation was performed on samples. Bacterial primers selected from the 16S rRNA region for the bacterial genome and ITS1 and ITS4 (internal transcribed spacer) were used for the identification of DNA. Next generation sequence analysis (NGS) and taxonomic analyses were performed at the level of bacterial phylum, class, order, family, genus, and species. Alpha and beta diversity indexes were used. The linear discriminant analysis (LDA) effect size method (LEfSe) was applied to identify a microbial taxon specific to ALS disease.

RESULTS: The relative abundances of the Succinivibrionaceae and Lachnospiraceae families were significantly lower in patients. The dominant families among patients were Streptococcaceae and Ruminococcaceae, while the dominant families among healthy controls were Bacteroidaceae and Succinivibrionaceae. The LEfSe analysis revealed that four families (Atopobiaceae, Actinomycetaceae, Erysipelatoclostridiaceae, Peptococcacceae) differed significantly between the patients and healthy controls (LDA values> 2.5, p < 0.05).

CONCLUSION: Comparison with family members living in the same house is the strength of this study. We found that there were changes in the microbiota of the patients, consistent with the literature. Studies that analyze the composition of the gut microbiota in the predisease period may be needed to understand whether dysbiosis is caused by the mechanisms inherent in the disease or whether it is dysbiosis that initiates the disease.}, } @article {pmid39050823, year = {2024}, author = {Min, JH and Sarlus, H and Harris, RA}, title = {Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1408159}, pmid = {39050823}, issn = {1662-5099}, abstract = {The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.}, } @article {pmid39053342, year = {2024}, author = {Hideyama, T and Teramoto, S and Kato, H and Terashi, H and Kwak, S and Aizawa, H}, title = {Negative features of sporadic amyotrophic lateral sclerosis: Motor neurons of Onuf's nucleus survive in ADAR2-conditional knockout mice.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123142}, doi = {10.1016/j.jns.2024.123142}, pmid = {39053342}, issn = {1878-5883}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Adenosine Deaminase/genetics/deficiency/metabolism ; *Motor Neurons/pathology/metabolism ; *RNA-Binding Proteins/genetics/metabolism ; Mice ; *Mice, Knockout ; DNA-Binding Proteins/genetics/metabolism ; Disease Models, Animal ; Receptors, AMPA/genetics/metabolism ; Mice, Transgenic ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) do not develop oculomotor disturbances and vesicorectal dysfunction until end-stage disease owing to the survival of certain motor neurons (MNs), including oculomotor neurons and MNs within Onuf's nucleus. In sporadic ALS, adenosine deaminase acting on RNA 2 (ADAR2)-mediated editing of GluA2 mRNA at the Q/R site is compromised in lower MNs. We previously developed genetically modified mice with a conditional knockout of ADAR2 in cholinergic neurons (ADAR2[flox/flox]/VAChT-Cre, Fast; AR2). These mice displayed slow and progressive lower motor neuron death with TAR DNA-binding protein 43 (TDP-43) pathology, attributable to insufficient editing at the GluA2 Q/R site due to ADAR2 deficiency. MN death was more common in fast-fatigable MNs owing to differential vulnerability under conditions of ADAR2 deficiency. Although facial and hypoglossal nerves were impaired in AR2 mice, cell death did not occur within the oculomotor nerve nucleus, as observed in patients with sporadic ALS. Since the basis for avoiding cystorectal damage in ALS is unknown, we compared the features of Onuf's nucleus MNs in 12-month-old AR2 mice with those in age-matched wild-type mice. Although the number of MNs was not significantly lower in AR2 mice, the neurons exhibited a shrunken morphology and TDP-43 pathology. Onuf's nucleus MNs could survive in an ADAR2-deficient state and mainly included fast fatigue-resistant (FR) and slow (S) MNs. In summary, FR and S MNs show increased resilience to ADAR2 deficiency, potentially participating in an important neuronal death avoidance mechanism in ALS.}, } @article {pmid39054069, year = {2024}, author = {Wong, HC and Lang, AE and Stein, C and Drerup, CM}, title = {ALS-Linked VapB P56S Mutation Alters Neuronal Mitochondrial Turnover at the Synapse.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {44}, number = {35}, pages = {}, pmid = {39054069}, issn = {1529-2401}, support = {R01 NS124692/NS/NINDS NIH HHS/United States ; T32 GM007133/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Zebrafish ; *Mitochondria/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Synapses/metabolism/genetics ; *Animals, Genetically Modified ; Vesicular Transport Proteins/genetics/metabolism ; Neurons/metabolism ; Humans ; Mutation ; Endoplasmic Reticulum/metabolism/genetics ; Mitophagy/genetics/physiology ; Zebrafish Proteins/genetics/metabolism ; }, abstract = {Mitochondrial population maintenance in neurons is essential for neuron function and survival. Contact sites between mitochondria and the endoplasmic reticulum (ER) are poised to regulate mitochondrial homeostasis in neurons. These contact sites can facilitate transfer of calcium and lipids between the organelles and have been shown to regulate aspects of mitochondrial dynamics. Vesicle-associated membrane protein-associated protein B (VapB) is an ER membrane protein present at a subset of ER-mitochondrial contact sites. A proline-to-serine mutation in VapB at amino acid 56 (P56S) correlates with susceptibility to amyotrophic lateral sclerosis (ALS) type 8. Given the relationship between failed mitochondrial health and neurodegenerative disease, we investigated the function of VapB in mitochondrial population maintenance. We demonstrated that transgenic expression of VapB[P56S] in zebrafish larvae (sex undetermined) increased mitochondrial biogenesis, causing increased mitochondrial population size in the axon terminal. Expression of wild-type VapB did not alter biogenesis but, instead, increased mitophagy in the axon terminal. Using genetic manipulations to independently increase mitochondrial biogenesis, we show that biogenesis is normally balanced by mitophagy to maintain a constant mitochondrial population size. VapB[P56S] transgenics fail to increase mitophagy to compensate for the increase in mitochondrial biogenesis, suggesting an impaired mitophagic response. Finally, using a synthetic ER-mitochondrial tether, we show that VapB's function in mitochondrial turnover is likely independent of ER-mitochondrial tethering by contact sites. Our findings demonstrate that VapB can control mitochondrial turnover in the axon terminal, and this function is altered by the P56S ALS-linked mutation.}, } @article {pmid39054363, year = {2024}, author = {Weishaupt, JH and Körtvélyessy, P and Schumann, P and Valkadinov, I and Weyen, U and Hesebeck-Brinckmann, J and Weishaupt, K and Endres, M and Andersen, PM and Regensburger, M and Dreger, M and Koch, JC and Conrad, J and Meyer, T}, title = {Tofersen decreases neurofilament levels supporting the pathogenesis of the SOD1 p.D91A variant in amyotrophic lateral sclerosis patients.}, journal = {Communications medicine}, volume = {4}, number = {1}, pages = {150}, pmid = {39054363}, issn = {2730-664X}, abstract = {BACKGROUND: Since the antisense oligonucleotide tofersen has recently become available for the treatment of amyotrophic lateral sclerosis (ALS) caused by mutations in SOD1, determining the causality of the over 230 SOD1 variants has become even more important. The most common SOD1 variant worldwide is p.D91A (c.272A > C), whose causality for ALS is contested when in a heterozygous state. The reason is the high allele frequency of SOD1[D91A] in Europe, exceeding 1% in Finno-Scandinavia.

METHODS: We present the clinical disease course and serum neurofilament light chain (NfL) results of treating 11 patients either homo- or heterozygous for the SOD1[D91A] allele for up to 16 months with tofersen.

RESULTS: Tofersen decreases serum neurofilament levels (sNFL), which are associated with the ALS progression rate, in the 6 ALS patients homozygous for SOD1[D91A]. We observe significantly lower sNfL levels in the 5 patients heterozygous for SOD1[D91A]. The results indicate that both mono- and bi-allelic SOD1[D91A] are causally relevant targets, with a possibly reduced effect size of SOD1[D91Ahet].

CONCLUSIONS: The finding is relevant for decision making regarding tofersen treatment, patient counseling and inclusion of SOD1[D91A] patients in drug trials. As far as we are aware, the approach is conceptually new since it provides evidence for the causality of an ALS variant based on a biomarker response to gene-specific treatment.}, } @article {pmid39054501, year = {2024}, author = {Rahimi Darehbagh, R and Seyedoshohadaei, SA and Ramezani, R and Rezaei, N}, title = {Stem cell therapies for neurological disorders: current progress, challenges, and future perspectives.}, journal = {European journal of medical research}, volume = {29}, number = {1}, pages = {386}, pmid = {39054501}, issn = {2047-783X}, mesh = {Humans ; *Nervous System Diseases/therapy ; *Stem Cell Transplantation/methods/trends ; Animals ; Cell- and Tissue-Based Therapy/methods/trends ; Neural Stem Cells/transplantation/physiology ; }, abstract = {Stem cell-based therapies have emerged as a promising approach for treating various neurological disorders by harnessing the regenerative potential of stem cells to restore damaged neural tissue and circuitry. This comprehensive review provides an in-depth analysis of the current state of stem cell applications in primary neurological conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other related disorders. The review begins with a detailed introduction to stem cell biology, discussing the types, sources, and mechanisms of action of stem cells in neurological therapies. It then critically examines the preclinical evidence from animal models and early human trials investigating the safety, feasibility, and efficacy of different stem cell types, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs). While ESCs have been studied extensively in preclinical models, clinical trials have primarily focused on adult stem cells such as MSCs and NSCs, as well as iPSCs and their derivatives. We critically assess the current state of research for each cell type, highlighting their potential applications and limitations in different neurological conditions. The review synthesizes key findings from recent, high-quality studies for each neurological condition, discussing cell manufacturing, delivery methods, and therapeutic outcomes. While the potential of stem cells to replace lost neurons and directly reconstruct neural circuits is highlighted, the review emphasizes the critical role of paracrine and immunomodulatory mechanisms in mediating the therapeutic effects of stem cells in most neurological disorders. The article also explores the challenges and limitations associated with translating stem cell therapies into clinical practice, including issues related to cell sourcing, scalability, safety, and regulatory considerations. Furthermore, it discusses future directions and opportunities for advancing stem cell-based treatments, such as gene editing, biomaterials, personalized iPSC-derived therapies, and novel delivery strategies. The review concludes by emphasizing the transformative potential of stem cell therapies in revolutionizing the treatment of neurological disorders while acknowledging the need for rigorous clinical trials, standardized protocols, and multidisciplinary collaboration to realize their full therapeutic promise.}, } @article {pmid39054893, year = {2024}, author = {Rajput, SS and Singh, SB and Subramanyam, D and Patil, S}, title = {Soft glassy rheology of single cells with pathogenic protein aggregates.}, journal = {Soft matter}, volume = {20}, number = {31}, pages = {6266-6274}, doi = {10.1039/d4sm00595c}, pmid = {39054893}, issn = {1744-6848}, mesh = {*Rheology ; Animals ; *Hemocytes/metabolism ; Protein Aggregates ; Viscosity ; Endocytosis ; Actins/metabolism/chemistry ; Single-Cell Analysis ; Microscopy, Atomic Force ; }, abstract = {A correlation between the mechanical properties of cells and various diseases has been emerging in recent years. Atomic force microscopy (AFM) has been widely used to measure a single cell's apparent Young's modulus by treating it as a fully elastic object. More recently, quantitative characterization of the complete viscoelasticity of single cells has become possible. We performed AFM-based nano-indentation experiments on hemocytes isolated from third instar larvae to determine their viscoelasticity and found that live hemocytes, like many other cells, follow a scale-free power-law rheology (PLR) akin to soft glasses. Further, we examined the changes in the rheological response of hemocytes in the presence of pathogenic protein aggregates known to cause neurodegenerative diseases such as Huntington's disorder and amyotrophic lateral sclerosis. Our results show that cells lose their fluidity and appear more solid-like in the presence of certain aggregates, in a manner correlated to actin reorganization. More solid-like cells also display reduced intracellular transport through clathrin-mediated endocytosis (CME). However, the cell's rheology remains largely unaffected and is similar to that of wild-type (WT) hemocytes, if aggregates do not perturb the actin organization and CME. Moreover, the fluid-like nature was significantly recovered when actin organization was rescued by overexpressing specific actin interacting proteins or chaperones. Our study, for the first time, underscores a direct correlation between parameters governing glassy dynamics, actin organization and CME.}, } @article {pmid39056295, year = {2025}, author = {Lindamood, HL and Liu, TM and Read, TA and Vitriol, EA}, title = {Using ALS to understand profilin 1's diverse roles in cellular physiology.}, journal = {Cytoskeleton (Hoboken, N.J.)}, volume = {82}, number = {3}, pages = {111-129}, pmid = {39056295}, issn = {1949-3592}, support = {R35 GM137959/GM/NIGMS NIH HHS/United States ; }, mesh = {*Profilins/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; }, abstract = {Profilin is an actin monomer-binding protein whose role in actin polymerization has been studied for nearly 50 years. While its principal biochemical features are now well understood, many questions remain about how profilin controls diverse processes within the cell. Dysregulation of profilin has been implicated in a broad range of human diseases, including neurodegeneration, inflammatory disorders, cardiac disease, and cancer. For example, mutations in the profilin 1 gene (PFN1) can cause amyotrophic lateral sclerosis (ALS), although the precise mechanisms that drive neurodegeneration remain unclear. While initial work suggested proteostasis and actin cytoskeleton defects as the main pathological pathways, multiple novel functions for PFN1 have since been discovered that may also contribute to ALS, including the regulation of nucleocytoplasmic transport, stress granules, mitochondria, and microtubules. Here, we will review these newly discovered roles for PFN1, speculate on their contribution to ALS, and discuss how defects in actin can contribute to these processes. By understanding profilin 1's involvement in ALS pathogenesis, we hope to gain insight into this functionally complex protein with significant influence over cellular physiology.}, } @article {pmid39056697, year = {2024}, author = {Christidi, F and Kleinerova, J and Tan, EL and Delaney, S and Tacheva, A and Hengeveld, JC and Doherty, MA and McLaughlin, RL and Hardiman, O and Siah, WF and Chang, KM and Lope, J and Bede, P}, title = {Limbic Network and Papez Circuit Involvement in ALS: Imaging and Clinical Profiles in GGGGCC Hexanucleotide Carriers in C9orf72 and C9orf72-Negative Patients.}, journal = {Biology}, volume = {13}, number = {7}, pages = {}, pmid = {39056697}, issn = {2079-7737}, support = {JPND-Cofund-2-2019-1 & HRB EIA-2017-019//HRB/ ; }, abstract = {Background: While frontotemporal involvement is increasingly recognized in Amyotrophic lateral sclerosis (ALS), the degeneration of limbic networks remains poorly characterized, despite growing evidence of amnestic deficits, impaired emotional processing and deficits in social cognition. Methods: A prospective neuroimaging study was conducted with 204 individuals with ALS and 111 healthy controls. Patients were stratified for hexanucleotide expansion status in C9orf72. A deep-learning-based segmentation approach was implemented to segment the nucleus accumbens, hypothalamus, fornix, mammillary body, basal forebrain and septal nuclei. The cortical, subcortical and white matter components of the Papez circuit were also systematically evaluated. Results: Hexanucleotide repeat expansion carriers exhibited bilateral amygdala, hypothalamus and nucleus accumbens atrophy, and C9orf72 negative patients showed bilateral basal forebrain volume reductions compared to controls. Both patient groups showed left rostral anterior cingulate atrophy, left entorhinal cortex thinning and cingulum and fornix alterations, irrespective of the genotype. Fornix, cingulum, posterior cingulate, nucleus accumbens, amygdala and hypothalamus degeneration was more marked in C9orf72-positive ALS patients. Conclusions: Our results highlighted that mesial temporal and parasagittal subcortical degeneration is not unique to C9orf72 carriers. Our radiological findings were consistent with neuropsychological observations and highlighted the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype.}, } @article {pmid39057679, year = {2024}, author = {Parvanovova, P and Hnilicova, P and Kolisek, M and Tatarkova, Z and Halasova, E and Kurca, E and Holubcikova, S and Koprusakova, MT and Baranovicova, E}, title = {Disturbances in Muscle Energy Metabolism in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Metabolites}, volume = {14}, number = {7}, pages = {}, pmid = {39057679}, issn = {2218-1989}, support = {1/0371/21//VEGA/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease type of motor neuron disorder characterized by degeneration of the upper and lower motor neurons resulting in dysfunction of the somatic muscles of the body. The ALS condition is manifested in progressive skeletal muscle atrophy and spasticity. It leads to death, mostly due to respiratory failure. Within the pathophysiology of the disease, muscle energy metabolism seems to be an important part. In our study, we used blood plasma from 25 patients with ALS diagnosed by definitive El Escorial criteria according to ALSFR-R (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) criteria and 25 age and sex-matched subjects. Aside from standard clinical biochemical parameters, we used the NMR (nuclear magnetic resonance) metabolomics approach to determine relative plasma levels of metabolites. We observed a decrease in total protein level in blood; however, despite accelerated skeletal muscle catabolism characteristic for ALS patients, we did not detect changes in plasma levels of essential amino acids. When focused on alterations in energy metabolism within muscle, compromised creatine uptake was accompanied by decreased plasma creatinine. We did not observe changes in plasma levels of BCAAs (branched chain amino acids; leucine, isoleucine, valine); however, the observed decrease in plasma levels of all three BCKAs (branched chain alpha-keto acids derived from BCAAs) suggests enhanced utilization of BCKAs as energy substrate. Glutamine, found to be increased in blood plasma in ALS patients, besides serving for ammonia detoxification, could also be considered a potential TCA (tricarboxylic acid) cycle contributor in times of decreased pyruvate utilization. When analyzing the data by using a cross-validated Random Forest algorithm, it finished with an AUC of 0.92, oob error of 8%, and an MCC (Matthew's correlation coefficient) of 0.84 when relative plasma levels of metabolites were used as input variables. Although the discriminatory power of the system used was promising, additional features are needed to create a robust discriminatory model.}, } @article {pmid39058450, year = {2024}, author = {Baumgartner, D and Mušová, Z and Zídková, J and Hedvičáková, P and Vlčková, E and Joppeková, L and Kramářová, T and Fajkusová, L and Stránecký, V and Geryk, J and Votýpka, P and Mazanec, R}, title = {Genetic Landscape of Amyotrophic Lateral Sclerosis in Czech Patients.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {5}, pages = {1035-1048}, pmid = {39058450}, issn = {2214-3602}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Czech Republic ; Male ; Middle Aged ; Female ; *C9orf72 Protein/genetics ; Aged ; *DNA Repeat Expansion ; Adult ; *Frontotemporal Dementia/genetics ; RNA-Binding Protein FUS/genetics ; Cohort Studies ; DNA-Binding Proteins/genetics ; Protein Serine-Threonine Kinases/genetics ; Age of Onset ; Genetic Predisposition to Disease ; High-Throughput Nucleotide Sequencing ; }, abstract = {BACKGROUND: Genetic factors are involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS) and constitute a link to its association with frontotemporal dementia (FTD). Gene-targeted therapies for some forms of ALS (C9orf72, SOD1) have recently gained momentum. Genetic architecture in Czech ALS patients has not been comprehensively assessed so far.

OBJECTIVE: We aimed to deliver pilot data on the genetic landscape of ALS in our country.

METHODS: A cohort of patients with ALS (n = 88), recruited from two Czech Neuromuscular Centers, was assessed for hexanucleotide repeat expansion (HRE) in C9orf72 and also for genetic variations in other 36 ALS-linked genes via next-generation sequencing (NGS). Nine patients (10.1%) had a familial ALS. Further, we analyzed two subgroups of sporadic patients - with concomitant FTD (n = 7) and with young-onset of the disease (n = 22).

RESULTS: We detected the pathogenic HRE in C9orf72 in 12 patients (13.5%) and three other pathogenic variants in FUS, TARDBP and TBK1, each in one patient. Additional 7 novel and 9 rare known variants with uncertain causal significance have been detected in 15 patients. Three sporadic patients with FTD (42.9%) were harbouring a pathogenic variant (all HRE in C9orf72). Surprisingly, none of the young-onset sporadic patients harboured a pathogenic variant and we detected no pathogenic SOD1 variant in our cohort.

CONCLUSION: Our findings resemble those from other European populations, with the highest prevalence of HRE in the C9orf72 gene. Further, our findings suggest a possibility of a missing genetic variability among young-onset patients.}, } @article {pmid39059072, year = {2024}, author = {Grieco, I and Bassani, D and Trevisan, L and Salmaso, V and Cescon, E and Prencipe, F and Da Ros, T and Martinez-Gonzalez, L and Martinez, A and Spalluto, G and Moro, S and Federico, S}, title = {7-Amino-[1,2,4]triazolo[1,5-a][1,3,5]triazines as CK1δ inhibitors: Exploring substitutions at the 2 and 5-positions.}, journal = {Bioorganic chemistry}, volume = {151}, number = {}, pages = {107659}, doi = {10.1016/j.bioorg.2024.107659}, pmid = {39059072}, issn = {1090-2120}, mesh = {*Protein Kinase Inhibitors/pharmacology/chemistry/chemical synthesis ; Humans ; *Casein Kinase Idelta/antagonists & inhibitors/metabolism ; Structure-Activity Relationship ; Molecular Structure ; Triazines/chemistry/pharmacology/chemical synthesis ; Dose-Response Relationship, Drug ; Triazoles/chemistry/pharmacology/chemical synthesis ; Animals ; Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Molecular Docking Simulation ; }, abstract = {CK1δ is a serine-threonine kinase involved in several pathological conditions including neuroinflammation and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Specifically, it seems that an inhibition of CK1δ could have a neuroprotective effect in these conditions. Here, a series of [1,2,4]triazolo[1,5-a][1,3,5]triazines were developed as ATP-competitive CK1δ inhibitors. Both positions 2 and 5 have been explored leading to a total of ten compounds exhibiting IC50s comprised between 29.1 µM and 2.08 µM. Three of the four most potent compounds (IC50 < 3 µM) bear a thiophene ring at the 2 position. All compounds have been submitted to computational studies that identified the chain composed of at least 2 atoms (e.g., nitrogen and carbon atoms) at the 5 position as crucial to determine a key bidentate hydrogen bond with Leu85 of CK1δ. Most potent compounds have been tested in vitro, resulting passively permeable to the blood-brain barrier and, safe and slight neuroprotective on a neuronal cell model. These results encourage to further structural optimize the series to obtain more potent CK1δ inhibitors as possible neuroprotective agents to be tested on models of the above-mentioned neurodegenerative diseases.}, } @article {pmid39059260, year = {2024}, author = {Luo, L and Jiang, L and Chen, T and Zhao, Z and Kang, C and Chen, D and Long, Y}, title = {Analysis of spatiotemporal changes mechanism of cell wall biopolymers and monosaccharide components in kiwifruit during Botryosphaeria dothidea infection.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {322}, number = {}, pages = {124837}, doi = {10.1016/j.saa.2024.124837}, pmid = {39059260}, issn = {1873-3557}, mesh = {*Cell Wall/chemistry ; *Ascomycota/chemistry ; *Plant Diseases/microbiology ; *Monosaccharides/analysis ; *Actinidia/microbiology/chemistry ; *Spectrum Analysis, Raman/methods ; Fruit/microbiology/chemistry ; Biopolymers/chemistry/analysis ; Pectins/chemistry/metabolism ; Polysaccharides ; }, abstract = {To further reveal the interaction mechanism between plants and pathogens, this study used confocal Raman microscopy spectroscopy (CRM) combined with chemometrics to visualize the biopolymers distribution of kiwifruit cell walls at different infection stages at the cellular micro level. Simultaneously, the changes in the content of various monosaccharides in fruit were studied at the molecular level using high-performance liquid chromatography (HPLC). There were significant differences in the composition of various nutrient components in the cell wall structure of kiwifruit at different infection times after infection by Botryosphaeria dothidea. PCA could cluster samples with infection time of 0-9 d into different infection stages, and SVM was used to predict the PCA classification results, the accuracy >96 %. Multivariate curve resolution-alternating least squares (MCR-ALS) helped to identify single substance spectra and concentration signals from mixed spectral signals. The pure substance chemical imaging maps of low methylated pectin (LMP), high methylated pectin (HMP), cellulose, hemicellulose, and lignin were obtained by analyzing the resolved concentration data. The imaging results showed that the lignin content in the kiwifruit cell wall increased significantly to resist pathogens infection after the infection of B. dothidea. With the development of infection, B. dothidea decomposed various substances in the host cell walls, allowing them to penetrate the interior of fruit cells. This caused significant changes in the form, structure, and distribution of various chemicals on the fruit cell walls in time and space. HPLC showed that glucose was the main carbon source and energy substance obtained by pathogens from kiwifruit during infection. The contents of galactose and arabinose, which maintained the structure and function of the fruit cell walls, decreased significantly and the cell wall structure was destroyed in the late stage of pathogens infection. This study provided a new perspective on the cellular structure changes caused by pathogenic infection of fruit and the defense response process of fruit and provided effective references for further research on the mechanisms of host-pathogen interactions in fruit infected by pathogens.}, } @article {pmid39059406, year = {2024}, author = {Petri, S}, title = {Targeting C9orf72 in people with ALS.}, journal = {The Lancet. Neurology}, volume = {23}, number = {9}, pages = {850-852}, doi = {10.1016/S1474-4422(24)00284-9}, pmid = {39059406}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; }, } @article {pmid39059407, year = {2024}, author = {van den Berg, LH and Rothstein, JD and Shaw, PJ and Babu, S and Benatar, M and Bucelli, RC and Genge, A and Glass, JD and Hardiman, O and Libri, V and Mobach, T and Oskarsson, B and Pattee, GL and Ravits, J and Shaw, CE and Weber, M and Zinman, L and Jafar-Nejad, P and Rigo, F and Lin, L and Ferguson, TA and Gotter, AL and Graham, D and Monine, M and Inra, J and Sinks, S and Eraly, S and Garafalo, S and Fradette, S}, title = {Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study.}, journal = {The Lancet. Neurology}, volume = {23}, number = {9}, pages = {901-912}, doi = {10.1016/S1474-4422(24)00216-3}, pmid = {39059407}, issn = {1474-4465}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Double-Blind Method ; *C9orf72 Protein/genetics ; *Oligonucleotides, Antisense/pharmacokinetics/administration & dosage/adverse effects/pharmacology ; Aged ; Adult ; Dose-Response Relationship, Drug ; }, abstract = {BACKGROUND: Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS.

METHODS: This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1-6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1-3 and about 6 months for cohorts 4-6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed.

FINDINGS: Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator.

INTERPRETATION: On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS.

FUNDING: Biogen.}, } @article {pmid39059442, year = {2024}, author = {Kilim, O and Báskay, J and Biricz, A and Bedőházi, Z and Pollner, P and Csabai, I}, title = {Transfer learning may explain pigeons' ability to detect cancer in histopathology.}, journal = {Bioinspiration & biomimetics}, volume = {19}, number = {5}, pages = {}, doi = {10.1088/1748-3190/ad6825}, pmid = {39059442}, issn = {1748-3190}, mesh = {Animals ; *Columbidae/physiology ; *Neoplasms/pathology/diagnostic imaging ; *Neural Networks, Computer ; Machine Learning ; Flight, Animal/physiology ; }, abstract = {Pigeons' unexpected competence in learning to categorize unseen histopathological images has remained an unexplained discovery for almost a decade (Levensonet al2015PLoS One10e0141357). Could it be that knowledge transferred from their bird's-eye views of the earth's surface gleaned during flight contributes to this ability? Employing a simulation-based verification strategy, we recapitulate this biological phenomenon with a machine-learning analog. We model pigeons' visual experience during flight with the self-supervised pre-training of a deep neural network on BirdsEyeViewNet; our large-scale aerial imagery dataset. As an analog of the differential food reinforcement performed in Levensonet al's study 2015PLoS One10e0141357), we apply transfer learning from this pre-trained model to the same Hematoxylin and Eosin (H&E) histopathology and radiology images and tasks that the pigeons were trained and tested on. The study demonstrates that pre-training neural networks with bird's-eye view data results in close agreement with pigeons' performance. These results support transfer learning as a reasonable computational model of pigeon representation learning. This is further validated with six large-scale downstream classification tasks using H&E stained whole slide image datasets representing diverse cancer types.}, } @article {pmid39060265, year = {2024}, author = {Doi, H and Kageyama, I and Katoh-Fukui, Y and Hattori, A and Fukami, M and Shimura, N}, title = {Homozygous 6-bp deletion of IGFALS in a prepubertal boy with short stature.}, journal = {Human genome variation}, volume = {11}, number = {1}, pages = {27}, pmid = {39060265}, issn = {2054-345X}, abstract = {Biallelic IGFALS variants lead to acid‒labile subunit (ALS) deficiency characterized by growth hormone resistance with or without delayed puberty. Here, we report a prepubertal boy with a homozygous 2-amino acid deletion within the fourth N-glycosylation motif (c.1103_1108del, p.N368_S370delinsT) associated with parental consanguinity. He showed short stature consistent with ALS deficiency. This case expands the mutation spectrum of IGFALS to include the elimination of only one N-glycosylation motif of ALS.}, } @article {pmid39060317, year = {2024}, author = {Wu, J and Zhang, G and Zhang, L and Ye, S and Huang, T and Fan, D}, title = {The integrity of the corticospinal tract and corpus callosum, and the risk of ALS: univariable and multivariable Mendelian randomization.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {17216}, pmid = {39060317}, issn = {2045-2322}, support = {81873784//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/pathology ; *Mendelian Randomization Analysis ; *Pyramidal Tracts/diagnostic imaging/pathology ; *Corpus Callosum/diagnostic imaging/pathology ; *Genome-Wide Association Study ; Risk Factors ; Male ; Female ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; White Matter/diagnostic imaging/pathology ; Diffusion Magnetic Resonance Imaging ; Anisotropy ; }, abstract = {Studies suggest that amyotrophic lateral sclerosis (ALS) compromises the integrity of white matter fiber tracts, primarily affecting motor fibers. However, it remains uncertain whether the integrity of these fibers influences the risk of ALS. We performed bidirectional two-sample Mendelian randomization (MR) and multivariable MR analyses to evaluate the associative relationships between the integrity of fiber tracts [including the corticospinal tract (CST) and corpus callosum (CC)] and the risk of ALS. Genetic instrumental variables for specific fiber tracts were obtained from published genome-wide association studies (GWASs), including 33,292 European individuals from five diffusion magnetic resonance imaging (dMRI) datasets. Summary-level GWAS data for ALS were derived from 27,205 ALS patients and 110,881 controls. The MR results suggested that an increase in the first principal component (PC1) of fractional anisotropy (FA) in the genu of the CC (GCC) was correlated with an increased risk of ALS (PFDR = 0.001, odds ratio = 1.363, 95% confidence interval 1.178-1.577). Although other neuroimaging phenotypes [mean diffusivity in the CST, radial diffusivity (RD) in the CST, FA in the GCC, PC1 in the body of the CC (BCC), PC1 in the CST, and RD in the GCC] did not pass correction, they were also considered to have suggestive associations with the risk of ALS. No evidence revealed that ALS caused changes in the integrity of fiber tracts. In summary, the results of this study provide genetic support for the potential association between the integrity of specific fiber tracts and the risk of ALS. Greater fiber integrity in the GCC and BCC may be a risk factor for ALS, while greater fiber integrity in the CST may have a protective effect on ALS. This study provides insights into ALS development.}, } @article {pmid39060854, year = {2025}, author = {Raymond, J and Nair, T and Gwathmey, KG and Larson, T and Horton, DK and Mehta, P}, title = {Racial Disparities in the Diagnosis and Prognosis of ALS Patients in the United States.}, journal = {Journal of racial and ethnic health disparities}, volume = {12}, number = {5}, pages = {2915-2921}, pmid = {39060854}, issn = {2196-8837}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/ethnology/therapy ; *Black or African American/statistics & numerical data ; *Health Status Disparities ; *Healthcare Disparities/ethnology ; Prognosis ; Registries ; United States/epidemiology ; *White/statistics & numerical data ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease with largely unknown etiology. This study compares racial differences in clinical characteristics of ALS patients enrolled in the National ALS Registry (Registry).

METHODS: Data from ALS patients who completed the Registry's online clinical survey during 2013-2022 were analyzed to determine characteristics such as site of onset, associated symptoms, time of symptom onset to diagnosis, and pharmacological and non-pharmacological interventions for White, Black, and other race patients.

RESULTS: Surveys were completed by 4242 participants. Findings revealed that Black ALS patients were more likely to be diagnosed at a younger age, to have arm or hand initial site of onset, and to experience pneumonia than were White ALS patients. ALS patients of other races were more likely than White ALS patients to be diagnosed at a younger age and to experience twitching. The mean interval between the first sign of weakness and an ALS diagnosis for Black patients was almost 24 months, statistically greater than that of White (p = 0.0374; 16 months) and other race patients (p = 0.0518; 15.8 months). The mean interval between problems with speech until diagnosis was shorter for White patients (6.3 months) than for Black patients (17.7 months) and other race patients (14.8 months).

CONCLUSIONS AND RELEVANCE: Registry data shows racial disparities still exist in the diagnosis and clinical characteristics of ALS patients. Increased recruitment of non-White ALS patients and better characterization of symptom onset between races might aid clinicians in diagnosing ALS sooner, leading to earlier therapeutic interventions.}, } @article {pmid39060907, year = {2025}, author = {Asai, Y and Yano, K and Higashino, T and Yoshihara, D and Sakiyama, H and Eguchi, H and Fukushima, K and Suzuki, K and Fujiwara, N}, title = {The Ile35 Residue of the ALS-Associated Mutant SOD1 Plays a Crucial Role in the Intracellular Aggregation of the Molecule.}, journal = {Molecular neurobiology}, volume = {62}, number = {2}, pages = {2023-2038}, pmid = {39060907}, issn = {1559-1182}, support = {22K11870//Japan Society for the Promotion of Science/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/enzymology/pathology ; Superoxide Dismutase-1 ; Humans ; *Mutation/genetics ; *Protein Aggregates ; *Superoxide Dismutase/genetics/metabolism/chemistry ; Animals ; *Intracellular Space/metabolism ; *Protein Aggregation, Pathological ; Green Fluorescent Proteins/metabolism ; *Mutant Proteins/metabolism/chemistry ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an unknown pathogenesis. It has been reported that mutations in the gene for Cu/Zn superoxide dismutase (SOD1) cause familial ALS. Mutant SOD1 undergoes aggregation and forms amyloid more easily, and SOD1-immunopositive inclusions have been observed in the spinal cords of ALS patients. Because of this, SOD1 aggregation is thought to be related to the pathogenesis of ALS. Some core regions of amyloid have been identified, but the issue of whether these regions form aggregates in living cells remains unclear, and the mechanism responsible for intracellular SOD1 aggregation also remains unclear. The findings reported in this study indicate that the aggregation of the ALS-linked mutant SOD1-EGFP was significantly enhanced when the BioID2 gene was fused to the N-terminus of the mutant SOD1-EGFP plasmid for cellular expression. Expression of a series of BioID2-(C-terminal deletion peptides of SOD1)-EGFP permitted us to identify 1-35 as a minimal N-terminal sequence and Ile35 as an essential amino acid residue that contributes to the intracellular aggregation of SOD1. The findings also showed that an additional substitution of Ile35 with Ser into the ALS mutant SOD1 resulted in the significant suppression of aggregate formation. The fact that no Ile35 mutations have been reported to date in ALS patients indicates that all ALS mutant SOD1s contain Ile35. Taken together, we propose that Ile35 plays a pivotal role in the aggregation of the ALS-linked SOD1 and that this study will contribute to our understanding of the mechanism responsible for SOD1 aggregation.}, } @article {pmid39061402, year = {2024}, author = {Correia, JP and Gromicho, M and Pronto-Laborinho, AC and Oliveira Santos, M and de Carvalho, M}, title = {Creatine Kinase and Respiratory Decline in Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {14}, number = {7}, pages = {}, pmid = {39061402}, issn = {2076-3425}, abstract = {Respiratory dysfunction is an important hallmark of amyotrophic lateral sclerosis (ALS). Elevation of creatine kinase (CK) has been reported in 23-75% of ALS patients, but the underlying mechanisms remain unknown. This work aims to enlighten the role of CK as a prognostic factor of respiratory dysfunction in ALS. A retrospective analysis of demographic and clinical variables, CK, functional decline per month (ΔFS), forced vital capacity (%FVC), and mean amplitude of the phrenic nerve compound motor action potential (pCMAP) in 319 ALS patients was conducted. These measurements were evaluated at study entry, and patients were followed from the moment of first observation until death or last follow-up visit. High CK values were defined as above the 90th percentile (CK ≥ P90) adjusted to sex. We analyzed survival and time to non-invasive ventilation (NIV) as proxies for respiratory impairment. Linear regression analysis revealed that high CK was associated with male sex (p < 0.001), spinal onset (p = 0.018), and FVC ≥ 80% (p = 0.038). CK was 23.4% higher in spinal-onset ALS patients (p < 0.001). High CK levels were not linked with an increased risk of death (p = 0.334) in Cox multivariate regression analysis. CK ≥ P90 (HR = 1.001, p = 0.038), shorter disease duration (HR = 0.937, p < 0.001), lower pCMAP (HR = 0.082, p < 0.001), and higher ΔFS (HR = 1.968, p < 0.001) were risk factors for respiratory failure. The association between high CK levels and poorer respiratory outcomes could derive from cellular metabolic stress or a specific phenotype associated with faster respiratory decline. Our study suggests that CK measurement at diagnosis should be more extensively investigated as a possible marker of poor respiratory outcome in future studies, including a larger population of patients.}, } @article {pmid39061876, year = {2024}, author = {Magalhães, RSS and Monteiro Neto, JR and Ribeiro, GD and Paranhos, LH and Eleutherio, ECA}, title = {Trehalose Protects against Superoxide Dismutase 1 Proteinopathy in an Amyotrophic Lateral Sclerosis Model.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {7}, pages = {}, pmid = {39061876}, issn = {2076-3921}, support = {PROBRAL 88881.371325/2019-01//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)/ ; CNE 201.174/2022 and Posdoc Nota 10 202.267/2019//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; Universal 401780/2023-6//National Council for Scientific and Technological Development/ ; }, abstract = {This work aimed to study the effect of trehalose in protecting cells against Sod1 proteinopathy associated with amyotrophic lateral sclerosis (ALS). Humanized yeast cells in which native Sod1 was replaced by wild-type human Sod1 or an ALS mutant (WT-A4V Sod1 heterodimer) were used as the experimental model. Cells were treated with 10% trehalose (p/v) before or after the appearance of hSod1 proteinopathy induced by oxidative stress. In both conditions, trehalose reduced the number of cells with Sod1 inclusions, increased Sod1 activity, and decreased the levels of intracellular oxidation, demonstrating that trehalose avoids Sod1 misfolding and loss of function in response to oxidative stress. The survival rates of ALS Sod1 cells stressed in the presence of trehalose were 60% higher than in their absence. Treatment with trehalose after the appearance of Sod1 inclusions in cells expressing WT Sod1 doubled longevity; after 5 days, non-treated cells did not survive, but 15% of cells treated with sugar were still alive. Altogether, our results emphasize the potential of trehalose as a novel therapy, which might be applied preventively in ALS patients with a family history of the disease or after diagnosis in ALS patients who discover the disease following the first symptoms.}, } @article {pmid39062592, year = {2024}, author = {Gao, J and Sterling, E and Hankin, R and Sikal, A and Yao, Y}, title = {Therapeutics Targeting Skeletal Muscle in Amyotrophic Lateral Sclerosis.}, journal = {Biomolecules}, volume = {14}, number = {7}, pages = {}, pmid = {39062592}, issn = {2218-273X}, support = {W81XWH2210261//United States Department of Defense/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/therapy ; Humans ; *Muscle, Skeletal/metabolism/pathology ; Animals ; Neuromuscular Junction/metabolism/pathology ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neuromuscular disease characterized by progressive motor neuron degeneration, neuromuscular junction dismantling, and muscle wasting. The pathological and therapeutic studies of ALS have long been neurocentric. However, recent insights have highlighted the significance of peripheral tissue, particularly skeletal muscle, in disease pathology and treatment. This is evidenced by restricted ALS-like muscle atrophy, which can retrogradely induce neuromuscular junction and motor neuron degeneration. Moreover, therapeutics targeting skeletal muscles can effectively decelerate disease progression by modulating muscle satellite cells for muscle repair, suppressing inflammation, and promoting the recovery or regeneration of the neuromuscular junction. This review summarizes and discusses therapeutic strategies targeting skeletal muscles for ALS treatment. It aims to provide a comprehensive reference for the development of novel therapeutics targeting skeletal muscles, potentially ameliorating the progression of ALS.}, } @article {pmid39062967, year = {2024}, author = {Kisielewska, M and Filipski, M and Sebastianka, K and Karaś, D and Molik, K and Choromańska, A}, title = {Investigation into the Neuroprotective and Therapeutic Potential of Plant-Derived Chk2 Inhibitors.}, journal = {International journal of molecular sciences}, volume = {25}, number = {14}, pages = {}, pmid = {39062967}, issn = {1422-0067}, mesh = {*Checkpoint Kinase 2/metabolism/antagonists & inhibitors ; Humans ; Animals ; Protein Kinase Inhibitors/pharmacology/therapeutic use/chemistry ; Neuroprotective Agents/pharmacology/therapeutic use ; Neoplasms/drug therapy ; DNA Damage/drug effects ; DNA Repair/drug effects ; }, abstract = {Nature provides us with a rich source of compounds with a wide range of applications, including the creation of innovative drugs. Despite advancements in chemically synthesized therapeutics, natural compounds are increasingly significant, especially in cancer treatment, a leading cause of death globally. One promising approach involves the use of natural inhibitors of checkpoint kinase 2 (Chk2), a critical regulator of DNA repair, cell cycle arrest, and apoptosis. Chk2's activation in response to DNA damage can lead to apoptosis or DNA repair, influencing glycolysis and mitochondrial function. In cancer therapy, inhibiting Chk2 can disrupt DNA repair and cell cycle progression, promoting cancer cell death and enhancing the efficacy of radiotherapy and chemotherapy. Additionally, Chk2 inhibitors can safeguard non-cancerous cells during these treatments by inhibiting p53-dependent apoptosis. Beyond oncology, Chk2 inhibition shows potential in treating hepatitis C virus (HCV) infections, as the virus relies on Chk2 for RNA replication in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), in which DNA damage plays a crucial role. Plant-derived Chk2 inhibitors, such as artemetin, rhamnetin, and curcumin, offer a promising future for treating various diseases with potentially milder side effects and broader metabolic impacts compared to conventional therapies. The review aims to underscore the immense potential of natural Chk2 inhibitors in various therapeutic contexts, particularly in oncology and the treatment of other diseases involving DNA damage and repair mechanisms. These natural Chk2 inhibitors hold significant promise for revolutionizing the landscape of cancer treatment and other diseases. Further research into these compounds could lead to the development of innovative therapies that offer hope for the future with fewer side effects and enhanced efficacy.}, } @article {pmid39063053, year = {2024}, author = {Alanazi, N and Fitzgerald, M and Hume, P and Hellewell, S and Horncastle, A and Anyaegbu, C and Papini, MG and Hargreaves, N and Halicki, M and Entwistle, I and Hind, K and Chazot, P}, title = {Concussion-Related Biomarker Variations in Retired Rugby Players and Implications for Neurodegenerative Disease Risk: The UK Rugby Health Study.}, journal = {International journal of molecular sciences}, volume = {25}, number = {14}, pages = {}, pmid = {39063053}, issn = {1422-0067}, mesh = {Humans ; *Biomarkers/blood ; Male ; *Brain Concussion/blood/epidemiology ; Middle Aged ; United Kingdom/epidemiology ; *Retirement ; *Football/injuries ; Adult ; *Athletes ; *Neurodegenerative Diseases/blood/epidemiology/etiology ; Rugby ; tau Proteins/blood ; Risk Factors ; Retinol-Binding Proteins, Plasma/metabolism ; Athletic Injuries/blood/epidemiology ; }, abstract = {The health and well-being of retired rugby union and league players, particularly regarding the long-term effects of concussions, are of major concern. Concussion has been identified as a major risk factor for neurodegenerative diseases, such as Alzheimer's and Amyotrophic Lateral Sclerosis (ALS), in athletes engaged in contact sports. This study aimed to assess differences in specific biomarkers between UK-based retired rugby players with a history of concussion and a non-contact sports group, focusing on biomarkers associated with Alzheimer's, ALS, and CTE. We randomly selected a sample of male retired rugby or non-contact sport athletes (n = 56). The mean age was 41.84 ± 6.44, and the mean years since retirement from the sport was 7.76 ± 6.69 for participants with a history of substantial concussions (>5 concussions in their career) (n = 30). The mean age was 45.75 ± 11.52, and the mean years since retirement was 6.75 ± 4.64 for the healthy controls (n = 26). Serum biomarkers (t-tau, RBP-4, SAA, Nf-L, and retinol), plasma cytokines, and biomarkers associated with serum-derived exosomes (Aβ42, p-tau181, p-tau217, and p-tau231) were analyzed using validated commercial ELISA assays. The results of the selected biomarkers were compared between the two groups. Biomarkers including t-tau and p-tau181 were significantly elevated in the history of the substantial concussion group compared to the non-contact sports group (t-tau: p < 0.01; p-tau181: p < 0.05). Although between-group differences in p-tau217, p-tau231, SAA, Nf-L, retinol, and Aβ42 were not significantly different, there was a trend for higher levels of Aβ42, p-tau217, and p-tau231 in the concussed group. Interestingly, the serum-derived exosome sizes were significantly larger (p < 0.01), and serum RBP-4 levels were significantly reduced (p < 0.05) in the highly concussed group. These findings indicate that retired athletes with a history of multiple concussions during their careers have altered serum measurements of exosome size, t-tau, p-tau181, and RBP-4. These biomarkers should be explored further for the prediction of future neurodegenerative outcomes, including ALS, in those with a history of concussion.}, } @article {pmid39063341, year = {2024}, author = {Lagrange, E and Vernoux, JP and Chambon, C and Camu, W and Spencer, PS}, title = {Cramp-Fasciculation Syndrome Associated with Natural and Added Chemicals in Popular Food Items.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {14}, pages = {}, pmid = {39063341}, issn = {2304-8158}, abstract = {Cramp-fasciculation syndrome (CFS) is a rare and benign neuromuscular disorder that may initially masquerade as motor neuron disease/amyotrophic lateral sclerosis. While CFS may have a familial disposition, we report on cases associated with high consumption of popular food items. One set of patients reversibly experienced acute onset of headache, flushing, muscle stiffness and fasciculations following the consumption of umami-flavored food containing a large concentration of monosodium glutamate. A second group of patients consuming food derived from lupin seed developed acute cholinergic toxicity, CFS, and, with chronic intake, significant, self-limiting, but incompletely reversible upper and lower motor neuron deficits. While these cases may improve our knowledge about the possible causes of CFS, our series also demonstrates that excessive consumption of some popular foods is not harmless. This warrants further research on their safety at all stages of human development from a neurological point of view.}, } @article {pmid39065892, year = {2024}, author = {Liu, K and Guan, X and Ren, X and Wu, J}, title = {Disciplining a Rubidium Atomic Clock Based on Adaptive Kalman Filter.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {14}, pages = {}, pmid = {39065892}, issn = {1424-8220}, abstract = {Rubidium atomic clocks have been used extensively in various fields, with applications such as a core component of Global Navigation Satellite Systems (GNSS). However, they exhibit inherently poor long-term stability. This paper presents the development of a control system for rubidium atomic clocks. It introduces an adaptive Kalman filtering algorithm for the disciplining of a rubidium atomic clock, utilizing autocovariance least squares (ALS) to estimate the clock's noise parameters. The experimental results demonstrate that the proposed algorithm achieves a high estimation accuracy. The standard deviation of the clock error between the steered rubidium atomic clock 1 Pulse Per Second (1PPS) and Coordinated Universal Time (UTC) provided by the National Time Service Center (NTSC) is better than 2.568 nanoseconds(ns), with peak-to-peak values improving to within 11.358 ns. Notably, its frequency stability is reduced to 3.06 × 10[-13] @100,000 s. The results for the rubidium atomic clock demonstrate that the adaptive Kalman filtering algorithm proposed herein constitutes an accurate and effective control strategy for the rubidium atomic clock discipline.}, } @article {pmid39066735, year = {2024}, author = {Reis, PVM and Vargas, BS and Rebelo, RA and Massafera, MP and Prado, FM and Oreliana, H and de Oliveira, HV and Freitas, FP and Ronsein, GE and Miyamoto, S and Di Mascio, P and Medeiros, MHG}, title = {Quantitative Analysis of Glutathione and Carnosine Adducts with 4-Hydroxy-2-nonenal in Muscle in a hSOD1[G93A] ALS Rat Model.}, journal = {Chemical research in toxicology}, volume = {37}, number = {8}, pages = {1306-1314}, pmid = {39066735}, issn = {1520-5010}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Aldehydes/metabolism/chemistry ; *Carnosine/metabolism ; *Glutathione/metabolism ; Rats ; *Disease Models, Animal ; Muscle, Skeletal/metabolism ; Humans ; Superoxide Dismutase/metabolism ; Male ; Chromatography, High Pressure Liquid ; Rats, Transgenic ; Superoxide Dismutase-1/metabolism ; Rats, Sprague-Dawley ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the dysfunction and death of motor neurons through multifactorial mechanisms that remain unclear. ALS has been recognized as a multisystemic disease, and the potential role of skeletal muscle in disease progression has been investigated. Reactive aldehydes formed as secondary lipid peroxidation products in the redox processes react with biomolecules, such as DNA, proteins, and amino acids, resulting in cytotoxic effects. 4-Hydroxy-2-nonenal (HNE) levels are elevated in the spinal cord motor neurons of ALS patients, and HNE-modified proteins have been identified in the spinal cord tissue of an ALS transgenic mice model, suggesting that reactive aldehydes can contribute to motor neuron degeneration in ALS. One biological pathway of aldehyde detoxification involves conjugation with glutathione (GSH) or carnosine (Car). Here, the detection and quantification of Car, GSH, GSSG (glutathione disulfide), and the corresponding adducts with HNE, Car-HNE, and GS-HNE, were performed in muscle and liver tissues of a hSOD1[G93A] ALS rat model by reverse-phase high-performance liquid chromatography coupled to electrospray ion trap tandem mass spectrometry in the selected reaction monitoring mode. A significant increase in the levels of GS-HNE and Car-HNE was observed in the muscle tissue of the end-stage ALS animals. Therefore, analyzing variations in the levels of these adducts in ALS animal tissue is crucial from a toxicological perspective and can contribute to the development of new therapeutic strategies.}, } @article {pmid39066921, year = {2024}, author = {Guarnaccia, M and Morello, G and La Cognata, V and La Bella, V and Conforti, FL and Cavallaro, S}, title = {Increased copy-number variant load of associated risk genes in sporadic cases of amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {316}, pmid = {39066921}, issn = {1420-9071}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *DNA Copy Number Variations/genetics ; Female ; *Genetic Predisposition to Disease ; Middle Aged ; Male ; Aged ; Risk Factors ; Polymorphism, Single Nucleotide ; Adult ; Case-Control Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disease characterized by selective loss of motor neurons in the brainstem and spinal cord. Several genetic factors have been associated to ALS, ranging from causal genes and potential risk factors to disease modifiers. The search for pathogenic variants in these genes has mostly focused on single nucleotide variants (SNVs) while relatively understudied and not fully elucidated is the contribution of structural variants, such as copy number variations (CNVs). Here, we applied an exon-centric aCGH method to investigate, in sporadic ALS patients, the load of CNVs in 131 genes previously associated to ALS. Our approach revealed that CNV load, defined as the total number of CNVs or their size, was significantly higher in ALS cases than controls. About 87% of patients harbored multiple CNVs in ALS-related genes, and 75% structural variants compromised genes directly implicated in ALS pathogenesis (C9orf72, CHCHD10, EPHA4, FUS, HNRNPA1, KIF5A, NEK1, OPTN, PFN1, SOD1, TARDBP, TBK1, UBQLN2, UNC13A, VAPB, VCP). CNV load was also associated to higher onset age and disease progression rate. Although the contribution of individual CNVs in ALS is still unknown, their extensive load in disease-related genes may have relevant implications for the diagnostic, prognostic and therapeutical management of this devastating disorder.}, } @article {pmid39067491, year = {2024}, author = {Cheung, SW and Willis, EF and Simmons, DG and Bellingham, MC and Noakes, PG}, title = {Phagocytosis of aggrecan-positive perineuronal nets surrounding motor neurons by reactive microglia expressing MMP-9 in TDP-43[Q331K] ALS model mice.}, journal = {Neurobiology of disease}, volume = {200}, number = {}, pages = {106614}, doi = {10.1016/j.nbd.2024.106614}, pmid = {39067491}, issn = {1095-953X}, mesh = {Animals ; Mice ; *Aggrecans/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Disease Models, Animal ; DNA-Binding Proteins/metabolism/genetics ; *Matrix Metalloproteinase 9/metabolism ; Mice, Transgenic ; *Microglia/metabolism ; *Motor Neurons/metabolism/pathology ; *Phagocytosis/physiology ; Spinal Cord/metabolism/pathology ; }, abstract = {Perineuronal nets (PNNs) are extracellular matrix structures that surround excitable neurons and their proximal dendrites. PNNs play an important role in neuroprotection against oxidative stress. Oxidative stress within motor neurons can act as a trigger for neuronal death, and this has been implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). We therefore characterised PNNs around alpha motor neurons and the possible contributing cellular factors in the mutant TDP-43[Q331K] transgenic mouse, a slow onset ALS mouse model. PNNs around alpha motor neurons showed significant loss at mid-stage disease in TDP-43[Q331K] mice compared to wild type strain control mice. PNN loss coincided with an increased expression of matrix metallopeptidase-9 (MMP-9), an endopeptidase known to cleave PNNs, within the ventral horn. During mid-stage disease, increased numbers of microglia and astrocytes expressing MMP-9 were present in the ventral horn of TDP-43[Q331K] mice. In addition, TDP-43[Q331K] mice showed increased levels of aggrecan, a PNN component, in the ventral horn by microglia and astrocytes during this period. Elevated aggrecan levels within glia were accompanied by an increase in fractalkine expression, a chemotaxic protein responsible for the recruitment of microglia, in alpha motor neurons of onset and mid-stage TDP-43[Q331K] mice. Following PNN loss, alpha motor neurons in mid-stage TDP-43[Q331K] mice showed increased 3-nitrotyrosine expression, an indicator of protein oxidation. Together, our observations along with previous PNN research provide suggests a possible model whereby microglia and astrocytes expressing MMP-9 degrade PNNs surrounding alpha motor neurons in the TDP-43[Q331K] mouse. This loss of nets may expose alpha-motor neurons to oxidative damage leading to degeneration of the alpha motor neurons in the TDP-43[Q331K] ALS mouse model.}, } @article {pmid39068922, year = {2024}, author = {Srivastava, K and Arshad, F and Mujawar, WJ and Cranberg, L and Rajeshwaran, J and Afsar, M and Thanissery, N and Desai, V and Keerthana, BS and Shubhangi, B and Vengalil, S and Nashi, S and Baskar, D and Polavarapu, K and Preethish-Kumar, V and Alladi, S and Nalini, A}, title = {Cognitive and Behavioral Profile of Patients with Amyotrophic Lateral Sclerosis Spectrum in the Indian Context.}, journal = {Dementia and geriatric cognitive disorders}, volume = {53}, number = {6}, pages = {310-320}, doi = {10.1159/000540018}, pmid = {39068922}, issn = {1421-9824}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; Middle Aged ; India/epidemiology ; *Frontotemporal Dementia/psychology ; *Neuropsychological Tests ; *Cognitive Dysfunction/psychology ; Aged ; Cognition/physiology ; Adult ; Executive Function ; Case-Control Studies ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is characterized by motor, cognitive, and behavioral impairment. There is a paucity of evidence about the cognitive/behavioral features of ALS patients from India. We aimed to investigate the cognitive/behavioral profile of ALS spectrum disorders in the Indian context.

METHODS: Sixty patients with ALS spectrum and 40 age-, gender-, and education-matched healthy controls were recruited. The scales used were Addenbrooke's Cognitive Examination (ACE-III), Clinical Dementia Rating (CDR) scale, and Frontal Systems Behavior (FrSBe) Scale.

RESULTS: The mean age of the overall cohort was 55 years, and male-to-female ratio was 2.5:1. The mean duration of illness of the cohort was 16 months. Patients were classified as ALS with normal cognition (ALS-cn, n = 21), mild cognitive or behavioral deficits (ALS-ci/-bi, n = 28), and frontotemporal dementia (ALS-FTD, n = 11). ALS-cn had poorer scores compared to healthy controls in global cognition, memory, and language (p < 0.05). ALS-ci/-bi performed poorer than healthy controls on all cognitive domains (p < 0.05). ALS-FTD had poorer scores than healthy controls and ALS-cn on all cognitive domains (p < 0.001). Behavioral assessment showed an increase in apathy among all subtypes. ALS-FTD showed significant worsening in disinhibition and executive function compared to ALS-cn and ALS-ci/-bi.

CONCLUSION: Our findings suggest that there are key cognitive and behavior characteristics in Indian patients with ALS spectrum. This further strengthens the evidence of a cognitive continuum in ALS and FTD in a diverse context and highlights the importance of meticulous evaluation and correct diagnosis that would assist in better management.}, } @article {pmid39069095, year = {2024}, author = {Ho, PC and Hsieh, TC and Tsai, KJ}, title = {TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: From pathomechanisms to therapeutic strategies.}, journal = {Ageing research reviews}, volume = {100}, number = {}, pages = {102441}, doi = {10.1016/j.arr.2024.102441}, pmid = {39069095}, issn = {1872-9649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics/therapy ; *Frontotemporal Lobar Degeneration/metabolism/pathology/therapy/genetics ; *TDP-43 Proteinopathies/metabolism/pathology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; Autophagy/physiology ; }, abstract = {Proteostasis failure is a common pathological characteristic in neurodegenerative diseases. Revitalizing clearance systems could effectively mitigate these diseases. The transactivation response (TAR) DNA-binding protein 43 (TDP-43) plays a critical role as an RNA/DNA-binding protein in RNA metabolism and synaptic function. Accumulation of TDP-43 aggregates in the central nervous system is a hallmark of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Autophagy, a major and highly conserved degradation pathway, holds the potential for degrading aggregated TDP-43 and alleviating FTLD/ALS. This review explores the causes of TDP-43 aggregation, FTLD/ALS-related genes, key autophagy factors, and autophagy-based therapeutic strategies targeting TDP-43 proteinopathy. Understanding the underlying pathological mechanisms of TDP-43 proteinopathy can facilitate therapeutic interventions.}, } @article {pmid39069396, year = {2024}, author = {Codron, P and Millecamps, S and Corcia, P}, title = {EVolution in ALS diagnosis: molecular markers in extracellular vesicles.}, journal = {Trends in molecular medicine}, volume = {30}, number = {12}, pages = {1097-1099}, doi = {10.1016/j.molmed.2024.07.006}, pmid = {39069396}, issn = {1471-499X}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/metabolism/genetics ; Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {The identification of biomarkers for amyotrophic lateral sclerosis (ALS) is a central issue in disease research. In a recent article, Chatterjee et al. show that blood extracellular vesicles (EVs) with high levels of transactive response DNA-binding protein 43 (TDP-43) accurately discriminate patients with ALS from controls and correlate with disease severity, providing a promising biomarker for early diagnosis and monitoring.}, } @article {pmid39070547, year = {2024}, author = {Kannan, A and Gangadharan Leela, S and Branzei, D and Gangwani, L}, title = {Role of senataxin in R-loop-mediated neurodegeneration.}, journal = {Brain communications}, volume = {6}, number = {4}, pages = {fcae239}, pmid = {39070547}, issn = {2632-1297}, support = {R01 NS115834/NS/NINDS NIH HHS/United States ; }, abstract = {Senataxin is an RNA:DNA helicase that plays an important role in the resolution of RNA:DNA hybrids (R-loops) formed during transcription. R-loops are involved in the regulation of biological processes such as immunoglobulin class switching, gene expression and DNA repair. Excessive accumulation of R-loops results in DNA damage and loss of genomic integrity. Senataxin is critical for maintaining optimal levels of R-loops to prevent DNA damage and acts as a genome guardian. Within the nucleus, senataxin interacts with various RNA processing factors and DNA damage response and repair proteins. Senataxin interactors include survival motor neuron and zinc finger protein 1, with whom it co-localizes in sub-nuclear bodies. Despite its ubiquitous expression, mutations in senataxin specifically affect neurons and result in distinct neurodegenerative diseases such as amyotrophic lateral sclerosis type 4 and ataxia with oculomotor apraxia type 2, which are attributed to the gain-of-function and the loss-of-function mutations in senataxin, respectively. In addition, low levels of senataxin (loss-of-function) in spinal muscular atrophy result in the accumulation of R-loops causing DNA damage and motor neuron degeneration. Senataxin may play multiple functions in diverse cellular processes; however, its emerging role in R-loop resolution and maintenance of genomic integrity is gaining attention in the field of neurodegenerative diseases. In this review, we highlight the role of senataxin in R-loop resolution and its potential as a therapeutic target to treat neurodegenerative diseases.}, } @article {pmid39071287, year = {2024}, author = {Tchounwou, C and Jobanputra, AJ and Lasher, D and Fletcher, BJ and Jacinto, J and Bhaduri, A and Best, RL and Fisher, WS and Ewert, KK and Li, Y and Feinstein, SC and Safinya, CR}, title = {Mixtures of Intrinsically Disordered Neuronal Protein Tau and Anionic Liposomes Reveal Distinct Anionic Liposome-Tau Complexes Coexisting with Tau Liquid-Liquid Phase Separated Coacervates.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39071287}, issn = {2692-8205}, support = {R01 NS035010/NS/NINDS NIH HHS/United States ; }, abstract = {Tau, an intrinsically disordered neuronal protein and polyampholyte with an overall positive charge, is a microtubule (MT) associated protein, which binds to anionic domains of MTs and suppresses their dynamic instability. Aberrant tau-MT interactions are implicated in Alzheimer's and other neurodegenerative diseases. Here, we studied the interactions between full length human protein tau and other negatively charged binding substrates, as revealed by differential-interference-contrast (DIC) and fluorescence microscopy. As a binding substrate, we chose anionic liposomes (ALs) containing either 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS, -1e) or 1,2-dioleoyl-sn-glycero-3-phosphatidylglycerol (DOPG, -1e) mixed with zwitterionic 1,2dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) to mimic anionic plasma membranes of axons where tau resides. At low salt concentrations (0 to 10 mM KCl or NaCl) with minimal charge screening, reaction mixtures of tau and ALs resulted in the formation of distinct states of AL-tau complexes coexisting with liquid-liquid phase separated tau self-coacervates arising from the polyampholytic nature of tau containing cationic and anionic domains. AL-tau complexes exhibited distinct types of morphologies. This included, large ≈20-30 micron tau-decorated giant vesicles with additional smaller liposomes with bound tau attached to the giant vesicles, and tau-mediated finite-size assemblies of small liposomes. As the ionic strength of the solution was increased to near and above physiological salt concentrations for 1:1 electrolytes (≈150 mM), AL-tau complexes remained stable while tau self-coacervate droplets were found to dissolve indicative of breaking of (anionic/cationic) electrostatic bonds between tau chains due to increased charge screening. The findings are consistent with the hypothesis that distinct cationic domains of tau may interact with anionic lipid domains of the lumen facing monolayer of the axon plasma membrane suggesting the possibility of transient yet robust interactions at physiologically relevant ionic strengths.}, } @article {pmid39071309, year = {2024}, author = {Yousefian-Jazi, A and Kim, S and Choi, SH and Chu, J and Nguyen, PT and Park, U and Lim, K and Hwang, H and Lee, K and Kim, Y and Hyeon, SJ and Rhim, H and Ryu, HL and Lim, G and Stein, TD and Ryu, H and Lee, J}, title = {Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.07.15.603186}, pmid = {39071309}, issn = {2692-8205}, support = {R01 NS109537/NS/NINDS NIH HHS/United States ; }, abstract = {Genetic changes and epigenetic modifications are associated with neuronal dysfunction in the pathogenesis of neurodegenerative disorders. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear. Here, we identified an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element, using convolutional neural network. The enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits. Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.}, } @article {pmid39071530, year = {2024}, author = {Gaspar, AD and Banayat, AC}, title = {Undergraduate Student Nurses' Satisfaction, Self-confidence, and Perception of High-fidelity Simulation-based Learning on Critically-ill Patients.}, journal = {Acta medica Philippina}, volume = {58}, number = {12}, pages = {110-117}, pmid = {39071530}, issn = {2094-9278}, abstract = {BACKGROUND AND OBJECTIVE: Replicating critical care practice settings in high-fidelity simulation (HFS) provides more learning opportunities to develop competencies, improve self-confidence, and learner satisfaction in a safe environment. Simulation is increasingly adopted globally as an alternative teaching strategy. Yet, data on the HFS experience of Filipino undergraduate nursing students is limited. This study describes the satisfaction, self-confidence, and perception of undergraduate nursing students on the use of HFS-based learning on critically-ill adult and pediatric patients requiring advanced life support (ALS).

METHODS: A quantitative, descriptive, correlational study was conducted using purposive sampling on all fourth-year BS Nursing students enrolled in Critical Care Nursing course in a state university. Data were collected through an online survey on demographic data, and the students' perceptions towards high-fidelity simulation-based learning (SBL) using three tools, namely: Simulation Design Scale, Educational Practices Questionnaire, and Student Satisfaction and Self-confidence in Learning. T-test and ANOVA were used to compare the means of the variables. Bivariate analysis (Pearson's product-moment correlation) was performed to find the relationship between variables.

RESULTS: A total of 86 students participated in the survey. Overall, the students were highly satisfied with the simulation experience (4.46 out of 5.0, SD=0.47), and had high ratings of self-confidence in SBL (4.44 out of 5.0, SD=0.42). Overall satisfaction level was positively related to student's perception on simulation design (r=0.61, p<0.01) and educational practices (r=0.59, p<0.01). Similarly, the students' overall self-confidence with SBL was also positively correlated with their perceptions of the simulation design (r=0.32, p<0.01), and educational practices (r=0.34, p<0.01).

CONCLUSION: Effective use of technology through HFS-based learning is useful in increasing satisfaction and self-confidence of Filipino undergraduate nursing students in caring for critically-ill patients needing ALS. Educators must highly consider all parameters of simulation design and educational practices in planning and implementing HFS-based learning to achieve meaningful learner experience.}, } @article {pmid39072497, year = {2025}, author = {Alonso, JP and Ini, N and Villarejo, A and Belizán, M and Roberti, J}, title = {Amyotrophic lateral sclerosis in Argentina: unveiling the burden of treatment through patient and caregiver perspectives.}, journal = {Disability and rehabilitation}, volume = {47}, number = {7}, pages = {1828-1835}, doi = {10.1080/09638288.2024.2385732}, pmid = {39072497}, issn = {1464-5165}, mesh = {Humans ; Argentina ; *Amyotrophic Lateral Sclerosis/psychology/therapy/rehabilitation/diagnosis/economics ; *Caregivers/psychology ; Female ; Male ; Middle Aged ; *Cost of Illness ; Qualitative Research ; Aged ; Interviews as Topic ; Adult ; Activities of Daily Living ; }, abstract = {PURPOSE: To examine the burden of treatment (BoT) experienced by people with Amyotrophic Lateral Sclerosis (ALS) in Argentina.

METHODS: Qualitative methodological design based on semi-structured interviews. Nineteen semi-structured interviews were conducted (PwALS = 7, informal caregivers= 12). The interview guides were designed based on the literature and BoT theory. Data were analysed following a framework analysis approach.

RESULTS: The research highlighted the arduous journey toward obtaining a diagnosis, marked by delays influenced by healthcare system inefficiencies, lack of disease awareness and pandemic-related anxiety. Receiving the diagnosis was a destabilising experience, triggering the need to reframe self-identity, a new reality. As the disease progressed, patients encountered significant challenges in their daily activities and basic tasks, affecting their ability to work, communicate, and manage personal care. The burden extended beyond the patients to their primary caregivers. Access to specialised care, bureaucratic complexities in securing treatment, and the financial impact of managing the disease posed substantial challenges.

CONCLUSION: The findings offer valuable insights into the experiences of PwALS and their caregivers in Argentina. They underscore the need for increased disease awareness, improved access to specialised care, and enhanced support networks to alleviate the burdens PwALS and their families face.}, } @article {pmid39072727, year = {2024}, author = {Defilippi, V and Petereit, J and Handlos, VJL and Notterpek, L}, title = {Quantitative proteomics unveils known and previously unrecognized alterations in neuropathic nerves.}, journal = {Journal of neurochemistry}, volume = {168}, number = {9}, pages = {3154-3170}, pmid = {39072727}, issn = {1471-4159}, support = {P20 GM130459/GM/NIGMS NIH HHS/United States ; GM104944/NH/NIH HHS/United States ; P20 GM103440/GM/NIGMS NIH HHS/United States ; P20GM130459/NH/NIH HHS/United States ; GM103440/NH/NIH HHS/United States ; U54 GM104944/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Proteomics/methods ; Mice ; Charcot-Marie-Tooth Disease/genetics/metabolism/pathology ; Myelin Proteins/genetics/metabolism ; Peripheral Nerves/metabolism/pathology ; Mice, Inbred C57BL ; Male ; Peripheral Nervous System Diseases/genetics/metabolism/pathology ; Female ; }, abstract = {Charcot-Marie-Tooth disease type 1E (CMT1E) is an inherited autosomal dominant peripheral neuropathy caused by mutations in the peripheral myelin protein 22 (PMP22) gene. The identical leucine-to-proline (L16P) amino acid substitution in PMP22 is carried by the Trembler J (TrJ) mouse and is found in CMT1E patients presenting with early-onset disease. Peripheral nerves of patients diagnosed with CMT1E display a complex and varied histopathology, including Schwann cell hyperproliferation, abnormally thin myelin, axonal degeneration, and subaxonal morphological changes. Here, we have taken an unbiased data-independent analysis (DIA) mass spectrometry (MS) approach to quantify proteins from nerves of 3-week-old, age and genetic strain-matched wild-type (Wt) and heterozygous TrJ mice. Nerve proteins were dissolved in lysis buffer and digested into peptide fragments, and protein groups were quantified by liquid chromatography-mass spectrometry (LC-MS). A linear model determined statistically significant differences between the study groups, and proteins with an adjusted p-value of less than 0.05 were deemed significant. This untargeted proteomics approach identified 3759 quality-controlled protein groups, of which 884 demonstrated differential expression between the two genotypes. Gene ontology (GO) terms related to myelin and myelin maintenance confirm published data while revealing a previously undetected prominent decrease in peripheral myelin protein 2. The dataset corroborates the described pathophysiology of TrJ nerves, including elevated activity in the proteasome-lysosomal pathways, alterations in protein trafficking, and an increase in three macrophage-associated proteins. Previously unrecognized perturbations in RNA processing pathways and GO terms were also discovered. Proteomic abnormalities that overlap with other human neurological disorders besides CMT include Lafora Disease and Amyotrophic Lateral Sclerosis. Overall, this study confirms and extends current knowledge on the cellular pathophysiology in TrJ neuropathic nerves and provides novel insights for future examinations. Recognition of shared pathomechanisms across discrete neurological disorders offers opportunities for innovative disease-modifying therapeutics that could be effective for distinct neuropathies.}, } @article {pmid39072749, year = {2025}, author = {Stevenor, BA and Burgess, Y and Sampson, G and McBride, NL and Gugiu, MR and Copella, J and Davis, J and Wu, B and Panchal, AR}, title = {Examining the Reliability and Validity of the ALS Certification Examinations with the Inclusion of Clinical Judgment: An Update on the ALS Examination Redesign.}, journal = {Prehospital emergency care}, volume = {29}, number = {3}, pages = {289-295}, doi = {10.1080/10903127.2024.2379879}, pmid = {39072749}, issn = {1545-0066}, mesh = {Humans ; Reproducibility of Results ; *Certification/standards ; *Emergency Medical Technicians/standards/education ; Psychometrics ; *Clinical Competence/standards ; *Educational Measurement/methods/standards ; *Emergency Medical Services/standards ; *Advanced Cardiac Life Support/standards ; Male ; Female ; }, abstract = {OBJECTIVES: Clinical judgment describes the process an emergency medical service clinician uses to evaluate problems and make decisions in the out-of-hospital setting. As part of the redesign of the Advanced Life Support (ALS) certification examinations, the National Registry of Emergency Medical Technicians is developing and evaluating items that measure clinical judgment, with the intention of assessing these as a new domain in the ALS certification examinations. In this study, we provide evidence around the redesign by evaluating the reliability and validity of the advanced emergency medical technician (AEMT) and paramedic certification examinations when clinical judgment is included as a sixth domain along with the five current domains.

METHODS: Pretest (i.e., pilot, unscored) clinical judgment items were included as a new sixth clinical judgment domain. We then used the combination of operational (i.e., scored) and pretest items for all six domains and scored the redesigned AEMT and paramedic certification examinations. We evaluated the psychometric properties of these ALS examinations within the Rasch measurement framework with multiple assessments of reliability and validity including item-level statistics (e.g., mean-square infit and outfit, local dependence) and examination-level statistics (e.g., person reliability, item reliability, item separation, decision consistency, decision accuracy). Wright Maps were produced to evaluate whether the examination item difficulty statistics aligned with the candidate ability continuum.

RESULTS: The total population of all examination forms included were 20,136 (AEMT 4,983; paramedic 15,153). The Rasch-based statistics for the redesigned AEMT and paramedic examinations, for both item and examination-level statistics, were well within the psychometric standard values. Wright maps demonstrated that the developed items fall along the candidate ability continuum for both examinations. Further, the distribution of clinical judgment item difficulties fell within the current item distribution, providing evidence that these new items are of similar difficulty to the items measuring the five current domains.

CONCLUSION: We demonstrate strong reliability and validity evidence to support that the integrity of the examinations is upheld with the addition of clinical judgment items, while also providing a more robust candidate evaluation. Most importantly, the pass/fail decisions that candidates receive accurately reflect their level of ALS knowledge at the entry-level.}, } @article {pmid39072769, year = {2024}, author = {Turner, J and Bruels, CC and Daugherty, AL and Estrella, EA and Stafki, S and Syeda, SB and Littel, HR and Pais, L and Ganesh, VS and Lidov, HGW and Paine, SML and Maddison, P and Harrison, RE and Straub, V and Ghosh, PS and Pacak, CA and Kunkel, LM and Draper, I and Topf, A and Kang, PB}, title = {Dominant stop-loss HNRNPA1 variants in juvenile-onset myopathy.}, journal = {Muscle & nerve}, volume = {70}, number = {4}, pages = {843-850}, pmid = {39072769}, issn = {1097-4598}, support = {//Muscular Dystrophy UK/ ; //Ultragenyx/ ; R01 HG009141/HG/NHGRI NIH HHS/United States ; //Coalition to Cure Calpain 3/ ; //LGMD2I Research Fund/ ; R01HG009141/HG/NHGRI NIH HHS/United States ; //Kurt+Peter Foundation/ ; UM1HG008900//National Heart, Lung and Blood Institute/ ; //Sanofi Genzyme/ ; UM1 HG008900/HG/NHGRI NIH HHS/United States ; P50 HD105351/HD/NICHD NIH HHS/United States ; //Bernard F. and Alva B. Gimbel Foundation/ ; //LGMD2D Foundation/ ; //Samantha J. Brazzo Foundation/ ; /EY/NEI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; Female ; Adolescent ; Muscular Diseases/genetics ; Muscle, Skeletal/pathology ; Young Adult ; Phenotype ; }, abstract = {INTRODUCTION/AIMS: Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis-like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals with monoallelic stop loss variants affecting the same codon of HNRNPA1.

METHODS: Two individuals with unsolved juvenile-onset myopathy were enrolled under approved institutional protocols. Phenotype data were collected and genetic analyses were performed, including whole-exome sequencing (WES).

RESULTS: The two probands (MNOT002-01 and K1440-01) showed a similar onset of slowly progressive extremity and facial weakness in early adolescence. K1440-01 presented with facial weakness, winged scapula, elevated serum creatine kinase (CK) levels, and mild neck weakness. MNOT002-01 also exhibited elevated CK levels along with facial weakness, cardiomyopathy, respiratory dysfunction, pectus excavatum, a mildly rigid spine, and loss of ambulation. On quadriceps muscle biopsy, K1440-01 displayed rounded myofibers, mild variation in fiber diameter, and type 2 fiber hypertrophy, while MNOT002-01 displayed rimmed vacuoles. Monoallelic stop-loss variants in HNRNPA1 were identified for both probands: c.1119A>C p.*373Tyrext*6 (K1440-01) and c.1118A>C p.*373Serext*6 (MNOT002-01) affect the same codon and are both predicted to lead to the addition of six amino acids before termination at an alternative stop codon.

DISCUSSION: Both stop-loss variants in our probands are likely pathogenic. Our findings contribute to the disease characterization of pathogenic variants in HNRNPA1. This gene should be screened in clinical diagnostic testing of unsolved cases of sporadic or dominant juvenile-onset myopathy.}, } @article {pmid39073146, year = {2024}, author = {Bublitz, SK and Eham, M and Ellrott, H and Littger, B and Richter, J and Lorenzl, S}, title = {Homecare amyotrophic lateral sclerosis (ALS): A multidisciplinary, home-based model of care for patients with ALS and their caregivers.}, journal = {Muscle & nerve}, volume = {70}, number = {5}, pages = {937-943}, doi = {10.1002/mus.28218}, pmid = {39073146}, issn = {1097-4598}, support = {//Bavarian Ministry of Health/ ; //Krankenhaus Agatharied/ ; //Dr. Mähler-Linke Stiftung/ ; //ALS Hilfe Bayern e.V./ ; //Marion von Tessin-Stiftung/ ; //Archdiocese München and Freising/ ; //Amylyx Pharmaceuticals Germany GmbH/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Male ; Female ; *Caregivers/psychology ; Middle Aged ; Aged ; *Home Care Services ; Pilot Projects ; Longitudinal Studies ; Patient Satisfaction ; Patient Care Team ; Adult ; Palliative Care ; Cohort Studies ; Germany ; Terminal Care ; Aged, 80 and over ; }, abstract = {INTRODUCTION/AIMS: Multidisciplinary care for patients with amyotrophic lateral sclerosis (ALS) is recommended in international guidelines, but reaches its limits when immobility increases. This pilot project addresses this gap by delivering home-based, specialized, multiprofessional support to ALS patients who are not able to attend outpatient care. The study assessed the feasibility of this model of care and the satisfaction of both patients and caregivers.

METHODS: This was a longitudinal cohort study of patients with ALS and their caregivers in the surroundings of Munich, Germany. Patients were regularly visited at home by a multiprofessional team (neurologists/palliative care physicians, nurse, social worker, chaplain).

RESULTS: A total of 94 patients with ALS were included in the homecare project and 88 patients and 74 caregivers were enrolled in the accompanying study. The mean care duration was 221 days, enabling 61% of the 49 deceased patients to die at home. Notably, 20% of patients chose a way to hasten death. Patient satisfaction (ICECAP Supportive Care Measure [SCM]: 23.7/28, CollaboRATE: 10.6/12) and caregiver perception of the end-of-life phase (Caregiver Evaluation of the Quality of End-Of-Life Care [CEQUEL]: 24.9/26) were high.

DISCUSSION: This pilot project successfully implemented specialized, home-based multidisciplinary care for ALS patients and caregivers, demonstrating both feasibility and high satisfaction. The program enabled a large proportion of patients to remain in their homes, reducing the need for hospital care. The multiprofessional approach, including neuropalliative, psychosocial and spiritual support provided comprehensive care that addressed needs of patients and caregivers. Further research is warranted to explore cost-effectiveness.}, } @article {pmid39073225, year = {2024}, author = {Liu, X and Xue, H and Wirdefeldt, K and Song, H and Smedby, K and Fang, F and Liu, Q}, title = {Clonal hematopoiesis of indeterminate potential and risk of neurodegenerative diseases.}, journal = {Journal of internal medicine}, volume = {296}, number = {4}, pages = {327-335}, doi = {10.1111/joim.20001}, pmid = {39073225}, issn = {1365-2796}, support = {//Initial Founding for High Level Talented Scholars in Nanfang Hospital/ ; 2023G001//Southern Medical University/ ; 2021-00696//Swedish Research Council (JPND)/ ; P1030//Initial Founding for Postdoc in Greater Bay Area Institute of Precision Medicine (Guangzhou)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/epidemiology ; Female ; Male ; *Clonal Hematopoiesis/genetics ; Middle Aged ; Aged ; Risk Factors ; DNA Methyltransferase 3A ; United Kingdom/epidemiology ; Cohort Studies ; DNA (Cytosine-5-)-Methyltransferases/genetics ; Repressor Proteins/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Parkinson Disease/genetics ; DNA-Binding Proteins ; Dioxygenases ; }, abstract = {BACKGROUND: Little is known regarding the association between clonal hematopoiesis of indeterminate potential (CHIP) and risk of neurodegenerative diseases.

OBJECTIVE: To estimate the risk of neurodegenerative diseases among individuals with CHIP.

METHODS: We conducted a community-based cohort study based on UK Biobank and used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of any neurodegenerative disease, subtypes of neurodegenerative diseases (including primary neurodegenerative diseases, vascular neurodegenerative diseases, and other neurodegenerative diseases), and specific diagnoses of neurodegenerative diseases (i.e., amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], and Parkinson's disease [PD]) associated with CHIP.

RESULTS: We identified 14,440 individuals with CHIP and 450,907 individuals without CHIP. Individuals with CHIP had an increased risk of any neurodegenerative disease (HR 1.10, 95% CI: 1.01-1.19). We also observed a statistically significantly increased risk for vascular neurodegenerative diseases (HR 1.31, 95% CI 1.05-1.63) and ALS (HR 1.50, 95% CI 1.05-2.15). An increased risk was also noted for other neurodegenerative diseases (HR 1.13, 95% CI 0.97-1.32), although not statistically significant. Null association was noted for primary neurodegenerative diseases (HR 1.06, 95% CI 0.96-1.17), AD (HR 1.04, 95% CI 0.88-1.23), and PD (HR 1.02, 95% CI 0.86-1.21). The risk increase in any neurodegenerative disease was mainly observed for DNMT3A-mutant CHIP, ASXL1-mutant CHIP, or SRSF2-mutant CHIP.

CONCLUSION: Individuals with CHIP were at an increased risk of neurodegenerative diseases, primarily vascular neurodegenerative diseases and ALS, but potentially also other neurodegenerative diseases. These findings suggest potential shared mechanisms between CHIP and neurodegenerative diseases.}, } @article {pmid39073531, year = {2024}, author = {Moglia, C and Palumbo, F and Botto, R and Iazzolino, B and Ticozzi, N and Calvo, A and Leombruni, P and , }, title = {Prognostic communication in amyotrophic lateral sclerosis: findings from a Nationwide Italian survey.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {12}, pages = {5787-5794}, pmid = {39073531}, issn = {1590-3478}, support = {RF-2016-02362405//Ministero della Salute/ ; 23C306//Ministero della Salute/ ; 101017598//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis ; Humans ; Italy ; Prognosis ; *Neurologists ; *Attitude of Health Personnel ; Communication ; Surveys and Questionnaires ; Male ; Female ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease with a highly variable prognosis. Among the proposed prognostic models, the European Network for the cure of ALS (ENCALS) survival model has demonstrated good predictive performance. However, few studies have examined prognostic communication and the diffusion of prognostic algorithms in ALS care.

OBJECTIVE: To investigate neurologists' attitudes toward prognostic communication and their knowledge and utilization of the ENCALS survival model in clinical practice.

METHODS: A web-based survey was administered between May 2021 and March 2022 to the 40 Italian ALS Centers members of the Motor Neuron Disease Study Group of the Italian Society of Neurology.

RESULTS: Twenty-two out of 40 (55.0%) Italian ALS Centers responded to the survey, totaling 37 responses. The model was known by 27 (73.0%) respondents. However, it was predominantly utilized for research (81.1%) rather than for clinical prognostic communication (7.4%). Major obstacles to prognostic communication included the unpredictability of disease course, fear of a negative impact on patients or caregivers, dysfunctional reaction to diagnosis, and cognitive impairment. Nonetheless, the model was viewed as potentially useful for improving clinical management, increasing disease awareness, and facilitating care planning, especially end-of-life planning.

CONCLUSIONS: Despite the widespread recognition and positive perceptions of the ENCALS survival model among Italian neurologists with expertise in ALS, its implementation in clinical practice remains limited. Addressing this disparity may require systematic investigations and targeted training to integrate tailored prognostic communication into ALS care protocols, aligning with the growing availability of prognostic tools for ALS.}, } @article {pmid39073543, year = {2024}, author = {Litvinov, VV and Freynd, GG}, title = {[Clinical and morphologic characterization of Pick's dementia: case report and review of the literature].}, journal = {Arkhiv patologii}, volume = {86}, number = {4}, pages = {51-57}, doi = {10.17116/patol20248604151}, pmid = {39073543}, issn = {0004-1955}, mesh = {Humans ; *Cerebral Cortex/metabolism/pathology ; *Pick Disease of the Brain/pathology/diagnosis ; tau Proteins/metabolism ; }, abstract = {Diseases morphologically characterized by frontotemporal lobar degeneration have relatively recently been considered as a group of frontotemporal dementias. This group is characterized by a tendency to early clinical onset of dementia, common genetic and morphological features, as well as a possible association with diseases such as amyotrophic lateral sclerosis and atypical parkinsonism syndrome. Historically, Pick's dementia (Pick's disease) was described as the first of the frontotemporal dementias, which is morphologically characterized by the presence of argyrophilic Pick's bodies represented by 3R-tau protein in the neurons of the cerebral cortex. Despite the characteristic clinical and morphological picture due to the relative rarity, the diagnosis of Pick's dementia is infrequently made by both clinicians and pathologists. The article presents current data on frontotemporal dementia. A case of Pick's dementia with characteristic clinical manifestations in the form of early onset of behavioral and personality disorders, as well as specific morphological changes in the brain, is described.}, } @article {pmid39073874, year = {2024}, author = {Gatch, AJ and Ding, F}, title = {TDP-43 Promotes Amyloid-Beta Toxicity by Delaying Fibril Maturation via Direct Molecular Interaction.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {15}, pages = {2936-2953}, pmid = {39073874}, issn = {1948-7193}, support = {P20 GM121342/GM/NIGMS NIH HHS/United States ; R35 GM145409/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyloid beta-Peptides/metabolism ; *DNA-Binding Proteins/metabolism ; Humans ; *Molecular Dynamics Simulation ; *Amyloid/metabolism ; Protein Binding ; Alzheimer Disease/metabolism ; }, abstract = {Amyloid-β (Aβ) is a peptide that undergoes self-assembly into amyloid fibrils, which compose the hallmark plaques observed in Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) is a protein with mislocalization and aggregation implicated in amyotrophic lateral sclerosis and other neurodegenerative diseases. Recent work suggests that TDP-43 may interact with Aβ, inhibiting the formation of amyloid fibrils and worsening AD pathology, but the molecular details of their interaction remain unknown. Using all-atom discrete molecular dynamics simulations, we systematically investigated the direct molecular interaction between Aβ and TDP-43. We found that Aβ monomers were able to bind near the flexible nuclear localization sequence of the N-terminal domain (NTD) of TDP-43, adopting β-sheet rich conformations that were promoted by the interaction. Furthermore, Aβ associated with the nucleic acid binding interface of the tandem RNA recognition motifs of TDP-43 via electrostatic interactions. Using the computational peptide array method, we found the strongest C-terminal domain interaction with Aβ to be within the amyloidogenic core region of TDP-43. With experimental evidence suggesting that the NTD is necessary for inhibiting Aβ fibril growth, we also simulated the NTD with an Aβ40 fibril seed. We found that the NTD was able to strongly bind the elongation surface of the fibril seed via extensive hydrogen bonding and could also diffuse along the lateral surface via electrostatic interactions. Our results suggest that TDP-43 binding to the elongation surface, thereby sterically blocking Aβ monomer addition, is responsible for the experimentally observed inhibition of fibril growth. We conclude that TDP-43 may promote Aβ toxicity by stabilizing the oligomeric state and kinetically delaying fibril maturation.}, } @article {pmid39075493, year = {2024}, author = {Mangal, AL and Mücke, M and Rolke, R and Appelmann, I}, title = {Advance directives in amyotrophic lateral sclerosis - a systematic review and meta-analysis.}, journal = {BMC palliative care}, volume = {23}, number = {1}, pages = {191}, pmid = {39075493}, issn = {1472-684X}, mesh = {*Amyotrophic Lateral Sclerosis/psychology/therapy/complications ; Humans ; *Advance Directives/statistics & numerical data/psychology ; Advance Care Planning/statistics & numerical data/standards ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motoneuron. It is associated with a life expectancy of 2-4 years after diagnosis. Individuals experience paralysis, dysphagia, respiratory failure and loss of communicative function, rendering advance care planning (ACP) critically important. This systematic review primarily aimed to internationally compare the application of advance directives (AD) and ACP in ALS. Its secondary aim was to identify ACP preferences, identify fields for future research and to generate recommendations for improving patient care through ACP.

METHODS: We conducted a systematic literature review and meta-analysis. Five electronic databases (Embase, Medline, Scopus, PsycInfo and CENTRAL) were searched for qualitative and quantitative primary literature from 1999 to 2024. Cross-references were used to identify additional publications. Study selection was performed based on inclusion criteria. Number and content of AD were extracted systematically. After statistical analysis consecutive meta-analysis was performed for international differences and changes over time. Quality assessment of studies was performed using the MMAT (Mixed Methods Appraisal Tool). PROSPERO Registration (June 07, 2021) : CRD42021248040.

RESULTS: A total of 998 records was screened of which 26 were included in the synthesis. An increase in publication numbers of 88.9% was observed from 1999 to 2024. Results regarding use and content of AD were heterogeneous and international differences were detected. AD were signed in 60.4% of records (1,629 / 2,696 patients). The number of AD decreased over time when separating the review period in two decades (1st 1999-2011: 78% vs. 2nd 2012-2024: 42%). Study quality was superior in qualitative and mixed method designs compared to quantitative studies.

CONCLUSION: Further prospective studies should include detailed analyses on preferences regarding ventilation and artificial nutrition in ALS and should encompass countries of the global south. Despite the complexity of ACP with regard to individual patient needs, ACP should be part of each individual support plan for ALS patients and should specifically comprise a discussion on the preferred place of death. The available disease-specific AD documents should be preferred.}, } @article {pmid39075842, year = {2025}, author = {Lomnicka, I and Dubey, S and Waller, P and Vora, D and Dirikolu, L}, title = {Development and validation of general plasma screening method for performance enhancing drugs in racehorses utilizing liquid chromatography-high-resolution mass spectrometry (LC-HRMS).}, journal = {Drug testing and analysis}, volume = {17}, number = {6}, pages = {735-750}, doi = {10.1002/dta.3774}, pmid = {39075842}, issn = {1942-7611}, support = {//Louisiana State Racing Commission, New Orleans, LA 70119/ ; }, mesh = {Horses/blood ; Animals ; *Doping in Sports ; *Substance Abuse Detection/methods/veterinary ; Solid Phase Extraction/methods ; Chromatography, High Pressure Liquid/methods ; *Performance-Enhancing Substances/blood ; *Mass Spectrometry/methods ; Limit of Detection ; Chromatography, Liquid/methods ; High-Throughput Screening Assays/methods ; Tandem Mass Spectrometry/methods ; }, abstract = {The screening of drugs in plasma and urine often requires initial extraction (such as liquid-liquid extraction and solid-phase extraction) before the samples are submitted to instrumental analyses. These extraction procedures are often laborious and time-consuming. In this manuscript, a high-throughput automated assay based on liquid chromatography-high-resolution mass spectrometry (LC-HRMS) suitable for use as an initial testing procedure covering multiple classes of compounds prohibited in horse racing is described. The assay requires a 600-μL plasma aliquot, which is subjected to solid phase extraction (SPE) using OASIS HLB 96-well SPE with Biotage Extrahera system, evaporation, and reconstitution in a 96-well collection plate. LC-HRMS analyses were carried out on a Thermo Q-Exactive Mass spectrometer coupled with Thermo UHPLC system equipped with Thermo Accela ALS 2.4.0 autosampler linked to ACE Excel column. Drug targets were detected by retention time and accurate mass, with a mass tolerance window of 5 ppm in positive and negative ionization mode. The screening method was validated for over 300 drug targets in a 13-min run. Validation data including sensitivity, specificity, extraction recovery, and precision are presented. As the method employs full-scan mass spectrometry, unlimited number of drug targets can theoretically be incorporated into this method.}, } @article {pmid39075908, year = {2025}, author = {Araúzo-Bravo, MJ and Gerovska, D and Schwab, M and Kretz, A}, title = {Small extrachromosomal circular DNA in amyotrophic lateral sclerosis matter.}, journal = {Neural regeneration research}, volume = {20}, number = {5}, pages = {1411-1413}, pmid = {39075908}, issn = {1673-5374}, } @article {pmid39075916, year = {2025}, author = {Wu, J and Ye, S and Liu, X and Xu, Y and Fan, D}, title = {The burden of upper motor neuron involvement is correlated with the bilateral limb involvement interval in patients with amyotrophic lateral sclerosis: a retrospective observational study.}, journal = {Neural regeneration research}, volume = {20}, number = {5}, pages = {1505-1512}, pmid = {39075916}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202505000-00032/figure1/v/2024-07-28T173839Z/r/image-tiff Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons. Early bilateral limb involvement significantly affects patients' daily lives and may lead them to be confined to bed. However, the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is unclear. To address this issue, we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022. A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral sclerosis. We used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis patients. Multiple factor analyses revealed that higher upper motor neuron scores (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 1.01-1.09, P = 0.018), onset in the left limb (HR = 0.72, 95% CI = 0.58-0.89, P = 0.002), and a horizontal pattern of progression (HR = 0.46, 95% CI = 0.37-0.58, P < 0.001) were risk factors for a shorter interval until bilateral limb involvement. The results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis patients. These findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.}, } @article {pmid39076207, year = {2024}, author = {Zheng, W and He, J and Chen, L and Yu, W and Zhang, N and Liu, X and Fan, D}, title = {Genetic link between KIF1A mutations and amyotrophic lateral sclerosis: evidence from whole-exome sequencing.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1421841}, pmid = {39076207}, issn = {1663-4365}, abstract = {OBJECTIVES: Genetics have been shown to have a substantial impact on amyotrophic lateral sclerosis (ALS). The ALS process involves defects in axonal transport and cytoskeletal dynamics. It has been identified that KIF1A, responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS.

METHODS: The analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and KIF1A. For patients with KIF1A gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis.

RESULTS: In our cohort, the KIF1A mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between KIF1A and ALS, the missense mutation p.A1083T (c.3247G>A) was shown to cosegregate with disease. The mutations related to ALS in our study were primarily located in the cargo-binding region at the C-terminal, as opposed to the mutations of motor domain at the N-terminal of KIF1A which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the KIF1A gene. KIF5A is a more frequent determinant of ALS in the European population, while KIF1A accounts for a similar proportion of ALS in both the European and Chinese populations.

CONCLUSION: Our investigation revealed that mutations in the C-terminus of KIF1A could increase the risk of ALS, support the pathogenic role of KIF1A in ALS and expand the phenotypic and genetic spectrum of KIF1A-related ALS.}, } @article {pmid39076845, year = {2024}, author = {Liu, X and Chen, L and Ye, S and Liu, X and Zhang, Y and Fan, D}, title = {Postural instability and lower extremity dysfunction in upper motor neuron-dominant amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1406109}, pmid = {39076845}, issn = {1664-2295}, abstract = {BACKGROUND: Upper motor neuron-dominant ALS (UMND ALS) is recognized to have early onset and good prognosis, but may have a rapid decline in motor function due to gait instability in the early stage. We investigated changes in lower extremity function in UMND ALS, particularly UMND ALS patients accompanied with postural instability or repeated falls (UMND ALS plus).

RESULTS: Among the 2,353 ALS patients reviewed, 211 (9.0%) had UMND ALS. UMND ALS had a longer diagnosis delay and restricted symptoms. Although UMND ALS patients had better lower extremity function and strength than matched classic ALS patients on first evaluation, there was no difference in the time of needing assistance or not being able to walk after disease onset. In contrast, UMND ALS plus has severe UMN symptoms and a more rapid decline in motor function. The lower extremity function was no better than that in the matched classic ALS. The prognosis of UMND ALS and UMND ALS plus were significantly better than those of overall ALS.

CONCLUSION: UMND ALS has restricted symptoms but has a rapid decline in lower extremity function in the early stage of the disease. The motor function decline of UMND ALS plus is as fast as classic ALS. Whether these patients represent a distinct subgroup of ALS deserves further investigation.}, } @article {pmid39079069, year = {2024}, author = {Fournier, CN}, title = {Learning From the Exception and Not the Rule: Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.}, journal = {Neurology}, volume = {103}, number = {4}, pages = {e209780}, doi = {10.1212/WNL.0000000000209780}, pmid = {39079069}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Phenotype ; }, } @article {pmid39079071, year = {2024}, author = {Crayle, JI and Rampersaud, E and Myers, JR and Wuu, J and Taylor, JP and Wu, G and Benatar, M and Bedlack, RS}, title = {Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.}, journal = {Neurology}, volume = {103}, number = {4}, pages = {e209696}, pmid = {39079071}, issn = {1526-632X}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; Cohort Studies ; *Genome-Wide Association Study ; *Phenotype ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Whole Genome Sequencing ; }, abstract = {BACKGROUND AND OBJECTIVES: The term "ALS Reversal" describes patients who initially meet diagnostic criteria for amyotrophic lateral sclerosis (ALS) or had clinical features most consistent with progressive muscular atrophy (PMA) but subsequently demonstrated substantial and sustained clinical improvement. The objective of this genome-wide association study (GWAS) was to identify correlates of this unusual clinical phenotype.

METHODS: Participants were recruited from a previously created database of individuals with the ALS Reversal phenotype. Whole-genome sequencing (WGS) data were compared with ethnicity-matched patients with typically progressive ALS enrolled through the CReATe Consortium's Phenotype-Genotype-Biomarker (PGB) study. These results were replicated using an independent ethnically matched WGS data set from Target ALS. Significant results were further explored with available databases of genetic regulatory markers and expression quantitative trait loci (eQTL) analysis.

RESULTS: WGS from 22 participants with documented ALS Reversals was compared with the PGB primary cohort (n = 103) and the Target ALS validation cohort (n = 140). Two genetic loci met predefined criteria for statistical significance (two-sided permutation p ≤ 0.01) and remained plausible after fine-mapping. The lead single nucleotide variant (SNV) from the first locus was rs4242007 (primary cohort GWAS OR = 12.0, 95% CI 4.1 to 34.6), which is in an IGFBP7 intron and is in near-perfect linkage disequilibrium with a SNV in the IGFBP7 promoter region. Both SNVs are associated with decreased frontal cortex IGFBP7 expression in eQTL data sets. Notably, 3 Reversals, but none of the typically progressive individuals (n = 243), were homozygous for rs4242007. The importance of the second locus, located near GRIP1, is uncertain given the absence of an associated effect on nearby gene transcription.

DISCUSSION: We found a significant association between the Reversal phenotype and an IGFBP7 noncoding SNV that is associated with IGFBP7 expression. This is biologically relevant as IGFBP7 is a reported inhibitor of the insulin growth factor-1 (IGF-1) receptor that activates the possibly neuroprotective IGF-1 signaling pathway. This finding is limited by small sample size but suggests that there may be merit in further exploration of IGF-1 pathway signaling as a therapeutic mechanism for ALS.

This study was registered with ClinicalTrials.gov (NCT03464903) on March 14, 2018. The first participant was enrolled on June 22, 2018.}, } @article {pmid39079696, year = {2024}, author = {Tress, F and Luecke, E and Stegemann-Koniszewski, S and Lux, A and Singla, A and Schreiber, J}, title = {Prediction of nocturnal ventilation by pulmonary function testing in patients with amyotrophic lateral sclerosis.}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {78}, number = {9}, pages = {626-633}, doi = {10.1055/a-2349-0936}, pmid = {39079696}, issn = {1438-8790}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/therapy/diagnosis/complications ; Female ; Male ; Aged ; *Respiratory Function Tests ; Retrospective Studies ; Middle Aged ; Noninvasive Ventilation/methods ; Sensitivity and Specificity ; Reproducibility of Results ; Respiratory Insufficiency/therapy/physiopathology/etiology/diagnosis ; Polysomnography/methods ; Circadian Rhythm/physiology ; }, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS) prognosis is poor due to progressive weakening of the respiratory muscles. Survival and quality of life can be improved by noninvasive ventilation (NIV), which is initially applied while sleeping. The indication for NIV is based on pulmonary function testing (PFT) and polysomnography (PSG) with capnography (tCO2). While it is desirable to predict nocturnal ventilation by waking PFT in ALS, the parameters suited for reliable predictions remain elusive.

METHODS: We retrospectively analyzed parameters derived from PFT (spirometry, body plethysmography, diffusion capacity, respiratory muscle testing) and blood gas analysis, PSG and tCO2 in 42 patients with ALS (27 men, 15 women, age 69 ± 12.1 years) and performed Spearman's correlation analysis of daytime waking parameters and nighttime sleep parameters.

RESULTS: 28 patients (66.7%) showed restrictive impairment of ventilation and 15 patients (48.3%) showed insufficiency of the respiratory musculature. There was no obstructive impairment of ventilation. We did not observe any significant correlations between any single daytime PFT parameter with nocturnal pCO2. However, there were significant correlations between the ratios PIF/PEF, MEF50/MIF50, DLCO/VA as well as FEV1/FVC and nocturnal pCO2. Highly normal FEV1/FVC and Krogh-Factor (DLCOc/VA) indicated nocturnal hypercapnia. Furthermore, waking hypercapnia, concentrations of bicarbonate and base excess were each positively correlated with nocturnal hypercapnia.

CONCLUSIONS: Waking PFT is not a good predictor of nocturnal ventilation. Inspiratory parameters as well as the ratios FEV1/FVC and DLCO/VA performed best and should be included in the interpretation. Our analyses confirm the relevance of inspiratory muscle weakness in ALS. PSG and tCO2 remain the gold standard for the assessment of nocturnal ventilation.}, } @article {pmid39080220, year = {2025}, author = {Han, M and Raymond, J and Larson, TC and Mehta, P and Horton, DK}, title = {Correction to: Comparison of Demographics: National Amyotrophic Lateral Sclerosis Registry and Clinical Trials Data.}, journal = {Journal of racial and ethnic health disparities}, volume = {12}, number = {4}, pages = {2821}, doi = {10.1007/s40615-024-02110-0}, pmid = {39080220}, issn = {2196-8837}, } @article {pmid39083229, year = {2024}, author = {Kaji, R and Izumi, Y and Oki, R}, title = {Ultra-high dose methylcobalamin and other emerging therapies for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {593-602}, doi = {10.1097/WCO.0000000000001311}, pmid = {39083229}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Vitamin B 12/analogs & derivatives/therapeutic use/administration & dosage ; Clinical Trials as Topic ; }, abstract = {PURPOSE OF REVIEW: Recent development in understanding the pathophysiology of amyotrophic lateral sclerosis (ALS) has led to increasing number of promising test drugs in the pipeline along with the existing ones. We will review these agents focusing on ultra-high dose methylcobalamin, which is pending approval in Japan. Clinical trial design best suited for ALS will also be discussed.

RECENT FINDINGS: The most recent phase 3 trial (JETALS) of ultra-high dose methylcobalamin demonstrated significant slowing of ALSFRSR changes (0.5/month), with marked reduction of serum homocysteine levels in the initial double-blind period. The post hoc analysis of the previous phase 2/3 study (E761 trial; Eisai) showed that it prolonged survival of ALS patients, if started within 1 year of onset, but the previous studies suggested its efficacy even in later stages, depending upon the rate of progression. Phase 3 trial of AMX0035 or Relyvrio on the other hand showed negative results despite the promising phase 2 data. The latter did not adjust the disease progression rate before entry.

SUMMARY: Ultra-high dose methylcobalamin is not a vitamin supplement but a novel disease-modifying therapy for ALS, and it emphasizes homocysteine as a key factor in the disease process. Clinical trial design must include entering patients early and with similar rates of progression using pretrial observation periods for meaningful results, since ALS is a chronologically heterogenous condition with similar phenotypes.}, } @article {pmid39084211, year = {2024}, author = {Sharma, S and Gilberto, VS and Rask, J and Chatterjee, A and Nagpal, P}, title = {Inflammasome-Inhibiting Nanoligomers Are Neuroprotective against Space-Induced Pathology in Healthy and Diseased Three-Dimensional Human Motor and Prefrontal Cortex Brain Organoids.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {16}, pages = {3009-3021}, doi = {10.1021/acschemneuro.4c00160}, pmid = {39084211}, issn = {1948-7193}, mesh = {Humans ; *Prefrontal Cortex/drug effects/metabolism ; *Organoids/drug effects ; *Inflammasomes/metabolism ; Neuroprotective Agents/pharmacology ; Space Flight ; Weightlessness ; Neurodegenerative Diseases ; Alzheimer Disease/pathology/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Frontotemporal Dementia/metabolism ; }, abstract = {The microgravity and space environment has been linked to deficits in neuromuscular and cognitive capabilities, hypothesized to occur due to accelerated aging and neurodegeneration in space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk to astronauts and space tourists and is being actively investigated for the development of appropriate countermeasures. However, such space-induced neuropathology offers an opportunity for accelerated screening of therapeutic targets and lead molecules for treating neurodegenerative diseases. Here, we show a proof-of-concept high-throughput target screening (on Earth), target validation, and mitigation of microgravity-induced neuropathology using our Nanoligomer platform, onboard the 43-day SpaceX CRS-29 mission to the International Space Station. First, comparing 3D healthy and diseased prefrontal cortex (PFC, for cognition) and motor neuron (MN, for neuromuscular function) organoids, we assessed space-induced pathology using biomarkers relevant to Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Both healthy and diseased PFC and MN organoids showed significantly enhanced neurodegeneration in space, as measured through relevant disease biomarkers, when compared to their respective Earth controls. Second, we tested the top two lead molecules, NI112 that targeted NF-κB and NI113 that targeted IL-6. We observed that these Nanoligomers significantly mitigate the AD, FTD, and ALS relevant biomarkers like amyloid beta-42 (Aβ42), phosphorylated tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), and others. Moreover, the 43-day Nanoligomer treatment of these brain organoids did not appear to cause any observable toxicity or safety issues in the target organoid tissue, suggesting good tolerability for these molecules in the brain at physiologically relevant doses. Together, these results show significant potential for both the development and translation of NI112 and NI113 molecules as potential neuroprotective countermeasures for safer space travel and demonstrate the usefulness of the space environment for rapid, high-throughput screening of targets and lead molecules for clinical translation. We assert that the use of microgravity in drug development and screening may ultimately benefit millions of patients suffering from debilitating neurodegenerative diseases on Earth.}, } @article {pmid39084570, year = {2024}, author = {Liu, J and Zhao, W and Guo, J and Kang, K and Li, H and Yang, X and Li, J and Wang, Q and Qiao, H}, title = {Electroacupuncture alleviates motor dysfunction by regulating neuromuscular junction disruption and neuronal degeneration in SOD1[G93A] mice.}, journal = {Brain research bulletin}, volume = {216}, number = {}, pages = {111036}, doi = {10.1016/j.brainresbull.2024.111036}, pmid = {39084570}, issn = {1873-2747}, mesh = {Animals ; *Electroacupuncture/methods ; *Neuromuscular Junction/pathology/metabolism ; *Motor Neurons/pathology/physiology ; *Mice, Transgenic ; Mice ; *Amyotrophic Lateral Sclerosis/therapy/pathology/genetics ; Disease Models, Animal ; Male ; Nerve Degeneration/therapy/pathology ; Muscle, Skeletal/pathology ; Superoxide Dismutase-1/genetics/metabolism ; Sciatic Nerve/injuries/pathology ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by the progressive destruction of the neuromuscular junction (NMJ) and the degeneration of motor neurons, eventually leading to atrophy and paralysis of voluntary muscles responsible for motion and breathing. NMJs, synaptic connections between motor neurons and skeletal muscle fibers, are extremely fragile in ALS. To determine the effects of early electroacupuncture (EA) intervention on nerve reinnervation and regeneration following injury, a model of sciatic nerve injury (SNI) was first established using SOD1[G93A] mice, and early electroacupuncture (EA) intervention was conducted at Baihui (DU20), and bilateral Zusanli (ST36). The results revealed that EA increased the Sciatic nerve Functional Index, the structural integrity of the gastrocnemius muscles, and the cross-sectional area of muscle fibers, as well as up-regulated the expression of acetylcholinesterase and facilitated the co-location of α7 nicotinic acetate choline receptors and α-actinin. Overall, these results suggested that EA can promote the repair and regeneration of injured nerves and delay NMJ degeneration in SOD1[G93A]-SNI mice. Moreover, analysis of the cerebral cortex demonstrated that EA alleviated cortical motor neuron damage in SOD1[G93A] mice, potentially attributed to the inhibition of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway and the release of interferon-β suppressing the activation of natural killer cells and the secretion of interferon-γ, thereby further inhibiting microglial activation and the expression of inflammatory factors. In summary, EA delayed the degeneration of NMJ and mitigated the loss of cortical motor neurons, thus delaying disease onset, accompanied by alleviation of muscle atrophy and improvements in motor function in SOD1[G93A] mice.}, } @article {pmid39084788, year = {2024}, author = {Ohta, K and Kawamata, E and Hori, T and Sada, Y}, title = {Connecting genes to whole plants in dilution effect of target-site ALS inhibitor resistance of Schoenoplectiella juncoides (Roxb.) Lye (Cyperaceae).}, journal = {Pesticide biochemistry and physiology}, volume = {203}, number = {}, pages = {105984}, doi = {10.1016/j.pestbp.2024.105984}, pmid = {39084788}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Cyperaceae/genetics/drug effects ; Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Mutation ; Genes, Plant ; }, abstract = {This study focuses on dilution effect of target-site resistance (TSR) to acetolactate synthase (ALS) inhibitors in Schoenoplectiella juncoides, which harbors two ALS genes, ALS1 and ALS2. We assessed gene expression, enzyme activity, and whole-plant resistance profiles across four S. juncoides lines: the susceptible line, the parental resistant lines with a homozygous mutation in either ALS1 or ALS2, and the bred progeny line with homozygous mutations in both ALS1 and ALS2. Gene expression and enzyme function showed a proportional relationship that the expression ratios of ALS1 to ALS2, approximately 70:30, were consistent with the functional ratio predicted by the double-sigmoidal plateau positions observed in enzyme assays. However, at the whole-plant level, resistance did not correlate to the putative abundance of susceptible enzyme, but the parental lines showed similar resistance to each other despite different enzyme-level resistances. This suggests a non-proportional mechanism in the reflection of physiological enzymatic profiles to whole-plant resistance profiles. These findings highlight the complexity of herbicide resistance and the need for further research to understand the mechanisms that influence resistance outcomes. Understanding these relationships is essential for developing strategies to manage herbicide resistance effectively.}, } @article {pmid39084789, year = {2024}, author = {Wang, H and Zhang, Y and Ren, Y and Liu, Y and Feng, Z and Dong, L}, title = {Mechanism of multiple resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon in Avena fatua L. from China.}, journal = {Pesticide biochemistry and physiology}, volume = {203}, number = {}, pages = {105985}, doi = {10.1016/j.pestbp.2024.105985}, pmid = {39084789}, issn = {1095-9939}, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Oxazoles/pharmacology ; China ; *Phenylurea Compounds/pharmacology ; *Acetyl-CoA Carboxylase/genetics/metabolism ; *Propionates/pharmacology ; *Acetolactate Synthase/genetics/metabolism ; Poaceae/drug effects ; Phenylpropionates/pharmacology ; Plant Proteins/genetics/metabolism ; Sulfonylurea Compounds ; }, abstract = {Avena fatua L. is one of the most damaging and malignant weeds in wheat fields in China. Fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon, which belong to Acetyl-CoA carboxylase- (ACCase), acetolactate synthase- (ALS), and photosystem II- (PS II) inhibitors, respectively, are commonly used in wheat fields and have a long history of use on A. fatua. An A. fatua population (R) resistant to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon was collected from a wheat field in 2020. This study explored the mechanisms of target site resistance (TSR) and non-target site resistance (NTSR) in the multi-resistant A. fatua. Whole-plant bioassays showed that the R population had evolved high resistance to fenoxaprop-P-ethyl and moderate resistance to mesosulfuron-methyl and isoproturon. However, no mutations were detected in the ACCase, ALS, or psbA genes in the R population. In addition, the ACCase and ALS gene expression levels in the R group were significantly higher than those in the susceptible population (S) after treatment with fenoxaprop-P-ethyl or mesosulfuron-methyl. In vitro ACCase and ALS activity assays showed that ACCase and ALS from the R population were insensitive to fenoxaprop and mesosulfuron-methyl, respectively, with resistance indices 6.12-fold and 17.46-fold higher than those of the S population. Furthermore, pretreatment with P450 inhibitors significantly (P < 0.05) reversed the multi-resistant A. fatua's resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon. Sethoxydim, flucarbazone‑sodium, chlortoluron, and cypyrafluone were effective in controlling multi-resistance A. fatua. Therefore, the overexpression of ACCase and ALS to synthesize sufficient herbicide-targeting proteins, along with P450-mediated metabolism, conferred resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon in the R population.}, } @article {pmid39085618, year = {2024}, author = {Müller, KJ and Schmidbauer, ML and Schönecker, S and Kamm, K and Pelz, JO and Holzapfel, K and Papadopoulou, M and Bakola, E and Tsivgoulis, G and Naumann, M and Hermann, A and Walter, U and Dimitriadis, K and Reilich, P and Schöberl, F}, title = {Diagnostic accuracy and confounders of vagus nerve ultrasound in amyotrophic lateral sclerosis-a single-center case series and pooled individual patient data meta-analysis.}, journal = {Journal of neurology}, volume = {271}, number = {9}, pages = {6255-6263}, pmid = {39085618}, issn = {1432-1459}, support = {DFG TRR 338//Deutsche Forschungsgemeinschaft/ ; DFG TRR 274//Deutsche Forschungsgemeinschaft/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis ; Humans ; Male ; Aged ; Female ; Middle Aged ; *Ultrasonography ; *Vagus Nerve/diagnostic imaging ; }, abstract = {BACKGROUND: Several single-center studies proposed utility of vagus nerve (VN) ultrasound for detecting disease severity, autonomic dysfunction, and bulbar phenotype in amyotrophic lateral sclerosis (ALS). However, the resulting body of literature shows opposing results, leaving considerable uncertainty on the clinical benefits of VN ultrasound in ALS.

METHODS: Relevant studies were identified up to 04/2024 and individual patient data (IPD) obtained from the respective authors were pooled with a so far unpublished cohort (from Munich). An IPD meta-analysis of 109 patients with probable or definite ALS (El Escorial criteria) and available VN cross-sectional area (CSA) was performed, with age, sex, ALS Functional Rating Scale-revised (ALSFRS-R), disease duration, and bulbar phenotype as independent variables.

RESULTS: Mean age was 65 years (± 12) and 47% of patients (± 12) had bulbar ALS. Mean ALSFRS-R was 38 (± 7), and mean duration was 18 months (± 18). VN atrophy was highly prevalent [left: 67% (± 5), mean CSA 1.6mm[2] (± 0.6); right: 78% (± 21), mean CSA 1.8 mm[2] (± 0.7)]. VN CSA correlated with disease duration (mean slope: left - 0.01; right - 0.01), but not with ALSFRS-R (mean slope: left 0.004; mean slope: right - 0.002). Test accuracy for phenotyping bulbar vs. non-bulbar ALS was poor (summary receiver operating characteristic area under the curve: left 0.496; right 0.572).

CONCLUSION: VN atrophy in ALS is highly prevalent and correlates with disease duration, but not with ALSFRS-R. VN CSA is insufficient to differentiate bulbar from non-bulbar ALS phenotypes. Further studies are warranted to analyze the link between VN atrophy, autonomic impairment, and survival in ALS.}, } @article {pmid39086006, year = {2024}, author = {An, TJ and Jang, S and Hering, K and Vazquez, R and Scalia, J and Berry, JD and Kalva, SP and Arellano, RS}, title = {Gastrostomy placement in patients with amyotrophic lateral sclerosis: assessment of risk factors for post-procedural respiratory failure.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {680-686}, doi = {10.1080/21678421.2024.2384994}, pmid = {39086006}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/surgery ; *Gastrostomy/methods ; Male ; Female ; Middle Aged ; Aged ; Retrospective Studies ; *Respiratory Insufficiency/etiology ; Risk Factors ; Adult ; Aged, 80 and over ; Deglutition Disorders/etiology/epidemiology ; }, abstract = {OBJECTIVE: Radiologically inserted gastrostomy placement may be performed in patients with dysphagia secondary to amyotrophic lateral sclerosis (ALS). This study assessed technical outcomes and complications related to gastrostomy placement in patients with ALS.

METHODS: A retrospective review of patients with ALS who underwent gastrostomy placement between 2021 and 2023 was performed. Patient demographics, medical history, ALS disease manifestations, survival, and post-procedural complications were obtained from the electronic medical record. Technical outcomes related to gastrostomy placement were obtained from operative notes and review of procedural imaging.

RESULTS: A total of 100 patients were included in the study. The mean duration of ALS diagnosis at time of gastrostomy placement was 1.3 +/-1.2 years. The mean slow vital capacity at time of gastrostomy placement was 54.0 +/-20.2% (range 10-155%). Technical success was 100%, with 91 placed using fluoroscopic guidance and 9 placed with computed tomography guidance. Eighty-three percent of gastrostomies were performed as outpatient procedures, while 17/100 patients were admitted following the procedure for monitoring. Post-procedural adverse events were noted in 21/100 patients (15 mild and 6 moderate or greater). Three patients developed respiratory failure after gastrostomy tube placement and died within 1-week post-procedure. Lower pre-procedural slow vital capacity was associated with higher risk of post-procedural respiratory failure (p = 0.0003*).

CONCLUSIONS: Gastrostomy placement in patients with ALS has a high technical success rate and may be performed safely in the outpatient setting in appropriate patients. Patients with low slow vital capacity related to ALS should be admitted post-procedurally for airway monitoring and support.}, } @article {pmid39086545, year = {2024}, author = {Carrera-Juliá, S and Obrador, E and López-Blanch, R and Oriol-Caballo, M and Moreno-Murciano, P and Estrela, JM}, title = {Ketogenic effect of coconut oil in ALS patients.}, journal = {Frontiers in nutrition}, volume = {11}, number = {}, pages = {1429498}, pmid = {39086545}, issn = {2296-861X}, abstract = {A recent pilot study in amyotrophic lateral sclerosis (ALS) patients analyzed the effect of a Mediterranean diet (MeDi) supplemented with nicotinamide riboside (NR, a NAD[+] promoter), pterostilbene (PTER, a natural antioxidant) and/or coconut oil on anthropometric variables in ALS patients. The results suggested that the MeDi supplemented with NR, PTER and coconut oil is the nutritional intervention showing the greatest benefits at anthropometric levels. Over the last 30 years, glucose intolerance has been reported in ALS patients. Thus, suggesting that an alternative source of energy may be preferential for motor neurons to survive. Ketone bodies (KBs), provided through a MeDi with a lower carbohydrate content but enriched with medium chain triglycerides, could be a therapeutic alternative to improve the neuromotor alterations associated with the disease. Nevertheless, the use of a coconut oil-supplemented diet, as potentially ketogenic, is a matter of controversy. In the present report we show that a MeDi supplemented with coconut oil increases the levels of circulating KBs in ALS patients.}, } @article {pmid39086635, year = {2024}, author = {Pérez-Holanda, S}, title = {Non-participation of asymptomatic candidates in screening protocols reduces early diagnosis and worsens prognosis of colorectal cancer.}, journal = {World journal of gastroenterology}, volume = {30}, number = {26}, pages = {3198-3200}, pmid = {39086635}, issn = {2219-2840}, mesh = {Humans ; *Colorectal Neoplasms/diagnosis ; *Early Detection of Cancer/methods/statistics & numerical data ; Prognosis ; Asymptomatic Diseases ; Mass Screening/methods/statistics & numerical data ; Japan/epidemiology ; Neoplasm Staging ; Colonoscopy/statistics & numerical data ; }, abstract = {The Agatsuma et al's study shows that despite the evidence of the benefits of an early colorectal cancer (CRC) diagnosis, through screening in asymptomatic subjects, up to 50% of candidates reject this option and many of those affected are diagnosed later, in advanced stages. The efficacy of screening programs has been well-established for several years, which reduces the risk of CRC morbidity and mortality, without taking into account the test used for screening, or other tools. Nevertheless, a significant proportion of patients remain unscreened, so understanding the factors involved, as well as the barriers of the population to adherence is the first step to possibly modify the participation rate. These barriers could include a full range of social and political aspects, especially the type of financial provision of each health service. In Japan, health services are universal, and this advantageous situation makes it easier for citizens to access to these services, contributing to the detection of various diseases, including CRC. Interestingly, the symptomatic CRC group had a lower early-stage diagnosis rate than the patients detected during follow-up for other comorbidities, and symptomatic and cancer screening groups showed similar early-stage diagnosis.}, } @article {pmid39086672, year = {2023}, author = {Pasinelli, P and Meyer, K and Ferraiuolo, L and Culibrk, RA and Sattler, R}, title = {Editorial: The role of glial cells in neurodegeneration.}, journal = {Frontiers in molecular medicine}, volume = {3}, number = {}, pages = {1337286}, doi = {10.3389/fmmed.2023.1337286}, pmid = {39086672}, issn = {2674-0095}, support = {T32 AG044402/AG/NIA NIH HHS/United States ; }, } @article {pmid39086676, year = {2023}, author = {Stoklund Dittlau, K and Van Den Bosch, L}, title = {Why should we care about astrocytes in a motor neuron disease?.}, journal = {Frontiers in molecular medicine}, volume = {3}, number = {}, pages = {1047540}, pmid = {39086676}, issn = {2674-0095}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults, causing progressive degeneration of motor neurons, which results in muscle atrophy, respiratory failure and ultimately death of the patients. The pathogenesis of ALS is complex, and extensive efforts have focused on unravelling the underlying molecular mechanisms with a large emphasis on the dying motor neurons. However, a recent shift in focus towards the supporting glial population has revealed a large contribution and influence in ALS, which stresses the need to explore this area in more detail. Especially studies into astrocytes, the residential homeostatic supporter cells of neurons, have revealed a remarkable astrocytic dysfunction in ALS, and therefore could present a target for new and promising therapeutic entry points. In this review, we provide an overview of general astrocyte function and summarize the current literature on the role of astrocytes in ALS by categorizing the potentially underlying molecular mechanisms. We discuss the current efforts in astrocyte-targeted therapy, and highlight the potential and shortcomings of available models.}, } @article {pmid39086926, year = {2024}, author = {Tilliole, P and Fix, S and Godin, JD}, title = {hnRNPs: roles in neurodevelopment and implication for brain disorders.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1411639}, pmid = {39086926}, issn = {1662-5099}, abstract = {Heterogeneous nuclear ribonucleoproteins (hnRNPs) constitute a family of multifunctional RNA-binding proteins able to process nuclear pre-mRNAs into mature mRNAs and regulate gene expression in multiple ways. They comprise at least 20 different members in mammals, named from A (HNRNP A1) to U (HNRNP U). Many of these proteins are components of the spliceosome complex and can modulate alternative splicing in a tissue-specific manner. Notably, while genes encoding hnRNPs exhibit ubiquitous expression, increasing evidence associate these proteins to various neurodevelopmental and neurodegenerative disorders, such as intellectual disability, epilepsy, microcephaly, amyotrophic lateral sclerosis, or dementias, highlighting their crucial role in the central nervous system. This review explores the evolution of the hnRNPs family, highlighting the emergence of numerous new members within this family, and sheds light on their implications for brain development.}, } @article {pmid39087137, year = {2024}, author = {Chisthi, MM}, title = {Unveiling the potential of electrocautery-enhanced lumen-apposing metal stents in endoscopic ultrasound-guided biliary drainage.}, journal = {World journal of gastrointestinal surgery}, volume = {16}, number = {7}, pages = {1956-1959}, pmid = {39087137}, issn = {1948-9366}, abstract = {This editorial delves into Peng et al's article, published in the World Journal of Gastrointestinal Surgery. Peng et al's meta-analysis investigates the effectiveness of electrocautery-enhanced lumen-apposing metal stents (ECE-LAMS) in ultrasound-guided biliary drainage for alleviating malignant biliary obstruction. Examining 14 studies encompassing 620 participants, the research underscores a robust technical success rate of 96.7%, highlighting the efficacy of ECE-LAMS, particularly in challenging cases which have failed endoscopic retrograde cholangio pancreatography. A clinical success rate of 91.0% underscores its impact on symptom alleviation, while a reasonably tolerable adverse event rate of 17.5% is observed. However, the 7.3% re-intervention rate stresses the need for post-procedural monitoring. Subgroup analyses validate consistent outcomes, bolstering the applicability of ECE-LAMS. These findings advocate for the adoption of ECE-LAMS as an appropriate approach for biliary palliation, urging further exploration in real-world clinical contexts. They offer valuable insights for optimizing interventions targeting malignant biliary obstruction management.}, } @article {pmid39088003, year = {2024}, author = {Lai, HJ and Kuo, YC and Ting, CH and Yang, CC and Kao, CH and Tsai, YC and Chao, CC and Hsueh, HW and Hsieh, PF and Chang, HY and Wang, IF and Tsai, LK}, title = {Increase of HCN current in SOD1-associated amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {12}, pages = {4240-4253}, doi = {10.1093/brain/awae248}, pmid = {39088003}, issn = {1460-2156}, support = {108-2314-B-002-082-MY3//Ministry of Science and Technology, ROC/ ; MQ999//National Taiwan University Hospital/ ; 112-BIH001//National Taiwan University Hospital Hsinchu branch/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Animals ; *Superoxide Dismutase-1/genetics ; Mice ; Male ; Female ; *Mice, Transgenic ; *Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics/metabolism ; Middle Aged ; Aged ; Axons/metabolism ; Disease Models, Animal ; Potassium Channels/metabolism/genetics ; Adult ; }, abstract = {The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is based mainly on clinical presentations, and the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NETs) to investigate axonal membrane properties and chemical precipitation, followed by ELISA analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-voltage threshold curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the current-voltage threshold curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72 or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely to be associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the current-voltage threshold curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partly prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes to familial ALS patients and ALS mice with mutant SOD1, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the current-voltage threshold curve was attributable to an elevation in the HCN current in SOD1-associated ALS.}, } @article {pmid39088455, year = {2024}, author = {Bonthron, C and Burley, S and Broadhead, MJ and Metodieva, V and Grant, SGN and Chandran, S and Miles, GB}, title = {Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS.}, journal = {PloS one}, volume = {19}, number = {8}, pages = {e0306423}, pmid = {39088455}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology/metabolism/genetics ; Animals ; *Astrocytes/metabolism/pathology ; Mice ; *Disease Models, Animal ; *Coculture Techniques ; *Synapses/metabolism/physiology ; *Motor Neurons/metabolism/pathology/physiology ; *Spinal Cord/metabolism/pathology ; Humans ; Excitatory Postsynaptic Potentials ; Mice, Transgenic ; Cells, Cultured ; Synaptic Transmission ; }, abstract = {Hyperexcitability of motor neurons and spinal cord motor circuitry has been widely reported in the early stages of Amyotrophic Lateral Sclerosis (ALS). Changes in the relative amount of excitatory to inhibitory inputs onto a neuron (E:I synaptic ratio), possibly through a developmental shift in synapse formation in favour of excitatory transmission, could underlie pathological hyperexcitability. Given that astrocytes play a major role in early synaptogenesis and are implicated in ALS pathogenesis, their potential contribution to disease mechanisms involving synaptic imbalances and subsequent hyperexcitability is also of great interest. In order to assess E:I ratios in ALS, we utilised a novel primary spinal neuron / astrocyte co-culture system, derived from neonatal mice, in which synapses are formed in vitro. Using multiple ALS mouse models we found that no combination of astrocyte or neuron genotype produced alterations in E:I synaptic ratios assessed using pre- and post-synaptic anatomical markers. Similarly, we observed that ephrin-B1, a major contact-dependent astrocytic synaptogenic protein, was not differentially expressed by ALS primary astrocytes. Further to this, analysis of E:I ratios across the entire grey matter of the lumbar spinal cord in young (post-natal day 16-19) ALS mice revealed no differences versus controls. Finally, analysis in co-cultures of human iPSC-derived motor neurons and astrocytes harbouring the pathogenic C9orf72 hexanucleotide repeat expansion showed no evidence of a bias toward excitatory versus inhibitory synapse formation. We therefore conclude, utilising multiple ALS models, that we do not observe significant changes in the relative abundance of excitatory versus inhibitory synapses as would be expected if imbalances in synaptic inputs contribute to early hyperexcitability.}, } @article {pmid39091098, year = {2025}, author = {Annetta, MG and Barbato, G and Pisciaroli, E and Marche, B and Sabatelli, M and Pittiruti, M}, title = {Central venous catheter-related thrombosis in patients with amyotrophic lateral sclerosis.}, journal = {The journal of vascular access}, volume = {26}, number = {4}, pages = {1180-1186}, doi = {10.1177/11297298241262821}, pmid = {39091098}, issn = {1724-6032}, mesh = {Humans ; Retrospective Studies ; *Catheterization, Central Venous/adverse effects/instrumentation ; Male ; Female ; Middle Aged ; Risk Factors ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/complications ; *Central Venous Catheters ; *Catheterization, Peripheral/adverse effects/instrumentation ; Quadriplegia/diagnosis ; Time Factors ; Adult ; Paraplegia/diagnosis/complications ; *Upper Extremity Deep Vein Thrombosis/etiology/prevention & control/diagnostic imaging ; Risk Assessment ; Treatment Outcome ; Catheters, Indwelling ; }, abstract = {BACKGROUND: Central venous catheterization may be required in patients with amyotrophic lateral sclerosis (ALS) for parenteral nutrition, antibiotic treatment, or blood sampling. Different venous access devices can be taken into consideration-centrally inserted central catheters (CICC), peripherally inserted central catheters (PICC), and femorally inserted central catheters (FICCs)-depending on the clinical conditions of the patients. Regardless of the type of access, the presence of paraplegia or tetraplegia is commonly considered a risk factor for catheter-related thrombosis (CRT).

METHOD: This retrospective study analyzes the rate of CRT and other non-infectious complications associated with central venous access in a cohort of 115 patients with paraplegia or tetraplegia, most of them affected by ALS (n = 109).

RESULTS: In a period of 34 months, from January 2021 to October 2023, we inserted 75 FICCs, 29 CICCs, and 11 PICCs. PICCs were inserted only in patients with preserved motility of the upper limbs. All devices were inserted by trained operators adopting appropriate insertion bundles. We had no immediate or early complication. Though antithrombotic prophylaxis was adopted only in 61.7% of patients, we had no symptomatic CRT. Other non-infectious complications were infrequent (4 out of 115 patients).

CONCLUSION: These results suggest (a) that the presence of paraplegia or tetraplegia is not necessarily associated with an increased risk of CRT, (b) that the adoption of well-designed insertion bundles plays a key role in minimizing non-infectious complications, and (c) that the insertion of FICCs by direct cannulation of the superficial femoral vein at mid-thigh in paraplegic/tetraplegic patients may have the same advantages which have been described in the general population.}, } @article {pmid39091255, year = {2024}, author = {Roggenbuck, J and Kaschalk, M and Eustace, R and Vicini, L and Gokun, Y and Harms, MB and Kolb, SJ}, title = {The Answer ALS return of results study: Answering the duty to disclose.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {743-750}, doi = {10.1080/21678421.2024.2385004}, pmid = {39091255}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/psychology ; Male ; Female ; Middle Aged ; *Genetic Testing/methods ; *Disclosure ; Aged ; Adult ; Prospective Studies ; }, abstract = {Objective: The Return of Answer ALS Results (RoAR) Study was designed to provide a mechanism for participants in Answer ALS, a large, prospectively designed natural history and biorepository study to receive select clinical genetic testing results and study participants' experience with the results disclosure. Methods: Participants consented to receive results of five ALS genes (C9orf72, SOD1, FUS, TARDP, TBK1) and/or 59 medically actionable genes as designated by the American College of Medical Genetics. Patient-reported genetic testing outcomes were measured via a post-disclosure survey. Results: Of 645 eligible Answer ALS enrollees, 143 (22%) enrolled and completed participation in RoAR. Pathogenic variants were identified in 22/143 (15.4%) participants, including 13/143 (9.0%) in ALS genes and 9/143 (6.3%) in ACMG genes. Participant-reported measures of result utility indicated the research result disclosure was as or more successful than published patient-reported outcomes of result disclosure the clinical setting. Conclusions: This study serves as a model of a "disclosure study" to share results from genomic research with participants who were not initially offered the option to receive results, and our findings can inform the design of future, large scale genomic projects to empower research participants to access their genetic information.}, } @article {pmid39091344, year = {2024}, author = {Goffin, L and Lemoine, D and Clotman, F}, title = {Potential contribution of spinal interneurons to the etiopathogenesis of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1434404}, pmid = {39091344}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) consists of a group of adult-onset fatal and incurable neurodegenerative disorders characterized by the progressive death of motor neurons (MNs) throughout the central nervous system (CNS). At first, ALS was considered to be an MN disease, caused by cell-autonomous mechanisms acting specifically in MNs. Accordingly, data from ALS patients and ALS animal models revealed alterations in excitability in multiple neuronal populations, including MNs, which were associated with a variety of cellular perturbations such as protein aggregation, ribonucleic acid (RNA) metabolism defects, calcium dyshomeostasis, modified electrophysiological properties, and autophagy malfunctions. However, experimental evidence rapidly demonstrated the involvement of other types of cells, including glial cells, in the etiopathogenesis of ALS through non-cell autonomous mechanisms. Surprisingly, the contribution of pre-motor interneurons (INs), which regulate MN activity and could therefore critically modulate their excitability at the onset or during the progression of the disease, has to date been severely underestimated. In this article, we review in detail how spinal pre-motor INs are affected in ALS and their possible involvement in the etiopathogenesis of the disease.}, } @article {pmid39091345, year = {2024}, author = {Hernández, CA and Peikert, K and Qiao, M and Darras, A and de Wilde, JRA and Bos, J and Leibowitz, M and Galea, I and Wagner, C and Rab, MAE and Walker, RH and Hermann, A and van Beers, EJ and van Wijk, R and Kaestner, L}, title = {Osmotic gradient ektacytometry - a novel diagnostic approach for neuroacanthocytosis syndromes.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1406969}, pmid = {39091345}, issn = {1662-4548}, abstract = {INTRODUCTION: The unique red blood cell (RBC) properties that characterize the rare neuroacanthocytosis syndromes (NAS) have prompted the exploration of osmotic gradient ektacytometry (Osmoscan) as a diagnostic tool for these disorders. In this exploratory study, we assessed if Osmoscans can discriminate NAS from other neurodegenerative diseases.

METHODS: A comprehensive assessment was conducted using Osmoscan on a diverse group of patients, including healthy controls (n = 9), neuroacanthocytosis syndrome patients (n = 6, 2 VPS13A and 4 XK disease), Parkinson's disease patients (n = 6), Huntington's disease patients (n = 5), and amyotrophic lateral sclerosis patients (n = 4). Concurrently, we collected and analyzed RBC indices and patients' characteristics.

RESULTS: Statistically significant changes were observed in NAS patients compared to healthy controls and other conditions, specifically in osmolality at minimal elongation index (Omin), maximal elongation index (EImax), the osmolality at half maximal elongation index in the hyperosmotic part of the curve (Ohyper), and the width of the curve close to the osmolality at maximal elongation index (Omax-width).

DISCUSSION: This study represents an initial exploration of RBC properties from NAS patients using osmotic gradient ektacytometry. While specific parameters exhibited differences, only Ohyper and Omax-width yielded 100% specificity for other neurodegenerative diseases. Moreover, unique correlations between Osmoscan parameters and RBC indices in NAS versus controls were identified, such as osmolality at maximal elongation index (Omax) vs. mean cellular hemoglobin content (MCH) and minimal elongation index (EImin) vs. red blood cell distribution width (RDW). Given the limited sample size, further studies are essential to establish diagnostic guidelines based on these findings.}, } @article {pmid39091724, year = {2024}, author = {Lv, G and Sayles, NM and Huang, Y and Mancinelli, CD and McAvoy, K and Shneider, NA and Manfredi, G and Kawamata, H and Eliezer, D}, title = {Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39091724}, issn = {2692-8205}, support = {P30 CA016087/CA/NCI NIH HHS/United States ; RF1 AG066493/AG/NIA NIH HHS/United States ; S10 OD028556/OD/NIH HHS/United States ; U01 NS134684/NS/NINDS NIH HHS/United States ; R35 NS122209/NS/NINDS NIH HHS/United States ; S10 OD016320/OD/NIH HHS/United States ; F31 HL154651/HL/NHLBI NIH HHS/United States ; F31 AG077836/AG/NIA NIH HHS/United States ; }, abstract = {CHCHD10 is mutated in rare cases of FTD and ALS and aggregates in mouse models of disease. Here we show that the disordered N-terminal domain of CHCHD10 forms amyloid fibrils and report their cryoEM structure. Disease-associated mutations cannot be accommodated by the WT fibril structure, while sequence differences between CHCHD10 and CHCHD2 are tolerated, explaining the co-aggregation of the two proteins and linking CHCHD10 and CHCHD2 amyloid fibrils to neurodegeneration.}, } @article {pmid39092466, year = {2024}, author = {Soubannier, V and Chaineau, M and Gursu, L and Lépine, S and Kalaydjian, D and Sirois, J and Haghi, G and Rouleau, G and Durcan, TM and Stifani, S}, title = {Early nuclear phenotypes and reactive transformation in human iPSC-derived astrocytes from ALS patients with SOD1 mutations.}, journal = {Glia}, volume = {72}, number = {11}, pages = {2079-2094}, doi = {10.1002/glia.24598}, pmid = {39092466}, issn = {1098-1136}, support = {//ALS Canada/Brain Canada Hudson Translational Team Grant/ ; //Canada First Research Excellence Fund/ ; //ALS Canada/Brain Canada Discovery Grant/ ; }, mesh = {Humans ; *Astrocytes/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Mutation ; *Phenotype ; Cells, Cultured ; Cell Nucleus/metabolism ; Motor Neurons/pathology/metabolism ; Oxidative Stress/physiology/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive death of motor neurons (MNs). Glial cells play roles in MN degeneration in ALS. More specifically, astrocytes with mutations in the ALS-associated gene Cu/Zn superoxide dismutase 1 (SOD1) promote MN death. The mechanisms by which SOD1-mutated astrocytes reduce MN survival are incompletely understood. To characterize the impact of SOD1 mutations on astrocyte physiology, we generated astrocytes from human induced pluripotent stem cell (iPSC) derived from ALS patients carrying SOD1 mutations, together with control isogenic iPSCs. We report that astrocytes harboring SOD1(A4V) and SOD1(D90A) mutations exhibit molecular and morphological changes indicative of reactive astrogliosis when compared to isogenic astrocytes. We show further that a number of nuclear phenotypes precede, or coincide with, reactive transformation. These include increased nuclear oxidative stress and DNA damage, and accumulation of the SOD1 protein in the nucleus. These findings reveal early cell-autonomous phenotypes in SOD1-mutated astrocytes that may contribute to the acquisition of a reactive phenotype involved in alterations of astrocyte-MN communication in ALS.}, } @article {pmid39094561, year = {2024}, author = {Gomes, C and Huang, KC and Harkin, J and Baker, A and Hughes, JM and Pan, Y and Tutrow, K and VanderWall, KB and Lavekar, SS and Hernandez, M and Cummins, TR and Canfield, SG and Meyer, JS}, title = {Induction of astrocyte reactivity promotes neurodegeneration in human pluripotent stem cell models.}, journal = {Stem cell reports}, volume = {19}, number = {8}, pages = {1122-1136}, pmid = {39094561}, issn = {2213-6711}, support = {R01 EY033022/EY/NEI NIH HHS/United States ; U24 EY033269/EY/NEI NIH HHS/United States ; R01 NS053422/NS/NINDS NIH HHS/United States ; UL1 TR002529/TR/NCATS NIH HHS/United States ; }, mesh = {*Astrocytes/metabolism ; Humans ; *Pluripotent Stem Cells/metabolism/cytology ; *Coculture Techniques ; Neurodegenerative Diseases/metabolism/pathology ; Complement C3/metabolism ; Cell Differentiation ; Neurons/metabolism ; Alzheimer Disease/pathology/metabolism ; Phagocytosis ; Blood-Brain Barrier/metabolism ; Glaucoma/pathology/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Calcium/metabolism ; Phenotype ; }, abstract = {Reactive astrocytes are known to exert detrimental effects upon neurons in several neurodegenerative diseases, yet our understanding of how astrocytes promote neurotoxicity remains incomplete, especially in human systems. In this study, we leveraged human pluripotent stem cell (hPSC) models to examine how reactivity alters astrocyte function and mediates neurodegeneration. hPSC-derived astrocytes were induced to a reactive phenotype, at which point they exhibited a hypertrophic profile and increased complement C3 expression. Functionally, reactive astrocytes displayed decreased intracellular calcium, elevated phagocytic capacity, and decreased contribution to the blood-brain barrier. Subsequently, co-culture of reactive astrocytes with a variety of neuronal cell types promoted morphological and functional alterations. Furthermore, when reactivity was induced in astrocytes from patient-specific hPSCs (glaucoma, Alzheimer's disease, and amyotrophic lateral sclerosis), the reactive state exacerbated astrocytic disease-associated phenotypes. These results demonstrate how reactive astrocytes modulate neurodegeneration, significantly contributing to our understanding of a role for reactive astrocytes in neurodegenerative diseases.}, } @article {pmid39095145, year = {2024}, author = {Sheers, NL and Andersen, T and Chatwin, M}, title = {Airway Clearance in Neuromuscular Disease.}, journal = {Sleep medicine clinics}, volume = {19}, number = {3}, pages = {485-496}, doi = {10.1016/j.jsmc.2024.04.009}, pmid = {39095145}, issn = {1556-4088}, mesh = {Humans ; *Neuromuscular Diseases/therapy/physiopathology ; Respiratory Therapy/methods ; Cough/therapy/physiopathology ; Airway Management/methods ; }, abstract = {High-quality respiratory care and airway clearance is essential for people with neuromuscular disease (pwNMD) as respiratory tract infections are a major cause of morbidity and mortality. This review expands on published guidelines by highlighting the role of cough peak flow along with other options for cough evaluation, and discusses recent key research findings which have influenced the practice of respiratory therapy for pwNMD.}, } @article {pmid39096043, year = {2024}, author = {Rabadi, MH and Russell, KA and Xu, C}, title = {Veterans with familial ALS and bulbar and respiratory presentations at onset had shorter survival.}, journal = {Science progress}, volume = {107}, number = {3}, pages = {368504241262902}, pmid = {39096043}, issn = {2047-7163}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology/genetics/diagnosis ; Middle Aged ; Male ; *Veterans/statistics & numerical data ; Female ; Aged ; Age of Onset ; Prognosis ; Kaplan-Meier Estimate ; }, abstract = {OBJECTIVE: We sought to characterize the clinical prognostic factors in veterans with amyotrophic lateral sclerosis (ALS) followed in our ALS clinic.

BACKGROUND: ALS is a rare, progressive neurodegenerative condition associated with decreased survival compared to that in the normal population.

METHOD: The electronic medical records of 105 veterans diagnosed with ALS who are followed in our ALS clinic between 2010 and 2021 were reviewed. Approval from the institutional review board was obtained from the study protocol. Demographic and clinical variables included age at symptom onset, age at initial evaluation, survival (from symptom onset to death), gender, site of onset (appendicular, bulbar, and respiratory), initial amyotrophic lateral sclerosis functional-related score-revised (ALSFRS-R), total functional independence measure (TFIM) scores, initial forced vital capacity (FVC), and interventions (Riluzole, gastrostomy, noninvasive ventilation [NIV], and tracheostomy). Normally distributed data was expressed as mean ± standard deviation. Fischer's exact analysis of the distribution differences of categorical data. The Kaplan-Meier plot analyzed the time-to-event.

RESULTS: The mean (SD) age at symptom onset was 62.0 (11.1) years, age at diagnosis was 65 (11) years, with 72% of the patients being over 60 years at diagnosis. The median survival time from symptom onset was 4.12 (3) years. Limb-onset ALS (appendicular) was the most frequent (52%) followed by bulbar-onset ALS (43%). The mean ALSFRS-R and TFIM scores were 31 (8) and 91 (25), respectively. Family history (familial), bulbar, and respiratory presentation at diagnosis were associated with shorter survival times.

CONCLUSION: This study suggests that of the clinical prognostic factors veterans with familial ALS, bulbar, and respiratory onset at presentations had shorter survival. The presence of Agent Orange, PEG placement, and NIV did not affect survival.}, } @article {pmid39096334, year = {2025}, author = {Paterson, M and Doeltgen, S and Francis, R}, title = {Sensory Changes Related to Swallowing in Motor Neurone Disease.}, journal = {Dysphagia}, volume = {40}, number = {2}, pages = {407-418}, pmid = {39096334}, issn = {1432-0460}, mesh = {Humans ; *Deglutition Disorders/physiopathology/etiology ; *Motor Neuron Disease/complications/physiopathology ; *Deglutition/physiology ; *Sensation Disorders/etiology/physiopathology ; *Sensation/physiology ; }, abstract = {Dysphagia is common in motor neurone disease (MND) and associated with negative health and psychosocial outcomes. Although largely considered a motor disease, a growing body of evidence suggests that MND can also affect the sensory system. As intact sensation is vital for safe swallowing, and sensory changes can influence the clinical management of dysphagia in people living with MND, this review evaluated and summarised the current evidence for sensory changes related to swallowing in MND. Of 3,481 articles originally identified, 29 met the inclusion criteria. Of these, 20 studies reported sensory changes, which included laryngeal sensation, taste, gag reflex, cough reflex, tongue sensation, smell, palatal and pharyngeal sensation, silent aspiration, and undefined sensation of the swallowing mechanism. Sensory changes were either described as decreased (n = 16) or heightened (n = 4). In the remaining nine studies, sensory function was reported as unaffected. The presence of changes to sensory function related to swallowing in MND remains inconclusive, although an increasing number of studies report sensory changes in some sensory domains. Future research is needed to evaluate the prevalence of sensory changes in MND and how such changes may influence dysphagia and its management.}, } @article {pmid39096593, year = {2024}, author = {Ozeloglu, IG and Akman Aydin, E}, title = {Combining features on vertical ground reaction force signal analysis for multiclass diagnosing neurodegenerative diseases.}, journal = {International journal of medical informatics}, volume = {191}, number = {}, pages = {105542}, doi = {10.1016/j.ijmedinf.2024.105542}, pmid = {39096593}, issn = {1872-8243}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; Male ; Female ; Middle Aged ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis ; Support Vector Machine ; Parkinson Disease/diagnosis ; Neural Networks, Computer ; Huntington Disease/diagnosis/physiopathology ; Signal Processing, Computer-Assisted ; Gait/physiology ; Algorithms ; }, abstract = {Neurodegenerative diseases (NDDs), which are caused by the degeneration of neurons and their functions, affect a significant part of the world's population. Although gait disorders are one of the critical and common markers to determine the presence of NDDs, diagnosing which NDD the patients have among a group of NDDs using gait data is still a significant challenge to be addressed. In this study, we addressed the multi-class classification of NDDs and aim to diagnose Parkinson's disease (PD), Amyotrophic lateral sclerosis disease (AD), and Huntington's disease (HD) from a group containing NDDs and healthy control subjects. We also examined the impact of disease-specific identified features derived from VGRF signals. Detrended Fluctuation Analysis (DFA), Dynamic Time Warping (DTW) and Autocorrelation (AC) were used for feature extraction on Vertical Ground Reaction Force (VGRF) signals. To compare the performance of the features, we employed Support Vector Machines, K-Nearest Neighbors, and Neural Networks as classifiers. In three-class problem addressing the classification of AD, PD and HD 93.3% accuracy rate was achieved, while in the four classes case, in which NDDs and HC groups were considered together, 93.5% accuracy rate was yielded. Considering the disease-specific impact of features, it is revealed that while DFA based features diagnose patients with AD with the highest accuracy, DTW has been shown to be more successful in diagnosing PD. AC based features provided the highest accuracy in diagnosing HD. Although gait disorder is common for NDDs, each disease may have its own distinctive gait rhythms; therefore, it is important to identify disease-specific patterns and parameters for the diagnosis of each disease. To increase the diagnostic accuracy, it is necessary to use a combination of features, which were effective for each disease diagnosis. Determining a limited number of disease-specific features would provide NDD diagnostic systems suitable to be deployed in edge-computing environments.}, } @article {pmid39097310, year = {2024}, author = {Christian, CS and Nkonki, L and Desmond, C and Hoegfeldt, C and Dube, S and Rochat, T and Stein, A}, title = {Protocol of a cost-effectiveness analysis of a combined intervention for depression and parenting compared with enhanced standard of care for perinatally depressed, HIV-positive women and their infants in rural South Africa.}, journal = {BMJ open}, volume = {14}, number = {8}, pages = {e082977}, pmid = {39097310}, issn = {2044-6055}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/P006965/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Female ; Humans ; Infant ; Infant, Newborn ; Pregnancy ; *Cost-Effectiveness Analysis/methods ; Depression/therapy ; Depression, Postpartum/therapy/economics ; *HIV Infections ; Parenting ; Randomized Controlled Trials as Topic ; Rural Population ; South Africa ; Standard of Care ; Research Design ; }, abstract = {INTRODUCTION: Poverty, HIV and perinatal depression represent a triple threat to public health in sub-Saharan Africa because of their combined negative effects on parenting and child development. In the resource-constrained context of low-income and middle-income countries, a lay-counsellor-delivered intervention that combines a psychological and parenting intervention could offer the potential to mitigate the consequences of perinatal depression while also optimising scarce resources for healthcare.Measuring the cost-effectiveness of such a novel intervention will help decision-makers to better understand the relative costs and effects associated with replicating the intervention, thereby supporting evidence-based decision-making. This protocol sets out the methodological framework for analysing the cost-effectiveness of a cluster randomised controlled trial (RCT) that compares a combined intervention to enhanced standard of care when treating depressed, HIV-positive pregnant women and their infants in rural South Africa.

METHODS AND ANALYSIS: This cost-effectiveness analysis (CEA) protocol complies with the Consolidated Health Economic Evaluation Reporting Standards 2022 checklist. A societal perspective will be chosen.The proposed methods will determine the cost and efficiency of implementing the intervention as per the randomised control trial protocol, as well as the cost of replicating the intervention in a non-research setting. The costs will be calculated using an appropriately adjusted version of the Standardised Early Childhood Development Costing Tool.Primary health outcomes will be used in combination with costs to determine the cost per improvement in maternal perinatal depression at 12 months postnatal and the cost per improvement in child cognitive development at 24 months of age. To facilitate priority setting, the incremental cost-effectiveness ratios for improvements in child cognitive development will be ranked against six other child cognitive-development interventions according to Verguet et al's methodology (2022).A combination of activity-based and ingredient-based costing approaches will be used to identify, measure and value activities and inputs for all alternatives. Outcomes data will be sourced from the RCT team.

ETHICS AND DISSEMINATION: The University of Oxford is the sponsor of the CEA. Ethics approval has been obtained from the Human Sciences Research Council (HSRC, #REC 5/23/08/17), South Africa and the Oxford Tropical Research Ethics Committee (OxTREC #31-17), UK.Consent for publication is not applicable since no participant data are used in this protocol.We plan to disseminate the CEA results to key policymakers and researchers in the form of a policy brief, meetings and academic papers.

TRIAL REGISTRATION DETAILS: ISRCTN registry #11 284 870 (14/11/2017) and SANCTR DOH-27-102020-9097 (17/11/2017).}, } @article {pmid39097602, year = {2024}, author = {Lehmann, J and Aly, A and Steffke, C and Fabbio, L and Mayer, V and Dikwella, N and Halablab, K and Roselli, F and Seiffert, S and Boeckers, TM and Brenner, D and Kabashi, E and Mulaw, M and Ho, R and Catanese, A}, title = {Heterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons.}, journal = {Cell death & disease}, volume = {15}, number = {8}, pages = {560}, pmid = {39097602}, issn = {2041-4889}, support = {SFB 1506-Project 01//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 2019_A111//Else Kröner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation)/ ; }, mesh = {Humans ; *Tumor Suppressor Protein p53/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Synaptotagmins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Heterozygote ; Phenotype ; Induced Pluripotent Stem Cells/metabolism/pathology ; Cell Differentiation/genetics ; Gene Knockout Techniques ; }, abstract = {Spinal motor neurons (MNs) represent a highly vulnerable cellular population, which is affected in fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we show that the heterozygous loss of SYT13 is sufficient to trigger a neurodegenerative phenotype resembling those observed in ALS and SMA. SYT13[+/-] hiPSC-derived MNs displayed a progressive manifestation of typical neurodegenerative hallmarks such as loss of synaptic contacts and accumulation of aberrant aggregates. Moreover, analysis of the SYT13[+/-] transcriptome revealed a significant impairment in biological mechanisms involved in motoneuron specification and spinal cord differentiation. This transcriptional portrait also strikingly correlated with ALS signatures, displaying a significant convergence toward the expression of pro-apoptotic and pro-inflammatory genes, which are controlled by the transcription factor TP53. Our data show for the first time that the heterozygous loss of a single member of the synaptotagmin family, SYT13, is sufficient to trigger a series of abnormal alterations leading to MN sufferance, thus revealing novel insights into the selective vulnerability of this cell population.}, } @article {pmid39097850, year = {2024}, author = {Luan, T and Li, Q and Huang, Z and Feng, Y and Xu, D and Zhou, Y and Hu, Y and Wang, T}, title = {Axonopathy Underlying Amyotrophic Lateral Sclerosis: Unraveling Complex Pathways and Therapeutic Insights.}, journal = {Neuroscience bulletin}, volume = {40}, number = {11}, pages = {1789-1810}, pmid = {39097850}, issn = {1995-8218}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/therapy ; Animals ; *Axons/pathology/metabolism ; Mitochondria/metabolism ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by progressive axonopathy, jointly leading to the dying back of the motor neuron, disrupting both nerve signaling and motor control. In this review, we highlight the roles of axonopathy in ALS progression, driven by the interplay of multiple factors including defective trafficking machinery, protein aggregation, and mitochondrial dysfunction. Dysfunctional intracellular transport, caused by disruptions in microtubules, molecular motors, and adaptors, has been identified as a key contributor to disease progression. Aberrant protein aggregation involving TDP-43, FUS, SOD1, and dipeptide repeat proteins further amplifies neuronal toxicity. Mitochondrial defects lead to ATP depletion, oxidative stress, and Ca[2+] imbalance, which are regarded as key factors underlying the loss of neuromuscular junctions and axonopathy. Mitigating these defects through interventions including neurotrophic treatments offers therapeutic potential. Collaborative research efforts aim to unravel ALS complexities, opening avenues for holistic interventions that target diverse pathological mechanisms.}, } @article {pmid39098187, year = {2024}, author = {R K Roy, A and Noohi, F and Morris, NA and Ljubenkov, P and Heuer, H and Fong, J and Hall, M and Lario Lago, A and Rankin, KP and Miller, BL and Boxer, AL and Rosen, HJ and Seeley, WW and Perry, DC and Yokoyama, JS and Lee, SE and Sturm, VE}, title = {Basal parasympathetic deficits in C9orf72 hexanucleotide repeat expansion carriers relate to smaller frontoinsula and thalamus volume and lower empathy.}, journal = {NeuroImage. Clinical}, volume = {43}, number = {}, pages = {103649}, pmid = {39098187}, issn = {2213-1582}, support = {R01 AG071756/AG/NIA NIH HHS/United States ; R01 AG058233/AG/NIA NIH HHS/United States ; R01 AG052496/AG/NIA NIH HHS/United States ; R01 AG062758/AG/NIA NIH HHS/United States ; R01 AG059794/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Middle Aged ; *C9orf72 Protein/genetics ; Aged ; *Empathy/physiology ; *Frontotemporal Dementia/genetics/physiopathology/pathology/diagnostic imaging ; *DNA Repeat Expansion/genetics ; *Magnetic Resonance Imaging/methods ; *Parasympathetic Nervous System/physiopathology ; *Thalamus/diagnostic imaging/physiopathology/pathology ; *Cognitive Dysfunction/physiopathology/genetics/diagnostic imaging/etiology/pathology ; Heterozygote ; Respiratory Sinus Arrhythmia/physiology ; Cerebral Cortex/diagnostic imaging/physiopathology/pathology ; }, abstract = {Diminished basal parasympathetic nervous system activity is a feature of frontotemporal dementia that relates to left frontoinsula dysfunction and empathy impairment. Individuals with a pathogenic expansion of the hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, provide a unique opportunity to examine whether parasympathetic activity is disrupted in genetic forms of frontotemporal dementia and to investigate when parasympathetic deficits manifest in the pathophysiological cascade. We measured baseline respiratory sinus arrhythmia, a parasympathetic measure of heart rate variability, over two minutes in a sample of 102 participants that included 19 asymptomatic expansion carriers (C9[+] asymp), 14 expansion carriers with mild cognitive impairment (C9[+] MCI), 16 symptomatic expansion carriers with frontotemporal dementia (C9[+] FTD), and 53 expansion-negative healthy controls (C9[-] HC) who also underwent structural magnetic resonance imaging. In follow-up analyses, we compared baseline respiratory sinus arrhythmia in the C9[+] FTD group with an independent age-, sex-, and clinical severity-matched group of 26 people with sporadic behavioral variant frontotemporal dementia. The Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating-Sum of Boxes score was used to quantify behavioral symptom severity, and informant ratings on the Interpersonal Reactivity Index provided measures of participants' current emotional (empathic concern) and cognitive (perspective-taking) empathy. Results indicated that the C9[+] FTD group had lower baseline respiratory sinus arrhythmia than the C9[+] MCI, C9[+] asymp, and C9[-] HC groups, a deficit that was comparable to that of sporadic behavioral variant frontotemporal dementia. Linear regression analyses indicated that lower baseline respiratory sinus arrhythmia was associated with worse behavioral symptom severity and lower empathic concern and perspective-taking across the C9orf72 expansion carrier clinical spectrum. Whole-brain voxel-based morphometry analyses in participants with C9orf72 pathogenic expansions found that lower baseline respiratory sinus arrhythmia correlated with smaller gray matter volume in the left frontoinsula and bilateral thalamus, key structures that support parasympathetic function, and in the bilateral parietal lobes, occipital lobes, and cerebellum, regions that are also vulnerable in individuals with C9orf72 expansions. This study provides novel evidence that basal parasympathetic functioning is diminished in FTD due to C9orf72 expansions and suggests that baseline respiratory sinus arrhythmia may be a potential non-invasive biomarker that is sensitive to behavioral symptoms in the early stages of disease.}, } @article {pmid39098618, year = {2024}, author = {Koehn, LM and Jalaldeen, R and Pelle, J and Nicolazzo, JA}, title = {Plasma, brain and spinal cord concentrations of caffeine are reduced in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis following oral administration.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {203}, number = {}, pages = {114434}, doi = {10.1016/j.ejpb.2024.114434}, pmid = {39098618}, issn = {1873-3441}, mesh = {Animals ; *Caffeine/administration & dosage/pharmacokinetics ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Spinal Cord/metabolism/drug effects ; Male ; Female ; Mice ; Administration, Oral ; *Brain/metabolism/drug effects ; *Disease Models, Animal ; *Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Digoxin/pharmacokinetics/administration & dosage ; Sulfasalazine/pharmacokinetics/administration & dosage ; Intestinal Absorption/drug effects/physiology ; }, abstract = {Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114-120 male and female SOD1[G93A] mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of 70 kDa fluorescein isothiocyanate-dextran (FITC-dextran) and the ex vivo intestinal permeability of caffeine were assessed. The area under the plasma concentration-time curves (AUCplasma) of digoxin and sulfasalazine were not significantly different between SOD1[G93A] and WT mice for both sexes. However, the AUCplasma of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1[G93A] compared to WT mice, which was associated with lower AUCbrain (female: 0.76-fold, male: 0.80-fold) and AUCspinal cord (female: 0.81-fold, male: 0.82-fold). The AUCstomach of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1[G93A] compared to WT mice, suggesting reduced gastric emptying in SOD1[G93A] mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and ex vivo intestinal permeability of caffeine (0.52-fold) in male SOD1[G93A] compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1[G93A] mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range.}, } @article {pmid39098767, year = {2025}, author = {Endo, F}, title = {Deciphering the spectrum of astrocyte diversity: Insights into molecular, morphological, and functional dimensions in health and neurodegenerative diseases.}, journal = {Neuroscience research}, volume = {210}, number = {}, pages = {1-10}, doi = {10.1016/j.neures.2024.07.008}, pmid = {39098767}, issn = {1872-8111}, mesh = {Humans ; *Astrocytes/pathology/physiology/metabolism ; *Neurodegenerative Diseases/pathology/metabolism/physiopathology ; Animals ; }, abstract = {Astrocytes are the most abundant and morphologically complex glial cells that play active roles in the central nervous system (CNS). Recent research has identified shared and region-specific astrocytic genes and functions, elucidated the cellular origins of their regional diversity, and uncovered the molecular networks for astrocyte morphology, which are essential for their functional complexity. Reactive astrocytes exhibit a wide range of functional diversity in a context-specific manner in CNS disorders. This review discusses recent advances in understanding the molecular and morphological diversity of astrocytes in healthy individuals and those with neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis.}, } @article {pmid39099169, year = {2024}, author = {Wang, J and Qiu, Y and Yang, L and Wang, J and He, J and Tang, C and Yang, Z and Hong, W and Yang, B and He, Q and Weng, Q}, title = {Preserving mitochondrial homeostasis protects against drug-induced liver injury via inducing OPTN (optineurin)-dependent Mitophagy.}, journal = {Autophagy}, volume = {20}, number = {12}, pages = {2677-2696}, pmid = {39099169}, issn = {1554-8635}, mesh = {*Mitophagy/drug effects/physiology ; *Homeostasis/drug effects ; *Membrane Transport Proteins/metabolism ; Animals ; *Cell Cycle Proteins/metabolism ; Humans ; *Valosin Containing Protein/metabolism ; *Chemical and Drug Induced Liver Injury/metabolism ; *Hepatocytes/metabolism/drug effects ; Mitochondria/metabolism/drug effects ; Mice ; Transcription Factor TFIIIA/metabolism/genetics ; Mice, Inbred C57BL ; Beclin-1/metabolism ; Mitochondria, Liver/metabolism/drug effects ; }, abstract = {Disruption of mitochondrial function is observed in multiple drug-induced liver injuries (DILIs), a significant global health threat. However, how the mitochondrial dysfunction occurs and whether maintain mitochondrial homeostasis is beneficial for DILIs remains unclear. Here, we show that defective mitophagy by OPTN (optineurin) ablation causes disrupted mitochondrial homeostasis and aggravates hepatocytes necrosis in DILIs, while OPTN overexpression protects against DILI depending on its mitophagic function. Notably, mass spectrometry analysis identifies a new mitochondrial substrate, GCDH (glutaryl-CoA dehydrogenase), which can be selectively recruited by OPTN for mitophagic degradation, and a new cofactor, VCP (valosin containing protein) that interacts with OPTN to stabilize BECN1 during phagophore assembly, thus boosting OPTN-mediated mitophagy initiation to clear damaged mitochondria and preserve mitochondrial homeostasis in DILIs. Then, the accumulation of OPTN in different DILIs is further validated with a protective effect, and pyridoxine is screened and established to alleviate DILIs by inducing OPTN-mediated mitophagy. Collectively, our findings uncover a dual role of OPTN in mitophagy initiation and implicate the preservation of mitochondrial homeostasis via inducing OPTN-mediated mitophagy as a potential therapeutic approach for DILIs.Abbreviation: AILI: acetaminophen-induced liver injury; ALS: amyotrophic lateral sclerosis; APAP: acetaminophen; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DILI: drug-induced liver injury; FL: full length; GCDH: glutaryl-CoA dehydrogenase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GO: gene ontology; GSEA: gene set enrichment analysis; GPT/ALT: glutamic - pyruvic transaminase; INH: isoniazid; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MST: microscale thermophoresis; MT-CO2/COX-II: mitochondrially encoded cytochrome c oxidase II; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TSN: toosendanin; VCP: valosin containing protein, WIPI2: WD repeat domain, phosphoinositide interacting 2.}, } @article {pmid39099373, year = {2024}, author = {Serangeli, I and Diamanti, T and De Jaco, A and Miranda, E}, title = {Role of mitochondria-endoplasmic reticulum contacts in neurodegenerative, neurodevelopmental and neuropsychiatric conditions.}, journal = {The European journal of neuroscience}, volume = {60}, number = {5}, pages = {5040-5068}, doi = {10.1111/ejn.16485}, pmid = {39099373}, issn = {1460-9568}, support = {//Sapienza Università di Roma/ ; //Sapienza University of Rome/ ; }, mesh = {Humans ; *Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Endoplasmic Reticulum/metabolism ; Animals ; *Neurodevelopmental Disorders/metabolism ; *Mental Disorders/metabolism/physiopathology ; Mitochondria Associated Membranes ; }, abstract = {Mitochondria-endoplasmic reticulum contacts (MERCs) mediate a close and continuous communication between both organelles that is essential for the transfer of calcium and lipids to mitochondria, necessary for cellular signalling and metabolic pathways. Their structural and molecular characterisation has shown the involvement of many proteins that bridge the membranes of the two organelles and maintain the structural stability and function of these contacts. The crosstalk between the two organelles is fundamental for proper neuronal function and is now recognised as a component of many neurological disorders. In fact, an increasing proportion of MERC proteins take part in the molecular and cellular basis of pathologies affecting the nervous system. Here we review the alterations in MERCs that have been reported for these pathologies, from neurodevelopmental and neuropsychiatric disorders to neurodegenerative diseases. Although mitochondrial abnormalities in these debilitating conditions have been extensively attributed to the high energy demand of neurons, a distinct role for MERCs is emerging as a new field of research. Understanding the molecular details of such alterations may open the way to new paths of therapeutic intervention.}, } @article {pmid39100390, year = {2024}, author = {Johnson, G and Tabner, A and Tilbury, N and Wesson, A and Hughes, GD and Elder, R and Bryson, P}, title = {Development of an algorithm to guide management of cardiorespiratory arrest in a diving bell.}, journal = {Resuscitation plus}, volume = {19}, number = {}, pages = {100724}, pmid = {39100390}, issn = {2666-5204}, abstract = {AIM: The management of cardiorespiratory arrest in a diving bell presents multiple clinical, technical, and environmental considerations that standard resuscitation algorithms do not address, and no situation-specific algorithm exists. The development and testing of an algorithm to guide the management of cardiorespiratory arrest in a bell is described.

METHODS: An iterative approach to algorithm development was used. Phase 1 involved a small multidisciplinary group and took place in a simulation centre and a decommissioned diving bell. The algorithm was then refined in a purpose-build simulation complex with repeated simulation by a group of divers, and with input from industry experts. ALS principles were followed unless contextual or technical factors necessitated deviation.

RESULTS: Clinical and technical aspects of the resuscitation are addressed. Key priorities that conflict with standard ALS principles are: prioritisation of rescue breaths; use of mechanical CPR when available; and the provision of CPR with the casualty in a seated position where necessary.

CONCLUSION: This is the first algorithm to guide the delivery of resuscitation in a diving bell. It incorporates adapted ALS principles and available data concerning compression technique effectiveness, and was informed by industry and clinical expertise. It provides guiding principles that can be adapted to setting-specific needs, and we would encourage its industry-wide international adoption.}, } @article {pmid39101354, year = {2024}, author = {Faleco, FA and Machado, FM and Bobadilla, LK and Tranel, PJ and Stoltenberg, D and Werle, R}, title = {Resistance to protoporphyrinogen oxidase inhibitors in giant ragweed (Ambrosia trifida).}, journal = {Pest management science}, volume = {80}, number = {12}, pages = {6211-6221}, doi = {10.1002/ps.8349}, pmid = {39101354}, issn = {1526-4998}, mesh = {*Protoporphyrinogen Oxidase/genetics/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Ambrosia ; Plant Weeds/drug effects/genetics/enzymology ; Plant Proteins/genetics/metabolism ; Acetolactate Synthase/genetics/antagonists & inhibitors ; Enzyme Inhibitors/pharmacology ; Weed Control ; }, abstract = {BACKGROUND: Giant ragweed (Ambrosia trifida L.) is one of the most troublesome weed species in corn (Zea mays L.) and soybean [Glycine max (L.) Merr.] cropping systems. Following numerous reports in 2018 of suspected herbicide resistance in several Ambrosia trifida populations from Wisconsin, our objective was to characterize the response of these accessions to acetolactate synthase (ALS), enolpyruvyl shikimate phosphate synthase (EPSPS), and protoporphyrinogen oxidase (PPO) inhibitors applied POST.

RESULTS: Four accessions (AT1, AT4, AT6, and AT10) exhibited ≥ 50% plant survival after exposure to the cloransulam 3× rate. Two accessions (AT8 and AT10) and one accession (AT2) exhibited ≥ 50% plant survival after exposure to glyphosate and fomesafen 1× rates, respectively. The AT10 accession exhibited multiple resistance to cloransulam and glyphosate. The AT12 accession was 28.8-fold resistant to fomesafen and 3.7-fold resistant to lactofen. A codon change in PPX2 conferring a R98L substitution was identified as the most likely mechanism conferring PPO-inhibitor resistance.

CONCLUSION: To our knowledge, this is the first confirmed case of PPO-inhibitor resistance in Ambrosia trifida globally and we identified the genetic mutation likely conferring resistance. Proactive and diversified integrated weed management strategies are of paramount importance for sustainable long-term Ambrosia trifida management. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid39101689, year = {2024}, author = {Simão, S and Oliveira Santos, M and Gromicho, M and Pavão Martins, I and De Carvalho, M}, title = {Cognitive reserve as a modulator of cognitive decline and of behavioral symptoms in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {726-736}, doi = {10.1080/21678421.2024.2385684}, pmid = {39101689}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology/complications/physiopathology ; Male ; Female ; *Cognitive Reserve/physiology ; Middle Aged ; *Cognitive Dysfunction/etiology/genetics/physiopathology/psychology ; Aged ; Neuropsychological Tests ; Behavioral Symptoms/etiology ; C9orf72 Protein/genetics ; Prospective Studies ; Adult ; Executive Function/physiology ; }, abstract = {Introduction: Amyotrophic lateral sclerosis (ALS) has heterogeneous manifestations ranging from motor neuron degeneration to cognitive and behavioral impairment. This study aims to clarify the interactions between cognition and behavioral symptoms with relevant disease predictors and with cognitive reserve (CR), quantified through education, physical activity, and occupation proxies. Methods: A prospective sample of 162 ALS patients and 61 controls were evaluated with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) (dependent variable), a Cognitive Reserve Index questionnaire (CRIq) and demographic data (age and sex), and, for patients, clinical variables: disease duration, site of onset, the ALS Functional Rating Scale (ALSFRS), forced vital capacity (FVC), and gene mutation chromosome 9 open reading frame 72 (C9orf72) (independent variables). Multiple regression and mediation analyses were performed to predict cognitive and behavioral symptoms. Results: For the ALS group, the statistical model explained 38.8% of variance in ECAS total (p < 0.001), 59.4% of executive functions (p < 0.001), and 55% of behavioral symptoms (p < 0.001). For controls, it accounted for 52.8% of variance in ECAS total (p < 0.001). Interaction effects and mediation analysis showed CR is an ECAS total modulator, with a differential effect within groups (p < 0.001). Verbal fluency was the single best cognitive score to differentiate patients from controls (p = 0.004), and the gene mutation C9orf72 was found to be a behavioral symptom' predictor in patients (p = 0.009). Conclusion: This study supports the proposed concept that CR acts as a cognitive modulator in ALS patients and healthy individuals. Moreover, CR also modulates behavioral manifestations in ALS.}, } @article {pmid39102937, year = {2024}, author = {Ali, F and Tang, Z and Mo, G and Zhang, B and Ling, X and Qiu, Z}, title = {Taxonomic and functional changes in wheat rhizosphere microbiome caused by imidazoline-based herbicide and genetic modification.}, journal = {Environmental research}, volume = {262}, number = {Pt 2}, pages = {119726}, doi = {10.1016/j.envres.2024.119726}, pmid = {39102937}, issn = {1096-0953}, mesh = {*Triticum/microbiology/genetics ; *Rhizosphere ; *Herbicides/toxicity ; *Microbiota/drug effects ; Soil Microbiology ; Plants, Genetically Modified/microbiology ; Imidazolines ; Imidazoles/toxicity ; Acetolactate Synthase/genetics ; Soil Pollutants/toxicity ; Bacteria/drug effects/genetics/classification ; }, abstract = {Genetically modified (GM) crop cultivation has received a lot of attention in recent years due to the substantial public debate. Consequently, an in-depth investigation of excessively used GM herbicide-tolerant crops is a vital step for the biosafety of genetically modified plants. Several studies have been conducted to study the impact of transgenic GM crops on soil microbial composition; however, research into the effects of non-transgenic GM crops is inadequate. In the current work, high-throughput sequencing was used to evaluate the impact of the acetolactate synthase (ALS)-mutant (WK170B), its control (YN19B), and the imazamox (IM) herbicide on the wheat rhizobiome. Under normal growth conditions, our work revealed a minimal impact of ALS-mutant WK170B on the rhizosphere microbiome compared to the control YN10B, except for some cyanobacterial microorganisms that showed a significant increase in abundance. This suggests that the gene mutation could potentially have a beneficial impact on the bacterial communities present in the rhizosphere. Following IM exposure, taxonomic analysis revealed a significant reduction in the relative abundance of Ralstonia pickettii and an unidentified member of the genus Ancylothrix 8 PC. Analyses of both alpha and beta diversity revealed a statistically significant increase in both microbial richness and species diversity. IM-induced relative abundance modulation was also evident through Linear discriminant analysis Effect Size (LEfSe), MetaStat, and heatmap analyses. The SIMPER analysis revealed that the microbial taxa Massilia, Limnobacter, Hydrogenophaga, Ralstonia, Nitrospira, and Ramlibacter exhibited the highest vulnerability to IM exposure. The functional attributes analysis revealed that the relative abundance of genes associated with the extracellular matrix-receptor interaction, which is responsible for structural support and stress response, increased significantly following IM exposure. Collectively, our study identifies key microbial taxa in the wheat rhizobiome that are sensitive to IM herbicides and provides a foundation for assessing the environmental risks associated with IM herbicide use.}, } @article {pmid39103493, year = {2024}, author = {Talaia, G and Bentley-DeSousa, A and Ferguson, SM}, title = {Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition.}, journal = {The EMBO journal}, volume = {43}, number = {18}, pages = {3948-3967}, pmid = {39103493}, issn = {1460-2075}, support = {R01 GM105718/GM/NIGMS NIH HHS/United States ; ASAP-000580//Michael J. Fox Foundation for Parkinson's Research (MJFF)/ ; ASAP-000580//Aligning Science Across Parkinson's (ASAP)/ ; GM105718//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {Humans ; *Amino Acids/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Frontotemporal Dementia/metabolism/genetics/pathology ; HEK293 Cells ; *Lysosomes/metabolism ; *Mechanistic Target of Rapamycin Complex 1/metabolism/genetics ; Phosphorylation ; *Protein Serine-Threonine Kinases/metabolism/genetics ; rab GTP-Binding Proteins/metabolism/genetics ; *rab7 GTP-Binding Proteins ; Signal Transduction ; }, abstract = {Lysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. This lysosomal TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD.}, } @article {pmid39103661, year = {2024}, author = {Tomasicchio, G and Martines, G and Tartaglia, N and Buonfantino, M and Restini, E and Carlucci, B and Giove, C and Dezi, A and Ranieri, C and Logrieco, G and Vincenti, L and Ambrosi, A and Altomare, DF and De Fazio, M and Picciariello, A}, title = {Suture reinforcement using a modified cyanoacrylate glue to prevent anastomotic leak in colorectal surgery: a prospective multicentre randomized trial : The Rectal Anastomotic seaL (ReAL) trial.}, journal = {Techniques in coloproctology}, volume = {28}, number = {1}, pages = {95}, pmid = {39103661}, issn = {1128-045X}, mesh = {Humans ; *Anastomotic Leak/prevention & control/etiology ; Female ; Male ; Prospective Studies ; Aged ; Middle Aged ; *Cyanoacrylates/administration & dosage ; *Anastomosis, Surgical/adverse effects/methods ; *Rectum/surgery ; Tissue Adhesives/therapeutic use ; Suture Techniques ; Rectal Neoplasms/surgery ; Treatment Outcome ; }, abstract = {BACKGROUND: Anastomotic leakage (AL) is the most frequent life-threating complication following colorectal surgery. Several attempts have been made to prevent AL. This prospective, randomized, multicentre trial aimed to evaluate the safety and efficacy of nebulised modified cyanoacrylate in preventing AL after rectal surgery.

METHODS: Patients submitted to colorectal surgery for carcinoma of the high-medium rectum across five high-volume centres between June 2021 and January 2023 entered the study and were randomized into group A (anastomotic reinforcement with cyanoacrylate) and group B (no reinforcement) and followed up for 30 days. Anastomotic reinforcement was performed via nebulisation of 1 mL of a modified cyanoacrylate glue. Preoperative features and intraoperative and postoperative results were recorded and compared. The study was registered at ClinicalTrials.gov (ID number NCT03941938).

RESULTS: Out of 152 patients, 133 (control group, n = 72; cyanoacrylate group, n = 61) completed the follow-up. ALs were detected in nine patients (12.5%) in the control group (four grade B and five grade C) and in four patients (6.6%), in the cyanoacrylate group (three grade B and one grade C); however, despite this trend, the differences were not statistically significant (p = 0.36). However, Clavien-Dindo complications grade > 2 were significantly higher in the control group (12.5% vs. 3.3%, p = 0.04). No adverse effects related to the glue application were reported.

CONCLUSION: The role of modified cyanoacrylate application in AL prevention remains unclear. However its use to seal colorectal anastomoses is safe and could help to reduce severe postoperative complications.}, } @article {pmid39104446, year = {2024}, author = {Higgins, S and Dlamini, S and Hattingh, M and Rambharose, S and Theron, E and Stassen, W}, title = {Views and perceptions of advanced life support practitioners on initiating, withholding and terminating resuscitation in out-of-hospital cardiac arrest in the Emergency Medical Services of South Africa.}, journal = {Resuscitation plus}, volume = {19}, number = {}, pages = {100709}, pmid = {39104446}, issn = {2666-5204}, abstract = {INTRODUCTION: This study aimed to explore the views and perceptions of Advanced Life Support (ALS) practitioners in two South African provinces on initiating, withholding, and terminating resuscitation in OHCA.

METHODOLOGY: Semi-structured one-on-one interviews were conducted with operational ALS practitioners working within the prehospital setting in the Western Cape and Free State provinces. Recorded interviews were transcribed and subjected to inductive-dominant, manifest content analysis. After familiarisation with the data, meaning units were condensed, codes were applied and collated into categories that were then assessed, reviewed, and refined repeatedly.

RESULTS: A total of 18 ALS providers were interviewed. Five main categories were developed from the data analysis: 1) assessment of prognosis, 2) internal factors affecting decision-making, 3) external factors affecting decision-making, 4) system challenges, and 5) ideas for improvement. Factors influencing the assessment of prognosis were history, clinical presentation, and response to resuscitation. Internal factors affecting decision-making were driven by emotion and contemplation. External factors affecting decision-making included family, safety, and disposition. System challenges relating to bystander response and resources were identified. Ideas for improvement in training and support were brought forward.

CONCLUSION: Many factors influence OHCA decision-making in the Western Cape and Free State provinces, and numerous system challenges have been identified. The findings of this study can be used as a frame of reference for prehospital emergency care personnel and contribute to the development of context-specific guidelines.}, } @article {pmid39104562, year = {2024}, author = {Haikal, A and Ali, AR}, title = {Chemical composition and toxicity studies on Lantana camara L. flower essential oil and its in silico binding and pharmacokinetics to superoxide dismutase 1 for amyotrophic lateral sclerosis (ALS) therapy.}, journal = {RSC advances}, volume = {14}, number = {33}, pages = {24250-24264}, pmid = {39104562}, issn = {2046-2069}, abstract = {Using the gas chromatography mass spectrometry method, the chemical components of essential oil from flowers of Lantana camara growing in Egypt are analyzed. Through this investigation, 22 chemicals from floral oil were identified. Most of the oil is made up of sesquiterpene caryophyllene (15.51%) and monoterpene sabinene (14.90%). When the oil's composition was compared to oils extracted from the same plant on several continents, we observed that the essential components were largely the same with some difference in proportions and some compounds due to geographical differences. A molecular docking study of essential oil components was conducted with human superoxide dismutase 1, a target involved in the pathophysiology of amyotrophic lateral sclerosis (ALS). Isospathulenol showed a comparable docking score to the reference ligand bound to the dismutase enzyme. Isospathulenol showed a reasonable drug score with some safety concerns. In addition, isospathulenol is predicted to have high GI absorption, good permeability through the blood-brain barrier and reasonable bioavailability score with ease access to synthetic modifications. In addition, the same compound is devoid from any violation to Lipinski rules or any PAINS alerts. This may establish the promising characteristics of such a compound to be optimized into potential drug candidates for treatment of ALS.}, } @article {pmid39104673, year = {2024}, author = {Rezvani, S and Hosseini-Zahraei, SH and Tootchi, A and Guger, C and Chaibakhsh, Y and Saberi, A and Chaibakhsh, A}, title = {A review on the performance of brain-computer interface systems used for patients with locked-in and completely locked-in syndrome.}, journal = {Cognitive neurodynamics}, volume = {18}, number = {4}, pages = {1419-1443}, pmid = {39104673}, issn = {1871-4080}, abstract = {Patients with locked-in syndrome (LIS) and complete locked-in syndrome (CLIS) own a fully functional brain restricted within a non-functional body. In order to help LIS patients stay connected with their surroundings, brain-computer interfaces (BCIs) and related technologies have emerged. BCIs translate brain activity into actions that can be performed by external devices enabling LIS patients to communicate, leading to an increase in their quality of life. The past decade has seen the rapid development of BCIs that have the potential to be used for patients with locked-in syndrome, from which a great deal is tested only on healthy subjects and not on actual patients. This study aims to (1) provide the readers with a comprehensive study that contributes to this growing area of research by exploring the performance of BCIs tested specifically on LIS and CLIS patients, (2) give an overview of different modalities and paradigms used in different stages of the locked-in syndrome, and (3) discuss the contributions and limitations of BCIs introduced for the LIS and CLIS patients in the state-of-the-art and lay a groundwork for researchers interested in this field.}, } @article {pmid39105912, year = {2024}, author = {Andrysiak, K and Stępniewski, J and Spaczyńska-Boczar, M and Łapicka-Bodzioch, K and Słowik, A and Dulak, J}, title = {Generation of Human-Induced Pluripotent Stem Cells from Peripheral Blood Mononuclear Cells of C9ORF72-Associated Amyotrophic Lateral Sclerosis Patients.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2835}, number = {}, pages = {135-146}, pmid = {39105912}, issn = {1940-6029}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics/metabolism ; Cell Culture Techniques/methods ; *Cell Differentiation ; Cellular Reprogramming ; DNA Repeat Expansion ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Leukocytes, Mononuclear/metabolism ; }, abstract = {Disease modeling of neuromuscular disorders, such as amyotrophic lateral sclerosis (ALS), is hindered by limited accessibility of affected cells. This problem can be overcome by generation of human induced pluripotent stem cells (hiPSC), which can be then differentiated into required cells. Here, we describe the detailed protocol of hiPSC establishment from peripheral blood mononuclear cells (PBMC) of two ALS patients with detected expansion of G4C2 (GGGGCC) repeats in the first intron of C9ORF72 gene, known to be linked with the most common form of familial ALS.Successful PBMC reprogramming with non-integrating Sendai vectors was confirmed by expression of pluripotency markers: OCT4, NANOG, SSEA4, and TRA-1-60 in obtained hiPSC and their ability to differentiate into cells of three germ layers.The generated ALS-patient-specific hiPSC create a possibility for deciphering molecular basis of this devastating neuromuscular disease.}, } @article {pmid39106020, year = {2024}, author = {Mirmotahari, SA and Aliomrani, M and Hassanzadeh, F and Sirous, H and Rostami, M}, title = {Hybrid derivatives containing dimethyl fumarate and benzothiazole scaffolds for the potential treatment of multiple sclerosis; in silico & in vivo study.}, journal = {Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences}, volume = {32}, number = {2}, pages = {599-615}, pmid = {39106020}, issn = {2008-2231}, mesh = {*Dimethyl Fumarate/pharmacology/chemistry ; *Multiple Sclerosis/drug therapy ; Animals ; *Molecular Docking Simulation ; *Benzothiazoles/chemistry/pharmacology ; *Riluzole/pharmacology/chemistry ; Mice ; *Mice, Inbred C57BL ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; Male ; Cuprizone ; Disease Models, Animal ; Computer Simulation ; Neuroprotective Agents/pharmacology/chemistry ; Remyelination/drug effects ; }, abstract = {BACKGROUND: Multiple Sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the CNS. Riluzole and dimethyl fumarate (DMF) are two FDA-approved drugs to treat amyotrophic lateral sclerosis (ALS) and MS. Riluzole (a benzothiazole derivative) inhibits glutamate release from nerve terminals by antagonizing the N-Methyl-D-Aspartate (NMDA) receptor, and DMF upregulates anti-oxidative pathways.

OBJECTIVES: Herein, using molecular hybridization strategy, we synthesized some new hybrid structures of Riluzole and DMF through some common successive synthetic pathways for evaluating their potential activity for remyelination in MS treatment.

METHODS: Molecular docking experiments assessed the binding affinity of proposed structures to the NMDA active site. The designed structures were synthesized and purified based on well-known chemical synthesis procedures. Afterward, in vivo evaluation for their activity was done in the C57Bl/6 Cuprizone-induced demyelination MS model.

RESULTS AND CONCLUSION: The proposed derivatives were recognized to be potent enough based on docking studies (ΔGbind of all derivatives were -7.2 to -7.52 compare to the Ifenprodil (-6.98) and Riluzole (-4.42)). The correct structures of desired derivatives were confirmed using spectroscopic methods. Based on in vivo studies, D4 and D6 derivatives exhibited the best pharmacological results, although only D6 showed a statistically significant difference compared to the control. Also, for D4 and D6 derivatives, myelin staining confirmed reduced degeneration in the corpus callosum. Consequently, D4 and D6 derivatives are promising candidates for developing new NMDA antagonists with therapeutic value against MS disorders.}, } @article {pmid39106168, year = {2024}, author = {Glineburg, MR and Yildirim, E and Gomez, N and Rodriguez, G and Pak, J and Li, X and Altheim, C and Waksmacki, J and McInerney, GM and Barmada, SJ and Todd, PK}, title = {Stress granule formation helps to mitigate neurodegeneration.}, journal = {Nucleic acids research}, volume = {52}, number = {16}, pages = {9745-9759}, pmid = {39106168}, issn = {1362-4962}, support = {R01 NS086810/NS/NINDS NIH HHS/United States ; F31 NS115257/NS/NINDS NIH HHS/United States ; 2018-03843//Swedish Research Council/ ; P50 HD104463/HD/NICHD NIH HHS/United States ; //Ann Arbor Active Against ALS/ ; T32 NS076401/NS/NINDS NIH HHS/United States ; T32 GM007863/GM/NIGMS NIH HHS/United States ; BLRD BX004842//Veterans Affairs/ ; I01 BX004842/BX/BLRD VA/United States ; P50HD104463/NH/NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Stress Granules/metabolism ; *Neurodegenerative Diseases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; *Neurons/metabolism ; *Frontotemporal Dementia/metabolism/genetics ; RNA Recognition Motif Proteins/metabolism/genetics ; Drosophila Proteins/metabolism/genetics ; Poly-ADP-Ribose Binding Proteins/metabolism/genetics ; Mice ; Drosophila melanogaster/metabolism/genetics ; RNA Helicases/metabolism/genetics ; Ataxia/genetics/metabolism ; DNA Helicases/metabolism/genetics ; Alphavirus/genetics/metabolism ; Rats ; Carrier Proteins/metabolism ; Drosophila/metabolism ; Cytoplasmic Granules/metabolism ; Stress, Physiological ; DNA-Binding Proteins ; }, abstract = {Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known. To address this, we took advantage of the alphavirus protein nsP3, which selectively binds dimers of the central stress granule nucleator protein G3BP and markedly reduces stress granule formation without directly impacting the protein translational inhibitory pathways that trigger stress granule formation. In Drosophila and rodent neurons, reducing stress granule formation with nsP3 had modest impacts on lifespan even in the setting of serial stress pathway induction. In contrast, reducing stress granule formation in models of ataxia, amyotrophic lateral sclerosis and frontotemporal dementia largely exacerbated disease phenotypes. These data support a model whereby stress granules mitigate, rather than promote, neurodegenerative cascades.}, } @article {pmid39106320, year = {2024}, author = {Dong, D and Zhang, Z and Li, Y and Latallo, MJ and Wang, S and Nelson, B and Wu, R and Krishnan, G and Gao, FB and Wu, B and Sun, S}, title = {Poly-GR repeats associated with ALS/FTD gene C9ORF72 impair translation elongation and induce a ribotoxic stress response in neurons.}, journal = {Science signaling}, volume = {17}, number = {848}, pages = {eadl1030}, pmid = {39106320}, issn = {1937-9145}, support = {RF1 NS101986/NS/NINDS NIH HHS/United States ; R21 AG072078/AG/NIA NIH HHS/United States ; T32 GM008403/GM/NIGMS NIH HHS/United States ; R01 NS107347/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *DNA Repeat Expansion/genetics ; Peptide Chain Elongation, Translational ; p38 Mitogen-Activated Protein Kinases/metabolism/genetics ; Stress, Physiological/genetics ; Ribosomes/metabolism/genetics ; }, abstract = {Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion results in multiple dipeptide repeat proteins, among which arginine-rich poly-GR proteins are highly toxic to neurons and decrease the rate of protein synthesis. We investigated whether the effect on protein synthesis contributes to neuronal dysfunction and degeneration. We found that the expression of poly-GR proteins inhibited global translation by perturbing translation elongation. In iPSC-differentiated neurons, the translation of transcripts with relatively slow elongation rates was further slowed, and stalled, by poly-GR. Elongation stalling increased ribosome collisions and induced a ribotoxic stress response (RSR) mediated by ZAKα that increased the phosphorylation of the kinase p38 and promoted cell death. Knockdown of ZAKα or pharmacological inhibition of p38 ameliorated poly-GR-induced toxicity and improved the survival of iPSC-derived neurons from patients with C9ORF72-ALS/FTD. Our findings suggest that targeting the RSR may be neuroprotective in patients with ALS/FTD caused by repeat expansion in C9ORF72.}, } @article {pmid39107037, year = {2025}, author = {Jang, DG and Dou, JF and Koubek, EJ and Teener, S and Zhou, L and Bakulski, KM and Mukherjee, B and Batterman, SA and Feldman, EL and Goutman, SA}, title = {Multiple metal exposures associate with higher amyotrophic lateral sclerosis risk and mortality independent of genetic risk and correlate to self-reported exposures: a case-control study.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {4}, pages = {329-339}, pmid = {39107037}, issn = {1468-330X}, support = {R01TS000344/ACL/ACL HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/genetics/blood/urine ; Male ; Female ; Middle Aged ; Case-Control Studies ; Aged ; *Metals/urine/blood/adverse effects ; *Environmental Exposure/adverse effects ; Copper/urine/blood ; Polymorphism, Single Nucleotide ; Risk Factors ; Genome-Wide Association Study ; Self Report ; Adult ; Selenium/blood/urine ; Genetic Predisposition to Disease ; Zinc/urine/blood ; }, abstract = {BACKGROUND: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival and exposure sources.

METHODS: Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. ORs and HRs for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected single-nucleotide polymorphisms.

RESULTS: Plasma and urine samples from 454 ALS and 294 control participants were analysed. Elevated levels of individual metals, including copper, selenium and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62, p<0.001; urine, OR=3.10, CI=2.43-3.97, p<0.001) and poorer ALS survival (plasma, HR=1.37, CI=1.20-1.58, p<0.001; urine, HR=1.44, CI=1.23-1.67, p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures were associated with measured plasma and urine metals.

CONCLUSION: Metals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression.}, } @article {pmid39107374, year = {2024}, author = {Monselise, EB and Vyazmensky, M and Scherf, T and Batushansky, A and Fishov, I}, title = {D-Glutamate production by stressed Escherichia coli gives a clue for the hypothetical induction mechanism of the ALS disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {18247}, pmid = {39107374}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/microbiology ; *Escherichia coli/metabolism ; *Glutamic Acid/metabolism ; Humans ; Stress, Physiological ; Complement C1q/metabolism ; Nitrogen/metabolism ; Carbon/metabolism ; }, abstract = {In the search for the origin of Amyotrophic Lateral Sclerosis disease (ALS), we hypothesized earlier (Monselise, 2019) that D-amino acids produced by stressed microbiome may serve as inducers of the disease development. Many examples of D-amino acid accumulation under various stress conditions were demonstrated in prokaryotic and eukaryotic cells. In this work, wild-type Escherichia coli, members of the digestive system, were subjected to carbon and nitrogen starvation stress. Using NMR and LC-MS techniques, we found for the first time that D-glutamate accumulated in the stressed bacteria but not in control cells. These results together with the existing knowledge, allow us to suggest a new insight into the pathway of ALS development: D-glutamate, produced by the stressed microbiome, induces neurobiochemical miscommunication setting on C1q of the complement system. Proving this insight may have great importance in preventive medicine of such MND modern-age diseases as ALS, Alzheimer, and Parkinson.}, } @article {pmid39108272, year = {2024}, author = {De Federicis, D and Bassani, C and Chiarelli, RR and Montini, F and Giordano, A and Esposito, F and Riva, N and Quattrini, A and Martinelli, V and Filippi, M and Farina, C}, title = {Circulating MAIT cells in multiple sclerosis and amyotrophic lateral sclerosis.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1436717}, pmid = {39108272}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/blood ; *Mucosal-Associated Invariant T Cells/immunology/metabolism ; Male ; Middle Aged ; Female ; Adult ; Aged ; Multiple Sclerosis/immunology/blood ; CD8-Positive T-Lymphocytes/immunology/metabolism ; Biomarkers ; Flow Cytometry ; }, abstract = {Neurological disorders, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), may be associated with alterations in blood cell composition and phenotype. Here, we focused our attention on circulating mucosal-associated invariant T (MAIT) cells, a CD8[+] T cell memory population expressing the invariant Vα7.2 region in the T cell receptor and high surface levels of the CD161 marker. Transcriptomics data relative to peripheral blood mononuclear cells (PBMC) highlighted downregulation of CD161 and other MAIT-associated markers in progressive MS and not relapsing remitting (RR)-MS when gene expressions relative to each disease course were compared to those from healthy controls. Multiparametric flow cytometry of freshly isolated PBMC samples from untreated RR-MS, primary or secondary progressive MS (PP- or SP-MS), ALS and age- and sex-matched healthy controls revealed specific loss of circulating CD8[+] MAIT cells in PP-MS and no other MS courses or another neurological disorder such as ALS. Overall, these observations point to the existence of immunological changes in blood specific for the primary progressive course of MS that may support clinical definition of disease.}, } @article {pmid39108340, year = {2024}, author = {Tröger, J and Dörr, F and Schwed, L and Linz, N and König, A and Thies, T and Barbe, MT and Orozco-Arroyave, JR and Rusz, J}, title = {An automatic measure for speech intelligibility in dysarthrias-validation across multiple languages and neurological disorders.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1440986}, pmid = {39108340}, issn = {2673-253X}, abstract = {INTRODUCTION: Dysarthria, a motor speech disorder caused by muscle weakness or paralysis, severely impacts speech intelligibility and quality of life. The condition is prevalent in motor speech disorders such as Parkinson's disease (PD), atypical parkinsonism such as progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Improving intelligibility is not only an outcome that matters to patients but can also play a critical role as an endpoint in clinical research and drug development. This study validates a digital measure for speech intelligibility, the ki: SB-M intelligibility score, across various motor speech disorders and languages following the Digital Medicine Society (DiMe) V3 framework.

METHODS: The study used four datasets: healthy controls (HCs) and patients with PD, HD, PSP, and ALS from Czech, Colombian, and German populations. Participants' speech intelligibility was assessed using the ki: SB-M intelligibility score, which is derived from automatic speech recognition (ASR) systems. Verification with inter-ASR reliability and temporal consistency, analytical validation with correlations to gold standard clinical dysarthria scores in each disease, and clinical validation with group comparisons between HCs and patients were performed.

RESULTS: Verification showed good to excellent inter-rater reliability between ASR systems and fair to good consistency. Analytical validation revealed significant correlations between the SB-M intelligibility score and established clinical measures for speech impairments across all patient groups and languages. Clinical validation demonstrated significant differences in intelligibility scores between pathological groups and healthy controls, indicating the measure's discriminative capability.

DISCUSSION: The ki: SB-M intelligibility score is a reliable, valid, and clinically relevant tool for assessing speech intelligibility in motor speech disorders. It holds promise for improving clinical trials through automated, objective, and scalable assessments. Future studies should explore its utility in monitoring disease progression and therapeutic efficacy as well as add data from further dysarthrias to the validation.}, } @article {pmid39110593, year = {2024}, author = {Hoh, KL and Mu, B and See, T and Ng, AYE and Ng, AQE and Zhang, D}, title = {VAP-mediated membrane-tethering mechanisms implicate ER-PM contact function in pH homeostasis.}, journal = {Cell reports}, volume = {43}, number = {8}, pages = {114592}, doi = {10.1016/j.celrep.2024.114592}, pmid = {39110593}, issn = {2211-1247}, mesh = {*Endoplasmic Reticulum/metabolism ; Hydrogen-Ion Concentration ; *Homeostasis ; *Cell Membrane/metabolism ; Humans ; *Schizosaccharomyces/metabolism ; Schizosaccharomyces pombe Proteins/metabolism ; Vesicular Transport Proteins/metabolism/genetics ; Protein Binding ; Membrane Proteins/metabolism ; Phospholipids/metabolism ; Mutation ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Vesicle-associated membrane protein (VAMP)-associated proteins (VAPs) are highly conserved endoplasmic reticulum (ER)-resident proteins that establish ER contacts with multiple membrane compartments in many eukaryotes. However, VAP-mediated membrane-tethering mechanisms remain ambiguous. Here, focusing on fission yeast ER-plasma membrane (PM) contact formation, using systematic interactome analyses and quantitative microscopy, we predict a non-VAP-protein direct binding-based ER-PM coupling. We further reveal that VAP-anionic phospholipid interactions may underlie ER-PM association and define the pH-responsive nature of VAP-tethered membrane contacts. Such conserved interactions with anionic phospholipids are generally defective in amyotrophic lateral sclerosis-associated human VAPB mutant. Moreover, we identify a conserved FFAT-like motif locating at the autoinhibitory hotspot of the essential PM proton pump Pma1. This modulatory VAP-Pma1 interaction appears crucial for pH homeostasis. We thus propose an ingenious strategy for maintaining intracellular pH by coupling Pma1 modulation with pH-sensory ER-PM contacts via VAP-mediated interactions.}, } @article {pmid39111227, year = {2024}, author = {Torghabeh, FA and Moghadam, EA and Hosseini, SA}, title = {Simultaneous time-frequency analysis of gait signals of both legs in classifying neurodegenerative diseases.}, journal = {Gait & posture}, volume = {113}, number = {}, pages = {443-451}, doi = {10.1016/j.gaitpost.2024.07.302}, pmid = {39111227}, issn = {1879-2219}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/physiopathology ; *Gait Analysis/methods ; Gait Disorders, Neurologic/classification/diagnosis/physiopathology/etiology ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/classification ; Wavelet Analysis ; Male ; Female ; Middle Aged ; Parkinson Disease/diagnosis/physiopathology/classification ; Deep Learning ; Signal Processing, Computer-Assisted ; Case-Control Studies ; Huntington Disease/physiopathology/diagnosis/classification ; Aged ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) pose significant challenges due to their debilitating nature and limited therapeutic options. Accurate and timely diagnosis is crucial for optimizing patient care and treatment strategies. Gait analysis, utilizing wearable sensors, has shown promise in assessing motor abnormalities associated with NDDs.

RESEARCH QUESTION: Research Question 1 To what extent can analyzing the interaction of both limbs in the time-frequency domain serve as a suitable methodology for accurately classifying NDDs? Research Question 2 How effective is the utilization of color-coded images, in conjunction with deep transfer learning models, for the classification of NDDs?

METHODS: GaitNDD database was used, comprising recordings from patients with Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, and healthy controls. The gait signals underwent signal preparation, wavelet coherence analysis, and principal component analysis for feature enhancement. Deep transfer learning models (AlexNet, GoogLeNet, SqueezeNet) were employed for classification. Performance metrics, including accuracy, sensitivity, specificity, precision, and F1 score, were evaluated using 5-fold cross-validation.

RESULTS: The classification performance of the models varied depending on the time window used. For 5-second gait signal segments, AlexNet achieved an accuracy of 95.91 %, while GoogLeNet and SqueezeNet achieved accuracies of 96.49 % and 92.73 %, respectively. For 10-second segments, AlexNet outperformed other models with an accuracy of 99.20 %, while GoogLeNet and SqueezeNet achieved accuracies of 96.75 % and 95.00 %, respectively. Statistical tests confirmed the significance of the extracted features, indicating their discriminative power for classification.

SIGNIFICANCE: The proposed method demonstrated superior performance compared to previous studies, offering a non-invasive and cost-effective approach for the automated diagnosis of NDDs. By analyzing the interaction between both legs during walking using wavelet coherence, and utilizing deep transfer learning models, accurate classification of NDDs was achieved.}, } @article {pmid39111522, year = {2024}, author = {Li, Q and Zhu, W and Wen, X and Zang, Z and Da, Y and Lu, J}, title = {Different baseline functional patterns of the frontal cortex in amyotrophic lateral sclerosis patients with Corticospinal tract hyperintensity.}, journal = {Brain research}, volume = {1844}, number = {}, pages = {149140}, doi = {10.1016/j.brainres.2024.149140}, pmid = {39111522}, issn = {1872-6240}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; *Pyramidal Tracts/physiopathology/diagnostic imaging ; Middle Aged ; *Magnetic Resonance Imaging/methods ; *Frontal Lobe/physiopathology/diagnostic imaging ; Aged ; Adult ; Brain Mapping/methods ; }, abstract = {Nearly half of the amyotrophic lateral sclerosis (ALS) patients showed hyperintensity of the corticospinal tract (CST+), yet whether brain functional pattern differs between CST+and CST- patients remains obscure. In the current study, 19 ALS CST+, 41 ALS CST- patients and 37 healthy controls (HC) underwent resting state fMRI scans. We estimated local activity and connectivity patterns via the Amplitude of Low Frequency Fluctuations (ALFF) and the Network-Based Statistic (NBS) approaches respectively. The ALS CST+patients did not differ from the CST- patients in amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) score and disease duration. ALFF of the superior frontal gyrus (SFG) and the inferior frontal gyrus pars opercularis (OIFG) were highest in the HC and lowest in the ALS CST- patients, resulting in significant group differences (PFWE<0.05). NBS analysis revealed a frontal network consisting of connections between SFG, OIFG, orbital frontal gyrus, middle cingulate cortex and the basal ganglia, which exhibited HC>ALS CST+ > ALS CST- group differences (PFWE=0.037) as well. The ALFF of the OIFG was significantly correlated with ALSFRS-R (R=0.34, P=0.028) and mean connectivity of the frontal network was trend-wise significantly correlated with disease duration (R=-0.31, P=0.052) in the ALS CST- patients. However, these correlations were insignificant in ALS CST+patients (P values > 0.8). In conclusion, The ALS CST+patients exhibited different patterns of baseline functional activity and connectivity in the frontal cortex which may indicate a functional compensatory effect.}, } @article {pmid39111585, year = {2024}, author = {Bischoff, KE and Liera, D and Tang, J and Madugala, N and Cohen, E and Galea, MD and Lindenberger, E and Pantilat, SZ and Lomen-Hoerth, C}, title = {Development and Piloting of a Bereaved Care Partner Survey to Inform Quality Improvement in ALS Supportive Care.}, journal = {Journal of pain and symptom management}, volume = {68}, number = {5}, pages = {467-476.e2}, doi = {10.1016/j.jpainsymman.2024.07.031}, pmid = {39111585}, issn = {1873-6513}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Quality Improvement ; Pilot Projects ; *Bereavement ; Female ; Male ; *Palliative Care ; Caregivers ; Middle Aged ; Aged ; Surveys and Questionnaires ; Adult ; }, abstract = {OBJECTIVES: Bereaved care partner surveys typically focus on the experience with care in the final days of life. We sought to develop and pilot a novel bereaved care partner survey to understand experiences with ALS supportive care provided throughout the illness and identify opportunities for quality improvement.

METHODS: We developed the survey using a multisite, interdisciplinary consensus process involving ALS and palliative care clinicians as well as patient advocates. We then piloted the survey at a single site via video interviews with care partners of patients who died from ALS between three and 15 months prior. Qualitative findings were analyzed using Rapid Qualitative Analysis.

RESULTS: The survey includes 17 core questions and nine demographic items. Questions inquire about whether the patient and care partner received adequate help with physical symptoms, emotional and practical needs, education about the illness and how to provide hands-on care, preparing for what was to come, and bereavement. They also query whether care was person-centered and consistent with the patient's values and preferences. During the pilot with 18 bereaved care partners, the tool generated detailed feedback about aspects of care to preserve as well as how to improve ALS supportive care.

DISCUSSION: We developed and piloted a bereaved care partner survey to understand and improve the quality of ALS supportive care, which was found to be feasible and acceptable. Next steps include testing it at additional centers in order to generate learnings that can advance ALS supportive care in ways that are meaningful to patients and care partners.}, } @article {pmid39112530, year = {2024}, author = {Tu, S and Li, T and Carroll, AS and Mahoney, CJ and Huynh, W and Park, SB and Henderson, R and Vucic, S and Kiernan, MC and Lin, CS}, title = {Central neurodegeneration in Kennedy's disease accompanies peripheral motor dysfunction.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {18331}, pmid = {39112530}, issn = {2045-2322}, mesh = {Humans ; Male ; Middle Aged ; Female ; Aged ; *Bulbo-Spinal Atrophy, X-Linked/physiopathology/pathology ; Adult ; Amyotrophic Lateral Sclerosis/physiopathology/pathology/diagnostic imaging ; Brain/diagnostic imaging/pathology/physiopathology ; Magnetic Resonance Imaging ; White Matter/diagnostic imaging/pathology/physiopathology ; }, abstract = {Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease (KD), is a rare hereditary neuromuscular disorder demonstrating commonalities with amyotrophic lateral sclerosis (ALS). The current study aimed to define functional and central nervous system abnormalities associated with SBMA pathology, their interaction, and to identify novel clinical markers for quantifying disease activity. 27 study participants (12 SBMA; 8 ALS; 7 Control) were recruited. SBMA patients underwent comprehensive motor and sensory functional assessments, and neurophysiological testing. All participants underwent whole-brain structural and diffusion MRI. SBMA patients demonstrated marked peripheral motor and sensory abnormalities across clinical assessments. Increased abnormalities on neurological examination were significantly associated with increased disease duration in SBMA patients (R[2] = 0.85, p < 0.01). Widespread juxtacortical axonal degeneration of corticospinal white matter tracts were detected in SBMA patients (premotor; motor; somatosensory; p < 0.05), relative to controls. Increased axial diffusivity was significantly correlated with total neuropathy score in SBMA patients across left premotor (R[2] = 0.59, p < 0.01), motor (R[2] = 0.63, p < 0.01), and somatosensory (R[2] = 0.61, p < 0.01) tracts. The present series has identified involvement of motor and sensory brain regions in SBMA, associated with disease duration and increasing severity of peripheral neuropathy. Quantification of annualized brain MRI together with Total Neuropathy Score may represent a novel approach for clinical monitoring.}, } @article {pmid39113334, year = {2024}, author = {Khadilkar, V and Lad, S and Mondkar, S and Yewale, S and Dange, N and Wagle, S and Khadilkar, A}, title = {Pediatric Advanced Life Support Tape for Indian Children.}, journal = {Indian pediatrics}, volume = {61}, number = {10}, pages = {961-965}, pmid = {39113334}, issn = {0974-7559}, mesh = {Humans ; India ; Male ; Female ; Child, Preschool ; Child ; *Body Height ; *Body Weight ; *Anthropometry/instrumentation ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To design a specific advanced life support (ALS) tape based on recent Indian multicenter height/length and weight data to accurately estimate the weight from the recumbent length.

METHODS: We designed the new ALS tape by matching the median weights to median heights/lengths from the recently published Indian multicenter growth data, maintaining the same color codes as the Broselow tape. The accuracy of weight estimation for the newly designed ALS tape was validated and compared with the Broselow estimated weights at a tertiary care hospital.

RESULTS: The color (weight) band matched median heights (cm) from the new ALS tape were higher (53.0 vs 53.9 for grey, 63.1 vs 67.4 for pink, 70.6 vs 76.4 for red, 79 vs 85.5 for purple, 89.6 vs 95.5 for yellow, 101.9 vs 107.5 for white, 126.1 vs 130.5 for orange and 137 vs 140.5 for green) than the Broselow tape. For every color band on the newly designed ALS tape, a sizable proportion of children (27% for grey, 78% for pink, 83% for red, 38% for purple, 63% for yellow, 41% for white, 35% for blue, 54% for orange) recorded a higher Broselow color band, suggesting overestimated weights at each color band. The percentage difference in the estimated weight from the actual weight was very small (-0.5% for under-5 years and 0.2% for older children) using the new ALS tape as compared to Broselow tape.

CONCLUSION: This Indianized ALS tape estimated Indian children's weights more accurately. Use of the newly designed ALS tape may reduce the errors in calculating emergency medications, fluids and equipment sizes. Further studies are required to validate this tape in pediatric emergency departments in India.}, } @article {pmid39113457, year = {2024}, author = {Pervushina, EV and Kutlubaev, MA and Saifullina, EV and Gaisina, EV and Smakova, LA and Khidiyatova, IM}, title = {[Amyotrophic lateral sclerosis associated with a new pathogenic variant of the ERBB4 gene].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {7}, pages = {165-168}, doi = {10.17116/jnevro2024124071165}, pmid = {39113457}, issn = {1997-7298}, mesh = {Humans ; *Receptor, ErbB-4/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; Male ; Middle Aged ; Disease Progression ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a sporadic disease in most of the cases; in 10-15% of cases genetic forms are recorded. A genetic form of ALS associated with the mutation in the ERBB4 gene (ALS19) has been reported in 2013. A protein encoded by the ERBB4 is probably involved in ubiquitous component of the pathogenesis of ALS. We present a case of ALS associated with a new pathogenic variant of the ERBB4 gene, with early bulbar onset and slow progression of the disease within 10 years.}, } @article {pmid39113924, year = {2024}, author = {Ueta, Y and Kanbayashi, T and Miyaji, Y and Hatanaka, Y and Tachiyama, K and Takahashi, K and Terashi, H and Aizawa, H and Sonoo, M}, title = {The speed of completion of the decremental responses on repetitive nerve stimulation.}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {211-216}, pmid = {39113924}, issn = {2467-981X}, abstract = {OBJECTIVE: It is generally believed that the decremental response in repetitive nerve stimulation (RNS) stabilizes at the fourth or fifth response. We have a preliminary impression that the decremental response approaches a plateau earlier in proximal muscles than in distal muscles. We investigated the speed of the completion of the decremental response in different muscles.

METHODS: The "decrement completion ratio (DCR)" in the second or third response (DCR2 or DCR3) was defined as the ratio of the decremental percentage of the second or third response to that of the fourth response. Patients showing more than 10% decremental response both in the abductor pollicis (APB) and deltoid muscles were retrospectively extracted from our EMG database. The DCR2 and DCR3 were compared between two muscles in patients with myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS).

RESULTS: Identified subjects consisted of 11patients with MG and 11 patients with ALS. Multiple regression analysis revealed that only the difference of muscle influenced on DCR2 and DCR3, with no contribution from the different disorder (MG or ALS) or the initial amplitude of the compound muscle action potential (CMAP). Both DCR2 and DCR3 were significantly higher in deltoid than in APB. In ALS, the normalized CMAP amplitude was not different between APB and deltoid whereas the decremental percentage was significantly higher in deltoid, suggesting a lower safety factor of the neuromuscular transmission in proximal muscles.

CONCLUSIONS: The decremental response completed more rapidly in deltoid than in APB which may be related to the lower safety factor also documented by this study.

SIGNIFICANCE: Unexpected early completion of the decrement such as at the second response in RNS is not a technical error but may be an extreme of the rapid completion in deltoid, a proximal muscle.}, } @article {pmid39114608, year = {2024}, author = {Koike, Y}, title = {Abnormal Splicing Events due to Loss of Nuclear Function of TDP-43: Pathophysiology and Perspectives.}, journal = {JMA journal}, volume = {7}, number = {3}, pages = {313-318}, pmid = {39114608}, issn = {2433-3298}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with a progressive and fatal course. They are often comorbid and share the same molecular spectrum. Their key pathological features are the formation of the aggregation of TDP-43, an RNA-binding protein, in the cytoplasm and its depletion from the nucleus in the central nervous system. In the nucleus, TDP-43 regulates several aspects of RNA metabolism, ranging from RNA transcription and alternative splicing to RNA transport. Suppressing the aberrant splicing events during RNA processing is one of the significant functions of TDP-43. This function is impaired when TDP-43 becomes depleted from the nucleus. Several critical cryptic splicing targets of TDP-43 have recently emerged, such as STMN2, UNC13A, and others. UNC13A is an important ALS/FTD risk gene, and the genetic variations, single nucleotide polymorphisms, cause disease via the increased susceptibility for cryptic exon inclusion under the TDP-43 dysfunction. Moreover, TDP-43 has an autoregulatory mechanism that regulates the splicing of its mRNA (TARDBP mRNA) in the healthy state. This study provides recent findings on the splicing regulatory function of TDP-43 and discusses the prospects of using these aberrant splicing events as efficient biomarkers.}, } @article {pmid39115327, year = {2024}, author = {Lescouzères, L and Patten, SA}, title = {Promising animal models for amyotrophic lateral sclerosis drug discovery: a comprehensive update.}, journal = {Expert opinion on drug discovery}, volume = {19}, number = {10}, pages = {1213-1233}, doi = {10.1080/17460441.2024.2387791}, pmid = {39115327}, issn = {1746-045X}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; Humans ; *Disease Models, Animal ; *Drug Discovery/methods ; Mice ; Genetic Therapy/methods ; Translational Research, Biomedical/methods ; Induced Pluripotent Stem Cells ; Drug Development/methods ; Caenorhabditis elegans ; Motor Neurons/drug effects ; Zebrafish ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Several animal models have been generated to understand ALS pathogenesis. They have provided valuable insight into disease mechanisms and the development of therapeutic strategies.

AREAS COVERED: In this review, the authors provide a concise overview of simple genetic model organisms, including C. elegans, Drosophila, zebrafish, and mouse genetic models that have been generated to study ALS. They emphasize the benefits of each model and their application in translational research for discovering new chemicals, gene therapy approaches, and antibody-based strategies for treating ALS.

EXPERT OPINION: Significant progress is being made in identifying new therapeutic targets for ALS. This progress is being enabled by promising animal models of the disease using increasingly effective genetic and pharmacological strategies. There are still challenges to be overcome in order to achieve improved success rates for translating drugs from animal models to clinics for treating ALS. Several promising future directions include the establishment of novel preclinical protocol standards, as well as the combination of animal models with human induced pluripotent stem cells (iPSCs).}, } @article {pmid39115673, year = {2025}, author = {Mishra, Y and Kumar, A and Kaundal, RK}, title = {Mitochondrial Dysfunction is a Crucial Immune Checkpoint for Neuroinflammation and Neurodegeneration: mtDAMPs in Focus.}, journal = {Molecular neurobiology}, volume = {62}, number = {6}, pages = {6715-6747}, pmid = {39115673}, issn = {1559-1182}, support = {EEQ/2021/000875//Science & Engineering Research Board (SERB), Department of Science and Technology, Govt of India/ ; }, mesh = {Humans ; Animals ; *Mitochondria/metabolism/pathology/immunology ; *Neuroinflammatory Diseases/immunology/pathology/metabolism ; *Neurodegenerative Diseases/immunology/pathology/metabolism ; Immunity, Innate ; *Nerve Degeneration/immunology/pathology ; *Inflammation/immunology/pathology ; }, abstract = {Neuroinflammation is a pivotal factor in the progression of both age-related and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Mitochondria, essential for neuronal health due to their roles in energy production, calcium buffering, and oxidative stress regulation, become increasingly susceptible to dysfunction under conditions of metabolic stress, aging, or injury. Impaired mitophagy in aged or injured neurons leads to the accumulation of dysfunctional mitochondria, which release mitochondrial-derived damage-associated molecular patterns (mtDAMPs). These mtDAMPs act as immune checkpoints, activating pattern recognition receptors (PRRs) and triggering innate immune signaling pathways. This activation initiates inflammatory responses in neurons and brain-resident immune cells, releasing cytokines and chemokines that damage adjacent healthy neurons and recruit peripheral immune cells, further amplifying neuroinflammation and neurodegeneration. Long-term mitochondrial dysfunction perpetuates a chronic inflammatory state, exacerbating neuronal injury and contributing additional immunogenic components to the extracellular environment. Emerging evidence highlights the critical role of mtDAMPs in initiating and sustaining neuroinflammation, with circulating levels of these molecules potentially serving as biomarkers for disease progression. This review explores the mechanisms of mtDAMP release due to mitochondrial dysfunction, their interaction with PRRs, and the subsequent activation of inflammatory pathways. We also discuss the role of mtDAMP-triggered innate immune responses in exacerbating both acute and chronic neuroinflammation and neurodegeneration. Targeting dysfunctional mitochondria and mtDAMPs with pharmacological agents presents a promising strategy for mitigating the initiation and progression of neuropathological conditions.}, } @article {pmid39116263, year = {2024}, author = {Aguilar-Vázquez, CA and Aguilar-Castillo, SJ and Raymundo-Carrillo, AD}, title = {[Electrodiagnostic support in an atypical form of amyotrophic lateral sclerosis (Vulpian-Bernhardt syndrome)].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {62}, number = {1}, pages = {1-8}, pmid = {39116263}, issn = {2448-5667}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/mortality/therapy ; *Electrodiagnosis/methods ; }, abstract = {BACKGROUND: Vulpian-Bernhardt syndrome is an atypical form of the motor neuron disease described since the 19th century. The importance of a timely diagnosis lies in the increased survival present in this variant. Due to the clinical rarity and complex diagnosis we report a clinical case of this disease, which is why we describe the typical clinical presentation, the diagnostic approach, and we make a bibliographic review of this neurodegenerative disorder as well.

CLINICAL CASE: Latin American man whose clinical case onset was characterized by thoracic asymmetric and increasing limb weakness, showing affection from distal to proximal upper limbs area. Subsequently, symptoms worsened to the point of limiting day-to-day activities and conditioning patient's physical independence. Physical examination was consistent with motor neuron disease. Nerve conduction studies were performed and confirmed findings compatible with motor neuron involvement limited to thoracic limbs.

CONCLUSION: Vulpian-Bernhardt syndrome is an uncommon form of motor neuron disease. Due to the rarity of its presentation, it is frequent to confuse clinical profile even for trained physicians. The importance of electrodiagnosis relies in identifying the neurogenic origin of the disease, as well as the active denervation and reinnervation data. Considering that with this syndrome patients have a longer survival than with the classic form of amyotrophic lateral sclerosis, it is important to have a clear diagnosis approach in order to provide a better quality of life and supportive treatment.}, } @article {pmid39116527, year = {2024}, author = {Ceron-Codorniu, M and Torres, P and Fernàndez-Bernal, A and Rico-Rios, S and Serrano, JC and Miralles, MP and Beltran, M and Garcera, A and Soler, RM and Pamplona, R and Portero-Otín, M}, title = {TDP-43 dysfunction leads to bioenergetic failure and lipid metabolic rewiring in human cells.}, journal = {Redox biology}, volume = {75}, number = {}, pages = {103301}, pmid = {39116527}, issn = {2213-2317}, mesh = {Humans ; *Energy Metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *Lipid Metabolism ; HeLa Cells ; *Adenosine Triphosphate/metabolism ; Induced Pluripotent Stem Cells/metabolism/cytology ; Coenzyme A Ligases/metabolism/genetics ; Motor Neurons/metabolism/pathology ; Cell Survival ; Oxygen Consumption ; Ferroptosis ; Long-Chain-Fatty-Acid-CoA Ligase ; }, abstract = {The dysfunction of TAR DNA-binding protein 43 (TDP-43) is implicated in various neurodegenerative diseases, though the specific contributions of its toxic gain-of-function versus loss-of-function effects remain unclear. This study investigates the impact of TARDBP loss on cellular metabolism and viability using human-induced pluripotent stem cell-derived motor neurons and HeLa cells. TARDBP silencing led to reduced metabolic activity and cell growth, accompanied by neurite degeneration and decreased oxygen consumption rates in both cell types. Notably, TARDBP depletion induced a metabolic shift, impairing ATP production, increasing metabolic inflexibility, and elevating free radical production, indicating a critical role for TDP-43 in maintaining cellular bioenergetics. Furthermore, TARDBP loss triggered non-apoptotic cell death, increased ACSL4 expression, and reprogrammed lipid metabolism towards lipid droplet accumulation, while paradoxically enhancing resilience to ferroptosis inducers. Overall, our findings highlight those essential cellular traits such as ATP production, metabolic activity, oxygen consumption, and cell survival are highly dependent on TARDBP function.}, } @article {pmid39116956, year = {2024}, author = {Yang, N and Shi, L and Xu, P and Ren, F and Li, C and Qi, X}, title = {Identification of potential drug targets for amyotrophic lateral sclerosis by Mendelian randomization analysis based on brain and plasma proteomics.}, journal = {Experimental gerontology}, volume = {195}, number = {}, pages = {112538}, doi = {10.1016/j.exger.2024.112538}, pmid = {39116956}, issn = {1873-6815}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/drug therapy ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Proteomics/methods ; *Brain/metabolism ; *Protein Interaction Maps ; Anoctamins/genetics ; Bayes Theorem ; Blood Proteins/analysis/metabolism ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic lateral sclerosis as a fatal neurodegenerative disease currently lacks effective therapeutic agents. Thus, finding new therapeutic targets to drive disease treatment is necessary. In this study, we utilized brain and plasma proteins as genetic instruments obtained from genome-wide association studies to conduct a Mendelian randomization analysis to identify potential drug targets for amyotrophic lateral sclerosis. Additionally, we validated our results externally using other datasets. We also used Bayesian co-localization analysis and phenotype scanning. Furthermore, we constructed a protein-protein interaction network to elucidate potential correlations between the identified proteins and existing targets. Mendelian randomization analysis indicated that elevated levels of ANO5 (OR = 1.30; 95 % CI, 1.14-1.49; P = 1.52E-04), SCFD1 (OR = 3.82; 95 % CI, 2.39-6.10; P = 2.19E-08), and SIGLEC9 (OR = 1.05; 95% CI, 1.03-1.07; P = 4.71E-05) are associated with an increased risk of amyotrophic lateral sclerosis, with external validation supporting these findings. Co-localization analysis confirmed that ANO5, SCFD1, and SIGLEC9 (coloc.abf-PPH4 = 0.848, 0.984, and 0.945, respectively) shared the same variant with amyotrophic lateral sclerosis, further substantiating potential role of these proteins as a therapeutic target. There are interactive relationships between the potential proteins and existing targets of amyotrophic lateral sclerosis. Our findings suggested that elevated levels of ANO5, SCFD1, and SIGLEC9 are connected with an increased risk of amyotrophic lateral sclerosis and might be promising therapeutic targets. However, further exploration is necessary to fully understand the underlying mechanisms involved.}, } @article {pmid39117043, year = {2024}, author = {Curtisi, J and Ellis-Wittenhagen, J and Kokanovich, T and Volk-Craft, B}, title = {Compassionate Ventilator Release in Patients With Neuromuscular Disease: A Two-Case Comparison.}, journal = {Journal of pain and symptom management}, volume = {68}, number = {5}, pages = {e392-e396}, doi = {10.1016/j.jpainsymman.2024.07.028}, pmid = {39117043}, issn = {1873-6513}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/complications/therapy ; Dyspnea/therapy/etiology ; Myasthenia Gravis/therapy/complications ; Neuromuscular Diseases/complications/therapy ; *Respiration, Artificial ; Terminal Care ; Ventilator Weaning ; }, abstract = {Dyspnea, the subjective sensation of breathlessness, is a distressing and potentially traumatic symptom. Dyspnea associated with mechanical ventilation may contribute to intensive care unit (ICU) associated post-traumatic stress disorder and impaired quality of life. Dyspnea is both difficult to alleviate and a cause of significant distress to patients, their loved ones, and care providers People living with neuromuscular disease, such as amyotrophic lateral sclerosis (ALS) or myasthenia gravis (MG), often rely on a ventilator at late stages of illness due to complications of progressive respiratory muscle weakness and paralysis. When unable to wean from the ventilator, conversations turn towards goals of care and release from the ventilator for comfort and end of life (EOL). Patients with and without neuromuscular disease have high risk for dyspnea at EOL upon ventilator liberation. Although limited recommendations have been published specific to patients with ALS, no guidelines currently exist for the terminal liberation from mechanical ventilation in patients experiencing respiratory muscle insufficiency from a neuromuscular disease. Further research on this topic is needed, including creation of a protocol for ventilator release in patients with neuromuscular disease. The following case reports detail the dissimilar EOL experiences of two patients with different forms of neuromuscular disease.}, } @article {pmid39117455, year = {2024}, author = {Lam, AYW and Tsuboyama, K and Tadakuma, H and Tomari, Y}, title = {DNAJA2 and Hero11 mediate similar conformational extension and aggregation suppression of TDP-43.}, journal = {RNA (New York, N.Y.)}, volume = {30}, number = {11}, pages = {1422-1436}, pmid = {39117455}, issn = {1469-9001}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/chemistry/genetics ; Fluorescence Resonance Energy Transfer ; Molecular Chaperones/metabolism/chemistry/genetics ; Protein Aggregates ; Protein Aggregation, Pathological/genetics/metabolism ; Protein Conformation ; RNA-Binding Proteins/metabolism/genetics/chemistry ; Chromosomal Proteins, Non-Histone/genetics ; HSP40 Heat-Shock Proteins ; }, abstract = {Many RNA-binding proteins (RBPs) contain low-complexity domains (LCDs) with prion-like compositions. These long intrinsically disordered regions regulate their solubility, contributing to their physiological roles in RNA processing and organization. However, this also makes these RBPs prone to pathological misfolding and aggregation that are characteristic of neurodegenerative diseases. For example, TAR DNA-binding protein 43 (TDP-43) forms pathological aggregates associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While molecular chaperones are well-known suppressors of these aberrant events, we recently reported that highly disordered, hydrophilic, and charged heat-resistant obscure (Hero) proteins may have similar effects. Specifically, Hero proteins can maintain the activity of other proteins from denaturing conditions in vitro, while their overexpression can suppress cellular aggregation and toxicity associated with aggregation-prone proteins. However, it is unclear how these protective effects are achieved. Here, we used single-molecule FRET to monitor the conformations of the aggregation-prone prion-like LCD of TDP-43. While we observed high conformational heterogeneity in wild-type LCD, the ALS-associated mutation A315T promoted collapsed conformations. In contrast, an Hsp40 chaperone, DNAJA2, and a Hero protein, Hero11, stabilized extended states of the LCD, consistent with their ability to suppress the aggregation of TDP-43. Our results link single-molecule effects on conformation to macro effects on bulk aggregation, where a Hero protein, like a chaperone, can maintain the conformational integrity of a client protein to prevent its aggregation.}, } @article {pmid39117616, year = {2024}, author = {Ramzan, F and Kumar, A and Abrar, F and Gray, RAV and Campbell, ZE and Liao, LMQ and Dang, A and Akanni, O and Guyn, C and Martin, DDO}, title = {Fatty links between multisystem proteinopathy and small VCP-interacting protein.}, journal = {Cell death discovery}, volume = {10}, number = {1}, pages = {358}, pmid = {39117616}, issn = {2058-7716}, abstract = {Multisystem proteinopathy (MSP) is a rare, dominantly inherited disorder that includes a cluster of diseases, including frontotemporal dementia, inclusion body myopathy, and Paget's disease of bone. MSP is caused by mutations in the gene encoding valosin-containing protein (VCP). Patients with the same mutation, even within the same family, can present with a different combination of any or all of the above diseases, along with amyotrophic lateral sclerosis (ALS). The pleiotropic effects may be linked to the greater than 50 VCP co-factors that direct VCP's many roles in the cell. Small VCP-interacting protein (SVIP) is a small protein that directs VCP to autophagosomes and lysosomes. We found that SVIP directs VCP localization to lysosomes in an acylation-dependent manner. We demonstrate that SVIP is myristoylated at Glycine 2 and palmitoylated at Cysteines 4 and 7. Acylation of SVIP is required to mediate cell death in the presence of the MSP-associated VCP variant (R155H-VCP), whereas blocking SVIP myristoylation prevents cytotoxicity. Therefore, SVIP acylation may present a novel target in MSP.}, } @article {pmid39117623, year = {2024}, author = {Hale, OJ and Wells, TR and Mead, RJ and Cooper, HJ}, title = {Mass spectrometry imaging of SOD1 protein-metal complexes in SOD1G93A transgenic mice implicates demetalation with pathology.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {6518}, pmid = {39117623}, issn = {2041-1723}, support = {EP/S002979/1//RCUK | Engineering and Physical Sciences Research Council (EPSRC)/ ; EP/S002979/1//RCUK | Engineering and Physical Sciences Research Council (EPSRC)/ ; BB/S019456/1//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; }, mesh = {Animals ; *Mice, Transgenic ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Spinal Cord/metabolism/pathology ; *Mass Spectrometry/methods ; *Brain/metabolism/diagnostic imaging/pathology ; Copper/metabolism ; Zinc/metabolism ; Humans ; Superoxide Dismutase/metabolism/genetics/chemistry ; Mutation ; Protein Processing, Post-Translational ; Protein Multimerization ; Disease Models, Animal ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons in the central nervous system (CNS). Mutations in the metalloenzyme SOD1 are associated with inherited forms of ALS and cause a toxic gain of function thought to be mediated by dimer destabilization and misfolding. SOD1 binds two Cu and two Zn ions in its homodimeric form. We have applied native ambient mass spectrometry imaging to visualize the spatial distributions of intact metal-bound SOD1[G93A] complexes in SOD1[G93A] transgenic mouse spinal cord and brain sections and evaluated them against disease pathology. The molecular specificity of our approach reveals that metal-deficient SOD1[G93A] species are abundant in CNS structures correlating with ALS pathology whereas fully metalated SOD1[G93A] species are homogenously distributed. Monomer abundance did not correlate with pathology. We also show that the dimer-destabilizing post-translational modification, glutathionylation, has limited influence on the spatial distribution of SOD1 dimers.}, } @article {pmid39118204, year = {2024}, author = {Fang, SY and Tsai, PC and Jih, KY and Hsu, FC and Liao, YC and Yang, CC and Lee, YC}, title = {TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive amyotrophic lateral sclerosis through a haploinsufficiency mechanism.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {87}, number = {10}, pages = {920-926}, pmid = {39118204}, issn = {1728-7731}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; *Protein Serine-Threonine Kinases/genetics ; Adult ; *Haploinsufficiency ; *Age of Onset ; Disease Progression ; }, abstract = {BACKGROUND: TBK1 variants have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia spectrum disorder. The current study elucidated the clinical and molecular genetic features of a novel TBK1 variant identified in a patient with young-onset, rapidly progressive ALS.

METHODS: The coding regions of TBK1 , SOD1 , TARDBP , and FUS were genetically analyzed using Sanger sequencing. Repeat-primed polymerase chain reaction (PCR) was used to survey the GGGGCC repeat in C9ORF72 . The study participant underwent a comprehensive clinical evaluation. The functional effects of the TBK1 variant were analyzed through in vitro transfection studies.

RESULTS: We identified a novel frameshift truncating TBK1 variant, c.456_457delGT (p.Y153Qfs*9), in a man with ALS. The disease initially manifested as right hand weakness at the age of 39 years but progressed rapidly, with the revised ALS Functional Rating Scale score declining at an average monthly rate of 1.92 points in the first year after diagnosis. The patient had no cognitive dysfunction. However, Technetium-99m single photon emission tomography indicated hypoperfusion in his bilateral superior and middle frontal cortices. In vitro studies revealed that the p.Y153Qfs*9 variant resulted in a truncated TBK1 protein product, reduced TBK1 protein expression, loss of kinase function, reduced interaction with optineurin, and impaired dimerization.

CONCLUSION: The heterozygous TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive ALS through a haploinsufficiency mechanism.}, } @article {pmid39119372, year = {2024}, author = {Maristany, AJ and Sa, BC and Murray, C and Subramaniam, AB and Oldak, SE}, title = {Psychiatric Manifestations of Neurological Diseases: A Narrative Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64152}, pmid = {39119372}, issn = {2168-8184}, abstract = {Neurological diseases often manifest with psychiatric symptoms, profoundly impacting patients' well-being and treatment outcomes. This comprehensive review examines the psychiatric manifestations associated with Alzheimer's disease, frontotemporal dementia (FTD), Parkinson's disease, multiple sclerosis (MS), stroke, epilepsy, Huntington's disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and multiple system atrophy (MSA). Key psychiatric symptoms include agitation, depression, anxiety, apathy, hallucinations, impulsivity, and aggression across these diseases. In addition, ethical considerations in treating these symptoms are paramount, particularly regarding genetic testing implications, end-of-life discussions, informed consent, and equitable access to innovative treatments. Effective management necessitates interdisciplinary collaboration, personalized interventions, and a focus on patient autonomy. Understanding the psychiatric burden of neurological diseases is crucial for enhancing patients' quality of life. Further research is needed to elucidate underlying mechanisms and develop targeted interventions. This review underscores the importance of comprehensive assessment and ethical treatment practices to address psychiatric manifestations effectively.}, } @article {pmid39119436, year = {2024}, author = {Galeazzi, L and Holzman, J and Porporatti, A and Rochefort, J}, title = {Lingual Fasciculation as a Point of Call for the Diagnosis of Amyotrophic Lateral Sclerosis: A Literature Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64153}, pmid = {39119436}, issn = {2168-8184}, abstract = {BACKGROUND AND AIM: Dental surgeons often play a pivotal role in the initial detection of lingual fasciculations (LFs). These involuntary micro-movements of the tongue can serve as early clinical indicators of neurodegenerative diseases, with amyotrophic lateral sclerosis (ALS) being the most concerning. Therefore, it is imperative to educate dental surgeons on identifying LF and understanding the potential underlying pathologies.

OBJECTIVES: This study aimed to pinpoint the pathologies in which LFs could emerge as an early clinical marker. Our review focused on articles delineating patient populations exhibiting LF within broader pathological contexts, encompassing neurological and other conditions, with the aim of elucidating their etiologies.

METHODS: We conducted a comprehensive literature review across four databases (PubMed, Embase, Web of Science, and Scopus). Two authors independently extracted data, with consultation from a third author when necessary. Eligible articles included those describing patients with LFs, detailing the methods of detection, diagnosis, and associated pathologies.

RESULTS: Our review identified 22 articles encompassing 153 patients with LF, with an average age of 45.8 years and a female prevalence of 43%. Electromyography and ultrasound emerged as the predominant detection methods. ALS constituted the primary diagnosis in the majority of cases (91%). Additionally, other conditions diagnosed included Machado-Joseph disease (0.046%), familial transthyretin amyloid neuropathy (0.013%), Brown-Vialetto-Van-Laere syndrome (0.006%), chronic inflammatory demyelinating polyneuropathy (0.006%), bulbospinal amyotrophy or Kennedy's disease (0.006%), and osmotic demyelination syndrome (0.006%). LF secondary to organophosphate poisoning was also documented. Symptoms associated with LF encompassed taste alterations, dysphagia, difficulty swallowing, and slurred speech.

CONCLUSION: While primarily indicative of ALS, LFs may also signal diverse underlying pathologies. Healthcare practitioners should be vigilant in their detection and expedite patient referrals to facilitate early integration into care protocols.}, } @article {pmid39119557, year = {2024}, author = {Fogarty, MJ and Drieberg-Thompson, JR and Bellingham, MC and Noakes, PG}, title = {Timeline of hypoglossal motor neuron death and intrinsic tongue muscle denervation in high-copy number SOD1[G93A] mice.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1422943}, pmid = {39119557}, issn = {1664-2295}, support = {R01 AG086136/AG/NIA NIH HHS/United States ; R56 HL166204/HL/NHLBI NIH HHS/United States ; }, abstract = {In amyotrophic lateral sclerosis (ALS) postmortem tissue and the SOD1 mouse model at mid-disease, death of hypoglossal motor neurons (XII MNs) is evident. These XII MNs innervate the intrinsic and extrinsic tongue muscles, and despite their importance in many oral and lingual motor behaviours that are affected by ALS (e.g., swallowing, speech, and respiratory functions), little is known about the timing and extent of tongue muscle denervation. Here in the well-characterised SOD1[G93A] (high-copy) mouse model, we evaluated XII MN numbers and intrinsic tongue muscle innervation using standard histopathological approaches, which included stereological evaluation of Nissl-stained brainstem, and the presynaptic and postsynaptic evaluation of neuromuscular junctions (NMJs), using synapsin, neurofilament, and α-bungarotoxin immunolabelling, at presymptomatic, onset, mid-disease, and endstage timepoints. We found that reduction in XII MN size at onset preceded reduced XII MN survival, while the denervation of tongue muscle did not appear until the endstage. Our study suggests that denervation-induced weakness may not be the most pertinent feature of orolingual deficits in ALS. Efforts to preserve oral and respiratory functions of XII MNs are incredibly important if we are to influence patient outcomes.}, } @article {pmid39120329, year = {2024}, author = {Steffke, C and Agarwal, S and Kabashi, E and Catanese, A}, title = {Overexpression of Toxic Poly(Glycine-Alanine) Aggregates in Primary Neuronal Cultures Induces Time-Dependent Autophagic and Synaptic Alterations but Subtle Activity Impairments.}, journal = {Cells}, volume = {13}, number = {15}, pages = {}, pmid = {39120329}, issn = {2073-4409}, mesh = {*Autophagy ; *Neurons/metabolism ; Animals ; *Synapses/metabolism ; *C9orf72 Protein/genetics/metabolism ; Cells, Cultured ; Peptides/metabolism ; Humans ; Protein Aggregates ; }, abstract = {The pathogenic expansion of the intronic GGGGCC hexanucleotide located in the non-coding region of the C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation leads to the accumulation of toxic RNA foci and dipeptide repeats (DPRs), as well as reduced levels of the C9orf72 protein. Thus, both gain and loss of function are coexisting pathogenic aspects linked to C9orf72-ALS/FTD. Synaptic alterations have been largely described in C9orf72 models, but it is still not clear which aspect of the pathology mostly contributes to these impairments. To address this question, we investigated the dynamic changes occurring over time at the synapse upon accumulation of poly(GA), the most abundant DPR. Overexpression of this toxic form induced a drastic loss of synaptic proteins in primary neuron cultures, anticipating autophagic defects. Surprisingly, the dramatic impairment characterizing the synaptic proteome was not fully matched by changes in network properties. In fact, high-density multi-electrode array analysis highlighted only minor reductions in the spike number and firing rate of poly(GA) neurons. Our data show that the toxic gain of function linked to C9orf72 affects the synaptic proteome but exerts only minor effects on the network activity.}, } @article {pmid39121134, year = {2024}, author = {Roos, A and Häusler, M and Kollipara, L and Topf, A and Preusse, C and Stucka, R and Nolte, K and Strom, T and Berutti, R and Jiang, X and Koll, R and Lochmüller, H and Schacht, SM and Zahedi, RP and Weis, J and Senderek, J}, title = {HNRNPA1 de novo Variant Associated with Early Childhood Onset, Rapidly Progressive Generalized Myopathy.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {5}, pages = {1131-1137}, pmid = {39121134}, issn = {2214-3602}, mesh = {Humans ; Female ; *Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; *Muscular Diseases/genetics ; Disease Progression ; Age of Onset ; Muscle, Skeletal/pathology ; Phenotype ; Mutation ; Child ; }, abstract = {HNRNPA1 variants are known to cause degenerative motoneuron and muscle diseases which manifests in middle age or later. We report on a girl with early childhood onset, rapidly progressive generalized myopathy including ultrastructural findings in line with a proteinopathy. Proteomics of patient-derived muscle and combined screening of genomic data for copy number variations identified a HNRNPA1 de novo intragenic deletion as causative for the phenotype. Our report expands the spectrum of HNRNPA1-related diseases towards early-childhood onset and adds HNRNPA1 to the growing list of ALS and myopathy genes for which certain mutations may cause severe pediatric phenotypes.}, } @article {pmid39122006, year = {2024}, author = {Chen, X and Wei, Q and Yang, Z and Chen, X and Guo, S and Jiang, M and Wang, M}, title = {Structural basis for RNA recognition by the C-terminal RRM domain of human RBM45.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {9}, pages = {107640}, pmid = {39122006}, issn = {1083-351X}, mesh = {Humans ; *RNA-Binding Proteins/metabolism/chemistry/genetics ; *RNA/metabolism/chemistry ; Crystallography, X-Ray ; Protein Domains ; Protein Binding ; DNA, Single-Stranded/metabolism/chemistry/genetics ; Models, Molecular ; Nerve Tissue Proteins ; }, abstract = {RBM45 is an RNA-binding protein with roles in neural development by regulating RNA splicing. Its dysfunction and aggregation are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). RBM45 harbors three RRM domains that potentially bind RNA. While the recognitions of RNA by its N-terminal tandem RRM domains (RRM1 and RRM2) have been well understood, the RNA-binding property of its C-terminal RRM (RRM3) remains unclear. In this work, we identified that the RRM3 of the RBM45 sequence specifically binds RNA with a GACG sequence, similar but not identical to those recognized by the RRM1 and RRM2. Further, we determined the crystal structure of RBM45[RRM3] in complex with a GACG sequence-containing single-stranded DNA. Our structural results, together with the RNA-binding assays of mutants at key amino acid residues, revealed the molecular mechanism by which RBM45[RRM3] recognizes an RNA sequence. Our finding on the RNA-binding property of the individual RRM module of RBM45 provides the foundation for unraveling the RNA-binding characteristics of full-length RBM45 and for understanding the biological functions of RBM45.}, } @article {pmid39122262, year = {2024}, author = {Wang, S and Jiang, Q and Zheng, X and Wei, Q and Lin, J and Yang, T and Xiao, Y and Li, C and Shang, H}, title = {Genotype-phenotype correlation of SQSTM1 variants in patients with amyotrophic lateral sclerosis.}, journal = {Journal of medical genetics}, volume = {61}, number = {10}, pages = {966-972}, doi = {10.1136/jmg-2023-109569}, pmid = {39122262}, issn = {1468-6244}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology/epidemiology ; Frontotemporal Dementia/genetics/pathology ; Gene Frequency ; *Genetic Association Studies ; Genetic Predisposition to Disease ; Genotype ; Mutation ; Phenotype ; *Sequestosome-1 Protein/genetics ; Young Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND: Several variants of sequestosome 1 (SQSTM1) were screened in patients with amyotrophic lateral sclerosis (ALS), while the pathogenicity and genotype-phenotype correlation remains unclear.

METHODS: We screened variants of SQSTM1 gene in 2011 Chinese patients with ALS and performed a burden analysis focusing on the rare variants. Furthermore, we conducted a comprehensive analysis of patients with variants of SQSTM1 gene in patients with ALS from our cohort and published studies.

RESULTS: In our cohort, we identified 32 patients with 25 different SQSTM1 variants with a mutant frequency of 1.6%. Notably, 26% (5/19) of the patients with ALS with SQSTM1 variant in our cohort had comorbid cognitive impairment and 43% (3/7) of them had behavioural variant frontotemporal dementia (FTD). Our meta-analysis found a total frequency of SQSTM1 variants in 7183 patients with ALS was 2.4%; burden analysis indicated that patients with ALS had enrichment of ultra-rare (minor allele frequency<0.01%) probably pathogenic variants in SQSTM1. Most variants were missense variants and distributed in various domains of p62 protein, some of which might be related to comorbidities of Paget's disease of bone and FTD.

CONCLUSION: Our study established the largest cohort of patients with ALS with SQSTM1 variants, expanded the mutation spectrum and investigated the genotype-phenotype correlations of SQSTM1 variants.}, } @article {pmid39122453, year = {2024}, author = {Khan, S and Bano, N and Ahamad, S and John, U and Dar, NJ and Bhat, SA}, title = {Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms.}, journal = {Aging and disease}, volume = {16}, number = {5}, pages = {2504-2543}, pmid = {39122453}, issn = {2152-5250}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/physiopathology ; *Mitochondria/metabolism/pathology ; Oxidative Stress ; *Ferroptosis/physiology ; Mitophagy ; Animals ; Energy Metabolism ; }, abstract = {Mitochondrial dysfunction plays a pivotal role in the development of age-related diseases, particularly neurodegenerative disorders. The etiology of mitochondrial dysfunction involves a multitude of factors that remain elusive. This review centers on elucidating the role(s) of excitotoxicity, oxytosis/ferroptosis and neurodegeneration within the context of mitochondrial bioenergetics, biogenesis, mitophagy and oxidative stress and explores their intricate interplay in the pathogenesis of neurodegenerative diseases. The effective coordination of mitochondrial turnover processes, notably mitophagy and biogenesis, is assumed to be critically important for cellular resilience and longevity. However, the age-associated decrease in mitophagy impedes the elimination of dysfunctional mitochondria, consequently impairing mitochondrial biogenesis. This deleterious cascade results in the accumulation of damaged mitochondria and deterioration of cellular functions. Both excitotoxicity and oxytosis/ferroptosis have been demonstrated to contribute significantly to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS). Excitotoxicity, characterized by excessive glutamate signaling, initiates a cascade of events involving calcium dysregulation, energy depletion, and oxidative stress and is intricately linked to mitochondrial dysfunction. Furthermore, emerging concepts surrounding oxytosis/ferroptosis underscore the importance of iron-dependent lipid peroxidation and mitochondrial engagement in the pathogenesis of neurodegeneration. This review not only discusses the individual contributions of excitotoxicity and ferroptosis but also emphasizes their convergence with mitochondrial dysfunction, a key driver of neurodegenerative diseases. Understanding the intricate crosstalk between excitotoxicity, oxytosis/ferroptosis, and mitochondrial dysfunction holds potential to pave the way for mitochondrion-targeted therapeutic strategies. Such strategies, with a focus on bioenergetics, biogenesis, mitophagy, and oxidative stress, emerge as promising avenues for therapeutic intervention.}, } @article {pmid39122743, year = {2024}, author = {Shin, B and Kwon, Y and Mittaz, M and Kim, H and Xu, X and Kim, E and Lee, YJ and Lee, J and Yeo, WH and Choo, HJ}, title = {All-in-one wearable drug efficacy assessment systems for bulbar muscle function using amyotrophic lateral sclerosis animal models.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {6803}, pmid = {39122743}, issn = {2041-1723}, support = {R21 EB031535/EB/NIBIB NIH HHS/United States ; UL1 TR002378/TR/NCATS NIH HHS/United States ; R21EB031535//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/drug therapy ; Animals ; *Disease Models, Animal ; *Wearable Electronic Devices ; *Electromyography/methods ; Drug Evaluation, Preclinical ; Deglutition Disorders/physiopathology/etiology ; Muscle, Skeletal/drug effects/physiopathology/innervation ; Humans ; Male ; Motor Neurons/drug effects/physiology ; Rats ; }, abstract = {Preclinical studies are crucial for developing amyotrophic lateral sclerosis drugs. Current FDA-approved drugs have been created by monitoring limb muscle function and histological analysis of amyotrophic lateral sclerosis model animals. Drug candidates for this disease have yet to be tested for bulbar-onset type due to the limitations of traditional preclinical tools: excessive animal use and discrete detection of disease progress. Here, our study introduces an all-in-one, wireless, integrated wearable system for facilitating continuous drug efficacy assessment of dysphagia-related muscles in animals during natural eating behaviors. By incorporating a kirigami-based strain-isolation mechanism, this device mounted on the skin of animals mitigates electromyography signal contamination caused by unpredictable animal movements. Our findings indicate this system, measuring the progression of motor neuron denervation, offers high precision in monitoring drug effects on dysphagia-responsible bulbar muscles. This study paves the way for more humane and efficient approaches to developing treatment solutions for degenerative neuromuscular diseases.}, } @article {pmid39123212, year = {2024}, author = {Wang, X and Pan, W and Sun, C and Yang, H and Cheng, Z and Yan, F and Ma, G and Shang, Y and Zhang, R and Gao, C and Liu, L and Zhang, H}, title = {Creating large-scale genetic diversity in Arabidopsis via base editing-mediated deep artificial evolution.}, journal = {Genome biology}, volume = {25}, number = {1}, pages = {215}, pmid = {39123212}, issn = {1474-760X}, support = {TSQN202103160//Taishan Scholar Foundation of Shandong Province/ ; ZR202103010168//Excellent Youth Foundation of Shandong Scientific Committee/ ; 2022YFD1201700//National Key R&D Program of China/ ; }, mesh = {*Arabidopsis/genetics ; *Gene Editing/methods ; *Genetic Variation ; CRISPR-Cas Systems ; Directed Molecular Evolution ; Alleles ; Mutation ; Plant Breeding/methods ; Herbicide Resistance/genetics ; }, abstract = {BACKGROUND: Base editing is a powerful tool for artificial evolution to create allelic diversity and improve agronomic traits. However, the great evolutionary potential for every sgRNA target has been overlooked. And there is currently no high-throughput method for generating and characterizing as many changes in a single target as possible based on large mutant pools to permit rapid gene directed evolution in plants.

RESULTS: In this study, we establish an efficient germline-specific evolution system to screen beneficial alleles in Arabidopsis which could be applied for crop improvement. This system is based on a strong egg cell-specific cytosine base editor and the large seed production of Arabidopsis, which enables each T1 plant with unedited wild type alleles to produce thousands of independent T2 mutant lines. It has the ability of creating a wide range of mutant lines, including those containing atypical base substitutions, and as well providing a space- and labor-saving way to store and screen the resulting mutant libraries. Using this system, we efficiently generate herbicide-resistant EPSPS, ALS, and HPPD variants that could be used in crop breeding.

CONCLUSIONS: Here, we demonstrate the significant potential of base editing-mediated artificial evolution for each sgRNA target and devised an efficient system for conducting deep evolution to harness this potential.}, } @article {pmid39124808, year = {2024}, author = {Miyaue, N and Yamanishi, Y and Ito, Y and Ando, R and Nagai, M}, title = {CSF Neopterin Levels Are Elevated in Various Neurological Diseases and Aging.}, journal = {Journal of clinical medicine}, volume = {13}, number = {15}, pages = {}, pmid = {39124808}, issn = {2077-0383}, abstract = {Background/Objectives: Cerebrospinal fluid (CSF) neopterin reflects inflammation of the central nervous system (CNS) and is a potentially useful biomarker for neuroinflammatory assessment and differential diagnosis. However, its optimal cut-off level in adult patients with neurological disease has not been established and it has not been adequately studied in controls. We aimed to determine its usefulness as a biomarker of neuroinflammation and the effect of age on its level. Methods: In this retrospective study, CSF neopterin was evaluated in 652 patients in 38 disease groups. Its levels were analyzed with high-performance liquid chromatography with fluorometric detection. Results: A receiver operating characteristic analysis revealed that the optimal cut-off value of 33.57 pmol/mL for CSF neopterin distinguished the control and meningitis/encephalitis groups with a sensitivity of 100.0% and specificity of 94.4%. In the control group, which consisted of 170 participants (99 men and 71 women; mean ± standard deviation age, 52.56 ± 17.99 years), age was significantly positively correlated with CSF protein (r = 0.474, p < 0.001) and CSF neopterin (r = 0.476, p < 0.001) levels but not with CSF cell count (r = 0.144, p = 0.061). Both male and female controls exhibited significant increases in CSF neopterin levels with age. Similarly, the CSF neopterin level was significantly positively correlated with age in patients with amyotrophic lateral sclerosis, independently of disease duration and respiratory function. Conclusions: CSF neopterin levels were elevated in patients with various CNS diseases, reflecting CNS inflammation; they were also elevated with age. Prospective studies are required to establish CSF neopterin as a sensitive biomarker of neuroinflammation.}, } @article {pmid39125740, year = {2024}, author = {Bernard, E and Cluse, F and Bohic, A and Hermier, M and Raoul, C and Leblanc, P and Guissart, C}, title = {A Novel De Novo Missense Mutation in KIF1A Associated with Young-Onset Upper-Limb Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {15}, pages = {}, pmid = {39125740}, issn = {1422-0067}, mesh = {Humans ; *Kinesins/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Female ; *Mutation, Missense ; Adult ; Upper Extremity/physiopathology/pathology ; Magnetic Resonance Imaging ; }, abstract = {We investigate the etiology of amyotrophic lateral sclerosis (ALS) in a 35-year-old woman presenting with progressive weakness in her left upper limb. Prior to sequencing, a comprehensive neurological work-up was performed, including neurological examination, electrophysiology, biomarker assessment, and brain and spinal cord MRI. Six months before evaluation, the patient experienced weakness and atrophy in her left hand, accompanied by brisk reflexes and Hoffman sign in the same arm. Electroneuromyography revealed lower motor neuron involvement in three body regions. Neurofilament light chains were elevated in her cerebrospinal fluid. Brain imaging showed asymmetrical T2 hyperintensity of the corticospinal tracts and T2 linear hypointensity of the precentral gyri. Trio genome sequencing identified a likely pathogenic de novo variant in the KIF1A gene (NM_001244008.2): c.574A>G, p.(Ile192Val). Pathogenic variants in KIF1A have been associated with a wide range of neurological manifestations called KIF1A-associated neurological diseases (KAND). This report describes a likely pathogenic de novo variant in KIF1A associated with ALS, expanding the phenotypic spectrum of KAND and our understanding of the pathophysiology of ALS.}, } @article {pmid39126066, year = {2024}, author = {Mejzini, R and Caruthers, MH and Schafer, B and Kostov, O and Sudheendran, K and Ciba, M and Danielsen, M and Wilton, S and Akkari, PA and Flynn, LL}, title = {Allele-Selective Thiomorpholino Antisense Oligonucleotides as a Therapeutic Approach for Fused-in-Sarcoma Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {15}, pages = {}, pmid = {39126066}, issn = {1422-0067}, support = {2322//Motor Neurone Disease Research Australia/ ; }, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use/genetics ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; *RNA-Binding Protein FUS/genetics ; *Alleles ; Fibroblasts/metabolism/drug effects ; Gene Knockdown Techniques ; Morpholinos/therapeutic use/genetics ; }, abstract = {Pathogenic variations in the fused in sarcoma (FUS) gene are associated with rare and aggressive forms of amyotrophic lateral sclerosis (ALS). As FUS-ALS is a dominant disease, a targeted, allele-selective approach to FUS knockdown is most suitable. Antisense oligonucleotides (AOs) are a promising therapeutic platform for treating such diseases. In this study, we have explored the potential for allele-selective knockdown of FUS. Gapmer-type AOs targeted to two common neutral polymorphisms in FUS were designed and evaluated in human fibroblasts. AOs had either methoxyethyl (MOE) or thiomorpholino (TMO) modifications. We found that the TMO modification improved allele selectivity and efficacy for the lead sequences when compared to the MOE counterparts. After TMO-modified gapmer knockdown of the target allele, up to 93% of FUS transcripts detected were from the non-target allele. Compared to MOE-modified AOs, the TMO-modified AOs also demonstrated reduced formation of structured nuclear inclusions and SFPQ aggregation that can be triggered by phosphorothioate-containing AOs. How overall length and gap length of the TMO-modified AOs affected allele selectivity, efficiency and off-target gene knockdown was also evaluated. We have shown that allele-selective knockdown of FUS may be a viable therapeutic strategy for treating FUS-ALS and demonstrated the benefits of the TMO modification for allele-selective applications.}, } @article {pmid39126144, year = {2024}, author = {Briones, MRS and Campos, JH and Ferreira, RC and Schneper, L and Santos, IM and Antoneli, FM and , and Broach, JR}, title = {Mitochondrial genome variants associated with amyotrophic lateral sclerosis and their haplogroup distribution.}, journal = {Muscle & nerve}, volume = {70}, number = {4}, pages = {862-872}, pmid = {39126144}, issn = {1097-4598}, support = {//Tow Foundation/ ; //NIH/ ; 2013/07838-0//FAPESP/ ; 2014/25602-6//FAPESP/ ; //CAPES/ ; 303912/2017-0//CNPq/ ; T32 LM012415/LM/NLM NIH HHS/United States ; 19-SI-459//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genome, Mitochondrial/genetics ; Male ; Female ; *Genome-Wide Association Study ; Middle Aged ; Haplotypes ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease/genetics ; Aged ; Genetic Variation/genetics ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) may be familial or sporadic, and twin studies have revealed that even sporadic forms have a significant genetic component. Variants in 55 nuclear genes have been associated with ALS and although mitochondrial dysfunction is observed in ALS, variants in mitochondrial genomes (mitogenomes) have not yet been tested for association with ALS. The aim of this study was to determine whether mitogenome variants are associated with ALS.

METHODS: We conducted a genome-wide association study (GWAS) in mitogenomes of 1965 ALS patients and 2547 controls.

RESULTS: We identified 51 mitogenome variants with p values <10[-7], of which 13 had odds ratios (ORs) >1, in genes RNR1, ND1, CO1, CO3, ND5, ND6, and CYB, while 38 variants had OR <1 in genes RNR1, RNA2, ND1, ND2, CO2, ATP8, ATP6, CO3, ND3, ND4, ND5, ND6, and CYB. The frequencies of haplogroups H, U, and L, the most frequent in our ALS data set, were the same in different onset sites (bulbar, limb, spinal, and axial). Also, intra-haplogroup GWAS revealed unique ALS-associated variants in haplogroups L and U.

DISCUSSION: Our study shows that mitogenome single nucleotide variants (SNVs) are associated with ALS and suggests that these SNVs could be included in routine genetic testing for ALS and that mitochondrial replacement therapy has the potential to serve as a basis for ALS treatment.}, } @article {pmid39126203, year = {2024}, author = {Tabuchi, R and Momozawa, Y and Hayashi, Y and Noma, H and Ichijo, H and Fujisawa, T}, title = {SoDCoD: a comprehensive database of Cu/Zn superoxide dismutase conformational diversity caused by ALS-linked gene mutations and other perturbations.}, journal = {Database : the journal of biological databases and curation}, volume = {2024}, number = {}, pages = {0}, pmid = {39126203}, issn = {1758-0463}, support = {JP21H04760 JP22H04636 JP22H04804 JP22K06610 JP23K14143//Japan Society for the Promotion of Science/ ; JP21gm5010001//Japan Agency for Medical Research and Development/ ; //SERIKA FUND/ ; 2023-ISMCRP-2033//the ISM Cooperative Research Program/ ; //the researcher exchange promotion program of ROIS (Research Organization of Information and Systems)/ ; JPMJMS2022-18//Japan Science and Technology Agency/ ; JP21H04760 JP22H04636 JP22H04804 JP22K06610 JP23K14143//Japan Society for the Promotion of Science/ ; JP21gm5010001//Japan Agency for Medical Research and Development/ ; //SERIKA FUND/ ; 2023-ISMCRP-2033//the ISM Cooperative Research Program/ ; //the researcher exchange promotion program of ROIS (Research Organization of Information and Systems)/ ; JPMJMS2022-18//Japan Science and Technology Agency/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/enzymology ; Humans ; *Mutation ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; Databases, Protein ; Protein Conformation ; Databases, Genetic ; Superoxide Dismutase/genetics/chemistry/metabolism ; }, abstract = {A structural alteration in copper/zinc superoxide dismutase (SOD1) is one of the common features caused by amyotrophic lateral sclerosis (ALS)-linked mutations. Although a large number of SOD1 variants have been reported in ALS patients, the detailed structural properties of each variant are not well summarized. We present SoDCoD, a database of superoxide dismutase conformational diversity, collecting our comprehensive biochemical analyses of the structural changes in SOD1 caused by ALS-linked gene mutations and other perturbations. SoDCoD version 1.0 contains information about the properties of 188 types of SOD1 mutants, including structural changes and their binding to Derlin-1, as well as a set of genes contributing to the proteostasis of mutant-like wild-type SOD1. This database provides valuable insights into the diagnosis and treatment of ALS, particularly by targeting conformational alterations in SOD1. Database URL: https://fujisawagroup.github.io/SoDCoDweb/.}, } @article {pmid39126786, year = {2024}, author = {Neumann, M and Kothare, H and Ramanarayanan, V}, title = {Multimodal speech biomarkers for remote monitoring of ALS disease progression.}, journal = {Computers in biology and medicine}, volume = {180}, number = {}, pages = {108949}, pmid = {39126786}, issn = {1879-0534}, support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; *Disease Progression ; Female ; Middle Aged ; Aged ; Speech/physiology ; Biomarkers ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that severely impacts affected persons' speech and motor functions, yet early detection and tracking of disease progression remain challenging. The current gold standard for monitoring ALS progression, the ALS functional rating scale - revised (ALSFRS-R), is based on subjective ratings of symptom severity, and may not capture subtle but clinically meaningful changes due to a lack of granularity. Multimodal speech measures which can be automatically collected from patients in a remote fashion allow us to bridge this gap because they are continuous-valued and therefore, potentially more granular at capturing disease progression. Here we investigate the responsiveness and sensitivity of multimodal speech measures in persons with ALS (pALS) collected via a remote patient monitoring platform in an effort to quantify how long it takes to detect a clinically-meaningful change associated with disease progression. We recorded audio and video from 278 participants and automatically extracted multimodal speech biomarkers (acoustic, orofacial, linguistic) from the data. We find that the timing alignment of pALS speech relative to a canonical elicitation of the same prompt and the number of words used to describe a picture are the most responsive measures at detecting such change in both pALS with bulbar (n = 36) and non-bulbar onset (n = 107). Interestingly, the responsiveness of these measures is stable even at small sample sizes. We further found that certain speech measures are sensitive enough to track bulbar decline even when there is no patient-reported clinical change, i.e. the ALSFRS-R speech score remains unchanged at 3 out of a total possible score of 4. The findings of this study have the potential to facilitate improved, accelerated and cost-effective clinical trials and care.}, } @article {pmid39126873, year = {2024}, author = {Vacchiano, V and Di Stasi, V and Teodorani, L and Faini, C and Morabito, F and Liguori, R}, title = {Comparative assessment of MScanFit MUNE and quantitative EMG in amyotrophic lateral sclerosis diagnosis: A prospective study.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {166}, number = {}, pages = {66-73}, doi = {10.1016/j.clinph.2024.07.017}, pmid = {39126873}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Electromyography/methods ; Male ; Female ; Middle Aged ; Aged ; Prospective Studies ; *Motor Neurons/physiology ; *Action Potentials/physiology ; *Muscle, Skeletal/physiopathology ; Adult ; }, abstract = {OBJECTIVE: Motor Unit Number Estimation (MUNE) techniques are crucial in assessing lower motor neuron loss. MScanFit MUNE (MScanFit) is a novel tool which estimates MUNE values from compound muscle action potential (CMAP) scans by considering the probabilistic nature of motor unit firing. We conducted a prospective study to evaluate the diagnostic utility of MScanFit compared to quantitative electromyography (qEMG) in ALS patients.

METHODS: We enrolled 35 patients diagnosed with amyotrophic lateral sclerosis (ALS) and 14 healthy controls, assessing qEMG and MScanFit MUNE in abductor pollicis brevis, abductor digiti minimi and tibialis anterior muscles.

RESULTS: We found higher sensitivity of qEMG in detecting abnormalities compared to MScanFit, with a high concordance rate between the two techniques. Notably, a few muscles exhibited abnormal MUNE but normal qEMG findings, suggesting a potential complementary role for MScanFit in ALS diagnosis. Neurophysiological parameters from MScanFit showed good correlations with qEMG measures. Subclinical neurophysiological involvement was observed in muscles with normal strength, emphasizing the importance of sensitive diagnostic tools.

CONCLUSION: MScanFit demonstrated validity in distinguishing ALS patients from healthy subjects and correlated well with qEMG parameters.

SIGNIFICANCE: Our study confirmed the diagnostic utility of MScanFit MUNE in ALS, highlighting its role as a supplementary diagnostic tool.}, } @article {pmid39127445, year = {2024}, author = {Wang, MY and Zhou, Y and Li, WL and Zhu, LQ and Liu, D}, title = {Friend or foe: Lactate in neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102452}, doi = {10.1016/j.arr.2024.102452}, pmid = {39127445}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Lactic Acid/metabolism ; Animals ; }, abstract = {Lactate, a byproduct of glycolysis, was considered as a metabolic waste until identified by studies on the Warburg effect. Increasing evidence elucidates that lactate functions as energy fuel, signaling molecule, and donor for protein lactylation. Altered lactate utilization is a common metabolic feature of the onset and progression of neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease. This review offers an overview of lactate metabolism from the perspective of production, transportation and clearance, and the role of lactate in neurodegenerative progression, as well as a summary of protein lactylation and the signaling function of lactate in neurodegenerative diseases. Besides, this review delves into the dual roles of changed lactate metabolism during neurodegeneration and explores prospective therapeutic methods targeting lactate. We propose that elucidating the correlation between lactate and neurodegeneration is pivotal for exploring innovative therapeutic interventions for neurodegenerative diseases.}, } @article {pmid39128005, year = {2024}, author = {Knupp, J and Chen, YJ and Wang, E and Arvan, P and Tsai, B}, title = {Sigma-1 receptor recruits LC3 mRNA to ER-associated omegasomes to promote localized LC3 translation enabling functional autophagy.}, journal = {Cell reports}, volume = {43}, number = {8}, pages = {114619}, pmid = {39128005}, issn = {2211-1247}, support = {F31 DK128868/DK/NIDDK NIH HHS/United States ; P30 DK020572/DK/NIDDK NIH HHS/United States ; R01 AI170514/AI/NIAID NIH HHS/United States ; R01 DK111174/DK/NIDDK NIH HHS/United States ; }, mesh = {*Receptors, sigma/metabolism/genetics ; *Sigma-1 Receptor ; *Autophagy ; *Microtubule-Associated Proteins/metabolism/genetics ; *Endoplasmic Reticulum/metabolism ; Humans ; *RNA, Messenger/metabolism/genetics ; *3' Untranslated Regions/genetics ; *Protein Biosynthesis ; Ribosomes/metabolism ; Animals ; Autophagosomes/metabolism ; HeLa Cells ; }, abstract = {Autophagosome formation initiated on the endoplasmic reticulum (ER)-associated omegasome requires LC3. Translational regulation of LC3 biosynthesis is unexplored. Here we demonstrate that LC3 mRNA is recruited to omegasomes by directly binding to the ER transmembrane Sigma-1 receptor (S1R). Cell-based and in vitro reconstitution experiments show that S1R interacts with the 3' UTR of LC3 mRNA and ribosomes to promote LC3 translation. Strikingly, the 3' UTR of LC3 is also required for LC3 protein lipidation, thereby linking the mRNA-3' UTR to LC3 function. An autophagy-defective S1R mutant responsible for amyotrophic lateral sclerosis cannot bind LC3 mRNA or induce LC3 translation. We propose a model wherein S1R de-represses LC3 mRNA via its 3' UTR at the ER, enabling LC3 biosynthesis and lipidation. Because several other LC3-related proteins use the same mechanism, our data reveal a conserved pathway for localized translation essential for autophagosome biogenesis with insights illuminating the molecular basis of a neurodegenerative disease.}, } @article {pmid39128727, year = {2024}, author = {George, G and Ajayan, A and Varkey, J and Pandey, NK and Chen, J and Langen, R}, title = {TDP43 and huntingtin Exon-1 undergo a conformationally specific interaction that strongly alters the fibril formation of both proteins.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {9}, pages = {107660}, pmid = {39128727}, issn = {1083-351X}, support = {R01 NS118859/NS/NINDS NIH HHS/United States ; R01 NS120704/NS/NINDS NIH HHS/United States ; R01 NS125769/NS/NINDS NIH HHS/United States ; }, mesh = {*Huntingtin Protein/metabolism/genetics/chemistry ; Humans ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; *Exons ; Amyloid/metabolism/chemistry ; Protein Aggregates ; Protein Aggregation, Pathological/metabolism/genetics ; Protein Binding ; Protein Conformation ; Protein Domains ; }, abstract = {Protein aggregation is a common feature of many neurodegenerative diseases. In Huntington's disease, mutant huntingtin is the primary aggregating protein, but the aggregation of other proteins, such as TDP43, is likely to further contribute to toxicity. Moreover, mutant huntingtin is also a risk factor for TDP pathology in ALS. Despite this co-pathology of huntingtin and TDP43, it remains unknown whether these amyloidogenic proteins directly interact with each other. Using a combination of biophysical methods, we show that the aggregation-prone regions of both proteins, huntingtin exon-1 (Httex1) and the TDP43 low complexity domain (TDP43-LCD), interact in a conformationally specific manner. This interaction significantly slows Httex1 aggregation, while it accelerates TDP43-LCD aggregation. A key intermediate responsible for both effects is a complex formed by liquid TDP43-LCD condensates and Httex1 fibrils. This complex shields seeding competent surfaces of Httex1 fibrils from Httex1 monomers, which are excluded from the condensates. In contrast, TDP43-LCD condensates undergo an accelerated liquid-to-solid transition upon exposure to Httex1 fibrils. Cellular studies show co-aggregation of untagged Httex1 with TDP43. This interaction causes mislocalization of TDP43, which has been linked to TDP43 toxicity. The protection from Httex1 aggregation in lieu of TDP43-LCD aggregation is interesting, as it mirrors what has been found in disease models, namely that TDP43 can protect from huntingtin toxicity, while mutant huntingtin can promote TDP43 pathology. These results suggest that direct protein interaction could, at least in part, be responsible for the linked pathologies of both proteins.}, } @article {pmid39128808, year = {2024}, author = {Farhangian, M and Azarafrouz, F and Valian, N and Dargahi, L}, title = {The role of interferon beta in neurological diseases and its potential therapeutic relevance.}, journal = {European journal of pharmacology}, volume = {981}, number = {}, pages = {176882}, doi = {10.1016/j.ejphar.2024.176882}, pmid = {39128808}, issn = {1879-0712}, mesh = {Humans ; Animals ; *Interferon-beta/therapeutic use/metabolism ; Nervous System Diseases/drug therapy/metabolism ; Signal Transduction/drug effects ; }, abstract = {Interferon beta (IFNβ) is a member of the type-1 interferon family and has various immunomodulatory functions in neuropathological conditions. Although the level of IFNβ is low under healthy conditions, it is increased during inflammatory processes to protect the central nervous system (CNS). In particular, microglia and astrocytes are the main sources of IFNβ upon inflammatory insult in the CNS. The protective effects of IFNβ are well characterized in reducing the progression of multiple sclerosis (MS); however, little is understood about its effects in other neurological/neurodegenerative diseases. In this review, different types of IFNs and their signaling pathways will be described. Then we will focus on the potential role and therapeutic effect of IFNβ in several CNS-related diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, spinal cord injury, prion disease and spinocerebellar ataxia 7.}, } @article {pmid39130445, year = {2024}, author = {Phipps, AJ and Dwyer, S and Collins, JM and Kabir, F and Atkinson, RA and Chowdhury, MA and Matthews, L and Dixit, D and Terry, RS and Smith, J and Gueven, N and Bennett, W and Cook, AL and King, AE and Perry, S}, title = {HDAC6 inhibition as a mechanism to prevent neurodegeneration in the mSOD1[G93A] mouse model of ALS.}, journal = {Heliyon}, volume = {10}, number = {14}, pages = {e34587}, pmid = {39130445}, issn = {2405-8440}, abstract = {The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One emerging dichotomy is that protection of the neuronal cell soma does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a mechanism to stabilize axons, prevent axonal loss and neurodegeneration in ALS. This study used an orally dosed potent HDAC6 inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1[G93A] mouse model of ALS. Co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1[G93A] mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS.}, } @article {pmid39131911, year = {2024}, author = {Ikeda, A and Meng, H and Taniguchi, D and Mio, M and Funayama, M and Nishioka, K and Yoshida, M and Li, Y and Yoshino, H and Inoshita, T and Shiba-Fukushima, K and Okubo, Y and Sakurai, T and Amo, T and Aiba, I and Saito, Y and Saito, Y and Murayama, S and Atsuta, N and Nakamura, R and Tohnai, G and Izumi, Y and Morita, M and Tamura, A and Kano, O and Oda, M and Kuwabara, S and Yamashita, T and Sone, J and Kaji, R and Sobue, G and Imai, Y and Hattori, N}, title = {CHCHD2 P14L, found in amyotrophic lateral sclerosis, exhibits cytoplasmic mislocalization and alters Ca[2+] homeostasis.}, journal = {PNAS nexus}, volume = {3}, number = {8}, pages = {pgae319}, pmid = {39131911}, issn = {2752-6542}, abstract = {CHCHD2 and CHCHD10, linked to Parkinson's disease and amyotrophic lateral sclerosis-frontotemporal dementia (ALS), respectively, are mitochondrial intermembrane proteins that form a heterodimer. This study aimed to investigate the impact of the CHCHD2 P14L variant, implicated in ALS, on mitochondrial function and its subsequent effects on cellular homeostasis. The missense variant of CHCHD2, P14L, found in a cohort of patients with ALS, mislocalized CHCHD2 to the cytoplasm, leaving CHCHD10 in the mitochondria. Drosophila lacking the CHCHD2 ortholog exhibited mitochondrial degeneration. In contrast, human CHCHD2 P14L, but not wild-type human CHCHD2, failed to suppress this degeneration, suggesting that P14L is a pathogenic variant. The mitochondrial Ca[2+] buffering capacity was reduced in Drosophila neurons expressing human CHCHD2 P14L. The altered Ca[2+]-buffering phenotype was also observed in cultured human neuroblastoma SH-SY5Y cells expressing CHCHD2 P14L. In these cells, transient elevation of cytoplasmic Ca[2+] facilitated the activation of calpain and caspase-3, accompanied by the processing and insolubilization of TDP-43. These observations suggest that CHCHD2 P14L causes abnormal Ca[2+] dynamics and TDP-43 aggregation, reflecting the pathophysiology of ALS.}, } @article {pmid39134031, year = {2025}, author = {Aziz, M and Kniep, I and Ondruschka, B and Püschel, K and Hessler, C}, title = {Cement Leakage after Augmentation of Osteoporotic Vertebral Bodies.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {2}, pages = {146-152}, doi = {10.1055/a-2343-4100}, pmid = {39134031}, issn = {1864-6743}, mesh = {Humans ; Female ; *Bone Cements/adverse effects ; Male ; Aged ; Aged, 80 and over ; Middle Aged ; *Spinal Fractures/surgery/mortality ; Germany/epidemiology ; Risk Factors ; *Vertebroplasty/statistics & numerical data/mortality ; *Osteoporotic Fractures/surgery/mortality ; *Extravasation of Diagnostic and Therapeutic Materials/mortality ; Adult ; Retrospective Studies ; *Postoperative Complications/mortality ; }, abstract = {Der Zementaustritt ist die häufigste Komplikation bei der Zementaugmentation von Wirbelkörpern. In der vorliegenden Studie wurden die Zementaustrittsraten bei Zementaugmentationen an der Wirbelsäule untersucht und potenzielle Risikofaktoren für einen Zementaustritt identifiziert.Es wurden 140 Fälle von 131 Patienten und Patientinnen und 9 Verstorbenen ausgewertet. Insgesamt wurden 258 zementaugmentierte Wirbelkörper untersucht. Die Daten dafür stammen aus den Krankenhausdokumentationen von 131 Patienten und Patientinnen, die sich in 2 orthopädisch-unfallchirurgischen Kliniken in der BRD solchen Operationen unterzogen, sowie aus den Untersuchungen von 9 Sterbefällen im Institut für Rechtsmedizin der Universitätsklinikums Hamburg-Eppendorf.Zementaustritte wurden in 64 der 140 Fälle (45,7%) ermittelt. Lokale Zementaustritte waren mit 73,4% (n = 47) die häufigste Austrittsart. Venöse Austritte wurden in 15 Fällen (23,4%) und Lungenzementembolisationen in 2 Fällen (3,1%) evaluiert. Innerhalb des Kollektivs der retrospektiv untersuchten Fälle (n = 131) erlitt lediglich 1 Patient (0,8%) einen symptomatischen Zementaustritt. Als Risikofaktoren für Zementaustritte konnten Zementaugmentationen von Frakturen an Lendenwirbelkörpern sowie eine hohe applizierte Zementmenge identifiziert werden.Sowohl die Daten in der assoziierten Literatur als auch die Ergebnisse dieser Arbeit belegen eine hohe Inzidenz von Zementaustritten nach Wirbelkörperaugmentationen. Trotz des geringen prozentualen Anteils symptomatischer Fälle sollten bei der Planung und Durchführung von Zementaugmentationen an Wirbelkörpern die möglichen Einflussfaktoren für einen Zementaustritt berücksichtigt und in die OP-Planung einbezogen werden.}, } @article {pmid39134599, year = {2024}, author = {Mikawy, NN and Magdy, N and Mohamed, MH and El-Kosasy, AM}, title = {Green highly sensitive and selective spectroscopic detection of guaifenesin in multiple dosage forms and spiked human plasma.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {18694}, pmid = {39134599}, issn = {2045-2322}, mesh = {*Guaifenesin/analysis/administration & dosage ; Humans ; *Limit of Detection ; *Spectrometry, Fluorescence/methods ; Tablets ; Green Chemistry Technology/methods ; }, abstract = {Guaifenesin (GUA) is determined in dosage forms and plasma using two methods. The spectrofluorimetric technique relies on the measurement of native fluorescence intensity at 302 nm upon excitation wavelength "223 nm". The method was validated according to ICH and FDA guidelines. A concentration range of 0.1-1.1 μg/mL was used, with limit of detection (LOD) and quantification (LOQ) values 0.03 and 0.08 µg/mL, respectively. This method was used to measure GUA in tablets and plasma, with %recovery of 100.44% ± 0.037 and 101.03% ± 0.751. Furthermore, multivariate chemometric-assisted spectrophotometric methods are used for the determination of GUA, paracetamol (PARA), oxomemazine (OXO), and sodium benzoate (SB) in their lab mixtures. The concentration ranges of 2.0-10.0, 4.0-16.0, 2.0-10.0, and 3.0-10.0 µg/mL for OXO, GUA, PARA, and SB; respectively, were used. LOD and LOQ were 0.33, 0.68, 0.28, and 0.29 µg/mL, and 1.00, 2.06, 0.84, and 0.87 µg/mL for PARA, GUA, OXO, and SB. For the suppository application, the partial least square (PLS) model was used with %recovery 98.49% ± 0.5, 98.51% ± 0.64, 100.21% ± 0.36 & 98.13% ± 0.51, although the multivariate curve resolution alternating least-squares (MCR-ALS) model was used with %recovery 101.39 ± 0.45, 99.19 ± 0.2, 100.24 ± 0.12, and 98.61 ± 0.32 for OXO, GUA, PARA, and SB. Analytical Eco-scale and Analytical Greenness Assessment were used to assess the greenness level of our techniques.}, } @article {pmid39134696, year = {2024}, author = {Visser, BS and Lipiński, WP and Spruijt, E}, title = {The role of biomolecular condensates in protein aggregation.}, journal = {Nature reviews. Chemistry}, volume = {8}, number = {9}, pages = {686-700}, pmid = {39134696}, issn = {2397-3358}, mesh = {Humans ; *Biomolecular Condensates/metabolism/chemistry ; *Protein Aggregates ; Neurodegenerative Diseases/metabolism ; Amyloid/metabolism/chemistry ; Protein Aggregation, Pathological/metabolism ; Proteins/chemistry/metabolism ; }, abstract = {There is an increasing amount of evidence that biomolecular condensates are linked to neurodegenerative diseases associated with protein aggregation, such as Alzheimer's disease and amyotrophic lateral sclerosis, although the mechanisms underlying this link remain elusive. In this Review, we summarize the possible connections between condensates and protein aggregation. We consider both liquid-to-solid transitions of phase-separated proteins and the partitioning of proteins into host condensates. We distinguish five key factors by which the physical and chemical environment of a condensate can influence protein aggregation, and we discuss their relevance in studies of protein aggregation in the presence of biomolecular condensates: increasing the local concentration of proteins, providing a distinct chemical microenvironment, introducing an interface wherein proteins can localize, changing the energy landscape of aggregation pathways, and the presence of chaperones in condensates. Analysing the role of biomolecular condensates in protein aggregation may be essential for a full understanding of amyloid formation and offers a new perspective that can help in developing new therapeutic strategies for the prevention and treatment of neurodegenerative diseases.}, } @article {pmid39135084, year = {2024}, author = {Ma, H and Zhu, M and Chen, M and Li, X and Feng, X}, title = {The role of macrophage plasticity in neurodegenerative diseases.}, journal = {Biomarker research}, volume = {12}, number = {1}, pages = {81}, pmid = {39135084}, issn = {2050-7771}, support = {PX2023037//Beijing Municipal Administration of Hospitals Incubating Program/ ; }, abstract = {Tissue-resident macrophages and recruited macrophages play pivotal roles in innate immunity and the maintenance of brain homeostasis. Investigating the involvement of these macrophage populations in eliciting pathological changes associated with neurodegenerative diseases has been a focal point of research. Dysregulated states of macrophages can compromise clearance mechanisms for pathological proteins such as amyloid-β (Aβ) in Alzheimer's disease (AD) and TDP-43 in Amyotrophic lateral sclerosis (ALS). Additionally, recent evidence suggests that abnormalities in the peripheral clearance of pathological proteins are implicated in the pathogenesis and progression of neurodegenerative diseases. Furthermore, numerous genome-wide association studies have linked genetic risk factors, which alter the functionality of various immune cells, to the accumulation of pathological proteins. This review aims to unravel the intricacies of macrophage biology in both homeostatic conditions and neurodegenerative disorders. To this end, we initially provide an overview of the modifications in receptor and gene expression observed in diverse macrophage subsets throughout development. Subsequently, we outlined the roles of resident macrophages and recruited macrophages in neurodegenerative diseases and the progress of targeted therapy. Finally, we describe the latest advances in macrophage imaging methods and measurement of inflammation, which may provide information and related treatment strategies that hold promise for informing the design of future investigations and therapeutic interventions.}, } @article {pmid39137976, year = {2025}, author = {Pavey, N and Hannaford, A and Higashihara, M and van den Bos, M and Geevasinga, N and Vucic, S and Menon, P}, title = {Cortical inexcitability in ALS: correlating a clinical phenotype.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {3}, pages = {219-225}, pmid = {39137976}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality ; Male ; Female ; Middle Aged ; Transcranial Magnetic Stimulation ; Phenotype ; Aged ; Cross-Sectional Studies ; *Motor Cortex/physiopathology ; Adult ; Evoked Potentials, Motor/physiology ; Motor Neurons/physiology ; Neural Inhibition/physiology ; }, abstract = {BACKGROUND: Cortical inexcitability, a less studied feature of upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis (ALS), was identified in a large cross-sectional cohort of ALS patients and their demographic and clinical characteristics were contrasted with normal or hyperexcitable ALS cohorts to assess the impact of cortical inexcitability on ALS phenotype and survival.

METHODS: Threshold-tracking transcranial magnetic stimulation (TMS) technique with measurement of mean short interval intracortical inhibition (SICI) differentiated ALS patients into three groups (1) inexcitable (no TMS response at maximal stimulator output in the setting of preserved lower motor neuron (LMN) function), (2) hyperexcitable (SICI≤5.5%) and (3) normal cortical excitability (SICI>5.5%). Clinical phenotyping and neurophysiological assessment of LMN function were undertaken, and survival was recorded in the entire cohort.

RESULTS: 417 ALS patients were recruited, of whom 26.4% exhibited cortical inexcitability. Cortical inexcitability was associated with a younger age of disease onset (p<0.05), advanced Awaji criteria (p<0.01) and Kings stage (p<0.01) scores. Additionally, patients with cortical inexcitability had higher UMN score (p<0.01), lower revised ALS Functional Rating Scale score (p<0.01) and reduced upper limb strength score (MRC UL, p<0.01). Patient survival (p=0.398) was comparable across the groups, despite lower riluzole use in the cortical inexcitability patient group (p<0.05).

CONCLUSION: The present study established that cortical inexcitability was associated with a phenotype characterised by prominent UMN signs, greater motor and functional decline, and a younger age of onset. The present findings inform patient management and could improve patient stratification in clinical trials.}, } @article {pmid39138039, year = {2024}, author = {Candelo, E and Vasudevan, SS and Orellana, D and Williams, AM and Rutt, AL}, title = {Exploring the Impact of Amyotrophic Lateral Sclerosis on Otolaryngological Functions.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2024.07.025}, pmid = {39138039}, issn = {1873-4588}, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons at the spinal or bulbar level.

OBJECTIVE: We aim to describe the most frequent otolaryngology (ORL) complaints and voice disturbances in patients with bulbar onset ALS.

DESIGN: Retrospective cohort study.

SETTING: Single-center study with combined ORL and ALS clinic evaluation.

PARTICIPANTS: Patients with a confirmed diagnosis of ALS following an ORL visit and who underwent comprehensive voice assessments between January 2021 and January 2023.

EXPOSURE: Objective voice assessments.

MAIN OUTCOMES AND MEASURES: Glottal functional index (GFI), voice handicap index (VHI), reflux system index (RSI), and voice quality characteristics such as shimmer, jitter, maximum phonation time (MPT), and other essential parameters were assessed.

RESULTS: One hundred and thirty-three patients (age 62.17 ± 10.79, 54.48% female) were included. Three patients were referred from the ORL department to the ALS clinic. The most frequent symptoms were; dysphagia, dysarthria, facial weakness, pseudobulbar affect, and sialorrhea. The mean of forced vital capacity was 59.85%, EAT-10 15.91 ± 11.66, RSI 25.84 ± 9.03, GFI 14.12 ± 5.58, VHI-10 42.81 ± 34.94, MPT 15.22 s ± 8.06. Many patients reported voice impairments mainly related to spastic dysarthria and the combination of lower and upper motor neuron dysarthria, hypernasality, reduced verbal expression, and articulatory accuracy. Shimmer was increased to 8.46% ± 7.20, and jitter to 2.26% ± 1.39.

CONCLUSIONS AND RELEVANCE: Based on our cohort, this population with bulbar onset ALS has a higher frequency of voice disturbance characterized by hypernasality, spastic dysarthria, and reduced verbal expression.

LEVEL OF EVIDENCE: Level 3.}, } @article {pmid39138120, year = {2025}, author = {Euler, L and Deinert, K and Wagener, F and Walpurgis, K and Thevis, M}, title = {Identification of human metabolites of fast skeletal troponin activators Tirasemtiv and Reldesemtiv for doping control purposes.}, journal = {Drug testing and analysis}, volume = {17}, number = {6}, pages = {812-824}, pmid = {39138120}, issn = {1942-7611}, support = {//Federal Ministry of Interior, Building and Community/ ; //Manfred-Donike-Institute for Doping Analysis/ ; }, mesh = {Humans ; *Doping in Sports/prevention & control ; *Substance Abuse Detection/methods ; Microsomes, Liver/metabolism ; Tandem Mass Spectrometry/methods ; Male ; Cell Line ; Pyridines ; Pyrimidines ; Pyrroles ; }, abstract = {The fast skeletal troponin activators (FSTAs) Reldesemtiv and Tirasemtiv were developed for patients suffering from neuro-degenerative diseases of the motor nervous system, e.g. amyotrophic lateral sclerosis (ALS). The drug candidates can increase the sensitivity of troponin C to calcium by selectively activating the troponin complex resulting in increased skeletal muscle contraction. Although the development of the drug candidates is currently discontinued because of missed end points in phase III clinical studies with patients with ALS, phase I clinical trials showed an increase in muscle contraction force in healthy humans. This effect could be abused by athletes to enhance performance in sports. As the substances are listed on the 2024 edition of the World Anti-Doping Agency's Prohibited List, the aim of this study was to identify and characterize metabolites of Reldesemtiv and Tirasemtiv to ensure their reliable identification in doping control analyses. The biotransformation of the drug candidates was studied in vitro using pooled human liver microsomes and 3D cultivated human hepatic cells of the cell line HepaRG, yielding a total of 11 metabolites of Reldesemtiv and eight of Tirasemtiv. In addition, a human elimination study was conducted to investigate the metabolism and elimination profile of Tirasemtiv and Reldesemtiv in vivo, suggesting the N-glucuronide of Tirasemtiv and hydroxylated 3-fluoro-2-(3-fluoro-1-methylcyclobutyl)pyridine as well as its glucuronide as suitable target analytes for routine doping controls. Applying a validating HPLC-MS/MS method, optimized to detect Reldesemtiv and Tirasemtiv in human urine, microdosing (50 μg) of each substance was traceable for 24-72 h.}, } @article {pmid39138578, year = {2024}, author = {Wasielewska, JM and Chaves, JCS and Cabral-da-Silva, MC and Pecoraro, M and Viljoen, SJ and Nguyen, TH and Bella, V and Oikari, LE and Ooi, L and White, AR}, title = {A patient-derived amyotrophic lateral sclerosis blood-brain barrier model for focused ultrasound-mediated anti-TDP-43 antibody delivery.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {65}, pmid = {39138578}, issn = {2045-8118}, support = {PhD Scholarship//University of Queensland/ ; PhD Top-Up Scholarship//QIMR Berghofer Medical Research Institute/ ; APP1125796 and 1118452//National Health and Medical Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; *Microbubbles ; *DNA-Binding Proteins/metabolism ; Drug Delivery Systems/methods ; Endothelial Cells/metabolism ; Antibodies/administration & dosage ; Ultrasonic Waves ; Cells, Cultured ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development is the non-invasive therapeutic access to the motor cortex currently limited by the presence of the blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS[+ MB]) treatment is an emerging technology that was successfully used in ALS patients to temporarily open the cortical BBB. However, FUS[+ MB]-mediated drug delivery across ALS patients' BBB has not yet been reported. Similarly, the effects of FUS[+ MB] on human ALS BBB cells remain unexplored.

METHODS: Here we established the first FUS[+ MB]-compatible, fully-human ALS patient-cell-derived BBB model based on induced brain endothelial-like cells (iBECs) to study anti-TDP-43 antibody delivery and FUS[+ MB] bioeffects in vitro.

RESULTS: Generated ALS iBECs recapitulated disease-specific hallmarks of BBB pathology, including reduced BBB integrity and permeability, and TDP-43 proteinopathy. The results also identified differences between sporadic ALS and familial (C9orf72 expansion carrying) ALS iBECs reflecting patient heterogeneity associated with disease subgroups. Studies in these models revealed successful ALS iBEC monolayer opening in vitro with no adverse cellular effects of FUS[+ MB] as reflected by lactate dehydrogenase (LDH) release viability assay and the lack of visible monolayer damage or morphology change in FUS[+ MB] treated cells. This was accompanied by the molecular bioeffects of FUS[+ MB] in ALS iBECs including changes in expression of tight and adherens junction markers, and drug transporter and inflammatory mediators, with sporadic and C9orf72 ALS iBECs generating transient specific responses. Additionally, we demonstrated an effective increase in the delivery of anti-TDP-43 antibody with FUS[+ MB] in C9orf72 (2.7-fold) and sporadic (1.9-fold) ALS iBECs providing the first proof-of-concept evidence that FUS[+ MB] can be used to enhance the permeability of large molecule therapeutics across the BBB in a human ALS in vitro model.

CONCLUSIONS: Together, this study describes the first characterisation of cellular and molecular responses of ALS iBECs to FUS[+ MB] and provides a fully-human platform for FUS[+ MB]-mediated drug delivery screening on an ALS BBB in vitro model.}, } @article {pmid39138961, year = {2024}, author = {Rosano, A and Bicaj, M and Cillerai, M and Ponzano, M and Cabona, C and Gemelli, C and Caponnetto, C and Pardini, M and Signori, A and Uccelli, A and Schenone, A and Ferraro, PM}, title = {Psychological resilience is protective against cognitive deterioration in motor neuron diseases.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {717-725}, doi = {10.1080/21678421.2024.2385690}, pmid = {39138961}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Resilience, Psychological ; *Motor Neuron Disease/psychology/complications ; Aged ; *Cognitive Dysfunction/psychology/etiology ; Neuropsychological Tests ; Longitudinal Studies ; Adult ; }, abstract = {OBJECTIVES: Recent studies suggest that psychological resilience (PR) is associated with more well-preserved cognition in healthy subjects (HS), but an investigation of such phenomenon in patients with motor neuron diseases (MNDs) is still lacking. The aim of our study was therefore to evaluate PR and its relationship with baseline cognitive/behavioral and mood symptoms, as well as longitudinal cognitive functioning, in MNDs.

METHODS: 94 MND patients and 87 demographically matched HS were enrolled. PR was assessed using the Connor-Davidson Resilience Scale (CD-RISC). Patients were further evaluated both at baseline and every 6 months for cognitive/behavioral disturbances using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), and for mood symptoms using the Hospital Anxiety and Depression Scale (HADS). CD-RISC scores were compared between patients and HS using the Mann-Whitney U test, and regression models were applied to evaluate the role of CD-RISC scores in predicting baseline cognitive/behavioral and mood measures, as well as longitudinal cognitive performances, in MND patients.

RESULTS: MND cases showed significantly greater PR compared to HS (p from <0.001 to 0.02). In MNDs, higher PR levels were significant predictors of both greater cognitive performance (p from 0.01 to 0.05) and milder mood symptoms (p from <0.001 to 0.04) at baseline, as well as less severe memory decline (p from 0.001 to 0.04) longitudinally.

CONCLUSIONS: PR is an important protective factor against the onset and evolution of cognitive/mood disturbances in MNDs, suggesting the usefulness of resilience enhancement psychological interventions to prevent or delay cognitive and mood disorders in these neurodegenerative conditions.}, } @article {pmid39139312, year = {2024}, author = {Kaur, B and Samagh, N and Narang, A and Paliwal, S}, title = {Anesthetic Management of a Neurosurgical Patient With Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64492}, pmid = {39139312}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive form of neurological disorder that affects both the upper and lower motor neurons. Anesthesia management in these patients is always challenging as they can develop respiratory complications because of pre-existing muscle involvement. We report a middle-aged male with ALS posted for chronic subdural hematoma evacuation (CSDH) surgery. Surgery was done under scalp block with monitored anesthesia care. The choice of anesthesia in these patients should be one that interferes the least with the disease pattern while still providing optimal conditions for surgery.}, } @article {pmid39139642, year = {2024}, author = {Liu, X and Li, Y and Huang, L and Kuang, Y and Wu, X and Ma, X and Zhao, B and Lan, J}, title = {Unlocking the therapeutic potential of P2X7 receptor: a comprehensive review of its role in neurodegenerative disorders.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1450704}, pmid = {39139642}, issn = {1663-9812}, abstract = {The P2X7 receptor (P2X7R), an ATP-gated ion channel, has emerged as a crucial player in neuroinflammation and a promising therapeutic target for neurodegenerative disorders. This review explores the current understanding of P2X7R's structure, activation, and physiological roles, focusing on its expression and function in microglial cells. The article examines the receptor's involvement in calcium signaling, microglial activation, and polarization, as well as its role in the pathogenesis of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. The review highlights the complex nature of P2X7R signaling, discussing its potential neuroprotective and neurotoxic effects depending on the disease stage and context. It also addresses the development of P2X7R antagonists and their progress in clinical trials, identifying key research gaps and future perspectives for P2X7R-targeted therapy development. By providing a comprehensive overview of the current state of knowledge and future directions, this review serves as a valuable resource for researchers and clinicians interested in exploring the therapeutic potential of targeting P2X7R for the treatment of neurodegenerative disorders.}, } @article {pmid39140323, year = {2024}, author = {Nakamura, T and He, X and Hattori, N and Hida, E and Hirata, M}, title = {Dilemma in patients with amyotrophic lateral sclerosis and expectations from brain-machine interfaces.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2386516}, pmid = {39140323}, issn = {1365-2060}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Brain-Computer Interfaces ; Male ; Female ; Middle Aged ; Aged ; Surveys and Questionnaires ; *Motivation ; *Caregivers/psychology ; *Anxiety/psychology/etiology ; Adult ; Tracheostomy ; Caregiver Burden/psychology ; Locked-In Syndrome/psychology ; }, abstract = {OBJECTIVE: We hypothesized that patients with amyotrophic lateral sclerosis (ALS) face a dilemma between motivation to live and difficulty in living, and brain-machine interfaces (BMIs) can reduce this dilemma. This study aimed to investigate the present situation of patients with ALS and their expectations from BMIs.

MATERIALS AND METHODS: Our survey design consisted of an anonymous mail-in questionnaire comprising questions regarding the use of tracheostomy positive pressure ventilation (TPPV), motivation to live, anxiety about the totally locked-in state (TLS), anxiety about caregiver burden, and expectations regarding the use of BMI. Primary outcomes were scores for motivation to live and anxiety about caregiver burden and the TLS. Outcomes were evaluated using the visual analogue scale.

RESULTS: Among 460 participants, 286 (62.6%) were already supported by or had decided to use TPPV. The median scores for motivation to live, anxiety about TLS, and anxiety about caregiver burden were 8.0, 9.0, and 7.0, respectively. Overall, 49% of patients intended to use BMI. Among patients who had refused TPPV, 15.9% intended to use BMI and TPPV. Significant factors for the use of BMI were motivation to live (p = .003), anxiety about TLS (p < .001), younger age (p < .001), and advanced disease stage (p < .001).

CONCLUSIONS: These results clearly revealed a serious dilemma among patients with ALS between motivation to live and their anxiety about TLS and caregiver burden. Patients expected BMI to reduce this dilemma. Thus, the development of better BMIs may meet these expectations.}, } @article {pmid39141064, year = {2024}, author = {Wiesenfarth, M and Forouhideh-Wiesenfarth, Y and Elmas, Z and Parlak, Ö and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Günther, K and Fröhlich, E and Knehr, A and Simak, T and Bachhuber, F and Regensburger, M and Petri, S and Klopstock, T and Reilich, P and Schöberl, F and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Tumani, H and Brenner, D and Dorst, J and Ludolph, AC}, title = {Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6667-6679}, pmid = {39141064}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Superoxide Dismutase-1/genetics ; Male ; Female ; Germany ; Middle Aged ; Aged ; *Disease Progression ; Mutation ; Adult ; Phenotype ; }, abstract = {Pathogenic variants in the Cu/Zn superoxide dismutase (SOD1) gene can be detected in approximately 2% of sporadic and 11% of familial amyotrophic lateral sclerosis (ALS) patients in Europe. We analyzed the clinical phenotypes of 83 SOD1-ALS patients focusing on patients carrying the most frequent (likely) pathogenic variants (R116G, D91A, L145F) in Germany. Moreover, we describe the effect of tofersen treatment on ten patients carrying these variants. R116G patients showed the most aggressive course of disease with a median survival of 22.0 months compared to 198.0 months in D91A and 87.0 months in L145F patients (HR 7.71, 95% CI 2.89-20.58 vs. D91A; p < 0.001 and HR 4.25, 95% CI 1.55-11.67 vs. L145F; p = 0.02). Moreover, R116G patients had the fastest median ALSFRS-R progression rate with 0.12 (IQR 0.07-0.20) points lost per month. Median diagnostic delay was 10.0 months (IQR 5.5-11.5) and therefore shorter compared to 57.5 months (IQR 14.0-83.0) in D91A (p < 0.001) and 21.5 months (IQR 5.8-38.8) in L145F (p = 0.21) carriers. As opposed to D91A carriers (50.0%), 96.2% of R116G (p < 0.001) and 100.0% of L145F (p = 0.04) patients reported a positive family history. During tofersen treatment, all patients showed a reduction of neurofilament light chain (NfL) serum levels, independent of the SOD1 variant. Patients with SOD1-ALS carrying R116G, D91A, or L145F variants show commonalities, but also differences in their clinical phenotype, including a faster progression rate with shorter survival in R116G, and a comparatively benign disease course in D91A carriers.}, } @article {pmid39141853, year = {2024}, author = {Card, NS and Wairagkar, M and Iacobacci, C and Hou, X and Singer-Clark, T and Willett, FR and Kunz, EM and Fan, C and Vahdati Nia, M and Deo, DR and Srinivasan, A and Choi, EY and Glasser, MF and Hochberg, LR and Henderson, JM and Shahlaie, K and Stavisky, SD and Brandman, DM}, title = {An Accurate and Rapidly Calibrating Speech Neuroprosthesis.}, journal = {The New England journal of medicine}, volume = {391}, number = {7}, pages = {609-618}, pmid = {39141853}, issn = {1533-4406}, support = {U01DC17844/DC/NIDCD NIH HHS/United States ; AL220043//Congressionally Directed Medical Research Programs/ ; U01 DC019430/DC/NIDCD NIH HHS/United States ; R01 MH060974/MH/NIMH NIH HHS/United States ; 872146SPI//Simons Foundation/ ; A2295-R//U.S. Department of Veterans Affairs/ ; DP2DC021055/DC/NIDCD NIH HHS/United States ; U01DC019430/DC/NIDCD NIH HHS/United States ; I01 RX002295/RX/RRD VA/United States ; DP2 DC021055/DC/NIDCD NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/rehabilitation ; *Brain-Computer Interfaces ; Calibration ; Communication Devices for People with Disabilities ; *Dysarthria/rehabilitation/etiology ; Electrodes, Implanted ; Microelectrodes ; Quadriplegia/etiology/rehabilitation ; *Speech ; }, abstract = {BACKGROUND: Brain-computer interfaces can enable communication for people with paralysis by transforming cortical activity associated with attempted speech into text on a computer screen. Communication with brain-computer interfaces has been restricted by extensive training requirements and limited accuracy.

METHODS: A 45-year-old man with amyotrophic lateral sclerosis (ALS) with tetraparesis and severe dysarthria underwent surgical implantation of four microelectrode arrays into his left ventral precentral gyrus 5 years after the onset of the illness; these arrays recorded neural activity from 256 intracortical electrodes. We report the results of decoding his cortical neural activity as he attempted to speak in both prompted and unstructured conversational contexts. Decoded words were displayed on a screen and then vocalized with the use of text-to-speech software designed to sound like his pre-ALS voice.

RESULTS: On the first day of use (25 days after surgery), the neuroprosthesis achieved 99.6% accuracy with a 50-word vocabulary. Calibration of the neuroprosthesis required 30 minutes of cortical recordings while the participant attempted to speak, followed by subsequent processing. On the second day, after 1.4 additional hours of system training, the neuroprosthesis achieved 90.2% accuracy using a 125,000-word vocabulary. With further training data, the neuroprosthesis sustained 97.5% accuracy over a period of 8.4 months after surgical implantation, and the participant used it to communicate in self-paced conversations at a rate of approximately 32 words per minute for more than 248 cumulative hours.

CONCLUSIONS: In a person with ALS and severe dysarthria, an intracortical speech neuroprosthesis reached a level of performance suitable to restore conversational communication after brief training. (Funded by the Office of the Assistant Secretary of Defense for Health Affairs and others; BrainGate2 ClinicalTrials.gov number, NCT00912041.).}, } @article {pmid39141854, year = {2024}, author = {Vansteensel, MJ and Leinders, S and Branco, MP and Crone, NE and Denison, T and Freudenburg, ZV and Geukes, SH and Gosselaar, PH and Raemaekers, M and Schippers, A and Verberne, M and Aarnoutse, EJ and Ramsey, NF}, title = {Longevity of a Brain-Computer Interface for Amyotrophic Lateral Sclerosis.}, journal = {The New England journal of medicine}, volume = {391}, number = {7}, pages = {619-626}, pmid = {39141854}, issn = {1533-4406}, support = {INTENSE, 17619//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; UH3 NS114439/NS/NINDS NIH HHS/United States ; U01DC016686/DC/NIDCD NIH HHS/United States ; U01 DC016686/DC/NIDCD NIH HHS/United States ; UH3NS114439/NS/NINDS NIH HHS/United States ; UGT7685, Economic Affairs SSM06011 and STW 12803//Netherlands Institute of Government/ ; }, mesh = {Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/rehabilitation ; *Atrophy/diagnostic imaging/etiology/prevention & control ; Brain/diagnostic imaging ; *Brain-Computer Interfaces ; Communication Devices for People with Disabilities ; Time Factors ; Treatment Failure ; Electrodes, Implanted ; }, abstract = {The durability of communication with the use of brain-computer interfaces in persons with progressive neurodegenerative disease has not been extensively examined. We report on 7 years of independent at-home use of an implanted brain-computer interface for communication by a person with advanced amyotrophic lateral sclerosis (ALS), the inception of which was reported in 2016. The frequency of at-home use increased over time to compensate for gradual loss of control of an eye-gaze-tracking device, followed by a progressive decrease in use starting 6 years after implantation. At-home use ended when control of the brain-computer interface became unreliable. No signs of technical malfunction were found. Instead, the amplitude of neural signals declined, and computed tomographic imaging revealed progressive atrophy, which suggested that ALS-related neurodegeneration ultimately rendered the brain-computer interface ineffective after years of successful use, although alternative explanations are plausible. (Funded by the National Institute on Deafness and Other Communication Disorders and others; ClinicalTrials.gov number, NCT02224469.).}, } @article {pmid39142444, year = {2024}, author = {Tan, X and Su, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Feng, H}, title = {RBM5 induces motor neuron apoptosis in hSOD1[G93A]-related amyotrophic lateral sclerosis by inhibiting Rac1/AKT pathways.}, journal = {Brain research bulletin}, volume = {216}, number = {}, pages = {111049}, doi = {10.1016/j.brainresbull.2024.111049}, pmid = {39142444}, issn = {1873-2747}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *rac1 GTP-Binding Protein/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Apoptosis/physiology ; *RNA-Binding Proteins/metabolism/genetics ; Mice ; Humans ; *Signal Transduction/physiology ; *Proto-Oncogene Proteins c-akt/metabolism ; Mice, Transgenic ; Superoxide Dismutase/metabolism/genetics ; Male ; DNA-Binding Proteins ; Cell Cycle Proteins ; Tumor Suppressor Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder distinguished by gradual depletion of motor neurons. RNA binding motif protein 5 (RBM5), an abundantly expressed RNA-binding protein, plays a critical role in the process of cellular death. However, little is known about the role of RBM5 in the pathogenesis of ALS. Here, we found that RBM5 was upregulated in ALS hSOD1[G93A]-NSC34 cell models and hSOD1[G93A] mice due to a reduction of miR-141-5p. The upregulation of RBM5 increased the apoptosis of motor neurons by inhibiting Rac1-mediated neuroprotection. In contrast, genetic knockdown of RBM5 rescued motor neurons from hSOD1[G93A]-induced degeneration by activating Rac1 signaling. The neuroprotective effect of RBM5-knockdown was significantly inhibited by the Rac1 inhibitor, NSC23766. These findings suggest that RBM5 could potentially serve as a therapeutic target in ALS by activating the Rac1 signalling.}, } @article {pmid39143255, year = {2024}, author = {Gehlen, M and Schwarz-Eywill, M and Mahn, K and Pfeiffer, A and Bauer, JM and Maier, A}, title = {[Sonography of muscles : Rheumatology-Neurology-Geriatrics-Sports medicine-Orthopedics].}, journal = {Zeitschrift fur Rheumatologie}, volume = {83}, number = {10}, pages = {829-843}, pmid = {39143255}, issn = {1435-1250}, mesh = {Humans ; *Ultrasonography/methods ; Magnetic Resonance Imaging ; Rheumatology/methods ; Muscle, Skeletal/diagnostic imaging ; Athletic Injuries/diagnostic imaging ; Sarcopenia/diagnostic imaging ; Sports Medicine/methods ; Rheumatic Diseases/diagnostic imaging ; Geriatrics ; Aged ; Neurology ; Muscular Diseases/diagnostic imaging ; Evidence-Based Medicine ; }, abstract = {Muscle sonography is used in rheumatology, neurology, geriatrics, sports medicine and orthopedics. Muscular atrophy with fatty and connective tissue degeneration can be visualized and must be interpreted in conjunction with the sonographic findings of the supplying nerves. Sonography is becoming increasingly more important for the early diagnosis of sarcopenia in rheumatology, geriatrics and osteology. Even if its significance has not yet been conclusively clarified, many publications confirm the high reliability of the method. Sonography can ideally be used in addition to magnetic resonance imaging (MRI) in the diagnostics of myositis as it can speed up the diagnosis, muscle groups that were not imaged by MRI can also be assessed sonographically and all muscle groups can be examined during the course of the procedure. Sonography also helps to make a quick and uncomplicated diagnosis of many sports injuries in addition to MRI and is therefore the basis for a targeted therapeutic approach.}, } @article {pmid39144033, year = {2024}, author = {Xiao, XY and Zeng, JY and Cao, YB and Tang, Y and Zou, ZY and Li, JQ and Chen, HJ}, title = {Cortical microstructural abnormalities in amyotrophic lateral sclerosis: a gray matter-based spatial statistics study.}, journal = {Quantitative imaging in medicine and surgery}, volume = {14}, number = {8}, pages = {5774-5788}, pmid = {39144033}, issn = {2223-4292}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS)-related white-matter microstructural abnormalities have received considerable attention; however, gray-matter structural abnormalities have not been fully elucidated. This study aimed to evaluate cortical microstructural abnormalities in ALS and determine their association with disease severity.

METHODS: This study included 34 patients with ALS and 30 healthy controls. Diffusion-weighted data were used to estimate neurite orientation dispersion and density imaging (NODDI) parameters, including neurite density index (NDI) and orientation dispersion index (ODI). We performed gray matter-based spatial statistics (GBSS) in a voxel-wise manner to determine the cortical microstructure difference. We used the revised ALS Functional Rating Scale (ALSFRS-R) to assess disease severity and conducted a correlation analysis between NODDI parameters and ALSFRS-R.

RESULTS: In patients with ALS, the NDI reduction involved several cortical regions [primarily the precentral gyrus, postcentral gyrus, temporal cortex, prefrontal cortex, occipital cortex, and posterior parietal cortex; family-wise error (FWE)-corrected P<0.05]. ODI decreased in relatively few cortical regions (including the precentral gyrus, postcentral gyrus, prefrontal cortex, and inferior parietal lobule; FWE-corrected P<0.05). The NDI value in the left precentral and postcentral gyrus was positively correlated with the ALS disease severity (FWE-corrected P<0.05).

CONCLUSIONS: The decreases in NDI and ODI involved both motor-related and extra-motor regions and indicated the presence of gray-matter microstructural impairment in ALS. NODDI parameters are potential imaging biomarkers for evaluating disease severity in vivo. Our results showed that GBSS is a feasible method for identifying abnormalities in the cortical microstructure of patients with ALS.}, } @article {pmid39144302, year = {2024}, author = {Chen, XF and Lin, JP and Zhou, H and Kang, BZ and Nayak, R and Gao, L and Jiang, SS and Wang, F}, title = {The relationship between the collagen score at the anastomotic site of esophageal squamous cell carcinoma and anastomotic leakage.}, journal = {Journal of thoracic disease}, volume = {16}, number = {7}, pages = {4515-4524}, pmid = {39144302}, issn = {2072-1439}, abstract = {BACKGROUND: Anastomotic leakage (AL) has always been one of the most serious complications of esophagectomy with gastric conduit reconstruction. There are many strong risk factors for AL in clinical practice. Notably, the tension at the esophagogastric anastomosis and the blood supply to the gastric conduit directly affect the integrity of the anastomosis. However, there has been a lack of quantitative research on the tension and blood supply of the gastric conduit. Changes in extracellular matrix collagen reflect tension and blood supply, which affect the quality of the anastomosis. This study aimed to establish a quantitative collagen score to describe changes in the collagen structure in the extracellular matrix and to identify patients at high risk of postoperative AL.

METHODS: A retrospective study of 213 patients was conducted. Clinical and pathological data were collected at baseline. Optical imaging of the "donut" specimen at the anastomotic gastric end and collagen feature extraction were performed. Least absolute shrinkage and selection operator (LASSO) regression models were used to select the significant collagen features, compute collagen scores, and validate the predictive efficacy of the collagen scores for ALs.

RESULTS: LASSO regression analysis revealed three collagen-related parameters in the gastric donuts: histogram mean, histogram variance, and histogram energy. Based on this analysis, we established a formula to calculate the collagen score. The results of the univariate analysis revealed significant differences in the preoperative low albumin values (P=0.002) and collagen scores between the AL and non-AL groups (P=0.001), while the results of the multivariate analysis revealed significant differences in the collagen scores between the AL and non-AL groups (P=0.002). The areas under the curve (AUCs) of the experimental and validation cohorts were 0.978 [95% confidence interval (CI): 0.931-0.996] and 0.900 (95% CI: 0.824-0.951), respectively.

CONCLUSIONS: The collagen score established herein was shown to be related to AL and can be used to predict AL in patients who underwent esophagectomy.}, } @article {pmid39144569, year = {2024}, author = {Choudhury, C and Egleton, JE and Butcher, NJ and Russell, AJ and Minchin, RF}, title = {Small Molecule Inhibitors of Arylamine N-Acetyltransferase 1 Attenuate Cellular Respiration.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {8}, pages = {2326-2332}, pmid = {39144569}, issn = {2575-9108}, abstract = {Arylamine N-acetyltransferase 1 (NAT1) expression has been shown to attenuate mitochondrial function, suggesting it is a promising drug target in diseases of mitochondrial dysfunction. Here, several second-generation naphthoquinones have been investigated as small molecule inhibitors of NAT1. The results show that the compounds inhibit both in vitro and in whole cells. A lead compound (Cmp350) was further investigated for its ability to alter mitochondrial metabolism in MDA-MB-231 cells. At concentrations that inhibited NAT1 by over 85%, no overt toxicity was observed. Moreover, the inhibitor decreased basal respiration and reserve respiratory capacity without affecting ATP production. Cells treated with Cmp350 were almost exclusively dependent on glucose as a fuel source. We postulate that Cmp350 is an excellent lead compound for the development of NAT1-targeted inhibitors as both experimental tools and therapeutics in the treatment of hypermetabolic diseases such as amyotrophic lateral sclerosis, cancer cachexia, and sepsis.}, } @article {pmid39144751, year = {2024}, author = {Szebényi, K and Vargová, I and Petrova, V and Turečková, J and Gibbons, GM and Řehořová, M and Abdelgawad, M and Sándor, A and Marekova, D and Kwok, JCF and Jendelová, P and Fawcett, JW and Lakatos, A}, title = {Inhibition of PHLDA3 expression in human superoxide dismutase 1-mutant amyotrophic lateral sclerosis astrocytes protects against neurotoxicity.}, journal = {Brain communications}, volume = {6}, number = {4}, pages = {fcae244}, pmid = {39144751}, issn = {2632-1297}, abstract = {Pleckstrin homology-like domain family A-member 3 (PHLDA3) has recently been identified as a player in adaptive and maladaptive cellular stress pathways. The outcome of pleckstrin homology-like domain family A-member 3 signalling was shown to vary across different cell types and states. It emerges that its expression and protein level are highly increased in amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Whether it orchestrates a supportive or detrimental function remains unexplored in the context of neurodegenerative pathologies. To directly address the role of pleckstrin homology-like domain family A-member 3 in healthy and ALS astrocytes, we used overexpression and knockdown strategies. We generated cultures of primary mouse astrocytes and also human astrocytes from control and ALS patient-derived induced pluripotent stem cells harbouring the superoxide dismutase 1 mutation. Then, we assessed astrocyte viability and the impact of their secretome on oxidative stress responses in human stem cell-derived cortical and spinal neuronal cultures. Here, we show that PHLDA3 overexpression or knockdown in control astrocytes does not significantly affect astrocyte viability or reactive oxygen species production. However, PHLDA3 knockdown in ALS astrocytes diminishes reactive oxygen species concentrations in their supernatants, indicating that pleckstrin homology-like domain family A-member 3 can facilitate stress responses in cells with altered homeostasis. In support, supernatants of PHLDA3-silenced ALS and even control spinal astrocytes with a lower pleckstrin homology-like domain family A-member 3 protein content could prevent sodium arsenite-induced stress granule formation in spinal neurons. Our findings provide evidence that reducing pleckstrin homology-like domain family A-member 3 levels may transform astrocytes into a more neurosupportive state relevant to targeting non-cell autonomous ALS pathology.}, } @article {pmid39145609, year = {2024}, author = {Adil, O and Adeyeye, C and Shamsi, MH}, title = {Electrografted Laser-Induced Graphene: Direct Detection of Neurodegenerative Disease Biomarker in Cerebrospinal Fluid.}, journal = {ACS sensors}, volume = {9}, number = {9}, pages = {4748-4757}, doi = {10.1021/acssensors.4c01150}, pmid = {39145609}, issn = {2379-3694}, support = {R15 GM147885/GM/NIGMS NIH HHS/United States ; }, mesh = {*Graphite/chemistry ; Humans ; *Biomarkers/cerebrospinal fluid ; *Electrochemical Techniques/methods ; *Lasers ; Immunoassay/methods ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Electrodes ; Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; Limit of Detection ; Biosensing Techniques/methods ; }, abstract = {There are more than 50 neurodegenerative disorders, and amyotrophic lateral sclerosis (ALS) is one of the most common disorders that poses diagnostic and treatment challenges. The poly glycine-proline (polyGP) dipeptide repeat is a toxic protein that has been recognized as a pharmacodynamic biomarker of C9orf72-associated (c9+) ALS, a subtype of ALS that originates from genetic mutation. Early detection of polyGP will help healthcare providers start timely gene therapy. Herein, we developed a label-free electrochemical immunoassay for the simple detection of polyGP in unprocessed cerebrospinal fluid (CSF) samples collected from ALS patients in the National ALS Biorepository. For the first time, an electrografted laser-induced graphene (E-LIG) electrode system was employed in a sandwich format to detect polyGP using a label-free electrochemical impedance technique. The results show that the E-LIG-modified surface exhibited high sensitivity and selectivity in buffer and CSF media with limit of detection values of 0.19 and 0.27 ng/mL, respectively. The precision of the calibration model was better in CSF than in the buffer. The E-LIG immunosensor can easily select polyGP targets in the presence of other dipeptide proteins translated from the c9 gene. Further study with CSF samples from ALS patients demonstrated that the label-free E-LIG-based immunosensor not only quantified polyGP in the complex CSF matrix but also distinguished between c9+ and non-c9- ALS patients.}, } @article {pmid39145860, year = {2024}, author = {Gondo, TF and Huang, F and Marungruang, N and Heyman-Lindén, L and Turner, C}, title = {Investigating the quality of extraction and quantification of bioactive compounds in berries through liquid chromatography and multivariate curve resolution.}, journal = {Analytical and bioanalytical chemistry}, volume = {416}, number = {24}, pages = {5387-5400}, pmid = {39145860}, issn = {1618-2650}, support = {2018-01863//Svenska Forskningsrådet Formas/ ; }, mesh = {*Fruit/chemistry ; Multivariate Analysis ; Chromatography, Liquid/methods ; Polyphenols/analysis ; Least-Squares Analysis ; Plant Extracts/chemistry ; Anthocyanins/analysis/chemistry ; Phenols/analysis/chemistry ; Chromatography, High Pressure Liquid/methods ; Antioxidants/analysis/chemistry ; }, abstract = {Berries are a rich source of natural antioxidant compounds, which are essential to profile, as they add to their nutritional value. However, the complexity of the matrix and the structural diversity of these compounds pose challenges in extraction and chromatographic separation. By relying on multivariate curve resolution alternating least squares (MCR-ALS) ability to extract components from complex spectral mixtures, our study evaluates the contributions of various extraction techniques to interference, extractability, and quantifying different groups of overlapping compounds using liquid chromatography diode array detection (LC-DAD) data. Additionally, the combination of these methods extends its applicability to evaluate polyphenol degradation in stored berry smoothies, where evolving factor analysis (EFA) is also used to elucidate degradation products. Results indicate that among the extraction techniques, ultrasonication-assisted extraction employing 1% formic acid in methanol demonstrated superior extractability and selectivity for the different phenolic compound groups, compared with both pressurized liquid extraction and centrifugation of the fresh berry smoothie. Employing MCR-ALS on the LC-DAD data enabled reliable estimation of total amounts of compound classes with high spectral overlaps. Degradation studies revealed significant temperature-dependent effects on anthocyanins, with at least 50% degradation after 7 months of storage at room temperature, while refrigeration and freezing maintained fair stability for at least 12 months. The EFA model estimated phenolic derivatives as the main possible degradation products. These findings enhance the reliability of quantifying polyphenolic compounds and understanding their stability during the storage of berry products.}, } @article {pmid39146246, year = {2024}, author = {Hutten, S and Chen, JX and Isaacs, AM and Dormann, D}, title = {Poly-GR Impairs PRMT1-Mediated Arginine Methylation of Disease-Linked RNA-Binding Proteins by Acting as a Substrate Sink.}, journal = {Biochemistry}, volume = {63}, number = {17}, pages = {2141-2152}, doi = {10.1021/acs.biochem.4c00308}, pmid = {39146246}, issn = {1520-4995}, mesh = {*Protein-Arginine N-Methyltransferases/metabolism/genetics ; Humans ; *Arginine/metabolism ; Methylation ; *Repressor Proteins/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Frontotemporal Dementia/metabolism/genetics ; C9orf72 Protein/metabolism/genetics ; HEK293 Cells ; }, abstract = {Dipeptide repeat proteins (DPRs) are aberrant protein species found in C9orf72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative diseases characterized by the cytoplasmic mislocalization and aggregation of RNA-binding proteins (RBPs). In particular, arginine (R)-rich DPRs (poly-GR and poly-PR) have been suggested to promiscuously interact with multiple cellular proteins and thereby exert high cytotoxicity. Components of the protein arginine methylation machinery have been identified as modulators of DPR toxicity and/or potential cellular interactors of R-rich DPRs; however, the molecular details and consequences of such an interaction are currently not well understood. Here, we demonstrate that several members of the family of protein arginine methyltransferases (PRMTs) can directly interact with R-rich DPRs in vitro and in the cytosol. In vitro, R-rich DPRs reduce solubility and promote phase separation of PRMT1, the main enzyme responsible for asymmetric arginine-dimethylation (ADMA) in mammalian cells, in a concentration- and length-dependent manner. Moreover, we demonstrate that poly-GR interferes more efficiently than poly-PR with PRMT1-mediated arginine methylation of RBPs such as hnRNPA3. We additionally show by two alternative approaches that poly-GR itself is a substrate for PRMT1-mediated arginine dimethylation. We propose that poly-GR may act as a direct competitor for arginine methylation of cellular PRMT1 targets, such as disease-linked RBPs.}, } @article {pmid39146722, year = {2024}, author = {Ginanneschi, F and Pucci, B and Casali, S and Lissandri, C and Giannini, F and Rossi, A}, title = {Factors associated with Edinburgh Cognitive and Behavioural ALS Screen (ECAS) alteration at time of diagnosis, in amyotrophic lateral sclerosis.}, journal = {Clinical neurology and neurosurgery}, volume = {245}, number = {}, pages = {108499}, doi = {10.1016/j.clineuro.2024.108499}, pmid = {39146722}, issn = {1872-6968}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Male ; Female ; Middle Aged ; Aged ; C9orf72 Protein/genetics ; Neuropsychological Tests ; Adult ; Mutation ; Cohort Studies ; }, abstract = {BACKGROUND: Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a validated assessment designed to screen cognitive functions and behavioral disorders in amyotrophic lateral sclerosis (ALS). Objective of this study is to determine the factors associated with ECAS impairment in a cohort of ALS patients without a co-morbid diagnosis of dementia, at the time of diagnosis.

METHODS: We enrolled 71 non-demented ALS patient. We collected clinical and demographic data, ALS familiarity, analysis of the most commonly mutated genes in ALS, ALS Milano Torino Staging System and ALS Functional Rate Scale revised scores, progression rate; finally, we recorded whether symptoms onset involved spinal or bulbar area. The alteration of the ECAS was estimated based on age and education-adjusted-validated cut off for each of the items included in ECAS. A multivariable regression analysis was done.

RESULTS: The significant determinants of ECAS alterations were: bulbar onset in both ALS-specific test and total ECAS score; bulbar onset and familiarity in ALS-non-specific test; finally, familiarity and diagnosis delay in ALS-behavioral test. All the subjects carrying C9orf72 mutations had alteration of both total ECAS score and ALS-specific tests.

DISCUSSION: At diagnosis, bulbar-onset ALS, family history, diagnosis delay and C9orf72 hexanucleotide repeat expansion may contribute to impairment of ECAS.}, } @article {pmid39146816, year = {2025}, author = {Sun, Q and Chai, L and Yang, X and Zhang, W and Li, Z}, title = {Hollow tubular sea-urchin structure with high catalytic activity of NiCo2Se4@CS2 cathodes for high-performance Al/S batteries.}, journal = {Journal of colloid and interface science}, volume = {677}, number = {Pt B}, pages = {284-292}, doi = {10.1016/j.jcis.2024.08.071}, pmid = {39146816}, issn = {1095-7103}, abstract = {The shuttle effect of aluminum polysulfides (AlPSs) have been a source of concern for studying Al/S batteries. Due to the weak adsorption of CS composites, research on cathode materials for Al/S batteries has been delayed. As it is generally known that Al2S3 decomposition demands a large Gibbs free energy, this work has tried to reduce the Al2S3 decomposition potential energy. Herein, the Ni/Co bimetallic selenide reduces the energy barrier conversion and mitigates the polarization effects, while morphology control enables the storage and anchoring of S, alleviating the shuttle effect. Additionally, the intermediate products serve as single-atom catalysts, increasing the active sites, synergistically enhancing the ion diffusion kinetics. DFT calculations verify that NiCo2Se4 has a moderate Gibbs free energy change during the rate-limiting step of S reduction and the most robust adsorption energy to Al2S3. NiCo2Se4@CS2/Al has a remaining capacity of 135 mAh/g after 450 cycles (at 200 mA g[-1]), pioneering novel ideas for the development of Al/S batteries.}, } @article {pmid39146882, year = {2024}, author = {Aizawa, H and Nagumo, S and Hideyama, T and Kato, H and Kwak, S and Terashi, H and Suzuki, Y and Kimura, T}, title = {Morphometric analysis of spinal motor neuron degeneration in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {464}, number = {}, pages = {123177}, doi = {10.1016/j.jns.2024.123177}, pmid = {39146882}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Male ; Female ; Middle Aged ; Aged ; *DNA-Binding Proteins/metabolism ; *Spinal Cord/pathology/metabolism ; *Nerve Degeneration/pathology ; Anterior Horn Cells/pathology ; Motor Neurons/pathology/metabolism ; }, abstract = {OBJECTIVES: This study aimed to clarify the relationship between 43-kDa TAR DNA-binding protein (TDP-43) pathology and spinal cord anterior horn motor neuron (AHMN) atrophy in sporadic amyotrophic lateral sclerosis (SALS).

METHODS: Eight patients with SALS and 12 controls were included in this study. Formalin-fixed specimens of lumbar spinal cord samples were paraffin-embedded and sectioned at the level of the fourth lumbar spinal cord with a 4 μm thickness. Using a microscope, the long diameters of the neurons with nucleoli were measured in spinal AHMNs stained with an anti-SMI-32 antibody. AHMNs were divided into medial and lateral nuclei for statistical analysis. We also used previously reported data to measure the long diameter of AHMNs with initial TDP-43 pathology, in which TDP-43 was present both in the nucleus and cytoplasm.

RESULTS: The long diameter of the lumbar spinal AHMNs in patients with SALS was smaller in the medial nucleus (42.54 ± 9.33 μm, n = 24) and the lateral nucleus (49.41 ± 13.86 μm, n = 129) than in controls (medial nucleus: 55.84 ± 13.49 μm, n = 85, p < 0.001; lateral nucleus: 62.39 ± 13.29 μm, n = 756, p < 0.001, Mann-Whitney U test). All 21 motor neurons with initial TDP-43 pathology were in the lateral nucleus, and their long diameter (67.60 ± 18.3 μm, p = 0.352) was not significantly different from that of controls.

CONCLUSION: Motor neuron atrophy in SALS does not occur during the initial stages of TDP-43 pathology, and TDP-43 pathology is already advanced in the atrophied motor neurons.}, } @article {pmid39147172, year = {2024}, author = {Acton, S and O'Donnell, MM and Periyasamy, K and Dixit, B and Eishingdrelo, H and Hill, C and Paul Ross, R and Chesnel, L}, title = {LPA3 agonist-producing Bacillus velezensis ADS024 is efficacious in multiple neuroinflammatory disease models.}, journal = {Brain, behavior, and immunity}, volume = {121}, number = {}, pages = {384-402}, doi = {10.1016/j.bbi.2024.08.024}, pmid = {39147172}, issn = {1090-2139}, mesh = {*Bacillus/metabolism ; Animals ; Mice ; Humans ; *Neuroinflammatory Diseases/metabolism ; Disease Models, Animal ; Mice, Inbred C57BL ; Multiple Sclerosis/metabolism ; Male ; Encephalomyelitis, Autoimmune, Experimental/metabolism ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {Neuroinflammation is a common component of neurological disorders. In the gut-brain-immune axis, bacteria and their metabolites are now thought to play a role in the modulation of the nervous and immune systems which may impact neuroinflammation. In this respect, commensal bacteria of humans have recently been shown to produce metabolites that mimic endogenous G-protein coupled receptor (GPCR) ligands. To date, it has not been established whether plant commensal bacteria, which may be ingested by animals including humans, can impact the gut-brain-immune axis via GPCR agonism. We screened an isopropanol (IPA) extract of the plant commensal Bacillus velezensis ADS024, a non-engrafting live biotherapeutic product (LBP) with anti-inflammatory properties isolated from human feces, against a panel of 168 GPCRs and identified strong agonism of the lysophosphatidic acid (LPA) receptor LPA3. The ADS024 IPA extracted material (ADS024-IPA) did not agonize LPA2, and only very weakly agonized LPA1. The agonism of LPA3 was inhibited by the reversible LPA1/3 antagonist Ki16425. ADS024-IPA signaled downstream of LPA3 through G-protein-induced calcium release, recruitment of β-arrestin, and recruitment of the neurodegeneration-associated proteins 14-3-3γ, ε and ζ but did not recruit the β isoform. Since LPA3 agonism was previously indirectly implicated in the reduction of pathology in models of Parkinson's disease (PD) and multiple sclerosis (MS) by use of the nonselective antagonist Ki16425, and since we identified an LPA3-specific agonist within ADS024, we sought to examine whether LPA3 might indeed be part of a broad underlying mechanism to control neuroinflammation. We tested oral treatment of ADS024 in multiple models of neuroinflammatory diseases using three models of PD, two models of MS, and a model each of amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and chemo-induced peripheral neuropathy (CIPN). ADS024 treatment improved model-specific functional effects including improvements in motor movement, breathing and swallowing, and allodynia suggesting that ADS024 treatment impacted a universal underlying neuroinflammatory mechanism regardless of the initiating cause of disease. We used the MOG-EAE mouse model to examine early events after disease initiation and found that ADS024 attenuated the increase in circulating lymphocytes and changes in neutrophil subtypes, and ADS024 attenuated the early loss of cell-surface LPA3 receptor expression on circulating white blood cells. ADS024 efficacy was partially inhibited by Ki16425 in vivo suggesting LPA3 may be part of its mechanism. Altogether, these data suggest that ADS024 and its LPA3 agonism activity should be investigated further as a possible treatment for diseases with a neuroinflammatory component.}, } @article {pmid39149866, year = {2024}, author = {Cabeza-Fernández, S and Hernández-Rojas, R and Casillas-Bajo, A and Patel, N and de la Fuente, AG and Cabedo, H and Gomez-Sanchez, JA}, title = {Schwann cell JUN expression worsens motor performance in an amyotrophic lateral sclerosis mouse model.}, journal = {Glia}, volume = {72}, number = {12}, pages = {2178-2189}, doi = {10.1002/glia.24604}, pmid = {39149866}, issn = {1098-1136}, support = {PID2019-109762RB-I00//Agencia Estatal de Investigación/ ; PID2022-141062OB-I00//Agencia Estatal de Investigación/ ; CIPROM/2021/048//Conselleria d'Educació, Investigació, Cultura i Esport/ ; GRISOLIAP/2021/026//Conselleria d'Educació, Investigació, Cultura i Esport/ ; }, mesh = {Animals ; *Schwann Cells/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism/physiopathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Motor Neurons/pathology/metabolism ; Proto-Oncogene Proteins c-jun/metabolism/genetics ; Mice ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/genetics/metabolism ; Axons/pathology/metabolism/physiology ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by motor neuron death and distal axonopathy. Despite its clinical severity and profound impact in the patients and their families, many questions about its pathogenesis remain still unclear, including the role of Schwann cells and axon-glial signaling in disease progression. Upon axonal injury, upregulation of JUN transcription factor promotes Schwann cell reprogramming into a repair phenotype that favors axon regrowth and neuronal survival. To study the potential role of repair Schwann cells on motoneuron survival in amyotrophic lateral sclerosis, we generated a mouse line that over-expresses JUN in the Schwann cells of the SOD1[G93A] mutant, a mouse model of this disease. Then, we explored disease progression by evaluating survival, motor performance and histology of peripheral nerves and spinal cord of these mice. We found that Schwann cell JUN overexpression does not prevent axon degeneration neither motor neuron death in the SOD1[G93A] mice. Instead, it induces a partial demyelination of medium and large size axons, worsening motor performance and resulting in more aggressive disease phenotype.}, } @article {pmid39150867, year = {2025}, author = {Pienaar, K and Kelaita, P and Murphy, D}, title = {COVID-19 and the biopolitics of stigma in public housing: dividing practices and community boundaries in pandemic times.}, journal = {Health sociology review : the journal of the Health Section of the Australian Sociological Association}, volume = {34}, number = {2}, pages = {167-182}, doi = {10.1080/14461242.2024.2390019}, pmid = {39150867}, issn = {1839-3551}, mesh = {Humans ; *COVID-19/epidemiology/psychology/prevention & control ; *Social Stigma ; *Public Housing ; SARS-CoV-2 ; Interviews as Topic ; Australia/epidemiology ; Pandemics ; Female ; Male ; Politics ; }, abstract = {The COVID-19 'hard lockdowns' in Melbourne, Australia in 2020 targeted public housing estates thus trading on perceptions of risk associated with public housing as some of the most stigmatised sites in post-industrial cities. This article draws on interviews with Melbourne public housing tenants on their experience of COVID-19 lockdowns to analyse the place of stigma in residents' accounts. Pairing Wacquant et al's (2014) concept of 'territorial stigma' with sociological work on the biopolitics of stigma we consider the dynamics of stigma, tracing how it functions to delimit community boundaries and justify pandemic containment measures. Residents navigate multiple layers of stigma, including stereotypes of public housing, normative judgements of neighbouring residents, and a broader public housing system riven with structural issues. Members of these communities are both the targets of stigma and seek to distance themselves from those seen as vectors of stigma. Our participants report mobilising social distancing strategies couched in normative assessments of perceived risk based on physical appearance, presumed drug use and past conduct. We explore the implications of these enactments of territorial stigma and trace the logics of abjection that construct public housing as deprived urban zones, home to abject 'Others' perceived as threatening the health of the community.}, } @article {pmid39152573, year = {2024}, author = {Dubbioso, R and Iannotti, FA and Senerchia, G and Verde, R and Iuzzolino, VV and Spisto, M and Fasolino, I and Manganelli, F and Di Marzo, V and Piscitelli, F}, title = {Circulating endocannabinoidome signatures of disease activity in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {10}, pages = {e16400}, pmid = {39152573}, issn = {1468-1331}, support = {E53D23019760001//National Recovery and Resilience Plan (NRRP)/ ; E53D23011330006//Ministry of University and Research (MUR)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood ; *Endocannabinoids/blood ; Male ; Female ; Middle Aged ; Aged ; Adult ; Disease Progression ; Longitudinal Studies ; Biomarkers/blood ; }, abstract = {BACKGROUND AND PURPOSE: Preclinical studies of amyotrophic lateral sclerosis (ALS) have shown altered endocannabinoid (eCB) signalling that may contribute to the disease. Results from human studies are sparse and inconclusive. The aim of this study was to determine the association between serum levels of eCBs or their congeners, the so-called endocannabinoidome, and disease status and activity in ALS patients.

METHODS: Serum concentrations of 2-arachidonoylglycerol and N-arachidonoylethanolamine (AEA), and AEA congeners palmitoylethanolamide (PEA), oleoylethanolamide (OEA), eicosapentaenoylethanolamide (EPEA), 2-docosahexaenoylglycerol (2-DHG) and docosahexaenoylethanolamide (DHEA) were measured in samples from 65 ALS patients, 32 healthy controls (HCs) and 16 neurological disease controls (NALS). A subset of 46 ALS patients underwent a longitudinal study. Disease activity and progression were correlated with eCB and congener levels.

RESULTS: Most circulating mediators were higher in ALS than HCs (all p < 0.001), but not NALS. Across clinical stages, ALS patients showed increased levels of PEA, OEA and EPEA (all p < 0.02), which were confirmed by the longitudinal study (all p < 0.03). Serum PEA and OEA levels were independent predictors of survival and OEA levels were higher in patients complaining of appetite loss. Cluster analysis revealed two distinct profiles of circulating mediators associated with corresponding patterns of disease activity (severe vs. mild). Patients belonging to the 'severe' cluster showed significantly higher levels of OEA and PEA and lower levels of 2-DHG compared to NALS and HCs.

CONCLUSION: Circulating endocannabinoidome profiles are indicative of disease activity, thus possibly paving the way to a personalized, rather than a 'one-fits-all', therapeutic approach targeting the endocannabinoidome.}, } @article {pmid39153108, year = {2024}, author = {Hosseini, L and Babaie, S and Shahabi, P and Fekri, K and Shafiee-Kandjani, AR and Mafikandi, V and Maghsoumi-Norouzabad, L and Abolhasanpour, N}, title = {Klotho: molecular mechanisms and emerging therapeutics in central nervous system diseases.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {913}, pmid = {39153108}, issn = {1573-4978}, mesh = {*Klotho Proteins ; Humans ; *Central Nervous System Diseases/metabolism/drug therapy ; *Signal Transduction ; Animals ; Oxidative Stress ; Glucuronidase/metabolism/genetics ; Autophagy ; Aging/metabolism/genetics ; }, abstract = {Klotho is recognized as an aging-suppressor protein that is implicated in a variety of processes and signaling pathways. The anti-inflammatory, anti-apoptotic, anti-oxidant, and anti-tumor bioactivities of klotho have extended its application in neurosciences and made the protein popular for its lifespan-extending capacity. Furthermore, it has been demonstrated that klotho levels would reduce with aging and numerous pathologies, particularly those related to the central nervous system (CNS). Evidence supports the idea that klotho can be a key therapeutic target in CNS diseases such as amyotrophic lateral sclerosis, Parkinson's disease, stroke, and Alzheimer's disease. Reviewing the literature suggests that the upregulation of klotho expression regulates various signaling pathways related to autophagy, oxidative stress, inflammation, cognition, and ferroptosis in neurological disorders. Therefore, it has been of great interest to develop drugs or agents that boost or restore klotho levels. In this regard, the present review was designed and aimed to gather the delegated documents regarding the therapeutic potential of Klotho in CNS diseases focusing on the molecular and cellular mechanisms.}, } @article {pmid39153346, year = {2025}, author = {Khazaei, K and Roshandel, P and Parastar, H}, title = {Visible-short wavelength near infrared hyperspectral imaging coupled with multivariate curve resolution-alternating least squares for diagnosis of breast cancer.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {324}, number = {}, pages = {124966}, doi = {10.1016/j.saa.2024.124966}, pmid = {39153346}, issn = {1873-3557}, mesh = {Humans ; Female ; *Breast Neoplasms/diagnosis ; Least-Squares Analysis ; *Principal Component Analysis ; *Spectroscopy, Near-Infrared/methods ; *Hyperspectral Imaging/methods ; Multivariate Analysis ; Discriminant Analysis ; }, abstract = {This study investigates the application of visible-short wavelength near-infrared hyperspectral imaging (Vis-SWNIR HSI) in the wavelength range of 400-950 nm and advanced chemometric techniques for diagnosing breast cancer (BC). The research involved 56 ex-vivo samples encompassing both cancerous and non-cancerous breast tissue from females. First, HSI images were analyzed using multivariate curve resolution-alternating least squares (MCR-ALS) to exploit pure spatial and spectral profiles of active components. Then, the MCR-ALS resolved spatial profiles were arranged in a new data matrix for exploration and discrimination between benign and cancerous tissue samples using principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA). The PLS-DA classification accuracy of 82.1 % showed the potential of HSI and chemometrics for non-invasive detection of BC. Additionally, the resolved spectral profiles by MCR-ALS can be used to track the changes in the breast tissue during cancer and treatment. It is concluded that the proposed strategy in this work can effectively differentiate between cancerous and non-cancerous breast tissue and pave the way for further studies and potential clinical implementation of this innovative approach, offering a promising avenue for improving early detection and treatment outcomes in BC patients.}, } @article {pmid39153378, year = {2024}, author = {Maramai, S and Saletti, M and Paolino, M and Giuliani, G and Cazzola, J and Spaiardi, P and Talpo, F and Frosini, M and Pifferi, A and Ballarotto, M and Carotti, A and Poggialini, F and Vagaggini, C and Dreassi, E and Giorgi, G and Dondio, G and Cappelli, A and Rosario Biella, G and Anzini, M}, title = {Novel multitarget directed ligands inspired by riluzole: A serendipitous synthesis of substituted benzo[b][1,4]thiazepines potentially useful as neuroprotective agents.}, journal = {Bioorganic & medicinal chemistry}, volume = {112}, number = {}, pages = {117872}, doi = {10.1016/j.bmc.2024.117872}, pmid = {39153378}, issn = {1464-3391}, mesh = {Animals ; Humans ; Dose-Response Relationship, Drug ; Ligands ; Molecular Structure ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; *Riluzole/pharmacology/chemical synthesis/chemistry ; Structure-Activity Relationship ; Thiazepines/chemical synthesis/chemistry/pharmacology ; }, abstract = {Riluzole, the first clinically approved treatment for amyotrophic lateral sclerosis (ALS), represents a successful example of a drug endowed with a multimodal mechanism of action. In recent years, different series of riluzole-based compounds have been reported, including several agents acting as Multi-Target-Directed Ligands (MTLDs) endowed with neuroprotective effects. Aiming at identical twin structures inspired by riluzole (2a-c), a synthetic procedure was planned, but the reactivity of the system took a different path, leading to the serendipitous isolation of benzo[b][1,4]thiazepines 3a-c and expanded intermediates N-cyano-benzo[b][1,4]thiazepines 4a-c, which were fully characterized. The newly obtained structures 3a-c, bearing riluzole key elements, were initially tested in an in vitro ischemia/reperfusion injury protocol, simulating the cerebral stroke. Results identified compound 3b as the most effective in reverting the injury caused by an ischemia-like condition, and its activity was comparable, or even higher than that of riluzole, exhibiting a concentration-dependent neuroprotective effect. Moreover, derivative 3b completely reverted the release of Lactate Dehydrogenase (LDH), lowering the values to those of the control slices. Based on its very promising pharmacological properties, compound 3b was then selected to assess its effects on voltage-dependent Na[+] and K[+] currents. The results indicated that derivative 3b induced a multifaceted inhibitory effect on voltage-gated currents in SH-SY5Y differentiated neurons, suggesting its possible applications in epilepsy and stroke management, other than ALS. Accordingly, brain penetration was also measured for 3b, as it represents an elegant example of a MTDL and opens the way to further ex-vivo and/or in-vivo characterization.}, } @article {pmid39154744, year = {2024}, author = {Li, JN and Sechi, A and Tosti, A}, title = {Response to Costa Fechine et al's "Correlation of clinical and trichoscopy features with the degree of histologic inflammation in lichen planopilaris and frontal fibrosing alopecia in a cross-sectional study".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {6}, pages = {e187-e188}, doi = {10.1016/j.jaad.2024.07.1495}, pmid = {39154744}, issn = {1097-6787}, } @article {pmid39154745, year = {2024}, author = {Vu, D and Park, M and Alhusayen, R}, title = {Response to Chawla et al, "Response to Vu et al's "Efficacy of moxifloxacin as a mono-antibiotic therapy for hidradenitis suppurativa: A retrospective cohort study"".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {6}, pages = {e177-e178}, doi = {10.1016/j.jaad.2024.08.013}, pmid = {39154745}, issn = {1097-6787}, } @article {pmid39154890, year = {2024}, author = {Brebner, C and Asamoah-Boaheng, M and Zaidel, B and Yap, J and Scheuermeyer, F and Mok, V and Hutton, J and Meckler, G and Schlamp, R and Christenson, J and Grunau, B}, title = {The association of intravenous vs. humeral-intraosseous vascular access with patient outcomes in adult out-of-hospital cardiac arrests.}, journal = {Resuscitation}, volume = {202}, number = {}, pages = {110360}, doi = {10.1016/j.resuscitation.2024.110360}, pmid = {39154890}, issn = {1873-1570}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; *Infusions, Intraosseous/methods ; Middle Aged ; *Cardiopulmonary Resuscitation/methods ; *Registries ; Aged ; Humerus ; Emergency Medical Services/methods ; Treatment Outcome ; Adult ; Propensity Score ; }, abstract = {AIM: While intravenous (IV) vascular access for out-of-hospital cardiac arrest (OHCA) resuscitation is standard, humeral-intraosseous (IO) access is commonly used, despite few supporting data. We investigated the association between IV vs. humeral-IO and outcomes.

METHODS: We utilized BC Cardiac Arrest Registry data, including adult OHCA where the first-attempted intra-arrest vascular access route performed by advanced life support (ALS)-trained paramedics was IV or humeral-IO. We fit a propensity-score adjusted model with inverse probability treatment weighting to estimate the association between IV vs. humeral-IO routes and favorable neurological outcomes (CPC 1-2) and survival at hospital discharge. We repeated models within subgroups defined by initial cardiac rhythm.

RESULTS: We included 2,112 cases; the first-attempted route was IV (n = 1,575) or humeral-IO (n = 537). Time intervals from ALS-paramedic on-scene arrival to vascular access (6.6 vs. 6.9 min) and epinephrine administration (9.0 vs. 9.3 min) were similar between IV and IO groups, respectively. Among IV and humeral-IO groups, 98 (6.2%) and 20 (3.7%) had favorable neurological outcomes. Compared to humeral-IO, an IV-first approach was associated with improved hospital-discharge favorable neurological outcomes (AOR 1.7; 95% CI 1.1-2.7) and survival (AOR 1.5; 95% CI 1.0-2.3). Among shockable rhythm cases, an IV-first approach was associated with improved favorable neurological outcomes (AOR 4.2; 95% CI 2.1-8.2), but not among non-shockable rhythm cases (AOR 0.73; 95% CI 0.39-1.4).

CONCLUSION: An IV-first approach, compared to humeral-IO, for intra-arrest resuscitation was associated with an improved odds of favorable neurological outcomes and survival to hospital discharge. This association was seen among an initial shockable rhythm, but not non-shockable rhythm, subgroups.}, } @article {pmid39156432, year = {2024}, author = {Kaye, AD and Sala, KR and Dethloff, D and Norton, M and Moss, C and Plessala, MJ and Derouen, AG and Lopez Torres, Y and Kim, J and Tirumala, S and Shekoohi, S and Varrassi, G}, title = {The Evolving Use of Gold Nanoparticles as a Possible Reversal Agent for the Symptoms of Neurodegenerative Diseases: A Narrative Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64846}, pmid = {39156432}, issn = {2168-8184}, abstract = {Neurodegenerative diseases are broadly hallmarked by impaired energy metabolism and toxic intracellular accumulations such as damaged organelles or reactive oxygen species (ROS). Gold nanoparticles readily cross the blood-brain barrier and increase nicotinamide adenine dinucleotide + hydrogen (NADH) oxidation to nicotinamide adenine dinucleotide (NAD+), which is vital for intracellular energy generation, cellular repair, and protection from ROS. Thus, the use of gold nanoparticles to treat and potentially reverse cellular injury seen in neurodegenerative disease has been an area of ongoing research. This systematic review explores current literature regarding the use of gold nanoparticle therapy in the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). In vitro studies of CNM-Au8 (Clene Nanomedicine, Salt Lake City, UT) have been shown to reduce TDP-43 aggregates associated with ALS. These studies also exhibited the neuroprotective effects of CNM-Au8 in rat primary neurons exposed to amyloid-beta peptides, which are associated with Alzheimer's disease. In animal models of MS, oral delivery of CNM-Au8 was demonstrated to produce robust and significant remyelination activity, oligodendrocyte maturation, and expression of myelin markers. In these same MS animal models, CNM-Au8 improved the motor function of cuprizone-treated mice in both open-field and kinematic gait studies. Recent phase II trials of CNM-Au8 in 13 patients with Parkinson's disease and 11 patients with stable relapsing MS demonstrated a statistically significant increase in the NAD+/NADH ratio across two cohorts. As the current data repeatedly suggest, these gold nanoparticles are efficacious for the treatment and reversal of symptoms across these varying neurodegenerative pathologies. Further opportunities exist for increasing human trials and eventually incorporating this new technology into existing treatment regimens.}, } @article {pmid39156974, year = {2024}, author = {Fenili, G and Scaricamazza, S and Ferri, A and Valle, C and Paronetto, MP}, title = {Physical exercise in amyotrophic lateral sclerosis: a potential co-adjuvant therapeutic option to counteract disease progression.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1421566}, pmid = {39156974}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the selective degeneration of upper and lower motor neurons, leading to progressive muscle weakness and atrophy. The mean survival time is two to five years. Although the hunt for drugs has greatly advanced over the past decade, no cure is available for ALS yet. The role of intense physical activity in the etiology of ALS has been debated for several decades without reaching a clear conclusion. The benefits of organized physical activity on fitness and mental health have been widely described. Indeed, by acting on specific mechanisms, physical activity can influence the physiology of several chronic conditions. It was shown to improve skeletal muscle metabolism and regeneration, neurogenesis, mitochondrial biogenesis, and antioxidant defense. Interestingly, all these pathways are involved in ALS pathology. This review will provide a broad overview of the effect of different exercise protocols on the onset and progression of ALS, both in humans and in animal models. Furthermore, we will discuss challenges and opportunities to exploit physiological responses of imposed exercise training for therapeutic purposes.}, } @article {pmid39157517, year = {2024}, author = {Zhang, Y and Zhang, Q and Liu, Q and Zhao, Y and Xu, W and Hong, C and Xu, C and Qi, X and Qi, X and Liu, B}, title = {Fine mapping and functional validation of the maize nicosulfuron-resistance gene CYP81A9.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1443413}, pmid = {39157517}, issn = {1664-462X}, abstract = {Nicosulfuron, a widely utilized herbicide, is detrimental to some maize varieties due to their sensitivity. Developing tolerant varieties with resistance genes is an economical and effective way to alleviate phytotoxicity. In this study, map-based cloning revealed that the maize resistance gene to nicosulfuron is Zm00001eb214410 (CYP81A9), which encodes a cytochrome P450 monooxygenase. qRT- PCR results showed that CYP81A9 expression in the susceptible line JS188 was significantly reduced compared to the resistant line B73 during 0-192 hours following 80 mg/L nicosulfuron spraying. Meanwhile, a CYP81A9 overexpression line exhibited normal growth under a 20-fold nicosulfuron concentration (1600 mg/L), while the transgenic acceptor background material Zong31 did not survive. Correspondingly, silencing CYP81A9 through CRISPR/Cas9 mutagenesis and premature transcription termination mutant EMS4-06e182 resulted in the loss of nicosulfuron resistance in maize. Acetolactate Synthase (ALS), the target enzyme of nicosulfuron, exhibited significantly reduced activity in the roots, stems, and leaves of susceptible maize post-nicosulfuron spraying. The CYP81A9 expression in the susceptible material was positively correlated with ALS activity in vivo. Therefore, this study identified CYP81A9 as the key gene regulating nicosulfuron resistance in maize and discovered three distinct haplotypes of CYP81A9, thereby laying a solid foundation for further exploration of the underlying resistance mechanisms.}, } @article {pmid39158304, year = {2024}, author = {Tong, Z and Zhang, X and Guo, X and Wu, G and Cao, S and Zhang, Y and Meng, X and Wang, T and Wang, Y and Song, Y and Yang, R and Du, Z}, title = {Delivery of Yersinia pestis antigens via Escherichia coli outer membrane vesicles offered improved protection against plague.}, journal = {mSphere}, volume = {9}, number = {9}, pages = {e0033024}, pmid = {39158304}, issn = {2379-5042}, mesh = {Animals ; *Plague/prevention & control/immunology ; *Antigens, Bacterial/immunology/genetics ; *Bacterial Outer Membrane Proteins/immunology/genetics ; *Escherichia coli/genetics/immunology ; *Yersinia pestis/immunology/genetics ; Mice ; *Pore Forming Cytotoxic Proteins/immunology/genetics ; *Plague Vaccine/immunology/administration & dosage/genetics ; Female ; *Antibodies, Bacterial/blood/immunology ; Mice, Inbred BALB C ; Recombinant Fusion Proteins/immunology/genetics ; Bacterial Outer Membrane/immunology ; Bacterial Proteins ; }, abstract = {Outer membrane vesicles (OMVs) from Gram-negative bacteria can be used as a vaccine platform to deliver heterologous antigens. Here, the major protective antigens of Yersinia pestis, F1 and LcrV, were fused either with the leader sequence or the transmembrane domain of the outer membrane protein A (OmpA), resulting in chimeric proteins OmpA-ls-F1V and OmpA46-159-F1V, respectively. We show that OmpA-ls-F1V and OmpA46-159-F1V can be successfully delivered into the lumen and membrane of the OMVs of Escherichia coli, respectively. Mutation of ompA but not tolR in E. coli enhanced the delivery efficiency of OmpA-ls-F1V into OMVs. The OmpA-ls-F1V protein comprises up to 20% of the total protein in OMVs derived from the ompA mutant (OMVdA-ALS-F1V), a proportion significantly higher than the 1% observed for OmpA46-159-F1V in OMVs produced by an ompA mutant that expresses OmpA46-159-F1V, referred to as OMVdA-LATM5-F1V. Intramuscular (i.m.) immunization of mice with OMVdA-ALS-F1V induced significantly higher levels of serum anti-LcrV and anti-F1 IgG, and provided higher efficacy in protection against subcutaneous (s.c.) Y. pestis infection compared to OMVdA-LATM5-F1V and the purified recombinant F1V (rF1V) protein adsorbed to aluminum hydroxide. The three-dose i.m. immunization with OMVdA-ALS-F1V, administered at 14-day intervals, provides complete protection to mice against s.c. infection with 130 LD50 of Y. pestis 201 and conferred 80% against intranasal (i.n.) challenge with 11.4 LD50 of Y. pestis 201. Taken together, our findings indicate that the engineered OMVs containing F1V fused with the leader sequence of OmpA provide significantly higher protection than rF1V against both s.c. and i.n. infection of Y. pestis and more balanced Th1/Th2 responses.IMPORTANCEThe two major protective antigens of Y. pestis, LcrV and F1, have demonstrated the ability to elicit systemic and local mucosal immune responses as subunit vaccines. However, these vaccines have failed to provide adequate protection against pneumonic plague in African green monkeys. Here, Y. pestis F1 and LcrV antigens were successfully incorporated into the lumen and the surface of the outer membrane vesicles (OMVs) of E. coli by fusion either with the leader sequence or the transmembrane domain of OmpA. We compared the humoral immune response elicited by these OMV formulations and their protective efficacy in mice against Y. pestis. Our results demonstrate that the plague OMV vaccine candidates can induce robust protective immunity against both s.c. and i.n. Y. pestis infections, surpassing the effectiveness of rF1V. In addition, immunization with OMVs generated a relatively balanced Th1/Th2 immune response compared to rF1V immunization. These findings underscore the potential of OMVs-based plague vaccines for further development.}, } @article {pmid39161942, year = {2024}, author = {Marcu, IR and Rogoveanu, OC and Pădureanu, R and Pădureanu, V and Dop, D}, title = {Diagnostic elements in amyotrophic lateral sclerosis: A case report.}, journal = {Biomedical reports}, volume = {21}, number = {4}, pages = {141}, pmid = {39161942}, issn = {2049-9442}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurological disease that involves the degeneration of both upper and lower motor neurons responsible for controlling voluntary muscle activity. Most people with ALS die within 3-5 years due to respiratory failure. The current study presents the case of a 68-year-old woman diagnosed with ALS based on the subjective and objective findings from the patient's initial physiotherapy assessment and on neurophysiological tests. Physiotherapy interventions are aiming to maintain the patient's strength, balance and functional independence for as long as possible. The present case report aimed to highlight that a multidisciplinary team approach is necessary for the management of a progressive degenerative disease such as ALS.}, } @article {pmid39162129, year = {2024}, author = {Mazzini, L and De Marchi, F and Buzanska, L and Follenzi, A and Glover, JC and Gelati, M and Lombardi, I and Maioli, M and Mesa-Herrera, F and Mitrečić, D and Olgasi, C and Pivoriūnas, A and Sanchez-Pernaute, R and Sgromo, C and Zychowicz, M and Vescovi, A and Ferrari, D}, title = {Current status and new avenues of stem cell-based preclinical and therapeutic approaches in amyotrophic lateral sclerosis.}, journal = {Expert opinion on biological therapy}, volume = {24}, number = {9}, pages = {933-954}, doi = {10.1080/14712598.2024.2392307}, pmid = {39162129}, issn = {1744-7682}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; Animals ; *Stem Cell Transplantation ; Disease Models, Animal ; Clinical Trials as Topic ; }, abstract = {INTRODUCTION: Cell therapy development represents a critical challenge in amyotrophic lateral sclerosis (ALS) research. Despite more than 20 years of basic and clinical research, no definitive safety and efficacy results of cell-based therapies for ALS have been published.

AREAS COVERED: This review summarizes advances using stem cells (SCs) in pre-clinical studies to promote clinical translation and in clinical trials to treat ALS. New technologies have been developed and new experimental in vitro and animal models are now available to facilitate pre-clinical research in this field and to determine the most promising approaches to pursue in patients. New clinical trial designs aimed at developing personalized SC-based treatment with biological endpoints are being defined.

EXPERT OPINION: Knowledge of the basic biology of ALS and on the use of SCs to study and potentially treat ALS continues to grow. However, a consensus has yet to emerge on how best to translate these results into therapeutic applications. The selection and follow-up of patients should be based on clinical, biological, and molecular criteria. Planning of SC-based clinical trials should be coordinated with patient profiling genetically and molecularly to achieve personalized treatment. Much work within basic and clinical research is still needed to successfully transition SC therapy in ALS.}, } @article {pmid39163111, year = {2025}, author = {Fenoy, A}, title = {Scientific plurality and amyotrophic lateral sclerosis (ALS): A philosophical and historical perspective on Charcot's texts.}, journal = {Journal of the history of the neurosciences}, volume = {34}, number = {2}, pages = {133-142}, doi = {10.1080/0964704X.2024.2380635}, pmid = {39163111}, issn = {1744-5213}, mesh = {*Amyotrophic Lateral Sclerosis/history ; Humans ; History, 20th Century ; History, 19th Century ; }, abstract = {The history of amyotrophic lateral sclerosis (ALS)-also known as Charcot's disease, Lou Gehrig's disease, and motor neuron disease (MND)-freezes the texts of the scientist and physician Jean-Martin Charcot in a hagiographic narrative describing a brilliant discovery, based on the anatomo-clinical method. This narrative is often used by biologists and physicians as a reference point. This article shows that the use of the hagiographic register faces limitations. In particular, it obscures points of interest from Charcot's texts on ALS, such as the epistemological and ontological implications of scientific plurality in medicine. Although Charcot recognized the importance of scientific plurality in medicine, he prioritized the approaches and conferred the most important epistemic authority on clinical and pathological observations. In his view, animal modeling remains secondary to the understanding of disease. The concept of ALS and its diagnostic operability are the result of symptoms and lesions. By studying the past, we can highlight the specific features of the present. Today, although the ALS concept retains its diagnostic and clinical relevance, it is increasingly called into question in etiological and mechanistic research. Despite these differences, Charcot's reflections are a reminder of the importance of theoretical thinking on scientific plurality, all the more so today in the context of ALS research, in which combining different approaches is increasingly valued to understand the phenotypic and genetic heterogeneity of ALS.}, } @article {pmid39163156, year = {2024}, author = {Takahashi, K and Hamada, Y and Kobayashi, M and Kobayashi, S and Kanbayashi, T and Hatanaka, Y and Nakayama, T and Imafuku, I and Matsuno, H and Iguchi, Y and Katada, F and Fukutake, T and Ando, T and Mikata, T and Usui, T and Uchino, K and Nishiyama, K and Sonoo, M}, title = {Utility of the Repetitive Nerve Stimulation Test and Needle EMG in the Trapezius Muscle for the Early Diagnosis of ALS.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {1}, pages = {1-11}, doi = {10.1097/CND.0000000000000479}, pmid = {39163156}, issn = {1537-1611}, support = {19K07966 and 22K07524//Ministry of Education, Science, Sports and Culture of Japan/ ; 19ek0109252h0003//AMED/ ; }, mesh = {Humans ; *Electromyography/methods ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Aged ; Retrospective Studies ; *Electric Stimulation ; *Superficial Back Muscles/physiopathology ; *Sensitivity and Specificity ; Adult ; Early Diagnosis ; }, abstract = {OBJECTIVES: To document the utility of decremental responses in the repetitive nerve stimulation test (RNS) and spontaneous activities in needle electromyography (EMG) in the trapezius muscle for the diagnosis of amyotrophic lateral sclerosis.

METHODS: Subjects were retrospectively identified from our EMG database. Cervical spondylosis was represented as a disease control group. We investigated the sensitivity and specificity of RNS and EMG in the trapezius muscle and those of diagnostic criteria including the Gold Coast criteria (GCC).

RESULTS: We reviewed 120 patients with amyotrophic lateral sclerosis and 17 patients with cervical spondylosis. "RNS or EMG" achieved the highest sensitivity (85%). The specificity was the highest for RNS (94%). Addition of RNS of the deltoid muscle achieved 98% sensitivity in the upper-limb onset amyotrophic lateral sclerosis. The sensitivity of the GCC was very high (88%).

CONCLUSIONS: Neurophysiological parameters investigated in this study having close to 100% specificities or sensitivities are useful as complements to the GCC.}, } @article {pmid39163160, year = {2024}, author = {Purcell, N and Manousakis, G}, title = {Diverse Phenotypic Presentation of the Welander Distal Myopathy Founder Mutation, With Myopathy and Amyotrophic Lateral Sclerosis in the Same Family.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {1}, pages = {42-46}, doi = {10.1097/CND.0000000000000501}, pmid = {39163160}, issn = {1537-1611}, mesh = {Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; *Distal Myopathies/genetics/diagnosis ; Founder Effect ; *Mutation ; *Pedigree ; *Phenotype ; T-Cell Intracellular Antigen-1/genetics ; Aged ; Aged, 80 and over ; }, abstract = {Welander distal myopathy is a rare myopathy with prominent and early involvement of distal upper extremity muscles, prevalent in individuals of Scandinavian origin, and caused by a founder mutation in the cytotoxic granule-associated RNA-binding protein (T-cell intracellular antigen-1; TIA1), E384K. Different pathogenic variants in the TIA1 gene, distinct from the founder 1, have recently been associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), suggesting that TIA1-related disorders belong to the group of multisystem proteinopathies. We describe the first case of a two-generation family with the founder E384K TIA1 mutation demonstrating phenotypic variability; the mother manifested as Welander myopathy, whereas 2 daughters manifested as ALS. No other genetic cause of ALS was found in 1 of the affected daughters. We also discuss the possible mechanisms explaining this pleotropic presentation of the founder mutation.}, } @article {pmid39163164, year = {2025}, author = {Raggi, A and Serretti, A and Ferri, R}, title = {The P300 component of the auditory event-related potential in adult psychiatric and neurologic disorders: a narrative review of clinical and experimental evidence.}, journal = {International clinical psychopharmacology}, volume = {40}, number = {5}, pages = {259-274}, doi = {10.1097/YIC.0000000000000566}, pmid = {39163164}, issn = {1473-5857}, mesh = {Humans ; *Event-Related Potentials, P300/physiology ; *Mental Disorders/physiopathology/diagnosis ; *Nervous System Diseases/physiopathology/diagnosis ; *Evoked Potentials, Auditory/physiology ; Adult ; Electroencephalography ; Neuropsychological Tests ; }, abstract = {The auditory P300 wave, also known as P3b, is an event-related potential component thought to reflect central information processes involved in stimulus evaluation or categorization. It is typically elicited using the oddball paradigm, which involves mixing low-probability target items with high-probability standard stimuli. Its latency is associated with the timing of cognitive processes such as stimulus evaluation and response preparation, while its amplitude is related to the amount of attentional resources engaged during the task. Despite decades of use in research settings, its application in clinical practice has been limited. Prolongation of latencies and reduction of amplitudes in the auditory P3b have been observed in both psychiatric and neurological conditions. This includes cases where traditional neuropsychological tests are challenging due to severe motor or speech dysfunctions, or in conditions characterized by subtle cognitive deficits. Additionally, specific laterality patterns in psychoses and a loss of P300 habituation in migraines have been described. The wealth of experimental evidence supports the use of this evoked potential, which can be elicited through a relatively simple paradigm, for objectively evaluating cognition in psychiatric and neurological patients, particularly in follow-up assessments. Therefore, the auditory P300 appears to be a valuable tool for monitoring the clinical course of patients with mental and neurological disorders in certain circumstances.}, } @article {pmid39165755, year = {2023}, author = {Bustos, LM and Sattler, R}, title = {The Fault in Our Astrocytes - cause or casualties of proteinopathies of ALS/FTD and other neurodegenerative diseases?.}, journal = {Frontiers in molecular medicine}, volume = {3}, number = {}, pages = {1075805}, pmid = {39165755}, issn = {2674-0095}, support = {R21 NS125861/NS/NINDS NIH HHS/United States ; }, abstract = {Many neurodegenerative diseases fall under the class of diseases known as proteinopathies, whereby the structure and localization of specific proteins become abnormal. These aberrant proteins often aggregate within cells which disrupts vital homeostatic and physiological cellular functions, ultimately contributing to cell death. Although neurodegenerative disease research is typically neurocentric, there is evidence supporting the role of non-neuronal cells in the pathogenesis of these diseases. Specifically, the role of astrocytes in neurodegenerative diseases has been an ever-growing area of research. Astrocytes are one of the most abundant cell types in the central nervous system (CNS) and provide an array of essential homeostatic functions that are disrupted in neurodegenerative diseases. Astrocytes can exhibit a reactive phenotype that is characterized by molecular changes, as well as changes in morphology and function. In neurodegenerative diseases, there is potential for reactive astrocytes to assume a loss-of-function phenotype in homeostatic operations such as synapse maintenance, neuronal metabolic support, and facilitating cell-cell communication between glia and neurons. They are also able to concurrently exhibit gain-of-function phenotypes that can be destructive to neural networks and the astrocytes themselves. Additionally, astrocytes have been shown to internalize disease related proteins and reflect similar or exacerbated pathology that has been observed in neurons. Here, we review several major neurodegenerative disease-specific proteinopathies and what is known about their presence in astrocytes and the potential consequences regarding cell and non-cell autonomous neurodegeneration.}, } @article {pmid39167140, year = {2024}, author = {Yu, L and Wu, N and Choi, O and Nguyen, KD}, title = {Inhibition of glycolytic reprogramming suppresses innate immune-mediated inflammation in experimental amyotrophic lateral sclerosis.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {73}, number = {11}, pages = {1847-1857}, pmid = {39167140}, issn = {1420-908X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/immunology/drug therapy ; *Immunity, Innate/drug effects ; *Glycolysis/drug effects ; *Spinal Cord/immunology/pathology/drug effects/metabolism ; *Mice, Transgenic ; Mice ; Inflammation ; Male ; Disease Models, Animal ; Monocytes/drug effects/immunology ; Mice, Inbred C57BL ; Microglia/drug effects/immunology/metabolism ; Female ; }, abstract = {BACKGROUND: Innate immune activation has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, metabolic pathways that govern this bioenergetically demanding process in ALS remains elusive. Here we investigated whether and how immunometabolic transformation of innate immune cells contributes to disease progression in an experimental model of this neurodegenerative disease.

METHODS: We utilized multidimensional flow cytometry and integrative metabolomics to characterize the immunometabolic phenotype of circulating and spinal cord innate immune cells in the B6SJL-Tg(SOD1*G93A)1Gur/J model of ALS (SOD1-G93A) at various disease stages (before vs. after the onset of motor dysfunction). Behavioral and survival analyses were also conducted to determine the impact of an energy-regulating compound on innate immune cell metabolism, inflammation, and disease development.

RESULTS: Temporally coordinated accumulation of circulating inflammatory Ly6C + monocytes and spinal cord F4/80 + CD45[hi] infiltrates precedes the onset of motor dysfunction in SOD1-G93A mice. Subsequent metabolomic analysis reveals that this phenomenon is accompanied by glycolytic reprogramming of spinal cord inflammatory CD11b + cells, comprising both resident F4/80 + CD45[low] microglia and F4/80 + CD45[hi] infiltrates. Furthermore, pharmacologic inhibition of glycolysis by ZLN005, a small molecule activator of Ppargc1a, restrains inflammatory glycolytic activation of spinal cord CD11b + cells, enhances motor function, and prolongs survival in SOD1-G93A mice.

CONCLUSIONS: These observations suggest that modulation of inflammatory glycolytic reprogramming of innate immune cells may represent a promising therapeutic approach in ALS.}, } @article {pmid39167487, year = {2024}, author = {Alirzayeva, H and Loureiro, R and Koyuncu, S and Hommen, F and Nabawi, Y and Zhang, WH and Dao, TTP and Wehrmann, M and Lee, HJ and Vilchez, D}, title = {ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes.}, journal = {Cell reports}, volume = {43}, number = {8}, pages = {114626}, doi = {10.1016/j.celrep.2024.114626}, pmid = {39167487}, issn = {2211-1247}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Histones/metabolism ; *RNA-Binding Protein FUS/metabolism/genetics ; *Caenorhabditis elegans/metabolism/genetics ; Animals ; *Mutation/genetics ; *Poly (ADP-Ribose) Polymerase-1/metabolism/genetics ; Motor Neurons/metabolism/pathology ; Poly ADP Ribosylation ; Induced Pluripotent Stem Cells/metabolism ; Protein Binding ; }, abstract = {The majority of severe early-onset and juvenile cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the FUS gene, resulting in rapid disease progression. Mutant FUS accumulates within stress granules (SGs), thereby affecting the dynamics of these ribonucleoprotein complexes. Here, we define the interactome of the severe mutant FUS[P525L] variant in human induced pluripotent stem cell (iPSC)-derived motor neurons. We find increased interaction of FUS[P525L] with the PARP1 enzyme, promoting poly-ADP-ribosylation (PARylation) and binding of FUS to histone H1.2. Inhibiting PARylation or reducing H1.2 levels alleviates mutant FUS aggregation, SG alterations, and apoptosis in human motor neurons. Conversely, elevated H1.2 levels exacerbate FUS-ALS phenotypes, driven by the internally disordered terminal domains of H1.2. In C. elegans models, knockdown of H1.2 and PARP1 orthologs also decreases FUS[P525L] aggregation and neurodegeneration, whereas H1.2 overexpression worsens ALS-related changes. Our findings indicate a link between PARylation, H1.2, and FUS with potential therapeutic implications.}, } @article {pmid39168358, year = {2024}, author = {Ueno, Y and Morishima, Y and Hata, T and Shindo, A and Murata, H and Saito, T and Nakamura, Y and Shindo, K}, title = {Current progress in microRNA profiling of circulating extracellular vesicles in amyotrophic lateral sclerosis: A systematic review.}, journal = {Neurobiology of disease}, volume = {200}, number = {}, pages = {106639}, doi = {10.1016/j.nbd.2024.106639}, pmid = {39168358}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/diagnosis ; Biomarkers/blood ; *Extracellular Vesicles/metabolism/genetics ; *MicroRNAs/blood/genetics ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons, leading to death resulting mainly from respiratory failure, for which there is currently no curative treatment. Underlying pathological mechanisms for the development of ALS are diverse and have yet to be elucidated. Non-invasive testing to isolate circulating molecules including microRNA to diagnose ALS has been reported, but circulating extracellular vesicle (EV)-derived microRNA has not been fully studied in the ALS population.

METHODS: A systematic literature review to explore studies investigating the profile of microRNAs in EVs from blood samples of ALS patients was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.

RESULTS: Eleven studies including a total of 263 patients with ALS were included in the present systematic review. The majority of patients had sporadic ALS, though a small number of patients with ALS having genetic mutations were included. Seven studies used plasma-derived EVs, and the remaining four studies used serum-derived EVs. RNA sequencing or microarrays were used in eight studies, and quantitative PCR was used in eight studies, of which five studies used RNA sequencing or microarrays for screening and quantitative PCR for validation. There was overlap of miR-199a-3p and miR-199a-5p in three studies.

CONCLUSIONS: Overall, the systematic review addressed the current advances in the profiling of microRNAs in circulating EVs of ALS patients. Blood samples, isolation of EVs, and microRNA analysis were diverse. Although there was an overlap of miR-199a-3p and miR-199a-5p, collection of further evidence is warranted.}, } @article {pmid39168577, year = {2024}, author = {Rai, SP and Ansari, AH and Singh, D and Singh, S}, title = {Coffee, antioxidants, and brain inflammation.}, journal = {Progress in brain research}, volume = {289}, number = {}, pages = {123-150}, doi = {10.1016/bs.pbr.2024.06.005}, pmid = {39168577}, issn = {1875-7855}, mesh = {*Coffee/chemistry ; Humans ; *Antioxidants/pharmacology ; Animals ; Neurodegenerative Diseases ; Encephalitis ; Caffeine/pharmacology/administration & dosage ; Neuroinflammatory Diseases ; }, abstract = {Coffee is the most popular beverage in the world and, aside from tea and water, the most often consumed caffeine-containing beverage. Because of its high caffeine concentration, it is typically classified as a stimulant. There are other bioactive ingredients in coffee besides caffeine. The coffee beverage is a blend of several bioactive substances, including diterpenes (cafestol and kahweol), alkaloids (caffeine and trigonelline), and polyphenols (particularly chlorogenic acids in green beans and caffeic acid in roasted coffee beans). Caffeine has also been linked to additional beneficial benefits such as antioxidant and anti-inflammatory properties, which change cellular redox and inflammatory status in a dose-dependent manner. Pyrocatechol, a constituent of roasted coffee that is created when chlorogenic acid is thermally broken down, has anti-inflammatory properties as well. It is postulated that coffee consumption reduces neuroinflammation, which is intimately linked to the onset of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). This review provides an overview of the most recent studies regarding coffee's possible benefits in preventing brain inflammation and neurodegenerative disorders.}, } @article {pmid39168583, year = {2024}, author = {Memudu, AE and Olukade, BA and Adebayo, OS and Raza, ML}, title = {Coffee and amyotrophic lateral sclerosis (ALS).}, journal = {Progress in brain research}, volume = {289}, number = {}, pages = {81-105}, doi = {10.1016/bs.pbr.2024.06.003}, pmid = {39168583}, issn = {1875-7855}, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Humans ; *Coffee ; Animals ; Neuroprotective Agents/pharmacology ; Oxidative Stress/physiology/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive loss of motor neurons. The effective treatments for ALS remain elusive, necessitating exploration into novel preventive strategies. ALS pathogenesis is triggered by oxidative stress which results in neuroinflammation, exicitotoxicity and neuronal cell death. Nutritional mechanism for halting progression of neurodegeneration is through dietary compounds with antioxidants, anti-inflammatory or neuromodulating activity. Coffee is a widely consumed beverage made up of polyphenols, caffeine and other compounds with possible antioxidants and neuro-protective roles. It is important to say that various epidemiological studies have documented association between coffee intake and ALS. This chapter is aimed to present a comprehensive review of existing literature on coffee consumption and ALS, involving epidemiological studies, preclinical research, and its mechanism of actions in animal model of ALS. It highlights key findings regarding the potential neuroprotective properties of coffee constituents such as caffeine, polyphenols, and other bioactive compounds. Furthermore, it discusses possible pathways through which coffee may modulate ALS pathogenesis, including suppressing oxidative stress and neuroinflammation while boosting adenosine function via the adenosine receptor two on the motor neuron cells membrane in the spinal cord to enhance motor function via the corticospinal tract. Overall, this chapter underscores the significance of further research to unravel the specific mechanisms by which coffee exerts its neuroprotective effects in ALS, with the ultimate goal of identifying dietary strategies for ALS prevention and management.}, } @article {pmid39170062, year = {2024}, author = {Wang, H and Yao, G and He, K and Wang, Z and Cheng, CK}, title = {ACL reconstruction combined with anterolateral structures reconstruction for treating ACL rupture and knee injuries: a finite element analysis.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {12}, number = {}, pages = {1437684}, pmid = {39170062}, issn = {2296-4185}, abstract = {Introduction: The biomechanical indication for combining anterolateral structures reconstruction (ASLR) with ACL reconstruction (ACLR) to reduce pivot shift in the knee remains unclear. This study aims to investigate knee functionality after ACL rupture with different combinations of injuries, and to compare the effectiveness of ALSR with ACLR for treating these injuries. Methods: A validated finite element model of a human cadaveric knee was used to simulate pivot shift tests on the joint in different states, including 1) an intact knee; 2) after isolated ACL rupture; 3) after ACL rupture combined with different knee injuries or defect, including a posterior tibial slope (PTS) of 20°, an injury to the anterolateral structures (ALS) and an injury to the posterior meniscotibial ligament of the lateral meniscus (LP); 4) after treating the different injuries using isolated ACLR; v. after treating the different injuries using ACLR with ALSR. The knee kinematics, maximum von Mises stress (Max.S) on the tibial articular cartilage (TC) and force in the ACL graft were compared among the different simulation groups. Results and discussion: Comparing with isolated ACL rupture, combined injury to the ALS caused the largest knee laxity, when a combined PTS of 20° induced the largest Max.S on the TC. The joint stability and Max.S on the TC in the knee with an isolated ACL rupture or a combined rupture of ACL and LP were restored to the intact level after being treated with isolated ACLR. The knee biomechanics after a combined rupture of ACL and ALS were restored to the intact level only when being treated with a combination of ACLR and ALSR using a large graft diameter (6 mm) for ALSR. However, for the knee after ACL rupture combined with a PTS of 20°, the ATT and Max.S on the TC were still greater than the intact knee even after being treated with a combination of ACLR and ALSR. The finite element analysis showed that ACLR should include ALSR when treating ACL ruptures accompanied by ALS rupture. However, pivot shift in knees with a PTS of 20° was not eliminated even after a combined ACLR and ALSR.}, } @article {pmid39170125, year = {2024}, author = {Wenzhi, Y and Xiangyi, L and Dongsheng, F}, title = {The prion-like effect and prion-like protein targeting strategy in amyotrophic lateral sclerosis.}, journal = {Heliyon}, volume = {10}, number = {15}, pages = {e34963}, pmid = {39170125}, issn = {2405-8440}, abstract = {Pathological proteins in amyotrophic lateral sclerosis (ALS), such as superoxide dismutase 1, TAR DNA-binding protein 43, and fused in sarcoma, exhibit a prion-like pattern. All these proteins have a low-complexity domain and seeding activity in cells. In this review, we summarize the studies on the prion-like effect of these proteins and list six prion-like protein targeting strategies that we believe have potential for ALS therapy, including antisense oligonucleotides, antibody-based technology, peptide, protein chaperone, autophagy enhancement, and heteromultivalent compounds. Considering the pathological complexity and heterogeneity of ALS, we believe that the final solution to ALS therapy is most likely to be an individualized cocktail therapy, including clearance of toxicity, blockage of pathological progress, and protection of neurons.}, } @article {pmid39170265, year = {2024}, author = {Pain, O and Jones, A and Al Khleifat, A and Agarwal, D and Hramyka, D and Karoui, H and Kubica, J and Llewellyn, DJ and Ranson, JM and Yao, Z and Iacoangeli, A and Al-Chalabi, A}, title = {Harnessing transcriptomic signals for amyotrophic lateral sclerosis to identify novel drugs and enhance risk prediction.}, journal = {Heliyon}, volume = {10}, number = {15}, pages = {e35342}, pmid = {39170265}, issn = {2405-8440}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates common genetic association results from the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing opportunities, and enhancing prediction of ALS risk and clinical characteristics.

METHODS: Genes associated with ALS were identified using GWAS summary statistic methodology including SuSiE SNP-based fine-mapping, and transcriptome- and proteome-wide association study (TWAS/PWAS) analyses. Using several approaches, gene associations were integrated with the DrugTargetor drug-gene interaction database to identify drugs that could be repurposed for the treatment of ALS. Furthermore, ALS gene associations from TWAS were combined with observed blood expression in two external ALS case-control datasets to calculate polytranscriptomic scores and evaluate their utility for prediction of ALS risk and clinical characteristics, including site of onset, age at onset, and survival.

RESULTS: SNP-based fine-mapping, TWAS and PWAS identified 118 genes associated with ALS, with TWAS and PWAS providing novel mechanistic insights. Drug repurposing analyses identified six drugs significantly enriched for interactions with ALS associated genes, though directionality could not be determined. Additionally, drug class enrichment analysis showed gene signatures linked to calcium channel blockers may reduce ALS risk, whereas antiepileptic drugs may increase ALS risk. Across the two observed expression target samples, ALS polytranscriptomic scores significantly predicted ALS risk (R [2] = 5.1 %; p-value = 3.2 × 10[-27]) and clinical characteristics.

CONCLUSIONS: Functionally-informed analyses of ALS GWAS summary statistics identified novel mechanistic insights into ALS aetiology, highlighted several therapeutic research avenues, and enabled statistically significant prediction of ALS risk.}, } @article {pmid39170988, year = {2024}, author = {Baroni, LM and Funari, MP and So Taa Kum, A and Bestetti, AM and de Oliveira, LB and de Carvalho, MF and Franzini, TAP and de Moura, DTH and Bernardo, WM and de Moura, EGH}, title = {Endoscopic Versus Surgical Treatment for Ampullary Lesions: A Systematic Review With Meta-Analysis.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e65076}, pmid = {39170988}, issn = {2168-8184}, abstract = {Ampullary lesions (ALs) can be treated through either an endoscopic approach (EA) or a surgical approach (SA). However, it is important to note that EAs carry a significant risk of incomplete resection, while opting for surgical interventions can result in substantial morbidity. We performed a systematic review and meta-analysis for R0 resection, recurrence, adverse events in general, major adverse events, mortality, and length of hospital stay between SAs and EAs. Electronic databases were searched from inception to 2023. We identified nine independent studies. The risk difference was -0.32 (95% CI: -0.50, -0.15; p <0.001) for R0, 0.12 (95% CI: 0.06, 0.19; p < 0.001) for recurrence, -0.22 (95% CI: -0.43, 0.00; p 0.05) for overall adverse events, -0.11 (95% CI: -0.32, 0.10; p = 0.31) for major complications, -0.01 (95% CI: -0.02, 0.01; p = 0.43) for mortality, and -14.69 (95% CI: -19.91, -9.47; p < 0.001) for length of hospital stay. As expected, our data suggest a higher complete resection rate and lower recurrence from surgical interventions, but this is associated with an elevated risk of adverse events and a longer hospital stay.}, } @article {pmid39171600, year = {2025}, author = {Nogueira-Machado, JA and das Chagas Lima E Silva, F and Rocha-Silva, F and Gomes, N}, title = {Amyotrophic Lateral Sclerosis (ALS): An Overview of Genetic and Metabolic Signaling Mechanisms.}, journal = {CNS & neurological disorders drug targets}, volume = {24}, number = {2}, pages = {83-90}, pmid = {39171600}, issn = {1996-3181}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Signal Transduction/genetics/physiology ; Mutation/genetics ; Animals ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, and incurable disease. Sporadic (sALS) accounts for ninety percent of ALS cases, while familial ALS (fALS) accounts for around ten percent. Reports have identified over 30 different forms of familial ALS. Multiple types of fALS exhibit comparable symptoms with mutations in different genes and possibly with different predominant metabolic signals. Clinical diagnosis takes into account patient history but not genetic mutations, misfolded proteins, or metabolic signaling. As research on genetics and metabolic pathways advances, it is expected that the intricate complexity of ALS will compound further. Clinicians discuss whether a gene's presence is a cause of the disease or just an association or consequence. They believe that a mutant gene alone is insufficient to diagnose ALS. ALS, often perceived as a single disease, appears to be a complex collection of diseases with similar symptoms. This review highlights gene mutations, metabolic pathways, and muscle-neuron interactions.}, } @article {pmid39172789, year = {2024}, author = {Ahmed, R and Liang, M and Hudson, RP and Rangadurai, AK and Huang, SK and Forman-Kay, JD and Kay, LE}, title = {Atomic resolution map of the solvent interactions driving SOD1 unfolding in CAPRIN1 condensates.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {35}, pages = {e2408554121}, pmid = {39172789}, issn = {1091-6490}, support = {FND-503573//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; 2015-04347//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; FDN-148375//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; PJT-190060//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; }, mesh = {*Superoxide Dismutase-1/chemistry/metabolism/genetics ; Humans ; *Solvents/chemistry ; Protein Unfolding ; Protein Binding ; Protein Folding ; Models, Molecular ; Stress Granules/metabolism/chemistry ; RNA-Binding Proteins/metabolism/chemistry ; Protein Conformation ; Magnetic Resonance Spectroscopy ; }, abstract = {Biomolecules can be sequestered into membrane-less compartments, referred to as biomolecular condensates. Experimental and computational methods have helped define the physical-chemical properties of condensates. Less is known about how the high macromolecule concentrations in condensed phases contribute "solvent" interactions that can remodel the free-energy landscape of other condensate-resident proteins, altering thermally accessible conformations and, in turn, modulating function. Here, we use solution NMR spectroscopy to obtain atomic resolution insights into the interactions between the immature form of superoxide dismutase 1 (SOD1), which can mislocalize and aggregate in stress granules, and the RNA-binding protein CAPRIN1, a component of stress granules. NMR studies of CAPRIN1:SOD1 interactions, focused on both unfolded and folded SOD1 states in mixed phase and demixed CAPRIN1-based condensates, establish that CAPRIN1 shifts the SOD1 folding equilibrium toward the unfolded state through preferential interactions with the unfolded ensemble, with little change to the structure of the folded conformation. Key contacts between CAPRIN1 and the H80-H120 region of unfolded SOD1 are identified, as well as SOD1 interaction sites near both the arginine-rich and aromatic-rich regions of CAPRIN1. Unfolding of immature SOD1 in the CAPRIN1 condensed phase is shown to be coupled to aggregation, while a more stable zinc-bound, dimeric form of SOD1 is less susceptible to unfolding when solvated by CAPRIN1. Our work underscores the impact of the condensate solvent environment on the conformational states of resident proteins and supports the hypothesis that ALS mutations that decrease metal binding or dimerization function as drivers of aggregation in condensates.}, } @article {pmid39173710, year = {2025}, author = {Weber, MP and Strobel, RJ and Norman, AV and Kareddy, A and Young, A and Young, S and El Moheb, M and Noona, SWW and Wisniewski, AM and Quader, M and Mazzeffi, M and Yarboro, LT and Teman, NR}, title = {Cardiac Surgical Unit-Advanced Life Support-certified centers are associated with improved failure to rescue after cardiac arrest: A propensity score-matched analysis.}, journal = {The Journal of thoracic and cardiovascular surgery}, volume = {169}, number = {4}, pages = {1271-1281}, doi = {10.1016/j.jtcvs.2024.08.014}, pmid = {39173710}, issn = {1097-685X}, support = {T32 HL007849/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Heart Arrest/therapy/mortality ; Female ; Propensity Score ; Middle Aged ; Aged ; *Advanced Cardiac Life Support/standards/education ; *Certification ; *Cardiac Surgical Procedures/adverse effects ; *Failure to Rescue, Health Care/statistics & numerical data ; Retrospective Studies ; }, abstract = {OBJECTIVE: The impact of Cardiac Surgical Unit-Advanced Life Support (CSU-ALS) training on failure to rescue after cardiac arrest (FTR-CA) is unknown. We hypothesized that institutional CSU-ALS certification would be associated with lower FTR-CA.

METHODS: Patients undergoing Society of Thoracic Surgeons index operations from 2020 to 2023 from a regional collaborative were analyzed. Each institution was surveyed regarding its status as a CSU-ALS-certified center. Patients stratified by CSU-ALS certification were 1:1 propensity score matched with subsequent multivariable model reviewing associations with FTR-CA.

RESULTS: A total of 12,209 patients were included in the study period across 15 institutions. Eight centers reported CSU-ALS certification. After propensity score matching, 2 patient cohorts were formed (n = 3557). Patients at CSU-ALS centers had greater rates of intensive care unit readmission (3.9% vs 2.3%, P < .01) and total operating room time (340 minutes vs 323 minutes, P < .01). Hospital readmission was less likely in the CSU-ALS centers (9.0% vs 10.1%, P < .01). There was no difference in the rate of postoperative cardiac arrest (1.8% vs 2.2%, P = .24) or operative mortality (2.5% vs 2.9%, P = .30). After risk adjustment, CSU-ALS centers (odds ratio, 0.30; 95% confidence interval, 0.12-0.72, P < .01) and greater-volume centers (odds ratio, 0.15; confidence interval, 0.03-0.74, P = .02) had reduced odds of FTR-CA.

CONCLUSIONS: Centers with CSU-ALS certification are associated with a lower risk-adjusted likelihood of FTR-CA. This highlights the importance of well-trained staff and treatment algorithms in the care of patients postcardiac surgery.}, } @article {pmid39174002, year = {2024}, author = {Javaudin, F and Papin, M and Le Bastard, Q and Thibault, M and Boishardy, T and Brau, F and Laribi, S and Petrovic, T and Peluchon, T and Markarian, T and Volteau, C and Arnaudet, I and Pes, P and Le Conte, P}, title = {Early point-of-care echocardiography as a predictive factor for absence of return of spontaneous circulatory in out-of-hospital cardiac arrests: A multicentre observational study.}, journal = {Resuscitation}, volume = {203}, number = {}, pages = {110373}, doi = {10.1016/j.resuscitation.2024.110373}, pmid = {39174002}, issn = {1873-1570}, mesh = {Humans ; Male ; Female ; *Out-of-Hospital Cardiac Arrest/therapy ; Aged ; Prospective Studies ; Middle Aged ; *Echocardiography/methods ; *Cardiopulmonary Resuscitation/methods ; *Return of Spontaneous Circulation ; *Predictive Value of Tests ; Point-of-Care Systems ; Prognosis ; }, abstract = {INTRODUCTION: Early assessment of the prognosis of a patient in cardiac arrest during cardiopulmonary resuscitation is highly challenging. This study aims to evaluate the predictive outcome value of early point-of-care ultrasound (POCUS) in out-of-hospital settings.

METHODS: This observational, prospective, multicentre study's primary endpoint was the positive predictive value (PPV) of POCUS cardiac standstill within the first 12 min of advanced life support (ALS) initiation in determining the absence of return of spontaneous circulation (ROSC). A multivariate logistic regression model was constructed with adjustments for known predictive variables typically used in termination of resuscitation (TOR) rules.

RESULTS: A total of 293 patients were analysed, with a mean age of 66.6 ± 14.6 years, and a majority were men (75.8%). POCUS was performed on average 7.9 ± 2.6 min after ALS initiation. Among patients with cardiac standstill (72.4%), 16.0% achieved ROSC compared with 48.2% in those with visible cardiac motions. The PPV of early POCUS cardiac standstill for the absence of ROSC was 84.0%, 95% CI [78.3-88.6]. In multivariable analysis, only POCUS cardiac standstill (adjusted odds ratio [aOR] 3.89, 95% CI [1.86-8.17]) and end-tidal CO2 (ETCO2) value ≤37 mmHg (aOR 4.27, 95% CI [2.21-8.25]) were associated with the absence of ROSC.

CONCLUSION: Early POCUS cardiac standstill during CPR for out-of-hospital cardiac arrest was a reliable predictor of the absence of ROSC. However, its presence alone was not sufficient to determine the termination of resuscitation efforts.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03494153. Registered March 29, 2018.}, } @article {pmid39174072, year = {2024}, author = {Yoon, R and Wong, JP and Chung-Lee, L and Akbarian, A and Abdulai, AF and Hou, R and Ho, M and Zinaic, R and Anoushka, A}, title = {Scoping review protocol: what is the state of evidence for the use of communication apps with immigrant seniors in long-term care and community settings?.}, journal = {BMJ open}, volume = {14}, number = {8}, pages = {e089939}, pmid = {39174072}, issn = {2044-6055}, mesh = {Humans ; *Emigrants and Immigrants ; *Long-Term Care ; *Mobile Applications ; Aged ; Research Design ; Communication Barriers ; Scoping Reviews as Topic ; }, abstract = {INTRODUCTION: First language care is critical for older immigrant adults with limited English proficiency, especially in long-term care settings where most residents require staff assistance and experience complex chronic conditions, resulting in multiple communication interactions where language poses a barrier. Although there are a myriad of cultural-language translation apps and devices available, there is a gap in both research and practice on the acceptability and feasibility of these digital resources within the context of long-term care and community settings for older immigrant adults, from a cultural relevance and digital health equity perspective. Our paper outlines a scoping review protocol to examine the state of the literature on the extent to which cultural-language translation apps are used in long-term care settings and community-based elder care. We will also examine the extent to which such apps bridge or further gaps in equitable, accessible and acceptable care for older immigrant adults with limited English language proficiency.

METHODS AND ANALYSIS: This scoping review protocol will employ an adapted five-stage framework outlined by Arksey and O'Malley guided by enhancements recommended by Levac et al and Colquhoun et al. Using the Joanna Briggs Institute's population, concept and context framework, we defined the scope of the scoping review by identifying the target population, concepts for investigation and the context within which the research is situated. We will conduct a search of the literature from 2005 to 2024 using five bibliographic databases from health sciences (Healthstar OVID, MEDLINE OVID and Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO), engineering (Engineering Village Elsevier) and a cross-disciplinary database (Web of Science Clarivate). The research team will adopt a critical, equity-focused approach for the scoping review by integrating Richardson et al's framework for Digital Health Equity into our analysis of the findings. This will ensure that health and social equity perspectives are integrated within our methodology and analytical lens. Our analysis will specifically examine selected studies for their engagement with health equity and their ability to address issues such as ageism, ableism and the digital divide within geriatric care.

ETHICS AND DISSEMINATION: Ethics approval is not required for this scoping review as it involves secondary analysis of published works and no primary data collection involving human subjects. Findings of the review will be shared with community partners and disseminated through publications, conferences and peer-reviewed publications.}, } @article {pmid39174305, year = {2025}, author = {Mohamed Yusoff, AA and Mohd Khair, SZN}, title = {Unraveling mitochondrial dysfunction: comprehensive perspectives on its impact on neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {36}, number = {1}, pages = {53-90}, pmid = {39174305}, issn = {2191-0200}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Mitochondria/metabolism ; Animals ; Mitochondrial Dynamics/physiology ; Mitochondrial Diseases/metabolism ; Mitophagy/physiology ; }, abstract = {Neurodegenerative diseases represent a significant challenge to modern medicine, with their complex etiology and progressive nature posing hurdles to effective treatment strategies. Among the various contributing factors, mitochondrial dysfunction has emerged as a pivotal player in the pathogenesis of several neurodegenerative disorders. This review paper provides a comprehensive overview of how mitochondrial impairment contributes to the development of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, driven by bioenergetic defects, biogenesis impairment, alterations in mitochondrial dynamics (such as fusion or fission), disruptions in calcium buffering, lipid metabolism dysregulation and mitophagy dysfunction. It also covers current therapeutic interventions targeting mitochondrial dysfunction in these diseases.}, } @article {pmid39174694, year = {2024}, author = {Layalle, S and Aimond, F and Brugioti, V and Guissart, C and Raoul, C and Soustelle, L}, title = {The ALS-associated KIF5A P986L variant is not pathogenic for Drosophila motoneurons.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {19540}, pmid = {39174694}, issn = {2045-2322}, mesh = {Animals ; *Kinesins/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mutation ; Humans ; Drosophila Proteins/genetics/metabolism ; Drosophila ; Neuromuscular Junction/metabolism/pathology ; Drosophila melanogaster/genetics ; Synaptic Transmission/genetics ; Disease Models, Animal ; Axons/metabolism/pathology ; Larva/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by the death of motoneurons. Several mutations in the KIF5A gene have been identified in patients with ALS. Some mutations affect the splicing sites of exon 27 leading to its deletion (Δ27 mutation). KIF5A Δ27 is aggregation-prone and pathogenic for motoneurons due to a toxic gain of function. Another mutation found to be enriched in ALS patients is a proline/leucine substitution at position 986 (P986L mutation). Bioinformatic analyses strongly suggest that this variant is benign. Our study aims to conduct functional studies in Drosophila to classify the KIF5A P986L variant. When expressed in motoneurons, KIF5A P986L does not modify the morphology of larval NMJ or the synaptic transmission. In addition, KIF5A P986L is uniformly distributed in axons and does not disturb mitochondria distribution. Locomotion at larval and adult stages is not affected by KIF5A P986L. Finally, both KIF5A WT and P986L expression in adult motoneurons extend median lifespan compared to control flies. Altogether, our data show that the KIF5A P986L variant is not pathogenic for motoneurons and may represent a hypomorphic allele, although it is not causative for ALS.}, } @article {pmid39174972, year = {2024}, author = {Zhou, J and Li, F and Jia, B and Wu, Z and Huang, Z and He, M and Weng, H and So, KF and Qu, W and Fu, QL and Zhou, L}, title = {Intranasal delivery of small extracellular vesicles reduces the progress of amyotrophic lateral sclerosis and the overactivation of complement-coagulation cascade and NF-ĸB signaling in SOD1[G93A] mice.}, journal = {Journal of nanobiotechnology}, volume = {22}, number = {1}, pages = {503}, pmid = {39174972}, issn = {1477-3155}, support = {202310183302//2023 University Innovation and Entrepreneurship Training Plan/ ; 2022YFA1104900//National Key Research and Development Program of China/ ; 2021B1515120062//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023B03J1233, 20220600003//Guangzhou Key R&D Program/ ; }, mesh = {Animals ; Male ; Mice ; Administration, Intranasal ; *Amyotrophic Lateral Sclerosis/metabolism ; Blood Coagulation ; Disease Models, Animal ; *Extracellular Vesicles/metabolism ; Mesenchymal Stem Cells/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/metabolism ; *NF-kappa B/metabolism ; *Signal Transduction ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive motoneuron degeneration, and effective clinical treatments are lacking. In this study, we evaluated whether intranasal delivery of mesenchymal stem cell-derived small extracellular vesicles (sEVs) is a strategy for ALS therapy using SOD1[G93A] mice. In vivo tracing showed that intranasally-delivered sEVs entered the central nervous system and were extensively taken up by spinal neurons and some microglia. SOD1[G93A] mice that intranasally received sEV administration showed significant improvements in motor performances and survival time. After sEV administration, pathological changes, including spinal motoneuron death and synaptic denervation, axon demyelination, neuromuscular junction degeneration and electrophysiological defects, and mitochondrial vacuolization were remarkably alleviated. sEV administration attenuated the elevation of proinflammatory cytokines and glial responses. Proteomics and transcriptomics analysis revealed upregulation of the complement and coagulation cascade and NF-ĸB signaling pathway in SOD1[G93A] mouse spinal cords, which was significantly inhibited by sEV administration. The changes were further confirmed by detecting C1q and NF-ĸB expression using Western blots. In conclusion, intranasal administration of sEVs effectively delays the progression of ALS by inhibiting neuroinflammation and overactivation of the complement and coagulation cascades and NF-ĸB signaling pathway and is a potential option for ALS therapy.}, } @article {pmid39175128, year = {2024}, author = {Wu, A and Lee, D and Xiong, WC}, title = {VPS35 or retromer as a potential target for neurodegenerative disorders: barriers to progress.}, journal = {Expert opinion on therapeutic targets}, volume = {28}, number = {8}, pages = {701-712}, pmid = {39175128}, issn = {1744-7631}, support = {R01 AG045781/AG/NIA NIH HHS/United States ; RF1 AG045781/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology/drug therapy ; *Vesicular Transport Proteins/metabolism ; Animals ; *Molecular Targeted Therapy ; Protein Transport ; Parkinson Disease/physiopathology/drug therapy ; Mutation, Missense ; Drug Development ; }, abstract = {INTRODUCTION: Vacuolar Protein Sorting 35 (VPS35) is pivotal in the retromer complex, governing transmembrane protein trafficking within cells, and its dysfunction is implicated in neurodegenerative diseases. A missense mutation, Asp620Asn (D620N), specifically ties to familial late-onset Parkinson's, while reduced VPS35 levels are observed in Alzheimer's, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and tauopathies. VPS35's absence in certain neurons during development can initiate neurodegeneration, highlighting its necessity for neural health. Present therapeutic research mainly targets the clearance of harmful protein aggregates and symptom management. Innovative treatments focusing on VPS35 are under investigation, although fully understanding the mechanisms and optimal targeting strategies remain a challenge.

AREAS COVERED: This review offers a detailed account of VPS35's discovery, its role in neurodegenerative mechanisms - especially in Parkinson's and Alzheimer's - and its link to other disorders. It shines alight on recent insights into VPS35's function in development, disease, and as a therapeutic target.

EXPERT OPINION: VPS35 is integral to cellular function and disease association, making it a significant candidate for developing therapies. Progress in modulating VPS35's activity may lead to breakthrough treatments that not only slow disease progression but may also act as biomarkers for neurodegeneration risk, marking a step forward in managing these complex conditions.}, } @article {pmid39176177, year = {2024}, author = {Al Dera, H and AlQahtani, B}, title = {Molecular mechanisms and antisense oligonucleotide therapies of familial amyotrophic lateral sclerosis.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {3}, pages = {102271}, pmid = {39176177}, issn = {2162-2531}, abstract = {Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, presents considerable challenges in both diagnosis and treatment. It is categorized into sporadic and familial amyotrophic lateral sclerosis (fALS); the latter accounts for approximately 10% of cases and is primarily inherited in an autosomal dominant manner. This review summarizes the molecular genetics of fALS, highlighting key mutations that contribute to its pathogenesis, such as mutations in SOD1, FUS, and C9orf72. Central to this discourse is exploring antisense oligonucleotides (ASOs) that target these genetic aberrations, providing a promising therapeutic strategy. This review provides a detailed overview of the molecular mechanisms underlying fALS and the potential therapeutic value of ASOs, offering new insights into treating neurodegenerative diseases.}, } @article {pmid39176644, year = {2024}, author = {Turner, J and Impey, S and Gibbons, F and Bolger, A and Stephens, G and Hederman, L and Hamed, R and O'Meara, C and de la Varga, F and Kommala, J and Nicholson, M and Farrell, D and Galvin, M and Heverin, M and Mac Domhnaill, É and McFarlane, R and Meldrum, D and Murray, D and Hardiman, O}, title = {Data and Process Harmonisation of Multi-National, Multi-Site Research Data.}, journal = {Studies in health technology and informatics}, volume = {316}, number = {}, pages = {1411-1412}, doi = {10.3233/SHTI240675}, pmid = {39176644}, issn = {1879-8365}, mesh = {Humans ; *Data Collection ; Amyotrophic Lateral Sclerosis/therapy ; Biomedical Research ; }, abstract = {To achieve a single fully harmonised research data set suitable for analysis from data collected at multiple sites requires not only semantic integration of collection concepts and convergence onto single collection units, but harmonisation of data collection processes. We describe our experience of identifying harmonisation challenges in the Precision ALS project, with particular focus on process alignment challenges in a multi-site multi-national research data collection project.}, } @article {pmid39176909, year = {2024}, author = {Tiffet, T and Pikaar, A and Trombert-Paviot, B and Jaulent, MC and Bousquet, C}, title = {Comparing a Large Language Model with Previous Deep Learning Models on Named Entity Recognition of Adverse Drug Events.}, journal = {Studies in health technology and informatics}, volume = {316}, number = {}, pages = {781-785}, doi = {10.3233/SHTI240528}, pmid = {39176909}, issn = {1879-8365}, mesh = {*Deep Learning ; *Drug-Related Side Effects and Adverse Reactions ; Humans ; Natural Language Processing ; Adverse Drug Reaction Reporting Systems ; }, abstract = {The ability to fine-tune pre-trained deep learning models to learn how to process a downstream task using a large training set allow to significantly improve performances of named entity recognition. Large language models are recent models based on the Transformers architecture that may be conditioned on a new task with in-context learning, by providing a series of instructions or prompt. These models only require few examples and such approach is defined as few shot learning. Our objective was to compare performances of named entity recognition of adverse drug events between state of the art deep learning models fine-tuned on Pubmed abstracts and a large language model using few-shot learning. Hussain et al's state of the art model (PMID: 34422092) significantly outperformed the ChatGPT-3.5 model (F1-Score: 97.6% vs 86.0%). Few-shot learning is a convenient way to perform named entity recognition when training examples are rare, but performances are still inferior to those of a deep learning model fine-tuned with several training examples. Perspectives are to evaluate few-shot prompting with GPT-4 and perform fine-tuning on GPT-3.5.}, } @article {pmid39177131, year = {2024}, author = {Sheremeta, CL and Yarlagadda, S and Smythe, ML and Noakes, PG}, title = {Prostaglandins in the Inflamed Central Nervous System: Potential Therapeutic Targets.}, journal = {Current drug targets}, volume = {25}, number = {13}, pages = {885-908}, pmid = {39177131}, issn = {1873-5592}, support = {Project grant,//Muscular Dystrophy Association/ ; }, mesh = {Humans ; *Prostaglandins/metabolism ; Animals ; *Central Nervous System/metabolism/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Signal Transduction/drug effects ; Multiple Sclerosis/drug therapy/metabolism ; Inflammation/drug therapy/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Central Nervous System Diseases/drug therapy/metabolism ; }, abstract = {The global burden of neurological disorders is evident, yet there remains limited efficacious therapeutics for their treatment. There is a growing recognition of the role of inflammation in diseases of the central nervous system (CNS); among the numerous inflammatory mediators involved, prostaglandins play a crucial role. Prostaglandins are small lipid mediators derived from arachidonic acid via multi-enzymatic pathways. The actions of prostaglandins are varied, with each prostaglandin having a specific role in maintaining homeostasis. In the CNS, prostaglandins can have neuroprotective or neurotoxic properties depending on their specific G-protein receptor. These G-protein receptors have varying subfamilies, tissue distribution, and signal transduction cascades. Further studies into the impact of prostaglandins in CNS-based diseases may contribute to the clarification of their actions, hopefully leading to the development of efficacious therapeutic strategies. This review focuses on the roles played by prostaglandins in neural degeneration, with a focus on Alzheimer's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis in both preclinical and clinical settings. We further discuss current prostaglandin-related agonists and antagonists concerning suggestions for their use as future therapeutics.}, } @article {pmid39177232, year = {2024}, author = {Witzel, S and Huss, A and Nagel, G and Rosenbohm, A and Rothenbacher, D and Peter, RS and Bäzner, H and Börtlein, A and Dempewolf, S and Schabet, M and Hecht, M and Kohler, A and Opherk, C and Naegele, A and Sommer, N and Lindner, A and Alexudis, C and Bachhuber, F and Halbgebauer, S and Brenner, D and Ruf, W and Weiland, U and Mayer, B and Schuster, J and Dorst, J and Tumani, H and Ludolph, AC and , }, title = {Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {96}, number = {6}, pages = {1040-1057}, doi = {10.1002/ana.27054}, pmid = {39177232}, issn = {1531-8249}, support = {577631//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; *Biomarkers/blood ; *Neurofilament Proteins/blood ; Middle Aged ; Female ; Male ; Aged ; Prognosis ; Intermediate Filaments/metabolism ; Adult ; }, abstract = {OBJECTIVE: Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations.

METHODS: We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders.

RESULTS: Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels.

INTERPRETATION: Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024;96:1040-1057.}, } @article {pmid39178140, year = {2024}, author = {Briois, V and Itié, JP and Polian, A and King, A and Traore, AS and Marceau, E and Ersen, O and La Fontaine, C and Barthe, L and Beauvois, A and Roudenko, O and Belin, S}, title = {Hyperspectral full-field quick-EXAFS imaging at the ROCK beamline for monitoring micrometre-sized heterogeneity of functional materials under process conditions.}, journal = {Journal of synchrotron radiation}, volume = {31}, number = {Pt 5}, pages = {1084-1104}, pmid = {39178140}, issn = {1600-5775}, support = {ANR-10-EQPX-0045//Agence Nationale de la Recherche/ ; ANR-20-CE42-007//Agence Nationale de la Recherche/ ; ANR-07-Stock-E-0 PULSSE//Agence Nationale de la Recherche/ ; }, abstract = {Full-field transmission X-ray microscopy has been recently implemented at the hard X-ray ROCK-SOLEIL quick-EXAFS beamline, adding micrometre spatial resolution to the second time resolution characterizing the beamline. Benefiting from a beam size versatility due to the beamline focusing optics, full-field hyperspectral XANES imaging has been successfully used at the Fe K-edge for monitoring the pressure-induced spin transition of a 150 µm × 150 µm Fe(o-phen)2(NCS)2 single crystal and the charge of millimetre-sized LiFePO4 battery electrodes. Hyperspectral imaging over 2000 eV has been reported for the simultaneous monitoring of Fe and Cu speciation changes during activation of a FeCu bimetallic catalyst along a millimetre-sized catalyst bed. Strategies of data acquisition and post-data analysis using Jupyter notebooks and multivariate data analysis are presented, and the gain obtained using full-field hyperspectral quick-EXAFS imaging for studies of functional materials under process conditions in comparison with macroscopic information obtained by non-spatially resolved quick-EXAFS techniques is discussed.}, } @article {pmid39179240, year = {2025}, author = {Sisti, HM and Beebe, A and Gabrielsson, E and Bishop, M}, title = {Postmovement Beta Rebound in Real and Imagined Movement.}, journal = {Motor control}, volume = {29}, number = {1}, pages = {53-68}, pmid = {39179240}, issn = {1087-1640}, support = {P20 GM103449/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Imagination/physiology ; Male ; Female ; Adult ; *Beta Rhythm/physiology ; *Electroencephalography ; *Movement/physiology ; *Psychomotor Performance/physiology ; Young Adult ; Sensorimotor Cortex/physiology ; }, abstract = {Movement disorders, such as stroke and amyotrophic lateral sclerosis, result in loss of upper limb function and, hence, severe impairments of bimanual coordination. Although motor imagery is increasingly used to enhance neurorehabilitation, cognitive and neurophysiological parameters that inform effective strategies remain elusive. The aim of the present study is to elucidate the neural dynamics that underlie learning during real and imagined movement using both unimanual and bimanual coordination patterns. The post movement beta rebound (PMBR) has been implicated as a biomarker of motor control and therefore was the focus of this study. Healthy adults (n = 21) learned a visuomotor tracking task in a single session using either one or both hands while brainwaves were captured using electroencephalography. Postmovement beta rebound was evident in the sensorimotor cortex for both unimanual and bimanual conditions. Task-related power of the beta band demonstrated that actual unimanual movement requires greater contralateral activity compared with both actual bimanual movement and imagined movement of either condition. Notably, the PMBR was evident even in imagined movement, although to a lesser extent than real movement. Neurophysiological results support a functional role for beta band in movement. Results of these data may inform neurorehabilitation strategies for patients recovering from movement disorders of the upper limbs.}, } @article {pmid39180054, year = {2024}, author = {Spittel, S and Meyer, T and Weyen, U and Grehl, T and Weydt, P and Steinbach, R and Petri, S and Baum, P and Metelmann, M and Sperfeld, AD and Kettemann, D and Norden, J and Rödiger, A and Ilse, B and Grosskreutz, J and Hildebrandt, B and Walter, B and Münch, C and Maier, A}, title = {User expectations and experiences of an assistive robotic arm in amyotrophic lateral sclerosis: a multicenter observational study.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {42}, pmid = {39180054}, issn = {2524-3489}, abstract = {OBJECTIVE: Robotic arms are innovative assistive devices for ALS patients with progressive motor deficits of arms and hands. The objective was to explore the patients´ expectations towards a robotic arm system and to assess the actual experiences after the provision of the device.

METHODS: A prospective observational study was conducted at 9 ALS centers in Germany. ALS-related functional deficits were assessed using the ALS-Functional Rating Scale-revised (ALSFRS-R). Motor deficit of the upper limbs was determined using a subscore of three arm-related items of the ALSFRS-R (items 4-6; range 0-12 points). User expectations before provision (expectation group, n = 85) and user experiences after provision (experience group, n = 14) with the device (JACO Assistive Robotic Device, Kinova, Boisbriand, QC, Canada) were assessed.

RESULTS: In the total cohort, mean ALSFRS-R subscore for arm function was 1.7 (SD: 2.0, 0-9) demonstrating a severe functional deficit of the upper limbs. In the expectation group (n = 85), the following use cases of the robotic arm have been prioritized: handling objects (89%), close-body movements (88%), pressing buttons (87%), serving drinks (86%), and opening cabinets and doors (85%). In the experience group (n = 14), handling objects (79%), serving drinks (79%), near-body movements (71%), pushing buttons (71%), serving food (64%), and opening doors (64%) were the most frequent used cases. Most patients used the device daily (71.4%, n = 10), and 28.6% (n = 4) several times a week. All patients of the experience group found the device helpful, felt safe while using the device, and were satisfied with its reliability. NPS of the assistive robotic arm revealed 64% "promoters" (strong recommendation), 29% "indifferents" (uncertain recommendation) and 7% "detractors" (no recommendation). Total NPS was + 57 demonstrating strong patient satisfaction.

CONCLUSIONS: Initiation of procurement with a robotic assistive arm was confined to patients with severe functional deficit of the upper limbs. User experience underlined the wide spectrum of use cases of assistive robotic arms in ALS. The positive user experience together with high satisfaction underscore that robotic arm systems serve as a valuable treatment option in ALS patients with severe motor deficits of the arms.}, } @article {pmid39180568, year = {2024}, author = {Yang, J and Tang, C}, title = {Causal relationship between imaging-derived phenotypes and neurodegenerative diseases: a Mendelian randomization study.}, journal = {Mammalian genome : official journal of the International Mammalian Genome Society}, volume = {35}, number = {4}, pages = {711-723}, pmid = {39180568}, issn = {1432-1777}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/diagnostic imaging ; *Phenotype ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging ; Alzheimer Disease/genetics/diagnostic imaging ; Frontotemporal Dementia/genetics/diagnostic imaging/pathology ; Parkinson Disease/genetics/diagnostic imaging ; Brain/diagnostic imaging/pathology/metabolism ; Multiple Sclerosis/genetics/diagnostic imaging ; Neuroimaging/methods ; }, abstract = {Neurodegenerative diseases are incurable conditions that lead to gradual and progressive deterioration of brain function in patients. With the aging population, the prevalence of these diseases is expected to increase, posing a significant economic burden on society. Imaging techniques play a crucial role in the diagnosis and monitoring of neurodegenerative diseases. This study utilized a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between different imaging-derived phenotypes (IDP) in the brain and neurodegenerative diseases. Multiple MR methods were employed to minimize bias and obtain reliable estimates of the potential causal relationship between the variable exposures of interest and the outcomes. The study found potential causal relationships between different IDPs and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and frontotemporal dementia (FTD). Specifically, the study identified potential causal relationships between 2 different types of IDPs and AD, 8 different types of IDPs and PD, 11 different types of imaging-derived phenotypes and ALS, 1 type of IDP and MS, and 1 type of IDP and FTD. This study provides new insights for the prevention, diagnosis, and treatment of neurodegenerative diseases, offering important clues for understanding the pathogenesis of these diseases and developing relevant intervention strategies.}, } @article {pmid39180748, year = {2024}, author = {Liu, Z and Zhang, H and Lu, K and Chen, L and Zhang, Y and Xu, Z and Zhou, H and Sun, J and Xu, M and Ouyang, Q and Thompson, GJ and Yang, Y and Su, N and Cai, X and Cao, L and Zhao, Y and Jiang, L and Zheng, Y and Zhang, X}, title = {Low-intensity pulsed ultrasound modulates disease progression in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Cell reports}, volume = {43}, number = {9}, pages = {114660}, doi = {10.1016/j.celrep.2024.114660}, pmid = {39180748}, issn = {2211-1247}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy/metabolism ; *Disease Models, Animal ; Mice ; *Disease Progression ; *Ultrasonic Waves ; *Mice, Transgenic ; *Motor Cortex/pathology/metabolism ; TRPV Cation Channels/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Cerebrovascular Circulation ; Ultrasonic Therapy/methods ; Mice, Inbred C57BL ; Male ; Endothelial Cells/metabolism ; Motor Neurons/pathology/metabolism ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord, and there are no effective drug treatments. Low-intensity pulsed ultrasound (LIPUS) has garnered attention as a promising noninvasive neuromodulation method. In this study, we investigate its effects on the motor cortex and underlying mechanisms using the SOD1[G93A] mouse model of ALS. Our results show that LIPUS treatment delays disease onset and prolongs lifespan in ALS mice. LIPUS significantly increases cerebral blood flow in the motor cortex by preserving vascular endothelial cell integrity and increasing microvascular density, which may be mediated via the ion channel TRPV4. RNA sequencing analysis reveals that LIPUS substantially reduces the expression of genes associated with neuroinflammation. These findings suggest that LIPUS applied to the motor cortex may represent a potentially effective therapeutic tool for the treatment of ALS.}, } @article {pmid39180957, year = {2024}, author = {Harkins, AL and Ambegaokar, PP and Keeler, AM}, title = {Immune responses to central nervous system directed adeno-associated virus gene therapy: Does direct CNS delivery make a difference?.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {4}, pages = {e00435}, pmid = {39180957}, issn = {1878-7479}, support = {P01 HL158506/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Dependovirus/genetics/immunology ; *Genetic Therapy/methods ; *Genetic Vectors/immunology/administration & dosage ; Animals ; Central Nervous System/immunology ; Gene Transfer Techniques ; Central Nervous System Diseases/therapy/immunology ; }, abstract = {Adeno-associated virus (AAV) mediated gene therapy is a leading gene delivery platform with potential to transform the landscape of treatment for neurological disorders. While AAV is deemed non-immunogenic compared to other viral vectors, adverse immune reactions have been observed in the clinic, raising concerns. As the central nervous system (CNS) has a tightly regulated immune system, characterized by a degree of tolerance, it has been considered a unique target for AAV gene therapy. AAV vectors have shown promising results for the treatment of several CNS disorders including Spinal Muscular Atrophy, Giant Axonal Neuropathy, Amyotrophic Lateral Sclerosis, Tay Sachs Disease, Parkinson's Disease, and others, demonstrating safety and success. The Food and Drug Administration (FDA) approval of Zolgensma and European Medicines Agency (EMA) approval of Upstaza, for Spinal Muscular Atrophy (SMA) and Aromatic l-amino acid decarboxylase deficiency (AADC) respectively, represent this success, all while highlighting significant differences in immune responses to AAV, particularly with regards to therapeutic administration route. AAV therapies like Upstaza that are injected directly into the immune-specialized brain have been characterized by mild immune response profiles and minor adverse events, whereas therapies like Zolgensma that are injected systemically demonstrate more robust immune stimulation and off-target toxicities. Despite these contrasting parallels, these therapeutics and others in the clinic have demonstrated clinical benefit for patients, warranting further exploration of immune responses to CNS-directed AAV clinical trials. Thus, in this review, we discuss effects of different routes of AAV administration on eliciting local and peripheral immune responses specifically observed in CNS-targeted trials.}, } @article {pmid39181135, year = {2024}, author = {Wu, R and Ye, Y and Dong, D and Zhang, Z and Wang, S and Li, Y and Wright, N and Redding-Ochoa, J and Chang, K and Xu, S and Tu, X and Zhu, C and Ostrow, LW and Roca, X and Troncoso, JC and Wu, B and Sun, S}, title = {Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS.}, journal = {Neuron}, volume = {112}, number = {20}, pages = {3434-3451.e11}, pmid = {39181135}, issn = {1097-4199}, support = {P30 AG066507/AG/NIA NIH HHS/United States ; R01 NS127925/NS/NINDS NIH HHS/United States ; R01 NS107347/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; R01 AG078948/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Mice ; Animals ; *RNA Splicing/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; DNA Repeat Expansion/genetics ; Neurons/metabolism ; Male ; Female ; }, abstract = {Expansion of an intronic (GGGGCC)n repeat within the C9ORF72 gene is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (C9-FTD/ALS), characterized with aberrant repeat RNA foci and noncanonical translation-produced dipeptide repeat (DPR) protein inclusions. Here, we elucidate that the (GGGGCC)n repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics. Moreover, the essential nuclear speckle scaffold protein SRRM2 is sequestered into the poly-GR cytoplasmic inclusions in the C9-FTD/ALS mouse model and patient postmortem tissues, exacerbating the nuclear speckle dysfunction. Impaired nuclear speckle integrity induces global exon skipping and intron retention in human iPSC-derived neurons and causes neuronal toxicity. Similar alternative splicing changes can be found in C9-FTD/ALS patient postmortem tissues. This work identified novel molecular mechanisms of global RNA splicing defects caused by impaired nuclear speckle function in C9-FTD/ALS and revealed novel potential biomarkers or therapeutic targets.}, } @article {pmid39181183, year = {2024}, author = {Ko, YH and Lokareddy, RK and Doll, SG and Yeggoni, DP and Girdhar, A and Mawn, I and Klim, JR and Rizvi, NF and Meyers, R and Gillilan, RE and Guo, L and Cingolani, G}, title = {Single Acetylation-mimetic Mutation in TDP-43 Nuclear Localization Signal Disrupts Importin α1/β Signaling.}, journal = {Journal of molecular biology}, volume = {436}, number = {20}, pages = {168751}, pmid = {39181183}, issn = {1089-8638}, support = {P30 GM124166/GM/NIGMS NIH HHS/United States ; RF1 NS121143/NS/NINDS NIH HHS/United States ; R21 NS128396/NS/NINDS NIH HHS/United States ; S10 OD017987/OD/NIH HHS/United States ; R01 NS121143/NS/NINDS NIH HHS/United States ; R35 GM140733/GM/NIGMS NIH HHS/United States ; S10 OD023479/OD/NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; }, mesh = {*Nuclear Localization Signals/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *alpha Karyopherins/metabolism/genetics ; *beta Karyopherins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Acetylation ; *Signal Transduction ; Mutation ; Protein Processing, Post-Translational ; Active Transport, Cell Nucleus ; Protein Binding ; Cell Nucleus/metabolism ; }, abstract = {Cytoplasmic aggregation of the TAR-DNA binding protein of 43 kDa (TDP-43) is the hallmark of sporadic amyotrophic lateral sclerosis (ALS). Most ALS patients with TDP-43 aggregates in neurons and glia do not have mutations in the TDP-43 gene but contain aberrantly post-translationally modified TDP-43. Here, we found that a single acetylation-mimetic mutation (K82Q) near the TDP-43 minor Nuclear Localization Signal (NLS) box, which mimics a post-translational modification identified in an ALS patient, can lead to TDP-43 mislocalization to the cytoplasm and irreversible aggregation. We demonstrate that the acetylation mimetic disrupts binding to importins, halting nuclear import and preventing importin α1/β anti-aggregation activity. We propose that perturbations near the NLS are an additional mechanism by which a cellular insult other than a genetically inherited mutation leads to TDP-43 aggregation and loss of function. Our findings are relevant to deciphering the molecular etiology of sporadic ALS.}, } @article {pmid39181624, year = {2024}, author = {Mousele, C and Holden, D and Gnanapavan, S}, title = {Neurofilaments in neurologic disease.}, journal = {Advances in clinical chemistry}, volume = {123}, number = {}, pages = {65-128}, doi = {10.1016/bs.acc.2024.06.010}, pmid = {39181624}, issn = {2162-9471}, mesh = {Humans ; *Nervous System Diseases/pathology/metabolism/diagnosis ; *Biomarkers ; Neurofilament Proteins/cerebrospinal fluid/metabolism ; Intermediate Filaments/metabolism ; Animals ; }, abstract = {Neurofilaments (NFs), major cytoskeletal constituents of neurons, have emerged as universal biomarkers of neuronal injury. Neuroaxonal damage underlies permanent disability in various neurological conditions. It is crucial to accurately quantify and longitudinally monitor this damage to evaluate disease progression, evaluate treatment effectiveness, contribute to novel treatment development, and offer prognostic insights. Neurofilaments show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. New assays with high sensitivity allow reliable measurement of neurofilaments in body fluids and open avenues to investigate their role in neurological disorders. This book chapter will delve into the evolving landscape of neurofilaments, starting with their structure and cellular functions within neurons. It will then provide a comprehensive overview of their broad clinical value as biomarkers in diseases affecting the central or peripheral nervous system.}, } @article {pmid39182146, year = {2024}, author = {Kill, C and Manegold, RK and Fistera, D and Risse, J}, title = {Airway management and ventilation techniques in resuscitation during advanced life support: an update.}, journal = {Journal of anesthesia, analgesia and critical care}, volume = {4}, number = {1}, pages = {58}, pmid = {39182146}, issn = {2731-3786}, abstract = {For many years, ventilation has been an essential part of advanced life support (ALS) in cardiopulmonary resuscitation (CPR). Nevertheless, there is little evidence about the best method of ventilation during resuscitation for both out-of-hospital cardiac arrest (OHCA) and inhospital cardiac arrest (IHCA) patients. Effective ventilation is one of the two main keys to successful resuscitation. In this context, the question always arises as to which airway management, along with which ventilation mode, constitutes the best strategy. Conventional ventilation modes are not designed for cardiac arrest and show important limitations that must be considered when used in CPR. Manual ventilation without the use of an automated transport ventilator (ATV) could be shown to be uncontrolled in applied volumes and pressures and should be avoided. Mechanical ventilation with an ATV is therefore superior to manual ventilation, but both volume- and pressure-controlled ventilation modes are significantly influenced by chest compressions. With the newly designed chest compression synchronized ventilation (CCSV), a special ventilation mode for resuscitation is available. Further research should be conducted to obtain more evidence of the effect of ventilation during CPR on outcomes following OHCA and not only about how to secure the airway for ventilation during CPR.}, } @article {pmid39182178, year = {2024}, author = {Serizawa, S}, title = {Exploration of the Factors Impacting Sustained Clinical Care by Multidisciplinary Professionals for Amyotrophic Lateral Sclerosis.}, journal = {The Tokai journal of experimental and clinical medicine}, volume = {49}, number = {3}, pages = {110-116}, pmid = {39182178}, issn = {2185-2243}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Surveys and Questionnaires ; *Patient Care Team ; Japan ; Female ; Male ; Self-Assessment ; Motivation ; Health Personnel ; Middle Aged ; Adult ; Time Factors ; }, abstract = {OBJECTIVE: This study examined the experiences of multidisciplinary medical professionals in providing daily clinical care for patients with amyotrophic lateral sclerosis (ALS), with a focus placed on their persistence in sustaining clinical care for this patient group.

METHODS: A questionnaire survey was administered to multidisciplinary medical professionals involved in ALS care at three hospitals in western Kanagawa Prefecture, Japan. The questionnaire results were used to examine the relationships between years of medical experience, years of ALS care experience, self-evaluation, and motivation to continue providing clinical care to patients with ALS.

RESULTS: Of the 269 questionnaires distributed and 164 collected by the multidisciplinary medical professionals, 143 (53%) were deemed valid. Analysis revealed an association between "years of medical experience" with both "self-assessment of clinical care for ALS patients practice experience" and "commitment to continue clinical care for ALS patients," as well as between "years of ALS medical experience" and "self-assessment of clinical care for ALS patients."

CONCLUSION: Medical professionals with more than ten years of medical experience expressed their commitment to continue providing medical care in a comprehensive self-assessment of both the positive and negative aspects of their practice. Negative evaluations can be used to identify and improve ALS medical practices.}, } @article {pmid39182251, year = {2024}, author = {Peng, Y and Liu, G and Li, S and Li, Z and Song, J}, title = {A machine learning system for artificial ligaments with desired mechanical properties in ACL reconstruction applications.}, journal = {Journal of the mechanical behavior of biomedical materials}, volume = {159}, number = {}, pages = {106691}, doi = {10.1016/j.jmbbm.2024.106691}, pmid = {39182251}, issn = {1878-0180}, mesh = {*Machine Learning ; *Mechanical Phenomena ; *Anterior Cruciate Ligament Reconstruction/methods ; Materials Testing ; Humans ; Anterior Cruciate Ligament/surgery ; Neural Networks, Computer ; Biomechanical Phenomena ; Ligaments/surgery ; Artificial Organs ; Mechanical Tests ; }, abstract = {The anterior cruciate ligament is one of the important tissues to maintain the stability of the human knee joint, but it is difficult for this ligament to self-heal after injury. Consequently, transplantation of artificial ligaments (ALs) has gained widespread attention as an important alternative treatment method in recent years. However, accurately predicting the intricate mechanical properties of ALs remains a formidable challenge, particularly when employing theoretical frameworks such as braiding theory. This obstacle presents a significant impediment to achieving optimal AL design. Therefore, in this study, a high-precision machine learning model based on an artificial neural network was developed to rapidly and accurately predict the mechanical properties of ALs. The results showed that the proposed model achieved a reduction of 45.22% and 50.17% in the normalized root mean square error on the testing set when compared to traditional machine learning models (Random Forest and Support Vector Machine), demonstrating its higher accuracy. In addition, the design of ALs with desired mechanical properties was achieved by optimizing the braiding parameters, and its effectiveness was verified through experiments. The mechanical properties of the prepared ALs were able to fully meet the desired targets and were at least 2% higher. Finally, the influence weights of different braiding parameters on the mechanical properties of ALs were analyzed by feature importance.}, } @article {pmid39182589, year = {2024}, author = {Pupillo, E and Bianchi, E and Bonetto, V and Pasetto, L and Bendotti, C and Paganoni, S and Mandrioli, J and Mazzini, L and , }, title = {Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis.}, journal = {Brain, behavior, and immunity}, volume = {122}, number = {}, pages = {456-462}, doi = {10.1016/j.bbi.2024.08.044}, pmid = {39182589}, issn = {1090-2139}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology ; Male ; Female ; Middle Aged ; Double-Blind Method ; Vital Capacity ; Aged ; *Disease Progression ; Biomarkers/blood ; Treatment Outcome ; Adult ; Neurofilament Proteins ; }, abstract = {BACKGROUND: Positive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS).

OBJECTIVE: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation.

STUDY DESIGN AND SETTINGS: A randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial's last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated.

RESULTS: Mean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL - RNS60 group; 3.3 years in low NfL - placebo group; 1.9 years in high NfL - RNS60 group; 1.8 years in high NfL - placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 - RNS60 group; 2.3 years in low MCP-1 - placebo group; 2.8 years in high MCP-1 - RNS60 group; 2.6 years in high MCP-1 - placebo group) levels at baseline.

CONCLUSIONS AND RELEVANCE: In this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug's effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival.

TRIAL REGISTRATION: Study preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.}, } @article {pmid39182937, year = {2024}, author = {Silva, ST and Costa, IM and Souza, AA and Pondofe, K and Melo, LP and Resqueti, VR and Valentim, R and Gonçalves, F and Ribeiro, TS}, title = {Physical therapy for the management of global function, fatigue and quality of life in amyotrophic lateral sclerosis: systematic review and meta-analyses.}, journal = {BMJ open}, volume = {14}, number = {8}, pages = {e076541}, pmid = {39182937}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Quality of Life ; *Physical Therapy Modalities ; *Fatigue/therapy/etiology ; Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVES: To critically evaluate the effectiveness of physical therapy interventions in improving global function, quality of life and fatigue in individuals with amyotrophic lateral sclerosis (ALS).

DESIGN: Systematic review and meta-analyses.

DATA SOURCES: MEDLINE, EMBASE, Cochrane Library (CENTRAL) and Physiotherapy Evidence Database (PEDro) were searched through 31 January 2023.

ELIGIBILITY CRITERIA: We included randomised clinical trials (RCTs) that compared physical therapy interventions that act on global function, fatigue and quality of life in individuals with ALS with any other non-physiotherapeutic methods and techniques, placebo or non-intervention. The primary outcome measure was the evaluation of global function. Secondary outcomes were quality of life, fatigue and adverse events.

DATA EXTRACTION AND SYNTHESIS: Two independent authors used a researcher-developed extraction form and the Rayyan software to search, screen and code included studies. The risk of bias was assessed using the PEDro scale. Meta-analyses were conducted employing random effects. Outcomes were succinctly presented in Grading of Recommendations, Assessment, Development and Evaluation evidence profiles.

RESULTS: Our searches identified 39 415 references. After study selection, three studies were included in the review. Such studies involved 62 participants with a mean age of 54.6 years. In the evaluated trials, 40 were male, while 22 participants were female. Regarding the type of onset of the disease, 58 participants had spinal onset of ALS, and four had bulbar.

CONCLUSIONS: Physical therapy intervention may improve the global function of individuals with ALS in the short term; however, clinically, it was inconclusive. In terms of quality of life and fatigue, physical therapy intervention is not more effective than control in the short term. Adverse events are not increased by physical therapy intervention in the short term. Due to significant methodological flaws, small sample sizes, wide CIs and clinical interpretation, our confidence in the effect estimate is limited.

PROSPERO REGISTRATION NUMBER: CRD42021251350.}, } @article {pmid39183185, year = {2024}, author = {Adiningrat, DP and Schlund, M and Skidmore, AK and Abdullah, H and Wang, T and Heurich, M}, title = {Mapping temperate old-growth forests in Central Europe using ALS and Sentinel-2A multispectral data.}, journal = {Environmental monitoring and assessment}, volume = {196}, number = {9}, pages = {841}, pmid = {39183185}, issn = {1573-2959}, support = {397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; }, mesh = {*Forests ; *Environmental Monitoring/methods ; Europe ; *Remote Sensing Technology ; Conservation of Natural Resources/methods ; Biodiversity ; Satellite Imagery ; Climate Change ; Lasers ; }, abstract = {Old-growth forests are essential to preserve biodiversity and play an important role in sequestering carbon and mitigating climate change. However, their existence across Europe is vulnerable due to the scarcity of their distribution, logging, and environmental threats. Therefore, providing the current status of old-growth forests across Europe is essential to aiding informed conservation efforts and sustainable forest management. Remote sensing techniques have proven effective for mapping and monitoring forests over large areas. However, relying solely on remote sensing spectral or structural information cannot capture comprehensive horizontal and vertical structure complexity profiles associated with old-growth forest characteristics. To overcome this issue, we combined spectral information from Sentinel-2A multispectral imagery with 3D structural information from high-density point clouds of airborne laser scanning (ALS) imagery to map old-growth forests over an extended area. Four features from the ALS data and fifteen from Sentinel-2A comprising raw band (spectral reflectance), vegetation indices (VIs), and texture were selected to create three datasets used in the classification process using the random forest algorithm. The results demonstrated that combining ALS and Sentinel-2A features improved the classification performance and yielded the highest accuracy for old-growth class, with an F1-score of 92% and producer's and user's accuracies of 93% and 90%, respectively. The findings suggest that features from ALS and Sentinel-2A data sensitive to forest structure are essential for identifying old-growth forests. Integrating open-access satellite imageries, such as Sentinel-2A and ALS data, can benefit forest managers, stakeholders, and conservationists in monitoring old-growth forest preservation across a broader spatial extent.}, } @article {pmid39183919, year = {2024}, author = {Ma, S and Cao, Y and Shi, YF and Shang, C and He, L and Liu, ZP}, title = {Data-driven discovery of active phosphine ligand space for cross-coupling reactions.}, journal = {Chemical science}, volume = {15}, number = {33}, pages = {13359-13368}, pmid = {39183919}, issn = {2041-6520}, abstract = {The design of highly active catalysts is a main theme in organic chemistry, but it still relies heavily on expert experience. Herein, powered by machine-learning global structure exploration, we forge a Metal-Phosphine Catalyst Database (MPCD) with a meticulously designed ligand replacement energy metric, a key descriptor to describe the metal-ligand interactions. It pushes the rational design of organometallic catalysts to a quantitative era, where a ±10 kJ mol[-1] window of relative ligand binding strength, a so-called active ligand space (ALS), is identified for highly effective catalyst screening. We highlight the chemistry interpretability and effectiveness of ALS for various C-N, C-C and C-S cross-coupling reactions via a Sabatier-principle-based volcano plot and demonstrate its predictive power in discovering low-cost ligands in catalyzing Suzuki cross-coupling involving aryl chloride. The advent of the MPCD provides a data-driven new route for speeding up organometallic catalysis and other applications.}, } @article {pmid39184100, year = {2024}, author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M}, title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-4750719/v1}, pmid = {39184100}, issn = {2693-5015}, support = {R01 DA054992/DA/NIDA NIH HHS/United States ; }, abstract = {Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.}, } @article {pmid39184484, year = {2024}, author = {Ozceylan, O and Sezgin-Bayindir, Z}, title = {Current Overview on the Use of Nanosized Drug Delivery Systems in the Treatment of Neurodegenerative Diseases.}, journal = {ACS omega}, volume = {9}, number = {33}, pages = {35223-35242}, pmid = {39184484}, issn = {2470-1343}, abstract = {Neurodegenerative diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, prion disease, and Huntington's disease, present a growing health concern as human life expectancy increases. Despite this, effective treatments to halt disease progression remain elusive due to various factors, including challenges in drug delivery across physiological barriers like the blood-brain barrier and patient compliance issues leading to treatment discontinuation. In response, innovative treatment approaches leveraging noninvasive techniques with higher patient compliance are emerging as promising alternatives. This Review aims to synthesize current treatment options and the challenges encountered in managing neurodegenerative diseases, while also exploring innovative treatment modalities. Specifically, noninvasive strategies such as intranasal administration and nanosized drug delivery systems are gaining prominence for their potential to enhance treatment efficacy and patient adherence. Nanosized drug delivery systems, including liposomes, polymeric micelles, and nanoparticles, are evaluated within the context of outstanding studies. The advantages and disadvantages of these approaches are discussed, providing insights into their therapeutic potential and limitations. Through this comprehensive examination, this Review contributes to the ongoing discourse surrounding the development of effective treatments for neurodegenerative diseases.}, } @article {pmid39185360, year = {2024}, author = {Di Lazzaro, V and Ranieri, F and Doretti, A and Boscarino, M and Maderna, L and Colombo, E and Soranna, D and Zambon, A and Ticozzi, N and Musumeci, G and Capone, F and Silani, V}, title = {Transcranial static magnetic stimulation for amyotrophic lateral sclerosis: a bicentric, randomised, double-blind placebo-controlled phase 2 trial.}, journal = {The Lancet regional health. Europe}, volume = {45}, number = {}, pages = {101019}, pmid = {39185360}, issn = {2666-7762}, abstract = {BACKGROUND: Enhanced glutamatergic transmission leading to motor neuron death is considered the major pathophysiological mechanism of amyotrophic lateral sclerosis (ALS). Motor cortex excitability can be suppressed by transcranial static magnetic stimulation (tSMS), thus tSMS can be evaluated as a potential treatment for ALS. The aim of present study was to investigate the efficacy and safety of tSMS in ALS.

METHODS: In this phase 2 trial, we randomly assigned ALS patients to receive daily tSMS or placebo stimulation over a period of 6 months. For each participant we calculated mean disease monthly progression rate (MPR) as the variation of the total ALS Functional Rating Scale-Revised (ALSRFS-R) score, before the beginning of the treatment (over a period of at least three months) and over the six-month treatment period. The primary efficacy outcome was the difference in MPR before and after the beginning of treatment. Secondary outcomes included safety and tolerability, compliance, and changes in corticospinal output. A long-term follow-up of 18 months was performed in all patients who completed the six-month treatment considering a composite endpoint event (tracheostomy or death). Trial registered at ClinicalTrials.gov, ID: NCT04393467, status: closed.

FINDINGS: Forty participants were randomly assigned to real (n = 21) or placebo stimulation (n = 19). Thirty-two participants (18 real and 14 placebo) completed the 6-month treatment. The MPR did not show statistically significant differences between the two arms during the pre-treatment (mean ± Standard deviation; Real: 1.02 ± 0.62, Sham: 1.02 ± 0.57, p-value = 1.00) and treatment period (Real: 0.90 ± 0.55, Sham: 0.94 ± 0.55, p-value = 0.83). Results for secondary clinical endpoints showed that the treatment is feasible and safe, being compliance with tSMS high. The change in corticospinal output did not differ significantly between the two groups. At the end of the long-term follow-up of 18 months, patients of real group had a statistically significant higher tracheostomy-free survival compared with patients of placebo group (Hazard Ratio = 0.27 95% Confidence interval 0.09-0.80, p-value = 0.019).

INTERPRETATION: tSMS did not modify disease progression during the 6 months of treatment. However, long-term follow-up revealed a substantial increase in tracheostomy free survival in patients treated with real stimulation supporting the evaluation of tSMS in larger and more prolonged studies.

FUNDING: The "Fondazione 'Nicola Irti' per le opere di carità e di cultura", Rome, Italy, supported present study.}, } @article {pmid39185513, year = {2024}, author = {Benatar, M and Macklin, EA and Malaspina, A and Rogers, ML and Hornstein, E and Lombardi, V and Renfrey, D and Shepheard, S and Magen, I and Cohen, Y and Granit, V and Statland, JM and Heckmann, JM and Rademakers, R and McHutchison, CA and Petrucelli, L and McMillan, CT and Wuu, J}, title = {Prognostic Clinical and Biological Markers for Amyotrophic Lateral Sclerosis Disease Progression: Validation and Implications for Clinical Trial Design and Analysis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39185513}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; R01 AG066152/AG/NIA NIH HHS/United States ; U01 NS107027/NS/NINDS NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R01 NS109260/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; T32 AG076411/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used.

METHODS: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75[ECD], plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated.

FINDINGS: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40pg/ml and >100pg/ml correspond to future ALSFRS-R slopes of ~0.5 and 1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ~25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75[ECD], and plasma miR-181ab is more limited.

INTERPRETATION: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency.

FUNDING: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).}, } @article {pmid39187026, year = {2024}, author = {Rezaei, K and Mastali, G and Abbasgholinejad, E and Bafrani, MA and Shahmohammadi, A and Sadri, Z and Zahed, MA}, title = {Cadmium neurotoxicity: Insights into behavioral effect and neurodegenerative diseases.}, journal = {Chemosphere}, volume = {364}, number = {}, pages = {143180}, doi = {10.1016/j.chemosphere.2024.143180}, pmid = {39187026}, issn = {1879-1298}, mesh = {*Cadmium/toxicity ; Humans ; *Neurodegenerative Diseases/chemically induced ; Animals ; Environmental Pollutants/toxicity ; Brain/drug effects/metabolism ; Neurotoxicity Syndromes/etiology ; Neurons/drug effects ; }, abstract = {Cadmium (Cd) induced neurotoxicity has become a growing concern due to its potential adverse effects on the Central Nervous System. Cd is a Heavy Metal (HM) that is released into the environment, through several industrial processes. It poses a risk to the health of the community by polluting air, water, and soil. Cd builds up in the brain and other neural tissues, raising concerns about its effect on the nervous system due to its prolonged biological half-life. Cd can enter into the neurons, hence increasing the production of Reactive Oxygen Species (ROS) in them and impairing their antioxidant defenses. Cd disrupts the Calcium (Ca[2+]) balance in neurons, affects the function of the mitochondria, and triggers cell death pathways. As a result of these pathways, the path to the development of many neurological diseases affected by environmental factors, especially Cd, such as Alzheimer's Disease (AD) and Amyotrophic Lateral Sclerosis (ALS) is facilitated. There are cognitive deficits associated with long exposure to Cd. Memory disorders are present in both animals and humans. Cd alters the brain's function and performance in critical periods. There are lifelong consequences of Cd exposure during critical brain development stages. The susceptibility to neurotoxic effects is increased by interactions with a variety of risk factors. Cd poses risks to neuronal function and behavior, potentially contributing to neurodegenerative diseases like Parkinson's disease (PD) and AD as well as cognitive issues. This article offers a comprehensive overview of Cd-induced neurotoxicity, encompassing risk assessment, adverse effect levels, and illuminating intricate pathways.}, } @article {pmid39187176, year = {2025}, author = {Althobaiti, NA}, title = {Heavy metals exposure and Alzheimer's disease: Underlying mechanisms and advancing therapeutic approaches.}, journal = {Behavioural brain research}, volume = {476}, number = {}, pages = {115212}, doi = {10.1016/j.bbr.2024.115212}, pmid = {39187176}, issn = {1872-7549}, mesh = {Humans ; *Alzheimer Disease/chemically induced ; *Metals, Heavy/adverse effects ; Animals ; Oxidative Stress/drug effects/physiology ; Environmental Exposure/adverse effects ; Brain/drug effects/metabolism ; }, abstract = {Heavy metals such as lead, cadmium, mercury, and arsenic are prevalent in the environment due to both natural and anthropogenic sources, leading to significant public health concerns. These heavy metals are known to cause damage to the nervous system, potentially leading to a range of neurological conditions including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and attention-deficit hyperactivity disorder (ADHD). The present study examines the complex relationship between heavy metal exposure and AD, focusing on the underlying mechanisms of toxicity and potential therapeutic approaches. This review article highlights how these metals can impair brain function through mechanisms such as oxidative stress, inflammation, and neurotransmitter disruption, ultimately contributing to neurodegenerative diseases like AD. It also addresses the challenges in diagnosing heavy metal-induced cognitive impairments and emphasizes the need for further research to explore effective treatment strategies and preventive measures against heavy metal exposure.}, } @article {pmid39187240, year = {2025}, author = {Lenz, M and Egenolf, P and Menzhausen, J and Heck, V and Perera, A and Eysel, P and Scheyerer, M and Oikonomidis, S}, title = {Clinical Outcome after Endoscopic Facet Denervation in Patients with Chronic Low Back Pain.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {2}, pages = {167-175}, doi = {10.1055/a-2348-1186}, pmid = {39187240}, issn = {1864-6743}, mesh = {Humans ; *Low Back Pain/surgery/diagnosis ; Male ; Female ; *Zygapophyseal Joint/surgery/innervation ; *Denervation/methods ; Middle Aged ; Treatment Outcome ; Retrospective Studies ; Adult ; Aged ; *Chronic Pain/surgery/diagnosis ; *Endoscopy/methods ; Pain Measurement ; Risk Factors ; }, abstract = {In mehreren Studien wurde berichtet, dass Kreuzschmerzen in der Bevölkerung mit bis zu 85% eine hohe Prävalenz aufweisen. Die perkutane Radiofrequenz-Facettengelenkdenervation (PRFD) ist heute der Goldstandard bei der Rhizotomie von chronischen Kreuzschmerzen (CLBP). Bisher veröffentlichte Studien zeigen jedoch kontroverse Ergebnisse über die Wirksamkeit der PRFD. Ziel dieser Studie war es daher, den Einsatz der endoskopischen Facettengelenkdenervation (EJE) zur Behandlung chronischer Kreuzschmerzen zu analysieren und potenzielle Risikofaktoren zu ermitteln, die die Indikationen für den Eingriff einschränken könnten.Wir haben retrospektiv 31 Patienten in die Studie eingeschlossen, die seit mindestens 24 Monaten an chronische Kreuzschmerzen leiden. Alle Patienten wurden einer endoskopischen Facettengelenkdenervation unterzogen und mussten postoperativ ODI-, COMI-, EQ-5D- und VRS-Scores ausfüllen, wobei die Nachbeobachtungszeit mindestens 12 Monate betrug. Zur Analyse der Korrelationen wurden grundlegende Patientendaten erfasst.Bei allen gemessenen klinischen Werten, wie ODI, COMI, EQ-5D und VRS, wurde eine signifikante Verbesserung festgestellt. Während das beste Ergebnis bei der 3-monatigen Nachuntersuchung erzielt wurde, wurde bei der 12-monatigen Nachuntersuchung eine leichte Verschlechterung festgestellt. Im Vergleich zu den präoperativen Scores wurde jedoch ein signifikanter Nutzen festgestellt. 28/31 Patienten (93,3%) berichteten bei der Nachuntersuchung nach 12 Monaten über geringere Schmerzen und waren mit dem Verfahren zufrieden. Älteres Alter und psychiatrische Vorerkrankungen wurden als potenzielle Risikofaktoren identifiziert, die mit einem schlechteren Ergebnis einhergehen. Postoperative Komplikationen wie Hämatome, eine Sensibilitätsstörung und eine vorübergehende Muskelschwäche der unteren Extremitäten wurden selten beobachtet.Die endoskopische Facettengelenkdenervation zeigte eine signifikante Verbesserung der klinischen Ergebnisse und der VRS im Vergleich zu den präoperativen Werten von Patienten mit einer mindestens 12 Monate bestehenden chronischen Kreuzschmerzen vor der Operation. Ältere Patienten und Patienten mit psychiatrischen Vorerkrankungen profitieren weniger von dem Eingriff.}, } @article {pmid39187524, year = {2024}, author = {Femiano, C and Bruno, A and Gilio, L and Buttari, F and Dolcetti, E and Galifi, G and Azzolini, F and Borrelli, A and Furlan, R and Finardi, A and Musella, A and Mandolesi, G and Storto, M and Centonze, D and Stampanoni Bassi, M}, title = {Inflammatory signature in amyotrophic lateral sclerosis predicting disease progression.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {19796}, pmid = {39187524}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Female ; Male ; *Disease Progression ; Middle Aged ; *Cytokines/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Cross-Sectional Studies ; Aged ; Inflammation/cerebrospinal fluid ; Principal Component Analysis ; Adult ; Prognosis ; Case-Control Studies ; }, abstract = {Experimental studies identified a role of neuroinflammation in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the role of inflammatory molecules as diagnostic and prognostic biomarkers in patients with ALS is unclear. In this cross-sectional study, the cerebrospinal fluid (CSF) levels of a set of inflammatory cytokines and chemokines were analyzed in 56 newly diagnosed ALS patients and in 47 age- and sex-matched control patients without inflammatory or degenerative neurological disorders. The molecules analyzed included: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-17, granulocyte colony stimulating factor (GCSF), macrophage inflammatory protein (MIP)-1a, MIP-1b, tumor necrosis factors (TNF), eotaxin. Principal component analysis (PCA) was used to explore possible associations between CSF molecules and ALS diagnosis. In addition, we analyzed the association between CSF cytokine profiles and clinical characteristics, including the disease progression rate score, and peripheral inflammation assessed using the Neutrophil-to-lymphocyte ratio (NLR). PCA identified six principal components (PCs) explaining 70.67% of the total variance in the CSF cytokine set. The principal component (PC1) explained 26.8% of variance and showed a positive load with CSF levels of IL-9, IL-4, GCSF, IL-7, IL-17, IL-13, IL-6, IL-1β, TNF, and IL-2. Logistic regression showed a significant association between PC1 and ALS diagnosis. In addition, in ALS patients, the same component was significantly associated with higher disease progression rate score and positively correlated with NLR. CSF inflammatory activation in present in ALS at the time of diagnosis and may characterize patients at higher risk for disease progression.}, } @article {pmid39188590, year = {2024}, author = {Roca-Pereira, S and Domínguez, R and Moreno León, I and Colomina, MJ and Martínez Yélamos, A and Martínez Yélamos, S and Povedano, M and Andrés-Benito, P}, title = {Increased CXCL12, a potential CSF biomarker for differential diagnosis of amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {4}, pages = {fcae271}, pmid = {39188590}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a debilitating and lethal neurodegenerative disorder marked by the gradual deterioration of motor neurons. Diagnosing amyotrophic lateral sclerosis is challenging due to the lack of reliable diagnostic tools, with clinical assessment being the primary criterion. Recently, increased levels of neurofilament light chain in CSF have been considered a useful biomarker in disease, correlating with disease progression but not specific for diagnosis. This study utilized enzyme-linked immunosorbent assay to measure CSF C-X-C motif chemokine ligand 12 levels in healthy controls, amyotrophic lateral sclerosis patients and patients with amyotrophic lateral sclerosis-mimic disorders, assessing its potential as a diagnostic biomarker and comparing it with neurofilament light chain levels. Our results confirmed previous findings, showing increased C-X-C motif chemokine ligand 12 levels in amyotrophic lateral sclerosis patients compared to healthy control (797.07 ± 31.84 pg/mL versus 316.15 ± 16.6 pg/mL; P = 0.000) and increased CSF neurofilament light chain levels in amyotrophic lateral sclerosis (4565.63 ± 263.77 pg/mL) compared to healthy control (847.86 ± 214.37 pg/mL; P = 0.000). Increased C-X-C motif chemokine ligand levels were specific to amyotrophic lateral sclerosis, not seen in amyotrophic lateral sclerosis-mimic conditions like myelopathies (252.20 ± 23.16 pg/mL; P = 0.000), inflammatory polyneuropathies (270.24 ± 32.23 pg/mL; P = 0.000) and other mimic diseases (228.91 ± 29.20 pg/mL; P = 0.000). In contrast, CSF neurofilament light chain levels in amyotrophic lateral sclerosis overlapped with those in myelopathies (2900.11 ± 872.20 pg/mL; P = 0.821) and other mimic diseases (3169.75 ± 1096.65 pg/mL; P = 0.63), but not with inflammatory polyneuropathies (1156.4 ± 356.6 pg/mL; P = 0.000). Receiver operating characteristic curve analysis indicated significant differences between the area under the curve values of C-X-C motif chemokine ligand and neurofilament light chain in their diagnostic capacities. C-X-C motif chemokine ligand could differentiate between amyotrophic lateral sclerosis and myelopathies (area under the curve 0.99 ± 0.005), inflammatory polyneuropathies (area under the curve 0.962 ± 0.027) and other mimic diseases (area under the curve 1.00 ± 0.00), whereas neurofilament light chain was only effective in inflammatory polyneuropathies cases (area under the curve 0.92 ± 0.048), not in myelopathies (area under the curve 0.71 ± 0.09) or other mimic diseases (area under the curve 0.69 ± 0.14). We also evaluated C-X-C motif chemokine ligand levels in plasma [amyotrophic lateral sclerosis (2022 ± 81.8 pg/mL) versus healthy control (1739.43 ± 77.3 pg/mL; P = 0.015)] but found CSF determination (area under the curve 0.97 ± 0.012) to be more accurate than plasma determination (area under the curve 0.65 ± 0.063). In plasma, single molecule array (SIMOA) neurofilament light chain determination [amyotrophic lateral sclerosis (86.00 ± 12.23 pg/mL) versus healthy control (12.69 ± 1.15 pg/mL); P = 0.000] was more accurate than plasma C-X-C motif chemokine ligand 12 (area under the curve 0.98 ± 0.01405). These findings suggest that CSF C-X-C motif chemokine ligand 12 levels can enhance diagnostic specificity in distinguishing amyotrophic lateral sclerosis from amyotrophic lateral sclerosis-mimic disorders, compared to neurofilament light chain. Larger studies are needed to validate these results, but C-X-C motif chemokine ligand 12 determination shows promising diagnostic potential.}, } @article {pmid39189114, year = {2024}, author = {Rivera Flores, IV and Monopoli, K and Jackson, S and Echeverria, D and O'Reilly, D and Brown, RH and Khvorova, A}, title = {Near Sequence Homology Does Not Guarantee siRNA Cross-Species Efficacy.}, journal = {Nucleic acid therapeutics}, volume = {34}, number = {5}, pages = {234-244}, pmid = {39189114}, issn = {2159-3345}, support = {R01 NS104022/NS/NINDS NIH HHS/United States ; S10 OD020012/OD/NIH HHS/United States ; T32 GM135751/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *RNA, Small Interfering/genetics/chemistry ; Humans ; Dogs ; Mice ; Rats ; *Superoxide Dismutase-1/genetics ; *Species Specificity ; Sheep ; Base Pair Mismatch/genetics ; Cell Line ; }, abstract = {Small interfering RNAs (siRNAs) represent a novel class of drugs capable of potent and sustained modulation of genes across various tissues. Preclinical development of siRNAs necessitates assessing efficacy and toxicity in animal models. While identifying therapeutic leads with cross-species activity can expedite development, it may compromise efficacy and be infeasible for certain gene targets. Here, we investigate whether deriving species-active siRNAs from potent human-targeting leads-an approach termed mismatch conversion-can yield potent compounds. We systematically altered potent siRNAs targeting human genes associated with diseases-SOD1 (ALS), JAK1 (inflammation), and HTT (HD)-to generate species-matching variants with full complementarity to their target in NHPs, mice, rats, sheep, and dogs. Variants potency and efficacy were measured in corresponding cell lines. We demonstrate that sequence, position, and number of mismatches significantly influence the ability to generate potent species-active compounds via mismatch conversion. Across tested sequences, mismatch conversion strategy ability to identify a species-active lead varied from 0% to 70%. For SOD1, lead compounds identified from species-focus screening in mouse and dog cells were more potent than leads obtained from mismatch conversion. Thus, a focused screening of therapeutic lead and model compounds may represent a more reliable strategy for the clinical advancement of siRNAs.}, } @article {pmid39190080, year = {2024}, author = {Jensen, BK}, title = {Astrocyte-Neuron Interactions Contributing to Amyotrophic Lateral Sclerosis Progression.}, journal = {Advances in neurobiology}, volume = {39}, number = {}, pages = {285-318}, pmid = {39190080}, issn = {2190-5215}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Astrocytes/metabolism ; *Disease Progression ; *Motor Neurons/metabolism/pathology ; *Cell Communication/physiology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex disease impacting motor neurons of the brain, brainstem, and spinal cord. Disease etiology is quite heterogeneous with over 40 genes causing the disease and a vast ~90% of patients having no prior family history. Astrocytes are major contributors to ALS, particularly through involvement in accelerating disease progression. Through study of genetic forms of disease including SOD1, TDP43, FUS, C9orf72, VCP, TBK1, and more recently patient-derived cells from sporadic individuals, many biological mechanisms have been identified to cause intrinsic or glial-mediated neurotoxicity to motor neurons. Overall, many of the normally supportive and beneficial roles that astrocytes contribute to neuronal health and survival instead switch to become deleterious and neurotoxic. While the exact pathways may differ based on disease-origin, altered astrocyte-neuron communication is a common feature of ALS. Within this chapter, distinct genetic forms are examined in detail, along with what is known from sporadic patient-derived cells. Overall, this chapter highlights the interplay between astrocytes and neurons in this complex disease and describes the key features underlying: astrocyte-mediated motor neuron toxicity, excitotoxicity, oxidative/nitrosative stress, protein dyshomeostasis, metabolic imbalance, inflammation, trophic factor withdrawal, blood-brain/blood-spinal cord barrier involvement, disease spreading, and the extracellular matrix/cell adhesion/TGF-β signaling pathways.}, } @article {pmid39190906, year = {2024}, author = {Yu, J and Chen, S and Zhang, H and Zhang, S and Dong, D}, title = {Patterns of the Health and Economic Burden of 33 Rare Diseases in China: Nationwide Web-Based Study.}, journal = {JMIR public health and surveillance}, volume = {10}, number = {}, pages = {e57353}, pmid = {39190906}, issn = {2369-2960}, mesh = {Humans ; China/epidemiology ; *Rare Diseases/epidemiology/economics ; Male ; Adult ; Female ; Cross-Sectional Studies ; Middle Aged ; *Cost of Illness ; Adolescent ; Child ; *Internet ; Child, Preschool ; Young Adult ; Surveys and Questionnaires ; Aged ; Infant ; }, abstract = {BACKGROUND: Rare diseases (RDs) affect millions of individuals collectively worldwide, contributing to significant burdens on patients and families in various aspects. However, there is a lack of evidence on the underlying patterns of burdens among diverse RDs for informing targeted social and health policies to address the unmet needs of this vulnerable population.

OBJECTIVE: This study aimed to examine the underlying patterns of the health and economic burden of 33 different RDs in China and identify the potential determinants.

METHODS: A nationwide internet-based cross-sectional survey was conducted in China between 2019 and 2020. Physical and mental health burden was measured by health-related quality of life. Economic burden was evaluated based on the proportions of direct medical, direct nonmedical, and indirect costs relative to household income. We used cluster analysis to identify patterns of health and economic burdens and conducted multinomial logistic regression to explore potential predictors of cluster membership.

RESULTS: The study included 8454 adults and 8491 children affected by 33 RDs. The following 3 clusters were identified: "extremely high burden" (representing 92/8454, 1.1% and 19/8491, 0.2% of adult and pediatric patients, respectively), "overall high burden" (5933/8454, 70.2% and 4864/8491, 57.3%, respectively), and "overall low burden" (2429/8454, 28.7% and 3608/8491, 42.5%, respectively). Wilson disease, Marfan syndrome, and Langerhans cell histiocytosis more likely resulted in an "extremely high burden" than others. Poverty was significantly associated with being in this extremely high burden group. Diseases causing neuromuscular symptoms and requiring long-term treatment (eg, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Dravet syndrome) were prevalent in the "overall high burden" group. Key predictors of this group included older age, lower socioeconomic status, diagnostic delay, and comorbidity.

CONCLUSIONS: This study provides novel and valuable evidence on the burden of RDs in developing regions like China. The findings reveal significant disparities in the impact of RDs, emphasizing the need for targeted health care interventions and policies.}, } @article {pmid39191031, year = {2024}, author = {He, Q and Wang, Y and Zhao, F and Wei, S and Li, X and Zeng, G}, title = {APE1: A critical focus in neurodegenerative conditions.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {179}, number = {}, pages = {117332}, doi = {10.1016/j.biopha.2024.117332}, pmid = {39191031}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism ; Animals ; }, abstract = {The global growth of the aging population has resulted in an increased prevalence of neurodegenerative diseases, characterized by the progressive loss of central nervous system (CNS) structure and function. Given the high incidence and debilitating nature of neurodegenerative diseases, there is an urgent need to identify potential biomarkers and novel therapeutic targets thereof. Apurinic/apyrimidinic endonuclease 1 (APE1), has been implicated in several neurodegenerative diseases, as having a significant role. Abnormal APE1 expression has been observed in conditions including Alzheimer's disease, stroke, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and epilepsy. However, whether this dysregulation is protective or harmful remains unclear. This review aims to comprehensively review the current understanding of the involvement of APE1 in neurodegenerative diseases.}, } @article {pmid39191178, year = {2024}, author = {Ruotolo, G and D'Anzi, A and Giovenale, AMG and Giacometti, C and Ferrari, D and Vulcano, E and D'Asdia, C and Lattante, S and Sabatelli, M and Codazzi, F and Consalez, G and Marano, M and Di Lazzaro, V and Pennuto, M and Vescovi, A and Rosati, J}, title = {Induced pluripotent stem cell production (CSSi019-A)(14432) from an asymptomatic subject carrying a expansion of C9orf72 gene.}, journal = {Stem cell research}, volume = {81}, number = {}, pages = {103540}, doi = {10.1016/j.scr.2024.103540}, pmid = {39191178}, issn = {1876-7753}, mesh = {*Induced Pluripotent Stem Cells/metabolism ; Humans ; *C9orf72 Protein/genetics/metabolism ; Aged ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; DNA Repeat Expansion ; Male ; Female ; }, abstract = {One of the genetic mutations most associated with the onset of amyotrophic lateral sclerosis, both in sporadic and familial cases, is the expansion of the C9orf72 gene. The presence of more than 30 repeats (GGGGCC) correlates with uncertain ALS symptomatology. Here we collected a dermal biopsy from a subject carrying 36 hexanucleotide repeats and reprogrammed it into an induced pluripotent stem cell line. Despite the number of repeat elements, the subject had no symptoms at the age of the biopsy (76 years), thus resulting in a healthy carrier of the mutation.}, } @article {pmid39191336, year = {2024}, author = {Sirtori, CR and Castiglione, S and Pavanello, C}, title = {Metformin: From diabetes to cancer to prolongation of life.}, journal = {Pharmacological research}, volume = {208}, number = {}, pages = {107367}, doi = {10.1016/j.phrs.2024.107367}, pmid = {39191336}, issn = {1096-1186}, mesh = {Humans ; *Metformin/therapeutic use/pharmacology ; Animals ; *Neoplasms/drug therapy/metabolism ; *Hypoglycemic Agents/therapeutic use/pharmacology ; *Diabetes Mellitus/drug therapy/metabolism ; Longevity/drug effects ; Antineoplastic Agents/therapeutic use/pharmacology ; }, abstract = {The metformin molecule dates back to over a century, but its clinical use started in the '50s. Since then, its use in diabetics has grown constantly, with over 150 million users today. The therapeutic profile also expanded, with improved understanding of novel mechanisms. Metformin has a major activity on insulin resistance, by acting on the insulin receptors and mitochondria, most likely by activation of the adenosine monophosphate-activated kinase. These and associated mechanisms lead to significant lipid lowering and body weight loss. An anti-cancer action has come up in recent years, with mechanisms partly dependent on the mitochondrial activity and also on phosphatidylinositol 3-kinase resistance occurring in some malignant tumors. The potential of metformin to raise life-length is the object of large ongoing studies and of several basic and clinical investigations. The present review article will attempt to investigate the basic mechanisms behind these diverse activities and the potential clinical benefits. Metformin may act on transcriptional activity by histone modification, DNA methylation and miRNAs. An activity on age-associated inflammation (inflammaging) may occur via activation of the nuclear factor erythroid 2 related factor and changes in gut microbiota. A senolytic activity, leading to reduction of cells with the senescent associated secretory phenotype, may be crucial in lifespan prolongation as well as in ancillary properties in age-associated diseases, such as Parkinson's disease. Telomere prolongation may be related to the activity on mitochondrial respiratory factor 1 and on peroxisome gamma proliferator coactivator 1-alpha. Very recent observations on the potential to act on the most severe neurological disorders, such as amyotrophic lateral sclerosis and frontotemporal dementia, have raised considerable hope.}, } @article {pmid39192451, year = {2024}, author = {Yan, Y and Huang, SY and Feng, YJ and Zhao, CY and Sheng, GX and Chen, J and Jiang, JJ and Gao, F and Mao, SS}, title = {[Pediatric amyotrophic lateral sclerosis caused by FUS gene variation in 2 cases].}, journal = {Zhonghua er ke za zhi = Chinese journal of pediatrics}, volume = {62}, number = {9}, pages = {893-895}, doi = {10.3760/cma.j.cn112140-20240315-00184}, pmid = {39192451}, issn = {0578-1310}, mesh = {Female ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; DNA Mutational Analysis ; Exons ; Fatal Outcome ; Heterozygote ; *Mutation ; *RNA-Binding Protein FUS/genetics ; Child ; Adolescent ; }, } @article {pmid39192497, year = {2024}, author = {Lee, I and Garret, MA and Wuu, J and Harrington, EA and Berry, JD and Miller, TM and Harms, M and Benatar, M and Shneider, N}, title = {Body mass index is lower in asymptomatic C9orf72 expansion carriers but not in SOD1 pathogenic variant carriers compared to gene negatives.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {672-679}, pmid = {39192497}, issn = {2167-9223}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; R01 NS105479/NS/NINDS NIH HHS/United States ; RF1 NS105479/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *C9orf72 Protein/genetics ; *Body Mass Index ; *Superoxide Dismutase-1/genetics ; Middle Aged ; *Heterozygote ; Adult ; Cohort Studies ; Genotype ; DNA Repeat Expansion/genetics ; Aged ; }, abstract = {Objective: To examine the relationship between body mass index (BMI) and genotype among pre-symptomatic carriers of different pathogenic variants associated with amyotrophic lateral sclerosis. Methods: C9orf72+ carriers, SOD1+ carriers, and pathogenic variant negative controls (Gene-Negatives) were included from 3 largely independent cohorts: ALS Families Project (ALS-Families); Dominantly inherited ALS (DIALS); and Pre-symptomatic Familial ALS (Pre-fALS). First reported (ALS-Families) or measured (DIALS and Pre-fALS) weight and height were used to calculate BMI. Age at weight measurement, self-reported sex (male vs. female), and highest education (high school or below vs. college education vs. graduate school or above) were extracted. The associations between BMI and genotype in each cohort were examined with multivariable linear regression models, adjusted for age, sex, and education. Results: A total of 223 C9orf72+ carriers, 135 SOD1+ carriers, and 191 Gene-Negatives were included, deriving from ALS-Families (n = 114, median age 46, 37% male), DIALS (n = 221, median age 46, 30% male), and Pre-fALS (n = 214, median age 44, 39% male). Adjusting for age, sex, and education, the mean BMI of C9orf72+ carriers was lower than Gene-Negatives by 2.4 units (95% confidence interval [CI] = 0.3-4.6, p = 0.02) in ALS-Families; 2.7 units (95% CI = 0.9-4.4, p = 0.003) in DIALS; and 1.9 units (95% CI = 0.5-4.2, p = 0.12) in Pre-fALS. There were no significant differences in BMI between SOD1+ carriers and Gene-Negatives in any of the 3 cohorts. Conclusions: Compared to Gene-Negatives, average BMI is lower in asymptomatic C9orf72+ carriers across 3 cohorts while no significant difference was found between Gene-Negatives and SOD1+ carriers.}, } @article {pmid39192797, year = {2024}, author = {Luo, RC and Wu, XY and Yu, WW and Zheng, YJ and Wang, D}, title = {[Research progress on the relationship between TRAF6 and neurodegenerative diseases].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {76}, number = {4}, pages = {653-662}, pmid = {39192797}, issn = {0371-0874}, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism/etiology ; Amyotrophic Lateral Sclerosis/metabolism/physiopathology/genetics/etiology ; Multiple Sclerosis/metabolism/physiopathology/etiology ; *Neurodegenerative Diseases/metabolism/etiology ; Parkinson Disease/metabolism/physiopathology ; *TNF Receptor-Associated Factor 6/metabolism/genetics/physiology ; Ubiquitination ; Intracellular Signaling Peptides and Proteins ; }, abstract = {Given the increasing trend of aging population in the world, neurodegenerative diseases (NDDs), a common type of diseases that mostly occur in the elderly, have attracted much more attention. It has been shown that tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in the regulation of neuroinflammation, an important pathological feature of NDDs, and affects the occurrence and development of NDDs. Most importantly, the regulatory effect of TRAF6 is related to its ubiquitination. Therefore, in the present paper, the molecular structure, biological function, and ubiquitination mechanism of TRAF6, and its relationship with some common NDDs, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, were analyzed and summarized. The possible molecular mechanisms by which TRAF6 regulates the occurrence of NDDs were also elucidated, providing a theoretical basis for exploring the etiology and treatment of NDDs.}, } @article {pmid39192891, year = {2024}, author = {Murtazina, A and Subbotin, D and Kuchina, A and Gilvanova, O and Degterev, D and Shchagina, O and Cherevatova, T and Bulakh, M and Sherstyukova, D and Ryzhkova, O and Kurushina, O and Skoblov, M and Borovikov, A and Kutsev, S}, title = {Asymmetric scapuloperoneal phenotype of MATR3-related distal myopathy: case series.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1414928}, pmid = {39192891}, issn = {1664-8021}, abstract = {Recent research has sparked a discussion on the spectrum of diseases linked to the MATR3 gene associated with amyotrophic lateral sclerosis and distal myopathy with vocal cord and pharyngeal weakness (VCPDM). To date, fewer than 50 cases of VCPDM have been reported in the literature. We aim to build upon the work of previous researchers by gathering additional information about VCPDM. In this study, we present six patients from four unrelated families affected by VCPDM. Our observations include patients exhibiting both the typical phenotype associated with MATR3-related distal myopathy and rare symptomatic manifestations of the disease. Notably, two cases presented with an asymmetric scapuloperoneal phenotype, leading in one case to an initial misdiagnosis of facioscapulohumeral muscular dystrophy.}, } @article {pmid39193017, year = {2024}, author = {Chen, X and Cai, L and Fan, W and Yang, Q and Mao, X and Yao, L}, title = {Causal relationships between rheumatoid arthritis and neurodegenerative diseases: a two-sample univariable and multivariable Mendelian randomization study.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1439344}, pmid = {39193017}, issn = {2296-858X}, abstract = {BACKGROUND: Observational research has highlighted a potential relationship between rheumatoid arthritis (RA) and neurodegenerative diseases (NDs). However, the confirmation of a causal connection is impeded by the inherent limitations of such studies, including vulnerability to confounding factors and the possibility of reverse causality. This study employs a two-sample Mendelian randomization (MR) approach to assess the causal impact of RA on three NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

METHODS: We aggregated data from genome-wide association studies (GWASs) targeting RA or NDs within populations of European descent. Single nucleotide polymorphisms (SNPs) with robust associations to RA were identified as instrumental variables (IVs). To estimate the association between RA and AD, PD, and ALS, we utilized the inverse variance weighted (IVW) method in our univariable MR (UVMR) analysis. Validation of the IVW results ensued through supplementary analyses using MR-Egger and weighted median methods. The multivariable MR (MVMR) analysis was conducted, adjusting for body mass index (BMI), alcohol drinking, and type 2 diabetes mellitus (T2DM).

RESULTS: The UVMR analysis, based on the IVW method, revealed a significantly positive causal association between RA and late-onset (LO) AD (OR [95% CI] = 1.084 [1.020-1.153]; p = 9.980 × 10[-3]), while suggesting a possible inverse relationship with PD (OR [95% CI] = 0.727 [0.563-0.938]; p = 0.014). Our study did not detect any causal connections between RA and early-onset (EO) AD, atypical or mixed (AM) AD, and ALS (all p > 0.05). The MVMR analysis results indicated that after adjusting for alcohol drinking, RA remains a risk factor for LOAD (OR [95% CI] = 1.094 [1.024-1.169]; p = 0.008). However, MVMR analysis revealed no causal connections between RA and PD after adjustments for BMI, alcohol drinking, or T2DM (all p > 0.05). Sensitivity analyses showed no evidence of heterogeneity and horizontal pleiotropy.

CONCLUSIONS: This research provides genetic evidence indicating that RA potentially causes an increased risk of developing LOAD and PD. Such a revelation underscores the importance for individuals suffering from RA to be vigilant about the potential emergence of LOAD and PD. Ongoing monitoring and prompt detection are essential for successfully managing and intervening in this possible risk.}, } @article {pmid39193573, year = {2024}, author = {Soresi, M and Giannitrapani, L}, title = {Glucagon-like peptide 1 agonists are potentially useful drugs for treating metabolic dysfunction-associated steatotic liver disease.}, journal = {World journal of gastroenterology}, volume = {30}, number = {30}, pages = {3541-3547}, pmid = {39193573}, issn = {2219-2840}, mesh = {Humans ; *Non-alcoholic Fatty Liver Disease/drug therapy/pathology/metabolism ; *Glucagon-Like Peptides/therapeutic use ; Liver/drug effects/pathology/metabolism ; Insulin Resistance ; Drug Therapy, Combination/methods ; Glucagon-Like Peptide 1/agonists/metabolism ; Treatment Outcome ; Hypoglycemic Agents/therapeutic use/pharmacology ; Disease Progression ; Incretins/therapeutic use ; *Glucagon-Like Peptide-1 Receptor Agonists ; Semaglutide ; Glucagon-Like Peptide-1 Receptor ; }, abstract = {In this editorial, we comment on Yin et al's recently published Letter to the editor. In particular, we focus on the potential use of glucagon-like peptide 1 receptor agonists (GLP-1RAs) alone, but even more so in combination therapy, as one of the most promising therapies in metabolic dysfunction-associated steatotic liver disease (MASLD), the new definition of an old condition, non-alcoholic fatty liver disease, which aims to better define the spectrum of steatotic pathology. It is well known that GLP-1RAs, having shown outstanding performance in fat loss, weight loss, and improvement of insulin resistance, could play a role in protecting the liver from progressive damage. Several clinical trials have shown that, among GLP-1RAs, semaglutide is a safe, well-studied therapeutic choice for MASLD patients; however, most studies demonstrate that, while semaglutide can reduce steatosis, including steatohepatitis histological signs (in terms of inflammatory cell infiltration and hepatocyte ballooning), it does not improve fibrosis. Combinations of therapies with different but complementary mechanisms of action are considered the best way to improve efficiency and slow disease progression due to the complex pathophysiology of the disease. In particular, GLP-1RAs associated with antifibrotic drug therapy, dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA or GLP-1 and glucagon RAs have promoted greater improvement in hepatic steatosis, liver biochemistry, and non-invasive fibrosis tests than monotherapy. Therefore, although to date there are no definitive indications from international drug agencies, there is the hope that soon the therapeutic lines in the most advanced phase of study will be able to provide a therapy for MASLD, one that will certainly include the use of GLP-1RAs as combination therapy.}, } @article {pmid39193833, year = {2025}, author = {Jalaiei, A and Asadi, MR and Daneshmandpour, Y and Rezazadeh, M and Ghafouri-Fard, S}, title = {Clinical, molecular, physiologic, and therapeutic feature of patients with CHRNA4 and CHRNB2 deficiency: A systematic review.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16200}, doi = {10.1111/jnc.16200}, pmid = {39193833}, issn = {1471-4159}, mesh = {Humans ; *Receptors, Nicotinic/genetics ; Mutation/genetics ; Neurodegenerative Diseases/genetics/metabolism ; }, abstract = {The α4β2 nAChRs are crucial ion channels that control neurotransmitter release and play a role in various physiologic and pathologic processes. CHRNA4 encodes the α4-nAChRs, while CHRNB2 encodes the β2-nAChRs. Recent studies have found different variants of α4β2-nAChRs in individuals with conditions such as AD, ADHD, ALS, PD, and brain abnormalities. We conducted a scoping review following a six-stage methodology structure and adhering to PRISMA guidelines. We systematically reviewed articles using relevant keywords up to October 2, 2023. In this summary, we cover the clinical symptoms reported, the genes and protein structure of CHRNA4 and CHRNB2, mutations in these genes, inheritance patterns, the functional impact of mutations and polymorphisms in CHRNA4 and CHRNB2, and the epidemiology of these diseases. Recent research indicates that nAChRs may play a significant role in neurodegenerative disorders, possibly impacting neuronal function through yet undiscovered regulatory pathways. Studying how nAChRs interact with disease-related aggregates in neurodegenerative conditions may lead to new treatment options for these disorders.}, } @article {pmid39194682, year = {2024}, author = {Sacharczuk, M and Mickael, ME and Kubick, N and Kamińska, A and Horbańczuk, JO and Atanasov, AG and Religa, P and Ławiński, M}, title = {The Current Landscape of Hypotheses Describing the Contribution of CD4+ Heterogeneous Populations to ALS.}, journal = {Current issues in molecular biology}, volume = {46}, number = {8}, pages = {7846-7861}, pmid = {39194682}, issn = {1467-3045}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a poorly understood and fatal disease. It has a low prevalence and a 2-4 year survival period. Various theories and hypotheses relating to its development process have been proposed, albeit with no breakthrough in its treatment. Recently, the role of the adaptive immune system in ALS, particularly CD4+ T cells, has begun to be investigated. CD4+ T cells are a heterogeneous group of immune cells. They include highly pro-inflammatory types such as Th1 and Th17, as well as highly anti-inflammatory cells such as Tregs. However, the landscape of the role of CD4+ T cells in ALS is still not clearly understood. This review covers current hypotheses that elucidate how various CD4+ T cells can contribute to ALS development. These hypotheses include the SWITCH model, which suggests that, in the early stages of the disease, Tregs are highly capable of regulating the immune response. However, in the later stages of the disease, it seems that pro-inflammatory cells such as Th1 and Th17 are capable of overwhelming Treg function. The reason why this occurs is not known. Several research groups have proposed that CD4+ T cells as a whole might experience aging. Others have proposed that gamma delta T cells might directly target Tregs. Additionally, other research groups have argued that less well-known CD4+ T cells, such as Emoes+ CD4+ T cells, may be directly responsible for neuron death by producing granzyme B. We propose that the ALS landscape is highly complicated and that there is more than one feasible hypothesis. However, it is critical to take into consideration the differences in the ability of different populations of CD4+ T cells to infiltrate the blood-brain barrier, taking into account the brain region and the time of infiltration. Shedding more light on these still obscure factors can help to create a personalized therapy capable of regaining the balance of power in the battle between the anti-inflammatory and pro-inflammatory cells in the central nervous system of ALS patients.}, } @article {pmid39196396, year = {2024}, author = {Radakovic, R and Carroll, A and Altiero, A and Reichwein, C and Walsh, S and Niven, E and Abrahams, S and Simmons, Z}, title = {Self-perceived quality of life, cognitive and behavioural impairment in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6822-6838}, pmid = {39196396}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; Male ; *Quality of Life/psychology ; Female ; Middle Aged ; Cross-Sectional Studies ; Aged ; Cognitive Dysfunction/etiology/physiopathology/psychology ; Cohort Studies ; Self Concept ; Mental Disorders/psychology/etiology ; Adult ; }, abstract = {BACKGROUND: Self-perceived quality of life (QoL) is important in amyotrophic lateral sclerosis (ALS). Although caregiver burden and strain have been related to cognitive and behavioural impairment, there has been no comprehensive research looking at these impairments and how they may influence self-perceived QoL subdomains.

AIMS: To explore how cognitive and behavioural impairment are related to different areas of self-perceived QoL using disease-specific measures.

METHODS: This was a quantitative, cross-sectional, observational cohort study, utilising existing specialist ALS clinic data. Clinical and demographic variables were available as well as multidimensional measures, ALS-specific QoL Short Form (ALSsQoL-SF) results and the data from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Group comparison and regression analyses were performed.

RESULTS: Data from 121 participants with ALS were analysed. 61.2% (N = 74) had either cognitive and/or behavioural impairment, with 28.9% (N = 35) with cognitive impairment (ALSci), 14.1% (N = 17) with behavioural impairment (ALSbi) and 18.2% (N = 22) with both (ALScbi). 38.8% (N = 47) were classified as having no impairments (ALSni). Those with ALSbi had significantly lower QoL in the domains of negative emotions and the interaction with people and the environment compared to those with ALSci and ALSni (ps < 0.05). Further, those with ALScbi had significantly lower QoL in the intimacy domains than those with ALSci and ALSni (ps < 0.05). Regression analysis showed specific cognitive and behavioural (inclusive of psychosis) predictors associated with specific QoL subdomains.

CONCLUSIONS: Behavioural impairments effect QoL in specific subdomains, namely relating to internalising (negative emotions) and externalising (interaction with people and the environment subdomains, intimacy).}, } @article {pmid39197036, year = {2025}, author = {Sapaly, D and Cheguillaume, F and Weill, L and Clerc, Z and Biondi, O and Bendris, S and Buon, C and Slika, R and Piller, E and Sundaram, VK and da Silva Ramos, A and Amador, MDM and Lenglet, T and Debs, R and Le Forestier, N and Pradat, PF and Salachas, F and Lacomblez, L and Hesters, A and Borderie, D and Devos, D and Desnuelle, C and Rolland, AS and Periou, B and Vasseur, S and Chapart, M and Le Ber, I and Fauret-Amsellem, AL and Millecamps, S and Maisonobe, T and Leonard-Louis, S and Behin, A and Authier, FJ and Evangelista, T and Charbonnier, F and Bruneteau, G}, title = {Dysregulation of muscle cholesterol transport in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {3}, pages = {788-802}, pmid = {39197036}, issn = {1460-2156}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Male ; *Cholesterol/metabolism ; Middle Aged ; Female ; *Muscle, Skeletal/metabolism/pathology ; Aged ; Adult ; Intracellular Signaling Peptides and Proteins ; Niemann-Pick C1 Protein ; Carrier Proteins/metabolism/genetics ; Biological Transport ; Vesicular Transport Proteins ; Muscle Fibers, Skeletal/metabolism ; Membrane Glycoproteins/metabolism/genetics ; Cells, Cultured ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, with a typical lifespan of 3-5 years. Altered metabolism is a key feature of ALS that strongly influences prognosis, with an increase in whole body energy expenditure and changes in skeletal muscle metabolism, including greater reliance on fat oxidation. Dyslipidaemia has been described in ALS as part of the metabolic dysregulation, but its role in the pathophysiology of the disease remains controversial. Among the lipids, cholesterol is of particular interest as a vital component of cell membranes, playing a key role in signal transduction and mitochondrial function in muscle. The aim of this study was to investigate whether motor dysfunction in ALS might be associated with dysregulation of muscle cholesterol metabolism. We determined cholesterol content and analysed the expression of key determinants of the cholesterol metabolism pathway in muscle biopsies from 13 ALS patients and 10 asymptomatic ALS-mutation gene carriers compared to 16 control subjects. Using human control primary myotubes, we investigated the potential contribution of cholesterol dyshomeostasis to reliance on mitochondrial fatty acid. We found that cholesterol accumulates in the skeletal muscle of ALS patients and that cholesterol overload significantly correlates with disease severity evaluated by the Revised ALS Functional Rating Scale. These defects are associated with overexpression of the genes of the lysosomal cholesterol transporters Niemann-Pick type C1 (NPC1) and 2 (NPC2), which are required for cholesterol transfer from late endosomes/lysosomes to cellular membranes. Most notably, a significant increase in NPC2 mRNA levels could be detected in muscle samples from asymptomatic ALS-mutation carriers, long before disease onset. We found that filipin-stained unesterified cholesterol accumulated in the lysosomal compartment in ALS muscle samples, suggesting dysfunction of the NPC1/2 system. Accordingly, we report here that experimental NPC1 inhibition or lysosomal pH alteration in human primary myotubes was sufficient to induce the overexpression of NPC1 and NPC2 mRNA. Finally, acute NPC1 inhibition in human control myotubes induced a shift towards a preferential use of fatty acids, thus reproducing the metabolic defect characteristic of ALS muscle. We conclude that cholesterol homeostasis is dysregulated in ALS muscle from the presymptomatic stage. Targeting NPC1/2 dysfunction may be a new therapeutic strategy for ALS to restore muscle energy metabolism and slow motor symptom progression.}, } @article {pmid39197801, year = {2025}, author = {Zhan, Y and Huang, J and Tang, X and Du, B and Yang, B}, title = {Semen Strychni Pulveratum and vomicine alleviate neuroinflammation in amyotrophic lateral sclerosis through cGAS-STING-TBK1 pathway.}, journal = {Journal of ethnopharmacology}, volume = {336}, number = {}, pages = {118741}, doi = {10.1016/j.jep.2024.118741}, pmid = {39197801}, issn = {1872-7573}, mesh = {Animals ; *Protein Serine-Threonine Kinases/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mice ; *Membrane Proteins/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Nucleotidyltransferases/metabolism ; Male ; Signal Transduction/drug effects ; Mice, Transgenic ; Neuroinflammatory Diseases/drug therapy ; Spinal Cord/drug effects/metabolism/pathology ; Disease Models, Animal ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fetal neuromuscular disorder characterized by the gradual deterioration of motor neurons. Semen Strychni pulveratum (SSP), a processed version of Semen Strychni (SS) powder, is widely used to treat ALS in China. Vomicine is one of the most primary components of SS. However, their pharmacological effects and mechanisms for ALS remain elusive.

AIM OF THE STUDY: This study aimed to evaluate the neuroprotective and anti-neuroinflammatory effects of SSP and vomicine, as well as to explore their protective roles in ALS and the underlying mechanisms.

MATERIALS AND METHODS: In vivo, 8-week-old hSOD1-WT mice and hSOD1-G93A mice were orally administered different concentrations of SSP (SSP-L = 5.46 mg/ml, SSP-M = 10.92 mg/ml or SSP-H = 16.38 mg/ml) once every other day for 8 weeks. A series of experiments, including body weight measurement, footprint tests, Hematoxylin & Eosin staining, and Nissl staining, were performed to evaluate the preventive effect of SSP. Immunofluorescence staining, western blotting, and RT-qPCR were subsequently performed to evaluate activation of the cGAS-STING-TBK1 pathway in the spinal cord. In vitro, hSOD1[G93A] NSC-34 cells were treated with vomicine to further explore the pharmacological mechanism of vomicine in the treatment of ALS via the cGAS-STING-TBK1 pathway.

RESULTS: SSP improved motor function, body weight loss, gastrocnemius muscle atrophy, and motor neuron loss in the spine and cortex of hSOD1-G93A mice. Furthermore, the cGAS-STING-TBK1 pathway was activated in the spinal cord of hSOD1-G93A mice, with activation predominantly observed in neurons and microglia. However, the levels of cGAS, STING, and pTBK1 proteins and cGAS, IRF3, IL-6, and IL-1β mRNA were reversed following intervention with SSP. Vomicine not only downregulated the levels of cGAS, TBK1, IL-6 and IFN-β mRNA, but also the levels of cGAS and STING protein in hSOD1[G93A] NSC-34 cells.

CONCLUSION: This study demonstrated that SSP and vomicine exert neuroprotective and anti-neuroinflammatory effects in the treatment of ALS. SSP and vomicine may reduce neuroinflammation by regulating the cGAS-STING-TBK1 pathway, and could thereby play a role in ALS treatment.}, } @article {pmid39198773, year = {2024}, author = {Lei, Y and Zhang, X and Liu, H and Xu, Z and Xu, P}, title = {Amyotrophic lateral sclerosis associated with Sjögren's syndrome: a case report.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {300}, pmid = {39198773}, issn = {1471-2377}, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/drug therapy/pathology ; *Sjogren's Syndrome/complications/diagnosis/drug therapy/pathology ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a chronic and progressive neurodegenerative disorder with an unknown cause. The development of amyotrophic lateral sclerosis (ALS) is believed to be linked to an immune response. Monocytes/macrophages and T cells are key players in the disease's advancement. Monitoring levels of cytokines in the blood can help forecast patient outcomes, while immunotherapy shows promise in alleviating symptoms for certain individuals.

CASE PRESENTATION: A 56-year-old male patient was admitted to the hospital due to progressive limb weakness persisting for eight months. The neurological examination revealed impairments in both upper and lower motor neurons, as well as sensory anomalies, without corresponding signs. Electrophysiological examination results indicated extensive neuronal damage and multiple peripheral nerve impairments, thereby the diagnosis was ALS. One month ago, the patient began experiencing symptoms of dry mouth and a bitter taste. Following tests for rheumatic immune-related antibodies and a lip gland biopsy, a diagnosis of Sjögren's syndrome (SS) was proposed. Despite treatment with medications such as hormones (methylprednisolone), immunosuppressants (hydroxychloroquine sulfate), and riluzole, the symptoms did not significantly improve, but also did not worsen.

CONCLUSION: It is recommended to include screening for SS in the standard assessment of ALS. Furthermore, research should focus on understanding the immune mechanisms involved in ALS, providing new insights for the diagnosis and treatment of ALS in conjunction with SS.}, } @article {pmid39199129, year = {2024}, author = {Percio, A and Cicchinelli, M and Masci, D and Summo, M and Urbani, A and Greco, V}, title = {Oxidative Cysteine Post Translational Modifications Drive the Redox Code Underlying Neurodegeneration and Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {8}, pages = {}, pmid = {39199129}, issn = {2076-3921}, abstract = {Redox dysregulation, an imbalance between oxidants and antioxidants, is crucial in the pathogenesis of various neurodegenerative diseases. Within this context, the "redoxome" encompasses the network of redox molecules collaborating to maintain cellular redox balance and signaling. Among these, cysteine-sensitive proteins are fundamental for this homeostasis. Due to their reactive thiol groups, cysteine (Cys) residues are particularly susceptible to oxidative post-translational modifications (PTMs) induced by free radicals (reactive oxygen, nitrogen, and sulfur species) which profoundly affect protein functions. Cys-PTMs, forming what is referred to as "cysteinet" in the redox proteome, are essential for redox signaling in both physiological and pathological conditions, including neurodegeneration. Such modifications significantly influence protein misfolding and aggregation, key hallmarks of neurodegenerative diseases such as Alzheimer's, Parkinson's, and notably, amyotrophic lateral sclerosis (ALS). This review aims to explore the complex landscape of cysteine PTMs in the cellular redox environment, elucidating their impact on neurodegeneration at protein level. By investigating specific cysteine-sensitive proteins and the regulatory networks involved, particular emphasis is placed on the link between redox dysregulation and ALS, highlighting this pathology as a prime example of a neurodegenerative disease wherein such redox dysregulation is a distinct hallmark.}, } @article {pmid39199265, year = {2024}, author = {Proaño, B and Benlloch, M and Sancho-Castillo, S and Privado, J and Bargues-Navarro, G and Sanchis-Sanchis, CE and Martínez Bolós, P and Carriquí-Suárez, AB and Cubero-Plazas, L and Platero Armero, JL and Escriva, D and Ceron, JJ and Tvarijonaviciute, A and de la Rubia Ortí, JE}, title = {Paraoxonase I Activity and Its Relationship with Nutrition in Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {8}, pages = {}, pmid = {39199265}, issn = {2076-3921}, support = {2021-203-003//Catholic University of Valencia San Vicente Mártir/ ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration, with oxidative stress playing a key role. Paraoxonase 1 (PON1) is an antioxidant enzyme that may influence ALS progression. This study aimed to establish a predictive model for the influence of PON1 activity on functionality in ALS patients and explore its relationship with nutrition. Methods: In this observational cross-sectional study, 70 ALS patients underwent assessments of PON1 activity, lipid profile, functional capacity, respiratory function, and heart rate variability. A structural equation model was developed to determine the relationships between variables. Nutritional intake was analyzed in 65 patients. Results: The predictive model showed that PON1 activity and LDL levels positively influenced functionality, both directly and indirectly through respiratory capacity. Heart rate variability moderately predicted functionality independently. HDL levels were not significantly associated with functionality. Weak to moderate correlations were found between PON1 activity and intake of certain nutrients, with positive associations for monounsaturated fats and vitamin D, and negative associations for carbohydrates, proteins, and some micronutrients. Conclusions: PON1 activity appears to play an important role in ALS patient functionality, both directly and through effects on respiratory capacity. However, its relationship with nutritional intake was not strongly evident in this sample population.}, } @article {pmid39199454, year = {2024}, author = {Calma, AD and van den Bos, M and Pavey, N and Santos Silva, C and Menon, P and Vucic, S}, title = {Physiological Biomarkers of Upper Motor Neuron Dysfunction in ALS.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199454}, issn = {2076-3425}, abstract = {Upper motor neuron (UMN) dysfunction is an important feature of amyotrophic lateral sclerosis (ALS) for the diagnosis and understanding of pathogenesis. The identification of UMN signs forms the basis of ALS diagnosis, although may be difficult to discern, especially in the setting of severe muscle weakness. Transcranial magnetic stimulation (TMS) techniques have yielded objective physiological biomarkers of UMN dysfunction in ALS, enabling the interrogation of cortical and subcortical neuronal networks with diagnostic, pathophysiological, and prognostic implications. Transcranial magnetic stimulation techniques have provided pertinent pathogenic insights and yielded novel diagnostic and prognostic biomarkers. Cortical hyperexcitability, as heralded by a reduction in short interval intracortical inhibition (SICI) and an increase in short interval intracortical facilitation (SICF), has been associated with lower motor neuron degeneration, patterns of disease evolution, as well as the development of specific ALS clinical features including the split hand phenomenon. Reduction in SICI has also emerged as a potential diagnostic aid in ALS. More recently, physiological distinct inhibitory and facilitatory cortical interneuronal circuits have been identified, which have been shown to contribute to ALS pathogenesis. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction. Resting-state EEG is a novel neurophysiological technique developed for directly interrogating cortical neuronal networks in ALS, that have yielded potentially useful physiological biomarkers of UMN dysfunction. The present review discusses physiological biomarkers of UMN dysfunction in ALS, encompassing conventional and novel TMS techniques developed to interrogate the functional integrity of the corticomotoneuronal system, focusing on pathogenic, diagnostic, and prognostic utility.}, } @article {pmid39199498, year = {2024}, author = {Kleinerova, J and McKenna, MC and Finnegan, M and Tacheva, A and Garcia-Gallardo, A and Mohammed, R and Tan, EL and Christidi, F and Hardiman, O and Hutchinson, S and Bede, P}, title = {Clinical, Cortical, Subcortical, and White Matter Features of Right Temporal Variant FTD.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199498}, issn = {2076-3425}, support = {JPND-Cofund-2-2019-1 & HRB EIA-2017-019//HRB/ ; }, abstract = {UNLABELLED: The distinct clinical and radiological characteristics of right temporal variant FTD have only been recently recognized.

METHODS: Eight patients with right temporal variant FTD were prospectively recruited and underwent a standardised neuropsychological assessment, clinical MRI, and quantitative neuroimaging.

RESULTS: Our voxelwise grey analyses captured bilateral anterior and mesial temporal grey matter atrophy with a clear right-sided predominance. Bilateral hippocampal involvement was also observed, as well as disease burden in the right insular and opercula regions. White matter integrity alterations were also bilateral in anterior temporal and sub-insular regions with a clear right-hemispheric predominance. Extra-temporal white matter alterations have also been observed in orbitofrontal and parietal regions. Significant bilateral but right-predominant thalamus, putamen, hippocampus, and amygdala atrophy was identified based on subcortical segmentation. The clinical profile of our patients was dominated by progressive indifference, decline in motivation, loss of interest in previously cherished activities, incremental social withdrawal, difficulty recognising people, progressive language deficits, increasingly rigid routines, and repetitive behaviours.

CONCLUSIONS: Right temporal variant FTD has an insidious onset and may be mistaken for depression at symptom onset. It manifests in a combination of apathy, language, and behavioural features. Quantitative MR imaging captures a characteristic bilateral but right-predominant temporal imaging signature with extra-temporal frontal and parietal involvement.}, } @article {pmid39199512, year = {2024}, author = {Turner, N and Faull, C and Palmer, J and Armstrong, A and Bedford, J and Turner, MR and Wilson, E}, title = {Understanding Quality of Life for People with Motor Neurone Disease Who Use Tracheostomy Ventilation and Family Members: A Scoping Review.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199512}, issn = {2076-3425}, support = {Wilson/Oct21/968-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Tracheostomy ventilation (TV) can increase survival time for people living with motor neurone disease (MND); however, the use of TV varies between countries. Concerns regarding anticipated quality of life (QoL) are among the reasons given by healthcare professionals for not recommending this intervention, yet little is known about QoL in this context. This scoping review was conducted to examine the evidence on QoL for those with MND who use TV and family members involved in their care. Using the methodological guidance of the Joanna Briggs Institute, 23 papers were identified for inclusion, and findings were inductively analysed to identify key themes. We found that people living with MND tend to rate QoL post TV more positively than anticipated by healthcare professionals or family members. QoL was found to be related to positive relationships and activities the person could maintain. Feeling able to make a choice and an adequate level of financial resources were also important factors. Family members tended to experience lower QoL, associated with the uncertainty surrounding an emergency procedure and the complexity of subsequently required care. More evidence on QoL from the perspectives of people with MND who use TV is needed to support decision making and inform guidance.}, } @article {pmid39199527, year = {2024}, author = {Ail, BE and Ramele, R and Gambini, J and Santos, JM}, title = {An Intrinsically Explainable Method to Decode P300 Waveforms from EEG Signal Plots Based on Convolutional Neural Networks.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199527}, issn = {2076-3425}, support = {ITBACyT-2020//Instituto Tecnológico de Buenos Aires (ITBA)/ ; }, abstract = {This work proposes an intrinsically explainable, straightforward method to decode P300 waveforms from electroencephalography (EEG) signals, overcoming the black box nature of deep learning techniques. The proposed method allows convolutional neural networks to decode information from images, an area where they have achieved astonishing performance. By plotting the EEG signal as an image, it can be both visually interpreted by physicians and technicians and detected by the network, offering a straightforward way of explaining the decision. The identification of this pattern is used to implement a P300-based speller device, which can serve as an alternative communication channel for persons affected by amyotrophic lateral sclerosis (ALS). This method is validated by identifying this signal by performing a brain-computer interface simulation on a public dataset from ALS patients. Letter identification rates from the speller on the dataset show that this method can identify the P300 signature on the set of 8 patients. The proposed approach achieves similar performance to other state-of-the-art proposals while providing clinically relevant explainability (XAI).}, } @article {pmid39200158, year = {2024}, author = {Zhao, M and Wang, J and Liu, M and Xu, Y and Huang, J and Zhang, Y and He, J and Gu, A and Liu, M and Liu, X}, title = {KIF1A, R1457Q, and P1688L Mutations Induce Protein Abnormal Aggregation and Autophagy Impairment in iPSC-Derived Motor Neurons.}, journal = {Biomedicines}, volume = {12}, number = {8}, pages = {}, pmid = {39200158}, issn = {2227-9059}, support = {2016YFC0905100//the National Key Research and Development Program of China/ ; 2021JJ30801//the Natural Science Foundation of Hunan Province, China/ ; kq2202077//the Natural Science Foundation of Changsha, China/ ; CX20230291//the Postgraduate Freedom Explo-ration Project of Central South University/ ; }, abstract = {Mutations in the C-terminal of KIF1A (Kinesin family member 1A) may lead to amyotrophic lateral sclerosis (ALS) through unknown mechanisms that are not yet understood. Using iPSC reprogramming technology and motor neuron differentiation techniques, we generated iPSCs from a healthy donor and two ALS patients with KIF1A mutations (R1457Q and P1688L) and differentiated them into spinal motor neurons (iPSC-MN) to investigate KIF1A-related ALS pathology. Our in vitro iPSC-iMN model faithfully recapitulated specific aspects of the disease, such as neurite fragmentation. Through this model, we observed that these mutations led to KIF1A aggregation at the proximal axon of motor neurons and abnormal accumulation of its transport cargo, LAMP1, resulting in autophagy dysfunction and cell death. RNAseq analysis also indicated that the functions of the extracellular matrix, structure, and cell adhesion were significantly disturbed. Notably, using rapamycin during motor neuron differentiation can effectively prevent motor neuron death.}, } @article {pmid39200200, year = {2024}, author = {Yoo, JK and Kwon, SH and Yoon, SH and Lee, JE and Jeon, JE and Chung, JH and Lee, SY}, title = {Preservation of Vocal Function in Amyotrophic Lateral Sclerosis (ALS) Patients Following Percutaneous Dilatational Tracheostomy (PDT) and Adjuvant Therapies.}, journal = {Biomedicines}, volume = {12}, number = {8}, pages = {}, pmid = {39200200}, issn = {2227-9059}, abstract = {UNLABELLED: The study aimed to evaluate the efficacy of percutaneous dilatational tracheostomy (PDT) combined with adjuvant therapies in preserving vocal function in amyotrophic lateral sclerosis (ALS) patients.

METHODS: We performed a retrospective analysis of 47 ALS patients who underwent PDT at the Rodem Hospital from 2021 to 2023. Post-operatively, these patients were provided with a comprehensive treatment plan that included regenerative injection therapy, low-frequency electrical stimulation, respiratory rehabilitation, and swallowing rehabilitation therapy. Additionally, a balloon reduction program was implemented for effective tracheostomy tube (T-tube) management. The preservation of vocal functions was evaluated 4 weeks following the procedure.

RESULTS: While some patients maintained or slightly improved their ALSFRS-R speech scores, the overall trend indicated a decrease in speech scores post-PDT. This suggests that PDT in combination with adjuvant therapies may not universally improve vocal function, but can help maintain it in certain cases.

CONCLUSIONS: Our findings indicate that PDT combined with mesotherapy, low-frequency electrical stimulation, and swallowing rehabilitation therapy may play a role in maintaining vocal function in limb type ALS patients, though further research is needed to optimize patient management and to validate these results.}, } @article {pmid39200952, year = {2024}, author = {Schwarzenbacher, L and Wassermann, L and Rezar-Dreindl, S and Reiter, GS and Schmidt-Erfurth, U and Stifter, E}, title = {An Analysis of Ocular Biometrics: A Comprehensive Retrospective Study in a Large Cohort of Pediatric Cataract Patients.}, journal = {Journal of clinical medicine}, volume = {13}, number = {16}, pages = {}, pmid = {39200952}, issn = {2077-0383}, abstract = {Objectives: This study aims to provide a comprehensive analysis of ocular biometric parameters in pediatric patients with cataracts to optimize surgical outcomes. By evaluating various biometric data, we seek to enhance the decision-making process for intraocular lens (IOL) placement, particularly with advanced technologies like femtosecond lasers. Methods: This retrospective comparative study included pediatric patients with cataracts who underwent ocular biometric measurements and cataract extraction with anterior vitrectomy at the Medical University of Vienna between January 2019 and December 2021. Parameters measured included corneal diameter (CD), axial length (AL), corneal thickness (CT) and flat and steep keratometry (Kf and Ks). The study explored the correlations between these parameters and IOL placement. Results: A total of 136 eyes from 68 pediatric patients were included in the study. Significant positive correlations were found between corneal diameter, age and AL. The mean CD was 11.4 mm, mean AL was 19.5 mm, CT was 581.2 ± 51.8 µm, Kf was 7.76 ± 0.55 mm and Ks 7.41 ± 0.59 mm, respectively. Older pediatric patients with larger corneal diameters and longer ALs were more likely to receive in-the-bag IOL implantation. Conversely, younger patients often required alternative IOL placements or remained aphakic. Our data indicated that over 95% of the study population and all patients aged one year and older had a corneal diameter of 10 mm or larger. Conclusions: Detailed ocular biometric analysis is crucial for optimizing both surgical outcomes and postoperative care in pediatric cataract patients. The positive correlations between CD, age and AL underline the importance of individualized surgical planning tailored to each patient's unique anatomical features. Additionally, our findings suggest that the use of a femtosecond laser is both feasible and safe for pediatric patients aged one year and older, potentially offering enhanced surgical precision and improved outcomes.}, } @article {pmid39201350, year = {2024}, author = {Bedja-Iacona, L and Richard, E and Marouillat, S and Brulard, C and Alouane, T and Beltran, S and Andres, CR and Blasco, H and Corcia, P and Veyrat-Durebex, C and Vourc'h, P}, title = {Post-Translational Variants of Major Proteins in Amyotrophic Lateral Sclerosis Provide New Insights into the Pathophysiology of the Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201350}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Protein Processing, Post-Translational ; *Superoxide Dismutase-1/genetics/metabolism ; *RNA-Binding Protein FUS/metabolism/genetics ; DNA-Binding Proteins/metabolism/genetics ; Protein Serine-Threonine Kinases/metabolism/genetics ; Mutation ; Animals ; Phosphorylation ; Acetylation ; }, abstract = {Post-translational modifications (PTMs) affecting proteins during or after their synthesis play a crucial role in their localization and function. The modification of these PTMs under pathophysiological conditions, i.e., their appearance, disappearance, or variation in quantity caused by a pathological environment or a mutation, corresponds to post-translational variants (PTVs). These PTVs can be directly or indirectly involved in the pathophysiology of diseases. Here, we present the PTMs and PTVs of four major amyotrophic lateral sclerosis (ALS) proteins, SOD1, TDP-43, FUS, and TBK1. These modifications involve acetylation, phosphorylation, methylation, ubiquitination, SUMOylation, and enzymatic cleavage. We list the PTM positions known to be mutated in ALS patients and discuss the roles of PTVs in the pathophysiological processes of ALS. In-depth knowledge of the PTMs and PTVs of ALS proteins is needed to better understand their role in the disease. We believe it is also crucial for developing new therapies that may be more effective in ALS.}, } @article {pmid39201466, year = {2024}, author = {Strong, MJ and McLellan, C and Kaplanis, B and Droppelmann, CA and Junop, M}, title = {Phase Separation of SARS-CoV-2 Nucleocapsid Protein with TDP-43 Is Dependent on C-Terminus Domains.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201466}, issn = {1422-0067}, support = {201806SOP-411481/CAPMC/CIHR/Canada ; not applicable//Temerty Family Foundation/ ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry ; Humans ; *SARS-CoV-2/metabolism/chemistry ; *Coronavirus Nucleocapsid Proteins/metabolism/chemistry/genetics ; *Protein Domains ; COVID-19/virology/metabolism ; Protein Binding ; Biomolecular Condensates/metabolism/chemistry ; RNA, Viral/metabolism/genetics ; Phosphoproteins/metabolism/chemistry ; Phase Separation ; }, abstract = {The SARS-CoV-2 nucleocapsid protein (N protein) is critical in viral replication by undergoing liquid-liquid phase separation to seed the formation of a ribonucleoprotein (RNP) complex to drive viral genomic RNA (gRNA) translation and in suppressing both stress granules and processing bodies, which is postulated to increase uncoated gRNA availability. The N protein can also form biomolecular condensates with a broad range of host endogenous proteins including RNA binding proteins (RBPs). Amongst these RBPs are proteins that are associated with pathological, neuronal, and glial cytoplasmic inclusions across several adult-onset neurodegenerative disorders, including TAR DNA binding protein 43 kDa (TDP-43) which forms pathological inclusions in over 95% of amyotrophic lateral sclerosis cases. In this study, we demonstrate that the N protein can form biomolecular condensates with TDP-43 and that this is dependent on the N protein C-terminus domain (N-CTD) and the intrinsically disordered C-terminus domain of TDP-43. This process is markedly accelerated in the presence of RNA. In silico modeling suggests that the biomolecular condensate that forms in the presence of RNA is composed of an N protein quadriplex in which the intrinsically disordered TDP-43 C terminus domain is incorporated.}, } @article {pmid39201731, year = {2024}, author = {Fang, C and Wu, J and Liang, W}, title = {Systematic Investigation of Aluminum Stress-Related Genes and Their Critical Roles in Plants.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201731}, issn = {1422-0067}, support = {242102111164; 222301420106//Key R&D and Promotion Projects in Henan Province; Henan Science & Technology Research and Development Plan Joint Fund/ ; }, mesh = {*Aluminum/toxicity ; *Stress, Physiological/genetics ; *Gene Expression Regulation, Plant/drug effects ; Plant Proteins/genetics/metabolism ; Zea mays/genetics/growth & development/metabolism/drug effects ; Plants/genetics/metabolism/drug effects ; Genes, Plant ; }, abstract = {Aluminum (Al) stress is a dominant obstacle for plant growth in acidic soil, which accounts for approximately 40-50% of the world's potential arable land. The identification and characterization of Al stress response (Al-SR) genes in Arabidopsis, rice, and other plants have deepened our understanding of Al's molecular mechanisms. However, as a crop sensitive to acidic soil, only eight Al-SR genes have been identified and functionally characterized in maize. In this review, we summarize the Al-SR genes in plants, including their classifications, subcellular localizations, expression organs, functions, and primarily molecular regulatory networks. Moreover, we predict 166 putative Al-SR genes in maize based on orthologue analyses, facilitating a comprehensive understanding of the impact of Al stress on maize growth and development. Finally, we highlight the potential applications of alleviating Al toxicity in crop production. This review deepens our understanding of the Al response in plants and provides a blueprint for alleviating Al toxicity in crop production.}, } @article {pmid39201793, year = {2024}, author = {Martin, LJ and Koh, SJ and Price, A and Park, D and Kim, BW}, title = {Nuclear Localization of Human SOD1 in Motor Neurons in Mouse Model and Patient Amyotrophic Lateral Sclerosis: Possible Links to Cholinergic Phenotype, NADPH Oxidase, Oxidative Stress, and DNA Damage.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201793}, issn = {1422-0067}, support = {R01 NS052098/NS/NINDS NIH HHS/United States ; R01 AG016282/AG/NIA NIH HHS/United States ; R01 NS034100/NS/NINDS NIH HHS/United States ; NS34100/NS/NINDS NIH HHS/United States ; R01 NS079348/NS/NINDS NIH HHS/United States ; R01 NS065895/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Cell Nucleus/metabolism ; Disease Models, Animal ; *DNA Damage ; *Induced Pluripotent Stem Cells/metabolism ; Mice, Transgenic ; *Motor Neurons/metabolism/pathology ; NADPH Oxidases/metabolism/genetics ; *Oxidative Stress ; Phenotype ; Spinal Cord/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease that causes degeneration of motor neurons (MNs) and paralysis. ALS can be caused by mutations in the gene that encodes copper/zinc superoxide dismutase (SOD1). SOD1 is known mostly as a cytosolic antioxidant protein, but SOD1 is also in the nucleus of non-transgenic (tg) and human SOD1 (hSOD1) tg mouse MNs. SOD1's nuclear presence in different cell types and subnuclear compartmentations are unknown, as are the nuclear functions of SOD1. We examined hSOD1 nuclear localization and DNA damage in tg mice expressing mutated and wildtype variants of hSOD1 (hSOD1-G93A and hSOD1-wildtype). We also studied ALS patient-derived induced pluripotent stem (iPS) cells to determine the nuclear presence of SOD1 in undifferentiated and differentiated MNs. In hSOD1-G93A and hSOD1-wildtype tg mice, choline acetyltransferase (ChAT)-positive MNs had nuclear hSOD1, but while hSOD1-wildtype mouse MNs also had nuclear ChAT, hSOD1-G93A mouse MNs showed symptom-related loss of nuclear ChAT. The interneurons had preserved parvalbumin nuclear positivity in hSOD1-G93A mice. hSOD1-G93A was seen less commonly in spinal cord astrocytes and, notably, oligodendrocytes, but as the disease emerged, the oligodendrocytes had increased mutant hSOD1 nuclear presence. Brain and spinal cord subcellular fractionation identified mutant hSOD1 in soluble nuclear extracts of the brain and spinal cord, but mutant hSOD1 was concentrated in the chromatin nuclear extract only in the spinal cord. Nuclear extracts from mutant hSOD1 tg mouse spinal cords had altered protein nitration, footprinting peroxynitrite presence, and the intact nuclear extracts had strongly increased superoxide production as well as the active NADPH oxidase marker, p47phox. The comet assay showed that MNs from hSOD1-G93A mice progressively (6-14 weeks of age) accumulated DNA single-strand breaks. Ablation of the NCF1 gene, encoding p47phox, and pharmacological inhibition of NADPH oxidase with systemic treatment of apocynin (10 mg/kg, ip) extended the mean lifespan of hSOD1-G93A mice by about 25% and mitigated genomic DNA damage progression. In human postmortem CNS, SOD1 was found in the nucleus of neurons and glia; nuclear SOD1 was increased in degenerating neurons in ALS cases and formed inclusions. Human iPS cells had nuclear SOD1 during directed differentiation to MNs, but mutant SOD1-expressing cells failed to establish wildtype MN nuclear SOD1 levels. We conclude that SOD1 has a prominent nuclear presence in the central nervous system, perhaps adopting aberrant contexts to participate in ALS pathobiology.}, } @article {pmid39202683, year = {2024}, author = {Gianferrari, G and Zucchi, E and Martinelli, I and Simonini, C and Fini, N and Ferro, S and Mercati, A and Ferri, L and Filippini, T and Vinceti, M and Mandrioli, J}, title = {Trends in Hospital Admissions for Patients with Amyotrophic Lateral Sclerosis: Insights from a Retrospective Cohort Study in a Province in Northern Italy.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {8}, pages = {}, pmid = {39202683}, issn = {2075-1729}, support = {//Servizio sanitario dell'Emilia-Romagna/ ; not available//Emilia Romagna Regional Health Authority/ ; }, abstract = {ALS is characterized by a highly heterogeneous course, ranging from slow and uncomplicated to rapid progression with severe extra-motor manifestations. This study investigated ALS-related hospitalizations and their connection to clinical aspects, comorbidities, and prognosis. We performed a retrospective cohort study including patients residing in Modena, Italy, newly diagnosed between 2007 and 2017 and followed up until 31 December 2022. Data were obtained from the Emilia Romagna ALS registry, regional hospitals, and medical records. Among the 249 patients, there were 492 hospital admissions, excluding those for diagnostic purposes; 63% of the patients had at least one hospitalization post-diagnosis, with an average stay of 19.90 ± 23.68 days. Younger patients were more likely to be hospitalized multiple times and experienced longer stays (44.23 ± 51.71 days if <65 years; 26.46 ± 36.02 days if older, p < 0.001). Patients who were hospitalized at least once more frequently underwent gastrostomy (64.97%) or non-invasive (66.24%) and invasive (46.50%) ventilation compared to those never hospitalized (21.74%, 31.52%, 13.04%, respectively, p < 0.001 for all). Emergency procedures led to longer hospitalizations (62.84 ± 48.91 days for non-invasive ventilation in emergencies vs. 39.88 ± 46.46 days electively, p = 0.012). Tracheostomy-free survival was not affected by hospitalizations. In conclusion, younger ALS patients undergo frequent and prolonged hospitalizations, especially after emergency interventions, although these do not correlate with reduced survival.}, } @article {pmid39203762, year = {2024}, author = {Zarco-Martín, MT and Freire, C and Andreo-López, MC and Leyva-Martínez, S and Fernández-Soto, ML}, title = {Malnutrition in Amyotrophic Lateral Sclerosis: Insights from Morphofunctional Assessment and Global Leadership Initiative on Malnutrition Criteria.}, journal = {Nutrients}, volume = {16}, number = {16}, pages = {}, pmid = {39203762}, issn = {2072-6643}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Female ; Male ; *Malnutrition/epidemiology/diagnosis ; Middle Aged ; Aged ; Cross-Sectional Studies ; *Nutrition Assessment ; Hand Strength ; Prevalence ; Nutritional Status ; Electric Impedance ; Severity of Illness Index ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease frequently accompanied by malnutrition due to weight loss, increased energy expenditure, and muscle mass loss. This study aimed to evaluate morphofunctional assessment tools as predictors of malnutrition and to investigate their relationship with muscle status and disease severity in ALS patients. A cross-sectional study was conducted with 45 ALS patients at the San Cecilio University Hospital in Granada. Malnutrition was assessed using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Morphofunctional assessment was performed using Bioimpedance Vectorial Analysis (BIVA), handgrip strength (HGS), and Short Physical Performance Battery (SPPB). Malnutrition prevalence was 38% according to GLIM criteria. Significant differences were observed between malnourished and non-malnourished groups in age (70 ± 9 vs. 62 ± 10 years, p = 0.01), sex (female prevalence: 58.8% vs. 25.0%, p = 0.02), dysphagia prevalence (83% vs. 29%, p < 0.001), PEG/PRG use (35.3% vs. 3.6%, p = 0.01), and ALSFRS-R scores (30 ± 12 vs. 34 ± 12, p = 0.02). Malnourished patients had lower values in anthropometric measurements, muscle mass obtained by BIVA, and phase angle (PA) (4.05 ± 0.8° vs. 5.09 ± 0.8°, p < 0.001). No significant differences were found in muscle strength or functional status. PA showed significant correlations with muscle strength (r = 0.52, p < 0.001) and muscle mass measures (r = 0.48, p < 0.001). Moreover, PA was associated with poorer disease progression and physical performance. In our sample, BIVA metrics such as PA (<4.3°), SPA (<-0.8), body cell mass (<9.2 kg/m), and extracellular water (>49.75%) were identified as malnutrition risk factors. The study underscores the critical importance of comprehensive morphofunctional assessment and the use of advanced diagnostic criteria, for early identification and intervention in malnutrition among people with ALS. Further research is warranted to validate these findings and develop targeted nutritional strategies into routine clinical practice.}, } @article {pmid39204338, year = {2024}, author = {O'Neill, R and Yoo, O and Burcham, P and Lim, LY}, title = {Edaravone for the Treatment of Motor Neurone Disease: A Critical Review of Approved and Alternative Formulations against a Proposed Quality Target Product Profile.}, journal = {Pharmaceutics}, volume = {16}, number = {8}, pages = {}, pmid = {39204338}, issn = {1999-4923}, support = {000990//Australian Government Research Training Program, Stan Perron Charitable Foundation/ ; }, abstract = {Edaravone is one of two main drugs for treating motor neurone disease (MND). This review proposes a specific quality target product profile (QTPP) for edaravone following an appraisal of the issues accounting for the poor clinical uptake of the approved IV and oral liquid edaravone formulations. This is followed by a review of the alternative oral formulations of edaravone described in the published patent and journal literature against the QTPP. A total of 14 texts published by six research groups on 18 novel oral formulations of edaravone for the treatment of MND have been reviewed. The alternative oral formulations included liquid and solid formulations developed with cyclodextrins, lipids, surfactants, co-surfactants, alkalising agents, tablet excipients, and co-solvents. Most were intended to deliver edaravone for drug absorption in the lower gastrointestinal tract (GIT); however, there were also four formulations targeting the oral mucosal absorption of edaravone to avoid first-pass metabolism. All the novel formulations improved the aqueous solubility, stability, and oral bioavailability (BA) of edaravone compared to an aqueous suspension of edaravone. A common limitation of the published formulations is the lack of MND-patient-centred data. Except for TW001, no other formulations have been trialled in MND patients. To meet the QTPP of an oral edaravone formulation for MND patients, it is recommended that a tablet of appropriate size and with acceptable taste and stability be designed for the effective sublingual or buccal absorption of edaravone. This tablet should be designed with input from the MND community.}, } @article {pmid39204741, year = {2024}, author = {Xu, X and Zhao, B and Shen, B and Qi, Z and Wang, J and Cui, H and Li, B and Chen, S and Wang, G and Liu, X}, title = {Using RNA-Seq Analysis to Select Key Genes Related to Seed Dormancy in ALS-Inhibiting Resistant Descurainia sophia with Pro-197-Thr Mutation.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {16}, pages = {}, pmid = {39204741}, issn = {2223-7747}, support = {2024060203//Basic Research Funds of Hebei Academy of Agriculture and Forestry Sciences/ ; 2023LYS03//HAAFS Youth Innovation Fund Project/ ; 2022KJCXZX-LYS-13//HAAFS Science and Technology Innovation Special Project/ ; }, abstract = {Flixweed (Descurainia sophia) is a weed that seriously affects wheat fields in China. Over the past 20 years, it has evolved resistance to the herbicide tribenuron-methyl. In the present study, a resistant D. sophia population with a Pro-197-Thr mutation of acetolactate synthetase (ALS) was found to have a resistance index of 457.37 for tribenuron-methyl. Under the same growth conditions, the seeds of resistant (R) and susceptible (S) populations exhibited similar vitality but the germination rates of R seeds were higher than those of S seeds. This result demonstrated that seed dormancy periods were shorter in the R seeds. RNA-Seq transcriptome analysis was then used to choose candidate genes that could regulate seed dormancy pathways in the R population. A total of 504,976,046 clean reads were selected from nine RNA-Seq libraries and assembled into 79,729 unigenes. Among these, 33,476 unigenes were assigned to 51 GO subgroups, and 26,117 unigenes were assigned to 20 KEGG secondary metabolic pathways. Next, 2473 differentially expressed genes (DEGs) were divided into three groups, as follows: G-24 h (germinating seeds) vs. D (dormant seeds); G-48 h (germinated seeds) vs. D; and G-48 h vs. G-24 h. From these 2473 DEGs, 8 were selected as candidate dormancy unigenes for the R population if their expression levels continuously decreased during the seed germination progress and their functional annotations were related to plant seed dormancy. One candidate unigene was annotated as CYP707A2; two unigenes were annotated as the transcription factors TGA4 and TGA2; one unigene was annotated as the cystathionine beta-synthase gene; and four unigenes could not be annotated as any gene listed in the six public databases. However, qRT-PCR-validated results showed that, during the germination of R seeds, the expression of the three candidate unigenes first decreased and then increased, indicating that they may have other growth-regulating functions in R populations. In brief, the dormancy function of the eight candidate dormancy unigenes needs to be further studied.}, } @article {pmid39205388, year = {2024}, author = {Jafarinia, H and Van der Giessen, E and Onck, PR}, title = {C9orf72 polyPR interaction with the nuclear pore complex.}, journal = {Biophysical journal}, volume = {123}, number = {20}, pages = {3533-3539}, pmid = {39205388}, issn = {1542-0086}, mesh = {*Nuclear Pore/metabolism/chemistry ; *C9orf72 Protein/genetics/metabolism/chemistry ; *Molecular Dynamics Simulation ; Nuclear Pore Complex Proteins/metabolism/chemistry/genetics ; Protein Binding ; Saccharomyces cerevisiae/metabolism/genetics ; Active Transport, Cell Nucleus ; Humans ; }, abstract = {The C9orf72 gene associated with amyotrophic lateral sclerosis/frontotemporal dementia is translated to five dipeptide repeat proteins, among which poly-proline-arginine (PR) is the most toxic in cell and animal models, contributing to a variety of cellular defects. It has been proposed that polyPR disrupts nucleocytoplasmic transport (NCT) through several mechanisms including accumulation in the nuclear pore complex (NPC), accumulation in the nucleolus, and direct interactions with transport receptors. The NPC, which is the key regulator of transport between the cytoplasm and nucleus, plays a central role in these suggested mechanisms. Exploring polyPR interaction with the NPC provides valuable insight into the molecular details of polyPR-mediated NCT defects. To address this, we use coarse-grained molecular dynamics models of polyPR and the yeast NPC lined with intrinsically disordered FG-nucleoporins (FG-Nups). Our findings indicate no aggregation of polyPR within the NPC or permanent binding to FG-Nups. Instead, polyPR translocates through the NPC, following a trajectory through the central low-density region of the pore. In the case of longer polyPRs, we observe a higher energy barrier for translocation and a narrower translocation channel. Our study shows that polyPR and FG-Nups are mainly engaged in steric interactions inside the NPC with only a small contribution of specific cation-pi, hydrophobic, and electrostatic interactions, allowing polyPR to overcome the entropic barrier of the NPC in a size-dependent manner.}, } @article {pmid39206217, year = {2024}, author = {Uzelac, Z and Schwäble, B and Dorst, J and Rosenbohm, A and Wollinsky, K and Wurster, CD and Steinbreier, JS and Ludolph, AC}, title = {Pattern of pareses in 5q-spinal muscular atrophy.}, journal = {Therapeutic advances in neurological disorders}, volume = {17}, number = {}, pages = {17562864241263420}, pmid = {39206217}, issn = {1756-2856}, abstract = {BACKGROUND: This prospective study investigates the pattern of pareses in 5q-associated spinal muscular atrophy (SMA) to identify disease-specific characteristics and potential differences from amyotrophic lateral sclerosis (ALS) and spinobulbar muscular atrophy (SBMA). Detailed knowledge about pareses patterns in SMA facilitates differential diagnosis and supports therapeutic monitoring.

METHODS: Between January 2021, and June 2021, 66 SMA patients (59.1% male, aged 33.6 ± 15.2 years) were included in the study. Most patients had SMA type II (n = 28) or SMA type III (n = 28), seven patients had SMA type I, and three patients had SMA type IV. We analyzed the pattern of pareses using the UK Medical Research Council (MRC) scoring system.

RESULTS: In both, upper and lower limbs muscle weakness was less pronounced in distal (upper limbs: MRC median 3.0 (interquartile range 1.5-3.5); lower limbs: 1.5 (0.5-3.0)) compared to proximal muscle groups (upper limbs: 2.0 (1.5-2.6); p < 0.001; lower limbs: 0.5 (0.5-1.5); p < 0.001). Thenar muscles were stronger than other small hand muscles (3.0 (2.0-3.5) vs 3.0 (1.5-3.5); p = 0.004). Muscles had more strength in upper (2.3 (1.5-3.1)) compared to lower limbs (1.1 (0.5-2.3); p < 0.001) and in flexors compared to extensors.

CONCLUSION: We identified a specific pattern of muscle paresis in SMA which is different from the pattern of paresis in ALS and SBMA. As a rule of thumb, the pattern of pareses is similar, but not identical to ALS in distal, but different in proximal muscle groups.}, } @article {pmid39206288, year = {2024}, author = {Cui, Y and Li, C and Ke, B and Xiao, Y and Wang, S and Jiang, Q and Zheng, X and Lin, J and Huang, J and Shang, H}, title = {Protective role of serum albumin in dementia: a prospective study from United Kingdom biobank.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1458184}, pmid = {39206288}, issn = {1664-2295}, abstract = {BACKGROUND: A number of studies have explored the link between neurodegenerative disorders (NDDs) and albumin, the main protein in human plasma. However, the results have been inconsistent, highlighting the necessity for a detailed systemic analysis.

METHODS: Utilizing data from the United Kingdom Biobank, we investigated the relationship between baseline levels of serum and urine albumin and the occurrence of common NDDs, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and dementia, employing Cox proportional hazards regression analysis.

RESULTS: Our results reveal that elevated baseline serum albumin levels are linked to a decreased risk of developing dementia (beta = -0.024, SE = 0.004, p < 0.001). Subgroup and interaction analyses highlighted the impact of factors like body mass index (BMI), age, and alcohol consumption on this relationship. Specifically, participants with higher BMI, younger age, or lower alcohol intake exhibited a stronger protective effect. On the other hand, a higher baseline level of urine microalbumin was connected to a slight increase in dementia risk (beta = 0.003, SE = 3.30E-04, p < 0.001). No significant associations were found between albumin levels and the risk of PD or ALS.

CONCLUSION: Our study underscores the potential role of serum albumin as a biomarker associated with reduced dementia risk. These findings contribute valuable insights into the understanding of albumin's impact on NDDs, suggesting its utility as a biomarker for dementia in clinical settings and informing future therapeutic strategies in clinical trials.}, } @article {pmid39206899, year = {2024}, author = {Ma, J and Liu, J and Chen, S and Zhang, W and Wang, T and Cao, M and Yang, Y and Du, Y and Cui, G and Du, Z}, title = {Understanding the Mechanism of Ferroptosis in Neurodegenerative Diseases.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {8}, pages = {291}, doi = {10.31083/j.fbl2908291}, pmid = {39206899}, issn = {2768-6698}, support = {81602893//National Natural Science Foundation of China (NSFC)/ ; ZR2015YL049//Natural Science Foundation of Shandong Province/ ; ZR2021MH218//Natural Science Foundation of Shandong Province/ ; ZR2022MH184//Natural Science Foundation of Shandong Province/ ; 202104020224//Shandong Province Medical and Health Technology Development Plan/ ; 202312010854//Shandong Province Medical and Health Technology Development Plan/ ; Z-2023114//Shandong Province Traditional Chinese Medicine Science and Technology Plan/ ; 202328074//Jinan Science and Technology Plan/ ; }, mesh = {*Ferroptosis/physiology ; Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Iron/metabolism ; Animals ; Neurons/metabolism/pathology ; }, abstract = {Neurodegenerative disorders are typified by the progressive degeneration and subsequent apoptosis of neuronal cells. They encompass a spectrum of conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, brian ischemia, brian injury, and neurodegeneration with brain iron accumulation (NBIA). Despite the considerable heterogeneity in their clinical presentation, pathophysiological underpinning and disease trajectory, a universal feature of these disorders is the functional deterioration of the nervous system concomitant with neuronal apoptosis. Ferroptosis is an iron (Fe)-dependent form of programmed cell death that has been implicated in the pathogenesis of these conditions. It is intricately associated with intracellular Fe metabolism and lipid homeostasis. The accumulation of Fe is observed in a variety of neurodegenerative diseases and has been linked to their etiology and progression, although its precise role in these pathologies has yet to be elucidated. This review aims to elucidate the characteristics and regulatory mechanisms of ferroptosis, its association with neurodegenerative diseases, and recent advances in ferroptosis-targeted therapeutic strategies. Ferroptosis may therefore be a critical area for future research into neurodegenerative diseases.}, } @article {pmid39207268, year = {2024}, author = {Han, H and Guo, G and Zhang, S and Peng, R and Xia, C}, title = {Reduced Surface Area for the Oxygen Reduction Reaction in Porous Electrode via Electrical Conductivity Relaxation.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {30}, number = {68}, pages = {e202402785}, doi = {10.1002/chem.202402785}, pmid = {39207268}, issn = {1521-3765}, support = {(2021YFB4001401//the National Key R&D Program of China/ ; 52272247//the National Natural Science Foundation of China/ ; }, abstract = {Oxygen reduction reaction (ORR) performance of porous electrodes is critical for solid oxide fuel cells (SOFCs). However, the effects of gas diffusion on the ORR in porous media need further investigation, although some issues, such as nonthermal surface oxygen exchange, have been attributed to gas diffusion. Herein, La0.6Sr0.4Co0.2Fe0.8O3-δ (LSCF) with various porosity, pore radii, and gas permeability were investigated via the electrical conductivity relaxation method and analysed via the distributed of characteristic time (DCT) model. The ORR is revealed with three characteristic times, which are gas diffusion, oxygen exchange via the surface corresponding to small pores, and oxygen exchange to large pores. Gas diffusion delays the oxygen surface exchange reaction, resulting in a very low chemical oxygen surface exchange coefficient compared with that obtained with dense samples under the assumption that all the surfaces are active for the ORR. Reduced surface area is thus defined to quantitatively represent the gas diffusion effects. The reduced surface area increases with increasing gas permeability, demonstrating the importance of electrode engineering for fast gas transport. Moreover, reduced surface area is suggested for replacing the specific surface area to calculate the electrode polarization impedance via the ALS model.}, } @article {pmid39207520, year = {2024}, author = {Bjelica, B and Petri, S}, title = {Narrative review of diagnosis, management and treatment of dysphagia and sialorrhea in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6508-6513}, pmid = {39207520}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/diagnosis ; *Sialorrhea/etiology/therapy/diagnosis ; *Deglutition Disorders/etiology/therapy/diagnosis/physiopathology ; Disease Management ; }, abstract = {The degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) frequently leads bulbar symptoms like dysarthria, dysphagia, and sialorrhea, in approximately one-third of cases being the initial symptom. Throughout the disease, more than two-thirds of ALS patients experience dysphagia, regardless of the region of onset. In this review, we aimed to offer an updated overview of dysphagia and sialorrhea in ALS, covering its diagnosis, monitoring, and treatment in clinical practice. Regular assessment of dysphagia and sialorrhea during each patient visit is essential and should be a standard aspect of ALS care. Early discussion of potential treatments such as high-calorie diets or percutaneous endoscopic gastrostomy (PEG) is crucial. Furthermore, this review highlights and discusses potential areas for improvement in both clinical practice and research.}, } @article {pmid39207709, year = {2024}, author = {Awogbindin, I and Wanklin, M and Verkhratsky, A and Tremblay, MÈ}, title = {Microglia in Neurodegenerative Diseases.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {497-512}, pmid = {39207709}, issn = {2190-5215}, mesh = {*Microglia/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism ; Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/physiopathology ; Animals ; Parkinson Disease/metabolism ; }, abstract = {Neurodegenerative diseases are manifested by a progressive death of neural cells, resulting in the deterioration of central nervous system (CNS) functions, ultimately leading to specific behavioural and cognitive symptoms associated with affected brain regions. Several neurodegenerative disorders are caused by genetic variants or mutations, although the majority of cases are sporadic and linked to various environmental risk factors, with yet an unknown aetiology. Neuroglial changes are fundamental and often lead to the pathophysiology of neurodegenerative diseases. In particular, microglial cells, which are essential for maintaining CNS health, become compromised in their physiological functions with the exposure to environmental risk factors, genetic variants or mutations, as well as disease pathology. In this chapter, we cover the contribution of neuroglia, especially microglia, to several neurodegenerative diseases, including Nasu-Hakola disease, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, infectious disease-associated neurodegeneration, and metal-precipitated neurodegeneration. Future research perspectives for the field pertaining to the therapeutic targeting of microglia across these disease conditions are also discussed.}, } @article {pmid39207711, year = {2024}, author = {Holtman, IR and Glass, CK and Nott, A}, title = {Interpretation of Neurodegenerative GWAS Risk Alleles in Microglia and their Interplay with Other Cell Types.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {531-544}, pmid = {39207711}, issn = {2190-5215}, mesh = {Humans ; *Microglia/metabolism ; *Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics ; *Genetic Predisposition to Disease ; Alleles ; Alzheimer Disease/genetics ; }, abstract = {Microglia have been implicated in numerous neurodegenerative and neuroinflammatory disorders; however, the causal contribution of this immune cell type is frequently debated. Genetic studies offer a unique vantage point in that they infer causality over a secondary consequence. Genome-wide association studies (GWASs) have identified hundreds of loci in the genome that are associated with susceptibility to neurodegenerative disorders. GWAS studies implicate microglia in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and to a lesser degree suggest a role for microglia in vascular dementia (VaD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and other neurodegenerative and neuropsychiatric disorders. The contribution and function of GWAS risk loci on disease progression is an ongoing field of study, in which large genomic datasets, and an extensive framework of computational tools, have proven to be crucial. Several GWAS risk loci are shared between disorders, pointing towards common pleiotropic mechanisms. In this chapter, we introduce key concepts in GWAS and post-GWAS interpretation of neurodegenerative disorders, with a focus on GWAS risk genes implicated in microglia, their interplay with other cell types and shared convergence of GWAS risk loci on microglia.}, } @article {pmid39207717, year = {2024}, author = {Ling, Y and Crotti, A}, title = {Emerging Microglial Therapies and Targets in Clinical Trial.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {623-637}, pmid = {39207717}, issn = {2190-5215}, mesh = {*Microglia/metabolism ; Humans ; Clinical Trials as Topic ; Neurodegenerative Diseases/drug therapy/therapy/metabolism ; Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Modulation of microglia function for treatment of neurodegenerative and neuropsychiatric disorders is an emerging field of neuroscience drug development. This is largely attributed to human genetic association studies combined with biological evidence indicating that the innate immune system acts as a causal contributor superimposed on the reactive component of neuronal loss in neurological dysfunction. The identification of disease risk gene variants that encode immune-modulatory proteins in microglia provides tools to evaluate how microglia cellular function or dysfunction affect neuronal health. The development of clinical stage therapeutic compounds that modify myeloid cell function enables us to investigate how modulating microglia function could become a transformational approach to mitigate neurological disorders. Improving our ability to boost microglia-promoting homeostatic and reparative functions hopefully will translate into achieving a better outcome for patients affected by neurological diseases. In this chapter, we aim to provide an overview of the microglial emerging therapies and targets being studied in current clinical trials.}, } @article {pmid39208794, year = {2024}, author = {Choi, ES and Hnath, B and Sha, CM and Dokholyan, NV}, title = {Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells.}, journal = {Structure (London, England : 1993)}, volume = {32}, number = {10}, pages = {1776-1792.e5}, pmid = {39208794}, issn = {1878-4186}, support = {R35 GM134864/GM/NIGMS NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; Male ; Mice ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Brain/metabolism ; Cell Cycle Proteins ; Models, Molecular ; *Motor Neurons/metabolism ; Muscle, Skeletal/metabolism ; *Protein Binding ; *Protein Multimerization ; *Septins/metabolism/genetics/chemistry ; Spinal Cord/metabolism ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; }, abstract = {Misfolded species of superoxide dismutase 1 (SOD1) are associated with increased death in amyotrophic lateral sclerosis (ALS) models compared to insoluble protein aggregates. The mechanism by which structurally independent SOD1 trimers cause cellular toxicity is unknown but may drive disease pathology. Here, we uncovered the SOD1 trimer interactome-a map of potential tissue-selective protein-binding partners in the brain, spinal cord, and skeletal muscle. We identified binding partners and key pathways associated with SOD1 trimers and found that trimers may affect normal cellular functions such as dendritic spine morphogenesis and synaptic function in the central nervous system and cellular metabolism in skeletal muscle. We discovered SOD1 trimer-selective enrichment of genes. We performed detailed computational and biochemical characterization of SOD1 trimer protein binding for septin-7. Our investigation highlights key proteins and pathways within distinct tissues, revealing a plausible intersection of genetic and pathophysiological mechanisms in ALS through interactions involving SOD1 trimers.}, } @article {pmid39209824, year = {2024}, author = {Vieira de Sá, R and Sudria-Lopez, E and Cañizares Luna, M and Harschnitz, O and van den Heuvel, DMA and Kling, S and Vonk, D and Westeneng, HJ and Karst, H and Bloemenkamp, L and Varderidou-Minasian, S and Schlegel, DK and Mars, M and Broekhoven, MH and van Kronenburg, NCH and Adolfs, Y and Vangoor, VR and de Jongh, R and Ljubikj, T and Peeters, L and Seeler, S and Mocholi, E and Basak, O and Gordon, D and Giuliani, F and Verhoeff, T and Korsten, G and Calafat Pla, T and Venø, MT and Kjems, J and Talbot, K and van Es, MA and Veldink, JH and van den Berg, LH and Zelina, P and Pasterkamp, RJ}, title = {ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {7484}, pmid = {39209824}, issn = {2041-1723}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Ataxin-2/genetics/metabolism ; Humans ; Animals ; *Peptides/metabolism/genetics ; Mice ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; *Disease Models, Animal ; *Mice, Transgenic ; DNA-Binding Proteins/genetics/metabolism ; Phenotype ; Male ; Female ; Mitochondria/metabolism ; Neurites/metabolism ; }, abstract = {Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we combine patient-derived and mouse models to dissect the effects of ATXN2 intermediate expansions in an ALS background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage and abnormal electrophysiological properties compared to healthy control and other familial ALS mutations. In TDP-43[Tg]-ALS mice, ATXN2-Q33 causes reduced motor function, NMJ alterations, neuron degeneration and altered in vitro stress granule dynamics. Furthermore, gene expression changes related to mitochondrial function and inflammatory response are detected and confirmed at the cellular level in mice and human neuron and organoid models. Together, these results define pathogenic defects underlying ATXN2-ALS and provide a framework for future research into ATXN2-dependent pathogenesis and therapy.}, } @article {pmid39209890, year = {2024}, author = {Prabhakaran, A and Thirumoorthi, P and Sri Dhivya Krishnan, K}, title = {Design and development of an intelligent zone based master electronic control unit for power optimization in electric vehicles.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {20142}, pmid = {39209890}, issn = {2045-2322}, abstract = {The development of electric vehicles (EVs) has been incremental because EVs satisfy a significant demand for energy sources. Electronic control unit (ECU) is an important component that processes the electric signals received from various sensors for generating the control signals for the actuators. Automotive control systems were initially operated manually throughout the automotive revolution based on the responses of input signals received from ECUs and drivers. Most of the functions in EV are controlled by the ECU and every ECU consumes power at all times even if it is not in use. The larger power consumption of passive ECUs like adaptive lighting systems (ALS), automatic wiper systems (AWS) brake light systems (BLS), etc., affect the life of ECUs and the range of EVs. This article is primarily concerned with limiting power consumption by switching the power supply to the passive ECUs based on their requirements. Hence, to achieve the objective, the intelligent zone (i-zone) based master ECU is triggered to activate the slave ECUs. Designing suites including Proteus and KiCAD were used for designing the circuits including master as well as slave ECU. This prototype is built using three secondary ECUs such as ALS & AWS and BLS which are controlled using i-zone-based master ECU. The performance of this implemented design is evaluated, and it is discovered that almost 40% of the battery consumption is reduced. This i-zone-based master ECU and all its slave ECUs manage power while ensuring the safety and reliability of EVs.}, } @article {pmid39210467, year = {2024}, author = {Faggioli, G and Menotti, L and Marchesin, S and Chió, A and Dagliati, A and de Carvalho, M and Gromicho, M and Manera, U and Tavazzi, E and Di Nunzio, GM and Silvello, G and Ferro, N}, title = {An extensible and unifying approach to retrospective clinical data modeling: the BrainTeaser Ontology.}, journal = {Journal of biomedical semantics}, volume = {15}, number = {1}, pages = {16}, pmid = {39210467}, issn = {2041-1480}, support = {101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; }, mesh = {*Biological Ontologies ; Humans ; Retrospective Studies ; Amyotrophic Lateral Sclerosis ; Multiple Sclerosis ; Semantics ; }, abstract = {Automatic disease progression prediction models require large amounts of training data, which are seldom available, especially when it comes to rare diseases. A possible solution is to integrate data from different medical centres. Nevertheless, various centres often follow diverse data collection procedures and assign different semantics to collected data. Ontologies, used as schemas for interoperable knowledge bases, represent a state-of-the-art solution to homologate the semantics and foster data integration from various sources. This work presents the BrainTeaser Ontology (BTO), an ontology that models the clinical data associated with two brain-related rare diseases (ALS and MS) in a comprehensive and modular manner. BTO assists in organizing and standardizing the data collected during patient follow-up. It was created by harmonizing schemas currently used by multiple medical centers into a common ontology, following a bottom-up approach. As a result, BTO effectively addresses the practical data collection needs of various real-world situations and promotes data portability and interoperability. BTO captures various clinical occurrences, such as disease onset, symptoms, diagnostic and therapeutic procedures, and relapses, using an event-based approach. Developed in collaboration with medical partners and domain experts, BTO offers a holistic view of ALS and MS for supporting the representation of retrospective and prospective data. Furthermore, BTO adheres to Open Science and FAIR (Findable, Accessible, Interoperable, and Reusable) principles, making it a reliable framework for developing predictive tools to aid in medical decision-making and patient care. Although BTO is designed for ALS and MS, its modular structure makes it easily extendable to other brain-related diseases, showcasing its potential for broader applicability.Database URL https://zenodo.org/records/7886998 .}, } @article {pmid39210549, year = {2024}, author = {Yeo, CJJ and Simmons, Z}, title = {Caring for people living with ALS in Korea: challenges and possible paths forward.}, journal = {Muscle & nerve}, volume = {70}, number = {5}, pages = {881-883}, doi = {10.1002/mus.28241}, pmid = {39210549}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Republic of Korea/epidemiology ; Caregivers/psychology ; }, } @article {pmid39211392, year = {2024}, author = {Matsuo, K and Nagamatsu, J and Nagata, K and Umeda, R and Shiota, T and Morimoto, S and Suzuki, N and Aoki, M and Okano, H and Nakamori, M and Nishihara, H}, title = {Establishment of a novel amyotrophic lateral sclerosis patient (TARDBP [N345K/+])-derived brain microvascular endothelial cell model reveals defective Wnt/β-catenin signaling: investigating diffusion barrier dysfunction and immune cell interaction.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1357204}, pmid = {39211392}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease for which there is currently no curative treatment. The blood-brain barrier (BBB), multiple physiological functions formed by mainly specialized brain microvascular endothelial cells (BMECs), serves as a gatekeeper to protect the central nervous system (CNS) from harmful molecules in the blood and aberrant immune cell infiltration. The accumulation of evidence indicating that alterations in the peripheral milieu can contribute to neurodegeneration within the CNS suggests that the BBB may be a previously overlooked factor in the pathogenesis of ALS. Animal models suggest BBB breakdown may precede neurodegeneration and link BBB alteration to the disease progression or even onset. However, the lack of a useful patient-derived model hampers understanding the pathomechanisms of BBB dysfunction and the development of BBB-targeted therapies. In this study, we differentiated BMEC-like cells from human induced pluripotent stem cells (hiPSCs) derived from ALS patients to investigate BMEC functions in ALS patients. TARDBP [N345K/+] carrying patient-derived BMEC-like cells exhibited increased permeability to small molecules due to loss of tight junction in the absence of neurodegeneration or neuroinflammation, highlighting that BMEC abnormalities in ALS are not merely secondary consequences of disease progression. Furthermore, they exhibited increased expression of cell surface adhesion molecules like ICAM-1 and VCAM-1, leading to enhanced immune cell adhesion. BMEC-like cells derived from hiPSCs with other types of TARDBP gene mutations (TARDBP [K263E/K263E] and TARDBP [G295S/G295S]) introduced by genome editing technology did not show such BMEC dysfunction compared to the isogenic control. Interestingly, transactive response DNA-binding protein 43 (TDP-43) was mislocalized to cytoplasm in TARDBP [N345K/+] carrying model. Wnt/β-catenin signaling was downregulated in the ALS patient (TARDBP [N345K/+])-derived BMEC-like cells and its activation rescued the leaky barrier phenotype and settled down VCAM-1 expressions. These results indicate that TARDBP [N345K/+] carrying model recapitulated BMEC abnormalities reported in brain samples of ALS patients. This novel patient-derived BMEC-like cell is useful for the further analysis of the involvement of vascular barrier dysfunctions in the pathogenesis of ALS and for promoting therapeutic drug discovery targeting BMEC.}, } @article {pmid39215326, year = {2024}, author = {Carlton, J and Powell, P and Rowen, D and Williams, C and Griffiths, AW and Hobson, E and McDermott, C}, title = {Development of a novel patient reported outcome measure for health-related quality of life in amyotrophic lateral sclerosis (PROQuALS): study protocol.}, journal = {Health and quality of life outcomes}, volume = {22}, number = {1}, pages = {69}, pmid = {39215326}, issn = {1477-7525}, mesh = {*Amyotrophic Lateral Sclerosis/psychology/therapy ; Humans ; *Quality of Life/psychology ; *Patient Reported Outcome Measures ; Surveys and Questionnaires ; Research Design ; Psychometrics ; Cost-Benefit Analysis ; }, abstract = {BACKGROUND: Patient reported outcome measures (PROMs) can be used to assess the impact of health conditions upon an individual's health-related quality of life (HRQoL). Whilst PROMs have been used to quantify the HRQoL impact of amyotrophic lateral sclerosis (ALS), existing instruments may not fully capture what matters to people living with ALS (plwALS) or be appropriate to be used directly to inform the cost-effectiveness of new treatments. This highlights a need for a new condition-specific PROM that can both capture what's important to plwALS and be used in economic evaluation. This study has two key aims: 1) to produce a novel PROM for measuring HRQoL in plwALS (PROQuALS). 2) to value a set of items from the novel PROM to generate an associated preference-weighted measure (PWM) that will enable utility values to be generated.

METHODS: A mixed-methods study design will be conducted across three stages. Stage 1 involves concept elicitation and the generation of draft PROM content from a robust and comprehensive systematic review of HRQoL in ALS, with input from plwALS. Stage 2 consists of cognitive debriefing of the draft PROM content to ascertain its content validity (Stage 2a), followed by a psychometric survey (Stage 2b) to assess statistical performance. Evidence from Stage 2 will be used to make decisions on the final content and format of the novel PROM. Stage 3 will involve valuation and econometric modeling using health economics methods to generate preference weights, so a PWM derived from the novel PROM can be used in the cost-effectiveness analyses of treatments. Patient and clinical advisory groups will have critical, collaborative input throughout the project.

DISCUSSION: The novel PROM will be designed to comprehensively assess important aspects of HRQoL to plwALS and to quantify HRQoL in terms of subjective impact. The PROQuALS measure will be available for use in research and healthcare settings. The associated PWM component will extend and enable the use of PROQuALS in cost-effective analyses of new treatments for ALS.

TRIAL REGISTRATION: Not applicable.}, } @article {pmid39215690, year = {2024}, author = {Suwa, S and Ando, M and Nakashima, T and Horii, S and Anai, T and Takeyama, H}, title = {In Situ Raman Hyperspectral Analysis of Microbial Colonies for Secondary Metabolites Screening.}, journal = {Analytical chemistry}, volume = {96}, number = {37}, pages = {14909-14917}, pmid = {39215690}, issn = {1520-6882}, mesh = {*Spectrum Analysis, Raman/methods ; *Escherichia coli/metabolism/isolation & purification ; Anti-Bacterial Agents/analysis/metabolism ; Streptomyces/metabolism ; Least-Squares Analysis ; }, abstract = {Since the discovery of penicillin, a vast array of microbial antibiotics has been identified and applied in the medical field. Globally, the search for drug candidates via microbial screening is ongoing. Traditional screening methods, however, are time-consuming and require labor-intensive sample processing, significantly reducing throughput. This research introduces a Raman spectroscopy-based screening system tailored to the in situ analysis of microbial colonies on solid culture media. Employing multivariate curve resolution-alternating least-squares (MCR-ALS) for spectral decomposition, our approach reveals the production of secondary metabolites at the single colony level. We enhanced the microbial culture method, enabling direct, high signal-to-noise (S/N) ratio Raman spectroscopic measurements of colonies of Escherichia coli and actinomycetes species. Through semisupervised MCR analysis using the known spectra of actinorhodin and undecylprodigiosin as references, we accurately assessed the production of these compounds by Streptomyces coelicolor A3(2). Furthermore, we herein successfully detected the production of amphotericin B by Streptomyces nodosus, even in the absence of prior spectral information. This demonstrates the potential of our technique in the discovery of secondary metabolites. In addition to enabling the detection of the above-mentioned compounds, this analysis revealed the heterogeneity of the spatial distribution of their production in each colony. Our technique makes a significant contribution to the advancement of microbial screening, offering a rapid, efficient alternative to conventional methods and opening avenues for secondary metabolites discovery.}, } @article {pmid39215697, year = {2024}, author = {Burrows, DJ and McGown, A and Abduljabbar, O and Castelli, LM and Shaw, PJ and Hautbergue, GM and Ramesh, TM}, title = {RAN Translation of C9orf72-Related Dipeptide Repeat Proteins in Zebrafish Recapitulates Hallmarks of Amyotrophic Lateral Sclerosis and Identifies Hypothermia as a Therapeutic Strategy.}, journal = {Annals of neurology}, volume = {96}, number = {6}, pages = {1058-1069}, doi = {10.1002/ana.27068}, pmid = {39215697}, issn = {1531-8249}, support = {Apr17/854-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R024162/1/MRC_/Medical Research Council/United Kingdom ; BB/S005277/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; *Zebrafish ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; *Animals, Genetically Modified ; *Disease Models, Animal ; *Dipeptides ; Hypothermia, Induced/methods ; Frontotemporal Dementia/genetics/metabolism ; Humans ; Protein Biosynthesis/genetics/physiology ; }, abstract = {OBJECTIVE: Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A large body of evidence implicates dipeptide repeats (DPRs) proteins as one of the main drivers of neuronal injury in cell and animal models.

METHODS: A pure repeat-associated non-AUG (RAN) translation zebrafish model of C9orf72-ALS/FTD was generated. Embryonic and adult transgenic zebrafish lysates were investigated for the presence of RAN-translated DPR species and adult-onset motor deficits. Using C9orf72 cell models as well as embryonic C9orf72-ALS/FTD zebrafish, hypothermic-therapeutic temperature management (TTM) was explored as a potential therapeutic option for C9orf72-ALS/FTD.

RESULTS: Here, we describe a pure RAN translation zebrafish model of C9orf72-ALS/FTD that exhibits significant RAN-translated DPR pathology and progressive motor decline. We further demonstrate that hypothermic-TTM results in a profound reduction in DPR species in C9orf72-ALS/FTD cell models as well as embryonic C9orf72-ALS/FTD zebrafish.

INTERPRETATION: The transgenic model detailed in this paper provides a medium throughput in vivo research tool to further investigate the role of RAN-translation in C9orf72-ALS/FTD and further understand the mechanisms that underpin neuroprotective strategies. Hypothermic-TTM presents a viable therapeutic avenue to explore in the context of C9orf72-ALS/FTD. ANN NEUROL 2024;96:1058-1069.}, } @article {pmid39216080, year = {2024}, author = {Mazurie, Z and Branchereau, P and Cattaert, D and Henkous, N and Savona-Baron, C and Vouimba, RM}, title = {Acute stress differently modulates interneurons excitability and synaptic plasticity in the primary motor cortex of wild-type and SOD1[G93A] mouse model of ALS.}, journal = {The Journal of physiology}, volume = {602}, number = {19}, pages = {4987-5015}, doi = {10.1113/JP285210}, pmid = {39216080}, issn = {1469-7793}, support = {GPR BRAIN-2030//Université de Bordeaux (University of Bordeaux)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics ; *Interneurons/physiology ; *Neuronal Plasticity ; *Motor Cortex/physiopathology ; Mice ; Male ; *Mice, Transgenic ; Disease Models, Animal ; Stress, Psychological/physiopathology ; Superoxide Dismutase-1/genetics ; Mice, Inbred C57BL ; }, abstract = {Primary motor cortex (M1) network stability depends on activity of inhibitory interneurons, for which susceptibility to stress was previously demonstrated in limbic regions. Hyperexcitability in M1 following changes in the excitatory/inhibitory balance is a key pathological hallmark of amyotrophic lateral sclerosis (ALS). Using electrophysiological approaches, we assessed the impact of acute restraint stress on inhibitory interneurons excitability and global synaptic plasticity in M1 of the SOD1[G93A] ALS mouse model at a late pre-symptomatic stage (10-12.5 weeks). Based on their firing type (continuous, discontinuous, with accommodation or not) and electrophysiological characteristics (resting potential, rheobase, firing frequency), interneurons from M1 slices were separated into four clusters, labelled from 1 to 4. Among them, only interneurons from the first cluster, presenting continuous firing with few accommodations, tended to show increased excitability in wild-type (WT) and decreased excitability in SOD1[G93A] animals following stress. In vivo analyses of evoked field potentials showed that stress suppressed the theta burst-induced plasticity of an excitatory component (N1) recorded in the superficial layers of M1 in WT, with no impact on an inhibitory complex (N2-P1) from the deeper layers. In SOD1[G93A] mice, stress did not affect N1 but suppressed the N2-P1 plasticity. These data suggest that stress can alter M1 network functioning in a different manner in WT and SOD1[G93A] mice, possibly through changes of inhibitory interneurons excitability and synaptic plasticity. This suggests that stress-induced activity changes in M1 may therefore influence ALS outcomes. KEY POINTS: Disruption of the excitatory/inhibitory balance in the primary motor cortex (M1) has been linked to cortical hyperexcitability development, a key pathological hallmark of amyotrophic lateral sclerosis (ALS). Psychological stress was reported to influence excitatory/inhibitory balance in limbic regions, but very little is known about its influence on the M1 functioning under physiological or pathological conditions. Our study revealed that acute stress influences the excitatory/inhibitory balance within the M1, through changes in interneurons excitability along with network plasticity. Such changes were different in pathological (SOD1[G93A] ALS mouse model) vs. physiological (wild-type) conditions. The results of our study help us to better understand how stress modulates the M1 and highlight the need to further characterize stress-induced motor cortex changes because it may be of importance when evaluating ALS outcomes.}, } @article {pmid39216161, year = {2024}, author = {Wang, J and Qi, J and Ouyang, Y and Zhou, S and Qin, L and Zhang, B and Bai, L and Pan, L}, title = {The mutation Asp-376-Glu in the ALS gene confers resistance to mesosulfuron-methyl in Beckmannia syzigachne.}, journal = {Plant physiology and biochemistry : PPB}, volume = {215}, number = {}, pages = {109083}, doi = {10.1016/j.plaphy.2024.109083}, pmid = {39216161}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Sulfonylurea Compounds/pharmacology ; *Mutation ; Plant Proteins/genetics/metabolism ; Poaceae/genetics/drug effects ; Molecular Docking Simulation ; Plant Weeds/genetics/drug effects ; }, abstract = {Understanding the mechanisms by which weeds develop herbicide resistance is crucial for managing resistance effectively and optimizing herbicide use. Beckmannia syzigachne, a harmful grass weed prevalent in wheat and rice-wheat rotation areas, poses a significant threat to crop productivity. A field herbicide resistance survey identified a resistant population with a new ALS mutation (Asp-376-Glu). The Glu-376-Asp population displayed varying resistance levels to seven ALS herbicides, verified using the dCAPS method. qRT-PCR analysis showed that no significant difference existed in the ALS gene expression between the Asp-376-Glu and S populations. P450 and GST inhibitors failed to reverse resistance to mesosulfuron-methyl, suggesting no involvement of P450- and GST-based metabolic resistance. Molecular docking indicated that the Asp-376-Glu mutation reduces the binding affinity between ALS-inhibitors and BsALS. The findings provide valuable insights into herbicide resistance mechanisms for weed resistance control.}, } @article {pmid39217293, year = {2024}, author = {Aljthalin, R and Albalawi, R and Alyahya, A and Alhathlool, R and Alhashemi, M}, title = {Multiple sclerosis and amyotrophic lateral sclerosis: is there an association or a red flag? A case report and literature review.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {307}, pmid = {39217293}, issn = {1471-2377}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/pathology ; Middle Aged ; *Multiple Sclerosis/complications/diagnosis/pathology ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that causes damage to the myelin and axons and is caused by genetic or environmental factors. Amyotrophic lateral sclerosis (ALS) is characterized by rapidly progressive degeneration of the motor neurons resulting in the presence of upper and lower motor-neuron signs and symptoms.

CASE PRESENTATION: A 46-year-old female patient presented with symmetrical weakness of the lower limbs and numbness that developed over weeks. Magnetic resonance imaging (MRI) of the brain exhibited typical demyelination features, high signal abnormality involving the periventricular and subcortical white matter, and an oval-shaped lesion. The patient was diagnosed with MS based on the clinical presentation and radiological examination. However, there was rapid progression of the symptoms, involvement of bulbar dysfunction, and muscle atrophy. Furthermore, the patient did not respond to acute therapy and immunotherapy, which made the diagnosis of MS less likely or suggested that it could be associated with another diagnosis. Her neurophysiological test met the criteria of ALS, and she was started on riluzole.

LITERATURE REVIEW: We reviewed all articles from 1986 to 2023, and there were 32 reported cases describing the co-occurrence of ALS and MS in different populations. Our case is the 33rd, and to our knowledge, it is the only case reported in the Middle East and specifically in Saudi Arabia. The main proposed mechanism according to postmortem examinations is a combination of degenerative and inflammatory processes with a cascade of production of reactive oxygen species and nitric oxide, which lead to cell death and apoptosis during concomitant ALS with MS.

CONCLUSION: The co-occurrence of ALS and MS is extremely rare, but it can be explained by pathogenesis related to neurodegeneration, inflammation, or genetic susceptibility. Rapid progressive motor and bulbar symptoms could be red-flag symptoms, extensive evaluation might be needed for these patients.}, } @article {pmid39217855, year = {2024}, author = {Zhang, J and Chen, K and Chen, Y and Hua, L and Chen, S and Chen, X and Zou, L and Li, S and Yang, X and Shen, Y}, title = {Pathology reduction and motor behavior improvement associated with ultrasound-mediated delivery of arctiin to the motor cortex in a mutant SOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {Ultrasonics}, volume = {144}, number = {}, pages = {107449}, doi = {10.1016/j.ultras.2024.107449}, pmid = {39217855}, issn = {1874-9968}, mesh = {Animals ; Male ; Mice ; *Amyotrophic Lateral Sclerosis ; *Disease Models, Animal ; Drug Delivery Systems ; Furans/pharmacology/administration & dosage ; Glucosides/pharmacology/administration & dosage ; *Mice, Transgenic ; Microbubbles ; *Motor Cortex/drug effects/physiopathology ; Mutation ; Superoxide Dismutase-1/genetics ; Ultrasonic Therapy/methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is marked by the deterioration of both cortical and spinal cord motor neurons. Despite the underlying causes of the disease remain elusive, there has been a growing attention on the well-being of cortical motor neurons in recent times. Focused ultrasound combined with microbubbles (FUS/MB) for opening the blood-brain barrier (BBB) provides a means for drug delivery to specific brain regions, holding significant promise for the treatment of neurological disorders.

OBJECTIVES: We aim to explore the outcomes of FUS/MB-mediated delivery of arctiin (Arc), a natural compound with anti-inflammatory activities, to the cerebral motor cortex area by using a transgenic ALS mouse model.

METHODS: The ALS mouse model with the SOD1[G93A] mutation was used and subjected to daily Arc administration with FUS/MB treatment twice a week. After six-week treatments, the motor performance was assessed by grip strength, wire hanging, and climbing-pole tests. Mouse brains, spinal cords and gastrocnemius muscle were harvested for histological staining.

RESULTS: Compared with the mice given Arc administration only, the combined treatments of FUS/MB with Arc induced further mitigation of the motor function decline, accompanied by improved health of the gastrocnemius muscle. Furthermore, notable neuroprotective effect was evidenced by the amelioration of motor neuron failure in the cortex and lumbar spinal cord.

CONCLUSION: These preliminary results indicated that the combined treatment of FUS/MB and arctiin exerted a potentially beneficial effect on neuromuscular function in the ALS disease.}, } @article {pmid39218010, year = {2024}, author = {Shojaie, A and Al Khleifat, A and Garrahy, S and Habash-Bailey, H and Thomson, R and Opie-Martin, S and Javidnia, S and Leigh, PN and Al-Chalabi, A}, title = {Investigating the impact of socioeconomic status on amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {702-707}, pmid = {39218010}, issn = {2167-9223}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/economics ; Male ; Female ; Middle Aged ; *Social Class ; Aged ; Adult ; Age of Onset ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the gradual death of motor neurons in the brain and spinal cord, leading to fatal paralysis. Socioeconomic status (SES) is a measure of an individual's shared economic and social status, which has been shown to have an association with health outcomes. Understanding the impact of SES on health conditions is crucial, as it can influence and be influenced by health-related variables. The role of socioeconomic status in influencing the risk and progression of ALS has not been established, and understanding the various factors that impact ALS is important in developing strategies for treatment and prevention. To investigate this relationship, we recruited 413 participants with definite, probable, or possible ALS according to the El Escorial criteria, from three tertiary centers in London, Sheffield, and Birmingham. Logistic regression was used to examine the association between case-control status, socioeconomic criteria, and ALS risk. Linear regression was used to examine the association between age of onset and socioeconomic variables. Two sensitivity analyses were performed, one using an alternative occupational classifier, and the other using Mendelian Randomization analysis to examine association. There was no significant relationship between any variables and ALS risk. We found an inverse relationship between mean lifetime salary and age of ALS onset (Beta = -0.157, p = 0.011), but no effect of education or occupation on the age of onset. The finding was confirmed in both sensitivity analyses and in Mendelian Randomization. We find that a higher salary is associated with a younger age of ALS onset taking into account sex, occupation, years of education, and clinical presentation.}, } @article {pmid39218293, year = {2024}, author = {Dibaj, P and Safavi-Abbasi, S and Asadollahi, E}, title = {In vivo spectrally unmixed multi-photon imaging of longitudinal axon-glia changes in injured spinal white matter.}, journal = {Neuroscience letters}, volume = {841}, number = {}, pages = {137959}, doi = {10.1016/j.neulet.2024.137959}, pmid = {39218293}, issn = {1872-7972}, mesh = {Animals ; *White Matter/pathology/metabolism/diagnostic imaging ; *Spinal Cord Injuries/pathology/metabolism/diagnostic imaging ; *Axons/pathology/metabolism ; *Mice, Transgenic ; Neuroglia/metabolism/pathology ; Mice ; Microscopy, Fluorescence, Multiphoton/methods ; Spinal Cord/pathology/metabolism ; Microglia/metabolism/pathology ; Astrocytes/metabolism/pathology ; }, abstract = {Understanding the sequence of cellular responses and their contributions to pathomorphogical changes in spinal white matter injuries is a prerequisite for developing efficient therapeutic strategies for spinal cord injury (SCI) as well as neurodegenerative and inflammatory diseases of the spinal cord such as amyotrophic lateral sclerosis and multiple sclerosis. We have developed several types of surgical procedures suitable for acute one-time and chronic recurrent in vivo multiphoton microscopy of spinal white matter [1]. Sophisticated surgical procedures were combined with transgenic mouse technology to image spinal tissue labeled with up to four fluorescent proteins (FPs) in axons, astrocytes, microglia, and blood vessels. To clearly separate the simultaneously excited FPs, spectral unmixing including iterative procedures was performed after imaging the diversely labeled spinal white matter with a custom-made 4-channel two-photon laser-scanning microscope. In our longitudinal multicellular studies of injured spinal white matter, we imaged axonal dynamics and invasion of microglia and astrocytes for a time course of over 200 days after SCI. Our methods offer ideal platforms for investigating acute and chronic cellular dynamics, cell-cell interactions, and metabolite fluctuations in health and disease as well as pharmacological manipulations in vivo.}, } @article {pmid39218769, year = {2024}, author = {Sun, J and Zhang, Y}, title = {Microbiome and micronutrient in ALS: From novel mechanisms to new treatments.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {6}, pages = {e00441}, pmid = {39218769}, issn = {1878-7479}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK105118/DK/NIDDK NIH HHS/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/metabolism/therapy ; Humans ; *Micronutrients/metabolism ; *Gastrointestinal Microbiome/physiology ; Animals ; Dysbiosis ; Microbiota/physiology ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disorder. Despite extensive studies, it remains challenging to treat ALS. Recent ALS studies have shown dysbiosis (e.g., loss of microbial diversity and beneficial function in the gut microbiota) is correlated with intestinal inflammation and change of intestinal integrity in ALS. The novel concepts and the roles of microbiome and microbial metabolites through the gut-microbiome-neuron axis in ALS pathogenesis have been slowly recognized by the neurology research field. Here, we will discuss the recent progress of microbiome, including bacteria, fungi, and viruses, in the ALS research. We will discuss our understanding of microbial metabolites in ALS. Micronutrition refers to the intake of essential vitamins, minerals, and other micronutrients. We will summarize the literation related to micronutrition and ALS. Furthermore, we will consider the mutual interactions of microbiome and micronutrition in the ALS progression and treatment. We further propose that the mechanistic and translational studies that shift from suspension of disbelief to cogent ingenuity, and from bench study to bed-side application, should allow new strategies of diagnosis and treatment for ALS.}, } @article {pmid39222049, year = {2024}, author = {Santangelo, S and Invernizzi, S and Sorce, MN and Casiraghi, V and Peverelli, S and Brusati, A and Colombrita, C and Ticozzi, N and Silani, V and Bossolasco, P and Ratti, A}, title = {NEK1 haploinsufficiency worsens DNA damage, but not defective ciliogenesis, in C9ORF72 patient-derived iPSC-motoneurons.}, journal = {Human molecular genetics}, volume = {33}, number = {21}, pages = {1900-1907}, pmid = {39222049}, issn = {1460-2083}, support = {GR-2016-02364373//BIBLIOSAN/ ; PSR 2021//Italian Ministery of Health/ ; }, mesh = {*Induced Pluripotent Stem Cells/metabolism ; Humans ; *NIMA-Related Kinase 1/genetics ; *DNA Damage/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics/metabolism ; *Haploinsufficiency/genetics ; *Motor Neurons/metabolism/pathology ; *Frontotemporal Dementia/genetics/pathology ; *Cilia/genetics/pathology/metabolism ; Cell Differentiation/genetics ; DNA Repeat Expansion/genetics ; Mutation ; }, abstract = {The hexanucleotide G4C2 repeat expansion (HRE) in C9ORF72 gene is the major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to both loss- and gain-of-function pathomechanisms. The wide clinical heterogeneity among C9ORF72 patients suggests potential modifying genetic and epigenetic factors. Notably, C9ORF72 HRE often co-occurs with other rare variants in ALS/FTD-associated genes, such as NEK1, which encodes for a kinase involved in multiple cell pathways, including DNA damage response and ciliogenesis. In this study, we generated induced pluripotent stem cells (iPSCs) and differentiated motoneurons (iPSC-MNs) from an ALS patient carrying both C9ORF72 HRE and a NEK1 loss-of-function mutation to investigate the biological effect of NEK1 haploinsufficiency on C9ORF72 pathology in a condition of oligogenicity. Double mutant C9ORF72/NEK1 cells showed increased pathological C9ORF72 RNA foci in iPSCs and higher DNA damage levels in iPSC-MNs compared to single mutant C9ORF72 cells, but no effect on DNA damage response. When we analysed the primary cilium, we observed a defective ciliogenesis in C9ORF72 iPSC-MNs which was not worsened by NEK1 haploinsufficiency in the double mutant iPSC-MNs. Altogether, our study shows that NEK1 haploinsufficiency influences differently DNA damage and cilia length, potentially acting as a modifier at biological level in an in vitro ALS patient-derived disease model of C9ORF72 pathology.}, } @article {pmid39223525, year = {2024}, author = {Iakovleva, V and Verde, F and Cinnante, C and Sillani, A and Conte, G and Corsini, E and Ciusani, E and Erbetta, A and Silani, V and Ticozzi, N}, title = {Duropathy as a rare motor neuron disease mimic: from bibrachial amyotrophy to infratentorial superficial siderosis.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {309}, pmid = {39223525}, issn = {1471-2377}, support = {PNC-E3-2022-23683266//Italian Ministry of Education and Research (MUR)/ ; }, mesh = {Humans ; Male ; Middle Aged ; *Motor Neuron Disease/diagnosis/complications/diagnostic imaging ; *Siderosis/complications/diagnosis/diagnostic imaging ; Magnetic Resonance Imaging/methods ; Diagnosis, Differential ; Dura Mater/diagnostic imaging/pathology ; }, abstract = {BACKGROUND: Bibrachial amyotrophy associated with an extradural CSF collection and infratentorial superficial siderosis (SS) are rare conditions that may occasionally mimic ALS. Both disorders are assumed to be due to dural tears.

CASE PRESENTATION: A 53-year-old man presented with a 7-year history of slowly progressive asymmetric bibrachial amyotrophy. Initially, a diagnosis of atypical motor neuron disease (MND) was made. At re-evaluation 11 years later, upper limb wasting and weakness had further progressed and were accompanied by sensorineural hearing loss. MRI of the brain and spine demonstrated extensive supra- and infratentorial SS (including the surface of the whole spinal cord) as well as a ventral longitudinal intraspinal fluid collection (VLISFC) extending along almost the entire thoracic spine. Osteodegenerative changes were observed at C5-C7 level, with osteophytes protruding posteriorly. The bony spurs at C6-C7 level were hypothesized to have lesioned the dura, causing a CSF leak and thus a VLISFC. Review of the MRI acquired at first evaluation showed that the VLISFC was already present at that time (actually beginning at C7 level), whereas the SS was not. 19 years after the onset of upper limb weakness, the patient additionally developed parkinsonism. Response to levodopa, brain scintigraphy with [123]I-ioflupane and brain MRI with nigrosome 1 evaluation were consistent with idiopathic Parkinson's disease (PD). On the latest follow-up 21 years after symptom onset, the VLISFC was unchanged, as were upper arm weakness and wasting.

CONCLUSIONS: Based on the long-term follow-up, we could establish that, while the evidence of the VLISFC was concomitant with the clinical presentation of upper limb amyotrophy and weakness, the radiological signs of SS appeared later. This suggests that SS was not per se the cause of the ALS-like clinical picture, but rather a long-term sequela of a dural leak. The latter was instead the causative lesion, giving rise to a VLISFC which compressed the cervical motor roots. Dural tears can actually cause several symptoms, and further studies are needed to elucidate the pathophysiological correlates of "duropathies". Finally, as iron metabolism has been implicated in PD, the co-occurrence of PD with SS deserves further investigation.}, } @article {pmid39224887, year = {2024}, author = {Yang, J and Tian, M and Zhang, L and Xin, C and Huo, J and Liu, Q and Dong, H and Li, R and Liu, Y}, title = {Assessment of Rab geranylgeranyltransferase subunit beta in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1447461}, pmid = {39224887}, issn = {1664-2295}, abstract = {INTRODUCTION: Geranylgeranyltransferase Subunit Beta (RABGGTB) was expressed at higher levels in patients with Amyotrophic lateral sclerosis (ALS) compared with healthy controls. This study aims to observe the expression of RABGGTB in different cells from patients with ALS and different diseases.

METHODS: In this case-control study, we collected peripheral blood from patients with ALS and healthy controls, and compared the expression of RABGGTB in natural killer cells (NK), T cells and B cells between patients with ALS and healthy controls by flow cytometry. And compared the expression of RABGGTB in monocytes and monocyte-derived macrophages from patients with ALS, Parkinson's disease (PD), acute cerebrovascular disease (ACVD), and healthy controls by flow cytometry and immunofluorescence. Then flow cytometry was used to detect the expression of RABGGTB in monocytes from SOD1G93A mice and WT mice.

RESULTS: The expression of RABGGTB was not significantly changed in NK cells, cytotoxic T cells (CTL), helper T cells (Th), regulatory T cells (Treg), and B cells from patients with ALS compared to healthy controls. And the expression of RABGGTB in monocytes and monocyte-derived macrophages was higher in the ALS group than in the PD, ACVD and control group. The expression of RABGGTB was significantly higher in monocytes of SOD1G93A mice compared to WT mice.

CONCLUSION: These findings suggest that RABGGTB expression was increased in monocytes and monocyte-derived macrophages from patients with ALS, not in NK, CTL, Th, Treg, and B cells. Future studies are needed to find the clinical implication of RABGGTB in ALS.}, } @article {pmid39224919, year = {2024}, author = {Kiernan, MC and Kaji, R}, title = {Emerging concepts and therapies for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {558-559}, doi = {10.1097/WCO.0000000000001308}, pmid = {39224919}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; }, } @article {pmid39225106, year = {2024}, author = {Białobrodzka, E and Flis, DJ and Akdogan, B and Borkowska, A and Wieckowski, MR and Antosiewicz, J and Zischka, H and Dzik, KP and Kaczor, JJ and Ziolkowski, W}, title = {Amyotrophic Lateral Sclerosis and swim training affect copper metabolism in skeletal muscle in a mouse model of disease.}, journal = {Muscle & nerve}, volume = {70}, number = {5}, pages = {1111-1118}, doi = {10.1002/mus.28237}, pmid = {39225106}, issn = {1097-4598}, support = {//Narodowe Centrum Nauki/ ; DEC-2013/09/NZ7/02538//National Science Centre/ ; 2020/39/B/NZ7/03366//National Science Centre/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Muscle, Skeletal/metabolism ; Mice ; *Copper/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; *Swimming ; Superoxide Dismutase/metabolism ; Copper-Transporting ATPases/metabolism/genetics ; Physical Conditioning, Animal/physiology ; Superoxide Dismutase-1/metabolism/genetics ; Adenosine Triphosphatases/metabolism ; Cation Transport Proteins/metabolism ; Male ; Copper Transporter 1/metabolism ; }, abstract = {INTRODUCTION/AIMS: Swim training and regulation of copper metabolism result in clinical benefits in amyotrophic lateral sclerosis (ALS) mice. Therefore, the study aimed to determine whether swim training improves copper metabolism by modifying copper metabolism in the skeletal muscles of ALS mice.

METHODS: SOD1G93A mice (n = 6 per group) were used as the ALS model, and wild-type B6SJL (WT) mice as controls (n = 6). Mice with ALS were analyzed before the onset of ALS (ALS BEFORE), at baseline ALS (first disease symptoms, trained and untrained, ALS ONSET), and at the end of ALS (last stage disease, trained and untrained, ALS TERMINAL). Copper concentrations and the level of copper metabolism proteins in the skeletal muscles of the lower leg were determined.

RESULTS: ALS disease caused a reduction in the copper concentration in ALS TERMINAL untrained mice compared with the ALS BEFORE (10.43 ± 1.81 and 38.67 ± 11.50 μg/mg, respectively, p = .0213). The copper chaperon for SOD1 protein, which supplies copper to SOD1, and ATPase7a protein (copper exporter), increased at the terminal stage of disease by 57% (p = .0021) and 34% (p = .0372), while the CTR1 protein (copper importer) decreased by 45% (p = .002). Swim training moderately affected the copper concentration and the concentrations of proteins responsible for copper metabolism in skeletal muscles.

DISCUSSION: The results show disturbances in skeletal muscle copper metabolism associated with ALS progression, which is moderately affected by swim training. From a clinical point of view, exercise in water for ALS patients should be an essential element of rehabilitation for maintaining quality of life.}, } @article {pmid39225243, year = {2024}, author = {Liang, J and Zhu, Y and Liu, S and Kuang, B and Tian, Z and Zhang, L and Yang, S and Lin, M and Chen, N and Liu, X and Ai, Q and Yang, Y}, title = {Progress of Exosomal MicroRNAs and Traditional Chinese Medicine Monomers in Neurodegenerative Diseases.}, journal = {Phytotherapy research : PTR}, volume = {38}, number = {11}, pages = {5323-5349}, doi = {10.1002/ptr.8322}, pmid = {39225243}, issn = {1099-1573}, support = {//The Key Discipline of Biological Engineering of Hunan University of Chinese Medicine [2018] No. 3/ ; 22JBZ052//Hunan University of Chinese Medicine Discipline Construction Project/ ; 202329-2//Key Project of Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University/ ; 2021JJ30512//Hunan Natural Science Foundation/ ; 2022JJ40313//Hunan Natural Science Foundation/ ; 2022JJ40456//Hunan Natural Science Foundation/ ; 2023JJ60126//Hunan Natural Science Foundation/ ; 2023JJ60471//Hunan Natural Science Foundation/ ; 21B0354//Outstanding Youth Project of Hunan Education Department/ ; B2023061//Scientific Research Project of Hunan Provincial Administration of Traditional Chinese Medicine/ ; //Hunan University of Chinese Medicine First-class Disciple Construction Project of Chinese Material Medica/ ; kq2014091//Changsha Natural Science Foundation/ ; kq2202269//Changsha Natural Science Foundation/ ; //The First-class Discipline Construction Project of Chemical Engineering and Technology of Hunan University of Traditional Chinese Medicine/ ; 212010//Special Scientific and Technological Project for Comprehensive Utilization of Ampelopsis grossedentata Resources of Hunan Qiankun Biotechnology Co., Ltd/ ; 2019xjjj001//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; 2021XJJJ028//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; U2202214//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Exosomes/metabolism ; *MicroRNAs/genetics ; *Neurodegenerative Diseases/drug therapy ; *Medicine, Chinese Traditional/methods ; Drugs, Chinese Herbal/pharmacology ; Animals ; }, abstract = {Exosomes, extracellular vesicles secreted by various cells, actively participate in intercellular communication by facilitating the exchange of crucial molecular information such as DNA, RNA, and lipids. Within this intricate network, microRNAs, endogenous non-coding small RNAs, emerge as pivotal regulators of post-transcriptional gene expression, significantly influencing the development of neurodegenerative diseases. The historical prominence of traditional Chinese medicine (TCM) in clinical practice in China underscores its enduring significance. Notably, TCM monomers, serving as active constituents within herbal medicine, assume a critical role in the treatment of neurodegenerative diseases, particularly in mitigating oxidative stress, inhibiting apoptosis, and reducing inflammation. This comprehensive review aims to delineate the specific involvement of exosomal microRNAs in various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. Furthermore, the exploration extends to the application of TCM monomers, elucidating their efficacy as therapeutic agents in these conditions. Additionally, the review examines the utilization of exosomes as drug delivery carriers in the context of neurodegenerative diseases, providing a nuanced understanding of the potential synergies between TCM and modern therapeutic approaches. This synthesis of knowledge aims to contribute to the advancement of our comprehension of the intricate molecular mechanisms underlying neurodegeneration and the potential therapeutic avenues offered by TCcom interventions.}, } @article {pmid39226692, year = {2024}, author = {Kwon, S and Kim, B and Han, KD and Jung, W and Cho, EB and Shin, DW and Min, JH}, title = {Risk of depression in amyotrophic lateral sclerosis: A nationwide cohort study in South Korea.}, journal = {Journal of psychiatric research}, volume = {178}, number = {}, pages = {414-420}, doi = {10.1016/j.jpsychires.2024.08.030}, pmid = {39226692}, issn = {1879-1379}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Republic of Korea/epidemiology ; Male ; Female ; Middle Aged ; Aged ; *Depression/epidemiology ; Adult ; Cohort Studies ; Proportional Hazards Models ; }, abstract = {Depression is frequently reported in amyotrophic lateral sclerosis (ALS) due to the disastrous prognosis of progressive motor impairment, but the risk of depression in ALS is still unclear. Therefore, we investigated the risk of depression in ALS and analyzed the effect of ALS-related physical disability on the risk of developing depression using the Korean National Health Insurance Service (KNHIS) database. A total of 2241 ALS patients, as defined by the International Classification Diseases (ICD, G12.21) and Rare Intractable Disease codes (V123), and 1:10 sex- and age-matched controls were selected from the KNHIS. After applying exclusion criteria (non-participation in national health screening, history of depression, or having missing data), 595 ALS patients and 9896 non-ALS individuals were finally selected. Primary outcome is newly diagnosed depression during follow-up duration defined by ICD code (F32 or F33). A Cox regression model was used to examine the hazard ratios (HRs) after adjustment for potential confounders. During the follow-up period, 283 cases of depression in the ALS group and 1547 in the controls were recorded. The adjusted HR for depression in ALS was 9.1 (95% confidence interval [CI] 7.87-10.60). The risk of depression was slightly higher in the disabled ALS group (aHR 10.1, 95% CI 7.98-12.67) than in the non-disabled ALS group (aHR 8.78, 95% CI 7.42-10.39). The relative risk of depression was higher in younger patients than in older patients, and in obese patients than in non-obese patients. Our study showed that ALS patients have an increased risk of depression compared to non-ALS individuals.}, } @article {pmid39226712, year = {2024}, author = {Santos Silva, C and Gormicho, M and Simão, S and Pronto-Laborinho, AC and Alves, I and Pinto, S and Oliveira Santos, M and de Carvalho, M}, title = {C9orf72 gene repeat expansion phenotype profile of motor neurone disease in Portugal.}, journal = {Journal of the neurological sciences}, volume = {465}, number = {}, pages = {123208}, doi = {10.1016/j.jns.2024.123208}, pmid = {39226712}, issn = {1878-5883}, mesh = {Humans ; Male ; Portugal/epidemiology ; Female ; Middle Aged ; *C9orf72 Protein/genetics ; *Motor Neuron Disease/genetics/epidemiology ; Aged ; *Phenotype ; *DNA Repeat Expansion/genetics ; Cohort Studies ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; }, abstract = {BACKGROUND: C9orf72 gene repeat expansion (C9RE) is the most frequent gene variant associated with amyotrophic lateral sclerosis (ALS). We aimed to study the phenotype of motor neurone disease (MND) patients with C9RE in a Portuguese cohort.

METHODS: Demographical and clinical data of MND patients with (C9RE+) and without C9RE were compared. ALS al Rating Scale-Revised (ALSFRS-R) and Edinburgh Cognitive and Behavioural ALS Screen (ECAS) were used to evaluate functional and cognitive performance, respectively. Survival analysis was performed using Kaplan Meier log-rank test and Cox proportional hazards model.

RESULTS: We included 761 patients of whom 61 (8.0 %) were C9RE+. C9RE+ patients had a higher frequency of ALS (95.1 vs 78.4 %, p = 0.002), and lower frequency of progressive muscular atrophy (3.3 vs 16.7 %, p = 0.006). C9RE+ was associated with earlier age of onset (58.1 vs 62.6 years, p = 0.003) and more frequent MND family history (65.5 vs 11.4 %, p < 0.001). Gender, ethnicity, onset site, diagnostic delay, disease progression rate until diagnosis (ΔF), ALSFRS-R and time until non-invasive ventilation did not differ between groups. Cognitive/behavioural symptoms and ECAS did not differ between groups, except a worse visuospatial score in C9RE+ group (p = 0.035). Death rate was 1.8 and 1.6 times higher in C9RE+ patients with MND and ALS, respectively. Significant survival prognostic factors in C9RE+ group were diagnosis delay (HR = 0.96, 95 %CI 0.92-0.99, p = 0.008) and ΔF (HR = 1.93, 95 %CI 1.26-2.96, p = 0.002).

CONCLUSION: Our study corroborates most previous cohorts' findings, but harbours some singularities regarding onset site, phenotype, and cognitive profile, that contribute to a better understanding of C9RE epidemiology.}, } @article {pmid39226927, year = {2024}, author = {Cossu, L and Cappon, G and Facchinetti, A}, title = {Adaptive and self-learning Bayesian filtering algorithm to statistically characterize and improve signal-to-noise ratio of heart-rate data in wearable devices.}, journal = {Journal of the Royal Society, Interface}, volume = {21}, number = {218}, pages = {20240222}, pmid = {39226927}, issn = {1742-5662}, support = {//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Bayes Theorem ; *Wearable Electronic Devices ; *Heart Rate/physiology ; *Algorithms ; *Signal-To-Noise Ratio ; Male ; Female ; Signal Processing, Computer-Assisted ; }, abstract = {The use of wearable sensors to monitor vital signs is increasingly important in assessing individual health. However, their accuracy often falls short of that of dedicated medical devices, limiting their usefulness in a clinical setting. This study introduces a new Bayesian filtering (BF) algorithm that is designed to learn the statistical characteristics of signal and noise, allowing for optimal smoothing. The algorithm is able to adapt to changes in the signal-to-noise ratio (SNR) over time, improving performance through windowed analysis and Bayesian criterion-based smoothing. By evaluating the algorithm on heart-rate (HR) data collected from Garmin Vivoactive 4 smartwatches worn by individuals with amyotrophic lateral sclerosis and multiple sclerosis, it is demonstrated that BF provides superior SNR tracking and smoothing compared with non-adaptive methods. The results show that BF accurately captures SNR variability, reducing the root mean square error from 2.84 bpm to 1.21 bpm and the mean absolute relative error from 3.46% to 1.36%. These findings highlight the potential of BF as a preprocessing tool to enhance signal quality from wearable sensors, particularly in HR data, thereby expanding their applications in clinical and research settings.}, } @article {pmid39227337, year = {2024}, author = {Choi, SJ and Yoo, SH and Lee, SY and Sung, JJ}, title = {Withdrawal of Life-Sustaining Mechanical Ventilation for a Patient With Amyotrophic Lateral Sclerosis in Locked-In Syndrome.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {20}, number = {5}, pages = {537-538}, pmid = {39227337}, issn = {1738-6586}, support = {NRF-2018R1A5A2025964/NRF/National Research Foundation of Korea/Korea ; }, } @article {pmid39227882, year = {2024}, author = {Zelina, P and de Ruiter, AA and Kolsteeg, C and van Ginneken, I and Vos, HR and Supiot, LF and Burgering, BMT and Meye, FJ and Veldink, JH and van den Berg, LH and Pasterkamp, RJ}, title = {ALS-associated C21ORF2 variant disrupts DNA damage repair, mitochondrial metabolism, neuronal excitability and NEK1 levels in human motor neurons.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {144}, pmid = {39227882}, issn = {2051-5960}, support = {TOTALS//Stichting ALS Nederland/ ; GoALS//Stichting ALS Nederland/ ; MAXOMOD//E-Rare/ ; TRIAGE//JPND/ ; X-omics initiative//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; EScORIAL//H2020 European Research Council/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; DNA Damage ; DNA Repair/genetics ; *Induced Pluripotent Stem Cells/metabolism ; *Mitochondria/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; Mutation ; *NIMA-Related Kinase 1/genetics/metabolism ; *Zebrafish ; Cytoskeletal Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease leading to motor neuron loss. Currently mutations in > 40 genes have been linked to ALS, but the contribution of many genes and genetic mutations to the ALS pathogenic process remains poorly understood. Therefore, we first performed comparative interactome analyses of five recently discovered ALS-associated proteins (C21ORF2, KIF5A, NEK1, TBK1, and TUBA4A) which highlighted many novel binding partners, and both unique and shared interactors. The analysis further identified C21ORF2 as a strongly connected protein. The role of C21ORF2 in neurons and in the nervous system, and of ALS-associated C21ORF2 variants is largely unknown. Therefore, we combined human iPSC-derived motor neurons with other models and different molecular cell biological approaches to characterize the potential pathogenic effects of C21ORF2 mutations in ALS. First, our data show C21ORF2 expression in ALS-relevant mouse and human neurons, such as spinal and cortical motor neurons. Further, the prominent ALS-associated variant C21ORF2-V58L caused increased apoptosis in mouse neurons and movement defects in zebrafish embryos. iPSC-derived motor neurons from C21ORF2-V58L-ALS patients, but not isogenic controls, show increased apoptosis, and changes in DNA damage response, mitochondria and neuronal excitability. In addition, C21ORF2-V58L induced post-transcriptional downregulation of NEK1, an ALS-associated protein implicated in apoptosis and DDR. In all, our study defines the pathogenic molecular and cellular effects of ALS-associated C21ORF2 mutations and implicates impaired post-transcriptional regulation of NEK1 downstream of mutant C21ORF72 in ALS.}, } @article {pmid39229019, year = {2025}, author = {Erwin, AL and Fernandez, MG and Chang, ML and Attili, D and Bekier, M and Pinarbasi, ES and Russ, JE and Sutanto, R and Thomas, D and Shen, X and Baldridge, RD and Tank, EMH and Barmada, SJ and Mosalaganti, S}, title = {Molecular Visualization of Neuronal TDP43 Pathology In Situ.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39229019}, issn = {2692-8205}, support = {DP2 GM150019/GM/NIGMS NIH HHS/United States ; S10 OD030275/OD/NIH HHS/United States ; R37 NS113943/NS/NINDS NIH HHS/United States ; T32 GM007544/GM/NIGMS NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; T32 GM141840/GM/NIGMS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; F31 NS134123/NS/NINDS NIH HHS/United States ; R35 GM128592/GM/NIGMS NIH HHS/United States ; }, abstract = {Nuclear exclusion and cytoplasmic accumulation of the RNA-binding protein TDP43 are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite this, the origin and ultrastructure of cytosolic TDP43 deposits remain unknown. Accumulating evidence suggests that abnormal RNA homeostasis can drive pathological TDP43 mislocalization, thereby enhancing RNA misprocessing due to the loss of nuclear TDP43, and engendering a cycle that ultimately leads to cell death. Here, we demonstrate that the addition of small monovalent oligonucleotides successfully recapitulates pathological TDP43 mislocalization and aggregation, aberrant splicing, and degeneration in iPSC-derived neurons (iNeurons). By employing a tailored multimodal in situ cryo-correlative light and electron microscopy pipeline, we examine the localization and aggregation of TDP43 in near-native conditions. We discover that mislocalized TDP43 accumulates and forms ordered fibrils within autophagosomes and lysosomes in iNeurons, as well as in ALS/FTLD patient tissue. We provide the first high-resolution snapshots of TDP43 aggregates in situ, delivering an unprecedented view of the earliest pathogenic events underlying ALS, FTLD, and related TDP43 proteinopathies.}, } @article {pmid39229047, year = {2024}, author = {Wairagkar, M and Card, NS and Singer-Clark, T and Hou, X and Iacobacci, C and Hochberg, LR and Brandman, DM and Stavisky, SD}, title = {An instantaneous voice synthesis neuroprosthesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39229047}, issn = {2692-8205}, support = {DP2 DC021055/DC/NIDCD NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; }, abstract = {Brain computer interfaces (BCIs) have the potential to restore communication to people who have lost the ability to speak due to neurological disease or injury. BCIs have been used to translate the neural correlates of attempted speech into text[1-3]. However, text communication fails to capture the nuances of human speech such as prosody, intonation and immediately hearing one's own voice. Here, we demonstrate a "brain-to-voice" neuroprosthesis that instantaneously synthesizes voice with closed-loop audio feedback by decoding neural activity from 256 microelectrodes implanted into the ventral precentral gyrus of a man with amyotrophic lateral sclerosis and severe dysarthria. We overcame the challenge of lacking ground-truth speech for training the neural decoder and were able to accurately synthesize his voice. Along with phonemic content, we were also able to decode paralinguistic features from intracortical activity, enabling the participant to modulate his BCI-synthesized voice in real-time to change intonation, emphasize words, and sing short melodies. These results demonstrate the feasibility of enabling people with paralysis to speak intelligibly and expressively through a BCI.}, } @article {pmid39229486, year = {2024}, author = {Rivers-Auty, J and Hoyle, C and Pointer, A and Lawrence, C and Pickering-Brown, S and Brough, D and Ryan, S}, title = {C9orf72 dipeptides activate the NLRP3 inflammasome.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae282}, pmid = {39229486}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases with considerable clinical, genetic and pathological overlap. The most common cause of both diseases is a hexanucleotide repeat expansion in C9orf72. The expansion is translated to produce five toxic dipeptides, which aggregate in patient brain. Neuroinflammation is a feature of frontotemporal dementia and amyotrophic lateral sclerosis; however, its causes are unknown. The nod-like receptor family, pyrin domain-containing 3 inflammasome is implicated in several other neurodegenerative diseases as a driver of damaging inflammation. The inflammasome is a multi-protein complex which forms in immune cells in response to tissue damage, pathogens or aggregating proteins. Inflammasome activation is observed in models of other neurodegenerative diseases such as Alzheimer's disease, and inflammasome inhibition rescues cognitive decline in rodent models of Alzheimer's disease. Here, we show that a dipeptide arising from the C9orf72 expansion, poly-glycine-arginine, activated the inflammasome in microglia and macrophages, leading to secretion of the pro-inflammatory cytokine, interleukin-1β. Poly-glycine-arginine also activated the inflammasome in organotypic hippocampal slice cultures, and immunofluorescence imaging demonstrated formation of inflammasome specks in response to poly-glycine-arginine. Several clinically available anti-inflammatory drugs rescued poly-glycine-arginine-induced inflammasome activation. These data suggest that C9orf72 dipeptides contribute to the neuroinflammation observed in patients, and highlight the inflammasome as a potential therapeutic target for frontotemporal dementia and amyotrophic lateral sclerosis.}, } @article {pmid39229489, year = {2024}, author = {Feng, F and Feng, G and Liu, J and Hao, W and Huang, W and Bi, X and Li, M and Wang, H and Yang, F and He, Z and Bai, J and Wang, H and Ma, G and Xu, B and Shu, N and Huang, X}, title = {Different patterns of structural network impairments in two amyotrophic lateral sclerosis subtypes driven by [18]F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid imaging.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae222}, pmid = {39229489}, issn = {2632-1297}, abstract = {The structural network damages in amyotrophic lateral sclerosis patients are evident but contradictory due to the high heterogeneity of the disease. We hypothesized that patterns of structural network impairments would be different in amyotrophic lateral sclerosis subtypes by a data-driven method using [18]F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid imaging. The data of positron emission tomography, structural MRI and diffusion tensor imaging in fifty patients with amyotrophic lateral sclerosis and 23 healthy controls were collected by a [18]F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid. Two amyotrophic lateral sclerosis subtypes were identified as the optimal cluster based on grey matter volume and standardized uptake value ratio. Network metrics at the global, local and connection levels were compared to explore the impaired patterns of structural networks in the identified subtypes. Compared with healthy controls, the two amyotrophic lateral sclerosis subtypes displayed a pattern of a locally impaired structural network centralized in the sensorimotor network and a pattern of an extensively impaired structural network in the whole brain. When comparing the two amyotrophic lateral sclerosis subgroups by a support vector machine classifier based on the decreases in nodal efficiency of structural network, the individualized network scores were obtained in every amyotrophic lateral sclerosis patient and demonstrated a positive correlation with disease severity. We clustered two amyotrophic lateral sclerosis subtypes by a data-driven method, which encompassed different patterns of structural network impairments. Our results imply that amyotrophic lateral sclerosis may possess the intrinsic damaged pattern of white matter network and thus provide a latent direction for stratification in clinical research.}, } @article {pmid39230722, year = {2024}, author = {Chalitsios, CV and Ley, H and Gao, J and Turner, MR and Thompson, AG}, title = {Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6956-6969}, pmid = {39230722}, issn = {1432-1459}, support = {MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; Thompson/Apr23/896-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/epidemiology ; *Apolipoproteins/antagonists & inhibitors/blood/genetics ; *Frontotemporal Dementia/blood/genetics/epidemiology ; Hypolipidemic Agents/pharmacology/therapeutic use ; Lipids/blood ; Mendelian Randomization Analysis ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have clinical, pathological and genetic overlapping. Lipid pathways are implicated in ALS. This study examined the effect of blood lipid levels on ALS, FTD risk, and survival in ALS.

METHODS: A systematic review and meta-analysis of high and low-density lipoprotein cholesterol (HDL-c and LDL-c), total cholesterol, triglycerides, apolipoproteins B and A1 levels with ALS was performed. Two-sample Mendelian randomisation (MR) analysis sought the causal effects of these exposures on ALS, FTD, and survival in ALS. The effect of lipid-lowering drugs was also examined using genetic proxies for targets of lipid-lowering medications.

RESULTS: Three cohort studies met the inclusion criteria for meta-analysis. Meta-analysis indicated an association between higher LDL-c (HRper mmol/L = 1.07, 95%CI:1.02-1.12; I 2 =18%) and lower HDL-c (HRper mmol/L = 0.83, 95%CI:0.74-0.94; I 2 =0%) with an increased risk of ALS. MR suggested causal effects of higher LDL-c (ORIVW = 1.085, 95%:CI 1.008-1.168, pFDR = 0.0406), total cholesterol (ORIVW = 1.081, 95%:CI 1.013-1.154, pFDR = 0.0458) and apolipoprotein B (ORIVW = 1.104, 95%:CI 1.041-1.171, pFDR = 0.0061) increasing ALS risk, and higher apolipoprotein B level increasing FTD risk (ORIVW = 1.424, 95%CI 1.072-1.829, pFDR = 0.0382). Reducing LDL-c through APOB inhibition was associated with lower ALS (ORIVW = 0.84, 95%CI 0.759-0.929, pFDR = 0.00275) and FTD risk (ORIVW = 0.581, 95%CI 0.387-0.874, pFDR = 0.0362).

CONCLUSION: These data support the influence of LDL-c and total cholesterol on ALS risk and apolipoprotein B on the risk of ALS and FTD. Potential APOB inhibition might decrease the risk of sporadic ALS and FTD. Further work in monogenic forms of ALS and FTD is necessary to determine whether blood lipids influence penetrance and phenotype.}, } @article {pmid39231048, year = {2024}, author = {Trescato, I and Tavazzi, E and Vettoretti, M and Gatta, R and Vasta, R and Chio, A and Camillo, BD}, title = {DYNAMITE: Integrating Archetypal Analysis and Process Mining for Interpretable Disease Progression Modelling.}, journal = {IEEE journal of biomedical and health informatics}, volume = {28}, number = {12}, pages = {7553-7564}, doi = {10.1109/JBHI.2024.3453602}, pmid = {39231048}, issn = {2168-2208}, mesh = {Humans ; *Disease Progression ; *Data Mining/methods ; Amyotrophic Lateral Sclerosis/physiopathology ; }, abstract = {DYNAMITE, an acronym for DYNamic Archetypal analysis for MIning disease TrajEctories, is a new methodology developed specifically to model disease progression by exploiting information available in longitudinal clinical datasets. First, archetypal analysis is applied to data organised in matrix form, with the aim of finding extreme and representative disease states (archetypes) linked to the original data through convex coefficients. Then, each original observation is associated with a single archetype based on their similarity; finally, an event log is created encoding the progression of disease states for each patient in terms of archetype states. In the last stage of the procedure, archetypal analysis is coupled with process mining, which allows the event log archetypes to be visualised graphically as sequences of disease states, allowing the clinical trajectories of patients to be extracted and examined. As a proof of concept, we applied the proposed method to data from a cohort of amyotrophic lateral sclerosis patients whose progression was monitored using the 12-item ALSFRS-R questionnaire. Without any a priori knowledge, DYNAMITE identified six archetypes clearly describing different types and severity of impairment and provided reliable clinical trajectories consistent with the prognosis of amyotrophic lateral sclerosis patients. DYNAMITE offers high interpretability at every stage of the analysis, which makes it particularly suitable for use in healthcare where explainability is paramount, and enables analysis of clinical trajectories at both individual and population levels.}, } @article {pmid39231437, year = {2024}, author = {Chu, HS and Oh, J}, title = {Family Caregivers' Experiences of People With Amyotrophic Lateral Sclerosis Undergoing Gastrostomy Tube Feeding.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {56}, number = {6}, pages = {224-228}, pmid = {39231437}, issn = {1945-2810}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/nursing/psychology ; *Caregivers/psychology ; *Enteral Nutrition ; *Gastrostomy ; Female ; Male ; Middle Aged ; Republic of Korea ; *Qualitative Research ; Adult ; Aged ; Stress, Psychological ; Interviews as Topic ; }, abstract = {INTRODUCTION: In amyotrophic lateral sclerosis (ALS) patients with impaired swallowing function, gastrostomy tube (G-tube) placement is recommended, but significantly increases the caregiving burden on families. This study aimed to describe the experiences of family caregivers of patients with ALS receiving home enteral nutrition through a G-tube. METHOD: Using purposive sampling, 8 family caregivers participated in the study. Data collection was conducted between February 2021 and October 2022 at a university hospital in Seoul, Korea. Semistructured face-to-face interviews were used to collect data until saturation. Data were analyzed using Krippendorff's content analysis approach. RESULTS: Qualitative analysis of the data revealed 3 main themes regarding caregiving. The emerging themes included psychological distress, unmet practical needs, and the struggle to provide care. CONCLUSION: After a G-tube placement, family caregivers experience various emotional stresses and have numerous unmet practical needs. Healthcare professionals caring for people with ALS receiving enteral nutrition should provide a tailored support program that addresses the specific needs of these family caregivers.}, } @article {pmid39231554, year = {2024}, author = {Gong, Z and Deng, W and Li, Z and Tang, J and Zhang, M}, title = {Association between apathy and caregiver burden in patients with amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {BMJ open}, volume = {14}, number = {9}, pages = {e080803}, pmid = {39231554}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Male ; Female ; Cross-Sectional Studies ; *Apathy ; Middle Aged ; *Anxiety/psychology/etiology ; *Depression/psychology/etiology ; China/epidemiology ; *Caregiver Burden/psychology ; Aged ; Caregivers/psychology ; Adult ; Cognitive Dysfunction/etiology/psychology ; Psychiatric Status Rating Scales ; Logistic Models ; Cost of Illness ; }, abstract = {OBJECTIVES: To investigate the relationship among patients' apathy, cognitive impairment, depression, anxiety, and caregiver burden in amyotrophic lateral sclerosis (ALS).

DESIGN: A cross-sectional study design was used.

SETTING: The study was conducted at a tertiary hospital in Wuhan, Hubei, China.

PARTICIPANTS: A total of 109 patients with ALS and their caregivers were included.

OUTCOME MEASURES: Patients with ALS were screened using the Edinburgh Cognitive and Behavioural Screen, Beck Depression Inventory-II, Generalised Anxiety Disorder-7 and Apathy Scale to assess their cognition, depression, anxiety and apathy, respectively. The primary caregivers completed the Zarit Burden Interview. The association between apathy, cognitive impairment, depression, anxiety and caregiver burden was analysed using logistic regression. Mediation models were employed to investigate the mediating effect of patients' apathy on the relationship between depression/anxiety and caregiver burden.

RESULTS: Patients in the high caregiver burden group exhibited significantly higher levels of depression, anxiety and apathy compared with those in the low caregiver burden group (p<0.05). There was a positive association observed between caregiver burden and disease course (rs=0.198, p<0.05), depression (rs=0.189, p<0.05), anxiety (rs=0.257, p<0.05) and apathy (rs=0.388, p<0.05). There was a negative association between caregiver burden and the Revised ALS Functional Rating Scale (rs=-0.275, p<0.05). Apathy was an independent risk factor for higher caregiver burden (OR 1.121, 95% CI 1.041 to 1.206, p<0.05). Apathy fully mediated the relationship between depression and caregiver burden (β=0.35, 95% CI 0.16 to 0.54, p<0.05) while partially mediating the relationship between anxiety and caregiver burden (β=0.34, 95% CI 0.16 to 0.52, p<0.05).

CONCLUSIONS: Apathy, depression and anxiety exerted a detrimental impact on caregiver burden in individuals with ALS. Apathy played a mediating role in the relationship between depression and caregiver burden and between anxiety and caregiver burden. These findings underscore the importance of identifying apathy and developing interventions for its management within the context of ALS.}, } @article {pmid39231585, year = {2025}, author = {Kato, C and Morimoto, S and Takahashi, S and Namba, S and Wang, QS and Okada, Y and Okano, H}, title = {Spinal cord motor neuron phenotypes and polygenic risk scores in sporadic amyotrophic lateral sclerosis: deciphering the disease pathology and therapeutic potential of ropinirole hydrochloride.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {2}, pages = {199-201}, pmid = {39231585}, issn = {1468-330X}, } @article {pmid39232248, year = {2024}, author = {Borchert, GA and Shanks, ME and Whitfield, J and Clouston, P and Raji, S and Sperring, S and Thompson, JA and Xue, K and De Silva, SR and Downes, SM and MacLaren, RE and Cehajic-Kapetanovic, J}, title = {Expanding the genotypic and phenotypic spectra with a novel variant in the ciliopathy gene, CFAP410, associated with selective cone degeneration.}, journal = {Ophthalmic genetics}, volume = {45}, number = {6}, pages = {633-639}, pmid = {39232248}, issn = {1744-5094}, mesh = {Humans ; Female ; Adult ; *Ciliopathies/genetics ; *Pedigree ; *Phenotype ; Retrospective Studies ; Genotype ; Cone Dystrophy/genetics/diagnosis ; Consanguinity ; Visual Acuity/physiology ; Tomography, Optical Coherence ; Mutation ; Homozygote ; }, abstract = {BACKGROUND: CFAP410 (Cilia and Flagella Associated Protein 410) encodes a protein that has an important role in the development and function of cilia. In ophthalmology, pathogenic variants in CFAP410 have been described in association with cone rod dystrophy, retinitis pigmentosa, with or without macular staphyloma, or with systemic abnormalities such as skeletal dysplasia and amyotrophic lateral sclerosis. Herein, we report a consanguineous family with a novel homozygous CFAP410 c.335_346del variant with cone only degeneration and no systemic features.

METHODS: A retrospective analysis of ophthalmic history, examination, retinal imaging, electrophysiology and microperimetry was performed as well as genetic testing with in silico pathogenicity predictions and a literature review.

RESULTS: A systemically well 28-year-old female of Pakistani ethnicity with parental consanguinity and no relevant family history, presented with childhood-onset poor central vision and photophobia. Best-corrected visual acuity and colour vision were reduced (0.5 LogMAR, 6/17 Ishihara plates (right) and 0.6 LogMAR, 3/17 Ishihara plates (left). Fundus examination showed no pigmentary retinopathy, no macular staphyloma and autofluorescence was unremarkable. Optical coherence tomography showed subtle signs of intermittent disruption of the ellipsoid zone. Microperimetry demonstrated a reduction in central retinal sensitivity. Electrodiagnostic testing confirmed a reduction in cone-driven responses. Whole-genome sequencing identified an in-frame homozygous deletion of 12 base pairs at c.335_346del in CFAP410.

CONCLUSIONS: The non-syndromic cone dystrophy phenotype reported herein expands the genotypic and phenotypic spectra of CFAP410-associated ciliopathies and highlights the need for light of potential future genetic therapies.}, } @article {pmid39232594, year = {2024}, author = {Martínez-Payá, JJ and Ríos-Díaz, J and Del Baño-Aledo, ME and Hervás, D and Tembl-Ferrairó, JI and Sevilla-Mantecón, T and Vázquez-Costa, JF}, title = {The cross-sectional area of the median nerve: An independent prognostic biomarker in amyotrophic lateral sclerosis.}, journal = {Neurologia}, volume = {39}, number = {7}, pages = {564-572}, doi = {10.1016/j.nrleng.2024.07.003}, pmid = {39232594}, issn = {2173-5808}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Male ; Middle Aged ; Female ; *Median Nerve/diagnostic imaging ; Prognosis ; *Biomarkers ; Aged ; *Ultrasonography ; Disease Progression ; Cohort Studies ; }, abstract = {INTRODUCTION: Ultrasound changes in the cross-sectional area of the median nerve (CSAmn) could be of interest as biomarkers in patients with amyotrophic lateral sclerosis (ALS).

METHODS: Eighty-four ALS patients (51 men [60.7%]; mean 62.0 [SD 11.46] years old) and forty-six controls (27 men [58.7%]; mean 59.9 [SD 8.08] years old) of two different cohorts were recruited between September 2013 and February 2018. The CSAmn was measured bilaterally in each cohort, by two different examiners with two different ultrasound machines (one in each cohort). Its association with clinical variables (disease duration, muscle strength, disability, progression rate and tracheostomy-free survival) was assessed.

RESULTS: The CSAmn was smaller in patients than in controls, and the study cohort did not influence its values. A mild correlation between the strength of the wrist flexor and the CSAmn was found. In the multivariable analysis, the probability of this association being true was 90%. In the cox regression, both a faster progression rate and a larger CSAmn independently predicted poor survival (HR=4.29, [Cr.I95%: 2.71-6.80], p<0.001; and HR=1.14, [Cr.I95%: 1.03-1.25], p=0.01), after adjusting by age, body mass index, bulbar onset, and diagnostic delay.

CONCLUSIONS: The CSAmn is an easy to assess biomarker that seems reliable and reproducible. Our data also suggest that it could act as a progression and prognostic biomarker in ALS patients. Longitudinal studies with repeated measures are warranted to confirm its usefulness in the clinical practice.}, } @article {pmid39233146, year = {2024}, author = {Wang, H and Liu, S and Sun, Y and Chen, C and Hu, Z and Li, Q and Long, J and Yan, Q and Liang, J and Lin, Y and Yang, S and Lin, M and Liu, X and Wang, H and Yu, J and Yi, F and Tan, Y and Yang, Y and Chen, N and Ai, Q}, title = {Target modulation of glycolytic pathways as a new strategy for the treatment of neuroinflammatory diseases.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102472}, doi = {10.1016/j.arr.2024.102472}, pmid = {39233146}, issn = {1872-9649}, mesh = {Humans ; *Glycolysis/physiology ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Animals ; Aging/metabolism ; }, abstract = {Neuroinflammation is an innate and adaptive immune response initiated by the release of inflammatory mediators from various immune cells in response to harmful stimuli. While initially beneficial and protective, prolonged or excessive neuroinflammation has been identified in clinical and experimental studies as a key pathological driver of numerous neurological diseases and an accelerant of the aging process. Glycolysis, the metabolic process that converts glucose to pyruvate or lactate to produce adenosine 5'-triphosphate (ATP), is often dysregulated in many neuroinflammatory disorders and in the affected nerve cells. Enhancing glucose availability and uptake, as well as increasing glycolytic flux through pharmacological or genetic manipulation of glycolytic enzymes, has shown potential protective effects in several animal models of neuroinflammatory diseases. Modulating the glycolytic pathway to improve glucose metabolism and ATP production may help alleviate energy deficiencies associated with these conditions. In this review, we examine six neuroinflammatory diseases-stroke, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and depression-and provide evidence supporting the role of glycolysis in their treatment. We also explore the potential link between inflammation-induced aging and glycolysis. Additionally, we briefly discuss the critical role of glycolysis in three types of neuronal cells-neurons, microglia, and astrocytes-within physiological processes. This review highlights the significance of glycolysis in the pathology of neuroinflammatory diseases and its relevance to the aging process.}, } @article {pmid39233624, year = {2024}, author = {Garnier, M and Camdessanché, JP and Cassereau, J and Codron, P}, title = {From suspicion to diagnosis: exploration strategy for suspected amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2398199}, pmid = {39233624}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; Diagnosis, Differential ; Electromyography/methods ; }, abstract = {The diagnosis of amyotrophic lateral sclerosis (ALS) is based on evidence of upper and lower motor neuron degeneration in the bulbar, cervical, thoracic, and lumbar regions in a patient with progressive motor weakness, in the absence of differential diagnosis. Despite these well-defined criteria, ALS can be difficult to diagnose, given the wide variety of clinical phenotypes. Indeed, the central or peripheral location of the disease varies with a spectrum ranging from predominantly central to exclusively peripheral, symptoms can be extensive or limited to the limbs, bulbar area or respiratory muscles, and the duration of the disease may range from a few months to several decades. In the absence of a specific test, the diagnostic strategy relies on clinical, electrophysiological, biological and radiological investigations to confirm the disease and exclude ALS mimics. The main challenge is to establish a diagnosis based on robust clinical and paraclinical evidence without delaying treatment initiation by increasing the number of additional tests. This approach requires a thorough knowledge of the phenotypes of ALS and its main differential diagnoses.}, } @article {pmid39233852, year = {2024}, author = {Gilbert, JW and Kennedy, Z and Godinho, BMDC and Summers, A and Weiss, A and Echeverria, D and Bramato, B and McHugh, N and Cooper, D and Yamada, K and Hassler, M and Tran, H and Gao, FB and Brown, RH and Khvorova, A}, title = {Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {3}, pages = {102291}, pmid = {39233852}, issn = {2162-2531}, support = {R01 NS104022/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; }, abstract = {A hexanucleotide (G4C2) repeat expansion (HRE) within intron one of C9ORF72 is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). C9ORF72 haploinsufficiency, formation of RNA foci, and production of dipeptide repeat (DPR) proteins have been proposed as mechanisms of disease. Here, we report the first example of disease-modifying siRNAs for C9ORF72 driven ALS/FTD. Using a combination of reporter assay and primary cortical neurons derived from a C9-ALS/FTD mouse model, we screened a panel of more than 150 fully chemically stabilized siRNAs targeting different C9ORF72 transcriptional variants. We demonstrate the lack of correlation between siRNA efficacy in reporter assay versus native environment; repeat-containing C9ORF72 mRNA variants are found to preferentially localize to the nucleus, and thus C9ORF72 mRNA accessibility and intracellular localization have a dominant impact on functional RNAi. Using a C9-ALS/FTD mouse model, we demonstrate that divalent siRNAs targeting C9ORF72 mRNA variants specifically or non-selectively reduce the expression of C9ORF72 mRNA and significantly reduce DPR proteins. Interestingly, siRNA silencing all C9ORF72 mRNA transcripts was more effective in removing intranuclear mRNA aggregates than targeting only HRE-containing C9ORF72 mRNA transcripts. Combined, these data support RNAi-based degradation of C9ORF72 as a potential therapeutic paradigm.}, } @article {pmid39234934, year = {2024}, author = {Mao, M and Zeng, W and Zheng, Y and Fan, W and Yao, Y}, title = {Fasudil attenuates syncytin-1-mediated activation of microglia and impairments of motor neurons and motor function in mice.}, journal = {Drug development research}, volume = {85}, number = {6}, pages = {e22254}, doi = {10.1002/ddr.22254}, pmid = {39234934}, issn = {1098-2299}, support = {81860245//National Natural Science Foundation of China/ ; [2019]5664//Department of Science and Technology of Guizhou Province/ ; GZSYBS[2017]01//Doctor Fund of Guizhou Provincial People's Hospital/ ; GZSYQN[2018]09//Youth Fund of Guizhou Provincial People's Hospital/ ; }, mesh = {Animals ; *Microglia/drug effects/metabolism ; *Motor Neurons/drug effects/metabolism ; Mice ; *Mice, Inbred C57BL ; *1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/pharmacology ; Gene Products, env ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Pregnancy Proteins/metabolism ; Male ; Cytokines/metabolism ; Disease Models, Animal ; Motor Activity/drug effects ; Spinal Cord/metabolism/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Syncytin-1 (Syn), an envelope glycoprotein encoded by the env gene of the human endogenous retrovirus-W family, has been resorted to be highly expressed in biopsies from the muscles from ALS patients; however, the specific regulatory role of Syn during ALS progression remains uncovered. In this study, C57BL/6 mice were injected with adeno-associated virus-overexpressing Syn, with or without Fasudil administration. The Syn expression was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry analysis. The histological change of anterior tibial muscles was determined by hematoxylin-eosin staining. Qualitative ultrastructural analysis of electron micrographs obtained from lumbar spinal cords was carried out. Serum inflammatory cytokines were assessed by enzyme linked immunosorbent assay (ELISA) assay and motor function was recorded using Basso, Beattie, and Bresnahan (BBB) scoring, climbing test and treadmill running test. Immunofluorescence and western blot assays were conducted to examine microglial- and motor neurons-related proteins. Syn overexpression significantly caused systemic inflammatory response, muscle tissue lesions, and motor dysfunction in mice. Meanwhile, Syn overexpression promoted the impairment of motor neuron, evidenced by the damaged structure of the neurons and reduced expression of microtubule-associated protein 2, HB9, neuronal nuclei and neuron-specific enolase in Syn-induced mice. In addition, Syn overexpression greatly promoted the expression of CD16/CD32 and inducible nitric oxide synthase (M1 phenotype markers), and reduced the expression of CD206 and arginase 1 (M2 phenotype markers). Importantly, the above changes caused by Syn overexpression were partly abolished by Fasudil administration. This study provides evidence that Syn-activated microglia plays a pivotal role during the progression of ALS.}, } @article {pmid39235524, year = {2024}, author = {Poletti, B and Aiello, EN and Consonni, M and Iazzolino, B and Torre, S and Solca, F and Faltracco, V and Telesca, A and Palumbo, F and Dalla Bella, E and Bersano, E and Riva, N and Verde, F and Messina, S and Doretti, A and Maranzano, A and Morelli, C and Calvo, A and Silani, V and Lauria, G and Chiò, A and Ticozzi, N}, title = {Prevalence and motor-functional correlates of frontotemporal-spectrum disorders in a large cohort of non-demented ALS patients.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6944-6955}, pmid = {39235524}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/physiopathology/complications ; Male ; Female ; Middle Aged ; Aged ; Prevalence ; Frontotemporal Dementia/physiopathology/epidemiology ; Cohort Studies ; Neuropsychological Tests ; Disease Progression ; Adult ; }, abstract = {BACKGROUND: This study aimed at (1) delivering generalizable estimates of the prevalence of frontotemporal-spectrum disorders (FTSDs) in non-demented ALS patients and (2) exploring their motor-functional correlates.

METHODS: N = 808 ALS patients without FTD were assessed for motor-functional outcomes-i.e., disease duration, severity (ALSFRS-R), progression rate (ΔFS), and stage (King's and Milano-Torino-MiToS-systems)-cognition-via the cognitive section of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS)-and behaviour-via the ECAS-Carer Interview. Neuropsychological phenotypes were retrieved via Strong's revised criteria-i.e., ALS cognitively and behaviourally normal (ALScbn) or cognitively and/or behaviourally impaired (ALSci/bi/cbi).

RESULTS: Defective ECAS-Total performances were detected in ~ 29% of patients, with the ECAS-Executive being failed by the highest number of patients (~ 30%), followed by the ECAS-Language, -Fluency, and -Memory (~ 15-17%) and -Visuospatial (~ %8). Apathy was the most frequent behavioural change (~ 28%), followed by loss of sympathy/empathy (~ 13%); remaining symptoms were reported in < 4% of patients. The distribution of Strong's classifications was as follows: ALScbn: 46.7%; ALSci/bi/cbi: 22.9%/20.0%/10.4%. Multinomial regressions on Strong's classifications revealed that lower ALSFRS-R scores were associated with a higher probability of ALSbi and ALScbi classifications (p ≤ .008). Higher King's and MiToS stages were associated with a higher probability of ALSbi classification (p ≤ .031).

CONCLUSIONS: FTSDs affect ~ 50% of non-demented ALS patients, with cognitive deficits being as frequent as behavioural changes. A higher degree of motor-functional involvement is associated with worse behavioural outcomes-with this link being weaker for cognitive deficits.}, } @article {pmid39236307, year = {2024}, author = {Doneddu, PE and Gallo, C and Gentile, L and Cocito, D and Falzone, Y and Di Stefano, V and Inghilleri, M and Cosentino, G and Matà, S and Mazzeo, A and Filosto, M and Peci, E and Sorrenti, B and Brighina, F and Moret, F and Vegezzi, E and Sperti, M and Risi, B and Nobile-Orazio, E and , }, title = {Comparison of the diagnostic accuracy of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society and American Association of Electrodiagnostic Medicine diagnostic criteria for multifocal motor neuropathy.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16444}, pmid = {39236307}, issn = {1468-1331}, support = {IIR-ITA-BXLT-001955/ IISR-2017-104226//Takeda Italia SPA/ ; //Fondazione Humanitas per la Ricerca/ ; }, mesh = {Humans ; Male ; Middle Aged ; Female ; *Electrodiagnosis/standards/methods ; *Sensitivity and Specificity ; Retrospective Studies ; Aged ; *Neural Conduction/physiology ; *Societies, Medical/standards ; *Polyneuropathies/diagnosis/physiopathology ; Adult ; Europe ; Motor Neuron Disease/diagnosis/physiopathology ; United States ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; }, abstract = {BACKGROUND AND PURPOSE: This study was undertaken to compare the sensitivity and specificity of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria for multifocal motor neuropathy (MMN) with those of the American Association of Electrodiagnostic Medicine (AAEM).

METHODS: Sensitivity and specificity of the two sets of criteria were retrospectively evaluated in 53 patients with MMN and 280 controls with axonal peripheral neuropathy, inflammatory demyelinating polyneuropathy, or amyotrophic lateral sclerosis. Comparison of the utility of nerve conduction studies with different numbers of nerves examined was also assessed.

RESULTS: The 2010 EFNS/PNS criteria had a sensitivity of 47% for definite MMN and 57% for probable/definite MMN, whereas the AAEM criteria had a sensitivity of 28% for definite MMN and 53% for probable/definite MMN. The sensitivity of the AAEM criteria was higher when utilizing area compared to amplitude reduction to define conduction block. Using supportive criteria, the sensitivity of the 2010 EFNS/PNS criteria for probable/definite MMN increased to 64%, and an additional 36% patients fulfilled the criteria (possible MMN). Specificity values for definite and probable/definite MMN were slightly higher with the AAEM criteria (100%) compared to the EFNS/PNS criteria (98.5% and 97%). Extended nerve conduction studies yielded slightly increased diagnostic sensitivity for both sets of criteria without significantly affecting specificity.

CONCLUSIONS: In our patient populations, the 2010 EFNS/PNS criteria demonstrated higher sensitivity but slightly lower specificity compared to the AAEM criteria. Extended nerve conduction studies are advised to achieve slightly higher sensitivity while maintaining very high specificity.}, } @article {pmid39236792, year = {2024}, author = {Hattori, H and Osumi, K and Tanaka, M and Arai, T and Nishimura, K and Yamamoto, N and Sakamoto, K and Goto, Y and Sugawara, Y}, title = {Discovery of 5-phenyl-3-ureidothiophene-2-carboxamides as protective agents for ALS patient iPSC-derived motor neurons.}, journal = {Bioorganic & medicinal chemistry letters}, volume = {113}, number = {}, pages = {129935}, doi = {10.1016/j.bmcl.2024.129935}, pmid = {39236792}, issn = {1464-3405}, mesh = {Humans ; *Induced Pluripotent Stem Cells/drug effects/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Motor Neurons/drug effects/metabolism ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; *Drug Discovery ; Structure-Activity Relationship ; Molecular Structure ; Thiophenes/chemistry/pharmacology/chemical synthesis ; Protein Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Protein Kinase Inhibitors/pharmacology/chemistry/chemical synthesis ; Dose-Response Relationship, Drug ; Superoxide Dismutase-1/metabolism/genetics ; Intracellular Signaling Peptides and Proteins ; }, abstract = {We discovered novel neuroprotective compounds by phenotypic screening using SOD1-mutant amyotrophic lateral sclerosis (ALS) patient induced pluripotent stem cell (iPSC)-derived motor neurons. Mechanistic analysis showed that the protective effect of initial hit compound 1 was likely due to the inhibition of MAP4Ks, including MAP4K4, a member of the MAP4K kinase family. Structural transformation led to compound 15f, which showed improved MAP4K4 inhibitory activity and superior neuroprotective effects compared to 1 in motor neurons. The results suggest that structural optimization based on MAP4K4 inhibitory activity might improve the neuroprotective effect of this series of compounds.}, } @article {pmid39236857, year = {2024}, author = {Reiter, RJ and Sharma, RN and Manucha, W and Rosales-Corral, S and Almieda Chuffa, LG and Loh, D and Luchetti, F and Balduini, W and Govitrapong, P}, title = {Dysfunctional mitochondria in age-related neurodegeneration: Utility of melatonin as an antioxidant treatment.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102480}, doi = {10.1016/j.arr.2024.102480}, pmid = {39236857}, issn = {1872-9649}, mesh = {*Melatonin/metabolism/pharmacology/therapeutic use ; Humans ; *Antioxidants/pharmacology/therapeutic use ; *Mitochondria/metabolism/drug effects ; *Aging/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; Oxidative Stress/drug effects ; }, abstract = {Mitochondria functionally degrade as neurons age. Degenerative changes cause inefficient oxidative phosphorylation (OXPHOS) and elevated electron leakage from the electron transport chain (ETC) promoting increased intramitochondrial generation of damaging reactive oxygen and reactive nitrogen species (ROS and RNS). The associated progressive accumulation of molecular damage causes an increasingly rapid decline in mitochondrial physiology contributing to aging. Melatonin, a multifunctional free radical scavenger and indirect antioxidant, is synthesized in the mitochondrial matrix of neurons. Melatonin reduces electron leakage from the ETC and elevates ATP production; it also detoxifies ROS/RNS and via the SIRT3/FOXO pathway it upregulates activities of superoxide dismutase 2 and glutathione peroxidase. Melatonin also influences glucose processing by neurons. In neurogenerative diseases, neurons often adopt Warburg-type metabolism which excludes pyruvate from the mitochondria causing reduced intramitochondrial acetyl coenzyme A production. Acetyl coenzyme A supports the citric acid cycle and OXPHOS. Additionally, acetyl coenzyme A is a required co-substrate for arylalkylamine-N-acetyl transferase, which rate limits melatonin synthesis; therefore, melatonin production is diminished in cells that experience Warburg-type metabolism making mitochondria more vulnerable to oxidative stress. Moreover, endogenously produced melatonin diminishes during aging, further increasing oxidative damage to mitochondrial components. More normal mitochondrial physiology is preserved in aging neurons with melatonin supplementation.}, } @article {pmid39239063, year = {2024}, author = {Pezeshgi, S and Ghaderi, S and Mohammadi, S and Karimi, N and Ziaadini, B and Mohammadi, M and Fatehi, F}, title = {Diffusion tensor imaging biomarkers and clinical assessments in amyotrophic lateral sclerosis (ALS) patients: an exploratory study.}, journal = {Annals of medicine and surgery (2012)}, volume = {86}, number = {9}, pages = {5080-5090}, pmid = {39239063}, issn = {2049-0801}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Biomarkers are needed to improve diagnosis, gauge progression, and evaluate treatment. Diffusion tensor imaging (DTI) is a promising biomarker for detecting microstructural alterations in the white matter tracts. This study aimed to assess DTI metrics as biomarkers and to examine their relationship with clinical assessments in patients with ALS. Eleven patients with ALS and 21 healthy controls (HCs) underwent 3T MRI with DTI. DTI metrics, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), were compared between key motor and extra-motor tract groups. Group comparisons and correlations between DTI metrics also correlated with clinical scores of disability (ALSFRS-R), muscle strength (dynamometry), and motor unit loss (MUNIX). Widespread differences were found between patients with ALS and HCs in DTI metrics, including decreased FA and increased diffusivity metrics. However, MD and RD are more sensitive metrics for detecting white matter changes in patients with ALS. Significant interhemispheric correlations between the tract DTI metrics were also observed. DTI metrics showed symmetry between the hemispheres and correlated with the clinical assessments. MD, RD, and AD increases significantly correlated with lower ALSFRS-R and MUNIX scores and weaker dynamometry results. DTI reveals microstructural damage along the motor and extra-motor regions in ALS patients. DTI metrics can serve as quantitative neuroimaging biomarkers for diagnosis, prognosis, monitoring of progression, and treatment. Combined analysis of imaging, electrodiagnostic, and functional biomarkers shows potential for characterizing disease pathophysiology and progression.}, } @article {pmid39239150, year = {2024}, author = {Vidovic, M and Lapp, HS and Weber, C and Plitzko, L and Seifert, M and Steinacker, P and Otto, M and Hermann, A and Günther, R}, title = {Comparative analysis of neurofilaments and biomarkers of muscular damage in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae288}, pmid = {39239150}, issn = {2632-1297}, abstract = {Diagnosis of the fatal neurodegenerative disease amyotrophic lateral sclerosis is challenging. Neurofilaments, indicative of neuronal damage, along with creatine kinase, creatinine, myoglobin, and troponin T, representing muscular damage, have been identified as promising fluid biomarkers. This study aims to comprehensively assess and compare their diagnostic and prognostic potential in a 'real-world' cohort of patients with amyotrophic lateral sclerosis. About 77 patients with amyotrophic lateral sclerosis and its clinical variants, and 26 age- and sex-matched controls with various neuromuscular and neurodegenerative diseases, were retrospectively included in this monocentric, cross-sectional study. Neurofilaments in cerebrospinal fluid and biomarkers of muscular damage in serum were measured and correlated with demographic features, motor function, survival time, clinical phenotypes, and the extent of upper and lower motor neuron involvement. Neurofilament, myoglobin, and troponin T concentrations were higher in patients with amyotrophic lateral sclerosis compared to disease controls. Higher neurofilament levels correlated with lower motor function and faster disease progression rate, while higher creatine kinase and creatinine concentrations were linked to preserved motor function. In contrast, troponin T elevation indicated poorer fine and gross motor functions. Increased neurofilament levels were associated with shorter survival, whereas biomarkers of muscular damage lacked survival correlation. Neurofilament concentrations were higher in classical amyotrophic lateral sclerosis than in progressive muscular atrophy, while myoglobin and troponin T levels were elevated in progressive muscular atrophy compared to primary lateral sclerosis. Neurofilaments were predominantly linked to upper motor neuron involvement. Our findings confirmed the robust diagnostic and prognostic value of neurofilaments in amyotrophic lateral sclerosis. Elevated neurofilament concentrations were associated with higher disease severity, faster disease progression, shorter survival, and predominant upper motor neuron degeneration. Biomarkers of muscular damage were inferior in distinguishing amyotrophic lateral sclerosis from other neuromuscular and neurodegenerative diseases. However, they may serve as complementary biomarkers and support in discriminating clinical variants of amyotrophic lateral sclerosis.}, } @article {pmid39239358, year = {2024}, author = {Segerstrom, SC and Kasarskis, EJ}, title = {The Seattle Amyotrophic Lateral Sclerosis (ALS) Patient Project Database: observational, longitudinal, dyadic characterization of people with ALS and their partners.}, journal = {Health psychology and behavioral medicine}, volume = {12}, number = {1}, pages = {2396137}, pmid = {39239358}, issn = {2164-2850}, support = {R03 NS128748/NS/NINDS NIH HHS/United States ; R16 NS129748/NS/NINDS NIH HHS/United States ; }, abstract = {INTRODUCTION: The median survival time in ALS is approximately 3 years, but survival times range from less than a year to more than 10 years and much variance in disease course remains to be explained. As is true for physical outcomes, there is considerable variance in QOL, which is influenced by psychological health, coping, and social support, among other psychosocial factors. The Seattle ALS Patient Project Database (SALSPPD) provides a unique opportunity for researchers to address established and novel hypotheses about disease progression and QOL in ALS.

METHODS: The SALSPPD is a longitudinal dataset of people with ALS (n = 143) and their partners (spouses, significant others, or caregivers; n = 123) from clinics and community-based ALS support groups. Participants were interviewed in their homes every 3 months for up to 18 months between March 1987 and August 1989. Follow-up phone calls were completed in 1990, 1994, and 2008, primarily to ascertain disease outcomes.

RESULTS: The provided data dictionary includes details of the over 500 variables measured in the study, which have been subsetted into domain datasets. Domains address physical, psychological, social, and behavioral status on the person with ALS and their partners. Missing data were coded according to their mechanism. Data are available in two formats: The person-level (wide) databases and the time-level (long) databases.

DISCUSSION: The SALSPPD will provide a rich resource to scientists interested in the natural history of ALS, psychosocial effects on ALS outcomes and vice versa, and psychosocial and disease outcomes of treatments.}, } @article {pmid39240038, year = {2024}, author = {García-Casanova, PH and Pérez-Martínez, P and Sevilla, T and Doménech, R and León, M and Vázquez-Costa, JF}, title = {Impact of SARS-CoV-2 infection and COVID-19 pandemic on the morbidity and mortality of amyotrophic lateral sclerosis patients in Valencia, Spain.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16465}, pmid = {39240038}, issn = {1468-1331}, support = {JR19/00030//Instituto de Salud Carlos III/ ; PI 21/00737//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *COVID-19/mortality/epidemiology ; *Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Spain/epidemiology ; Female ; Male ; Middle Aged ; Aged ; *Hospitalization/statistics & numerical data ; Risk Factors ; Noninvasive Ventilation/statistics & numerical data ; Pandemics ; SARS-CoV-2 ; }, abstract = {BACKGROUND AND PURPOSE: The purpose was to describe the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalization for coronavirus disease 2019 (COVID-19) and related death and to assess the impact of the pandemic in the survival of amyotrophic lateral sclerosis (ALS) patients.

METHODS: The risk of SARS-CoV-2 infection, hospitalization for COVID-19 and related death was assessed in ALS patients alive between March 2020 and July 2022. To evaluate its impact in the overall survival of ALS patients, the survival of patients who died before and during the pandemic was compared.

RESULTS: Amongst 263 ALS patients alive during the pandemic, 62 got infected during the study period (infection rate 14.34 per 100 person-years). Most infections (68%) occurred during the sixth wave (November 2021 to January 2022) and most patients (67%) were vaccinated at the time of infection. The hospitalization rate due to COVID-19 was 4.16 per 100 person-years. The multivariable model confirmed non-invasive ventilation (NIV) use prior to infection as a risk factor for hospitalization (odds ratio [OR] = 7.96, p = 0.003) and COVID-19 vaccination as a protective factor (OR = 0.093, p = 0.025) independent of age, sex and gastrostomy. Within 30 days after infection, 7% of non-ventilated patients started NIV and five patients (8.06%) died, of whom four were previously ventilated. The median survival of ALS patients was similar before and during the pandemic and no effect was found in the Cox regression model (hazard ratio 1.02, p = 0.89).

CONCLUSIONS: This study shows a high risk of severe COVID-19 amongst ALS patients requiring NIV. Nevertheless, the pandemic showed no impact in the overall survival of ALS patients, probably due to a high vaccination rate and an adequate access to healthcare resources.}, } @article {pmid39241118, year = {2024}, author = {Sharkey, RJ and Cortese, F and Goodyear, BG and Korngut, LW and Jacob, SM and Sharkey, KA and Kalra, S and Nguyen, MD and Frayne, R and Pfeffer, G}, title = {Longitudinal analysis of glymphatic function in amyotrophic lateral sclerosis and primary lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {12}, pages = {4026-4032}, pmid = {39241118}, issn = {1460-2156}, support = {//ALS Society of Canada/ ; //Barry Barrett Foundation/ ; //Rose Family Foundation/ ; //Hotchkiss Brain Institute/ ; /CAPMC/CIHR/Canada ; //Brain Canada Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; *Glymphatic System/diagnostic imaging ; *Diffusion Tensor Imaging ; Disease Progression ; White Matter/diagnostic imaging/pathology ; Adult ; Motor Neuron Disease/physiopathology/diagnostic imaging/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons in the brain and spinal cord. Accumulation of misfolded proteins is central to the pathogenesis of ALS and the glymphatic system is emerging as a potential therapeutic target to reduce proteinopathy. Using diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) to assess glymphatic function, we performed a longitudinal analysis of glymphatic function in ALS and compared it to a disorder in the motor neuron disease spectrum, primary lateral sclerosis (PLS). From a cohort of 45 participants from the Calgary site in the CALSNIC study (Canadian ALS Neuroimaging Consortium), including 18 ALS, 5 PLS and 22 control participants, DTI-ALPS was analysed and correlated to clinical features (age, sex, disease presentation, disease severity and progression rate) and white matter hyperintensity burden. This included longitudinal measurements at three time points, 4 months apart. The DTI-ALPS index was reduced in ALS participants compared with PLS and control participants across all three time points. There was no association with clinical factors; however, the index tended to decline with advancing age. Our study suggests heterogeneity in glymphatic dysfunction in motor neuron diseases that may be related to the underlying pathogenesis.}, } @article {pmid39241471, year = {2024}, author = {Casiraghi, V and Milone, I and Brusati, A and Peverelli, S and Doretti, A and Poletti, B and Maderna, L and Morelli, C and Ticozzi, N and Silani, V and Verde, F and Ratti, A}, title = {Quantification of serum TDP-43 and neurofilament light chain in patients with amyotrophic lateral sclerosis stratified by UNC13A genotype.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123210}, doi = {10.1016/j.jns.2024.123210}, pmid = {39241471}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/diagnosis ; Female ; Male ; *Neurofilament Proteins/blood/genetics ; Middle Aged ; Aged ; *Polymorphism, Single Nucleotide ; *DNA-Binding Proteins/genetics/blood ; *Genotype ; Biomarkers/blood ; Cohort Studies ; Adult ; Nerve Tissue Proteins ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition affecting upper and/or lower motor neurons and characterized neuropathologically by TDP-43 proteinopathy. Given its role in ALS pathobiology, it is currently under debate whether TDP-43 might represent a suitable ALS biomarker to be measured in patients' biofluids. The rs12608932 A > C single nucleotide polymorphism in the UNC13A gene is a risk factor for ALS and patients homozygous for the high-risk C allele display a higher burden of TDP-43 neuropathology than homozygotes for the low-risk A allele, although the association with TDP-43 levels in biofluids has never been evaluated. In this study, we measured serum levels of TDP-43 and neurofilament light chain (NFL) by Simoa technology in a cohort of 69 ALS patients stratified according to the UNC13A rs12608932 genotype compared to 43 neurologically healthy controls. By multiple linear regression analysis, serum TDP-43 was significantly elevated in ALS patients compared to controls, with UNC13A AA and AC, but not CC, ALS patients showing higher serum TDP-43 levels than controls. We also confirmed that serum NFL concentration was increased in ALS patients, without any correlation with the UNC13A genotype. Our results indicate that serum TDP-43 is higher in ALS patients compared to controls and that, in contrast to NFL, this increase is specifically associated with the UNC13A rs12608932 AA and AC genotypes, but not with the high-risk CC genotype. Studies in larger cohorts will be needed to confirm these findings and to elucidate the biological link between serum TDP-43 levels and UNC13A genotype.}, } @article {pmid39241508, year = {2024}, author = {Zheng, X and Liu, J and Wang, S and Xiao, Y and Jiang, Q and Li, C and Shang, H}, title = {Total physical activity, plant-based diet and neurodegenerative diseases: A prospective cohort study of the UK biobank.}, journal = {Parkinsonism & related disorders}, volume = {128}, number = {}, pages = {107125}, doi = {10.1016/j.parkreldis.2024.107125}, pmid = {39241508}, issn = {1873-5126}, mesh = {Humans ; Male ; Female ; *Exercise/physiology ; Middle Aged ; United Kingdom/epidemiology ; Aged ; *Diet, Vegetarian ; *Neurodegenerative Diseases/epidemiology ; *Biological Specimen Banks ; Prospective Studies ; Alzheimer Disease/epidemiology ; Parkinson Disease/epidemiology ; Amyotrophic Lateral Sclerosis/epidemiology ; Adult ; Cohort Studies ; Diet, Plant-Based ; UK Biobank ; }, abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) result from a complex interplay of genetic, environmental and aging factors. A balanced diet and adequate physical activity (PA) are recognized as pivotal components among modifiable environmental factors. The independent impact on NDD incidence has been previously debated. This investigation seeks to delineate the association between PA and NDDs across various levels of adherence to a plant-based diet.

METHODS: In this study, a cohort of 368,934 participants from the UK Biobank was analyzed. Total physical activity (TPA) levels and healthful plant-based diet index (hPDI) were calculated and categorized. A multiple adjusted Cox model was utilized to evaluate the influence of TPA and hPDI on common NDDs, respectively.

RESULTS: Finally, 4602 identified cases diagnosed as Alzheimer's disease (AD), Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS). We found that higher TPA was significantly associated with a reduced risk of developing AD (Q3: HR 0.87; Q4: HR 0.78) and PD (Q3: HR 0.86; Q4: HR 0.81). The protective effect was further accentuated with adherence to a plant-based diet. However, these connections were not observed in the analysis of ALS regardless of dietary patterns.

CONCLUSION: Our findings underscore a significant association between higher TPA and reduced risks of AD and PD, with an enhanced effect observed in conjunction with a plant-based diet. This study contributes to addressing the knowledge gap regarding the combined impact of TPA and a plant-based diet on NDDs occurrence, providing insights into potential underlying mechanisms.}, } @article {pmid39242198, year = {2024}, author = {Grassano, M and Canosa, A and D'Alfonso, S and Corrado, L and Brodini, G and Koumantakis, E and Cugnasco, P and Manera, U and Vasta, R and Palumbo, F and Mazzini, L and Gallone, S and Moglia, C and Dewan, R and Chia, R and Ding, J and Dalgard, C and Gibbs, RJ and Scholz, S and Calvo, A and Traynor, B and Chio, A}, title = {Intermediate HTT CAG repeats worsen disease severity in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {1}, pages = {100-102}, pmid = {39242198}, issn = {1468-330X}, support = {Z01 AG000933/ImNIH/Intramural NIH HHS/United States ; ZIA NS003154/ImNIH/Intramural NIH HHS/United States ; }, } @article {pmid39242252, year = {2024}, author = {Benmoussa, A and Assernannas, I and Maatoui-Belabbes, H and Dahmaoui, N and Qachouh, M and Cherkaoui, S and Lamchaheb, M and Rachid, M and Madani, A and Khoubila, N}, title = {[Acquired bone marrow aplasia in children and young adults under the age of 30: Experience of the Pediatric Hematology and Oncology Department of the 20 August Hospital, Casablanca].}, journal = {Bulletin du cancer}, volume = {111}, number = {10}, pages = {944-954}, doi = {10.1016/j.bulcan.2024.06.010}, pmid = {39242252}, issn = {1769-6917}, mesh = {Humans ; Male ; Female ; Infant ; Child, Preschool ; Child ; Adolescent ; Adult ; *Anemia, Aplastic/mortality/therapy ; Morocco/epidemiology ; Retrospective Studies ; Prognosis ; Time-to-Treatment ; *Cyclosporine/therapeutic use ; *Antilymphocyte Serum/therapeutic use ; *Hematopoietic Stem Cell Transplantation ; Treatment Outcome ; Delayed Diagnosis ; }, abstract = {Bone marrow aplasia is a rare and serious hematologic disorder. Although benign, it is a hematologic disorder whose prognosis can be poor and whose spontaneous development can be fatal. Treatment is long, difficult and costly. In developing countries, the mortality rate is high due to the difficulties of therapeutic management, both supportive and specific. We conducted a retrospective study of 92 cases of AM identified in the Pediatric Hematology and Oncology Department of the 20 Août University Hospital in Casablanca over a 10-year period (January 2010-January 2020). In this work, we present an overview of the situation and highlight the difficulties encountered in the management of AM in the Pediatric Hematology and Oncology Department of the University Hospital of Casablanca. In our study, the mean age was 19 years, ranging from 3 months to 29 years, with a peak in the 15-20 age group. The sex ratio (M/F) was 2.06, with a male predominance of 67%. In our series, only 35% of patients had complete bone marrow failure. An anemic syndrome was present in 92% of patients, and hemorrhagic and infectious syndromes were present in 70% and 41% of patients, respectively. The median time from diagnosis to treatment was 82 days. According to the Camitta score, 31% of our patients had mild AM, 41% had severe AM, and 28% had very severe AM. After etiologic evaluation, we concluded that 90% of the patients had idiopathic bone marrow aplasia, 2% had constitutional bone marrow aplasia, and 8% of the patients were suspected to have secondary bone marrow aplasia: post-hepatitis (3 cases), toxic (2 cases), drug-induced (1 case), and aplastic PNH (1 case). Mortality in the first three months after diagnosis was 21%. Sixty-nine percent of our patients received specific treatment: 28 were treated with cyclosporin (CIS) alone as first-line therapy, 20 received a combination of antilymphocyte serum (ALS) and cyclosporin, 2 received hematopoietic stem cell transplantation (HSCT), while 3 were treated with androgens alone. The overall response rate was 30% with CIS, 42% with ALS+CIS and 100% with HSCT. In our study, the overall death rate was 44%, while the one-year survival rate was 40%. It is important to note that septic shock was the leading cause of death (53% of deaths), followed by hemorrhagic shock (24%). This highlights the lack of hemodynamic resuscitation and symptomatic treatment. Our multivariate study defined the following risk factors as predictive of worse survival: age greater than 16 years (RR: 3.28; CI: 1.29-8.33; P=0.012), PNN less than 200 or very severe bone marrow aplasia (RR: 3.01; 1.1-8.08; P=0.028), and failure to receive any specific treatment (RR: 4.07; 1.77-9.35; P=0.0003). The high overall mortality in our series was due to several factors: inaccessibility to effective therapies, delayed diagnosis, failure to initiate specific treatment, inadequate symptomatic treatment, and geographical and financial inaccessibility.}, } @article {pmid39242281, year = {2025}, author = {Amalia, R and Prasetya Wibawa, A and Surya Aditya, R and Andana Pohan, R and Tetteng, B and Zuhroh, L and Ainy Sadijah, N}, title = {Enhancing caregiver well being by integrating mindfulness and technology in amyotrophic lateral sclerosis care.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {131}, number = {}, pages = {110819}, doi = {10.1016/j.jocn.2024.110819}, pmid = {39242281}, issn = {1532-2653}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/psychology ; Humans ; *Mindfulness/methods ; *Caregivers/psychology ; *Quality of Life ; Mobile Applications ; Stress, Psychological/therapy/psychology ; }, abstract = {This letter discusses the pressing issue of caregiver burden in Amyotrophic Lateral Sclerosis (ALS) care, emphasizing the potential of mindfulness practices to alleviate stress and improve quality of life for caregivers. The integration of digital platforms, such as mindfulness apps, offers an accessible and effective solution, particularly in resource-limited settings. By adopting these strategies, we can enhance caregiver well-being and overall patient care, making it a crucial consideration for global health interventions.}, } @article {pmid39242576, year = {2024}, author = {Phillips, MCL and Picard, M}, title = {Neurodegenerative disorders, metabolic icebergs, and mitohormesis.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {46}, pmid = {39242576}, issn = {2047-9158}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *Mitochondria/metabolism ; Hormesis/physiology ; Animals ; }, abstract = {Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders.}, } @article {pmid39242803, year = {2024}, author = {Monselise, EB and Vyazmensky, M and Scherf, T and Batushansky, A and Fishov, I}, title = {Author Correction: D-Glutamate production by stressed Escherichia coli gives a clue for the hypothetical induction mechanism of the ALS disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {20873}, doi = {10.1038/s41598-024-71813-5}, pmid = {39242803}, issn = {2045-2322}, } @article {pmid39243146, year = {2024}, author = {Jimenez, JV and Tang, MJ and Wilson, MW and Morrison, AH and Ackrivo, J and Choi, PJ}, title = {Initiation of noninvasive ventilation in patients with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {5}, pages = {1099-1103}, doi = {10.1002/mus.28250}, pmid = {39243146}, issn = {1097-4598}, support = {NIH NHLBI K23 HL-151879//Muscular Dystrophy Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/complications ; *Noninvasive Ventilation/methods ; Female ; Male ; Middle Aged ; Aged ; Retrospective Studies ; *Respiratory Insufficiency/therapy/etiology/physiopathology ; Vital Capacity/physiology ; Hypercapnia/therapy/etiology/physiopathology ; Cohort Studies ; }, abstract = {INTRODUCTION/AIMS: Noninvasive ventilation (NIV) has been shown to improve survival and symptom burden in patients with amyotrophic lateral sclerosis (ALS). However, limited data exist regarding the clinical and physiological parameters at the time of NIV initiation. This study aimed to describe the clinical characteristics and respiratory physiological markers in a cohort of ALS patients with chronic respiratory failure.

METHODS: This is a single-center retrospective cohort study of patients with ALS assessed for NIV initiation between February 2012 and January 2021. NIV was initiated based on insurance eligibility criteria: daytime hypercapnia, defined by partial pressure of carbon dioxide (PaCO2) >45 mm Hg using diurnal transcutaneous CO2 (TcCO2) as a surrogate, a maximal inspiratory pressure (MIP) <60 cmH2O or forced vital capacity (FVC) <50% predicted normal.

RESULTS: We identified 335 patients with ALS and chronic respiratory failure referred to an outpatient home ventilation clinic for NIV initiation. The mean age was 64 years ±11; 151 (45%) were female, 326 (97%) were white, and 100 (29%) had bulbar-onset ALS. At the time of NIV initiation, the mean FVC was 64% ± 19%, the mean MIP; 41 cmH2O ± 17, and diurnal TcCO2; 40 ± 6 mmHg. The most common reasons for NIV initiation were MIP <60 cmH2O (58%) and multiple concomitant indications (28%). Within 1 year of NIV initiation, 126 (37%) patients were deceased.

DISCUSSION: We found that impairment in inspiratory force was the most common reason for NIV initiation and often preceded significant declines in FVC.}, } @article {pmid39243983, year = {2025}, author = {Mohan, M and Mannan, A and Nauriyal, A and Singh, TG}, title = {Emerging targets in amyotrophic lateral sclerosis (ALS): The promise of ATP-binding cassette (ABC) transporter modulation.}, journal = {Behavioural brain research}, volume = {476}, number = {}, pages = {115242}, doi = {10.1016/j.bbr.2024.115242}, pmid = {39243983}, issn = {1872-7549}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; Animals ; *ATP-Binding Cassette Transporters/metabolism ; Signal Transduction/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative primarily affecting motor neurons, leading to disability and neuronal death, and ATP-Binding Cassette (ABC) transporter due to their role in drug efflux and modulation of various cellular pathways contributes to the pathogenesis of ALS. In this article, we extensively investigated various molecular and mechanistic pathways linking ALS transporter to the pathogenesis of ALS; this involves inflammatory pathways such as Mitogen-Activated Protein Kinase (MAPK), Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt), Toll-Like Receptor (TLR), Glycogen Synthase Kinase 3β (GSK-3β), Nuclear Factor Kappa-B (NF-κB), and Cyclooxygenase (COX). Oxidative pathways such as Astrocytes, Glutamate, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Sirtuin 1 (SIRT-1), Forkhead box protein O (FOXO), Extracellular signal-regulated kinase (ERK). Additionally, we delve into the role of autophagic pathways like TAR DNA-binding protein 43 (TDP-43), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and lastly, the apoptotic pathways. Furthermore, by understanding these intricate interactions, we aim to develop novel therapeutic strategies targeting ABC transporters, improving drug delivery, and ultimately offering a promising avenue for treating ALS.}, } @article {pmid39244645, year = {2025}, author = {Tang, IW and Hansen, J and Dickerson, AS and Weisskopf, MG}, title = {Occupational lead exposure and amyotrophic lateral sclerosis survival in the Danish National Patient Registry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {124-131}, pmid = {39244645}, issn = {2167-9223}, support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; R01 ES019188/ES/NIEHS NIH HHS/United States ; T32 ES007069/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/epidemiology/diagnosis ; Male ; Denmark/epidemiology ; Female ; *Registries ; Middle Aged ; *Occupational Exposure/adverse effects ; Aged ; *Lead/adverse effects ; Adult ; }, abstract = {OBJECTIVES: We investigated the relationship between occupational lead exposure and amyotrophic lateral sclerosis (ALS) survival in Denmark.

METHODS: We identified 2,161 ALS cases diagnosed from 1982 to 2013 with at least 5 years of employment history before ALS diagnosis, via the Danish National Patient Registry. Cases were followed until March 2017. We defined lead exposure as never employed in a lead job, ever employed in a lead job, and ever employed in a lead job by exposure probability (<50% vs. ≥50%), excluding jobs held in the 5 years before diagnosis in main analyses. Survival was evaluated using Cox proportional hazards models and stratified by sex and age of diagnosis.

RESULTS: Median age of diagnosis was 63.5 years, and individuals in lead-exposed jobs were diagnosed at a younger age. Adjusted hazard ratios (aHR) were slightly decreased for men ever lead-exposed (aHR:0.92, 95%CI: 0.80, 1.05) and more so among those diagnosed at age 60-69 (lead ≥ 50% aHR: 0.66, 95%CI: 0.45, 0.98), but reversed for men diagnosed at age 70 and later (aHR: 2.03, 95%CI: 1.13, 3.64). No apparent pattern was observed among women.

CONCLUSIONS: Occupational lead exposure contributed to shorter survival among men diagnosed at older ages. The inverse associations observed for men diagnosed earlier could relate to possible healthy worker hire effect or health advantages of working in lead-exposed jobs. Our results are consistent with an adverse impact of lead exposure on ALS survival at older ages, with the age at which lead's effects on survival worsen later on among those in lead-exposed jobs.}, } @article {pmid39246264, year = {2024}, author = {Iseli, LM and Poppe, C and Wangmo, T}, title = {Receiving and adjusting to a diagnosis of ALS: A qualitative study with informal caregivers.}, journal = {Palliative & supportive care}, volume = {}, number = {}, pages = {1-7}, doi = {10.1017/S1478951524001044}, pmid = {39246264}, issn = {1478-9523}, abstract = {OBJECTIVES: Diagnosis of amyotrophic lateral sclerosis (ALS) takes more than 1year from detection of first symptoms. The paper seeks to understand the ALS diagnostic process and adjustment from the perspective of informal caregivers.

METHODS: The data stems from an interview study with 9 current and 13 bereaved informal caregivers of people with ALS in Switzerland. The interviews were analyzed using thematic analysis.

RESULTS: We identified 3 key themes pertaining to ALS diagnosis. In the first theme, we present the close involvement of informal caregivers in the "diagnosis journey." Highlighted within this theme is the important role they play, which ultimately leads to diagnosis of ALS avoiding further delays. Second, we relay their perceptions on "diagnosis communication pitfalls" where they underlined empathy and planning from the part of medical professional, while communicating the terminal diagnosis of ALS. Participants' reactions and adjustments post-ALS diagnosis are described in "the aftermath of diagnosis." In this third theme, we highlight participants' shock and their need to rethink overall life plans and roles in their family.

SIGNIFICANCE OF THE RESULTS: Diagnosis communication that is clear, empathetic, and adjusted to the needs of the patients as well as their caregivers is critical. More work is needed to improve diagnosis communication for ALS patients. Receiving the diagnosis of ALS leads to complete changes in life of caregivers. It is therefore necessary that medical professionals provide adequate support that allows them to plan for their future.}, } @article {pmid39246712, year = {2024}, author = {Calderón-Garcidueñas, L and Cejudo-Ruiz, FR and Stommel, EW and González-Maciel, A and Reynoso-Robles, R and Torres-Jardón, R and Tehuacanero-Cuapa, S and Rodríguez-Gómez, A and Bautista, F and Goguitchaichvili, A and Pérez-Guille, BE and Soriano-Rosales, RE and Koseoglu, E and Mukherjee, PS}, title = {Single-domain magnetic particles with motion behavior under electromagnetic AC and DC fields are a fatal cargo in Metropolitan Mexico City pediatric and young adult early Alzheimer, Parkinson, frontotemporal lobar degeneration and amyotrophic lateral sclerosis and in ALS patients.}, journal = {Frontiers in human neuroscience}, volume = {18}, number = {}, pages = {1411849}, pmid = {39246712}, issn = {1662-5161}, abstract = {Metropolitan Mexico City (MMC) children and young adults exhibit overlapping Alzheimer and Parkinsons' diseases (AD, PD) and TAR DNA-binding protein 43 pathology with magnetic ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs). We studied magnetophoresis, electron microscopy and energy-dispersive X-ray spectrometry in 203 brain samples from 14 children, 27 adults, and 27 ALS cases/controls. Saturation isothermal remanent magnetization (SIRM), capturing magnetically unstable FeNPs ~ 20nm, was higher in caudate, thalamus, hippocampus, putamen, and motor regions with subcortical vs. cortical higher SIRM in MMC ≤ 40y. Motion behavior was associated with magnetic exposures 25-100 mT and children exhibited IRM saturated curves at 50-300 mT associated to change in NPs position and/or orientation in situ. Targeted magnetic profiles moving under AC/AD magnetic fields could distinguish ALS vs. controls. Motor neuron magnetic NPs accumulation potentially interferes with action potentials, ion channels, nuclear pores and enhances the membrane insertion process when coated with lipopolysaccharides. TEM and EDX showed 7-20 nm NP Fe, Ti, Co, Ni, V, Hg, W, Al, Zn, Ag, Si, S, Br, Ce, La, and Pr in abnormal neural and vascular organelles. Brain accumulation of magnetic unstable particles start in childhood and cytotoxic, hyperthermia, free radical formation, and NPs motion associated to 30-50 μT (DC magnetic fields) are critical given ubiquitous electric and magnetic fields exposures could induce motion behavior and neural damage. Magnetic UFPM/NPs are a fatal brain cargo in children's brains, and a preventable AD, PD, FTLD, ALS environmental threat. Billions of people are at risk. We are clearly poisoning ourselves.}, } @article {pmid39246739, year = {2024}, author = {Li, S and Gui, J and Passarelli, MN and Andrew, AS and Sullivan, KM and Cornell, KA and Traynor, BJ and Stark, A and Chia, R and Kuenzler, RM and Pioro, EP and Bradley, WG and Stommel, EW}, title = {Genome-Wide and Transcriptome-Wide Association Studies on Northern New England and Ohio Amyotrophic Lateral Sclerosis Cohorts.}, journal = {Neurology. Genetics}, volume = {10}, number = {5}, pages = {e200188}, pmid = {39246739}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an age-associated, fatal neurodegenerative disorder causing progressive paralysis and respiratory failure. The genetic architecture of ALS is still largely unknown.

METHODS: We performed a genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) to understand genetic risk factors for ALS using a population-based case-control study of 435 ALS cases and 279 controls from Northern New England and Ohio. Single nucleotide polymorphism (SNP) genotyping was conducted using the Illumina NeuroChip array. Odds ratios were estimated using covariate-adjusted logistic regression. We also performed a genome-wide SNP-smoking interaction screening. TWAS analyses used PrediXcan to estimate associations between predicted gene expression levels across 15 tissues (13 brain tissues, skeletal muscle, and whole blood) and ALS risk.

RESULTS: GWAS analyses identified the p.A382T missense variant (rs367543041, p = 3.95E-6) in the TARDBP gene, which has previously been reported in association with increased ALS risk and was found to share a close affinity with the Sardinian haplotype. Both GWAS and TWAS analyses suggested that ZNF235 is associated with decreased ALS risk.

DISCUSSION: Our results support the need for future evaluation to clarify the role of these potential genetic risk factors for ALS and to understand genetic susceptibility to environmental risk factors.}, } @article {pmid39249104, year = {2024}, author = {Hafsteinsdóttir, B and Farman, H and Lagerström, N and Zetterberg, H and Andersen, O and Novakova, L and Nellgård, B and Rosén, H and Malmeström, C and Rosenstein, I and Lycke, J and Axelsson, M}, title = {Neurofilament light chain as a diagnostic and prognostic biomarker in Guillain-Barré syndrome.}, journal = {Journal of neurology}, volume = {271}, number = {11}, pages = {7282-7293}, pmid = {39249104}, issn = {1432-1459}, support = {ALFGBG-722081//Swedish State Support for Clinical Research/ ; }, mesh = {Humans ; *Guillain-Barre Syndrome/blood/diagnosis/cerebrospinal fluid ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Female ; Male ; Middle Aged ; *Biomarkers/blood/cerebrospinal fluid ; Adult ; Prognosis ; Aged ; Amyotrophic Lateral Sclerosis/blood/diagnosis/cerebrospinal fluid ; }, abstract = {BACKGROUND: Elevated neurofilament light chain (NfL) levels are associated with worse prognosis in Guillain-Barré syndrome (GBS). Our objectives were to determine the utility of serum NfL (sNfL), cerebrospinal fluid (CSF)/serum NfL ratio and NfL index as prognostic and diagnostic biomarkers for GBS.

METHODS: We measured NfL in serum and/or CSF obtained from 96 GBS patients between 1989 and 2014 in western Sweden. The sNfL Z-scores, NfL ratios and NfL indices were calculated. Outcome was determined with the GBS disability scale (GBSDS) at 3 and 12 months. NfL parameters in GBS were compared with healthy controls (HC), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

RESULTS: The sNfL Z-score was higher for GBSDS > 2 at 3 months (median [IQR], 3.5 ng/L [3.2-4.0], vs 2.6 [1.7-3.4], p = 0.008) and at 12 months (3.6 ng/L [3.5-3.8] vs 2.6 [1.8-3.5], p = 0.049). NfL ratio and index were not associated with outcome. The area under the curve (AUC) for sNfL Z-score was 0.76 (95% CI 0.58-0.93, p < 0.0001) for GBSDS > 2 at 3 months. NfL ratio and index were lower in GBS than HC, MS, and ALS. The AUC for the NfL ratio was 0.66 (95% CI 0.55-0.78, p = 0.0018) and for the NfL index 0.86 (95% CI 0.78-0.93, p < 0.0001).

DISCUSSION: Our results confirm sNfL as prognostic biomarker for GBS and the precision was improved using the age-adjusted sNfL Z score. NfL index and Qalb are potential diagnostic biomarkers for GBS.}, } @article {pmid39249108, year = {2024}, author = {Jin, W and Boss, J and Bakulski, KM and Goutman, SA and Feldman, EL and Fritsche, LG and Mukherjee, B}, title = {Improving prediction models of amyotrophic lateral sclerosis (ALS) using polygenic, pre-existing conditions, and survey-based risk scores in the UK Biobank.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6923-6934}, pmid = {39249108}, issn = {1432-1459}, support = {R01TS000344/CC/CDC HHS/United States ; 20-IIA-532//ALS Association/ ; K23 ES027221/ES/NIEHS NIH HHS/United States ; K23ES027221/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology/diagnosis ; Humans ; United Kingdom/epidemiology ; *Multifactorial Inheritance ; Male ; Female ; Middle Aged ; *Biological Specimen Banks ; Aged ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Adult ; Phenotype ; UK Biobank ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) causes profound impairments in neurological function, and a cure for this devastating disease remains elusive. This study aimed to identify pre-disposing genetic, phenotypic, and exposure-related factors for amyotrophic lateral sclerosis using multi-modal data and assess their joint predictive potential.

METHODS: Utilizing data from the UK (United Kingdom) Biobank, we analyzed an unrelated set of 292 ALS cases and 408,831 controls of European descent. Two polygenic risk scores (PRS) are constructed: "GWAS Hits PRS" and "PRS-CS," reflecting oligogenic and polygenic ALS risk profiles, respectively. Time-restricted phenome-wide association studies (PheWAS) were performed to identify pre-existing conditions increasing ALS risk, integrated into phenotypic risk scores (PheRS). A poly-exposure score ("PXS") captures the influence of environmental exposures measured through survey questionnaires. We evaluate the performance of these scores for predicting ALS incidence and stratifying risk, adjusting for baseline demographic covariates.

RESULTS: Both PRSs modestly predicted ALS diagnosis but with increased predictive power when combined (covariate-adjusted receiver operating characteristic [AAUC] = 0.584 [0.525, 0.639]). PheRS incorporated diagnoses 1 year before ALS onset (PheRS1) modestly discriminated cases from controls (AAUC = 0.515 [0.472, 0.564]). The "PXS" did not significantly predict ALS. However, a model incorporating PRSs and PheRS1 improved the prediction of ALS (AAUC = 0.604 [0.547, 0.667]), outperforming a model combining all risk scores. This combined risk score identified the top 10% of risk score distribution with a fourfold higher ALS risk (95% CI [2.04, 7.73]) versus those in the 40%-60% range.

DISCUSSION: By leveraging UK Biobank data, our study uncovers pre-disposing ALS factors, highlighting the improved effectiveness of multi-factorial prediction models to identify individuals at highest risk for ALS.}, } @article {pmid39250425, year = {2025}, author = {Neuhaus, D and Rost, T and Haas, T and Wendebourg, MJ and Schulze, K and Schlaeger, R and Scheurer, E and Lenz, C}, title = {Comparative analysis of in situ and ex situ postmortem brain MRI: Evaluating volumetry, DTI, and relaxometry.}, journal = {Magnetic resonance in medicine}, volume = {93}, number = {1}, pages = {213-227}, doi = {10.1002/mrm.30264}, pmid = {39250425}, issn = {1522-2594}, support = {//Stiftung zur Foerderung der gastroenterologischen und der allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung/ ; //Neuromuscular Research Association Basel/ ; }, mesh = {*Postmortem Imaging/methods ; *Brain/diagnostic imaging/drug effects/pathology ; *Diffusion Tensor Imaging/instrumentation/methods ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Organ Size ; Tissue Fixation/methods ; *Formaldehyde/chemistry ; Anisotropy ; Humans ; Male ; Middle Aged ; Aged ; *Magnetic Resonance Imaging/instrumentation/methods ; }, abstract = {PURPOSE: To compare postmortem in situ with ex situ MRI parameters, including volumetry, diffusion tensor imaging (DTI), and relaxometry for assessing methodology-induced alterations, which is a crucial prerequisite when performing MRI biomarker validation.

METHODS: MRI whole-brain scans of five deceased patients with amyotrophic lateral sclerosis were performed at 3 T. In situ scans were conducted within 32 h after death (SD 18 h), and ex situ scans after brain extraction and 3 months of formalin fixation. The imaging protocol included MP2RAGE, DTI, and multi-contrast spin-echo and multi-echo gradient-echo sequences. Volumetry, fractional anisotropy, mean diffusivity, T1, T2, and T 2 * $$ {T} _2^{\ast } $$ have been assessed for specific brain regions.

RESULTS: When comparing ex situ to in situ values, the following results were obtained. Deep gray matter as well as the thalamus and the hippocampus showed a reduced volume. Fractional anisotropy was reduced in the cortex and the whole brain. Mean diffusivity was decreased in white matter and deep gray matter. T1 and T2 were reduced in all investigated structures, whereas T 2 * $$ {T} _2^{\ast } $$ was increased in the cortex.

CONCLUSION: The results of this study show that the volumes and MRI parameters of several brain regions are potentially affected by tissue extraction and subsequent formalin fixation, suggesting that methodological alterations are present in ex situ MRI. To avoid overlap of indistinguishable methodological and disease-related changes, we recommend performing in situ postmortem MRI as an additional intermediate step for in vivo MRI biomarker validation.}, } @article {pmid39251025, year = {2025}, author = {Del Rosso, JQ and Zaenglein, A and Callender, V and Schlosser, B and Graber, E and Keri, J and Weiss, J}, title = {Response to Reynolds et al's "Guidelines of care for the management of acne vulgaris".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {1}, pages = {e15}, doi = {10.1016/j.jaad.2024.07.1528}, pmid = {39251025}, issn = {1097-6787}, } @article {pmid39251159, year = {2024}, author = {Liu, Y and Chen, H and Zhang, Z and Wang, J}, title = {Development of an integrated framework for dissecting source-oriented ecological and health risks of heavy metals in soils.}, journal = {Chemosphere}, volume = {364}, number = {}, pages = {143299}, doi = {10.1016/j.chemosphere.2024.143299}, pmid = {39251159}, issn = {1879-1298}, mesh = {*Metals, Heavy/analysis ; *Soil Pollutants/analysis ; Environmental Exposure/statistics & numerical data ; Risk Assessment ; Soil/chemistry ; }, abstract = {Heavy metals (HMs) in soils pose significant risks on ecosystem and human health. To design targeted regulatory measures for mitigating and controlling the risk, it is necessary to accurately identify the pollution sources and environmental risks of soil HMs, as well as to reveal the linkages between them. To date, yet systematic investigation aimed at deciphering the links between source apportionment of soil HMs and their associated environmental risks is still lacking. To fill the gap, an integrated framework has been developed in this study and applied for dissecting the source-sink relationship and source-oriented ecological and health risks of soil HMs in Shanxi, a province with rich coal resource, in which long-term coal mining activities in history has resulted in soil HMs pollution and unavoidably posed environmental risks. Two advanced receptor models, multivariate curve resolution alternating least squares based on maximum likelihood principal component analysis (MCR-ALS/MLPCA) and multilinear engine 2 (ME2), have been employed for apportioning the potential sources, and their apportionment results are jointly incorporated into a modified ecological risk index and a probabilistic health risk assessment model for identifying the source-oriented ecological and health risks posed by soil metals. The results show that the soils in study area have been polluted by HMs (i.e., Cd, Cr, Hg and As) to varying degrees. Industrial activities (35%-35.8%), agricultural activities (11.1%-20.5%), atmospheric deposition (10.5%-13%) and mix source (31.5%-42.6%) are apportioned as the main contributors of soil HMs in the area. The source-oriented ecological risk assessment suggests Hg has presented significant ecological risk and largely contributed by the sources from atmospheric deposition and industrial activities. The source-oriented health risk assessment shows the non-carcinogenic hazard level and carcinogenic risk posed by soil HMs in the study area are acceptable. Relatively, industrial activities and mix source have contributed more on the health risks.}, } @article {pmid39251203, year = {2025}, author = {Rolf, O and Blana, A and Hagedorn, P}, title = {Implantation of Reverse Shoulder Endoprothesis Using Navigation.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {2}, pages = {176-180}, doi = {10.1055/a-2346-9916}, pmid = {39251203}, issn = {1864-6743}, abstract = {Die Implantation einer inversen Schulterendoprothese (TEP) stellt eine bewährte Methode zur Schmerzlinderung und Schulterfunktionsverbesserung dar. Die Ergebnisse variieren je nach Patientenalter, Krankheitsgrad und Erfahrung des Operateurs. Indikationen für eine inverse TEP sind vielfältig, von der Defektarthropathie bis hin zu Frakturen. Aktuelle Studien zeigen verbesserte Überlebensraten und reduzierte Komplikationen nach primärer Implantation. Die präoperative Planung mittels 3-D-CT oder MRT gilt als Goldstandard. Patientenspezifische Instrumente (PSI) wurden eingeführt, sind jedoch mit Kosten und Wartezeit verbunden. Die Navigation mit "Augmented Reality" (AR) bietet eine effizientere Alternative. Die intraoperative Übertragung der Planung auf den Patienten erfolgt über AR-Brillen und ermöglicht Echtzeitinformationen, wodurch der Chirurg den Blick vom Situs nicht abwenden muss. Dies optimiert den Workflow und bietet potenziell präzisere Implantationsresultate. Zusammenfassend bietet die Kombination von 3-D-Planung, Navigation und AR eine vielversprechende Methode für präzise und effiziente Implantationen von inversen Schulterendoprothesen. Allerdings steht der Nachweis verbesserter Standzeiten und Funktionsscores noch aus.}, } @article {pmid39251386, year = {2024}, author = {Liddell, JR and Hilton, JBW and Wang, YJ and Billings, JL and Nikseresht, S and Kysenius, K and Fuller-Jackson, JP and Hare, DJ and Crouch, PJ}, title = {Decreased spinal cord motor neuron numbers in mice depleted of central nervous system copper.}, journal = {Metallomics : integrated biometal science}, volume = {16}, number = {9}, pages = {}, pmid = {39251386}, issn = {1756-591X}, support = {//National Health and Medical Research Council/ ; }, mesh = {Animals ; *Copper/metabolism ; *Motor Neurons/metabolism/pathology ; *Spinal Cord/metabolism/pathology ; Mice ; *Copper Transporter 1/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Central Nervous System/metabolism ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Disrupted copper availability in the central nervous system (CNS) is implicated as a significant feature of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Solute carrier family 31 member 1 (Slc31a1; Ctr1) governs copper uptake in mammalian cells and mutations affecting Slc31a1 are associated with severe neurological abnormalities. Here, we examined the impact of decreased CNS copper caused by ubiquitous heterozygosity for functional Slc31a1 on spinal cord motor neurons in Slc31a1+/- mice. Congruent with the CNS being relatively susceptible to disrupted copper availability, brain and spinal cord tissue from Slc31a1+/- mice contained significantly less copper than wild-type littermates, even though copper levels in other tissues were unaffected. Slc31a1+/- mice had less spinal cord α-motor neurons compared to wild-type littermates, but they did not develop any overt physical signs of motor impairment. By contrast, ALS model SOD1G37R mice had fewer α-motor neurons than control mice and exhibited clear signs of motor function impairment. With the expression of Slc31a1 notwithstanding, spinal cord expression of genes related to copper handling revealed only minor differences between Slc31a1+/- and wild-type mice. This contrasted with SOD1G37R mice where changes in the expression of copper handling genes were pronounced. Similarly, the expression of genes related to toxic glial activation was unchanged in spinal cords from Slc31a1+/- mice but highly upregulated in SOD1G37R mice. Together, results from the Slc31a1+/- mice and SOD1G37R mice indicate that although depleted CNS copper has a significant impact on spinal cord motor neuron numbers, the manifestation of overt ALS-like motor impairment requires additional factors.}, } @article {pmid39252332, year = {2024}, author = {Li, LS and Tong, Y and Yuan, C and Zhang, W}, title = {Evaluation of diagnostic value and Mendelian randomization study of appendicitis hub genes obtained by WGCNA analysis.}, journal = {Medicine}, volume = {103}, number = {36}, pages = {e39307}, pmid = {39252332}, issn = {1536-5964}, mesh = {Humans ; *Appendicitis/genetics/diagnosis ; *Mendelian Randomization Analysis ; Gene Expression Profiling/methods ; ROC Curve ; Gene Regulatory Networks ; Nomograms ; Gastrointestinal Microbiome/genetics ; }, abstract = {The timely and precise diagnosis of appendicitis was deemed essential. This study sought to examine the diagnostic significance of hub genes linked to appendicitis and to delve deeper into the pathophysiology of the condition. Differential gene expression analysis revealed distinct genes in the appendicitis group compared to other abdominal pain group, while weighted gene co-expression network analysis identified appendicitis-associated modules. Further analysis of common genes was conducted using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis. The diagnostic efficiency of hub genes was explored through the use of nomograms and receiver operator characteristic curves. Additionally, immunoinfiltration analysis was performed to investigate the immune cell infiltration in both groups. The causal relationship between hub genes and appendicitis, as well as gut microbiota and appendicitis, was ultimately examined through Mendelian randomization. By conducting differential expression analysis and weighted gene co-expression network analysis, a total of 757 common genes were identified. Subsequent Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses revealed that these common genes were primarily associated with positive regulation of cell adhesion, focal adhesion, protein serine kinase activity, and amyotrophic lateral sclerosis. Utilizing Cytoscape software, the top 10 genes with the highest degree of interaction were identified as RPS3A, RPSA, RPL5, RPL37A, RPS27L, FLT3LG, ARL6IP1, RPL32, MRPL3, and GSPT1. Evaluation using nomograms and receiver operator characteristic curves demonstrated the diagnostic value of these hub genes. Ultimately, a causal relationship between hub genes and appendicitis was not identified in our study. Nevertheless, our findings indicate that appendicitis is correlated with 9 gut microbiota. This study identified 5 hub genes, specifically HSP90AA1, RPL5, MYC, CD44, and RPS3A, which exhibit diagnostic significance of appendicitis. Furthermore, the elucidation of these hub genes aids in enhancing our comprehension of the molecular pathways implicated in the development of appendicitis.}, } @article {pmid39253499, year = {2024}, author = {Thompson, EG and Spead, O and Akerman, SC and Curcio, C and Zaepfel, BL and Kent, ER and Philips, T and Vijayakumar, BG and Zacco, A and Zhou, W and Nagappan, G and Rothstein, JD}, title = {A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV-C9ORF72 (G4C2)66 mouse model.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39253499}, issn = {2692-8205}, support = {F32 NS120940/NS/NINDS NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. Despite displaying key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis, the AAV-(G4C2)66 mouse model in this study exhibits negligible neuronal loss, no motor deficits, and functionally unimpaired TAR DNA-binding protein-43 (TDP-43). While our findings indicate and support that this is a robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease associated neurodegeneration, TDP-43 dysfunction, gliosis, and motor performance. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.}, } @article {pmid39253877, year = {2024}, author = {Thornburg-Suresh, EJC and Summers, DW}, title = {Microtubules, Membranes, and Movement: New Roles for Stathmin-2 in Axon Integrity.}, journal = {Journal of neuroscience research}, volume = {102}, number = {9}, pages = {e25382}, pmid = {39253877}, issn = {1097-4547}, support = {R01 NS126191/NS/NINDS NIH HHS/United States ; R01NS126191/NH/NIH HHS/United States ; }, mesh = {*Stathmin/metabolism ; *Microtubules/metabolism ; Humans ; *Axons/metabolism/physiology ; Animals ; Cell Membrane/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; }, abstract = {Neurons establish functional connections responsible for how we perceive and react to the world around us. Communication from a neuron to its target cell occurs through a long projection called an axon. Axon distances can exceed 1 m in length in humans and require a dynamic microtubule cytoskeleton for growth during development and maintenance in adulthood. Stathmins are microtubule-associated proteins that function as relays between kinase signaling and microtubule polymerization. In this review, we describe the prolific role of Stathmins in microtubule homeostasis with an emphasis on emerging roles for Stathmin-2 (Stmn2) in axon integrity and neurodegeneration. Stmn2 levels are altered in Amyotrophic Lateral Sclerosis and loss of Stmn2 provokes motor and sensory neuropathies. There is growing potential for employing Stmn2 as a disease biomarker or even a therapeutic target. Meeting this potential requires a mechanistic understanding of emerging complexity in Stmn2 function. In particular, Stmn2 palmitoylation has a surprising contribution to axon maintenance through undefined mechanisms linking membrane association, tubulin interaction, and axon transport. Exploring these connections will reveal new insight on neuronal cell biology and novel opportunities for disease intervention.}, } @article {pmid39254482, year = {2025}, author = {García-Parra, B and Guiu, JM and Povedano, M and Modamio, P}, title = {A scoping review of the role of managed entry agreements in upcoming drugs for amyotrophic lateral sclerosis: learning from the case of spinal muscular atrophy.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {48-57}, doi = {10.1080/21678421.2024.2400522}, pmid = {39254482}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/economics ; Humans ; *Muscular Atrophy, Spinal/drug therapy/economics ; }, abstract = {INTRODUCTION: The therapeutic options for spinal muscular atrophy (SMA) are encouraging. However, there is currently no cure for amyotrophic lateral sclerosis (ALS). The clinical and economic uncertainty surrounding innovative treatments for rare neurodegenerative diseases makes it necessary to understand managed entry agreements (MEAs). The aim of this study was to review whether models of MEAs in SMA could be extrapolated to ALS.

METHODS: We performed a scoping review with information on MEAs on SMA in Web of Science (WOS), PubMed, Lyfegen Library, the National Institute for Health and Care Excellence (NICE), and the Canadian Agency for Drugs and Technologies in Health (CADTH).

RESULTS: We found 45 results in WOS and PubMed. After an initial survey, 10 were reviewed to assess eligibility, and three were selected. We obtained 44 results from Lyfegen Library, and three results each from NICE and CADTH.

CONCLUSION: The main objective of MEAs is to reduce uncertainty in the financing of drugs with a high budgetary impact and clinical concerns, as is the case with drugs for SMA and ALS. While the information available on MEAs in SMA is scarce, some conceptual models are publicly available. MEAs for long-term treatments for SMA could be used for the design of MEAs in ALS because of their similarities in economic and clinical uncertainty.}, } @article {pmid39254548, year = {2025}, author = {Zhang, M and Xiang, C and Niu, R and He, X and Luo, W and Liu, W and Gu, R}, title = {Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders: drug stability, targeting efficiency, and safety.}, journal = {Neural regeneration research}, volume = {20}, number = {7}, pages = {1883-1899}, pmid = {39254548}, issn = {1673-5374}, abstract = {Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied. However, their inability to cross the blood-brain barrier hampers the clinical translation of these therapeutic strategies. Liposomes are nanoparticles composed of lipid bilayers, which can effectively encapsulate drugs and improve drug delivery across the blood-brain barrier and into brain tissue through their targeting and permeability. Therefore, they can potentially treat traumatic and nontraumatic central nervous system diseases. In this review, we outlined the common properties and preparation methods of liposomes, including thin-film hydration, reverse-phase evaporation, solvent injection techniques, detergent removal methods, and microfluidics techniques. Afterwards, we comprehensively discussed the current applications of liposomes in central nervous system diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, and brain tumors. Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials. Additionally, their application as drug delivery systems in clinical practice faces challenges such as drug stability, targeting efficiency, and safety. Therefore, we proposed development strategies related to liposomes to further promote their development in neurological disease research.}, } @article {pmid39254699, year = {2024}, author = {Maccabeo, A and Pateri, MI and Pili, F and Pilotto, S and Pierri, V and Muroni, A and Ercoli, T and Montisci, R and Marchetti, MF and Martis, A and Fazzini, L and Defazio, G and Puligheddu, M and Borghero, G}, title = {Takotsubo syndrome in a Sardinian amyotrophic lateral sclerosis cohort.}, journal = {Journal of neurology}, volume = {271}, number = {12}, pages = {7489-7493}, pmid = {39254699}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications/physiopathology ; *Takotsubo Cardiomyopathy/physiopathology/epidemiology/etiology ; Female ; Italy/epidemiology ; Aged ; Middle Aged ; Retrospective Studies ; Cohort Studies ; Male ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is known to be associated with varying degrees of autonomic and cardiovascular dysfunction. Recent case reports showed that ALS may be linked to Takotsubo syndrome (TTS). We assessed the frequency of TTS in an incident ALS cohort from Sardinia, Italy, and investigated the relationship of TTS with ALS course.

METHODS: We retrospectively examined a 10-year (2010-2019) incident cohort of ALS patients of Sardinian ancestry, reported TTS frequency and patients' clinical characteristics. Following, we checked for TTS among patients with ALS onset after 2019 and focused on the same features as for the incident cohort.

RESULTS: Our incident cohort included 344 ALS patients and 5 of them (1.45%) developed TTS. All were female and their median onset age was 71.5 years (IQR 62.75-77). Two patients had spinal and three bulbar onset, though all patients had bulbar involvement and were at an advanced stage of disease (ALSFRS ≤ 25, King's ≥ 3) at TTS diagnosis. We identified a potential TTS trigger in three patients (hospitalization for PEG placement, pneumonia). Among patients who had ALS onset after 2019, we identified a further TTS case and described it.

CONCLUSION: TTS is not a rare condition in ALS. Female sex, bulbar involvement, and later age of disease onset may be important risk factors for developing this cardiac condition and a physical or psychological trigger is often observed. Despite autonomic dysfunction in ALS has been already demonstrated, the precise physiopathological mechanism underlying TTS needs to be further clarified.}, } @article {pmid39255062, year = {2024}, author = {Germeys, C and Vandoorne, T and Davie, K and Poovathingal, S and Heeren, K and Vermeire, W and Nami, F and Moisse, M and Quaegebeur, A and Sierksma, A and Rué, L and Sicart, A and Eykens, C and De Cock, L and De Strooper, B and Carmeliet, P and Van Damme, P and De Bock, K and Van Den Bosch, L}, title = {Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response.}, journal = {Cell reports}, volume = {43}, number = {9}, pages = {114719}, doi = {10.1016/j.celrep.2024.114719}, pmid = {39255062}, issn = {2211-1247}, support = {/ERC_/European Research Council/International ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Astrocytes/metabolism ; Disease Models, Animal ; Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors/genetics/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Interferons/metabolism ; *Motor Neurons/metabolism ; *Zebrafish/metabolism ; }, abstract = {Neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating cellular inflammation and metabolism. Using an oligonucleotide-based and a genetic approach, we showed that the downregulation of Egln2 protected motor neurons and mitigated the ALS phenotype in two zebrafish models and a mouse model of ALS. Single-nucleus RNA sequencing of the murine spinal cord revealed that the loss of EGLN2 induced an astrocyte-specific downregulation of interferon-stimulated genes, mediated via the stimulator of interferon genes (STING) protein. In addition, we found that the genetic deletion of EGLN2 restored this interferon response in patient induced pluripotent stem cell (iPSC)-derived astrocytes, confirming the link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a motor neuron protective target normalizing the astrocytic interferon-dependent inflammatory axis in vivo, as well as in patient-derived cells.}, } @article {pmid39255192, year = {2024}, author = {Hwang, RD and Lu, Y and Tang, Q and Periz, G and Park, G and Li, X and Xiang, Q and Liu, Y and Zhang, T and Wang, J}, title = {DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {39255192}, issn = {2050-084X}, support = {R01 NS128494/NS/NINDS NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; NS074324/NH/NIH HHS/United States ; NS089616/NH/NIH HHS/United States ; NS128494/NH/NIH HHS/United States ; NS110098/NH/NIH HHS/United States ; }, mesh = {Animals ; *Proteasome Endopeptidase Complex/metabolism ; *Proteostasis ; Humans ; Drosophila/metabolism ; Autophagy ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Neurons/metabolism ; Drosophila melanogaster/metabolism/genetics ; }, abstract = {Proteotoxic stress impairs cellular homeostasis and underlies the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, the loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 in Drosophila and mammalian neurons. DBT is upregulated in the tissues of ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.}, } @article {pmid39257530, year = {2024}, author = {Baird, MC and Likhite, SB and Vetter, TA and Caporale, JR and Girard, HB and Roussel, FS and Howard, AE and Schwartz, MK and Reed, AR and Kaleem, A and Zhang, X and Meyer, KC}, title = {Combination AAV therapy with galectin-1 and SOD1 downregulation demonstrates superior therapeutic effect in a severe ALS mouse model.}, journal = {Molecular therapy. Methods & clinical development}, volume = {32}, number = {3}, pages = {101312}, pmid = {39257530}, issn = {2329-0501}, abstract = {Neuroinflammation is a miscreant in accelerating progression of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, treatments targeting neuroinflammation alone have led to disappointing results in clinical trials. Both neuronal and non-neuronal cell types have been implicated in the pathogenesis of ALS, and multiple studies have shown correction of each cell type has beneficial effects on disease outcome. Previously, we shown that AAV9-mediated superoxide dismutase 1 (SOD1) suppression in motor neurons and astrocytes significantly improves motor function and extends survival in ALS mouse models. Despite neuron and astrocyte correction, ALS mice still succumb to death with microgliosis observed in endpoint tissue. Therefore, we hypothesized that the optimal therapeutic approach will target and simultaneously correct motor neurons, astrocytes, and microglia. Here, we developed a novel approach to indirectly target microglia with galectin-1 (Gal1) and combined this with our previously established AAV9.SOD1.short hairpin RNA treatment. We show Gal1 conditioning of SOD1 [G93A] microglia decreases inflammatory markers and rescues motor neuron death in vitro. When paired with SOD1 downregulation, we found a synergistic effect of combination treatment in vivo and show a significant extension of survival of SOD1 [G93A] mice over SOD1 suppression alone. These results highlight the importance of targeting inflammatory microglia as a critical component in future therapeutic development.}, } @article {pmid39258586, year = {2025}, author = {Sommers-Spijkerman, M and Zwarts-Engelbert, A and Kruitwagen-Van Reenen, E and Van Eijk, RPA and Visser-Meily, JMA and Heijmans, E and Austin, J and Drossaert, C and Bohlmeijer, E and Beelen, A}, title = {Acceptability and potential benefit of a self-compassion intervention for people living with amyotrophic lateral sclerosis: a mixed methods pilot study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {29-39}, doi = {10.1080/21678421.2024.2400516}, pmid = {39258586}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; Pilot Projects ; Female ; Male ; Middle Aged ; *Empathy/physiology ; Aged ; *Adaptation, Psychological ; *Caregivers/psychology ; Adult ; Surveys and Questionnaires ; Psychological Distress ; *Self Concept ; }, abstract = {OBJECTIVE: This proof-of-concept study aimed to explore the acceptability and potential benefit of a self-guided online self-compassion intervention to aid resilient coping and reduce emotional distress among patients and caregivers living with ALS.

METHODS: A single-arm pilot study was conducted in 20 adults living with ALS either as a patient or as a caregiver. Acceptability was examined using questionnaires (n = 20) and semi-structured interviews (n = 9). Potential benefit was assessed as changes in self-compassion, self-criticism and emotional distress, determined using psychological questionnaires at 3 and 6 weeks. Questionnaires were analyzed using linear mixed-effects models and interview data using inductive thematic analysis.

RESULTS: Out of 20 participants who started the intervention, 16 completed the study (80%). The majority of study completers (12/16) were satisfied with the intervention, but the data suggest room for improvement in terms of personalization. Qualitative data revealed multiple psychological benefits of using the intervention, including self-kindness, emotional self-awareness and savoring. Although not statistically significant, quantitative data showed positive trends with increased self-compassion (mean difference: 2.07; 95% CI: -.5.76 - 1.63) and reduced self-criticism (mean difference: -2.62; 95% CI: -.1.97 - 7.23) and emotional distress (mean difference: -2.49; 95% CI: -.51 - 5.50) at week 6 compared to baseline.

CONCLUSIONS: The findings suggest that a self-compassion intervention is acceptable to people living with ALS, but its beneficial effects and the mechanisms involved have yet to be established in larger and more diverse samples, using controlled designs.}, } @article {pmid39258588, year = {2025}, author = {Walsh, S and Simmons, Z and Miyamoto, S and Geronimo, A}, title = {A nurse coaching intervention to improve support to individuals living with ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {22-28}, doi = {10.1080/21678421.2024.2399154}, pmid = {39258588}, issn = {2167-9223}, support = {UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/nursing ; Male ; Female ; Middle Aged ; *Quality of Life/psychology ; *Mentoring/methods ; Aged ; Self Efficacy ; Motivational Interviewing/methods ; Caregivers/psychology ; Adult ; }, abstract = {OBJECTIVE: Health coaching may supplement the multidisciplinary ALS clinic model to facilitate patient-centered health behavior change. The aim of this study was to determine the effects of nurse health coaching (NHC) on the quality of life and self-efficacy of individuals living with ALS.

METHODS: Twenty-nine participants were randomized at 1:1 to the standard of care and coaching arms. All participants attended multidisciplinary ALS clinic visits quarterly, at which times they completed assessments of quality of life and self-efficacy. Those in the coaching arm participated in monthly coaching with a nurse coach over 12 months. The coaching sessions utilized motivational interviewing to identify personal goals along with barriers and solutions to achieve them. Linear mixed-effect models were used to quantify the effect of coaching on quality of life and self-efficacy outcomes. Thematic analysis was performed to summarize the participants' experiences with coaching.

RESULTS: Adherence to the coaching intervention was good. No effects of coaching were observed on the primary outcomes of quality of life and self-efficacy, although debriefed participants reported that they would recommend it to others. Patients and caregivers reflected on the impacts of coaching that extended beyond the pre-defined study outcomes and measures put in place to gauge effectiveness.

CONCLUSIONS: The elicited qualitative themes illustrating patient experience of coaching demonstrate the utility of nurse coaching as an important adjunct support to complement the multidisciplinary ALS clinic model.}, } @article {pmid39258714, year = {2024}, author = {Winroth, I and Börjesson, A and Andersen, PM and Karlsson, T}, title = {Cognitive deficits in ALS patients with SOD1 mutations.}, journal = {Journal of clinical and experimental neuropsychology}, volume = {46}, number = {7}, pages = {669-682}, doi = {10.1080/13803395.2024.2393366}, pmid = {39258714}, issn = {1744-411X}, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/genetics/complications/physiopathology ; *Superoxide Dismutase-1/genetics ; Middle Aged ; *Mutation ; Aged ; *Neuropsychological Tests ; Cognitive Dysfunction/physiopathology/genetics/etiology ; Adult ; Memory, Short-Term/physiology ; C9orf72 Protein/genetics ; Bayes Theorem ; }, abstract = {OBJECTIVE: Cognitive decline is common in patients with amyotrophic lateral sclerosis (ALS), especially in carriers of the mutation C9ORF72HRE. However, cognitive impairment is poorly understood in carriers of mutations in other genes causing ALS. We performed a comprehensive neuropsychological testing in patients with mutations in the SOD1 (mSOD1) gene.

METHODS: We examined 5 cognitive domains in 48 symptomatic patients with either hereditary or sporadic ALS. These were compared with 37 matched controls.

RESULTS: Carriers of SOD1-mutations and sporadic ALS had circumscribed deficits, but in a pattern different from C9ORF72HRE. All groups had deficits in working memory, although mSOD1-carriers significantly outperform sporadic ALS and C9ORF72HRE in an attention-driven visuospatial task involving copying a complex figure. Carriers of the D90A-SOD1 mutation overall performed as well as or better than carriers of other SOD1-mutations, except complex working memory. Bayesian analyses suggest (with evidence of moderate strength) that tasks involving the language domain did not differ between controls, mSOD1 and sporadic ALS.

CONCLUSION: Distinct cognitive impairments are prevalent in different ALS-syndromes and vary in patients with different pathogenic SOD1 mutations. The type and degree of impairment differed depending on genotype and was significantly least pronounced in patients homozygous for the D90A SOD1 mutation. The presence of cognitive deficits may influence optimal clinical management and intervention. We propose that cognitive assessment should be included in the routine examination of new patients suspected of ALS. Neuropsychological assessment is an under-recognized outcome parameter in clinical drug trials.}, } @article {pmid39258740, year = {2025}, author = {O'Connell, C and Kavanaugh, MS and Cummings, C and Genge, A}, title = {How to break the news in amyotrophic lateral sclerosis/motor neuron disease: practical guidelines from experts.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {5-14}, doi = {10.1080/21678421.2024.2397517}, pmid = {39258740}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/diagnosis ; Quality of Life/psychology ; *Communication ; *Motor Neuron Disease/psychology ; *Practice Guidelines as Topic/standards ; }, abstract = {In amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), it is necessary to communicate difficult news during the initial diagnosis and throughout the disease trajectory as the condition progresses. However, delivering difficult news to people with ALS/MND is an emotionally demanding task for healthcare and allied health professionals-one for which many feel ill-prepared because of limited training in this area. Ineffective communication of difficult news damages the patient-provider relationship and negatively impacts patient quality of life (QoL). To address this issue, we developed the A-L S-PIKES protocol based on available literature and our extensive clinical experience. It provides easy-to-follow, stepwise guidelines to effectively deliver difficult news to people with ALS/MND (PALS) that includes: Advance Preparation (preparing for the discussion logistically and emotionally); Location & Setting (creating a comfortable setting that fosters rapport); Patient's Perceptions (assessing PALS' understanding and perception of their condition); Invitation (seeking PALS' permission to share information); Knowledge (sharing information in a clear, understandable manner); Emotion/Empathy (addressing emotions with empathy and providing emotional support); and Strategy & Summary (summarizing the discussion and collaboratively developing a plan of action). A-L S-PIKES provides practical guidelines on how to prepare for and conduct these challenging conversations. It emphasizes effective communication tailored to the individual needs of PALS and their families, empathy, sensitivity, and support for PALS' emotional well-being and autonomy. The aim of A-L S-PIKES is to both enhance skills and confidence in delivering difficult news and to improve the QoL of PALS and their families. Future studies should systematically evaluate the feasibility and effectiveness of A-L S-PIKES to establish its utility in clinical practice.}, } @article {pmid39258797, year = {2024}, author = {Coppedè, F}, title = {DNA methylation in amyotrophic lateral sclerosis: where do we stand and what is next?.}, journal = {Epigenomics}, volume = {16}, number = {17}, pages = {1185-1196}, pmid = {39258797}, issn = {1750-192X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *DNA Methylation ; Epigenesis, Genetic ; }, abstract = {Genes involved in immune response, inflammation and metabolism are among those most likely affected by changes in DNA methylation (DNAm) and expression levels in amyotrophic lateral sclerosis (ALS) tissues. Unfortunately, it is still largely unclear whether any of these changes precede the onset of disease symptoms or whether most of them are the result of the muscular and metabolic changes that follow symptoms onset. In this article the author discusses the strengths and limitations of the available studies of DNAm in ALS and provides some suggestions on what, in his opinion, could be done in the near future for a better understanding of the DNAm changes occurring in ALS, their link with environmental exposures and their potential clinical utility.}, } @article {pmid39259763, year = {2024}, author = {Caredio, D and Koderman, M and Frontzek, KJ and Sorce, S and Nuvolone, M and Bremer, J and Mariutti, G and Schwarz, P and Madrigal, L and Mitrovic, M and Sellitto, S and Streichenberger, N and Scheckel, C and Aguzzi, A}, title = {Prion diseases disrupt glutamate/glutamine metabolism in skeletal muscle.}, journal = {PLoS pathogens}, volume = {20}, number = {9}, pages = {e1012552}, pmid = {39259763}, issn = {1553-7374}, support = {278611/ERC_/European Research Council/International ; 179040/SNSF_/Swiss National Science Foundation/Switzerland ; RGP0001/2022//Human Frontiers Science Program/ ; }, mesh = {Animals ; *Muscle, Skeletal/metabolism/pathology ; *Glutamine/metabolism ; *Glutamic Acid/metabolism ; Mice ; *Prion Diseases/metabolism/genetics ; Humans ; Glutamate-Ammonia Ligase/metabolism ; Creutzfeldt-Jakob Syndrome/metabolism/pathology/genetics ; Female ; Mice, Inbred C57BL ; }, abstract = {In prion diseases (PrDs), aggregates of misfolded prion protein (PrPSc) accumulate not only in the brain but also in extraneural organs. This raises the question whether prion-specific pathologies arise also extraneurally. Here we sequenced mRNA transcripts in skeletal muscle, spleen and blood of prion-inoculated mice at eight timepoints during disease progression. We detected gene-expression changes in all three organs, with skeletal muscle showing the most consistent alterations. The glutamate-ammonia ligase (GLUL) gene exhibited uniform upregulation in skeletal muscles of mice infected with three distinct scrapie prion strains (RML, ME7, and 22L) and in victims of human sporadic Creutzfeldt-Jakob disease. GLUL dysregulation was accompanied by changes in glutamate/glutamine metabolism, leading to reduced glutamate levels in skeletal muscle. None of these changes were observed in skeletal muscle of humans with amyotrophic lateral sclerosis, Alzheimer's disease, or dementia with Lewy bodies, suggesting that they are specific to prion diseases. These findings reveal an unexpected metabolic dimension of prion infections and point to a potential role for GLUL dysregulation in the glutamate/glutamine metabolism in prion-affected skeletal muscle.}, } @article {pmid39260140, year = {2024}, author = {Emori, S and Kume, K and Nakayama, Y and Ito, H and Kawakami, H}, title = {C9orf72 repeat expansions in Wakayama: One potential cause of amyotrophic lateral sclerosis in the Kii Peninsula, Japan.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123209}, doi = {10.1016/j.jns.2024.123209}, pmid = {39260140}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *C9orf72 Protein/genetics ; Japan/epidemiology ; Male ; Female ; *DNA Repeat Expansion/genetics ; Middle Aged ; Aged ; Proteins/genetics ; Adult ; Aged, 80 and over ; Genetic Predisposition to Disease/genetics ; Haplotypes ; }, abstract = {A cluster of cases of amyotrophic lateral sclerosis (ALS) exists in the southern part of the Kii Peninsula in Japan. Although both genetic and environmental factors are thought to be causative, the critical cause of this cluster has not been identified. C9orf72 is the most common genetic factor in both familial and sporadic C9orf72-related ALS in people of European ancestry, but it is rare among Japanese populations. However, a previous report revealed that the frequency of C9orf72-related ALS was significantly higher in the cluster area. We evaluated the proportion of C9orf72 hexanucleotide repeat expansions in 99 cases of ALS diagnosed in Wakayama Prefecture, including the cluster area, by using repeat-primed polymerase chain reaction and fluorescence fragment length analysis. We found that 2 of the 99 patients (0 % of those with familial ALS and 2.4 % of those with sporadic ALS) had hexanucleotide repeat expansions in C9orf72, and long-read sequencing revealed that these expansions were causative. No expansions were observed among 90 patients with Parkinson's disease or among 90 healthy controls. Haplotype analysis with long-read sequencing data revealed that the two patients with repeat expansions shared the common haplotype with that previously reported in Finnish patients with C9orf72-related ALS, which suggests a founder effect. C9orf72 was thought to be a rare causative gene in Japan, but this study revealed that it may be relatively common in Wakayama Prefecture.}, } @article {pmid39260416, year = {2024}, author = {Arseni, D and Nonaka, T and Jacobsen, MH and Murzin, AG and Cracco, L and Peak-Chew, SY and Garringer, HJ and Kawakami, I and Suzuki, H and Onaya, M and Saito, Y and Murayama, S and Geula, C and Vidal, R and Newell, KL and Mesulam, M and Ghetti, B and Hasegawa, M and Ryskeldi-Falcon, B}, title = {Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C.}, journal = {Nature}, volume = {634}, number = {8034}, pages = {662-668}, pmid = {39260416}, issn = {1476-4687}, support = {R01 AG077444/AG/NIA NIH HHS/United States ; RF1 AG071177/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; U01 NS110437/NS/NINDS NIH HHS/United States ; R01 NS085770/NS/NINDS NIH HHS/United States ; P30 AG013854/AG/NIA NIH HHS/United States ; R01 AG056258/AG/NIA NIH HHS/United States ; R01 DC008552/DC/NIDCD NIH HHS/United States ; RF1 NS110437/NS/NINDS NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; R01 AG080001/AG/NIA NIH HHS/United States ; R01 AG071177/AG/NIA NIH HHS/United States ; R01 NS137469/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyloid/chemistry/metabolism/ultrastructure ; *Annexins/chemistry/metabolism/ultrastructure ; Aphasia/complications/metabolism ; *Brain/metabolism/pathology/ultrastructure ; Cryoelectron Microscopy ; *DNA-Binding Proteins/chemistry/metabolism/ultrastructure ; *Frontotemporal Dementia/classification/complications/metabolism ; Models, Molecular ; Protein Multimerization ; }, abstract = {Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system[1]. Human genetic studies have established a causal role for protein assembly in neurodegeneration[2]. However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in cryo-electron microscopy have enabled the structures of the protein filaments to be determined from the brains of patients[1]. All neurodegenerative diseases studied to date have been characterized by the self-assembly of proteins in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) types A and B[3,4]. Here we used cryo-electron microscopy to determine filament structures from the brains of individuals with FTLD-TDP type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/G284-N345 and ANXA11 residues L39-Y74 from their respective low-complexity domains. Regions of TDP-43 and ANXA11 that were previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as an approximately 22 kDa N-terminal fragment lacking the annexin core domain. Immunohistochemistry of brain sections showed the colocalization of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP type C. This work establishes a central role for ANXA11 in FTLD-TDP type C. The unprecedented formation of heteromeric amyloid filaments in the human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.}, } @article {pmid39260590, year = {2024}, author = {Petel Légaré, V and Harji, ZA and Rampal, CJ and Antonicka, H and Gurberg, TJN and Persia, O and Rodríguez, EC and Shoubridge, EA and Armstrong, GAB}, title = {CHCHD10[P80L] knock-in zebrafish display a mild ALS-like phenotype.}, journal = {Experimental neurology}, volume = {382}, number = {}, pages = {114945}, doi = {10.1016/j.expneurol.2024.114945}, pmid = {39260590}, issn = {1090-2430}, mesh = {Animals ; *Zebrafish ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Phenotype ; *Mitochondrial Proteins/genetics ; Zebrafish Proteins/genetics ; Motor Neurons/metabolism/pathology ; Gene Knock-In Techniques ; Animals, Genetically Modified ; Disease Models, Animal ; Neuromuscular Junction/pathology/genetics/metabolism ; }, abstract = {Mutations in the nuclear-encoded mitochondrial gene CHCHD10 have been observed in patients with a spectrum of diseases that include amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathogenic nature of disease-associated variants of CHCHD10 we generated a zebrafish knock-in (KI) model expressing the orthologous ALS-associated CHCHD10[P80L] variant (zebrafish: Chchd10[P83L]). Larval chchd10[P83L/P83L] fish displayed reduced Chchd10 protein expression levels, motor impairment, reduced survival and abnormal neuromuscular junctions (NMJ). These deficits were not accompanied by changes in transcripts involved in the integrated stress response (ISR), phenocopying previous findings in our knockout (chchd10[-/-]). Adult, 11-month old chchd10[P83L/P83L] zebrafish, displayed smaller slow- and fast-twitch muscle cell cross-sectional areas compared to wild type zebrafish muscle cells. Motoneurons in the spinal cord of chchd10[P83L/P83L] zebrafish displayed similar cross-sectional areas to that of wild type motor neurons and significantly fewer motor neurons were observed when compared to chchd2[-/-] adult spinal cords. Bulk RNA sequencing using whole spinal cords of 7-month old fish revealed transcriptional changes associated with neuroinflammation, apoptosis, amino acid metabolism and mt-DNA inflammatory response in our chchd10[P83L/P83L] model. The findings presented here, suggest that the CHCHD10[P80L] variant confers an ALS-like phenotype when expressed in zebrafish.}, } @article {pmid39261725, year = {2024}, author = {Abe, P and Lavalley, A and Morassut, I and Santinha, AJ and Roig-Puiggros, S and Javed, A and Klingler, E and Baumann, N and Prados, J and Platt, RJ and Jabaudon, D}, title = {Molecular programs guiding arealization of descending cortical pathways.}, journal = {Nature}, volume = {634}, number = {8034}, pages = {644-651}, pmid = {39261725}, issn = {1476-4687}, mesh = {Animals ; Female ; Male ; Mice ; Axons/metabolism ; Gene Expression Regulation, Developmental ; Motor Cortex/cytology/metabolism ; *Neocortex/anatomy & histology/cytology/metabolism ; *Neural Pathways ; *Neurons/metabolism/cytology ; Single-Cell Gene Expression Analysis ; Transcription Factors/metabolism ; }, abstract = {Layer 5 extratelencephalic (ET) neurons are present across neocortical areas and send axons to multiple subcortical targets[1-6]. Two cardinal subtypes exist[7,8]: (1) Slco2a1-expressing neurons (ETdist), which predominate in the motor cortex and project distally to the pons, medulla and spinal cord; and (2) Nprs1- or Hpgd-expressing neurons (ETprox), which predominate in the visual cortex and project more proximally to the pons and thalamus. An understanding of how area-specific ETdist and ETprox emerge during development is important because they are critical for fine motor skills and are susceptible to spinal cord injury and amyotrophic lateral sclerosis[9-12]. Here, using cross-areal mapping of axonal projections in the mouse neocortex, we identify the subtype-specific developmental dynamics of ET neurons. Whereas subsets of ETprox emerge by pruning of ETdist axons, others emerge de novo. We outline corresponding subtype-specific developmental transcriptional programs using single-nucleus sequencing. Leveraging these findings, we use postnatal in vivo knockdown of subtype-specific transcription factors to reprogram ET neuron connectivity towards more proximal targets. Together, these results show the functional transcriptional programs driving ET neuron diversity and uncover cell subtype-specific gene regulatory networks that can be manipulated to direct target specificity in motor corticofugal pathways.}, } @article {pmid39262980, year = {2024}, author = {Joshi, R and Goswami, D and Saha, P and Hole, A and Mandhare, P and Wadke, R and Murthy, PR and Borgohain, S and C, MK and Kapoor, S}, title = {Serum Raman spectroscopy: Unearthing the snapshot of distinct metabolic profile in patients with congenital heart defects (CHDs).}, journal = {Heliyon}, volume = {10}, number = {16}, pages = {e34575}, pmid = {39262980}, issn = {2405-8440}, abstract = {In the present study, efficacy of minimally-invasive serum Raman spectroscopy (SRS) in stratification of congenital heart diseases was explored. Blood was collected from 62 subjects [42 congenital heart defect (CHD) patients (19 with atrial septal defect, 13 with ventricular septal defect and 10 with tetralogy of fallot) and 20 controls], and serum separated. Raman spectra of sera were recorded, pre-processed and subjected to spectral and multivariate analyses. Multivariate curve resolution-alternating least squares (MCR-ALS) analyses indicated alterations in lipid and protein levels between the study groups. Principal Component Analysis (PCA) and Principal Component based Linear Discriminant Analysis (PC-LDA), cross-validated with Leave-one-out cross validation (LOOCV), were employed to study stratification between the different groups. CHD could be classified from controls with 76 % efficiency. The different CHD subtypes could be distinguished with efficiencies as high as ∼90 %. To the best of our knowledge, differentiation between controls and CHDs as well as the stratification between controls and CHDs subtypes was for the first time successfully accomplished by serum-based Raman spectroscopy.}, } @article {pmid39263607, year = {2024}, author = {He, D and He, X and Shen, D and Liu, L and Yang, X and Hao, M and Wang, Y and Li, Y and Liu, Q and Liu, M and Wang, J and Zhang, X and Cui, L}, title = {Loss-of-function variants in RNA binding motif protein X-linked induce neuronal defects contributing to amyotrophic lateral sclerosis pathogenesis.}, journal = {MedComm}, volume = {5}, number = {9}, pages = {e712}, pmid = {39263607}, issn = {2688-2663}, abstract = {Despite being one of the most prevalent RNA modifications, the role of N6-methyladenosine (m6A) in amyotrophic lateral sclerosis (ALS) remains ambiguous. In this investigation, we explore the contribution of genetic defects of m6A-related genes to ALS pathogenesis. We scrutinized the mutation landscape of m6A genes through a comprehensive analysis of whole-exome sequencing cohorts, encompassing 508 ALS patients and 1660 population-matched controls. Our findings reveal a noteworthy enrichment of RNA binding motif protein X-linked (RBMX) variants among ALS patients, with a significant correlation between pathogenic m6A variants and adverse clinical outcomes. Furthermore, Rbmx knockdown in NSC-34 cells overexpressing mutant TDP43[Q331K] results in cell death mediated by an augmented p53 response. Similarly, RBMX knockdown in ALS motor neurons derived from induced pluripotent stem cells (iPSCs) manifests morphological defects and activation of the p53 pathway. Transcriptional analysis using publicly available single-cell sequencing data from the primary motor cortex indicates that RBMX-regulated genes selectively influence excitatory neurons and exhibit enrichment in ALS-implicated pathways. Through integrated analyses, our study underscores the emerging roles played by RBMX in ALS, suggesting a potential nexus between the disease and dysregulated m6A-mediated mRNA metabolism.}, } @article {pmid39264557, year = {2024}, author = {Grigoryev, PN and Gaptrakhmanova, GA and Plotnikova, AA and Zefirov, AL and Mukhamedyarov, MA}, title = {Endocytosis of Synaptic Vesicle in Motor Nerve Endings of FUS Transgenic Mice with a Model of Amyotrophic Lateral Sclerosis.}, journal = {Bulletin of experimental biology and medicine}, volume = {177}, number = {4}, pages = {449-453}, pmid = {39264557}, issn = {1573-8221}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/physiopathology ; Diaphragm/innervation/metabolism/physiopathology ; *Disease Models, Animal ; *Endocytosis/physiology ; Fluorescent Dyes/metabolism ; Imidazoles/pharmacology ; Mice, Transgenic ; *Motor Neurons/metabolism/pathology ; Nerve Endings/metabolism ; Pyridinium Compounds/metabolism ; Quaternary Ammonium Compounds/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; Synaptic Transmission/physiology/genetics ; *Synaptic Vesicles/metabolism ; }, abstract = {In experiments on the motor nerve endings of the diaphragm of transgenic FUS mice with a model of amyotrophic lateral sclerosis at the pre-symptomatic stage of the disease, the processes of transmitter release and endocytosis of synaptic vesicles were studied. In FUS mice, the intensity of transmitter release during high-frequency stimulation of the motor nerve (50 imp/sec) was lowered. At the same duration of stimulation, the loading of fluorescent dye FM1-43 was lower in FUS mice. However, at the time of stimulation, during which an equal number of quanta are released in wild-type and FUS mice, no differences in the intensity of dye loading were found. Thus, endocytosis is not the key factor in the mechanism of synaptic dysfunction in FUS mice at the pre-symptomatic stage.}, } @article {pmid39264833, year = {2024}, author = {Su, B and He, Z and Liu, J and Li, M and Huang, X}, title = {Mangiferin activates the nuclear factor erythroid 2-related factor pathway to protect SOD1-G93A induced NSC-34 motor neurons from oxidative stress and apoptosis.}, journal = {Journal of biochemical and molecular toxicology}, volume = {38}, number = {10}, pages = {e23849}, doi = {10.1002/jbt.23849}, pmid = {39264833}, issn = {1099-0461}, mesh = {*Xanthones/pharmacology ; *NF-E2-Related Factor 2/metabolism/genetics ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; Mice ; Animals ; *Motor Neurons/metabolism/drug effects/pathology ; *Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Cell Line ; Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; NAD(P)H Dehydrogenase (Quinone)/metabolism/genetics ; }, abstract = {One of the main factors in the pathophysiology of amyotrophic lateral sclerosis is oxidative stress. Mangiferin (MF), a natural plant polyphenol, has anti-inflammatory and antioxidant effects. The aim of our study was to investigate the protective effects and mechanisms of MF in the hSOD1-G93A ALS cell model. Our result revealed that MF treatment reduced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), decreased oxidative damage, and reduced apoptosis. Additionally, it was observed that MF significantly increased the synthesis of the antioxidant genes hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase 1, which are downstream of the Nrf2 signaling pathway, and increased the expression and activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 knockdown greatly promoted apoptosis, which was reversed by MF treatment. To summarize, MF promoted the Nrf2 pathway and scavenged MDA and ROS to protect the ALS cell model.}, } @article {pmid39266192, year = {2024}, author = {Chiappini, FA and Pinto, L and Alcaraz, MR and Omidikia, N and Goicoechea, HC and Olivieri, AC}, title = {Multivariate curve resolution-alternating least-squares and second-order advantage in first-order calibration. A systematic characterisation for three-component analytical systems.}, journal = {Analytica chimica acta}, volume = {1328}, number = {}, pages = {343159}, doi = {10.1016/j.aca.2024.343159}, pmid = {39266192}, issn = {1873-4324}, abstract = {BACKGROUND: Recent interest has been focused on the application of multivariate curve resolution-alternating least-squares (MCR-ALS) to systems involving the measurement of first-order and non-bilinear second-order data. The latter pose important challenges to bilinear decomposition models, due to the phenomenon of rotational ambiguity in the solutions, even under the application of the full set of chemical constraints that is usually employed in MCR-ALS calibration.

RESULTS: After the analysis of several simulated and experimental datasets, important conclusions regarding the role of the selectivity patterns in the constituent spectra have been drawn concerning the achievement of the second-order advantage. Theoretical considerations based on the calculation of the areas of feasible solutions helped to support the observations regarding the predictive ability of MCR- ALS in the various datasets.

SIGNIFICANCE: The understanding of the impact of rotational ambiguity in obtaining the second-order advantage with both first-order and non-bilinear second-order data is of paramount importance in the future development of analytical protocols of complex samples.}, } @article {pmid39267142, year = {2024}, author = {Wang, YM and Yan, J and Williams, SK and Fairless, R and Bading, H}, title = {TwinF interface inhibitor FP802 prevents retinal ganglion cell loss in a mouse model of amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {149}, pmid = {39267142}, issn = {2051-5960}, support = {BA 1007/7-1//Deutsche Forschungsgemeinschaft/ ; FOR 2289//Deutsche Forschungsgemeinschaft/ ; Advanced Grant 233024//HORIZON EUROPE European Research Council/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; *Retinal Ganglion Cells/drug effects/pathology/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; Mice ; Electroretinography ; Mice, Inbred C57BL ; Neuroprotective Agents/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism ; Humans ; Basic Helix-Loop-Helix Proteins/metabolism ; }, abstract = {Motor neuron loss is well recognized in amyotrophic lateral sclerosis (ALS), but research on retinal ganglion cells (RGCs) is limited. Ocular symptoms are generally not considered classic ALS symptoms, although RGCs and spinal motor neurons share certain cell pathologies, including hallmark signs of glutamate neurotoxicity, which may be triggered by activation of extrasynaptic NMDA receptors (NMDARs). To explore potential novel strategies to prevent ALS-associated death of RGCs, we utilized inhibition of the TwinF interface, a new pharmacological principle that detoxifies extrasynaptic NMDARs by disrupting the NMDAR/TRPM4 death signaling complex. Using the ALS mouse model SOD1[G93A], we found that the small molecule TwinF interface inhibitor FP802 prevents the loss of RGCs, improves pattern electroretinogram (pERG) performance, increases the retinal expression of Bdnf, and restores the retinal expression of the immediate early genes, Inhibin beta A and Npas4. Thus, FP802 not only prevents, as recently described, death of spinal motor neurons in SOD1[G93A] mice, but it also mitigates ALS-associated retinal damage. TwinF interface inhibitors have great potential for alleviating neuro-ophthalmologic symptoms in ALS patients and offer a promising new avenue for therapeutic intervention.}, } @article {pmid39268298, year = {2024}, author = {Contractor, RN and Shah, M and Manwell, W and Dempsey, KJ and Simhadri, P}, title = {Jean-Martin Charcot: Pioneer of Neurology.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e66762}, pmid = {39268298}, issn = {2168-8184}, abstract = {Jean-Martin Charcot, born on November 29, 1825, in Paris, France, is known as the father of neurology. During a time when neurology was not yet a recognized medical specialty, Charcot's pioneering contributions significantly advanced the field. Charcot's use of the anatomo-clinical method, which correlates clinical symptoms with anatomical findings, led to the discovery and characterization of numerous neurological conditions, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Charcot's joint, and Charcot-Marie-Tooth (CMT) disease. His methodical approach to documenting clinical signs and conducting post-mortem examinations revolutionized neurological research and diagnosis, laying the groundwork for modern neurology. The anatomo-clinical methods continue to be a vital tool in neurological research and practice today. Charcot's work extended beyond clinical practice, influencing the study of neurology through his role as an educator and mentor to many, including Sigmund Freud. Despite some controversies and a reputation for being difficult to work with, Charcot's legacy endures, with his initial discoveries fostering greater awareness and the development of therapies for various neurological disorders.}, } @article {pmid39268612, year = {2025}, author = {Meyer, T and Schumann, P and Grehl, T and Weyen, U and Petri, S and Rödiger, A and Steinbach, R and Grosskreutz, J and Bernsen, S and Weydt, P and Wolf, J and Günther, R and Vidovic, M and Baum, P and Metelmann, M and Weishaupt, JH and Streubel, B and Kasper, DC and Koc, Y and Kettemann, D and Norden, J and Schmitt, P and Walter, B and Münch, C and Spittel, S and Maier, A and Körtvélyessy, P}, title = {SOD1 gene screening in ALS - frequency of mutations, patients' attitudes to genetic information and transition to tofersen treatment in a multi-center program.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {162-171}, doi = {10.1080/21678421.2024.2401131}, pmid = {39268612}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Superoxide Dismutase-1/genetics ; Male ; Female ; *Genetic Testing/methods ; Middle Aged ; *Mutation/genetics ; Aged ; Germany ; Adult ; C9orf72 Protein/genetics ; RNA-Binding Protein FUS/genetics ; }, abstract = {OBJECTIVE: To report the frequency of pathogenic SOD1 gene variants in a screening program in amyotrophic lateral sclerosis (ALS), and the clinical practice of transition to an expanded access program (EAP) of tofersen treatment.

METHODS: From October 2021 to February 2024, at 11 ALS centers in Germany genetic testing for SOD1, FUS, TARDBP, and C9orf72 was performed. Patients were offered to opt for notification either about all genetic variants or SOD1 variants relevant for tofersen therapy. The transition to the EAP with tofersen was assessed.

RESULTS: 1935 patients were screened (94.7% sporadic ALS). 48.8% (n = 928) opted for notification of treatment-relevant information. Genetic variants were found as follows: SOD1 (likely) pathogenic variants (class 4/5) 1.8% (n = 34), variants of unknown significance (class 3) 0.8% (n = 16), FUS (class 4/5) 0.9% (n = 17), TARDBP (class 4/5) 1.3% (n = 25), C9orf72 hexanucleotide repeat expansion 7.0% (n = 135). In SOD1-ALS (encompassing class 3-5 variants, n = 50), 68.0% (n = 34) reported a negative family history. 74.0% (n = 37) of SOD1-ALS patients - which represent 1.9% of all participants of the screening program - were transitioned to tofersen. Median duration from start of genetic testing to treatment was 94 days (57 to 295 days). Eight patients declined treatment whereas five individuals died before initiation of therapy.

CONCLUSION: The finding of SOD1 variants in patients with a negative family history underscores the need for a broad genetic screening in ALS. In SOD1-ALS, the treatment option with tofersen was mostly utilized. The wide range in the transition time to tofersen calls for a SOD1-ALS management program.}, } @article {pmid39268841, year = {2024}, author = {Xing, C and Luo, M and Sheng, Q and Zhu, Z and Yu, D and Huang, J and He, D and Zhang, M and Fan, W and Chen, D}, title = {Silk Fabric Functionalized by Nanosilver Enabling the Wearable Sensing for Biomechanics and Biomolecules.}, journal = {ACS applied materials & interfaces}, volume = {16}, number = {38}, pages = {51669-51678}, doi = {10.1021/acsami.4c10253}, pmid = {39268841}, issn = {1944-8252}, mesh = {*Wearable Electronic Devices ; *Silver/chemistry ; *Silk/chemistry ; Humans ; *Metal Nanoparticles/chemistry ; Biomechanical Phenomena ; Textiles ; Biosensing Techniques/instrumentation/methods ; Spectrum Analysis, Raman ; }, abstract = {Integrating biomechanical and biomolecular sensing mechanisms into wearable devices is a formidable challenge and key to acquiring personalized health management. To address this, we have developed an innovative multifunctional sensor enabled by plasma functionalized silk fabric, which possesses multimodal sensing capabilities for biomechanics and biomolecules. A seed-mediated in situ growth method was employed to coat silver nanoparticles (AgNPs) onto silk fibers, resulting in silk fibers functionalized with AgNPs (SFs@Ag) that exhibit both piezoresistive response and localized surface plasmon resonance effects. The SFs@Ag membrane enables accurate detection of mechanical pressure and specific biomolecules during wearable sensing, offering a versatile solution for comprehensive personalized health monitoring. Additionally, a machine learning algorithm has been established to specifically recognize muscle strain signals, potentially extending to the diagnosis and monitoring of neuromuscular disorders such as amyotrophic lateral sclerosis (ALS). Unlike electromyography, which detects large muscles in clinical medicine, sensing data for tiny muscles enhance our understanding of muscle coordination using the SFs@Ag sensor. This detection model provides feasibility for the early detection and prevention of neuromuscular diseases. Beyond muscle stress and strain sensing, biomolecular detection is a critical addition to achieving effective health management. In this study, we developed highly sensitive surface-enhanced Raman scattering (SERS) detection for wearable health monitoring. Finite-difference time-domain numerical simulations ware utilized to analyze the efficacy of the SFs@Ag sensor for wearable SERS sensing of biomolecules. Based on the specific SERS spectra, automatic extraction of signals of sweat molecules was also achieved. In summary, the SFs@Ag sensor bridges the gap between biomechanical and biomolecular sensing in wearable applications, providing significant value for personalized health management.}, } @article {pmid39269505, year = {2024}, author = {Denis, PA and Laranjeira, JAS and Martins, NF and Sambrano, JR}, title = {Codoped germanene with 3p and 4p elements elements.}, journal = {Journal of molecular modeling}, volume = {30}, number = {10}, pages = {331}, pmid = {39269505}, issn = {0948-5023}, abstract = {CONTEXT: The relentless need for new materials to be used in electronic devices has opened new research directions in materials science. One of them involves using two-dimensional materials, among which there is current interest in using germanene. The heteroatom doping of germanene has been proposed as a possible approach to fine-tuning its electronic properties. However, this procedure is complicated because locating the dopants with a specific arrangement is challenging, thus achieving reproducibility. To avoid this problem, we propose the codoping of germanene to understand if dopants prefer to be agglomerated as observed for graphene or if they prefer to adopt a random disposition. Herein, we employed first-principles calculations to study 21 codoped germanene systems with one 3p (Al, Si, P, and S) and one 4p (Ga, As, and Se) element. Our results indicate that in the cases of AlP, AlS, GaP, GaS, GaAs, and GaSe codoped germanene, the dopants show a tendency to be located in specific lattice positions. The ortho disposition of dopants is preferred for AlP, AlS, GaP and GaS codoped germanene and their 4p counterparts GaAs and GaSe codoped germanene, and the materials showed interesting electronic properties making them suitable to develop germanene-based electronic materials.

METHODS: We utilized the M06-L, HSE06 methods accompanied by the 6-31G* basis sets to perform periodic boundary conditions calculations as implemented in Gaussian 09. The unit cells were sampled employing 100 k-points for geometry optimizations and 2000 k-points for electronic properties The ultrafine grid was employed. Results were visualized employing Gaussview 5.0.1. In addition to this, we performed B3LYP-D3 periodic calculations as implemented in CRYSTAL17.}, } @article {pmid39270519, year = {2024}, author = {Nishiyama, M and Koreki, A and Isose, S and Takeda, T and Ishikawa, A and Kokubun, S and Saito, Y and Ito, K and Arai, K and Takahashi, N and Motoda, Y and Kuwabara, S and Honda, K}, title = {Factors associated with psychological distress in patients with amyotrophic lateral sclerosis: A retrospective medical records study.}, journal = {Journal of psychosomatic research}, volume = {187}, number = {}, pages = {111915}, doi = {10.1016/j.jpsychores.2024.111915}, pmid = {39270519}, issn = {1879-1360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; Middle Aged ; *Psychological Distress ; Aged ; Retrospective Studies ; Adult ; Depression/psychology ; Stress, Psychological/psychology ; Surveys and Questionnaires ; Risk Factors ; Sex Factors ; }, abstract = {OBJECTIVE: Although psychological distress is a prevalent issue among patients with amyotrophic lateral sclerosis (ALS) and can impact survival, the risk factors contributing to this distress remain insufficiently understood.

METHODS: Patients with ALS who completed the Profile of Mood States (POMS) between June 2017 and March 2022 were included. Participants with moderate to severe cognitive decline were excluded, resulting in the recruitment of 121 patients. The associations between POMS profiles and clinical characteristics were analyzed. Physical motor symptoms were evaluated using the Revised ALS Functional Rating Scale (ALSFRS-R) for objective measurement and the 40-item ALS Assessment Questionnaire (ALSAQ-40) for subjective assessment.

RESULTS: Our model, employing the ALSFRS-R, revealed significant factors associated with overall psychological distress, as assessed by the POMS, including upper limb symptoms, the presence of sleep apnea syndrome, older age at onset, and male sex, with an inverse association with tracheostomy. The POMS subscale scores revealed that anger and depression were significantly associated with upper limb symptoms. The second model, which employed subjective scales, yielded similar results, reinforcing the robustness of our findings. Moreover, subjective bulbar symptoms on the ALSAQ-40 were significantly associated with psychological distress, particularly in female patients.

CONCLUSION: This study identified the main clinical characteristics significantly associated with psychological distress in patients with ALS. Our findings may be useful in developing individualized psychological management strategies for these patients.}, } @article {pmid39270623, year = {2024}, author = {Benatar, M and Macklin, EA and Malaspina, A and Rogers, ML and Hornstein, E and Lombardi, V and Renfrey, D and Shepheard, S and Magen, I and Cohen, Y and Granit, V and Statland, JM and Heckmann, JM and Rademakers, R and McHutchison, CA and Petrucelli, L and McMillan, CT and Wuu, J and , }, title = {Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis.}, journal = {EBioMedicine}, volume = {108}, number = {}, pages = {105323}, pmid = {39270623}, issn = {2352-3964}, support = {P01 NS084974/NS/NINDS NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; U01 NS107027/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/mortality ; *Biomarkers/blood ; *Clinical Trials as Topic ; *Disease Progression ; Neurofilament Proteins/blood ; Prognosis ; Research Design ; Multicenter Studies as Topic ; }, abstract = {BACKGROUND: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used.

METHODS: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75[ECD], plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated.

FINDINGS: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40 pg/mL and >100 pg/mL correspond to future ALSFRS-R slopes of ∼0.5 and ∼1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75[ECD], and plasma miR-181ab is more limited.

INTERPRETATION: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency.

FUNDING: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).}, } @article {pmid39270726, year = {2024}, author = {Roos, AK and Stenvall, E and Kockum, ES and Grönlund, KÅ and Alstermark, H and Wuolikainen, A and Andersen, PM and Nordin, A and Forsberg, KME}, title = {Small striatal huntingtin inclusions in patients with motor neuron disease with reduced penetrance and intermediate HTT gene expansions.}, journal = {Human molecular genetics}, volume = {33}, number = {22}, pages = {1966-1974}, pmid = {39270726}, issn = {1460-2083}, support = {//Umea University/ ; Nos.FO 2022-0309//Swedish Brain Foundation/ ; 2012-3167//Swedish Research Council/ ; //Research and Development Unit/ ; JLL-980693//Region Jämtland Härjedalen/ ; 2012.0091//Knut and Alice Wallenberg Foundation/ ; //Neuroförbundet patient organization/ ; 2023.16//Ulla-Carin Lindquist Foundation/ ; RV-993493//Västerbotten County Council/ ; //King Gustaf V:s and Queen Victoria's Freemason's Foundation/ ; //Börje Salming ALS Foundation/ ; }, mesh = {Humans ; *Huntingtin Protein/genetics/metabolism ; *Penetrance ; Male ; Female ; *Motor Neuron Disease/genetics/pathology/metabolism ; Middle Aged ; Aged ; *C9orf72 Protein/genetics/metabolism ; *DNA Repeat Expansion/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Inclusion Bodies/metabolism/genetics/pathology ; Alleles ; Adult ; Huntington Disease/genetics/pathology/metabolism ; Cohort Studies ; Corpus Striatum/metabolism/pathology ; }, abstract = {Short tandem repeat expansions in the human genome are overrepresented in a variety of neurological disorders. It was recently shown that huntingtin (HTT) repeat expansions with full penetrance, i.e. 40 or more CAG repeats, which normally cause Huntington's disease (HD), are overrepresented in patients with amyotrophic lateral sclerosis (ALS). Whether patients carrying HTT repeat expansions with reduced penetrance, (36-39 CAG repeats), or alleles with intermediate penetrance, (27-35 CAG repeats), have an increased risk of ALS has not yet been investigated. Here, we examined the role of HTT repeat expansions in a motor neuron disease (MND) cohort, searched for expanded HTT alleles, and investigated correlations with phenotype and neuropathology. MND patients harboring C9ORF72 hexanucleotide repeat expansions (HREs) were included, to investigate whether HTT repeat expansions were more common in this group. We found a high prevalence of intermediate (range 5.63%-6.61%) and reduced penetrance (range 0.57%-0.66%) HTT gene expansions in this cohort compared to other populations of European ancestry, but no differences between the MND cohort and the control cohort were observed, regardless of C9ORF72HRE status. Upon autopsy of three patients with intermediate or reduced penetrance HTT alleles, huntingtin inclusions were observed in the caudate nucleus and frontal lobe, but no significant somatic mosaicism was detected in different parts of the nervous system. Thus, we demonstrate, for the first time, huntingtin inclusions in individuals with MND and intermediate and reduced penetrance HTT repeat expansions but more clinicopathological investigations are needed to further understand the impact of HTT gene expansion-related pleiotropy.}, } @article {pmid39271636, year = {2025}, author = {Wang, Y and Ju, R and Jiang, J and Mao, L and Li, X and Deng, M}, title = {Concomitant presence of a novel ARPP21 variant and CNVs in Chinese familial amyotrophic lateral sclerosis-frontotemporal dementia patients.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {1}, pages = {195-205}, pmid = {39271636}, issn = {1590-3478}, support = {No. 82273915//National Natural Science Foundation of China/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; China ; *DNA Copy Number Variations/genetics ; East Asian People/genetics ; *Frontotemporal Dementia/genetics ; Pedigree ; Profilins/genetics ; Whole Genome Sequencing ; *Phosphoproteins/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the degeneration of motor neurons and progressive muscle weakness. Heredity plays an important part in the pathogenesis of ALS. Recently, with the emergence of the oligogenic pathogenic mechanism in ALS and the ongoing discovery of new mutated genes and genomic variants, there is an emerging need for larger-scale and more comprehensive genetic screenings in higher resolution. In this study, we performed whole-genome sequencing (WGS) on 34 familial ALS probands lacking the most common disease-causing mutations to explore the genetic landscape of Chinese ALS patients further. Among them, we identified a novel ARPP21 c.1231G > A (p.Glu411Lys) variant and two copy number variations (CNVs) affecting the PFN1 and RBCK1 genes in a patient with ALS-frontotemporal dementia (FTD). This marks the first report of an ARPP21 variant in Chinese ALS-FTD patients, providing fresh evidence for the association between ARPP21 and ALS. Our findings also underscore the potential role of CNVs in ALS-FTD, suggesting that the cumulative effect of multiple rare variants may contribute to disease onset. Furthermore, compared to the averages in our cohort and the reported Chinese ALS population, this patient displayed a shorter survival time and more rapid disease progression, suggesting the possibility of an oligogenic mechanism in disease pathogenesis. Further research will contribute to a deeper understanding of the rare mutations and their interactions, thus advancing our understanding of the genetic mechanisms underlying ALS and ALS-FTD.}, } @article {pmid39271680, year = {2024}, author = {Shan, Y and Zhang, M and Tao, E and Wang, J and Wei, N and Lu, Y and Liu, Q and Hao, K and Zhou, F and Wang, G}, title = {Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges.}, journal = {Signal transduction and targeted therapy}, volume = {9}, number = {1}, pages = {242}, pmid = {39271680}, issn = {2059-3635}, support = {82104184//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82373949//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82073928//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; *Mesenchymal Stem Cells/metabolism/cytology ; *Mesenchymal Stem Cell Transplantation ; Graft vs Host Disease/therapy ; Translational Research, Biomedical ; Amyotrophic Lateral Sclerosis/therapy ; }, abstract = {Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.}, } @article {pmid39271939, year = {2024}, author = {Yu, Y and Pang, D and Huang, J and Li, C and Cui, Y and Shang, H}, title = {Downregulation of Lnc-ABCA12-3 modulates UBQLN1 expression and protein homeostasis pathways in amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {21383}, pmid = {39271939}, issn = {2045-2322}, support = {2022NSFSC0750//The Sichuan Science and Technology Program/ ; 81871000//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *RNA, Long Noncoding/genetics/metabolism ; *Autophagy-Related Proteins/genetics/metabolism ; *Down-Regulation ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Apoptosis/genetics ; Female ; Proteostasis ; Male ; Middle Aged ; Autophagy/genetics ; Oxidative Stress ; Gene Expression Regulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration. Dysregulation of long non-coding RNAs (lncRNAs) has been implicated in ALS pathogenesis but their roles remain unclear. Previous studies found lnc-ABCA12-3 was downregulated in ALS patients. We aim to characterize the expression and function of lnc-ABCA12-3 in ALS and explore its mechanisms of action. Lnc-ABCA12-3 expression was analyzed in PBMCs from ALS patients and correlated with clinical outcomes. Effect of modulating lnc-ABCA12-3 expression was assessed in cell models using assays of apoptosis, protein homeostasis and pathway analysis. RNA pull-down and interaction studies were performed to identify lnc-ABCA12-3 binding partners. Lnc-ABCA12-3 was downregulated in ALS patients, correlating with faster progression and shorter survival. Overexpression of lnc-ABAC12-3 conferred protection against oxidative stress-induced apoptosis, while knockdown lnc-ABCA12-3 enhanced cell death. Lnc-ABCA12-3 maintained protein quality control pathways, including ubiquitination, autophagy and stress granule formation, by regulating the ubiquitin shuttle protein UBQLN1. This study identified lnc-ABCA12-3 as a novel regulatory lncRNA implicated in ALS pathogenesis by modulating cellular survival and stress responses through interactions with UBQLN1, influencing disease progression. Lnc-ABCA12-3 may influence ALS through regulating protein homeostasis pathways.}, } @article {pmid39273079, year = {2024}, author = {Lundt, S and Ding, S}, title = {Potential Therapeutic Interventions Targeting NAD[+] Metabolism for ALS.}, journal = {Cells}, volume = {13}, number = {17}, pages = {}, pmid = {39273079}, issn = {2073-4409}, support = {R01NS069726/NS/NINDS NIH HHS/United States ; R01 NS123023/NS/NINDS NIH HHS/United States ; R21 AG080715/AG/NIA NIH HHS/United States ; R01 NS069726/NS/NINDS NIH HHS/United States ; R21AG080715/AG/NIA NIH HHS/United States ; R01NS123023/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *NAD/metabolism ; Humans ; Animals ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons. While there have been many potential factors implicated for ALS development, such as oxidative stress and mitochondrial dysfunction, no exact mechanism has been determined at this time. Nicotinamide adenine dinucleotide (NAD[+]) is one of the most abundant metabolites in mammalian cells and is crucial for a broad range of cellular functions from DNA repair to energy homeostasis. NAD[+] can be synthesized from three different intracellular pathways, but it is the NAD[+] salvage pathway that generates the largest proportion of NAD[+]. Impaired NAD[+] homeostasis has been connected to aging and neurodegenerative disease-related dysfunctions. In ALS mice, NAD[+] homeostasis is potentially disrupted prior to the appearance of physical symptoms and is significantly reduced in the nervous system at the end stage. Treatments targeting NAD[+] metabolism, either by administering NAD[+] precursor metabolites or small molecules that alter NAD[+]-dependent enzyme activity, have shown strong beneficial effects in ALS disease models. Here, we review the therapeutic interventions targeting NAD[+] metabolism for ALS and their effects on the most prominent pathological aspects of ALS in animal and cell models.}, } @article {pmid39273435, year = {2024}, author = {Di Chiano, M and Sallustio, F and Fiocco, D and Rocchetti, MT and Spano, G and Pontrelli, P and Moschetta, A and Gesualdo, L and Gadaleta, RM and Gallone, A}, title = {Psychobiotic Properties of Lactiplantibacillus plantarum in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {17}, pages = {}, pmid = {39273435}, issn = {1422-0067}, support = {1062//PON "RICERCA E INNOVAZIONE" 2014-2020-Innovazione/ ; Call for tender No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union - Next Generation EU//National Recovery and Resilience Plan (NRRP)/ ; Concession Decree No. 1550 of 11 October 2022 adopted by the Italian Ministry of University and Research, CUP D93C22000890001//Italian Ministry of University and Research, CUP D93C22000890001/ ; Codice progetto n. 2022H9MPZ5//MIUR- PRIN Progetti di Ricerca di Rilevante Interesse Nazionale 2022/ ; Id. 23239//AIRC IG 2019/ ; Call for tender No. 3138 of 16/12/2021 of Italian Ministry of University and Research funded by the European Union//National Recovery and Resilience Plan (NRRP)/ ; Project code: CN00000041, CUP H93C22000430007//NextGenerationEU/ ; PNRR-MR1-2022-12376395//European Union - Next Generation EU - PNRR M6C2/ ; "POFACS" - ARS01_00640 -", D.D. 1211/2020 and 1104/2021//Italian Ministry of University and Research (MIUR)/ ; PRA-HE 2021//University of Foggia/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/microbiology/metabolism ; *Gastrointestinal Microbiome ; *Probiotics/therapeutic use ; Dysbiosis/microbiology ; Brain-Gut Axis ; Animals ; }, abstract = {Neurodegenerative disorders are the main cause of cognitive and physical disabilities, affect millions of people worldwide, and their incidence is on the rise. Emerging evidence pinpoints a disturbance of the communication of the gut-brain axis, and in particular to gut microbial dysbiosis, as one of the contributors to the pathogenesis of these diseases. In fact, dysbiosis has been associated with neuro-inflammatory processes, hyperactivation of the neuronal immune system, impaired cognitive functions, aging, depression, sleeping disorders, and anxiety. With the rapid advance in metagenomics, metabolomics, and big data analysis, together with a multidisciplinary approach, a new horizon has just emerged in the fields of translational neurodegenerative disease. In fact, recent studies focusing on taxonomic profiling and leaky gut in the pathogenesis of neurodegenerative disorders are not only shedding light on an overlooked field but are also creating opportunities for biomarker discovery and development of new therapeutic and adjuvant strategies to treat these disorders. Lactiplantibacillus plantarum (LBP) strains are emerging as promising psychobiotics for the treatment of these diseases. In fact, LBP strains are able to promote eubiosis, increase the enrichment of bacteria producing beneficial metabolites such as short-chain fatty acids, boost the production of neurotransmitters, and support the homeostasis of the gut-brain axis. In this review, we summarize the current knowledge on the role of the gut microbiota in the pathogenesis of neurodegenerative disorders with a particular focus on the benefits of LBP strains in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, autism, anxiety, and depression.}, } @article {pmid39273694, year = {2024}, author = {Evangelisti, C and Ramadan, S and Orlacchio, A and Panza, E}, title = {Experimental Cell Models for Investigating Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {17}, pages = {}, pmid = {39273694}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/pathology/metabolism ; Animals ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Organoids/pathology ; Models, Biological ; }, abstract = {Experimental models play a pivotal role in biomedical research, facilitating the understanding of disease mechanisms and the development of novel therapeutics. This is particularly true for neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and motor neuron disease, which present complex challenges for research and therapy development. In this work, we review the recent literature about experimental models and motor neuron disease. We identified three main categories of models that are highly studied by scientists. In fact, experimental models for investigating these diseases encompass a variety of approaches, including modeling the patient's cell culture, patient-derived induced pluripotent stem cells, and organoids. Each model offers unique advantages and limitations, providing researchers with a range of tools to address complex biological questions. Here, we discuss the characteristics, applications, and recent advancements in terms of each model system, highlighting their contributions to advancing biomedical knowledge and translational research.}, } @article {pmid39273978, year = {2024}, author = {Wu, Z and Liu, S and Zhang, X and Qian, X and Chen, Z and Zhao, H and Wan, H and Yin, N and Li, J and Qu, C and Du, H}, title = {Genome-Wide Characterization of Alfin-like Genes in Brassica napus and Functional Analyses of BnaAL02 and BnaAL28 in Response to Nitrogen and Phosphorus Deficiency.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {17}, pages = {}, pmid = {39273978}, issn = {2223-7747}, support = {32072094//National Key Research and Development Program of China/ ; 2023NSCQ-MSX3166//Natural Science Foundation of Chongqing/ ; }, abstract = {Alfin-like proteins (ALs) form a plant-specific transcription factor (TF) gene family involved in the regulation of plant growth and development, and abiotic stress response. In this study, 30 ALs were identified in Brassica napus ecotype 'Zhongshuang 11' genome (BnaALs), and unevenly distributed on 15 chromosomes. Structural characteristic analysis showed that all of the BnaALs contained two highly conserved domains: the N terminal DUF3594 domain and the C-terminal PHD-finger domain. The BnaALs were classified into four groups (Group I-IV), supported by conserved intron-exon and protein motif structures in each group. The allopolyploid event between B. oleracea and B. rapa ancestors and the small-scale duplication events in B. napus both contributed to the large BnaALs expansion. The promoter regions of BnaALs contained multiple abiotic stress cis-elements. The BnaALs in I-IV groups were mainly expressed in cotyledon, petal, root, silique, and seed tissues, and the duplicated gene pairs shared highly similar expression patterns. RNA-seq and RT-qPCR analysis showed that BnaALs were obviously induced by low nitrogen (LN) and low phosphorus (LP) treatments in roots. Overexpressing BnaAL02 and BnaAL28 in Arabidopsis demonstrated their functions in response to LN and LP stresses. BnaAL28 enhanced primary roots' (PRs) length and lateral roots' (LRs) number under LP and LN conditions, where BnaAL02 can inhibit LR numbers under the two conditions. They can promote root hair (RH) elongation under LP conditions; however, they suppressed RH elongation under LN conditions. Our result provides new insight into the functional dissection of this family in response to nutrient stresses in plants.}, } @article {pmid39275316, year = {2024}, author = {Hamm, JD and Laferrère, B and Albu, JB and Kini, S and Pi-Sunyer, X and Kissileff, HR}, title = {Responsiveness and Reliability of a Sipping Device to Measure Motivation in Normal-Weight Individuals and Bariatric Surgery Patients.}, journal = {Nutrients}, volume = {16}, number = {17}, pages = {}, pmid = {39275316}, issn = {2072-6643}, support = {R01 DK108643/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Motivation ; *Bariatric Surgery ; Female ; Male ; Adult ; Reproducibility of Results ; Middle Aged ; Obesity/surgery/psychology ; Taste ; Beverages ; Sweetening Agents ; Feeding Behavior/psychology ; }, abstract = {There is an urgent need to measure the motivation to taste a sweet fluid in order to determine the influence of sweet tastes on the potential choices and consumption of beverages in patients with obesity. Current methods utilize either survey instruments or arbitrary operant tasks. The sipometer enables the participant to utilize an actual ingestive behavioral response to measure motivation during access to beverages on either ad libitum (AL) or progressive time ratio (PR) schedules. We determined the sipometer's responsiveness and reliability as a test of change in motivation for sweet tastes after bariatric surgery. Participants (58 patients and 28 controls, BMI: 18.5-24.9 kg/m[2]) sham-consumed an aspartame-sweetened (S) and non-sweetened (N) beverage under AL and PR schedules at a pre-surgery/baseline and a 3-month and 24-month visit (patients only). Cumulative pressure (CumPres), a measure of effort, was the sum of the pressures exerted during sipping under each condition. Baseline CumPres for PRS was higher than ALS and ALN in patients (p < 0.03) and higher than PRN in controls (p = 0.009). At 3 months, CumPres did not differ amongst conditions in patients, but CumPres for PRS was higher than all other conditions in controls (p < 0.0005). There were no baseline group differences; however, patients' CumPres for PRS was lower than controls' at 3 months (p = 0.002). Patients' CumPres for PRS decreased non-significantly between the baseline and 3 months but increased at 24 months compared to 3 months (p = 0.025) and was no different from baseline. Controls' CumPres for PRS increased at 3 months (p = 0.0359), but CumPres for all conditions was correlated between visits (p's < 0.038). The sipometer is a reliable and sensitive measure of motivation to consume sweet beverages and may reflect changes in post-operative energy intake.}, } @article {pmid39276073, year = {2025}, author = {Raymond, J and Berry, JD and Larson, T and Horton, DK and Mehta, P}, title = {Effects of COVID-19 on motor neuron disease mortality in the United States: a population-based cross-sectional study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {149-156}, doi = {10.1080/21678421.2024.2401621}, pmid = {39276073}, issn = {2167-9223}, mesh = {Humans ; *COVID-19/epidemiology/mortality ; *Motor Neuron Disease/mortality/epidemiology ; United States/epidemiology ; Male ; Female ; Middle Aged ; Aged ; Adult ; Cross-Sectional Studies ; Aged, 80 and over ; Young Adult ; SARS-CoV-2 ; }, abstract = {BACKGROUND: In March 2020, the World Health Organization declared the coronavirus disease 2019 (COVID-19) to be a pandemic, stating that those with underlying health conditions are most susceptible, including motor neuron disease (MND).

OBJECTIVE: To examine the effect the COVID-19 pandemic had on deaths from MND in the United States.

METHODS: Death certificate data for all MND deaths aged 20 years and older were analyzed from 2017 to 2019 (pre-COVID), then expanded to include 2020 and 2021 (COVID) deaths to evaluate if COVID-19 impacted MND deaths.

RESULTS: The average number of MND deaths documented during the COVID-19 years was 8009, up from 7485 MND deaths pre-COVID. The age-adjusted mortality rate among the non-Hispanic population increased during COVID to 2.78 per 100,000 persons (95% CI = 2.73-2.82) from 1.81 (95% CI = 1.78-1.84). The Hispanic population also saw an increase in mortality rate during COVID (1.61, 95% CI = 1.51-1.71) compared with pre-COVID (1.10, 95% CI = 1.03-1.17). Decedent's home as a place of death also saw a mortality rate increase during COVID (1.51, 95% CI = 1.48-1.54) compared with pre-COVID (1.30, 95% CI = 1.27-1.32). For the Hispanic population, the rate peaked at 80-84 years pre-COVID, but for the COVID years, the rate peaked earlier, at 75-79 years.

CONCLUSION: The total number of MND deaths was greater during COVID than in the preceding years. The analysis suggests there might have been a consequence of circumstances surrounding the global pandemic and the associated restrictions.}, } @article {pmid39277361, year = {2024}, author = {Liu, L and Zou, Y and Guan, Y and Yang, C and Ji, M}, title = {Diverse mechanisms confer bensulfuron-methyl resistance in Schoenoplectiella juncoides (Roxb.) lye.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106034}, doi = {10.1016/j.pestbp.2024.106034}, pmid = {39277361}, issn = {1095-9939}, mesh = {*Sulfonylurea Compounds/pharmacology ; Herbicide Resistance/genetics ; Herbicides/pharmacology ; Mutation ; Glutathione Transferase/metabolism/genetics ; }, abstract = {The effectiveness of bensulfuron-methyl in controlling Schoenoplectiella juncoides (Roxb.) Lye has significantly decreased in rice fields in China. Hence, a bensulfuron-methyl-resistant S. juncoides population (W15) was collected from Dandong City, Liaoning Province, China, to investigate the underlying resistance mechanisms. Whole-plant dose-response experiments and ALS activity assay confirmed that W15 has evolved high-level resistance to bensulfuron-methyl compared with the susceptible S. juncoides population (W4). Molecular analysis revealed a Pro-197-Ser mutation in ALS1, while there was no significant difference in the relative ALS gene expression between W15 and W4. LC-MS/MS analysis showed W15 metabolized bensulfuron-methyl more rapidly than W4. Furthermore, bensulfuron-methyl resistance in W15 was significantly alleviated by malathion and 4-chloro-7-nitrobenzoxadiazole (NBD-Cl). Glutathione S-transferase activity was higher in W15 than in W4. Meanwhile, W15 displayed cross-resistance to halosulfuron-methyl and multi-resistance to MCPA-Na. In summary, these findings demonstrated for the first time that both target- and non-target-site resistance are relevant in the resistance of S. juncoides to bensulfuron-methyl.}, } @article {pmid39277365, year = {2024}, author = {Guan, Y and Liu, L and Zou, Y and Yang, C and Ji, M}, title = {Involvement of P450s in the metabolic resistance of Digitaria sanguinalis (L.) Scop. To ALS-inhibiting herbicides.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106038}, doi = {10.1016/j.pestbp.2024.106038}, pmid = {39277365}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology/toxicity ; *Acetolactate Synthase/metabolism/genetics/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; *Digitaria/drug effects ; Sulfonylurea Compounds/pharmacology ; Plant Weeds/drug effects/metabolism ; Plant Proteins/genetics/metabolism ; Pyridines ; }, abstract = {Weed resistance to a range of herbicides has rapidly evolved, often with different mechanisms of action. The resulting uninhibited growth of weeds poses demonstrable threats to crop production and sustainable agriculture. Digitaria sanguinalis (L.) Scop., a troublesome weed in corn and other agricultural fields, has developed resistance to herbicides that inhibiting ALS (Acetolactate Synthase), such as nicosulfuron. Understanding the weed's resistance patterns and mechanisms is crucial. However, little is known of the non-target site resistance (NTSR) mechanisms of D. sanguinalis owing to a lack of relevant genome sequences and other materials. Therefore, in this study, a population of D.sanguinalis presenting multiple resistance was tested and found that its high level of resistance to ALS-inhibiting herbicides was not associated with target-related alterations.Administration of P450 inhibitors reversed the resistance to ALS-inhibiting herbicides. Following the application of ALS-inhibiting herbicides, the activities of NADPH-P450 reductase and p-nitroanisole O-demethylase (PNOD) were notably greater in the resistant population of D. sanguinalis than those in the susceptible population. The results suggested P450 enzyme familyplays a major role in the metabolic resistance mechanism, that increased P450 enzyme activity promote cross-resistance in D. sanguinalis to ALS-inhibiting herbicides. RNA-seq analysis showed that five genes from the P450 family (CYP709B2, CYP714C2, CYP71A1, CYP76C2, and CYP81E8) were upregulated in resistant D. sanguinalis. In conclusion, the upregulation of several P450 genes is responsible for establishing resistance to ALS-inhibiting herbicides in D. sanguinalis.}, } @article {pmid39277366, year = {2024}, author = {Weng, WF and Yao, X and Zhao, M and Fang, Z and Yang, S and Ruan, JJ}, title = {Novel mutations in acetolactate synthase confer high levels of resistance to tribenuron-methyl in Fagopyrum tataricum.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106039}, doi = {10.1016/j.pestbp.2024.106039}, pmid = {39277366}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Fagopyrum/genetics/drug effects ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Arylsulfonates/pharmacology ; *Mutation ; Plant Proteins/genetics/metabolism ; }, abstract = {Tartary buckwheat (Fagopyrum tataricum) field weeds are rich in species, with many weeds causing reduced quality, yield, and crop failure. The selection of herbicide-resistant Tartary buckwheat varieties, while applying low-toxicity and efficient herbicides as a complementary weed control system, is one way to improve Tartary buckwheat yield and quality. Therefore, the development of herbicide-resistant varieties is important for the breeding of Tartary buckwheat. In this experiment, 50 mM ethyl methyl sulfonate solution was used to treat Tartary buckwheat seeds (M1) and then planted in the field. Harvested seeds (M2) were planted in the experiment field of Guizhou University, and when seedlings had 5-7 leaves, the seedlings were sprayed with 166 mg/L tribenuron-methyl (TBM). A total of 15 resistant plants were obtained, of which three were highly resistant. Using the homologous cloning method, an acetolactate synthase (ALS) gene encoding 547 amino acids was identified in Tartary buckwheat. A GTG (valine) to GGA (glycine) mutation (V409G) occurred at position 409 of the ALS gene in the high tribenuron-methyl resistant mutant sm113. The dm36 mutant harbored a double mutation, a deletion mutation at position 405, and a GTG (valine) to GGA (glycine) mutation (V411G) at position 411. The dm110 mutant underwent a double mutation: an ATG (methionine) to AGG (arginine) mutation (M333R) at position 333 and an insertion mutation at position 372. The synthesis of Chl a, Chl b, total Chl, and Car was significantly inhibited by TBM treatment. TBM was more efficient at suppressing the growth of wild-type plants than that of mutant plants. Antioxidant enzyme activities such as ascorbate peroxidase, peroxidase, and superoxide dismutase were significantly higher in resistant plants than in wild-type after spraying with TBM; malondialdehyde content was significantly lower than in wild-type plants after spraying with TBM. Plants with a single-site mutation in the ALS gene could survive, but their growth was affected by herbicide application. In contrast, plants with dual-site mutations in the ALS gene were not affected, indicating that plants with dual-site mutations in the ALS gene showed higher levels of resistance than plants with a single-site mutation in the ALS gene.}, } @article {pmid39277385, year = {2024}, author = {Porri, A and Panozzo, S and Tekeste Sisay, M and Scarabel, L and Lerchl, J and Milani, A}, title = {3D structure of acetolactate synthase explains why the Asp-376-Glu point mutation does not give the same resistance level to different imidazolinone herbicides.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106070}, doi = {10.1016/j.pestbp.2024.106070}, pmid = {39277385}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism/chemistry ; *Herbicides/pharmacology/chemistry ; *Herbicide Resistance/genetics ; *Imidazoles/pharmacology/chemistry ; *Amaranthus/drug effects/genetics ; *Point Mutation ; Sorghum/genetics/drug effects ; Molecular Docking Simulation ; Plant Proteins/genetics/metabolism/chemistry ; Nicotinic Acids/pharmacology ; Niacin/analogs & derivatives ; }, abstract = {Resistance to ALS-inhibiting herbicides has dramatically increased worldwide due to the persisting evolution of target site mutations that reduce the affinity between the herbicide and the target. We evaluated the effect of the well-known ALS Asp-376-Glu target site mutation on different imidazolinone herbicides, including imazamox and imazethapyr. Greenhouse dose response experiments indicate that the Amaranthus retroflexus biotype carrying Asp-376-Glu was fully controlled by applying the field recommended dose of imazamox, whereas it displayed high level of resistance to imazethapyr. Likewise, Sorghum halepense, carrying Asp-376-Glu showed resistance to field recommended doses of imazethapyr but not of imazamox. Biochemical inhibition and kinetic characterization of the Asp-376-Glu mutant enzyme heterologously expressed using different plant sequence backbones, indicate that the Asp-376-Glu shows high level of insensitivity to imazethapyr but not to imazamox, corroborating the greenhouse results. Docking simulations revealed that imazamox can still inhibit the Asp-376-Glu mutant enzyme through a chalcogen interaction between the oxygen of the ligand and the sulfur atom of the ALS Met200, while imazethapyr does not create such interaction. These results explain the different sensitivity of the Asp-376-Glu mutation towards imidazolinone herbicides, thus providing novel information that can be exploited for defining stewardship guidelines to manage fields infested by weeds harboring the Asp-376-Glu mutation.}, } @article {pmid39278909, year = {2024}, author = {Reis, ALG and Maximino, JR and Lage, LAPC and Gomes, HR and Pereira, J and Brofman, PRS and Senegaglia, AC and Rebelatto, CLK and Daga, DR and Paiva, WS and Chadi, G}, title = {Proteomic analysis of cerebrospinal fluid of amyotrophic lateral sclerosis patients in the presence of autologous bone marrow derived mesenchymal stem cells.}, journal = {Stem cell research & therapy}, volume = {15}, number = {1}, pages = {301}, pmid = {39278909}, issn = {1757-6512}, support = {401922/2014-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 836458/2016//Ministério da Saúde/ ; 1701/22//Financiadora de Estudos e Projetos/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/therapy/metabolism ; Apolipoprotein A-I/cerebrospinal fluid/metabolism ; Apolipoproteins E/metabolism/genetics/cerebrospinal fluid ; Bone Marrow Cells/metabolism ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/metabolism ; Protein Interaction Maps ; *Proteomics/methods ; *Transplantation, Autologous ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressive motoneuron degenerative disorder. There are still no drugs capable of slowing disease evolution or improving life quality of ALS patients. Thus, autologous stem cell therapy has emerged as an alternative treatment regime to be investigated in clinical ALS.

METHOD: Using Proteomics and Protein-Protein Interaction Network analyses combined with bioinformatics, the possible cellular mechanisms and molecular targets related to mesenchymal stem cells (MSCs, 1 × 10[6] cells/kg, intrathecally in the lumbar region of the spine) were investigated in cerebrospinal fluid (CSF) of ALS patients who received intrathecal infusions of autologous bone marrow-derived MSCs thirty days after cell therapy. Data are available via ProteomeXchange with identifier PXD053129.

RESULTS: Proteomics revealed 220 deregulated proteins in CSF of ALS subjects treated with MSCs compared to CSF collected from the same patients prior to MSCs infusion. Bioinformatics enriched analyses highlighted events of Extracellular matrix and Cell adhesion molecules as well as related key targets APOA1, APOE, APP, C4A, C5, FGA, FGB, FGG and PLG in the CSF of cell treated ALS subjects.

CONCLUSIONS: Extracellular matrix and cell adhesion molecules as well as their related highlighted components have emerged as key targets of autologous MSCs in CSF of ALS patients.

TRIAL REGISTRATION: Clinicaltrial.gov identifier NCT0291768. Registered 28 September 2016.}, } @article {pmid39279053, year = {2024}, author = {Lin, PH and Yao, HY and Huang, L and Fu, CC and Yao, XL and Lian, C and Zhang, SF and Lai, WD and Lin, GY and Liao, S and Yang, J and Mao, ZF and Liu, D and Long, BY and Yue, JJ and Gao, C and Long, YM}, title = {Autoimmune astrocytopathy double negative for AQP4-IgG and GFAP-IgG: Retrospective research of clinical practice, biomarkers, and pathology.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {9}, pages = {e70042}, pmid = {39279053}, issn = {1755-5949}, support = {2022A1515110143//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515010225//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022-LCYJ-YYDZX-04//Multi-center Project of The Second Affiliated Hospital of Guangzhou Medical University/ ; }, mesh = {Humans ; *Glial Fibrillary Acidic Protein/cerebrospinal fluid/immunology ; Female ; Male ; *Aquaporin 4/immunology ; Middle Aged ; *Astrocytes/immunology/metabolism/pathology ; Retrospective Studies ; Adult ; *Biomarkers/cerebrospinal fluid/blood ; Aged ; *Immunoglobulin G/cerebrospinal fluid/blood ; Neurofilament Proteins/cerebrospinal fluid/blood ; Autoantibodies/cerebrospinal fluid/blood ; Young Adult ; Adolescent ; }, abstract = {OBJECTIVE: The objective of this study is to investigate the presence of astrocyte antibodies in patients, excluding aquaporin-4 or glial fibrillary acidic protein (GFAP) antibodies, while evaluating associated biomarkers and pathologies.

METHODS: Patient serum and cerebrospinal fluid (CSF) were tested for antibodies using tissue- and cell-based assays. Neurofilament light chain (NFL) and GFAP in the CSF were detected using single-molecule array (SIMOA).

RESULTS: 116 patients accepted SIMOA. Fifteen functional neurological disorders patients without antibodies were designated as controls. Thirty-five patients were positive for astrocyte antibodies (Anti-GFAP: 7; Anti-AQP4: 7; unknown antibodies: 21, designed as the double-negative group, DNAP). The most frequent phenotype of DNAP was encephalitis (42.9%), followed by myelitis (23.8%), movement disorders (19.0%), and amyotrophic lateral sclerosis-like (ALS-like) disease (14.2%). The levels of CSF GFAP and NFL in DNAP were higher than in the control (GFAP: 1967.29 [776.60-13214.47] vs 475.38 [16.80-943.60] pg/mL, p < 0.001; NFL: 549.11 [162.08-2462.61] vs 214.18 [81.60-349.60] pg/mL, p = 0.002). GFAP levels decreased in DNAP (n = 5) after immunotherapy (2446.75 [1583.45-6277.33] vs 1380.46 [272.16-2005.80] pg/mL, p = 0.043), while there was no difference in NFL levels (2273.78 [162.08-2462.61] vs 890.42 [645.06-3168.06] pg/mL, p = 0.893). Two brain biopsy patterns were observed: one exhibited prominent tissue proliferation and hypertrophic astrocytes, with local loss of astrocytes, while the other showed severe astrocyte depletion with loss of neurofilaments around the vessels. Eighteen patients received immunotherapy, and improved except one with ALS-like symptoms. We identified anti-vimentin in this patient.

DISCUSSION: There are unidentified astrocyte antibodies. The manifestations of double-negativity are heterogeneous; nevertheless, the pathology and biomarkers remain consistent with astrocytopathy. Immunotherapy is effective.}, } @article {pmid39279312, year = {2024}, author = {Banaszak-Ziemska, M and Rojek, A and Niedziela, M}, title = {Genetic analysis of the PAPP-A2 gene and evaluation of free IGF-1, IGFBP-5, and ALS concentrations in a group of 22 patients with idiopathic short stature.}, journal = {Endokrynologia Polska}, volume = {75}, number = {4}, pages = {428-437}, doi = {10.5603/ep.100030}, pmid = {39279312}, issn = {2299-8306}, mesh = {Humans ; *Pregnancy-Associated Plasma Protein-A/genetics/metabolism/analysis ; Female ; *Insulin-Like Growth Factor I/genetics/analysis/metabolism ; Male ; Child ; Adolescent ; *Insulin-Like Growth Factor Binding Protein 5/genetics ; Carrier Proteins/genetics ; Glycoproteins/genetics/blood ; Growth Disorders/genetics/blood ; Mutation ; Child, Preschool ; }, abstract = {INTRODUCTION: Short stature is one of the main reasons for consultation in outpatient clinics and paediatric endocrinology departments and is defined as height below the 3rd centile or less than -2 standard deviations (SDs).

MATERIAL AND METHODS: The study's overarching aim was to analyse the PAPP-A2 gene at mutation sites described to date and at exons 3, 4, and 5, which encode the fragment of the catalytic domain with the active site of the pregnancy-associated plasma protein A2 (PAPP-A2) protein. The secondary aims of the study were clinical and auxological analysis of a group of patients with idiopathic short stature and biochemical analysis of growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis parameters not assessed as part of the routine diagnosis of short stature, such as free IGF-1, insulin-like growth factor binding protein 5 (IGFBP-5), and acid-labile subunit (ALS) levels. Molecular analysis of the PAPP-A2 gene was performed using polymerase chain reaction (PCR) and direct sequencing. Biochemical analysis of free IGF-1, IGFBP-5, and ALS was performed by enzyme-linked immunosorbent assay (ELISA).

RESULTS: The mean height standard deviation score (HSDS) in the study group was -2.95. None of the patients exhibited previously described mutations in the PAPP-A2 gene or mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein. In 4 patients, the known, non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 was found.

CONCLUSIONS: Free IGF-1 levels correlate better with height and HSDS than total IGF-1 levels. The previously described mutations in the PAPP-A2 gene and mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein were not detected; only the known and non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 of the PAPP-A2 gene was observed.}, } @article {pmid39280119, year = {2024}, author = {Banack, SA and Dunlop, RA and Mehta, P and Mitsumoto, H and Wood, SP and Han, M and Cox, PA}, title = {A microRNA diagnostic biomarker for amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae268}, pmid = {39280119}, issn = {2632-1297}, abstract = {Blood-based diagnostic biomarkers for amyotrophic lateral sclerosis will improve patient outcomes and positively impact novel drug development. Critical to the development of such biomarkers is robust method validation, optimization and replication with adequate sample sizes and neurological disease comparative blood samples. We sought to test an amyotrophic lateral sclerosis biomarker derived from diverse samples to determine if it is disease specific. Extracellular vesicles were extracted from blood plasma obtained from individuals diagnosed with amyotrophic lateral sclerosis, primary lateral sclerosis, Parkinson's disease and healthy controls. Immunoaffinity purification was used to create a neural-enriched extracellular vesicle fraction. MicroRNAs were measured across sample cohorts using real-time polymerase chain reaction. A Kruskal-Wallis test was used to assess differences in plasma microRNAs followed by post hoc Mann-Whitney tests to compare disease groups. Diagnostic accuracy was determined using a machine learning algorithm and a logistic regression model. We identified an eight-microRNA diagnostic signature for blood samples from amyotrophic lateral sclerosis patients with high sensitivity and specificity and an area under the curve calculation of 98% with clear statistical separation from neurological controls. The eight identified microRNAs represent disease-related biological processes consistent with amyotrophic lateral sclerosis. The direction and magnitude of gene fold regulation are consistent across four separate patient cohorts with real-time polymerase chain reaction analyses conducted in two laboratories from diverse samples and sample collection procedures. We propose that this diagnostic signature could be an aid to neurologists to supplement current clinical metrics used to diagnose amyotrophic lateral sclerosis.}, } @article {pmid39280372, year = {2024}, author = {Nishiwaki, T and Oya, A and Fujie, A and Kanaji, A}, title = {Higher Incidence of Venous Thromboembolism in Anterolateral Approach in Lateral Position Compared to Anterolateral Supine and Direct Anterior Approaches in Minimally Invasive Total Hip Arthroplasty.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e66831}, pmid = {39280372}, issn = {2168-8184}, abstract = {INTRODUCTION: Venous thromboembolism (VTE) remains a major complication after total hip arthroplasty (THA), irrespective of the surgical approach. This study investigated the incidence of VTE in patients undergoing THA through intermuscular minimally invasive surgical techniques, which included a direct anterior approach (DAA), an anterolateral approach (AL), and an anterolateral supine approach (ALS), at a single institution.

METHODS: A hundred consecutive patients treated with each surgical approach were evaluated. Plasma D-dimer levels one month preoperatively and one day postoperatively, operative time, and intraoperative blood loss were recorded, and the presence of VTE was evaluated based on multidetector-row computed tomography performed the day after surgery. Student's t-test and Pearson's chi-square test or one-way analysis of variance were used in statistical analysis.

RESULTS: No differences among the groups in terms of age, height, weight, operative time, intraoperative bleeding, and preoperative and postoperative D-dimer levels were observed. The overall incidence of VTE was 21%. The incidences of VTE were 30% in AL, 17% in ALS, and 16% in DAA, representing a significantly higher rate in AL than in ALS and DAA (P=0.025). The incidences of VTE on the operated side were 19% in AL, 13% in ALS, and 12% in DAA, with no statistically significant differences. The incidences of VTE on the non-operated side were 22% in AL, 9% in ALS, and 8% in DAA; these differences were statistically significant (P=0.0045).

DISCUSSION: Results showed that the incidence of VTE was significantly higher in AL than in ALS and DAA, especially for the non-operated side.}, } @article {pmid39280794, year = {2024}, author = {Ren, K and Wang, Q and Jiang, D and Liu, E and Alsmaan, J and Jiang, R and Rutkove, SB and Tian, F}, title = {A comprehensive review of electrophysiological techniques in amyotrophic lateral sclerosis research.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1435619}, pmid = {39280794}, issn = {1662-5102}, support = {R01 NS055099/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, is characterized by progressive motor neuron degeneration, leading to widespread weakness and respiratory failure. While a variety of mechanisms have been proposed as causes of this disease, a full understanding remains elusive. Electrophysiological alterations, including increased motor axon excitability, likely play an important role in disease progression. There remains a critical need for non-animal disease models that can integrate electrophysiological tools to better understand underlying mechanisms, track disease progression, and evaluate potential therapeutic interventions. This review explores the integration of electrophysiological technologies with ALS disease models. It covers cellular and clinical electrophysiological tools and their applications in ALS research. Additionally, we examine conventional animal models and highlight advancements in humanized models and 3D organoid technologies. By bridging the gap between these models, we aim to enhance our understanding of ALS pathogenesis and facilitate the development of new therapeutic strategies.}, } @article {pmid39280885, year = {2024}, author = {Robinson, SE and Findlay, AR and Li, S and Wang, F and Schiava, M and Daw, J and Diaz-Manera, J and Chou, TF and Weihl, CC}, title = {Elevated VCP ATPase Activity Correlates With Disease Onset in Multisystem Proteinopathy-1.}, journal = {Neurology. Genetics}, volume = {10}, number = {5}, pages = {e200191}, pmid = {39280885}, issn = {2376-7839}, support = {K24 AR073317/AR/NIAMS NIH HHS/United States ; R01 AG031867/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVES: Multisystem proteinopathy-1 (MSP1) is a late onset disease with >50 pathogenic variants in p97/VCP. MSP1 patients have multiple phenotypes that include inclusion body myopathy, Paget disease of the bone, amyotrophic lateral sclerosis, and frontotemporal dementia. There have been no clear genotype-phenotype correlations. We sought to identify genotype-phenotype correlations and associate these with VCP intrinsic ATPase activity.

METHODS: Patients with MSP1 were identified from the literature and the Cure VCP patient registry. Age at onset and at loss of ambulation were collated. VCP intrinsic ATPase activity was evaluated from recombinant purified protein.

RESULTS: Among the 5 most common pathogenic VCP variants in MSP1 patients, R155C patients had the earliest average age at onset (38.15 ± 9.78). This correlated with higher ATPase activity. Evaluation of 5 variants confirmed an inverse correlation between age at onset and ATPase activity (r = -0.94, p = 0.01).

DISCUSSION: Previous studies have reported that VCP pathogenic variants are "hyperactive." Whether this elevation in VCP ATPase activity is relevant to disease is unclear. Our study supports that in vitro VCP activity correlates with disease onset and may guide the prognosis of patients with rare or unreported variants. Moreover, it suggests that inhibition of VCP ATPase activity in MSP1 may be therapeutic.}, } @article {pmid39281332, year = {2022}, author = {Kirikae, H and Harada, R and Hosaka, T and Misu, T and Ando, D and Warita, H and Endo, T and Sonobe, S and Niizuma, K and Aoki, M}, title = {Case Report: Vertebro-vertebral arteriovenous fistula showing symptoms mimicking ALS: Diagnostic imaging supports accurate differentiation between ALS and mimicking conditions.}, journal = {F1000Research}, volume = {11}, number = {}, pages = {546}, pmid = {39281332}, issn = {2046-1402}, abstract = {We report a rare case of a vertebro-vertebral arteriovenous fistula (VVAVF) manifesting as amyotrophic lateral sclerosis (ALS). A 76-year-old female patient presented with progressive weakness, muscle atrophy, fasciculation, and preserved deep tendon reflexes in the right upper limb. Electrophysiological testing showed lower motor neuron dysfunction. The patient was suspected to have ALS, but cervical magnetic resonance imaging (MRI) revealed enlarged blood vessels in the spinal canal, which compressed the cervical spinal cord and nerve roots. Angiography showed a shunt from the right vertebral artery to the right intervertebral vein and the vertebral venous plexus; therefore, the patient was diagnosed with VVAVF. Transarterial embolization was performed to obliterate the shunt, and weakness in the patient's right upper limb subsequently improved. It is worth considering VVAVF as a differential diagnosis of ALS-like diseases.}, } @article {pmid39281855, year = {2024}, author = {Jones, VM and Thompson, LDR and Pettus, JR and Green, DC and Lefferts, JA and Shah, PS and Tsongalis, GJ and Sajed, DP and Guilmette, JM and Lewis, JS and Fisch, AS and Tafe, LJ and Kerr, DA}, title = {Angiomyolipomatous Lesions of the Nasal Cavity (Sinonasal Angioleiomyoma with Adipocytic Differentiation): A Multi-Institutional Immunohistochemical and Molecular Study.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39281855}, issn = {2693-5015}, support = {P30 CA023108/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Mesenchymal neoplasms composed of vascular, smooth muscle, and adipocytic components are uncommon in the nasal cavity. While angioleiomyoma (AL) is a smooth muscle tumor in the Head & Neck WHO classification, it is considered of pericytic origin in the Skin as well as Soft Tissue and Bone classifications. For nasal AL with an adipocytic component, the terms AL with adipocytic differentiation and angiomyolipoma (AML) have been applied, among others. AML is a type of perivascular epithelioid cell tumor (PEComa), most often arising in the kidney, sometimes associated with the tuberous sclerosis complex (TSC). It is uncertain whether nasal cavity AML and AL are best considered hamartomas or neoplasms, as their genetics are largely unexplored.

METHODS: We performed a multi-institutional retrospective study of nasal cavity mesenchymal lesions. Patient demographics, clinical histories, and histologic and immunohistochemical findings were collected. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and analyzed by SNP-based chromosomal microarray, targeted RNA fusion sequencing, and whole-exome sequencing.

RESULTS: Fifteen lesions (3 to 42 mm) were identified predominantly in male (87%) patients with a median age of 60. Patients typically presented with obstructive symptoms, and none had a history of TSC. One AL was a recurrence from six years prior; 11 cases showed no recurrence (median 4.7 years, range: 0.88-12.4). Morphologically, 11 AMLs contained 30-80% smooth muscle, 10-25% vasculature, and 2-60% adipose tissue, while four ALs contained 70-80% smooth muscle and 20-30% vasculature. Other histologic observations included surface ulceration, vascular thrombosis, chronic inflammation, and myxoid change; no well-developed epithelioid cell morphology was identified. Immunohistochemically, all cases were positive for smooth muscle markers (actin and/or desmin) and negative for melanocytic markers. Molecular analysis revealed loss of 3p and 11q in a single AML. No other known pathogenic copy number or molecular alterations were seen, including in TSC1/2, TFE3, or NOTCH2.

CONCLUSION: Nasal cavity AML lacks morphologic, immunophenotypic, and genetic features of PEComa family AMLs. The significant histologic overlap between nasal AML and AL without distinguishing molecular features in either entity suggests "sinonasal angioleiomyoma with adipocytic differentiation" may be the most appropriate terminology for hybrid vascular and smooth muscle lesions containing adipocytic components.}, } @article {pmid39282230, year = {2024}, author = {Tsai, YC and Brown, KA and Bernardi, MT and Harting, J and Clelland, CD}, title = {Single-Molecule Sequencing of the C9orf72 Repeat Expansion in Patient iPSCs.}, journal = {Bio-protocol}, volume = {14}, number = {17}, pages = {e5060}, pmid = {39282230}, issn = {2331-8325}, support = {K08 NS112330/NS/NINDS NIH HHS/United States ; R01 AG072052/AG/NIA NIH HHS/United States ; TL1 TR001871/TR/NCATS NIH HHS/United States ; U19 NS132303/NS/NINDS NIH HHS/United States ; }, abstract = {A hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). C9orf72 repeat expansions are currently identified with long-range PCR or Southern blot for clinical and research purposes, but these methods lack accuracy and sensitivity. The GC-rich and repetitive content of the region cannot be amplified by PCR, which leads traditional sequencing approaches to fail. We turned instead to PacBio single-molecule sequencing to detect and size the C9orf72 repeat expansion without amplification. We isolated high molecular weight genomic DNA from patient-derived iPSCs of varying repeat lengths and then excised the region containing the C9orf72 repeat expansion from naked DNA with a CRISPR/Cas9 system. We added adapters to the cut ends, capturing the target region for sequencing on PacBio's Sequel, Sequel II, or Sequel IIe. This approach enriches the C9orf72 repeat region without amplification and allows the repeat expansion to be consistently and accurately sized, even for repeats in the thousands. Key features • This protocol is adapted from PacBio's previous "no-amp targeted sequencing utilizing the CRISPR-Cas9 system." • Optimized for sizing C9orf72 repeat expansions in patient-derived iPSCs and applicable to DNA from any cell type, blood, or tissue. • Requires high molecular weight naked DNA. • Compatible with Sequel I and II but not Revio.}, } @article {pmid39283487, year = {2024}, author = {Zufiría, M and Pikatza-Menoio, O and Garciandia-Arcelus, M and Bengoetxea, X and Jiménez, A and Elicegui, A and Levchuk, M and Arnold-García, O and Ondaro, J and Iruzubieta, P and Rodríguez-Gómez, L and Fernández-Pelayo, U and Muñoz-Oreja, M and Aiastui, A and García-Verdugo, JM and Herranz-Pérez, V and Zulaica, M and Poza, JJ and Ruiz-Onandi, R and Fernández-Torrón, R and Espinal, JB and Bonilla, M and Lersundi, A and Fernández-Eulate, G and Riancho, J and Vallejo-Illarramendi, A and Holt, IJ and Sáenz, A and Malfatti, E and Duguez, S and Blázquez, L and López de Munain, A and Gerenu, G and Gil-Bea, F and Alonso-Martín, S}, title = {Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {43}, pmid = {39283487}, issn = {1432-0533}, support = {CB06/05/1126//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; PI2020/08-1//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; P18/01066//Instituto de Salud Carlos III/ ; PI19/00175//Instituto de Salud Carlos III/ ; PI21/00153//Instituto de Salud Carlos III/ ; PI22/00433//Instituto de Salud Carlos III/ ; IJC2019-039965-I//Instituto de Salud Carlos III/ ; 2020-CIEN-000057-01//Diputación Foral de Gipuzkoa/ ; 2021-CIEN-000020-01//Diputación Foral de Gipuzkoa/ ; 2019-FELL-000010-01//Diputación Foral de Gipuzkoa/ ; 2020-FELL-000016-02-01//Diputación Foral de Gipuzkoa/ ; 2021-FELL-000013-02-01//Diputación Foral de Gipuzkoa/ ; BIO17/ND/023/BD//EiTB Maratoia/ ; 2015111122//Osasun Saila, Eusko Jaurlaritzako/ ; 2017222027//Osasun Saila, Eusko Jaurlaritzako/ ; 2018111042//Osasun Saila, Eusko Jaurlaritzako/ ; 2019222020//Osasun Saila, Eusko Jaurlaritzako/ ; 2020111032//Osasun Saila, Eusko Jaurlaritzako/ ; 2020333043//Osasun Saila, Eusko Jaurlaritzako/ ; 2021333050//Osasun Saila, Eusko Jaurlaritzako/ ; PRE_2015_1_0023//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2019_1_0339//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2020_1_0122//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2020_1_0191//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2020_1_0119//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2018_1_0095//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2021_1_0125//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2018_1_0253//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; NEURODEGENPROT//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PIF18/317//Euskal Herriko Unibertsitatea/ ; RYC2018-024397-I//Spanish National Plan for Scientific and Technical Research and Innovation/ ; RF/2019/001//Ikerbasque, Basque Foundation for Science/ ; RF/2023/010//Ikerbasque, Basque Foundation for Science/ ; PP/2022/003//Ikerbasque, Basque Foundation for Science/ ; BIO19/ROCHE/017/BD//Roche España/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Animals ; *Muscle, Skeletal/metabolism/pathology ; *Forkhead Box Protein O1/metabolism/genetics ; DNA-Binding Proteins/genetics/metabolism ; Male ; RNA-Binding Protein FUS/genetics/metabolism ; Female ; Drosophila ; Muscle Development/physiology ; Middle Aged ; Aged ; Motor Neurons/metabolism/pathology ; Myoblasts/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.}, } @article {pmid39283513, year = {2025}, author = {Koopmann, A and Hoffmann, S and Riegler, A and Cordes, J and Kiefer, F}, title = {[Factors influencing hospital readmission rates in alcohol use disorder].}, journal = {Der Nervenarzt}, volume = {96}, number = {3}, pages = {278-283}, pmid = {39283513}, issn = {1433-0407}, mesh = {Humans ; *Patient Readmission/statistics & numerical data ; Male ; Female ; Middle Aged ; *Alcoholism/epidemiology/therapy/diagnosis/rehabilitation ; Germany/epidemiology ; Retrospective Studies ; Risk Factors ; Adult ; Comorbidity ; *Substance Withdrawal Syndrome/epidemiology ; Treatment Outcome ; Aged ; }, abstract = {BACKGROUND: According to data from the Federal Statistical Office, the diagnosis of alcohol use disorder (AUD) (F 10) is the second most common main diagnosis for hospital treatment. Those affected by this disorder are often repeatedly hospitalized at short intervals due to relapses; however, little is known about the factors that influence readmission rates after initial treatment.

AIM OF THE STUDY: The aim of this retrospective analysis is to analyze the effects of treatment type (qualified withdrawal treatment (QE) versus physical detoxification) and discharge mode on the probability of readmission in alcohol-dependent patients after inpatient treatment.

MATERIAL AND METHODS: Data from 981 male and female alcohol-dependent patients who completed either qualified withdrawal treatment (QE) (68% men; mean age 47.6 years) or inpatient detoxification (74% men; mean age 48.0 years) were analyzed. Predictors of regular discharge were determined separately for both types of treatment using stepwise logistic regression.

RESULTS: Patients who had completed a qualified withdrawal treatment were significantly more likely to be regularly discharged. Regular completion of the qualified withdrawal treatment (QE) led to a relative reduction in the readmission rate of 25.64% within 1 year compared to a physical detoxification.

CONCLUSION: In order to prevent readmission and chronic courses of alcohol use disorder (AUD), qualified withdrawal treatment should always be recommended to affected patients instead of physical detoxification. Aktuelle Daten des Statistischen Bundesamtes für das Jahr 2022 zeigen, dass die Diagnose "Psychische und Verhaltensstörungen durch Alkohol (F 10.X)" die zweithäufigste Hauptdiagnose bei Krankenhausbehandlungen darstellt [13]. Im Gesundheitssystem entstehen durch dieses Erkrankungsbild und seine somatischen und psychischen Folgeerkrankungen jährlich ca. 10 Mrd. € direkte Kosten [13]. Dieser Sachverhalt wird dadurch kontrastiert, dass die Krankenkassen die qualifizierte Entzugsbehandlung (QE) als leitliniengerechte Goldstandardtherapie [4] wiederholt infrage stellen [10].}, } @article {pmid39286389, year = {2024}, author = {Willman, M and Patel, G and Lucke-Wold, B}, title = {T lymphocyte proportion in Alzheimer's disease prognosis.}, journal = {World journal of clinical cases}, volume = {12}, number = {26}, pages = {6001-6003}, pmid = {39286389}, issn = {2307-8960}, abstract = {Bai et al investigate the predictive value of T lymphocyte proportion in Alzheimer's disease (AD) prognosis. Through a retrospective study involving 62 AD patients, they found that a decrease in T lymphocyte proportion correlated with a poorer prognosis, as indicated by higher modified Rankin scale scores. While the study highlights the potential of T lymphocyte proportion as a prognostic marker, it suggests the need for larger, multicenter studies to enhance generalizability and validity. Additionally, future research could use cognitive exams when evaluating prognosis and delve into immune mechanisms underlying AD progression. Despite limitations inherent in retrospective designs, Bai et al's work contributes to understanding the immune system's role in AD prognosis, paving the way for further exploration in this under-researched area.}, } @article {pmid39286440, year = {2024}, author = {Kew, SYN and Mok, SY and Goh, CH}, title = {Machine learning and brain-computer interface approaches in prognosis and individualized care strategies for individuals with amyotrophic lateral sclerosis: A systematic review.}, journal = {MethodsX}, volume = {13}, number = {}, pages = {102765}, pmid = {39286440}, issn = {2215-0161}, abstract = {Amyotrophic lateral sclerosis (ALS) characterized by progressive degeneration of motor neurons is a debilitating disease, posing substantial challenges in both prognosis and daily life assistance. However, with the advancement of machine learning (ML) which is renowned for tackling many real-world settings, it can offer unprecedented opportunities in prognostic studies and facilitate individuals with ALS in motor-imagery tasks. ML models, such as random forests (RF), have emerged as the most common and effective algorithms for predicting disease progression and survival time in ALS. The findings revealed that RF models had an excellent predictive performance for ALS, with a testing R2 of 0.524 and minimal treatment effects of 0.0717 for patient survival time. Despite significant limitations in sample size, with a maximum of 18 participants, which may not adequately reflect the population diversity being studied, ML approaches have been effectively applied to ALS datasets, and numerous prognostic models have been tested using neuroimaging data, longitudinal datasets, and core clinical variables. In many literatures, the constraints of ML models are seldom explicitly enunciated. Therefore, the main objective of this research is to provide a review of the most significant studies on the usage of ML models for analyzing ALS. This review covers a variation of ML algorithms involved in applications in ALS prognosis besides, leveraging ML to improve the efficacy of brain-computer interfaces (BCIs) for ALS individuals in later stages with restricted voluntary muscular control. The key future advances in individualized care and ALS prognosis may include the advancement of more personalized care aids that enable real-time input and ongoing validation of ML in diverse healthcare contexts.}, } @article {pmid39287472, year = {2024}, author = {Kasperkiewicz, M}, title = {Letter to the Editor: Comment on Bocanegra-Oyola et al's "Clinical Characteristics of Ocular Mucous Membrane Pemphigoid: A Systematic Review and Meta-Analysis".}, journal = {Ocular immunology and inflammation}, volume = {32}, number = {10}, pages = {2622-2623}, doi = {10.1080/09273948.2024.2404105}, pmid = {39287472}, issn = {1744-5078}, mesh = {Humans ; Diagnosis, Differential ; *Pemphigoid, Benign Mucous Membrane/diagnosis ; Meta-Analysis as Topic ; }, abstract = {The work by Bocanegra-Oyola et al. provides a qualitative analysis and meta-analysis of ocular pemphigoid characteristics. This correspondence discusses the need for diagnostic process optimization to better differentiate between ocular pemphigoid and its mimicker pseudopemphigoid.}, } @article {pmid39287519, year = {2024}, author = {Wendebourg, MJ and Kesenheimer, E and Sander, L and Weigel, M and Weidensteiner, C and Haas, T and Madoerin, P and Diebold, M and Deigendesch, N and Neuhaus, D and Naumann, N and Neuwirth, C and Braun, N and Weber, M and Granziera, C and Scheurer, E and Lenz, C and Schweikert, K and Sinnreich, M and Lieb, J and Bieri, O and Schlaeger, R}, title = {The Lateral Corticospinal Tract Sign: An MRI Marker for Amyotrophic Lateral Sclerosis.}, journal = {Radiology}, volume = {312}, number = {3}, pages = {e231630}, doi = {10.1148/radiol.231630}, pmid = {39287519}, issn = {1527-1315}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Prospective Studies ; *Pyramidal Tracts/diagnostic imaging/pathology ; Sensitivity and Specificity ; }, abstract = {Background Radially sampled averaged magnetization inversion-recovery acquisition (rAMIRA) imaging shows hyperintensity in the lateral corticospinal tract (CST) in patients with motor neuron diseases. Purpose To systematically determine the accuracy of the lateral corticospinal tract sign for detecting patients with amyotrophic lateral sclerosis (ALS) at rAMIRA MRI. Materials and Methods This study included prospectively acquired data from participants in ALS and other motor neuron disease imaging studies at the University Hospital Basel, Switzerland. All participants underwent 3-T axial two-dimensional rAMIRA imaging at four cervical intervertebral disk levels. The lateral CST sign was defined as spinal cord white matter hyperintensity dorsolateral to the anterior horns, with higher signal intensity than in the dorsal columns on axial rAMIRA images. Marker accuracy was assessed in a study data set and in an independent validation data set. Postmortem rAMIRA imaging and histopathologic analysis were performed in one participant who died during the study. Results Participants with ALS (study data set: 38 participants [mean age, 61 years; IQR, 15 years], 22 male participants; validation data set: 10 participants [mean age, 61 years; IQR, 21 years], seven male participants), post-polio syndrome (study data set: 25 participants [mean age, 68 years; IQR, 8 years], 12 male participants), spinal muscular atrophy (study data set: 10 participants [mean age, 43 years; IQR, 14 years], eight male participants; validation data set: five participants [mean age, 38 years; IQR, 19 years], two male participants), and healthy control participants (study data set: 60 participants [mean age, 57 years; IQR, 20 years], 36 male participants; validation data set: 10 participants [mean age, 44 years; IQR, 17 years], seven male participants) were included. The sensitivity and specificity of rAMIRA for ALS were 60% (23 of 38) and 97% (91 of 94) in the study data set and 100% (10 of 10) and 93% (14 of 15) in the validation data set, respectively. Histopathologic analysis showed distinct loss of myelinated axons in the localization of the hyperintensities observed at rAMIRA imaging performed in situ and after organ extraction. Conclusion The recently defined marker at rAMIRA MRI may be a promising tool for assessing upper motor neuron degeneration in the lateral CST in patients with ALS. Clinical trials registration no. NCT03561623, NCT05764434, NCT06137612 © RSNA, 2024 Supplemental material is available for this article.}, } @article {pmid39287680, year = {2024}, author = {Castelnovo, V and Canu, E and Aiello, EN and Curti, B and Sibilla, E and Torre, S and Freri, F and Tripodi, C and Lumaca, L and Spinelli, EG and Schito, P and Russo, T and Falzone, Y and Verde, F and Silani, V and Ticozzi, N and Sturm, VE and Rankin, KP and Gorno-Tempini, ML and Poletti, B and Filippi, M and Agosta, F}, title = {How to detect affect recognition alterations in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {11}, pages = {7208-7221}, pmid = {39287680}, issn = {1432-1459}, support = {StG-2016_714388_NeuroTRACK//FP7 Ideas: European Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; Male ; Female ; Middle Aged ; Aged ; *Neuropsychological Tests ; Recognition, Psychology/physiology ; Cognitive Dysfunction/diagnosis/etiology/physiopathology ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To define the clinical usability of an affect recognition (AR) battery-the Comprehensive Affect Testing System (CATS)-in an Italian sample of patients with amyotrophic lateral sclerosis (ALS).

METHODS: 96 ALS patients and 116 healthy controls underwent a neuropsychological assessment including the AR subtests of the abbreviated version of the CATS (CATS-A). CATS-A AR subtests and their global score (CATS-A AR Quotient, ARQ) were assessed for their factorial, convergent, and divergent validity. The diagnostic accuracy of each CATS-A AR measure in discriminating ALS patients with cognitive impairment from cognitively normal controls and patients was tested via receiver-operating characteristics analyses. Optimal cut-offs were identified for CATS-A AR measures yielding an acceptable AUC value (≥ .70). The ability of CATS-A ARQ to discriminate between different ALS cognitive phenotypes was also tested. Gray-matter (GM) volumes of controls, ALS with normal (ALS-nARQ), and impaired ARQ score (ALS-iARQ) were compared using ANCOVA models.

RESULTS: CATS-A AR subtests and ARQ proved to have moderate-to-strong convergent and divergent validity. Almost all considered CATS-A measures reached acceptable accuracy and diagnostic power (AUC range = .79-.83). ARQ showed to be the best diagnostic measure (sensitivity = .80; specificity = .75) and discriminated between different ALS cognitive phenotypes. Compared to ALS-nARQ, ALS-iARQ patients showed reduced GM volumes in the right anterior cingulate, right middle frontal, left inferior temporal, and superior occipital regions.

CONCLUSIONS: The AR subtests of the CATS-A, and in particular the CATS-A ARQ, are sound measures of AR in ALS. AR deficits may be a valid marker of frontotemporal involvement in these patients.}, } @article {pmid39288267, year = {2024}, author = {Liu, H and Zhao, XF and Lu, YN and Hayes, LR and Wang, J}, title = {CRISPR/Cas13d targeting suppresses repeat-associated non-AUG translation of C9orf72 hexanucleotide repeat RNA.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {21}, pages = {}, pmid = {39288267}, issn = {1558-8238}, support = {R01 NS123538/NS/NINDS NIH HHS/United States ; R01 NS128494/NS/NINDS NIH HHS/United States ; R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy/metabolism ; *CRISPR-Cas Systems ; Mice ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *DNA Repeat Expansion/genetics ; *Mice, Transgenic ; Protein Biosynthesis ; Induced Pluripotent Stem Cells/metabolism ; RNA/genetics/metabolism ; Motor Neurons/metabolism/pathology ; }, abstract = {A hexanucleotide GGGGCC repeat expansion in the non-coding region of the C9orf72 gene is the most common genetic mutation identified in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The resulting repeat RNA and dipeptide repeat proteins from non-conventional repeat translation have been recognized as important markers associated with the diseases. CRISPR/Cas13d, a powerful RNA-targeting tool, has faced challenges in effectively targeting RNA with stable secondary structures. Here we report that CRISPR/Cas13d can be optimized to specifically target GGGGCC repeat RNA. Our results demonstrate that the CRISPR/Cas13d system can be harnessed to significantly diminish the translation of poly-dipeptides originating from the GGGGCC repeat RNA. This efficacy has been validated in various cell types, including induced pluripotent stem cells and differentiated motor neurons originating from C9orf72-ALS patients, as well as in C9orf72 repeat transgenic mice. These findings demonstrate the application of CRISPR/Cas13d in targeting RNA with intricate higher-order structures and suggest a potential therapeutic approach for ALS and FTD.}, } @article {pmid39289025, year = {2024}, author = {Dunlop, CL and Kilpatrick, C and Jones, L and Bonet, M and Allegranzi, B and Brizuela, V and Graham, W and Thompson, A and Cheshire, J and Lissauer, D}, title = {Adapting the WHO hand hygiene 'reminders in the workplace' to improve acceptability for healthcare workers in maternity settings worldwide: a mixed methods study.}, journal = {BMJ open}, volume = {14}, number = {9}, pages = {e083132}, pmid = {39289025}, issn = {2044-6055}, support = {001/WHO_/World Health Organization/International ; }, mesh = {Humans ; *Hand Hygiene ; *Focus Groups ; Female ; *World Health Organization ; *Health Personnel/psychology ; Workplace ; Attitude of Health Personnel ; Reminder Systems ; Adult ; Male ; Cross Infection/prevention & control ; Surveys and Questionnaires ; Hospitals, Maternity ; Developing Countries ; Guideline Adherence ; Interviews as Topic ; }, abstract = {INTRODUCTION: Hand hygiene is key in preventing healthcare-associated infections, but it is challenging in maternity settings due to high patient turnover, frequent emergencies and volume of aseptic procedures. We sought to investigate if adaptions to the WHO hand hygiene reminders could improve their acceptability in maternity settings globally, and use these findings to develop new reminders specific to maternity settings.

METHODS: Informed by Sekhon et al's acceptability framework, we conducted an online survey, semi-structured interviews and a focus group examining the three WHO central hand hygiene reminders ('your five moments of hand hygiene', 'how to hand wash' and 'how to hand rub') and their acceptability in maternity settings. A convergent mixed-methods study design was followed. Findings were examined overall and by country income status. A WHO expert working group tested the integrated findings, further refined results and developed recommendations to improve acceptability for use in the global maternity community. Findings were used to inform the development of two novel and acceptable hand hygiene reminders for use in high-income country (HIC) and low- and middle-income country (LMIC) maternity settings.

RESULTS: Participation in the survey (n=342), semi-structured interviews (n=12) and focus group (n=7) spanned 51 countries (14 HICs and 37 LMICs). The highest scoring acceptability constructs were clarity of the intervention (intervention coherence), confidence in performance (self-efficacy), and alignment with personal values (ethicality). The lowest performing were perceived difficulty (burden) and how the intervention made the participant feel (affective attitude). Overfamiliarity reduced acceptability in HICs (perceived effectiveness). In LMICs, resource availability was a barrier to implementation (opportunity cost). Two new reminders were developed based on the findings, using inclusive female images, and clinical examples from maternity settings.

CONCLUSION: Following methodologically robust adaptation, two novel and inclusive maternity-specific hand hygiene reminders have been developed for use in both HIC and LMICs.}, } @article {pmid39289471, year = {2024}, author = {Jawdat, O and Rucker, J and Nakano, T and Takeno, K and Statland, J and Pasnoor, M and Dimachkie, MM and Sabus, C and Badawi, Y and Hunt, SL and Tomioka, NH and Gunewardena, S and Bloomer, C and Wilkins, HM and Herbelin, L and Barohn, RJ and Nishimune, H}, title = {Resistance exercise in early-stage ALS patients, ALSFRS-R, Sickness Impact Profile ALS-19, and muscle transcriptome: a pilot study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {21729}, pmid = {39289471}, issn = {2045-2322}, support = {P30 GM122731/GM/NIGMS NIH HHS/United States ; R01NS078214/NS/NINDS NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; R01 NS078214/NS/NINDS NIH HHS/United States ; U54 HD090216/HD/NICHD NIH HHS/United States ; S10 OD021743/OD/NIH HHS/United States ; 19K24690//Japan Society for the Promotion of Science/ ; UL1 TR002366/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Pilot Projects ; Male ; *Resistance Training ; Female ; Middle Aged ; *Transcriptome ; *Muscle Strength ; Aged ; Adult ; Quadriceps Muscle/metabolism/physiopathology ; Muscle, Skeletal/metabolism/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) patients lack effective treatments to maintain motor and neuromuscular function. This study aimed to evaluate the effect of a home-based exercise program on muscle strength, ALS scores, and transcriptome in ALS patients, Clinical Trials.gov #NCT03201991 (28/06/2017). An open-label, non-randomized pilot clinical trial was conducted in seven individuals with early-stage ALS. Participants were given 3 months of home-based resistance exercise focusing on the quadriceps muscles. The strength of exercised muscle was evaluated using bilateral quadriceps strength with manual muscle testing, handheld dynamometers, five times sit-to-stand, and Timed-Up-and-Go before and after the exercise program. In addition, changes in the Sickness Impact Profile ALS-19 (SIP/ALS-19) as the functional outcome measure and the transcriptome of exercised muscles were compared before and after the exercise. The primary outcome of muscle strength did not change significantly by the exercise program. The exercise program maintained the SIP/ALS-19 and the ALS Functional Rating Scale-Revised (ALSFRS-R). Transcriptome analysis revealed that exercise reverted the expression level of genes decreased in ALS, including parvalbumin. Three months of moderately intense strength and conditioning exercise maintained muscle strength of the exercised muscle and ALSFRS-R scores and had a positive effect on patients' muscle transcriptome.}, } @article {pmid39289761, year = {2024}, author = {van der Geest, AT and Jakobs, CE and Ljubikj, T and Huffels, CFM and Cañizares Luna, M and Vieira de Sá, R and Adolfs, Y and de Wit, M and Rutten, DH and Kaal, M and Zwartkruis, MM and Carcolé, M and Groen, EJN and Hol, EM and Basak, O and Isaacs, AM and Westeneng, HJ and van den Berg, LH and Veldink, JH and Schlegel, DK and Pasterkamp, RJ}, title = {Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {152}, pmid = {39289761}, issn = {2051-5960}, support = {TOTALS//Stichting ALS Nederland/ ; ALS-on-a-chip//Stichting ALS Nederland/ ; MUS-ALS//Stichting ALS Nederland/ ; ATAXALS//Stichting ALS Nederland/ ; GoALS//Stichting ALS Nederland/ ; INTEGRALS//E-Rare/ ; TRIAGE//JPND/ ; EScORIAL/ERC_/European Research Council/International ; }, mesh = {Humans ; *Organoids/pathology ; *Frontotemporal Dementia/genetics/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics ; *Induced Pluripotent Stem Cells/pathology ; *Synapses/pathology/genetics ; Male ; Female ; Cerebral Cortex/pathology ; DNA Repeat Expansion/genetics ; }, abstract = {A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls. Our work revealed the presence of all three C9-HRE-related molecular pathologies and developmental stage-dependent size phenotypes in cerebral organoids from C9-ALS/FTD patients. In addition, single-cell RNA sequencing identified changes in cell type abundance and distribution in C9-ALS/FTD organoids, including a reduction in the number of deep layer cortical neurons and the distribution of neural progenitors. Further, molecular and cellular analyses and patch-clamp electrophysiology detected various changes in synapse structure and function. Intriguingly, organoids from all presymptomatic C9-HRE carriers displayed C9-HRE molecular pathology, whereas the extent to which more downstream cellular defects, as found in C9-ALS/FTD models, were detected varied for the different presymptomatic C9-HRE cases. Together, these results unveil early changes in 3D human brain tissue organization and synaptic connectivity in C9-ALS/FTD that likely constitute initial pathologies crucial for understanding disease onset and the design of therapeutic strategies.}, } @article {pmid39290715, year = {2024}, author = {Huang, L and Liu, M and Tang, J and Gong, Z and Li, Z and Yang, Y and Zhang, M}, title = {The role of ALDH2 rs671 polymorphism and C-reactive protein in the phenotypes of male ALS patients.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1397991}, pmid = {39290715}, issn = {1662-4548}, abstract = {BACKGROUND: The aldehyde dehydrogenase 2 (ALDH2) rs671 (A) allele has been implicated in neurodegeneration, potentially through oxidative and inflammatory pathways. The study aims to investigate the effects of the ALDH2 rs671 (A) allele and high sensitivity C-reactive protein (hs-CRP) on the clinical phenotypes of amyotrophic lateral sclerosis (ALS) in male and female patients.

METHODS: Clinical data and ALDH2 rs671 genotype of 143 ALS patients, including 85 males and 58 females, were collected from January 2018 to December 2022. All patients underwent assessment using the Chinese version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Complete blood count and metabolic profiles were measured. Clinical and laboratory parameters were compared between carriers and non-carriers of the rs671 (A) allele in males and females, respectively. The significant parameters and rs671 (A) Allele were included in multivariate linear regression models to identify potential contributors to motor and cognitive impairment. Mediation analysis was employed to evaluate any mediation effects.

RESULTS: Male patients carrying rs671 (A) allele exhibited higher levels of hs-CRP than non-carriers (1.70 mg/L vs. 0.50 mg/L, p = 0.006). The rs671 (A) allele was identified as an independent risk factor for faster disease progression only in male patients (β = 0.274, 95% CI = 0.048-0.499, p = 0.018). The effect of the rs671 (A) allele on the executive function in male patients was fully mediated by hs-CRP (Indirect effect = -1.790, 95% CI = -4.555--0.225). No effects of the rs671 (A) allele or hs-CRP were observed in female ALS patients. The effects of the ALDH2 rs671 (A) allele and the mediating role of hs-CRP in male patients remained significant in the sensitivity analyses.

CONCLUSION: The ALDH2 rs671 (A) allele contributed to faster disease progression and hs-CRP mediated cognitive impairment in male ALS patients.}, } @article {pmid39290830, year = {2024}, author = {Noches, V and Campos-Melo, D and Droppelmann, CA and Strong, MJ}, title = {Epigenetics in the formation of pathological aggregates in amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1417961}, pmid = {39290830}, issn = {1662-5099}, abstract = {The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is accompanied by the formation of a broad array of cytoplasmic and nuclear neuronal inclusions (protein aggregates) largely containing RNA-binding proteins such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma/translocated in liposarcoma (FUS/TLS). This process is driven by a liquid-to-solid phase separation generally from proteins in membrane-less organelles giving rise to pathological biomolecular condensates. The formation of these protein aggregates suggests a fundamental alteration in the mRNA expression or the levels of the proteins involved. Considering the role of the epigenome in gene expression, alterations in DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA modifications become highly relevant to understanding how this pathological process takes effect. In this review, we explore the evidence that links epigenetic mechanisms with the formation of protein aggregates in ALS. We propose that a greater understanding of the role of the epigenome and how this inter-relates with the formation of pathological LLPS in ALS will provide an attractive therapeutic target.}, } @article {pmid39291146, year = {2023}, author = {Mathew, AM and Bhuvanendran, S and Nair, RS and K Radhakrishnan, A}, title = {Exploring the anti-inflammatory activities, mechanism of action and prospective drug delivery systems of tocotrienol to target neurodegenerative diseases.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {338}, pmid = {39291146}, issn = {2046-1402}, abstract = {A major cause of death in the elderly worldwide is attributed to neurodegenerative diseases, such as AD (Alzheimer's disease), PD (Parkinson's disease), ALS (Amyotrophic lateral sclerosis), FRDA (Friedreich's ataxia), VaD (Vascular dementia) etc. These can be caused due to multiple factors such as genetic, physiological problems like stroke or tumor, or even external causes like viruses, toxins, or chemicals. T3s (tocotrienols) exhibit various bioactive properties where it acts as an antioxidant, anti-inflammatory, anti-tumorigenic, and cholesterol lowering agent. Since T3 interferes with and influences several anti-inflammatory mechanisms, it aids in combating inflammatory responses that lead to disease progression. T3s are found to have a profound neuroprotective ability, however, due to their poor oral bioavailability, their full potential could not be exploited. Hence there is a need to explore other drug delivery techniques, especially focusing on aspects of nanotechnology. In this review paper we explore the anti-inflammatory mechanisms of T3 to apply it in the treatment of neurodegenerative diseases and also discusses the possibilities of nano methods of administering tocotrienols to target neurodegenerative diseases.}, } @article {pmid39291166, year = {2024}, author = {Gianferrari, G and Cuoghi Costantini, R and Crippa, V and Carra, S and Bonetto, V and Pansarasa, O and Cereda, C and Zucchi, E and Martinelli, I and Simonini, C and Vicini, R and Fini, N and Trojsi, F and Passaniti, C and Ticozzi, N and Doretti, A and Diamanti, L and Fiamingo, G and Conte, A and Dalla Bella, E and D'Errico, E and Scarian, E and Pasetto, L and Antoniani, F and Galli, V and Casarotto, E and , and D'Amico, R and Poletti, A and Mandrioli, J}, title = {Colchicine treatment in amyotrophic lateral sclerosis: safety, biological and clinical effects in a randomized clinical trial.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae304}, pmid = {39291166}, issn = {2632-1297}, abstract = {In preclinical studies, the anti-inflammatory drug colchicine, which has never been tested in amyotrophic lateral sclerosis, enhanced the expression of autophagy factors and inhibited accumulation of transactive response DNA-binding protein 43 kDa, a known histopathological marker of amyotrophic lateral sclerosis. This multicentre, randomized, double-blind trial enrolled patients with probable or definite amyotrophic lateral sclerosis who experienced symptom onset within the past 18 months. Patients were randomly assigned in a 1:1:1 ratio to receive colchicine at a dose of 0.005 mg/kg/day, 0.01 mg/kg/day or placebo for a treatment period of 30 weeks. The number of positive responders, defined as patients with a decrease lesser than 4 points in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score during the 30-week treatment period, was the primary outcome. Disease progression, survival, safety and quality of life at the end of treatment were the secondary clinical outcomes. Secondary biological outcomes included changes from baseline to treatment end of stress granule and autophagy responses, transactive response DNA-binding protein 43 kDa, neurofilament accumulation and extracellular vesicle secretion, between the colchicine and placebo groups. Fifty-four patients were randomized to receive colchicine (n = 18 for each colchicine arm) or placebo (n = 18). The number of positive responders did not differ between the placebo and colchicine groups: 2 out of 18 patients (11.1%) in the placebo group, 5 out of 18 patients (27.8%) in the colchicine 0.005 mg/kg/day group (odds ratio = 3.1, 97.5% confidence interval 0.4-37.2, P = 0.22) and 1 out of 18 patients (5.6%) in the colchicine 0.01 mg/kg/day group (odds ratio = 0.5, 97.5% confidence interval 0.01-10.2, P = 0.55). During treatment, a slower Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised decline was detected in patients receiving colchicine 0.005 mg/kg/day (mean difference = 0.53, 97.5% confidence interval 0.07-0.99, P = 0.011). Eight patients experienced adverse events in placebo arm (44.4%), three in colchicine 0.005 mg/kg/day (16.7%) and seven in colchicine 0.01 mg/kg/day arm (35.9%). The differences in adverse events were not statistically significant. In conclusion, colchicine treatment was safe for amyotrophic lateral sclerosis patients. Further studies are required to better understand mechanisms of action and clinical effects of colchicine in this condition.}, } @article {pmid39291248, year = {2024}, author = {Senerchia, G and Dubbioso, R}, title = {Non-invasive brain stimulation therapy in amyotrophic lateral sclerosis: are we ready for clinical use?.}, journal = {The Lancet regional health. Europe}, volume = {45}, number = {}, pages = {101055}, pmid = {39291248}, issn = {2666-7762}, } @article {pmid39292338, year = {2025}, author = {Zhang, H and Gao, C and Yang, D and Nie, L and He, K and Chen, C and Li, S and Huang, G and Zhou, L and Huang, X and Wu, D and Liu, J and Huang, Z and Wang, J and Li, W and Zhang, Z and Yang, X and Zou, L}, title = {Urolithin a Improves Motor Dysfunction Induced by Copper Exposure in SOD1[G93A] Transgenic Mice Via Activation of Mitophagy.}, journal = {Molecular neurobiology}, volume = {62}, number = {6}, pages = {6922-6937}, pmid = {39292338}, issn = {1559-1182}, mesh = {Animals ; Mice, Transgenic ; *Copper/toxicity ; *Mitophagy/drug effects ; *Coumarins/pharmacology/therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy/pathology/physiopathology ; Mice ; Motor Neurons/drug effects/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Mitochondria/drug effects/metabolism ; Spinal Cord/pathology/drug effects/metabolism ; Male ; Astrocytes/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease pathologically characterized by selective degeneration of motor neurons resulting in a catastrophic loss of motor function. The present study aimed to investigate the effect of copper (Cu) exposure on progression of ALS and explore the therapeutic effect and mechanism of Urolithin A (UA) on ALS. 0.13 PPM copper chloride drinking water was administrated in SOD1[G93A] transgenic mice at 6 weeks, UA at a dosage of 50 mg/kg/day was given for 6 weeks after a 7-week Cu exposure. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl and Immunohistochemistry Staining. Proteomics analysis, Western blotting and ELISA were conducted to detect protein expression. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. Cu-exposure worsened motor function, promoted muscle fibrosis, loss of motor neurons, and astrocyte and microglial activation. It also induced abnormal changes in mitochondria-related biological processes, leading to a significant reduction in ATP levels and an increase in MDA levels. Upregulation of P62 and downregulation of Parkin, PINK1, and LAMP1 were revealed in SOD1[G93A] mice with Cu exposure. Administration of UA activated mitophagy, modulated mitochondria dysfunction, reduced neuroinflammation, and improved gastrocnemius muscle atrophy and motor dysfunction in SOD1[G93A] mice with Cu exposure. Mitophagy plays critical role in ALS exacerbated by Cu exposure. UA administration may be a promising treatment strategy for ALS.}, } @article {pmid39292414, year = {2024}, author = {Ataman, R and Alhasani, R and Auneau-Enjalbert, L and Quigley, A and Michael, HU and Ahmed, S}, title = {The psychometric properties of the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system in neurorehabilitation populations: a systematic review.}, journal = {Journal of patient-reported outcomes}, volume = {8}, number = {1}, pages = {106}, pmid = {39292414}, issn = {2509-8020}, support = {36053//Canadian Foundation of Innovation and the Ministry of Health of Quebec/ ; }, mesh = {Humans ; *Nervous System Diseases/rehabilitation/psychology/diagnosis ; *Neurological Rehabilitation/methods ; *Psychometrics/methods ; *Quality of Life/psychology ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To systematically review the literature of existing evidence on the measurement properties of the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system among neurorehabilitation populations.

DATA SOURCES: The Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) guided this systematic review in which we searched nine electronic databases and registries, and hand-searched reference lists of included articles.

STUDY SELECTION: Two independent reviewers screened selected articles and extracted data from 28 included studies.

DATA EXTRACTION: COSMIN's approach guided extraction and synthesizing measurement properties evidence (insufficient, sufficient), and the modified GRADE approach guided synthesizing evidence quality (very-low, low, moderate, high) by diagnosis.

DATA SYNTHESIS: Neuro-QoL has sufficient measurement properties when used by individuals with Huntington's disease, Multiple Sclerosis, Parkinson's disease, stroke, lupus, cognitive decline, and amyotrophic lateral sclerosis. The strongest evidence is for the first four conditions, where test-retest reliability, construct validity, and responsiveness are nearly always sufficient (GRADE: moderate-high). Structural validity is assessed only in multiple sclerosis and stroke but is often insufficient (GRADE: moderate-high). Criterion validity is sufficient in some stroke and Huntington's disease domains (GRADE: high). Item response theory analyses were reported for some stroke domains only. There is limited, mixed evidence for responsiveness and measurement error (GRADE: moderate-high), and no cross-cultural validity evidence CONCLUSIONS: Neuro-QoL domains can describe and evaluate patients with Huntington's disease, multiple sclerosis, Parkinson's disease, and stroke, but predictive validity evidence would be beneficial. In the other conditions captured in this review, a limited number of Neuro-QoL domains have evidence for descriptive use only. For these conditions, further evidence of structural validity, measurement error, cross-cultural validity and predictive validity would enhance the use and interpretation of Neuro-QoL.}, } @article {pmid39292611, year = {2024}, author = {Xu, Z and Tang, J and Gong, Y and Zhang, J and Zou, Y}, title = {Atomistic Insights into the Stabilization of TDP-43 Protofibrils by ATP.}, journal = {Journal of chemical information and modeling}, volume = {64}, number = {19}, pages = {7639-7649}, doi = {10.1021/acs.jcim.4c01140}, pmid = {39292611}, issn = {1549-960X}, mesh = {*Adenosine Triphosphate/metabolism ; *Molecular Dynamics Simulation ; *DNA-Binding Proteins/chemistry/metabolism ; Humans ; Protein Stability ; Hydrogen Bonding ; }, abstract = {The aberrant accumulation of the transactive response deoxyribonucleic acid (DNA)-binding protein of 43 kDa (TDP-43) aggregates in the cytoplasm of motor neurons is the main pathological hallmark of amyotrophic lateral sclerosis (ALS). Previous experiments reported that adenosine triphosphate (ATP), the universal energy currency for all living cells, could induce aggregation and enhance the folding of TDP-43 fibrillar aggregates. However, the significance of ATP on TDP-43 fibrillation and the mechanism behind it remain elusive. In this work, we conducted multiple atomistic molecular dynamics (MD) simulations totaling 20 μs to search the critical nucleus size of TDP-43282-360 and investigate the impact of ATP molecules on preformed protofibrils. The results reveal that the trimer is the critical nucleus for TDP-43282-360 fibril formation and the tetramer is the minimal stable nucleus. When ATP molecules bind to the TDP-43282-360 trimer and tetramer, they can consolidate the TDP-43282-360 protofibrils by increasing the content of the β-sheet structure and promoting the formation of hydrogen bonds (H-bonds). Binding site analyses show that the N-terminus of TDP-43282-360 protofibrils is the main binding site of ATP, and R293 dominates the direct binding of ATP. Further analyses reveal that the π-π, cation-π, salt bridge, and H-bonding interactions together contribute to the binding of ATP to TDP-43282-360 protofibrils. This study decoded the detailed stabilization mechanism of protofibrillar TDP-43282-360 oligomers by ATP, and may provide new avenues for the development of drug design against ALS.}, } @article {pmid39292682, year = {2024}, author = {Tang, X and Li, Q and Huang, G and Pei, X and Chen, Z and Huang, Y and Zhao, S and Guo, T and Liu, Z}, title = {Immediate efficacy of auricular acupuncture combined with active exercise in the treatment of acute lumbar sprains in 10 minutes: Protocol of a randomized controlled trial.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0308801}, pmid = {39292682}, issn = {1932-6203}, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Acupuncture, Ear/methods ; Combined Modality Therapy ; *Exercise Therapy/methods ; Low Back Pain/therapy ; Lumbar Vertebrae/physiopathology ; Lumbosacral Region ; Pain Measurement ; Prospective Studies ; Range of Motion, Articular ; Sprains and Strains/therapy ; Treatment Outcome ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Acute lumbar sprain (ALS) is common musculoskeletal disorder characterized by severe low back pain and activity limitation, which significantly impacts the patient's work and life. Immediate relief of pain and restoration of mobility in a short period of time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of this combined treatment for ALS within 10 minutes.

METHODS: This is a single-center, prospective, randomized clinical trial. 128 eligible patients with ALS will be randomly allocated in a 1:1 ratio to either the auricular acupuncture (AA) group or the sham auricular acupuncture (SAA) group. All patients will receive a single 10-minute treatment. The primary outcome will be the change in pain intensity after 10 minutes of treatment. The secondary outcomes include changes in pain intensity at other time points (2, 5 minutes), changes in lumbar range of motion (ROM) at different time points, blinded assessment, treatment effect expectancy scale evaluation, and treatment satisfaction scale evaluation. All participants will be included in the analysis according to the intention-to-treat principle.

DISCUSSION: This is the first randomized controlled trial to assess the immediate efficacy of AA combined with active exercise for ALS. The findings of this study are expected to provide a simple and rapid treatment for ALS in clinical.

TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2400083740. Registered 30 April 2024.}, } @article {pmid39292705, year = {2024}, author = {Minnella, A and McCusker, KP and Amagata, A and Trias, B and Weetall, M and Latham, JC and O'Neill, S and Wyse, RK and Klein, MB and Trimmer, JK}, title = {Targeting ferroptosis with the lipoxygenase inhibitor PTC-041 as a therapeutic strategy for the treatment of Parkinson's disease.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0309893}, pmid = {39292705}, issn = {1932-6203}, mesh = {Animals ; *Ferroptosis/drug effects ; *Lipoxygenase Inhibitors/pharmacology/therapeutic use ; Humans ; *Parkinson Disease/drug therapy/metabolism/pathology ; Rats ; Mice ; alpha-Synuclein/metabolism ; Lipid Peroxidation/drug effects ; Neurons/drug effects/metabolism/pathology ; Fibroblasts/drug effects/metabolism ; Arachidonate 15-Lipoxygenase/metabolism ; Cells, Cultured ; Male ; }, abstract = {Parkinson's disease is the second most common neurodegenerative disorder, affecting nearly 10 million people worldwide. Ferroptosis, a recently identified form of regulated cell death characterized by 15-lipoxygenase-mediated hydroperoxidation of membrane lipids, has been implicated in neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Pharmacological inhibition of 15 -lipoxygenase to prevent iron- and lipid peroxidation-associated ferroptotic cell death is a rational strategy for the treatment of Parkinson's disease. We report here the characterization of PTC-041 as an anti-ferroptotic reductive lipoxygenase inhibitor developed for the treatment of Parkinson's disease. In these studies, PTC-041 potently protects primary human Parkinson's disease patient-derived fibroblasts from lipid peroxidation and subsequent ferroptotic cell death and prevents ferroptosis-related neuronal loss and astrogliosis in primary rat neuronal cultures. Additionally, PTC-041 prevents ferroptotic-mediated α-synuclein protein aggregation and nitrosylation in vitro, suggesting a potential role for anti-ferroptotic lipoxygenase inhibitors in mitigating pathogenic aspects of synucleinopathies such as Parkinson's disease. We further found that PTC-041 protects against synucleinopathy in vivo, demonstrating that PTC-041 treatment of Line 61 transgenic mice protects against α-synuclein aggregation and phosphorylation as well as prevents associated neuronal and non-neuronal cell death. Finally, we show that. PTC-041 protects against 6-hydroxydopamine-induced motor deficits in a hemiparkinsonian rat model, further validating the potential therapeutic benefits of lipoxygenase inhibitors in the treatment of Parkinson's disease.}, } @article {pmid39293008, year = {2024}, author = {Ramirez, V and Kittrell, P and Jackson, C and Clegg, A and Allegretti, A}, title = {Sexual Intimacy in Persons with Amyotrophic Lateral Sclerosis and their Partners: A Pilot Study.}, journal = {Journal of allied health}, volume = {53}, number = {3}, pages = {212-217}, pmid = {39293008}, issn = {1945-404X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Pilot Projects ; Male ; Female ; Middle Aged ; *Sexual Partners/psychology ; Aged ; Sexual Behavior ; Adult ; Quality of Life ; }, abstract = {OBJECTIVE: The objective of this study was to describe concerns experienced among persons with amyotrophic lateral sclerosis (PALS) and their partners regarding sexual intimacy, as well as preferences regarding discussion of the topic with healthcare providers.

METHODS: A total of 27 survey responses including 13 PALS and 14 partners were received. Surveys included both quantitative and qualitative data addressing the importance of sexual intimacy to quality of life, assistance required to participate in sexual intimacy, concerns for safety, and preferred timing and method of discussing/receiving information from healthcare professionals.

RESULTS: 100% of respondents stated they had never been asked about sexual intimacy by any healthcare provider. 92% of participants agreed ALS had affected their ability to express sexual intimacy. Participants discussed loss of intimacy as due to muscle weakness, respiratory concerns, and role change among other contributors to the overall experienced change in expression of sexual intimacy. With regards to their preferred method of receiving/discussing information on the effect of ALS on sexual intimacy, 48% of participants preferred use of an online video series, 44% chose a pamphlet, 24% chose a one-on-one discussion with a healthcare provider, and 12% chose a private conversation with their partner and healthcare provider.

CONCLUSIONS: The findings greatly illustrate the difficulties and concerns experienced with sexual intimacy among PALS and their partners as well as the preferred methods for receiving information on the topic.}, } @article {pmid39293800, year = {2024}, author = {Gao, J and Chai, N and Wang, T and Han, Z and Chen, J and Lin, G and Wu, Y and Bi, L}, title = {A new technique of percutaneous minimally invasive surgery assisted by magnetic resonance neurography.}, journal = {Bone & joint open}, volume = {5}, number = {9}, pages = {776-784}, pmid = {39293800}, issn = {2633-1462}, abstract = {AIMS: In order to release the contracture band completely without damaging normal tissues (such as the sciatic nerve) in the surgical treatment of gluteal muscle contracture (GMC), we tried to display the relationship between normal tissue and contracture bands by magnetic resonance neurography (MRN) images, and to predesign a minimally invasive surgery based on the MRN images in advance.

METHODS: A total of 30 patients (60 hips) were included in this study. MRN scans of the pelvis were performed before surgery. The contracture band shape and external rotation angle (ERA) of the proximal femur were also analyzed. Then, the minimally invasive GMC releasing surgery was performed based on the images and measurements, and during the operation, incision lengths, surgery duration, intraoperative bleeding, and complications were recorded; the time of the first postoperative off-bed activity was also recorded. Furthermore, the patients' clinical functions were evaluated by means of Hip Outcome Score (HOS) and Ye et al's objective assessments, respectively.

RESULTS: The contracture bands exhibited three typical types of shape - feather-like, striped, and mixed shapes - in MR images. Guided by MRN images, we designed minimally invasive approaches directed to each hip. These approaches resulted in a shortened incision length in each hip (0.3 cm (SD 0.1)), shorter surgery duration (25.3 minutes (SD 5.8)), less intraoperative bleeding (8.0 ml (SD 3.6)), and shorter time between the end of the operation and the patient's first off-bed activity (17.2 hours (SD 2.0)) in each patient. Meanwhile, no serious postoperative complications occurred in all patients. The mean HOS-Sports subscale of patients increased from 71.0 (SD 5.3) to 94.83 (SD 4.24) at six months postoperatively (p < 0.001). The follow-up outcomes from all patients were "good" and "excellent", based on objective assessments.

CONCLUSION: Preoperative MRN analysis can be used to facilitate the determination of the relationship between contracture band and normal tissues. The minimally invasive surgical design via MRN can avoid nerve damage and improve the release effect.}, } @article {pmid39294194, year = {2024}, author = {Luthi-Carter, R and Cappelli, S and Le Roux-Bourdieu, M and Tentillier, N and Quinn, JP and Petrozziello, T and Gopalakrishnan, L and Sethi, P and Choudhary, H and Bartolini, G and Gebara, E and Stuani, C and Font, L and An, J and Ortega, V and Sage, J and Kosa, E and Trombetta, BA and Simeone, R and Seredenina, T and Afroz, T and Berry, JD and Arnold, SE and Carlyle, BC and Adolfsson, O and Sadri-Vakili, G and Buratti, E and Bowser, R and Agbas, A}, title = {Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {21837}, pmid = {39294194}, issn = {2045-2322}, support = {P30 AG062421/AG/NIA NIH HHS/United States ; Industry-Led Consortium Project Grant//Target ALS Foundation/ ; BB-2022-C5//Target ALS Foundation/ ; }, mesh = {Humans ; *Blood Platelets/metabolism ; *DNA-Binding Proteins/metabolism ; *Neurodegenerative Diseases/blood/metabolism ; *Biological Specimen Banks ; Amyotrophic Lateral Sclerosis/blood/metabolism/pathology ; Biomarkers/blood ; Cytosol/metabolism ; }, abstract = {The TAR DNA Binding Protein 43 (TDP-43) has been implicated in the pathogenesis of human neurodegenerative diseases and exhibits hallmark neuropathology in amyotrophic lateral sclerosis (ALS). Here, we explore its tractability as a plasma biomarker of disease and describe its localization and possible functions in the cytosol of platelets. Novel TDP-43 immunoassays were developed on three different technical platforms and qualified for specificity, signal-to-noise ratio, detection range, variation, spike recovery and dilution linearity in human plasma samples. Surprisingly, implementation of these assays demonstrated that biobank-archived plasma samples yielded considerable heterogeneity in TDP-43 levels. Importantly, subsequent investigation attributed these differences to variable platelet recovery. Fractionations of fresh blood revealed that ≥ 95% of the TDP-43 in platelet-containing plasma was compartmentalized within the platelet cytosol. We reasoned that this highly concentrated source of TDP-43 comprised an interesting substrate for biochemical analyses. Additional characterization of platelets revealed the presence of the disease-associated phosphoserine 409/410 TDP-43 proteoform and many neuron- and astrocyte-expressed TDP-43 mRNA targets. Considering these striking similarities, we propose that TDP-43 may serve analogous functional roles in platelets and synapses, and that the study of platelet TDP-43 might provide a window into disease-related TDP-43 dyshomeostasis in the central nervous system.}, } @article {pmid39295118, year = {2024}, author = {Berry, JD and Paganoni, S and Harms, MB and Shneider, N and Andrews, J and Miller, TM and Babu, S and Sherman, AV and Harris, BT and Provenzano, FA and Phatnani, HP and Shefner, J and Garret, MA and Ladha, SS and Tsou, AY and Mohan, P and Igne, C and , and Bowser, R}, title = {Access for ALL in ALS: A large-scale, inclusive, collaborative consortium to unlock the molecular and genetic mechanisms of amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {6}, pages = {1140-1150}, pmid = {39295118}, issn = {1097-4598}, support = {OT2 NS136938/NS/NINDS NIH HHS/United States ; OT2 NS136939/NS/NINDS NIH HHS/United States ; 1OT2NS136939-01//National Institute of Neurological Disorders and Stroke, NIH/ ; 1OT2NS136938-01//National Institute of Neurological Disorders and Stroke, NIH/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; United States ; Biomedical Research ; National Institutes of Health (U.S.) ; }, abstract = {Recent progress in therapeutics for amyotrophic lateral sclerosis (ALS) has spurred development and imbued the field of ALS with hope for more breakthroughs, yet substantial scientific gaps persist. This unmet need remains a stark reminder that innovative paradigms are needed to invigorate ALS research. To move toward more informative, targeted, and personalized drug development, the National Institutes of Health (NIH) established a national ALS clinical research consortium called Access for ALL in ALS (ALL ALS). This new consortium is a multi-institutional effort that aims to organize the ALS clinical research landscape in the United States. ALL ALS is operating in partnership with several stakeholders to operationalize the recommendations of the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) Public Private Partnership. ALL ALS will provide a large-scale, centralized, and readily accessible infrastructure for the collection and storage of a wide range of data from people living with ALS (symptomatic cohort) or who may be at risk of developing ALS (asymptomatic ALS gene carriers). Importantly, ALL ALS is designed to encourage community engagement, equity, and inclusion. The consortium is prioritizing the enrollment of geographically, ethnoculturally, and socioeconomically diverse participants. Collected data include longitudinal clinical data and biofluids, genomic, and digital biomarkers that will be harmonized and linked to the central Accelerating Medicines Partnership for ALS (AMP ALS) portal for sharing with the research community. The aim of ALL ALS is to deliver a comprehensive, inclusive, open-science dataset to help researchers answer important scientific questions of clinical relevance in ALS.}, } @article {pmid39295200, year = {2025}, author = {Zhang, Z and He, X and Wang, J and Cui, J and Shi, B}, title = {The correlation between social support, coping style, advance care planning readiness, and quality of life in patients with amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {40-47}, doi = {10.1080/21678421.2024.2400520}, pmid = {39295200}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; Male ; Female ; Cross-Sectional Studies ; *Quality of Life/psychology ; *Social Support ; Middle Aged ; *Advance Care Planning ; *Adaptation, Psychological/physiology ; Aged ; Adult ; China ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: The primary goal for clinical healthcare professionals is to enhance the quality of life (QOL) of patients with amyotrophic lateral sclerosis (ALS). This study aimed to explore the correlation between social support, coping style, advance care planning (ACP) readiness, and QOL in patients with ALS. We also sought to analyze the mediating effect of coping style and ACP readiness between social support and QOL, and to provide insights for developing targeted interventions to improve patients' QOL.

METHODS: A cross-sectional design was used, with participants recruited through convenience sampling in Tianjin, China. Statistical analysis included the t-test, analysis of variance, correlation analysis, and mediating effect analysis.

RESULTS: The study included 215 participants. The QOL of patients with ALS was at a medium level, with significant correlations between social support, coping style, ACP readiness, and QOL (all p < 0.01). The direct effect of social support on QOL was 0.403 (p = 0.018), accounting for 41.85% of the total effect. The total indirect effect of social support on QOL through coping style and ACP readiness was 0.560 (p < 0.001), accounting for 58.15% of the total effect. The chain mediating effect involving facing, avoiding, and ACP readiness accounted for 16.72%.

CONCLUSION: Social support directly influenced QOL and had an indirect impact through coping style and ACP readiness. Healthcare professionals can improve the QOL of patients with ALS by enhancing social support, disease-coping ability, and ACP readiness in clinical practice.}, } @article {pmid39296911, year = {2024}, author = {Odat, RM and Alomari, O and Elgenidy, A}, title = {Evaluation of the gold cost criteria as a diagnostic criteria of amyotrophic lateral sclerosis.}, journal = {eNeurologicalSci}, volume = {37}, number = {}, pages = {100524}, pmid = {39296911}, issn = {2405-6502}, } @article {pmid39296960, year = {2024}, author = {Keilholz, AN and Pathak, I and Smith, CL and Osman, KL and Smith, L and Oti, G and Golzy, M and Ma, L and Lever, TE and Nichols, NL}, title = {Tongue exercise ameliorates structural and functional upper airway deficits in a rodent model of hypoglossal motor neuron loss.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1441529}, pmid = {39296960}, issn = {1664-2295}, support = {R01 HL153612/HL/NHLBI NIH HHS/United States ; T32 OD011126/OD/NIH HHS/United States ; }, abstract = {INTRODUCTION: Tongue weakness and atrophy can lead to deficits in the vital functions of breathing and swallowing in patients with motor neuron diseases (MNDs; e.g., amyotrophic lateral sclerosis (ALS) and pseudobulbar palsy), often resulting in aspiration pneumonia, respiratory failure, and death. Available treatments for patients with MNDs are largely palliative; thus, there is a critical need for therapies targeting preservation of upper airway function and suggesting a role for tongue exercise in patients with MNDs. Here, we leveraged our inducible rodent model of hypoglossal (XII) motor neuron degeneration to investigate the effects of a strength endurance tongue exercise program on upper airway structure and function. Our model was created through intralingual injection of cholera toxin B conjugated to saporin (CTB-SAP) into the genioglossus muscle of the tongue to induce targeted death of XII motor neurons.

METHODS: Rats in this study were allocated to 4 experimental groups that received intralingual injection of either CTB-SAP or unconjugated CTB + SAP (i.e., control) +/- tongue exercise. Following tongue exercise exposure, we evaluated the effect on respiratory function (via plethysmography), macrostructure [via magnetic resonance imaging (MRI) of the upper airway and tongue], and ultrafine structure [via ex vivo magnetic resonance spectroscopy (MRS) of the tongue] with a focus on lipid profiles.

RESULTS: Results showed that sham exercise-treated CTB-SAP rats have evidence of upper airway restriction (i.e., reduced airflow) and structural changes present in the upper airway (i.e., airway compression) when compared to CTB-SAP + exercise rats and control rats +/- tongue exercise, which was ameliorated with tongue exercise. Additionally, CTB-SAP + sham exercise rats have evidence of increased lipid expression in the tongue consistent with previously observed tongue hypertrophy when compared to CTB-SAP + exercise rats or control rats +/- tongue exercise.

CONCLUSION: These findings provide further evidence that a strength endurance tongue exercise program may be a viable therapeutic treatment option in patients with XII motor neuron degeneration in MNDs such as ALS. Future directions will focus on investigating the underlying mechanism responsible for tongue exercise-induced plasticity in the hypoglossal-tongue axis, particularly inflammatory associated factors such as BDNF.}, } @article {pmid39297377, year = {2024}, author = {Akyuz, E and Aslan, FS and Gokce, E and Ilmaz, O and Topcu, F and Kakac, S}, title = {Extracellular vesicle and CRISPR gene therapy: Current applications in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.}, journal = {The European journal of neuroscience}, volume = {60}, number = {8}, pages = {6057-6090}, doi = {10.1111/ejn.16541}, pmid = {39297377}, issn = {1460-9568}, mesh = {Humans ; *Genetic Therapy/methods ; *Extracellular Vesicles/metabolism/genetics ; *CRISPR-Cas Systems ; *Huntington Disease/therapy/genetics ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Parkinson Disease/therapy/genetics ; *Alzheimer Disease/therapy/genetics ; Animals ; Gene Editing/methods ; Neurodegenerative Diseases/therapy/genetics ; }, abstract = {Neurodegenerative diseases are characterized by progressive deterioration of the nervous system. Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are prominently life-threatening examples of neurodegenerative diseases. The complexity of the pathophysiology in neurodegenerative diseases causes difficulties in diagnosing. Although the drugs temporarily help to correct specific symptoms including memory loss and degeneration, a complete treatment has not been found yet. New therapeutic approaches have been developed to understand and treat the underlying pathogenesis of neurodegenerative diseases. With this purpose, clustered-regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) technology has recently suggested a new treatment option. Editing of the genome is carried out by insertion and deletion processes on DNA. Safe delivery of the CRISPR/Cas system to the targeted cells without affecting surrounding cells is frequently investigated. Extracellular vesicles (EVs), that is exosomes, have recently been used in CRISPR/Cas studies. In this review, CRISPR/Cas and EV approaches used for diagnosis and/or treatment in AD, PD, ALS, and HD are reviewed. CRISPR/Cas and EV technologies, which stand out as new therapeutic approaches, may offer a definitive treatment option in neurodegenerative diseases.}, } @article {pmid39297678, year = {2024}, author = {Paoletti, O and Hyeraci, G and Finochietti, M and Celani, MG and Bacigalupo, I and Lombardi, N and Crescioli, G and Tuccori, M and Cascini, S and Gini, R and Addis, A and Kirchmayer, U and , }, title = {Pharmacological and non-pharmacological treatments in amyotrophic lateral sclerosis: an Italian real-world data study.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16470}, pmid = {39297678}, issn = {1468-1331}, support = {//Agenzia Italiana del Farmaco, Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology/drug therapy ; Italy/epidemiology ; *Riluzole/therapeutic use ; Female ; Male ; Aged ; Middle Aged ; Neuroprotective Agents/therapeutic use ; }, abstract = {BACKGROUND AND PURPOSE: The purpose was to describe the use patterns of pharmacological and non-pharmacological therapies and investigate potential determinants of riluzole use in patients newly diagnosed with amyotrophic lateral sclerosis (ALS) in three Italian regions.

METHODS: Amyotrophic lateral sclerosis patients were selected from administrative healthcare databases of Latium, Tuscany and Umbria from 1 January 2014 to 31 December 2019 based on hospital- and disease-specific co-payment exemption data. The first trace of ALS was considered the index date. Incident ALS cases were those without a trace of ALS during the 3-year look back. Patients were described in terms of demographics, clinical characteristics and drug use at baseline, and were classified into four categories based on riluzole use in the 2 years before and 1 year after the index date: prevalent, incident, former users and non-users. Use of symptomatic pharmacological and non-pharmacological therapies was described across these categories during 12 months after the index date. Determinants of riluzole use were also investigated.

RESULTS AND CONCLUSIONS: A total of 1636 ALS incident subjects were detected in the three regions, mainly aged 65-74 years. Patients were generally fragile with a high prevalence of comorbidities at baseline. Riluzole was used by 27.4% of the overall study cohort at baseline and steeply increased in the first year after the index date differently between regions (Latium 61.2%, Tuscany 85.0%, Umbria 76.5%), with about half of the subjects being incident users. In the 12 months after the index date, also symptomatic therapies increased, in riluzole users and non-users. Determinants analysis showed that higher patient severity and complexity were associated with a lower likelihood of being treated with riluzole.}, } @article {pmid39299050, year = {2024}, author = {Eshak, D and Arumugam, M}, title = {Unveiling therapeutic biomarkers and druggable targets in ALS: An integrative microarray analysis, molecular docking, and structural dynamic studies.}, journal = {Computational biology and chemistry}, volume = {113}, number = {}, pages = {108211}, doi = {10.1016/j.compbiolchem.2024.108211}, pmid = {39299050}, issn = {1476-928X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Molecular Docking Simulation ; *Biomarkers/metabolism/analysis/blood ; Microarray Analysis ; Molecular Dynamics Simulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a debilitating neurodegenerative disorder characterized by the progressive degeneration of nerve cells in the brain and spinal cord. Despite extensive research, its precise etiology remains elusive, and early diagnosis is challenging due to the absence of specific tests. This study aimed to identify potential blood-based biomarkers for early ALS detection and monitoring using datasets from whole blood samples (GSE112680) and oligodendrocytes, astrocytes, and fibroblasts (GSE87385) obtained from the NCBI-GEO repository. Through bioinformatics analysis, including protein-protein interactions and molecular pathway analyses, we identified differentially expressed genes (DEGs) associated with ALS. Notably, ALS2, ADH7, ALDH8A1, ALDH3B1, ABHD2, ABHD17B, ABHD12, ABHD13, PGAM2, AURKB, ANAPC11, VAPA, UNC45B, and TNNT2 emerged as top-ranked DEGs, implicated in drug metabolism, protein depalmytilation, and the AKT/mTOR signaling pathways. Among these, AurKB established as a potential therapeutic biomarker with relevance to various neurological conditions. Consequently, AurKB was selected for identifying potential therapeutic molecules and utilized for in silico structural characterization studies. Exploration of the IMPATT database led to the discovery of a lead compound similar to Fostamatinib, currently used for AurKB. Initial molecular docking and MMGBSA-based binding energy analysis were followed by molecular dynamics simulation (MDS) and free energy landscape (FEL) analysis to validate the ligand's binding efficacy and understand dynamic processes within the biological system. The identified potential biomarkers and lead molecule provide novel insights into the correlation between blood cell transcripts and ALS pathology, paving the way for blood-based diagnostic tools for early ALS detection and ongoing disease monitoring.}, } @article {pmid39299156, year = {2024}, author = {Caswell, G and Wilson, E}, title = {The impact of home mechanical ventilation on the time and manner of death for those with Motor neurone disease (MND): A qualitative study of bereaved family members.}, journal = {Social science & medicine (1982)}, volume = {360}, number = {}, pages = {117345}, doi = {10.1016/j.socscimed.2024.117345}, pmid = {39299156}, issn = {1873-5347}, mesh = {Humans ; *Motor Neuron Disease/psychology/complications ; *Qualitative Research ; Male ; Female ; *Respiration, Artificial/psychology ; Middle Aged ; *Family/psychology ; United Kingdom ; Aged ; *Bereavement ; Attitude to Death ; Adult ; Terminal Care/psychology/methods ; Home Care Services ; Time Factors ; Aged, 80 and over ; }, abstract = {Motor neurone disease (MND) is a progressive neurodegenerative disorder which is ultimately terminal. It causes muscle weakness which can lead to the need for assistance in breathing, for some with the disease. This paper draws on qualitative research using semi-structured interviews with 32 people bereaved by the death of a family member with MND who was dependent on home mechanical ventilation, from across the United Kingdom. Interviews explored how the end-of-life of a person who had used non-invasive ventilation to assist their breathing was experienced by participants, who had cared about, and for them. Four themes are used to examine the impact of dependent ventilation technology on the experience of dying on the part of bereaved family members. Themes are: accompanied dying, planned withdrawal of ventilation, blurred time of death, time post-death. The perception and experience of time was a key component across all four themes. Ventilator technology played a critical role in sustaining life, but it could also contribute to a complex dynamic where the realities of death were mediated or obscured. This raises ethical, emotional, and existential considerations, both for the individuals receiving ventilator support and their families, as well as for healthcare professionals involved in end-of-life care.}, } @article {pmid39299489, year = {2024}, author = {Le, NT and Chu, N and Joshi, G and Higgins, NR and Nebie, O and Adelakun, N and Butts, M and Monteiro, MJ}, title = {Prion protein pathology in Ubiquilin 2 models of ALS.}, journal = {Neurobiology of disease}, volume = {201}, number = {}, pages = {106674}, pmid = {39299489}, issn = {1095-953X}, support = {K22 CA241105/CA/NCI NIH HHS/United States ; R01 NS098243/NS/NINDS NIH HHS/United States ; R35 GM151124/GM/NIGMS NIH HHS/United States ; RF1 NS098243/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; Humans ; *Autophagy-Related Proteins/metabolism/genetics ; Mice ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; Mutation ; Disease Models, Animal ; Induced Pluripotent Stem Cells/metabolism/pathology ; Prion Proteins/metabolism/genetics ; Inclusion Bodies/metabolism/pathology ; Neurons/metabolism/pathology ; Mice, Transgenic ; }, abstract = {Mutations in UBQLN2 cause ALS and frontotemporal dementia (FTD). The pathological signature in UBQLN2 cases is deposition of highly unusual types of inclusions in the brain and spinal cord that stain positive for UBQLN2. However, what role these inclusions play in pathogenesis remains unclear. Here we show cellular prion protein (PrP[C]) is found in UBQLN2 inclusions in both mouse and human neuronal induced pluripotent (IPSC) models of UBQLN2 mutations, evidenced by the presence of aggregated forms of PrP[C] with UBQLN2 inclusions. Turnover studies indicated that the P497H UBQLN2 mutation slows PrP[C] protein degradation and leads to mislocalization of PrP[C] in the cytoplasm. Immunoprecipitation studies indicated UBQLN2 and PrP[C] bind together in a complex. The abnormalities in PrP[C] caused by UBQLN2 mutations may be relevant in disease pathogenesis.}, } @article {pmid39299508, year = {2024}, author = {Shetty, P and Ren, Y and Dillon, D and Mcleod, A and Nishijima, D and Taylor, SL and , }, title = {Derivation of a clinical decision rule for termination of resuscitation in non-traumatic pediatric out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {204}, number = {}, pages = {110400}, pmid = {39299508}, issn = {1873-1570}, support = {K38 HL165363/HL/NHLBI NIH HHS/United States ; UL1 TR001860/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; Retrospective Studies ; Child ; *Clinical Decision Rules ; *Cardiopulmonary Resuscitation/methods ; Child, Preschool ; Emergency Medical Services/methods ; Medical Futility ; Adolescent ; Infant ; Resuscitation Orders ; Withholding Treatment/standards ; }, abstract = {AIM: Prehospital termination of resuscitation (ToR) rules are used to predict medical futility in adult out-of-hospital cardiac arrest (OHCA), however, the available evidence for pediatric patients is limited. The primary aim of this study is to derive a Pediatric Termination of Resuscitation (PToR) prediction rule for use in pediatric non-traumatic OHCA patients.

METHODS: We analyzed a retrospective cohort of pediatric OHCA patients within the CARES database over a 10-year period (2013-2022). We split the dataset into training and test datasets and fit logistic regressions with Least Absolute Shrinkage and Selection Operator (LASSO) to select predictor variables and estimate predictive test characteristics for the primary outcome of death and a secondary composite outcome of death or survival to hospital discharge with unfavorable neurologic status.

RESULTS: We analyzed a sample of 21,240 children where 2,326 (11.0%) survived to hospital discharge, and 1,894 (8.9%) survived to hospital discharge with favorable neurologic status. We derived a PToR rule for death demonstrating a specificity of 99.1% and a positive predictive value (PPV) of 99.8% and a PToR rule for death or survival with poor neurologic status with a specificity of 99.7% and PPV of 99.9% within the test dataset.

CONCLUSION: We derived a clinical prediction rule with high specificity and positive predictive value in prehospital settings utilizing Advanced Life Support (ALS) providers which may inform termination of resuscitation considerations in pediatric patients. Further prospective and validation studies will be necessary to define the appropriateness and applicability of these PToR criteria for routine use.}, } @article {pmid39299905, year = {2024}, author = {Hetz, C and Thielen, P and Matus, S and Nassif, M and Court, F and Kiffin, R and Martinez, G and Cuervo, AM and Brown, RH and Glimcher, LH}, title = {Corrigendum: XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy.}, journal = {Genes & development}, volume = {38}, number = {15-16}, pages = {785}, doi = {10.1101/gad.352249.124}, pmid = {39299905}, issn = {1549-5477}, } @article {pmid39300071, year = {2024}, author = {Castelli, S and Desideri, E and Laureti, L and Felice, F and De Cristofaro, A and Scaricamazza, S and Lazzarino, G and Ciriolo, MR and Ciccarone, F}, title = {N-acetylaspartate promotes glycolytic-to-oxidative fiber-type switch and resistance to atrophic stimuli in myotubes.}, journal = {Cell death & disease}, volume = {15}, number = {9}, pages = {686}, pmid = {39300071}, issn = {2041-4889}, support = {GR-2019-1236998//Ministero della Salute (Ministry of Health, Italy)/ ; MNESYS PNRR - MUR PE00000006//Ministero della Salute (Ministry of Health, Italy)/ ; }, mesh = {Animals ; *Glycolysis/drug effects ; *Muscle Fibers, Skeletal/metabolism/drug effects ; Mice ; *Aspartic Acid/metabolism/analogs & derivatives ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; Oxidation-Reduction ; Cell Line ; Mice, Transgenic ; }, abstract = {N-acetylaspartate (NAA) is a neuronal metabolite that can be extruded in extracellular fluids and whose blood concentration increases in several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Aspartoacylase (ASPA) is the enzyme responsible for NAA breakdown. It is abundantly expressed in skeletal muscle and most other human tissues, but the role of NAA catabolism in the periphery is largely neglected. Here we demonstrate that NAA treatment of differentiated C2C12 muscle cells increases lipid turnover, mitochondrial biogenesis and oxidative metabolism at the expense of glycolysis. These effects were ascribed to NAA catabolism, as CRISPR/Cas9 ASPA KO cells are insensitive to NAA administration. Moreover, the metabolic switch induced by NAA was associated with an augmented resistance to atrophic stimuli. Consistently with in vitro results, SOD1-G93A ALS mice show an increase in ASPA levels in those muscles undergoing the glycolytic to oxidative switch during the disease course. The impact of NAA on the metabolism and resistance capability of myotubes supports a role for this metabolite in the phenotypical adaptations of skeletal muscle in neuromuscular disorders.}, } @article {pmid39300421, year = {2024}, author = {Koçkaya, PD and Alvur, TM and Odabaşı, O}, title = {Empowering medical students: bridging gaps with high-fidelity simulations; a mixed-methods study on self-efficacy.}, journal = {BMC medical education}, volume = {24}, number = {1}, pages = {1026}, pmid = {39300421}, issn = {1472-6920}, mesh = {Humans ; *Self Efficacy ; *Students, Medical/psychology ; Prospective Studies ; *Clinical Competence ; Male ; Female ; Cardiopulmonary Resuscitation/education ; Simulation Training ; Adult ; Emergency Medicine/education ; High Fidelity Simulation Training ; Young Adult ; Focus Groups ; Education, Medical, Undergraduate/methods ; Empowerment ; }, abstract = {BACKGROUND: High-fidelity simulations play a crucial role in preparing for high-mortality events like cardiopulmonary arrest, emphasizing the need for rapid and accurate intervention. Proficiency in cardiopulmonary resuscitation(CPR) requires a strong self-efficacy(SE); training for both is crucial. This study assesses the impact of Advanced Life Support(ALS) simulation on SE changes in final-year medical students.

METHODS: This mixed-methods prospective simulation study involved medical students in emergency medicine internships, examining self-efficacy perceptions regarding ALS technical skills(ALS-SEP). A comparison was made between students who underwent scenario-based ALS simulation training and those who did not. Competencies in chest compression skills were assessed, and the concordance between ALS-SEP scores and observed CPR performances were evaluated. Focus group interviews were conducted and analyzed using content analysis techniques.

RESULTS: The study involved 80 students, with 53 in the experimental group(EG) and 27 in the control group(CG). The EG, underwent simulation training, showed a significantly higher ALS-SEP change than the CG(p < 0.05). However, there was low concordance between pre-simulation SEP and actual performance. Compression skills success rates were inadequate. Qualitative analysis revealed main themes as"learning"(32.6%), "self-efficacy"(29%), "simulation method"(21.3%), and "development"(16.5%).

DISCUSSION: Post-simulation, students reported improved SEP and increased readiness for future interventions. The findings and qualitative statements support the effectiveness of simulation practices in bridging the gap between SEP and performance. Utilizing simulation-based ALS training enhances learners' belief in their capabilities, raises awareness of their competencies, and encourages reflective thinking. Given the importance of high SEP for ALS, simulation trainings correlating self-efficacy perception and performance may significantly reduce potential medical errors stemming from a disparity between perceived capability and actual performance.}, } @article {pmid39300574, year = {2024}, author = {Ashkaran, F and Seyedalipour, B and Baziyar, P and Hosseinkhani, S}, title = {Mutation/metal deficiency in the "electrostatic loop" enhanced aggregation process in apo/holo SOD1 variants: implications for ALS diseases.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {177}, pmid = {39300574}, issn = {2661-801X}, abstract = {Despite the many mechanisms it has created to prevent unfolding and aggregation of proteins, many diseases are caused by abnormal folding of proteins, which are called misfolding diseases. During this process, proteins undergo structural changes and become stable, insoluble beta-sheet aggregates called amyloid fibrils. Mutations/disruptions in metal ion homeostasis in the ALS-associated metalloenzyme superoxide dismutase (SOD1) reduce conformational stability, consistent with the protein aggregation hypothesis for neurodegenerative diseases. However, the exact mechanism of involvement is not well understood. Hence, to understand the role of mutation/ metal deficiency in SOD1 misfolding and aggregation, we investigated the effects of apo/holo SOD1 variants on structural properties using biophysical/experimental techniques. The MD results support the idea that the mutation/metal deficiency can lead to a change in conformation. The increased content of β-sheet structures in apo/holo SOD1 variants can be attributed to the aggregation tendency, which was confirmed by FTIR spectroscopy and dictionary of secondary structure in proteins (DSSP) results. Thermodynamic studies of GdnHCl showed that metal deficiency/mutation/intramolecular S-S reduction together are required to initiate misfolding/aggregation of SOD1. The results showed that apo/holo SOD1 variants under destabilizing conditions induced amyloid aggregates at physiological pH, which were detected by ThT/ANS fluorescence, as well as further confirmation of amyloid/amorphous species by TEM. This study confirms that mutations in the electrostatic loop of SOD1 lead to structural abnormalities, including changes in hydrophobicity, reduced disulfide bonds, and an increased propensity for protein denaturation. This process facilitates the formation of amyloid/amorphous aggregates ALS-associated.}, } @article {pmid39300745, year = {2024}, author = {Guo, Y and Ma, G and Wang, Y and Lin, T and Hu, Y and Zang, T}, title = {Causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity.}, journal = {Aging cell}, volume = {23}, number = {11}, pages = {e14271}, pmid = {39300745}, issn = {1474-9726}, support = {62371161//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Longevity/genetics ; *Neurodegenerative Diseases/genetics ; *Epigenesis, Genetic ; *Aging/genetics ; *Genome-Wide Association Study ; Mendelian Randomization Analysis ; }, abstract = {The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large-scale genome-wide association study summary statistics data for four measures of epigenetic age (GrimAge, PhenoAge, IEAA, and HannumAge) (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6618-482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Main analyses were conducted using multiplicative random effects inverse-variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (IVW beta = -0.309, 95% CI: -0.38 to -0.24, p = 1.51E-19). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = -0.10, 95% CI: -0.188 to -0.013, p = 0.02). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD. In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms.}, } @article {pmid39301564, year = {2024}, author = {Barnard, J and Hunt, R and Yucel, M and Mazaud, D and Smith, BN and Fanto, M}, title = {Human TDP43 is required for ALS‑related annexin A11 toxicity in Drosophila.}, journal = {Biomedical reports}, volume = {21}, number = {5}, pages = {165}, pmid = {39301564}, issn = {2049-9442}, abstract = {Genomics allows identification of genes and mutations associated with amyotrophic lateral sclerosis (ALS). Mutations in annexin A11 (ANXA11) are responsible for ~1% of all familial ALS and fronto-temporal dementia cases. The present study used the fruit fly, Drosophila melanogaster, to assess the mechanism of toxicity of ANXA11 mutants in residues that are conserved in the fly ANXB11 protein, the closest homolog to human ANXA11. In immune fluorescence, lifespan and negative geotaxis assays ANXA11 mutants, while displaying some degree of alteration in localization and function, did not exert any relevant organism toxicity in Drosophila. However, they showed a specific interaction with human TAR DNA-binding protein (TDP43). The present study illustrated that the ANXA11 mutants interact with human TDP43, but not the fly TAR DNA-binding protein-43 homolog (TBPH) or other ALS-associated genes such as super oxide dismutase 1, to shorten lifespan and increase negative geotaxis defects. This sheds light both on the mechanisms underlying ALS, further elucidating the intricate molecular network implicated in ALS and placing ANXA11 as a key player in its pathology, and on the complexity of using Drosophila as a model organism for researching genes in ALS.}, } @article {pmid39302063, year = {2024}, author = {Khanna, RK and Catanese, S and Mortemousque, G and Mureau, N and Emond, P and Pisella, PJ and Blasco, H and Corcia, P}, title = {Exploring amyotrophic lateral sclerosis through the visual system: A systematic review.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16475}, pmid = {39302063}, issn = {1468-1331}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Humans ; Vision Disorders/etiology/physiopathology ; Visual Pathways/physiopathology ; }, abstract = {BACKGROUND AND PURPOSE: The human visual system relies on neural networks throughout the brain that are easily accessible for tests exploring eye structures and movements. Over the past two decades, investigations have been carried out on both afferent and efferent components of the visual system in people with amyotrophic lateral sclerosis (ALS). This approach might represent an innovative biomarker research strategy to better characterise the phenotypic variability of ALS. The purpose of this review was to determine whether exploring the visual system of patients with ALS (pwALS) is an effective strategy.

METHODS: The Medline and Web of science databases were searched for studies with terms relating to ALS and vision. Of 1146 references identified, 43 articles were included.

RESULTS: In this review article, both afferent and efferent components of the visual system were found to be impaired in pwALS in the absence of visual complaint, thereby contributing to the hypothesis that ALS is a multisystem disease with sensory involvement. Of note, some areas of the eye remain unexplored (i.e., tears, and retinal function using electroretinography).

CONCLUSIONS: According to the findings available in the literature, investigating the oculomotor system and exploring the ocular surface could represent two key promising strategies to identify new diagnostic biomarkers in pwALS. Further longitudinal studies are needed to identify relevant indicators of disease progression and response to therapeutic intervention.}, } @article {pmid39302099, year = {2024}, author = {Haider, R and Shipley, B and Surewicz, K and Hinczewski, M and Surewicz, WK}, title = {Pathological C-terminal phosphomimetic substitutions alter the mechanism of liquid-liquid phase separation of TDP-43 low complexity domain.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {10}, pages = {e5179}, pmid = {39302099}, issn = {1469-896X}, support = {F30 AG071339/AG/NIA NIH HHS/United States ; F30 AG071339-03/NH/NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; T32 NS077888/NH/NIH HHS/United States ; T32 GM007250/NH/NIH HHS/United States ; RF1 AG061797/NH/NIH HHS/United States ; }, mesh = {*DNA-Binding Proteins/chemistry/metabolism/genetics ; Humans ; Phosphorylation ; *Protein Domains ; Molecular Dynamics Simulation ; Amino Acid Substitution ; Liquid-Liquid Extraction ; Phase Separation ; }, abstract = {C-terminally phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) marks the proteinaceous inclusions that characterize a number of age-related neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration and Alzheimer's disease. TDP-43 phosphorylation at S403/S404 and (especially) at S409/S410 is, in fact, accepted as a biomarker of proteinopathy. These residues are located within the low complexity domain (LCD), which also drives the protein's liquid-liquid phase separation (LLPS). The impact of phosphorylation at these LCD sites on phase separation of the protein is a topic of great interest, as these post-translational modifications and LLPS are both implicated in proteinopathies. Here, we employed a combination of experimental and simulation-based approaches to explore this question on a phosphomimetic model of the TDP-43 LCD. Our turbidity and fluorescence microscopy data show that phosphomimetic Ser-to-Asp substitutions at residues S403, S404, S409 and S410 alter the LLPS behavior of TDP-43 LCD. In particular, unlike the LLPS of unmodified protein, LLPS of the phosphomimetic variants displays a biphasic dependence on salt concentration. Through coarse-grained modeling, we find that this biphasic salt dependence is derived from an altered mechanism of phase separation, in which LLPS-driving short-range intermolecular hydrophobic interactions are modulated by long-range attractive electrostatic interactions. Overall, this in vitro and in silico study provides a physiochemical foundation for understanding the impact of pathologically relevant C-terminal phosphorylation on the LLPS of TDP-43 in a more complex cellular environment.}, } @article {pmid39302926, year = {2024}, author = {Chung, YM and Hu, CS and Sun, E and Tseng, HC}, title = {Morphological multiparameter filtration and persistent homology in mitochondrial image analysis.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0310157}, pmid = {39302926}, issn = {1932-6203}, mesh = {Humans ; *Mitochondria/metabolism/genetics ; *Membrane Transport Proteins/genetics/metabolism ; *Image Processing, Computer-Assisted/methods ; Cell Cycle Proteins/genetics/metabolism ; Transcription Factor TFIIIA/genetics/metabolism ; Mutation ; Software ; }, abstract = {The complexity of branching and curvilinear morphology of a complete mitochondrial network within each cell is challenging to analyze and quantify. To address this challenge, we developed an image analysis technique using persistent homology with a multiparameter filtration framework, combining image processing techniques in mathematical morphology. We show that such filtrations contain both topological and geometric information about complex cellular organelle structures, which allows a software program to extract meaningful features. Using this information, we also develop a connectivity index that describes the morphology of the branching patterns. As proof of concept, we utilize this approach to study how mitochondrial networks are altered by genetic changes in the Optineurin gene. Mutations in the autophagy gene Optineurin (OPTN) are associated with primary open-angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS), and Paget's disease of the bone, but the pathophysiological mechanism is unclear. We utilized the proposed mathematical morphology-based multiparameter filtration and persistent homology approach to analyze and quantitatively compare how changes in the OPTN gene alter mitochondrial structures from their normal interconnected, tubular morphology into scattered, fragmented pieces.}, } @article {pmid39304897, year = {2024}, author = {Ortiz, DA and Peregrín, N and Valencia, M and Vinueza-Gavilanes, R and Marín-Ordovas, E and Ferrero, R and Nicolás, MJ and González-Aseguinolaza, G and Arrasate, M and Aragón, T}, title = {GCN2 inhibition reduces mutant SOD1 clustering and toxicity and delays disease progression in an amyotrophic lateral sclerosis mouse model.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {49}, pmid = {39304897}, issn = {2047-9158}, support = {BFU2017-90043-P//Ministerio de Ciencia e Innovación, Gobierno de España/ ; PID2020-120497RB-I00//Ministerio de Ciencia y Universidades, Gobierno de España/ ; Proyecto Intramural IdisNa 2022//Navarra Institute for Health Research (IdiSNA)/ ; Proyectos I+D, 2017//Fundación para la Investigación Médica Aplicada/ ; AC Predoctoral Fellowship//Fundación para la Investigación Médica Aplicada/ ; 270-2018-922//República de Panamá, Programa de Becas IFARHU-SENACYT/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Animals ; *Disease Progression ; *Disease Models, Animal ; Mice ; *Superoxide Dismutase-1/genetics ; *Mice, Transgenic ; Protein Serine-Threonine Kinases/genetics/antagonists & inhibitors ; Humans ; Mutation/genetics ; }, } @article {pmid39305271, year = {2024}, author = {Panzetta, ME and Valdivia, RH}, title = {Akkermansia in the gastrointestinal tract as a modifier of human health.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2406379}, pmid = {39305271}, issn = {1949-0984}, support = {R01 AI142376/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; *Akkermansia/physiology ; Animals ; *Gastrointestinal Tract/microbiology ; Gastrointestinal Diseases/microbiology ; }, abstract = {Akkermansia sp are common members of the human gut microbiota. Multiple reports have emerged linking the abundance of A. muciniphila to health benefits and disease risk in humans and animals. This review highlights findings linking Akkermansia species in the gastrointestinal (GI) tract to health outcomes across a spectrum of disorders, encompassing those that affect the digestive, respiratory, urinary, and central nervous systems. The mechanism through which Akkermansia exerts a beneficial versus a detrimental effect on health is likely dependent on the genetic makeup of the host metabolic capacity and immunomodulatory properties of the strain, the competition or cooperation with other members of the host microbiota, as well as synergy with co-administered therapies.}, } @article {pmid39305312, year = {2024}, author = {Torres, P and Rico-Rios, S and Ceron-Codorniu, M and Santacreu-Vilaseca, M and Seoane-Miraz, D and Jad, Y and Ayala, V and Mariño, G and Beltran, M and Miralles, MP and Andrés-Benito, P and Fernandez-Irigoyen, J and Santamaria, E and López-Otín, C and Soler, RM and Povedano, M and Ferrer, I and Pamplona, R and Wood, MJA and Varela, MA and Portero-Otin, M}, title = {TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {45}, pmid = {39305312}, issn = {1432-0533}, support = {PI 20-00155//Instituto de Salud Carlos III/ ; 23-00176//Instituto de Salud Carlos III/ ; Programa Margarita Salas//Ministerio de Universidades/ ; SGR//Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya/ ; Ayuda Unzue//Fundación Luzon/ ; }, mesh = {Animals ; *Autophagy-Related Proteins/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Microtubule-Associated Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Cysteine Endopeptidases/metabolism/genetics ; Male ; Spinal Cord/metabolism/pathology ; Autophagy/physiology ; Mice, Knockout ; RNA Splicing/genetics ; Female ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Oligonucleotides, Antisense/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b[-/-] mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.}, } @article {pmid39305776, year = {2024}, author = {Lichtfouse, J and Courtier, A and Vergunst, AC and Giannoni, P}, title = {Effects of environmental concentrations of toxins BMAA and its isomers DAB and AEG on zebrafish larvae.}, journal = {Ecotoxicology and environmental safety}, volume = {285}, number = {}, pages = {117045}, doi = {10.1016/j.ecoenv.2024.117045}, pmid = {39305776}, issn = {1090-2414}, mesh = {Animals ; *Zebrafish ; *Amino Acids, Diamino/toxicity ; *Cyanobacteria Toxins ; *Water Pollutants, Chemical/toxicity ; *Larva/drug effects ; Aminobutyrates/toxicity ; Glycine/toxicity/analogs & derivatives ; Embryo, Nonmammalian/drug effects ; Toxicity Tests, Acute ; Embryonic Development/drug effects ; Isomerism ; }, abstract = {The increasing concern over the environmental presence of β-N-Methylamino-L-alanine (BMAA), a toxin primarily produced by cyanobacteria and diatoms, has stimulated numerous studies to evaluate the risk for exposed populations, mainly aquatic organisms and humans. This study focuses on the toxicity of environmental concentrations of BMAA and its isomers, l-2,4 diaminobutyric acid dihydrochloride (DAB) and N-(2-aminoethyl) glycine (AEG) on zebrafish embryo development (ng.L[-1]). Presence of BMAA in various environments, including aquatic sources, air, and desert crusts, has raised concerns due to its potential link to neurodegenerative diseases such as the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). Despite its known toxicity at high concentrations, there is limited information on the effects of environmental concentrations of BMAA and its isomers. These isomers are often found in association with BMAA and have been detected in seafood intended for human consumption, indicating potential risks from bioaccumulation and biomagnification. Zebrafish embryos have been chosen as a model due to their relevance for embryonic development and toxicity studies. The study employed fish embryo acute toxicity tests and behavioural analyses to specifically assess the sublethal effects of BMAA, DAB, and AEG. The results demonstrated larval mortality rates between 0 % and 3.75 %, while morphological defects were detected across all tested concentrations for each molecule. Behavioural analyses showed alterations in swimming behaviour. Unexpectedly, the changes in morphology and locomotion of the zebrafish larvae were detected more frequently at the lowest concentrations tested, suggesting potential non-monotonic dose responses. Overall, this research underscores the environmental risks associated with BMAA and its isomers, highlighting the importance of continuous monitoring and understanding of their sublethal effects on aquatic organisms and potential implications for human health. Further studies are warranted to elucidate the mechanisms of toxicity, evaluate long-term effects, and assess the risks associated with chronic exposure to these toxins.}, } @article {pmid39307005, year = {2024}, author = {Austin, JM and Bailey, R and Velazquez, SG and Sainath, H and Jackson, C}, title = {Clinical effectiveness of medical marijuana in patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123243}, doi = {10.1016/j.jns.2024.123243}, pmid = {39307005}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; *Medical Marijuana/therapeutic use ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Treatment Outcome ; Disease Progression ; Cohort Studies ; Adult ; Anxiety/drug therapy/etiology ; }, abstract = {Following legalization, Medical Marijuana (MM), has been used to treat the symptoms of Amyotrophic Lateral Sclerosis (ALS), yet data regarding Medical Marijuana's efficacy is lacking. Thus, we conducted a retrospective cohort study to assess Medical Marijuana's impact on ALS symptoms and progression. We reviewed the charts of all ALS patients treated in our clinic over a two-year period to collect data related to the primary outcome measures of symptoms of pain, poor appetite, anxiety, spasticity, insomnia, ALSFRS-R score, BMI, and MM use. Two groups were defined: a control group with target symptoms but no MM prescription, and a test group that filled a MM prescription, including a subgroup on MM for ≥3 visits. Outcomes were correlations between MM usage and symptom prevalence, and between MM usage and BMI and ALSFRS-R decline slope, analyzed using descriptive statistics and qualitative analysis via local regression. Data included 344 ALS patients. We found MM use correlated with alleviation of pain, poor appetite, and anxiety in the short term, but not with spasticity or insomnia. There was no correlation between MM use BMI maintenance. Notably, MM usage correlated with faster ALS progression, although patients using MM exhibited higher symptom burden and progressed faster than controls even pre-MM prescription. In conclusion, MM shows correlation with managing pain, poor appetite, and short-term anxiety in ALS, but is also correlated with faster disease progression based on ALSFRS-R scores. We suggest a multi-center, randomized controlled trial to evaluate both the clinical efficacy and safety of MM in the treatment of ALS.}, } @article {pmid39307154, year = {2024}, author = {Pal, S and Chataway, J and Swingler, R and Macleod, MR and Carragher, NO and Hardingham, G and Selvaraj, BT and Smith, C and Wong, C and Newton, J and Lyle, D and Stenson, A and Dakin, RS and Ihenacho, A and Colville, S and Mehta, AR and Stallard, N and Carpenter, JR and Parker, RA and Keerie, C and Weir, CJ and Virgo, B and Morris, S and Waters, N and Gray, B and MacDonald, D and MacDonald, E and Parmar, MKB and Chandran, S and , }, title = {Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1097-1107}, doi = {10.1016/S1474-4422(24)00326-0}, pmid = {39307154}, issn = {1474-4465}, mesh = {Humans ; *Trazodone/therapeutic use/pharmacology ; Male ; Middle Aged ; Female ; Aged ; *Memantine/therapeutic use ; Double-Blind Method ; *Motor Neuron Disease/drug therapy ; Treatment Outcome ; Adult ; }, abstract = {BACKGROUND: Motor neuron disease represents a group of progressive and incurable diseases that are characterised by selective loss of motor neurons, resulting in an urgent need for rapid identification of effective disease-modifying therapies. The MND SMART trial aims to test the safety and efficacy of promising interventions efficiently and definitively against a single contemporaneous placebo control group. We now report results of the stage two interim analysis for memantine and trazodone.

METHODS: MND SMART is an investigator-led, phase 3, double-blind, placebo-controlled, multiarm, multistage, randomised, adaptive platform trial recruiting at 20 hospital centres in the UK. Individuals older than 18 years with a confirmed diagnosis of either amyotrophic lateral sclerosis classified by the revised El Escorial criteria, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy, regardless of disease duration, were eligible for screening. Participants were randomised (1:1:1) to receive oral trazodone 200 mg once a day, oral memantine 20 mg once a day, or matched placebo using a computer-generated minimisation algorithm delivered via a secure web-based system. Co-primary outcome measures were clinical functioning, measured by rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R), and survival. Comparisons were conducted in four stages, with predefined criteria for stopping at the end of stages one and two. We report interim analysis from the stage two results, which was done when 100 participants per group (excluding long survivors, defined as >8 years since diagnosis at baseline) completed a minimum of 12 months of follow-up for the candidate investigational medicinal products. The trial is registered on the European Clinical Trials Registry, 2019-000099-41, and ClinicalTrials.gov, NCT04302870, and is ongoing.

FINDINGS: Between Feb 27, 2020, and July 24, 2023 (database lock for interim analysis two), 554 people with a motor neuron disease were randomly allocated to memantine (183 [33%]), trazodone (185 [33%]), or placebo (186 [34%]). The primary interim analysis population comprised 530 participants, of whom 175 (33%) had been allocated memantine, 175 (33%) had been allocated trazodone, and 180 (34%) had been allocated placebo. Over 12 months of follow-up, the mean rate of change per month in ALSFRS-R was -0·650 for memantine, -0·625 for trazodone, and -0·655 for placebo (memantine versus placebo estimated mean difference 0·033, one-sided 90% CI lower level -0·085; one-sided p=0·36; trazodone vs placebo: 0·065, -0·051; one-sided p=0·24). The one-sided p values were both above the significance threshold of 10%, indicating that neither memantine nor trazodone groups met the criteria for continuation. There were 483 participants with at least one adverse event (145 [77%] on placebo, 170 [91%] on memantine, and 168 [90%] on trazodone). There were 88 participants with at least one serious adverse event (37 [20%] on memantine, 27 [14%] on trazodone, and 24 [13%] on placebo). A total of 11 serious adverse event led to treatment discontinuation. There was no survival difference between comparisons, with 49 deaths in the memantine group, 52 deaths in the trazodone group, and 48 deaths in the placebo group.

INTERPRETATION: Neither memantine nor trazodone improved efficacy outcomes compared with placebo. This result is sufficiently powered to warrant no further testing of trazodone or memantine in motor neuron disease at the doses evaluated in this study. The multiarm multistage design shows important benefits in reducing the time, cost, and participant numbers to reach a definitive result.

FUNDING: The Euan MacDonald Centre, MND Scotland, My Name'5 Doddie Foundation, and Baillie Gifford.}, } @article {pmid39307464, year = {2024}, author = {Kalykaki, M and Rubio-Tomás, T and Tavernarakis, N}, title = {The role of mitochondria in cytokine and chemokine signalling during ageing.}, journal = {Mechanisms of ageing and development}, volume = {222}, number = {}, pages = {111993}, doi = {10.1016/j.mad.2024.111993}, pmid = {39307464}, issn = {1872-6216}, mesh = {Humans ; *Mitochondria/metabolism ; *Aging/metabolism ; *Signal Transduction ; *Inflammation/metabolism ; *Cytokines/metabolism ; Animals ; Chemokines/metabolism ; Cellular Senescence/physiology ; }, abstract = {Ageing is accompanied by a persistent, low-level inflammation, termed "inflammageing", which contributes to the pathogenesis of age-related diseases. Mitochondria fulfil multiple roles in host immune responses, while mitochondrial dysfunction, a hallmark of ageing, has been shown to promote chronic inflammatory states by regulating the production of cytokines and chemokines. In this review, we aim to disentangle the molecular mechanisms underlying this process. We describe the role of mitochondrial signalling components such as mitochondrial DNA, mitochondrial RNA, N-formylated peptides, ROS, cardiolipin, cytochrome c, mitochondrial metabolites, potassium efflux and mitochondrial calcium in the age-related immune system activation. Furthermore, we discuss the effect of age-related decline in mitochondrial quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy and UPR[mt], in inflammatory states upon ageing. In addition, we focus on the dynamic relationship between mitochondrial dysfunction and cellular senescence and its role in regulating the secretion of pro-inflammatory molecules by senescent cells. Finally, we review the existing literature regarding mitochondrial dysfunction and inflammation in specific age-related pathological conditions, including neurodegenerative diseases (Alzheimer's and Parkinson's disease, and amyotrophic lateral sclerosis), osteoarthritis and sarcopenia.}, } @article {pmid39310519, year = {2024}, author = {Albadawi, EA}, title = {Microstructural Changes in the Corpus Callosum in Neurodegenerative Diseases.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e67378}, pmid = {39310519}, issn = {2168-8184}, abstract = {The corpus callosum, the largest white matter structure in the brain, plays a crucial role in interhemispheric communication and cognitive function. This review examines the microstructural changes observed in the corpus callosum across various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). New neuroimaging studies, mainly those that use diffusion tensor imaging (DTI) and advanced tractography methods, were put together to show how changes have happened in the organization of white matter and the connections between them. Some of the most common ways the corpus callosum breaks down are discussed, including less fractional anisotropy, higher mean diffusivity, and atrophy in certain regions. The relationship between these microstructural changes and cognitive decline, motor dysfunction, and disease progression is explored. Additionally, we consider the potential of corpus callosum imaging as a biomarker for early disease detection and monitoring. Studies show that people with these disorders have lower fractional anisotropy and higher mean diffusivity in the corpus callosum, often in ways that are specific to the disease. These changes often happen before gray matter atrophy and are linked to symptoms, which suggests that the corpus callosum could be used as an early sign of neurodegeneration. The review also highlights the implications of these findings for understanding disease mechanisms and developing therapeutic strategies. Future directions, including the application of advanced imaging techniques and longitudinal studies, are discussed to elucidate the role of corpus callosum degeneration in neurodegenerative processes. This review underscores the importance of the corpus callosum in understanding the pathophysiology of neurodegenerative diseases and its potential as a target for therapeutic interventions.}, } @article {pmid39310990, year = {2024}, author = {Vallejo Herrera, MJ and Vallejo Herrera, V and Del Toro Ortega, A and Tapia Guerrero, MJ}, title = {[Radiological versus endoscopic gastrostomy in patients with amyotrophic lateral sclerosis].}, journal = {Nutricion hospitalaria}, volume = {41}, number = {6}, pages = {1160-1164}, doi = {10.20960/nh.05190}, pmid = {39310990}, issn = {1699-5198}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Gastrostomy/methods/adverse effects ; Middle Aged ; Retrospective Studies ; Male ; Female ; *Enteral Nutrition/methods ; Aged ; Deglutition Disorders/etiology ; Adult ; Treatment Outcome ; Radiography ; }, abstract = {IIntroduction: patients with amyotrophic lateral sclerosis (ALS) require nutritional support, in most cases with enteral nutrition through gastrostomy, either endoscopic (PEG) or radiological (PRG). Objectives: to analyze the characteristics of patients with ALS at the time of PEG/PRG placement, and to compare the efficacy and safety of PRG versus PEG. Methods: a retrospective descriptive study. All patients with ALS who required gastrostomy in the last 3 years (2021-2023) in our hospital were recruited (4 PEG and 6 PRG). Demographic and nutritional parameters were analyzed. Results: ten patients were included, with an average age of 57 years. All patients presented with dysphagia and received oral or tube supplements prior to gastrostomy placement. The average duration of enteral nutrition was approximately 50 months, with a mortality rate of 30 % at 12 months after gastrostomy. The success rate of PEG and PRG was similar, with no complications. All patients developed deterioration of respiratory function, even after nutritional support. Conclusion: gastrostomy should be indicated as soon as a patient is at risk of aspiration pneumonia or when weight loss begins. Although the nutritional benefit of gastrostomy is well established, there is currently a delay between diagnosis and placement of approximately 4 years. PRG appears to be safer than PEG in patients with ALS and respiratory failure.}, } @article {pmid39311028, year = {2024}, author = {Driver, MD and Postema, J and Onck, PR}, title = {The Effect of Dipeptide Repeat Proteins on FUS/TDP43-RNA Condensation in C9orf72 ALS/FTD.}, journal = {The journal of physical chemistry. B}, volume = {128}, number = {39}, pages = {9405-9417}, pmid = {39311028}, issn = {1520-5207}, mesh = {*RNA-Binding Protein FUS/chemistry/metabolism/genetics ; *C9orf72 Protein/chemistry/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Dipeptides/chemistry/metabolism ; *RNA/chemistry/metabolism ; Humans ; *Molecular Dynamics Simulation ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; *Frontotemporal Dementia/genetics/metabolism ; }, abstract = {Condensation of RNA binding proteins (RBPs) with RNA is essential for cellular function. The most common familial cause of the diseases ALS and FTD is C9orf72 repeat expansion disorders that produce dipeptide repeat proteins (DPRs). We explore the hypothesis that DPRs disrupt the native condensation behavior of RBPs and RNA through molecular interactions resulting in toxicity. FUS and TDP43 are two RBPs known to be affected in ALS/FTD. We use our previously developed 1-bead-per-amino acid and a newly developed 3-bead-per-nucleotide molecular dynamics model to explore ternary phase diagrams of FUS/TDP43-RNA-DPR systems. We show that the most toxic arginine containing DPRs (R-DPRs) can disrupt the RBP condensates through cation-π interactions and can strongly sequester RNA through electrostatic interactions. The native droplet morphologies are already modified at small additions of R-DPRs leading to non-native FUS/TDP43-encapsulated condensates with a marbled RNA/DPR core.}, } @article {pmid39311315, year = {2025}, author = {Ortiz-Corredor, F and Correa-Arrieta, C and Forero Diaz, JJ and Castellar-Leones, S and Gil-Salcedo, A}, title = {Profiles of disease progression and predictors of mortality in Colombian patients with amyotrophic lateral sclerosis: a comprehensive longitudinal study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {141-148}, doi = {10.1080/21678421.2024.2405587}, pmid = {39311315}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis ; *Disease Progression ; Female ; Colombia/epidemiology ; Male ; Middle Aged ; Longitudinal Studies ; Retrospective Studies ; Aged ; Prognosis ; Adult ; }, abstract = {OBJECTIVE: This study aimed to assess the prognostic value of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) in predicting mortality and characterizing disease progression patterns in ALS patients in Colombia.

METHODS: We conducted a retrospective longitudinal analysis of 537 ALS patients from the Roosevelt Institute Rehabilitation Service between October 2008 and October 2022. The study excluded nine patients due to incomplete data, resulting in 528 individuals in the analysis. ALS diagnoses were confirmed using the revised El Escorial and Gold Coast criteria. Disease progression was assessed using the ALSFRS-R, and mortality data were sourced from follow-up calls and a national database. Statistical analysis included Cox proportional hazards models to identify mortality predictors and Growth Mixture Modeling (GMM) to explore ALS progression trajectories.

RESULTS: The majority of the cohort (63.8%) deceased within the 84-month follow-up period. Survival analysis revealed that each point increase in the ALSFRS-R rate was associated with a 2.22-fold (95% CI =1.99-2.48, p < 0.001) increased risk of mortality. In the population with data from two clinical visits, the ALSFRS-R rate based on initial assessments predicted mortality more effectively over 36 months than the rate based on two evaluations. GMM identified three distinct progression trajectories: slow, intermediate, and rapid decliners.

CONCLUSIONS: The ALSFRS-R rate, derived from self-reported symptom onset, significantly predicts mortality, underscoring its value in clinical assessments. This study highlights the heterogeneity in disease progression among Colombian ALS patients, indicating the necessity for personalized treatment approaches based on individual progression trajectories. Further studies are needed to refine these predictive models and improve patient management and outcomes.}, } @article {pmid39311426, year = {2024}, author = {Azzolino, D and Piras, R and Zulueta, A and Lucchi, T and Lunetta, C}, title = {Amyotrophic lateral sclerosis as a disease model of sarcopenia.}, journal = {Age and ageing}, volume = {53}, number = {9}, pages = {}, doi = {10.1093/ageing/afae209}, pmid = {39311426}, issn = {1468-2834}, mesh = {Humans ; *Sarcopenia/physiopathology/diagnosis ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; *Muscle, Skeletal/pathology/physiopathology ; Aging/pathology ; Animals ; Age Factors ; Aged ; Risk Factors ; }, abstract = {Sarcopenia, the progressive decline of muscle mass and function, has traditionally been viewed as an age-related process leading to a broad range of adverse outcomes. However, it has been widely reported that sarcopenia can occur earlier in life in association with various conditions (i.e. disease-related sarcopenia), including neuromuscular disorders. As early as 2010, the European Working Group on Sarcopenia in Older People included neurodegenerative diseases characterised by motor neuron loss among the mechanisms underlying sarcopenia. Despite some differences in pathogenetic mechanisms, both amyotrophic lateral sclerosis (ALS) and age-related sarcopenia share common characteristics, such as the loss of motor units and muscle fibre atrophy, oxidative stress, mitochondrial dysfunction and inflammation. The histology of older muscle shows fibre size heterogeneity, fibre grouping and a loss of satellite cells, similar to what is observed in ALS patients. Regrettably, the sarcopenic process in ALS patients has been largely overlooked, and literature on the condition in this patient group is very scarce. Some instruments used for the assessment of sarcopenia in older people could also be applied to ALS patients. At this time, there is no approved specific pharmacological treatment to reverse damage to motor neurons or cure ALS, just as there is none for sarcopenia. However, some agents targeting the muscle, like myostatin and mammalian target of rapamycin inhibitors, are under investigation both in the sarcopenia and ALS context. The development of new therapeutic agents targeting the skeletal muscle may indeed be beneficial to both ALS patients and older people with sarcopenia.}, } @article {pmid39312484, year = {2024}, author = {Okada, K and Ito, D and Morimoto, S and Kato, C and Oguma, Y and Warita, H and Suzuki, N and Aoki, M and Kuramoto, J and Kobayashi, R and Shinozaki, M and Ikawa, M and Nakahara, J and Takahashi, S and Nishimoto, Y and Shibata, S and Okano, H}, title = {Multiple lines of evidence for disruption of nuclear lamina and nucleoporins in FUS amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {11}, pages = {3933-3948}, pmid = {39312484}, issn = {1460-2156}, support = {21H02812//Japan Society for the Promotion of Science/ ; JP20ek0109395//Japan Agency for Medical Research and Development/ ; //Takeda Science Foundation/ ; //The Yukihiko Miyata Memorial Trust for ALS Research/ ; //Yoshio Koide/ ; //Japan ALS Association/ ; //Daiichi Sankyo Foundation of Life Science/ ; //Keio Medical Association and Keio University Grant-in-Aid for Encouragement of Young Medical Scientists/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *RNA-Binding Protein FUS/genetics/metabolism ; Mice ; Humans ; *Nuclear Pore Complex Proteins/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Nuclear Lamina/metabolism ; Disease Models, Animal ; Male ; Mice, Transgenic ; Spinal Cord/metabolism/pathology ; Female ; Mutation ; }, abstract = {Advanced pathological and genetic approaches have revealed that mutations in fused in sarcoma/translated in liposarcoma (FUS/TLS), which is pivotal for DNA repair, alternative splicing, translation and RNA transport, cause familial amyotrophic lateral sclerosis (ALS). The generation of suitable animal models for ALS is essential for understanding its pathogenesis and developing therapies. Therefore, we used CRISPR-Cas9 to generate FUS-ALS mutation in the non-classical nuclear localization signal (NLS), H517D (mouse position: H509D) and genome-edited mice. Fus WT/H509D mice showed progressive motor impairment (accelerating rotarod and DigiGait system) with age, which was associated with the loss of motor neurons and disruption of the nuclear lamina and nucleoporins and DNA damage in spinal cord motor neurons. We confirmed the validity of our model by showing that nuclear lamina and nucleoporin disruption were observed in lower motor neurons differentiated from patient-derived human induced pluripotent stem cells (hiPSC-LMNs) with FUS-H517D and in the post-mortem spinal cord of patients with ALS. RNA sequence analysis revealed that most nuclear lamina and nucleoporin-linking genes were significantly decreased in FUS-H517D hiPSC-LMNs. This evidence suggests that disruption of the nuclear lamina and nucleoporins is crucial for ALS pathomechanisms. Combined with patient-derived hiPSC-LMNs and autopsy samples, this mouse model might provide a more reliable understanding of ALS pathogenesis and might aid in the development of therapeutic strategies.}, } @article {pmid39312574, year = {2024}, author = {Plessis-Belair, J and Ravano, K and Han, E and Janniello, A and Molina, C and Sher, RB}, title = {NEMF mutations in mice illustrate how Importin-β specific nuclear transport defects recapitulate neurodegenerative disease hallmarks.}, journal = {PLoS genetics}, volume = {20}, number = {9}, pages = {e1011411}, pmid = {39312574}, issn = {1553-7404}, support = {R01 AG079898/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *beta Karyopherins/metabolism/genetics ; *Active Transport, Cell Nucleus/genetics ; Mice ; Humans ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Disease Models, Animal ; Mutation ; ran GTP-Binding Protein/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Cell Nucleus/metabolism/genetics ; Frontotemporal Dementia/genetics/metabolism/pathology ; Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; Alzheimer Disease/genetics/metabolism/pathology ; }, abstract = {Pathological disruption of Nucleocytoplasmic Transport (NCT), such as the mis-localization of nuclear pore complex proteins (Nups), nuclear transport receptors, Ran-GTPase, and RanGAP1, are seen in both animal models and in familial and sporadic forms of amyotrophic lateral sclerosis (ALS), frontal temporal dementia and frontal temporal lobar degeneration (FTD\FTLD), and Alzheimer's and Alzheimer's Related Dementias (AD/ADRD). However, the question of whether these alterations represent a primary cause, or a downstream consequence of disease is unclear, and what upstream factors may account for these defects are unknown. Here, we report four key findings that shed light on the upstream causal role of Importin-β-specific nuclear transport defects in disease onset. First, taking advantage of two novel mouse models of NEMF neurodegeneration (NemfR86S and NemfR487G) that recapitulate many cellular and biochemical aspects of neurodegenerative diseases, we find an Importin-β-specific nuclear import block. Second, we observe cytoplasmic mis-localization and aggregation of multiple proteins implicated in the pathogenesis of ALS/FTD and AD/ADRD, including TDP43, Importin-β, RanGap1, and Ran. These findings are further supported by a pathological interaction between Importin-β and the mutant NEMFR86S protein in cytoplasmic accumulations. Third, we identify similar transcriptional dysregulation in key genes associated with neurodegenerative disease. Lastly, we show that even transient pharmaceutical inhibition of Importin-β in both mouse and human neuronal and non-neuronal cells induces key proteinopathies and transcriptional alterations seen in our mouse models and in neurodegeneration. Our convergent results between mouse and human neuronal and non-neuronal cellular biology provide mechanistic evidence that many of the mis-localized proteins and dysregulated transcriptional events seen in multiple neurodegenerative diseases may in fact arise primarily from a primary upstream defect in Importin- β nuclear import. These findings have critical implications for investigating how sporadic forms of neurodegeneration may arise from presently unidentified genetic and environmental perturbations in Importin-β function.}, } @article {pmid39313211, year = {2025}, author = {Rahimi, M and Al Masry, Z and Templeton, JM and Schneider, S and Poellabauer, C}, title = {A Comprehensive Multifunctional Approach for Measuring Parkinson's Disease Severity.}, journal = {Applied clinical informatics}, volume = {16}, number = {1}, pages = {11-23}, pmid = {39313211}, issn = {1869-0327}, mesh = {Humans ; *Parkinson Disease/diagnosis/physiopathology ; Male ; Female ; *Severity of Illness Index ; Aged ; Middle Aged ; Neuropsychological Tests ; Machine Learning ; }, abstract = {OBJECTIVES: This research study aims to advance the staging of Parkinson's disease (PD) by incorporating machine learning to assess and include a broader multifunctional spectrum of neurocognitive symptoms in the staging schemes beyond motor-centric assessments. Specifically, we provide a novel framework to modernize and personalize PD staging more objectively by proposing a hybrid feature scoring approach.

METHODS: We recruited 37 individuals diagnosed with PD, each of whom completed a series of tablet-based neurocognitive tests assessing motor, memory, speech, executive functions, and tasks ranging in complexity from single to multifunctional. Then, the collected data were used to develop a hybrid feature scoring system to calculate a weighted vector for each function. We evaluated the current PD staging schemes and developed a new approach based on the features selected and extracted using random forest and principal component analysis.

RESULTS: Our findings indicate a substantial bias in current PD staging systems toward fine motor skills, that is, other neurological functions (memory, speech, executive function, etc.) do not map into current PD stages as well as fine motor skills do. The results demonstrate that a more accurate and personalized assessment of PD severity could be achieved by including a more exhaustive range of neurocognitive functions in the staging systems either by involving multiple functions in a unified staging score or by designing a function-specific staging system.

CONCLUSION: The proposed hybrid feature score approach provides a comprehensive understanding of PD by highlighting the need for a staging system that covers various neurocognitive functions. This approach could potentially lead to more effective, objective, and personalized treatment strategies. Further, this proposed methodology could be adapted to other neurodegenerative conditions such as Alzheimer's disease or amyotrophic lateral sclerosis.}, } @article {pmid39313484, year = {2025}, author = {Funai, A and Hayashi, K and Kawata, A and Nakayama, Y and Matsuda, C and Haraguchi, M and Takahashi, K and Komori, T}, title = {An autopsy report of a long-survival case of familial amyotrophic lateral sclerosis with SOD1 G93S gene mutation: Lack of SOD1-positive inclusion in the remaining neurons.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {45}, number = {1}, pages = {60-65}, doi = {10.1111/neup.13004}, pmid = {39313484}, issn = {1440-1789}, support = {22H03398//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; Male ; Aged ; *Amyotrophic Lateral Sclerosis/enzymology/genetics ; *Superoxide Dismutase-1/genetics ; Fatal Outcome ; Autopsy ; *Mutation/genetics ; Time Factors ; *Motor Neurons/enzymology ; }, abstract = {We describe the case of a 70-year-old Japanese man with familial amyotrophic lateral sclerosis (fALS) associated with a p.Gly93Ser mutation in the copper/zinc superoxide dismutase (SOD1) gene. This mutation is one of the relatively rare SOD1 mutations, with only one previous autopsy report, and is known for its longer disease duration. As previously reported, the patient had weakness in the lower limbs at age 33, followed by dysphagia, dysesthesia in the lower limbs, and autonomic dysfunction. He required mechanical ventilation at age 44 and died of acute pancreatitis at age 70. Neuropathologically, multisystem degeneration was observed beyond lesions typical of familial ALS with posterior column involvement. In addition, there was no SOD1-positive inclusion in the remaining motor neurons. The absence of SOD1-positive inclusion is a rare feature observed predominantly in long survival cases with SOD1 gene mutations. We hypothesize that the considerably lower amount of abnormal SOD1 protein in the motor neuron cells might explain our patient's extraordinarily long clinical course.}, } @article {pmid39313512, year = {2024}, author = {Khan, AF and Iturria-Medina, Y}, title = {Beyond the usual suspects: multi-factorial computational models in the search for neurodegenerative disease mechanisms.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {386}, pmid = {39313512}, issn = {2158-3188}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/physiopathology ; *Neuroimaging/methods ; *Brain/diagnostic imaging/physiopathology ; Disease Progression ; Biomarkers ; Alzheimer Disease/diagnostic imaging/physiopathology ; Computer Simulation ; }, abstract = {From Alzheimer's disease to amyotrophic lateral sclerosis, the molecular cascades underlying neurodegenerative disorders remain poorly understood. The clinical view of neurodegeneration is confounded by symptomatic heterogeneity and mixed pathology in almost every patient. While the underlying physiological alterations originate, proliferate, and propagate potentially decades before symptomatic onset, the complexity and inaccessibility of the living brain limit direct observation over a patient's lifespan. Consequently, there is a critical need for robust computational methods to support the search for causal mechanisms of neurodegeneration by distinguishing pathogenic processes from consequential alterations, and inter-individual variability from intra-individual progression. Recently, promising advances have been made by data-driven spatiotemporal modeling of the brain, based on in vivo neuroimaging and biospecimen markers. These methods include disease progression models comparing the temporal evolution of various biomarkers, causal models linking interacting biological processes, network propagation models reproducing the spatial spreading of pathology, and biophysical models spanning cellular- to network-scale phenomena. In this review, we discuss various computational approaches for integrating cross-sectional, longitudinal, and multi-modal data, primarily from large observational neuroimaging studies, to understand (i) the temporal ordering of physiological alterations, i(i) their spatial relationships to the brain's molecular and cellular architecture, (iii) mechanistic interactions between biological processes, and (iv) the macroscopic effects of microscopic factors. We consider the extents to which computational models can evaluate mechanistic hypotheses, explore applications such as improving treatment selection, and discuss how model-informed insights can lay the groundwork for a pathobiological redefinition of neurodegenerative disorders.}, } @article {pmid39314138, year = {2025}, author = {Lv, Y and Li, H}, title = {Blood diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2556-2570}, pmid = {39314138}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited. The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain, brainstem, and spinal cord, as well as abnormal protein deposition in the cytoplasm of neurons and glial cells. The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid, blood, and even urine. Among these biomarkers, neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system, while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles. Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity. However, there are challenges in using neurofilament light chain to differentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury. Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment, oxygen saturation, and the glomerular filtration rate. TAR DNA-binding protein 43, a pathological protein associated with amyotrophic lateral sclerosis, is emerging as a promising biomarker, particularly with advancements in exosome-related research. Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers; however, they show potential in predicting disease prognosis. Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years, the quest for definitive diagnostic and prognostic biomarkers remains a formidable challenge. This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.}, } @article {pmid39314333, year = {2024}, author = {Guha, A and Si, Y and Smith, R and Kazamel, M and Jiang, N and Smith, KA and Thalacker-Mercer, A and Singh, BK and Ho, R and Andrabi, SA and Pereira, JDTDS and Salgado, JS and Agrawal, M and Velic, EH and King, PH}, title = {The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39314333}, issn = {2692-8205}, support = {I01 BX002466/BX/BLRD VA/United States ; I01 BX006231/BX/BLRD VA/United States ; R01 NS092651/NS/NINDS NIH HHS/United States ; R21 NS111275/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1[G93A] mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, β-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1[G93A] or exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.}, } @article {pmid39314491, year = {2024}, author = {Guerra San Juan, I and Brunner, J and Eggan, K and Toonen, RF and Verhage, M}, title = {KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39314491}, issn = {2692-8205}, support = {R01 NS089742/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in the microtubule binding motor protein, kinesin family member 5A (KIF5A), cause the fatal motor neuron disease, Amyotrophic Lateral Sclerosis. While KIF5 family members transport a variety of cargos along axons, it is still unclear which cargos are affected by KIF5A mutations. We generated KIF5A null mutant human motor neurons to investigate the impact of KIF5A loss on the transport of various cargoes and its effect on motor neuron function at two different timepoints in vitro. The absence of KIF5A resulted in reduced neurite complexity in young motor neurons (DIV14) and significant defects in axonal regeneration capacity at all developmental stages. KIF5A loss did not affect neurofilament transport but resulted in decreased mitochondria motility and anterograde speed at DIV42. More prominently, KIF5A depletion strongly reduced anterograde transport of SFPQ-associated RNA granules in DIV42 motor neuron axons. We conclude that KIF5A most prominently functions in human motor neurons to promote axonal regrowth after injury as well as to anterogradely transport mitochondria and, to a larger extent, SFPQ-associated RNA granules in a time-dependent manner.}, } @article {pmid39314515, year = {2025}, author = {He, D and Wang, X and Hao, M and Shen, D and Yang, X and Liu, M and Li, Y and Wang, J and Cui, L}, title = {Mutational and transcriptional profiling of cuproptosis-associated genes in amyotrophic lateral sclerosis.}, journal = {Genes & diseases}, volume = {12}, number = {1}, pages = {101208}, pmid = {39314515}, issn = {2352-3042}, } @article {pmid39315251, year = {2024}, author = {Maitra, S and Baek, M and Choe, YJ and Kim, NC}, title = {FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10S59L by reducing the PINK1/Parkin pathway.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39315251}, issn = {2693-5015}, support = {R56 NS112296/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing CHCHD10[S59L], and human cell models expressing CHCHD10[S59L], we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10[S59L]. Evidences using in vitro, in vivo genetic, and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10[S59L]-induced diseases.

METHODS: An in vivo human cell culture and in vivo Drosophila models expressing CHCHD10[S59L] mutant were utilized in this study to evaluate the effect of PDE4 inhibitors in PINK-parkin mediated cytotoxicity through immunohistochemical and seahorse assays. Data were analysed using one-way ANOVA and post-hoc Dunnett's test for statistical significance.

RESULTS: We investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10[S59L]-induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10[S59L]-induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H[S81L]. Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10[S59L].

CONCLUSION: These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10[S59L]-induced ALS-FTD and possibly other related diseases, and that disease treatment with PDE4 inhibitors should include careful consideration of the PINK1/Parkin pathway, as it is generally recognized as a protective pathway.}, } @article {pmid39315308, year = {2024}, author = {Abati, E and Gagliardi, D and Manini, A and Del Bo, R and Ronchi, D and Meneri, M and Beretta, F and Sarno, A and Rizzo, F and Monfrini, E and Di Fonzo, A and Pellecchia, MT and Brusati, A and Silani, V and Comi, GP and Ratti, A and Verde, F and Ticozzi, N and Corti, S}, title = {Investigating the prevalence of MFN2 mutations in amyotrophic lateral sclerosis: insights from an Italian cohort.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae312}, pmid = {39315308}, issn = {2632-1297}, abstract = {The MFN2 gene encodes mitofusin 2, a key protein for mitochondrial fusion, transport, maintenance and cell communication. MFN2 mutations are primarily linked to Charcot-Marie-Tooth disease type 2A. However, a few cases of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis/frontotemporal dementia phenotypes with concomitant MFN2 mutations have been previously reported. This study examines the clinical and genetic characteristics of an Italian cohort of amyotrophic lateral sclerosis patients with rare, non-synonymous MFN2 mutations. A group of patients (n = 385) diagnosed with amyotrophic lateral sclerosis at our Neurology Units between 2008 and 2023 underwent comprehensive molecular testing, including MFN2. After excluding pathogenic mutations in the main amyotrophic lateral sclerosis-related genes (i.e. C9orf72, SOD1, FUS and TARDBP), MFN2 variants were classified based on the American College of Medical Genetics and Genomics guidelines, and demographic and clinical data of MFN2-mutated patients were retrieved. We identified 12 rare, heterozygous, non-synonymous MFN2 variants in 19 individuals (4.9%). Eight of these variants, carried by nine patients (2.3%), were either pathogenic, likely pathogenic or variants of unknown significance according to the American College of Medical Genetics and Genomics guidelines. Among these patients, four exhibited a familial pattern of inheritance. The observed phenotypes included classic and bulbar amyotrophic lateral sclerosis, amyotrophic lateral sclerosis/frontotemporal dementia, flail arm, flail leg and progressive muscular atrophy. Median survival after disease onset was extremely variable, ranging from less than 1 to 13 years. This study investigates the prevalence of rare, non-synonymous MFN2 variants within an Italian cohort of amyotrophic lateral sclerosis patients, who have been extensively investigated, enhancing our knowledge of the underlying phenotypic spectrum. Further research is needed to understand whether MFN2 mutations contribute to motor neuron disease and to what extent. Improving our knowledge regarding the genetic basis of amyotrophic lateral sclerosis is crucial both in a diagnostic and therapeutic perspective.}, } @article {pmid39315390, year = {2024}, author = {Douglas, AGL and Thompson, AG and Turner, MR and Talbot, K}, title = {Personalised penetrance estimation for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {BMJ neurology open}, volume = {6}, number = {2}, pages = {e000792}, pmid = {39315390}, issn = {2632-6140}, abstract = {BACKGROUND: C9orf72 hexanucleotide repeat expansions are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in European populations. Variable disease penetrance between families presents a challenge for genetic counselling of at-risk relatives and reduces the predictive utility of testing asymptomatic relatives. We have developed a novel model for estimating penetrance in individual families affected by C9orf72 using available family history information, allowing the calculation of personalised risk estimates.

METHODS: Published aggregated age-of-onset data for C9orf72-related ALS/FTD were used to generate age-related cumulative relative risks for at-risk relatives within pedigrees. Age-related relative risks are combined with a priori chance of individuals carrying an expansion based on known pedigree information. Penetrance is calculated as a number of affected individuals divided by the sum of cumulative age-related risks of relatives being affected by 80 years.

RESULTS: This method allows family-specific penetrance to be estimated from family history and at-risk relatives' personalised age-related ALS/FTD risks to be calculated and illustrated graphically. Penetrance reduces as the number and age of at-risk unaffected relatives increases.

CONCLUSIONS: Family history remains the best indicator of penetrance in C9orf72 expansion carriers. Calculating family-specific penetrance can aid genetic counselling by allowing at-risk relatives a more accurate understanding of their individual risk.}, } @article {pmid39316038, year = {2025}, author = {Olsen, CG and Malmberg, VN and Fahlström, M and Alstadhaug, KB and Bjørnå, IK and Braathen, GJ and Bråthen, G and Demic, N and Hallerstig, E and Hogenesch, I and Horn, MA and Kampman, MT and Kleveland, G and Ljøstad, U and Maniaol, A and Morsund, ÅH and Nakken, O and Schlüter, K and Schuler, S and Seim, E and Flemmen, HØ and Tysnes, OB and Holmøy, T and Høyer, H}, title = {Amyotrophic lateral sclerosis caused by the C9orf72 expansion in Norway - prevalence, ancestry, clinical characteristics and sociodemographic status.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {132-140}, doi = {10.1080/21678421.2024.2405118}, pmid = {39316038}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Female ; Norway/epidemiology ; *C9orf72 Protein/genetics ; Middle Aged ; Aged ; Prevalence ; Adult ; *DNA Repeat Expansion/genetics ; *Proteins/genetics ; Aged, 80 and over ; }, abstract = {OBJECTIVE: The most common genetic cause of amyotrophic lateral sclerosis (ALS) is the C9orf72 expansion. A high incidence of this expansion has been detected in Sweden and Finland. This Norwegian population-based study aimed to identify the prevalence, geographic distribution, ancestry, and relatedness of ALS patients with a C9orf72 expansion (C9pos). Further, we compared C9pos and C9neg patients' clinical presentation, family history of ALS and other neurodegenerative disorders, and sociodemographic status.

METHODS: We recruited ALS patients from all 17 Departments of neurology in Norway. Blood samples and questionnaires regarding clinical characteristics, sociodemographic status and family history of ALS, and other neurodegenerative disorders were collected. The C9orf72 expansion was examined for all patients.

RESULTS: The study enrolled 500 ALS patients, 8.8% of whom were C9pos, with half being sporadic ALS cases. The proportion of C9pos cases differed between regions, ranging from 17.9% in the Northern region to 1.9% in the Western region. The majority of C9pos patients had non-Finnish European descent and were not closely related. C9pos patients exhibited a significantly shorter mean survival time, had a higher frequency of relatives with ALS or dementia, and were more often unmarried/single and childless than C9neg patients.

CONCLUSION: C9pos patients constitute a large portion of the Norwegian ALS population. Ancestry and relatedness do not adequately explain regional differences. Relying on clinical information to identify C9pos patients has proven to be challenging. Half of C9pos patients were reported as having sporadic ALS, underlining the importance of carefully assessing family history and the need for genetic testing.}, } @article {pmid39316061, year = {2025}, author = {Yang, W and Liu, X and Fan, D}, title = {Low CD3 level is a risk factor for amyotrophic lateral sclerosis: a Mendelian randomization study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {64-72}, doi = {10.1080/21678421.2024.2407408}, pmid = {39316061}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/immunology ; Humans ; *Mendelian Randomization Analysis/methods ; *CD3 Complex/genetics/metabolism ; Risk Factors ; Genetic Predisposition to Disease/genetics ; Male ; Female ; Polymorphism, Single Nucleotide/genetics ; CD8-Positive T-Lymphocytes/metabolism/immunology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by neuronal degeneration of the spinal cord and brain and believed to be related to the immune system. In this study, our aim is to use Mendelian randomization (MR) to search for immune markers related to ALS. A total of 731 immune cell traits were included in this study. MR analysis was used to identify the causality between 731 immune cell traits (with 3,757 Europeans) and ALS (with 138,086 Europeans). Colocalization analysis was used to verify the found causality, protein-protein interaction prediction was used to look for the interacting proteins that are known to be involved in ALS. We found low expression levels of CD3 on central memory CD8+ T cell is risk factor for ALS (OR = 0.90, 95% CI: 0.86-0.95, P = 0.0000303). CD3 can interact with three ALS-related proteins: VCP, HLA-DRA and HLA-DRB5, which are associated with adaptive immune response. Our study reported for the first time that low-level CD3 is a risk factor for ALS and the possible mechanism, which could provide a potential strategy for ALS diagnosis and therapy.}, } @article {pmid39316747, year = {2024}, author = {de Calbiac, H and Renault, S and Haouy, G and Jung, V and Roger, K and Zhou, Q and Campanari, ML and Chentout, L and Demy, DL and Marian, A and Goudin, N and Edbauer, D and Guerrera, C and Ciura, S and Kabashi, E}, title = {Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.}, journal = {Autophagy}, volume = {20}, number = {10}, pages = {2164-2185}, pmid = {39316747}, issn = {1554-8635}, mesh = {*Motor Neurons/metabolism/pathology ; Animals ; *C9orf72 Protein/genetics/metabolism ; *Zebrafish ; *Mitophagy/genetics ; *Apoptosis/genetics ; Humans ; *Autophagy/genetics/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Dipeptides/pharmacology/metabolism ; Loss of Function Mutation/genetics ; Mitochondria/metabolism ; Disease Models, Animal ; }, abstract = {The GGGGCC hexanucleotide repeat expansion (HRE) of the C9orf72 gene is the most frequent cause of amyotrophic lateral sclerosis (ALS), a devastative neurodegenerative disease characterized by motor neuron degeneration. C9orf72 HRE is associated with lowered levels of C9orf72 expression and its translation results in the production of dipeptide-repeats (DPRs). To recapitulate C9orf72-related ALS disease in vivo, we developed a zebrafish model where we expressed glycine-proline (GP) DPR in a c9orf72 knockdown context. We report that C9orf72 gain- and loss-of-function properties act synergistically to induce motor neuron degeneration and paralysis with poly(GP) accumulating preferentially within motor neurons along with Sqstm1/p62 aggregation indicating macroautophagy/autophagy deficits. Poly(GP) levels were shown to accumulate upon c9orf72 downregulation and were comparable to levels assessed in autopsy samples of patients carrying C9orf72 HRE. Chemical boosting of autophagy using rapamycin or apilimod, is able to rescue motor deficits. Proteomics analysis of zebrafish-purified motor neurons unravels mitochondria dysfunction confirmed through a comparative analysis of previously published C9orf72 iPSC-derived motor neurons. Consistently, 3D-reconstructions of motor neuron demonstrate that poly(GP) aggregates colocalize to mitochondria, thus inducing their elongation and swelling and the failure of their processing by mitophagy, with mitophagy activation through urolithin A preventing locomotor deficits. Finally, we report apoptotic-related increased amounts of cleaved Casp3 (caspase 3, apoptosis-related cysteine peptidase) and rescue of motor neuron degeneration by constitutive inhibition of Casp9 or treatment with decylubiquinone. Here we provide evidence of key pathogenic steps in C9ALS-FTD that can be targeted through pharmacological avenues, thus raising new therapeutic perspectives for ALS patients.}, } @article {pmid39317352, year = {2025}, author = {Kleinerova, J and Garcia-Gallardo, A and Tacheva, A and Bede, P}, title = {Subcortical grey matter involvement in ALS and PLS - vulnerable hubs of cortico-cortical and cortico-basal circuits: extrapyramidal, cognitive, bulbar and respiratory correlates.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {1-4}, doi = {10.1080/21678421.2024.2405130}, pmid = {39317352}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/pathology/complications ; *Cerebral Cortex/pathology/physiopathology/diagnostic imaging ; *Gray Matter/pathology/diagnostic imaging/physiopathology ; *Nerve Net/pathology/physiopathology ; Neural Pathways/pathology/physiopathology/diagnostic imaging ; }, abstract = {Evidence from neuroimaging studies suggests that the cardinal clinical manifestations of ALS stem from the dysfunction of specific neural networks. The majority of cortico-cortical and cortico-basal networks are physiologically relayed by deep cerebral and cerebellar grey matter nuclei which have been increasingly implicated in the pathophysiology of ALS. A series of recent human imaging papers revealed volume reductions, shape deformations, metabolic alterations and more recently, susceptibility changes in hippocampal subfields, thalamic, striatal, amygdalar and cerebellar nuclei. Thalamic changes have been identified in presymptomatic mutation carriers long before symptom onset and longitudinal studies have consistently confirmed progressive subcortical degeneration during the symptomatic phase of the disease. The dysfunction of circuits relayed by specific subcortical nuclei has been associated with apathy, amnestic deficits, limbic symptoms, extrapyramidal manifestations, sensory disturbances, pseudobulbar affect and cerebellar deficits. In light of emerging imaging data, the clinical heterogeneity of ALS is probably best approached from a network integrity perspective. Accordingly, the comprehensive assessment of subcortical grey matter nuclei seems imperative to untangle complex clinical phenomena in ALS.}, } @article {pmid39317854, year = {2025}, author = {Khoshdooz, S and Abbasi, H and Abbasi, MM}, title = {Iron-Status Indicators and HFE Gene Polymorphisms in Individuals with Amyotrophic Lateral Sclerosis: An Umbrella Review of Meta-analyses and Systematic Reviews.}, journal = {Biological trace element research}, volume = {203}, number = {6}, pages = {2974-2985}, pmid = {39317854}, issn = {1559-0720}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood ; Humans ; *Hemochromatosis Protein/genetics ; *Iron/blood/metabolism ; Systematic Reviews as Topic ; *Polymorphism, Genetic ; Meta-Analysis as Topic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons. Recent meta-analyses and systematic reviews suggest that HFE gene polymorphisms and iron-associated biomarkers may play a key role in the risk and occurrence of ALS. This umbrella study aimed to explore the roles of HFE gene polymorphisms and iron-associated biomarkers in individuals with ALS. A thorough search of three online scientific databases, namely Scopus, Web of Science, and PubMed, was conducted from their inception until September 13, 2024. The screening and selection processes were executed based on the PICO framework and eligibility criteria, followed by two independent reviewers. The Assessment of Multiple Systematic Reviews (AMSTAR)-2 and GRADE tools were utilized to assess the methodological quality and the certainty of evidence. Through an advanced search, 101 records were retrieved, of which eight meta-analyses and systematic reviews were selected for this umbrella review. A significant increase in iron concentrations was found in individuals with ALS compared to healthy controls (SMD, 0.26; 95% CI - 0.05, 0.57). Conversely, selected meta-analyses reported that serum transferrin concentrations in ALS patients were lower compared to healthy controls (SMD, - 0.15; 95% CI - 0.36, 0.05). Furthermore, mutations in H63D polymorphisms resulted in a 13% significant increase in the risk of ALS (OR, 1.13; 95% CI 1.05, 1.22). Our umbrella study of meta-analyses and systematic reviews reveals that individuals with ALS have lower serum concentrations of transferrin compared to healthy controls. Additionally, the H63D polymorphism in the HFE gene is associated with a slight increase in the risk of ALS. Future research should investigate broader aspects of iron-related biomarkers and HFE genes to elucidate their roles in ALS pathogenesis. Registration: Our umbrella study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the identification number CRD42024559032 (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024559032).}, } @article {pmid39318236, year = {2025}, author = {Majewski, S and Klein, P and Boillée, S and Clarke, BE and Patani, R}, title = {Towards an integrated approach for understanding glia in Amyotrophic Lateral Sclerosis.}, journal = {Glia}, volume = {73}, number = {3}, pages = {591-607}, pmid = {39318236}, issn = {1098-1136}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism ; Humans ; *Neuroglia/metabolism/pathology ; Animals ; }, abstract = {Substantial advances in technology are permitting a high resolution understanding of the salience of glia, and have helped us to transcend decades of predominantly neuron-centric research. In particular, recent advances in 'omic' technologies have enabled unique insights into glial biology, shedding light on the cellular and molecular aspects of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we review studies using omic techniques to attempt to understand the role of glia in ALS across different model systems and post mortem tissue. We also address caveats that should be considered when interpreting such studies, and how some of these may be mitigated through either using a multi-omic approach and/or careful low throughput, high fidelity orthogonal validation with particular emphasis on functional validation. Finally, we consider emerging technologies and their potential relevance in deepening our understanding of glia in ALS.}, } @article {pmid39318842, year = {2024}, author = {Emary, PC and Turner, AJ}, title = {Cervical spondylotic myelopathy in a 68-year-old man diagnosed with amyotrophic lateral sclerosis.}, journal = {The Journal of the Canadian Chiropractic Association}, volume = {68}, number = {2}, pages = {172-176}, pmid = {39318842}, issn = {0008-3194}, abstract = {Owing to similar clinical presentations, cervical spondylotic myelopathy can mimic other neurological disorders. In this imaging case review (ICR), we describe a case of cervical spondylotic myelopathy in a patient diagnosed with amyotrophic lateral sclerosis. The key clinical features, imaging findings and differential diagnoses of cervical spondylotic myelopathy compared with amyotrophic lateral sclerosis are also presented.}, } @article {pmid39319809, year = {2024}, author = {Karra, R and Rice, AD and Hardcastle, A and V Lara, J and Hollen, A and Glenn, M and Munn, R and Hannan, P and Arcaris, B and Derksen, D and Spaite, DW and Gaither, JB}, title = {Telemedical Direction to Optimize Resource Utilization in a Rural Emergency Medical Services System.}, journal = {The western journal of emergency medicine}, volume = {25}, number = {5}, pages = {777-783}, pmid = {39319809}, issn = {1936-9018}, mesh = {Humans ; Retrospective Studies ; *Telemedicine ; *Emergency Medical Services ; *Rural Health Services ; Female ; *Emergency Medical Technicians ; Male ; Chest Pain/therapy ; Middle Aged ; Pilot Projects ; Adult ; }, abstract = {BACKGROUND: Telemedicine remains an underused tool in rural emergency medical servces (EMS) systems. Rural emergency medical technicians (EMT) and paramedics cite concerns that telemedicine could increase Advanced Life Support (ALS) transports, extend on-scene times, and face challenges related to connectivity as barriers to implementation. Our aim in this project was to implement a telemedicine system in a rural EMS setting and assess the impact of telemedicine on EMS management of patients with chest pain while evaluating some of the perceived barriers.

METHODS: This study was a mixed-methods, retrospective review of quality assurance data collected prior to and after implementation of a telemedicine program targeting patients with chest pain. We compared quantitative data from the 12-month pre-implementation phase to data from 15 months post-implementation. Patients were included if they had a chief complaint of chest pain or a 12-lead electrocardiogram had been obtained. The primary outcome was the rate of ALS transport before and after program implementation. Secondary outcomes included EMS call response times and EMS agency performance on quality improvement benchmarks. Qualitative data were also collected after each telemedicine encounter to evaluate paramedic/EMT and EMS physician perception of call quality.

RESULTS: The telemedicine pilot project was implemented in September 2020. Overall, there were 58 successful encounters. For this analysis, we included 38 patients in both the pre-implementation period (September 9, 2019-September 10, 2020) and the post-implementation period (September 11, 2020-December 5, 2021). Among this population, the ALS transport rate was 42% before and 45% after implementation (odds ratio 1.11; 95% confidence interval 0.45-2.76). The EMS median out-of-service times were 47 minutes before, and 33 minutes after (P = 0.07). Overall, 64% of paramedics/EMTs and 89% of EMS physicians rated the telemedicine call quality as "good."

CONCLUSION: In this rural EMS system, a telehealth platform was successfully used to connect paramedics/EMTs to board-certified EMS physicians over a 15-month period. Telemedicine use did not alter rates of ALS transports and did not increase on-scene time. The majority of paramedics/EMTs and EMS physicians rated the quality of the telemedicine connection as "good."}, } @article {pmid39321879, year = {2024}, author = {Lei, T and Zhang, X and Fu, G and Luo, S and Zhao, Z and Deng, S and Li, C and Cui, Z and Cao, J and Chen, P and Yang, H}, title = {Advances in human cellular mechanistic understanding and drug discovery of brain organoids for neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102517}, doi = {10.1016/j.arr.2024.102517}, pmid = {39321879}, issn = {1872-9649}, mesh = {Humans ; *Organoids/drug effects/pathology ; *Neurodegenerative Diseases/pathology/drug therapy ; *Drug Discovery/methods ; *Brain/pathology/drug effects ; Animals ; }, abstract = {The prevalence of neurodegenerative diseases (NDs) is increasing rapidly as the aging population accelerates, and there are still no treatments to halt or reverse the progression of these diseases. While traditional 2D cultures and animal models fail to translate into effective therapies benefit patients, 3D cultured human brain organoids (hBOs) facilitate the use of non-invasive methods to capture patient data. The purpose of this study was to review the research and application of hBO in disease models and drug screening in NDs. The pluripotent stem cells are induced in multiple stages to form cerebral organoids, brain region-specific organoids and their derived brain cells, which exhibit complex brain-like structures and perform electrophysiological activities. The brain region-specific organoids and their derived neurons or glial cells contribute to the understanding of the pathogenesis of NDs and the efficient development of drugs, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Glial-rich brain organoids facilitate the study of glial function and neuroinflammation, including astrocytes, microglia, and oligodendrocytes. Further research on the maturation enhancement, vascularization and multi-organoid assembly of hBO will help to enhance the research and application of NDs cellular models.}, } @article {pmid39322357, year = {2024}, author = {Mehta, RI and Ranjan, M and Haut, MW and Carpenter, JS and Rezai, AR}, title = {Focused Ultrasound for Neurodegenerative Diseases.}, journal = {Magnetic resonance imaging clinics of North America}, volume = {32}, number = {4}, pages = {681-698}, doi = {10.1016/j.mric.2024.03.001}, pmid = {39322357}, issn = {1557-9786}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging ; Ultrasonic Therapy/methods ; Brain/diagnostic imaging ; Animals ; }, abstract = {Neurodegenerative diseases are a leading cause of death and disability and pose a looming global public health crisis. Despite progress in understanding biological and molecular factors associated with these disorders and their progression, effective disease modifying treatments are presently limited. Focused ultrasound (FUS) is an emerging therapeutic strategy for Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In these contexts, applications of FUS include neuroablation, neuromodulation, and/or blood-brain barrier opening with and without facilitated intracerebral drug delivery. Here, the authors review preclinical evidence and current and emerging applications of FUS for neurodegenerative diseases and summarize future directions in the field.}, } @article {pmid39323783, year = {2024}, author = {You, J and Maksimovic, K and Metri, MN and Schoeppe, A and Chen, K and Lee, J and Santos, JR and Youssef, MMM and Salter, MW and Park, J}, title = {Knockout of Dectin-1 does not modify disease onset or progression in a MATR3 S85C knock-in mouse model of ALS.}, journal = {Heliyon}, volume = {10}, number = {18}, pages = {e37926}, pmid = {39323783}, issn = {2405-8440}, abstract = {Microglia have been increasingly implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Dectin-1, encoded by the Clec7a gene, is highly upregulated in a specific microglial response state called disease-associated microglia (DAM) in various neurodegenerative conditions. However, the role of Dectin-1 in ALS is undetermined. Here, we show that Clec7a mRNA upregulation occurs in central nervous system (CNS) regions that exhibit neurodegeneration in a MATR3 S85C knock-in mouse model (Matr3 [S85C/S85C]) of ALS. Furthermore, a significant increase in the number of Dectin-1[+] microglia coincides with the onset of motor deficits, and this number increases with disease progression. We demonstrate that the knockout of Dectin-1 does not affect survival, motor function, neurodegeneration, or microglial responses in Matr3 [S85C/S85C] mice. These findings suggest that Dectin-1 does not play a role in modifying ALS onset or progression.}, } @article {pmid39323817, year = {2024}, author = {Zeng, A and Huang, Y and Xin, J and Li, J and Qiu, W and Zhang, M}, title = {Progress and recommendations of developing occupational exposure limits for noise-A systematic review.}, journal = {Heliyon}, volume = {10}, number = {18}, pages = {e37878}, pmid = {39323817}, issn = {2405-8440}, support = {R01 DC015990/DC/NIDCD NIH HHS/United States ; }, abstract = {OBJECTIVE: Noise exposure limit is one of the critical measures to prevent noise-induced hearing loss (NIHL). This review aimed to review the progress and recommendations for developing occupational exposure limits (OELs) for workplace noise.

METHODS: A systematic review was used. Thirty-eight national or international organizations' noise exposure standards (including OEL) and laws, regulations, and guidelines for noise exposure control were analyzed. Articles on recommendations for revising noise OEL standards between 2000 and 2023 were selected.

RESULTS: The definition of different noise types (especially for non-steady and impulsive noise) varied worldwide, and the used 8-h OEL varied from 80 to 90 dB(A). Maximum sound pressure level (Lmax) and noise dose for industrial noise and peak sound pressure level (Lpeak) for impulsive noise have been incorporated into the OELs. Countries developed noise risk management measures based on OELs, action levels (ALs), and exposure risk ratio or classification. The risk of co-exposure to noise and ototoxic organic substances and the effects of noise on susceptible populations were concerns in EU country standards. Scholars suggested revising the existing noise exposure standards based on noise's temporal structure (expressed by kurtosis), effective noise level, impulsive noise OEL, action level, and key factors of risk assessment.

CONCLUSIONS: Indicators such as Lmax, noise dose, Lpeak, and action level can be incorporated into noise OELs. Developing noise OEL standards should consider the co-exposure of noise and ototoxic substances, HPD's noise attenuation, susceptible groups, and noise's temporal structure.}, } @article {pmid39323877, year = {2024}, author = {Engelberg-Cook, E and Shah, JS and Teixeira da Silva Hucke, A and Vera-Garcia, DV and Dagher, JE and Donahue, MH and Belzil, VV and Oskarsson, B}, title = {Prognostic Factors and Epidemiology of Amyotrophic Lateral Sclerosis in Southeastern United States.}, journal = {Mayo Clinic proceedings. Innovations, quality & outcomes}, volume = {8}, number = {5}, pages = {482-492}, pmid = {39323877}, issn = {2542-4548}, support = {R01 AG067151/AG/NIA NIH HHS/United States ; R01 NS129032/NS/NINDS NIH HHS/United States ; RF1 NS129032/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: To assess the performance of known survival predictors and evaluate their stratification capability in patients with amyotrophic lateral sclerosis (ALS).

PATIENTS AND METHODS: We analyzed demographic and clinical variables collected at the Mayo Clinic, Florida ALS center during the first clinical visit of 1442 (100%) patients with ALS.

RESULTS: Our cohort had a median (interquartile range [IQR]) age at diagnosis of 64.8 (57-72) years; 1350 (92%) were non-Hispanic White; and 771 (53.5%) were male. The median (IQR) diagnostic delay was 10.1 (6-18) months, body mass index was 25.4 (23-49), and forced vital capacity was 72% (52%-87%). Approximately 12% of patients tested carried a pathologic C9orf72 hexanucleotide repeat expansion. Median (IQR) ALS functional rating scale-revised score was 35 (29-40) and ALS cognitive behavioral screen score was 15 (12-17). The median (IQR) survival after diagnosis was 17.2 (9-31) months, and survival from symptom onset was 30 (20-48) months. We found that older age decreased forced vital capacity, and fast-progressing ALS functional rating scale-revised scores significantly (P<.0001) influence survival curves and associated hazard risk.

CONCLUSION: Although results obtained from our cohort are consistent with other reports (eg, men with spinal onset experience a longer survival than women with bulbar onset), they remind us of the complexity of the disease's natural history and the limited prognostic power of the most common clinical predictors.}, } @article {pmid39324867, year = {2024}, author = {Li, J and Gao, C and Wang, Q and Liu, J and Xie, Z and Zhao, Y and Yu, M and Zheng, Y and Lv, H and Zhang, W and Yuan, Y and Meng, L and Deng, J and Wang, Z}, title = {Elevated serum circulating cell-free mitochondrial DNA in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16493}, pmid = {39324867}, issn = {1468-1331}, support = {82071409//National Natural Science Foundation of China/ ; 82101469//National Natural Science Foundation of China/ ; 82171846//National Natural Science Foundation of China/ ; U20A20356//National Natural Science Foundation of China/ ; 2022-4-40716//Capitals Funds for Health Improvement and Research/ ; 20220484017//Beijing Nova Program/ ; 20230484403//Beijing Nova Program/ ; 2023CX05//Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital/ ; 2023HQ03//National High Level Hospital Clinical Research Funding (High Quality Clinical Research Project of Peking University First Hospital/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics ; Male ; Female ; *DNA, Mitochondrial/blood/genetics ; Middle Aged ; Aged ; *Interleukin-6/blood ; *Cell-Free Nucleic Acids/blood ; *Superoxide Dismutase-1/blood/genetics ; Mutation ; Adult ; Biomarkers/blood ; }, abstract = {BACKGROUND AND PURPOSE: The substantial role of inflammation in amyotrophic lateral sclerosis (ALS) is gaining support from recent research. Studies indicate that circulating cell-free mitochondrial DNA (ccf-mtDNA) can activate the immune system and is associated with neurodegenerative diseases. This research was designed to quantify ccf-mtDNA levels in the serum of ALS patients.

METHODS: The medical records of ALS patients were reviewed. Serum ccf-mtDNA levels of patients with ALS (n = 62) and age-matched healthy controls (n = 46) were measured and compared. Additionally, serum interleukin-6 (IL-6) levels were measured using an enzyme-linked immunosorbent assay in 26 ALS patients. Correlations between variables were analyzed.

RESULTS: Serum ccf-mtDNA was notably higher in the patients with ALS. When stratified by genotype, the superoxide dismutase 1 (SOD1) mutation group showed the greatest increase in ccf-mtDNA levels relative to other ALS patients. Among all 108 individuals, a cut-off set at 1.1 × 10[5] mtDNA copies on a receiver-operating characteristic curve identified patients with ALS with 80.7% sensitivity and 50.0% specificity; the area under the curve was 0.69 (p < 0.001). Furthermore, serum ccf-mtDNA levels correlated negatively with the progression rate of ALS (ΔFS; rs = -0.26, p = 0.044), but not the ALSFRS-R score (rs = 0.06, p = 0.625). Importantly, the correlation between ccf-mtDNA and ΔFS was more pronounced in the SOD1 mutation group (rs = -0.62, p = 0.018). Lastly, a significant positive association was observed between serum ccf-mtDNA levels and IL-6 levels in ALS (r s= 0.41, p = 0.038).

CONCLUSION: Our study found increased serum ccf-mtDNA in ALS patients, suggesting a link to inflammatory processes and disease mechanism. Moreover, ccf-mtDNA could be an indicator for ALS progression, especially in those with the SOD1 mutation.}, } @article {pmid39326369, year = {2024}, author = {Suzuki, Y and Adachi, T and Yoshida, K and Sakuwa, M and Hanajima, R}, title = {Psychiatric symptoms and TDP-43 pathology in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123249}, doi = {10.1016/j.jns.2024.123249}, pmid = {39326369}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/psychology ; Male ; Female ; Aged ; *DNA-Binding Proteins/metabolism ; Middle Aged ; Mental Disorders/etiology/pathology/metabolism ; Brain/pathology/metabolism ; Aged, 80 and over ; Neurons/pathology/metabolism ; }, abstract = {BACKGROUND: ALS is not a pure motor neuron disease but co-occurs with cognitive impairment and psychiatric symptoms. The neuropathological origin of the psychiatric symptoms is unclear. This study examined the association between the psychiatric symptoms and neuropathology of ALS.

METHODS: We investigated the clinicopathological characteristics of 15 autopsy cases of ALS, including neuronal loss, gliosis, and the burden of TDP-43 pathology. We divided TDP-43-positive structures by morphology into four categories (neuronal cytoplasmic inclusion, dystrophic neurite, dot, and glial cytoplasmic inclusion) and gave each a semiquantitative score in nine brain regions. Braak neurofibrillary tangle stage, Thal amyloid phase, Lewy-related pathology, and argyrophilic grains were also assessed.

RESULTS: Of the 15 ALS patients, seven had presented with psychiatric symptoms and eight had not. Significantly higher TDP-43 pathology scores were found in the group with psychiatric symptoms in the temporal tip, transentorhinal cortex, entorhinal cortex, subiculum, and the hippocampal CA1 region and dentate gyrus. Cognitive impairment was not significantly associated with the degree of TDP-43 pathology. There were no significant differences in the degree of neuronal loss/gliosis or in other concurrent pathologies between patients with and without psychiatric symptoms. Morphological evaluation showed that neuronal cytoplasmic inclusions, dystrophic neurites, and dots tended to be more common in the group with psychiatric symptoms.

CONCLUSION: Psychiatric symptoms in ALS may be related to TDP-43 pathology in the perforant pathway. (224 words).}, } @article {pmid39327159, year = {2024}, author = {Vassallu, F and Igaz, LM}, title = {TDP-43 nuclear condensation and neurodegenerative proteinopathies.}, journal = {Trends in neurosciences}, volume = {47}, number = {11}, pages = {849-850}, doi = {10.1016/j.tins.2024.09.003}, pmid = {39327159}, issn = {1878-108X}, mesh = {Animals ; Humans ; Cell Nucleus/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Neurodegenerative Diseases/metabolism ; *TDP-43 Proteinopathies/metabolism/genetics/pathology ; }, abstract = {RNA-binding proteins (RBPs) can undergo phase separation and form condensates, processes that, in turn, can be critical for their functionality. In a recent study, Huang, Ellis, and colleagues show that cellular stress can trigger transient alterations in nuclear TAR DNA-binding protein 43 (TDP-43), leading to changes crucial for proper neuronal function. These findings have implications for understanding neurological TDP-43 proteinopathies.}, } @article {pmid39327888, year = {2024}, author = {Fitri, HU and Saputra, R and Suhardita, K and Suarta, IM and Oktasari, M and Aminah, S and Laras, PB}, title = {Digging deeper: A critique of the mediation study of spirituality in ALS patients.}, journal = {Palliative & supportive care}, volume = {22}, number = {5}, pages = {1550-1551}, doi = {10.1017/S1478951524001275}, pmid = {39327888}, issn = {1478-9523}, } @article {pmid39328012, year = {2024}, author = {Cui, Y and Chen, J and Li, H and Zheng, D and Shi, X}, title = {The causal association between epilepsy and amyotrophic lateral sclerosis: A two-sample Mendelian randomization study.}, journal = {Brain and behavior}, volume = {14}, number = {10}, pages = {e70018}, pmid = {39328012}, issn = {2162-3279}, support = {2023A03J0438//Science and Technology Program of Guangzhou/ ; 2020A1515010063//Natural Science Foundation of Guangdong Province/ ; 2023A1515011047//Natural Science Foundation of Guangdong Province/ ; //Guangzhou Research-oriented Hospital/ ; //Guangzhou High-level Clinical Key Specialty/ ; 2022A1515220119//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2021-2023//Guangzhou Municipal Key Discipline in Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Mendelian Randomization Analysis ; *Epilepsy/genetics/epidemiology/etiology ; *Genome-Wide Association Study ; Causality ; }, abstract = {OBJECTIVES: Epilepsy and amyotrophic lateral sclerosis (ALS) are common neurological disorders. The association between the two disorders has been raised in observational studies. However, it is uncertain to what extent they have mutual causal effects. In this study, we aimed to investigate their causal association using a two-sample Mendelian randomization (MR) method.

METHODS: We performed a two-sample bidirectional MR analysis to evaluate the causal association of epilepsy with the risk of ALS. Publicly published genome-wide association study statistics for epilepsy and ALS were used in the study. The primary analysis included genetic variants with a p value of less than 1 × 10[-5] as instrumental variables. We applied several alternative methods, including inverse variance weighting, weighted median, simple mode, weighted mode, MR-Egger regression and MR pleiotropy residual sum and outlier, and statistical graphs to assess the associations of epilepsy and its subtype with the risk of ALS. Reverse MR analyses were also performed to examine the association of ALS with the risk of epilepsy.

RESULTS: The primary MR analysis found no causal effect of epilepsy on risk of ALS (odds ration [OR]: 1.133, 95% confidence interval [CI]: 0.964-1.332, p = .130). Among subtypes of epilepsy, it also failed to observe any causal association between general epilepsy and ALS (OR: 1.036, 95% CI: 0.969-1.108, P = .300). However, focal epilepsy contributed to an increase in the risk of ALS (OR: 1.177, 95% CI: 1.027-1.348, p = .019). Moreover, the investigation of reverse causalities did not reveal significant results.

CONCLUSIONS: The current study supports a causal influence of focal epilepsy on ALS risk. Future studies are needed to explore its potential role in ALS.}, } @article {pmid39328135, year = {2025}, author = {Sharma, S and Mehan, S and Khan, Z and Tiwari, A and Kumar, A and Gupta, GD and Narula, AS and Kalfin, R}, title = {Exploring the Neuroprotective Potential of Icariin through Modulation of Neural Pathways in the Treatment of Neurological Diseases.}, journal = {Current molecular medicine}, volume = {25}, number = {8}, pages = {962-979}, pmid = {39328135}, issn = {1875-5666}, support = {CRG/2021/001009//DST-SERB, Govt. Of India/ ; }, mesh = {Humans ; *Flavonoids/therapeutic use/pharmacology/chemistry ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; Signal Transduction/drug effects ; *Nervous System Diseases/drug therapy/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Neuropathological diseases involve the death of neurons and the aggregation of proteins with altered properties in the brain. Proteins are used at the molecular level to categorize neurodegenerative disorders, emphasizing the importance of protein-processing mechanisms in their development. Natural herbal phytoconstituents, such as icariin, have addressed these neurological complications. Icariin, the principal compound in Epimedium, has been studied for its antineuroinflammatory, anti-oxidative, and antiapoptotic properties. Recent scientific investigations have shown that icariin exhibits promising therapeutic and preventive properties for mental and neurodegenerative disorders. In preclinical, icariin has been shown to inhibit amyloid development and reduce the expression of APP and BACE-1. Previous preclinical studies have demonstrated that icariin can regulate proinflammatory responses in neurological conditions like Parkinson's disease, depression, cerebral ischemia, ALS, and multiple sclerosis. Studies have shown that icariin possesses neuroprotective properties by modulating signaling pathways and crossing the blood-brain barrier, suggesting its potential to address various neurocomplications. This review aims to establish a foundation for future clinical investigations by examining the existing literature on icariin and exploring its potential therapeutic implications in treating neurodegenerative disorders and neuropsychiatric conditions. Future research may address numerous concerns and yield captivating findings with far-reaching implications for various aspects of icariin.}, } @article {pmid39328853, year = {2024}, author = {Ali, M and Ramadan, A and Surani, S}, title = {Obstructive sleep apnea-hypopnea syndrome immunological relationship.}, journal = {World journal of clinical cases}, volume = {12}, number = {27}, pages = {6011-6014}, pmid = {39328853}, issn = {2307-8960}, abstract = {Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a complex disorder characterized by symptoms resulting from intermittent hypoxia and hypopnea, with research indicating a crucial role of immune system dysregulation and genetic variations in its pathogenesis. A recent Zhao et al study utilizes Mendelian randomization analysis to explore the causal relationship between immune cell characteristics and OSAHS. The study identifies specific lymphocyte subsets associated with OSAHS, providing valuable insights into the disease's pathophysiology and potential targets for therapeutic intervention. The findings underscore the significance of genetic and immunological factors in sleep disorders, offering a fresh perspective on OSAHS's complexities. Compared to existing literature, Zhao et al's study stands out for its focus on genetic markers and specific immune responses associated with OSAHS, expanding upon previous research primarily centered on systemic inflammation. In conclusion, the study represents a significant advancement in the field, shedding light on the causal role of immune cells in OSAHS and paving the way for future research and targeted treatments.}, } @article {pmid39329381, year = {2025}, author = {Lee, I and Vestrucci, M and Lee, S and Rosenbaum, M and Mitsumoto, H}, title = {Blood glycated hemoglobin level is not associated with disease progression in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {175-179}, pmid = {39329381}, issn = {2167-9223}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; *Glycated Hemoglobin/metabolism ; Male ; Female ; *Disease Progression ; Middle Aged ; Aged ; Cohort Studies ; *Blood Glucose/metabolism ; }, abstract = {OBJECTIVE: A high glycemic index and high glycemic load diet has been associated with slower progression of amyotrophic lateral sclerosis (ALS), suggesting a benefit from high blood glucose levels. We examined the association between average blood glucose level and ALS progression in two independent cohorts.

METHODS: Sporadic ALS patients enrolled in the ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS) who completed a 3-month follow-up visit and had available blood samples were included. Hemoglobin A1c (HbA1c) was measured from whole blood collected at the 3-month follow-up. From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we included ALS patients with one or more HbA1c measurements at enrollment and available death information. Associations between HbA1c with revised ALS functional rating scale (ALSFRS-R)/ALSFRS total score change, and tracheostomy-free survival/survival were examined in these cohorts using linear regression, linear mixed-effects models, and Cox proportional hazard models, adjusted for covariates.

RESULTS: In the ALS COSMOS cohort (n = 193), HbA1c level was not significantly associated with the change in the ALSFRS-R total score from baseline to the 3-month follow-up (p = 0.8) nor baseline to the 6-month follow-up (p = 0.4). No significant association was found between HbA1c level and tracheostomy-free survival (p = 0.8). In the PRO-ACT cohort (n = 928), no significant association was found between HbA1c level and the rate of ALSFRS decline in the first 200 days (p = 0.81 for interaction) nor between HbA1c level and survival (p = 0.45).

INTERPRETATION: We did not find convincing evidence that mean blood glucose level is associated with disease progression among ALS patients.}, } @article {pmid39329756, year = {2024}, author = {Trainito, A and Muscarà, C and Gugliandolo, A and Chiricosta, L and Salamone, S and Pollastro, F and Mazzon, E and D'Angiolini, S}, title = {Cannabinol (CBN) Influences the Ion Channels and Synaptic-Related Genes in NSC-34 Cell Line: A Transcriptomic Study.}, journal = {Cells}, volume = {13}, number = {18}, pages = {}, pmid = {39329756}, issn = {2073-4409}, support = {Current Research Funds 2024//Ministero della Salute/ ; }, mesh = {*Ion Channels/metabolism/genetics ; Animals ; *Synapses/metabolism/drug effects ; *Transcriptome/drug effects/genetics ; Mice ; Cell Line ; Gene Expression Profiling ; Cannabinoids/pharmacology ; Humans ; Gene Expression Regulation/drug effects ; }, abstract = {Neurological disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and schizophrenia are associated with altered neuronal excitability, resulting from dysfunctions in the molecular architecture and physiological regulation of ion channels and synaptic transmission. Ion channels and synapses are regarded as suitable therapeutic targets in modern pharmacology. Cannabinoids have received great attention as an original therapeutic approach for their effects on human health due to their ability to modulate the neurotransmitter release through interaction with the endocannabinoid system. In our study, we explored the effect of cannabinol (CBN) through next-generation sequencing analysis of NSC-34 cell physiology. Our findings revealed that CBN strongly influences the ontologies related to ion channels and synapse activity at all doses tested. Specifically, the genes coding for calcium and potassium voltage-gated channel subunits, and the glutamatergic and GABAergic receptors (Cacna1b, Cacna1h, Cacng8, Kcnc3, Kcnd1, Kcnd2, Kcnj4, Grik5, Grik1, Slc17a7, Gabra5), were up-regulated. Conversely, the genes involved into serotoninergic and cholinergic pathways (Htr3a, Htr3b, Htr1b, Chrna3, Chrnb2, Chrnb4), were down-regulated. These findings highlight the influence of CBN in the expression of genes involved into ion influx and synaptic transmission.}, } @article {pmid39330700, year = {2024}, author = {Everett, WH and Bucelli, RC}, title = {Tofersen for SOD1 ALS.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {5}, pages = {149-160}, pmid = {39330700}, issn = {1758-2032}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Oligonucleotides/therapeutic use ; *Superoxide Dismutase-1/antagonists & inhibitors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition affecting the motor system. The heterogenous nature of ALS complicates trial design. Genetic forms of ALS present an opportunity to intervene in a less heterogeneous population. ALS associated with gain of function mutations in SOD1 make 'knock-down' strategies an attractive therapeutic approach. Tofersen, an antisense oligonucleotide that reduces expression of SOD1 via RNAase mediated degradation of SOD1 mRNA, has shown robust effects on ALS biomarkers. While a Phase III trial of tofersen failed to meet its primary end point, open label extension data suggests that tofersen slows progression of SOD1 ALS.}, } @article {pmid39332091, year = {2024}, author = {Sharma, O and Kaur Grewal, A and Khan, H and Gurjeet Singh, T}, title = {Exploring the nexus of cGAS STING pathway in neurodegenerative terrain: A therapeutic odyssey.}, journal = {International immunopharmacology}, volume = {142}, number = {Pt B}, pages = {113205}, doi = {10.1016/j.intimp.2024.113205}, pmid = {39332091}, issn = {1878-1705}, mesh = {Humans ; *Membrane Proteins/metabolism/genetics ; Animals ; *Neurodegenerative Diseases/drug therapy/immunology/metabolism ; *Nucleotidyltransferases/metabolism/genetics ; *Signal Transduction ; Immunity, Innate ; STING Protein ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; }, abstract = {By detecting and responding to cytosolic DNA, the cGAS STING pathway regulates the innate immune responses bymediatinginflammatory reactions and antiviral defense. Thederegulation and modification of this system have been linked to variousneurodegenerative diseases like AD, PD and ALS. Accumulation of tau protein and Aβ aggregates to activate the pathway and releases neuroinflammatory cytokines which accelerates neuronal dysfunction and cognitive impairment as the symptom of AD. Similarly, in PD Alpha-synuclein aggregates activate the cGAS STING pathway and regulate the neuroinflammation and oxidative stress. In ALS, mutation of the genes causes the activation of the pathway which leads to motor neuron degeneration. Alteration of the cGAS STING pathway also leads to mitochondrial dysfunction and impaired autophagy. Preclinical investigations of AD, PD, and ALS animal models showed that STING pathway inhibitors reduced inflammation and improved neurological outcomes and modulators of the cGAS STING pathway may treat these neurodegenerative disorders. In this review we focus on the fact thatneuroinflammation, neuronal dysfunction, and various disease progressions can be treated byaltering the cGAS STING pathway. Understanding the processes and creating specific interventions for this route may offer new treatments for these terrible illnesses.}, } @article {pmid39333504, year = {2024}, author = {Cozzi, M and Magri, S and Tedesco, B and Patelli, G and Ferrari, V and Casarotto, E and Chierichetti, M and Pramaggiore, P and Cornaggia, L and Piccolella, M and Galbiati, M and Rusmini, P and Crippa, V and Mandrioli, J and Pareyson, D and Pisciotta, C and D'Arrigo, S and Ratti, A and Nanetti, L and Mariotti, C and Sarto, E and Pensato, V and Gellera, C and Di Bella, D and Cristofani, RM and Taroni, F and Poletti, A}, title = {Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders.}, journal = {Cell death & disease}, volume = {15}, number = {9}, pages = {692}, pmid = {39333504}, issn = {2041-4889}, support = {GGP19128//Fondazione Telethon (Telethon Foundation)/ ; 23236//AFM-Téléthon (French Muscular Dystrophy Association)/ ; PRIN n. 2022EFLFL8//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN n. P2022B5J32//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; Scientific Exchange Grant n. 9643//European Molecular Biology Organization (EMBO)/ ; 2021-1544//Fondazione Cariplo (Cariplo Foundation)/ ; 2021-1544//Fondazione Cariplo (Cariplo Foundation)/ ; RF-2018-12367768//Ministero della Salute (Ministry of Health, Italy)/ ; RRC 2023//Ministero della Salute (Ministry of Health, Italy)/ ; }, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Charcot-Marie-Tooth Disease/genetics/metabolism/pathology ; *Kinesins/metabolism/genetics ; Mitochondria/metabolism/genetics ; *Mutation/genetics ; Neurodegenerative Diseases/genetics/metabolism/pathology ; *Neurodevelopmental Disorders/genetics/metabolism/pathology ; }, abstract = {Mutations targeting distinct domains of the neuron-specific kinesin KIF5A associate with different neurodegenerative/neurodevelopmental disorders, but the molecular bases of this clinical heterogeneity are unknown. We characterised five key mutants covering the whole spectrum of KIF5A-related phenotypes: spastic paraplegia (SPG, R17Q and R280C), Charcot-Marie-Tooth disease (CMT, R864*), amyotrophic lateral sclerosis (ALS, N999Vfs*40), and neonatal intractable myoclonus (NEIMY, C975Vfs*73) KIF5A mutants. CMT-R864*-KIF5A and ALS-N999Vfs*40-KIF5A showed impaired autoinhibition and peripheral localisation accompanied by altered mitochondrial distribution, suggesting transport competence disruption. ALS-N999Vfs*40-KIF5A formed SQSTM1/p62-positive inclusions sequestering WT-KIF5A, indicating a gain of toxic function. SPG-R17Q-KIF5A and ALS-N999Vfs*40-KIF5A evidenced a shorter half-life compared to WT-KIF5A, and proteasomal blockage determined their accumulation into detergent-insoluble inclusions. Interestingly, SPG-R280C-KIF5A and ALS-N999Vfs*40-KIF5A both competed for degradation with proteasomal substrates. Finally, NEIMY-C975Vfs*73-KIF5A displayed a similar, but more severe aberrant behaviour compared to ALS-N999Vfs*40-KIF5A; these two mutants share an abnormal tail but cause disorders on the opposite end of KIF5A-linked phenotypic spectrum. Thus, our observations support the pathogenicity of novel KIF5A mutants, highlight abnormalities of recurrent variants, and demonstrate that both unique and shared mechanisms underpin KIF5A-related diseases.}, } @article {pmid39334720, year = {2024}, author = {Munteanu, C and Galaction, AI and Turnea, M and Blendea, CD and Rotariu, M and Poștaru, M}, title = {Redox Homeostasis, Gut Microbiota, and Epigenetics in Neurodegenerative Diseases: A Systematic Review.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {39334720}, issn = {2076-3921}, abstract = {Neurodegenerative diseases encompass a spectrum of disorders marked by the progressive degeneration of the structure and function of the nervous system. These conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS), often lead to severe cognitive and motor deficits. A critical component of neurodegenerative disease pathologies is the imbalance between pro-oxidant and antioxidant mechanisms, culminating in oxidative stress. The brain's high oxygen consumption and lipid-rich environment make it particularly vulnerable to oxidative damage. Pro-oxidants such as reactive nitrogen species (RNS) and reactive oxygen species (ROS) are continuously generated during normal metabolism, counteracted by enzymatic and non-enzymatic antioxidant defenses. In neurodegenerative diseases, this balance is disrupted, leading to neuronal damage. This systematic review explores the roles of oxidative stress, gut microbiota, and epigenetic modifications in neurodegenerative diseases, aiming to elucidate the interplay between these factors and identify potential therapeutic strategies. We conducted a comprehensive search of articles published in 2024 across major databases, focusing on studies examining the relationships between redox homeostasis, gut microbiota, and epigenetic changes in neurodegeneration. A total of 161 studies were included, comprising clinical trials, observational studies, and experimental research. Our findings reveal that oxidative stress plays a central role in the pathogenesis of neurodegenerative diseases, with gut microbiota composition and epigenetic modifications significantly influencing redox balance. Specific bacterial taxa and epigenetic markers were identified as potential modulators of oxidative stress, suggesting novel avenues for therapeutic intervention. Moreover, recent evidence from human and animal studies supports the emerging concept of targeting redox homeostasis through microbiota and epigenetic therapies. Future research should focus on validating these targets in clinical settings and exploring the potential for personalized medicine strategies based on individual microbiota and epigenetic profiles.}, } @article {pmid39334843, year = {2024}, author = {Lucchi, C and Simonini, C and Rustichelli, C and Avallone, R and Zucchi, E and Martinelli, I and Biagini, G and Mandrioli, J}, title = {Reduced Levels of Neurosteroids in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients.}, journal = {Biomolecules}, volume = {14}, number = {9}, pages = {}, pmid = {39334843}, issn = {2218-273X}, support = {Ricerca Finalizzata bando 2021 (RF-2021-12373036)//Ministero della Salute/ ; bando FAR 2021, Progetti di ricerca Interdisciplinari Mission Oriented, NEURALS project//University of Modena and Reggio Emilia/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/cerebrospinal fluid ; Humans ; Middle Aged ; Male ; Female ; *Neurosteroids/cerebrospinal fluid ; Case-Control Studies ; Aged ; Biomarkers/cerebrospinal fluid ; Pregnanolone/cerebrospinal fluid ; Adult ; Pregnenolone/cerebrospinal fluid ; Progesterone/cerebrospinal fluid ; Testosterone/cerebrospinal fluid ; Chromatography, Liquid ; Tandem Mass Spectrometry ; }, abstract = {Produced by the mitochondria and endoplasmic reticulum, neurosteroids such as allopregnanolone are neuroprotective molecules that influence various neuronal functions and regulate neuroinflammation. They are reduced in neurodegenerative diseases, while in the Wobbler mouse model, allopregnanolone and its precursor progesterone showed protective effects on motor neuron degeneration. This single-center case-control study included 37 patients with amyotrophic lateral sclerosis (ALS) and 28 healthy controls. Cerebrospinal fluid (CSF) neurosteroid levels were quantified using liquid chromatography-electrospray tandem mass spectrometry and compared between the two cohorts. Neurosteroid concentrations have been correlated with neuroinflammation and neurodegeneration biomarkers detected through an automated immunoassay, along with disease features and progression. Pregnenolone, progesterone, allopregnanolone, pregnanolone, and testosterone levels were significantly lower in ALS patients' CSF compared to healthy controls. A significant inverse correlation was found between neurofilament and neurosteroid levels. Neurosteroid concentrations did not correlate with disease progression, phenotype, genotype, or survival prediction. Our study suggests the independence of the disease features and its progression, from the dysregulation of neurosteroids in ALS patients' CSF. This neurosteroid reduction may relate to disease pathogenesis or be a consequence of disease-related processes, warranting further research. The inverse correlation between neurosteroids and neurofilament levels may indicate a failure of compensatory neuroprotective mechanisms against neurodegeneration.}, } @article {pmid39334855, year = {2024}, author = {Hasan, A and Staveley, BE}, title = {Bcl-2 Orthologues, Buffy and Debcl, Can Suppress Drp1-Dependent Age-Related Phenotypes in Drosophila.}, journal = {Biomolecules}, volume = {14}, number = {9}, pages = {}, pmid = {39334855}, issn = {2218-273X}, support = {RGPIN-2016-04828//Natural Sciences and Engineering Research Council/ ; }, mesh = {Animals ; *Aging/genetics/metabolism ; Cytoskeletal Proteins ; *Drosophila melanogaster/genetics/metabolism ; *Drosophila Proteins/metabolism/genetics ; Dynamins/genetics/metabolism ; GTP-Binding Proteins ; Longevity/genetics ; Mitochondrial Proteins/genetics/metabolism ; Phenotype ; *Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; *Membrane Proteins/metabolism ; }, abstract = {The relationship of Amyotrophic Lateral Sclerosis, Parkinson's disease, and other age-related neurodegenerative diseases with mitochondrial dysfunction has led to our study of the mitochondrial fission gene Drp1 in Drosophila melanogaster and aspects of aging. Previously, the Drp1 protein has been demonstrated to interact with the Drosophila Bcl-2 mitochondrial proteins, and Drp1 mutations can lead to mitochondrial dysfunction and neuronal loss. In this study, the Dopa decarboxylase-Gal4 (Ddc-Gal4) transgene was exploited to direct the expression of Drp1 and Drp1-RNAi transgenes in select neurons. Here, the knockdown of Drp1 seems to compromise locomotor function throughout life but does not alter longevity. The co-expression of Buffy suppresses the poor climbing induced by the knockdown of the Drp1 function. The consequences of Drp1 overexpression, which specifically reduced median lifespan and diminished climbing abilities over time, can be suppressed through the directed co-overexpression of pro-survival Bcl-2 gene Buffy or by the co-knockdown of the pro-cell death Bcl-2 homologue Debcl. Alteration of the expression of Drp1 acts to phenocopy neurodegenerative disease phenotypes in Drosophila, while overexpression of Buffy can counteract or rescue these phenotypes to improve overall health. The diminished healthy aging due to either the overexpression of Drp1 or the RNA interference of Drp1 has produced novel Drosophila models for investigating mechanisms underlying neurodegenerative disease.}, } @article {pmid39335395, year = {2024}, author = {Ore, A and Angelastro, JM and Giulivi, C}, title = {Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases.}, journal = {Brain sciences}, volume = {14}, number = {9}, pages = {}, pmid = {39335395}, issn = {2076-3425}, support = {R21 NS128751/NS/NINDS NIH HHS/United States ; }, abstract = {The role of mitochondria in neurodegenerative diseases is crucial, and recent developments have highlighted its significance in cell therapy. Mitochondrial dysfunction has been implicated in various neurodegenerative disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases. Understanding the impact of mitochondrial biology on these conditions can provide valuable insights for developing targeted cell therapies. This mini-review refocuses on mitochondria and emphasizes the potential of therapies leveraging mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, stem cell-derived secretions, and extracellular vesicles. Mesenchymal stem cell-mediated mitochondria transfer is highlighted for restoring mitochondrial health in cells with dysfunctional mitochondria. Additionally, attention is paid to gene-editing techniques such as mito-CRISPR, mitoTALENs, mito-ZNFs, and DdCBEs to ensure the safety and efficacy of stem cell treatments. Challenges and future directions are also discussed, including the possible tumorigenic effects of stem cells, off-target effects, disease targeting, immune rejection, and ethical issues.}, } @article {pmid39335582, year = {2024}, author = {Carata, E and Muci, M and Mariano, S and Panzarini, E}, title = {BV2 Microglial Cell Activation/Polarization Is Influenced by Extracellular Vesicles Released from Mutated SOD1 NSC-34 Motoneuron-like Cells.}, journal = {Biomedicines}, volume = {12}, number = {9}, pages = {}, pmid = {39335582}, issn = {2227-9059}, abstract = {Microglia-mediated neuroinflammation is a key player in the pathogenesis of amyotrophic lateral sclerosis (ALS) as it can contribute to the progressive degeneration of motor neurons (MNs). Here, we investigated the role of mSOD1 NSC-34 MN-like cell-derived extracellular vesicles (EVs) in inducing the activation of BV2 microglial cells. NSC-34-released EVs were isolated by culture medium differential ultracentrifugation to obtain two fractions, one containing small EVs (diameter < 200 nm) and the other containing large EVs (diameter > 200 nm). BV2 cells were incubated with the two EV fractions for 12, 24, and 48 h to evaluate 1) the state of microglial inflammation through RT-PCR of IL-1β, IL-6, IL-4, and IL-10 and 2) the expression of proteins involved in inflammasome activation (IL-β and caspase 1), cell death (caspase 3), and glial cell recruitment (CXCR1), and presence of the TGFβ cytokine receptor (TGFβ-R2). The obtained results suggest a mSOD1 type-dependent polarization of BV2 cells towards an early neurotoxic phenotype and a late neuroprotective status, with an appearance of mixed M1 and M2 microglia subpopulations. A significant role in driving microglial cell activation is played by the TGFβ/CX3CR1 axis. Therefore, targeting the dysregulated microglial response and modulating neuroinflammation could hold promise as a therapeutic strategy for ALS.}, } @article {pmid39335997, year = {2024}, author = {Dork, J and Mangan, E and Burns, L and Dimenstein, E}, title = {Affective Instability: Impact of Fluctuating Emotions on Regulation and Psychological Well-Being.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {14}, number = {9}, pages = {}, pmid = {39335997}, issn = {2076-328X}, abstract = {Previous research has focused on understanding the occurrence of intense and fluctuating emotions and the ability to manage these emotions and affective states. These phenomena have been, respectively, labeled as affective instability and emotion regulation and have been studied among individuals diagnosed with borderline personality disorder (BPD), attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), and post-traumatic stress disorder (PTSD). Previous findings suggest that affective instability may be associated with poorer psychological well-being. The present study aims to investigate the general tendency of affective instability and capacity for emotional regulation among college students, regardless of a previous psychological diagnosis, and to understand the relationship between these processes and psychological well-being. Three questionnaires were administered to measure levels of affective instability, the ability to manage fluctuating affective states, and overall psychological well-being. The findings suggest that (1) individuals with diagnoses experience affective lability and difficulty regulating emotions at a greater rate than those without, (2) higher affective lability scores are consistent with more significant emotion dysregulation and lower overall psychological well-being, and (3) scores on the Affective lability Scale (ALS) and the Difficulties in Emotional Regulation Scale (DERS) are reliable predictors of one's estimated Global Assessment of Functioning (GAF) scores. Although causation has not been established, the evidence suggests that individuals with diagnoses experience greater difficulty in regulating their emotions, have greater affective lability, and experience diminished psychological well-being and day-to-day functionality. Certain anecdotal evidence suggests that emotional lability can be endogenous and affect multiple aspects of an individual's social, occupational, and personal life. By revising the existing literature and the present findings, the authors provide insights into the significance of endogenous factors in the context of affective lability and offer suggestions for future research.}, } @article {pmid39336146, year = {2024}, author = {Duranti, E and Villa, C}, title = {From Brain to Muscle: The Role of Muscle Tissue in Neurodegenerative Disorders.}, journal = {Biology}, volume = {13}, number = {9}, pages = {}, pmid = {39336146}, issn = {2079-7737}, abstract = {Neurodegenerative diseases (NDs), like amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), primarily affect the central nervous system, leading to progressive neuronal loss and motor and cognitive dysfunction. However, recent studies have revealed that muscle tissue also plays a significant role in these diseases. ALS is characterized by severe muscle wasting as a result of motor neuron degeneration, as well as alterations in gene expression, protein aggregation, and oxidative stress. Muscle atrophy and mitochondrial dysfunction are also observed in AD, which may exacerbate cognitive decline due to systemic metabolic dysregulation. PD patients exhibit muscle fiber atrophy, altered muscle composition, and α-synuclein aggregation within muscle cells, contributing to motor symptoms and disease progression. Systemic inflammation and impaired protein degradation pathways are common among these disorders, highlighting muscle tissue as a key player in disease progression. Understanding these muscle-related changes offers potential therapeutic avenues, such as targeting mitochondrial function, reducing inflammation, and promoting muscle regeneration with exercise and pharmacological interventions. This review emphasizes the importance of considering an integrative approach to neurodegenerative disease research, considering both central and peripheral pathological mechanisms, in order to develop more effective treatments and improve patient outcomes.}, } @article {pmid39336748, year = {2024}, author = {Chami, AA and Bedja-Iacona, L and Richard, E and Lanznaster, D and Marouillat, S and Veyrat-Durebex, C and Andres, CR and Corcia, P and Blasco, H and Vourc'h, P}, title = {N-Terminal Fragments of TDP-43-In Vitro Analysis and Implication in the Pathophysiology of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.}, journal = {Genes}, volume = {15}, number = {9}, pages = {}, pmid = {39336748}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; HEK293 Cells ; Protein Domains ; Cell Survival/genetics ; }, abstract = {Abnormal cytoplasmic aggregates containing the TDP-43 protein and its fragments are present in the central nervous system of the majority of patients with amyotrophic lateral sclerosis (ALS) and in patients with frontotemporal lobar degeneration (FTLD). Many studies have focused on the C-terminal cleavage products of TDP-43 (CTFs), but few have focused on the N-terminal products (NTFs), yet several works and their protein domain composition support the involvement of NTFs in pathophysiology. In the present study, we expressed six NTFs of TDP-43, normally generated in vivo by proteases or following the presence of pathogenic genetic truncating variants, in HEK-293T cells. The N-terminal domain (NTD) alone was not sufficient to produce aggregates. Fragments containing the NTD and all or part of the RRM1 domain produced nuclear aggregates without affecting cell viability. Only large fragments also containing the RRM2 domain, with or without the glycine-rich domain, produced cytoplasmic aggregates. Of these, only NTFs containing even a very short portion of the glycine-rich domain caused a reduction in cell viability. Our results provide insights into the involvement of different TDP-43 domains in the formation of nuclear or cytoplasmic aggregates and support the idea that work on the development of therapeutic molecules targeting TDP-43 must also take into account NTFs and, in particular, those containing even a small part of the glycine-rich domain.}, } @article {pmid39336788, year = {2024}, author = {Tourtourikov, I and Todorov, T and Angelov, T and Chamova, T and Tournev, I and Mitev, V and Todorova, A}, title = {Genetic Modifiers of ALS: The Impact of Chromogranin B P413L in a Bulgarian ALS Cohort.}, journal = {Genes}, volume = {15}, number = {9}, pages = {}, pmid = {39336788}, issn = {2073-4425}, support = {Grant No. D-148/ 03.08.2023//Medical University of Sofia/ ; National Recovery and Resilience Plan of the Republic of Bulgaria, project № BG-RRP-2.004-0004-C01//European Union-NextGenerationEU/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Bulgaria ; Middle Aged ; Aged ; Adult ; *Genetic Predisposition to Disease ; *Chromogranin B/genetics ; Age of Onset ; Alleles ; Genotype ; Polymorphism, Single Nucleotide ; Cohort Studies ; Gene Frequency ; Kaplan-Meier Estimate ; }, abstract = {This study investigated the role of the CHGB P413L variant (rs742710) in sporadic amyotrophic lateral sclerosis (sALS) within the Bulgarian population. We analyzed 150 patients with sALS (85 male and 65 female) for the presence of this variant, its potential impact on disease susceptibility, and age of onset. Genotyping was performed using PCR amplification and direct Sanger sequencing. Statistical analyses included comparisons with control data from GnomAD v2.1.1, one-way ANOVA, and Kaplan-Meier survival analysis. Results revealed a higher frequency of the minor T allele in patients with sALS compared to all control groups and a statistically significant increase in carrier genotypes compared to non-Finnish Europeans (χ[2] = 15.4572, p = 0.000440). However, the impact on age of onset was less clear, with no statistically significant differences observed across genotypes or between carriers and non-carriers of the T allele. Kaplan-Meier analysis suggested a potential 2.5-year-earlier onset in T allele carriers, but the small sample size of carriers limits the reliability of this finding. Our study provides evidence for an association between the CHGB P413L variant and sALS susceptibility in the Bulgarian population, while its effect on age of onset remains uncertain, highlighting the need for further research in larger, diverse cohorts.}, } @article {pmid39337251, year = {2024}, author = {Escudier, O and Zhang, Y and Whiting, A and Chazot, P}, title = {Evaluation of a Synthetic Retinoid, Ellorarxine, in the NSC-34 Cell Model of Motor Neuron Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337251}, issn = {1422-0067}, mesh = {Animals ; Mice ; *Neuroprotective Agents/pharmacology ; Retinoids/pharmacology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Cell Line ; Humans ; Receptors, AMPA/metabolism ; Motor Neurons/drug effects/metabolism/pathology ; Benzoates/pharmacology ; Motor Neuron Disease/drug therapy/metabolism/pathology ; Calcium/metabolism ; Neurites/drug effects/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease worldwide and is characterized by progressive muscle atrophy. There are currently two approved treatments, but they only relieve symptoms briefly and do not cure the disease. The main hindrance to research is the complex cause of ALS, with its pathogenesis not yet fully elucidated. Retinoids (vitamin A derivatives) appear to be essential in neuronal cells and have been implicated in ALS pathogenesis. This study explores 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)ethylnyl]benzoic acid (Ellorarxine, or DC645 or NVG0645), a leading synthetic retinoic acid, discussing its pharmacological mechanisms, neuroprotective properties, and relevance to ALS. The potential therapeutic effect of Ellorarxine was analyzed in vitro using the WT and SOD1G93A NSC-34 cell model of ALS at an administered concentration of 0.3-30 nM. Histological, functional, and biochemical analyses were performed. Elorarxine significantly increased MAP2 expression and neurite length, increased AMPA receptor GluA2 expression and raised intracellular Ca[2+] baseline, increased level of excitability, and reduced Ca[2+] spike during depolarization in neurites. Ellorarxine also displayed both antioxidant and anti-inflammatory effects. Overall, these results suggest Ellorarxine shows relevance and promise as a novel therapeutic strategy for treatment of ALS.}, } @article {pmid39337436, year = {2024}, author = {Guo, D and Liu, Z and Zhou, J and Ke, C and Li, D}, title = {Significance of Programmed Cell Death Pathways in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337436}, issn = {1422-0067}, support = {2023Y9415//Joint Funds for the innovation of science and Technology, Fujian province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Signal Transduction ; Animals ; *Apoptosis ; Ferroptosis ; Neurons/metabolism/pathology ; }, abstract = {Programmed cell death (PCD) is a form of cell death distinct from accidental cell death (ACD) and is also referred to as regulated cell death (RCD). Typically, PCD signaling events are precisely regulated by various biomolecules in both spatial and temporal contexts to promote neuronal development, establish neural architecture, and shape the central nervous system (CNS), although the role of PCD extends beyond the CNS. Abnormalities in PCD signaling cascades contribute to the irreversible loss of neuronal cells and function, leading to the onset and progression of neurodegenerative diseases. In this review, we summarize the molecular processes and features of different modalities of PCD, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, and other novel forms of PCD, and their effects on the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), multiple sclerosis (MS), traumatic brain injury (TBI), and stroke. Additionally, we examine the key factors involved in these PCD signaling pathways and discuss the potential for their development as therapeutic targets and strategies. Therefore, therapeutic strategies targeting the inhibition or facilitation of PCD signaling pathways offer a promising approach for clinical applications in treating neurodegenerative diseases.}, } @article {pmid39337454, year = {2024}, author = {Rizea, RE and Corlatescu, AD and Costin, HP and Dumitru, A and Ciurea, AV}, title = {Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337454}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis/physiopathology/metabolism/genetics ; Humans ; Biomarkers ; Genetic Therapy/methods ; Oxidative Stress ; Animals ; Mitochondria/metabolism ; }, abstract = {This review offers an in-depth examination of amyotrophic lateral sclerosis (ALS), addressing its epidemiology, pathophysiology, clinical presentation, diagnostic techniques, and current as well as emerging treatments. The purpose is to condense key findings and illustrate the complexity of ALS, which is shaped by both genetic and environmental influences. We reviewed the literature to discuss recent advancements in understanding molecular mechanisms such as protein misfolding, mitochondrial dysfunction, oxidative stress, and axonal transport defects, which are critical for identifying potential therapeutic targets. Significant progress has been made in refining diagnostic criteria and identifying biomarkers, leading to earlier and more precise diagnoses. Although current drug treatments provide some benefits, there is a clear need for more effective therapies. Emerging treatments, such as gene therapy and stem cell therapy, show potential in modifying disease progression and improving the quality of life for ALS patients. The review emphasizes the importance of continued research to address challenges such as disease variability and the limited effectiveness of existing treatments. Future research should concentrate on further exploring the molecular foundations of ALS and developing new therapeutic approaches. The implications for clinical practice include ensuring the accessibility of new treatments and that healthcare systems are equipped to support ongoing research and patient care.}, } @article {pmid39337560, year = {2024}, author = {Malaguarnera, M and Cabrera-Pastor, A}, title = {Emerging Role of Extracellular Vesicles as Biomarkers in Neurodegenerative Diseases and Their Clinical and Therapeutic Potential in Central Nervous System Pathologies.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337560}, issn = {1422-0067}, support = {PI23/00204//Instituto de Salud Carlos III (ISCIII) through the project "PI23/00204" and co-funded by the European Union; and Conselleria de Educación/Innovación, Universidades, Ciencia y Sociedad Digital, subvenciones para la realización de proyectos de I+D+i desarro/ ; CIGE/083//This research was funded by Instituto de Salud Carlos III (ISCIII) through the project "PI23/00204" and co-funded by the European Union; and Conselleria de Educación/Innovación, Universidades, Ciencia y Sociedad Digital, subvenciones para la realización d/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/therapy/metabolism/diagnosis ; Animals ; Central Nervous System Diseases/metabolism/therapy/diagnosis ; Blood-Brain Barrier/metabolism ; }, abstract = {The emerging role of extracellular vesicles (EVs) in central nervous system (CNS) diseases is gaining significant interest, particularly their applications as diagnostic biomarkers and therapeutic agents. EVs are involved in intercellular communication and are secreted by all cell types. They contain specific markers and a diverse cargo such as proteins, lipids, and nucleic acids, reflecting the physiological and pathological state of their originating cells. Their reduced immunogenicity and ability to cross the blood-brain barrier make them promising candidates for both biomarkers and therapeutic agents. In the context of CNS diseases, EVs have shown promise as biomarkers isolable from different body fluids, providing a non-invasive method for diagnosing CNS diseases and monitoring disease progression. This makes them useful for the early detection and monitoring of diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, where specific alterations in EVs content can be detected. Additionally, EVs derived from stem cells show potential in promoting tissue regeneration and repairing damaged tissues. An evaluation has been conducted on the current clinical trials studying EVs for CNS diseases, focusing on their application, treatment protocols, and obtained results. This review aims to explore the potential of EVs as diagnostic markers and therapeutic carriers for CNS diseases, highlighting their significant advantages and ongoing clinical trials evaluating their efficacy.}, } @article {pmid39337696, year = {2024}, author = {Niazi, SK}, title = {Bioavailability as Proof to Authorize the Clinical Testing of Neurodegenerative Drugs-Protocols and Advice for the FDA to Meet the ALS Act Vision.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337696}, issn = {1422-0067}, mesh = {Humans ; *United States Food and Drug Administration ; United States ; *Drug Approval ; *Biological Availability ; *Amyotrophic Lateral Sclerosis/drug therapy ; Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; Clinical Trials as Topic ; }, abstract = {Although decades of intensive drug discovery efforts to treat neurodegenerative disorders (NDs) have failed, around half a million patients in more than 2000 studies continue being tested, costing over USD 100 billion, despite the conclusion that even those drugs which have been approved have no better effect than a placebo. The US Food and Drug Administration (FDA) has established multiple programs to innovate the treatment of rare diseases, particularly NDs, providing millions of USD in funding primarily by encouraging novel clinical trials to account for issues related to study sizes and adopting multi-arm studies to account for patient dropouts. Instead, the FDA should focus on the primary reason for failure: the poor bioavailability of drugs reaching the brain (generally 0.1% at most) due to the blood-brain barrier (BBB). There are several solutions to enhance entry into the brain, and the FDA must require proof of significant entry into the brain as the prerequisite to approving Investigational New Drug (IND) applications. The FDA should also rely on factors other than biomarkers to confirm efficacy, as these are rarely relevant to clinical use. This study summarizes how the drugs used to treat NDs can be made effective and how the FDA should change its guidelines for IND approval of these drugs.}, } @article {pmid39337908, year = {2024}, author = {Wang, R and Chen, L and Zhang, Y and Sun, B and Liang, M}, title = {Expression Changes of miRNAs in Humans and Animal Models of Amyotrophic Lateral Sclerosis and Their Potential Application for Clinical Diagnosis.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {9}, pages = {}, pmid = {39337908}, issn = {2075-1729}, support = {YJXJ-JZ-2021-0014//Scientific Research Project of Beijing Yicheng Cooperative Development Foundation in 2021-Public welfare projects of rare disease related topics/ ; KM202310858001//R&D Program of Beijing Municipal Education Commission/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease. Current detection methods can only confirm the diagnosis at the onset of the disease, missing the critical window for early treatment. Recent studies using animal models have found that detecting changes in miRNA sites can predict the onset and severity of the disease in its early stages, facilitating early diagnosis and treatment. miRNAs show expression changes in motor neurons that connect the brain, spinal cord, and brain stem, as well as in the skeletal muscle in mouse models of ALS. Clinically, expression changes in some miRNAs in patients align with those in mouse models, such as the upregulation of miR-29b in the brain and the upregulation of miR-206 in the skeletal muscle. This study provides an overview of some miRNA study findings in humans as well as in animal models, including SOD1, FUS, TDP-43, and C9orf72 transgenic mice and wobbler mice, highlighting the potential of miRNAs as diagnostic markers for ALS. miR-21 and miR-206 are aberrantly expressed in both mouse model and patient samples, positioning them as key potential diagnostic markers in ALS. Additionally, miR-29a, miR-29b, miR-181a, and miR-142-3p have shown aberrant expression in both types of samples and show promise as clinical targets for ALS. Finally, miR-1197 and miR-486b-5p have been recently identified as aberrantly expressed miRNAs in mouse models for ALS, although further studies are needed to determine their viability as diagnostic targets.}, } @article {pmid39338563, year = {2024}, author = {Dow, CT and Pierce, ES and Sechi, LA}, title = {Mycobacterium paratuberculosis: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?.}, journal = {Microorganisms}, volume = {12}, number = {9}, pages = {}, pmid = {39338563}, issn = {2076-2607}, abstract = {Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV-promoting pathological conditions, including the development of autoimmunity, neurodegenerative disease and cancer. What infections trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases, Crohn's disease, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA) and autoimmune thyroiditis. MAP is also associated with Alzheimer's disease (AD) and Parkinson's disease (PD). Autoimmune diabetes, MS and RA are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation, including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via the un-silencing of HERV. We examine the link between the ever-increasing number of MAP-associated diseases and the MAP/HERV intersection with these diverse medical conditions, and propose treatment opportunities based upon this association.}, } @article {pmid39338620, year = {2024}, author = {Razzaq, Z and Brahimi, N and Rehman, HZU and Khan, ZH}, title = {Intelligent Control System for Brain-Controlled Mobile Robot Using Self-Learning Neuro-Fuzzy Approach.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {18}, pages = {}, pmid = {39338620}, issn = {1424-8220}, mesh = {*Fuzzy Logic ; *Robotics/methods ; Humans ; *Brain-Computer Interfaces ; *Electroencephalography/methods ; Algorithms ; Brain/physiology ; Neural Networks, Computer ; Machine Learning ; }, abstract = {Brain-computer interface (BCI) provides direct communication and control between the human brain and physical devices. It is achieved by converting EEG signals into control commands. Such interfaces have significantly improved the lives of disabled individuals suffering from neurological disorders-such as stroke, amyotrophic lateral sclerosis (ALS), and spinal cord injury-by extending their movement range and thereby promoting self-independence. Brain-controlled mobile robots, however, often face challenges in safety and control performance due to the inherent limitations of BCIs. This paper proposes a shared control scheme for brain-controlled mobile robots by utilizing fuzzy logic to enhance safety, control performance, and robustness. The proposed scheme is developed by combining a self-learning neuro-fuzzy (SLNF) controller with an obstacle avoidance controller (OAC). The SLNF controller robustly tracks the user's intentions, and the OAC ensures the safety of the mobile robot following the BCI commands. Furthermore, SLNF is a model-free controller that can learn as well as update its parameters online, diminishing the effect of disturbances. The experimental results prove the efficacy and robustness of the proposed SLNF controller including a higher task completion rate of 94.29% (compared to 79.29%, and 92.86% for Direct BCI and Fuzzy-PID, respectively), a shorter average task completion time of 85.31 s (compared to 92.01 s and 86.16 s for Direct BCI and Fuzzy-PID, respectively), and reduced settling time and overshoot.}, } @article {pmid39340290, year = {2025}, author = {Alves, I and Gromicho, M and Oliveira Santos, M and Pinto, S and de Carvalho, M}, title = {Assessing disease progression in ALS: prognostic subgroups and outliers.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {58-63}, doi = {10.1080/21678421.2024.2407412}, pmid = {39340290}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/mortality ; *Disease Progression ; Male ; Female ; Middle Aged ; Prognosis ; Aged ; Adult ; Cohort Studies ; }, abstract = {BACKGROUND: The rate of disease progression, measured by the decline of ALS Functional Rating Scale-Revised (ALSFRS-R) from symptom onset to diagnosis (ΔFS) is a well-established prognostic biomarker for predicting survival. Objectives: This study aims to categorize a large patient cohort based on the initial ΔFS and subsequently investigate survival deviations from the expected prognosis defined by ΔFS.

METHODS: 1056 ALS patients were stratified into three progression categories based on their ΔFS: slow progressors (below 25th percentile), intermediate progressors (between 25th and 75th percentiles), and fast progressors (above 75th percentile). Survival outcomes were classified as short survivors (<2 years), average survivors (2-5 years), and long survivors (>5 years). Clinical and demographic characteristics within each subgroup were then analyzed.

RESULTS: ΔFS stratification yielded cutoff values of <0.29, 0.29-1.03, and >1.03 points/month. Long survivors comprised 26% and 21% were short survivors. Six percent of the fast progressors had a life expectancy of more than 5 years, and none of the clinical and demographic characteristics analyzed could fully explain this discrepancy. Conversely, 13% of intermediate progressors lived less than 2 years, according to a short-diagnostic delay in these patients.

DISCUSSION: Our study reaffirms ΔFS as a prognostic biomarker for ALS. We disclosed outliers defying anticipated patterns. The observed shift in progression categories underscores the non-linear nature of disease progression. Genetic and unknown biological reasons may explain these deviations. Further research is needed to fully understand modulation of ALS survival.}, } @article {pmid39340452, year = {2024}, author = {Tchounwou, C and Jobanputra, AJ and Lasher, D and Fletcher, BJ and Jacinto, J and Bhaduri, A and Best, RL and Fisher, WS and Ewert, KK and Li, Y and Feinstein, SC and Safinya, CR}, title = {Mixtures of Intrinsically Disordered Neuronal Protein Tau and Anionic Liposomes Reveal Distinct Anionic Liposome-Tau Complexes Coexisting with Tau Liquid-Liquid Phase-Separated Coacervates.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {40}, number = {40}, pages = {21041-21051}, doi = {10.1021/acs.langmuir.4c02471}, pmid = {39340452}, issn = {1520-5827}, mesh = {*tau Proteins/chemistry/metabolism ; *Liposomes/chemistry ; *Anions/chemistry ; Humans ; Phosphatidylcholines/chemistry ; Phosphatidylserines/chemistry ; Phosphatidylglycerols/chemistry ; Intrinsically Disordered Proteins/chemistry ; }, abstract = {Tau, an intrinsically disordered neuronal protein and polyampholyte with an overall positive charge, is a microtubule (MT) associated protein that binds to anionic domains of MTs and suppresses their dynamic instability. Aberrant tau-MT interactions are implicated in Alzheimer's and other neurodegenerative diseases. Here, we studied the interactions between full-length human protein tau and other negatively charged binding substrates, as revealed by differential interference contrast (DIC) and fluorescence microscopy. As a binding substrate, we chose anionic liposomes (ALs) containing either 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS, -1e) or 1,2-dioleoyl-sn-glycero-3-phosphatidylglycerol (DOPG, -1e) mixed with zwitterionic 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) to mimic anionic plasma membranes of axons where tau resides. At low salt concentrations (0 to 10 mM KCl or NaCl) with minimal charge screening, reaction mixtures of tau and ALs resulted in the formation of distinct states of AL-tau complexes coexisting with liquid-liquid phase-separated tau self-coacervates arising from the polyampholytic nature of tau containing cationic and anionic domains. AL-tau complexes (i.e. tau-lipoplexes) exhibited distinct types of morphologies. This included large ∼20-30 μm tau-decorated giant vesicles with additional smaller liposomes with bound tau attached to the giant vesicles and tau-mediated finite-size assemblies of small liposomes. As the salt concentration was increased to near and above 150 mM for 1:1 electrolytes, AL-tau complexes remained stable, while tau self-coacervate droplets were found to dissolve, indicative of the breaking of (anionic/cationic) electrostatic bonds between tau chains due to increased charge screening. The findings are consistent with the hypothesis that distinct cationic domains of tau may interact with anionic lipid domains of the lumen-facing monolayer of the axon's plasma membrane, suggesting the possibility of transient yet robust interactions near relevant ionic strengths found in neurons.}, } @article {pmid39340541, year = {2024}, author = {Gagliardi, D and Rizzuti, M and Masrori, P and Saccomanno, D and Del Bo, R and Sali, L and Meneri, M and Scarcella, S and Milone, I and Hersmus, N and Ratti, A and Ticozzi, N and Silani, V and Poesen, K and Van Damme, P and Comi, GP and Corti, S and Verde, F}, title = {Exploiting the role of CSF NfL, CHIT1, and miR-181b as potential diagnostic and prognostic biomarkers for ALS.}, journal = {Journal of neurology}, volume = {271}, number = {12}, pages = {7557-7571}, pmid = {39340541}, issn = {1432-1459}, support = {RF-2018-12366357//Ministero della Salute/ ; RF-2021-12374238//Ministero della Salute/ ; GR-2016-02364373//Ministero della Salute/ ; Ricerca corrente//Ministero della Salute/ ; C1//VIB, KU Leuven/ ; 'Opening the Future' Fund//VIB, KU Leuven/ ; FWO-Vlaanderen//Fund for Scientific Research Flanders/ ; T003519N//TBM grant from FWO-Vlaanderen/ ; G077121N//FWO-Vlaanderen/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/genetics ; Female ; Male ; *Neurofilament Proteins/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Middle Aged ; *Hexosaminidases/cerebrospinal fluid ; Aged ; *MicroRNAs/cerebrospinal fluid ; Prognosis ; Adult ; Cohort Studies ; Disease Progression ; Aged, 80 and over ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder characterized by relentless and progressive loss of motor neurons. A molecular diagnosis, supported by the identification of specific biomarkers, might promote the definition of multiple biological subtypes of ALS, improving patient stratification and providing prognostic information. Here, we investigated the levels of neurofilament light chain (NfL), chitotriosidase (CHIT1) and microRNA-181b (miR-181b) in the cerebrospinal fluid (CSF) of ALS subjects (N = 210) as well as neurologically healthy and neurological disease controls (N = 218, including N = 74 with other neurodegenerative diseases) from a large European multicentric cohort, evaluating their specific or combined utility as diagnostic and prognostic biomarkers. NfL, CHIT1 and miR-181b all showed significantly higher levels in ALS subjects compared to controls, with NfL showing the most effective diagnostic performance. Importantly, all three biomarkers were increased compared to neurodegenerative disease controls and, specifically, to patients with Alzheimer's disease (AD; N = 44), with NfL and CHIT1 being also higher in ALS than in alpha-synucleinopathies (N = 22). Notably, ALS patients displayed increased CHIT1 levels despite having, compared to controls, a higher prevalence of a polymorphism lowering CHIT1 expression. While no relationship was found between CSF miR-181b and clinical measures in ALS (disease duration, functional disability, and disease progression rate), CSF NfL was the best independent predictor of disease progression and survival. This study deepens our knowledge of ALS biomarkers, highlighting the relative specificity of CHIT1 for ALS among neurodegenerative diseases and appraising the potential diagnostic utility of CSF miR-181b.}, } @article {pmid39340590, year = {2024}, author = {Ghiasvand, K and Amirfazli, M and Moghimi, P and Safari, F and Takhshid, MA}, title = {The role of neuron-like cell lines and primary neuron cell models in unraveling the complexity of neurodegenerative diseases: a comprehensive review.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {1024}, doi = {10.1007/s11033-024-09964-x}, pmid = {39340590}, issn = {1573-4978}, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Neurons/metabolism ; Animals ; Coculture Techniques/methods ; Cell Line ; Models, Biological ; Alzheimer Disease/pathology/genetics ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by the progressive loss of neurons. As to developing effective therapeutic interventions, it is crucial to understand the underlying mechanisms of NDs. Cellular models have become invaluable tools for studying the complex pathogenesis of NDs, offering insights into disease mechanisms, determining potential therapeutic targets, and aiding in drug discovery. This review provides a comprehensive overview of various cellular models used in ND research, focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Cell lines, such as SH-SY5Y and PC12 cells, have emerged as valuable tools due to their ease of use, reproducibility, and scalability. Additionally, co-culture models, involving the growth of distinct cell types like neurons and astrocytes together, are highlighted for simulating brain interactions and microenvironment. While cell lines cannot fully replicate the complexity of the human brain, they provide a scalable method for examining important aspects of neurodegenerative diseases. Advancements in cell line technologies, including the incorporation of patient-specific genetic variants and improved co-culture models, hold promise for enhancing our understanding and expediting the development of effective treatments. Integrating multiple cellular models and advanced technologies offers the potential for significant progress in unraveling the intricacies of these debilitating diseases and improving patient outcomes.}, } @article {pmid39340874, year = {2024}, author = {Xiong, Z and Zeng, Q and Hu, Y and Lai, C and Wu, H}, title = {Optineurin inhibits IBDV replication via interacting with VP1.}, journal = {Veterinary microbiology}, volume = {298}, number = {}, pages = {110261}, doi = {10.1016/j.vetmic.2024.110261}, pmid = {39340874}, issn = {1873-2542}, mesh = {*Virus Replication ; Animals ; *Infectious bursal disease virus/physiology ; *Chickens ; Membrane Transport Proteins/metabolism/genetics ; Cell Cycle Proteins/metabolism/genetics ; Poultry Diseases/virology ; Humans ; Ubiquitination ; Birnaviridae Infections/veterinary/virology ; Cell Line ; Capsid Proteins/metabolism/genetics ; Transcription Factor TFIIIA/metabolism/genetics ; HEK293 Cells ; }, abstract = {Avibirnavirus, specifically Infectious Bursal Disease Virus (IBDV), is a highly contagious pathogen that causes significant economic losses in the poultry industry. The polymerase protein VP1 of IBDV is critical to the viral life cycle, facilitating the synthesis of viral mRNA and the genome. Previous studies have suggested that various host factors influence the regulation of IBDV polymerase activity. In this study, we identified that IBDV infection induces the expression of optineurin (OPTN), a mitophagy receptor and a protein associated with amyotrophic lateral sclerosis (ALS), as well as a negative regulator of interferon I production. The induced expression of OPTN acts as a suppressor of IBDV replication, a function dependent on its ubiquitin-binding domain (UBAN). Furthermore, we demonstrated that OPTN exerts its antiviral effects through direct interactions with VP1 and VP3, which inhibit the polymerase activity of VP1 by preventing K63-linked ubiquitination of VP1. To our knowledge, this study is the first to report that OPTN, upregulated during IBDV infection, functions as a novel antiviral host factor that limits the virus's replicative capacity, offering a potential target for anti-IBDV therapeutic strategies.}, } @article {pmid39340928, year = {2024}, author = {Dahl, R and Bezprozvanny, I}, title = {SERCA pump as a novel therapeutic target for treating neurodegenerative disorders.}, journal = {Biochemical and biophysical research communications}, volume = {734}, number = {}, pages = {150748}, doi = {10.1016/j.bbrc.2024.150748}, pmid = {39340928}, issn = {1090-2104}, support = {R01 AG071310/AG/NIA NIH HHS/United States ; R56 AG078337/AG/NIA NIH HHS/United States ; R42 AG062001/AG/NIA NIH HHS/United States ; }, mesh = {*Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Humans ; Animals ; Disease Models, Animal ; Allosteric Regulation/drug effects ; Molecular Targeted Therapy/methods ; *Neuroprotective Agents/pharmacology/therapeutic use ; Calcium Signaling/drug effects ; Calcium/metabolism ; }, abstract = {The neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Spinocerebellar ataxias (SCAs), present an enormous medical, social, financial and scientific problem. Despite intense research into the causes of these disorders, only marginal progress has been made in the clinic and no cures exist for any of them. Most of the scientific effort has been focused on identification of the major causes of these diseases and on developing ways to target them, such as targeting amyloid accumulation for AD or targeting expression of mutant Huntingtin for HD. Calcium (Ca[2+]) signaling has long been proposed to play an important role in the pathogenesis of neurodegenerative disorders, but blockers of Ca[2+] channels and Ca[2+] signaling proteins have not been translated to clinic primarily due to side effects related to the important roles of target molecules for these compounds at the peripheral tissues. In this review article, we would like to discuss an idea that recently identified positive allosteric modulators (PAMs) of the sarco-endoplasmic reticulum calcium (SERCA) pump may provide a promising approach to develop therapeutic compounds for treatment of these disorders. This hypothesis is supported by the preclinical data obtained with animal models of AD and PD. The first critical test of this idea will be an imminent phase I study that will offer an opportunity to evaluate potential side effects of this class of compounds in humans.}, } @article {pmid39341507, year = {2024}, author = {Sivalingam, AM}, title = {Advances in understanding biomarkers and treating neurological diseases - Role of the cerebellar dysfunction and emerging therapies.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102519}, doi = {10.1016/j.arr.2024.102519}, pmid = {39341507}, issn = {1872-9649}, mesh = {Humans ; *Biomarkers/metabolism ; Animals ; *Cerebellar Diseases/therapy/diagnosis/metabolism/genetics ; Genetic Therapy/methods/trends ; Nervous System Diseases/therapy/diagnosis/metabolism ; Cerebellum/metabolism/pathology ; }, abstract = {Cerebellar dysfunction is increasingly recognized as a critical factor in various neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Research has revealed distinct cerebellar atrophy patterns in conditions such as AD and multiple system atrophy, and studies in mice have highlighted its impact on motor control and cognitive functions. Emerging research into autism spectrum disorder (ASD) has identified key targets, such as elevated levels of chemokine receptors and ZIC family genes. Biomarkers, including cerebrospinal fluid (CSF), genetic markers, and advances in AI and bioinformatics, are enhancing early diagnosis and personalized treatment across neurodegenerative disorders. Notable advancements include improved diagnostic tools, gene therapy, and novel clinical trials. Despite progress, challenges such as the bloodbrain barrier and neuroinflammation persist. Current therapies for AD, PD, HD, and ALS, including antisense oligonucleotides and stem cell treatments, show promise but require further investigation. A comprehensive approach that integrates diagnostic methods and innovative therapies is essential for effective management and improved patient outcomes.}, } @article {pmid39341656, year = {2024}, author = {Paris, A and Lakatos, A}, title = {Cell and gene therapy for amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {205}, number = {}, pages = {217-241}, doi = {10.1016/B978-0-323-90120-8.00017-4}, pmid = {39341656}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; *Genetic Therapy/methods ; Animals ; Cell- and Tissue-Based Therapy/methods/trends ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disorder with rapidly progressive skeletal muscle weakness, which can also cause a variable cognitive deficit. Genetic causes are only identified in approximately 10% of all cases, with complex genotype-phenotype associations, making it challenging to identify treatment targets. What further hampers therapeutic development is a broad heterogeneity in mechanisms, possible targets, and disturbances across various cell types, aside from the cortical and spinal motor neurons that lie at the heart of the pathology of ALS. Over the last decade, significant progress in biotechnologic techniques, cell and ribonucleic acid (RNA) engineering, animal models, and patient-specific human stem cell and organoid models have accelerated both mechanistic and therapeutic discoveries. The growing number of clinical trials mirrors this. This chapter reviews the current state of human preclinical models supporting trial strategies as well as recent clinical cell and gene therapy approaches.}, } @article {pmid39341837, year = {2024}, author = {Hollingworth, D and Thomas, F and Page, DA and Fouda, MA and De Castro, RL and Sula, A and Mykhaylyk, VB and Kelly, G and Ulmschneider, MB and Ruben, PC and Wallace, BA}, title = {Structural basis for the rescue of hyperexcitable cells by the amyotrophic lateral sclerosis drug Riluzole.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8426}, pmid = {39341837}, issn = {2041-1723}, support = {CC1078/WT_/Wellcome Trust/United Kingdom ; BB/105581//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; mutiple grants//Diamond Light Source/ ; BB/V0183511//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; CF2-100001//Rosetrees Trust/ ; BB/S017844//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; studentship//Wellcome Trust (Wellcome)/ ; }, mesh = {*Riluzole/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; Humans ; *Neuroprotective Agents/pharmacology ; Voltage-Gated Sodium Channels/metabolism/chemistry ; HEK293 Cells ; Animals ; Sodium/metabolism ; Motor Neurons/drug effects/metabolism ; }, abstract = {Neuronal hyperexcitability is a key element of many neurodegenerative disorders including the motor neuron disease Amyotrophic Lateral Sclerosis (ALS), where it occurs associated with elevated late sodium current (INaL). INaL results from incomplete inactivation of voltage-gated sodium channels (VGSCs) after their opening and shapes physiological membrane excitability. However, dysfunctional increases can cause hyperexcitability-associated diseases. Here we reveal the atypical binding mechanism which explains how the neuroprotective ALS-treatment drug riluzole stabilises VGSCs in their inactivated state to cause the suppression of INaL that leads to reversed cellular overexcitability. Riluzole accumulates in the membrane and enters VGSCs through openings to their membrane-accessible fenestrations. Riluzole binds within these fenestrations to stabilise the inactivated channel state, allowing for the selective allosteric inhibition of INaL without the physical block of Na[+] conduction associated with traditional channel pore binding VGSC drugs. We further demonstrate that riluzole can reproduce these effects on a disease variant of the non-neuronal VGSC isoform Nav1.4, where pathologically increased INaL is caused directly by mutation. Overall, we identify a model for VGSC inhibition that produces effects consistent with the inhibitory action of riluzole observed in models of ALS. Our findings will aid future drug design and supports research directed towards riluzole repurposing.}, } @article {pmid39342484, year = {2025}, author = {Deneubourg, C and Salimi Dafsari, H and Lowe, S and Martinez-Cotrina, A and Mazaud, D and Park, SH and Vergani, V and Almacellas Barbanoj, A and Maroofian, R and Averdunk, L and Ghayoor-Karimiani, E and Jayawant, S and Mignot, C and Keren, B and Peters, R and Kamath, A and Mattas, L and Verma, S and Silwal, A and Distelmaier, F and Houlden, H and Lignani, G and Antebi, A and Jepson, J and Jungbluth, H and Fanto, M}, title = {Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in Drosophila and Vici syndrome patients.}, journal = {Autophagy}, volume = {21}, number = {2}, pages = {447-459}, pmid = {39342484}, issn = {1554-8635}, mesh = {Animals ; *Autophagy/genetics ; Humans ; Drosophila melanogaster/metabolism ; *Drosophila Proteins/metabolism/genetics ; *Agenesis of Corpus Callosum/genetics/metabolism/pathology/physiopathology ; *Epilepsy/genetics/metabolism/pathology ; Autophagosomes/metabolism ; Mutation/genetics ; Seizures ; Proteotoxic Stress ; Autophagy-Related Proteins ; Vesicular Transport Proteins ; Cataract ; }, abstract = {Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 (EPG5) gene that is crucial for autophagosome-lysosome fusion and autophagic clearance. Here, we used Drosophila melanogaster to study the importance of Epg5 in development, aging, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with Drosophila predictions.Abbreviations: AD: Alzheimer's disease; ALS-FTD: Amyotrophic Lateral Sclerosis-FrontoTemoporal Dementia; DART: Drosophila Arousal Tracking; ECoG: electrocorticogram; EEG: electroencephalogram; EPG5: ectopic P-granules 5 autophagy tethering factor; KA: kainic acid; MBs: mushroom bodies; MRI magnetic resonance imaging; MTOR: mechanistic target of rapamycin kinase; PD: Parkinson's disease; TSC: TSC complex; VS: Vici syndrome.}, } @article {pmid39343443, year = {2024}, author = {O'Brien, D and Shaw, PJ}, title = {New developments in the diagnosis and management of motor neuron disease.}, journal = {British medical bulletin}, volume = {152}, number = {1}, pages = {4-15}, doi = {10.1093/bmb/ldae010}, pmid = {39343443}, issn = {1471-8391}, support = {NIHR 203321//NIHR Sheffield Biomedical Research Centre/ ; 972-797//AMBRoSIA Biosampling Programme/ ; 764-780//MNDA (Sheffield Care and Research Centre for Motor Neuron Disorders/ ; }, mesh = {Humans ; *Motor Neuron Disease/therapy/diagnosis ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {INTRODUCTION: Motor neuron disease (MND) is a devastating neurodegenerative disease characterized by progressive muscle weakness.

SOURCES OF DATA: PubMed, MEDLINE, and Cochrane databases were searched for articles to March 2024. Searches involved the terms 'motor neuron disease' or 'amyotrophic lateral sclerosis' and 'epidemiology', 'diagnosis', 'clinical', 'genetic', 'management', 'treatment', or 'trial'.

AREAS OF AGREEMENT: Evidence-based management involves riluzole, multidisciplinary care, provision of noninvasive ventilation and gastrostomy, and symptomatic treatments. Tofersen should be offered to treat SOD1-MND.

AREAS OF CONTROVERSY: Edaravone and Relyvrio are approved treatments in the USA, but insufficient evidence was found to support approval in the UK and Europe.

GROWING POINTS: The discovery of neurofilaments as MND biomarkers, growth of platform trials and development of novel therapies provide optimism for more powerful neuroprotective therapies.

Further work should focus on the elucidation of environmental causes of MND, gene-environment interactions, and advanced cellular models of disease.}, } @article {pmid39343990, year = {2024}, author = {Xia, L and Qiu, Y and Li, J and Xu, M and Dong, Z}, title = {The Potential Role of Artemisinins Against Neurodegenerative Diseases.}, journal = {The American journal of Chinese medicine}, volume = {52}, number = {6}, pages = {1641-1660}, doi = {10.1142/S0192415X24500642}, pmid = {39343990}, issn = {1793-6853}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Artemisinins/pharmacology ; *Neuroprotective Agents/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Parkinson Disease/drug therapy/metabolism ; Ferroptosis/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy ; Huntington Disease/drug therapy/metabolism ; Autophagy/drug effects ; }, abstract = {Artemisinin (ART) and its derivatives, collectively referred to as artemisinins (ARTs), have been approved for the treatment of malaria for decades. ARTs are converted into dihydroartemisinin (DHA), the only active form, which is reductive in vivo. In this review, we provide a brief overview of the neuroprotective potential of ARTs and the underlying mechanisms on several of the most common neurodegenerative diseases, particularly considering their potential application in those associated with cognitive and motor impairments including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). ARTs act as autophagy balancers to alleviate AD and PD. They inhibit neuroinflammatory responses by regulating phosphorylation of signal transduction proteins, such as AKT, PI3K, ERK, NF-κB, p38 MAPK, IκBα. In addition, ARTs regulate GABAergic signaling in a dose-dependent manner. Although they competitively inhibit the binding of gephyrin to GABAergic receptors, low doses of ARTs enhance GABAergic signaling. ARTs can also inhibit ferroptosis, activate the Akt/Bcl-2, AMPK, or ERK/CREB pathways to reduce oxidative stress, and maintain mitochondrial homeostasis, protecting neurons from oxidative stress injury. More importantly, ARTs structurally combine with and suppress β-Amyloid (A[Formula: see text]-induced neurotoxicity, reduce P-tau, and maintain O-GlcNAcylation/Phosphorylation balance, leading to relieved pathological changes in neurodegenerative diseases. Collectively, these natural properties endow ARTs with unique potential for application in neurodegenerative diseases.}, } @article {pmid39344189, year = {2025}, author = {Khorshidi, Z and Adibi, I and Ghasemi, M}, title = {Association between cerebrospinal fluid chitotriosidase level and amyotrophic lateral sclerosis: a systematic review.}, journal = {Hormone molecular biology and clinical investigation}, volume = {46}, number = {1}, pages = {13-19}, pmid = {39344189}, issn = {1868-1891}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; *Hexosaminidases/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; }, abstract = {INTRODUCTION: One of the fatal and debilitating neurodegenerative diseases is amyotrophic lateral sclerosis (ALS). Increasing age is one of the risk factors of ALS. Considering that the elderly population in the world is increasing, it is very important to identify useful and effective diagnostic and treatment methods. The purpose of this systematic review is to determine the relationship between chitotriosidase (CHIT1) level and ALS disorder.

CONTENT: Keywords "Amyotrophic Lateral Sclerosis", "Gehrig* Disease", "Charcot Disease", "Guam Disease", ALS, CHIT1 and chitotriosidase were searched in PubMed, Scopus, Web of Science and Science Direct databases without time limit on September 2023. Hundred twenty studies were obtained by searching, and finally, 14 studies were included in this study using the inclusion and exclusion criteria. In all 14 selected studies, the level of biomarker CHIT1 in the CSF of ALS patients was significantly higher than that of healthy control and disease control groups. But, in 8 studies that included 3 groups, no significant difference was observed between the CHIT1 levels in the two control groups. Six studies have reported the amount of CHIT1 level quantitatively. Among these 6 studies, in 5 studies CHIT1 level in disease control was higher than healthy control (not significant) and in only one study CHIT1 level was higher in healthy control compared to disease control (not significant).

SUMMARY AND OUTLOOK: In all 14 studies, a multifold increase in CHIT1 levels has been observed in patients compared to healthy and disease control groups. Therefore, based on the findings of the studies, this study confirms the relationship between CHIT1 increase and ALS disorder.}, } @article {pmid39344228, year = {2024}, author = {Li, P and Tao, Z and Zhao, X}, title = {The Role of Osteopontin (OPN) in Regulating Microglia Phagocytosis in Nervous System Diseases.}, journal = {Journal of integrative neuroscience}, volume = {23}, number = {9}, pages = {169}, doi = {10.31083/j.jin2309169}, pmid = {39344228}, issn = {0219-6352}, mesh = {*Osteopontin/metabolism/physiology ; *Microglia/metabolism/physiology ; *Phagocytosis/physiology ; Animals ; Humans ; Nervous System Diseases/metabolism ; }, abstract = {Phagocytosis is the process by which certain cells or organelles internalise foreign substances by engulfing them and then digesting or disposing of them. Microglia are the main resident phagocytic cells in the brain. It is generally believed that microglia/macrophages play a role in guiding the brain's repair and functional recovery processes. However, the resident and invading immune cells of the central nervous system can also exacerbate tissue damage by stimulating inflammation and engulfing viable neurons. The functional consequences of microglial phagocytosis remain largely unexplored. Overall, phagocytosis is considered a beneficial phenomenon in acute brain injury because it eliminates dead cells and induces an anti-inflammatory response. Osteopontin (OPN) is a phosphorylated glycoprotein induced by injury in various tissues, including brain tissue. In acute brain injuries such as hemorrhagic stroke and ischemic stroke, OPN is generally believed to have anti-inflammatory effects. OPN can promote the reconstruction of the blood-brain barrier and up-regulate the scavenger receptor CD36. But in chronic diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), OPN can cause microglia to engulf neurons and worsen disease progression. We explored the role of OPN in promoting microglial phagocytosis in nervous system disorders.}, } @article {pmid39344431, year = {2025}, author = {Quail, NPA and Leighton, DJ and Newton, J and Davidson, S and Kelly, L and McKeown, A and Chandran, S and Pal, S and Gorrie, GH}, title = {Influences of Specialist Palliative Care Team Input, Advance Care Planning, Non-Invasive Ventilation and Gastrostomy Status on Unscheduled Hospital Admissions and Place of Death for People with Motor Neuron Disease: A Retrospective Cohort Analysis.}, journal = {Journal of palliative care}, volume = {40}, number = {1}, pages = {89-97}, doi = {10.1177/08258597241283179}, pmid = {39344431}, issn = {2369-5293}, mesh = {Humans ; Male ; *Motor Neuron Disease/therapy/mortality ; Female ; *Advance Care Planning/statistics & numerical data ; Retrospective Studies ; Aged ; *Gastrostomy/statistics & numerical data ; Middle Aged ; *Palliative Care/statistics & numerical data ; *Noninvasive Ventilation/statistics & numerical data ; Aged, 80 and over ; Scotland ; Cohort Studies ; Hospitalization/statistics & numerical data ; Terminal Care/statistics & numerical data ; Adult ; }, abstract = {Objective: Motor neuron disease is a rapidly progressing neurological condition. People with life-limiting conditions generally prefer to die at home and avoid hospital admissions, with Specialist Palliative Care Team involvement often pivotal. Our aim was to investigate the role of advance care planning, Specialist Palliative Care Team input and other relevant variables on place of death and unscheduled hospital admissions in a Scottish population of people with motor neuron disease. Methods: National CARE-MND audit data, primary and secondary care data, and local Palliative Care records were interrogated. Chi-square, point-biserial correlation and binary logistic regression analysed associations (p < 0.05 statistically significant). Participants (188) were deceased, having a verified motor neuron disease diagnosis between 2015-2017, diagnosis occurring ≥28 days before death. Results: Advance care planning and Specialist Palliative Care Team input of ≥28 days were associated with increased odds of dying outside hospital (BLR:OR 3.937, CI 1.558-9.948, p = 0.004 and OR 2.657, CI 1.135-6.222, p = 0.024 respectively). Non-invasive ventilation decreased the odds of dying outside hospital (BLR:OR 0.311, CI 0.124-0.781, p = 0.013). Having a gastrostomy increased odds of ≥1 admissions in the last year of life (BLR:OR 5.142, CI 1.715-15.417, p = 0.003). Statistical significance was retained with removal of gastrostomy-related complications. Conclusion: Early Specialist Palliative Care input and advance care planning may increase the likelihood of death outside of hospital for persons with motor neuron disease. Further research is warranted into barriers of facilitating death outside of hospital with home non-invasive ventilation use and the association between gastrostomy status and unscheduled admissions.}, } @article {pmid39345438, year = {2024}, author = {Elsayyid, M and Tanis, JE and Yu, Y}, title = {In-cell processing enables rapid and in-depth proteome analysis of low-input Caenorhabditis elegans.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39345438}, issn = {2692-8205}, support = {P20 GM104316/GM/NIGMS NIH HHS/United States ; R01 GM135433/GM/NIGMS NIH HHS/United States ; T32 GM133395/GM/NIGMS NIH HHS/United States ; }, abstract = {Caenorhabditis elegans is a widely used genetic model organism, however, the worm cuticle complicates extraction of intracellular proteins, a prerequisite for typical bottom-up proteomics. Conventional physical disruption procedures are not only time-consuming, but can also cause significant sample loss, making it difficult to perform proteomics with low-input samples. Here, for the first time, we present an on-filter in-cell (OFIC) processing approach, which can digest C. elegans proteins directly in the cells of the organism after methanol fixation. With OFIC processing and single-shot LCMS analysis, we identified over 9,400 proteins from a sample of only 200 worms, the largest C. elegans proteome reported to date that did not require fractionation or enrichment. We systematically evaluated the performance of the OFIC approach by comparing it with conventional lysis-based methods. Our data suggest equivalent and unbiased performance of OFIC processing for C. elegans proteome identification and quantitation. We further evaluated the OFIC approach with even lower input samples, then used this method to determine how the proteome is impacted by loss of superoxide dismutase sod-1, the ortholog of human SOD-1, a gene associated with amyotrophic lateral sclerosis (ALS). Analysis of 8,800 proteins from only 50 worms as the initial input showed that loss of sod-1 affects the abundance of proteins required for stress response, ribosome biogenesis, and metabolism. In conclusion, our streamlined OFIC approach, which can be broadly applied to other systems, minimizes sample loss while offering the simplest workflow reported to date for C. elegans proteomics analysis.}, } @article {pmid39345637, year = {2025}, author = {Morgan, KJ and Carley, E and Coyne, AN and Rothstein, JD and Lusk, CP and King, MC}, title = {Visualizing nuclear pore complex plasticity with pan-Expansion Microscopy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39345637}, issn = {2692-8205}, support = {F31 HL158119/HL/NHLBI NIH HHS/United States ; R01 GM129308/GM/NIGMS NIH HHS/United States ; R01 NS122236/NS/NINDS NIH HHS/United States ; R21 AR081661/AR/NIAMS NIH HHS/United States ; }, abstract = {The exploration of cell-type and environmentally-responsive nuclear pore complex (NPC) plasticity requires new, accessible tools. Using pan-Expansion Microscopy (pan-ExM), NPCs were identified by machine learning-facilitated segmentation with resolved cytoplasmic rings (CR), inner rings (IR) and nuclear rings (NR). They exhibited a large range of diameters with a bias for dilated NPCs at the basal nuclear surface in clusters suggestive of local islands of nuclear envelope (NE) tension. Whereas hyperosmotic shock constricted NPCs analogously to those found in annulate lamellae (AL), depletion of LINC complexes specifically eliminated the modest nuclear surface diameter biases. Therefore, LINC complexes may contribute locally to nuclear envelope tension to toggle NPC diameter between dilated, but not constricted, states. Lastly, POM121 shifts from the NR to the IR specifically in induced pluripotent stem cell derived neurons (iPSNs) from a patient with C9orf72 amyotrophic lateral sclerosis (ALS). Thus, pan-ExM is a powerful tool to visualize NPC plasticity in physiological and pathological contexts at single NPC resolution.}, } @article {pmid39346681, year = {2024}, author = {Fisher, RMA and Torrente, MP}, title = {Histone post-translational modification and heterochromatin alterations in neurodegeneration: revealing novel disease pathways and potential therapeutics.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1456052}, pmid = {39346681}, issn = {1662-5099}, support = {R15 NS125394/NS/NINDS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), Frontotemporal Dementia (FTD), and Amyotrophic lateral sclerosis (ALS) are complex and fatal neurodegenerative diseases. While current treatments for these diseases do alleviate some symptoms, there is an imperative need for novel treatments able to stop their progression. For all of these ailments, most cases occur sporadically and have no known genetic cause. Only a small percentage of patients bear known mutations which occur in a multitude of genes. Hence, it is clear that genetic factors alone do not explain disease occurrence. Chromatin, a DNA-histone complex whose basic unit is the nucleosome, is divided into euchromatin, an open form accessible to the transcriptional machinery, and heterochromatin, which is closed and transcriptionally inactive. Protruding out of the nucleosome, histone tails undergo post-translational modifications (PTMs) including methylation, acetylation, and phosphorylation which occur at specific residues and are connected to different chromatin structural states and regulate access to transcriptional machinery. Epigenetic mechanisms, including histone PTMs and changes in chromatin structure, could help explain neurodegenerative disease processes and illuminate novel treatment targets. Recent research has revealed that changes in histone PTMs and heterochromatin loss or gain are connected to neurodegeneration. Here, we review evidence for epigenetic changes occurring in AD, PD, and FTD/ALS. We focus specifically on alterations in the histone PTMs landscape, changes in the expression of histone modifying enzymes and chromatin remodelers as well as the consequences of these changes in heterochromatin structure. We also highlight the potential for epigenetic therapies in neurodegenerative disease treatment. Given their reversibility and pharmacological accessibility, epigenetic mechanisms provide a promising avenue for novel treatments. Altogether, these findings underscore the need for thorough characterization of epigenetic mechanisms and chromatin structure in neurodegeneration.}, } @article {pmid39346793, year = {2024}, author = {Ghaderi, S and Mohammadi, S and Fatehi, F}, title = {Calcium accumulation or iron deposition: Delving into the temporal sequence of amyotrophic lateral sclerosis pathophysiology in the primary motor cortex.}, journal = {Ibrain}, volume = {10}, number = {3}, pages = {375-377}, pmid = {39346793}, issn = {2769-2795}, abstract = {Amyotrophic lateral sclerosis (ALS) causes progressive motor neuron degeneration, but an in vivo understanding of its early pathology remains limited. A recent study used topographic layer imaging to investigate iron and calcium accumulation in the primary motor cortex (M1) of patients with ALS compared with controls. Despite the preserved cortical thickness, ALS patients showed increased iron in layer 6 and calcium accumulation in layer 5a and the superficial layer. Calcium accumulation was particularly prominent in the low-myelin borders, potentially preceding the demyelination. This study reveals a novel in vivo pathology in ALS, suggesting that calcium dysregulation may precede iron accumulation and contribute to early M1 cell degeneration. Further investigation using quantitative susceptibility mapping and complementary techniques, such as diffusion kurtosis imaging, along with ultrahigh-field magnetic resonance imaging, into the role of calcium and early intervention strategies is warranted.}, } @article {pmid39347334, year = {2024}, author = {Aljehani, NS and Al-Gunaid, ST and Hobani, AH and Alhinti, MF and Khubrani, YA and Abu-Hamoud, LM and Alrayes, AA and Alharbi, LB and Sultan, AA and Turkistani, DA and Naiser, SS and Albraik, L and Alakel, AM and Alotaibi, M and Asiri, AY}, title = {Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e68008}, pmid = {39347334}, issn = {2168-8184}, abstract = {The blood-brain barrier (BBB) presents a significant challenge in treating Alzheimer's disease, as it restricts the delivery of therapeutic medications to brain tissue. Reversible breaking of the BBB using low-intensity focused ultrasound guided by magnetic resonance imaging (MRI) may benefit patients with Alzheimer's disease and other neurological illnesses, such as brain tumors, amyotrophic lateral sclerosis, and Parkinson's disease. This systematic study and meta-analysis aimed to assess aducanumab and the ultrasonography of BBB opening in Alzheimer's patients. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), the study was conducted by searching six digital repositories for relevant scholarly literature, focusing on English papers published between 2015 and 2024; the data was extracted using an Excel sheet, and data was analyzed using Revman 5.4.1 software. The study's findings indicate that the groups receiving ultrasound and aducanumab treatment benefited from it; however, overall, the effect was not statistically significant (P=0.29) at 95% CI 0.86 (0.75, 1.00). With regard to side effects, the results indicate that the treatment had fewer side effects compared to the control group; however, the difference was not statistically significant (p=0.94) at 95% CI 0.93 (0.70, 1.22). The study found a positive effect of ultrasound and aducanumab on the treatment groups, but it was not statistically significant. The control group had less side effects than the treatment group. Therefore, future studies should focus on the quantity or combination of the drug that yields more effective results.}, } @article {pmid39347895, year = {2025}, author = {Yin, KF and Chen, T and Gu, XJ and Jiang, Z and Su, WM and Duan, QQ and Wen, XJ and Cao, B and Li, JR and Chi, LY and Chen, YP}, title = {Identification of Potential Causal Genes for Neurodegenerative Diseases by Mitochondria-Related Genome-Wide Mendelian Randomization.}, journal = {Molecular neurobiology}, volume = {62}, number = {3}, pages = {3892-3902}, pmid = {39347895}, issn = {1559-1182}, support = {2022NSFSC0749//National Natural Science Fund of Sichuan/ ; 2023HXFH032//1·3·5 project for disciplines of excellence-Clinical Research Fund, West China Hospital, Sichuan University/ ; 2022YFC2703101//National Key Research and Development Program of China/ ; 2023YFS0269//Science and Technology Bureau Fund of Sichuan Province/ ; 81971188//National Natural Science Fund of China/ ; C2023124417//National Innovation and Entrepreneurship Training Program for College Students/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis/methods ; *Neurodegenerative Diseases/genetics ; *Genome-Wide Association Study/methods ; *Mitochondria/genetics ; *Genetic Predisposition to Disease ; DNA, Mitochondrial/genetics ; Quantitative Trait Loci/genetics ; Bayes Theorem ; }, abstract = {Current research lacks comprehensive investigations into the potential causal link between mitochondrial-related genes and the risk of neurodegenerative diseases (NDDs). We aimed to identify potential causative genes for five NDDs through an examination of mitochondrial-related gene expression levels. Through the integration of summary statistics from expression quantitative trait loci (eQTL) datasets (human blood and brain tissue), mitochondrial DNA copy number (mtDNA-CN), and genome-wide association studies (GWAS) datasets of five NDDs from European ancestry, we conducted a Mendelian randomization (MR) analysis to explore the potential causal relationship between mitochondrial-related genes and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Sensitivity analysis and Bayesian colocalization were employed to validate this causal relationship. Through MR analysis, we have identified potential causal relationships between 12 mitochondria-related genes and AD, PD, ALS, and FTD overlapping with motor neuron disease (FTD_MND) in human blood or brain tissue. Bayesian colocalization analysis further confirms 9 causal genes, including NDUFS2, EARS2, and MRPL41 for AD; NDUFAF2, MALSU1, and METTL8 for PD; MYO19 and MRM1 for ALS; and FASTKD1 for FTD_MND. Importantly, in both human blood and brain tissue, NDUFS2 exhibits a significant pathogenic effect on AD, while NDUFAF2 demonstrates a robust protective effect on PD. Additionally, the mtDNA-CN plays a protected role in LBD (OR = 0.62, p = 0.031). This study presents evidence establishing a causal relationship between mitochondrial dysfunction and NDDs. Furthermore, the identified candidate genes may serve as potential targets for drug development aimed at preventing NDDs.}, } @article {pmid39349054, year = {2025}, author = {Simpson, JT and Nordham, KD and Tatum, D and Haut, ER and Ali, A and Maher, Z and Goldberg, AJ and Tatebe, LC and Chang, G and Taghavi, S and Raza, S and Toraih, E and Mendiola Plá, M and Ninokawa, S and Anderson, C and Maluso, P and Keating, J and Burruss, S and Reeves, M and Craugh, LE and Shatz, DV and Bhupathi, A and Spalding, MC and LaRiccia, A and Bird, E and Noorbakhsh, MR and Babowice, J and Nelson, MC and Jacobson, LE and Williams, J and Vella, M and Dellonte, K and Hayward, TZ and Holler, E and Lieser, MJ and Berne, JD and Mederos, DR and Askari, R and Okafor, B and Etchill, E and Fang, R and Roche, SL and Whittenburg, L and Bernard, AC and Haan, JM and Lightwine, KL and Norwood, SH and Murry, J and Gamber, MA and Carrick, MM and Bugaev, N and Tatar, A}, title = {Stop the Bleed-Wait for the Ambulance or Get in the Car and Drive? A Post Hoc Analysis of an EAST Multicenter Trial.}, journal = {The American surgeon}, volume = {91}, number = {2}, pages = {233-241}, doi = {10.1177/00031348241265135}, pmid = {39349054}, issn = {1555-9823}, mesh = {Humans ; Male ; Female ; Adult ; Middle Aged ; *Ambulances ; *Hemorrhage/prevention & control/etiology/mortality/therapy ; *Wounds, Penetrating/therapy/mortality/complications ; *Transportation of Patients/methods ; Trauma Centers ; *Emergency Medical Services/methods ; Propensity Score ; }, abstract = {Background: The Stop the Bleed campaign gives bystanders an active role in prehospital hemorrhage control. Whether extending bystanders' role to private vehicle transport (PVT) for urban penetrating trauma improves survival is unknown, but past research has found benefit to police and PVT. We hypothesized that for penetrating trauma in an urban environment, where prehospital procedures have been proven harmful, PVT improves outcomes compared to any EMS or advanced life support (ALS) transport.Methods: Post-hoc analysis of an EAST multicenter trial was performed on adult patients with penetrating torso/proximal extremity trauma at 25 urban trauma centers from 5/2019-5/2020. Patients were allocated to PVT and any EMS or ALS transport using nearest neighbor propensity score matching. Univariate analyses included Wilcoxon signed rank or McNemar's Test and logistic regression.Results: Of 1999 penetrating trauma patients in urban settings, 397 (19.9%) had PVT, 1433 (71.7%) ALS transport, and 169 (8.5%) basic life support (BLS) transport. Propensity matching yielded 778 patients, distributed equally into balanced groups. PVT patients were primarily male (90.5%), Black (71.2%), and sustained gunshot wounds (68.9%). ALS transport had significantly higher ED mortality (3.9% vs 1.9%, P = 0.03). There was no difference in in-hospital mortality rate, hospital LOS, or complications for all EMS or ALS only transport patients.Conclusion: Compared to PVT, ALS, which provides more prehospital procedures than BLS, provided no survival benefit for penetrating trauma patients in urban settings. Bystander education incorporating PVT for early arrival of penetrating trauma patients in urban settings to definitive care merits further investigation.}, } @article {pmid39349171, year = {2024}, author = {Khanna, RK and Catanese, S and Mortemousque, G and Dupuy, C and Lefevre, A and Emond, P and Beltran, S and Gissot, V and Pisella, PJ and Blasco, H and Corcia, P}, title = {Metabolomics of basal tears in amyotrophic lateral sclerosis: A cross-sectional study.}, journal = {The ocular surface}, volume = {34}, number = {}, pages = {363-369}, doi = {10.1016/j.jtos.2024.09.005}, pmid = {39349171}, issn = {1937-5913}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnosis ; Male ; Female ; Prospective Studies ; Middle Aged ; *Metabolomics/methods ; Cross-Sectional Studies ; Aged ; *Tears/metabolism ; Case-Control Studies ; Biomarkers/metabolism ; Chromatography, High Pressure Liquid ; Adult ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) clinical variability, along with the lack of conclusive diagnostic instruments, result in average diagnosis delays of 9 months. This study aimed to assess whether metabolomic profiling of basal tears in ALS patients could act as a biological marker for diagnosing ALS, predicting prognosis, and discriminating between endophenotypes.

METHODS: A single-center prospective case-control study was conducted in France from September 2021 to March 2023 including patients with ALS according to the revised EI Escorial criteria. Two microliters of basal tears were collected using microcapillary glass tubes and analyzed with ultra-high performance liquid chromatography coupled with mass spectrometry. Both univariate and multivariate analyses were performed.

RESULTS: Twenty-five patients with ALS and 30 controls were included. No significant differences in metabolite levels were found between ALS and control groups (p > 0.05). The basal tear metabolome significantly discriminated bulbar and spinal forms of ALS based on 6 metabolites, among which 5 were decreased (aniline, trigonelline, caffeine, theophylline and methyl beta-D-galactoside) in the bulbar form and 1 was decreased in the spinal form (dodecanedioic acid).

CONCLUSION: This study represents the first prospective analysis of basal tear metabolomics in individuals with ALS. Despite the inability to distinguish between ALS patients and controls based on metabolic signatures, these findings could contribute to understanding the phenotypic diversity of ALS. Notably, distinct metabolic profiles were identified that differentiate between the bulbar and spinal forms of the disease.}, } @article {pmid39349916, year = {2025}, author = {Soliman, R and Onbool, E and Omran, K and Fahmy, N}, title = {Clinical and epidemiological characteristics of amyotrophic lateral sclerosis in an Egyptian cohort.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {3}, pages = {1225-1236}, pmid = {39349916}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/physiopathology ; Egypt/epidemiology ; Male ; Female ; Middle Aged ; Adult ; Age of Onset ; Disease Progression ; Prospective Studies ; Aged ; Cohort Studies ; Young Adult ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive loss of motor neurons. It is a growing and underestimated disease, prompting this epidemiological study to describe the characteristics of ALS in Egyptian patients.

METHODS: This is a prospective hospital based study. ALS patients were recruited consecutively from Neuromuscular Unit in Ain Shams university Hospital from December 2018 to June 2023. Demographic data and disease related parameters were recorded.

RESULTS: 203 ALS patients had a mean age of onset equal 39 years and an inter quartile range IQR of (28.00-51.00). 76% of the cases were spinal onset ALS. Median disease duration was 2 years with IQR of (1-4 years); male to female ratio was 2.5:1; 18% of patients were familial ALS (FALS), while 19% were Juvenile ALS (JALS). Median diagnostic delay was 12 ± (6-36) months. Median Amyotrophic Lateral Sclerosis Functional Rating Scale Revised scores (ALSFRS-R) at presentation was 34.5 IQR of (26.00-40.00). Also, the mean rate of disease progression ALSFRS-R decline [points/month] was 0.76 ± 0.51.

CONCLUSION: Our cohort was characterized by a younger age of onset, male predominance, more familial cases, within average Initial ALSFRS-R scores as well as diagnostic delay. Juvenile ALS patients were much more common in our population. These findings suggest an influential presence of genetic and epigenetic factors affecting the clinical phenotype of Egyptian ALS patients.}, } @article {pmid39350404, year = {2025}, author = {Mohan, M and Mannan, A and Kakkar, C and Singh, TG}, title = {Nrf2 and Ferroptosis: Exploring Translational Avenues for Therapeutic Approaches to Neurological Diseases.}, journal = {Current drug targets}, volume = {26}, number = {1}, pages = {33-58}, pmid = {39350404}, issn = {1873-5592}, mesh = {*Ferroptosis/physiology/drug effects ; Humans ; *NF-E2-Related Factor 2/metabolism/genetics ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; Iron/metabolism ; }, abstract = {Nrf2, a crucial protein involved in defense mechanisms, particularly oxidative stress, plays a significant role in neurological diseases (NDs) by reducing oxidative stress and inflammation. NDs, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, stroke, epilepsy, schizophrenia, depression, and autism, exhibit ferroptosis, iron-dependent regulated cell death resulting from lipid and iron-dependent reactive oxygen species (ROS) accumulation. Nrf2 has been shown to play a critical role in regulating ferroptosis in NDs. Age-related decline in Nrf2 expression and its target genes (HO-1, Nqo-1, and Trx) coincides with increased iron-mediated cell death, leading to ND onset. The modulation of iron-dependent cell death and ferroptosis by Nrf2 through various cellular and molecular mechanisms offers a potential therapeutic pathway for understanding the pathological processes underlying these NDs. This review emphasizes the mechanistic role of Nrf2 and ferroptosis in multiple NDs, providing valuable insights for future research and therapeutic approaches.}, } @article {pmid39351260, year = {2024}, author = {Gao, FQ and Zhu, JQ and Feng, XD}, title = {Innovative mesenchymal stem cell treatments for fatty liver disease.}, journal = {World journal of stem cells}, volume = {16}, number = {9}, pages = {846-853}, pmid = {39351260}, issn = {1948-0210}, abstract = {The incidence of non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) is increasing year by year due to changes in the contemporary environment and dietary structure, and is an important public health problem worldwide. There is an urgent need to continuously improve the understanding of their disease mechanisms and develop novel therapeutic strategies. Mesenchymal stem cells (MSCs) have shown promise as a potential therapeutic strategy in therapeutic studies of NAFLD and ALD. NAFLD and ALD have different triggers and their specific mechanisms of disease progression are different, but both involve disease processes such as hepatocellular steatosis and potential fibrosis, cirrhosis, and even hepatocellular carcinoma. MSCs have metabolic regulatory, anti-apoptotic, antioxidant, and immunomodulatory effects that together promote liver injury repair and functional recovery, and have demonstrated positive results in preclinical studies. This editorial is a continuum of Jiang et al's review focusing on the advantages and limitations of MSCs and their derivatives as therapeutics for NAFLD and ALD. They detail how MSCs attenuate the progression of NAFLD by modulating molecular pathways involved in glucolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. Based on recent advances, we discuss MSCs and their derivatives as therapeutic strategies for NAFLD and ALD, providing useful information for their clinical application.}, } @article {pmid39351695, year = {2024}, author = {Wang, PS and Yang, XX and Wei, Q and Lv, YT and Wu, ZY and Li, HF}, title = {Clinical characterization and founder effect analysis in Chinese amyotrophic lateral sclerosis patients with SOD1 common variants.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2407522}, pmid = {39351695}, issn = {1365-2060}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Age of Onset ; *Amyotrophic Lateral Sclerosis/genetics ; China/epidemiology ; East Asian People ; Exome Sequencing ; *Founder Effect ; Genetic Association Studies ; Haplotypes ; Mutation ; Phenotype ; *Superoxide Dismutase-1/genetics ; }, abstract = {OBJECTIVE: In the Asian population, SOD1 variants are the most common cause of amyotrophic lateral sclerosis (ALS). To date, more than 200 variants have been reported in SOD1. This study aimed to summarize the genotype-phenotype correlation and determine whether the patients carrying common variants derive from a common ancestor.

METHODS: A total of 103 sporadic ALS (SALS) and 11 familial ALS (FALS) probands were included and variants were screened by whole exome sequencing. Functional analyses were performed on fibroblasts derived from patients with SOD1 p.V48A and control. Haplotype analysis was performed in the probands with p.H47R or p.V48A and their familial members.

RESULTS: A total of 25 SOD1 variants were identified in 44 probands, in which p.H47R, p.V48A and p.C112Y variants were the most common variants. 94.3% and 60% of patients with p.H47R or p.V48A had lower limb onset with predominant lower motor neurons (LMNs) involvement. Patients with p.H47R had a slow progression and prolonged survival time, while patients with p.V48A exhibited a duration of 2-5 years. Patients with p.C112Y variant showed remarkable phenotypic variation in age at onset and disease course. SOD1[V48A] fibroblasts showed mutant SOD1 aggregate formation, enhanced intracellular reactive oxygen species level, and decreased mitochondrial membrane potential compared to the control fibroblast. Haplotype analysis showed that seven families had two different haplotypes. p.H47R and p.V48A variants did not originate from a common founder.

CONCLUSIONS: Our study expanded the understanding of the genotype-phenotype correlation of ALS with SOD1 variants and revealed that the common p.H47R or p.V48A variant did not have a founder effect.}, } @article {pmid39352708, year = {2024}, author = {Crose, JJ and Crose, A and Ransom, JT and Lightner, AL}, title = {Bone marrow mesenchymal stem cell-derived extracellular vesicle infusion for amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {3-4}, pages = {111-117}, pmid = {39352708}, issn = {1758-2032}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Extracellular Vesicles ; Male ; Middle Aged ; Female ; Pilot Projects ; Aged ; Mesenchymal Stem Cells ; Mesenchymal Stem Cell Transplantation/methods ; Infusions, Intravenous ; Adult ; Treatment Outcome ; }, abstract = {Background: In this pilot safety study, we hypothesized that a human bone marrow stem cell-derived extracellular vesicle (hBM-MSC EV) investigational product (IP) would be safe and exhibit potential efficacy in amyotrophic lateral sclerosis (ALS) patients.Methods: Ten ALS patients received two 10-ml intravenous infusions of the IP given 1 month apart and evaluated over 3 months.Results: There were no serious adverse events or adverse events related to the IP and 30% of subjects' ALS functional rating scale-revised (ALSFRS-R) scores did not decline.Conclusion: HBM-MSC EVs appear safe in ALS patients. This early investigation suggests a controlled study of EVs for the treatment of ALS is warranted.}, } @article {pmid39352715, year = {2024}, author = {Sung, SF and Hu, YH and Chen, CY}, title = {Disambiguating Clinical Abbreviations by One-to-All Classification: Algorithm Development and Validation Study.}, journal = {JMIR medical informatics}, volume = {12}, number = {}, pages = {e56955}, pmid = {39352715}, issn = {2291-9694}, mesh = {*Natural Language Processing ; *Electronic Health Records ; Humans ; *Algorithms ; *Abbreviations as Topic ; }, abstract = {BACKGROUND: Electronic medical records store extensive patient data and serve as a comprehensive repository, including textual medical records like surgical and imaging reports. Their utility in clinical decision support systems is substantial, but the widespread use of ambiguous and unstandardized abbreviations in clinical documents poses challenges for natural language processing in clinical decision support systems. Efficient abbreviation disambiguation methods are needed for effective information extraction.

OBJECTIVE: This study aims to enhance the one-to-all (OTA) framework for clinical abbreviation expansion, which uses a single model to predict multiple abbreviation meanings. The objective is to improve OTA by developing context-candidate pairs and optimizing word embeddings in Bidirectional Encoder Representations From Transformers (BERT), evaluating the model's efficacy in expanding clinical abbreviations using real data.

METHODS: Three datasets were used: Medical Subject Headings Word Sense Disambiguation, University of Minnesota, and Chia-Yi Christian Hospital from Ditmanson Medical Foundation Chia-Yi Christian Hospital. Texts containing polysemous abbreviations were preprocessed and formatted for BERT. The study involved fine-tuning pretrained models, ClinicalBERT and BlueBERT, generating dataset pairs for training and testing based on Huang et al's method.

RESULTS: BlueBERT achieved macro- and microaccuracies of 95.41% and 95.16%, respectively, on the Medical Subject Headings Word Sense Disambiguation dataset. It improved macroaccuracy by 0.54%-1.53% compared to two baselines, long short-term memory and deepBioWSD with random embedding. On the University of Minnesota dataset, BlueBERT recorded macro- and microaccuracies of 98.40% and 98.22%, respectively. Against the baselines of Word2Vec + support vector machine and BioWordVec + support vector machine, BlueBERT demonstrated a macroaccuracy improvement of 2.61%-4.13%.

CONCLUSIONS: This research preliminarily validated the effectiveness of the OTA method for abbreviation disambiguation in medical texts, demonstrating the potential to enhance both clinical staff efficiency and research effectiveness.}, } @article {pmid39353548, year = {2025}, author = {Bosco, DB and Kremen, V and Haruwaka, K and Zhao, S and Wang, L and Ebner, BA and Zheng, J and Xie, M and Dheer, A and Perry, JF and Barath, A and Nguyen, AT and Worrell, GA and Wu, LJ}, title = {Microglial TREM2 promotes phagocytic clearance of damaged neurons after status epilepticus.}, journal = {Brain, behavior, and immunity}, volume = {123}, number = {}, pages = {540-555}, pmid = {39353548}, issn = {1090-2139}, support = {R35 NS132326/NS/NINDS NIH HHS/United States ; RF1 AG082314/AG/NIA NIH HHS/United States ; R01 NS088627/NS/NINDS NIH HHS/United States ; R01 NS112144/NS/NINDS NIH HHS/United States ; R01 AG082314/AG/NIA NIH HHS/United States ; UH3 NS123066/NS/NINDS NIH HHS/United States ; }, mesh = {*Receptors, Immunologic/metabolism/genetics ; Animals ; *Status Epilepticus/metabolism/genetics ; *Microglia/metabolism ; *Membrane Glycoproteins/metabolism/genetics ; *Mice, Knockout ; Male ; *Phagocytosis/physiology/genetics ; Mice ; *Neurons/metabolism ; Humans ; Disease Models, Animal ; Kainic Acid ; Mice, Inbred C57BL ; Epilepsy, Temporal Lobe/metabolism/genetics ; Seizures/metabolism/genetics ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; }, abstract = {In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. Microglial TREM2 plays an important role in neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis. However, little is known about how TREM2 affects microglial function within epileptogenesis. To investigate this, we utilized male TREM2 knockout (KO) mice within the intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both the severity of acute status epilepticus and the number of spontaneous recurrent seizures characteristic of chronic focal epilepsy. Phagocytic clearance of damaged neurons by microglia was also impaired by TREM2 KO and reduced phagocytic activity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between expression of the microglial phagocytic marker CD68 and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity are important to epileptogenic pathology.}, } @article {pmid39355053, year = {2023}, author = {Cortés Mancera, EA and Sinisterra Solis, FA and Romero-Castellanos, FR and Diaz-Meneses, IE and Kerik-Rotenberg, NE}, title = {[18]F-FDG PET/CT as a molecular biomarker in the diagnosis of amyotrophic lateral sclerosis associated with prostate cancer and progressive supranuclear palsy: A case report.}, journal = {Frontiers in nuclear medicine}, volume = {3}, number = {}, pages = {1137875}, pmid = {39355053}, issn = {2673-8880}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative, multisystem disorder. Its clinical presentation typically consists of progressive focal muscle atrophy and weakness. In addition to motor disorders, the association between ALS and cancer has been researched, such as frontotemporal dementia and progressive supranuclear palsy. The diagnosis is based primarily on the clinical history, physical examination, electrodiagnostic tests (with an EMG needle), and neuroimaging, such as MRI and [18]F-FDG PET/CT.

PRESENTATION OF THE CASE: A 67-year-old male patient was diagnosed with prostate adenocarcinoma with a clinical picture of muscle weakness in the lower limbs that caused falls and was associated with fasciculations in the thighs and arms, alterations in the tone of voice, poor memory, and difficulty articulating words. In the neurological assessment, he described walking supported by a walker with decreased strength in both lower limbs and sensitivity without alterations. The diagnoses of upper and lower motor neuron disease and probable ALS were integrated. Furthermore, the probable coexistence of frontotemporal dementia/disorder (FDD) with ALS was considered. The main findings in the [18]F-FDG PET/CT study was hypometabolism in the cortex of the bilateral motor and premotor areas, the anterior cingulate, both caudate and putamen, a metabolic pattern compatible with ALS, and progressive supranuclear palsy.

CONCLUSION: Through the PET/CT studies, we demonstrated a case in which ALS, prostate cancer and progressive supranuclear palsy coexisted molecularly; it was clinically difficult to diagnose. Molecular imaging has potential in the diagnostic and prognostic evaluation of ALS. It is crucial to identify the disease early and reliably through metabolic patterns that allow us to confirm the disease or differentiate it from other pathologies.}, } @article {pmid39355247, year = {2024}, author = {Yang, JL and Wu, JY and Liu, JJ and Zheng, GQ}, title = {Herbal medicines for SOD1[G93A] mice of amyotrophic lateral sclerosis: preclinical evidence and possible immunologic mechanism.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1433929}, pmid = {39355247}, issn = {1664-3224}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/immunology/genetics ; Animals ; Mice ; *Disease Models, Animal ; Mice, Transgenic ; Humans ; Superoxide Dismutase-1/genetics ; Herbal Medicine ; }, abstract = {Currently, there is no cure or effective treatment for Amyotrophic Lateral Sclerosis (ALS). The mechanisms underlying ALS remain unclear, with immunological factors potentially playing a significant role. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), a systematic review of preclinical studies was conducted, searching seven databases including PubMed, covering literature from the inception of the databases to April 10, 2024. Methodological quality of the included literature was assessed using CAMARADES, while the risk of bias in the included studies was evaluated using SYRCLE's ROB tool. Review Manager 5.4.1 statistical software was used for meta-analysis of the outcomes. The scoping review followed the Joanna Briggs Institute Methodological Guidelines and reporting of this review followed the PRISMA-extension for Scoping Reviews (PRISMA -ScR) checklist to explore the immunological mechanisms of Herbal Medicine (HM) in treating ALS. This systematic review and meta-analysis involved 18 studies with a total of 443 animals. The studies scored between 4 to 8 for methodological quality and 3 to 7 for risk of bias, both summing up to 10.A remarkable effects of HM in ALS mice, including onset time(Standardized Mean Difference(SMD): 1.75, 95% Confidence Interval(CI) (1.14 ~ 2.36), Z = 5.60, P < 0.01), survival time(SMD = 1.42, 95% CI (0.79 ~ 2.04), Z = 4.44, P < 0.01), stride length(SMD=1.90, 95% CI (1.21 to 2.59), Z = 5.39, P < 0.01) and duration time (Mean Difference(MD)=6.79, 95% CI [-0.28, 13.87], Z=1.88, P =0.06), showing HM's certain efficiency in treating ALS mice. The scoping review ultimately included 35 articles for review. HMs may treat ALS through mechanisms such as combating oxidative stress, excitatory amino acid toxicity, and calcium cytotoxicity, understanding and exploring the mechanisms will bring hope to patients. Individual herbs and their formulations within HM address ALS through a variety of immune pathways, including safeguarding the blood-brain barrier, countering neuroinflammation, impeding complement system activation, mitigating natural killer cell toxicity, and regulating T cell-mediated immune pathways. The preclinical evidence supports the utilization of HM as a conventional treatment for ALS mice. Growing evidence indicates that HM may potentially delay neurological degeneration in ALS by activating diverse signaling pathways, especially immune pathways.}, } @article {pmid39355693, year = {2024}, author = {Leger, D and Bater, S and Paulin, MV and Linn, K and Taylor, S and Shelton, GD}, title = {Presumptive motor neuron degeneration in an adult cat.}, journal = {The Canadian veterinary journal = La revue veterinaire canadienne}, volume = {65}, number = {10}, pages = {1034-1040}, pmid = {39355693}, issn = {0008-5286}, mesh = {Cats ; Male ; Animals ; *Cat Diseases/pathology/diagnosis/drug therapy ; *Motor Neuron Disease/veterinary/pathology/diagnosis ; Prednisolone/therapeutic use ; Immunosuppressive Agents/therapeutic use ; Motor Neurons/pathology ; Muscular Atrophy/veterinary/pathology ; Muscle, Skeletal/pathology ; }, abstract = {An 8-year-old neutered male Bengal cat was referred because of a 1-year history of progressive and relapsing generalized muscle weakness and muscle atrophy. Before referral, the cat was treated with immunosuppressive doses of oral prednisolone, intermittently for 6 mo, and had responded well when the immunosuppressive dose was maintained. Generalized paresis, diffuse muscle atrophy, and diminished spinal reflexes were present in all limbs, consistent with a generalized lower motor neuron disease. Histopathologic evaluation of muscle biopsies confirmed a pattern of muscle fiber atrophy consistent with chronic and severe denervation. No specific abnormalities were identified in the nerve biopsy or within intramuscular nerve branches. A presumptive antemortem diagnosis of an adult-onset motor neuron degeneration resembling amyotrophic lateral sclerosis (ALS) or spinal muscle atrophy was suspected. However, given the response to immunosuppressive doses of corticosteroids, an autoimmune process or other degenerative process could not be definitively excluded. Key clinical message: In this case, an adult cat had a chronic, progressive history of lower motor neuron weakness and absent spinal reflexes; biopsies revealed a neurogenic pattern of muscle fiber atrophy and histologically normal peripheral nerve and intramuscular nerve branches. Although reports of motor neuron disease are rare in the veterinary literature, this case report highlights the importance of muscle and nerve biopsies that lead to a presumptive diagnosis of motor neuron degeneration.}, } @article {pmid39359088, year = {2025}, author = {Kim, K}, title = {Carboplatin restores neuronal toxicity in FUS-linked amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {8}, pages = {2319-2320}, pmid = {39359088}, issn = {1673-5374}, } @article {pmid39360074, year = {2024}, author = {Puri, SN and Raghuveer, R and Jachak, S and Tikhile, P}, title = {Exploring the Impact of Personalized Physical Therapy on a Patient With Motor Neuron Disorder: A Case Study.}, journal = {Cureus}, volume = {16}, number = {9}, pages = {e68373}, pmid = {39360074}, issn = {2168-8184}, abstract = {This case study examines the effect of a tailor-made physiotherapy regimen on an 85-year-old male patient who was suffering from bulbar motor neuron disease (MND) and had a history of stroke and COVID-19. The physiotherapy plan was designed to strategically address the patient's respiratory issues, generalized weakness affecting limb muscles, and speech and swallowing difficulties. Frequent evaluations made it possible to adjust the treatment plan, emphasizing a holistic strategy to improve the patient's overall quality of life. Improvements in scores on multiple functional scales and manual muscle testing were shown by outcome measures and follow-up evaluations. This case emphasizes how important customized physiotherapy is for maximizing functional outcomes and enhancing the quality of life for patients dealing with the complicated conditions of bulbar MND.}, } @article {pmid39360554, year = {2025}, author = {Quigley, S and McNamara, B and Cronin, S}, title = {Alteration in ornithine metabolism due to mutation in ALDH18A1 masquerading as ALS in pregnancy.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {172-174}, doi = {10.1080/21678421.2024.2410982}, pmid = {39360554}, issn = {2167-9223}, mesh = {Humans ; Female ; Pregnancy ; Adult ; *Mutation/genetics ; *Ornithine/metabolism ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Aldehyde Dehydrogenase/genetics ; *Pregnancy Complications/genetics/diagnosis ; *Spastic Paraplegia, Hereditary/genetics/diagnosis ; Diagnosis, Differential ; }, abstract = {Clinical onset and exacerbation of autosomal dominant SPG9A hereditary spastic paraplegia, including reversible wasting, has been described during pregnancy. SPG9A is due to ALDH18A1 mutations resulting in proline and ornithine deficiency. We present the case of a 29 year old primagravida at 32 weeks who presented with six months of upper limb amyotrophic wasting on a background unrecognized progressive spasticity due to SPG9A. The wasting reversed significantly following delivery. Our report highlights the unusual clinical features including cataract and joint laxity which may suggest SPG9A, echoes the existing descriptions of pregnancy-related provocation of amyotrophy in this condition and documents the outcome of two subsequent pregnancies following dietary intervention.}, } @article {pmid39360635, year = {2024}, author = {Abbassi, Y and Cappelli, S and Spagnolo, E and Gennari, A and Visani, G and Barattucci, S and Paron, F and Stuani, C and Droppelmann, CA and Strong, MJ and Buratti, E}, title = {Axon guidance genes are regulated by TDP-43 and RGNEF through long-intron removal.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {38}, number = {19}, pages = {e70081}, doi = {10.1096/fj.202400743RR}, pmid = {39360635}, issn = {1530-6860}, support = {//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (AriSLA)/ ; //Temetry Family Foundation/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; Humans ; Introns ; Guanine Nucleotide Exchange Factors/metabolism/genetics ; Animals ; Axon Guidance/genetics ; Motor Neurons/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Gene Expression Regulation ; }, abstract = {Rho guanine nucleotide exchange factor (RGNEF) is a guanine nucleotide exchange factor (GEF) mainly involved in regulating the activity of Rho-family GTPases. It is a bi-functional protein, acting both as a guanine exchange factor and as an RNA-binding protein. RGNEF is known to act as a destabilizing factor of neurofilament light chain RNA (NEFL) and it could potentially contribute to their sequestration in nuclear cytoplasmic inclusions. Most importantly, RGNEF inclusions in the spinal motor neurons of ALS patients have been shown to co-localize with inclusions of TDP-43, the major well-known RNA-binding protein aggregating in the brain and spinal cord of human patients. Therefore, it can be hypothesized that loss-of-function of both proteins following aggregation may contribute to motor neuron death/survival in ALS patients. To further characterize their relationship, we have compared the transcriptomic profiles of neuronal cells depleted of TDP-43 and RGNEF and show that these two factors predominantly act in an antagonistic manner when regulating the expression of axon guidance genes. From a mechanistic point of view, our experiments show that the effect of these genes on the processivity of long introns can explain their mode of action. Taken together, our results show that loss-of-function of factors co-aggregating with TDP-43 can potentially affect the expression of commonly regulated neuronal genes in a very significant manner, potentially acting as disease modifiers. This finding further highlights that neurodegenerative processes at the RNA level are the result of combinatorial interactions between different RNA-binding factors that can be co-aggregated in neuronal cells. A deeper understanding of these complex scenarios may lead to a better understanding of pathogenic mechanisms occurring in patients, where more than one specific protein may be aggregating in their neurons.}, } @article {pmid39361759, year = {2024}, author = {Wilkins, OG and Chien, MZYJ and Wlaschin, JJ and Barattucci, S and Harley, P and Mattedi, F and Mehta, PR and Pisliakova, M and Ryadnov, E and Keuss, MJ and Thompson, D and Digby, H and Knez, L and Simkin, RL and Diaz, JA and Zanovello, M and Brown, AL and Darbey, A and Karda, R and Fisher, EMC and Cunningham, TJ and Le Pichon, CE and Ule, J and Fratta, P}, title = {Creation of de novo cryptic splicing for ALS and FTD precision medicine.}, journal = {Science (New York, N.Y.)}, volume = {386}, number = {6717}, pages = {61-69}, pmid = {39361759}, issn = {1095-9203}, support = {ZIA HD008966/ImNIH/Intramural NIH HHS/United States ; MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; 215593/WT_/Wellcome Trust/United Kingdom ; CC0102/WT_/Wellcome Trust/United Kingdom ; CC0102/MRC_/Medical Research Council/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Deep Learning ; *DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/therapy ; Gene Editing ; HEK293 Cells ; *Precision Medicine ; RNA Splice Sites ; *RNA Splicing ; RNA-Binding Proteins/metabolism/genetics ; }, abstract = {Loss of function of the RNA-binding protein TDP-43 (TDP-LOF) is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here we describe TDP-REG, which exploits the specificity of cryptic splicing induced by TDP-LOF to drive protein expression when and where the disease process occurs. The SpliceNouveau algorithm combines deep learning with rational design to generate customizable cryptic splicing events within protein-coding sequences. We demonstrate that expression of TDP-REG reporters is tightly coupled to TDP-LOF in vitro and in vivo. TDP-REG enables genomic prime editing to ablate the UNC13A cryptic donor splice site specifically upon TDP-LOF. Finally, we design TDP-REG vectors encoding a TDP-43/Raver1 fusion protein that rescues key pathological cryptic splicing events, paving the way for the development of precision therapies for TDP43-related disorders.}, } @article {pmid39361871, year = {2025}, author = {Fernandes, JPM and Garcia, LP and Gouhie, FA and Pereira, RC and Santos, DFD}, title = {Association between motor neuron disease and HIV infection: A systematic review of case reports.}, journal = {International journal of STD & AIDS}, volume = {36}, number = {1}, pages = {24-35}, doi = {10.1177/09564624241288283}, pmid = {39361871}, issn = {1758-1052}, mesh = {Humans ; *HIV Infections/drug therapy/complications ; *Motor Neuron Disease/complications ; Adult ; Male ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; Female ; Middle Aged ; Riluzole/therapeutic use ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a well-known group of neurodegenerative diseases, with amyotrophic lateral sclerosis (ALS) being the most common form. Since 1985, a possible association between MND/ALS and HIV infection has been described.

METHODS: We performed a systematic review of case reports and case series involving people living with HIV with MND/ALS through PubMed, Bireme, Embase, and Lilacs databases. The risk of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tool for Case Reports.

RESULTS: We analyzed 36 articles presenting 88 cases. The mean age was 41.6 years. Antiretroviral therapy (ART) was used by 89.8% and riluzole by 16.9%. First signs and symptoms were similarly present on cervical/upper (25%) and lumbosacral/lower limbs (23.9%), mostly with fasciculations (69.8%) and hyperreflexia (58.8%). MND had a progressive course in 32.9% patients and a clinical improve in 54.6% following ART. The mean survival of the 32 patients who died was 12.3 months and the mean survival of the living patients was 62 months. Respiratory failure was the main cause of death (35.7%).

CONCLUSIONS: MND/ALS may present differently in the people living with HIV as a rapidly progressive disease in younger people but with the potential to improve weakness and survival through antiretroviral therapy.}, } @article {pmid39362568, year = {2024}, author = {Velasquez, E and Savchenko, E and Marmolejo-Martínez-Artesero, S and Challuau, D and Aebi, A and Pomeshchik, Y and Lamas, NJ and Vihinen, M and Rezeli, M and Schneider, B and Raoul, C and Roybon, L}, title = {TNFα prevents FGF4-mediated rescue of astrocyte dysfunction and reactivity in human ALS models.}, journal = {Neurobiology of disease}, volume = {201}, number = {}, pages = {106687}, doi = {10.1016/j.nbd.2024.106687}, pmid = {39362568}, issn = {1095-953X}, mesh = {*Astrocytes/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Animals ; Mice ; *Tumor Necrosis Factor-alpha/metabolism ; *Fibroblast Growth Factor 4/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Spinal Cord/metabolism/pathology ; }, abstract = {Astrocytes play a crucial role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder marked by the degeneration of motor neurons (MNs) in the central nervous system. Although astrocytes in ALS are known to be toxic to MNs, the pathological changes leading to their neurotoxic phenotype remain poorly understood. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) carrying the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1) to examine early cellular pathways and network changes. Proteomic analysis revealed that ALS astrocytes are both dysfunctional and reactive compared to control astrocytes. We identified significant alterations in the levels of proteins linked to ALS pathology and the innate immune cGAS-STING pathway. Furthermore, we found that ALS astrocyte reactivity differs from that of control astrocytes treated with tumor necrosis factor alpha (TNFα), a key cytokine in inflammatory reactions. We then evaluated the potential of fibroblast growth factor (FGF) 2, 4, 16, and 18 to reverse ALS astrocyte phenotype. Among these, FGF4 successfully reversed ALS astrocyte dysfunction and reactivity in vitro. When delivered to the spinal cord of the SOD1[G93A] mouse model of ALS, FGF4 lowered astrocyte reactivity. However, this was not sufficient to protect MNs from cell death. Further analysis indicated that TNFα abrogated the reactivity reduction achieved by FGF4, suggesting that complete rescue of the ALS phenotype by FGF4 is hindered by ongoing complex neuroinflammatory processes in vivo. In summary, our data demonstrate that astrocytes generated from ALS iPSCs are inherently dysfunctional and exhibit an immune reactive phenotype. Effectively targeting astrocyte dysfunction and reactivity in vivo may help mitigate ALS and prevent MN death.}, } @article {pmid39362869, year = {2024}, author = {Ma, YY and Li, X and Yu, ZY and Luo, T and Tan, CR and Bai, YD and Xu, G and Sun, BD and Bu, XL and Liu, YH and Jin, WS and Gao, YQ and Zhou, XF and Liu, J and Wang, YJ}, title = {Oral antioxidant edaravone protects against cognitive deficits induced by chronic hypobaric hypoxia at high altitudes.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {415}, pmid = {39362869}, issn = {2158-3188}, support = {92249305//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; *Edaravone/pharmacology/administration & dosage ; *Cognitive Dysfunction/etiology/drug therapy/prevention & control ; Mice ; *Oxidative Stress/drug effects ; Male ; *Hypoxia/complications/drug therapy/metabolism ; *Altitude ; Antioxidants/pharmacology/administration & dosage ; Mice, Inbred C57BL ; Administration, Oral ; Hippocampus/drug effects/metabolism ; Disease Models, Animal ; Free Radical Scavengers/administration & dosage/pharmacology ; Brain/drug effects/metabolism ; }, abstract = {Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas.}, } @article {pmid39363348, year = {2024}, author = {Chevalier, E and Audrain, M and Ratnam, M and Ollier, R and Fuchs, A and Piorkowska, K and Pfeifer, A and Kosco-Vilbois, M and Seredenina, T and Afroz, T}, title = {Targeting the TDP-43 low complexity domain blocks spreading of pathology in a mouse model of ALS/FTD.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {156}, pmid = {39363348}, issn = {2051-5960}, support = {P01 AG019724/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; Mice ; *Disease Models, Animal ; *Frontotemporal Dementia/pathology/metabolism ; *Antibodies, Monoclonal/pharmacology ; Humans ; Mice, Transgenic ; }, abstract = {Abnormal cytoplasmic localization and accumulation of pathological transactive response DNA binding protein of 43 kDa (TDP-43) underlies several devastating diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). A key element is the correlation between disease progression and spatio-temporal propagation of TDP-43-mediated pathology in the central nervous system. Several lines of evidence support the concept of templated aggregation and cell to cell spreading of pathological TDP-43. To further investigate this mechanism in vivo, we explored the efficacy of capturing and masking the seeding-competent region of extracellular TDP-43 species. For this, we generated a novel monoclonal antibody (mAb), ACI-6677, that targets the pathogenic protease-resistant amyloid core of TDP-43. ACI-6677 has a picomolar binding affinity for TDP-43 and is capable of binding to all C-terminal TDP-43 fragments. In vitro, ACI-6677 inhibited TDP-43 aggregation and boosted removal of pathological TDP-43 aggregates by phagocytosis. When injecting FTLD-TDP brain extracts unilaterally in the CamKIIa-hTDP-43NLSm mouse model, ACI-6677 significantly limited the induction of phosphorylated TDP-43 (pTDP-43) inclusions. Strikingly, on the contralateral side, the mAb significantly prevented pTDP-43 inclusion appearance exemplifying blocking of the spreading process. Taken together, these data demonstrate for the first time that an immunotherapy targeting the protease-resistant amyloid core of TDP-43 has the potential to restrict spreading, substantially slowing or stopping progression of disease.}, } @article {pmid39363643, year = {2025}, author = {Capelle, DP and Sabirin, W and Zulhairy-Liong, NA and Edgar, S and Goh, KJ and Ahmad-Annuar, A and Shahrizaila, N}, title = {Multistep modeling applied to a Malaysian ALS registry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {157-161}, doi = {10.1080/21678421.2024.2410280}, pmid = {39363643}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; *Registries ; Malaysia/epidemiology ; Male ; Female ; Middle Aged ; Aged ; Adult ; Disease Progression ; Incidence ; Age of Onset ; }, abstract = {OBJECTIVE: To apply the multistep model of pathogenesis in amyotrophic lateral sclerosis (ALS) to data from a multiethnic Malaysian registry.

METHODS: Clinical data, including age at symptom onset, was collected from 289 patients who presented to our multidisciplinary clinic from 2016 until 2024. A least squares linear regression model was constructed from the logarithm of approximated incidence and the logarithm of age. Population incidence was approximated by adjusting the absolute numbers of patients in 5 year groups by the size of the general population in the respective age group.

RESULTS: A linear relationship between log of incidence versus log of age was observed, with a slope of 4.57 (95% CI, 3.3-5.8) and an r[2] value of 0.93, suggesting a 6-step process.

CONCLUSION: Progression toward symptom onset in Malaysian ALS patients appears consistent with a multistep model of disease as observed in other cohorts.}, } @article {pmid39364217, year = {2024}, author = {Samuel Olajide, T and Oyerinde, TO and Omotosho, OI and Okeowo, OM and Olajide, OJ and Ijomone, OM}, title = {Microglial senescence in neurodegeneration: Insights, implications, and therapeutic opportunities.}, journal = {Neuroprotection (Chichester, England)}, volume = {2}, number = {3}, pages = {182-195}, pmid = {39364217}, issn = {2770-730X}, support = {K43 TW011920/TW/FIC NIH HHS/United States ; }, abstract = {The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression. Recent research has linked disease-associated microglia to their transition into a senescent state-characterized by irreversible cell cycle arrest-in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets. This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.}, } @article {pmid39364420, year = {2024}, author = {Aiello, EN and Contarino, VE and Conte, G and Solca, F and Curti, B and Maranzano, A and Torre, S and Casale, S and Doretti, A and Colombo, E and Verde, F and Silani, V and Liu, C and Cinnante, C and Triulzi, FM and Morelli, C and Poletti, B and Ticozzi, N}, title = {QSM-detected iron accumulation in the cerebellar gray matter is selectively associated with executive dysfunction in non-demented ALS patients.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1426841}, pmid = {39364420}, issn = {1664-2295}, abstract = {BACKGROUND: This study aimed to assess whether quantitative susceptibility imaging (QSM)-based measures of iron accumulation in the cerebellum predict cognitive and behavioral features in non-demented amyotrophic lateral sclerosis (ALS) patients.

METHODS: A total of ALS patients underwent 3-T MRI and a clinical assessment using the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Regression models were applied to each subscale of the cognitive section of the ECAS and the ECAS-Carer Interview to examine the effect of QSM-based measures in white and gray matter (WM; GM) of the cerebellum, separately for right, left, and bilateral cerebellar regions of interest (ROIs). These effects were compared to those of cerebellar volumetrics in WM/GM, right and left hemispheres while controlling for demographics, disease status, and total intracranial volume.

RESULTS: Higher QSM measures of the cerebellar GM on the left, right, and bilateral sides significantly predicted (ps ≤ 0.003) a greater number of errors on the executive functioning (EF) subscale of the ECAS (ECAS-EF). Moreover, higher GM-related, QSM measures of the cerebellum were associated with an increased probability of a below-cut-off performance on the ECAS-EF (ps ≤ 0.024). No significant effects were observed for QSM measures of the cerebellar WM or for volumetric measures on the ECAS-EF. Other ECAS measures showed no significant effects. Bilateral QSM measures of the cerebellar GM also selectively predicted performance on backward digit span and social cognition tasks.

DISCUSSION: Iron accumulation within the cerebellar GM, particularly in the cerebellar cortices, may be associated with executive functioning deficits in non-demented ALS patients. Therefore, QSM-based measures could be useful for identifying the neural correlates of extra-motor cognitive deficits in ALS patients.}, } @article {pmid39365785, year = {2024}, author = {Putri, KD and Guntoro, D and Ardie, SW and Hariyadi, }, title = {A new amino acid substitution in the MvALS1 gene of metsulfuron-methyl resistant biotypes Monochoria vaginalis (Burm. f.) C. Presl from West Java, Indonesia.}, journal = {PloS one}, volume = {19}, number = {10}, pages = {e0308465}, pmid = {39365785}, issn = {1932-6203}, mesh = {Indonesia ; *Arylsulfonates/pharmacology ; *Amino Acid Substitution ; *Herbicide Resistance/genetics ; Herbicides/pharmacology ; Plant Proteins/genetics ; Mutation ; }, abstract = {The most bothersome weed in rice fields in the Indonesian province of West Java is Monochoria vaginalis (Burm. F.) C. Presl, an aquatic herbaceous plant. Metsulfuron-methyl has long been used in wetland rice in West Java with a high enough intensity. However, the case of Monochoria vaginalis resistance to metsulfuron-methyl herbicides in Indonesia has not been widely reported and investigated. The study aims to (1) classify the resistance level of M. vaginalis toward metsulfuron-methyl, (2) identify Target Site Resistance (TSR) mechanism mutations in the MvALS1 gene of the resistant biotype of M. vaginalis. The Whole Plant Pot Test method was utilized to assess the resistance level of Monochoria vaginalis. Following that, all samples were subjected to DNA sequencing using the PCR method to identify mutations in the MvALS1 gene from the resistant biotype. After then, this study used DUET, a server with an integrated computational methodology, to anticipate the effect of mutations on protein stability. The result showed that Monochoria vaginalis from Rawamerta, Karawang showed a moderate level of resistance to metsulfuron-methyl with a resistance ratio of 6.00, Patokbeusi, Subang showed a low level of resistance to metsulfuron-methyl with a resistance ratio of 3.89, compared to susceptible Monochoria vaginalis. Nucleotide base alignment in the MvALS1 gene revealed that base substitutions occurred in the Monochoria vaginalis biotype from Rawamerta and Patokbeusi, resulting in 5 amino acid substitutions: Ser-64-Ala, Asp-66-Glu, Asn-240-Asp, Glu-426-Asn, and Ser-469-Asn and Sukra: Ser-64-Ala, Asp-66-Glu, and Asn-240-Asp. The analysis showed that S64A, D66E, and N240D stabilize the protein, whereas E426N and S469N destabilize it. This study confirms for the first time that Ser-64-Ala, Asn-240-Asp, and Glu-426-Asn amino acid mutations were found in cases of M. vaginalis resistance to metsulfuron-methyl (ALS inhibitor).}, } @article {pmid39366938, year = {2024}, author = {Hutchings, AJ and Hambrecht, B and Veh, A and Giridhar, NJ and Zare, A and Angerer, C and Ohnesorge, T and Schenke, M and Selvaraj, BT and Chandran, S and Sterneckert, J and Petri, S and Seeger, B and Briese, M and Stigloher, C and Bischler, T and Hermann, A and Damme, M and Sendtner, M and Lüningschrör, P}, title = {Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8622}, pmid = {39366938}, issn = {2041-1723}, support = {LU 2347/3-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; VORAN-2 16LW066//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; }, mesh = {Animals ; Humans ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Autophagy ; Disease Models, Animal ; Exocytosis ; *Guanine Nucleotide Exchange Factors/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism ; Lysosomes/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; *Motor Neurons/metabolism ; Presynaptic Terminals/metabolism ; rab GTP-Binding Proteins/metabolism/genetics ; *Superoxide Dismutase-1/metabolism/genetics ; }, abstract = {Increasing evidence suggests an essential function for autophagy in unconventional protein secretion (UPS). However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated guanine exchange factor Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into autophagosomal carriers, which subsequently fuse with secretory lysosomal-related organelles (LROs). Exocytosis of LROs to release Sod1 into the extracellular milieu requires the activation of the small GTPase Rab26 by Plekhg5. Deletion of Plekhg5 in mice leads to the accumulation of Sod1 in LROs at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1[G93A] following deletion of Plekhg5 in SOD1[G93A] mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human iPSC-derived motoneurons we show that reduced levels of PLEKHG5 cause an impaired secretion of ALS-linked SOD1. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway.}, } @article {pmid39367160, year = {2024}, author = {Metzger, M and Dukic, S and McMackin, R and Giglia, E and Mitchell, M and Bista, S and Costello, E and Peelo, C and Tadjine, Y and Sirenko, V and McManus, L and Buxo, T and Fasano, A and Chipika, R and Pinto-Grau, M and Schuster, C and Heverin, M and Coffey, A and Broderick, M and Iyer, PM and Mohr, K and Gavin, B and Pender, N and Bede, P and Muthuraman, M and Hardiman, O and Nasseroleslami, B}, title = {Distinct Longitudinal Changes in EEG Measures Reflecting Functional Network Disruption in ALS Cognitive Phenotypes.}, journal = {Brain topography}, volume = {38}, number = {1}, pages = {3}, pmid = {39367160}, issn = {1573-6792}, support = {HRA-POR-2013-246; MRCG-2018-02 and HRB ILP-POR-2022-046//Health Research Board of Ireland/ ; IceBucket Award; MRCG2018-02 to B.N., McManus/Apr22/888-791 to L.M. and McMackin/Oct20/972-799 to R.M//Irish/UK Motor Neurone Disease Research Foundation/ ; Project-ID 424778381-TRR 295//Deutsche Forschungsgemeinschaft/ ; Emerging Investigator Award HRB-EIA-2017-019//Health Research Board of Ireland/ ; GOIPD/2015/213 to B.N. and GOIPG/2017/1014 to R.M.//Irish Research Council/ ; /WT_/Wellcome Trust/United Kingdom ; 16/ ERCD/3854 and Royal Society/SFI URF\R1\221917 to L.M./SFI_/Science Foundation Ireland/Ireland ; multi-year grant 20-IIA-546//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; *Electroencephalography/methods ; Middle Aged ; Longitudinal Studies ; Aged ; Phenotype ; Brain/physiopathology ; Cognition/physiology ; Disease Progression ; Cognitive Dysfunction/physiopathology ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterised primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. We have shown previously that resting-state EEG captures dysfunction in motor and cognitive networks in ALS. However, the longitudinal development of these dysfunctional patterns, especially in networks linked with cognitive-behavioural functions, remains unclear. Longitudinal studies on non-motor changes in ALS are essential to further develop our understanding of disease progression, improve care and enhance the evaluation of new treatments. To address this gap, we examined 124 ALS individuals with 128-channel resting-state EEG recordings, categorised by cognitive impairment (ALSci, n = 25), behavioural impairment (ALSbi, n = 58), or non-impaired (ALSncbi, n = 53), with 12 participants meeting the criteria for both ALSci and ALSbi. Using linear mixed-effects models, we characterised the general and phenotype-specific longitudinal changes in brain network, and their association with cognitive performance, behaviour changes, fine motor symptoms, and survival. Our findings revealed a significant decline in [Formula: see text]-band spectral power over time in the temporal region along with increased [Formula: see text]-band power in the fronto-temporal region in the ALS group. ALSncbi participants showed widespread β-band synchrony decrease, while ALSci participants exhibited increased co-modulation correlated with verbal fluency decline. Longitudinal network-level changes were specific of ALS subgroups and correlated with motor, cognitive, and behavioural decline, as well as with survival. Spectral EEG measures can longitudinally track abnormal network patterns, serving as a candidate stratification tool for clinical trials and personalised treatments in ALS.}, } @article {pmid39367212, year = {2024}, author = {Cogan, G and Zaki, MS and Issa, M and Keren, B and Guillaud-Bataille, M and Renaldo, F and Isapof, A and Lallemant, P and Stevanin, G and Guillot-Noel, L and Courtin, T and Buratti, J and Freihuber, C and Gleeson, JG and Howarth, R and Durr, A and de Sainte Agathe, JM and Mignot, C}, title = {Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis.}, journal = {Human genetics}, volume = {143}, number = {11}, pages = {1353-1362}, pmid = {39367212}, issn = {1432-1203}, support = {R01 NS098004/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *Paraparesis, Spastic/genetics ; *Pedigree ; Child ; Adolescent ; Adult ; Membrane Proteins/genetics ; Alleles ; Phenotype ; Mutation ; Child, Preschool ; Young Adult ; Intellectual Disability/genetics ; }, abstract = {Biallelic variants in the ERLIN1 gene were recently reported as the cause of two motor neuron degeneration diseases, SPG62 and a recessive form of amyotrophic lateral sclerosis. However, only 12 individuals from five pedigrees have been identified so far. Thus, the description of the disease remains limited. Following the discovery of a homozygous pathogenic variant in a girl with SPG62, presenting with intellectual disability, and epilepsy, we gathered the largest series of SPG62 cases reported so far (13 individuals) to better understand the phenotype associated with ERLIN1. We collected molecular and clinical data for 13 individuals from six families with ERLIN1 biallelic variants. We performed RNA-seq analyses to characterize intronic variants and used Alphafold and a transcripts database to characterize the molecular consequences of the variants. We identified three new variants suspected to alter the bell-shaped ring formed by the ERLIN1/ERLIN2 complex. Affected individuals had childhood-onset paraparesis with slow progression. Six individuals presented with gait ataxia and three had superficial sensory loss. Aside from our proband, none had intellectual disability or epilepsy. Biallelic pathogenic ERLIN1 variants induce a rare, predominantly pure, spastic paraparesis, with possible cerebellar and peripheral nerve involvement.}, } @article {pmid39367309, year = {2024}, author = {Makled, AF and Ali, SAM and Labeeb, AZ and Salman, SS and Shebl, DZM and Hegazy, SG and Sabal, MS}, title = {Characterization of Candida species isolated from clinical specimens: insights into virulence traits, antifungal resistance and molecular profiles.}, journal = {BMC microbiology}, volume = {24}, number = {1}, pages = {388}, pmid = {39367309}, issn = {1471-2180}, mesh = {Humans ; *Candida/genetics/pathogenicity/drug effects/isolation & purification/classification ; *Drug Resistance, Fungal/genetics ; *Antifungal Agents/pharmacology ; *Virulence Factors/genetics ; *Candidiasis/microbiology ; *Biofilms/growth & development ; *Microbial Sensitivity Tests ; Virulence/genetics ; Multiplex Polymerase Chain Reaction ; Male ; Female ; Adult ; Middle Aged ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Candida species have emerged as a significant cause of opportunistic infections. Alongside the expression of various virulence factors, the rise of antifungal resistance among Candida species presents a considerable clinical challenge.

AIM: This study aimed to identify different Candida species isolated from clinical specimens, evaluate their antifungal sensitivity patterns, identify key genes regulating virulence mechanisms using multiplex PCR and to assess any correlation between their virulence profiles and antifungal resistance patterns.

METHOD: A total of 100 Candida spp. was isolated from 630 different clinical specimens and identified to the species level. Their antifungal susceptibility was phenotypically evaluated in accordance with CLSI guidelines using the Vitek-2 Compact System. Virulence markers, including biofilm formation capacity, protease production, melanin production, coagulase production and hemolysin production, were also phenotypically detected. The genetic determinants for biofilm formation and extracellular hydrolytic enzymes were assessed using a multiplex PCR assay.

RESULTS: The prevalence of Candida spp. was 15.9%, with C. albicans (48%) and C. glabrata (16%) being the most common. C. albicans showed the highest virulence, with strong biofilm formation, and high proteinase and melanin production. Multiplex PCR revealed Hlp in 22.0%, Hwp in 80.0%, Als in 56.0%, and Sap genes in 56.0% of isolates. Virulence genes were more common in C. albicans than in non-albicans Candida (NAC). Resistance patterns significantly correlated with virulence profiles, with notable associations between flucytosine resistance and the presence of Hlp and Hwp genes.

CONCLUSION: The significant correlation between virulent markers such as germination, coagulase, hemolysin production and resistance patterns among different Candida isolates is crucial for predicting the severity and outcomes of Candida infections. This understanding aids in guiding tailored treatment strategies.}, } @article {pmid39367779, year = {2025}, author = {Duran, S and Aydogdu, A}, title = {The effect of structured psychoeducation for caregivers of ALS patients on perceived stress, psychological resilience and self-compassion.}, journal = {Health education research}, volume = {40}, number = {1}, pages = {}, doi = {10.1093/her/cyae031}, pmid = {39367779}, issn = {1465-3648}, mesh = {Humans ; *Caregivers/psychology/education ; Male ; Female ; *Amyotrophic Lateral Sclerosis/psychology ; *Resilience, Psychological ; Middle Aged ; *Empathy ; *Stress, Psychological/prevention & control/psychology ; Adaptation, Psychological ; Adult ; Aged ; Turkey ; Surveys and Questionnaires ; }, abstract = {Patients diagnosed with amyotrophic lateral sclerosis (ALS) become dependent on caregivers to meet their daily needs and perform personal care activities. For this reason, ALS is a disease that can challenge both the patient and the caregiver physically, mentally and socially. Supporting the caregiver indirectly affects the patient's quality of care and mental well-being. Therefore, this study aimed to determine the effect of a structured psychoeducation program on coping with stress, psychological resilience and self-compassion in caregivers of ALS patients. This quasi-experimental study with a pre-test-post-test control group was conducted with caregivers of 62 ALS patients in Türkiye. The study was conducted between July 2023 and February 2024. A psychoeducation program was applied to five different groups via zoom application for 6 weeks each. The survey form, Perceived Stress Scale, Brief Resilience Scale and Short Form of Self-Compassion Questionnaire were used as measurement tools. The chi-squared test and paired samples t-test were used to analyze the data. While there was no significant difference between the intervention group and the control group in the pre-test in terms of their mean scores on the coping with stress inventory, short psychological resilience scale and self-compassion scale, at the post-test, psychological resilience and self-compassion scores were significantly higher in the intervention group. This study revealed that psychoeducational programs that support caregivers are effective in increasing psychological resilience and self-compassion.}, } @article {pmid39368179, year = {2025}, author = {Brito, ALB and Cardoso, IF and Viegas, LP and Fausto, R}, title = {Semi-quantitative chemometric models for characterization of mixtures of sugars using infrared spectral data.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {326}, number = {}, pages = {125225}, doi = {10.1016/j.saa.2024.125225}, pmid = {39368179}, issn = {1873-3557}, mesh = {*Chemometrics/methods ; *Models, Chemical ; *Sugars/analysis ; Spectrophotometry, Infrared ; Principal Component Analysis ; Multivariate Analysis ; Least-Squares Analysis ; }, abstract = {Sugars (saccharides) are sweet-tasting carbohydrates that are abundant in foods and play very important roles in living organisms, particularly as sources and stores of energy, and as structural elements in cellular membranes. They are desirable therapeutic targets, as they participate in multiple metabolic processes as fundamental elements. However, the physicochemical characterization of sugars is a challenging task, mostly due to the structural similarity shared by the large diversity of compounds of this family. The need for fast, accurate enough, and cost-effective analytical methods for these substances is of extreme relevance, in particular because of the recently increasing importance of carbohydrates in Medicine and food industry. With this in view, this work focused on the development of chemometric models for semi-quantitative analysis of samples of different types of sugars (glucose, galactose, mannitol, sorbose and fructose) using infrared spectra as data, as an example of application of a novel approach, where the Principal Component Analysis (PCA) score plots are used to estimate the composition (weight-%) of the mixtures of the sugars. In these plots, polygonal geometric shapes emerge in the vectorial space of the most significant principal components, that allow grouping different types of samples on the vertices, edges, faces and interior of the polygons according to the composition of the samples. This approach was applied successfully to mixtures of up to 5 sugars and shown to appropriately extract the compositional information from the hyper-redundant complex spectral data. Thought the method has been applied here to a specific problem, it shall be considered as a general procedure for the semi-quantitative analysis of other types of mixtures and applicable to other types of data reflecting their composition. In fact, the methodology appears as an efficient tool to solve three main general problems: (i) use hyper-redundant (in variables) data, as spectral information, directly and with minimum pre-treatment, to evaluate semi-quantitatively the composition of mixtures; (ii) do this for systems which produce data that can be considered rather similar; and (iii) do it for a number of substances present in the mixtures that might be greater than that usually considered in chemistry, which in general is limited to 3 components. In addition, this work also demonstrates that, similarly to the developed analysis based on the PCA score plots, the Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS) chemometric method can also be used successfully for the qualitative (when used without any previous knowledge of the components present in the samples) or semi-quantitative (when the pure components spectral profiles are provided as references) analyses of mixtures of (at least) up to 5 distinct sugars.}, } @article {pmid39368746, year = {2024}, author = {Sharma, R and Mehan, S and Khan, Z and Das Gupta, G and Narula, AS}, title = {Therapeutic potential of oleanolic acid in modulation of PI3K/Akt/mTOR/STAT-3/GSK-3β signaling pathways and neuroprotection against methylmercury-induced neurodegeneration.}, journal = {Neurochemistry international}, volume = {180}, number = {}, pages = {105876}, doi = {10.1016/j.neuint.2024.105876}, pmid = {39368746}, issn = {1872-9754}, mesh = {Animals ; *Oleanolic Acid/pharmacology/therapeutic use ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; Male ; *Methylmercury Compounds/toxicity ; *Glycogen Synthase Kinase 3 beta/metabolism ; *TOR Serine-Threonine Kinases/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Phosphatidylinositol 3-Kinases/metabolism ; Rats, Wistar ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Neuroprotection/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that gradually deteriorates motor neurons, leading to demyelination, muscle weakness, and eventually respiratory failure. The disease involves several pathological processes, such as increased glutamate levels, mitochondrial dysfunction, and persistent neuroinflammation, often exacerbated by environmental toxins like mercury. This study explores the therapeutic potential of Olea europaea active phytoconstituents oleanolic acid (OLA) against ALS by targeting the overactivated PI3K/Akt/mTOR/STAT-3/GSK-3β signalling pathways. Methods involved in-silico studies, in vitro and in vivo experiments in which varying doses of methylmercury 5 mg/kg, p.o. and OLA (100 and 200 mg/kg, i.p.) were administered to rats for 42 days. Behavioural assessments, gross morphological, histopathological, and neurochemical parameters were measured in cerebrospinal fluid (CSF), blood plasma, and brain homogenates (cerebral cortex, hippocampus, striatum, midbrain, cerebellum) along with complete blood count (CBC) analysis. Results revealed OLA's significant neuroprotective properties. OLA effectively modulated targeted pathways, reducing pro-inflammatory cytokines, restoring normal levels of myelin basic protein (MBP) and neurofilament light chain (NEFL), and reducing histopathological changes. Gross pathological studies indicated less tissue damage, while CBC analysis showed improved hematology parameters. Additionally, the combination of OLA and edaravone (10 mg/kg, i.p.) demonstrated enhanced efficacy, improving motor functions and extending survival in ALS model rats. In conclusion, OLA exhibits significant therapeutic potential for ALS, acting as a potent modulator of key pathological signaling pathways. The findings suggest the feasibility of integrating OLA into existing treatment regimens, potentially improving clinical outcomes for ALS patients. However, further research must validate these findings in human clinical trials.}, } @article {pmid39369616, year = {2024}, author = {Zhao, Y and Li, X and Wang, K and Iyer, G and Sakowski, SA and Zhao, L and Teener, S and Bakulski, KM and Dou, JF and Traynor, BJ and Karnovsky, A and Batterman, SA and Feldman, EL and Sartor, MA and Goutman, SA}, title = {Epigenetic age acceleration is associated with occupational exposures, sex, and survival in amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {109}, number = {}, pages = {105383}, pmid = {39369616}, issn = {2352-3964}, support = {R01 TS000289/TS/ATSDR CDC HHS/United States ; R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/etiology/mortality ; Male ; Female ; *Epigenesis, Genetic ; *Occupational Exposure/adverse effects ; Middle Aged ; *DNA Methylation ; Aged ; Sex Factors ; Aging/genetics ; Case-Control Studies ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is linked to ageing and genetic and environmental risk factors, yet underlying mechanisms are incompletely understood. We aimed to evaluate epigenetic age acceleration (EAA), i.e., DNA methylation (DNAm) age acceleration, and its association with ALS case status and survival.

METHODS: In this study, we included 428 ALS and 288 control samples collected between 2011 and 2021. We calculated EAA using the GrimAge residual method from ALS and control blood samples and grouped participants with ALS into three ageing groups (fast, normal, slow). We associated EAA with ALS case status and survival, stratified by sex, and correlated it with environmental and biological factors through occupational exposure assessments, immune cell proportions, and transcriptome changes.

FINDINGS: Participants with ALS had higher average EAA by 1.80 ± 0.30 years (p < 0.0001) versus controls. Participants with ALS in the fast ageing group had a hazard ratio of 1.52 (95% confidence interval 1.16-2.00, p = 0.0028) referenced to the normal ageing group. In males, this hazard ratio was 1.55 (95% confidence interval 1.11-2.17, p = 0.010), and EAA was positively correlated with high-risk occupational exposures including particulate matter (adj.p < 0.0001) and metals (adj.p = 0.0087). Also, in male participants with ALS, EAA was positively correlated with neutrophil proportions and was negatively correlated with CD4+ T cell proportions. Pathways dysregulated in participants with ALS with fast ageing included spliceosome, nucleocytoplasmic transport, axon guidance, and interferons.

INTERPRETATION: EAA was associated with ALS case status and, at least in males, with shorter survival after diagnosis. The effect of EAA on ALS was partially explained by occupational exposures and immune cell proportions in a sex-dependent manner. These findings highlight the complex interactions of ageing and exposures in ALS.

FUNDING: NIH, CDC/National ALS Registry, ALS Association, Dr. Randall Whitcomb Fund for ALS Genetics, Peter Clark Fund for ALS Research, Sinai Medical Staff Foundation, Scott L. Pranger ALS Clinic Fund, NeuroNetwork Therapeutic Discovery Fund, NeuroNetwork for Emerging Therapies.}, } @article {pmid39369804, year = {2024}, author = {Daniels, N and Bindoff, AD and Vickers, JC and King, AE and Collins, JM}, title = {Vulnerability of neurofilament-expressing neurons in frontotemporal dementia.}, journal = {Molecular and cellular neurosciences}, volume = {131}, number = {}, pages = {103974}, doi = {10.1016/j.mcn.2024.103974}, pmid = {39369804}, issn = {1095-9327}, mesh = {Humans ; *Frontotemporal Dementia/metabolism/genetics/pathology ; Aged ; *Neurons/metabolism/pathology ; *Neurofilament Proteins/metabolism ; Female ; Male ; Middle Aged ; *tau Proteins/metabolism/genetics ; Aged, 80 and over ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Frontotemporal dementia (FTD) is an umbrella term for several early onset dementias, that are caused by frontotemporal lobar degeneration (FTLD), which involves the atrophy of the frontal and temporal lobes of the brain. Neuron loss in the frontal and temporal lobes is a characteristic feature of FTLD, however the selective vulnerability of different neuronal populations in this group of diseases is not fully understood. Neurofilament-expressing neurons have been shown to be selectively vulnerable in other neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, therefore we sought to investigate whether this neuronal population is vulnerable in FTLD. We also examined whether neuronal sub-type vulnerability differed between FTLD with TDP-43 inclusions (FTLD-TDP) and FTLD with tau inclusions (FTLD-Tau). Post-mortem human tissue from the superior frontal gyrus (SFG) of FTLD-TDP (n = 15), FTLD-Tau (n = 8) and aged Control cases (n = 6) was immunolabelled using antibodies against non-phosphorylated neurofilaments (SMI32 antibody), calretinin and NeuN, to explore neuronal cell loss. The presence of non-phosphorylated neurofilament immunolabelling in axons of the SFG white matter was also quantified as a measure of axon pathology, as axonal neurofilaments are normally phosphorylated. We demonstrate the selective loss of neurofilament-expressing neurons in both FTLD-TDP and FTLD-Tau cases compared to aged Controls. We also show that non-phosphorylated neurofilament axonal pathology in the SFG white matter was associated with increasing age, but not FTLD. This data suggests neurofilament-expressing neurons are vulnerable in both FTLD-TDP and FTLD-Tau.}, } @article {pmid39370211, year = {2024}, author = {Kajitani, GS and Xavier, G and Villena-Rueda, BE and Karia, BTR and Santoro, ML}, title = {Extracellular vesicles in neurodegenerative, mental, and other neurological disorders: Perspectives into mechanisms, biomarker potential, and therapeutic implications.}, journal = {Current topics in membranes}, volume = {94}, number = {}, pages = {299-336}, doi = {10.1016/bs.ctm.2024.06.002}, pmid = {39370211}, issn = {1063-5823}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; *Biomarkers/metabolism ; Mental Disorders/metabolism/drug therapy/therapy ; Animals ; Nervous System Diseases/metabolism/pathology ; }, abstract = {Extracellular vesicles (EVs) are produced, secreted, and targeted by most human cells, including cells that compose nervous system tissues. EVs carry several types of biomolecules, such as lipids, proteins and microRNA, and can function as signaling agents in physiological and pathological processes. In this chapter, we will focus on EVs and their cargo secreted by brain cells, especially neurons and glia, and how these aspects are affected in pathological conditions. The chapter covers neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, as well as several psychiatric disorders, namely schizophrenia, autism spectrum disorder and major depressive disorder. This chapter also addresses other types of neurological dysfunctions, epilepsy and traumatic brain injury. EVs can cross the blood brain barrier, and thus brain EVs may be detected in more accessible peripheral tissue, such as circulating blood. Alterations in EV composition and contents can therefore impart valuable clues into the molecular etiology of these disorders, and serve biomarkers regarding disease prevalence, progression and treatment. EVs can also be used to carry drugs and biomolecules into brain tissue, considered as a promising drug delivery agent for neurological diseases. Therefore, although this area of research is still in its early development, it offers great potential in further elucidating and in treating neurological disorders.}, } @article {pmid39371161, year = {2024}, author = {Angrick, M and Luo, S and Rabbani, Q and Joshi, S and Candrea, DN and Milsap, GW and Gordon, CR and Rosenblatt, K and Clawson, L and Maragakis, N and Tenore, FV and Fifer, MS and Ramsey, NF and Crone, NE}, title = {Real-time detection of spoken speech from unlabeled ECoG signals: A pilot study with an ALS participant.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39371161}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: Brain-Computer Interfaces (BCIs) hold significant promise for restoring communication in individuals with partial or complete loss of the ability to speak due to paralysis from amyotrophic lateral sclerosis (ALS), brainstem stroke, and other neurological disorders. Many of the approaches to speech decoding reported in the BCI literature have required time-aligned target representations to allow successful training - a major challenge when translating such approaches to people who have already lost their voice.

APPROACH: In this pilot study, we made a first step toward scenarios in which no ground truth is available. We utilized a graph-based clustering approach to identify temporal segments of speech production from electrocorticographic (ECoG) signals alone. We then used the estimated speech segments to train a voice activity detection (VAD) model using only ECoG signals. We evaluated our approach using held-out open-loop recordings of a single dysarthric clinical trial participant living with ALS, and we compared the resulting performance to previous solutions trained with ground truth acoustic voice recordings.

MAIN RESULTS: Our approach achieves a median error rate of around 0.5 seconds with respect to the actual spoken speech. Embedded into a real-time BCI, our approach is capable of providing VAD results with a latency of only 10 ms.

SIGNIFICANCE: To the best of our knowledge, our results show for the first time that speech activity can be predicted purely from unlabeled ECoG signals, a crucial step toward individuals who cannot provide this information anymore due to their neurological condition, such as patients with locked-in syndrome.

CLINICAL TRIAL INFORMATION: ClinicalTrials.gov, registration number NCT03567213.}, } @article {pmid39371851, year = {2024}, author = {Po, K and Olaivar, M}, title = {Juvenile Amyotrophic Lateral Sclerosis: A Case Report of a Rare and Aggressive Presentation in a 22-Year-Old Filipino Male.}, journal = {Cureus}, volume = {16}, number = {9}, pages = {e68579}, pmid = {39371851}, issn = {2168-8184}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disorder primarily affecting adults, but juvenile-onset ALS is exceptionally rare. We report a rare case of a 22-year-old Filipino male patient who exhibited early-onset weakness, muscle atrophy, and tongue fasciculations, followed by rapidly progressive dysphagia and respiratory distress. Electromyography - Nerve Conduction Velocity (EMG-NCV) findings showed evidence for a chronic, active predominantly motor neuronal-axonal loss type of neuropathy involving the tongue and limb muscles bilaterally consistent with a motor neuron disease. The patient was treated with riluzole with no significant improvement in symptoms. Despite multidisciplinary interventions, the disease rapidly progressed, highlighting the challenges in managing juvenile ALS cases. This case report emphasizes the importance of considering ALS in the differential diagnosis of progressive motor dysfunction in younger patients and the complexities involved in their care.}, } @article {pmid39372031, year = {2024}, author = {Pillai, M and Jha, SK}, title = {Conformational Enigma of TDP-43 Misfolding in Neurodegenerative Disorders.}, journal = {ACS omega}, volume = {9}, number = {39}, pages = {40286-40297}, pmid = {39372031}, issn = {2470-1343}, abstract = {Misfolding and aggregation of the protein remain some of the most common phenomena observed in neurodegeneration. While there exist multiple neurodegenerative disorders characterized by accumulation of distinct proteins, what remains particularly interesting is the ability of these proteins to undergo a conformational change to form aggregates. TDP-43 is one such nucleic acid binding protein whose misfolding is associated with many neurogenerative diseases including amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). TDP-43 protein assumes several different conformations and oligomeric states under the diseased condition. In this review, we explore the intrinsic relationship between the conformational variability of TDP-43 protein, with a particular focus on the RRM domains, and its propensity to undergo aggregation. We further emphasize the probable mechanism behind the formation of these conformations and suggest a potential diagnostic and therapeutic strategy in the context of these conformational states of the protein.}, } @article {pmid39373307, year = {2025}, author = {Rajagopalan, V and Pioro, EP}, title = {Graph theory network analysis reveals widespread white matter damage in brains of patients with classic ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {85-92}, doi = {10.1080/21678421.2024.2410281}, pmid = {39373307}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; *White Matter/diagnostic imaging/pathology ; Middle Aged ; Magnetic Resonance Imaging ; *Brain/pathology/diagnostic imaging ; Aged ; Gray Matter/diagnostic imaging/pathology ; Adult ; Image Processing, Computer-Assisted ; *Nerve Net/diagnostic imaging/pathology ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) exhibits several different presentations and clinical phenotypes. Of these, classic ALS (ALS-Cl), which is the most common phenotype, presents with relatively equal amounts of upper motor neuron and lower motor neuron signs. Magnetic resonance imaging (MRI) provides a noninvasive way to assess central nervous system damage in these patients. To our knowledge no study is available where exploratory whole brain grey matter (GM) and white matter (WM) network analysis is performed considering only the ALS-Cl subgroup of ALS patients.

METHODS: GM voxel-based morphometry analysis and WM network analysis using graph theory was performed in the MRI dataset of 14 neurologic controls and 25 ALS-Cl patients.

RESULTS AND CONCLUSIONS: No significant GM differences were observed between ALS-Cl and neurologic controls. WM network revealed significant (p < 0.05) reduction and increase in degree measure in several extramotor brain regions of ALS-Cl patients. Both global and local graph metrics revealed significant abnormal values in ALS-Cl patients when compared to neurologic controls. Significant WM changes in ALS-Cl patients with no significant GM changes suggest that neurodegeneration may onset as an "axonopathy" in this ALS subtype.}, } @article {pmid39373990, year = {2024}, author = {Appel, SH and Thonhoff, JR}, title = {Barriers to Tofersen Therapy for Variant SOD1-Mediated ALS.}, journal = {JAMA neurology}, volume = {81}, number = {12}, pages = {1239-1240}, doi = {10.1001/jamaneurol.2024.3331}, pmid = {39373990}, issn = {2168-6157}, } @article {pmid39374680, year = {2024}, author = {Tirassa, P and Rosso, P and Fico, E and Marenco, M and Mallone, F and Gharbiya, M and Lambiase, A and Severini, C}, title = {Perspective role of Substance P in Amyotrophic Lateral Sclerosis: From neuronal vulnerability to neuroprotection.}, journal = {Neuroscience and biobehavioral reviews}, volume = {167}, number = {}, pages = {105914}, doi = {10.1016/j.neubiorev.2024.105914}, pmid = {39374680}, issn = {1873-7528}, mesh = {*Substance P/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Humans ; Animals ; Receptors, Neurokinin-1/metabolism ; Neuroprotection/physiology ; Motor Neurons/metabolism/physiology ; }, abstract = {The neuropeptide Substance P (SP) and its preferred Neurokinin1 Receptor (NK1R) are known to participate in the physiopathology of neurodegenerative diseases and mainly exert a neuroprotective role. In the present work, we have described the involvement of SP and NK1R in Amyotrophic Lateral Sclerosis (ALS). This was demonstrated by the detection of altered levels of SP in the brain, spinal cord and cerebrospinal fluid (CSF) of patients and preclinical models of ALS, and by its ability to inhibit excitotoxicity-induced neurodegeneration in ALS animal models. These data are supported by results indicating an excitatory effect of SP at the motor neuron (MN) level, which promotes locomotor activity. ALS patients are characterized by a differential susceptibility to MNs degeneration, since sphincters and extraocular muscles are classically spared. It is hypothesized that SP may play a role in the maintenance of the ocular system and the innervation of the pelvic floor by contributing directly or indirectly to the selective resistance of this subset of MNs.}, } @article {pmid39374890, year = {2024}, author = {Zhang, J and Liu, L and Li, M and Liu, H and Gong, X and Tang, Y and Zhang, Y and Zhou, X and Lin, Z and Guo, H and Pan, L}, title = {Molecular Basis of the Recognition of the Active Rab8a by Optineurin.}, journal = {Journal of molecular biology}, volume = {436}, number = {22}, pages = {168811}, doi = {10.1016/j.jmb.2024.168811}, pmid = {39374890}, issn = {1089-8638}, mesh = {*rab GTP-Binding Proteins/metabolism/chemistry/genetics ; *Cell Cycle Proteins/metabolism/chemistry/genetics ; *Membrane Transport Proteins/metabolism/chemistry/genetics ; Humans ; *Protein Binding ; *Transcription Factor TFIIIA/metabolism/genetics/chemistry ; Models, Molecular ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Crystallography, X-Ray ; GTPase-Activating Proteins/metabolism/chemistry/genetics ; Mutation ; Protein Conformation ; }, abstract = {Optineurin (OPTN), a multifunctional adaptor protein in mammals, plays critical roles in many cellular processes, such as vesicular trafficking and autophagy. Notably, mutations in optineurin are directly associated with many human diseases, such as amyotrophic lateral sclerosis (ALS). OPTN can specifically recognize Rab8a and the GTPase-activating protein TBC1D17, and facilitate the inactivation of Rab8a mediated by TBC1D17, but with poorly understood mechanism. Here, using biochemical and structural approaches, we systematically characterize the interaction between OPTN and Rab8a, revealing that OPTN selectively recognizes the GTP-bound active Rab8a through its leucine-zipper domain (LZD). The determined crystal structure of OPTN LZD in complex with the active Rab8a not only elucidates the detailed binding mechanism of OPTN with Rab8a but also uncovers a unique binding mode of Rab8a with its effectors. Furthermore, we demonstrate that the central coiled-coil domain of OPTN and the active Rab8a can simultaneously interact with the TBC domain of TBC1D17 to form a ternary complex. Finally, based on the OPTN LZD/Rab8a complex structure and relevant biochemical analyses, we also evaluate several known ALS-associated mutations found in the LZD of OPTN. Collectively, our findings provide mechanistic insights into the interaction of OPTN with Rab8a, expanding our understanding of the binding modes of Rab8a with its effectors and the potential etiology of diseases caused by OPTN mutations.}, } @article {pmid39375041, year = {2024}, author = {Shah, NM and Rossel, A and Abdulaziz, B and Sheridan, S and Madden-Scott, S and Radcliffe, G and D'Cruz, R and Suh, ES and Steier, J and Hart, N and Murphy, PB and Ramsay, M and Kaltsakas, G}, title = {Effect of nostril occlusion and mouth sealing in the measurement of sniff nasal inspiratory pressure.}, journal = {Thorax}, volume = {80}, number = {1}, pages = {42-44}, doi = {10.1136/thorax-2024-221910}, pmid = {39375041}, issn = {1468-3296}, mesh = {Humans ; Male ; Female ; Middle Aged ; Aged ; *Respiratory Muscles/physiology/physiopathology ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Inhalation/physiology ; *Mouth ; Adult ; Nose ; Muscle Strength/physiology ; Respiratory Function Tests/methods ; }, abstract = {Sniff nasal inspiratory pressure (SNIP) is used to assess respiratory muscle strength in neuromuscular diseases like amyotrophic lateral sclerosis (ALS). The effect of contralateral nostril occlusion and mouth sealing on SNIP measurement are unclear. 81 participants were included (16 healthy, 39 patients with limb-onset ALS and 26 patients with bulbar-onset ALS). SNIP was obtained with combinations of mouth open/sealed and contralateral nostril open/occluded. Occluding the contralateral nostril (with mouth closed) increased SNIP by 12 cmH2O (95% CI 4, 20; p=0.003) in the healthy participants, by 9 cmH2O (95% CI 5, 12; p<0.001) in the limb-onset cohort and by 10 cmH2O (95% CI 5, 14; p<0.001) in the bulbar-onset cohort. Opening the mouth decreased SNIP by 19 cmH2O (95% CI 5, 34; p<0.009) in healthy participants, by 8 cmH2O (95% CI 4, 13; p<0.001) in the limb-onset cohort and by 13 cmH2O (95% CI 7, 19; p<0.001) in the bulbar-onset cohort. With contralateral nostril occlusion, 11% fewer individuals would have qualified for non-invasive ventilation. In conclusion, contralateral nostril occlusion increased SNIP compared with standard technique, likely reflecting true strength. Opening the mouth reduced SNIP, emphasising the need for good mouth sealing. Documenting SNIP technique is important for longitudinal assessments and clinical decision-making.}, } @article {pmid39375835, year = {2024}, author = {Altomare, D and Bracca, V and Premi, E and Micheli, A and Cotelli, MS and Gasparotti, R and Alberici, A and Borroni, B}, title = {Clinical and imaging correlates of hyperorality in syndromes associated with frontotemporal lobar degeneration.}, journal = {Psychiatry and clinical neurosciences}, volume = {78}, number = {12}, pages = {818-825}, pmid = {39375835}, issn = {1440-1819}, mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; *Frontotemporal Lobar Degeneration/diagnostic imaging/pathology/physiopathology ; Retrospective Studies ; *Frontotemporal Dementia/diagnostic imaging/physiopathology/pathology ; Longitudinal Studies ; Magnetic Resonance Imaging ; Amyotrophic Lateral Sclerosis/diagnostic imaging/complications ; }, abstract = {AIM: Empirical research investigating hyperorality in syndromes associated with frontotemporal lobar degeneration (FTLD) is limited. The present study aims to assess and describe hyperorality and its clinical and imaging correlates in patients with FTLD-associated syndromes.

METHODS: This retrospective longitudinal study included consecutive patients with FTLD who underwent a clinical, cognitive, and behavioral assessment. The presence and severity of hyperorality was assessed using the Frontal Behavior Inventory.

RESULTS: A total of 712 patients with FTLD were included in the study. Hyperorality was reported by 29% (204 of 712 [95% CI: 25-32%]) of patients; was more frequent in those with severe dementia than in those with prodromal or mild to moderate dementia (P < 0.05); was associated with younger age (odds ratio [OR] = 0.96 [95% CI: 0.94-0.99]), (P = 0.003) and positive family history for dementia (OR = 2.03 [95% CI: 1.18-3.49], P = 0.010); was overall more probable in the behavioral variant of frontotemporal dementia (bvFTD) and frontotemporal dementia with amyotrophic lateral sclerosis phenotypes, and less probable in other language or motor phenotypes; and was associated with higher severity of neuropsychiatric symptoms (OR = 1.08 [95% CI: 1.06-1.10], P < 0.001) and with the presence of several behavioral symptoms (P < 0.05). Moreover, hyperorality severity increased over time only in patients with bvFTD (β = +0.15, P = 0.011) or semantic variant of primary progressive aphasia (β = +0.34, P = 0.010). Finally, the presence of hyperorality was significantly associated with greater atrophy in the right anterior insula and right orbitofrontal region (false discovery rate-corrected P < 0.05).

CONCLUSION: Hyperorality is common in certain FTLD-associated syndromes. Understanding its correlates can help clinicians define pharmacological and educational interventions and clarify related anatomical circuits.}, } @article {pmid39376212, year = {2024}, author = {Tomiyama, ALMR and Cartarozzi, LP and de Oliveira Coser, L and Chiarotto, GB and Oliveira, ALR}, title = {Corrigendum: Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1[G93A] mice.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1493884}, doi = {10.3389/fncel.2024.1493884}, pmid = {39376212}, issn = {1662-5102}, abstract = {[This corrects the article DOI: 10.3389/fncel.2023.1211486.].}, } @article {pmid39376539, year = {2024}, author = {Kouchmeshky, A and Whiting, A and McCaffery, P}, title = {Neuroprotective effects of ellorarxine in neuronal models of degeneration.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1422294}, pmid = {39376539}, issn = {1662-4548}, abstract = {INTRODUCTION: Retinoic acid (RA) was first recognised to be important for the central nervous system (CNS) in its developmental regulatory role and, given this action, it has been proposed in the adult CNS to regulate plasticity and promote regeneration. These types of roles have included support of neurogenesis, induction of neurite outgrowth, and protection from neuronal death. These functions are predominantly mediated by the retinoic acid receptor (RAR) transcription factor, and hence agonists for the RARs have been tested in a variety of models of neurodegeneration. This present study employs several in vitro models less explored for the action of RAR agonists to reverse neurodegeneration.

METHODS: A series of assays are used in which neuronal cells are placed under the types of stress that have been linked to neurodegeneration, in particular amyotrophic lateral sclerosis (ALS), and the neuroprotective influence of a new potent agonist for RAR, ellorarxine, is tested out. In these assays, neuronal cells were subjected to excitotoxic stress induced by glutamate, proteostasis disruption caused by epoxomicin, and oxidative stress leading to stress granule formation triggered by sodium arsenite.

RESULTS: Ellorarxine effectively reversed neuronal death in excitotoxic and proteostasis disruption assays and mitigated stress granule formation induced by sodium arsenite. This study also highlights for the first time the novel observation of RAR modulation of stress granules, although it is unknown whether this change in stress granules will be neuroprotective or potentially regenerative. Furthermore, the distribution of RAR agonists following intraperitoneal injection was assessed in mice, revealing preferential accumulation in the central nervous system, particularly in the spinal cord, compared to the liver. Gene expression studies in the spinal cord demonstrated that ellorarxine induces transcriptional changes at a low dose (0.01 mg/kg).

DISCUSSION: These findings underscore the therapeutic potential of RAR agonists, such as ellorarxine, for ALS and potentially other neurodegenerative diseases.}, } @article {pmid39377567, year = {2025}, author = {Rani, P and Rajak, BK and Mahato, GK and Rathore, RS and Chandra, G and Singh, DV}, title = {Strategic lead compound design and development utilizing computer-aided drug discovery (CADD) to address herbicide-resistant Phalaris minor in wheat fields.}, journal = {Pest management science}, volume = {81}, number = {5}, pages = {2469-2479}, doi = {10.1002/ps.8455}, pmid = {39377567}, issn = {1526-4998}, support = {//Science and Engineering Research Board, India/ ; //Department of Biotechnology, Ministry of Science and Technology, India/ ; //Department of Science and Technology, Ministry of Science and Technology, India/ ; }, mesh = {*Herbicide Resistance ; *Herbicides/pharmacology/chemistry ; *Triticum/growth & development ; *Drug Discovery/methods ; *Weed Control/methods ; *Phalaris/drug effects ; *Drug Design ; Plant Weeds/drug effects ; Computer-Aided Design ; Molecular Docking Simulation ; }, abstract = {Wheat (Triticum aestivum) is a vital cereal crop and a staple food source worldwide. However, wheat grain productivity has significantly declined as a consequence of infestations by Phalaris minor. Traditional weed control methods have proven inadequate owing to the physiological similarities between P. minor and wheat during early growth stages. Consequently, farmers have turned to herbicides, targeting acetyl-CoA carboxylase (ACCase), acetolactate synthase (ALS) and photosystem II (PSII). Isoproturon targeting PSII was introduced in mid-1970s, to manage P. minor infestations. Despite their effectiveness, the repetitive use of these herbicides has led to the development of herbicide-resistant P. minor biotypes, posing a significant challenge to wheat productivity. To address this issue, there is a pressing need for innovative weed management strategies and the discovery of novel herbicide molecules. The integration of computer-aided drug discovery (CADD) techniques has emerged as a promising approach in herbicide research, that facilitates the identification of herbicide targets and enables the screening of large chemical libraries for potential herbicide-like molecules. By employing techniques such as homology modelling, molecular docking, molecular dynamics simulation and pharmacophore modelling, CADD has become a rapid and cost-effective medium to accelerate the herbicide discovery process significantly. This approach not only reduces the dependency on traditional experimental methods, but also enhances the precision and efficacy of herbicide development. This article underscores the critical role of bioinformatics and CADD in developing next-generation herbicides, offering new hope for sustainable weed management and improved wheat cultivation practices. © 2024 Society of Chemical Industry.}, } @article {pmid39378421, year = {2024}, author = {Knox, L and Coates, E and Griffiths, A and Ali, Y and Hobson, E and McDermott, C}, title = {Development and Evaluation of the Telehealth in Motor Neuron Disease System: The TIME Study Protocol.}, journal = {JMIR research protocols}, volume = {13}, number = {}, pages = {e57685}, pmid = {39378421}, issn = {1929-0748}, support = {//National Institute for Health and Care Research (NIHR) /NHS, Department of Health and Social Care/ ; }, mesh = {*Motor Neuron Disease/therapy ; Humans ; *Telemedicine ; Surveys and Questionnaires ; Caregivers/psychology ; }, abstract = {BACKGROUND: For more responsive care provision for motor neuron disease and caregivers, a digital system called Telehealth in MND-Care (TiM-C) was created. TiM-C sends regular symptom questionnaires to users; their responses are sent to health care professionals (HCPs). To enable people with motor neuron disease to participate in research studies more easily, a parallel platform was developed from TiM-C, called Telehealth in MND-Research (TiM-R). TiM-R can advertise studies, collect data, and make them available to MND researchers.

OBJECTIVE: This study has 4 work packages (WPs) to facilitate service approval, codevelop the TiM systems, and evaluate the service. Each WP aims to understand (1) what helps and hinders the approval of the TiM-C system as a National Health Service; (2) what aspects of MND care and research are currently unmet and can be addressed through the TiM-C and TiM-R systems; (3) how TiM-C influences MND care, from the perspective of people with motor neuron disease, their caregivers, and HCPs; and (4) the costs and benefits associated with TiM-C.

METHODS: WP1 will use semistructured interviews with 10-15 people involved in the approval of TiM-C to understand the barriers and facilitators to governance processes. WP2 will use individual and group interviews with 25-35 users (people with motor neuron disease, caregivers, HCPs, MND researchers, and industry) of TiM-C and TiM-R to understand the current unmet needs of these user groups and how TiM services can be developed to meet these needs. WP3 will use a process evaluation involving 5 elements; local context, engagement, user experiences, service impact, and mechanisms of action. A range of methods, including audits, analysis of routine data, questionnaires, interviews, and observations will be used with people with motor neuron disease, caregivers, and HCPs, both those using the system and those who declined the service when invited. WP4 will use data collected through the process evaluation and known costs to conduct a cost-consequence and budget impact analysis to explore the cost-benefit of the TiM-C service. Most data collected will be qualitative, with thematic and framework analysis used to develop themes from transcripts and observations. Descriptive statistics or t tests and chi-square tests will be used to describe and analyze quantitative data.

RESULTS: This study has received ethical approval and has begun recruitment in 1 site. Further, 13 specialist MND centers will adopt TiM-C and the TIME study, beginning in July 2024. The study will conclude in November 2026 and a final report will be produced 3 months after the completion date.

CONCLUSIONS: This study will facilitate the implementation and development of TiM-C and TiM-R and fully evaluate the TiM-C service, enabling informed decision-making among health care providers regarding continued involvement and contribute to the wider literature relating to how technology-enabled care services can affect clinical care.

DERR1-10.2196/57685.}, } @article {pmid39378530, year = {2025}, author = {Meng, T and Wu, W and Wang, B and Li, C and Li, J and Liu, J and Wang, J and Qie, R}, title = {Treating chronic pulmonary heart disease with traditional Chinese medicine: Systematic evaluation and mechanistic insights into the resolving phlegm and activating blood approach.}, journal = {Heart & lung : the journal of critical care}, volume = {69}, number = {}, pages = {111-126}, doi = {10.1016/j.hrtlng.2024.09.017}, pmid = {39378530}, issn = {1527-3288}, mesh = {Humans ; Chronic Disease ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Medicine, Chinese Traditional/methods ; *Pulmonary Heart Disease/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Chronic Pulmonary Heart Disease (CPHD) significantly impacts global health, especially among middle-aged and older adults. In China, the Traditional Chinese Medicine (TCM) technique of Resolving Phlegm and Activating Blood (RPAB) is widely used to treat CPHD, although high-quality evidence supporting its efficacy remains limited.

OBJECTIVES: The purpose of this study was to rigorously assess the clinical efficacy of RPAB for CPHD and elucidate the mechanisms underlying its primary herbal components.

METHODS: Through a detailed search of literature in both Chinese and English and strict inclusion and exclusion criteria, 18 randomized controlled trials (RCTs) were selected for meta-analysis. We identified RPAB's core herbal combinations using association rule analysis. This method statistically analyzes the frequency and correlation of herbal medicine usage. We then analyzed the chemical components of these combinations and investigated their potential intervention mechanisms on CPHD through network pharmacology.

RESULTS: The combination of RPAB with Western medicine was superior to Western medicine alone in improving blood gas analysis and pulmonary function and reducing plasma viscosity in CPHD patients. The core herbal combination identified was Astragalus membranaceus (Fisch.) Bunge, Ligusticum chuanxiong Hort. ex S. H. Qiu & al., and Stellaria alsine Grimm (ALS). This combination targeted 588 therapeutic and 27 core targets. It influenced ten core compounds across 34 pathways, primarily through the chemokine signaling pathway and the JAK-STAT signaling pathway.

CONCLUSION: RPAB with Western medicine significantly improves CPHD treatment outcomes. The study highlights the therapeutic potential of the ALS combination, which operates through multiple pathways to remodel pulmonary arteries, decrease inflammation, and lessen oxidative stress. These insights support the clinical application of RPAB in CPHD treatment and open new avenues for research and therapeutic development.}, } @article {pmid39378795, year = {2024}, author = {Lehto, A and Schumacher, J and Kasper, E and Teipel, S and Hermann, A and Prudlo, J}, title = {Loss of the ipsilateral silent period in amyotrophic lateral sclerosis is associated with reduced white matter integrity in the motor section of the corpus callosum.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123267}, doi = {10.1016/j.jns.2024.123267}, pmid = {39378795}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/psychology ; *Corpus Callosum/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *White Matter/diagnostic imaging/pathology ; *Transcranial Magnetic Stimulation/methods ; Aged ; *Motor Cortex/diagnostic imaging/pathology/physiopathology ; Diffusion Tensor Imaging ; Functional Laterality/physiology ; Diffusion Magnetic Resonance Imaging/methods ; Adult ; Neural Inhibition/physiology ; Evoked Potentials, Motor/physiology ; }, abstract = {OBJECTIVE: Interhemispheric neurons in the motor section of the corpus callosum have an inhibitory effect on neurons of the contralateral motor cortex. Three quarters of patients with amyotrophic laterals sclerosis (ALS) show impaired transcallosal inhibition. We aimed to investigate whether structural changes co-occur with this functional impairment and to explore its phenotypic correlates.

METHODS: The demographic, clinical, and neuropsychological data of 127 ALS patients were analysed. Transcallosal inhibition was assessed with an ipsilateral silent period (iSP) protocol using transcranial magnetic stimulation. Patients were categorised based on an iSP response or its loss, and the groups were characterised by demographic, clinical, and neuropsychological variables. Diffusion-weighted images from a subset of 63 patients were analysed using tractography, and white matter (WM) structural integrity metrics were compared across groups.

RESULTS: 54 % of patients displayed iSP loss. The average free-water-corrected fractional anisotropy values within the callosal tract between the primary motor cortices were lower for patients with iSP loss compared to patients with an iSP response. There were no group differences based on other diffusivity metrics. The groups did not differ regarding any of the demographic, clinical, or neuropsychological variables.

INTERPRETATION: We found reduced WM integrity in the motor section of the corpus callosum that differentiated ALS patients with iSP loss from patients with an iSP response, but with a small effect size. Nevertheless, the underlying pathological substrate and potential genetic drivers for these structural and functional changes in a subset of ALS patients remain to be satisfactorily investigated.}, } @article {pmid39379597, year = {2024}, author = {Fontdevila, L and Povedano, M and Domínguez, R and Boada, J and Serrano, JC and Pamplona, R and Ayala, V and Portero-Otín, M}, title = {Examining the complex Interplay between gut microbiota abundance and short-chain fatty acid production in amyotrophic lateral sclerosis patients shortly after onset of disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {23497}, pmid = {39379597}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/microbiology/metabolism ; *Gastrointestinal Microbiome ; Male ; *Fatty Acids, Volatile/metabolism ; Female ; Middle Aged ; Aged ; Adult ; Case-Control Studies ; }, abstract = {This study aimed to assess differences in the enteral microbiome of relatively recent-onset amyotrophic lateral sclerosis (ALS) patients (< 6-15 months since symptom onset) compared to healthy individuals, focusing on short-chain fatty acids (SCFAs) as potential mediators of host metabolism. We included 28 volunteers (16 ALS, 12 controls) with informed consent. No significant effect of ALS on alpha diversity (measuring the variety and abundance of species within a single sample, and indicating the health and complexity of the microbiome) was observed, but ALS patients had higher abundances of Fusobacteria and Acidobacteria. ALS subtypes influenced specific species, with increased Fusobacteria and Tenericutes in spinal ALS compared to bulbar ALS. ALS patients showed increased Enterobacter, Clostridium, Veillonella, Dialister, Turicibacter, and Acidaminococcus species and decreased Prevotella, Lactobacillus, and Butyricimonas. Correlations between species varied between ALS patients and healthy individuals and among ALS subtypes. No significant differences in SCFA concentrations were found, but spinal ALS samples showed a trend towards decreased propionate content. Relationships between SCFAs and phyla colonization differed by disease status. This study suggests distinct enteral microbiome characteristics in ALS patients, though the implications are unclear. Further research is needed to determine if these differences are causative or consequential and to explore their potential as diagnostic or therapeutic targets. The study also underscores the heterogeneity of microbiome constraints in ALS and the need for more research into ALS and SCFA metabolism.}, } @article {pmid39380150, year = {2024}, author = {Meshram, VD and Balaji, R and Saravanan, P and Subbamanda, Y and Deeksha, W and Bajpai, A and Joshi, H and Bhargava, A and Patel, BK}, title = {Computational Insights Into the Mechanism of EGCG's Binding and Inhibition of the TDP-43 Aggregation.}, journal = {Chemical biology & drug design}, volume = {104}, number = {4}, pages = {e14640}, doi = {10.1111/cbdd.14640}, pmid = {39380150}, issn = {1747-0285}, support = {//Science and Engineering Research Board ; Department of Science and Technology/ ; SRG/2022/002109;SERB/CRG/2021/006856//Science Engineering Research Board, Govt. of India/ ; IFA20-PH-256//Deprartment of Science and Technology, Ministry of Science and Technology, Govt. of India, Inspire faculty fellowship/ ; }, mesh = {*Catechin/analogs & derivatives/chemistry/pharmacology/metabolism ; *DNA-Binding Proteins/metabolism/chemistry/antagonists & inhibitors ; Humans ; *Molecular Dynamics Simulation ; *Molecular Docking Simulation ; *Protein Binding ; Binding Sites ; Thermodynamics ; Protein Aggregates/drug effects ; Protein Domains ; }, abstract = {Misfolding and aggregation of TAR DNA-binding protein, TDP-43, is linked to devastating proteinopathies such as ALS. Therefore, targeting TDP-43's aggregation is significant for therapeutics. Recently, green tea polyphenol, EGCG, was observed to promote non-toxic TDP-43 oligomer formation disallowing TDP-43 aggregation. Here, we investigated if the anti-aggregation effect of EGCG is mediated via EGCG's binding to TDP-43. In silico molecular docking and molecular dynamics (MD) simulation suggest a strong binding of EGCG with TDP-43's aggregation-prone C-terminal domain (CTD). Three replicas, each having 800 ns MD simulation of the EGCG-TDP-43-CTD complex, yielded a high negative binding free energy (ΔG) inferring a stable complex formation. Simulation snapshots show that EGCG forms close and long-lasting contacts with TDP-43's Phe-313 and Ala-341 residues, which were previously identified for monomer recruitment in CTD's aggregation. Notably, stable physical interactions between TDP-43 and EGCG were also detected in vitro using TTC staining and isothermal titration calorimetry which revealed a high-affinity binding site of EGCG on TDP-43 (Kd, 7.8 μM; ΔG, -6.9 kcal/mol). Additionally, TDP-43 co-incubated with EGCG was non-cytotoxic when added to HEK293 cells. In summary, EGCG's binding to TDP-43 and blocking of residues important for aggregation can be a possible mechanism of its anti-aggregation effects on TDP-43.}, } @article {pmid39381934, year = {2025}, author = {Calati, R and Tambuzzi, S and Gravagnuolo, R and Muscatiello, L and Magrin, ME and Crippa, F and Madeddu, F and Zoja, R and Gentile, G}, title = {Suicide in prison in the North of Italy (1993-2022): a case-control study examining differences between suicides inside and outside prison.}, journal = {International clinical psychopharmacology}, volume = {40}, number = {5}, pages = {288-294}, doi = {10.1097/YIC.0000000000000569}, pmid = {39381934}, issn = {1473-5857}, mesh = {Humans ; Italy/epidemiology ; Male ; Female ; Adult ; *Prisoners/statistics & numerical data/psychology ; Middle Aged ; Case-Control Studies ; *Suicide/statistics & numerical data/ethnology ; *Prisons/statistics & numerical data ; Risk Factors ; Young Adult ; Substance-Related Disorders/epidemiology ; }, abstract = {Prisoners constitute a group at suicide risk, showing higher relative rates of suicides than the general population. However, there is limited knowledge about the characteristics of those who die by suicide in Italian prisons. Based on the total sample of suicides of the Institute of Forensic Medicine of Milan (1993-2022), suicides in prison (N = 120) were matched by age and gender with cases that occurred outside prison (N = 300) and compared with them. The considered variables were sociodemographic, clinical, and suicide-related. Univariate analyses and logistic regression model were performed. In univariate analyses, suicides in prison showed higher rates of ethnicity different from white Caucasian, lower rates of depression, higher rates of alcoholism, addiction, respiratory system diseases, hepatitis, and amyotrophic lateral sclerosis, lower use of any medication, and in particular psychotropic medications, and a higher percentage of violent suicide method versus nonviolent compared to suicides outside prison. In the logistic regression model, ethnicity, depression, and addiction were the only features differentiating suicides in prison from ones outside prison. Particular attention should be paid to inmates with non-white ethnicity and those with addiction. Ensuring adequate access to psychiatric care and implementing comprehensive suicide prevention strategies within Italian prisons is crucial.}, } @article {pmid39381976, year = {2024}, author = {Grassano, M and Moglia, C and Palumbo, F and Koumantakis, E and Cugnasco, P and Callegaro, S and Canosa, A and Manera, U and Vasta, R and De Mattei, F and Matteoni, E and Fuda, G and Salamone, P and Marchese, G and Casale, F and De Marchi, F and Mazzini, L and Mora, G and Calvo, A and Chiò, A}, title = {Reply to "Comprehensive Analysis of Sex Differences in Amyotrophic Lateral Sclerosis Prognosis and Disease Progression".}, journal = {Annals of neurology}, volume = {96}, number = {5}, pages = {1029}, doi = {10.1002/ana.27095}, pmid = {39381976}, issn = {1531-8249}, support = {//ALS Association/ ; //American Brain Foundation/ ; //American Academy of Neurology/ ; }, } @article {pmid39382075, year = {2025}, author = {Liang, B and Khan, M and Storts, H and Zhang, EH and Zheng, X and Xing, X and Claybon, H and Wilson, J and Li, C and Jin, N and Fishel, R and Miles, WO and Wang, JJ}, title = {Riluzole Enhancing Anti-PD-1 Efficacy by Activating cGAS/STING Signaling in Colorectal Cancer.}, journal = {Molecular cancer therapeutics}, volume = {24}, number = {1}, pages = {131-140}, pmid = {39382075}, issn = {1538-8514}, support = {R01 CA251753/CA/NCI NIH HHS/United States ; R01 CA208063/CA/NCI NIH HHS/United States ; R01CA215389//National Cancer Institute (NCI)/ ; P30 CA016058/CA/NCI NIH HHS/United States ; R01 CA215389/CA/NCI NIH HHS/United States ; R01 CA067007/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Nucleotidyltransferases/metabolism ; *Colorectal Neoplasms/drug therapy/metabolism/pathology ; Mice ; *Membrane Proteins/metabolism ; Humans ; *Signal Transduction/drug effects ; *Programmed Cell Death 1 Receptor/antagonists & inhibitors/metabolism ; *Riluzole/pharmacology/therapeutic use ; CD8-Positive T-Lymphocytes/drug effects/immunology/metabolism ; Cell Line, Tumor ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; STING Protein ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; }, abstract = {Colorectal cancer is the second leading cause of cancer mortality in the United States. Although immune checkpoint blockade therapies including anti-PD-1/PD-L1 have been successful in treating a subset of patients with colorectal cancer, the response rates remain low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune-competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in colon cancer cells, resulting in increased expression of IFNβ and IFNβ-regulated genes including CXCL10. Inhibition of ataxia telangiectasia mutated (ATM), but not ATM-related, resulted in a synergistic increase in IFNβ expression, suggesting that riluzole induces ATM-mediated damage response that contributes to cGAS/STING activation. Depletion of cGAS or STING significantly attenuated riluzole-induced expression of IFNβ and CXCL10 as well as increase of intratumoral CD8+ T cells and suppression of tumor growth. These results indicate that riluzole-mediated tumor infiltration of CD8+ T cells and attenuation of tumor growth is dependent on tumor cell-intrinsic STING activation. To determine whether riluzole treatment primes the tumor microenvironment for immune checkpoint modulation, riluzole was combined with anti-PD-1 treatment. This combination showed greater efficacy than either single agent and strongly suppressed tumor growth in vivo. Taken together, our studies indicate that riluzole activates cGAS/STING-mediated innate immune responses, which might be exploited to sensitize colorectal tumors to anti-PD-1/PD-L1 therapies.}, } @article {pmid39385408, year = {2024}, author = {Shekhar, AC and Alexander, A and Simms, M and Jahan, M and Haugen, A and Lu, M and Ball, R and Clement, J}, title = {Ambulance Transports from NCAA Division 1 Football Games.}, journal = {Prehospital and disaster medicine}, volume = {39}, number = {3}, pages = {266-269}, pmid = {39385408}, issn = {1945-1938}, mesh = {Humans ; *Ambulances ; Male ; Cross-Sectional Studies ; *Football ; Female ; Young Adult ; Minnesota ; Adult ; Emergency Medical Services ; Universities ; Adolescent ; Crowding ; }, abstract = {INTRODUCTION: There is significant public health interest towards providing medical care at mass-gathering events. Furthermore, mass gatherings have the potential to have a detrimental impact on the availability of already-limited municipal Emergency Medical Services (EMS) resources. This study presents a cross-sectional descriptive analysis to report broad trends regarding patients who were transported from National Collegiate Athletic Association (NCAA) Division 1 collegiate football games at a major public university in order to better inform emergency preparedness and resource planning for mass gatherings.

METHODS: Patient care reports (PCRs) from ambulance transports originating from varsity collegiate football games at the University of Minnesota across six years were examined. Pertinent information was abstracted from each PCR.

RESULTS: Across the six years of data, there were a total of 73 patient transports originating from NCAA collegiate football games: 45.2% (n = 33) were male, and the median age was 22 years. Alcohol-related chief complaints were involved in 50.7% (n = 37) of transports. In total, 31.5% of patients had an initial Glasgow Coma Scale (GCS) of less than 15. The majority (65.8%; n = 48; 0.11 per 10,000 attendees) were transported by Basic Life Support (BLS) ambulances. The remaining patients (34.2%; n = 25; 0.06 per 10,000 attendees) were transported by Advanced Life Support (ALS) ambulances and were more likely to be older, have abnormal vital signs, and have a lower GCS.

CONCLUSIONS: This analysis of ambulance transports from NCAA Division 1 collegiate football games emphasizes the prevalence of alcohol-related chief complaints, but also underscores the likelihood of more life-threatening conditions at mass gatherings. These results and additional research will help inform emergency preparedness at mass-gathering events.}, } @article {pmid39385461, year = {2025}, author = {Li, X and Wicks, P and Brown, A and Shivaprasad, A and Greene, M and Crayle, J and Barnes, B and Jhooty, S and Ratner, D and Olby, N and Glass, JD and Jackson, C and Cole, N and Armon, C and Mascias Cadavid, J and Pattee, G and Mcdermott, CJ and Chang, V and Maragakis, N and Bertorini, T and Bowser, R and Bedlack, R}, title = {ALSUntangled #76: Wahls protocol.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {181-185}, doi = {10.1080/21678421.2024.2407407}, pmid = {39385461}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diet therapy ; Humans ; Fatty Acids, Omega-3 ; Animals ; *Diet/methods ; }, abstract = {The Wahls diet is a modified Paleolithic diet that emphasizes dark green leafy vegetables, colorful fruits, high-quality animal proteins, and omega-3 polyunsaturated fatty acids, while limiting grains, legumes, dairy products, sugar, and processed foods containing proinflammatory omega-6 fatty acids. The Wahls diet may reduce inflammation, oxidative stress, and mitochondrial dysfunction and has plausible mechanisms for slowing amyotrophic lateral sclerosis (ALS) progression. However, research on its dietary components in the ALS animal models has yielded conflicting results. Though multiple cohort studies suggest high carotenoids, omega-3 fatty acids and fruit intake are associated with reduced ALS risks, neither the diet nor its components has been demonstrated to slow down ALS progression in case studies or clinical trials. On the contrary, the Wahls diet, a restrictive, low-carbohydrate and low glycemic index diet, caused an average weight loss of 7.2% BMI in multiple sclerosis clinical trials, which is a significant concern for people living with amyotrophic lateral sclerosis (PALS) as weight loss is associated with faster ALS progression and shorter survival. Considering the above, we cannot endorse the Wahls diet for slowing ALS progression.}, } @article {pmid39385724, year = {2025}, author = {van den Bos, MAJ and Menon, P and Pavey, N and Higashihara, M and Kiernan, MC and Vucic, S}, title = {Direct interrogation of cortical interneuron circuits in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {4}, pages = {1169-1179}, doi = {10.1093/brain/awae317}, pmid = {39385724}, issn = {1460-2156}, support = {//MND Research Australia/ ; #2021/GNT2010812//NHMRC/ ; //Millhouse Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Male ; *Interneurons/physiology ; Transcranial Magnetic Stimulation/methods ; Middle Aged ; Female ; Aged ; Electroencephalography/methods ; *Motor Cortex/physiopathology ; Evoked Potentials, Motor/physiology ; Adult ; }, abstract = {Cortical hyperexcitability is a key pathogenic feature of amyotrophic lateral sclerosis (ALS), believed to be mediated through complex interplay of cortical interneurons. To date, there has been no technological approach to facilitate the direct capture of cortical interneuron function. Through combination of transcranial magnetic stimulation (TMS) with advanced EEG, the present study examined GABAergic dysfunction in ALS by recording focused cortical output whilst applying TMS over the primary motor cortex contralateral to the site of symptom onset. Using both a single-pulse and a novel inhibitory paired-pulse paradigm, TMS-EEG studies were undertaken on 21 ALS patients and results compared with healthy controls. TMS responses captured by EEG form a discrete waveform known as the transcranial evoked potential (TEP), with positive (P) or upward deflections occurring at 30 (P30), 60 (P60) and 190 ms (P190) after TMS stimulus. Negative (N) or downward deflections occur at 44 (N44), 100 (N100) and 280 ms (N280) after TMS stimulus. The single-pulse TEPs recorded in ALS patients demonstrated novel differences suggestive of cortical GABAergic dysfunction. When compared with controls, the N100 component was significantly reduced (P < 0.05), whereas the P190 component increased (P < 0.05) in ALS patients. Additionally, the N44 component was correlated with muscle weakness (r = -0.501, P < 0.05). These findings were supported by reduced paired-pulse inhibition of TEP components in ALS patients (P60, P < 0.01; N100, P < 0.005), consistent with dysfunction of cortical interneuronal GABAA-ergic circuits. Furthermore, the reduction in short-interval intracortical inhibition, as reflected by changes in paired-pulse inhibition of the N100 component, was associated with longer disease duration in ALS patients (r = -0.698, P < 0.001). In conclusion, intensive and focused interrogation of the motor cortex using novel TMS-EEG combined technologies has established localized dysfunction of GABAergic circuits, supporting the notion that cortical hyperexcitability is mediated by cortical disinhibition in ALS. Dysfunction of GABAergic circuits was correlated with greater clinical disability and disease duration, implying pathophysiological significance.}, } @article {pmid39385824, year = {2024}, author = {Chen, L and Chen, J and Weng, W and Wu, M and Zhou, X and Yan, P}, title = {Bibliometric analysis of microRNAs and Parkinson's disease from 2014 to 2023.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1466186}, pmid = {39385824}, issn = {1664-2295}, abstract = {BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons. Recent research has emphasized a significant correlation between microRNAs (miRNAs) and PD. To identify key research areas, provide a comprehensive overview of current research in various fields, and propose potential directions for future studies, a bibliometric analysis was conducted on the involvement of miRNAs in Parkinson's disease from 2014 to 2023.

METHODS: Relevant literature records were collected from the Web of Science Core Collection on February 29, 2024. Subsequently, the data underwent analysis using the Bibliometrix R package and VOSviewer (version 1.6.19).

RESULTS: The annual scientific publications on miRNAs and Parkinson's disease demonstrated an increasing trend, with an annual growth rate of 12.67%. China, the United States, and India emerged as the top three most productive countries/regions. The University of Barcelona had the highest annual publications, followed by Central South University and the Helmholtz Association. The INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES held the top position in terms of H-index and total citations, reflecting its extensive influence and prolific publication output. Kim, J., Junn, E., Hébert, S.S., and Doxakis, E. were the most frequently co-cited authors in the field. Based on the analysis of keywords, the most frequently occurring terms included "alpha-synuclein," "neurodegenerative disease," "exosome," "neuroinflammation," "oxidative stress," "autophagy," and "amyotrophic lateral sclerosis," which have emerged as prominent research topics. Concurrently, there has been notable interest in topics such as "ceRNA," "lncRNAs," "mitochondrial dysfunction," and "circular RNA."

CONCLUSION: This study focused on identifying emerging trends and critical research topics in the bibliometric analysis of microRNAs related to Parkinson's disease. These findings highlight the diverse research landscape and evolving trend of miRNA-related research in PD. The field of miRNA research in Parkinson's disease is actively exploring the underlying mechanisms of miRNA function, identifying potential diagnostic markers, and developing innovative therapeutic strategies. The results of our study offer significant contributions to researchers' ability to track contemporary developments and guide the trajectory of future research in this domain.}, } @article {pmid39386324, year = {2024}, author = {Ross, CW and Loudermilk, EL and O'Brien, JJ and Snitker, G}, title = {Lidar-derived structural-complexity data across four experimental forests.}, journal = {Data in brief}, volume = {57}, number = {}, pages = {110955}, pmid = {39386324}, issn = {2352-3409}, abstract = {Structural complexity refers to the three-dimensional arrangement and variability of both biotic and abiotic components of an ecosystem. Metrics that characterize structural complexity are often used to manage various aspects of ecosystem function, such as light transmittance, wildlife habitat, and biological diversity. Additionally, these metrics aid in evaluating resilience to disturbance events, including hurricanes, bark-beetle outbreaks, and wildfire. Recent advances in wildland fire modelling have facilitated the integration of forest structural complexity metrics into the QUIC-Fire model, enabling real-time prediction of fire spread and behaviour by simulating interactions between fire, weather, topography, and forest structure. While QUIC-Fire is designed to be highly adaptable, model performance depends on the availability and accuracy of local data inputs. Expanding the model's usability across different regions can be facilitated by the availability of more comprehensive and high-quality data. Thus, the primary goal behind the data products we developed was to establish a basis for collaborative research across various disciplines, particularly within the focal areas of the Southern Research Station, such as forestry, wildland fire, hydrology, soil science, and cultural resources at Bent Creek, Coweeta, Escambia, and Hitchiti Experimental Forests (EFs). Airborne laser scanning (ALS) was used to collect point-cloud data for each EF during the leaf-off season to minimize interference from foliage. Subsequent processing of the raw lidar data involved outlier detection and filtering, ground and non-ground classification, and the computation of a variety of metrics representing various aspects of topography and forest structure at both the pixel-level and the tree-level. Pixel-level topographic data products include: digital elevation model (DEM), slope, aspect, topographic position index (TPI), topographic roughness index (TRI), roughness, and flow direction. Forest structural-complexity metrics include canopy height, foliar height diversity (FHD), vertical distribution ratio (VDR), canopy rugosity, crown relief ratio (CRR), understory complexity index (UCI), vertical complexity index (VCI), canopy cover, mean vegetation height, and the standard deviation of vegetation height. Tree-level data products were computed from the point cloud using multiple algorithms to perform individual tree detection (ITD) and individual tree segmentation (ITS). The datasets have been harmonized and are openly accessible through the USDA Forest Service Research Data Archive.}, } @article {pmid39386447, year = {2024}, author = {Rodemer, W and Ra, I and Jia, E and Gujral, J and Zhang, B and Hoxha, K and Xing, B and Mehta, S and Farag, M and Porta, S and Jensen, FE and Talos, DM and Lee, VM}, title = {Hyperexcitability precedes CA3 hippocampal neurodegeneration in a dox-regulatable TDP-43 mouse model of ALS-FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.09.24.612703}, pmid = {39386447}, issn = {2692-8205}, support = {R01 NS101156/NS/NINDS NIH HHS/United States ; }, abstract = {UNLABELLED: Neuronal hyperexcitability is a hallmark of amyotrophic lateral sclerosis (ALS) but its relationship with the TDP-43 aggregates that comprise the predominant pathology in over 90% of ALS cases remains unclear. Emerging evidence in tissue and slice culture models indicate that TDP-43 pathology induces neuronal hyperexcitability suggesting it may be responsible for the excitotoxicity long believed to be a major driver of ALS neuron death. Here, we characterized hyperexcitability and neurodegeneration in the hippocampus of doxycycline-regulatable rNLS8 mice (NEFH-tTA x tetO-hTDP-43ΔNLS), followed by treatment with AAV encoded DREADDs and anti-seizure medications to measure the effect on behavioral function and neurodegeneration. We found that approximately half of the CA3 neurons in the dorsal hippocampus are lost between 4 and 6 weeks after TDP-43ΔNLS induction. Neurodegeneration was preceded by selective hyperexcitability in the mossy fiber - CA3 circuit, leading us to hypothesize that glutamate excitotoxicity may be a significant contributor to neurodegeneration in this model. Interestingly, hippocampal injection of AAV encoded inhibitory DREADDs (hM4Di) and daily activation with CNO ligand rescued anxiety deficits on elevated zero maze (EZM) but did not reduce neurodegeneration. Therapeutic doses of the anti-seizure medications, valproic acid and levetiracetam, did not improve behavior or prevent neurodegeneration. These results highlight the complexity of TDP-43 - induced alterations to neuronal excitability and suggest that whereas targeting hyperexcitability can meliorate some behavioral deficits, it may not be sufficient to halt or slow neurodegeneration in TDP-43-related proteinopathies.

SIGNIFICANCE STATEMENT: Cytoplasmic aggregates of TAR DNA Binding Protein 43 (TDP-43) are the predominant pathology in over 90% of Amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) cases. Understanding how TDP-43 pathology promotes neurodegeneration may lead to therapeutic strategies to slow disease progression in humans. Recent reports in mouse and cell culture models suggest loss-of-normal TDP-43 function may drive neuronal hyperexcitability, a key physiological hallmark of ALS and possible contributor to neurodegeneration. In this study, we identified region-specific hyperexcitability that precedes neurodegeneration in the inducible rNLS8 TDP-43 mouse model. Suppressing hyperexcitability with chemogenetics improved behavioral function but did not reduce hippocampal neuron loss. Anti-seizure medications had no beneficial effects suggesting directly targeting hyperexcitability may not be therapeutically effective.}, } @article {pmid39386496, year = {2024}, author = {El-Khatib, SM and Vagadia, AR and Le, ACD and Ng, DQ and Baulch, JE and Du, M and Tan, Z and Xu, X and Chan, A and Acharya, MM}, title = {BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.09.23.614590}, pmid = {39386496}, issn = {2692-8205}, support = {R01 CA251110/CA/NCI NIH HHS/United States ; R01 CA276212/CA/NCI NIH HHS/United States ; }, abstract = {Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo . In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT+Veh with the RT+RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.}, } @article {pmid39386562, year = {2024}, author = {Dargan, R and Mikheenko, A and Johnson, NL and Packer, B and Li, Z and Craig, EJ and Sarbanes, SL and Bereda, C and Mehta, PR and Keuss, M and Nalls, MA and Qi, YA and Weller, CA and Fratta, P and Ryan, VH}, title = {Altered mRNA transport and local translation in iNeurons with RNA binding protein knockdown.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386562}, issn = {2692-8205}, support = {ZIA AG000547/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Neurons rely on mRNA transport and local translation to facilitate rapid protein synthesis in processes far from the cell body. These processes allow precise spatial and temporal control of translation and are mediated by RNA binding proteins (RBPs), including those known to be associated with neurodegenerative diseases. Here, we use proteomics, transcriptomics, and microscopy to investigate the impact of RBP knockdown on mRNA transport and local translation in iPSC-derived neurons. We find thousands of transcripts enriched in neurites and that many of these transcripts are locally translated, possibly due to the shorter length of transcripts in neurites. Loss of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS)-associated RBPs TDP-43 and hnRNPA1 lead to distinct alterations in the neuritic proteome and transcriptome. TDP-43 knockdown (KD) leads to increased neuritic mRNA and translation. In contrast, hnRNPA1 leads to increased neuritic mRNA, but not translation, and more moderate effects on local mRNA profiles, possibly due to compensation by hnRNPA3. These results highlight the crucial role of FTD/ALS-associated RBPs in mRNA transport and local translation in neurons and the importance of these processes in neuron health and disease.}, } @article {pmid39389563, year = {2025}, author = {Feindt, B and Roth, A and Heyde, CE and Behrens, J and Feist, B and Kasprick, L and Sultzer, R and Baerwald, C}, title = {GeriNOT in the Surgical Inpatient Setting.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {2}, pages = {137-145}, doi = {10.1055/a-2343-4014}, pmid = {39389563}, issn = {1864-6743}, mesh = {Humans ; Female ; Aged ; Male ; Aged, 80 and over ; *Geriatric Assessment/methods/statistics & numerical data ; Germany/epidemiology ; Retrospective Studies ; *Femoral Fractures/surgery/epidemiology/diagnosis ; Hip Fractures/surgery/epidemiology ; *Spinal Fractures/surgery/epidemiology/diagnosis ; }, abstract = {Die Richtlinie des Gemeinsamen Bundesausschusses (G-BA) über Maßnahmen zur Qualitätssicherung zur Versorgung von Patient*innen mit hüftgelenknaher Femurfraktur verpflichtet Krankenhäuser zum Einsatz eines validierten geriatrischen Screeninginstruments. Die systematische Anwendung des GeriNOT mit prozessproduzierter Datenerhebung im Akutaufnahmeprozess durch Integration in das Krankenhausinformationssystem (KIS) ermöglicht die Identifikation von Risikopotenzialen auch in anderen geriatrischen Diagnosegruppen.Mit Einbindung des GeriNOT in den Akutaufnahmeprozess wurde geprüft, ob auch andere vulnerable geriatrische Diagnosegruppen von einer frühzeitig eingeleiteten Risikoidentifikation profitieren können.Datengrundlage dieser Untersuchung bildete eine retrospektive bizentrische Erhebung elektronischer Fallakten (Mai 2014 bis April 2015, n = 3443). Aus diesem Primärdatensatz wurde die Subgruppe stationärer Akutaufnahmen (n = 821) der Orthopädie/Unfallchirurgie eines Zentrums in Bezug auf die Endpunkte "Inanspruchnahme bedarfsgerechter poststationärer Pflegeleistungen" und "Neueinzug in stationäre Dauer-/Kurzzeitpflege" analysiert. Es wurden Prädiktionskraft und Klassifikationsgenauigkeit von GeriNOT dieser ab 70-jährigen Personen in Diagnosegruppen für die definierten Endpunkte beurteilt: Akutaufnahmen insgesamt, Frakturen insgesamt, hüftgelenknahe Femurfraktur und Wirbelsäulenerkrankungen inklusive Wirbelsäulenfrakturen.Im Untersuchungszeitraum wurden 821 Personen akutstationär aufgenommen. Das mittlere Alter betrug 81,4 ± 6,8 Jahre (n = 821; 68,1% Frauen, 31,9% Männer). Folgende Diagnosegruppen wurden gebildet und analysiert: Frakturen insgesamt (n = 490), Wirbelsäulenerkrankungen (n = 265), davon Wirbelsäulenfrakturen (n = 174), hüftgelenknahe Femurfraktur (n = 108). In der Gesamtgruppe (n = 821; MW = 4,279; SD = 2,180) und in den Diagnosegruppen lag der Mittelwert des GeriNOT-Scores über dem Schwellenwert ≥ 4. In der Gruppe der hüftgelenknahen Femurfraktur wurde der höchste Wert ermittelt (MW = 4,852; SD = 2,022), der niedrigste in der Gruppe der Wirbelsäulenfrakturen (MW = 4,177; SD = 2,171). In der Aufnahmesituation bez. behandlungsbedürftiger Diagnosen, Polypharmazie und bereits in Anspruch genommener Pflegeleistungen unterschieden sich die Diagnosegruppen nur geringfügig. Einweisungen aus stationärer Kurz- und Dauerpflege erfolgten in der Gesamtgruppe (n = 821) in 16,44% der Fälle, am häufigsten mit 31,48% in der Gruppe der hüftgelenknahen Femurfraktur, hingegen am seltensten in der Diagnosegruppe der Wirbelsäulenerkrankungen mit 6,79%. GeriNOT detektierte für diese Gruppe ein erhöhtes Risiko in Bezug auf die definierten Endpunkte. Nur 4,26% aller Patient*innen mit identifiziertem geriatrischen Risikopotenzial wurden akutgeriatrisch weiterversorgt.Die Ergebnisse zeigten ein erhöhtes geriatrisches Risiko in allen analysierten Diagnosegruppen, am stärksten innerhalb der Gruppe der Wirbelsäulenerkrankungen. Der KIS-gestützte Einsatz des GeriNOT initiiert die systematische Risikoidentifikation im akutstationären Aufnahmemanagement. Die fallbegleitende Ergebnisvisualisierung in den KIS-Arbeitsplätzen könnte als Ausgangspunkt für die nachfolgende Anwendung von Assessmentinstrumenten und risikoadjustierter Behandlungspfade genutzt werden. Mit diesen Erkenntnissen könnte das Patientenoutcome potenziell positiv beeinflusst werden.}, } @article {pmid39389966, year = {2024}, author = {Kamemura, K and Kozono, R and Tando, M and Okumura, M and Koga, D and Kusumi, S and Tamai, K and Okumura, A and Sekine, S and Kamiyama, D and Chihara, T}, title = {Secretion of endoplasmic reticulum protein VAPB/ALS8 requires topological inversion.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8777}, pmid = {39389966}, issn = {2041-1723}, support = {P40 OD010949/OD/NIH HHS/United States ; R01 NS107558/NS/NINDS NIH HHS/United States ; 21K18236//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 21H02479//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; }, mesh = {*Endoplasmic Reticulum/metabolism ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Vesicular Transport Proteins/metabolism/genetics ; Cell Membrane/metabolism ; Mutation ; Protein Domains ; Membrane Proteins/metabolism/genetics ; HEK293 Cells ; Matrix Metalloproteinase 1/metabolism/genetics ; Protein Transport ; }, abstract = {VAMP-associated protein (VAP) is a type IV integral transmembrane protein at the endoplasmic reticulum (ER). Mutations in human VAPB/ALS8 are associated with amyotrophic lateral sclerosis (ALS). The N-terminal major sperm protein (MSP) domain of VAPB (Drosophila Vap33) is cleaved, secreted, and acts as a signaling ligand for several cell-surface receptors. Although extracellular functions of VAPB are beginning to be understood, it is unknown how the VAPB/Vap33 MSP domain facing the cytosol is secreted to the extracellular space. Here we show that Vap33 is transported to the plasma membrane, where the MSP domain is exposed extracellularly by topological inversion. The externalized MSP domain is cleaved by Matrix metalloproteinase 1/2 (Mmp1/2). Overexpression of Mmp1 restores decreased levels of extracellular MSP domain derived from ALS8-associated Vap33 mutants. We propose an unprecedented secretion mechanism for an ER-resident membrane protein, which may contribute to ALS8 pathogenesis.}, } @article {pmid39390534, year = {2024}, author = {Xu, M and Li, B and Li, C and Chai, P and Qiu, Q and Zheng, Z and Chen, Q and Luo, D and Xu, X and Zhou, C}, title = {Is longer axial length protective of vision-threatening diabetic retinopathy across different ages? A multicenter cohort of 736 patients.}, journal = {International journal of retina and vitreous}, volume = {10}, number = {1}, pages = {74}, pmid = {39390534}, issn = {2056-9920}, support = {22QA1407500//Shanghai Science and Technology Development Foundation/ ; SHWSRS [2022-65]//Shanghai Rising Stars of Medical Talent Youth Development Program/ ; CTCCR-2021C01//Clinical Research Innovation Plan of Shanghai General Hospital/ ; 82471104//National Natural Science Foundation of China/ ; }, abstract = {PURPOSE: Vision-threatening diabetic retinopathy (VTDR) included severe non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR) and clinically significant diabetic macular edema (DME). To compare the axial length (AL) and assess its influence on VTDR across different ages.

METHODS: A retrospective cohort study. Medical chart review was performed in 736 consecutive patients with VTDR. The patients were divided into young (≤ 45 years) and elderly group (> 45 years) based on their age at the diagnosis of VTDR. After at least one year of standardized treatments, all eligible patients were followed up. The main outcome measures included the presence of tractional retinal detachment (TRD) involving foveal, final best-corrected visual acuity (BCVA), the development of neovascular glaucoma (NVG), and recurrent vitreous hemorrhage (VH) post-vitrectomy. ALs were compared between two age groups. The impact of AL on clinical outcomes was determined by logistic analyses after controlling for systemic parameters.

RESULTS: The study included 144 patients ≤ 45 years and 592 patients > 45 years. Young patients had significantly longer AL than elderly participants (23.9 mm vs 23.0 mm, p < 0.001). Over a median follow-up of 25.9 months, a larger proportion of young patients developed TRD (34.7% vs 16.2%, p < 0.001) and recurrent VH (18.6% vs 10.3%, p = 0.040) than elderly patients. In elderly group, longer AL is an independent protective factor in preventing TRD (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.4-0.7; P < 0.001). However, this beneficial effect was not observed in young patients.

CONCLUSIONS: Young patients with VTDR exhibited significantly longer AL but more aggressive clinical signs with compromised prognosis. In elderly group, a longer AL independently reduced the risk of TRD, while this protective effect did not exist for young patients.}, } @article {pmid39390590, year = {2024}, author = {Vanderhaeghe, S and Prerad, J and Tharkeshwar, AK and Goethals, E and Vints, K and Beckers, J and Scheveneels, W and Debroux, E and Princen, K and Van Damme, P and Fivaz, M and Griffioen, G and Van Den Bosch, L}, title = {A pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {161}, pmid = {39390590}, issn = {2051-5960}, support = {HBC.2019.2575//VLAIO Baekeland mandate/ ; 030383//Flanders Innovation & Entrepreneurship (VLAIO)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Valosin Containing Protein/genetics/metabolism ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Mitochondria/metabolism/pathology ; *Mitochondrial Permeability Transition Pore/metabolism ; *Mutation ; Cell Line, Tumor ; Membrane Potential, Mitochondrial/genetics ; Mitochondrial Membrane Transport Proteins/genetics/metabolism ; Calcium/metabolism ; }, abstract = {Valosin-containing protein (VCP) is a ubiquitously expressed type II AAA[+] ATPase protein, implicated in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study aimed to explore the impact of the disease-causing VCP[R191Q/wt] mutation on mitochondrial function using a CRISPR/Cas9-engineered neuroblastoma cell line. Mitochondria in these cells are enlarged, with a depolarized mitochondrial membrane potential associated with increased respiration and electron transport chain activity. Our results indicate that mitochondrial hypermetabolism could be caused, at least partially, by increased calcium-induced opening of the permeability transition pore (mPTP), leading to mild mitochondrial uncoupling. In conclusion, our findings reveal a central role of the ALS/FTD gene VCP in maintaining mitochondrial homeostasis and suggest a model of pathogenesis based on progressive alterations in mPTP physiology and mitochondrial energetics.}, } @article {pmid39390661, year = {2024}, author = {Howard, IM and Babu, S and Carter, C and Sakowski, SA and Kurent, JE and Cudkowicz, ME and Feldman, EL}, title = {Priorities and Recommendations to Make ALS a Livable Disease Emanating from the 2024 National Academies of Sciences, Engineering, and Medicine Report Living with ALS.}, journal = {Annals of neurology}, volume = {96}, number = {6}, pages = {1035-1039}, pmid = {39390661}, issn = {1531-8249}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; OT2 NS136938/NS/NINDS NIH HHS/United States ; U01 NS077179/NS/NINDS NIH HHS/United States ; //Charles H. Abdalian, Jr. ALS Research Fund/ ; OT2 NS136939/NS/NINDS NIH HHS/United States ; //NeuroNetwork for Emerging Therapies/ ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01TS000344/ACL/ACL HHS/United States ; //American Academy of Neurology/ ; //ALS One/ ; //ALS Association/ ; UF1 NS131791/NS/NINDS NIH HHS/United States ; R01TS000327//Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry/ ; 1U01NS136021-01/NH/NIH HHS/United States ; 1U01NS136020-01/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; U01 NS136020/NS/NINDS NIH HHS/United States ; R01TS000344/ACL/ACL HHS/United States ; //Scott L. Pranger/ ; //The Sean M. Healey & AMG Center for ALS/ ; 1U01NS077179-01/NH/NIH HHS/United States ; //Muscular Dystrophy Association/ ; U01 NS136021/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; //The Neurological Clinical Research Institute/ ; UF1NS131791-01/NH/NIH HHS/United States ; 1OT2NS136938-1/NH/NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; //ALS Finding a Cure/ ; OT2NS136939/NH/NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis ; Humans ; United States ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentless, fatal neurodegenerative disease. The progressive loss of voluntary muscle function, diagnostic delays, lack of effective treatments, and challenges accessing multidisciplinary care and resources have tremendous impact on quality of life. The congressionally directed ALS committee of the National Academies of Science, Engineering, and Medicine, in their 2024 report "Living with ALS," recommends critical actions for specific United States stakeholders to make ALS a livable disease over the next decade. This review summarizes the context and recommendations of the report. Advocacy efforts are critical to make these recommendations a reality for the ALS community. ANN NEUROL 2024;96:1035-1039.}, } @article {pmid39390888, year = {2024}, author = {Boran, HE and Kılınç, H and Kurtkaya Koçak, Ö and Yanık, E and Kuruoğlu, HR and Cengiz, B}, title = {Somatosensory temporal discrimination analysis reveals impaired processing in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {6}, pages = {1257-1262}, doi = {10.1002/mus.28278}, pmid = {39390888}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Evoked Potentials, Somatosensory/physiology ; Aged ; *Somatosensory Cortex/physiopathology ; Adult ; Hand/physiopathology ; Sensory Thresholds/physiology ; }, abstract = {INTRODUCTION/AIMS: While amyotrophic lateral sclerosis (ALS) is primarily characterized as a motor system disorder, there is a growing body of evidence indicating sensory involvement. This study aimed to examine the hypothesis that somatosensory processing is impaired in ALS.

METHODS: Study participants were ALS patients followed at the Neuromuscular Outpatient Unit, as well as healthy volunteers, from March 2021 to July 2023. The Medical Research Council (MRC) sum score was calculated for nine muscle groups bilaterally. The clinical status of patients was evaluated with the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Penn Upper Motor Neuron core. Somatosensory temporal discrimination thresholds (STDTs) were recorded on the medial and lateral parts of both hands. Somatosensory cortex excitability was investigated with the paired somatosensory evoked potentials (SEP) paradigm in a subgroup.

RESULTS: Increased STD values were detected in ALS patients compared to controls in both medial (107.66 ± 35 ms vs. 82.7 ± 32.5 ms, p = .001) and lateral (106.5 ± 34.5 ms vs. 82.9 ± 31.3 ms, p = .002) hands. There were no significant differences in STDTs among ALS patients across four regions (medial and lateral parts of the right and left hands). Amplitude ratios obtained from the paired-pulse SEP paradigm were approximately 1 for all interstimulus intervals (ISIs). STDTs did not show any correlations with motor findings or scales.

DISCUSSION: Somatosensory processing appears to be compromised among ALS patients. The lack of correlation between impaired STDT and motor findings implies that it is a purely sensory deficit in ALS.}, } @article {pmid39391382, year = {2024}, author = {Osaro, E and Fajardo-Rojas, F and Cooper, GM and Gómez-Gualdrón, D and Colón, YJ}, title = {Active learning of alchemical adsorption simulations; towards a universal adsorption model.}, journal = {Chemical science}, volume = {15}, number = {42}, pages = {17671-17684}, pmid = {39391382}, issn = {2041-6520}, abstract = {Adsorption is a fundamental process studied in materials science and engineering because it plays a critical role in various applications, including gas storage and separation. Understanding and predicting gas adsorption within porous materials demands comprehensive computational simulations that are often resource intensive, limiting the identification of promising materials. Active learning (AL) methods offer an effective strategy to reduce the computational burden by selectively acquiring critical data for model training. Metal-organic frameworks (MOFs) exhibit immense potential across various adsorption applications due to their porous structure and their modular nature, leading to diverse pore sizes and chemistry that serve as an ideal platform to develop adsorption models. Here, we demonstrate the efficacy of AL in predicting gas adsorption within MOFs using "alchemical" molecules and their interactions as surrogates for real molecules. We first applied AL separately to each MOF, reducing the training dataset size by 57.5% while retaining predictive accuracy. Subsequently, we amalgamated the refined datasets across 1800 MOFs to train a multilayer perceptron (MLP) model, successfully predicting adsorption of real molecules. Furthermore, by integrating MOF features into the AL framework using principal component analysis (PCA), we navigated MOF space effectively, achieving high predictive accuracy with only a subset of MOFs. Our results highlight AL's efficiency in reducing dataset size, enhancing model performance, and offering insights into adsorption phenomenon in large datasets of MOFs. This study underscores AL's crucial role in advancing computational material science and developing more accurate and less data intensive models for gas adsorption in porous materials.}, } @article {pmid39391721, year = {2024}, author = {Hodgson, RE and Rayment, JA and Huang, WP and Sanchez Avila, A and Ellis, BCS and Lin, YH and Soni, N and Hautbergue, GM and Shelkovnikova, TA}, title = {C9orf72 poly-PR forms anisotropic condensates causative of nuclear TDP-43 pathology.}, journal = {iScience}, volume = {27}, number = {10}, pages = {110937}, pmid = {39391721}, issn = {2589-0042}, support = {MR/W028522/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Proteinaceous inclusions formed by C9orf72-derived dipeptide-repeat (DPR) proteins are a histopathological hallmark in ∼50% of familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) cases. However, DPR aggregation/inclusion formation could not be efficiently recapitulated in cell models for four out of five DPRs. In this study, using optogenetics, we achieved chemical-free poly-PR condensation/aggregation in cultured cells including human motor neurons, with spatial and temporal control. Strikingly, nuclear poly-PR condensates had anisotropic, hollow-center appearance, resembling TDP-43 anisosomes, and their growth was limited by RNA. These condensates induced abnormal TDP-43 granulation in the nucleus without stress response activation. Cytoplasmic poly-PR aggregates forming under prolonged opto-stimulation were more persistent than its nuclear condensates, selectively sequestered TDP-43 in a demixed state and surrounded spontaneous stress granules. Thus, poly-PR condensation accompanied by nuclear TDP-43 dysfunction may constitute an early pathological event in C9-ALS/FTD. Anisosome-type condensates of disease-linked proteins may represent a common molecular species in neurodegenerative disease.}, } @article {pmid39392096, year = {2024}, author = {}, title = {Correction to "Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis".}, journal = {The European journal of neuroscience}, volume = {60}, number = {8}, pages = {6125-6126}, doi = {10.1111/ejn.16562}, pmid = {39392096}, issn = {1460-9568}, } @article {pmid39392186, year = {2025}, author = {Corcia, P and Piras, R and Lunetta, C}, title = {Why is the treatment and management of amyotrophic lateral sclerosis so difficult?.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {1}, pages = {1-3}, doi = {10.1080/14737175.2024.2415002}, pmid = {39392186}, issn = {1744-8360}, } @article {pmid39393030, year = {2024}, author = {Aamodt, WW and Sun, C and Dahodwala, N and Elser, H and Schneider, ALC and Farrar, JT and Coe, NB and Willis, AW}, title = {End-of-Life Health Care Service Use and Cost Among Medicare Decedents With Neurodegenerative Diseases.}, journal = {Neurology}, volume = {103}, number = {9}, pages = {e209925}, pmid = {39393030}, issn = {1526-632X}, support = {K23 AG086669/AG/NIA NIH HHS/United States ; K24 AG075234/AG/NIA NIH HHS/United States ; L30 AG089647/AG/NIA NIH HHS/United States ; RF1 NS132673/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; United States ; Male ; Female ; *Medicare/economics/statistics & numerical data ; Aged ; Retrospective Studies ; *Terminal Care/economics/statistics & numerical data ; Aged, 80 and over ; *Neurodegenerative Diseases/economics/therapy/epidemiology ; Patient Acceptance of Health Care/statistics & numerical data ; Health Care Costs/statistics & numerical data ; Emergency Service, Hospital/statistics & numerical data/economics ; Parkinson Disease/economics/therapy/epidemiology ; Hospice Care/economics/statistics & numerical data ; Alzheimer Disease/economics/therapy/epidemiology ; Amyotrophic Lateral Sclerosis/economics/therapy/epidemiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Although neurodegenerative diseases are a leading cause of death, little is known about health care utilization and cost during the end-of-life (EoL) period or how it compares with that of other life-limiting conditions. We aimed to describe and compare resource utilization among US Medicare decedents with neurodegenerative diseases with decedents with cancer.

METHODS: We conducted a retrospective study of Medicare Part A and B beneficiaries with Alzheimer disease (AD), Parkinson disease (PD), or amyotrophic lateral sclerosis (ALS) who died in 2018. Decedents diagnosed with malignant brain tumors or pancreatic cancer served as non-neurodegenerative comparators. Descriptive analyses examined demographic and clinical characteristics in the last year of life. The probabilities and associated costs of emergency department (ED), inpatient, skilled nursing facility (SNF), and hospice utilization during the last 12 and 6 months of life were also compared between persons with neurodegenerative diseases and cancer, adjusting for sociodemographic factors and comorbidity burden.

RESULTS: A total of 1,126,799 Medicare beneficiaries died in 2018, of which 357,926 had a qualifying diagnosis. Persons with neurodegenerative diseases were older and more frequently received Medicaid assistance than persons with brain or pancreatic cancer. In all groups, health care service utilization increased over the last year of life, and total costs were predominantly attributable to inpatient care. In the last 6 months of life, neurologist care was infrequent among patients with neurodegenerative disease (AD: 1.5%; PD: 8.6%; ALS: 32.0%). Persons with neurodegenerative diseases as compared to persons with malignant brain tumors also had greater odds of ED use (AD: adjusted odds ratio [aOR] 1.17, 95% CI 1.11-1.23; PD: aOR 1.18, 95% CI 1.11-1.25; ALS: aOR 1.11, 95% CI 1.01-1.23), lower odds of hospitalization (AD: aOR 0.64, 95% CI 0.60-0.68; PD: aOR 0.65, 95% CI 0.61-0.69; ALS: aOR 0.33, 95% CI 0.30-0.37), and lower odds of hospice enrollment (AD: aOR 0.33, 95% CI 0.31-0.36; PD: aOR 0.33, 95% CI 0.31-0.36; ALS: aOR 0.41, 95% CI 0.36-0.46). The findings were similar in pancreatic cancer.

DISCUSSION: Persons with neurodegenerative diseases in the United States are more likely to visit the ED and less likely to use inpatient and hospice services at EoL than persons with brain or pancreatic cancer. These group differences may stem from prognostic uncertainty and reflect inadequate EoL care practices, requiring further investigation to ensure more timely palliative care and hospice referrals.}, } @article {pmid39393594, year = {2024}, author = {Coppieters, R and Bouzigues, A and Jiskoot, L and Montembeault, M and Tee, BL and , and Rohrer, JD and Bruffaerts, R}, title = {A systematic review of the quantitative markers of speech and language of the frontotemporal degeneration spectrum and their potential for cross-linguistic implementation.}, journal = {Neuroscience and biobehavioral reviews}, volume = {167}, number = {}, pages = {105909}, doi = {10.1016/j.neubiorev.2024.105909}, pmid = {39393594}, issn = {1873-7528}, mesh = {Humans ; *Frontotemporal Dementia/physiopathology/diagnosis ; *Speech/physiology ; Linguistics ; Language ; Biomarkers ; }, abstract = {Frontotemporal dementia (FTD) is a neurodegenerative disease spectrum with an urgent need for reliable biomarkers for early diagnosis and monitoring. Speech and language changes occur in the early stages of FTD and offer a potential non-invasive, early, and accessible diagnostic tool. The use of speech and language markers in this disease spectrum is limited by the fact that most studies investigate English-speaking patients. This systematic review examines the literature on psychoacoustic and linguistic features of speech that occur across the FTD spectrum across as many different languages as possible. 76 papers were identified that investigate psychoacoustic and linguistic markers in discursive speech. 75 % of these papers studied English-speaking patients. The most generalizable features found across different languages, are speech rate, articulation rate, pause frequency, total pause duration, noun-verb ratio, and total number of nouns. While there are clear interlinguistic differences across patient groups, the results show promise for implementation of cross-linguistic markers of speech and language across the FTD spectrum particularly for psychoacoustic features.}, } @article {pmid39394860, year = {2024}, author = {Zhao, J and Kong, D and Zhang, G and Zhang, S and Wu, Y and Dai, C and Chen, Y and Yang, Y and Liu, Y and Wei, D}, title = {An Efficient CRISPR/Cas Cooperative Shearing Platform for Clinical Diagnostics Applications.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {52}, pages = {e202411705}, doi = {10.1002/anie.202411705}, pmid = {39394860}, issn = {1521-3773}, support = {22304031, 61890940//National Natural Science Foundation of China/ ; 2021YFC2301100//the National Key R&D Program of China/ ; XDB30000000//the Strategic Priority Research Program of the Chinese Academy of Sciences/ ; 23XD1420200//the Program of Shanghai Academic Research Leaders/ ; DP2020036//the Chong-qing Bayu Scholar Program/ ; 2023M730635//the China Postdoctoral Science Foundation/ ; T2425006//National Science Fund for Distinguished Young Scholars/ ; }, mesh = {*CRISPR-Cas Systems/genetics ; Humans ; Electrochemical Techniques ; Amyotrophic Lateral Sclerosis/diagnosis/genetics ; }, abstract = {The CRISPR/Cas system is a powerful genome editing tool and possesses widespread applications in molecular diagnostics, therapeutics and genetic engineering. But easy folding of the target sequences causes remarkable deterioration of the recognition and shear efficiency in the case of single Cas-CRISPR RNA (crRNA) duplex. Here, we develop a CRISPR/Cas cooperative shearing (CRISPR-CS) system. Compared with traditional CRISPR/Cas system, two CRISPR/Cas-crRNA duplexes simultaneously recognize different sites in the target sequence, increasing recognition possibility and shearing efficiency. Cooperative shearing cuts more methylene blue-ssDNA reporters on the electrode, enabling unamplified nucleic acid electrochemical assay in less than 5 minutes with a detection limit of 9.5×10[-20] M, 2 to 9 orders of magnitude lower than those of other electrochemical assays. The CRISPR-CS platform detects monkeypox, human papilloma virus and amyotrophic lateral sclerosis with an accuracy up to 98.1 %, demonstrating the potential application of the efficient cooperative shearing.}, } @article {pmid39395475, year = {2024}, author = {Kim, SY and Kim, M and Park, K and Hong, S}, title = {A systematic review on analytical methods of the neurotoxin β-N-methylamino-L-alanine (BMAA), and its causative microalgae and distribution in the environment.}, journal = {Chemosphere}, volume = {366}, number = {}, pages = {143487}, doi = {10.1016/j.chemosphere.2024.143487}, pmid = {39395475}, issn = {1879-1298}, mesh = {*Amino Acids, Diamino/analysis ; *Microalgae/metabolism ; *Cyanobacteria Toxins ; *Neurotoxins/analysis ; *Cyanobacteria/metabolism ; *Tandem Mass Spectrometry ; *Environmental Monitoring/methods ; Ecosystem ; Chromatography, Liquid ; Diatoms/metabolism ; Water Pollutants, Chemical/analysis/metabolism ; }, abstract = {β-N-Methylamino-L-alanine (BMAA), a neurotoxin produced by various microalgal groups, is associated with neurodegenerative diseases and is considered a major environmental factor potentially linked to sporadic amyotrophic lateral sclerosis. This study systematically reviews the analytical methods used to study BMAA in publications from 2019 to the present. It also investigates the causative microalgae of BMAA and its geographical distributions in aquatic ecosystems based on studies conducted since 2003. A comprehensive search using the Web of Science database revealed that hydrolysis for extraction (67%), followed by quantification using LC-MS/MS (LC: 84%; MS/MS: 88%), is the most commonly employed method in BMAA analysis. Among analytical methods, RPLC-MS/MS had the highest percentage (88%) of BMAA-positive results and included a high number of quality control (QC) assessments. Various genera of cyanobacteria and diatoms have been reported to produce BMAA. The widespread geographical distribution of BMAA across diverse ecosystems highlights significant environmental and public health concerns. Notably, BMAA accumulation and biomagnification are likely more potent in marine or brackish water ecosystems than in freshwater ecosystems, potentially amplifying its ecological impacts. Future research should prioritize advanced, sensitive methods, particularly LC-MS/MS with as many QC assessments as possible, and should expand investigations to identify novel microalgal producers and previously uncharted geographical areas, with a special focus on marine or brackish water ecosystems. This effort will enhance our understanding of the environmental distribution and impacts of BMAA.}, } @article {pmid39395630, year = {2024}, author = {Yeewa, R and Sangphukieo, A and Jantaree, P and Wongkummool, W and Yamsri, T and Poompouang, S and Chaiyawat, P and Lo Piccolo, L and Jantrapirom, S}, title = {ERO1A inhibition mitigates neuronal ER stress and ameliorates UBQLN2[ALS] phenotypes in Drosophila melanogaster.}, journal = {Progress in neurobiology}, volume = {242}, number = {}, pages = {102674}, doi = {10.1016/j.pneurobio.2024.102674}, pmid = {39395630}, issn = {1873-5118}, mesh = {Animals ; *Drosophila melanogaster ; *Endoplasmic Reticulum Stress/drug effects/physiology ; *Drosophila Proteins/metabolism/genetics ; *Neurons/metabolism/drug effects ; Phenotype ; Autophagy-Related Proteins/metabolism/genetics ; Disease Models, Animal ; Animals, Genetically Modified ; Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Modulating the ER stress pathway holds therapeutic promise for neurodegenerative diseases; however, identifying optimal targets remains challenging. In this study, we conducted an unbiased screening to systematically search for commonly up-regulated proteins in ER stress-related neurodegenerative conditions, with endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) emerging as a significant hit. Further experiments conducted in the model organism Drosophila melanogaster demonstrated that elevated levels of Drosophila ERO1A (ERO1L) were indeed detrimental to neurons. Conversely, genetic suppression or pharmacological inhibition of ERO1L activity provided neuroprotection under ER stress and extended the lifespan of flies. To translate these findings, we performed a genetic modifier screening and underscored significant neuroprotective effects against UBQLN2[ALS] pathology. Additionally, administration of the chemical probe inhibitor of ERO1A, known as EN460, enhanced locomotive functions and neuromuscular junction (NMJ) morphology in Drosophila UBQLN2[ALS] model. Mechanistically, targeting ERO1L during environmental or pathological ER stress mitigated proteotoxic stress by lowering either the PERK or IRE1 branches of the unfolded protein response (UPR). These findings suggest ERO1A as a promising therapeutic target in UBQLN2[ALS] and other ER stress-related conditions.}, } @article {pmid39395841, year = {2024}, author = {Tran, M and Rhee, J and Hu, W and Magin, P and Shulruf, B}, title = {General practice trainee, supervisor and educator perspectives on the transitions in postgraduate training: a scoping review.}, journal = {Family medicine and community health}, volume = {12}, number = {4}, pages = {}, pmid = {39395841}, issn = {2009-8774}, mesh = {Humans ; *General Practice/education ; Education, Medical, Graduate ; General Practitioners/education ; Students, Medical/psychology ; }, abstract = {UNLABELLED: Transitions are a period and a process, through which there is a longitudinal adaptation in response to changing circumstances in clinical practice and responsibilities. While the experience of the transition in medical student learning and in hospital-based specialty training programmes are well described and researched, the experience of the transition in community-based postgraduate general practitioner (GP) training has not been described comprehensively.

OBJECTIVE: We aimed to identify, and categorise, the formative experiences of transitions in GP training and their impacts on personal and professional development.

DESIGN: We adopted Levac et al's scoping review methodology. Of 1543 retrieved records, 76 were selected for data extraction. Based on a combined model of the socioecological and multiple and multi-dimensional theories of transitions, data relating to the experiences of transitions were organised into contextual themes: being physical, psychosocial, organisational culture and chronological.

ELIGIBILITY CRITERIA: Empirical studies focused on general practice trainees or training, that discussed the transitions experienced in general practice training and that were published in English were included.

INFORMATION SOURCES: PubMed, MEDLINE and Web of Science databases were searched in January 2024 with no date limits for empirical studies on the transition experiences of GP into, and through, training.

RESULTS: Our findings describe context-dependent formative experiences which advance, or impede, learning and development. Time is a significant modulator of the factors contributing to more negative experiences, with some initially adverse experiences becoming more positive. Identification of the inflection point that represents a shift from initially adverse to more positive experiences of transitions may help moderate expectations for learning and performance at different stages of training.

CONCLUSION: Challenges in training can either advance development and contribute positively to professional identity formation and clinical competency, or detract from learning and potentially contribute to burnout and attrition from training programmes. These findings will assist future research in identifying predictive factors of positive and adverse experiences of transitions and may strengthen existing and nascent GP training programmes. The findings are transferable to other community-based specialty training programmes.}, } @article {pmid39396264, year = {2024}, author = {Bermudo Fuenmayor, S and Serrano Castro, PJ and Quiroga Subirana, P and López Palmero, S and Requena Mullor, MM and Parrón Carreño, T}, title = {Design and validation of a questionnaire for monitoring neurological dysphagia and respiratory deterioration in patients with amyotrophic lateral sclerosis (DEREDELA).}, journal = {Neurologia}, volume = {39}, number = {8}, pages = {666-674}, doi = {10.1016/j.nrleng.2024.09.003}, pmid = {39396264}, issn = {2173-5808}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; Humans ; *Deglutition Disorders/diagnosis/etiology ; Surveys and Questionnaires ; Male ; Female ; Reproducibility of Results ; Middle Aged ; Aged ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a degenerative disease of unknown origin that affects the motor neurons. It has a rapid, fatal course.

METHOD: For this study, an initial questionnaire of eleven items was developed by experts in the field, who evaluated the suitability and relevance of the items.

RESULTS: The questionnaire was then applied to a pilot group of 22 patients diagnosed with ALS. Confirmatory factor analysis, based on estimating maximum likelihood, confirmed the three domains detected in the exploratory factor analysis. The reliability of the scale was tested using Cronbach's α (0.801) and the Kaiser-Meyer-Olkin test (0.770) confirmed the construct validity.

CONCLUSIONS: The DEREDELA questionnaire is valid, in terms of its content, for monitoring the neurological dysphagia and respiratory deterioration suffered by patients diagnosed with ALS.}, } @article {pmid39396709, year = {2024}, author = {Wu, J and Wu, J and Chen, T and Cai, J and Ren, R}, title = {Protein aggregation and its affecting mechanisms in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {180}, number = {}, pages = {105880}, doi = {10.1016/j.neuint.2024.105880}, pmid = {39396709}, issn = {1872-9754}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Protein Aggregation, Pathological/metabolism ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; Protein Aggregates/physiology ; tau Proteins/metabolism ; }, abstract = {Protein aggregation serves as a critical pathological marker in a spectrum of neurodegenerative diseases (NDs), including the formation of amyloid β (Aβ) and Tau neurofibrillary tangles in Alzheimer's disease, as well as α-Synuclein (α-Syn) aggregates in Parkinson's disease, Parkinson's disease-related dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). A significant proportion of patients with amyotrophic lateral sclerosis (ALS) exhibit TDP-43 aggregates. Moreover, a confluence of brain protein pathologies, such as Aβ, Tau, α-Syn, and TDP-43, has been identified in individual NDs cases, highlighting the intricate interplay among these proteins that is garnering heightened scrutiny. Importantly, protein aggregation is modulated by an array of factors, with burgeoning evidence suggesting that it frequently results from perturbations in protein homeostasis, influenced by the cellular membrane milieu, metal ion concentrations, post-translational modifications, and genetic mutations. This review delves into the pathological underpinnings of protein aggregation across various NDs and elucidates the intercommunication among disparate proteins within the same disease context. Additionally, we examine the pathogenic mechanisms by which diverse factors impinge upon protein aggregation, offering fresh perspectives for the future therapeutic intervention of NDs.}, } @article {pmid39396990, year = {2024}, author = {Hazell, G and McCallion, E and Ahlskog, N and Sutton, ER and Okoh, M and Shaqoura, EIH and Hoolachan, JM and Scaife, T and Iqbal, S and Bhomra, A and Kordala, AJ and Scamps, F and Raoul, C and Wood, MJA and Bowerman, M}, title = {Exercise, disease state and sex influence the beneficial effects of Fn14-depletion on survival and muscle pathology in the SOD1[G93A] amyotrophic lateral sclerosis (ALS) mouse model.}, journal = {Skeletal muscle}, volume = {14}, number = {1}, pages = {23}, pmid = {39396990}, issn = {2044-5040}, support = {SBF006/1162/AMS_/Academy of Medical Sciences/United Kingdom ; SBF006/1162/AMS_/Academy of Medical Sciences/United Kingdom ; MR/Y003640/1/MRC_/Medical Research Council/United Kingdom ; MR/Y003640/1/MRC_/Medical Research Council/United Kingdom ; 18GRO-PS48-0114//Muscular Dystrophy UK/ ; 18GRO-PS48-0114//Muscular Dystrophy UK/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *TWEAK Receptor/metabolism/genetics ; *Muscle, Skeletal/metabolism/pathology ; Male ; Female ; *Disease Models, Animal ; *Mice, Transgenic ; Mice ; Physical Conditioning, Animal ; Mice, Knockout ; Cytokine TWEAK/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease. Accumulating evidence strongly suggests that intrinsic muscle defects exist and contribute to disease progression, including imbalances in whole-body metabolic homeostasis. We have previously reported that tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor inducible 14 (Fn14) are significantly upregulated in skeletal muscle of the SOD1[G93A] ALS mouse model. While antagonising TWEAK did not impact survival, we did observe positive effects in skeletal muscle. Given that Fn14 has been proposed as the main effector of the TWEAK/Fn14 activity and that Fn14 can act independently from TWEAK in muscle, we suggest that manipulating Fn14 instead of TWEAK in the SOD1[G93A] ALS mice could lead to differential and potentially improved benefits.

METHODS: We thus investigated the contribution of Fn14 to disease phenotypes in the SOD1[G93A] ALS mice. To do so, Fn14 knockout mice (Fn14[-/-]) were crossed onto the SOD1[G93A] background to generate SOD1[G93A];Fn14[-/-] mice. Investigations were performed on both unexercised and exercised (rotarod and/or grid test) animals (wild type (WT), Fn14[-/-], SOD1[G93A] and SOD1[G93A];Fn14[-/-]).

RESULTS: Here, we firstly confirm that the TWEAK/Fn14 pathway is dysregulated in skeletal muscle of SOD1[G93A] mice. We then show that Fn14-depleted SOD1[G93A] mice display increased lifespan, myofiber size, neuromuscular junction endplate area as well as altered expression of known molecular effectors of the TWEAK/Fn14 pathway, without an impact on motor function. Importantly, we also observe a complex interaction between exercise (rotarod and grid test), genotype, disease state and sex that influences the overall effects of Fn14 deletion on survival, expression of known molecular effectors of the TWEAK/Fn14 pathway, expression of myosin heavy chain isoforms and myofiber size.

CONCLUSIONS: Our study provides further insights on the different roles of the TWEAK/Fn14 pathway in pathological skeletal muscle and how they can be influenced by age, disease, sex and exercise. This is particularly relevant in the ALS field, where combinatorial therapies that include exercise regimens are currently being explored. As such, a better understanding and consideration of the interactions between treatments, muscle metabolism, sex and exercise will be of importance in future studies.}, } @article {pmid39397192, year = {2024}, author = {Hamdi, N and Mueller, K and Hamza, A and Soliman, R and Onbool, E and Omran, K and Ocab, O and Freischmidt, A and Siebert, R and Ludolph, A and Fahmy, N}, title = {First insights into genotype and phenotype of familial amyotrophic lateral sclerosis in Egypt: early onset and high consanguinity.}, journal = {Frontiers of medicine}, volume = {18}, number = {6}, pages = {1115-1118}, pmid = {39397192}, issn = {2095-0225}, } @article {pmid39399380, year = {2024}, author = {Cossu, L and Cappon, G and Facchinetti, A}, title = {Automated pipeline for denoising, missing data processing, and feature extraction for signals acquired via wearable devices in multiple sclerosis and amyotrophic lateral sclerosis applications.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1402943}, pmid = {39399380}, issn = {2673-253X}, abstract = {INTRODUCTION: The incorporation of health-related sensors in wearable devices has increased their use as essential monitoring tools for a wide range of clinical applications. However, the signals obtained from these devices often present challenges such as artifacts, spikes, high-frequency noise, and data gaps, which impede their direct exploitation. Additionally, clinically relevant features are not always readily available. This problem is particularly critical within the H2020 BRAINTEASER project, funded by the European Community, which aims at developing models for the progression of Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS) using data from wearable devices.

METHODS: The objective of this study is to present the automated pipeline developed to process signals and extract features from the Garmin Vivoactive 4 smartwatch, which has been chosen as the primary wearable device in the BRAINTEASER project. The proposed pipeline includes a signal processing step, which applies retiming, gap-filling, and denoising algorithms to enhance the quality of the data. The feature extraction step, on the other hand, utilizes clinical partners' knowledge and feedback to select the most relevant variables for analysis.

RESULTS: The performance and effectiveness of the proposed automated pipeline have been evaluated through pivotal beta testing sessions, which demonstrated the ability of the pipeline to improve the data quality and extract features from the data. Further clinical validation of the extracted features will be performed in the upcoming steps of the BRAINTEASER project.

DISCUSSION: Developed in Python, this pipeline can be used by researchers for automated signal processing and feature extraction from wearable devices. It can also be easily adapted or modified to suit the specific requirements of different scenarios.}, } @article {pmid39400020, year = {2026}, author = {Ali, A and Emad, NA and Sultana, N and Waheed, A and Aqil, M and Sultana, Y and Mujeeb, M}, title = {Navigating into the Paradigm of Nose-to-brain Delivery of Nanotherapeutics and their Repurposing as Nanotheranostics for Neurodegenerative Diseases.}, journal = {CNS & neurological disorders drug targets}, volume = {25}, number = {3}, pages = {174-194}, doi = {10.2174/0118715273319597240927044906}, pmid = {39400020}, issn = {1996-3181}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Drug Repositioning/methods ; *Brain/drug effects/metabolism ; Administration, Intranasal ; *Drug Delivery Systems/methods ; *Theranostic Nanomedicine/methods ; Neuroprotective Agents/administration & dosage ; *Nanoparticles/administration & dosage ; Blood-Brain Barrier/drug effects ; }, abstract = {Repurposing drugs for neurodegenerative diseases using the nose-to-brain route of administration is an intriguing concept with potential benefits. The nose-to-brain route involves delivering drugs directly to the brain via the olfactory or trigeminal pathways, bypassing the blood-brain barrier, which can improve drug efficacy and reduce systemic side effects. Treatment of numerous neurodegenerative diseases such as Multiple sclerosis, Amyotrophic lateral sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases has been attempted using this route of administration. These drugs may include neuroprotective agents, anti-inflammatory drugs, antioxidants, or diseasemodifying therapies. Nanotheranostics, which integrates therapeutic and diagnostic functions in a nanosystem, improves treatment precision and efficacy. Repurposing nanotherapeutics as nanotheranostics for neurodegenerative diseases through the nose-to-brain route of administration holds great potential for both diagnosis and treatment. This review highlights the various mechanisms engaged in transporting nanocarriers from nose-to-brain and the proposed fate of these nanocarriers using different live imaging techniques. Additionally, the discussion covers the recent combinatorial therapeutic approaches and theranostic applications of various nanocarriers used for neurodegenerative diseases through the nose-to-brain. Toxicity to the CNS and nasal mucosa and regulatory considerations about these delivery systems are also deliberated. Overall, repurposed nanoparticles designed as nanotheranostic agents offer a versatile platform for precise diagnosis, targeted therapy, and personalized management of neurodegenerative diseases, holding great promise for improving patient care and advancing our understanding of these complex disorders.}, } @article {pmid39400557, year = {2024}, author = {Gelpi, E and Reinecke, R and Gaig, C and Iranzo, A and Sabater, L and Molina-Porcel, L and Aldecoa, I and Endmayr, V and Högl, B and Schmutzhard, E and Poewe, W and Pfausler, B and Popovic, M and Pretnar-Oblak, J and Leypoldt, F and Matschke, J and Glatzel, M and Erro, EM and Jerico, I and Caballero, MC and Zelaya, MV and Mariotto, S and Heidbreder, A and Kalev, O and Weis, S and Macher, S and Berger-Sieczkowski, E and Ferrari, J and Reisinger, C and Klupp, N and Tienari, P and Rautila, O and Niemelä, M and Yilmazer-Hanke, D and Guasp, M and Bloem, B and Van Gaalen, J and Kusters, B and Titulaer, M and Fransen, NL and Santamaria, J and Dawson, T and Holton, JL and Ling, H and Revesz, T and Myllykangas, L and Budka, H and Kovacs, GG and Lewerenz, J and Dalmau, J and Graus, F and Koneczny, I and Höftberger, R}, title = {Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {53}, pmid = {39400557}, issn = {1432-0533}, support = {SYNABS//Austrian Science Fund/ ; I6565-B//Austrian Science Fund/ ; T996-B30//Austrian Science Fund/ ; 01GM2208B//Bundesministerium für Bildung und Forschung/ ; 01GM2208A//Bundesministerium für Bildung und Forschung/ ; PI21/00165//Instituto de Salud Carlos III/ ; PI21/00165//Instituto de Salud Carlos III/ ; N° 825575//Horizon 2020 Framework Programme/ ; 341007//Tekniikan Akatemia/ ; TYH2022316//Helsingin Yliopisto/ ; }, mesh = {Humans ; *Tauopathies/pathology/immunology ; Middle Aged ; *Brain Stem/pathology/metabolism/immunology ; Male ; Female ; Aged ; Aged, 80 and over ; *tau Proteins/metabolism/immunology ; *Cell Adhesion Molecules, Neuronal/metabolism/immunology ; Adult ; Autoantibodies/immunology ; DNA-Binding Proteins/metabolism ; }, abstract = {Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median < 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: stage 1 mild neurodegeneration without overt or only minimal tau pathology, stage 2 moderate neurodegeneration and mild/ moderate tauopathy and stage 3 prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series.}, } @article {pmid39401249, year = {2024}, author = {Pérez de la Lastra Aranda, C and Tosat-Bitrián, C and Porras, G and Dafinca, R and Muñoz-Torrero, D and Talbot, K and Martín-Requero, Á and Martínez, A and Palomo, V}, title = {Proteome Aggregation in Cells Derived from Amyotrophic Lateral Sclerosis Patients for Personalized Drug Evaluation.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {21}, pages = {3945-3953}, doi = {10.1021/acschemneuro.4c00328}, pmid = {39401249}, issn = {1948-7193}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy/pathology ; *Proteome/metabolism ; Precision Medicine/methods ; Motor Neurons/metabolism/drug effects ; Lymphocytes/metabolism/drug effects ; Protein Aggregates/drug effects/physiology ; Induced Pluripotent Stem Cells/metabolism/drug effects ; Protein Aggregation, Pathological/metabolism ; DNA-Binding Proteins/metabolism ; Drug Evaluation, Preclinical/methods ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that currently lacks effective therapy. Given the heterogeneity of clinical and molecular profiles of ALS patients, personalized diagnostics and pathological characterization represent a powerful strategy to optimize patient stratification, thereby enabling personalized treatment. Immortalized lymphocytes from sporadic and genetic ALS patients recapitulate some pathological hallmarks of the disease, facilitating the fundamental task of drug screening. However, the molecular aggregation of ALS has not been characterized in this patient-derived cellular model. Indeed, protein aggregation is one of the most prominent features of neurodegenerative diseases, and therefore, models to test drugs against personalized pathological aggregation could help discover improved therapies. With this work, we aimed to characterize the aggregation profile of ALS immortalized lymphocytes and test several drug candidates with different mechanisms of action. In addition, we have evaluated the molecular aggregation in motor neurons derived from two hiPSC cell lines corresponding to ALS patients with different mutations in TARDBP. The results provide valuable insight into the different characterization of sporadic and genetic ALS patients' immortalized lymphocytes, their differential response to drug treatment, and the usefulness of proteome homeostasis characterization in patients' cells.}, } @article {pmid39401554, year = {2025}, author = {Duarte, RRR and Nixon, DF and Powell, TR}, title = {Ancient viral DNA in the human genome linked to neurodegenerative diseases.}, journal = {Brain, behavior, and immunity}, volume = {123}, number = {}, pages = {765-770}, pmid = {39401554}, issn = {1090-2139}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/virology ; *Endogenous Retroviruses/genetics ; *Genome, Human ; Genome-Wide Association Study ; DNA, Viral/genetics ; Amyotrophic Lateral Sclerosis/genetics/virology ; Multiple Sclerosis/genetics/virology ; Genetic Predisposition to Disease/genetics ; Brain/metabolism/virology ; Parkinson Disease/genetics/virology ; Male ; Female ; }, abstract = {BACKGROUND: Human endogenous retroviruses (HERVs) are sequences in the human genome that originated from infections with ancient retroviruses during our evolution. Previous studies have linked HERVs to neurodegenerative diseases, but defining their role in aetiology has been challenging. Here, we used a retrotranscriptome-wide association study (rTWAS) approach to assess the relationships between genetic risk for neurodegenerative diseases and HERV expression in the brain, calculated with genomic precision.

METHODS: We analysed genetic association statistics pertaining to Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson's disease, using HERV expression models calculated from 792 cortical samples. Robust risk factors were considered those that survived multiple testing correction in the primary analysis, which were also significant in conditional and joint analyses, and that had a posterior inclusion probability above 0.5 in fine-mapping analyses.

RESULTS: The primary analysis identified 12 HERV expression signatures associated with neurodegenerative disease susceptibility. We found one HERV expression signature robustly associated with amyotrophic lateral sclerosis on chromosome 12q14 (MER61_12q14.2) and one robustly associated with multiple sclerosis on chromosome 1p36 (ERVLE_1p36.32a). A co-expression analysis suggested that these HERVs are involved in homophilic cell adhesion via plasma membrane adhesion molecules.

CONCLUSIONS: We found HERV expression profiles robustly associated with amyotrophic lateral sclerosis and multiple sclerosis susceptibility, highlighting novel risk mechanisms underlying neurodegenerative disease, and offering potential new targets for therapeutic intervention.}, } @article {pmid39402174, year = {2025}, author = {Jellinger, KA}, title = {The spectrum of behavioral disorders in amyotrophic lateral sclerosis: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {2}, pages = {217-236}, pmid = {39402174}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/pathology/psychology ; *Mental Disorders/etiology/physiopathology ; *Brain/physiopathology/pathology ; }, abstract = {Behavioral disorders, with an average prevalence of 30-60% are important non-motor symptoms in amyotrophic lateral sclerosis (ALS) that have a negative impact on prognosis, management and quality of life, yet the underlying neurobiology is poorly understood. Among people with ALS, apathy, fatigue, anxiety, irritability and other behavioral symptoms are the most prominent, although less frequent than cognitive impairment. The present review explores the current understanding of behavioral changes in ALS with particular emphasis on our current knowledge about their structural and functional brain correlates, substantiating a multisystem degeneration with particular dysfunction of frontal-subcortical circuits and dysfunction of fronto-striatal, frontotemporal and other essential brain systems. The natural history of behavioral dysfunctions in ALS and their relationship to frontotemporal lobe degeneration (FTLD) are not fully understood, although they form a clinical continuum, suggesting a differential vulnerability of non-motor brain networks, ALS being considered a brain network disorder. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of behavioral impairment in ALS. Treatment of both ALS and co-morbid behavioral disorders is a multidisciplinary task, but whereas no causal or disease-modifying therapies for ALS are available, symptomatic treatment of a variety of behavioral symptoms plays a pivotal role in patient care, although the management of behavioral symptoms in clinical care still remains limited.}, } @article {pmid39402245, year = {2024}, author = {Wood, H}, title = {Altered muscle cholesterol transport in ALS.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {11}, pages = {643}, doi = {10.1038/s41582-024-01029-8}, pmid = {39402245}, issn = {1759-4766}, } @article {pmid39403300, year = {2024}, author = {Aminianfar, A and Fatemi, MH and Azimi, F}, title = {Comprehensive characterization of volatile compounds in Iranian black teas using chemometric analysis of GC-MS fingerprints.}, journal = {Food chemistry: X}, volume = {24}, number = {}, pages = {101859}, pmid = {39403300}, issn = {2590-1575}, abstract = {Black tea, a widely popular non-alcoholic beverage, is renowned for its unique aroma and has attracted significant attention due to its complex composition. However, the chemical profile of Iranian tea remains largely unexplored. In this research, black tea samples from key tea cultivation regions in four geographical areas in northern Iran were firstly analyzed using headspace solid-phase microextraction followed by gas chromatography-mass spectrometry (HS-SPME-GC-MS) to separate, identify, and quantify their volatile organic compounds. Subsequently, employing a robust investigative strategy, we utilized for the first time the well-known multivariate curve resolution-alternating least square (MCR-ALS) method as a deconvolution technique to analyze the complex GC-MS peak clusters of tea samples. This approach effectively addressed challenges such as severe baseline drifts, overlapping peaks, and background noise, enabling the identification of minor components responsible for the distinct flavors and tastes across various samples. The MCR-ALS technique significantly improved the resolution of spectral and elution profiles, enabling both qualitative and semi-quantitative analysis of tea constituents. Qualitative analysis involved comparing resolved peak profiles to theoretical spectra, along with retention indices, while semi-quantification was conducted using the overall volume integration (OVI) approach for volatile compounds, providing a more accurate correlation between peak areas and concentrations. The application of chemometric tools in GC-MS analysis increased the number of recognized components in four tea samples, expanding from 54 to 256 components, all with concentrations exceeding 0.1 %. Among them, 32 volatile compounds were present in every tea sample. Hydrocarbons (including alkenes, alkanes, cycloalkanes, monoterpenes and sesquiterpenes), esters and alcohols were the three major chemical classes, comprising 78 % of the total relative content of volatile compounds. Analyzing black teas from four distinct regions revealed variations not only in their volatile components but also in their relative proportions. This integrated approach provides a comprehensive understanding of the volatile chemical profiles in Iranian black teas, enhances knowledge about their unique characteristics across diverse geographical origin, and lays the groundwork for quality improvement.}, } @article {pmid39403566, year = {2024}, author = {Biswas, DD and Sethi, R and Woldeyohannes, Y and Scarrow, ER and El Haddad, L and Lee, J and ElMallah, MK}, title = {Respiratory pathology in the TDP-43 transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1430875}, pmid = {39403566}, issn = {1664-042X}, support = {R21 NS098131/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in death within 2-5 years of diagnosis. Respiratory failure is the most common cause of death in ALS. Mutations in the transactive response DNA binding protein 43 (TDP-43) encoded by the TARDBP gene are associated with abnormal cellular aggregates in neurons of patients with both familial and sporadic ALS. The role of these abnormal aggregates on breathing is unclear. Since respiratory failure is a major cause of death in ALS, we sought to determine the role of TDP-43 mutations on the respiratory motor unit in the Prp-hTDP-43[A315T] mouse model - a model that expresses human TDP-43 containing the A315T mutation. We assessed breathing using whole-body plethysmography, and investigated neuropathology in hypoglossal and phrenic respiratory motor units. Postmortem studies included quantification of hypoglossal and putative phrenic motor neurons, activated microglia and astrocytes in respiratory control centers, and assessment of hypoglossal and phrenic nerves of TDP43[A315T] mice. The male TDP43[A315T] mice display an early onset of rapid progression of disease, and premature death (less than 15 weeks) compared to control mice and compared to female TDP43[A315T] mice who die between 20 and 35 weeks of age. The TDP43[A315T] mice have progressive and profound breathing deficits at baseline and during a respiratory challenge. Histologically, hypoglossal and putative phrenic motor neurons of TDP43[A315T] mice are decreased and have increased microglial and astrocyte activation, indicating pronounced neurodegeneration and neuroinflammation. Further, there is axonopathy and demyelination in the hypoglossal and phrenic nerve of TDP43[A315T] mice. Thus, the TDP-43[A315T] mice have significant respiratory pathology and neuropathology, which makes them a useful translatable model for the study of novel therapies on breathing in ALS.}, } @article {pmid39404532, year = {2024}, author = {Tanioka, S and Wu, B and Ballmer, SW}, title = {Experimental demonstration of frequency- downconverted arm-length stabilization for a future upgraded gravitational wave detector.}, journal = {Optics letters}, volume = {49}, number = {20}, pages = {5763-5766}, doi = {10.1364/OL.534141}, pmid = {39404532}, issn = {1539-4794}, abstract = {Ground-based laser interferometric gravitational wave detectors (GWDs) consist of multiple optical cavity systems whose lengths need to be interferometrically controlled. An arm-length stabilization (ALS) system has played an important role in bringing these interferometers into an operational state and enhancing their duty cycle. The sensitivity of these detectors can be improved if the thermal noise of their test mass mirror coatings is reduced. Crystalline AlGaAs coatings are a promising candidate for this. However, the current ALS system with a frequency-doubled 532 nm light is no longer an option with AlGaAs coatings because the 532 nm light is absorbed by AlGaAs coatings due to the narrow bandgap of GaAs. Therefore, alternative locking schemes must be developed. In this Letter, we describe an experimental demonstration of a novel ALS scheme, to the best of our knowledge, which is compatible with AlGaAs coatings. This ALS scheme will enable the use of AlGaAs coatings in current and future terrestrial gravitational wave detectors.}, } @article {pmid39404920, year = {2025}, author = {Aiello, EN and Curti, B and Torre, S and De Luca, G and Maranzano, A and Colombo, E and Gendarini, C and Cocuzza, A and Messina, S and Doretti, A and Verde, F and Morelli, C and Silani, V and Ticozzi, N and Poletti, B}, title = {Clinical usefulness of the Verbal Fluency Index (VFI) in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {2}, pages = {775-782}, pmid = {39404920}, issn = {1590-3478}, support = {NA//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/psychology/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Neuropsychological Tests ; *Verbal Behavior/physiology ; Executive Function/physiology ; Severity of Illness Index ; Italy ; }, abstract = {BACKGROUND: This study aimed at assessing the clinical utility of the Verbal Fluency Index (VFI) over a classical phonemic verbal fluency test in Italian-speaking amyotrophic lateral sclerosis (ALS) patients.

METHODS: N = 343 non-demented ALS patients and N = 226 healthy controls (HCs) were administered the Verbal fluency - S task from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The associations between the number of words produced (NoW), the time to read words aloud (TRW) and the VFI (computed as [(60"-TRW)/NoW]) on one hand and both bulbar/respiratory scores from the ALS Functional Rating Scale - Revised (ALSFRS-R) and the ECAS-Executive on the other were tested. Italian norms for the NoW and the VFI were derived in HCs via the Equivalent Score method. Patients were classified based on their impaired/unimpaired performances on the NoW and the VFI (NoW-VFI-; NoW-VFI+; NoW + VFI-; NoW + VFI+), with these groups being compared on ECAS-Executive scores.

RESULTS: The VFI, but neither the NoW nor the TRW, were related to ALSFRS-Bulbar/-Respiratory scores; VFI and NoW measures, but not the TRW, were related to the ECAS-Executive (p < .001). The NoW slightly overestimated the number of executively impaired patients when compared to the VFI (31.1% vs. 26.8%, respectively). Patients with a defective VFI score - regardless of whether they presented or not with a below-cutoff NoW - reported worse ECAS-Executive scores than NoW + VFI + ones.

CONCLUSIONS: The present reports support the use of the Italian VFI as a mean to validly assess ALS patients' executive status by limiting the effect of motor disabilities that might undermine their speech rate.}, } @article {pmid39405005, year = {2024}, author = {Cheng, JL and Cook, AL and Talbot, J and Perry, S}, title = {How is Excitotoxicity Being Modelled in iPSC-Derived Neurons?.}, journal = {Neurotoxicity research}, volume = {42}, number = {5}, pages = {43}, pmid = {39405005}, issn = {1476-3524}, mesh = {*Induced Pluripotent Stem Cells/drug effects/physiology ; Humans ; *Neurons/drug effects/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Cell Differentiation/drug effects/physiology ; }, abstract = {Excitotoxicity linked either to environmental causes (pesticide and cyanotoxin exposure), excitatory neurotransmitter imbalance, or to intrinsic neuronal hyperexcitability, is a pathological mechanism central to neurodegeneration in amyotrophic lateral sclerosis (ALS). Investigation of excitotoxic mechanisms using in vitro and in vivo animal models has been central to understanding ALS mechanisms of disease. In particular, advances in induced pluripotent stem cell (iPSC) technologies now provide human cell-based models that are readily amenable to environmental and network-based excitotoxic manipulations. The cell-type specific differentiation of iPSC, combined with approaches to modelling excitotoxicity that include editing of disease-associated gene variants, chemogenetics, and environmental risk-associated exposures make iPSC primed to examine gene-environment interactions and disease-associated excitotoxic mechanisms. Critical to this is knowledge of which neurotransmitter receptor subunits are expressed by iPSC-derived neuronal cultures being studied, how their activity responds to antagonists and agonists of these receptors, and how to interpret data derived from multi-parameter electrophysiological recordings. This review explores how iPSC-based studies have contributed to our understanding of ALS-linked excitotoxicity and highlights novel approaches to inducing excitotoxicity in iPSC-derived neurons to further our understanding of its pathological pathways.}, } @article {pmid39406000, year = {2024}, author = {Zhang, L and Du, Y and Deng, Y and Bai, T and Wang, J and Wang, W and Ji, M}, title = {Mutations in target gene confers resistance to acetolactate synthase inhibitors in Echinochloa phyllopogon.}, journal = {Plant physiology and biochemistry : PPB}, volume = {216}, number = {}, pages = {109194}, doi = {10.1016/j.plaphy.2024.109194}, pmid = {39406000}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Echinochloa/genetics/drug effects/enzymology ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Mutation ; *Plant Proteins/genetics/metabolism ; Plants, Genetically Modified ; Enzyme Inhibitors/pharmacology ; Arabidopsis/genetics/enzymology/drug effects ; Molecular Docking Simulation ; Sulfonamides ; Uridine/analogs & derivatives ; }, abstract = {Echinochloa phyllopogon is a noxious weed that can harm rice over prolonged periods. Recently, a penoxsulam-resistant variant of E. phyllopogon with a mutation in the acetolactate synthase (ALS) gene was collected in Northeastern China. In the present study, the molecular mechanism underlying herbicide resistance in mutant populations was evaluated. The GR50 and IC50 values of the herbicide-resistant mutant 1-11 were 27.0- and 21.4-fold higher than those of the susceptible population 2-31, respectively. In addition, pre-application of malathion reduced the GR50 value of the resistant population. Additionally, mutant populations developed cross-resistance to other ALS inhibitors. E. phyllopogon ALS sequencing showed a Trp-574-Leu mutation in ALS2 variant 1-11. Molecular docking showed that the Trp-574-Leu substitution reduced the number of hydrogen bonds and altered the interaction between penoxsulam and ALS2. Transgenic Arabidopsis plants harboring the ALS2 mutant gene also showed resistance to penoxsulam and other ALS inhibitors. Overall, our study demonstrated that the Trp-574-Leu mutation and P450-mediated metabolic resistance lead to the cross-resistance of E. phyllopogon to ALS inhibitors.}, } @article {pmid39406341, year = {2024}, author = {López-Royo, T and Moreno-Martínez, L and Zaragoza, P and García-Redondo, A and Manzano, R and Osta, R}, title = {Differentially expressed lncRNAs in SOD1[G93A] mice skeletal muscle: H19, Myhas and Neat1 as potential biomarkers in amyotrophic lateral sclerosis.}, journal = {Open biology}, volume = {14}, number = {10}, pages = {240015}, pmid = {39406341}, issn = {2046-2441}, support = {//Gobierno de Aragón/ ; //Instituto de Salud Carlos III/ ; //European Union/ ; //Gobierno de España/ ; //Center for Biomedical Research/ ; }, mesh = {*RNA, Long Noncoding/genetics/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Muscle, Skeletal/metabolism/pathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Biomarkers/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Humans ; Gene Expression Regulation ; Gene Expression Profiling ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by progressive motor function and muscle mass loss. Despite extensive research in the field, the underlying causes of ALS remain incompletely understood, contributing to the absence of specific diagnostic and prognostic biomarkers and effective therapies. This study investigates the expression of long-non-coding RNAs (lncRNAs) in skeletal muscle as a potential source of biomarkers and therapeutic targets for the disease. The expression profiles of 12 lncRNAs, selected from the literature, were evaluated across different disease stages in tissue and muscle biopsies from the SOD1[G93A] transgenic mouse model of ALS. Nine out of the 12 lncRNAs were differentially expressed, with Pvt1, H19 and Neat1 showing notable increases in the symptomatic stages of the disease, and suggesting their potential as candidate biomarkers to support diagnosis and key players in muscle pathophysiology in ALS. Furthermore, the progression of Myhas and H19 RNA levels across disease stages correlated with longevity in the SOD1[G93A] animal model, effectively discriminating between long- and short-term survival individuals, thereby highlighting their potential as prognostic indicators. These findings underscore the involvement of lncRNAs, especially H19 and Myhas, in ALS pathophysiology, offering novel insights for diagnostic, prognostic and therapeutic targets.}, } @article {pmid39406675, year = {2025}, author = {Schilfarth, P and Réginault, T and Mathis, S and Le Masson, G and Pillet, O and Grassion, L}, title = {Changes in Non-invasive Ventilation Compliance in Patients With Amyotrophic Lateral Sclerosis: A Post-hoc Analysis.}, journal = {Archivos de bronconeumologia}, volume = {61}, number = {1}, pages = {47-49}, doi = {10.1016/j.arbres.2024.09.003}, pmid = {39406675}, issn = {1579-2129}, } @article {pmid39407580, year = {2024}, author = {Forleo, T and Giannossa, LC and De Juan Capdevila, A and Lagioia, G and Mangone, A}, title = {Hats Off to Modeling! Profiling Early Synthetic Dyes on Historic Woolen Samples with ATR-FTIR Spectroscopy and Multivariate Curve Resolution-Alternating Least Square Algorithm.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {19}, pages = {}, pmid = {39407580}, issn = {1420-3049}, abstract = {This research focuses on analyzing wool samples dyed with synthetic dyes from the early 20th century. A methodology to identify and distinguish wool fibers dyed with azo, triphenylmethane, and xanthene dyes, which are no longer in use, using the ATR-FTIR spectra, is presented. Firstly, the dataset was subjected to PCA, which revealed the similarities and differences among the samples, illustrating a distribution pattern based on dye classes. MCR-ALS was employed to extract the spectral profiles of the dyed fibers, thereby enhancing the efficacy of the analytical techniques and extracting the comprehensive information from a single instrument. The combination of ATR-FTIR spectroscopy with chemometric methods, such as PCA and MCR-ALS, has proven to be an effective strategy for identifying and differentiating wool fibers dyed with early azo, triphenylmethane, and xanthene dyes. This approach has demonstrated particular effectiveness in enabling rapid analysis without requiring sampling or pretreatment. Moreover, the analysis is supported by thorough bibliographic research on these no longer used colorants. In order to maximize the potential of non-destructive spectroscopic techniques, such as ATR-FTIR, the approach used has proven to be crucial. This study underscores how chemometric techniques expand the capabilities of spectroscopy, extracting extensive information from a single instrument and aligning with the goals of cultural heritage analysis.}, } @article {pmid39407861, year = {2024}, author = {Proaño, B and Cuerda-Ballester, M and Daroqui-Pajares, N and Del Moral-López, N and Seguí-Sala, F and Martí-Serer, L and Calisaya Zambrana, CK and Benlloch, M and de la Rubia Ortí, JE}, title = {Clinical and Sociodemographic Factors Related to Amyotrophic Lateral Sclerosis in Spain: A Pilot Study.}, journal = {Journal of clinical medicine}, volume = {13}, number = {19}, pages = {}, pmid = {39407861}, issn = {2077-0383}, support = {2021-203-003//Catholic University of Valencia San Vicente Mártir/ ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknow etiology. Male sex is a well stablished risk factor, but other factors such as early and adult life expositions show contradictory evidence. Aim: to explore the link of clinical, sociodemographic, and occupational factors with ALS patients in Spain and the impact of these factors in functionality. Methods: A cross-sectional study was conducted with ALS patients and healthy controls. Registered variables were smoking, arterial hypertension, diabetes mellitus type 2, previous cancer to reproductive organs or breast, occupational exposure, and early life exposures. Functionality in ALS patients was compared according to each exposure. Results: The ALS group consisted of 59 participants and the control group of 90 participants. ALS patients showed a significant association with previous cancer (p = 0.011), occupational exposure (p < 0.001), and older siblings (p = 0.029). ALS patients presented significant differences in BMI according to hypertension and older-sibling factors. Moreover, respiratory function was affected in patients with previous cancer (p = 0.031). Conclusions: Occupational exposure and previous cancer to reproductive organs or breast could be linked to ALS patients. In addition, hypertension and previous cancer could affect their BMI and respiratory function. Other factors such as longer smoking periods and exposition to older siblings could also characterize ALS patients.}, } @article {pmid39408173, year = {2024}, author = {Rolling, J and Fath, M and Zanfonato, T and Durpoix, A and Mengin, AC and Schröder, CM}, title = {EMDR-Teens-cPTSD: Efficacy of Eye Movement Desensitization and Reprocessing in Adolescents with Complex PTSD Secondary to Childhood Abuse: A Case Series.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {19}, pages = {}, pmid = {39408173}, issn = {2227-9032}, abstract = {Background: Mental healthcare for children and adolescents with a history of childhood abuse constitutes a major public health issue. Indeed, abuse exposes children to severe and complex post-traumatic stress disorder (cPTSD) but also to neurodevelopmental and psychological repercussions impacting the developmental trajectory. Trauma-focused care is essential to avoid the chronicization of symptoms and disorders. Objective: The aim of this prospective case series study was to investigate the efficacy of eye movement desensitization and reprocessing (EMDR) on complex post-traumatic symptoms and associated psychiatric disorders in adolescents with a history of abuse. Method: Twenty-two adolescents, aged 12 to 17, who had been abused during childhood were included. All adolescents met ICD-11 criteria for complex PTSD. Subjective measures of PTSD and associated psychiatric disorders were taken before (T0) and after 3 months of EMDR therapy (T1). Results: The average PTSD symptom score on the CPTS-RI significantly decreased from 40.2 to 34.4 after EMDR, indicating improvement in post-traumatic symptoms. A significant decrease in the average depression score (CDI from 18.2 at T0 to 10.6 at T1), anxiety score (R-CMAS from 21.3 at T0 to 13.3 at T1), emotional regulation score (ALS from 29 at T0 to 10.8 at T1), insomnia score (ISI from 18.5 at T0 to T1 of 9.2 at T1), and harmful use of alcohol and drugs score (ADOSPA from 2.3 at T0 to 0.3 at T1) was observed after EMDR therapy, as well as an increase in quality of life (CBCL 4-16 score from 57.9 at T0 to 77.4 at T1). Conclusions: The results of this study are encouraging and suggest that EMDR may be effective in the symptom management reducing post-traumatic symptoms and certain comorbid disorders frequently seen in adolescents who have experienced childhood abuse. Further research is needed on adolescent populations suffering from cPTSD (e.g., randomized controlled trials with control groups and other therapies or evaluating the action of the different phases of the study).}, } @article {pmid39408720, year = {2024}, author = {Du, X and Dong, Q and Zhu, J and Li, L and Yu, X and Liu, R}, title = {Rutin Ameliorates ALS Pathology by Reducing SOD1 Aggregation and Neuroinflammation in an SOD1-G93A Mouse Model.}, journal = {International journal of molecular sciences}, volume = {25}, number = {19}, pages = {}, pmid = {39408720}, issn = {1422-0067}, support = {XDB39050600//Strategic Priority Research Program of Chinese Academy of Sciences/ ; 82150107//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Rutin/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; Mice ; *Superoxide Dismutase-1/metabolism/genetics ; *Disease Models, Animal ; *Mice, Transgenic ; *Spinal Cord/drug effects/metabolism/pathology ; Motor Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Neuroinflammatory Diseases/drug therapy/metabolism ; Humans ; Protein Aggregation, Pathological/drug therapy/metabolism ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of motor neurons, with limited effective treatments. Recently, the exploration of natural products has unveiled their potential in exerting neuroprotective effects, offering a promising avenue for ALS therapy. In this study, the therapeutic effects of rutin, a natural flavonoid glycoside with neuroprotective properties, were evaluated in a superoxide dismutase 1 (SOD1)-G93A mouse model of ALS. We showed that rutin reduced the level of SOD1 aggregation and diminished glial cell activation in spinal cords and brainstems, resulting in significantly improved motor function and motor neuron restoration in SOD1-G93A mice. Our findings indicated that rutin's multi-targeted approach to SOD1-related pathology makes it a promising candidate for the treatment of ALS.}, } @article {pmid39410995, year = {2024}, author = {Zaninotto, AL and Makary, MM and Rowe, HP and Eshghi, M and Tseng, CJ and Chan, J and Zürcher, NR and Hooker, J and Lewis, A and Keegan, M and Gifford, RF and Green, JR and Babu, S}, title = {Speech motor impairment in ALS is associated with multiregional cortical thinning beyond primary motor cortex.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1451177}, pmid = {39410995}, issn = {1664-2295}, support = {K23 DC019179/DC/NIDCD NIH HHS/United States ; }, abstract = {INTRODUCTION: Cortical thinning is well-documented in individuals with amyotrophic lateral sclerosis (ALS), yet its association with speech deterioration remains understudied. This study characterizes anatomical changes in the brain within the context of speech impairment patterns in individuals with ALS, providing insight into the disease's multiregional spread and biology.

METHODS: To evaluate patterns of cortical thickness in speakers with ALS with and without functional speech changes compared to healthy controls (HCs) using whole-brain and region of interest (ROI) analyses. Forty individuals with ALS and 22 HCs underwent a T1-weighted 3-Tesla magnetic resonance imaging (MRI). Individuals with ALS were divided into two groups based on the preserved speech [ps-ALS] (n = 18) or deteriorated speech [ds-ALS] (n = 22) as measured by the ALSFRSF-R speech subscore (=4 or <4 points, respectively). Sixteen a priori-defined and automatically segmented cortical and subcortical brain ROIs were selected based on their previously documented roles in speech production. Two cortical thickness analyses were performed: (1) group-level whole-brain surface-based analyses and (2) group-level ROI analyses. A case study of 6 ALS individuals examined the cortical thickness, and their speech was characterized using quantitative and qualitative measures.

RESULTS: Based on the group-level whole-brain surface-based analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in the left primary motor and somatosensory cortices and the right inferior parietal lobe with its adjacent lateral occipital cortical regions. The ps-ALS group demonstrated no significant cortical thinning compared to HCs. Based on the group-level ROI analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in bilateral middle motor cortices, right posterior dorsal premotor cortex, and left anterior cingulate cortex. The case study analysis revealed that ALS speakers with speech features characteristic of spastic dysarthria exhibited cortical thinning, while those with speech features characteristic of flaccid dysarthria did not.

DISCUSSION: Individuals with ALS have anatomical changes involving multiregional neocortical areas beyond the primary motor cortex that may manifest as subjective (i.e., clinical judgment) and objective (i.e., speaking rate) changes in speech production. Further longitudinal work in ALS is needed to better understand the link between MRI cortical thickness changes and bulbar dysfunction.}, } @article {pmid39411168, year = {2024}, author = {An, D and Han, J and Fang, P and Bu, Y and Ji, G and Liu, M and Deng, J and Song, X}, title = {Evidence for the potential role of m6A modification in regulating autophagy in models of amyotrophic lateral sclerosis.}, journal = {CytoJournal}, volume = {21}, number = {}, pages = {33}, pmid = {39411168}, issn = {0974-5963}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Research indicates that N6-methyladenosine (m6A) modification plays a crucial role in cellular autophagy during ALS development. This study investigates the role of autophagy in ALS, with a focus on the effect of messenger ribonucleic acid m6A methylation modification on disease progression.

MATERIAL AND METHODS: We compared m6A levels and regulatory molecule expressions in transgenic superoxide dismutase (SOD1)-G93A and non-transgenic mice, categorized into end-stage and control groups, using quantitative polymerase chain reaction and Western blotting. The NSC-34 cell line, which was modified to model ALS, enabled the investigation of apoptosis, autophagy, and autophagy disruption through terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assays, Western blotting, and fluorescent staining.

RESULTS: Our findings indicate significantly elevated m6A methylation levels in ALS mice (0.262 ± 0.005) compared with the controls (0.231 ± 0.003) and in the ALS model cells (0.242±0.005) relative to those belonging to the wild-type control group (0.183 ± 0.007). Furthermore, the proteins involved in m6A RNA modification differed between groups, which suggest impaired autophagy flux in the ALS models.

CONCLUSION: These results suggest that m6A methylation may accelerate ALS progression through the disruption of autophagic processes. Our study underscores the role of m6A methylation in the pathology of ALS and proposes the targeting of m6A methylation as a potential therapeutic strategy for disease treatment. Although this study primarily used transgenic SOD1-G93A mice and NSC-34 cell models to investigate ALS pathology, potential differences in disease mechanisms between animal models and humans must be considered. Although a correlation was detected between m6A methylation levels and autophagy disruption in ALS, the study primarily established an association rather than provided detailed mechanistic insights.}, } @article {pmid39412227, year = {2025}, author = {Mascías Cadavid, J and Radakovic, R and Radakovic, C and Moran Benito, Y and Marín Esteban, S and Rodríguez-Santos, F and Salas Campos, T}, title = {Spanish adaptation of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {375-378}, doi = {10.1080/21678421.2024.2416665}, pmid = {39412227}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology/physiopathology ; Female ; Male ; Middle Aged ; *Disability Evaluation ; Aged ; Reproducibility of Results ; Psychometrics/methods ; Spain ; Adult ; Severity of Illness Index ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized functional decline, traditionally measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). The Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) is an alternative comprehensive, detailed functional disability measure for people with ALS (pwALS), not yet translated to Spanish. The aim of this study was to translate and validate the Spanish ROADS. 53 Spanish speaking pwALS were recruited. They completed the ALSFRS-R and Spanish ROADS. Reliability (internal consistency, intra-class correlation) and validity (ALSFRS-R total and item-total correlations) were determined. The Spanish ROADS internal consistency reliability was excellent (Cronbach's standardized alpha = 0.94), the test-retest reliability intra-class correlation value was 0.93. There was a strong significant correlation between the Spanish ROADS and ALSFRS-R totals (rs(52) = .89, p < .001). Additionally, the ALSFRS-R subscales and ROADS items correlations showed domain-to-item specific expected significant correlations. The Spanish ROADS is a psychometrically robust, valid and reliable measure for quantifying functional disability for pwALS.}, } @article {pmid39412565, year = {2024}, author = {Sangari, S and Lackmy-Vallee, A and Preuilh, A and Peyre, I and Pradat, PF and Marchand-Pauvert, V}, title = {Synaptic dynamics linked to widespread elevation of H-reflex before peripheral denervation in amyotrophic lateral sclerosis.}, journal = {Journal of neurophysiology}, volume = {132}, number = {5}, pages = {1541-1560}, doi = {10.1152/jn.00144.2024}, pmid = {39412565}, issn = {1522-1598}, support = {VMarchand/2013//ARSLA/ ; DdT1 2015- 2; CTL/SS/2016-0029/no 16597//AFM-Telethon/ ; FTL AAP7/2015//Fondation Thierry Latran (Thierry Latran Foundation)/ ; }, mesh = {Humans ; *H-Reflex/physiology ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Evoked Potentials, Motor/physiology ; *Muscle, Skeletal/physiopathology/physiology ; Aged ; Adult ; Excitatory Postsynaptic Potentials/physiology ; Riluzole/pharmacology ; Motor Neurons/physiology ; }, abstract = {Changes in Hoffmann reflex (H-reflex) exhibit heterogeneity among patients with amyotrophic lateral sclerosis (ALS), likely due to phenotype diversity. Current knowledge primarily focuses on soleus H-reflex, which may demonstrate an initial increase before subsequent decline throughout the disease course. The main objective was to investigate other muscles, to determine whether H-reflex changes could be associated with patient phenotype (onset site, functional disabilities). Additional experiments were performed to elucidate the neurophysiological mechanisms underlying H-reflex modifications. In age- and sex-matched groups of control subjects and patients, we compared H-reflex recruitment curves in soleus, quadriceps, and forearm flexors. Additionally, we examined H-reflex and motor evoked potential (MEP) recruitment curves in quadriceps. Last, to assess potential changes in monosynaptic excitatory postsynaptic potentials (EPSPs) of both peripheral and cortical origins, we analyzed peristimulus time histograms (PSTHs) and peristimulus frequencygrams (PSFs) of single motor units, along with H-reflex occurrence after paired-pulse stimuli. The ratio between maximal amplitudes of H-reflex and direct motor response increased in all muscles, irrespective of disease onset, and was found positively correlated with exaggerated osteotendinous reflexes and spasticity but depressed in patients on riluzole. This finding was accompanied by a reduction in MEP size and no changes in PSTH, PSF, and paired-pulse H-reflex probability. It is speculated that spinal interneurons may compensate for potential depression of monosynaptic EPSPs in ALS. From a clinical perspective, although the added value of H-reflex to osteotendinous reflex evaluation may be limited, it can serve as a valuable quantitative biomarker of pyramidal dysfunction in clinical trials.NEW & NOTEWORTHY Without significant evidence of peripheral denervation, H-reflex enhancement appears to be a widespread phenomenon, regardless of disease onset site. This increase is likely associated with a decrease in inhibitory control over presynaptic transmission of the synapse between muscle group Ia afferents and motoneurons. Although the link to exaggerated osteotendinous reflexes and spasticity implies a restricted role in identifying a pyramidal syndrome, its quantitative aspect positions the H-reflex as a valuable biomarker in clinical trials.}, } @article {pmid39412921, year = {2024}, author = {Bahador, M and Soltaninejad, S and Mobasheri, M}, title = {Correlation of new two-dimensional geometrical parameters to lung and heart dose-volume parameters in breast cancer radiation therapy.}, journal = {Journal of cancer research and therapeutics}, volume = {20}, number = {5}, pages = {1570-1577}, doi = {10.4103/jcrt.jcrt_2351_23}, pmid = {39412921}, issn = {1998-4138}, mesh = {Humans ; Female ; *Heart/radiation effects/diagnostic imaging ; *Radiotherapy Dosage ; *Radiotherapy Planning, Computer-Assisted/methods ; *Lung/radiation effects/diagnostic imaging/pathology ; *Breast Neoplasms/radiotherapy/pathology ; *Organs at Risk/radiation effects ; Tomography, X-Ray Computed/methods ; ROC Curve ; Middle Aged ; }, abstract = {OBJECTIVE: To develop new two-dimensional geometric parameters for pulmonary and cardiac dose estimation in left-sided breast cancer radiation therapy without dose-volume histogram (DVH).

METHODS: On the CT image of 90 patients with left breast cancer, treatment planning was performed using two opposed tangent fields with/without supraclavicular. The field-in-field technique and 6MV photons were used. From DVH dosimetric parameters of mean dose, Vx (x (Gy) =5, 10, 15, 20, 30, 40, 50) were calculated, and from heart and lung outlines on the beam's eye view, new geometric parameters of percent of lung area in tangent and supraclavicular fields (%area of the lung in the tangent (ALT), %ALS) and percent of heart in tangent field (%area of the heart in the tangent (AHT)) were measured. Correlation, regression, and diagnostic performance by receiver operating characteristic curve (ROC) were investigated for statistical analysis.

RESULTS: The Pearson coefficient between %ALT and Vx (x = 10, 15, 20, 30, 40) show strong correlation in patient treatment with only opposed tangents (>0.85) and weaker in treatment by opposed tangents with supraclavicular (0.56-0.88), the %ALS indicate weak correlation (<0.5) and %AHT show strong correlation (0.93-0.98). The regression analysis shows a positive relation between %ALT and mean dose (R2 = 0.8), V20Gy (R2 = 0.9) in the lung (tangent treatment), and between %AHT and mean dose (R2 = 0.9), V20Gy (R2 = 1.0) in the heart. The ROC analysis shows by %ALT <20.3 for treatment by just opposed fields, %ALT <22.1% for treatment tangents with supra, and %AHT <11.6%, practical lung and heart dose constraints are addressed.

CONCLUSION: The proposed geometric parameters could replace previous one-dimensional maximum and central distances for predicting doses to lung and heart.

ADVANCES IN KNOWLEDGE: This study presents simple geometric parameters that could estimate pulmonary and cardiac dose in left breast cancer treatment from a 2D radiograph.}, } @article {pmid39413009, year = {2024}, author = {Ralbovsky, NM and Zhang, Y and Williams, DM and McKelvey, CA and Smith, JP}, title = {Machine Learning and Hyperspectral Imaging for Analysis of Human Papillomaviruses (HPV) Vaccine Self-Healing Particles.}, journal = {Analytical chemistry}, volume = {96}, number = {43}, pages = {17118-17127}, doi = {10.1021/acs.analchem.4c02327}, pmid = {39413009}, issn = {1520-6882}, mesh = {*Papillomavirus Vaccines/immunology ; *Machine Learning ; Humans ; Vaccines, Virus-Like Particle ; Human Papillomavirus Viruses ; }, abstract = {Human papillomaviruses (HPV) are known to cause a variety of diseases, including cervical cancer and genital warts. HPV is a highly prevalent virus and is considered the most common sexually transmitted disease. Because of the risks associated with HPV, Gardasil, a quadrivalent recombinant vaccine, was developed by Merck & Co., Inc., Rahway, NJ, USA, and approved by the Food and Drug Administration (FDA) in 2006. The second generation of the vaccine, Gardasil9, was subsequently approved by the FDA in 2014, providing significant protection against HPV. The HPV vaccine may be given as 2 or 3 doses; however, vaccine administration as a single dose with a sustained release mechanism may potentially offer benefits to meet emerging health needs. To explore this, HPV vaccines were formulated within microporous self-healing particles (SHPs) to enable potential controlled release of HPV virus-like particle (VLP) antigen. Machine learning, in the form of multivariate curve resolution-alternating least-squares (MCR-ALS), with Raman hyperspectral imaging was used to determine the molecular identity and spatial distribution of all relevant species within this HPV vaccine formulation. The results indicate that machine learning with Raman hyperspectral imaging was able to spatially resolve HPV VLP antigens within SHP vaccines for the first time, providing crucial information necessary for vaccine development.}, } @article {pmid39414899, year = {2024}, author = {Kawata, S and Seki, S and Nishiura, A and Kitaoka, Y and Iwamori, K and Fukada, SI and Kogo, M and Tanaka, S}, title = {Preservation of masseter muscle until the end stage in the SOD1G93A mouse model for ALS.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {24279}, pmid = {39414899}, issn = {2045-2322}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics ; *Masseter Muscle/pathology ; *Disease Models, Animal ; Mice ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Satellite Cells, Skeletal Muscle/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) progressively impairs motor neurons, leading to muscle weakness and loss of voluntary muscle control. This study compared the effects of SOD1 mutation on masticatory and limb muscles from disease onset to death in ALS model mice. Notably, limb muscles begin to atrophy soon after ALS-like phenotype appear, whereas masticatory muscles maintain their volume and function in later stages. Our analysis showed that, unlike limb muscles, masticatory muscles retain their normal structure and cell makeup throughout most of the disease course. We found an increase in the number of muscle satellite cells (SCs), which are essential for muscle repair, in masticatory muscles. In addition, we observed no reduction in the number of muscle nuclei and no muscle fibre-type switching in masticatory muscles. This indicates that masticatory muscles have a higher resistance to ALS-related damage than limb muscles, likely because of differences in cell composition and repair mechanisms. Understanding why masticatory muscles are less affected by ALS could lead to the development of new treatments. This study highlights the importance of studying different muscle groups in ALS to clarify disease aetiology and mechanisms.}, } @article {pmid39415277, year = {2024}, author = {Abdelnaby, R and Shabib, AS and El Din Moawad, MH and Salem, T and Wagih Youssef Awad, M and Awad, PD and Maallem, I and Atwan, H and Rabie, SA and Mohamed, KA and Abdelmageed, H and Karkour, AM and Elsayed, M and Cartwright, MS}, title = {Nerve ultrasound in amyotrophic lateral sclerosis: systematic review and meta-analysis.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {47}, pmid = {39415277}, issn = {2524-3489}, abstract = {BACKGROUND/ AIM: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, causing progressive atrophy of muscles, hypertonia, and paralysis. This study aimed to evaluate the current evidence and effectiveness of ultrasound in investigating nerve cross-sectional area (CSA) of peripheral nerves, vagus and cervical roots in those with ALS compared with healthy controls and to pool the CSA measurements.

METHODS: A systematic search was conducted on Cochrane, Clarivate Web of Science, PubMed, Scopus, and Embase for the mesh terms nerve, ultrasonography, and amyotrophic lateral sclerosis. A quality assessment was performed using the New-Ottawa scale. In addition, a double-arm meta-analysis using Review Manager 5 software version 5.4 was performed.

RESULTS: From the seventeen studies included in this review, the overall mean difference showed that individuals with ALS had a significantly smaller CSA in comparison to healthy controls for median, ulnar, C6 root, and phrenic nerves. However, no significant difference in the CSA was found in radial, vagal, sural, and tibial nerves.

DISCUSSION: This study confirmed results of some of the included studies regards the anatomic sites, where nerve atrophy in ALS could be detected to potentially support the diagnosis of ALS. However, we recommend further large, prospective studies to assess the diagnostic value of these anatomical sites for the diagnosis of ALS.

CONCLUSIONS: Our findings confirmed specific anatomic sites to differentiate ALS patients from healthy controls through ultrasound. However, these findings cannot be used to confirm the ALS diagnosis, but rather assist in differentiating it from other diagnoses.

TRIAL REGISTRATION: Retrospectively registered on July 30th 2024 in PROSPERO (PROSPERO (york.ac.uk)) with ID574702.}, } @article {pmid39415649, year = {2024}, author = {Kim, Y and O, JH and Cho, H and Ye, S}, title = {Recognized cases of amyotrophic lateral sclerosis in automobile workers by the Korean Epidemiologic Investigation Evaluation Committee.}, journal = {Annals of occupational and environmental medicine}, volume = {36}, number = {}, pages = {e28}, pmid = {39415649}, issn = {2052-4374}, abstract = {BACKGROUND: Three automobile company workers (one from Factory D and two from Factory E) were diagnosed with amyotrophic lateral sclerosis. The Korean Epidemiologic Investigation and Evaluation Committee determined that there is considerable scientific evidence supporting the association between amyotrophic lateral sclerosis and combined exposure to heavy metals, organic solvents, and diesel exhaust at the manufacturing plant.

CASE PRESENTATION: Patient A, who primarily engaged in engine processing and completed vehicle inspection at Factory D, was exposed to considerable amounts of heavy metals and organic solvents during medium- and large-engine processing, welding, and painting for over 23 years. Additionally, the patient was likely exposed to diesel exhaust for 33 years from forklifts delivering engines in the workshop. Patients B and C, who were responsible for engine assembly, ignition testing, and engine shipment at Factory E since around 1990, were exposed to lead and benzene from gasoline during engine ignition tests in the engine department for 15 and 16 years, respectively. They also encountered welding fumes, heavy metals, and organic solvents during welding and painting tasks. In addition, Patients B and C were continuously exposed to diesel exhaust from logistics vehicles on standby during work hours for 25 and 30 years, respectively.

CONCLUSIONS: Although the specific level of lead exposure causing amyotrophic lateral sclerosis remains undetermined, numerous studies have consistently reported a relationship between lead exposure and disease development. Limited evidence suggests that exposure to organic solvents and diesel exhaust may increase the risk of amyotrophic lateral sclerosis. Therefore, the Epidemiological Investigation and Evaluation Committee concluded that the three patients' work-related exposure to heavy metals, organic solvents, and diesel exhaust is significantly supported by scientific evidence as a cause of their amyotrophic lateral sclerosis.}, } @article {pmid39416104, year = {2024}, author = {Gunner, G and Basu, H and Lu, Y and Bergstresser, M and Neel, D and Choi, SY and Chiu, IM}, title = {Gasdermin D is activated but does not drive neurodegeneration in SOD1 [G93A] model of ALS: Implications for targeting pyroptosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.10.10.617609}, pmid = {39416104}, issn = {2692-8205}, support = {T32 AG000222/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, microgliosis, and neuroinflammation. While pyroptosis, an inflammatory form of programmed cell death, has been implicated in ALS, the specific role of Gasdermin D (GSDMD) - the primary executioner of pyroptosis - remains unexplored. In this study, we examined the function of GSDMD in the well-established SOD1 [G93A] mouse model of ALS. Our results showed robust GSDMD activation in the spinal cords of SOD1 [G93A] animals across two strain backgrounds, with elevated expression in Iba1+ microglia. To explore its role in disease progression, we bred B6.SOD1 [G93A] mice onto a GSDMD - deficient background. In comparing SOD1 [G93A] ; Gsdmd +/+ and SOD1 [G93A] ; Gsdmd -/- mice, we found that Gsdmd loss did not affect disease onset, weight loss, or grip strength decline in either male or female animals. Notably, GSDMD deficiency resulted in a modest but statistically significant increase in mortality in SOD1 [G93A] mice. Moreover, GSDMD absence had minimal impact on astrogliosis, microgliosis and motor neuron loss. These findings show that while GSDMD is activated in the ALS mouse model, its loss does not mitigate key ALS behavioral phenotypes, gliosis or motor neuron loss. This study provides insights into the potential therapeutic relevance of targeting pyroptosis and inflammatory pathways in ALS.}, } @article {pmid39416141, year = {2024}, author = {Winkelsas, A and Apfel, A and Johnson, B and Harmison, G and Li, D and Cheung, V and Grunseich, C}, title = {Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39416141}, issn = {2692-8205}, support = {R21 ES034919/ES/NIEHS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels without affecting the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele, while sparing the wild-type allele, and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference, highlighting the potential of allele-specific siRNA as a therapeutic approach for ALS4.}, } @article {pmid39418491, year = {2025}, author = {Kumar, R and Ghai, S and Finelli, A and Klotz, L and Kinnaird, A and Mannas, M and Bhindi, B and Sanchez-Salas, R and Anidjar, M and Ahmad, A and Chin, J and Inman, B and Perlis, N}, title = {The use of focal therapy for the treatment of prostate cancer in Canada Where are we, how did we get here, and where are we going?.}, journal = {Canadian Urological Association journal = Journal de l'Association des urologues du Canada}, volume = {19}, number = {2}, pages = {63-72}, pmid = {39418491}, issn = {1911-6470}, abstract = {INTRODUCTION: Focal therapy is an emerging treatment for localized prostate cancer (PCa). The objectives of this review were to: 1) review how focal therapies are regulated and approved; 2) summarize the scope and quality of the literature regarding safety, efficacy, and side-effects; and 3) outline ongoing clinical trials of focal therapy in Canada.

METHODS: Using the PRISMA framework for scoping reviews, we searched PubMed, Embase, and Cochrane from 2021-2024, complementing Hopstaken et al's search up to 2020. We focused on studies reporting functional and oncologic outcomes. Additionally, we examined the FDA database for regulatory details and ongoing trials in Canada via ClinicalTrials.gov.

RESULTS: FDA approval for prostate tissue ablation was granted to high-intensity focused ultrasound (HIFU) in 2015 via the de novo pathway; other therapies followed the 510(k) route, citing equivalence to predicate devices. Most studies are in early stages, primarily single-arm, prospective cohort designs. Oncologic outcomes like cancer detection and survival rates, alongside functional data, such as adverse events and erectile function, were assessed. Recurrence-free survival at 48 months ranged from 58-92%, pad-free rates were greater than 95%, and rates of new-onset erectile dysfunction were variable, ranging from no change to 50%. Rates of serious adverse events were low, ranging from 0-14%. Three Canadian clinical trials are actively enrolling participants, and five private clinics were found offering private HIFU, irreversible electroporation, or transurethral ultrasound ablation.

CONCLUSIONS: Focal therapy technologies have gained regulatory approval for prostate tissue ablation, and aside from provincial support for cryoablation in Alberta, are available to Canadians through private payment or clinical trials. Many studies demonstrate promising cancer control and impressive functional outcomes but are limited by their short followup and lack of comparator group. Clinical trial or registry participation should be prioritized to ensure an evidence-based integration into current prostate cancer treatment approaches.}, } @article {pmid39419034, year = {2025}, author = {Wijegunawardana, D and Nayak, A and Vishal, SS and Venkatesh, N and Gopal, PP}, title = {Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43 ribonucleoprotein condensates disrupting mRNA transport and local translation in neurons.}, journal = {Developmental cell}, volume = {60}, number = {2}, pages = {253-269.e5}, pmid = {39419034}, issn = {1878-1551}, support = {R01 NS122907/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Peptides/metabolism/genetics ; *RNA, Messenger/metabolism/genetics ; *Ataxin-2/metabolism/genetics ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; Rats ; *Motor Neurons/metabolism ; *Ribonucleoproteins/metabolism ; *Protein Biosynthesis ; *RNA Transport ; *Neurons/metabolism ; Axons/metabolism ; Humans ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Nerve Tissue Proteins/metabolism/genetics ; }, abstract = {Altered RNA metabolism and misregulation of transactive response DNA-binding protein of 43 kDa (TDP-43), an essential RNA-binding protein (RBP), define amyotrophic lateral sclerosis (ALS). Intermediate-length polyglutamine (polyQ) expansions of Ataxin-2, a like-Sm (LSm) RBP, are associated with increased risk for ALS, but the underlying biological mechanisms remain unknown. Here, we studied the spatiotemporal dynamics and mRNA regulatory functions of TDP-43 and Ataxin-2 ribonucleoprotein (RNP) condensates in rodent (rat) primary cortical neurons and mouse motor neuron axons in vivo. We report that Ataxin-2 polyQ expansions aberrantly sequester TDP-43 within RNP condensates and disrupt both its motility along the axon and liquid-like properties. We provide evidence that Ataxin-2 governs motility and translation of neuronal RNP condensates and that Ataxin-2 polyQ expansions fundamentally perturb spatial localization of mRNA and suppress local translation. Overall, our results support a model in which Ataxin-2 polyQ expansions disrupt stability, localization, and/or translation of critical axonal and cytoskeletal mRNAs, particularly important for motor neuron integrity.}, } @article {pmid39419433, year = {2025}, author = {Majumder, P and Hsu, TI and Hu, CJ and Huang, JK and Lee, YC and Hsieh, YC and Ahsan, A and Huang, CC}, title = {Potential role of solid lipid curcumin particle (SLCP) as estrogen replacement therapy in mitigating TDP-43-related neuropathy in the mouse model of ALS disease.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {114999}, doi = {10.1016/j.expneurol.2024.114999}, pmid = {39419433}, issn = {1090-2430}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mice ; Female ; *Disease Models, Animal ; Male ; *DNA-Binding Proteins/metabolism/genetics ; *Estrogen Replacement Therapy/methods ; *Curcumin/pharmacology/administration & dosage/therapeutic use ; Mice, Transgenic ; Aromatase/metabolism ; Estradiol/pharmacology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) was first identified in 1869, but it wasn't until the 2014 Ice Bucket Challenge that widespread attention was drawn to the disease. Since then, substantial research has been dedicated to developing treatments for ALS. Despite this, only three drugs - riluzole, edaravone and AMX0035, have been approved for clinical use, and they can only temporarily alleviate mild symptoms without significant disease modification or cure. Therefore, there remains a critical unmet need to identify disease modifying or curative therapies for ALS. The higher incidence and more severe progression of ALS and FTLD (frontotemporal lobar degeneration) observed in men and postmenopausal woman compared to young women suggests that sex hormones may significantly influence disease onset and progression. In both animal models and human clinical studies, 17β estradiol (E2) has been shown to delay and improve the outcomes of many neurodegenerative diseases. Here, we examined the role of TDP-43 in the regulation of estrogen-related enzymes, CYP19A1 and CYP3A4. In addition, we examined the impact of curcumin on the regulation of estrogen E2 levels and TDP-43-associated neuropathy as a potential therapeutic strategy for the treatment of FTLD and ALS.

METHODS: Prp-TDP-43[A315T] mice was used as a model of ALS/FTLD to examine the expression patterns of E2 and its biosynthesis and degradation enzymes, CYP19A1 and CYP3A4. Moreover, the molecular mechanisms and the potency of solid lipid curcumin particles (SLCP) as an E2 replacement therapy for TDP-43 associated neuropathy was analyzed. We further examined the survival rates and the pathological TDP43 patterns in female and male Prp-TDP-43[A315T] mice administrated with or without SLCP. In addition, the changed expression levels of enzymes corresponding to E2 biosynthesis and degradation in the spinal cord of female and male Prp-TDP-43[A315T] mice with or without SLCP were determined.

RESULTS: We found that in addition to E2, the expression patterns of CYP19A1 and CYP3A4 proteins differed between Prp-TDP-43[A315T] mice compared to wild-type control, suggesting that toxic phosphorylated TDP43 oligomers may disrupt the balance between CYP19A1 and CYP3A4 expression, leading to reduced estrogen biosynthesis and accelerated degradation. In addition, we found that oral administration of SLCP prolonged the survival rates in female Prp-TDP-43[A315T] mice and significantly reduced the pathological insoluble phosphorylated TDP-43 species. Furthermore, SLCP attenuated disease progression associated with TDP-43-related neuropathies through modulating estrogen biosynthesis and the activity of CYP450 enzymes.

CONCLUSIONS: Our results showed that Prp-TDP-43[A315T] mice exhibit altered estradiol levels. Moreover, we demonstrated the efficacy of SLCP as an estrogen replacement therapy in mitigating TDP-43-associated disease progression and pathogenesis. These findings suggest that SLCP could be a promising strategy to induce E2 expression for the treatment of ALS and FTLD.}, } @article {pmid39419765, year = {2024}, author = {Johns, AE and Taga, A and Charalampopoulou, A and Gross, SK and Rust, K and McCray, BA and Sullivan, JM and Maragakis, NJ}, title = {Exploring P2X7 receptor antagonism as a therapeutic target for neuroprotection in an hiPSC motor neuron model.}, journal = {Stem cells translational medicine}, volume = {13}, number = {12}, pages = {1198-1212}, pmid = {39419765}, issn = {2157-6580}, support = {R01 NS117604/NS/NINDS NIH HHS/United States ; R25 NS065729/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Motor Neurons/metabolism/drug effects ; *Receptors, Purinergic P2X7/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Purinergic P2X Receptor Antagonists/pharmacology ; Animals ; Adenosine Triphosphate/metabolism ; Neuroprotection/drug effects ; Mice ; Rats ; }, abstract = {ATP is present in negligible concentrations in the interstitium of healthy tissues but accumulates to significantly higher concentrations in an inflammatory microenvironment. ATP binds to 2 categories of purine receptors on the surface of cells, the ionotropic P2X receptors and metabotropic P2Y receptors. Included in the family of ionotropic purine receptors is P2X7 (P2X7R), a non-specific cation channel with unique functional and structural properties that suggest it has distinct roles in pathological conditions marked by increased extracellular ATP. The role of P2X7R has previously been explored in microglia and astrocytes within the context of neuroinflammation, however the presence of P2X7R on human motor neurons and its potential role in neurodegenerative diseases has not been the focus of the current literature. We leveraged the use of human iPSC-derived spinal motor neurons (hiPSC-MN) as well as human and rodent tissue to demonstrate the expression of P2X7R on motor neurons. We extend this observation to demonstrate that these receptors are functionally active on hiPSC-MN and that ATP can directly induce death via P2X7R activation in a dose dependent manner. Finally, using a highly specific P2X7R blocker, we demonstrate how modulation of P2X7R activation on motor neurons is neuroprotective and could provide a unique pharmacologic target for ATP-induced MN death that is distinct from the role of ATP as a modulator of neuroinflammation.}, } @article {pmid39420987, year = {2024}, author = {Sun, H and Tang, Q and Yan, X and Xie, W and Xu, Y and Zhang, W}, title = {Cathepsins and neurological diseases: a Mendelian randomization study.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1454369}, pmid = {39420987}, issn = {1662-4548}, abstract = {BACKGROUND: The causal relationship between cathepsins and neurological diseases remains uncertain. To address this, we utilized a two-sample Mendelian randomization (MR) approach to assess the potential causal effect of cathepsins on the development of neurological diseases.

METHODS: This study conducted a two-sample two-way MR study using pooled data from published genome-wide association studies to evaluate the relationship between 10 cathepsins (B, D, E, F, G, H, L2, O, S, and Z) and 7 neurological diseases, which included ischemic stroke, cerebral hemorrhage, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and epilepsy. The analysis employed various methods such as inverse variance weighting (IVW), weighted median, MR Egger regression, MR pleiotropy residual sum and outlier, Cochran Q statistic, and leave-one-out analysis.

RESULTS: We found a causal relationship between cathepsins and neurological diseases, including Cathepsin B and Parkinson's disease (IVW odds ratio (OR): 0.89, 95% confidence interval (CI): 0.83, 0.95, p = 0.001); Cathepsin D and Parkinson's disease (OR: 0.80, 95%CI: 0.68, 0.95, p = 0.012); Cathepsin E and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.09, p = 0.015); Cathepsin O and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.021). Reverse MR analyses revealed that multiple sclerosis and Cathepsin E (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.030). There is currently no significant relationship has been found between other cathepsins and neurological diseases.

CONCLUSION: Our study reveals a causal relationship between Cathepsins B, D, E, and O and neurological diseases, offering valuable insights for research aimed at improving the diagnosis and treatment of such conditions.}, } @article {pmid39422938, year = {2024}, author = {Pappolla, MA and Wu, P and Fang, X and Poeggeler, B and Sambamurti, K and Wisniewski, T and Perry, G}, title = {Stem Cell Interventions in Neurology: From Bench to Bedside.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {101}, number = {s1}, pages = {S395-S416}, doi = {10.3233/JAD-230897}, pmid = {39422938}, issn = {1875-8908}, mesh = {Humans ; Animals ; *Stem Cell Transplantation/methods/trends ; Nervous System Diseases/therapy ; Neurology/trends/methods ; Translational Research, Biomedical/trends ; Neural Stem Cells/transplantation ; }, abstract = {Stem cell therapies are progressively redefining the treatment landscape for a spectrum of neurological and age-related disorders. This review discusses the molecular and functional attributes of stem cells, emphasizing the roles of neural stem cells and mesenchymal stem cells in the context of neurological diseases such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, Parkinson's disease, and Alzheimer's disease. The review also explores the potential of stem cells in addressing the aging process. The paper analyzes stem cells' intrinsic properties of self-renewal, differentiation, and paracrine effects, alongside the importance of laboratory-modified stem cells like induced pluripotent stem cells and transgenic stem cells. Insights into disease-specific stem cell treatments are offered, reviewing both successes and challenges in the field. This includes the translational difficulties from rodent studies to human trials. The review concludes by acknowledging the uncharted territories that warrant further investigation, emphasizing the potential roles of stem cell-derived exosomes and indole-related molecules, and aiming at providing a basic understanding of stem cell therapies.}, } @article {pmid39423873, year = {2024}, author = {Thapa, R and Moglad, E and Afzal, M and Gupta, G and Bhat, AA and Hassan Almalki, W and Kazmi, I and Alzarea, SI and Pant, K and Singh, TG and Singh, SK and Ali, H}, title = {The role of sirtuin 1 in ageing and neurodegenerative disease: A molecular perspective.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102545}, doi = {10.1016/j.arr.2024.102545}, pmid = {39423873}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Sirtuin 1/metabolism ; *Aging/metabolism/genetics ; Animals ; Oxidative Stress/physiology ; }, abstract = {Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, has emerged as a key regulator of cellular processes linked to ageing and neurodegeneration. SIRT1 modulates various signalling pathways, including those involved in autophagy, oxidative stress, and mitochondrial function, which are critical in the pathogenesis of neurodegenerative diseases. This review explores the therapeutic potential of SIRT1 in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Preclinical studies have demonstrated that SIRT1 activators, such as resveratrol, SRT1720, and SRT2104, can alleviate disease symptoms by reducing oxidative stress, enhancing autophagic flux, and promoting neuronal survival. Ongoing clinical trials are evaluating the efficacy of these SIRT1 activators, providing hope for future therapeutic strategies targeting SIRT1 in neurodegenerative diseases. This review explores the role of SIRT1 in ageing and neurodegenerative diseases, with a particular focus on its molecular mechanisms, therapeutic potential, and clinical applications.}, } @article {pmid39424348, year = {2025}, author = {Yoganathan, S and Kumar, M and Aaron, R and Rangan, SR and Umakant, BS and Thomas, M and Oommen, SP and Danda, S}, title = {Phenotype and Genotype of Children with ALS2 gene-Related Disorder.}, journal = {Neuropediatrics}, volume = {56}, number = {1}, pages = {20-28}, doi = {10.1055/s-0044-1791256}, pmid = {39424348}, issn = {1439-1899}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Phenotype ; Child ; *Guanine Nucleotide Exchange Factors/genetics ; Genotype ; Child, Preschool ; *Spastic Paraplegia, Hereditary/genetics/physiopathology ; Adolescent ; Pedigree ; Infant ; }, abstract = {INTRODUCTION: The Alsin Rho Guanine Nucleotide Exchange Factor (ALS2) gene encodes a protein alsin that functions as a guanine nucleotide exchange factor. The variations in ALS2 gene leads to degeneration of upper motor neurons of the corticospinal tract. The phenotypes resulting from variants in ALS2 gene are infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM # 607225), juvenile primary lateral sclerosis (JPLS, OMIM # 606353), and juvenile amyotrophic lateral sclerosis (JALS, OMIM # 205100). Our study objectives were to describe the clinical phenotype and genotype of children with an established diagnosis of ALS2 gene-related disorder.

METHODS: The clinical details, laboratory data, and genotype findings of children with an established diagnosis of ALS2 gene-related disorder were collected from the hospital electronic database after obtaining institutional review board approval.

RESULTS: One family with three affected siblings, a second family with a proband and an affected fetus, and a third family with two affected siblings with ALS2 gene variants were identified. IAHSP was diagnosed in all of our patients with variants in ALS2 gene. The clinical findings observed in our patients were insidious onset progressive spastic paraparesis, contractures, and dysarthria. Nonsense variants were observed in four patients while frameshift variant was observed in one family. Novel variants in ALS2 gene were identified in two unrelated families.

CONCLUSION: ALS2 mutation results in rare neurodegenerative disorders with the clinical spectrum encompassing IAHSP, JPLS, and JALS disorders. In view of allelic heterogeneity described in the literature, more research studies are needed for establishing genotype-phenotype correlation in patients with ALS2 gene-related disorder.}, } @article {pmid39424548, year = {2024}, author = {Andrews, JA}, title = {A new era of drug discovery for amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1070-1072}, doi = {10.1016/S1474-4422(24)00407-1}, pmid = {39424548}, issn = {1474-4465}, } @article {pmid39424560, year = {2024}, author = {Koch, JC and Leha, A and Bidner, H and Cordts, I and Dorst, J and Günther, R and Zeller, D and Braun, N and Metelmann, M and Corcia, P and De La Cruz, E and Weydt, P and Meyer, T and Großkreutz, J and Soriani, MH and Attarian, S and Weishaupt, JH and Weyen, U and Kuttler, J and Zurek, G and Rogers, ML and Feneberg, E and Deschauer, M and Neuwirth, C and Wuu, J and Ludolph, AC and Schmidt, J and Remane, Y and Camu, W and Friede, T and Benatar, M and Weber, M and Lingor, P and , }, title = {Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1133-1146}, pmid = {39424560}, issn = {1474-4465}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/therapeutic use/pharmacology/adverse effects ; Middle Aged ; Male ; Double-Blind Method ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; Aged ; Adult ; *rho-Associated Kinases/antagonists & inhibitors ; *Protein Kinase Inhibitors/adverse effects/therapeutic use/administration & dosage ; Treatment Outcome ; Aged, 80 and over ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis.

METHODS: ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed.

FINDINGS: Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI -0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (-0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI -0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and -0·03 (-0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group.

INTERPRETATION: Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug.

FUNDING: Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases".}, } @article {pmid39424561, year = {2024}, author = {Crow, YJ}, title = {CNS disease associated with enhanced type I interferon signalling.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1158-1168}, pmid = {39424561}, issn = {1474-4465}, support = {786142/ERC_/European Research Council/International ; MC_UU_00035/11/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Interferon Type I/metabolism/immunology ; *Signal Transduction ; Animals ; Central Nervous System Diseases/immunology/metabolism ; }, abstract = {The ability to mount an interferon-mediated innate immune response is essential in protection against neurotropic viruses, but antiviral type I interferons also have neurotoxic potential. The production of type I interferons can be triggered by self-derived nucleic acids, and the brain can be susceptible to inappropriate upregulation of type I interferon signalling. Homoeostatic dysregulation of type I interferons has been implicated in rare inborn errors of immunity (referred to as type I interferonopathies) and more common neurodegenerative disorders (eg, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis). Recent developments include new insights into the pathogenesis of these disorders that involve dysregulated type I interferon signalling, as well as advances in their diagnosis and management. The role of type I interferons in brain cellular health suggests the future therapeutic potential of approaches that target these interferons and their signalling.}, } @article {pmid39424648, year = {2024}, author = {Chartier, C and Godard, J and Durand, S and Humeau-Heurtier, A and Menetrier, E and Allain, P and Besnard, J}, title = {Combinations of physical and cognitive training for subcortical neurodegenerative diseases with physical, cognitive and behavioral symptoms: a systematic review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {12}, pages = {5571-5589}, pmid = {39424648}, issn = {1590-3478}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Behavioral Symptoms/therapy/etiology ; Cognitive Behavioral Therapy/methods ; Exercise Therapy/methods ; Cognitive Dysfunction/therapy/rehabilitation/etiology ; Cognitive Training ; }, abstract = {BACKGROUND: The onset of the symptoms of subcortical NDs is due to a unique part of the brain which strengthens the idea of reciprocal influence of physical activity and cognitive training in improving clinical symptoms. Consequently, protocols combining the two stimulations are becoming increasingly popular in NDs. Our threefold aim was to (A) describe the different combinations of physical and cognitive training used to alleviate the motor and cognitive symptoms of patients with subcortical neurodegenerative disorders, (B) compare the effects of these different combinations (sequential, dual tasking, synergical) on symptoms, and (C) recommend approaches for further studies.

METHODS: We conducted literature searches of PubMed, BASE and ACM, to carry out a systematic review of randomized controlled trials and controlled trials of combined physical and cognitive training among patients with Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Lewy body dementia, spinocerebellar ataxia, Friedreich's ataxia, and progressive supranuclear palsy. Physical, neuropsychological, behavioral outcomes were considered. The Cochrane risk-of-bias tool was used to verify the critical appraisal.

RESULTS: Twenty-one studies focused on Parkinson's disease with 940 participants were included. Despites promising benefits on cognitive and physical function, our results revealed discrepant findings for research on combined training.

DISCUSSION: Inconsistencies were linked to the choice of tests, the functions that were targeted, disease progression, and trainings. There was a dearth of follow-up data.

CONCLUSIONS: Differences between combined training are unclear, particularly regarding the role of cognitive load. Future studies should focus on comparing the feasibility, tolerability, and effectiveness of different combinations of motor-cognitive training.}, } @article {pmid39424779, year = {2024}, author = {Wu, H and Wang, LC and Sow, BM and Leow, D and Zhu, J and Gallo, KM and Wilsbach, K and Gupta, R and Ostrow, LW and Yeo, CJJ and Sobota, RM and Li, R}, title = {TDP43 aggregation at ER-exit sites impairs ER-to-Golgi transport.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9026}, pmid = {39424779}, issn = {2041-1723}, support = {A-0007081-00-00//Ministry of Education - Singapore (MOE)/ ; NRF-MSG-2023-0001//National Research Foundation Singapore (National Research Foundation-Prime Minister's office, Republic of Singapore)/ ; NRF-SIS "SingMass"//A*STAR | Singapore Institute of Manufacturing Technology (Singapore Institute of Manufacturing Technology - A STAR)/ ; }, mesh = {Humans ; *Golgi Apparatus/metabolism ; *Endoplasmic Reticulum/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Protein Transport ; Protein Aggregates ; Motor Neurons/metabolism ; HeLa Cells ; HEK293 Cells ; }, abstract = {Protein aggregation plays key roles in age-related degenerative diseases, but how different proteins coalesce to form inclusions that vary in composition, morphology, molecular dynamics and confer physiological consequences is poorly understood. Here we employ a general reporter based on mutant Hsp104 to identify proteins forming aggregates in human cells under common proteotoxic stress. We identify over 300 proteins that form different inclusions containing subsets of aggregating proteins. In particular, TDP43, implicated in Amyotrophic Lateral Sclerosis (ALS), partitions dynamically between two distinct types of aggregates: stress granule and a previously unknown non-dynamic (solid-like) inclusion at the ER exit sites (ERES). TDP43-ERES co-aggregation is induced by diverse proteotoxic stresses and observed in the motor neurons of ALS patients. Such aggregation causes retention of secretory cargos at ERES and therefore delays ER-to-Golgi transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patients.}, } @article {pmid39425590, year = {2025}, author = {Zhu, L and Li, Y and Yu, X and Chen, Y and Zhang, J and Pang, C and Xie, J and Gao, L and Du, L and Cao, W and Fan, D and Cui, C and Yu, H and Deng, B}, title = {Fighting Amyotrophic Lateral Sclerosis by Protecting the Liver? A Prospective Cohort Study.}, journal = {Annals of neurology}, volume = {97}, number = {2}, pages = {270-280}, doi = {10.1002/ana.27115}, pmid = {39425590}, issn = {1531-8249}, support = {12101460//National Natural Science Foundation of China/ ; 81901273//National Natural Science Foundation of China/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnostic imaging/complications ; Male ; Female ; Middle Aged ; Prospective Studies ; Aged ; Magnetic Resonance Imaging ; Risk Factors ; *Liver Diseases/diagnostic imaging/epidemiology/complications ; Cohort Studies ; *Liver/diagnostic imaging ; Adult ; }, abstract = {BACKGROUND: Previous studies have observed liver abnormalities in amyotrophic lateral sclerosis (ALS) patients. This study aimed to investigate whether early signs of liver disease, measured by magnetic resonance imaging-derived iron-corrected T1-mapping (cT1), are risk factors for developing ALS.

METHODS: cT1 and proton density fat fraction were measured and automatically analyzed using LiverMultiScan® software. The Fibrosis-4 index was calculated using an established formula based on age and blood markers. Cox proportional hazard models were used to examine the relationship between liver disease, liver biomarkers, and incident ALS.

RESULTS: In a cohort of 533,707 individuals from UK Biobank, 24 ALS cases were identified among 28,328 participants with liver disease during the follow-up period. Among a total of 33,959 individuals with complete liver imaging data, 15 incident ALS cases were observed during a median follow-up period of 5.6 years. Individuals with liver disease had a higher risk of developing ALS, with an adjusted hazard ratio of 7.35 (95% CI 4.47-12.09; p < 0.001). An increase in cT1 was also associated with a higher risk of ALS. After adjusting for age, sex, Townsend deprivation index, smoking status, alcohol intake frequency, body mass index, proton density fat fraction, Fibrosis-4, and metabolic syndrome, an increase in cT1 remained significantly associated with a higher risk of ALS, with an adjusted hazard ratio of 3.15 (95% CI 1.79-5.55) per 1-SD increase. Sensitivity analyses confirmed these robust results.

INTERPRETATION: Liver disease activity, indicated by cT1, increases the risk of developing ALS, independent of metabolic syndrome, liver fat, or fibrosis. ANN NEUROL 2025;97:270-280.}, } @article {pmid39425598, year = {2024}, author = {Zhang, L and Zhou, X and Cha, S}, title = {Comprehensive Analysis of Sex Differences in Amyotrophic Lateral Sclerosis Prognosis and Disease Progression.}, journal = {Annals of neurology}, volume = {96}, number = {5}, pages = {1028}, doi = {10.1002/ana.27092}, pmid = {39425598}, issn = {1531-8249}, } @article {pmid39426615, year = {2024}, author = {Mackness, BC and Morgan, BR and Deveau, LM and Kathuria, SV and Zitzewitz, JA and Massi, F}, title = {A Hydrophobic Core Stabilizes the Residual Structure in the RRM2 Intermediate State of the ALS-linked Protein TDP-43.}, journal = {Journal of molecular biology}, volume = {436}, number = {22}, pages = {168823}, pmid = {39426615}, issn = {1089-8638}, support = {P41 GM103622/GM/NIGMS NIH HHS/United States ; R01 GM054836/GM/NIGMS NIH HHS/United States ; R01 GM137529/GM/NIGMS NIH HHS/United States ; //DOE/ ; }, mesh = {*Protein Folding ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Hydrophobic and Hydrophilic Interactions ; *Molecular Dynamics Simulation ; Protein Structure, Secondary ; Protein Stability ; RNA Recognition Motif/genetics ; Protein Conformation ; Models, Molecular ; }, abstract = {Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43 (TAR DNA-binding protein-43), using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.}, } @article {pmid39427550, year = {2024}, author = {Pan, Y and Sun, X and Tian, Y and Yu, M and Luo, Y and Sun, X}, title = {L-NRB alleviates amyotrophic lateral sclerosis by regulating P11-Htr4 signaling pathway.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {180}, number = {}, pages = {117588}, doi = {10.1016/j.biopha.2024.117588}, pmid = {39427550}, issn = {1950-6007}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; *Signal Transduction/drug effects ; Mice ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Transgenic ; Male ; Benzofurans/pharmacology/therapeutic use ; Disease Models, Animal ; Motor Neurons/drug effects/pathology/metabolism ; Apoptosis/drug effects ; Mice, Inbred C57BL ; }, abstract = {INTRODUCTION: L-NRB is a compound formed as a ring cleavage product of butylphthalide and borneol in a molar ratio 1:2. This study aimed to explore the therapeutic effect of L-NRB on amyotrophic lateral sclerosis (ALS) and its possible mechanism.

METHODS: SOD1-G93A mice were used as an ALS model. Behavioral tests, histopathological staining, Nissl staining, immunohistochemistry, enzyme-linked immunosorbent assays, and Western blotting were used to analyze the therapeutic effect. The underlying mechanism of L-NRB in treating ALS was investigated using transcriptomic analyses.

RESULTS: It was found that L-NRB alleviated motor dysfunction, pathological changes in the gastrocnemius muscle, and motor neuron injuries. The results indicated that L-NRB had a neuroprotective function associated with the inhibition of neuroinflammation. The anti-apoptotic effect of L-NRB was found to be related to the regulation of the P11-Htr4 signaling pathway.

CONCLUSION: In summary, the results demonstrated the therapeutic effect of L-NRB on ALS and suggest a promising new therapeutic candidate for ALS.}, } @article {pmid39428001, year = {2025}, author = {Simoes, FA and Christoforidou, E and Cassel, R and Dupuis, L and Hafezparast, M}, title = {Severe dynein dysfunction in cholinergic neurons exacerbates ALS-like phenotypes in a new mouse model.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1871}, number = {1}, pages = {167540}, doi = {10.1016/j.bbadis.2024.167540}, pmid = {39428001}, issn = {1879-260X}, mesh = {Animals ; *Disease Models, Animal ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Phenotype ; *Cholinergic Neurons/metabolism/pathology ; Cytoplasmic Dyneins/metabolism/genetics ; Neuromuscular Junction/metabolism/pathology ; DNA-Binding Proteins/genetics/metabolism ; Mice, Knockout ; Male ; Dyneins/metabolism/genetics ; Point Mutation ; }, abstract = {Cytoplasmic dynein 1, a motor protein essential for retrograde axonal transport, is increasingly implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). In this study, we developed a novel mouse model that combines the Legs at odd angles (Loa, F580Y) point mutation in the dynein heavy chain with a cholinergic neuron-specific knockout of the dynein heavy chain. This model, for the first time, allows us to investigate the impact of Loa allele exclusivity in these neurons into adulthood. Our findings reveal that this selective increase in dynein dysfunction exacerbated the phenotypes observed in heterozygous Loa mice including pre-wean survival, reduced body weight and grip strength. Additionally, it induced ALS-like pathology in neuromuscular junctions (NMJs) not seen in heterozygous Loa mice. Notably, we also found a previously unobserved significant increase in neurons displaying TDP-43 puncta in both Loa mutants, suggesting early TDP-43 mislocalisation - a hallmark of ALS. The novel model also exhibited a concurrent rise in p62 puncta that did not co-localise with TDP-43, indicating broader impairments in autophagic clearance mechanisms. Overall, this new model underscores the fact that dynein impairment alone can induce ALS-like pathology and provides a valuable platform to further explore the role of dynein in ALS.}, } @article {pmid39428248, year = {2024}, author = {Luo, N and Wang, J and Zhang, ZY and Zhao, XY and Huang, RR and Wu, QY}, title = {[Research progress on Pb-induced neurotoxicity through glial cells].}, journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]}, volume = {58}, number = {10}, pages = {1610-1615}, doi = {10.3760/cma.j.cn112150-20240513-00382}, pmid = {39428248}, issn = {0253-9624}, support = {8217348282, 82173554, 82101593//National Natural Science Foundation of China/ ; }, mesh = {*Neuroglia/drug effects ; Humans ; *Lead/toxicity ; }, abstract = {Lead is one of the most important occupational hazards in China, and occupational exposure is the leading cause of lead poisoning. Lead can be absorbed by the body through air, food, drinking water and skin, and accumulate in multiple organs in the body, posing health risks to humans, especially to lead workers. Many previous studies have shown that lead can affect the function of glial cells such as microglia, astrocytes and oligodendrocytes, resulting in irreversible neurological damage. This article provides an overview of the neurotoxic mechanism induced by lead through glial cells, elucidates that lead can induce neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and reviews the relationship between lead and glial cells, in order to provide reference for further research on the neurotoxic mechanism of lead on glial cells.}, } @article {pmid39428436, year = {2024}, author = {Assialioui, A and Marco-Pascual, C and Torrente-Segarra, V and Domínguez, R and Santos, N and Peñafiel, J and Juanola, X and Povedano, M and Ferrer, I}, title = {Microvascular abnormalities in skin capillaries of individuals with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {24648}, pmid = {39428436}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Middle Aged ; Male ; *Capillaries/pathology ; Female ; *Skin/blood supply/pathology ; Aged ; Microscopic Angioscopy ; Case-Control Studies ; Adult ; }, abstract = {This is the first study aimed to detect morphological abnormalities in vivo in the skin capillaries of amyotrophic lateral sclerosis patients (ALS). Videocapillaroscopy assessed subungueal capillaries in 28 ALS patients (cases) and 35 controls (p = 0.42). The mean age was 61.46 and 61.23 years, respectively (p > 0.99). No statistically significant differences were observed between the groups regarding dominant hand, arterial hypertension, dyslipidemia, diabetes mellitus, active smoker, and former smoker variables. 78.57% of cases had spinal onset and 21.43% bulbar. The median disease duration (time between the onset of symptoms and the date of videocapillarscopy) was 29.71 months. Dilated capillaries were detected in 17.8% of cases and 11.43% of controls (p = 0.49). The median of capillary diameter in cases was 10.15 µm and 8.72 µm in controls (p = 0.011). 35.71% of cases and 2.86% of controls had severe capillary tortuosities (p < 0.001). Ramified capillaries were observed in 46.43% of cases and 11.43% of controls (p < 0.002). Micro-hemorrhages were only observed in 10.71% of cases. No significant correlations were observed between disease duration and dilated capillaries, tortuosity, ramified capillaries, and micro-hemorrhages. The present in vivo study shows abnormalities in the skin capillaries of ALS patients that do not depend on disease duration.}, } @article {pmid39428513, year = {2024}, author = {Shibasaki, N and Konishi, K and Nishiyama, Y and Miyagawa, T and Numayama, T}, title = {[A case of amyotrophic lateral sclerosis managed by tracheostomy and invasive ventilation in which air leaks occurred at the cuff].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {64}, number = {11}, pages = {789-793}, doi = {10.5692/clinicalneurol.cn-001990}, pmid = {39428513}, issn = {1882-0654}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/therapy ; Middle Aged ; *Tracheostomy ; *Respiration, Artificial ; Tomography, X-Ray Computed ; Trachea/diagnostic imaging ; Air ; Pressure ; Treatment Outcome ; }, abstract = {The patient was a 64-year-old woman who had been diagnosed with amyotrophic lateral sclerosis 8 years ago, and had been under artificial ventilation with tracheotomy for 6 years. Computed tomography indicated a dilated tracheal diameter of 29.6 ‍mm at the cuff, and a high cuff pressure of 80 ‍cmH2O. An adjustable flange tracheostomy tube with an optional length setting was used to extend the effective length by 28 ‍mm. A previously evident air leak disappeared with the change in cuff level, and cuff pressure decreased to 25 ‍cmH2O. X-ray images indicated a reduction in the size of the previous cuff area. Tracheal dilatation due to improper management of cuff pressure is a contributing factor to air leakage at the cuff area, and using an adjustable flange tracheostomy tube in an effort to resolve such air leaks is a valid option.}, } @article {pmid39431590, year = {2025}, author = {Correa-Arrieta, C and Castellar-Leones, S and Forero Diaz, JJ and Peña-Preciado, M and Ortiz-Corredor, F}, title = {Slowly progressing Amyotrophic lateral sclerosis associated with the F21L variant in the SOD1 gene: Demographic and clinical characteristics.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {354-357}, doi = {10.1080/21678421.2024.2416669}, pmid = {39431590}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/diagnosis ; Female ; Male ; Middle Aged ; Disease Progression ; *Superoxide Dismutase-1/genetics ; Adult ; Aged ; Colombia/epidemiology ; *Mutation/genetics ; Age of Onset ; }, abstract = {INTRODUCTION/OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which genetic variants can significantly influence clinical presentation and prognosis. This study aims to describe the demographic and clinical characteristics of ALS patients carrying the SOD1: c.63C > G (p.Phe21Leu) [NM_000454.4] variant, as treated at a national reference center in Colombia.

METHODS: A descriptive study was conducted on patients identified with the SOD1: c.63C > G (p.Phe21Leu) [NM_000454.4] variant, selected from the database of a neuromuscular disease center in Colombia. Demographic and clinical data were collected through medical records and patient interviews. Molecular analysis was performed using PCR and automated sequencing to confirm the presence of the variant.

RESULTS: Eleven patients with SOD1: c.63C > G (p.Phe21Leu) [NM_000454.4] variant were identified. The mean age at onset was 48.4 years, with a mean disease duration of 76.7 months. The majority (90.9%) exhibited a slowly progressive course, predominantly with spinal onset and no cognitive impairment. Bulbar symptoms developed in 72.2% of the patients, and 81.8% required noninvasive ventilation. A family history of ALS or other neurodegenerative disorders was present in 54.5% of the patients.

CONCLUSIONS: The SOD1: c.63C > G (p.Phe21Leu) [NM_000454.4] variant is associated with a slowly progressive ALS phenotype, characterized by predominant lower motor neuron involvement and delayed onset of bulbar and respiratory symptoms. This variant appears to be predominantly distributed in central Colombia. Early detection of this variant may enable timely interventions and personalized care plans. Further research is required to establish a definitive causal relationship between this variant and the observed clinical course.}, } @article {pmid39431591, year = {2025}, author = {Sheers, NL and Hannan, LM and Rautela, L and Graco, M and Jones, J and Retica, S and Saravanan, K and Burgess, N and McGaw, R and Donovan, A and Clohessy, T and Chao, C and Charles, C and Howard, ME and Berlowitz, DJ}, title = {NIV@Home: a pilot randomized controlled trial of in-home noninvasive ventilation initiation compared to a single-day admission model.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {239-248}, doi = {10.1080/21678421.2024.2416668}, pmid = {39431591}, issn = {2167-9223}, mesh = {Humans ; *Noninvasive Ventilation/methods ; Male ; Pilot Projects ; Female ; Middle Aged ; Aged ; *Home Care Services ; Single-Blind Method ; *Respiratory Insufficiency/therapy/etiology ; *Neuromuscular Diseases/complications/therapy ; Quality of Life ; Adult ; Polysomnography ; }, abstract = {Objective: Noninvasive ventilation (NIV) is the primary treatment for respiratory insufficiency in neuromuscular disease. NIV implementation is usually conducted within hospitals; however, in-home implementation with intensive follow-up is an effective alternative. This pilot study aimed to assess model feasibility, acceptability, and NIV usage at 12-weeks after a single visit in-home implementation of NIV with remote monitoring follow-up (NIV@Home) compared to an in-hospital day admission NIV initiation plus planned polysomnography (Usual care). Methods: A single-blinded randomized controlled trial (www.anzctr.org.au ACTRN12620000682943) of adults with neuromuscular disease referred for NIV implementation. Participants were stratified by disease (MND or Other diagnoses) and bulbar symptoms before randomization to NIV@Home or Usual care, with follow-up at 12-weeks. The primary outcome was NIV usage. Secondary outcomes included feasibility, health-related quality of life, symptoms, carer burden, and NIV experience (semi-structured qualitative interviews). Results: Twenty-three participants (MND bulbar = 9, MND non-bulbar = 11, Other = 3) were randomized (NIV@Home = 9). No statistical differences were observed in the percentage of MND participants using NIV for >4 hours/day (NIV@Home = 33% vs. Usual care = 60%, p = 0.370), average use (NIV@Home = 2.4 [1.5-9.3] vs. 5.3 [1.8-7.0] hours/day, p = 0.568), or secondary outcomes. In-home NIV implementation was feasible and safe but took more therapist time (NIV@Home = 278 [270-305] vs. 172 [130-200] minutes, p < 0.001). Participants in the NIV@Home group reported substantial advantages to receiving care in home. Conclusion: In-home NIV implementation is feasible and acceptable to people with MND but requires more therapist time. Larger studies are required to determine whether there are clinically important differences between this model of NIV initiation and a traditional hospital-based model.}, } @article {pmid39432435, year = {2025}, author = {Anjaneyulu, J and Godbole, A}, title = {Small organism models for mode of action research on anti-ageing and nootropic herbs, foods, and formulations.}, journal = {Nutritional neuroscience}, volume = {28}, number = {6}, pages = {744-762}, doi = {10.1080/1028415X.2024.2409128}, pmid = {39432435}, issn = {1476-8305}, mesh = {Animals ; *Aging/drug effects ; *Neurodegenerative Diseases/prevention & control/drug therapy ; Humans ; *Disease Models, Animal ; Zebrafish ; *Plant Extracts/pharmacology ; }, abstract = {With global increase in ageing population along with increasing age-related neurodegenerative diseases (NDs), development of sustainable, safe and effective solutions for promoting healthy ageing and preventing diseases has become a priority. Traditional healthcare systems/medicines prescribe several herbs, foods and formulations to promote healthy ageing and prevent and/or treat age-related diseases. However, the scientific data elucidating their mechanism of action is very limited and deeper research using different models is warranted for timely and wider use. The clinical studies and research with higher model organisms, although useful, have several practical, technical, and financial limitations. Conversely, small organism models like Yeast, Roundworm, Fruit fly, and Zebrafish, which have genetic similarities to humans, can replicate the disease features and provide behavioural, cellular and molecular insights. The common features of ageing and NDs, like amyloid protein aggregations, oxidative stress, energy dysregulation, inflammation and neurodegeneration can be mimicked in the small organism models for Alzheimer's, Parkinson's, Huntington's diseases, and Amyotrophic Lateral Sclerosis. This review focuses on small organism model- based research unveiling interesting modes of action and synergistic effects of herbal extracts, foods, and formulations, which are indicated especially for healthy ageing and management of NDs. This will provide leads for the quick and sustainable development of scientifically evaluated solutions for clinically relevant, age-related conditions.}, } @article {pmid39432543, year = {2024}, author = {Liu, X and Dong, L and Li, S and Li, Z and Wang, Y and Mao, Z and Deng, L}, title = {Improving AGB estimations by integrating tree height and crown radius from multisource remote sensing.}, journal = {PloS one}, volume = {19}, number = {10}, pages = {e0311642}, pmid = {39432543}, issn = {1932-6203}, mesh = {*Biomass ; *Trees/growth & development ; *Remote Sensing Technology/methods ; *Forests ; }, abstract = {Precise estimation of forest above ground biomass (AGB) is essential for assessing its ecological functions and determining forest carbon stocks. It is difficult to directly obtain diameter at breast height (DBH) based on remote sensing imagery. Therefore, it is crucial to accurately estimate the AGB with features extracted directly from RS. This paper demonstrates the feasibility of estimating AGB from crown radius (R) and tree height (H) features extracted from multi-source RS data. Accurate information on tree height (H), crown radius (R), and diameter at breast height (DBH) can be obtained through point clouds generated by airborne laser scanning (ALS) and terrestrial laser scanning (TLS), respectively. Nine allometric growth equations were used to fit coniferous forests (Larix principis-rupprechtii) and broadleaf forests (Fraxinus chinensis and Sophora japonica). The fitting performance of models constructed using only "H" or "R" was compared with that of models constructed using both combined. The results showed that the quadratic polynomial model constructed with "H+R" fitted the AGB estimation better in each vegetation type, especially in the scenario of mixed tall and short coniferous forests, in which the R2 and RMSE were 0.9282 and 25.30 kg (rRMSE 17.31%), respectively. Therefore, using high-resolution data to extract crown radius and tree height can achieve high-precision, global-scale estimation of forest above ground biomass.}, } @article {pmid39433597, year = {2024}, author = {Candrea, DN and Shah, S and Luo, S and Angrick, M and Rabbani, Q and Coogan, C and Milsap, GW and Nathan, KC and Wester, BA and Anderson, WS and Rosenblatt, KR and Uchil, A and Clawson, L and Maragakis, NJ and Vansteensel, MJ and Tenore, FV and Ramsey, NF and Fifer, MS and Crone, NE}, title = {A click-based electrocorticographic brain-computer interface enables long-term high-performance switch scan spelling.}, journal = {Communications medicine}, volume = {4}, number = {1}, pages = {207}, pmid = {39433597}, issn = {2730-664X}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Brain-computer interfaces (BCIs) can restore communication for movement- and/or speech-impaired individuals by enabling neural control of computer typing applications. Single command click detectors provide a basic yet highly functional capability.

METHODS: We sought to test the performance and long-term stability of click decoding using a chronically implanted high density electrocorticographic (ECoG) BCI with coverage of the sensorimotor cortex in a human clinical trial participant (ClinicalTrials.gov, NCT03567213) with amyotrophic lateral sclerosis. We trained the participant's click detector using a small amount of training data (<44 min across 4 days) collected up to 21 days prior to BCI use, and then tested it over a period of 90 days without any retraining or updating.

RESULTS: Using a click detector to navigate a switch scanning speller interface, the study participant can maintain a median spelling rate of 10.2 characters per min. Though a transient reduction in signal power modulation can interrupt usage of a fixed model, a new click detector can achieve comparable performance despite being trained with even less data (<15 min, within 1 day).

CONCLUSIONS: These results demonstrate that a click detector can be trained with a small ECoG dataset while retaining robust performance for extended periods, providing functional text-based communication to BCI users.}, } @article {pmid39434103, year = {2024}, author = {Sun, S and Chen, Y and Yun, Y and Zhao, B and Ren, Q and Sun, X and Meng, X and Yan, C and Lin, P and Liu, S}, title = {Elevated peripheral inflammation is associated with choroid plexus enlargement in independent sporadic amyotrophic lateral sclerosis cohorts.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {83}, pmid = {39434103}, issn = {2045-8118}, support = {qnts202306347//Taishan Young Scholar Program/ ; ZR2024MH178//Shandong Provincial Natural Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnostic imaging/pathology ; Male ; *Choroid Plexus/diagnostic imaging/pathology ; Female ; Middle Aged ; *Inflammation/blood/diagnostic imaging ; *Magnetic Resonance Imaging ; Cohort Studies ; Aged ; Adult ; }, abstract = {BACKGROUND: Using neuroimaging techniques, growing evidence has suggested that the choroid plexus (CP) volume is enlarged in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Notably, the CP has been suggested to play an important role in inflammation-induced CNS damage under disease conditions. However, to our knowledge, no study has investigated the relationships between peripheral inflammation and CP volume in sporadic ALS patients. Thus, in this study, we aimed to verify CP enlargement and explore its association with peripheral inflammation in vivo in independent ALS cohorts.

METHODS: Based on structural MRI data, CP volume was measured using Gaussian mixture models and further manually corrected in two independent cohorts of sporadic ALS patients and healthy controls (HCs). Serum inflammatory protein levels were measured using a novel high-sensitivity Olink proximity extension assay (PEA) technique. Xtreme gradient boosting (XGBoost) was used to explore the contribution of peripheral inflammatory factors to CP enlargement. Then, partial correlation analyses were performed.

RESULTS: CP volumes were significantly higher in ALS patients than in HCs in the independent cohorts. Compared with HCs, serum levels of CRP, IL-6, CXCL10, and 35 other inflammatory factors were significantly increased in ALS patients. Using the XGBoost approach, we established a model-based importance of features, and the top three predictors of CP volume in ALS patients were CRP, IL-6, and CXCL10 (with gains of 0.24, 0.18, and 0.15, respectively). Correlation analyses revealed that CRP, IL-6, and CXCL10 were significantly associated with CP volume in ALS patients (r = 0.462 ∼ 0.636, p < 0.001).

CONCLUSION: Our study is the first to reveal a consistent and replicable contribution of peripheral inflammation to CP enlargement in vivo in sporadic ALS patients. Given that CP enlargement has been recently detected in other brain diseases, these findings should consider extending to other disease conditions with a peripheral inflammatory component.}, } @article {pmid39434139, year = {2024}, author = {Agah, E and Mojtabavi, H and Behkar, A and Heidari, A and Ajdari, A and Shaka, Z and Mousavi, SV and Firoozeh, N and Tafakhori, A and Rezaei, N}, title = {CSF and blood levels of Neurofilaments, T-Tau, P-Tau, and Abeta-42 in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of translational medicine}, volume = {22}, number = {1}, pages = {953}, pmid = {39434139}, issn = {1479-5876}, mesh = {Humans ; *Amyloid beta-Peptides/cerebrospinal fluid/blood ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/diagnosis ; Biomarkers/blood/cerebrospinal fluid ; Neurofilament Proteins/blood/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid/blood ; Phosphorylation ; Publication Bias ; *tau Proteins/cerebrospinal fluid/blood ; }, abstract = {Recent literature suggests that markers of neuroaxonal damage, such as neurofilaments and tau protein, might serve as potential biomarkers for ALS. We conducted this systematic review and meta-analysis study to compare cerebrospinal fluid (CSF) and blood levels of total tau (t-tau), phosphorylated tau (p-tau), amyloid beta peptide 42 (Abeta-42), and neurofilaments in ALS patients and controls. A systematic search of Cochrane Library, PubMed, Embase, and ISI Web of Science was conducted on March 18, 2022, and updated on January 26, 2023. Observational studies that compared the concentrations of neurofilament light chain (NfL), neurofilament heavy chain (NFH), t-tau, p-tau, or Abeta-42 in CSF or peripheral blood of ALS patients and controls were included. Data from relevant studies were independently extracted and screened for quality using a standard tool, by at least two authors. Meta-analysis was conducted when a minimum of 3 studies reported the same biomarker within the same biofluid. A total of 100 studies were eligible for at least one meta-analysis. CSF and blood levels of NfL (standardized mean difference (SMD) [95% CI]; CSF: 1.46 [1.25-1.68]; blood: 1.35 [1.09-1.60]) and NFH (CSF: 1.32 [1.13-1.50], blood: 0.90 [0.58-1.22]) were significantly higher in ALS patients compared with controls. The pooled differences between ALS patients and controls were not significant for CSF t-tau, blood t-tau, and CSF Abeta-42, but CSF p-tau was lower in ALS patients (-0.27 [-0.47- -0.07]). Significantly decreased p-tau/t-tau ratios were found in ALS patients compared with controls (-0.84 [-1.16- -0.53]). Heterogeneity was considerable in most of our meta-analyses. CSF and blood neurofilament levels, as well as the CSF p-tau/t-tau ratio, might be potential candidates for improving ALS diagnosis. Further research is warranted to better understand the underlying mechanisms and the clinical implications of these biomarker alterations.}, } @article {pmid39435635, year = {2025}, author = {Yang, X and Gao, X and Jiang, X and Yue, K and Luo, P}, title = {Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3076-3094}, pmid = {39435635}, issn = {1673-5374}, abstract = {Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases. Owing to their therapeutic properties and ability to cross the blood-brain barrier, extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions, including ischemic stroke, traumatic brain injury, neurodegenerative diseases, glioma, and psychosis. However, the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body. To address these limitations, multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles, thereby enabling the delivery of therapeutic contents to specific tissues or cells. Therefore, this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles, exploring their applications in treating traumatic brain injury, ischemic stroke, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, glioma, and psychosis. Additionally, we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases. This review offers new insights for developing highly targeted therapies in this field.}, } @article {pmid39435791, year = {2024}, author = {Brylev, LV and Bryukhov, VV and Druzhinina, ES and Kovalchuk, MO}, title = {[Lower motor neuron disease with MRI «snake eyes» pattern].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {9}, pages = {141-144}, doi = {10.17116/jnevro2024124091141}, pmid = {39435791}, issn = {1997-7298}, mesh = {Humans ; *Magnetic Resonance Imaging ; *Motor Neuron Disease/diagnostic imaging/diagnosis ; Motor Neurons/pathology ; *Pyramidal Tracts/diagnostic imaging ; }, abstract = {Motor neuron disease with isolated or predominant lesion of the lower motor neuron at one level of the pyramidal tract is a rare diagnostic finding. In the article, we analyze the case of a patient with asymmetric lesion of the inferior motor neuron at the cervical level: clinical manifestations, results of additional studies and dynamic observation of the patient. Special attention is paid to the MRI picture of changes in the pyramidal tracts in the cervical region, which have been called the «snake eyes» in the literature, and the impact of this finding on the diagnosis and prognosis of the disease.}, } @article {pmid39436522, year = {2025}, author = {Ma, J and Wen, Q and Pang, X and Huang, S and Zhang, J and Wang, J and Chang, X and Guo, J and Zhang, W}, title = {Correction to: Fasciculation score: a sensitive biomarker in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {1}, pages = {525-526}, doi = {10.1007/s10072-024-07807-y}, pmid = {39436522}, issn = {1590-3478}, } @article {pmid39436867, year = {2025}, author = {Firozjae, AA and Shiran, MR and Rashidi, M}, title = {The neuropharmacological and clinical effects of lutein: a systematic review.}, journal = {Hormone molecular biology and clinical investigation}, volume = {46}, number = {1}, pages = {27-38}, pmid = {39436867}, issn = {1868-1891}, mesh = {*Lutein/therapeutic use/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; }, abstract = {OBJECTIVES: Neurodegenerative diseases are defined by specific protein accumulation and anatomic vulnerability leading to neuronal loss. Some studies have shown that lutein may have an effect on neurodegenerative diseases. As most of the neurodegenerative diseases don't have certain cure and therapies focus on symptom control, Lutein may be a complementary treatment. Due to controversies in studies investigating lutein effect on neurodegenerative diseases, we decided to perform a systematic review on these studies.

METHODS: A systematic search was carried out in the available databases. We used all MeSH terms and relevant keywords. Studies that reported relationship between lutein and any neurodegenerative disease were included.

RESULTS: We found 278 studies. After removing duplicates, screening by titles and abstracts and excluding irrelevant papers, 17 articles were included in this study. Fourteen studies investigated Alzheimer's disease, 2 studies Parkinson's disease and 1 study Amyotrophic lateral sclerosis. 1/17 study found that high serum levels of lutein at baseline were associated with a lower risk of AD mortality and lutein effect on lipid profile have been investigated in 2/17 studies. Also, 1/17 study has been shown that high intake of lutein may reduce the risk of ALS progression.

CONCLUSIONS: 4/17 studies confirm that lutein can improve cognitive function. 8/17 studies demonstrate a reduction in the progression of AD, and 2/17 studies indicate an improvement in lipid profiles. However, some studies did not find any significant associations. Additionally, there is a limited number of studies investigating the effects of lutein on other neurodegenerative diseases.}, } @article {pmid39437787, year = {2024}, author = {Saez-Atienzar, S and Souza, CDS and Chia, R and Beal, SN and Lorenzini, I and Huang, R and Levy, J and Burciu, C and Ding, J and Gibbs, JR and Jones, A and Dewan, R and Pensato, V and Peverelli, S and Corrado, L and van Vugt, JJFA and van Rheenen, W and Tunca, C and Bayraktar, E and Xia, M and , and , and , and , and Iacoangeli, A and Shatunov, A and Tiloca, C and Ticozzi, N and Verde, F and Mazzini, L and Kenna, K and Al Khleifat, A and Opie-Martin, S and Raggi, F and Filosto, M and Piccinelli, SC and Padovani, A and Gagliardi, S and Inghilleri, M and Ferlini, A and Vasta, R and Calvo, A and Moglia, C and Canosa, A and Manera, U and Grassano, M and Mandrioli, J and Mora, G and Lunetta, C and Tanel, R and Trojsi, F and Cardinali, P and Gallone, S and Brunetti, M and Galimberti, D and Serpente, M and Fenoglio, C and Scarpini, E and Comi, GP and Corti, S and Del Bo, R and Ceroni, M and Pinter, GL and Taroni, F and Bella, ED and Bersano, E and Curtis, CJ and Lee, SH and Chung, R and Patel, H and Morrison, KE and Cooper-Knock, J and Shaw, PJ and Breen, G and Dobson, RJB and Dalgard, CL and , and Scholz, SW and Al-Chalabi, A and van den Berg, LH and McLaughlin, R and Hardiman, O and Cereda, C and Sorarù, G and D'Alfonso, S and Chandran, S and Pal, S and Ratti, A and Gellera, C and Johnson, K and Doucet-O'Hare, T and Pasternack, N and Wang, T and Nath, A and Siciliano, G and Silani, V and Başak, AN and Veldink, JH and Camu, W and Glass, JD and Landers, JE and Chiò, A and Sattler, R and Shaw, CE and Ferraiuolo, L and Fogh, I and Traynor, BJ}, title = {Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data.}, journal = {Cell genomics}, volume = {4}, number = {11}, pages = {100679}, pmid = {39437787}, issn = {2666-979X}, support = {R35 NS127253/NS/NINDS NIH HHS/United States ; ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; ZIA AG000934/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Drug Repositioning ; *Frontotemporal Dementia/genetics/drug therapy ; Genomics/methods ; Riluzole/therapeutic use ; Male ; Female ; Neuroprotective Agents/therapeutic use/pharmacology ; DNA Repeat Expansion/genetics ; }, abstract = {Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. VIDEO ABSTRACT.}, } @article {pmid39439710, year = {2024}, author = {Kelser, BM and Teichner, EM and Subtirelu, RC and Hoss, KN}, title = {A review of proposed mechanisms for neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1370580}, pmid = {39439710}, issn = {1663-4365}, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneers like Virginia Lee and John Trojanowski have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases. The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation. Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases.}, } @article {pmid39440303, year = {2024}, author = {Dafinca, R and Tosat-Bitrian, C and Carroll, E and Vahsen, BF and Gilbert-Jaramillo, J and Scaber, J and Feneberg, E and Johnson, E and Talbot, K}, title = {Dynactin-1 mediates rescue of impaired axonal transport due to reduced mitochondrial bioenergetics in amyotrophic lateral sclerosis motor neurons.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae350}, pmid = {39440303}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. A key pathological signature of ALS is the cytoplasmic mislocalization and aggregation of TDP-43 in affected motor neurons, which is found in 97% of cases. Recent reports have shown that mitochondrial dysfunction plays a significant role in motor neuron degeneration in ALS, and TDP-43 modulates several mitochondrial transcripts. In this study, we used induced pluripotent stem cell-derived motor neurons from ALS patients with TDP-43 mutations and a transgenic TDP-43[M337V] mouse model to determine how TDP-43 mutations alter mitochondrial function and axonal transport. We detected significantly reduced mitochondrial respiration and ATP production in patient induced pluripotent stem cell-derived motor neurons, linked to an interaction between TDP-43[M337V] with ATPB and COX5A. A downstream reduction in speed of retrograde axonal transport in patient induced pluripotent stem cell-derived motor neurons was detected, which correlated with downregulation of the motor protein complex, DCTN1/dynein. Overexpression of DCTN1 in patient induced pluripotent stem cell-derived motor neurons significantly increased the percentage of retrograde travelling mitochondria and reduced the percentage of stationary mitochondria. This study shows that ALS induced pluripotent stem cell-derived motor neurons with mutations in TDP-43 have deficiencies in essential mitochondrial functions with downstream effects on retrograde axonal transport, which can be partially rescued by DCTN1 overexpression.}, } @article {pmid39440770, year = {2025}, author = {Allowitz, K and Taylor, J and Harames, K and Yoo, J and Baloch, O and Ramana, KV}, title = {Oxidative Stress-mediated Lipid Peroxidation-derived Lipid Aldehydes in the Pathophysiology of Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {23}, number = {6}, pages = {671-685}, pmid = {39440770}, issn = {1875-6190}, mesh = {Humans ; *Oxidative Stress/physiology ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Lipid Peroxidation/physiology ; *Aldehydes/metabolism ; Animals ; }, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis cause damage and gradual loss of neurons affecting the central nervous system. Neurodegenerative diseases are most commonly seen in the ageing process. Ageing causes increased reactive oxygen species and decreased mitochondrial ATP generation, resulting in redox imbalance and oxidative stress. Oxidative stress-generated free radicals cause damage to membrane lipids containing polyunsaturated fatty acids, leading to the formation of toxic lipid aldehyde products such as 4- hydroxynonenal and malondialdehyde. Several studies have shown that lipid peroxidation-derived aldehyde products form adducts with cellular proteins, altering their structure and function. Thus, these lipid aldehydes could act as secondary signaling intermediates, modifying important metabolic pathways, and contributing to the pathophysiology of several human diseases, including neurodegenerative disorders. Additionally, they could serve as biomarkers for disease progression. This narrative review article discusses the biological and clinical significance of oxidative stress-mediated lipid peroxidation-derived lipid aldehydes in the pathophysiology of various neurodegenerative diseases.}, } @article {pmid39441015, year = {2025}, author = {Liu, Y and Li, Y and Zhang, P}, title = {Stress granules and organelles: coordinating cellular responses in health and disease.}, journal = {Protein & cell}, volume = {16}, number = {6}, pages = {418-438}, pmid = {39441015}, issn = {1674-8018}, support = {2023YFC3505000//National Key Research and Development Project of China/ ; 7244365//Beijing Natural Science Foundation of China/ ; }, mesh = {Humans ; *Stress Granules/metabolism/pathology ; *Organelles/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; *Stress, Physiological ; *Cytoplasmic Granules/metabolism ; }, abstract = {Membrane-bound organelles and membraneless organelles (MLOs) coordinate various biological processes within eukaryotic cells. Among these, stress granules (SGs) are significant cytoplasmic MLOs that form in response to cellular stress, exhibiting liquid-like properties alongside stable substructures. SGs interact with diverse organelles, thereby influencing cellular pathways that are critical in both health and disease contexts. This review discusses the interplay between SGs and organelles and explores the methodologies employed to analyze interactions between SGs and other MLOs. Furthermore, it highlights the pivotal roles SGs play in regulating cellular responses and the pathogenesis of amyotrophic lateral sclerosis. Gaining insights into these interactions is essential for deciphering the mechanisms underlying both physiological processes and pathological conditions.}, } @article {pmid39441150, year = {2024}, author = {Hamad, AA and Alkhawaldeh, IM and Abbas, A and Elaraby, A and Meshref, M}, title = {Incidence and risk factors of venous thromboembolism in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {La Tunisie medicale}, volume = {102}, number = {10}, pages = {610-515}, pmid = {39441150}, issn = {2724-7031}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/complications ; Humans ; *Venous Thromboembolism/epidemiology/etiology ; Incidence ; Risk Factors ; Male ; Female ; }, abstract = {AIMS: This systematic review and meta-analysis aimed to determine the annual incidence rate of venous thromboembolism (VTE) and identify risk factors of VTE in amyotrophic lateral sclerosis (ALS) patients.

METHODS: A comprehensive search of three databases was conducted up to April 8, 2024, to identify longitudinal studies reporting VTE incidence in ALS patients. The included studies were either prospective or retrospective, following up with ALS patients. Quality assessment was performed using the NIH tool for observational cohort studies. Meta-analysis was conducted using Open Meta Analyst, employing a random-effect model. Subgroup, Meta-regression, and sensitivity analyses were also carried out.

RESULTS: Our analysis included eight studies comprising a total of 26,758 ALS patients that met the inclusion criteria. The pooled annual incidence of VTE across all studies was found to be 22 cases per 1,000 person-year (95% CI = 18 to 27). Subgroup analysis revealed that the annual incidence of VTE in males was 19 cases per 1,000 person-year (95% CI = 15 to 22), while in females, it was 20 cases per 1,000 person-year (95% CI = 16 to 25). Leave-one-out analysis demonstrated that the incidence ranged from 21 to 28 cases per 1,000 person-year when excluding each study individually. Meta-regression analysis did not find a significant association between age and the risk of VTE (P = 0.079). Based on the included studies, risk factors of VTE in ALS patients included a history of VTE, non-invasive ventilation, immobility, and decreased functional status.

CONCLUSION: Patients with ALS face a higher risk of developing VTE compared to individuals of the same age. These findings underscore the importance of implementing preventive measures and closely monitoring VTE in ALS patients.}, } @article {pmid39443410, year = {2024}, author = {Zhang, T and Rui, W and Sun, Y and Tian, Y and Li, Q and Zhang, Q and Zhao, Y and Liu, Z and Wang, T}, title = {Identification of nitric oxide-mediated necroptosis as the predominant death route in Parkinson's disease.}, journal = {Molecular biomedicine}, volume = {5}, number = {1}, pages = {44}, pmid = {39443410}, issn = {2662-8651}, mesh = {*Necroptosis ; *Parkinson Disease/pathology/metabolism/genetics ; *Nitric Oxide/metabolism ; Humans ; Animals ; Mice ; Neurons/metabolism/pathology ; Signal Transduction ; Male ; Brain/pathology/metabolism ; Alzheimer Disease/pathology/metabolism/genetics ; Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; Membrane Potential, Mitochondrial ; }, abstract = {Parkinson's disease (PD) involves multiple forms of neuronal cell death, but the dominant pathway involved in disease progression remains unclear. This study employed RNA sequencing (RNA-seq) of brain tissue to explore gene expression patterns across different stages of PD. Using the Scaden deep learning algorithm, we predicted neurocyte subtypes and modelled dynamic interactions for five classic cell death pathways to identify the predominant routes of neuronal death during PD progression. Our cell type-specific analysis revealed an increasing shift towards necroptosis, which was strongly correlated with nitric oxide synthase (NOS) expression across most neuronal subtypes. In vitro experiments confirmed that nitric oxide (NO) is a key mediator of necroptosis, leading to nuclear shrinkage and decreased mitochondrial membrane potential via phosphorylation of the PIP1/PIP3/MLKL signalling cascade. Importantly, specific necroptosis inhibitors significantly mitigated neuronal damage in both in vitro and in vivo PD models. Further analysis revealed that NO-mediated necroptosis is prevalent in early-onset Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) and across multiple brain regions but not in brain tumours. Our findings suggest that NO-mediated necroptosis is a critical pathway in PD and other neurodegenerative disorders, providing potential targets for therapeutic intervention.}, } @article {pmid39443862, year = {2024}, author = {Paulin, J and Lahti, M and Riihimäki, H and Hänninen, J and Vesanen, T and Koivisto, M and Peltonen, LM}, title = {The rate and predictors of violence against EMS personnel.}, journal = {BMC emergency medicine}, volume = {24}, number = {1}, pages = {200}, pmid = {39443862}, issn = {1471-227X}, mesh = {Humans ; Male ; Retrospective Studies ; Female ; Finland ; Adult ; Middle Aged ; *Emergency Medical Technicians/statistics & numerical data ; Emergency Medical Services/statistics & numerical data ; Workplace Violence/statistics & numerical data ; Violence/statistics & numerical data ; Logistic Models ; Electronic Health Records ; }, abstract = {BACKGROUND: Violence against Emergency Medical Services (EMS) personnel vary between studies. Current studies are mainly based on self-reporting, thus other designs are needed to provide more perspective. The purpose of this study was to explore the rate and predictors of violent behavior targeted at EMS personnel by exploring the Electronic patient care records (ePCR) documentation by EMS personnel.

METHODS: This was a retrospective cohort study of EMS patients in Finland. The data were collected from three regions between 1st June and 30th November 2018. Text mining and manual evaluation were used to identify and explore predictors of violence targeted at EMS personnel from the ePCR narratives. Multivariable logistic regressions were used to determine factors that were independently associated with violent behavior. The results are presented with odds ratios (ORs) with 95% confidence intervals (CIs).

RESULTS: The EMS personnel reported experiences of violence in a total of 297 identified missions (0.7%) of all EMS missions (n = 40,263). The violence was mostly verbal (62.3%) and the most common violence perpetrator was the patient (98.0%). The police were alarmed to many missions where violence was reported (40.7%). Sometimes violence occurred suddenly although the police were present. The multivariable logistic regression model indicates that violence occurred typically in urban areas (OR 1.699; 95% CI 1.283 to 2.248), at weekend nights (OR 1.357; 95% CI 1.043 to 1.765), by male (OR 1.501; 95% CI 1.160 to 1.942), and patients influenced by alcohol (OR 3.464; 95% CI 2.644 to 4.538). A NEWS2 score of 3 in any parameter (vs. score 0-4, OR 2.386; 95% CI: 1.788 to 3.185) and ALS unit type (vs. BLS, OR 1.373; 95% CI: 1.009 to 1.866) increased the likelihood as well.

CONCLUSIONS: The documentation in ePCRs show low rates of violence targeted at EMS personnel. However, violence is a multidimensional phenomenon connected to unfamiliar patients, rushed situations, and an uncontrolled environment. This means that the EMS personnels' safety cannot be ensured in all situations. Therefore, a balance between safety margins and treating patients needs to be considered.}, } @article {pmid39444004, year = {2024}, author = {Hoshino, T and Mukai, A and Yamashita, H and Misawa, H and Urushitani, M and Tashiro, Y and Matsuzawa, SI and Takahashi, R}, title = {NDRG1 upregulation by ubiquitin proteasome system dysfunction aggravates neurodegeneration.}, journal = {Molecular brain}, volume = {17}, number = {1}, pages = {77}, pmid = {39444004}, issn = {1756-6606}, support = {16H01695//Japan Society for the Promotion of Science/ ; }, mesh = {Animals ; *Up-Regulation/genetics ; *Cell Cycle Proteins/metabolism/genetics ; *Proteasome Endopeptidase Complex/metabolism ; Mice ; *Ubiquitin/metabolism ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; Cell Line, Tumor ; Motor Neurons/metabolism/pathology ; Nerve Degeneration/pathology ; Cell Death ; Humans ; N-myc Downstream-Regulated Gene 1 Protein ; }, abstract = {Protein turnover is crucial for cell survival, and the impairment of proteostasis leads to cell death. Aging is associated with a decline in proteostasis, as the progressive accumulation of damaged proteins is a hallmark of age-related disorders such as neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We previously discovered that the declining function of the ubiquitin-proteasome system (UPS) in motor neurons contributes to sporadic ALS pathologies, such as progressive motor neuron loss, protein accumulation, and glial activation. However, the mechanisms of UPS dysfunction-induced cell damage, such as cell death and aggregation, are not fully understood. This study used transcriptome analysis of motor neurons with UPS dysfunction and found that the expression of N-myc downstream regulated 1 (NDRG1) gets upregulated by UPS dysfunction. Additionally, the upregulation of NDRG1 induces cell death in the Neuro2a mouse neuroblastoma cell line. These results suggest that NDRG1 is a potential marker for UPS dysfunction and may play a role in neurodegeneration, such as that seen in ALS.}, } @article {pmid39444183, year = {2025}, author = {Alici, H and Uversky, VN and Kang, DE and Woo, JA and Coskuner-Weber, O}, title = {Effects of the Amyotrophic Lateral Sclerosis-related Q108P Mutation on the Structural Ensemble Characteristics of CHCHD10.}, journal = {Current protein & peptide science}, volume = {26}, number = {3}, pages = {201-212}, pmid = {39444183}, issn = {1875-5550}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; Molecular Dynamics Simulation ; *Mitochondrial Proteins/genetics/chemistry/metabolism ; *Mutation ; Principal Component Analysis ; Thermodynamics ; Protein Conformation ; }, abstract = {INTRODUCTION: The Q108P pathological variant of the mitochondrial Coiled-Coil-Helix-- Coiled-Coil-Helix Domain-Containing Protein 10 (CHCHD10) has been implicated in amyotrophic lateral sclerosis (ALS). Both the wild-type and CHCHD10[Q108P] proteins exhibit intrinsically disordered regions, posing challenges for structural studies with conventional experimental tools.

METHODS: This study presents the foundational characterization of the structural features of CHCHD10[Q108P] and compares them with those of the wild-type counterpart. We conducted multiple run molecular dynamics simulations and bioinformatics analyses.

RESULTS: Our findings reveal distinct differences in structural properties, free energy surfaces, and the outputs of principal component analysis between these two proteins. These results contribute significantly to the comprehension of CHCHD10 and its Q108P variant in terms of pathology, biochemistry, and structural biology.

CONCLUSION: The reported structural properties hold promise for informing the development of more effective treatments for ALS.}, } @article {pmid39447539, year = {2024}, author = {Zhu, H}, title = {Interference of nuclear speckles: A nexus of RNA foci, dipeptide repeats, and mis-splicing in C9ORF72 ALS/FTD.}, journal = {Neuron}, volume = {112}, number = {20}, pages = {3375-3377}, doi = {10.1016/j.neuron.2024.10.001}, pmid = {39447539}, issn = {1097-4199}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics/metabolism ; *RNA Splicing/genetics ; Dipeptides/metabolism ; DNA Repeat Expansion/genetics ; Proteins/genetics/metabolism ; RNA/genetics ; }, abstract = {In this issue of Neuron, Wu et al.[1] show that nuclear speckle proteins are sequestered by both nuclear RNA foci and cytoplasmic dipeptide repeat aggregates in C9ORF72-ALS/FTD. Consequently, dysregulation of splicing induces widespread splicing alterations and contributes to neurodegeneration.}, } @article {pmid39448670, year = {2024}, author = {Stankiewicz-Kosyl, M and Wińska-Krysiak, M and Wrochna, M and Haliniarz, M and Marcinkowska, K}, title = {Regional diversity of the ALS gene and hormesis due to tribenuron-methyl in Centaurea cyanus L.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {25197}, pmid = {39448670}, issn = {2045-2322}, support = {BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; }, mesh = {*Acetolactate Synthase/genetics ; *Hormesis ; *Herbicides/pharmacology ; *Centaurea/genetics ; Arylsulfonates/pharmacology ; Herbicide Resistance/genetics ; Mutation ; Poland ; Plant Proteins/genetics ; Genetic Variation ; }, abstract = {Centaurea cyanus L. is a common field weed in Eastern Europe but only in Poland biotypes of this species with resistance to acetolactate synthase (ALS) inhibitors have been confirmed. This phenomenon is constantly developing and spreading to consecutive regions of Poland. This study aimed to assess the response of selected Polish C. cyanus populations to tribenuron-methyl and to analyse the genetic variability of the ALS gene of C. cyanus populations resistant to ALS inhibitors. Between 2017 and 2021, 13 seed samples were collected from eastern Poland and a dose-response study with tribenuron-methyl was performed. Eleven populations resistant to tribenuron-methyl were identified. All populations from this study as well as 6 additional resistant populations characterised in the previous dose-response studies were subjected to molecular analysis of the ALS gene. Target-site resistance due to mutations P197S, P197Q, P197T and P197A were identified in 8 populations from Warmia-Masuria and Podlaskie provinces. This is the first case of target-site resistance (TSR) in C. cyanus confirmed by sequencing of the ALS gene. Moreover in some resistant plants, ten changes in the amino acid ALS sequence were identified in comparison to those in the susceptible ones. In none of the populations were all mutations detected in the same individual. The highest frequency of mutations was detected in Warmia-Masuria province. Some C. cyanus populations resistant to ALS inhibitors showed hormesis effect concerning shoot fresh weight after tribenuron-methyl treatment. Stimulation due to half the recommended dose of tribenuron-methyl was the highest and the difference between untreated and treated plants was statistically significant in two populations from Warmia-Masuria and in one from Podlaskie province.}, } @article {pmid39449162, year = {2024}, author = {Zhu, Y and Zhang, Y and Li, M and Bai, J and Wang, H and Pang, X and Du, R and Wang, J and Huang, X}, title = {Prognostic Value of Systemic Inflammation, Nutritional Status and Sarcopenia in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {15}, number = {6}, pages = {2743-2755}, pmid = {39449162}, issn = {2190-6009}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/mortality/blood ; Female ; Male ; *Nutritional Status ; *Sarcopenia/etiology/blood ; Middle Aged ; Prognosis ; *Inflammation/blood ; Aged ; Biomarkers/blood ; Proportional Hazards Models ; ROC Curve ; Kaplan-Meier Estimate ; Adult ; }, abstract = {BACKGROUND: Nutritional status, systemic inflammatory responses and muscle mass are associated with the prognosis of patients with amyotrophic lateral sclerosis (ALS). However, the optimal biomarker for predicting prognosis remains unclear. This study aimed to identify the optimal indicators of survival among the nutrition-based, inflammation-based and muscle mass-related markers for ALS patients.

METHODS: We enrolled ALS patients from January 2014 to December 2019. Experienced neurologists followed up with the participants until January 2022. This study included a total of 17 nutritional, systemic inflammatory or muscle mass-related indicators. Maximally selected rank statistics determined the cut-off points for these indicators. Kaplan-Meier estimation was used to assess survival. Uni- and multivariate Cox proportional hazards models were used to determine the effects of indicators on survival. Finally, time-dependent receiver operating characteristic (time-ROC) curves and the C-index were calculated to evaluate the predictive efficacy of different indicators.

RESULTS: A total of 506 patients with ALS were enrolled in this study, including 288 males (56.9%) and 218 females (43.1%), with a mean age of 54.2 ± 10.5 years. Among these ALS patients, 334 cases (68.0%) either died or underwent tracheotomy. In univariate Cox proportional hazards regression, 11 indicators were significantly associated with ALS survival (p < 0.05). And systemic immune inflammation (SII), platelet-to-lymphocyte ratio (PLR), modified geriatric nutritional risk index (mGNRI), creatinine and sarcopenia index (SI, (creatinine/cystatin C) × 100) were determined as independent predictors (p < 0.05) in multivariate Cox proportional hazards regression. A higher SI predicted longer survival (hazard ratio, 0.59; 95% confidence interval [CI], 0.46-0.76; p < 0.001). The results of time-ROC and C-index analyses indicated that SI had the best predictive efficacy for ALS survival, with a C-index of 0.65 (95% CI, 0.54-0.75) for 1-year, 0.61 (95% CI, 0.57-0.65) for 3-year and 0.59 (95% CI, 0.55-0.62) for 5-year survival. Across different subgroups, SI had the highest C-index in men and women, limb onset and aged < 60 year ALS patients, compared with other indicators. However, cystatin C was the best indicator for predicting the survival of ALS patients with bulbar onset, whereas the prognostic nutritional index (PNI) was the best for those aged ≥60 years.

CONCLUSIONS: The serum SI demonstrates superior prognostic ability compared to other inflammation-based, nutrition-based and muscle mass-related indicators for patients with ALS. Given its simplicity and availability, it is well suited for clinical use in evaluating the prognosis of ALS patients.}, } @article {pmid39449457, year = {2024}, author = {Rosa, D and Ingrande, L and Marcomini, I and Poliani, A and Villa, G and Sodano, M and Manara, DF}, title = {Perceived Pain in People Living with Amyotrophic Lateral Sclerosis-A Scoping Review.}, journal = {Nursing reports (Pavia, Italy)}, volume = {14}, number = {4}, pages = {3023-3039}, pmid = {39449457}, issn = {2039-4403}, abstract = {(1) Background: Pain is a common symptom in patients with Amyotrophic Lateral Sclerosis (ALS). There are no evidence-based pharmacological treatments for pain in ALS; recommendations are based on guidelines for chronic non-oncological pain and clinical experience. The aim is to map the literature on how people with ALS experience pain, and how this affects their daily activities and social relationships. (2) Methods: This scoping review included studies concerning patients with spinal/bulbar ALS aged ≥ 18 years who experience pain, focusing on perception, characteristics, treatment, and impact on quality of life. Temporal and linguistic criteria were applied when searching the MEDLINE, CINAHL, and SCOPUS databases. (3) Results: The management of pain in these patients is complex and involves the use of anti-inflammatory drugs, analgesics, and opioids. Pain is associated with other conditions such as depression and anxiety, which contribute to a deterioration in the quality of life. Moreover, pain may also negatively influence patient compliance with prescribed treatment regimens and the quality of care they perceive themselves to be receiving. (4) Conclusions: It is of the most importance to identify effective ways to assess and treat this issue, with health care professionals taking an active role in this process.}, } @article {pmid39449756, year = {2024}, author = {Filipi, T and Tureckova, J and Vanatko, O and Chmelova, M and Kubiskova, M and Sirotova, N and Matejkova, S and Vargova, L and Anderova, M}, title = {ALS-like pathology diminishes swelling of spinal astrocytes in the SOD1 animal model.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1472374}, pmid = {39449756}, issn = {1662-5102}, abstract = {Astrocytes are crucial for the functioning of the nervous system as they maintain the ion homeostasis via volume regulation. Pathological states, such as amyotrophic lateral sclerosis (ALS), affect astrocytes and might even cause a loss of such functions. In this study, we examined astrocytic swelling/volume recovery in both the brain and spinal cord of the SOD1 animal model to determine the level of their impairment caused by the ALS-like pathology. Astrocyte volume changes were measured in acute brain or spinal cord slices during and after exposure to hyperkalemia. We then compared the results with alterations of extracellular space (ECS) diffusion parameters, morphological changes, expression of the Kir4.1 channel and the potassium concentration measured in the cerebrospinal fluid, to further disclose the link between potassium and astrocytes in the ALS-like pathology. Morphological analysis revealed astrogliosis in both the motor cortex and the ventral horns of the SOD1 spinal cord. The activated morphology of SOD1 spinal astrocytes was associated with the results from volume measurements, which showed decreased swelling of these cells during hyperkalemia. Furthermore, we observed lower shrinkage of ECS in the SOD1 spinal ventral horns. Immunohistochemical analysis then confirmed decreased expression of the Kir4.1 channel in the SOD1 spinal cord, which corresponded with the diminished volume regulation. Despite astrogliosis, cortical astrocytes in SOD1 mice did not show alterations in swelling nor changes in Kir4.1 expression, and we did not identify significant changes in ECS parameters. Moreover, the potassium level in the cerebrospinal fluid did not deviate from the physiological concentration. The results we obtained thus suggest that ALS-like pathology causes impaired potassium uptake associated with Kir4.1 downregulation in the spinal astrocytes, but based on our data from the cortex, the functional impairment seems to be independent of the morphological state.}, } @article {pmid39451238, year = {2024}, author = {Crescioli, C and Paronetto, MP}, title = {The Emerging Role of Phosphodiesterase 5 Inhibition in Neurological Disorders: The State of the Art.}, journal = {Cells}, volume = {13}, number = {20}, pages = {}, pmid = {39451238}, issn = {2073-4409}, mesh = {Humans ; *Phosphodiesterase 5 Inhibitors/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; Animals ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Neuroinflammatory Diseases/drug therapy/metabolism ; }, abstract = {Growing evidence suggests that neuroinflammation is not just a consequence of neurodegeneration in pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease or Amyotrophic lateral sclerosis, but it is rather a determinant factor, which plays a pivotal role in the onset and progression of these disorders. Neuroinflammation can affect cells and processes in the central nervous system (CNS) as well as immune cells, and might precede protein aggregation, which is a hallmark of the neurodegenerative process. Standard treatment methods are far from being able to counteract inflammation and delay neurodegeneration. Remarkably, phosphodiesterase 5 inhibitors (PDE5is), which represent potent vasoactive drugs used as a first-line treatment for erectile dysfunction (ED), display important anti-inflammatory effects through cyclic guanosine monophosphate (cGMP) level stabilization. Since PDE5 hydrolyzes cGMP, several studies positioned PDE5 as a therapeutic target, and more specifically, PDE5is as potential alternative strategies for the treatment of a variety of neurological disorders. Indeed, PDE5is can limit neuroinflammation and enhance synaptic plasticity, with beneficial effects on cognitive function and memory. The aim of this review is to provide an overview of some of the main processes underlying neuroinflammation and neurodegeneration which may be potential targets for PDE5is, focusing on sildenafil, the most extensively studied. Current strategies using PDEis for the treatment of neurodegenerative diseases will be summarized.}, } @article {pmid39451396, year = {2024}, author = {Yang, CH and Huang, JL and Tsai, LK and Taniar, D and Pai, TW}, title = {An Effective DNA Methylation Biomarker Screening Mechanism for Amyotrophic Lateral Sclerosis (ALS) Based on Comorbidities and Gene Function Analysis.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {39451396}, issn = {2306-5354}, support = {MOST 111-2221-E-027-113-414 MY2//National Science and Technology Council (Taiwan)/ ; NSTC113-2221-E-027-109//National Science and Technology Council (Taiwan)/ ; MOST104-2321-B-019-009//National Science and Technology Council (Taiwan)/ ; }, abstract = {This study used epigenomic methylation differential expression analysis to identify primary biomarkers in patients with amyotrophic lateral sclerosis (ALS). We combined electronic medical record datasets from MIMIC-IV (United States) and NHIRD (Taiwan) to explore ALS comorbidities in depth and discover any comorbidity-related biomarkers. We also applied word2vec to these two clinical diagnostic medical databases to measure similarities between ALS and other similar diseases and evaluated the statistical assessment of the odds ratio to discover significant comorbidities for ALS subjects. Important and representative DNA methylation biomarker candidates could be effectively selected by cross-comparing similar diseases to ALS, comorbidity-related genes, and differentially expressed methylation loci for ALS subjects. The screened epigenomic and comorbidity-related biomarkers were clustered based on their genetic functions. The candidate DNA methylation biomarkers associated with ALS were comprehensively discovered. Gene ontology annotations were then applied to analyze and cluster the candidate biomarkers into three different groups based on gene function annotations. The results showed that a potential testing kit for ALS detection can be composed of SOD3, CACNA1H, and ERBB4 for effective early screening of ALS using blood samples. By developing an effective DNA methylation biomarker screening mechanism, early detection and prophylactic treatment of high-risk ALS patients can be achieved.}, } @article {pmid39451800, year = {2024}, author = {Drăgoi, MV and Nisipeanu, I and Frimu, A and Tălîngă, AM and Hadăr, A and Dobrescu, TG and Suciu, CP and Manea, AR}, title = {Real-Time Home Automation System Using BCI Technology.}, journal = {Biomimetics (Basel, Switzerland)}, volume = {9}, number = {10}, pages = {}, pmid = {39451800}, issn = {2313-7673}, abstract = {A Brain-Computer Interface (BCI) processes and converts brain signals to provide commands to output devices to carry out certain tasks. The main purpose of BCIs is to replace or restore the missing or damaged functions of disabled people, including in neuromuscular disorders like Amyotrophic Lateral Sclerosis (ALS), cerebral palsy, stroke, or spinal cord injury. Hence, a BCI does not use neuromuscular output pathways; it bypasses traditional neuromuscular pathways by directly interpreting brain signals to command devices. Scientists have used several techniques like electroencephalography (EEG) and intracortical and electrocorticographic (ECoG) techniques to collect brain signals that are used to control robotic arms, prosthetics, wheelchairs, and several other devices. A non-invasive method of EEG is used for collecting and monitoring the signals of the brain. Implementing EEG-based BCI technology in home automation systems may facilitate a wide range of tasks for people with disabilities. It is important to assist and empower individuals with paralysis to engage with existing home automation systems and gadgets in this particular situation. This paper proposes a home security system to control a door and a light using an EEG-based BCI. The system prototype consists of the EMOTIV Insight™ headset, Raspberry Pi 4, a servo motor to open/close the door, and an LED. The system can be very helpful for disabled people, including arm amputees who cannot close or open doors or use a remote control to turn on or turn off lights. The system includes an application made in Flutter to receive notifications on a smartphone related to the status of the door and the LEDs. The disabled person can control the door as well as the LED using his/her brain signals detected by the EMOTIV Insight™ headset.}, } @article {pmid39451992, year = {2024}, author = {Ozdinler, PH}, title = {Sleep Apnea and Amyotrophic Lateral Sclerosis: Cause, Correlation, Any Relation?.}, journal = {Brain sciences}, volume = {14}, number = {10}, pages = {}, pmid = {39451992}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with progressive neurodegeneration, affecting both the cortical and the spinal component of the motor neuron circuitry in patients. The cellular and molecular basis of selective neuronal vulnerability is beginning to emerge. Yet, there are no effective cures for ALS, which affects more than 200,000 people worldwide each year. Recent studies highlight the importance of the glymphatic system and its proper function for the clearance of the cerebral spinal fluid, which is achieved mostly during the sleep period. Therefore, a potential link between problems with sleep and neurodegenerative diseases has been postulated. This paper discusses the present understanding of this potential correlation.}, } @article {pmid39454934, year = {2025}, author = {Takeda, T and Her, YR and Kim, JK and Jha, NN and Monani, UR}, title = {A variant of the Hspa8 synaptic chaperone modifies disease in a SOD1[G86R] mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {115024}, pmid = {39454934}, issn = {1090-2430}, support = {R01 NS104218/NS/NINDS NIH HHS/United States ; R01 NS123292/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *HSC70 Heat-Shock Proteins/metabolism/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Motor Neurons/pathology/metabolism ; Humans ; Mutation ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8[G470R] in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it.}, } @article {pmid39455931, year = {2024}, author = {Martínez, P and Silva, M and Abarzúa, S and Tevy, MF and Jaimovich, E and Constantine-Paton, M and Bustos, FJ and van Zundert, B}, title = {Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {185}, pmid = {39455931}, issn = {1528-3658}, support = {1181645//Agencia Nacional de Investigación y Desarrollo/ ; DI-06-24/REG//UNAB/ ; 1221745//Agencia Nacional de Investigación y Desarrollo/ ; 21151265//Agencia Nacional de Investigación y Desarrollo/ ; R01-638 EY014420//National Institute of Mental Health and Neurosciences/ ; R01-EY014074//National Institute of Mental Health and Neurosciences/ ; R03 EY014420/EY/NEI NIH HHS/United States ; 1151293//Agencia Nacional de Investigación y Desarrollo/ ; 13220203 explorador//Agencia Nacional de Investigación y Desarrollo/ ; NCN2023_32//Agencia Nacional de Investigación y Desarrollo/ ; }, mesh = {Animals ; *Muscle Fibers, Skeletal/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Mitochondria/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Humans ; *Mice, Transgenic ; *Axonal Transport ; Cell Death ; Disease Models, Animal ; Mutation ; Cells, Cultured ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1[G93A] (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2 + transients and reactive oxygen species (i.e., H2O2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.}, } @article {pmid39455963, year = {2024}, author = {Alexander, E and Leong, KW}, title = {Discovery of nanobodies: a comprehensive review of their applications and potential over the past five years.}, journal = {Journal of nanobiotechnology}, volume = {22}, number = {1}, pages = {661}, pmid = {39455963}, issn = {1477-3155}, mesh = {*Single-Domain Antibodies/chemistry ; Humans ; Animals ; *SARS-CoV-2/immunology ; COVID-19/virology/immunology ; Neurodegenerative Diseases/drug therapy ; }, abstract = {Nanobodies (Nbs) are antibody fragments derived from heavy-chain-only IgG antibodies found in the Camelidae family as well as cartilaginous fish. Their unique structural and functional properties, such as their small size, the ability to be engineered for high antigen-binding affinity, stability under extreme conditions, and ease of production, have made them promising tools for diagnostics and therapeutics. This potential was realized in 2018 with the approval of caplacizumab, the world's first Nb-based drug. Currently, Nbs are being investigated in clinical trials for a broad range of treatments, including targeted therapies against PDL1 and Epidermal Growth Factor Receptor (EGFR), cardiovascular diseases, inflammatory conditions, and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. They are also being studied for their potential for detecting and imaging autoimmune conditions and infectious diseases such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A variety of methods are now available to generate target-specific Nbs quickly and efficiently at low costs, increasing their accessibility. This article examines these diverse applications of Nbs and their promising roles. Only the most recent articles published in the last five years have been used to summarize the most advanced developments in the field.}, } @article {pmid39456026, year = {2024}, author = {Albagli, EA and Calliari, A and Gendron, TF and Zhang, YJ}, title = {HDGFL2 cryptic protein: a portal to detection and diagnosis in neurodegenerative disease.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {79}, pmid = {39456026}, issn = {1750-1326}, support = {P01NS084974/NS/NINDS NIH HHS/United States ; U19AG063911/AG/NIA NIH HHS/United States ; R21NS127331/NS/NINDS NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R21 NS127331/NS/NINDS NIH HHS/United States ; R01NS121125/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R01NS117461/NS/NINDS NIH HHS/United States ; Target ALS//Target ALS/ ; R01 NS117461/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P30AG062677/AG/NIA NIH HHS/United States ; R01 AG085307/AG/NIA NIH HHS/United States ; R01AG085307/AG/NIA NIH HHS/United States ; }, } @article {pmid39456257, year = {2024}, author = {Perni, M and Mannini, B}, title = {Targeting Protein Aggregation in ALS.}, journal = {Biomolecules}, volume = {14}, number = {10}, pages = {}, pmid = {39456257}, issn = {2218-273X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates ; Animals ; }, abstract = {Proteinopathies involve the abnormal accumulation of specific proteins. Maintaining the balance of the proteome is a finely regulated process managed by a complex network of cellular machinery responsible for protein synthesis, folding, and degradation. However, stress and ageing can disrupt this balance, leading to widespread protein aggregation. Currently, several therapies targeting protein aggregation are in clinical trials for ALS. These approaches mainly focus on two strategies: addressing proteins that are prone to aggregation due to mutations and targeting the cellular mechanisms that maintain protein homeostasis to prevent aggregation. This review will cover these emerging drugs. Advances in ALS research not only offer hope for better outcomes for ALS patients but also provide valuable insights and methodologies that can benefit the broader field of neurodegenerative disease drug discovery.}, } @article {pmid39456494, year = {2024}, author = {De Stefano, S and Tiberi, M and Salvatori, I and De Bardi, M and Gimenez, J and Pirshayan, M and Greco, V and Borsellino, G and Ferri, A and Valle, C and Mercuri, NB and Chiurchiù, V and Spalloni, A and Longone, P}, title = {Hydrogen Sulfide Modulates Astrocytic Toxicity in Mouse Spinal Cord Cultures: Implications for Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {10}, pages = {}, pmid = {39456494}, issn = {2076-3921}, abstract = {Hydrogen sulfide (H2S), a known inhibitor of the electron transport chain, is endogenously produced in the periphery as well as in the central nervous system, where is mainly generated by glial cells. It affects, as a cellular signaling molecule, many different biochemical processes. In the central nervous system, depending on its concentration, it can be protective or damaging to neurons. In the study, we have demonstrated, in a primary mouse spinal cord cultures, that it is particularly harmful to motor neurons, is produced by glial cells, and is stimulated by inflammation. However, its role on glial cells, especially astrocytes, is still under-investigated. The present study was designed to evaluate the impact of H2S on astrocytes and their phenotypic heterogeneity, together with the functionality and homeostasis of mitochondria in primary spinal cord cultures. We found that H2S modulates astrocytes' morphological changes and their phenotypic transformation, exerts toxic properties by decreasing ATP production and the mitochondrial respiration rate, disturbs mitochondrial depolarization, and alters the energetic metabolism. These results further support the hypothesis that H2S is a toxic mediator, mainly released by astrocytes, possibly acting as an autocrine factor toward astrocytes, and probably involved in the non-cell autonomous mechanisms leading to motor neuron death.}, } @article {pmid39456682, year = {2024}, author = {Alshehri, RS and Abuzinadah, AR and Alrawaili, MS and Alotaibi, MK and Alsufyani, HA and Alshanketi, RM and AlShareef, AA}, title = {A Review of Biomarkers of Amyotrophic Lateral Sclerosis: A Pathophysiologic Approach.}, journal = {International journal of molecular sciences}, volume = {25}, number = {20}, pages = {}, pmid = {39456682}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/physiopathology/diagnosis ; Humans ; *Biomarkers/metabolism ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. The heterogeneous nature of ALS at the clinical, genetic, and pathological levels makes it challenging to develop diagnostic and prognostic tools that fit all disease phenotypes. Limitations associated with the functional scales and the qualitative nature of mainstay electrophysiological testing prompt the investigation of more objective quantitative assessment. Biofluid biomarkers have the potential to fill that gap by providing evidence of a disease process potentially early in the disease, its progression, and its response to therapy. In contrast to other neurodegenerative diseases, no biomarker has yet been validated in clinical use for ALS. Several fluid biomarkers have been investigated in clinical studies in ALS. Biofluid biomarkers reflect the different pathophysiological processes, from protein aggregation to muscle denervation. This review takes a pathophysiologic approach to summarizing the findings of clinical studies utilizing quantitative biofluid biomarkers in ALS, discusses the utility and shortcomings of each biomarker, and highlights the superiority of neurofilaments as biomarkers of neurodegeneration over other candidate biomarkers.}, } @article {pmid39457466, year = {2024}, author = {Moriyama, H and Yokota, T}, title = {Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457466}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; Humans ; *Superoxide Dismutase-1/genetics ; *Oligonucleotides, Antisense/therapeutic use/genetics ; *Mutation ; Animals ; Oligonucleotides/therapeutic use/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a refractory neurodegenerative disease characterized by the degeneration and loss of motor neurons, typically resulting in death within five years of onset. There have been few effective treatments, making the development of robust therapies an urgent challenge. Genetic mutations have been identified as contributors to ALS, with mutations in superoxide dismutase 1 (SOD1), which neutralizes the harmful reactive oxygen species superoxide, accounting for approximately 2% of all ALS cases. To counteract the toxic gain of function caused by SOD1 mutations, therapeutic strategies aimed at suppressing SOD1 gene expression have shown promise. Antisense oligonucleotide (ASO) is an artificially synthesized, short, single-stranded DNA/RNA molecule that binds to target RNA to alter gene expression, representing a next-generation therapeutic approach. In 2023, tofersen became the first ASO drug approved by the FDA for ALS. Administered intrathecally, tofersen specifically binds to SOD1 mRNA, inhibiting the production of toxic SOD1 protein, thereby improving biomarkers of ALS. The long-term efficacy and safety of tofersen require further validation, and the development of more optimized treatment protocols is essential. A series of studies and therapeutic developments related to SOD1 mutations have advanced the understanding of ALS pathophysiology and significantly contributed to treatment strategies for central nervous system disorders. This review focuses on an overview of SOD1 mutations and the development process of tofersen, aiming to deepen the understanding of advancements in ALS research and discuss future challenges and directions for ASO therapy.}, } @article {pmid39457468, year = {2024}, author = {Boura, I and Giannopoulou, IA and Pavlaki, V and Xiromerisiou, G and Mitsias, P and Spanaki, C}, title = {FIG4-Related Parkinsonism and the Particularities of the I41T Mutation: A Review of the Literature.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457468}, issn = {2073-4425}, mesh = {Humans ; *Parkinsonian Disorders/genetics/pathology/diagnostic imaging ; *Charcot-Marie-Tooth Disease/genetics/pathology ; *Flavoproteins/genetics ; Female ; Male ; Mutation, Missense ; Middle Aged ; Mutation ; Adult ; Phosphoric Monoester Hydrolases ; }, abstract = {Background/Objectives: The genetic underpinnings of Parkinson's disease (PD) and parkinsonism have drawn increasing attention in recent years. Mutations in the Factor-Induced Gene 4 (FIG4) have been implicated in various neurological disorders, including Charcot-Marie-Tooth disease type 4J (CMT4J), amyotrophic lateral sclerosis (ALS), and Yunis-Varón syndrome. This review aims to explore the association between FIG4 mutations and parkinsonism, with a specific focus on the rare missense mutation p.Ile41Thr (I41T). Methods: We identified 12 cases from 10 different families in which parkinsonism was reported in conjunction with CMT4J polyneuropathy. All cases involved the I41T mutation in a compound heterozygous state, combined with a FIG4 loss-of-function mutation. Data from clinical observations, neuroimaging studies, and genetic analyses were evaluated to understand the characteristics of parkinsonism in these patients. Results: In all 12 cases, parkinsonism developed either concurrently or following the onset of CMT4J neuropathy, but was never observed in isolation. Cases of both early- and late-onset parkinsonism were identified, reflecting similarities to genetic forms of parkinsonism with autosomal recessive inheritance. Imaging studies, including Dopamine transporter Single Photon Emission Computed Tomography (DaTscan) and brain magnetic resonance imaging (MRI), revealed abnormalities indicative of neurodegeneration, consistent with findings in other neurodegenerative disorders. Conclusions: The co-occurrence of parkinsonism with CMT4J in patients carrying the I41T mutation suggests an expanded spectrum of FIG4-related disorders, potentially implicating the same molecular mechanisms seen in other neurodegenerative disorders. Further research into FIG4-mediated pathways may offer valuable insights into potential therapeutic targets for disorders of both the central and peripheral nervous systems.}, } @article {pmid39457470, year = {2024}, author = {Trabacca, A and Ferrante, C and Oliva, MC and Fanizza, I and Gallo, I and De Rinaldis, M}, title = {Update on Inherited Pediatric Motor Neuron Diseases: Clinical Features and Outcome.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457470}, issn = {2073-4425}, support = {2024//The Italian Health Ministry - Ricerca Corrente/ ; }, mesh = {Humans ; *Motor Neuron Disease/genetics/pathology ; Child ; Mutation ; Muscular Atrophy, Spinal/genetics/pathology/diagnosis ; Exome Sequencing ; }, abstract = {BACKGROUND: Inherited pediatric motor neuron diseases (MNDs) are a group of neurodegenerative disorders characterized by the degeneration of motor neurons in the brain and the spinal cord. These diseases can manifest as early as infancy and originate from inherited pathogenic mutations in known genes. Key clinical features of MNDs include muscle weakness, hypotonia, and atrophy due to the degeneration of lower motor neurons or spasticity, hypertonia, and hyperreflexia caused by upper motor neuron dysfunction. The course of the disease varies among individuals and is influenced by the specific subtype.

METHODS: We performed a non-systematic, narrative clinical review, employing a systematic methodology for the literature search and article selection to delineate the features of hereditary pediatric motor neuron diseases.

RESULTS: The growing availability of advanced molecular testing, such as whole-exome sequencing (WES) and whole-genome sequencing (WGS), has expanded the range of identified genetic factors. These advancements provide insights into the genetic complexity and underlying mechanisms of these disorders. As more MND-related genes are discovered, the accumulating genetic data will help prioritize promising candidate genes for future research. In some cases, targeted treatments based on specific genetic mechanisms have already emerged, underscoring the critical role of early and timely diagnosis in improving patient outcomes. Common MNDs include amyotrophic lateral sclerosis, spinal muscular atrophy, and bulbar spinal muscular atrophy.

CONCLUSION: This narrative clinical review covers the clinical presentation, genetics, molecular features, and pathophysiology of inherited pediatric MNDs.}, } @article {pmid38316966, year = {2024}, author = {Naruse, H and Ishiura, H and Esaki, K and Mitsui, J and Satake, W and Greimel, P and Shingai, N and Machino, Y and Kokubo, Y and Hamaguchi, H and Oda, T and Ikkaku, T and Yokota, I and Takahashi, Y and Suzuki, Y and Matsukawa, T and Goto, J and Koh, K and Takiyama, Y and Morishita, S and Yoshikawa, T and Tsuji, S and Toda, T}, title = {SPTLC2 variants are associated with early-onset ALS and FTD due to aberrant sphingolipid synthesis.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {4}, pages = {946-957}, pmid = {38316966}, issn = {2328-9503}, support = {21K07512//Japan Society for the Promotion of Science/ ; 22K15724//Japan Society for the Promotion of Science/ ; //Ministry of Health, Labour and Welfare/ ; JP22ek0109617//Japan Agency for Medical Research and Development/ ; JP23ek0109617//Japan Agency for Medical Research and Development/ ; }, mesh = {Adult ; Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Serine C-Palmitoyltransferase/genetics ; *Neurodegenerative Diseases ; Sphingolipids ; Ceramides ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early-onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies.

METHODS: Our research commenced with an in-depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early-onset ALS (onset age of <40 years). This involved whole-exome sequencing, trio analysis, protein structure analysis, and sphingolipid measurements. Subsequently, we expanded our analysis to 62 probands with early-onset ALS and further included 440 patients with adult-onset ALS and 1163 healthy controls to assess the prevalence of identified genetic variants.

RESULTS: We identified heterozygous variants in the serine palmitoyltransferase long chain base subunit 2 (SPTLC2) gene in patients with early-onset ALS. These variants, located in a region closely adjacent to ORMDL3, bear similarities to SPTLC1 variants previously implicated in early-onset ALS. Patients with ALS carrying these SPTLC2 variants displayed elevated plasma ceramide levels, indicative of increased serine palmitoyltransferase (SPT) activity leading to sphingolipid overproduction.

INTERPRETATION: Our study revealed novel SPTLC2 variants in patients with early-onset ALS exhibiting frontotemporal dementia. The combination of genetic evidence and the observed elevation in plasma ceramide levels establishes a crucial link between dysregulated sphingolipid metabolism and ALS pathogenesis. These findings expand our understanding of ALS's genetic diversity and highlight the distinct roles of gene defects within SPT subunits in its development.}, } @article {pmid38317225, year = {2024}, author = {Liddell, JR and Hilton, JBW and Kysenius, K and Billings, JL and Nikseresht, S and McInnes, LE and Hare, DJ and Paul, B and Mercer, SW and Belaidi, AA and Ayton, S and Roberts, BR and Beckman, JS and McLean, CA and White, AR and Donnelly, PS and Bush, AI and Crouch, PJ}, title = {Microglial ferroptotic stress causes non-cell autonomous neuronal death.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {14}, pmid = {38317225}, issn = {1750-1326}, mesh = {Mice ; Animals ; Humans ; Microglia/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/metabolism ; *Neurodegenerative Diseases/metabolism ; Cell Death ; Disease Models, Animal ; }, abstract = {BACKGROUND: Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved.

METHODS: To elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). We utilised the SOD1[G37R] mouse model of ALS and a CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo.

RESULTS: We found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from human cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Further, we show the molecular correlation between ferroptosis and neurotoxic astrocytes evident in human ALS-affected spinal cord is recapitulated in the SOD1[G37R] mouse model where treatment with a CNS-permeant ferroptosis inhibitor, Cu[II](atsm), ameliorated these markers and was neuroprotective.

CONCLUSIONS: By showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.}, } @article {pmid38317639, year = {2024}, author = {Verma, S and Vats, A and Ahuja, V and Vats, K and Khurana, S and Vats, Y and Gourie-Devi, M and Wajid, S and Ganguly, NK and Chakraborti, P and Taneja, V}, title = {Functional consequences of familial ALS-associated SOD1[L84F] in neuronal and muscle cells.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {38}, number = {3}, pages = {e23461}, doi = {10.1096/fj.202301979R}, pmid = {38317639}, issn = {1530-6860}, support = {09/591(0150)/2018-EMR-I//Council of Scientific and Industrial Research, India (CSIR)/ ; 3/1/2/151/Neuro/2021-NCD-I//Indian Council of Medical Research (ICMR)/ ; 2020-2641/CMB/ADHOC-BMS//Indian Council of Medical Research (ICMR)/ ; 211610027970//University Grants Commission (UGC)/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Muscle Cells/metabolism ; Mutation ; *Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder characterized by progressive skeletal muscle denervation and loss of motor neurons that results in muscle atrophy and eventual death due to respiratory failure. Previously, we identified a novel SOD1[L84F] variation in a familial ALS case. In this study, we examined the functional consequences of SOD1[L84F] overexpression in the mouse motor neuron cell line (NSC-34). The cells expressing SOD1[L84F] showed increased oxidative stress and increased cell death. Interestingly, SOD1[L84F] destabilized the native dimer and formed high molecular weight SDS-resistant protein aggregates. Furthermore, SOD1[L84F] also decreased the percentage of differentiated cells and significantly reduced neurite length. A plethora of evidence suggested active involvement of skeletal muscle in disease initiation and progression. We observed differential processing of the mutant SOD1 and perturbations of cellular machinery in NSC-34 and muscle cell line C2C12. Unlike neuronal cells, mutant protein failed to accumulate in muscle cells probably due to the activated autophagy, as evidenced by increased LC3-II and reduced p62. Further, SOD1[L84F] altered mitochondrial dynamics only in NSC-34. In addition, microarray analysis also revealed huge variations in differentially expressed genes between NSC-34 and C2C12. Interestingly, SOD1[L84F] hampered the endogenous FUS autoregulatory mechanism in NSC-34 by downregulating retention of introns 6 and 7 resulting in a two-fold upregulation of FUS. No such changes were observed in C2C12. Our findings strongly suggest the differential processing and response towards the mutant SOD1 in neuronal and muscle cell lines.}, } @article {pmid38317984, year = {2024}, author = {Harvey, C and Weinreich, M and Lee, JAK and Shaw, AC and Ferraiuolo, L and Mortiboys, H and Zhang, S and Hop, PJ and Zwamborn, RAJ and van Eijk, K and Julian, TH and Moll, T and Iacoangeli, A and Al Khleifat, A and Quinn, JP and Pfaff, AL and Kõks, S and Poulton, J and Battle, SL and Arking, DE and Snyder, MP and , and Veldink, JH and Kenna, KP and Shaw, PJ and Cooper-Knock, J}, title = {Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis.}, journal = {Heliyon}, volume = {10}, number = {3}, pages = {e24975}, pmid = {38317984}, issn = {2405-8440}, support = {S10 OD025212/OD/NIH HHS/United States ; R56 NS073873/NS/NINDS NIH HHS/United States ; R01 NS073873/NS/NINDS NIH HHS/United States ; R01 HL101388/HL/NHLBI NIH HHS/United States ; P50 HL083800/HL/NHLBI NIH HHS/United States ; P30 DK116074/DK/NIDDK NIH HHS/United States ; R01 HL122939/HL/NHLBI NIH HHS/United States ; UM1 HG009442/HG/NHGRI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving selective vulnerability of energy-intensive motor neurons (MNs). It has been unclear whether mitochondrial function is an upstream driver or a downstream modifier of neurotoxicity. We separated upstream genetic determinants of mitochondrial function, including genetic variation within the mitochondrial genome or autosomes; from downstream changeable factors including mitochondrial DNA copy number (mtCN). Across three cohorts including 6,437 ALS patients, we discovered that a set of mitochondrial haplotypes, chosen because they are linked to measurements of mitochondrial function, are a determinant of ALS survival following disease onset, but do not modify ALS risk. One particular haplotype appeared to be neuroprotective and was significantly over-represented in two cohorts of long-surviving ALS patients. Causal inference for mitochondrial function was achievable using mitochondrial haplotypes, but not autosomal SNPs in traditional Mendelian randomization (MR). Furthermore, rare loss-of-function genetic variants within, and reduced MN expression of, ACADM and DNA2 lead to ∼50 % shorter ALS survival; both proteins are implicated in mitochondrial function. Both mtCN and cellular vulnerability are linked to DNA2 function in ALS patient-derived neurons. Finally, MtCN responds dynamically to the onset of ALS independently of mitochondrial haplotype, and is correlated with disease severity. We conclude that, based on the genetic measures we have employed, mitochondrial function is a therapeutic target for amelioration of disease severity but not prevention of ALS.}, } @article {pmid38318246, year = {2024}, author = {Izquierdo-Condoy, JS and Arias Rodríguez, FD and Duque-Sánchez, E and Alegría N, N and Rojas Cadena, M and Naranjo-Lara, P and Mendoza, AP and Jima-Sanmartín, J and Casanova, DA and García, B and Giraldo, NC}, title = {Assessment of preparedness and proficiency in basic and advanced life support among nursing professionals: a cross-sectional study.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1328573}, pmid = {38318246}, issn = {2296-858X}, abstract = {BACKGROUND: Cardiac diseases are among the leading causes of death worldwide, including sudden cardiac arrest in particular. Nursing professionals are often the first to encounter these scenarios in various settings. Adequate preparation and competent knowledge among nurses significantly impact survival rates positively.

AIM: To describe the state of knowledge about Basic and Advanced Life Support guidelines among Ecuadorian nursing professionals.

METHODOLOGY: A nationwide, descriptive, cross-sectional study was conducted from February to April 2023 among Ecuadorian nursing professionals. Participants were invited through official social media groups such as WhatsApp and Facebook. The study utilized a self-administered online questionnaire to evaluate theoretical knowledge of Basic Life Support (BLS) and Advanced Life Support (ALS). Knowledge scores were assigned based on the number of correct answers on the tests. T-tests and one-way ANOVA were used to examine relationships between knowledge scores and demographic and academic training variables.

RESULTS: A total of 217 nursing professionals participated in the study. The majority of the participants were female (77.4%) and held a university degree (79.9%). Among them, only 44.7% claimed to have obtained a BLS training certificate at least once, and 19.4% had ALS certification. The overall BLS knowledge score (4.8/10 ± 1.8 points) was higher than the ALS score (4.3/10 ± 1.8 points). Participants who had obtained BLS certification and those who used evidence-based summaries as a source of extracurricular training achieved higher BLS and ALS knowledge scores.

CONCLUSION: Ecuadorian nursing professionals in this study exhibited a significant deficiency in theoretical knowledge of BLS and ALS. Formal training and preparation positively impact life support knowledge. Support and inclusion of Ecuadorian nurses in training and academic preparation programs beginning at the undergraduate level are essential for promoting life support knowledge and improving outcomes.}, } @article {pmid38318390, year = {2024}, author = {Komine, O and Ohnuma, S and Hinohara, K and Hara, Y and Shimada, M and Akashi, T and Watanabe, S and Sobue, A and Kawade, N and Ogi, T and Yamanaka, K}, title = {Genetic background variation impacts microglial heterogeneity and disease progression in amyotrophic lateral sclerosis model mice.}, journal = {iScience}, volume = {27}, number = {2}, pages = {108872}, pmid = {38318390}, issn = {2589-0042}, abstract = {Recent single-cell analyses have revealed the complexity of microglial heterogeneity in brain development, aging, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Disease-associated microglia (DAMs) have been identified in ALS mice model, but their role in ALS pathology remains unclear. The effect of genetic background variations on microglial heterogeneity and functions remains unknown. Herein, we established and analyzed two mice models of ALS with distinct genetic backgrounds of C57BL/6 and BALB/c. We observed that the change in genetic background from C57BL/6 to BALB/c affected microglial heterogeneity and ALS pathology and its progression, likely due to the defective induction of neurotrophic factor-secreting DAMs and impaired microglial survival. Single-cell analyses of ALS mice revealed new markers for each microglial subtype and a possible association between microglial heterogeneity and systemic immune environments. Thus, we highlighted the role of microglia in ALS pathology and importance of genetic background variations in modulating microglial functions.}, } @article {pmid38318443, year = {2024}, author = {Plasencia-Salini, R and Havens, AP and Miller, KM}, title = {Biometry challenges in the longest eyes we have encountered to date.}, journal = {American journal of ophthalmology case reports}, volume = {33}, number = {}, pages = {101997}, pmid = {38318443}, issn = {2451-9936}, abstract = {PURPOSE: This report aims to present biometry challenges and solutions for a patient with the longest eyes we have encountered to date.

OBSERVATIONS: A 41-year-old woman with a history of Crouzon syndrome, extreme axial myopia, and posterior segment staphylomas was referred for cataract evaluation. Optical biometry was attempted using two partial coherence interferometry and optical low-coherence reflectometry devices that were available in 2011. Neither device could measure the axial length (AL) of either eye, unfortunately. We were able to measure them by A scan ultrasound, however, with results of 40.59 mm for the right eye and 38.29 mm for the left eye. Shortly thereafter, she underwent uncomplicated phacoemulsification with posterior chamber intraocular lens implantation under topical anesthesia. Twelve years later, she returned for repeat optical biometry with 3 newer generation devices, 2 of which utilized swept-source optical coherence tomography (SS-OCT). Only 1 SS-OCT device, the Argos biometer, was able to obtain AL measurements, and they were 40.54 mm and 40.84 mm for the right and left eyes, respectively.

CONCLUSIONS AND IMPORTANCE: Biometry measurement using optical biometers on a patient with ALs greater than 40 mm was impossible in 2011 because of the relatively short gate for acceptable readings. Ultrasound biometry can also be challenging due to the presence of posterior staphylomas. However, a newer SS-OCT with a longer AL measurement capability enabled readings to be obtained more recently.}, } @article {pmid38318532, year = {2024}, author = {Geng, Y and Cai, Q}, title = {Role of C9orf72 hexanucleotide repeat expansions in ALS/FTD pathogenesis.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1322720}, pmid = {38318532}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurological disorders that share neurodegenerative pathways and features. The most prevalent genetic causes of ALS/FTD is the GGGGCC hexanucleotide repeat expansions in the first intron region of the chromosome 9 open reading frame 72 (C9orf72) gene. In this review, we comprehensively summarize the accumulating evidences elucidating the pathogenic mechanism associated with hexanucleotide repeat expansions in ALS/FTD. These mechanisms encompass the structural polymorphism of DNA and transcribed RNA, the formation of RNA foci via phase separation, and the cytoplasmic accumulation and toxicities of dipeptide-repeat proteins. Additionally, the formation of G-quadruplex structures significantly impairs the expression and normal function of the C9orf72 protein. We also discuss the sequestration of specific RNA binding proteins by GGGGCC RNA, which further contributes to the toxicity of C9orf72 hexanucleotide repeat expansions. The deeper understanding of the pathogenic mechanism of hexanucleotide repeat expansions in ALS/FTD provides multiple potential drug targets for these devastating diseases.}, } @article {pmid38318827, year = {2024}, author = {Motamedy, S and Soltani, B and Kameshki, H and Kermani, AA and Amleshi, RS and Nazeri, M and Shabani, M}, title = {The Therapeutic Potential and Molecular Mechanisms Underlying the Neuroprotective Effects of Sativex[®] - A Cannabis-derived Spray.}, journal = {Mini reviews in medicinal chemistry}, volume = {24}, number = {15}, pages = {1427-1448}, pmid = {38318827}, issn = {1875-5607}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Cannabidiol/pharmacology/therapeutic use/chemistry ; *Plant Extracts/chemistry/pharmacology ; *Dronabinol/pharmacology/chemistry/therapeutic use ; Animals ; Multiple Sclerosis/drug therapy ; Cannabis/chemistry ; Drug Combinations ; }, abstract = {Sativex is a cannabis-based medicine that comes in the form of an oromucosal spray. It contains equal amounts of Δ9-tetrahydrocannabinol and cannabidiol, two compounds derived from cannabis plants. Sativex has been shown to have positive effects on symptoms of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and sleep disorders. It also has analgesic, antiinflammatory, antitumoral, and neuroprotective properties, which make it a potential treatment option for other neurological disorders. The article reviews the results of recent preclinical and clinical studies that support the therapeutic potential of Sativex and the molecular mechanisms behind its neuroprotective benefits in various neurological disorders. The article also discusses the possible advantages and disadvantages of using Sativex as a neurotherapeutic agent, such as its safety, efficacy, availability, and legal status.}, } @article {pmid38318860, year = {2024}, author = {Jhooty, S and Barkhaus, P and Brown, A and Mascias Cadavid, J and Carter, GT and Crayle, J and Heiman-Patterson, T and Li, X and Mallon, E and Mcdermott, C and Mushannen, T and Pattee, G and Ratner, D and Wicks, P and Wiedau, M and Bedlack, R}, title = {ALSUntangled #74: Withania Somnifera (Ashwagandha).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {805-808}, doi = {10.1080/21678421.2024.2311721}, pmid = {38318860}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Withania ; Animals ; *Plant Extracts/therapeutic use ; Phytotherapy/methods ; }, abstract = {ALSUntangled reviews alternative and off-label treatments on behalf of people with ALS (PALS) who ask about them. Here, we review withania somnifera (WS) commonly known as ashwagandha or winter cherry. WS has plausible mechanisms for slowing ALS progression because of its effects on inflammation, oxidative stress, autophagy, mitochondrial function, and apoptosis. Preclinical trials demonstrate that WS slows disease progression in multiple different animal models of ALS. Of the five individuals we found who described using WS for their ALS, two individuals reported moderate benefit while none reported experiencing any significant side effects. There is currently one clinical trial using WS to treat PALS; the results are not yet published. There are no serious side effects associated with WS and the associated cost of this treatment is low. Based on the above information, WS appears to us to be a good candidate for future ALS trials.}, } @article {pmid38320749, year = {2024}, author = {Lee, I and Nandakumar, R and Haeusler, RA}, title = {Alteration of serum bile acids in amyotrophic lateral sclerosis.}, journal = {Lipids}, volume = {59}, number = {4}, pages = {85-91}, pmid = {38320749}, issn = {1558-9307}, support = {K23NS131586/NH/NIH HHS/United States ; R01 DK115825/DK/NIDDK NIH HHS/United States ; //American Brain Foundation/ ; //American Academy of Neurology/ ; ULTR001873//National Center for Advancing Translational Sciences, National Institutes of Health/ ; K23 NS131586/NS/NINDS NIH HHS/United States ; R01DK115825/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics ; Male ; Female ; Middle Aged ; *Bile Acids and Salts/blood ; Case-Control Studies ; Adult ; Aged ; }, abstract = {Hydrophilic endogenous bile acids ursodeoxycholic acid (UDCA), tauroursodeoxycholic acid (TUDCA), and glucourosodeoxycholic acid (GUDCA) have suggested neuroprotective effects. We performed a case-control study to examine the association between ALS diagnosis and serum levels of bile acids. Sporadic and familial ALS patients, age- and sex-matched healthy controls, and presymptomatic gene carriers who donated blood samples were included. Non-fasted serum samples stored at -80°C were used for the analysis. Serum bile acid levels were measured by liquid chromatography-mass spectrometry (LC-MS). Concentrations of 15 bile acids were obtained, 5 non-conjugated and 10 conjugated, and compared between ALS versus control groups (presymptomatic gene carriers + healthy controls) using the Wilcoxon-Rank-Sum test. In total, 80 participants were included: 31 ALS (17 sporadic and 14 familial ALS); 49 controls (22 gene carriers, 27 healthy controls). The mean age was 50 years old and 50% were male. In the ALS group, 45% had familial disease with a pathogenic variant in C9orf72 (29%), TARDBP (10%), FUS (3%), and CHCHD10 (3%) genes. In the control group, 43% carried pathogenic variants: C9orf72 (27%), SOD1 (10%), and FUS (6%). The serum levels of UDCA, TUDCA, and GUDCA trended higher in the ALS group compared to controls (median 27 vs. 7 nM, 4 vs. 3 nM, 110 vs. 47 nM, p-values 0.04, 0.06, 0.04, respectively). No significant group differences were found in other bile acids serum levels. In conclusion, the serum level of UDCA, TUDCA, GUDCA trended higher in ALS patients compared to controls, and no evidence of deficiencies was found.}, } @article {pmid38320753, year = {2024}, author = {Khan, M and Chen, XXL and Dias, M and Santos, JR and Kour, S and You, J and van Bruggen, R and Youssef, MMM and Wan, YW and Liu, Z and Rosenfeld, JA and Tan, Q and Pandey, UB and Yalamanchili, HK and Park, J}, title = {MATR3 pathogenic variants differentially impair its cryptic splicing repression function.}, journal = {FEBS letters}, volume = {598}, number = {4}, pages = {415-436}, doi = {10.1002/1873-3468.14806}, pmid = {38320753}, issn = {1873-3468}, support = {58-3092-0-001//National Institute of Food and Agriculture/ ; //Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Exons/genetics ; RNA-Binding Proteins/genetics/metabolism ; RNA ; Nuclear Matrix-Associated Proteins/genetics ; }, abstract = {Matrin-3 (MATR3) is an RNA-binding protein implicated in neurodegenerative and neurodevelopmental diseases. However, little is known regarding the role of MATR3 in cryptic splicing within the context of functional genes and how disease-associated variants impact this function. We show that loss of MATR3 leads to cryptic exon inclusion in many transcripts. We reveal that ALS-linked S85C pathogenic variant reduces MATR3 solubility but does not impair RNA binding. In parallel, we report a novel neurodevelopmental disease-associated M548T variant, located in the RRM2 domain, which reduces protein solubility and impairs RNA binding and cryptic splicing repression functions of MATR3. Altogether, our research identifies cryptic events within functional genes and demonstrates how disease-associated variants impact MATR3 cryptic splicing repression function.}, } @article {pmid38321352, year = {2024}, author = {Sathyamurthy, VH and Nagarajan, Y and Parvathi, VD}, title = {Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS): A New Axis in Neuronal Degeneration and Regeneration.}, journal = {Molecular neurobiology}, volume = {61}, number = {9}, pages = {6528-6538}, pmid = {38321352}, issn = {1559-1182}, mesh = {Humans ; Animals ; *Mitochondria/metabolism ; *Endoplasmic Reticulum/metabolism ; Nerve Degeneration/pathology ; Nerve Regeneration/physiology ; Neurons/metabolism/pathology ; Neurodegenerative Diseases/metabolism/pathology ; Mitochondria Associated Membranes ; }, abstract = {Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS) are dynamic structures whose physiological interaction is vital to direct life and death of the cell. A bevy of tethering proteins, mitofusin-1/2 (Mfn-1/2), glucose-regulated protein-75 (Grp-75), voltage-dependent anion channel-1 (VDAC1), and dynamic-related protein-1 (Drp1), plays an integral role in establishing and regulating this intricate intracellular communication. Dysregulation of this interplay leads to various neurodegenerative disorders, like Alzheimer's disease (AD), Parkinson's disease (PD), stroke, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Although there is an absence of a well-defined molecular background that dictates the pathway of MERCS, adequate exploration has resulted in preliminary data that suggests its cardinal role in neuroregeneration. The juxtaposition of mitochondria and ER has a critical function in cell senescence, thus regulating regeneration. Axonal regeneration and brain tissue regeneration, using reactive astrocytes, are studied most extensively. Overexpression of Grp-75 promoted axonal regeneration post a nerve injury. Attempts have been made to exploit MERCS as potential therapeutic drug targets for enhancing neuroregeneration and impeding neurodegeneration. Novel strategies have been developed to aid the delivery of mitochondria into the neuronal cell body, which in turn establishes a network with the presiding ER resulting in contact site formation. The fascinating aspect of this mechanism is that despite the lack of inherent regenerative capacity in neurons, it can be induced by modifying MERCS.}, } @article {pmid38322130, year = {2023}, author = {Polverino, F and Sampaolo, S and Capuozzo, A and Fasolino, M and Aliberti, M and Satta, E and Santoriello, C and Polverino, M}, title = {Diagnosis of amyotrophic lateral sclerosis by respiratory function test.}, journal = {Multidisciplinary respiratory medicine}, volume = {18}, number = {1}, pages = {941}, pmid = {38322130}, issn = {1828-695X}, abstract = {The diagnostic criterion for amyotrophic lateral sclerosis (ALS) based on the findings of concomitant clinical and electrophysiological evidence of upper and lower motor neuron involvement may remain unsatisfied for months and in some patients, even for years in the early stage of the disease. Since respiratory involvement is an onset symptom of ALS in only 1-3% of patients, pulmonary assessment has never been considered useful in the early diagnosis of ALS. However, studies on pulmonary function are lacking, especially in those early stages where neurologic tests are also inconclusive. In contrast to the scarcity of data in the early stages, as the disease progresses, it is increasingly enriched by a rich set of symptoms and positive respiratory tests until respiratory failure occurs, which represents the main cause of death in ALS. Hereby we analyze the main pulmonary function tests (PFT) in the various stages of the disease, up to the recent evidence for the possibility of an early diagnosis.}, } @article {pmid38323488, year = {2024}, author = {Downing, NR and Scafide, KN and Ali, Z and Hayat, MJ}, title = {Visibility of inflicted bruises by alternate light: Results of a randomized controlled trial.}, journal = {Journal of forensic sciences}, volume = {69}, number = {3}, pages = {880-887}, doi = {10.1111/1556-4029.15481}, pmid = {38323488}, issn = {1556-4029}, support = {2016-DN-BX-0147//National Institute of Justice, Office of Justice Programs, U.S. Department of Justice/ ; }, mesh = {Humans ; *Contusions/pathology ; Male ; Female ; Adult ; *Cross-Over Studies ; *Skin Pigmentation ; *Light ; Young Adult ; Middle Aged ; }, abstract = {Difficulty visualizing bruises resulting from interpersonal violence, especially in individuals with dark skin, contributes to disparities in access to justice. The purpose of this analysis was to compare bruise visibility of detected injuries using white light versus alternate light sources (ALS). Visibility was assessed using the 5-point Bruise Visibility Scale (BVS) for white light and the ALS Visibility Scale (AVS) for ALS. Bruises were induced using controlled application of a paintball to the upper arm on 157 healthy adults across six skin color categories. Using a crossover design, the light source used first to assess the bruise (white light or ALS) was randomized. Each bruise was examined up to 21 times over 4 weeks using white light and 10 combinations of wavelengths (350 nanometer [nm] - 535 nm) and colored filters (yellow, orange, and red). Multilevel modeling was used to analyze the repeated measures data with a total 20,103 bruise assessments. Results revealed 415 nm with yellow filter resulted in an almost 0.5-point increase in BVS/AVS score across all skin colors (Estimate = 0.46; 95% CI: 0.43, 0.49; p < 0.001), a clinically significant improvement in ability to visualize bruises. Conversely, 515 nm (Estimate = -0.80; 95% CI: -0.84, -0.76; p < 0.001) and 535 nm (Estimate = -0.64, 95% CI: -0.67, -0.60; p < 0.001) with red filter resulted in more than 0.5-point decrease in BVS/AVS score. The use of ALS is supported by the data and results in improved bruise visibility during medical forensic examinations.}, } @article {pmid38323575, year = {2024}, author = {Hamatani, T and Atsuta, N and Sano, F and Nakamura, R and Hayashi, Y and Sobue, G}, title = {ALSFRS-R decline rate prior to baseline is not useful for stratifying subsequent progression of functional decline.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {388-399}, doi = {10.1080/21678421.2024.2309989}, pmid = {38323575}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Disease Progression ; Prognosis ; Registries ; Databases, Factual ; }, abstract = {OBJECTIVE: One of the difficulties in developing a novel drug for patients with amyotrophic lateral sclerosis (ALS) is the significant variation in the clinical course. To control this variation, a 12-week run-in period is used in some clinical trials. Based on the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) change during the run-in period, only moderate progressors are selected in some clinical trials. Some reports showed that the ALSFRS-R progression rate was associated with survival. However, it is unclear whether the ALSFRS-R change in the run-in period is a useful prognostic factor of the ALSFRS-R change from baseline. In addition, we explore the inclusion criteria that could control the variability in ALS-function progression without setting a run-in period.

METHODS: We utilized the Japanese and US ALS registry databases (JaCALS and PRO-ACT). Patients were classified into three populations (rapid, moderate, and slow progressors) based on the ALSFRS-R change prior to baseline. We also classified patients into three prognostic populations based on the ALSFRS-R change from baseline. We confirmed whether each of the three populations were matched with their respective three prognostic populations.

RESULTS: Our data showed that the three groups classified by the ALSFRS-R change during the 12 weeks prior to baseline or by the rate of progression from onset to baseline did not accord with the three prognostic groups.

CONCLUSIONS: Our results showed that the ALSFRS-R change in the run-in period or from onset to baseline is not useful for stratifying subsequent progression of functional decline in clinical trials.}, } @article {pmid38323662, year = {2024}, author = {Garcés, P and Amaro, A and Montecino, M and van Zundert, B}, title = {Inorganic polyphosphate: from basic research to diagnostic and therapeutic opportunities in ALS/FTD.}, journal = {Biochemical Society transactions}, volume = {52}, number = {1}, pages = {123-135}, doi = {10.1042/BST20230257}, pmid = {38323662}, issn = {1470-8752}, mesh = {Animals ; Mice ; Humans ; *Frontotemporal Dementia/metabolism/therapy ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/metabolism ; Polyphosphates ; *Alzheimer Disease ; *Parkinson Disease ; Mammals ; }, abstract = {Inorganic polyphosphate (polyP) is a simple, negatively charged biopolymer with chain lengths ranging from just a few to over a thousand ortho-phosphate (Pi) residues. polyP is detected in every cell type across all organisms in nature thus far analyzed. Despite its structural simplicity, polyP has been shown to play important roles in a remarkably broad spectrum of biological processes, including blood coagulation, bone mineralization and inflammation. Furthermore, polyP has been implicated in brain function and the neurodegenerative diseases amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease and Parkinson's disease. In this review, we first address the challenges associated with identifying mammalian polyP metabolizing enzymes, such as Nudt3, and quantifying polyP levels in brain tissue, cultured neural cells and cerebrospinal fluid. Subsequently, we focus on recent studies that unveil how the excessive release of polyP by human and mouse ALS/FTD astrocytes contributes to these devastating diseases by inducing hyperexcitability, leading to motoneuron death. Potential implications of elevated polyP levels in ALS/FTD patients for innovative diagnostic and therapeutic approaches are explored. It is emphasized, however, that caution is required in targeting polyP in the brain due to its diverse physiological functions, serving as an energy source, a chelator for divalent cations and a scaffold for amyloidogenic proteins. Reducing polyP levels, especially in neurons, might thus have adverse effects in brain functioning. Finally, we discuss how activated mast cells and platelets also can significantly contribute to ALS progression, as they can massively release polyP.}, } @article {pmid38324041, year = {2024}, author = {Harris, CM and Higgins, C and Mehta, AK}, title = {Trends in Specialty Palliative Care Service Utilization and In-Hospital Outcomes for Patients With Amyotrophic Lateral Sclerosis.}, journal = {Journal of palliative medicine}, volume = {27}, number = {4}, pages = {521-525}, doi = {10.1089/jpm.2023.0444}, pmid = {38324041}, issn = {1557-7740}, mesh = {Humans ; United States ; *Palliative Care ; *Amyotrophic Lateral Sclerosis/therapy ; Hospitals ; Hospitalization ; Patients ; }, abstract = {Background: Hospitalized people with amyotrophic lateral sclerosis (ALS) may benefit from specialty palliative care services (sPCS). Objective: To describe access to in-hospital sPCS for people with ALS (pALS). Methods: We compared years 2010-2011 to 2018-2019, and conducted trend analyses of sPCS from 2010 to 2019 stratified by race. Results: Of 103,193 pALS admitted during the study period, 13,885 (13.4%) received sPCS. Rates of sPCS increased over time (2010-2011: 8.9% vs. 2018-2019: 16.6%; p < 0.01). From 2010 to 2019, there was an increase in sPCS (p-trend<0.01) for all studied racial groups. Conclusions: Access to palliative care has increased over time for pALS admitted to hospitals in the United States.}, } @article {pmid38324182, year = {2024}, author = {Jiang, Z and Gu, XJ and Su, WM and Duan, QQ and Yin, KF and Ren, YL and Wang, Y and Cao, B and Chen, YP}, title = {Discovery and Exploration of Lipid-Modifying Drug Targets for ALS by Mendelian Randomization.}, journal = {Molecular neurobiology}, volume = {61}, number = {9}, pages = {6572-6583}, pmid = {38324182}, issn = {1559-1182}, support = {2022YFC2703101//the National Key Research and Development Program of China/ ; 2022NSFSC0749//the National Natural Science Fund of Sichuan/ ; 2021YFS0051//the Science and Technology Bureau Fund of Sichuan Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Mendelian Randomization Analysis ; Phenotype ; Drug Discovery ; Polymorphism, Single Nucleotide/genetics ; Lipids/blood ; Molecular Targeted Therapy ; Genetic Predisposition to Disease ; }, abstract = {Observational studies have faced challenges in identifying replicable causes for amyotrophic lateral sclerosis (ALS). To address this, we employed an unbiased and data-driven approach to discover and explore potential causal exposures using two-sample Mendelian randomization (MR) analyses. In the phenotype discovery stage, we assessed 3948 environmental exposures from the UK Biobank and utilized ALS summary statistics (Europeans, 20,806 cases, 59,804 controls) as the outcome within a phenome-wide MR pipeline. Through a range of sensitivity analyses, two medication traits were identified to be protective for ALS. In the target exploration stage, we further conducted drug target MR analyses using the latest and trans-ethnic summary data on lipid-related traits and ALS (Europeans, 27,205 cases, 110,881 controls; East Asians, 1234 cases, 2850 controls). Our aim was to explore potential causal drug targets through six lipid-modifying effects. These comprehensive analyses revealed significant findings. Specifically, "cholesterol-lowering medication" and "atorvastatin" survived predefined criteria in the phenotype discovery stage and exhibited a protective effect on ALS. Further in the target exploration stage, we demonstrated that the therapeutic effect of APOB through LDL-lowering was associated with reduced ALS liability in Europeans (OR = 0.835, P = 5.61E - 5). Additionally, the therapeutic effect of APOA1 and LDLR through TC-lowering was associated with reduced ALS liability in East Asians (APOA1, OR = 0.859, P = 5.38E - 4; LDLR, OR = 0.910, P = 2.73E - 5). Overall, we propose potential protective effects of cholesterol-lowering drugs or statins on ALS risk from thousands of exposures. Our research also suggests APOB, APOA1, and LDLR as novel therapeutic targets for ALS and supports their potential protective mechanisms may be mediated by LDL-lowering or TC-lowering effects.}, } @article {pmid38325382, year = {2024}, author = {Yan, J and Wang, YM and Hellwig, A and Bading, H}, title = {TwinF interface inhibitor FP802 stops loss of motor neurons and mitigates disease progression in a mouse model of ALS.}, journal = {Cell reports. Medicine}, volume = {5}, number = {2}, pages = {101413}, pmid = {38325382}, issn = {2666-3791}, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; Superoxide Dismutase/metabolism/pharmacology/therapeutic use ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Disease Models, Animal ; Disease Progression ; *TRPM Cation Channels ; }, abstract = {Toxic signaling by extrasynaptic NMDA receptors (eNMDARs) is considered an important promoter of amyotrophic lateral sclerosis (ALS) disease progression. To exploit this therapeutically, we take advantage of TwinF interface (TI) inhibition, a pharmacological principle that, contrary to classical NMDAR pharmacology, allows selective elimination of eNMDAR-mediated toxicity via disruption of the NMDAR/TRPM4 death signaling complex while sparing the vital physiological functions of synaptic NMDARs. Post-disease onset treatment of the SOD1[G93A] ALS mouse model with FP802, a modified TI inhibitor with a safe pharmacology profile, stops the progressive loss of motor neurons in the spinal cord, resulting in a reduction in the serum biomarker neurofilament light chain, improved motor performance, and an extension of life expectancy. FP802 also effectively blocks NMDA-induced death of neurons in ALS patient-derived forebrain organoids. These results establish eNMDAR toxicity as a key player in ALS pathogenesis. TI inhibitors may provide an effective treatment option for ALS patients.}, } @article {pmid38325473, year = {2024}, author = {Xu, Y and Nie, J and Lu, C and Hu, C and Chen, Y and Ma, Y and Huang, Y and Lu, L}, title = {Effects and mechanisms of bisphenols exposure on neurodegenerative diseases risk: A systemic review.}, journal = {The Science of the total environment}, volume = {919}, number = {}, pages = {170670}, doi = {10.1016/j.scitotenv.2024.170670}, pmid = {38325473}, issn = {1879-1026}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/chemically induced ; *Alzheimer Disease ; *Parkinson Disease/etiology/metabolism ; Brain/metabolism ; Oxidative Stress/physiology ; }, abstract = {Environmental bisphenols (BPs) pose a global threat to human health because of their extensive use as additives in plastic products. BP residues are increasing in various environmental media (i.e., water, soil, and indoor dust) and biological and human samples (i.e., serum and brain). Both epidemiological and animal studies have determined an association between exposure to BPs and an increased risk of neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis), including cognitive abnormalities and behavioral disturbances. Hence, understanding the biological responses to different BPs is essential for prevention, and treatment. This study provides an overview of the underlying pathogenic molecular mechanisms as a valuable basis for understanding neurodegenerative disease responses to BPs, including accumulation of misfolded proteins, reduction of tyrosine hydroxylase and dopamine, abnormal hormone signaling, neuronal death, oxidative stress, calcium homeostasis, and inflammation. These findings provide new insights into the neurotoxic potential of BPs and ultimately contribute to a comprehensive health risk evaluation.}, } @article {pmid38325718, year = {2024}, author = {Cuevas, EP and Martinez-Gonzalez, L and Gordillo, C and Tosat-Bitrián, C and Pérez de la Lastra, C and Sáenz, A and Gil, C and Palomo, V and Martin-Requero, Á and Martinez, A}, title = {Casein kinase 1 inhibitor avoids TDP-43 pathology propagation in a patient-derived cellular model of amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {192}, number = {}, pages = {106430}, doi = {10.1016/j.nbd.2024.106430}, pmid = {38325718}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Casein Kinase I ; *Neurodegenerative Diseases ; *Neuroblastoma ; DNA-Binding Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease without a cure to reverse its progression. Its main hallmark is the nuclear protein TDP-43, which undergoes different post-translational modifications leading to a loss of function in the nucleus and an increase in toxicity in the cytoplasm. Previous reports have indicated that pathogenic TDP-43 exhibits prion-like propagation in various contexts. With the aim of advancing therapeutics focused on preventing the propagation of TDP-43 pathology, we studied the potential role of pathogenic TDP-43 in lymphoblasts from sporadic ALS patients. We used lymphoblastoid cell lines from sporadic ALS patients as a source of pathogenic forms of TDP-43, and healthy human cells (lymphoblasts, myoblasts, neuroblastoma SH-SY5Y, or osteosarcoma U2OS) as recipient cells to investigate the seeding and spread of TDP-43 proteinopathy. Furthermore, we evaluated the potential of targeting TDP-43 phosphorylation with a CK-1 inhibitor to prevent the propagation of the pathology. The results presented herein indicate that pathogenic forms of TDP-43 are secreted into the extracellular medium of sporadic ALS lymphoblasts and could be transported by extracellular vesicles, spreading TDP-43 pathology to healthy cells. Moreover, tunneling nanotubes have also been discovered in pathological cells and may be involved in the transport of TDP-43. Interestingly, targeting TDP-43 phosphorylation with an in-house designed CK-1 inhibitor (IGS2.7) was sufficient to halt TDP-43 pathology transmission, in addition to its known effects on restoring the homeostasis of TDP-43 protein in patients-derived cells.}, } @article {pmid38328053, year = {2024}, author = {Yan, X and Kuster, D and Mohanty, P and Nijssen, J and Pombo-García, K and Rizuan, A and Franzmann, TM and Sergeeva, A and Passos, PM and George, L and Wang, SH and Shenoy, J and Danielson, HL and Honigmann, A and Ayala, YM and Fawzi, NL and Mittal, J and Alberti, S and Hyman, AA}, title = {Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38328053}, issn = {2692-8205}, support = {R01 NS114289/NS/NINDS NIH HHS/United States ; }, abstract = {Cytosolic aggregation of the nuclear protein TDP-43 is associated with many neurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstrate that TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond a threshold, and the other is oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to a dynamic TDP-43 enriched phase within stress granules, which subsequently transitions into pathological aggregates. Mechanistically, intra-condensate demixing is triggered by local unfolding of the RRM1 domain for intermolecular disulfide bond formation and by increased hydrophobic patch interactions in the C-terminal domain. By engineering TDP-43 variants resistant to intra-condensate demixing, we successfully eliminate pathological TDP-43 aggregates in cells. We conclude that up-concentration inside condensates and simultaneous exposure to environmental stress could be a general pathway for protein aggregation, with intra-condensate demixing constituting a key intermediate step.}, } @article {pmid38328059, year = {2024}, author = {Zeng, Y and Lovchykova, A and Akiyama, T and Liu, C and Guo, C and Jawahar, VM and Sianto, O and Calliari, A and Prudencio, M and Dickson, DW and Petrucelli, L and Gitler, AD}, title = {TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38328059}, issn = {2692-8205}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; R01 NS120992/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; T32 AG047126/AG/NIA NIH HHS/United States ; RF1 NS120992/NS/NINDS NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; R35 NS097263/NS/NINDS NIH HHS/United States ; }, abstract = {In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus. TDP-43 loss leads to cryptic exon inclusion but a role in other RNA processing events remains unresolved. Here, we show that loss of TDP-43 causes widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.}, } @article {pmid38328178, year = {2024}, author = {Arnold, FJ and Cui, Y and Michels, S and Colwin, MR and Stockford, C and Ye, W and Tam, OH and Menon, S and Situ, WG and Ehsani, KCK and Howard, S and Hammell, MG and Li, W and La Spada, AR}, title = {TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in ALS/FTD and related disorders.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.22.576709}, pmid = {38328178}, issn = {2692-8205}, support = {R01 NS118570/NS/NINDS NIH HHS/United States ; RF1 NS118570/NS/NINDS NIH HHS/United States ; }, abstract = {Nuclear clearance and cytoplasmic aggregation of the RNA-binding protein TDP-43 are observed in many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and fronto- temporal dementia (FTD). Although TDP-43 dysregulation of splicing has emerged as a key event in these diseases, TDP-43 can also regulate polyadenylation; yet, this has not been adequately studied. Here, we applied the dynamic analysis of polyadenylation from RNA-seq (DaPars) tool to ALS/FTD transcriptome datasets, and report extensive alternative polyadenylation (APA) upon TDP-43 alteration in ALS/FTD cell models and postmortem ALS/FTD neuronal nuclei. Importantly, many identified APA genes highlight pathways implicated in ALS/FTD pathogenesis. To determine the functional significance of APA elicited by TDP-43 nuclear depletion, we examined microtubule affinity regulating kinase 3 (MARK3). Nuclear loss of TDP-43 yielded increased expression of MARK3 transcripts with longer 3'UTRs, resulting in greater transcript stability and elevated MARK3 protein levels, which promotes increased neuronal tau S262 phosphorylation. Our findings define changes in polyadenylation site selection as a previously unrecognized feature of TDP-43-driven disease pathology in ALS/FTD and highlight a potentially novel mechanistic link between TDP-43 dysfunction and tau regulation.}, } @article {pmid38329887, year = {2024}, author = {Sanghai, N and Vuong, B and Burak Berk, A and Afridi, MSK and Tranmer, GK}, title = {Current Small Molecule-Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics.}, journal = {ChemMedChem}, volume = {19}, number = {9}, pages = {e202300705}, doi = {10.1002/cmdc.202300705}, pmid = {38329887}, issn = {1860-7187}, support = {//Department of Human Anatomy and Cell Science, University of Manitoba/ ; //College of Pharmacy, Department of Pharmacology & Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Small Molecule Libraries/chemistry/pharmacology/chemical synthesis ; *Neuroprotective Agents/chemistry/pharmacology/chemical synthesis ; Blood-Brain Barrier/metabolism/drug effects ; Chemistry, Pharmaceutical ; Molecular Structure ; }, abstract = {Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS) possess multifactorial aetiologies. In recent years, our understanding of the biochemical and molecular pathways across NDDs has increased, however, new advances in small molecule-based therapeutic strategies targeting NDDs are obscure and scarce. Moreover, NDDs have been studied for more than five decades, however, there is a paucity of drugs that can treat NDDs. Further, the highly lipoidal blood-brain barrier (BBB) limits the uptake of many therapeutic molecules into the brain and is a complicating factor in the development of new agents to treat neurodegeneration. Considering the highly complex nature of NDDs, the association of multiple risk factors, and the challenges to overcome the BBB junction, medicinal chemists have developed small organic molecule-based novel approaches to target NDDs over the last few decades, such as designing lipophilic molecules and applying prodrug strategies. Attempts have been made to utilize a multitarget approach to modulate different biochemical molecular pathways involved in NDDs, in addition to, medicinal chemists making better decisions in identifying optimized drug candidates for the central nervous system (CNS) by using web-based computational tools. To increase the clinical success of these drug candidates, an in vitro assay modeling the BBB has been utilized by medicinal chemists in the pre-clinical phase as a further screening measure of small organic molecules. Herein, we examine some of the intriguing strategies taken by medicinal chemists to design small organic molecules to combat NDDs, with the intention of increasing our awareness of neurodegenerative therapeutics.}, } @article {pmid38330475, year = {2024}, author = {Stavros, K}, title = {Genetic Myelopathies.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {30}, number = {1}, pages = {119-132}, pmid = {38330475}, issn = {1538-6899}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Muscular Atrophy, Spinal/diagnosis ; *Spastic Paraplegia, Hereditary/diagnosis ; *Spinal Cord Diseases/diagnosis/genetics/therapy ; }, abstract = {OBJECTIVE: This article provides an overview of genetic myelopathies, a diverse group of inherited, degenerative conditions that may be broadly categorized as motor neuron disorders, disorders of spinocerebellar degeneration, leukodystrophies, and hereditary spastic paraplegia. Clinical examples from each category are provided to illustrate the spectrum of genetic myelopathies and their distinguishing features that aid in differentiating genetic myelopathies from potentially treatable acquired causes of myelopathy.

LATEST DEVELOPMENTS: Advances in genetic testing have vastly enhanced current knowledge of genetic myelopathies and the ability to diagnose and provide appropriate counseling to patients and their families. However, potential health care disparities in access to genetic testing is a topic that must be further explored. Although treatment for most of these conditions is typically supportive, there have been recent therapeutic breakthroughs in treatments for amyotrophic lateral sclerosis, spinal muscular atrophy, and Friedreich ataxia.

ESSENTIAL POINTS: Genetic myelopathies may present with chronic and progressive symptoms, a family history of similar symptoms, and involvement of other structures outside of the spinal cord. Imaging often shows spinal cord atrophy, but cord signal change is rare. Exclusion of reversible causes of myelopathy is a key step in the diagnosis. There are many different causes of genetic myelopathies, and in some cases, symptoms may overlap, which underscores the utility of genetic testing in confirming the precise underlying neurologic condition.}, } @article {pmid38330924, year = {2024}, author = {Leedasawat, P and Sangvatanakul, P and Tungsukruthai, P and Kamalashiran, C and Phetkate, P and Patarajierapun, P and Sriyakul, K}, title = {The Efficacy and Safety of Chinese Eye Exercise of Acupoints in Dry Eye Patients: A Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {149-159}, doi = {10.1159/000536516}, pmid = {38330924}, issn = {2504-2106}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Acupuncture Points ; *Acupuncture Therapy/methods ; *Dry Eye Syndromes/therapy ; Single-Blind Method ; Thailand ; Treatment Outcome ; }, abstract = {INTRODUCTION: Dry eye disorder (DED) is a growing global issue linked to excessive digital screen time. Chinese eye exercise of acupoint (CEA), a set of self-massages on shared Chinese acupuncture (CA), has been used to reduce visual-related ocular symptoms and possibly as an alternative treatment for DED. This study aimed to assess the efficacy and safety of CEA.

METHODS: A single-blind randomized controlled trial was conducted at Thammasat University Hospital in Thailand, recruiting 56 participants aged 20-60 years, equally divided into two groups: the treatment group with CEA and the control group with standard lid hygiene treatment (STD). The intervention program lasted 12 weeks.

MAIN OUTCOME MEASURES: Ocular Surface Disease Index (OSDI), tear break-up time (TBUT), Schirmer-I test (SIT), corneal surface staining (CSS), and self-recorded forms for safety and adverse effects were measured at baseline, week 4, and week 12. An independent sample t test, paired t test, and repeated measures (ANOVA) were used to compare results between both groups, study visits, and primary and secondary outcome measurements, respectively. The p values <0.05 were considered statistically significant.

RESULTS: The characteristics were not statistically different between both groups at the baseline. The mean OSDI scores were significantly reduced in both groups at week 4 and week 12 compared to baseline (p value <0.05). Additionally, both CEA and STD showed significant improvement in TBUT and SIT (p value <0.05). CSS was significantly improved only in the CEA groups (p value <0.05). No significant differences were observed between the study groups, except for SIT at week 12 (p value <0.05). For the safety, there were no adverse side effects in either group.

CONCLUSION: CEA seemed to be as effective as STD in improving the OSDI, TBUT, and SIT of DED without causing any side effects.

UNLABELLED: EinleitungDas Trockene Auge (Dry eye disorder, DED) ist weltweit ein zunehmendes Problem, das mit übermässiger Bildschirmarbeit zusammenhängt. Die chinesische Augenübung der Akupunkturpunkte (Chinese eye exercise of acupoint, CEA), eine Reihe von Selbstmassagen an gemeinsamen CA-Akupunkturpunkten, wird zur Linderung visusbezogener Augensymptome und als mögliche alternative Behandlung für DED eingesetzt. Mit dieser Studie sollte die Wirksamkeit und Sicherheit von CEA bewertet werden.MethodenAm Thammasat-Universitätsklinikum in Thailand wurde eine einfach verblindete, randomisierte, kontrollierte Studie mit 56 Teilnehmern im Alter von 20 bis 60 Jahren durchgeführt, die zu gleichen Teilen zwei Gruppen zugewiesen wurden: die Behandlungsgruppe mit CEA und die Kontrollgruppe, die die Standard-Lidhygienebehandlung erhielt (STD). Das Interventionsprogramm dauerte 12 Wochen. Die Haupt-Zielkriterien, der Ocular Surface Disease Index (OSDI), die Tränenfilmaufreisszeit (tear break-up time, TBUT), der Schirmer-I-Test (SIT), das Corneal Surface Staining (CSS) und Selbstauskunftsformulare zur Sicherheit und zu unerwünschten Wirkungen wurden zu Beginn der Behandlung, in Woche 4 und in Woche 12 ermittelt. Für den Vergleich der Ergebnisse zwischen den beiden Gruppen, den Studienvisiten bzw. den primären und sekundären Zielkriterien wurden ein t Test für unabhängige Stichproben, ein t Test für paarige Stichproben und eine ANOVA mit Messwiederholungen verwendet. p-Werte <0,05 galten als statistisch signifikant.ErgebnisseHinsichtlich der Merkmale bestand zwischen den beiden Gruppen kein statistischer Unterschied bei Studienbeginn. In beiden Gruppen fielen die mittleren OSDI-Scores in Woche 4 und Woche 12 im Vergleich zum Ausgangswert signifikant geringer aus (p-Wert <0,05). Darüber hinaus zeigten sowohl die CEA- als auch die STD-Gruppe eine signifikante Verbesserung der TBUT- und SIT-Werte (p-Wert <0,05). Das CSS verbesserte sich nur in der CEA-Gruppe signifikant (p-Wert <0,05). Zwischen den Studiengruppen waren keine signifikanten Unterschiede zu beobachten, ausser beim SIT in Woche 12 (p-Wert <0,05). Was die Sicherheit betrifft, so traten in beiden Gruppen keine unerwünschten Nebenwirkungen auf.SchlussfolgerungDie CEA schien die OSDI-, TBUT- und SIT-Werte bei DED ebenso wirksam zu verbessern wie die Standardbehandlung, ohne Nebenwirkungen zu verursachen.}, } @article {pmid38330929, year = {2024}, author = {Fronczek, M and Kopacz, K and Kopacz, Ł and Padula, G}, title = {The Role of Objective Movement Analysis in the Control of Yoga Asanas: A Case Study.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {201-209}, doi = {10.1159/000535312}, pmid = {38330929}, issn = {2504-2106}, mesh = {*Yoga ; Humans ; Female ; Adult ; Electromyography ; *Muscle, Skeletal/physiology ; *Postural Balance/physiology ; Movement/physiology ; Biomechanical Phenomena ; }, abstract = {INTRODUCTION: Yoga is classified as a form of complementary and alternative medicine. It can be used in many disciplines including physiotherapy, medicine, and sport. The objective of the study was to identify possible biomechanical problems during yoga practice and to minimize the risk of injury.

CASE PRESENTATION: Objective evaluation of the symmetry of asanas, balance, stability, and muscle tension was provided in case of a 37-year-old woman, practicing mainly aerial and Hatha yoga for 6 years. The bigger body tilt and deviations in center of pressure (COP) parameters were observed in tadasana during forward examinations. In tadasana, the highest muscle activity was observed in the rectus femoris. In case of forward tadasana observation, the highest activity was found in the gastrocnemius and in the lumbar portion of the erector spinae. During backward tadasana trial, the most active were the tibialis anterior and rectus femoris muscles. In garudasana and natarajasana, the symmetry of the trunk position in relation to the lower limbs was observed, regardless of the supporting limb. In the same way, COP parameters in garudasana were similar regardless of the supporting limb. However, in natarajasana, the higher COP displacement parameters were observed in the case of the nondominant supporting limb. As for the electromyographic evaluation of garudasana and natarajasana, the highest muscle activity was observed in the lumbar portion of the erector spinae. In chakrasana, a slightly greater angle of the hip extension was observed in the left hip. A higher muscle activity in chakrasana was observed in the lumbar portion of the right erector spinae. In sirsasana, no significant displacements of the cervical spine were observed, but a higher activity of the left sternocleidomastoid muscle was found.

CONCLUSION: With the use of objective movement analysis, possible biomechanical problems were identified. Attention should be paid to the normalization of the tension in the lumbar part of the right erector spinae and the right sternocleidomastoid muscle, as well as to the balance training in positions on the nondominant lower limb. Objective movement analysis can be a useful tool for instructors or physiotherapists to adjust yoga programs and correct asanas in order to avoid future injuries.

UNLABELLED: EinleitungYoga gilt als Form der Komplementär- und Alternativmedizin. Es ist in vielen Disziplinen einsetzbar, von Physiotherapie über Medizin bis Sport. Das Ziel dieser Studie war es, mögliche biomechanische Probleme bei der Ausübung von Yoga zu identifizieren, um das Verletzungsrisiko zu minimieren.Vorstellung des FallsEine objektive Beurteilung der Symmetrie der Asanas, des Gleichgewichts, der Stabilität und der Muskelspannung erfolgte bei einer 37-jährigen Frau, die seit 6 Jahren hauptsächlich Aerial- und Hatha-Yoga praktiziert. Stärkere Körperneigung und Abweichungen bei Druckmittelpunkt-Parametern wurden in Tadasana bei der Vorwärts-Beobachtung festgestellt. In Tadasana wurde die höchste Muskelaktivität im Rectus femoris beobachtet. Bei der Tadasana-Vorwärts-Beobachtung war die höchste Aktivität im Gastrocnemius und im lumbalen Anteil des Erector spinae zu verzeichnen. Während der Tadasana-Rückwärts-Übung waren die aktivsten Muskeln der Tibialis anterior und Rectus femoris. In Garudasana und Natarajasana wurde die Symmetrie der Rumpfposition im Verhältnis zu den unteren Gliedmaßen unabhängig von der belasteten Gliedmaße beobachtet. Ebenso waren die Parameter des Druckmittelpunkts (DMP) in Garudasana unabhängig von der belasteten Gliedmaße vergleichbar. In Natarajasana wurden jedoch höhere Parameter der DMP-Verschiebung bei der nicht-dominanten belasteten Gliedmaße beobachtet. Bei der elektromyografischen Auswertung von Garudasana und Natarajasana wurde die höchste Muskelaktivität im lumbalen Anteil des Erector spinae beobachtet. In Chakrasana wurde ein etwas größerer Winkel der Hüftstreckung im linken Hüftgelenk beobachtet. Eine höhere Muskelaktivität in Chakrasana wurde im lumbalen Anteil des rechten Erector spinae beobachtet. In Sirsasana wurden keine signifikanten Verschiebungen der Halswirbelsäule beobachtet, jedoch war eine höhere Aktivität des linken Sternocleidomastoideus zu verzeichnen.SchlussfolgerungMit Hilfe einer objektiven Bewegungsanalyse wurden mögliche biomechanische Probleme identifiziert. Mit besonderer Aufmerksamkeit sollte auf die Normalisierung der Spannung im lumbalen Anteil des rechten Erector spinae und des rechten Sternocleidomastoideus sowie auf die Schulung des Gleichgewichts in Positionen auf der nicht-dominanten unteren Extremität geachtet werden. Die objektive Bewegungsanalyse kann ein nützliches Instrument für Instruktoren oder Physiotherapeuten sein, um Yoga-Programme anzupassen und Asanas zu korrigieren, um Verletzungen vorzubeugen.}, } @article {pmid38330934, year = {2024}, author = {Yang, L and Li, Y and Zhang, S and Qian, H and Xu, W and Yu, J}, title = {Efficacy of Acupuncture Combined with Traditional Chinese Medicine Fumigation Therapy in Sequelae of Pelvic Inflammatory Disease: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {175-186}, doi = {10.1159/000536101}, pmid = {38330934}, issn = {2504-2106}, mesh = {Humans ; *Acupuncture Therapy/methods ; *Fumigation/methods ; *Medicine, Chinese Traditional/methods ; *Pelvic Inflammatory Disease/therapy ; Combined Modality Therapy ; Female ; }, abstract = {BACKGROUND AND OBJECTIVE: Acupuncture combined with traditional Chinese medicine fumigation is increasingly being used in treating sequelae of pelvic inflammatory disease (SPID). However, there is a lack of meta-analysis on the effectiveness of acupuncture combined with traditional Chinese medicine fumigation in treating SPID. The aim of this study was to assess the feasibility of combining acupuncture with traditional Chinese medicine fumigation in the treatment of SPID.

METHODS: We searched eight databases for studies on acupuncture combined with traditional Chinese medicine fumigation for the treatment of SPID from the date of establishment to October 29, 2022. We assessed the quality of included studies by using the Cochrane bias risk tool. Pooled results were expressed as risk ratios (RRs), with a 95% confidence interval (CI). In addition, we identified sources of heterogeneity by sensitivity analysis, assessed publication bias by Egger's test, and assessed the quality of the evidence by Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). All statistical analyses were performed by Review Manager 5.3 and Stata 14.

RESULTS: Finally, seven studies with a total of 663 participants were included. We found a significant difference in the total effective rate in the acupuncture combined with the fumigation group compared with the acupuncture group in the treatment of SPID (RR = 1.17, 95% CI [1.09, 1.25], p = 0.0001 < 0.05; I2 = 0%; 6 trials), and a significant difference in the total effective rate in the acupuncture combined with fumigation group compared with the fumigation group in the treatment of SPID (RR = 1.42, 95% CI [1.21, 1.66], p = 0.0001 < 0.05; 5 trials).

CONCLUSION: The clinical efficacy of acupuncture combined with herbal fumigation in the treatment of SPID is relatively good. Larger scale studies are needed in the future.

UNLABELLED: Hintergrund und ZielAkupunktur in Kombination mit Fumigation, einem Verfahren der Traditionellen Chinesischen Medizin, wird zunehmend in der Behandlung von Folgeerscheinungen von Beckenentzündungen (SPID; sequelae of pelvic inflammatory disease) eingesetzt. Es mangelt jedoch an Metaanalysen zur Wirksamkeit der Akupunktur in Kombination mit Fumigation gemäß der Traditionellen Chinesischen Medizin in der Behandlung von SPID. Das Ziel dieser Studie ist die Beurteilung der Machbarkeit der Kombination aus Akupunktur und Fumigation gemäß der Traditionellen Chinesischen Medizin in der Behandlung von SPID.MethodenWir durchsuchten acht Datenbanken nach Studien zur Akupunktur in Kombination mit Fumigation gemäß der Traditionellen Chinesischen Medizin in der Behandlung von Folgeerscheinungen von SPID von der Einrichtung bis zum 29. Oktober 2022. Wir beurteilten die Qualität der eingeschlossenen Studien mit dem Cochrane-Tool zur Bewertung des Bias-Risikos. Die gepoolten Ergebnisse wurden als Risikoquotient (RR; risk ratio) mit 95%-Konfidenzintervall (KI) ausgedrückt. Zusätzlich identifizierten wir Quellen für Heterogenität mittels Sensitivitätsanalyse, beurteilten den Publikations-Bias mittels Egger-Test und bewerteten die Qualität der Evidenz nach Grad der Empfehlungsstärke, Beurteilung, Entwicklung und Evaluierung (GRADE). Alle statistischen Analysen erfolgten mit Review Manager 5.3 und Stata 14.ErgebnisseIm Endeffekt wurden 7 Studien mit insgesamt 663 Teilnehmern eingeschlossen. Wir fanden einen signifikanten Unterschied in der Gesamt-Effektivitätsrate bei der Gruppe, die zur Behandlung von SPID Akupunktur in Kombination mit Fumigation erhielt, im Vergleich zur reinen Akupunkturgruppe (RR = 1,17; 95%-KI [1,09; 1,25]; p = 0,0001 < 0,05; I2-Wert = 0%; 6 Studien), und einen signifikanten Unterschied in der Gesamt-Effektivitätsrate bei der Gruppe, die zur Behandlung von SPID Akupunktur in Kombination mit Fumigation erhielt, im Vergleich zur reinen Fumigationsgruppe (RR = 1,42; 95%-KI [1,21; 1,66]; p = 0,0001 < 0,05; 5 Studien).SchlussfolgerungDie klinische Wirksamkeit der Akupunktur in Kombination mit Kräuter-Fumigation zur Behandlung von SPID ist relativ gut. Zukünftig sind größere Studien erforderlich.}, } @article {pmid38331161, year = {2024}, author = {Golia, MT and Frigerio, R and Pucci, S and Sironi, F and Margotta, C and Pasetto, L and Testori, C and Berrone, E and Ingravalle, F and Chiari, M and Gori, A and Duchi, R and Perota, A and Bergamaschi, L and D'Angelo, A and Cagnotti, G and Galli, C and Corona, C and Bonetto, V and Bendotti, C and Cretich, M and Colombo, SF and Verderio, C}, title = {Changes in glial cell activation and extracellular vesicles production precede the onset of disease symptoms in transgenic hSOD1[G93A] pigs.}, journal = {Experimental neurology}, volume = {374}, number = {}, pages = {114716}, doi = {10.1016/j.expneurol.2024.114716}, pmid = {38331161}, issn = {1090-2430}, mesh = {Mice ; Animals ; Humans ; Swine ; Superoxide Dismutase-1/genetics ; Motor Neurons/metabolism ; Superoxide Dismutase/genetics ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/pathology ; Spinal Cord/pathology ; Neuroglia/pathology ; *Extracellular Vesicles ; Biomarkers/metabolism ; Peptides/metabolism ; Disease Models, Animal ; }, abstract = {SOD1 gene is associated with progressive motor neuron degeneration in the familiar forms of amyotrophic lateral sclerosis. Although studies on mutant human SOD1 transgenic rodent models have provided important insights into disease pathogenesis, they have not led to the discovery of early biomarkers or effective therapies in human disease. The recent generation of a transgenic swine model expressing the human pathological hSOD1[G93A] gene, which recapitulates the course of human disease, represents an interesting tool for the identification of early disease mechanisms and diagnostic biomarkers. Here, we analyze the activation state of CNS cells in transgenic pigs during the disease course and investigate whether changes in neuronal and glial cell activation state can be reflected by the amount of extracellular vesicles they release in biological fluids. To assess the activation state of neural cells, we performed a biochemical characterization of neurons and glial cells in the spinal cords of hSOD1[G93A] pigs during the disease course. Quantification of EVs of CNS cell origin was performed in cerebrospinal fluid and plasma of transgenic pigs at different disease stages by Western blot and peptide microarray analyses. We report an early activation of oligodendrocytes in hSOD1[G93A] transgenic tissue followed by astrocyte and microglia activation, especially in animals with motor symptoms. At late asymptomatic stage, EV production from astrocytes and microglia is increased in the cerebrospinal fluid, but not in the plasma, of transgenic pigs reflecting donor cell activation in the spinal cord. Estimation of EV production by biochemical analyses is corroborated by direct quantification of neuron- and microglia-derived EVs in the cerebrospinal fluid by a Membrane Sensing Peptide enabled on-chip analysis that provides fast results and low sample consumption. Collectively, our data indicate that alteration in astrocytic EV production precedes the onset of disease symptoms in the hSOD[G93A] swine model, mirroring donor cell activation in the spinal cord, and suggest that EV measurements from the cells first activated in the ALS pig model, i.e. OPCs, may further improve early disease detection.}, } @article {pmid38332489, year = {2024}, author = {Dandl, S and Bender, A and Hothorn, T}, title = {Heterogeneous treatment effect estimation for observational data using model-based forests.}, journal = {Statistical methods in medical research}, volume = {33}, number = {3}, pages = {392-413}, pmid = {38332489}, issn = {1477-0334}, mesh = {Humans ; *Treatment Effect Heterogeneity ; Riluzole ; *Amyotrophic Lateral Sclerosis ; Linear Models ; }, abstract = {The estimation of heterogeneous treatment effects has attracted considerable interest in many disciplines, most prominently in medicine and economics. Contemporary research has so far primarily focused on continuous and binary responses where heterogeneous treatment effects are traditionally estimated by a linear model, which allows the estimation of constant or heterogeneous effects even under certain model misspecifications. More complex models for survival, count, or ordinal outcomes require stricter assumptions to reliably estimate the treatment effect. Most importantly, the noncollapsibility issue necessitates the joint estimation of treatment and prognostic effects. Model-based forests allow simultaneous estimation of covariate-dependent treatment and prognostic effects, but only for randomized trials. In this paper, we propose modifications to model-based forests to address the confounding issue in observational data. In particular, we evaluate an orthogonalization strategy originally proposed by Robinson (1988, Econometrica) in the context of model-based forests targeting heterogeneous treatment effect estimation in generalized linear models and transformation models. We found that this strategy reduces confounding effects in a simulated study with various outcome distributions. We demonstrate the practical aspects of heterogeneous treatment effect estimation for survival and ordinal outcomes by an assessment of the potentially heterogeneous effect of Riluzole on the progress of Amyotrophic Lateral Sclerosis.}, } @article {pmid38332698, year = {2024}, author = {Sung, JH and Baek, SH and Park, JW and Lee, JH and Son, MH and Kim, BJ}, title = {Dynamic suprahyoid muscle ultrasound in assessing oropharyngeal dysphagia in neurological disorders.}, journal = {European journal of physical and rehabilitation medicine}, volume = {60}, number = {2}, pages = {233-244}, pmid = {38332698}, issn = {1973-9095}, mesh = {Humans ; *Deglutition Disorders/diagnostic imaging/etiology ; Cross-Sectional Studies ; Deglutition/physiology ; *Stroke/complications/diagnostic imaging ; Ultrasonography ; Muscles ; }, abstract = {BACKGROUND: Appropriate evaluation and management of dysphagia are essential in neurological disorders. However, there is currently a lack of a simple yet reliable method for dysphagia evaluation.

AIM: This study aimed to investigate the usefulness of new dynamic M-mode ultrasonography (US) parameters of suprahyoid muscle (SHM) to evaluate dysphagia.

DESIGN: Prospective observational, cross-sectional study.

SETTING: Inpatient setting at neurology department of tertiary medical center.

POPULATION: A total of 89 patients with dysphagia and 175 healthy volunteers were enrolled in the study. Patients were subdivided into mild and severe dysphagia groups depending on the need for dietary changes and disease classification, which included amyotrophic lateral sclerosis, peripheral neuromuscular diseases, and stroke.

METHODS: Dynamic M-mode US was performed during swallowing to obtain the SHM thickness (the baseline thickness of the SHM), SHM displacement (peak-to-peak amplitude of SHM movement), SHM difference (SHM displacement - SHM thickness), SHM ratio (SHM displacement/SHM thickness), peak-to-peak time, and total duration. A videofluoroscopic swallowing study (VFSS) was performed.

RESULTS: Significant differences were found in SHM displacement and SHM difference according to dysphagia severity (P<0.001). The SHM ratio, total duration (P<0.001), and peak-to-peak time (P=0.001) differed significantly according to the patients' underlying diseases. The pharyngeal delay time and penetration-aspiration scale from the VFSS demonstrated significant negative correlations with SHM displacement and difference (P<0.001). By combining SHM difference and total duration, patients with dysphagia could be distinguished from healthy controls, with the highest negative predictive value of 95.6%.

CONCLUSIONS: Dynamic M-mode US of the SHM provided added value in evaluating the severity of dysphagia and differentiating swallowing mechanics of dysphagia related to underlying neurological disorders.

Dynamic M-mode US of the SHM can serve as a supportive tool for rapid screening and repetitive follow-up of patients with dysphagia, which would contribute to dysphagia rehabilitation in patients with various neurological disorders.}, } @article {pmid38332900, year = {2024}, author = {Du, L and Pang, Y}, title = {Identifying Regenerated Saplings by Stratifying Forest Overstory Using Airborne LiDAR Data.}, journal = {Plant phenomics (Washington, D.C.)}, volume = {6}, number = {}, pages = {0145}, pmid = {38332900}, issn = {2643-6515}, abstract = {Identifying the spatiotemporal distributions and phenotypic characteristics of understory saplings is beneficial in exploring the internal mechanisms of plant regeneration and providing technical assistances for continues cover forest management. However, it is challenging to detect the understory saplings using 2-dimensional (2D) spectral information produced by conventional optical remotely sensed data. This study proposed an automatic method to detect the regenerated understory saplings based on the 3D structural information from aerial laser scanning (ALS) data. By delineating individual tree crown using the improved spectral clustering algorithm, we successfully removed the overstory canopy and associated trunk points. Then, individual understory saplings were segmented using an adaptive-mean-shift-based clustering algorithm. This method was tested in an experimental forest farm of North China. Our results showed that the detection rates of understory saplings ranged from 94.41% to 152.78%, and the matching rates increased from 62.59% to 95.65% as canopy closure went down. The ALS-based sapling heights well captured the variations of field measurements [R[2] = 0.71, N = 3,241, root mean square error (RMSE) = 0.26 m, P < 0.01] and terrestrial laser scanning (TLS)-based measurements (R[2] = 0.78, N =443, RMSE = 0.23 m, P < 0.01). The ALS-based sapling crown width was comparable with TLS-based measurements (R[2] = 0.64, N = 443, RMSE = 0.24 m). This study provides a solution for the quantification of understory saplings, which can be used to improve forest ecosystem resilence through regulating the dynamics of forest gaps to better utilize light resources.}, } @article {pmid38334027, year = {2024}, author = {Cao, YB and Wu, Y and Dong, QY and Huang, NX and Zou, ZY and Chen, HJ}, title = {Neurite orientation dispersion and density imaging quantifies microstructural impairment in the thalamus and its connectivity in amyotrophic lateral sclerosis.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {2}, pages = {e14616}, pmid = {38334027}, issn = {1755-5949}, support = {2022QNA022//Fujian Provincial Health Technology Project/ ; 2023CXA009//Fujian Provincial Health Technology Project/ ; 62201265//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurites ; Diffusion Tensor Imaging/methods ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Thalamus/diagnostic imaging ; Neural Pathways/diagnostic imaging ; }, abstract = {AIMS: To evaluate microstructural impairment in the thalamus and thalamocortical connectivity using neurite orientation dispersion and density imaging (NODDI) in amyotrophic lateral sclerosis (ALS).

METHODS: This study included 47 healthy controls and 43 ALS patients, whose structural and diffusion-weighted data were collected. We used state-of-the-art parallel transport tractography to identify thalamocortical pathways in individual spaces. Thalamus was then parcellated into six subregions based on its connectivity pattern with the priori defined cortical (i.e., prefrontal/motor/somatosensory/temporal/posterior-parietal/occipital) regions. For each of the thalamic and cortical subregions and thalamo-cortical tracts, we compared the following NODDI metrics between groups: orientation dispersion index (ODI), neurite density index (NDI), and isotropic volume fraction (ISO). We also used these metrics to conduct receiver operating characteristic curve (ROC) analyses and Spearman correlation.

RESULTS: In ALS patients, we found decreased ODI and increased ISO in the thalamic subregion connecting the left motor cortex and other extramotor (e.g., somatosensory and occipital) cortex (Bonferroni-corrected p < 0.05). NDI decreased in the bilateral thalamo-motor and thalamo-somatosensory tracts and in the right thalamo-posterior-parietal and thalamo-occipital tracts (Bonferroni-corrected p < 0.05). NDI reduction in the bilateral thalamo-motor tract (p = 0.017 and 0.009) and left thalamo-somatosensory tract (p = 0.029) was correlated with disease severity. In thalamo-cortical tracts, NDI yielded a higher effect size during between-group comparisons and a greater area under ROC (p < 0.05) compared with conventional diffusion tensor imaging metrics.

CONCLUSIONS: Microstructural impairment in the thalamus and thalamocortical connectivity is the hallmark of ALS. NODDI improved the detection of disrupted thalamo-cortical connectivity in ALS.}, } @article {pmid38334254, year = {2024}, author = {Mohammadi, S and Ghaderi, S and Fatehi, F}, title = {MRI biomarkers and neuropsychological assessments of hippocampal and parahippocampal regions affected by ALS: A systematic review.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {2}, pages = {e14578}, pmid = {38334254}, issn = {1755-5949}, mesh = {Humans ; *Hippocampus/diagnostic imaging/pathology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/psychology/pathology/metabolism ; *Magnetic Resonance Imaging ; *Neuropsychological Tests ; *Biomarkers/metabolism ; Parahippocampal Gyrus/diagnostic imaging/pathology ; }, abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive motor and extra-motor neurodegenerative disease. This systematic review aimed to examine MRI biomarkers and neuropsychological assessments of the hippocampal and parahippocampal regions in patients with ALS.

METHODS: A systematic review was conducted in the Scopus and PubMed databases for studies published between January 2000 and July 2023. The inclusion criteria were (1) MRI studies to assess hippocampal and parahippocampal regions in ALS patients, and (2) studies reporting neuropsychological data in patients with ALS.

RESULTS: A total of 46 studies were included. Structural MRI revealed hippocampal atrophy, especially in ALS-FTD, involving specific subregions (CA1, dentate gyrus). Disease progression and genetic factors impacted atrophy patterns. Diffusion tensor imaging (DTI) showed increased mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and decreased fractional anisotropy (FA) in the hippocampal tracts and adjacent regions, indicating loss of neuronal and white matter integrity. Functional MRI (fMRI) revealed reduced functional connectivity (FC) between the hippocampus, parahippocampus, and other regions, suggesting disrupted networks. Perfusion MRI showed hypoperfusion in parahippocampal gyri. Magnetic resonance spectroscopy (MRS) found changes in the hippocampus, indicating neuronal loss. Neuropsychological tests showed associations between poorer memory and hippocampal atrophy or connectivity changes. CA1-2, dentate gyrus, and fimbria atrophy were correlated with worse memory.

CONCLUSIONS: The hippocampus and the connected regions are involved in ALS. Hippocampal atrophy disrupted connectivity and metabolite changes correlate with cognitive and functional decline. Specific subregions can be particularly affected. The hippocampus is a potential biomarker for disease monitoring and prognosis.}, } @article {pmid38334356, year = {2024}, author = {Kleinveld, VEA and Keritam, O and Horlings, CGC and Cetin, H and Wanschitz, J and Hotter, A and Zirch, LS and Zimprich, F and Topakian, R and Müller, P and Oel, D and Quasthoff, S and Erdler, M and Rauschka, H and Grinzinger, S and Jecel, J and Gaulhofer, P and Castek, B and Stadler, K and Löscher, WN}, title = {Multifocal motor neuropathy as a mimic of amyotrophic lateral sclerosis: Serum neurofilament light chain as a reliable diagnostic biomarker.}, journal = {Muscle & nerve}, volume = {69}, number = {4}, pages = {422-427}, doi = {10.1002/mus.28054}, pmid = {38334356}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers ; Intermediate Filaments ; Prognosis ; *Polyneuropathies/diagnosis ; Neurofilament Proteins ; }, abstract = {INTRODUCTION/AIMS: The clinical presentation of multifocal motor neuropathy (MMN) may mimic early amyotrophic lateral sclerosis (ALS) with predominant lower motor neuron (LMN) involvement, posing a diagnostic challenge. Both diseases have specific treatments and prognoses, highlighting the importance of early diagnosis. The aim of this study was to assess the diagnostic value of serum neurofilament light chain (NfL) in differentiating MMN from LMN dominant ALS.

METHODS: NfL was measured in serum in n = 37 patients with MMN and n = 37 age- and sex-matched patients with LMN dominant ALS, to determine the diagnostic accuracy. Clinical and demographic data were obtained at the time of NfL sampling.

RESULTS: Serum NfL concentration was significantly lower in MMN patients compared to ALS patients (mean 20.7 pg/mL vs. 59.4 pg/mL, p < .01). NfL demonstrated good diagnostic value in discriminating the two groups (AUC 0.985 [95% CI 0.963-1.000], sensitivity 94.6%, specificity 100%, cut-off 44.00 pg/mL).

DISCUSSION: NfL could be a helpful tool in differentiating MMN from LMN dominant ALS in those patients in whom electrophysiological and clinical examinations remain inconclusive early in the diagnostic process.}, } @article {pmid38334609, year = {2024}, author = {Noori, L and Saqagandomabadi, V and Di Felice, V and David, S and Caruso Bavisotto, C and Bucchieri, F and Cappello, F and Conway de Macario, E and Macario, AJL and Scalia, F}, title = {Putative Roles and Therapeutic Potential of the Chaperone System in Amyotrophic Lateral Sclerosis and Multiple Sclerosis.}, journal = {Cells}, volume = {13}, number = {3}, pages = {}, pmid = {38334609}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Multiple Sclerosis/therapy ; Molecular Chaperones/metabolism ; Heat-Shock Proteins/metabolism ; }, abstract = {The putative pathogenic roles and therapeutic potential of the chaperone system (CS) in amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are reviewed to provide a bibliographic and conceptual platform for launching research on the diagnostic and therapeutic applications of CS components. Various studies suggest that dysfunction of the CS contributes to the pathogenesis of ALS and MS, and here, we identify some of the implicated CS members. The physiology and pathophysiology of the CS members can be properly understood if they are studied or experimentally or clinically manipulated for diagnostic or therapeutic purposes, bearing in mind that they belong to a physiological system with multiple interacting and dynamic components, widespread throughout the body, intra- and extracellularly. Molecular chaperones, some called heat shock protein (Hsp), are the chief components of the CS, whose canonical functions are cytoprotective. However, abnormal chaperones can be etiopathogenic factors in a wide range of disorders, chaperonopathies, including ALS and MS, according to the data reviewed. Chaperones typically form teams, and these build functional networks to maintain protein homeostasis, the canonical role of the CS. However, members of the CS also display non-canonical functions unrelated to protein homeostasis. Therefore, chaperones and other members of the CS, if abnormal, may disturb not only protein synthesis, maturation, and migration but also other physiological processes. Thus, in elucidating the role of CS components in ALS and MS, one must look at protein homeostasis abnormalities and beyond, following the clues emerging from the works discussed here.}, } @article {pmid38334639, year = {2024}, author = {Cunha-Oliveira, T and Montezinho, L and Simões, RF and Carvalho, M and Ferreiro, E and Silva, FSG}, title = {Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {3}, pages = {}, pmid = {38334639}, issn = {2073-4409}, support = {PTDC/MED-FAR/29391/2017//Fundação para a Ciência e Tecnologia/ ; POCI-01-0145-FEDER-029391//Fundação para a Ciência e Tecnologia/ ; PTDC/BTM-SAL/29297/2017//Fundação para a Ciência e Tecnologia/ ; POCI-01-0145-FEDER-029297//Fundação para a Ciência e Tecnologia/ ; PTDC/BTM-ORG/0055/2021//Fundação para a Ciência e Tecnologia/ ; DL57/2016/CP1448/CT0016//Fundação para a Ciência e Tecnologia/ ; CEECIND/00322/2017//Fundação para a Ciência e Tecnologia/ ; 2022.00011.CEECIND//Fundação para a Ciência e Tecnologia/ ; UIDP/04539/2020//Fundação para a Ciência e Tecnologia/ ; UIDB/04539/2020//Fundação para a Ciência e Tecnologia/ ; UIDB/00081/2020//Fundação para a Ciência e Tecnologia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; Motor Neurons/pathology ; Apoptosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, for which current treatment options are limited. Recent studies have shed light on the role of mitochondria in ALS pathogenesis, making them an attractive therapeutic intervention target. This review contains a very comprehensive critical description of the involvement of mitochondria and mitochondria-mediated mechanisms in ALS. The review covers several key areas related to mitochondria in ALS, including impaired mitochondrial function, mitochondrial bioenergetics, reactive oxygen species, metabolic processes and energy metabolism, mitochondrial dynamics, turnover, autophagy and mitophagy, impaired mitochondrial transport, and apoptosis. This review also highlights preclinical and clinical studies that have investigated various mitochondria-targeted therapies for ALS treatment. These include strategies to improve mitochondrial function, such as the use of dichloroacetate, ketogenic and high-fat diets, acetyl-carnitine, and mitochondria-targeted antioxidants. Additionally, antiapoptotic agents, like the mPTP-targeting agents minocycline and rasagiline, are discussed. The paper aims to contribute to the identification of effective mitochondria-targeted therapies for ALS treatment by synthesizing the current understanding of the role of mitochondria in ALS pathogenesis and reviewing potential convergent therapeutic interventions. The complex interplay between mitochondria and the pathogenic mechanisms of ALS holds promise for the development of novel treatment strategies to combat this devastating disease.}, } @article {pmid38334818, year = {2024}, author = {Hoek, AG and Dal Canto, E and Wenker, E and Bindraban, N and Handoko, ML and Elders, PJM and Beulens, JWJ}, title = {Epidemiology of heart failure in diabetes: a disease in disguise.}, journal = {Diabetologia}, volume = {67}, number = {4}, pages = {574-601}, pmid = {38334818}, issn = {1432-0428}, support = {91718304/ZONMW_/ZonMw/Netherlands ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/epidemiology/complications ; *Heart Failure/epidemiology/physiopathology ; Incidence ; Prevalence ; Stroke Volume/physiology ; Ventricular Dysfunction, Left/epidemiology/physiopathology ; Echocardiography ; }, abstract = {Left ventricular diastolic dysfunction (LVDD) without symptoms, and heart failure (HF) with preserved ejection fraction (HFpEF) represent the most common phenotypes of HF in individuals with type 2 diabetes mellitus, and are more common than HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF) and left ventricular systolic dysfunction (LVSD) in these individuals. However, diagnostic criteria for HF have changed over the years, resulting in heterogeneity in the prevalence/incidence rates reported in different studies. We aimed to give an overview of the diagnosis and epidemiology of HF in type 2 diabetes, using both a narrative and systematic review approach; we focus narratively on diagnosing (using the 2021 European Society of Cardiology [ESC] guidelines) and screening for HF in type 2 diabetes. We performed an updated (2016-October 2022) systematic review and meta-analysis of studies reporting the prevalence and incidence of HF subtypes in adults ≥18 years with type 2 diabetes, using echocardiographic data. Embase and MEDLINE databases were searched and data were assessed using random-effects meta-analyses, with findings presented as forest plots. From the 5015 studies found, 209 were screened using the full-text article. In total, 57 studies were included, together with 29 studies that were identified in a prior meta-analysis; these studies reported on the prevalence of LVSD (n=25 studies, 24,460 individuals), LVDD (n=65 studies, 25,729 individuals), HFrEF (n=4 studies, 4090 individuals), HFmrEF (n=2 studies, 2442 individuals) and/or HFpEF (n=8 studies, 5292 individuals), and on HF incidence (n=7 studies, 17,935 individuals). Using Hoy et al's risk-of-bias tool, we found that the studies included generally had a high risk of bias. They showed a prevalence of 43% (95% CI 37%, 50%) for LVDD, 17% (95% CI 7%, 35%) for HFpEF, 6% (95% CI 3%, 10%) for LVSD, 7% (95% CI 3%, 15%) for HFrEF, and 12% (95% CI 7%, 22%) for HFmrEF. For LVDD, grade I was found to be most prevalent. Additionally, we reported a higher incidence rate of HFpEF (7% [95% CI 4%, 11%]) than HFrEF 4% [95% CI 3%, 7%]). The evidence is limited by the heterogeneity of the diagnostic criteria over the years. The systematic section of this review provides new insights on the prevalence/incidence of HF in type 2 diabetes, unveiling a large pre-clinical target group with LVDD/HFpEF in which disease progression could be halted by early recognition and treatment.Registration PROSPERO ID CRD42022368035.}, } @article {pmid38335961, year = {2024}, author = {Klickstein, JA and Johnson, MA and Antonoudiou, P and Maguire, J and Paulo, JA and Gygi, SP and Weihl, C and Raman, M}, title = {ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons.}, journal = {Stem cell reports}, volume = {19}, number = {3}, pages = {366-382}, pmid = {38335961}, issn = {2213-6711}, support = {R01 GM127557/GM/NIGMS NIH HHS/United States ; R01 NS102937/NS/NINDS NIH HHS/United States ; P50 MH122379/MH/NIMH NIH HHS/United States ; R01 GM067945/GM/NIGMS NIH HHS/United States ; R01 AA026256/AA/NIAAA NIH HHS/United States ; R01 MH128235/MH/NIMH NIH HHS/United States ; K24 AR073317/AR/NIAMS NIH HHS/United States ; R01 AG031867/AG/NIA NIH HHS/United States ; R21 NS123631/NS/NINDS NIH HHS/United States ; K12 GM133314/GM/NIGMS NIH HHS/United States ; R01 GM132129/GM/NIGMS NIH HHS/United States ; R01 NS105628/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Induced Pluripotent Stem Cells ; Macroautophagy ; Motor Neurons ; Mutation ; Valosin Containing Protein ; }, abstract = {Mutations in the AAA+ ATPase p97 cause multisystem proteinopathy 1, which includes amyotrophic lateral sclerosis; however, the pathogenic mechanisms that contribute to motor neuron loss remain obscure. Here, we use two induced pluripotent stem cell models differentiated into spinal motor neurons to investigate how p97 mutations perturb the motor neuron proteome. Using quantitative proteomics, we find that motor neurons harboring the p97 R155H mutation have deficits in the selective autophagy of lysosomes (lysophagy). p97 R155H motor neurons are unable to clear damaged lysosomes and have reduced viability. Lysosomes in mutant motor neurons have increased pH compared with wild-type cells. The clearance of damaged lysosomes involves UBXD1-p97 interaction, which is disrupted in mutant motor neurons. Finally, inhibition of the ATPase activity of p97 using the inhibitor CB-5083 rescues lysophagy defects in mutant motor neurons. These results add to the evidence that endo-lysosomal dysfunction is a key aspect of disease pathogenesis in p97-related disorders.}, } @article {pmid38336279, year = {2024}, author = {Costa-Pinto, S and Gonçalves-Ribeiro, J and Tedim-Moreira, J and Socodato, R and Relvas, JB and Sebastião, AM and Vaz, SH}, title = {Communication defects with astroglia contribute to early impairments in the motor cortex plasticity of SOD1[G93A] mice.}, journal = {Neurobiology of disease}, volume = {193}, number = {}, pages = {106435}, doi = {10.1016/j.nbd.2024.106435}, pmid = {38336279}, issn = {1095-953X}, mesh = {Mice ; Animals ; Astrocytes/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; *Motor Cortex ; *Neurodegenerative Diseases/metabolism ; Proteomics ; Disease Models, Animal ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, involving the selective degeneration of cortical upper synapses in the primary motor cortex (M1). Excitotoxicity in ALS occurs due to an imbalance between excitation and inhibition, closely linked to the loss/gain of astrocytic function. Using the ALS SOD1[G93A] mice, we investigated the astrocytic contribution for the electrophysiological alterations observed in the M1 of SOD1[G93A] mice, throughout disease progression. Results showed that astrocytes are involved in synaptic dysfunction observed in presymptomatic SOD1[G93A] mice, since astrocytic glutamate transport currents are diminished and pharmacological inhibition of astrocytes only impaired long-term potentiation and basal transmission in wild-type mice. Proteomic analysis revealed major differences in neuronal transmission, metabolism, and immune system in upper synapses, confirming early communication deficits between neurons and astroglia. These results provide valuable insights into the early impact of upper synapses in ALS and the lack of supportive functions of cortical astrocytes, highlighting the possibility of manipulating astrocytes to improve synaptic function.}, } @article {pmid38336286, year = {2024}, author = {Lomeli, N and Pearre, DC and Cruz, M and Di, K and Ricks-Oddie, JL and Bota, DA}, title = {Cisplatin induces BDNF downregulation in middle-aged female rat model while BDNF enhancement attenuates cisplatin neurotoxicity.}, journal = {Experimental neurology}, volume = {375}, number = {}, pages = {114717}, pmid = {38336286}, issn = {1090-2430}, support = {TL1 TR001415/TR/NCATS NIH HHS/United States ; T32 NS082174/NS/NINDS NIH HHS/United States ; R01 CA263806/CA/NCI NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; T32 CA060396/CA/NCI NIH HHS/United States ; P30 CA062203/CA/NCI NIH HHS/United States ; K08 NS072234/NS/NINDS NIH HHS/United States ; }, mesh = {Rats ; Animals ; Female ; *Cisplatin/toxicity ; *Brain-Derived Neurotrophic Factor/metabolism ; Rats, Sprague-Dawley ; Down-Regulation ; Quality of Life ; Riluzole/pharmacology ; Hippocampus/metabolism ; Disks Large Homolog 4 Protein ; }, abstract = {Cancer-related cognitive impairments (CRCI) are neurological complications associated with cancer treatment, and greatly affect cancer survivors' quality of life. Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis, learning and memory. The reduction of BDNF is associated with the decrease in cognitive function in various neurological disorders. Few pre-clinical studies have reported on the effects of chemotherapy and medical stress on BDNF levels and cognition. The present study aimed to compare the effects of medical stress and cisplatin on serum BDNF levels and cognitive function in 9-month-old female Sprague Dawley rats to age-matched controls. Serum BDNF levels were collected longitudinally during cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-cisplatin initiation. Terminal BDNF levels were collected 24 weeks after cisplatin initiation. In cultured hippocampal neurons, we screened three neuroprotective agents, riluzole (an approved treatment for amyotrophic lateral sclerosis), as well as the ampakines CX546 and CX1739. We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD-95) puncta. Cisplatin and exposure to medical stress reduced serum BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological BDNF augmentation protected neurons against cisplatin-induced reductions in dendritic branching and PSD-95. Ampakines (CX546 and CX1739) and riluzole did not affect the antitumor efficacy of cisplatin in vitro. In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels on cognitive function, although future studies are warranted to assess the efficacy of BDNF enhancement in vivo on synaptic plasticity. Collectively, our results indicate that cancer treatment exerts long-lasting changes in BDNF levels, and support BDNF enhancement as a potential preventative approach to target CRCI with therapeutics that are FDA approved and/or in clinical study for other indications.}, } @article {pmid38336910, year = {2024}, author = {Kokubo, Y and Morimoto, S and Yoshida, M}, title = {Questioning the cycad theory of Kii ALS-PDC causation.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {3}, pages = {194}, pmid = {38336910}, issn = {1759-4766}, mesh = {Humans ; *Parkinsonian Disorders ; *Amyotrophic Lateral Sclerosis/etiology/complications ; }, } @article {pmid38336911, year = {2024}, author = {Menšíková, K and Rosales, R and Colosimo, C and Spencer, P and Lannuzel, A and Ugawa, Y and Sasaki, R and Giménez-Roldán, S and Matej, R and Tuckova, L and Hrabos, D and Kolarikova, K and Vodicka, R and Vrtel, R and Strnad, M and Hlustik, P and Otruba, P and Prochazka, M and Bares, M and Boluda, S and Buee, L and Ransmayr, G and Kaňovský, P}, title = {Reply to: Questioning the cycad theory of Kii ALS-PDC causation.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {3}, pages = {195-196}, pmid = {38336911}, issn = {1759-4766}, mesh = {Humans ; *Parkinsonian Disorders ; *Amyotrophic Lateral Sclerosis/etiology/complications ; }, } @article {pmid38337058, year = {2024}, author = {Choi, BJ and Park, MH and Jin, HK and Bae, JS}, title = {Acid sphingomyelinase as a pathological and therapeutic target in neurological disorders: focus on Alzheimer's disease.}, journal = {Experimental & molecular medicine}, volume = {56}, number = {2}, pages = {301-310}, pmid = {38337058}, issn = {2092-6413}, mesh = {Animals ; Humans ; Mice ; *Alzheimer Disease/drug therapy ; Brain ; *Multiple Sclerosis ; *Nervous System Diseases ; Sphingomyelin Phosphodiesterase/genetics ; }, abstract = {Over the past decade, numerous studies have highlighted the importance of acid sphingomyelinase (ASM) in disease treatment in humans. This enzyme functions primarily to generate ceramide, maintain the cellular membrane, and regulate cellular function. However, in the blood and brain of patients with neurological disorders, including major depression, ischemic stroke, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer's disease (AD), elevated ASM levels significantly suggest disease onset or progression. In these diseases, increased ASM is profoundly involved in neuronal death, abnormal autophagy, neuroinflammation, blood-brain barrier disruption, hippocampal neurogenesis loss, and immune cell dysfunction. Moreover, genetic and pharmacological inhibition of ASM can prevent or ameliorate various diseases. The therapeutic effects of ASM inhibition have prompted the urgent need to develop ASM inhibitors, and several ASM inhibitors have been identified. In this review, we summarize the current knowledge on the critical roles and mechanisms of ASM in brain cells and blood that are associated with different neuropathological features, especially those observed in AD. Furthermore, we elucidate the potential possibility and limitations of existing ASM-targeting drugs according to experimental studies in neurological disorder mouse models.}, } @article {pmid38337170, year = {2024}, author = {White, S and O'Cathain, A and Halliday, V and Bradburn, M and McDermott, CJ}, title = {Supporting people with Motor Neuron Disease (MND) to make decisions about gastrostomy feeding tube placement: a survey of UK healthcare professionals' practice and beliefs.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {290-298}, pmid = {38337170}, issn = {2167-9223}, mesh = {Humans ; Gastrostomy ; *Amyotrophic Lateral Sclerosis ; Cross-Sectional Studies ; *Motor Neuron Disease/surgery ; United Kingdom ; Delivery of Health Care ; }, abstract = {OBJECTIVE: Understand the practice and beliefs of healthcare professionals (HCPs) supporting the decision-making of people with MND (pwMND) about gastrostomy placement, including identifying differences between professions.

METHODS: An online cross-sectional survey disseminated to HCPs who support the decision-making of pwMND about gastrostomy placement.

RESULTS: A total of 139 participants completed the survey including representation from a range of healthcare professions. A third (36/101, 36%) initiated discussions about gastrostomy later in practice than they believed was ideal. In relation to the outcome of declining compared to accepting gastrostomy, participants were more likely to discuss aspiration (80% vs. 68%), choking (76% vs. 58%) and prognosis (36% vs. 22%). Participants believed gastrostomies should be placed after a mean 8.1% weight loss since symptom-onset. More participants favored gastrostomy placement before pwMND presented with respiratory symptoms (45%) compared to onset of dysphagia (11%). Half believed pwMND placed gastrostomies too late. Participants were more likely to 'often'/'always' recommend pwMND to have a gastrostomy (23%) than continue without (7%) or decline (4%) gastrostomy, when believing these were the best option for pwMND. Nurses and dietitians discussed the broadest range of information, while doctors were more likely to discuss mortality risk and prognosis.

CONCLUSION: There is variation in HCPs practice and beliefs about initiating discussions, the sharing of information and recommendations, and timing, about gastrostomy placement. The information shared varies by profession and there is evidence of sub-optimal communication between HCPs. Further research is required to understand how these findings may impact on the decision-making of pwMND about gastrostomy.}, } @article {pmid38337635, year = {2024}, author = {Carrera-Juliá, S and Estrela, JM and Zacarés, M and Navarro, MÁ and Vega-Bello, MJ and de la Rubia Ortí, JE and Moreno, ML and Drehmer, E}, title = {Nutritional, Clinical and Sociodemographic Profiles of Spanish Patients with Amyotrophic Lateral Sclerosis.}, journal = {Nutrients}, volume = {16}, number = {3}, pages = {}, pmid = {38337635}, issn = {2072-6643}, support = {2017-216-001//Valencia Catholic University Saint Vincent Martyr/ ; OTR2017-18255INVES//University of Valencia/ ; }, mesh = {Male ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Energy Intake ; Cross-Sectional Studies ; *Neurodegenerative Diseases ; Nutritional Status ; Diet/adverse effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic and progressive neurodegenerative disease that leads to the loss of motor neurons. The dietary intake of ALS patients is thought to influence the prognosis and progression of the disease. The aim of this study was to examine the nutritional, clinical and sociodemographic characteristics of ALS patients in Spain. A cross-sectional descriptive study with demographics, clinical anamnesis and anthropometric assessment was carried out. Nutritional intake was recorded and compared with dietary reference intakes (DRI). Forty subjects (25 males; 15 females) aged 54.7 ± 10.17 were included in the study. The mean weight and height were 67.99 ± 8.85 kg and 167.83 ± 8.79 cm, respectively. Clinical phenotype, time to diagnosis, year of onset and family history were not associated with the place of origin. Clinical phenotype had no influence on time of diagnosis. Caloric and protein intakes were adequate, while carbohydrate, vitamin B8 and iodine intakes were significantly lower than the DRI. Lipids; vitamins B1, B2, B3, B5, B6, B12, C and E; sodium; phosphorus; and selenium intakes were significantly higher than the recommended nutritional standards. ALS patients, who are homogeneously distributed throughout our national territory, should modify their dietary habits to minimize ultra-processed products and prioritize foods rich in healthy fats and fiber.}, } @article {pmid38338823, year = {2024}, author = {Moreno-Martinez, L and Macías-Redondo, S and Strunk, M and Guillén-Antonini, MI and Lunetta, C and Tarlarini, C and Penco, S and Calvo, AC and Osta, R and Schoorlemmer, J}, title = {New Insights into Endogenous Retrovirus-K Transcripts in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38338823}, issn = {1422-0067}, support = {Ayuda de Colegios de Farmacéuticos//Fundación Mehuer, Sevilla, Spain/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Endogenous Retroviruses/genetics ; Leukocytes, Mononuclear/metabolism ; Brain/metabolism ; Brain Stem/metabolism ; }, abstract = {Retroviral reverse transcriptase activity and the increased expression of human endogenous retroviruses (HERVs) are associated with amyotrophic lateral sclerosis (ALS). We were interested in confirming HERVK overexpression in the ALS brain, its use as an accessory diagnostic marker for ALS, and its potential interplay with neuroinflammation. Using qPCR to analyze HERVK expression in peripheral blood mononuclear cells (PBMCs) and in postmortem brain samples from ALS patients, no significant differences were observed between patients and control subjects. By contrast, we report alterations in the expression patterns of specific HERVK copies, especially in the brainstem. Out of 27 HERVK copies sampled, the relative expression of 17 loci was >1.2-fold changed in samples from ALS patients. In particular, the relative expression of two HERVK copies (Chr3-3 and Chr3-5) was significantly different in brainstem samples from ALS patients compared with controls. Further qPCR analysis of inflammation markers in brain samples revealed a significant increase in NLRP3 levels, while TNFA, IL6, and GZMB showed slight decreases. We cannot confirm global HERVK overexpression in ALS, but we can report the ALS-specific overexpression of selected HERVK copies in the ALS brain. Our data are compatible with the requirement for better patient stratification and support the potential importance of particular HERVK copies in ALS.}, } @article {pmid38338857, year = {2024}, author = {Venegas, S and Alarcón, C and Araya, J and Gatica, M and Morin, V and Tarifeño-Saldivia, E and Uribe, E}, title = {Biodegradation of Polystyrene by Galleria mellonella: Identification of Potential Enzymes Involved in the Degradative Pathway.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38338857}, issn = {1422-0067}, support = {VRID 220.037.026-M//University of Concepción/ ; }, mesh = {Animals ; *Polystyrenes/metabolism ; Chromatography, Liquid ; Proteomics ; Tandem Mass Spectrometry ; *Moths/microbiology ; Larva/metabolism ; Biodegradation, Environmental ; }, abstract = {Galleria mellonella is a lepidopteran whose larval stage has shown the ability to degrade polystyrene (PS), one of the most recalcitrant plastics to biodegradation. In the present study, we fed G. mellonella larvae with PS for 54 days and determined candidate enzymes for its degradation. We first confirmed the biodegradation of PS by Fourier transform infrared spectroscopy- Attenuated total reflectance (FTIR-ATR) and then identified candidate enzymes in the larval gut by proteomic analysis using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Two of these proteins have structural similarities to the styrene-degrading enzymes described so far. In addition, potential hydrolases, isomerases, dehydrogenases, and oxidases were identified that show little similarity to the bacterial enzymes that degrade styrene. However, their response to a diet based solely on polystyrene makes them interesting candidates as a potential new group of polystyrene-metabolizing enzymes in eukaryotes.}, } @article {pmid38338912, year = {2024}, author = {Duranti, E and Cordani, N and Villa, C}, title = {Edaravone: A Novel Possible Drug for Cancer Treatment?.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38338912}, issn = {1422-0067}, mesh = {Humans ; Edaravone/therapeutic use ; *Neuroprotective Agents/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy ; Antioxidants/therapeutic use ; *Neoplasms/drug therapy/chemically induced ; Free Radical Scavengers/pharmacology ; }, abstract = {Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.}, } @article {pmid38339026, year = {2024}, author = {Potenza, RL and Armida, M and Popoli, P}, title = {Can Some Anticancer Drugs Be Repurposed to Treat Amyotrophic Lateral Sclerosis? A Brief Narrative Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38339026}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Motor Neuron Disease ; *Antineoplastic Agents/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare progressive motor neuron disease that, due to its high complexity, still lacks effective treatments. Development of a new drug is a highly costly and time-consuming process, and the repositioning of approved drugs can represent an efficient strategy to provide therapeutic opportunities. This is particularly true for rare diseases, which are characterised by small patient populations and therefore attract little commercial interest. Based on the overlap between the biological background of cancer and neurodegeneration, the repurposing of antineoplastic drugs for ALS has been suggested. The objective of this narrative review was to summarise the current experimental evidence on the use of approved anticancer drugs in ALS. Specifically, anticancer drugs belonging to different classes were found to act on mechanisms involved in the ALS pathogenesis, and some of them proved to exert beneficial effects in ALS models. However, additional studies are necessary to confirm the real therapeutic potential of anticancer drugs for repositioning in ALS treatment.}, } @article {pmid38339035, year = {2024}, author = {Sun, Y and Islam, S and Michikawa, M and Zou, K}, title = {Presenilin: A Multi-Functional Molecule in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38339035}, issn = {1422-0067}, support = {C19K07846//The Grant-in-Aid for Scientific Research/ ; 22K07352//The Ministry of Education, Culture, Sports, Science, and Technology, Japan./ ; JP20dk0207050h0001 and JP20de010702//AMED/ ; no//The 24th General Assembly of the Japanese Association of Medical Sciences/ ; no//Daiko Foundation/ ; no//Hirose International Scholarship Foundation/ ; no//Hori Sciences and Arts Foundation/ ; no//Daiwa Securities Foundation/ ; no//Hirose Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; *Neurodegenerative Diseases/etiology ; Amyloid Precursor Protein Secretases/metabolism ; Presenilin-1/genetics/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Apolipoproteins E ; Presenilin-2/genetics/metabolism ; }, abstract = {Presenilin, a transmembrane protein primarily known for its role in Alzheimer's disease (AD) as part of the γ-secretase complex, has garnered increased attention due to its multifaceted functions in various cellular processes. Recent investigations have unveiled a plethora of functions beyond its amyloidogenic role. This review aims to provide a comprehensive overview of presenilin's diverse roles in AD and other neurodegenerative disorders. It includes a summary of well-known substrates of presenilin, such as its involvement in amyloid precursor protein (APP) processing and Notch signaling, along with other functions. Additionally, it highlights newly discovered functions, such as trafficking function, regulation of ferritin expression, apolipoprotein E (ApoE) secretion, the interaction of ApoE and presenilin, and the Aβ42-to-Aβ40-converting activity of ACE. This updated perspective underscores the evolving landscape of presenilin research, emphasizing its broader impact beyond established pathways. The incorporation of these novel findings accentuates the dynamic nature of presenilin's involvement in cellular processes, further advancing our comprehension of its multifaceted roles in neurodegenerative disorders. By synthesizing evidence from a range of studies, this review sheds light on the intricate web of presenilin functions and their implications in health and disease.}, } @article {pmid38339149, year = {2024}, author = {Lee, A and Henderson, R and Aylward, J and McCombe, P}, title = {Gut Symptoms, Gut Dysbiosis and Gut-Derived Toxins in ALS.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38339149}, issn = {1422-0067}, support = {There were no grant numbers//Wesley Medical Research/ ; There were no grant numbers//MND Research Australia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/etiology ; Dysbiosis/etiology ; *Gastrointestinal Microbiome/physiology ; Brain ; }, abstract = {Many pathogenetic mechanisms have been proposed for amyotrophic lateral sclerosis (ALS). Recently, there have been emerging suggestions of a possible role for the gut microbiota. Gut microbiota have a range of functions and could influence ALS by several mechanisms. Here, we review the possible role of gut-derived neurotoxins/excitotoxins. We review the evidence of gut symptoms and gut dysbiosis in ALS. We then examine a possible role for gut-derived toxins by reviewing the evidence that these molecules are toxic to the central nervous system, evidence of their association with ALS, the existence of biochemical pathways by which these molecules could be produced by the gut microbiota and existence of mechanisms of transport from the gut to the blood and brain. We then present evidence that there are increased levels of these toxins in the blood of some ALS patients. We review the effects of therapies that attempt to alter the gut microbiota or ameliorate the biochemical effects of gut toxins. It is possible that gut dysbiosis contributes to elevated levels of toxins and that these could potentially contribute to ALS pathogenesis, but more work is required.}, } @article {pmid38340017, year = {2024}, author = {Kim, JS and Park, M and Park, S and Chae, J and Hong, YH and Park, KS and Sung, JJ and Choi, SJ}, title = {Prognosis of amyotrophic lateral sclerosis patients after tracheostomy invasive ventilation in Korea.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {271-281}, doi = {10.1080/21678421.2024.2314064}, pmid = {38340017}, issn = {2167-9223}, mesh = {Humans ; Male ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/surgery ; *Noninvasive Ventilation ; Retrospective Studies ; Tracheostomy ; Prognosis ; Republic of Korea/epidemiology ; }, abstract = {Background: Tracheostomy invasive ventilation (TIV) is applied to a subset of amyotrophic lateral sclerosis (ALS) patients; however, its frequency and impact on prognosis vary across countries. Methods: We conducted a nationwide retrospective cohort study using Korean National Health Insurance claims data. All patients diagnosed with sporadic ALS from 2012 to 2017 were included, with the observation period until 2020. The survival time between the TIV and non-TIV groups was compared using propensity score matching analysis, and prognostic factors were assessed within the TIV group. Results: This study included 3484 ALS patients (mean [standard deviation] age, 62.4 [11.9] years, 60.4% male), among whom 1230 (35.3%) underwent TIV. After 1:1 propensity score matching, the survival duration between the two groups was not significantly different (28 vs. 25 months, p = 0.057). Cox regression indicated that older age (hazard ratios [HRs] for each decade compared to <40 years: 3.89, 3.83, 5.30, 6.78, and 8.40 [≥80 years]; p < 0.005 for all) and lower income (HR, 1.28; 95% confidence interval [CI], 1.09-1.52; p = 0.003) negatively impacted survival, while gastrostomy (HR, 0.57; 95% CI, 0.50-0.66; p < 0.001) and supportive care services (HR, 0.43; 95% CI, 0.32-0.59; p < 0.001) were associated with prolonged survival. Conclusions: TIV was administered to more than one-third of Korean ALS patients without significant survival prolongation. Older age, lower income, lack of gastrostomy, and insufficient supportive care were independent poor prognostic factors for survival, underscoring the importance of comprehensive management for ALS patients.}, } @article {pmid38342829, year = {2024}, author = {Bottinelli, C and Baradian, P and Poly, A and Hoizey, G and Chatenay, C}, title = {Identification and quantification of both isomers of hexahydrocannabinol, (9R)-hexahydrocannabinol and (9S)-hexahydrocannabinol, in three different matrices by mass spectrometry.}, journal = {Rapid communications in mass spectrometry : RCM}, volume = {38}, number = {7}, pages = {e9711}, doi = {10.1002/rcm.9711}, pmid = {38342829}, issn = {1097-0231}, mesh = {Tandem Mass Spectrometry/methods ; Reproducibility of Results ; *Cannabinoids/analysis ; *Cannabidiol/analysis ; Gas Chromatography-Mass Spectrometry/methods ; Dronabinol ; }, abstract = {CONTEXT: Hexahydrocannabinol (HHC), a compound derived from synthetic production using cannabidiol (CBD) or delta-9-tetrahydrocannabinol (Δ[9] -THC), has gained recent attention due to its presence in seized materials across Europe. Sold legally in various forms, HHC poses potential health risks, particularly as a legal alternative to THC in some countries. Despite its historical description in the 1940s, limited toxicology data, pharmacological understanding, and analytical methods for HHC exist.

METHOD: This study proposes analytical techniques using mass spectrometry to detect, identify, and quantify (9R)-HHC and (9S)-HHC, concurrently with THC and CBD in various matrices, including oral fluid, whole blood, and seized material. Three distinct methods were employed for different matrices: GC/MS for seized material, GC/MS/MS for whole blood, and UHPLC/MS/MS for oral fluid. Methods were validated qualitatively for oral fluid with a FLOQSwab® device and quantitatively in whole blood and seized material according to Peters et al's recommendations and ICH guidelines.

RESULTS: Validated methods were considered reliable in detecting and quantifying HHC isomers in terms of repeatability, reproducibility, and linearity with r[2] systematically >0.992. These methods were applied to authentic cases, including seized materials and biological samples from traffic control (whole blood and oral fluid). In seized materials, (9R)-HHC levels ranged from 2.09% to 8.85% and (9R)-HHC/(9S)-HHC ratios varied from 1.36 to 2.68. In whole blood sample, (9R)-HHC and (9S)-HHC concentrations were, respectively, 2.38 and 1.39 ng/mL. For all analyzed samples, cannabinoids such as THC and CBD were also detected.

CONCLUSION: This research contributes analytical insights into differentiating and simultaneously analyzing (9R)-HHC and (9S)-HHC, using widely applicable mass spectrometric methods. The study emphasizes the need for vigilance among toxicologists, as new semisynthetic cannabinoids continue to emerge in Europe, with potential health implications. The findings underscore the importance of reliable analytical methods for monitoring these compounds in forensic and clinical settings.}, } @article {pmid38343431, year = {2024}, author = {Olesen, LK and la Cour, K and Nimmon, L and With, H and Handberg, C}, title = {Experiences of an Online Palliative Rehabilitation Programme for Spousal Caregivers of People With Amyotrophic Lateral Sclerosis and Cognitive and/or Behavioural Impairments: A Qualitative Interpretive Study.}, journal = {Advances in rehabilitation science and practice}, volume = {13}, number = {}, pages = {27536351241227860}, pmid = {38343431}, issn = {2753-6351}, abstract = {PURPOSE: The purpose of this study was to understand how spousal caregivers of people with amyotrophic lateral sclerosis and cognitive and/or behavioural impairments felt about the EMBRACE intervention.

MATERIALS AND METHODS: A qualitative interpretive study, using individual semi-structured interviews pre- and post-participation in a palliative rehabilitation blended learning programme, was applied. In total, 13 spousal caregivers were interviewed pre-intervention and 10 of them post-intervention.

RESULTS: Three overarching themes were identified: Striving to Obtain Control in Everyday Life, Peer support Across the Illness Trajectory and The Complexity of Relations. Information provided in targeted videos and sharing experiences with peers in virtual group meetings were beneficial to comprehend, manage and find meaning in everyday challenges related to being a caregiver.

CONCLUSION: The EMBRACE intervention helped spousal caregivers cope with everyday needs and challenges related to being a caregiver. EMBRACE was found to support and strengthen the participants in gaining more control in everyday life, creating a sense of coherence. Through targeted videos and discussions with peers, the participants felt prepared for the illness trajectory of their relative. Peer support promoted resilient functioning and reduced their feelings of loneliness.

CLINICAL TRIAL REGISTRATION: This study was registered on clinicaltrials.gov under the name: A Complex Intervention Study on a Palliative Rehabilitation Blended Learning Programme to Support Relatives and Health Care Providers of People with ALS and Cognitive Impairments in Coping with Challenges. ID no. NCT04638608. URL: https://clinicaltrials.gov/ct2/results?cond=&term=NCT04638608&cntry=&state=&city=&dist=.}, } @article {pmid38343836, year = {2024}, author = {Hobson, R and Levy, SHS and Flaherty, D and Xiao, H and Ciener, B and Reddy, H and Singal, C and Kim, CY and Teich, AF and Shneider, NA and Bradshaw, EM and Elyaman, W}, title = {Clonal CD8 T Cells Accumulate in the Leptomeninges and Communicate with Microglia in Human Neurodegeneration.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38343836}, issn = {2693-5015}, support = {P30 CA013696/CA/NCI NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; }, abstract = {Murine studies have highlighted a crucial role for immune cells in the meninges in surveilling the central nervous system (CNS) and influencing neuroinflammation. However, how meningeal immunity is altered in human neurodegeneration and its effects on CNS inflammation is understudied. We performed the first single-cell analysis of the transcriptomes and T cell receptor (TCR) repertoire of 104,635 immune cells from 55 postmortem human brain and leptomeningeal tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. RNA and TCR sequencing from paired leptomeninges and brain allowed us to perform lineage tracing to identify the spatial trajectory of clonal T cells in the CNS and its borders. We propose that T cells activated in the brain emigrate to and establish residency in the leptomeninges where they likely contribute to impairments in lymphatic drainage and remotely to CNS inflammation by producing IFNγ and other cytokines. We identified regulatory networks local to the meninges including NK cell-mediated CD8 T cell killing which likely help to control meningeal inflammation. Collectively, these findings provide not only a foundation for future studies into brain border immune surveillance but also highlight important intercellular dynamics that could be leveraged to modulate neuroinflammation.}, } @article {pmid38343852, year = {2024}, author = {Mitra, J and Dharmalingam, P and Kodavati, M and Guerrero, EN and Rao, KS and Garruto, RM and Hegde, ML}, title = {Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38343852}, issn = {2693-5015}, support = {R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {TDP-43 mislocalization and aggregation are key pathological features of motor neuron diseases (MND) including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, transgenic hTDP-43 WT or ΔNLS-overexpression animal models mainly capture late-stages TDP-43 proteinopathy, and do not provide a complete understanding of early motor neuron-specific pathology during pre-symptomatic phases. We have now addressed this shortcoming by generating a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43ΔNLS variant of mouse Tdp-43. This variant is either expressed conditionally in whole mice or specifically in the motor neurons. The mice exhibit loss of nuclear Tdp-43 concomitant with its cytosolic accumulation and aggregation in targeted cells, leading to increased DNA double-strand breaks (DSBs), signs of inflammation and DNA damage-associated cellular senescence. Notably, unlike WT Tdp43 which functionally interacts with Xrcc4 and DNA Ligase 4, the key DSB repair proteins in the non-homologous end-joining (NHEJ) pathway, the Tdp-43ΔNLS mutant sequesters them into cytosolic aggregates, exacerbating neuronal damage in mice brain. The mutant mice also exhibit myogenic degeneration in limb muscles and distinct motor deficits, consistent with the characteristics of MND. Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43ΔNLS mutant, independent of TDP-43 overexpression or other confounding etiological factors. Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to further characterize the early-stage progression of MND and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.}, } @article {pmid38344317, year = {2022}, author = {Baziyar, P and Seyedalipour, B and Hosseinkhani, S and Nazifi, E}, title = {Development of In Silico Analysis and Molecular Dynamics Simulation on L67P and D76Y Mutants of the Human Superoxide Dismutase 1(hSOD1) Related to Amyotrophic Lateral Sclerosis.}, journal = {Iranian journal of biotechnology}, volume = {20}, number = {4}, pages = {e3178}, pmid = {38344317}, issn = {1728-3043}, abstract = {BACKGROUND: One neurodegenerative disorder that is caused by a mutation in the hSOD1 gene is Amyotrophic lateral sclerosis (ALS).

OBJECTIVES: The current study was developed in order to evaluate the effect exerted by two ALS-associated point mutations, L67P and D76Y are located in the metal-binding loop, on structural characterization of hSOD1 protein using molecular dynamics (MD) simulations and computational predictions.

MATERIALS AND METHODS: In this study, GROMACS was utilized to perform molecular dynamics simulations along with 9 different algorithms such as Predict SNP, PhD-SNP, MAPP, PolyPhen-1, Polyphen-2, SNP, SIFT, SNP&GO, and PMUT for predicting and also evaluating the mutational effect on the structural and conformational characterization of hSOD1.

RESULTS: Our study was done by several programs predicting the destabilizing and harmful effect exerted by mutant hSOD1. The deleterious effect of L67P mutation was predicted by MAPP and PhD-SNP algorithms, and D76Y mutation was predicted by 9 algorithms. Comparative studies that were conducted on mutants and wild-type indicated the altar in flexibility and protein conformational stability influenced the metal-binding loop's conformation. The outcomes of the MD exhibited an increase and decrease of flexibility for D76Y and L67P mutants compared to the wild type, respectively. On the other hand, analysis of the gyration radius indicated lower and higher compactness for D76Y and L67P, respectively, suggesting that replacing amino acid at the metal-binding loop can alter the protein compactness compared with the protein the wild type.

CONCLUSIONS: Overall, these findings provided insight into the effect of mutations on the hSOD1, which leads to neurodegeneration disorders in humans. The results show that the mutations of L67P and D76Y influence the stability of protein conformational and flexibility associated with ALS disease. Thus, results of such mutations are can be a prerequisite to achieve a thorough understanding of ALS pathogenicity.}, } @article {pmid38345477, year = {2024}, author = {Zhu, H and Dalvi, U and Cazenave, W and Cattaert, D and Branchereau, P}, title = {Excitatory action of low frequency depolarizing GABA/glycine synaptic inputs is prevalent in prenatal spinal SOD1[G93A] motoneurons.}, journal = {The Journal of physiology}, volume = {602}, number = {5}, pages = {913-932}, doi = {10.1113/JP285105}, pmid = {38345477}, issn = {1469-7793}, support = {AAP2018//Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone/ ; 23185//AFM-TELETHON/ ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis ; Glycine/pharmacology ; Superoxide Dismutase-1/genetics ; Spinal Cord/physiology ; Chlorides ; *Neurodegenerative Diseases ; Mice, Transgenic ; Motor Neurons/physiology ; gamma-Aminobutyric Acid/pharmacology ; Disease Models, Animal ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by progressive motor neuron degeneration and muscle paralysis. Recent evidence suggests the dysfunction of inhibitory signalling in ALS motor neurons. We have shown that embryonic day (E)17.5 spinal motoneurons (MNs) of the SOD1[G93A] mouse model of ALS exhibit an altered chloride homeostasis. At this prenatal stage, inhibition of spinal motoneurons (MNs) is mediated by depolarizing GABAergic/glycinergic postsynaptic potentials (dGPSPs). Here, using an ex vivo preparation and patch clamp recording from MNs with a chloride equilibrium set below spike threshold, we report that low input resistance (Rin) E17.5 MNs from the SOD1[G93A] ALS mouse model do not correctly integrate dGPSPs evoked by electrical stimulations of GABA/glycine inputs at different frequencies. Indeed, firing activity of most wild-type (WT) MNs with low Rin was inhibited by incoming dGPSPs, whereas low Rin SOD1[G93A] MNs were excited or exhibited a dual response (excited by low frequency dGPSPs and inhibited by high frequency dGPSPs). Simulation highlighted the importance of the GABA/glycine input density and showed that pure excitation could be obtained in SOD-like MNs by moving GABA/glycine input away from the cell body to dendrites. This was in agreement with confocal imaging showing a lack of peri-somatic inhibitory terminals in SOD1[G93A] MNs compared to WT littermates. Putative fast ALS-vulnerable MNs with low Rin are therefore lacking functional inhibition at the near-term prenatal stage. KEY POINTS: We analysed the integration of GABAergic/glycinergic synaptic events by embryonic spinal motoneurons (MNs) in a mouse model of the amyotrophic lateral sclerosis (ALS) neurodegenerative disease. We found that GABAergic/glycinergic synaptic events do not properly inhibit ALS MNs with low input resistance, most probably corresponding to future vulnerable MNs. We used a neuron model to highlight the importance of the GABA/glycine terminal location and density in the integration of the GABAergic/glycinergic synaptic events. Confocal imaging showed a lack of GABA/glycine terminals on the cell body of ALS MNs. The present study suggests that putative ALS vulnerable MNs with low Rin lack functional inhibition at the near-term stage.}, } @article {pmid38347315, year = {2024}, author = {Huang, SL and Shen, YL and Peng, WY and Ye, K and Zheng, H}, title = {Edaravone for patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Acta neurologica Belgica}, volume = {124}, number = {3}, pages = {895-904}, pmid = {38347315}, issn = {2240-2993}, support = {no. 2021JDTD0007//Sichuan Province Science and Technology Support Program/ ; }, mesh = {*Edaravone/therapeutic use ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Free Radical Scavengers/therapeutic use ; Randomized Controlled Trials as Topic/methods ; Treatment Outcome ; }, abstract = {BACKGROUND AND OBJECTIVE: The effectiveness and long-term efficacy of edaravone, a recommended treatment for amyotrophic lateral sclerosis (ALS), has not been examined in real-world settings. This study aims to evaluate the effectiveness and long-term efficacy of edaravone.

METHODS: The OVID Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases were searched for articles published between January 1, 2000, and May 1, 2023. Two investigators independently screened the retrieved articles for randomized controlled trials (RCTs), cohort studies, or single-arm trials that evaluated the effect of edaravone on amyotrophic lateral sclerosis (ALS). The risk of bias was evaluated using the revised Cochrane Risk-of-Bias (RoB 2.0) tool for randomized controlled trials (RCTs) and the Risk-of-Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. The primary outcome was the ALSFRS-R score assessed at month 6, with secondary outcomes including the ALSFRS-R scores evaluated at months 9, 12, and 18, forced vital capacity (FVC), and adverse events. The certainty of evidence was assessed using the GRADE approach.

RESULTS: The analysis included 16 studies with a total of 4828 participants. Among these, four were randomized controlled trials (RCTs) and 12 were observational studies. Of the RCTs, four were rated as having a low risk of bias, while six of the observational studies were rated as having a low risk of bias. Edaravone was associated with slightly slower progression in the reduction of ALSFRS-R score at month 6 compared to placebo (mean difference 1.01, 95%CI -0.87 to 3.09, p = 0.293), as shown by evidence from RCTs. However, observational studies did not show any benefit of adding edaravone to routine practice (mean difference 1.85, 95%CI -2.05 to 5.75, p = 0.352). The change from baseline in ALSFRS-R score was -2.1, -4.04, -7.5, -6.82, and -7.9 at months 3, 6, 9, 12, and 18, respectively. The GRADE assessment indicated moderate certainty for evidence from RCTs, while evidence from observational studies had very low certainty.

CONCLUSION: Due to the limited number of studies and confounding issues in observational studies, further examination of the added benefits of edaravone to routine practice is necessary through RCTs, particularly regarding its long-term efficacy.}, } @article {pmid38347638, year = {2024}, author = {Li, W and Li, HL and Wang, JZ and Liu, R and Wang, X}, title = {Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases.}, journal = {Cell & bioscience}, volume = {14}, number = {1}, pages = {22}, pmid = {38347638}, issn = {2045-3701}, support = {92049107//National Natural Science Foundation of China/ ; 82071440//National Natural Science Foundation of China/ ; 31929002//National Natural Science Foundation of China/ ; }, abstract = {Protein post-translational modifications (PPTMs) refer to a series of chemical modifications that occur after the synthesis of protein. Proteins undergo different modifications such as phosphorylation, acetylation, ubiquitination, and so on. These modifications can alter the protein's structure, function, and interaction, thereby regulating its biological activity. In neurodegenerative diseases, several proteins undergo abnormal post-translational modifications, which leads to aggregation and abnormal deposition of protein, thus resulting in neuronal death and related diseases. For example, the main pathological features of Alzheimer's disease are the aggregation of beta-amyloid protein and abnormal phosphorylation of tau protein. The abnormal ubiquitination and loss of α-synuclein are related to the onset of Parkinson's disease. Other neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis, and so on are also connected with abnormal PPTMs. Therefore, studying the abnormal PPTMs in neurodegenerative diseases is critical for understanding the mechanism of these diseases and the development of significant therapeutic strategies. This work reviews the implications of PPTMs in neurodegenerative diseases and discusses the relevant therapeutic strategies.}, } @article {pmid38347806, year = {2024}, author = {Lao, Z and Tang, Y and Dong, X and Tan, Y and Li, X and Liu, X and Li, L and Guo, C and Wei, G}, title = {Elucidating the reversible and irreversible self-assembly mechanisms of low-complexity aromatic-rich kinked peptides and steric zipper peptides.}, journal = {Nanoscale}, volume = {16}, number = {8}, pages = {4025-4038}, doi = {10.1039/d3nr05130g}, pmid = {38347806}, issn = {2040-3372}, mesh = {Protein Conformation ; *Amyloid/chemistry ; *Peptides/chemistry ; Molecular Dynamics Simulation ; Protein Conformation, beta-Strand ; }, abstract = {Many RNA-binding proteins such as fused-in sarcoma (FUS) can self-assemble into reversible liquid droplets and fibrils through the self-association of their low-complexity (LC) domains. Recent experiments have revealed that SYG-rich segments in the FUS LC domains play critical roles in the reversible self-assembly behaviors of FUS. These FUS LC segments alone can self-assemble into reversible kinked fibrils, which are markedly different from the canonical irreversible steric zipper β-sheet fibrils. However, the molecular determinants underlying the reversible and irreversible self-assembly are poorly understood. Herein we conducted extensive all-atom and coarse-grained molecular dynamics simulations of four representative hexapeptides: two low-complexity aromatic-rich kinked peptides from the amyotrophic lateral sclerosis-related FUS protein, FUS37-42 (SYSGYS) and FUS54-59 (SYSSYG); and two steric zipper peptides from Alzheimer's-associated Aβ and Tau proteins, Aβ16-21 (KLVFFA) and Tau306-311 (VQIVYK). We dissected their reversible and irreversible self-assembly dynamics, predicted their phase separation behaviors, and elucidated the underpinning molecular interactions. Our simulations showed that alternating stickers (Tyr) and spacers (Gly and Ser) in FUS37-42 and FUS54-59 facilitate the formation of highly dynamic coil-rich oligomers and lead to reversible self-assembly, while consecutive hydrophobic residues of LVFF in Aβ16-21 and IVY in Tau306-311 act as hydrophobic patches, favoring the formation of stable β-sheet-rich oligomers and driving the irreversible self-assembly. Intriguingly, we found that FUS37-42 and FUS54-59 peptides, possessing the same amino acid composition and the same number of sticker and spacer residues, display differential self-assembly propensities. This finding suggests that the self-assembly behaviors of FUS peptides are fine-tuned by the site-specific patterning of spacer residues (Ser and Gly). This study provides significant mechanistic insights into reversible and irreversible peptide self-assembly, which would be helpful for understanding the molecular mechanisms underlying the formation of biological liquid condensates and pathological solid amyloid fibrils.}, } @article {pmid38347888, year = {2024}, author = {Aoun, SM and O'Brien, MR and Knighting, K}, title = {Using the Carers' Alert Thermometer tool to identify needs and support family caregivers of people with motor neurone disease: moving beyond needs assessments.}, journal = {Palliative care and social practice}, volume = {18}, number = {}, pages = {26323524241228306}, pmid = {38347888}, issn = {2632-3524}, abstract = {BACKGROUND: Family caregivers of people with motor neurone disease (MND) experience adverse health outcomes as a result of their caregiving experience. This may be alleviated if their support needs are identified and addressed in a systematic and timely manner. The objective of this pilot study was to assess the feasibility and relevance of the Carers' Alert Thermometer (CAT) in home-based care, from the perspective of MND family caregivers. The tool provides a formal structure to facilitate discussions with caregivers to enable needs to be addressed.

METHODS: This mixed-method study was conducted in Western Australia (2020-2021). Forty-one caregivers and five MND Advisors participated in trialling the CAT intervention which consisted of two encounters with Advisors (6-8 weeks apart) to identify and address support needs through action plans. Caregivers' feedback was obtained via telephone interviews and a thematic analysis was undertaken.

RESULTS: Thirty caregivers completed two CAT assessments. Caregivers identified support priorities of managing their feelings and worries, providing emotional or spiritual care, information about the person's condition and how their care needs might change. Seventeen caregivers were interviewed and found that this assessment process adequately addressed their needs and it should be continued, it brought the focus onto them to clarify problems and work through solutions. The improvements that were suggested by them, including better information/education in palliative care, led to the development of an online support/information toolkit, which served to empower caregivers and staff by accessing relevant information and resources.

CONCLUSIONS: The CAT demonstrated utility for triaging caregivers most in need of additional support and those whom signposting to additional information and self-directed access to support was most appropriate. For any tool to become an integrated part of care, service provider support is key for implementation, allowing for the time resource required and an appropriate education and support structure. MND Associations have an important role in building stronger partnerships with supportive community networks, through compassionate communities models of care, to address the identified needs of MND families in a more sustainable and wholistic manner. Needs assessment is a means towards building this capacity between formal and informal networks.}, } @article {pmid38348026, year = {2024}, author = {Tang, C and Lei, X and Ding, Y and Yang, S and Ma, Y and He, D}, title = {Causal relationship between immune cells and neurodegenerative diseases: a two-sample Mendelian randomisation study.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1339649}, pmid = {38348026}, issn = {1664-3224}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; Causality ; *Multiple Sclerosis/genetics ; }, abstract = {BACKGROUND: There is increasing evidence that the types of immune cells are associated with various neurodegenerative diseases. However, it is currently unclear whether these associations reflect causal relationships.

OBJECTIVE: To elucidate the causal relationship between immune cells and neurodegenerative diseases, we conducted a two-sample Mendelian randomization (MR) analysis.

MATERIALS AND METHODS: The exposure and outcome GWAS data used in this study were obtained from an open-access database (https://gwas.mrcieu.ac.uk/), the study employed two-sample MR analysis to assess the causal relationship between 731 immune cell features and four neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). All immune cell data was obtained from Multiple MR methods were used to minimize bias and obtain reliable estimates of the causal relationship between the variables of interest and the outcomes. Instrumental variable selection criteria were restricted to ensure the accuracy and effectiveness of the causal relationship between species of immune cells and the risk of these neurodegenerative diseases.

RESULTS: The study identified potential causal relationships between various immune cells and different neurodegenerative diseases. Specifically, we found that 8 different types of immune cells have potential causal relationships with AD, 1 type of immune cells has potential causal relationships with PD, 6 different types of immune cells have potential causal relationships with ALS, and 6 different types of immune cells have potential causal relationships with MS.

CONCLUSION: Our study, through genetic means, demonstrates close causal associations between the specific types of immune cells and AD, PD, ALS and MS, providing useful guidance for future clinical researches.}, } @article {pmid38348223, year = {2024}, author = {Orfali, R and Alwatban, AZ and Orfali, RS and Lau, L and Chea, N and Alotaibi, AM and Nam, YW and Zhang, M}, title = {Oxidative stress and ion channels in neurodegenerative diseases.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1320086}, pmid = {38348223}, issn = {1664-042X}, support = {R33 NS101182/NS/NINDS NIH HHS/United States ; }, abstract = {Numerous neurodegenerative diseases result from altered ion channel function and mutations. The intracellular redox status can significantly alter the gating characteristics of ion channels. Abundant neurodegenerative diseases associated with oxidative stress have been documented, including Parkinson's, Alzheimer's, spinocerebellar ataxia, amyotrophic lateral sclerosis, and Huntington's disease. Reactive oxygen and nitrogen species compounds trigger posttranslational alterations that target specific sites within the subunits responsible for channel assembly. These alterations include the adjustment of cysteine residues through redox reactions induced by reactive oxygen species (ROS), nitration, and S-nitrosylation assisted by nitric oxide of tyrosine residues through peroxynitrite. Several ion channels have been directly investigated for their functional responses to oxidizing agents and oxidative stress. This review primarily explores the relationship and potential links between oxidative stress and ion channels in neurodegenerative conditions, such as cerebellar ataxias and Parkinson's disease. The potential correlation between oxidative stress and ion channels could hold promise for developing innovative therapies for common neurodegenerative diseases.}, } @article {pmid38349395, year = {2024}, author = {Soni, S and Lukhey, MS and Thawkar, BS and Chintamaneni, M and Kaur, G and Joshi, H and Ramniwas, S and Tuli, HS}, title = {A current review on P2X7 receptor antagonist patents in the treatment of neuroinflammatory disorders: a patent review on antagonists.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {397}, number = {7}, pages = {4643-4656}, pmid = {38349395}, issn = {1432-1912}, mesh = {*Patents as Topic ; Humans ; *Receptors, Purinergic P2X7/metabolism ; *Purinergic P2X Receptor Antagonists/therapeutic use/pharmacology ; Animals ; *Neuroinflammatory Diseases/drug therapy ; }, abstract = {Chronic inflammation is defined by an activated microglial state linked to all neurological disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (a motor neuron disease that affects the brain and spinal cord). P2X7 receptors (P2X7R) are ATP-activated ion-gated channels present on microglial surfaces. Prolonged ATP release under pathological settings results in sustained P2X7R activation, which leads to inflammasome development and cytokine release. P2X7R and its enabling roles have recently been linked to neurodegenerative diseases, making it a potential research subject. This research provides an overview of current patents for chemicals, biologics, and medicinal applications. The World Intellectual Property Organization (WIPO), European Patent Office (EPO, Espacenet), and the United States Patent and Trademark Office (USPTO) databases were searched for patents using the keywords "P2X7R and Neuroinflammation." During the study period from 2015 to 2021, 103 patents were examined. The countries that protected these innovations were the United States, PCT (Patent Cooperation Treaty states), Europe, Canada, Australia, and India. Janssen Pharmaceutica NV had the most applications, followed by Acetelion Pharmaceuticals LTD., Renovis Inc., Kelly Michael G, Kincaid Jhon, Merck Patent GMBH, H Lundbeck A/S, and many more. The P2X7R is a possible diagnostic and therapeutic target for cancer, pain disorders, and inflammation. For P2X7 R, several compounds have been discovered and are presently the subject of clinical trial investigations. This study featured patents for P2X7R antagonists, which help treat conditions including neuroinflammation.}, } @article {pmid38349514, year = {2024}, author = {Xu, Y and Lin, F and Liao, G and Sun, J and Chen, W and Zhang, L}, title = {Ripks and Neuroinflammation.}, journal = {Molecular neurobiology}, volume = {61}, number = {9}, pages = {6771-6787}, pmid = {38349514}, issn = {1559-1182}, support = {81971098//National Natural Science Foundation of China/ ; 82104144//National Natural Science Foundation of China/ ; }, mesh = {*Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Humans ; Animals ; *Neuroinflammatory Diseases/metabolism/pathology ; Inflammation/pathology/metabolism ; }, abstract = {Neuroinflammation is an immune response in the central nervous system and poses a significant threat to human health. Studies have shown that the receptor serine/threonine protein kinase family (RIPK) family, a popular research target in inflammation, has been shown to play an essential role in neuroinflammation. It is significant to note that the previous reviews have only examined the link between RIPK1 and neuroinflammation. However, it has yet to systematically analyze the relationship between the RIPK family and neuroinflammation. Activation of RIPK1 promotes neuroinflammation. RIPK1 and RIPK3 are responsible for the control of cell death, including apoptosis, necrosis, and inflammation. RIPK1 and RIPK3 regulate inflammatory responses through the release of damage in necroptosis. RIPK1 and RIPK3 regulate inflammatory responses by releasing damage-associated molecular patterns (DAMPs) during necrosis. In addition, activated RIPK1 nuclear translocation and its interaction with the BAF complex leads to upregulation of chromatin modification and inflammatory gene expression, thereby triggering inflammation. Although RIPK2 is not directly involved in regulating cell death, it is considered an essential target for treating neurological inflammation. When the peptidoglycan receptor detects peptidoglycan IE-DAP or MDP in bacteria, it prompts NOD1 and NOD2 to recruit RIPK2 and activate the XIAP E3 ligase. This leads to the K63 ubiquitination of RIPK2. This is followed by LUBAC-mediated linear ubiquitination, which activates NF-KB and MAPK pathways to produce cytokines and chemokines. In conclusion, there are seven known members of the RIPK family, but RIPK4, RIPK5, RIPK6, and RIPK7 have not been linked to neuroinflammation. This article seeks to explore the potential of RIPK1, RIPK2, and RIPK3 kinases as therapeutic interventions for neuroinflammation, which is associated with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ischemic stroke, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI).}, } @article {pmid38349516, year = {2024}, author = {Xin, Z and Xin, C and Huo, J and Liu, Q and Dong, H and Li, R and Liu, Y}, title = {Neuroprotective Effect of a Multistrain Probiotic Mixture in SOD1[G93A] Mice by Reducing SOD1 Aggregation and Targeting the Microbiota-Gut-Brain Axis.}, journal = {Molecular neurobiology}, volume = {61}, number = {12}, pages = {10051-10071}, pmid = {38349516}, issn = {1559-1182}, support = {H2021206310//the Natural Science Foundation of Hebei Province/ ; zh2018004//the Key Project of Technical Health Research and Achievement Transformation of Hebei Provincial Department of Health/ ; }, mesh = {Animals ; *Probiotics/pharmacology ; *Gastrointestinal Microbiome/drug effects ; *Superoxide Dismutase-1/metabolism/genetics ; *Mice, Transgenic ; *Neuroprotective Agents/pharmacology ; *Amyotrophic Lateral Sclerosis/pathology ; Brain-Gut Axis/drug effects/physiology ; Mice ; Autophagy/drug effects ; Brain/drug effects/metabolism ; Spinal Cord/drug effects/metabolism/pathology ; Protein Aggregates/drug effects ; Mice, Inbred C57BL ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the selective loss of motor neurons. A bidirectional communication system known as the "microbiota-gut-brain" axis has a regulatory function in neurodegenerative disorders. The impact of probiotics on ALS through the "microbiota-gut-brain" axis remains uncertain. A longitudinal investigation was conducted to examine the alterations in the structure of the ileum and colon in mutant superoxide dismutase 1 (SOD1[G93A]) transgenic mice models of ALS by using immunofluorescence and Western blotting. Subsequently, the mice were administered a multistrain probiotic mixture (LBE) or vehicle orally, starting from 60 days of age until the terminal stage of the disease. The effects of these agents on the behavior, gut microbiota, microbial metabolites, and pathological processes of the spinal and intestine of SOD1[G93A] mice were analyzed, with a focus on exploring potential protective mechanisms. SOD1[G93A] mice exhibit various structural abnormalities in the intestine. Oral administration of LBE improved the proinflammatory response, reduced aberrant superoxide dismutase 1 (SOD1) aggregation, and protected neuronal cells in the intestine and spinal cord of SOD1[G93A] mice. Furthermore, LBE treatment resulted in a change in intestinal microbiota, an increase in short-chain fatty acid levels, and an enhancement in autophagy flux. SOD1[G93A] mice exhibited various structural abnormalities in the intestine. LBE can improve the proinflammatory response, reduce aberrant SOD1 aggregation, and protect neuronal cells in the spinal cord and intestine of SOD1[G93A] mice. The positive effect of LBE can be attributed to increased short-chain fatty acids and enhanced autophagy flux.}, } @article {pmid38350046, year = {2024}, author = {Holdom, CJ and Janse van Mantgem, MR and He, J and Howe, SL and McCombe, PA and Fan, D and van den Berg, LH and Henderson, RD and van Eijk, R and Steyn, FJ and Ngo, ST}, title = {Variation in Resting Metabolic Rate Affects Identification of Metabolic Change in Geographically Distinct Cohorts of Patients With ALS.}, journal = {Neurology}, volume = {102}, number = {5}, pages = {e208117}, doi = {10.1212/WNL.0000000000208117}, pmid = {38350046}, issn = {1526-632X}, mesh = {Humans ; *Basal Metabolism ; Energy Metabolism ; *Amyotrophic Lateral Sclerosis/epidemiology/metabolism ; Australia/epidemiology ; Body Composition ; }, abstract = {BACKGROUND AND OBJECTIVES: Altered metabolism is observed in amyotrophic lateral sclerosis (ALS). However, without a standardized methodology to define metabolic changes, our understanding of factors contributing to and the clinical significance of altered metabolism in ALS is limited.

METHODS: We aimed to determine how geographic variation in metabolic rates influences estimates and accuracy of predicted resting energy expenditure (REE) in patients with ALS and controls, while validating the effectiveness of cohort-specific approaches in predicting altered metabolic rate in ALS. Participants from 3 geographically distinct sites across Australia, China, and the Netherlands underwent REE assessments, and we considered 22 unique equations for estimating REE. Analyses evaluated equation performance and the influence of demographics on metabolic status. Comparisons were made using standardized and local reference values to identify metabolic alterations.

RESULTS: 606 participants were included from Australia (patients with ALS: 140, controls: 154), the Netherlands (patients with ALS: 79, controls: 37) and China (patients with ALS: 67, controls: 129). Measured REE was variable across geographic cohorts, with fat-free mass contributing to this variation across all patients (p = 0.002 to p < 0.001). Of the 22 predication equations assessed, the Sabounchi Structure 4 (S4) equation performed relatively well across all control cohorts. Use of prediction thresholds generated using data from Australian controls generally increased the prevalence of hypermetabolism in Chinese (55%, [43%-67%]) and Dutch (44%, [33%-55%]) cases when compared with Australian cases (30%, [22%-38%]). Adjustment of prediction thresholds to consider geographically distinct characteristics from matched control cohorts resulted in a decrease in the proportion of hypermetabolic cases in Chinese and Dutch cohorts (25%-31% vs 55% and 20%-34% vs 43%-44%, respectively), and increased prevalence of hypometabolism in Dutch cases with ALS (1% to 8%-10%).

DISCUSSION: The identification of hypermetabolism in ALS is influenced by the formulae and demographic-specific prediction thresholds used for defining alterations in metabolic rate. A consensus approach is needed for identification of metabolic changes in ALS and will facilitate improved understanding of the cause and clinical significance of this in ALS.}, } @article {pmid38350049, year = {2024}, author = {Urushitani, M and Nakamura, R}, title = {Hypermetabolism in Amyotrophic Lateral Sclerosis: Step Ahead Toward Global Consensus.}, journal = {Neurology}, volume = {102}, number = {5}, pages = {e209179}, doi = {10.1212/WNL.0000000000209179}, pmid = {38350049}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Consensus ; }, } @article {pmid38350967, year = {2024}, author = {Rodriguez-Mogeda, C and van Ansenwoude, CMJ and van der Molen, L and Strijbis, EMM and Mebius, RE and de Vries, HE}, title = {The role of CD56[bright] NK cells in neurodegenerative disorders.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {48}, pmid = {38350967}, issn = {1742-2094}, mesh = {Humans ; Killer Cells, Natural ; Cytokines ; Cell Differentiation ; *Antineoplastic Agents ; *Neurodegenerative Diseases ; }, abstract = {Emerging evidence suggests a potential role for natural killer (NK) cells in neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. However, the precise function of NK cells in these diseases remains ambiguous. The existence of two NK cell subsets, CD56[bright] and CD56[dim] NK cells, complicates the understanding of the contribution of NK cells in neurodegeneration as their functions within the context of neurodegenerative diseases may differ significantly. CD56[bright] NK cells are potent cytokine secretors and are considered more immunoregulatory and less terminally differentiated than their mostly cytotoxic CD56[dim] counterparts. Hence, this review focusses on NK cells, specifically on CD56[bright] NK cells, and their role in neurodegenerative diseases. Moreover, it explores the mechanisms underlying their ability to enter the central nervous system. By consolidating current knowledge, we aim to provide a comprehensive overview on the role of CD56[bright] NK cells in neurodegenerative diseases. Elucidating their impact on neurodegeneration may have implications for future therapeutic interventions, potentially ameliorating disease pathogenesis.}, } @article {pmid38351547, year = {2024}, author = {Park, JJ and Chow, SM and Epskamp, S and Molenaar, PCM}, title = {Subgrouping with Chain Graphical VAR Models.}, journal = {Multivariate behavioral research}, volume = {59}, number = {3}, pages = {543-565}, pmid = {38351547}, issn = {1532-7906}, support = {U24 AA027684/AA/NIAAA NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Monte Carlo Method ; *Models, Statistical ; *Computer Simulation/statistics & numerical data ; Data Interpretation, Statistical ; Least-Squares Analysis ; }, abstract = {Recent years have seen the emergence of an "idio-thetic" class of methods to bridge the gap between nomothetic and idiographic inference. These methods describe nomothetic trends in idiographic processes by pooling intraindividual information across individuals to inform group-level inference or vice versa. The current work introduces a novel "idio-thetic" model: the subgrouped chain graphical vector autoregression (scGVAR). The scGVAR is unique in its ability to identify subgroups of individuals who share common dynamic network structures in both lag(1) and contemporaneous effects. Results from Monte Carlo simulations indicate that the scGVAR shows promise over similar approaches when clusters of individuals differ in their contemporaneous dynamics and in showing increased sensitivity in detecting nuanced group differences while keeping Type-I error rates low. In contrast, a competing approach-the Alternating Least Squares VAR (ALS VAR) performs well when groups were separated by larger distances. Further considerations are provided regarding applications of the ALS VAR and scGVAR on real data and the strengths and limitations of both methods.}, } @article {pmid38352350, year = {2024}, author = {Gomez, N and Hsieh, C and Li, X and Dykstra, M and Waksmacki, J and Altheim, C and Bechar, Y and Klim, J and Zaepfel, B and Rothstein, J and Tank, EE and Barmada, SJ}, title = {Counter-regulation of RNA stability by UPF1 and TDP43.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.31.578310}, pmid = {38352350}, issn = {2692-8205}, support = {R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; T32 GM007863/GM/NIGMS NIH HHS/United States ; T32 GM145470/GM/NIGMS NIH HHS/United States ; }, abstract = {RNA quality control is crucial for proper regulation of gene expression. Disruption of nonsense mediated mRNA decay (NMD), the primary RNA decay pathway responsible for the degradation of transcripts containing premature termination codons (PTCs), can disrupt development and lead to multiple diseases in humans and other animals. Similarly, therapies targeting NMD may have applications in hematological, neoplastic and neurological disorders. As such, tools capable of accurately quantifying NMD status could be invaluable for investigations of disease pathogenesis and biomarker identification. Toward this end, we assemble, validate, and apply a next-generation sequencing approach (NMDq) for identifying and measuring the abundance of PTC-containing transcripts. After validating NMDq performance and confirming its utility for tracking RNA surveillance, we apply it to determine pathway activity in two neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) characterized by RNA misprocessing and abnormal RNA stability. Despite the genetic and pathologic evidence implicating dysfunctional RNA metabolism, and NMD in particular, in these conditions, we detected no significant differences in PTC-encoding transcripts in ALS models or disease. Contrary to expectations, overexpression of the master NMD regulator UPF1 had little effect on the clearance of transcripts with PTCs, but rather restored RNA homeostasis through differential use and decay of alternatively poly-adenylated isoforms. Together, these data suggest that canonical NMD is not a significant contributor to ALS/FTD pathogenesis, and that UPF1 promotes neuronal survival by regulating transcripts with abnormally long 3'UTRs.}, } @article {pmid38352376, year = {2024}, author = {Amado, DA and Robbins, AB and Smith, AR and Whiteman, KR and Chillon Bosch, G and Chen, Y and Fuller, JA and Izda, A and Nelson, S and Dichter, AI and Monteys, AM and Davidson, BL}, title = {AAV-based delivery of RNAi targeting Ataxin-2 improves survival, strength, and pathology in mouse models of rapidly and slowly progressive sporadic ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.31.578314}, pmid = {38352376}, issn = {2692-8205}, support = {K08 NS114106/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron death due to nuclear loss and cytoplasmic aggregation of the splice factor TDP-43. Pathologic TDP-43 associates with stress granules (SGs) and downregulating the SG-associated protein Ataxin-2 (Atxn2) using antisense oligonucleotides (ASO) prolongs survival in the TAR4/4 sporadic ALS mouse model, a strategy now in clinical trials. Here, we used AAV-mediated RNAi delivery to achieve lasting and targeted Atxn2 knockdown after a single injection. To achieve this, a novel AAV with improved transduction potency of our target cells was used to deliver Atxn2 -targeting miRNAs. Mouse dosing studies demonstrated 55% Atxn2 knockdown in frontal cortex and 25% knockdown throughout brainstem and spinal cord after intracerebroventricular injection at a dose 40x lower than used in other recent studies. In TAR4/4 mice, miAtxn2 treatment increased mean and median survival by 54% and 45% respectively (p<0.0003). Mice showed robust improvement across strength-related measures ranging from 24-75%. Interestingly, treated mice showed increased vertical activity above wildtype, suggesting unmasking of an FTD phenotype with improved strength. Histologically, lower motor neuron survival improved with a concomitant reduction in CNS inflammatory markers. Additionally, phosphorylated TDP-43 was reduced to wildtype levels. Bulk RNA sequencing revealed correction of 153 genes in the markedly dysregulated transcriptome of mutant mice, several of which are described in the human ALS literature. In slow progressing hemizygous mice, treatment rescued weight loss and improved gait at late time points. Cumulatively the data support the utility of AAV-mediated RNAi against Atxn2 as a robust and translatable treatment strategy for sporadic ALS.}, } @article {pmid38352403, year = {2024}, author = {Sirtori, R and Gregoire, M and Collins, A and Santangelo, S and Chatragadda, B and Cullen, R and Ratti, A and Fallini, C}, title = {Altered nuclear envelope homeostasis is a key pathogenic event in C9ORF72-linked ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.02.01.578318}, pmid = {38352403}, issn = {2692-8205}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; R01 NS116143/NS/NINDS NIH HHS/United States ; }, abstract = {ALS and FTD are complex neurodegenerative disorders that primarily affects motor neurons in the brain and spinal cord, and cortical neurons in the frontal lobe. Although the pathogenesis of ALS/FTD is unclear, recent research spotlights nucleocytoplasmic transport impairment, DNA damage, and nuclear abnormalities as drivers of neuronal death. In this study, we show that loss of nuclear envelope (NE) integrity is a key pathology associated with nuclear pore complex (NPC) injury in C9ORF72 mutant neurons. Importantly, we show that mechanical stresses generated by cytoskeletal forces on the NE can lead to NPC injury, loss of nuclear integrity, and accumulation of DNA damage. Importantly, we demonstrate that restoring NE tensional homeostasis, by disconnecting the nucleus from the cytoskeleton, can rescue NPC injury and reduce DNA damage in C9ORF72 mutant cells. Together, our data suggest that modulation of NE homeostasis and repair may represent a novel and promising therapeutic target for ALS/FTD.}, } @article {pmid38352429, year = {2024}, author = {Alessandrini, F and Wright, M and Kurosaki, T and Maquat, LE and Kiskinis, E}, title = {ALS-Associated TDP-43 Dysfunction Compromises UPF1-Dependent mRNA Metabolism Pathways Including Alternative Polyadenylation and 3'UTR Length.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.31.578311}, pmid = {38352429}, issn = {2692-8205}, abstract = {UPF1-mediated decay entails several mRNA surveillance pathways that play a crucial role in cellular homeostasis. However, the precise role of UPF1 in postmitotic neurons remains unresolved, as does its activity in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease characterized by TDP-43 pathology and disrupted mRNA metabolism. Here, we used human iPSC-derived spinal motor neurons (MNs) to identify mRNAs subject to UPF1 degradation by integrating RNA-seq before and after UPF1 knockdown with RIP-seq to identify RNAs that co-immunoprecipitate with the active form of phosphorylated UPF1. We define a stringent set of bona fide UPF1 targets in MNs that are functionally enriched for autophagy and structurally enriched for GC-rich and long 3' UTRs but not for premature termination codon (PTC)-containing transcripts. TDP-43 depletion in iPSC-derived MNs reduces UPF1 phosphorylation and consequently post-transcriptional upregulation of UPF1 targets, suggesting that TDP-43 dysfunction compromises UPF1-mediated mRNA surveillance. Intriguingly, our datasets reveal that UPF1 and TDP-43 regulate alternative polyadenylation and 3'UTR length of mRNAs associated with synaptic and axonal function, a process that we find to be compromised in ALS models in vitro and ALS patient tissue. Our study provides a comprehensive description of UPF1-mediated mRNA decay activity in neurons, reveals overlapping roles between UPF1 and TDP-43 in regulating 3'UTR length, and offers novel insight into the intricate interplay between RNA metabolism and neurodegeneration in ALS.}, } @article {pmid38353166, year = {2024}, author = {Hart, AA and Swenson, A and Narayanan, NS and Simmering, JE}, title = {Rurality modifies the association between symptoms and the diagnosis of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {517-527}, pmid = {38353166}, issn = {2167-9223}, support = {K12 TR004382/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Male ; Female ; Middle Aged ; *Rural Population/statistics & numerical data ; Aged ; Adult ; United States/epidemiology ; Urban Population/statistics & numerical data ; }, abstract = {OBJECTIVE: We utilized national claims-based data to identify the change in odds of diagnosis of ALS following possible-ALS-symptoms-and whether the change varies in urban/rural areas.

METHODS: Insurance claims were obtained from the Merative MarketScan databases, 2001-2021 in the United States. Individuals with incident ALS were identified and matched on age, sex, and enrollment period to individuals without ALS. For all individuals, claims for 8 possible-ALS-symptoms in the time before any ALS diagnosis were identified. We then used conditional logistic regression to estimate the odds of being diagnosed with ALS following these symptoms and whether the association varied by urban/rural location.

RESULTS: 19,226 individuals with ALS were matched to 96,126 controls. Patients with ALS were more likely to live in an urban area (87.0% vs 84.5%). Of those with ALS 84% had 1+ of our 8 possible-ALS-symptom compared to 51% of controls. After adjustment for confounders, having possible-ALS-symptoms increased the odds of a future ALS diagnosis by nearly 5-fold. A dose-response pattern was present with increasing odds as the number of symptoms increased. In all models, urban areas were associated with increased odds of diagnosis with ALS while the effect of having a symptom was smaller in urban places. Urban cases of ALS are diagnosed at younger ages.

CONCLUSIONS: These results suggest symptoms may appear and be noted years before the diagnosis of ALS. Additionally, rural patients are diagnosed at later ages with a greater dependence on symptoms than urban patients. These results highlight potential improvements for screening for ALS.}, } @article {pmid38354654, year = {2024}, author = {Li, M and Zhao, Z and Zhang, Y and Guo, X and Zhang, Y and Wang, J and Liu, Y and Yang, L and Mou, W and Zhang, X and Gao, H}, title = {Chemometrics combined with comprehensive two-dimensional gas chromatography-mass spectrometry for the identification of Baijiu vintage.}, journal = {Food chemistry}, volume = {444}, number = {}, pages = {138690}, doi = {10.1016/j.foodchem.2024.138690}, pmid = {38354654}, issn = {1873-7072}, mesh = {Gas Chromatography-Mass Spectrometry/methods ; *Chemometrics ; Least-Squares Analysis ; }, abstract = {The identification of baijiu vintage is crucial for quality assessment and economic value determination. However, its complex composition and multifaceted influences pose significant technical challenges, necessitating research into its aging mechanisms and the development of related identification methods. This study utilized Chemometrics in conjunction with GC × GC-TOFMS for Baijiu Vintage identification. Data compression achieved a reduction of over 1000-fold without compromising key information, enabling analysis on many samples and get their changing regular in a big matrix by MCR. Subsequently, MCR-ALS facilitated the extraction of physical and chemical meaningful information related to baijiu vintage. Key MCR principal components suitable for qualitative and quantitative assessments were selected using CARS-PLS. The regression model demonstrated errors of less than one year. Furthermore, a PLS-DA model provided 30 MCR principal components as potential markers. The research results provide technical support for baijiu vintage identification and lay the groundwork for studying the changing patterns of flavor compounds in baijiu.}, } @article {pmid38354672, year = {2024}, author = {Aradhye, P and Jha, S and Saha, P and Patwardhan, RS and Noothalapati, H and Krishna, CM and Patwardhan, S}, title = {Distinct spectral signatures unfold ECM stiffness-triggered biochemical changes in breast cancer cells.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {311}, number = {}, pages = {123994}, doi = {10.1016/j.saa.2024.123994}, pmid = {38354672}, issn = {1873-3557}, mesh = {Humans ; Female ; *Breast Neoplasms/metabolism ; Extracellular Matrix/chemistry/metabolism ; Collagen/analysis ; }, abstract = {Cancer progression often accompanies the stiffening of extracellular matrix (ECM) in and around the tumor, owing to extra deposition and cross-linking of collagen. Stiff ECM has been linked with poor prognosis and is known to fuel invasion and metastasis, notably in breast cancer. However, the underlying biochemical or metabolic changes and the cognate molecular signatures remain elusive. Here, we explored Raman spectroscopy to unveil the spectral fingerprints of breast cancer cells in response to extracellular mechanical cues. Using stiffness-tuneable hydrogels, we showed that cells grown on stiff ECM displayed morphological changes with high proliferation. We further demonstrated that Raman Spectroscopy, a label-free and non-invasive technique, could provide comprehensive information about the biochemical environment of breast cancer cells in response to varying ECM stiffness. Raman spectroscopic analysis classified the cells into distinct clusters based on principal component-based linear discriminant analysis (PC-LDA). Multivariate curve resolution-alternating least squares (MCR-ALS) analysis indicated that cells cultured on stiff ECM exhibited elevated nucleic acid content and lesser lipids. Interestingly, increased intensity of Raman bands corresponding to cytochrome-c was also observed in stiff ECM conditions, suggesting mitochondrial modulation. The key findings harboured by spectral profiles were also corroborated by transmission electron microscopy, confirming altered metabolic status as reflected by increased mitochondria number and decreased lipid droplets in response to ECM stiffening. Collectively, these findings not only give the spectral signatures for mechanoresponse but also provide the landscape of biochemical changes in response to ECM stiffening.}, } @article {pmid38354985, year = {2024}, author = {Zamani, A and Thomas, E and Wright, DK}, title = {Sex biology in amyotrophic lateral sclerosis.}, journal = {Ageing research reviews}, volume = {95}, number = {}, pages = {102228}, doi = {10.1016/j.arr.2024.102228}, pmid = {38354985}, issn = {1872-9649}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Brain/pathology ; Biology ; }, abstract = {Although sex differences in amyotrophic lateral sclerosis (ALS) have not been studied systematically, numerous clinical and preclinical studies have shown sex to be influential in disease prognosis. Moreover, with the development of advanced imaging tools, the difference between male and female brain in structure and function and their response to neurodegeneration are more definitive. As discussed in this review, ALS patients exhibit a sex bias pertaining to the features of the disease, and their clinical, pathological, (and pathophysiological) phenotypes. Several epidemiological studies have indicated that this sex disparity stems from various aetiologies, including sex-specific brain structure and neural functioning, genetic predisposition, age, gonadal hormones, susceptibility to traumatic brain injury (TBI)/head trauma and lifestyle factors.}, } @article {pmid38355792, year = {2024}, author = {Hruska-Plochan, M and Wiersma, VI and Betz, KM and Mallona, I and Ronchi, S and Maniecka, Z and Hock, EM and Tantardini, E and Laferriere, F and Sahadevan, S and Hoop, V and Delvendahl, I and Pérez-Berlanga, M and Gatta, B and Panatta, M and van der Bourg, A and Bohaciakova, D and Sharma, P and De Vos, L and Frontzek, K and Aguzzi, A and Lashley, T and Robinson, MD and Karayannis, T and Mueller, M and Hierlemann, A and Polymenidou, M}, title = {A model of human neural networks reveals NPTX2 pathology in ALS and FTLD.}, journal = {Nature}, volume = {626}, number = {8001}, pages = {1073-1083}, pmid = {38355792}, issn = {1476-4687}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *C-Reactive Protein/metabolism ; *DNA-Binding Proteins/deficiency/metabolism ; *Frontotemporal Lobar Degeneration/metabolism/pathology ; *Nerve Net/metabolism/pathology ; *Nerve Tissue Proteins/metabolism ; Neural Stem Cells/cytology ; Neuroglia/cytology ; *Neurons/cytology/metabolism ; Reproducibility of Results ; Pentraxins ; }, abstract = {Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies[1], which involve human-specific mechanisms[2-5] that cannot be directly studied in animal models. Here, to explore the emergence and consequences of TDP-43 pathologies, we generated induced pluripotent stem cell-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors[6]. Single-cell transcriptomics and comparison to independent neural stem cells[7] showed that iCoMoNSCs are uniquely homogenous and self-renewing. Differentiated iCoMoNSCs formed a self-organized multicellular system consisting of synaptically connected and electrophysiologically active neurons, which matured into long-lived functional networks (which we designate iNets). Neuronal and glial maturation in iNets was similar to that of cortical organoids[8]. Overexpression of wild-type TDP-43 in a minority of neurons within iNets led to progressive fragmentation and aggregation of the protein, resulting in a partial loss of function and neurotoxicity. Single-cell transcriptomics revealed a novel set of misregulated RNA targets in TDP-43-overexpressing neurons and in patients with TDP-43 proteinopathies exhibiting a loss of nuclear TDP-43. The strongest misregulated target encoded the synaptic protein NPTX2, the levels of which are controlled by TDP-43 binding on its 3' untranslated region. When NPTX2 was overexpressed in iNets, it exhibited neurotoxicity, whereas correcting NPTX2 misregulation partially rescued neurons from TDP-43-induced neurodegeneration. Notably, NPTX2 was consistently misaccumulated in neurons from patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby revealing a TDP-43-dependent pathway of neurotoxicity.}, } @article {pmid38356047, year = {2024}, author = {Wimmer, N and Müller, HP and Metze, P and Rasche, V and Ludolph, AC and Kassubek, J}, title = {The central pattern of weakness of ALS: Morphological correlates in whole-body muscle MRI.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {4}, pages = {1000-1010}, pmid = {38356047}, issn = {2328-9503}, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Whole Body Imaging ; Muscle, Skeletal/pathology ; Paresis ; }, abstract = {OBJECTIVE: Monosynaptically cortically innervated α-motoneurons are early and strongly involved in amyotrophic lateral sclerosis (ALS). Consequently, the muscles that receive the strongest direct corticomotoneuronal input are the clinically most affected. To objectify this concept in vivo through morphological image correlates, whole-body magnetic resonance imaging (MRI) with muscle signal analysis was performed in patients with ALS compared to healthy controls.

METHODS: Modified Dixon-based whole-body MRI was acquired in patients with ALS (n = 33) and matched healthy controls (n = 30). Manual labeling of limb muscle MRI was performed, and a specific subset of nine muscles, selected as pairs of muscle groups with different corticomotoneuronal input, was analyzed per subject based on their volume, fat fraction, and functional remaining muscle area (fRMA).

RESULTS: Statistical analysis of 978 muscles in total revealed significantly decreased volumes, decreased fRMA, and increased fat fraction in the muscles of patients with ALS compared to controls. The clinical degree of pareses of directly innervated muscles was significantly worse than that of less directly innervated muscles in each comparison. The muscles receiving stronger direct corticomotoneuronal input showed more pronounced morphological involvement compared to those with less monosynaptic corticomotoneuronal input (fRMA, significant in three pairwise comparisons).

INTERPRETATION: In conclusion, whole-body MRI-based muscle analysis provided additional evidence for a characteristic pattern of pareses in ALS. This technical approach (parameterization and quantification of muscle alterations from MRI) to patients with ALS could pave the way for the future establishment of a diagnostic algorithm of muscle MRI for ALS and may serve as a biomarker.}, } @article {pmid38356886, year = {2024}, author = {Giardina, E and Mandich, P and Ghidoni, R and Ticozzi, N and Rossi, G and Fenoglio, C and Tiziano, FD and Esposito, F and Capellari, S and Nacmias, B and Mineri, R and Campopiano, R and Di Pilla, L and Sammarone, F and Zampatti, S and Peconi, C and De Angelis, F and Palmieri, I and Galandra, C and Nicodemo, E and Origone, P and Gotta, F and Ponti, C and Nicsanu, R and Benussi, L and Peverelli, S and Ratti, A and Ricci, M and Di Fede, G and Magri, S and Serpente, M and Lattante, S and Domi, T and Carrera, P and Saltimbanco, E and Bagnoli, S and Ingannato, A and Albanese, A and Tagliavini, F and Lodi, R and Caltagirone, C and Gambardella, S and Valente, EM and Silani, V}, title = {Distribution of the C9orf72 hexanucleotide repeat expansion in healthy subjects: a multicenter study promoted by the Italian IRCCS network of neuroscience and neurorehabilitation.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1284459}, pmid = {38356886}, issn = {1664-2295}, abstract = {INTRODUCTION: High repeat expansion (HRE) alleles in C9orf72 have been linked to both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); ranges for intermediate allelic expansions have not been defined yet, and clinical interpretation of molecular data lacks a defined genotype-phenotype association. In this study, we provide results from a large multicenter epidemiological study reporting the distribution of C9orf72 repeats in healthy elderly from the Italian population.

METHODS: A total of 967 samples were collected from neurologically evaluated healthy individuals over 70 years of age in the 13 institutes participating in the RIN (IRCCS Network of Neuroscience and Neurorehabilitation) based in Italy. All samples were genotyped using the AmplideXPCR/CE C9orf72 Kit (Asuragen, Inc.), using standardized protocols that have been validated through blind proficiency testing.

RESULTS: All samples carried hexanucleotide G4C2 expansion alleles in the normal range. All samples were characterized by alleles with less than 25 repeats. In particular, 93.7% of samples showed a number of repeats ≤10, 99.9% ≤20 repeats, and 100% ≤25 repeats.

CONCLUSION: This study describes the distribution of hexanucleotide G4C2 expansion alleles in an Italian healthy population, providing a definition of alleles associated with the neurological healthy phenotype. Moreover, this study provides an effective model of federation between institutes, highlighting the importance of sharing genomic data and standardizing analysis techniques, promoting translational research. Data derived from the study may improve genetic counseling and future studies on ALS/FTD.}, } @article {pmid38357638, year = {2024}, author = {Gerritzen, EV and Lee, AR and McDermott, O and Coulson, N and Orrell, M}, title = {Online peer support for people with Amyotrophic Lateral Sclerosis (ALS): a narrative synthesis systematic review.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1138530}, pmid = {38357638}, issn = {2673-253X}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) significantly impacts the lives of people with the diagnosis and their families. A supportive social environment is important for people with ALS to adopt effective coping strategies and health behaviours, and reduce depressive symptoms. Peer support can provide a supportive social environment and can happen in-person and online. Advantages of online peer support are that people can engage from their own home, at their own time and pace, and that it offers a variety of different platforms and modes of communication.

OBJECTIVES: To (1) explore the benefits and challenges of online peer support for people with ALS, and (2) identify successful elements of online peer support for people with ALS.

METHODS: The method selected for this systematic review was a narrative synthesis. Six databases were systematically searched in April 2020 for articles published between 1989 and 2020. The search was updated in June 2022. The quality of the included studies was assessed with the Critical Appraisal Skills Programme qualitative research checklist.

RESULTS: 10,987 unique articles were identified through the systematic database search. Of those, 9 were included in this review. One of the main benefits of online peer support was that people could communicate using text rather than needing verbal communication, which can be challenging for some with ALS. Successful elements included using profile pages and graphics to identify others with similar or relevant experiences. Challenges included ALS symptoms which could make it difficult to use technological devices.

CONCLUSIONS: Peer support can provide a non-judgmental and supportive environment for people with ALS, in which they can exchange experiences and emotional support, which can help people in developing adaptive coping strategies. However, ALS symptoms may make it more difficult for people to use technological devices and engage in online peer support. More research is needed to identify what kind of specific barriers people with ALS experience, and how these could be overcome.}, } @article {pmid38358049, year = {2024}, author = {Milani, A and Panozzo, S and Grazia, TM and Scarabel, L}, title = {Development of a rapid detection assay for acetolactate synthase inhibitors resistance in three Amaranthus weed species through loop-mediated isothermal amplification.}, journal = {Journal of the science of food and agriculture}, volume = {104}, number = {9}, pages = {5522-5532}, doi = {10.1002/jsfa.13385}, pmid = {38358049}, issn = {1097-0010}, support = {//Regione Emilia-Romagna/ ; }, mesh = {*Amaranthus/genetics/drug effects ; *Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Nucleic Acid Amplification Techniques/methods ; *Herbicide Resistance/genetics ; *Plant Weeds/drug effects/genetics ; *Plant Proteins/genetics/metabolism ; *Herbicides/pharmacology ; Enzyme Inhibitors/pharmacology ; Molecular Diagnostic Techniques ; }, abstract = {BACKGROUND: The early detection of herbicide resistance in weeds is a key factor to avoid herbicide waste and improve agriculture sustainability. The present study aimed to develop and validate an allele-specific loop-mediated isothermal amplification (AS-LAMP) assay for the quick on-site detection of the resistance-endowing point mutation Trp-574-Leu in the acetolactate synthase (ALS) gene in three widely diffused Amaranthus weed species: Amaranthus retroflexus, Amaranthus hybridus and Amaranthus tuberculatus.

RESULTS: The AS-LAMP protocol was developed on wild-type and ALS-mutant plants of the three species and revealed that the amplification approach with only the primer set specific for the mutant allele (574-Leu) was the most promising. The validation and estimation of the AS-LAMP performance evaluated by comparing the results with those of the molecular marker (cleaved amplified polymorphic sequences) indicated that, although the sensitivity and specificity were relatively high in all species (overall 100 and > 65%, respectively), precision was high for A. hybridus L. and A. retroflexus L. (75 and 79%, respectively), but quite low for A. tuberculatus (Moq.) J. D. Sauer (59%). The LAMP assay was also effective on crude genomic DNA extraction, allowing the quick detection of mutant plants in field situation (on site resistance detection).

CONCLUSION: The proposed AS-LAMP method has proven to be a promising technique for rapid detection of resistance as a result of Trp-574-Leu on the two monoecious weedy Amaranthus species but resulted less effective in the genetically variable dioecious species A. tuberculatus. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid38358553, year = {2024}, author = {Brakemeier, S and Lipka, J and Schlag, M and Kleinschnitz, C and Hagenacker, T}, title = {Risdiplam improves subjective swallowing quality in non-ambulatory adult patients with 5q-spinal muscular atrophy despite advanced motor impairment.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2649-2657}, pmid = {38358553}, issn = {1432-1459}, mesh = {Humans ; Male ; Female ; Middle Aged ; Adult ; *Deglutition Disorders/etiology/physiopathology/drug therapy ; Pyrimidines/therapeutic use/pharmacology ; Aged ; Spinal Muscular Atrophies of Childhood/drug therapy/physiopathology/complications ; Treatment Outcome ; Deglutition/physiology/drug effects ; Prospective Studies ; Muscular Atrophy, Spinal/drug therapy/physiopathology ; Young Adult ; *Azo Compounds ; }, abstract = {BACKGROUND: 5q-associated spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons with consecutive weakness and atrophy of the limb, respiratory, and bulbar muscles. While trunk and limb motor function improve or stabilize in adults with SMA under nusinersen and risdiplam treatment, the efficacy on bulbar function in this age group of patients remains uncertain. However, it is important to assess bulbar dysfunction, which frequently occurs in the disease course and is associated with increased morbidity and mortality.

METHODS: Bulbar function was evaluated prospectively in 25 non-ambulatory adults with type 2 and 3 SMA before and 4 and 12 months after risdiplam treatment initiation using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (b-ALSFRS-R). Extremity function was assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM).

RESULTS: Subjective swallowing quality, measured with the SSQ, improved after 12 months of therapy with risdiplam. For the b-ALSFRS-R, a non-significant trend towards improvement was observed. The RULM score improved after 12 months of risdiplam therapy, but not the HFMSE score. HFMSE and RULM scores did not correlate with the SSQ but the b-ALSFRS-R score at baseline.

CONCLUSIONS: The improvement in subjective swallowing quality under risdiplam treatment, despite an advanced disease stage with severe motor deficits, strengthens the importance of a standardized bulbar assessment in addition to established motor scores. This may reveal relevant treatment effects and help individualize treatment decisions in the future.}, } @article {pmid38359044, year = {2024}, author = {Vieira, FG and Tassinari, VR and Kidd, JD and Moreno, A and Thompson, K and Perrin, S and Gill, A and Hatzipetros, T}, title = {PERK modulation, with GSK2606414, Sephin1 or salubrinal, failed to produce therapeutic benefits in the SOD1G93A mouse model of ALS.}, journal = {PloS one}, volume = {19}, number = {2}, pages = {e0292190}, pmid = {38359044}, issn = {1932-6203}, mesh = {Mice ; Humans ; Animals ; *Guanabenz/pharmacology/therapeutic use/*analogs & derivatives ; eIF-2 Kinase/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Clonidine ; Unfolded Protein Response ; Adrenergic alpha-2 Receptor Agonists ; Adenine/*analogs & derivatives ; *Cinnamates ; *Indoles ; Thiourea/*analogs & derivatives ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has been linked to overactivity of the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) pathway, both in ALS patients and mouse models. However, attempts to pharmacologically modulate PERK for therapeutic benefit have yielded inconsistent and often conflicting results. This study sought to address these discrepancies by comprehensively evaluating three commonly used, CNS-penetrant, PERK modulators (GSK2606414, salubrinal, and Sephin1) in the same experimental models, with the goal of assessing the viability of targeting the PERK pathway as a therapeutic strategy for ALS. To achieve this goal, a tunicamycin-challenge assay was developed using wild-type mice to monitor changes in liver UPR gene expression in response to PERK pathway modulation. Subsequently, multiple dosing regimens of each PERK modulator were tested in standardized, well-powered, gender-matched, and litter-matched survival efficacy studies using the SOD1G93A mouse model of ALS. The alpha-2-adrenergic receptor agonist clonidine was also tested to elucidate the results obtained from the Sephin1, and of the previously reported guanabenz studies, by comparing the effects of presence or absence of α-2 agonism. The results revealed that targeting PERK may not be an ideal approach for ALS treatment. Inhibiting PERK with GSK2606414 or activating it with salubrinal did not confer therapeutic benefits. While Sephin1 showed some promising therapeutic effects, it appears that these outcomes were mediated through PERK-independent mechanisms. Clonidine also produced some favorable therapeutic effects, which were unexpected and not linked to the UPR. In conclusion, this study highlights the challenges of pharmacologically targeting PERK for therapeutic purposes in the SOD1G93A mouse model and suggests that exploring other targets within, and outside, the UPR may be more promising avenues for ALS treatment.}, } @article {pmid38360060, year = {2024}, author = {El-Ghazouly, DE and Yassien, RI}, title = {Bisphosphonate's effect on the tongue in adult male albino rats and the possible protective role of rutin: light and scanning electron microscopic study.}, journal = {Anatomy & cell biology}, volume = {57}, number = {1}, pages = {129-142}, pmid = {38360060}, issn = {2093-3665}, abstract = {Alendronate sodium (ALS) is a nitrogen-containing bisphosphonate used for the treatment of different bone disorders. However, its adverse effect on oral soft tissue has been detected. Rutin (RUT) is natural flavonoid with antioxidant and anti-inflammatory properties. This work aimed to investigate the possible effect of ALS on the tongue of adult male albino rats and to evaluate the possible protective role of RUT. Forty adult male albino rats were equally divided into four groups: group I (control), group II (RUT): Received RUT 50 mg/kg, group III (ALS): Received ALS 1 mg/kg, group IV (ALS+RUT): Received ALS and RUT with the same doses as pervious groups. The drugs were given once daily for 5 weeks. Tongue specimens were taken and processed for light and scanning electron microscopic inspection. ALS treated group revealed structural changes in the tongue in the form of decrease in the height of the filiform papillae with blunt ends, marked atrophy in some papillae with areas of focal loss, loss of some epithelial cells, pyknotic nuclei and cytoplasmic vacuoles in some epithelial cells. The lamina propria showed inflammatory cellular infiltration with congested blood vessels. Statistically, there were highly significant decrease in the number of proliferating cell nuclear antigen immunopositive cells, area percentage of Bcl-2 immunoexpression and highly significant increase in the collagen content compared to control group. Administration of RUT with ALS minimizes these changes. RUT protected the rat tongue against the histological and immunohistochemical changes induced by ALS through its antioxidant and anti-inflammatory properties.}, } @article {pmid38362496, year = {2024}, author = {Hoyer, LL and Freeman, BA and Hogan, EK and Hernandez, AG}, title = {Use of a Candida albicans SC5314 PacBio HiFi reads dataset to close gaps in the reference genome assembly, reveal a subtelomeric gene family, and produce accurate phased allelic sequences.}, journal = {Frontiers in cellular and infection microbiology}, volume = {14}, number = {}, pages = {1329438}, pmid = {38362496}, issn = {2235-2988}, support = {R15 DE026401/DE/NIDCR NIH HHS/United States ; }, mesh = {*Candida albicans/genetics ; *Genome, Fungal ; Base Sequence ; Repetitive Sequences, Nucleic Acid ; Telomere/genetics ; Sequence Analysis, DNA/methods ; High-Throughput Nucleotide Sequencing ; }, abstract = {Candida albicans SC5314 is the most-often used strain for molecular manipulation of the species. The SC5314 reference genome sequence is the result of considerable effort from many scientists and has advanced research into fungal biology and pathogenesis. Although the resource is highly developed and presented in a phased diploid format, the sequence includes gaps and does not extend to the telomeres on its eight chromosome pairs. Accurate SC5314 genome assembly is complicated by the presence of extensive repeated sequences and considerable allelic length variation at some loci. Advances in genome sequencing technology provide the tools to obtain highly accurate long-read data that span even the most-difficult-to-assemble genome regions. Here, we describe derivation of a PacBio HiFi data set and creation of a collapsed haploid telomere-to-telomere assembly of the SC5314 genome (ASM3268872v1) that revealed previously unknown features of the strain. ASM3268872v1 subtelomeric distances were up to 19 kb larger than in the reference genome and revealed a family of highly conserved DNA helicase-encoding genes at 10 of the 16 chromosome ends. We also describe alignments of individual HiFi reads to deduce accurate diploid sequences for the most notoriously difficult-to-assemble C. albicans genes: the agglutinin-like sequence (ALS) gene family. We provide a tutorial that demonstrates how the HiFi reads can be visualized to explore any region of interest. Availability of the HiFi reads data set and the ASM3268872v1 comparative guide assembly will streamline research efforts because accurate diploid sequences can be derived using simple in silico methods rather than time-consuming laboratory-bench approaches.}, } @article {pmid38363426, year = {2024}, author = {Tziortzouda, P and Steyaert, J and Scheveneels, W and Sicart, A and Stoklund Dittlau, K and Barbosa Correia, AM and Burg, T and Pal, A and Hermann, A and Van Damme, P and Moens, TG and Van Den Bosch, L}, title = {PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {41}, pmid = {38363426}, issn = {1432-0533}, support = {P40 OD018537/OD/NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; Glycogen Synthase Kinase 3/genetics/metabolism ; Protein Phosphatase 2/genetics/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; *Neurodegenerative Diseases/pathology ; Kinesins/genetics/metabolism ; Motor Neurons/metabolism ; Drosophila/genetics/metabolism ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which currently lacks effective treatments. Mutations in the RNA-binding protein FUS are a common cause of familial ALS, accounting for around 4% of the cases. Understanding the mechanisms by which mutant FUS becomes toxic to neurons can provide insight into the pathogenesis of both familial and sporadic ALS. We have previously observed that overexpression of wild-type or ALS-mutant FUS in Drosophila motor neurons is toxic, which allowed us to screen for novel genetic modifiers of the disease. Using a genome-wide screening approach, we identified Protein Phosphatase 2A (PP2A) and Glycogen Synthase Kinase 3 (GSK3) as novel modifiers of FUS-ALS. Loss of function or pharmacological inhibition of either protein rescued FUS-associated lethality in Drosophila. Consistent with a conserved role in disease pathogenesis, pharmacological inhibition of both proteins rescued disease-relevant phenotypes, including mitochondrial trafficking defects and neuromuscular junction failure, in patient iPSC-derived spinal motor neurons (iPSC-sMNs). In FUS-ALS flies, mice, and human iPSC-sMNs, we observed reduced GSK3 inhibitory phosphorylation, suggesting that FUS dysfunction results in GSK3 hyperactivity. Furthermore, we found that PP2A acts upstream of GSK3, affecting its inhibitory phosphorylation. GSK3 has previously been linked to kinesin-1 hyperphosphorylation. We observed this in both flies and iPSC-sMNs, and we rescued this hyperphosphorylation by inhibiting GSK3 or PP2A. Moreover, increasing the level of kinesin-1 expression in our Drosophila model strongly rescued toxicity, confirming the relevance of kinesin-1 hyperphosphorylation. Our data provide in vivo evidence that PP2A and GSK3 are disease modifiers, and reveal an unexplored mechanistic link between PP2A, GSK3, and kinesin-1, that may be central to the pathogenesis of FUS-ALS and sporadic forms of the disease.}, } @article {pmid38364912, year = {2024}, author = {Du, L and Roy, S and Wang, P and Li, Z and Qiu, X and Zhang, Y and Yuan, J and Guo, B}, title = {Unveiling the future: Advancements in MRI imaging for neurodegenerative disorders.}, journal = {Ageing research reviews}, volume = {95}, number = {}, pages = {102230}, doi = {10.1016/j.arr.2024.102230}, pmid = {38364912}, issn = {1872-9649}, mesh = {Humans ; *Diffusion Tensor Imaging/methods ; Artificial Intelligence ; Brain/pathology ; Magnetic Resonance Imaging/methods ; *Neurodegenerative Diseases/pathology ; }, abstract = {Neurodegenerative disorders represent a significant and growing global health challenge, necessitating continuous advancements in diagnostic tools for accurate and early detection. This work explores the recent progress in Magnetic Resonance Imaging (MRI) techniques and their application in the realm of neurodegenerative disorders. The introductory section provides a comprehensive overview of the study's background, significance, and objectives. Recognizing the current challenges associated with conventional MRI, the manuscript delves into advanced imaging techniques such as high-resolution structural imaging (HR-MRI), functional MRI (fMRI), diffusion tensor imaging (DTI), and positron emission tomography-MRI (PET-MRI) fusion. Each technique is critically examined regarding its potential to address theranostic limitations and contribute to a more nuanced understanding of the underlying pathology. A substantial portion of the work is dedicated to exploring the applications of advanced MRI in specific neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS). In addressing the future landscape, the manuscript examines technological advances, including the integration of machine learning and artificial intelligence in neuroimaging. The conclusion summarizes key findings, outlines implications for future research, and underscores the importance of these advancements in reshaping our understanding and approach to neurodegenerative disorders.}, } @article {pmid38366598, year = {2024}, author = {Ke, YD and van Hummel, A and Au, C and Chan, G and Lee, WS and van der Hoven, J and Przybyla, M and Deng, Y and Sabale, M and Morey, N and Bertz, J and Feiten, A and Ippati, S and Stevens, CH and Yang, S and Gladbach, A and Haass, NK and Kril, JJ and Blair, IP and Delerue, F and Ittner, LM}, title = {Targeting 14-3-3θ-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia mice.}, journal = {Neuron}, volume = {112}, number = {8}, pages = {1249-1264.e8}, doi = {10.1016/j.neuron.2024.01.022}, pmid = {38366598}, issn = {1097-4199}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/metabolism ; Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by cytoplasmic deposition of the nuclear TAR-binding protein 43 (TDP-43). Although cytoplasmic re-localization of TDP-43 is a key event in the pathogenesis of ALS/FTD, the underlying mechanisms remain unknown. Here, we identified a non-canonical interaction between 14-3-3θ and TDP-43, which regulates nuclear-cytoplasmic shuttling. Neuronal 14-3-3θ levels were increased in sporadic ALS and FTD with TDP-43 pathology. Pathogenic TDP-43 showed increased interaction with 14-3-3θ, resulting in cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43, resembling pathological changes in disease. Harnessing this increased affinity of 14-3-3θ for pathogenic TDP-43, we devised a gene therapy vector targeting TDP-43 pathology, which mitigated functional deficits and neurodegeneration in different ALS/FTD mouse models expressing mutant or non-mutant TDP-43, including when already symptomatic at the time of treatment. Our study identified 14-3-3θ as a mediator of cytoplasmic TDP-43 localization with implications for ALS/FTD pathogenesis and therapy.}, } @article {pmid38367047, year = {2024}, author = {Sun, W and Liu, SH and Wei, XJ and Sun, H and Ma, ZW and Yu, XF}, title = {Potential of neuroimaging as a biomarker in amyotrophic lateral sclerosis: from structure to metabolism.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2238-2257}, pmid = {38367047}, issn = {1432-1459}, support = {No. JLSWSRCZX2023-13//the Medical and Health Talents Special Foundation of Jilin Province/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Humans ; *Neuroimaging/methods/standards ; *Biomarkers/metabolism ; Brain/diagnostic imaging/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration. The development of ALS involves metabolite alterations leading to tissue lesions in the nervous system. Recent advances in neuroimaging have significantly improved our understanding of the underlying pathophysiology of ALS, with findings supporting the corticoefferent axonal disease progression theory. Current studies on neuroimaging in ALS have demonstrated inconsistencies, which may be due to small sample sizes, insufficient statistical power, overinterpretation of findings, and the inherent heterogeneity of ALS. Deriving meaningful conclusions solely from individual imaging metrics in ALS studies remains challenging, and integrating multimodal imaging techniques shows promise for detecting valuable ALS biomarkers. In addition to giving an overview of the principles and techniques of different neuroimaging modalities, this review describes the potential of neuroimaging biomarkers in the diagnosis and prognostication of ALS. We provide an insight into the underlying pathology, highlighting the need for standardized protocols and multicenter collaborations to advance ALS research.}, } @article {pmid38367681, year = {2024}, author = {Arsuffi-Marcon, R and Souza, LG and Santos-Miranda, A and Joviano-Santos, JV}, title = {Neurotoxicity of Pyrethroids in neurodegenerative diseases: From animals' models to humans' studies.}, journal = {Chemico-biological interactions}, volume = {391}, number = {}, pages = {110911}, doi = {10.1016/j.cbi.2024.110911}, pmid = {38367681}, issn = {1872-7786}, mesh = {Animals ; Humans ; *Pyrethrins/toxicity ; *Insecticides/toxicity ; *Neurodegenerative Diseases/chemically induced ; *Neurotoxicity Syndromes ; *Pesticides/toxicity ; Mammals ; }, abstract = {Neurodegenerative diseases are associated with diverse symptoms, both motor and mental. Genetic and environmental factors can trigger neurodegenerative diseases. Chemicals as pesticides are constantly used in agriculture and also domestically. In this regard, pyrethroids (PY), are a class of insecticides in which its main mechanism of action is through disruption of voltage-dependent sodium channels function in insects. However, in mammals, they can also induce oxidative stress and enzyme dysfunction. This review investigates the association between PY and neurodegenerative diseases as Alzheimer's, Huntington's, Parkinson's, Amyotrophic Lateral Sclerosis, and Autism in animal models and humans. Published works using specific and non-specific models for these diseases were selected. We showed a tendency toward the development and/or aggravating of these neurodegenerative diseases following exposure to PYs. In animal models, the biochemical mechanisms of the diseases and their interaction with the insecticides are more deeply investigated. Nonetheless, only a few studies considered the specific model for each type of disease to analyze the impacts of the exposure. The choice of a specific model during the research is an important step and our review highlights the knowledge gaps of PYs effects using these models reinforcing the importance of them during the design of the experiments.}, } @article {pmid38367748, year = {2024}, author = {La Cognata, V and Morello, G and Guarnaccia, M and Cavallaro, S}, title = {The multifaceted role of the CXC chemokines and receptors signaling axes in ALS pathophysiology.}, journal = {Progress in neurobiology}, volume = {235}, number = {}, pages = {102587}, doi = {10.1016/j.pneurobio.2024.102587}, pmid = {38367748}, issn = {1873-5118}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Signal Transduction ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease with complex genetic basis and still no clear etiology. Multiple intertwined layers of immune system-related dysfunctions and neuroinflammatory mechanisms are emerging as substantial determinants in ALS onset and progression. In this review, we collect the increasingly arising evidence implicating four main CXC chemokines/cognate receptors signaling axes (CXCR1/2-CXCL1/2/8; CXCR3-CXCL9/10/11; CXCR4/7-CXCL12; CXCR5-CXCL13) in the pathophysiology of ALS. Findings in preclinical models implicate these signaling pathways in motor neuron toxicity and neuroprotection, while in ALS patients dysregulation of CXCLs/CXCRs has been shown at both central and peripheral levels. Immunological monitoring of CXC-ligands in ALS may allow tracking of disease progression, while pharmacological modulation of CXC-receptors provides a novel therapeutic strategy. A deeper understanding of the interplay between CXC-mediated neuroinflammation and ALS is crucial to advance research into treatments for this debilitating uncurable disorder.}, } @article {pmid38367882, year = {2024}, author = {Godoy-Corchuelo, JM and Ali, Z and Brito Armas, JM and Martins-Bach, AB and García-Toledo, I and Fernández-Beltrán, LC and López-Carbonero, JI and Bascuñana, P and Spring, S and Jimenez-Coca, I and Muñoz de Bustillo Alfaro, RA and Sánchez-Barrena, MJ and Nair, RR and Nieman, BJ and Lerch, JP and Miller, KL and Ozdinler, HP and Fisher, EMC and Cunningham, TJ and Acevedo-Arozena, A and Corrochano, S}, title = {TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43.}, journal = {Neurobiology of disease}, volume = {193}, number = {}, pages = {106437}, pmid = {38367882}, issn = {1095-953X}, support = {MC_EX_MR/N501931/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Child, Preschool ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Brain/metabolism ; Cognition ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology ; *TDP-43 Proteinopathies/genetics/pathology ; }, abstract = {TDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as "TDP-43 proteinopathies". Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of ∼50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually associated with ALS, many clinical reports have linked these mutations to cognitive impairments and/or FTD, but also to other neurodegenerative disorders including Parkinsonism (PD) or progressive supranuclear palsy (PSP). TDP-43 is a ubiquitously expressed, highly conserved RNA-binding protein that is involved in many cellular processes, mainly RNA metabolism. To investigate systemic pathological mechanisms in TDP-43 proteinopathies, aiming to capture the pleiotropic effects of TDP-43 mutations, we have further characterised a mouse model carrying a point mutation (M323K) within the endogenous Tardbp gene. Homozygous mutant mice developed cognitive and behavioural deficits as early as 3 months of age. This was coupled with significant brain structural abnormalities, mainly in the cortex, hippocampus, and white matter fibres, together with progressive cortical interneuron degeneration and neuroinflammation. At the motor level, progressive phenotypes appeared around 6 months of age. Thus, cognitive phenotypes appeared to be of a developmental origin with a mild associated progressive neurodegeneration, while the motor and neuromuscular phenotypes seemed neurodegenerative, underlined by a progressive loss of upper and lower motor neurons as well as distal denervation. This is accompanied by progressive elevated TDP-43 protein and mRNA levels in cortex and spinal cord of homozygous mutant mice from 3 months of age, together with increased cytoplasmic TDP-43 mislocalisation in cortex, hippocampus, hypothalamus, and spinal cord at 12 months of age. In conclusion, we find that Tardbp M323K homozygous mutant mice model many aspects of human TDP-43 proteinopathies, evidencing a dual role for TDP-43 in brain morphogenesis as well as in the maintenance of the motor system, making them an ideal in vivo model system to study the complex biology of TDP-43.}, } @article {pmid38368936, year = {2024}, author = {Herman, M and Randall, GW and Spiegel, JL and Maldonado, DJ and Simoes, S}, title = {Endo-lysosomal dysfunction in neurodegenerative diseases: opinion on current progress and future direction in the use of exosomes as biomarkers.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {379}, number = {1899}, pages = {20220387}, pmid = {38368936}, issn = {1471-2970}, support = {P30 AG066462/AG/NIA NIH HHS/United States ; R01 AG071868/AG/NIA NIH HHS/United States ; R21 AG070768/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Exosomes ; *Alzheimer Disease/diagnosis ; Lysosomes/metabolism ; Biomarkers/metabolism ; }, abstract = {Over the past two decades, increased research has highlighted the connection between endosomal trafficking defects and neurodegeneration. The endo-lysosomal network is an important, complex cellular system specialized in the transport of proteins, lipids, and other metabolites, essential for cell homeostasis. Disruption of this pathway is linked to a wide range of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and frontotemporal dementia. Furthermore, there is strong evidence that defects in this pathway create opportunities for diagnostic and therapeutic intervention. In this Opinion piece, we concisely address the role of endo-lysosomal dysfunction in five neurodegenerative diseases and discuss how future research can investigate this intracellular pathway, including extracellular vesicles with a specific focus on exosomes for the identification of novel disease biomarkers. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.}, } @article {pmid38369520, year = {2024}, author = {Adashek, JJ and Pandya, C and Maragakis, NJ and De, P and Cohen, PR and Kato, S and Kurzrock, R}, title = {Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer.}, journal = {BMC medicine}, volume = {22}, number = {1}, pages = {74}, pmid = {38369520}, issn = {1741-7015}, support = {U10 CA180888/CA/NCI NIH HHS/United States ; UG1 CA233198/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Neoplasms/genetics ; *Neuregulin-1/genetics/metabolism ; *Receptor, ErbB-4/genetics/metabolism ; Signal Transduction ; }, abstract = {BACKGROUND: Neuregulin-1 (NRG1) is implicated in both cancer and neurologic diseases such as amyotrophic lateral sclerosis (ALS); however, to date, there has been little cross-field discussion between neurology and oncology in regard to these genes and their functions.

MAIN BODY: Approximately 0.15-0.5% of cancers harbor NRG1 fusions that upregulate NRG1 activity and hence that of the cognate ERBB3/ERBB4 (HER3/HER4) receptors; abrogating this activity with small molecule inhibitors/antibodies shows preliminary tissue-agnostic anti-cancer activity. Notably, ERBB/HER pharmacologic suppression is devoid of neurologic toxicity. Even so, in ALS, attenuated ERBB4/HER4 receptor activity (due to loss-of-function germline mutations or other mechanisms in sporadic disease) is implicated; indeed, ERBB4/HER4 is designated ALS19. Further, secreted-type NRG1 isoforms may be upregulated (perhaps via a feedback loop) and could contribute to ALS pathogenesis through aberrant glial cell stimulation via enhanced activity of other (e.g., ERBB1-3/HER1-3) receptors and downstream pathways. Hence, pan-ERBB inhibitors, already in use for cancer, may be agents worthy of testing in ALS.

CONCLUSION: Common signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.}, } @article {pmid38370434, year = {2024}, author = {Chen, C and Qi, J and Li, Y and Li, D and Wu, L and Li, R and Chen, Q and Sun, N}, title = {Applications of Raman spectroscopy in the diagnosis and monitoring of neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1301107}, pmid = {38370434}, issn = {1662-4548}, abstract = {Raman scattering is an inelastic light scattering that occurs in a manner reflective of the molecular vibrations of molecular structures and chemical conditions in a given sample of interest. Energy changes in the scattered light can be assessed to determine the vibration mode and associated molecular and chemical conditions within the sample, providing a molecular fingerprint suitable for sample identification and characterization. Raman spectroscopy represents a particularly promising approach to the molecular analysis of many diseases owing to clinical advantages including its instantaneous nature and associated high degree of stability, as well as its ability to yield signal outputs corresponding to a single molecule type without any interference from other molecules as a result of its narrow peak width. This technology is thus ideally suited to the simultaneous assessment of multiple analytes. Neurodegenerative diseases represent an increasingly significant threat to global public health owing to progressive population aging, imposing a severe physical and social burden on affected patients who tend to develop cognitive and/or motor deficits beginning between the ages of 50 and 70. Owing to a relatively limited understanding of the etiological basis for these diseases, treatments are lacking for the most common neurodegenerative diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The present review was formulated with the goal of briefly explaining the principle of Raman spectroscopy and discussing its potential applications in the diagnosis and evaluation of neurodegenerative diseases, with a particular emphasis on the research prospects of this novel technological platform.}, } @article {pmid38371336, year = {2024}, author = {Barnabe, A and Genestet, S and Gut-Gobert, C and Rivalain, C and Noury, JB and Goret, M and Barnier, A and De Moreuil, C and Espinasse, B and Le Mao, R and Leroyer, C and Couturaud, F and Tromeur, C}, title = {Venous thromboembolism and amyotrophic lateral sclerosis: the Venous Thrombo-Embolism and Sclerosis Lateral Amyotrophic study.}, journal = {Research and practice in thrombosis and haemostasis}, volume = {8}, number = {1}, pages = {102287}, pmid = {38371336}, issn = {2475-0379}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease. Given the inflammatory nature of ALS and the high number of ALS-related clinical circumstances (eg, prolonged immobilization and infections), patients with ALS may have a high risk of venous thromboembolism (VTE).

OBJECTIVES: To determine the annual incidence rate of VTE and the predictors of VTE in patients with ALS.

METHODS: We analyzed a prospective cohort of patients with ALS diagnosed between 2009 and 2019 followed in the Brest University Hospital ALS Centre.

RESULTS: Among 227 patients with ALS, VTE occurred in 19 patients during a median follow-up period of 717 days (IQR, 488-1308), yielding an annual incidence rate of 2.93% (95% CI, 1.88%-4.53%). Predictors for VTE were a family history of VTE (hazard ratio [HR], 15.24; 95% CI, 1.72-134.84; P = .01), the presence of noninvasive ventilation at ALS diagnosis (HR, 6.98; 95% CI, 1.09-44.59; P = .04) and a short time (ie, <213 days) between first symptoms and ALS diagnosis (HR, 5.48; 95% CI, 1.57-19.11; P = .01). Recurrent VTE occurred within 3 months after stopping anticoagulation in 5 patients (26.3%).

CONCLUSION: The annual incidence of VTE in patients with ALS is high. Predictive factors of VTE were a VTE history, noninvasive ventilation, and a short time between first symptoms of ALS and ALS diagnosis.}, } @article {pmid38371486, year = {2024}, author = {Strang, P and Schultz, T and Ozanne, A}, title = {Partly unequal receipt of healthcare in last month of life in amyotrophic lateral sclerosis: a retrospective cohort study of the Stockholm region.}, journal = {Upsala journal of medical sciences}, volume = {129}, number = {}, pages = {}, pmid = {38371486}, issn = {2000-1967}, mesh = {Aged ; Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/therapy ; Delivery of Health Care ; *Dementia/therapy ; *Frailty ; Palliative Care ; Retrospective Studies ; }, abstract = {CONTEXT: In amyotrophic lateral sclerosis (ALS), equal care is important, given that the disease often has complex symptoms at the end of life.

OBJECTIVES: The aim was to study the possible associations between demographic and clinical factors, including age, sex, and frailty, with acute healthcare utilization in the last month of life, measured by emergency room (ER) visits, admissions to acute hospitals and, acute hospitals as place of death, among patients with ALS. A second aim was to study whether receipt of specialized palliative care (SPC) affects above-mentioned healthcare utilization.

METHODS: Observational, retrospective study based on Region Stockholm's administrative data warehouse (VAL) in Sweden. Data were retrieved for 2015-2021 and analyzed with descriptive statistics and logistic regression models.

RESULTS: All deceased patients (n = 448) ≥18 years with ALS were included. The mean age was 70.5 years, 46% were women and 58% had risk of frailty according to Hospital Frailty Risk Score (HFRS). Ninety-nine (22%) were nursing home residents and 49% received SPC. The receipt of SPC in patients with ALS was equal in relation to gender, socio-economic standing, frailty, and age <75 years. Patients ≥75 years, those with dementia and/or residing in nursing homes (NH) were less likely to receive SPC (P = 0.01, P = 0.03 and P = 0.002, respectively). Receipt of SPC reduced ER visits (29% vs. 48%, P < 0.001) and deaths at hospital (12% vs. 48%, P <0.001). Patients who were frail, had a higher risk of ER visits and were more likely to die at an acute hospital setting (P < 0.001 and P = 0.004). NH residents were less likely to have ER visits and to die in hospital (P = 0.002 and P = 0.005).

CONCLUSIONS: The results indicate partly unequal distribution of palliative care, however the actual, individual preferences cannot be deducted from registry studies. All patients with ALS should be offered SPC when needed.

KEY MESSAGE: This register study shows that receipt of SPC in patients with ALS is equal in relation to gender, socioeconomic standing, frailty, and age <75 years, while those ≥75 years, with dementia, or residing in NH were somewhat less likely to receive SPC. Receipt of SPC reduces ER visits and acute hospital admissions.}, } @article {pmid38372421, year = {2024}, author = {Miquel, E and Villarino, R and Martínez-Palma, L and Cassina, A and Cassina, P}, title = {Pyruvate dehydrogenase kinase 2 knockdown restores the ability of amyotrophic lateral sclerosis-linked SOD1G93A rat astrocytes to support motor neuron survival by increasing mitochondrial respiration.}, journal = {Glia}, volume = {72}, number = {5}, pages = {999-1011}, doi = {10.1002/glia.24516}, pmid = {38372421}, issn = {1098-1136}, support = {//Programa de Desarrollo de las Ciencias Básicas (PEDECIBA)/ ; FCE_1_2019_1_156461//Agencia Nacional de Investigación e Innovación/ ; }, mesh = {Animals ; Rats ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Astrocytes/metabolism ; Cells, Cultured ; Disease Models, Animal ; Motor Neurons/metabolism ; *Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics/metabolism ; Respiration ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration. Various studies using cellular and animal models of ALS indicate that there is a complex interplay between MN and neighboring non-neuronal cells, such as astrocytes, resulting in noncell autonomous neurodegeneration. Astrocytes in ALS exhibit a lower ability to support MN survival than nondisease-associated ones, which is strongly correlated with low-mitochondrial respiratory activity. Indeed, pharmacological inhibition of pyruvate dehydrogenase kinase (PDK) led to an increase in the mitochondrial oxidative phosphorylation pathway as the primary source of cell energy in SOD1G93A astrocytes and restored the survival of MN. Among the four PDK isoforms, PDK2 is ubiquitously expressed in astrocytes and presents low expression levels in neurons. Herein, we hypothesize whether selective knockdown of PDK2 in astrocytes may increase mitochondrial activity and, in turn, reduce SOD1G93A-associated toxicity. To assess this, cultured neonatal SOD1G93A rat astrocytes were incubated with specific PDK2 siRNA. This treatment resulted in a reduction of the enzyme expression with a concomitant decrease in the phosphorylation rate of the pyruvate dehydrogenase complex. In addition, PDK2-silenced SOD1G93A astrocytes exhibited restored mitochondrial bioenergetics parameters, adopting a more complex mitochondrial network. This treatment also decreased lipid droplet content in SOD1G93A astrocytes, suggesting a switch in energetic metabolism. Significantly, PDK2 knockdown increased the ability of SOD1G93A astrocytes to support MN survival, further supporting the major role of astrocyte mitochondrial respiratory activity in astrocyte-MN interactions. These results suggest that PDK2 silencing could be a cell-specific therapeutic tool to slow the progression of ALS.}, } @article {pmid38372747, year = {2024}, author = {Yang, T and Li, C and Wei, Q and Pang, D and Cheng, Y and Huang, J and Lin, J and Xiao, Y and Jiang, Q and Wang, S and Shang, H}, title = {Genome-wide DNA methylation analysis related to ALS patient progression and survival.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2672-2683}, pmid = {38372747}, issn = {1432-1459}, support = {82371430//National Natural Science Foundation of China/ ; 82101485//National Natural Science Foundation of China/ ; 2022ZDZX0023//Sichuan Science and Technology Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/mortality ; *DNA Methylation ; Male ; Female ; *Disease Progression ; Middle Aged ; Aged ; Epigenesis, Genetic ; Genome-Wide Association Study ; Follow-Up Studies ; }, abstract = {BACKGROUND: Epigenetics contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the DNA methylation profiles associated with clinical heterogeneity in disease progression and survival among patients.

METHODS: We included a cohort of 41 patients with sporadic ALS, with a median follow-up of 86.9 months, and 27 rigorously matched healthy controls. Blood-based genome-wide DNA methylation analysis was conducted.

RESULTS: A total of 948 progression rate-associated differentially methylated positions, 298 progression rate-associated differentially methylated regions (R-DMRs), 590 survival time-associated DMPs, and 197 survival time-associated DMRs (S-DMRs) were identified, using complementary grouping strategies. Enrichment analysis of differentially methylated genes highlighted the involvement of synapses and axons in ALS progression and survival. Clinical analysis revealed a positive correlation between the average methylation levels of the R-DMR in PRDM8 and disease progression rate (r = 0.479, p = 0.002). Conversely, there was an inverse correlation between the average methylation levels of the R-DMR in ANKRD33 and disease progression rate (r = - 0.476, p = 0.002). In addition, patients with higher methylation levels within the S-DMR of ZNF696 experienced longer survival (p = 0.016), while those with elevated methylation levels in the S-DMR of RAI1 had shorter survival (p = 0.006).

CONCLUSION: DNA methylation holds promise as a potential biomarker for tracking disease progression and predicting survival outcome and also offers targets for precision medicine.}, } @article {pmid38372843, year = {2024}, author = {Katerelos, A and Alexopoulos, P and Economou, P and Polychronopoulos, P and Chroni, E}, title = {Correction to: Cognitive function in amyotrophic lateral sclerosis: a cross‑sectional and prospective pragmatic clinical study with review of the literature.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {2407}, doi = {10.1007/s10072-024-07408-9}, pmid = {38372843}, issn = {1590-3478}, } @article {pmid38374041, year = {2024}, author = {San Gil, R and Pascovici, D and Venturato, J and Brown-Wright, H and Mehta, P and Madrid San Martin, L and Wu, J and Luan, W and Chui, YK and Bademosi, AT and Swaminathan, S and Naidoo, S and Berning, BA and Wright, AL and Keating, SS and Curtis, MA and Faull, RLM and Lee, JD and Ngo, ST and Lee, A and Morsch, M and Chung, RS and Scotter, E and Lisowski, L and Mirzaei, M and Walker, AK}, title = {A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {1508}, pmid = {38374041}, issn = {2041-1723}, support = {1140386//Department of Health | National Health and Medical Research Council (NHMRC)/ ; /MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/metabolism ; *Frontotemporal Lobar Degeneration/metabolism ; Neurons/metabolism ; Proteomics ; *TDP-43 Proteinopathies/metabolism ; *Protein Aggregates ; }, abstract = {Understanding the mechanisms that drive TDP-43 pathology is integral to combating amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases. Here we generated a longitudinal quantitative proteomic map of the cortex from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD, and developed a complementary open-access webtool, TDP-map (https://shiny.rcc.uq.edu.au/TDP-map/). We identified distinct protein subsets enriched for diverse biological pathways with temporal alterations in protein abundance, including increases in protein folding factors prior to disease onset. This included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, which also co-localized with TDP-43 pathology in diseased human motor cortex. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. Together, these findings reveal molecular mechanisms at distinct stages of ALS and FTLD progression and suggest that protein folding factors could be protective in neurodegenerative diseases.}, } @article {pmid38374589, year = {2025}, author = {Mehdipour, A and Teshler, L and Dal Bello-Haas, V and Bouchard, V and Kuspinar, A}, title = {Translation of the Preference-Based Amyotrophic Lateral Sclerosis Scale into French.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {52}, number = {1}, pages = {129-131}, doi = {10.1017/cjn.2024.18}, pmid = {38374589}, issn = {0317-1671}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis ; Canada ; Male ; Female ; Translating ; Middle Aged ; Language ; Translations ; Surveys and Questionnaires ; Aged ; }, abstract = {The objective of this study was to translate the Preference-Based Amyotrophic Lateral Sclerosis Scale to French-Canadian. After the scale underwent forward and back translations, the expert committee examined the translated versions and found minor grammatical errors and suggested idioms to be changed to better represent French-Canadian language. Cognitive debriefing interviews were carried out to assess the pre-final version for clarity, and minor changes were made. Consensus from the expert committee and people with amyotrophic lateral sclerosis on the measure's clarity, word choice, and meaning were achieved, resulting in the final French version of the Preference-Based Amyotrophic Lateral Sclerosis Scale.}, } @article {pmid38374770, year = {2024}, author = {Pavey, N and Hannaford, A and van den Bos, M and Kiernan, MC and Menon, P and Vucic, S}, title = {Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {7}, pages = {2344-2356}, doi = {10.1093/brain/awae049}, pmid = {38374770}, issn = {1460-2156}, support = {//MND Research Australia/ ; 2001261//NHMRC/ ; 2010812//National Health & Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Transcranial Magnetic Stimulation/methods ; *Motor Cortex/physiopathology ; Aged ; *Evoked Potentials, Motor/physiology ; Adult ; Nerve Net/physiopathology ; Neural Inhibition/physiology ; Electromyography ; }, abstract = {Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilized to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation and stimulus response curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior, lateral-medial and anterior-posterior direction. Mean SICI, between interstimulus interval of 1-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in posterior-anterior (P = 0.044) and lateral-medial (P = 0.005) but not the anterior-posterior (P = 0.08) directions. A significant correlation between mean SICI oriented in a posterior-anterior direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between interstimulus interval 1-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in posterior-anterior (P = 0.035) and lateral-medial (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the anterior-posterior direction was comparable between ALS and controls (P = 0.482). The index of excitation was significantly increased in ALS patients when recorded with the TMS coil oriented in posterior-anterior (P = 0.041) and lateral-medial (P = 0.003) directions. In ALS patients, a significant increase in the stimulus response curve gradient was evident compared to controls when recorded with TMS coil oriented in posterior-anterior (P < 0.001), lateral-medial (P < 0.001) and anterior-posterior (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets.}, } @article {pmid38375749, year = {2024}, author = {Awassa, J and Soulé, S and Cornu, D and Ruby, C and El-Kirat-Chatel, S}, title = {Understanding the nanoscale adhesion forces between the fungal pathogen Candida albicans and antimicrobial zinc-based layered double hydroxides using single-cell and single-particle force spectroscopy.}, journal = {Nanoscale}, volume = {16}, number = {10}, pages = {5383-5394}, doi = {10.1039/d3nr06027f}, pmid = {38375749}, issn = {2040-3372}, mesh = {Humans ; *Candida albicans ; *Antifungal Agents/pharmacology ; Hydroxides/pharmacology/chemistry ; Zinc/pharmacology/chemistry ; Spectrum Analysis ; *Zinc Compounds ; }, abstract = {Antifungal resistance has become a very serious concern, and Candida albicans is considered one of the most opportunistic fungal pathogens responsible for several human infections. In this context, the use of new antifungal agents such as zinc-based layered double hydroxides to fight such fungal pathogens is considered one possible means to help limit the problem of antifungal resistance. In this study, we show that ZnAl LDH nanoparticles exhibit remarkable antifungal properties against C. albicans and cause serious cell wall damage, as revealed by growth tests and atomic force microscopy (AFM) imaging. To further link the antifungal activity of ZnAl LDHs to their adhesive behaviors toward C. albicans cells, AFM-based single-cell spectroscopy and single-particle force spectroscopy were used to probe the nanoscale adhesive interactions. The force spectroscopy analysis revealed that antimicrobial ZnAl LDHs exhibit specific surface interactions with C. albicans cells, demonstrating remarkable force magnitudes and adhesion frequencies in comparison with non-antifungal negative controls, e.g., Al-coated substrates and MgAl LDHs, which showed limited interactions with C. albicans cells. Force signatures suggest that such adhesive interactions may be attributed to the presence of agglutinin-like sequence (Als) adhesive proteins at the cell wall surface of C. albicans cells. Our findings propose the presence of a strong correlation between the antifungal effect provided by ZnAl LDHs and their nanoscale adhesive interactions with C. albicans cells at both the single-cell and single-particle levels. Therefore, ZnAl LDHs could interact with C. albicans fungal pathogens by specific adhesive interactions through which they adhere to fungal cells, leading to their damage and subsequent growth inhibition.}, } @article {pmid38376483, year = {2024}, author = {Lee, D and Jeong, HC and Kim, SY and Chung, JY and Cho, SH and Kim, KA and Cho, JH and Ko, BS and Cha, IJ and Chung, CG and Kim, ES and Lee, SB}, title = {A comparison study of pathological features and drug efficacy between Drosophila models of C9orf72 ALS/FTD.}, journal = {Molecules and cells}, volume = {47}, number = {1}, pages = {100005}, pmid = {38376483}, issn = {0219-1032}, mesh = {Animals ; Drosophila/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; *Frontotemporal Dementia ; *Neurodegenerative Diseases ; Levamisole/*analogs & derivatives ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a complex genetic basis, presenting both in familial and sporadic forms. The hexanucleotide (G4C2) repeat expansion in the C9orf72 gene, which triggers distinct pathogenic mechanisms, has been identified as a major contributor to familial and sporadic Amyotrophic lateral sclerosis cases. Animal models have proven pivotal in understanding these mechanisms; however, discrepancies between models due to variable transgene sequence, expression levels, and toxicity profiles complicate the translation of findings. Herein, we provide a systematic comparison of 7 publicly available Drosophila transgenes modeling the G4C2 expansion under uniform conditions, evaluating variations in their toxicity profiles. Further, we tested 3 previously characterized disease-modifying drugs in selected lines to uncover discrepancies among the tested strains. Our study not only deepens our understanding of the C9orf72 G4C2 mutations but also presents a framework for comparing constructs with minute structural differences. This work may be used to inform experimental designs to better model disease mechanisms and help guide the development of targeted interventions for neurodegenerative diseases, thus bridging the gap between model-based research and therapeutic application.}, } @article {pmid38376500, year = {2024}, author = {Krajewski, E and Lee, J and Olmstead, AJ and Simmons, Z}, title = {Comparison of Vowel and Sentence Intelligibility in People With Dysarthria Secondary to Amyotrophic Lateral Sclerosis.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {4}, pages = {1117-1126}, doi = {10.1044/2024_JSLHR-23-00497}, pmid = {38376500}, issn = {1558-9102}, abstract = {PURPOSE: In this study, we examined the utility of vowel intelligibility testing for assessing the impact of dysarthria on speech characteristics in people with amyotrophic lateral sclerosis (ALS). We tested the sensitivity and specificity of overall vowel identification, as well as that of vowel-specific identification, to dysarthria presence and severity. We additionally examined the relationship between vowel intelligibility and sentence intelligibility.

METHOD: Twenty-three people with ALS and 22 age- and sex-matched control speakers produced sentences from the Speech Intelligibility Test (SIT), as well as 10 American English monophthongs in /h/-vowel-/d/ words for the vowel intelligibility test (VIT). Data for SIT and VIT scores came from 135 listeners. Diagnostic accuracy of VIT measures was evaluated using the area under the curve of receiver operator characteristics. We then examined differences between control speakers, speakers with mild dysarthria, and speakers with severe dysarthria in their relationship between SIT and VIT scores.

RESULTS: The results suggest that the overall vowel intelligibility score showed high sensitivity and specificity in differentiating between speakers with and without dysarthria, even those with milder symptoms. In addition, single-vowel identification scores showed at least acceptable group differentiation between the mild and severe dysarthria groups, though fewer single vowels were acceptable discriminators between the control group and the group with mild dysarthria. Identification accuracy of /ɪ/ in particular showed excellent discrimination across all groups. Examination of the relationship between SIT and VIT scores suggests a severity-specific relationship. Speakers with SIT scores above 70% generally had higher SIT than VIT scores, whereas speakers with SIT below 70% generally had higher VIT than SIT scores.

DISCUSSION: Vowel intelligibility testing can detect speech impairments in speakers with mild dysarthria and residual articulatory function in speakers with severe dysarthria. Vowel intelligibility testing may, therefore, be a useful addition to intelligibility testing for individuals with dysarthria.}, } @article {pmid38377183, year = {2024}, author = {Brar, S and Ganesh, S and Karegowda, M}, title = {Clinical outcomes and rotational stability after implantation of a monofocal toric intraocular lens with textured haptics in normal vs high axial lengths.}, journal = {Journal of cataract and refractive surgery}, volume = {50}, number = {7}, pages = {718-723}, doi = {10.1097/j.jcrs.0000000000001429}, pmid = {38377183}, issn = {1873-4502}, mesh = {Humans ; Retrospective Studies ; *Lens Implantation, Intraocular ; *Lenses, Intraocular ; *Visual Acuity/physiology ; Female ; *Phacoemulsification ; Male ; *Axial Length, Eye/pathology ; *Refraction, Ocular/physiology ; *Pseudophakia/physiopathology ; Middle Aged ; *Astigmatism/physiopathology/surgery ; Prosthesis Design ; Aged ; Rotation ; Treatment Outcome ; }, abstract = {PURPOSE: To compare the clinical outcomes and rotational stability after implantation of a toric intraocular lens (IOL) with textured haptics in eyes with normal vs high axial lengths (ALs).

SETTING: Nethradhama Superspeciality Eye Hospital, Bangalore, India.

DESIGN: 2-arm, retrospective comparative study.

METHODS: This retrospective study included 114 eyes of 114 patients who underwent femtolaser cataract surgery followed by implantation of the HOYA Vivinex Toric monofocal IOL (Model XY1A-SP), of which 62 and 52 eyes belonged to normal (≤23.9 mm) and high (≥24 mm) AL groups, respectively. 1 week and 3 months postoperatively, clinical outcomes and rotational stability of the toric IOL was evaluated.

RESULTS: 3 months postoperatively, % eyes achieving refractive astigmatism accuracy within ≤0.50 diopter, was 100% (n = 62) in the normal vs 94% (n = 49) in the high AL group. All eyes that is, 100% (n = 62) in the normal and 96.15% (n = 50) eyes in the high myopia group were <5 degrees of the intended axis. The mean change in postoperative rotation from 1 week to 3 months was 0.28 ± 0.09 degrees in the normal, and 0.30 ± 1.11 degrees in the high AL group (P = .80). No significant correlation was observed between AL and white-to-white diameter with 1-week postoperative rotation values. No eye required repositioning of toric IOL for significant misalignment.

CONCLUSIONS: No significant differences were observed for clinical outcomes and postoperative rotational stability between eyes with normal and high ALs, suggesting excellent rotational stability of the Vivinex Toric IOL with textured haptics in all eyes, irrespective of the preoperative AL measurements.}, } @article {pmid38377583, year = {2024}, author = {Zhao, S and Solem, C}, title = {Thiamine-Starved Lactococcus lactis for Producing Food-Grade Pyruvate.}, journal = {Journal of agricultural and food chemistry}, volume = {72}, number = {9}, pages = {4858-4868}, doi = {10.1021/acs.jafc.3c09216}, pmid = {38377583}, issn = {1520-5118}, mesh = {*Pyruvic Acid/metabolism ; *Lactococcus lactis/genetics/metabolism ; Thiamine/metabolism ; Diacetyl/metabolism ; L-Lactate Dehydrogenase/metabolism ; Lactic Acid/metabolism ; Butter ; *Lactates ; }, abstract = {Lactococcus lactis is a safe lactic acid bacterium widely used in dairy fermentations. Normally, its main fermentation product is lactic acid; however, L. lactis can be persuaded into producing other compounds, e.g., through genetic engineering. Here, we have explored the possibility of rewiring the metabolism of L. lactis into producing pyruvate without using genetic tools. Depriving the thiamine-auxotrophic and lactate dehydrogenase-deficient L. lactis strain RD1M5 of thiamine efficiently shut down two enzymes at the pyruvate branch, the thiamine pyrophosphate (TPP) dependent pyruvate dehydrogenase (PDHc) and α-acetolactate synthase (ALS). After eliminating the remaining enzyme acting on pyruvate, the highly oxygen-sensitive pyruvate formate lyase (PFL), by simple aeration, the outcome was pyruvate production. Pyruvate could be generated by nongrowing cells and cells growing in a substrate low in thiamine, e.g., Florisil-treated milk. Pyruvate is a precursor for the butter aroma compound diacetyl. Using an α-acetolactate decarboxylase deficient L. lactis strain, pyruvate could be converted to α-acetolactate and diacetyl. Summing up, by starving L. lactis for thiamine, secretion of pyruvate could be attained. The food-grade pyruvate produced has many applications, e.g., as an antioxidant or be used to make butter aroma.}, } @article {pmid38377779, year = {2024}, author = {Sapienza, S and Tedeschi, V and Apicella, B and Pannaccione, A and Russo, C and Sisalli, MJ and Magliocca, G and Loffredo, S and Secondo, A}, title = {Ultrafine particulate matter pollution and dysfunction of endoplasmic reticulum Ca[2+] store: A pathomechanism shared with amyotrophic lateral sclerosis motor neurons?.}, journal = {Ecotoxicology and environmental safety}, volume = {273}, number = {}, pages = {116104}, doi = {10.1016/j.ecoenv.2024.116104}, pmid = {38377779}, issn = {1090-2414}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/chemically induced/genetics/metabolism ; Endoplasmic Reticulum/metabolism ; Motor Neurons/metabolism ; Proteomics ; Primary Cell Culture ; *Particulate Matter/adverse effects ; Endoplasmic Reticulum Stress ; Calcium/metabolism ; Disease Models, Animal ; }, abstract = {Increased risk of neurodegenerative diseases has been envisaged for air pollution exposure. On the other hand, environmental risk factors, including air pollution, have been suggested for Amyotrophic Lateral Sclerosis (ALS) pathomechanism. Therefore, the neurotoxicity of ultrafine particulate matter (PM0.1) (PM < 0.1 μm size) and its sub-20 nm nanoparticle fraction (NP20) has been investigated in motor neuronal-like cells and primary cortical neurons, mainly affected in ALS. The present data showed that PM0.1 and NP20 exposure induced endoplasmic reticulum (ER) stress, as occurred in cortex and spinal cord of ALS mice carrying G93A mutation in SOD1 gene. Furthermore, NSC-34 motor neuronal-like cells exposed to PM0.1 and NP20 shared the same proteomic profile on some apoptotic factors with motor neurons treated with the L-BMAA, a neurotoxin inducing Amyotrophic Lateral Sclerosis/Parkinson-Dementia Complex (ALS/PDC). Of note ER stress induced by PM0.1 and NP20 in motor neurons was associated to pathological changes in ER morphology and dramatic reduction of organellar Ca[2+] level through the dysregulation of the Ca[2+]-pumps SERCA2 and SERCA3, the Ca[2+]-sensor STIM1, and the Ca[2+]-release channels RyR3 and IP3R3. Furthermore, the mechanism deputed to ER Ca[2+] refilling (e.g. the so called store operated calcium entry-SOCE) and the relative currents ICRAC were also altered by PM0.1 and NP20 exposure. Additionally, these carbonaceous particles caused the exacerbation of L-BMAA-induced ER stress and Caspase-9 activation. In conclusion, this study shows that PM0.1 and NP20 induced the aberrant expression of ER proteins leading to dysmorphic ER, organellar Ca[2+] dysfunction, ER stress and neurotoxicity, providing putative correlations with the neurodegenerative process occurring in ALS.}, } @article {pmid38377980, year = {2024}, author = {Ariana, S and Amjadi, N and Kazemi, SN and Ahmadli, Z}, title = {The Use of Evening Primrose Oil for Cervical Ripening in Low-Risk Women with Term Pregnancy: A Randomized Double-Blinded Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {215-221}, doi = {10.1159/000535585}, pmid = {38377980}, issn = {2504-2106}, mesh = {Humans ; Female ; Pregnancy ; Adult ; Double-Blind Method ; *Plant Oils/therapeutic use ; *Oenothera biennis ; *gamma-Linolenic Acid/therapeutic use/administration & dosage ; *Linoleic Acids/therapeutic use ; *Cervical Ripening/drug effects ; Young Adult ; Iran ; }, abstract = {BACKGROUND: Several methods have been developed for cervical ripening. The data regarding the efficiency of evening primrose oil (EPO) are inconsistent. The purpose of this study was to investigate the outcomes of EPO use on cervical ripening in low-risk women with term pregnancy.

PATIENTS AND METHODS: Low-risk term pregnant women referred to the obstetrics clinic of Imam Hossein Hospital in Tehran who were eligible according to the inclusion were randomized either to the case or control group. The case group received 1,000 mg vaginal EPO capsule, and the other group received a vaginal placebo capsule daily, similar to the original drug. The primary outcome was Bishop score, while the duration of labor phases and the inducing procedures were the secondary outcomes.

RESULTS: Forty-eight participants were randomized to each group and were considered for data analysis. Although Bishop score was not statistically different before the intervention, it was significantly higher in case group compared to the placebo group after the intervention (EPO = 5.83 ± 1.68, placebo = 5.19 ± 1.52, p value = 0.002). Four participants in the case group and two in the control group underwent cesarean section (p value = 0.677). The need for labor induction was significantly higher in the placebo group than EPO group (oxytocin injection: 10.4% vs. 31.3%, p value = 0.012, amniotomy: 75% vs. 41.7, p value = 0.001).

CONCLUSION: The vaginal use of EPO could be considered as a safe and efficient approach for cervical ripening in low-risk term pregnant women.

UNLABELLED: HintergrundEs wurden verschiedene Methoden zur Zervixreifung entwickelt. Die Daten zur Wirksamkeit von Nachtkerzenöl (evening primrose oil, EPO) sind uneinheitlich. Mit dieser Studie sollen die Ergebnisse der Anwendung von EPO zur Zervixreifung bei Frauen mit niedrigem Risiko und termingerechter Schwangerschaft untersucht werden.Patientinnen und MethodenSchwangere Frauen mit niedrigem Risiko und termingerechter Schwangerschaft, die in die Geburtsklinik des Imam-Hossein-Krankenhauses in Teheran eingewiesen wurden und gemäss den Einschlusskriterien für die Teilnahme infrage kamen, wurden randomisiert der Fall- oder der Kontrollgruppe zugewiesen. Die Fallgruppe erhielt 1.000 mg EPO als Vaginalkapseln, während die andere Gruppe täglich eine vaginale Placebokapsel erhielt, die dem Originalpräparat ähnelte. Primäres Zielkriterium war der Bishop-Score und sekundäre Zielkriterien waren die Dauer der Wehenphasen sowie die Verfahren zur Geburtseinleitung.ErgebnisseJeder Gruppe wurden randomisiert 48 Teilnehmerinnen zugewiesen und bei der Datenanalyse berücksichtigt. Während vor der Intervention kein statistisch signifikanter Unterschied im Bishop-Score bestand, fiel dieser nach der Intervention in der Fallgruppe signifikant höher aus als in der Placebogruppe (EPO = 5,83 ± 1,68, Placebo = 5,19 ± 1,52, p-Wert = 0,002). Bei vier Teilnehmerinnen in der Fallgruppe und zwei in der Kontrollgruppe wurde ein Kaiserschnitt durchgeführt (p-Wert = 0,677). Die Notwendigkeit einer Weheneinleitung war in der Placebogruppe signifikant höher als in der EPO-Gruppe (Oxytocin-Injektion: 10,4% vs. 31,3%, p-Wert = 0,012, Amniotomie: 75% vs. 41,7%, p-Wert = 0,001).SchlussfolgerungDie vaginale Anwendung von EPO kann als sicherer und wirksamer Ansatz zur Zervixreifung bei Frauen mit niedrigem Risiko und termingerechter Schwangerschaft angesehen werden.}, } @article {pmid38378504, year = {2024}, author = {Pollmann, AS and Nguyen, MTD and Keyeutat, M and Danis, É and Durr, GM and Agoumi, Y and Jabbour, S}, title = {Refractive outcomes of immediately sequential bilateral cataract surgery in eyes with long and short axial lengths.}, journal = {BMC ophthalmology}, volume = {24}, number = {1}, pages = {77}, pmid = {38378504}, issn = {1471-2415}, mesh = {Humans ; Visual Acuity ; Lens Implantation, Intraocular/adverse effects ; Retrospective Studies ; *Lenses, Intraocular/adverse effects ; Refraction, Ocular ; *Refractive Errors/etiology ; Biometry ; Axial Length, Eye ; *Cataract/complications ; *Cataract Extraction/adverse effects ; }, abstract = {PURPOSE: To report the refractive outcomes of long (≥25.00 mm) and short (≤22.00 mm) axial length (AL) eyes undergoing immediately sequential bilateral cataract surgery (ISBCS).

METHODS: In this retrospective cohort study, patients who underwent ISBCS were identified and eyes of patients with bilateral long and short ALs were included. Pre- and postoperative biometry, autorefraction, and ocular comorbidities or complications were recorded. The primary outcome was the mean refractive prediction error.

RESULTS: Thirty-seven patients (74 eyes) with long ALs and 18 patients (36 eyes) with short ALs were included. The means ± standard deviations of the ALs were 26.40 ± 1.38 mm and 21.44 ± 0.46 mm in the long and short AL groups, respectively. In long AL eyes, the mean absolute error from the biometry-predicted refraction was - 0.16 ± 0.46 D, corresponding to 74% of eyes achieving a refraction within ±0.50 D of the predicted value. In short AL eyes, the mean absolute error was - 0.63 ± 0.73 D, corresponding to 44% of eyes achieving a refraction within ±0.50 D of the predicted value. Eight (44.4%) patients with short AL eyes had a myopic deviation greater than ±0.50 D from the predicted result in both eyes.

CONCLUSIONS: Compared to patients with long AL eyes, ISBCS in patients with short ALs had a wider variance in refractive outcome and a lower rate of achieving a postoperative refraction within ±0.50 D of the predicted target.}, } @article {pmid38378788, year = {2024}, author = {Rim, C and You, MJ and Nahm, M and Kwon, MS}, title = {Emerging role of senescent microglia in brain aging-related neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {10}, pmid = {38378788}, issn = {2047-9158}, support = {2023R1A2C1006622//National Research Foundation (NRF)/ ; RS-2023-00265515//National Research Foundation (NRF)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; Microglia/pathology ; Brain/pathology ; Cellular Senescence ; *Amyotrophic Lateral Sclerosis/pathology ; }, abstract = {Brain aging is a recognized risk factor for neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), but the intricate interplay between brain aging and the pathogenesis of these conditions remains inadequately understood. Cellular senescence is considered to contribute to cellular dysfunction and inflammaging. According to the threshold theory of senescent cell accumulation, the vulnerability to neurodegenerative diseases is associated with the rates of senescent cell generation and clearance within the brain. Given the role of microglia in eliminating senescent cells, the accumulation of senescent microglia may lead to the acceleration of brain aging, contributing to inflammaging and increased vulnerability to neurodegenerative diseases. In this review, we propose the idea that the senescence of microglia, which is notably vulnerable to aging, could potentially serve as a central catalyst in the progression of neurodegenerative diseases. The senescent microglia are emerging as a promising target for mitigating neurodegenerative diseases.}, } @article {pmid38378992, year = {2024}, author = {Song, M and Qiang, Y and Zhao, X and Song, F}, title = {Cyclin-dependent Kinase 5 and Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {61}, number = {10}, pages = {7287-7302}, pmid = {38378992}, issn = {1559-1182}, mesh = {Humans ; *Neurodegenerative Diseases/enzymology/metabolism ; *Cyclin-Dependent Kinase 5/metabolism ; Animals ; Oxidative Stress/physiology ; Mitochondria/metabolism ; }, abstract = {Neurodegenerative diseases are a group of diseases characterized by the progressive loss of neurons, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. These diseases have a high incidence and mortality rate globally, placing a heavy burden on patients and their families. The pathogenesis of neurodegenerative diseases is complex, and there are no effective treatments at present. Cyclin-dependent kinase 5 is a proline-directed serine/threonine protein kinase that is closely related to the development and function of the nervous system. Under physiological conditions, it is involved in regulating the process of neuronal proliferation, differentiation, migration, and synaptic plasticity. Moreover, there is increasing evidence that cyclin-dependent kinase 5 also plays an important role in the pathogenesis of neurodegenerative diseases. In this review, we address the biological characteristics of cyclin-dependent kinase 5 and its role in neurodegenerative diseases. In particular, this review highlights the underlying mechanistic linkages between cyclin-dependent kinase 5 and mitochondrial dysfunction, oxidative stress and neuroinflammation in the context of neurodegeneration. Finally, we also summarize the currently available cyclin-dependent kinase 5 inhibitors and their prospects for the treatment of neurodegenerative diseases. Taken together, a better understanding of the molecular mechanisms of cyclin-dependent kinase 5 involved in neurodegenerative diseases can lead to the development of new strategies for the prevention and treatment of these devastating diseases.}, } @article {pmid38379946, year = {2024}, author = {El-Mastouri, Z and Košnarová, P and Hamouzová, K and Alimi, E and Soukup, J}, title = {Insight into the herbicide resistance patterns in Lolium rigidum populations in Tunisian and Moroccan wheat regions.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1331725}, pmid = {38379946}, issn = {1664-462X}, abstract = {Rigid ryegrass (Lolium rigidum Gaud.) is one of the most troublesome weeds in Moroccan and Tunisian cereal crop fields. In total, 19 rigid ryegrass field populations were randomly selected in northern wheat crop areas of Morocco and Tunisia to examine the patterns of herbicide resistance to acetolactate synthase (ALS)- and acetyl-CoA carboxylase (ACCase)-inhibiting herbicides. Greenhouse experiments confirmed reduced sensitivity to ALS- and/or ACCase-inhibiting herbicides in all L. rigidum populations. The occurrence of target-site resistance (TSR) was tested using high-throughput genotyping. The advent of next-generation sequencing (NGS) has enabled easy identification of causal mutations and confirmed the presence of ALS and ACCase mutations at specific codons conferring TSR. Thirteen populations showed resistance to ALS-inhibiting herbicides associated with point mutations in positions Pro-197-Thr, Pro-197-Ser, Pro-197-Leu, Pro-197-Gln and Trp-574-Leu, while resistance to ACCase-inhibiting herbicides was detected in 18 populations in positions Asp-2078-Val, Trp-2027-Cys, Ile-1781-Leu, Gly-2096-Ala, and Ile-2041-Asn of the enzymes conferring TSR. Additionally, dose-response experiments with pyroxsulam applied after the inhibition of cytochrome P450 monooxygenase by malathion showed an increase in sensitivity in two out of seven highly resistant (HR) rigid ryegrass populations. This demonstrates the presence of non-target-site resistance (NTSR) in some ryegrass populations. Further evidence of NTSR was investigated in dose-response experiments with pyroxsulam, following pretreatment with the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl), which partially reversed resistance in only a few individuals of two L. rigidum populations. Hence, our study confirms the existence of multiple and cross-resistance to ALS- and ACCase-inhibiting herbicides in L. rigidum from Morocco and Tunisia with both TSR and NTSR mechanisms. These results emphasize local resistance management as an important tool to detect and mitigate gene flow from rigid ryegrass populations where resistance has evolved.}, } @article {pmid38380436, year = {2024}, author = {Nakaso, K}, title = {Roles of Microglia in Neurodegenerative Diseases.}, journal = {Yonago acta medica}, volume = {67}, number = {1}, pages = {1-8}, pmid = {38380436}, issn = {0513-5710}, abstract = {In recent years, microglia have attracted attention owing to their roles in various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Microglia, which are brain-resident macrophages, not only act as immune cells but also perform other functions in the body. Interestingly, they exert contrasting effects on different neurodegenerative diseases. In addition to the previously reported M1 (toxic) and M2 (protective) types, microglia now also include disease-associated microglia owing to a more elaborate classification. Understanding this detailed classification is necessary to elucidate the association between microglia and neurodegenerative diseases. In this review, we discuss the diverse roles of microglia in neurodegenerative diseases and highlight their potential as therapeutic targets.}, } @article {pmid38381071, year = {2024}, author = {Scherer, NM and Maurel, C and Graus, MS and McAlary, L and Richter, G and Radford, RAW and Hogan, A and Don, EK and Lee, A and Yerbury, J and Francois, M and Chung, RS and Morsch, M}, title = {RNA-binding properties orchestrate TDP-43 homeostasis through condensate formation in vivo.}, journal = {Nucleic acids research}, volume = {52}, number = {9}, pages = {5301-5319}, pmid = {38381071}, issn = {1362-4962}, support = {//Bill Gole Postdoctoral Fellowship/ ; //Motor Neuron Disease Research Australia/ ; //FightMND funding/ ; R21DA056320/NS/NINDS NIH HHS/United States ; //Snow Foundation Fellowship/ ; /MH/NIMH NIH HHS/United States ; //Macquarie University/ ; //Snow Foundation/ ; //National Health and Medical Research Council/ ; //NHMRC/ ; R21 DA056320/DA/NIDA NIH HHS/United States ; //ALS Foundation Netherlands/ ; }, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Biomolecular Condensates/metabolism ; Cell Nucleus/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Homeostasis ; *Motor Neurons/metabolism ; Mutation ; Protein Binding ; Protein Processing, Post-Translational ; RNA/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; }, abstract = {Insoluble cytoplasmic aggregate formation of the RNA-binding protein TDP-43 is a major hallmark of neurodegenerative diseases including Amyotrophic Lateral Sclerosis. TDP-43 localizes predominantly in the nucleus, arranging itself into dynamic condensates through liquid-liquid phase separation (LLPS). Mutations and post-translational modifications can alter the condensation properties of TDP-43, contributing to the transition of liquid-like biomolecular condensates into solid-like aggregates. However, to date it has been a challenge to study the dynamics of this process in vivo. We demonstrate through live imaging that human TDP-43 undergoes nuclear condensation in spinal motor neurons in a living animal. RNA-binding deficiencies as well as post-translational modifications can lead to aberrant condensation and altered TDP-43 compartmentalization. Single-molecule tracking revealed an altered mobility profile for RNA-binding deficient TDP-43. Overall, these results provide a critically needed in vivo characterization of TDP-43 condensation, demonstrate phase separation as an important regulatory mechanism of TDP-43 accessibility, and identify a molecular mechanism of how functional TDP-43 can be regulated.}, } @article {pmid38381392, year = {2024}, author = {Miah, MM and Zinnia, MA and Tabassum, N and Islam, ABMMK}, title = {Association between DPP6 gene rs10260404 polymorphism and increased risk of sporadic amyotrophic lateral sclerosis (sALS): a meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {7}, pages = {3225-3243}, pmid = {38381392}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *Genetic Predisposition to Disease/genetics ; *Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics ; *Polymorphism, Single Nucleotide ; Case-Control Studies ; Nerve Tissue Proteins ; Potassium Channels ; }, abstract = {BACKGROUND: Sporadic amyotrophic lateral sclerosis (sALS) is a severe neurodegenerative disease characterized by continuous diminution of motor neurons in the brain and spinal cord. Earlier studies indicated that the DPP6 gene variant has a role in the development of sALS. This meta-analysis was designed to uncover the role of rs10260404 polymorphism of the DPP6 gene and its association with sALS.

METHODS: All case-control articles published prior to October 2022 on the association between DPP6 (rs10260404) polymorphism and sALS risk were systematically extracted from different databases which include PubMed, PubMed Central, and Google Scholar. Overall odds ratios (ORs) and "95% confidence intervals (CIs)" were summarized for various genetic models. Subgroup and heterogeneity assessments were performed. Egger's and "Begg's tests were applied to evaluate publication bias. Trial sequential analysis (TSA) and false-positive report probability (FPRP) were performed.

RESULTS: Nine case-control studies containing 4202 sALS cases and 4444 healthy controls were included in the meta-analysis. A significant association of the DPP6 (rs10260404) variant with an increased sALS risk in overall pooled subjects under allelic model [C allele vs. T allele, OR = 1.149, 95% CI (1.010-1.307), p-value = 0.035], dominant model [CC + CT vs. TT, OR = 1.165, 95% CI (1.067-1.273), p-value = 0.001], and homozygote comparison [CC vs. TT, OR = 1.421, 95% CI (1.003-2.011), p-value = 0.048] were observed. Moreover, in subgroup analysis by nationality, remarkable associations were detected in Dutch, Irish, American, and Swedish under allelic, dominant, and homozygote models. Additionally, stratification analysis by ethnicity exhibited an association with sALS risk among Caucasians and Americans under different genetic models. Interestingly, none of the models found any significant association with Asians.

CONCLUSION: The present meta-analysis indicates that DPP6 (rs10260404) polymorphism could be a candidate risk factor for sALS predisposition.}, } @article {pmid38381447, year = {2024}, author = {Bahr, T and Vu, TA and Tuttle, JJ and Iezzi, R}, title = {Deep Learning and Machine Learning Algorithms for Retinal Image Analysis in Neurodegenerative Disease: Systematic Review of Datasets and Models.}, journal = {Translational vision science & technology}, volume = {13}, number = {2}, pages = {16}, pmid = {38381447}, issn = {2164-2591}, mesh = {Humans ; Algorithms ; *Alzheimer Disease/diagnostic imaging ; *Deep Learning ; Machine Learning ; *Neurodegenerative Diseases/diagnostic imaging ; Datasets as Topic ; *Retina/diagnostic imaging ; }, abstract = {PURPOSE: Retinal images contain rich biomarker information for neurodegenerative disease. Recently, deep learning models have been used for automated neurodegenerative disease diagnosis and risk prediction using retinal images with good results.

METHODS: In this review, we systematically report studies with datasets of retinal images from patients with neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and others. We also review and characterize the models in the current literature which have been used for classification, regression, or segmentation problems using retinal images in patients with neurodegenerative diseases.

RESULTS: Our review found several existing datasets and models with various imaging modalities primarily in patients with Alzheimer's disease, with most datasets on the order of tens to a few hundred images. We found limited data available for the other neurodegenerative diseases. Although cross-sectional imaging data for Alzheimer's disease is becoming more abundant, datasets with longitudinal imaging of any disease are lacking.

CONCLUSIONS: The use of bilateral and multimodal imaging together with metadata seems to improve model performance, thus multimodal bilateral image datasets with patient metadata are needed. We identified several deep learning tools that have been useful in this context including feature extraction algorithms specifically for retinal images, retinal image preprocessing techniques, transfer learning, feature fusion, and attention mapping. Importantly, we also consider the limitations common to these models in real-world clinical applications.

TRANSLATIONAL RELEVANCE: This systematic review evaluates the deep learning models and retinal features relevant in the evaluation of retinal images of patients with neurodegenerative disease.}, } @article {pmid38381656, year = {2024}, author = {Wang, XX and Chen, WZ and Li, C and Xu, RS}, title = {Current potential pathogenic mechanisms of copper-zinc superoxide dismutase 1 (SOD1) in amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {5}, pages = {549-563}, pmid = {38381656}, issn = {2191-0200}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Superoxide Dismutase-1/metabolism/genetics ; Animals ; Motor Neurons/metabolism/pathology ; Oxidative Stress/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease which damages upper and lower motor neurons (UMN and LMN) innervating the muscles of the trunk, extremities, head, neck and face in cerebrum, brain stem and spinal cord, which results in the progressive weakness, atrophy and fasciculation of muscle innervated by the related UMN and LMN, accompanying with the pathological signs leaded by the cortical spinal lateral tract lesion. The pathogenesis about ALS is not fully understood, and no specific drugs are available to cure and prevent the progression of this disease at present. In this review, we reviewed the structure and associated functions of copper-zinc superoxide dismutase 1 (SOD1), discuss why SOD1 is crucial to the pathogenesis of ALS, and outline the pathogenic mechanisms of SOD1 in ALS that have been identified at recent years, including glutamate-related excitotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, axonal transport disruption, prion-like propagation, and the non-cytologic toxicity of glial cells. This review will help us to deeply understand the current progression in this field of SOD1 pathogenic mechanisms in ALS.}, } @article {pmid38382464, year = {2024}, author = {Smith, HL and Chaytow, H and Gillingwater, TH}, title = {Excitotoxicity and ALS: New therapy targets an old mechanism.}, journal = {Cell reports. Medicine}, volume = {5}, number = {2}, pages = {101423}, pmid = {38382464}, issn = {2666-3791}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Mice, Transgenic ; Motor Neurons/metabolism ; Superoxide Dismutase/metabolism ; Disease Models, Animal ; }, abstract = {Excitotoxicity-induced cell death in motor neurons is a major therapeutic target for amyotrophic lateral sclerosis (ALS). Yan et al.[1] present a novel compound to specifically disrupt extra-synaptic NMDAR complexes, extending the lifespan of the SOD1[G93A] ALS mouse and ameliorating cell death.}, } @article {pmid38382562, year = {2024}, author = {Berezutskyi, V and Berezutska, M}, title = {Rare Example of abnormal vocal resonance: a case from Balzac's novel.}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {78}, number = {8}, pages = {556-560}, doi = {10.1055/a-2248-9672}, pmid = {38382562}, issn = {1438-8790}, mesh = {Adolescent ; Humans ; Male ; Diagnosis, Differential ; Rare Diseases ; *Singing ; Tuberculosis, Pulmonary/diagnosis ; Voice Disorders/diagnosis/etiology ; Medicine in Literature ; }, abstract = {Ungewöhnliche klinische Fälle wecken bei praktizierenden Ärzten immer wieder Interesse und ermöglichen es ihnen, ihre Wissensbasis zu erweitern und ihre Fähigkeiten zum klinischen Denken zu verbessern. Der Zweck dieser Studie besteht darin, einen klinischen Fall von Stimmresonanz beim Singen bei einem schwindsüchtigen Teenager aus dem Roman "Der Landarzt" von Honoré de Balzac unter Verwendung induktiver und deduktiver Methoden des klinischen Denkens zu analysieren. Stimmresonanzen beim Singen in Schwindsucht können als pathognomonisches Zeichen für eine kavernöse Tuberkulose gewertet werden, da nur mit dem Bronchus verbundene Hohlräume als Helmholtz-Resonator wirken. Trotz der Einzigartigkeit ist das Gehäuse durchaus realistisch, da es nicht im Widerspruch zu den Gesetzen der Akustik steht. Praktizierende Ärzte verfügen über die Kenntnisse der medizinischen Physik, Morphologie und Physiologie, die zum Verständnis der Pathogenese der klinischen Manifestation einer Lungenhöhle erforderlich sind. Dieser Fall zeigt deutlich die Vor- und Nachteile klinischer Denkmethoden, die in der Praxis eingesetzt werden. Dank der Kombination aus Originalität und Realismus kann der Fall von Stimmresonanz aus Balzacs Roman "Der Landarzt" seinen rechtmäßigen Platz in der persönlichen Sammlung klinischer Fälle eines jeden Lungenarztes einnehmen.}, } @article {pmid38382647, year = {2024}, author = {Huang, TN and Shih, YT and Yen, TL and Hsueh, YP}, title = {Vcp overexpression and leucine supplementation extend lifespan and ameliorate neuromuscular junction phenotypes of a SOD1G93A-ALS mouse model.}, journal = {Human molecular genetics}, volume = {33}, number = {11}, pages = {935-944}, pmid = {38382647}, issn = {1460-2083}, support = {AS-CFII-108-104//Transgenic Core Facility/ ; //Animal Facility of the Institute of Molecular Biology, Academia Sinica/ ; }, mesh = {Animals ; *Valosin Containing Protein/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Disease Models, Animal ; Mice ; *Neuromuscular Junction/metabolism ; Female ; Male ; *Longevity/genetics ; *Mice, Transgenic ; *Leucine/pharmacology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Phenotype ; Superoxide Dismutase/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; Humans ; Adenosine Triphosphatases/genetics/metabolism ; }, abstract = {Many genes with distinct molecular functions have been linked to genetically heterogeneous amyotrophic lateral sclerosis (ALS), including SuperOxide Dismutase 1 (SOD1) and Valosin-Containing Protein (VCP). SOD1 converts superoxide to oxygen and hydrogen peroxide. VCP acts as a chaperon to regulate protein degradation and synthesis and various other cellular responses. Although the functions of these two genes differ, in the current report we show that overexpression of wild-type VCP in mice enhances lifespan and maintains the size of neuromuscular junctions (NMJs) of both male and female SOD1G93A mice, a well-known ALS mouse model. Although VCP exerts multiple functions, its regulation of ER formation and consequent protein synthesis has been shown to play the most important role in controlling dendritic spine formation and social and memory behaviors. Given that SOD1 mutation results in protein accumulation and aggregation, it may direct VCP to the protein degradation pathway, thereby impairing protein synthesis. Since we previously showed that the protein synthesis defects caused by Vcp deficiency can be improved by leucine supplementation, to confirm the role of the VCP-protein synthesis pathway in SOD1-linked ALS, we applied leucine supplementation to SOD1G93A mice and, similar to Vcp overexpression, we found that it extends SOD1G93A mouse lifespan. In addition, the phenotypes of reduced muscle strength and fewer NMJs of SOD1G93A mice are also improved by leucine supplementation. These results support the existence of crosstalk between SOD1 and VCP and suggest a critical role for protein synthesis in ASL. Our study also implies a potential therapeutic treatment for ALS.}, } @article {pmid38382884, year = {2024}, author = {Jiao, LL and Dong, HL and Liu, MM and Wu, PL and Cao, Y and Zhang, Y and Gao, FG and Zhu, HY}, title = {The potential roles of salivary biomarkers in neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {193}, number = {}, pages = {106442}, doi = {10.1016/j.nbd.2024.106442}, pmid = {38382884}, issn = {1095-953X}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; Reproducibility of Results ; *Parkinson Disease/metabolism ; *Alzheimer Disease ; *Huntington Disease/diagnosis ; Biomarkers ; }, abstract = {Current research efforts on neurodegenerative diseases are focused on identifying novel and reliable biomarkers for early diagnosis and insight into disease progression. Salivary analysis is gaining increasing interest as a promising source of biomarkers and matrices for measuring neurodegenerative diseases. Saliva collection offers multiple advantages over the currently detected biofluids as it is easily accessible, non-invasive, and repeatable, allowing early diagnosis and timely treatment of the diseases. Here, we review the existing findings on salivary biomarkers and address the potential value in diagnosing neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Based on the available research, β-amyloid, tau protein, α-synuclein, DJ-1, Huntington protein in saliva profiles display reliability and validity as the biomarkers of neurodegenerative diseases.}, } @article {pmid38383499, year = {2024}, author = {Halcrow, PW and Quansah, DNK and Kumar, N and Steiner, JP and Nath, A and Geiger, JD}, title = {HERV-K (HML-2) Envelope Protein Induces Mitochondrial Depolarization and Neurotoxicity via Endolysosome Iron Dyshomeostasis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {44}, number = {14}, pages = {}, pmid = {38383499}, issn = {1529-2401}, support = {R01 NS065957/NS/NINDS NIH HHS/United States ; U54 GM115458/GM/NIGMS NIH HHS/United States ; R01 MH119000/MH/NIMH NIH HHS/United States ; R01 DA032444/DA/NIDA NIH HHS/United States ; R01 GM100329/GM/NIGMS NIH HHS/United States ; ZIA NS003130/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Endogenous Retroviruses ; *Amyotrophic Lateral Sclerosis/pathology ; Iron ; Reactive Oxygen Species ; *Neuroblastoma ; *Neurotoxicity Syndromes ; Arginine ; }, abstract = {Human endogenous retroviruses (HERVs) are associated with the pathogenesis of amyotrophic lateral sclerosis (ALS); a disease characterized by motor neuron degeneration and cell death. The HERV-K subtype HML-2 envelope protein (HERV-K Env) is expressed in the brain, spinal cord, and cerebrospinal fluid of people living with ALS and through CD98 receptor-linked interactions causes neurodegeneration. HERV-K Env-induced increases in oxidative stress are implicated in the pathogenesis of ALS, and ferrous iron (Fe[2+]) generates reactive oxygen species (ROS). Endolysosome stores of Fe[2+] are central to iron trafficking and endolysosome deacidification releases Fe[2+] into the cytoplasm. Because HERV-K Env is an arginine-rich protein that is likely endocytosed and arginine is a pH-elevating amino acid, it is important to determine HERV-K Env effects on endolysosome pH and whether HERV-K Env-induced neurotoxicity is downstream of Fe[2+] released from endolysosomes. Here, we showed using SH-SY5Y human neuroblastoma cells and primary cultures of human cortical neurons (HCNs, information on age and sex was not available) that HERV-K Env (1) is endocytosed via CD98 receptors, (2) concentration dependently deacidified endolysosomes, (3) decreased endolysosome Fe[2+] concentrations, (4) increased cytosolic and mitochondrial Fe[2+] and ROS levels, (5) depolarized mitochondrial membrane potential, and (6) induced cell death, effects blocked by an antibody against the CD98 receptor and by the endolysosome iron chelator deferoxamine. Thus, HERV-K Env-induced increases in cytosolic and mitochondrial Fe[2+] and ROS as well as cell death appear to be mechanistically caused by HERV-K Env endocytosis, endolysosome deacidification, and endolysosome Fe[2+] efflux into the cytoplasm.}, } @article {pmid38383503, year = {2024}, author = {Vidovic, M and Menschikowski, M and Freigang, M and Lapp, HS and Günther, R}, title = {Macrophage inclusions in cerebrospinal fluid following treatment initiation with antisense oligonucleotide therapies in motor neuron diseases.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {11}, pmid = {38383503}, issn = {2524-3489}, abstract = {5q-associated spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are two distinct neurological disorders leading to degeneration of lower motor neurons. The antisense oligonucleotides (ASOs) nusinersen and tofersen are novel disease-modifying agents for these diseases, respectively. In the context of ASO treatment, the cytological characteristics and composition of cerebrospinal fluid (CSF) have recently garnered particular interest. This report presents a case series of CSF cytology findings in two patients with SMA and ALS revealing comparable unspecified macrophage inclusions following treatment initiation with nusinersen and tofersen. Yet, the presence of these "asophages" in the treatment course of two different ASOs is of unclear significance. While both treatments have been well tolerated, this phenomenon warrants attention, given the long-term nature of these treatments.}, } @article {pmid38383591, year = {2024}, author = {Verheijen, BM and Chung, C and Thompson, B and Kim, H and Nakahara, A and Anink, JJ and Mills, JD and , and Lee, JH and Aronica, E and Oyanagi, K and Kakita, A and Gout, JF and Vermulst, M}, title = {The cycad genotoxin methylazoxymethanol, linked to Guam ALS/PDC, induces transcriptional mutagenesis.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {30}, pmid = {38383591}, issn = {2051-5960}, support = {R01 AG054641/AG/NIA NIH HHS/United States ; R01 AG083065/AG/NIA NIH HHS/United States ; R01AG054641/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Mutagens ; Guam ; Methylazoxymethanol Acetate/*analogs & derivatives ; Mutagenesis ; *Amyotrophic Lateral Sclerosis/genetics ; }, } @article {pmid38384337, year = {2024}, author = {Wiesenfarth, M and Dorst, J and Brenner, D and Elmas, Z and Parlak, Ö and Uzelac, Z and Kandler, K and Mayer, K and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Bachhuber, F and Simak, T and Günther, K and Fröhlich, E and Knehr, A and Regensburger, M and German, A and Petri, S and Grosskreutz, J and Klopstock, T and Reilich, P and Schöberl, F and Hagenacker, T and Weyen, U and Günther, R and Vidovic, M and Jentsch, M and Haarmeier, T and Weydt, P and Valkadinov, I and Hesebeck-Brinckmann, J and Conrad, J and Weishaupt, JH and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Senel, M and Tumani, H and Ludolph, AC}, title = {Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.}, journal = {EClinicalMedicine}, volume = {69}, number = {}, pages = {102495}, pmid = {38384337}, issn = {2589-5370}, abstract = {BACKGROUND: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated.

METHODS: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events.

FINDINGS: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported.

INTERPRETATION: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction.

FUNDING: No funding was received towards this study.}, } @article {pmid38385052, year = {2024}, author = {Cherin, N and Patel, S and Jukic, M}, title = {Delayed amyotrophic lateral sclerosis diagnosis with subtle cardiac manifestations: Was anchoring bias contributory?.}, journal = {Clinical case reports}, volume = {12}, number = {2}, pages = {e8544}, pmid = {38385052}, issn = {2050-0904}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disease affecting both upper and lower motor neurons. Throughout medical training, it is taught that the most recognizable clinical presentation involves both motor and bulbar changes. Given the complexity of the diagnosis however, it is no surprise that there is significant multisystem involvement secondary to the autonomic dysfunction associated with the disease. The clinical cognitive biases that exist due to prior educational training and patient provided chief complaint can mislead clinicians and prevent a holistic, inclusive approach toward each patient encounter. This can delay diagnosis and increase unnecessary healthcare spending. In a disease with such a poor prognosis, this effect can be catastrophic, resulting in unacceptable medical, functional, and psychosocial outcomes. As clinicians, it is imperative to acknowledge these cognitive biases through introspection, which can improve clinical outcomes and ultimately patient quality of life for those facing this devastating disease. We report a case of a 55-year-old female who presented with a chief complaint of palpitations and minimal slurred speech on multiple encounters, subsequently leading to a focused cardiovascular workup. It was not until after several hospital encounters that a thorough functional and neuromuscular exam was performed, which ultimately helped to broaden the differential and lead to the diagnosis of ALS. Unfortunately, due to this delayed diagnosis, the patient's functionality was beyond repair. Given the underlying cognitive biases that are present in all clinicians, we hypothesize this patient's sex, presenting symptom, and primary chief complaint misled clinicians to perform limited history and physical examinations, therefore, leading to a narrowed differential. If diagnosed in a timely fashion, vital services such as rehabilitation could have provided this patient with the necessary medical, functional, and psychosocial support to face this devastating disease.}, } @article {pmid38386047, year = {2024}, author = {Imrell, S and Fang, F and Ingre, C and Sennfält, S}, title = {Increased incidence of motor neuron disease in Sweden: a population-based study during 2002-2021.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2730-2735}, pmid = {38386047}, issn = {1432-1459}, support = {Swedish Research Grant DNR 2019-01088//Vetenskapsrådet/ ; }, mesh = {Humans ; Sweden/epidemiology ; Male ; Female ; Incidence ; Aged ; *Motor Neuron Disease/epidemiology ; Middle Aged ; Aged, 80 and over ; Adult ; *Registries ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Motor neuron diseases (MND), with amyotrophic lateral sclerosis constituting most cases, are rare conditions of unknown etiology. There have been reports of an increase in incidence during the latter half of the twentieth century in various Western countries, including Sweden. This study provides updated data on the incidence of MND in Sweden during the last 20 years.

METHODS: Data was obtained from the Swedish National Patient Register on individuals diagnosed with MND from 2002 to 2021 and analysed in relation to group level data for the entire Swedish population. Incidence rates were calculated and presented in relation to year, age, sex, and region.

RESULTS: In the early 2000s, there was a crude incidence rate of 3.5-3.7 per 100,000 person-years, which then increased to 4.0-4.6 from 2008 onward. Age standardization to the starting year (2002) partially mitigated this increase. The incidence rate was greater among men compared to women and was highest within the age range of 70 to 84 years. There were indications of a higher incidence rate in the northernmost parts of the country, although the difference was not statistically significant.

CONCLUSIONS: The incidence rate of MND in Sweden now seems to have surpassed 4 cases per 100,000 person-years. This is higher when compared to both other European countries and previous Swedish studies. It remains to be determined if this increase reflects an actual increasing incidence of MND in Sweden or is due to other factors such as better registry coverage.}, } @article {pmid38388775, year = {2024}, author = {Pang, D and Yu, Y and Zhao, B and Huang, J and Cui, Y and Li, T and Li, C and Shang, H}, title = {The Long Non-Coding RNA NR3C2-8:1 Promotes p53-Mediated Apoptosis through the miR-129-5p/USP10 Axis in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {61}, number = {10}, pages = {7466-7480}, pmid = {38388775}, issn = {1559-1182}, support = {81871000//National Natural Science Foundation of China/ ; 2022NSFSC0750//Sichuan Province Science and Technology Support Program/ ; }, mesh = {*RNA, Long Noncoding/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Tumor Suppressor Protein p53/metabolism/genetics ; *Apoptosis/genetics ; *MicroRNAs/genetics/metabolism ; *Ubiquitin Thiolesterase/genetics/metabolism ; Male ; Signal Transduction/genetics ; Up-Regulation/genetics ; Base Sequence ; }, abstract = {Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is a form of apoptosis, but the mechanisms underlying this neuronal cell death remain unclear. Numerous studies demonstrate abnormally elevated and active p53 in the central nervous system of ALS patients. Activation of p53-regulated pro-apoptotic signaling pathways may trigger motor neuron death. We previously reported decreased expression of the long non-coding RNA NR3C2-8:1 (Lnc-NR3C) in leukocytes of ALS patients. Here, we show lnc-NR3C promotes p53-mediated cell death in ALS by upregulating USP10 and promoting lnc-NR3C-triggered p53 activation, resulting in cell death. Conversely, lnc-NR3C knockdown inhibited USP10-triggered p53 activation, thereby protecting cells against oxidative stress. As a competitive endogenous RNA, lnc-NR3C competitively binds miR-129-5p, regulating the usp10/p53 axis. Elucidating the link between Lnc-NR3C and the USP10/p53 axis in an ALS cell model reveals a role for long non-coding RNAs in activating apoptosis. This provides new therapeutic opportunities in ALS.}, } @article {pmid38389123, year = {2024}, author = {Sainouchi, M and Oginezawa, S and Tada, M and Ishihara, T and Onodera, O and Kakita, A}, title = {Slow disease progression and characteristic TDP-43 inclusions in a patient with familial amyotrophic lateral sclerosis carrying a TARDBP G357S variant.}, journal = {Neuropathology and applied neurobiology}, volume = {50}, number = {1}, pages = {e12966}, doi = {10.1111/nan.12966}, pmid = {38389123}, issn = {1365-2990}, support = {22H02995//JSPS/ ; 23H00434//JSPS/ ; 21K07272//JSPS/ ; JP23jm0210097//AMED-SICORP/ ; //Grants-in Aid from the Research Committee of CNS Degenerative Diseases/ ; //Research on Policy Planning and Evaluation for Rare and Intractable Diseases/ ; //Health, Labour and Welfare Sciences Research Grants/ ; //Ministry of Health, Labour and Welfare, Japan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Disease Progression ; DNA-Binding Proteins/genetics ; Mutation ; }, } @article {pmid38389222, year = {2024}, author = {Consonni, M and Faltracco, V and Dalla Bella, E and Telesca, A and Bersano, E and Nigri, A and Demichelis, G and Medina, JP and Bruzzone, MG and Lauria, G}, title = {Loneliness as neurobehavioral issue in amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {5}, pages = {1122-1134}, pmid = {38389222}, issn = {2328-9503}, support = {2015-0023//Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia/ ; 1157625//Fondo Europeo di Sviluppo Regionale, Regione Lombardia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology/diagnostic imaging ; Male ; *Loneliness/psychology ; Female ; Aged ; Middle Aged ; *Quality of Life ; Magnetic Resonance Imaging ; Cognitive Dysfunction/etiology/physiopathology/diagnostic imaging ; Depression/physiopathology ; }, abstract = {OBJECTIVE: In elderly people loneliness represents a risk factor for dementia and may negatively impact on mental and physical health. The specific contribute of loneliness to cognitive and behavioral functioning have not yet been determined in amyotrophic lateral sclerosis (ALS). Our hypothesis was that loneliness may be related to motor dysfunction with a negative impact on cognitive and behavioral decline, possibly related to specific cortical involvement.

METHODS: In 200 ALS patients (ALSpts) and 50 healthy controls (HCs) we measured loneliness, mood, and quality of life (QoL). ALSpts underwent comprehensive clinical, genetic, and neuropsychological assessment to define phenotypes. Seventy-seven ALSpts performed 3T MRI scans to measure cortical thickness. Between-group, partial correlation and regression analyses were used to examined clinical, neuropsychological, and cortical signatures of loneliness.

RESULTS: Feelings of loneliness were documented in 38% of ALSpts (ALS/L+pts) and in 47% of HCs. In both groups loneliness was associated with anxiety (P < 0.001), depression (P ≤ 0.005), and poor QoL (P < 0.001). ALS/L+pts had similar motor dysfunctions and cognitive abilities than non-lonely ALSpts, but distinct behavioral profiles (P ≤ 0.005) and frontoparietal involvement (P < 0.05). Loneliness in ALS is related to behavioral changes, apathy, and emotional dysregulation (P < 0.001).

INTERPRETATION: Our cross-sectional study indicates that, in ALS, the satisfaction of social environment is associated with a sense of life well-being that is not limited to the motor status, proving instead that loneliness can impact on disease-related neurobehavioral changes with a possible flashback on brain architecture. This suggests that sociality could promote personal resilience against behavioral and affective decline in ALS.}, } @article {pmid38389507, year = {2024}, author = {Al Ojaimi, Y and Slek, C and Osman, S and Alarcan, H and Marouillat, S and Corcia, P and Vourc'h, P and Lanznaster, D and Blasco, H}, title = {The effect of pH alterations on TDP-43 in a cellular model of amyotrophic lateral sclerosis.}, journal = {Biochemistry and biophysics reports}, volume = {38}, number = {}, pages = {101664}, pmid = {38389507}, issn = {2405-5808}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. The pathophysiology of ALS is not well understood but TDP-43 proteinopathy (aggregation and mislocalization) is one of the major phenomena described. Several factors can influence TDP-43 behavior such as mild pH alterations that can induce conformational changes in recombinant TDP-43, increasing its propensity to aggregate. However to our knowledge, no studies have been conducted yet in a cellular setting, in the context of ALS. We therefore tested the effect of cellular pH alterations on the localization, aggregation, and phosphorylation of TDP-43. HEK293T cells overexpressing wildtype TDP-43 were incubated for 1 h with solutions of different pH (6.4, 7.2, and 8). Incubation of cells for 1 h in solutions of pH 6.4 and 8 led to an increase in TDP-43-positive puncta. This was accompanied by the mislocalization of TDP-43 from the nucleus to the cytoplasm. Our results suggest that small alterations in cellular pH affect TDP-43 and increase its mislocalization into cytoplasmic TDP-43-positive puncta, which might suggest a role of TDP-43 in the response of cells to pH alterations.}, } @article {pmid38389786, year = {2024}, author = {Berthiaume, AA and Reda, SM and Kleist, KN and Setti, SE and Wu, W and Johnston, JL and Taylor, RW and Stein, LR and Moebius, HJ and Church, KJ}, title = {ATH-1105, a small-molecule positive modulator of the neurotrophic HGF system, is neuroprotective, preserves neuromotor function, and extends survival in preclinical models of ALS.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1348157}, pmid = {38389786}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder, primarily affects the motor neurons of the brain and spinal cord. Like other neurodegenerative conditions, ongoing pathological processes such as increased inflammation, excitotoxicity, and protein accumulation contribute to neuronal death. Hepatocyte growth factor (HGF) signaling through the MET receptor promotes pro-survival, anti-apoptotic, and anti-inflammatory effects in multiple cell types, including the neurons and support cells of the nervous system. This pleiotropic system is therefore a potential therapeutic target for treatment of neurodegenerative disorders such as ALS. Here, we test the effects of ATH-1105, a small-molecule positive modulator of the HGF signaling system, in preclinical models of ALS.

METHODS: In vitro, the impact of ATH-1105 on HGF-mediated signaling was assessed via phosphorylation assays for MET, extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Neuroprotective effects of ATH-1105 were evaluated in rat primary neuron models including spinal motor neurons, motor neuron-astrocyte cocultures, and motor neuron-human muscle cocultures. The anti-inflammatory effects of ATH-1105 were evaluated in microglia- and macrophage-like cell systems exposed to lipopolysaccharide (LPS). In vivo, the impact of daily oral treatment with ATH-1105 was evaluated in Prp-TDP43[A315T] hemizygous transgenic ALS mice.

RESULTS: In vitro, ATH-1105 augmented phosphorylation of MET, ERK, and AKT. ATH-1105 attenuated glutamate-mediated excitotoxicity in primary motor neurons and motor neuron- astrocyte cocultures, and had protective effects on motor neurons and neuromuscular junctions in motor neuron-muscle cocultures. ATH-1105 mitigated LPS-induced inflammation in microglia- and macrophage-like cell systems. In vivo, ATH-1105 treatment resulted in improved motor and nerve function, sciatic nerve axon and myelin integrity, and survival in ALS mice. Treatment with ATH-1105 also led to reductions in levels of plasma biomarkers of inflammation and neurodegeneration, along with decreased pathological protein accumulation (phospho-TDP-43) in the sciatic nerve. Additionally, both early intervention (treatment initiation at 1 month of age) and delayed intervention (treatment initiation at 2 months of age) with ATH-1105 produced benefits in this preclinical model of ALS.

DISCUSSION: The consistent neuroprotective and anti-inflammatory effects demonstrated by ATH-1105 preclinically provide a compelling rationale for therapeutic interventions that leverage the positive modulation of the HGF pathway as a treatment for ALS.}, } @article {pmid38390945, year = {2024}, author = {Fukatsu, S and Sashi, H and Shirai, R and Takagi, N and Oizumi, H and Yamamoto, M and Ohbuchi, K and Miyamoto, Y and Yamauchi, J}, title = {Rab11a Controls Cell Shape via C9orf72 Protein: Possible Relationships to Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTDALS) Type 1.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {31}, number = {1}, pages = {100-116}, pmid = {38390945}, issn = {1873-149X}, abstract = {Abnormal nucleotide insertions of C9orf72, which forms a complex with Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) protein and WD repeat-containing protein 41 (WDR41) protein, are associated with an autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 1 (FTDALS1). The differentially expressed in normal and neoplastic cells (DENN) domain-containing C9orf72 and its complex with SMCR8 and WDR41 function as a guanine-nucleotide exchange factor for Rab GTP/GDP-binding proteins (Rab GEF, also called Rab activator). Among Rab proteins serving as major effectors, there exists Rab11a. However, it remains to be established which Rab protein is related to promoting or sustaining neuronal morphogenesis or homeostasis. In this study, we describe that the knockdown of Rab11a decreases the expression levels of neuronal differentiation marker proteins, as well as the elongation of neurite-like processes, using N1E-115 cells, a well-utilized neuronal differentiation model. Similar results were obtained in primary cortical neurons. In contrast, the knockdown of Rab11b, a Rab11a homolog, did not significantly affect their cell morphological changes. It is of note that treatment with hesperetin, a citrus flavonoid (also known as Vitamin P), recovered the neuronal morphological phenotypes induced by Rab11a knockdown. Also, the knockdown of Rab11a or Rab11b led to a decrease in glial marker expression levels and in morphological changes in FBD-102b cells, which serve as the oligodendroglial differentiation model. Rab11a is specifically involved in the regulation of neuronal morphological differentiation. The knockdown effect mimicking the loss of function of C9orf72 is reversed by treatment with hesperetin. These findings may reveal a clue for identifying one of the potential molecular and cellular phenotypes underlying FTDALS1.}, } @article {pmid38390994, year = {2024}, author = {Nájera-Maldonado, JM and Salazar, R and Alvarez-Fitz, P and Acevedo-Quiroz, M and Flores-Alfaro, E and Hernández-Sotelo, D and Espinoza-Rojo, M and Ramírez, M}, title = {Phenolic Compounds of Therapeutic Interest in Neuroprotection.}, journal = {Journal of xenobiotics}, volume = {14}, number = {1}, pages = {227-246}, pmid = {38390994}, issn = {2039-4713}, support = {A1-S-34290 to Monica Ramirez//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; }, abstract = {The number of elderly people is projected to double in the next 50 years worldwide, resulting in an increased prevalence of neurodegenerative diseases. Aging causes changes in brain tissue homeostasis, thus contributing to the development of neurodegenerative disorders. Current treatments are not entirely effective, so alternative treatments or adjuvant agents are being actively sought. Antioxidant properties of phenolic compounds are of particular interest for neurodegenerative diseases whose psychopathological mechanisms strongly rely on oxidative stress at the brain level. Moreover, phenolic compounds display other advantages such as the permeability of the blood-brain barrier (BBB) and the interesting molecular mechanisms that we reviewed in this work. We began by briefly outlining the physiopathology of neurodegenerative diseases to understand the mechanisms that result in irreversible brain damage, then we provided an overall classification of the phenolic compounds that would be addressed later. We reviewed in vitro and in vivo studies, as well as some clinical trials in which neuroprotective mechanisms were demonstrated in models of different neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), ischemia, and traumatic brain injury (TBI).}, } @article {pmid38391731, year = {2024}, author = {Manera, U and Torrieri, MC and Moglia, C and Canosa, A and Vasta, R and Palumbo, F and Matteoni, E and Cabras, S and Grassano, M and Bombaci, A and Mattei, A and Bellocchia, M and Tabbia, G and Ribolla, F and Chiò, A and Calvo, A}, title = {Calculated Maximal Volume Ventilation (cMVV) as a Marker of Early Respiratory Failure in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Brain sciences}, volume = {14}, number = {2}, pages = {}, pmid = {38391731}, issn = {2076-3425}, support = {GA101017598//European Union's Horizon 2020/ ; RF-2016-02362405//the Italian Ministry of Health/ ; 2017SNW5MB//Italian Ministry of Education, University and Research/ ; 259867//European Commission's Health Seventh Framework Programme/ ; Strength, ALS-Care and Brain-Mend projects//Joint Programme-Neurodegenerative Disease Research/ ; Department of Excellence grant//Italian Ministry of University and Research/ ; }, abstract = {Respiratory failure assessment is among the most debatable research topics in amyotrophic lateral sclerosis (ALS) clinical research due to the wide heterogeneity of its presentation. Among the different pulmonary function tests (PFTs), maximal voluntary ventilation (MVV) has shown potential utility as a diagnostic and monitoring marker, able to capture early respiratory modification in neuromuscular disorders. In the present study, we explored calculated MVV (cMVV) as a prognostic biomarker in a center-based, retrospective ALS population belonging to the Piemonte and Valle d'Aosta registry for ALS (PARALS). A Spearman's correlation analysis with clinical data and PFTs showed a good correlation of cMVV with forced vital capacity (FVC) and a moderate correlation with some other features such as bulbar involvement, ALSFRS-R total score, blood oxygen (pO2), carbonate (HCO3[-]), and base excess (BE), measured with arterial blood gas analysis. Both the Cox proportional hazard models for survival and the time to non-invasive ventilation (NIV) measurement highlighted that cMVV at diagnosis (considering cMVV(40) ≥ 80) is able to stratify patients across different risk levels for death/tracheostomy and NIV indication, especially considering patients with FVC% ≥ 80. In conclusion, cMVV is a useful marker of early respiratory failure in ALS, and is easily derivable from standard PFTs, especially in asymptomatic ALS patients with normal FVC measures.}, } @article {pmid38391732, year = {2024}, author = {Yang, K and Liu, Y and Zhang, M}, title = {The Diverse Roles of Reactive Astrocytes in the Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {14}, number = {2}, pages = {}, pmid = {38391732}, issn = {2076-3425}, support = {82271478//National Natural Science Foundation of China/ ; }, abstract = {Astrocytes displaying reactive phenotypes are characterized by their ability to remodel morphologically, molecularly, and functionally in response to pathological stimuli. This process results in the loss of their typical astrocyte functions and the acquisition of neurotoxic or neuroprotective roles. A growing body of research indicates that these reactive astrocytes play a pivotal role in the pathogenesis of amyotrophic lateral sclerosis (ALS), involving calcium homeostasis imbalance, mitochondrial dysfunction, abnormal lipid and lactate metabolism, glutamate excitotoxicity, etc. This review summarizes the characteristics of reactive astrocytes, their role in the pathogenesis of ALS, and recent advancements in astrocyte-targeting strategies.}, } @article {pmid38391754, year = {2024}, author = {Leão Batista Simões, J and Webler Eichler, S and Raitz Siqueira, ML and de Carvalho Braga, G and Bagatini, MD}, title = {Amyotrophic Lateral Sclerosis in Long-COVID Scenario and the Therapeutic Potential of the Purinergic System in Neuromodulation.}, journal = {Brain sciences}, volume = {14}, number = {2}, pages = {}, pmid = {38391754}, issn = {2076-3425}, support = {Proj. No 404256/2021-0 and 310606/2021-7).//National Council for Scientific and Technological Development/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) involves the degeneration of motor neurons and debilitating and possibly fatal symptoms. The COVID-19 pandemic directly affected the quality of life of this group, and the SARS-CoV-2 infection accelerated the present neuroinflammatory process. Furthermore, studies indicate that the infection may have led to the development of the pathology. Thus, the scenario after this pandemic presents "long-lasting COVID" as a disease that affects people who have been infected. From this perspective, studying the pathophysiology behind ALS associated with SARS-CoV-2 infection and possible supporting therapies becomes necessary when we understand the impact on the quality of life of these patients. Thus, the purinergic system was trained to demonstrate how its modulation can add to the treatment, reduce disease progression, and result in better prognoses. From our studies, we highlight the P2X7, P2X4, and A2AR receptors and how their activity can directly influence the ALS pathway.}, } @article {pmid38392208, year = {2024}, author = {Fukatsu, S and Okawa, M and Okabe, M and Cho, M and Isogai, M and Yokoi, T and Shirai, R and Oizumi, H and Yamamoto, M and Ohbuchi, K and Miyamoto, Y and Yamauchi, J}, title = {Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr.}, journal = {Current issues in molecular biology}, volume = {46}, number = {2}, pages = {1398-1412}, pmid = {38392208}, issn = {1467-3045}, abstract = {Some charged multivesicular body protein 2B (CHMP2B) mutations are associated with autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTDALS7). The main aim of this study is to clarify the relationship between the expression of mutated CHMP2B protein displaying FTD symptoms and defective neuronal differentiation. First, we illustrate that the expression of CHMP2B with the Asp148Tyr (D148Y) mutation, which preferentially displays FTD phenotypes, blunts neurite process elongation in rat primary cortical neurons. Similar results were observed in the N1E-115 cell line, a model that undergoes neurite elongation. Second, these effects were also accompanied by changes in neuronal differentiation marker protein expression. Third, wild-type CHMP2B protein was indeed localized in the endosomal sorting complexes required to transport (ESCRT)-like structures throughout the cytoplasm. In contrast, CHMP2B with the D148Y mutation exhibited aggregation-like structures and accumulated in the Golgi body. Fourth, among currently known Golgi stress regulators, the expression levels of Hsp47, which has protective effects on the Golgi body, were decreased in cells expressing CHMP2B with the D148Y mutation. Fifth, Arf4, another Golgi stress-signaling molecule, was increased in mutant-expressing cells. Finally, when transfecting Hsp47 or knocking down Arf4 with small interfering (si)RNA, cellular phenotypes in mutant-expressing cells were recovered. These results suggest that CHMP2B with the D148Y mutation, acting through Golgi stress signaling, is negatively involved in the regulation of neuronal cell morphological differentiation, providing evidence that a molecule controlling Golgi stress may be one of the potential FTD therapeutic targets at the molecular and cellular levels.}, } @article {pmid38392286, year = {2024}, author = {Jackson, WS and Bauer, S and Kaczmarczyk, L and Magadi, SS}, title = {Selective Vulnerability to Neurodegenerative Disease: Insights from Cell Type-Specific Translatome Studies.}, journal = {Biology}, volume = {13}, number = {2}, pages = {}, pmid = {38392286}, issn = {2079-7737}, support = {grant # 990868//the Konung Gustaf V:s och Drottning Victorias Stiftelse; the Wallenberg Center for Molecular Medicine;the Hereditary Disease Foundation/ ; }, abstract = {Neurodegenerative diseases (NDs) manifest a wide variety of clinical symptoms depending on the affected brain regions. Gaining insights into why certain regions are resistant while others are susceptible is vital for advancing therapeutic strategies. While gene expression changes offer clues about disease responses across brain regions, the mixture of cell types therein obscures experimental results. In recent years, methods that analyze the transcriptomes of individual cells (e.g., single-cell RNA sequencing or scRNAseq) have been widely used and have provided invaluable insights into specific cell types. Concurrently, transgene-based techniques that dissect cell type-specific translatomes (CSTs) in model systems, like RiboTag and bacTRAP, offer unique advantages but have received less attention. This review juxtaposes the merits and drawbacks of both methodologies, focusing on the use of CSTs in understanding conditions like amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Alzheimer's disease (AD), and specific prion diseases like fatal familial insomnia (FFI), genetic Creutzfeldt-Jakob disease (gCJD), and acquired prion disease. We conclude by discussing the emerging trends observed across multiple diseases and emerging methods.}, } @article {pmid38392311, year = {2024}, author = {Dratch, L and Bardakjian, TM and Johnson, K and Babaian, N and Gonzalez-Alegre, P and Elman, L and Quinn, C and Guo, MH and Scherer, SS and Amado, DA}, title = {The Importance of Offering Exome or Genome Sequencing in Adult Neuromuscular Clinics.}, journal = {Biology}, volume = {13}, number = {2}, pages = {}, pmid = {38392311}, issn = {2079-7737}, support = {K08 NS114106/NS/NINDS NIH HHS/United States ; }, abstract = {Advances in gene-specific therapeutics for patients with neuromuscular disorders (NMDs) have brought increased attention to the importance of genetic diagnosis. Genetic testing practices vary among adult neuromuscular clinics, with multi-gene panel testing currently being the most common approach; follow-up testing using broad-based methods, such as exome or genome sequencing, is less consistently offered. Here, we use five case examples to illustrate the unique ability of broad-based testing to improve diagnostic yield, resulting in identification of SORD-neuropathy, HADHB-related disease, ATXN2-ALS, MECP2 related progressive gait decline and spasticity, and DNMT1-related cerebellar ataxia, deafness, narcolepsy, and hereditary sensory neuropathy type 1E. We describe in each case the technological advantages that enabled identification of the causal gene, and the resultant clinical and personal implications for the patient, demonstrating the importance of offering exome or genome sequencing to adults with NMDs.}, } @article {pmid38393299, year = {2024}, author = {García-Parra, B and Guiu, JM and Povedano, M and Mariño, EL and Modamio, P}, title = {Geographical distribution of clinical trials in amyotrophic lateral sclerosis: a scoping review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {376-381}, doi = {10.1080/21678421.2024.2320881}, pmid = {38393299}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/therapy ; Belgium ; France ; Germany ; United Kingdom ; }, abstract = {Introduction: Clinical trials location is determined by many factors, including the availability of patient populations, regulatory environment, scientific expertise, and cost considerations. In clinical drug development of amyotrophic lateral sclerosis (ALS), where genetic differences have been described and may be related to geographic setting, this could have implications for the clinical interpretation of results in underrepresented geographic settings. Objective: The aim of this study was to review country participation in ALS clinical research based on available data from clinical trial registries and databases. Methods: We performed a scoping review with available information about clinical trials on ALS in ClinicalTrials.gov (CT), EU clinical trials register (EudraCT), WHO International Clinical Trials Registry Platform (ICTRP) and Web of Science (WOS). Inclusion criteria were clinical trials in phase 2 and 3 to treat ALS, recruiting or active not recruiting, from 23/06/2018 to 23/06/2023. Results: The total number of clinical trials identified were 188; 54 studies in CT, 38 in EudraCT, 47 in ICTRP and 49 in WOS. We identified 77 clinical trials after deleting duplicates and applying exclusion criteria. The countries with most studies conducted were the US with 35 studies (10.9%), followed by the United Kingdom, Belgium, France and Germany with 21 studies each one of them (6.5%). Conclusion: The data obtained in our review showed a non-homogeneous distribution in clinical trials at the international level, which may influence the interpretation of the results obtained.}, } @article {pmid38393638, year = {2024}, author = {Gowda, VK and Babu, S and Kinhal, U and Srinivasan, VM}, title = {Amyotrophic Lateral Sclerosis due to ALS2 Pathogenic Variant Masquerading as Cerebral Palsy.}, journal = {Indian journal of pediatrics}, volume = {91}, number = {8}, pages = {872}, pmid = {38393638}, issn = {0973-7693}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Cerebral Palsy/diagnosis ; Diagnosis, Differential ; Male ; Guanine Nucleotide Exchange Factors/genetics ; }, } @article {pmid38394210, year = {2024}, author = {Chang, YJ and Lin, KT and Shih, O and Yang, CH and Chuang, CY and Fang, MH and Lai, WB and Lee, YC and Kuo, HC and Hung, SC and Yao, CK and Jeng, US and Chen, YR}, title = {Sulfated disaccharide protects membrane and DNA damages from arginine-rich dipeptide repeats in ALS.}, journal = {Science advances}, volume = {10}, number = {8}, pages = {eadj0347}, pmid = {38394210}, issn = {2375-2548}, mesh = {Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Dipeptides/pharmacology ; Arginine/genetics ; Sulfates ; Drosophila/genetics ; DNA Damage ; DNA Repeat Expansion ; C9orf72 Protein/genetics/metabolism ; }, abstract = {Hexanucleotide repeat expansion in C9ORF72 (C9) is the most prevalent mutation among amyotrophic lateral sclerosis (ALS) patients. The patients carry over ~30 to hundreds or thousands of repeats translated to dipeptide repeats (DPRs) where poly-glycine-arginine (GR) and poly-proline-arginine (PR) are most toxic. The structure-function relationship is still unknown. Here, we examined the minimal neurotoxic repeat number of poly-GR and found that extension of the repeat number led to a loose helical structure disrupting plasma and nuclear membrane. Poly-GR/PR bound to nucleotides and interfered with transcription. We screened and identified a sulfated disaccharide that bound to poly-GR/PR and rescued poly-GR/PR-induced toxicity in neuroblastoma and C9-ALS-iPSC-derived motor neurons. The compound rescued the shortened life span and defective locomotion in poly-GR/PR expressing Drosophila model and improved motor behavior in poly-GR-injected mouse model. Overall, our results reveal structural and toxicity mechanisms for poly-GR/PR and facilitate therapeutic development for C9-ALS.}, } @article {pmid38394955, year = {2024}, author = {Lim, JX and Fong, E and Goh, C and Ng, LP and Low, DCY and Seow, WT and Low, SYY}, title = {Complex lumbosacral spinal cord lipomas: A longitudinal study on outcomes from a Singapore children's hospital.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {121}, number = {}, pages = {119-128}, doi = {10.1016/j.jocn.2024.02.017}, pmid = {38394955}, issn = {1532-2653}, mesh = {Child ; Humans ; Infant ; Longitudinal Studies ; Retrospective Studies ; Treatment Outcome ; Singapore/epidemiology ; *Spinal Cord Neoplasms/diagnostic imaging/surgery ; Spinal Cord ; *Lipoma/surgery ; Hospitals ; Lumbosacral Region/surgery ; }, abstract = {BACKGROUND: Total/near-total resection (TR/NTR) of complex lumbosacral lipomas (CSL) is reported to be associated with better long-term functional outcomes and lower symptomatic re-tethering rates. We report our institutional experience for CSL resection in affected children.

METHODS: This is a single-institution, retrospective study. Inclusion criteria consist of patients with CSL with dorsal, transitional and chaotic lipomas based on Pang et al's classification. The study population is divided into 2 groups: asymptomatic patients with a normal preoperative workup referred to as 'prophylactic intent' and 'therapeutic intent' for those with pre-existing neuro-urological symptoms. Primary aims are to review factors that affect post-operative clean intermittent catheterization (CIC), functional outcomes based on Necker functional score (NFS), and re-tethering rates.

RESULTS: 122 patients were included from 2000 to 2021. There were 32 dorsal lipomas (26.2 %), 74 transitional lipomas (60.7 %), and 16 chaotic lipomas (13.1 %). 82 % patients achieved TR/NTR. Favourable NFS at 1-year was 48.2 %. The re-tethering rate was 6.6 %. After multivariable analysis, post-operative CIC was associated with median age at surgery (p = 0.026), lipoma type (p = 0.029), conus height (p = 0.048) and prophylactic intent (p < 0.001). Next, extent of lipoma resection (p = 0.012) and the post-operative CSF leak (p = 0.004) were associated with re-tethering. Favourable NFS was associated with lipoma type (p = 0.047) and prophylactic intent surgery (p < 0.001).

CONCLUSIONS: Our experience shows that TR/NTR for CSL is a feasible option to prevent functional deterioration and re-tethering. Efforts are needed to work on factors associated with post-operative CIC.}, } @article {pmid38395927, year = {2024}, author = {Baranova, A and Zhao, Q and Cao, H and Chandhoke, V and Zhang, F}, title = {Causal influences of neuropsychiatric disorders on Alzheimer's disease.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {114}, pmid = {38395927}, issn = {2158-3188}, mesh = {Humans ; *Alzheimer Disease/genetics ; *Schizophrenia/epidemiology/genetics ; *Parkinson Disease/genetics ; *Attention Deficit Disorder with Hyperactivity/genetics ; *Migraine Disorders/genetics ; Genome-Wide Association Study ; }, abstract = {Previous studies have observed a significant comorbidity between Alzheimer's disease (AD) and some other neuropsychiatric disorders. However, the mechanistic connections between neuropsychiatric disorders and AD are not well understood. We conducted a Mendelian randomization analysis to appraise the potential influences of 18 neurodegenerative and neuropsychiatric disorders on AD. We found that four disorders are causally associated with increased risk for AD, including bipolar disorder (BD) (OR: 1.09), migraine (OR: 1.09), schizophrenia (OR: 1.05), and Parkinson's disease (PD) (OR: 1.07), while attention-deficit/hyperactivity disorder (ADHD) was associated with a decreased risk for AD (OR: 0.80). In case of amyotrophic lateral sclerosis (OR: 1.04) and Tourette's syndrome (OR: 1.05), there was suggestive evidence of their causal effects of on AD. Our study shows that genetic components predisposing to BD, migraine, schizophrenia, and PD may promote the development of AD, while ADHD may be associated with a reduced risk of AD. The treatments aimed at alleviating neuropsychiatric diseases with earlier onset may also influence the risk of AD-related cognitive decline, which is typically observed later in life.}, } @article {pmid38395965, year = {2024}, author = {Markovinovic, A and Martín-Guerrero, SM and Mórotz, GM and Salam, S and Gomez-Suaga, P and Paillusson, S and Greig, J and Lee, Y and Mitchell, JC and Noble, W and Miller, CCJ}, title = {Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca[2+] and synaptic defects.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {32}, pmid = {38395965}, issn = {2051-5960}, support = {MR/R022666/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Calcium/metabolism ; Endoplasmic Reticulum/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; Protein Tyrosine Phosphatases/metabolism ; Synapses/pathology ; TDP-43 Proteinopathies/metabolism ; *Vesicular Transport Proteins/genetics ; Mitochondrial Proteins ; DNA-Binding Proteins ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically linked major neurodegenerative diseases. Notably, TAR DNA-binding protein-43 (TDP43) accumulations are hallmark pathologies of FTD/ALS and mutations in the gene encoding TDP43 cause familial FTD/ALS. There are no cures for FTD/ALS. FTD/ALS display damage to a broad range of physiological functions, many of which are regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by the VAPB-PTPIP51 tethering proteins that serve to recruit regions of ER to the mitochondrial surface so as to facilitate inter-organelle communications. Several studies have now shown that disrupted ER-mitochondria signaling including breaking of the VAPB-PTPIP51 tethers are features of FTD/ALS and that for TDP43 and other familial genetic FTD/ALS insults, this involves activation of glycogen kinase-3β (GSK3β). Such findings have prompted suggestions that correcting damage to ER-mitochondria signaling and the VAPB-PTPIP51 interaction may be broadly therapeutic. Here we provide evidence to support this notion. We show that overexpression of VAPB or PTPIP51 to enhance ER-mitochondria signaling corrects mutant TDP43 induced damage to inositol 1,4,5-trisphosphate (IP3) receptor delivery of Ca[2+] to mitochondria which is a primary function of the VAPB-PTPIP51 tethers, and to synaptic function. Moreover, we show that ursodeoxycholic acid (UDCA), an FDA approved drug linked to FTD/ALS and other neurodegenerative diseases therapy and whose precise therapeutic target is unclear, corrects TDP43 linked damage to the VAPB-PTPIP51 interaction. We also show that this effect involves inhibition of TDP43 mediated activation of GSK3β. Thus, correcting damage to the VAPB-PTPIP51 tethers may have therapeutic value for FTD/ALS and other age-related neurodegenerative diseases.}, } @article {pmid38396337, year = {2024}, author = {Genge, A and Cedarbaum, JM and Shefner, J and Chio, A and Al-Chalabi, A and Van Damme, P and McDermott, C and Glass, J and Berry, J and van Eijk, RPA and Fournier, C and Grosskreutz, J and Andrews, J and Bertone, V and Bunte, TM and Couillard, M and Cummings, C and Kittle, G and Polzer, J and Salmon, K and Straub, C and van den Berg, LH}, title = {The ALSFRS-R Summit: a global call to action on the use of the ALSFRS-R in ALS clinical trials.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {382-387}, doi = {10.1080/21678421.2024.2320880}, pmid = {38396337}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Severity of Illness Index ; Disease Progression ; }, abstract = {The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was developed more than 25 years ago as an instrument to monitor functional change over time in patients with ALS. It has since been revised and extended to meet the needs of high data quality in ALS trials (ALSFRS-R), however a full re-validation of the scale was not completed. Despite this, the scale has remained a primary outcome measure in clinical trials. We convened a group of clinical trialists to discuss and explore opportunities to improve the scale and propose alternative measures. In this meeting report, we present a call to action on the use of the ALSFRS-Revised scale in clinical trials, focusing on the need for (1) harmonization of the ALSFRS-R administration globally, (2) alignment on a set of recommendations for clinical trial design and statistical analysis plans (SAPs), and (3) use of additional outcome measures.}, } @article {pmid38396386, year = {2016}, author = {Aimo, J and Promancio, E and Damiani, PC}, title = {Determination of reducing sugars in foodstuff applying multivariate second-order calibration.}, journal = {Analytical methods : advancing methods and applications}, volume = {8}, number = {23}, pages = {4617-4631}, doi = {10.1039/c6ay00964f}, pmid = {38396386}, issn = {1759-9679}, abstract = {In the present report, a chemometrics-assisted second-order kinetic-spectrophotometric method has been developed for determining reducing sugars, glucose, fructose and lactose, in food samples, based on the reaction with hexacyanoferrate, HCF, at 70 °C in alkaline medium. A suitable experimental design helped us to establish the conditions (pH, temperature, and HCF concentration) for optimal sensitivity and selectivity among analytes. Second order data were recorded by measuring the absorbance of unreacted HCF in the spectral range of 370 to 470 nm for five minutes using a diode array. A calibration set of samples was prepared according to a central composite design containing the three sugars for training the algorithms. Validation samples containing only the analytes were prepared for checking the reliability of the algorithms. In this particular system, identical profiles for sample components are obtained in the spèctral dimension corresponding to unreacted HCF. Moreover, two kinds of interferents may be present: sample components active in the spectral region at which HCF absorbs as well as potential reducing interferents, causing linear dependence, since they provide identical profiles in spectral dimension to those of the analytes of interest. In the present work, MCR-ALS in the spectral augmentation mode was the only algorithm that could successfully resolve linear dependence. Satisfactory results were obtained by applying MCR-ALS in the spectral augmentation mode in order to achieve a second order advantage for the determination of fructose and glucose in validation samples, in test samples containing the two kinds of interferents and in real food samples, providing LODs of 4.0 and 5.0 mg L[-1], respectively. However, bad results were obtained for lactose which may be due to its low sensitivity in the augmented dimension. Good results were also obtained by applying U-PLS/RBL and N-PLS/RBL for determining simultaneously the three sugars in validation samples and in test samples containing only active spectral interferents. Finally, lactose and also, glucose and fructose, were successfully quantified in real milk samples, with LODmin = 1.0 mg L[-1], 1.0 mg L[-1] and 0.1 mg L[-1] and LODmax = 3.5, 3.8 and 4.4 mg L[-1], respectively, using UPLS/RBL, and LODmin of 1.3, 1.1 and 0.1 mg L[-1] and LODmax of 4.0, 4.3 and 4.9 mg L[-1] for lactose, glucose and fructose, respectively, for NPLS/RBL. Results for real samples in all cases were statistically comparable to those obtained by applying a reference method based on HPLC (High Performance Liquid Chromatography).}, } @article {pmid38396946, year = {2024}, author = {Anilkumar, AK and Vij, P and Lopez, S and Leslie, SM and Doxtater, K and Khan, MM and Yallapu, MM and Chauhan, SC and Maestre, GE and Tripathi, MK}, title = {Long Non-Coding RNAs: New Insights in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {4}, pages = {}, pmid = {38396946}, issn = {1422-0067}, support = {P30 AG066546/AG/NIA NIH HHS/United States ; R16 GM146696/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/pathology ; *RNA, Long Noncoding/genetics ; *Alzheimer Disease ; *Parkinson Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are gradually becoming a burden to society. The adverse effects and mortality/morbidity rates associated with these NDDs are a cause of many healthcare concerns. The pathologic alterations of NDDs are related to mitochondrial dysfunction, oxidative stress, and inflammation, which further stimulate the progression of NDDs. Recently, long non-coding RNAs (lncRNAs) have attracted ample attention as critical mediators in the pathology of NDDs. However, there is a significant gap in understanding the biological function, molecular mechanisms, and potential importance of lncRNAs in NDDs. This review documents the current research on lncRNAs and their implications in NDDs. We further summarize the potential implication of lncRNAs to serve as novel therapeutic targets and biomarkers for patients with NDDs.}, } @article {pmid38396996, year = {2024}, author = {Firdaus, Z and Li, X}, title = {Unraveling the Genetic Landscape of Neurological Disorders: Insights into Pathogenesis, Techniques for Variant Identification, and Therapeutic Approaches.}, journal = {International journal of molecular sciences}, volume = {25}, number = {4}, pages = {}, pmid = {38396996}, issn = {1422-0067}, support = {R01 DK126662/DK/NIDDK NIH HHS/United States ; R01 DK129241/DK/NIDDK NIH HHS/United States ; R01 DK129241 and DK126662/NH/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy/pathology ; *Parkinson Disease/genetics/therapy/pathology ; *Alzheimer Disease/pathology ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Genetic abnormalities play a crucial role in the development of neurodegenerative disorders (NDDs). Genetic exploration has indeed contributed to unraveling the molecular complexities responsible for the etiology and progression of various NDDs. The intricate nature of rare and common variants in NDDs contributes to a limited understanding of the genetic risk factors associated with them. Advancements in next-generation sequencing have made whole-genome sequencing and whole-exome sequencing possible, allowing the identification of rare variants with substantial effects, and improving the understanding of both Mendelian and complex neurological conditions. The resurgence of gene therapy holds the promise of targeting the etiology of diseases and ensuring a sustained correction. This approach is particularly enticing for neurodegenerative diseases, where traditional pharmacological methods have fallen short. In the context of our exploration of the genetic epidemiology of the three most prevalent NDDs-amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease, our primary goal is to underscore the progress made in the development of next-generation sequencing. This progress aims to enhance our understanding of the disease mechanisms and explore gene-based therapies for NDDs. Throughout this review, we focus on genetic variations, methodologies for their identification, the associated pathophysiology, and the promising potential of gene therapy. Ultimately, our objective is to provide a comprehensive and forward-looking perspective on the emerging research arena of NDDs.}, } @article {pmid38397838, year = {2024}, author = {Peggion, C and Calì, T and Brini, M}, title = {Mitochondria Dysfunction and Neuroinflammation in Neurodegeneration: Who Comes First?.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {2}, pages = {}, pmid = {38397838}, issn = {2076-3921}, abstract = {Neurodegenerative diseases (NDs) encompass an assorted array of disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, each characterised by distinct clinical manifestations and underlying pathological mechanisms. While some cases have a genetic basis, many NDs occur sporadically. Despite their differences, these diseases commonly feature chronic neuroinflammation as a hallmark. Consensus has recently been reached on the possibility that mitochondria dysfunction and protein aggregation can mutually contribute to the activation of neuroinflammatory response and thus to the onset and progression of these disorders. In the present review, we discuss the contribution of mitochondria dysfunction and neuroinflammation to the aetiology and progression of NDs, highlighting the possibility that new potential therapeutic targets can be identified to tackle neurodegenerative processes and alleviate the progression of these pathologies.}, } @article {pmid38397958, year = {2024}, author = {Borrego-Hernández, D and Vázquez-Costa, JF and Domínguez-Rubio, R and Expósito-Blázquez, L and Aller, E and Padró-Miquel, A and García-Casanova, P and Colomina, MJ and Martín-Arriscado, C and Osta, R and Cordero-Vázquez, P and Esteban-Pérez, J and Povedano-Panadés, M and García-Redondo, A}, title = {Intermediate Repeat Expansion in the ATXN2 Gene as a Risk Factor in the ALS and FTD Spanish Population.}, journal = {Biomedicines}, volume = {12}, number = {2}, pages = {}, pmid = {38397958}, issn = {2227-9059}, support = {17/00491//Instituto de Salud Carlos III/ ; 21/00286//Instituto de Salud Carlos III/ ; JR19/00030//Instituto de Salud Carlos III/ ; 2021/00737//Instituto de Salud Carlos III/ ; 2017/0653//STOPELA/ ; BOCM142-17/09/2019 pg.105//Spanish Health Ministry/ ; }, abstract = {Intermediate CAG expansions in the gene ataxin-2 (ATXN2) are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different genetic backgrounds. The aim of this study was to assess the relationship of intermediate CAG expansions in ATXN2 with the risk and phenotype of ALS and FTD in the Spanish population. Repeat-primed PCR was performed in 620 ALS and 137 FTD patients in three referral centers in Spain to determine the exact number of CAG repeats. In our cohort, ≥27 CAG repeats in ATXN2 were associated with a higher risk of developing ALS (odds ratio [OR] = 2.666 [1.471-4.882]; p = 0.0013) but not FTD (odds ratio [OR] = 1.446 [0.558-3.574]; p = 0.44). Moreover, ALS patients with ≥27 CAG repeats in ATXN2 showed a shorter survival rate compared to those with <27 repeats (hazard ratio [HR] 1.74 [1.18, 2.56], p = 0.005), more frequent limb onset (odds ratio [OR] = 2.34 [1.093-4.936]; p = 0.028) and a family history of ALS (odds ratio [OR] = 2.538 [1.375-4.634]; p = 0.002). Intermediate CAG expansions of ≥27 repeats in ATXN2 are associated with ALS risk but not with FTD in the Spanish population. ALS patients carrying an intermediate expansion in ATXN2 show more frequent limb onset but a worse prognosis than those without expansions. In patients carrying C9orf72 expansions, the intermediate ATXN2 expansion might increase the penetrance and modify the phenotype.}, } @article {pmid38399373, year = {2024}, author = {Cha, Y and Kagalwala, MN and Ross, J}, title = {Navigating the Frontiers of Machine Learning in Neurodegenerative Disease Therapeutics.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {2}, pages = {}, pmid = {38399373}, issn = {1424-8247}, abstract = {Recent advances in machine learning hold tremendous potential for enhancing the way we develop new medicines. Over the years, machine learning has been adopted in nearly all facets of drug discovery, including patient stratification, lead discovery, biomarker development, and clinical trial design. In this review, we will discuss the latest developments linking machine learning and CNS drug discovery. While machine learning has aided our understanding of chronic diseases like Alzheimer's disease and Parkinson's disease, only modest effective therapies currently exist. We highlight promising new efforts led by academia and emerging biotech companies to leverage machine learning for exploring new therapies. These approaches aim to not only accelerate drug development but to improve the detection and treatment of neurodegenerative diseases.}, } @article {pmid38399458, year = {2024}, author = {Al Shaer, D and Al Musaimi, O and Albericio, F and de la Torre, BG}, title = {2023 FDA TIDES (Peptides and Oligonucleotides) Harvest.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {2}, pages = {}, pmid = {38399458}, issn = {1424-8247}, abstract = {A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The four approved oligonucleotides are indicated for various types of disorders, including amyotrophic lateral sclerosis, geographic atrophy, primary hyperoxaluria type 1, and polyneuropathy of hereditary transthyretin-mediated amyloidosis. All oligonucleotides show chemically modified structures to enhance their stability and therapeutic effectiveness as antisense or aptamer oligomers. Some of them demonstrate various types of conjugation to driving ligands. The approved peptides comprise various structures, including linear, cyclic, and lipopeptides, and have diverse applications. Interestingly, the FDA has granted its first orphan drug designation for a peptide-based drug as a highly selective chemokine antagonist. Furthermore, Rett syndrome has found its first-ever core symptoms treatment, which is also peptide-based. Here, we analyze the TIDES approved in 2023 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects.}, } @article {pmid38399543, year = {2024}, author = {Karagul, S and Senol, S and Karakose, O and Uzunoglu, K and Kayaalp, C}, title = {One Anastomosis Gastric Bypass versus Roux-en-Y Gastric Bypass: A Randomized Prospective Trial.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {2}, pages = {}, pmid = {38399543}, issn = {1648-9144}, mesh = {Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; *Gastric Bypass/methods ; Prospective Studies ; *Obesity, Morbid/surgery ; Comorbidity ; Weight Loss ; Retrospective Studies ; }, abstract = {Background and Objectives: One anastomosis gastric bypass (OAGB) and Roux-en-Y gastric bypass (RYGB) surgeries are effective methods used in bariatric surgery. There are limited randomized studies comparing these procedures over more than 2 years. Here, we aimed to compare the 3-year results of two bariatric procedures. Materials and Methods: Patients included in this randomized prospective study were compared in OAGB and RYGB groups. A total of 55 patients, aged between 18 and 65, were eligible for the study. Thirteen patients who did not accept randomization were excluded. Patients were evaluated at 6, 12, 24, and 36 months postoperatively. Results: Three patients were excluded from the study due to loss of communication during the clinical follow-up and one due to death by amyotrophic lateral sclerosis, which started in the eighth month after surgery. The study was completed with a total of 38 patients (OAGB; n = 20, RYGB; n = 18). Patients in the two groups were similar in terms of age, gender, body mass index (BMI), and obesity-related comorbidities. At the end of 3-year follow-up, BMI in the OAGB and RYGB groups was 28.80 ± 4.53 kg/m[2] and 29.17 ± 5.36 kg/m[2], respectively (p = 0.822). Percentage total weight loss (TWL%) was similar. No significant differences were found between the groups regarding percentage excess weight loss (EWL%). Remission of comorbidities was similar. De novo refluxes developed in four OAGB patients; there were no occurrences of these in RYGB patients (p = 0.066). Conclusions: Both OAGB and RYGB are effective in the treatment of morbid obesity. The two procedures are similarly successful in terms of obesity-related comorbidities.}, } @article {pmid38400247, year = {2024}, author = {Cano, LA and Albarracín, AL and Pizá, AG and García-Cena, CE and Fernández-Jover, E and Farfán, FD}, title = {Assessing Cognitive Workload in Motor Decision-Making through Functional Connectivity Analysis: Towards Early Detection and Monitoring of Neurodegenerative Diseases.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {4}, pages = {}, pmid = {38400247}, issn = {1424-8220}, mesh = {Male ; Female ; Humans ; Young Adult ; Adult ; *Neurodegenerative Diseases/diagnosis ; Cerebral Cortex ; Muscle, Skeletal/physiology ; Electromyography ; Electroencephalography/methods ; Cognition ; }, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and frontotemporal dementia, among others, are increasingly prevalent in the global population. The clinical diagnosis of these NDs is based on the detection and characterization of motor and non-motor symptoms. However, when these diagnoses are made, the subjects are often in advanced stages where neuromuscular alterations are frequently irreversible. In this context, we propose a methodology to evaluate the cognitive workload (CWL) of motor tasks involving decision-making processes. CWL is a concept widely used to address the balance between task demand and the subject's available resources to complete that task. In this study, multiple models for motor planning during a motor decision-making task were developed by recording EEG and EMG signals in n=17 healthy volunteers (9 males, 8 females, age 28.66±8.8 years). In the proposed test, volunteers have to make decisions about which hand should be moved based on the onset of a visual stimulus. We computed functional connectivity between the cortex and muscles, as well as among muscles using both corticomuscular and intermuscular coherence. Despite three models being generated, just one of them had strong performance. The results showed two types of motor decision-making processes depending on the hand to move. Moreover, the central processing of decision-making for the left hand movement can be accurately estimated using behavioral measures such as planning time combined with peripheral recordings like EMG signals. The models provided in this study could be considered as a methodological foundation to detect neuromuscular alterations in asymptomatic patients, as well as to monitor the process of a degenerative disease.}, } @article {pmid38400897, year = {2024}, author = {Pirasteh, A and Shamseini Ghiyasvand, M and Pouladian, M}, title = {EEG-based brain-computer interface methods with the aim of rehabilitating advanced stage ALS patients.}, journal = {Disability and rehabilitation. Assistive technology}, volume = {19}, number = {8}, pages = {3183-3193}, doi = {10.1080/17483107.2024.2316312}, pmid = {38400897}, issn = {1748-3115}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology ; *Brain-Computer Interfaces ; *Electroencephalography ; Support Vector Machine ; Neural Networks, Computer ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that leads to progressive muscle weakness and paralysis, ultimately resulting in the loss of ability to communicate and control the environment. EEG-based Brain-Computer Interface (BCI) methods have shown promise in providing communication and control with the aim of rehabilitating ALS patients. In particular, P300-based BCI has been widely studied and used for ALS rehabilitation. Other EEG-based BCI methods, such as Motor Imagery (MI) based BCI and Hybrid BCI, have also shown promise in ALS rehabilitation. Nonetheless, EEG-based BCI methods hold great potential for improvement. This review article introduces and reviews FFT, WPD, CSP, CSSP, CSP, and GC feature extraction methods. The Common Spatial Pattern (CSP) is an efficient and common technique for extracting data properties used in BCI systems. In addition, Linear Discriminant Analysis (LDA), Support Vector Machine (SVM), Neural Networks (NN), and Deep Learning (DL) classification methods were introduced and reviewed. SVM is the most appropriate classifier due to its insensitivity to the curse of dimensionality. Also, DL is used in the design of BCI systems and is a good choice for BCI systems based on motor imagery with big datasets. Despite the progress made in the field, there are still challenges to overcome, such as improving the accuracy and reliability of EEG signal detection and developing more intuitive and user-friendly interfaces By using BCI, disabled patients can communicate with their caregivers and control their environment using various devices, including wheelchairs, and robotic arms.}, } @article {pmid38401191, year = {2024}, author = {Lemon, R}, title = {The Corticospinal System and Amyotrophic Lateral Sclerosis: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {160}, number = {}, pages = {56-67}, doi = {10.1016/j.clinph.2024.02.001}, pmid = {38401191}, issn = {1872-8952}, mesh = {Animals ; Humans ; *Pyramidal Tracts/physiology ; *Amyotrophic Lateral Sclerosis ; Motor Neurons/physiology ; Primates ; Axons ; }, abstract = {Corticospinal neurons located in motor areas of the cerebral neocortex project corticospinal axons which synapse with the spinal network; a parallel corticobulbar system projects to the cranial motor network and to brainstem motor pathways. The primate corticospinal system has a widespread cortical origin and an extensive range of different fibre diameters, including thick, fast-conducting axons. Direct cortico-motoneuronal (CM) projections from the motor cortex to arm and hand alpha motoneurons are a recent evolutionary feature, that is well developed in dexterous primates and particularly in humans. Many of these projections originate from the caudal subdivision of area 4 ('new' M1: primary motor cortex). They arise from corticospinal neurons of varied soma size, including those with fast- and relatively slow-conducting axons. This CM system has been shown to be involved in the control of skilled movements, carried out with fractionation of the distal extremities and at low force levels. During movement, corticospinal neurons are activated quite differently from 'lower' motoneurons, and there is no simple or fixed functional relationship between a so-called 'upper' motoneuron and its target lower motoneuron. There are key differences in the organisation and function of the corticospinal and CM system in primates versus non-primates, such as rodents. These differences need to be recognized when making the choice of animal model for understanding disorders such as amyotrophic lateral sclerosis (ALS). In this neurodegenerative brain disease there is a selective loss of fast-conducting corticospinal axons, and their synaptic connections, and this is reflected in responses to non-invasive cortical stimuli and measures of cortico-muscular coherence. The loss of CM connections influencing distal limb muscles results in a differential loss of muscle strength or 'split-hand' phenotype. Importantly, there is also a unique impairment in the coordination of skilled hand tasks that require fractionation of digit movement. Scores on validated tests of skilled hand function could be used to assess disease progression.}, } @article {pmid38401571, year = {2024}, author = {Cheng, F and Chapman, T and Zhang, S and Morsch, M and Chung, R and Lee, A and Rayner, SL}, title = {Understanding age-related pathologic changes in TDP-43 functions and the consequence on RNA splicing and signalling in health and disease.}, journal = {Ageing research reviews}, volume = {96}, number = {}, pages = {102246}, doi = {10.1016/j.arr.2024.102246}, pmid = {38401571}, issn = {1872-9649}, mesh = {Humans ; RNA Splicing ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics ; DNA-Binding Proteins/genetics/metabolism ; Neurons/metabolism ; }, abstract = {TAR DNA binding protein-43 (TDP-43) is a key component in RNA splicing which plays a crucial role in the aging process. In neurodegenerative diseases such as amyotrophic lateral sclerosis, frontotemporal dementia and limbic-predominant age-related TDP-43 encephalopathy, TDP-43 can be mutated, mislocalised out of the nucleus of neurons and glial cells and form cytoplasmic inclusions. These TDP-43 alterations can lead to its RNA splicing dysregulation and contribute to mis-splicing of various types of RNA, such as mRNA, microRNA, and circular RNA. These changes can result in the generation of an altered transcriptome and proteome within cells, ultimately changing the diversity and quantity of gene products. In this review, we summarise the findings of novel atypical RNAs resulting from TDP-43 dysfunction and their potential as biomarkers or targets for therapeutic development.}, } @article {pmid38402886, year = {2024}, author = {Baudin, E and Goichot, B and Berruti, A and Hadoux, J and Moalla, S and Laboureau, S and Nölting, S and de la Fouchardière, C and Kienitz, T and Deutschbein, T and Zovato, S and Amar, L and Haissaguerre, M and Timmers, H and Niccoli, P and Faggiano, A and Angokai, M and Lamartina, L and Luca, F and Cosentini, D and Hahner, S and Beuschlein, F and Attard, M and Texier, M and Fassnacht, M and , and , }, title = {Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial.}, journal = {Lancet (London, England)}, volume = {403}, number = {10431}, pages = {1061-1070}, doi = {10.1016/S0140-6736(23)02554-0}, pmid = {38402886}, issn = {1474-547X}, mesh = {Adult ; Humans ; Adolescent ; Sunitinib/therapeutic use ; *Pheochromocytoma/drug therapy/etiology ; Progression-Free Survival ; *Hypertension/etiology ; *Adrenal Gland Neoplasms/drug therapy/etiology ; Double-Blind Method ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; }, abstract = {BACKGROUND: No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas.

METHODS: FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). Primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1). On the basis of a two-step Simon model, we aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month progression-free survival rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. This trial is registered with ClinicalTrials.gov, number NCT01371201, and is closed for enrolment.

FINDINGS: From Dec 1, 2011, to Jan 31, 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enrolled (39 patients per group). 25 (32%) of 78 patients had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month progression-free survival in 14 of 39 patients (36% [90% CI 23-50]) in the sunitinib group. In the placebo group, the 12-month progression-free survival in seven of 39 patients was 19% (90% CI 11-31), validating the hypotheses of our study design. The most frequent grade 3 or 4 adverse events were asthenia (seven [18%] of 39 and one [3%] of 39), hypertension (five [13%] and four [10%]), and back or bone pain (one [3%] and three [8%]) in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group: these deaths were due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding. Only the latter event was considered drug related. Two deaths occurred in the placebo group due to aspiration pneumonia and septic shock.

INTERPRETATION: This first randomised trial supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas.

FUNDING: French Ministry of Health, through the National Institute for Cancer, German Ministry of Education and Research, and the German Research Foundation within the CRC/Transregio 205/2, EU Seventh Framework Programme, and a private donator grant.}, } @article {pmid38403286, year = {2024}, author = {Fan, H and Zhang, M and Wen, J and Wang, S and Yuan, M and Sun, H and Shu, L and Yang, X and Pu, Y and Cai, Z}, title = {Microglia in brain aging: An overview of recent basic science and clinical research developments.}, journal = {Journal of biomedical research}, volume = {38}, number = {2}, pages = {122-136}, pmid = {38403286}, issn = {1674-8301}, abstract = {Aging is characterized by progressive degeneration of tissues and organs, and it is positively associated with an increased mortality rate. The brain, as one of the most significantly affected organs, experiences age-related changes, including abnormal neuronal activity, dysfunctional calcium homeostasis, dysregulated mitochondrial function, and increased levels of reactive oxygen species. These changes collectively contribute to cognitive deterioration. Aging is also a key risk factor for neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. For many years, neurodegenerative disease investigations have primarily focused on neurons, with less attention given to microglial cells. However, recently, microglial homeostasis has emerged as an important mediator in neurological disease pathogenesis. Here, we provide an overview of brain aging from the perspective of the microglia. In doing so, we present the current knowledge on the correlation between brain aging and the microglia, summarize recent progress of investigations about the microglia in normal aging, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, and then discuss the correlation between the senescent microglia and the brain, which will culminate with a presentation of the molecular complexity involved in the microglia in brain aging with suggestions for healthy aging.}, } @article {pmid38403672, year = {2024}, author = {Wang, H and Chen, N and Jian, F and Zhang, Z and Tai, H and Pan, H}, title = {Amyotrophic lateral sclerosis and myasthenia gravis overlaps syndrome: a series of case report.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {7}, pages = {3549-3553}, pmid = {38403672}, issn = {1590-3478}, mesh = {Humans ; *Myasthenia Gravis/diagnosis/complications ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Middle Aged ; Male ; Female ; Aged ; }, } @article {pmid38404316, year = {2024}, author = {Dunn, KJ and Matlock, A and Funkenbusch, G and Yaqoob, Z and So, PTC and Berger, AJ}, title = {Optical diffraction tomography for assessing single cell models in angular light scattering.}, journal = {Biomedical optics express}, volume = {15}, number = {2}, pages = {973-990}, pmid = {38404316}, issn = {2156-7085}, support = {P41 EB015871/EB/NIBIB NIH HHS/United States ; R01 DA045549/DA/NIDA NIH HHS/United States ; R01 HL158102/HL/NHLBI NIH HHS/United States ; R21 GM140613/GM/NIGMS NIH HHS/United States ; }, abstract = {Angularly resolved light scattering (ALS) has become a useful tool for assessing the size and refractive index of biological scatterers at cellular and organelle length scales. Sizing organelle populations with ALS relies on Mie scattering theory models, which require significant assumptions about the object, including spherical scatterers and a homogeneous medium. These assumptions may incur greater error at the single cell level, where there are fewer scatterers to be averaged over. We investigate the validity of these assumptions using 3D refractive index (RI) tomograms measured via optical diffraction tomography (ODT). We compute the angular scattering on digitally manipulated tomograms with increasingly strong model assumptions, including RI-matched immersion media, homogeneous cytosol, and spherical organelles. We also compare the tomogram-computed angular scattering to experimental measurements of angular scattering from the same cells to ensure that the ODT-based approach accurately models angular scattering. We show that enforced RI-matching with the immersion medium and a homogeneous cytosol significantly affects the angular scattering intensity shape, suggesting that these assumptions can reduce the accuracy of size distribution estimates.}, } @article {pmid38404440, year = {2024}, author = {Lee, SH and Pham, D and Kosa, E and Agbas, A}, title = {Human Platelet Derived Mitochondrial OPA-1 Isoforms and Interaction With TDP-43 in Neurodegenerative Diseases.}, journal = {Missouri medicine}, volume = {121}, number = {1}, pages = {87-92}, pmid = {38404440}, issn = {0026-6620}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA, Mitochondrial/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Mitochondria/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Protein Isoforms/metabolism ; *GTP Phosphohydrolases/genetics/metabolism ; }, abstract = {Optic atrophy 1(OPA1) is a GTPase protein that controls mitochondrial fusion, cristae integrity, and mtDNA maintenance. In neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), the mitochondrial network morphology is compromised. Studies on TAR-DNA binding protein 43 (TDP-43) has been the focus in our lab. OPA1 and TDP-43 interaction may shed a light on how aberrant TDP-43 interacts with OPA1, which will lead to mitochondrial dysfunction. The preliminary study tested the idea of whether OPA1 and TDP-43 are physically interacting in human platelet derived mitochondria obtained from healthy human subjects.}, } @article {pmid38404827, year = {2024}, author = {Liu, Y and Chang, Y and Jiang, X and Mei, H and Cao, Y and Wu, D and Xie, R and Jiang, W and Vasquez, E and Wu, Y and Lin, S and Cao, Y}, title = {Analysis of the role of PANoptosis in seizures via integrated bioinformatics analysis and experimental validation.}, journal = {Heliyon}, volume = {10}, number = {4}, pages = {e26219}, pmid = {38404827}, issn = {2405-8440}, abstract = {BACKGROUND: Epilepsy is recognized as the most common chronic neurological condition among children, and hippocampal neuronal cell death has been identified as a crucial factor in the pathophysiological processes underlying seizures. In recent studies, PANoptosis, a newly characterized form of cell death, has emerged as a significant contributor to the development of various neurological disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. PANoptosis involves the simultaneous activation of pyroptosis, apoptosis, and necroptosis within the same population of cells. However, its specific role in the context of seizures remains to be fully elucidated. Further investigation is required to uncover the precise involvement of PANoptosis in the pathogenesis of seizures and to better understand its potential implications for the development of targeted therapeutic approaches in epilepsy.

METHODS: In this study, the gene expression data of the hippocampus following the administration of kainic acid (KA) or NaCl was obtained from the Gene Expression Omnibus (GEO) database. The PANoptosis-related gene set was compiled from the GeneCards database and previous literature. Time series analysis was performed to analyze the temporal expression patterns of the PANoptosis-related genes. Gene set variation analysis (GSVA), Gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) were employed to explore potential biological mechanisms underlying PANoptosis and its role in seizures. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were utilized to identify pivotal gene modules and PANoptosis-related genes associated with the pathophysiological processes underlying seizures. To validate the expression of PANoptosis-related genes, Western blotting or quantitative real-time polymerase chain reaction (qRT-PCR) assays were conducted. These experimental validations were performed in human blood samples, animal models, and cell models to verify the expression patterns of the PANoptosis-related genes and their relevance to epilepsy.

RESULTS: The GSVA analysis performed in this study demonstrated that PANoptosis-related genes have the potential to distinguish between the control group and KA-induced epileptic mice. This suggests that the expression patterns of these genes are significantly altered in response to KA-induced epilepsy. Furthermore, the Weighted gene co-expression network analysis (WGCNA) identified the blue module as being highly associated with epileptic phenotypes. This module consists of genes that exhibit correlated expression patterns specifically related to epilepsy. Within the blue module, 10 genes were further identified as biomarker genes for epilepsy. These genes include MLKL, IRF1, RIPK1, GSDMD, CASP1, CASP8, ZBP1, CASP6, PYCARD, and IL18. These genes likely play critical roles in the pathophysiology of epilepsy and could serve as potential biomarkers for diagnosing or monitoring the condition.

CONCLUSION: In conclusion, our study suggests that the hippocampal neuronal cell death in epilepsy may be closely related to PANoptosis, a novel form of cell death, which provides insights into the underlying pathophysiological processes of epilepsy and helps the development of novel therapeutic approaches for epilepsy.}, } @article {pmid38405076, year = {2024}, author = {Dittlau, KS and Chandrasekaran, A and Freude, K and Van Den Bosch, L}, title = {Generation of Human Induced Pluripotent Stem Cell (hiPSC)-Derived Astrocytes for Amyotrophic Lateral Sclerosis and Other Neurodegenerative Disease Studies.}, journal = {Bio-protocol}, volume = {14}, number = {4}, pages = {e4936}, pmid = {38405076}, issn = {2331-8325}, abstract = {Astrocytes are increasingly recognized for their important role in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). In ALS, astrocytes shift from their primary function of providing neuronal homeostatic support towards a reactive and toxic role, which overall contributes to neuronal toxicity and cell death. Currently, our knowledge on these processes is incomplete, and time-efficient and reproducible model systems in a human context are therefore required to understand and therapeutically modulate the toxic astrocytic response for future treatment options. Here, we present an efficient and straightforward protocol to generate human induced pluripotent stem cell (hiPSC)-derived astrocytes implementing a differentiation scheme based on small molecules. Through an initial 25 days, hiPSCs are differentiated into astrocytes, which are matured for 4+ weeks. The hiPSC-derived astrocytes can be cryopreserved at every passage during differentiation and maturation. This provides convenient pauses in the protocol as well as cell banking opportunities, thereby limiting the need to continuously start from hiPSCs. The protocol has already proven valuable in ALS research but can be adapted to any desired research field where astrocytes are of interest. Key features • This protocol requires preexisting experience in hiPSC culturing for a successful outcome. • The protocol relies on a small molecule differentiation scheme and an easy-to-follow methodology, which can be paused at several time points. • The protocol generates >50 × 10[6] astrocytes per differentiation, which can be cryopreserved at every passage, ensuring a large-scale experimental output.}, } @article {pmid38405340, year = {2024}, author = {Sun, W and Wei, C}, title = {Causal Relationship Between Ferritin and Neuropsychiatric Disorders: A Two-Sample Mendelian Randomization Study.}, journal = {Journal of Alzheimer's disease reports}, volume = {8}, number = {1}, pages = {257-266}, pmid = {38405340}, issn = {2542-4823}, abstract = {BACKGROUND: Previous observational research has indicated a correlation between ferritin levels and neuropsychiatric disorders, although the causal relationship remains uncertain.

OBJECTIVE: The objective of this study was to investigate the potential causal link between plasma ferritin levels and neuropsychiatric disorders.

METHODS: A two-sample Mendelian randomization (MR) study was conducted, wherein genetic instruments associated with ferritin were obtained from a previously published genome-wide association study (GWAS). Summary statistics pertaining to neuropsychiatric disorders were derived from five distinct GWAS datasets. The primary MR analysis employed the inverse variance weighted (IVW) method and was corroborated by additional methods including MR-Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses were employed to identify potential pleiotropy and heterogeneity in the results.

RESULTS: The fixed effects IVW method revealed a statistically significant causal relationship between plasma ferritin level and the occurrence of Alzheimer's disease (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.00-1.12, p = 0.037), as well as Parkinson's disease (OR = 1.06, 95% CI: 1.00-1.13, p = 0.041). Various sensitivity analyses were conducted, which demonstrated no substantial heterogeneity or pleiotropy. Conversely, no compelling evidence was found to support a causal association between ferritin and amyotrophic lateral sclerosis, schizophrenia, or major depressive disorder.

CONCLUSIONS: This MR study provides evidence at the genetic level for a causal relationship between plasma ferritin and an increased risk of Alzheimer's disease and Parkinson's disease. The exact genetic mechanisms underlying this connection necessitate further investigation.}, } @article {pmid38408684, year = {2024}, author = {Dithmar, S and Zare, A and Salehi, S and Briese, M and Sendtner, M}, title = {hnRNP R regulates mitochondrial movement and membrane potential in axons of motoneurons.}, journal = {Neurobiology of disease}, volume = {193}, number = {}, pages = {106454}, doi = {10.1016/j.nbd.2024.106454}, pmid = {38408684}, issn = {1095-953X}, mesh = {Membrane Potentials ; *Motor Neurons/metabolism ; *Axons/pathology ; Heterogeneous-Nuclear Ribonucleoproteins/genetics/metabolism ; Mitochondria/metabolism ; }, abstract = {Axonal mitochondria defects are early events in the pathogenesis of motoneuron disorders such as spinal muscular atrophy and amyotrophic lateral sclerosis. The RNA-binding protein hnRNP R interacts with different motoneuron disease-related proteins such as SMN and TDP-43 and has important roles in axons of motoneurons, including axonal mRNA transport. However, whether hnRNP R also modulates axonal mitochondria is currently unknown. Here, we show that axonal mitochondria exhibit altered function and motility in hnRNP R-deficient motoneurons. Motoneurons lacking hnRNP R show decreased anterograde and increased retrograde transport of mitochondria in axons. Furthermore, hnRNP R-deficiency leads to mitochondrial hyperpolarization, caused by decreased complex I and reversed complex V activity within the respiratory chain. Taken together, our data indicate a role for hnRNP R in regulating transport and maintaining functionality of axonal mitochondria in motoneurons.}, } @article {pmid38408864, year = {2024}, author = {Odierna, GL and Vucic, S and Dyer, M and Dickson, T and Woodhouse, A and Blizzard, C}, title = {How do we get from hyperexcitability to excitotoxicity in amyotrophic lateral sclerosis?.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {5}, pages = {1610-1621}, pmid = {38408864}, issn = {1460-2156}, support = {//Motor Neuron Disease Research Australia/ ; //National Health and Medical Research Council of Australia/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; *Motor Neurons/physiology ; *Glutamic Acid/metabolism ; Animals ; Motor Cortex/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease that, at present, has no effective cure. Evidence of increased circulating glutamate and hyperexcitability of the motor cortex in patients with amyotrophic lateral sclerosis have provided an empirical support base for the 'dying forward' excitotoxicity hypothesis. The hypothesis postulates that increased activation of upper motor neurons spreads pathology to lower motor neurons in the spinal cord in the form of excessive glutamate release, which triggers excitotoxic processes. Many clinical trials have focused on therapies that target excitotoxicity via dampening neuronal activation, but not all are effective. As such, there is a growing tension between the rising tide of evidence for the 'dying forward' excitotoxicity hypothesis and the failure of therapies that target neuronal activation. One possible solution to these contradictory outcomes is that our interpretation of the current evidence requires revision in the context of appreciating the complexity of the nervous system and the limitations of the neurobiological assays we use to study it. In this review we provide an evaluation of evidence relevant to the 'dying forward' excitotoxicity hypothesis and by doing so, identify key gaps in our knowledge that need to be addressed. We hope to provide a road map from hyperexcitability to excitotoxicity so that we can better develop therapies for patients suffering from amyotrophic lateral sclerosis. We conclude that studies of upper motor neuron activity and their synaptic output will play a decisive role in the future of amyotrophic lateral sclerosis therapy.}, } @article {pmid38409193, year = {2024}, author = {Chang, HY and Wang, IF}, title = {Restoring functional TDP-43 oligomers in ALS and laminopathic cellular models through baicalein-induced reconfiguration of TDP-43 aggregates.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {4620}, pmid = {38409193}, issn = {2045-2322}, support = {ND-01-003//Garage Brain Science/ ; ND-01-003//Garage Brain Science/ ; TDP-01//YeeFan Med Inc./ ; TDP-01//YeeFan Med Inc./ ; }, mesh = {Humans ; *Progeria/genetics ; Lamin Type A/genetics ; *Aging, Premature ; DNA-Binding Proteins/genetics ; *Flavanones ; }, abstract = {A group of misfolded prone-to-aggregate domains in disease-causing proteins has recently been shown to adopt unique conformations that play a role in fundamental biological processes. These processes include the formation of membrane-less sub-organelles, alternative splicing, and gene activation and silencing. The cellular responses are regulated by the conformational switching of prone-to-aggregate domains, independently of changes in RNA or protein expression levels. Given this, targeting the misfolded states of disease-causing proteins to redirect them towards their physiological conformations is emerging as an effective therapeutic strategy for diseases caused by protein misfolding. In our study, we successfully identified baicalein as a potent structure-correcting agent. Our findings demonstrate that baicalein can reconfigure existing TDP-43 aggregates into an oligomeric state both in vitro and in disease cells. This transformation effectively restores the bioactivity of misfolded TDP-43 proteins in cellular models of ALS and premature aging in progeria. Impressively, in progeria cells where defective lamin A interferes with TDP-43-mediated exon skipping, the formation of pathological TDP-43 aggregates is promoted. Baicalein, however, restores the functionality of TDP-43 and mitigates nuclear shape defects in these laminopathic cells. This establishes a connection between lamin A and TDP-43 in the context of aging. Our findings suggest that targeting physiological TDP-43 oligomers could offer a promising therapeutic avenue for treating aging-associated disorders.}, } @article {pmid38409777, year = {2024}, author = {Rabadi, MH and Russell, KC and Xu, C}, title = {Predictors of Mortality in Veterans with Amyotrophic Lateral Sclerosis: Respiratory Status and Speech Disorder at Presentation.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {30}, number = {}, pages = {e943288}, pmid = {38409777}, issn = {1643-3750}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Speech ; Dysarthria ; *Veterans ; Disease Progression ; }, abstract = {BACKGROUND There is a lack of accurate models to predict amyotrophic lateral sclerosis (ALS) disease course and outcomes. As a result, risk assessment and counseling, the timing of interventions, and their stratification in clinical trials are difficult. This study aimed to evaluate the association between symptoms at presentation and mortality. MATERIAL AND METHODS A single veterans hospital reviewed the electronic records of 105 veterans with ALS who were periodically followed in our ALS clinic between 2010 and 2021. A survival decision tree (≤3 or >3 years) was generated based on the statistical median survival of our data. The variables known to influence survival when alive were compared to patients who died. RESULTS The (mean±SD) age at onset was 62±11 years, M/F ratio 101: 4, and 90% were non-Hispanic whites. The initial score for the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) was 31±8.3. Dysarthria and shortness of breath (SOB) were present on initial presentation in 52 (49.5%) and 32 (30.5%) patients, respectively. Deaths occurred in 80 (76.2%) patients during the study period. The main cause of death was respiratory disease (failure and pneumonia, n=43 53.75%). Patients survived for >3 years on initial presentation with normal respiration and speech, compared to ≤3 years of survival in patients with dysarthria and SOB, irrespective of age. CONCLUSIONS This study suggests that for veterans with ALS, the main predictors of shorter survival were respiratory status and speech disorder on initial presentation to the clinic.}, } @article {pmid38410712, year = {2024}, author = {Moretti, A and Pietersen, PI and Hassan, M and Shafiek, H and Prosch, H and Tarnoki, AD and Annema, JT and Munavvar, M and Bonta, PI and de Wever, W and Juul, AD}, title = {ERS International Congress 2023: highlights from the Clinical Techniques, Imaging and Endoscopy Assembly.}, journal = {ERJ open research}, volume = {10}, number = {1}, pages = {}, pmid = {38410712}, issn = {2312-0541}, abstract = {The Clinical Techniques, Imaging and Endoscopy Assembly is involved in the diagnosis and treatment of several pulmonary diseases, as demonstrated at the 2023 European Respiratory Society (ERS) International Congress in Milan, Italy. From interventional pulmonology, the congress included several exciting results for the use of bronchoscopy in lung cancer, including augmented fluoroscopy, robotic-assisted bronchoscopy and cryobiopsies. In obstructive lung disease, the latest results on bronchoscopic treatment of emphysema with hyperinflation and chronic bronchitis were presented. Research on using cryobiopsies to diagnose interstitial lung disease was further explored, with the aims of elevating diagnostic yield and minimising risk. For imaging, the latest updates in using artificial intelligence to overcome the increased workload of radiologists were of great interest. Novel imaging in sarcoidosis explored the use of magnetic resonance imaging, photon-counting computed tomography and positron emission tomography/computed tomography in the diagnostic work-up. Lung cancer screening is still a hot topic and new results were presented regarding incorporation of biomarkers, identifying knowledge gaps and improving screening programmes. The use of ultrasound in respiratory medicine is an expanding field, which was demonstrated by the large variety in studies presented at the 2023 ERS Congress. Ultrasound of the diaphragm in patients with amyotrophic lateral sclerosis and myasthenia gravis was used to assess movements and predict respiratory fatigue. Furthermore, studies using ultrasound to diagnose or monitor pulmonary disease were presented. The congress also included studies regarding the training and assessment of competencies as an important part of implementing ultrasound in clinical practice.}, } @article {pmid38411261, year = {2024}, author = {Sakowski, SA and Koubek, EJ and Chen, KS and Goutman, SA and Feldman, EL}, title = {Role of the Exposome in Neurodegenerative Disease: Recent Insights and Future Directions.}, journal = {Annals of neurology}, volume = {95}, number = {4}, pages = {635-652}, pmid = {38411261}, issn = {1531-8249}, support = {R01TS000327/CC/CDC HHS/United States ; R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01TS000289/CC/CDC HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000289/TS/ATSDR CDC HHS/United States ; R01TS000289/ACL/ACL HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; P30 DK020572/DK/NIDDK NIH HHS/United States ; K23ES027221/NH/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Exposome ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; }, abstract = {Neurodegenerative diseases are increasing in prevalence and place a significant burden on society. The causes are multifactorial and complex, and increasing evidence suggests a dynamic interplay between genes and the environment, emphasizing the importance of identifying and understanding the role of lifelong exposures, known as the exposome, on the nervous system. This review provides an overview of recent advances toward defining neurodegenerative disease exposomes, focusing on Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We present the current state of the field based on emerging data, elaborate on key themes and potential mechanisms, and conclude with limitations and future directions. ANN NEUROL 2024;95:635-652.}, } @article {pmid38411425, year = {2024}, author = {D'Urso, B and Weil, R and Génin, P}, title = {[Optineurin and mitochondrial dysfunction in neurodegeneration].}, journal = {Medecine sciences : M/S}, volume = {40}, number = {2}, pages = {167-175}, doi = {10.1051/medsci/2023220}, pmid = {38411425}, issn = {1958-5381}, mesh = {Humans ; Ubiquitin ; *Amyotrophic Lateral Sclerosis/genetics ; Cytosol ; Mitochondria/genetics ; *Mitochondrial Diseases ; }, abstract = {Optineurin (OPTN) is a multifunctional protein playing a crucial role as a receptor in selective autophagy. OPTN gene mutations are linked to diseases such as normal-tension glaucoma and amyotrophic lateral sclerosis. Recognized as a critical receptor for mitophagy, OPTN is pivotal in selectively degrading damaged mitochondria. This process is essential to prevent their accumulation, the generation of reactive oxygen species, and the release of pro-apoptotic factors. Mitophagy's quality control is governed by the PINK1 kinase and the cytosolic ubiquitin ligase Parkin, whose mutations are associated with Parkinson's disease. This review highlights recent insights emphasizing OPTN's role in mitophagy and its potential involvement in neurodegenerative diseases.}, } @article {pmid38412259, year = {2024}, author = {Tseng, YJ and Krans, A and Malik, I and Deng, X and Yildirim, E and Ovunc, S and Tank, EMH and Jansen-West, K and Kaufhold, R and Gomez, NB and Sher, R and Petrucelli, L and Barmada, SJ and Todd, PK}, title = {Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats.}, journal = {Nucleic acids research}, volume = {52}, number = {10}, pages = {5928-5949}, pmid = {38412259}, issn = {1362-4962}, support = {R01 NS086810/NS/NINDS NIH HHS/United States ; //Alzheimer's Association Research Fellowship/ ; RF1 AG062077/AG/NIA NIH HHS/United States ; T32 GM007863/GM/NIGMS NIH HHS/United States ; BX004842//VA BLRD/ ; I01 BX004842/BX/BLRD VA/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; //Cellular and Molecular Biology Graduate Program, University of Michigan/ ; R35 NS097273/NS/NINDS NIH HHS/United States ; P50HD104463/GF/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Ataxia ; *C9orf72 Protein/genetics/metabolism ; DNA Repeat Expansion/genetics ; Fragile X Messenger Ribonucleoprotein 1/genetics/metabolism ; Fragile X Syndrome/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; GC Rich Sequence ; HEK293 Cells ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism ; *Protein Biosynthesis ; Ribosomes/metabolism/genetics ; Tremor ; *Trinucleotide Repeat Expansion/genetics ; *Ribosomal Proteins/metabolism ; }, abstract = {A GGGGCC (G4C2) hexanucleotide repeat expansion in C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), while a CGG trinucleotide repeat expansion in FMR1 leads to the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). These GC-rich repeats form RNA secondary structures that support repeat-associated non-AUG (RAN) translation of toxic proteins that contribute to disease pathogenesis. Here we assessed whether these same repeats might trigger stalling and interfere with translational elongation. We find that depletion of ribosome-associated quality control (RQC) factors NEMF, LTN1 and ANKZF1 markedly boost RAN translation product accumulation from both G4C2 and CGG repeats while overexpression of these factors reduces RAN production in both reporter assays and C9ALS/FTD patient iPSC-derived neurons. We also detected partially made products from both G4C2 and CGG repeats whose abundance increased with RQC factor depletion. Repeat RNA sequence, rather than amino acid content, is central to the impact of RQC factor depletion on RAN translation-suggesting a role for RNA secondary structure in these processes. Together, these findings suggest that ribosomal stalling and RQC pathway activation during RAN translation inhibits the generation of toxic RAN products. We propose augmenting RQC activity as a therapeutic strategy in GC-rich repeat expansion disorders.}, } @article {pmid38412787, year = {2024}, author = {Zhan, ZQ and Huang, ZM and Zhou, HB and Xie, ZX and Chen, YZ and Luo, YH and Chen, PZ and Kang, JQ and Cheng, ZJ and Sun, B}, title = {Gastroesophageal reflux disease with 6 neurodegenerative and psychiatric disorders: Genetic correlations, causality, and potential molecular mechanisms.}, journal = {Journal of psychiatric research}, volume = {172}, number = {}, pages = {244-253}, doi = {10.1016/j.jpsychires.2024.02.030}, pmid = {38412787}, issn = {1879-1379}, mesh = {Humans ; *Sleep Initiation and Maintenance Disorders ; *Major Depressive Disorder/epidemiology/genetics ; *Mental Disorders/epidemiology/genetics ; Anxiety Disorders/epidemiology/genetics ; *Gastroesophageal Reflux/epidemiology/genetics ; Genome-Wide Association Study ; }, abstract = {The comorbidities between gastroesophageal reflux disease (GERD) and various neurodegenerative and psychiatric disorders have been widely reported. However, the genetic correlations, causal relationships, and underlying mechanisms linking GERD to these disorders remain largely unknown. Here, we conducted a bidirectional Mendelian randomization (MR) analysis to determine the causality between GERD and 6 neurodegenerative and psychiatric disorders. Sensitivity analyses and multivariable MR were performed to test the robustness of our findings. Linkage disequilibrium score regression was used to assess the genetic correlation between these diseases as affected by heredity. Multiple bioinformatics tools combining two machine learning algorithms were applied to further investigate the potential mechanisms underlying these diseases. We found that genetically predicted GERD significantly increased the risk of Alzheimer's disease, major depressive disorder, and anxiety disorders. There might be a bidirectional relationship between GERD and insomnia. GERD has varying degrees of genetic correlations with AD, ALS, anxiety disorders, insomnia, and depressive disorder. Bioinformatics analyses revealed the hub shared genes and the common pathways between GERD and 6 neurodegenerative and psychiatric disorders. Our findings demonstrated the complex nature of the genetic architecture across these diseases and clarified their causality, highlighting that treatments for the cure or remission of GERD may serve as potential strategies for preventing and managing neurodegenerative and psychiatric disorders.}, } @article {pmid38413232, year = {2024}, author = {Chun, C and Lee, JH and Bothwell, M and Nghiem, P and Smith, AST and Mack, DL}, title = {Human Motor Neurons Elicit Pathological Hallmarks of ALS and Reveal Potential Biomarkers of the Disease in Response to Prolonged IFNγ Exposure.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {44}, number = {16}, pages = {}, pmid = {38413232}, issn = {1529-2401}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; R03 TR004009/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; B7-H1 Antigen/metabolism ; Biomarkers ; DNA-Binding Proteins/genetics ; *Induced Pluripotent Stem Cells/metabolism ; Interferon-gamma/metabolism/pharmacology ; Motor Neurons/drug effects/metabolism/pathology ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder marked by progressive motor neuron degeneration and muscle denervation. A recent transcriptomic study integrating a wide range of human ALS samples revealed that the upregulation of p53, a downstream target of inflammatory stress, is commonly detected in familial and sporadic ALS cases by a mechanism linked to a transactive response DNA-binding protein 43 (TDP-43) dysfunction. In this study, we show that prolonged interferon-gamma (IFNγ) treatment of human induced pluripotent stem cell-derived spinal motor neurons results in a severe cytoplasmic aggregation of TDP-43. TDP-43 dysfunction resulting from either IFNγ exposure or an ALS-associated TDP-43 mutation was associated with the activation of the p53 pathway. This was accompanied by the hyperactivation of neuronal firing, followed by the complete loss of their electrophysiological function. Through a comparative single-cell transcriptome analysis, we have identified significant alterations in ALS-associated genes in motor neurons exposed to IFNγ, implicating their direct involvement in ALS pathology. Interestingly, IFNγ was found to induce significant levels of programmed death-ligand 1 (PD-L1) expression in motor neurons without affecting the levels of any other immune checkpoint proteins. This finding suggests a potential role of excessive PD-L1 expression in ALS development, given that PD-L1 was recently reported to impair neuronal firing ability in mice. Our findings suggest that exposing motor neurons to IFNγ could directly derive ALS pathogenesis, even without the presence of the inherent genetic mutation or functional glia component. Furthermore, this study provides a comprehensive list of potential candidate genes for future immunotherapeutic targets with which to treat sporadic forms of ALS, which account for 90% of all reported cases.}, } @article {pmid38414054, year = {2024}, author = {Ma, YY and Li, X and Yu, JT and Wang, YJ}, title = {Therapeutics for neurodegenerative diseases by targeting the gut microbiome: from bench to bedside.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {12}, pmid = {38414054}, issn = {2047-9158}, support = {92249305//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Gastrointestinal Microbiome ; *Amyotrophic Lateral Sclerosis ; *Alzheimer Disease ; *Parkinson Disease/therapy ; }, abstract = {The aetiologies and origins of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), are complex and multifaceted. A growing body of evidence suggests that the gut microbiome plays crucial roles in the development and progression of neurodegenerative diseases. Clinicians have come to realize that therapeutics targeting the gut microbiome have the potential to halt the progression of neurodegenerative diseases. This narrative review examines the alterations in the gut microbiome in AD, PD, ALS and HD, highlighting the close relationship between the gut microbiome and the brain in neurodegenerative diseases. Processes that mediate the gut microbiome-brain communication in neurodegenerative diseases, including the immunological, vagus nerve and circulatory pathways, are evaluated. Furthermore, we summarize potential therapeutics for neurodegenerative diseases that modify the gut microbiome and its metabolites, including diets, probiotics and prebiotics, microbial metabolites, antibacterials and faecal microbiome transplantation. Finally, current challenges and future directions are discussed.}, } @article {pmid38415587, year = {2024}, author = {Koehn, LM and Steele, JR and Schittenhelm, RB and Turner, BJ and Nicolazzo, JA}, title = {Sex-Dependent Changes to the Intestinal and Hepatic Abundance of Drug Transporters and Metabolizing Enzymes in the SOD1[G93A] Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Molecular pharmaceutics}, volume = {21}, number = {4}, pages = {1756-1767}, doi = {10.1021/acs.molpharmaceut.3c01089}, pmid = {38415587}, issn = {1543-8392}, mesh = {Animals ; Female ; Humans ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; Disease Models, Animal ; Liver/metabolism ; Mice, Transgenic ; *Organic Anion Transporters/metabolism ; Proteomics ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by death and dysfunction of motor neurons that result in a rapidly progressing loss of motor function. While there are some data on alterations at the blood-brain barrier (BBB) in ALS and their potential impact on CNS trafficking of drugs, little is reported on the impact of this disease on the expression of drug-handling proteins in the small intestine and liver. This may impact the dosing of the many medicines that individuals with ALS are prescribed. In the present study, a proteomic evaluation was performed on small intestine and liver samples from postnatal day 120 SOD1[G93A] mice (a model of familial ALS that harbors a human mutant form of superoxide dismutase 1) and wild-type (WT) littermates (n = 7/genotype/sex). Untargeted, quantitative proteomics was undertaken using either label-based [tandem mass tag (TMT)] or label-free [data-independent acquisition (DIA)] acquisition strategies on high-resolution mass spectrometric instrumentation. Copper chaperone for superoxide dismutase (CCS) was significantly higher in SOD1[G93A] samples compared to the WT samples for both sexes and tissues, therefore representing a potential biomarker for ALS in this mouse model. Relative to WT mice, male SOD1[G93A] mice had significantly different proteins (Padj < 0.05, |fold-change|>1.2) in the small intestine (male 22, female 1) and liver (male 140, female 3). This included an up-regulation of intestinal transporters for dietary glucose [solute carrier (SLC) SLC5A1] and cholesterol (Niemann-Pick c1-like 1), as well as for several drugs (e.g., SLC15A1), in the male SOD1[G93A] mice. There was both an up-regulation (e.g., SLCO2A1) and down-regulation (ammonium transporter rh type b) of transporters in the male SOD1[G93A] liver. In addition, there was both an up-regulation (e.g., phosphoenolpyruvate carboxykinase) and down-regulation (e.g., carboxylesterase 1) of metabolizing enzymes in the male SOD1[G93A] liver. This proteomic data set identified male-specific changes to key small intestinal and hepatic transporters and metabolizing enzymes that may have important implications for the bioavailability of nutrients and drugs in individuals with ALS.}, } @article {pmid38415696, year = {2024}, author = {Didcote, L and Vitoratou, S and Al-Chalabi, A and Goldstein, LH}, title = {What is the extent of reliability and validity evidence for screening tools for cognitive and behavioral change in people with ALS? A systematic review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {437-451}, pmid = {38415696}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis/complications ; Reproducibility of Results ; Neuropsychological Tests/standards ; Cognitive Dysfunction/diagnosis/etiology ; }, abstract = {OBJECTIVE: This systematic review provides an updated summary of the existing literature on the validity of screening tools for cognitive and behavioral impairment in people with Amyotrophic Lateral Sclerosis (pwALS), and also focuses on their reliability.

METHOD: The following cognitive and behavioral screening tools were assessed in this review: the Edinburgh Cognitive and Behavioral ALS Screen (ECAS); the ALS Cognitive Behavioral Screen (ALS-CBS), the Mini Addenbrooke's Cognitive Examination (Mini-ACE), the Beaumont Behavioral Interview (BBI); the MND Behavior Scale (MiND-B); and the ALS-FTD Questionnaire (ALS-FTD-Q). A search, using Medline, PsychINFO and Embase (21/09/2023), generated 37 results after exclusion criteria were applied. Evidence of internal consistency, item-total correlations, inter-rater reliability, clinical validity, convergent validity, and structural validity were extracted and assessed and risk of bias was evaluated.

RESULTS: The cognitive component of the ECAS was the tool with most evidence of reliability and validity for the assessment of cognitive impairment in ALS. It is well-suited to accommodate physical symptoms of ALS. For behavioral assessment, the BBI or ALS-FTD-Q had the most evidence of reliability and validity. The BBI is more thorough, but the ALS-FTD-Q is briefer.

CONCLUSIONS: There is good but limited evidence for the reliability and validity of cognitive and behavioral screens. Further evidence of clinical and convergent validity would increase confidence in their clinical and research use.}, } @article {pmid38416402, year = {2024}, author = {Wolff, AW and Peine, J and Höfler, J and Zurek, G and Hemker, C and Lingor, P}, title = {SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants.}, journal = {CNS drugs}, volume = {38}, number = {4}, pages = {291-302}, pmid = {38416402}, issn = {1179-1934}, support = {2017_T05//Else Kröner-Fresenius-Stiftung/ForTra GmbH/ ; }, mesh = {Male ; Humans ; Female ; *rho-Associated Kinases ; Biological Availability ; Healthy Volunteers ; *Protein Kinase Inhibitors/adverse effects ; Chronic Disease ; Administration, Oral ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/*analogs & derivatives ; }, abstract = {BACKGROUND: The intravenous (IV) formulation of Rho-kinase (ROCK) inhibitor fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995. Additionally, fasudil has shown promising preclinical results for various chronic diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and dementia, in which long-term intravenous (IV) administration might not be suitable.

OBJECTIVE: The objective of this study was to assess the absolute bioavailability of oral, in comparison to IV, application of the approved formulation of fasudil (ERIL®) and to evaluate the safety and tolerability of the oral application of fasudil.

METHODS: This was a phase I, single-center, open-label, randomized, two period cross-over clinical trial in healthy women and men. By applying a cross-over design, each subject served as their own control. Two treatments were investigated, separated by a wash out phase of at least 3 days. Oral fasudil was administered once on day 1 to assess pharmacokinetics and three times on day 2, at an interval of 8 ± 1 h, to assess safety and gastrointestinal tolerability. For pharmacometrics of IV fasudil, it was administered once on day 1. Plasma profiles of fasudil and its active metabolite hydroxyfasudil after oral or IV administration were measured by liquid chromatography electrospray tandem mass spectrometry. Tolerability was assessed as proportion of subjects without significant drug intolerance, and safety was assessed by the proportion of subjects without clinical or laboratory treatment-associated serious adverse events. Gastrointestinal safety was assessed by applying the gastrointestinal symptom rating scale (GSRS).

RESULTS: Fourteen subjects aged 30-70 years were included in this trial. After oral administration, fasudil concentrations in blood were mostly very low [1.4 g/L; coefficient of variation (CV) 41.0%]. After IV application, the peak concentration was 100.6 µg/L (CV 74.2%); however, a high variance in peak concentrations were assessed for both treatments. The maximal concentrations of hydroxyfasudil in blood were similar after oral and IV treatment [111.6 µg/L (CV 24.1%) and 108.4 µg/L (CV 19.7%), respectively]. Exposure of hydroxyfasudil (assessed as AUC0-tz) differed between both treatments, with 449 µg × h/L after IV treatment and 309 µg × h/L after oral treatment. Therefore, the absolute bioavailability of hydroxyfasudil after the oral treatment was approximately 69% of the IV treatment. No serious adverse events (SAEs) occurred during this trial, and good tolerability of oral fasudil (90 mg/day) was documented.

CONCLUSIONS: Oral fasudil was generally well tolerated in the studied population, and no safety concerns were identified. However, systemic bioavailability of oral hydroxyfasudil corresponded to 69%, and dose adjustments need to considered. The results presented here lay grounds for future trials of fasudil in chronic diseases, which require an oral long-term application. This trial was registered with EudraCT (no. 2019-001805-26).}, } @article {pmid38417402, year = {2024}, author = {Hu, N and Soh, KL and Japar, S and Li, T}, title = {Ear-Marking Relief: A Meta-Analysis on the Efficacy of Auricular Acupressure in Alleviating Anxiety Disorders.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {266-277}, doi = {10.1159/000537734}, pmid = {38417402}, issn = {2504-2106}, mesh = {Humans ; *Acupressure ; *Anxiety Disorders/therapy ; Randomized Controlled Trials as Topic ; Auriculotherapy/methods ; }, abstract = {BACKGROUND: The increasing worldwide mental health crisis, notably anxiety, emphasizes the urgency for available and effective interventions. Traditional therapies, although beneficial, pose limitations due to their considerable costs and possible adverse effects, thereby inviting alternative treatments such as auricular acupressure (AA). This non-pharmacological, integrative method, underpinned by Eastern and Western medical principles, presents a significant prospect for managing anxiety.

OBJECTIVE: This study aims to evaluate the existing evidence on the efficacy of AA in reducing anxiety, as elucidated through a systematic review.

METHODS: A comprehensive search of randomized controlled trials was conducted across various databases: the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), Wan Fang, and Database for Chinese Technical Periodicals (VIP). Two reviewers retrieved the pertinent studies and assessed their methodological quality. A meta-analysis was then conducted, incorporating data from all relevant time points.

RESULTS: Upon examining 25 studies encompassing 1,909 participants, it was discerned that AA significantly diminished anxiety (SMD = -1.1074; 95% confidence interval, -1.348 to -0.801; z = 7.70, p < 0.01). Subgroup analyses indicated that neither an increased number of auricular points nor extended intervention augmented effects. Larger effect sizes were associated with probing and avoidance of sham acupressure. Notably, 23 of the 25 studies exhibited some bias, suggesting further research is necessary.

CONCLUSIONS: The extant evidence advocates for AA as an effective supplementary intervention that reduces patient anxiety. The results hint at a potential placebo effect elicited by sham acupressure, necessitating rigorous control group definitions in future inquiries. The study findings suggest that fewer acupressure points and shorter intervention durations could effectively alleviate anxiety symptoms. Nonetheless, the significant heterogeneity across the studies underscores the requirement for more stringent research methodologies to substantiate these conclusions.

UNLABELLED: HintergrundDie weltweit zunehmende Krise der psychischen Gesundheit, vor allem von Angstzuständen, zeigt, dass dringend verfügbare und wirksame Interventionen erforderlich sind. Herkömmliche Therapien sind zwar hilfreich, werden aber durch ihre hohen Kosten und möglichen unerwünschten Wirkungen eingeschränkt, so dass alternative Behandlungen wie die Ohrakupressur gefragt sind. Diese nicht-pharmakologische, integrative Methode, die sich auf östliche und westliche medizinische Prinzipien stützt, stellt eine bedeutsame Perspektive für die Behandlung von Angstzuständen dar.ZielZiel dieser Studie ist es, die vorhandenen Evidenzen für die Wirksamkeit der Ohrakupressur (auricular acupressure, AA) zur Verringerung von Angstzuständen, die in einer systematischen Übersichtsarbeit ermittelt wurden, zu bewerten.MethodenEs wurde eine umfassende Suche nach randomisierten kontrollierten Studien in verschiedenen Datenbanken durchgeführt: Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), Wan Fang und Database for Chinese Technical Periodicals (VIP). Zwei Gutachter suchten die einschlägigen Studien heraus und bewerteten ihre methodische Qualität. Anschliessend erfolgte eine Metaanalyse, bei der Daten aller relevanten Zeitpunkte berücksichtigt wurden.Ergebnisse:Die Untersuchung von 25 Studien mit 1’909 Teilnehmern ergab, dass die Ohrakupressur (AA) Angstzustände signifikant verringerte (SMD = −1,1074; 95%-KI: −1,348 bis −0,801; z = 7,70, p < 0,01). Subgruppenanalysen zeigten, dass die Effekte weder durch eine höhere Anzahl von Ohrpunkten noch durch eine längere Intervention verstärkt wurden. Grössere Effektstärken waren mit Sondenverwendung und Vermeidung von Scheinakupressur assoziiert. Hervorzuheben ist, dass 23 der 25 Studien eine gewisse Verzerrung aufwiesen, weshalb weitere Untersuchungen erforderlich sind.SchlussfolgerungenDie vorhandene Evidenzlage stützt die Ohrakupressur (AA) als wirksame unterstützende Intervention, die die Angst der Patienten verringert. Die Ergebnisse deuten auf einen potenziellen Placeboeffekt durch Scheinakupressur hin, so dass in künftigen Untersuchungen strenge Kontrollgruppendefinitionen erforderlich sind. Die Studienergebnisse sprechen dafür, dass eine geringere Anzahl von Akupressurpunkten und kürzere Interventionszeiten die Angstsymptome wirksam lindern können. Die starke Heterogenität der Studien zeigt allerdings, dass strengere wissenschaftliche Methoden erforderlich sind, um diese Schlussfolgerungen zu untermauern.}, } @article {pmid38417517, year = {2024}, author = {Li, M and Qiu, J and Yan, G and Zheng, X and Li, A}, title = {How does the neurotoxin β-N-methylamino-L-alanine exist in biological matrices and cause toxicity?.}, journal = {The Science of the total environment}, volume = {922}, number = {}, pages = {171255}, doi = {10.1016/j.scitotenv.2024.171255}, pmid = {38417517}, issn = {1879-1026}, mesh = {Animals ; Humans ; *Neurotoxins/chemistry ; *Amino Acids, Diamino/toxicity/chemistry ; Cyanobacteria Toxins ; Oxidative Stress ; }, abstract = {The neurotoxin β-N-methylamino-L-alanine (BMAA) has been deemed as a risk factor for some neurodegenerative diseases such as amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). This possible link has been proved in some primate models and cell cultures with the appearance that BMAA exposure can cause excitotoxicity, formation of protein aggregates, and/or oxidative stress. The neurotoxin BMAA extensively exists in the environment and can be transferred through the food web to human beings. In this review, the occurrence, toxicological mechanisms, and characteristics of BMAA were comprehensively summarized, and proteins and peptides were speculated as its possible binding substances in biological matrices. It is difficult to compare the published data from previous studies due to the inconsistent analytical methods and components of BMAA. The binding characteristics of BMAA should be focused on to improve our understanding of its health risk to human health in the future.}, } @article {pmid38418214, year = {2024}, author = {Otani, R and Shibuya, K and Suzuki, YI and Suichi, T and Morooka, M and Aotsuka, Y and Ogushi, M and Kuwabara, S}, title = {Effects of motor cortical and peripheral axonal hyperexcitability on survival in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {8}, pages = {730-736}, doi = {10.1136/jnnp-2023-333039}, pmid = {38418214}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality ; Male ; Female ; Middle Aged ; *Motor Cortex/physiopathology ; *Transcranial Magnetic Stimulation ; *Axons/physiology ; Aged ; Motor Neurons/physiology ; Evoked Potentials, Motor/physiology ; Adult ; Prognosis ; }, abstract = {BACKGROUND: Increased 'cortical' and 'peripheral' excitability are reportedly associated with shorter survival in amyotrophic lateral sclerosis (ALS) patients, suggesting that hyperexcitability contributes to motor neuron death. However, whether upper or lower motor function has a greater impact on survival is unclear. We aimed to investigate the component that strongly impacts the prognosis of ALS.

METHODS: A total of 103 consecutive patients with ALS who underwent cortical (threshold tracking transcranial magnetic stimulation (TMS)) and motor nerve excitability tests were included. Motor cortical excitability was evaluated using short-interval intracortical inhibition (SICI) during TMS. Motor axonal excitability was assessed using the strength-duration time constant (SDTC). Survival time was defined as the time from examination to death or tracheostomy.

RESULTS: Compared with healthy subjects, patients with ALS had lower SICI and longer SDTC (p<0.05), indicating increased excitability of cortical motor neurons and motor axons. According to the SICI and SDTC findings, patients were divided into the following four groups: 'cortical high and peripheral high (high-high)', 'high-low', 'low-high' and 'low-low' groups. In Kaplan-Meier curves, the 'high-high' and 'low-high' groups showed significantly shorter survival than the other groups. Multivariate analysis revealed that increased cortical (HR=5.3, p<0.05) and peripheral (HR=20.0, p<0.001) excitability were significantly associated with shorter survival.

CONCLUSIONS: In patients with ALS, both motor cortical and peripheral hyperexcitability independently affected survival time, with peripheral hyperexcitability having a greater impact on shorter survival. The modulation of neuronal/axonal excitability is a potential therapeutic target for ALS.}, } @article {pmid38418571, year = {2024}, author = {Kumar, S and Bhowmik, R and Oh, JM and Abdelgawad, MA and Ghoneim, MM and Al-Serwi, RH and Kim, H and Mathew, B}, title = {Machine learning driven web-based app platform for the discovery of monoamine oxidase B inhibitors.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {4868}, pmid = {38418571}, issn = {2045-2322}, mesh = {Humans ; Molecular Docking Simulation ; *Mobile Applications ; Monoamine Oxidase/metabolism ; Monoamine Oxidase Inhibitors/chemistry ; *Neurodegenerative Diseases/drug therapy ; Dopamine Agents/pharmacology ; Internet ; Structure-Activity Relationship ; }, abstract = {Monoamine oxidases (MAOs), specifically MAO-A and MAO-B, play important roles in the breakdown of monoamine neurotransmitters. Therefore, MAO inhibitors are crucial for treating various neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). In this study, we developed a novel cheminformatics pipeline by generating three diverse molecular feature-based machine learning-assisted quantitative structural activity relationship (ML-QSAR) models concerning MAO-B inhibition. PubChem fingerprints, substructure fingerprints, and one-dimensional (1D) and two-dimensional (2D) molecular descriptors were implemented to unravel the structural insights responsible for decoding the origin of MAO-B inhibition in 249 non-reductant molecules. Based on a random forest ML algorithm, the final PubChem fingerprint, substructure fingerprint, and 1D and 2D molecular descriptor prediction models demonstrated significant robustness, with correlation coefficients of 0.9863, 0.9796, and 0.9852, respectively. The significant features of each predictive model responsible for MAO-B inhibition were extracted using a comprehensive variance importance plot (VIP) and correlation matrix analysis. The final predictive models were further developed as a web application, MAO-B-pred (https://mao-b-pred.streamlit.app/), to allow users to predict the bioactivity of molecules against MAO-B. Molecular docking and dynamics studies were conducted to gain insight into the atomic-level molecular interactions between the ligand-receptor complexes. These findings were compared with the structural features obtained from the ML-QSAR models, which supported the mechanistic understanding of the binding phenomena. The presented models have the potential to serve as tools for identifying crucial molecular characteristics for the rational design of MAO-B target inhibitors, which may be used to develop effective drugs for neurodegenerative disorders.}, } @article {pmid38418587, year = {2024}, author = {Thiry, L and Sirois, J and Durcan, TM and Stifani, S}, title = {Generation of human iPSC-derived phrenic-like motor neurons to model respiratory motor neuron degeneration in ALS.}, journal = {Communications biology}, volume = {7}, number = {1}, pages = {238}, pmid = {38418587}, issn = {2399-3642}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/physiology ; Diaphragm ; *Respiration Disorders/metabolism ; Nerve Degeneration ; }, abstract = {The fatal motor neuron (MN) disease Amyotrophic Lateral Sclerosis (ALS) is characterized by progressive MN degeneration. Phrenic MNs (phMNs) controlling the activity of the diaphragm are prone to degeneration in ALS, leading to death by respiratory failure. Understanding of the mechanisms of phMN degeneration in ALS is limited, mainly because human experimental models to study phMNs are lacking. Here we describe a method enabling the derivation of phrenic-like MNs from human iPSCs (hiPSC-phMNs) within 30 days. This protocol uses an optimized combination of small molecules followed by cell-sorting based on a cell-surface protein enriched in hiPSC-phMNs, and is highly reproducible using several hiPSC lines. We show further that hiPSC-phMNs harbouring ALS-associated amplification of the C9orf72 gene progressively lose their electrophysiological activity and undergo increased death compared to isogenic controls. These studies establish a previously unavailable protocol to generate human phMNs offering a disease-relevant system to study mechanisms of respiratory MN dysfunction.}, } @article {pmid38421467, year = {2024}, author = {Zhong, X and Li, C and Li, Y and Huang, Y and Liu, J and Jiang, A and Chen, J and Peng, Y}, title = {IRAK-M Plays A Role in the Pathology of Amyotrophic Lateral Sclerosis Through Suppressing the Activation of Microglia.}, journal = {Molecular neurobiology}, volume = {61}, number = {10}, pages = {7603-7610}, pmid = {38421467}, issn = {1559-1182}, support = {81901239//National Natural Science Foundation of China/ ; 82171354//National Natural Science Foundation of China/ ; 202201010924//Science and Technology Projects in Guangzhou/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Microglia/metabolism/pathology ; *Interleukin-1 Receptor-Associated Kinases/metabolism/genetics ; *Mice, Transgenic ; *Spinal Cord/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Dependovirus/genetics ; Mice ; RNA, Messenger/metabolism/genetics ; Interleukin-1beta/metabolism ; Disease Models, Animal ; Mice, Inbred C57BL ; Humans ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Microglial activation plays a crucial role in the disease progression in amyotrophic lateral sclerosis (ALS). Interleukin receptor-associated kinases-M (IRAK-M) is an important negative regulatory factor in the Toll-like receptor 4 (TLR4) pathway during microglia activation, and its mechanism in this process is still unclear. In the present study, we aimed to investigate the dynamic changes of IRAK-M and its protective effects for motor neurons in SOD1-G93A mouse model of ALS. qPCR (Real-time Quantitative PCR Detecting System) were used to examine the mRNA levels of IRAK-M in the spinal cord in both SOD1-G93A mice and their age-matched wild type (WT) littermates at 60, 100 and 140 days of age. We established an adeno-associated virus 9 (AAV9)-based platform by which IRAK-M was targeted mostly to microglial cells to investigate whether this approach could provide a protection in the SOD1-G93A mouse. Compared with age-matched WT mice, IRAK-M mRNA level was elevated at 100 and 140 days in the anterior horn region of spinal cords in the SOD1-G93A mouse. AAV9-IRAK-M treated SOD1-G93A mice showed reduction of IL-1β mRNA levels and significant improvements in the numbers of spinal motor neurons in spinal cord. Mice also showed previously reduction of muscle atrophy. Our data revealed the dynamic changes of IRAK-M during ALS pathological progression and demonstrated that an AAV9-IRAK-M delivery was an effective and translatable therapeutic approach for ALS. These findings may help identify potential molecular targets for ALS therapy.}, } @article {pmid38421827, year = {2024}, author = {Zhang, Y and Li, Y and Bin, S and Cheng, X and Niu, Q}, title = {A Neglected Gene: The Role of the ANG Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {16}, number = {1}, pages = {13-32}, pmid = {38421827}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with a poor prognosis. To date, more than 40 ALS-related genes have been identified. However, there is still a lack of targeted therapeutic drugs for the treatment of ALS, especially for patients with acute onset and severe disease. A series of studies reported missense heterozygous mutations with loss of function in the coding region of the ANG gene in ALS patients. ANG deficiency is related to the pathogenesis of ALS, but the underlying mechanism has not been determined. This article aimed to synthesize and consolidate the knowledge of the pathological mechanism of ALS induced by ANG mutation and provide a theoretical basis for ALS diagnosis and targeted therapy. This article further delves into the mechanisms underlying the current understanding of the structure and function of the ANG gene, the association between ANG and ALS, and its pathogenesis. Mutations in ANG may lead to the development of ALS through the loss of neuroprotective function, induction of oxidative stress, or inhibition of rRNA synthesis. ANG mutations and genetic and environmental factors may cause disease heterogeneity and more severe disease than in ALS patients with the wild-type gene. Exploring this mechanism is expected to provide a new approach for ALS treatment through increasing ANG expression or angiogenin activity. However, the related study is still in its infancy; therefore, this article also highlights the need for further exploration of the application of ANG gene mutations in clinical trials and animal experiments is needed to achieve improved early diagnosis and treatment of ALS.}, } @article {pmid38424114, year = {2024}, author = {Bridges, LR}, title = {RNA as a component of scrapie fibrils.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {5011}, pmid = {38424114}, issn = {2045-2322}, support = {P41 GM103311/GM/NIGMS NIH HHS/United States ; R01 GM129325/GM/NIGMS NIH HHS/United States ; }, mesh = {Cricetinae ; Animals ; Sheep ; Humans ; *Scrapie ; RNA ; Cytoskeleton ; *Alzheimer Disease ; Microscopy, Electron ; Cryoelectron Microscopy ; Amyloid/chemistry ; }, abstract = {Recently, electron cryo-microscopy (cryo-EM) maps of fibrils from the brains of mice and hamsters with five infectious scrapie strains have been published and deposited in the electron microscopy data bank (EMDB). As noted by the primary authors, the fibrils contain a second component other than protein. The aim of the present study was to identify the nature of this second component in the published maps using an in silico approach. Extra densities (EDs) containing this component were continuous, straight, axial, at right angles to protein rungs and within hydrogen-bonding distance of protein, consistent with a structural role. EDs co-located with strips of basic residues, notably lysines, and formed a conspicuous cladding over parts of the N-terminal lobe of the protein. A Y-shaped polymer consistent with RNA was found, in places forming a single chain and at one location forming a duplex, comprising two antiparallel chains, and raising the intriguing possibility of replicative behaviour. To reflect the monotonous nature of the protein interface, it is suggested that the RNA may be a short tandem repeat. Fibrils from brains of patients with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other neurodegenerations also contain EDs and may be of a similar aetiology.}, } @article {pmid38424324, year = {2024}, author = {Milioto, C and Carcolé, M and Giblin, A and Coneys, R and Attrebi, O and Ahmed, M and Harris, SS and Lee, BI and Yang, M and Ellingford, RA and Nirujogi, RS and Biggs, D and Salomonsson, S and Zanovello, M and de Oliveira, P and Katona, E and Glaria, I and Mikheenko, A and Geary, B and Udine, E and Vaizoglu, D and Anoar, S and Jotangiya, K and Crowley, G and Smeeth, DM and Adams, ML and Niccoli, T and Rademakers, R and van Blitterswijk, M and Devoy, A and Hong, S and Partridge, L and Coyne, AN and Fratta, P and Alessi, DR and Davies, B and Busche, MA and Greensmith, L and Fisher, EMC and Isaacs, AM}, title = {PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons.}, journal = {Nature neuroscience}, volume = {27}, number = {4}, pages = {643-655}, pmid = {38424324}, issn = {1546-1726}, support = {MR/V003585/1/MRC_/Medical Research Council/United Kingdom ; G0601056/MRC_/Medical Research Council/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; MC_EX_MR/N501931/1/MRC_/Medical Research Council/United Kingdom ; MR/S017003/1/MRC_/Medical Research Council/United Kingdom ; G0801110/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; Mice ; *Frontotemporal Dementia/pathology ; *Amyotrophic Lateral Sclerosis/metabolism ; Transforming Growth Factor beta1 ; C9orf72 Protein/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; Drosophila ; Extracellular Matrix/metabolism ; Dipeptides/metabolism ; DNA Repeat Expansion/genetics ; }, abstract = {Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72 dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. TGF-β1 was one of the top predicted regulators of this ECM signature and polyGR expression in human induced pluripotent stem cell neurons was sufficient to induce TGF-β1 followed by COL6A1. Knockdown of TGF-β1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-β1 or COL6A1 in induced pluripotent stem cell-derived motor neurons of patients with C9ALS/FTD protected against glutamate-induced cell death. Altogether, our findings reveal a neuroprotective and conserved ECM signature in C9ALS/FTD.}, } @article {pmid38426231, year = {2024}, author = {Young, CA and Chaouch, A and Mcdermott, CJ and Al-Chalabi, A and Chhetri, SK and Talbot, K and Malaspina, A and Mills, R and Tennant, A}, title = {Improving the measurement properties of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R): deriving a valid measurement total for the calculation of change.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {400-409}, pmid = {38426231}, issn = {2167-9223}, support = {MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Factor Analysis, Statistical ; Disease Progression ; }, abstract = {BACKGROUND: The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score is a widely used measure of functional status in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS), but recent evidence has raised doubts about its validity. The objective was to examine the measurement properties of the ALSFRS-R, aiming to produce valid measurement from all 12 scale items.

METHOD: Longitudinal ALSFRS-R data were collected between 2013-2020 from 1120 people with ALS recruited from 35 centers, together with other scales in the Trajectories of Outcomes in Neurological Conditions-ALS (TONiC-ALS) study. The ALSFRS-R was analyzed by confirmatory factor analysis (CFA), Rasch Analysis (RA) and Mokken scaling.

RESULTS: No definite factor structure of the ALSFRS-R was confirmed by CFA. RA revealed the raw score total to be invalid even at the ordinal level because of multidimensionality; valid interval level subscale measures could be found for the Bulbar, Fine-Motor and Gross-Motor domains but the Respiratory domain was only valid at an ordinal level. All four domains resolved into a single valid, interval level measure by using a bifactor RA. The smallest detectable difference was 10.4% of the range of the interval scale.

CONCLUSION: A total ALSFRS-R ordinal raw score can lead to inferential bias in clinical trial results due to its non-linear nature. On the interval level transformation, more than 5 points difference is required before a statistically significant detectable difference can be observed. Transformation to interval level data should be mandatory in clinical trials.}, } @article {pmid38426489, year = {2024}, author = {Rotem, RS and Bellavia, A and Paganoni, S and Weisskopf, MG}, title = {Medication use and risk of amyotrophic lateral sclerosis: using machine learning for an exposome-wide screen of a large clinical database.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {367-375}, pmid = {38426489}, issn = {2167-9223}, support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; R21 NS099910/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/etiology ; *Exposome ; Bayes Theorem ; Machine Learning ; Vitamin E ; }, abstract = {BACKGROUND: Accumulating evidence suggests that non-genetic factors have important etiologic roles in amyotrophic lateral sclerosis (ALS), yet identification of specific culprit factors has been challenging. Many medications target biological pathways implicated in ALS pathogenesis, and screening large pharmacologic datasets for signals could greatly accelerate the identification of risk-modulating pharmacologic factors for ALS.

METHOD: We conducted a high-dimensional screening of patients' history of medication use and ALS risk using an advanced machine learning approach based on gradient-boosted decision trees coupled with Bayesian model optimization and repeated data sampling. Clinical and medication dispensing data were obtained from a large Israeli health fund for 501 ALS cases and 4,998 matched controls using a lag period of 3 or 5 years prior to ALS diagnosis for ascertaining medication exposure.

RESULTS: Of over 1,000 different medication classes, we identified 8 classes that were consistently associated with increased ALS risk across independently trained models, where most are indicated for control of symptoms implicated in ALS. Some suggestive protective effects were also observed, notably for vitamin E.

DISCUSSION: Our results indicate that use of certain medications well before the typically recognized prodromal period was associated with ALS risk. This could result because these medications increase ALS risk or could indicate that ALS symptoms can manifest well before suggested prodromal periods. The results also provide further evidence that vitamin E may be a protective factor for ALS. Targeted studies should be performed to elucidate the possible pathophysiological mechanisms while providing insights for therapeutics design.}, } @article {pmid38426720, year = {2024}, author = {Pei, Y and Liu, S and Wang, L and Chen, C and Hu, M and Xue, Y and Guan, D and Xie, L and Liao, H and Zhou, J and Zhang, H}, title = {Design, Synthesis, and Biological Evaluation of Eukaryotic Initiation Factor 2B (eIF2B) Activators.}, journal = {ChemMedChem}, volume = {19}, number = {11}, pages = {e202300716}, doi = {10.1002/cmdc.202300716}, pmid = {38426720}, issn = {1860-7187}, support = {LG202103-02-08//Lingang Laboratory/ ; }, mesh = {Humans ; *Activating Transcription Factor 4/metabolism ; *Drug Design ; HeLa Cells ; Structure-Activity Relationship ; *Eukaryotic Initiation Factor-2B/metabolism/antagonists & inhibitors ; Molecular Structure ; Dose-Response Relationship, Drug ; Oxadiazoles/pharmacology/chemistry/chemical synthesis ; }, abstract = {The eukaryotic initiation factor 2B (eIF2B) is a key regulator in protein-regulated signaling pathways and is closely related to the function of the central nervous system. Modulating eIF2B could retard the process of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and vanishing white matter disease (VWM) et al. Here, we designed and synthesized a series of novel eIF2B activators containing oxadiazole fragments. The activating effects of compounds on eIF2B were investigated through testing the inhibition of ATF4 expression. Of all the targeted compounds, compounds 21 and 29 exhibited potent inhibition on ATF4 expression with IC50 values of 32.43 nM and 47.71 nM, respectively, which were stronger than that of ISRIB (IC50=67.90 nM). ATF4 mRNA assay showed that these two compounds could restore ATF4 mRNA to normal levels in thapsigargin-stimulated HeLa cells. Protein Translation assay showed that both compounds were effective in restoring protein synthesis. Compound potency assay showed that both compounds had similar potency to ISRIB with EC50 values of 5.844 and 37.70 nM. Cytotoxicity assay revealed that compounds 21 and 29 had low toxicity and were worth further investigation.}, } @article {pmid38427163, year = {2024}, author = {Cioffi, E and Gioiosa, V and Tessa, A and Petrucci, A and Trovato, R and Santorelli, FM and Casali, C}, title = {Hereditary spastic paraparesis type 18 (SPG18): new ERLIN2 variants in a series of Italian patients, shedding light upon genetic and phenotypic variability.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {8}, pages = {3845-3852}, pmid = {38427163}, issn = {1590-3478}, mesh = {Humans ; Italy ; Male ; Female ; *Phenotype ; Adult ; *Membrane Proteins/genetics ; Middle Aged ; Mutation ; Spastic Paraplegia, Hereditary/genetics ; }, abstract = {INTRODUCTION: Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG18 is a rare, early-onset, complicated HSP, first reported as linked to biallelic ERLIN2 mutations. Recent cases of late-onset, pure HSP with monoallelic ERLIN2 variants prompt inquiries into the zygosity of such genetic conditions. The observed relationship between phenotype and mode of inheritance suggests a potential dominant negative effect of mutated ERLIN2 protein, potentially resulting in a milder phenotype. This speculation suggests that a wider range of HSP genes could be linked to various inheritance patterns.

PURPOSE AND BACKGROUND: With documented cases of HSP loci exhibiting both dominant and recessive patterns, this study emphasizes that the concept of zygosity is no longer a limiting factor in the establishment of molecular diagnoses for HSP. Recent cases have demonstrated phenoconversion in SPG18, from HSP to an amyotrophic lateral sclerosis (ALS)-like syndrome.

METHODS AND RESULTS: This report highlights two cases out of five exhibiting HSP-ALS phenoconversion, discussing an observed prevalence in autosomal dominant SPG18. Additionally, the study emphasizes the relatively high incidence of the c.502G>A variant in monoallelic SPG18 cases. This mutation appears to be particularly common in cases of HSPALS phenoconversion, indicating its potential role as a hotspot for a distinctive SPG18 phenotype with an ALS-like syndrome.

CONCLUSIONS: Clinicians need to be aware that patients with HSP may show ALS signs and symptoms. On the other hand, HSP panels must be included in genetic testing methods for instances of familial ALS.}, } @article {pmid38427251, year = {2024}, author = {Niccolai, E and Martinelli, I and Quaranta, G and Nannini, G and Zucchi, E and De Maio, F and Gianferrari, G and Bibbò, S and Cammarota, G and Mandrioli, J and Masucci, L and Amedei, A}, title = {Fecal Microbiota Transplantation in Amyotrophic Lateral Sclerosis: Clinical Protocol and Evaluation of Microbiota Immunity Axis.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2761}, number = {}, pages = {373-396}, pmid = {38427251}, issn = {1940-6029}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Fecal Microbiota Transplantation ; *Gastrointestinal Microbiome/physiology ; *Microbiota ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; }, abstract = {The fecal microbial transplantation (FMT) is a therapeutic transplant of fecal microbiota from healthy donors to patients. This practice is aimed at restoring eubiosis and rebalancing the enteric and systemic immune responses, and then eliminating pathogenic triggers of multiple disease, including neurodegenerative diseases. Alterations of gut microbiota (GM) affect the central nervous system (CNS) health, impacting neuro-immune interactions, synaptic plasticity, myelination, and skeletal muscle function. T-regulatory lymphocytes (Treg) are among the most important players in the pathogenesis of amyotrophic lateral sclerosis (ALS), altering the disease course. Along with circulating neuropeptides, other immune cells, and the gut-brain axis, the GM influences immunological tolerance and controls Treg's number and suppressive functions. A double-blind, controlled, multicenter study on FMT in ALS patients has been designed to evaluate if FMT can modulate neuroinflammation, by restoring Treg number, thus modifying disease activity and progression.}, } @article {pmid38427252, year = {2024}, author = {Rajaratnam, S and Pradhan, SS and Naik, AA and Sivaramakrishnan, V}, title = {Integrated Multi-Omics Analysis and Validation in Yeast Model of Amyotrophic Lateral Sclerosis.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2761}, number = {}, pages = {397-419}, pmid = {38427252}, issn = {1940-6029}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Saccharomyces cerevisiae/genetics ; Multiomics ; Software ; Gene Expression Profiling ; }, abstract = {Transcriptomics is a complex process that involves raw data extraction, normalization, differential gene expression, and analysis. The Gene Expression Omnibus (GEO) database at the National Center for Biotechnology Information (NCBI) is a repository of experimental datasets. Amyotrophic lateral sclerosis (ALS) datasets are deposited by various scientists and research investigators to expand the horizon of scientific knowledge. R-statistical tools are the most common ways for conducting these kinds of studies. The first step is the identification of appropriate datasets. Since the raw data is available in a variety of formats, a large array of software is used for extraction and analysis. Normalization is conducted for the datasets using NetworkAnalyst. Differential analysis is further conducted on the normalized data to identify significantly enriched genes. The significant genes are then grouped into pathways. The results were validated using yeast model of ALS in which the yeast is transformed with ALS plasmids encoding genes associated with ALS. The resulting GFP-tagged protein aggregates are imaged using fluorescence microscopy and subsequently validated using filter retardation assay and quantified using ImageJ software. Functional role of different genes is studied using metabolite treatment and knockout studies.}, } @article {pmid38427990, year = {2024}, author = {El-Hajj, VG and Daller, C and Fletcher-Sandersjöö, A and Gharios, M and Bydon, M and Söderman, M and Jabbour, P and Edström, E and Elmi-Terander, A and Arnberg, F}, title = {The negative impact of treatment delays on the long-term neurological outcomes of spinal dural arteriovenous fistulas: a longitudinal cohort study.}, journal = {Neurosurgical focus}, volume = {56}, number = {3}, pages = {E14}, doi = {10.3171/2023.12.FOCUS23703}, pmid = {38427990}, issn = {1092-0684}, mesh = {Humans ; Male ; Aged ; Female ; Cohort Studies ; Longitudinal Studies ; Retrospective Studies ; *Treatment Delay ; *Central Nervous System Vascular Malformations/complications/surgery ; }, abstract = {OBJECTIVE: Dural arteriovenous fistulas are rare vascular malformations that affect the brain and spinal cord. Spinal dural arteriovenous fistulas (sdAVFs) are the most frequently encountered vascular malformation affecting the spinal cord. The object of this study was to evaluate the impact of treatment delays on the long-term neurological outcomes of either open surgical or interventional treatment of sdAVFs.

METHODS: In this retrospective, population-based cohort study, the authors examined consecutive patients with diagnosed sdAVFs at a tertiary care center between 2005 and 2020. Patients were assessed using the Aminoff-Logue disability scale (ALS) at various time points including symptom onset, primary care visit, first specialist outpatient visit, as well as both short and long-term follow-ups. The postoperative long-term ALS gait and bladder grades constituted the primary outcomes of the study.

RESULTS: Among the 34 patients included in the study, the median age was 65 years, and there was a male predominance (71%). Most lesions were in the lumbar region (47%). Significant worsening in ALS gait and bladder grades was observed preoperatively, followed by postoperative improvements (p < 0.05). There was no difference in outcomes between surgical and endovascular treatments. Older age (OR 1.10, 95% CI 1.03-1.17, p = 0.007), worse preoperative ALS gait grades (OR 5.12, 95% CI 2.18-12.4, p < 0.001), and longer time from first specialist outpatient visit to first treatment (OR 1.00, 95% CI 1.00-1.01, p = 0.040) were independently associated with worse long-term gait outcomes. Only the preoperative ALS bladder score was a predictor of worse long-term bladder function (OR 92.7, 95% CI 28.0-306.7, p < 0.001).

CONCLUSIONS: Both surgical and endovascular treatments for sdAVFs led to significant neurological improvements. However, treatment delays were associated with less favorable long-term outcomes. Prompt diagnosis and early intervention prior to symptom progression may enhance recovery and help to preserve neurological function.}, } @article {pmid38428126, year = {2024}, author = {Wahbeh, F and Restifo, D and Laws, S and Pawar, A and Parikh, NS}, title = {Impact of tobacco smoking on disease-specific outcomes in common neurological disorders: A scoping review.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {122}, number = {}, pages = {10-18}, pmid = {38428126}, issn = {1532-2653}, support = {K23 AG073524/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Smoking Cessation ; Smoking/adverse effects/epidemiology ; Tobacco Smoking ; *Stroke/epidemiology/etiology/therapy ; *Multiple Sclerosis ; }, abstract = {Although the association of smoking with the risk of incident neurological disorders is well established, less is known about the impact of smoking and smoking cessation on outcomes of these conditions. The objective of this scoping review was to synthesize what is known about the impact of smoking and smoking cessation on disease-specific outcomes for seven common neurological disorders. We included 67 studies on the association of smoking and smoking cessation on disease-specific outcomes. For multiple sclerosis, smoking was associated with greater clinical and radiological disease progression, relapses, risk for disease-related death, cognitive decline, and mood symptoms, in addition to reduced treatment effectiveness. For stroke and transient ischemic attack, smoking was associated with greater rates of stroke recurrence, post-stroke cardiovascular outcomes, post-stroke mortality, post-stroke cognitive impairment, and functional impairment. In patients with cognitive impairment and dementia, smoking was associated with faster cognitive decline, and smoking was also associated with greater cognitive decline in Parkinson's disease, but not motor symptom worsening. Patients with amyotrophic lateral sclerosis who smoked faced increased mortality. Last, in patients with cluster headache, smoking was associated with more frequent and longer cluster attack periods. Conversely, for multiple sclerosis and stroke, smoking cessation was associated with improved disease-specific outcomes. In summary, whereas smoking is detrimentally associated with disease-specific outcomes in common neurological conditions, there is growing evidence that smoking cessation may improve outcomes. Effective smoking cessation interventions should be leveraged in the management of common neurological disorders to improve patient outcomes.}, } @article {pmid38428228, year = {2024}, author = {Masroor, A and Zaidi, N and Nabi, F and Malik, S and Zehra, S and Arjmand, F and Naseem, N and Khan, RH}, title = {Biophysical insight into anti-amyloidogenic nature of novel ionic Co(II)(phen)(H2O)4][+][glycinate][-] chemotherapeutic drug candidate against human lysozyme aggregation.}, journal = {Biophysical chemistry}, volume = {308}, number = {}, pages = {107214}, doi = {10.1016/j.bpc.2024.107214}, pmid = {38428228}, issn = {1873-4200}, mesh = {Humans ; *Amyloid/chemistry ; Muramidase/chemistry ; Molecular Docking Simulation ; *Amyloidosis/drug therapy/metabolism ; Dynamic Light Scattering ; Protein Aggregates ; }, abstract = {In the recent past, there has been an ever-increasing interest in the search for metal-based therapeutic drug candidates for protein misfolding disorders (PMDs) particularly neurodegenerative disorders such as Alzheimer's, Parkinson's, Prion's diseases, and amyotrophic lateral sclerosis. Also, different amyloidogenic variants of human lysozyme (HL) are involved in hereditary systemic amyloidosis. Metallo-therapeutic agents are extensively studied as antitumor agents, however, they are relatively unexplored for the treatment of non-neuropathic amyloidoses. In this work, inhibition potential of a novel ionic cobalt(II) therapeutic agent (CoTA) of the formulation [Co(phen)(H2O)4][+][glycinate][-] is evaluated against HL fibrillation. Various biophysical techniques viz., dye-binding assays, dynamic light scattering (DLS), differential scanning calorimetry (DSC), electron microscopy, and molecular docking experiments validate the proposed mechanism of inhibition of HL fibrillation by CoTA. The experimental corroborative results of these studies reveal that CoTA can suppress and slow down HL fibrillation at physiological temperature and pH. DLS and 1-anilino-8-naphthalenesulfonate (ANS) assay show that reduced fibrillation in the presence of CoTA is marked by a significant decrease in the size and hydrophobicity of the aggregates. Fluorescence quenching and molecular docking results demonstrate that CoTA binds moderately to the aggregation-prone region of HL (Kb = 6.6 × 10[4] M[-1]), thereby, inhibiting HL fibrillation. In addition, far-UV CD and DSC show that binding of CoTA to HL does not cause any change in the stability of HL. More importantly, CoTA attenuates membrane damaging effects of HL aggregates against RBCs. This study identifies inorganic metal complexes as a therapeutic intervention for systemic amyloidosis.}, } @article {pmid38428880, year = {2024}, author = {Hu, CJ and Chen, PC and Padmanabhan, N and Zahn, A and Ho, CM and Wang, K and Yen, Y}, title = {A new potential therapeutic approach for ALS: A case report with NGS analysis.}, journal = {Medicine}, volume = {103}, number = {9}, pages = {e37401}, pmid = {38428880}, issn = {1536-5964}, mesh = {Humans ; Male ; Aged ; Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/genetics ; Artificial Intelligence ; Treatment Outcome ; *Hypotension/drug therapy ; }, abstract = {RATIONALE: Amyotrophic lateral sclerosis (ALS) poses a significant clinical challenge due to its rapid progression and limited treatment options, often leading to deadly outcomes. Looking for effective therapeutic interventions is critical to improve patient outcomes in ALS.

PATIENT CONCERNS: The patient, a 75-year-old East Asian male, manifested an insidious onset of right-hand weakness advancing with dysarthria. Comprehensive Next-generation sequencing analysis identified variants in specific genes consistent with ALS diagnosis.

DIAGNOSES: ALS diagnosis is based on El Escorial diagnostic criteria.

INTERVENTIONS: This study introduces a novel therapeutic approach using artificial intelligence phenotypic response surface (AI-PRS) technology to customize personalized drug-dose combinations for ALS. The patient underwent a series of phases of AI-PRS-assisted trials, initially incorporating a 4-drug combination of Ibudilast, Riluzole, Tamoxifen, and Ropinirole. Biomarkers and regular clinical assessments, including nerve conduction velocity, F-wave, H-reflex, electromyography, and motor unit action potential, were monitored to comprehensively evaluate treatment efficacy.

OUTCOMES: Neurophysiological assessments supported the ALS diagnosis and revealed the co-presence of diabetic polyneuropathy. Hypotension during the trial necessitated an adaptation to a 2-drug combinational trial (ibudilast and riluzole). Disease progression assessment shifted exclusively to clinical tests of muscle strength, aligning with the patient's well-being.

LESSONS: The study raises the significance of personalized therapeutic strategies in ALS by AI-PRS. It also emphasizes the adaptability of interventions based on patient-specific responses. The encountered hypotension incident highlights the importance of attentive monitoring and personalized adjustments in treatment plans. The described therapy using AI-PRS, offering personalized drug-dose combinations technology is a potential approach in treating ALS. The promising outcomes warrant further evaluation in clinical trials for searching a personalized, more effective combinational treatment for ALS patients.}, } @article {pmid38429156, year = {2024}, author = {Corcia, P and Couratier, P}, title = {Spreading of motor neuron degeneration in ALS is not so random.}, journal = {Revue neurologique}, volume = {180}, number = {6}, pages = {475-476}, doi = {10.1016/j.neurol.2024.02.384}, pmid = {38429156}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnosis ; *Motor Neurons/pathology/physiology ; *Nerve Degeneration/pathology ; }, } @article {pmid38429379, year = {2024}, author = {de Luzy, IR and Lee, MK and Mobley, WC and Studer, L}, title = {Lessons from inducible pluripotent stem cell models on neuronal senescence in aging and neurodegeneration.}, journal = {Nature aging}, volume = {4}, number = {3}, pages = {309-318}, pmid = {38429379}, issn = {2662-8465}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 AG054720/AG/NIA NIH HHS/United States ; R01 AG070154/AG/NIA NIH HHS/United States ; ASAP-020370//Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; Aging ; Cellular Senescence/physiology ; Neurons ; *Pluripotent Stem Cells ; }, abstract = {Age remains the central risk factor for many neurodegenerative diseases including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Although the mechanisms of aging are complex, the age-related accumulation of senescent cells in neurodegeneration is well documented and their clearance can alleviate disease-related features in preclinical models. Senescence-like characteristics are observed in both neuronal and glial lineages, but their relative contribution to aging and neurodegeneration remains unclear. Human pluripotent stem cell-derived neurons provide an experimental model system to induce neuronal senescence. However, the extensive heterogeneity in the profile of senescent neurons and the methods to assess senescence remain major challenges. Here, we review the evidence of cellular senescence in neuronal aging and disease, discuss human pluripotent stem cell-based model systems used to investigate neuronal senescence and propose a panel of cellular and molecular hallmarks to characterize senescent neurons. Understanding the role of neuronal senescence may yield novel therapeutic opportunities in neurodegenerative disease.}, } @article {pmid38429713, year = {2024}, author = {Hagenaar, DA and Bindels-de Heus, KGCB and van Gils, MM and van den Berg, L and Ten Hoopen, LW and Affourtit, P and Pel, JJM and Joosten, KFM and Hillegers, MHJ and Moll, HA and de Wit, MY and Dieleman, GC and Mous, SE}, title = {Outcome measures in Angelman syndrome.}, journal = {Journal of neurodevelopmental disorders}, volume = {16}, number = {1}, pages = {6}, pmid = {38429713}, issn = {1866-1955}, support = {B17-04A//Stichting Vrienden van het Sophia/ ; }, mesh = {Child ; Humans ; *Angelman Syndrome/complications/diagnosis ; Reproducibility of Results ; Body Composition ; Plethysmography/methods ; Electric Impedance ; }, abstract = {BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a tendency towards hyperphagia and weight gain. The characteristics of AS make it difficult to measure these children's functioning with standard clinical tests. Feasible outcome measures are needed to measure current functioning and change over time, in clinical practice and clinical trials.

AIM: Our first aim is to assess the feasibility of several functional tests. We target domains of neurocognitive functioning and physical growth using the following measurement methods: eye-tracking, functional Near-Infrared Spectroscopy (fNIRS), indirect calorimetry, bio-impedance analysis (BIA), and BOD POD (air-displacement plethysmography). Our second aim is to explore the results of the above measures, in order to better understand the AS phenotype.

METHODS: The study sample consisted of 28 children with AS aged 2-18 years. We defined an outcome measure as feasible when (1) at least 70% of participants successfully finished the measurement and (2) at least 60% of those participants had acceptable data quality. Adaptations to the test procedure and reasons for early termination were noted. Parents rated acceptability and importance and were invited to make recommendations to increase feasibility. The results of the measures were explored.

RESULTS: Outcome measures obtained with eye-tracking and BOD POD met the definition of feasibility, while fNIRS, indirect calorimetry, and BIA did not. The most important reasons for early termination of measurements were showing signs of protest, inability to sit still and poor/no calibration (eye-tracking specific). Post-calibration was often applied to obtain valid eye-tracking results. Parents rated the BOD POD als most acceptable and fNIRS as least acceptable for their child. All outcome measures were rated to be important. Exploratory results indicated longer reaction times to high salient visual stimuli (eye-tracking) as well as high body fat percentage (BOD POD).

CONCLUSIONS: Eye-tracking and BOD POD are feasible measurement methods for children with AS. Eye-tracking was successfully used to assess visual orienting functions in the current study and (with some practical adaptations) can potentially be used to assess other outcomes as well. BOD POD was successfully used to examine body composition.

TRIAL REGISTRATION: Registered d.d. 23-04-2020 under number 'NL8550' in the Dutch Trial Register: https://onderzoekmetmensen.nl/en/trial/23075.}, } @article {pmid38429818, year = {2024}, author = {Darabi, S and Ariaei, A and Rustamzadeh, A and Afshari, D and Charkhat Gorgich, EA and Darabi, L}, title = {Cerebrospinal fluid and blood exosomes as biomarkers for amyotrophic lateral sclerosis; a systematic review.}, journal = {Diagnostic pathology}, volume = {19}, number = {1}, pages = {47}, pmid = {38429818}, issn = {1746-1596}, mesh = {Humans ; *Exosomes ; *Amyotrophic Lateral Sclerosis/diagnosis ; Superoxide Dismutase-1 ; Biomarkers ; DNA-Binding Proteins ; Disease Progression ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease. Due to the limited knowledge about potential biomarkers that help in early diagnosis and monitoring disease progression, today's diagnoses are based on ruling out other diseases, neurography, and electromyography examination, which takes a time-consuming procedure.

METHODS: PubMed, ScienceDirect, and Web of Science were explored to extract articles published from January 2015 to June 2023. In the searching strategy following keywords were included; amyotrophic lateral sclerosis, biomarkers, cerebrospinal fluid, serum, and plama.

RESULTS: A total number of 6 studies describing fluid-based exosomal biomarkers were included in this study. Aggregated proteins including SOD1, TDP-43, pTDP-43, and FUS could be detected in the microvesicles (MVs). Moreover, TDP-43 and NFL extracted from plasma exosomes could be used as prognostic biomarkers. Also, downregulated miR-27a-3p detected through exoEasy Maxi and exoQuick Kit in the plasma could be measured as a diagnostic biomarker. Eventually, the upregulated level of CORO1A could be used to monitor disease progression.

CONCLUSION: Based on the results, each biomarker alone is insufficient to evaluate ALS. CNS-derived exosomes contain multiple ALS-related biomarkers (SOD1, TDP-43, pTDP-43, FUS, and miRNAs) that are detectable in cerebrospinal fluid and blood is a proper alternation. Exosome detecting kits listed as exoEasy, ExoQuick, Exo-spin, ME kit, ExoQuick Plus, and Exo-Flow, are helpful to reach this purpose.}, } @article {pmid38429929, year = {2024}, author = {Schuster, KH and Zalon, AJ and DiFranco, DM and Putka, AF and Stec, NR and Jarrah, SI and Naeem, A and Haque, Z and Zhang, H and Guan, Y and McLoughlin, HS}, title = {ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {32}, number = {5}, pages = {1359-1372}, pmid = {38429929}, issn = {1525-0024}, support = {R01 NS122751/NS/NINDS NIH HHS/United States ; R35 GM133346/GM/NIGMS NIH HHS/United States ; U01 NS106670/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Oligodendroglia/metabolism ; Mice ; *Machado-Joseph Disease/genetics/therapy/pathology/metabolism ; *Oligonucleotides, Antisense ; *Disease Models, Animal ; *Ataxin-3/genetics/metabolism ; Humans ; Repressor Proteins/genetics/metabolism ; Mice, Transgenic ; }, abstract = {Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventive or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease is caused by a CAG repeat expansion in the mutant gene, ATXN3, producing an enlarged polyglutamine tract in the mutant protein. Similar to other paradigmatic neurodegenerative diseases, studies evaluating the pathogenic mechanism focus primarily on neuronal implications. Consequently, therapeutic interventions often overlook non-neuronal contributions to disease. Our lab recently reported that oligodendrocytes display some of the earliest and most progressive dysfunction in SCA3 mice. Evidence of disease-associated oligodendrocyte signatures has also been reported in other neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Here, we assess the effects of anti-ATXN3 antisense oligonucleotide (ASO) treatment on oligodendrocyte dysfunction in premanifest and symptomatic SCA3 mice. We report a severe, but modifiable, deficit in oligodendrocyte maturation caused by the toxic gain-of-function of mutant ATXN3 early in SCA3 disease that is transcriptionally, biochemically, and functionally rescued with anti-ATXN3 ASO. Our results highlight the promising use of an ASO therapy across neurodegenerative diseases that requires glial targeting in addition to affected neuronal populations.}, } @article {pmid38430248, year = {2024}, author = {Ullah, I and Uddin, S and Zhao, L and Wang, X and Li, H}, title = {Autophagy and UPS pathway contribute to nicotine-induced protection effect in Parkinson's disease.}, journal = {Experimental brain research}, volume = {242}, number = {4}, pages = {971-986}, pmid = {38430248}, issn = {1432-1106}, support = {81403145//National Natural Science Foundation of China/ ; 20JR10RA602//Natural Science Foundation of Gansu Province/ ; lzujbky- 2017-206//Fundamental Research Funds for the Central Universities/ ; lzujbky-2018-136//Fundamental Research Funds for the Central Universities/ ; 2019HZ-02//Science and Technology Program of Gansu Province/ ; 2010-1-154//Science and Technology Program of Gansu Province/ ; }, mesh = {Animals ; Humans ; Aged ; *Parkinson Disease/drug therapy/metabolism ; Nicotine/pharmacology/metabolism ; Caenorhabditis elegans/metabolism ; Lipofuscin/metabolism/pharmacology ; alpha-Synuclein/metabolism/pharmacology ; *Neurodegenerative Diseases/metabolism ; Dopaminergic Neurons/metabolism ; Autophagy ; }, abstract = {The gradual nature of age-related neurodegeneration causes Parkinson's disease (PD) and impairs movement, memory, intellectual ability, and social interaction. One of the most prevalent neurodegenerative conditions affecting the central nervous system (CNS) among the elderly is PD. PD affects both motor and cognitive functions. Degeneration of dopaminergic (DA) neurons and buildup of the protein α-synuclein (α-Syn) in the substantia nigra pars compacta (SNpc) are two major causes of this disorder. Both UPS and ALS systems serve to eliminate α-Syn. Autophagy and UPS deficits, shortened life duration, and lipofuscin buildup accelerate PD. This sickness has no cure. Innovative therapies are halting PD progression. Bioactive phytochemicals may provide older individuals with a natural substitute to help delay the onset of neurodegenerative illnesses. This study examines whether nicotine helps transgenic C. elegans PD models. According to numerous studies, nicotine enhances synaptic plasticity and dopaminergic neuronal survival. Upgrades UPS pathways, increases autophagy, and decreases oxidative stress and mitochondrial dysfunction. At 100, 150, and 200 µM nicotine levels, worms showed reduced α-Syn aggregation, repaired DA neurotoxicity after 6-OHDA intoxication, increased lifetime, and reduced lipofuscin accumulation. Furthermore, nicotine triggered autophagy and UPS. We revealed nicotine's potential as a UPS and autophagy activator to prevent PD and other neurodegenerative diseases.}, } @article {pmid38430277, year = {2024}, author = {Jagaraj, CJ and Shadfar, S and Kashani, SA and Saravanabavan, S and Farzana, F and Atkin, JD}, title = {Molecular hallmarks of ageing in amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {111}, pmid = {38430277}, issn = {1420-9071}, support = {1095215//National Institute for Dementia Research/ ; Peter Stearne Familial MND Research Grant//Motor Neurone Disease Australia/ ; Linda Rynalski Bridge Funding Grant//Motor Neurone Disease Australia/ ; 51909/00//FightMND/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Longevity ; Autophagy/genetics ; Brain ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, severely debilitating and rapidly progressing disorder affecting motor neurons in the brain, brainstem, and spinal cord. Unfortunately, there are few effective treatments, thus there remains a critical need to find novel interventions that can mitigate against its effects. Whilst the aetiology of ALS remains unclear, ageing is the major risk factor. Ageing is a slowly progressive process marked by functional decline of an organism over its lifespan. However, it remains unclear how ageing promotes the risk of ALS. At the molecular and cellular level there are specific hallmarks characteristic of normal ageing. These hallmarks are highly inter-related and overlap significantly with each other. Moreover, whilst ageing is a normal process, there are striking similarities at the molecular level between these factors and neurodegeneration in ALS. Nine ageing hallmarks were originally proposed: genomic instability, loss of telomeres, senescence, epigenetic modifications, dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion, and altered inter-cellular communication. However, these were recently (2023) expanded to include dysregulation of autophagy, inflammation and dysbiosis. Hence, given the latest updates to these hallmarks, and their close association to disease processes in ALS, a new examination of their relationship to pathophysiology is warranted. In this review, we describe possible mechanisms by which normal ageing impacts on neurodegenerative mechanisms implicated in ALS, and new therapeutic interventions that may arise from this.}, } @article {pmid38430933, year = {2024}, author = {Li, D and Zhou, L and Cao, Z and Wang, J and Yang, H and Lyu, M and Zhang, Y and Yang, R and Wang, J and Bian, Y and Xu, W and Wang, Y}, title = {Associations of environmental factors with neurodegeneration: An exposome-wide Mendelian randomization investigation.}, journal = {Ageing research reviews}, volume = {95}, number = {}, pages = {102254}, doi = {10.1016/j.arr.2024.102254}, pmid = {38430933}, issn = {1872-9649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Exposome ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Alzheimer Disease/genetics ; *Parkinson Disease ; *Multiple Sclerosis/genetics ; }, abstract = {Neurodegenerative diseases (NDDs) remain a global health challenge. Previous studies have reported potential links between environmental factors and NDDs, however, findings remain controversial across studies and elusive to be interpreted as evidence of robust causal associations. In this study, we comprehensively explored the causal associations of the common environmental factors with major NDDs including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), based on updated large-scale genome-wide association study data through two-sample Mendelian randomization (MR) approach. Our results indicated that, overall, 28 significant sets of exposure-outcome causal association evidence were detected, 12 of which were previously underestimated and newly identified, including average weekly beer plus cider intake, strenuous sports or other exercises, diastolic blood pressure, and body fat percentage with AD, alcohol intake frequency with PD, apolipoprotein B, systolic blood pressure, and forced expiratory volume in 1 s (FEV1) with ALS, and alcohol intake frequency, hip circumference, forced vital capacity, and FEV1 with MS. Moreover, the causal effects of several environmental factors on NDDs were found to overlap. From a triangulation perspective, our investigation provided insights into understanding the associations of environmental factors with NDDs, providing causality-oriented evidence to establish the risk profile of NDDs.}, } @article {pmid38431694, year = {2024}, author = {Mouhamed, AA and Nadim, AH and Mostafa, NM and Eltanany, BM}, title = {Application of smart chemometric models for spectra resolution and determination of challenging multi-action quaternary mixture: statistical comparison with greenness assessment.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {44}, pmid = {38431694}, issn = {2661-801X}, abstract = {A multivariate spectrophotometric method is a potential approach that enables discrimination of spectra of components in complex matrices (e.g., pharmaceutical formulation) serving as a substitution method for chromatography. Four green smart multivariate spectrophotometric models were proposed and validated, including principal component regression (PCR), partial least-squares (PLS), multivariate curve resolution-alternating least squares (MCR-ALS), and artificial neural networks (ANN). The developed chemometric models were compared to resolve highly overlapping spectra of Paracetamol (PARA), Chlorpheniramine maleate (CPM), Caffeine (CAF), and Ascorbic acid (ASC). The four multivariate calibration models were assessed via recoveries percent, and root mean square error of prediction. Hence, the proposed models were efficiently applied with no need for any preliminary separation step. The models were utilized to analyze the studied components in their combined pharmaceutical formulation (Grippostad® C capsules). Analytical GREEnness Metric Approach (AGREE) and eco-scale tools were applied to assess the greenness of the established models and found to be 0.77 and 85, respectively. Moreover, the proposed models have been compared to official ones showing no considerable variations in accuracy and precision. Therefore, these models can be highly advantageous for conducting standard pharmaceutical analysis of the substances researched within product testing laboratories.}, } @article {pmid38431829, year = {2024}, author = {Yuan, W and Lin, J and Wang, J and Wang, C and Shan, Y and Jing, W and Fei, Z and Pan, W}, title = {Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 2: Modulation of hypoxia, redox status, and mitochondrial protection in a neuroblastoma cell line, SH-SY5Y.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {62}, number = {4}, pages = {162-168}, doi = {10.5414/CP204505}, pmid = {38431829}, issn = {0946-1965}, mesh = {Humans ; *Medicine, Chinese Traditional ; Kaempferols/pharmacology ; Cell Line, Tumor ; Network Pharmacology ; *Neuroblastoma/drug therapy/metabolism ; Oxidation-Reduction ; Hypoxia/drug therapy ; Treatment Outcome ; }, abstract = {OBJECTIVE: To examine the mitochondrial protective effects of icariin, naringenin, kaempferol, and formononetin, potentially active agents in Bu-Shen-Jian-Pi formula (BSJP) identified using network pharmacology analysis.

MATERIALS AND METHODS: Mitochondrial protection activity was determined using a hypoxia-reoxygenation in vitro model based on the neuroblastoma cell line SH-SY5Y and measurements of anti-ferroptotic activity.

RESULTS: Icariin, naringenin, kaempferol, and formononetin showed mitochondrial protective activity involving diverse signaling pathways. The cytoprotective effects of formononetin depended on the inhibition of ferroptosis. Hypoxia-reoxygenation stimulation induced ferroptosis in SH-SY5Y cells.

DISCUSSION: Ferroptosis is a key mechanism in nervous system diseases and is associated with hypoxia-reoxygenation injury. Naringenin and kaempferol were devoid of anti-ferroptotic activity.

CONCLUSION: Evidence has been obtained showing that the core components: icariin, naringenin, kaempferol, and formononetin in BSJP formula have anti-hypoxic and mitochondrial protective activity of potential clinical importance in the treatment of amyotrophic lateral sclerosis and patients with symptoms of hypoxia.}, } @article {pmid38431830, year = {2024}, author = {Li, R and Han, X and Wang, Q and Wang, C and Jing, W and Zhang, H and Wang, J and Pan, W}, title = {Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 3: Alleviation of hypoxia, muscle-wasting, and modulation of redox functions in amyotrophic lateral sclerosis.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {62}, number = {4}, pages = {169-177}, doi = {10.5414/CP204520}, pmid = {38431830}, issn = {0946-1965}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/diagnosis ; Medicine, Chinese Traditional ; Network Pharmacology ; Treatment Outcome ; Hypoxia ; Cholecalciferol ; Muscles ; Disease Progression ; }, abstract = {OBJECTIVE: The aim of this clinical study is to obtain evidence for the clinical efficacy of Bu-Shen-Jian-Pi formula (BSJP), a traditional Chinese medicine, used for the treatment of amyotrophic lateral sclerosis, a relatively rare, progressive and usually fatal disease possibly associated with alterations in tissue redox status, hypoxia, and muscular injury.

BACKGROUND: The active agents in BSJP formula[†] causing apoptosis, modulation of redox changes, and alterations in the immune status have been studied previously by us using cell cultures. The findings from these investigations have been incorporated into pharmacology databases employed in our analysis of BSJP using network pharmacology analysis/artifical intelligence. This information has been used here in the design of the investigation and to optimize evaluation of the clinical efficacy and usefulness of this herbal medicine, as far as possible using evidence-based medicine criteria.

MATERIALS AND METHODS: The design of the study was a randomized multi-center, controlled clinical trial in 127 patients with confirmed diagnoses of amyotrophic lateral sclerosis. Patients and investigator were double-blinded. Clinical efficacy was determined using the Amyotrophic Lateral Sclerosis Symptom Score in Integrative Treatment Scale (ALS-SSIT) and the Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R), together with tests of limb muscle strength using the manual muscle test (MMT), forced vital capacity (FVC), and clinical chemistry laboratory tests over a 20-week observation period.

RESULTS: The scores of ALS-SSIT in the BSJP group increased significantly (22%) after treatment. The ALSFRS-R score in the BSJP group decreased significantly after treatment (19%). The rate of decrease in muscle function (MMT score) in most BSJP patients was lower than that in the control group, where the differences in the scores for the trapezius and triceps brachii were statistically significant compared to the control group. The fall in FVC in the BJSP group was significantly slower than in the control group. There were no marked differences observed in the frequency of side effects. Serum vitamin D3 levels in the BSJP group showed greater increases compared to the control group.

CONCLUSION: BSJP treatment reduced the rate of progression of amyotrophic lateral sclerosis according to the ALS-SSITS and ALSFRS scores and significantly reduced the rate of deterioration in muscle function in the limbs of amyotrophic lateral sclerosis patients. The modes of action of BSJP in treating amyotrophic lateral sclerosis are probably diverse and multi targeted, some of which may involve regulation of serum vitamin D3 and alleviation of the impairments in liver and kidney function.}, } @article {pmid38431841, year = {2024}, author = {Gao, C and Shi, Q and Pan, X and Chen, J and Zhang, Y and Lang, J and Wen, S and Liu, X and Cheng, TL and Lei, K}, title = {Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis.}, journal = {Cell reports}, volume = {43}, number = {3}, pages = {113892}, doi = {10.1016/j.celrep.2024.113892}, pmid = {38431841}, issn = {2211-1247}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology ; Proteins/genetics ; Dipeptides/pharmacology/metabolism ; DNA Repeat Expansion ; }, abstract = {Hexanucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Due to the lack of trunk neuromuscular organoids (NMOs) from ALS patients' induced pluripotent stem cells (iPSCs), an organoid system was missing to model the trunk spinal neuromuscular neurodegeneration. With the C9orf72 ALS patient-derived iPSCs and isogenic controls, we used an NMO system containing trunk spinal cord neural and peripheral muscular tissues to show that the ALS NMOs could model peripheral defects in ALS, including contraction weakness, neural denervation, and loss of Schwann cells. The neurons and astrocytes in ALS NMOs manifested the RNA foci and dipeptide repeat proteins. Acute treatment with the unfolded protein response inhibitor GSK2606414 increased the glutamatergic muscular contraction 2-fold and reduced the dipeptide repeat protein aggregation and autophagy. This study provides an organoid system for spinal neuromuscular pathologies in ALS and its application for drug testing.}, } @article {pmid38432041, year = {2024}, author = {Yu, W and Wang, H and Li, M and Yang, F and Bai, J and Song, H and Huang, X}, title = {Prognostic value of geriatric nutritional risk index in patients with amyotrophic lateral sclerosis.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {122}, number = {}, pages = {19-24}, doi = {10.1016/j.jocn.2024.02.011}, pmid = {38432041}, issn = {1532-2653}, mesh = {Humans ; Aged ; Prognosis ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Delayed Diagnosis ; Nutritional Status ; Disease Progression ; Risk Factors ; Retrospective Studies ; }, abstract = {BACKGROUND: The geriatric nutritional risk index (GNRI) is a prognostic indicator for several diseases, meanwhile, nutrition and inflammation play important roles in the disease progression of amyotrophic lateral sclerosis (ALS). However, the association between the GNRI and ALS remains unknown.

METHODS: 443 patients diagnosed with ALS were divided into two groups based on the GNRI levels. Associations between GNRI and survival time were analyzed using Kaplan-Meier curves and compared by the log-rank test. Univariate and multivariate analyses were used to assess their prognostic values for survival time. Spearman correlation analysis was used to evaluate the correlation coefficients between GNRI and other clinical variables.

RESULTS: No significant differences were found in diagnostic delay between the two groups. The onset age and disease progression rate (DPR) were significantly lower in high GNRI group while forced vital capacity (FVC), revised version of the ALS functional rating scale (ALSFRS-R), serum albumin and body mass index (BMI) were significantly lower in low GNRI group. Lower GNRI levels were linked with shorter ALS patients' survival time by Kaplan-Meier curves. The univariate and multivariate analysis identified the onset age, gender, onset site, diagnostic delay, DRP and GNRI as predictors of survival time in patients with ALS.

CONCLUSION: Nutritional status was closely corelated with ALS progression. The GNRI may be used as a potential prognostic indictor for ALS patients.}, } @article {pmid38432083, year = {2024}, author = {Straczkiewicz, M and Karas, M and Johnson, SA and Burke, KM and Scheier, Z and Royse, TB and Calcagno, N and Clark, A and Iyer, A and Berry, JD and Onnela, JP}, title = {Upper limb movements as digital biomarkers in people with ALS.}, journal = {EBioMedicine}, volume = {101}, number = {}, pages = {105036}, pmid = {38432083}, issn = {2352-3964}, support = {U01 HL145386/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Upper Extremity ; Wrist ; Disease Progression ; Biomarkers ; }, abstract = {BACKGROUND: Objective evaluation of people with amyotrophic lateral sclerosis (PALS) in free-living settings is challenging. The introduction of portable digital devices, such as wearables and smartphones, may improve quantifying disease progression and hasten therapeutic development. However, there is a need for tools to characterize upper limb movements in neurologic disease and disability.

METHODS: Twenty PALS wore a wearable accelerometer, ActiGraph Insight Watch, on their wrist for six months. They also used Beiwe, a smartphone application that collected self-entry ALS Functional Rating Scale-Revised (ALSFRS-RSE) survey responses every 1-4 weeks. We developed several measures that quantify count and duration of upper limb movements: flexion, extension, supination, and pronation. New measures were compared against ALSFRS-RSE total score (Q1-12), and individual responses to specific questions related to handwriting (Q4), cutting food (Q5), dressing and performing hygiene (Q6), and turning in bed and adjusting bed clothes (Q7). Additional analysis considered adjusting for total activity counts (TAC).

FINDINGS: At baseline, PALS with higher Q1-12 performed more upper limb movements, and these movements were faster compared to individuals with more advanced disease. Most upper limb movement metrics had statistically significant change over time, indicating declining function either by decreasing count metrics or by increasing duration metric. All count and duration metrics were significantly associated with Q1-12, flexion and extension counts were significantly associated with Q6 and Q7, supination and pronation counts were also associated with Q4. All duration metrics were associated with Q6 and Q7. All duration metrics retained their statistical significance after adjusting for TAC.

INTERPRETATION: Wearable accelerometer data can be used to generate digital biomarkers on upper limb movements and facilitate patient monitoring in free-living environments. The presented method offers interpretable monitoring of patients' functioning and versatile tracking of disease progression in the limb of interest.

FUNDING: Mitsubishi-Tanabe Pharma Holdings America, Inc.}, } @article {pmid38433895, year = {2024}, author = {Lépine, S and Nauleau-Javaudin, A and Deneault, E and Chen, CX and Abdian, N and Franco-Flores, AK and Haghi, G and Castellanos-Montiel, MJ and Maussion, G and Chaineau, M and Durcan, TM}, title = {Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons.}, journal = {iScience}, volume = {27}, number = {3}, pages = {109166}, pmid = {38433895}, issn = {2589-0042}, abstract = {Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 is a pathological hallmark of the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS). Furthermore, while mutations in TARDBP (encoding TDP-43) have been associated with ALS, the pathogenic consequences of these mutations remain poorly understood. Using CRISPR-Cas9, we engineered two homozygous knock-in induced pluripotent stem cell lines carrying mutations in TARDBP encoding TDP-43[A382T] and TDP-43[G348C], two common yet understudied ALS TDP-43 variants. Motor neurons (MNs) differentiated from knock-in iPSCs had normal viability and displayed no significant changes in TDP-43 subcellular localization, phosphorylation, solubility, or aggregation compared with isogenic control MNs. However, our results highlight synaptic impairments in both TDP-43[A382T] and TDP-43[G348C] MN cultures, as reflected in synapse abnormalities and alterations in spontaneous neuronal activity. Collectively, our findings suggest that MN dysfunction may precede the occurrence of TDP-43 pathology and neurodegeneration in ALS and further implicate synaptic and excitability defects in the pathobiology of this disease.}, } @article {pmid38434715, year = {2024}, author = {Kumar, R and Blackband, J and Wagle Shukla, A}, title = {Rhythmic Jaw Movements in Amyotrophic Lateral Sclerosis: Is It Clonus or Tremor?.}, journal = {Tremor and other hyperkinetic movements (New York, N.Y.)}, volume = {14}, number = {}, pages = {8}, pmid = {38434715}, issn = {2160-8288}, mesh = {Humans ; Tremor/etiology ; *Essential Tremor/diagnosis ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis/complications ; Movement ; Reflex, Abnormal ; }, abstract = {BACKGROUND: Jaw clonus refers to involuntary, rhythmic jaw contractions induced by a hyperactive trigeminal nerve stretch reflex; however, the movements, when triggered without a stretch, can be confused with a tremor.

PHENOMENOLOGY SHOWN: This video demonstrates a patient with amyotrophic lateral sclerosis presenting with rapid rhythmic jaw movements seen at rest, alongside a power spectrum analysis revealing a narrow high-frequency peak of 10 Hz.

EDUCATIONAL VALUE: Rhythmic jaw movements are seen in many disorders such as Parkinson's disease, essential tremor, tardive syndromes, and cranial myorhythmias; however, a high-frequency movement, regardless of clonus or tremor, can indicate amyotrophic lateral sclerosis when accompanied by typical upper and lower motor neuron signs.

HIGHLIGHTS: The presented video abstract shows a patient with amyotrophic lateral sclerosis with rhythmic jaw movements seen at rest. A power spectrum analysis of the rhythmic movements revealed a 10 Hz peak, a frequency higher than those seen in patients with Parkinson's disease, essential tremor, myorhythmia, and tardive syndromes.}, } @article {pmid38435055, year = {2024}, author = {Peterson, IL and Thompson, AD and Scholpa, NE and Largent-Milnes, T and Schnellmann, RG}, title = {Isolation and monoculture of functional primary astrocytes from the adult mouse spinal cord.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1367473}, pmid = {38435055}, issn = {1662-4548}, support = {F32 DE022499/DE/NIDCR NIH HHS/United States ; T32 ES007091/ES/NIEHS NIH HHS/United States ; P30 ES006694/ES/NIEHS NIH HHS/United States ; IK2 BX005218/BX/BLRD VA/United States ; I01 BX004868/BX/BLRD VA/United States ; T32 HL007249/HL/NHLBI NIH HHS/United States ; R01 NS126752/NS/NINDS NIH HHS/United States ; }, abstract = {Astrocytes are a widely heterogenic cell population that play major roles in central nervous system (CNS) homeostasis and neurotransmission, as well as in various neuropathologies, including spinal cord injury (SCI), traumatic brain injury, and neurodegenerative diseases, such as amyotrophic lateral sclerosis. Spinal cord astrocytes have distinct differences from those in the brain and accurate modeling of disease states is necessary for understanding disease progression and developing therapeutic interventions. Several limitations to modeling spinal cord astrocytes in vitro exist, including lack of commercially available adult-derived cells, lack of purchasable astrocytes with different genotypes, as well as time-consuming and costly in-house primary cell isolations that often result in low yield due to small tissue volume. To address these issues, we developed an efficient adult mouse spinal cord astrocyte isolation method that utilizes enzymatic digestion, debris filtration, and multiple ACSA-2 magnetic microbead purification cycles to achieve an astrocyte monoculture purity of ≅93-98%, based on all markers assessed. Importantly, the isolated cells contain active mitochondria and express key astrocyte markers including ACSA-1, ACSA-2, EAAT2, and GFAP. Furthermore, this isolation method can be applied to the spinal cord of male and female mice, mice subjected to SCI, and genetically modified mice. We present a primary adult mouse spinal cord astrocyte isolation protocol focused on purity, viability, and length of isolation that can be applied to a multitude of models and aid in targeted research on spinal-cord related CNS processes and pathologies.}, } @article {pmid38435120, year = {2024}, author = {Duan, C and Kang, M and Pan, X and Gan, Z and Huang, V and Li, G and Place, RF and Li, LC}, title = {Intrathecal administration of a novel siRNA modality extends survival and improves motor function in the SOD1[G93A] ALS mouse model.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {1}, pages = {102147}, pmid = {38435120}, issn = {2162-2531}, abstract = {Antisense oligonucleotides (ASOs) were the first modality to pioneer targeted gene knockdown in the treatment of amyotrophic lateral sclerosis (ALS) caused by mutant superoxide dismutase 1 (SOD1). RNA interference (RNAi) is another mechanism of gene silencing in which short interfering RNAs (siRNAs) effectively degrade complementary transcripts. However, delivery to extrahepatic tissues like the CNS has been a bottleneck in the clinical development of RNAi. Herein, we identify potent siRNA duplexes for the knockdown of human SOD1 in which medicinal chemistry and conjugation to an accessory oligonucleotide (ACO) enable activity in CNS tissues. Local delivery via intracerebroventricular or intrathecal injection into SOD1[G93A] mice delayed disease progression and extended animal survival with superior efficacy compared with an ASO resembling tofersen in sequence and chemistry. Treatment also prevented disease-related declines in motor function, including improvements in animal mobility, muscle strength, and coordination. The ACO itself does not target any specific complementary nucleic acid sequence; rather, it imparts benefits conducive to bioavailability and delivery through its chemistry. The complete conjugate (i.e., siRNA-ACO) represents a novel modality for delivery of duplex RNA (e.g., siRNA) to the CNS that is currently being tested in the clinic for treatment of ALS.}, } @article {pmid38435594, year = {2024}, author = {Wei, J and Yan, H and Shao, X and Zhao, L and Han, L and Yan, P and Wang, S}, title = {A machine learning-based hybrid recommender framework for smart medical systems.}, journal = {PeerJ. Computer science}, volume = {10}, number = {}, pages = {e1880}, pmid = {38435594}, issn = {2376-5992}, abstract = {This article presents a hybrid recommender framework for smart medical systems by introducing two methods to improve service level evaluations and doctor recommendations for patients. The first method uses big data techniques and deep learning algorithms to develop a registration review system in medical institutions. This system outperforms conventional evaluation methods, thus achieving higher accuracy. The second method implements the term frequency and inverse document frequency (TF-IDF) algorithm to construct a model based on the patient's symptom vector space, incorporating score weighting, modified cosine similarity, and K-means clustering. Then, the alternating least squares (ALS) matrix decomposition and user collaborative filtering algorithm are applied to calculate patients' predicted scores for doctors and recommend top-performing doctors. Experimental results show significant improvements in metrics called precision and recall rates compared to conventional methods, making the proposed approach a practical solution for department triage and doctor recommendation in medical appointment platforms.}, } @article {pmid38441932, year = {2024}, author = {Gomathy, SB and Das, A and Srivastava, AK}, title = {Flail Leg Phenotype in Familial Amyotrophic Lateral Sclerosis: Think of a Cause With Something to Offer.}, journal = {Journal of clinical neuromuscular disease}, volume = {25}, number = {3}, pages = {144-145}, doi = {10.1097/CND.0000000000000471}, pmid = {38441932}, issn = {1537-1611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/genetics ; Leg ; }, } @article {pmid38441935, year = {2024}, author = {Finsterer, J}, title = {Whether Clenbuterol Is Beneficial in Sporadic ALS Can Only Be Answered Through Appropriately Designed Studies.}, journal = {Journal of clinical neuromuscular disease}, volume = {25}, number = {3}, pages = {150-151}, doi = {10.1097/CND.0000000000000475}, pmid = {38441935}, issn = {1537-1611}, mesh = {Humans ; *Clenbuterol/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; }, } @article {pmid38443479, year = {2024}, author = {Fyfe, I}, title = {α-Synuclein seeds in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {4}, pages = {203}, pmid = {38443479}, issn = {1759-4766}, mesh = {Humans ; *alpha-Synuclein ; *Amyotrophic Lateral Sclerosis ; }, } @article {pmid38443601, year = {2024}, author = {Spence, H and Waldron, FM and Saleeb, RS and Brown, AL and Rifai, OM and Gilodi, M and Read, F and Roberts, K and Milne, G and Wilkinson, D and O'Shaughnessy, J and Pastore, A and Fratta, P and Shneider, N and Tartaglia, GG and Zacco, E and Horrocks, MH and Gregory, JM}, title = {RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides with STMN-2 cryptic splicing and precedes clinical manifestation in ALS.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {50}, pmid = {38443601}, issn = {1432-0533}, support = {MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; R01 NS127186/NS/NINDS NIH HHS/United States ; R01NS127186/GF/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Aptamers, Nucleotide ; DNA-Binding Proteins/genetics ; RNA Splicing ; Antibodies ; }, abstract = {TDP-43 is an aggregation-prone protein which accumulates in the hallmark pathological inclusions of amyotrophic lateral sclerosis (ALS). However, the analysis of deeply phenotyped human post-mortem samples has shown that TDP-43 aggregation, revealed by standard antibody methods, correlates poorly with symptom manifestation. Recent identification of cryptic-splicing events, such as the detection of Stathmin-2 (STMN-2) cryptic exons, are providing evidence implicating TDP-43 loss-of-function as a potential driving pathomechanism but the temporal nature of TDP-43 loss and its relation to the disease process and clinical phenotype is not known. To address these outstanding questions, we used a novel RNA aptamer, TDP-43[APT], to detect TDP-43 pathology and used single molecule in situ hybridization to sensitively reveal TDP-43 loss-of-function and applied these in a deeply phenotyped human post-mortem tissue cohort. We demonstrate that TDP-43[APT] identifies pathological TDP-43, detecting aggregation events that cannot be detected by classical antibody stains. We show that nuclear TDP-43 pathology is an early event, occurring prior to cytoplasmic accumulation and is associated with loss-of-function measured by coincident STMN-2 cryptic splicing pathology. Crucially, we show that these pathological features of TDP-43 loss-of-function precede the clinical inflection point and are not required for region specific clinical manifestation. Furthermore, we demonstrate that gain-of-function in the form of extensive cytoplasmic accumulation, but not loss-of-function, is the primary molecular correlate of clinical manifestation. Taken together, our findings demonstrate implications for early diagnostics as the presence of STMN-2 cryptic exons and early TDP-43 aggregation events could be detected prior to symptom onset, holding promise for early intervention in ALS.}, } @article {pmid38443977, year = {2024}, author = {Duan, QQ and Wang, H and Su, WM and Gu, XJ and Shen, XF and Jiang, Z and Ren, YL and Cao, B and Li, GB and Wang, Y and Chen, YP}, title = {TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro.}, journal = {BMC medicine}, volume = {22}, number = {1}, pages = {96}, pmid = {38443977}, issn = {1741-7015}, support = {2022YFC2703101//the National Key Research and Development Program of China/ ; 2021YFS0051//Sichuan Province Science and Technology Support Program/ ; 2023YFS0269//Sichuan Province Science and Technology Support Program/ ; 81971188//the National Natural Science Fund of China/ ; 2022NSFSC0749//the National Natural Science Fund of Sichuan/ ; 2023HXFH032//the 1·3·5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Drug Repositioning ; Mendelian Randomization Analysis ; Protein Serine-Threonine Kinases/genetics ; *Aminopyridines ; }, abstract = {BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment.

METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models.

RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation.

CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.}, } @article {pmid38444607, year = {2024}, author = {Uozumi, R and Mori, K and Gotoh, S and Miyamoto, T and Kondo, S and Yamashita, T and Kawabe, Y and Tagami, S and Akamine, S and Ikeda, M}, title = {PABPC1 mediates degradation of C9orf72-FTLD/ALS GGGGCC repeat RNA.}, journal = {iScience}, volume = {27}, number = {3}, pages = {109303}, pmid = {38444607}, issn = {2589-0042}, abstract = {GGGGCC hexanucleotide repeat expansion in C9orf72 causes frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Expanded GGGGCC repeat RNA accumulates within RNA foci and is translated into toxic dipeptide repeat proteins; thus, efficient repeat RNA degradation may alleviate diseases. hnRNPA3, one of the repeat RNA-binding proteins, has been implicated in the destabilization of repeat RNA. Using APEX2-mediated proximity biotinylation, here, we demonstrate PABPC1, a cytoplasmic poly (A)-binding protein, interacts with hnRNPA3. Knockdown of PABPC1 increased the accumulation of repeat RNA and RNA foci to the same extent as the knockdown of hnRNPA3. Proximity ligation assays indicated PABPC1-hnRNPA3 and PABPC1-RNA exosomes, a complex that degrades repeat RNA, preferentially co-localized when repeat RNA was present. Our results suggest that PABPC1 functions as a mediator of polyadenylated GGGGCC repeat RNA degradation through interactions with hnRNPA3 and RNA exosome complex.}, } @article {pmid38445096, year = {2024}, author = {Shabber, SM and Sumesh, EP}, title = {AFM signal model for dysarthric speech classification using speech biomarkers.}, journal = {Frontiers in human neuroscience}, volume = {18}, number = {}, pages = {1346297}, pmid = {38445096}, issn = {1662-5161}, abstract = {Neurological disorders include various conditions affecting the brain, spinal cord, and nervous system which results in reduced performance in different organs and muscles throughout the human body. Dysarthia is a neurological disorder that significantly impairs an individual's ability to effectively communicate through speech. Individuals with dysarthria are characterized by muscle weakness that results in slow, slurred, and less intelligible speech production. An efficient identification of speech disorders at the beginning stages helps doctors suggest proper medications. The classification of dysarthric speech assumes a pivotal role as a diagnostic tool, enabling accurate differentiation between healthy speech patterns and those affected by dysarthria. Achieving a clear distinction between dysarthric speech and the speech of healthy individuals is made possible through the application of advanced machine learning techniques. In this work, we conducted feature extraction by utilizing the Amplitude and frequency modulated (AFM) signal model, resulting in the generation of a comprehensive array of unique features. A method involving Fourier-Bessel series expansion is employed to separate various components within a complex speech signal into distinct elements. Subsequently, the Discrete Energy Separation Algorithm is utilized to extract essential parameters, namely the Amplitude envelope and Instantaneous frequency, from each component within the speech signal. To ensure the robustness and applicability of our findings, we harnessed data from various sources, including TORGO, UA Speech, and Parkinson datasets. Furthermore, the classifier's performance was evaluated based on multiple measures such as the area under the curve, F1-Score, sensitivity, and accuracy, encompassing KNN, SVM, LDA, NB, and Boosted Tree. Our analyses resulted in classification accuracies ranging from 85 to 97.8% and the F1-score ranging between 0.90 and 0.97.}, } @article {pmid38445369, year = {2024}, author = {Nishimura, K and Sanchez-Molano, J and Kerr, N and Pressman, Y and Silvera, R and Khan, A and Gajavelli, S and Bramlett, HM and Dietrich, WD}, title = {Beneficial Effects of Human Schwann Cell-Derived Exosomes in Mitigating Secondary Damage After Penetrating Ballistic-Like Brain Injury.}, journal = {Journal of neurotrauma}, volume = {41}, number = {21-22}, pages = {2395-2412}, pmid = {38445369}, issn = {1557-9042}, support = {R37 NS133195/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Rats, Sprague-Dawley ; Male ; Rats ; *Exosomes/metabolism/transplantation ; Humans ; *Schwann Cells/metabolism ; *Head Injuries, Penetrating ; }, abstract = {There is a growing body of evidence that the delivery of cell-derived exosomes normally involved in intracellular communication can reduce secondary injury mechanisms after brain and spinal cord injury and improve outcomes. Exosomes are nanometer-sized vesicles that are released by Schwann cells and may have neuroprotective effects by reducing post-traumatic inflammatory processes as well as promoting tissue healing and functional recovery. The purpose of this study was to evaluate the beneficial effects of human Schwann-cell exosomes (hSC-Exos) in a severe model of penetrating ballistic-like brain injury (PBBI) in rats and investigate effects on multiple outcomes. Human Schwann cell processing protocols followed Current Good Manufacturing Practices (cGMP) with exosome extraction and purification steps approved by the Food and Drug Administration for an expanded access single ALS patient Investigational New Drug. Anesthetized male Sprague-Dawley rats (280-350g) underwent PBBI surgery or Sham procedures and, starting 30 min after injury, received either a dose of hSC-Exos or phosphate-buffered saline through the jugular vein. At 48h after PBBI, flow cytometry analysis of cortical tissue revealed that hSC-Exos administration reduced the number of activated microglia and levels of caspase-1, a marker of inflammasome activation. Neuropathological analysis at 21 days showed that hSC-Exos treatment after PBBI significantly reduced overall contusion volume and decreased the frequency of Iba-1 positive activated and amoeboid microglia by immunocytochemical analysis. This study revealed that the systemic administration of hSC-Exos is neuroprotective in a model of severe TBI and reduces secondary inflammatory injury mechanisms and histopathological damage. The administration of hSC-Exos represents a clinically relevant cell-based therapy to limit the detrimental effects of neurotrauma or other progressive neurological injuries by impacting multiple pathophysiological events and promoting neurological recovery.}, } @article {pmid38446760, year = {2024}, author = {Unni, S and Kommu, P and Aouti, S and Nalli, Y and Bharath, MMS and Ali, A and Padmanabhan, B}, title = {Structural insights into the modulation Of SOD1 aggregation By a fungal metabolite Phialomustin-B: Therapeutic potential in ALS.}, journal = {PloS one}, volume = {19}, number = {3}, pages = {e0298196}, pmid = {38446760}, issn = {1932-6203}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Cytoskeleton ; Muscular Atrophy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal human motor neuron disease leading to muscle atrophy and paralysis. Mutations in superoxide dismutase 1 (SOD1) are associated with familial ALS (fALS). The SOD1 mutants in ALS have a toxic-gain of function by destabilizing the functional SOD1 homodimer, consequently inducing fibril-like aggregation with a cytotoxic non-native trimer intermediate. Therefore, reducing SOD1 oligomerization via chemical modulators is an optimal therapy in ALS. Here, we report the discovery of Phialomustin-B, an unsaturated secondary metabolite from the endophytic fungus Phialophora mustea, as a modulator of SOD1 aggregation. The crystal structure of the SOD1-Phialomustin complex refined to 1.90 Å resolution demonstrated for the first time that the ligand binds to the dimer interface and the lateral region near the electrostatic loop. The aggregation analyses of SOD1WT and the disease mutant SOD1A4V revealed that Phialomustin-B reduces cytotoxic trimerization. We propose that Phialomustin-B is a potent lead molecule with therapeutic potential in fALS.}, } @article {pmid38447450, year = {2024}, author = {Malacarne, C and Giagnorio, E and Chirizzi, C and Cattaneo, M and Saraceno, F and Cavalcante, P and Bonanno, S and Mantegazza, R and Moreno-Manzano, V and Lauria, G and Metrangolo, P and Bombelli, FB and Marcuzzo, S}, title = {FM19G11-loaded nanoparticles modulate energetic status and production of reactive oxygen species in myoblasts from ALS mice.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {173}, number = {}, pages = {116380}, doi = {10.1016/j.biopha.2024.116380}, pmid = {38447450}, issn = {1950-6007}, mesh = {Mice ; Animals ; Superoxide Dismutase-1/metabolism ; Reactive Oxygen Species/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neurodegenerative Diseases/pathology ; Myoblasts/metabolism ; *Nanoparticles ; Atrophy/pathology ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase/metabolism ; *Benzamides ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Considerable evidence indicates that early skeletal muscle atrophy plays a crucial role in the disease pathogenesis, leading to an altered muscle-motor neuron crosstalk that, in turn, may contribute to motor neuron degeneration. Currently, there is no effective treatment for ALS, highlighting the need to dig deeper into the pathological mechanisms for developing innovative therapeutic strategies. FM19G11 is a novel drug able to modulate the global cellular metabolism, but its effects on ALS skeletal muscle atrophy and mitochondrial metabolism have never been evaluated, yet. This study investigated whether FM19G11-loaded nanoparticles (NPs) may affect the bioenergetic status in myoblasts isolated from G93A-SOD1 mice at different disease stages. We found that FM19G1-loaded NP treatment was able to increase transcriptional levels of Akt1, Akt3, Mef2a, Mef2c and Ucp2, which are key genes associated with cell proliferation (Akt1, Akt3), muscle differentiation (Mef2c), and mitochondrial activity (Ucp2), in G93A-SOD1 myoblasts. These cells also showed a significant reduction of mitochondrial area and networks, in addition to decreased ROS production after treatment with FM19G11-loaded NPs, suggesting a ROS clearance upon the amelioration of mitochondrial dynamics. Our overall findings demonstrate a significant impact of FM19G11-loaded NPs on muscle cell function and bioenergetic status in G93A-SOD1 myoblasts, thus promising to open new avenues towards possible adoption of FM19G11-based nanotherapies to slow muscle degeneration in the frame of ALS and muscle disorders.}, } @article {pmid38448302, year = {2024}, author = {Heskamp, L and Birkbeck, MG and Hall, J and Schofield, IS and Bashford, J and Williams, TL and De Oliveira, HM and Whittaker, RG and Blamire, AM}, title = {Whole-body fasciculation detection in amyotrophic lateral sclerosis using motor unit MRI.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {161}, number = {}, pages = {246-255}, doi = {10.1016/j.clinph.2024.02.016}, pmid = {38448302}, issn = {1872-8952}, support = {BASHFORD/JUN16/947-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/P000983/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; Middle Aged ; *Fasciculation/physiopathology/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Aged ; *Electromyography/methods ; Muscle, Skeletal/physiopathology/diagnostic imaging ; Adult ; Motor Neurons/physiology ; Tongue/physiopathology/diagnostic imaging ; }, abstract = {OBJECTIVE: Compare fasciculation rates between amyotrophic lateral sclerosis (ALS) patients and healthy controls in body regions relevant for diagnosing ALS using motor unit MRI (MUMRI) at baseline and 6 months follow-up, and relate this to single-channel surface EMG (SEMG).

METHODS: Tongue, biceps brachii, paraspinals and lower legs were assessed with MUMRI and biceps brachii and soleus with SEMG in 10 healthy controls and 10 patients (9 typical ALS, 1 primary lateral sclerosis [PLS]).

RESULTS: MUMRI-detected fasciculation rates in typical ALS patients were higher compared to healthy controls for biceps brachii (2.40 ± 1.90 cm[-3]min[-1]vs. 0.04 ± 0.10 cm[-3]min[-1], p = 0.004), paraspinals (1.14 ± 1.61 cm[-3]min[-1]vs. 0.02 ± 0.02 cm[-3]min[-1], p = 0.016) and lower legs (1.42 ± 1.27 cm[-3]min[-1]vs. 0.13 ± 0.10 cm[-3]min[-1], p = 0.004), but not tongue (1.41 ± 1.94 cm[-3]min[-1]vs. 0.18 ± 0.18 cm[-3]min[-1], p = 0.556). The PLS patient showed no fasciculation. At baseline, 6/9 ALS patients had increased fasciculation rates compared to healthy controls in at least 2 body regions. At follow-up every patient had increased fasciculation rates in at least 2 body regions. The MUMRI-detected fasciculation rate correlated with SEMG-detected fasciculation rates (τ = 0.475, p = 0.006).

CONCLUSION: MUMRI can non-invasively image fasciculation in multiple body regions and appears sensitive to disease progression in individual patients.

SIGNIFICANCE: MUMRI has potential as diagnostic tool for ALS.}, } @article {pmid38450645, year = {2024}, author = {Roychowdhury, S and Joshi, D and Singh, VK and Faruq, M and Das, P}, title = {Genetic and in silico analysis of Indian sporadic young onset patient with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {589-599}, doi = {10.1080/21678421.2024.2324896}, pmid = {38450645}, issn = {2167-9223}, mesh = {Humans ; Age of Onset ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/diagnosis ; *Computer Simulation ; Exome Sequencing ; India/epidemiology ; Mutation, Missense/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an old onset devastating neurodegenerative disorder. Young-onset ALS cases especially sporadic ones who are between 25 and 45 years are rarely affected by the disease. Despite the identification of numerous candidate genes associated with ALS, the etiology of the disease remains elusive due to extreme genetic and phenotypic variability. The advent of affordable whole exome sequencing (WES) has opened new avenues for unraveling the disease's pathophysiology better.

METHODS AND RESULTS: We aimed to determine the genetic basis of an Indian-origin, young onset sporadic ALS patient with very rapid deterioration of the disease course without any cognitive decline who was screened for mutations in major ALS candidate genes by WES. Variants detected were reconfirmed by Sanger sequencing. The clinicopathological features were investigated and two heterozygous missense variants were identified: R452W, not previously associated with ALS, present in one of the four conserved C terminal domains in ANXA11 and R208W in SIGMAR1, respectively. Both of these variants were predicted to be damaging by pathogenicity prediction tools and various in silico methods.

CONCLUSION: Our study revealed two potentially pathogenic variants in two ALS candidate genes. The genetic makeup of ALS patients from India has been the subject of a few prior studies, but none of them examined ANXA11 and SIGMAR1 genes so far. These results establish the framework for additional research into the pathogenic processes behind these variations that result in sporadic ALS disease and further our understanding of the genetic makeup of Indian ALS patients.}, } @article {pmid38451707, year = {2024}, author = {Clayton, EL and Huggon, L and Cousin, MA and Mizielinska, S}, title = {Synaptopathy: presynaptic convergence in frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {7}, pages = {2289-2307}, pmid = {38451707}, issn = {1460-2156}, support = {P2003//Epilepsy Research UK/ ; /ALZS_/Alzheimer's Society/United Kingdom ; //UK Dementia Research Institute/ ; //UK Medical Research Council/ ; 529508//Simons Foundation/ ; 204954/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; //Alzheimer's Research UK/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; *Frontotemporal Dementia/genetics/pathology/physiopathology ; *Synapses/pathology ; *Presynaptic Terminals/pathology/metabolism ; Animals ; Mutation ; }, abstract = {Frontotemporal dementia and amyotrophic lateral sclerosis are common forms of neurodegenerative disease that share overlapping genetics and pathologies. Crucially, no significantly disease-modifying treatments are available for either disease. Identifying the earliest changes that initiate neuronal dysfunction is important for designing effective intervention therapeutics. The genes mutated in genetic forms of frontotemporal dementia and amyotrophic lateral sclerosis have diverse cellular functions, and multiple disease mechanisms have been proposed for both. Identification of a convergent disease mechanism in frontotemporal dementia and amyotrophic lateral sclerosis would focus research for a targetable pathway, which could potentially effectively treat all forms of frontotemporal dementia and amyotrophic lateral sclerosis (both familial and sporadic). Synaptopathies are diseases resulting from physiological dysfunction of synapses, and define the earliest stages in multiple neuronal diseases, with synapse loss a key feature in dementia. At the presynapse, the process of synaptic vesicle recruitment, fusion and recycling is necessary for activity-dependent neurotransmitter release. The unique distal location of the presynaptic terminal means the tight spatio-temporal control of presynaptic homeostasis is dependent on efficient local protein translation and degradation. Recently, numerous publications have shown that mutations associated with frontotemporal dementia and amyotrophic lateral sclerosis present with synaptopathy characterized by presynaptic dysfunction. This review will describe the complex local signalling and membrane trafficking events that occur at the presynapse to facilitate neurotransmission and will summarize recent publications linking frontotemporal dementia/amyotrophic lateral sclerosis genetic mutations to presynaptic function. This evidence indicates that presynaptic synaptopathy is an early and convergent event in frontotemporal dementia and amyotrophic lateral sclerosis and illustrates the need for further research in this area, to identify potential therapeutic targets with the ability to impact this convergent pathomechanism.}, } @article {pmid38452377, year = {2024}, author = {Rajabi, D and Khanmohammadi, S and Rezaei, N}, title = {The role of long noncoding RNAs in amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {5}, pages = {533-547}, pmid = {38452377}, issn = {2191-0200}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *RNA, Long Noncoding/genetics/metabolism ; Animals ; RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a poor prognosis leading to death. The diagnosis and treatment of ALS are inherently challenging due to its complex pathomechanism. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides involved in different cellular processes, incisively gene expression. In recent years, more studies have been conducted on lncRNA classes and interference in different disease pathologies, showing their promising contribution to diagnosing and treating neurodegenerative diseases. In this review, we discussed the role of lncRNAs like NEAT1 and C9orf72-as in ALS pathogenesis mechanisms caused by mutations in different genes, including TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), superoxide dismutase type 1 (SOD1). NEAT1 is a well-established lncRNA in ALS pathogenesis; hence, we elaborate on its involvement in forming paraspeckles, stress response, inflammatory response, and apoptosis. Furthermore, antisense lncRNAs (as-lncRNAs), a key group of transcripts from the opposite strand of genes, including ZEB1-AS1 and ATXN2-AS, are discussed as newly identified components in the pathology of ALS. Ultimately, we review the current standing of using lncRNAs as biomarkers and therapeutic agents and the future vision of further studies on lncRNA applications.}, } @article {pmid38455726, year = {2024}, author = {Liu, L and Wu, L and Li, Z and Fang, Y and Ju, B and Zhang, S and Bai, L and Pan, L}, title = {The Pro-197-Thr mutation in the ALS gene confers novel resistance patterns to ALS-inhibiting herbicides in Bromus japonicus in China.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1348815}, pmid = {38455726}, issn = {1664-462X}, abstract = {INTRODUCTION: Bromus japonicus is one of the most notorious agricultural weeds in China. The long-term use of ALS-inhibiting herbicides has led to rapid evolution of herbicide resistance in B. japonicus. B. japonicus population (BJ-R) surviving mesosulfuron-methyl treatment was collected from wheatland. Here, we aimed to confirm the resistance mechanisms in this putative resistant population.

METHODS: The dose-reponse tests were used to test the resistance level of the B. japonicus to ALS-inhibiting herbicides. Pretreatment with P450 and GST inhibitors and GST activity assays were used to determine whether P450 or GST was involved in the resistance of the BJ-R population. Sanger sequencing was used to analyse the ALS mutation of the BJ-R population. RT-qPCR was used to confirm the the expression levels of the ALS gene in mesosulfuron-methyl -resistant (BJ-R) and-susceptible (BJ-S) B. japonicus. An in vitro ALS activity assay was used to determine the ALS activity of the BJ-R and BJ-S populations. Homology modelling and docking were used to determine the binding energy of the BJ-R and BJ-S populations with ALS-inhibiting herbicides.

RESULTS: B. japonicus population (BJ-R) was confirmed to be 454- and 2.7-fold resistant to the SU herbicides mesosulfuron-methyl and nicosulfuron, and 7.3-, 2.3-, 1.1- and 10.8-fold resistant to the IMI herbicide imazamox, the TP herbicide penoxsulam, the PTB herbicide pyribenzoxim and the SCT herbicide flucarbazone-sodium, respectively, compared with its susceptible counterpart (BJ-S). Neither a P450 inhibitor nor a GST inhibitor could reverse the level of resistance to mesosulfuron-methyl in BJ-R. In addition, no significant differences in GST activity were found between the BJ-R and BJ-S. ALS gene sequencing revealed a Pro-197-Thr mutation in BJ-R, and the gene expression had no significant differences between the BJ-R and BJ-S. The ALS activity of BJ-R was 106-fold more tolerant to mesosulfuron-methyl than that of BJ-S. Molecular docking showed that the binding energy of the ALS active site and mesosulfuron-methyl was changed from -6.67 to -4.57 kcal mol[-1] due to the mutation at position 197.

DISCUSSION: These results suggested that the Pro-197-Thr mutation was the main reason for the high resistance level of BJ-R to mesosulfuron-methyl. Unlike previous reports of the cross-resistance pattern conferred by this mutation, we firstly documented that the Pro-197-Thr mutation confers broad cross-resistance spectrums to ALS-inhibiting herbicides in B. japonicus.}, } @article {pmid38456112, year = {2024}, author = {Saidi, NA and Abdul Karim, NS and Ismail, A and Raja Othman, RNF and Kasah, NHA and Yaakub, A and Ngoo, QZ}, title = {Does the Difference in Axial Length Affect the Refractive Outcome?.}, journal = {The Malaysian journal of medical sciences : MJMS}, volume = {31}, number = {1}, pages = {71-75}, pmid = {38456112}, issn = {1394-195X}, abstract = {BACKGROUND: The purpose of this study is to compare axial length (AL) and the refractive outcome after phacoemulsification surgery from 2014 to 2019 at Hospital Sultanah Nur Zahirah, Terengganu, Malaysia.

METHOD: This was a retrospective record review of all cataract patients who met the inclusion criteria and underwent uneventful superior wound phacoemulsification with nontoric intraocular lens (IOL) by a single surgeon from 2014 to 2019. Using optical biometry or immersion technique, the preoperative AL determined solely via the Sanders, Retzlaff and Kraff 2 (SRK2) formula was selected. The postoperative spherical equivalent (SE) at 6 weeks-12 weeks was retrieved. Using Statistical Package for the Social Sciences version 24.0, the mean differences between targeted and actual postoperative SE were analysed based on the AL.

RESULT: In this study, 490 eyes of 472 patients aged 25 years old-88 years old (mean age 65.72 years old [SD 8.83]) were involved. There were 162 eyes (33%) in Group A (< 23 mm), 189 eyes (39%) in Group B (23.01 mm-24.0 mm) and 139 eyes (28%) in Group C (> 24.0 mm). The mean AL was 23.63 mm (SD 1.19). The mean differences between the targeted and actual postoperative SE were: -0.09 D (SD 0.60) in Group A, -0.07 D (SD 0.53) in Group B and -0.16 D (SD 0.52) in Group C. No significant difference was found between these groups (P = 0.327).

CONCLUSION: There was no significant difference in the refractive outcome using the SRK2 formula in different ALs after phacoemulsification surgery. Hence, there is no reason to modify or adjust the targeted SE based on AL.}, } @article {pmid38457337, year = {2024}, author = {Fiore, APZP and Maity, S and Jeffery, L and An, D and Rendleman, J and Iannitelli, D and Choi, H and Mazzoni, E and Vogel, C}, title = {Identification of molecular signatures defines the differential proteostasis response in induced spinal and cranial motor neurons.}, journal = {Cell reports}, volume = {43}, number = {3}, pages = {113885}, pmid = {38457337}, issn = {2211-1247}, support = {R01 GM113237/GM/NIGMS NIH HHS/United States ; R35 GM127089/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Proteostasis/physiology ; Proteome/metabolism ; Motor Neurons/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Stress ; }, abstract = {Amyotrophic lateral sclerosis damages proteostasis, affecting spinal and upper motor neurons earlier than a subset of cranial motor neurons. To aid disease understanding, we exposed induced cranial and spinal motor neurons (iCrMNs and iSpMNs) to proteotoxic stress, under which iCrMNs showed superior survival, quantifying the transcriptome and proteome for >8,200 genes at 0, 12, and 36 h. Two-thirds of the proteome showed cell-type differences. iSpMN-enriched proteins related to DNA/RNA metabolism, and iCrMN-enriched proteins acted in the endoplasmic reticulum (ER)/ER chaperone complex, tRNA aminoacylation, mitochondria, and the plasma/synaptic membrane, suggesting that iCrMNs expressed higher levels of proteins supporting proteostasis and neuronal function. When investigating the increased proteasome levels in iCrMNs, we showed that the activity of the 26S proteasome, but not of the 20S proteasome, was higher in iCrMNs than in iSpMNs, even after a stress-induced decrease. We identified Ublcp1 as an iCrMN-specific regulator of the nuclear 26S activity.}, } @article {pmid38457412, year = {2024}, author = {Nowicka, N and Zglejc-Waszak, K and Juranek, J and Korytko, A and Wąsowicz, K and Chmielewska-Krzesińska, M and Wojtkiewicz, J}, title = {Novel insights into RAGE signaling pathways during the progression of amyotrophic lateral sclerosis in RAGE-deficient SOD1 G93A mice.}, journal = {PloS one}, volume = {19}, number = {3}, pages = {e0299567}, pmid = {38457412}, issn = {1932-6203}, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Disease Models, Animal ; Disease Progression ; Mice, Transgenic ; *Neurodegenerative Diseases ; Prospective Studies ; Receptor for Advanced Glycation End Products/genetics ; Signal Transduction ; Superoxide Dismutase/genetics/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is neurodegenerative disease characterized by a progressive loss of motor neurons resulting in paralysis and muscle atrophy. One of the most prospective hypothesis on the ALS pathogenesis suggests that excessive inflammation and advanced glycation end-products (AGEs) accumulation play a crucial role in the development of ALS in patients and SOD1 G93A mice. Hence, we may speculate that RAGE, receptor for advanced glycation end-products and its proinflammatory ligands such as: HMGB1, S100B and CML contribute to ALS pathogenesis. The aim of our studies was to decipher the role of RAGE as well as provide insight into RAGE signaling pathways during the progression of ALS in SOD1 G93A and RAGE-deficient SOD1 G93A mice. In our study, we observed alternations in molecular pattern of proinflammatory RAGE ligands during progression of disease in RAGE KO SOD1 G93A mice compared to SOD1 G93A mice. Moreover, we observed that the amount of beta actin (ACTB) as well as Glial fibrillary acidic protein (GFAP) was elevated in SOD1 G93A mice when compared to mice with deletion of RAGE. These data contributes to our understanding of implications of RAGE and its ligands in pathogenesis of ALS and highlight potential targeted therapeutic interventions at the early stage of this devastating disease. Moreover, inhibition of the molecular cross-talk between RAGE and its proinflammatory ligands may abolish neuroinflammation, gliosis and motor neuron damage in SOD1 G93A mice. Hence, we hypothesize that attenuated interaction of RAGE with its proinflammatory ligands may improve well-being and health status during ALS in SOD1 G93A mice. Therefore, we emphasize that the inhibition of RAGE signaling pathway may be a therapeutic target for neurodegenerative diseases.}, } @article {pmid38457872, year = {2024}, author = {Chaghazardi, M and Kashanian, S and Nazari, M and Omidfar, K and Shariati-Rad, M and Joseph, Y and Rahimi, P}, title = {Mercury (II) sensing using a simple turn-on fluorescent graphene oxide based aptasensor in serum and water samples.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {313}, number = {}, pages = {124057}, doi = {10.1016/j.saa.2024.124057}, pmid = {38457872}, issn = {1873-3557}, mesh = {*Mercury ; Fluorescence Resonance Energy Transfer/methods ; Fluorometry/methods ; Water ; Limit of Detection ; Oligonucleotides ; *Graphite ; *Biosensing Techniques/methods ; *Aptamers, Nucleotide/metabolism ; }, abstract = {A simple, highly sensitive, and selective fluorometric aptasensing platform based on aptamer and graphene oxide (GO) is proposed for the determination of mercury (II) ion (Hg[2+]). In the designed assay, two aptamer probes, a carboxy-fluorescein (FAM) labeled aptamer (aptamer A) and its complementary (aptamer B) with partial complement containing several mismatches and GO as the quencher were used. In the absence of Hg[2+], both A and B aptamers were adsorbed on the surface of GO by π-π-stacking, leading to fluorescence quenching of FAM due to fluorescence resonance energy transfer (FRET). Upon exposure to Hg[2+], the A and B aptamer strands bind Hg[2+] and form T-Hg[2+]-T complexes, leading to the formation of a stable double-stranded aptamer. The double-stranded aptamer is detached from the GO surface, resulting in the recovery of FAM fluorescence. The fluorescence intensity (FI) of the developed sensor was correlated with the Hg[2+] concentration under optimized experimental conditions in two wide linear ranges, even in the presence of 10 divalent cations as interferences. The linear ranges were obtained from 200.0 to 900.0 fM and 5.0 to 33.0 pM, a limit of detection (LOD) of 106.0 fM, and a limit of quantification (LOQ) of 321.3 fM. The concentration of Hg[2+] was determined in five real samples containing three water and two serum samples, using spiking and standard addition methods and the results were compared with the spiked amounts and atomic absorption (AAS) as standard method respectively, with acceptable recoveries. Furthermore, in the standard addition method, to overcome the effects of matrix influence of real samples in quantitative predictions, the excitation-emission matrix (EEM) data for samples was simultaneously analyzed by multivariate curve resolution with alternating least squares (MCR-ALS) as a second-order standard addition method (SOSAM).}, } @article {pmid38458688, year = {2024}, author = {Xu, X and Zhao, B and Li, B and Shen, B and Qi, Z and Wang, J and Cui, H and Chen, S and Wang, G and Liu, X}, title = {Diverse ALS mutations and cross-and multiple-resistance to ALS and EPSPS inhibitors in flucarbazone‑sodium-resistant Bromus japonicus populations from Hebei province, China.}, journal = {Pesticide biochemistry and physiology}, volume = {199}, number = {}, pages = {105794}, doi = {10.1016/j.pestbp.2024.105794}, pmid = {38458688}, issn = {1095-9939}, mesh = {Bromus/metabolism ; *Herbicides/pharmacology ; Mutation ; China ; Herbicide Resistance/genetics ; *Acetolactate Synthase/metabolism ; *Sulfonamides ; *Triazoles ; }, abstract = {Japanese brome (Bromus japonicus) has become one of the main weeds in wheat fields in Hebei province of China and causes a large decrease of wheat production. A total of 44 putative resistant and 2 susceptible Japanese brome populations were collected in the 2021/2022 crop season from Hebei province of China to determine resistance levels to flucarbazone‑sodium and to investigate the diversity of acetolactate synthase (ALS) mutations, as well as to confirm the cross-and multiple-resistance levels to ALS and EPSPS (5-enolpyruvate shikimate-3-phosphate synthetase) inhibitors. Whole plant bioassay results showed that 15 out of 44 populations tested or 34% were resistant to flucarbazone‑sodium. The resistance indices of Japanese brome to flucarbazone‑sodium ranged from 43 to 1977. The resistant populations were mainly distributed in Baoding and Shijiazhuang districts, and there was only one resistant population in Langfang district. Resistant Japanese brome had diverse ALS mutations, including Pro-197-Ser, -Thr, -Arg and Asp-376-Glu. The incidence of Pro-197-Ser mutation was the highest at 68%. Application of the CYP450 inhibitor malathion suggested that CYP450 was involved in metabolic resistance in a population without an ALS mutation. The population with Pro-197-Thr mutation evolved weak cross-resistance to mesosulfuron-methyl and pyroxsulam, and it is in the process of evolving multiple-resistance to glyphosate.}, } @article {pmid38459455, year = {2024}, author = {Nandeep, ER and Mamidi, RS and Pagidoju, S and Pamidi, S and Mummadi, MK and Reddy G, VR and Babu, CK and Reddy N, S and Geddam, JB}, title = {Comparison of Janani Suraksha Yojana (JSY) and augmented Arogya Laxmi scheme (ALS) in improving maternal and child health outcomes in urban settlements of Hyderabad, South India.}, journal = {BMC pregnancy and childbirth}, volume = {24}, number = {1}, pages = {188}, pmid = {38459455}, issn = {1471-2393}, support = {Grant A/C No. 241//ICMR-ICSSR Joint Research Programme/ ; Grant A/C No. 241//ICMR-ICSSR Joint Research Programme/ ; }, mesh = {Infant, Newborn ; Child ; Pregnancy ; Female ; Humans ; *Maternal Health Services ; Cross-Sectional Studies ; Prenatal Care ; India/epidemiology ; Outcome Assessment, Health Care ; Delivery, Obstetric ; }, abstract = {BACKGROUND: India accounts for the largest number of global neonatal deaths with around 20 per 1000 live births. To improve the utilization of government services for institutional deliveries, Augmented Arogya Laxmi Scheme (ALS) was launched in Telangana state of southern India. This study assessed the effectiveness of the Janani Suraksha Yojana (JSY), which combines cash assistance with delivery and post-delivery care, in comparison to ALS in improving the outcomes related to antenatal, natal, and postnatal care in urban settlements of Hyderabad, Telangana, southern India.

METHODS: This was a two-year cross-sectional study conducted in 14 urban settlements of Hyderabad city from September 2017- August 2019. All mothers delivered during the 18 months preceding the survey were enrolled after a written informed consent. Field investigators collected data on variables related to socio-demographic characteristics, awareness, and utilization of JSY and ALS programs. Variables related to antenatal history, antenatal care, complications during birth, delivery outcomes, newborn care, and postnatal care till 28 days were assessed. We used multivariable logistic regression model to examine the association between the different maternal, child, and socio-demographic characteristics of the two study groups.

RESULTS: A total of 926 mothers were beneficiaries of Janani Suraksha Yojana (JSY) program while 933 mothers were beneficiaries of augmented Arogya Laxmi Scheme (ALS). Mothers in ALS group (AOR 1.71; 95% CI 1.21-2.43) were at increased odds of having more than eight antenatal care (ANC) visits compared to the mothers availing JSY. Mothers in ALS group were at decreased odds of having complications like severe pain in the abdomen (AOR 0.43; 95% CI 0.22-0.86), swelling of legs or feet (AOR 0.59; 95% CI 0.44-0.80) compared to mothers in JSY group. Children of mothers in the ALS group had increased odds of receiving breastfeeding within 30 minutes of birth (AOR 1.46; 95% CI 1.13-1.88) compared to children of mothers in JSY group.

CONCLUSIONS: The newly launched augmented ALS led to the increased utilization of the government health facilities and improved the maternal and child health outcomes.}, } @article {pmid38459794, year = {2024}, author = {Campagne, S}, title = {U1 snRNP Biogenesis Defects in Neurodegenerative Diseases.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {25}, number = {9}, pages = {e202300864}, doi = {10.1002/cbic.202300864}, pmid = {38459794}, issn = {1439-7633}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Ribonucleoprotein, U1 Small Nuclear/metabolism/chemistry ; }, abstract = {The U1 small ribonucleoprotein (U1 snRNP) plays a pivotal role in the intricate process of gene expression, specifically within nuclear RNA processing. By initiating the splicing reaction and modulating 3'-end processing, U1 snRNP exerts precise control over RNA metabolism and gene expression. This ribonucleoparticle is abundantly present, and its complex biogenesis necessitates shuttling between the nuclear and cytoplasmic compartments. Over the past three decades, extensive research has illuminated the crucial connection between disrupted U snRNP biogenesis and several prominent human diseases, notably various neurodegenerative conditions. The perturbation of U1 snRNP homeostasis has been firmly established in diseases such as Spinal Muscular Atrophy, Pontocerebellar hypoplasia, and FUS-mediated Amyotrophic Lateral Sclerosis. Intriguingly, compelling evidence suggests a potential correlation in Fronto-temporal dementia and Alzheimer's disease as well. Although the U snRNP biogenesis pathway is conserved across all eukaryotic cells, neurons, in particular, appear to be highly susceptible to alterations in spliceosome homeostasis. In contrast, other cell types exhibit a greater resilience to such disturbances. This vulnerability underscores the intricate relationship between U1 snRNP dynamics and the health of neuronal cells, shedding light on potential avenues for understanding and addressing neurodegenerative disorders.}, } @article {pmid38461154, year = {2024}, author = {Kodavati, M and Wang, H and Guo, W and Mitra, J and Hegde, PM and Provasek, V and Rao, VHM and Vedula, I and Zhang, A and Mitra, S and Tomkinson, AE and Hamilton, DJ and Van Den Bosch, L and Hegde, ML}, title = {FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {2156}, pmid = {38461154}, issn = {2041-1723}, support = {R01 NS094535/NS/NINDS NIH HHS/United States ; R01 ES012512/ES/NIEHS NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA, Mitochondrial/genetics ; Ligases/metabolism ; Mice, Transgenic ; *Mitochondrial Diseases ; *Motor Neuron Disease/genetics/metabolism ; Mutation ; *RNA-Binding Protein FUS/genetics/metabolism ; DNA Ligase ATP/genetics/metabolism ; }, abstract = {This study establishes the physiological role of Fused in Sarcoma (FUS) in mitochondrial DNA (mtDNA) repair and highlights its implications to the pathogenesis of FUS-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Endogenous FUS interacts with and recruits mtDNA Ligase IIIα (mtLig3) to DNA damage sites within mitochondria, a relationship essential for maintaining mtDNA repair and integrity in healthy cells. Using ALS patient-derived FUS mutant cell lines, a transgenic mouse model, and human autopsy samples, we discovered that compromised FUS functionality hinders mtLig3's repair role, resulting in increased mtDNA damage and mutations. These alterations cause various manifestations of mitochondrial dysfunction, particularly under stress conditions relevant to disease pathology. Importantly, rectifying FUS mutations in patient-derived induced pluripotent cells (iPSCs) preserves mtDNA integrity. Similarly, targeted introduction of human DNA Ligase 1 restores repair mechanisms and mitochondrial activity in FUS mutant cells, suggesting a potential therapeutic approach. Our findings unveil FUS's critical role in mitochondrial health and mtDNA repair, offering valuable insights into the mechanisms underlying mitochondrial dysfunction in FUS-associated motor neuron disease.}, } @article {pmid38461753, year = {2024}, author = {Eceiza, MV and Jimenez-Martinez, C and Gil-Monreal, M and Barco-Antoñanzas, M and Font-Farre, M and Huybrechts, M and van der Hoorn, RL and Cuypers, A and Royuela, M and Zabalza, A}, title = {Role of glutathione S-transferases in the mode of action of herbicides that inhibit amino acid synthesis in Amaranthus palmeri.}, journal = {Plant physiology and biochemistry : PPB}, volume = {208}, number = {}, pages = {108506}, doi = {10.1016/j.plaphy.2024.108506}, pmid = {38461753}, issn = {1873-2690}, mesh = {*Herbicides/pharmacology/metabolism ; *Amaranthus ; Hydrogen Peroxide/metabolism ; Herbicide Resistance ; Glyphosate ; Glutathione/metabolism ; Transferases/metabolism ; }, abstract = {Acetolactate synthase inhibitors (ALS inhibitors) and glyphosate are two classes of herbicides that act by inhibiting an enzyme in the biosynthetic pathway of branched-chain or aromatic amino acids, respectively. Besides amino acid synthesis inhibition, both herbicides trigger similar physiological effects in plants. The main aim of this study was to evaluate the role of glutathione metabolism, with special emphasis on glutathione S-transferases (GSTs), in the mode of action of glyphosate and ALS inhibitors in Amaranthus palmeri. For that purpose, plants belonging to a glyphosate-sensitive (GLS) and a glyphosate-resistant (GLR) population were treated with different doses of glyphosate, and plants belonging to an ALS-inhibitor sensitive (AIS) and an ALS-inhibitor resistant (AIR) population were treated with different doses of the ALS inhibitor nicosulfuron. Glutathione-related contents, GST activity, and related gene expressions (glutamate-cysteine ligase, glutathione reductase, Phi GST and Tau GST) were analysed in leaves. According to the results of the analytical determinations, there were virtually no basal differences between GLS and GLR plants or between AIS and AIR plants. Glutathione synthesis and turnover did not follow a clear pattern in response to herbicides, but GST activity and gene expression (especially Phi GSTs) increased with both herbicides in treated sensitive plants, possibly related to the rocketing H2O2 accumulation. As GSTs offered the clearest results, these were further investigated with a multiple resistant (MR) population, compressing target-site resistance to both glyphosate and the ALS inhibitor pyrithiobac. As in single-resistant plants, measured parameters in the MR population were unaffected by herbicides, meaning that the increase in GST activity and expression occurs due to herbicide interactions with the target enzymes.}, } @article {pmid38461796, year = {2024}, author = {Saranya, KR and Vimina, ER and Pinto, FR}, title = {TransNeT-CGP: A cluster-based comorbid gene prioritization by integrating transcriptomics and network-topological features.}, journal = {Computational biology and chemistry}, volume = {110}, number = {}, pages = {108038}, doi = {10.1016/j.compbiolchem.2024.108038}, pmid = {38461796}, issn = {1476-928X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Protein Interaction Maps/genetics ; Cluster Analysis ; Transcriptome/genetics ; Algorithms ; Gene Regulatory Networks ; Female ; Computational Biology ; Comorbidity ; Muscular Atrophy, Spinal/genetics ; Ovarian Neoplasms/genetics ; }, abstract = {The local disruptions caused by the genes of one disease can influence the pathways associated with the other diseases resulting in comorbidity. For gene therapies, it is necessary to prioritize the key genes that regulate common biological mechanisms to tackle the issues caused by overlapping diseases. This work proposes a clustering-based computational approach for prioritising the comorbid genes within the overlapping disease modules by analyzing Protein-Protein Interaction networks. For this, a sub-network with gene interactions of the disease pair was extracted from the interactome. The edge weights are assigned by combining the pairwise gene expression correlation and betweenness centrality scores. Further, a weighted graph clustering algorithm is applied and dominant nodes of high-density clusters are ranked based on clustering coefficients and neighborhood connectivity. Case studies based on neurodegenerative diseases such as Amyotrophic Lateral Sclerosis- Spinal Muscular Atrophy (ALS-SMA) pair and cancers such as Ovarian Carcinoma-Invasive Ductal Breast Carcinoma (OC-IDBC) pair were conducted to examine the efficacy of the proposed method. To identify the mechanistic role of top-ranked genes, we used Functional and Pathway enrichment analysis, connectivity analysis with leave-one-out (LOO) method, analysis of associated disease-related protein complexes, and prioritization tools such as TOPPGENE and Heml2.0. From pathway analysis, it was observed that the top 10 genes obtained using the proposed method were associated with 10 pathways in ALS-SMA comorbidity and 15 in the case of OC-IDBC, while that in similar methods like SAPDSB and S2B were 4, 6 respectively for ALS-SMA and 9, 10 respectively for OC-IDBC. In both case studies, 70 % of the disease-specific benchmark protein complexes were linked to top-ranked genes of the proposed method while that of SAPDSB and S2B were 55 % and 60 % respectively. Additionally, it was found that the removal of the top 10 genes disconnect the network into 14 distinct components in the case of ALS-SMA and 9 in the case of OC-IDBC. The experimental results shows that the proposed method can be effectively used for identifying key genes in comorbidity and can offer insights about the intricate molecular relationship driving comorbid diseases.}, } @article {pmid38462589, year = {2024}, author = {Ding, F and Sun, Q and Long, C and Rasmussen, RN and Peng, S and Xu, Q and Kang, N and Song, W and Weikop, P and Goldman, SA and Nedergaard, M}, title = {Dysregulation of extracellular potassium distinguishes healthy ageing from neurodegeneration.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {5}, pages = {1726-1739}, pmid = {38462589}, issn = {1460-2156}, support = {U19 NS128613/NS/NINDS NIH HHS/United States ; R01AT012312/NH/NIH HHS/United States ; R01 NS110776/NS/NINDS NIH HHS/United States ; R01 AT011439/AT/NCCIH NIH HHS/United States ; R01 AT012312/AT/NCCIH NIH HHS/United States ; R01 HL122578/HL/NHLBI NIH HHS/United States ; R01 AG072298/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Potassium/metabolism ; *Aging/metabolism ; Mice ; *Neurodegenerative Diseases/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Alzheimer Disease/metabolism/genetics ; Mice, Transgenic ; Potassium Channels, Inwardly Rectifying/metabolism/genetics ; Male ; Mice, Inbred C57BL ; Neurons/metabolism ; Humans ; Disease Models, Animal ; Cerebral Cortex/metabolism ; Huntington Disease/metabolism/genetics ; Female ; Astrocytes/metabolism ; Kcnj10 Channel ; }, abstract = {Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal ageing. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis is a potential mediator of neuronal injury as K+ elevations increase excitatory activity. The dysregulation of extracellular K+ and potassium channel expressions during neurodegeneration could contribute to this distinction. Here we measured the cortical extracellular K+ concentration ([K+]e) in awake wild-type mice as well as murine models of neurodegeneration using K+-sensitive microelectrodes. Unexpectedly, aged wild-type mice exhibited significantly lower cortical [K+]e than young mice. In contrast, cortical [K+]e was consistently elevated in Alzheimer's disease (APP/PS1), amyotrophic lateral sclerosis (ALS) (SOD1G93A) and Huntington's disease (R6/2) models. Cortical resting [K+]e correlated inversely with neuronal density and the [K+]e buffering rate but correlated positively with the predicted neuronal firing rate. Screening of astrocyte-selective genomic datasets revealed a number of potassium channel genes that were downregulated in these disease models but not in normal ageing. In particular, the inwardly rectifying potassium channel Kcnj10 was downregulated in ALS and Huntington's disease models but not in normal ageing, while Fxyd1 and Slc1a3, each of which acts as a negative regulator of potassium uptake, were each upregulated by astrocytes in both Alzheimer's disease and ALS models. Chronic elevation of [K+]e in response to changes in gene expression and the attendant neuronal hyperexcitability may drive the neuronal loss characteristic of these neurodegenerative diseases. These observations suggest that the dysregulation of extracellular K+ homeostasis in a number of neurodegenerative diseases could be due to aberrant astrocytic K+ buffering and as such, highlight a fundamental role for glial dysfunction in neurodegeneration.}, } @article {pmid38463392, year = {2024}, author = {Chen, Y and Mateski, J and Gerace, L and Wheeler, J and Burl, J and Prakash, B and Svedin, C and Amrick, R and Adams, BD}, title = {Non-coding RNAs and neuroinflammation: implications for neurological disorders.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {249}, number = {}, pages = {10120}, pmid = {38463392}, issn = {1535-3699}, mesh = {Humans ; Neuroinflammatory Diseases ; *Nervous System Diseases/genetics ; Microglia/metabolism ; *MicroRNAs/genetics/metabolism ; Cytokines/metabolism ; Chemokines/metabolism ; }, abstract = {Neuroinflammation is considered a balanced inflammatory response important in the intrinsic repair process after injury or infection. Under chronic states of disease, injury, or infection, persistent neuroinflammation results in a heightened presence of cytokines, chemokines, and reactive oxygen species that result in tissue damage. In the CNS, the surrounding microglia normally contain macrophages and other innate immune cells that perform active immune surveillance. The resulting cytokines produced by these macrophages affect the growth, development, and responsiveness of the microglia present in both white and gray matter regions of the CNS. Controlling the levels of these cytokines ultimately improves neurocognitive function and results in the repair of lesions associated with neurologic disease. MicroRNAs (miRNAs) are master regulators of the genome and subsequently control the activity of inflammatory responses crucial in sustaining a robust and acute immunological response towards an acute infection while dampening pathways that result in heightened levels of cytokines and chemokines associated with chronic neuroinflammation. Numerous reports have directly implicated miRNAs in controlling the abundance and activity of interleukins, TGF-B, NF-kB, and toll-like receptor-signaling intrinsically linked with the development of neurological disorders such as Parkinson's, ALS, epilepsy, Alzheimer's, and neuromuscular degeneration. This review is focused on discussing the role miRNAs play in regulating or initiating these chronic neurological states, many of which maintain the level and/or activity of neuron-specific secondary messengers. Dysregulated miRNAs present in the microglia, astrocytes, oligodendrocytes, and epididymal cells, contribute to an overall glial-specific inflammatory niche that impacts the activity of neuronal conductivity, signaling action potentials, neurotransmitter robustness, neuron-neuron specific communication, and neuron-muscular connections. Understanding which miRNAs regulate microglial activation is a crucial step forward in developing non-coding RNA-based therapeutics to treat and potentially correct the behavioral and cognitive deficits typically found in patients suffering from chronic neuroinflammation.}, } @article {pmid38463699, year = {2024}, author = {Van Schoor, E and Strubbe, D and Braems, E and Weishaupt, J and Ludolph, AC and Van Damme, P and Thal, DR and Bercier, V and Van Den Bosch, L}, title = {TUBA4A downregulation as observed in ALS post-mortem motor cortex causes ALS-related abnormalities in zebrafish.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1340240}, pmid = {38463699}, issn = {1662-5102}, abstract = {Disease-associated variants of TUBA4A (alpha-tubulin 4A) have recently been identified in familial ALS. Interestingly, a downregulation of TUBA4A protein expression was observed in familial as well as sporadic ALS brain tissue. To investigate whether a decreased TUBA4A expression could be a driving factor in ALS pathogenesis, we assessed whether TUBA4A knockdown in zebrafish could recapitulate an ALS-like phenotype. For this, we injected an antisense oligonucleotide morpholino in zebrafish embryos targeting the zebrafish TUBA4A orthologue. An antibody against synaptic vesicle 2 was used to visualize motor axons in the spinal cord, allowing the analysis of embryonic ventral root projections. Motor behavior was assessed using the touch-evoked escape response. In post-mortem ALS motor cortex, we observed reduced TUBA4A levels. The knockdown of the zebrafish TUBA4A orthologue induced a motor axonopathy and a significantly disturbed motor behavior. Both phenotypes were dose-dependent and could be rescued by the addition of human wild-type TUBA4A mRNA. Thus, TUBA4A downregulation as observed in ALS post-mortem motor cortex could be modeled in zebrafish and induced a motor axonopathy and motor behavior defects reflecting a motor neuron disease phenotype, as previously described in embryonic zebrafish models of ALS. The rescue with human wild-type TUBA4A mRNA suggests functional conservation and strengthens the causal relation between TUBA4A protein levels and phenotype severity. Furthermore, the loss of TUBA4A induces significant changes in post-translational modifications of tubulin, such as acetylation, detyrosination and polyglutamylation. Our data unveil an important role for TUBA4A in ALS pathogenesis, and extend the relevance of TUBA4A to the majority of ALS patients, in addition to cases bearing TUBA4A mutations.}, } @article {pmid38464028, year = {2024}, author = {Silvestri, B and Mochi, M and Mawrie, D and de Turris, V and Colantoni, A and Borhy, B and Medici, M and Anderson, EN and Garone, MG and Zammerilla, CP and Pandey, UB and Rosa, A}, title = {HuD (ELAVL4) gain-of-function impairs neuromuscular junctions and induces apoptosis in in vitro and in vivo models of amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38464028}, issn = {2692-8205}, support = {R01 NS081303/NS/NINDS NIH HHS/United States ; }, abstract = {Early defects at the neuromuscular junction (NMJ) are among the first hallmarks of the progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS). According to the "dying back" hypothesis, disruption of the NMJ not only precedes, but is also a trigger for the subsequent degeneration of the motoneuron in both sporadic and familial ALS, including ALS caused by the severe FUS pathogenic variant P525L. However, the mechanisms linking genetic and environmental factors to NMJ defects remain elusive. By taking advantage of co-cultures of motoneurons and skeletal muscle derived from human induced pluripotent stem cells (iPSCs), we show that the neural RNA binding protein HuD (ELAVL4) may underlie NMJ defects and apoptosis in FUS-ALS. HuD overexpression in motoneurons phenocopies the severe FUS[P525L] mutation, while HuD knockdown in FUS[P525L] co-cultures produces phenotypic rescue. We validated these findings in vivo in a Drosophila FUS-ALS model. Neuronal-restricted overexpression of the HuD-related gene, elav, produces per se a motor phenotype, while neuronal-restricted elav knockdown significantly rescues motor dysfunction caused by FUS. Finally, we show that HuD levels increase upon oxidative stress in human motoneurons and in sporadic ALS patients with an oxidative stress signature. On these bases, we propose HuD as an important player downstream of FUS mutation in familial ALS, with potential implications for sporadic ALS related to oxidative stress.}, } @article {pmid38464104, year = {2025}, author = {Das, T and Zaidi, FK and Farag, M and Ruff, KM and Mahendran, TS and Singh, A and Gui, X and Messing, J and Paul Taylor, J and Banerjee, PR and Pappu, RV and Mittag, T}, title = {Tunable metastability of condensates reconciles their dual roles in amyloid fibril formation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38464104}, issn = {2692-8205}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; R01 NS121114/NS/NINDS NIH HHS/United States ; R35 GM138186/GM/NIGMS NIH HHS/United States ; R35 NS097974/NS/NINDS NIH HHS/United States ; }, abstract = {Stress granules form via co-condensation of RNA-binding proteins containing prion-like low complexity domains (PLCDs) with RNA molecules. Homotypic interactions among PLCDs can drive amyloid fibril formation that is enhanced by ALS-associated mutations. We report that condensation- versus fibril-driving homotypic interactions are separable for A1-LCD, the PLCD of hnRNPA1. Separable interactions lead to thermodynamically metastable condensates and globally stable fibrils. Interiors of condensates suppress fibril formation whereas interfaces have the opposite effect. ALS-associated mutations enhance the stability of fibrils and weaken condensate metastability, thus enhancing the rate of fibril formation. We designed mutations to enhance A1-LCD condensate metastability and discovered that stress granule disassembly in cells can be restored even when the designed variants carry ALS-causing mutations. Therefore, fibril formation can be suppressed by condensate interiors that function as sinks. Condensate sink potentials are influenced by their metastability, which is tunable through separable interactions even among minority components of stress granules.}, } @article {pmid38464233, year = {2024}, author = {Jang, DG and Dou, J and Koubek, EJ and Teener, S and Zhao, L and Bakulski, KM and Mukherjee, B and Batterman, SA and Feldman, EL and Goutman, SA}, title = {Metal mixtures associate with higher amyotrophic lateral sclerosis risk and mortality independent of genetic risk and correlate to self-reported exposures: a case-control study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38464233}, support = {R01TS000344/ACL/ACL HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, abstract = {BACKGROUND: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival, and exposure sources.

METHODS: Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. Odds and hazard ratios for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected SNPs.

RESULTS: Plasma and urine samples from 454 ALS and 294 control participants were analyzed. Elevated levels of individual metals, including copper, selenium, and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62, p<0.001; urine, OR=3.10, CI=2.43-3.97, p<0.001) and poorer ALS survival (plasma, HR=1.42, CI=1.24-1.63, p<0.001; urine, HR=1.52, CI=1.31-1.76, p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures associated with measured plasma and urine metals.

CONCLUSION: Metals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression.}, } @article {pmid38464738, year = {2023}, author = {Kekenadze, M and Rocca, C and Turchetti, V and Nagy, S and Kvirkvelia, N and Vashadze, S and Kvaratskhelia, E and Beridze, M and Kaiyrzhanov, R and Houlden, H}, title = {Analysis of C9orf72 repeat expansions in Georgian patients with Amyotrophic lateral sclerosis (ALS).}, journal = {F1000Research}, volume = {12}, number = {}, pages = {1113}, pmid = {38464738}, issn = {2046-1402}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; Middle Aged ; *DNA Repeat Expansion/genetics ; Aged ; Male ; Female ; Adult ; Aged, 80 and over ; Georgia (Republic) ; *Proteins/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder that affects the upper and lower motor neurons. Several genetic risk factors have been identified in the past decade with a hexanucleotide repeat expansion in the C9orf72 gene being the most significant. However, the presence of C9orf72 repeat expansion has not been examined in the Transcaucasian region, therefore we aimed to analyse its frequency in Georgian patients with ALS.

METHODS: We included 64 self-reported Georgian patients with ALS from different parts of the country, fulfilling the Gold Coast criteria. To investigate the presence of an expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9orf72 gene, we performed Repeat-Primed PCR (RP-PCR).

RESULTS: In total, 62 sporadic and two familial ALS cases were identified. Patients were aged 26 to 84 years with a mean age of 58.3 years at disease onset. Bulbar onset was observed in 21.88%, upper limb onset in 34.38%, and lower limb onset in 43.75% of the patients. Frontotemporal dementia (FTD) fulfilling the Strong criteria was diagnosed in seven patients (10.94%). C9orf72 repeat expansion was detected in only one case using RP-PCR; the patient had a family history of dementia.

CONCLUSIONS: Our results indicate that C9orf72 hexanucleotide expansion does not belong to the major genetic risk factor of ALS in Georgian patients. Further genetic studies in a bigger study population are needed to reveal the genetic causes of ALS in the Transcaucasian population.}, } @article {pmid38465478, year = {2024}, author = {Wendebourg, MJ and Weigel, M and Weidensteiner, C and Sander, L and Kesenheimer, E and Naumann, N and Haas, T and Madoerin, P and Braun, N and Neuwirth, C and Weber, M and Jahn, K and Kappos, L and Granziera, C and Schweikert, K and Sinnreich, M and Bieri, O and Schlaeger, R}, title = {Cervical and thoracic spinal cord gray matter atrophy is associated with disability in patients with amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {6}, pages = {e16268}, pmid = {38465478}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/physiopathology/complications ; Female ; Middle Aged ; Male ; *Gray Matter/diagnostic imaging/pathology ; Aged ; *Magnetic Resonance Imaging ; *Atrophy/pathology ; Cervical Cord/diagnostic imaging/pathology ; Thoracic Vertebrae/diagnostic imaging ; Spinal Cord/diagnostic imaging/pathology ; Cervical Vertebrae/diagnostic imaging ; White Matter/diagnostic imaging/pathology ; }, abstract = {BACKGROUND AND PURPOSE: In amyotrophic lateral sclerosis (ALS), there is an unmet need for more precise patient characterization through quantitative, ideally operator-independent, assessments of disease extent and severity. Radially sampled averaged magnetization inversion recovery acquisitions (rAMIRA) magnetic resonance imaging enables gray matter (GM) and white matter (WM) area quantitation in the cervical and thoracic spinal cord (SC) with optimized contrast. We aimed to investigate rAMIRA-derived SC GM and SC WM areas and their association with clinical phenotype and disability in ALS.

METHODS: A total of 36 patients with ALS (mean [SD] age 61.7 [12.6] years, 14 women) and 36 healthy, age- and sex-matched controls (HCs; mean [SD] age 63.1 [12.1] years, 14 women) underwent two-dimensional axial rAMIRA imaging at the inter-vertebral disc levels C2/3-C5/C6 and the lumbar enlargement level Tmax. ALS Functional Rating Scale-revised (ALSFRS-R) score, muscle strength, and sniff nasal inspiratory pressure (SNIP) were assessed.

RESULTS: Compared to HCs, GM and WM areas were reduced in patients at all cervical levels (p < 0.0001). GM area (p = 0.0001), but not WM area, was reduced at Tmax. Patients with King's Stage 3 showed significant GM atrophy at all levels, while patients with King's Stage 1 showed significant GM atrophy selectively at Tmax. SC GM area was significantly associated with muscle force at corresponding myotomes. GM area at C3/C4 was associated with ALSFRS-R (p < 0.001) and SNIP (p = 0.0016).

CONCLUSION: Patients with ALS assessed by rAMIRA imaging show significant cervical and thoracic SC GM and SC WM atrophy. SC GM area correlates with muscle strength and clinical disability. GM area reduction at Tmax may be an early disease sign. Longitudinal studies are warranted.}, } @article {pmid38465877, year = {2024}, author = {Young, CA and Chaouch, A and Mcdermott, CJ and Al-Chalabi, A and Chhetri, SK and Talbot, K and Harrower, T and Orrell, RW and Annadale, J and Hanemann, CO and Scalfari, A and Tennant, A and Mills, R and , }, title = {Dyspnea (breathlessness) in amyotrophic lateral sclerosis/motor neuron disease: prevalence, progression, severity, and correlates.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {475-485}, pmid = {38465877}, issn = {2167-9223}, mesh = {Humans ; *Dyspnea/physiopathology/diagnosis/epidemiology/etiology ; Male ; Female ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/physiopathology/complications ; Middle Aged ; Aged ; *Disease Progression ; Prevalence ; *Severity of Illness Index ; Motor Neuron Disease/epidemiology/physiopathology/diagnosis/complications ; Quality of Life ; Adult ; }, abstract = {OBJECTIVE: Dyspnea, or breathlessness, is an important symptom in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). We examined the measurement properties of the Dyspnea-12.

METHODS: Rasch analysis enabled conversion of raw Dyspnea-12 scores to interval level metric equivalents. Converted data were used to perform trajectory modeling; those following different trajectories were compared for demographic, clinical, symptom, and functioning characteristics. Logistic regression examined differences between distinct trajectories.

RESULTS: In 1022 people, at baseline, mean metric Dyspnea-12 was 7.6 (SD 9.3). 49.8% had dyspnea, severe in 12.6%. Trajectory analysis over 28 months revealed three breathlessness trajectories: group 1 reported none at baseline/follow-up (42.7%); group 2 significantly increased over time (9.4%); group 3 had a much higher level at baseline which rose over follow-up (47.9%). Group 3 had worse outcomes on all symptoms, functioning and quality of life; compared to group 1, their odds of: respiratory onset sixfold greater; King's stage ≥3 2.9 greater; increased odds of being bothered by choking, head drop, fasciculations, and muscle cramps; fatigue and anxiety also elevated (p < .01).

CONCLUSION: Dyspnea is a cardinal symptom in ALS/MND and can be quickly measured using the Dyspnea-12. Raw scores can easily be converted to interval level measurement, for valid change scores and trajectory modeling. Dyspnea trajectories reveal different patterns, showing that clinical services must provide monitoring which is customized to individual patient need. Almost half of this large population had worsening dyspnea, confirming the importance of respiratory monitoring and interventions being integrated into routine ALS care.}, } @article {pmid38466738, year = {2024}, author = {Pelletier, C and Shaw, S and Alsayegh, S and Brown, AJP and Lorenz, A}, title = {Candida auris undergoes adhesin-dependent and -independent cellular aggregation.}, journal = {PLoS pathogens}, volume = {20}, number = {3}, pages = {e1012076}, pmid = {38466738}, issn = {1553-7374}, support = {MR/M026663/1/MRC_/Medical Research Council/United Kingdom ; MR/M026663/2/MRC_/Medical Research Council/United Kingdom ; MR/V033417/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Antifungal Agents/therapeutic use ; *Candida/genetics ; Candida auris ; Virulence ; Drug Resistance, Fungal ; Adhesins, Bacterial/metabolism ; Microbial Sensitivity Tests ; }, abstract = {Candida auris is a fungal pathogen of humans responsible for nosocomial infections with high mortality rates. High levels of resistance to antifungal drugs and environmental persistence mean these infections are difficult to treat and eradicate from a healthcare setting. Understanding the life cycle and the genetics of this fungus underpinning clinically relevant traits, such as antifungal resistance and virulence, is of the utmost importance to develop novel treatments and therapies. Epidemiological and genomic studies have identified five geographical clades (I-V), which display phenotypic and genomic differences. Aggregation of cells, a phenotype primarily of clade III strains, has been linked to reduced virulence in some infection models. The aggregation phenotype has thus been associated with conferring an advantage for (skin) colonisation rather than for systemic infection. However, strains with different clade affiliations were compared to infer the effects of different morphologies on virulence. This makes it difficult to distinguish morphology-dependent causes from clade-specific or even strain-specific genetic factors. Here, we identify two different types of aggregation: one induced by antifungal treatment which is a result of a cell separation defect; and a second which is controlled by growth conditions and only occurs in strains with the ability to aggregate. The latter aggregation type depends on an ALS-family adhesin which is differentially expressed during aggregation in an aggregative C. auris strain. Finally, we demonstrate that macrophages cannot clear aggregates, suggesting that aggregation might after all provide a benefit during systemic infection and could facilitate long-term persistence in the host.}, } @article {pmid38466778, year = {2024}, author = {Salaikumaran, MR and Gopal, PP}, title = {Rational Design of TDP-43 Derived α-Helical Peptide Inhibitors: An In Silico Strategy to Prevent TDP-43 Aggregation in Neurodegenerative Disorders.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {6}, pages = {1096-1109}, pmid = {38466778}, issn = {1948-7193}, support = {R01 NS122907/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Protein Conformation, alpha-Helical ; Molecular Docking Simulation ; *Peptides/pharmacology ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {TDP-43, an essential RNA/DNA-binding protein, is central to the pathology of neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. Pathological mislocalization and aggregation of TDP-43 disrupt RNA splicing, mRNA stability, and mRNA transport, thereby impairing neuronal function and survival. The formation of amyloid-like TDP-43 filaments is largely facilitated by the destabilization of an α-helical segment within the disordered C-terminal region. In this study, we hypothesized that preventing the destabilization of the α-helical domain could potentially halt the growth of these pathological filaments. To explore this, we utilized a range of in silico techniques to design and evaluate peptide-based therapeutics that bind to pathological TDP-43 amyloid-like filament crystal structures and resist β sheet conversion. Our computational approaches, including biophysical and secondary structure property prediction, molecular docking, 3D structure prediction, and molecular dynamics simulations, were used to assess the structure, stability, and binding affinity of these peptides in relation to pathological TDP-43 filaments. The results of our in silico analyses identified a selection of promising peptides which displayed a stable α-helical structure, exhibited an increased number of intramolecular hydrogen bonds within the helical domain, and demonstrated high binding affinities for pathological TDP-43 amyloid-like filaments. Molecular dynamics simulations provided further support for the structural and thermodynamic stability of these peptides, as they exhibited lower root-mean-square deviation and more favorable free energy landscapes over 300 ns. These findings establish α-helical propensity peptides as potential lead molecules for the development of novel therapeutics against TDP-43 aggregation. This structure-based computational approach for the rational design of peptide inhibitors opens a new direction in the search for effective interventions for ALS, FTD, and other related neurodegenerative diseases. The peptides identified as the most promising candidates in this study are currently subject to further testing and validation through both in vitro and in vivo experiments.}, } @article {pmid38467605, year = {2024}, author = {Zhong, J and Wang, C and Zhang, D and Yao, X and Zhao, Q and Huang, X and Lin, F and Xue, C and Wang, Y and He, R and Li, XY and Li, Q and Wang, M and Zhao, S and Afridi, SK and Zhou, W and Wang, Z and Xu, Y and Xu, Z}, title = {PCDHA9 as a candidate gene for amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {2189}, pmid = {38467605}, issn = {2041-1723}, support = {32061143026, 31921002,32330038, 32394030//National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund)/ ; 82171412//National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund)/ ; 2021ZD0202300//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; }, mesh = {Humans ; Mice ; Animals ; Aged ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Mice, Transgenic ; Motor Neurons/metabolism ; Spinal Cord/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. To identify additional genetic factors, we analyzed exome sequences in a large cohort of Chinese ALS patients and found a homozygous variant (p.L700P) in PCDHA9 in three unrelated patients. We generated Pcdhα9 mutant mice harboring either orthologous point mutation or deletion mutation. These mice develop progressive spinal motor loss, muscle atrophy, and structural/functional abnormalities of the neuromuscular junction, leading to paralysis and early lethality. TDP-43 pathology is detected in the spinal motor neurons of aged mutant mice. Mechanistically, we demonstrate that Pcdha9 mutation causes aberrant activation of FAK and PYK2 in aging spinal cord, and dramatically reduced NKA-α1 expression in motor neurons. Our single nucleus multi-omics analysis reveals disturbed signaling involved in cell adhesion, ion transport, synapse organization, and neuronal survival in aged mutant mice. Together, our results present PCDHA9 as a potential ALS gene and provide insights into its pathogenesis.}, } @article {pmid38467696, year = {2024}, author = {Hilton, JBW and Kysenius, K and Liddell, JR and Mercer, SW and Paul, B and Beckman, JS and McLean, CA and White, AR and Donnelly, PS and Bush, AI and Hare, DJ and Roberts, BR and Crouch, PJ}, title = {Evidence for disrupted copper availability in human spinal cord supports Cu[II](atsm) as a treatment option for sporadic cases of ALS.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {5929}, pmid = {38467696}, issn = {2045-2322}, mesh = {Humans ; Mice ; Animals ; Copper/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Mice, Transgenic ; Spinal Cord/metabolism ; Ceruloplasmin/metabolism ; Disease Models, Animal ; *Thiosemicarbazones ; *Coordination Complexes ; }, abstract = {The copper compound Cu[II](atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Cu[II](atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for Cu[II](atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for Cu[II](atsm) involving copper availability may also be pertinent to sporadic cases of ALS.}, } @article {pmid38468041, year = {2024}, author = {Davidson, JM and Zhang, L and Yue, GH and Di Ieva, A}, title = {Fractal Dimension Studies of the Brain Shape in Aging and Neurodegenerative Diseases.}, journal = {Advances in neurobiology}, volume = {36}, number = {}, pages = {329-363}, pmid = {38468041}, issn = {2190-5215}, mesh = {Humans ; Adult ; *Neurodegenerative Diseases/diagnostic imaging/pathology ; Fractals ; Gray Matter/diagnostic imaging/pathology ; Aging ; Cerebellum/diagnostic imaging/pathology ; }, abstract = {The fractal dimension is a morphometric measure that has been used to investigate the changes of brain shape complexity in aging and neurodegenerative diseases. This chapter reviews fractal dimension studies in aging and neurodegenerative disorders in the literature. Research has shown that the fractal dimension of the left cerebral hemisphere increases until adolescence and then decreases with aging, while the fractal dimension of the right hemisphere continues to increase until adulthood. Studies in neurodegenerative diseases demonstrated a decline in the fractal dimension of the gray matter and white matter in Alzheimer's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia. In multiple sclerosis, the white matter fractal dimension decreases, but conversely, the fractal dimension of the gray matter increases at specific stages of disease. There is also a decline in the gray matter fractal dimension in frontotemporal dementia and multiple system atrophy of the cerebellar type and in the white matter fractal dimension in epilepsy and stroke. Region-specific changes in fractal dimension have also been found in Huntington's disease and Parkinson's disease. Associations were found between the fractal dimension and clinical scores, showing the potential of the fractal dimension as a marker to monitor brain shape changes in normal or pathological processes and predict cognitive or motor function.}, } @article {pmid38468172, year = {2024}, author = {Chang, MC}, title = {Letter to the Editor Regarding "Cervical Spondylotic Amyotrophy Initially Misdiagnosed as Amyotrophic Lateral Sclerosis".}, journal = {World neurosurgery}, volume = {183}, number = {}, pages = {269}, doi = {10.1016/j.wneu.2023.10.122}, pmid = {38468172}, issn = {1878-8769}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Muscular Atrophy ; Muscle, Skeletal ; *Spondylosis/diagnosis ; Diagnostic Errors ; Cervical Vertebrae ; }, } @article {pmid38468173, year = {2024}, author = {Yu, Z and Zhang, H and Wang, Y}, title = {In Reply to the Letter to the Editor Regarding "Cervical Spondylotic Amyotrophy Initially Misdiagnosed as Amyotrophic Lateral Sclerosis".}, journal = {World neurosurgery}, volume = {183}, number = {}, pages = {270}, doi = {10.1016/j.wneu.2023.12.140}, pmid = {38468173}, issn = {1878-8769}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Muscular Atrophy ; Muscle, Skeletal ; *Spondylosis/diagnosis ; Diagnostic Errors ; }, } @article {pmid38469573, year = {2024}, author = {Broce, IJ and Sirkis, DW and Nillo, RM and Bonham, LW and Lee, SE and Miller, BL and Castruita, PA and Sturm, VE and Sugrue, LS and Desikan, RS and Yokoyama, JS}, title = {C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1258996}, pmid = {38469573}, issn = {1662-4548}, support = {R01 AG052496/AG/NIA NIH HHS/United States ; T32 AG058529/AG/NIA NIH HHS/United States ; R25 NS117367/NS/NINDS NIH HHS/United States ; R01 AG058233/AG/NIA NIH HHS/United States ; K01 AG070376/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis.

METHODS: We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, and cerebellum) with average gene expression values for 15,633 protein-coding genes, including 54 genes known to be associated with ALS, FTD, or ALS-FTD. We then performed imaging transcriptomic analyses to evaluate whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n = 19) compared to controls (n = 23). Lastly, we explored whether genes with significant C9orf72 imaging transcriptomic correlations (i.e., "C9orf72 imaging transcriptomic network") were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways.

RESULTS: A total of 2,120 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 imaging transcriptomic network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic neurons in the spinal cord and brainstem and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with protein ubiquitination, autophagy, cellular response to DNA damage, endoplasmic reticulum to Golgi vesicle-mediated transport, among others.

CONCLUSION: Considered together, we identified a network of C9orf72 associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.}, } @article {pmid38469975, year = {2024}, author = {Nigri, A and Stanziano, M and Fedeli, D and Manera, U and Ferraro, S and Medina Carrion, JP and Palermo, S and Lequio, L and Denegri, F and Agosta, F and Spinelli, EG and Filippi, M and Grisoli, M and Valentini, MC and De Mattei, F and Canosa, A and Calvo, A and Chiò, A and Bruzzone, MG and Moglia, C}, title = {Distinct neural signatures of pulvinar in C9orf72 amyotrophic lateral sclerosis mutation carriers and noncarriers.}, journal = {European journal of neurology}, volume = {31}, number = {6}, pages = {e16266}, pmid = {38469975}, issn = {1468-1331}, support = {2017SNW5MB//Ministero dell'Università e della Ricerca/ ; FP7/2007-2013//European Commission's Health Seventh Framework Programme/ ; 259867//European Commission's Health Seventh Framework Programme/ ; GR-2019-12371291//Ministero della Salute/ ; RF-2016-02362405//Ministero della Salute/ ; RRC//Ministero della Salute/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/physiopathology/pathology ; *C9orf72 Protein/genetics ; Frontotemporal Dementia/genetics/physiopathology/diagnostic imaging/pathology ; Heterozygote ; *Magnetic Resonance Imaging ; *Mutation ; *Pulvinar/diagnostic imaging/physiopathology/pathology ; }, abstract = {BACKGROUND AND PURPOSE: Thalamic alterations have been reported as a major feature in presymptomatic and symptomatic patients carrying the C9orf72 mutation across the frontotemporal dementia-amyotrophic lateral sclerosis (ALS) spectrum. Specifically, the pulvinar, a high-order thalamic nucleus and timekeeper for large-scale cortical networks, has been hypothesized to be involved in C9orf72-related neurodegenerative diseases. We investigated whether pulvinar volume can be useful for differential diagnosis in ALS C9orf72 mutation carriers and noncarriers and how underlying functional connectivity changes affect this region.

METHODS: We studied 19 ALS C9orf72 mutation carriers (ALSC9+) accurately matched with wild-type ALS (ALSC9-) and ALS mimic (ALSmimic) patients using structural and resting-state functional magnetic resonance imaging data. Pulvinar volume was computed using automatic segmentation. Seed-to-voxel functional connectivity analyses were performed using seeds from a pulvinar functional parcellation.

RESULTS: Pulvinar structural integrity had high discriminative values for ALSC9+ patients compared to ALSmimic (area under the curve [AUC] = 0.86) and ALSC9- (AUC = 0.77) patients, yielding a volume cutpoint of approximately 0.23%. Compared to ALSmimic, ALSC9- showed increased anterior, inferior, and lateral pulvinar connections with bilateral occipital-temporal-parietal regions, whereas ALSC9+ showed no differences. ALSC9+ patients when compared to ALSC9- patients showed reduced pulvinar-occipital connectivity for anterior and inferior pulvinar seeds.

CONCLUSIONS: Pulvinar volume could be a differential biomarker closely related to the C9orf72 mutation. A pulvinar-cortical circuit dysfunction might play a critical role in disease progression and development, in both the genetic phenotype and ALS wild-type patients.}, } @article {pmid38470068, year = {2024}, author = {Van Damme, P and Al-Chalabi, A and Andersen, PM and Chiò, A and Couratier, P and De Carvalho, M and Hardiman, O and Kuźma-Kozakiewicz, M and Ludolph, A and McDermott, CJ and Mora, JS and Petri, S and Probyn, K and Reviers, E and Salachas, F and Silani, V and Tysnes, OB and van den Berg, LH and Villanueva, G and Weber, M}, title = {European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).}, journal = {European journal of neurology}, volume = {31}, number = {6}, pages = {e16264}, pmid = {38470068}, issn = {1468-1331}, support = {//ERN Euro-NMD/ ; //European Academy of Neurology/ ; //ALS Liga Belgium/ ; //EUpALS/ ; //ENCALS/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Europe ; Neurology/standards/methods ; Neuromuscular Diseases/therapy ; }, abstract = {BACKGROUND: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS).

METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available.

RESULTS: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management.

CONCLUSIONS: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.}, } @article {pmid38470552, year = {2024}, author = {Zou, W and Li, M and Wang, X and Lu, H and Hao, Y and Chen, D and Zhu, S and Ji, D and Zhang, Z and Zhou, P and Cao, Y}, title = {Preimplantation genetic testing for monogenic disorders (PGT-M) offers an alternative strategy to prevent children from being born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes: a retrospective study.}, journal = {Journal of assisted reproduction and genetics}, volume = {41}, number = {5}, pages = {1245-1259}, pmid = {38470552}, issn = {1573-7330}, support = {82001635//the National Natural Science Foundation of China/ ; 2021YFC2700901//the National Key R&D Program of China/ ; 202204295107020012//the Clinical Medical research transformation Project of Anhui Province/ ; 2022LCX015//the Foundation for Selected Scientists Studying Abroad of Anhui Province/ ; gxyqZD2022027//Program for Outstanding Young Talents in University of Anhui/ ; 202003a07020012//Major Science and Technology Project of Anhui province/ ; }, mesh = {Humans ; *Preimplantation Diagnosis/methods ; Female ; Pregnancy ; *Genetic Testing/methods ; *Metabolic Diseases/genetics/pathology ; Retrospective Studies ; Male ; Nervous System Diseases/genetics ; Phenotype ; Adult ; Child ; Embryo Transfer ; Mutation/genetics ; }, abstract = {BACKGROUND: Preimplantation genetic testing for monogenic disorders (PGT-M) is now widely used as an effective strategy to prevent various monogenic or chromosomal diseases.

MATERIAL AND METHODS: In this retrospective study, couples with a family history of hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes and/or carrying the pathogenic genes underwent PGT-M to prevent children from inheriting disease-causing gene mutations from their parents and developing known genetic diseases. After PGT-M, unaffected (i.e., normal) embryos after genetic detection were transferred into the uterus of their corresponding mothers.

RESULTS: A total of 43 carrier couples with the following hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes underwent PGT-M: Duchenne muscular dystrophy (13 families); methylmalonic acidemia (7 families); spinal muscular atrophy (5 families); infantile neuroaxonal dystrophy and intellectual developmental disorder (3 families each); Cockayne syndrome (2 families); Menkes disease, spinocerebellar ataxia, glycine encephalopathy with epilepsy, Charcot-Marie-Tooth disease, mucopolysaccharidosis, Aicardi-Goutieres syndrome, adrenoleukodystrophy, phenylketonuria, amyotrophic lateral sclerosis, and Dravet syndrome (1 family each). After 53 PGT-M cycles, the final transferable embryo rate was 12.45%, the clinical pregnancy rate was 74.19%, and the live birth rate was 89.47%; a total of 18 unaffected (i.e., healthy) children were born to these families.

CONCLUSIONS: This study highlights the importance of PGT-M in preventing children born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes.}, } @article {pmid38470574, year = {2024}, author = {Pan, H and Wang, Y and Li, Z and Chu, X and Teng, B and Gao, H}, title = {A Complete Scheme for Multi-Character Classification Using EEG Signals From Speech Imagery.}, journal = {IEEE transactions on bio-medical engineering}, volume = {71}, number = {8}, pages = {2454-2462}, doi = {10.1109/TBME.2024.3376603}, pmid = {38470574}, issn = {1558-2531}, mesh = {Humans ; *Electroencephalography/methods ; *Signal Processing, Computer-Assisted ; *Speech/physiology ; *Brain-Computer Interfaces ; Algorithms ; Wavelet Analysis ; Imagination/physiology ; Adult ; Male ; Female ; Neural Networks, Computer ; }, abstract = {Some classification studies of brain-computer interface (BCI) based on speech imagery show potential for improving communication skills in patients with amyotrophic lateral sclerosis (ALS). However, current research on speech imagery is limited in scope and primarily focuses on vowels or a few selected words. In this paper, we propose a complete research scheme for multi-character classification based on EEG signals derived from speech imagery. Firstly, we record 31 speech imagery contents, including 26 alphabets and five commonly used punctuation marks, from seven subjects using a 32-channel electroencephalogram (EEG) device. Secondly, we introduce the wavelet scattering transform (WST), which shares a structural resemblance to Convolutional Neural Networks (CNNs), for feature extraction. The WST is a knowledge-driven technique that preserves high-frequency information and maintains the deformation stability of EEG signals. To reduce the dimensionality of wavelet scattering coefficient features, we employ Kernel Principal Component Analysis (KPCA). Finally, the reduced features are fed into an Extreme Gradient Boosting (XGBoost) classifier within a multi-classification framework. The XGBoost classifier is optimized through hyperparameter tuning using grid search and 10-fold cross-validation, resulting in an average accuracy of 78.73% for the multi-character classification task. We utilize t-Distributed Stochastic Neighbor Embedding (t-SNE) technology to visualize the low-dimensional representation of multi-character speech imagery. This visualization effectively enables us to observe the clustering of similar characters. The experimental results demonstrate the effectiveness of our proposed multi-character classification scheme. Furthermore, our classification categories and accuracy exceed those reported in existing research.}, } @article {pmid38471489, year = {2024}, author = {D'Souza, A and Zink, K and Langhorst, J and Wildner, M and Stupp, C and Keil, T}, title = {How Effective Is Drinking Natural Mineral Water against Heartburn from Functional Dyspepsia, Gastroesophageal Reflux Disease, or Other Causes? A Systematic Review of Clinical Intervention Studies.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {253-265}, pmid = {38471489}, issn = {2504-2106}, mesh = {Humans ; *Mineral Waters/therapeutic use ; *Gastroesophageal Reflux/therapy/drug therapy ; *Heartburn/drug therapy ; *Dyspepsia/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: For centuries, spring and other natural waters have been recommended as external or internal remedies for numerous diseases. For studies that examined the effects of drinking mineral waters against heartburn, gastroesophageal reflux disease (GERD), or functional dyspepsia, a systematic review is lacking.

OBJECTIVES: The main aim of this systematic review was to examine the effects of drinking natural mineral waters on heartburn from various causes by identifying all published intervention studies and critically appraising their methods as well as summarizing their results.

METHODS: We systematically searched the largest medical literature database MEDLINE, further relevant web sources, and gray literature for randomized and nonrandomized trials, with or without control groups, up to September 2021 and no language restrictions. Further inclusion criteria were adult patients with heartburn, drinking cure with natural mineral water as the intervention, compared to no or other interventions (care-as-usual, waiting list). We defined the reduction of heartburn symptoms and duration of disease episodes as primary and quality of life as secondary outcomes. Two reviewers independently carried out the study quality assessments (risk of bias) using the National Institutes of Health-Study Quality Assessment Tools.

RESULTS: Nine trials comprising 393 patients from Italy, Russia, Ukraine, and Germany fulfilled all inclusion criteria. We identified three randomized controlled trials (all with poor methodological quality), plus six before-after (pre/post) intervention studies without a control group. The intervention groups of the three comparative trials seemed to show a stronger reduction of self-reported heartburn symptoms, and duration of heartburn episodes than the respective control groups; however, they all had poor methodological quality.

CONCLUSION: Based on the best available evidence of clinical studies, we cannot recommend or advise against drinking natural mineral waters as a treatment for heartburn. The potential benefits of natural mineral waters that were reported in some studies with a lower evidence level (e.g., lacking a control group) should be verified by good quality randomized clinical trials with adequate comparison groups and longer follow-up periods.

UNLABELLED: HintergrundSeit Jahrhunderten werden Quell- und andere natürliche Wässer als äußerliche oder innerliche Heilmittel für zahlreiche Krankheiten empfohlen. Für Studien, die die Wirkung des Trinkens von Mineralwasser gegen Sodbrennen, gastroösophageale Refluxkrankheit (GERD) oder funktionelle Dyspepsie untersuchten, fehlt eine systematische Übersicht.ZielsetzungDas Hauptziel dieser systematischen Übersichtsarbeit war es, die Auswirkungen von Trinkkuren mit natürlichen Mineralwässern auf Sodbrennen verschiedener Ursachen zu untersuchen, indem alle veröffentlichten Interventionsstudien identifiziert und ihre Methoden kritisch bewertet sowie ihre Ergebnisse zusammengefasst wurden.MethodenWir durchsuchten systematisch die größte medizinische Literaturdatenbank MEDLINE, weitere relevante Internetquellen und graue Literatur nach randomisierten und nicht-randomisierten Studien, mit oder ohne Kontrollgruppen, bis September 2021 und ohne sprachliche Einschränkungen. Weitere Einschlusskriterien waren erwachsene Patienten mit Sodbrennen, Trinkkur mit natürlichem Mineralwasser als Intervention, im Vergleich zu keiner oder anderen Interventionen (care-as-usual, Warteliste). Wir definierten die Abnahme der Symptome des Sodbrennens und die Dauer der Krankheitsepisoden als primäre und die Lebensqualität als sekundäre Endpunkte. Zwei Gutachter bewerteten unabhängig voneinander die Qualität der Studien (Verzerrungsrisiko) anhand der National Institutes of Health-Study Quality Assessment Tools.ErgebnisseNeun Studien mit 393 Patienten aus Italien, Russland, der Ukraine und Deutschland erfüllten alle Einschlusskriterien. Wir identifizierten drei randomisierte kontrollierte Studien (alle mit schlechter methodischer Qualität) sowie sechs Vorher-Nachher-Studien (Prä-/Post-Studien) ohne Kontrollgruppe. Die Interventionsgruppen der drei randomisierten Vergleichsstudien schienen eine stärkere Verringerung der selbstberichteten Symptome und der Dauer der Episoden des Sodbrennens zu zeigen als die jeweiligen Kontrollgruppen, allerdings waren sie alle von schlechter methodischer Qualität.SchlussfolgerungAuf der Grundlage der besten verfügbaren Belege aus klinischen Studien können wir das Trinken natürlicher Mineralwässer zur Behandlung von Sodbrennen weder empfehlen noch davon abraten. Die potenziellen Vorteile natürlicher Mineralwässer, die in einigen Studien mit geringerer Evidenz (z. B. ohne Kontrollgruppe) berichtet wurden, sollten durch qualitativ hochwertige randomisierte klinische Studien mit angemessenen Vergleichsgruppen und längeren Nachbeobachtungszeiträumen überprüft werden.}, } @article {pmid38472048, year = {2024}, author = {Silva-Hucha, S and Fernández de Sevilla, ME and Humphreys, KM and Benson, FE and Franco, JM and Pozo, D and Pastor, AM and Morcuende, S}, title = {VEGF expression disparities in brainstem motor neurons of the SOD1[G93A] ALS model: Correlations with neuronal vulnerability.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {3}, pages = {e00340}, pmid = {38472048}, issn = {1878-7479}, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Brain Stem/metabolism ; Disease Models, Animal ; Mice, Transgenic ; *Motor Neurons/metabolism/pathology ; Superoxide Dismutase/metabolism/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; *Vascular Endothelial Growth Factor A/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neuromuscular disease characterized by severe muscle weakness mainly due to degeneration and death of motor neurons. A peculiarity of the neurodegenerative processes is the variable susceptibility among distinct neuronal populations, exemplified by the contrasting resilience of motor neurons innervating the ocular motor system and the more vulnerable facial and hypoglossal motor neurons. The crucial role of vascular endothelial growth factor (VEGF) as a neuroprotective factor in the nervous system is well-established since a deficit of VEGF has been related to motoneuronal degeneration. In this study, we investigated the survival of ocular, facial, and hypoglossal motor neurons utilizing the murine SOD1[G93A] ALS model at various stages of the disease. Our primary objective was to determine whether the survival of the different brainstem motor neurons was linked to disparate VEGF expression levels in resilient and susceptible motor neurons throughout neurodegeneration. Our findings revealed a selective loss of motor neurons exclusively within the vulnerable nuclei. Furthermore, a significantly higher level of VEGF was detected in the more resistant motor neurons, the extraocular ones. We also examined whether TDP-43 dynamics in the brainstem motor neuron of SOD mice was altered. Our data suggests that the increased VEGF levels observed in extraocular motor neurons may potentially underlie their resistance during the neurodegenerative processes in ALS in a TDP-43-independent manner. Our work might help to better understand the underlying mechanisms of selective vulnerability of motor neurons in ALS.}, } @article {pmid38472280, year = {2024}, author = {Safren, N and Dao, TP and Mohan, HM and Huang, C and Trotter, B and Castañeda, CA and Paulson, H and Barmada, S and Sharkey, LM}, title = {Pathogenic mutations in UBQLN2 exhibit diverse aggregation propensity and neurotoxicity.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {6049}, pmid = {38472280}, issn = {2045-2322}, support = {R01 GM136946/GM/NIGMS NIH HHS/United States ; R01GM136946./GF/NIH HHS/United States ; R01NS097542-01/GF/NIH HHS/United States ; R35 NS122302/NS/NINDS NIH HHS/United States ; R35NS122302/GF/NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/metabolism ; Autophagy-Related Proteins/genetics ; Mutation ; Adaptor Proteins, Signal Transducing/metabolism ; }, abstract = {The ubiquitin-adaptor protein UBQLN2 promotes degradation of several aggregate-prone proteins implicated in neurodegenerative diseases. Missense UBQLN2 mutations also cause X-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previously we demonstrated that the liquid-like properties of UBQLN2 molecular assemblies are altered by a specific pathogenic mutation, P506T, and that the propensity of UBQLN2 to aggregate correlated with neurotoxicity. Here, we systematically assess the effects of multiple, spatially distinct ALS/FTD-linked missense mutations on UBQLN2 aggregation propensity, neurotoxicity, phase separation, and autophagic flux. In contrast to what we observed for the P506T mutation, no other tested pathogenic mutant exhibited a clear correlation between aggregation propensity and neurotoxicity. These results emphasize the unique nature of pathogenic UBQLN2 mutations and argue against a generalizable link between aggregation propensity and neurodegeneration in UBQLN2-linked ALS/FTD.}, } @article {pmid38473944, year = {2024}, author = {Scarian, E and Viola, C and Dragoni, F and Di Gerlando, R and Rizzo, B and Diamanti, L and Gagliardi, S and Bordoni, M and Pansarasa, O}, title = {New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {5}, pages = {}, pmid = {38473944}, issn = {1422-0067}, support = {Ricerca Corrente 2022-2024//Ministero della Salute/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress/physiology ; Antioxidants/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Inflammation/drug therapy ; }, abstract = {Oxidative stress (OS) and inflammation are two important and well-studied pathological hallmarks of neurodegenerative diseases (NDDs). Due to elevated oxygen consumption, the high presence of easily oxidizable polyunsaturated fatty acids and the weak antioxidant defenses, the brain is particularly vulnerable to oxidative injury. Uncertainty exists over whether these deficits contribute to the development of NDDs or are solely a consequence of neuronal degeneration. Furthermore, these two pathological hallmarks are linked, and it is known that OS can affect the inflammatory response. In this review, we will overview the last findings about these two pathways in the principal NDDs. Moreover, we will focus more in depth on amyotrophic lateral sclerosis (ALS) to understand how anti-inflammatory and antioxidants drugs have been used for the treatment of this still incurable motor neuron (MN) disease. Finally, we will analyze the principal past and actual clinical trials and the future perspectives in the study of these two pathological mechanisms.}, } @article {pmid38474192, year = {2024}, author = {Yamashita, T and Abe, K}, title = {Update on Antioxidant Therapy with Edaravone: Expanding Applications in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {5}, pages = {}, pmid = {38474192}, issn = {1422-0067}, support = {23K08543, 21K19572//Grant-in-Aid for Scientific Research/ ; }, mesh = {Animals ; Female ; Pregnancy ; *Amyotrophic Lateral Sclerosis/drug therapy ; Antioxidants/therapeutic use ; Antipyrine ; Edaravone/pharmacology/therapeutic use ; Free Radical Scavengers/pharmacology ; *Neurodegenerative Diseases/drug therapy ; *Neuroprotective Agents/pharmacology ; Placenta ; }, abstract = {The brain is susceptible to oxidative stress, which is associated with various neurological diseases. Edaravone (MCI-186, 3-methyl-1 pheny-2-pyrazolin-5-one), a free radical scavenger, has promising effects by quenching hydroxyl radicals (∙OH) and inhibiting both ∙OH-dependent and ∙OH-independent lipid peroxidation. Edaravone was initially developed in Japan as a neuroprotective agent for acute cerebral infarction and was later applied clinically to treat amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. There is accumulating evidence for the therapeutic effects of edaravone in a wide range of diseases related to oxidative stress, including ischemic stroke, ALS, Alzheimer's disease, and placental ischemia. These neuroprotective effects have expanded the potential applications of edaravone. Data from experimental animal models support its safety for long-term use, implying broader applications in various neurodegenerative diseases. In this review, we explain the unique characteristics of edaravone, summarize recent findings for specific diseases, and discuss its prospects for future therapeutic applications.}, } @article {pmid38474336, year = {2024}, author = {Aksoy, YA and Cole, AJ and Deng, W and Hesselson, D}, title = {Zebrafish CCNF and FUS Mediate Stress-Specific Motor Responses.}, journal = {Cells}, volume = {13}, number = {5}, pages = {}, pmid = {38474336}, issn = {2073-4409}, support = {APP1095215//NHMRC/ ; APP1063981//NHMRC/ ; DP140103233/ARC/Ames Research Center NASA/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Cyclins/metabolism ; Motor Neurons/pathology ; *Neurodegenerative Diseases/metabolism ; Proteins/metabolism ; *RNA-Binding Protein FUS/genetics/metabolism ; *Zebrafish/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of motor neurons. Mutations in the cyclin F (CCNF) and fused in sarcoma (FUS) genes have been associated with ALS pathology. In this study, we aimed to investigate the functional role of CCNF and FUS in ALS by using genome editing techniques to generate zebrafish models with genetic disruptions in these genes. Sequence comparisons showed significant homology between human and zebrafish CCNF and FUS proteins. We used CRISPR/Cas9 and TALEN-mediated genome editing to generate targeted disruptions in the zebrafish ccnf and fus genes. Ccnf-deficient zebrafish exhibited abnormal motor neuron development and axonal outgrowth, whereas Fus-deficient zebrafish did not exhibit developmental abnormalities or axonopathies in primary motor neurons. However, Fus-deficient zebrafish displayed motor impairments in response to oxidative and endoplasmic reticulum stress. The Ccnf-deficient zebrafish were only sensitized to endoplasmic reticulum stress, indicating that ALS genes have overlapping as well as unique cellular functions. These zebrafish models provide valuable platforms for studying the functional consequences of CCNF and FUS mutations in ALS pathogenesis. Furthermore, these zebrafish models expand the drug screening toolkit used to evaluate possible ALS treatments.}, } @article {pmid38474399, year = {2024}, author = {Manora, L and Borlongan, CV and Garbuzova-Davis, S}, title = {Cellular and Noncellular Approaches for Repairing the Damaged Blood-CNS-Barrier in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {5}, pages = {}, pmid = {38474399}, issn = {2073-4409}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; R21 NS132576/NS/NINDS NIH HHS/United States ; 1R21NS132576-01/NS/NINDS NIH HHS/United States ; 1R01NS090962/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Endothelial Cells/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Stem Cells/metabolism ; }, abstract = {Numerous reports have demonstrated the breakdown of the blood-CNS barrier (B-CNS-B) in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Re-establishing barrier integrity in the CNS is critical to prevent further motor neuron degeneration from harmful components in systemic circulation. Potential therapeutic strategies for repairing the B-CNS-B may be achieved by the replacement of damaged endothelial cells (ECs) via stem cell administration or enhancement of endogenous EC survival through the delivery of bioactive particles secreted by stem cells. These cellular and noncellular approaches are thoroughly discussed in the present review. Specific attention is given to certain stem cell types for EC replacement. Also, various nanoparticles secreted by stem cells as well as other biomolecules are elucidated as promising agents for endogenous EC repair. Although the noted in vitro and in vivo studies show the feasibility of the proposed therapeutic approaches to the repair of the B-CNS-B in ALS, further investigation is needed prior to clinical transition.}, } @article {pmid38474416, year = {2024}, author = {Tzeplaeff, L and Jürs, AV and Wohnrade, C and Demleitner, AF}, title = {Unraveling the Heterogeneity of ALS-A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials.}, journal = {Cells}, volume = {13}, number = {5}, pages = {}, pmid = {38474416}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Treatment Outcome ; Clinical Trials as Topic ; }, abstract = {Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular.}, } @article {pmid38474719, year = {2024}, author = {Noor Eddin, A and Alfuwais, M and Noor Eddin, R and Alkattan, K and Yaqinuddin, A}, title = {Gut-Modulating Agents and Amyotrophic Lateral Sclerosis: Current Evidence and Future Perspectives.}, journal = {Nutrients}, volume = {16}, number = {5}, pages = {}, pmid = {38474719}, issn = {2072-6643}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Dysbiosis/etiology ; *Gastrointestinal Microbiome/physiology ; *Microbiota ; Disease Progression ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a highly fatal neurodegenerative disorder characterized by the progressive wasting and paralysis of voluntary muscle. Despite extensive research, the etiology of ALS remains elusive, and effective treatment options are limited. However, recent evidence implicates gut dysbiosis and gut-brain axis (GBA) dysfunction in ALS pathogenesis. Alterations to the composition and diversity of microbial communities within the gut flora have been consistently observed in ALS patients. These changes are often correlated with disease progression and patient outcome, suggesting that GBA modulation may have therapeutic potential. Indeed, targeting the gut microbiota has been shown to be neuroprotective in several animal models, alleviating motor symptoms and mitigating disease progression. However, the translation of these findings to human patients is challenging due to the complexity of ALS pathology and the varying diversity of gut microbiota. This review comprehensively summarizes the current literature on ALS-related gut dysbiosis, focusing on the implications of GBA dysfunction. It delineates three main mechanisms by which dysbiosis contributes to ALS pathology: compromised intestinal barrier integrity, metabolic dysfunction, and immune dysregulation. It also examines preclinical evidence on the therapeutic potential of gut-microbiota-modulating agents (categorized as prebiotics, probiotics, and postbiotics) in ALS.}, } @article {pmid38477419, year = {2024}, author = {de Fátima Dos Santos Sampaio, M and de Paiva, YB and Sampaio, TB and Pereira, MG and Coimbra, NC}, title = {Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders.}, journal = {Basic & clinical pharmacology & toxicology}, volume = {134}, number = {5}, pages = {574-601}, doi = {10.1111/bcpt.13997}, pmid = {38477419}, issn = {1742-7843}, support = {2014/11869-0//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2020/15050-7//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; PDJ grant 155489/2018-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; Research Grant (NAP-USP-NuPNE; process IaPq2012-15//Universidade de São Paulo/ ; 374/2022//Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo/ ; 302605/2021-5//CNPq/ ; 301341/2015-0//CNPq/ ; 301905/2010-0//CNPq/ ; 155489/2018-6//CNPq/ ; }, mesh = {Humans ; *Cannabidiol/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy ; *Multiple Sclerosis/drug therapy ; Receptor, Serotonin, 5-HT1A/therapeutic use ; *Cannabinoids/pharmacology/therapeutic use ; *Epilepsy/drug therapy ; *Mental Disorders/drug therapy ; Comorbidity ; }, abstract = {Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system-related receptors and other molecular targets, such as the 5-HT1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5-HT1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5-HT1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.}, } @article {pmid38477424, year = {2025}, author = {Steigerwald, CG and Bertolini, C and McElhiney, M and Bergner, AL and Harms, MB and Harrington, EA}, title = {Individuals' experiences in genetic counseling and predictive testing for familial amyotrophic lateral sclerosis.}, journal = {Journal of genetic counseling}, volume = {34}, number = {1}, pages = {e1890}, doi = {10.1002/jgc4.1890}, pmid = {38477424}, issn = {1573-3599}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology/diagnosis ; *Genetic Counseling/psychology ; *Genetic Testing ; Male ; Female ; Middle Aged ; Adult ; Surveys and Questionnaires ; Aged ; }, abstract = {As clinical genetic testing in the amyotrophic lateral sclerosis (ALS) diagnostic setting increases, the identification of at-risk family members has also expanded. No practice guidelines specifically for predictive genetic testing exist, and few studies about the psychological impacts of testing in this subgroup have occurred, limiting the ability to tailor recommendations and counseling in this community. We surveyed asymptomatic individuals at risk for inheriting an ALS-associated gene mutation. The 80-question survey was designed using a combination of validated measures (General Anxiety Disorder; FACToR; Decision Regret Scale) and original items. Ninety participants completed the survey, including those who completed predictive genetic testing (N = 42) and those who did not (N = 48). Gene positive individuals experienced greater negativity, uncertainty, and overall psychological impairment (p = 0.002; p < 0.001; p = 0.001). Individuals who had not undergone testing reported thinking about their risk multiple times per day and experiencing more decisional regret than those who tested (p = 0.006). In terms of decision-making, being prepared for potential clinical drug trials was a more important potential benefit among those who underwent testing (p = 0.026). Participants valuing preparedness for clinical drug trials supports the concept that genetic testing for ALS will increase as research in gene-targeted therapeutics progresses. This study describes factors relevant to the genetic testing decision-making process and adaptation to results from the perspective of at-risk individuals, which can ultimately guide genetic counseling practice in this population.}, } @article {pmid38478117, year = {2024}, author = {Marques, C and Held, A and Dorfman, K and Sung, J and Song, C and Kavuturu, AS and Aguilar, C and Russo, T and Oakley, DH and Albers, MW and Hyman, BT and Petrucelli, L and Lagier-Tourenne, C and Wainger, BJ}, title = {Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {56}, pmid = {38478117}, issn = {1432-0533}, support = {R01 AG058063/AG/NIA NIH HHS/United States ; RF1 NS127407/NS/NINDS NIH HHS/United States ; R01 AG078377/AG/NIA NIH HHS/United States ; DP2 NS106664/NS/NINDS NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; RF1NS127407/NH/NIH HHS/United States ; DP2-NS106664/NH/NIH HHS/United States ; F32 NS114319/NS/NINDS NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; F32NS114319/NH/NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; *Pick Disease of the Brain ; STING Protein ; }, abstract = {The stimulator of interferon genes (STING) pathway has been implicated in neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS). While prior studies have focused on STING within immune cells, little is known about STING within neurons. Here, we document neuronal activation of the STING pathway in human postmortem cortical and spinal motor neurons from individuals affected by familial or sporadic ALS. This process takes place selectively in the most vulnerable cortical and spinal motor neurons but not in neurons that are less affected by the disease. Concordant STING activation in layer V cortical motor neurons occurs in a mouse model of C9orf72 repeat-associated ALS and frontotemporal dementia (FTD). To establish that STING activation occurs in a neuron-autonomous manner, we demonstrate the integrity of the STING signaling pathway, including both upstream activators and downstream innate immune response effectors, in dissociated mouse cortical neurons and neurons derived from control human induced pluripotent stem cells (iPSCs). Human iPSC-derived neurons harboring different familial ALS-causing mutations exhibit increased STING signaling with DNA damage as a main driver. The elevated downstream inflammatory markers present in ALS iPSC-derived neurons can be suppressed with a STING inhibitor. Our results reveal an immunophenotype that consists of innate immune signaling driven by the STING pathway and occurs specifically within vulnerable neurons in ALS/FTD.}, } @article {pmid38478631, year = {2024}, author = {Scekic-Zahirovic, J and Benetton, C and Brunet, A and Ye, X and Logunov, E and Douchamps, V and Megat, S and Andry, V and Kan, VWY and Stuart-Lopez, G and Gilet, J and Guillot, SJ and Dirrig-Grosch, S and Gorin, C and Trombini, M and Dieterle, S and Sinniger, J and Fischer, M and René, F and Gunes, Z and Kessler, P and Dupuis, L and Pradat, PF and Goumon, Y and Goutagny, R and Marchand-Pauvert, V and Liebscher, S and Rouaux, C}, title = {Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency.}, journal = {Science translational medicine}, volume = {16}, number = {738}, pages = {eadg3665}, doi = {10.1126/scitranslmed.adg3665}, pmid = {38478631}, issn = {1946-6242}, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Spinal Cord/metabolism ; Norepinephrine/*deficiency ; Disease Models, Animal ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; *Autonomic Nervous System Diseases ; Dopamine beta-Hydroxylase/*deficiency ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1[G86R] and Fus[ΔNLS/+] ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1[G93A] and Fus[ΔNLS/+] mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.}, } @article {pmid38479182, year = {2024}, author = {Nie, L and He, K and Qiu, C and Li, Q and Xiong, B and Gao, C and Zhang, X and Jing, M and Wu, W and Liu, J and Zhang, G and Zhang, Z and Yang, X and Sun, Y and Wang, Y}, title = {Tetramethylpyrazine Nitrone alleviates D-galactose-induced murine skeletal muscle aging and motor deficits by activating the AMPK signaling pathway.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {173}, number = {}, pages = {116415}, doi = {10.1016/j.biopha.2024.116415}, pmid = {38479182}, issn = {1950-6007}, mesh = {Mice ; Animals ; *Galactose ; AMP-Activated Protein Kinases ; *Neuroprotective Agents/pharmacology ; Aging ; Signal Transduction ; Muscle, Skeletal ; *Pyrazines ; }, abstract = {Tetramethylpyrazine nitrone (TBN), a novel derivative of tetramethylpyrazine (TMP) designed and synthesized by our group, possesses multi-functional mechanisms of action and displays broad protective effects in vitro and in animal models of age-related brain disorders such as stroke, Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's disease (PD). In the present report, we investigated the effects of TBN on aging, specifically on muscle aging and the associated decline of motor functions. Using a D-galactose-induced aging mouse model, we found that TBN could reverse the levels of several senescence and aging markers including p16, p21, ceramides, and telomere length and increase the wet-weight ratio of gastrocnemius muscle tissue, demonstrating its efficacy in ameliorating muscle aging. Additionally, the pharmacological effects of TBN on motor deficits (gait analysis, pole-climbing test and grip strength test), muscle fibrosis (hematoxylin & eosin (HE), Masson staining, and αSMA staining), inflammatory response (IL-1β, IL-6, and TNF-α), and mitochondrial function (ATP, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were also confirmed in the D-galactose-induced aging models. Further experiments demonstrated that TBN alleviated muscle aging and improved the decline of age-related motor deficits through an AMPK-dependent mechanism. These findings highlight the significance of TBN as a potential anti-aging agent to combat the occurrence and development of aging and age-related diseases.}, } @article {pmid38481294, year = {2024}, author = {Laforest, M and Martin, SL and Bisaillon, K and Soufiane, B and Meloche, S and Tardif, FJ and Page, E}, title = {The ancestral karyotype of the Heliantheae Alliance, herbicide resistance, and human allergens: Insights from the genomes of common and giant ragweed.}, journal = {The plant genome}, volume = {17}, number = {2}, pages = {e20442}, pmid = {38481294}, issn = {1940-3372}, support = {J-001751//Agriculture and Agri-Food Canada/ ; J-002275//Agriculture and Agri-Food Canada/ ; }, mesh = {*Ambrosia/genetics ; *Allergens/genetics ; *Herbicide Resistance/genetics ; *Genome, Plant ; Humans ; Karyotype ; Herbicides/pharmacology ; Chromosomes, Plant ; }, abstract = {Ambrosia artemisiifolia and Ambrosia trifida (Asteraceae) are important pest species and the two greatest sources of aeroallergens globally. Here, we took advantage of a hybrid to simplify genome assembly and present chromosome-level assemblies for both species. These assemblies show high levels of completeness with Benchmarking Universal Single-Copy Ortholog (BUSCO) scores of 94.5% for A. artemisiifolia and 96.1% for A. trifida and long terminal repeat (LTR) Assembly Index values of 26.6 and 23.6, respectively. The genomes were annotated using RNA data identifying 41,642 genes in A. artemisiifolia and 50,203 in A. trifida. More than half of the genome is composed of repetitive elements, with 62% in A. artemisiifolia and 69% in A. trifida. Single copies of herbicide resistance-associated genes PPX2L, HPPD, and ALS were found, while two copies of the EPSPS gene were identified; this latter observation may reveal a possible mechanism of resistance to the herbicide glyphosate. Ten of the 12 main allergenicity genes were also localized, some forming clusters with several copies, especially in A. artemisiifolia. The evolution of genome structure has differed among these two species. The genome of A. trifida has undergone greater rearrangement, possibly the result of chromoplexy. In contrast, the genome of A. artemisiifolia retains a structure that makes the allotetraploidization of the most recent common ancestor of the Heliantheae Alliance the clearest feature of its genome. When compared to other Heliantheae Alliance species, this allowed us to reconstruct the common ancestor's karyotype-a key step for furthering of our understanding of the evolution and diversification of this economically and allergenically important group.}, } @article {pmid38481899, year = {2024}, author = {El-Ghanem, M and Abdulrazeq, H and Brasiliense, L and Abbad, H and Aguilar-Salinas, P and Al-Mufti, F and Dumont, T}, title = {Outcomes of Mechanical Thrombectomy in Patients With Neurological Disorders: A National Inpatient Sample Database Analysis.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e54063}, pmid = {38481899}, issn = {2168-8184}, abstract = {INTRODUCTION: Mechanical thrombectomy (MT) has changed the standard of care for patients presenting with acute ischemic stroke (AIS). The window of treatment has significantly increased the number of patients who would benefit from intervention and operators may be confronted with patients harboring preexistent neurological disorders. Still, the epidemiology of patients with AIS and neurological disorders has not been established.

METHODS: This is a retrospective study, which utilizes data from the National Inpatient Sample (NIS) between 2012 and 2016. Patients with the major neurological comorbidities in the study were included: Alzheimer's dementia (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and myasthenia gravis (MG). These patients were divided into groups and analyzed based on discharged home status, length of hospital stay (LOS), and inpatient mortality. These outcomes were also compared between patients who underwent MT versus those who did not.

RESULTS: In this study, 460,070 patients with AIS were identified and included. MT was performed less often when the patient had a neurological diagnosis compared to those without a neurological disease (p<0.0001). However, patients with AIS who have underlying neurological disorders such as AD, PD, and MS have shown similar outcomes after MT to those who do not have these disorders.

CONCLUSION: Patients with preexisting neurological disorders were less likely to undergo MT. Further studies are required to elucidate the implications of having a neurological disorder in the setting of an AIS.}, } @article {pmid38483107, year = {2024}, author = {Adari, MD and Pandian, BA and Gaines, TA and Prasad, PV and Jugulam, M}, title = {Confirmation and characterization of the first case of acetolactate synthase (ALS)-inhibitor resistance in Japanese brome (Bromus japonicus) in the US.}, journal = {Pest management science}, volume = {80}, number = {8}, pages = {3717-3725}, doi = {10.1002/ps.8074}, pmid = {38483107}, issn = {1526-4998}, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Bromus/enzymology/drug effects/genetics ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Kansas ; *Plant Proteins/genetics/metabolism/antagonists & inhibitors ; Plant Weeds/drug effects/genetics/enzymology ; }, abstract = {BACKGROUND: Japanese brome (Bromus japonicus Thumb.) is one of the problematic annual weeds in winter wheat (Triticum aestivum L.) and is generally controlled by acetolactate synthase (ALS) inhibitors. Repeated use of the ALS inhibitor propoxycarbazone-Na resulted in the evolution of resistance to this herbicide in three B. japonicus populations, i.e., R1, R2, and R3 in Kansas (KS). However, the level of resistance and mechanism conferring resistance in these populations is unknown. The objectives of this research were to (i) evaluate the level of resistance to propoxycarbazone-Na in R1, R2, and R3 in comparison with a known susceptible population (S1), (ii) investigate the mechanism of resistance involved in conferring ALS-inhibitor resistance, and (iii) investigate the cross-resistance to other ALS inhibitors.

RESULTS: Dose-response (0 to 16x; x = 44 g ai ha[-1] of propoxycarbazone-Na) assay indicated 167, 125, and 667-fold resistance in R1, R2 and R3 populations, respectively, compared to S1 population. ALS gene sequencing confirmed the mutations resulting in amino acid substitutions, i.e., Pro-197-Thr (R3, R1)/Ser (R2, R1) bestowing resistance to these ALS inhibitors. Such amino acid substitutions also showed differential cross-resistance to sulfosulfuron, mesosulfuron-methyl, pyroxsulam, and imazamox among resistant populations. Pretreatment with malathion (a cytochrome P450 enzyme-inhibitor) followed by imazamox treatment suggested cross-resistance to this herbicide possibly via metabolism only in R3 population.

CONCLUSION: Overall, these results confirm the first case of target-site based resistance to ALS inhibitors in B. japonicus in the US, highlighting the need for exploring herbicides with alternative modes of action to enhance weed control in winter wheat. © 2024 Society of Chemical Industry.}, } @article {pmid38483313, year = {2024}, author = {Jafarinia, H and van der Giessen, E and Onck, PR}, title = {C9orf72 polyPR directly binds to various nuclear transport components.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38483313}, issn = {2050-084X}, support = {Building Blocks of Life//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; }, mesh = {Active Transport, Cell Nucleus ; C9orf72 Protein/genetics ; *Nuclear Localization Signals ; *Amino Acids ; Arginine ; }, abstract = {The disruption of nucleocytoplasmic transport (NCT) is an important mechanism in neurodegenerative diseases. In the case of C9orf72-ALS, trafficking of macromolecules through the nuclear pore complex (NPC) might get frustrated by the binding of C9orf72-translated arginine-containing dipeptide repeat proteins (R-DPRs) to the Kapβ family of nuclear transport receptors. Besides Kapβs, several other types of transport components have been linked to NCT impairments in R-DPR-expressed cells, but the molecular origin of these observations has not been clarified. Here, we adopt a coarse-grained molecular dynamics model at amino acid resolution to study the direct interaction between polyPR, the most toxic DPR, and various nuclear transport components to elucidate the binding mechanisms and provide a complete picture of potential polyPR-mediated NCT defects. We found polyPR to directly bind to several isoforms of the Impα family, CAS (the specific exporter of Impα) and RanGAP. We observe no binding between polyPR and Ran. Longer polyPRs at lower salt concentrations also make contact with RanGEF and NTF2. Analyzing the polyPR contact sites on the transport components reveals that polyPR potentially interferes with RanGTP/RanGDP binding, with nuclear localization signal (NLS)-containing cargoes (cargo-NLS) binding to Impα, with cargo-NLS release from Impα, and with Impα export from the nucleus. The abundance of polyPR-binding sites on multiple transport components combined with the inherent polyPR length dependence makes direct polyPR interference of NCT a potential mechanistic pathway of C9orf72 toxicity.}, } @article {pmid38483631, year = {2024}, author = {Perera, A and Brock, O and Ahmed, A and Shaw, C and Ashkan, K}, title = {Taking the knife to neurodegeneration: a review of surgical gene therapy delivery to the CNS.}, journal = {Acta neurochirurgica}, volume = {166}, number = {1}, pages = {136}, pmid = {38483631}, issn = {0942-0940}, mesh = {Humans ; *Central Nervous System ; Genetic Therapy/methods ; Genetic Vectors ; *Neurodegenerative Diseases/genetics/therapy ; }, abstract = {Gene supplementation and editing for neurodegenerative disorders has emerged in recent years as the understanding of the genetic mechanisms underlying several neurodegenerative disorders increases. The most common medium to deliver genetic material to cells is via viral vectors; and with respect to the central nervous system, adeno-associated viral (AAV) vectors are a popular choice. The most successful example of AAV-based gene therapy for neurodegenerative disorders is Zolgensma© which is a transformative intravenous therapy given to babies with spinal muscular atrophy. However, the field has stalled in achieving safe drug delivery to the central nervous system in adults for which treatments for disorders such as amyotrophic lateral sclerosis are desperately needed. Surgical gene therapy delivery has been proposed as a potential solution to this problem. While the field of the so-called regenerative neurosurgery has yielded pre-clinical optimism, several challenges have emerged. This review seeks to explore the field of regenerative neurosurgery with respect to AAV-based gene therapy for neurodegenerative diseases, its progress so far and the challenges that need to be overcome.}, } @article {pmid38484224, year = {2024}, author = {Sun, Y and Pahwa, S and Vasireddy, RP and Barty, A and Raslau, FD}, title = {Pearls & Oy-sters: Bibrachial Amyotrophy From a Dural Tear.}, journal = {Neurology}, volume = {102}, number = {7}, pages = {e209256}, doi = {10.1212/WNL.0000000000209256}, pmid = {38484224}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Spinal Cord Diseases ; *Intracranial Hypotension ; Magnetic Resonance Imaging ; Neck ; }, abstract = {Bibrachial amyotrophy signifies a clinical phenotype characterized by weakness in both upper extremities with preserved strength in the face, neck, and lower extremities. The underlying causes of bibrachial amyotrophy are broad. We report a patient exhibiting bibrachial amyotrophy who initially received a diagnosis of amyotrophic lateral sclerosis (ALS); however, his clinical course and NCS/EMG were atypical for ALS. Further evaluation demonstrated dural tears with CSF leak, resulting in a compressive extradural fluid collection, ventral myelopathy, and intracranial hypotension. Dural tear and ALS have overlapping features, including the manifestation of the bibrachial amyotrophy phenotype and the presence of T2 hyperintensities in the anterior horn cells, recognized by an "owl's eye" appearance on spine MRI. Clinical and radiologic vigilance is required to identify rare cases of dural tear causing ventral myelopathy that manifest as bibrachial amyotrophy.}, } @article {pmid38487369, year = {2024}, author = {Fagnani, E and Bonì, F and Seneci, P and Gornati, D and Muzio, L and Mastrangelo, E and Milani, M}, title = {Stabilization of the retromer complex: Analysis of novel binding sites of bis-1,3-phenyl guanylhydrazone 2a to the VPS29/VPS35 interface.}, journal = {Computational and structural biotechnology journal}, volume = {23}, number = {}, pages = {1088-1093}, pmid = {38487369}, issn = {2001-0370}, abstract = {The stabilization of the retromer protein complex can be effective in the treatment of different neurological disorders. Following the identification of bis-1,3-phenyl guanylhydrazone 2a as an effective new compound for the treatment of amyotrophic lateral sclerosis, in this work we analyze the possible binding sites of this molecule to the VPS35/VPS29 dimer of the retromer complex. Our results show that the affinity for different sites of the protein assembly depends on compound charge and therefore slight changes in the cell microenvironment could promote different binding states. Finally, we describe a novel binding site located in a deep cleft between VPS29 and VPS35 that should be further explored to select novel molecular chaperones for the stabilization of the retromer complex.}, } @article {pmid38487377, year = {2024}, author = {Hirsch, AG and Wright, EA and Nordberg, CM and DeWalle, J and Stains, EL and Kennalley, AL and Zhang, J and Tusing, LD and Piper, BJ}, title = {Dispensaries and Medical Marijuana Certifications and Indications: Unveiling the Geographic Connections in Pennsylvania, USA.}, journal = {Medical cannabis and cannabinoids}, volume = {7}, number = {1}, pages = {34-43}, pmid = {38487377}, issn = {2504-3889}, abstract = {INTRODUCTION: Pennsylvania opened its first medical marijuana (MMJ) dispensary in 2018. Qualifying conditions include six conditions determined to have no or insufficient evidence to support or refute MMJ effectiveness. We conducted a study to describe MMJ dispensary access in Pennsylvania and to determine whether dispensary proximity was associated with MMJ certifications and community demographics.

METHODS: Using data from the Pennsylvania Department of Health, we geocoded MMJ dispensary locations and linked them to US Census Bureau data. We created dispensary access measures from the population-weighted centroid of Zip Code Tabulation Areas (ZCTAs): distance to nearest dispensary and density of dispensaries within a 15-min drive. We evaluated associations between dispensary access and the proportion of adults who received MMJ certification and the proportion of certifications for low evidence conditions (amyotrophic lateral sclerosis, epilepsy, glaucoma, Huntington's disease, opioid use disorder, and Parkinson's disease) using negative binomial modeling, adjusting for community features. To evaluate associations racial and ethnic composition of communities and distance to nearest dispensary, we used logistic regression to estimate the odds ratios (OR) and 95% confidence intervals (CI), adjusting for median income.

RESULTS: Distance and density of MMJ dispensaries were associated with the proportion of the ZCTA population certified and the proportion of certifications for insufficient evidence conditions. Compared to ZCTAs with no dispensary within 15 min, the proportion of adults certified increased by up to 31% and the proportion of certifications for insufficient evidence decreased by up to 22% for ZCTAs with two dispensaries. From 2018 to 2021, the odds of being within five miles of a dispensary was up to 20 times higher in ZCTAs with the highest proportions of individuals who were not White (2019: OR: 20.14, CI: 10.7-37.8) and more than double in ZCTAs with the highest proportion of Hispanic individuals (2018: OR: 2.81, CI: 1.51-5.24), compared to ZCTAs with the lowest proportions.

CONCLUSIONS: Greater dispensary access was associated with the proportions of certified residents and certifications for low evidence conditions. Whether these patterns are due to differences in accessibility or demand is unknown. Associations between community demographics and dispensary proximity may indicate MMJ access differences.}, } @article {pmid38487578, year = {2024}, author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD}, title = {Association between CNS-active drugs and risk of Alzheimer's and age-related neurodegenerative diseases.}, journal = {Frontiers in psychiatry}, volume = {15}, number = {}, pages = {1358568}, pmid = {38487578}, issn = {1664-0640}, support = {P01 AG026572/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; R01 AG057931/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVE: As neuropsychiatric conditions can increase the risk of age-related neurodegenerative diseases (NDDs), the impact of CNS-active drugs on the risk of developing Alzheimer's Disease (AD), non-AD dementia, Multiple Sclerosis (MS), Parkinson's Disease (PD) and Amyotrophic Lateral Sclerosis (ALS) was investigated.

RESEARCH DESIGN AND METHODS: A retrospective cohort analysis of a medical claims dataset over a 10 year span was conducted in patients aged 60 years or older. Participants were propensity score matched for comorbidity severity and demographic parameters. Relative risk (RR) ratios and 95% confidence intervals (CI) were determined for age-related NDDs. Cumulative hazard ratios and treatment duration were determined to assess the association between CNS-active drugs and NDDs at different ages and treatment duration intervals.

RESULTS: In 309,128 patients who met inclusion criteria, exposure to CNS-active drugs was associated with a decreased risk of AD (0.86% vs 1.73%, RR: 0.50; 95% CI: 0.47-0.53; p <.0001) and all NDDs (3.13% vs 5.76%, RR: 0.54; 95% CI: 0.53-0.56; p <.0001). Analysis of impact of drug class on risk of AD indicated that antidepressant, sedative, anticonvulsant, and stimulant medications were associated with significantly reduced risk of AD whereas atypical antipsychotics were associated with increased AD risk. The greatest risk reduction for AD and NDDs occurred in patients aged 70 years or older with a protective effect only in patients with long-term therapy (>3 years). Furthermore, responders to these therapeutics were characterized by diagnosed obesity and higher prescriptions of anti-inflammatory drugs and menopausal hormonal therapy, compared to patients with a diagnosis of AD (non-responders). Addition of a second CNS-active drug was associated with greater reduction in AD risk compared to monotherapy, with the combination of a Z-drug and an SNRI associated with greatest AD risk reduction.

CONCLUSION: Collectively, these findings indicate that CNS-active drugs were associated with reduced risk of developing AD and other age-related NDDs. The exception was atypical antipsychotics, which increased risk. Potential use of combination therapy with atypical antipsychotics could mitigate the risk conferred by these drugs. Evidence from these analyses advance precision prevention strategies to reduce the risk of age-related NDDs in persons with neuropsychiatric disorders.}, } @article {pmid38488546, year = {2024}, author = {Yang, Y and Cheng, Q and Gao, J and Kim, WS}, title = {Status of biomarker development for frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {10}, pages = {2117-2118}, pmid = {38488546}, issn = {1673-5374}, } @article {pmid38489867, year = {2024}, author = {Tausendfreund, O and Bidlingmaier, M and Martini, S and Müller, K and Rippl, M and Schilbach, K and Schmidmaier, R and Drey, M}, title = {Growth hormone treatment in aged patients with comorbidities: A systematic review.}, journal = {Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {75}, number = {}, pages = {101584}, doi = {10.1016/j.ghir.2024.101584}, pmid = {38489867}, issn = {1532-2238}, mesh = {Aged ; Humans ; Comorbidity ; Growth Hormone ; *Human Growth Hormone/adverse effects/therapeutic use ; Insulin-Like Growth Factor I ; Quality of Life ; Randomized Controlled Trials as Topic ; *Aging/pathology ; }, abstract = {OBJECTIVE: Hormonal substitution with growth hormone in aged patients remains a debated research topic and is rarely initiated in clinical practice. This reluctance may originate from concerns about adverse effects and the uncritical use as an anti-aging agent. Nevertheless, beneficial effects for selected patients suffering from certain acute and chronic illnesses could justify its use at an advanced age. This systematic review analyzes randomized controlled studies of GH interventions in older patients with different comorbidities to assess both, beneficial and harmful effects.

DESIGN: A systematic search strategy was implemented to identify relevant studies from PubMed, MEDLINE, and The Cochrane Library.

INCLUSION CRITERIA: participants aged over 65 years, randomized controlled trials involving human growth hormone (GH) and presence of at least one additional comorbidity independent of a flawed somatotropic axis.

RESULTS: The eight eligible studies encompassed various comorbidities including osteoporosis, frailty, chronic heart failure, hip fracture, amyotrophic lateral sclerosis and hemodialysis. Outcomes varied, including changes in body composition, physical performance, strength, bone mineral density, cardiovascular parameters, quality of life and housing situation. Study protocols differed greatly in GH application frequency (daily, 2nd day or 3×/week), doses (0.41 mg-2.6 mg; mean 1.3 mg per 60 kg patient) and duration (1-12 months; mean 7 months). Mild dose-related side effects were reported, alongside noticeable positive impacts particularly on body composition, functionality, and quality of life.

CONCLUSION: Despite limited evidence, GH treatment might offer diverse benefits with few adverse effects. Further research with IGF-I dependent indication and clear outcomes, incorporating IGF-I dependent GH titration in older adults is warranted.}, } @article {pmid38490025, year = {2024}, author = {Turco, A and Primiceri, E and Chiriacò, MS and La Pesa, V and Ferrara, F and Riva, N and Quattrini, A and Romano, A and Maruccio, G}, title = {Advancing amyotrophic lateral sclerosis disease diagnosis: A lab-on-chip electrochemical immunosensor for ultra-sensitive TDP-43 protein detection and monitoring in serum patients'.}, journal = {Talanta}, volume = {273}, number = {}, pages = {125866}, doi = {10.1016/j.talanta.2024.125866}, pmid = {38490025}, issn = {1873-3573}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Polymers ; *Biosensing Techniques ; *Neurodegenerative Diseases ; Reproducibility of Results ; Immunoassay ; Pyrroles ; DNA-Binding Proteins/metabolism ; Biomarkers/metabolism ; }, abstract = {The global increase in population aging has led to a rise in neurodegenerative diseases (NDs), posing significant challenges to public health. Developing selective and specific biomarkers for early diagnosis and drug development is crucial addressing the growing burden of NDs. In this context, the RNA-binding protein TDP-43 has emerged as a promising biomarker for amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and TDP-43-associated proteinopathies. However, existing detection methods suffer from limitations such as cost, complexity, and operator dependence. Here, we present a novel electrochemical biosensor integrated into a lab-on-chip (LoC) platform to detect TDP-43. The sensor utilizes electrosynthesized polypyrrole derivatives with carboxylic groups for transducer functionalization, enabling targeted immobilization of TDP-43 antibodies. Differential pulsed voltammetry (DPV) is used for the indirect detection and quantification of TDP-43. The chip exhibits rapid response, good reproducibility, a linear detection range, and sensitivity from 0.01 ng/mL to 25 ng/mL of TDP-43 protein concentration with a LOD = 10 pg/mL. Furthermore, successful TDP-43 detection in complex matrices like serum of ALS patients and healthy individuals demonstrates its potential as a point-of-care diagnostic device. This electrochemical biosensor integrated into a chip offers good sensitivity, rapid response, and robust performance, providing a promising avenue for advancing neurodegenerative disease diagnostics and therapeutic development.}, } @article {pmid38490215, year = {2024}, author = {Reilich, P}, title = {[Multidimensional care for people with ALS and their families].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {92}, number = {3}, pages = {70-71}, doi = {10.1055/a-2240-8802}, pmid = {38490215}, issn = {1439-3522}, } @article {pmid38490348, year = {2024}, author = {Chatterjee, A and Kumar, S and Roy Sarkar, S and Halder, R and Kumari, R and Banerjee, S and Sarkar, B}, title = {Dietary polyphenols represent a phytotherapeutic alternative for gut dysbiosis associated neurodegeneration: A systematic review.}, journal = {The Journal of nutritional biochemistry}, volume = {129}, number = {}, pages = {109622}, doi = {10.1016/j.jnutbio.2024.109622}, pmid = {38490348}, issn = {1873-4847}, mesh = {*Polyphenols/pharmacology ; *Dysbiosis/drug therapy ; *Gastrointestinal Microbiome/drug effects ; Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; Oxidative Stress/drug effects ; Phytotherapy ; Prebiotics ; Diet ; }, abstract = {Globally, neurodegeneration and cerebrovascular disease are common and growing causes of morbidity and mortality. Pathophysiology of this group of diseases encompasses various factors from oxidative stress to gut microbial dysbiosis. The study of the etiology and mechanisms of oxidative stress as well as gut dysbiosis-induced neurodegeneration in Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, autism spectrum disorder, and Huntington's disease has recently received a lot of attention. Numerous studies lend credence to the notion that changes in the intestinal microbiota and enteric neuroimmune system have an impact on the initiation and severity of these diseases. The prebiotic role of polyphenols can influence the makeup of the gut microbiota in neurodegenerative disorders by modulating intracellular signalling pathways. Metabolites of polyphenols function directly as neurotransmitters by crossing the blood-brain barrier or indirectly via influencing the cerebrovascular system. This assessment aims to bring forth an interlink between the consumption of polyphenols biotransformed by gut microbiota which in turn modulate the gut microbial diversity and biochemical changes in the brain. This systematic review will further augment research towards the association of dietary polyphenols in the management of gut dysbiosis-associated neurodegenerative diseases.}, } @article {pmid38491210, year = {2024}, author = {He, D and Yang, X and Liu, L and Shen, D and Liu, Q and Liu, M and Zhang, X and Cui, L}, title = {Dysregulated N[6]-methyladenosine modification in peripheral immune cells contributes to the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Frontiers of medicine}, volume = {18}, number = {2}, pages = {285-302}, pmid = {38491210}, issn = {2095-0225}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/immunology ; *Adenosine/analogs & derivatives/metabolism ; Humans ; Animals ; Female ; Mice ; Male ; Middle Aged ; Aged ; Case-Control Studies ; RAW 264.7 Cells ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurogenerative disorder with uncertain origins. Emerging evidence implicates N6-methyladenosine (m[6]A) modification in ALS pathogenesis. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and liquid chromatography-mass spectrometry were utilized for m[6]A profiling in peripheral immune cells and serum proteome analysis, respectively, in patients with ALS (n = 16) and controls (n = 6). The single-cell transcriptomic dataset (GSE174332) of primary motor cortex was further analyzed to illuminate the biological implications of differentially methylated genes and cell communication changes. Analysis of peripheral immune cells revealed extensive RNA hypermethylation, highlighting candidate genes with differential m[6]A modification and expression, including C-X3-C motif chemokine receptor 1 (CX3CR1). In RAW264.7 macrophages, disrupted CX3CR1 signaling affected chemotaxis, potentially influencing immune cell migration in ALS. Serum proteome analysis demonstrated the role of dysregulated immune cell migration in ALS. Cell type-specific expression variations of these genes in the central nervous system (CNS), particularly microglia, were observed. Intercellular communication between neurons and glial cells was selectively altered in ALS CNS. This integrated approach underscores m[6]A dysregulation in immune cells as a potential ALS contributor.}, } @article {pmid38491246, year = {2024}, author = {Musarò, A and Dobrowolny, G and Cambieri, C and Libonati, L and Moret, F and Casola, I and Laurenzi, G and Garibaldi, M and Inghilleri, M and Ceccanti, M}, title = {MiR206 and 423-3p Are Differently Modulated in Fast and Slow-Progressing Amyotrophic Lateral Sclerosis Patients.}, journal = {Neuromolecular medicine}, volume = {26}, number = {1}, pages = {5}, pmid = {38491246}, issn = {1559-1174}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Disease Progression ; *MicroRNAs/genetics ; Research Design ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neuromuscular disease with a wide disease progression. Despite several efforts to develop efficient biomarkers, many concerns about the available ones still need to be addressed. MicroRNA (miR) are non-coding RNAs that can modulate molecular circuits and are involved in ALS pathogenic mechanisms. 22 fast and 23 slow-progressing-defined ALS patients were recruited. ALSFRS-R, strength, respiratory function, nerve conduction studies, and creatine kinase were evaluated at the baseline and after 6 months of follow-up. The mean monthly reduction of the previous variables (progression index - PI) was calculated. MiR206, 133a-3p, 151a-5p, 199a-5p, and 423-3p were dosed. The univariate analysis showed an independent reduction of miR206 and an increase of miR423-3p in patients with a slow slope of ALSFRS-R and weakness, respectively. MiR206 and 423-3p are differently modulated in fast and slow-progressing ALS patients, suggesting a role for microRNAs in prognosis and therapeutic target.}, } @article {pmid38492239, year = {2024}, author = {Johnson, CN and Sojitra, KA and Sohn, EJ and Moreno-Romero, AK and Baudin, A and Xu, X and Mittal, J and Libich, DS}, title = {Insights into Molecular Diversity within the FUS/EWS/TAF15 Protein Family: Unraveling Phase Separation of the N-Terminal Low-Complexity Domain from RNA-Binding Protein EWS.}, journal = {Journal of the American Chemical Society}, volume = {146}, number = {12}, pages = {8071-8085}, pmid = {38492239}, issn = {1520-5126}, support = {R01 GM136917/GM/NIGMS NIH HHS/United States ; R01 GM140127/GM/NIGMS NIH HHS/United States ; R35 GM153388/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; RNA-Binding Protein EWS/metabolism ; RNA-Binding Protein FUS/metabolism ; Phase Separation ; *Sarcoma, Ewing/genetics/metabolism/pathology ; Proteins/metabolism ; Tyrosine ; *TATA-Binding Protein Associated Factors/genetics/metabolism ; }, abstract = {The FET protein family, comprising FUS, EWS, and TAF15, plays crucial roles in mRNA maturation, transcriptional regulation, and DNA damage response. Clinically, they are linked to Ewing family tumors and neurodegenerative diseases such as amyotrophic lateral sclerosis. The fusion protein EWS::FLI1, the causative mutation of Ewing sarcoma, arises from a genomic translocation that fuses a portion of the low-complexity domain (LCD) of EWS (EWS[LCD]) with the DNA binding domain of the ETS transcription factor FLI1. This fusion protein modifies transcriptional programs and disrupts native EWS functions, such as splicing. The exact role of the intrinsically disordered EWS[LCD] remains a topic of active investigation, but its ability to phase separate and form biomolecular condensates is believed to be central to EWS::FLI1's oncogenic properties. Here, we used paramagnetic relaxation enhancement NMR, microscopy, and all-atom molecular dynamics (MD) simulations to better understand the self-association and phase separation tendencies of the EWS[LCD]. Our NMR data and mutational analysis suggest that a higher density and proximity of tyrosine residues amplify the likelihood of condensate formation. MD simulations revealed that the tyrosine-rich termini exhibit compact conformations with unique contact networks and provided critical input on the relationship between contacts formed within a single molecule (intramolecular) and inside the condensed phase (intermolecular). These findings enhance our understanding of FET proteins' condensate-forming capabilities and underline differences between EWS, FUS, and TAF15.}, } @article {pmid38493058, year = {2024}, author = {Milani, M and Della Valle, I and Rossi, S and Fabbrizio, P and Margotta, C and Nardo, G and Cozzolino, M and D'Ambrosi, N and Apolloni, S}, title = {Neuroprotective effects of niclosamide on disease progression via inflammatory pathways modulation in SOD1-G93A and FUS-associated amyotrophic lateral sclerosis models.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {3}, pages = {e00346}, pmid = {38493058}, issn = {1878-7479}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Disease Models, Animal ; *Disease Progression ; Inflammation/drug therapy ; Mice, Transgenic ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Niclosamide/pharmacology/therapeutic use ; RNA-Binding Protein FUS/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease influenced by genetic, epigenetic, and environmental factors, resulting in dysfunction in cellular and molecular pathways. The limited efficacy of current treatments highlights the need for combination therapies targeting multiple aspects of the disease. Niclosamide, an anthelminthic drug listed as an essential medicine, has been repurposed in clinical trials for different diseases due to its anti-inflammatory and anti-fibrotic properties. Niclosamide can inhibit various molecular pathways (e.g., STAT3, mTOR) that are dysregulated in ALS, suggesting its potential to disrupt these altered mechanisms associated with the pathology. We administered niclosamide intraperitoneally to two transgenic murine models, SOD1-G93A and FUS mice, mimicking key pathological processes of ALS. The treatment was initiated at the onset of symptoms, and we assessed disease progression by neurological scores, rotarod and wire tests, and monitored survival. Furthermore, we investigated cellular and molecular mechanisms affected by niclosamide in the spinal cord and muscle of ALS mice. In both models, the administration of niclosamide resulted in a slowdown of disease progression, an increase in survival rates, and an improvement in tissue pathology. This was characterised by reduced gliosis, motor neuron loss, muscle atrophy, and inflammatory pathways. Based on these results, our findings demonstrate that niclosamide can impact multiple pathways involved in ALS. This multi-targeted approach leads to a slowdown in the progression of the disease, positioning niclosamide as a promising candidate for repurposing in the treatment of ALS.}, } @article {pmid38495583, year = {2024}, author = {Uy, G and Farrell, LN and Faheem, SF and Kinne, LE and Adore, MG and Im, SH and Fairman, R}, title = {The Effects of poly-GA and poly-PR C9orf72 Dipeptide Repeats on Sleep Patterns in Drosophila melanogaster.}, journal = {microPublication biology}, volume = {2024}, number = {}, pages = {}, pmid = {38495583}, issn = {2578-9430}, support = {P40 OD018537/OD/NIH HHS/United States ; }, abstract = {C9orf72 is the most common familial gene associated with amyotrophic lateral sclerosis (ALS). Dipeptide repeats (DPRs) encoded by an expanded nucleotide repeat sequence in the C9orf72 gene were found in the sleep-related neurons of patients, indicating a role of DPRs in ALS-associated sleep disruptions. Poly-GA or poly-PR DPRs were expressed in male Drosophila melanogaster to study their effect on sleep . Poly-PR expression caused sleep disruptions while poly-GA expression did not. This study validates the use of Drosophila as an in vivo model system for exploring the roles of DPRs in perturbing the underlying molecular mechanisms in sleep regulation.}, } @article {pmid38496202, year = {2024}, author = {da Silva Alves, C and Barroso, T and Gerardo, A and Almeida, T and Maduro, S and Boléo-Tomé, JP and Liberato, H}, title = {Forced Expiratory Volume in One Second Quotient (FEV1Q) as a Prognostic Factor in Amyotrophic Lateral Sclerosis Patients: Comparing Its Predictive Value to Other Lung Function Measurements.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e54176}, pmid = {38496202}, issn = {2168-8184}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting the first and second motor neurons. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) have conventionally served as indicators of respiratory muscle strength. Recently, FEV1Q (FEV1 divided by the sex-specific first percentile values of absolute FEV1 in adults with lung disease) has been suggested as a predictor of mortality. While FVC has been utilized as a prognostic factor, FEV1Q has not yet been examined.

METHODS: This retrospective unicenter study evaluated FEV1Q as a predictor of mortality in ALS patients, comparing its predictive efficacy with other measurements, including FEV1, FVC, sniff nasal inspiratory pressure, and maximal inspiratory pressure. The study utilized univariate analysis for each variable employing the Cox proportional hazards model to determine the statistical significance and predictive power of each measurement.

RESULTS: Forty-five patients were included, female predominant (60%) and an average age at diagnosis of 69.2 ± 11 years. Almost all (95%) met the criteria for non-invasive ventilation (NIV) and initiated (93%) during the study period, a mean of 137 days after diagnosis. The mortality rate observed was 57%, occurring at a median of 398 days post-diagnosis. On average, patients underwent 1.7 pulmonary function tests, revealing a decline in various parameters, including FEV1, FEV1Q, and FVC. However, only FEV1Q was a statistically significant predictor of mortality (p < 0.0083) in a Cox regression analysis. A negative coefficient for FEV1Q indicated that higher values were associated with a reduced mortality risk, with an average FEV1Q of 2.68 observed at the time of death.

CONCLUSION: FEV1Q emerged as the only statistically significant predictor of mortality among the evaluated respiratory measurements in ALS patients. This study is the first to focus on applying FEV1Q in the clinical evaluation of ALS, marking an initial step in understanding its potential role in patient follow-up. However, further studies are needed before these findings can be incorporated into clinical practice.}, } @article {pmid38496415, year = {2024}, author = {Suazo, KF and Mishra, V and Maity, S and Auger, SA and Justyna, K and Petre, A and Ottoboni, L and Ongaro, J and Corti, SP and Lotti, F and Przedborski, S and Distefano, MD}, title = {Improved synthesis and application of an alkyne-functionalized isoprenoid analogue to study the prenylomes of motor neurons, astrocytes and their stem cell progenitors.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38496415}, issn = {2692-8205}, support = {R01 NS107442/NS/NINDS NIH HHS/United States ; P30 CA077598/CA/NCI NIH HHS/United States ; R21 NS101575/NS/NINDS NIH HHS/United States ; T32 AG029796/AG/NIA NIH HHS/United States ; T32 GM132029/GM/NIGMS NIH HHS/United States ; R35 GM141853/GM/NIGMS NIH HHS/United States ; }, abstract = {Protein prenylation is one example of a broad class of post-translational modifications where proteins are covalently linked to various hydrophobic moieties. To globally identify and monitor levels of all prenylated proteins in a cell simultaneously, our laboratory and others have developed chemical proteomic approaches that rely on the metabolic incorporation of isoprenoid analogues bearing bio-orthogonal functionality followed by enrichment and subsequent quantitative proteomic analysis. Here, several improvements in the synthesis of the alkyne-containing isoprenoid analogue C15AlkOPP are reported to improve synthetic efficiency. Next, metabolic labeling with C15AlkOPP was optimized to obtain useful levels of metabolic incorporation of the probe in several types of primary cells. Those conditions were then used to study the prenylomes of motor neurons (ES-MNs), astrocytes (ES-As), and their embryonic stem cell progenitors (ESCs), which allowed for the identification of 54 prenylated proteins from ESCs, 50 from ES-MNs and 84 from ES-As, representing all types of prenylation. Bioinformatic analysis revealed specific enriched pathways, including nervous system development, chemokine signaling, Rho GTPase signaling, and adhesion. Hierarchical clustering showed that most enriched pathways in all three cell types are related to GTPase activity and vesicular transport. In contrast, STRING analysis showed significant interactions in two populations that appear to be cell type dependent. The data provided herein demonstrates that robust incorporation of C15AlkOPP can be obtained in ES-MNs and related primary cells purified via magnetic-activated cell sorting allowing the identification and quantification of numerous prenylated proteins. These results suggest that metabolic labeling with C15AlkOPP should be an effective approach for investigating the role of prenylated proteins in primary cells in both normal cells and disease pathologies, including ALS.}, } @article {pmid38496572, year = {2024}, author = {Cameron, B and Torres-Hernandez, L and Montague, VL and Lewis, KA and Smith, H and Fox, J and Guo, X and Kalb, RG and George, L}, title = {Titin is a nucleolar protein in neurons.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38496572}, issn = {2693-5015}, support = {P20 GM103474/GM/NIGMS NIH HHS/United States ; R15 NS090384/NS/NINDS NIH HHS/United States ; }, abstract = {Titin is the largest protein produced by living cells and its function as a molecular spring in striated muscle is well characterized (1, 2). Here we demonstrate that titin isoforms in the same size range as found in muscle are prominent neuronal proteins in both the central and peripheral nervous systems, including motor neurons in the spinal cord and brain. Within these neurons, titin localizes to the dense fibrillar component of the nucleolus, the site of ribosomal RNA biogenesis and modification, and a critical site of dysfunction in neurodegenerative disease (3-5). Additionally, we show that the levels of both titin mRNA and protein are altered in the spinal cord of SOD1[G93A] mice, a commonly used model of amyotrophic lateral sclerosis, indicating that titin mediated nucleolar events may in fact contribute to the pathobiology of disease.}, } @article {pmid38498118, year = {2024}, author = {Khanna, RK and Catanese, S and Blasco, H and Pisella, PJ and Corcia, P}, title = {Corneal nerves and amyotrophic lateral sclerosis: an in vivo corneal confocal imaging study.}, journal = {Journal of neurology}, volume = {271}, number = {6}, pages = {3370-3377}, pmid = {38498118}, issn = {1432-1459}, support = {2021//Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone/ ; 2021//Novartis-Société Française d'Ophtalmologie./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/physiopathology ; *Microscopy, Confocal ; Male ; *Cornea/innervation/diagnostic imaging/pathology ; Female ; Middle Aged ; Aged ; Case-Control Studies ; Prospective Studies ; Nerve Fibers/pathology ; Adult ; }, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disorder. Diagnosis is challenging due to its clinical heterogeneity and the absence of definitive diagnostic tools, leading to delays averaging between 9.1 and 27 months. In vivo corneal confocal microscopy, assessing the sub-basal nerve plexus of the cornea, has been proposed as a potential biomarker for ALS. We aimed to determine whether the assessment of corneal nerves using in vivo confocal microscopy can serve as an imaging biomarker for ALS.

METHODS: A single-centre prospective case-control study was conducted in France from September 2021 to March 2023 including patients with ALS according to the revised EI Escorial criteria. The corneal sub-basal nerve plexus was analysed using in vivo confocal microscopy. An automated algorithm (ACCMetrics) was used to evaluate corneal parameters: nerve fibre density, nerve branch density, nerve fibre length, nerve fibre area, nerve total branch density, nerve fibre width, and nerve fractal dimension.

RESULTS: Twenty-two patients with ALS and 30 controls were included. No significant differences were found between ALS and control groups for all corneal parameters (p > 0.05). Corneal sensitivity did not differ between groups, and no correlation was identified between corneal nerve parameters and ALS disease duration, severity and rate of progression (p > 0.05).

CONCLUSIONS: The present study does not support the use of in vivo corneal confocal microscopy as an early diagnostic or prognostic tool for ALS. Further research, especially longitudinal investigations, is needed to understand any potential corneal innervation changes as ALS progresses.}, } @article {pmid38498721, year = {2024}, author = {Kertesz, A and Finger, E and Munoz, DG}, title = {Progress in Primary Progressive Aphasia: A Review.}, journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology}, volume = {37}, number = {1}, pages = {3-12}, pmid = {38498721}, issn = {1543-3641}, mesh = {Humans ; *Frontotemporal Dementia/diagnosis/genetics ; *Supranuclear Palsy, Progressive/genetics/pathology ; Syndrome ; *Aphasia, Primary Progressive ; }, abstract = {We present a review of the definition, classification, and epidemiology of primary progressive aphasia (PPA); an update of the taxonomy of the clinical syndrome of PPA; and recent advances in the neuroanatomy, pathology, and genetics of PPA, as well as the search for biomarkers and treatment. PPA studies that have contributed to concepts of language organization and disease propagation in neurodegeneration are also reviewed. In addition, the issues of heterogeneity versus the relationships of the clinical phenotypes and their relationship to biological, pathological, and genetic advances are discussed, as is PPA's relationship to other conditions such as frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, Pick disease, and amyotrophic lateral sclerosis. Arguments are presented in favor of considering these conditions as one entity versus many.}, } @article {pmid38499161, year = {2024}, author = {Bashir, S and Aiman, A and Shahid, M and Chaudhary, AA and Sami, N and Basir, SF and Hassan, I and Islam, A}, title = {Amyloid-induced neurodegeneration: A comprehensive review through aggregomics perception of proteins in health and pathology.}, journal = {Ageing research reviews}, volume = {96}, number = {}, pages = {102276}, doi = {10.1016/j.arr.2024.102276}, pmid = {38499161}, issn = {1872-9649}, mesh = {Humans ; Amyloid/metabolism ; *Amyloidosis/metabolism ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/metabolism ; Amyloidogenic Proteins ; Perception ; }, abstract = {Amyloidosis of protein caused by fibrillation and aggregation are some of the most exciting new edges not only in protein sciences but also in molecular medicines. The present review discusses recent advancements in the field of neurodegenerative diseases and therapeutic applications with ongoing clinical trials, featuring new areas of protein misfolding resulting in aggregation. The endogenous accretion of protein fibrils having fibrillar morphology symbolizes the beginning of neuro-disorders. Prognostic amyloidosis is prominent in numerous degenerative infections such as Alzheimer's and Parkinson's disease, Amyotrophic lateral sclerosis (ALS), etc. However, the molecular basis determining the intracellular or extracellular evidence of aggregates, playing a significant role as a causative factor in neurodegeneration is still unclear. Structural conversions and protein self-assembly resulting in the formation of amyloid oligomers and fibrils are important events in the pathophysiology of the disease. This comprehensive review sheds light on the evolving landscape of potential treatment modalities, highlighting the ongoing clinical trials and the potential socio-economic impact of novel therapeutic interventions in the realm of neurodegenerative diseases. Furthermore, many drugs are undergoing different levels of clinical trials that would certainly help in treating these disorders and will surely improve the socio-impact of human life.}, } @article {pmid38499333, year = {2024}, author = {Turner, MR}, title = {We need to talk about brain donation.}, journal = {Practical neurology}, volume = {24}, number = {3}, pages = {183-184}, doi = {10.1136/pn-2024-004102}, pmid = {38499333}, issn = {1474-7766}, mesh = {Humans ; *Tissue and Organ Procurement ; Tissue Donors ; Brain/diagnostic imaging ; Brain Death/diagnosis ; }, } @article {pmid38499486, year = {2024}, author = {Jia, J and Fan, H and Wan, X and Fang, Y and Li, Z and Tang, Y and Zhang, Y and Huang, J and Fang, D}, title = {FUS reads histone H3K36me3 to regulate alternative polyadenylation.}, journal = {Nucleic acids research}, volume = {52}, number = {10}, pages = {5549-5571}, pmid = {38499486}, issn = {1362-4962}, support = {2022YFA1302800//National Key R&D Program of China/ ; 32361133547//National Natural Science Foundation of China/ ; 2019QN81005//Fundamental Research Funds for the Central Universities/ ; LZ24C060001//Natural Science Foundation of China/ ; 2022SKLS-KFKT002//Shanghai Jiao Tong University School of Medicine/ ; }, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Cell Differentiation/genetics ; Chromatin/metabolism/genetics ; HEK293 Cells ; *Histones/metabolism/genetics ; Mitochondria/metabolism/genetics ; Mouse Embryonic Stem Cells ; Mutation ; *Polyadenylation/genetics ; *RNA-Binding Protein FUS/genetics/metabolism ; Cell Line ; Protein Domains ; }, abstract = {Complex organisms generate differential gene expression through the same set of DNA sequences in distinct cells. The communication between chromatin and RNA regulates cellular behavior in tissues. However, little is known about how chromatin, especially histone modifications, regulates RNA polyadenylation. In this study, we found that FUS was recruited to chromatin by H3K36me3 at gene bodies. The H3K36me3 recognition of FUS was mediated by the proline residues in the ZNF domain. After these proline residues were mutated or H3K36me3 was abolished, FUS dissociated from chromatin and bound more to RNA, resulting in an increase in polyadenylation sites far from stop codons genome-wide. A proline mutation corresponding to a mutation in amyotrophic lateral sclerosis contributed to the hyperactivation of mitochondria and hyperdifferentiation in mouse embryonic stem cells. These findings reveal that FUS is an H3K36me3 reader protein that links chromatin-mediated alternative polyadenylation to human disease.}, } @article {pmid38499535, year = {2024}, author = {Chen, S and Puri, A and Bell, B and Fritsche, J and Palacios, HH and Balch, M and Sprunger, ML and Howard, MK and Ryan, JJ and Haines, JN and Patti, GJ and Davis, AA and Jackrel, ME}, title = {HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {2436}, pmid = {38499535}, issn = {2041-1723}, support = {R35 GM128772/GM/NIGMS NIH HHS/United States ; K08 NS101118/NS/NINDS NIH HHS/United States ; F31 NS120512/NS/NINDS NIH HHS/United States ; F31 GM140622/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *alpha-Synuclein/genetics/metabolism ; Amyloid/metabolism ; High-Temperature Requirement A Serine Peptidase 1/genetics/metabolism ; *Parkinson Disease/genetics/metabolism ; Lewy Bodies/metabolism ; }, abstract = {Parkinson's disease (PD) is closely linked to α-synuclein (α-syn) misfolding and accumulation in Lewy bodies. The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer's disease, and inactivating mutations to mitochondrial HTRA2 are implicated in PD. Here, we report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The protease domain of HTRA1 is necessary and sufficient for inhibiting aggregation, yet this activity is proteolytically-independent. Further, HTRA1 disaggregates preformed α-syn fibrils, rendering them incapable of seeding aggregation of endogenous α-syn, while reducing HTRA1 expression promotes α-syn seeding. HTRA1 remodels α-syn fibrils by targeting the NAC domain, the key domain catalyzing α-syn amyloidogenesis. Finally, HTRA1 detoxifies α-syn fibrils and prevents formation of hyperphosphorylated α-syn accumulations in primary neurons. Our findings suggest that HTRA1 may be a therapeutic target for a range of neurodegenerative disorders.}, } @article {pmid38500677, year = {2024}, author = {Zhou, L and Xu, R}, title = {Invertebrate genetic models of amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1328578}, pmid = {38500677}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease characterized by the progressive death of motor neurons in the cerebral cortex, brain stem, and spinal cord. The exact mechanisms underlying the pathogenesis of ALS remain unclear. The current consensus regarding the pathogenesis of ALS suggests that the interaction between genetic susceptibility and harmful environmental factors is a promising cause of ALS onset. The investigation of putative harmful environmental factors has been the subject of several ongoing studies, but the use of transgenic animal models to study ALS has provided valuable information on the onset of ALS. Here, we review the current common invertebrate genetic models used to study the pathology, pathophysiology, and pathogenesis of ALS. The considerations of the usage, advantages, disadvantages, costs, and availability of each invertebrate model will also be discussed.}, } @article {pmid38500808, year = {2024}, author = {, }, title = {Retraction: CSF p-tau as a potential cognition impairment biomarker in ALS.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1392563}, doi = {10.3389/fneur.2024.1392563}, pmid = {38500808}, issn = {1664-2295}, abstract = {[This retracts the article DOI: 10.3389/fneur.2022.991143.].}, } @article {pmid38501453, year = {2024}, author = {Erb, MK and Calcagno, N and Brown, R and Burke, KM and Scheier, ZA and Iyer, AS and Clark, A and Higgins, MP and Keegan, M and Gupta, AS and Johnson, SA and Chew, S and Berry, JD}, title = {Longitudinal comparison of the self-administered ALSFRS-RSE and ALSFRS-R as functional outcome measures in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {570-580}, doi = {10.1080/21678421.2024.2322549}, pmid = {38501453}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/psychology ; Male ; Female ; Longitudinal Studies ; Middle Aged ; Aged ; Self Report ; Outcome Assessment, Health Care/methods ; Smartphone ; Mobile Applications ; Adult ; }, abstract = {OBJECTIVE: Test the feasibility, adherence rates and optimal frequency of digital, remote assessments using the ALSFRS-RSE via a customized smartphone-based app.

METHODS: This fully remote, longitudinal study was conducted over a 24-week period, with virtual visits every 3 months and weekly digital assessments. 19 ALS participants completed digital assessments via smartphone, including a digital version of the ALSFRS-RSE and mood survey. Interclass correlation coefficients (ICC) and Bland-Altman plots were used to assess agreement between staff-administered and self-reported ALSFRS-R pairs. Longitudinal change was evaluated using ANCOVA models and linear mixed models, including impact of mood and time of day. Impact of frequency of administration of the ALSFRS-RSE on precision of the estimate slope was tested using a mixed effects model.

RESULTS: In our ALS cohort, digital assessments were well-accepted and adherence was robust, with completion rates of 86%. There was excellent agreement between the digital self-entry and staff-administered scores computing multiple ICCs (ICC range = 0.925-0.961), with scores on the ALSFRS-RSE slightly higher (1.304 points). Digital assessments were associated with increased precision of the slope, resulting in higher standardized response mean estimates for higher frequencies, though benefit appeared to diminish at biweekly and weekly frequency. Effects of participant mood and time of day on total ALSFRS-RSE score were evaluated but were minimal and not statistically significant.

CONCLUSION: Remote collection of digital patient-reported outcomes of functional status such as the ALSFRS-RSE yield more accurate estimates of change over time and provide a broader understanding of the lived experience of people with ALS.}, } @article {pmid38503116, year = {2024}, author = {Opitz, DL}, title = {Editorial: Re-enchanting the vocation of science.}, journal = {Endeavour}, volume = {48}, number = {1}, pages = {100920}, doi = {10.1016/j.endeavour.2024.100920}, pmid = {38503116}, issn = {1873-1929}, mesh = {Occupations ; Retirement ; *Science ; }, abstract = {This editorial introduces the collection, "Specialists with Spirit: Re-Enchanting the Vocation of Science," co-edited by Dorien Daling and Hanneke Hoekstra. The collection offers a tribute to the eminent historian of science, Klaas van Berkel, commemorating his retirement from the University of Groningen. The papers compel us to consider the ongoing tensions between knowledge production and the social, political, and economic constraints faced by scholars, a theme that Max Weber famously addressed in his 1917 lecture, Wissenschaft als Beruf, which the collection's contributors revisit as they consider a range of historical and contemporary questions concerning science and its study by historians.}, } @article {pmid38504285, year = {2024}, author = {Papaiz, F and Dourado, MET and de Medeiros Valentim, RA and Pinto, R and de Morais, AHF and Arrais, JP}, title = {Ensemble-imbalance-based classification for amyotrophic lateral sclerosis prognostic prediction: identifying short-survival patients at diagnosis.}, journal = {BMC medical informatics and decision making}, volume = {24}, number = {1}, pages = {80}, pmid = {38504285}, issn = {1472-6947}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Prognosis ; Machine Learning ; }, abstract = {Prognosticating Amyotrophic Lateral Sclerosis (ALS) presents a formidable challenge due to patients exhibiting different onset sites, progression rates, and survival times. In this study, we have developed and evaluated Machine Learning (ML) algorithms that integrate Ensemble and Imbalance Learning techniques to classify patients into Short and Non-Short survival groups based on data collected during diagnosis. We aimed to identify individuals at high risk of mortality within 24 months of symptom onset through analysis of patient data commonly encountered in daily clinical practice. Our Ensemble-Imbalance approach underwent evaluation employing six ML algorithms as base classifiers. Remarkably, our results outperformed those of individual algorithms, achieving a Balanced Accuracy of 88% and a Sensitivity of 96%. Additionally, we used the Shapley Additive Explanations framework to elucidate the decision-making process of the top-performing model, pinpointing the most important features and their correlations with the target prediction. Furthermore, we presented helpful tools to visualize and compare patient similarities, offering valuable insights. Confirming the obtained results, our approach could aid physicians in devising personalized treatment plans at the time of diagnosis or serve as an inclusion/exclusion criterion in clinical trials.}, } @article {pmid38504592, year = {2024}, author = {Hamilton, HL and Akther, M and Anis, S and Colwell, CB and Vargas, MR and Pehar, M}, title = {Nicotinamide Adenine Dinucleotide Precursor Supplementation Modulates Neurite Complexity and Survival in Motor Neurons from Amyotrophic Lateral Sclerosis Models.}, journal = {Antioxidants & redox signaling}, volume = {41}, number = {7-9}, pages = {573-589}, pmid = {38504592}, issn = {1557-7716}, support = {R01 NS089640/NS/NINDS NIH HHS/United States ; R01 NS100835/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Motor Neurons/metabolism/pathology/drug effects ; Mice ; Humans ; *Disease Models, Animal ; *NAD/metabolism ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Neurites/metabolism/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Nicotinamide Mononucleotide/pharmacology/metabolism ; Neuroprotective Agents/pharmacology ; DNA-Binding Proteins/metabolism/genetics ; Cell Survival/drug effects ; Dietary Supplements ; }, abstract = {Aims: Increasing nicotinamide adenine dinucleotide (NAD[+]) availability has been proposed as a therapeutic approach to prevent neurodegeneration in amyotrophic lateral sclerosis (ALS). Accordingly, NAD[+] precursor supplementation appears to exert neuroprotective effects in ALS patients and mouse models. The mechanisms mediating neuroprotection remain uncertain but could involve changes in multiple cell types. We investigated a potential direct effect of the NAD[+] precursor nicotinamide mononucleotide (NMN) on the health of cultured induced pluripotent stem cell (iPSC)-derived human motor neurons and in motor neurons isolated from two ALS mouse models, that is, mice overexpressing wild-type transactive response DNA binding protein-43 (TDP-43) or the ALS-linked human superoxide dismutase 1 with the G93A mutation (hSOD1[G93A]). Results: NMN treatment increased the complexity of neuronal processes in motor neurons isolated from both mouse models and in iPSC-derived human motor neurons. In addition, NMN prevented neuronal death induced by trophic factor deprivation. In mouse and human motor neurons expressing ALS-linked mutant superoxide dismutase 1, NMN induced an increase in glutathione levels, but this effect was not observed in nontransgenic or TDP-43 overexpressing motor neurons. In contrast, NMN treatment normalized the TDP-43 cytoplasmic mislocalization induced by its overexpression. Innovation: NMN can directly act on motor neurons to increase the growth and complexity of neuronal processes and prevent the death induced by trophic factor deprivation. Conclusion: Our results support a direct beneficial effect of NAD[+] precursor supplementation on the maintenance of the neuritic arbor in motor neurons. Importantly, this was observed in motor neurons isolated from two different ALS models, with and without involvement of TDP-43 pathology, supporting its therapeutic potential in sporadic and familial ALS. Antioxid. Redox Signal. 41, 573-589.}, } @article {pmid38504632, year = {2024}, author = {Higashihara, M and Pavey, N and Menon, P and van den Bos, M and Shibuya, K and Kuwabara, S and Kiernan, MC and Koinuma, M and Vucic, S}, title = {Reduction in short interval intracortical inhibition from the early stage reflects the pathophysiology in amyotrophic lateral sclerosis: A meta-analysis study.}, journal = {European journal of neurology}, volume = {31}, number = {7}, pages = {e16281}, pmid = {38504632}, issn = {1468-1331}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; *Transcranial Magnetic Stimulation ; *Neural Inhibition/physiology ; *Motor Cortex/physiopathology ; Evoked Potentials, Motor/physiology ; }, abstract = {BACKGROUND AND PURPOSE: Cortical hyperexcitability has been identified as a diagnostic and pathogenic biomarker of amyotrophic lateral sclerosis (ALS). Cortical excitability is assessed by transcranial magnetic stimulation (TMS), a non-invasive neurophysiological technique. The TMS biomarkers exhibiting highest sensitivity for cortical hyperexcitability in ALS remain to be elucidated. A meta-analysis was performed to determine the TMS biomarkers exhibiting the highest sensitivity for cortical hyperexcitability in ALS.

METHODS: A systematic literature review was conducted of all relevant studies published in the English language by searching PubMed, MEDLINE, Embase and Scopus electronic databases from 1 January 2006 to 28 February 2023. Inclusion criteria included studies reporting the utility of threshold tracking TMS (serial ascending method) in ALS and controls.

RESULTS: In total, more than 2500 participants, incorporating 1530 ALS patients and 1102 controls (healthy, 907; neuromuscular, 195) were assessed with threshold tracking TMS across 25 studies. Significant reduction of mean short interval intracortical inhibition (interstimulus interval 1-7 ms) exhibited the highest standardized mean difference with moderate heterogeneity (-0.994, 95% confidence interval -1.12 to -0.873, p < 0.001; Q = 38.61, p < 0.05; I[2] = 40%). The reduction of cortical silent period duration along with an increase in motor evoked potential amplitude and intracortical facilitation also exhibited significant, albeit smaller, standardized mean differences.

CONCLUSION: This large meta-analysis study disclosed that mean short interval intracortical inhibition reduction exhibited the highest sensitivity for cortical hyperexcitability in ALS. Combined findings from this meta-analysis suggest that research strategies aimed at understanding the cause of inhibitory interneuronal circuit dysfunction could enhance understanding of ALS pathogenesis.}, } @article {pmid38504981, year = {2024}, author = {Cao, W and Cao, Z and Tang, L and Xu, C and Fan, D}, title = {Immune-mediated diseases are associated with a higher risk of ALS incidence: a prospective cohort study from the UK Biobank.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1356132}, pmid = {38504981}, issn = {1664-3224}, mesh = {Male ; Female ; Humans ; Prospective Studies ; UK Biobank ; *Amyotrophic Lateral Sclerosis/epidemiology ; Biological Specimen Banks ; Incidence ; *Immune System Diseases ; }, abstract = {OBJECTIVE: The occurrence of immune-mediated diseases (IMDs) in amyotrophic lateral sclerosis (ALS) patients is widely reported. However, whether IMDs and ALS is a simple coexistence or if there exists causal relationships between the two has been a subject of great interest to researchers.

METHODS: A total of 454,444 participants from the prospective cohort of UK Biobank were recruited to investigate the longitudinal association between IMDs and ALS. Previously any IMDs and organ specific IMDs were analyzed in relation to the following incident ALS by Cox-proportional hazard models. Subgroup analyses were performed to explore the covariates of these relationships.

RESULTS: After adjusting for potential covariates, the multivariate analysis showed that any IMDs were associated with an increased risk of ALS incidence (HR:1.42, 95%CI:1.03-1.94). IMDs of the endocrine-system and the intestinal-system were associated with increased risk of ALS incidence (endocrine-system IMDs: HR:3.01, 95%CI:1.49-6.06; intestinal system IMDs: HR:2.07, 95%CI: 1.14-3.77). Subgroup analyses revealed that immune burden, including IMD duration and the severity of inflammation had specific effects on the IMD-ALS association. In participants with IMD duration≥10 years or CRP≥1.3mg/L or females, previous IMDs increased the risk of incident ALS; however, in participants with IMD duration <10 years or CRP<1.3mg/L or males, IMDs had no effect on incident ALS.

INTERPRETATION: Our study provides evidence that previous any IMDs and endocrine-system and the intestinal-system specific IMDs are associated with an increased risk of developing ALS in females, but not in males.}, } @article {pmid38505242, year = {2022}, author = {Mendive-Tapia, L and Mendive-Tapia, D and Zhao, C and Gordon, D and Benson, S and Bromley, MJ and Wang, W and Wu, J and Kopp, A and Ackermann, L and Vendrell, M}, title = {Rationales Design von Phe-BODIPY-Aminosäuren als fluorogene Bausteine für den peptidbasierten Nachweis von Candida-Infektionen im Harntrakt.}, journal = {Angewandte Chemie (Weinheim an der Bergstrasse, Germany)}, volume = {134}, number = {17}, pages = {e202117218}, pmid = {38505242}, issn = {0044-8249}, support = {/WT_/Wellcome Trust/United Kingdom ; }, } @article {pmid38505513, year = {2023}, author = {Kamp, N and Krenn, P and Avian, M and Sass, O}, title = {Comparability of multi-temporal DTMs derived from different LiDAR platforms: Error sources and uncertainties in the application of geomorphic impact studies.}, journal = {Earth surface processes and landforms}, volume = {48}, number = {6}, pages = {1152-1175}, pmid = {38505513}, issn = {1096-9837}, abstract = {Multi-temporal digital terrain models (DTMs) derived from airborne or uncrewed aerial vehicle (UAV)-borne light detection and ranging (LiDAR) platforms are frequently used tools in geomorphic impact studies. Accurate estimation of mobilized sediments from multi-temporal DTMs is indispensable for hazard assessment. To study volumetric changes in alpine environments it is crucial to identify and discuss different kind of error sources in multi-temporal data. We subdivided errors into those caused by data acquisition, data processing, and spatial properties of the terrain. In terms of the quantification of surface changes, the propagation of errors can lead to high uncertainties. Three alpine catchments with different LiDAR point clouds of different origins (airborne laser scanning [ALS], UAV-borne laser scanning [ULS]), varying point densities, accuracies and qualities were analysed, and used as basis for interpolating DTMs. The workflow was developed in the Schöttlbach area in Styria and later applied to further catchments in Austria. The main aim of the presented work is a comprehensive DTM uncertainty analysis specially designed for geomorphic impact studies, with a resulting uncertainty analysis serving as input for a change detection tool. Our findings reveal that geomorphic impact studies need the careful distinction between actual surface changes and different data uncertainties. ULS combines the benefits of terrestrial laser scanning with all the benefits of ALS. However, the use of ULS data does not necessarily improve the results of the analysis since the high level of detail is not always helpful in geomorphic impact studies. In order to make the different point clouds and DTMs comparable the quality of the ULS point cloud had to be reduced to fit the accuracy of the reference data (older ALS point clouds). Using a point cloud with a high point density with a regular planimetric point spacing and less data gaps, in the best case collected during leaf-off conditions (e.g., cross-flight strategy) turned out to be sufficient for our geomorphic research purposes.}, } @article {pmid38505660, year = {2021}, author = {Romero, E and Jones, BS and Hogg, BN and Rué Casamajo, A and Hayes, MA and Flitsch, SL and Turner, NJ and Schnepel, C}, title = {Enzymkatalysierte späte Modifizierungen: Besser spät als nie.}, journal = {Angewandte Chemie (Weinheim an der Bergstrasse, Germany)}, volume = {133}, number = {31}, pages = {16962-16993}, pmid = {38505660}, issn = {0044-8249}, } @article {pmid38505661, year = {2023}, author = {Alix, JJP and Plesia, M and Schooling, CN and Dudgeon, AP and Kendall, CA and Kadirkamanathan, V and McDermott, CJ and Gorman, GS and Taylor, RW and Mead, RJ and Shaw, PJ and Day, JC}, title = {Non-negative matrix factorisation of Raman spectra finds common patterns relating to neuromuscular disease across differing equipment configurations, preclinical models and human tissue.}, journal = {Journal of Raman spectroscopy : JRS}, volume = {54}, number = {3}, pages = {258-268}, pmid = {38505661}, issn = {0377-0486}, support = {/WT_/Wellcome Trust/United Kingdom ; MC_PC_15034/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Raman spectroscopy shows promise as a biomarker for complex nerve and muscle (neuromuscular) diseases. To maximise its potential, several challenges remain. These include the sensitivity to different instrument configurations, translation across preclinical/human tissues and the development of multivariate analytics that can derive interpretable spectral outputs for disease identification. Nonnegative matrix factorisation (NMF) can extract features from high-dimensional data sets and the nonnegative constraint results in physically realistic outputs. In this study, we have undertaken NMF on Raman spectra of muscle obtained from different clinical and preclinical settings. First, we obtained and combined Raman spectra from human patients with mitochondrial disease and healthy volunteers, using both a commercial microscope and in-house fibre optic probe. NMF was applied across all data, and spectral patterns common to both equipment configurations were identified. Linear discriminant models utilising these patterns were able to accurately classify disease states (accuracy 70.2-84.5%). Next, we applied NMF to spectra obtained from the mdx mouse model of a Duchenne muscular dystrophy and patients with dystrophic muscle conditions. Spectral fingerprints common to mouse/human were obtained and able to accurately identify disease (accuracy 79.5-98.8%). We conclude that NMF can be used to analyse Raman data across different equipment configurations and the preclinical/clinical divide. Thus, the application of NMF decomposition methods could enhance the potential of Raman spectroscopy for the study of fatal neuromuscular diseases.}, } @article {pmid38505770, year = {2024}, author = {Shi, J and Wang, Z and Yi, M and Xie, S and Zhang, X and Tao, D and Liu, Y and Yang, Y}, title = {Evidence based on Mendelian randomization and colocalization analysis strengthens causal relationships between structural changes in specific brain regions and risk of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1333782}, pmid = {38505770}, issn = {1662-4548}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord with a poor prognosis. Previous studies have observed cognitive decline and changes in brain morphometry in ALS patients. However, it remains unclear whether the brain structural alterations contribute to the risk of ALS. In this study, we conducted a bidirectional two-sample Mendelian randomization (MR) and colocalization analysis to investigate this causal relationship.

METHODS: Summary data of genome-wide association study were obtained for ALS and the brain structures, including surface area (SA), thickness and volume of subcortical structures. Inverse-variance weighted (IVW) method was used as the main estimate approach. Sensitivity analysis was conducted detect heterogeneity and pleiotropy. Colocalization analysis was performed to calculate the posterior probability of causal variation and identify the common genes.

RESULTS: In the forward MR analysis, we found positive associations between the SA in four cortical regions (lingual, parahippocampal, pericalcarine, and middle temporal) and the risk of ALS. Additionally, decreased thickness in nine cortical regions (caudal anterior cingulate, frontal pole, fusiform, inferior temporal, lateral occipital, lateral orbitofrontal, pars orbitalis, pars triangularis, and pericalcarine) was significantly associated with a higher risk of ALS. In the reverse MR analysis, genetically predicted ALS was associated with reduced thickness in the bankssts and increased thickness in the caudal middle frontal, inferior parietal, medial orbitofrontal, and superior temporal regions. Colocalization analysis revealed the presence of shared causal variants between the two traits.

CONCLUSION: Our results suggest that altered brain morphometry in individuals with high ALS risk may be genetically mediated. The causal associations of widespread multifocal extra-motor atrophy in frontal and temporal lobes with ALS risk support the notion of a continuum between ALS and frontotemporal dementia. These findings enhance our understanding of the cortical structural patterns in ALS and shed light on potentially viable therapeutic targets.}, } @article {pmid38505945, year = {2024}, author = {Kutlubaev, MA and Areprintseva, DK and Radakovic, R and Pervushina, EV}, title = {Psychometric properties of the Russian version of the Edinburgh cognitive and behavioral amyotrophic lateral sclerosis screen.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {785-787}, doi = {10.1080/21678421.2024.2328579}, pmid = {38505945}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis/complications ; Male ; Female ; Middle Aged ; *Psychometrics/methods ; Aged ; Russia/epidemiology ; Reproducibility of Results ; *Neuropsychological Tests/statistics & numerical data ; Adult ; Cognitive Dysfunction/diagnosis/etiology/psychology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition with observable cognitive and behavioral impairment. The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a tool developed specifically for people with ALS (pwALS) and previously translated into Russian, but the psychometric properties have not yet been explored. The aim was to explore and determine the psychometric properties of the Russian-version of ECAS (ECAS-R).

METHODS: 56 Russian speaking pwALS, 32 of their caregivers and 26 healthy controls were recruited for the study. They completed the ECAS-R, Patient Health Questionnaire-9 (PHQ-9) and Montreal Cognitive Assessment (MoCA). King Staging System was also utilized. Internal consistency, divergent and convergent validity, as well as culturally-derived cutoff scores of ECAS-R were determined.

RESULTS: The internal consistency of ECAS-R was good (Cronbach's alpha = 0.73). Convergent validity was observed though a strong correlation between the ECAS-R and MoCA scores. No correlation between ECAS-R and PHQ-9 were observed in terms of divergent validity. Based on culturally-derived cutoff scores, 64.2% (N = 36) of pwALS displayed cognitive impairment, with the most affected cognitive domains as executive function and language. Apathy was the most common behavioral impairment for pwALS followed by a loss of sympathy/empathy.

CONCLUSIONS: The ECAS-R is valid and reliable tool for the screening for the cognitive and behavioral impairment in Russian-speaking pwALS, with culturally-derived cutoffs presented.}, } @article {pmid38506473, year = {2024}, author = {Lillo, P and Zitko, P and Godoy-Reyes, G and Asenjo, G and Sáez, D and Cea, G and Navarrete, P and Valenzuela, D and Hughes, R and Heverin, M and Logroscino, G and Hardiman, O}, title = {Incidence of amyotrophic lateral sclerosis in Chile.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {528-532}, doi = {10.1080/21678421.2024.2329706}, pmid = {38506473}, issn = {2167-9223}, support = {R01 TS000242/TS/ATSDR CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Male ; Female ; Chile/epidemiology ; Incidence ; Middle Aged ; Aged ; Adult ; Cohort Studies ; Aged, 80 and over ; Survival Rate/trends ; Registries ; }, abstract = {OBJECTIVE: This study aimed to estimate amyotrophic lateral sclerosis (ALS) incidence and survival rates in the Metropolitan region of Chile.

METHODS: We conducted a cohort study of ALS cases in the Metropolitan Region from 2016 to 2019. A total of 219 ALS patients were recruited from Corporación ELA-Chile registry, in collaboration with neurologists from Sociedad de Neurología, Psiquiatría y Neurocirugía de Chile. We calculated incidence rates by sex and age and determined median survival from onset and diagnosis. Survival analysis used the Kaplan-Meier statistic, estimating hazard ratios for age, sex, time from symptom onset and from diagnosis using a Weibull regression model. All analyses were done using R 4.1.0.

RESULTS: Overall, ALS diagnosis incidence was 0.97 cases per 100,000 inhabitants, peaking in the 70-79 age group and declining thereafter. The male-to-female ratio was 1.23. The median time to death from diagnosis was 2.3 years (95% confidence interval [CI]: 1.9-2.5), and from the first symptom, it was 3.1 years (95% CI: 2.8-3.5).

CONCLUSIONS: This is the first population-based study reporting ALS incidence and survival rates in Chile's Metropolitan region. Incidence resembled other Latin American studies. Median survival from diagnosis and from the first symptom were in line with previous findings. Our results corroborated lower ALS rates in Latin America, consistent with prior research.}, } @article {pmid38508480, year = {2024}, author = {Bager, P and Hvas, CL and Dahlerup, JF}, title = {Severe Fatigue in Inflammatory Bowel Disease: Dopaminergic Therapy With Modafinil or Vitamin Therapy With Thiamine.}, journal = {Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association}, volume = {22}, number = {11}, pages = {2348-2349}, doi = {10.1016/j.cgh.2024.03.002}, pmid = {38508480}, issn = {1542-7714}, mesh = {Humans ; *Modafinil/therapeutic use ; *Fatigue/drug therapy ; *Inflammatory Bowel Diseases/drug therapy/complications ; *Thiamine/therapeutic use ; Treatment Outcome ; Male ; Female ; Middle Aged ; }, abstract = {We found Moulton et al's[1] illustrative case series of 10 patients with inflammatory bowel disease (IBD) and chronic fatigue, all presenting with depression, particularly interesting. [1] Among the patients, 8 previously had undergone treatment with multiple psychotropic medications, and 2 had active IBD as indicated by increased fecal calprotectin levels. Remarkably, all 10 patients responded positively to open-label treatment with modafinil, a central nervous system stimulant that blocks dopamine reuptake transport, which resulted in an impressive improvement in their fatigue symptoms. At baseline, the self-reported mean fatigue score was 16, measured on the IBD Fatigue Assessment Scale (IBD-FAS), which ranges up to 20, and with levels higher than 11 indicating severe fatigue. After 6 months of modafinil treatment, the mean fatigue score was 6.7.[1].}, } @article {pmid38509062, year = {2024}, author = {Funes, S and Jung, J and Gadd, DH and Mosqueda, M and Zhong, J and Shankaracharya, and Unger, M and Stallworth, K and Cameron, D and Rotunno, MS and Dawes, P and Fowler-Magaw, M and Keagle, PJ and McDonough, JA and Boopathy, S and Sena-Esteves, M and Nickerson, JA and Lutz, C and Skarnes, WC and Lim, ET and Schafer, DP and Massi, F and Landers, JE and Bosco, DA}, title = {Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {2497}, pmid = {38509062}, issn = {2041-1723}, support = {RF1 AG068281/AG/NIA NIH HHS/United States ; R21 NS120126/NS/NINDS NIH HHS/United States ; R01 AG068281/AG/NIA NIH HHS/United States ; R01 GM147677/GM/NIGMS NIH HHS/United States ; R01 NS108769/NS/NINDS NIH HHS/United States ; R01 MH113743/MH/NIMH NIH HHS/United States ; R01 NS117533/NS/NINDS NIH HHS/United States ; R01 GM137529/GM/NIGMS NIH HHS/United States ; U54 OD020351/OD/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Microglia/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Profilins/metabolism ; *Neurodegenerative Diseases ; Mutation ; }, abstract = {Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibited evidence of lipid dysmetabolism, autophagy dysregulation and deficient phagocytosis, a canonical microglia function. Mutant PFN1 also displayed enhanced binding affinity for PI3P, a critical signaling molecule involved in autophagic and endocytic processing. Our cumulative data implicate a gain-of-toxic function for mutant PFN1 within the autophagic and endo-lysosomal pathways, as administration of rapamycin rescued phagocytic dysfunction in ALS-PFN1 iMGs. These outcomes demonstrate the utility of iMGs for neurodegenerative disease research and implicate microglial vesicular degradation pathways in the pathogenesis of these disorders.}, } @article {pmid38510000, year = {2024}, author = {Ditan, ID and Turalde, CWR}, title = {Treatment gaps in the care of amyotrophic lateral sclerosis in the Philippines: A scoping review.}, journal = {Heliyon}, volume = {10}, number = {6}, pages = {e27944}, pmid = {38510000}, issn = {2405-8440}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease affecting both the upper and lower motor neurons. Much of the management of ALS is supportive with the goal of maximizing patient quality of life. While the Philippines was participative in the "Ice Bucket Challenge" in 2014, it is up for investigation whether substantial changes occurred to improve healthcare for ALS patients. This study aims to evaluate the treatment gaps in the management of ALS in the Philippines through a scoping review. Data on epidemiology, health systems, and pharmacotherapy available regarding ALS in the local setting were synthesized. Nine articles were included. As of July 2023, there were only four indexed studies on ALS from the Philippines. Five of the included articles investigated ALS in Filipino populations but were not authored by Filipinos nor affiliated with Philippine institutions. The available literature showed a distinct lack of local ALS epidemiologic data, as well as limited availability in diagnostic centers, medications, health financing options, and digestible information for Filipinos. The limitations in managing ALS in the country are multifactorial - from political, medical, and social. It is imperative to establish a national database, financing systems, support groups, and accessible diagnostic centers for ALS patients.}, } @article {pmid38511059, year = {2024}, author = {Casado Gama, H and Amorós, MA and Andrade de Araújo, M and Sha, CM and Vieira, MPS and Torres, RGD and Souza, GF and Junkes, JA and Dokholyan, NV and Leite Góes Gitaí, D and Duzzioni, M}, title = {Systematic review and meta-analysis of dysregulated microRNAs derived from liquid biopsies as biomarkers for amyotrophic lateral sclerosis.}, journal = {Non-coding RNA research}, volume = {9}, number = {2}, pages = {523-535}, pmid = {38511059}, issn = {2468-0540}, support = {R35 GM134864/GM/NIGMS NIH HHS/United States ; }, abstract = {The discovery of disease-specific biomarkers, such as microRNAs (miRNAs), holds the potential to transform the landscape of Amyotrophic Lateral Sclerosis (ALS) by facilitating timely diagnosis, monitoring treatment response, and accelerating drug discovery. Such advancement could ultimately improve the quality of life and survival rates for ALS patients. Despite more than a decade of research, no miRNA biomarker candidate has been translated into clinical practice. We conducted a systematic review and meta-analysis to quantitatively synthesize data from original studies that analyzed miRNA expression from liquid biopsies via PCR and compared them to healthy controls. Our analysis encompasses 807 miRNA observations from 31 studies, stratified according to their source tissue. We identified consistently dysregulated miRNAs in serum (hsa-miR-3665, -4530, -4745-5p, -206); blood (hsa-miR-338-3p, -183-5p); cerebrospinal fluid (hsa-miR-34a-3p); plasma (hsa-miR-206); and neural-enriched extracellular vesicles from plasma (hsa-miR-146a-5p, -151a-5p, -10b-5p, -29b-3p, and -4454). The meta-analyses provided further support for the upregulation of hsa-miR-206, hsa-miR-338-3p, hsa-miR-146a-5p and hsa-miR-151a-5p, and downregulation of hsa-miR-183-5p, hsa-miR-10b-5p, hsa-miR-29b-3p, and hsa-miR-4454 as consistent indicators of ALS across independent studies. Our findings provide valuable insights into the current understanding of miRNAs' dysregulated expression in ALS patients and on the researchers' choices of methodology. This work contributes to the ongoing efforts towards discovering disease-specific biomarkers.}, } @article {pmid38511172, year = {2024}, author = {Rossi, JJ}, title = {Accessory oligos for neuronal delivery of therapeutic siRNAs for ALS.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {2}, pages = {102153}, pmid = {38511172}, issn = {2162-2531}, } @article {pmid38511649, year = {2024}, author = {Craig, RA and De Vicente, J and Estrada, AA and Feng, JA and Lexa, KW and Canet, MJ and Dowdle, WE and Erickson, RI and Flores, BN and Haddick, PCG and Kane, LA and Lewcock, JW and Moerke, NJ and Poda, SB and Sweeney, Z and Takahashi, RH and Tong, V and Wang, J and Yulyaningsih, E and Solanoy, H and Scearce-Levie, K and Sanchez, PE and Tang, L and Xu, M and Zhang, R and Osipov, M}, title = {Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases.}, journal = {Journal of medicinal chemistry}, volume = {67}, number = {7}, pages = {5758-5782}, doi = {10.1021/acs.jmedchem.3c02422}, pmid = {38511649}, issn = {1520-4804}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mutation ; Eukaryotic Initiation Factor-2B/genetics/metabolism ; Brain/metabolism ; *Leukoencephalopathies/metabolism ; }, abstract = {Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design. These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS.}, } @article {pmid38511674, year = {2024}, author = {Amesaka, H and Hara, M and Sakai, Y and Shintani, A and Sue, K and Yamanaka, T and Tanaka, SI and Furukawa, Y}, title = {Engineering a monobody specific to monomeric Cu/Zn-superoxide dismutase associated with amyotrophic lateral sclerosis.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {4}, pages = {e4961}, pmid = {38511674}, issn = {1469-896X}, support = {19H05765//Grants-in-Aid for Scientific Research on Innovative Areas/ ; 20H05516//Grants-in-Aid for Scientific Research on Innovative Areas/ ; 22H02768//Scientific Research (B)/ ; 21K05386//Scientific Research (C)/ ; 22K19389//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; }, mesh = {Humans ; Superoxide Dismutase-1/chemistry ; *Amyotrophic Lateral Sclerosis/genetics ; Protein Folding ; Superoxide Dismutase/chemistry ; Saccharomyces cerevisiae/metabolism ; Zinc/metabolism ; Mutation ; }, abstract = {Misfolding of mutant Cu/Zn-superoxide dismutase (SOD1) has been implicated in familial form of amyotrophic lateral sclerosis (ALS). A natively folded SOD1 forms a tight homodimer, and the dimer dissociation has been proposed to trigger the oligomerization/aggregation of SOD1. Besides increasing demand for probes allowing the detection of monomerized forms of SOD1 in various applications, the development of probes has been limited to conventional antibodies. Here, we have developed Mb(S4) monobody, a small synthetic binding protein based on the fibronectin type III scaffold, that recognizes a monomeric but not dimeric form of SOD1 by performing combinatorial library selections using phage and yeast-surface display methods. Although Mb(S4) was characterized by its excellent selectivity to the monomeric conformation of SOD1, the monomeric SOD1/Mb(S4) complex was not so stable (apparent Kd ~ μM) as to be detected in conventional pull-down experiments. Instead, the complex of Mb(S4) with monomeric but not dimeric SOD1 was successfully trapped by proximity-enabled chemical crosslinking even when reacted in the cell lysates. We thus anticipate that Mb(S4) binding followed by chemical crosslinking would be a useful strategy for in vitro and also ex vivo detection of the monomeric SOD1 proteins.}, } @article {pmid38512130, year = {2024}, author = {Pak, V and Adewale, Q and Bzdok, D and Dadar, M and Zeighami, Y and Iturria-Medina, Y}, title = {Distinctive whole-brain cell types predict tissue damage patterns in thirteen neurodegenerative conditions.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38512130}, issn = {2050-084X}, support = {CIHR Project Grant 2020/CAPMC/CIHR/Canada ; }, mesh = {Humans ; Brain ; *Neurodegenerative Diseases ; Neurons ; *Parkinson Disease ; Brain Mapping ; }, abstract = {For over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most neurodegenerative studies focus on neuronal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell types' contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical cell types extensively predicts tissue damage in 13 neurodegenerative conditions, including early- and late-onset Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, mutations in presenilin-1, and 3 clinical variants of frontotemporal lobar degeneration (behavioral variant, semantic and non-fluent primary progressive aphasia) along with associated three-repeat and four-repeat tauopathies and TDP43 proteinopathies types A and C. We reconstructed comprehensive whole-brain reference maps of cellular abundance for six major cell types and identified characteristic axes of spatial overlapping with atrophy. Our results support the strong mediating role of non-neuronal cells, primarily microglia and astrocytes, in spatial vulnerability to tissue loss in neurodegeneration, with distinct and shared across-disorder pathomechanisms. These observations provide critical insights into the multicellular pathophysiology underlying spatiotemporal advance in neurodegeneration. Notably, they also emphasize the need to exceed the current neuro-centric view of brain diseases, supporting the imperative for cell-specific therapeutic targets in neurodegeneration.}, } @article {pmid38512820, year = {2024}, author = {Bartolomé-Nafría, A and García-Pardo, J and Ventura, S}, title = {Mutations in human prion-like domains: pathogenic but not always amyloidogenic.}, journal = {Prion}, volume = {18}, number = {1}, pages = {28-39}, pmid = {38512820}, issn = {1933-690X}, mesh = {Humans ; *Prions/metabolism ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Mutation ; }, abstract = {Heterogeneous nuclear ribonucleoproteins (hnRNPs) are multifunctional proteins with integral roles in RNA metabolism and the regulation of alternative splicing. These proteins typically contain prion-like domains of low complexity (PrLDs or LCDs) that govern their assembly into either functional or pathological amyloid fibrils. To date, over 60 mutations targeting the LCDs of hnRNPs have been identified and associated with a spectrum of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). The cryo-EM structures of pathological and functional fibrils formed by different hnRNPs have been recently elucidated, including those of hnRNPA1, hnRNPA2, hnRNPDL-2, TDP-43, and FUS. In this review, we discuss the structural features of these amyloid assemblies, placing particular emphasis on scrutinizing the impact of prevalent disease-associated mutations mapping within their LCDs. By performing systematic energy calculations, we reveal a prevailing trend of destabilizing effects induced by these mutations in the amyloid structure, challenging the traditionally assumed correlation between pathogenicity and amyloidogenic propensity. Understanding the molecular basis of this discrepancy might provide insights for developing targeted therapeutic strategies to combat hnRNP-associated diseases.}, } @article {pmid38514515, year = {2024}, author = {Finsterer, J}, title = {Amyotrophic Lateral Sclerosis due to ALS2 Pathogenic Variant Masquerading as Cerebral Palsy: Correspondence.}, journal = {Indian journal of pediatrics}, volume = {91}, number = {9}, pages = {988}, pmid = {38514515}, issn = {0973-7693}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Cerebral Palsy/diagnosis ; Diagnosis, Differential ; Guanine Nucleotide Exchange Factors/genetics ; Female ; Child, Preschool ; }, } @article {pmid38514815, year = {2024}, author = {Baxter, RC}, title = {Endocrine and cellular physiology and pathology of the insulin-like growth factor acid-labile subunit.}, journal = {Nature reviews. Endocrinology}, volume = {20}, number = {7}, pages = {414-425}, pmid = {38514815}, issn = {1759-5037}, mesh = {Humans ; Animals ; *Glycoproteins/metabolism ; Carrier Proteins/metabolism ; Insulin-Like Growth Factor I/metabolism ; Mice ; Insulin-Like Growth Factor Binding Proteins/metabolism/physiology ; Insulin-Like Growth Factor II/metabolism ; Endocrine System/metabolism ; Insulin-Like Peptides ; }, abstract = {The acid-labile subunit (ALS) of the insulin-like growth factor (IGF) binding protein (IGFBP) complex, encoded in humans by IGFALS, has a vital role in regulating the endocrine transport and bioavailability of IGF-1 and IGF-2. Accordingly, ALS has a considerable influence on postnatal growth and metabolism. ALS is a leucine-rich glycoprotein that forms high-affinity ternary complexes with IGFBP-3 or IGFBP-5 when they are occupied by either IGF-1 or IGF-2. These complexes constitute a stable reservoir of circulating IGFs, blocking the potentially hypoglycaemic activity of unbound IGFs. ALS is primarily synthesized by hepatocytes and its expression is lower in non-hepatic tissues. ALS synthesis is strongly induced by growth hormone and suppressed by IL-1β, thus potentially serving as a marker of growth hormone secretion and/or activity and of inflammation. IGFALS mutations in humans and Igfals deletion in mice cause modest growth retardation and pubertal delay, accompanied by decreased osteogenesis and enhanced adipogenesis. In hepatocellular carcinoma, IGFALS is described as a tumour suppressor; however, its contribution to other cancers is not well delineated. This Review addresses the endocrine physiology and pathology of ALS, discusses the latest cell and proteomic studies that suggest emerging cellular roles for ALS and outlines its involvement in other disease states.}, } @article {pmid38515326, year = {2024}, author = {Lee, DY and Kwon, YN and Lee, K and Kim, SJ and Sung, JJ}, title = {Dual effects of TGF-β inhibitor in ALS - inhibit contracture and neurodegeneration.}, journal = {Journal of neurochemistry}, volume = {168}, number = {9}, pages = {2495-2514}, doi = {10.1111/jnc.16102}, pmid = {38515326}, issn = {1471-4159}, support = {2018R1A5A2025964//National Research Foundation of Korea (NRF) Grant/ ; 2019M3C7A1031867//National Research Foundation of Korea (NRF) Grant/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Mice ; *Transforming Growth Factor beta/metabolism/antagonists & inhibitors ; *Contracture/drug therapy/prevention & control ; Mice, Transgenic ; Male ; Mice, Inbred C57BL ; Piperidines/pharmacology/therapeutic use ; Humans ; }, abstract = {As persistent elevation of transforming growth factor-β (TGF-β) promotes fibrosis of muscles and joints and accelerates disease progression in amyotrophic lateral sclerosis (ALS), we investigated whether inhibition of TGF-β would be effective against both exacerbations. The effects of TGF-β and its inhibitor on myoblasts and fibroblasts were tested in vitro and confirmed in vivo, and the dual action of a TGF-β inhibitor in ameliorating the pathogenic role of TGF-β in ALS mice was identified. In the peripheral neuromuscular system, fibrosis in the muscles and joint cavities induced by excessive TGF-β causes joint contracture and muscular degeneration, which leads to motor dysfunction. In an ALS mouse model, an increase in TGF-β in the central nervous system (CNS), consistent with astrocyte activity, was associated with M1 microglial activity and pro-inflammatory conditions, as well as with neuronal cell death. Treatment with the TGF-β inhibitor halofuginone could prevent musculoskeletal fibrosis, resulting in the alleviation of joint contracture and delay of motor deterioration in ALS mice. Halofuginone could also reduce glial cell-induced neuroinflammation and neuronal apoptosis. These dual therapeutic effects on both the neuromuscular system and the CNS were observed from the beginning to the end stages of ALS; as a result, treatment with a TGF-β inhibitor from the early stage of disease delayed the time of symptom exacerbation in ALS mice, which led to prolonged survival.}, } @article {pmid38515451, year = {2024}, author = {Zoccolella, S and Milella, G and Giugno, A and Devitofrancesco, V and Damato, R and Tamburrino, L and Misceo, S and Filardi, M and Logroscino, G}, title = {Neurophysiological indices for split phenomena: correlation with age and sex and potential implications in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1371953}, pmid = {38515451}, issn = {1664-2295}, abstract = {BACKGROUND: Split phenomena (SP) are characterized by patterns of differential muscle wasting and atrophy, which are highly prevalent in amyotrophic lateral sclerosis (ALS) patients. Several neurophysiological indicators, including the split-hand index (SHI), split-leg index (SLI), and split-elbow index (SEI), have been proposed to assess SP. Nevertheless, their cutoff values and the impact of age and sex on these measures remain unclear.

METHODS: We prospectively collected neurophysiological data from 300 healthy adult subjects. The following indices were measured from compound muscle action potentials (CMAPs): SHI [abductor pollicis brevis (APBcmap) x first dorsal interosseous (FDI)cmap/adductor digiti minimi (ADMcmap)], SEI (BICEPScmap/TRICEPScmap), SLI (extensor digit brevis (EDB)cmap/abductor Hallucis (AH)cmap), and the neurophysiological ratios APBcmap /ADMcmap and FDIcmap/ADMcmap. Multiple linear regression analysis was used to investigate the association between age, sex, CMAPs, and neurophysiological indicators.

RESULTS: The median SHI was 10.4, with a median APBcmap/ADMcmap ratio of 0.9 and a median FDIcmap/ADMcmap ratio of 1.2. The median SEI was 1.6 (IQR:1.1-2.4) and the median SLI was 0.7 (IQR:0.5-1.0). Negative associations were observed between age, most of the CMAPs, and all the neurophysiological indices, except for SLI. The male subjects exhibited significantly higher CMAP values for the first dorsal interosseous (FDI), biceps, and SHI compared to the female participants.

CONCLUSION: Our findings highlight the importance of age- and sex-adjusted normative data for SP indices, which could enhance their diagnostic accuracy and clinical utility in patients with ALS. The SL index appears to be the most reliable indicator, as it showed no significant association with age or sex.}, } @article {pmid38515787, year = {2024}, author = {Wang, L and Fang, X and Ling, B and Wang, F and Xia, Y and Zhang, W and Zhong, T and Wang, X}, title = {Research progress on ferroptosis in the pathogenesis and treatment of neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1359453}, pmid = {38515787}, issn = {1662-5102}, abstract = {Globally, millions of individuals are impacted by neurodegenerative disorders including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD). Although a great deal of energy and financial resources have been invested in disease-related research, breakthroughs in therapeutic approaches remain elusive. The breakdown of cells usually happens together with the onset of neurodegenerative diseases. However, the mechanism that triggers neuronal loss is unknown. Lipid peroxidation, which is iron-dependent, causes a specific type of cell death called ferroptosis, and there is evidence its involvement in the pathogenic cascade of neurodegenerative diseases. However, the specific mechanisms are still not well known. The present article highlights the basic processes that underlie ferroptosis and the corresponding signaling networks. Furthermore, it provides an overview and discussion of current research on the role of ferroptosis across a variety of neurodegenerative conditions.}, } @article {pmid38516187, year = {2024}, author = {Dudas, EF and Tully, MD and Foldes, T and Kelly, G and Tartaglia, GG and Pastore, A}, title = {The structural properties of full-length annexin A11.}, journal = {Frontiers in molecular biosciences}, volume = {11}, number = {}, pages = {1347741}, pmid = {38516187}, issn = {2296-889X}, support = {FC001029/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Annexin A11 (ANXA11) is a calcium-dependent phospholipid-binding protein belonging to the annexin protein family and implicated in the neurodegenerative amyotrophic lateral sclerosis. Structurally, ANXA11 contains a conserved calcium-binding C-terminal domain common to all annexins and a putative intrinsically unfolded N-terminus specific for ANXA11. Little is known about the structure and functions of this region of the protein. By analogy with annexin A1, it was suggested that residues 38 to 59 within the ANXA11 N-terminus could form a helical region that would be involved in interactions. Interestingly, this region contains residues that, when mutated, may lead to clinical manifestations. In the present study, we have studied the structural features of the full-length protein with special attention to the N-terminal region using a combination of biophysical techniques which include nuclear magnetic resonance and small angle X-ray scattering. We show that the N-terminus is intrinsically disordered and that the overall features of the protein are not markedly affected by the presence of calcium. We also analyzed the 38-59 helix hypothesis using synthetic peptides spanning both the wild-type sequence and clinically relevant mutations. We show that the peptides have a remarkable character typical of a native helix and that mutations do not alter the behaviour suggesting that they are required for interactions rather than being structurally important. Our work paves the way to a more thorough understanding of the ANXA11 functions.}, } @article {pmid38516553, year = {2023}, author = {Aishwarya, R and Abdullah, CS and Remex, NS and Nitu, S and Hartman, B and King, J and Bhuiyan, MAN and Rom, O and Miriyala, S and Panchatcharam, M and Orr, AW and Kevil, CG and Bhuiyan, MS}, title = {Pathological Sequelae Associated with Skeletal Muscle Atrophy and Histopathology in G93A*SOD1 Mice.}, journal = {Muscles (Basel, Switzerland)}, volume = {2}, number = {1}, pages = {51-74}, pmid = {38516553}, issn = {2813-0413}, support = {R00 HL150233/HL/NHLBI NIH HHS/United States ; K99 HL150233/HL/NHLBI NIH HHS/United States ; R01 DK134011/DK/NIDDK NIH HHS/United States ; 20POST35210789 - CHOWDHURY ABDULLAH/AHA/American Heart Association-American Stroke Association/United States ; R21 AA026708/AA/NIAAA NIH HHS/United States ; R00 HL122354/HL/NHLBI NIH HHS/United States ; R01 HL152723/HL/NHLBI NIH HHS/United States ; P20 GM121307/GM/NIGMS NIH HHS/United States ; R01 HL098435/HL/NHLBI NIH HHS/United States ; R01 HL133497/HL/NHLBI NIH HHS/United States ; K99 HL122354/HL/NHLBI NIH HHS/United States ; R01 HL149264/HL/NHLBI NIH HHS/United States ; R15 HL141998/HL/NHLBI NIH HHS/United States ; R01 HL145753/HL/NHLBI NIH HHS/United States ; R01 HL141155/HL/NHLBI NIH HHS/United States ; R21 AA025744/AA/NIAAA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex systemic disease that primarily involves motor neuron dysfunction and skeletal muscle atrophy. One commonly used mouse model to study ALS was generated by transgenic expression of a mutant form of human superoxide dismutase 1 (SOD1) gene harboring a single amino acid substitution of glycine to alanine at codon 93 (G93A*SOD1). Although mutant-SOD1 is ubiquitously expressed in G93A*SOD1 mice, a detailed analysis of the skeletal muscle expression pattern of the mutant protein and the resultant muscle pathology were never performed. Using different skeletal muscles isolated from G93A*SOD1 mice, we extensively characterized the pathological sequelae of histological, molecular, ultrastructural, and biochemical alterations. Muscle atrophy in G93A*SOD1 mice was associated with increased and differential expression of mutant-SOD1 across myofibers and increased MuRF1 protein level. In addition, high collagen deposition and myopathic changes sections accompanied the reduced muscle strength in the G93A*SOD1 mice. Furthermore, all the muscles in G93A*SOD1 mice showed altered protein levels associated with different signaling pathways, including inflammation, mitochondrial membrane transport, mitochondrial lipid uptake, and antioxidant enzymes. In addition, the mutant-SOD1 protein was found in the mitochondrial fraction in the muscles from G93A*SOD1 mice, which was accompanied by vacuolized and abnormal mitochondria, altered OXPHOS and PDH complex protein levels, and defects in mitochondrial respiration. Overall, we reported the pathological sequelae observed in the skeletal muscles of G93A*SOD1 mice resulting from the whole-body mutant-SOD1 protein expression.}, } @article {pmid38516735, year = {2024}, author = {Li, X and Bedlack, R}, title = {Evaluating emerging drugs in phase II & III for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on emerging drugs}, volume = {29}, number = {2}, pages = {93-102}, doi = {10.1080/14728214.2024.2333420}, pmid = {38516735}, issn = {1744-7623}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Humans ; *Drug Development ; *Drugs, Investigational/pharmacology ; Animals ; *Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Drug Design ; Molecular Targeted Therapy ; Research Design ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis is a rapidly progressive motor neuron disorder causing severe disability and premature death. Owing to the advances in uncovering ALS pathophysiology, efficient clinical trial design and research advocacy program, several disease-modifying drugs have been approved for treating ALS. Despite this progress, ALS remains a rapidly disabling and life shortening condition. There is a critical need for more effective therapies.

AREAS COVERED: Here, we reviewed the emerging ALS therapeutics undergoing phase II & III clinical trials. To identify the investigational drugs, we searched ALS and phase II/III trials that are active and recruiting or not yet recruiting on clinicaltrials.gov and Pharmaprojects database.

EXPERT OPINION: The current pipeline is larger and more diverse than ever, with drugs targeting potential genetic and retroviral causes of ALS and drugs targeting a wide array of downstream pathways, including RNA metabolism, protein aggregation, integrated stress response and neuroinflammation.We remain most excited about those that target direct causes of ALS, e.g. antisense oligonucleotides targeting causative genes. Drugs that eliminate abnormal protein aggregates are also up-and-coming. Eventually, because of the heterogeneity of ALS pathophysiology, biomarkers that determine which biological events are most important for an individual ALS patient are needed.}, } @article {pmid38516846, year = {2024}, author = {Kanazawa, T and Sato, W and Raveney, BJE and Takewaki, D and Kimura, A and Yamaguchi, H and Yokoi, Y and Saika, R and Takahashi, Y and Fujita, T and Saiki, S and Tamaoka, A and Oki, S and Yamamura, T}, title = {Pathogenic Potential of Eomesodermin-Expressing T-Helper Cells in Neurodegenerative Diseases.}, journal = {Annals of neurology}, volume = {95}, number = {6}, pages = {1093-1098}, doi = {10.1002/ana.26920}, pmid = {38516846}, issn = {1531-8249}, support = {16ek0109097h0002//Japan Multiple Sclerosis Society/ ; 17ek0109097h0003//Kato Memorial Trust for Nambyo Research/ ; 16ek0109155h0002//Mitsubishi Foundation/ ; 17ek0109155h0003//Practical Research Project for Rare/intractable Diseases from Japan Agency for Medical Research and Development, AMED/ ; 20FC0201//JSPS KAKENHI/ ; 30-5//National Institute of Neuroscience Intramural Research/ ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Alzheimer Disease/immunology/pathology/metabolism ; Amyotrophic Lateral Sclerosis/immunology ; Granzymes/metabolism ; *Neurodegenerative Diseases/immunology ; *T-Box Domain Proteins/metabolism ; *T-Lymphocytes, Helper-Inducer/immunology ; }, abstract = {Eomesodermin-expressing (Eomes[+]) T-helper (Th) cells show cytotoxic characteristics in secondary progressive multiple sclerosis. We found that Eomes[+] Th cell frequency was increased in the peripheral blood of amyotrophic lateral sclerosis and Alzheimer's disease patients. Furthermore, granzyme B production by Th cells from such patients was high compared with controls. A high frequency of Eomes[+] Th cells was observed in the initial (acutely progressive) stage of amyotrophic lateral sclerosis, and a positive correlation between Eomes[+] Th cell frequency and cognitive decline was observed in Alzheimer's disease patients. Therefore, Eomes[+] Th cells may be involved in the pathology of amyotrophic lateral sclerosis and Alzheimer's disease. ANN NEUROL 2024;95:1093-1098.}, } @article {pmid38517332, year = {2024}, author = {Brenner, D and Sieverding, K and Srinidhi, J and Zellner, S and Secker, C and Yilmaz, R and Dyckow, J and Amr, S and Ponomarenko, A and Tunaboylu, E and Douahem, Y and Schlag, JS and Rodríguez Martínez, L and Kislinger, G and Niemann, C and Nalbach, K and Ruf, WP and Uhl, J and Hollenbeck, J and Schirmer, L and Catanese, A and Lobsiger, CS and Danzer, KM and Yilmazer-Hanke, D and Münch, C and Koch, P and Freischmidt, A and Fetting, M and Behrends, C and Parlato, R and Weishaupt, JH}, title = {A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice.}, journal = {The Journal of experimental medicine}, volume = {221}, number = {5}, pages = {}, pmid = {38517332}, issn = {1540-9538}, support = {//Medical Faculty Mannheim of Heidelberg University/ ; //University of Ulm/ ; 10.22.2.022MN//Fritz Thyssen Foundation/ ; 2022_EKES.18//Else Kröner-Fresenius-Stiftung/ ; //Frick Foundation for ALS Research/ ; WE 2791/7-1//Deutsche Forschungsgemeinschaft/ ; //Agence Nationale de la Recherche/ ; //Charité/ ; //Stifterverband für die Deutsche Wissenschaft/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Motor Neurons/pathology ; Mutation ; Neuroinflammatory Diseases ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics/metabolism ; }, abstract = {Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p.E696K mutation causes presymptomatic onset of autophagolysosomal dysfunction in neurons precipitating the accumulation of damaged lysosomes. This is followed by a progressive, age-dependent motor neuron disease. Contrary to the phenotype of mice with full Tbk1 knock-out, RIPK/TNF-α-dependent hepatic, neuronal necroptosis, and overt autoinflammation were not detected. Our in vivo results indicate autophagolysosomal dysfunction as a trigger for neurodegeneration and a promising therapeutic target in TBK1-ALS/FTD.}, } @article {pmid38517530, year = {2024}, author = {Kotsia, E and Chroni, E and Alexandropoulou, A and Mills, C and Veltsista, D and Kefalopoulou, ZM and Michou, E}, title = {Dysphagia Assessments as Criteria in the 'Decision-Making Process' for Percutaneous Endoscopic Gastrostomy Placement in People with Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Dysphagia}, volume = {39}, number = {6}, pages = {977-988}, pmid = {38517530}, issn = {1432-0460}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Deglutition Disorders/etiology ; *Gastrostomy/methods ; *Clinical Decision-Making/methods ; Male ; Female ; }, abstract = {To review the assessment methods of dysphagia as a criterion for the decision-making process for Percutaneous Endoscopic Gastrostomy (PEG) placement in patients with Amyotrophic Lateral Sclerosis (ALS). Systematic review. A search was conducted in three databases (EMBASE, CINAHL, PUBMED) in December 2022 and updated in July 2023. Two reviewers independently screened, selected, and extracted data. Study quality was appraised using the Joanna Briggs Institute Critical Appraisal Tools. Systematic review registration number in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42022385461. The searches identified 240 records. The 10 eligible studies included 2 case reports, 4 retrospective studies, 3 prospective studies, and 1 cohort observational study. Study quality was low, with most studies having moderate to high risk of bias. Dysphagia is a common criterion for decision-making. Dysphagia assessment is usually in the form of either self-reports, objective instrumental assessments, or both. Dysphagia is a common criterion for the decision-making process, yet is missing in clinical guidelines. Establishing the optimal means of dysphagia assessment is important for timely decision-making procedures, so that life-threatening consequences of dysphagia are minimized.}, } @article {pmid38517792, year = {2024}, author = {Calderón-Garcidueñas, L and Ayala, A and Mukherjee, PS}, title = {2024 United States Elections: Air Pollution, Neurodegeneration, Neuropsychiatric, and Neurodevelopmental Disorders. Who Cares?.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {98}, number = {4}, pages = {1277-1282}, pmid = {38517792}, issn = {1875-8908}, mesh = {Humans ; United States/epidemiology ; Adult ; *Air Pollutants/adverse effects ; *Air Pollution/adverse effects/analysis ; Particulate Matter ; *Alzheimer Disease ; *Neurodevelopmental Disorders/epidemiology/etiology ; }, abstract = {Air pollution exposures ought to be of significant interest for the United States (US) public as health issues will play a role in the 2024 elections. Citizens are not aware of the harmful brain impact of exposures to ubiquitous anthropogenic combustion emissions and friction-derived nanoparticles, industrial nanoplastics, the growing risk of wildfires, and the smoke plumes of soot. Ample consideration of pediatric and early adulthood hallmarks of Alzheimer's disease, Parkinson's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis and associations with neuropsychiatric and neurodevelopmental disorders in the process of setting, reviewing, and implementing standards for particulate matter (PM)2.5, ultrafine PM, and industrial nanoparticles must be of interest to US citizens.}, } @article {pmid38519722, year = {2024}, author = {Gowda, VK and Babu, S and Kinhal, U and Srinivasan, VM}, title = {Amyotrophic Lateral Sclerosis due to ALS2 Pathogenic Variant Masquerading as Cerebral Palsy: Authors' Reply.}, journal = {Indian journal of pediatrics}, volume = {91}, number = {9}, pages = {989}, pmid = {38519722}, issn = {0973-7693}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Cerebral Palsy/diagnosis ; Diagnosis, Differential ; }, } @article {pmid38519870, year = {2024}, author = {Genuis, SK and Luth, W and Magnussen, C and Vande Velde, C and Taylor, D and , and Johnston, WS}, title = {Patient engagement in research: lessons learned from CAPTURE ALS, a longitudinal observational ALS study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {634-643}, doi = {10.1080/21678421.2024.2328599}, pmid = {38519870}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Longitudinal Studies ; *Patient Participation/psychology/statistics & numerical data ; Canada/epidemiology ; Male ; Biomedical Research ; Female ; }, abstract = {OBJECTIVE: There are compelling ethical and practical reasons for patient engagement in research (PEIR), however, evidence for best practices remains limited. We investigated PEIR as implemented in CAPTURE ALS, a longitudinal observational study, from study inception through the first 2.5 years of operations.

METHODS: Data were drawn from three engagement initiatives: a community-led letter-writing campaign; consultation with patient and caregiver focus groups; and a study-embedded 'participant partner advisory council' (PPAC). Data were derived retrospectively from study documentation. We used the International Association of Public Participation (IAP2) participation spectrum as a framework for investigation.

RESULTS: 2401 letters from community members to the Canadian government affirmed study objectives and advocated for funding. Feedback from focus group consultation influenced study design and supported the study's data-sharing plan. PPAC collaboration shaped all aspects of the study. Contributions included: co-creation of governance documents, input on study protocols and public-facing communication, and development of engagement webinars for study participants and feedback surveys. Effective communication practices fostered collaboration and helped avoid tokenistic engagement. CAPTURE ALS encompassed all IAP2 participation levels.

CONCLUSIONS: CAPTURE ALS was shaped by meaningful engagement initiatives over the course of the study. Lessons learned included: begin early and embed PEIR within research; build relationships and foster mutual learning; be flexible, open to adaptation, and seek diversity. Primary challenges included funding for early implementation, time needed to maintain relationships, and attrition due to disease progression. All IAP2 participation levels contributed to meaningful PEIR. 'Empowerment' was demonstrated through advocacy.}, } @article {pmid38520939, year = {2024}, author = {Ko, S and Yamasaki, R and Okui, T and Shiraishi, W and Watanabe, M and Hashimoto, Y and Kobayakawa, Y and Kusunoki, S and Kira, JI and Isobe, N}, title = {A nationwide survey of facial onset sensory and motor neuronopathy in Japan.}, journal = {Journal of the neurological sciences}, volume = {459}, number = {}, pages = {122957}, doi = {10.1016/j.jns.2024.122957}, pmid = {38520939}, issn = {1878-5883}, mesh = {Humans ; Japan/epidemiology ; *Amyotrophic Lateral Sclerosis ; Neurologic Examination ; Face ; }, abstract = {The epidemiology and etiology of facial onset sensory and motor neuronopathy (FOSMN), a rare syndrome that initiates with facial sensory disturbances followed by bulbar symptoms, remain unknown. To estimate the prevalence of FOSMN in Japan and establish the characteristics of this disease, we conducted a nationwide epidemiological survey. In the primary survey, we received answers from 604 facilities (49.8%), leading to an estimated number of 35.8 (95% confidential interval: 21.5-50.2) FOSMN cases in Japan. The secondary survey collected detailed clinical and laboratory data from 21 cases. Decreased or absent corneal and pharyngeal reflexes were present in over 85% of the cases. Electrophysiological analyses detected blink reflex test abnormalities in 94.1% of the examined cases. Immunotherapy was administered in 81% of cases and all patients received intravenous immunoglobulin. Among them, 35.3% were judged to have temporary beneficial effects evaluated by the physicians in charge. Immunotherapy tended to be effective in the early stage of disease. The spreading pattern of motor and sensory symptoms differed between cases and the characteristics of the motor-dominant and sensory-dominant cases were distinct. Cases with motor-dominant progression appeared to mimic amyotrophic lateral sclerosis. This is the first nationwide epidemiological survey of FOSMN in Japan. The clinical course of FOSMN is highly variable and motor-dominant cases developed a more severe condition than other types of cases. Because clinical interventions tend to be effective in the early phase of the disease, an early diagnosis is desirable.}, } @article {pmid38521060, year = {2024}, author = {Pineda, SS and Lee, H and Ulloa-Navas, MJ and Linville, RM and Garcia, FJ and Galani, K and Engelberg-Cook, E and Castanedes, MC and Fitzwalter, BE and Pregent, LJ and Gardashli, ME and DeTure, M and Vera-Garcia, DV and Hucke, ATS and Oskarsson, BE and Murray, ME and Dickson, DW and Heiman, M and Belzil, VV and Kellis, M}, title = {Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD.}, journal = {Cell}, volume = {187}, number = {8}, pages = {1971-1989.e16}, pmid = {38521060}, issn = {1097-4172}, support = {R35 NS127327/NS/NINDS NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; F32 NS128067/NS/NINDS NIH HHS/United States ; T32 EB019940/EB/NIBIB NIH HHS/United States ; R01 AG067151/AG/NIA NIH HHS/United States ; U01 NS110453/NS/NINDS NIH HHS/United States ; R56 AG067151/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Frontotemporal Dementia/genetics ; *Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; Gene Expression Profiling ; Neurons/metabolism ; *Prefrontal Cortex/metabolism/pathology ; Single-Cell Gene Expression Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share many clinical, pathological, and genetic features, but a detailed understanding of their associated transcriptional alterations across vulnerable cortical cell types is lacking. Here, we report a high-resolution, comparative single-cell molecular atlas of the human primary motor and dorsolateral prefrontal cortices and their transcriptional alterations in sporadic and familial ALS and FTLD. By integrating transcriptional and genetic information, we identify known and previously unidentified vulnerable populations in cortical layer 5 and show that ALS- and FTLD-implicated motor and spindle neurons possess a virtually indistinguishable molecular identity. We implicate potential disease mechanisms affecting these cell types as well as non-neuronal drivers of pathogenesis. Finally, we show that neuron loss in cortical layer 5 tracks more closely with transcriptional identity rather than cellular morphology and extends beyond previously reported vulnerable cell types.}, } @article {pmid38521615, year = {2024}, author = {Ramos, R and Kaouk, J}, title = {Reply to Alessandro Guercio, Antonio Franco, Elisa Mancini, et al's Letter to the Editor re: Roxana Ramos, Ethan Ferguson, Mahmoud Abou Zeinab, et al. Single-port Transvesical Robot-assisted Simple Prostatectomy: Surgical Technique and Clinical Outcomes. Eur Urol. 2024;85:445-456.}, journal = {European urology}, volume = {85}, number = {6}, pages = {e171-e172}, doi = {10.1016/j.eururo.2024.03.020}, pmid = {38521615}, issn = {1873-7560}, mesh = {Humans ; Male ; *Prostatectomy/methods ; *Robotic Surgical Procedures ; Treatment Outcome ; }, } @article {pmid38522244, year = {2024}, author = {Swash, M}, title = {Timing initiation of non-invasive ventilation in management of ALS.}, journal = {Journal of the neurological sciences}, volume = {459}, number = {}, pages = {122972}, doi = {10.1016/j.jns.2024.122972}, pmid = {38522244}, issn = {1878-5883}, mesh = {Humans ; *Noninvasive Ventilation ; *Amyotrophic Lateral Sclerosis/therapy ; *Respiratory Insufficiency ; }, } @article {pmid38522245, year = {2024}, author = {Geronimo, A and Simmons, Z}, title = {Remote pulmonary function testing allows for early identification of need for non-invasive ventilation in a subset of persons with ALS.}, journal = {Journal of the neurological sciences}, volume = {459}, number = {}, pages = {122971}, doi = {10.1016/j.jns.2024.122971}, pmid = {38522245}, issn = {1878-5883}, support = {UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Noninvasive Ventilation ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; *Respiratory Insufficiency/diagnosis/etiology/therapy ; Respiratory Function Tests ; Physical Examination ; }, abstract = {The traditional ALS multidisciplinary clinical practice of quarterly respiratory assessment may leave some individuals in danger of developing untreated respiratory insufficiency between visits or beginning non-invasive ventilation (NIV) later than would be optimal. Remote, or home-based, pulmonary function testing (rPFT) allows patients with ALS to perform regular respiratory testing at more frequent intervals in the home. The aim of this study was to determine the clinical benefit of weekly rPFT compared to standard, quarterly in-clinic respiratory assessments: the number of individuals with earlier identification of NIV need, the magnitude of this advance notice, and the individual factors predicting benefit. Participants with ALS (n = 39) completed rPFT training via telemedicine and then completed one year of weekly self-guided assessments in the home. Over this period, 17 individuals exhibited remotely-measured FVC dropping below 50% of predicted, the value often used for recommendation of NIV initiation. In 13 individuals with clinical detection of this event, the median and range of advance notice of need for NIV was 53 (-61-294) days. Prescription of NIV occurred for 21 individuals on the study, six of whom began NIV as a result of remote testing, prior to indication of need as determined by in-person assessments. Weekly home assessments appeared to be of greatest clinical value in a subset of patients with low baseline respiratory test values and rapid respiratory decline. This has potential implications for clinical management of ALS as well as the conduct of clinical trials that rely on respiratory endpoints.}, } @article {pmid38522514, year = {2024}, author = {Pokrishevsky, E and DuVal, MG and McAlary, L and Louadi, S and Pozzi, S and Roman, A and Plotkin, SS and Dijkstra, A and Julien, JP and Allison, WT and Cashman, NR}, title = {Tryptophan residues in TDP-43 and SOD1 modulate the cross-seeding and toxicity of SOD1.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {5}, pages = {107207}, pmid = {38522514}, issn = {1083-351X}, mesh = {Humans ; *Tryptophan/metabolism ; *Zebrafish ; Animals ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; *DNA-Binding Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Protein Folding ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons. Neuronal superoxide dismutase-1 (SOD1) inclusion bodies are characteristic of familial ALS with SOD1 mutations, while a hallmark of sporadic ALS is inclusions containing aggregated WT TAR DNA-binding protein 43 (TDP-43). We show here that co-expression of mutant or WT TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein SOD1[G85R]-GFP in human cell cultures and promotes synergistic axonopathy in zebrafish. Intriguingly, this pathological interaction is modulated by natively solvent-exposed tryptophans in SOD1 (tryptophan-32) and TDP-43 RNA-recognition motif RRM1 (tryptophan-172), in concert with natively sequestered TDP-43 N-terminal domain tryptophan-68. TDP-43 RRM1 intrabodies reduce WT SOD1 misfolding in human cell cultures, via blocking tryptophan-172. Tryptophan-68 becomes antibody-accessible in aggregated TDP-43 in sporadic ALS motor neurons and cell culture. 5-fluorouridine inhibits TDP-43-induced G85R-GFP SOD1 aggregation in human cell cultures and ameliorates axonopathy in zebrafish, via its interaction with SOD1 tryptophan-32. Collectively, our results establish a novel and potentially druggable tryptophan-mediated mechanism whereby two principal ALS disease effector proteins might directly interact in disease.}, } @article {pmid38522733, year = {2024}, author = {Rupp, D and Heuser, N and Sassen, MC and Betz, S and Volberg, C and Glass, S}, title = {Resuscitation (un-)wanted: Does anyone care? A retrospective real data analysis.}, journal = {Resuscitation}, volume = {198}, number = {}, pages = {110189}, doi = {10.1016/j.resuscitation.2024.110189}, pmid = {38522733}, issn = {1873-1570}, mesh = {Humans ; Retrospective Studies ; *Out-of-Hospital Cardiac Arrest/therapy ; Male ; Female ; Aged ; Aged, 80 and over ; *Cardiopulmonary Resuscitation/statistics & numerical data/methods ; *Emergency Medical Services/statistics & numerical data/methods ; Germany ; *Resuscitation Orders ; Middle Aged ; Advance Directives/statistics & numerical data ; }, abstract = {BACKGROUND AND OBJECTIVES: In case of out-of-hospital cardiac arrest (OHCA) personnel of the emergency medical services (EMS) are regularly confronted with advanced directives (AD) and do-not-attempt-resuscitation (DNACPR) orders. The authors conducted a retrospective analysis of EMS operation protocols to examine the prevalence of DNACPR in case of OHCA and the influence of a presented DNACPR on CPR-duration, performed Advanced-Life-Support (ALS) measures and decision making.

MATERIALS AND METHODS: Retrospective analysis of prehospital medical documentation of all resuscitation incidents in a German county with 250,000 inhabitants from 1 January 2016 to 31 December 2022. Combined with data from the structured CPR team-feedback database patients characteristics, measures and course of the CPR were analysed. Statistic testing with significance level p < 0.05.

RESULTS: In total n = 1,474 CPR events were analysed. Patients with DNACPR vs. no DNACPR: n = 263 (17.8%) vs. n = 1,211 (82.2%). Age: 80.0 ± 10.3 years vs. 68.0 ± 13.9 years; p < 0.001. Patients with ASA-status III/IV: n = 214 (81.3%) vs. n = 616 (50.9%); p < 0.001. Initial layperson-CPR: n = 148 (56.3%) vs. n = 647 (55.7%); p = 0.40. Airway management: n = 185 (70.3%) vs. n = 1,069 (88.3%); p < 0.001. With DNACPR CPR-duration initiated layperson-CPR vs. no layperson-CPR: 19:14 min (10:43-25:55 min) vs. 12:40 min (06:35-20:03 min); p < 0.001.

CONCLUSION: In case of CPR EMS-personnel are often confronted with DNACPR-orders. Patients are older and have more previous diseases than patients without DNACPR. Initiated layperson-CPR might lead to misinterpretation of patients will with impact on CPR-duration and unwanted measures. Awareness of this issue should be created through measures such as training programs in particular to train staff in the interpretation and legal admissibility of ADs.}, } @article {pmid38522911, year = {2024}, author = {Urushitani, M and Warita, H and Atsuta, N and Izumi, Y and Kano, O and Shimizu, T and Nakayama, Y and Narita, Y and Nodera, H and Fujita, T and Mizoguchi, K and Morita, M and Aoki, M}, title = {The clinical practice guideline for the management of amyotrophic lateral sclerosis in Japan-update 2023.}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {64}, number = {4}, pages = {252-271}, doi = {10.5692/clinicalneurol.cn-001946}, pmid = {38522911}, issn = {1882-0654}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis ; Disease Progression ; Evidence-Based Medicine ; Japan ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset intractable motor neuron disease characterized by selective degeneration of cortical neurons in the frontotemporal lobe and motor neurons in the brainstem and spinal cord. Impairment of these neural networks causes progressive muscle atrophy and weakness that spreads throughout the body, resulting in life-threatening bulbar palsy and respiratory muscle paralysis. However, no therapeutic strategy has yet been established to halt ALS progression. Although evidence for clinical practice in ALS remains insufficient, novel research findings have steadily accumulated in recent years. To provide updated evidence-based or expert consensus recommendations for the diagnosis and management of ALS, the ALS Clinical Practice Guideline Development Committee, approved by the Japanese Society of Neurology, revised and published the Japanese clinical practice guidelines for the management of ALS in 2023. In this guideline, disease-modifying therapies that have accumulated evidence from randomized controlled trials were defined as "Clinical Questions," in which the level of evidence was determined by systematic reviews. In contrast, "Questions and Answers" were defined as issues of clinically important but insufficient evidence, according to reports of a small number of cases, observational studies, and expert opinions. Based on a literature search performed in February 2022, recommendations were reached by consensus, determined by an independent panel, reviewed by external reviewers, and submitted for public comments by Japanese Society of Neurology members before publication. In this article, we summarize the revised Japanese guidelines for ALS, highlighting the regional and cultural diversity of care processes and decision-making. The guidelines cover a broad range of essential topics such as etiology, diagnostic criteria, disease monitoring and treatments, management of symptoms, respiration, rehabilitation, nutrition, metabolism, patient instructions, and various types of care support. We believe that this summary will help improve the daily clinical practice for individuals living with ALS and their caregivers.}, } @article {pmid38524401, year = {2024}, author = {Pota, V and Sansone, P and De Sarno, S and Aurilio, C and Coppolino, F and Barbarisi, M and Barbato, F and Fiore, M and Cosenza, G and Passavanti, MB and Pace, MC}, title = {Amyotrophic Lateral Sclerosis and Pain: A Narrative Review from Pain Assessment to Therapy.}, journal = {Behavioural neurology}, volume = {2024}, number = {}, pages = {1228194}, pmid = {38524401}, issn = {1875-8584}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Pain Measurement ; Quality of Life ; *Neurodegenerative Diseases/complications ; Pain/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent neurodegenerative disease of the motor system that affects upper and lower motor neurons, leading to progressive muscle weakness, spasticity, atrophy, and respiratory failure, with a life expectancy of 2-5 years after symptom onset. In addition to motor symptoms, patients with ALS have a multitude of nonmotor symptoms; in fact, it is currently considered a multisystem disease. The purpose of our narrative review is to evaluate the different types of pain, the correlation between pain and the disease's stages, the pain assessment tools in ALS patients, and the available therapies focusing above all on the benefits of cannabis use. Pain is an underestimated and undertreated symptom that, in the last few years, has received more attention from research because it has a strong impact on the quality of life of these patients. The prevalence of pain is between 15% and 85% of ALS patients, and the studies on the type and intensity of pain are controversial. The absence of pain assessment tools validated in the ALS population and the dissimilar study designs influence the knowledge of ALS pain and consequently the pharmacological therapy. Several studies suggest that ALS is associated with changes in the endocannabinoid system, and the use of cannabis could slow the disease progression due to its neuroprotective action and act on pain, spasticity, cramps, sialorrhea, and depression. Our research has shown high patients' satisfaction with the use of cannabis for the treatment of spasticity and related pain. However, especially due to the ethical problems and the lack of interest of pharmaceutical companies, further studies are needed to ensure the most appropriate care for ALS patients.}, } @article {pmid38524510, year = {2024}, author = {Liu, YX and Xu, Y}, title = {Enhancing competency of clinical research nurses: A comprehensive training and evaluation framework.}, journal = {World journal of clinical cases}, volume = {12}, number = {7}, pages = {1378-1381}, pmid = {38524510}, issn = {2307-8960}, abstract = {The Sun et al's training program for clinical research nurses (CRNs) in the World Journal of Clinical Cases is a comprehensive and scientific approach. It includes structured frameworks for CRN training, aiming to improve CRN competency. This program emphasizes practical abilities, updates training content, and improves evaluation methods. The cultivation of CRN talents focuses on enhancing the training system, establishing a multifaceted evaluation framework, and continuously refining the training programs. Regular feedback and evaluation are essential to improve CRNs' competency in practical settings.}, } @article {pmid38524582, year = {2024}, author = {Yamamoto, Y and Fujita, K and Yamazaki, H and Haji, S and Osaki, Y and Izumi, Y}, title = {Constipation in patients with motor neuron disease: A retrospective longitudinal study.}, journal = {Heliyon}, volume = {10}, number = {6}, pages = {e27951}, pmid = {38524582}, issn = {2405-8440}, abstract = {BACKGROUND: Constipation has been recently recognized as a complication associated with motor and autonomic dysfunction in patients with motor neuron disease (MND), typified by amyotrophic lateral sclerosis (ALS). However, the long-term characteristics of constipation remain unclear in patients with MND. We longitudinally investigated the prevalence and risk factors of constipation in a consecutive cohort of patients with MND.

METHODS: Data from Japanese patients with MND enrolled in a single-center registry from June 2017 to December 2021 were retrospectively investigated. The diagnosis of ALS was based on the updated Awaji criteria, and other MND subtypes were also included. The presence or absence of constipation symptoms was determined by referring to the Rome III criteria. The clinical backgrounds and symptoms of patients with and without constipation were compared.

RESULTS: Among 155 consecutive patients (female, 63; age, 66.5 ± 12.4 years), 30.3% had constipation at diagnosis and 52.9% after a median follow-up of 18 months. Univariate analysis showed that female sex, use of tracheostomy and invasive ventilation, and delivery of enteral nutrition were more frequent in the constipation group. The Revised Amyotrophic Lateral Sclerosis Functional Rating Scale score was significantly lower in the constipation group, especially for the sub-items related to physical motor function. Multivariate analysis showed that the use of enteral nutrition was an independent risk of constipation, with an odds ratio of 3.69 (95% CI, 1.49-9.17; p = 0.005).

CONCLUSION: Constipation had a high prevalence in patients with MND with impaired motor function. Controlling defecation is important in patients with MND, especially during enteral nutrition.}, } @article {pmid38525350, year = {2024}, author = {Gosik, R and Caldara, R and Toševski, I and Skuhrovec, J}, title = {Description of immature stages of Rhinusa species (Coleoptera, Curculionidae, Mecinini) with a focus on diagnostic morphological characters at the species and genus levels.}, journal = {ZooKeys}, volume = {1195}, number = {}, pages = {1-94}, pmid = {38525350}, issn = {1313-2989}, abstract = {The mature larvae of the following fourteen Rhinusa species are described and illustrated: Rhinusaantirrhini (Paykull, 1800), R.asellus (Gravenhorst, 1807), R.collina (Gyllenhal, 1813), R.eversmanni (Rosenschoeld, 1838), R.florum (Rubsaamen, 1895), R.herbarum (H. Brisout de Barneville, 1862), R.incana (Kirsch, 1881), R.linariae (Panzer, 1796), R.melas (Boheman, 1838), R.neta (Germar, 1821), R.pilosa (Gyllenhal, 1838), R.rara Toševski & Caldara, 2015, R.tetra (Fabricius, 1792), and R.vestita (Germar, 1821). The pupae of thirteen of them (except R.incana) were also described. The comparison of larval morphological characters and plant preferences provides evidence supporting the existence of different species groups previously established according to a phylogenetic analysis based on adult morphological characters. The following diagnostic attributes distinguishing the genus Rhinusa are highlighted. For the larvae: (1) pronotal shield indistinct; (2) thoracic prodorsal fold small or even vestigial; (3) abdominal postdorsal folds (especially of segments III-VII) high or even in the form of conical protuberances; (4) cuticle of abdominal segments densely covered with asperities; (5) cuticle without dark spots or dark pigmentation; (6) head suboval, rarely round; (7) labrum usually with 2 als; (8) des1 short or absent, rarely elongated; and (9) fs1-3 usually absent or minute. For the pupae: (1) body stout; (2) head protuberances always present; (3) pronotal protuberances (if present), separated at bases of the pronotum, always wider than higher; (4) abdominal protuberance usually present, wide or round; (5) femora usually with a single fes; and (6) urogomphi short or vestigial. Keys to the larvae and pupae described here are provided. All the characters used for identification are illustrated by photographs or drawings. Biological and distribution data, including new information, are provided for all the species studied.}, } @article {pmid38525545, year = {2024}, author = {Alpert, EA and Assaf, J and Nama, A and Pliner, R and Jaffe, E}, title = {Secondary Ambulance Transfers During the Mass-Casualty Terrorist Attack in Israel on October 7, 2023.}, journal = {Prehospital and disaster medicine}, volume = {39}, number = {2}, pages = {224-227}, doi = {10.1017/S1049023X24000153}, pmid = {38525545}, issn = {1945-1938}, mesh = {Israel ; Humans ; *Mass Casualty Incidents ; *Ambulances ; *Terrorism ; Emergency Medical Services/organization & administration ; Patient Transfer ; }, abstract = {On October 7, 2023, Israel experienced the worst terror attack in its history - 1,200 people were killed, 239 people were taken hostage, and 1,455 people were wounded. This mass-casualty event (MCE) was more specifically a mega terrorist attack. Due to the overwhelming number of victims who arrived at the two closest hospitals, it became necessary to implement secondary transfers to centers in other areas of the country. Historically, secondary transfer has been implemented in MCEs but usually for the transfer of critical patients from a Level 2 or Level 3 Trauma Center to a Level 1 Center. Magen David Adom (MDA), Israel's National Emergency Pre-Hospital Medical Organization, is designated by the Health Ministry as the incident command at any MCE. On October 7, in addition to the primary transport of victims by ambulance to hospitals throughout Israel, they secondarily transported patients from the two closest hospitals - the Soroka Medical Center (SMC; Level 1 Trauma Center) in Beersheba and the Barzilai Medical Center (BMC; Level 2 Trauma Center) in Ashkelon. Secondary transport began five hours after the event started and continued for approximately 12 hours. During this time, the terrorist infiltration was still on-going. Soroka received 650 victims and secondarily transferred 26, including five in Advanced Life Support (ALS) ambulances. Barzilai received 372 and secondarily transferred 38. These coordinated secondary transfers helped relieve the overwhelmed primary hospitals and are an essential component of any MCE strategy.}, } @article {pmid38525704, year = {2024}, author = {Shirai, R and Yamauchi, J}, title = {Emerging Evidence of Golgi Stress Signaling for Neuropathies.}, journal = {Neurology international}, volume = {16}, number = {2}, pages = {334-348}, pmid = {38525704}, issn = {2035-8385}, abstract = {The Golgi apparatus is an intracellular organelle that modifies cargo, which is transported extracellularly through the nucleus, endoplasmic reticulum, and plasma membrane in order. First, the general function of the Golgi is reviewed and, then, Golgi stress signaling is discussed. In addition to the six main Golgi signaling pathways, two pathways that have been increasingly reported in recent years are described in this review. The focus then shifts to neurological disorders, examining Golgi stress reported in major neurological disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. The review also encompasses findings related to other diseases, including hypomyelinating leukodystrophy, frontotemporal spectrum disorder/amyotrophic lateral sclerosis, microcephaly, Wilson's disease, and prion disease. Most of these neurological disorders cause Golgi fragmentation and Golgi stress. As a result, strong signals may act to induce apoptosis.}, } @article {pmid38526287, year = {2024}, author = {Chen, W and Jiang, S and Li, S and Li, C and Xu, R}, title = {OSMR is a potential driver of inflammation in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {11}, pages = {2513-2521}, pmid = {38526287}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202419110-00031/figure1/v/2024-03-08T184507Z/r/image-tiff Amyotrophic lateral sclerosis is a neurodegenerative disease, and the molecular mechanism underlying its pathology remains poorly understood. However, inflammation is known to play an important role in the development of this condition. To identify driver genes that affect the inflammatory response in amyotrophic lateral sclerosis, as well as potential treatment targets, it is crucial to analyze brain tissue samples from patients with both sporadic amyotrophic lateral sclerosis and C9orf72-related amyotrophic lateral sclerosis. Therefore, in this study we used a network-driven gene analysis tool, NetBID2.0, which is based on SJARACNe, a scalable algorithm for the reconstruction of accurate cellular networks, to experimentally analyze sequencing data from patients with sporadic amyotrophic lateral sclerosis. The results showed that the OSMR gene is pathogenic in amyotrophic lateral sclerosis and participates in the progression of amyotrophic lateral sclerosis by mediating the neuroinflammatory response. Furthermore, there were differences in OSMR activity and expression between patients with sporadic amyotrophic lateral sclerosis and those with C9orf72-related amyotrophic lateral sclerosis. These findings suggest that OSMR may be a diagnostic and prognostic marker for amyotrophic lateral sclerosis.}, } @article {pmid38527450, year = {2023}, author = {Cheong, I and Du, Y and Smith, G and Hua, J and Li, X and Pantelyat, A}, title = {Cerebral Tau Deposition in Comorbid Progressive Supranuclear Palsy and Amyotrophic Lateral Sclerosis: An [18F]-Flortaucipir and 7T MRI Study.}, journal = {Neuro-degenerative diseases}, volume = {23}, number = {3-4}, pages = {35-42}, pmid = {38527450}, issn = {1660-2862}, support = {K23 AG059891/AG/NIA NIH HHS/United States ; R01 AG059390/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Brain/diagnostic imaging/metabolism ; *Carbolines ; *Magnetic Resonance Imaging/methods ; *Positron-Emission Tomography/methods ; *Supranuclear Palsy, Progressive/diagnostic imaging/metabolism ; *tau Proteins/metabolism ; }, abstract = {INTRODUCTION: Progressive supranuclear palsy (PSP) is a four-repeat tauopathy characterized by multiple clinicopathologic subtypes. Advanced neuroimaging techniques have shown an early ability to distinguish PSP subtypes noninvasively for improved diagnosis. This study utilized tau PET imaging and MRI techniques at 7T to determine the neuroimaging profile of a participant with comorbid PSP and amyotrophic lateral sclerosis (ALS).

METHOD: [18F]-flortaucipir PET imaging was performed on one participant with PSP-ALS, one participant with typical PSP (Richardson's syndrome; PSP-RS), and 15 healthy control volunteers. Standardized uptake value ratio (SUVR) in each brain region was compared between PSP participants and controls. Quantitative susceptibility mapping (QSM) and inflow-based vascular-space occupancy MRI at 7T were performed on the two PSP participants and on two age-matched healthy controls to evaluate for differences in regional brain iron content and arteriolar cerebral blood volume (CBVa), respectively.

RESULTS: In the participant with PSP-ALS, the precentral gyrus demonstrated the highest [18F]-flortaucipir uptake of all brain regions relative to controls (z-score 1.94). In the participant with PSP-RS, [18F]-flortaucipir uptake relative to controls was highest in subcortical regions, including the pallidum, thalamus, hippocampus, and brainstem (z-scores 1.08, 1.41, 1.49, 1.32, respectively). Susceptibility values as a measure of brain iron content were higher in the globus pallidus and substantia nigra than in the midbrain and pons in each participant, regardless of group. CBVa values tended to be higher in the subcortical gray matter in PSP participants than in controls, although large measurement variability was noted in controls across multiple regions.

CONCLUSION: In vivo tau PET imaging of an individual with PSP-ALS overlap demonstrated increased tau burden in the motor cortex that was not observed in PSP-RS or control participants. Consistent with prior PET studies, tau burden in PSP-RS was mainly observed in subcortical regions, including the brainstem and basal ganglia. QSM data suggest that off-target binding to iron may account for some but not all of the increased [18F]-flortaucipir uptake in the basal ganglia in PSP-RS. These findings support existing evidence that tau PET imaging can distinguish among PSP subtypes by detecting distinct regional patterns of tau deposition in the brain. Larger studies are needed to determine whether CBVa is sensitive to changes in brain microvasculature in PSP.}, } @article {pmid38528673, year = {2024}, author = {Howard, J and Mazanderani, F and Keenan, KF and Turner, MR and Locock, L}, title = {Fluctuating salience in those living with genetic risk of motor neuron disease: A qualitative interview study.}, journal = {Health expectations : an international journal of public participation in health care and health policy}, volume = {27}, number = {2}, pages = {e14024}, pmid = {38528673}, issn = {1369-7625}, support = {Locock/Sept19/941-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Adult ; Child ; Humans ; *Motor Neuron Disease/genetics/diagnosis/psychology ; *Amyotrophic Lateral Sclerosis/diagnosis/pathology ; Qualitative Research ; Uncertainty ; Emotions ; }, abstract = {BACKGROUND: Motor neuron disease (MND) (also known as amyotrophic lateral sclerosis) is a life-limiting neurodegenerative condition. In up to 20% of people with MND, a pathogenic variant associated with autosomal dominant inheritance can be identified. Children of people carrying a pathogenic variant have a 50% chance of inheriting this and a higher, although harder to predict, chance of developing the disease compared to the general adult population. This paper explores the experience of living with the genetic risk of MND.

METHODS: We undertook a UK-based interview study with 35 individuals, including: 7 people living with genetically-mediated forms of MND; 24 asymptomatic relatives, the majority of whom had an increased risk of developing the disease; and 4 unrelated partners.

RESULTS: We explore how individuals make sense of genetic risk, unpacking the interplay between genetic knowledge, personal perception, experiences of the disease in the family, age and life stage and the implications that living with risk has for different aspects of their lives. We balance an emphasis on the emotional and psychological impact described by participants, with a recognition that the salience of risk fluctuates over time. Furthermore, we highlight the diverse strategies and approaches people employ to live well in the face of uncertainty and the complex ways they engage with the possibility of developing symptoms in the future. Finally, we outline the need for open-ended, tailored support and information provision.

CONCLUSIONS: Drawing on wider literature on genetic risk, we foreground how knowledge of MND risk can disrupt individuals' taken-for-granted assumptions on life and perceptions of the future, but also its contextuality, whereby its relevance becomes more prominent at critical junctures. This research has been used in the development of a public-facing resource on the healthtalk.org website.

People with experience of living with genetic risk were involved throughout the design and conduct of the study and advised on aspects including the topic guide, sampling and recruitment and the developing analysis. Two patient and public involvement contributors joined a formal advisory panel.}, } @article {pmid38531340, year = {2024}, author = {Lee, KH and Kim, MH and Kim, J and Nam, HJ}, title = {Acupuncture for Tinnitus: A Scoping Review of Clinical Studies.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {292-301}, pmid = {38531340}, issn = {2504-2106}, mesh = {Humans ; *Acupuncture Therapy/methods ; *Tinnitus/therapy ; Randomized Controlled Trials as Topic ; Acupuncture Points ; }, abstract = {BACKGROUND: Acupuncture treatment for tinnitus has received attention owing to its potential as an alternative to conventional treatment modalities. We conducted a scoping review to identify detailed information on acupuncture treatment methods used in clinical studies and to provide useful information for practitioners, patients, and researchers.

METHODS: MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Research Information Sharing Service (RISS), DataBase Periodical Information Academic (DBPIA), and the China National Knowledge Infrastructure (CNKI) were searched from their inception to December 2023. This review included single-arm trials, open-label randomized controlled trials (RCTs), and double-blind RCTs using needle-type acupuncture to treat tinnitus in English, Chinese, and Korean. We investigated basic and detailed information on the acupuncture treatment methods, assessment methods, and study outcomes. Network analysis was also conducted to evaluate the centrality between acupoints in the double-blind RCTs.

RESULTS: We included 106 articles. There were 11 single-arm trials, 90 open-label RCTs, and 5 double-blind RCTs. Most (89.6%) of these studies were conducted in China. Manual acupuncture was the most common type of acupuncture in treatment group. A total of 119 acupuncture points were used 1,138 times. The most frequently used acupoints were local points around the ear (TE17, GB2, SI19, and TE21). Both local and distant acupoints were used simultaneously in these studies. The treatment duration of 20-39 days, 10 to 19 sessions of treatment, the mean acupuncture duration of 30 min, needle diameter of 0.30 mm × 40 mm, and needling depth over 30 mm and less than 50 mm were confirmed as the most common.

CONCLUSION: These study outcomes will enable future acupuncture studies on tinnitus to perform more effective and standardized acupuncture treatments in selecting acupoints and procedures. Furthermore, the study has implications for informing clinicians and students about more impactful acupuncture strategies for addressing tinnitus.

UNLABELLED: HintergrundDie Anwendung von Akupunktur bei Tinnitus erhält seit einiger Zeit Aufmerksamkeit als potenzielle Alternative zu konventionellen Behandlungsmodalitäten. Wir führten einen Scoping-Review durch, um detaillierte Informationen zu den in klinischen Studien angewandten Akupunktur-Behandlungsmethoden zu sammeln und nützliche Informationen für Praktiker, Patienten und Forscher bereitzustellen.MethodenMEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Research Information Sharing Service (RISS), DataBase Periodical Information Academic (DBPIA) und die China National Knowledge Infrastructure (CNKI) wurden von ihrem jeweiligen Beginn bis Dezember 2023 durchsucht. In diese Übersichtsarbeit wurden einarmige Studien, offene, randomisierte, kontrollierte Studien (RCTs) sowie doppelt verblindete RCTs zu Nadel-Akupunktur zur Behandlung von Tinnitus in englischer, chinesischer und koreanischer Sprache einbezogen. Wir untersuchten grundlegende und detaillierte Informationen zu den Akupunktur-Behandlungsmethoden, Untersuchungsmethoden und Studienergebnissen. Außerdem wurden Netzwerkanalysen zur Beurteilung der Zentralität zwischen Akupunkten in den doppelt verblindeten RCTs durchgeführt.Ergebnisse106 Artikel wurden eingeschlossen. Sie behandelten 11 einarmige Studien, 90 offene RCTs und 5 doppelt verblindete RCTs. Die meisten (89,6%) dieser Studien waren in China durchgeführt worden. Manuelle Akupunktur war die häufigste Form der Akupunktur in den Behandlungsgruppen. 119 Akupunkturpunkte wurden insgesamt 1’138 Mal verwendet. Die am häufigsten verwendeten Akupunkte waren lokale Punkte im Bereich des Ohrs (TE17, GB2, SI19 und TE21). Jedoch wurden in den Studien lokale und entfernte Akupunkte gleichzeitig angewendet. Außerdem wurde festgestellt, dass die Behandlungsdauer am häufigsten 20 bis 39 Tage betrug, die Zahl der Sitzungen 10 bis 19, die mittlere Akupunkturdauer 30 Minuten, die Nadelgröße 0.30 mm × 40 mm und die Einstichtiefe zwischen 30 mm und weniger als 50 mm.SchlussfolgerungDiese Studienergebnisse bieten eine Grundlage für künftige Studien zu Akupunktur bei Tinnitus, um durch die Auswahl der Akupunkte und Verfahren wirksamere und standardisierte Akupunkturbehandlungen durchzuführen. Darüber hinaus hat die Studie Implikationen für die Aufklärung von Praktikern und Schülern über wirkungsvollere Akupunkturstrategien zur Behandlung von Tinnitus.}, } @article {pmid38531462, year = {2024}, author = {Oliveira, NAS and Pinho, BR and Pinto, J and Guedes de Pinho, P and Oliveira, JMA}, title = {Edaravone counteracts redox and metabolic disruptions in an emerging zebrafish model of sporadic ALS.}, journal = {Free radical biology & medicine}, volume = {217}, number = {}, pages = {126-140}, doi = {10.1016/j.freeradbiomed.2024.03.016}, pmid = {38531462}, issn = {1873-4596}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Edaravone ; Zebrafish ; *Neurodegenerative Diseases ; Oxidation-Reduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which the death of motor neurons leads to loss of muscle function. Additionally, cognitive and circadian disruptions are common in ALS patients, contributing to disease progression and burden. Most ALS cases are sporadic, and environmental exposures contribute to their aetiology. However, animal models of these sporadic ALS cases are scarce. The small vertebrate zebrafish is a leading organism to model neurodegenerative diseases; previous studies have proposed bisphenol A (BPA) or β-methylamino-l-alanine (BMAA) exposure to model sporadic ALS in zebrafish, damaging motor neurons and altering motor responses. Here we characterise the face and predictive validity of sporadic ALS models, showing their potential for the mechanistic study of ALS drugs. We phenotypically characterise the BPA and BMAA-induced models, going beyond motor activity and motor axon morphology, to include circadian, redox, proteostasis, and metabolomic phenotypes, and assessing their predictive validity for ALS modelling. BPA or BMAA exposure induced concentration-dependent activity impairments. Also, exposure to BPA but not BMAA induced motor axonopathy and circadian alterations in zebrafish larvae. Our further study of the BPA model revealed loss of habituation to repetitive startles, increased oxidative damage, endoplasmic reticulum (ER) stress, and metabolome abnormalities. The BPA-induced model shows predictive validity, since the approved ALS drug edaravone counteracted BPA-induced motor phenotypes, ER stress, and metabolic disruptions. Overall, BPA exposure is a promising model of ALS-related redox and ER imbalances, contributing to fulfil an unmet need for validated sporadic ALS models.}, } @article {pmid38531942, year = {2024}, author = {Son, B and Lee, J and Ryu, S and Park, Y and Kim, SH}, title = {Timing and impact of percutaneous endoscopic gastrostomy insertion in patients with amyotrophic lateral sclerosis: a comprehensive analysis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {7103}, pmid = {38531942}, issn = {2045-2322}, support = {BK21 FOUR//National Research Foundation of Korea/ ; RS-2023-00265515//National Research Foundation of Korea/ ; }, mesh = {Humans ; Gastrostomy/methods ; *Amyotrophic Lateral Sclerosis ; Retrospective Studies ; *Deglutition Disorders ; Weight Loss ; }, abstract = {Dysphagia is common in amyotrophic lateral sclerosis (ALS) patients, often requiring percutaneous endoscopic gastrostomy (PEG) for enteral nutrition. We retrospectively analyzed data from 188 Korean patients with ALS who underwent PEG tube insertion at five-time points: symptom onset (t1), diagnosis (t2), recommended time for gastrostomy (t3), PEG insertion (t4), and one-year post-insertion (t5). The recommended time point for gastrostomy (T-rec for gastrostomy) was defined as the earlier time point between a weight loss of more than 10% and advanced dysphagia indicated by the ALSFRS-R swallowing subscore of 2 or less. The T-rec for gastrostomy was reached at 22 months after symptom onset, followed by PEG insertion at 30 months, resulting in an 8-month delay. During the delay, the ALSFRS-R declined most rapidly at 1.7 points/month, compared to 0.8 points/month from symptom onset to diagnosis, 0.7 points/month from diagnosis to T-rec for gastrostomy, and 0.6 points/month after the PEG insertion. It is crucial to discuss PEG insertion before significant weight loss or severe dysphagia occurs and minimize the delay between the recommended time for gastrostomy and the actual PEG insertion. A stratified and individualized multidisciplinary team approach with careful symptom monitoring and proactive management plans, including early PEG insertion, should be prioritized to improve patient outcomes.}, } @article {pmid38532923, year = {2023}, author = {Howson, PJ}, title = {Foreign language acquisition of perceptually similar segments: evidence from Lower Sorbian.}, journal = {Open research Europe}, volume = {3}, number = {}, pages = {56}, pmid = {38532923}, issn = {2732-5121}, abstract = {Lower Sorbian is a moribund language spoken in Eastern Germany that features a three-way sibilant contrast, /s, ʂ, ɕ/. The vast majority of L1 speakers are above eighty years of age and virtually no young Sorbians learn Lower Sorbian as their first language. There are language revitalization programs in place, but this means that virtually all Lower Sorbian speakers are L2 learners whose first language is German. German, as opposed to Lower Sorbian, has a two-way sibilant contrast, /s, ʃ/. So, Lower Sorbian learners need to acquire a perceptually similar sibilant contrast, /ʂ, ɕ/, that commonly assimilates with a single L1 segment, /ʃ/. The two-to-one assimilation makes acquisition difficult. In this project, I examine the acquisition of the three-way sibilant contrast using ultrasound technology. The ultrasound data revealed that learners in the contemporary context do not produce a distinction between /ʂ, ɕ/ and only learners at an advanced level who had significant exposure to L1 speakers have acquired a three-way sibilant distinction. The findings are put into the context of models of L2 acquisition and generalized implications for foreign language acquisition are discussed.}, } @article {pmid38533300, year = {2024}, author = {Moskvin, SV}, title = {A brief literature review of low-level laser therapy for treating amyotrophic lateral sclerosis and confirmation of its effectiveness.}, journal = {BioMedicine}, volume = {14}, number = {1}, pages = {1-9}, pmid = {38533300}, issn = {2211-8020}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a steadily progressive course due to the death of central and peripheral motor neurons responsible for voluntary movements. Low-level laser therapy (LLLT) is a treatment method unique in its universality and efficacy, particularly for neurodegenerative diseases.

METHODS: In this review, we discuss the effect and application of LLLT in the treatment of ALS. A literature search for English and Russian publications for the keywords "Amyotrophic Lateral Sclerosis", "Low-Level Laser Therapy" was performed using PubMed, Scopus, Google Scholar, Web of Science and Russian Science Citation Index (RSCI) databases.

RESULTS: The article provided a brief literature review, substantiated the potential use of low-level laser therapy for ALS. The particular techniques of LLLT were developed.

CONCLUSION: Based on the results of several studies and many years of successful experience with low-level laser therapy in Russia we conclude that a LLLT technique, including intravenous laser blood illumination (ILBI), noninvasive laser blood illumination (NLBI), and local exposure, is a promising treatment method for ALS.}, } @article {pmid38533726, year = {2024}, author = {Alix, JJP and Plesia, M and Dudgeon, AP and Kendall, CA and Hewamadduma, C and Hadjivassiliou, M and Gorman, GS and Taylor, RW and McDermott, CJ and Shaw, PJ and Mead, RJ and Day, JC}, title = {Conformational fingerprinting with Raman spectroscopy reveals protein structure as a translational biomarker of muscle pathology.}, journal = {The Analyst}, volume = {149}, number = {9}, pages = {2738-2746}, pmid = {38533726}, issn = {1364-5528}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Spectrum Analysis, Raman/methods ; Humans ; Animals ; *Biomarkers/analysis ; *Muscular Dystrophy, Duchenne/pathology/diagnosis ; Muscle, Skeletal/chemistry/pathology ; Mice ; Amyotrophic Lateral Sclerosis/diagnosis/pathology ; Male ; }, abstract = {Neuromuscular disorders are a group of conditions that can result in weakness of skeletal muscles. Examples include fatal diseases such as amyotrophic lateral sclerosis and conditions associated with high morbidity such as myopathies (muscle diseases). Many of these disorders are known to have abnormal protein folding and protein aggregates. Thus, easy to apply methods for the detection of such changes may prove useful diagnostic biomarkers. Raman spectroscopy has shown early promise in the detection of muscle pathology in neuromuscular disorders and is well suited to characterising the conformational profiles relating to protein secondary structure. In this work, we assess if Raman spectroscopy can detect differences in protein structure in muscle in the setting of neuromuscular disease. We utilise in vivo Raman spectroscopy measurements from preclinical models of amyotrophic lateral sclerosis and the myopathy Duchenne muscular dystrophy, together with ex vivo measurements of human muscle samples from individuals with and without myopathy. Using quantitative conformation profiling and matrix factorisation we demonstrate that quantitative 'conformational fingerprinting' can be used to identify changes in protein folding in muscle. Notably, myopathic conditions in both preclinical models and human samples manifested a significant reduction in α-helix structures, with concomitant increases in β-sheet and, to a lesser extent, nonregular configurations. Spectral patterns derived through non-negative matrix factorisation were able to identify myopathy with a high accuracy (79% in mouse, 78% in human tissue). This work demonstrates the potential of conformational fingerprinting as an interpretable biomarker for neuromuscular disorders.}, } @article {pmid38533934, year = {2024}, author = {Deutsch, AJ}, title = {PICking out progressive PIC alterations in amyotrophic lateral sclerosis.}, journal = {Journal of neurophysiology}, volume = {131}, number = {5}, pages = {822-824}, pmid = {38533934}, issn = {1522-1598}, support = {NS091836//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS131816/NS/NINDS NIH HHS/United States ; R01 AG067758/AG/NIA NIH HHS/United States ; AG067758//HHS | NIH | National Institute on Aging (NIA)/ ; R01 NS091836/NS/NINDS NIH HHS/United States ; NS131816//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Humans ; *Motor Neurons/physiology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motoneuron death. Alterations to motoneuron excitability in ALS are suspected to contribute to motoneuron degeneration. Therefore, mechanisms underlying changes in motoneuron excitability are being thoroughly investigated. A recent publication from Trajano et al. (Trajano GS, Orssatto LB, McCombe PA, Rivlin W, Tang L, Henderson RD. J Physiol 601: 4723-4735, 2023) examined temporal changes to persistent inward currents (PICs) in ALS patients. They show that delta frequency (ΔF, an estimate of PICs) has opposite temporal trends in stronger and weaker muscles of ALS patients. This study is very important to aid in the understanding of disease mechanisms. This Neuro Forum article explores some important considerations for interpreting the results of this study, including treatment effects, potential sex differences, and a lack of comparison to healthy individuals.}, } @article {pmid38534336, year = {2024}, author = {Sonkodi, B}, title = {Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism.}, journal = {Cells}, volume = {13}, number = {6}, pages = {}, pmid = {38534336}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Syndecan-3 ; Mechanotransduction, Cellular ; *Channelopathies ; *Neurodegenerative Diseases ; Protons ; Proprioception/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a mysterious lethal multisystem neurodegenerative disease that gradually leads to the progressive loss of motor neurons. A recent non-contact dying-back injury mechanism theory for ALS proposed that the primary damage is an acquired irreversible intrafusal proprioceptive terminal Piezo2 channelopathy with underlying genetic and environmental risk factors. Underpinning this is the theory that excessively prolonged proprioceptive mechanotransduction under allostasis may induce dysfunctionality in mitochondria, leading to Piezo2 channelopathy. This microinjury is suggested to provide one gateway from physiology to pathophysiology. The chronic, but not irreversible, form of this Piezo2 channelopathy is implicated in many diseases with unknown etiology. Dry eye disease is one of them where replenishing synthetic proteoglycans promote nerve regeneration. Syndecans, especially syndecan-3, are proposed as the first critical link in this hierarchical ordered depletory pathomechanism as proton-collecting/distributing antennas; hence, they may play a role in ALS pathomechanism onset. Even more importantly, the shedding or charge-altering variants of Syndecan-3 may contribute to the Piezo2 channelopathy-induced disruption of the Piezo2-initiated proton-based ultrafast long-range signaling through VGLUT1 and VGLUT2. Thus, these alterations may not only cause disruption to ultrafast signaling to the hippocampus in conscious proprioception, but could disrupt the ultrafast proprioceptive signaling feedback to the motoneurons. Correspondingly, an inert Piezo2-initiated proton-based ultrafast signaled proprioceptive skeletal system is coming to light that is suggested to be progressively lost in ALS. In addition, the lost functional link of the MyoD family of inhibitor proteins, as auxiliary subunits of Piezo2, may not only contribute to the theorized acquired Piezo2 channelopathy, but may explain how these microinjured ion channels evolve to be principal transcription activators.}, } @article {pmid38534355, year = {2024}, author = {Cohen, J and Mathew, A and Dourvetakis, KD and Sanchez-Guerrero, E and Pangeni, RP and Gurusamy, N and Aenlle, KK and Ravindran, G and Twahir, A and Isler, D and Sosa-Garcia, SR and Llizo, A and Bested, AC and Theoharides, TC and Klimas, NG and Kempuraj, D}, title = {Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders.}, journal = {Cells}, volume = {13}, number = {6}, pages = {}, pmid = {38534355}, issn = {2073-4409}, mesh = {Humans ; Neuroinflammatory Diseases ; Endothelial Cells ; *Induced Pluripotent Stem Cells ; *Neurodegenerative Diseases ; Inflammation ; }, abstract = {Neuroinflammatory and neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood-brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.}, } @article {pmid38535014, year = {2024}, author = {Goudie, A and Blaivas, M and Horn, R and Lien, WC and Michels, G and Wastl, D and Dietrich, CF}, title = {Ultrasound during Advanced Life Support-Help or Harm?.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, pmid = {38535014}, issn = {2075-4418}, abstract = {Ultrasound is used in cardiopulmonary resuscitation (CPR) and advanced life support (ALS). However, there is divergence between the recommendations of many emergency and critical care societies who support its use and the recommendations of many international resuscitation organizations who either recommend against its use or recommend it only in limited circumstances. Ultrasound offers potential benefits of detecting reversable causes of cardiac arrest, allowing specific interventions. However, it also risks interfering with ALS protocols and increasing unhelpful interventions. As with many interventions in ALS, the evidence base for ultrasound use is weak, and well-designed randomized trials are needed. This paper reviews the current theory and evidence for harms and benefits.}, } @article {pmid38535081, year = {2024}, author = {Liampas, I and Danga, F and Kyriakoulopoulou, P and Siokas, V and Stamati, P and Messinis, L and Dardiotis, E and Nasios, G}, title = {The Contribution of Functional Near-Infrared Spectroscopy (fNIRS) to the Study of Neurodegenerative Disorders: A Narrative Review.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, pmid = {38535081}, issn = {2075-4418}, abstract = {Functional near-infrared spectroscopy (fNIRS) is an innovative neuroimaging method that offers several advantages over other commonly used modalities. This narrative review investigated the potential contribution of this method to the study of neurodegenerative disorders. Thirty-four studies involving patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), frontotemporal dementia (FTD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) and healthy controls were reviewed. Overall, it was revealed that the prefrontal cortex of individuals with MCI may engage compensatory mechanisms to support declining brain functions. A rightward shift was suggested to compensate for the loss of the left prefrontal capacity in the course of cognitive decline. In parallel, some studies reported the failure of compensatory mechanisms in MCI and early AD; this lack of appropriate hemodynamic responses may serve as an early biomarker of neurodegeneration. One article assessing FTD demonstrated a heterogeneous cortical activation pattern compared to AD, indicating that fNIRS may contribute to the challenging distinction of these conditions. Regarding PD, there was evidence that cognitive resources (especially executive function) were recruited to compensate for locomotor impairments. As for ALS, fNIRS data support the involvement of extra-motor networks in ALS, even in the absence of measurable cognitive impairment.}, } @article {pmid38536565, year = {2024}, author = {Vernikouskaya, I and Müller, HP and Ludolph, AC and Kassubek, J and Rasche, V}, title = {AI-assisted automatic MRI-based tongue volume evaluation in motor neuron disease (MND).}, journal = {International journal of computer assisted radiology and surgery}, volume = {19}, number = {8}, pages = {1579-1587}, pmid = {38536565}, issn = {1861-6429}, mesh = {Humans ; *Tongue/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; *Motor Neuron Disease/diagnostic imaging/diagnosis ; Male ; Female ; Middle Aged ; Aged ; *Neural Networks, Computer ; Pilot Projects ; Imaging, Three-Dimensional/methods ; Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis ; Adult ; }, abstract = {PURPOSE: Motor neuron disease (MND) causes damage to the upper and lower motor neurons including the motor cranial nerves, the latter resulting in bulbar involvement with atrophy of the tongue muscle. To measure tongue atrophy, an operator independent automatic segmentation of the tongue is crucial. The aim of this study was to apply convolutional neural network (CNN) to MRI data in order to determine the volume of the tongue.

METHODS: A single triplanar CNN of U-Net architecture trained on axial, coronal, and sagittal planes was used for the segmentation of the tongue in MRI scans of the head. The 3D volumes were processed slice-wise across the three orientations and the predictions were merged using different voting strategies. This approach was developed using MRI datasets from 20 patients with 'classical' spinal amyotrophic lateral sclerosis (ALS) and 20 healthy controls and, in a pilot study, applied to the tongue volume quantification to 19 controls and 19 ALS patients with the variant progressive bulbar palsy (PBP).

RESULTS: Consensus models with softmax averaging and majority voting achieved highest segmentation accuracy and outperformed predictions on single orientations and consensus models with union and unanimous voting. At the group level, reduction in tongue volume was not observed in classical spinal ALS, but was significant in the PBP group, as compared to controls.

CONCLUSION: Utilizing single U-Net trained on three orthogonal orientations with consequent merging of respective orientations in an optimized consensus model reduces the number of erroneous detections and improves the segmentation of the tongue. The CNN-based automatic segmentation allows for accurate quantification of the tongue volumes in all subjects. The application to the ALS variant PBP showed significant reduction of the tongue volume in these patients and opens the way for unbiased future longitudinal studies in diseases affecting tongue volume.}, } @article {pmid38538227, year = {2024}, author = {Tan, EL and Lope, J and Bede, P}, title = {Harnessing Big Data in Amyotrophic Lateral Sclerosis: Machine Learning Applications for Clinical Practice and Pharmaceutical Trials.}, journal = {Journal of integrative neuroscience}, volume = {23}, number = {3}, pages = {58}, doi = {10.31083/j.jin2303058}, pmid = {38538227}, issn = {0219-6352}, support = {HRB EIA-2017-019/HRBI_/Health Research Board/Ireland ; JPND-Cofund-2-2019-/HRBI_/Health Research Board/Ireland ; SFI SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Big Data ; Biomarkers ; Machine Learning ; }, abstract = {The arrival of genotype-specific therapies in amyotrophic lateral sclerosis (ALS) signals the dawn of precision medicine in motor neuron diseases (MNDs). After decades of academic studies in ALS, we are now witnessing tangible clinical advances. An ever increasing number of well-designed descriptive studies have been published in recent years, characterizing typical disease-burden patterns in vivo and post mortem. Phenotype- and genotype-associated traits and "typical" propagation patterns have been described based on longitudinal clinical and biomarker data. The practical caveat of these studies is that they report "group-level", stereotyped trajectories representative of ALS as a whole. In the clinical setting, however, "group-level" biomarker signatures have limited practical relevance and what matters is the meaningful interpretation of data from a single individual. The increasing availability of large normative data sets, national registries, extant academic data, consortium repositories, and emerging data platforms now permit the meaningful interpretation of individual biomarker profiles and allow the categorization of single patients into relevant diagnostic, phenotypic, and prognostic categories. A variety of machine learning (ML) strategies have been recently explored in MND to demonstrate the feasibility of interpreting data from a single patient. Despite the considerable clinical prospects of classification models, a number of pragmatic challenges need to be overcome to unleash the full potential of ML in ALS. Cohort size limitations, administrative hurdles, data harmonization challenges, regulatory differences, methodological obstacles, and financial implications and are just some of the barriers to readily implement ML in routine clinical practice. Despite these challenges, machine-learning strategies are likely to be firmly integrated in clinical decision-making and pharmacological trials in the near future.}, } @article {pmid38538275, year = {2024}, author = {Ceccarelli, L and Verriello, L and Pauletto, G and Valente, M and Spadea, L and Salati, C and Zeppieri, M and Ius, T}, title = {The Role of Human Pluripotent Stem Cells in Amyotrophic Lateral Sclerosis: From Biological Mechanism to Practical Implications.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {3}, pages = {114}, doi = {10.31083/j.fbl2903114}, pmid = {38538275}, issn = {2768-6698}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Motor Neurons/metabolism ; *Pluripotent Stem Cells/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, characterized by progressive loss of both upper and lower motor neurons, resulting in clinical features such as muscle weakness, paralysis, and ultimately, respiratory failure. Nowadays, there is not effective treatment to reverse the progression of the disease, that leads to death within 3-5 years after the onset. Nevertheless, the induced pluripotent stem cells (iPS) technology could be the answer, providing disease modelling, drug testing, and cell-based therapies for this pathology. The aim of this work was to conduct a literature review of the past 5 years about the role of iPS in ALS, to better define the neurobiological mechanisms involved in the pathogenesis and the potential future therapies. The review also deals with advanced and currently available technologies used to reprogram cell lines and generate human motor neurons in vitro, which represent the source to study the pathological processes, the relationship between phenotype and genotype, the disease progression and the potential therapeutic targets of these group of disorders. Specific treatment options with stem cells involve Advance Gene Editing Technology, neuroprotective agents, and cells or exosomes transplantation, aimed to replace dead or damaged nerve cells. In summary, this review comprehensively addresses the role of human pluripotent stem cells (hPSCs) in motor neuron diseases (MND), with a focus on physiopathology, diagnostic and prognostic implications, specific and potential future treatment options. Understanding the biological mechanisms and practical implications of hPSCs in MND is crucial for advancing therapeutic strategies and improving outcomes for patients affected by these devastating diseases.}, } @article {pmid38538647, year = {2024}, author = {Wang, X and Chen, H and Chang, Z and Zhang, J and Xie, D}, title = {Genetic causal role of body mass index in multiple neurological diseases.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {7256}, pmid = {38538647}, issn = {2045-2322}, support = {82274493//National Natural Science Foundation of China/ ; 81874389//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Body Mass Index ; *Amyotrophic Lateral Sclerosis/genetics ; Genome-Wide Association Study ; *Nervous System Diseases/genetics ; *Parkinson Disease/genetics ; *Multiple Sclerosis/genetics ; *Alzheimer Disease/genetics ; *Ischemic Stroke ; Mendelian Randomization Analysis ; Obesity/genetics ; }, abstract = {Body mass index (BMI) is a crucial health indicator for obesity. With the progression of socio-economic status and alterations in lifestyle, an increasing number of global populations are at risk of obesity. Given the complexity and severity of neurological diseases, early identification of risk factors is vital for the diagnosis and prognosis of such diseases. In this study, we employed Mendelian randomization (MR) analysis utilizing the most comprehensive genome-wide association study (GWAS) data to date. We selected single nucleotide polymorphisms (SNPs) that are unaffected by confounding factors and reverse causality as instrumental variables. These variables were used to evaluate the genetic and causal relationships between Body Mass Index (BMI) and various neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Ischemic Stroke (IS), and Epilepsy (EP). The Inverse Variance Weighted (IVW) analysis indicated that there was no significant causal relationship between Body Mass Index (BMI) indicators and PD (P-value = 0.511), AD (P-value = 0.076), ALS (P-value = 0.641), EP (P-value = 0.380). However, a causal relationship was found between BMI indicators and MS (P-value = 0.035), and IS (P-value = 0.000), with the BMI index positively correlated with the risk of both diseases. The Cochran's Q test for MR-IVW showed no heterogeneity in the MR analysis results between the BMI index and the neurological diseases (P > 0.05). The Egger intercept test for pleiotropy revealed no horizontal pleiotropy detected in any of the neurological diseases studied (P > 0.05). It was found that there was no causal relationship between BMI and PD, AD, ALS, EP, and a genetic causal association with MS, and IS. Meanwhile, the increase in BMI can lead to a higher risk of MS and IS, which reveals the critical role of obesity as a risk factor for specific neurological diseases in the pathogenesis of the diseases.}, } @article {pmid38540369, year = {2024}, author = {Souza, PVS and Serrano, PL and Farias, IB and Machado, RIL and Badia, BML and Oliveira, HB and Barbosa, AS and Pereira, CA and Moreira, VF and Chieia, MAT and Barbosa, AR and Braga, VL and Pinto, WBVR and Oliveira, ASB}, title = {Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges.}, journal = {Genes}, volume = {15}, number = {3}, pages = {}, pmid = {38540369}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Motor Neurons ; Neuroimaging ; }, abstract = {Juvenile Amyotrophic Lateral Sclerosis is a genetically heterogeneous neurodegenerative disorder, which is frequently misdiagnosed due to low clinical suspicion and little knowledge about disease characteristics. More than 20 different genetic loci have been associated with both sporadic and familial juvenile Amyotrophic Lateral Sclerosis. Currently, almost 40% of cases have an identifiable monogenic basis; type 6, associated with FUS gene variants, is the most prevalent globally. Despite several upper motor neuron-dominant forms being generally associated with long-standing motor symptoms and slowly progressive course, certain subtypes with lower motor neuron-dominant features and early bulbar compromise lead to rapidly progressive motor handicap. For some monogenic forms, there is a well-established genotypic-phenotypic correlation. There are no specific biochemical and neuroimaging biomarkers for the diagnosis of juvenile Amyotrophic Lateral Sclerosis. There are several inherited neurodegenerative and neurometabolic disorders which can lead to the signs of motor neuron impairment. This review emphasizes the importance of high clinical suspicion, assessment, and proper diagnostic work-up for juvenile Amyotrophic Lateral Sclerosis.}, } @article {pmid38540370, year = {2024}, author = {Ivantsik, O and John, A and Kydonopoulou, K and Mitropoulos, K and Gerou, S and Ali, BR and Patrinos, GP}, title = {Novel Pathogenic Variants Leading to Sporadic Amyotrophic Lateral Sclerosis in Greek Patients.}, journal = {Genes}, volume = {15}, number = {3}, pages = {}, pmid = {38540370}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Mutation ; Superoxide Dismutase-1/genetics ; Greece ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease that affects motor neurons, leading to paralysis and death usually 3-5 years after the onset of symptoms. The investigation of both sporadic and familial ALS highlighted four main genes that contribute to the pathogenesis of the disease: SOD1, FUS, TARDBP and C9orf72. This study aims to provide a comprehensive investigation of genetic variants found in SOD1, FUS and TARDBP genes in Greek sporadic ALS (sALS) cases. Our sequencing analysis of the coding regions of the abovementioned genes that include the majority of the variants that lead to ALS in 32 sALS patients and 3 healthy relatives revealed 6 variants in SOD1, 19 variants in FUS and 37 variants in TARDBP, of which the SOD1 p.D90A and the FUS c.*356G>A (rs886051940) variants have been previously associated with ALS, while two novel nonsense pathogenic variants were also identified, namely FUS p.R241* and TDP-43 p.Y214*. Our study contributes to the worldwide effort toward clarifying the genetic basis of sALS to better understand the disease's molecular pathology.}, } @article {pmid38540591, year = {2024}, author = {Brito, O and Fregonezi, G and Pondofe, K and Vieira, RGDS and Ribeiro, T and Dourado Júnior, ME and Fidelix, EC and Nagem, D and Valentim, R and Sarmento, A and Resqueti, V}, title = {Assessment of the Clinical and Functional Health Status of Patients with Amyotrophic Lateral Sclerosis during the COVID-19 Pandemic in Brazil Using Telemedicine.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {6}, pages = {}, pmid = {38540591}, issn = {2227-9032}, support = {2021OB805920//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 305960/2021-0//National Council for Scientific and Technological Development/ ; 316937/2021-5//National Council for Scientific and Technological Development/ ; }, abstract = {This study aimed to monitor the clinical and functional progression of patients with amyotrophic lateral sclerosis (ALS) and adjust ventilatory support during the COVID-19 pandemic in Brazil using telemedicine. This longitudinal case series included five evaluations from January 2019 to June 2021. The first and second assessments were performed in person and consisted of pulmonary function, respiratory muscle strength, functionality (ALS Functional Rating Scale-Revised [ALSFRS-R]) and disease staging (King's College criteria). The use of non-invasive ventilation (NIV), ALSFRS-R, and disease staging were assessed in the third, fourth, and fifth assessments during the COVID-19 pandemic, using telemedicine. The rate of functional decline was calculated by the difference in the total score of ALSFRS-R between evaluations. A cutoff of 0.77 in the ALSFRS-R was used to characterize the speed of functional decline. Eleven patients (mean age of 51 years, eight males) were assessed. The total score of the ALSFRS-R (p < 0.01) and its motor domain (p < 0.01) reduced significantly during the pandemic. NIV prescription increased from 54.4% to 83.3%. Telemedicine helped with the clinical and functional follow-up of patients with ALS.}, } @article {pmid38540709, year = {2024}, author = {Stoklund Dittlau, K and Freude, K}, title = {Astrocytes: The Stars in Neurodegeneration?.}, journal = {Biomolecules}, volume = {14}, number = {3}, pages = {}, pmid = {38540709}, issn = {2218-273X}, support = {R434-2023-242//Lundbeck Foundation/ ; 2078-00002B//Innovation Fund Denmark/ ; NNF21OC0071571//Novo Nordisk Foundation/ ; N/A//Alzheimer Foundation Denmark/ ; }, mesh = {Humans ; Astrocytes/physiology ; *Neurodegenerative Diseases ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis/therapy ; }, abstract = {Today, neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, and as the average human lifespan increases, similarly grows the number of patients. For many decades, cognitive and motoric decline has been explained by the very apparent deterioration of neurons in various regions of the brain and spinal cord. However, more recent studies show that disease progression is greatly influenced by the vast population of glial cells. Astrocytes are traditionally considered star-shaped cells on which neurons rely heavily for their optimal homeostasis and survival. Increasing amounts of evidence depict how astrocytes lose their supportive functions while simultaneously gaining toxic properties during neurodegeneration. Many of these changes are similar across various neurodegenerative diseases, and in this review, we highlight these commonalities. We discuss how astrocyte dysfunction drives neuronal demise across a wide range of neurodegenerative diseases, but rather than categorizing based on disease, we aim to provide an overview based on currently known mechanisms. As such, this review delivers a different perspective on the disease causes of neurodegeneration in the hope to encourage further cross-disease studies into shared disease mechanisms, which might ultimately disclose potentially common therapeutic entry points across a wide panel of neurodegenerative diseases.}, } @article {pmid38540776, year = {2024}, author = {Hughes, LS and Fröhlich, A and Pfaff, AL and Bubb, VJ and Quinn, JP and Kõks, S}, title = {Exploring SVA Insertion Polymorphisms in Shaping Differential Gene Expressions in the Central Nervous System.}, journal = {Biomolecules}, volume = {14}, number = {3}, pages = {}, pmid = {38540776}, issn = {2218-273X}, support = {1234//Andrzej Wlodarski Memorial Research Fund/ ; 1234//Multiple Sclerosis Western Australia/ ; }, mesh = {Humans ; *Retroelements ; *Amyotrophic Lateral Sclerosis/genetics ; Minisatellite Repeats ; DNA Transposable Elements ; Central Nervous System ; Gene Expression ; }, abstract = {Transposable elements (TEs) are repetitive elements which make up around 45% of the human genome. A class of TEs, known as SINE-VNTR-Alu (SVA), demonstrate the capacity to mobilise throughout the genome, resulting in SVA polymorphisms for their presence or absence within the population. Although studies have previously highlighted the involvement of TEs within neurodegenerative diseases, such as Parkinson's disease and amyotrophic lateral sclerosis (ALS), the exact mechanism has yet to be identified. In this study, we used whole-genome sequencing and RNA sequencing data of ALS patients and healthy controls from the New York Genome Centre ALS Consortium to elucidate the influence of reference SVA elements on gene expressions genome-wide within central nervous system (CNS) tissues. To investigate this, we applied a matrix expression quantitative trait loci analysis and demonstrate that reference SVA insertion polymorphisms can significantly modulate the expression of numerous genes, preferentially in the trans position and in a tissue-specific manner. We also highlight that SVAs significantly regulate mitochondrial genes as well as genes within the HLA and MAPT loci, previously associated within neurodegenerative diseases. In conclusion, this study continues to bring to light the effects of polymorphic SVAs on gene regulation and further highlights the importance of TEs within disease pathology.}, } @article {pmid38540795, year = {2024}, author = {Gascón, E and Zaragoza, P and Calvo, AC and Osta, R}, title = {Sporadic Amyotrophic Lateral Sclerosis Skeletal Muscle Transcriptome Analysis: A Comprehensive Examination of Differentially Expressed Genes.}, journal = {Biomolecules}, volume = {14}, number = {3}, pages = {}, pmid = {38540795}, issn = {2218-273X}, support = {PI17/00949//Instituto de Salud Carlos III/ ; A19_23R//"LAGENBIO GRUPO INVESTIGACION"/ ; CIBER-358 NED-612-CB18/05/00037//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; }, mesh = {Humans ; Transcriptome/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; Muscle, Skeletal/metabolism ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) that comprises sporadic (sALS) and familial (fALS) cases, is a devastating neurodegenerative disorder characterized by progressive degeneration of motor neurons, leading to muscle atrophy and various clinical manifestations. However, the complex underlying mechanisms affecting this disease are not yet known. On the other hand, there is also no good prognosis of the disease due to the lack of biomarkers and therapeutic targets. Therefore, in this study, by means of bioinformatics analysis, sALS-affected muscle tissue was analyzed using the GEO GSE41414 dataset, identifying 397 differentially expressed genes (DEGs). Functional analysis revealed 320 up-regulated DEGs associated with muscle development and 77 down-regulated DEGs linked to energy metabolism. Protein-protein interaction network analysis identified 20 hub genes, including EIF4A1, HNRNPR and NDUFA4. Furthermore, miRNA target gene networks revealed 17 miRNAs linked to hub genes, with hsa-mir-206, hsa-mir-133b and hsa-mir-100-5p having been previously implicated in ALS. This study presents new potential biomarkers and therapeutic targets for ALS by correlating the information obtained with a comprehensive literature review, providing new potential targets to study their role in ALS.}, } @article {pmid38542223, year = {2024}, author = {Salvatori, I and Nesci, V and Spalloni, A and Marabitti, V and Muzzi, M and Zenuni, H and Scaricamazza, S and Rosina, M and Fenili, G and Goglia, M and Boffa, L and Massa, R and Moreno, S and Mercuri, NB and Nazio, F and Longone, P and Ferri, A and Valle, C}, title = {Trimetazidine Improves Mitochondrial Dysfunction in SOD1[G93A] Cellular Models of Amyotrophic Lateral Sclerosis through Autophagy Activation.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542223}, issn = {1422-0067}, support = {CNR IFT DBA.AD005.225 -NUTRAGE- FOE2021//National Research Council/ ; RF-2019-12369105//Ministero della Salute/ ; HyperALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; 'Unraveling the protective effects of NOS1AP in the rescue of TDP-43 loss of function pathological mechanisms//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; Ref. 27019//Italian Association for Cancer Research/ ; Prot. GeCoWEB n. A0375-2020- 36668//Regione Lazio/ ; The Grant of Excellence Departments 2023-2027//Ministero dell'Università e Ricerca Italy/ ; }, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/metabolism ; *Trimetazidine/pharmacology/therapeutic use ; Mice, Transgenic ; Leukocytes, Mononuclear/metabolism ; Superoxide Dismutase/metabolism ; Autophagy ; *Mitochondrial Diseases ; Disease Models, Animal ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is considered the prototype of motor neuron disease, characterized by motor neuron loss and muscle waste. A well-established pathogenic hallmark of ALS is mitochondrial failure, leading to bioenergetic deficits. So far, pharmacological interventions for the disease have proven ineffective. Trimetazidine (TMZ) is described as a metabolic modulator acting on different cellular pathways. Its efficacy in enhancing muscular and cardiovascular performance has been widely described, although its molecular target remains elusive. We addressed the molecular mechanisms underlying TMZ action on neuronal experimental paradigms. To this aim, we treated murine SOD1[G93A]-model-derived primary cultures of cortical and spinal enriched motor neurons, as well as a murine motor-neuron-like cell line overexpressing SOD1[G93A], with TMZ. We first characterized the bioenergetic profile of the cell cultures, demonstrating significant mitochondrial dysfunction that is reversed by acute TMZ treatments. We then investigated the effect of TMZ in promoting autophagy processes and its impact on mitochondrial morphology. Finally, we demonstrated the effectiveness of TMZ in terms of the mitochondrial functionality of ALS-rpatient-derived peripheral blood mononuclear cells (PBMCs). In summary, our results emphasize the concept that targeting mitochondrial dysfunction may represent an effective therapeutic strategy for ALS. The findings demonstrate that TMZ enhances mitochondrial performance in motor neuron cells by activating autophagy processes, particularly mitophagy. Although further investigations are needed to elucidate the precise molecular pathways involved, these results hold critical implications for the development of more effective and specific derivatives of TMZ for ALS treatment.}, } @article {pmid38542306, year = {2024}, author = {Marshall Moscon, SL and Connor, JR}, title = {HFE Mutations in Neurodegenerative Disease as a Model of Hormesis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542306}, issn = {1422-0067}, mesh = {Mice ; Animals ; *Neurodegenerative Diseases/genetics ; Hemochromatosis Protein/genetics ; Histocompatibility Antigens Class I/genetics ; Hormesis ; Mutation ; Iron/metabolism ; }, abstract = {Common variants in the iron regulatory protein HFE contribute to systematically increased iron levels, yet the effects in the brain are not fully characterized. It is commonly believed that iron dysregulation is a key contributor to neurodegenerative disease due to iron's ability to catalyze reactive oxygen species production. However, whether HFE variants exacerbate or protect against neurodegeneration has been heavily debated. Some claim that mutated HFE exacerbates oxidative stress and neuroinflammation, thus predisposing carriers to neurodegeneration-linked pathologies. However, H63D HFE has also been shown to slow the progression of multiple neurodegenerative diseases and to protect against environmental toxins that cause neurodegeneration. These conflicting results showcase the need to further understand the contribution of HFE variants to neurodegenerative disease heterogeneity. Data from mouse models consistently demonstrate robust neuroprotection against toxins known to increase the risk of neurodegenerative disease. This may represent an adaptive, or hormetic, response to increased iron, which leaves cells better protected against future stressors. This review describes the current research regarding the contribution of HFE variants to neurodegenerative disease prognosis in the context of a hormetic model. To our knowledge, this is the first time that a hormetic model for neurodegenerative disease has been presented.}, } @article {pmid38542497, year = {2024}, author = {Nemeth, C and Banik, NL and Haque, A}, title = {Disruption of Neuromuscular Junction Following Spinal Cord Injury and Motor Neuron Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542497}, issn = {1422-0067}, support = {R21 NS118393/NS/NINDS NIH HHS/United States ; I01 BX001262/BX/BLRD VA/United States ; 1R21NS118393-01/NH/NIH HHS/United States ; I01 BX004269/BX/BLRD VA/United States ; I01 BX006101/BX/BLRD VA/United States ; IK6 BX005964/BX/BLRD VA/United States ; }, mesh = {Humans ; Neuromuscular Junction/metabolism ; Motor Neurons/metabolism ; Muscle Fibers, Skeletal/metabolism ; Spinal Cord/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Spinal Cord Injuries/metabolism ; }, abstract = {The neuromuscular junction (NMJ) is a crucial structure that connects the cholinergic motor neurons to the muscle fibers and allows for muscle contraction and movement. Despite the interruption of the supraspinal pathways that occurs in spinal cord injury (SCI), the NMJ, innervated by motor neurons below the injury site, has been found to remain intact. This highlights the importance of studying the NMJ in rodent models of various nervous system disorders, such as amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). The NMJ is also involved in myasthenic disorders, such as myasthenia gravis (MG), and is vulnerable to neurotoxin damage. Thus, it is important to analyze the integrity of the NMJ in rodent models during the early stages of the disease, as this may allow for a better understanding of the condition and potential treatment options. The spinal cord also plays a crucial role in the functioning of the NMJ, as the junction relays information from the spinal cord to the muscle fibers, and the integrity of the NMJ could be disrupted by SCI. Therefore, it is vital to study SCI and muscle function when studying NMJ disorders. This review discusses the formation and function of the NMJ after SCI and potential interventions that may reverse or improve NMJ dysfunction, such as exercise, nutrition, and trophic factors.}, } @article {pmid38542501, year = {2024}, author = {Niu, Y and Pal, A and Szewczyk, B and Japtok, J and Naumann, M and Glaß, H and Hermann, A}, title = {Cell-Type-Dependent Recruitment Dynamics of FUS Protein at Laser-Induced DNA Damage Sites.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542501}, issn = {1422-0067}, support = {na//Nomis Foundation/ ; na//Hermann und Lilly Schilling-Stiftung/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; DNA Damage ; Mutation ; }, abstract = {Increased signs of DNA damage have been associated to aging and neurodegenerative diseases. DNA damage repair mechanisms are tightly regulated and involve different pathways depending on cell types and proliferative vs. postmitotic states. Amongst them, fused in sarcoma (FUS) was reported to be involved in different pathways of single- and double-strand break repair, including an early recruitment to DNA damage. FUS is a ubiquitously expressed protein, but if mutated, leads to a more or less selective motor neurodegeneration, causing amyotrophic lateral sclerosis (ALS). Of note, ALS-causing mutation leads to impaired DNA damage repair. We thus asked whether FUS recruitment dynamics differ across different cell types putatively contributing to such cell-type-specific vulnerability. For this, we generated engineered human induced pluripotent stem cells carrying wild-type FUS-eGFP and analyzed different derivatives from these, combining a laser micro-irradiation technique and a workflow to analyze the real-time process of FUS at DNA damage sites. All cells showed FUS recruitment to DNA damage sites except for hiPSC, with only 70% of cells recruiting FUS. In-depth analysis of the kinetics of FUS recruitment at DNA damage sites revealed differences among cellular types in response to laser-irradiation-induced DNA damage. Our work suggests a cell-type-dependent recruitment behavior of FUS during the DNA damage response and repair procedure. The presented workflow might be a valuable tool for studying the proteins recruited at the DNA damage site in a real-time course.}, } @article {pmid38544185, year = {2024}, author = {Albán-Escobar, M and Navarrete-Arroyo, P and De la Cruz-Guevara, DR and Tobar-Quevedo, J}, title = {Assistance Device Based on SSVEP-BCI Online to Control a 6-DOF Robotic Arm.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {6}, pages = {}, pmid = {38544185}, issn = {1424-8220}, mesh = {Humans ; *Brain-Computer Interfaces ; *Robotic Surgical Procedures ; Electroencephalography/methods ; *Self-Help Devices ; Evoked Potentials, Visual ; Photic Stimulation ; }, abstract = {This paper explores the potential benefits of integrating a brain-computer interface (BCI) utilizing the visual-evoked potential paradigm (SSVEP) with a six-degrees-of-freedom (6-DOF) robotic arm to enhance rehabilitation tools. The SSVEP-BCI employs electroencephalography (EEG) as a method of measuring neural responses inside the occipital lobe in reaction to pre-established visual stimulus frequencies. The BCI offline and online studies yielded accuracy rates of 75% and 83%, respectively, indicating the efficacy of the system in accurately detecting and capturing user intent. The robotic arm achieves planar motion by utilizing a total of five control frequencies. The results of this experiment exhibited a high level of precision and consistency, as indicated by the recorded values of ±0.85 and ±1.49 cm for accuracy and repeatability, respectively. Moreover, during the performance tests conducted with the task of constructing a square within each plane, the system demonstrated accuracy of 79% and 83%. The use of SSVEP-BCI and a robotic arm together shows promise and sets a solid foundation for the development of assistive technologies that aim to improve the health of people with amyotrophic lateral sclerosis, spina bifida, and other related diseases.}, } @article {pmid38548126, year = {2024}, author = {Krut', VG and Kalinichenko, AL and Maltsev, DI and Jappy, D and Shevchenko, EK and Podgorny, OV and Belousov, VV}, title = {Optogenetic and chemogenetic approaches for modeling neurological disorders in vivo.}, journal = {Progress in neurobiology}, volume = {235}, number = {}, pages = {102600}, doi = {10.1016/j.pneurobio.2024.102600}, pmid = {38548126}, issn = {1873-5118}, mesh = {Animals ; Humans ; Optogenetics/methods ; *Epilepsy ; Models, Animal ; *Parkinson Disease ; Neuropathology ; }, abstract = {Animal models of human neurological disorders provide valuable experimental tools which enable us to study various aspects of disorder pathogeneses, ranging from structural abnormalities and disrupted metabolism and signaling to motor and mental deficits, and allow us to test novel therapies in preclinical studies. To be valid, these animal models should recapitulate complex pathological features at the molecular, cellular, tissue, and behavioral levels as closely as possible to those observed in human subjects. Pathological states resembling known human neurological disorders can be induced in animal species by toxins, genetic factors, lesioning, or exposure to extreme conditions. In recent years, novel animal models recapitulating neuropathologies in humans have been introduced. These animal models are based on synthetic biology approaches: opto- and chemogenetics. In this paper, we review recent opto- and chemogenetics-based animal models of human neurological disorders. These models allow for the creation of pathological states by disrupting specific processes at the cellular level. The artificial pathological states mimic a range of human neurological disorders, such as aging-related dementia, Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, epilepsy, and ataxias. Opto- and chemogenetics provide new opportunities unavailable with other animal models of human neurological disorders. These techniques enable researchers to induce neuropathological states varying in severity and ranging from acute to chronic. We also discuss future directions for the development and application of synthetic biology approaches for modeling neurological disorders.}, } @article {pmid38548305, year = {2024}, author = {Tilsley, P and Moutiez, A and Brodovitch, A and Mendili, MME and Testud, B and Zaaraoui, W and Verschueren, A and Attarian, S and Guye, M and Boucraut, J and Grapperon, AM and Stellmann, JP}, title = {Neurofilament Light Chain Levels Interact with Neurodegenerative Patterns and Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {AJNR. American journal of neuroradiology}, volume = {45}, number = {4}, pages = {494-503}, pmid = {38548305}, issn = {1936-959X}, mesh = {Male ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Retrospective Studies ; Prospective Studies ; *Neurodegenerative Diseases ; Intermediate Filaments ; Motor Neurons/pathology ; Magnetic Resonance Imaging/methods ; Atrophy/pathology ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving rapid motor neuron degeneration leading to brain, primarily precentral, atrophy. Neurofilament light chains are a robust prognostic biomarker highly specific to ALS, yet associations between neurofilament light chains and MR imaging outcomes are not well-understood. We investigated the role of neurofilament light chains as mediators among neuroradiologic assessments, precentral neurodegeneration, and disability in ALS.

MATERIALS AND METHODS: We retrospectively analyzed a prospective cohort of 29 patients with ALS (mean age, 56 [SD, 12] years; 18 men) and 36 controls (mean age, 49 [SD, 11] years; 18 men). Patients underwent 3T (n = 19) or 7T (n = 10) MR imaging, serum (n = 23) and CSF (n = 15) neurofilament light chains, and clinical (n = 29) and electrophysiologic (n = 27) assessments. The control group had equivalent 3T (n = 25) or 7T (n = 11) MR imaging. Two trained neuroradiologists performed blinded qualitative assessments of MR imaging anomalies (n = 29 patients, n = 36 controls). Associations between precentral cortical thickness and neurofilament light chains and clinical and electrophysiologic data were analyzed.

RESULTS: We observed extensive cortical thinning in patients compared with controls. MR imaging analyses showed significant associations between precentral cortical thickness and bulbar or arm impairment following distributions corresponding to the motor homunculus. Finally, uncorrected results showed positive interactions among precentral cortical thickness, serum neurofilament light chains, and electrophysiologic outcomes. Qualitative MR imaging anomalies including global atrophy (P = .003) and FLAIR corticospinal tract hypersignal anomalies (P = .033), correlated positively with serum neurofilament light chains.

CONCLUSIONS: Serum neurofilament light chains may be an important mediator between clinical symptoms and neuronal loss according to cortical thickness. Furthermore, MR imaging anomalies might have underestimated prognostic value because they seem to indicate higher serum neurofilament light chain levels.}, } @article {pmid38548323, year = {2024}, author = {Goldacre, R and Trubshaw, M and Morris, EJA and Talbot, K and Goldacre, MJ and Thompson, AG and Turner, MR}, title = {Venous thromboembolism risk in amyotrophic lateral sclerosis: a hospital record-linkage study.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {10}, pages = {912-918}, pmid = {38548323}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications ; *Venous Thromboembolism/epidemiology/prevention & control ; Male ; Female ; Aged ; Middle Aged ; Retrospective Studies ; Incidence ; England/epidemiology ; Risk Factors ; Adult ; Aged, 80 and over ; Medical Record Linkage ; Case-Control Studies ; Pulmonary Embolism/epidemiology ; }, abstract = {BACKGROUND: Venous thromboembolism (VTE) can occur in amyotrophic lateral sclerosis (ALS) and pulmonary embolism causes death in a minority of cases. The benefits of preventing VTE must be weighed against the risks. An accurate estimate of the incidence of VTE in ALS is crucial to assessing this balance.

METHODS: This retrospective record-linkage cohort study derived data from the Hospital Episode Statistics database, covering admissions to England's hospitals from 1 April 2003 to 31 December 2019 and included 21 163 patients with ALS and 17 425 337 controls. Follow-up began at index admission and ended at VTE admission, death or 2 years (whichever came sooner). Adjusted HRs (aHRs) for VTE were calculated, controlling for confounders.

RESULTS: The incidence of VTE in the ALS cohort was 18.8/1000 person-years. The relative risk of VTE in ALS was significantly greater than in controls (aHR 2.7, 95% CI 2.4 to 3.0). The relative risk of VTE in patients with ALS under 65 years was five times higher than controls (aHR 5.34, 95% CI 4.6 to 6.2), and higher than that of patients over 65 years compared with controls (aHR 1.86, 95% CI 1.62 to 2.12).

CONCLUSIONS: Patients with ALS are at a higher risk of developing VTE, but this is similar in magnitude to that reported in other chronic neurological conditions associated with immobility, such as multiple sclerosis, which do not routinely receive VTE prophylaxis. Those with ALS below the median age of symptom onset have a notably higher relative risk. A reappraisal of the case for routine antithrombotic therapy in those diagnosed with ALS now requires a randomised controlled trial.}, } @article {pmid38548902, year = {2024}, author = {Cicardi, ME and Kankate, V and Sriramoji, S and Krishnamurthy, K and Markandaiah, SS and Verdone, BM and Girdhar, A and Nelson, A and Rivas, LB and Boehringer, A and Haeusler, AR and Pasinelli, P and Guo, L and Trotti, D}, title = {The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD.}, journal = {Communications biology}, volume = {7}, number = {1}, pages = {376}, pmid = {38548902}, issn = {2399-3642}, support = {RF1 NS114128/NS/NINDS NIH HHS/United States ; R21 NS090912/NS/NINDS NIH HHS/United States ; R01 NS109150/NS/NINDS NIH HHS/United States ; R01 NS114128/NS/NINDS NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Active Transport, Cell Nucleus ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics/metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; }, abstract = {Expanded intronic G4C2 repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These intronic repeats are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and neurotoxic. Here, we report that Kapβ2 and GR interact, co-aggregating, in cultured neurons in-vitro and CNS tissue in-vivo. Importantly, this interaction significantly decreased the risk of death of cultured GR-expressing neurons. Downregulation of Kapβ2 is detrimental to their survival, whereas increased Kapβ2 levels mitigated GR-mediated neurotoxicity. As expected, GR-expressing neurons displayed TDP-43 nuclear loss. Raising Kapβ2 levels did not restore TDP-43 into the nucleus, nor did alter the dynamic properties of GR aggregates. Overall, our findings support the design of therapeutic strategies aimed at up-regulating Kapβ2 expression levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.}, } @article {pmid38549627, year = {2024}, author = {Turner, M and Belli, A and Castellani, RJ}, title = {Changes in Brain Structure and Function in a Multisport Cohort of Retired Female and Male Athletes, Many Years after Suffering a Concussion: Implications for Neuroplasticity and Neurodegenerative Disease Pathogenesis.}, journal = {Journal of Alzheimer's disease reports}, volume = {8}, number = {1}, pages = {501-516}, pmid = {38549627}, issn = {2542-4823}, support = {P30 AG072977/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Cumulative effects of traumatic brain injury is of increasing concern, especially with respect to its role in the etiology and pathogenesis of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

OBJECTIVE: Compare regional brain volume and connectivity between athletes with a history of concussion and controls.

METHODS: We evaluated whole-brain volumetric effects with Bayesian regression models and functional connectivity with network-based statistics, in 125 retired athletes (a mean of 11 reported concussions) and 36 matched controls.

RESULTS: Brain regions significantly lower in volume in the concussed group included the middle frontal gyrus, hippocampus, supramarginal gyrus, temporal pole, and inferior frontal gyrus. Conversely, brain regions significantly larger included the hippocampal and collateral sulcus, middle occipital gyrus, medial orbital gyrus, caudate nucleus, lateral orbital gyrus, and medial postcentral gyrus. Functional connectivity analyses revealed increased edge strength, most marked in motor domains. Numerous edges of this network strengthened in athletes were significantly weakened with concussion. Aligned to meta-analytic neuroimaging data, the observed changes suggest functional enhancement within the motor, sensory, coordination, balance, and visual processing domains in athletes, attenuated by concussive head injury with a negative impact on memory and language.

CONCLUSIONS: These findings suggest that engagement in sport may benefit the brain across numerous domains, but also highlights the potentially damaging effects of concussive head injury. Future studies with longitudinal cohorts including autopsy examination are needed to determine whether the latter reflects tissue loss from brain shearing, or the onset of a progressive Alzheimer's disease like proteinopathy.}, } @article {pmid38550565, year = {2024}, author = {Di Nardo, AA and Prochiantz, A}, title = {Therapeutic value of homeoprotein signaling pathways.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1359523}, pmid = {38550565}, issn = {1662-4548}, abstract = {Cell signaling based on homeoprotein transfer is a pathway with developmental and physiological functions. For a few transcription factors of this family, primarily ENGRAILED1, ENGRAILED2 and OTX2, their physiological functions have led to therapeutic strategies in animal models of human diseases, including Parkinson's disease, amyotrophic lateral sclerosis, amblyopia and anxiety-related disorders. In mesencephalic dopaminergic neurons which degenerate in Parkinson's disease, ENGRAILED1/2 have cell autonomous activities, but their transducing properties enables their use as therapeutic proteins. In contrast, in spinal alpha-motoneurons, which are lost in amyotrophic lateral sclerosis, ENGRAILED1 is supplied by V1 interneurons. Thus, its use as a therapeutic protein to protect alpha-motoneurons against degeneration mimics its normal non-cell autonomous neurotrophic activity. OTX2, synthesized and secreted by the choroid plexus, is transferred to parvalbumin interneurons and exerts regulatory functions controlling cerebral cortex plasticity. Understanding the latter OTX2 function has led to strategies for manipulating visual acuity and anxiety-like behavior in adult mice. In this review, we describe these cases and what is known about the involved molecular mechanisms. Because the transduction sequences are conserved in most of the few hundred homeoproteins, we argue how this family of molecules constitutes an important reservoir of physiological knowledge, with potential consequences in the search for new therapeutic strategies.}, } @article {pmid38551974, year = {2024}, author = {Jiménez-García, AM and Bonnel, G and Álvarez-Mota, A and Arias, N}, title = {Current perspectives on neuromodulation in ALS patients: A systematic review and meta-analysis.}, journal = {PloS one}, volume = {19}, number = {3}, pages = {e0300671}, pmid = {38551974}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Quality of Life ; *Neurodegenerative Diseases ; Exercise Therapy/methods ; Muscle Spasticity ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, resulting in muscle weakness, paralysis, and eventually patient mortality. In recent years, neuromodulation techniques have emerged as promising potential therapeutic approaches to slow disease progression and improve the quality of life of ALS patients. A systematic review was conducted until August 8, 2023, to evaluate the neuromodulation methods used and their potential in the treatment of ALS. The search strategy was applied in the Cochrane Central database, incorporating results from other databases such as PubMed, Embase, CTgov, CINAHL, and ICTRP. Following the exclusion of papers that did not fulfil the inclusion criteria, a total of 2090 records were found, leaving a total of 10 studies. R software was used to conduct meta-analyses based on the effect sizes between the experimental and control groups. This revealed differences in muscle stretch measures with manual muscle testing (p = 0.012) and resting motor threshold (p = 0.0457), but not with voluntary isometric contraction (p = 0.1883). The functionality of ALS was also different (p = 0.007), but not the quality of life. Although intracortical facilitation was not seen in motor cortex 1 (M1) (p = 0.1338), short-interval intracortical inhibition of M1 was significant (p = 0.0001). BDNF showed no differences that were statistically significant (p = 0.2297). Neuromodulation-based treatments are proposed as a promising therapeutic approach for ALS that can produce effects on muscle function, spasticity, and intracortical connections through electrical, magnetic, and photonic stimulation. Photobiomodulation stands out as an innovative approach that uses specific wavelengths to influence mitochondria, with the aim of improving mitochondrial function and reducing excitotoxicity. The lack of reliable placebo controls and the variation in stimulation frequency are some of the drawbacks of neuromodulation.}, } @article {pmid38552376, year = {2024}, author = {Donayeva, A and Abdelazim, IA and Amanzholkyzy, A}, title = {Regarding cornual pregnancy as a rare entity of ectopic pregnancy: A case report.}, journal = {International journal of surgery case reports}, volume = {118}, number = {}, pages = {109574}, pmid = {38552376}, issn = {2210-2612}, abstract = {The published Toumi et al's article is somewhat confusing to the readers. The cornual pregnancy (CP) defined as a pregnancy that occurs in a rudimentary horn of a uterus with a Müllerian anomaly according to William's textbook. The interstitial ectopic pregnancy (IEP) occurs in the interstitial part of the fallopian tube where it crosses the uterine muscular to enter the uterine cavity. The IEP sonographic findings include an empty uterus with an eccentrically placed gestational sac, located ≥1 cm from the endometrial margin and bordered by ≤ 5 mm myometrial rim.}, } @article {pmid38552475, year = {2024}, author = {Offroy, M and Marchetti, M and Kauffmann, TH and Bourson, P and Duponchel, L and Savarese, L and Mechling, JM}, title = {Using clustering as pre-processing in the framework of signal unmixing for exhaustive exploration of archaeological artefacts in Raman imaging.}, journal = {Talanta}, volume = {274}, number = {}, pages = {125955}, doi = {10.1016/j.talanta.2024.125955}, pmid = {38552475}, issn = {1873-3573}, abstract = {Analytical chemistry on archaeological material is an essential part of modern archaeological investigations and from year to year, instrumental improvement has made it possible to generate data at a high spatial and temporal frequency. In particular, Raman spectral imaging can be successfully applied in archaeological research by its simplicity of implementation to study past human societies through the analysis of their material remains. This technique makes it possible to simultaneously obtain spatial and spectral information by preserving sample integrity. However, because of the inherent complexity of the samples in Archaeology (e.g. seniority, fragility, lack or full absence of any information about its composition), chemical interpretation can be difficult at first glance. Indeed, specific problems of spectral selectivity related to unexpected chemical compounds could appear due to their state of conservation. Furthermore, detecting minor compounds becomes challenging as major components impose their contributions in the acquired spectra. Therefore, a relevant chemometric approach has been introduced in this context to characterize distinct spectral sources in a Raman imaging dataset of an archaeological specimen - a mosaic fragment. The fragment was unearthed during the Ruscino archaeological dig on the outskirts of Perpignan, France. It dates back to the oppidum period. The aim is to extract selective spectral information from pixel clustering analysis in order to enhance the initial optimisation step within the Multivariate Curve Resolution and Alternating Least-Squares (MCR-ALS) algorithm, a well-known signal unmixing technique. The underlying principle of the MCR-ALS is that the acquired spectra can be expressed as linear combinations of pure spectra of all individual components present in the chemical system under study. Sometimes it can be difficult to obtain the desired results through the algorithm, particularly if initial estimates of spectral or concentration profiles are inaccurate due to complex signals, noise or lack of selectivity, resulting in rank deficiency (i.e. a poor estimation of the total number of pure signals). For this reason, an innovative threshold-based clustering algorithm, combined with multiple Orthogonal Projection Approaches (OPA), has been developed to improve matrix rank investigation and thus the initialisation step of the MCR-ALS approach before optimisation. The effective analysis of Raman imaging data for an archaeological mosaic played a crucial role in uncovering significant chemical information about a particular biogenic material. This insight sheds light on the origins of mortar manufacture during the oppidum period.}, } @article {pmid38552851, year = {2024}, author = {Yang, L and Guttman, L and Dawson, VL and Dawson, TM}, title = {Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke.}, journal = {Biochemical pharmacology}, volume = {228}, number = {}, pages = {116174}, pmid = {38552851}, issn = {1873-2968}, support = {R01 AG085688/AG/NIA NIH HHS/United States ; R01 NS067525/NS/NINDS NIH HHS/United States ; R37 NS067525/NS/NINDS NIH HHS/United States ; T32 GM135083/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Stroke/drug therapy/metabolism/therapy ; *Parthanatos/drug effects/physiology ; Neuroprotective Agents/therapeutic use ; }, abstract = {Parthanatos is a cell death signaling pathway that has emerged as a compelling target for pharmaceutical intervention. It plays a pivotal role in the neuron loss and neuroinflammation that occurs in Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and stroke. There are currently no treatments available to humans to prevent cell death in any of these diseases. This review provides an in-depth examination of the current understanding of the Parthanatos mechanism, with a particular focus on its implications in neuroinflammation and various diseases discussed herein. Furthermore, we thoroughly review potential intervention targets within the Parthanatos pathway. We dissect recent progress in inhibitory strategies, complimented by a detailed structural analysis of key Parthanatos executioners, PARP-1, AIF, and MIF, along with an assessment of their established inhibitors. We hope to introduce a new perspective on the feasibility of targeting components within the Parthanatos pathway, emphasizing its potential to bring about transformative outcomes in therapeutic interventions. By delineating therapeutic opportunities and known targets, we seek to emphasize the imperative of blocking Parthanatos as a precursor to developing disease-modifying treatments. This comprehensive exploration aims to catalyze a paradigm shift in our understanding of potential neurodegenerative disease therapeutics, advocating for the pursuit of effective interventions centered around Parthanatos inhibition.}, } @article {pmid38553272, year = {2024}, author = {Desmaison, A and Truffert, A and Pereira, B and Camdessanché, JP and Moisset, X and Guy, N}, title = {Upper motor neuron assessment in amyotrophic lateral sclerosis using the patellar tendon reflex and motor-evoked potentials to the lower limbs.}, journal = {Revue neurologique}, volume = {180}, number = {7}, pages = {632-641}, doi = {10.1016/j.neurol.2024.01.006}, pmid = {38553272}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/pathology ; Male ; Middle Aged ; Female ; Aged ; *Evoked Potentials, Motor/physiology ; *Motor Neurons/physiology ; Adult ; *Lower Extremity/physiopathology ; Electromyography/methods ; Reflex, Stretch/physiology ; Aged, 80 and over ; Sensitivity and Specificity ; Reflex/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) diagnosis relies on signs of progressive damage to both lower motoneuron (LMN), given by clinical examination and electromyography (EMG), and upper motoneuron (UMN), given by clinical examination only. Recognition of UMN involvement, however, is still difficult, so that diagnostic delay often remains too long. Shortening the time to clinical and genetic diagnosis is essential in order to provide accurate information to patients and families, avoid time-consuming investigations and for appropriate care management. This study investigates whether combined patellar tendon reflex recording with motor-evoked potentials to the lower limbs (T-MEP-LL) is relevant to assess corticospinal function in ALS, so that it might serve as a tool improving diagnosis. T-MEP-LL were recorded in 135 patients with suspected motor neuron disease (MND) from February 2010 to March 2021. The sensitivity, specificity, and ability to improve diagnosis when added to Awaji and Gold Coast criteria were determined. The main finding of the study is that T-MEP-LL can detect UMN dysfunction with a 70% sensitivity and 63% specificity when UMN clinical signs are lacking. The sensitivity reaches 82% when considering all MND patients. Moreover, at first evaluation, using T-MEP-LL to quantify reflex briskness and to measure central conduction time, can improve the diagnostic accuracy. T-MEP-LL is easy to perform and does not need any electrical stimulation, making the test rapid, and painless. By the simultaneous quantification of both UMN and LMN system, it could also help to identify different phenotype with more accuracy than clinical examination in this broad-spectrum pathology. The question whether T-MEP-LL could further be a real biomarker need further prospective studies.}, } @article {pmid38554151, year = {2024}, author = {Campos-Díaz, A and Morejón-García, P and Monte-Serrano, E and Ros-Pardo, D and Marcos-Alcalde, I and Gómez-Puertas, P and Lazo, PA}, title = {Pathogenic effects of Leu200Pro and Arg387His VRK1 protein variants on phosphorylation targets and H4K16 acetylation in distal hereditary motor neuropathy.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {102}, number = {6}, pages = {801-817}, pmid = {38554151}, issn = {1432-1440}, support = {PID2019-105610RB-I00//Agencia Estatal de Investigación/ ; PID2022-139598OB-I00//Agencia Estatal de Investigación/ ; RED2018-102801-T//Agencia Estatal de Investigación/ ; RTC-2017-6494-1//Agencia Estatal de Investigación/ ; RTI2018-094434-B-I00//Agencia Estatal de Investigación/ ; CSI264P20//Consejería de Educación, Junta de Castilla y León/ ; CLC-2017-01//Consejería de Educación, Junta de Castilla y León/ ; CSI004-18//Consejería de Educación, Junta de Castilla y León/ ; FPU20/02978//Ministerio de Universidades/ ; FPU16/01883//Ministerio de Universidades/ ; }, mesh = {Humans ; Acetylation ; *Histones/metabolism ; Phosphorylation ; *Protein Serine-Threonine Kinases/metabolism/genetics ; *Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Male ; Female ; DNA-Binding Proteins/genetics/metabolism ; Middle Aged ; Motor Neuron Disease/genetics/metabolism ; Nuclear Proteins/genetics/metabolism ; }, abstract = {Rare recessive variants in the human VRK1 gene are associated with several motor neuron diseases (MND), such as amyotrophic lateral sclerosis, spinal muscular atrophy, or distal hereditary motor neuropathies (dHMN). A case with dHMN carrying two novel VRK1 gene variants, expressing Leu200Pro (L200P) and Arg387His (R387H) variant proteins, identified that these protein variants are functionally different. The Leu200Pro variant shares with several variants in the catalytic domain the loss of the kinase activity on different substrates, such as histones, p53, or coilin. However, the distal Arg387His variant and the distal Trp375* (W375X) chinese variant, both located at the end of the low complexity C-terminal region and proximal to the termination codon, retain their catalytic activity on some substrates, and mechanistically their functional impairment is different. The L200P variant, as well as most VRK1 pathogenic variants, impairs the phosphorylation of BAF and histone H4K16 acetylation, which are required for DNA attachment to the nuclear envelope and chromatin accessibility to DNA repair mechanisms, respectively. The R387H variant impairs phosphorylation of H2AX, an early step in different types of DNA damage responses. The functional variability of VRK1 protein variants and their different combinations are a likely contributor to the clinical phenotypic heterogeneity of motor neuron and neurological diseases associated with rare VRK1 pathogenic variants. KEY MESSAGES: VRK1 variants implicated in motor neuron diseases are functionally different. The L200P variant is kinase inactive, and the R387H variant is partially active. VRK1 variants alter H4K16 acetylation and loss of coilin and BAF phosphorylation. VRK1 variants alter Cajal bodies and DNA damage responses. VRK1 variant combination determines the neurological phenotype heterogeneity.}, } @article {pmid38554281, year = {2024}, author = {Dermentzaki, G and Furlan, M and Tanaka, I and Leonardi, T and Rinchetti, P and Passos, PMS and Bastos, A and Ayala, YM and Hanna, JH and Przedborski, S and Bonanomi, D and Pelizzola, M and Lotti, F}, title = {Depletion of Mettl3 in cholinergic neurons causes adult-onset neuromuscular degeneration.}, journal = {Cell reports}, volume = {43}, number = {4}, pages = {113999}, pmid = {38554281}, issn = {2211-1247}, support = {R01 AG084965/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Adenosine/metabolism/analogs & derivatives ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Cholinergic Neurons/metabolism/pathology ; DNA-Binding Proteins/metabolism/genetics ; *Methyltransferases/metabolism/genetics ; Motor Neurons/metabolism/pathology ; *Neuromuscular Diseases/metabolism/pathology ; }, abstract = {Motor neuron (MN) demise is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Post-transcriptional gene regulation can control RNA's fate, and defects in RNA processing are critical determinants of MN degeneration. N[6]-methyladenosine (m[6]A) is a post-transcriptional RNA modification that controls diverse aspects of RNA metabolism. To assess the m[6]A requirement in MNs, we depleted the m[6]A methyltransferase-like 3 (METTL3) in cells and mice. METTL3 depletion in embryonic stem cell-derived MNs has profound and selective effects on survival and neurite outgrowth. Mice with cholinergic neuron-specific METTL3 depletion display a progressive decline in motor behavior, accompanied by MN loss and muscle denervation, culminating in paralysis and death. Reader proteins convey m[6]A effects, and their silencing phenocopies METTL3 depletion. Among the m[6]A targets, we identified transactive response DNA-binding protein 43 (TDP-43) and discovered that its expression is under epitranscriptomic control. Thus, impaired m[6]A signaling disrupts MN homeostasis and triggers neurodegeneration conceivably through TDP-43 deregulation.}, } @article {pmid38555304, year = {2024}, author = {Cheng, CJ and Su, JJ}, title = {Detecting muscle-specific kinase myasthenia gravis in atypical presentations.}, journal = {Acta neurologica Belgica}, volume = {124}, number = {5}, pages = {1733-1735}, pmid = {38555304}, issn = {2240-2993}, } @article {pmid38556190, year = {2024}, author = {Fu, X and Zhang, Z and Hayes, LR and Wright, N and Asbury, J and Li, S and Ye, Y and Sun, S}, title = {DDX3X overexpression decreases dipeptide repeat proteins in a mouse model of C9ORF72-ALS/FTD.}, journal = {Experimental neurology}, volume = {376}, number = {}, pages = {114768}, pmid = {38556190}, issn = {1090-2430}, support = {R21 AG072078/AG/NIA NIH HHS/United States ; R01 NS123538/NS/NINDS NIH HHS/United States ; R01 NS107347/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *DEAD-box RNA Helicases/genetics/metabolism ; Dipeptides/metabolism ; *Disease Models, Animal ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Mice, Transgenic ; }, abstract = {Hexanucleotide repeat expansion in C9ORF72 (C9) is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One of the proposed pathogenic mechanisms is the neurotoxicity arising from dipeptide repeat (DPR) proteins produced by repeat-associated non-AUG (RAN) translation. Therefore, reducing DPR levels emerges as a potential therapeutic strategy for C9ORF72-ALS/FTD. We previously identified an RNA helicase, DEAD-box helicase 3 X-linked (DDX3X), modulates RAN translation. DDX3X overexpression decreases poly-GP accumulation in C9ORF72-ALS/FTD patient-derived induced pluripotent stem cell (iPSC)-differentiated neurons (iPSNs) and reduces the glutamate-induced neurotoxicity. In this study, we examined the in vivo efficacy of DDX3X overexpression using a mouse model. We expressed exogenous DDX3X or GFP in the central nervous system (CNS) of the C9-500 ALS/FTD BAC transgenic or non-transgenic control mice using adeno-associated virus serotype 9 (AAV9). The DPR levels were significantly reduced in the brains of DDX3X-expressing C9-BAC mice compared to the GFP control even twelve months after virus delivery. Additionally, p62 aggregation was also decreased. No neuronal loss or neuroinflammatory response were detected in the DDX3X overexpressing C9-BAC mice. This work demonstrates that DDX3X overexpression effectively reduces DPR levels in vivo without provoking neuroinflammation or neurotoxicity, suggesting the potential of increasing DDX3X expression as a therapeutic strategy for C9ORF72-ALS/FTD.}, } @article {pmid38557366, year = {2024}, author = {Sopranzi, FM and Faragalli, A and Pompili, M and Carle, F and Gesuita, R and Ceravolo, MG}, title = {Incidence of amyotrophic lateral sclerosis before and during the COVID-19 pandemic: evidence from an 8-year population-based study in Central Italy based on healthcare utilization databases.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {554-562}, doi = {10.1080/21678421.2024.2336127}, pmid = {38557366}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Italy/epidemiology ; Male ; Female ; Aged ; *COVID-19/epidemiology ; Incidence ; Middle Aged ; Longitudinal Studies ; Databases, Factual ; Aged, 80 and over ; Patient Acceptance of Health Care/statistics & numerical data ; Adult ; SARS-CoV-2 ; Hospitalization/statistics & numerical data ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder with a high multidimensional burden, with an obscure etiopathogenesis.

METHODS: We designed a longitudinal, population-based study of people residing in Central Italy (Marche Region) who were beneficiaries of the National Health System. People with an unprecedented ALS hospitalization (335.20 ICD-9 CM) or tagged with an ALS exemption between 2014 and 2021 were considered incident cases. ALS cases residing in the region for <3 years or with an active ALS exemption or hospitalized for ALS before 2014 were excluded. We used secondary sources to identify new ALS diagnoses. The regional referral center for ALS's database was used to test the accuracy of secondary sources in detecting cases. ALS mean incidence was compared to that reported in similar studies conducted in Italy. The incidence rate trend adjusted by sex and age was evaluated using the Poisson regression model.

RESULTS: We detected 425 new ALS cases (median age: 70y) in the 2014-2021 period, with a mean incidence of 3.5:100,000 py (95%CI: 3.2-3.8; M:F = 1.2), similar to that reported in similar studies conducted in Italy. No trend was observed during 2014-2019. After including 2020-2021 in the model, we observed a mean decrease in incidence of 5.8% (95% CI 2.0%; 9.5%, p = 0.003).

CONCLUSION: We show a decrease in the incidence rate of ALS in Marche, during the 2014-2021 period, as a possible outcome of a delayed neurological assessment and diagnosis during the pandemic. An ad hoc developed identification algorithm, based on healthcare utilization databases, is a valuable tool to assess the health impact of global contingencies.}, } @article {pmid38557405, year = {2024}, author = {Goutman, SA and Boss, J and Jang, DG and Piecuch, C and Farid, H and Batra, M and Mukherjee, B and Feldman, EL and Batterman, SA}, title = {Residential exposure associations with ALS risk, survival, and phenotype: a Michigan-based case-control study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {543-553}, pmid = {38557405}, issn = {2167-9223}, support = {K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Female ; Male ; Michigan/epidemiology ; Case-Control Studies ; *Environmental Exposure/adverse effects/statistics & numerical data ; Middle Aged ; Aged ; Risk Factors ; *Phenotype ; Adult ; }, abstract = {BACKGROUND: Environmental exposures impact amyotrophic lateral sclerosis (ALS) risk and progression, a fatal and progressive neurodegenerative disease. Better characterization of these exposures is needed to decrease disease burden.

OBJECTIVE: To identify exposures in the residential setting that associate with ALS risk, survival, and onset segment.

METHODS: ALS and control participants recruited from University of Michigan completed a survey that ascertained exposure risks in the residential setting. ALS risk was assessed using logistic regression models followed by latent profile analysis to consider exposure profiles. A case-only analysis considered the contribution of the residential exposure variables via a Cox proportional hazards model for survival outcomes and multinomial logistic regression for onset segment, a polytomous outcome.

RESULTS: This study included 367 ALS and 255 control participants. Twelve residential variables were associated with ALS risk after correcting for multiple comparison testing, with storage in an attached garage of chemical products including gasoline or kerosene (odds ratio (OR) = 1.14, padjusted < 0.001), gasoline-powered equipment (OR = 1.16, padjusted < 0.001), and lawn care products (OR = 1.15, padjusted < 0.001) representing the top three risk factors sorted by padjusted. Latent profile analysis indicated that storage of these chemical products in both attached and detached garages increased ALS risk. Although residential variables were not associated with poorer ALS survival following multiple testing corrections, storing pesticides, lawn care products, and woodworking supplies in the home were associated with shorter ALS survival using nominal p values. No exposures were associated with ALS onset segment.

CONCLUSION: Residential exposures may be important modifiable components of the ALS susceptibility and prognosis exposome.}, } @article {pmid38558150, year = {2024}, author = {Pensato, U and Cortelli, P}, title = {Soccer (football) and brain health.}, journal = {Journal of neurology}, volume = {271}, number = {6}, pages = {3019-3029}, pmid = {38558150}, issn = {1432-1459}, mesh = {Humans ; *Soccer/injuries ; *Brain Concussion/complications/epidemiology/etiology ; Athletic Injuries/complications ; Brain/physiopathology ; Chronic Traumatic Encephalopathy/etiology ; }, abstract = {Soccer is one of the most popular sports worldwide, played by over 270 million people and followed by many more. Several brain health benefits are promoted by practising soccer and physical exercise at large, which helps contrast the cognitive decline associated with ageing by enhancing neurogenesis processes. However, sport-related concussions have been increasingly recognised as a pressing public health concern, not only due to their acute impact but also, more importantly, due to mounting evidence indicating an elevated risk for the development of neurological sequelae following recurrent head traumas, especially chronic traumatic encephalopathy (CTE). While soccer players experience less frequent concussions compared with other contact or combat sports, such as American football or boxing, it stands alone in its purposeful use of the head to hit the ball (headings), setting its players apart as the only athletes exposed to intentional, sub-concussive head impacts. Additionally, an association between soccer and amyotrophic lateral sclerosis has been consistently observed, suggesting a potential "soccer-specific" risk factor. In this review, we discuss the neurological sequelae related to soccer playing, the emerging evidence of a detrimental effect related to recurrent headings, and the need for implementation of comprehensive strategies aimed at preventing and managing the burden of head impact in soccer.}, } @article {pmid38558260, year = {2024}, author = {Fonteh, CN and Patnaik, JL and Grove, NC and Lynch, AM and Pantcheva, MB and Christopher, KL}, title = {Refractive outcomes using Barrett formulas and patient characteristics of cataract surgery patients with and without prior LASIK/PRK.}, journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie}, volume = {262}, number = {9}, pages = {2937-2944}, pmid = {38558260}, issn = {1435-702X}, mesh = {Humans ; Retrospective Studies ; Female ; Male ; *Photorefractive Keratectomy/methods ; *Visual Acuity/physiology ; *Refraction, Ocular/physiology ; *Keratomileusis, Laser In Situ/methods ; Aged ; *Lasers, Excimer/therapeutic use ; Middle Aged ; Cataract Extraction/methods ; Follow-Up Studies ; Refractive Errors/physiopathology/diagnosis ; Treatment Outcome ; Myopia/surgery/physiopathology ; Axial Length, Eye/pathology ; }, abstract = {PURPOSE: The goal of this study is to describe characteristics of cataract surgery patients who previously underwent laser in situ keratomileusis/photorefractive keratectomy (LASIK/PRK) in comparison to non-LASIK/PRK cataract surgery patients including psychiatric comorbidities, as well as describe refractive prediction error after cataract surgery while accounting for axial length (AL) using the Barrett True-K and Barrett Universal II formulas.

METHODS: This was a retrospective study of patients from the University of Colorado Cataract Outcomes Registry. The primary outcomes were refraction prediction error (RPE), mean absolute RPE, and median absolute RPE. Outcomes were stratified by five axial length groups. Univariate and multivariate models for RPE were stratified by the AL group.

RESULTS: Two hundred eighty-one eyes with prior LASIK/PRK and 3101 eyes without are included in the study. Patients with prior LASIK/PRK were significantly younger: 67.0 vs 69.9 years, p < 0.0001. The LASIK/PRK group had significantly better mean pre-operative BCVA in comparison to the non-LASIK group, logMAR 0.204 vs logMAR 0.288, p = 0.003. The LASIK/PRK group had significantly lower rates of cardiovascular disease (18.5% vs 29.3%, p < 0.001), hypertension (49.1% vs 59.3%, p < 0.012), and type 2 diabetes (10.7% vs 26.0%, p < 0.001), and no significant difference in psychiatric disease. The absolute RPE was higher for the LASIK group for all ALs, but only significantly higher for eyes with AL less than 25 mm.

CONCLUSION: Patient eyes with prior LASIK/PRK surgery undergoing cataract surgery were significantly younger, had significantly less comorbidities, and a significantly better pre-operative BCVA. Using the Barrett formulas, absolute prediction error for eyes with longer ALs was not significantly worse for LASIK/PRK eyes than those without and the difference was smaller for eyes with longer AL.}, } @article {pmid38559165, year = {2024}, author = {Sirtori, R and Gregoire, M and Potts, E and Collins, A and Donatelli, L and Fallini, C}, title = {LINC complex alterations are a hallmark of sporadic and familial ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.03.08.584123}, pmid = {38559165}, issn = {2692-8205}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects motor neurons, leading to progressive muscle weakness and loss of voluntary muscle control. While the exact cause of ALS is not fully understood, emerging research suggests that dysfunction of the nuclear envelope (NE) may contribute to disease pathogenesis and progression. The NE plays a role in ALS through several mechanisms, including nuclear pore defects, nucleocytoplasmic transport impairment, accumulation of mislocalized proteins, and nuclear morphology abnormalities. The LINC complex is the second biggest multi-protein complex in the NE and consists of the SUN1/2 proteins spanning the inner nuclear membrane and Nesprin proteins embedded in the outer membrane. The LINC complex, by interacting with both the nuclear lamina and the cytoskeleton, transmits mechanical forces to the nucleus regulating its morphology and functional homeostasis. In this study we show extensive alterations to the LINC complex in motor and cortical iPSC-derived neurons and spinal cord organoids carrying the ALS causative mutation in the C9ORF72 gene (C9). Importantly, we show that such alterations are present in vivo in a cohort of sporadic ALS and C9-ALS postmortem spinal cord and motor cortex biopsies. We also found that LINC complex disruption strongly correlated with nuclear morphological alterations occurring in ALS neurons, independently of TDP43 mislocalization. Altogether, our data establish morphological and functional alterations to the LINC complex as important events in ALS pathogenic cascade, making this pathway a possible target for both biomarker and therapy development.}, } @article {pmid38559706, year = {2024}, author = {Bhor, S and Tonny, SH and Dinesh, S and Sharma, S}, title = {Computational screening of damaging nsSNPs in human SOD1 genes associated with amyotrophic lateral sclerosis identifies destabilising effects of G38R and G42D mutations through in silico evaluation.}, journal = {In silico pharmacology}, volume = {12}, number = {1}, pages = {20}, pmid = {38559706}, issn = {2193-9616}, abstract = {Amyotrophic lateral sclerosis (ALS), a complicated neurodegenerative disorder affected by hereditary and environmental variables, is a condition. In this study, the genetic makeup of ALS is investigated, with a focus on the SOD1 gene's single-nucleotide polymorphisms (SNPs) and their ability to affect disease risk. Eleven high-risk missense variations that may impair the functionality of the SOD1 protein were discovered after a thorough examination of SNPs in the SOD1 gene. These mutations were chosen using a variety of prediction approaches, highlighting their importance in the aetiology of ALS. Notably, it was discovered that the stability of the SOD1 wild-type protein structure was compromised by the G38R and G42D SOD1 variants. Additionally, Edaravone, a possible ALS medication, showed a greater affinity for binding mutant SOD1 structures, pointing to potential personalised treatment possibilities. The high-risk SNPs discovered in this investigation seem to have functional effects, especially on the stability of proteins and their interactions with other molecules. This study clarifies the complex genetics of ALS and offers insights into how these genetic variations may affect the effectiveness of therapeutic interventions, particularly in the context of edaravone. In this study advances our knowledge of the genetic mechanisms causing ALS vulnerability and prospective therapeutic strategies. Future studies are necessary to confirm these results and close the gap between individualised clinical applications and improved ALS care.}, } @article {pmid38560897, year = {2024}, author = {Minatoguchi, S and Fujita, Y and Niizuma, K and Tominaga, T and Yamashita, T and Abe, K and Dezawa, M}, title = {Donor Muse Cell Treatment Without HLA-Matching Tests and Immunosuppressant Treatment.}, journal = {Stem cells translational medicine}, volume = {13}, number = {6}, pages = {532-545}, pmid = {38560897}, issn = {2157-6580}, support = {//New Energy and Industrial Technology Development Organization/ ; //Japan Agency for Medical Research and Development/ ; //Ministry of Education, Culture, Sports, Science and Technology/ ; //Japan Society for the Promotion of Science/ ; //SENSHIN Medical Research Foundation/ ; //Life Science Institute Inc/ ; }, mesh = {Humans ; *Mesenchymal Stem Cells/cytology/metabolism ; Mesenchymal Stem Cell Transplantation/methods ; Immunosuppressive Agents/pharmacology/therapeutic use ; HLA Antigens/metabolism ; Cell Differentiation ; Animals ; Histocompatibility Testing/methods ; }, abstract = {The strength of stem cell therapy is the regeneration of tissues by synergistic pleiotropic effects. Among many stem cell types, mesenchymal stem cells (MSCs) that are comprised of heterogenous population are widely used for clinical applications with the expectation of pleiotropic bystander effects. Muse cells are pluripotent-like/macrophage-like stem cells distributed in the bone marrow, peripheral blood, and organ connective tissues as cells positive for the pluripotent surface marker stage-specific-embryonic antigen -3. Muse cells comprise ~1% to several percent of MSCs. While Muse cells and MSCs share several characteristics, such as mesenchymal surface marker expression and their bystander effects, Muse cells exhibit unique characteristics not observed in MSCs. These unique characteristics of Muse cells include selective homing to damaged tissue after intravenous injection rather than being trapped in the lung like MSCs, replacement of a wide range of damaged/apoptotic cells by differentiation through phagocytosis, and long-lasting immunotolerance for donor cell use. In this review, we focus on the basic properties of Muse cells clarified through preclinical studies and clinical trials conducted by intravenous injection of donor-Muse cells without HLA-matching tests or immunosuppressant treatment. MSCs are considered to differentiate into osteogenic, chondrogenic, and adipogenic cells, whereas the range of their differentiation has long been debated. Muse cells may provide clues to the wide-ranging differentiation potential of MSCs that are observed with low frequency. Furthermore, the utilization of Muse cells may provide a novel strategy for clinical treatment.}, } @article {pmid38560980, year = {2024}, author = {Xiang, SR and Ma, Q and Dong, J and Ren, YF and Lin, JZ and Zheng, C and Xiao, P and You, FM}, title = {Contrasting Effects of Music Therapy and Aromatherapy on Perioperative Anxiety: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {278-291}, doi = {10.1159/000538425}, pmid = {38560980}, issn = {2504-2106}, mesh = {*Aromatherapy ; *Music Therapy ; Humans ; *Anxiety/therapy ; Heart Rate ; }, abstract = {INTRODUCTION: Music therapy and aromatherapy have been demonstrated effective for perioperative anxiety. However, the available studies have indicated discordant results about which adjunct treatment is better for perioperative anxiety. Therefore, we conducted this meta-analysis to explore the contrasting effects between them.

METHODS: Six electronic databases were searched for clinical trials evaluating the efficacy of music therapy compared with aromatherapy in alleviating perioperative anxiety. The primary outcome was the postintervention anxiety level. Secondary outcomes included differences in blood pressure and heart rate before and after the intervention as well as pain scores at intraoperative and postoperative time points. The study protocol was registered on PROSPERO (CRD42021249737).

RESULTS: Twelve studies (894 patients) were included. The anxiety level showed no statistically significant difference (SMD, 0.28; 95% CI: -0.12, 0.68; p = 0.17). The analysis of blood pressure and heart rate also did not identify statistically significant differences. Notably, the pain scores at the intraoperative time point suggested that aromatherapy was superior to music therapy (WMD, 0.29 cm; 95% CI: 0.05, 0.52; p = 0.02), while those at 4 h after surgery indicated the opposite results (WMD, -0.48 cm; 95% CI: -0.60, -0.36; p < 0.001).

CONCLUSION: Low-to-moderate quality evidence suggests that music therapy and aromatherapy have similar potential to relieve perioperative anxiety. The potential data indicate that the two therapies have different benefits in intervention duration and age distribution. More direct high-quality comparisons are encouraged in the future to verify this point.

UNLABELLED: EinleitungMusik- und Aromatherapie haben sich bei perioperativen Angstzuständen als wirksam erwiesen. Die verfügbaren Studien zeigten jedoch widersprüchliche Ergebnisse zur Frage, welche adjuvante Therapie bei perioperativen Angstzuständen besser ist. Daher führten wir die vorliegende Metaanalyse durch, um die unterschiedlichen Effekte der beiden Therapien zu untersuchen.MethodenSechs (6) elektronische Datenbanken wurden nach klinischen Studien zur Wirksamkeit von Musiktherapie im Vergleich zur Aromatherapie bei der Linderung perioperativer Angstzustände durchsucht. Primäres Zielkriterium war das Angstniveau nach der Intervention. Die sekundären Zielkriterien umfassten die Unterschiede bei Blutdruck und Herzfrequenz vor und nach der Intervention sowie die Schmerz-Scores zu intra- und postoperativen Zeitpunkten. Das Studienprotokoll wurde auf PROSPERO (CRD42021249737) registriert.ErgebnisseZwölf (12) Studien (894 Patienten) wurden eingeschlossen. Das Angstniveau zeigte keinen statistisch signifikanten Unterschied (SMD, 0,28; 95%-KI: −0,12, 0,68, p = 0,17) und auch die Analyse von Blutdruck und Herzfrequenz ergab keine statistisch signifikanten Unterschiede. Insbesondere die Schmerz-Scores zum intraoperativen Zeitpunkt sprachen dafür, dass die Aromatherapie gegenüber der Musiktherapie überlegen war (WMD, 0,29 cm; 95%-KI: 0,05, 0,52; p = 0,02), während die Werte 4 Stunden nach der Operation gegenteilige Ergebnisse zeigten (WMD, −0,48 cm; 95%-KI: −0,60, −0,36, p < 0,001).SchlussfolgerungEvidenzen von geringer bis mässiger Qualität deuten darauf hin, dass Musik- und Aromatherapie ein vergleichbares Potenzial bei der Linderung perioperativer Ängste besitzen. Die potenziellen Daten zeigen, dass die beiden Therapien unterschiedliche Vorteile hinsichtlich Interventionsdauer und Altersverteilung haben. Künftig sollten mehr direkte und qualitativ hochwertige Vergleiche durchgeführt werden, um diesen Aspekt zu überprüfen.}, } @article {pmid38561079, year = {2024}, author = {Liu, X and Yu, Y and Garcia, LA and Au, ML and Tran, M and Zhang, J and Lou, A and Liu, Y and Wu, H}, title = {A grape-supplemented diet prevented ultraviolet (UV) radiation-induced cataract by regulating Nrf2 and XIAP pathways.}, journal = {The Journal of nutritional biochemistry}, volume = {129}, number = {}, pages = {109636}, pmid = {38561079}, issn = {1873-4847}, support = {R21 EY033941/EY/NEI NIH HHS/United States ; R25 HL125447/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Mice ; Anthocyanins/pharmacology ; *Cataract/prevention & control/metabolism/etiology ; *Dietary Supplements ; Glutathione/metabolism ; Lens, Crystalline/metabolism/radiation effects/drug effects ; Mice, Inbred C57BL ; *NF-E2-Related Factor 2/metabolism ; Resveratrol/pharmacology ; Signal Transduction/drug effects ; *Ultraviolet Rays/adverse effects ; *Vitis/chemistry ; *X-Linked Inhibitor of Apoptosis Protein/metabolism ; }, abstract = {The purpose of this study is to investigate if grape consumption, in the form of grape powder (GP), could protect against ultraviolet (UV)-induced cataract. Mice were fed with the regular diet, sugar placebo diet, or a grape diet (regular diet supplemented with 5%, 10%, and 15% GP) for 3 months. The mice were then exposed to UV radiation to induce cataract. The results showed that the GP diet dose-dependently inhibited UV-induced cataract and preserved glutathione pools. Interestingly, UV-induced Nrf2 activation was abolished in the groups on the GP diet, suggesting GP consumption may improve redox homeostasis in the lens, making Nrf2 activation unnecessary. For molecular target prediction, a total of 471 proteins regulated by GP were identified using Agilent Literature Search (ALS) software. Among these targets, the X-linked inhibitor of apoptosis (XIAP) was correlated with all of the main active ingredients of GP, including resveratrol, catechin, quercetin, and anthocyanins. Our data confirmed that GP prevented UV-induced suppression of XIAP, indicating that XIAP might be one of the critical molecular targets of GP. In conclusion, this study demonstrated that GP protected the lens from UV-induced cataract development in mice. The protective effects of GP may be attributed to its ability to improve redox homeostasis and activate the XIAP-mediated antiapoptotic pathway.}, } @article {pmid38561605, year = {2024}, author = {Singh, K and Gupta, JK and Kumar, S and Soni, U}, title = {A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Bioactive Peptides.}, journal = {Current protein & peptide science}, volume = {25}, number = {7}, pages = {507-526}, pmid = {38561605}, issn = {1875-5550}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Peptides/therapeutic use/chemistry/pharmacology ; Animals ; Alzheimer Disease/drug therapy/metabolism/pathology ; Parkinson Disease/drug therapy/metabolism/pathology ; Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; Oxidative Stress/drug effects ; Huntington Disease/drug therapy/metabolism/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Cholinesterase Inhibitors/therapeutic use/pharmacology/chemistry ; }, abstract = {Neurodegenerative disorders, which include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a significant and growing global health challenge. Current therapies predominantly focus on symptom management rather than altering disease progression. In this review, we discuss the major therapeutic strategies in practice for these disorders, highlighting their limitations. For AD, the mainstay treatments are cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. For PD, dopamine replacement therapies, including levodopa, are commonly used. HD is managed primarily with symptomatic treatments, and reusable extends survival in ALS. However, none of these therapies halts or substantially slows the neurodegenerative process. In contrast, this review highlights emerging research into bioactive peptides as potential therapeutic agents. These naturally occurring or synthetically designed molecules can interact with specific cellular targets, potentially modulating disease processes. Preclinical studies suggest that bioactive peptides may mitigate oxidative stress, inflammation, and protein misfolding, which are common pathological features in neurodegenerative diseases. Clinical trials using bioactive peptides for neurodegeneration are limited but show promising initial results. For instance, hemiacetal, a γ-secretase inhibitor peptide, has shown potential in AD by reducing amyloid-beta production, though its development was discontinued due to side effects. Despite these advancements, many challenges remain, including identifying optimal peptides, confirming their mechanisms of action, and overcoming obstacles related to their delivery to the brain. Future research should prioritize the discovery and development of novel bioactive peptides and improve our understanding of their pharmacokinetics and pharmacodynamics. Ultimately, this approach may lead to more effective therapies for neurodegenerative disorders, moving beyond symptom management to potentially modify the course of these devastating diseases.}, } @article {pmid38562780, year = {2024}, author = {Krus, KL and Benitez, AM and Strickland, A and Milbrandt, J and Bloom, AJ and DiAntonio, A}, title = {Reduced STMN2 and pathogenic TDP-43, two hallmarks of ALS, synergize to accelerate motor decline in mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38562780}, issn = {2692-8205}, support = {R37 NS065053/NS/NINDS NIH HHS/United States ; R01 NS087632/NS/NINDS NIH HHS/United States ; RF1 AG013730/AG/NIA NIH HHS/United States ; R01 NS119812/NS/NINDS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; }, abstract = {Pathological TDP-43 loss from the nucleus and cytoplasmic aggregation occurs in almost all cases of ALS and half of frontotemporal dementia patients. Stathmin2 (Stmn2) is a key target of TDP-43 regulation and aberrantly spliced Stmn2 mRNA is found in patients with ALS, frontotemporal dementia, and Alzheimer's Disease. STMN2 participates in the axon injury response and its depletion in vivo partially replicates ALS-like symptoms including progressive motor deficits and distal NMJ denervation. The interaction between STMN2 loss and TDP-43 dysfunction has not been studied in mice because TDP-43 regulates human but not murine Stmn2 splicing. Therefore, we generated trans-heterozygous mice that lack one functional copy of Stmn2 and express one mutant TDP-43[Q331K] knock-in allele to investigate whether reduced STMN2 function exacerbates TDP-43-dependent pathology. Indeed, we observe synergy between these two alleles, resulting in an early onset, progressive motor deficit. Surprisingly, this behavioral defect is not accompanied by detectable neuropathology in the brain, spinal cord, peripheral nerves or at neuromuscular junctions (NMJs). However, the trans-heterozygous mice exhibit abnormal mitochondrial morphology in their distal axons and NMJs. As both STMN2 and TDP-43 affect mitochondrial dynamics, and neuronal mitochondrial dysfunction is a cardinal feature of many neurodegenerative diseases, this abnormality likely contributes to the observed motor deficit. These findings demonstrate that partial loss of STMN2 significantly exacerbates TDP-43-associated phenotypes, suggesting that STMN2 restoration could ameliorate TDP-43 related disease before the onset of degeneration.}, } @article {pmid38563035, year = {2024}, author = {Fu, Y and Huang, XQ and Qu, HB and Ge, YZ and Ru, XL}, title = {Tandem Mass Tag-Based Proteomic Analysis of Normal and Degenerated Human Intervertebral Discs.}, journal = {Journal of pain research}, volume = {17}, number = {}, pages = {1313-1326}, pmid = {38563035}, issn = {1178-7090}, abstract = {BACKGROUND: Intervertebral disc degeneration (IVDD) is the main cause of low back pain (LBP), but the specific regulatory factors, pathways and specific molecular mechanisms remain unclear.

METHODS: We identified and quantitatively analyzed Pfirrmann Grade II (n=3) and Pfirrmann Grade IV (n=3) pulposus samples via MRI. The differential abundance of proteins in the samples was determined and quantitatively analyzed by relative and absolute quantitative analysis of the isotope marker levels combined with the liquid chromatography-tandem mass spectrometry (LC‒MSMS/MS).

RESULTS: A total of 70 proteins (30 significantly increased proteins (> 1.2-fold change) and 40 significantly decreased proteins (< 0.8-fold change)) showed different levels among the groups. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology (GO) enrichment analyses and Western blot analysis showed that CYCS, RAC1, and PSMD14 may play important roles in IVDD and that Epstein‒Barr virus infection, viral myocarditis, colorectal cancer, nonalcoholic fatty liver disease (NAFLD) and amyotrophic lateral sclerosis (ALS) are the main pathways involved in IVDD.

CONCLUSION: CYCS, RAC1 and PSMD14 may play important roles in IVDD, and Epstein‒Barr virus infection, viral myocarditis, colorectal cancer, NAFLD and ALS may be the main pathways involved in IVDD.}, } @article {pmid38563056, year = {2024}, author = {Umar, TP and Jain, N and Papageorgakopoulou, M and Shaheen, RS and Alsamhori, JF and Muzzamil, M and Kostiks, A}, title = {Artificial intelligence for screening and diagnosis of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {425-436}, doi = {10.1080/21678421.2024.2334836}, pmid = {38563056}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Humans ; *Artificial Intelligence ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurological disease that leads to progressive motor function degeneration. Diagnosing ALS is challenging due to the absence of a specific detection test. The use of artificial intelligence (AI) can assist in the investigation and treatment of ALS.

METHODS: We searched seven databases for literature on the application of AI in the early diagnosis and screening of ALS in humans. The findings were summarized using random-effects summary receiver operating characteristic curve. The risk of bias (RoB) analysis was carried out using QUADAS-2 or QUADAS-C tools.

RESULTS: In the 34 analyzed studies, a meta-prevalence of 47% for ALS was noted. For ALS detection, the pooled sensitivity of AI models was 94.3% (95% CI - 63.2% to 99.4%) with a pooled specificity of 98.9% (95% CI - 92.4% to 99.9%). For ALS classification, the pooled sensitivity of AI models was 90.9% (95% CI - 86.5% to 93.9%) with a pooled specificity of 92.3% (95% CI - 84.8% to 96.3%). Based on type of input for classification, the pooled sensitivity of AI models for gait, electromyography, and magnetic resonance signals was 91.2%, 92.6%, and 82.2%, respectively. The pooled specificity for gait, electromyography, and magnetic resonance signals was 94.1%, 96.5%, and 77.3%, respectively.

CONCLUSIONS: Although AI can play a significant role in the screening and diagnosis of ALS due to its high sensitivities and specificities, concerns remain regarding quality of evidence reported in the literature.}, } @article {pmid38563162, year = {2024}, author = {Pastora, LE and Namburu, NS and Arora, K and Christov, PP and Wilson, JT}, title = {STING-Pathway Inhibiting Nanoparticles (SPINs) as a Platform for Treatment of Inflammatory Diseases.}, journal = {ACS applied bio materials}, volume = {7}, number = {8}, pages = {4867-4878}, pmid = {38563162}, issn = {2576-6422}, support = {T32 DK101003/DK/NIDDK NIH HHS/United States ; P30 DK058404/DK/NIDDK NIH HHS/United States ; }, mesh = {*Membrane Proteins/metabolism/antagonists & inhibitors ; *Nanoparticles/chemistry ; Animals ; Mice ; Inflammation/drug therapy ; Humans ; Biocompatible Materials/chemistry/pharmacology ; Particle Size ; Materials Testing ; Nucleotidyltransferases/antagonists & inhibitors/metabolism ; Signal Transduction/drug effects ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; STING Protein ; }, abstract = {Aberrant activation of the cyclic GMP-AMP synthase (cGAS)/Stimulator of Interferon Genes (STING) pathway has been implicated in the development and progression of a myriad of inflammatory diseases including colitis, nonalcoholic steatohepatitis, amyotrophic lateral sclerosis (ALS), and age-related macular degeneration. Thus, STING pathway inhibitors could have therapeutic application in many of these inflammatory conditions. The cGAS inhibitor RU.521 and the STING inhibitor H-151 have shown promise as therapeutics in mouse models of colitis, ALS, and more. However, these agents require frequent high-dose intraperitoneal injections, which may limit translatability. Furthermore, long-term use of systemically administered cGAS/STING inhibitors may leave patients vulnerable to viral infections and cancer. Thus, localized or targeted inhibition of the cGAS/STING pathway may be an attractive, broadly applicable treatment for a variety of STING pathway-driven ailments. Here we describe STING-Pathway Inhibiting Nanoparticles (SPINS)-poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with RU.521 and H-151-as a platform for enhanced and sustained inhibition of cGAS/STING signaling. We demonstrate that SPINs are equally or more effective at inhibiting type-I interferon responses induced by cytosolic DNA than free H-151 or RU.521. Additionally, we describe a SPIN formulation in which PLGA is coemulsified with poly(benzoyloxypropyl methacrylamide) (P(HPMA-Bz)), which significantly improves drug loading and allows for tunable release of H-151 over a period of days to over a week by varying P(HPMA-Bz) content. Finally, we find that all SPIN formulations were as potent or more potent in inhibiting cGAS/STING signaling in primary murine macrophages, resulting in decreased expression of inflammatory M1-like macrophage markers. Therefore, our study provides an in vitro proof-of-concept for nanoparticle delivery of STING pathway inhibitors and positions SPINs as a potential platform for slowing or reversing the onset or progression of cGAS/STING-driven inflammatory conditions.}, } @article {pmid38564847, year = {2024}, author = {Rajagopalan, V and Pioro, EP}, title = {Differing patterns of cortical grey matter pathology identified by multifractal analysis in UMN-predominant ALS patients with and without corticospinal tract hyperintensity.}, journal = {Journal of the neurological sciences}, volume = {459}, number = {}, pages = {122945}, doi = {10.1016/j.jns.2024.122945}, pmid = {38564847}, issn = {1878-5883}, mesh = {Humans ; *Gray Matter/diagnostic imaging/pathology ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/pathology ; Pyramidal Tracts/diagnostic imaging ; Brain/pathology ; Magnetic Resonance Imaging/methods ; }, abstract = {The pathological hallmarks of amyotrophic lateral sclerosis (ALS) are degeneration of the primary motor cortex grey matter (GM) and corticospinal tract (CST) resulting in upper motor neuron (UMN) dysfunction. Conventional brain magnetic resonance imaging (MRI) shows abnormal CST hyperintensity in some UMN-predominant ALS patients (ALS-CST+) but not in others (ALS-CST-). In addition to the CST differences, we aimed to determine whether GM degeneration differs between ALS-CST+ and ALS-CST- patients by cortical thickness (CT), voxel-based morphometry (VBM) and fractal dimension analyses. We hypothesized that MRI multifractal (MF) measures could differentiate between neurologic controls (n = 14) and UMN-predominant ALS patients as well as between patient subgroups (ALS-CST+, n = 21 vs ALS-CST-, n = 27). No significant differences were observed in CT or GM VBM in any brain regions between patients and controls or between ALS subgroups. MF analyses were performed separately on GM of the whole brain, of frontal, parietal, occipital, and temporal lobes as well as of cerebellum. Estimating MF measures D (Q = 0), D (Q = 1), D (Q = 2), Δf, Δα of frontal lobe GM classified neurologic controls, ALS-CST+ and ALS-CST- groups with 98% accuracy and > 95% in F1, recall, precision and specificity scores. Classification accuracy was only 74% when using whole brain MF measures and < 70% for other brain lobes. We demonstrate that MF analysis can distinguish UMN-predominant ALS subgroups based on GM changes, which the more commonly used quantitative approaches of CT and VBM cannot.}, } @article {pmid38565200, year = {2024}, author = {Stierwalt, J and Stierwalt, JAG and Clark, H and Burda, A and Benavidez Kiley, H and Collins, E and Kortemeyer, M and Miller, E and Peckenschneider, G and Schieltz, E and Shah, Y and Simon, K}, title = {Factors Affecting Performance on a Screening Tool in Persons with Amyotrophic Lateral Sclerosis.}, journal = {Seminars in speech and language}, volume = {45}, number = {3}, pages = {228-241}, doi = {10.1055/s-0044-1785447}, pmid = {38565200}, issn = {1098-9056}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications ; Male ; Female ; Middle Aged ; Aged ; Retrospective Studies ; Cognitive Dysfunction/diagnosis ; Neuropsychological Tests ; Frontotemporal Dementia/diagnosis/psychology ; Adult ; Aged, 80 and over ; }, abstract = {Persons with amyotrophic lateral sclerosis (PALS) are at risk of developing cognitive impairments and frontotemporal dementia (FTD). This study examined the relationship between performance of the ALS-Cognitive Behavioral Screen (ALS-CBS) and the demographic parameters of sex, education, time post-ALS diagnosis, and severity of symptoms. Data were collected retrospectively from 69 participants seen at the Mayo Clinic. Correlations were conducted on the ALS-CBS total scores and subsection scores and the above listed parameters; t-tests were conducted between participant subgroups. No statistically significant relationships or differences occurred between the ALS-CBS or its subsections and the variables measured with exception of age and the attention subsection. Older participants had lower ALS-CBS attention subsection scores. Based on the ALS-CBS scores, most participants had some degree of cognitive impairments: 43 had suspected cognitive impairment, 8 had suspected FTD; 18 fell within the normal range of cognitive function. Overall, the variables of sex, education, time post-diagnosis, and severity of symptoms do not appear to influence ALS-CBS scores. It is recommended cognitive screenings be completed for all PALS due to the high risk for developing cognitive impairments and FTD. Such knowledge can help clinicians develop assessment and treatment plans.}, } @article {pmid38565306, year = {2024}, author = {Zhang, Y and Li, J and Guo, K and Wang, T and Gao, L and Sun, Z and Ma, C and Wang, C and Tian, Y and Zheng, X}, title = {Strigolactones alleviate AlCl3 stress by vacuolar compartmentalization and cell wall blocking in apple.}, journal = {The Plant journal : for cell and molecular biology}, volume = {119}, number = {1}, pages = {197-217}, doi = {10.1111/tpj.16753}, pmid = {38565306}, issn = {1365-313X}, support = {//Breeding Plan of Shandong Provincial Qingchuang Research Team/ ; SDAIT-06-06//Modern Agricultural Technology Industry System of Shandong province/ ; 32001336//National Natural Science Foundation of China/ ; 32102351//National Natural Science Foundation of China/ ; 32172542//National Natural Science Foundation of China/ ; 32372674//National Natural Science Foundation of China/ ; }, mesh = {*Malus/genetics/metabolism/drug effects ; *Vacuoles/metabolism ; *Cell Wall/metabolism/drug effects ; *Aluminum Chloride ; *Plant Proteins/genetics/metabolism ; *Gene Expression Regulation, Plant/drug effects ; Lactones/metabolism/pharmacology ; Plants, Genetically Modified ; Stress, Physiological ; Plant Roots/metabolism/genetics/drug effects ; Heterocyclic Compounds, 3-Ring/metabolism/pharmacology ; Transcription Factors/metabolism/genetics ; Promoter Regions, Genetic ; }, abstract = {Poor management and excess fertilization of apple (Malus domestica Borkh.) orchards are causing increasingly serious soil acidification, resulting in Al toxicity and direct poisoning of roots. Strigolactones (SLs) are reported to be involved in plant responses to abiotic stress, but their role and mechanism under AlCl3 stress remain unknown. Here, we found that applying 1 μm GR24 (an SL analoge) significantly alleviated AlCl3 stress of M26 apple rootstock, mainly by blocking the movement of Al through cell wall and by vacuolar compartmentalization of Al. RNA-seq analysis identified the core transcription factor gene MdWRKY53, and overexpressing MdWRKY53 enhanced AlCl3 tolerance in transgenic apple plants through the same mechanism as GR24. Subsequently, we identified MdPMEI45 (encoding pectin methylesterase inhibitor) and MdALS3 (encoding an Al transporter) as downstream target genes of MdWRKY53 using chromatin immunoprecipitation followed by sequencing (ChIP-seq). GR24 enhanced the interaction between MdWRKY53 and the transcription factor MdTCP15, further increasing the binding of MdWRKY53 to the MdPMEI45 promoter and inducing MdPMEI45 expression to prevent Al from crossing cell wall. MdWRKY53 also bound to the promoter of MdALS3 and enhanced its transcription to compartmentalize Al in vacuoles under AlCl3 stress. We therefore identified two modules involved in alleviating AlCl3 stress in woody plant apple: the SL-WRKY+TCP-PMEI module required for excluding external Al by blocking the entry of Al[3+] into cells and the SL-WRKY-ALS module allowing internal detoxification of Al through vacuolar compartmentalization. These findings lay a foundation for the practical application of SLs in agriculture.}, } @article {pmid38567799, year = {2024}, author = {Wang, XJ and Cornell, PY and Belanger, E and Thomas, KS}, title = {Do end-of-life outcomes differ by assisted living memory-care designation?.}, journal = {Journal of the American Geriatrics Society}, volume = {72}, number = {8}, pages = {2491-2499}, pmid = {38567799}, issn = {1532-5415}, support = {R01 AG057746/AG/NIA NIH HHS/United States ; R01 AG066902/AG/NIA NIH HHS/United States ; R01AG066902/AG/NIA NIH HHS/United States ; R01AG057746/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Assisted Living Facilities/statistics & numerical data ; Aged, 80 and over ; United States ; *Terminal Care/statistics & numerical data ; Aged ; *Medicare/statistics & numerical data ; Prospective Studies ; *Hospice Care/statistics & numerical data ; Alzheimer Disease/mortality/therapy ; Dementia/mortality/therapy ; }, abstract = {BACKGROUND: Residential care/assisted living (RC/AL) is an increasingly common place of end-of-life care for persons with Alzheimer's disease and related dementia (ADRD), who have unique care needs as their health declines. Approximately 22% of RC/ALs provide specialized memory care (memory-care RC/AL). Understanding how end-of-life outcomes differ by memory care among residents with ADRD could facilitate aging/dying in place for this population. The objective of this paper is to examine if end-of-life outcomes (i.e., mortality, hospice use, and number of days receiving hospice in the last month of life) differ between residents with ADRD who moved to memory-care RC/AL, compared with residents with ADRD who moved to RC/AL without memory care (general RC/AL).

METHODS: Prospective cohort of 15,152 fee-for-service Medicare beneficiaries with ADRD who moved to large RC/AL (> = 25 beds) between 2016 and 2018. We used inverse probability treatment weighting to account for observable differences between memory-care and general RC/AL residents. Two-part models estimated the difference by memory care in the number of days receiving hospice care in the last months of life among RC/AL decedents.

RESULTS: The unadjusted mortality rates were 13.4% in general RC/AL and 15.8% in memory-care RC/AL with an adjusted difference of 1.3 percentage points higher mortality among memory-care RC/AL residents (p = 0.04). Hospice use was 8% and 10.6% among general and memory-care RC/AL residents, respectively, with an adjusted difference of 1.4 percentage points (p = 0.01) higher in memory care. Two-part models showed that decedents in memory-care RC/AL spent about 1.4 more days receiving hospice care in the last month of life (p = 0.02).

CONCLUSION: We find a higher mortality rate and higher rate of hospice use among memory-care RC/AL residents. These findings suggest that memory care may attract residents closer to the end of life and/or promote hospice use at the end of life.}, } @article {pmid38568044, year = {2024}, author = {Calvo, A and Moglia, C and Canosa, A and Manera, U and Vasta, R and Grassano, M and Daviddi, M and De Mattei, F and Matteoni, E and Gallone, S and Brunetti, M and Sbaiz, L and Cabras, S and Peotta, L and Palumbo, F and Iazzolino, B and Mora, G and Chiò, A}, title = {High Frequency of Cognitive and Behavioral Impairment in Amyotrophic Lateral Sclerosis Patients with SOD1 Pathogenic Variants.}, journal = {Annals of neurology}, volume = {96}, number = {1}, pages = {150-158}, doi = {10.1002/ana.26928}, pmid = {38568044}, issn = {1531-8249}, support = {RF-2016-02362405//Ministero della Salute/ ; 101017598//HORIZON EUROPE Health/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; 259867//FP7 Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology/complications ; Male ; Female ; *Superoxide Dismutase-1/genetics ; Aged ; Middle Aged ; *Cognitive Dysfunction/genetics/psychology ; Adult ; }, abstract = {OBJECTIVE: While the cognitive-behavioral characteristics of amyotrophic lateral sclerosis (ALS) patients carrying C9orf72 pathological repeat expansion have been extensively studied, our understanding of those carrying SOD1 variants is mostly based on case reports. The aim of this paper is to extensively explore the cognitive-behavioral characteristics of a cohort of ALS patients carrying pathogenetic variants of SOD1 gene, comparing them to patients without pathogenetic variants of 46 ALS-related genes (wild-type [WT]-ALS) and healthy controls.

METHODS: All ALS patients seen at the Turin ALS expert center in the 2009-2021 period who underwent both cognitive/behavioral and extensive genetic testing were eligible to be included in the study. Only patients with SOD1 pathogenetic variants (n = 28) (SOD1-ALS) and WT-ALS (n = 829) were enrolled in the study. A series of 129 controls was also included.

RESULTS: Among the 28 SOD1-ALS patients, 16 (57.1%) had normal cognitive function, 5 (17.9%) isolated cognitive impairment (ALSci) (17.9%), 6 (21.4%) isolated behavioral impairment (ALSbi), 1 (3.6%) cognitive and behavioral impairment (ALScbi), and no one ALS-FTD. SOD1-ALS performed worse than controls in all explored domains, in particular Social Cognition and Language domains. SOD1-ALS patients had similar scores in all tests compared to WT-ALS, except the Story-based Empathy Task (SET), where they performed worse.

INTERPRETATION: Cognitive-behavioral impairment is much more common in SOD1 patients than previously assumed. SOD1-ALS are characterized by a more frequent impairment of Social Cognition and, less markedly, of Language domains. These findings have relevant implication both in the clinical and in the research setting, also considering recently approved treatment for SOD1-ALS. ANN NEUROL 2024;96:150-158.}, } @article {pmid38568048, year = {2024}, author = {Grassano, M and Moglia, C and Palumbo, F and Koumantakis, E and Cugnasco, P and Callegaro, S and Canosa, A and Manera, U and Vasta, R and De Mattei, F and Matteoni, E and Fuda, G and Salamone, P and Marchese, G and Casale, F and De Marchi, F and Mazzini, L and Mora, G and Calvo, A and Chiò, A}, title = {Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis.}, journal = {Annals of neurology}, volume = {96}, number = {1}, pages = {159-169}, doi = {10.1002/ana.26933}, pmid = {38568048}, issn = {1531-8249}, support = {2017SNW5MB//Ministero dell'Università e della Ricerca/ ; RF-2016-02362405//Ministero della Salute/ ; //American Academy of Neurology/ ; //Joint Programme Neurodegenerative Disease Research (JPND)/ ; 259867//Seventh Framework Programme/ ; //ALS Association/ ; //American Brain Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology ; Male ; Female ; *Disease Progression ; Middle Aged ; Aged ; *Sex Characteristics ; Vital Capacity/physiology ; Cohort Studies ; Registries ; Sex Factors ; Prognosis ; Survival Analysis ; Adult ; }, abstract = {OBJECTIVE: To investigate sex-related differences in amyotrophic lateral sclerosis (ALS) prognosis and their contributing factors.

METHODS: Our primary cohort was the Piemonte and Aosta Register for ALS (PARALS); the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and the Answer ALS databases were used for validation. Survival analyses were conducted accounting for age and onset site. The roles of forced vital capacity and weight decline were explored through a causal mediation analysis. Survival and disease progression rates were also evaluated after propensity score matching.

RESULTS: The PARALS cohort included 1,890 individuals (44.8% women). Men showed shorter survival when stratified by onset site (spinal onset HR 1.20, 95% CI 1.00-1.44, p = 0.0439; bulbar onset HR 1.36, 95% CI 1.09-1.70, p = 0.006917), although women had a steeper functional decline (+0.10 ALSFRS-R points/month, 95% CI 0.07-0.15, p < 0.00001) regardless of onset site. Instead, men showed worse respiratory decline (-4.2 forced vital capacity%/month, 95% CI -6.3 to -2.2, p < 0.0001) and faster weight loss (-0.15 kg/month, 95% CI -0.25 to -0.05, p = 0.0030). Causal mediation analysis showed that respiratory function and weight loss were pivotal in sex-related survival differences. Analysis of patients from PRO-ACT (n = 1,394, 40.9% women) and Answer ALS (n = 849, 37.2% women) confirmed these trends.

INTERPRETATION: The shorter survival in men is linked to worse respiratory function and weight loss rather than a faster disease progression. These findings emphasize the importance of considering sex-specific factors in understanding ALS pathophysiology and designing tailored therapeutic strategies. ANN NEUROL 2024;96:159-169.}, } @article {pmid38568213, year = {2024}, author = {Feichtner, A and Enzler, F and Kugler, V and Hoppe, K and Mair, S and Kremser, L and Lindner, H and Huber, RG and Stelzl, U and Stefan, E and Torres-Quesada, O}, title = {Phosphorylation of the compartmentalized PKA substrate TAF15 regulates RNA-protein interactions.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {162}, pmid = {38568213}, issn = {1420-9071}, support = {255310//Österreichische Krebshilfe Tirol/ ; P 35159/FWF_/Austrian Science Fund FWF/Austria ; P32960//Austrian Science Fund/ ; I5406//Austrian Science Fund/ ; P 32960/FWF_/Austrian Science Fund FWF/Austria ; 235872//Tiroler Wissenschaftsförderung/ ; P30441//Austrian Science Fund/ ; P 30441/FWF_/Austrian Science Fund FWF/Austria ; Concrete//Horizon 2020 Framework Programme/ ; P35159//Austrian Science Fund/ ; }, mesh = {Humans ; Cyclic AMP-Dependent Protein Kinases ; Phosphorylation ; Cyclic AMP ; *Amyotrophic Lateral Sclerosis ; RNA ; *TATA-Binding Protein Associated Factors ; }, abstract = {Spatiotemporal-controlled second messengers alter molecular interactions of central signaling nodes for ensuring physiological signal transmission. One prototypical second messenger molecule which modulates kinase signal transmission is the cyclic-adenosine monophosphate (cAMP). The main proteinogenic cellular effectors of cAMP are compartmentalized protein kinase A (PKA) complexes. Their cell-type specific compositions precisely coordinate substrate phosphorylation and proper signal propagation which is indispensable for numerous cell-type specific functions. Here we present evidence that TAF15, which is implicated in the etiology of amyotrophic lateral sclerosis, represents a novel nuclear PKA substrate. In cross-linking and immunoprecipitation experiments (iCLIP) we showed that TAF15 phosphorylation alters the binding to target transcripts related to mRNA maturation, splicing and protein-binding related functions. TAF15 appears to be one of multiple PKA substrates that undergo RNA-binding dynamics upon phosphorylation. We observed that the activation of the cAMP-PKA signaling axis caused a change in the composition of a collection of RNA species that interact with TAF15. This observation appears to be a broader principle in the regulation of molecular interactions, as we identified a significant enrichment of RNA-binding proteins within endogenous PKA complexes. We assume that phosphorylation of RNA-binding domains adds another layer of regulation to binary protein-RNAs interactions with consequences to RNA features including binding specificities, localization, abundance and composition.}, } @article {pmid38570009, year = {2024}, author = {Fernández Comaduran, M and Minotti, S and Jacob-Tomas, S and Rizwan, J and Larochelle, N and Robitaille, R and Sephton, CF and Vera, M and Nalbantoglu, JN and Durham, HD}, title = {Impact of histone deacetylase inhibition and arimoclomol on heat shock protein expression and disease biomarkers in primary culture models of familial ALS.}, journal = {Cell stress & chaperones}, volume = {29}, number = {3}, pages = {359-380}, pmid = {38570009}, issn = {1466-1268}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy ; *Histone Deacetylase Inhibitors/pharmacology ; *Biomarkers/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Humans ; *Motor Neurons/metabolism/drug effects/pathology ; Animals ; HSP70 Heat-Shock Proteins/metabolism/genetics ; HSC70 Heat-Shock Proteins/metabolism/genetics ; Hydroxylamines/pharmacology ; Cells, Cultured ; RNA-Binding Protein FUS/metabolism/genetics ; Superoxide Dismutase-1/metabolism/genetics ; }, abstract = {Protein misfolding and mislocalization are common themes in neurodegenerative disorders, including motor neuron disease, and amyotrophic lateral sclerosis (ALS). Maintaining proteostasis is a crosscutting therapeutic target, including the upregulation of heat shock proteins (HSP) to increase chaperoning capacity. Motor neurons have a high threshold for upregulating stress-inducible HSPA1A, but constitutively express high levels of HSPA8. This study compared the expression of these HSPs in cultured motor neurons expressing three variants linked to familial ALS: TAR DNA binding protein 43 kDa (TDP-43)[G348C], fused in sarcoma (FUS)[R521G], or superoxide dismutase I (SOD1)[G93A]. All variants were poor inducers of Hspa1a, and reduced levels of Hspa8 mRNA and protein, indicating multiple compromises in chaperoning capacity. To promote HSP expression, cultures were treated with the putative HSP coinducer, arimoclomol, and class I histone deacetylase inhibitors, to promote active chromatin for transcription, and with the combination. Treatments had variable, often different effects on the expression of Hspa1a and Hspa8, depending on the ALS variant expressed, mRNA distribution (somata and dendrites), and biomarker of toxicity measured (histone acetylation, maintaining nuclear TDP-43 and the neuronal Brm/Brg-associated factor chromatin remodeling complex component Brg1, mitochondrial transport, FUS aggregation). Overall, histone deacetylase inhibition alone was effective on more measures than arimoclomol. As in the FUS model, arimoclomol failed to induce HSPA1A or preserve Hspa8 mRNA in the TDP-43 model, despite preserving nuclear TDP-43 and Brg1, indicating neuroprotective properties other than HSP induction. The data speak to the complexity of drug mechanisms against multiple biomarkers of ALS pathogenesis, as well as to the importance of HSPA8 for neuronal proteostasis in both somata and dendrites.}, } @article {pmid38570593, year = {2024}, author = {van Stuijvenberg, OC and Broekman, MLD and Wolff, SEC and Bredenoord, AL and Jongsma, KR}, title = {Developer perspectives on the ethics of AI-driven neural implants: a qualitative study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {7880}, pmid = {38570593}, issn = {2045-2322}, support = {17619//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; }, mesh = {*Artificial Intelligence ; Reproducibility of Results ; Qualitative Research ; Focus Groups ; *Cochlear Implants ; }, abstract = {Convergence of neural implants with artificial intelligence (AI) presents opportunities for the development of novel neural implants and improvement of existing neurotechnologies. While such technological innovation carries great promise for the restoration of neurological functions, they also raise ethical challenges. Developers of AI-driven neural implants possess valuable knowledge on the possibilities, limitations and challenges raised by these innovations; yet their perspectives are underrepresented in academic literature. This study aims to explore perspectives of developers of neurotechnology to outline ethical implications of three AI-driven neural implants: a cochlear implant, a visual neural implant, and a motor intention decoding speech-brain-computer-interface. We conducted semi-structured focus groups with developers (n = 19) of AI-driven neural implants. Respondents shared ethically relevant considerations about AI-driven neural implants that we clustered into three themes: (1) design aspects; (2) challenges in clinical trials; (3) impact on users and society. Developers considered accuracy and reliability of AI-driven neural implants conditional for users' safety, authenticity, and mental privacy. These needs were magnified by the convergence with AI. Yet, the need for accuracy and reliability may also conflict with potential benefits of AI in terms of efficiency and complex data interpretation. We discuss strategies to mitigate these challenges.}, } @article {pmid38574339, year = {2024}, author = {Meyers, EE and Brizzi, KT}, title = {Analgesic Strategies in Patients With Amyotrophic Lateral Sclerosis #477.}, journal = {Journal of palliative medicine}, volume = {27}, number = {4}, pages = {565-566}, doi = {10.1089/jpm.2024.0014}, pmid = {38574339}, issn = {1557-7740}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Patients ; }, } @article {pmid38574876, year = {2024}, author = {Watt, CL and Smith, IC and Rice, J and Murphy, R and Breiner, A and Duff, MLV and Nogo, D and Bush, SH and McNeely, S and Buenger, U and Zehrt, B and Zwicker, J}, title = {Qualitative Analysis of Initial Palliative Care Consultations in Amyotrophic Lateral Sclerosis.}, journal = {Journal of pain and symptom management}, volume = {68}, number = {1}, pages = {43-52.e2}, doi = {10.1016/j.jpainsymman.2024.03.024}, pmid = {38574876}, issn = {1873-6513}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Palliative Care ; Male ; Female ; Middle Aged ; *Caregivers/psychology ; Aged ; *Referral and Consultation ; Prospective Studies ; *Qualitative Research ; COVID-19 ; Adult ; Advance Care Planning ; Feasibility Studies ; }, abstract = {BACKGROUND: Palliative care (PC) benefits patients with amyotrophic lateral sclerosis (ALS), however the needs of patients and caregivers and the optimal timing of PC discussions remains unclear. This study reports the analysis of PC consult notes from a larger feasibility trial. The specific aims of this analysis were to i) identify the PC needs of patients with ALS via qualitative analysis and ii) identify characteristics of patients and caregivers that could predict specific PC needs.

METHODS: This study was nested within a nonrandomized, prospective study of patients with ALS (and their caregivers) being treated at a multidisciplinary ALS clinic. Exclusion criteria of the main study were age <18 years, inability to complete questionnaires, and prior receipt of PC. All patients were offered a PC consultation (PCC); those who accepted were included in this nested study. Consultation notes were reviewed and thematic and content analyses were conducted. The occurrence of themes across patient and caregiver contextual variables were examined.

RESULTS: Thirty-two PCCs were completed between October 2020 and April 2022. Six major themes were identified: PC roles (with subthemes encompassing the spectrum of specialist PC practice including symptom management and advance care planning), engagement with PC, patients' concerns for their caregivers, caregiver-specific concerns, finances, and COVID-19. An average of 12 topics were discussed per PCC (range = 3-22). Discussion of advance care planning, care coordination, and symptom management was common, and these topics were not discussed more frequently in PCCs with patients with lower functional status, more bulbar symptoms, or lower quality of life. Time from diagnosis did not impact topics of discussion. Patients reporting more symptoms of depression more frequently required psychological support, particularly regarding loss of independence, employment, and leisure activities.

DISCUSSION: Patients with ALS and their caregivers have a wide range of PC needs. These needs vary irrespective of time from diagnosis, functional status, or quality of life, therefore PCC is recommended for all patients with ALS. PCC should be individualized based on patient and caregiver preferences.

The study was registered with ClinicalTrials.gov (NCT04257760; https://clinicaltrials.gov/ct2/show/NCT04257760) on February 6, 2020. The first enrollment occurred on October 20, 2020.}, } @article {pmid38575115, year = {2024}, author = {Temkin-Greener, H and Guo, W and McGarry, B and Cai, S}, title = {Serious Mental Illness in Assisted Living Communities: Association with Nursing Home Placement.}, journal = {Journal of the American Medical Directors Association}, volume = {25}, number = {5}, pages = {917-922}, pmid = {38575115}, issn = {1538-9375}, support = {R01 HS026893/HS/AHRQ HHS/United States ; }, mesh = {Humans ; *Mental Disorders ; Medicare ; Aged ; Aged, 80 and over ; Dementia/epidemiology ; United States ; *Nursing Homes ; *Assisted Living Facilities ; Major Depressive Disorder/epidemiology ; Bipolar Disorder/epidemiology ; Schizophrenia/epidemiology ; Retrospective Studies ; Male ; Female ; }, abstract = {OBJECTIVES: Assess prevalence of serious mental illness (SMI) alone, and co-occurring with Alzheimer disease and related dementias (ADRD), among Medicare beneficiaries in assisted living (AL). Examine the association between permanent nursing home (NH) placement and SMI, among residents with and without ADRD.

DESIGN: 2018-2019 retrospective cohort of Medicare beneficiaries in AL. Residents were followed for up to 2 years to track their NH placement. We used data from the Medicare Enrollment Database, the Medicare Beneficiary Summary File, Minimum Data Set, and a national directory of state-licensed AL communities. AL residents were identified using a validated, previously reported 9-digit zip code methodology.

SETTING AND PARTICIPANTS: A cross-sectional study sample included 289,350 Medicare beneficiaries in 17,265 AL communities across 50 states and in the District of Columbia.

METHODS: The outcome was permanent NH placement: a continuous stay for more than 90 days. Key independent variable was presence of SMI-schizophrenia, bipolar disorder, and major depression. Other covariates included sociodemographic factors and presence of other chronic conditions, including ADRD. A linear probability model with robust SEs, and AL-level random effects, was used to test the association between SMI diagnoses, ADRD, and their interactions on NH placement.

RESULTS: More than half (55.65%) of AL residents had a diagnosis of SMI, among them 93.2% had major depression, 28.5% schizophrenia, and 22.2% bipolar disorder. Individuals with schizophrenia and bipolar disorder had a significantly lower probability of NH placement, a 32% and a 15% decrease relative to the cohort mean, respectively. Placement risk was significantly greater for residents with ADRD compared to those without, increasing for those who also had schizophrenia or bipolar disorder, 12.9% and 1.5% relative to the sample mean, respectively.

CONCLUSION AND IMPLICATIONS: Presence of schizophrenia and bipolar disorder, in conjunction with ADRD, significantly increases the risk of long-term NH placement, suggesting that ALs may not be well prepared to care for these residents.}, } @article {pmid38575127, year = {2024}, author = {Zhang, T and Wang, Z and Li, Y and Zhou, B and Liu, Y and Li, J and Wang, R and Lv, Q and Li, C and Zhang, Y and Su, R}, title = {Genetic diversity and population structure in five Inner Mongolia cashmere goat populations using whole-genome genotyping.}, journal = {Animal bioscience}, volume = {37}, number = {7}, pages = {1168-1176}, pmid = {38575127}, issn = {2765-0189}, support = {2021ZD0012//Science and technology major project of Inner Mongolia Autonomous Region/ ; 2021GG0086//Inner Mongolia Autonomous Region Science and Technology Research Project/ ; NJYT22038//Inner Mongolia Inner Mongolia Autonomous Region/ ; NMGIRT2322//Program for Innovative Research Team in Universities of Inner Mongolia Autonomous Region/ ; CARS-39//China Agriculture Research System of MOF and MARA/ ; }, abstract = {OBJECTIVE: As a charismatic species, cashmere goats have rich genetic resources. In the Inner Mongolia Autonomous Region, there are three cashmere goat varieties named and approved by the state. These goats are renowned for their high cashmere production and superior cashmere quality. Therefore, it is vitally important to protect their genetic resources as they will serve as breeding material for developing new varieties in the future.

METHODS: Three breeds including Inner Mongolia cashmere goats (IMCG), Hanshan White cashmere goats (HS), and Ujimqin white cashmere goats (WZMQ) were studied. IMCG were of three types: Aerbas (AEBS), Erlangshan (ELS), and Alashan (ALS). Nine DNA samples were collected for each population, and they were genomically re-sequenced to obtain high-depth data. The genetic diversity parameters of each population were estimated to determine selection intensity. Principal component analysis, phylogenetic tree construction and genetic differentiation parameter estimation were performed to determine genetic relationships among populations.

RESULTS: Samples from the 45 individuals from the five goat populations were sequenced, and 30,601,671 raw single nucleotide polymorphisms (SNPs) obtained. Then, variant calling was conducted using the reference genome, and 17,214,526 SNPs were retained after quality control. Individual sequencing depth of individuals ranged from 21.13× to 46.18×, with an average of 28.5×. In the AEBS, locus polymorphism (79.28) and expected heterozygosity (0.2554) proportions were the lowest, and the homologous consistency ratio (0.1021) and average inbreeding coefficient (0.1348) were the highest, indicating that this population had strong selection intensity. Conversely, ALS and WZMQ selection intensity was relatively low. Genetic distance between HS and the other four populations was relatively high, and genetic exchange existed among the other four populations.

CONCLUSION: The Inner Mongolia cashmere goat (AEBS type) population has a relatively high selection intensity and a low genetic diversity. The IMCG (ALS type) and WZMQ populations had relatively low selection intensity and high genetic diversity. The genetic distance between HS and the other four populations was relatively high, with a moderate degree of differentiation. Overall, these genetic variations provide a solid foundation for resource identification of Inner Mongolia Autonomous Region cashmere goats in the future.}, } @article {pmid38575486, year = {2024}, author = {Chandran, SK and Doucet, M}, title = {Neurogenic Dysphagia.}, journal = {Otolaryngologic clinics of North America}, volume = {57}, number = {4}, pages = {589-597}, doi = {10.1016/j.otc.2024.02.023}, pmid = {38575486}, issn = {1557-8259}, mesh = {Humans ; *Deglutition Disorders/etiology/therapy/diagnosis ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Multiple Sclerosis/complications ; Parkinson Disease/complications ; Stroke/complications ; }, abstract = {This article provides an overview of neurogenic dysphagia, describing the evaluation and management of swallowing dysfunction in various neurologic diseases. The article will focus on stroke, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis.}, } @article {pmid38575965, year = {2024}, author = {Daudelin, D and Westerhaus, A and Zhang, N and Leyder, E and Savonenko, A and Sockanathan, S}, title = {Loss of GDE2 leads to complex behavioral changes including memory impairment.}, journal = {Behavioral and brain functions : BBF}, volume = {20}, number = {1}, pages = {7}, pmid = {38575965}, issn = {1744-9081}, support = {RF1AG062671/NH/NIH HHS/United States ; F31 AG079539/AG/NIA NIH HHS/United States ; T32NS091018/NH/NIH HHS/United States ; T32GM007445/NH/NIH HHS/United States ; RF1 AG062671/AG/NIA NIH HHS/United States ; T32 NS091018/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Animals ; Female ; Humans ; Mice ; *Alzheimer Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; Memory ; Memory Disorders/genetics ; Mice, Transgenic ; *Neurodegenerative Diseases/genetics ; Phosphoric Diester Hydrolases ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are debilitating neurodegenerative diseases for which there are currently no cures. Familial cases with known genetic causes make up less than 10% of these diseases, and little is known about the underlying mechanisms that contribute to sporadic disease. Accordingly, it is important to expand investigations into possible pathways that may contribute to disease pathophysiology. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a membrane-bound enzyme that acts at the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers distinct proteins to the membrane. GDE2 abnormally accumulates in intracellular compartments in the brain of patients with AD, ALS, and ALS/FTD, indicative of GDE2 dysfunction. Mice lacking GDE2 (Gde2KO) show neurodegenerative changes such as neuronal loss, reduced synaptic proteins and synapse loss, and increased Aβ deposition, raising the possibility that GDE2 disruption in disease might contribute to disease pathophysiology. However, the effect of GDE2 loss on behavioral function and learning/memory has not been characterized.

RESULTS: Here, we show that GDE2 is expressed throughout the adult mouse brain in areas including the cortex, hippocampus, habenula, thalamus, and amygdala. Gde2KO and WT mice were tested in a set of behavioral tasks between 7 and 16 months of age. Compared to WT, Gde2KO mice display moderate hyperactivity that becomes more pronounced with age across a variety of behavioral tests assessing novelty-induced exploratory activity. Additionally, Gde2KO mice show reduced startle response, with females showing additional defects in prepulse inhibition. No changes in anxiety-associated behaviors were found, but Gde2KOs show reduced sociability. Notably, aged Gde2KO mice demonstrate impaired short/long-term spatial memory and cued fear memory/secondary contextual fear acquisition.

CONCLUSIONS: Taken together, these observations suggest that loss of GDE2 leads to behavioral deficits, some of which are seen in neurodegenerative disease models, implying that loss of GDE2 may be an important contributor to phenotypes associated with neurodegeneration.}, } @article {pmid38576194, year = {2024}, author = {Rutkove, SB and McIlduff, CE and Stommel, E and Levy, S and Smith, C and Gutierrez, H and Verga, S and Samaan, S and Yator, C and Nanda, A and Pastel, L and Doussan, A and Phipps, K and Murphy, E and Halter, R}, title = {Assessing pulmonary function in ALS using electrical impedance tomography.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {581-588}, pmid = {38576194}, issn = {2167-9223}, support = {R21 NS118434/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/diagnosis ; Female ; Male ; Middle Aged ; *Electric Impedance ; *Respiratory Function Tests/methods ; Aged ; Tomography/methods ; Adult ; Reproducibility of Results ; Vital Capacity/physiology ; Lung/physiopathology/diagnostic imaging ; }, abstract = {OBJECTIVE: We sought to determine whether thoracic electrical impedance tomography (EIT) could characterize pulmonary function in amyotrophic lateral sclerosis (ALS) patients, including those with facial weakness. Thoracic EIT is a noninvasive, technology in which a multi-electrode belt is placed across the chest, producing real-time impedance imaging of the chest during breathing.

METHODS: We enrolled 32 ALS patients and 32 age- and sex-matched healthy controls (HCs) without underlying lung disease. All participants had EIT measurements performed simultaneously with standard pulmonary function tests (PFTs), including slow and forced vital capacity (SVC and FVC) in upright and supine positions and maximal inspiratory and expiratory pressures (MIPs and MEPs, respectively). Intraclass correlation coefficients (ICCs) were calculated to assess the immediate reproducibility of EIT measurements and Pearson's correlations were used to explore the relationships between EIT and PFT values.

RESULTS: Data from 30 ALS patients and 27 HCs were analyzed. Immediate upright SVC reproducibility was very high (ICC 0.98). Correlations were generally strongest between EIT and spirometry measures, with R values ranging from 0.64 to 0.82 (p < 0.001) in the ALS cohort. There were less robust correlations between EIT values and both MIPs and MEPs in the ALS patients, with R values ranging from 0.33 to 0.44. There was no significant difference for patients with and without facial weakness. There were no reported adverse events.

CONCLUSION: EIT-based pulmonary measures hold the promise of providing an alternative approach for lung function assessment in ALS patients. Based on these early results, further development and study of this technology are warranted.}, } @article {pmid38576758, year = {2024}, author = {Gonzalez, FM and Cohens, FG}, title = {Predicting outcomes after kidney transplantation: Can Pareto's rules help us to do so?.}, journal = {World journal of transplantation}, volume = {14}, number = {1}, pages = {90149}, pmid = {38576758}, issn = {2220-3230}, abstract = {Kidney transplantation is the best option for kidney replacement therapy, even considering that most of the times the grafts do not survive as long as their recipients. In the Khalil et al's experience, published in this issue of the Journal, they analyze their second kidney graft survival and describe those significant predictors of early loss. This editorial comments on the results and put in perspec tive that most of the times, long-term graft survival could be inadvertently jeopardized if the immunosuppressive therapy is reduced or withdrawn for any reason, and that it could happen frequently if the transplant physician intends to innovate with the clinical care without proper evidence-based data.}, } @article {pmid38577753, year = {2024}, author = {Yellepeddi, VK and Race, JA and McFarland, MM and Constance, JE and Fanaeian, E and Murphy, NA}, title = {Effectiveness of atropine in managing sialorrhea: A systematic review and meta-analysis.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {62}, number = {6}, pages = {267-277}, doi = {10.5414/CP204538}, pmid = {38577753}, issn = {0946-1965}, mesh = {*Sialorrhea/drug therapy ; Humans ; *Atropine/therapeutic use ; Treatment Outcome ; Salivation/drug effects ; }, abstract = {OBJECTIVES: To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling.

MATERIALS AND METHODS: We included randomized controlled studies, quasi-randomized trials, case reports, clinical trials, systematic reviews, and meta-analyses assessing the use of atropine in patients with sialorrhea or drooling. The endpoints were reduction in salivary flow rate, amount of saliva secreted, reduction in clinical symptoms of sialorrhea, death rattle intensity, or reduction in drooling intensity as measured by an objective scale such as the drooling intensity scale.

RESULTS: A total of 56 studies with 2,378 patients were included in the systematic review. The underlying disease states included brain injury, amyotrophic lateral sclerosis, cerebral palsy, clozapine- and perphenazine-induced sialorrhea, Parkinson's disease, and terminal illness. The routes of atropine administration included sublingual, intravenous, subcutaneous, oral tablet or solution, and direct injection of atropine into parotid glands or at the base of the tongue. The generalized estimated equation regression models showed that sublingual administration is superior to oral and subcutaneous routes.

CONCLUSION: Atropine is efficacious in managing sialorrhea in most disease states. Sublingual administration of atropine is superior to other routes of administration in reducing salivary flow in patients with sialorrhea.}, } @article {pmid38577970, year = {2024}, author = {Barreto-Núñez, R and Béland, LC and Boutej, H and Picher-Martel, V and Dupré, N and Barbeito, L and Kriz, J}, title = {Chronically activated microglia in ALS gradually lose their immune functions and develop unconventional proteome.}, journal = {Glia}, volume = {72}, number = {7}, pages = {1319-1339}, doi = {10.1002/glia.24531}, pmid = {38577970}, issn = {1098-1136}, support = {//ALS Society of Canada/ ; //Fondation Brain Canada/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/immunology/pathology/genetics ; *Microglia/metabolism/immunology ; Animals ; *Proteome/metabolism ; Mice ; *Mice, Transgenic ; Spinal Cord/metabolism/pathology/immunology ; Disease Models, Animal ; Phagocytosis/physiology ; Humans ; Female ; Mice, Inbred C57BL ; Male ; }, abstract = {Neuroinflammation and chronic activation of microglial cells are the prominent features of amyotrophic lateral sclerosis (ALS) pathology. While alterations in the mRNA profile of diseased microglia have been well documented, the actual microglia proteome remains poorly characterized. Here we performed a functional characterization together with proteome analyses of microglial cells at different stages of disease in the SOD1-G93A model of ALS. Functional analyses of microglia derived from the lumbar spinal cord of symptomatic mice revealed: (i) remarkably high mitotic index (close to 100% cells are Ki67+) (ii) significant decrease in phagocytic capacity when compared to age-matched control microglia, and (iii) diminished response to innate immune challenges in vitro and in vivo. Proteome analysis revealed a development of two distinct molecular signatures at early and advanced stages of disease. While at early stages of disease, we identified several proteins implicated in microglia immune functions such as GPNMB, HMBOX1, at advanced stages of disease microglia signature at protein level was characterized with a robust upregulation of several unconventional proteins including rootletin, major vaults proteins and STK38. Upregulation of GPNMB and rootletin has been also found in the spinal cord samples of sporadic ALS. Remarkably, the top biological functions of microglia, in particular in the advanced disease, were not related to immunity/immune response, but were highly enriched in terms linked to RNA metabolism. Together, our results suggest that, over the course of disease, chronically activated microglia develop unconventional protein signatures and gradually lose their immune identity ultimately turning into functionally inefficient immune cells.}, } @article {pmid38579683, year = {2024}, author = {Lai, JD and Berlind, JE and Fricklas, G and Lie, C and Urenda, JP and Lam, K and Sta Maria, N and Jacobs, R and Yu, V and Zhao, Z and Ichida, JK}, title = {KCNJ2 inhibition mitigates mechanical injury in a human brain organoid model of traumatic brain injury.}, journal = {Cell stem cell}, volume = {31}, number = {4}, pages = {519-536.e8}, doi = {10.1016/j.stem.2024.03.004}, pmid = {38579683}, issn = {1875-9777}, support = {RF1 NS122060/NS/NINDS NIH HHS/United States ; F31 NS117075/NS/NINDS NIH HHS/United States ; R01 NS097850/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/etiology/pathology ; Brain/metabolism ; *Brain Injuries, Traumatic/drug therapy/metabolism/therapy ; C9orf72 Protein/metabolism ; DNA-Binding Proteins/metabolism ; *Frontotemporal Dementia/etiology/pathology ; *Neurodegenerative Diseases/etiology/pathology ; *Potassium Channels, Inwardly Rectifying/antagonists & inhibitors/metabolism ; }, abstract = {Traumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain and which strategies most potently mitigate these processes. We developed a high-intensity ultrasound platform to inflict mechanical injury to induced pluripotent stem cell (iPSC)-derived cortical organoids. Mechanically injured organoids elicit classic hallmarks of TBI, including neuronal death, tau phosphorylation, and TDP-43 nuclear egress. We found that deep-layer neurons were particularly vulnerable to injury and that TDP-43 proteinopathy promotes cell death. Injured organoids derived from C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) patients displayed exacerbated TDP-43 dysfunction. Using genome-wide CRISPR interference screening, we identified a mechanosensory channel, KCNJ2, whose inhibition potently mitigated neurodegenerative processes in vitro and in vivo, including in C9ORF72 ALS/FTD organoids. Thus, targeting KCNJ2 may reduce acute neuronal death after brain injury, and we present a scalable, genetically flexible cerebral organoid model that may enable the identification of additional modifiers of mechanical stress.}, } @article {pmid38580817, year = {2024}, author = {Irwin, KE and Jasin, P and Braunstein, KE and Sinha, IR and Garret, MA and Bowden, KD and Chang, K and Troncoso, JC and Moghekar, A and Oh, ES and Raitcheva, D and Bartlett, D and Miller, T and Berry, JD and Traynor, BJ and Ling, JP and Wong, PC}, title = {Author Correction: A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD.}, journal = {Nature medicine}, volume = {30}, number = {5}, pages = {1504}, doi = {10.1038/s41591-024-02966-z}, pmid = {38580817}, issn = {1546-170X}, } @article {pmid38582030, year = {2024}, author = {van Unnik, JWJ and Meyjes, M and Janse van Mantgem, MR and van den Berg, LH and van Eijk, RPA}, title = {Remote monitoring of amyotrophic lateral sclerosis using wearable sensors detects differences in disease progression and survival: a prospective cohort study.}, journal = {EBioMedicine}, volume = {103}, number = {}, pages = {105104}, pmid = {38582030}, issn = {2352-3964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/physiopathology ; Male ; Female ; *Disease Progression ; *Wearable Electronic Devices ; Middle Aged ; Prospective Studies ; Aged ; Accelerometry/instrumentation ; Prognosis ; Remote Sensing Technology/instrumentation/methods ; Adult ; }, abstract = {BACKGROUND: There is an urgent need for objective and sensitive measures to quantify clinical disease progression and gauge the response to treatment in clinical trials for amyotrophic lateral sclerosis (ALS). Here, we evaluate the ability of an accelerometer-derived outcome to detect differential clinical disease progression and assess its longitudinal associations with overall survival in patients with ALS.

METHODS: Patients with ALS wore an accelerometer on the hip for 3-7 days, every 2-3 months during a multi-year observation period. An accelerometer-derived outcome, the Vertical Movement Index (VMI), was calculated, together with predicted disease progression rates, and jointly analysed with overall survival. The clinical utility of VMI was evaluated using comparisons to patient-reported functionality, while the impact of various monitoring schemes on empirical power was explored through simulations.

FINDINGS: In total, 97 patients (70.1% male) wore the accelerometer for 1995 days, for a total of 27,701 h. The VMI was highly discriminatory for predicted disease progression rates, revealing faster rates of decline in patients with a worse predicted prognosis compared to those with a better predicted prognosis (p < 0.0001). The VMI was strongly associated with the hazard for death (HR 0.20, 95% CI: 0.09-0.44, p < 0.0001), where a decrease of 0.19-0.41 unit was associated with reduced ambulatory status. Recommendations for future studies using accelerometery are provided.

INTERPRETATION: The results serve as motivation to incorporate accelerometer-derived outcomes in clinical trials, which is essential for further validation of these markers to meaningful endpoints.

FUNDING: Stichting ALS Nederland (TRICALS-Reactive-II).}, } @article {pmid38582774, year = {2024}, author = {Zhang, H and Guo, H and Li, D and Zhang, Y and Zhang, S and Kang, W and Liu, C and Le, W and Wang, L and Li, D and Dai, B}, title = {Halogen doped graphene quantum dots modulate TDP-43 phase separation and aggregation in the nucleus.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {2980}, pmid = {38582774}, issn = {2041-1723}, support = {82188101//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32171236//National Natural Science Foundation of China (National Science Foundation of China)/ ; 92353302//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32170683//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; *Graphite ; Phase Separation ; *Quantum Dots ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {TDP-43 is implicated in the dynamic formation of nuclear bodies and stress granules through phase separation. In diseased states, it can further condense into pathological aggregates in the nucleus and cytoplasm, contributing to the onset of amyotrophic lateral sclerosis. In this study, we evaluate the effect of graphene quantum dots (GQDs) with different functional groups on TDP-43's phase separation and aggregation in various cellular locations. We find that halogen atom-doped GQDs (GQDs-Cl, Cl-GQDs-OH) penetrate the nuclear envelope, inhibiting the assembly of TDP-43 nuclear bodies and stress granules under oxidative stress or hyperosmotic environments, and reduce amyloid aggregates and disease-associated phosphorylation of TDP-43. Mechanistic analysis reveals GQDs-Cl and Cl-GQDs-OH modulate TDP-43 phase separation through hydrophobic and electrostatic interactions. Our findings highlight the potential of GQDs-Cl and Cl-GQDs-OH in modulating nuclear protein condensation and pathological aggregation, offering direction for the innovative design of GQDs to modulate protein phase separation and aggregation.}, } @article {pmid38583129, year = {2024}, author = {Thal, DR and Gawor, K and Moonen, S}, title = {Regulated cell death and its role in Alzheimer's disease and amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {69}, pmid = {38583129}, issn = {1432-0533}, support = {22-AAIIA-963171/ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Regulated Cell Death ; Cell Death ; Motor Neurons ; }, abstract = {Despite considerable research efforts, it is still not clear which mechanisms underlie neuronal cell death in neurodegenerative diseases. During the last 20 years, multiple pathways have been identified that can execute regulated cell death (RCD). Among these RCD pathways, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-related cell death, and lysosome-dependent cell death have been intensively investigated. Although RCD consists of numerous individual pathways, multiple common proteins have been identified that allow shifting from one cell death pathway to another. Another layer of complexity is added by mechanisms such as the endosomal machinery, able to regulate the activation of some RCD pathways, preventing cell death. In addition, restricted axonal degeneration and synaptic pruning can occur as a result of RCD activation without loss of the cell body. RCD plays a complex role in neurodegenerative processes, varying across different disorders. It has been shown that RCD is differentially involved in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), among the most common neurodegenerative diseases. In AD, neuronal loss is associated with the activation of not only necroptosis, but also pyroptosis. In ALS, on the other hand, motor neuron death is not linked to canonical necroptosis, whereas pyroptosis pathway activation is seen in white matter microglia. Despite these differences in the activation of RCD pathways in AD and ALS, the accumulation of protein aggregates immunoreactive for p62/SQSTM1 (sequestosome 1) is a common event in both diseases and many other neurodegenerative disorders. In this review, we describe the major RCD pathways with clear activation in AD and ALS, the main interactions between these pathways, as well as their differential and similar involvement in these disorders. Finally, we will discuss targeting RCD as an innovative therapeutic concept for neurodegenerative diseases, such as AD and ALS. Considering that the execution of RCD or "cellular suicide" represents the final stage in neurodegeneration, it seems crucial to prevent neuronal death in patients by targeting RCD. This would offer valuable time to address upstream events in the pathological cascade by keeping the neurons alive.}, } @article {pmid38583622, year = {2024}, author = {Newell, ME and Babbrah, A and Aravindan, A and Rathnam, R and Kiernan, R and Driver, EM and Bowes, DA and Halden, RU}, title = {Prevalence rates of neurodegenerative diseases versus human exposures to heavy metals across the United States.}, journal = {The Science of the total environment}, volume = {928}, number = {}, pages = {172260}, doi = {10.1016/j.scitotenv.2024.172260}, pmid = {38583622}, issn = {1879-1026}, mesh = {*Metals, Heavy/analysis ; Humans ; United States/epidemiology ; *Environmental Exposure/statistics & numerical data ; Prevalence ; *Neurodegenerative Diseases/epidemiology/chemically induced ; Environmental Monitoring ; }, abstract = {Novel means are needed to identify individuals and subpopulations susceptible to and afflicted by neurodegenerative diseases (NDDs). This study aimed to utilize geographic distribution of heavy metal sources and sinks to investigate a potential human health risk of developing NDDs. Known or hypothesized environmental factors driving disease prevalence of Alzheimer's Disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS) are heavy metals, including arsenic (As), cadmium (Cd), manganese (Mn) and mercury (Hg). Lead (Pb) has been associated with AD and ALS. Analyzable mediums of human exposure to heavy metals (i.e., toxic metals and metalloids), or proxies thereof, include infant blood, topsoil, sewage sludge, and well water. U.S. concentrations of heavy metals in topsoil, sewage sludge, well water, and infant blood were mapped and compared to prevalence rates of major NDDs. Data from federal and state agencies (i.e., CDC, EPA, and the US Geological Survey) on heavy metal concentrations, age distribution, and NDD prevalence rates were geographically represented and statistically analyzed to quantify possible correlations. Aside from an expected significant association between NDD prevalence and age (p < 0.0001), we found significant associations between the prevalence of the sum of three major NDDs with: Pb in topsoil (p = 0.0433); Cd (p < 0.0001) and Pb (p < 0.0001) in sewage sludge; Pb in infant blood (p < 0.0001). Concentrations in sewage sludge of Cd and Pb were significantly correlated with NDD prevalence rates with an odds ratio of 2.91 (2.04, 4.225 95%CI) and 4.084 (3.14, 5.312 95%CI), respectively. The presence of toxic metals in the U.S. environment in multiple matrices, including sewage sludge, was found to be significantly associated with NDD prevalence. This is the first use of sewage sludge as an environmental proxy matrix to infer risk of developing NDDs.}, } @article {pmid38583636, year = {2024}, author = {do Prado Schneidewind, FCC and de Castilho, PF and Galvão, F and de Andrade Dos Santos, JV and da Silva Dantas, FG and Negri, M and da Silva Pinto, L and Moraes, CAF and Freitas, J and de Souza, PRB and Nogueira, CR and de Oliveira, KMP}, title = {Effects of bioconversion by Battus polydamas on the chemical composition of Aristolochia spp. and evaluation of antimicrobial activity and biocompatibility.}, journal = {Fitoterapia}, volume = {175}, number = {}, pages = {105949}, doi = {10.1016/j.fitote.2024.105949}, pmid = {38583636}, issn = {1873-6971}, mesh = {*Aristolochia/chemistry ; Animals ; *Plant Extracts/pharmacology/chemistry ; Larva/drug effects ; Phytochemicals/pharmacology/isolation & purification ; Microbial Sensitivity Tests ; Humans ; Antioxidants/pharmacology ; Bacillus cereus/drug effects ; Anti-Infective Agents/pharmacology/chemistry ; Anti-Bacterial Agents/pharmacology/chemistry ; Moths/drug effects ; }, abstract = {Aristolochia plants are emblematic from an ethnopharmacological viewpoint and are know to possess numerous biological properties, including antiseptic. However, the medicinal potential of these species is debatable because of their representative chemical constituents, aristolochic acids (AAs) and aristolactams (ALs), which are associated, for instance, with nephropathy and cancer. These contrasting issues have stimulated the development of approaches intended to detoxification of aristoloquiaceous biomasses, among which is included the bioconversion method using larvae of the specialist phytophagous insect Battus polydamas, previously shown to be viable for chemical diversification and to reduce toxicity. Thus, eleven Aristolochia spp. were bioconverted, and the antimicrobial activities of the plant methanolic extracts and its respective bioconversion products were evaluated. The best results were found for Aristolochia esperanzae, Aristolochia gibertii, and Aristolochia ringens against Bacillus cereus, with MIC ranging from 7.8 to 31.25 μg/mL. These three species were selected for chemical, antioxidant, cytotoxic, hemolytic, and mutagenic analyses. Chemical analysis revealed 65 compounds, 21 of them possible bioconversion products. The extracts showed potential to inhibit the formation and degradation of B. cereus biofilms. Extracts of A. gibertii and its bioconverted biomass showed antioxidant activity comparable to dibutylhydroxytoluene (BHT) standard. Bioconversion decreased the hemolytic activity of A. esperanzae and the cytotoxicities of A. esperanzae and A. gibertii. None of the extracts was found to be mutagenic. The bioactivities of the fecal extracts were maintained, and biocompatibility was improved. Therefore, the results obtained in this study reveal positive expectations about the natural detoxification process of the Aristolochia species.}, } @article {pmid38583639, year = {2024}, author = {Genin, EC and di Borgo, PP and Lorivel, T and Hugues, S and Farinelli, M and Mauri-Crouzet, A and Lespinasse, F and Godin, L and Paquis-Flucklinger, V and Petit-Paitel, A}, title = {CHCHD10[S59L/+] mouse model: Behavioral and neuropathological features of frontotemporal dementia.}, journal = {Neurobiology of disease}, volume = {195}, number = {}, pages = {106498}, doi = {10.1016/j.nbd.2024.106498}, pmid = {38583639}, issn = {1095-953X}, mesh = {Animals ; *Frontotemporal Dementia/pathology/genetics ; *Disease Models, Animal ; Mice ; *Mitochondrial Proteins/genetics/metabolism ; Mice, Transgenic ; Behavior, Animal/physiology ; Male ; Long-Term Potentiation/physiology ; Mice, Inbred C57BL ; Hippocampus/pathology/metabolism ; }, abstract = {CHCHD10-related disease causes a spectrum of clinical presentations including mitochondrial myopathy, cardiomyopathy, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We generated a knock-in mouse model bearing the p.Ser59Leu (S59L) CHCHD10 variant. Chchd10[S59L/+] mice have been shown to phenotypically replicate the disorders observed in patients: myopathy with mtDNA instability, cardiomyopathy and typical ALS features (protein aggregation, neuromuscular junction degeneration and spinal motor neuron loss). Here, we conducted a comprehensive behavioral, electrophysiological and neuropathological assessment of Chchd10[S59L/+] mice. These animals show impaired learning and memory capacities with reduced long-term potentiation (LTP) measured at the Perforant Pathway-Dentate Gyrus (PP-DG) synapses. In the hippocampus of Chchd10[S59L/+] mice, neuropathological studies show the involvement of protein aggregates, activation of the integrated stress response (ISR) and neuroinflammation in the degenerative process. These findings contribute to decipher mechanisms associated with CHCHD10 variants linking mitochondrial dysfunction and neuronal death. They also validate the Chchd10[S59L/+] mice as a relevant model for FTD, which can be used for preclinical studies to test new therapeutic strategies for this devastating disease.}, } @article {pmid38583866, year = {2024}, author = {Lee, SH and Hong, WP and Kim, YS and Park, J and Lim, HJ}, title = {Dual-dispatch protocols and return of spontaneous circulation in patients with out-of-hospital cardiac arrest: a nationwide observational study.}, journal = {Clinical and experimental emergency medicine}, volume = {11}, number = {3}, pages = {276-285}, pmid = {38583866}, issn = {2383-4625}, abstract = {OBJECTIVE: The Korean National Fire Agency conducted a pilot project examining Advanced Life Support (ALS) protocols, including epinephrine administration, to improve survival among patients suffering out-of-hospital cardiac arrest (OHCA). In this study, we aimed to evaluate the effects of the Korean National Fire Agency ALS protocol on prehospital return of spontaneous circulation (ROSC) in patients with OHCA.

METHODS: This study included patients with adult-presumed cardiac arrest between January and December 2020. The main factor of interest was ambulance type according to ALS protocol, which was divided into dedicated ALS ambulance (DA), smartphone-based ALS ambulance (SALS), and non-DA, and the main analysis factor was prehospital ROSC. Multivariate logistic regression analysis was performed.

RESULTS: During the study period, a total of 18,031 adult patients with OHCA was treated by the emergency medical services, including 7,520 DAs (41.71%), 2,622 SALSs (14.54%), and 7,889 non-DAs (43.75%). The prehospital ROSC ratio was 13.19% for DA, 11.17% for SALS, and 7.91% for non-DA (P<0.01). Compared with that of the DA group, the odds ratios (95% confidence interval) for prehospital ROSC ratio were 0.97 (0.82-1.15) in the SALS group and 0.57 (0.50-0.65) in the non-DA group. The prehospital ROSC ratio of the DA group was higher than those of the non-DA group and the SALS group.

CONCLUSION: ALS protocol intervention was associated with prehospital ROSC rates. Therefore, continuous efforts to promote systemic implementation of the ALS protocol to improve OHCA outcomes are necessary.}, } @article {pmid38585368, year = {2024}, author = {Jamet, M and Dupuis, L and Gonzalez De Aguilar, JL}, title = {Oligodendrocytes in amyotrophic lateral sclerosis and frontotemporal dementia: the new players on stage.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1375330}, pmid = {38585368}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal adult-onset neurodegenerative disorders that share clinical, neuropathological and genetic features, which forms part of a multi-system disease spectrum. The pathological process leading to ALS and FTD is the result of the combination of multiple mechanisms that operate within specific populations of neurons and glial cells. The implication of oligodendrocytes has been the subject of a number of studies conducted on patients and related animal models. In this review we summarize our current knowledge on the alterations specific to myelin and the oligodendrocyte lineage occurring in ALS and FTD. We also consider different ways by which specific oligodendroglial alterations influence neurodegeneration and highlight the important role of oligodendrocytes in these two intrinsically associated neurodegenerative diseases.}, } @article {pmid38585517, year = {2023}, author = {Firstenfeld, AJ and Listorti, J and Jalaff, N and Loaiza Orozco, CP and Navarrete Gosdenovich, F and Schurr, T}, title = {Add-on treatment with Cerebrolysin improves clinical symptoms in patients with ALS: results from a prospective, single-center, placebo-controlled, randomized, double-blind, phase II study.}, journal = {Journal of medicine and life}, volume = {16}, number = {12}, pages = {1750-1755}, pmid = {38585517}, issn = {1844-3117}, mesh = {Humans ; *Amino Acids ; *Amyotrophic Lateral Sclerosis/drug therapy/diagnosis ; *Neuroprotective Agents/therapeutic use ; Prospective Studies ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and progressive neurodegenerative disease with limited treatment options available. Cerebrolysin is a drug candidate for the treatment of ALS because of its neuroprotective and neuroregenerative effects. We initiated a pilot clinical study of a combination of Cerebrolysin and riluzole to assess the therapeutic benefit of Cerebrolysin as an add-on treatment on clinical signs and symptoms in outpatients with ALS. Twenty patients with a clinically definitive diagnosis of ALS were enrolled and randomly assigned in a 1:1 ratio to receive Cerebrolysin or placebo. All patients received 50 mg of riluzole PO twice daily as a standard treatment. Patients in the Cerebrolysin group received intravenous injections of 10 mL of Cerebrolysin once daily, five days a week for the first month and three days a week for the next two months. Analysis of the ALS Functional Rating Scale - revised at Month 1 (primary outcome measure), showed a significant treatment effect in favor of Cerebrolysin with a 2.3-point improvement from baseline to Month 1 compared to a 0.9-point decrease in patients on placebo (P=0.005). The effect was maintained over the three-month study period, and the beneficial effect of Cerebrolysin over placebo was also evident in the secondary outcome measures. The safety analysis showed that the combination of riluzole and Cerebrolyisn was well tolerated. Our results demonstrate for the first time a significant clinical effect of Cerebrolysin in improving functional outcomes in patients with ALS and suggest that Cerebrolysin has potential as a novel therapeutic option for ALS.}, } @article {pmid38585631, year = {2024}, author = {Pinilla-González, V and Montecinos-Barrientos, B and Martin-Kommer, C and Chichiarelli, S and Saso, L and Rodrigo, R}, title = {Exploring antioxidant strategies in the pathogenesis of ALS.}, journal = {Open life sciences}, volume = {19}, number = {1}, pages = {20220842}, pmid = {38585631}, issn = {2391-5412}, abstract = {The central nervous system is essential for maintaining homeostasis and controlling the body's physiological functions. However, its biochemical characteristics make it highly vulnerable to oxidative damage, which is a common factor in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). ALS is a leading cause of motor neuron disease, characterized by a rapidly progressing and incurable condition. ALS often results in death from respiratory failure within 3-5 years from the onset of the first symptoms, underscoring the urgent need to address this medical challenge. The aim of this study is to present available data supporting the role of oxidative stress in the mechanisms underlying ALS and to discuss potential antioxidant therapies currently in development. These therapies aim to improve the quality of life and life expectancy for patients affected by this devastating disease.}, } @article {pmid38585660, year = {2024}, author = {Zhang, H and Chen, C and Zhang, EE and Huang, X}, title = {TDP-43 deficiency in suprachiasmatic nucleus perturbs rhythmicity of neuroactivity in prefrontal cortex.}, journal = {iScience}, volume = {27}, number = {4}, pages = {109522}, pmid = {38585660}, issn = {2589-0042}, abstract = {Individuals within the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD) often experience disruptive mental behaviors and sleep-wake disturbances. The hallmark of ALS/FTD is the pathological involvement of TAR DNA-binding protein 43 (TDP-43). Understanding the role of TDP-43 in the circadian clock holds promise for addressing these behavioral abnormalities. In this study, we unveil TDP-43 as a pivotal regulator of the circadian clock. TDP-43 knockdown induces intracellular arrhythmicity, disrupts transcriptional activation regulation, and diminishes clock genes expression. Moreover, our experiments in adult mouse reveal that TDP-43 knockdown, specifically within the suprachiasmatic nucleus (SCN), induces locomotor arrhythmia, arrhythmic c-Fos expression, and depression-like behavior. This observation offers valuable insights into the substantial impact of TDP-43 on the behavioral aberrations associated with ALS/FTD. In summary, our study illuminates the significance of TDP-43 in circadian regulation, shedding light on the circadian regulatory mechanisms that may elucidate the pathological underpinnings of ALS/FTD.}, } @article {pmid38585669, year = {2024}, author = {Novy, C and Busk, ØL and Tysnes, OB and Landa, SS and Aanjesen, TN and Alstadhaug, KB and Bjerknes, TL and Bjørnå, IK and Bråthen, G and Dahl, E and Demic, N and Fahlström, M and Flemmen, HØ and Hallerstig, E and HogenEsch, I and Kampman, MT and Kleveland, G and Kvernmo, HB and Ljøstad, U and Maniaol, A and Morsund, AH and Nakken, O and Olsen, CG and Schlüter, K and Utvik, MS and Yaseen, R and Holla, ØL and Holmøy, T and Høyer, H}, title = {Repeat expansions in AR, ATXN1, ATXN2 and HTT in Norwegian patients diagnosed with amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {2}, pages = {fcae087}, pmid = {38585669}, issn = {2632-1297}, abstract = {Genetic repeat expansions cause neuronal degeneration in amyotrophic lateral sclerosis as well as other neurodegenerative disorders such as spinocerebellar ataxia, Huntington's disease and Kennedy's disease. Repeat expansions in the same gene can cause multiple clinical phenotypes. We aimed to characterize repeat expansions in a Norwegian amyotrophic lateral sclerosis cohort. Norwegian amyotrophic lateral sclerosis patients (n = 414) and neurologically healthy controls adjusted for age and gender (n = 713) were investigated for repeat expansions in AR, ATXN1, ATXN2 and HTT using short read exome sequencing and the ExpansionHunter software. Five amyotrophic lateral sclerosis patients (1.2%) and two controls (0.3%) carried ≥36 repeats in HTT (P = 0.032), and seven amyotrophic lateral sclerosis patients (1.7%) and three controls (0.4%) carried ≥29 repeats in ATXN2 (P = 0.038). One male diagnosed with amyotrophic lateral sclerosis carried a pathogenic repeat expansion in AR, and his diagnosis was revised to Kennedy's disease. In ATXN1, 50 amyotrophic lateral sclerosis patients (12.1%) and 96 controls (13.5%) carried ≥33 repeats (P = 0.753). None of the patients with repeat expansions in ATXN2 or HTT had signs of Huntington's disease or spinocerebellar ataxia type 2, based on a re-evaluation of medical records. The diagnosis of amyotrophic lateral sclerosis was confirmed in all patients, with the exception of one patient who had primary lateral sclerosis. Our findings indicate that repeat expansions in HTT and ATXN2 are associated with increased likelihood of developing amyotrophic lateral sclerosis. Further studies are required to investigate the potential relationship between HTT repeat expansions and amyotrophic lateral sclerosis.}, } @article {pmid38585670, year = {2024}, author = {Cipriano, L and Minino, R and Liparoti, M and Polverino, A and Romano, A and Bonavita, S and Pirozzi, MA and Quarantelli, M and Jirsa, V and Sorrentino, G and Sorrentino, P and Troisi Lopez, E}, title = {Flexibility of brain dynamics is increased and predicts clinical impairment in relapsing-remitting but not in secondary progressive multiple sclerosis.}, journal = {Brain communications}, volume = {6}, number = {2}, pages = {fcae112}, pmid = {38585670}, issn = {2632-1297}, abstract = {Large-scale brain activity has long been investigated under the erroneous assumption of stationarity. Nowadays, we know that resting-state functional connectivity is characterized by aperiodic, scale-free bursts of activity (i.e. neuronal avalanches) that intermittently recruit different brain regions. These different patterns of activity represent a measure of brain flexibility, whose reduction has been found to predict clinical impairment in multiple neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease. Brain flexibility has been recently found increased in multiple sclerosis, but its relationship with clinical disability remains elusive. Also, potential differences in brain dynamics according to the multiple sclerosis clinical phenotypes remain unexplored so far. We performed a brain dynamics study quantifying brain flexibility utilizing the 'functional repertoire' (i.e. the number of configurations of active brain areas) through source reconstruction of magnetoencephalography signals in a cohort of 25 multiple sclerosis patients (10 relapsing-remitting multiple sclerosis and 15 secondary progressive multiple sclerosis) and 25 healthy controls. Multiple sclerosis patients showed a greater number of unique reconfigurations at fast time scales as compared with healthy controls. This difference was mainly driven by the relapsing-remitting multiple sclerosis phenotype, whereas no significant differences in brain dynamics were found between secondary progressive multiple sclerosis and healthy controls. Brain flexibility also showed a different predictive power on clinical disability according to the multiple sclerosis type. For the first time, we investigated brain dynamics in multiple sclerosis patients through high temporal resolution techniques, unveiling differences in brain flexibility according to the multiple sclerosis phenotype and its relationship with clinical disability.}, } @article {pmid38585725, year = {2024}, author = {Sinha, IR and Sandal, PS and Burns, GD and Mallika, AP and Irwin, KE and Cruz, ALF and Wang, V and Rodríguez, JL and Wong, PC and Ling, JP}, title = {Large-scale RNA-seq mining reveals ciclopirox triggers TDP-43 cryptic exons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38585725}, issn = {2692-8205}, support = {R01 NS095969/NS/NINDS NIH HHS/United States ; T32 NS091018/NS/NINDS NIH HHS/United States ; R33 NS115161/NS/NINDS NIH HHS/United States ; U01 FD008129/FD/FDA HHS/United States ; UH3 NS115608/NS/NINDS NIH HHS/United States ; }, abstract = {Nuclear clearance and cytoplasmic aggregation of TDP-43 in neurons, initially identified in ALS-FTD, are hallmark pathological features observed across a spectrum of neurodegenerative diseases. We previously found that TDP-43 loss-of-function leads to the transcriptome-wide inclusion of deleterious cryptic exons in brains and biofluids post-mortem as well as during the presymptomatic stage of ALS-FTD, but upstream mechanisms that lead to TDP-43 dysregulation remain unclear. Here, we developed a web-based resource (SnapMine) to determine the levels of TDP-43 cryptic exon inclusion across hundreds of thousands of publicly available RNA sequencing datasets. We established cryptic exon inclusion across a variety of human cells and tissues to provide ground truth references for future studies on TDP-43 dysregulation. We then explored studies that were entirely unrelated to TDP-43 or neurodegeneration and found that ciclopirox olamine (CPX), an FDA-approved antifungal, can trigger the inclusion of TDP-43-associated cryptic exons in a variety of mouse and human primary cells. CPX induction of cryptic exon occurs via heavy metal toxicity and oxidative stress, suggesting that similar vulnerabilities could play a role in neurodegeneration. Our work demonstrates how diverse datasets can be linked through common biological features and underscores that public archives of sequencing data represent a vastly underutilized resource with tremendous potential for uncovering novel insights into complex biological mechanisms and diseases.}, } @article {pmid38585774, year = {2024}, author = {Yu, M and Xu, J and Dutta, R and Trapp, B and Pieper, AA and Cheng, F}, title = {Network medicine informed multi-omics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38585774}, issn = {2692-8205}, support = {R21 AG083003/AG/NIA NIH HHS/United States ; R01 AG082118/AG/NIA NIH HHS/United States ; R56 AG074001/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; RF1 NS133812/NS/NINDS NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; R01 AG076448/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. To date, the challenge to establishing effective treatment for ALS remains formidable, partly due to inadequate translation of existing human genetic findings into actionable ALS-specific pathobiology for subsequent therapeutic development. This study evaluates the feasibility of network medicine methodology via integrating human brain-specific multi-omics data to prioritize drug targets and repurposable treatments for ALS. Using human brain-specific genome-wide quantitative trait loci (x-QTLs) under a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in various known ALS pathobiological pathways, including regulation of T cell activation, monocyte differentiation, and lymphocyte proliferation. Specifically, we leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on brain-specific expression quantitative trait loci (QTL) (eQTL), protein QTLs (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Applying network proximity analysis of predicted ALS-associated gene-coding targets and existing drug-target networks under the human protein-protein interactome (PPI) model, we identified a set of potential repurposable drugs (including Diazoxide, Gefitinib, Paliperidone, and Dimethyltryptamine) for ALS. Subsequent validation established preclinical and clinical evidence for top-prioritized repurposable drugs. In summary, we presented a network-based multi-omics framework to identify potential drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.}, } @article {pmid38585891, year = {2024}, author = {Antonucci, S and Caron, G and Dikwella, N and Krishnamurty, SS and Harster, A and Zarrin, H and Tahanis, A and Heuvel, FO and Danner, SM and Ludolph, AC and Grycz, K and Bączyk, M and Zytnicki, D and Roselli, F}, title = {Spinal motoneuron excitability is homeostatically-regulated through β-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38585891}, issn = {2692-8205}, support = {R01 NS110953/NS/NINDS NIH HHS/United States ; R01 NS112304/NS/NINDS NIH HHS/United States ; R01 NS115900/NS/NINDS NIH HHS/United States ; }, abstract = {Homeostatic feedback loops are essential to stabilize the activity of neurons and neuronal networks. It has been hypothesized that, in the context of Amyotrophic Lateral Sclerosis (ALS), an excessive gain in feedback loops might hyper- or hypo-excite motoneurons (MNs) and contribute to the pathogenesis. Here, we investigated how the neuromodulation of MN intrinsic properties is homeostatically controlled in presymptomatic adult SOD1(G93A) mice and in the age-matched control WT mice. First, we determined that β2 and β3- adrenergic receptors, which are Gs-coupled receptors and subject to tight and robust feedback loops, are specifically expressed in spinal MNs of both SOD1 and WT mice at P45. We then demonstrated that these receptors elicit a so-far overlooked neuromodulation of the firing and excitability properties of MNs. These electrical properties are homeostatically regulated following receptor engagement, which triggers ion channel transcriptional changes and downregulates those receptors. These homeostatic feedbacks are not dysregulated in presymptomatic SOD1 mice, and they set the MN excitability upon β-adrenergic neuromodulation.}, } @article {pmid38585910, year = {2024}, author = {Jin, W and Boss, J and Bakulski, KM and Goutman, SA and Feldman, EL and Fritsche, LG and Mukherjee, B}, title = {Improving prediction models of amyotrophic lateral sclerosis (ALS) using polygenic, pre-existing conditions, and survey-based risk scores in the UK Biobank.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38585910}, support = {R01TS000344/ACL/ACL HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) causes profound impairments in neurological function and a cure for this devastating disease remains elusive. Early detection and risk stratification are crucial for timely intervention and improving patient outcomes. This study aimed to identify predisposing genetic, phenotypic, and exposure-related factors for Amyotrophic lateral sclerosis using multi-modal data and assess their joint predictive potential.

METHODS: Utilizing data from the UK Biobank, we analyzed an unrelated set of 292 ALS cases and 408,831 controls of European descent. Two polygenic risk scores (PRS) are constructed: "GWAS Hits PRS" and "PRS-CS," reflecting oligogenic and polygenic ALS risk profiles, respectively. Time-restricted phenome-wide association studies (PheWAS) were performed to identify pre-existing conditions increasing ALS risk, integrated into phenotypic risk scores (PheRS). A poly-exposure score ("PXS") captures the influence of environmental exposures measured through survey questionnaires. We evaluate the performance of these scores for predicting ALS incidence and stratifying risk, adjusting for baseline demographic covariates.

RESULTS: Both PRSs modestly predicted ALS diagnosis, but with increased predictive power when combined (covariate-adjusted receiver operating characteristic [AAUC] = 0.584 [0.525, 0.639]). PheRS incorporated diagnoses 1 year before ALS onset (PheRS1) modestly discriminated cases from controls (AAUC = 0.515 [0.472, 0.564]). The "PXS" did not significantly predict ALS. However, a model incorporating PRSs and PheRS1 improved prediction of ALS (AAUC = 0.604 [0.547, 0.667]), outperforming a model combining all risk scores. This combined risk score identified the top 10% of risk score distribution with a 4-fold higher ALS risk (95% CI: [2.04, 7.73]) versus those in the 40%-60% range.

DISCUSSIONS: By leveraging UK Biobank data, our study uncovers predisposing ALS factors, highlighting the improved effectiveness of multi-factorial prediction models to identify individuals at highest risk for ALS.}, } @article {pmid38585915, year = {2024}, author = {Martin, EJ and Santacruz, C and Mitevska, A and Jones, IE and Krishnan, G and Gao, FB and Finan, JD and Kiskinis, E}, title = {Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derived C9orf72-associated ALS/FTD motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38585915}, issn = {2692-8205}, support = {RF1 NS101986/NS/NINDS NIH HHS/United States ; R01 NS134166/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; R01 NS113935/NS/NINDS NIH HHS/United States ; R01 NS104219/NS/NINDS NIH HHS/United States ; }, abstract = {A hexanucleotide repeat expansion (HRE) in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, patients with the HRE exhibit a wide disparity in clinical presentation and age of symptom onset suggesting an interplay between genetic background and environmental stressors. Neurotrauma as a result of traumatic brain or spinal cord injury has been shown to increase the risk of ALS/FTD in epidemiological studies. Here, we combine patient-specific induced pluripotent stem cells (iPSCs) with a custom-built device to deliver biofidelic stretch trauma to C9orf72 patient and isogenic control motor neurons (MNs) in vitro. We find that mutant but not control MNs exhibit selective degeneration after a single incident of severe trauma, which can be partially rescued by pretreatment with a C9orf72 antisense oligonucleotide. A single incident of mild trauma does not cause degeneration but leads to cytoplasmic accumulation of TDP-43 in C9orf72 MNs. This mislocalization, which only occurs briefly in isogenic controls, is eventually restored in C9orf72 MNs after 6 days. Lastly, repeated mild trauma ablates the ability of patient MNs to recover. These findings highlight alterations in TDP-43 dynamics in C9orf72 ALS/FTD patient MNs following traumatic injury and demonstrate that neurotrauma compounds neuropathology in C9orf72 ALS/FTD. More broadly, our work establishes an in vitro platform that can be used to interrogate the mechanistic interactions between ALS/FTD and neurotrauma.}, } @article {pmid38585945, year = {2024}, author = {Haider, R and Shipley, B and Surewicz, K and Hinczewski, M and Surewicz, WK}, title = {Pathological C-terminal phosphomimetic substitutions alter the mechanism of liquid-liquid phase separation of TDP-43 low complexity domain.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38585945}, issn = {2692-8205}, support = {RF1 AG061797/AG/NIA NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; T32 NS077888/NS/NINDS NIH HHS/United States ; }, abstract = {C-terminally phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) marks the proteinaceous inclusions that characterize a number of age-related neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration and Alzheimer's disease. TDP-43 phosphorylation at S403/S404, and especially at S409/S410, is in fact accepted as a biomarker of proteinopathy. These residues are located within the low complexity domain (LCD), which also drives the protein's liquid-liquid phase separation (LLPS). The impact of phosphorylation at these LCD sites on phase separation of the protein is a topic of great interest, as these post-translational modifications and LLPS are both implicated in proteinopathies. Here, we employed a combination of experimental and simulation-based approaches to explore this question on a phosphomimetic model of the TDP-43 LCD. Our turbidity and fluorescence microscopy data show that Ser-to-Asp substitutions at residues S403, S404, S409 and S410 alter the LLPS behavior of TDP-43 LCD. In particular, in contrast to the unmodified protein, the phosphomimetic variants display a biphasic dependence on salt concentration. Through coarse-grained modeling, we find that this biphasic salt dependence is derived from an altered mechanism of phase separation, in which LLPS-driving short-range intermolecular hydrophobic interactions are modulated by long-range attractive electrostatic interactions. Overall, this in vitro and in silico study provides a physiochemical foundation for understanding the impact of pathologically-relevant C-terminal phosphorylation on the LLPS of the TDP-43 in a more complex cellular environment.}, } @article {pmid38586597, year = {2024}, author = {Zhang, T and Bao, L and Chen, H}, title = {Review of Phenotypic Heterogeneity of Neuronal Intranuclear Inclusion Disease and NOTCH2NLC-Related GGC Repeat Expansion Disorders.}, journal = {Neurology. Genetics}, volume = {10}, number = {2}, pages = {e200132}, pmid = {38586597}, issn = {2376-7839}, abstract = {Neuronal intranuclear inclusion disease (NIID) is an underdiagnosed neurodegenerative disorder caused by pathogenic GGC expansions in NOTCH2NLC. However, an increasing number of reports of NOTCH2NLC GGC expansions in patients with Alzheimer disease, essential tremor, Parkinson disease, amyotrophic lateral sclerosis, and oculopharyngodistal myopathy have led to the proposal of a new concept known as NOTCH2NLC-related GGC repeat expansion disorders (NREDs). The majority of studies have mainly focused on screening for NOTCH2NLC GGC repeat variation in populations previously diagnosed with the associated disease, subsequently presenting it as a novel causative gene for the condition. These studies appear to be clinically relevant but do have their limitations because they may incorrectly regard the lack of MRI abnormalities as an exclusion criterion for NIID or overlook concomitant clinical presentations not typically observed in the associated diseases. Besides, in many instances within these reports, patients lack pathologic evidence or undergo long-term follow-up to conclusively rule out NIID. In this review, we will systematically review the research on NOTCH2NLC 5' untranslated region GGC repeat expansions and their association with related neurologic disorders, explaining the limitations of the relevant reports. Furthermore, we will integrate subsequent studies to further demonstrate that these patients actually experienced distinct clinical phenotypes of NIID.}, } @article {pmid38588013, year = {2024}, author = {El Hajj, R and Al Sagheer, T and Ballout, N}, title = {Optogenetics in chronic neurodegenerative diseases, controlling the brain with light: A systematic review.}, journal = {Journal of neuroscience research}, volume = {102}, number = {4}, pages = {e25321}, doi = {10.1002/jnr.25321}, pmid = {38588013}, issn = {1097-4547}, mesh = {*Optogenetics/methods ; Animals ; *Neurodegenerative Diseases/therapy/genetics ; Humans ; *Brain/metabolism ; Disease Models, Animal ; Neurons/physiology/metabolism ; Deep Brain Stimulation/methods ; }, abstract = {Neurodegenerative diseases are progressive disorders characterized by synaptic loss and neuronal death. Optogenetics combines optical and genetic methods to control the activity of specific cell types. The efficacy of this approach in neurodegenerative diseases has been investigated in many reviews, however, none of them tackled it systematically. Our study aimed to review systematically the findings of optogenetics and its potential applications in animal models of chronic neurodegenerative diseases and compare it with deep brain stimulation and designer receptors exclusively activated by designer drugs techniques. The search strategy was performed based on the PRISMA guidelines and the risk of bias was assessed following the Systematic Review Centre for Laboratory Animal Experimentation tool. A total of 247 articles were found, of which 53 were suitable for the qualitative analysis. Our data revealed that optogenetic manipulation of distinct neurons in the brain is efficient in rescuing memory impairment, alleviating neuroinflammation, and reducing plaque pathology in Alzheimer's disease. Similarly, this technique shows an advanced understanding of the contribution of various neurons involved in the basal ganglia pathways with Parkinson's disease motor symptoms and pathology. However, the optogenetic application using animal models of Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis was limited. Optogenetics is a promising technique that enhanced our knowledge in the research of neurodegenerative diseases and addressed potential therapeutic solutions for managing these diseases' symptoms and delaying their progression. Nevertheless, advanced investigations should be considered to improve optogenetic tools' efficacy and safety to pave the way for their translatability to the clinic.}, } @article {pmid38589279, year = {2024}, author = {Iwasaki, Y}, title = {[Neuropathology of the Neurodegenerative Diseases].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {4}, pages = {343-351}, doi = {10.11477/mf.1416202611}, pmid = {38589279}, issn = {1881-6096}, mesh = {Humans ; tau Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; *Tauopathies/metabolism/pathology ; *Pick Disease of the Brain/metabolism/pathology ; *Frontotemporal Dementia ; *Frontotemporal Lobar Degeneration ; *Multiple System Atrophy ; DNA-Binding Proteins/metabolism ; }, abstract = {A definite diagnosis of neurodegenerative diseases is required for neuropathological examination during an autopsy. Each neurodegenerative disease has specific vulnerable regions and affected systems (system degeneration), and is typified by an accumulation of abnormal protein with the formation of characteristic morphological aggregates in the nerve and glial cells, called proteinopathy. The most common neurodegenerative diseases are tauopathy, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD); α-synucleinopathy, including multiple system atrophy (MSA); and TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). PSP and CBD show characteristic tau-positive astrocytic inclusions known as tufted astrocytes and astrocytic plaques, respectively. PiD shows tau-positive neuronal inclusions termed Pick bodies. MSA is characterized by α-synuclein-positive oligodendroglial inclusions, called glial cytoplasmic inclusions. ALS- and FTLD-TDP show TDP-43-positive neuronal inclusions, such as skein-like and round inclusions. Huntington's disease shows polyglutamine-positive neuronal inclusions, and Creutzfeldt-Jakob disease shows diffuse deposition of granular prions in the neuropil. The atypical proteins in these diseases have abnormal conformational properties. A comprehensive comparison of the clinical findings and neuropathological observations, including neuroanatomy and images acquired during life, is important to improve the sensitivity of clinical diagnosis.}, } @article {pmid38590640, year = {2024}, author = {Scaricamazza, S and Nesci, V and Salvatori, I and Fenili, G and Rosina, M and Gloriani, M and Paronetto, MP and Madaro, L and Ferri, A and Valle, C}, title = {Endurance exercise has a negative impact on the onset of SOD1-G93A ALS in female mice and affects the entire skeletal muscle-motor neuron axis.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1360099}, pmid = {38590640}, issn = {1663-9812}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by the degeneration of motor neurons that leads to muscle wasting and atrophy. Epidemiological and experimental evidence suggests a causal relationship between ALS and physical activity (PA). However, the impact of PA on motor neuron loss and sarcopenia is still debated, probably because of the heterogeneity and intensities of the proposed exercises. With this study, we aimed to clarify the effect of intense endurance exercise on the onset and progression of ALS in the SOD1-G93A mouse model.

METHODS: We randomly selected four groups of twelve 35-day-old female mice. SOD1-G93A and WT mice underwent intense endurance training on a motorized treadmill for 8 weeks, 5 days a week. During the training, we measured muscle strength, weight, and motor skills and compared them with the corresponding sedentary groups to define the disease onset. At the end of the eighth week, we analyzed the skeletal muscle-motor neuron axis by histological and molecular techniques.

RESULTS: Intense endurance exercise anticipates the onset of the disease by 1 week (age of the onset: trained SOD1-G93A = 63.17 ± 2.25 days old; sedentary SOD1-G93A = 70.75 ± 2.45 days old). In SOD1-G93A mice, intense endurance exercise hastens the muscular switch to a more oxidative phenotype and worsens the denervation process by dismantling neuromuscular junctions in the tibialis anterior, enhancing the Wallerian degeneration in the sciatic nerve, and promoting motor neuron loss in the spinal cord. The training exacerbates neuroinflammation, causing immune cell infiltration in the sciatic nerve and a faster activation of astrocytes and microglia in the spinal cord.

CONCLUSION: Intense endurance exercise, acting on skeletal muscles, worsens the pathological hallmarks of ALS, such as denervation and neuroinflammation, brings the onset forward, and accelerates the progression of the disease. Our findings show the potentiality of skeletal muscle as a target for both prognostic and therapeutic strategies; the preservation of skeletal muscle health by specific intervention could counteract the dying-back process and protect motor neurons from death. The physiological characteristics and accessibility of skeletal muscle further enhance its appeal as a therapeutic target.}, } @article {pmid38591179, year = {2024}, author = {Talbott, EO and Malek, AM and Arena, VC and Wu, F and Steffes, K and Sharma, RK and Buchanich, J and Rager, JR and Bear, T and Hoffman, CA and Lacomis, D and Donnelly, C and Mauna, J and Vena, JE}, title = {Case-control study of environmental toxins and risk of amyotrophic lateral sclerosis involving the national ALS registry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {533-542}, doi = {10.1080/21678421.2024.2336108}, pmid = {38591179}, issn = {2167-9223}, support = {R01 TS000272/TS/ATSDR CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/blood/chemically induced ; Male ; Female ; Middle Aged ; Case-Control Studies ; *Registries ; Aged ; Risk Factors ; *Environmental Exposure/adverse effects/statistics & numerical data ; Occupational Exposure/adverse effects/statistics & numerical data ; Pesticides/blood/adverse effects ; United States/epidemiology ; }, abstract = {OBJECTIVE: Neurotoxic chemicals are suggested in the etiology of amyotrophic lateral sclerosis (ALS). We examined the association of environmental and occupational risk factors including persistent organochlorine pesticides (OCPs) and ALS risk among cases from the Centers for Disease Control and Prevention National ALS Registry and age, sex, and county-matched controls.

METHODS: Participants completed a risk factor survey and provided a blood sample for OCP measurement. ALS cases were confirmed through the Registry. Conditional logistic regression assessed associations between ALS and risk factors including OCP levels.

RESULTS: 243 matched case-control pairs (61.7% male, mean [SD] age = 62.9 [10.1]) were included. Fifteen of the 29 OCPs examined had sufficient detectable levels for analysis. Modest correlations of self-reported years of exposure to residential pesticide mixtures and OCP serum levels were found (p<.001). Moreover, occupational exposure to lead including soldering and welding with lead/metal dust and use of lead paint/gasoline were significantly related to ALS risk (OR = 1.77, 95% CI: 1.11-2.83). Avocational gardening was a significant risk factor for ALS (OR = 1.57, 95% CI: 1.04-2.37). ALS risk increased for each 10 ng/g of α-Endosulfan (OR = 1.42, 95% CI: 1.14-1.77) and oxychlordane (OR = 1.24, 95% CI: 1.01-1.53). Heptachlor (detectable vs. nondetectable) was also associated with ALS risk (OR = 3.57, 95% CI: 1.50-8.52).

CONCLUSION: This national case-control study revealed both survey and serum levels of OCPs as risk factors for ALS. Despite the United States banning many OCPs in the 1970s and 1980s, their use abroad and long half-lives continue to exert possible neurotoxic health effects.}, } @article {pmid38591193, year = {2024}, author = {Rhodes, E and Alfa, S and Jin, HA and Massimo, L and Elman, L and Amado, D and Baer, M and Quinn, C and McMillan, CT}, title = {Cognitive reserve in ALS: the role of occupational skills and requirements.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {486-495}, pmid = {38591193}, issn = {2167-9223}, support = {K23 AG083124/AG/NIA NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; K01 AG061277/AG/NIA NIH HHS/United States ; K08 NS114106/NS/NINDS NIH HHS/United States ; P30 AG073105/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG054519/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/physiopathology/complications/diagnosis ; *Cognitive Reserve/physiology ; Male ; Female ; Middle Aged ; Aged ; Neuropsychological Tests ; Cognitive Dysfunction/etiology/physiopathology/diagnosis/psychology ; Adult ; Occupations ; }, abstract = {OBJECTIVE: Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative condition featuring variable degrees of motor and cognitive impairment. We assessed the impact of specific, empirically derived occupational skills and requirements on cognitive and motor functioning in ALS.

METHODS: Individuals with ALS (n = 150) were recruited from the University of Pennsylvania's Comprehensive ALS Clinic. The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) measured cognition, and the Penn Upper Motor Neuron (PUMNS) and ALS Functional Rating Scales (ALSFRS-R) measured motor symptoms. We derived 17 factors representing distinct occupational skills and requirements from the Occupational Information Network (O*NET), which were related to cognitive and motor scores using multiple linear regression.

RESULTS: Occupational roles involving greater reasoning ability (β = 2.12, p < .05), social ability (β = 1.73, p < .05), analytic skills, (β = 3.12, p < .01) and humanities knowledge (β = 1.83, p<.01) were associated with better performance on the ECAS, while jobs involving more exposure to environmental hazards (β=-2.57, p < .01) and technical skills (β=-2.16, p<.01) were associated with lower ECAS scores. Jobs requiring more precision skills (β = 1.91, p < .05) were associated with greater motor dysfunction on the PUMNS.

CONCLUSIONS: Occupational histories involving more cognitively complex skills and activities were related to preserved cognitive functioning in ALS consistent with the cognitive reserve hypothesis, while jobs with greater exposure to environmental hazards and technical demands were linked to poorer cognitive functioning. Jobs involving more repetitive movements were associated with worse motor functioning, possibly due to overuse. Occupational history provides insight into protective and risk factors for variable degrees of cognitive and motor dysfunction in ALS.}, } @article {pmid38591201, year = {2024}, author = {Roy, T and Padhi, S and Mazumder, R and Majee, C and Das, S and Monika, and Mishra, R and Kapoor, B}, title = {Alleviating Neurodegenerative Diseases Associated with Mitochondrial Defects by Therapeutic Biomolecules.}, journal = {Current topics in medicinal chemistry}, volume = {24}, number = {16}, pages = {1377-1407}, pmid = {38591201}, issn = {1873-4294}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Mitochondria/metabolism/drug effects ; *Antioxidants/pharmacology/chemistry ; Reactive Oxygen Species/metabolism ; Animals ; }, abstract = {Neurodegenerative diseases are emerging as a global health concern in the current scenario, and their association with mitochondrial defects has been a potential area of research. Mitochondria, one of the essential organelles of the cell, serve as the cell's powerhouse, producing energy and ensuring cellular health. Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and Pelizaeus-Merzbacher disease have been found to be primarily triggered by mitochondrial malfunction. One of the key byproducts of mitochondrial respiration, reactive oxygen species, also contributes significantly to mitochondrial DNA mutations that eventually cause mitochondrial breakdown. This review paper comprehensively examines the potential of therapeutic biomolecules, specifically mitochondria-specific antioxidants, in mitigating the impact of mitochondrial defects on neurodegenerative diseases. It provides a detailed analysis of the mechanisms involved in mitochondrial dysfunction, the potential therapeutic targets of these biomolecules, and their structureactivity relationship information are also discussed in this review. Various research articles and publications were used extensively in compiling the data, and the structures of biomolecules were prepared using software such as ChemDraw and ChemSketch. Crucial elements triggering mitochondrial abnormalities were identified and a tabular compilation of bioactive antioxidant compounds along with their therapeutic targets, was presented. Mitochondria-specific antioxidant therapy is an innovative and promising strategy for the management of neurodegenerative diseases associated with mitochondrial defects. This review provides a thorough summary of the current state of research and promising avenues of research and development in this field, emphasizing the importance of further investigations and clinical trials to elucidate their therapeutic benefits.}, } @article {pmid38591728, year = {2024}, author = {Koysuren, A and Temucin, CM}, title = {Concentric needle jitter analysis of the genioglossus muscle in patients with motor neuron disease.}, journal = {Neurological research}, volume = {46}, number = {6}, pages = {578-582}, doi = {10.1080/01616412.2024.2339096}, pmid = {38591728}, issn = {1743-1328}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Electromyography/methods ; *Motor Neuron Disease/physiopathology/diagnosis ; Aged ; *Muscle, Skeletal/physiopathology ; Adult ; Needles ; Tongue/physiopathology ; }, abstract = {OBJECTIVES: Difficulty relaxing the genioglossus muscle makes the evaluation of spontaneous activity problematic in patients with motor neuron disease (MND). We performed jitter analysis using conventional disposable concentric needle electrodes (CNEs) of the voluntarily activated genioglossus muscle in patients with and without MND to detect the denervation-reinnervation process.

METHODS: CNE jitter analysis was performed at the genioglossus muscle in 21 MND(+) patients and 22 MND(-) subjects. The jitter analysis was considered abnormal if the jitter values exceeded these limits for the mean consecutive difference (MCD) or the individual MCD in more than 10% of readings.

RESULTS: Seventeen MND(+) patients (81%) had at least three abnormal individual jitter values whereas denervation findings were obtained in eleven of them during the needle electromyographic examination at genioglossus muscle. None of the MND(-) subjects showed CNE jitter abnormality.

CONCLUSION: CNE jitter analysis of genioglossus muscle may provide an useful information that may be suggestive of a diagnosis of MND/ALS.}, } @article {pmid38591790, year = {2024}, author = {Lochner, RH and Arumanayagam, AS and Powell, SZ and Masdeu, JC and Pascual, B and Cykowski, MD}, title = {Anterior insula is more vulnerable than posterior insula to TDP-43 pathology in common dementias and ALS.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {5}, pages = {307-317}, pmid = {38591790}, issn = {1554-6578}, support = {R01 NS118584/NS/NINDS NIH HHS/United States ; RF1 NS118584/NS/NINDS NIH HHS/United States ; RF1NS118584/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/pathology ; *Dementia ; DNA-Binding Proteins ; Neurons/pathology ; *TDP-43 Proteinopathies/pathology ; }, abstract = {Based on the anatomic proximity, connectivity, and functional similarities between the anterior insula and amygdala, we tested the hypothesis that the anterior insula is an important focus in the progression of TDP-43 pathology in LATE-NC. Blinded to clinical and neuropathologic data, phospho-TDP (pTDP) inclusion pathology was assessed in paired anterior and posterior insula samples in 105 autopsied patients with Alzheimer disease, Lewy body disease, LATE-NC and hippocampal sclerosis (HS), amyotrophic lateral sclerosis (ALS), and other conditions. Insular pTDP pathology was present in 34.3% of the study cohort, most commonly as neuronal inclusions and/or short neurites in lamina II, and less commonly as subpial processes resembling those described in the amygdala region. Among positive samples, pTDP pathology was limited to the anterior insula (41.7%), or occurred in both anterior and posterior insula (58.3%); inclusion density was greater in anterior insula across all diseases (p < .001). pTDP pathology occurred in 46.7% of ALS samples, typically without a widespread TDP-43 proteinopathy. In LATE-NC, it was seen in 30.4% of samples (mostly LATE-NC stages 2 and 3), often co-occurring with basal forebrain pathology and comorbid HS, suggesting this is an important step in the evolution of this pathology beyond the medial temporal lobe.}, } @article {pmid38592845, year = {2024}, author = {Lerose, V and Ponticelli, M and Benedetto, N and Carlucci, V and Lela, L and Tzvetkov, NT and Milella, L}, title = {Withania somnifera (L.) Dunal, a Potential Source of Phytochemicals for Treating Neurodegenerative Diseases: A Systematic Review.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {6}, pages = {}, pmid = {38592845}, issn = {2223-7747}, support = {CUP: B34I20000320005//Project RESO - REsilienza e SOstenibilità delle filiere ortofrutticole e cerealicole per valorizzare i territori" - cod. identif. ARS01_01224 -/ ; CUP: G49J19001350004//Project SPIA-Valorization of by-products from the agro-food chain/ ; CUP: ECS00000036//Project NODES - Ecosistema dell'Innovazione "Nord Ovest Digitale e Sostenibile"/ ; }, abstract = {Withania somnifera (L.) Dunal is a medicinal plant belonging to the traditional Indian medical system, showing various therapeutic effects such as anti-cancer, anti-inflammatory, anti-microbial, anti-diabetic, and hepatoprotective activity. Of great interest is W. somnifera's potential beneficial effect against neurodegenerative diseases, since the authorized medicinal treatments can only delay disease progression and provide symptomatic relief and are not without side effects. A systematic search of PubMed and Scopus databases was performed to identify preclinical and clinical studies focusing on the applications of W. somnifera in preventing neurodegenerative diseases. Only English articles and those containing the keywords (Withania somnifera AND "neurodegenerative diseases", "neuroprotective effects", "Huntington", "Parkinson", "Alzheimer", "Amyotrophic Lateral Sclerosis", "neurological disorders") in the title or abstract were considered. Reviews, editorials, letters, meta-analyses, conference papers, short surveys, and book chapters were not considered. Selected articles were grouped by pathologies and summarized, considering the mechanism of action. The quality assessment and the risk of bias were performed using the Cochrane Handbook for Systematic Reviews of Interventions checklist. This review uses a systematic approach to summarize the results from 60 investigations to highlight the potential role of W. somnifera and its specialized metabolites in treating or preventing neurodegenerative diseases.}, } @article {pmid38593477, year = {2024}, author = {Lindborg, SR and Goyal, NA and Katz, J and Burford, M and Li, J and Kaspi, H and Abramov, N and Boulanger, B and Berry, JD and Nicholson, K and Mozaffar, T and Miller, R and Jenkins, L and Baloh, RH and Lewis, R and Staff, NP and Owegi, MA and Dagher, B and Blondheim-Shraga, NR and Gothelf, Y and Levy, YS and Kern, R and Aricha, R and Windebank, AJ and Bowser, R and Brown, RH and Cudkowicz, ME}, title = {Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes.}, journal = {Muscle & nerve}, volume = {69}, number = {6}, pages = {719-729}, doi = {10.1002/mus.28093}, pmid = {38593477}, issn = {1097-4598}, support = {//California Institute for Regenerative Medicine/ ; //I AM ALS/ ; //ALS Association/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/drug therapy/diagnosis ; *Biomarkers/cerebrospinal fluid ; Double-Blind Method ; *Neurofilament Proteins/cerebrospinal fluid ; Treatment Outcome ; }, abstract = {INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint.

METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R.

RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGFβ1], change galectin-1, all p < .01), with baseline NfL and LAP/TGFβ1 remaining (p < .05) when disease characteristics (p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037).

DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.}, } @article {pmid38593537, year = {2024}, author = {Vijayakumar, S and Schwaighofer, A and Ramer, G and Lendl, B}, title = {Multivariate curve resolution -alternating least squares augmented with partial least squares baseline correction applied to mid-IR laser spectra resolves protein denaturation by reducing rotational ambiguity.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {315}, number = {}, pages = {124228}, doi = {10.1016/j.saa.2024.124228}, pmid = {38593537}, issn = {1873-3557}, abstract = {High spectral power density provided by advances in external cavity quantum cascade lasers (EC-QCL) have enabled increased transmission path lengths in mid-infrared (mid-IR) spectroscopy for more sensitive measurement of proteins in aqueous solutions. These extended path lengths also facilitate flow through measurements by avoiding congestion of the flow cell by protein aggregates. Despite the advantages presented by laser-based mid-IR spectroscopy of proteins, extraction of secondary structure information from spectra, especially in the presence of complex multi-component matrices with overlapping spectral features, remains an impediment that requires fine tuning of evaluation algorithms (e.g., band fitting, interpretation of second derivative spectra etc.). In this work, the use of multivariate curve resolution alternating least squares (MCR-ALS) for the analysis of a chemical de- and renaturation experiment has been demonstrated, since this technique offers the second-order advantage of extracting spectral signatures and concentration profiles even in the presence of unknown, uncalibrated constituents. Furthermore, we exhibit a partial least squares regression (PLSR) based subtraction of matrix component spectra prior to MCR-ALS as a method to obtain secondary structure information even in the absence of reference spectra. These approaches are showcased using the online reaction monitoring of the titration of β-lactoglobulin (β-LG) in water against the surfactants sodium dodecyl sulfate (SDS) and octaethylene glyol monododecyl ether (C12E8), using a commercially available laser-based IR spectrometer. Results for the automated PLSR correction plus MCR-ALS approach compare favorably to an MCR-ALS standalone approach using initial estimates as well as analysis of secondary structure using data processed with a manual baseline correction. The herein described chemometric approach suggests a way to simplify the challenge of handling complex matrices in protein structure analysis by isolating the background from the protein contributions, prior to analysis via other soft-modelling techniques. Consequently, the findings of this study indicate the suitability of online reaction monitoring through mid-IR spectroscopy combined with chemometric techniques as a potential tool in downstream quality control and process automation.}, } @article {pmid38593618, year = {2024}, author = {Chen, Y and Pei, X and Chen, L and Chen, L}, title = {A dynamic regulatory switch for phase separation of FUS protein: Zinc ions and zinc finger domain.}, journal = {Biochemical and biophysical research communications}, volume = {710}, number = {}, pages = {149862}, doi = {10.1016/j.bbrc.2024.149862}, pmid = {38593618}, issn = {1090-2104}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Cysteine/genetics ; Mutation ; Phase Separation ; *RNA-Binding Protein FUS/chemistry/genetics/metabolism ; Zinc/metabolism ; Zinc Fingers ; Protein Aggregates ; }, abstract = {Zinc is an important trace element in the human body, and its homeostasis is closely related to amyotrophic lateral sclerosis (ALS). Cytoplasmic FUS proteins from patients with ALS aggregate their important pathologic markers. Liquid-liquid phase separation (LLPS) of FUS can lead to its aggregation. However, whether and how zinc homeostasis affects the aggregation of disease-associated FUS proteins in the cytoplasm remains unclear. Here, we found that zinc ion enhances LLPS and promotes the aggregation in the cytoplasm for FUS protein. In the FUS, the cysteine of the zinc finger (ZnF), recognizes and binds to zinc ions, reducing droplet mobility and enhancing protein aggregation in the cytoplasm. The mutation of FUS cysteine disrupts the dynamic regulatory switch of zinc ions and ZnF, resulting in insensitivity to zinc ions. These results suggest that the dynamic regulation of LLPS by binding with zinc ions may be a widespread mechanism and provide a new understanding of neurological diseases such as ALS and other ZnF protein-related diseases.}, } @article {pmid38595691, year = {2024}, author = {McMackin, R and Tadjine, Y and Fasano, A and Mitchell, M and Heverin, M and Awiszus, F and Nasseroleslami, B and Carson, RG and Hardiman, O}, title = {Examining short interval intracortical inhibition with different transcranial magnetic stimulation-induced current directions in ALS.}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {120-129}, pmid = {38595691}, issn = {2467-981X}, abstract = {OBJECTIVE: To establish if induced current direction across the motor cortex alters the sensitivity of transcranial magnetic stimulation (TMS)-evoked short-interval intracortical inhibition (SICI) as an ALS biomarker.

METHODS: Threshold tracking-TMS was undertaken in 35 people with ALS and 39 controls. Using a coil orientation which induces posterior-anterior (PA)-directed current across the motor cortex, SICI (1 ms and 3 ms interstimulus intervals) and intracortical facilitation (ICF, 10 ms interstimulus interval) were recorded. SICI3ms was also recorded using a coil orientation which induces anterior-posterior (AP)-directed current across the motor cortex.

RESULTS: At group level, SICI3ms-PA (AUROC = 0.7), SICI3ms-AP (AUROC = 0.8) and SICI1ms (AUROC = 0.66) were substantially lower in those with ALS, although there was considerable interindividual heterogeneity. Averaging across interstimulus intervals (ISIs) marginally improved SICIPA sensitivity (AUROC = 0.76). Averaging SICI values across ISIs and orientations into a single SICI measure did not substantially improve sensitivity (AUROC = 0.81) compared to SICI3ms-AP alone. SICI3ms-AP and SICI3ms-PA did not significantly correlate (rho = 0.19, p = 0.313), while SICI1ms-PA and SICI3ms-PA did (rho = 0.37, p = 0.006). Further, those with ALS with the lowest SICI3ms-PA were not those with the lowest SICI3ms-AP. ICF was similar between groups (AUROC = 0.50).

CONCLUSIONS: SICIPA and SICIAP are uncorrelated measures of motor cortical inhibitory functions which are useful as distinct, unequally affected, measures of disinhibition in ALS.

SIGNIFICANCE: Examining both SICIPA and SICIAP may facilitate more comprehensive characterisation of motor cortical disinhibition in ALS.}, } @article {pmid38595767, year = {2024}, author = {Jia, H and Omar, AA and Xu, J and Dalmendray, J and Wang, Y and Feng, Y and Wang, W and Hu, Z and Grosser, JW and Wang, N}, title = {Generation of transgene-free canker-resistant Citrus sinensis cv. Hamlin in the T0 generation through Cas12a/CBE co-editing.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1385768}, pmid = {38595767}, issn = {1664-462X}, abstract = {Citrus canker disease affects citrus production. This disease is caused by Xanthomonas citri subsp. citri (Xcc). Previous studies confirmed that during Xcc infection, PthA4, a transcriptional activator like effector (TALE), is translocated from the pathogen to host plant cells. PthA4 binds to the effector binding elements (EBEs) in the promoter region of canker susceptibility gene LOB1 (EBEPthA4-LOBP) to activate its expression and subsequently cause canker symptoms. Previously, the Cas12a/CBE co-editing method was employed to disrupt EBEPthA4-LOBP of pummelo, which is highly homozygous. However, most commercial citrus cultivars are heterozygous hybrids and more difficult to generate homozygous/biallelic mutants. Here, we employed Cas12a/CBE co-editing method to edit EBEPthA4-LOBP of Hamlin (Citrus sinensis), a commercial heterozygous hybrid citrus cultivar grown worldwide. Binary vector GFP-p1380N-ttLbCas12a:LOBP1-mPBE:ALS2:ALS1 was constructed and shown to be functional via Xcc-facilitated agroinfiltration in Hamlin leaves. This construct allows the selection of transgene-free regenerants via GFP, edits ALS to generate chlorsulfuron-resistant regenerants as a selection marker for genome editing resulting from transient expression of the T-DNA via nCas9-mPBE:ALS2:ALS1, and edits gene(s) of interest (i.e., EBEPthA4-LOBP in this study) through ttLbCas12a, thus creating transgene-free citrus. Totally, 77 plantlets were produced. Among them, 8 plantlets were transgenic plants (#HamGFP1 - #HamGFP8), 4 plantlets were transgene-free (#HamNoGFP1 - #HamNoGFP4), and the rest were wild type. Among 4 transgene-free plantlets, three lines (#HamNoGFP1, #HamNoGFP2 and #HamNoGFP3) contained biallelic mutations in EBEpthA4, and one line (#HamNoGFP4) had homozygous mutations in EBEpthA4. We achieved 5.2% transgene-free homozygous/biallelic mutation efficiency for EBEPthA4-LOBP in C. sinensis cv. Hamlin, compared to 1.9% mutation efficiency for pummelo in a previous study. Importantly, the four transgene-free plantlets and 3 transgenic plantlets that survived were resistant against citrus canker. Taken together, Cas12a/CBE co-editing method has been successfully used to generate transgene-free canker-resistant C. sinensis cv. Hamlin in the T0 generation via biallelic/homozygous editing of EBEpthA4 of the canker susceptibility gene LOB1.}, } @article {pmid38595972, year = {2024}, author = {Zhou, L and Xie, M and Wang, X and Xu, R}, title = {The usage and advantages of several common amyotrophic lateral sclerosis animal models.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1341109}, pmid = {38595972}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis is a fatal, multigenic, multifactorial neurodegenerative disease characterized by upper and lower motor neuron loss. Animal models are essential for investigating pathogenesis and reflecting clinical manifestations, particularly in developing reasonable prevention and therapeutic methods for human diseases. Over the decades, researchers have established a host of different animal models in order to dissect amyotrophic lateral sclerosis (ALS), such as yeast, worms, flies, zebrafish, mice, rats, pigs, dogs, and more recently, non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms of motor neuron degeneration in ALS, contributing to the development of new promising therapeutics. In this review, we describe several common animal models in ALS, classified by the naturally occurring and experimentally induced, pointing out their features in modeling, the onset and progression of the pathology, and their specific pathological hallmarks. Moreover, we highlight the pros and cons aimed at helping the researcher select the most appropriate among those common experimental animal models when designing a preclinical ALS study.}, } @article {pmid38596011, year = {2024}, author = {Xu, CZ and Huan, X and Luo, SS and Zhong, HH and Zhao, CB and Chen, Y and Zou, ZY and Chen, S}, title = {Serum cytokines profile changes in amyotrophic lateral sclerosis.}, journal = {Heliyon}, volume = {10}, number = {7}, pages = {e28553}, pmid = {38596011}, issn = {2405-8440}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder, characterized by progressive limb weakness, dysphagia, dysphonia, and respiratory failure due to degeneration of upper and lower motor neurons. The pathogenesis of ALS is still unclear. Neuroinflammation has been found to be involved in its development and progression. Cytokines play a significant role in the inflammatory process. This study aims to identify novel biomarkers that may assist in the diagnosis of ALS.

METHODS: In Fujian Medical University Union Hospital and Huashan Hospital Fudan University, two independent centers, we prospectively recruited 50 ALS patients, and 41 healthy controls (25 ALS and 26 controls in the first stage and 25 ALS and 15 controls in the validation stage). An 18-plex Luminex kit was used to screen the serum cytokines levels in the first stage. Commercial ELISA kits were used to measure the levels of target cytokines in the validation stage. A single-molecule array HD-X platform was applied to assess the levels of serum neurofilament light chain (NFL).

RESULTS: The levels of serum IL-18 were markedly increased in patients with ALS in the first stage (p = 0.016). The ROC curve showed an area under the curve at 0.695 (95% CI 0.50-0.84) in distinguishing ALS patients from healthy controls. The IL-21 was decreased in elderly patients when grouped by 55 years old (the medium age). Furthermore, the IL-5, IL-13, IL-18, and NFL had a positive relationship with the disease progression of ALS. We also found that serum IL-18 was markedly increased in ALS patients in the validation stage (167.67 [148.25-175.59] vs 116.44 [102.43-122.19]pg/ml, p < 0.0015).

CONCLUSION: In this study, we identified systemic cytokine profile changes in the serum of ALS patients, especially the elevated IL-18, as well as the decreased IL-21 in elder patients. These changes in serum cytokine profiles may shed new light on an in-depth understanding of the immunopathogenic characteristics of ALS.}, } @article {pmid38596406, year = {2024}, author = {Tanaka, Y and Kozuma, L and Hino, H and Takeya, K and Eto, M}, title = {Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux.}, journal = {Biochemistry and biophysics reports}, volume = {38}, number = {}, pages = {101705}, pmid = {38596406}, issn = {2405-5808}, abstract = {(Macro)autophagy is a cellular degradation system for unnecessary materials, such as aggregate-prone TDP-43, a central molecule in neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Abemaciclib (Abe) and vacuolin-1 (Vac) treatments are known to induce vacuoles characterized by an autophagosome and a lysosome component, suggesting that they facilitate autophagosome-lysosome fusion. However, it remains unknown whether Abe and Vac suppress the accumulation of aggregate-prone TDP-43 by accelerating autophagic flux. In the present study, the Abe and Vac treatment dose-dependently reduced the GFP/RFP ratio in SH-SY5Y neuroblastoma cells stably expressing the autophagic flux marker GFP-LC3-RFP-LC3ΔG. Abe and Vac also increased the omegasome marker GFP-ATG13 signal and the autophagosome marker mCherry-LC3 localized to the lysosome marker LAMP1-GFP. The Abe and Vac treatment decreased the intracellular level of the lysosome marker LAMP1-GFP in SH-SY5Y cells stably expressing LAMP1-GFP, but did not increase the levels of LAMP1-GFP, the autophagosome marker LC3-II, or the multivesicular body marker TSG101 in the extracellular vesicle-enriched fraction. Moreover, Abe and Vac treatment autophagy-dependently inhibited GFP-tagged aggregate-prone TDP-43 accumulation. The results of a PI(3)P reporter assay using the fluorescent protein tagged-2 × FYVE and LAMP1-GFP indicated that Abe and Vac increased the intensity of the PI(3)P signal on lysosomes. A treatment with the VPS34 inhibitor wortmannin (WM) suppressed Abe-/Vac-facilitated autophagic flux and the degradation of GFP-tagged aggregate-prone TDP-43. Collectively, these results suggest that Abe and Vac degrade aggregate-prone TDP-43 by accelerating autophagosome formation and autophagosome-lysosome fusion through the formation of PI(3)P.}, } @article {pmid38596495, year = {2024}, author = {Dirjayanto, VJ and Audrey, J and Simadibrata, DM}, title = {Vonoprazan-amoxicillin dual regimen with Saccharomyces boulardii as a rescue therapy for Helicobacter pylori: Current perspectives and implications.}, journal = {World journal of gastroenterology}, volume = {30}, number = {10}, pages = {1280-1286}, pmid = {38596495}, issn = {2219-2840}, mesh = {Humans ; Amoxicillin/therapeutic use ; Anti-Bacterial Agents/adverse effects ; *Helicobacter pylori ; *Saccharomyces boulardii ; *Helicobacter Infections/drug therapy ; Clarithromycin/therapeutic use ; Drug Therapy, Combination ; Proton Pump Inhibitors/adverse effects ; H(+)-K(+)-Exchanging ATPase ; Ions/pharmacology/therapeutic use ; Treatment Outcome ; *Pyrroles ; *Sulfonamides ; }, abstract = {Yu et al's study in the World Journal of Gastroenterology (2023) introduced a novel regimen of Vonoprazan-amoxicillin dual therapy combined with Saccharomyces boulardii (S. boulardii) for the rescue therapy against Helicobacter pylori (H. pylori), a pathogen responsible for peptic ulcers and gastric cancer. Vonoprazan is a potassium-competitive acid blocker renowned for its rapid and long-lasting acid suppression, which is minimally affected by mealtime. Compared to proton pump inhibitors, which bind irreversibly to cysteine residues in the H[+]/K[+]-ATPase pump, Vonoprazan competes with the K[+] ions, prevents the ions from binding to the pump and blocks acid secretion. Concerns with increasing antibiotic resistance, effects on the gut microbiota, patient compliance, and side effects have led to the advent of a dual regimen for H. pylori. Previous studies suggested that S. boulardii plays a role in stabilizing the gut barrier which improves H. pylori eradication rate. With an acceptable safety profile, the dual-adjunct regimen was effective regardless of prior treatment failure and antibiotic resistance profile, thereby strengthening the applicability in clinical settings. Nonetheless, S. boulardii comes in various formulations and dosages, warranting further exploration into the optimal dosage for supplementation in rescue therapy. Additionally, larger, randomized, double-blinded controlled trials are warranted to confirm these promising results.}, } @article {pmid38596666, year = {2024}, author = {Sini, P and Galleri, G and Ciampelli, C and Galioto, M and Padedda, BM and Lugliè, A and Iaccarino, C and Crosio, C}, title = {Evaluation of cyanotoxin L-BMAA effect on α-synuclein and TDP43 proteinopathy.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1360068}, pmid = {38596666}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; alpha-Synuclein ; Cyanobacteria Toxins ; *Amino Acids, Diamino/toxicity ; *Parkinson Disease ; *Cyanobacteria ; }, abstract = {The complex interplay between genetic and environmental factors is considered the cause of neurodegenerative diseases including Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Among the environmental factors, toxins produced by cyanobacteria have received much attention due to the significant increase in cyanobacteria growth worldwide. In particular, L-BMAA toxin, produced by diverse taxa of cyanobacteria, dinoflagellates and diatoms, has been extensively correlated to neurodegeneration. The molecular mechanism of L-BMAA neurotoxicity is still cryptic and far from being understood. In this research article, we have investigated the molecular pathways altered by L-BMAA exposure in cell systems, highlighting a significant increase in specific stress pathways and an impairment in autophagic processes. Interestingly, these changes lead to the accumulation of both α-synuclein and TDP43, which are correlated with PD and ALS proteinopathy, respectively. Finally, we were able to demonstrate specific alterations of TDP43 WT or pathological mutants with respect to protein accumulation, aggregation and cytoplasmic translocation, some of the typical features of both sporadic and familial ALS.}, } @article {pmid38596778, year = {2024}, author = {Ramírez-Jarquín, JO and Tecalco-Cruz, AC and Lopez-Huerta, VG and Ramírez-Jarquín, UN}, title = {Editorial: Over 60 years of neurochemistry, the heritage of Dr. Ricardo Tapia.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1398127}, doi = {10.3389/fnmol.2024.1398127}, pmid = {38596778}, issn = {1662-5099}, } @article {pmid38597682, year = {2024}, author = {Kojak, N and Kuno, J and Fittipaldi, KE and Khan, A and Wenger, D and Glasser, M and Donnianni, RA and Tang, Y and Zhang, J and Huling, K and Ally, R and Mujica, AO and Turner, T and Magardino, G and Huang, PY and Kerk, SY and Droguett, G and Prissette, M and Rojas, J and Gomez, T and Gagliardi, A and Hunt, C and Rabinowitz, JS and Gong, G and Poueymirou, W and Chiao, E and Zambrowicz, B and Siao, CJ and Kajimura, D}, title = {Somatic and intergenerational G4C2 hexanucleotide repeat instability in a human C9orf72 knock-in mouse model.}, journal = {Nucleic acids research}, volume = {52}, number = {10}, pages = {5732-5755}, pmid = {38597682}, issn = {1362-4962}, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; Disease Models, Animal ; DNA Breaks, Double-Stranded ; *DNA Repeat Expansion/genetics ; Frontotemporal Dementia/genetics ; Gene Knock-In Techniques ; *Genomic Instability/genetics ; MutS Homolog 2 Protein/genetics ; }, abstract = {Expansion of a G4C2 repeat in the C9orf72 gene is associated with familial Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). To investigate the underlying mechanisms of repeat instability, which occurs both somatically and intergenerationally, we created a novel mouse model of familial ALS/FTD that harbors 96 copies of G4C2 repeats at a humanized C9orf72 locus. In mouse embryonic stem cells, we observed two modes of repeat expansion. First, we noted minor increases in repeat length per expansion event, which was dependent on a mismatch repair pathway protein Msh2. Second, we found major increases in repeat length per event when a DNA double- or single-strand break (DSB/SSB) was artificially introduced proximal to the repeats, and which was dependent on the homology-directed repair (HDR) pathway. In mice, the first mode primarily drove somatic repeat expansion. Major changes in repeat length, including expansion, were observed when SSB was introduced in one-cell embryos, or intergenerationally without DSB/SSB introduction if G4C2 repeats exceeded 400 copies, although spontaneous HDR-mediated expansion has yet to be identified. These findings provide a novel strategy to model repeat expansion in a non-human genome and offer insights into the mechanism behind C9orf72 G4C2 repeat instability.}, } @article {pmid38598318, year = {2024}, author = {Peng, J and Gao, S and Bi, JH and Shi, J and Jia, L and Pang, QF and Zhao, DM and Fu, Y and Ye, F}, title = {Design, Synthesis, and Biological Evaluation of Novel Purine Derivatives as Herbicide Safeners.}, journal = {Journal of agricultural and food chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jafc.3c08138}, pmid = {38598318}, issn = {1520-5118}, abstract = {Mesosulfuron-methyl, an inhibitor of acetolactate synthase (ALS), has been extensively used in wheats. However, it can damage wheat (Triticum aestivum) and even lead to crop death. Herbicide safeners selectively shield crops from such damage without compromising weed control. To mitigate the phytotoxicity of mesosulfuron-methyl in crops, several purine derivatives were developed based on active substructure splicing. The synthesized title compounds underwent thorough characterization using infrared spectroscopy, [1]H nuclear magnetic resonance ([1]H NMR), [13]C nuclear magnetic resonance ([13]C NMR), and high-resolution mass spectrometry. We evaluated chlorophyll and glutathione contents as well as various enzyme activities to evaluate the safer activity of these compounds. Compounds III-3 and III-7 exhibited superior activity compared with the safener mefenpyr-diethyl. Molecular structure analysis, along with predictions of absorption, distribution, metabolism, excretion, and toxicity, indicated that compound III-7 shared pharmacokinetic traits with the commercial safener mefenpyr-diethyl. Molecular docking simulations revealed that compound III-7 competitively bound to the ALS active site with mesosulfuron-methyl, elucidating the protective mechanism of the safeners. Overall, this study highlights purine derivatives as potential candidates for novel safener development.}, } @article {pmid38598868, year = {2024}, author = {Zhan, Y and Liu, H and Cao, Z and Qi, J and Bai, L and Pan, L}, title = {Target-site and non-target-site resistance mechanisms confer mesosulfuron-methyl resistance in Alopecurus aequalis.}, journal = {Plant physiology and biochemistry : PPB}, volume = {210}, number = {}, pages = {108597}, doi = {10.1016/j.plaphy.2024.108597}, pmid = {38598868}, issn = {1873-2690}, mesh = {*Herbicide Resistance/genetics ; *Sulfonylurea Compounds/pharmacology ; *Acetolactate Synthase/genetics/metabolism ; *Herbicides/pharmacology ; *Poaceae/genetics/drug effects/metabolism ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Plant Proteins/genetics/metabolism ; Glutathione Transferase/metabolism/genetics ; Imidazoles/pharmacology ; Gene Expression Regulation, Plant/drug effects ; Mutation ; Molecular Docking Simulation ; Benzoates ; Pyrimidines ; }, abstract = {BACKGROUND: Shortawn foxtail (Alopecurus aequalis Sobol.) is a noxious weed in China. The resistance of A. aequalis developed rapidly due to the long-term application of acetolactate synthase (ALS)-inhibiting herbicides. Here, a suspected mesosulfuron-methyl-resistant A. aequalis population, Aa-R, was collected from a wheat field in China.

RESULTS: A dose‒response test showed that the Aa-R population has evolved a high level of resistance to mesosulfuron-methyl, and its growth was suppressed by imazamox, pyroxsulam and bispyribac-sodium. ALS gene sequence analysis revealed that a known resistance-related mutation (Pro-197-Thr) was present in the Aa-R population. Moreover, ALS gene overexpression was detected in the Aa-R population. The mesosulfuron-methyl resistance could be reversed by cytochrome P450 monooxygenase (CYP450) and glutathione S-transferase (GST) inhibitors. In addition, enhanced metabolism of mesosulfuron-methyl was detected in the Aa-R population compared with the susceptible population. NADPH-cytochrome P450 reductase and GST activities were strongly inducible in the Aa-R population. One CYP450 gene, CYP74A2, and one GST gene, GST4, were constitutively upregulated in the Aa-R population. Molecular docking results showed the binding affinity of CYP74A2 and GST4 for the tested ALS-inhibiting herbicides, respectively.

CONCLUSION: This study confirmed that target-site resistance and non-target-site resistance involving CYP450 and GST were the main mechanisms involved in resistance in the mesosulfuron-methyl-resistant A. aequalis population.}, } @article {pmid38599171, year = {2024}, author = {Castro-Gomez, S and Heneka, MT}, title = {Innate immune activation in neurodegenerative diseases.}, journal = {Immunity}, volume = {57}, number = {4}, pages = {790-814}, doi = {10.1016/j.immuni.2024.03.010}, pmid = {38599171}, issn = {1097-4180}, mesh = {Humans ; *Neurodegenerative Diseases ; Receptors, Pattern Recognition ; Immune System ; Inflammation Mediators ; Immunity, Innate ; }, abstract = {Activation of the innate immune system following pattern recognition receptor binding has emerged as one of the major pathogenic mechanisms in neurodegenerative disease. Experimental, epidemiological, pathological, and genetic evidence underscores the meaning of innate immune activation during the prodromal as well as clinical phases of several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Importantly, innate immune activation and the subsequent release of inflammatory mediators contribute mechanistically to other hallmarks of neurodegenerative diseases such as aberrant proteostatis, pathological protein aggregation, cytoskeleton abnormalities, altered energy homeostasis, RNA and DNA defects, and synaptic and network disbalance and ultimately to the induction of neuronal cell death. In this review, we discuss common mechanisms of innate immune activation in neurodegeneration, with particular emphasis on the pattern recognition receptors (PRRs) and other receptors involved in the detection of damage-associated molecular patterns (DAMPs).}, } @article {pmid38600555, year = {2024}, author = {Liu, Y and Yan, D and Yang, L and Chen, X and Hu, C and Chen, M}, title = {Stathmin 2 is a potential treatment target for TDP-43 proteinopathy in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {20}, pmid = {38600555}, issn = {2047-9158}, support = {2023A1515010477//Guangdong Basic and Applied Basic Research Foundation/ ; 32000690//National Natural Science Foundation of China/ ; 2019B030335001//The Key-Area Research and Development Program of Guangdong Province,China/ ; 2023-Z04-103//The Key Medical and Health Projects of Panyu District Science and Technology Plan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; DNA-Binding Proteins/genetics ; *Stathmin/antagonists & inhibitors ; *TDP-43 Proteinopathies/drug therapy ; }, } @article {pmid38600725, year = {2024}, author = {Madhubala, D and Patra, A and Khan, MR and Mukherjee, AK}, title = {Phytomedicine for neurodegenerative diseases: The road ahead.}, journal = {Phytotherapy research : PTR}, volume = {38}, number = {6}, pages = {2993-3019}, doi = {10.1002/ptr.8192}, pmid = {38600725}, issn = {1099-1573}, support = {//IASST/ ; EMR/2017/001829//Science and Engineering Research Board/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Catechin/analogs & derivatives/therapeutic use/pharmacology ; *Phytotherapy ; Curcumin/therapeutic use/pharmacology ; Quercetin/pharmacology/therapeutic use ; Animals ; Cannabinoids/therapeutic use/pharmacology ; Apigenin/pharmacology/therapeutic use ; Blood-Brain Barrier/drug effects ; Phytochemicals/pharmacology/therapeutic use ; Plant Extracts/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative disorders (NDs) are among the most common causes of death across the globe. NDs are characterized by progressive damage to CNS neurons, leading to defects in specific brain functions such as memory, cognition, and movement. The most common NDs are Parkinson's, Alzheimer's, Huntington's, and amyotrophic lateral sclerosis (ALS). Despite extensive research, no therapeutics or medications against NDs have been proven to be effective. The current treatment of NDs involving symptom-based targeting of the disease pathogenesis has certain limitations, such as drug resistance, adverse side effects, poor blood-brain barrier permeability, and poor bioavailability of drugs. Some studies have shown that plant-derived natural compounds hold tremendous promise for treating and preventing NDs. Therefore, the primary objective of this review article is to critically analyze the properties and potency of some of the most studied phytomedicines, such as quercetin, curcumin, epigallocatechin gallate (EGCG), apigenin, and cannabinoids, and highlight their advantages and limitations for developing next-generation alternative treatments against NDs. Further extensive research on pre-clinical and clinical studies for developing plant-based drugs against NDs from bench to bedside is warranted.}, } @article {pmid38601118, year = {2024}, author = {Patel, GD and Liu, L and Li, A and Yang, YH and Shen, CC and Brand-Saberi, B and Yang, X}, title = {Mesenchymal stem cell-based therapies for treating well-studied neurological disorders: a systematic review.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1361723}, pmid = {38601118}, issn = {2296-858X}, abstract = {BACKGROUND: Millions of people across the globe are affected by conditions like Amyotrophic Lateral Sclerosis (ALS), Parkinson's Disease (PD), Multiple Sclerosis (MS), Spinal Cord Injury (SCI), and Traumatic Brain Injury (TBI), although most occurrences are common in the elderly population. This systematic review aims to highlight the safety of the procedures, their tolerability, and efficacy of the available therapies conducted over the years using mesenchymal stem cells (MSCs) in treating the neurological conditions mentioned above.

METHODS: PubMed was used to search for published data from clinical trials performed using mesenchymal stem cells. Studies that provided the necessary information that mentioned the efficacy and adverse effects of the treatment in patients were considered for this review.

RESULTS: In total, 43 manuscripts were selected after a strategic search, and these studies have been included in this systematic review. Most included studies reported the safety of the procedures used and the treatment's good tolerability, with mild adverse events such as fever, headache, mild pain at the injection site, or nausea being common. A few studies also reported death of some patients, attributed to the progression of the disease to severe stages before the treatment. Other severe events, such as respiratory or urinary infections reported in some studies, were not related to the treatment. Different parameters were used to evaluate the efficacy of the treatment based on the clinical condition of the patient.

CONCLUSION: Mesenchymal stem cells transplantation has so far proven to be safe and tolerable in select studies and patient types. This systematic review includes the results from the 43 selected studies in terms of safety and tolerability of the procedures, and several adverse events and therapeutic benefits during the follow-up period after administration of MSCs.}, } @article {pmid38601155, year = {2024}, author = {Du, R and Chen, P and Li, M and Zhu, Y and He, Z and Huang, X}, title = {Developing a novel immune infiltration-associated mitophagy prediction model for amyotrophic lateral sclerosis using bioinformatics strategies.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1360527}, pmid = {38601155}, issn = {1664-3224}, mesh = {Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Mitophagy/genetics ; *Neurodegenerative Diseases ; Computational Biology ; Databases, Factual ; Disease Models, Animal ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which leads to muscle weakness and eventual paralysis. Numerous studies have indicated that mitophagy and immune inflammation have a significant impact on the onset and advancement of ALS. Nevertheless, the possible diagnostic and prognostic significance of mitophagy-related genes associated with immune infiltration in ALS is uncertain. The purpose of this study is to create a predictive model for ALS using genes linked with mitophagy-associated immune infiltration.

METHODS: ALS gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. Univariate Cox analysis and machine learning methods were applied to analyze mitophagy-associated genes and develop a prognostic risk score model. Subsequently, functional and immune infiltration analyses were conducted to study the biological attributes and immune cell enrichment in individuals with ALS. Additionally, validation of identified feature genes in the prediction model was performed using ALS mouse models and ALS patients.

RESULTS: In this study, a comprehensive analysis revealed the identification of 22 mitophagy-related differential expression genes and 40 prognostic genes. Additionally, an 18-gene prognostic signature was identified with machine learning, which was utilized to construct a prognostic risk score model. Functional enrichment analysis demonstrated the enrichment of various pathways, including oxidative phosphorylation, unfolded proteins, KRAS, and mTOR signaling pathways, as well as other immune-related pathways. The analysis of immune infiltration revealed notable distinctions in certain congenital immune cells and adaptive immune cells between the low-risk and high-risk groups, particularly concerning the T lymphocyte subgroup. ALS mouse models and ALS clinical samples demonstrated consistent expression levels of four mitophagy-related immune infiltration genes (BCKDHA, JTB, KYNU, and GTF2H5) with the results of bioinformatics analysis.

CONCLUSION: This study has successfully devised and verified a pioneering prognostic predictive risk score for ALS, utilizing eighteen mitophagy-related genes. Furthermore, the findings indicate that four of these genes exhibit promising roles in the context of ALS prognostic.}, } @article {pmid38601572, year = {2024}, author = {Urigüen, JA and Ruiz de Gauna, S and Gutiérrez, JJ and Azcárate, I and Leturiondo, M and Redondo, K and Russell, JK and Daya, MR}, title = {Metrics of impulsiveness of manual chest compressions for out-of-hospital cardiopulmonary resuscitation.}, journal = {Heliyon}, volume = {10}, number = {7}, pages = {e28739}, pmid = {38601572}, issn = {2405-8440}, abstract = {AIM: Propose new metrics of impulsiveness of manual chest compressions (CCs) that account for shape and duration, separate the characteristics of the compressive part of the CC cycle from those of the recoil part, and are uncorrelated to CC depth and rate.

METHODS: We conducted a retrospective analysis of adult out-of-hospital cardiac arrest monitor-defibrillator recordings having CPR data. Specifically, episodes of adult patients with ≥ 1000 compressions free of leaning were examined. CCs were obtained from the depth signal of the valid episodes, and we calculated the novel metrics: compression area index (CAI), recoil area index (RAI), compression impulsiveness index (CII) and recoil impulsiveness index (RII). Generalized linear mixed-effects models and Jonckheere-Terpstra trend analyses were employed to measure differences between populations and trends, and the absolute value of Pearson's correlation coefficient |r| was used to report dependence between variables. Statistics are reported as median and interquartile range.

RESULTS: We analyzed 982,340 CCs corresponding to 453 episodes, for which we calculated their CAI, RAI and duty cycle (DC). We analyzed the metrics for various populations: age, sex, any ROSC achieved and disposition, and found that CAI was significantly different according to patient disposition and RAI relative to age and sex (p<0.05). None of the metrics was correlated strongly to depth or rate (|r| values of 0.22 or smaller), and all of them varied for CC series corresponding to the same rescuer over the course of resuscitation (ptrend<0.05). However, we observed that the metrics are not balanced, in that for any value of DC, CAI and RAI span almost their entire ranges.

CONCLUSION: The proposed metrics correctly and completely describe manual CC waveforms, improve upon the DC, since they depend on the signal waveform, and provide additional information to current indicators of quality CPR, depth and rate. Furthermore, they allow to differentiate the compressive and recoil parts of the CC cycle, reflecting influence of the rescuer (via CAI or CII) and of the biomechanics of the patient's chest (via RAI or RII). Thus, they have the potential to contribute to better understanding CPR dynamics and, eventually, to enhanced quality of CPR practice as additional indicators of proper manual CC technique.}, } @article {pmid38601850, year = {2024}, author = {Xiao, C and Gu, X and Feng, Y and Shen, J}, title = {Two-sample Mendelian randomization analysis of 91 circulating inflammatory protein levels and amyotrophic lateral sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1367106}, pmid = {38601850}, issn = {1663-4365}, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with poorly understood pathophysiology. Recent studies have highlighted systemic inflammation, especially the role of circulating inflammatory proteins, in ALS.

METHODS: This study investigates the potential causal link between these proteins and ALS. We employed a two-sample Mendelian Randomization(MR) approach, analyzing data from large-scale genome-wide association studies to explore the relationship between 91 circulating inflammatory proteins and ALS. This included various MR methods like MR Egger, weighted median, and inverse-variance weighted, complemented by sensitivity analyses for robust results.

RESULTS: Significant associations were observed between levels of inflammatory proteins, including Adenosine Deaminase, Interleukin-17C, Oncostatin-M, Leukemia Inhibitory Factor Receptor, and Osteoprotegerin, and ALS risk. Consistencies were noted across different P-value thresholds. Bidirectional MR suggested that ALS risk might influence levels of certain inflammatory proteins.

DISCUSSION: Our findings, via MR analysis, indicate a potential causal relationship between circulating inflammatory proteins and ALS. This sheds new light on ALS pathophysiology and suggests possible therapeutic targets. Further research is required to confirm these results and understand the specific roles of these proteins in ALS.}, } @article {pmid38602336, year = {2024}, author = {Zhang, QJ and Lin, J and Wang, YL and Chen, L and Ding, Y and Zheng, FZ and Song, HH and Lv, AW and Li, YY and Guo, QF and Lin, MT and Hu, W and Xu, LQ and Zhao, WL and Fang, L and Cui, MC and Fu, ZF and Chen, WJ and Zhang, J and Wang, ZQ and Wang, N and Fu, Y}, title = {Detection of pTDP-43 via routine muscle biopsy: A promising diagnostic biomarker for amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {6}, pages = {e13261}, pmid = {38602336}, issn = {1750-3639}, support = {2020Y9129//Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; 2021J01209//Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; 2021Y9156//Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; BPB-LMT2021//2021 Provincial Special Subsidy Funds for Health (Biobank Construction Project for Neurological Diseases)/ ; 82230039//National Natural Science Foundation of China/ ; 82371409//National Natural Science Foundation of China/ ; U2005201//National Natural Science Foundation of China/ ; U21A20360//National Natural Science Foundation of China/ ; 2022ZQNZD005//Major Scientific Research Program for Young and Middle-aged Health Professionals of Fujian Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnosis/genetics/metabolism ; Male ; Female ; Middle Aged ; Aged ; *Biomarkers/metabolism ; *DNA-Binding Proteins/metabolism ; Biopsy/methods ; *Muscle, Skeletal/pathology/metabolism ; Adult ; C9orf72 Protein/genetics ; Cohort Studies ; Phosphorylation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.}, } @article {pmid38603949, year = {2024}, author = {Shin-Yi Lin, C and Howells, J and Rutkove, S and Nandedkar, S and Neuwirth, C and Noto, YI and Shahrizaila, N and Whittaker, RG and Bostock, H and Burke, D and Tankisi, H}, title = {Neurophysiological and imaging biomarkers of lower motor neuron dysfunction in motor neuron diseases/amyotrophic lateral sclerosis: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {162}, number = {}, pages = {91-120}, doi = {10.1016/j.clinph.2024.03.015}, pmid = {38603949}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; *Motor Neurons/physiology ; *Motor Neuron Disease/physiopathology/diagnostic imaging/diagnosis ; *Biomarkers ; *Electromyography/methods ; *Neural Conduction/physiology ; }, abstract = {This chapter discusses comprehensive neurophysiological biomarkers utilised in motor neuron disease (MND) and, in particular, its commonest form, amyotrophic lateral sclerosis (ALS). These encompass the conventional techniques including nerve conduction studies (NCS), needle and high-density surface electromyography (EMG) and H-reflex studies as well as novel techniques. In the last two decades, new methods of assessing the loss of motor units in a muscle have been developed, that are more convenient than earlier methods of motor unit number estimation (MUNE),and may use either electrical stimulation (e.g. MScanFit MUNE) or voluntary activation (MUNIX). Electrical impedance myography (EIM) is another novel approach for the evaluation that relies upon the application and measurement of high-frequency, low-intensity electrical current. Nerve excitability techniques (NET) also provide insights into the function of an axon and reflect the changes in resting membrane potential, ion channel dysfunction and the structural integrity of the axon and myelin sheath. Furthermore, imaging ultrasound techniques as well as magnetic resonance imaging are capable of detecting the constituents of morphological changes in the nerve and muscle. The chapter provides a critical description of the ability of each technique to provide neurophysiological insight into the complex pathophysiology of MND/ALS. However, it is important to recognise the strengths and limitations of each approach in order to clarify utility. These neurophysiological biomarkers have demonstrated reliability, specificity and provide additional information to validate and assess lower motor neuron dysfunction. Their use has expanded the knowledge about MND/ALS and enhanced our understanding of the relationship between motor units, axons, reflexes and other neural circuits in relation to clinical features of patients with MND/ALS at different stages of the disease. Taken together, the ultimate goal is to aid early diagnosis, distinguish potential disease mimics, monitor and stage disease progression, quantify response to treatment and develop potential therapeutic interventions.}, } @article {pmid38605366, year = {2024}, author = {Aragón-González, A and Shaw, AC and Kok, JR and Roussel, FS and Santos Souza, CD and Granger, SM and Vetter, T and de Diego, Y and Meyer, KC and Beal, SN and Shaw, PJ and Ferraiuolo, L}, title = {C9ORF72 patient-derived endothelial cells drive blood-brain barrier disruption and contribute to neurotoxicity.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {34}, pmid = {38605366}, issn = {2045-8118}, support = {MR/W00416X/1/MRC_/Medical Research Council/United Kingdom ; 765704//Horizon 2020/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Blood-Brain Barrier/metabolism ; C9orf72 Protein/genetics/metabolism ; *Endothelial Cells/metabolism ; }, abstract = {The blood-brain barrier (BBB) serves as a highly intricate and dynamic interface connecting the brain and the bloodstream, playing a vital role in maintaining brain homeostasis. BBB dysfunction has been associated with multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS); however, the role of the BBB in neurodegeneration is understudied. We developed an ALS patient-derived model of the BBB by using cells derived from 5 patient donors carrying C9ORF72 mutations. Brain microvascular endothelial-like cells (BMEC-like cells) derived from C9ORF72-ALS patients showed altered gene expression, compromised barrier integrity, and increased P-glycoprotein transporter activity. In addition, mitochondrial metabolic tests demonstrated that C9ORF72-ALS BMECs display a significant decrease in basal glycolysis accompanied by increased basal and ATP-linked respiration. Moreover, our study reveals that C9-ALS derived astrocytes can further affect BMECs function and affect the expression of the glucose transporter Glut-1. Finally, C9ORF72 patient-derived BMECs form leaky barriers through a cell-autonomous mechanism and have neurotoxic properties towards motor neurons.}, } @article {pmid38606235, year = {2024}, author = {Frolov, A and Guzman, MA and Hayat, G and Martin, JR}, title = {Two Cases of Sporadic Amyotrophic Lateral Sclerosis With Contrasting Clinical Phenotypes: Genetic Insights.}, journal = {Cureus}, volume = {16}, number = {3}, pages = {e56023}, pmid = {38606235}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease that affects individuals of diverse racial and ethnic backgrounds. There is currently no cure for ALS, and the number of efficient disease-modifying drugs for ALS is limited to a few, despite the large number of clinical trials conducted in recent years. The latter could be attributed to the significant heterogeneity of ALS clinical phenotypes even in their familial forms. To address this issue, we conducted postmortem genetic screening of two female patients with sporadic ALS (sALS) and contrasting clinical phenotypes. The results demonstrated that despite their contrasting clinical phenotypes, both patients had rare pathologic/deleterious mutations in five genes: ACSM5, BBS12, HLA-DQB1, MUC20, and OBSCN, with mutations in three of those genes being identical: BBS12, HLA-DQB1, and MUC20. Additional groups of mutated genes linked to ALS, other neurologic disorders, and ALS-related pathologies were also identified. These data are consistent with a hypothesis that an individual could be primed for ALS via mutations in a specific set of genes not directly linked to ALS. The disease could be initiated by a concerted action of several mutated genes linked to ALS and the disease's clinical phenotype will evolve further through accessory gene mutations associated with other neurological disorders and ALS-related pathologies.}, } @article {pmid38606777, year = {2024}, author = {Babu, S and Nicholson, KA and Rothstein, JD and Swenson, A and Sampognaro, PJ and Pant, P and Macklin, EA and Spruill, S and Paganoni, S and Gendron, TF and Prudencio, M and Petrucelli, L and Nix, D and Landrette, S and Nkrumah, E and Fandrick, K and Edwards, J and Young, PR}, title = {Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {9}, pages = {2998-3008}, doi = {10.1093/brain/awae109}, pmid = {38606777}, issn = {1460-2156}, support = {//OrphAI Therapeutics/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Double-Blind Method ; Adult ; Aged ; *C9orf72 Protein/genetics ; Pyrazoles/therapeutic use/pharmacokinetics ; Treatment Outcome ; Biomarkers/blood ; Hydrazones ; Morpholines ; Pyrimidines ; }, abstract = {Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.}, } @article {pmid38607083, year = {2024}, author = {Tamberi, L and Belloni, A and Pugnaloni, A and Rippo, MR and Olivieri, F and Procopio, AD and Bronte, G}, title = {The Influence of Myeloid-Derived Suppressor Cell Expansion in Neuroinflammation and Neurodegenerative Diseases.}, journal = {Cells}, volume = {13}, number = {7}, pages = {}, pmid = {38607083}, issn = {2073-4409}, mesh = {Humans ; *Myeloid-Derived Suppressor Cells/pathology ; Neuroinflammatory Diseases ; *Neurodegenerative Diseases/pathology ; Inflammation/pathology ; Cell Proliferation ; }, abstract = {The neuro-immune axis has a crucial function both during physiological and pathological conditions. Among the immune cells, myeloid-derived suppressor cells (MDSCs) exert a pivotal role in regulating the immune response in many pathological conditions, influencing neuroinflammation and neurodegenerative disease progression. In chronic neuroinflammation, MDSCs could lead to exacerbation of the inflammatory state and eventually participate in the impairment of cognitive functions. To have a complete overview of the role of MDSCs in neurodegenerative diseases, research on PubMed for articles using a combination of terms made with Boolean operators was performed. According to the search strategy, 80 papers were retrieved. Among these, 44 papers met the eligibility criteria. The two subtypes of MDSCs, monocytic and polymorphonuclear MDSCs, behave differently in these diseases. The initial MDSC proliferation is fundamental for attenuating inflammation in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), but not in amyotrophic lateral sclerosis (ALS), where MDSC expansion leads to exacerbation of the disease. Moreover, the accumulation of MDSC subtypes in distinct organs changes during the disease. The proliferation of MDSC subtypes occurs at different disease stages and can influence the progression of each neurodegenerative disorder differently.}, } @article {pmid38607533, year = {2024}, author = {Trinchillo, A and Valente, V and Esposito, M and Migliaccio, M and Iovino, A and Picciocchi, M and Cuomo, N and Caccavale, C and Nocerino, C and De Rosa, L and Salvatore, E and Pierantoni, GM and Menchise, V and Paladino, S and Criscuolo, C}, title = {Expanding SPG18 clinical spectrum: autosomal dominant mutation causes complicated hereditary spastic paraplegia in a large family.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {9}, pages = {4373-4381}, pmid = {38607533}, issn = {1590-3478}, support = {PE0000006//Italian Ministry for University and Research/ ; }, mesh = {Humans ; *Spastic Paraplegia, Hereditary/genetics ; Female ; Male ; *Pedigree ; Adult ; *Membrane Proteins/genetics ; *Mutation ; Middle Aged ; Phenotype ; Young Adult ; Adolescent ; Genes, Dominant ; Child ; Aged ; }, abstract = {BACKGROUND: SPG18 is caused by mutations in the endoplasmic reticulum lipid raft associated 2 (ERLIN2) gene. Autosomal recessive (AR) mutations are usually associated with complicated hereditary spastic paraplegia (HSP), while autosomal dominant (AD) mutations use to cause pure SPG18.

AIM: To define the variegate clinical spectrum of the SPG18 and to evaluate a dominant negative effect of erlin2 (encoded by ERLIN2) on oligomerization as causing differences between AR and AD phenotypes.

METHODS: In a four-generation pedigree with an AD pattern, a spastic paraplegia multigene panel test was performed. Oligomerization of erlin2 was analyzed with velocity gradient assay in fibroblasts of the proband and healthy subjects.

RESULTS: Despite the common p.V168M mutation identified in ERLIN2, a phenoconversion to amyotrophic lateral sclerosis (ALS) was observed in the second generation, pure HSP in the third generation, and a complicated form with psychomotor delay and epilepsy in the fourth generation. Erlin2 oligomerization was found to be normal.

DISCUSSION: We report the first AD SPG18 family with a complicated phenotype, and we ruled out a dominant negative effect of V168M on erlin2 oligomerization. Therefore, our data do not support the hypothesis of a relationship between the mode of inheritance and the phenotype, but confirm the multifaceted nature of SPG18 on both genetic and clinical point of view. Clinicians should be aware of the importance of conducting an in-depth clinical evaluation to unmask all the possible manifestations associated to an only apparently pure SPG18 phenotype. We confirm the genotype-phenotype correlation between V168M and ALS emphasizing the value of close follow-up.}, } @article {pmid38608255, year = {2025}, author = {Igarashi, S and Hioki, S and Sakamaru, N and Suzuki, A and Kurokawa, M and Kato, E}, title = {Flavan-3-ols, flavonoids, anthocyanidins and triterpenoids induces TIE2 phosphorylation -a candidate target for the vascular protective effects.}, journal = {Natural product research}, volume = {39}, number = {12}, pages = {3481-3485}, doi = {10.1080/14786419.2024.2340049}, pmid = {38608255}, issn = {1478-6427}, mesh = {Humans ; *Anthocyanins/pharmacology/chemistry ; Phosphorylation/drug effects ; *Flavonoids/pharmacology/chemistry ; *Receptor, TIE-2/metabolism ; *Triterpenes/pharmacology/chemistry ; HeLa Cells ; Molecular Structure ; Endothelial Cells/drug effects ; }, abstract = {Vascular system is essential for the body to maintain health. Dysregulated vascular system leads to cardiovascular diseases and are observed in ischaemic stroke, Alzheimer's disease, amyotrophic lateral sclerosis, and diabetes. TIE2 is a tyrosine kinase receptor expressed on vascular endothelial cells and contributes to the maintenance of a vascular system. In this paper, we screened for natural products with an activity to induce phosphorylation of TIE2, which will be beneficial for protection of a vascular system. Employing HeLa cells expressing TIE2, flavan-3-ols, flavonoids, anthocyanidins and triterpenoids were identified as active compounds that induce TIE2 phosphorylation. Several of the identified compounds are previously reported to protect endothelial cells from inflammation. Thus, the result provided TIE2 as the candidate receptor protein of those compounds for the protective effect of endothelial cells and the identified compounds will be a good candidate for maintenance of a vascular system.}, } @article {pmid38608469, year = {2024}, author = {Lee, AF and Chang, YH and Chien, LT and Yang, SC and Chiang, WC}, title = {A comparison between intraosseous and intravenous access in patients with out-of-hospital cardiac arrest: A retrospective cohort study.}, journal = {The American journal of emergency medicine}, volume = {80}, number = {}, pages = {162-167}, doi = {10.1016/j.ajem.2024.04.009}, pmid = {38608469}, issn = {1532-8171}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy ; Retrospective Studies ; *Infusions, Intraosseous/methods ; Male ; Female ; Middle Aged ; Aged ; Taiwan ; Cardiopulmonary Resuscitation/methods ; Emergency Medical Services/methods ; Aged, 80 and over ; }, abstract = {INTRODUCTION: The optimal vascular access for patients with out-of-hospital cardiac arrest (OHCA) remains controversial. Increasing evidence supports intraosseous (IO) access due to faster medication administration and higher first-attempt success rates compared to intravenous (IV) access. However, the impact on patient outcomes has been inconclusive.

METHODS: This retrospective cohort study in Taoyuan City, Taiwan, from January 1, 2019, to December 31, 2022, included patients aged ≥18 years with non-traumatic OHCA resuscitated by emergency medical technician paramedics (EMT-Ps) with either IVs or IOs for final vascular access. The exclusion criteria were cardiac arrest en route to the hospital and resuscitation during the coronavirus pandemic (from May 1, 2022, to October 31, 2022). The primary and secondary outcomes were sustained ROSC (≥2 h) and cerebral performance category (CPC) 1-2, respectively. Univariate logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CI) for the primary analysis. Multivariable logistic regression was employed, with variables selected based on a p-value of <0.05 in the univariate analysis. The survival benefits of different insertion sites and subgroups like general ambulance teams (with a composition that includes fewer EMT-Ps and limited experience in using IO access) were also analyzed.

RESULTS: A total of 2003 patients were enrolled; 1602 received IV access and 401 IO access. The median patient age was 70 years, and most were male (66.6%). Compared to patients receiving IV access, the adjusted odds ratios (aORs) for primary and secondary outcomes in patients with IOs were 0.83 (95% confidence interval [CI], 0.61-1.11; p = 0.20) and 0.96 (95% CI, 0.39-2.40; p = 0.93), respectively. Different insertion sites showed no outcome differences. In the subgroups of females and patients resuscitated by general ambulance teams, the aORs for sustained ROSC were 0.55 (95% CI, 0.33-0.92; p = 0.02) and 0.62 (95% CI, 0.41-0.94; p = 0.02), respectively.

CONCLUSIONS: For patients with OHCA resuscitated by EMT-Ps, IO access was comparable to IV access regarding patient outcomes. However, in females and patients resuscitated by general ambulance teams, IV access might be favorable.}, } @article {pmid38609644, year = {2024}, author = {Khalil, M and Teunissen, CE and Lehmann, S and Otto, M and Piehl, F and Ziemssen, T and Bittner, S and Sormani, MP and Gattringer, T and Abu-Rumeileh, S and Thebault, S and Abdelhak, A and Green, A and Benkert, P and Kappos, L and Comabella, M and Tumani, H and Freedman, MS and Petzold, A and Blennow, K and Zetterberg, H and Leppert, D and Kuhle, J}, title = {Neurofilaments as biomarkers in neurological disorders - towards clinical application.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {5}, pages = {269-287}, pmid = {38609644}, issn = {1759-4766}, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Intermediate Filaments/metabolism ; *Nervous System Diseases/diagnosis/metabolism/blood ; *Neurofilament Proteins/blood/metabolism ; }, abstract = {Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice.}, } @article {pmid38609711, year = {2024}, author = {Lin, Y and Wang, S and Yang, Q}, title = {Identification of hub genes and diagnostic efficacy for triple-negative breast cancer through WGCNA and Mendelian randomization.}, journal = {Discover oncology}, volume = {15}, number = {1}, pages = {117}, pmid = {38609711}, issn = {2730-6011}, support = {3502Z20227344//Xiamen Science and Technology Plan Project/ ; }, abstract = {OBJECTIVE: Triple-negative breast cancer (TNBC) represents a particularly aggressive form of breast cancer with a poor prognosis due to a lack of targeted treatments resulting from limited a understanding of the underlying mechanisms. The aim of this study was the identification of hub genes for TNBC and assess their clinical applicability in predicting the disease.

METHODS: This study employed a combination of weighted gene co-expression network analysis (WGCNA) and differentially expressed genes (DEGs) to identify new susceptible modules and central genes in TNBC. The potential functional roles of the central genes were investigated using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. Furthermore, a predictive model and ROC curve were developed to assess the diagnostic performance of the identified central genes. The correlation between CCNB1 and immune cells proportion was also investigated. At last, a Mendelian randomization (MR) analysis utilizing Genome-Wide Association Study (GWAS) data was analyzed to establish the causal effect of CCNB1 level on TNBC.

RESULTS: WGCNA was applied to determine gene co-expression maps and identify the most relevant module. Through a screening process, 1585 candidate hub genes were subsequently identified with WGCNA and DEGs. GO and KEGG function enrichment analysis indicated that these core genes were related to various biological processes, such as organelle fission, chromosome segregation, nuclear division, mitotic cell cycle phase transition, the cell cycle, amyotrophic lateral sclerosis, and motor proteins. Using STRING and Cytoscape, the top five genes with high degrees were identified as CDC2, CCNB1, CCNA2, TOP2A, and CCNB2. The nomogram model demonstrated good performance in predicting TNBC risk and was proven effective in diagnosis, as evidenced by the receiver operating characteristic (ROC) curve. Further investigation revealed a causal association between CCNB1 and immune cell infiltrates in TNBC. Survival analysis revealed high expression of the CCNB1 gene leads to poorer prognosis in TNBC patients. Additionally, analysis using inverse variance weighting revealed that CCNB1 was linked to a 2.8% higher risk of TNBC (OR: 1.028, 95% CI 1.002-1.055, p = 0.032).

CONCLUSION: We established a co-expression network using the WGCNA methodology to detect pivotal genes associated with TNBC. This finding holds promise for advancing the creation of pre-symptomatic diagnostic tools and deepening our comprehension of the pathogenic mechanisms involved in TNBC risk genes.}, } @article {pmid38609750, year = {2024}, author = {Sellier, C and Corcia, P and Vourc'h, P and Dupuis, L}, title = {C9ORF72 hexanucleotide repeat expansion: From ALS and FTD to a broader pathogenic role?.}, journal = {Revue neurologique}, volume = {180}, number = {5}, pages = {417-428}, doi = {10.1016/j.neurol.2024.03.008}, pmid = {38609750}, issn = {0035-3787}, mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; *DNA Repeat Expansion ; Phenotype ; Genetic Association Studies/methods ; Proteins/genetics ; }, abstract = {The major gene underlying monogenic forms of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) is C9ORF72. The causative mutation in C9ORF72 is an abnormal hexanucleotide (G4C2) repeat expansion (HRE) located in the first intron of the gene. The aim of this review is to propose a comprehensive update on recent developments on clinical, biological and therapeutics aspects related to C9ORF72 in order to highlight the current understanding of genotype-phenotype correlations, and also on biological machinery leading to neuronal death. We will particularly focus on the broad phenotypic presentation of C9ORF72-related diseases, that goes well beyond the classical phenotypes observed in ALS and FTD patients. Last, we will comment the possible therapeutical hopes for patients carrying a C9ORF72 HRE.}, } @article {pmid38609957, year = {2024}, author = {Charrin, L and Romain-Scelle, N and Di-Filippo, C and Mercier, E and Balen, F and Tazarourte, K and Benhamed, A}, title = {Impact of delayed mobile medical team dispatch for respiratory distress calls: a propensity score matched study from a French emergency communication center.}, journal = {Scandinavian journal of trauma, resuscitation and emergency medicine}, volume = {32}, number = {1}, pages = {27}, pmid = {38609957}, issn = {1757-7241}, mesh = {Adult ; Humans ; Male ; Aged ; Cross-Sectional Studies ; Propensity Score ; *Communication ; *Catecholamines ; Dyspnea ; }, abstract = {BACKGROUND: Shortness of breath is a common complaint among individuals contacting emergency communication center (EMCCs). In some prehospital system, emergency medical services include an advanced life support (ALS)-capable team. Whether such team should be dispatched during the phone call or delayed until the BLS-capable paramedic team reports from the scene is unclear. We aimed to evaluate the impact of delayed MMT dispatch until receiving the paramedic review compared to immediate dispatch at the time of the call on patient outcomes.

METHODS: A cross-sectional study conducted in Lyon, France, using data obtained from the departmental EMCC during the period from January to December 2019. We included consecutive calls related to adult patients experiencing acute respiratory distress. Patients from the two groups (immediate mobile medical team (MMT) dispatch or delayed MMT dispatch) were matched on a propensity score, and a conditional weighted logistic regression assessed the adjusted odds ratios (ORs) for each outcome (mortality on days 0, 7 and 30).

RESULTS: A total of 870 calls (median age 72 [57-84], male 466 53.6%) were sought for analysis [614 (70.6%) "immediate MMT dispatch" and 256 (29.4%) "delayed MMT" groups]. The median time before MMT dispatch was 25.1 min longer in the delayed MMT group (30.7 [26.4-36.1] vs. 5.6 [3.9-8.8] min, p < 0.001). Patients subjected to a delayed MMT intervention were older (median age 78 [66-87] vs. 69 [53-83], p < 0.001) and more frequently highly dependent (16.3% vs. 8.6%, p < 0.001). A higher proportion of patients in the delayed MMT group required bag valve mask ventilation (47.3% vs. 39.1%, p = 0.03), noninvasive ventilation (24.6% vs. 20.0%, p = 0.13), endotracheal intubation (7.0% vs. 4.1%, p = 0.07) and catecholamine infusion (3.9% vs. 1.3%, p = 0.01). After propensity score matching, mortality at day 0 was higher in the delayed MMT group (9.8% vs. 4.2%, p = 0.002). Immediate MMT dispatch at the call was associated with a lower risk of mortality on day 0 (0.60 [0.38;0.82], p < 0.001) day 7 (0.50 [0.27;0.72], p < 0.001) and day 30 (0.56 [0.35;0.78], p < 0.001) CONCLUSIONS: This study suggests that the deployment of an MMT at call in patients in acute respiratory distress may result in decreased short to medium-term mortality compared to a delayed MMT following initial first aid assessment.}, } @article {pmid38610012, year = {2024}, author = {Liu, X and Shen, L and Wan, M and Xie, H and Wang, Z}, title = {Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles.}, journal = {Journal of nanobiotechnology}, volume = {22}, number = {1}, pages = {170}, pmid = {38610012}, issn = {1477-3155}, support = {82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 2020YFC2008500//National Key R&D Program of China/ ; }, mesh = {Humans ; Prospective Studies ; *Extracellular Vesicles ; *Exosomes ; *Parkinson Disease ; *Alzheimer Disease ; }, abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis epitomize a class of insidious and relentless neurological conditions that are difficult to cure. Conventional therapeutic regimens often fail due to the late onset of symptoms, which occurs well after irreversible neurodegeneration has begun. The integrity of the blood-brain barrier (BBB) further impedes efficacious drug delivery to the central nervous system, presenting a formidable challenge in the pharmacological treatment of NDDs. Recent scientific inquiries have shifted focus toward the peripheral biological systems, investigating their influence on central neuropathology through the lens of extracellular vesicles (EVs). These vesicles, distinguished by their ability to breach the BBB, are emerging as dual operatives in the context of NDDs, both as conveyors of pathogenic entities and as prospective vectors for therapeutic agents. This review critically summarizes the burgeoning evidence on the role of extracerebral EVs, particularly those originating from bone, adipose tissue, and gut microbiota, in modulating brain pathophysiology. It underscores the duplicity potential of peripheral EVs as modulators of disease progression and suggests their potential as novel vehicles for targeted therapeutic delivery, positing a transformative impact on the future landscape of NDD treatment strategies. Search strategy A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus from January 2000 to December 2023. The search combined the following terms using Boolean operators: "neurodegenerative disease" OR "Alzheimer's disease" OR "Parkinson's disease" OR "Amyotrophic lateral sclerosis" AND "extracellular vesicles" OR "exosomes" OR "outer membrane vesicles" AND "drug delivery systems" AND "blood-brain barrier". MeSH terms were employed when searching PubMed to refine the results. Studies were included if they were published in English, involved human subjects, and focused on the peripheral origins of EVs, specifically from bone, adipose tissue, and gut microbiota, and their association with related diseases such as osteoporosis, metabolic syndrome, and gut dysbiosis. Articles were excluded if they did not address the role of EVs in the context of NDDs or did not discuss therapeutic applications. The titles and abstracts of retrieved articles were screened using a dual-review process to ensure relevance and accuracy. The reference lists of selected articles were also examined to identify additional relevant studies.}, } @article {pmid38610119, year = {2024}, author = {Vandenbogaerde, I and Van den Block, L and Deliens, L and Carduff, E and van der Heide, A and De Bleecker, J and De Vleminck, A}, title = {Experiences with advance care planning in amyotrophic lateral sclerosis: Qualitative longitudinal study with people with amyotrophic lateral sclerosis and their family carers.}, journal = {Palliative medicine}, volume = {38}, number = {5}, pages = {572-581}, doi = {10.1177/02692163241242320}, pmid = {38610119}, issn = {1477-030X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Advance Care Planning ; Male ; Female ; *Caregivers/psychology ; Middle Aged ; Longitudinal Studies ; Aged ; *Qualitative Research ; Adult ; Aged, 80 and over ; Terminal Care/psychology ; }, abstract = {BACKGROUND: It is unclear when people with amyotrophic lateral sclerosis and their family carers think about their future, what they would prefer in terms of care, and how their ideas change over time.

AIM: Understanding experiences with advance care planning of persons with amyotrophic lateral sclerosis and their family carers-and if, when, how, and why these experiences change over time.

DESIGN: A qualitative longitudinal interview study. Analysis involved content analysis, followed by a two-step timeline method to describe changes in advance care planning experiences within and across participants.

SETTING/PARTICIPANTS: Nine persons with amyotrophic lateral sclerosis and nine family carers who were interviewed three times over a 9-month period.

RESULTS: All participants thought about future care, but few talked about it. Over time, advance care planning experiences were influenced by intertwined elements: (1) experienced physical decline and related future care needs; (2) how persons with amyotrophic lateral sclerosis identify themselves as patients; (3) obtaining information about diagnosis and prognosis; (4) professionals initiating conversations about medical aspects of end-of-life decisions; (5) balancing between hope to remain stable and worry about the future; and (6) protecting themselves and each other from worries about the future.

CONCLUSION: This study emphasizes how factors such as coping with the disease and relational dynamics shape individuals' thoughts about future care over time and how psychological, social, and medical factors are interwoven in advance care planning. The findings advocate for a process-oriented perspective, portraying advance care planning as an ongoing dialog, encompassing the needs, concerns, and emotions of both people with amyotrophic lateral sclerosis and their family carers.}, } @article {pmid38610192, year = {2024}, author = {Papadopoulou, M and Papapostolou, A and Dimakopoulos, R and Salakou, S and Koropouli, E and Fanouraki, S and Bakola, E and Moschovos, C and Tsivgoulis, G}, title = {Non-Pharmacological Interventions on Pain in Amyotrophic Lateral Sclerosis Patients: A Systematic Review and Meta-Analysis.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {38610192}, issn = {2227-9032}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons. Some ALS patients exhibit concomitant nonmotor signs; thus, ALS is considered a multisystemic disorder. Pain is an important nonmotor symptom. Observational and case-control studies report high frequency of pain in ALS patients and it has been correlated with depression and quality of life. There are no specific scales for the assessment of pain and no randomized controlled trials (RCTs) regarding the drug management of pain in ALS.

AIM: To systematically review the evidence for the nonpharmacological interventions (NPIs) in relieving pain in ALS, on March 2024, we searched the following databases: Pubmed, Scopus, Web of Science, and Cochrane. We also checked the bibliographies of trials identified to include further published or unpublished trials.

MAIN RESULTS: A total of 1003 records were identified. Finally, five RCTs including 131 patients (64 in the intervention group and 67 in the control group) were included for meta-analysis. The interventions of the included RCTs consisted of muscle exercise, combined aerobics-strength intervention, and osteopathic manual treatment. The meta-analysis did not find a statistically significant difference in favor of NPIs for alleviating pain in ALS patients.

CONCLUSIONS: ALS has a fulminant course and irreversibly leads to death. Pain in ALS patients, although a common nonmotor symptom, is often unrecognized and undertreated, and this is underlined by the lack of any RCTs on drug therapy for pain. Albeit NPIs are considered safe, as adverse effects are rarely reported, this systematic review did not provide sufficient evidence for a beneficial effect on pain. The scarceness of relevant literature highlights the need for future studies, with larger samples, more homogeneous in terms of interventions and population characteristics (stage of disease), and better choice of measurement scales to further investigate the efficacy, if any, of various pain interventions in ALS patients.}, } @article {pmid38610566, year = {2024}, author = {Maset-Roig, R and Caplliure-Llopis, J and de Bernardo, N and Privado, J and Alarcón-Jiménez, J and Martín-Ruiz, J and Botella-Navas, M and Villarón-Casales, C and Sancho-Cantus, D and de la Rubia Ortí, JE}, title = {Analysis of Heart Rate Variability in Individuals Affected by Amyotrophic Lateral Sclerosis.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {7}, pages = {}, pmid = {38610566}, issn = {1424-8220}, support = {2017-216-001//Catholic University of Valencia/ ; }, mesh = {Male ; Humans ; Female ; *Amyotrophic Lateral Sclerosis ; Heart Rate ; Autonomic Nervous System ; Health Status ; Heart ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) produces alterations in the autonomic nervous system (ANS), which explains the cardiac manifestations observed in patients. The assessment of heart rate variability (HRV) is what best reflects the activity of the ANS on heart rate. The Polar H7 Bluetooth[®] device proves to be a non-invasive and much faster technology than existing alternatives for this purpose.

OBJECTIVE: The goal of this study is to determine HRV using Polar H7 Bluetooth technology in ALS patients, comparing the obtained measurements with values from healthy individuals.

METHOD: The sample consisted of 124 participants: 68 diagnosed with ALS and 56 healthy individuals. Using Polar H7 Bluetooth technology and the ELITE HRV application, various HRV measurements were determined for all participants, specifically the HRV index, RMSSD, RMSSD LN, SDNN index, PNN50, LF, HF, LF/HF ratio, HR average, and HF peak frequency.

RESULTS: Statistically significant differences were observed between ALS patients and healthy individuals in the HRV index, RMSSD, RMSSD LN, SDNN index, PNN50, HF, and LF, where healthy individuals exhibited higher scores. For the HR average, the ALS group showed a higher value. Values were similar when comparing men and women with ALS, with only a higher HF peak frequency observed in women.

CONCLUSION: The Polar H7 Bluetooth[®] device is effective in determining heart rate variability alterations in ALS, being a promising prognostic tool for the disease.}, } @article {pmid38610601, year = {2024}, author = {Piñar-Gutiérrez, A and González-Gracia, L and Vázquez Gutiérrez, R and García-Rey, S and Jiménez-Sánchez, A and González-Navarro, I and Tatay-Domínguez, D and Garrancho-Domínguez, P and Remón-Ruiz, PJ and Martínez-Ortega, AJ and Serrano-Aguayo, P and Giménez-Andreu, MD and García-Fernández, FJ and Bozada-García, JM and Nacarino-Mejías, V and López-Iglesias, Á and Pereira-Cunill, JL and García-Luna, PP}, title = {Percutaneous Gastrostomies: Associated Complications in PUSH vs. PULL Techniques over 12 Years in a Referral Centre.}, journal = {Journal of clinical medicine}, volume = {13}, number = {7}, pages = {}, pmid = {38610601}, issn = {2077-0383}, abstract = {Objectives: To compare complications associated with percutaneous gastrostomies performed using PUSH and PULL techniques, whether endoscopic (PEG) or radiological (PRG), in a tertiary-level hospital. Methods: This was a prospective observational study. Adult patients who underwent percutaneous PULL or PUSH gastrostomy using PEG or PRG techniques at the Virgen del Rocio University Hospital and subsequently followed up in the Nutrition Unit between 2009-2020 were included. X2 tests or Fisher's test were used for the comparison of proportions when necessary. Univariate analysis was conducted to study risk factors for PRG-associated complications. Results: n = 423 (PULL = 181; PUSH = 242). The PULL technique was associated with a higher percentage of total complications (37.6% vs. 23.8%; p = 0.005), exudate (18.2% vs. 11.2%; p = 0.039), and irritation (3.3% vs. 0%; p = 0.006). In the total sample, there were 5 (1.1%) cases of peritonitis, 3 (0.7%) gastrocolic fistulas, and 1 (0.2%) death due to complications associated with gastrostomy. Gender, age, and different indications were not risk factors for a higher number of complications. The most common indications were neurological diseases (35.9%), head and neck cancer (29%), and amyotrophic lateral sclerosis (17.2%). Conclusions: The PULL technique was associated with more total complications than the PUSH technique, but both were shown to be safe techniques, as the majority of complications were minor.}, } @article {pmid38612448, year = {2024}, author = {Homma, H and Tanaka, H and Fujita, K and Okazawa, H}, title = {Necrosis Links Neurodegeneration and Neuroinflammation in Neurodegenerative Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {7}, pages = {}, pmid = {38612448}, issn = {1422-0067}, mesh = {Humans ; *HMGB1 Protein ; *Neurodegenerative Diseases ; Neuroinflammatory Diseases ; Necrosis ; Cell Death ; }, abstract = {The mechanisms of neuronal cell death in neurodegenerative disease remain incompletely understood, although recent studies have made significant advances. Apoptosis was previously considered to be the only mechanism of neuronal cell death in neurodegenerative diseases. However, recent findings have challenged this dogma, identifying new subtypes of necrotic neuronal cell death. The present review provides an updated summary of necrosis subtypes and discusses their potential roles in neurodegenerative cell death. Among numerous necrosis subtypes, including necroptosis, paraptosis, ferroptosis, and pyroptosis, transcriptional repression-induced atypical cell death (TRIAD) has been identified as a potential mechanism of neuronal cell death. TRIAD is induced by functional deficiency of TEAD-YAP and self-amplifies via the release of HMGB1. TRIAD is a feasible potential mechanism of neuronal cell death in Alzheimer's disease and other neurodegenerative diseases. In addition to induction of cell death, HMGB1 released during TRIAD activates brain inflammatory responses, which is a potential link between neurodegeneration and neuroinflammation.}, } @article {pmid38612591, year = {2024}, author = {Moțățăianu, A and Andone, S and Stoian, A and Bălașa, R and Huțanu, A and Sărmășan, E}, title = {A Potential Role of Interleukin-5 in the Pathogenesis and Progression of Amyotrophic Lateral Sclerosis: A New Molecular Perspective.}, journal = {International journal of molecular sciences}, volume = {25}, number = {7}, pages = {}, pmid = {38612591}, issn = {1422-0067}, support = {293/5/2020//University of Medicine and Pharmacy of Târgu Mureş/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Cytokines ; Disease Progression ; *Interleukin-5 ; Upper Extremity ; }, abstract = {Cumulative data suggest that neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis. The purpose of this work was to assess if patients with ALS present a specific peripheral cytokine profile and if it correlates with neurological disability assessed by ALSFRS-R, the rate of disease progression, and the pattern of disease progression (horizontal spreading [HSP] versus vertical spreading [VSP]). We determined the levels of 15 cytokines in the blood of 59 patients with ALS and 40 controls. We identified a positive correlation between levels of pro-inflammatory cytokines (interleukin [IL]-17F, IL-33, IL-31) and the age of ALS patients, as well as a positive correlation between IL-12p/70 and survival from ALS onset and ALS diagnosis. Additionally, there was a positive correlation between the ALSFRS-R score in the upper limb and respiratory domain and IL-5 levels. In our ALS cohort, the spreading pattern was 42% horizontal and 58% vertical, with patients with VSP showing a faster rate of ALS progression. Furthermore, we identified a negative correlation between IL-5 levels and the rate of disease progression, as well as a positive correlation between IL-5 and HSP of ALS. To the best of our knowledge, this is the first study reporting a "protective" role of IL-5 in ALS.}, } @article {pmid38612745, year = {2024}, author = {Ke, H and Chen, Y and Zhang, B and Duan, S and Ma, X and Ren, B and Wang, Y}, title = {Odorant Receptors Expressing and Antennal Lobes Architecture Are Linked to Caste Dimorphism in Asian Honeybee, Apis cerana (Hymenoptera: Apidae).}, journal = {International journal of molecular sciences}, volume = {25}, number = {7}, pages = {}, pmid = {38612745}, issn = {1422-0067}, support = {2023YFE0113600//National Key Research and Development Program "Intergovernmental international cooperation on science, technology and innovation"/ ; 20200402001NC//Natural Science Foundation of Jilin Province/ ; 20190301047NY//Natural Science Foundation of Jilin Province/ ; }, mesh = {Bees/genetics ; Animals ; *Hymenoptera ; Sex Characteristics ; Cell Communication ; Food ; *Receptors, Odorant/genetics ; }, abstract = {Insects heavily rely on the olfactory system for food, mating, and predator evasion. However, the caste-related olfactory differences in Apis cerana, a eusocial insect, remain unclear. To explore the peripheral and primary center of the olfactory system link to the caste dimorphism in A. cerana, transcriptome and immunohistochemistry studies on the odorant receptors (ORs) and architecture of antennal lobes (ALs) were performed on different castes. Through transcriptomesis, we found more olfactory receptor genes in queens and workers than in drones, which were further validated by RT-qPCR, indicating caste dimorphism. Meanwhile, ALs structure, including volume, surface area, and the number of glomeruli, demonstrated a close association with caste dimorphism. Particularly, drones had more macroglomeruli possibly for pheromone recognition. Interestingly, we found that the number of ORs and glomeruli ratio was nearly 1:1. Also, the ORs expression distribution pattern was very similar to the distribution of glomeruli volume. Our results suggest the existence of concurrent plasticity in both the peripheral olfactory system and ALs among different castes of A. cerana, highlighting the role of the olfactory system in labor division in insects.}, } @article {pmid38612804, year = {2024}, author = {Giri, PM and Banerjee, A and Ghosal, A and Layek, B}, title = {Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications.}, journal = {International journal of molecular sciences}, volume = {25}, number = {7}, pages = {}, pmid = {38612804}, issn = {1422-0067}, support = {P20 GM109024/GM/NIGMS NIH HHS/United States ; 2P20M109024/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Neuroinflammatory Diseases ; Inflammation/therapy ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Central Nervous System ; }, abstract = {Neurodegenerative disorders (NDs) have become increasingly common during the past three decades. Approximately 15% of the total population of the world is affected by some form of NDs, resulting in physical and cognitive disability. The most common NDs include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although NDs are caused by a complex interaction of genetic, environmental, and lifestyle variables, neuroinflammation is known to be associated with all NDs, often leading to permanent damage to neurons of the central nervous system. Furthermore, numerous emerging pieces of evidence have demonstrated that inflammation not only supports the progression of NDs but can also serve as an initiator. Hence, various medicines capable of preventing or reducing neuroinflammation have been investigated as ND treatments. While anti-inflammatory medicine has shown promising benefits in several preclinical models, clinical outcomes are often questionable. In this review, we discuss various NDs with their current treatment strategies, the role of neuroinflammation in the pathophysiology of NDs, and the use of anti-inflammatory agents as a potential therapeutic option.}, } @article {pmid38613054, year = {2024}, author = {López-Gómez, JJ and Izaola-Jauregui, O and Almansa-Ruiz, L and Jiménez-Sahagún, R and Primo-Martín, D and Pedraza-Hueso, MI and Ramos-Bachiller, B and González-Gutiérrez, J and De Luis-Román, D}, title = {Use of Muscle Ultrasonography in Morphofunctional Assessment of Amyotrophic Lateral Sclerosis (ALS).}, journal = {Nutrients}, volume = {16}, number = {7}, pages = {}, pmid = {38613054}, issn = {2072-6643}, mesh = {Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Body Mass Index ; *Deglutition Disorders ; *Malnutrition ; Quadriceps Muscle/diagnostic imaging ; Prospective Studies ; }, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a progressive disease with a high prevalence of malnutrition that can influence prognosis. The main objective of this study is to compare the validity of muscle ultrasonography in the diagnosis of malnutrition and the prognosis of patients with ALS.

METHODS: This is a prospective observational study that analyzes the nutritional status of patients at the beginning of nutritional monitoring. The morphofunctional assessment included the examination of anthropometric variables such as weight, height, body mass index (BMI), arm circumference, and calf circumference. Additionally, electrical bioimpedanciometry (BIA) was used to measure electrical parameters and estimate other relevant metrics. Muscle ultrasonography[®] (quadriceps rectus femoris (QRF)) assessed muscle mass parameters, including muscle area index (MARAI), anteroposterior diameter of the QRF (Y-axis) (cm), transverse diameter of the QRF (X-axis) (cm), and the sum of the quadriceps thickness (RF+VI) (cm), as well as muscle quality parameters such as echogenicity and the Y-X index.

RESULTS: A total of 37 patients diagnosed with amyotrophic lateral sclerosis (ALS) were included in this study. Of these patients, 51.4% were men. The mean age was 64.27 (12.59) years. A total of 54.1% of the patients had a bulbar onset of amyotrophic lateral sclerosis, and 45.9% had spinal onset. The percentage of subjects with malnutrition diagnosed by the Global Leadership Initiative on Malnutrition (GLIM) criteria was 45.9% of patients. There was a direct correlation between muscle mass parameters assessed by muscle ultrasonography (RF+VI) and active mass markers measured by bioimpedanciometry (body cellular mass index (BCMI) (r = 0.62; p < 0.01), fat-free mass index (FFMI) (r = 0.75; p < 0.01), and appendicular skeletal mass index (ASMI) (r = 0.69; p < 0.01)). There was a direct correlation between echogenicity and resistance (r = 0.44; p = 0.02), as well as between the fat-free mass index and the Y-X index (r = 0.36; p = 0.14). Additionally, there was a negative correlation between echogenicity and BCMI (r = -0.46; p < 0.01) and ASMI (r = 0.34; p = 0.06). Patients with low quadriceps thickness (male < 2.49 cm; female < 1.84 cm) showed an increased risk of hospital admission adjusted by age, sex, and presence of dysphagia (OR: 7.84 (CI 95%: 1.09-56.07); p-value = 0.04), and patients with low-quality mass (Y-X index < 0.35) had a higher risk of hospital admission adjusted by age, sex, and presence of dysphagia (OR: 19.83 (CI 95%: 1.77-222.46); p-value = 0.02).

CONCLUSIONS: In patients with ALS, ultrasonography echogenicity was inversely related to BCMI, FFMI, and ASMI, and the Y-X index was directly related to FFMI. The lowest quartiles of quadriceps thickness and Y-X index are risk factors for hospital admission.}, } @article {pmid38613779, year = {2024}, author = {Huang, Z and Zhou, Y and Liu, Y and Wang, J}, title = {Protocol to identify DNA-binding proteins recognizing nucleotide repeat dsDNAs.}, journal = {STAR protocols}, volume = {5}, number = {2}, pages = {103013}, pmid = {38613779}, issn = {2666-1667}, support = {R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS128494/NS/NINDS NIH HHS/United States ; }, mesh = {*DNA/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; Electrophoretic Mobility Shift Assay/methods ; C9orf72 Protein/genetics/metabolism ; Isotope Labeling/methods ; }, abstract = {DNA-binding proteins perform diverse functions, including regulating cellular growth and orchestrating chromatin architecture. Here, we present a protocol to discover proteins specifically interacting with a hexanucleotide repeat DNA, the expansion of which is known as the most frequent genetic cause of familial C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia. We describe steps to fish out DNA-binding proteins recognizing double-stranded repeat DNAs using a SILAC (stable isotope labelling by amino acids in cell culture)-based approach and validate the results using electrophoretic mobility shift assay. For complete details on the use and execution of this protocol, please refer to Liu et al.[1].}, } @article {pmid38613988, year = {2024}, author = {Ruotolo, G and D'Anzi, A and Casamassa, A and Mazzoni, M and Ferrari, D and Lombardi, I and Carletti, RM and D'Asdia, C and Torrente, I and Frezza, K and Lattante, S and Sabatelli, M and Pennuto, M and Vescovi, AL and Rosati, J}, title = {Generation of induced pluripotent stem cells (CSSi017-A)(12862) from an ALS patient carrying a repeat expansion in the C9orf72 gene.}, journal = {Stem cell research}, volume = {77}, number = {}, pages = {103412}, doi = {10.1016/j.scr.2024.103412}, pmid = {38613988}, issn = {1876-7753}, mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *DNA Repeat Expansion ; Cell Differentiation ; Fibroblasts/metabolism ; Cell Line ; Male ; }, abstract = {Genetic expansions of the hexanucleotide repeats (GGGGCC) in the C9orf72 gene appear in approximately 40% of patients with familial ALS and 7% of patients with sporadic ALS in the European population, making this mutation one of the most prevalent genetic mutations in ALS. Here, we generated a human induced pluripotent stem cell (hiPSC) line from the dermal fibroblasts of a patient carrying a 56-repeat expansion in an ALS disease-causing allele of C9orf72. These iPSCs showed stable amplification in vitro with normal karyotype and high expression of pluripotent markers and differentiated spontaneously in vivo into three germ layers.}, } @article {pmid38614367, year = {2024}, author = {Roghani, AK and Garcia, RI and Roghani, A and Reddy, A and Khemka, S and Reddy, RP and Pattoor, V and Jacob, M and Reddy, PH and Sehar, U}, title = {Treating Alzheimer's disease using nanoparticle-mediated drug delivery strategies/systems.}, journal = {Ageing research reviews}, volume = {97}, number = {}, pages = {102291}, doi = {10.1016/j.arr.2024.102291}, pmid = {38614367}, issn = {1872-9649}, support = {R01 AG069333/AG/NIA NIH HHS/United States ; RF1 AG079264/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Delivery Systems/methods ; Animals ; *Blood-Brain Barrier/drug effects/metabolism ; *Nanoparticles/administration & dosage ; Nanoparticle Drug Delivery System ; }, abstract = {The administration of promising medications for the treatment of neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) is significantly hampered by the blood-brain barrier (BBB). Nanotechnology has recently come to light as a viable strategy for overcoming this obstacle and improving drug delivery to the brain. With a focus on current developments and prospects, this review article examines the use of nanoparticles to overcome the BBB constraints to improve drug therapy for AD The potential for several nanoparticle-based approaches, such as those utilizing lipid-based, polymeric, and inorganic nanoparticles, to enhance drug transport across the BBB are highlighted. To shed insight on their involvement in aiding effective drug transport to the brain, methods of nanoparticle-mediated drug delivery, such as surface modifications, functionalization, and particular targeting ligands, are also investigated. The article also discusses the most recent findings on innovative medication formulations encapsulated within nanoparticles and the therapeutic effects they have shown in both preclinical and clinical testing. This sector has difficulties and restrictions, such as the need for increased safety, scalability, and translation to clinical applications. However, the major emphasis of this review aims to provide insight and contribute to the knowledge of how nanotechnology can potentially revolutionize the worldwide treatment of NDDs, particularly AD, to enhance clinical outcomes.}, } @article {pmid38615537, year = {2024}, author = {Xu, Z and Zhang, J and Tang, J and Gong, Y and Zou, Y and Zhang, Q}, title = {Dissecting the effect of ALS mutation S375G on the conformational properties and aggregation dynamics of TDP-43370-375 fragment.}, journal = {Biophysical chemistry}, volume = {310}, number = {}, pages = {107230}, doi = {10.1016/j.bpc.2024.107230}, pmid = {38615537}, issn = {1873-4200}, mesh = {*Molecular Dynamics Simulation ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *DNA-Binding Proteins/chemistry/genetics/metabolism ; *Mutation ; Protein Conformation ; Protein Aggregates ; Peptide Fragments/chemistry/genetics/metabolism ; }, abstract = {The aggregation of transactive response deoxyribonucleic acid (DNA) binding protein of 43 kDa (TDP-43) into ubiquitin-positive inclusions is closely associated with amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and chronic traumatic encephalopathy. The 370-375 fragment of TDP-43 ([370]GNNSYS[375], TDP-43370-375), the amyloidogenic hexapeptides, can be prone to forming pathogenic amyloid fibrils with the characteristic of steric zippers. Previous experiments reported the ALS-associated mutation, serine 375 substituted by glycine (S375G) is linked to early onset disease and protein aggregation of TDP-43. Based on this, it is necessary to explore the underlying molecular mechanisms. By utilizing all-atom molecular dynamics (MD) simulations of 102 μs in total, we investigated the impact of S375G mutation on the conformational ensembles and oligomerization dynamics of TDP-43370-375 peptides. Our replica exchange MD simulations show that S375G mutation could promote the unstructured conformation formation and induce peptides to form a loose packed oligomer, thus inhibiting the aggregation of TDP-43370-375. Further analyses suggest that S375G mutation displays a reduction effect on the number of total hydrogen bonds and contacts among TDP-43370-375 peptides. Hydrogen bonding and polar interactions among TDP-43370-375 peptides, as well as Y374-Y374 π-π stacking interaction, are attenuated by S375G mutation. Additional microsecond MD simulations demonstrate that S375G mutation could prohibit the conformational conversion to β-structure-rich aggregates and possess an inhibitory effect on the oligomerization dynamics of TDP-43370-375. This study offers for the first time of molecular insights into the S375G mutation affecting the aggregation of TDP-43370-375 at the atomic level, and may open new avenues in the development of future site-specific mutation therapeutics.}, } @article {pmid38615685, year = {2024}, author = {Beckers, J and Van Damme, P}, title = {Toxic gain-of-function mechanisms in C9orf72 ALS-FTD neurons drive autophagy and lysosome dysfunction.}, journal = {Autophagy}, volume = {20}, number = {9}, pages = {2102-2104}, pmid = {38615685}, issn = {1554-8635}, mesh = {*C9orf72 Protein/genetics/metabolism ; *Autophagy/genetics/physiology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Lysosomes/metabolism ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; Gain of Function Mutation/genetics ; DNA-Binding Proteins/metabolism/genetics ; Neurons/metabolism ; Sequestosome-1 Protein/metabolism/genetics ; }, abstract = {Hexanucleotide repeat expansions in the C9orf72 gene are the primary genetic cause for both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two related neurodegenerative diseases. Significant advances in the elucidation of the disease mechanisms responsible for C9orf72 ALS-FTD have revealed both a toxic gain-of-function and a loss-of-function mechanism as possible underlying disease cause. As the differential contribution of both gain and loss of function in C9orf72 ALS-FTD pathogenesis remains debated, we investigated disease mechanisms in motor neurons derived from both authentic human patient C9orf72 ALS-FTD iPSCs as well as a C9orf72 knockout iPSC line. We found that patient neurons presented with less motile and enlarged lysosomes, a decrease in autophagic flux and an increase in SQSTM1/p62 puncta and insoluble TARDBP/TDP-43 species. Importantly, we found that C9orf72 knockout barely has any influence on these phenotypes and mainly results in impaired endosomal maturation. Together, our data suggest that toxic gain-of-function, rather than loss-of-function, mechanisms in C9orf72 ALS-FTD impair the autophagy-lysosome system in neurons.}, } @article {pmid38617277, year = {2024}, author = {Liu, D and Webber, HC and Bian, F and Xu, Y and Prakash, M and Feng, X and Yang, M and Yang, H and You, IJ and Li, L and Liu, L and Liu, P and Huang, H and Chang, CY and Liu, L and Shah, SH and Torre, A and Welsbie, DS and Sun, Y and Duan, X and Goldberg, JL and Braun, M and Lansky, Z and Hu, Y}, title = {Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38617277}, issn = {2692-8205}, support = {R01 EY034353/EY/NEI NIH HHS/United States ; P30 EY026877/EY/NEI NIH HHS/United States ; R01 EY024932/EY/NEI NIH HHS/United States ; S10 OD025091/OD/NIH HHS/United States ; R01 EY032518/EY/NEI NIH HHS/United States ; R01 EY023295/EY/NEI NIH HHS/United States ; F32 EY029567/EY/NEI NIH HHS/United States ; R01 EY032159/EY/NEI NIH HHS/United States ; R01 EY025295/EY/NEI NIH HHS/United States ; S10 OD030452/OD/NIH HHS/United States ; }, abstract = {Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We found that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a striking decrease of axonal mitochondria. Surprisingly, we discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Encouragingly, overexpressing OPTN/TRAK1/KIF5B reverses not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes striking ON regeneration. Therefore, in addition to generating new animal models for NTG and ALS, our results establish OPTN as a novel facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.}, } @article {pmid38617322, year = {2024}, author = {Lowry, ER and Patel, T and Costa, JA and Chang, E and Tariq, S and Melikyan, H and Davis, IM and Aziz, S and Dermentzaki, G and Lotti, F and Wichterle, H}, title = {Embryonic motor neuron programming factors reactivate immature gene expression and suppress ALS pathologies in postnatal motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38617322}, issn = {2692-8205}, support = {R01 NS109217/NS/NINDS NIH HHS/United States ; K99 NS121136/NS/NINDS NIH HHS/United States ; R21 NS101575/NS/NINDS NIH HHS/United States ; R01 NS116141/NS/NINDS NIH HHS/United States ; R00 NS121136/NS/NINDS NIH HHS/United States ; R01 AG084965/AG/NIA NIH HHS/United States ; }, abstract = {Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resilience of young motor neurons could be restored by re-expression of the embryonic motor neuron selector transcription factors ISL1 and LHX3. We found that viral re-expression of ISL1 and LHX3 reactivates aspects of the youthful gene expression program in mature motor neurons and alleviates key disease-relevant phenotypes in the SOD1[G93A] mouse model of ALS. Our results suggest that redeployment of lineage-specific neuronal selector transcription factors can be an effective strategy to attenuate age-dependent phenotypes in neurodegenerative disease.}, } @article {pmid38617354, year = {2024}, author = {Lynch, EM and Pittman, S and Daw, J and Ikenaga, C and Chen, S and Dhavale, DD and Jackrel, ME and Ayala, YM and Kotzbauer, P and Ly, CV and Pestronk, A and Lloyd, TE and Weihl, CC}, title = {Seeding competent TDP-43 persists in human patient and mouse muscle.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38617354}, issn = {2692-8205}, support = {F32 NS124841/NS/NINDS NIH HHS/United States ; K24 AR073317/AR/NIAMS NIH HHS/United States ; R01 AG031867/AG/NIA NIH HHS/United States ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous system of some neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy (IBM). TDP-43 aggregates from ALS and FTD brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in IBM patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with IBM, IMNM and ALS we found that TDP-43 seeding capacity was specific to IBM. Surprisingly, TDP-43 seeding capacity anti-correlated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.}, } @article {pmid38621087, year = {2024}, author = {Zhuang, Y and Wang, Y and Yang, X and Ma, T}, title = {Visible light positioning system using a smartphone's built-in ambient light sensor and inertial measurement unit.}, journal = {Optics letters}, volume = {49}, number = {8}, pages = {2105-2108}, doi = {10.1364/OL.519674}, pmid = {38621087}, issn = {1539-4794}, abstract = {In recent years, the visible light positioning field has experienced remarkable advancements. However, smartphones find it difficult to identify light-emitting diode (LED) and extract each LED's light signal intensity due to the low-frequency and uneven sampling of built-in ambient light sensors (ALS, which is a photodiode that measures ambient light in lux units). Thus, traditional visible light positioning systems cannot be directly applied to smartphones. In this Letter, we propose a single-light visible light positioning system using a non-modulated LED as an emitter, the built-in ALS as the receiver, and the inertial measurement unit of the smartphone to assist in measuring the smartphone's attitude. It only requires the user to turn the smartphone by a few angles in a stationary position to estimate its current three-dimensional (3D) spatial position. This method does not require modification of the existing lighting system and consumes less power than the camera-based visible light positioning (VLP) systems. We have built an experimental site measuring 5 m × 5 m × 2.2 m to evaluate the performance of the positioning system, and the preliminary results show that the proposed system achieves sub-meter-level positioning accuracy.}, } @article {pmid38621131, year = {2024}, author = {Sachdev, A and Gill, K and Sckaff, M and Birk, AM and Aladesuyi Arogundade, O and Brown, KA and Chouhan, RS and Issagholian-Lewin, PO and Patel, E and Watry, HL and Bernardi, MT and Keough, KC and Tsai, YC and Smith, AST and Conklin, BR and Clelland, CD}, title = {Reversal of C9orf72 mutation-induced transcriptional dysregulation and pathology in cultured human neurons by allele-specific excision.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {17}, pages = {e2307814121}, pmid = {38621131}, issn = {1091-6490}, support = {P01 HL146366/HL/NHLBI NIH HHS/United States ; K08 NS112330/NS/NINDS NIH HHS/United States ; U19 NS132303/NS/NINDS NIH HHS/United States ; TL1 TR001871/TR/NCATS NIH HHS/United States ; R01 HL130533/HL/NHLBI NIH HHS/United States ; RF1 AG072052/AG/NIA NIH HHS/United States ; R01 AG072052/AG/NIA NIH HHS/United States ; R03 TR004009/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; C9orf72 Protein/genetics/metabolism ; Alleles ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/metabolism ; Motor Neurons/metabolism ; Mutation ; DNA Repeat Expansion/genetics ; Dipeptides/metabolism ; }, abstract = {Efforts to genetically reverse C9orf72 pathology have been hampered by our incomplete understanding of the regulation of this complex locus. We generated five different genomic excisions at the C9orf72 locus in a patient-derived induced pluripotent stem cell (iPSC) line and a non-diseased wild-type (WT) line (11 total isogenic lines), and examined gene expression and pathological hallmarks of C9 frontotemporal dementia/amyotrophic lateral sclerosis in motor neurons differentiated from these lines. Comparing the excisions in these isogenic series removed the confounding effects of different genomic backgrounds and allowed us to probe the effects of specific genomic changes. A coding single nucleotide polymorphism in the patient cell line allowed us to distinguish transcripts from the normal vs. mutant allele. Using digital droplet PCR (ddPCR), we determined that transcription from the mutant allele is upregulated at least 10-fold, and that sense transcription is independently regulated from each allele. Surprisingly, excision of the WT allele increased pathologic dipeptide repeat poly-GP expression from the mutant allele. Importantly, a single allele was sufficient to supply a normal amount of protein, suggesting that the C9orf72 gene is haplo-sufficient in induced motor neurons. Excision of the mutant repeat expansion reverted all pathology (RNA abnormalities, dipeptide repeat production, and TDP-43 pathology) and improved electrophysiological function, whereas silencing sense expression did not eliminate all dipeptide repeat proteins, presumably because of the antisense expression. These data increase our understanding of C9orf72 gene regulation and inform gene therapy approaches, including antisense oligonucleotides (ASOs) and CRISPR gene editing.}, } @article {pmid38621442, year = {2024}, author = {Dewangan, D and Joshi, A and Padhi, AK}, title = {Long-timescale atomistic simulations uncover loss-of-function mechanisms of uncharacterized Angiogenin mutants associated with ALS.}, journal = {Archives of biochemistry and biophysics}, volume = {756}, number = {}, pages = {110000}, doi = {10.1016/j.abb.2024.110000}, pmid = {38621442}, issn = {1096-0384}, mesh = {*Ribonuclease, Pancreatic/chemistry/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Molecular Dynamics Simulation ; Loss of Function Mutation ; Molecular Docking Simulation ; Mutation ; Protein Conformation ; Thermodynamics ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive degeneration of motor neurons, resulting in respiratory failure and mortality within 3-5 years. Mutations in the Angiogenin (ANG) cause loss of ribonucleolytic and nuclear translocation activities, contributing to ALS pathogenesis. This study focused on investigating two uncharacterized ANG mutations, T11S and R122H, newly identified in the Project Mine consortium. Using extensive computational analysis, including structural modeling and microsecond-timescale molecular dynamics (MD) simulations, we observed conformational changes in the catalytic residue His114 of ANG induced by T11S and R122H mutations. These alterations impaired ribonucleolytic activity, as inferred through molecular docking and binding free energy calculations. Gibbs free energy landscape and residue-residue interaction network analysis further supported our findings, revealing the energetic states and allosteric pathway from the mutated site to His114. Additionally, we assessed the binding of NCI-65828, an inhibitor of ribonucleolytic activity of ANG, and found reduced effectiveness in binding to T11S and R122H mutants when His114 assumed a non-native conformation. This highlights the crucial role of His114 and its association with ALS. Elucidating the relationship between physical structure and functional dynamics of frequently mutated ANG mutants is essential for understanding ALS pathogenesis and developing more effective therapeutic interventions.}, } @article {pmid38621696, year = {2025}, author = {Müller, F and Proske, A and Füchtmeier, B and Wulbrand, C}, title = {Are Process Changes Measurable? An Analysis of 4136 Proximal Femur Fractures over 16 Year.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {1}, pages = {27-34}, doi = {10.1055/a-2276-6440}, pmid = {38621696}, issn = {1864-6743}, mesh = {Humans ; Retrospective Studies ; Male ; Female ; Reoperation/statistics & numerical data ; Aged ; *Fracture Fixation, Internal/statistics & numerical data ; Trauma Centers ; Aged, 80 and over ; Middle Aged ; Germany/epidemiology ; *Hip Fractures/surgery/mortality ; Fracture Fixation, Intramedullary ; Postoperative Complications ; *Femoral Fractures/surgery ; Blood Transfusion/statistics & numerical data ; Adult ; Proximal Femoral Fractures ; }, abstract = {Prozessänderungen im perioperativen Setting werden selten analysiert, weil ihre Ergebnisse nicht unmittelbar fassbar sind und es einer hohen Fallzahl bedarf. Primäres Ziel war es, Prozessänderungen retrospektiv anhand proximaler Femurfrakturen (PF) zu evaluieren und deren Effekt mit verschiedenen Zielkriterien zu überprüfen. Sekundäres Ziel war die Definition möglicher Qualitätskriterien für die Versorgung von PF.Retrospektive Analyse der Datenbank eines Level-1-Traumazentrums zu PF. Eingeschlossen wurden alle osteosynthetisch und endoprothetisch versorgten PF im Behandlungszeitraum vom 01.01.2006 bis 31.12.2021. Der Zeitraum von 16 Jahren wurde für die Statistik trichotom aufgeteilt und die ersten 6 Jahre als Ausgangsbasis verwendet. Insgesamt 10 Prozessänderungen wurden in den folgenden 10 Jahren vorgenommen. Die Auswirkungen dieser Änderungen wurden anhand 1. der operativen Revisionsrate, 2. der Infektionsrate, 3. der perioperativen Transfusionsrate sowie 4. der 1-Jahres-Letalität überprüft.Insgesamt 4163 PF wurden analysiert. Hinsichtlich der Zielkriterien zeigten die Änderungen der ersten 5 Jahre (2012-2016; intramedulläres Verfahren für Osteosynthesen sowie Einwegabdeckung und Einwegkittel) den stärksten Effekt mit einer erstmaligen Senkung der operativen Revisionsrate unter 10% auf Dauer. Weitere Prozessoptimierungen der letzten 5 Jahre (2017-2021) erbrachten ebenfalls messbare Verbesserungen (Senkung der Infektions- und Transfusionsrate). Die 1-Jahres-Letalität blieb unverändert, auch während der COVID-19-Pandemie.Prozessänderungen bei PF führen nicht unmittelbar zu objektiv messbaren Verbesserungen. Rückblickend erscheint der Paradigmenwechsel von extra- auf intramedulläre Osteosynthese den höchsten Effekt erzielt zu haben, wenngleich über die letzten 10 Jahre eine schrittweise Besserung aller Zielkriterien eintrat - mit Ausnahme der Letalität. Als objektive Qualitätskontrolle sollte eine 1-Jahres-Revisionsrate unter 10% angestrebt sein.}, } @article {pmid38621743, year = {2024}, author = {Rezvykh, A and Shteinberg, D and Bronovitsky, E and Ustyugov, A and Funikov, S}, title = {Animal Models of FUS-Proteinopathy: A Systematic Review.}, journal = {Biochemistry. Biokhimiia}, volume = {89}, number = {Suppl 1}, pages = {S34-S56}, doi = {10.1134/S0006297924140037}, pmid = {38621743}, issn = {1608-3040}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; RNA-Binding Protein FUS/genetics/metabolism ; Motor Neurons/metabolism/pathology ; Cytoplasm/metabolism ; Mutation ; Disease Models, Animal ; }, abstract = {Mutations that disrupt the function of the DNA/RNA-binding protein FUS could cause amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. One of the key features in ALS pathogenesis is the formation of insoluble protein aggregates containing aberrant isoforms of the FUS protein in the cytoplasm of upper and lower motor neurons. Reproduction of human pathology in animal models is the main tool for studying FUS-associated pathology and searching for potential therapeutic agents for ALS treatment. In this review, we provide a systematic analysis of the role of FUS protein in ALS pathogenesis and an overview of the results of modelling FUS-proteinopathy in animals.}, } @article {pmid38621750, year = {2024}, author = {Kosmachevskaya, OV and Novikova, NN and Yakunin, SN and Topunov, AF}, title = {Formation of Supplementary Metal-Binding Centers in Proteins under Stress Conditions.}, journal = {Biochemistry. Biokhimiia}, volume = {89}, number = {Suppl 1}, pages = {S180-S204}, doi = {10.1134/S0006297924140104}, pmid = {38621750}, issn = {1608-3040}, mesh = {*Metals/chemistry/metabolism ; *Oxidative Stress ; Oxidation-Reduction ; Protein Processing, Post-Translational ; }, abstract = {In many proteins, supplementary metal-binding centers appear under stress conditions. They are known as aberrant or atypical sites. Physico-chemical properties of proteins are significantly changed after such metal binding, and very stable protein aggregates are formed, in which metals act as "cross-linking" agents. Supplementary metal-binding centers in proteins often arise as a result of posttranslational modifications caused by reactive oxygen and nitrogen species and reactive carbonyl compounds. New chemical groups formed as a result of these modifications can act as ligands for binding metal ions. Special attention is paid to the role of cysteine SH-groups in the formation of supplementary metal-binding centers, since these groups are the main target for the action of reactive species. Supplementary metal binding centers may also appear due to unmasking of amino acid residues when protein conformation changing. Appearance of such centers is usually considered as a pathological process. Such unilateral approach does not allow to obtain an integral view of the phenomenon, ignoring cases when formation of metal complexes with altered proteins is a way to adjust protein properties, activity, and stability under the changed redox conditions. The role of metals in protein aggregation is being studied actively, since it leads to formation of non-membranous organelles, liquid condensates, and solid conglomerates. Some proteins found in such aggregates are typical for various diseases, such as Alzheimer's and Huntington's diseases, amyotrophic lateral sclerosis, and some types of cancer.}, } @article {pmid38622643, year = {2024}, author = {Filipe, CB and Carreira, NR and Reis-Pina, P}, title = {Optimizing breathlessness management in amyotrophic lateral sclerosis: insights from a comprehensive systematic review.}, journal = {BMC palliative care}, volume = {23}, number = {1}, pages = {100}, pmid = {38622643}, issn = {1472-684X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Dyspnea/etiology/therapy ; Palliative Care/methods/standards ; Noninvasive Ventilation/methods/standards ; Quality of Life ; Analgesics, Opioid/therapeutic use ; }, abstract = {BACKGROUND: Breathlessness is a prevalent symptom affecting the quality of life (QOL) of Amyotrophic Lateral Sclerosis (ALS) patients. This systematic review explored the interventions for controlling breathlessness in ALS patients, emphasizing palliative care (PALC), non-invasive ventilation (NIV), opioids, and non-pharmacological strategies.

METHODS: A comprehensive search of PubMed, Cochrane Library, and Web of Science databases was conducted. Eligibility criteria encompassed adults with ALS or motor neuron disease experiencing breathlessness. Outcomes included QOL and symptom control. Study designs comprised qualitative studies, cohort studies, and randomized controlled trials.

RESULTS: Eight studies were included, most exhibiting low bias risk, comprising one randomized controlled trial, three cohort studies, two comparative retrospective studies, and two qualitative studies (interviews). Most studies originated from Europe, with one from the United States of America. The participants totaled 3423, with ALS patients constituting 95.6%. PALC consultations significantly improved symptom assessment, advance care planning, and discussions about goals of care. NIV demonstrated efficacy in managing breathlessness, with considerations for device limitations. Opioids were effective, though predominantly studied in non-ALS patients. Non-pharmacological strategies varied in efficacy among patients.

CONCLUSION: The findings underscore the need for individualized approaches in managing breathlessness in ALS. PALC, NIV, opioids, and non-pharmacological strategies each play a role, with unique considerations. Further research, especially ALS-specific self-management studies, is warranted.}, } @article {pmid38623278, year = {2024}, author = {Inci, OK and Basırlı, H and Can, M and Yanbul, S and Seyrantepe, V}, title = {Gangliosides as Therapeutic Targets for Neurodegenerative Diseases.}, journal = {Journal of lipids}, volume = {2024}, number = {}, pages = {4530255}, pmid = {38623278}, issn = {2090-3030}, abstract = {Gangliosides, sialic acid-containing glycosphingolipids, are abundant in cell membranes and primarily involved in controlling cell signaling and cell communication. The altered ganglioside pattern has been demonstrated in several neurodegenerative diseases, characterized during early-onset or infancy, emphasizing the significance of gangliosides in the brain. Enzymes required for the biosynthesis of gangliosides are linked to several devastating neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP). In this review, we summarized not only the critical roles of biosynthetic enzymes and their inhibitors in ganglioside metabolism but also the efficacy of treatment strategies of ganglioside to address their significance in those diseases.}, } @article {pmid38623842, year = {2024}, author = {Kaul, CM and Haller, M and Yang, J and Solomon, S and Khan, MR and Pitts, RA and Phillips, MS}, title = {The authors' reply to Jensen et al's Letter to the Editor.}, journal = {Infection control and hospital epidemiology}, volume = {45}, number = {6}, pages = {799-800}, doi = {10.1017/ice.2024.59}, pmid = {38623842}, issn = {1559-6834}, } @article {pmid38625400, year = {2024}, author = {Barel, D and Marom, D and Ponger, P and Kurolap, A and Bar-Shira, A and Kaplan-Ber, I and Mory, A and Abramovich, B and Yaron, Y and Drory, V and Baris Feldman, H}, title = {Genetic diagnosis and detection rates using C9orf72 repeat expansion and a multi-gene panel in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4258-4266}, pmid = {38625400}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/epidemiology ; *C9orf72 Protein/genetics ; Middle Aged ; Male ; Female ; *DNA Repeat Expansion/genetics ; Aged ; *Genetic Testing ; Israel/epidemiology ; Jews/genetics ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. It is mostly sporadic, with the C9orf72 repeat expansion being the most common genetic cause. While the prevalence of C9orf72-ALS in patients from different populations has been studied, data regarding the yield of C9orf72 compared to an ALS gene panel testing is limited.We aimed to explore the application of C9orf72 versus a gene panel in the general Israeli population. A total of 140 ALS patients attended our Neurogenetics Clinic throughout 2018-2023. Disease onset was between ages 60 and 69 years for most patients (34%); however, a quarter had an early-onset disease (< 50 years). Overall, 119 patients (85%) were genetically evaluated: 116 (97%) were tested for the C9orf72 repeat expansion and 64 (54%) underwent gene panel testing. The C9orf72 repeat expansion had a prevalence of 21% among Ashkenazi Jewish patients compared to 5.7% in non-Ashkenazi patients, while the gene panel had a higher yield in non-Ashkenazi patients with 14% disease-causing variants compared to 5.7% in Ashkenazi Jews. Among early-onset ALS patients, panel testing was positive in 12% compared to 2.9% for C9orf72.We suggest a testing strategy for the Israeli ALS patients: C9orf72 should be the first-tier test in Ashkenazi Jewish patients, while a gene panel should be considered as the first step in non-Ashkenazi and early-onset patients. Tiered testing has important implications for patient management, including prognosis, ongoing clinical trials, and prevention in future generations. Similar studies should be implemented worldwide to uncover the diverse ALS genetic architecture and facilitate tailored care.}, } @article {pmid38625649, year = {2024}, author = {Chen, L and Ye, S and Murphy, D and Wu, J and Zhang, H and Liu, H and Zou, B and Hou, G and Zhang, N and Yin, T and Smith, RA and Fan, D}, title = {Chinese Translation and Validation of the Center for Neurologic Study Lability Scale.}, journal = {Neurology and therapy}, volume = {13}, number = {3}, pages = {739-747}, pmid = {38625649}, issn = {2193-8253}, support = {81873784//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; }, abstract = {INTRODUCTION: Pseudobulbar palsy is a common symptom in patients with amyotrophic lateral sclerosis (ALS), but it is often underdiagnosed or misdiagnosed as other diseases. The Center for Neurologic Study Lability Scale (CNS-LS) is a self-report scale consisting of seven questions designed for evaluating pseudobulbar affect (PBA). The current study aimed to validate a Chinese version of the CNS-LS.

METHODS: The Chinese version of the CNS-LS was obtained through a standardized forward-backward translation and cultural adaptation. A total of 105 patients with ALS were recruited from the ALS database of Peking University Third Hospital in Beijing, China, to complete the CNS-LS. The reliability of the Chinese version was determined by the test-retest method, and receiver operating characteristic (ROC) analysis was performed for criterion validity.

RESULTS: Of 105 patients with ALS, 37 had symptoms of PBA and were diagnosed with that condition by neurologists. Forty-two patients completed the CNS-LS twice, and there was no statistically significant difference between the scores (Z = -0.896, p = 0.37). The Spearman correlation coefficient between the test and retest scores was 0.940 (p < 0.0005), and the Cronbach alpha coefficient was high (α = 0.905, n = 105). Scores of 12 or higher on the CNS-LS identified PBA with sensitivity of 0.919 and specificity of 0.882. The area under the ROC curve was 0.924.

CONCLUSION: The Chinese version of the CNS-LS demonstrated good sensitivity and specificity in the group of patients with ALS enrolled in this study. The CNS-LS should be a useful instrument for clinical and research purposes for patients in this language group.}, } @article {pmid38625841, year = {2025}, author = {Savant, R and Pradhan, RK and Bhagat, S and Mythri, RB and Varghese, AM and Vengalil, S and Nalini, A and Sathyaprabha, TN and Raju, TR and Vijayalakshmi, K}, title = {Enhanced levels of fractalkine and HSP60 in cerebrospinal fluid of sporadic amyotrophic lateral sclerosis patients.}, journal = {The International journal of neuroscience}, volume = {135}, number = {9}, pages = {1048-1058}, doi = {10.1080/00207454.2024.2344581}, pmid = {38625841}, issn = {1563-5279}, mesh = {Humans ; *Chaperonin 60/cerebrospinal fluid ; *Chemokine CX3CL1/cerebrospinal fluid ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid ; Middle Aged ; Female ; Male ; Aged ; Adult ; Biomarkers/cerebrospinal fluid ; Hexosaminidases/cerebrospinal fluid ; *Mitochondrial Proteins/cerebrospinal fluid ; Severity of Illness Index ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a multifactorial neurodegenerative disorder with a significant contribution of non-cell autonomous mechanisms to motor neuronal degeneration. Amongst a plethora of molecules, fractalkine (C-X3-C motif chemokine ligand 1), and Heat Shock Protein 60 (HSP60), are key modulators of microglial activation. The contribution of these molecules in Sporadic ALS (SALS) remains unexplored. To investigate this, fractalkine levels were estimated in Cerebrospinal fluid (CSF) of SALS patients (ALS-CSF; n = 44) by Enzyme-linked Immunosorbent Assay (ELISA) and correlated with clinical parameters including disease severity and duration. CSF HSP60 levels were estimated by Western blotting (ALS-CSF; n = 19). Also, CSF levels of Chitotriosidase-1 (CHIT-1), a microglia-specific neuroinflammatory molecule, were measured and its association, if any, with fractalkine and HSP60 was investigated. Both fractalkine and HSP60 levels were significantly elevated in ALS-CSF. Similar to our earlier observation, CHIT-1 levels were also upregulated. Fractalkine showed a moderate negative correlation with the ALS-Functional Rating Scale (ALSFRS) score indicating its significant rise in mild cases which plateaued in cases with high disease severity. However, no obvious correlation was found between fractalkine, HSP60, and CHIT-1. Our study hints that high fractalkine levels in mild cases might be conferring neuroprotection by combating microglial activation and highlights its importance as a novel therapeutic target for SALS. On the other hand, significantly enhanced levels of HSP60, a pro-inflammatory molecule, hint towards its role in accentuating microgliosis, although, it doesn't act synergistically with CHIT-1. Our study suggests that fractalkine and HSP60 act independently of CHIT-1 to suppress and accentuate neuroinflammation, respectively.}, } @article {pmid38626361, year = {2024}, author = {Murdock, BJ and Zhao, B and Pawlowski, KD and Famie, JP and Piecuch, CE and Webber-Davis, IF and Teener, SJ and Feldman, EL and Zhao, L and Goutman, SA}, title = {Peripheral Immune Profiles Predict ALS Progression in an Age- and Sex-Dependent Manner.}, journal = {Neurology(R) neuroimmunology & neuroinflammation}, volume = {11}, number = {3}, pages = {e200241}, pmid = {38626361}, issn = {2332-7812}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R21 NS102960/NS/NINDS NIH HHS/United States ; }, mesh = {Male ; Humans ; Female ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; Disease Progression ; Prognosis ; Biomarkers ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease whose pathobiology associates with peripheral blood immune cell levels and activation patterns in an age and sex-dependent manner. This study's objective was to identify immune profile associations with ALS progression, whether the associations are age and sex-specific, and whether immune profiles can predict a future disease course.

METHODS: Flow cytometry immune profiles (a combination of 22 peripheral blood immune markers) were generated for 241 participants with ALS and linked to ALS progression, using progression-free survival, which is a composite combining the revised ALS Functional Rating Scale and survival. Participants were first grouped by immune profiles using unsupervised hierarchical clustering, and clusters were associated with subsequent progression-free survival. Next, individual immune markers were associated with progression-free survival using least absolute shrinkage and selection operator-Cox regression. Analyses were stratified by age and sex to identify demographic-specific immune mechanisms. Finally, random forest determined the predictive power of immune profiles on ALS progression in the whole population and again stratified by age and sex.

RESULTS: Progression-free survival differed between clusters of participants with similar immune profiles, particularly reduced natural killer (NK)-cell activation associated with slower progression. Individual markers such as neutrophil levels and NK-cell NKp46 expression associated with faster ALS progression while overall NK-cell levels and NK-cell subpopulations associated with slower progression; the strength of these associations varied by age and sex. Adding these immune markers to prediction models dramatically increased short-term prediction compared with routine clinical prognostic variables alone, and the addition of NK-cell markers further improved the prediction accuracy in female participants.

DISCUSSION: Specific immune profiles likely contribute to ALS progression in an age and sex-dependent manner, and peripheral immune markers enhance the prediction of short-term clinical outcomes. These findings suggest a complex milieu of immune profiles associated with ALS progression, and more detailed immunophenotyping in ALS will facilitate personalized immunotherapeutics in ALS.}, } @article {pmid38627230, year = {2024}, author = {Taufik, SA and Ramli, N and Tan, AH and Lim, SY and Ghani, MTA and Shahrizaila, N}, title = {Longitudinal Changes in the Retinal Nerve Fiber Layer Thickness in Amyotrophic Lateral Sclerosis and Parkinson's Disease.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {20}, number = {3}, pages = {285-292}, pmid = {38627230}, issn = {1738-6586}, abstract = {BACKGROUND AND PURPOSE: There is increasing evidence that the anterior visual pathways are involved in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). This study investigated longitudinal changes in retinal nerve fiber layer (RNFL) thickness in patients with ALS and PD with the aim of better understanding their roles as biomarkers of disease progression.

METHODS: This study recruited 21 ALS patients, 19 age-matched PD patients, and 21 agematched healthy controls. Patient demographics and clinical scores relating to the respective diseases were documented. The RNFL thickness was measured using optical coherence tomography at baseline and after 6 months.

RESULTS: At baseline, the RNFL in the superior quadrant was significantly thinner in the patients with ALS than in healthy controls (109.90±22.41 µm vs. 127.81±17.05 µm [mean±standard deviation], p=0.008). The RNFL thickness did not differ significantly between the ALS and PD patients or between the PD patients and healthy controls. At 6 months, there was further significant RNFL thinning in patients with ALS, for both the overall thickness (baseline: median=94.5 µm, range=83.0-106.0 µm; follow-up: median=93.5 µm, range=82.5-104.5 µm, p=0.043) and the thickness in the inferior quadrant (median=126 µm, range=109.5-142.5 µm; and median=117.5 µm, range=98.5-136.5 µm; respectively, p=0.032). However, these changes were not correlated with the ALS functional scores. In contrast, the patients with PD did not demonstrate a significant change in RNFL thickness between the two time points.

CONCLUSIONS: The RNFL thickness is a promising biomarker of disease progression in patients with ALS but not in those with PD, which has a slower disease progression.}, } @article {pmid38627298, year = {2024}, author = {Hamad, AA and Amer, BE}, title = {Safety of masitinib in patients with neurodegenerative diseases: a meta-analysis of randomized controlled trials.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {7}, pages = {3503-3507}, pmid = {38627298}, issn = {1590-3478}, mesh = {Humans ; *Randomized Controlled Trials as Topic ; *Thiazoles/adverse effects/administration & dosage/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; *Piperidines/adverse effects/therapeutic use/administration & dosage ; *Benzamides/adverse effects/administration & dosage ; *Pyridines/adverse effects/administration & dosage/therapeutic use ; Protein Kinase Inhibitors/adverse effects/administration & dosage ; }, abstract = {OBJECTIVES: This meta-analysis aimed to examine the safety of masitinib in patients with neurodegenerative diseases.

METHODS: We considered randomized controlled trials (RCTs) comparing different doses of masitinib versus placebo. We performed our analysis using the R (v.4.3.0) programming language and the incidence of adverse events was pooled using risk ratio (RR) and 95% confidence interval (CI).

RESULTS: We included five RCTs, focusing on multiple sclerosis (MS), Alzheimer's disease (AD), and amyotrophic lateral sclerosis. The meta-analysis revealed a significantly higher incidence of adverse events in the masitinib group compared to the control group, regardless of adverse event grade and masitinib dose (RR = 1.12, 95% CI [1.07 to 1.17], P < 0.01). Adverse events categorized as severe, non-fatal serious, leading to dose reduction, and leading to permanent discontinuation also showed a higher incidence in the masitinib group (P ≤ 0.01). Subgroup analysis for AD and MS supported these findings. The pooled incidence of adverse events, regardless of their grade, was higher in the masitinib group for both the 3 mg/kg/d dose (RR = 1.13, P = 0.01) and the 4.5 mg/kg/d dose (RR = 1.11, P < 0.01). However, there was no significant difference between masitinib 3 mg/kg/d dose and placebo regarding severe and non-fatal serious adverse events for the.

CONCLUSION: Masitinib use in neurodegenerative diseases presents safety concerns that may impact patients' quality of life and require management. Further research is recommended to determine the optimal dose with minimal safety concerns in this patient population.}, } @article {pmid38627359, year = {2024}, author = {Magrì, A and Lipari, CLR and Caccamo, A and Battiato, G and Conti Nibali, S and De Pinto, V and Guarino, F and Messina, A}, title = {AAV-mediated upregulation of VDAC1 rescues the mitochondrial respiration and sirtuins expression in a SOD1 mouse model of inherited ALS.}, journal = {Cell death discovery}, volume = {10}, number = {1}, pages = {178}, pmid = {38627359}, issn = {2058-7716}, abstract = {Mitochondrial dysfunction represents one of the most common molecular hallmarks of both sporadic and familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder caused by the selective degeneration and death of motor neurons. The accumulation of misfolded proteins on and within mitochondria, as observed for SOD1 G93A mutant, correlates with a drastic reduction of mitochondrial respiration and the inhibition of metabolites exchanges, including ADP/ATP and NAD[+]/NADH, across the Voltage-Dependent Anion-selective Channel 1 (VDAC1), the most abundant channel protein of the outer mitochondrial membrane. Here, we show that the AAV-mediated upregulation of VDAC1 in the spinal cord of transgenic mice expressing SOD1 G93A completely rescues the mitochondrial respiratory profile. This correlates with the increased activity and levels of key regulators of mitochondrial functions and maintenance, namely the respiratory chain Complex I and the sirtuins (Sirt), especially Sirt3. Furthermore, the selective increase of these mitochondrial proteins is associated with an increase in Tom20 levels, the receptor subunit of the TOM complex. Overall, our results indicate that the overexpression of VDAC1 has beneficial effects on ALS-affected tissue by stabilizing the Complex I-Sirt3 axis.}, } @article {pmid38627418, year = {2024}, author = {Bales, I and Zhang, H}, title = {A six degrees-of-freedom cable-driven robotic platform for head-neck movement.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {8750}, pmid = {38627418}, issn = {2045-2322}, support = {2240508//National Science Foundation/ ; }, mesh = {Humans ; *Robotics/methods ; *Robotic Surgical Procedures ; Movement/physiology ; Head Movements/physiology ; *Exoskeleton Device ; *Nervous System Diseases ; }, abstract = {This paper introduces a novel cable-driven robotic platform that enables six degrees-of-freedom (DoF) natural head-neck movements. Poor postural control of the head-neck can be a debilitating symptom of neurological disorders such as amyotrophic lateral sclerosis and cerebral palsy. Current treatments using static neck collars are inadequate, and there is a need to develop new devices to empower movements and facilitate physical rehabilitation of the head-neck. State-of-the-art neck exoskeletons using lower DoF mechanisms with rigid linkages are limited by their hard motion constraints imposed on head-neck movements. By contrast, the cable-driven robot presented in this paper does not constrain motion and enables wide-range, 6-DoF control of the head-neck. We present the mechatronic design, validation, and control implementations of this robot, as well as a human experiment to demonstrate a potential use case of this versatile robot for rehabilitation. Participants were engaged in a target reaching task while the robot applied both assistive and resistive moments on the head during the task. Our results show that neck muscle activation increased by 19% when moving the head against resistance and decreased by 28-43% when assisted by the robot. Overall, these results provide a scientific justification for further research in enabling movement and identifying personalized rehabilitation for motor training. Beyond rehabilitation, other applications such as applying force perturbations on the head to study sensory integration and applying traction to achieve pain relief may benefit from the innovation of this robotic platform which is capable of applying controlled 6-DoF forces/moments on the head.}, } @article {pmid38628040, year = {2025}, author = {Howard, J and Forrest Keenan, K and Mazanderani, F and Turner, MR and Locock, L}, title = {Experiences of predictive genetic testing in inherited motor neuron disease: Findings from a qualitative interview study.}, journal = {Journal of genetic counseling}, volume = {34}, number = {1}, pages = {e1904}, pmid = {38628040}, issn = {1573-3599}, support = {Locock/Sept19/941-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; //University of Aberdeen/ ; }, mesh = {Humans ; *Motor Neuron Disease/genetics/diagnosis/psychology ; *Genetic Testing ; Female ; Male ; Middle Aged ; Adult ; Qualitative Research ; Interviews as Topic ; Aged ; }, abstract = {Predictive genetic testing is increasingly available for individuals with a heightened risk of motor neuron disease (MND). However, little is known about how they decide whether or not to get tested, and how they experience this process. This paper reports findings from a constructivist grounded theory-informed interview study with 24 family members of people with identified or suspected inherited MND (iMND). Fourteen did not know their genetic status, and nine had decided to have predictive testing, of whom six tested positive for the pathogenic gene variant identified in their family and three tested negative. One additional person was identified as negative through a parent's negative result. This paper explores the diverse ways people approached testing, and the many factors and motivations involved, based on personal attitudes and goals, experiences of living with genetic risk, and wider family considerations and circumstances. Results were met with a range of emotions; whatever the outcome, the news disrupted each person's view of the future, and they adapted in their own way and time. Support after results was variable and a perceived lack of support impacted coping and the ability to move forwards. This paper situates findings against literature on other genetic conditions, highlighting experiences as grounded in the unique characteristics of iMND. Thus, it emphasizes the need for disease-specific guidelines and support structures around predictive genetic testing in this context. Understanding people's experiences and responding to these needs is particularly timely given the uptake of testing amongst this group is anticipated to rise with increasing access to genetic testing for people with MND, and gene-specific clinical trials.}, } @article {pmid38628764, year = {2024}, author = {Zhao, T and Duan, S and Li, J and Zheng, H and Liu, C and Zhang, H and Luo, H and Xu, Y}, title = {Mapping of repeat-associated non-AUG (RAN) translation knowledge: A bibliometric analysis.}, journal = {Heliyon}, volume = {10}, number = {8}, pages = {e29141}, pmid = {38628764}, issn = {2405-8440}, abstract = {Over 50 genetic human disorders are attributed to the irregular expansion of microsatellites. These expanded microsatellite sequences can experience bidirectional transcription, leading to new reading frames. Beyond the standard AUG initiation or adjacent start codons, they are translated into proteins characterized by disease-causing amino acid repeats through repeat-associated non-AUG translation. Despite its significance, there's a discernible gap in comprehensive and objective articles on RAN translation. This study endeavors to evaluate and delineate the contemporary landscape and progress of RAN translation research via a bibliometric analysis. We sourced literature on RAN translation from the Web of Science Core Collection. Utilizing two bibliometric analysis tools, CiteSpace and VOSviewer, we gauged individual impacts and interactions by examining annual publications, journals, co-cited journals, countries/regions, institutions, authors, and co-cited authors. Following this, we assessed the co-occurrence and bursts of keywords and co-cited references to pinpoint research hotspots and trending in RAN translation. Between 2011 and 2022, 1317 authors across 359 institutions from 34 countries/regions contributed to 250 publications on RAN translation, spread across 118 academic journals. This article presents a systematic, objective, and comprehensive analysis of the current literature on RAN translation. Our findings emphasize that mechanisms related to C9orf72 ALS/FTD are pivotal topics in the realm of RAN translation, with cellular stress and the utilization of small molecule marking the trending research areas.}, } @article {pmid38628797, year = {2024}, author = {Sabnis, RW}, title = {Novel Isoxazolidines as RIPK1 Inhibitors for Treating Alzheimer's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis.}, journal = {ACS medicinal chemistry letters}, volume = {15}, number = {4}, pages = {447-448}, pmid = {38628797}, issn = {1948-5875}, abstract = {Provided herein are novel isoxazolidines as RIPK1 inhibitors, pharmaceutical compositions, use of such compounds in treating Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), and processes for preparing such compounds.}, } @article {pmid38628839, year = {2023}, author = {Uzunoglu-Ozyurek, E and Önal, G and Dökmeci, S}, title = {Investigating the Therapeutics Effects of Oral Cavity Derived Stem Cells on Neurodegenerative Diseases: A Systematic Review.}, journal = {Basic and clinical neuroscience}, volume = {14}, number = {5}, pages = {565-584}, pmid = {38628839}, issn = {2008-126X}, abstract = {INTRODUCTION: Published data obtained from in vitro and in vivo studies was reviewed systematically and analyzed critically to evaluate the effect of oral cavity-derived stem cells (OCDSCs) on the recovery or therapy of neurodegenerative diseases (NDs), such as Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), Huntington (HD) diseases, and Parkinson disease (PD).

METHODS: An electronic search was accomplished. References of included articles were also manually searched. Studies were critically evaluated for suitability against the inclusion/exclusion criteria and the data was extracted. Bias risk evaluation of the studies and evidence synthesis were conducted.

RESULTS: A total of 14 in vivo and 10 in vitro studies met the inclusion criteria. PD was induced in 10 in vivo and 7 in vitro studies, while AD was induced in 2 in vivo and 4 in vitro studies. Two studies (1 in vitro and 1 in vivo) evaluated ALS disease and 1 in vivo study evaluated HD. Moderate evidence was found for in vitro studies reporting the positive effect of OCDSCs on PD or AD recovery. Strong evidence was found for in vivo studies in which PD animal models were used; meanwhile, moderate evidence was found for the impact of OCDSCs on AD recovery. Limited evidence was found for in vivo studies evaluating HD and ALS.

CONCLUSION: Although studies reported favorable data regarding the OCDSCs on NDs, they presented a considerable risk of bias. Because of heterogeneous study characteristics, the current study recommends improving standardized methods to evaluate the therapeutic effects of OCDSCs on the NDs.}, } @article {pmid38630299, year = {2024}, author = {Wolff, A and Demleitner, AF and Feneberg, E and Lingor, P}, title = {[Smell the smoke before one sees the fire-The oligosymptomatic prodromal phase of neurodegenerative diseases].}, journal = {Der Nervenarzt}, volume = {95}, number = {8}, pages = {689-696}, pmid = {38630299}, issn = {1433-0407}, mesh = {*Neurodegenerative Diseases/diagnosis ; *Prodromal Symptoms ; Humans ; *Early Diagnosis ; *Biomarkers/blood ; Disease Progression ; }, abstract = {BACKGROUND: With the increasing development of disease-modifying causative treatment, the importance of early diagnosis and detection of asymptomatic or oligosymptomatic early stages of neurodegenerative diseases is increasing.

OBJECTIVE: Presentation of early stages of neurodegenerative diseases, diagnostic procedures for the early detection and possible treatment consequences.

MATERIAL AND METHODS: Selective literature search, discussion of basic research and expert recommendations.

RESULTS: Many neurodegenerative diseases have a prodromal phase preceding the manifest disease that can be diagnosed with current criteria. In this prodromal phase, those affected are often oligosymptomatic but in some cases can already be identified using biomarkers. These developments are already taken into account in diagnostic criteria for some of these prodromal phases. The prodromal phase, in turn, is preceded by an asymptomatic phase which, however, already shows molecular changes and can be identified by biomarkers in some diseases. The early identification and stratification of patients is particularly important when planning studies for disease-modifying treatment, and biomarkers are already being used in clinical trials for this purpose.

DISCUSSION: Biomarker-based identification of individuals in the prodromal phase of neurodegenerative diseases is already possible for some entities. People who show the first signs of a neurodegenerative disease can be referred to centers for clinical trials and observational studies.}, } @article {pmid38631307, year = {2024}, author = {Büssing, A and Recchia, DR and Ortiz, M}, title = {[Validierung eines Fragebogeninstrumentes zur Erfassung des Erlebens von Natur: Die Experience of Nature Scale].}, journal = {Complementary medicine research}, volume = {31}, number = {4}, pages = {309-318}, doi = {10.1159/000538807}, pmid = {38631307}, issn = {2504-2106}, mesh = {Humans ; Surveys and Questionnaires/standards ; Female ; Male ; Cross-Sectional Studies ; Adult ; Middle Aged ; Reproducibility of Results ; *Nature ; Psychometrics ; Aged ; Young Adult ; Adolescent ; }, abstract = {UNLABELLED: Hintergrund: In den letzten Jahren ist insbesondere die Natur als Ressource in das Interesse der gesundheitspsychologischen Forschung gerückt. In Ergänzung zum etablierten Konzept der Naturzuwendung als Haltung wurde ein For-schungsinstrument zum Naturerleben entwickelt, welches das subjektive, teilweise intentionale Erleben von Natur unter unterschiedlichen Aspekten beleuchtet. Dazu gehören insbesondere Natur als Erlebensraum, um sich von der Alltagsbelastung distanzieren zu können, um Auszeiten durch Ruhe und Stille finden zu können, um emotionale Ausgeglichenheit zu erlangen, Natur als Ort der Faszination und des Staunens, Naturerleben als Basis für einen verantwortlichen Umgang mit der Natur. Das Manuskript zeigt die Ergebnisse der Validierung des neu entwickelten Fragebogeninstrumentes zum Naturerleben. Methoden: Eine anonyme Online-Querschnittsstudie unter 441 Teilnehmenden wurde mit standardisierten Fragebogeninstrumenten zur Validie-rung der Experience of Nature Scale (ENS) mittels explorativer Faktoren- (Hauptkomponentenanalyse mit Varimax-Rotation) und Reliabilitätsanalysen (Cronbachs α) durchgeführt. Ergebnisse: Die explorative Faktorenanalyse der Naturerlebens-Skala mit 11 Items ergab drei Hauptfaktoren mit guter interner Kongruenz, die 71% der Varianz erklären: (1) Alltagsdistanzierung/Entspannung (Cronbachs α = 0,87), (2) Faszination Natur/Staunen (Cronbachs α = 0,82) und (3) Verantwortungsempfinden für Natur (Cronbachs α = 0,85). Diese Faktoren korrelierten stark mit der Naturverbundenheit (NR-6) und moderat bis stark mit Ehrfurcht/Dankbarkeit (GrAw-7) im Sinne der Konvergenzvalidität, aber nur marginal bis schwach mit psychologischem Wohlbefinden (WHO-5). Schlussfolgerungen: Die ENS zur Erfassung des affektiven Erlebens von Natur hat gute psychometrische Qua-litätsindizes und kann in künftigen Studien zur Bedeutung dieses Erlebens von Natur zum Beispiel als Prädiktor- oder Prozessvariable eingesetzt werden.

BACKGROUND: In recent years, nature as a resource in particular has become of interest in health psychology research. In addition to the established concept of nature-relatedness as an attitude, a research instrument was developed that focuses on the subjective experience of nature in different aspects. This includes nature as an area for experiencing, to distance oneself from the stress of everyday life, to find times for peace and quietness, as a place of fascination and amazement, resulting in greater emotional balance, and experiencing nature as a basis for a responsible approach to nature. Therefore, the newly developed instrument to assess nature experiences should be validated in a cohort of healthy volunteers.

METHODS: We conducted an anonymous cross-sectional analysis among 441 participants with standardized instruments to validate the Experience of Nature Scale (ENS) using exploratory factor analysis (principal component analysis with Varimax rotation) and reliability analysis (Cronbach’s α).

RESULTS: The exploratory factor analysis of the 11-item ENS revealed three main factors with good internal congruence, explaining 71% of the variance: (1) detachment from everyday life/relaxation (Cronbach’s α = 0.87), (2) fascination with nature/wondering (Cronbach’s α = 0.82), and (3) sense of responsibility for nature (Cronbach’s α = 0.85). In terms of convergent validity, the three factors correlated strongly with nature-relatedness (NR-6) and moderately to strongly with awe/gratitude (GrAw-7), but only marginally to weakly with psychological well-being (WHO-5).

CONCLUSIONS: The ENS for assessing the affective experience of nature shows good psychometric quality indices and could be used as a predictor and process variable in future studies addressing the meaning of this experience of nature.}, } @article {pmid38631798, year = {2024}, author = {Gerecht, RB and Nable, JV}, title = {Out-of-Hospital Cardiac Arrest.}, journal = {Cardiology clinics}, volume = {42}, number = {2}, pages = {317-331}, doi = {10.1016/j.ccl.2024.02.014}, pmid = {38631798}, issn = {1558-2264}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest ; *Cardiopulmonary Resuscitation ; *Emergency Medical Services ; }, abstract = {Survival from out-of-hospital cardiac arrest (OHCA) is predicated on a community and system-wide approach that includes rapid recognition of cardiac arrest, capable bystander CPR, effective basic and advanced life support (BLS and ALS) by EMS providers, and coordinated postresuscitation care. Management of these critically ill patients continues to evolve. This article focuses on the management of OHCA by EMS providers.}, } @article {pmid38632300, year = {2024}, author = {Shiramasa, Y and Yamamoto, R and Kashiwagi, N and Sasaki, F and Imai, S and Ike, M and Kitazawa, S and Kameda, T and Kitahara, R}, title = {An aberrant fused in sarcoma liquid droplet of amyotrophic lateral sclerosis pathological variant, R495X, accelerates liquid-solid phase transition.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {8914}, pmid = {38632300}, issn = {2045-2322}, support = {JP23H02626//JSPS KAKENHI/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Phase Transition ; *RNA-Binding Protein FUS/genetics/metabolism ; *Sarcoma ; }, abstract = {Intracellular aggregation of fused in sarcoma (FUS) is associated with the pathogenesis of familial amyotrophic lateral sclerosis (ALS). Under stress, FUS forms liquid droplets via liquid-liquid phase separation (LLPS). Two types of wild-type FUS LLPS exist in equilibrium: low-pressure LLPS (LP-LLPS) and high-pressure LLPS (HP-LLPS); the former dominates below 2 kbar and the latter over 2 kbar. Although several disease-type FUS variants have been identified, the molecular mechanism underlying accelerated cytoplasmic granule formation in ALS patients remains poorly understood. Herein, we report the reversible formation of the two LLPS states and the irreversible liquid-solid transition, namely droplet aging, of the ALS patient-type FUS variant R495X using fluorescence microscopy and ultraviolet-visible absorption spectroscopy combined with perturbations in pressure and temperature. Liquid-to-solid phase transition was accelerated in the HP-LLPS of R495X than in the wild-type variant; arginine slowed the aging of droplets at atmospheric conditions by inhibiting the formation of HP-LLPS more selectively compared to that of LP-LLPS. Our findings provide new insight into the mechanism by which R495X readily forms cytoplasmic aggregates. Targeting the aberrantly formed liquid droplets (the HP-LLPS state) of proteins with minimal impact on physiological functions could be a novel therapeutic strategy for LLPS-mediated protein diseases.}, } @article {pmid38632611, year = {2024}, author = {Dai, T and Lou, J and Kong, D and Li, J and Ren, Q and Chen, Y and Sun, S and Yun, Y and Sun, X and Yang, Y and Shao, K and Li, W and Zhao, Y and Meng, X and Yan, C and Lin, P and Liu, S}, title = {Choroid plexus enlargement in amyotrophic lateral sclerosis patients and its correlation with clinical disability and blood-CSF barrier permeability.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {36}, pmid = {38632611}, issn = {2045-8118}, support = {22-8-7-smjk-1-nsh//Qingdao Science and Technology Benefit People Demonstration Guide Special Project/ ; 2020M672067//China Postdoctoral Science Foundation/ ; NSFC82001354//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Humans ; Choroid Plexus ; *Amyotrophic Lateral Sclerosis ; Retrospective Studies ; *Neurodegenerative Diseases ; Capillary Permeability ; }, abstract = {BACKGROUND: Using in vivo neuroimaging techniques, growing evidence has demonstrated that the choroid plexus (CP) volume is enlarged in patients with several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. However, although animal and postmortem findings suggest that CP abnormalities are likely important pathological mechanisms underlying amyotrophic lateral sclerosis (ALS), the third most common neurodegenerative disease, no available study has been conducted to thoroughly assess CP abnormalities and their clinical relevance in vivo in ALS patients to date. Thus, we aimed to determine whether in vivo CP enlargement may occur in ALS patients. We also aimed to identify the relationships of CP volume with clinical disabilities and blood-CSF barrier (BCSFB) permeability in ALS patients.

METHODS: In this retrospective study, based on structural MRI data, CP volume was assessed using a Gaussian mixture model and underwent further manual correction in 155 ALS patients and 105 age- and sex-matched HCs from October 2021 to April 2023. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used to assess clinical disability. The CSF/serum albumin quotient (Qalb) was used to assess BCSFB permeability. Moreover, all the ALS patients completed genetic testing, and according to genetic testing, the ALS patients were further divided into genetic ALS subgroup and sporadic ALS subgroup.

RESULTS: We found that compared with HCs, ALS patients had a significantly higher CP volume (p < 0.001). Moreover, compared with HCs, CP volume was significantly increased in both ALS patients with and without known genetic mutations after family-wise error correction (p = 0.006 and p < 0.001, respectively), while there were no significant differences between the two ALS groups. Furthermore, the CP volume was significantly correlated with the ALSFRS-r score (r = -0.226; p = 0.005) and the Qalb (r = 0.479; p < 0.001) in ALS patients.

CONCLUSION: Our study first demonstrates CP enlargement in vivo in ALS patients, and continues to suggest an important pathogenetic role for CP abnormalities in ALS. Moreover, assessing CP volume is likely a noninvasive and easy-to-implement approach for screening BCSFB dysfunction in ALS patients.}, } @article {pmid38633814, year = {2025}, author = {Zhang, S and Moll, T and Rubin-Sigler, J and Tu, S and Li, S and Yuan, E and Liu, M and King, M and Alhathli, E and Treanor, C and Twelvetrees, A and Weinreich, M and Bonsall, S and Harvey, C and Gornall, S and Shaw, A and Ganssauge, J and Bhinge, A and Souza, CDS and Ferraiuolo, L and Hornstein, E and Shalem, O and Avila, A and Shelkovnikova, T and van Dijk, CH and Timpanaro, IS and Kenna, KP and Zeng, J and van Damme, P and Tsao, PS and Shaw, PJ and Ichida, JK and Cooper-Knock, J and Snyder, MP}, title = {Antisense oligonucleotide depletion of CCDC146 is a broad-spectrum therapeutic strategy for ALS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38633814}, support = {/WT_/Wellcome Trust/United Kingdom ; P50 HG007735/HG/NHGRI NIH HHS/United States ; R01 NS097850/NS/NINDS NIH HHS/United States ; R01 NS131409/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heritable and incurable disease defined by the degeneration of motor neurons (MNs), yet the genetics of ALS remain partially understood. Using a genomic deep learning-powered whole-genome analysis of 6,715 ALS patients, we identify four rare noncoding variants associated with patient survival, including chr7:76,009,472:C>T which is linked to a 70.6% reduction in survival. Genetic editing of this variant into iPSC-derived MNs increases CCDC146 expression and exacerbates ALS-specific phenotypes including TDP-43 mislocalization. We reveal that CCDC146 was located within the basal body of primary cilia in human MNs, and that cilia structure and function is impaired by CCDC146 overexpression but is restored by its depletion. Suppressing CCDC146 using an antisense oligonucleotide (ASO) completely rescues ALS-specific survival defects in neurons derived from both sporadic and familial patients, and it extends survival and reverses TDP-43 pathology in an aggressive ALS mouse model. Taken together, CCDC146 is a new modifier of ALS survival that acts via the primary cilia of MNs. ASO targeting of CCDC146 is a potential therapeutic approach for both sporadic and genetic forms of ALS, particularly because congenital absence of CCDC146 is well tolerated.}, } @article {pmid38635657, year = {2024}, author = {Castellanos Otero, P and Todd, TW and Shao, W and Jones, CJ and Huang, K and Daughrity, LM and Yue, M and Sheth, U and Gendron, TF and Prudencio, M and Oskarsson, B and Dickson, DW and Petrucelli, L and Zhang, YJ}, title = {Generation and characterization of monoclonal antibodies against pathologically phosphorylated TDP-43.}, journal = {PloS one}, volume = {19}, number = {4}, pages = {e0298080}, pmid = {38635657}, issn = {1932-6203}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; RF1 AG062171/AG/NIA NIH HHS/United States ; RF1 AG062077/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R21 NS127331/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 NS117461/NS/NINDS NIH HHS/United States ; P01 NS099114/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/pathology ; Antibodies, Monoclonal ; HEK293 Cells ; DNA-Binding Proteins/genetics ; *TDP-43 Proteinopathies ; }, abstract = {Inclusions containing TAR DNA binding protein 43 (TDP-43) are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). One of the disease-specific features of TDP-43 inclusions is the aberrant phosphorylation of TDP-43 at serines 409/410 (pS409/410). Here, we developed rabbit monoclonal antibodies (mAbs) that specifically detect pS409/410-TDP-43 in multiple model systems and FTD/ALS patient samples. Specifically, we identified three mAbs (26H10, 2E9 and 23A1) from spleen B cell clones that exhibit high specificity and sensitivity to pS409/410-TDP-43 peptides in an ELISA assay. Biochemical analyses revealed that pS409/410 of recombinant TDP-43 and of exogenous 25 kDa TDP-43 C-terminal fragments in cultured HEK293T cells are detected by all three mAbs. Moreover, the mAbs detect pS409/410-positive TDP-43 inclusions in the brains of FTD/ALS patients and mouse models of TDP-43 proteinopathy by immunohistochemistry. Our findings indicate that these mAbs are a valuable resource for investigating TDP-43 pathology both in vitro and in vivo.}, } @article {pmid38636436, year = {2024}, author = {Suazo, KF and Mishra, V and Maity, S and Auger, SA and Justyna, K and Petre, AM and Ottoboni, L and Ongaro, J and Corti, SP and Lotti, F and Przedborski, S and Distefano, MD}, title = {Improved synthesis and application of an alkyne-functionalized isoprenoid analogue to study the prenylomes of motor neurons, astrocytes and their stem cell progenitors.}, journal = {Bioorganic chemistry}, volume = {147}, number = {}, pages = {107365}, pmid = {38636436}, issn = {1090-2120}, support = {R01 NS107442/NS/NINDS NIH HHS/United States ; P30 CA077598/CA/NCI NIH HHS/United States ; R21 NS101575/NS/NINDS NIH HHS/United States ; T32 AG029796/AG/NIA NIH HHS/United States ; T32 GM132029/GM/NIGMS NIH HHS/United States ; R35 GM141853/GM/NIGMS NIH HHS/United States ; }, mesh = {*Astrocytes/metabolism/cytology ; Animals ; *Protein Prenylation ; *Alkynes/chemistry/chemical synthesis ; *Motor Neurons/metabolism/cytology ; Terpenes/chemistry/chemical synthesis/metabolism ; Mice ; Molecular Structure ; Cells, Cultured ; }, abstract = {Protein prenylation is one example of a broad class of post-translational modifications where proteins are covalently linked to various hydrophobic moieties. To globally identify and monitor levels of all prenylated proteins in a cell simultaneously, our laboratory and others have developed chemical proteomic approaches that rely on the metabolic incorporation of isoprenoid analogues bearing bio-orthogonal functionality followed by enrichment and subsequent quantitative proteomic analysis. Here, several improvements in the synthesis of the alkyne-containing isoprenoid analogue C15AlkOPP are reported to improve synthetic efficiency. Next, metabolic labeling with C15AlkOPP was optimized to obtain useful levels of metabolic incorporation of the probe in several types of primary cells. Those conditions were then used to study the prenylomes of motor neurons (ES-MNs), astrocytes (ES-As), and their embryonic stem cell progenitors (ESCs), which allowed for the identification of 54 prenylated proteins from ESCs, 50 from ES-MNs, and 84 from ES-As, representing all types of prenylation. Bioinformatic analysis revealed specific enriched pathways, including nervous system development, chemokine signaling, Rho GTPase signaling, and adhesion. Hierarchical clustering showed that most enriched pathways in all three cell types are related to GTPase activity and vesicular transport. In contrast, STRING analysis showed significant interactions in two populations that appear to be cell type dependent. The data provided herein demonstrates that robust incorporation of C15AlkOPP can be obtained in ES-MNs and related primary cells purified via magnetic-activated cell sorting allowing the identification and quantification of numerous prenylated proteins. These results suggest that metabolic labeling with C15AlkOPP should be an effective approach for investigating the role of prenylated proteins in primary cells in both normal cells and disease pathologies, including ALS.}, } @article {pmid38636451, year = {2024}, author = {Khalil, B and Da Cruz, S}, title = {14-3-3θ, a novel player in TDP-43 pathophysiology: Implications for ALS/FTD.}, journal = {Neuron}, volume = {112}, number = {8}, pages = {1197-1199}, doi = {10.1016/j.neuron.2024.03.025}, pmid = {38636451}, issn = {1097-4199}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; DNA-Binding Proteins/genetics ; *Frontotemporal Dementia/genetics ; Mice, Transgenic ; Neurons/pathology ; *TDP-43 Proteinopathies/genetics ; Disease Models, Animal ; }, abstract = {In this issue of Neuron, Ke et al.[1] report a novel non-canonical interaction between 14-3-3θ and TDP-43 that impacts loss-of-function and gain-of-toxic pathology in TDP-43 proteinopathies. The authors further provide proof of principle for a 14-3-3θ-targeted gene therapy to reduce TDP-43-induced deficits in transgenic TDP-43 mutant mice.}, } @article {pmid38638178, year = {2023}, author = {Fotouhi, M and Worrall, D and Ayoubi, R and Southern, K and McPherson, PS and Laflamme, C and , and , }, title = {A guide to selecting high-performing antibodies for RNA-binding protein TIA1 for use in Western Blot, immunoprecipitation and immunofluorescence.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {745}, pmid = {38638178}, issn = {2046-1402}, mesh = {T-Cell Intracellular Antigen-1/genetics ; *RNA-Binding Proteins ; Blotting, Western ; Fluorescent Antibody Technique ; Immunoprecipitation ; }, abstract = {A member of the RNA-binding protein family, T-cell intracellular antigen-1 (TIA1) regulates mRNA translation and splicing as well as cellular stress by promoting stress granule formation. Variants of the TIA1 gene have implications in neurogenerative disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Reproducible research on TIA1 would be enhanced with the availability of high-quality anti-TIA1 antibodies. In this study, we characterized twelve TIA1 commercial antibodies for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.}, } @article {pmid38638511, year = {2024}, author = {Finsel, J and Rosenbohm, A and Peter, RS and Bäzner, H and Börtlein, A and Dempewolf, S and Schabet, M and Hecht, M and Kohler, A and Opherk, C and Nägele, A and Sommer, N and Lindner, A and Rothenbacher, D and Ludolph, AC and Nagel, G and Lulé, DE}, title = {Coping as a resource to allow for psychosocial adjustment in fatal disease: results from patients with amyotrophic lateral sclerosis.}, journal = {Frontiers in psychology}, volume = {15}, number = {}, pages = {1361767}, pmid = {38638511}, issn = {1664-1078}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal disorder, which imposes a severe emotional burden on patients. Appropriate coping mechanisms may alleviate this burden and facilitate wellbeing, with social support known to be a successful coping strategy. This observational study aimed to determine the interplay of general coping traits of hope for success and fear of failure, coping behavior of social activity, and patients' wellbeing.

METHODS: In this cross-sectional study, patients with ALS from a clinical-epidemiological registry in Southwestern Germany were interviewed regarding coping traits (achievement-motivated behavior: hope for success and fear of failure), coping behavior of social activity, and psychosocial adjustment, determined using measures of depressiveness, anxiety [both measured by Hospital Anxiety and Depression Scale (HADS)], and quality of life [Anamnestic Comparative Self-Assessment (ACSA)]. Demographics, clinical [ALS Functional Rating Scale revised version (ALSFRS-R)], and survival data were recorded.

RESULTS: A total of 868 patients [60.70% male patients, mean age: 64.70 (±10.83) years, mean ALSFRS-R: 37.36 ± 7.07] were interviewed. Anxiety in patients was found to be associated with a high fear of failure. In contrast, a generally positive attitude in patients exemplified in high hopes for success was associated with better wellbeing. Finally, coping behavior of social activity explained up to 65% of the variance of depressiveness among the patients with ALS.

CONCLUSION: In this study, we present evidence that the wellbeing of patients with ALS is not an immediate fatalistic consequence of physical degradation but rather determined by coping traits and behavior, which may be trained to substantially increase the wellbeing of patients with ALS.}, } @article {pmid38640582, year = {2024}, author = {Ceccanti, M and Libonati, L and Moret, F and D'Andrea, E and Gori, MC and Bersani, FS and Inghilleri, M and Cambieri, C}, title = {Emotion recognition in amyotrophic lateral sclerosis in a dynamic environment.}, journal = {Journal of the neurological sciences}, volume = {460}, number = {}, pages = {123019}, doi = {10.1016/j.jns.2024.123019}, pmid = {38640582}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/physiopathology/complications ; Male ; Female ; Middle Aged ; *Emotions/physiology ; Aged ; *Facial Expression ; Neuropsychological Tests ; Recognition, Psychology/physiology ; Facial Recognition/physiology ; Adult ; }, abstract = {OBJECTIVE: The aim of our study was to measure the ability of ALS patients to process dynamic facial expressions as compared to a control group of healthy subjects and to correlate this ability in ALS patients with neuropsychological, clinical and neurological measures of the disease.

METHODS: Sixty-three ALS patients and 47 healthy controls were recruited. All the ALS patients also underwent i) the Geneva Emotion Recognition Test (GERT) in which ten actors express 14 types of dynamic emotions in brief video clips with audio, ii) the Edimburgh Cognitive and Behavioral ALS Screen (ECAS) test; iii) the ALS Functional Rating Scale Revised (ALSFRS-R) and iv) the Medical Research Council (MRC) for the evaluation of muscle strength. All the healthy subjects enrolled in the study underwent the GERT.

RESULTS: The recognition of irritation and pleasure was significantly different between ALS patients and the control group. The amusement, despair, irritation, joy, sadness and surprise had been falsely recognized differently between the two groups. Specific ALS cognitive impairment was associated with bulbar-onset phenotype (OR = 14,3889; 95%CI = 3,96-52,16). No association was observed between false emotion recognition and cognitive impairment (F(1,60)=,56,971, p=,45,333). The number of categorical errors was significantly higher in the ALS patients than in the control group (27,66 ± 7,28 vs 17,72 ± 5,29; t = 8723; p = 0.001).

CONCLUSIONS: ALS patients show deficits in the dynamic processing of a wide range of emotions. These deficits are not necessarily associated with a decline in higher cognitive functions: this could therefore lead to an underestimation of the phenomenon.}, } @article {pmid38641715, year = {2024}, author = {Udine, E and DeJesus-Hernandez, M and Tian, S and das Neves, SP and Crook, R and Finch, NA and Baker, MC and Pottier, C and Graff-Radford, NR and Boeve, BF and Petersen, RC and Knopman, DS and Josephs, KA and Oskarsson, B and Da Mesquita, S and Petrucelli, L and Gendron, TF and Dickson, DW and Rademakers, R and van Blitterswijk, M}, title = {Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {73}, pmid = {38641715}, issn = {1432-0533}, support = {R01 NS120992/NS/NINDS NIH HHS/United States ; R35 NS097261/NS/NINDS NIH HHS/United States ; R21 NS110994/NS/NINDS NIH HHS/United States ; UH3 NS103870/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 AG037491/AG/NIA NIH HHS/United States ; UG3 NS103870/NS/NINDS NIH HHS/United States ; R01 NS121125/NS/NINDS NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; RF1 AG080556/AG/NIA NIH HHS/United States ; RF1 NS123052/NS/NINDS NIH HHS/United States ; RF1 NS120992/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *Cerebellum/pathology ; DNA Repeat Expansion/genetics ; *Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; Gene Expression Profiling ; Transcriptome ; }, abstract = {The most prominent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a repeat expansion in the gene C9orf72. Importantly, the transcriptomic consequences of the C9orf72 repeat expansion remain largely unclear. Here, we used short-read RNA sequencing (RNAseq) to profile the cerebellar transcriptome, detecting alterations in patients with a C9orf72 repeat expansion. We focused on the cerebellum, since key C9orf72-related pathologies are abundant in this neuroanatomical region, yet TDP-43 pathology and neuronal loss are minimal. Consistent with previous work, we showed a reduction in the expression of the C9orf72 gene and an elevation in homeobox genes, when comparing patients with the expansion to both patients without the C9orf72 repeat expansion and control subjects. Interestingly, we identified more than 1000 alternative splicing events, including 4 in genes previously associated with ALS and/or FTLD. We also found an increase of cryptic splicing in C9orf72 patients compared to patients without the expansion and controls. Furthermore, we demonstrated that the expression level of select RNA-binding proteins is associated with cryptic splice junction inclusion. Overall, this study explores the presence of widespread transcriptomic changes in the cerebellum, a region not confounded by severe neurodegeneration, in post-mortem tissue from C9orf72 patients.}, } @article {pmid38642323, year = {2024}, author = {Ferrari, V and Conti, M and Bovenzi, R and Cerroni, R and Pierantozzi, M and Mercuri, NB and Stefani, A}, title = {Rare association between spinocerebellar ataxia and amyotrophic lateral sclerosis: a case series.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {9}, pages = {4367-4371}, pmid = {38642323}, issn = {1590-3478}, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/complications ; *Spinocerebellar Ataxias/genetics/complications/physiopathology ; *Ataxin-2/genetics ; Trinucleotide Repeat Expansion/genetics ; }, abstract = {INTRODUCTION: In this work, we describe a new case of association between SCA2 and MND.

CASE REPORT: A 58-year-old man who was diagnosed with spinocerebellar ataxia type 2 presented dysphagia and a significant decline in his ability to walk, with a reduction in autonomy and the need to use a wheelchair. We performed electromyography and electroneurography of the four limbs and of the cranial district and motor-evoked potentials to study upper and lower motor neurons. Referring to the revised El Escorial criteria of 2015, ALS diagnosis was made.

DISCUSSION: Considering different cases described in literature over the years, SCA2 could represent an important risk factor for developing ALS. In particular, the presence of alleles of ATXN2 with 27 and 28 CAG repeats seems to slightly decrease the risk of developing the disease, which would instead be progressively increased by the presence of alleles with 29, 30, 31, 32, and 33 repeats. The exact physiopathological mechanism by which the mutation increases the risk of developing the disease is currently unknown. Transcriptomic studies on mouse models have demonstrated the involvement of several pathways, including the innate immunity regulation by STING and the biosynthesis of fatty acid and cholesterol by SREBP.

CONCLUSION: CAG repeat expansions in the ATXN2 gene have been associated with variable neurological presentations, which include SCA2, ALS, Parkinsonism, or a combination of them. Further research is needed to understand the relationship between SCA2 and ALS better and explore molecular underlying mechanisms.}, } @article {pmid38643008, year = {2024}, author = {Zheng, Q and Zeng, Z and Tang, X and Ma, L}, title = {Impact of an ICU bed capacity optimisation method on the average length of stay and average cost of hospitalisation following implementation of China's open policy with respect to COVID-19: a difference-in-differences analysis based on information management system data from a tertiary hospital in southwest China.}, journal = {BMJ open}, volume = {14}, number = {4}, pages = {e078069}, pmid = {38643008}, issn = {2044-6055}, mesh = {Humans ; *COVID-19/epidemiology ; Length of Stay ; Tertiary Care Centers ; Hospitalization ; Intensive Care Units ; China/epidemiology ; Information Management ; }, abstract = {OBJECTIVES: Following the implementation of China's open policy with respect to COVID-19 on 7 December 2022, the influx of patients with infectious diseases has surged rapidly, necessitating hospitals to adopt temporary requisition and modification of ward beds to optimise hospital bed capacity and alleviate the burden of overcrowded patients. This study aims to investigate the effect of an intensive care unit (ICU) bed capacity optimisation method on the average length of stay (ALS) and average cost of hospitalisation (ACH) after the open policy of COVID-19 in China.

DESIGN AND SETTING: A difference-in-differences (DID) approach is employed to analyse and compare the ALS and ACH of patients in four modified ICUs and eight non-modified ICUs within a tertiary hospital located in southwest China. The analysis spans 2 months before and after the open policy, specifically from 5 October 2022 to 6 December 2022, and 7 December 2022 to 6 February 2023.

PARTICIPANTS: We used the daily data extracted from the hospital's information management system for a total of 5944 patients admitted by the outpatient and emergency access during the 2-month periods before and after the release of the open policy in China.

RESULTS: The findings indicate that the ICU bed optimisation method implemented by the tertiary hospital led to a significant reduction in ALS (HR -0.6764, 95% CI -1.0328 to -0.3201, p=0.000) and ACH (HR -0.2336, 95% CI -0.4741 to -0.0068, p=0.057) among ICU patients after implementation of the open policy. These results were robust across various sensitivity analyses. However, the effect of the optimisation method exhibits heterogeneity among patients admitted through the outpatient and emergency channels.

CONCLUSIONS: This study corroborates a significant positive impact of ICU bed optimisation in mitigating the shortage of medical resources following an epidemic outbreak. The findings hold theoretical and practical implications for identifying effective emergency coordination strategies in managing hospital bed resources during sudden public health emergency events. These insights contribute to the advancement of resource management practices and the promotion of experiences in dealing with public health emergencies.}, } @article {pmid38643019, year = {2024}, author = {Guo, J and You, L and Zhou, Y and Hu, J and Li, J and Yang, W and Tang, X and Sun, Y and Gu, Y and Dong, Y and Chen, X and Sato, C and Zinman, L and Rogaeva, E and Wang, J and Chen, Y and Zhang, M}, title = {Spatial enrichment and genomic analyses reveal the link of NOMO1 with amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {8}, pages = {2826-2841}, doi = {10.1093/brain/awae123}, pmid = {38643019}, issn = {1460-2156}, support = {82071430//National Natural Science Foundation of China/ ; 22ZR1466400//Shanghai Municipal Natural Science Foundation General Program/ ; //Fundamental Research Funds/ ; //Central Universities/ ; #2021ZD0201100//Science Innovation 2030 - Brain Science and Brain-Inspired Intelligence Technology Major Project/ ; //Ministry of Science and Technology/ ; //ALS Society of Canada and Canadian Consortium on Neurodegeneration in Aging/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; Mice ; Animals ; *Motor Cortex/metabolism/pathology ; Transcriptome ; Genomics/methods ; Prefrontal Cortex/metabolism/pathology ; Motor Neurons/metabolism/pathology ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease with uncertain genetic predisposition in most sporadic cases. The spatial architecture of cell types and gene expression are the basis of cell-cell interactions, biological function and disease pathology, but are not well investigated in the human motor cortex, a key ALS-relevant brain region. Recent studies indicated single nucleus transcriptomic features of motor neuron vulnerability in ALS motor cortex. However, the brain regional vulnerability of ALS-associated genes and the genetic link between region-specific genes and ALS risk remain largely unclear. Here, we developed an entropy-weighted differential gene expression matrix-based tool (SpatialE) to identify the spatial enrichment of gene sets in spatial transcriptomics. We benchmarked SpatialE against another enrichment tool (multimodal intersection analysis) using spatial transcriptomics data from both human and mouse brain tissues. To investigate regional vulnerability, we analysed three human motor cortex and two dorsolateral prefrontal cortex tissues for spatial enrichment of ALS-associated genes. We also used Cell2location to estimate the abundance of cell types in ALS-related cortex layers. To dissect the link of regionally expressed genes and ALS risk, we performed burden analyses of rare loss-of-function variants detected by whole-genome sequencing in ALS patients and controls, then analysed differential gene expression in the TargetALS RNA-sequencing dataset. SpatialE showed more accurate and specific spatial enrichment of regional cell type markers than multimodal intersection analysis in both mouse brain and human dorsolateral prefrontal cortex. Spatial transcriptomic analyses of human motor cortex showed heterogeneous cell types and spatial gene expression profiles. We found that 260 manually curated ALS-associated genes are significantly enriched in layer 5 of the motor cortex, with abundant expression of upper motor neurons and layer 5 excitatory neurons. Burden analyses of rare loss-of-function variants in Layer 5-associated genes nominated NOMO1 as a novel ALS-associated gene in a combined sample set of 6814 ALS patients and 3324 controls (P = 0.029). Gene expression analyses in CNS tissues revealed downregulation of NOMO1 in ALS, which is consistent with a loss-of-function disease mechanism. In conclusion, our integrated spatial transcriptomics and genomic analyses identified regional brain vulnerability in ALS and the association of a layer 5 gene (NOMO1) with ALS risk.}, } @article {pmid38643177, year = {2024}, author = {Jeszka, J and Hummel, D and Woźniewicz, M and Morinaka, T and Sone, Y and Crews, DE}, title = {Allostatic load and frailty do not covary significantly among older residents of Greater Poland.}, journal = {Journal of physiological anthropology}, volume = {43}, number = {1}, pages = {12}, pmid = {38643177}, issn = {1880-6805}, mesh = {Male ; Humans ; Female ; Aged ; *Allostasis/physiology ; *Frailty/epidemiology ; Poland/epidemiology ; Biomarkers ; Cohort Studies ; }, abstract = {BACKGROUND: Physiological dysregulation/allostatic load and the geriatric syndrome frailty increase with age. As a neurophysiological response system, allostasis supports survival by limiting stressor-related damage. Frailty reflects decreased strength, endurance, and physical abilities secondary to losses of muscle and bone with age. One suggestion, based on large cohort studies of person's ages 70 + years, is that frailty contributes to allostatic load at older ages. However, small community-based research has not confirmed this specific association.

METHODS: To further explore possible associations between allostatic load and frailty, we enrolled 211 residents of Greater Poland aged 55-91 years living in a small village (Nekla, N = 104) and an urban center and capital of Greater Poland (Poznan, N = 107). For each, we recorded age, self-reported sex, and residence and estimated a 10-biomarker allostatic load score (ALS) and an 8-biomarker frailty index. We anticipated the following: higher ALS and frailty among men and rural residents; for frailty but not ALS to be higher at older ages; significant associations of ALS with sex and place of residence, but not with age or frailty. The significance of observed associations was evaluated by t-tests and multivariate regression.

RESULTS: ALS did not vary significantly between men and women nor between Nekla and Poznan residents overall. However, women showed significantly higher frailty than men. Nekla men showed significantly higher ALS but not frailty, while Nekla women showed nonsignificantly higher ALS and lower frailty than Poznan. In multivariate analyses, neither age, nor sex, nor residence was associated with ALS. Conversely, age, sex, and residence, but not ALS, are associated significantly with frailty. In Nekla, both age and sex, but in Poznan only age, are associated with ALS. Among women, both age and residence, but among men, neither associated with ALS. In no case did ALS associate significantly with frailty.

CONCLUSION: In this sample, lifestyle factors associated with residence, age, and sex influence stress-related physiology, less so in women, while ALS and frailty do not covary, suggesting their underlying promoters are distinct. Similar complex associations of physiological dysregulation with frailty, age, sex, and residence likely exist within many local settings. Knowledge of this variation likely will aid in supporting health and healthcare services among seniors.}, } @article {pmid38643758, year = {2024}, author = {Aiello, EN and Solca, F and Torre, S and Colombo, E and Maranzano, A and De Lorenzo, A and Patisso, V and Treddenti, M and Curti, B and Morelli, C and Doretti, A and Verde, F and Ferrucci, R and Barbieri, S and Ruggiero, F and Priori, A and Silani, V and Ticozzi, N and Poletti, B}, title = {Longitudinal Feasibility of the Montreal Cognitive Assessment (MoCA) in Non-Demented ALS Patients.}, journal = {European neurology}, volume = {87}, number = {2}, pages = {79-83}, doi = {10.1159/000538828}, pmid = {38643758}, issn = {1421-9913}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Male ; Female ; *Feasibility Studies ; *Mental Status and Dementia Tests/standards ; Middle Aged ; Aged ; Longitudinal Studies ; Reproducibility of Results ; Cognitive Dysfunction/etiology/diagnosis ; Disease Progression ; Italy ; Neuropsychological Tests/standards ; }, abstract = {INTRODUCTION: The present study aimed at testing the longitudinal feasibility of the Montreal Cognitive Assessment (MoCA) in an Italian cohort of non-demented amyotrophic lateral sclerosis (ALS) patients.

METHODS: N = 39 non-demented ALS patients were followed-up at a 5-to-10-month interval (M = 6.8; SD = 1.4) with the MoCA and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Practice effects, test-retest reliability, and predictive validity (against follow-up ECAS scores) were assessed. Reliable change indices (RCIs) were derived via a regression-based approach by accounting for retest interval and baseline confounders (i.e., demographics, disease duration, and severity and progression rate).

RESULTS: At retest, 100% and 69.2% of patients completed the ECAS and the MoCA, respectively. Patients who could not complete the MoCA showed a slightly more severe and fast-progressing disease. The MoCA was not subject to practice effects (t[32] = -0.80; p = 0.429) and was reliable at retest (intra-class correlation = 0.82). Moreover, baseline MoCA scores predicted the ECAS at retest. RCIs were successfully derived - with baseline MoCA scores being the only significant predictor of retest performances (ps < 0.001).

CONCLUSIONS: As long as motor disabilities do not undermine its applicability, the MoCA appears to be longitudinally feasible at a 5-to-10-month interval in non-demented ALS patients. However, ALS-specific screeners - such as the ECAS - should be preferred whenever possible.}, } @article {pmid38644373, year = {2024}, author = {Niccolai, E and Pedone, M and Martinelli, I and Nannini, G and Baldi, S and Simonini, C and Di Gloria, L and Zucchi, E and Ramazzotti, M and Spezia, PG and Maggi, F and Quaranta, G and Masucci, L and Bartolucci, G and Stingo, FC and Mandrioli, J and Amedei, A}, title = {Amyotrophic lateral sclerosis stratification: unveiling patterns with virome, inflammation, and metabolism molecules.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4310-4325}, pmid = {38644373}, issn = {1432-1459}, support = {Grant-No. RF-2016-02361616//Ministero della Salute/ ; Grant no. B008-P00634//University of Florence/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/immunology ; Male ; Female ; Middle Aged ; Aged ; *Inflammation/blood ; *Virome ; Cytokines/blood ; Torque teno virus/genetics ; Fatty Acids, Nonesterified/blood ; Adult ; Biomarkers/blood ; DNA, Viral/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an untreatable and clinically heterogeneous condition primarily affecting motor neurons. The ongoing quest for reliable biomarkers that mirror the disease status and progression has led to investigations that extend beyond motor neurons' pathology, encompassing broader systemic factors such as metabolism, immunity, and the microbiome. Our study contributes to this effort by examining the potential role of microbiome-related components, including viral elements, such as torque tenovirus (TTV), and various inflammatory factors, in ALS. In our analysis of serum samples from 100 ALS patients and 34 healthy controls (HC), we evaluated 14 cytokines, TTV DNA load, and 18 free fatty acids (FFA). We found that the evaluated variables are effective in differentiating ALS patients from healthy controls. In addition, our research identifies four unique patient clusters, each characterized by distinct biological profiles. Intriguingly, no correlations were found with site of onset, sex, progression rate, phenotype, or C9ORF72 expansion. A remarkable aspect of our findings is the discovery of a gender-specific relationship between levels of 2-ethylhexanoic acid and patient survival. In addition to contributing to the growing body of evidence suggesting altered peripheral immune responses in ALS, our exploratory research underscores metabolic diversity challenging conventional clinical classifications. If our exploratory findings are validated by further research, they could significantly impact disease understanding and patient care customization. Identifying groups based on biological profiles might aid in clustering patients with varying responses to treatments.}, } @article {pmid38644578, year = {2024}, author = {Yao, Q and Long, C and Yi, P and Zhang, G and Wan, W and Rao, X and Ying, J and Liang, W and Hua, F}, title = {C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {4}, pages = {e14721}, pmid = {38644578}, issn = {1755-5949}, support = {jxsq2019201023//Jiangxi Province "Double Thousand Plan"/ ; 82060219//National Natural Science Foundation of China/ ; 82271234//National Natural Science Foundation of China/ ; 20212ACB216009//Natural Science Foundation of Jiangxi Province/ ; 20212BAB216048//Natural Science Foundation of Jiangxi Province/ ; 2019YNTD12003//Youth Team Project of the Second Affiliated Hospital of Nanchang University/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *CCAAT-Enhancer-Binding Protein-beta/metabolism/genetics ; *Disease Progression ; Animals ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment.

AIMS: Several studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD.

METHODS: A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded.

RESULTS: Overexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO).

DISCUSSION: The correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS).

CONCLUSION: The overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.}, } @article {pmid38644973, year = {2024}, author = {Gonzalez, D and Cuenca, X and Allende, ML}, title = {Knockdown of tgfb1a partially improves ALS phenotype in a transient zebrafish model.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1384085}, pmid = {38644973}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) corresponds to a neurodegenerative disorder marked by the progressive degeneration of both upper and lower motor neurons located in the brain, brainstem, and spinal cord. ALS can be broadly categorized into two main types: sporadic ALS (sALS), which constitutes approximately 90% of all cases, and familial ALS (fALS), which represents the remaining 10% of cases. Transforming growth factor type-β (TGF-β) is a cytokine involved in various cellular processes and pathological contexts, including inflammation and fibrosis. Elevated levels of TGF-β have been observed in the plasma and cerebrospinal fluid (CSF) of both ALS patients and mouse models. In this perspective, we explore the impact of the TGF-β signaling pathway using a transient zebrafish model for ALS. Our findings reveal that the knockdown of tgfb1a lead to a partial prevention of motor axon abnormalities and locomotor deficits in a transient ALS zebrafish model at 48 h post-fertilization (hpf). In this context, we delve into the proposed distinct roles of TGF-β in the progression of ALS. Indeed, some evidence suggests a dual role for TGF-β in ALS progression. Initially, it seems to exert a neuroprotective effect in the early stages, but paradoxically, it may contribute to disease progression in later stages. Consequently, we suggest that the TGF-β signaling pathway emerges as an attractive therapeutic target for treating ALS. Nevertheless, further research is crucial to comprehensively understand the nuanced role of TGF-β in the pathological context.}, } @article {pmid38645132, year = {2024}, author = {Caggiano, C and Morselli, M and Qian, X and Celona, B and Thompson, M and Wani, S and Tosevska, A and Taraszka, K and Heuer, G and Ngo, S and Steyn, F and Nestor, P and Wallace, L and McCombe, P and Heggie, S and Thorpe, K and McElligott, C and English, G and Henders, A and Henderson, R and Lomen-Hoerth, C and Wray, N and McRae, A and Pellegrini, M and Garton, F and Zaitlen, N}, title = {Tissue informative cell-free DNA methylation sites in amyotrophic lateral sclerosis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38645132}, support = {T32 NS048004/NS/NINDS NIH HHS/United States ; }, abstract = {Cell-free DNA (cfDNA) is increasingly recognized as a promising biomarker candidate for disease monitoring. However, its utility in neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS), remains underexplored. Existing biomarker discovery approaches are tailored to a specific disease context or are too expensive to be clinically practical. Here, we address these challenges through a new approach combining advances in molecular and computational technologies. First, we develop statistical tools to select tissue-informative DNA methylation sites relevant to a disease process of interest. We then employ a capture protocol to select these sites and perform targeted methylation sequencing. Multi-modal information about the DNA methylation patterns are then utilized in machine learning algorithms trained to predict disease status and disease progression. We applied our method to two independent cohorts of ALS patients and controls (n=192). Overall, we found that the targeted sites accurately predicted ALS status and replicated between cohorts. Additionally, we identified epigenetic features associated with ALS phenotypes, including disease severity. These findings highlight the potential of cfDNA as a non-invasive biomarker for ALS.}, } @article {pmid38645254, year = {2024}, author = {Card, NS and Wairagkar, M and Iacobacci, C and Hou, X and Singer-Clark, T and Willett, FR and Kunz, EM and Fan, C and Nia, MV and Deo, DR and Srinivasan, A and Choi, EY and Glasser, MF and Hochberg, LR and Henderson, JM and Shahlaie, K and Brandman, DM and Stavisky, SD}, title = {An accurate and rapidly calibrating speech neuroprosthesis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38645254}, support = {DP2 DC021055/DC/NIDCD NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; U01 DC019430/DC/NIDCD NIH HHS/United States ; }, abstract = {Brain-computer interfaces can enable rapid, intuitive communication for people with paralysis by transforming the cortical activity associated with attempted speech into text on a computer screen. Despite recent advances, communication with brain-computer interfaces has been restricted by extensive training data requirements and inaccurate word output. A man in his 40's with ALS with tetraparesis and severe dysarthria (ALSFRS-R = 23) was enrolled into the BrainGate2 clinical trial. He underwent surgical implantation of four microelectrode arrays into his left precentral gyrus, which recorded neural activity from 256 intracortical electrodes. We report a speech neuroprosthesis that decoded his neural activity as he attempted to speak in both prompted and unstructured conversational settings. Decoded words were displayed on a screen, then vocalized using text-to-speech software designed to sound like his pre-ALS voice. On the first day of system use, following 30 minutes of attempted speech training data, the neuroprosthesis achieved 99.6% accuracy with a 50-word vocabulary. On the second day, the size of the possible output vocabulary increased to 125,000 words, and, after 1.4 additional hours of training data, the neuroprosthesis achieved 90.2% accuracy. With further training data, the neuroprosthesis sustained 97.5% accuracy beyond eight months after surgical implantation. The participant has used the neuroprosthesis to communicate in self-paced conversations for over 248 hours. In an individual with ALS and severe dysarthria, an intracortical speech neuroprosthesis reached a level of performance suitable to restore naturalistic communication after a brief training period.}, } @article {pmid38646235, year = {2024}, author = {Hagino, T and Ochiai, S and Hagino, T and Furuya, N and Wako, M and Haro, H}, title = {Impacts of Segond Fractures on Anterior Cruciate Ligament Reconstruction Outcomes.}, journal = {Cureus}, volume = {16}, number = {3}, pages = {e56542}, pmid = {38646235}, issn = {2168-8184}, abstract = {INTRODUCTION: Segond fractures, characterized by avulsion injuries at the lateral tibial condyle's anterolateral structure (ALS) attachment, often coincide with anterior cruciate ligament (ACL) injuries, potentially leading to knee instability. However, the influence of Segond fractures on knee stability after ACL reconstruction remains uncertain. Despite documented ALS reconstructions, there is a lack of consensus regarding the assessment of ALS failure and the criteria for surgical interventions. This study aimed to determine if Segond fracture presence impacts ACL reconstruction outcomes, utilizing patient-reported subjective assessments and healthcare providers' objective evaluations.

MATERIALS AND METHODS: This retrospective study encompassed 639 patients (328 males, 311 females; mean age 26.9 years) who underwent ACL reconstruction, with a follow-up of at least one year. Subjects were divided into two groups: Segond fractures diagnosed through radiographic findings (Group S+, n = 17) and no Segond fractures (Group S-, n = 622). Clinical evaluation included the 36-item Short Form Survey (SF-36), Lysholm score, visual analog scale (VAS) for knee pain, knee injury and osteoarthritis outcome score (KOOS), and knee instability assessment via Telos SE (Telos Japan, Tokyo, Japan). Statistical comparisons were performed between the two groups.

RESULTS: At the final follow-up, all SF-36 subscales improved in all eight subscales compared to before surgery, reaching national standard scores; no significant inter-group differences were evident. Lysholm scores were 93.0 ± 12.1 (Group S+) and 91.7 ± 10.9 (Group S-) (P = 0.62), VAS for knee pain was 10.0 ± 18.0 (Group S+) and 11.9 ± 16.9 (Group S-) (P = 0.62), total KOOS was 89.0 ± 17.4 (Group S+) and 90.7 ± 9.9 (Group S-) (P = 0.39), and anterior tibial translation differences were 2.8 ± 3.0 mm (Group S+) and 2.7 ± 2.9 mm (Group S-) (P = 0.73). All these values represent postoperative measurements. No significant discrepancies existed between groups across evaluation methods.

CONCLUSIONS: This study's results suggest that Segond fractures have minimal impact on clinical ACL reconstruction outcomes, as assessed through both patient-reported subjective evaluations and objective healthcare provider evaluations. Segond fractures' significance in postoperative outcomes questions the necessity of ALS reconstruction.}, } @article {pmid38646691, year = {2024}, author = {Flynn, MB and Flynn, JF and Palacios, AM}, title = {Capitalizing on Hope: Questionable Marketing Approval and Pricing of a New ALS Drug.}, journal = {International journal of social determinants of health and health services}, volume = {54}, number = {4}, pages = {405-411}, doi = {10.1177/27551938241247778}, pmid = {38646691}, issn = {2755-1946}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/economics ; Humans ; *Drug Approval ; United States ; United States Food and Drug Administration ; Cost-Benefit Analysis ; }, abstract = {Regulatory agencies must balance patient demands to access new treatments for fatal diseases with limited treatment options while ensuring drug safety and efficacy. However, questionable U.S. regulatory actions resulted in the early approval of AMX0035 to treat amyotrophic lateral sclerosis (ALS) by reconvening advisory commissions to obtain positive decisions and designating the drug as a new molecular entity. Data from one randomized clinical trial suggests minimal delays in disease progression and longer survivability, but debate remains about the lack of confirmatory evidence of effectiveness owing to study limitations. A patient's decision-making process details the experience of using the drug, including perspectives on access, cost, effectiveness, and adverse effects. In line with the "nichebuster" business model, the drugmaker, Amylyx Pharmaceuticals, is charging US$158,000/year/patient and thus forecast to turn a profit on a drug with debatable clinical effectiveness prior to completing a Phase 3 trial. Early marketing approval, despite community demands, is unnecessary and may have reduced access because of the end of a compassionate use program, and the high price tag results in restricted coverage and high out-of-pocket costs. Also, the drug's key ingredients are available as a generic and a supplement.}, } @article {pmid38647181, year = {2024}, author = {Zejlon, C and Sennfält, S and Finnsson, J and Connolly, B and Petersson, S and Granberg, T and Ingre, C}, title = {Motor band sign is specific for amyotrophic lateral sclerosis and corresponds to motor symptoms.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {5}, pages = {1280-1289}, pmid = {38647181}, issn = {2328-9503}, support = {20190565//Region Stockholm and Karolinska Institutet through ALF Medicine/ ; 976444//Region Stockholm and Karolinska Institutet through ALF Medicine/ ; //Neuroförbundet/ ; //Svenska Frimurarorden/ ; //Ulla-Carin Lindquists stiftelse för ALS-forskning/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/genetics ; Male ; Female ; Middle Aged ; Aged ; *Magnetic Resonance Imaging ; *Motor Cortex/diagnostic imaging/physiopathology ; Prospective Studies ; Adult ; Sensitivity and Specificity ; C9orf72 Protein/genetics ; }, abstract = {OBJECTIVE: Magnetic resonance imaging can detect neurodegenerative iron accumulation in the motor cortex, called the motor band sign. This study aims to evaluate its sensitivity/specificity and correlations to symptomatology, biomarkers, and clinical outcome in amyotrophic lateral sclerosis.

METHODS: This prospective study consecutively enrolled 114 persons with amyotrophic lateral sclerosis and 79 mimics referred to Karolinska University Hospital, and also 31 healthy controls. All underwent 3-Tesla brain susceptibility-weighted imaging. Three raters independently assessed motor cortex susceptibility with total and regional motor band scores. Survival was evaluated at a median of 34.2 months after the imaging.

RESULTS: The motor band sign identified amyotrophic lateral sclerosis with a sensitivity of 59.6% and a specificity of 91.1% versus mimics and 96.8% versus controls. Higher motor band scores were more common with genetic risk factors (p = 0.032), especially with C9orf72 mutation, and were associated with higher neurofilament light levels (std. β 0.22, p = 0.019). Regional scores correlated strongly with focal symptoms (medial region vs. gross motor dysfunction, std. β -0.64, p = 0.001; intermediate region vs. fine motor dysfunction, std. β -0.51, p = 0.031; lateral region vs. bulbar symptoms std. β -0.71, p < 0.001). There were no associations with cognition, progression rate, or survival.

INTERPRETATION: In a real-life clinical setting, the motor band sign has high specificity but relatively low sensitivity for identifying amyotrophic lateral sclerosis. Associations with genetic risk factors, neurofilament levels and somatotopic correspondence to focal motor weakness suggest that the motor band sign could be a suitable biomarker for diagnostics and clinical trials in amyotrophic lateral sclerosis.}, } @article {pmid38647433, year = {2024}, author = {Mousavi, H and Rimaz, M and Zeynizadeh, B}, title = {Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {9}, pages = {1828-1881}, doi = {10.1021/acschemneuro.4c00055}, pmid = {38647433}, issn = {1948-7193}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Molecular Docking Simulation/methods ; Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Heterocyclic Compounds, 2-Ring/pharmacology/chemical synthesis/chemistry ; Structure-Activity Relationship ; }, abstract = {Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a-h), and hydrazine monohydrate (NH2NH2•H2O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a-h). After synthesis and characterization of the mentioned cinnolines (3a-h), the in silico multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2[(G2019S)], hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, and hDHODH, which have confirmed their functions and roles in the neurodegenerative diseases (NDs), based on molecular docking studies, and the obtained results were compared with a wide range of approved drugs and well-known (with IC50, EC50, etc.) compounds. In addition, in silico ADMET prediction analysis was performed to examine the prospective drug properties of the synthesized heterocyclic compounds (3a-h). The obtained results from the molecular docking studies and ADMET-related data demonstrated that these series of 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines (3a-h), especially hit ones, can really be turned into the potent core of new drugs for the treatment of neurodegenerative diseases (NDs), and/or due to the having some reactionable locations, they are able to have further organic reactions (such as cross-coupling reactions), and expansion of these compounds (for example, with using other types of aryl(or heteroaryl)glyoxal monohydrates) makes a new avenue for designing novel and efficient drugs for this purpose.}, } @article {pmid38648781, year = {2024}, author = {Ikegawa, Y and Fukuma, R and Sugano, H and Oshino, S and Tani, N and Tamura, K and Iimura, Y and Suzuki, H and Yamamoto, S and Fujita, Y and Nishimoto, S and Kishima, H and Yanagisawa, T}, title = {Text and image generation from intracranial electroencephalography using an embedding space for text and images.}, journal = {Journal of neural engineering}, volume = {21}, number = {3}, pages = {}, doi = {10.1088/1741-2552/ad417a}, pmid = {38648781}, issn = {1741-2552}, mesh = {Humans ; *Brain-Computer Interfaces ; Male ; Female ; *Electrocorticography/methods ; Adult ; Electroencephalography/methods ; Middle Aged ; Electrodes, Implanted ; Young Adult ; Photic Stimulation/methods ; }, abstract = {Objective.Invasive brain-computer interfaces (BCIs) are promising communication devices for severely paralyzed patients. Recent advances in intracranial electroencephalography (iEEG) coupled with natural language processing have enhanced communication speed and accuracy. It should be noted that such a speech BCI uses signals from the motor cortex. However, BCIs based on motor cortical activities may experience signal deterioration in users with motor cortical degenerative diseases such as amyotrophic lateral sclerosis. An alternative approach to using iEEG of the motor cortex is necessary to support patients with such conditions.Approach. In this study, a multimodal embedding of text and images was used to decode visual semantic information from iEEG signals of the visual cortex to generate text and images. We used contrastive language-image pretraining (CLIP) embedding to represent images presented to 17 patients implanted with electrodes in the occipital and temporal cortices. A CLIP image vector was inferred from the high-γpower of the iEEG signals recorded while viewing the images.Main results.Text was generated by CLIPCAP from the inferred CLIP vector with better-than-chance accuracy. Then, an image was created from the generated text using StableDiffusion with significant accuracy.Significance.The text and images generated from iEEG through the CLIP embedding vector can be used for improved communication.}, } @article {pmid38652017, year = {2024}, author = {Rahman, MU and Bano, S and Hong, X and Gu, RX and Chen, HF}, title = {Early Aggregation Mechanism of SOD128-38 Based on Force Field Parameter of 5-Cyano-Tryptophan.}, journal = {Journal of chemical information and modeling}, volume = {64}, number = {9}, pages = {3942-3952}, doi = {10.1021/acs.jcim.4c00289}, pmid = {38652017}, issn = {1549-960X}, mesh = {Humans ; Kinetics ; Markov Chains ; Molecular Dynamics Simulation ; *Protein Aggregates ; Protein Multimerization ; *Superoxide Dismutase-1/chemistry/metabolism ; *Tryptophan/chemistry/metabolism ; }, abstract = {The aggregation of superoxide dismutase 1 (SOD1) results in amyloid deposition and is involved in familial amyotrophic lateral sclerosis, a fatal motor neuron disease. There have been extensive studies of its aggregation mechanism. Noncanonical amino acid 5-cyano-tryptophan (5-CN-Trp), which has been incorporated into the amyloid segments of SOD1 as infrared probes to increase the structural sensitivity of IR spectroscopy, is found to accelerate the overall aggregation rate and potentially modulate the aggregation process. Despite these observations, the underlying mechanism remains elusive. Here, we optimized the force field parameters of 5-CN-Trp and then used molecular dynamics simulation along with the Markov state model on the SOD128-38 dimer to explore the kinetics of key intermediates in the presence and absence of 5-CN-Trp. Our findings indicate a significantly increased probability of protein aggregate formation in 5CN-Trp-modified ensembles compared to wildtype. Dimeric β-sheets of different natures were observed exclusively in the 5CN-Trp-modified peptides, contrasting with wildtype simulations. Free-energy calculations and detailed analyses of the dimer structure revealed augmented interstrand interactions attributed to 5-CN-Trp, which contributed more to peptide affinity than any other residues. These results explored the key events critical for the early nucleation of amyloid-prone proteins and also shed light on the practice of using noncanonical derivatives to study the aggregation mechanism.}, } @article {pmid38654338, year = {2024}, author = {Li, Y and Hu, Q and Wang, Q and Liu, T and Gao, M}, title = {Real-time ultrasound-guided sacral plexus block combined with mild sedation for hemorrhoidectomy and hemorrhoidal artery ligation in a patient with amyotrophic lateral sclerosis: a case report.}, journal = {Journal of medical case reports}, volume = {18}, number = {1}, pages = {205}, pmid = {38654338}, issn = {1752-1947}, mesh = {Humans ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications ; *Ultrasonography, Interventional ; *Hemorrhoidectomy/methods ; Ligation ; *Nerve Block/methods ; *Dexmedetomidine/administration & dosage ; *Lumbosacral Plexus/diagnostic imaging ; Hemorrhoids/surgery ; Hypnotics and Sedatives/administration & dosage ; Treatment Outcome ; }, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis present perioperative challenges for clinical anesthesiologists for anesthesia-associated complications.

CASE PRESENTATION: A 54-year-old Han woman with a 2-year history of amyotrophic lateral sclerosis was scheduled for hemorrhoidectomy and hemorrhoidal artery ligation. We performed real-time ultrasound-guided sacral plexus block with dexmedetomidine under standard monitoring. The anesthesia method met the surgical demands and avoided respiratory complications during the procedures. There was no neurological deterioration after the surgery and 3 months after, the patient was discharged.

CONCLUSIONS: Real-time ultrasound-guided sacral plexus block combined with mild sedation may be an effective and safe technique in patients with amyotrophic lateral sclerosis undergoing hemorrhoidectomy and hemorrhoidal artery ligation.}, } @article {pmid38655443, year = {2024}, author = {Zubair, AS and Saab, L and Scharer, K and Khokhar, B}, title = {Patients' experiences with methylcobalamin injections in amyotrophic lateral sclerosis.}, journal = {Brain circulation}, volume = {10}, number = {1}, pages = {60-66}, pmid = {38655443}, issn = {2455-4626}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with no definitive treatment. Vitamin B12 is not a Food and Drug Administration-approved treatment in the United States, although it has been prescribed off-label as ultra-high-dose methylcobalamin, which has been shown to be safe and effective in slowing functional decline in patients with ALS. This study evaluates the impact of Vitamin B12 injections on the quality of life of five patients.

METHODS: Semi-structured interviews were conducted with the patients and caregivers. The data was carefully read, coded, and organized into themes and sub-themes by two independent researchers.

RESULTS: The study found four themes and 11 subthemes from the data, including initial circumstances, administration of the injection, subjective experience with Vitamin B12, and outcomes and expectations. All participants recognized some benefits from Vitamin B12 injections, specifically increased energy, reduced fatigue, and improved balance. However, some patients had difficulty monitoring its specific effect due to the progressive nature of the disease.

DISCUSSION: The flexibility offered by this intervention is beneficial for patients with declining mobility and strength who wish to adapt their treatment to their schedule. This work is a modest call to fill the existing gap in the literature and push for more randomized controlled trials investigating and clarifying the effects of Vitamin B12 injections on disease progression, muscle function, and quality of life in a small but diverse pool of patients with ALS.}, } @article {pmid38655803, year = {2024}, author = {Temkin-Greener, H and Hua, Y and Cai, S}, title = {Assisted living residents with dementia: Disparities in mental health services pre and during COVID-19.}, journal = {Journal of the American Geriatrics Society}, volume = {72}, number = {6}, pages = {1760-1769}, pmid = {38655803}, issn = {1532-5415}, support = {RF1 AG063811/AG/NIA NIH HHS/United States ; R01HS026893/HS/AHRQ HHS/United States ; R01 AG073052/AG/NIA NIH HHS/United States ; RF1 AG073052/AG/NIA NIH HHS/United States ; RF1AG063811/AG/NIA NIH HHS/United States ; R01 HS026893/HS/AHRQ HHS/United States ; RF1AG073052/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/epidemiology ; United States/epidemiology ; Male ; Female ; *Assisted Living Facilities/statistics & numerical data ; Aged ; *Telemedicine/statistics & numerical data ; *Dementia/epidemiology/therapy ; *Medicare/statistics & numerical data ; *Mental Health Services/statistics & numerical data ; Aged, 80 and over ; *Healthcare Disparities/statistics & numerical data ; SARS-CoV-2 ; Medicaid/statistics & numerical data ; Health Services Accessibility/statistics & numerical data ; }, abstract = {BACKGROUND: Little is known about mental health among Medicare beneficiaries with Alzheimer's disease or related dementias (ADRD) who reside in assisted living (AL) communities. The COVID-19 pandemic may have curtailed ambulatory care access for these residents, but telehealth may have expanded it. We examined in-person and telehealth use of ambulatory mental health visits among AL residents with ADRD, pre and during the COVID pandemic, focusing on race/ethnicity and Medicare/Medicaid dual status.

METHODS: A CY2018 cohort of AL residents with ADRD was identified. Outcome was any quarterly in-person or telemedicine mental health visit based on national CY2019-2020 Medicare claims. Key independent variables were individual race/ethnicity and dual status and the AL-level proportion of dual residents. We estimated a linear probability model with random effects and robust standard errors. Quarterly indicators captured service use before and after the onset of the pandemic.

RESULTS: The study included 102,758 fee-for-service Medicare beneficiaries with ADRD in 13,400 ALs. One in five residents had any mental health visits prior to the COVID-19 pandemic. Black residents, and those with dual Medicare/Medicaid eligibility, were significantly less likely to use mental health services prior to and during the pandemic. There were no significant differences in visits via telemedicine by race/ethnicity or individual dual status. Residents in AL communities with a higher proportion of duals had a lower likelihood of visits before and during the pandemic.

CONCLUSIONS/IMPLICATIONS: Mental health service use among AL residents with ADRD was low and declining prior to the pandemic. Telehealth allowed for mental health visits to continue during the pandemic, albeit at a lower level. Residents in ALs with a higher proportion of duals were less likely to have in-person or telehealth visits. The results suggest that some ALs may find it difficult to assure mental health service provision to this vulnerable population.}, } @article {pmid38657132, year = {2025}, author = {Washington, KT and Mechling, CA and Pitzer, KA and Maiser, S and Mehta, AK}, title = {Identifying the Unmet Needs of People Living With Amyotrophic Lateral Sclerosis: A National Survey to Inform Interdisciplinary Palliative Care.}, journal = {The American journal of hospice & palliative care}, volume = {42}, number = {4}, pages = {326-333}, doi = {10.1177/10499091241248653}, pmid = {38657132}, issn = {1938-2715}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Palliative Care/organization & administration/psychology ; Male ; Female ; Quality of Life ; Middle Aged ; Aged ; Advance Care Planning/organization & administration ; Adult ; Disease Progression ; Terminal Care/psychology/organization & administration ; Surveys and Questionnaires ; Aged, 80 and over ; *Needs Assessment ; }, abstract = {Introduction/Aims: This national survey builds on previous qualitative research examining potential palliative care needs among people living with ALS (pALS) by quantifying and investigating relationships among pALS' stage of illness progression; physical, emotional, social, spiritual, and intimacy-related concerns; advance care planning behaviors; perceptions of feeling heard and understood by healthcare providers; and overall quality of life. Methods: Researchers partnered with national organizations to recruit pALS to participate in a one-time survey comprising items from validated instruments (eg, the ALS Specific Quality of Life Instrument-Revised) and researcher-generated measures. Data were analyzed using logistic and linear regression. Results: Among pALS (n = 112), many respondents indicated they had discussed their wishes for end-of-life care with family or friends, shared their wishes with providers, and documented their wishes in writing (79.5%, 49.1%, and 63.4%, respectively). Mean (M) quality of life scores were moderate (M ≈ 6 of 10). Illness stage was associated with documentation of end-of-life care wishes but not with having discussed these wishes with others or with overall quality of life. Reported emotional intimacy received was comparable to that desired (difference = .01 of 10); however, a greater desire for physical intimacy relative to that received was indicated (difference = 1.75 of 10). Discussion: Interdisciplinary palliative care teams may enhance ALS care by promoting advance care planning behaviors (particularly discussing one's wishes with healthcare providers), providing interventions to improve quality of life, and supporting pALS in navigating challenges related to physical intimacy.}, } @article {pmid38657488, year = {2024}, author = {Rezaee Semnani, M and Mirzaasgari, Z and Ariaei, A and Haghi Ashtiani, B}, title = {Evaluation of carotid Intima-Media Thickness (IMT) in amyotrophic lateral sclerosis disease using ultrasonography.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {124}, number = {}, pages = {67-72}, doi = {10.1016/j.jocn.2024.04.019}, pmid = {38657488}, issn = {1532-2653}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Male ; Female ; *Carotid Intima-Media Thickness ; Middle Aged ; Adult ; Aged ; Ultrasonography/methods ; Body Mass Index ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease with multi-mechanisms as; inflammation, oxidative stress, glutamate excitotoxicity, protein aggregation, etc. This study aimed to evaluate the carotid Intima-Media Thickness (IMT) in ALS and healthy groups, as a possible indicator of these mechanisms.

METHODS: 42 patients with ALS along with 53 normal age and body mass index (BMI) matched participants were recruited from the Firoozgar hospital. Carotid IMT values of the participants were measured using B-mode ultrasonography. Using Pearson correlation and logistic regression adjusting with age, BMI, and gender, the IMT values were assessed.

RESULTS: The mean right and left carotid IMT values of the ALS patients (0.66 ± 0.09) were significantly higher than normal participants (0.45 ± 0.10) (p < 0.001). In addition, the IMT values were highly correlated with the age (r = 0.632; p < 0.001) and the age of ALS onset (r = 0.595; p < 0.001), in contrast to the BMI. Moreover, the higher value of IMT was associated with an increasing risk of ALS with an odd ratio (OR) of 1.483 (95 % Confidence interval [1.026-2.144]). Eventually, evaluating IMT by classifying ALS patients based on the ALS Health State Scale (ALSHSS) from early to late stage revealed a non-linear increase in the OR (1.372, 1.898, 2.172, and 3.403).

CONCLUSION: The increased value of the carotid IMT independent of BMI in ALS could be assessed through ultrasonography as a convenient tool to evaluate the disease severity or possible systemic inflammation.}, } @article {pmid38657911, year = {2024}, author = {Liguori, F and Alberti, F and Amadio, S and Angelini, DF and Pilesi, E and Vitale, G and Tesoriere, G and Borsellino, G and Vernì, F and Volonté, C}, title = {Pan-neuronal expression of human mutant SOD1 in Drosophila impairs survival and motor performance, induces early neuroinflammation and chromosome aberrations.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1870}, number = {5}, pages = {167192}, doi = {10.1016/j.bbadis.2024.167192}, pmid = {38657911}, issn = {1879-260X}, mesh = {Animals ; *Superoxide Dismutase-1/genetics/metabolism ; Humans ; *Drosophila melanogaster/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Animals, Genetically Modified ; *Mutation ; *Chromosome Aberrations ; Drosophila Proteins/genetics/metabolism ; Motor Neurons/metabolism/pathology ; Disease Models, Animal ; Neuroinflammatory Diseases/genetics/metabolism/pathology ; Neurons/metabolism/pathology ; }, abstract = {Several mutations in the SOD1 gene encoding for the antioxidant enzyme Superoxide Dismutase 1, are associated with amyotrophic lateral sclerosis, a rare and devastating disease characterized by motor neuron degeneration and patients' death within 2-5 years from diagnosis. Motor neuron loss and related symptomatology manifest mostly in adult life and, to date, there is still a gap of knowledge on the precise cellular and molecular events preceding neurodegeneration. To deepen our awareness of the early phases of the disease, we leveraged two Drosophila melanogaster models pan-neuronally expressing either the mutation A4V or G85R of the human gene SOD1 (hSOD1[A4V] or hSOD1[G85R]). We demonstrate that pan-neuronal expression of the hSOD1[A4V] or hSOD1[G85R] pathogenic construct impairs survival and motor performance in transgenic flies. Moreover, protein and transcript analysis on fly heads indicates that mutant hSOD1 induction stimulates the glial marker Repo, up-regulates the IMD/Toll immune pathways through antimicrobial peptides and interferes with oxidative metabolism. Finally, cytological analysis of larval brains demonstrates hSOD1-induced chromosome aberrations. Of note, these parameters are found modulated in a timeframe when neurodegeneration is not detected. The novelty of our work is twofold: we have expressed for the first time hSOD1 mutations in all neurons of Drosophila and confirmed some ALS-related pathological phenotypes in these flies, confirming the power of SOD1 mutations in generating ALS-like phenotypes. Moreover, we have related SOD1 pathogenesis to chromosome aberrations and antimicrobial peptides up-regulation. These findings were unexplored in the SOD1-ALS field.}, } @article {pmid38658168, year = {2024}, author = {Jaroszynska, N and Salzinger, A and Tsarouchas, TM and Becker, CG and Becker, T and Lyons, DA and MacDonald, RB and Keatinge, M}, title = {C9ORF72 Deficiency Results in Neurodegeneration in the Zebrafish Retina.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {44}, number = {25}, pages = {}, pmid = {38658168}, issn = {1529-2401}, mesh = {Animals ; *Zebrafish ; Female ; *C9orf72 Protein/genetics/metabolism ; *Retina/metabolism/pathology ; Animals, Genetically Modified ; Zebrafish Proteins/genetics/metabolism/deficiency ; Proteins/genetics/metabolism ; Retinal Degeneration/genetics/metabolism/pathology ; Neurodegenerative Diseases/genetics/metabolism/pathology ; Spinal Cord/metabolism/pathology ; }, abstract = {Hexanucleotide repeat expansions within the gene C9ORF72 are the most common cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This disease-causing expansion leads to a reduction in C9ORF72 expression levels in patients, suggesting loss of C9ORF72 function could contribute to disease. To further understand the consequences of C9ORF72 deficiency in vivo, we generated a c9orf72 mutant zebrafish line. Analysis of the adult female spinal cords revealed no appreciable neurodegenerative pathology such as loss of motor neurons or increased levels of neuroinflammation. However, detailed examination of adult female c9orf72[-/-] retinas showed prominent neurodegenerative features, including a decrease in retinal thickness, gliosis, and an overall reduction in neurons of all subtypes. Analysis of rod and cone cells within the photoreceptor layer showed a disturbance in their outer segment structure and rhodopsin mislocalization from rod outer segments to their cell bodies and synaptic terminals. Thus, C9ORF72 may play a previously unappreciated role in retinal homeostasis and suggests C9ORF72 deficiency can induce tissue specific neuronal loss.}, } @article {pmid38661532, year = {2024}, author = {Li, A and Yi, J and Li, X and Dong, L and Ostrow, LW and Ma, J and Zhou, J}, title = {Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38661532}, issn = {2050-084X}, support = {R01 NS105621/NS/NINDS NIH HHS/United States ; R01 AG071676/AG/NIA NIH HHS/United States ; R01NS105621/NH/NIH HHS/United States ; R01AG071676/NH/NIH HHS/United States ; R01NS129219/NH/NIH HHS/United States ; R01 NS129219/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Neuromuscular Junction/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Mice ; *Satellite Cells, Skeletal Muscle/metabolism ; *Disease Models, Animal ; *Transcriptome ; Mice, Transgenic ; Oculomotor Muscles/innervation/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder characterized by progressive weakness of almost all skeletal muscles, whereas extraocular muscles (EOMs) are comparatively spared. While hindlimb and diaphragm muscles of end-stage SOD1G93A (G93A) mice (a familial ALS mouse model) exhibit severe denervation and depletion of Pax7[+]satellite cells (SCs), we found that the pool of SCs and the integrity of neuromuscular junctions (NMJs) are maintained in EOMs. In cell sorting profiles, SCs derived from hindlimb and diaphragm muscles of G93A mice exhibit denervation-related activation, whereas SCs from EOMs of G93A mice display spontaneous (non-denervation-related) activation, similar to SCs from wild-type mice. Specifically, cultured EOM SCs contain more abundant transcripts of axon guidance molecules, including Cxcl12, along with more sustainable renewability than the diaphragm and hindlimb counterparts under differentiation pressure. In neuromuscular co-culture assays, AAV-delivery of Cxcl12 to G93A-hindlimb SC-derived myotubes enhances motor neuron axon extension and innervation, recapitulating the innervation capacity of EOM SC-derived myotubes. G93A mice fed with sodium butyrate (NaBu) supplementation exhibited less NMJ loss in hindlimb and diaphragm muscles. Additionally, SCs derived from G93A hindlimb and diaphragm muscles displayed elevated expression of Cxcl12 and improved renewability following NaBu treatment in vitro. Thus, the NaBu-induced transcriptomic changes resembling the patterns of EOM SCs may contribute to the beneficial effects observed in G93A mice. More broadly, the distinct transcriptomic profile of EOM SCs may offer novel therapeutic targets to slow progressive neuromuscular functional decay in ALS and provide possible 'response biomarkers' in pre-clinical and clinical studies.}, } @article {pmid38662766, year = {2024}, author = {Stikvoort García, DJL and Goedee, HS and van Eijk, RPA and van Schelven, LJ and van den Berg, LH and Sleutjes, BTHM}, title = {Revisiting distinct nerve excitability patterns in patients with amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {8}, pages = {2842-2853}, pmid = {38662766}, issn = {1460-2156}, support = {AV20180012//Dutch ALS Foundation/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Male ; Female ; Middle Aged ; Aged ; *Motor Neurons/physiology ; Adult ; Action Potentials/physiology ; Principal Component Analysis ; Axons/physiology ; Membrane Potentials/physiology ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease, characterized by loss of central and peripheral motor neurons. Although the disease is clinically and genetically heterogeneous, axonal hyperexcitability is a commonly observed feature that has been suggested to reflect an early pathophysiological step linked to the neurodegenerative cascade. Therefore, it is important to clarify the mechanisms causing axonal hyperexcitability and how these relate to the clinical characteristics of patients. Measures derived directly from a nerve excitability recording are frequently used as study end points, although their biophysical basis is difficult to deduce. Mathematical models can aid in the interpretation but are reliable only when applied to group-averaged recordings. Consequently, model estimates of membrane properties cannot be compared with clinical characteristics or treatment effects in individual patients, posing a considerable limitation in heterogeneous diseases, such as amyotrophic lateral sclerosis. To address these challenges, we revisited nerve excitability using a new pattern analysis-based approach (principal component analysis). We evaluated disease-specific patterns of excitability changes and established their biophysical origins. Based on the observed patterns, we developed new compound measures of excitability that facilitate the implementation of this approach in clinical settings. We found that excitability changes in amyotrophic lateral sclerosis patients (n = 161, median disease duration = 11 months) were characterized by four unique patterns compared with controls (n = 50, age and sex matched). These four patterns were best explained by changes in resting membrane potential (modulated by Na+/K+ currents), slow potassium and sodium currents (modulated by their gating kinetics) and refractory properties of the nerve. Consequently, we were able to show that altered gating of slow potassium channels was associated with, and predictive of, the rate of progression of the disease on the amyotrophic lateral sclerosis functional rating scale. Based on these findings, we designed four composite measures that capture these properties to facilitate implementation outside this study. Our findings demonstrate that changes in nerve excitability in patients with amyotrophic lateral sclerosis are dominated by four distinct patterns, each with a distinct biophysical origin. Based on this new approach, we provide evidence that altered slow potassium-channel function might play a role in the rate of disease progression. The magnitudes of these patterns, quantified using a similar approach or our new composite measures, have potential as efficient measures to study membrane properties directly in amyotrophic lateral sclerosis patients, and thus aid prognostic stratification and trial design.}, } @article {pmid38662803, year = {2025}, author = {Martín-Rivada, Á and Martos-Moreno, GÁ and Guerra-Cantera, S and Campillo-Calatayud, A and Oxvig, C and Frystyk, J and Chowen, JA and Barrios, V and Argente, J}, title = {Prepubertal Children With Obesity Have High Free IGF-1 Levels and Accelerated Growth Despite Reduced Pappalysin Levels.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {110}, number = {3}, pages = {e622-e629}, doi = {10.1210/clinem/dgae288}, pmid = {38662803}, issn = {1945-7197}, support = {FIS-PI19/00166//Spanish Ministry of Health/ ; //Centro de Investigación Biomédica en Red Fisiopatología de Obesidad y Nutrición/ ; //Instituto Carlos III/ ; no. CD19/00008//Instituto de Salud Carlos III/ ; //Comunidad Autónoma de Madrid/ ; }, mesh = {Humans ; Male ; Female ; Child ; *Insulin-Like Growth Factor I/metabolism/analysis ; *Pediatric Obesity/blood/physiopathology ; *Pregnancy-Associated Plasma Protein-A/metabolism/analysis ; Glycoproteins/blood ; Intercellular Signaling Peptides and Proteins/blood ; Weight Loss/physiology ; Child, Preschool ; Body Mass Index ; }, abstract = {BACKGROUND: Prepubertal children with obesity frequently have enhanced growth, accelerated skeletal maturation, and changes in the growth hormone-insulin-like growth factor (GH-IGF) axis. However, the involvement of pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC1, STC2) as regulators of IGF bioavailability has not been studied in obesity.

OBJECTIVE: We aimed to determine the effects of childhood obesity and weight reduction on serum levels of PAPP-A, PAPP-A2, STC1, and STC2 and their relationship with IGF bioavailability, growth, and other components of the GH-IGF system.

METHODS: Prepubertal children with severe obesity (150, 50% males/females, age: 7.72 ± 2.05 years, BMI z-score: 4.95 ± 1.70, height z-score: 1.28 ± 1.04) were studied at diagnosis and after a minimum of 0.5 BMI z-score reduction. Two hundred and six healthy age- and sex-matched children were used as controls.

RESULTS: Children with obesity had decreased serum concentrations of PAPP-A, PAPP-A2 and STC2, but increased total and free IGF-I, intact IGFBP-3, acid-labile subunit (ALS), IGF-II, and insulin levels, with no difference in the free IGF-I/total IGF-I ratio. Neither the standardized body mass index (BMI) nor height correlated with any biochemical parameter analyzed. A decrease in IGF-II, insulin, and ALS with an increase in IGFBP-2 and -5, STC2, and PAPP-A were observed after weight loss.

CONCLUSION: Increased circulating total and free IGF-I, insulin, and IGF-II may all contribute to the increased rate of prepubertal growth and bone maturation observed in children with obesity, with STC2 possibly being involved.}, } @article {pmid38663088, year = {2024}, author = {Frost, B and Dubnau, J}, title = {The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders.}, journal = {Annual review of neuroscience}, volume = {47}, number = {1}, pages = {123-143}, doi = {10.1146/annurev-neuro-082823-020615}, pmid = {38663088}, issn = {1545-4126}, support = {R01 AG078788/AG/NIA NIH HHS/United States ; RF1 NS112391/NS/NINDS NIH HHS/United States ; RF1 AG076493/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Retroelements/genetics ; *Endogenous Retroviruses/genetics ; Animals ; *Aging/genetics ; DNA-Binding Proteins/genetics/metabolism ; tau Proteins/genetics/metabolism ; }, abstract = {Over 40% of the human genome is composed of retrotransposons, DNA species that hold the potential to replicate via an RNA intermediate and are evolutionarily related to retroviruses. Retrotransposons are most studied for their ability to jump within a genome, which can cause DNA damage and novel insertional mutations. Retrotransposon-encoded products, including viral-like proteins, double-stranded RNAs, and extrachromosomal circular DNAs, can also be potent activators of the innate immune system. A growing body of evidence suggests that retrotransposons are activated in age-related neurodegenerative disorders and that such activation causally contributes to neurotoxicity. Here we provide an overview of retrotransposon biology and outline evidence of retrotransposon activation in age-related neurodegenerative disorders, with an emphasis on those involving TAR-DNA binding protein-43 (TDP-43) and tau. Studies to date provide the basis for ongoing clinical trials and hold promise for innovative strategies to ameliorate the adverse effects of retrotransposon dysregulation in neurodegenerative disorders.}, } @article {pmid38663099, year = {2024}, author = {Polverino, A and Troisi Lopez, E and Liparoti, M and Minino, R and Romano, A and Cipriano, L and Trojsi, F and Jirsa, V and Sorrentino, G and Sorrentino, P}, title = {Altered spreading of fast aperiodic brain waves relates to disease duration in Amyotrophic Lateral Sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {163}, number = {}, pages = {14-21}, doi = {10.1016/j.clinph.2024.04.003}, pmid = {38663099}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Female ; Male ; Middle Aged ; *Magnetoencephalography/methods ; Aged ; Adult ; Brain Waves/physiology ; Brain/physiopathology ; }, abstract = {OBJECTIVE: To test the hypothesis that patients affected by Amyotrophic Lateral Sclerosis (ALS) show an altered spatio-temporal spreading of neuronal avalanches in the brain, and that this may related to the clinical picture.

METHODS: We obtained the source-reconstructed magnetoencephalography (MEG) signals from thirty-six ALS patients and forty-two healthy controls. Then, we used the construct of the avalanche transition matrix (ATM) and the corresponding network parameter nodal strength to quantify the changes in each region, since this parameter provides key information about which brain regions are mostly involved in the spreading avalanches.

RESULTS: ALS patients presented higher values of the nodal strength in both cortical and sub-cortical brain areas. This parameter correlated directly with disease duration.

CONCLUSIONS: In this work, we provide a deeper characterization of neuronal avalanches propagation in ALS, describing their spatio-temporal trajectories and identifying the brain regions most likely to be involved in the process. This makes it possible to recognize the brain areas that take part in the pathogenic mechanisms of ALS. Furthermore, the nodal strength of the involved regions correlates directly with disease duration.

SIGNIFICANCE: Our results corroborate the clinical relevance of aperiodic, fast large-scale brain activity as a biomarker of microscopic changes induced by neurophysiological processes.}, } @article {pmid38663103, year = {2024}, author = {Nozal, V and Fernández-Gómez, P and García-Rubia, A and Martínez-González, L and Cuevas, EP and Carro, E and Palomo, V and Martínez, A}, title = {Designing multitarget ligands for neurodegenerative diseases with improved permeability trough PLGA nanoencapsulation.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {175}, number = {}, pages = {116626}, doi = {10.1016/j.biopha.2024.116626}, pmid = {38663103}, issn = {1950-6007}, mesh = {*Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Ligands ; Humans ; *Blood-Brain Barrier/metabolism/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Permeability ; Nanoparticles/chemistry ; Drug Design ; Drug Compounding ; Amyloid beta-Peptides/metabolism ; Animals ; tau Proteins/metabolism ; }, abstract = {Multitarget ligands (MTLs) have emerged as an interesting alternative for addressing complex multifactorial pathologies such as neurodegenerative diseases. However, a common challenge associated with these compounds is often their high molecular weight and low solubility, which becomes a hurdle when trying to permeate over the blood-brain barrier (BBB). In this study, we have designed two new MTLs that modulate three pharmacological targets simultaneously (tau, beta-amyloid and TAR DNA-binding protein 43). To enhance their brain penetration, we have formulated organic polymeric nanoparticles using poly(lactic-co-glycolic acid). The characterization of the formulations, evaluation of their permeability through an in vitro BBB model, and assessment of their activity on disease-representative cellular models, such as Alzheimer's disease and amyotrophic lateral sclerosis, have been conducted. The results demonstrate the potential of the new MTLs and their nanoparticle encapsulation for the treatment of neurodegenerative diseases.}, } @article {pmid38664109, year = {2024}, author = {Hastings, RL and Valdez, G}, title = {Origin, identity, and function of terminal Schwann cells.}, journal = {Trends in neurosciences}, volume = {47}, number = {6}, pages = {432-446}, pmid = {38664109}, issn = {1878-108X}, support = {R56 AG077814/AG/NIA NIH HHS/United States ; R01 AG055545/AG/NIA NIH HHS/United States ; T32 AG041688/AG/NIA NIH HHS/United States ; R56 AG051501/AG/NIA NIH HHS/United States ; R21 NS106313/NS/NINDS NIH HHS/United States ; }, mesh = {*Schwann Cells/physiology ; Animals ; Humans ; }, abstract = {The highly specialized nonmyelinating glial cells present at somatic peripheral nerve endings, known collectively as terminal Schwann cells (TSCs), play critical roles in the development, function and repair of their motor and sensory axon terminals and innervating tissue. Over the past decades, research efforts across various vertebrate species have revealed that while TSCs are a diverse group of cells, they share a number of features among them. In this review, we summarize the state-of-knowledge about each TSC type and explore the opportunities that TSCs provide to treat conditions that afflict peripheral axon terminals.}, } @article {pmid38664831, year = {2024}, author = {Sirtori, R and J Gregoire, M and M Potts, E and Collins, A and Donatelli, L and Fallini, C}, title = {LINC complex alterations are a key feature of sporadic and familial ALS/FTD.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {69}, pmid = {38664831}, issn = {2051-5960}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; R01 NS116143/NS/NINDS NIH HHS/United States ; R01NS116143/NS/NINDS NIH HHS/United States ; P20GM103430/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Male ; Motor Neurons/pathology/metabolism ; Spinal Cord/pathology/metabolism ; Nuclear Envelope/metabolism/pathology ; Female ; Induced Pluripotent Stem Cells/metabolism/pathology ; Middle Aged ; Aged ; Motor Cortex/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects motor neurons, leading to progressive muscle weakness and loss of voluntary muscle control. While the exact cause of ALS is not fully understood, emerging research suggests that dysfunction of the nuclear envelope (NE) may contribute to disease pathogenesis and progression. The NE plays a role in ALS through several mechanisms, including nuclear pore defects, nucleocytoplasmic transport impairment, accumulation of mislocalized proteins, and nuclear morphology abnormalities. The LINC complex is the second biggest multi-protein complex in the NE and consists of the SUN1/2 proteins spanning the inner nuclear membrane and Nesprin proteins embedded in the outer membrane. The LINC complex, by interacting with both the nuclear lamina and the cytoskeleton, transmits mechanical forces to the nucleus regulating its morphology and functional homeostasis. In this study we show extensive alterations to the LINC complex in motor and cortical iPSC-derived neurons and spinal cord organoids carrying the ALS causative mutation in the C9ORF72 gene (C9). Importantly, we show that such alterations are present in vivo in a cohort of sporadic ALS and C9-ALS postmortem spinal cord and motor cortex specimens. We also found that LINC complex disruption strongly correlated with nuclear morphological alterations occurring in ALS neurons, independently of TDP43 mislocalization. Altogether, our data establish morphological and functional alterations to the LINC complex as important events in ALS pathogenic cascade, making this pathway a possible target for both biomarker and therapy development.}, } @article {pmid38665232, year = {2024}, author = {Yao, Y and Liu, H and Gu, Y and Xu, X and Zhang, X}, title = {A causal association between amyotrophic lateral sclerosis and atrial fibrillation: a two-sample Mendelian randomization study.}, journal = {Frontiers in cardiovascular medicine}, volume = {11}, number = {}, pages = {1351495}, pmid = {38665232}, issn = {2297-055X}, abstract = {OBJECTIVES: To look into the connection between amyotrophic lateral sclerosis (ALS) and atrial fibrillation (AF) using Mendelian randomization (MR).

METHODS: Two-sample MR was performed using genetic information from genome-wide association studies (GWAS). Genetic variants robustly associated with ALS and AF were used as instrumental variables. GWAS genetic data for ALS (n = 138,086, ncase = 27,205) and AF (n = 1,030,836, ncase = 60,620), publicly available from IEU Open. The specific MR protocols were Inverse variance-weighted (IVW), Simple mode, MR Egger, Weighted mode, and Weight median estimator (WME). Subsequently, the MR-Egger intercept and Cochran Q examine were used to evaluate instrumental variables (IVs)' heterogeneity and multiplicative effects (IVs). In addition, MR-PRESSO analysis was conducted to exclude any potential pleiotropy.

RESULTS: The IVW method demonstrated that ALS positively affected AF [OR: 1.062, 95% CI (1.004-1.122); P = 0.035]. Indeed, other MR methods were in accordance with the tendency of the IVW method (all OR > 1), and sensitivity testing verified the reliability of this MR result.

CONCLUSIONS: This MR study proves a positive causal connection between ALS and atrial fibrillation. Further studies are warranted to elucidate the mechanisms linking ALS and AF.}, } @article {pmid38666601, year = {2024}, author = {Officer, L and Armon, C and Barkhaus, P and Beauchamp, M and Benatar, M and Bertorini, T and Bowser, R and Bromberg, M and Brown, A and Carbunar, OM and Carter, GT and Crayle, J and Denson, K and Feldman, E and Fullam, T and Heiman-Patterson, T and Jackson, C and Jhooty, S and Levinson, D and Li, X and Linares, A and Mallon, E and Mascias Cadavid, J and Mcdermott, C and Mushannen, T and Ostrow, L and Patel, R and Pattee, G and Ratner, D and Sun, Y and Sladky, J and Wicks, P and Bedlack, R}, title = {ALSUntangled #75: Portable neuromodulation stimulator therapy.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {648-652}, doi = {10.1080/21678421.2024.2346825}, pmid = {38666601}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Electric Stimulation Therapy/methods/instrumentation ; }, abstract = {Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.}, } @article {pmid38666665, year = {2024}, author = {Forsberg, K and Karlsborg, M and Salvesen, L and Svenstrup, K and Winroth, I and Berntsson, H and M Andersen, P}, title = {[SOD1 gene therapy delays ALS disease progression].}, journal = {Lakartidningen}, volume = {121}, number = {}, pages = {}, pmid = {38666665}, issn = {1652-7518}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; *Superoxide Dismutase-1/genetics ; *Genetic Therapy ; *Disease Progression ; Male ; Middle Aged ; Mutation ; Oligonucleotides, Antisense/therapeutic use/administration & dosage ; Oligonucleotides/therapeutic use/administration & dosage ; }, abstract = {We present a patient with familial amyotrophic lateral sclerosis caused by an aggressive A4S mutation in the SOD1 gene. In 2020, the patient was enrolled in the VALOR SOD1 gene therapy phase-3 trial. At screening, the ALSFRS-R score was 41 (48 is normal) and the level of CSF-neurofilament L (an indicator of ongoing neuronal damage) was 11 000 ng/L (ref <650 ng/L). In the four years following enrollment, the patient received monthly intrathecal treatment with tofersen, an antisense oligonucleotide compound that inhibits SOD1 protein expression and hence lowers the synthesis of toxic SOD1 protein species. Side effects have been minimal and mostly attributed to the spinal taps. The patient remains ambulatory with an active social lifestyle. The ALSFRS-R score has in the past 18 months stabilized around 35-37, CSF-NfL is 1 290 ng/L and plasma-NfL is 12 (reference <13). This is the first documented arresting intervention in a patient with ALS in Sweden.}, } @article {pmid38666827, year = {2024}, author = {Ismail, M and Großmann, D and Hermann, A}, title = {Increased Vulnerability to Ferroptosis in FUS-ALS.}, journal = {Biology}, volume = {13}, number = {4}, pages = {}, pmid = {38666827}, issn = {2079-7737}, support = {NA//Hermann und Lilly Schilling-Stiftung/ ; }, abstract = {Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxide accumulation, plays a pivotal role in various pathological conditions, including neurodegenerative diseases. While reasonable evidence for ferroptosis exists, e.g., in Parkinson's disease or Alzheimer's disease, there are only a few reports on amyotrophic lateral sclerosis (ALS), a fast progressive and incurable neurodegenerative disease characterized by progressive motor neuron degeneration. Interestingly, initial studies have suggested that ferroptosis might be significantly involved in ALS. Key features of ferroptosis include oxidative stress, glutathione depletion, and alterations in mitochondrial morphology and function, mediated by proteins such as GPX4, xCT, ACSL4 FSP1, Nrf2, and TfR1. Induction of ferroptosis involves small molecule compounds like erastin and RSL3, which disrupt system Xc[-] and GPX4 activity, respectively, resulting in lipid peroxidation and cellular demise. Mutations in fused in sarcoma (FUS) are associated with familial ALS. Pathophysiological hallmarks of FUS-ALS involve mitochondrial dysfunction and oxidative damage, implicating ferroptosis as a putative cell-death pathway in motor neuron demise. However, a mechanistic understanding of ferroptosis in ALS, particularly FUS-ALS, remains limited. Here, we investigated the vulnerability to ferroptosis in FUS-ALS cell models, revealing mitochondrial disturbances and increased susceptibility to ferroptosis in cells harboring ALS-causing FUS mutations. This was accompanied by an altered expression of ferroptosis-associated proteins, particularly by a reduction in xCT expression, leading to cellular imbalance in the redox system and increased lipid peroxidation. Iron chelation with deferoxamine, as well as inhibition of the mitochondrial calcium uniporter (MCU), significantly alleviated ferroptotic cell death and lipid peroxidation. These findings suggest a link between ferroptosis and FUS-ALS, offering potential new therapeutic targets.}, } @article {pmid38667285, year = {2024}, author = {Alzahrani, FA and Riza, YM and Eid, TM and Almotairi, R and Scherschinski, L and Contreras, J and Nadeem, M and Perez, SE and Raikwar, SP and Jha, RM and Preul, MC and Ducruet, AF and Lawton, MT and Bhatia, K and Akhter, N and Ahmad, S}, title = {Exosomes in Vascular/Neurological Disorders and the Road Ahead.}, journal = {Cells}, volume = {13}, number = {8}, pages = {}, pmid = {38667285}, issn = {2073-4409}, mesh = {*Exosomes/metabolism ; Humans ; Animals ; Neurodegenerative Diseases/metabolism/pathology ; Vascular Diseases/metabolism/pathology ; Nervous System Diseases/metabolism/pathology ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and aneurysms, are characterized by the abnormal accumulation and aggregation of disease-causing proteins in the brain and spinal cord. Recent research suggests that proteins linked to these conditions can be secreted and transferred among cells using exosomes. The transmission of abnormal protein buildup and the gradual degeneration in the brains of impacted individuals might be supported by these exosomes. Furthermore, it has been reported that neuroprotective functions can also be attributed to exosomes in neurodegenerative diseases. The potential neuroprotective functions may play a role in preventing the formation of aggregates and abnormal accumulation of proteins associated with the disease. The present review summarizes the roles of exosomes in neurodegenerative diseases as well as elucidating their therapeutic potential in AD, PD, ALS, HD, stroke, and aneurysms. By elucidating these two aspects of exosomes, valuable insights into potential therapeutic targets for treating neurodegenerative diseases may be provided.}, } @article {pmid38667292, year = {2024}, author = {Ruffo, P and De Amicis, F and La Bella, V and Conforti, FL}, title = {Investigating Repeat Expansions in NIPA1, NOP56, and NOTCH2NLC Genes: A Closer Look at Amyotrophic Lateral Sclerosis Patients from Southern Italy.}, journal = {Cells}, volume = {13}, number = {8}, pages = {}, pmid = {38667292}, issn = {2073-4409}, support = {ex60%//Ministry for Instruction, University and Research/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; Case-Control Studies ; DNA Repeat Expansion/genetics ; Genetic Predisposition to Disease ; Italy ; Nuclear Proteins/genetics ; Membrane Proteins ; Nerve Tissue Proteins ; Intercellular Signaling Peptides and Proteins ; }, abstract = {The discovery of hexanucleotide repeats expansion (RE) in Chromosome 9 Open Reading frame 72 (C9orf72) as the major genetic cause of amyotrophic lateral sclerosis (ALS) and the association between intermediate repeats in Ataxin-2 (ATXN2) with the disorder suggest that repetitive sequences in the human genome play a significant role in ALS pathophysiology. Investigating the frequency of repeat expansions in ALS in different populations and ethnic groups is therefore of great importance. Based on these premises, this study aimed to define the frequency of REs in the NIPA1, NOP56, and NOTCH2NLC genes and the possible associations between phenotypes and the size of REs in the Italian population. Using repeat-primed-PCR and PCR-fragment analyses, we screened 302 El-Escorial-diagnosed ALS patients and compared the RE distribution to 167 age-, gender-, and ethnicity-matched healthy controls. While the REs distribution was similar between the ALS and control groups, a moderate association was observed between longer RE lengths and clinical features such as age at onset, gender, site of onset, and family history. In conclusion, this is the first study to screen ALS patients from southern Italy for REs in NIPA1, NOP56, and NOTCH2NLC genes, contributing to our understanding of ALS genetics. Our results highlighted that the extremely rare pathogenic REs in these genes do not allow an association with the disease.}, } @article {pmid38668754, year = {2024}, author = {Dogan, M and Teralı, K and Eroz, R and Kılıç, H and Gezdirici, A and Gönüllü, B}, title = {Discovery of a novel homozygous SOD1 truncating variant bolsters infantile SOD1 deficiency syndrome.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {580}, pmid = {38668754}, issn = {1573-4978}, mesh = {Child ; Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; Exome Sequencing ; Homozygote ; Pedigree ; Phenotype ; *Superoxide Dismutase-1/genetics ; Turkey ; Adolescent ; }, abstract = {OBJECTIVE: Superoxide dismutase 1 (SOD1) is an important antioxidant enzyme whose main function is to neutralise superoxide free radicals in the cytoplasm. Heterozygous variants in SOD1 are responsible for a substantial percentage of familial amyotrophic lateral sclerosis (ALS) cases. Recently, several reports have shown that biallelic loss of SOD1 function results in a novel phenotype called infantile SOD1 deficiency syndrome, which is consistent with a recessive pattern of inheritance and can be distinguished from typical (adult-onset) ALS.

METHODS: We documented detailed family histories and clinical data, followed by whole-exome sequencing and family co-segregation analysis through Sanger sequencing. To facilitate comparisons, relevant data from fifteen previously reported patients with SOD1-related neurodevelopmental disorders were included.

RESULTS: This study presents a new Turkish family with two affected children exhibiting severe delayed motor development, infancy-onset loss of motor skills, axial hypotonia, tetraspasticity, and impaired cognitive functions. Genetic analysis revealed a novel homozygous frameshift variant in SOD1 (c.248dupG [p.Asp84Argfs*8]), with computational biochemical studies shedding light on the mechanistic aspects of SOD1 dysfunction.

CONCLUSIONS: Our findings contribute an affirmative report of a fourth biallelic variant resulting in a severe clinical phenotype, reminiscent of those induced by previously identified homozygous loss-of-function SOD1 variants. This research not only advances our understanding of the pathogenesis of this debilitating neurological syndrome but also aligns with ongoing intensive efforts to comprehend and address SOD1-linked ALS.}, } @article {pmid38670433, year = {2024}, author = {Sitruk-Ware, R and Sussman, H and Brinton, R and Schumacher, M and Singer, P and Kumar, N and De Nicola, AF and El-Etr, M and Guennoun, R and V Borlongan, C}, title = {Nestorone (segesterone acetate) effects on neuroregeneration.}, journal = {Frontiers in neuroendocrinology}, volume = {73}, number = {}, pages = {101136}, doi = {10.1016/j.yfrne.2024.101136}, pmid = {38670433}, issn = {1095-6808}, mesh = {Animals ; Humans ; *Norprogesterones/pharmacology ; *Neuroprotective Agents/pharmacology ; Nerve Regeneration/drug effects/physiology ; Female ; }, abstract = {Nestorone® (segesterone acetate) is a progestin with a chemical structure closely related to progesterone with high affinity and selectivity for the progesterone receptor without significant interaction with other steroid receptors. It has been developed for female and male contraception and is FDA-approved in a first long-acting contraceptive vaginal system for female contraception. Its safety has been extensively demonstrated in both preclinical and clinical studies for contraceptive indications. Nestorone was found to display neuroprotective and neuroregenerative activity in animal models of various central nervous system diseases, including multiple sclerosis, stroke, and amyotrophic lateral sclerosis. Reviewed herein are neuroprotective and myelin- regenerating properties of Nestorone in various animal models and its translational potential as a therapeutic agent for debilitating neurological diseases for which limited therapeutic options are available (Table 1).}, } @article {pmid38670927, year = {2024}, author = {Quinn, C and Baer, M and Amado, DA and Kelley, M and Elman, L}, title = {A single ALS center experience with clinical use of sodium phenylbutyrate-taurursodiol.}, journal = {Muscle & nerve}, volume = {70}, number = {1}, pages = {148-151}, doi = {10.1002/mus.28096}, pmid = {38670927}, issn = {1097-4598}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; Middle Aged ; Aged ; Phenylbutyrates/therapeutic use ; Adult ; Retrospective Studies ; Drug Combinations ; }, abstract = {INTRODUCTION/AIMS: The aim of this study was to examine clinical utilization and discontinuation rates of sodium phenylbutyrate-taurursodiol (PB-TURSO) in a single Amyotrophic Lateral Sclerosis (ALS) center. PB-TURSO was approved by the United States Food and Drug Administration (FDA) in September 2022. Prior experience has been limited to clinical trials or expanded access protocols. In this manuscript, we discuss insurance approval rates, patient uptake, and discontinuation of PB-TURSO in a large academic center.

METHODS: Records of patients seen for clinical visits between January 2022 and May 2023 were reviewed. Demographic and clinical characteristics of our clinic population and those initiating PB-TURSO were obtained from our clinical database.

RESULTS: A total of 228 patients were seen during the observation period and 122 requested PB-TURSO prescriptions. 77% (94) were approved by insurance. 66% (65) of those who were approved or received free drug chose to start medication. 51% (34) of those who initiated PB-TURSO continued to take it through the end of the observation period. Four patients discontinued due to death during the observation period. Of the 29 patients who survived and discontinued, the main reasons for discontinuation were GI symptoms (17, 58.6%) and taste (8, 29.6%).

DISCUSSION: PB-TURSO was approved by insurance for most patients. The discontinuation rate was high and was driven largely by GI side effects and taste. Future considerations would include deeper examination of demographic trends, patient costs, side effects, and potential benefits in clinical practice.}, } @article {pmid38671062, year = {2024}, author = {Angrick, M and Luo, S and Rabbani, Q and Candrea, DN and Shah, S and Milsap, GW and Anderson, WS and Gordon, CR and Rosenblatt, KR and Clawson, L and Tippett, DC and Maragakis, N and Tenore, FV and Fifer, MS and Hermansky, H and Ramsey, NF and Crone, NE}, title = {Online speech synthesis using a chronically implanted brain-computer interface in an individual with ALS.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {9617}, pmid = {38671062}, issn = {2045-2322}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; NS114439/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Brain-Computer Interfaces ; *Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Male ; *Speech/physiology ; Middle Aged ; Electrodes, Implanted ; Electrocorticography ; }, abstract = {Brain-computer interfaces (BCIs) that reconstruct and synthesize speech using brain activity recorded with intracranial electrodes may pave the way toward novel communication interfaces for people who have lost their ability to speak, or who are at high risk of losing this ability, due to neurological disorders. Here, we report online synthesis of intelligible words using a chronically implanted brain-computer interface (BCI) in a man with impaired articulation due to ALS, participating in a clinical trial (ClinicalTrials.gov, NCT03567213) exploring different strategies for BCI communication. The 3-stage approach reported here relies on recurrent neural networks to identify, decode and synthesize speech from electrocorticographic (ECoG) signals acquired across motor, premotor and somatosensory cortices. We demonstrate a reliable BCI that synthesizes commands freely chosen and spoken by the participant from a vocabulary of 6 keywords previously used for decoding commands to control a communication board. Evaluation of the intelligibility of the synthesized speech indicates that 80% of the words can be correctly recognized by human listeners. Our results show that a speech-impaired individual with ALS can use a chronically implanted BCI to reliably produce synthesized words while preserving the participant's voice profile, and provide further evidence for the stability of ECoG for speech-based BCIs.}, } @article {pmid38671434, year = {2024}, author = {Ohlenburg, H and Arnemann, PH and Hessler, M and Görlich, D and Zarbock, A and Friederichs, H}, title = {Flipped Classroom: Improved team performance during resuscitation training through interactive pre-course content - a cluster-randomised controlled study.}, journal = {BMC medical education}, volume = {24}, number = {1}, pages = {459}, pmid = {38671434}, issn = {1472-6920}, mesh = {Humans ; *Patient Care Team ; *Resuscitation/education ; Female ; Male ; *Curriculum ; Germany ; Clinical Competence ; Problem-Based Learning ; Students, Medical ; Education, Medical, Undergraduate/methods ; Adult ; Educational Measurement ; Simulation Training ; }, abstract = {BACKGROUND: Resuscitation is a team effort, and it is increasingly acknowledged that team cooperation requires training. Staff shortages in many healthcare systems worldwide, as well as recent pandemic restrictions, limit opportunities for collaborative team training. To address this challenge, a learner-centred approach known as flipped learning has been successfully implemented. This model comprises self-directed, asynchronous pre-course learning, followed by knowledge application and skill training during in-class sessions. The existing evidence supports the effectiveness of this approach for the acquisition of cognitive skills, but it is uncertain whether the flipped classroom model is suitable for the acquisition of team skills. The objective of this study was to determine if a flipped classroom approach, with an online workshop prior to an instructor-led course could improve team performance and key resuscitation variables during classroom training.

METHODS: A single-centre, cluster-randomised, rater-blinded study was conducted on 114 final year medical students at a University Hospital in Germany. The study randomly assigned students to either the intervention or control group using a computer script. Each team, regardless of group, performed two advanced life support (ALS) scenarios on a simulator. The two groups differed in the order in which they completed the flipped e-learning curriculum. The intervention group started with the e-learning component, and the control group started with an ALS scenario. Simulators were used for recording and analysing resuscitation performance indicators, while professionals assessed team performance as a primary outcome.

RESULTS: The analysis was conducted on the data of 96 participants in 21 teams, comprising of 11 intervention groups and 10 control groups. The intervention teams achieved higher team performance ratings during the first scenario compared to the control teams (Estimated marginal mean of global rating: 7.5 vs 5.6, p < 0.01; performance score: 4.4 vs 3.8, p < 0.05; global score: 4.4 vs 3.7, p < 0.001). However, these differences were not observed in the second scenario, where both study groups had used the e-learning tool.

CONCLUSION: Flipped classroom approaches using learner-paced e-learning prior to hands-on training can improve team performance.

TRIAL REGISTRATION: German Clinical Trials Register (https://drks.de/search/de/trial/DRKS00013096).}, } @article {pmid38672412, year = {2024}, author = {Lachén-Montes, M and Cartas-Cejudo, P and Cortés, A and Anaya-Cubero, E and Peral, E and Ausín, K and Díaz-Peña, R and Fernández-Irigoyen, J and Santamaría, E}, title = {Involvement of Glucosamine 6 Phosphate Isomerase 2 (GNPDA2) Overproduction in β-Amyloid- and Tau P301L-Driven Pathomechanisms.}, journal = {Biomolecules}, volume = {14}, number = {4}, pages = {}, pmid = {38672412}, issn = {2218-273X}, support = {0011-1411-2020-000028 and 0011-1411-2023-000028//Gobierno de Navarra/ ; PID2019-110356RB-I00/AEI/10.13039/501100011033//Spanish Ministry of Science, Innovation and Universities/ ; }, mesh = {Animals ; Humans ; *Aldose-Ketose Isomerases/metabolism/genetics ; *Alzheimer Disease/metabolism/genetics/pathology ; *Amyloid beta-Peptides/metabolism ; Animals, Genetically Modified ; Cell Proliferation ; Epithelial Cells/metabolism ; Proteomics ; *tau Proteins/metabolism/genetics ; *Zebrafish/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative olfactory disorder affecting millions of people worldwide. Alterations in the hexosamine- or glucose-related pathways have been described through AD progression. Specifically, an alteration in glucosamine 6 phosphate isomerase 2 (GNPDA2) protein levels has been observed in olfactory areas of AD subjects. However, the biological role of GNPDA2 in neurodegeneration remains unknown. Using mass spectrometry, multiple GNPDA2 interactors were identified in human nasal epithelial cells (NECs) mainly involved in intraciliary transport. Moreover, GNPDA2 overexpression induced an increment in NEC proliferation rates, accompanied by transcriptomic alterations in Type II interferon signaling or cellular stress responses. In contrast, the presence of beta-amyloid or mutated Tau-P301L in GNPDA2-overexpressing NECs induced a slowdown in the proliferative capacity in parallel with a disruption in protein processing. The proteomic characterization of Tau-P301L transgenic zebrafish embryos demonstrated that GNPDA2 overexpression interfered with collagen biosynthesis and RNA/protein processing, without inducing additional changes in axonal outgrowth defects or neuronal cell death. In humans, a significant increase in serum GNPDA2 levels was observed across multiple neurological proteinopathies (AD, Lewy body dementia, progressive supranuclear palsy, mixed dementia and amyotrophic lateral sclerosis) (n = 215). These data shed new light on GNPDA2-dependent mechanisms associated with the neurodegenerative process beyond the hexosamine route.}, } @article {pmid38672416, year = {2024}, author = {Cheslow, L and Snook, AE and Waldman, SA}, title = {Biomarkers for Managing Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {14}, number = {4}, pages = {}, pmid = {38672416}, issn = {2218-273X}, support = {F30 NS125921/NS/NINDS NIH HHS/United States ; R01 CA206026/CA/NCI NIH HHS/United States ; 1R01 CA204881, 1R01 CA206026, 1R21 1NS130388, 1R01 DK1388341/NH/NIH HHS/United States ; R21 CA267087/CA/NCI NIH HHS/United States ; R21 NS130388/NS/NINDS NIH HHS/United States ; R21 CA286339/CA/NCI NIH HHS/United States ; R01 DK138834/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/metabolism/diagnosis/therapy ; *Alzheimer Disease/metabolism/diagnosis/therapy ; Amyotrophic Lateral Sclerosis/metabolism/therapy/diagnosis ; Parkinson Disease/metabolism/diagnosis/therapy ; Animals ; }, abstract = {Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track responses to therapy, and parse the causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD).}, } @article {pmid38672428, year = {2024}, author = {Cox, SN and Lo Giudice, C and Lavecchia, A and Poeta, ML and Chiara, M and Picardi, E and Pesole, G}, title = {Mitochondrial and Nuclear DNA Variants in Amyotrophic Lateral Sclerosis: Enrichment in the Mitochondrial Control Region and Sirtuin Pathway Genes in Spinal Cord Tissue.}, journal = {Biomolecules}, volume = {14}, number = {4}, pages = {}, pmid = {38672428}, issn = {2218-273X}, support = {UNIBA148- project code C1A93B75-CUP H94I20000410008//Research for Innovation (REFIN)-POR PUGLIA FESR-FSE 2014/2020/ ; CN_00000013//National Research Centers: "High Performance Computing, Big Data and Quantum Computing"/ ; CN_00000041//National Research Centers: "Gene Therapy and Drugs based on RNA Technology"/ ; PE_0000006//National Research Centers-Extended Partnerships: MNESYS/ ; IR0000010//ELIXIR-IT ELIXIRNextGenIT/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Spinal Cord/metabolism/pathology ; *DNA, Mitochondrial/genetics ; *Sirtuins/genetics/metabolism ; Male ; Female ; Middle Aged ; Mitochondria/genetics/metabolism ; Cell Nucleus/genetics/metabolism ; Aged ; Exome Sequencing ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive disease with prevalent mitochondrial dysfunctions affecting both upper and lower motor neurons in the motor cortex, brainstem, and spinal cord. Despite mitochondria having their own genome (mtDNA), in humans, most mitochondrial genes are encoded by the nuclear genome (nDNA). Our study aimed to simultaneously screen for nDNA and mtDNA genomes to assess for specific variant enrichment in ALS compared to control tissues. Here, we analysed whole exome (WES) and whole genome (WGS) sequencing data from spinal cord tissues, respectively, of 6 and 12 human donors. A total of 31,257 and 301,241 variants in nuclear-encoded mitochondrial genes were identified from WES and WGS, respectively, while mtDNA reads accounted for 73 and 332 variants. Despite technical differences, both datasets consistently revealed a specific enrichment of variants in the mitochondrial Control Region (CR) and in several of these genes directly associated with mitochondrial dynamics or with Sirtuin pathway genes within ALS tissues. Overall, our data support the hypothesis of a variant burden in specific genes, highlighting potential actionable targets for therapeutic interventions in ALS.}, } @article {pmid38672445, year = {2024}, author = {Esperante, IJ and Meyer, M and Banzan, C and Kruse, MS and Lima, A and Roig, P and Guennoun, R and Schumacher, M and De Nicola, AF and Gonzalez Deniselle, MC}, title = {Testosterone Reduces Myelin Abnormalities in the Wobbler Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Biomolecules}, volume = {14}, number = {4}, pages = {}, pmid = {38672445}, issn = {2218-273X}, support = {PICT 2019 Nº 3292//Ministerio de Ciencia, Tecnología e Innovación/ ; PIP 2022-2024 #11220210100091CO//CONICET/ ; }, mesh = {Animals ; Mice ; *Myelin Sheath/metabolism/drug effects ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Male ; *Disease Models, Animal ; *Testosterone/pharmacology ; Spinal Cord/metabolism/drug effects/pathology ; Excitatory Amino Acid Transporter 2/metabolism/genetics ; Microglia/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron degenerative disease that is associated with demyelination. The Wobbler (WR) mouse exhibits motoneuron degeneration, gliosis and myelin deterioration in the cervical spinal cord. Since male WRs display low testosterone (T) levels in the nervous system, we investigated if T modified myelin-relative parameters in WRs in the absence or presence of the aromatase inhibitor, anastrozole (A). We studied myelin by using luxol-fast-blue (LFB) staining, semithin sections, electron microscopy and myelin protein expression, density of IBA1[+] microglia and mRNA expression of inflammatory factors, and the glutamatergic parameters glutamine synthetase (GS) and the transporter GLT1. Controls and WR + T showed higher LFB, MBP and PLP staining, lower g-ratios and compact myelin than WRs and WR + T + A, and groups showing the rupture of myelin lamellae. WRs showed increased IBA1[+] cells and mRNA for CD11b and inflammatory factors (IL-18, TLR4, TNFαR1 and P2Y12R) vs. controls or WR + T. IBA1[+] cells, and CD11b were not reduced in WR + T + A, but inflammatory factors' mRNA remained low. A reduction of GS[+] cells and GLT-1 immunoreactivity was observed in WRs and WR + T + A vs. controls and WR + T. Clinically, WR + T but not WR + T + A showed enhanced muscle mass, grip strength and reduced paw abnormalities. Therefore, T effects involve myelin protection, a finding of potential clinical translation.}, } @article {pmid38674431, year = {2024}, author = {Shahim, P and Norato, G and Sinaii, N and Zetterberg, H and Blennow, K and Chan, L and Grunseich, C}, title = {Neurofilaments in Sporadic and Familial Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Genes}, volume = {15}, number = {4}, pages = {}, pmid = {38674431}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood/diagnosis/cerebrospinal fluid ; Humans ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Biomarkers/blood/cerebrospinal fluid ; Intermediate Filaments/metabolism/genetics ; Prognosis ; }, abstract = {BACKGROUND: Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and prognostic utility of neurofilaments in ALS.

METHODS: Studies were conducted in electronic databases (PubMed/MEDLINE, Embase, Web of Science, and Cochrane CENTRAL) from inception to 17 August 2023, and investigated neurofilament light (NfL) or phosphorylated neurofilament heavy chain (pNfH) in ALS. The study design, enrolment criteria, neurofilament concentrations, test accuracy, relationship between neurofilaments in cerebrospinal fluid (CSF) and blood, and clinical outcome were recorded. The protocol was registered with PROSPERO, CRD42022376939.

RESULTS: Sixty studies with 8801 participants were included. Both NfL and pNfH measured in CSF showed high sensitivity and specificity in distinguishing ALS from disease mimics. Both NfL and pNfH measured in CSF correlated with their corresponding levels in blood (plasma or serum); however, there were stronger correlations between CSF NfL and blood NfL. NfL measured in blood exhibited high sensitivity and specificity in distinguishing ALS from controls. Both higher levels of NfL and pNfH either measured in blood or CSF were correlated with more severe symptoms as assessed by the ALS Functional Rating Scale Revised score and with a faster disease progression rate; however, only blood NfL levels were associated with shorter survival.

DISCUSSION: Both NfL and pNfH measured in CSF or blood show high diagnostic utility and association with ALS functional scores and disease progression, while CSF NfL correlates strongly with blood (either plasma or serum) and is also associated with survival, supporting its use in clinical diagnostics and prognosis. Future work must be conducted in a prospective manner with standardized bio-specimen collection methods and analytical platforms, further improvement in immunoassays for quantification of pNfH in blood, and the identification of cut-offs across the ALS spectrum and controls.}, } @article {pmid38674548, year = {2024}, author = {Bai, L and Li, X and Guo, X and Chen, J and Yu, H and Cui, H}, title = {Distribution and Mechanism of Japanese Brome (Bromus japonicus) Resistance to ALS-Inhibiting Herbicides in China.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {8}, pages = {}, pmid = {38674548}, issn = {2223-7747}, support = {2023YFD1400501//National Key Research and Development Program of China and Technology Innovation Project, Chinese Academy of Agricultural Sciences./ ; }, abstract = {Bromus japonicus is a common monocot weed that occurs in major winter wheat fields in the Huang-Huai-Hai region of China. Pyroxsulam is a highly efficient and safe acetolactate synthase (ALS)-inhibiting herbicide that is widely used to control common weeds in wheat fields. However, B. japonicus populations in China have evolved resistance to pyroxsulam by different mutations in the ALS gene. To understand the resistance distribution, target-site resistance mechanisms, and cross-resistance patterns, 208 B. japonicus populations were collected from eight provinces. In the resistant population screening experiment, 59 populations from six provinces showed different resistance levels to pyroxsulam compared with the susceptible population, of which 17 B. japonicus populations with moderate or high levels of resistance to pyroxsulam were mainly from the Hebei (4), Shandong (4) and Shanxi (9) Provinces. Some resistant populations were selected to investigate the target site-resistance mechanism to the ALS-inhibiting herbicide pyroxsulam. Three pairs of primers were designed to amplify the ALS sequence, which was assembled into the complete ALS sequence with a length of 1932 bp. DNA sequencing of ALS revealed that four different ALS mutations (Pro-197-Ser, Pro-197-Thr, Pro-197-Phe and Asp-376-Glu) were found in 17 moderately or highly resistant populations. Subsequently, five resistant populations, QM21-41 with Pro-197-Ser, QM20-8 with Pro-197-Thr and Pro-197-Phe, and QM21-72, QM21-76 and QM21-79 with Asp-376-Glu mutations in ALS genes, were selected to characterize their cross-resistance patterns to ALS inhibitors. The QM21-41, QM20-8, QM21-72, QM21-76 and QM21-79 populations showed broad-spectrum cross-resistance to pyroxsulam, mesosulfuron-methyl and flucarbazone-sodium. This study is the first to report evolving cross-resistance to ALS-inhibiting herbicides due to Pro-197-Phe mutations in B. japonicus.}, } @article {pmid38674921, year = {2024}, author = {Wang, W and Pan, D and Liu, Q and Chen, X and Wang, S}, title = {L-Carnitine in the Treatment of Psychiatric and Neurological Manifestations: A Systematic Review.}, journal = {Nutrients}, volume = {16}, number = {8}, pages = {}, pmid = {38674921}, issn = {2072-6643}, mesh = {Humans ; *Carnitine/therapeutic use ; Dietary Supplements ; *Mental Disorders/drug therapy ; *Nervous System Diseases/drug therapy ; }, abstract = {OBJECTIVE: L-carnitine (LC), a vital nutritional supplement, plays a crucial role in myocardial health and exhibits significant cardioprotective effects. LC, being the principal constituent of clinical-grade supplements, finds extensive application in the recovery and treatment of diverse cardiovascular and cerebrovascular disorders. However, controversies persist regarding the utilization of LC in nervous system diseases, with varying effects observed across numerous mental and neurological disorders. This article primarily aims to gather and analyze database information to comprehensively summarize the therapeutic potential of LC in patients suffering from nervous system diseases while providing valuable references for further research.

METHODS: A comprehensive search was conducted in PubMed, Web Of Science, Embase, Ovid Medline, Cochrane Library and Clinicaltrials.gov databases. The literature pertaining to the impact of LC supplementation on neurological or psychiatric disorders in patients was reviewed up until November 2023. No language or temporal restrictions were imposed on the search.

RESULTS: A total of 1479 articles were retrieved, and after the removal of duplicates through both automated and manual exclusion processes, 962 articles remained. Subsequently, a meticulous re-screening led to the identification of 60 relevant articles. Among these, there were 12 publications focusing on hepatic encephalopathy (HE), while neurodegenerative diseases (NDs) and peripheral nervous system diseases (PNSDs) were represented by 9 and 6 articles, respectively. Additionally, stroke was addressed in five publications, whereas Raynaud's syndrome (RS) and cognitive disorder (CD) each had three dedicated studies. Furthermore, migraine, depression, and amyotrophic lateral sclerosis (ALS) each accounted for two publications. Lastly, one article was found for other symptoms under investigation.

CONCLUSION: In summary, LC has demonstrated favorable therapeutic effects in the management of HE, Alzheimer's disease (AD), carpal tunnel syndrome (CTS), CD, migraine, neurofibromatosis (NF), PNSDs, RS, and stroke. However, its efficacy appears to be relatively limited in conditions such as ALS, ataxia, attention deficit hyperactivity disorder (ADHD), depression, chronic fatigue syndrome (CFS), Down syndrome (DS), and sciatica.}, } @article {pmid38675428, year = {2024}, author = {Calenda, S and Catarzi, D and Varano, F and Vigiani, E and Volpini, R and Lambertucci, C and Spinaci, A and Trevisan, L and Grieco, I and Federico, S and Spalluto, G and Novello, G and Salmaso, V and Moro, S and Colotta, V}, title = {Structural Investigations on 2-Amidobenzimidazole Derivatives as New Inhibitors of Protein Kinase CK1 Delta.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {4}, pages = {}, pmid = {38675428}, issn = {1424-8247}, support = {RICATEN2021-2023Colotta//University of Florence/ ; 2017MT3993_004//Italian Ministry of University and Research-PRIN2017/ ; }, abstract = {Protein kinase CK1δ (CK1δ) is a serine-threonine/kinase that modulates different physiological processes, including the cell cycle, DNA repair, and apoptosis. CK1δ overexpression, and the consequent hyperphosphorylation of specific proteins, can lead to sleep disorders, cancer, and neurodegenerative diseases. CK1δ inhibitors showed anticancer properties as well as neuroprotective effects in cellular and animal models of Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis. To obtain new ATP-competitive CK1δ inhibitors, three sets of benzimidazole-2-amino derivatives were synthesized (1-32), bearing different substituents on the fused benzo ring (R) and diverse pyrazole-containing acyl moieties on the 2-amino group. The best-performing derivatives were those featuring the (1H-pyrazol-3-yl)-acetyl moiety on the benzimidazol-2-amino scaffold (13-32), which showed CK1δ inhibitor activity in the low micromolar range. Among the R substituents, 5-cyano was the most advantageous, leading to a compound endowed with nanomolar potency (23, IC50 = 98.6 nM). Molecular docking and dynamics studies were performed to point out the inhibitor-kinase interactions.}, } @article {pmid38676303, year = {2024}, author = {Zhao, W and Wang, R and Chen, M}, title = {Clinical analysis of air-leak syndrome following allogeneic hematopoietic stem cell transplantation in pediatric patients.}, journal = {Pediatric blood & cancer}, volume = {71}, number = {7}, pages = {e31008}, doi = {10.1002/pbc.31008}, pmid = {38676303}, issn = {1545-5017}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Male ; Female ; Retrospective Studies ; Child ; Child, Preschool ; Adolescent ; Infant ; Prognosis ; Survival Rate ; Follow-Up Studies ; Transplantation, Homologous ; Bronchiolitis Obliterans/etiology/mortality/therapy ; Pneumonia/etiology/mortality ; }, abstract = {BACKGROUND: Air-leak syndrome (ALS) is considered as an independent risk factor for poor prognosis in adult patients who had received hematopoietic stem cell transplantation (HSCT), and the 5-year overall survival (OS) of ALS is less than 30%. However, the clinical features of ALS among post-transplant pediatric patients have rarely been explored.

PROCEDURES: We retrospectively reviewed 2206 pediatric patients who had received an allo-HSCT between January 2013 and December 2019 at the Hebei Yanda Lu Daopei Hospital, and analyzed the role of ALS in prognosis following HSCT.

RESULTS: In our research, ALS was divided into two categories: 15 cases of bronchiolitis obliterans syndrome (BOS) and 13 cases of idiopathic pneumonia syndrome (IPS). Following treatment of the ALS, 18 patients survived (18/28, 64.3%), and 10 patients died of respiratory failure or infection (10/28, 35.7%).

CONCLUSIONS: The OS of ALS in Hebei Yanda Lu Daopei Hospital is significantly higher than others, and they were cited to be related to early diagnosis and timely FAM treatment in previous reports.}, } @article {pmid38676602, year = {2024}, author = {Presotto, A and Hernández, F and Vercellino, RB and Kruger, RD and Fontana, ML and Ureta, MS and Crepy, M and Auge, G and Caicedo, A}, title = {Introgression from local cultivars is a driver of agricultural adaptation in Argentinian weedy rice.}, journal = {Molecular ecology}, volume = {33}, number = {11}, pages = {e17368}, doi = {10.1111/mec.17368}, pmid = {38676602}, issn = {1365-294X}, support = {IOS-1032023//Division of Integrative Organismal Systems/ ; PICT 2019-00581//Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación/ ; }, mesh = {*Oryza/genetics ; *Herbicide Resistance/genetics ; Argentina ; *Acetolactate Synthase/genetics ; *Herbicides ; Plant Weeds/genetics ; Phenotype ; Genotype ; Adaptation, Physiological/genetics ; Crops, Agricultural/genetics ; Gene Flow ; Agriculture ; Mutation ; }, abstract = {Weedy rice, a pervasive and troublesome weed found across the globe, has often evolved through fertilization of rice cultivars with little importance of crop-weed gene flow. In Argentina, weedy rice has been reported as an important constraint since the early 1970s, and, in the last few years, strains with herbicide-resistance are suspected to evolve. Despite their importance, the origin and genetic composition of Argentinian weedy rice as well its adaptation to agricultural environments has not been explored so far. To study this, we conducted genotyping-by-sequencing on samples of Argentinian weedy and cultivated rice and compared them with published data from weedy, cultivated and wild rice accessions distributed worldwide. In addition, we conducted a phenotypic characterization for weedy-related traits, a herbicide resistance screening and genotyped accessions for known mutations in the acetolactate synthase (ALS) gene, which confers herbicide resistance. Our results revealed large phenotypic variability in Argentinian weedy rice. Most strains were resistant to ALS-inhibiting herbicides with a high frequency of the ALS mutation (A122T) present in Argentinian rice cultivars. Argentinian cultivars belonged to the three major genetic groups of rice: japonica, indica and aus while weeds were mostly aus or aus-indica admixed, resembling weedy rice strains from the Southern Cone region. Phylogenetic analysis supports a single origin for aus-like South American weeds, likely as seed contaminants from the United States, and then admixture with local indica cultivars. Our findings demonstrate that crop to weed introgression can facilitate rapid adaptation to agriculture environments.}, } @article {pmid38676626, year = {2024}, author = {Dash, BP and Freischmidt, A and Weishaupt, JH and Hermann, A}, title = {An integrative miRNA-mRNA expression analysis identifies miRNA signatures associated with SOD1 and TARDBP patient-derived motor neurons.}, journal = {Human molecular genetics}, volume = {33}, number = {15}, pages = {1300-1314}, doi = {10.1093/hmg/ddae072}, pmid = {38676626}, issn = {1460-2083}, support = {//Hermann and Lilly Schilling-Stiftung für medizinische Forschung im Stifterverband/ ; //Professorinnenprogramm III (University of Rostock) of the German/ ; }, mesh = {*MicroRNAs/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; *RNA, Messenger/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Gene Expression Profiling ; Gene Expression Regulation/genetics ; Transcriptome/genetics ; }, abstract = {MicroRNAs (miRNAs) are a subset of small non-coding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression of a variety of transcript targets. Therefore altered miRNA expression may result in the dysregulation of key genes and biological pathways that has been reported with the onset and progression of neurodegenerative diseases, such as Amyotrophic lateral sclerosis (ALS). ALS is marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Although the pathomechanism underlying molecular interactions of ALS remains poorly understood, alterations in RNA metabolism, including dysregulation of miRNA expression in familial as well as sporadic forms are still scarcely studied. In this study, we performed combined transcriptomic data and miRNA profiling in MN samples of the same samples of iPSC-derived MNs from SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls. We report a global upregulation of mature miRNAs, and suggest that differentially expressed (DE) miRNAs have a significant impact on mRNA-level in SOD1-, but not in TARDBP-linked ALS. Furthermore, in SOD1-ALS we identified dysregulated miRNAs such as miR-124-3p, miR-19b-3p and miR-218 and their potential targets previously implicated in important functional process and pathogenic pathways underlying ALS. These miRNAs may play key roles in the neuronal development and cell survival related functions in SOD1-ALS. Altogether, we provide evidence of miRNA regulated genes expression mainly in SOD1 rather than TDP43-ALS.}, } @article {pmid38676672, year = {2024}, author = {Kutlubaev, MA}, title = {[Promising approaches to the pathogenetic therapy of amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {4}, pages = {13-21}, doi = {10.17116/jnevro202412404113}, pmid = {38676672}, issn = {1997-7298}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Neuroprotective Agents/therapeutic use ; Genetic Therapy ; Antioxidants/therapeutic use ; Stem Cell Transplantation ; Gastrointestinal Microbiome ; Immunologic Factors/therapeutic use ; Immunomodulating Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis is a severe incurable disease of the nervous system. Currently only methods of palliative care for the patients with this disease are available. Few medications for the pathogenetic therapy are registered in some countries, i.e. riluzole, edaravon, sodium phenylbutyrate/taurursodiol as well as tofersen (conditionally). Their efficacy is relatively low. The main directions in the development of pathogenetic therapy of ALS include gene therapy, use of stem cells, immunomodulators, agents affecting gut microbiota. A search is also underway for low-molecular compounds with neuroprotective and antioxidant properties. Perspective direction is prevention of ALS. This will be possible when biomarkers for identification of patients in pre-manifest/prodromal stage are detected.}, } @article {pmid38676818, year = {2024}, author = {Kubat, GB and Picone, P}, title = {Skeletal muscle dysfunction in amyotrophic lateral sclerosis: a mitochondrial perspective and therapeutic approaches.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {9}, pages = {4121-4131}, pmid = {38676818}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/pathology ; *Muscle, Skeletal/physiopathology/pathology ; Animals ; Mitochondria/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease that results in the loss of motor neurons and severe skeletal muscle atrophy. The etiology of ALS is linked to skeletal muscle, which can activate a retrograde signaling cascade that destroys motor neurons. This is why satellite cells and mitochondria play a crucial role in the health and performance of skeletal muscles. This review presents current knowledge on the involvement of mitochondrial dysfunction, skeletal muscle atrophy, muscle satellite cells, and neuromuscular junction (NMJ) in ALS. It also discusses current therapeutic strategies, including exercise, drugs, stem cells, gene therapy, and the prospective use of mitochondrial transplantation as a viable therapeutic strategy.}, } @article {pmid38676932, year = {2024}, author = {Oppegaard, KR and Mayo, SJ and Armstrong, TS and Dokiparthi, V and Melisko, M and Levine, JD and Olshen, AB and Anguera, JA and Roy, R and Paul, S and Cooper, B and Conley, YP and Hammer, MJ and Miaskowski, C and Kober, KM}, title = {Neurodegenerative disease pathways are perturbed in patients with cancer who self-report cognitive changes and anxiety: A pathway impact analysis.}, journal = {Cancer}, volume = {130}, number = {16}, pages = {2834-2847}, pmid = {38676932}, issn = {1097-0142}, support = {//Sigma Theta Tau International Honor Society of Nursing-Alpha Eta Chapter/ ; //Leavitt PhD Student Scholarship/ ; R37 CA233774/CA/NCI NIH HHS/United States ; 5U54CA156734-12//University of Massachusetts Boston-Dana-Farber/Harvard Cancer Center U54 Comprehensive Partnership for Cancer Health Disparities Research/ ; //International Society of Nurses in Genetics/ ; CA233774/CA/NCI NIH HHS/United States ; CA082103/CA/NCI NIH HHS/United States ; T32NR016920/NR/NINR NIH HHS/United States ; CA134900/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *Anxiety ; Middle Aged ; *Neoplasms/psychology/complications ; *Neurodegenerative Diseases/psychology ; *Self Report ; Aged ; Signal Transduction ; Cognitive Dysfunction/etiology ; Adult ; }, abstract = {BACKGROUND: Cancer-related cognitive impairment (CRCI) and anxiety co-occur in patients with cancer. Little is known about mechanisms for the co-occurrence of these two symptoms. The purposes of this secondary analysis were to evaluate for perturbed pathways associated with the co-occurrence of self-reported CRCI and anxiety in patients with low versus high levels of these two symptoms and to identify potential mechanisms for the co-occurrence of CRCI and anxiety using biological processes common across any perturbed neurodegenerative disease pathways.

METHODS: Patients completed the Attentional Function Index and the Spielberger State-Trait Anxiety Inventory six times over two cycles of chemotherapy. Based on findings from a previous latent profile analysis, patients were grouped into none versus both high levels of these symptoms. Gene expression was quantified, and pathway impact analyses were performed. Signaling pathways for evaluation were defined with the Kyoto Encyclopedia of Genes and Genomes database.

RESULTS: A total of 451 patients had data available for analysis. Approximately 85.0% of patients were in the none class and 15.0% were in the both high class. Pathway impact analyses identified five perturbed pathways related to neurodegenerative diseases (i.e., amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, prion disease, and pathways of neurodegeneration-multiple diseases). Apoptosis, mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum stress were common biological processes across these pathways.

CONCLUSIONS: This study is the first to describe perturbations in neurodegenerative disease pathways associated with CRCI and anxiety in patients receiving chemotherapy. These findings provide new insights into potential targets for the development of mechanistically based interventions.}, } @article {pmid38677657, year = {2024}, author = {Ko, VI and Ong, K and Cleveland, DW and Yu, H and Ravits, JM}, title = {CK1δ/ε kinases regulate TDP-43 phosphorylation and are therapeutic targets for ALS-related TDP-43 hyperphosphorylation.}, journal = {Neurobiology of disease}, volume = {196}, number = {}, pages = {106516}, doi = {10.1016/j.nbd.2024.106516}, pmid = {38677657}, issn = {1095-953X}, support = {P30 NS047101/NS/NINDS NIH HHS/United States ; F32 AG059358/AG/NIA NIH HHS/United States ; K99 NS114162/NS/NINDS NIH HHS/United States ; R01 NS113517/NS/NINDS NIH HHS/United States ; }, mesh = {Phosphorylation ; *DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; *Casein Kinase Idelta/metabolism ; *Casein Kinase 1 epsilon/metabolism ; HEK293 Cells ; }, abstract = {Hyperphosphorylated TAR DNA-binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons is the neuropathological hallmark of amyotrophic lateral sclerosis (ALS) and a group of neurodegenerative diseases collectively referred to as TDP-43 proteinopathies that includes frontotemporal dementia, Alzheimer's disease, and limbic onset age-related TDP-43 encephalopathy. The mechanism of TDP-43 phosphorylation is poorly understood. Previously we reported casein kinase 1 epsilon gene (CSNK1E gene encoding CK1ε protein) as being tightly correlated with phosphorylated TDP-43 (pTDP-43) pathology. Here we pursued studies to investigate in cellular models and in vitro how CK1ε and CK1δ (a closely related family sub-member) mediate TDP-43 phosphorylation in disease. We first validated the binding interaction between TDP-43 and either CK1δ and CK1ε using kinase activity assays and predictive bioinformatic database. We utilized novel inducible cellular models that generated translocated phosphorylated TDP-43 (pTDP-43) and cytoplasmic aggregation. Reducing CK1 kinase activity with siRNA or small molecule chemical inhibitors resulted in significant reduction of pTDP-43, in both soluble and insoluble protein fractions. We also established CK1δ and CK1ε are the primary kinases that phosphorylate TDP-43 compared to CK2α, CDC7, ERK1/2, p38α/MAPK14, and TTBK1, other identified kinases that have been implicated in TDP-43 phosphorylation. Throughout our studies, we were careful to examine both the soluble and insoluble TDP-43 protein fractions, the critical protein fractions related to protein aggregation diseases. These results identify CK1s as critical kinases involved in TDP-43 hyperphosphorylation and aggregation in cellular models and in vitro, and in turn are potential therapeutic targets by way of CK1δ/ε inhibitors.}, } @article {pmid38677733, year = {2024}, author = {Keul, J and Sperling, S and Rohde, V and Mielke, D and Ninkovic, M}, title = {Riluzole Reverses a Number of Undesirable Effects of Dexamethasone in Glioblastoma Cells.}, journal = {Anticancer research}, volume = {44}, number = {5}, pages = {1829-1835}, doi = {10.21873/anticanres.16984}, pmid = {38677733}, issn = {1791-7530}, mesh = {*Riluzole/pharmacology ; Humans ; *Glioblastoma/drug therapy/pathology/metabolism ; *Dexamethasone/pharmacology ; *Cell Movement/drug effects ; Cell Line, Tumor ; Brain Neoplasms/drug therapy/pathology/metabolism ; Cell Survival/drug effects ; }, abstract = {BACKGROUND/AIM: Glioblastoma multiforme (GBM)-induced oedema is a major cause of morbidity and mortality among patients with GBM. Dexamethasone (Dex) is the most common corticosteroid used pre-operatively to control cerebral oedema in patients with GBM. Dex is associated with many side effects, and shorter overall survival and progression-free survival of patients with GBM. These negative effects of Dex highlight the need for combinational therapy. Riluzole (Ril), a drug used to treat amyotrophic lateral sclerosis (ALS), is thought to have potential as a treatment for various cancers, with clinical trials underway. Here, we investigated whether Ril could reverse some of the undesirable effects of Dex.

MATERIALS AND METHODS: The effect of Dex, Ril, and Ril-Dex treatment on cell migration was monitored using the xCELLigence system. Cell viability assays were performed using 3-(4, 5-dimethylthiazol)-2, 5-diphenyltetrazolium bromide (MTT). The expression of genes involved in migration, glucose metabolism, and stemness was examined using real-time polymerase chain reaction (PCR).

RESULTS: Pre-treating GBM cells with Ril reduced Dex-induced cell migration and altered Dex-induced effects on cell invasion, stem cell, and glucose metabolism markers. Furthermore, Ril remained effective in killing GBM cells in combination with Dex.

CONCLUSION: Ril, which acts as an anti-tumorigenic drug, mediates some of the negative effects of Dex; therefore, it could be a potential drug to manage the side effects of Dex therapy in GBM.}, } @article {pmid38678262, year = {2024}, author = {Xu, C and Mei, Y and Yang, R and Luo, Q and Zhang, J and Kou, X and Hu, J and Wang, Y and Li, Y and Chen, R and Zhang, Z and Yao, Y and Sima, J}, title = {Edaravone Dexborneol mitigates pathology in animal and cell culture models of Alzheimer's disease by inhibiting neuroinflammation and neuronal necroptosis.}, journal = {Cell & bioscience}, volume = {14}, number = {1}, pages = {55}, pmid = {38678262}, issn = {2045-3701}, support = {82173804//National Natural Science Foundation of China/ ; 82001144//National Natural Science Foundation of China/ ; 3150120042//High-Level Talents Start-up Funding of China Pharmaceutical University/ ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with limited disease-modifying treatments. Drug repositioning strategy has now emerged as a promising approach for anti-AD drug discovery. Using 5×FAD mice and Aβ-treated neurons in culture, we tested the efficacy of Y-2, a compounded drug containing the antioxidant Edaravone (Eda), a pyrazolone and (+)-Borneol, an anti-inflammatory diterpenoid from cinnamon, approved for use in amyotrophic lateral sclerosis patients.

RESULTS: We examined effects of Y-2 versus Eda alone by i.p. administered in 8-week-old 5×FAD mice (females) for 4 months by comparing cognitive function, Aβ pathologies, neuronal necroptosis and neuroinflammation. Using primary neurons and astrocytes, as well as neuronal and astrocytic cell lines, we elucidated the molecular mechanisms of Y-2 by examining neuronal injury, astrocyte-mediated inflammation and necroptosis. Here, we find that Y-2 improves cognitive function in AD mice. Histopathological data show that Y-2, better than Eda alone, markedly ameliorates Aβ pathologies including Aβ burden, astrogliosis/microgliosis, and Tau phosphorylation. In addition, Y-2 reduces Aβ-induced neuronal injury including neurite damage, mitochondrial impairment, reactive oxygen species production and NAD[+] depletion. Notably, Y-2 inhibits astrocyte-mediated neuroinflammation and attenuates TNF-α-triggered neuronal necroptosis in cell cultures and AD mice. RNA-seq further demonstrates that Y-2, compared to Eda, indeed upregulates anti-inflammation pathways in astrocytes.

CONCLUSIONS: Our findings infer that Y-2, better than Eda alone, mitigates AD pathology and may provide a potential drug candidate for AD treatment.}, } @article {pmid38679111, year = {2024}, author = {Thulasidharan, A and Garg, L and Tendulkar, S and Ratnaparkhi, GS}, title = {Age-dependent dynamics of neuronal VAPB[ALS] inclusions in the adult brain.}, journal = {Neurobiology of disease}, volume = {196}, number = {}, pages = {106517}, doi = {10.1016/j.nbd.2024.106517}, pmid = {38679111}, issn = {1095-953X}, support = {P40 OD018537/OD/NIH HHS/United States ; }, mesh = {Animals ; *Aging/metabolism/pathology/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Animals, Genetically Modified ; Autophagy/physiology ; *Brain/metabolism/pathology ; Disease Models, Animal ; Drosophila ; *Drosophila Proteins/metabolism/genetics ; *Inclusion Bodies/metabolism/pathology ; Neurons/metabolism/pathology ; Valosin Containing Protein/metabolism/genetics ; Carrier Proteins ; Membrane Proteins ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive and fatal disease, caused by the degeneration of upper and lower motor neurons within the brain and spinal cord in the ageing human. The dying neurons contain cytoplasmic inclusions linked to the onset and progression of the disease. Here, we use a Drosophila model of ALS8 (VAP[P58S]) to understand the modulation of these inclusions in the ageing adult brain. The adult VAP[P58S] fly shows progressive deterioration in motor function till its demise 25 days post-eclosion. The density of VAP[P58S]-positive brain inclusions is stable for 5-15 days of age. In contrast, adding a single copy of VAP[WT] to the VAP[P58S] animal leads to a large decrease in inclusion density with concomitant rescue of motor function and lifespan. ER stress, a contributing factor in disease, shows reduction with ageing for the disease model. Autophagy, rather than the Ubiquitin Proteasome system, is the dominant mechanism for aggregate clearance. We explored the ability of Drosophila Valosin-containing protein (VCP/TER94), the ALS14 locus, which is involved in cellular protein clearance, to regulate age-dependent aggregation. Contrary to expectation, TER94 overexpression increased VAP[P58S] punctae density, while its knockdown led to enhanced clearance. Expression of a dominant positive allele, TER94[R152H], further stabilised VAP[P58S] puncta, cementing roles for an ALS8-ALS14 axis. Our results are explained by a mechanism where autophagy is modulated by TER94 knockdown. Our study sheds light on the complex regulatory events involved in the neuronal maintenance of ALS8 aggregates, suggesting a context-dependent switch between proteasomal and autophagy-based mechanisms as the larvae develop into an adult. A deeper understanding of the nucleation and clearance of the inclusions, which affect cellular stress and function, is essential for understanding the initiation and progression of ALS.}, } @article {pmid38679739, year = {2024}, author = {Pérez Compte, D and Etourneau, L and Hesse, AM and Kraut, A and Barthelon, J and Sturm, N and Borges, H and Biennier, S and Courçon, M and de Saint Loup, M and Mignot, V and Costentin, C and Burger, T and Couté, Y and Bruley, C and Decaens, T and Jaquinod, M and Boursier, J and Brun, V}, title = {Plasma ALS and Gal-3BP differentiate early from advanced liver fibrosis in MASLD patients.}, journal = {Biomarker research}, volume = {12}, number = {1}, pages = {44}, pmid = {38679739}, issn = {2050-7771}, support = {[ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; }, abstract = {BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is estimated to affect 30% of the world's population, and its prevalence is increasing in line with obesity. Liver fibrosis is closely related to mortality, making it the most important clinical parameter for MASLD. It is currently assessed by liver biopsy - an invasive procedure that has some limitations. There is thus an urgent need for a reliable non-invasive means to diagnose earlier MASLD stages.

METHODS: A discovery study was performed on 158 plasma samples from histologically-characterised MASLD patients using mass spectrometry (MS)-based quantitative proteomics. Differentially abundant proteins were selected for verification by ELISA in the same cohort. They were subsequently validated in an independent MASLD cohort (n = 200).

RESULTS: From the 72 proteins differentially abundant between patients with early (F0-2) and advanced fibrosis (F3-4), we selected Insulin-like growth factor-binding protein complex acid labile subunit (ALS) and Galectin-3-binding protein (Gal-3BP) for further study. In our validation cohort, AUROCs with 95% CIs of 0.744 [0.673 - 0.816] and 0.735 [0.661 - 0.81] were obtained for ALS and Gal-3BP, respectively. Combining ALS and Gal-3BP improved the assessment of advanced liver fibrosis, giving an AUROC of 0.796 [0.731. 0.862]. The {ALS; Gal-3BP} model surpassed classic fibrosis panels in predicting advanced liver fibrosis.

CONCLUSIONS: Further investigations with complementary cohorts will be needed to confirm the usefulness of ALS and Gal-3BP individually and in combination with other biomarkers for diagnosis of liver fibrosis. With the availability of ELISA assays, these findings could be rapidly clinically translated, providing direct benefits for patients.}, } @article {pmid38681726, year = {2024}, author = {Grzanka, M and Joniec, A and Rogulski, J and Sobiech, Ł and Idziak, R and Loryś, B}, title = {Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control.}, journal = {Open life sciences}, volume = {19}, number = {1}, pages = {20220868}, pmid = {38681726}, issn = {2391-5412}, abstract = {Delayed sowing of winter cereals or unfavorable weather conditions in autumn may make it impossible to carry out herbicide treatment in autumn. In such cases, weed control should be started in the spring. During this time, the plantation should be protected as effectively as possible because the weeds are at an advanced stage of growth. Therefore, they are less sensitive to applied herbicides. In the treatment, it is worth using a mixture of different mechanisms of action. Studies were conducted to evaluate the effectiveness of a band of tribenuron-methyl, and MCPA applied as soluble granules in spring control of dicotyledonous in winter cereals. The biological efficacy of herbicides was estimated in the 25 field experiments on winter cereals in Poland. Postemergence, a spring application of tribenuron-methyl + MCPA, effectively controls the majority of weed species present in spring: Anthemis arvensis, Brassica napus, Capsella bursa-pastoris, Centaurea cyanus, Lamium purpureum, Matricaria chamomilla, Tripleurospermum inodorum, Stellaria media and Thlaspi arvense. Satisfactory control was confirmed for Veronica persica, Viola arvensis, and Galium aparine. Tribenuron-methyl with MCPA is recommended for application to winter cereals in spring. To prevent the development of resistance in weeds, it is advantageous to combine two active substances.}, } @article {pmid38682222, year = {2024}, author = {Huang, Q and Li, Q and Guo, JH}, title = {Causal Relationship between Sex Hormones and Risk of Developing Common Neurodegenerative Diseases: A Mendelian Randomization Study.}, journal = {Journal of integrative neuroscience}, volume = {23}, number = {4}, pages = {78}, doi = {10.31083/j.jin2304078}, pmid = {38682222}, issn = {0219-6352}, support = {2021ZD0201801//Science and Technology Innovation 2030 - Major program of "Brain Science and Brain-like Research"/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/epidemiology/genetics ; *Sex Hormone-Binding Globulin/analysis/metabolism ; Testosterone/blood ; Alzheimer Disease/epidemiology/genetics ; Estradiol/blood ; Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Parkinson Disease/genetics/epidemiology ; Gonadal Steroid Hormones/blood/metabolism ; Female ; Male ; }, abstract = {BACKGROUND: Neurodegenerative diseases are a group of unexplained disorders of the central nervous system, and studies have shown that a large number of genetic and environmental factors are associated with these diseases. Since these diseases show significant gender differences in epidemiology, sex hormones are thought to be strongly associated with these diseases. In this study, we used Mendelian randomization to explore the causal relationship between sex hormones and the risk of developing neurodegenerative diseases.

METHODS: We obtained genetic instrumental variables for sex hormones (sex hormone-binding globulin [SHBG], estradiol levels [EL], and bioavailable testosterone [BT]) separately through the Integrative Epidemiology Unit (IEU) database (https://gwas.mrcieu.ac.uk/). We analyzed the causal relationship of each with the risk of developing neurodegenerative diseases (Amyotrophic Lateral Sclerosis [ALS], Parkinson's disease [PD], and Alzheimer's disease [AD]) using inverse variance weighted (IVW) in Mendelian randomization. Data were then analyzed for sensitivity.

RESULTS: BT was negatively associated with the risk of developing ALS (odds ratio [OR] = 0.794; 95% confidence interval [95% CI] = 0.672-0.938; p = 0.006). EL and SHBG were not associated with a risk for developing neurodegenerative diseases (ALS, PD, AD).

CONCLUSIONS: Elevated BT is associated with a reduced risk of developing ALS. Further research is needed to investigate the underlying mechanisms of action for this correlation and how it can be used as a potential target of action to reduce the risk of developing ALS.}, } @article {pmid38682227, year = {2024}, author = {Mohammadi, S and Ghaderi, S and Mohammadi, M and Najafi Asli Pashaki, Z and Khatyal, R and Mohammadian, F and Mohammadjani, S}, title = {Thalamic Alterations in Motor Neuron Diseases: A Systematic Review of MRI Findings.}, journal = {Journal of integrative neuroscience}, volume = {23}, number = {4}, pages = {77}, doi = {10.31083/j.jin2304077}, pmid = {38682227}, issn = {0219-6352}, mesh = {Humans ; *Thalamus/diagnostic imaging/pathology/physiopathology ; *Motor Neuron Disease/diagnostic imaging/pathology/physiopathology ; *Magnetic Resonance Imaging ; Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/physiopathology ; }, abstract = {BACKGROUND: Motor neuron diseases (MNDs) are progressive neurodegenerative disorders characterized by motor impairment and non-motor symptoms. The involvement of the thalamus in MNDs, especially in conditions such as amyotrophic lateral sclerosis (ALS), and its interaction with frontotemporal dementia (FTD), has garnered increasing research interest. This systematic review analyzed magnetic resonance imaging (MRI) studies that focused on thalamic alterations in MNDs to understand the significance of these changes and their correlation with clinical outcomes.

METHODS: Following PRISMA 2020 guidelines, the PubMed and Scopus databases were searched from inception to June 2023 for studies related to MRI findings in the thalamus of patients with MNDs. Eligible studies included adult patients diagnosed with ALS or other forms of MND who underwent brain MRI, with outcomes related to thalamic alterations. Studies were evaluated for risk of bias using the Newcastle-Ottawa scale.

RESULTS: A total of 52 studies (including 3009 MND patients and 2181 healthy controls) used various MRI techniques, including volumetric analysis, diffusion tensor imaging, and functional MRI, to measure thalamic volume, connectivity, and other alterations. This review confirmed significant thalamic changes in MNDs, such as atrophy and microstructural degradation, which are associated with disease severity, progression, and functional disability. Thalamic involvement varies across different MND subtypes and is influenced by the presence of cognitive impairment and mutations in genes including chromosome 9 open reading frame 72 (C9orf72). The synthesis of findings across studies indicates that thalamic pathology is a prevalent early biomarker of MNDs that contributes to motor and cognitive deficits. The thalamus is a promising target for monitoring as its dysfunction underpins a variety of clinical symptoms in MNDs.

CONCLUSIONS: Thalamic alterations provide valuable insights into the pathophysiology and progression of MNDs. Multimodal MRI techniques are potent tools for detecting dynamic thalamic changes, indicating structural integrity, connectivity disruption, and metabolic activity.}, } @article {pmid38682649, year = {2024}, author = {Zhou, Q and Jiang, X and Zhang, X and Wang, D and Yang, G and Zhou, H and Wu, Y and Guo, F and Chen, M and Diao, G and Ni, L}, title = {Polyoxomolybdate-Based Metal-Organic Framework-Derived Cu-Embedded Molybdenum Dioxide Hybrid Nanoparticles as Highly Efficient Electrocatalysts for Al-S Batteries.}, journal = {ChemSusChem}, volume = {17}, number = {19}, pages = {e202400424}, doi = {10.1002/cssc.202400424}, pmid = {38682649}, issn = {1864-564X}, support = {21971221//National Natural Science Foundation of China/ ; 21401162//National Natural Science Foundation of China/ ; 21773203//National Natural Science Foundation of China/ ; KYCX22_3467//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; yzuxk202010//Yangzhou University Interdisciplinary Research Foundation for Chemistry Discipline/ ; //Colleges and Universities of Jiangsu Province/ ; //Lvyangjinfeng Talent Program of Yangzhou/ ; }, abstract = {High-performance rechargeable aluminum-sulfur batteries (RASB) have great potential for various applications owing to their high theoretical capacity, abundant sulfur resources, and good safety. Nevertheless, the practical application of RASB still faces several challenges, including the polysulfide shuttle phenomenon and low sulfur utilization efficiency. Here, we first developed a synergistic copper heterogeneous metal oxide MoO2 derived from polymolybdate-based metal-organic framework as an efficient catalyst for mitigating polysulfide diffusion. This composite enhances sulfur utilization and electrical conductivity of the cathode. DFT calculations and experimental results reveal the catalyst Cu/MoO2@C not only effectively anchors aluminum polysulfides (AlPSs) to mitigate the shuttle effect, but also significantly promotes the catalytic conversion of AlPSs on the sulfur cathode side during charging and discharging. The unique nanostructure contains abundant electrocatalytic active sites of oxide nanoparticles and Cu clusters, resulting in excellent electrochemical performance. Consequently, the established RASB exhibits an initial capacity of 875 mAh g[-1] at 500 mA g[-1] and maintains a capacity of 967 mAh g[-1] even at a high temperature of 50 °C.}, } @article {pmid38683209, year = {2024}, author = {Wohnrade, C and Seeliger, T and Gingele, S and Bjelica, B and Skripuletz, T and Petri, S}, title = {Diagnostic value of neurofilaments in differentiating motor neuron disease from multifocal motor neuropathy.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4441-4452}, pmid = {38683209}, issn = {1432-1459}, mesh = {Humans ; *Motor Neuron Disease/diagnosis/blood/cerebrospinal fluid/physiopathology ; Male ; Female ; Middle Aged ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Retrospective Studies ; Diagnosis, Differential ; Aged ; *Biomarkers/blood/cerebrospinal fluid ; *Polyneuropathies/diagnosis/blood/cerebrospinal fluid/physiopathology ; Adult ; }, abstract = {OBJECTIVE: To evaluate the performance of serum neurofilament light chain (NfL) and cerebrospinal fluid (CSF) phosphorylated neurofilament heavy chain (pNfH) as diagnostic biomarkers for the differentiation between motor neuron disease (MND) and multifocal motor neuropathy (MMN).

METHODS: This retrospective, monocentric study included 16 patients with MMN and 34 incident patients with MND. A subgroup of lower motor neuron (MN) dominant MND patients (n = 24) was analyzed separately. Serum NfL was measured using Ella automated immunoassay, and CSF pNfH was measured using enzyme-linked immunosorbent assay. Area under the curve (AUC), optimal cutoff values (Youden's index), and correlations with demographic characteristics were calculated.

RESULTS: Neurofilament concentrations were significantly higher in MND compared to MMN (p < 0.001), and serum NfL and CSF pNfH correlated strongly with each other (Spearman's rho 0.68, p < 0.001). Serum NfL (AUC 0.946, sensitivity and specificity 94%) and CSF pNfH (AUC 0.937, sensitivity 90.0%, specificity 100%) performed excellent in differentiating MND from MMN. Optimal cutoff values were ≥ 44.15 pg/mL (serum NfL) and ≥ 715.5 pg/mL (CSF pNfH), respectively. Similar results were found when restricting the MND cohort to lower MN dominant patients. Only one MMN patient had serum NfL above the cutoff. Two MND patients presented with neurofilament concentrations below the cutoffs, both featuring a slowly progressive disease.

CONCLUSION: Neurofilaments are valuable supportive biomarkers for the differentiation between MND and MMN. Serum NfL and CSF pNfH perform similarly well and elevated neurofilaments in case of diagnostic uncertainty underpin MND diagnosis.}, } @article {pmid38683778, year = {2024}, author = {Brennan, MR and Keast, DH and Bain, K and Bain, M and Lorentsen, B and Ayoub, N}, title = {Defining wound bed conformability: a new testing methodology to assess the relative swelling rise of foam dressings.}, journal = {Journal of wound care}, volume = {33}, number = {5}, pages = {312-323}, doi = {10.12968/jowc.2024.33.5.312}, pmid = {38683778}, issn = {0969-0700}, mesh = {Humans ; *Wound Healing ; *Bandages ; Reproducibility of Results ; Exudates and Transudates ; Materials Testing ; Wounds and Injuries/therapy ; }, abstract = {OBJECTIVE: Using a dressing that expands and conforms to the wound bed upon exudate absorption is one of the best ways to promote wound healing. While many products claim wound bed conformability, no externally replicated or verified test methodology had been developed to quantify a wound dressing's ability to conform to the wound bed. The Relative Swelling Rise (RSR) test methodology was developed to measure the relative swelling rise of foam dressings upon fluid absorption, and offers a quantifiable and easily replicated method to measure wound bed conformability.

METHOD: The RSR test method was developed, validated and reliability tested by Coloplast A/S, Denmark. External replication was provided by ALS Odense, Denmark (previously DB Lab). Circular fences provide a fixed diameter to apply and contain the fluid and prevent horizontal spreading in the test set-up. The swelling height is quantified relative to the fence's inner diameter, i.e., the ratio alpha (α), and allows evaluation of a material's ability to conform to the wound bed.

RESULTS: Biatain Silicone foam products (n=3, Coloplast A/S, Denmark) were tested, all afforded an average α-ratio from 0.30 to 0.60. The relative standard deviations were between 1-3%, demonstrating the strength of the test. Robustness of the methodology was demonstrated through the internal validation study, the reliability study, and both an internal and external replication study, as well as a systematic literature review and expert review of the construct, content, criterion and generalisability of the method.

CONCLUSION: Having a validated, effective and easily replicable testing method to quantify wound bed conformability of foam dressings is an important step towards achieving better healing outcomes.}, } @article {pmid38684907, year = {2024}, author = {Nelson, AT and Cicardi, ME and Markandaiah, SS and Han, JY and Philp, NJ and Welebob, E and Haeusler, AR and Pasinelli, P and Manfredi, G and Kawamata, H and Trotti, D}, title = {Glucose hypometabolism prompts RAN translation and exacerbates C9orf72-related ALS/FTD phenotypes.}, journal = {EMBO reports}, volume = {25}, number = {5}, pages = {2479-2510}, pmid = {38684907}, issn = {1469-3178}, support = {RF1 NS114128/NS/NINDS NIH HHS/United States ; W81XWH-21-1-0134//DOD | USA | MEDCOM | MRDC | U.S. Army Medical Research Acquisition Activity (USAMRAA)/ ; F31-NS118838//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS109150/NS/NINDS NIH HHS/United States ; RF1-NS114128//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 628389//Muscular Dystrophy Association (MDA)/ ; R35 NS122209/NS/NINDS NIH HHS/United States ; R21 NS090912/NS/NINDS NIH HHS/United States ; RO1-NS109150//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; F31 NS118838/NS/NINDS NIH HHS/United States ; RF1-AG057882//HHS | NIH | National Institute on Aging (NIA)/ ; RF1 AG057882/AG/NIA NIH HHS/United States ; R21-NS090912//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; Mice ; Adenosine Triphosphate/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Brain/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; Disease Models, Animal ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Glucose/metabolism ; Mice, Transgenic ; Neurons/metabolism ; *Phenotype ; Protein Biosynthesis ; *ran GTP-Binding Protein/metabolism ; }, abstract = {The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)n nucleotide repeat expansion (NRE) occurring in the first intron of the C9orf72 gene (C9). Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, but its role in disease pathogenesis is unknown. Here, we show alterations in glucose metabolic pathways and ATP levels in the brains of asymptomatic C9-BAC mice. We find that, through activation of the GCN2 kinase, glucose hypometabolism drives the production of dipeptide repeat proteins (DPRs), impairs the survival of C9 patient-derived neurons, and triggers motor dysfunction in C9-BAC mice. We also show that one of the arginine-rich DPRs (PR) could directly contribute to glucose metabolism and metabolic stress by inhibiting glucose uptake in neurons. Our findings provide a potential mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and suggest a feedforward loop model with potential opportunities for therapeutic intervention.}, } @article {pmid38685231, year = {2024}, author = {Deng, W and Yao, S and Li, Y and Yin, H and Yang, Q and Yuan, S}, title = {An Asp376Glu substitution and P450s-involved metabolism endow resistance to ALS inhibitors in an Ammannia auriculata Willd. Population.}, journal = {Pesticide biochemistry and physiology}, volume = {201}, number = {}, pages = {105911}, doi = {10.1016/j.pestbp.2024.105911}, pmid = {38685231}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors ; *Herbicides/pharmacology ; *Herbicide Resistance/genetics ; *Cytochrome P-450 Enzyme System/genetics/metabolism ; Malathion/pharmacology ; Sulfonylurea Compounds/pharmacology ; Plant Weeds/drug effects/genetics ; Amino Acid Substitution ; }, abstract = {Ammannia auriculata Willd. is a noxious broadleaf weed, commonly infesting rice ecosystems across southern China. A putative resistant A. auriculata population (AHSC-5) was sampled from a rice field of Anhui Province, where bensulfuron-methyl (BM) was unable to control its occurrence. This study aimed to determine the sensitivities of the AHSC-5 population to common-use herbicides, and to investigate the underlying resistance mechanisms. The bioassays showed that the AHSC-5 population was 138.1-fold resistant to BM, compared with the susceptible population (JSGL-1). Pretreatment of malathion reduced the resistance index to 19.5. ALS sequencing revealed an Asp376Glu substitution in the AHSC-5 population, and in vitro ALS activity assays found that 50% activity inhibition (I50) of BM in AHSC-5 was 75.4 times higher than that of JSGL-1. Moreover, the AHSC-5 population displayed cross-resistance to pyrazosulfuron-ethyl (10.6-fold), bispyribac‑sodium (3.6-fold), and imazethapyr (2.2-fold), and was in the process of evolving multiple resistance to synthetic auxin herbicides fluroxypyr (2.3-fold) and florpyrauxifen-benzyl (3.1-fold). This study proved the BM resistance in A. auriculata caused by the Asp376Glu mutation and P450-regulated metabolism. This multi-resistant population can still be controlled by penoxsulam, MCPA, bentazone, and carfentrazone-ethyl, which aids in developing targeted and effective weed management strategies.}, } @article {pmid38685248, year = {2024}, author = {Chtourou, M and Osuna, MD and Vázquez-García, JG and Lozano-Juste, J and De Prado, R and Torra, J and Souissi, T}, title = {Pro197Ser and the new Trp574Leu mutations together with enhanced metabolism contribute to cross-resistance to ALS inhibiting herbicides in Sinapis alba.}, journal = {Pesticide biochemistry and physiology}, volume = {201}, number = {}, pages = {105882}, doi = {10.1016/j.pestbp.2024.105882}, pmid = {38685248}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Herbicides/pharmacology ; *Herbicide Resistance/genetics ; *Sinapis/drug effects/genetics ; *Malathion/pharmacology ; *Mutation ; Plant Proteins/genetics/metabolism ; Arylsulfonates/pharmacology ; Molecular Docking Simulation ; Imidazoles/pharmacology ; }, abstract = {White mustard, (Sinapis alba), a problematic broadleaf weed in many Mediterranean countries in arable fields has been detected as resistant to tribenuron-methyl in Tunisia. Greenhouse and laboratory studies were conducted to characterize Target-Site Resistance (TSR) and the Non-Target Site Resistance (NTSR) mechanisms in two suspected white mustard biotypes. Herbicide dose-response experiments confirmed that the two S. alba biotypes were resistant to four dissimilar acetolactate synthase (ALS)-pinhibiting herbicide chemistries indicating the presence of cross-resistance mechanisms. The highest resistance factor (>144) was attributed to tribenuron-methyl herbicide and both R populations survived up to 64-fold the recommended field dose (18.7 g ai ha[-1]). In this study, the metabolism experiments with malathion (a cytochrome P450 inhibitor) showed that malathion reduced resistance to tribenuron-methyl and imazamox in both populations, indicating that P450 may be involved in the resistance. Sequence analysis of the ALS gene detected target site mutations in the two R biotypes, with amino acid substitutions Trp574Leu, the first report for the species, and Pro197Ser. Molecular docking analysis showed that ALS[Pro197Ser] enzyme cannot properly bind to tribenuron-methyl's aromatic ring due to a reduction in the number of hydrogen bonds, while imazamox can still bind. However, Trp574Leu can weaken the binding affinity between the mutated ALS enzyme and both herbicides with the loss of crucial interactions. This investigation provides substantial evidence for the risk of evolving multiple resistance in S. alba to auxin herbicides while deciphering the TSR and NTSR mechanisms conferring cross resistance to ALS inhibitors.}, } @article {pmid38685454, year = {2024}, author = {Gadri, Y and Avneri, A and Peleg, Z}, title = {Induced mutation in the SiALS gene offers new weed management opportunities for sesame crop.}, journal = {Plant science : an international journal of experimental plant biology}, volume = {345}, number = {}, pages = {112104}, doi = {10.1016/j.plantsci.2024.112104}, pmid = {38685454}, issn = {1873-2259}, mesh = {*Weed Control/methods ; *Herbicide Resistance/genetics ; *Sesamum/genetics/growth & development ; *Herbicides/pharmacology ; Acetolactate Synthase/genetics ; Plant Weeds/genetics/drug effects ; Plant Proteins/genetics/metabolism ; Mutation ; Crops, Agricultural/genetics/growth & development ; }, abstract = {Weeds are the primary biotic constraint affecting sesame growth and production. Here, we applied EMS mutagenesis to an elite sesame cultivar and discovered a novel point mutation in the sesame SiALS gene conferring resistance to imidazolinone, a group of acetolactate-synthase (ALS)-inhibitors. The mutant line exhibited high resistance to imazamox, an ALS-inhibitor, with hybrid plants displaying an intermediate response. Field-based validation confirmed the mutant line's substantial resistance, leading to a significantly higher yield under imazamox treatment. Under pre-emergence application of imazapic, the mutant plants sustained growth, whereas wild-type and weed were effectively controlled. Field trials using s-metolachlor and imazapic combined resulted in weed-free plots compared to untreated controls. Consequently, this treatment showed a significantly greater yield (2280 vs. 880 Kg ha[-1]) than the commercial practice (s-metolachlor). Overall, our study unveils the potential of utilizing this point mutation in sesame breeding programs, offering new opportunities for integrated weed management strategies for sesame cultivation. Developing herbicide-resistant crop plants holds promise for supporting sustainable production and addressing the challenges of weed infestations in sesame farming.}, } @article {pmid38686337, year = {2024}, author = {Felix, C and Johnston, JD and Owen, K and Shirima, E and Hinds, SR and Mandl, KD and Milinovich, A and Alberts, JL}, title = {Explainable machine learning for predicting conversion to neurological disease: Results from 52,939 medical records.}, journal = {Digital health}, volume = {10}, number = {}, pages = {20552076241249286}, pmid = {38686337}, issn = {2055-2076}, abstract = {OBJECTIVE: This study assesses the application of interpretable machine learning modeling using electronic medical record data for the prediction of conversion to neurological disease.

METHODS: A retrospective dataset of Cleveland Clinic patients diagnosed with Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, or Parkinson's disease, and matched controls based on age, sex, race, and ethnicity was compiled. Individualized risk prediction models were created using eXtreme Gradient Boosting for each neurological disease at four timepoints in patient history. The prediction models were assessed for transparency and fairness.

RESULTS: At timepoints 0-months, 12-months, 24-months, and 60-months prior to diagnosis, Alzheimer's disease models achieved the area under the receiver operating characteristic curve on a holdout test dataset of 0.794, 0.742, 0.709, and 0.645; amyotrophic lateral sclerosis of 0.883, 0.710, 0.658, and 0.620; multiple sclerosis of 0.922, 0.877, 0.849, and 0.781; and Parkinson's disease of 0.809, 0.738, 0.700, and 0.651, respectively.

CONCLUSIONS: The results demonstrate that electronic medical records contain latent information that can be used for risk stratification for neurological disorders. In particular, patient-reported outcomes, sleep assessments, falls data, additional disease diagnoses, and longitudinal changes in patient health, such as weight change, are important predictors.}, } @article {pmid38687737, year = {2024}, author = {Lumi, R and Petri, S and Siwy, J and Latosinska, A and Raad, J and Zürbig, P and Skripuletz, T and Mischak, H and Beige, J}, title = {Small peptide CSF fingerprint of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {4}, pages = {e0302280}, pmid = {38687737}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid ; Female ; Male ; Middle Aged ; Aged ; *Peptides/cerebrospinal fluid ; Proteomics/methods ; Adult ; Biomarkers/cerebrospinal fluid ; Case-Control Studies ; Tandem Mass Spectrometry ; Chromatography, Liquid ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by abnormal protein aggregation in the motor neurons. Present and earlier proteomic studies to characterize peptides in cerebrospinal fluid (CSF) associated with motoneuron pathology did not target low molecular weight proteins and peptides. We hypothesized that specific changes in CSF peptides or low molecular weight proteins are significantly altered in ALS, and that these changes may support deciphering molecular pathophysiology and even guide approaches towards therapeutic interventions.

METHODS: Cerebrospinal fluid (CSF) from 50 ALS patients and 50 non-ALS controls was collected, centrifuged immediately after collection, aliquoted into polypropylene test tubes, frozen within 30-40 min after the puncture, and stored at -80°C until use. Peptides were sequenced using capillary electrophoresis or liquid chromatography/mass spectrometry (CE-MS/MS or LC-MS/MS).

FINDINGS: In the CSF of 50 patients and 50 non-ALS controls 33 peptides were found, of which 14 could be sequenced using a non-lytic single-pot proteomic detection method, CE/MS. ALS deregulated peptides vs. controls included Integral membrane protein 2B, Neurosecretory protein VGF, Osteopontin, Neuroendocrine protein 7B2 (Secretogranin-V), EGF-containing fibulin-like extracellular matrix protein 1, Xylosyltransferase 1 XT-1, Chromogranin-A, Superoxide dismutase SOD-1, Secretogranin-1 (Chromogranin B), NR2F2 Nuclear Receptor Subfamily 2 Group F Member 2 and Collagen alpha-1(VII) chain.

INTERPRETATION: Most striking deregulations in CSF from ALS patients were found in VGF, Osteopontin, SOD-1 and EFEMP1 peptides. No associations of disease severity, duration and region of onset with sequenced peptides were found.}, } @article {pmid38689506, year = {2024}, author = {Parvizi, T and Klotz, S and Keritam, O and Caliskan, H and Imhof, S and König, T and Haider, L and Traub-Weidinger, T and Wagner, M and Brunet, T and Brugger, M and Zimprich, A and Rath, J and Stögmann, E and Gelpi, E and Cetin, H}, title = {Clinical heterogeneity within the ALS-FTD spectrum in a family with a homozygous optineurin mutation.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {6}, pages = {1579-1589}, pmid = {38689506}, issn = {2328-9503}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology/diagnosis ; *Membrane Transport Proteins/genetics ; *Cell Cycle Proteins/genetics ; *Frontotemporal Dementia/genetics/pathology/physiopathology ; Male ; Adult ; Female ; Pedigree ; Transcription Factor TFIIIA/genetics ; Siblings ; Frameshift Mutation ; Homozygote ; }, abstract = {OBJECTIVE: Mutations in the gene encoding for optineurin (OPTN) have been reported in the context of different neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. Based on single case reports, neuropathological data in OPTN mutation carriers have revealed transactive response DNA-binding protein 43 kDa (TDP-43) pathology, in addition to accumulations of tau and alpha-synuclein. Herein, we present two siblings from a consanguineous family with a homozygous frameshift mutation in the OPTN gene and different clinical presentations.

METHODS: Both affected siblings underwent (i) clinical, (ii) neurophysiological, (iii) neuropsychological, (iv) radiological, and (v) laboratory examinations, and (vi) whole-exome sequencing (WES). Postmortem histopathological examination was conducted in the index patient, who deceased at the age of 41.

RESULTS: The index patient developed rapidly progressing clinical features of upper and lower motor neuron dysfunction as well as apathy and cognitive deterioration at the age of 41. Autopsy revealed an ALS-FTLD pattern associated with prominent neuronal and oligodendroglial TDP-43 pathology, and an atypical limbic 4-repeat tau pathology reminiscent of argyrophilic grain disease. The brother of the index patient exhibited behavioral changes and mnestic deficits at the age of 38 and was diagnosed with behavioral FTD 5 years later, without any evidence of motor neuron dysfunction. WES revealed a homozygous frameshift mutation in the OPTN gene in both siblings (NM_001008212.2: c.1078_1079del; p.Lys360ValfsTer18).

INTERPRETATION: OPTN mutations can be associated with extensive TDP-43 pathology and limbic-predominant tauopathy and present with a heterogeneous clinical phenotype within the ALS-FTD spectrum within the same family.}, } @article {pmid38689650, year = {2024}, author = {Swindell, WR}, title = {Meta-analysis of differential gene expression in lower motor neurons isolated by laser capture microdissection from post-mortem ALS spinal cords.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1385114}, pmid = {38689650}, issn = {1664-8021}, abstract = {INTRODUCTION: ALS is a fatal neurodegenerative disease for which underlying mechanisms are incompletely understood. The motor neuron is a central player in ALS pathogenesis but different transcriptome signatures have been derived from bulk analysis of post-mortem tissue and iPSC-derived motor neurons (iPSC-MNs).

METHODS: This study performed a meta-analysis of six gene expression studies (microarray and RNA-seq) in which laser capture microdissection (LCM) was used to isolate lower motor neurons from post-mortem spinal cords of ALS and control (CTL) subjects. Differentially expressed genes (DEGs) with consistent ALS versus CTL expression differences across studies were identified.

RESULTS: The analysis identified 222 ALS-increased DEGs (FDR <0.10, SMD >0.80) and 278 ALS-decreased DEGs (FDR <0.10, SMD < -0.80). ALS-increased DEGs were linked to PI3K-AKT signaling, innate immunity, inflammation, motor neuron differentiation and extracellular matrix. ALS-decreased DEGs were associated with the ubiquitin-proteosome system, microtubules, axon growth, RNA-binding proteins and synaptic membrane. ALS-decreased DEG mRNAs frequently interacted with RNA-binding proteins (e.g., FUS, HuR). The complete set of DEGs (increased and decreased) overlapped significantly with genes near ALS-associated SNP loci (p < 0.01). Transcription factor target motifs with increased proximity to ALS-increased DEGs were identified, most notably DNA elements predicted to interact with forkhead transcription factors (e.g., FOXP1) and motor neuron and pancreas homeobox 1 (MNX1). Some of these DNA elements overlie ALS-associated SNPs within known enhancers and are predicted to have genotype-dependent MNX1 interactions. DEGs were compared to those identified from SOD1-G93A mice and bulk spinal cord segments or iPSC-MNs from ALS patients. There was good correspondence with transcriptome changes from SOD1-G93A mice (r ≤ 0.408) but most DEGs were not differentially expressed in bulk spinal cords or iPSC-MNs and transcriptome-wide effect size correlations were weak (bulk tissue: r ≤ 0.207, iPSC-MN: r ≤ 0.037).

CONCLUSION: This study defines a robust transcriptome signature from LCM-based motor neuron studies of post-mortem tissue from ALS and CTL subjects. This signature differs from those obtained from analysis of bulk spinal cord segments and iPSC-MNs. Results provide insight into mechanisms underlying gene dysregulation in ALS and highlight connections between these mechanisms, ALS genetics, and motor neuron biology.}, } @article {pmid38691665, year = {2024}, author = {Singh, P and Belliveau, P and Towle, J and Neculau, AE and Dima, L}, title = {Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis.}, journal = {American journal of therapeutics}, volume = {31}, number = {3}, pages = {e258-e267}, doi = {10.1097/MJT.0000000000001742}, pmid = {38691665}, issn = {1536-3686}, mesh = {*Edaravone/administration & dosage/pharmacology/therapeutic use ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neuroprotective Agents/administration & dosage/therapeutic use/adverse effects ; Administration, Oral ; Suspensions ; Biological Availability ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone.

MECHANISM OF ACTION: The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals.

PHARMACOKINETICS: Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5-9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates.

CLINICAL TRIALS: The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure.

THERAPEUTIC ADVANCE: Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting.}, } @article {pmid38692734, year = {2024}, author = {van Tartwijk, FW and Wunderlich, LCS and Mela, I and Makarchuk, S and Jakobs, MAH and Qamar, S and Franze, K and Kaminski Schierle, GS and St George-Hyslop, PH and Lin, JQ and Holt, CE and Kaminski, CF}, title = {Mutation of the ALS-/FTD-Associated RNA-Binding Protein FUS Affects Axonal Development.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {44}, number = {27}, pages = {}, pmid = {38692734}, issn = {1529-2401}, support = {772426/ERC_/European Research Council/International ; MR/K015850/1/MRC_/Medical Research Council/United Kingdom ; 109145/WT_/Wellcome Trust/United Kingdom ; MR/K02292X/1/MRC_/Medical Research Council/United Kingdom ; 215943/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*RNA-Binding Protein FUS/genetics/metabolism ; *Axons/pathology/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *Mutation ; Female ; Male ; Xenopus laevis ; Growth Cones/metabolism ; Humans ; Disease Models, Animal ; }, abstract = {Aberrant condensation and localization of the RNA-binding protein (RBP) fused in sarcoma (FUS) occur in variants of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Changes in RBP function are commonly associated with changes in axonal cytoskeletal organization and branching in neurodevelopmental disorders. Here, we asked whether branching defects also occur in vivo in a model of FUS-associated disease. We use two reported Xenopus models of ALS/FTD (of either sex), the ALS-associated mutant FUS(P525L) and a mimic of hypomethylated FUS, FUS(16R). Both mutants strongly reduced axonal complexity in vivo. We also observed an axon looping defect for FUS(P525L) in the target area, which presumably arises due to errors in stop cue signaling. To assess whether the loss of axon complexity also had a cue-independent component, we assessed axonal cytoskeletal integrity in vitro. Using a novel combination of fluorescence and atomic force microscopy, we found that mutant FUS reduced actin density in the growth cone, altering its mechanical properties. Therefore, FUS mutants may induce defects during early axonal development.}, } @article {pmid38694349, year = {2024}, author = {Amjadi, N and Mohammadi, S and Paybast, S and Dadkhah, P and Talayeh, M and Asemi, Z}, title = {A pregnant woman with amyotrophic lateral sclerosis from Iran: a case report.}, journal = {Annals of medicine and surgery (2012)}, volume = {86}, number = {5}, pages = {3013-3015}, pmid = {38694349}, issn = {2049-0801}, abstract = {INTRODUCTION AND IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, which is extremely rare during pregnancy. The severity of the disease affects the pregnancy outcome. The present study reports the first Iranian case of a woman with ALS overlapping pregnancy.

CASE PRESENTATION: The 27-year-old lady in her second pregnancy was admitted to the emergency department with labor pain at the 37th gestation week. Following a multidisciplinary team meeting, including a neurologist, maternal-fetal medicine specialist, and anesthesiologist, a decision was made for an emergent cesarean section under spinal anesthesia. The delivery was successful without any maternal or fetal complications. A 5-month follow-up revealed the stable neurologic status of the mother.

CLINICAL DISCUSSION: The combination of ALS and pregnancy is very rare because the disease is more common in elderly men. ALS management involves a multidisciplinary approach. Riluzole is a drug that can increase the survival of the patients. ALS does not affect on motor and sensory nerves of the uterus, so vaginal delivery might be possible. The main cause of cesarean section in patients with ALS is respiratory compromise, but four patients with uncomplicated vaginal deliveries have been reported. The neonatal outcome of most cases resulted in normal healthy infants.

CONCLUSION: Management of ALS in pregnancy is challenging because of respiratory concerns, so multidisciplinary team management is important.}, } @article {pmid38694387, year = {2024}, author = {Arora, H and Javed, B and Kutikuppala, LVS and Chaurasia, M and Khullar, K and Kannan, S and Golla, V}, title = {ST2 levels and neurodegenerative diseases: is this a significant relation?.}, journal = {Annals of medicine and surgery (2012)}, volume = {86}, number = {5}, pages = {2812-2817}, pmid = {38694387}, issn = {2049-0801}, abstract = {Interleukin-33 (IL-33), belonging to the interleukin-1 cytokine family, has a decoy receptor soluble ST2 (sST2). IL-33 is found in oligodendrocytes and astrocytes and is involved in central nervous system healing and repair, whereas ST2 is found in microglia and astrocytes. Some studies have found a link between changes in the IL-33/ST2 pathway and neurodegenerative disorders. This review article investigates the relationship between the interleukin-33 (IL-33)/ST2 pathway and neurodegenerative disorders. It was discovered that soluble st2 levels were increased. Furthermore, IL-33 levels were found to be lower in many neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis (ALS). The association with other disorders, such as ankylosing spondylitis, multiple sclerosis, and systemic lupus erythematosus (SLE), was also observed. Various studies suggest that ST2/IL-33 signalling may be pivotal in the disease modulation of neurodegenerative disorders. The serum sST2 level test can be useful in determining the inflammatory status and severity of illness in many neurodegenerative disorders. In this review, we will discuss recent findings concerning the interleukin-33 (IL-33)/ST2 pathway and its role in the diagnosis and treatment of diseases with neurodegeneration.}, } @article {pmid38695638, year = {2024}, author = {Fullam, T and Hunt, SL and Han, M and Denesia, J and Chandrashekhar, S and Jawdat, O and Piccione, E and Fernandes, JA and Statland, J}, title = {Outcomes after intervention for enteral nutrition in patients with amyotrophic lateral sclerosis in multidisciplinary clinics.}, journal = {Muscle & nerve}, volume = {70}, number = {1}, pages = {94-100}, pmid = {38695638}, issn = {1097-4598}, support = {UL1 TR002366/TR/NCATS NIH HHS/United States ; 10.13039/100000002/NH/NIH HHS/United States ; 10.13039/100000002/NH/NIH HHS/United States ; 10.13039/100005202//Muscular Dystrophy Association/ ; //FSHD Society/ ; //Friends of FSH Research/ ; //and FSHD Canada/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; Male ; Female ; *Enteral Nutrition/methods ; Aged ; Retrospective Studies ; Middle Aged ; *Gastrostomy ; Treatment Outcome ; Malnutrition/etiology/therapy ; Vital Capacity/physiology ; }, abstract = {INTRODUCTION/AIMS: Patients with amyotrophic lateral sclerosis (ALS) are susceptible to malnutrition, with appropriate management of nutritional interventions an active area of investigation. We sought to determine the impact of gastrostomy tube placement in ALS patients, exploring the correlation between forced vital capacity (FVC), malnutrition, and perioperative complications.

METHODS: A retrospective review was performed of clinically diagnosed ALS patients treated at two multidisciplinary clinics (University of Kansas, University of Nebraska) from January 2009 to September 2020 who were referred for gastrostomy. Data collected included demographics, disease characteristics, and key gastrostomy related dates/outcomes.

RESULTS: Two hundred thirty-nine patients were included with a median age of 65 years and median of 589 days from symptom onset to gastrostomy (interquartile range, 404-943). The population was predominantly Non-Hispanic White with bulbar-onset ALS. 30-day mortality was 4% and 30-day morbidity was 13%. Weight loss, body mass index, and predicted FVC at placement showed no increased 30-day morbidity or mortality association. Bulbar-onset ALS patients exhibited higher overall mortality postplacement than limb onset (odds ratio: 1.85, 95% confidence interval: 1.03-3.33). There was a 5% incidence of symptoms suggestive of refeeding syndrome.

DISCUSSION: Rates of major/minor complications and 30-day mortality related to gastrostomy placement in our population were similar compared with prior studies in ALS. The lack of difference in outcomes based on FVC at procedure may suggest this is not predictive of outcome, or perhaps, high-quality perioperative respiratory management. Alternative reasons may account for the increased morbidity and mortality of gastrostomy placement in the ALS population.}, } @article {pmid38695966, year = {2024}, author = {Mendes Ferreira, V and Caetano, A and Santos, L and Fernandes, M}, title = {FIG4-associated disease manifesting as rapidly progressive amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {9}, pages = {4609-4610}, pmid = {38695966}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; Flavoproteins/genetics ; Male ; Middle Aged ; Female ; Phosphoric Monoester Hydrolases ; }, } @article {pmid38696153, year = {2024}, author = {Chugunov, DA and Shmilovich, AA and Larina, MR and Goncharenko, SN and Moiseeva, TV and Ryauzova, ES and Fedorova, EV and Bukinich, AA}, title = {[Clinical and psychometric characteristics of cognitive and negative disorders in schizophrenia].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {4. Vyp. 2}, pages = {64-71}, doi = {10.17116/jnevro202412404264}, pmid = {38696153}, issn = {1997-7298}, mesh = {Humans ; Male ; Female ; Adult ; *Schizophrenia/diagnosis/complications ; *Psychometrics ; Middle Aged ; *Schizophrenic Psychology ; Cognition ; Neuropsychological Tests ; Cognition Disorders/diagnosis/etiology ; }, abstract = {OBJECTIVE: To establish the characteristics of clinical manifestations and cognitive tests in patients with schizophrenia, with a predominance of cognitive and negative disorders.

MATERIAL AND METHODS: We examined 76 patients, 66 in the main group, 10 in the comparison group, who were treated in Psychiatric Hospital No. 1 and Psychiatric Hospital No. 4 (Moscow). Clinical-psychopathological, psychometric and statistical methods were used. Features of cognitive functioning were studied using the Frontal Assessment Battery (FAB) and the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis (ALS) Screen (ECAS). Emotional intelligence scores were assessed using the Ekman Face Emotion Recognition (EFER) test.

RESULTS: Patients with schizophrenia showed dominance of one of 3 types of deficit symptoms: cognitive, emotional, and volitional. Cognitive functions were significantly reduced in patients with schizophrenia when compared with the comparison group (mean FAB score (M±SD) 13.44±2.97 in patients with schizophrenia vs. 16.10±1.70 in the comparison group; t=4.10; p<0.001). Cognitive functions were particularly reduced in patients with volitional deficit (mean EFER total score 42.40±9.0 in patients with volitional deficit vs. 47.21±633 in patients with cognitive deficit; t=2.12; p=0.039; mean FAB score 12.83±3.29 in patients with volitional deficit vs. 16.10±1.70 in the comparison group; t=4.24; p<0.001; mean ECAS score specific to ALS 78.80±9.07 in patients with volitional deficit vs. 84.50±6.71 in the comparison group; t=2.18; p=0.034).

CONCLUSION: The greatest contribution to the development of cognitive disorders in schizophrenia is made by dysfunction of frontal (especially) and temporal cortex. Executive functions, speech skills and verbal fluency are most severely damaged.}, } @article {pmid38696744, year = {2024}, author = {}, title = {Variation in Resting Metabolic Rate Affects Identification of Metabolic Change in Geographically Distinct Cohorts of Patients With ALS.}, journal = {Neurology}, volume = {102}, number = {10}, pages = {e209407}, doi = {10.1212/WNL.0000000000209407}, pmid = {38696744}, issn = {1526-632X}, } @article {pmid38697002, year = {2024}, author = {Su, T and Gan, Y and Ma, S and Wu, H and Lu, S and Zhi, M and Wang, B and Lu, Y and Yao, J}, title = {Graves' disease and the risk of five autoimmune diseases: A Mendelian randomization and colocalization study.}, journal = {Diabetes & metabolic syndrome}, volume = {18}, number = {5}, pages = {103023}, doi = {10.1016/j.dsx.2024.103023}, pmid = {38697002}, issn = {1878-0334}, mesh = {Humans ; *Graves Disease/genetics/epidemiology ; *Mendelian Randomization Analysis ; *Autoimmune Diseases/genetics/epidemiology ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Prognosis ; Risk Factors ; Crohn Disease/genetics/epidemiology ; Follow-Up Studies ; Lupus Erythematosus, Systemic/genetics/epidemiology ; Arthritis, Rheumatoid/genetics/epidemiology ; }, abstract = {BACKGROUND: Epidemiological studies have consistently demonstrated a high prevalence of concurrent autoimmune diseases in individuals with Graves' disease (GD).

OBJECTIVE: The objective of this study is to establish a causal association between GD and autoimmune diseases.

METHODS: We employed a two-sample Mendelian randomization (MR) to infer a causal association between GD and five autoimmune diseases, namely rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Crohn's disease (CD), ulcerative colitis (UC), and amyotrophic lateral sclerosis (ALS), in the East Asian and European population. Genetic correlations were explored through linkage disequilibrium score regression analysis (LDSC). Finally, colocalization analyses were performed to investigate possible genetic foundations.

RESULTS: Bidirectional MR analysis indicated that genetically predicted GD increased the risk of RA (Odds Ratio (OR): 1.34, 95 % Confidence Interval (CI): 1.21 to 1.47, P < 0.001) and SLE (OR: 1.21, 95%CI: 1.08 to 1.35, P < 0.001) in the East Asian population. In contrast, we found that genetically predicted RA (OR: 1.14, 95%CI: 1.05 to 1.24, P = 0.002) and SLE (OR: 1.10, 95%CI: 1.03 to 1.17, P = 0.003) were associated with a higher risk of GD. The results have been partially validated in European cohorts. Colocalization analysis suggested the potential existence of shared causal variants between GD and other autoimmune diseases. In particular, gene ARID5B may play an important role in the incidence of autoimmune diseases.

CONCLUSION: This study has confirmed that GD was associated with RA and SLE and found a possible key gene ARID5B. It may be necessary to strengthen detection to prevent the occurrence of comorbidities in clinical practice.}, } @article {pmid38697285, year = {2024}, author = {Tuerxun, K and Tang, RH and Abudoumijiti, A and Yusupu, Z and Aikebaier, A and Mijiti, S and Ibrahim, I and Cao, YL and Yasheng, A and Wu, YQ}, title = {Comparative proteomics analysis of samples from hepatic cystic echinococcosis patients using data-independent acquisition approach.}, journal = {Journal of proteomics}, volume = {301}, number = {}, pages = {105191}, doi = {10.1016/j.jprot.2024.105191}, pmid = {38697285}, issn = {1876-7737}, mesh = {*Proteomics/methods ; Humans ; *Echinococcus granulosus/metabolism ; Animals ; Helminth Proteins/metabolism/analysis ; Echinococcosis, Hepatic/metabolism/parasitology ; Proteome/analysis/metabolism ; }, abstract = {Cystic echinococcosis is a zoonotic disease resulting from infection caused by the larval stage of Echinococcus granulosus. This study aimed to assess the specific proteins that are potential candidates for the development of a vaccine against E. granulosus. The data-independent acquisition approach was employed to identify differentially expressed proteins (DEPs) in E. granulosus samples. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was employed to identify several noteworthy proteins. Results: The DEPs in E. granulosus samples were identified (245 pericystic wall vs. parasite-free yellowish granuloma (PYG, 1725 PY vs. PYG, 2274 PN vs. PYG). Further examination of these distinct proteins revealed their predominant enrichment in metabolic pathways, amyotrophic lateral sclerosis, and neurodegeneration-associated pathways. Notably, among these DEPs, SH3BGRL, MST1, TAGLN2, FABP5, UBE2V2, and RARRES2 exhibited significantly higher expression levels in the PYG group compared with the PY group (P < 0.05). The findings may contribute to the understanding of the pathological mechanisms underlying echinococcosis, providing valuable insights into the development of more effective diagnostic tools, treatment modalities, and preventive strategies. SIGNIFICANCE: CE is a major public health hazard in the western regions of China, Central Asia, South America, the Mediterranean countries, and eastern Africa. Echinococcus granulosus is responsible for zoonotic disease through infection Our analysis focuses on the proteins in various samples by data-dependent acquisition (DIA) for proteomic analysis. The importance of this research is to develop new strategies and targets to protect against E. granulosus infections in humans.}, } @article {pmid38697975, year = {2024}, author = {Tsitkov, S and Valentine, K and Kozareva, V and Donde, A and Frank, A and Lei, S and , and E Van Eyk, J and Finkbeiner, S and Rothstein, JD and Thompson, LM and Sareen, D and Svendsen, CN and Fraenkel, E}, title = {Disease related changes in ATAC-seq of iPSC-derived motor neuron lines from ALS patients and controls.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {3606}, pmid = {38697975}, issn = {2041-1723}, support = {RF1 AG057331/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; Male ; Female ; Middle Aged ; Case-Control Studies ; Chromatin/metabolism/genetics ; Aged ; Epigenomics/methods ; Chromatin Immunoprecipitation Sequencing/methods ; Disease Progression ; Epigenesis, Genetic ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing. Once these covariates are corrected for, we are able to identify ALS-specific signals in the data. Additionally, we find that the ATAC-seq data is able to predict ALS disease progression rates with similar accuracy to methods based on biomarkers and clinical status. These results suggest that iPSC-derived motor neurons recapitulate important disease-relevant epigenomic changes.}, } @article {pmid38700207, year = {2024}, author = {Keeley, O and Coyne, AN}, title = {Nuclear and degradative functions of the ESCRT-III pathway: implications for neurodegenerative disease.}, journal = {Nucleus (Austin, Tex.)}, volume = {15}, number = {1}, pages = {2349085}, pmid = {38700207}, issn = {1949-1042}, support = {R00 NS123242/NS/NINDS NIH HHS/United States ; R01 NS132836/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Endosomal Sorting Complexes Required for Transport/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Animals ; Cell Nucleus/metabolism ; Frontotemporal Dementia/metabolism/pathology/genetics ; Endosomes/metabolism ; }, abstract = {The ESCRT machinery plays a pivotal role in membrane-remodeling events across multiple cellular processes including nuclear envelope repair and reformation, nuclear pore complex surveillance, endolysosomal trafficking, and neuronal pruning. Alterations in ESCRT-III functionality have been associated with neurodegenerative diseases including Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's Disease (AD). In addition, mutations in specific ESCRT-III proteins have been identified in FTD/ALS. Thus, understanding how disruptions in the fundamental functions of this pathway and its individual protein components in the human central nervous system (CNS) may offer valuable insights into mechanisms underlying neurodegenerative disease pathogenesis and identification of potential therapeutic targets. In this review, we discuss ESCRT components, dynamics, and functions, with a focus on the ESCRT-III pathway. In addition, we explore the implications of altered ESCRT-III function for neurodegeneration with a primary emphasis on nuclear surveillance and endolysosomal trafficking within the CNS.}, } @article {pmid38702287, year = {2024}, author = {Tazir, M and Nouioua, S}, title = {Distal hereditary motor neuropathies.}, journal = {Revue neurologique}, volume = {180}, number = {10}, pages = {1031-1036}, doi = {10.1016/j.neurol.2023.09.005}, pmid = {38702287}, issn = {0035-3787}, mesh = {Humans ; *Hereditary Sensory and Motor Neuropathy/genetics/diagnosis/physiopathology ; Mutation ; Charcot-Marie-Tooth Disease/genetics/diagnosis/physiopathology/epidemiology ; }, abstract = {Distal hereditary motor neuropathies (dHMN) are a group of heterogeneous hereditary disorders characterized by a slowly progressive distal pure motor neuropathy. Electrophysiology, with normal motor and sensory conduction velocities, can suggest the diagnosis of dHMN and guide the genetic study. More than thirty genes are currently associated with HMNs, but around 60 to 70% of cases of dHMN remain uncharacterized genetically. Recent cohort studies showed that HSPB1, GARS, BICB2 and DNAJB2 are among the most frequent dHMN genes and that the prevalence of the disease was calculated as 2.14 and 2.3 per 100,000. The determination of the different genes involved in dHMNs made it possible to observe a genotypic overlap with some other neurogenetic disorders and other hereditary neuropathies such as CMT2, mainly with the HSPB1, HSPB8, BICD2 and TRPV4 genes of AD-inherited transmission and recently observed with SORD gene of AR transmission which seems relatively frequent and potentially curable. Distal hereditary motor neuropathy that predominates in the upper limbs is linked mainly to three genes: GARS, BSCL2 and REEP1, whereas dHMN with vocal cord palsy is associated with SLC5A7, DCTN1 and TRPV4 genes. Among the rare AR forms of dHMN like IGHMBP2 and DNAJB2, the SIGMAR1 gene mutations as well as VRK1 variants are associated with a motor neuropathy phenotype often associated with upper motoneuron involvement. The differential diagnosis of these latter arises with juvenile forms of amyotrophic lateral sclerosis, that could be caused also by variations of these genes, as well as hereditary spastic paraplegia. A differential diagnosis of dHMN related to Brown Vialetto Van Laere syndrome due to riboflavin transporter deficiency is important to consider because of the therapeutic possibility.}, } @article {pmid38703371, year = {2024}, author = {Thumbadoo, KM and Dieriks, BV and Murray, HC and Swanson, MEV and Yoo, JH and Mehrabi, NF and Turner, C and Dragunow, M and Faull, RLM and Curtis, MA and Siddique, T and Shaw, CE and Newell, KL and Henden, L and Williams, KL and Nicholson, GA and Scotter, EL}, title = {Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {10}, pages = {3547-3561}, pmid = {38703371}, issn = {1460-2156}, support = {//Amelia Pais-Rodriguez and Marcus Gerbich/ ; 16420//Michael J Fox Foundation/ ; //Health Research Council Sir Charles Hercus Health Research Fellowship/ ; //Marsden FastStart and Rutherford Discovery Fellowship/ ; 15-UOA-157//Royal Society of New Zealand/ ; //Alzheimer's Disease Research and Education/ ; //Sir Thomas and Lady Duncan Trust/ ; //Coker Family Trust/ ; 2011120//National Health and Medical Research Council of Australia/ ; //Neuron Disease NZ/ ; //Freemasons Foundation of New Zealand/ ; //Matteo de Nora/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Humans ; *Autophagy-Related Proteins/genetics/metabolism ; *Hippocampus/pathology/metabolism ; Male ; *Adaptor Proteins, Signal Transducing/genetics/metabolism ; Middle Aged ; Female ; Aged ; DNA-Binding Proteins/genetics/metabolism ; Adult ; C9orf72 Protein/genetics ; Cell Cycle Proteins/genetics/metabolism ; }, abstract = {Pathogenic variants in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterized by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial amyotrophic lateral sclerosis and/or frontotemporal dementia cases not caused by UBQLN2 pathogenic variants, particularly C9orf72-linked cases. This makes the mechanistic role of mutant ubiquilin 2 protein and the value of ubiquilin 2 pathology for predicting genotype unclear. Here we examine a cohort of 44 genotypically diverse amyotrophic lateral sclerosis cases with or without frontotemporal dementia, including eight cases with UBQLN2 variants [resulting in p.S222G, p.P497H, p.P506S, p.T487I (two cases) and p.P497L (three cases)]. Using multiplexed (five-label) fluorescent immunohistochemistry, we mapped the co-localization of ubiquilin 2 with phosphorylated TDP-43, dipeptide repeat aggregates and p62 in the hippocampus of controls (n = 6), or amyotrophic lateral sclerosis with or without frontotemporal dementia in sporadic (n = 20), unknown familial (n = 3), SOD1-linked (n = 1), FUS-linked (n = 1), C9orf72-linked (n = 5) and UBQLN2-linked (n = 8) cases. We differentiate between (i) ubiquilin 2 aggregation together with phosphorylated TDP-43 or dipeptide repeat proteins; and (ii) ubiquilin 2 self-aggregation promoted by UBQLN2 pathogenic variants that cause amyotrophic lateral sclerosis and/or frontotemporal dementia. Overall, we describe a hippocampal protein aggregation signature that fully distinguishes mutant from wild-type ubiquilin 2 in amyotrophic lateral sclerosis with or without frontotemporal dementia, whereby mutant ubiquilin 2 is more prone than wild-type to aggregate independently of driving factors. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2-linked disease.}, } @article {pmid38703513, year = {2024}, author = {El Khalfi, R and Maupoint, E and Chiavassa-Gandois, H and Goumarre, C and Filliole, A and Lapègue, F and Fabry, V and Acket, B and Laforet, A and Sans, N and Cintas, P and Faruch-Bilfeld, M}, title = {Assessment of whole-body muscle MRI for the early diagnosis of Amyotrophic Lateral Sclerosis.}, journal = {European journal of radiology}, volume = {176}, number = {}, pages = {111481}, doi = {10.1016/j.ejrad.2024.111481}, pmid = {38703513}, issn = {1872-7727}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Male ; Female ; Middle Aged ; *Whole Body Imaging/methods ; *Muscle, Skeletal/diagnostic imaging/pathology ; *Sensitivity and Specificity ; *Early Diagnosis ; *Magnetic Resonance Imaging/methods ; Reproducibility of Results ; Adult ; Aged ; }, abstract = {OBJECTIVES: To evaluate muscle signal abnormalities on whole-body muscle MRI with T2 and diffusion-weighted imaging in early ALS stages.

METHODS: 101 muscles were analyzed in newly diagnosed ALS patients and healthy controls on a whole-body MRI protocol including four-point T2-Dixon imaging and diffusion-weighted imaging (b0 and b800). Sensitivity and inter-observer agreement were assessed.

RESULTS: 15 patients (mean age, 64 +/- 12 [SD], 9 men) who met the Awaji-Shima criteria for definite, probable or possible ALS and 9 healthy controls were assessed (mean age, 53 +/- 13 [SD], 2 men). 61 % of the muscles assessed in ALS patients (62/101) showed signal hyperintensities on T2-weighted imaging, mainly in the upper and lower extremities (legs, hands and feet). ALS patients had a significantly higher number of involved muscles compared to healthy controls (p = 0,006). Diffusion-weighted imaging allowed for the detection of additional involvement in 22 muscles, thus improving the sensitivity of whole-body MRI from 60 % (using T2-weighted imaging only) up to 80 % (with the combination of T2-weighted and diffusion-weighted imaging).

CONCLUSIONS: ALS patients exhibited significant muscle signal abnormalities on T2-weighted and diffusion-weighted imaging in early disease stages. Whole-body MRI could be used for pre-EMG mapping of muscle involvement in order to choose suitable targets, thus improving early diagnosis.}, } @article {pmid38703699, year = {2024}, author = {Grapperon, AM and Harlay, V and Boucekine, M and Devos, D and Rolland, AS and Desnuelle, C and Delmont, E and Verschueren, A and Attarian, S}, title = {Could the motor unit number index be an early prognostic biomarker for amyotrophic lateral sclerosis?.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {163}, number = {}, pages = {47-55}, doi = {10.1016/j.clinph.2024.04.013}, pmid = {38703699}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/diagnosis ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; *Motor Neurons/physiology ; Prognosis ; *Disease Progression ; Biomarkers ; Adult ; Electromyography ; }, abstract = {OBJECTIVE: To evaluate the associations between motor unit number index (MUNIX) and disease progression and prognosis in amyotrophic lateral sclerosis (ALS) in a large-scale longitudinal study.

METHODS: MUNIX was performed at the patient's first visit, at 3, 6, and 12 months in 4 muscles. MUNIX data from the patients were compared with those from 38 age-matched healthy controls. Clinical data included the revised ALS functional rating scale (ALSFRS-R), the forced vital capacity (FVC), and the survival of the patients.

RESULTS: Eighty-two patients were included at baseline, 62 were evaluated at three months, 48 at six months, and 33 at twelve months. MUNIX score was lower in ALS patients compared to controls. At baseline, MUNIX was correlated with ALSFRS-R and FVC. Motor unit size index (MUSIX) was correlated with patient survival. Longitudinal analyses showed that MUNIX decline was greater than ALSFRS-R decline at each evaluation. A baseline MUNIX score greater than 378 predicted survival over the 12-month period with a sensitivity of 82% and a specificity of 56%.

CONCLUSIONS: This longitudinal study suggests that MUNIX could be an early quantitative marker of disease progression and prognosis in ALS.

SIGNIFICANCE: MUNIX might be considered as potential indicator for monitoring disease progression.}, } @article {pmid38703766, year = {2024}, author = {Alfahel, L and Gschwendtberger, T and Kozareva, V and Dumas, L and Gibbs, R and Kertser, A and Baruch, K and Zaccai, S and Kahn, J and Thau-Habermann, N and Eggenschwiler, R and Sterneckert, J and Hermann, A and Sundararaman, N and Vaibhav, V and Van Eyk, JE and Rafuse, VF and Fraenkel, E and Cantz, T and Petri, S and Israelson, A}, title = {Targeting low levels of MIF expression as a potential therapeutic strategy for ALS.}, journal = {Cell reports. Medicine}, volume = {5}, number = {5}, pages = {101546}, pmid = {38703766}, issn = {2666-3791}, mesh = {*Macrophage Migration-Inhibitory Factors/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology ; Animals ; Humans ; *Motor Neurons/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Induced Pluripotent Stem Cells/metabolism ; Intramolecular Oxidoreductases/metabolism/genetics ; Mice, Transgenic ; Dependovirus/genetics ; Disease Models, Animal ; Male ; Mutation/genetics ; Female ; Protein Folding ; }, abstract = {Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neuron (MN) loss. We previously discovered that macrophage migration inhibitory factor (MIF), whose levels are extremely low in spinal MNs, inhibits mutant SOD1 misfolding and toxicity. In this study, we show that a single peripheral injection of adeno-associated virus (AAV) delivering MIF into adult SOD1[G37R] mice significantly improves their motor function, delays disease progression, and extends survival. Moreover, MIF treatment reduces neuroinflammation and misfolded SOD1 accumulation, rescues MNs, and corrects dysregulated pathways as observed by proteomics and transcriptomics. Furthermore, we reveal low MIF levels in human induced pluripotent stem cell-derived MNs from familial ALS patients with different genetic mutations, as well as in post mortem tissues of sporadic ALS patients. Our findings indicate that peripheral MIF administration may provide a potential therapeutic mechanism for modulating misfolded SOD1 in vivo and disease outcome in ALS patients.}, } @article {pmid38705104, year = {2024}, author = {Dharmadasa, T and Pavey, N and Tu, S and Menon, P and Huynh, W and Mahoney, CJ and Timmins, HC and Higashihara, M and van den Bos, M and Shibuya, K and Kuwabara, S and Grosskreutz, J and Kiernan, MC and Vucic, S}, title = {Novel approaches to assessing upper motor neuron dysfunction in motor neuron disease/amyotrophic lateral sclerosis: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {163}, number = {}, pages = {68-89}, doi = {10.1016/j.clinph.2024.04.010}, pmid = {38705104}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Transcranial Magnetic Stimulation/methods ; *Motor Neuron Disease/physiopathology/diagnosis ; *Motor Neurons/physiology ; Evoked Potentials, Motor/physiology ; Motor Cortex/physiopathology/diagnostic imaging ; }, abstract = {Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility.}, } @article {pmid38705318, year = {2024}, author = {Mororó, MCC and Mahnke, LC and Assis, CRD and da Silva, RA and Cabrera, MP and Bezerra, RP and Carvalho Júnior, LB and Alves, MHME}, title = {Acetylcholinesterase purification from human erythrocytes using magnetic nanoparticles containing procainamide.}, journal = {International journal of biological macromolecules}, volume = {269}, number = {Pt 1}, pages = {132094}, doi = {10.1016/j.ijbiomac.2024.132094}, pmid = {38705318}, issn = {1879-0003}, mesh = {Humans ; *Acetylcholinesterase/chemistry/metabolism/isolation & purification ; *Erythrocytes/enzymology ; *Magnetite Nanoparticles/chemistry ; *Procainamide/chemistry ; Aniline Compounds/chemistry ; }, abstract = {This work presents a magnetic purification method of human erythrocyte Acetylcholinesterase (EC 3.1.1.7; AChE) based on affinity binding to procainamide (Proca) as ligand. Acetylcholinesterase is an acetylcholine-regulating enzyme found in different areas of the body and associated with various neurological disorders, such as Parkinson, Alzheymer and Amyotrophic Lateral Sclerosis. AChE from human erythrocyte purification has been attempted in recent years with low degree of purity. Here, magnetic nanoparticles (MNP) were synthesized and coated with polyaniline (PANI) and procainamide (PROCA) was covalently linked to the PANI. The extracted human erythrocyte AChE formed a complex with the MNP@PANI-PROCA and an external magnet separated it from the undesired proteins. Finally, the enzyme was collected by increasing the ionic strength. Experimental Box-Behnken design was developed to optimize this process of human erythrocyte AChE purification protocol. The enzyme was purified in all fifteen experiments. However, the best AChE purification result was achieved, about 2000 times purified, when 100 mg of MNP@PANI-PROCA was incubated for one hour with 4 ml hemolysate extract. The SDS-PAGE of this preparation presented a molecular weight of approximately 70 kDa, corroborating with few previous studies of AChE from erythrocyte purification.}, } @article {pmid38705786, year = {2024}, author = {Ishikawa, A and Takeda, T and Kokubun, S and Saito, Y and Isose, S and Ito, K and Arai, K and Sugiyama, A and Kuwabara, S and Honda, K}, title = {Putaminal hypointensity on T2-weighted MRI mimicking multiple system atrophy in amyotrophic lateral sclerosis: An autopsy case report.}, journal = {Journal of the neurological sciences}, volume = {460}, number = {}, pages = {123025}, doi = {10.1016/j.jns.2024.123025}, pmid = {38705786}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Multiple System Atrophy/diagnostic imaging/pathology ; *Magnetic Resonance Imaging ; *Autopsy ; Putamen/diagnostic imaging/pathology ; Male ; Diagnosis, Differential ; Middle Aged ; Aged ; Female ; }, } @article {pmid38705796, year = {2024}, author = {Grangeon, L and Wallon, D and Bourre, B and Guillaume, M and Guegan-Massardier, E and Guyant-Marechal, L and Liard, A and Sibert, L and Maltete, D}, title = {Development of an Objective Structured Clinical Examination (OSCE) to evaluate the diagnosis announcement of chronic neurological disease by residents in neurology.}, journal = {Revue neurologique}, volume = {180}, number = {7}, pages = {655-660}, doi = {10.1016/j.neurol.2024.02.390}, pmid = {38705796}, issn = {0035-3787}, mesh = {Humans ; *Neurology/standards/education ; *Internship and Residency/standards ; *Nervous System Diseases/diagnosis ; *Educational Measurement/methods ; Chronic Disease ; Male ; Female ; Adult ; Clinical Competence/standards ; Prospective Studies ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: There is little consensus on how to make a diagnosis announcement of severe chronic disease in neurology. Other medical specialties, such as oncology, have developed assessment methods similar to the Objective Structured Clinical Examination (OSCE) to address this issue. Here we report the implementation of an OSCE focused on the diagnosis announcement of chronic disease in neurology by residents.

OBJECTIVE: We aimed to evaluate the acceptability, feasibility and validity in routine practice of an OSCE combined with a theoretical course focused on diagnosis announcement in neurology.

METHOD: Eighteen neurology residents were prospectively included between 2019 and 2022. First, they answered a questionnaire on their previous level of training in diagnosis announcement. Second, in a practical session with a simulated patient, they made a 15-min diagnosis announcement and then had 5mins of immediate feedback with an expert observer, present in the room. The OSCE consisted of 4 different stations, with standardized scenarios dedicated to the announcement of multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Third, in a theory session, expert observers covered the essential theoretical points. All residents and expert observers completed an evaluation of the "practical session" and the "theory session".

RESULTS: Residents estimated their previous level of diagnosis announcement training at 3.1/5. The most feared announcements were AD and ALS. The "practical session" was rated at a mean of 4.1/5 by the residents and 4.8/5 by the expert observers, and the "theory session" at a mean of 4.7/5 by the residents and 5/5 by the expert observers. After the OSCEs, 11 residents felt more confident about making an announcement.

CONCLUSION: This study has shown a benefit of using an OSCE to learn how to make a diagnosis announcement of severe chronic disease in neurology. OSCEs could be used in many departments in routine practice and seem adapted to residents.}, } @article {pmid38706539, year = {2024}, author = {Rungan, S and Smith-Merry, J and Liu, HM and Drinkwater, A and Eastwood, J}, title = {School-Based Integrated Care Within Sydney Local Health District: A Qualitative Study About Partnerships Between the Education and Health Sectors.}, journal = {International journal of integrated care}, volume = {24}, number = {2}, pages = {13}, pmid = {38706539}, issn = {1568-4156}, abstract = {INTRODUCTION: The unmet physical and mental health needs of school-aged children (5-18 years) in New South Wales (NSW), stemming from poor access and engagement with healthcare, can be addressed by school-based integrated care (SBIC) models.This research aims to understand why and how partnerships between the health and education sector, in SBIC models, are important in providing care for children, and to identify the facilitating factors and barriers for implementation.

METHODS: A qualitative study was conducted using semi-structured interviews and thematic analysis. The principles of the 'Integrated People-Centred Health Service (IPCHS)' framework and Looman et al's (2021) implementation strategies for integrated care were considered.

RESULTS: Themes within IPCHS framework: Strategy 1: Engaging and empowering people and communities - community-driven models, improved access to healthcare, positive outcomes for children and families, 'connection', and service provision for marginalised populations; Strategy 2: Strengthening governance and accountability - system integration and developing evidence base; Strategy 3: Reorienting the model of care - shifting healthcare to schools reduces inequity and provides culturally safe practice; Strategy 4: Coordinating services within and across sectors - integrating care and stable workforce; Strategy 5: Creating an enabling environment: leadership, stakeholder commitment, and adequate resourcing.

DISCUSSION: Potential strategies for implementing SBIC models across NSW include community consultation and co-design; building multidisciplinary teams with new competencies and roles e.g. linkers and coordinators; collaborative and shared leadership; and alignment of operational systems while maintaining a balance between structure and flexibility.

CONCLUSION: SBIC models require high-level collaboration across sectors and with communities to provide a shift towards child and family centred care that improves engagement, access and outcomes in health delivery.}, } @article {pmid38706964, year = {2024}, author = {Edman, S and Horwath, O and Van der Stede, T and Blackwood, SJ and Moberg, I and Strömlind, H and Nordström, F and Ekblom, M and Katz, A and Apró, W and Moberg, M}, title = {Pro-Brain-Derived Neurotrophic Factor (BDNF), but Not Mature BDNF, Is Expressed in Human Skeletal Muscle: Implications for Exercise-Induced Neuroplasticity.}, journal = {Function (Oxford, England)}, volume = {5}, number = {3}, pages = {zqae005}, pmid = {38706964}, issn = {2633-8823}, mesh = {Adult ; Female ; Humans ; Male ; Young Adult ; *Brain-Derived Neurotrophic Factor/metabolism/blood ; *Exercise/physiology ; Lactic Acid/blood/metabolism ; *Muscle, Skeletal/metabolism ; *Neuronal Plasticity ; Protein Precursors/metabolism ; }, abstract = {Exercise promotes brain plasticity partly by stimulating increases in mature brain-derived neurotrophic factor (mBDNF), but the role of the pro-BDNF isoform in the regulation of BDNF metabolism in humans is unknown. We quantified the expression of pro-BDNF and mBDNF in human skeletal muscle and plasma at rest, after acute exercise (+/- lactate infusion), and after fasting. Pro-BDNF and mBDNF were analyzed with immunoblotting, enzyme-linked immunosorbent assay, immunohistochemistry, and quantitative polymerase chain reaction. Pro-BDNF was consistently and clearly detected in skeletal muscle (40-250 pg mg[-1] dry muscle), whereas mBDNF was not. All methods showed a 4-fold greater pro-BDNF expression in type I muscle fibers compared to type II fibers. Exercise resulted in elevated plasma levels of mBDNF (55%) and pro-BDNF (20%), as well as muscle levels of pro-BDNF (∼10%, all P < 0.05). Lactate infusion during exercise induced a significantly greater increase in plasma mBDNF (115%, P < 0.05) compared to control (saline infusion), with no effect on pro-BDNF levels in plasma or muscle. A 3-day fast resulted in a small increase in plasma pro-BDNF (∼10%, P < 0.05), with no effect on mBDNF. Pro-BDNF is highly expressed in human skeletal muscle, particularly in type I fibers, and is increased after exercise. While exercising with higher lactate augmented levels of plasma mBDNF, exercise-mediated increases in circulating mBDNF likely derive partly from release and cleavage of pro-BDNF from skeletal muscle, and partly from neural and other tissues. These findings have implications for preclinical and clinical work related to a wide range of neurological disorders such as Alzheimer's, clinical depression, and amyotrophic lateral sclerosis.}, } @article {pmid38708063, year = {2024}, author = {Maria, B and Massimo, G and Antonio, B and Giuseppe, S and Giovanna, BE}, title = {BerTime: A novel tool for supporting ALS algorithm application in clinical practice.}, journal = {Resuscitation plus}, volume = {18}, number = {}, pages = {100636}, pmid = {38708063}, issn = {2666-5204}, } @article {pmid38708921, year = {2024}, author = {Monteiro, KLC and Dos Santos Alcântara, MG and de Aquino, TM and da Silva-Júnior, EF}, title = {Insights on Natural Products Against Amyotrophic Lateral Sclerosis (ALS).}, journal = {Current neuropharmacology}, volume = {22}, number = {7}, pages = {1169-1188}, pmid = {38708921}, issn = {1875-6190}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Biological Products/therapeutic use/pharmacology ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Plants, Medicinal/chemistry ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes the death of motor neurons and consequent muscle paralysis. Despite many efforts to address it, current therapy targeting ALS remains limited, increasing the interest in complementary therapies. Over the years, several herbal preparations and medicinal plants have been studied to prevent and treat this disease, which has received remarkable attention due to their blood-brain barrier penetration properties and low toxicity. Thus, this review presents the therapeutic potential of a variety of medicinal herbs and their relationship with ALS and their physiopathological pathways.}, } @article {pmid38709037, year = {2024}, author = {Ketabforoush, A and Wang, M and Smith, CL and Arnold, WD and Nichols, NL}, title = {Assessing Rat Diaphragm Motor Unit Connectivity Outcome Measures as Quantitative Biomarkers of Phrenic Motor Neuron Degeneration and Compensation.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {206}, pages = {}, doi = {10.3791/66568}, pmid = {38709037}, issn = {1940-087X}, mesh = {Animals ; *Motor Neurons/pathology ; Rats ; *Phrenic Nerve ; *Diaphragm/innervation/physiopathology ; Biomarkers/analysis/metabolism ; Action Potentials/physiology ; Nerve Degeneration/pathology ; Rats, Sprague-Dawley ; }, abstract = {Loss of ventilatory muscle function is a consequence of motor neuron injury and neurodegeneration (e.g., cervical spinal cord injury and amyotrophic lateral sclerosis, respectively). Phrenic motor neurons are the final link between the central nervous system and muscle, and their respective motor units (groups of muscle fibers innervated by a single motor neuron) represent the smallest functional unit of the neuromuscular ventilatory system. Compound muscle action potential (CMAP), single motor unit potential (SMUP), and motor unit number estimation (MUNE) are established electrophysiological approaches that enable the longitudinal assessment of motor unit integrity in animal models over time but have mostly been applied to limb muscles. Therefore, the objectives of this study are to describe an approach in preclinical rodent studies that can be used longitudinally to quantify the phrenic MUNE, motor unit size (represented as SMUP), and CMAP, and then to demonstrate the utility of these approaches in a motor neuron loss model. Sensitive, objective, and translationally relevant biomarkers for neuronal injury, degeneration, and regeneration in motor neuron injury and diseases can significantly aid and accelerate experimental research discoveries to clinical testing.}, } @article {pmid38709603, year = {2024}, author = {Demaree, D and Brignone, J and Bromberg, M and Zhang, H}, title = {Preliminary Study on Effects of Neck Exoskeleton Structural Design in Patients With Amyotrophic Lateral Sclerosis.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {32}, number = {}, pages = {1841-1850}, doi = {10.1109/TNSRE.2024.3397584}, pmid = {38709603}, issn = {1558-0210}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; *Exoskeleton Device ; Female ; Middle Aged ; *Neck Muscles/physiopathology ; Biomechanical Phenomena ; Aged ; Electromyography ; Head Movements ; Neck/physiopathology ; Equipment Design ; Adult ; Muscle Weakness/physiopathology ; }, abstract = {Neck muscle weakness due to amyotrophic lateral sclerosis (ALS) can result in dropped head syndrome, adversely impacting the quality of life of those affected. Static neck collars are currently prescribed to hold the head in a fixed upright position. However, these braces are uncomfortable and do not allow any voluntary head-neck movements. By contrast, powered neck exoskeletons have the potential to enable head-neck movements. Our group has recently improved the mechanical structure of a state-of-the-art neck exoskeleton through a weighted optimization. To evaluate the effect of the structural changes, we conducted an experiment in which patients with ALS were asked to perform head-neck tracking tasks while using the two versions of the neck exoskeleton. We found that the neck muscle activation was significantly reduced when assisted by the structurally enhanced design compared to no assistance provided. The improved structure also improved kinematics tracking performance, allowing users to better achieve the desired head poses. In comparison, the previous design did not help reduce the muscle effort required to perform these tasks and even slightly worsened the kinematic tracking performance. It was also found that biomechanical benefits gained from using the structurally improved design were consistent across participants with both mild and severe neck weakness. Furthermore, we observed that participants preferred to use the powered neck exoskeletons to voluntarily move their heads and make eye contact during a conversation task rather than remain in a fixed upright position. Each of these findings highlights the importance of the structural design of neck exoskeletons in achieving desired biomechanical benefits and suggests that neck exoskeletons can be a viable method to improve the daily life of patients with ALS.}, } @article {pmid38711257, year = {2024}, author = {Horty, LG and Martin, T}, title = {Synthesis of Radiolabeled [[14]C]Rimsulfuron and Stable Isotope Labeled Rimsulfuron-[M + 3] to Support Crop Metabolism Studies for Reregistration.}, journal = {Journal of labelled compounds & radiopharmaceuticals}, volume = {67}, number = {7}, pages = {263-272}, doi = {10.1002/jlcr.4096}, pmid = {38711257}, issn = {1099-1344}, mesh = {*Carbon Radioisotopes/chemistry ; *Crops, Agricultural/metabolism ; *Isotope Labeling ; *Pyridines/chemistry/chemical synthesis ; Herbicides/chemical synthesis/chemistry ; Sulfonamides ; }, abstract = {Rimsulfuron is a sulfonylurea herbicide that controls grass and broadleaf weeds in maize, potatoes, fruits, nuts, and other crops. It can also be used as a burndown herbicide to clear invasive weed species along roadsides and other nonagricultural land. Rimsulfuron acts as an acetolactase synthase (ALS) inhibitor, blocking the synthesis of essential amino acids required for plant growth. As is common practice, rimsulfuron has been subject to periodic reviews by regulatory agencies for reregistration since its introduction into the market in the early 1990s. The goal of these reviews is to ensure that the herbicide carries out its intended use without creating adverse side effects to humans and the environment. Since scientific methods are continually evolving and being developed, global regulatory agencies can require additional studies to address data gaps for pesticide renewals. During this reregistration process for rimsulfuron, a new confined rotational crop study was required to address a data gap requested by the European Food Safety Authority (EFSA). Consequently, the corresponding pyridine and pyrimidine radiolabeled [[14]C]rimsulfuron and [M + 3] stable isotopes of rimsulfuron were synthesized for this study to support the reregistration process.}, } @article {pmid38711277, year = {2024}, author = {Vakilipour, P and Fekrvand, S}, title = {Brain-to-brain interface technology: A brief history, current state, and future goals.}, journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience}, volume = {84}, number = {5}, pages = {351-367}, doi = {10.1002/jdn.10334}, pmid = {38711277}, issn = {1873-474X}, mesh = {Humans ; *Brain-Computer Interfaces ; *Brain/physiology ; History, 20th Century ; History, 21st Century ; }, abstract = {A brain-to-brain interface (BBI), defined as a combination of neuroimaging and neurostimulation methods to extract and deliver information between brains directly without the need for the peripheral nervous system, is a budding communication technique. A BBI system is made up of two parts known as the brain-computer interface part, which reads a sender's brain activity and digitalizes it, and the computer-brain interface part, which writes the delivered brain activity to a receiving brain. As with other technologies, BBI systems have gone through an evolutionary process since they first appeared. The BBI systems have been employed for numerous purposes, including rehabilitation for post-stroke patients, communicating with patients suffering from amyotrophic lateral sclerosis, locked-in syndrome and speech problems following stroke. Also, it has been proposed that a BBI system could play an important role on future battlefields. This technology was not only employed for communicating between two human brains but also for making a direct communication path among different species through which motor or sensory commands could be sent and received. However, the application of BBI systems has provoked significant challenges to human rights principles due to their ability to access and manipulate human brain information. In this study, we aimed to review the brain-computer interface and computer-brain interface technologies as components of BBI systems, the development of BBI systems, applications of this technology, arising ethical issues and expectations for future use.}, } @article {pmid38711616, year = {2024}, author = {Chen, L and Chen, G and Zhang, M and Zhang, X}, title = {Modeling sporadic juvenile ALS in iPSC-derived motor neurons explores the pathogenesis of FUS[R503fs] mutation.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1364164}, pmid = {38711616}, issn = {1662-5102}, abstract = {INTRODUCTION: Fused in sarcoma (FUS) mutations represent the most common genetic etiology of juvenile amyotrophic lateral sclerosis (JALS), for which effective treatments are lacking. In a prior report, we identified a novel FUS mutation, c.1509dupA: p. R503fs (FUSR503fs), in a sporadic JALS patient.

METHODS: The physicochemical properties and structure of FUSR503fs protein were analyzed by software: Multi-electrode array (MEA) assay, calcium activity imaging assay and transcriptome analysis were used to explore the pathophysiological mechanism of iPSC derived motor neurons.

RESULTS: Structural analysis and predictions regarding physical and chemical properties of this mutation suggest that the reduction of phosphorylation and glycosylation sites, along with alterations in the amino acid sequence, may contribute to abnormal FUS accumulation within the cytoplasm and nucleus of induced pluripotent stem cell- derived motor neurons (MNs). Multi-electrode array and calcium activity imaging indicate diminished spontaneous electrical and calcium activity signals in MNs harboring the FUS[R503fs] mutation. Transcriptomic analysis reveals upregulation of genes associated with viral infection and downregulation of genes involved in neural function maintenance, such as the ATP6V1C2 gene. Treatment with ropinirole marginally mitigates the electrophysiological decline in FUS[R503fs] MNs, suggesting the utility of this cell model for mechanistic exploration and drug screening.

DISCUSSION: iPSCs-derived motor neurons from JALS patients are promising tools for drug screening. The pathological changes in motor neurons of FUS[R503fs] may occur earlier than in other known mutation types that have been reported.}, } @article {pmid38711658, year = {2024}, author = {Otero, G and Bolatto, C and Isasi, E and Cerri, S and Rodríguez, P and Boragno, D and Marco, M and Parada, C and Stancov, M and Cuitinho, MN and Olivera-Bravo, S}, title = {Adult aberrant astrocytes submitted to late passage cultivation lost differentiation markers and decreased their pro-inflammatory profile.}, journal = {Heliyon}, volume = {10}, number = {9}, pages = {e30360}, pmid = {38711658}, issn = {2405-8440}, abstract = {In amyotrophic lateral sclerosis (ALS), astrocytes are considered key players in some non-cell non-neuronal autonomous mechanisms that underlie motor neuron death. However, it is unknown how much of these deleterious features were permanently acquired. To assess this point, we evaluated if the most remarkable features of neurotoxic aberrant glial phenotypes (AbAs) isolated from paralytic rats of the ALS model G93A Cu/Zn superoxide dismutase 1 (SOD1) could remain upon long lasting cultivation. Real time PCR, immunolabelling and zymography analysis showed that upon many passages, AbAs preserved the cell proliferation capacity, mitochondrial function and response to different compounds that inhibit some key astrocyte functions but decreased the expression of parameters associated to cell lineage, homeostasis and inflammation. As these results are contrary to the sustained inflammatory status observed along disease progression in SOD1G93A rats, we propose that the most AbAs remarkable features related to homeostasis and neurotoxicity were not permanently acquired and might depend on the signaling coming from the injuring microenvironment present in the degenerating spinal cord of terminal rats.}, } @article {pmid38712171, year = {2024}, author = {Islam, Z and Polash, A and Suzawa, M and Chim, B and Kuhn, S and Sultana, S and Cutrona, N and Smith, PT and Kabat, J and Ganesan, S and Foroushani, A and Hafner, M and Muljo, SA}, title = {MATRIN3 deficiency triggers autoinflammation via cGAS-STING activation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38712171}, issn = {2692-8205}, support = {ZIA AI001185/ImNIH/Intramural NIH HHS/United States ; ZIA AR041205/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Interferon-stimulated genes (ISGs) comprise a program of immune effectors important for host immune defense. When uncontrolled, ISGs play a central role in interferonopathies and other inflammatory diseases. The mechanisms responsible for turning on ISGs are not completely known. By investigating MATRIN3 (MATR3), a nuclear RNA-binding protein mutated in familial ALS, we found that perturbing MATR3 results in elevated expression of ISGs. Using an integrative approach, we elucidate a pathway that leads to activation of cGAS-STING. This outlines a plausible mechanism for pathogenesis in a subset of ALS, and suggests new diagnostic and therapeutic approaches for this fatal disease.}, } @article {pmid38712174, year = {2025}, author = {Ozkan, A and Padmanabhan, HK and Shipman, SL and Azim, E and Kumar, P and Sadegh, C and Basak, AN and Macklis, JD}, title = {Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.04.21.590488}, pmid = {38712174}, issn = {2692-8205}, support = {DP1 NS106665/NS/NINDS NIH HHS/United States ; R01 NS045523/NS/NINDS NIH HHS/United States ; R01 NS049553/NS/NINDS NIH HHS/United States ; }, abstract = {Corticospinal neurons (CSN) centrally degenerate in amyotrophic lateral sclerosis (ALS), along with spinal motor neurons, and loss of voluntary motor function in spinal cord injury (SCI) results from damage to CSN axons. For functional regeneration of specifically affected neuronal circuitry in vivo , or for optimally informative disease modeling and/or therapeutic screening in vitro , it is important to reproduce the type or subtype of neurons involved. No such appropriate in vitro models exist with which to investigate CSN selective vulnerability and degeneration in ALS, or to investigate routes to regeneration of CSN circuitry for ALS or SCI, critically limiting the relevance of much research. Here, we identify that the HMG-domain transcription factor Sox6 is expressed by a subset of NG2+ endogenous cortical progenitors in postnatal and adult cortex, and that Sox6 suppresses a latent neurogenic program by repressing proneural Neurog2 expression by progenitors. We FACS-purify these progenitors from postnatal mouse cortex and establish a culture system to investigate their potential for directed differentiation into CSN. We then employ a multi-component construct with complementary and differentiation-sharpening transcriptional controls (activating Neurog2, Fezf2 , while antagonizing Olig2 with VP16:Olig2). We generate corticospinal-like neurons from SOX6+/NG2+ cortical progenitors, and find that these neurons differentiate with remarkable fidelity compared with corticospinal neurons in vivo . They possess appropriate morphological, molecular, transcriptomic, and electrophysiological characteristics, without characteristics of the alternate intracortical or other neuronal subtypes. We identify that these critical specifics of differentiation are not reproduced by commonly employed Neurog2 -driven differentiation. Neurons induced by Neurog2 instead exhibit aberrant multi-axon morphology and express molecular hallmarks of alternate cortical projection subtypes, often in mixed form. Together, this developmentally-based directed differentiation from cortical progenitors sets a precedent and foundation for in vitro mechanistic and therapeutic disease modeling, and toward regenerative neuronal repopulation and circuit repair.}, } @article {pmid38712849, year = {2024}, author = {Ludolph, AC and Corcia, P and Desnuelle, C and Heiman-Patterson, T and Mora, JS and Mansfield, CD and Couratier, P}, title = {Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice.}, journal = {Muscle & nerve}, volume = {70}, number = {1}, pages = {36-41}, doi = {10.1002/mus.28101}, pmid = {38712849}, issn = {1097-4598}, support = {//AB Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Clinical Trials as Topic/methods ; Disease Progression ; Outcome Assessment, Health Care/standards ; *Research Design ; Severity of Illness Index ; }, abstract = {The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post-onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post-onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post-onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design.}, } @article {pmid38713169, year = {2024}, author = {Nikel, LM and Talbot, K and Vahsen, BF}, title = {Recent insights from human induced pluripotent stem cell models into the role of microglia in amyotrophic lateral sclerosis.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {46}, number = {7}, pages = {e2400054}, doi = {10.1002/bies.202400054}, pmid = {38713169}, issn = {1521-1878}, support = {2023/MNDS/6400/753TALB//MND Scotland/ ; Talbot/Apr22/889-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism ; Humans ; *Microglia/metabolism/pathology ; *Motor Neurons/pathology/metabolism ; Coculture Techniques ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, primarily leading to the degeneration of motor neurons. The traditional focus on motor neuron-centric mechanisms has recently shifted towards understanding the contribution of non-neuronal cells, such as microglia, in ALS pathophysiology. Advances in induced pluripotent stem cell (iPSC) technology have enabled the generation of iPSC-derived microglia monocultures and co-cultures to investigate their role in ALS pathogenesis. Here, we briefly review the insights gained from these studies into the role of microglia in ALS. While iPSC-derived microglia monocultures have revealed intrinsic cellular dysfunction due to ALS-associated mutations, microglia-motor neuron co-culture studies have demonstrated neurotoxic effects of mutant microglia on motor neurons. Based on these findings, we briefly discuss currently unresolved questions and how they could be addressed in future studies. iPSC models hold promise for uncovering disease-relevant pathways in ALS and identifying potential therapeutic targets.}, } @article {pmid38715656, year = {2024}, author = {Paul, S and Dansithong, W and Gandelman, M and Figueroa, KP and Scoles, DR and Pulst, SM}, title = {Cerebellar Micro-RNA Profile in a Mouse Model of Spinocerebellar Ataxia Type 2.}, journal = {Neurology. Genetics}, volume = {10}, number = {2}, pages = {e200144}, pmid = {38715656}, issn = {2376-7839}, support = {R35 NS127253/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Micro-RNAs (miRNAs) are critical for regulating the expression of genes in multiple neurodegenerative diseases, but miRNAs have not been investigated in spinocerebellar ataxia type 2 (SCA2). SCA2, a dominantly inherited progressive neurodegenerative polyglutamine (polyQ) disease, is caused by a CAG repeat expansion in the ataxin-2 (ATXN2) gene. In this study, we determined miRNA transcriptomes in SCA2-BAC-ATXN2[Q72] transgenic mice.

METHODS: We assessed the expression of miRNAs in SCA2 transgenic mouse cerebella using the HiSeq Illumina sequencer. We used the miRNA target filter tool in Qiagen Ingenuity Pathway Analysis (IPA) to identify target genes of differentially expressed miRNAs (DEmiRs) within in the SCA2 mouse transcriptomes and then performed pathway analyses.

RESULTS: Our analysis revealed significant changes in the expression levels of multiple miRNAs in mice with SCA2. We identified 81 DEmiRs in mice with SCA2, with 52 miRNAs upregulated and 29 miRNAs downregulated after onset of rotarod deficit. Subsequent IPA processing enabled us to establish connections between these DEmiRs and specific biological regulatory functions. Furthermore, by using the IPA miRNA target filter, we identified target genes of DEmiRs in the SCA2-BAC-ATXN2[Q72] transcriptome data set and demonstrated their significant impact on several biological functional and disease pathways.

DISCUSSION: Our study establishes the role of both DEmiRs and their targets in SCA2 pathogenesis. By expressing mutant ATXN2 under the control of its endogenous regulatory elements in the SCA2-BAC-ATXN2[Q72] mouse model, we identified a set of DEmiRs that are shared across multiple neurodegenerative diseases including other SCAs, Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). There was a significant overlap of both DEmiRs and their targets of BAC-ATXN2[Q72] transcriptomes in dysregulated pathways that characterize SCA2. This observation also extended to dysregulated pathways in ALS, AD, and PD. DEmiRs identified in this study may represent therapeutic targets for neurodegeneration or lead to biomarkers for characterizing various neurodegenerative diseases.}, } @article {pmid38715858, year = {2021}, author = {Gupta, S and Sharma, U}, title = {Metabolomics of neurological disorders in India.}, journal = {Analytical science advances}, volume = {2}, number = {11-12}, pages = {594-610}, pmid = {38715858}, issn = {2628-5452}, abstract = {Metabolomics is the comprehensive study of the metabolome and its alterations within biological fluids and tissues. Over the years, applications of metabolomics have been explored in several areas, including personalised medicine in diseases, metabolome-wide association studies (MWAS), pharmacometabolomics and in combination with other branches of omics such as proteomics, transcriptomics and genomics. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy are the major analytical techniques widely employed in metabolomics. In addition, MS is coupled with chromatography techniques like gas chromatography (GC) and liquid chromatography (LC) to separate metabolites before analysis. These analytical techniques have made possible identification and quantification of large numbers of metabolites, encompassing characterization of diseases and facilitating a systematic and rational therapeutic strategy based on metabolic patterns. In recent years, the metabolomics approach has been used to obtain a deeper insight into the underlying biochemistry of neurodegenerative disorders and the discovery of biomarkers of clinical implications. The current review mainly focuses on an Indian perspective of metabolomics for the identification of metabolites and metabolic alterations serving as potential diagnostic biomarkers for neurological diseases including acute spinal cord injury, amyotrophic lateral sclerosis, tethered cord syndrome, spina bifida, stroke, Parkinson's disease, glioblastoma and neurological disorders with inborn errors of metabolism.}, } @article {pmid38716751, year = {2024}, author = {Schito, P and Manera, U and Russo, T and Cremona, G and Riboldi, E and Tettamanti, A and Agosta, F and Quattrini, A and Chiò, A and Filippi, M and Calvo, A and Riva, N}, title = {Use of the combination of spirometry, arterial blood gas analysis and overnight oximetry to predict the outcomes of patients affected by motor neuron disease: The Milan-Torin respiratory score (Mi-To-RS).}, journal = {European journal of neurology}, volume = {31}, number = {8}, pages = {e16316}, pmid = {38716751}, issn = {1468-1331}, support = {//Giovanni Marazzina Foundation/ ; }, mesh = {Humans ; Female ; Male ; Middle Aged ; Aged ; *Blood Gas Analysis/methods ; *Spirometry ; *Oximetry/methods ; *Motor Neuron Disease/blood/physiopathology/diagnosis ; Prognosis ; Retrospective Studies ; Adult ; }, abstract = {BACKGROUND AND PURPOSE: The use of multiple tests, including spirometry, arterial blood gas (ABG) analysis and overnight oximetry (OvOx), is highly recommended to monitor the respiratory function of patients with motor neuron disease (MND). In this study, we propose a composite score to simplify the respiratory management of MND patients and better stratify their prognosis.

MATERIALS AND METHODS: We screened the clinical charts of 471 non-ventilated MND patients referred to the Neuro-rehabilitation Unit of the San Raffaele Scientific Institute of Milan (January 2001-December 2019), collecting spirometric, ABG and OvOx parameters. To evaluate the prognostic role of each measurement, univariate Cox regression for death/tracheostomy was performed, and the variables associated with survival were selected to design a scoring system. Univariate and multivariate Cox regression analyses were then carried out to evaluate the prognostic role of the score. Finally, results were replicated in an independent cohort from the Turin ALS Center.

RESULTS: The study population included 450 patients. Six measurements were found to be significantly associated with survival and were selected to design a scoring system (maximum score = 8 points). Kaplan-Meier analysis showed significant stratification of survival and time to non-invasive mechanical ventilation adaptation according to score values, and multivariate analysis confirmed the independent effect of the respiratory score on survival of each cohort.

CONCLUSION: Forced vital capacity, ABG and OvOx parameters provide complementary information for the respiratory management and prognosis of MND patients and the combination of these parameters into a single score might help neurologists predict prognosis and guide decisions on the timing of the implementation of different diagnostic or therapeutic approaches.}, } @article {pmid38717009, year = {2024}, author = {Zhang, X and Sun, Y and Zhang, X and Shen, D and Shu, S and Yang, X and Liu, M and Cui, L and Liu, Q and Zhang, X}, title = {Genotype-phenotype association and functional analysis of hnRNPA1 mutations in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {600-607}, doi = {10.1080/21678421.2024.2346502}, pmid = {38717009}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; Male ; Middle Aged ; Female ; *Mutation/genetics ; *Genetic Association Studies/methods ; Adult ; Exome Sequencing ; Aged ; }, abstract = {BACKGROUND: Pathogenic variants in hnRNPA1 have been reported in amyotrophic lateral sclerosis (ALS) patients. However, studies on hnRNPA1 mutant spectrum and pathogenicity of variants were rare.

METHODS: We performed whole exome sequencing of ALS-associated genes and subsequent verification of rare variants in hnRNPA1 in our ALS patients. The hnRNPA1 mutations reported in literature were reviewed and combined with our results to determine the genotype-phenotype relationship. Functional analysis of the novel variant p.G195A was performed in vitro by transfection of mutant hnRNPA1 into 293T cell.

RESULTS: Among 207 ALS patients recruited, 3 rare hnRNPA1 variants were identified (mutant frequency 1.45%), including two recurrent mutations (p.P340S and p.G283R), and a novel rare variant p.G195A. In combination with previous reports, there are 27 ALS patients with 15 hnRNPA1 mutations identified. Disease onset age was 47.90 ± 1.52 years with predominant limb onset. The p.P340S mutation caused flail arm syndrome (FAS) in two independent families with extended life expectancy. The newly identified p.G195A mutation, lying at the start of the PrLD ("prion-like" domain)/LCD (low-complexity domain), causes local structural changes in 3D protein prediction. Upon sodium arsenite exposure, mutant hnRNPA1 retained in the nucleus but deficit of cytoplasmic G3BP1-positive stress granule clearance was observed. This is different from the p.P340S mutation which caused both cytoplasmic translocation and stress granule formation. No cytoplasmic TDP-43 translocation was observed.

CONCLUSION: Mutations in hnRNPA1 are overall minor in ALS patients. The p.P340S mutation is associated with manifestation of FAS. Mutations in LCD of hnRNPA1 cause stress granule misprocessing.}, } @article {pmid38717430, year = {2024}, author = {Boyce, D and Raymond, J and Larson, TC and Kirkland, E and Horton, DK and Mehta, P}, title = {What do you think caused your ALS? An analysis of the CDC national amyotrophic lateral sclerosis patient registry qualitative risk factor data using artificial intelligence and qualitative methodology.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {615-624}, pmid = {38717430}, issn = {2167-9223}, support = {CC999999/ImCDC/Intramural CDC HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/psychology/epidemiology ; Humans ; *Artificial Intelligence ; *Registries ; Male ; Female ; United States/epidemiology ; Risk Factors ; Middle Aged ; Centers for Disease Control and Prevention, U.S. ; Aged ; Adult ; Qualitative Research ; Natural Language Processing ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is an incurable, progressive neurodegenerative disease with a significant health burden and poorly understood etiology. This analysis assessed the narrative responses from 3,061 participants in the Centers for Disease Control and Prevention's National ALS Registry who answered the question, "What do you think caused your ALS?"

METHODS: Data analysis used qualitative methods and artificial intelligence (AI) using natural language processing (NLP), specifically, Bidirectional Encoder Representations from Transformers (BERT) to explore responses regarding participants' perceptions of the cause of their disease.

RESULTS: Both qualitative and AI analysis methods revealed several, often aligned themes, which pointed to perceived causes including genetic, environmental, and military exposures. However, the qualitative analysis revealed detailed themes and subthemes, providing a more comprehensive understanding of participants' perceptions. Although there were areas of alignment between AI and qualitative analysis, AI's broader categories did not capture the nuances discovered using the more traditional, qualitative approach. The qualitative analysis also revealed that the potential causes of ALS were described within narratives that sometimes indicate self-blame and other maladaptive coping mechanisms.

CONCLUSIONS: This analysis highlights the diverse range of factors that individuals with ALS consider as perceived causes for their disease. Understanding these perceptions can help clinicians to better support people living with ALS (PLWALS). The analysis highlights the benefits of using traditional qualitative methods to supplement or improve upon AI-based approaches. This rapidly evolving area of data science has the potential to remove barriers to accessing the rich narratives of people with lived experience.}, } @article {pmid38717875, year = {2024}, author = {Chen, M and Zhou, P}, title = {2CFastICA: A Novel Method for High Density Surface EMG Decomposition Based on Kernel Constrained FastICA and Correlation Constrained FastICA.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {32}, number = {}, pages = {2177-2186}, doi = {10.1109/TNSRE.2024.3398822}, pmid = {38717875}, issn = {1558-0210}, mesh = {*Electromyography/methods ; Humans ; *Algorithms ; *Signal-To-Noise Ratio ; Reproducibility of Results ; Signal Processing, Computer-Assisted ; Muscle, Skeletal/physiology ; Motor Neurons/physiology ; Computer Simulation ; Male ; Adult ; Female ; }, abstract = {This study presents a novel high density surface electromyography (EMG) decomposition method, named as 2CFastICA, because it incorporates two key algorithms: kernel constrained FastICA and correlation constrained FastICA. The former focuses on overcoming the local convergence of FastICA without requiring the peel-off strategy used in the progressive FastICA peel-off (PFP) framework. The latter further refines the output of kernel constrained FastICA by correcting possible erroneous or missed spikes. The two constrained FastICA algorithms supplement each other to warrant the decomposition performance. The 2CFastICA method was validated using simulated surface EMG signals with different motor unit numbers and signal to noise ratios (SNRs). Two source validation was also performed by simultaneous high density surface EMG and intramuscular EMG recordings, showing a matching rate (MR) of (97.2 ± 3.5)% for 170 common motor units. In addition, a different form of two source validation was also conducted taking advantages of the high density surface EMG characteristics of patients with amyotrophic lateral sclerosis, showing a MR of (99.4 ± 0.9)% for 34 common motor units from interference and sparse datasets. Both simulation and experimental results indicate that 2CFastICA can achieve similar decomposition performance to PFP. However, the efficiency of decomposition can be greatly improved by 2CFastICA since the complex signal processing procedures associated with the peel-off strategy are not required any more. Along with this paper, we also provide the MATLAB open source code of 2CFastICA for high density surface EMG decomposition.}, } @article {pmid38717990, year = {2024}, author = {Yu, X and Sun, J and Yang, Y and Zhang, J and Lu, Y and Tang, W}, title = {Enhanced Herbicide Metabolism and Target Site Mutation Enabled the Multiple Resistance to Cyhalofop-butyl, Florpyrauxifen-benzyl, and Penoxsulam in Echinochloa crus-galli.}, journal = {Journal of agricultural and food chemistry}, volume = {72}, number = {20}, pages = {11405-11414}, doi = {10.1021/acs.jafc.4c02450}, pmid = {38717990}, issn = {1520-5118}, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology/metabolism ; *Mutation ; *Echinochloa/genetics/drug effects/metabolism/growth & development ; *Plant Proteins/genetics/metabolism ; *Cytochrome P-450 Enzyme System/genetics/metabolism ; Acetyl-CoA Carboxylase/genetics/metabolism ; Plant Weeds/drug effects/genetics/metabolism ; Acetolactate Synthase/genetics/metabolism ; Butanes ; Nitriles ; Sulfonamides ; Uridine/analogs & derivatives ; }, abstract = {This study investigated the multiple herbicide resistance (MHR) mechanism of one Echinochloa crus-galli population that was resistant to florpyrauxifen-benzyl (FPB), cyhalofop-butyl (CHB), and penoxsulam (PEX). This population carried an Ala-122-Asn mutation in the acetolactate synthase (ALS) gene but no mutation in acetyl-CoA carboxylase (ACCase) and transport inhibitor response1 (TIR1) genes. The metabolism rate of PEX was 2-fold higher, and the production of florpyrauxifen-acid and cyhalofop-acid was lower in the resistant population. Malathion and 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) could reverse the resistance, suggesting that cytochrome P450 (CYP450) and glutathione S-transferase (GST) contribute to the enhanced metabolism. According to RNA-seq and qRT-PCR validation, two CYP450 genes (CYP71C42 and CYP71D55), one GST gene (GSTT2), two glycosyltransferase genes (rhamnosyltransferase 1 and IAAGLU), and two ABC transporter genes (ABCG1 and ABCG25) were induced by CHB, FPB, and PEX in the resistant population. This study revealed that the target mutant and enhanced metabolism were involved in the MHR mechanism in E. crus-galli.}, } @article {pmid38718295, year = {2024}, author = {Huang, J and Fu, Y and Wang, A and Shi, K and Peng, Y and Yi, Y and Yu, R and Gao, J and Feng, J and Jiang, G and Song, Q and Jiang, J and Chen, H and Gao, X}, title = {Brain Delivery of Protein Therapeutics by Cell Matrix-Inspired Biomimetic Nanocarrier.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {36}, number = {31}, pages = {e2405323}, doi = {10.1002/adma.202405323}, pmid = {38718295}, issn = {1521-4095}, support = {2022YFC2502800//National Key Research and Development Program of China/ ; 2023ZKZD21//Innovation Program of Shanghai Municipal Education Commission/ ; 81973272//National Natural Science Foundation of China/ ; 92068111//National Natural Science Foundation of China/ ; 81801212//National Natural Science Foundation of China/ ; 23S41900100//Shanghai Science and Technology Development Foundation/ ; 22QA1405000//Shanghai Science and Technology Development Foundation/ ; 21XD1422200//Shanghai Science and Technology Development Foundation/ ; SHSMU-ZDCX20211201//Innovative Research Team of High-Level Local Universities in Shanghai/ ; }, mesh = {Animals ; Mice ; *Biomimetic Materials/chemistry ; *Drug Carriers/chemistry ; *Blood-Brain Barrier/metabolism ; *Hyaluronic Acid/chemistry ; *Catalase/metabolism/chemistry ; *Brain/metabolism ; Nanoparticles/chemistry ; Protamines/chemistry ; Amyotrophic Lateral Sclerosis/drug therapy ; Disease Models, Animal ; Humans ; Brain Injuries/drug therapy/metabolism ; Biomimetics/methods ; }, abstract = {Protein therapeutics are anticipated to offer significant treatment options for central nervous system (CNS) diseases. However, the majority of proteins are unable to traverse the blood-brain barrier (BBB) and reach their CNS target sites. Inspired by the natural environment of active proteins, the cell matrix components hyaluronic acid (HA) and protamine (PRTM) are used to self-assemble with proteins to form a protein-loaded biomimetic core and then incorporated into ApoE3-reconstituted high-density lipoprotein (rHDL) to form a protein-loaded biomimetic nanocarrier (Protein-HA-PRTM-rHDL). This cell matrix-inspired biomimetic nanocarrier facilitates the penetration of protein therapeutics across the BBB and enables their access to intracellular target sites. Specifically, CAT-HA-PRTM-rHDL facilitates rapid intracellular delivery and release of catalase (CAT) via macropinocytosis-activated membrane fusion, resulting in improved spatial learning and memory in traumatic brain injury (TBI) model mice (significantly reduces the latency of TBI mice and doubles the number of crossing platforms), and enhances motor function and prolongs survival in amyotrophic lateral sclerosis (ALS) model mice (extended the median survival of ALS mice by more than 10 days). Collectively, this cell matrix-inspired nanoplatform enables the efficient CNS delivery of protein therapeutics and provides a novel approach for the treatment of CNS diseases.}, } @article {pmid38719860, year = {2024}, author = {Cusaro, CM and Capelli, E and Picco, AM and Brusoni, M}, title = {Incidence of resistance to ALS and ACCase inhibitors in Echinochloa species and soil microbial composition in Northern Italy.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {10544}, pmid = {38719860}, issn = {2045-2322}, support = {ECS00000036//MUR - M4C2 1.5 of PNRR funded by the European Union - NextGenerationEU/ ; }, mesh = {*Soil Microbiology ; Italy/epidemiology ; *Herbicide Resistance ; *Herbicides/pharmacology ; *Acetolactate Synthase/antagonists & inhibitors/genetics ; *Echinochloa/drug effects ; *Acetyl-CoA Carboxylase/genetics/antagonists & inhibitors ; Plant Weeds/drug effects ; Microbiota/drug effects ; Biodiversity ; Bacteria/drug effects/genetics/isolation & purification/classification ; Soil/chemistry ; Fungi/drug effects/isolation & purification/genetics ; }, abstract = {The increasing amount of weeds surviving herbicide represents a very serious problem for crop management. The interaction between microbial community of soil and herbicide resistance, along with the potential evolutive consequences, are still poorly known and need to be investigated to better understand the impact on agricultural management. In our study, we analyzed the microbial composition of soils in 32 farms, located in the Northern Italy rice-growing area (Lombardy) with the aim to evaluate the relationship between the microbial composition and the incidence of resistance to acetolactate synthase (ALS) and acetyl-CoA carboxylase (ACCase) inhibiting herbicides in Echinochloa species. We observed that the coverage of weeds survived herbicide treatment was higher than 60% in paddy fields with a low microbial biodiversity and less than 5% in those with a high microbial biodiversity. Fungal communities showed a greater reduction in richness than Bacteria. In soils with a reduced microbial diversity, a significant increase of some bacterial and fungal orders (i.e. Lactobacillales, Malasseziales and Diaporthales) was observed. Interestingly, we identified two different microbial profiles linked to the two conditions: high incidence of herbicide resistance (H-HeR) and low incidence of herbicide resistance (L-HeR). Overall, the results we obtained allow us to make hypotheses on the greater or lesser probability of herbicide resistance occurrence based on the composition of the soil microbiome and especially on the degree of biodiversity of the microbial communities.}, } @article {pmid38720470, year = {2024}, author = {Didcote, L and Al-Chalabi, A and Goldstein, LH}, title = {How the coronavirus pandemic affected the lives of people with ALS and their spouses in the UK from spouses' perspectives: a qualitative study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {625-633}, pmid = {38720470}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/epidemiology ; *Spouses/psychology ; *COVID-19/psychology/epidemiology ; Male ; Female ; Middle Aged ; *Qualitative Research ; Aged ; United Kingdom/epidemiology ; SARS-CoV-2 ; Caregivers/psychology ; Adult ; Anxiety/psychology/epidemiology ; }, abstract = {OBJECTIVE: This study set out to investigate, using qualitative methodology, the experiences of spouses of people with Amyotrophic Lateral Sclerosis (ALS) during the coronavirus pandemic, with particular focus on spouse distress and cognitive and behavioral change in people with ALS (pwALS).

METHODS: Qualitative semi-structured interviews of nine spouses of pwALS living in England were conducted between 11/09/2020 and 20/04/2021, focusing on spouses' perspectives of how their lives and the lives of pwALS were affected by the pandemic and related lockdowns. Interviews were subject to thematic analysis.

RESULTS: Four superordinate themes were identified from the spouses' interviews: (i) pandemic behaviors, which encompassed accounts of cautious behavior, relaxation of cautious behavior, and other people's attitudes to shielding the person with ALS; (ii) changes to daily life caused by the pandemic and progression of ALS; (iii) distress in spouses, which included anxiety, depression, and burden; and (iv) ALS-related behavioral impairment. Spouses also provided mixed accounts of telehealth care, pointing out its convenience but some felt that face-to-face appointments were preferable.

CONCLUSIONS: While many reactions to the pandemic reported by spouses of pwALS may have been similar to those of the general population or other vulnerable groups, interviews indicated the potential for the pandemic to have made more apparent certain aspects of behavioral change in pwALS with which carers may require support. Clinicians need to acknowledge spouses' concerns about the potential limitations of remote clinical consultations, enquire about cognitive and behavioral change, and consider how input should be best provided in such limiting circumstances.}, } @article {pmid38720484, year = {2024}, author = {Fernandes, JMA and Gondim, FAA}, title = {A homozygous p.Val120Leu (c.358G > C) SOD1 mutation led to slowly progressive amyotrophic lateral sclerosis in a Brazilian family.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {788-790}, doi = {10.1080/21678421.2024.2346824}, pmid = {38720484}, issn = {2167-9223}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Adult ; *Superoxide Dismutase-1/genetics ; Brazil ; *Mutation/genetics ; *Disease Progression ; Pedigree ; Superoxide Dismutase/genetics ; Homozygote ; Female ; Middle Aged ; Valine/genetics ; Leucine/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease usually associated with severe weakness and death within 2-5 years. SOD1 mutations cause hereditary ALS in autosomal dominant and rarely in recessive pattern. We describe a new phenotype of slowly progressive fALS due to homozygous SOD1 mutations (c.358G > C, p.Val120Leu) in a Brazilian family. We reviewed the medical chart and interviewed the index patient and other relatives. A 41-year-old man developed weakness in his legs, leading to frequent falls, followed over the next few months with progressive arm fasciculations and muscle atrophy. The SOD1 enzymatic activity in erythrocytes was slightly decreased. A genetic test panel disclosed homozygous SOD1 mutations (c.358G > C, p.Val120Leu). His asymptomatic parents also carried one mutant allele and 2 brothers and a sister had died with ALS. We reported a new family with homozygous SOD1 mutation and slowly progressive ALS course. Further studies are necessary to confirm whether this mutation can also lead to disease in heterozygosis with incomplete penetrance.}, } @article {pmid38720896, year = {2024}, author = {Zong, J and Yang, Y and Wang, H and Zhang, H and Yang, X and Yang, X}, title = {The two-directional prospective association between inflammatory bowel disease and neurodegenerative disorders: a systematic review and meta-analysis based on longitudinal studies.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1325908}, pmid = {38720896}, issn = {1664-3224}, mesh = {Humans ; *Inflammatory Bowel Diseases/complications ; *Neurodegenerative Diseases/epidemiology/etiology ; Longitudinal Studies ; Risk Factors ; Prospective Studies ; }, abstract = {OBJECTIVE: Previous studies reported possible connections between inflammatory bowel disease (IBD) and several neurodegenerative disorders. However, the comprehensive relationships between IBD and various neurodegenerative disorders were not summarized. We executed a meta-analysis of longitudinal studies to provide an estimate of the strength of the two-directional prospective association between IBD and neurodegenerative disorders.

METHODS: We accomplished a thorough bibliographic search of PubMed, Web of Science, Embase, PsycINFO, and Cochrane Library databases until June 2023 to locate relevant longitudinal studies. The extracted data were then analyzed via meta-analysis using either a fixed or random effects model.

RESULTS: The final analysis encompassed 27 studies. Individuals with IBD faced an increased risk of developing four neurodegenerative disorders than the general public, namely, Alzheimer's disease (hazard ratio[HR] = 1.35, 95% confidence interval [CI]: 1.03-1.77, P=0.031), dementia (HR =1.24, 95% CI: 1.13-1.36, P<0.001), multiple sclerosis (HR =2.07, 95% CI:1.42-3.02, P<0.001) and Parkinson's disease (HR =1.23, 95% CI:1.10-1.38, P<0.001). Two articles reported an increased incidence of amyotrophic lateral sclerosis or multiple system atrophy in IBD patients. Three studies investigated the prospective association between multiple sclerosis and IBD, revealing an elevated risk of the latter in patients with the former. (HR=1.87, 95% CI:1.66-2.10, P<0.001).

INTERPRETATION: These findings verified the two-directional relationship between the brain-gut axis, specifically demonstrating a heightened risk of various neurodegenerative diseases among IBD patients. It may be profitable to prepare screening strategies for IBD patients to find neurodegenerative diseases during the long-term course of treatment for IBD with a view to potential earlier diagnosis and treatment of neurodegenerative diseases, reducing public health and social burden.

PROSPERO (CRD42023437553).}, } @article {pmid38721118, year = {2024}, author = {Lu, L and Deng, Y and Xu, R}, title = {Current potential therapeutics of amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1402962}, pmid = {38721118}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating motor neurological disorder for which there is still no cure. The disease seriously jeopardizes the health and lifespan of adult populations. The authors extensively retrieved the current literature about clinical and experimental ALS treatments. Based on them, this review primarily focused on summarizing the current potential clinical usage and trialing therapeutics of ALS. Currently, the clinical ALS treatments have focused primarily on relieving symptoms to improve the quality of life yet. There are a number of therapeutic approaches such as medicine, gene therapy, neuron protectants, combination therapy and stem cells. Among them, Stem cells including embryonic stem cells, mesenchymal stem cells, neural stem cells, and many other types of stem cells have been used in ALS treatment, and although the short-term efficacy is good, it is worth exploring whether this improved efficacy leads to prolonged patient survival. In addition, the supportive treatments also exert an important effect on improving the quality of life and prolong the survival of ALS patients in absence of effectively care for stopping or reversing the progression of ALS.}, } @article {pmid38721655, year = {2024}, author = {Christoforidou, E and Moody, L and Joilin, G and Simoes, FA and Gordon, D and Talbot, K and Hafezparast, M}, title = {An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner.}, journal = {Disease models & mechanisms}, volume = {17}, number = {5}, pages = {}, pmid = {38721655}, issn = {1754-8411}, support = {//University of Sussex/ ; Hafezparast/Apr21/880-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; DOD/14/30-PF12794//My Name'5 Doddie Foundation/ ; }, mesh = {*Microglia/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *MicroRNAs/genetics/metabolism ; Animals ; Female ; *Mice, Transgenic ; Male ; *Mutation/genetics ; *Sex Characteristics ; DNA-Binding Proteins/genetics/metabolism ; Mice ; Extracellular Space/metabolism ; Humans ; Lipopolysaccharides/pharmacology ; Gene Expression Regulation ; }, abstract = {Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.}, } @article {pmid38722513, year = {2024}, author = {Sultana, J and Ragagnin, AMG and Parakh, S and Saravanabavan, S and Soo, KY and Vidal, M and Jagaraj, CJ and Ding, K and Wu, S and Shadfar, S and Don, EK and Deva, A and Nicholson, G and Rowe, DB and Blair, I and Yang, S and Atkin, JD}, title = {C9orf72-Associated Dipeptide Repeat Expansions Perturb ER-Golgi Vesicular Trafficking, Inducing Golgi Fragmentation and ER Stress, in ALS/FTD.}, journal = {Molecular neurobiology}, volume = {61}, number = {12}, pages = {10318-10338}, pmid = {38722513}, issn = {1559-1182}, support = {10305133//National Health and Medical Research Council/ ; 1086887//National Health and Medical Research Council/ ; 1095215//National Health and Medical Research Council/ ; 1176913//National Health and Medical Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Golgi Apparatus/metabolism ; *Endoplasmic Reticulum Stress/genetics ; *Endoplasmic Reticulum/metabolism ; *Dipeptides/metabolism ; *DNA Repeat Expansion/genetics ; Protein Transport ; }, abstract = {Hexanucleotide repeat expansions (HREs) in the chromosome 9 open reading frame 72 (C9orf72) gene are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both are debilitating neurodegenerative conditions affecting either motor neurons (ALS) in the brain and spinal cord or neurons in the frontal and/or temporal cortical lobes (FTD). HREs undergo repeat-associated non-ATG (RAN) translation on both sense and anti-sense strands, generating five distinct dipeptide repeat proteins (DPRs), poly-GA, -GR, -GP, -PA and -PR. Perturbed proteostasis is well-recognised in ALS pathogenesis, including processes affecting the endoplasmic reticulum (ER) and Golgi compartments. However, these mechanisms have not been well characterised for C9orf72-mediated ALS/FTD. In this study we demonstrate that C9orf72 DPRs polyGA, polyGR and polyGP (× 40 repeats) disrupt secretory protein transport from the ER to the Golgi apparatus in neuronal cells. Consistent with this finding, these DPRs also induce fragmentation of the Golgi apparatus, activate ER stress, and inhibit the formation of the omegasome, the precursor of the autophagosome that originates from ER membranes. We also demonstrate Golgi fragmentation in cells undergoing RAN translation that express polyGP. Furthermore, dysregulated ER-Golgi transport was confirmed in C9orf72 patient dermal fibroblasts. Evidence of aberrant ER-derived vesicles in spinal cord motor neurons from C9orf72 ALS patients compared to controls was also obtained. These data thus confirm that ER proteostasis and ER-Golgi transport is perturbed in C9orf72-ALS in the absence of protein over-expression. Hence this study identifies novel molecular mechanisms associated with the ER and Golgi compartments induced by the C9orf72 HRE.}, } @article {pmid38723752, year = {2024}, author = {Singh, K and Sethi, P and Datta, S and Chaudhary, JS and Kumar, S and Jain, D and Gupta, JK and Kumar, S and Guru, A and Panda, SP}, title = {Advances in gene therapy approaches targeting neuro-inflammation in neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {98}, number = {}, pages = {102321}, doi = {10.1016/j.arr.2024.102321}, pmid = {38723752}, issn = {1872-9649}, mesh = {Humans ; *Genetic Therapy/methods/trends ; *Neurodegenerative Diseases/therapy/genetics ; *Neuroinflammatory Diseases/therapy ; Animals ; }, abstract = {Over the last three decades, neurodegenerative diseases (NDs) have increased in frequency. About 15% of the world's population suffers from NDs in some capacity, which causes cognitive and physical impairment. Neurodegenerative diseases, including Amyotrophic Lateral Sclerosis, Parkinson's disease, Alzheimer's disease, and others represent a significant and growing global health challenge. Neuroinflammation is recognized to be related to all NDs, even though NDs are caused by a complex mix of genetic, environmental, and lifestyle factors. Numerous genes and pathways such as NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide, and COX are involved in triggering brain immune cells like astrocytes and microglia to secrete inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. In AD, the binding of Aβ with CD36, TLR4, and TLR6 receptors results in activation of microglia which start to produce proinflammatory cytokines and chemokines. Consequently, the pro-inflammatory cytokines worsen and spread neuroinflammation, causing the deterioration of healthy neurons and the impairment of brain functions. Gene therapy has emerged as a promising therapeutic approach to modulate the inflammatory response in NDs, offering potential neuroprotective effects and disease-modifying benefits. This review article focuses on recent advances in gene therapy strategies targeting neuroinflammation pathways in NDs. We discussed the molecular pathways involved in neuroinflammation, highlighted key genes and proteins implicated in these processes, and reviewed the latest preclinical and clinical studies utilizing gene therapy to modulate neuroinflammatory responses. Additionally, this review addressed the prospects and challenges in translating gene therapy approaches into effective treatments for NDs.}, } @article {pmid38723906, year = {2024}, author = {Koike, Y}, title = {Molecular mechanisms linking loss of TDP-43 function to amyotrophic lateral sclerosis/frontotemporal dementia-related genes.}, journal = {Neuroscience research}, volume = {208}, number = {}, pages = {1-7}, doi = {10.1016/j.neures.2024.05.001}, pmid = {38723906}, issn = {1872-8111}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Animals ; Polymorphism, Single Nucleotide ; Aging/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by nuclear depletion and cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43). TDP-43 plays a key role in regulating the splicing of numerous genes, including TARDBP. This review aims to delineate two aspects of ALS/FTD pathogenesis associated with TDP-43 function. First, we described novel mechanistic insights into the splicing of UNC13A, a TDP-43 target gene. Single nucleotide polymorphisms (SNPs) in UNC13A are the most common risk factors for ALS/FTD. We found that TDP-43 represses "cryptic exon" inclusion during UNC13A RNA splicing. A risk-associated SNP in this exon results in increased RNA levels of UNC13A retaining the cryptic exon. Second, we described the perturbation of the TDP-43 autoregulatory mechanism caused by age-related DNA demethylation. Aging is a major risk factor for sporadic ALS/FTD. Typically, TDP-43 levels are regulated via alternative splicing of TARDBP mRNA. This review focused on that TARDBP methylation is altered by aging, thereby disrupting TDP-43 autoregulation. It was found that demethylation reduces the efficiency of alternative splicing and increases TARDBP mRNA levels. Moreover, we demonstrated that, with aging, this region is demethylated in the human motor cortex and is associated with the early onset of ALS.}, } @article {pmid38723941, year = {2024}, author = {Doeleman, LC and Boomars, R and Radstok, A and Schober, P and Dellaert, Q and Hollmann, MW and Koster, RW and van Schuppen, H}, title = {Ventilation during cardiopulmonary resuscitation with mechanical chest compressions: How often are two insufflations being given during the 3-second ventilation pauses?.}, journal = {Resuscitation}, volume = {199}, number = {}, pages = {110234}, doi = {10.1016/j.resuscitation.2024.110234}, pmid = {38723941}, issn = {1873-1570}, mesh = {Humans ; *Cardiopulmonary Resuscitation/methods ; *Out-of-Hospital Cardiac Arrest/therapy ; Male ; Female ; *Insufflation/methods ; Middle Aged ; Prospective Studies ; *Heart Massage/methods ; Aged ; Netherlands ; Time Factors ; Respiration, Artificial/methods ; Emergency Medical Services/methods ; Registries ; }, abstract = {BACKGROUND: Mechanical chest compression devices in 30:2 mode provide 3-second pauses to allow for two insufflations. We aimed to determine how often two insufflations are provided in these ventilation pauses, in order to assess if prehospital providers are able to ventilate out-of-hospital cardiac arrest (OHCA) patients successfully during mechanical chest compressions.

METHODS: Data from OHCA cases of the regional ambulance service of Utrecht, The Netherlands, were prospectively collected in the UTrecht studygroup for OPtimal registry of cardIAc arrest database (UTOPIA). Compression pauses and insufflations were visualized on thoracic impedance and waveform capnography signals recorded by manual defibrillators. Ventilation pauses were analyzed for number of insufflations, duration of the subintervals of the ventilation cycles, and ratio of successfully providing two insufflations over the course of the resuscitation. Generalized linear mixed effects models were used to accurately estimate proportions and means.

RESULTS: In 250 cases, 8473 ventilation pauses were identified, of which 4305 (51%) included two insufflations. When corrected for non-independence of the data across repeated measures within the same subjects with a mixed effects analysis, two insufflations were successfully provided in 45% of ventilation pauses (95% CI: 40-50%). In 19% (95% CI: 16-22%) none were given.

CONCLUSION: Providing two insufflations during pauses in mechanical chest compressions is mostly unsuccessful. We recommend developing strategies to improve giving insufflations when using mechanical chest compression devices. Increasing the pause duration might help to improve insufflation success.}, } @article {pmid38724513, year = {2024}, author = {Zhou, T and Solis, NV and Marshall, M and Yao, Q and Garleb, R and Yang, M and Pearlman, E and Filler, SG and Liu, H}, title = {Hyphal Als proteins act as CR3 ligands to promote immune responses against Candida albicans.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {3926}, pmid = {38724513}, issn = {2041-1723}, support = {R01 GM117111/GM/NIGMS NIH HHS/United States ; R01 EY018612/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Mice ; beta-Glucans/metabolism/immunology ; Candida albicans/immunology ; *Candidiasis/immunology/microbiology ; CD11b Antigen/metabolism/immunology ; *CD18 Antigens/metabolism ; Dendritic Cells/immunology/metabolism ; *Fungal Proteins/metabolism/immunology ; *Lectins, C-Type/metabolism/immunology ; *Macrophages/immunology/metabolism ; Signal Transduction ; Interleukin-1beta ; }, abstract = {Patients with decreased levels of CD18 (β2 integrins) suffer from life-threatening bacterial and fungal infections. CD11b, the α subunit of integrin CR3 (CD11b/CD18, αMβ2), is essential for mice to fight against systemic Candida albicans infections. Live elongating C. albicans activates CR3 in immune cells. However, the hyphal ligands that activate CR3 are not well defined. Here, we discovered that the C. albicans Als family proteins are recognized by the I domain of CD11b in macrophages. This recognition synergizes with the β-glucan-bound lectin-like domain to activate CR3, thereby promoting Syk signaling and inflammasome activation. Dectin-2 activation serves as the "outside-in signaling" for CR3 activation at the entry site of incompletely sealed phagosomes, where a thick cuff of F-actin forms to strengthen the local interaction. In vitro, CD18 partially contributes to IL-1β release from dendritic cells induced by purified hyphal Als3. In vivo, Als3 is vital for C. albicans clearance in mouse kidneys. These findings uncover a novel family of ligands for the CR3 I domain that promotes fungal clearance.}, } @article {pmid38725125, year = {2024}, author = {Kim, D and Kim, S and Seok, JM and Shin, KJ and Oh, E and Jeon, MY and Park, J and Chang, HJ and Youn, J and Oh, J and Sohn, E and Park, J and Cho, JW and Kim, BJ}, title = {Establishment of a registry of clinical data and bioresources for rare nervous system diseases.}, journal = {Osong public health and research perspectives}, volume = {15}, number = {2}, pages = {174-181}, pmid = {38725125}, issn = {2210-9099}, support = {2023ER050600//National Institute of Health research/ ; }, abstract = {Rare diseases are predominantly genetic or inherited, and patients with these conditions frequently exhibit neurological symptoms. Diagnosing and treating many rare diseases is a complex challenge, and their low prevalence complicates the performance of research, which in turn hinders the advancement of therapeutic options. One strategy to address this issue is the creation of national or international registries for rare diseases, which can help researchers monitor and investigate their natural progression. In the Republic of Korea, we established a registry across 5 centers that focuses on 3 rare diseases, all of which are characterized by gait disturbances resulting from motor system dysfunction. The registry will collect clinical information and human bioresources from patients with amyotrophic lateral sclerosis, spinocerebellar ataxia, and hereditary spastic paraplegia. These resources will be stored at ICreaT and the National Biobank of Korea. Once the registry is complete, the data will be made publicly available for further research. Through this registry, our research team is dedicated to identifying genetic variants that are specific to Korean patients, uncovering biomarkers that show a strong correlation with clinical symptoms, and leveraging this information for early diagnosis and the development of treatments.}, } @article {pmid38726482, year = {2024}, author = {Henden, L and Fearnley, LG and Southwood, D and Smith, A and Rowe, DB and Kiernan, MC and Pamphlett, R and Bahlo, M and Blair, IP and Williams, KL}, title = {Short tandem repeat expansions in LRP12 are absent in cohorts of familial and sporadic amyotrophic lateral sclerosis patients of European ancestry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {644-647}, doi = {10.1080/21678421.2024.2348636}, pmid = {38726482}, issn = {2167-9223}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; Cohort Studies ; Trinucleotide Repeat Expansion ; *White People/genetics ; *Low Density Lipoprotein Receptor-Related Protein-1/genetics ; }, abstract = {In patients of Asian ancestry, a heterozygous CGG repeat expansion of >100 units in LRP12 is the cause of oculopharyngodistal myopathy type 1 (OPDM1). Repeat lengths of between 61 and 100 units have been associated with rare amyotrophic lateral sclerosis (ALS) cases of Asian ancestry, although with unusually long disease duration and without significant upper motor neuron involvement. This study sought to determine whether LRP12 CGG repeat expansions were also present in ALS patients of European ancestry. Whole-genome sequencing data from 608 sporadic ALS patients, 35 familial ALS probands, and 4703 neurologically normal controls were screened for LRP12 CGG expansions using ExpansionHunter v4. All individuals had LRP12 CGG repeat lengths within the normal range of 3-25 units. To date, LRP12 CGG repeat expansions have not been reported in ALS patients of European ancestry and may be limited to rare ALS patients of Asian ancestry and atypical clinical presentations.}, } @article {pmid38726604, year = {2024}, author = {López Gómez, JJ and Díaz Marín, C and Castillo-García, T and Larrad-Sainz, A and Gastaldo-Simeón, R and Juarros-Martínez, S and Leunda-Eizmendi, L and Civera Andrés, M and Matía Martín, P}, title = {[Medical nutrition therapy in amyotrophic lateral sclerosis - Do we act or react? A case report and multidisciplinary review].}, journal = {Nutricion hospitalaria}, volume = {41}, number = {3}, pages = {712-723}, doi = {10.20960/nh.05189}, pmid = {38726604}, issn = {1699-5198}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Malnutrition/etiology/therapy ; *Nutrition Therapy/methods ; Nutritional Status ; }, abstract = {Background: amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a progressive course. The current prevalence is between 3 and 6 cases/100,000. Malnutrition is closely related to patient prognosis in ALS. The implications of this conditions have been that we should recommend patient care in a multidisciplinary unit. Case report: the case presented shows the evolution of a patient with ALS. The patient was referred to different clinical departments after neurological evaluation and her nutritional, functional and respiratory status were assessed. There was no nutritional deterioration at diagnosis; however, intake was below energy-protein requirements. The clinical evolution of the patient showed a decrease in muscle mass with preservation of weight and fat mass. "Aggressive" measures to control nutritional status such as gastrostomy were rejected in the initial stages of the disease, but had to be carried out after development of dysphagia and associated malnutrition. This situation of progressive morphofunctional deterioration and the development of disease-related complications made essential the participation of different health services and professionals in its control. Dicussion: the management of ALS in a multidisciplinary manner allows to improve the course of the disease and the quality of life of both the patients and their families. Patient follow-up is based on the adjustment and management of complications. The basis of the relationship with these patients includes maintaining an adequate communication with them and their families, and ensuring joint decision-making about their condition.}, } @article {pmid38727285, year = {2024}, author = {Gao, Y and Lu, Y and Liang, X and Zhao, M and Yu, X and Fu, H and Yang, W}, title = {CD4[+] T-Cell Senescence in Neurodegenerative Disease: Pathogenesis and Potential Therapeutic Targets.}, journal = {Cells}, volume = {13}, number = {9}, pages = {}, pmid = {38727285}, issn = {2073-4409}, support = {20230505039ZP//Jilin Province Science and Technology Department/ ; }, mesh = {Animals ; Humans ; Aging/immunology/pathology ; *CD4-Positive T-Lymphocytes/immunology ; *Neurodegenerative Diseases/immunology/pathology/therapy ; *T-Cell Senescence ; }, abstract = {With the increasing proportion of the aging population, neurodegenerative diseases have become one of the major health issues in society. Neurodegenerative diseases (NDs), including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neurodegeneration associated with aging, leading to a gradual decline in cognitive, emotional, and motor functions in patients. The process of aging is a normal physiological process in human life and is accompanied by the aging of the immune system, which is known as immunosenescence. T-cells are an important part of the immune system, and their senescence is the main feature of immunosenescence. The appearance of senescent T-cells has been shown to potentially lead to chronic inflammation and tissue damage, with some studies indicating a direct link between T-cell senescence, inflammation, and neuronal damage. The role of these subsets with different functions in NDs is still under debate. A growing body of evidence suggests that in people with a ND, there is a prevalence of CD4[+] T-cell subsets exhibiting characteristics that are linked to senescence. This underscores the significance of CD4[+] T-cells in NDs. In this review, we summarize the classification and function of CD4[+] T-cell subpopulations, the characteristics of CD4[+] T-cell senescence, the potential roles of these cells in animal models and human studies of NDs, and therapeutic strategies targeting CD4[+] T-cell senescence.}, } @article {pmid38728654, year = {2024}, author = {McFarlane, R and Heverin, M and Walsh, C and Hardiman, O}, title = {Irish Amyotrophic Lateral Sclerosis Incidence: Age, Period, and Cohort Effects Using a Partial Least Squares Regression Model.}, journal = {Neurology}, volume = {102}, number = {11}, pages = {e209391}, doi = {10.1212/WNL.0000000000209391}, pmid = {38728654}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Ireland/epidemiology ; Incidence ; Aged ; Middle Aged ; Male ; Female ; Adult ; Least-Squares Analysis ; Aged, 80 and over ; Registries ; Age Factors ; Cohort Effect ; Cohort Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: To investigate the underlying reasons for variability in the incidence rate of amyotrophic lateral sclerosis (ALS) within the Irish population between the years 1996 and 2021.

METHODS: The Irish ALS register was used to calculate the incidence and to subsequently extract age at diagnosis (age), year of diagnosis (period), and date of birth (cohort) for all incident patients within the study period (n = 2,771). An age-period-cohort (APC) model using partial least squares regression was constructed to examine each component separately and their respective contribution to the incidence while minimizing the well-known identifiability problem of APC effects. A dummy regression model consisting of 5 periods, 19 cohorts, and 16 age groups was used to examine nonlinear relationships within the data over time. The CIs for each of these were estimated using the jackknife method.

RESULTS: The nonlinear model achieved R[2] of 99.43% with 2-component extraction. Age variation was evident with those in the ages 65-79 years contributing significantly to the incidence (βmax = 0.0746, SE = 0.000410, CI 0.00665-0.00826). However, those aged 25-60 years contributed significantly less (βmin = -0.00393, SE = 0.000291, CI -0.00454 to -0.00340). Each successive period showed an increase in the regression model coefficient suggesting an increasing incidence over time, independent of the other factors examined-an increase of β from -0.00489 (SE = 0.000264, CI -0.00541 to -0.00437) to 0.00973 (SE = 0.000418, CI 0.0105-0.00891). A cohort effect was demonstrated showing that the contribution of those born between 1927 and 1951 contributed to a significantly greater degree than the other birth cohorts (βmax = 0.00577, SE = 0.000432, CI 0.00493-0.00662).

DISCUSSION: Using the Irish population-based ALS Register, robust age, period, and cohort effects can be identified. The age effect may be accounted for by demographic shifts within the population. Changes in disease categorization, competing risks of death, and improved surveillance may account for period effects. The cohort effect may reflect lifestyle and environmental factors associated with the challenging economic circumstances in Ireland between 1927 and 1951. Age-period-cohort studies can help to account for changes in disease incidence and prevalence, providing additional insights into likely demographic and environmental factors that influence population-based disease risk.}, } @article {pmid38731036, year = {2024}, author = {Ueha, R and Miura, C and Matsumoto, N and Sato, T and Goto, T and Kondo, K}, title = {Vocal Fold Motion Impairment in Neurodegenerative Diseases.}, journal = {Journal of clinical medicine}, volume = {13}, number = {9}, pages = {}, pmid = {38731036}, issn = {2077-0383}, abstract = {Vocal fold motion impairment (VFMI) is the inappropriate movement of the vocal folds during respiration, leading to vocal fold adduction and/or abduction problems and causing respiratory and vocal impairments. Neurodegenerative diseases (NDDs) are a wide range of disorders characterized by progressive loss of neurons and deposition of altered proteins in the brain and peripheral organs. VFMI may be unrecognized in patients with NDDs. VFMI in NDDs is caused by the following: laryngeal muscle weakness due to muscular atrophy, caused by brainstem and motor neuron degeneration in amyotrophic lateral sclerosis; hyperactivity of laryngeal adductors in Parkinson's disease; and varying degrees of laryngeal adductor hypertonia and abductor paralysis in multiple system atrophy. Management of VFMI depends on whether there is a presence of glottic insufficiency or insufficient glottic opening with/without severe dysphagia. VFMI treatment options for glottic insufficiency range from surgical interventions, including injection laryngoplasty and medialization thyroplasty, to behavioral therapies; for insufficient glottic opening, various options are available based on the severity and underlying cause of the condition, including continuous positive airway pressure therapy, botulinum toxin injection, tracheostomy, vocal fold surgery, or a combination of interventions. In this review, we outline the mechanisms, clinical features, and management of VFMI in NDDs and provide a guide for physicians who may encounter these clinical features in their patients. NDDs are always progressive; hence, timely evaluation, proper diagnosis, and appropriate management of the patient will greatly affect their vocal, respiratory, and swallowing functions as well as their quality of life.}, } @article {pmid38732027, year = {2024}, author = {Cantara, S and Simoncelli, G and Ricci, C}, title = {Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.}, journal = {International journal of molecular sciences}, volume = {25}, number = {9}, pages = {}, pmid = {38732027}, issn = {1422-0067}, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use ; *Motor Neuron Disease/genetics/therapy ; Animals ; Muscular Atrophy, Spinal/therapy/genetics ; Amyotrophic Lateral Sclerosis/genetics/therapy ; }, abstract = {Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.}, } @article {pmid38732386, year = {2024}, author = {Zhang, Y and Zhao, A and Mu, L and Teng, X and Ma, Y and Li, R and Lei, K and Ji, L and Wang, X and Li, P}, title = {First Clarification of the Involvement of Glycosyltransferase MdUGT73CG22 in the Detoxification Metabolism of Nicosulfuron in Apple.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {38732386}, issn = {2223-7747}, support = {No. ZR202102180037//Shandong Provincial Natural Science Foundation of China/ ; No. LCUGYTD2022-04//Guangyue Young Scholar Innovation Team of Liaocheng University/ ; }, abstract = {Nicosulfuron, an acetolactate synthase (ALS) inhibitor herbicide, is a broad-spectrum and highly effective post-emergence herbicide. Glycosyltransferases (GTs) are widely found in organisms and transfer sugar molecules from donors to acceptors to form glycosides or sugar esters, thereby altering the physicochemical properties of the acceptor molecule, such as participating in detoxification. In this study, nine glycosyltransferases in group D of the apple glycosyltransferase family I were predicted to possibly be involved in the detoxification metabolism of ALS-inhibiting herbicides based on gene chip data published online. In order to confirm this, we analysed whether the expression of the nine glycosyltransferase genes in group D was induced by the previously reported ALS-inhibiting herbicides by real-time PCR (polymerase chain reaction). It was found that the ALS-inhibiting herbicide nicosulfuron significantly increased the expression of the MdUGT73CG22 gene in group D. Further investigation of the mechanism of action revealed that the apple glycosyltransferase MdUGT73CG22 glycosylated and modified nicosulfuron both in vivo and ex vivo to form nicosulfuron glycosides, which were involved in detoxification metabolism. In conclusion, a new glycosyltransferase, MdUGT73CG22, was identified for the first time in this study, which can glycosylate modifications of the ALS-inhibiting herbicide nicosulfuron and may be involved in the detoxification process in plants, which can help to further improve the knowledge of the non-targeted mechanism of herbicides.}, } @article {pmid38733354, year = {2024}, author = {Emile, R and Krisjanous, J and Banga, M and Kadirov, D}, title = {Healthcare access for pregnant women in a rural developing country context: Formal and informal institutional challenges.}, journal = {Health marketing quarterly}, volume = {41}, number = {3}, pages = {294-312}, doi = {10.1080/07359683.2024.2347047}, pmid = {38733354}, issn = {1545-0864}, mesh = {Humans ; Female ; *Health Services Accessibility ; Pregnancy ; *Rural Population ; *Developing Countries ; Adult ; Pregnant People/psychology ; }, abstract = {This study examines healthcare access for pregnant women in a rural developing country context. Drawing upon institutional theory and Levesque et al's model of access, the study finds pregnant women face challenges both of a formal and informal nature in accessing healthcare. The findings suggest the need for integrated and collaborative workings across formal and informal institutional networks. Theoretically, the study makes two contributions. First, it adds value to institutional theory by incorporating a dimension of access. Second, it builds upon Levesque et al.'s healthcare access framework by highlighting the role and significance of a third dimension-that is informal institutions, in addition to the current two-formal institutions and individual factors.}, } @article {pmid38733435, year = {2024}, author = {Liu, S and Hong, Y and Wang, BR and Wei, ZQ and Zhao, HD and Jiang, T and Zhang, YD and Shi, JQ}, title = {The presence and clinical significance of autoantibodies in amyotrophic lateral sclerosis: a narrative review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {9}, pages = {4133-4149}, pmid = {38733435}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/immunology/blood ; Humans ; *Autoantibodies/immunology/blood ; Clinical Relevance ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease, which is characterized by the selective loss of the upper and lower motor neurons. The pathogenesis of ALS remains to be elucidated and has been connected to genetic, environmental and immune conditions. Evidence from clinical and experimental studies has suggested that the immune system played an important role in ALS pathophysiology. Autoantibodies are essential components of the immune system. Several autoantibodies directed at antigens associated with ALS pathogenesis have been identified in the serum and/or cerebrospinal fluid of ALS patients. The aim of this review is to summarize the presence and clinical significance of autoantibodies in ALS.}, } @article {pmid38734122, year = {2024}, author = {Panchalingam, S and Kasivelu, G}, title = {Exploring the impact of circular RNA on ALS progression: A systematic review.}, journal = {Brain research}, volume = {1838}, number = {}, pages = {148990}, doi = {10.1016/j.brainres.2024.148990}, pmid = {38734122}, issn = {1872-6240}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *RNA, Circular/metabolism/genetics ; Humans ; *Disease Progression ; Animals ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease that damages motor neurons and causes gradual muscular weakening and paralysis. Although studies have linked a number of genetic and environmental factors to ALS, the specific causes and mechanisms of the disease are still unclear. The pivotal role of circular RNA in the pathogenesis of ALS is a newly emerging area of research. The term "circular RNA" describes a particular class of RNA molecule that, in contrast to most RNA molecules, has a closed-loop structure. According to recent research, circular RNA might be essential for the development and progression of ALS. It has been discovered that these circular RNAs support important cellular functions related to ALS, including protein turnover, mitochondrial function, RNA processing, and cellular transport. Gaining knowledge about the precise roles and processes of circular RNA in the development of ALS could assist in understanding the pathophysiology of the disease and possibly pave the way for the development of targeted therapies. However, the understanding of circular RNA in ALS is still limited, and more research is needed to fully elucidate its role. In order to gain a comprehensive understanding of the role of circRNAs in ALS, it is imperative to delve into the various mechanisms through which circRNAs may contribute to the development and progression of the disease. Examining the current status of circRNA research in ALS and offering insights into their potential as therapeutic targets and diagnostic markers are the primary objectives of this review.}, } @article {pmid38734896, year = {2024}, author = {Sun, S and Shen, Y and Zhang, X and Ding, N and Xu, Z and Zhang, Q and Li, L}, title = {The MuSK agonist antibody protects the neuromuscular junction and extends the lifespan in C9orf72-ALS mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {32}, number = {7}, pages = {2176-2189}, pmid = {38734896}, issn = {1525-0024}, mesh = {Animals ; *Neuromuscular Junction/metabolism/drug effects ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy ; *C9orf72 Protein/genetics/metabolism ; Humans ; *Disease Models, Animal ; *Receptor Protein-Tyrosine Kinases/metabolism/genetics ; Longevity/drug effects ; Motor Neurons/metabolism/drug effects ; Agrin/metabolism/genetics ; Mice, Transgenic ; Antibodies/pharmacology ; Receptors, Cholinergic/metabolism/genetics ; LDL-Receptor Related Proteins/metabolism/genetics ; }, abstract = {The disassembly of the neuromuscular junction (NMJ) is an early event in amyotrophic lateral sclerosis (ALS), ultimately leading to motor dysfunction and lethal respiratory paralysis. The hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common genetic mutation, and the dipeptide repeat (DPR) proteins have been shown to cause neurodegeneration. While no drugs can treat ALS patients efficiently, new treatment strategies are urgently needed. Here, we report that a MuSK agonist antibody alleviates poly-PR-induced NMJ deficits in C9orf72-ALS mice. The HB9-PR[F/F] mice, which express poly-PR proteins in motor neurons, exhibited impaired motor behavior and NMJ deficits. Mechanistically, poly-PR proteins interacted with Agrin to disrupt the interaction between Agrin and Lrp4, leading to attenuated activation of MuSK. Treatment with a MuSK agonist antibody rescued NMJ deficits, and extended the lifespan of C9orf72-ALS mice. Moreover, impaired NMJ transmission was observed in C9orf72-ALS patients. These findings identify the mechanism by which poly-PR proteins attenuate MuSK activation and NMJ transmission, highlighting the potential of promoting MuSK activation with an agonist antibody as a therapeutic strategy to protect NMJ function and prolong the lifespan of ALS patients.}, } @article {pmid38735139, year = {2024}, author = {Im, G and Choi, D}, title = {Molecular and physiological characterization of AIP1, encoding the acetolactate synthase regulatory subunit in rice.}, journal = {Biochemical and biophysical research communications}, volume = {718}, number = {}, pages = {150087}, doi = {10.1016/j.bbrc.2024.150087}, pmid = {38735139}, issn = {1090-2104}, mesh = {*Oryza/genetics/metabolism/enzymology ; *Acetolactate Synthase/genetics/metabolism ; *Plant Proteins/genetics/metabolism ; *Gene Expression Regulation, Plant ; Plants, Genetically Modified ; Stress, Physiological/genetics ; Amino Acids, Branched-Chain/metabolism ; Oxygen/metabolism ; Protein Subunits/metabolism/genetics ; }, abstract = {Flooding deprives plants of oxygen and thereby causes severe stress by interfering with energy production, leading to growth retardation. Enzymes and metabolites may help protect plants from waterlogging and hypoxic environmental conditions. Acetolactate synthase (ALS) is a key enzyme in the biosynthesis of branched-chain amino acids (BCAAs), providing the building blocks for proteins and various secondary metabolites. Additionally, under energy-poor conditions, free BCAAs can be used as an alternative energy source by mitochondria through a catabolic enzyme chain reaction. In this study, we characterized ALS-INTERACTING PROTEIN 1 (OsAIP1), which encodes the regulatory subunit of ALS in rice (Oryza sativa). This gene was expressed in all parts of the rice plant, and its expression level was significantly higher in submerged and low-oxygen environments. Rice transformants overexpressing OsAIP1 showed a higher survival rate under hypoxic stress than did non-transgenic control plants under the same conditions. The OsAIP1-overexpressing plants accumulated increased levels of BCAAs, demonstrating that OsAIP1 is an important factor in the hypoxia resistance mechanism. These results suggest that ALS proteins are part of a defense mechanism that improves the tolerance of plants to low-oxygen environments.}, } @article {pmid38735299, year = {2024}, author = {Gould, RL and McDermott, CJ and Thompson, BJ and Rawlinson, CV and Bursnall, M and Bradburn, M and Kumar, P and Turton, EJ and White, DA and Serfaty, MA and Graham, CD and McCracken, LM and Goldstein, LH and Al-Chalabi, A and Orrell, RW and Williams, T and Noad, R and Baker, I and Faull, C and Lambert, T and Chhetri, SK and Ealing, J and Hanratty, A and Radunovic, A and Gunawardana, N and Meadows, G and Gorrie, GH and Young, T and Lawrence, V and Cooper, C and Shaw, PJ and Howard, RJ and , }, title = {Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK.}, journal = {Lancet (London, England)}, volume = {403}, number = {10442}, pages = {2381-2394}, doi = {10.1016/S0140-6736(24)00533-6}, pmid = {38735299}, issn = {1474-547X}, support = {NIHR202421//NIHR/ ; }, mesh = {Humans ; *Quality of Life ; *Acceptance and Commitment Therapy/methods ; Male ; Female ; Middle Aged ; *Motor Neuron Disease/therapy/psychology ; United Kingdom ; Aged ; Treatment Outcome ; }, abstract = {BACKGROUND: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease.

METHODS: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391).

FINDINGS: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22-1·10]; d=0·46 [0·16-0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention.

INTERPRETATION: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services.

FUNDING: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.}, } @article {pmid38735361, year = {2024}, author = {D'Agostino, F and Agrò, FE and Petrosino, P and Ferri, C and Ristagno, G}, title = {Are instructors correctly gauging ventilation competence acquired by course attendees?.}, journal = {Resuscitation}, volume = {200}, number = {}, pages = {110240}, doi = {10.1016/j.resuscitation.2024.110240}, pmid = {38735361}, issn = {1873-1570}, mesh = {Humans ; *Clinical Competence/standards ; *Cardiopulmonary Resuscitation/education/standards/methods ; Respiration, Artificial/standards/methods/instrumentation ; Educational Measurement/methods ; Male ; Female ; Manikins ; Tidal Volume/physiology ; }, abstract = {Achievement of adequate ventilation skills during training courses is mainly based on instructors' perception of attendees' capability to ventilate with correct rate and chest compression:ventilation ratio, while leading to chest raising, as evidence of adequate tidal volume. Accuracy in evaluating ventilation competence was assessed in 20 ACLS provider course attendees, by comparing course instructors' evaluation with measures from a ventilation feedback device. According to course instructors, all candidates acquired adequate ventilation competence. However, data from the feedback device indicated a ventilation not aligned with current guidelines, with higher tidal volume and lower rate (p < 0.01). Deploying quality ventilation during CPR is a skill whose acquisition starts with effective training. Therefore, course instructors' capability to accurately evaluate attendees' ventilation maneuvers is crucial.}, } @article {pmid38738022, year = {2024}, author = {De Jesus-Morales, K and De Jesús-Rojas, W and Ramos-Benitez, MJ}, title = {Neutrophil-to-Lymphocyte Ratio Dynamics From Pre-diagnosis to End-Stage Amyotrophic Lateral Sclerosis (ALS): A Case Study on Association With Progression and Clinical Events.}, journal = {Cureus}, volume = {16}, number = {4}, pages = {e58109}, pmid = {38738022}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by the progressive degeneration of motor neurons, resulting in muscle weakness and paralysis. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential marker for monitoring disease severity and progression in ALS, yet longitudinal analyses of NLR are limited. Our study conducts an in-depth examination of NLR dynamics from before diagnosis through the disease's progression to its end stage. We analyze the case of a 56-year-old Puerto Rican male with ALS, tracking his NLR over 13 years - six years before and seven years after his diagnosis - alongside assessments of clinical symptoms and lung function. Our findings indicate that NLR values were initially normal but significantly increased with the onset of symptoms. NLR remained elevated above the normal range, with a notable exception during a period of edaravone therapy when levels normalized. The study demonstrates a clear elevation in NLR associated with ALS progression and critical clinical events, such as symptom onset, diagnosis, and the initiation of respiratory support. This research is, to our knowledge, the first to provide a detailed characterization of NLR changes from the pre-diagnostic phase to end-stage ALS, showing its correlation with clinical deterioration, decreased pulmonary function, and key clinical events. Our results contribute to the body of evidence on NLR's role in ALS while enhancing our understanding of ALS's natural progression.}, } @article {pmid38738213, year = {2023}, author = {Fan, C and Hahn, N and Kamdar, F and Avansino, D and Wilson, GH and Hochberg, L and Shenoy, KV and Henderson, JM and Willett, FR}, title = {Plug-and-Play Stability for Intracortical Brain-Computer Interfaces: A One-Year Demonstration of Seamless Brain-to-Text Communication.}, journal = {Advances in neural information processing systems}, volume = {36}, number = {}, pages = {42258-42270}, pmid = {38738213}, issn = {1049-5258}, support = {R01 DC014034/DC/NIDCD NIH HHS/United States ; R01 EB028171/EB/NIBIB NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; }, abstract = {Intracortical brain-computer interfaces (iBCIs) have shown promise for restoring rapid communication to people with neurological disorders such as amyotrophic lateral sclerosis (ALS). However, to maintain high performance over time, iBCIs typically need frequent recalibration to combat changes in the neural recordings that accrue over days. This requires iBCI users to stop using the iBCI and engage in supervised data collection, making the iBCI system hard to use. In this paper, we propose a method that enables self-recalibration of communication iBCIs without interrupting the user. Our method leverages large language models (LMs) to automatically correct errors in iBCI outputs. The self-recalibration process uses these corrected outputs ("pseudo-labels") to continually update the iBCI decoder online. Over a period of more than one year (403 days), we evaluated our Continual Online Recalibration with Pseudo-labels (CORP) framework with one clinical trial participant. CORP achieved a stable decoding accuracy of 93.84% in an online handwriting iBCI task, significantly outperforming other baseline methods. Notably, this is the longest-running iBCI stability demonstration involving a human participant. Our results provide the first evidence for long-term stabilization of a plug-and-play, high-performance communication iBCI, addressing a major barrier for the clinical translation of iBCIs.}, } @article {pmid38738637, year = {2024}, author = {Błaszczyk, L and Ryczek, M and Das, B and Mateja-Pluta, M and Bejger, M and Śliwiak, J and Nakatani, K and Kiliszek, A}, title = {Antisense RNA C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms a triplex-like structure and binds small synthetic ligand.}, journal = {Nucleic acids research}, volume = {52}, number = {11}, pages = {6707-6717}, pmid = {38738637}, issn = {1362-4962}, support = {UMO-2022/45/B/NZ7/03543//National Science Centre/ ; 22H00351//Japan Society for the Promotion of Science/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; *C9orf72 Protein/genetics/metabolism ; Humans ; Ligands ; RNA, Antisense/genetics/chemistry/metabolism ; Nucleic Acid Conformation ; DNA Repeat Expansion/genetics ; Crystallography, X-Ray ; Models, Molecular ; }, abstract = {The abnormal expansion of GGGGCC/GGCCCC hexanucleotide repeats (HR) in C9orf72 is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Structural polymorphisms of HR result in the multifactorial pathomechanism of ALS/FTD. Consequently, many ongoing studies are focused at developing therapies targeting pathogenic HR RNA. One of them involves small molecules blocking sequestration of important proteins, preventing formation of toxic nuclear foci. However, rational design of potential therapeutics is hindered by limited number of structural studies of RNA-ligand complexes. We determined the crystal structure of antisense HR RNA in complex with ANP77 ligand (1.1 Å resolution) and in the free form (0.92 and 1.5 Å resolution). HR RNA folds into a triplex structure composed of four RNA chains. ANP77 interacted with two neighboring single-stranded cytosines to form pseudo-canonical base pairs by adopting sandwich-like conformation and adjusting the position of its naphthyridine units to the helical twist of the RNA. In the unliganded structure, the cytosines formed a peculiar triplex i-motif, assembled by trans C•C+ pair and a third cytosine located at the Hoogsteen edge of the C•C+ pair. These results extend our knowledge of the structural polymorphisms of HR and can be used for rational design of small molecules targeting disease-related RNAs.}, } @article {pmid38738727, year = {2025}, author = {Bhushan, B and Singh, K and Kumar, S and Bhardwaj, A}, title = {Advancements in CRISPR-Based Therapies for Genetic Modulation in Neurodegenerative Disorders.}, journal = {Current gene therapy}, volume = {25}, number = {1}, pages = {34-45}, pmid = {38738727}, issn = {1875-5631}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/genetics ; *Genetic Therapy/methods ; *CRISPR-Cas Systems/genetics ; *Gene Editing/methods ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; Amyotrophic Lateral Sclerosis/therapy/genetics ; Parkinson Disease/therapy/genetics ; Mutation ; Huntington Disease/therapy/genetics ; }, abstract = {Neurodegenerative disorders pose significant challenges in the realm of healthcare, as these conditions manifest in complex, multifaceted ways, often attributed to genetic anomalies. With the emergence of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology, a new frontier has been unveiled in the quest for targeted, precise genetic manipulation. This abstract explores the recent advancements and potential applications of CRISPR-based therapies in addressing genetic components contributing to various neurodegenerative disorders. The review delves into the foundational principles of CRISPR technology, highlighting its unparalleled ability to edit genetic sequences with unprecedented precision. In addition, it talks about the latest progress in using CRISPR to target specific genetic mutations linked to neurodegenerative diseases like Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease. It talks about the most important studies and trials that show how well and safely CRISPR-based therapies work. This shows how this technology can change genetic variants that cause diseases. Notably, the discussion emphasizes the challenges and ethical considerations associated with the implementation of CRISPR in clinical settings, including off-target effects, delivery methods, and long-term implications. Furthermore, the article explores the prospects and potential hurdles in the widespread application of CRISPR technology for treating neurodegenerative disorders. It touches upon the need for continued research, improved delivery mechanisms, and ethical frameworks to ensure responsible and equitable access to these groundbreaking therapies.}, } @article {pmid38738747, year = {2024}, author = {de Araújo, CM and de Alcântara, C and Alencar, MA and da Gama, NAS and Cruzeiro, MM and França, MC and Jaeger, A and Camargos, ST and Machado, TH and de Souza, LC}, title = {Language impairment in sporadic and familial (type 8) amyotrophic lateral sclerosis: A comparative study.}, journal = {Muscle & nerve}, volume = {70}, number = {1}, pages = {130-139}, doi = {10.1002/mus.28109}, pmid = {38738747}, issn = {1097-4598}, support = {//Brazilian National Council for Scientific and Technological Development (CNPq)/ ; 001//CAPES/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Aged ; Language Disorders/etiology/diagnosis ; Adult ; Neuropsychological Tests ; Language Tests ; }, abstract = {INTRODUCTION/AIMS: Language is frequently affected in patients with sporadic amyotrophic lateral sclerosis (sALS), with reduced performance in naming, syntactic comprehension, grammatical expression, and orthographic processing. However, the language profile of patients with familial type 8 ALS (ALS8), linked to p.P56S VAPB mutation, remains unclear. We investigated language in patients with ALS8 by examining their auditory comprehension and verbal production.

METHODS: We included three groups of participants: (1) patients with sALS (n = 20), (2) patients with familial ALS8 (n = 22), and (3) healthy controls (n = 21). The groups were matched for age, sex, and education level. All participants underwent a comprehensive language battery, including the Boston Diagnostic Aphasia Examination, the reduced Token test, letter fluency, categorical fluency (animals), word definition from the Cambridge Semantic Memory Research Battery, and a narrative discourse analysis. Participants also were evaluated using Addenbrooke's Cognitive Exam-Revised Version, the Hospital Anxiety and Depression Scale, and the ALS Functional Rating Scale-Revised.

RESULTS: Compared to controls, sALS and ALS8 patients had impaired performance on oral (syntactic and phonological processing) comprehension and inappropriate discourse cohesion. sALS and ALS8 did not differ in any language measure. There was no correlation between language scores and functional and psychiatric scales.

DISCUSSION: ALS8 patients exhibit language deficits that are independent of motor features. These findings are consistent with the current evidence suggesting that ALS8 has prominent non-motor features.}, } @article {pmid38739752, year = {2024}, author = {Droppelmann, CA and Campos-Melo, D and Noches, V and McLellan, C and Szabla, R and Lyons, TA and Amzil, H and Withers, B and Kaplanis, B and Sonkar, KS and Simon, A and Buratti, E and Junop, M and Kramer, JM and Strong, MJ}, title = {Mitigation of TDP-43 toxic phenotype by an RGNEF fragment in amyotrophic lateral sclerosis models.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {6}, pages = {2053-2068}, pmid = {38739752}, issn = {1460-2156}, support = {P40 OD018537/OD/NIH HHS/United States ; //Temerty Family Foundation/ ; /CAPMC/CIHR/Canada ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; Humans ; *Disease Models, Animal ; *Guanine Nucleotide Exchange Factors/metabolism/genetics ; *Phenotype ; Drosophila ; Mice, Transgenic ; Drosophila Proteins/genetics/metabolism ; Male ; }, abstract = {Aggregation of the RNA-binding protein TAR DNA binding protein (TDP-43) is a hallmark of TDP-proteinopathies including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As TDP-43 aggregation and dysregulation are causative of neuronal death, there is a special interest in targeting this protein as a therapeutic approach. Previously, we found that TDP-43 extensively co-aggregated with the dual function protein GEF (guanine exchange factor) and RNA-binding protein rho guanine nucleotide exchange factor (RGNEF) in ALS patients. Here, we show that an N-terminal fragment of RGNEF (NF242) interacts directly with the RNA recognition motifs of TDP-43 competing with RNA and that the IPT/TIG domain of NF242 is essential for this interaction. Genetic expression of NF242 in a fruit fly ALS model overexpressing TDP-43 suppressed the neuropathological phenotype increasing lifespan, abolishing motor defects and preventing neurodegeneration. Intracerebroventricular injections of AAV9/NF242 in a severe TDP-43 murine model (rNLS8) improved lifespan and motor phenotype, and decreased neuroinflammation markers. Our results demonstrate an innovative way to target TDP-43 proteinopathies using a protein fragment with a strong affinity for TDP-43 aggregates and a mechanism that includes competition with RNA sequestration, suggesting a promising therapeutic strategy for TDP-43 proteinopathies such as ALS and FTD.}, } @article {pmid38739934, year = {2024}, author = {Xin, J and Huang, S and Wen, J and Li, Y and Li, A and Satyanarayanan, SK and Yao, X and Su, H}, title = {Drug Screening and Validation Targeting TDP-43 Proteinopathy for Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {16}, number = {2}, pages = {693-713}, pmid = {38739934}, issn = {2152-5250}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; *TDP-43 Proteinopathies/drug therapy/metabolism ; *DNA-Binding Proteins/metabolism ; Animals ; Drug Evaluation, Preclinical/methods ; Drug Discovery/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) stands as a rare, yet severely debilitating disorder marked by the deterioration of motor neurons (MNs) within the brain and spinal cord, which is accompanied by degenerated corticobulbar/corticospinal tracts and denervation in skeletal muscles. Despite ongoing research efforts, ALS remains incurable, attributed to its intricate pathogenic mechanisms. A notable feature in the pathology of ALS is the prevalence of TAR DNA-binding protein 43 (TDP-43) proteinopathy, detected in approximately 97% of ALS cases, underscoring its significance in the disease's progression. As a result, strategies targeting the aberrant TDP-43 protein have garnered attention as a potential avenue for ALS therapy. This review delves into the existing drug screening systems aimed at TDP-43 proteinopathy and the models employed for drug efficacy validation. It also explores the hurdles encountered in the quest to develop potent medications against TDP-43 proteinopathy, offering insights into the intricacies of drug discovery and development for ALS. Through this comprehensive analysis, the review sheds light on the critical aspects of identifying and advancing therapeutic solutions for ALS.}, } @article {pmid38739991, year = {2024}, author = {Li, X and Liu, N and Wu, D and Li, SC and Wang, Q and Zhang, DW and Song, LL and Huang, M and Chen, X and Li, W}, title = {Hippocampal transcriptomic analyses reveal the potential antiapoptotic mechanism of a novel anticonvulsant agent Q808 on pentylenetetrazol-induced epilepsy in rats.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {175}, number = {}, pages = {116746}, doi = {10.1016/j.biopha.2024.116746}, pmid = {38739991}, issn = {1950-6007}, mesh = {Animals ; *Pentylenetetrazole ; *Hippocampus/drug effects/metabolism/pathology ; *Apoptosis/drug effects ; *Anticonvulsants/pharmacology ; Male ; *Transcriptome/drug effects ; *Epilepsy/drug therapy/chemically induced/genetics ; *Gene Expression Profiling/methods ; Rats ; *Rats, Sprague-Dawley ; Disease Models, Animal ; Neurons/drug effects/metabolism/pathology ; Seizures/chemically induced/genetics/drug therapy ; }, abstract = {Brain apoptosis is one of the main causes of epileptogenesis. The antiapoptotic effect and potential mechanism of Q808, an innovative anticonvulsant chemical, have never been reported. In this study, the seizure stage and latency to reach stage 2 of pentylenetetrazol (PTZ) seizure rat model treated with Q808 were investigated. The morphological change and neuronal apoptosis in the hippocampus were detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, respectively. The hippocampal transcriptomic changes were observed using RNA sequencing (RNA-seq). The expression levels of hub genes were verified by quantitative reverse-transcription PCR (qRT-PCR). Results revealed that Q808 could allay the seizure score and prolong the stage 2 latency in seizure rats. The morphological changes of neurons and the number of apoptotic cells in the DG area were diminished by Q808 treatment. RNA-seq analysis revealed eight hub genes, including Map2k3, Nfs1, Chchd4, Hdac6, Siglec5, Slc35d3, Entpd1, and LOC103690108, and nine hub pathways among the control, PTZ, and Q808 groups. Hub gene Nfs1 was involved in the hub pathway sulfur relay system, and Map2k3 was involved in the eight remaining hub pathways, including Amyotrophic lateral sclerosis, Cellular senescence, Fc epsilon RI signaling pathway, GnRH signaling pathway, Influenza A, Rap1 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway. qRT-PCR confirmed that the mRNA levels of these hub genes were consistent with the RNA-seq results. Our findings might contribute to further studies exploring the new apoptosis mechanism and actions of Q808.}, } @article {pmid38741111, year = {2024}, author = {Maresova, P and Rezny, L and Bauer, P and Valko, M and Kuca, K}, title = {Nonpharmacological intervention therapies for dementia: potential break-even intervention price and savings for selected risk factors in the European healthcare system.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {1293}, pmid = {38741111}, issn = {1471-2458}, support = {ERDF No. CZ.02.1.01/0.0/0.0/18_069/0010054-IT4Neuro(degeneration)//Ministry of Education Youth and Sports/ ; Excellence 2022//UHK FIM/ ; }, mesh = {Humans ; *Dementia/economics/epidemiology/prevention & control ; Risk Factors ; Europe/epidemiology ; Cost Savings ; Aged ; Health Care Costs/statistics & numerical data ; Models, Theoretical ; Male ; Female ; Prevalence ; Aged, 80 and over ; Middle Aged ; }, abstract = {BACKGROUND: New effective treatments for dementia are lacking, and early prevention focusing on risk factors of dementia is important. Non-pharmacological intervention therapies aimed at these factors may provide a valuable tool for reducing the incidence of dementia. This study focused on the development of a mathematical model to predict the number of individuals with neurodegenerative diseases, specifically Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis. Scenarios for non-pharmacological intervention therapies based on risk factor reduction were also assessed. The estimated total costs and potential cost savings from societal were included.

METHODS: Based on demographic and financial data from the EU, a mathematical model was developed to predict the prevalence and resulting care costs of neurodegenerative diseases in the population. Each disease (Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis) used parameters that included prevalence, incidence, and death risk ratio, and the simulation is related to the age of the cohort and the disease stage.

RESULTS: A replicable simulation for predicting the prevalence and resulting cost of care for neurodegenerative diseases in the population exhibited an increase in treatment costs from 267 billion EUR in 2021 to 528 billion EUR by 2050 in the EU alone. Scenarios related to the reduction of the prevalence of dementia by up to 20% per decade led to total discounted treatment cost savings of up to 558 billion EUR.

CONCLUSION: The model indicates the magnitude of the financial burden placed on EU healthcare systems due to the growth in the population prevalence of neurodegenerative diseases in the coming decades. Lifestyle interventions based on reducing the most common risk factors could serve as a prevention strategy to reduce the incidence of dementia with substantial cost-savings potential. These findings could support the implementation of public health approaches throughout life to ultimately prevent premature mortality and promote a healthier and more active lifestyle in older individuals.}, } @article {pmid38741492, year = {2024}, author = {Kanda, S and Kanda, T}, title = {[Multifocal Motor Neuropathy].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {5}, pages = {526-533}, doi = {10.11477/mf.1416202639}, pmid = {38741492}, issn = {1881-6096}, mesh = {Humans ; *Polyneuropathies/physiopathology/diagnosis ; Immunoglobulins, Intravenous/therapeutic use/administration & dosage ; }, abstract = {Multifocal motor neuropathy (MMN), an acquired chronic progressive immune-mediated motor neuropathy, is characterized by asymmetrical distal upper limb muscle weakness and muscle atrophy without sensory impairment. Differentiation from amyotrophic lateral sclerosis is usually challenging, and electrophysiological studies show multifocal conduction blocks. Immunoglobulin (Ig)M GM1 antibodies are detected in approximately 50% of patients. In contrast to chronic inflammatory demyelinating polyneuropathy, corticosteroids are ineffective for management of MMN, and IVIg is the sole established treatment.}, } @article {pmid38742276, year = {2024}, author = {Cheung, SW and Bhavnani, E and Simmons, DG and Bellingham, MC and Noakes, PG}, title = {Perineuronal nets are phagocytosed by MMP-9 expressing microglia and astrocytes in the SOD1[G93A] ALS mouse model.}, journal = {Neuropathology and applied neurobiology}, volume = {50}, number = {3}, pages = {e12982}, doi = {10.1111/nan.12982}, pmid = {38742276}, issn = {1365-2990}, support = {GIC1842//Motor Neuron Disease Research Australia/ ; I2326//Motor Neuron Disease Research Australia/ ; GIV1842//Motor Neuron Disease Research Australia/ ; IG2326//Motor Neuron Disease Research Australia/ ; 1188169//National Health & Medical Research Council Australia/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Astrocytes/metabolism/pathology ; Disease Models, Animal ; Extracellular Matrix/metabolism/pathology ; *Matrix Metalloproteinase 9/metabolism ; Mice, Transgenic ; *Microglia/metabolism/pathology ; Motor Neurons/pathology/metabolism ; *Phagocytosis/physiology ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {AIMS: Perineuronal nets (PNNs) are an extracellular matrix structure that encases excitable neurons. PNNs play a role in neuroprotection against oxidative stress. Oxidative stress within motor neurons can trigger neuronal death, which has been implicated in amyotrophic lateral sclerosis (ALS). We investigated the spatio-temporal timeline of PNN breakdown and the contributing cellular factors in the SOD1[G93A] strain, a fast-onset ALS mouse model.

METHODS: This was conducted at the presymptomatic (P30), onset (P70), mid-stage (P130), and end-stage disease (P150) using immunofluorescent microscopy, as this characterisation has not been conducted in the SOD1[G93A] strain.

RESULTS: We observed a significant breakdown of PNNs around α-motor neurons in the ventral horn of onset and mid-stage disease SOD1[G93A] mice compared with wild-type controls. This was observed with increased numbers of microglia expressing matrix metallopeptidase-9 (MMP-9), an endopeptidase that degrades PNNs. Microglia also engulfed PNN components in the SOD1[G93A] mouse. Further increases in microglia and astrocyte number, MMP-9 expression, and engulfment of PNN components by glia were observed in mid-stage SOD1[G93A] mice. This was observed with increased expression of fractalkine, a signal for microglia engulfment, within α-motor neurons of SOD1[G93A] mice. Following PNN breakdown, α-motor neurons of onset and mid-stage SOD1[G93A] mice showed increased expression of 3-nitrotyrosine, a marker for protein oxidation, which could render them vulnerable to death.

CONCLUSIONS: Our observations suggest that increased numbers of MMP-9 expressing glia and their subsequent engulfment of PNNs around α-motor neurons render these neurons sensitive to oxidative damage and eventual death in the SOD1[G93A] ALS model mouse.}, } @article {pmid38742544, year = {2024}, author = {Donohue, C and Vasilopoulos, T and Wymer, JP and Plowman, EK}, title = {Relationship between pulmonary, cough, and swallowing functions in individuals with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {1}, pages = {140-147}, pmid = {38742544}, issn = {1097-4598}, support = {//Nancy McEwans Wilkins Fellowship for ALS Research Fund/ ; 1R01NS100859/NS/NINDS NIH HHS/United States ; R01 NS100859/NS/NINDS NIH HHS/United States ; //ALS Association/ ; //University of Florida McKnight Brain Institute and BREATHING Research and Therapeutics Center/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Male ; *Cough/physiopathology/etiology ; Female ; Middle Aged ; Aged ; *Deglutition/physiology ; *Deglutition Disorders/physiopathology/etiology ; Vital Capacity/physiology ; Adult ; Lung/physiopathology/diagnostic imaging ; Fluoroscopy ; Respiratory Function Tests ; }, abstract = {INTRODUCTION/AIMS: Evaluations of pulmonary, cough, and swallow function are frequently performed to assess disease progression in amyotrophic lateral sclerosis (ALS), yet the relationship between these functions remains unknown. We therefore aimed to determine relationships between these measures in individuals with ALS.

METHODS: One hundred individuals with ALS underwent standardized tests: forced vital capacity (FVC), maximum expiratory/inspiratory pressure (MEP, MIP), voluntary cough peak expiratory flow (PEF), and videofluoroscopic swallow evaluation (VF). Duplicate raters completed independent, blinded ratings using the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale. Descriptives, Spearman's Rho correlations, Kruskal-Wallis analyses, and Pearson's chi-squared tests were completed.

RESULTS: Mean and standard deviation across pulmonary and cough measures were FVC: 74.2% predicted (± 22.6), MEP: 91.6 cmH2O (± 46.4), MIP cmH2O: 61.1 (± 28.9), voluntary PEF: 352.7 L/min (± 141.6). DIGEST grades included: 0 (normal swallowing): 31%, 1 (mild dysphagia): 48%, 2 (moderate dysphagia): 10%, 3 (severe dysphagia): 10%, and 4 (life-threatening dysphagia): 1%. Positive correlations were observed: MEP-MIP: r = .76, MIP-PEF: r = .68, MEP-PEF: r = .61, MIP-FVC: r = .60, PEF-FVC: r = .49, and MEP-FVC: r = .46, p < .0001. MEP (p = .009) and PEF (p = .04) differed across DIGEST safety grades. Post hoc analyses revealed significant between group differences in MEP and PEF across DIGEST safety grades 0 versus 1 and grades 0 versus 3, (p < .05).

DISCUSSION: In this cohort of individuals with ALS, pulmonary function, and voluntary cough were associated. Expiratory metrics (MEP, PEF) were diminished in individuals with unsafe swallowing, increasing their risk for effectively defending the airway.}, } @article {pmid38742757, year = {2024}, author = {Shephard, VK and Brown, ML and Thompson, BA and Harpur, A and McAlary, L}, title = {Rapid classification of a novel ALS-causing I149S variant in superoxide dismutase-1.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {608-614}, doi = {10.1080/21678421.2024.2351177}, pmid = {38742757}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Superoxide Dismutase-1/genetics ; Middle Aged ; Male ; Female ; Mutation/genetics ; }, abstract = {Variants of the oxygen free radical scavenging enzyme superoxide dismutase-1 (SOD1) are associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). These variants occur in roughly 20% of familial ALS cases, and 1% of sporadic ALS cases. Here, we identified a novel SOD1 variant in a patient in their 50s who presented with movement deficiencies and neuropsychiatric features. The variant was heterozygous and resulted in the isoleucine at position 149 being substituted with a serine (I149S). In silico analysis predicted the variant to be destabilizing to the SOD1 protein structure. Expression of the SOD1[I149S] variant with a C-terminal EGFP tag in neuronal-like NSC-34 cells resulted in extensive inclusion formation and reduced cell viability. Immunoblotting revealed that the intramolecular disulphide between Cys57 and Cys146 was fully reduced for SOD1[I149S]. Furthermore, SOD1[I149S] was highly susceptible to proteolytic digestion, suggesting a large degree of instability to the protein fold. Finally, fluorescence correlation spectroscopy and native-PAGE of cell lysates showed that SOD1[I149S] was monomeric in solution in comparison to the dimeric SOD1[WT]. This experimental data was obtained within 3 months and resulted in the rapid re-classification of the variant from a variant of unknown significance (VUS) to a clinically actionable likely pathogenic variant.}, } @article {pmid38743164, year = {2024}, author = {Zoccolella, S and Milella, G and Giugno, A and Filardi, M and D'Errico, E and Tamburrino, L and Devitofrancesco, V and Damato, R and Piomboni, F and Misceo, S and Logroscino, G}, title = {Nerve conduction study on the split-hand plus index in Amyotrophic lateral sclerosis: correlations with lower motor neuron impairment.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {10}, pages = {4863-4870}, pmid = {38743164}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Neural Conduction/physiology ; Aged ; Case-Control Studies ; *Motor Neurons/physiology ; Hand/physiopathology ; Prospective Studies ; Action Potentials/physiology ; Median Nerve/physiopathology ; Adult ; Nerve Conduction Studies ; }, abstract = {INTRODUCTION: In the arms of patients with Amyotrophic lateral sclerosis (ALS) two peculiar patterns of dissociated muscular atrophy have been described: the split-hand sign (with predominant atrophy of the lateral aspect of the hand, compared to hypothenar eminence) and the split-hand-plus sign (SHPS), a predominant abductor pollicis brevis (ABP) atrophy with sparing of flexor pollicis longus (FPL).

AIMS: In this case-control study, we evaluated the diagnostic utility of a neurophysiological indicator of SHPS and assessed its association with clinical features.

METHODS: We prospectively studied 59 incident ALS patients, 61 patients with ALS-mimic disorders (OND) and 61 non-neurological controls (NNCs). ABP and FPL compound muscle action potentials (CMAP) amplitudes were obtained by supramaximal stimulation of median nerve at elbow. Split-hand plus index (SHPI) was calculated according to the formula: APB-CMAP/FPL-CMAP.

RESULTS: SHPI was significantly lower in ALS compared to OND patients and NNCs (p < 0.0001). SHPI value < 1 was observed in 2% of NNCs and 9% of OND patients and demonstrated an accuracy of 71% in differentiating ALS from OND and an accuracy of 74% in differentiating ALS from NNC. SHPI was associated with higher LMN score, and higher disease severity as quantified by the ALSFRS-r.

CONCLUSION: Our results indicate that SHPI is a reliable indicator to distinguish ALS patients from ONDs and NNCs. SHPI was significantly associated to the degree of lower motor neuron impairment but showed no association with upper motoneuron impairment.}, } @article {pmid38743390, year = {2024}, author = {Vignolo, M and Zuccarino, R and Truffelli, R and Gemelli, C and Giove, E and Ferraro, PM and Manunza, D and Trinchero, C and Cipollina, I and Lungu, M and Lizio, A and Gragnano, G and Cabona, C and Pardini, M and Caponnetto, C and Rao, F}, title = {Dog-assisted physiotherapy in amyotrophic lateral sclerosis: a randomized controlled pilot study.}, journal = {European journal of physical and rehabilitation medicine}, volume = {60}, number = {3}, pages = {470-476}, pmid = {38743390}, issn = {1973-9095}, mesh = {Humans ; Pilot Projects ; *Amyotrophic Lateral Sclerosis/rehabilitation ; Male ; Female ; Middle Aged ; *Animal Assisted Therapy/methods ; Aged ; *Physical Therapy Modalities ; Animals ; Dogs ; Treatment Outcome ; }, abstract = {BACKGROUND: Animal-assisted therapy (AAT) is an intervention in which the animal acts as a co-therapist. It has been mainly used in the context of patients with dementia, showing positive effects on psychological symptoms, but its potential as a physiotherapy treatment for patients with neuromuscular disorders, amyotrophic lateral sclerosis (ALS) in particular, has not yet been investigated.

AIM: The aim of the study was to evaluate the impact of AAT, specifically of dog-assisted therapy, on motor functions and psychological status in patients with ALS.

DESIGN: This study was a randomized controlled pilot study.

SETTING: The study was carried out at the Rehabilitation Unit NEuroMuscular Omnicenter (NEMO) of Arenzano, Genoa.

POPULATION: Sixty hospitalized ALS patients were enrolled.

METHODS: All patients ran a regular two-weeks neurorehabilitation program twice a day. For three days a week, in place of the morning traditional treatment, the AAT group performed a rehabilitation session with a simultaneous interaction with the therapy-dog, while the control group performed a traditional rehabilitation session. The outcome measures were the Timed Up and Go Test, the Short Physical Performance Battery (SPPB), the Six Minutes Walk Test, the Ten Meters walking Test and the Hospital Anxiety and Depression Scale.

RESULTS: Both groups showed an amelioration in motor scales. However, SPPB subscales as well as HADS scores showed a statistically significant improvement only in the AAT group (P values from <0.0001 to 0.0004). Additionally, across almost all motor and psychological measures, post-treatments values were significantly better for the AAT group (P values from <0.0001 to 0.01).

CONCLUSIONS: The obtained results not only suggest that AAT is comparable to traditional physiotherapy treatments, but also evidence that this type of treatment has greater beneficial effects on motor and psychological symptoms in patients with ALS.

This study provides first evidence that AAT is a powerful rehabilitation strategy in patients with ALS, improving both motor and psychological symptoms, and therefore possibly ameliorating quality of life.}, } @article {pmid38743595, year = {2024}, author = {Klose, V and Jesse, S and Lewerenz, J and Kassubek, J and Dorst, J and Rosenbohm, A and Nagel, G and Wernecke, D and Roselli, F and Tumani, H and Ludolph, AC}, title = {Blood-CSF barrier integrity in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {12}, pages = {4254-4264}, doi = {10.1093/brain/awae144}, pmid = {38743595}, issn = {1460-2156}, support = {443642953//Deutsche Zentrum für Neurodegenerative Erkrankungen (DZNE)/ ; 251293561//Danger Response, Disturbance Factors and Regenerative Potential after Acute Trauma/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Male ; Female ; Middle Aged ; Aged ; *Blood-Brain Barrier/metabolism ; Adult ; Albumins/metabolism ; Aged, 80 and over ; Cohort Studies ; }, abstract = {The integrity of the blood-CSF barrier plays a major role in inflammation, but also in shielding the CNS from external and systemic-potentially toxic-factors. Here we report results of measurements of the albumin quotient-which is thought to mirror the integrity of the blood-CSF barrier-in 1059 patients with amyotrophic lateral sclerosis. The results were compared with groups of patients suffering from Alzheimer's disease, facial palsy and tension headache. The albumin quotient, an accepted measure of the blood-CSF barrier integrity, was not significantly different from control populations. In addition, we found that the albumin quotient correlated with survival of the patients; this effect was mainly driven by male patients and influenced by age, body mass index and diabetes mellitus. We conclude that the blood-CSF barrier is intact in this large cohort of patients with amyotrophic lateral sclerosis and that the albumin quotient correlates with survival. Whether this is important for the pathogenesis of the disease, requires mechanistic studies.}, } @article {pmid38744216, year = {2024}, author = {Trivedi, RR and Archambault, AS and Pavlak, C and Gastaldi, M and Cantoni, C and Ghezzi, L and Cross, AH and Miller, TM and Wu, GF}, title = {Prevalence of anti-myelin oligodendrocyte glycoprotein antibodies across neuroinflammatory and neurodegenerative diseases.}, journal = {Journal of the neurological sciences}, volume = {461}, number = {}, pages = {123041}, doi = {10.1016/j.jns.2024.123041}, pmid = {38744216}, issn = {1878-5883}, support = {I01 CX002383/CX/CSRD VA/United States ; }, mesh = {*Myelin-Oligodendrocyte Glycoprotein/immunology ; Humans ; *Autoantibodies/blood ; Female ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/blood/immunology/diagnosis ; *Immunoglobulin G/blood ; Neurodegenerative Diseases/immunology/blood/diagnosis ; Aged ; Neuroinflammatory Diseases/immunology/blood ; Adult ; Multiple Sclerosis/immunology/blood ; Animals ; }, abstract = {Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in patients with CNS diseases, including MS and ALS. In total, 771 serum samples from the John L. Trotter MS Center and the Northeast ALS Consortium were examined using a live cell-based assay for detection of anti-MOG IgG1. Samples from three cohorts were tested in blinded fashion: healthy control (HC) subjects, patients with clinically diagnosed MOGAD, and an experimental group of ALS and MS patients. All samples from established MOGAD cases were positive for anti-MOG antibodies, while all HC samples were negative. Anti-MOG IgG1 was detected in 65 of 658 samples (9.9%) from MS subjects and 4 of 108 (3.7%) samples from ALS subjects. The presence of serum anti-MOG IgG1 in MS and ALS patients raises questions about the contribution of these antibodies to disease pathophysiology as well as accuracy of diagnostic approaches for CNS inflammatory diseases.}, } @article {pmid38745425, year = {2024}, author = {Nona, RJ and Henderson, RD and McCombe, PA}, title = {Neutrophil-to-lymphocyte ratio at diagnosis as a biomarker for survival of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {452-464}, doi = {10.1080/21678421.2024.2351187}, pmid = {38745425}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/blood/diagnosis/mortality ; Humans ; *Neutrophils ; *Lymphocytes ; Female ; Male ; Biomarkers/blood ; Middle Aged ; Aged ; }, abstract = {INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) has previously been reported to be associated with survival in ALS. To provide further information about the role of NLR as a biomarker in ALS, we performed a systematic review, analyzed data from our local cohort of ALS subjects and performed a meta-analysis.

METHODS: (1) The systematic review used established methods. (2) Using data from our cohort of subjects, we analyzed the association of NLR with survival. (3) Meta-analysis was performed using previous studies and our local data.

RESULTS: (1) In the systematic review, higher NLR was associated with shorter survival in all studies. (2) In our subjects, survival was significantly shorter in patients in the highest NLR groups. (3) Meta-analysis showed subjects with highest NLR tertile or with NLR >3 had significantly shorter survival than other subjects.

DISCUSSION: This study supports NLR as a biomarker in ALS; high NLR is associated with poor survival.}, } @article {pmid38745475, year = {2024}, author = {Katangwe-Chigamba, T and Flanagan, E and Mioshi, E}, title = {Implementation of the MiNDToolkit intervention for the management of behavioral symptoms in MND by healthcare professionals: a mixed-methods process evaluation.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {496-505}, pmid = {38745475}, issn = {2167-9223}, mesh = {Humans ; *Health Personnel/psychology/education ; Male ; Female ; *Motor Neuron Disease/psychology/therapy ; *Caregivers/psychology ; Behavioral Symptoms/therapy/etiology ; Middle Aged ; Adult ; Surveys and Questionnaires ; Feasibility Studies ; }, abstract = {OBJECTIVE: MiNDToolkit is a novel psychoeducational intervention for carers to support management of behavioral symptoms in people living with motor neuron disease (PlwMND). Implementation of MiNDToolkit involves delivery of an online intervention to carers, which is reinforced by trained healthcare professionals (HCPs).

METHODS: A mixed-methods process evaluation of the MiNDToolkit feasibility trial was conducted, focusing on reinforcement of the intervention by HCPs. Quantitative data, descriptively analyzed, were included from platform analytics, questionnaire, and 10 semi-structured interviews with HCPs. Interviews were transcribed verbatim; data were inductively analyzed using Reflective Thematic Analysis.

RESULTS: The MiNDToolkit training and platform is a beneficial and acceptable resource for HCPs with potential to increase knowledge and confidence in identifying and managing behavioral symptoms in MND. Implementation barriers included HCPs' perceptions that highlighting behavior changes would be burdensome to carers and assumptions that carers would take the initiative to ask for support from clinicians. Degree of intervention reinforcement varied, with most HCPs delegating intervention delivery solely to the online platform.

CONCLUSIONS: Implementation of the MiNDToolkit was viewed to be feasible and the platform thought to increase accessibility of support to carers. The flexible approach to delivery (online platform and optional HCP reinforcement) is acceptable as an intervention for supporting carers of PlwMND with behavioral symptoms. However, MiNDToolkit should not negate HCP involvement in providing medical and practical information to PlwMND and families. Future research should explore ways to incorporate support for carers in the management of PlwMND alongside standard care, alongside tools such as the MiNDToolkit.}, } @article {pmid38745521, year = {2024}, author = {Fernandez, A and Guenegou, L and Corcia, P and Bailly, N}, title = {The effect of social support on the emotional well-being of people with amyotrophic lateral sclerosis: Exploring the mediating role of spirituality.}, journal = {Palliative & supportive care}, volume = {}, number = {}, pages = {1-8}, doi = {10.1017/S1478951524000610}, pmid = {38745521}, issn = {1478-9523}, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that, so far, is considered always fatal. Treatments mainly consist in increasing survival and aim to improve the quality of life of people with ALS (pwALS). Social support and spirituality have been shown to play a key role in pwALS' quality of life. Our study explored it in depth by investigating the underlying mechanisms linking social support, spirituality, and emotional well-being.

METHODS: Thirty-six pwALS underwent a battery of tests evaluating emotional well-being (emotional well-being scale of the 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire), social support (6-item Social Support Questionnaire), and spiritual well-being (12-item Functional Assessment of Chronic Illness Therapy - Spiritual well-being). Our recruitment was web-based through the FILSLAN and the ARSLA websites as well as through Facebook® advertisements (ALS groups). Data were analyzed by Pearson correlation analysis and Process macro was used in an SPSS program to analyze the mediator variable effect.

RESULTS: Availability of social support, spiritual well-being, and 2 of its dimensions, i.e., meaning and peace, were positively correlated with emotional well-being. The mediational analyses showed that spiritual well-being, meaning, and peace act as mediators in the association between availability of social support and good emotional well-being.

SIGNIFICANCE OF RESULTS: Availability of social support and spirituality are essential for the emotional well-being of pwALS. Spirituality as a mediator between availability of social support and emotional well-being appears as real novel finding which could be explored further. Spiritual well-being, meaning, and peace appear as coping resources for pwALS. We provide practical guidance for professionals working with pwALS.}, } @article {pmid38745522, year = {2024}, author = {Mioshi, E and Grant, K and Flanagan, E and Heal, S and Copsey, H and Gould, RL and Hammond, M and Shepstone, L and Ashford, PA}, title = {An online intervention for carers to manage behavioral symptoms in motor neuron disease (MiNDToolkit): a randomized parallel multi-center feasibility trial.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {506-516}, pmid = {38745522}, issn = {2167-9223}, mesh = {Humans ; *Motor Neuron Disease/psychology/therapy ; Male ; Female ; *Caregivers/psychology ; *Feasibility Studies ; Middle Aged ; Aged ; Behavioral Symptoms/etiology/therapy ; Adult ; }, abstract = {BACKGROUND: Evidence on management of behavioral symptoms in motor neuron disease (MND) is lacking. The MiNDToolkit, an online psychoeducational platform, supports carers dealing with behavioral symptoms (BehSymp). The study objectives were to ascertain recruitment and retention rates, carer and healthcare professional (HCP) use of the platform, and completion of online assessments, to inform a full-scale trial. Design: Randomized, parallel, multi-center, feasibility trial.

SETTING: England and Wales, across diverse MND services; recruitment from July/21 to November/22; last participant follow-up in March/23.

PARTICIPANTS: Carers of people with motor neuron disease (PwMND) with BehSymp, recruited through MND services. After confirming eligibility, participants completed screening and baseline assessments online via the MiNDToolkit platform and were randomized centrally in a 1:1 ratio to MiNDToolkit or control.

INTERVENTION: MiNDToolkit offered tailored modules to carers for the 3-month study period. Carers in the intervention group could receive additional support from MiNDToolkit trained HCPs. The control group was offered access to the intervention at the end of the study. Data were collected on platform usage and psychosocial variables.

MAIN OUTCOMES: One hundred and fifty-one carers from 11 sites were invited to join the study (letter, face-to-face); 30 were screened; 29 were randomized. Fifteen people were allocated to the control arm; 14 to intervention. Carers were mostly female; median age for was 62.5 (IQR: 58, 68; intervention) and 57 (IQR: 56, 70; controls). Study retention was high (24/29 = 82.76%); carers engaged with the platform on average 14 times (median (IQR):14.0 (10.0, 18.5)) during the study period.

CONCLUSION: The MiNDToolkit study was feasible and well accepted by carers and trained HCPs. A definitive trial is warranted.}, } @article {pmid38746326, year = {2025}, author = {Spencer, BE and Xie, SX and Ohm, DT and Elman, L and Quinn, CC and Amado, D and Baer, M and Lee, EB and Van Deerlin, VM and Dratch, L and Massimo, L and Irwin, DJ and McMillan, CT}, title = {Cumulative Incidence of Motor and Cognitive Features in the ALS-FTD Spectrum.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.04.30.24306638}, pmid = {38746326}, support = {K08 NS114106/NS/NINDS NIH HHS/United States ; }, abstract = {UNLABELLED: In frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS), subsequent motor or cognitive-behavioral features, respectively, are associated with shorter survival. However, factors influencing subsequent feature development remain largely unexplored. In this study, we examined whether the presence of a C9orf72 expansion or the initial clinical syndrome was associated with increased risk of subsequent feature development in individuals with ALS and FTD. We performed a retrospective evaluation of the entire disease course of individuals with ALS and FTD who had neuropathological confirmation of TDP-43 proteinopathy at autopsy or a C9orf72 hexanucleotide repeat expansion. We examined the odds and hazard of subsequent feature development and assessed whether each was modified by the presence of a C9orf72 expansion or initial clinical syndrome. At autopsy, we evaluated the association between TDP-43 pathology burden in characteristic brain regions and features across the FTD-ALS spectrum. For individuals with ALS (n=168) and FTD (n=73), binary logistic regression revealed increased odds (OR=3.49[95% CI 1.64-7.80], p=0.002) for developing subsequent features in those with a C9orf72 expansion compared to those without and decreased odds (OR=0.25[95% CI 0.12-0.53], p<0.001) for developing subsequent features in those with an initial ALS clinical syndrome compared to those with an initial FTD clinical syndrome. Cox proportional hazard analyses revealed an increased hazard (HR=3.78[95% CI 1.86-7.65], p<0.001) for developing subsequent features in those with a C9orf72 expansion compared to those without. We observed a 94-month difference in the time after symptom onset of the initial clinical syndrome that a given person without a C9orf72 expansion reached the highest probability of developing subsequent features (0.12[95% CI (0.03-0.19], 113.00 months) and a person with a C9orf72 expansion surpassed that probability (0.13[95% CI 0.06-0.19], 19.00 months). Beyond C9orf72 expansion status, cox proportional hazard analyses revealed a decreased hazard (HR=0.48[95% CI 0.25-0.95], p=0.03) for developing subsequent features in those with an initial ALS clinical syndrome compared to those with an initial FTD clinical syndrome. Age at symptom onset and sex were not associated with development of subsequent features. The distribution of TDP-43 pathology across characteristic brain regions reflected both the initial clinical syndrome and subsequent features, with relatively preserved spinal cord only in FTD cases without subsequent motor features (p<0.0001) and relatively preserved neocortical regions only in ALS cases without subsequent cognitive-behavioral features (p<0.0001). These data highlight the need for clinician vigilance to detect the onset of subsequent motor and cognitive-behavioral features in patients carrying a C9orf72 expansion, regardless of initial clinical syndrome. C9orf72 clinical care can be enhanced through coordination between cognitive and neuromuscular clinics.

ABBREVIATED SUMMARY: Spencer et al. demonstrated both the presence of a C9orf72 expansion and the initial clinical syndrome modify risk of subsequent feature development in frontotemporal degeneration and amyotrophic lateral sclerosis, highlighting the need for clinician vigilance to detect the onset of subsequent motor and cognitive-behavioral features in this disease spectrum.}, } @article {pmid38747014, year = {2024}, author = {Gale, J and Aizenman, E}, title = {The physiological and pathophysiological roles of copper in the nervous system.}, journal = {The European journal of neuroscience}, volume = {60}, number = {1}, pages = {3505-3543}, pmid = {38747014}, issn = {1460-9568}, support = {R01 NS043277/NS/NINDS NIH HHS/United States ; 5T32AG021885/NH/NIH HHS/United States ; R56 NS043277/NS/NINDS NIH HHS/United States ; NS043277/NH/NIH HHS/United States ; T32 GM144300/GM/NIGMS NIH HHS/United States ; T32 AG021885/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Copper/metabolism ; Animals ; Homeostasis/physiology ; Nervous System/metabolism ; }, abstract = {Copper is a critical trace element in biological systems due the vast number of essential enzymes that require the metal as a cofactor, including cytochrome c oxidase, superoxide dismutase and dopamine-β-hydroxylase. Due its key role in oxidative metabolism, antioxidant defence and neurotransmitter synthesis, copper is particularly important for neuronal development and proper neuronal function. Moreover, increasing evidence suggests that copper also serves important functions in synaptic and network activity, the regulation of circadian rhythms, and arousal. However, it is important to note that because of copper's ability to redox cycle and generate reactive species, cellular levels of the metal must be tightly regulated to meet cellular needs while avoiding copper-induced oxidative stress. Therefore, it is essential that the intricate system of copper transporters, exporters, copper chaperones and copper trafficking proteins function properly and in coordinate fashion. Indeed, disorders of copper metabolism such as Menkes disease and Wilson disease, as well as diseases linked to dysfunction of copper-requiring enzymes, such as SOD1-linked amyotrophic lateral sclerosis, demonstrate the dramatic neurological consequences of altered copper homeostasis. In this review, we explore the physiological importance of copper in the nervous system as well as pathologies related to improper copper handling.}, } @article {pmid38747109, year = {2024}, author = {Bender, J and Kojeku, T and Preece, E}, title = {Grading lumbar foraminal stenosis - Interrater agreement of radiologists and radiology trainees before and after education of a standardised grading scale.}, journal = {Journal of medical imaging and radiation oncology}, volume = {68}, number = {5}, pages = {511-515}, doi = {10.1111/1754-9485.13669}, pmid = {38747109}, issn = {1754-9485}, mesh = {Humans ; *Spinal Stenosis/diagnostic imaging ; *Lumbar Vertebrae/diagnostic imaging ; *Observer Variation ; *Magnetic Resonance Imaging/methods ; *Radiologists ; Severity of Illness Index ; Radiology/education ; Reproducibility of Results ; Clinical Competence ; Male ; }, abstract = {INTRODUCTION: Lumbar foraminal stenosis is a key contributor to low back pain. Imaging, particularly MRI, is commonly used in the assessment of foraminal stenosis, contributing to treatment planning. The adoption of a standardised grading system to try and improve inter-rater agreement is thought to be of importance. Our study aims to assess the variability of grading lumbar foraminal stenosis amongst reporting doctors, determine whether education about a validated grading scale increases agreement, and determine if these changes persist over time.

METHODS: A single-site study involving MRI reporting registrars/radiologists was performed. Participants were shown select MRI images and asked to grade the degree of stenosis in each on a 4-point scale. Subsequently, they were educated about Lee et al's grading system and asked to re-grade the cases 1 and 6 weeks later. The level of agreement was calculated using Gwet's AC1 coefficient and Krippendorff's Alpha.

RESULTS: The baseline level of agreement was substantial (AC1 = 0.71). This decreased to a moderate level of agreement post-intervention (AC1 = 0.575 at 1-week, P-value 0.033 and AC1 = 0.598 at 6 weeks, P-value 0.012). A grading of severe stenosis was 21% more likely 6 weeks post-education.

CONCLUSION: The baseline agreement at our institution was substantial, thought to be due to the single-centre nature of the study. Moderate agreement was achieved after education regarding the Lee et al.'s scale, in-line with other studies, with changes maintained at 6 weeks, showing retention of the scale parameters. Grading of severe stenosis was more common post intervention.}, } @article {pmid38747354, year = {2024}, author = {Borghero, G and Pierri, V and Pili, F and Muroni, A and Ercoli, T and Pateri, MI and Pilotto, S and Maccabeo, A and Chiò, A and Defazio, G}, title = {Percutaneous gastrostomy, mechanical ventilation and survival in amyotrophic lateral sclerosis: an observational study in an incident cohort.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {563-569}, doi = {10.1080/21678421.2024.2351185}, pmid = {38747354}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy ; *Gastrostomy/methods ; Male ; Female ; Middle Aged ; Aged ; *Respiration, Artificial/statistics & numerical data ; Cohort Studies ; Retrospective Studies ; Enteral Nutrition/methods/statistics & numerical data ; Adult ; Noninvasive Ventilation/methods ; Survival Analysis ; }, abstract = {OBJECTIVE: To analyze disease-modifying effects of percutaneous endoscopic gastrostomy (PEG) insertion for supporting nutrition, noninvasive ventilation (NIV), and tracheostomy-assisted ('invasive') ventilation (TIV) in amyotrophic lateral sclerosis (ALS).

METHODS: We retrospectively analyzed survival in a large population-based incident cohort that was prospectively followed up in our center. Analysis considered several known ALS-related prognostic variables.

RESULTS: In this population, PEG and NIV in multivariable analysis significantly correlated to survival as computed by disease onset to death/tracheostomy. NIV was associated with better survival while PEG was associated with reduced survival. Other independent prognostic factors were age at ALS onset, diagnostic delay, and flail arm/leg and pure upper motor neuron (PUMN) phenotypes. The length of survival after TIV was significantly associated with age at ALS onset (inverse correlation) whereas other variables did not. The length of survival after TIV correlated to age at ALS onset in such a way that each additional year of age at ALS onset decreased survival by about 0.7 months. Patients who underwent both TIV and NIV did not experience a better survival than those who underwent TIV alone.

CONCLUSION: The lack of effect of enteral nutrition on ALS survival probably reflected the timing of PEG insertion in patients with more severe disease. By contrast, patients who used mechanical ventilation had an increased overall survival compared with non-ventilated ones. The study also provided new information showing that the combined use of NIV and TIV did not may prolong ALS survival as compared to TIV alone.}, } @article {pmid38748065, year = {2024}, author = {Lu, T and Luo, L and Yang, J and Cheng, X and Sun, J}, title = {Circulating Levels of T-Cell Traits and the Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.}, journal = {Molecular neurobiology}, volume = {61}, number = {12}, pages = {10529-10537}, pmid = {38748065}, issn = {1559-1182}, support = {WZ21M01 and WX20C35//the Wuhan Municipal Health Commission/ ; 2019YFC1708601//the National Key Research and Development Program of China/ ; SZ2021ZZ14//the Specific Fund of State Key Laboratory of Dampness Syndrome of Chinese Medicine/ ; 2017B030314176, 2018-75, and 2019-140//the Guangdong Provincial Key Laboratory of Research on Emergency in traditional Chinese medicine (TCM)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood ; Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; Risk Factors ; Genetic Predisposition to Disease ; T-Lymphocytes/immunology/metabolism ; Polymorphism, Single Nucleotide/genetics ; Receptors, CCR7/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) represents a rare and potentially fatal neurodegenerative disease. Diverse T-cell subsets could potentially exert diametrically opposite impacts upon ALS development. A two-sample Mendelian randomization (MR) analysis was performed to investigate the correlation between 244 T-cell subsets and ALS risk. Genetic instrumental variables were procured from a standard genome-wide association study (GWAS) that encompassed 244 T-cell subsets in 3757 individuals of European lineage. ALS-related data were collected from a GWAS comprising 20,806 ALS instances and 59,804 European control participants. Multiple sensitivity analyses were performed to verify the robustness of the significant results. Reverse MR analysis was used for delineating the effects of ALS on the characteristics of T-cells. After multiple comparison corrections, 24 out of the 244 subtypes demonstrated a potential association with ALS risk. Significantly, 75% of these associations encompassed the expression of the CD3 on diverse T-cell subtypes, revealing a highly consistent inverse relation to ALS risk. The proportion of T regulatory cells (Tregs) in CD4+ T cells and secreting Tregs in CD4+ T cells demonstrated negative associations with the risk of ALS. CCR7 expression on naive CD4+ T cells and CCR7 expression on naive CD8+ T cells showed positive associations with ALS risk. Certain T-cell subsets, particularly those identified by CD3 expression on terminally differentiated CD8+ T cells, proportions of Tregs, and CCR7 expression, indicated an association with ALS risk. These findings harmonize with and extend previous observational studies investigating the involvement of T lymphocyte subset-induced immunological processes in ALS.}, } @article {pmid38748695, year = {2024}, author = {Kim, HS and Woo, H and Choi, SJ and Baek, JG and Ryu, JS and Shin, HI and Park, KS and Beom, J}, title = {Factors associated with adherence to noninvasive positive pressure ventilation in amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0302515}, pmid = {38748695}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology ; Female ; Male ; Middle Aged ; *Positive-Pressure Respiration/methods ; *Noninvasive Ventilation ; Aged ; Retrospective Studies ; Blood Gas Analysis ; Length of Stay ; Patient Compliance ; Respiratory Function Tests ; Adult ; }, abstract = {INTRODUCTION: This cohort study aimed to investigate the factors associated with noninvasive positive pressure ventilation adherence and assess the long-term effects of noninvasive positive pressure ventilation adherence in patients with amyotrophic lateral sclerosis (ALS).

METHODS: The medical records of patients with ALS admitted to a tertiary hospital for noninvasive positive pressure ventilation initiation were retrospectively reviewed. Pulmonary function parameters, variables of blood gas analysis, the site of symptom onset, the time from onset and diagnosis to noninvasive positive pressure ventilation application, ALS Functional Rating Scale-Revised, neurophysiological index, and the length of hospital stay were evaluated. The adherence to noninvasive positive pressure ventilation was defined as the use of noninvasive positive pressure ventilation for ≥ 2 h/day or ≥ 4 h/day. The correlations between noninvasive positive pressure ventilation adherence or length of hospital stay and other clinical parameters were analyzed.

RESULTS: Fifty-one patients with ALS were included in the study. The time from onset and diagnosis to NIPPV application was reduced by 16 months in the adherent group than that in the non-adherent group; however, the parameters of blood gas analysis and pulmonary function tests did not differ significantly between the groups. Furthermore, the neurophysiological index of the abductor digiti minimi muscle was higher by 4.05 in the adherent group than that in the non-adherent group. The adherence to noninvasive positive pressure ventilation prolonged tracheostomy-free survival compared to that of non-adherence. Desaturation events, lower forced vital capacity, last pCO2, bicarbonate, and base excess, and higher differences in pCO2, were associated with an increase in the length of hospital stay.

CONCLUSIONS: Noninvasive positive pressure ventilation application shortly after symptom onset and ALS diagnosis in patients with CO2 retention and reduced forced vital capacity can be considered for successful adherence. Adherence to noninvasive positive pressure ventilation may result in reduced tracheostomy conversion rates and prolonged tracheostomy-free survival.}, } @article {pmid38748878, year = {2024}, author = {Koopman, M and Güngördü, L and Janssen, L and Seinstra, RI and Richmond, JE and Okerlund, N and Wardenaar, R and Islam, P and Hogewerf, W and Brown, AEX and Jorgensen, EM and Nollen, EAA}, title = {Rebalancing the motor circuit restores movement in a Caenorhabditis elegans model for TDP-43 toxicity.}, journal = {Cell reports}, volume = {43}, number = {5}, pages = {114204}, doi = {10.1016/j.celrep.2024.114204}, pmid = {38748878}, issn = {2211-1247}, support = {P40 OD010440/OD/NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/metabolism/genetics ; Cholinergic Neurons/metabolism ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; GABAergic Neurons/metabolism ; Locomotion ; Motor Neurons/metabolism ; Movement ; Synaptic Transmission ; *TDP-43 Proteinopathies/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis can be caused by abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons. Here, we use a C. elegans model for TDP-43-induced toxicity to identify the biological mechanisms that lead to disease-related phenotypes. By applying deep behavioral phenotyping and subsequent dissection of the neuromuscular circuit, we show that TDP-43 worms have profound defects in GABA neurons. Moreover, acetylcholine neurons appear functionally silenced. Enhancing functional output of repressed acetylcholine neurons at the level of, among others, G-protein-coupled receptors restores neurotransmission, but inefficiently rescues locomotion. Rebalancing the excitatory-to-inhibitory ratio in the neuromuscular system by simultaneous stimulation of the affected GABA- and acetylcholine neurons, however, not only synergizes the effects of boosting individual neurotransmitter systems, but instantaneously improves movement. Our results suggest that interventions accounting for the altered connectome may be more efficient in restoring motor function than those solely focusing on diseased neuron populations.}, } @article {pmid38749539, year = {2024}, author = {Schwartze, JT and Das, S and Suggitt, D and Baxter, J and Tunstall, S and Ronan, N and Stannard, H and Rezgui, A and Jafar, W and Baxter, DN}, title = {Ward-based in situ simulation: lessons learnt from a UK District General Hospital.}, journal = {BMJ open quality}, volume = {13}, number = {2}, pages = {}, pmid = {38749539}, issn = {2399-6641}, mesh = {Humans ; United Kingdom ; Male ; Female ; *Patient Care Team/standards/statistics & numerical data ; Hospitals, General/statistics & numerical data ; Clinical Competence/statistics & numerical data/standards ; Simulation Training/methods/statistics & numerical data/standards ; Hospitals, District/statistics & numerical data ; Adult ; Patient Safety/standards/statistics & numerical data ; }, abstract = {INTRODUCTION: In situ simulation (ISS) enables multiprofessional healthcare teams to train for real emergencies in their own working environment and identify latent patient safety threats. This study aimed to determine ISS impact on teamwork, technical skill performance, healthcare staff perception and latent error identification during simulated medical emergencies.

MATERIALS AND METHODS: Unannounced ISS sessions (n=14, n=75 staff members) using a high-fidelity mannequin were conducted in medical, paediatric and rehabilitation wards at Stepping Hill Hospital (Stockport National Health Service Foundation Trust, UK). Each session encompassed a 15 min simulation followed by a 15 min faculty-led debrief.

RESULTS: The clinical team score revealed low overall teamwork performances during simulated medical emergencies (mean±SEM: 4.3±0.5). Linear regression analysis revealed that overall communication (r=0.9, p<0.001), decision-making (r=0.77, p<0.001) and overall situational awareness (r=0.73, p=0.003) were the strongest statistically significant predictors of overall teamwork performance. Neither the number of attending healthcare professionals, their professional background, age, gender, degree of clinical experience, level of resuscitation training or previous simulation experience statistically significantly impacted on overall teamwork performance. ISS positively impacted on healthcare staff confidence and clinical training. Identified safety threats included unknown location of intraosseous kits, poor/absent airway management, incomplete A-E assessments, inability to activate the major haemorrhage protocol, unknown location/dose of epinephrine for anaphylaxis management, delayed administration of epinephrine and delayed/absence of attachment of pads to the defibrillator as well as absence of accessing ALS algorithms, poor chest compressions and passive behaviour during simulated cardiac arrests.

CONCLUSION: Poor demonstration of technical/non-technical skills mandate regular ISS interventions for healthcare professionals of all levels. ISS positively impacts on staff confidence and training and drives identification of latent errors enabling improvements in workplace systems and resources.}, } @article {pmid38749729, year = {2025}, author = {Kunieda, K and Hayashi, Y and Fujishima, I and Shimohata, T}, title = {Weight and Muscle Mass Loss Associated with Acute Disease Can Be Reversed with Appropriate Nutrition Therapy and Exercise in a Patient with Amyotrophic Lateral Sclerosis.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {64}, number = {1}, pages = {133-136}, pmid = {38749729}, issn = {1349-7235}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/rehabilitation/therapy/diet therapy/physiopathology ; Aged, 80 and over ; *Exercise Therapy/methods ; *Weight Loss/physiology ; Nutrition Therapy/methods ; Acute Disease ; Deglutition Disorders/etiology/rehabilitation/therapy/physiopathology ; Muscle Strength/physiology ; Body Composition ; Treatment Outcome ; }, abstract = {Nutritional interventions targeting weight loss are useful for the treatment of amyotrophic lateral sclerosis (ALS). However, the changes in body composition after nutritional intervention remain unclear. We herein present a patient with ALS who experienced an increased weight and muscle mass owing to nutritional therapy and physical exercise. An 86-year-old man presented with dysphagia and dysarthria. The patient was diagnosed with bulbar-type ALS. As weight loss progressed, a gastrostomy was performed. After 21 months of disease onset, gastrointestinal bleeding due to a bumper ulcer led to further weight loss (from 40.2 kg to 36.8 kg). The patient experienced difficulty walking and ingesting food orally. Although the total daily energy expenditure (TDEE) was estimated to be 1,122 kcal/day, an intake of 1,500 kcal/day beyond the calculated TDEE was administered. The patient continued to perform daily voluntary exercises in addition to his usual rehabilitation. After 5 months, his weight increased from 36.8 kg to 40.4 kg. Muscle mass increased from 25.1 kg to 30.1 kg, as measured using a multifrequency bioelectrical impedance device. Muscle strength improved from 8.5/10.0 kg to 15.0/18.0 kg in grip strength and from 15.2 kPa to 20.4 kPa in tongue pressure. The patient's physical and swallowing functions also improved. In patients with ALS, a decreased body weight and muscle mass due to acute disease may be improved by appropriate nutritional therapy and physical exercise.}, } @article {pmid38750212, year = {2024}, author = {Leventoux, N and Morimoto, S and Ishikawa, M and Nakamura, S and Ozawa, F and Kobayashi, R and Watanabe, H and Supakul, S and Okamoto, S and Zhou, Z and Kobayashi, H and Kato, C and Hirokawa, Y and Aiba, I and Takahashi, S and Shibata, S and Takao, M and Yoshida, M and Endo, F and Yamanaka, K and Kokubo, Y and Okano, H}, title = {Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {84}, pmid = {38750212}, issn = {1432-0533}, support = {JP15J03921//Japan Society for the Promotion of Science/ ; JP18K07368//Japan Society for the Promotion of Science/ ; JP18KK0239//Japan Society for the Promotion of Science/ ; JP19K17002//Japan Society for the Promotion of Science/ ; JP19K08002//Japan Society for the Promotion of Science/ ; JP21H05278//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP17K10083//Japan Society for the Promotion of Science/ ; JP20H03567//Japan Society for the Promotion of Science/ ; JP22K18388//Japan Society for the Promotion of Science/ ; JP23H02882//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; JP21K06417//Japan Society for the Promotion of Science/ ; JP18K06506//Japan Society for the Promotion of Science/ ; JP22H04923//Japan Society for the Promotion of Science/ ; JP25305030//Japan Society for the Promotion of Science/ ; JP15K09364//Japan Society for the Promotion of Science/ ; JP17H01689//Japan Society for the Promotion of Science/ ; JP18K07514//Japan Society for the Promotion of Science/ ; JP18K07368//Japan Society for the Promotion of Science/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP21F21410//Japan Society for the Promotion of Science/ ; JP21H05273//Japan Society for the Promotion of Science/ ; JP22KF0333//Japan Society for the Promotion of Science/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP22bm0804023//Japan Agency for Medical Research and Development/ ; JP22gm6510006//Japan Agency for Medical Research and Development/ ; JP21wm0425019//Japan Agency for Medical Research and Development/ ; JP17ek0109139//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP20ek0109395//Japan Agency for Medical Research and Development/ ; JP20ek0109329//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; H29-Nanchi-Ippan-085//Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases/ ; JP18KK0239//Japanese Foundation for Research and Promotion of Endoscopy/ ; JP16H06277//MEXT/ ; }, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *Astrocytes/pathology/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Mitochondria/pathology/metabolism ; *Mitochondrial Proteins/genetics/metabolism ; *Transcription Factors/genetics/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.}, } @article {pmid38751168, year = {2024}, author = {Raffaele, S and Nguyen, N and Milanese, M and Mannella, FC and Boccazzi, M and Frumento, G and Bonanno, G and Abbracchio, MP and Bonifacino, T and Fumagalli, M}, title = {Montelukast improves disease outcome in SOD1[G93A] female mice by counteracting oligodendrocyte dysfunction and aberrant glial reactivity.}, journal = {British journal of pharmacology}, volume = {181}, number = {18}, pages = {3303-3326}, doi = {10.1111/bph.16408}, pmid = {38751168}, issn = {1476-5381}, support = {GPR17ALS-1//AriSLA ETS - Fondazione Italiana di ricerca per la SLA/ ; 2017NSXP8J//Italian Ministry of University and Research (MUR)/ ; PE0000006//#NEXTGENERATIONEU (NGEU) and the Italian Ministry of University and Research (MUR), NRRP - National Recovery and Resilience Plan/ ; //Foundation Bellandi Bernardoni/ ; }, mesh = {Animals ; Female ; *Cyclopropanes/pharmacology ; *Quinolines/pharmacology ; *Acetates/pharmacology/therapeutic use ; *Oligodendroglia/drug effects/metabolism/pathology ; *Sulfides/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; *Mice, Transgenic ; Mice ; Male ; Receptors, Leukotriene/metabolism/genetics ; Receptors, G-Protein-Coupled/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Spinal Cord/drug effects/metabolism/pathology ; Microglia/drug effects/metabolism/pathology ; Nerve Tissue Proteins ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron (MN) loss and consequent muscle atrophy, for which no effective therapies are available. Recent findings reveal that disease progression is fuelled by early aberrant neuroinflammation and the loss of oligodendrocytes with neuroprotective and remyelinating properties. On this basis, pharmacological interventions capable of restoring a pro-regenerative local milieu and re-establish proper oligodendrocyte functions may be beneficial.

EXPERIMENTAL APPROACH: Here, we evaluated the in vivo therapeutic effects of montelukast (MTK), an antagonist of the oligodendroglial G protein-coupled receptor 17 (GPR17) and of cysteinyl-leukotriene receptor 1 (CysLT1R) receptors on microglia and astrocytes, in the SOD1[G93A] ALS mouse model. We chronically treated SOD1[G93A] mice with MTK, starting from the early symptomatic disease stage. Disease progression was assessed by behavioural and immunohistochemical approaches.

KEY RESULTS: Oral MTK treatment significantly extended survival probability, delayed body weight loss and ameliorated motor functionalityonly in female SOD1[G93A] mice. Noteworthy, MTK significantly restored oligodendrocyte maturation and induced significant changes in the reactive phenotype and morphological features of microglia/macrophages and astrocytes in the spinal cord of female SOD1[G93A] mice, suggesting enhanced pro-regenerative functions. Importantly, concomitant MN preservation has been detected after MTK administration. No beneficial effects were observed in male mice, highlighting a sex-based difference in the protective activity of MTK.

CONCLUSIONS AND IMPLICATIONS: Our results provide the first preclinical evidence indicating that repurposing of MTK, a safe and marketed anti-asthmatic drug, may be a promising sex-specific strategy for personalized ALS treatment.}, } @article {pmid38751620, year = {2024}, author = {Shojaei, M and Zhou, Q and Palumbo, G and Schaefer, R and Kaskinoro, J and Vehmaan-Kreula, P and Bartenstein, P and Brendel, M and Edbauer, D and Lindner, S}, title = {Development and Preclinical Evaluation of a Copper-64-Labeled Antibody Targeting Glycine-Alanine Dipeptides for PET Imaging of C9orf72-Associated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {5}, pages = {1404-1414}, pmid = {38751620}, issn = {2575-9108}, abstract = {Aggregating poly(glycine-alanine) (poly-GA) is derived from the unconventional translation of the pathogenic intronic hexanucleotide repeat expansion in the C9orf72 gene, which is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Poly-GA accumulates predominantly in neuronal cytoplasmic inclusions unique to C9orf72 ALS/FTD patients. Poly-GA is, therefore, a promising target for PET/CT imaging of FTD/ALS to monitor disease progression and therapeutic interventions. A novel [64]Cu-labeled anti-GA antibody (mAb1A12) targeting the poly-GA protein was developed and evaluated in a transgenic mouse model. It was obtained with high radiochemical purity (RCP), radiochemical yield (RCY), and specific activity, and showed high stability in vitro and ex vivo and specifically bound to poly-GA. The affinity of NODAGA-mAb1A12 for poly-GA was not affected by this modification. [[64]Cu]Cu-NODAGA-mAb1A12 was injected into transgenic mice expressing GFP-(GA)175 in excitatory neurons driven by Camk2a-Cre and in control littermates. PET/CT imaging was performed at 2, 20, and 40 h post-injection (p.i.) and revealed a higher accumulation in the cortex in transgenic mice than in wild-type mice, as reflected by higher standardized uptake value ratios (SUVR) using the cerebellum as the reference region. The organs were isolated for biodistribution and ex vivo autoradiography. Autoradiography revealed a higher cortex-to-cerebellum ratio in the transgenic mice than in the controls. Results from autoradiography were validated by immunohistochemistry and poly-GA immunoassays. Moreover, we confirmed antibody uptake in the CNS in a pharmacokinetic study of the perfused tissues. In summary, [[64]Cu]Cu-NODAGA-mAb1A12 demonstrated favorable in vitro characteristics and an increased relative binding in poly-GA transgenic mice compared to wild-type mice in vivo. Our results with this first-in-class radiotracer suggested that targeting poly-GA is a promising approach for PET/CT imaging in FTD/ALS.}, } @article {pmid38753768, year = {2024}, author = {Prasad, K and Hassan, MI and Raghuvanshi, S and Kumar, V}, title = {Understanding the relationship between cerebellum and the frontal-cortex region of C9orf72-related amyotrophic lateral sclerosis: A comparative analysis of genetic features.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0301267}, pmid = {38753768}, issn = {1932-6203}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; C9orf72 Protein/genetics/metabolism ; *Cerebellum/metabolism/pathology ; *Frontal Lobe/metabolism/pathology ; Frontotemporal Dementia/genetics/pathology/metabolism ; MicroRNAs/genetics/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative diseases for which at present no cure is available. Despite the extensive research the progress from diagnosis to prognosis in ALS and frontotemporal dementia (FTD) has been slow which represents suboptimal understanding of disease pathophysiological processes. In recent studies, several genes have been associated with the ALS and FTD diseases such as SOD1, TDP43, and TBK1, whereas the hexanucleotide GGGGCC repeat expansion (HRE) in C9orf72 gene is a most frequent cause of ALS and FTD, that has changed the understanding of these diseases.

METHODS: The goal of this study was to identify and spatially determine differential gene expression signature differences between cerebellum and frontal cortex in C9orf72-associated ALS (C9-ALS), to study the network properties of these differentially expressed genes, and to identify miRNAs targeting the common differentially expressed genes in both the tissues. This study thus highlights underlying differential cell susceptibilities to the disease mechanisms in C9-ALS and suggesting therapeutic target selection in C9-ALS.

RESULTS: In this manuscript, we have identified that the genes involved in neuron development, protein localization and transcription are mostly enriched in cerebellum of C9-ALS patients, while the UPR-related genes are enriched in the frontal cortex. Of note, UPR pathway genes were mostly dysregulated both in the C9-ALS cerebellum and frontal cortex. Overall, the data presented here show that defects in normal RNA processing and the UPR pathway are the pathological hallmarks of C9-ALS. Interestingly, the cerebellum showed more strong transcriptome changes than the frontal cortex.

CONCLUSION: Interestingly, the cerebellum region showed more significant transcriptomic changes as compared to the frontal cortex region suggesting its active participation in the disease process. This nuanced understanding may offer valuable insights for the development of targeted therapeutic strategies aimed at mitigating disease progression in C9-ALS.}, } @article {pmid38753998, year = {2025}, author = {Yin, Z and Yang, Z and Liu, Y and Zhao, L and Liang, F}, title = {Oxidative stress and neurodegenerative diseases: a bidirectional Mendelian randomization study.}, journal = {Nutritional neuroscience}, volume = {28}, number = {1}, pages = {107-115}, doi = {10.1080/1028415X.2024.2352195}, pmid = {38753998}, issn = {1476-8305}, mesh = {*Mendelian Randomization Analysis ; Humans ; *Oxidative Stress ; *Neurodegenerative Diseases/genetics ; *Genome-Wide Association Study ; Alzheimer Disease/genetics ; Uric Acid/blood ; Zinc/blood ; Amyotrophic Lateral Sclerosis/genetics ; Parkinson Disease/genetics ; alpha-Tocopherol/blood ; Biomarkers/blood ; }, abstract = {INTRODUCTION: Oxidative stress (OS) has been linked to neurodegenerative diseases in numerous epidemiological studies; however, whether it is a pathogenesis or a downstream factor remains controversial.

METHODS: A two-sample bidirectional Mendelian randomization (MR) analysis was implemented to examine evidence of causality of 15 OS injury markers with 3 major neurodegenerative diseases using available genome-wide association studies statistics. As a main approach, inverse-variance weighted (IVW) analysis was performed. The weighted-median (WM) analysis was used to validate the relationship. In order to investigate the existence of horizontal pleiotropy and correct the IVW estimate, the Radial MR approach was applied. To gauge the consistency and robustness of the findings, several sensitivity and pleiotropy analyses were used. For this analysis, p < 0.05 indicates a nominally causal association; according to the Bonferroni correction test, p < 0.0011 indicates a statistically significant causal association.

RESULTS: Via IVW and WM, in directional MR, it was genetically predicted that zinc was nominally causally correlated with the risk of Parkinson's disease but not after Bonferroni correction test; alpha-tocopherol was nominally causally correlated with the risk of Amyotrophic lateral sclerosis (ALS) but not after Bonferroni correction test; furthermore, in reverse MR, it was genetically predicted that Alzheimer's disease was causally correlated with uric acid but not after Bonferroni correction test. These above findings were stable across sensitivity and pleiotropy analyses.

CONCLUSIONS: Based on the current study, there is no authentic genetic causal association between OS biomarkers and neurodegenerative diseases. The complex relationship is required to be confirmed in future experimental research.}, } @article {pmid38755145, year = {2024}, author = {Garcia-Montojo, M and Fathi, S and Rastegar, C and Simula, ER and Doucet-O'Hare, T and Cheng, YHH and Abrams, RPM and Pasternack, N and Malik, N and Bachani, M and Disanza, B and Maric, D and Lee, MH and Wang, H and Santamaria, U and Li, W and Sampson, K and Lorenzo, JR and Sanchez, IE and Mezghrani, A and Li, Y and Sechi, LA and Pineda, S and Heiman, M and Kellis, M and Steiner, J and Nath, A}, title = {TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4163}, pmid = {38755145}, issn = {2041-1723}, support = {I01 BX002466/BX/BLRD VA/United States ; NS003130//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; Female ; Humans ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Asparaginase/genetics/metabolism ; Autoantigens/genetics/metabolism ; Brain/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Motor Cortex/metabolism/pathology ; *Neurons/metabolism/pathology ; *TDP-43 Proteinopathies/metabolism/pathology/genetics ; Endogenous Retroviruses/genetics/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology.}, } @article {pmid38756356, year = {2024}, author = {Rennie, O and Sharma, M and Helwa, N}, title = {Colorectal anastomotic leakage: a narrative review of definitions, grading systems, and consequences of leaks.}, journal = {Frontiers in surgery}, volume = {11}, number = {}, pages = {1371567}, pmid = {38756356}, issn = {2296-875X}, abstract = {BACKGROUND: Anastomotic leaks (ALs) are a significant and feared postoperative complication, with incidence of up to 30% despite advances in surgical techniques. With implications such as additional interventions, prolonged hospital stays, and hospital readmission, ALs have important impacts at the level of individual patients and healthcare providers, as well as healthcare systems as a whole. Challenges in developing unified definitions and grading systems for leaks have proved problematic, despite acknowledgement that colorectal AL is a critical issue in intestinal surgery with serious consequences. The aim of this study was to construct a narrative review of literature surrounding definitions and grading systems for ALs, and consequences of this postoperative complication.

METHODS: A literature review was conducted by examining databases including PubMed, Web of Science, OVID Embase, Google Scholar, and Cochrane library databases. Searches were performed with the following keywords: anastomosis, anastomotic leak, colorectal, surgery, grading system, complications, risk factors, and consequences. Publications that were retrieved underwent further assessment to ensure other relevant publications were identified and included.

RESULTS: A universally accepted definition and grading system for ALs continues to be lacking, leading to variability in reported incidence in the literature. Additional factors add to variability in estimates, including differences in the anastomotic site and institutional/individual differences in operative technique. Various groups have worked to publish guidelines for defining and grading AL, with the International Study Group of Rectal Cancer (ISGRC/ISREC) definition the current most recommended universal definition for colorectal AL. The burden of AL on patients, healthcare providers, and hospitals is well documented in evidence from leak consequences, such as increased morbidity and mortality, higher reoperation rates, and increased readmission rates, among others.

CONCLUSIONS: Colorectal AL remains a significant challenge in intestinal surgery, despite medical advancements. Understanding the progress made in defining and grading leaks, as well as the range of negative outcomes that arise from AL, is crucial in improving patient care, reduce surgical mortality, and drive further advancements in earlier detection and treatment of AL.}, } @article {pmid38757649, year = {2024}, author = {Lee, I and Mitsumoto, H and Lee, S and Kasarskis, E and Rosenbaum, M and Factor-Litvak, P and Nieves, JW}, title = {Reply to Glycemic Index/Load Effect on ALS Progression: Potential Interaction with Riluzole.}, journal = {Annals of neurology}, volume = {96}, number = {1}, pages = {208-209}, doi = {10.1002/ana.26971}, pmid = {38757649}, issn = {1531-8249}, support = {K23NS131586/NS/NINDS NIH HHS/United States ; K23NS131586/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Riluzole/therapeutic use/pharmacology ; *Disease Progression ; *Glycemic Index/drug effects ; Neuroprotective Agents/therapeutic use/pharmacology ; Blood Glucose/drug effects/metabolism ; }, } @article {pmid38758158, year = {2025}, author = {Zou, X and Shi, Y and Zhang, T and Huang, A and Cui, H and Wang, T}, title = {Electroacupuncture Combined with Chinese Herbal Medicine, Qidong Huoluo Granule, for Amyotrophic Lateral Sclerosis: An 8-Month Case Report.}, journal = {Alternative therapies in health and medicine}, volume = {31}, number = {4}, pages = {268-272}, pmid = {38758158}, issn = {1078-6791}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; Male ; Middle Aged ; *Electroacupuncture/methods ; *Drugs, Chinese Herbal/therapeutic use ; Combined Modality Therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult neurodegenerative disorder characterized by progressive muscle weakness and eventual paralysis, for which there is currently no curative treatment. Mainstream medical interventions primarily focus on providing supportive care. However, acupuncture offers promising avenues for alleviating symptoms and enhancing quality of life. Specific acupuncture points are targeted to address bulbar paralysis as well as paralysis affecting the upper and lower extremities.

OBJECTIVE: To investigate the efficacy of electroacupuncture combined with Chinese herbal medicine in delaying disease progression and alleviating symptoms of bulbar paralysis in patients with ALS.

CASE PRESENTATION: A 51-year-old male presented with a 4-year and 8-month history of weakness in his left arm and both legs, accompanied by muscle cramps and diminished coordination, which had rapidly worsened over the past year. ALS was diagnosed, and the patient was initiated on oral Riluzole (50 mg) and Qidong Huoluo granule, a Chinese herbal compound, administered twice daily. Concurrently, he underwent acupuncture treatment sessions twice weekly for over 8 months.

RESULTS: Following acupuncture therapy, the patient experienced gradual stabilization of symptoms, notably improvement in swallowing function. The combination of electroacupuncture and Qidong Huoluo granule resulted in sustained clinical enhancements post-treatment, including improvements in speech, coughing, articulation, and breathing.

CONCLUSION: Electroacupuncture therapy demonstrates the potential to slow disease progression and ameliorate symptoms of bulbar paralysis in ALS patients. However, further robust clinical research is imperative to explain the precise therapeutic role of electroacupuncture in managing this debilitating condition. Continued investigation into the efficacy and safety profile of electroacupuncture holds promise for advancing treatment modalities for ALS.}, } @article {pmid38758193, year = {2024}, author = {Oliveira Santos, M and de Carvalho, M}, title = {Profiling tofersen as a treatment of superoxide dismutase 1 amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {24}, number = {6}, pages = {549-553}, doi = {10.1080/14737175.2024.2355983}, pmid = {38758193}, issn = {1744-8360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Oligonucleotides/therapeutic use ; Oligonucleotides, Antisense/therapeutic use ; Biomarkers/blood ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disorder with a fatal outcome 3-5 years after disease onset due to respiratory complications. Superoxide dismutase 1 (SOD1) mutations are found in about 2% of all patients. Tofersen is a novel oligonucleotide antisense drug specifically developed to treat SOD1-ALS patients.

AREAS COVERED: Our review covers and discusses tofersen pharmacological properties and its phase I/II and III clinical trials results. Other available drugs and their limitations are also addressed.

EXPERT OPINION: VALOR study failed to meet the primary endpoint (change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale score from baseline to week 28, tofersen arm vs. placebo), but a significant reduction in plasma neurofilament light chain (NfL) levels was observed in tofersen arm (60% vs. 20%). PrefALS study has proposed plasma NfL has a potential biomarker for presymptomatic treatment, since it increases 6-12 months before phenoconversion. There is probably a delay between plasma NfL reduction and the clinical benefit. ATLAS study will allow more insights regarding tofersen clinical efficacy in disease progression rate, survival, and even disease onset delay in presymptomatic SOD1 carriers.}, } @article {pmid38758288, year = {2024}, author = {Qi, C and Kobayashi, R and Kawakatsu, S and Kametani, F and Scheres, SHW and Goedert, M and Hasegawa, M}, title = {Tau filaments with the chronic traumatic encephalopathy fold in a case of vacuolar tauopathy with VCP mutation D395G.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {86}, pmid = {38758288}, issn = {1432-0533}, support = {JSPS KAKENHI//Japanese society for the promotion of science/ ; JPMH20GB1002//Ministry of Health, Labour and Welfare/ ; JPMH23GB1003//Ministry of Health, Labour and Welfare/ ; MC_UP_A025-1013/MRC_/Medical Research Council/United Kingdom ; JP20K07922//Japanese society for the promotion of science/ ; MC_UP_A025_1013/MRC_/Medical Research Council/United Kingdom ; MC_U105184291/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Tauopathies/genetics/pathology ; *Chronic Traumatic Encephalopathy/pathology/genetics ; *tau Proteins/genetics/metabolism ; *Valosin Containing Protein/genetics ; *Mutation ; Vacuoles/pathology/ultrastructure ; Male ; Adenosine Triphosphatases/genetics ; Cell Cycle Proteins/genetics ; Middle Aged ; Frontotemporal Dementia/genetics/pathology ; Brain/pathology ; Female ; }, abstract = {Dominantly inherited mutation D395G in the gene encoding valosin-containing protein causes vacuolar tauopathy, a type of behavioural-variant frontotemporal dementia, with marked vacuolation and abundant filamentous tau inclusions made of all six brain isoforms. Here we report that tau inclusions were concentrated in layers II/III of the frontotemporal cortex in a case of vacuolar tauopathy. By electron cryomicroscopy, tau filaments had the chronic traumatic encephalopathy (CTE) fold. Tau inclusions of vacuolar tauopathy share this cortical location and the tau fold with CTE, subacute sclerosing panencephalitis and amyotrophic lateral sclerosis/parkinsonism-dementia complex, which are believed to be environmentally induced. Vacuolar tauopathy is the first inherited disease with the CTE tau fold.}, } @article {pmid38758353, year = {2024}, author = {Mavroudis, I and Alexiou, P and Petridis, F and Ciobica, A and Balmus, IM and Gireadă, B and Gurzu, IL and Novac, O and Novac, B}, title = {Patients' and caregivers' attitudes towards patient assisted suicide or euthanasia in amyotrophic lateral sclerosis-a meta-analysis.}, journal = {Acta neurologica Belgica}, volume = {124}, number = {5}, pages = {1489-1498}, pmid = {38758353}, issn = {2240-2993}, mesh = {*Amyotrophic Lateral Sclerosis/psychology ; Humans ; *Suicide, Assisted/psychology ; *Caregivers/psychology ; *Euthanasia/psychology ; Attitude to Death ; }, abstract = {Assisted suicide and euthanasia are long debated topics in amyotrophic lateral sclerosis (ALS) patients care. We conducted a meta-analysis to evaluate the attitudes of ALS patients and their caregivers toward physician-assisted suicide (PAS) and euthanasia. Also, we were interested to identify the factors associated with the positive or negative attitude of patients and caregivers towards PAS/euthanasia. A thorough search of the online databases (PubMed, Cochrane Library, and Web of Science) was conducted and eligibility criteria according to the PRISMA guidelines were used to include the studies in the current meta-analysis. The assessment of the quality of the selected studies was carried out using a pre-specified set of criteria by Cochrane. The studies that were selected for this meta-analysis suggested that the expression of the wish to die is more likely correlated with depression, anxiety, hopelessness, and lack of optimism. The overall prevalence of considering PAS/euthanasia significantly varies in a dependent manner over the cultural, legal, and societal factors. In this context, we found that the opinion on this topic can be deeply personal and may vary widely among individuals and communities. Lower quality of life and lower religiosity were associated with a positive attitude toward PAS/euthanasia. On the other hand, patients who are more religious are less likely to choose PAS/euthanasia. Gender does not appear to play a significant role in determining attitudes towards PAS/euthanasia in ALS patients. Other factors, such as education and psychological state, could also be important. In conclusion, end-of-life decisions in ALS patients are complex and require careful consideration of individual values, beliefs, and preferences. Understanding the factors that influence a patient's attitude towards PAS/euthanasia can help healthcare providers to offer appropriate care and support for these patients and their families.}, } @article {pmid38758376, year = {2024}, author = {Li, X and Song, C and Wang, Y and Wang, J and Tang, Q and Wu, Z and Zhou, Y and Sun, J and Jia, Y and Lin, Z and Li, S}, title = {Accuracy of 14 intraocular lens power calculation formulas in extremely long eyes.}, journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie}, volume = {262}, number = {11}, pages = {3619-3628}, pmid = {38758376}, issn = {1435-702X}, support = {2020SKC2002//Project Supported by Science and Technology Innovation Program of Socialization Investment of Hunan Province/ ; }, mesh = {Humans ; Retrospective Studies ; *Lenses, Intraocular ; *Refraction, Ocular/physiology ; *Axial Length, Eye ; Female ; Male ; Aged ; *Biometry/methods ; *Optics and Photonics ; Middle Aged ; Reproducibility of Results ; Visual Acuity ; Aged, 80 and over ; Adult ; Lens Implantation, Intraocular ; }, abstract = {PURPOSE: To compare the accuracy of 14 formulas in calculating intraocular lens (IOL) power in extremely long eyes with axial length (AL) over 30.0 mm.

METHODS: In this retrospective study, 211 eyes (211 patients) with ALs > 30.0 mm were successfully treated with cataract surgery without complications. Ocular biometric parameters were obtained from IOLMaster 700. Fourteen formulas were evaluated using the optimized A constants: Barrett Universal II (BUII), Kane, Emmetropia Verifying Optical (EVO) 2.0, PEARL-DGS, T2, SRK/T, Holladay 1, Holladay 2, Haigis and Wang-Koch AL adjusted formulas (SRK/Tmodified-W/K, Holladay 1modified-W/K, Holladay 1NP-modified-W/K, Holladay 2modified-W/K, Holladay 2NP-modified-W/K). The mean prediction error (PE) and standard deviation (SD), mean absolute errors (MAE), median absolute errors (MedAE), and the percentage of prediction errors (PEs) within ± 0.25 D, ± 0.50 D, ± 1.00 D were analyzed.

RESULTS: The Kane formula had the smallest MAE (0.43 D) and MedAE (0.34 D). The highest percentage of PE within ± 0.25 D was for EVO 2.0 (37.91%) and the Holladay 1NP-modified-W/K formulas (37.91%). The Kane formula had the highest percentage of PEs in the range of ± 0.50, ± 0.75, ± 1.00, and ± 2.00 D. There was no significant difference in PEs within ± 0.25, ± 0.50 ± 0.75 and ± 1.00 D between BUII, Kane, EVO 2.0 and Wang-Koch AL adjusted formulas (P > .05) by using Cochran's Q test. The Holladay 2modified-W/K formula has the lowest percentage of hyperopic outcomes (29.38%).

CONCLUSIONS: The BUII, Kane, EVO 2.0 and Wang-Koch AL adjusted formulas have comparable accuracy for IOL power calculation in eyes with ALs > 30.0 mm.}, } @article {pmid38759021, year = {2024}, author = {Pupillo, E and Al-Chalabi, A and Sassi, S and Arippol, E and Tinti, L and Vitelli, E and Copetti, M and Leone, MA and Bianchi, E}, title = {Methodological Quality of Clinical Trials in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {4}, pages = {749-765}, pmid = {38759021}, issn = {2214-3602}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Clinical Trials as Topic/standards ; *Research Design ; }, abstract = {BACKGROUND: More than 200 clinical trials have been performed worldwide in ALS so far, but no agents with substantial efficacy on disease progression have been found.

OBJECTIVE: To describe the methodological quality of all clinical trials performed in ALS and published before December 31, 2022.

METHODS: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses.

RESULTS: 213 trials were included. 47.4% manuscripts described preclinical study evaluation, with a positive effect in all. 67.6% of trials were conducted with a parallel-arm design, while 12.7% were cross-over studies; 77% were randomized, while in 5.6% historical-controls were used for comparison. 70% of trials were double blind. Participant inclusion allowed forced vital capacity (or corresponding slow vital capacity)<50% in 15% cases, between 55-65% in 21.6%, between 70-80% in 14.1% reports, and 49.3% of the evaluated manuscripts did not provide a minimum value for respiratory capacity at inclusion. Disease duration was < 6-months in 6 studies, 7-36 months in 68, 37-60 months in 24, 8 trials requested more than 1-month of disease duration, while in 107 reports a disease duration was not described. Dropout rate was ≥20% in 30.5% trials, while it was not reported for 8.5%.

CONCLUSION: The methodological quality of the included studies was highly variable. Major issues to be addressed in future ALS clinical trials include: the requirement for standard animal toxicology and phase I studies, the resource-intensive nature of phase II-III studies, adequate study methodology and design, a good results reporting.}, } @article {pmid38759454, year = {2024}, author = {Wei, Y and Zhong, S and Yang, H and Wang, X and Lv, B and Bian, Y and Pei, Y and Xu, C and Zhao, Q and Wu, Y and Luo, D and Wang, F and Sun, H and Chen, Y}, title = {Current therapy in amyotrophic lateral sclerosis (ALS): A review on past and future therapeutic strategies.}, journal = {European journal of medicinal chemistry}, volume = {272}, number = {}, pages = {116496}, doi = {10.1016/j.ejmech.2024.116496}, pmid = {38759454}, issn = {1768-3254}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the first and second motoneurons (MNs), associated with muscle weakness, paralysis and finally death. The exact etiology of the disease still remains unclear. Currently, efforts to develop novel ALS treatments which target specific pathomechanisms are being studied. The mechanisms of ALS pathogenesis involve multiple factors, such as protein aggregation, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, apoptosis, inflammation etc. Unfortunately, to date, there are only two FDA-approved drugs for ALS, riluzole and edavarone, without curative treatment for ALS. Herein, we give an overview of the many pathways and review the recent discovery and preclinical characterization of neuroprotective compounds. Meanwhile, drug combination and other therapeutic approaches are also reviewed. In the last part, we analyze the reasons of clinical failure and propose perspective on the treatment of ALS in the future.}, } @article {pmid38759788, year = {2024}, author = {Kumar, RP and Sivan, V and Bachir, H and Sarwar, SA and Ruzicka, F and O'Malley, GR and Lobo, P and Morales, IC and Cassimatis, ND and Hundal, JS and Patel, NV}, title = {Can Artificial Intelligence Mitigate Missed Diagnoses by Generating Differential Diagnoses for Neurosurgeons?.}, journal = {World neurosurgery}, volume = {187}, number = {}, pages = {e1083-e1088}, doi = {10.1016/j.wneu.2024.05.052}, pmid = {38759788}, issn = {1878-8769}, mesh = {Humans ; Diagnosis, Differential ; *Artificial Intelligence ; *Neurosurgeons ; *Missed Diagnosis ; Neurosurgery ; Diagnostic Errors ; }, abstract = {BACKGROUND/OBJECTIVE: Neurosurgery emphasizes the criticality of accurate differential diagnoses, with diagnostic delays posing significant health and economic challenges. As large language models (LLMs) emerge as transformative tools in healthcare, this study seeks to elucidate their role in assisting neurosurgeons with the differential diagnosis process, especially during preliminary consultations.

METHODS: This study employed 3 chat-based LLMs, ChatGPT (versions 3.5 and 4.0), Perplexity AI, and Bard AI, to evaluate their diagnostic accuracy. Each LLM was prompted using clinical vignettes, and their responses were recorded to generate differential diagnoses for 20 common and uncommon neurosurgical disorders. Disease-specific prompts were crafted using Dynamed, a clinical reference tool. The accuracy of the LLMs was determined based on their ability to identify the target disease within their top differential diagnoses correctly.

RESULTS: For the initial differential, ChatGPT 3.5 achieved an accuracy of 52.63%, while ChatGPT 4.0 performed slightly better at 53.68%. Perplexity AI and Bard AI demonstrated 40.00% and 29.47% accuracy, respectively. As the number of considered differentials increased from 2 to 5, ChatGPT 3.5 reached its peak accuracy of 77.89% for the top 5 differentials. Bard AI and Perplexity AI had varied performances, with Bard AI improving in the top 5 differentials at 62.11%. On a disease-specific note, the LLMs excelled in diagnosing conditions like epilepsy and cervical spine stenosis but faced challenges with more complex diseases such as Moyamoya disease and amyotrophic lateral sclerosis.

CONCLUSIONS: LLMs showcase the potential to enhance diagnostic accuracy and decrease the incidence of missed diagnoses in neurosurgery.}, } @article {pmid38759931, year = {2024}, author = {Guo, X and Zhang, Z and Gu, J and Ke, P and Liu, J and Meng, Y and Zheng, W and Que, W and Fan, R and Luo, J and Xiao, F}, title = {FUDNC1-dependent mitophagy ameliorate motor neuron death in an amyotrophic lateral sclerosis mouse model.}, journal = {Neurobiology of disease}, volume = {197}, number = {}, pages = {106534}, doi = {10.1016/j.nbd.2024.106534}, pmid = {38759931}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Mitophagy/physiology ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; Mice ; *Disease Models, Animal ; *Mitochondrial Proteins/metabolism/genetics ; Membrane Proteins/metabolism/genetics ; Humans ; Spinal Cord/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, yet effective treatment is lacking. Moreover, the underlying pathomechanisms of ALS remain unclear, with impaired mitophagy function being increasingly recognized as a contributing factor. FUN14 domain-containing protein 1 (FUNDC1) is an autophagy receptor localized to the outer mitochondrial membrane and a mitochondrial membrane protein that mediates mitophagy and therefore considered as important factor in neurodegenerative diseases. However, its specific role in ALS is not yet clear. Therefore, this study aimed to investigate the regulatory role of FUNDC1 in ALS and determine its regulatory mechanisms. ALS transgenic mice were obtained and maintained under standard conditions. Cell lines were generated by stable transfection with hSOD1[G93A] or control vectors. Mice received intrathecal injections of AAV9 vectors expressing FUNDC1 or EGFP. Motor function was assessed through behavioral tests, and histological and immunostaining analyses were performed. Colocalization analysis was conducted in transfected cells, and protein expression was evaluated via western blotting. We first observed that FUNDC1 was significantly downregulated in the spinal cord tissues of SOD1[G93A] mice. FUNDC1 overexpression considerably improved locomotor activity and prolonged survival time in SOD1[G93A] mice. Mechanistically, reduced expression of FUNDC1 resulted in decreased mitophagy, as indicated by decreased recruitment through LC3 in SOD1[G93A] mice and cellular models. Consequently, this led to increased mitochondrial accumulation and cell apoptosis, exacerbating the ALS phenotype. Furthermore, we identified transcription factor FOXD3 as an essential upstream factor of FUNDC1, resulting in reduced transcription of FUNDC1 in ALS lesions. This study suggests a novel strategy of targeting FUNDC1-mediated mitophagy for developing therapeutic interventions to mitigate disease progression and improve outcomes for ALS patients.}, } @article {pmid38760174, year = {2024}, author = {Pal, A and Grossmann, D and Glaß, H and Zimyanin, V and Günther, R and Catinozzi, M and Boeckers, TM and Sterneckert, J and Storkebaum, E and Petri, S and Wegner, F and Grill, SW and Pan-Montojo, F and Hermann, A}, title = {Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.}, journal = {Life science alliance}, volume = {7}, number = {8}, pages = {}, pmid = {38760174}, issn = {2575-1077}, support = {/ERC_/European Research Council/International ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *RNA-Binding Protein FUS/metabolism/genetics ; *Glycolates/metabolism/pharmacology ; *Mitochondria/metabolism ; *Protein Deglycase DJ-1/metabolism/genetics ; *Lactic Acid/metabolism ; *Superoxide Dismutase-1/metabolism/genetics ; Membrane Potential, Mitochondrial ; Motor Neurons/metabolism ; Lysosomes/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.}, } @article {pmid38760935, year = {2024}, author = {Fiadeiro, MB and Diogo, JC and Silva, AA and Kim, YS and Cristóvão, AC}, title = {NADPH Oxidases in Neurodegenerative Disorders: Mechanisms and Therapeutic Opportunities.}, journal = {Antioxidants & redox signaling}, volume = {41}, number = {7-9}, pages = {522-541}, doi = {10.1089/ars.2023.0002}, pmid = {38760935}, issn = {1557-7716}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *NADPH Oxidases/metabolism/antagonists & inhibitors ; *Reactive Oxygen Species/metabolism ; Animals ; Oxidative Stress ; }, abstract = {Significance: The nicotinamide adenine dinucleotide phosphate oxidase (NOX) enzyme family, located in the central nervous system, is recognized as a source of reactive oxygen species (ROS) in the brain. Despite its importance in cellular processes, excessive ROS generation leads to cell death and is involved in the pathogenesis of neurodegenerative disorders. Recent advances: NOX enzymes contribute to the development of neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and stroke, highlighting their potential as targets for future therapeutic development. This review will discuss NOX's contribution and therapeutic targeting potential in neurodegenerative diseases, focusing on PD, AD, ALS, and stroke. Critical issues: Homeostatic and physiological levels of ROS are crucial for regulating several processes, such as development, memory, neuronal signaling, and vascular homeostasis. However, NOX-mediated excessive ROS generation is deeply involved in the damage of DNA, proteins, and lipids, leading to cell death in the pathogenesis of a wide range of diseases, namely neurodegenerative diseases. Future directions: It is essential to understand the role of NOX homologs in neurodegenerative disorders and the pathological mechanisms undergoing neurodegeneration mediated by increased levels of ROS. This further knowledge will allow the development of new specific NOX inhibitors and their application for neurodegenerative disease therapeutics. Antioxid. Redox Signal. 41, 522-541.}, } @article {pmid38760965, year = {2024}, author = {Lee, SY and Yoo, SH and Cho, B and Kim, KH and Jang, MS and Shin, J and Hwang, I and Choi, SJ and Sung, JJ and Kim, MS}, title = {Burden and preparedness of care partners of people living with amyotrophic lateral sclerosis at home in Korea: A care partner survey.}, journal = {Muscle & nerve}, volume = {70}, number = {3}, pages = {306-315}, doi = {10.1002/mus.28115}, pmid = {38760965}, issn = {1097-4598}, support = {HC21C0115//Patient-Centered Clinical Research Coordinating Center(PACEN) funded by the Ministry of Health and Welfare, Republic of Korea/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology/nursing ; Male ; Republic of Korea/epidemiology ; Female ; *Caregivers/psychology ; Middle Aged ; Aged ; Adult ; Surveys and Questionnaires ; Depression/psychology/therapy/epidemiology ; Home Care Services ; Cost of Illness ; Tracheostomy ; Spouses/psychology ; Caregiver Burden/psychology ; }, abstract = {INTRODUCTION/AIMS: The care burden of people living with amyotrophic lateral sclerosis (pALS) increases with disease progression. This study aimed to investigate the home care status and preparedness of care partners of pALS (cALS) in Korea.

METHODS: An online survey was conducted with family care partners of patients diagnosed with ALS for over 1 year in 2022. The data collected included care time, depression evaluated using the patient health questionnaire-9 (PHQ-9), preparedness for caregiving scale (PCS), and caregiver competence scale (CCS). Results were compared based on whether the pALS underwent a tracheostomy or not.

RESULTS: Ninety-eight cALS of 98 pALS participated in the study, of whom 59 pALS had undergone tracheostomy. Among the cALS, 60.2% were spouses, and 34.7% were children. The cALS took care of the patients for 13 (8-20) hours/day (median, interquartile range [IQR]) on weekdays and 15 (10-24) h/day on weekends. Among the cALS, 91.8% were depressed, and 28.6% had severe depression. The median (IQR) PCS and CCS scores were low (11/32 (8-15) and 8/20 (8-11), respectively), and both were lower in those caring for patients without than with tracheostomy (p < .001 and p < .02, respectively). Most cALS (77.6%) wished to continue caring for their pALS at home.

DISCUSSION: Family care partners of pALS spend more than half of each day caring for patients and are often depressed. Most cALS preferred providing care at home, but felt ill-prepared. Designing home-based medical care is necessary for pALS to thrive at home.}, } @article {pmid38761668, year = {2024}, author = {Silani, V}, title = {Continuity of treatment in ALS: Benefits and challenges of maintaining riluzole over the course of the disease.}, journal = {Journal of the neurological sciences}, volume = {461}, number = {}, pages = {123038}, doi = {10.1016/j.jns.2024.123038}, pmid = {38761668}, issn = {1878-5883}, mesh = {Humans ; *Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neuroprotective Agents/therapeutic use ; Male ; Female ; Middle Aged ; }, } @article {pmid38762243, year = {2024}, author = {Ponzini, E}, title = {Tear biomarkers.}, journal = {Advances in clinical chemistry}, volume = {120}, number = {}, pages = {69-115}, doi = {10.1016/bs.acc.2024.03.002}, pmid = {38762243}, issn = {2162-9471}, mesh = {Humans ; *Tears/metabolism/chemistry ; *Biomarkers/analysis/metabolism ; Eye Diseases/diagnosis/metabolism ; }, abstract = {An extensive exploration of lacrimal fluid molecular biomarkers in understanding and diagnosing a spectrum of ocular and systemic diseases is presented. The chapter provides an overview of lacrimal fluid composition, elucidating the roles of proteins, lipids, metabolites, and nucleic acids within the tear film. Pooled versus single-tear analysis is discussed to underline the benefits and challenges associated with both approaches, offering insights into optimal strategies for tear sample analysis. Subsequently, an in-depth analysis of tear collection methods is presented, with a focus on Schirmer's test strips and microcapillary tubes methods. Alternative tear collection techniques are also explored, shedding light on their applicability and advantages. Variability factors, including age, sex, and diurnal fluctuations, are examined in the context of their impact on tear biomarker analysis. The main body of the chapter is dedicated to discussing specific biomarkers associated with ocular discomfort and a wide array of ocular diseases. From dry eye disease and thyroid-associated ophthalmopathy to keratoconus, age-related macular degeneration, diabetic retinopathy, and glaucoma, the intricate relationship between molecular biomarkers and these conditions is thoroughly dissected. Expanding beyond ocular pathologies, the chapter explores the applicability of tear biomarkers in diagnosing systemic diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and cancer. This broader perspective underscores the potential of lacrimal fluid analysis in offering non-invasive diagnostic tools for conditions with far-reaching implications.}, } @article {pmid38762656, year = {2024}, author = {Li, Z and Kang, H}, title = {Efficacy of non-pharmacological interventions for individuals with amyotrophic lateral sclerosis: systematic review and network meta-analysis of randomized control trials.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {11365}, pmid = {38762656}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/physiopathology ; Humans ; *Randomized Controlled Trials as Topic ; *Quality of Life ; Exercise Therapy/methods ; Treatment Outcome ; Muscle Strength ; }, abstract = {This network meta-analysis (NMA) aimed to compare the efficacy of five non-pharmacological interventions, including exercise intervention (EI), nutritional intervention (NI), respiratory intervention (RI), psychological intervention (PSI), and integrated physical intervention (IPI), on functional status, quality of life, muscle strength, pulmonary function, and safety in patients with amyotrophic lateral sclerosis (ALS). We searched nine databases, PubMed, Cochrane, Embase, Scopus, Web of Science, CNKI, CBM, WFPD, and CSTJ, for randomized controlled trials of ALS patients. The primary outcome was the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score. Secondary outcomes were the McGill Quality of Life Questionnaire (McGill-QoL), Medical Research Council (MRC)-sum score, Forced Vital Capacity (FVC), and Fatigue Severity Scale (FSS) score. This NMA was conducted using random-effect models to calculate the standard mean difference (SMD) and 95% confidence interval (CI). All types of supplemental interventions had some benefit for patients with ALS. EI had a beneficial effect on the ALSFRS-R score (SMD: 1.01; 95% CI 0.50-1.51), FVC (SMD: 0.78; 95% CI 0.02-1.55), McGill-QoL (SMD: 0.71 95% CI 0.33-1.08), and MRC (SMD: 1.11; 95% CI 0.08-2.14). RI had a beneficial effect on the ALSFRS-R score (SMD: 0.83 95% CI 0.12-1.55). IPI had a beneficial effect on the ALSFRS-R score (SMD: 0.65 95% CI 0.06-1.24). NI had a beneficial effect on the McGill-QoL (SMD: 0.63 95% CI 0.02-1.23). The current study findings support a multimodal intervention strategy with an emphasis on EI for slowing disease progression in patients with ALS.}, } @article {pmid38762759, year = {2024}, author = {Wang, Z and Xiong, S and Wu, Z and Wang, X and Gong, Y and Zhu, WG and Xu, X}, title = {VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of autophagy.}, journal = {Autophagy}, volume = {20}, number = {9}, pages = {2041-2054}, pmid = {38762759}, issn = {1554-8635}, mesh = {*Autophagy/physiology/genetics ; Humans ; *Valosin Containing Protein/metabolism/genetics ; *Beclin-1/metabolism ; *Ubiquitination ; Ataxin-3/metabolism/genetics ; Ubiquitin-Protein Ligases/metabolism ; HeLa Cells ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Stability ; HEK293 Cells ; Intracellular Signaling Peptides and Proteins ; }, abstract = {Macroautophagy/autophagy is essential for the degradation and recycling of cytoplasmic materials. The initiation of this process is determined by phosphatidylinositol-3-kinase (PtdIns3K) complex, which is regulated by factor BECN1 (beclin 1). UFMylation is a novel ubiquitin-like modification that has been demonstrated to modulate several cellular activities. However, the role of UFMylation in regulating autophagy has not been fully elucidated. Here, we found that VCP/p97 is UFMylated on K109 by the E3 UFL1 (UFM1 specific ligase 1) and this modification promotes BECN1 stabilization and assembly of the PtdIns3K complex, suggesting a role for VCP/p97 UFMylation in autophagy initiation. Mechanistically, VCP/p97 UFMylation stabilizes BECN1 through ATXN3 (ataxin 3)-mediated deubiquitination. As a key component of the PtdIns3K complex, stabilized BECN1 facilitates assembly of this complex. Re-expression of VCP/p97, but not the UFMylation-defective mutant, rescued the VCP/p97 depletion-induced increase in MAP1LC3B/LC3B protein expression. We also showed that several pathogenic VCP/p97 mutations identified in a variety of neurological disorders and cancers were associated with reduced UFMylation, thus implicating VCP/p97 UFMylation as a potential therapeutic target for these diseases. Abbreviation: ATG14:autophagy related 14; Baf A1:bafilomycin A1;CMT2Y: Charcot-Marie-Toothdisease, axonal, 2Y; CYB5R3: cytochromeb5 reductase 3; DDRGK1: DDRGK domain containing 1; DMEM:Dulbecco'smodified Eagle's medium;ER:endoplasmic reticulum; FBS:fetalbovine serum;FTDALS6:frontotemporaldementia and/or amyotrophic lateral sclerosis 6; IBMPFD1:inclusion bodymyopathy with early-onset Paget disease with or withoutfrontotemporal dementia 1; LC-MS/MS:liquid chromatography tandem mass spectrometry; MAP1LC3B/LC3B:microtubule associated protein 1 light chain 3 beta; MS: massspectrometry; NPLOC4: NPL4 homolog, ubiquitin recognition factor;PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3;PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K:phosphatidylinositol 3-kinase; RPL26: ribosomal protein L26; RPN1:ribophorin I; SQSTM1/p62: sequestosome 1; UBA5: ubiquitin likemodifier activating enzyme 5; UFC1: ubiquitin-fold modifierconjugating enzyme 1; UFD1: ubiquitin recognition factor in ERassociated degradation 1; UFL1: UFM1 specific ligase 1; UFM1:ubiquitin fold modifier 1; UFSP2: UFM1 specific peptidase 2; UVRAG:UV radiation resistance associated; VCP/p97: valosin containingprotein; WT: wild-type.}, } @article {pmid38763702, year = {2024}, author = {Dorrity, TJ and Shin, H and Gertie, JA and Chung, H}, title = {The Sixth Sense: Self-nucleic acid sensing in the brain.}, journal = {Advances in immunology}, volume = {161}, number = {}, pages = {53-83}, pmid = {38763702}, issn = {1557-8445}, support = {R01 AR050026/AR/NIAMS NIH HHS/United States ; R01 NS127802/NS/NINDS NIH HHS/United States ; T32 AR076953/AR/NIAMS NIH HHS/United States ; T32 GM145440/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Brain/metabolism/immunology ; Animals ; *Receptors, Pattern Recognition/metabolism ; *Immunity, Innate ; *Nucleic Acids/immunology/metabolism ; Homeostasis ; Signal Transduction ; }, abstract = {Our innate immune system uses pattern recognition receptors (PRRs) as a first line of defense to detect microbial ligands and initiate an immune response. Viral nucleic acids are key ligands for the activation of many PRRs and the induction of downstream inflammatory and antiviral effects. Initially it was thought that endogenous (self) nucleic acids rarely activated these PRRs, however emerging evidence indicates that endogenous nucleic acids are able to activate host PRRs in homeostasis and disease. In fact, many regulatory mechanisms are in place to finely control and regulate sensing of self-nucleic acids by PRRs. Sensing of self-nucleic acids is particularly important in the brain, as perturbations to nucleic acid sensing commonly leads to neuropathology. This review will highlight the role of nucleic acid sensors in the brain, both in disease and homeostasis. We also indicate the source of endogenous stimulatory nucleic acids where known and summarize future directions for the study of this growing field.}, } @article {pmid38765173, year = {2024}, author = {Souayah, N and Chen, H and Chong, ZZ and Patel, T and Pahwa, A and Menkes, DL and Cunningham, T}, title = {Novel strategy: Identifying new markers for demyelination in diabetic distal symmetrical polyneuropathy.}, journal = {Heliyon}, volume = {10}, number = {9}, pages = {e30419}, pmid = {38765173}, issn = {2405-8440}, abstract = {OBJECTIVE: To develop a novel strategy for identifying acquired demyelination in diabetic distal symmetrical polyneuropathy (DSP).

BACKGROUND: Motor nerve conduction velocity (CV) slowing in diabetic DSP exceeds expectations for pure axonal loss thus implicating superimposed acquired demyelination.

METHODS: After establishing demyelination confidence intervals by regression analysis of nerve conduction data from chronic inflammatory demyelinating polyneuropathy (CIDP), we prospectively studied CV slowing in 90 diabetic DSP patients with and without at least one motor nerve exhibiting CV slowing (groups A and B) into the demyelination range by American Academy of Neurology (AAN) criteria respectively and 95 amyotrophic lateral sclerosis (ALS) patients. Simultaneously, secretory phospholipase A2 (sPLA2) activity was assessed in both diabetic groups and 46 healthy controls.

RESULTS: No ALS patient exhibited CV slowing in more than two motor nerves based on AAN criteria or the confidence intervals. Group A demonstrated a significantly higher percentage of patients as compared to group B fulfilling the above criteria, with an additional criterion of at least one motor nerve exhibiting CV slowing in the demyelinating range and a corresponding F response in the demyelinating range by AAN criteria (70.3 % vs. 1.9 %; p < 0.0001). Urine sPLA2 activity was increased significantly in diabetic groups as compared to healthy controls (942.9 ± 978.0 vs. 591.6 ± 390.2 pmol/min/ml, p < 0.05), and in group A compared to Group B (1328.3 ± 1274.2 vs. 673.8 ± 576.9 pmol/min/ml, p < 0.01). More patients with elevated sPLA2 activity and more than 2 motor nerves with CV slowing in the AAN or the confidence intervals were identified in group A as compared to group B (35.1 % vs. 5.7 %, p < 0.001). Furthermore, 13.5 % of patients in diabetic DSP Group A, and no patients in diabetic DSP Group B, fulfilled an additional criterion of more than one motor nerve with CV slowing into the demyelinating range with its corresponding F response into the demyelinating range by AAN criteria.

CONCLUSION: A combination of regression analysis of electrodiagnostic data and a urine biological marker of systemic inflammation identifies a subgroup of diabetic DSP with superimposed acquired demyelination that may respond favorably to immunomodulatory therapy.}, } @article {pmid38765264, year = {2024}, author = {Colognesi, M and Shkodra, A and Gabbia, D and Kawamata, H and Manfredi, PL and Manfredi, G and De Martin, S}, title = {Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1384829}, pmid = {38765264}, issn = {1664-2295}, support = {R35 NS122209/NS/NINDS NIH HHS/United States ; }, abstract = {INTRODUCTION: The pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the demise of motor neurons has been linked to excitotoxicity caused by excessive calcium influx via N-methyl-D-aspartate receptors (NMDARs), suggesting that uncompetitive NMDAR antagonism could be a strategy to attenuate motor neuron degeneration. REL-1017, the dextro-isomer of racemic methadone, is a low-affinity uncompetitive NMDAR antagonist. Importantly, in humans REL-1017 has shown excellent tolerability in clinical trials for major depression.

METHODS: Here, we tested if REL-1017 improves the disease phenotypes in the G93A SOD1 mouse, a well-established model of familial ALS, by examining survival and motor functions, as well as the expression of genes and proteins involved in neuroplasticity.

RESULTS: We found a sex-dependent effect of REL-1017 in G93A SOD1 mice. A delay of ALS symptom onset, assessed as 10%-decrease of body weight (p < 0.01 vs. control untreated mice) and an extension of lifespan (p < 0.001 vs. control untreated mice) was observed in male G93A SOD1 mice. Female G93A SOD1 mice treated with REL-1017 showed an improvement of muscle strength (p < 0.01 vs. control untreated mice). Both males and females treated with REL-1017 showed a decrease in hind limb clasping. Sex-dependent effects of REL-1017 were also detected in molecular markers of neuronal plasticity (PSD95 and SYN1) in the spinal cord and in the GluN1 NMDAR subunit in quadricep muscles.

CONCLUSION: In conclusion, this study provides preclinical in vivo evidence supporting the clinical evaluation of REL-1017 in ALS.}, } @article {pmid38765269, year = {2024}, author = {Cheng, J and Niu, X and Li, H and Yang, Q and Du, K}, title = {Evaluation of the therapeutic effects of rehabilitation therapy on patients with amyotrophic lateral sclerosis-a meta-analysis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1389146}, pmid = {38765269}, issn = {1664-2295}, abstract = {OBJECTIVE: To investigate the effect of rehabilitation therapy on the global function, respiratory function, and quality of life in patients with amyotrophic lateral sclerosis (ALS).

METHODS: PubMed, Web of Science, and The National Library of Medicine (NLM) were systematically searched and the search period was between the date of database establishment and December 31, 2023. The outcome measures finally analyzed included the ALS functional rating scale/revised (ALSFRS/ALSFRS-R), forced vital capacity percentage predicted (FVC%), fatigue severity scale (FSS), and maximal expiratory pressure (MEP).

RESULTS: A total of 13 randomized controlled trials (RCTs) were included, and 5 outcome measures were pooled and analyzed. A total of 657 patients with ALS were enrolled, with 299 in the experimental group (rehabilitation therapy, such as resistance training, endurance training, aerobic training, respiratory muscle training, and standard rehabilitation therapy) and 358 in the control group (conventional interventions, such as simple joint movements or daily stretching). The ALSFRS scores were better in the experimental group than in the control group at 0-4 months (MD = 3.36, 95% CI: 0.82, 5.91, Z = 2.59, p = 0.009) and at 5-8 months (MD = 5.00, 95% CI: -2.42, 7.58, Z = 3.80, p < 0.001). Moreover, the ALSFRS-R scores of the experimental group was better than that of the control group at 5-8 months (MD = 2.83, 95% CI: 1.21, 4.45, Z = 3.42, p < 0.001) and 9-12 months (MD = 1.87, 95% CI: -0.37, 4.11, Z = 1.63, p = 0.10). It was also found that the MEP value of the experimental group was significantly better than that of the control group after intervention (MD = 18.49, 95% CI: 1.47, 35.50, Z = 2.13, p = 0.03). However, there were no significant differences in FVC% value and FSS scores at 0-5 months and 6-12 months between the two groups.

CONCLUSION: Rehabilitation therapy is helpful in improving the short-, medium-, and long-term global function score of patients with ALS, with positive effects on respiratory function.}, } @article {pmid38766825, year = {2025}, author = {Tedeschi, V and Sapienza, S and Ciancio, R and Canzoniero, LMT and Pannaccione, A and Secondo, A}, title = {Lysosomal Channels as New Molecular Targets in the Pharmacological Therapy of Neurodegenerative Diseases via Autophagy Regulation.}, journal = {Current neuropharmacology}, volume = {23}, number = {4}, pages = {375-383}, pmid = {38766825}, issn = {1875-6190}, support = {PE0000006//National Recovery and Resilience Plan (NRRP), project MNESYS/ ; }, mesh = {Humans ; *Autophagy/drug effects/physiology ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Lysosomes/metabolism/drug effects ; *Transient Receptor Potential Channels/metabolism ; *Calcium Channels/metabolism ; Molecular Targeted Therapy ; }, abstract = {Besides controlling several organellar functions, lysosomal channels also guide the catabolic "self-eating" process named autophagy, which is mainly involved in protein and organelle quality control. Neuronal cells are particularly sensitive to the rate of autophagic flux either under physiological conditions or during the degenerative process. Accordingly, neurodegeneration occurring in Parkinson's (PD), Alzheimer's (AD), and Huntington's Diseases (HD), and Amyotrophic Lateral Sclerosis (ALS) as well as Lysosomal Storage Diseases (LSD) is partially due to defective autophagy and accumulation of toxic aggregates. In this regard, dysfunction of lysosomal ionic homeostasis has been identified as a putative cause of aberrant autophagy. From a therapeutic perspective, Transient Receptor Potential Channel Mucolipin 1 (TRPML1) and Two-Pore Channel isoform 2 (TPC2), regulating lysosomal homeostasis, are now considered promising druggable targets in neurodegenerative diseases. Compelling evidence suggests that pharmacological modulation of TRPML1 and TPC2 may rescue the pathological phenotype associated with autophagy dysfunction in AD, PD, HD, ALS, and LSD. Although pharmacological repurposing has identified several already used drugs with the ability to modulate TPC2, and several tools are already available for the modulation of TRPML1, many efforts are necessary to design and test new entities with much higher specificity in order to reduce dysfunctional autophagy during neurodegeneration.}, } @article {pmid38767073, year = {2024}, author = {Napoletano, G and Circosta, F and Basile, G}, title = {Access to medically-assisted procreation: the withdrawal of paternal consent in the maze of law n. 40/2004.}, journal = {La Clinica terapeutica}, volume = {175}, number = {3}, pages = {163-167}, doi = {10.7417/CT.2024.5057}, pmid = {38767073}, issn = {1972-6007}, mesh = {Humans ; *Reproductive Techniques, Assisted/legislation & jurisprudence/ethics ; Italy ; Female ; Male ; Health Services Accessibility/legislation & jurisprudence ; Cryopreservation ; Parental Consent/legislation & jurisprudence ; Informed Consent/legislation & jurisprudence ; }, abstract = {The law (No.40/2004) stipulates that consent to Medically Assisted Procreation (MAP) remains irrevocable post ovum fertilization. Cryo-preservation introduces complexities, enabling embryo implantation requests after a couple's separation and the dissolution of the original parenthood plan. Constitutional Court Ruling No.161 in 2023 affirmed that the prohibition of revoking consent to MAP aligns with the Italian Constitution and the jurisprudence of the European Court of Human Rights. This delicate equilibrium of conflicting interests upholds human freedom, allowing consent revocation prior to ovocyte fertilization. Permitting revocation until implantation could inflict more significant harm: the infertile woman can in fact miss the opportunity to become a mother, impacting her psychophysical well-being and freedom of self-determination. Moreover, the embryo loses the chance to live, remaining in cryopreservation, which violates its dignity. Addressing this issue requires thorough communication by medical profession-als to inform couples about the limitations on consent revocation. An element of objectivity in terms of standards and evidence-based guidelines, from which norms must originate, is of utmost importance. Relying on broadly shared rules, especially at the international level, is vital in light of the unremitting scientific advances in MAP, as in other areas of medicine, which will open up new opportunities for which current legal/regulatory frameworks are inadequate.}, } @article {pmid38767482, year = {2025}, author = {Martinelli, I and Mandrioli, J and Ghezzi, A and Zucchi, E and Gianferrari, G and Simonini, C and Cavallieri, F and Valzania, F}, title = {Multifaceted superoxide dismutase 1 expression in amyotrophic lateral sclerosis patients: a rare occurrence?.}, journal = {Neural regeneration research}, volume = {20}, number = {1}, pages = {130-138}, pmid = {38767482}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex, brainstem, and spinal cord. While the typical clinical phenotype of ALS involves both upper and lower motor neurons, human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions, expanding the phenotype of ALS. Although superoxide dismutase 1 (SOD1) mutations represent a minority of ALS cases, the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies. Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1 (SOD1-ALS), no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation. In this narrative review, we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS. The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms, pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.}, } @article {pmid38767564, year = {2024}, author = {Natung, T and Pandey, I and Nongrum, B and Sekhose, EK}, title = {Comparison of Hill-RBF 3.0 with Barrett Universal II, SRK/T, Hoffer Q, Haigis, and Holladay 1 to predict the accuracy of post-cataract surgery refractive outcomes in Indian eyes.}, journal = {Indian journal of ophthalmology}, volume = {72}, number = {9}, pages = {1261-1266}, pmid = {38767564}, issn = {1998-3689}, mesh = {Humans ; Prospective Studies ; Male ; Female ; India/epidemiology ; *Refraction, Ocular/physiology ; Middle Aged ; *Visual Acuity/physiology ; Aged ; Follow-Up Studies ; Lenses, Intraocular ; Phacoemulsification ; Postoperative Period ; Lens Implantation, Intraocular ; Refractive Errors/physiopathology/diagnosis/epidemiology ; }, abstract = {PURPOSE: To compare Hill-RBF 3.0 with Barrett Universal II (BU II), SRK/T, Hoffer Q, Haigis, and Holladay 1 in predicting the accuracy of post-cataract surgery refractive outcomes in Indian eyes.

METHODS: In this prospective, comparative, observational study, consecutive patients with uncomplicated age-related cataracts undergoing uneventful phacoemulsification with posterior chamber intraocular lens (IOL) implantation were included. The mean absolute errors (MAEs) and median absolute errors were used to determine the accuracy of predicted postoperative target refractions.

RESULTS: A total of 219 eyes of 173 patients were enrolled. Based on the axial lengths (AL), the patients were classified into: AL <22 mm (short), 22-24.5 mm (normal), and >24.5 mm (long). BU II exhibited the lowest MAE for normal ALs (0.2683 ± 0.2790 D) as well as for the entire population (0.2764 ± 0.2764 D). For the short ALs, Hill RBF 3.0 exhibited the lowest MAE (0.3268 ± 0.3268 D), while for the long ALs, SRK/T showed the lowest MAE (0.2823 ± 0.2642 D). BU II exhibited the highest percentage of eyes of 57.5%, 95.4%, and 98.6% within ±0.25, ±0.75, and ±1.0 D of postoperative target refractions respectively, whereas Hill RBF 3.0 had the highest percentages of eyes (88.1%) within ±0.5 D of postoperative target refraction.

CONCLUSION: Hill-RBF 3.0 exhibited the least MAE for patients with short ALs, while BU II showed the least MAE for normal ALs as well as for the entire population and SRK/T for long ALs. This study is likely to aid surgeons in selecting the most appropriate IOL power formula, which thereby improves the refractive outcomes with utmost accuracy.}, } @article {pmid38768217, year = {2024}, author = {Petrauskas, A and Fortunati, DL and Kandi, AR and Pothapragada, SS and Agrawal, K and Singh, A and Huelsmeier, J and Hillebrand, J and Brown, G and Chaturvedi, D and Lee, J and Lim, C and Auburger, G and VijayRaghavan, K and Ramaswami, M and Bakthavachalu, B}, title = {Structured and disordered regions of Ataxin-2 contribute differently to the specificity and efficiency of mRNP granule formation.}, journal = {PLoS genetics}, volume = {20}, number = {5}, pages = {e1011251}, pmid = {38768217}, issn = {1553-7404}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Ataxin-2/genetics/metabolism ; Animals ; Humans ; *Ribonucleoproteins/genetics/metabolism ; *Drosophila Proteins/genetics/metabolism ; *Drosophila melanogaster/genetics/metabolism ; *RNA, Messenger/genetics/metabolism ; Poly(A)-Binding Proteins/metabolism/genetics ; Animals, Genetically Modified ; Cytoplasmic Granules/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Protein Biosynthesis ; RNA-Binding Proteins/genetics/metabolism ; Intrinsically Disordered Proteins/genetics/metabolism ; Nerve Tissue Proteins/genetics/metabolism ; DNA-Binding Proteins ; }, abstract = {Ataxin-2 (ATXN2) is a gene implicated in spinocerebellar ataxia type II (SCA2), amyotrophic lateral sclerosis (ALS) and Parkinsonism. The encoded protein is a therapeutic target for ALS and related conditions. ATXN2 (or Atx2 in insects) can function in translational activation, translational repression, mRNA stability and in the assembly of mRNP-granules, a process mediated by intrinsically disordered regions (IDRs). Previous work has shown that the LSm (Like-Sm) domain of Atx2, which can help stimulate mRNA translation, antagonizes mRNP-granule assembly. Here we advance these findings through a series of experiments on Drosophila and human Ataxin-2 proteins. Results of Targets of RNA Binding Proteins Identified by Editing (TRIBE), co-localization and immunoprecipitation experiments indicate that a polyA-binding protein (PABP) interacting, PAM2 motif of Ataxin-2 may be a major determinant of the mRNA and protein content of Ataxin-2 mRNP granules. Experiments with transgenic Drosophila indicate that while the Atx2-LSm domain may protect against neurodegeneration, structured PAM2- and unstructured IDR- interactions both support Atx2-induced cytotoxicity. Taken together, the data lead to a proposal for how Ataxin-2 interactions are remodelled during translational control and how structured and non-structured interactions contribute differently to the specificity and efficiency of RNP granule condensation as well as to neurodegeneration.}, } @article {pmid38769202, year = {2024}, author = {Benatar, M and Wuu, J and Huey, ED and McMillan, CT and Petersen, RC and Postuma, R and McHutchison, C and Dratch, L and Arias, JJ and Crawley, A and Houlden, H and McDermott, MP and Cai, X and Thakur, N and Boxer, A and Rosen, H and Boeve, BF and Dacks, P and Cosentino, S and Abrahams, S and Shneider, N and Lingor, P and Shefner, J and Andersen, PM and Al-Chalabi, A and Turner, MR and , }, title = {The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {6}, pages = {364-376}, pmid = {38769202}, issn = {1759-4766}, support = {U01 AG079850/AG/NIA NIH HHS/United States ; RF1 NS105479/NS/NINDS NIH HHS/United States ; R01 MH120794/MH/NIMH NIH HHS/United States ; K01 AG057796/AG/NIA NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; R01 NS105479/NS/NINDS NIH HHS/United States ; R01 AG062268/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/metabolism/pathology ; *Phenotype ; *Frontotemporal Dementia/genetics/diagnosis/metabolism ; Neurodegenerative Diseases/diagnosis/metabolism/genetics ; Biomarkers/metabolism ; }, abstract = {Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.}, } @article {pmid38770222, year = {2024}, author = {Lagrange, E and Loriot, MA and Chaudhary, NK and Schultz, P and Dirks, AC and Guissart, C and James, TY and Vernoux, JP and Camu, W and Tripathi, A and Spencer, PS}, title = {Corrected speciation and gyromitrin content of false morels linked to ALS patients with mostly slow-acetylator phenotypes.}, journal = {eNeurologicalSci}, volume = {35}, number = {}, pages = {100502}, pmid = {38770222}, issn = {2405-6502}, abstract = {A case-control study of sporadic amyotrophic lateral sclerosis (ALS) in a mountainous village in the French Alps discovered an association of cases with a history of eating wild fungi (false morels) collected locally and initially identified and erroneously reported as Gyromitra gigas. Specialist re-examination of dried specimens of the ALS-associated fungi demonstrated they were members of the G. esculenta group, namely G. venenata and G. esculenta, species that have been reported to contain substantially higher concentrations of gyromitrin than present in G. gigas. Gyromitrin is metabolized to monomethylhydrazine, which is responsible not only for the acute oral toxic and neurotoxic properties of false morels but also has genotoxic potential with proposed mechanistic relevance to the etiology of neurodegenerative disease. Most ALS patients had a slow- or intermediate-acetylator phenotype predicted by N-acetyltransferase-2 (NAT2) genotyping, which would increase the risk for neurotoxic and genotoxic effects of gyromitrin metabolites.}, } @article {pmid38771230, year = {2024}, author = {Maccabeo, A and Salustro, E and Sanna, M and Garau, P and Maioli, MA and Coa, R and Puligheddu, M and Borghero, G}, title = {Scleroderma-Polymyositis Overlap Syndrome as a Potential Bulbar Amyotrophic Lateral Sclerosis Mimic.}, journal = {Journal of clinical neuromuscular disease}, volume = {25}, number = {4}, pages = {199-200}, doi = {10.1097/CND.0000000000000467}, pmid = {38771230}, issn = {1537-1611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Diagnosis, Differential ; *Polymyositis/complications ; Scleroderma, Systemic/complications ; }, } @article {pmid38771698, year = {2024}, author = {Alarcan, H and Bruno, C and Emond, P and Raoul, C and Vourc'h, P and Corcia, P and Camu, W and Veyrune, JL and Garlanda, C and Locati, M and Juntas-Morales, R and Saker, S and Suehs, C and Masseguin, C and Kirby, J and Shaw, P and Malaspina, A and De Vos, J and Al-Chalabi, A and Leigh, PN and Tree, T and Bensimon, G and Blasco, H}, title = {Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis.}, journal = {Annals of the New York Academy of Sciences}, volume = {1536}, number = {1}, pages = {82-91}, doi = {10.1111/nyas.15147}, pmid = {38771698}, issn = {1749-6632}, support = {//National Institute of Health and Medical Research/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; *Interleukin-2/administration & dosage/metabolism ; *Metabolomics/methods ; *T-Lymphocytes, Regulatory/metabolism/drug effects/immunology ; Male ; Middle Aged ; Female ; Kynurenine/metabolism ; Aged ; Metabolome/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology.}, } @article {pmid38772669, year = {2024}, author = {Martínez Bilesio, AR and Puig-Castellví, F and Tauler, R and Sciara, M and Fay, F and Rasia, RM and Burdisso, P and García-Reiriz, AG}, title = {Multivariate curve resolution-based data fusion approaches applied in [1]H NMR metabolomic analysis of healthy cohorts.}, journal = {Analytica chimica acta}, volume = {1309}, number = {}, pages = {342689}, doi = {10.1016/j.aca.2024.342689}, pmid = {38772669}, issn = {1873-4324}, mesh = {Humans ; *Metabolomics/methods ; Male ; Female ; Multivariate Analysis ; Healthy Volunteers ; Adult ; Proton Magnetic Resonance Spectroscopy ; Cohort Studies ; Middle Aged ; Least-Squares Analysis ; Young Adult ; }, abstract = {BACKGROUND: Metabolomics plays a critical role in deciphering metabolic alterations within individuals, demanding the use of sophisticated analytical methodologies to navigate its intricate complexity. While many studies focus on single biofluid types, simultaneous analysis of multiple matrices enhances understanding of complex biological mechanisms. Consequently, the development of data fusion methods enabling multiblock analysis becomes essential for comprehensive insights into metabolic dynamics.

RESULTS: This study introduces a novel guideline for jointly analyzing diverse metabolomic datasets (serum, urine, metadata) with a focus on metabolic differences between groups within a healthy cohort. The guideline presents two fusion strategies, 'Low-Level data fusion' (LLDF) and 'Mid-Level data fusion' (MLDF), employing a sequential application of Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS), linking the outcomes of successive analyses. MCR-ALS is a versatile method for analyzing mixed data, adaptable at various stages of data processing-encompassing resonance integration, data compression, and exploratory analysis. The LLDF and MLDF strategies were applied to [1]H NMR spectral data extracted from urine and serum samples, coupled with biochemical metadata sourced from 145 healthy volunteers.

SIGNIFICANCE: Both methodologies effectively integrated and analysed multiblock datasets, unveiling the inherent data structure and variables associated with discernible factors among healthy cohorts. While both approaches successfully detected sex-related differences, the MLDF strategy uniquely revealed components linked to age. By applying this analysis, we aim to enhance the interpretation of intricate biological mechanisms and uncover variations that may not be easily discernible through individual data analysis.}, } @article {pmid38772930, year = {2024}, author = {Kherbek, H and Itoh, CY and Daley, C and Eggers, SD and Hinson, S and Sarker, P and Staff, NP and Pittock, SJ and Dubey, D}, title = {Clinical and serological insights into paraneoplastic brachial amyotrophic diplegia.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4620-4627}, pmid = {38772930}, issn = {1432-1459}, support = {238183//State of Minnesota's David J. Tomassoni ALS Research Grant Program/ ; }, mesh = {Humans ; Male ; Middle Aged ; Retrospective Studies ; Aged ; Female ; *Paraneoplastic Syndromes, Nervous System/immunology/diagnosis/blood ; Adult ; Autoantibodies/blood ; Brachial Plexus Neuropathies/etiology/diagnosis/physiopathology ; Carrier Proteins ; }, abstract = {BACKGROUND: Brachial amyotrophic diplegia (BAD) is typically linked to a neurodegenerative etiology such as amyotrophic lateral sclerosis (ALS). Clinical and serological characterizations of paraneoplastic neurologic syndromes resembling BAD are limited.

METHODS: A retrospective chart review of patients with BAD-like presentations was conducted. Clinical/paraclinical features of paraneoplastic BAD and neurodegenerative BAD cases were compared.

RESULTS: Between 2017 and 2023, 13 cases of BAD were identified, of these 10 were neurodegenerative BAD (ALS variant), and 3 cases associated with paraneoplastic autoimmunity. An additional paraneoplastic BAD case diagnosed in 2005 was included. LUZP4-IgG was detected in all four paraneoplastic cases, with coexisting KLHL11-IgG in three cases and ANNA1 (anti-Hu)-IgG in one case. Out of the four paraneoplastic cases, two patients had seminoma, while the remaining two had limited cancer investigation. Three patients exhibited bi-brachial weakness as the initial symptom before the onset of brainstem symptoms or seizures. Compared to BAD patients with a neurodegenerative etiology, a higher proportion of paraneoplastic cases had ataxia (75% vs 0%, p = 0.011). Other clinical features only detected in the paraneoplastic BAD group were vertigo (n = 2), hearing loss (n = 2) and ophthalmoplegia (n = 2). Electrodiagnostic studies in these patients revealed cervical myotome involvement, supportive of motor neuronopathy. All paraneoplastic cases but none of the neurodegenerative BAD cases exhibited inflammatory cerebrospinal fluid (CSF) findings (lymphocytic pleocytosis and/or supernumerary oligoclonal bands; p = 0.067). Despite the administration of immunotherapy and/or cancer treatment, none of the paraneoplastic patients reported clinical improvement.

DISCUSSION: BAD or bi-brachial neurogenic weakness is a rare phenotypic presentation associated with paraneoplastic autoimmunity. Co-existing features of brainstem dysfunction or cerebellar ataxia should prompt further paraneoplastic evaluation. Common serological and cancer associations among these cases include LUZP4-IgG and KLHL11-IgG, along with testicular germ cell tumors, respectively.}, } @article {pmid38774156, year = {2024}, author = {Canella, C and Braun, C and Witt, CM}, title = {Developing a digital mind body medicine supportive care intervention for people with amyotrophic lateral sclerosis using stakeholder engagement and design thinking.}, journal = {Digital health}, volume = {10}, number = {}, pages = {20552076241255928}, pmid = {38774156}, issn = {2055-2076}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis disease (ALS) is also called the disease of a thousand farewells. Consequently, it is important to offer supportive care interventions that can be applied continuously during the whole course of the disease. People with ALS are interested in complementary and integrative medicine. Due to ALS' progressive nature, digital solutions might be most feasible and accessible for people with ALS in the long-term.

OBJECTIVES: In our study, we explored with stakeholders which digital complementary and integrative medicine interventions and formats are considered as supportive for people with ALS, and which settings are needed by the people with ALS to incorporate the interventions in everyday life.

METHODS: We used a participatory research approach and conducted a stakeholder engagement process, applying a design thinking process with qualitative research methods (interviews, workshops).

RESULTS: Due to the unpredictable course of the disease on their loss of abilities, people with ALS welcome online settings because they are accessible and easy to implement in their daily life. Stakeholders considered the following implementation factors for a complementary and integrative medicine intervention as essential: short-term realization of planned interventions, short duration of interventions, and user-friendliness in terms of accessibility and applicability. Concerning the complementary and integrative medicine interventions, the people with ALS preferred mind body medicine interventions, such as breathing, mindfulness and relaxation exercises.

CONCLUSIONS: Short-term treatment intervals and short online mind body medicine interventions align with the needs of people with ALS. The complementary and integrative medicine interventions as well as the digital infrastructure must meet the special accessibility and applicability needs of people with ALS.}, } @article {pmid38775034, year = {2024}, author = {Brooks, BR}, title = {Letter to the Editor: Glycemic Index/Load Effect on Amyotrophic Lateral Sclerosis Progression: Potential Interaction with Riluzole.}, journal = {Annals of neurology}, volume = {96}, number = {1}, pages = {208}, doi = {10.1002/ana.26970}, pmid = {38775034}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Riluzole/therapeutic use ; *Disease Progression ; *Glycemic Index/drug effects ; Neuroprotective Agents/therapeutic use ; Blood Glucose/metabolism/drug effects ; }, } @article {pmid38775138, year = {2024}, author = {Calma, AD and Pavey, N and Menon, P and Vucic, S}, title = {Neuroinflammation in amyotrophic lateral sclerosis: pathogenic insights and therapeutic implications.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {585-592}, pmid = {38775138}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/immunology/therapy/genetics ; Humans ; *Neuroinflammatory Diseases/immunology ; Animals ; Immunity, Innate/immunology ; Inflammation/immunology ; }, abstract = {PURPOSE OF REVIEW: Neuroinflammation appears to be an important pathogenic process in amyotrophic lateral sclerosis (ALS). Dysfunction of central immune pathways, including activation of microglia and astrocytes, and peripherally derived immune cells, initiate noncell autonomous inflammatory mechanisms leading to degeneration. Cell autonomous pathways linked to ALS genetic mutations have been recently identified as contributing mechanism for neurodegeneration. The current review provides insights into the pathogenic importance of central and peripheral inflammatory processes in ALS pathogenesis and appraises their potential as therapeutic targets.

RECENT FINDINGS: ALS is a multistep process mediated by a complex interaction of genetic, epigenetic, and environmental factors. Noncell autonomous inflammatory pathways contribute to neurodegeneration in ALS. Activation of microglia and astrocytes, along with central nervous system infiltration of peripherally derived pro-inflammatory innate (NK-cells/monocytes) and adaptive (cell-mediated/humoral) immune cells, are characteristic of ALS. Dysfunction of regulatory T-cells, elevation of pro-inflammatory cytokines and dysbiosis of gut microbiome towards a pro-inflammatory phenotype, have been reported as pathogenic mechanisms in ALS.

SUMMARY: Dysregulation of adaptive and innate immunity is pathogenic in ALS, being associated with greater disease burden, more rapid disease course and reduced survival. Strategies aimed at modulating the pro-inflammatory immune components could be of therapeutic utility.}, } @article {pmid38775181, year = {2024}, author = {Marriott, H and Spargo, TP and Al Khleifat, A and Andersen, PM and Başak, NA and Cooper-Knock, J and Corcia, P and Couratier, P and de Carvalho, M and Drory, V and Gotkine, M and Landers, JE and McLaughlin, R and Pardina, JSM and Morrison, KE and Pinto, S and Shaw, CE and Shaw, PJ and Silani, V and Ticozzi, N and van Damme, P and van den Berg, LH and Vourc'h, P and Weber, M and Veldink, JH and , and Dobson, RJ and Schwab, P and Al-Chalabi, A and Iacoangeli, A}, title = {Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {7}, pages = {1775-1786}, pmid = {38775181}, issn = {2328-9503}, support = {//Maudsley NHS Foundation Trust/ ; 22-PDF-609//ALS Association Milton Safenowitz Research/ ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; //BHF British Heart Foundation/ ; //Darby Rimmer MND Foundation/ ; NIHR202421//National Institute for Health Research/ ; Al Khleifat/Oct21/975-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; //MND Scotland/ ; ES/L008238/1//Economic and Social Research Council/ ; //Alan Davidson Foundation/ ; /WT_/Wellcome Trust/United Kingdom ; //Alzheimer's Research UK/ ; //Rosetrees Trust/ ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; //My Name'5 Doddie Foundation/ ; //GlaxoSmithKline/ ; //MRC Medical Research Council/ ; //The NIHR Maudsley Biomedical Research Centre/ ; //Spastic Paraplegia Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Genetic Predisposition to Disease/genetics ; Mutation ; Mutation, Missense ; *Neurofilament Proteins/genetics ; Protein Domains/genetics ; }, abstract = {OBJECTIVE: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk.

METHODS: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta-analyses of published case-control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole-genome sequencing data.

RESULTS: Fixed-effects meta-analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13-9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14-1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18-1.77, pMadsen-Browning = 0.0007, pSKAT-O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86-4.37, pMadsen-Browning = 0.039), supporting the meta-analysis results. Finally, several tail in-frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricate architecture that requires further investigation.

INTERPRETATION: We showed that NEFH tail missense and in-frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered.}, } @article {pmid38775192, year = {2024}, author = {Ju, W and Ban, JJ and Im, HR and Ko, SH and Seo, J and Min, YG and Hong, YH and Choi, SJ and Sung, JJ}, title = {Association of serum Spp1 levels with disease progression in ALS and SBMA.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {7}, pages = {1809-1818}, pmid = {38775192}, issn = {2328-9503}, support = {2018R1A5A2025964//National Research Foundation of Korea/ ; 2020R1C1C1005122//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/physiopathology/diagnosis ; *Osteopontin/blood ; Male ; Female ; Middle Aged ; *Disease Progression ; Aged ; Biomarkers/blood ; Adult ; Neuroinflammatory Diseases/blood ; Cytokines/blood ; }, abstract = {OBJECTIVE: In comparison with amyotrophic lateral sclerosis (ALS), the contribution of neuroinflammation in spinobulbar muscular atrophy (SBMA) has been less explored. We investigated the role of neuroinflammation in the pathogenesis of ALS and SBMA by analyzing systemic inflammatory markers and osteopontin (Spp1).

METHODS: This study involved 105 ALS, 77 SBMA, and 55 healthy controls. We measured their systemic inflammatory markers, serum Spp1, and cytokine levels (interferon-γ, interleukin [IL]-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α, and IL-17A), investigated correlations between Spp1 levels and clinical features, and evaluated ALS survival rates according to Spp1 levels.

RESULTS: In the ALS group, systemic inflammatory markers were significantly higher than in the control and SBMA groups. Spp1 levels were observed to be higher in ALS patients, but the difference was not statistically significant among the study groups. Cytokine profiles were comparable. In ALS, higher Spp1 levels were correlated with lower ALS Functional Rating Scale-Revised (ALSFRS-R) scores (r = -0.25, p = 0.02) and faster disease progression rate (r = 0.37, p < 0.001). After adjusting for other prognostic indicators, high Spp1 levels were independently associated with shorter survival in ALS patients (hazard ratio 13.65, 95% confidence interval 2.57-72.53, p < 0.01).

INTERPRETATION: Neuroinflammation does not appear to be a primary contributor to the pathogenesis of SBMA. Serum Spp1 levels may serve as a reliable biomarker for disease progression and prognosis in ALS. These findings expand our understanding of these two distinct motor neuron disorders and offer a potential biomarker for future studies.}, } @article {pmid38775303, year = {2024}, author = {Zhang, J and Yang, F and Li, M and Zhu, Y and Huang, X}, title = {Quantitative evaluation of factors influencing the 3 Hz repetitive nerve stimulation test in patients with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {2}, pages = {194-203}, doi = {10.1002/mus.28165}, pmid = {38775303}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; Adult ; Electric Stimulation/methods ; Neuromuscular Junction/physiopathology ; Electromyography/methods ; }, abstract = {INTRODUCTION/AIMS: Previous studies have suggested that treatments targeting the neuromuscular junction (NMJ) may play a role in the treatment of amyotrophic lateral sclerosis (ALS). However, factors impacting repetitive nerve stimulation (RNS), a technique to evaluate NMJ function, have yet to be fully elucidated. We aimed to identify independent factors contributing to the decremental response of the accessory nerve and evaluated its value in ALS clinical practice.

METHODS: A total of 626 patients who were diagnosed with ALS and underwent 3 Hz RNS tests on the accessory nerve were enrolled. Data on their clinical and electrophysiological indicators were divided into a training set (collected from June 2016 to December 2022) and a test set (collected from January to August 2023). Stepwise regression was used in independent variable selection and model building.

RESULTS: Forty-two percent of patients had a decrement larger than 10% and 24% had a decrement larger than 15%. Onset age, sex, onset site, forced vital capacity (FVC) and motor unit potential (MUP) duration were independent factors contributing to the results of the RNS test. MUP duration had the greatest impact on decremental response, followed by FVC and onset age. The decremental response in females was larger than in males. Upper limb onset was found to contribute more to the decrement than lower limb or bulbar onset.

DISCUSSION: In patients with ALS, NMJ safety factor is reduced during re-innervation. Decremental response is affected by multiple factors, which needs to be considered in clinical trials targeting the NMJ in these patients.}, } @article {pmid38775852, year = {2024}, author = {Ebrahimi, P and Davoudi, E and Sadeghian, R and Zadeh, AZ and Razmi, E and Heidari, R and Morowvat, MH and Sadeghian, I}, title = {In vivo and ex vivo gene therapy for neurodegenerative diseases: a promise for disease modification.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {397}, number = {10}, pages = {7501-7530}, pmid = {38775852}, issn = {1432-1912}, support = {29849//Shiraz University of Medical Sciences/ ; }, mesh = {Humans ; *Genetic Therapy/methods ; Animals ; *Neurodegenerative Diseases/therapy/genetics ; Gene Editing/methods ; }, abstract = {Neurodegenerative diseases (NDDs), including AD, PD, HD, and ALS, represent a growing public health concern linked to aging and lifestyle factors, characterized by progressive nervous system damage leading to motor and cognitive deficits. Current therapeutics offer only symptomatic management, highlighting the urgent need for disease-modifying treatments. Gene therapy has emerged as a promising approach, targeting the underlying pathology of diseases with diverse strategies including gene replacement, gene silencing, and gene editing. This innovative therapeutic approach involves introducing functional genetic material to combat disease mechanisms, potentially offering long-term efficacy and disease modification. With advancements in genomics, structural biology, and gene editing tools such as CRISPR/Cas9, gene therapy holds significant promise for addressing the root causes of NDDs. Significant progress in preclinical and clinical studies has demonstrated the potential of in vivo and ex vivo gene therapy to treat various NDDs, offering a versatile and precise approach in comparison to conventional treatments. The current review describes various gene therapy approaches employed in preclinical and clinical studies for the treatment of NDDs, including AD, PD, HD, and ALS, and addresses some of the key translational challenges in this therapeutic approach.}, } @article {pmid38776297, year = {2024}, author = {Issa, NP and Aydin, S and Polley, E and Carberry, N and Garret, MA and Smith, S and Habib, AA and Baumgartner, NW and Soliven, B and Rezania, K}, title = {Intermuscular coherence as an early biomarker for amyotrophic lateral sclerosis: The protocol for a prospective, multicenter study.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0303053}, pmid = {38776297}, issn = {1932-6203}, support = {R01 NS116262/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Biomarkers/analysis ; *Electromyography/methods ; Motor Neurons/pathology ; Muscle, Skeletal/physiopathology/pathology ; Prospective Studies ; Multicenter Studies as Topic ; }, abstract = {OBJECTIVE: To describe the protocol of a prospective study to test the validity of intermuscular coherence (IMC) as a diagnostic tool and biomarker of upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS).

METHODS: This is a multicenter, prospective study. IMC of muscle pairs in the upper and lower limbs is gathered in ∼650 subjects across three groups using surface electrodes and conventional electromyography (EMG) machines. The following subjects will be tested: 1) neurotypical controls; 2) patients with symptomatology suggestive for early ALS but not meeting probable or definite ALS by Awaji Criteria; 3) patients with a known ALS mimic. The recruitment period is between 3/31/2021 and 12/31/2025. Written consent will be sought from the subject or the subject's legally authorized representative during enrollment.

RESULTS: The endpoints of this study include: 1) whether adding IMC to the Awaji ALS criteria improve its sensitivity in early ALS and can allow for diagnosis earlier; 2) constructing a database of IMC across different ages, genders, and ethnicities.

SIGNIFICANCE: This study may validate a new inexpensive, painless, and widely available tool for the diagnosis of ALS.}, } @article {pmid38776614, year = {2024}, author = {López-Figueroa, C and Domingo, M and Duignan, PJ and Cuvertoret-Sanz, M and Martí-García, B and Pintado, E and Martinez, M and Martínez, J}, title = {Air leak syndrome in animals: definition and pathogenesis.}, journal = {Journal of comparative pathology}, volume = {211}, number = {}, pages = {42-51}, doi = {10.1016/j.jcpa.2024.04.005}, pmid = {38776614}, issn = {1532-3129}, mesh = {Animals ; Cats ; *Pneumothorax/veterinary/etiology ; Dogs ; Mediastinal Emphysema/veterinary ; Retrospective Studies ; Cat Diseases/pathology ; Dog Diseases/pathology ; Female ; Male ; Subcutaneous Emphysema/veterinary/etiology ; Pneumoperitoneum/veterinary ; }, abstract = {Air leak syndrome (ALS) is described in human medicine as a constellation of clinical disorders including pneumomediastinum, pneumopericardium, pulmonary interstitial emphysema, pneumothorax, pneumoperitoneum, pneumoretroperitoneum and subcutaneous emphysema. The pathogenesis of ALS depends on the anatomy of the mediastinum and its associations with thoracic, abdominal and cervical connective tissues, as well as a physical phenomenon referred to as the Macklin effect. Various animal species develop diverse combinations of these lesions, although ALS has not been recognized in animals. However, this term aids pathologists in addressing this disease compilation. The aim of this retrospective study is to illustrate examples of ALS in animals by arbitrarily selecting 13 cases in dogs, cats, pinnipeds, sea otters and harbour porpoises. ALS can be classified into three groups based on aetiology: iatrogenic, secondary or spontaneous. Iatrogenic ALS was diagnosed in two cats with tracheal laceration following endotracheal intubation. Secondary ALS was identified in two dogs, one with acute respiratory distress syndrome and the other due to grass awn migration. Secondary ALS in pinnipeds was diagnosed following severe pulmonary parasitism, uraemic pneumonia and oesophageal perforation. The other marine mammals developed ALS following trauma. Spontaneous ALS was also diagnosed in one cat and one dog without any apparent predisposing causes.}, } @article {pmid38777186, year = {2024}, author = {Green, LJ and Brouha, B and Bhatia, N}, title = {Response to Bass et al's "Significant discordance in DermTech test results when paired with histopathology: Caveat emptor".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {3}, pages = {e79}, doi = {10.1016/j.jaad.2024.02.067}, pmid = {38777186}, issn = {1097-6787}, mesh = {Humans ; *Skin Neoplasms/pathology ; Dermoscopy ; Melanoma/pathology ; }, } @article {pmid38777640, year = {2024}, author = {Zhu, J and Yan, Y and Jiang, W and Zhang, S and Niu, X and Wan, S and Cong, Y and Hu, X and Zheng, B and Yang, Y}, title = {A Deep Learning Model for Automatically Quantifying the Anterior Segment in Ultrasound Biomicroscopy Images of Implantable Collamer Lens Candidates.}, journal = {Ultrasound in medicine & biology}, volume = {50}, number = {8}, pages = {1262-1272}, doi = {10.1016/j.ultrasmedbio.2024.05.004}, pmid = {38777640}, issn = {1879-291X}, mesh = {Humans ; *Microscopy, Acoustic/methods ; *Deep Learning ; *Anterior Eye Segment/diagnostic imaging ; Male ; Female ; Adult ; Phakic Intraocular Lenses ; Lens Implantation, Intraocular ; Young Adult ; Middle Aged ; Image Processing, Computer-Assisted/methods ; }, abstract = {OBJECTIVE: This study aimed to develop and evaluate a deep learning-based model that could automatically measure anterior segment (AS) parameters on preoperative ultrasound biomicroscopy (UBM) images of implantable Collamer lens (ICL) surgery candidates.

METHODS: A total of 1164 panoramic UBM images were preoperatively obtained from 321 patients who received ICL surgery in the Eye Center of Renmin Hospital of Wuhan University (Wuhan, China) to develop an imaging database. First, the UNet++ network was utilized to segment AS tissues automatically, such as corneal lens and iris. In addition, image processing techniques and geometric localization algorithms were developed to automatically identify the anatomical landmarks (ALs) of pupil diameter (PD), anterior chamber depth (ACD), angle-to-angle distance (ATA), and sulcus-to-sulcus distance (STS). Based on the results of the latter two processes, PD, ACD, ATA, and STS can be measured. Meanwhile, an external dataset of 294 images from Huangshi Aier Eye Hospital was employed to further assess the model's performance in other center. Lastly, a subset of 100 random images from the external test set was chosen to compare the performance of the model with senior experts.

RESULTS: Whether in the internal test dataset or external test dataset, using manual labeling as the reference standard, the models achieved a mean Dice coefficient exceeding 0.880. Additionally, the intra-class correlation coefficients (ICCs) of ALs' coordinates were all greater than 0.947, and the percentage of Euclidean distance distribution of ALs within 250 μm was over 95.24%.While the ICCs for PD, ACD, ATA, and STS were greater than 0.957, furthermore, the average relative error (ARE) of PD, ACD, ATA, and STS were below 2.41%. In terms of human versus machine performance, the ICCs between the measurements performed by the model and those by senior experts were all greater than 0.931.

CONCLUSION: A deep learning-based model could measure AS parameters using UBM images of ICL candidates, and exhibited a performance similar to that of a senior ophthalmologist.}, } @article {pmid38778483, year = {2024}, author = {Yan, J and Chen, H and Zhang, Y and Peng, L and Wang, Z and Lan, X and Yu, S and Yang, Y}, title = {Fecal microbiota transplantation significantly improved respiratory failure of amyotrophic lateral sclerosis.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2353396}, pmid = {38778483}, issn = {1949-0984}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/microbiology ; Bacteroides ; Faecalibacterium prausnitzii ; *Fecal Microbiota Transplantation ; Feces/microbiology ; Gastrointestinal Microbiome ; Respiration, Artificial ; *Respiratory Insufficiency/therapy/microbiology ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to respiratory failure, and eventually death. However, there is a lack of effective treatments for ALS. Here we report the results of fecal microbiota transplantation (FMT) in two patients with late-onset classic ALS with a Japan ALS severity classification of grade 5 who required tracheostomy and mechanical ventilation. In both patients, significant improvements in respiratory function were observed following two rounds of FMT, leading to weaning off mechanical ventilation. Their muscle strength improved, allowing for assisted standing and mobility. Other notable treatment responses included improved swallowing function and reduced muscle fasciculations. Metagenomic and metabolomic analysis revealed an increase in beneficial Bacteroides species (Bacteroides stercoris, Bacteroides uniformis, Bacteroides vulgatus), and Faecalibacterium prausnitzii after FMT, as well as elevated levels of metabolites involved in arginine biosynthesis and decreased levels of metabolites involved in branched-chain amino acid biosynthesis. These findings offer a potential rescue therapy for ALS with respiratory failure and provide new insights into ALS in general.}, } @article {pmid38778595, year = {2025}, author = {Jayaprakash, B and Savira, M and Mahmood, AAR and Prasanna, M}, title = {The Role of Stem Cell Therapies in the Treatment of Neurodegenerative Diseases.}, journal = {Current stem cell research & therapy}, volume = {20}, number = {2}, pages = {146-165}, doi = {10.2174/011574888X313112240510160102}, pmid = {38778595}, issn = {2212-3946}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; Animals ; Neural Stem Cells/transplantation ; Parkinson Disease/therapy ; }, abstract = {Cellular replacement therapy and genetic transfer in injured brains provide new pathways for treating human neurological illnesses. Current progress in the field focuses on the production of neurons and glial cells from many types of stem cells, such as embryonic, induced pluripotent, mesenchymal, and neural stem cells. This has led to a significant increase in research on brain transplantation treatments. Extended neurodegeneration results in the progressive decline of certain neuronal subtypes or whole neuronal cells. An analysis of the progress made in induced pluripotent and mesenchymal stem cells reveals their significant promise in disease modeling, regeneration, and medication screening. The requirement for stem cells in neurodegenerative disease studies has been crucial in recent years. Stem cells provide the potential for replacing impaired neurons, comprehending disease needs modeling, and creating efficient treatments, but they have many challenges in culturing and acceptability to the host immune cells. The need to use their potential in discovering novel therapies for diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis leads to promising therapy. This review examines the function of stem cells in the pathogenesis and treatment of Huntington's disease, Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review further examines hurdles such as immunological reactions and delivery systems intending to overcome these problems. This article offers a detailed viewpoint on the use of stem cell-based nanotherapies as revolutionary treatments for various neurological illnesses.}, } @article {pmid38778614, year = {2025}, author = {Zhou, H and Xia, Y and Zhu, R and Zhang, Y and Zhang, X and Zhang, Y and Wang, J}, title = {Ribosomal DNA and Neurological Disorders.}, journal = {Current molecular medicine}, volume = {25}, number = {5}, pages = {556-566}, pmid = {38778614}, issn = {1875-5666}, support = {G2022027010L//Ministry of Science and Technology of the People's Republic of China/ ; 82061138005//National Natural Science Foundation of China/ ; T2020009, 337/370//Hubei Provincial Department of Education/ ; }, mesh = {Humans ; *Nervous System Diseases/genetics/metabolism/pathology ; *DNA, Ribosomal/genetics/metabolism ; Animals ; Huntington Disease/genetics ; }, abstract = {Ribosomal DNA (rDNA) is important in the nucleolus and nuclear organization of human cells. Defective rDNA repeat maintenance has been reported to be closely associated with neurological disorders, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, depression, suicide, etc. However, there has not been a comprehensive review on the role of rDNA in these disorders. In this review, we have summarized the role of rDNA in major neurological disorders to sort out the correlation between rDNA and neurological diseases and provided insights for therapy with rDNA as a target.}, } @article {pmid38779353, year = {2024}, author = {Trubshaw, M and Gohil, C and Yoganathan, K and Kohl, O and Edmond, E and Proudfoot, M and Thompson, AG and Talbot, K and Stagg, CJ and Nobre, AC and Woolrich, M and Turner, MR}, title = {The cortical neurophysiological signature of amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {3}, pages = {fcae164}, pmid = {38779353}, issn = {2632-1297}, abstract = {The progressive loss of motor function characteristic of amyotrophic lateral sclerosis is associated with widespread cortical pathology extending beyond primary motor regions. Increasing muscle weakness reflects a dynamic, variably compensated brain network disorder. In the quest for biomarkers to accelerate therapeutic assessment, the high temporal resolution of magnetoencephalography is uniquely able to non-invasively capture micro-magnetic fields generated by neuronal activity across the entire cortex simultaneously. This study examined task-free magnetoencephalography to characterize the cortical oscillatory signature of amyotrophic lateral sclerosis for having potential as a pharmacodynamic biomarker. Eight to ten minutes of magnetoencephalography in the task-free, eyes-open state was recorded in amyotrophic lateral sclerosis (n = 36) and healthy age-matched controls (n = 51), followed by a structural MRI scan for co-registration. Extracted magnetoencephalography metrics from the delta, theta, alpha, beta, low-gamma, high-gamma frequency bands included oscillatory power (regional activity), 1/f exponent (complexity) and amplitude envelope correlation (connectivity). Groups were compared using a permutation-based general linear model with correction for multiple comparisons and confounders. To test whether the extracted metrics could predict disease severity, a random forest regression model was trained and evaluated using nested leave-one-out cross-validation. Amyotrophic lateral sclerosis was characterized by reduced sensorimotor beta band and increased high-gamma band power. Within the premotor cortex, increased disability was associated with a reduced 1/f exponent. Increased disability was more widely associated with increased global connectivity in the delta, theta and high-gamma bands. Intra-hemispherically, increased disability scores were particularly associated with increases in temporal connectivity and inter-hemispherically with increases in frontal and occipital connectivity. The random forest model achieved a coefficient of determination (R[2]) of 0.24. The combined reduction in cortical sensorimotor beta and rise in gamma power is compatible with the established hypothesis of loss of inhibitory, GABAergic interneuronal circuits in pathogenesis. A lower 1/f exponent potentially reflects a more excitable cortex and a pathology unique to amyotrophic lateral sclerosis when considered with the findings published in other neurodegenerative disorders. Power and complexity changes corroborate with the results from paired-pulse transcranial magnetic stimulation. Increased magnetoencephalography connectivity in worsening disability is thought to represent compensatory responses to a failing motor system. Restoration of cortical beta and gamma band power has significant potential to be tested in an experimental medicine setting. Magnetoencephalography-based measures have potential as sensitive outcome measures of therapeutic benefit in drug trials and may have a wider diagnostic value with further study, including as predictive markers in asymptomatic carriers of disease-causing genetic variants.}, } @article {pmid38779803, year = {2024}, author = {Zhu, L and Bai, D and Wang, X and Ou, K and Li, B and Jia, Q and Tan, Z and Liang, J and He, D and Yan, S and Wang, L and Li, S and Li, XJ and Yin, P}, title = {Pathologic TDP-43 downregulates myelin gene expression in the monkey brain.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {6}, pages = {e13277}, pmid = {38779803}, issn = {1750-3639}, support = {32270564//National Natural Science Foundation of China/ ; 81830032//National Natural Science Foundation of China/ ; 82071421//National Natural Science Foundation of China/ ; 82394422//National Natural Science Foundation of China/ ; 2021ZT09Y007//Department of Science and Technology of Guangdong Province/ ; 2018B030337001//Department of Science and Technology of Guangdong Province/ ; 2022A1515011205//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515010811//Basic and Applied Basic Research Foundation of Guangdong Province/ ; }, mesh = {Animals ; Male ; *Brain/metabolism/pathology ; Corpus Callosum/metabolism/pathology ; Demyelinating Diseases/pathology/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Down-Regulation ; Myelin Sheath/metabolism/pathology/genetics ; Oligodendroglia/metabolism/pathology ; Macaca fascicularis ; }, abstract = {Growing evidence indicates that non-neuronal oligodendrocyte plays an important role in Amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. In patient's brain, the impaired myelin structure is a pathological feature with the observation of TDP-43 in cytoplasm of oligodendrocyte. However, the mechanism underlying the gain of function by TDP-43 in oligodendrocytes, which are vital for the axonal integrity, remains unclear. Recently, we found that the primate-specific cleavage of truncated TDP-43 fragments occurred in cytoplasm of monkey neural cells. This finding opened up the avenue to investigate the myelin integrity affected by pathogenic TDP-43 in oligodendrocytes. In current study, we demonstrated that the truncated TDP-35 in oligodendrocytes specifically, could lead to the dysfunctional demyelination in corpus callosum of monkey. As a consequence of the interaction of myelin regulatory factor with the accumulated TDP-35 in cytoplasm, the downstream myelin-associated genes expression was downregulated at the transcriptional level. Our study aims to investigate the potential effect on myelin structure injury, affected by the truncated TDP-43 in oligodendrocyte, which provided the additional clues on the gain of function during the progressive pathogenesis and symptoms in TDP-43 related diseases.}, } @article {pmid38780595, year = {2024}, author = {da Gama, NAS and Queiroz, GAMC and de Alcântara, C and Cruzeiro, MM and Alencar, MA and Martins de Araújo, C and Gomide, GFD and de Souza, LC and Jaeger, A}, title = {Memory for emotional information in sporadic and Type 8 amyotrophic lateral sclerosis.}, journal = {Neuropsychology}, volume = {38}, number = {5}, pages = {465-474}, doi = {10.1037/neu0000957}, pmid = {38780595}, issn = {1931-1559}, support = {//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/physiopathology ; Male ; Female ; Middle Aged ; *Emotions/physiology ; Aged ; *Recognition, Psychology/physiology ; Memory Disorders/etiology/diagnosis ; Adult ; Memory, Episodic ; Neuropsychological Tests ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is often shown to cause episodic memory deficits. Here, we investigated whether such memory deficits are differentially expressed according to the emotional valence of stimuli and whether they are similarly reproduced in both individuals with sporadic ALS (sALS) and familial Type 8 ALS (ALS8).

METHOD: Twenty individuals with sALS, 18 individuals with ALS8, and 19 healthy controls were recruited for the study. After a neuropsychological and psychopathological assessment, all participants responded to a recognition memory test wherein images varying in terms of valence were initially shown. After a short interval, the images were shown again intermixed with new images, and the participants' task was to indicate whether each image was "old" or "new" and to estimate the confidence in their responses.

RESULTS: Both the sALS and the ALS8 groups showed significantly lower recognition of positive relative to negative valence images (d = 0.92 and d = 0.74, respectively), an effect that was completely absent for healthy controls (d = 0.17). These effects were qualified by a significant interaction involving the factors of valence and group (ηp² = 0.12).

CONCLUSIONS: The current findings demonstrate that sALS and ALS8 are associated with decreased recognition of emotional information, an effect that is nonetheless restricted to positive valence stimuli. (PsycInfo Database Record (c) 2024 APA, all rights reserved).}, } @article {pmid38780855, year = {2024}, author = {Burgio, F and Danesin, L and Wennberg, A and Tonini, E and Galetto, V and Sivieri, S and Giustiniani, A and Palmer, K and Meneghello, F and Sorarù, G and Zettin, M and Arcara, G and Benavides-Varela, S and Semenza, C}, title = {Financial and numerical abilities: patterns of dissociation in neurological and psychiatric diseases.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {10}, pages = {4779-4787}, pmid = {38780855}, issn = {1590-3478}, support = {GR-2018-12367927//Ministero della Salute/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Neuropsychological Tests ; Adult ; Aged ; Cognitive Dysfunction/etiology/physiopathology ; Mental Disorders/economics ; Schizophrenia/physiopathology/complications ; Brain Injuries, Traumatic/complications/psychology ; }, abstract = {The present work investigates whether financial abilities can be associated with numerical abilities and with general cognitive abilities. We compared performance on numerical and financial tests, and on tests routinely used to measure general cognitive performance, in healthy controls and in a group of people with heterogeneous pathological conditions including mild cognitive impairment, amyotrophic lateral sclerosis, traumatic brain injury, and schizophrenia. Patients showed lower performances in both numerical and financial abilities compared to controls. Numerical and financial skills were positively correlated in both groups, but they correlated poorly with measures of general cognitive functioning. Crucially, only basic financial tasks -such as counting currencies- but not advanced ones -like financial judgments- were associated with numerical or general cognitive functioning in logistic regression analyses. Conversely, advanced financial abilities, but not basic ones, were associated with abstract reasoning. At a qualitative analysis, we found that deficits in numerical and financial abilities might double dissociate. Similarly, we observed double dissociations between difficulties in financial abilities and cognitive deficits. In conclusion, financial abilities may be independent of numerical skills, and financial deficits are not always related to the presence of cognitive difficulties. These findings are important for both clinical and legal practice.}, } @article {pmid38781481, year = {2025}, author = {Zeng, Y and Guo, R and Cao, S and Chavarria Gonzalez, S and Pang, K and Liu, C and Yang, H}, title = {Mendelian randomization study supports relative carbohydrate intake as an independent risk factor for amyotrophic lateral sclerosis.}, journal = {Nutritional neuroscience}, volume = {28}, number = {1}, pages = {116-124}, doi = {10.1080/1028415X.2024.2352196}, pmid = {38781481}, issn = {1476-8305}, support = {G9815508/MRC_/Medical Research Council/United Kingdom ; MC_PC_15018/MRC_/Medical Research Council/United Kingdom ; MC_PC_19009/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Mendelian Randomization Analysis ; *Dietary Carbohydrates/administration & dosage ; Risk Factors ; *Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Diet ; Dietary Fats/administration & dosage ; Dietary Proteins/administration & dosage ; }, abstract = {OBJECTIVES: Observational studies suggested a potential correlation between dietary intake and amyotrophic lateral sclerosis (ALS), but conflicting findings exist and causality remains unclear. Here, we performed a Mendelian randomization (MR) analysis to evaluate the causal impact of relative intake of (i) carbohydrate, (ii) fat, and (iii) protein on ALS risk.

METHODS: The genome-wide association summary statistics of three dietary macronutrient intake traits and ALS were obtained. Initially, forward and reverse univariable MR (UVMR) analysis were conducted using the inverse variance weighted (IVW) method as the primary approach, supplemented by MR-Egger, weighted median, and maximum likelihood. Subsequently, multivariable MR (MVMR) analysis was performed to assess the independent causal effects of each dietary. Additionally, diverse sensitivity tests were conducted to evaluate the reliability of the MR analyses.

RESULTS: The forward UVMR analysis conducted by IVW indicated that relative carbohydrate intake significantly increased ALS risk. Furthermore, results from three other MR methods paralleled those from IVW. However, the other two dietary intake traits did not have a causative impact on ALS risk. The reverse UVMR analysis indicated that ALS did not causatively influence the three dietary intake traits. The MVMR analysis showed that after adjusting for the effects of the other two dietary intake traits, relative carbohydrate intake independently and significantly increased ALS risk. Sensitivity tests indicated no significant heterogeneity or horizontal pleiotropy.

DISCUSSION: MR analysis supported relative carbohydrate independently increasing ALS risk. Nevertheless, further validation of this finding in future large cohorts is required.}, } @article {pmid38782014, year = {2024}, author = {Hardiman, O}, title = {Amyotrophic lateral sclerosis: a lesson in translation.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {651-653}, doi = {10.1016/S1474-4422(24)00223-0}, pmid = {38782014}, issn = {1474-4465}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Translational Research, Biomedical ; }, } @article {pmid38782015, year = {2024}, author = {Benatar, M and Hansen, T and Rom, D and Geist, MA and Blaettler, T and Camu, W and Kuzma-Kozakiewicz, M and van den Berg, LH and Morales, RJ and Chio, A and Andersen, PM and Pradat, PF and Lange, D and Van Damme, P and Mora, G and Grudniak, M and Elliott, M and Petri, S and Olney, N and Ladha, S and Goyal, NA and Meyer, T and Hanna, MG and Quinn, C and Genge, A and Zinman, L and Jabari, D and Shoesmith, C and Ludolph, AC and Neuwirth, C and Nations, S and Shefner, JM and Turner, MR and Wuu, J and Bennett, R and Dang, H and Sundgreen, C and , }, title = {Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {687-699}, doi = {10.1016/S1474-4422(24)00134-0}, pmid = {38782015}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Double-Blind Method ; Middle Aged ; Aged ; *Neuroprotective Agents/therapeutic use/adverse effects ; Treatment Outcome ; Adult ; Hydroxylamines/therapeutic use/adverse effects/pharmacology ; Oxadiazoles/therapeutic use/adverse effects ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.

METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.

FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).

INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.

FUNDING: Orphazyme.}, } @article {pmid38782041, year = {2024}, author = {Hogan, DB and Maxwell, CJ and Dampf, H and McGrail, K and Estabrooks, CA and Poss, JW and Bakal, JA and Hoben, M}, title = {Excess Deaths in Assisted Living and Nursing Homes during the COVID-19 Pandemic in Alberta, Canada.}, journal = {Journal of the American Medical Directors Association}, volume = {25}, number = {7}, pages = {105032}, doi = {10.1016/j.jamda.2024.105032}, pmid = {38782041}, issn = {1538-9375}, mesh = {Humans ; *COVID-19/mortality/epidemiology ; *Nursing Homes ; Alberta/epidemiology ; *Assisted Living Facilities ; Male ; Female ; Aged ; Retrospective Studies ; Aged, 80 and over ; SARS-CoV-2 ; Pandemics ; Dementia/mortality/epidemiology ; Homes for the Aged/statistics & numerical data ; Cognitive Dysfunction/mortality/epidemiology ; Mortality/trends ; }, abstract = {OBJECTIVES: Assisted living (AL) is a significant and growing congregate care option for vulnerable older adults designed to reduce the use of nursing homes (NHs). However, work on excess mortality in congregate care during the COVID-19 pandemic has primarily focused on NHs with only a few US studies examining AL. The objective of this study was to assess excess mortality among AL and NH residents with and without dementia or significant cognitive impairment in Alberta, Canada, during the first 2 years of the COVID-19 pandemic, relative to the 3 years before.

DESIGN: Population-based, retrospective cohort study.

SETTING AND PARTICIPANTS: Residents who lived in an AL or NH facility operated or contracted by the Provincial health care system to provide publicly funded care in Alberta between January 1, 2017, and December 31, 2021.

METHODS: We used administrative health care data, including Resident Assessment Instrument - Home Care (RAI-HC, AL) and Minimum Data Set 2.0 (RAI-MDS 2.0, NHs) records, linked with data on residents' vital statistics, COVID-19 testing, emergency room registrations, and hospital stays. The outcome was excess deaths during COVID-19 (ie, the number of deaths beyond that expected based on pre-pandemic data), estimated, using overdispersed Poisson generalized linear models.

RESULTS: Overall, the risk of excess mortality [adjusted incidence rate ratio (95% confidence interval)] was higher in ALs than in NHs [1.20 (1.14-1.26) vs 1.10 (1.07-1.13)]. Weekly peaks in excess deaths coincided with COVID-19 pandemic waves and were higher among those with diagnosed dementia or significant cognitive impairment in both, AL and NHs.

CONCLUSIONS AND IMPLICATIONS: Finding excess mortality within both AL and NH facilities should lead to greater focus on infection prevention and control measures across all forms of congregate housing for vulnerable older adults. The specific needs of residents with dementia in particular will have to be addressed.}, } @article {pmid38782052, year = {2024}, author = {Bass, J and Hill, H and Jaworsky, C}, title = {Response to Green et al in reply to Bass et al's "Significant discordance in DermTech test results when paired with histopathology: Caveat emptor".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {3}, pages = {e81}, doi = {10.1016/j.jaad.2024.05.038}, pmid = {38782052}, issn = {1097-6787}, mesh = {Humans ; *Dermoscopy ; Skin Neoplasms/pathology ; }, } @article {pmid38782644, year = {2025}, author = {Corcia, P and Couratier, P and Ingre, C}, title = {Could PLS represent a UMN-predominant ALS syndrome?.}, journal = {Revue neurologique}, volume = {181}, number = {1-2}, pages = {52-57}, doi = {10.1016/j.neurol.2024.04.006}, pmid = {38782644}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/pathology ; *Motor Neuron Disease/diagnosis/pathology/classification ; *Motor Neurons/pathology/physiology ; Diagnosis, Differential ; Syndrome ; }, abstract = {Primary lateral sclerosis (PLS) is a motor neuron condition marked by pure upper motor neuron (UMN) degeneration. PLS represents around 3% of all motor neuron diseases. Classically the prognosis of PLS is less severe than those of amyotrophic lateral sclerosis (ALS). This explains the necessity to distinguish both conditions as early as possible. The key hallmark between the two diseases is the involvement of the lower motor neuron (LMN) system which is classically considered spared in PLS contrary to ALS. Although it seemed clinically easy to distinguish PLS from ALS with the aid of clinical and complementary examinations, there is a large body of evidence highlighting that the LMN system might be impaired in PLS. This led us to suggest that PLS might be considered as an almost pure UMN ALS phenotype.}, } @article {pmid38784093, year = {2024}, author = {Chen, W and Liu, X and Wan, P and Chen, Z and Chen, Y}, title = {Anti-artifacts techniques for neural recording front-ends in closed-loop brain-machine interface ICs.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1393206}, pmid = {38784093}, issn = {1662-4548}, abstract = {In recent years, thanks to the development of integrated circuits, clinical medicine has witnessed significant advancements, enabling more efficient and intelligent treatment approaches. Particularly in the field of neuromedical, the utilization of brain-machine interfaces (BMI) has revolutionized the treatment of neurological diseases such as amyotrophic lateral sclerosis, cerebral palsy, stroke, or spinal cord injury. The BMI acquires neural signals via recording circuits and analyze them to regulate neural stimulator circuits for effective neurological treatment. However, traditional BMI designs, which are often isolated, have given way to closed-loop brain-machine interfaces (CL-BMI) as a contemporary development trend. CL-BMI offers increased integration and accelerated response speed, marking a significant leap forward in neuromedicine. Nonetheless, this advancement comes with its challenges, notably the stimulation artifacts (SA) problem inherent to the structural characteristics of CL-BMI, which poses significant challenges on the neural recording front-ends (NRFE) site. This paper aims to provide a comprehensive overview of technologies addressing artifacts in the NRFE site within CL-BMI. Topics covered will include: (1) understanding and assessing artifacts; (2) exploring the impact of artifacts on traditional neural recording front-ends; (3) reviewing recent technological advancements aimed at addressing artifact-related issues; (4) summarizing and classifying the aforementioned technologies, along with an analysis of future trends.}, } @article {pmid38784406, year = {2024}, author = {Keselica, M and Peřan, D and Renza, M and Duška, F and Omáčka, D and Schnaubelt, S and Lulic, I and Sýkora, R}, title = {Efficiency of two-member crews in delivering prehospital advanced life support cardiopulmonary resuscitation: A scoping review.}, journal = {Resuscitation plus}, volume = {18}, number = {}, pages = {100661}, pmid = {38784406}, issn = {2666-5204}, abstract = {BACKGROUND: Advanced Life Support (ALS) during cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest (OHCA) is frequently administered by two-member crews. However, ALS CPR is mostly designed for larger crews, and the feasibility and efficacy of implementing ALS guidelines for only two rescuers remain unclear.

OBJECTIVE: This scoping review aims to examine the existing evidence and identify knowledge gaps in the efficiency of pre-hospital ALS CPR performed by two-member teams.

DESIGN: A comprehensive search was undertaken across the following databases: PubMed, Web of Science, SCOPUS, Cochrane Library Trials, and ClinicalTrials.gov. The search covered publications in English or German from January 1, 2005, to November 30, 2023. The review included studies that focused on ALS CPR procedures carried out by two-member teams in adult patients in either simulated or clinical settings.

RESULTS: A total of 22 articles were included in the qualitative synthesis. Seven topics in two-person prehospital ALS/CPR delivery were identified: 1) effect of team configuration on clinical outcome and CPR quality, 2) early airway management and ventilation techniques, 3) mechanical chest compressions, 4) prefilled syringes, 5) additional equipment, 6) adaptation of recommended ALS/CPR protocols, and 7) human factors.

CONCLUSION: There is a lack of comprehensive data regarding the adaptation of the recommended ALS algorithm in CPR for two-member crews. Although simulation studies indicate potential benefits arising from the employment of mechanical chest compression devices, prefilled syringes, and automation-assisted protocols, the current evidence is too limited to support specific modifications to existing guidelines.}, } @article {pmid38785530, year = {2024}, author = {Serrano, PL and Rodrigues, TPV and Pinto, LD and Pereira, IC and Farias, IB and Cavalheiro, RBR and Mendes, PM and Peixoto, KO and Barile, JP and Seneor, DD and Correa Silva, EG and Oliveira, ASB and Pinto, WBVR and Sgobbi, P}, title = {Assessing Chitinases and Neurofilament Light Chain as Biomarkers for Adult-Onset Leukodystrophies.}, journal = {Current issues in molecular biology}, volume = {46}, number = {5}, pages = {4309-4323}, pmid = {38785530}, issn = {1467-3045}, abstract = {Leukodystrophies represent a large and complex group of inherited disorders affecting the white matter of the central nervous system. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare leukodystrophy which still needs the proper identification of diagnostic, prognostic, and monitoring biomarkers. The aim of this study was to determine the diagnostic and prognostic value of chitinases and neurofilament light chain as biomarkers for ALSP. A cross-sectional study was performed to analyze cerebrospinal fluid levels of chitinases (chitotriosidase and chitinase 3-like 2) and neurofilament light chain in five different groups: (i) normal health individuals; (ii) patients with definitive diagnosis of ALSP and genetic confirmation; (iii) asymptomatic patients with CSF1R variants; (iv) patients with other adult-onset leukodystrophies; and (v) patients with amyotrophic lateral sclerosis (external control group). Chitinase levels showed a statistical correlation with clinical assessment parameters in ALSP patients. Chitinase levels were also distinct between ALSP and the other leukodystrophies. Significant differences were noted in the levels of chitinases and neurofilament light chain comparing symptomatic (ALSP) and asymptomatic individuals with CSF1R variants. This study is the first to establish chitinases as a potential biomarker for ALSP and confirms neurofilament light chain as a good biomarker for primary microgliopathies.}, } @article {pmid38785539, year = {2024}, author = {Pribac, M and Motataianu, A and Andone, S and Mardale, E and Nemeth, S}, title = {Bridging the Gap: Harnessing Plant Bioactive Molecules to Target Gut Microbiome Dysfunctions in Amyotrophic Lateral Sclerosis.}, journal = {Current issues in molecular biology}, volume = {46}, number = {5}, pages = {4471-4488}, pmid = {38785539}, issn = {1467-3045}, abstract = {The correlation between neurodegenerative diseases and the gut microbiome is increasingly evident, with amyotrophic lateral sclerosis (ALS) being particularly notable for its severity and lack of therapeutic options. The gut microbiota, implicated in the pathogenesis and development of ALS, plays a crucial role in the disease. Bioactive plant molecules, specifically volatile compounds in essential oils, offer a promising therapeutic avenue due to their anti-inflammatory properties and gut-modulating effects. Our narrative review aimed to identify microbiota-associated bacteria in ALS and analyze the benefits of administering bioactive plant molecules as much-needed therapeutic options in the management of this disease. A comprehensive search of PubMed database articles published before December 2023, encompassing research on cell, human, and animal ALS models, was conducted. After selecting, analyzing, and discussing key articles, bacteria linked to ALS pathogenesis and physiopathology were identified. Notably, positively highlighted bacteria included Akkermansia muciniphila (Verrucomicrobia phylum), Faecalibacterium prausnitzii, and Butyrivibrio spp. (Firmicutes phylum). Conversely, members of the Escherichia coli spp. (Proteobacteria phylum) and Ruminococcus spp. (Firmicutes phylum) stood out negatively in respect to ALS development. These bacteria were associated with molecular changes linked to ALS pathogenesis and evolution. Bioactive plant molecules can be directly associated with improvements in the microbiome, due to their role in reducing inflammation and oxidative stress, emerging as one of the most promising natural agents for enriching present-day ALS treatments.}, } @article {pmid38785754, year = {2024}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Farkhad, NK and Khodadoust, MA and Tavakol-Afshari, J}, title = {Evaluation of the Safety and Efficacy of Repeated Mesenchymal Stem Cell Transplantations in ALS Patients by Investigating Patients' Specific Immunological and Biochemical Biomarkers.}, journal = {Diseases (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {38785754}, issn = {2079-9721}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable disease. There are vigorous attempts to develop treatments to reduce the effects of this disease, and among these treatments is the transplantation of stem cells. This study aimed to retrospectively evaluate a mesenchymal stem cell (MSC) therapy cohort as a promising novel treatment modality by estimating some additional new parameters, such as immunological and biochemical factors.

METHODS: This study was designed as an open-label, one-arm cohort retrospective study to evaluate potential diagnostic biomarkers of repeated infusions of autologous-bone marrow-derived mesenchymal stem cells (BM-MSCs) in 15 confirmed patients with ALS, administered at a dose of 1 × 106 cells/kg BW with a one-month interval, in equal amounts in both an intravenous (IV) and intrathecal (IT) capacity simultaneously, via various biochemical (iron (Fe), ferritin, total-iron-binding capacity (TIBC), transferrin, and creatine kinase (CK)) and immunological parameters (tumor necrosis factor-alpha (TNF-α), neurofilament light chain (NFL), and glial-cell-derived neurotrophic factor (GDNF) levels, evaluated during the three-month follow-up period in serum and cerebrospinal fluid (CSF).

RESULTS: Our study indicated that, in the case of immunological biomarkers, TNF-α levels in the CSF showed a significant decrease at month three after transplantation compared with levels at month zero, and the p-value was p < 0.01. No statistically significant changes were observed for other immunological as well as biochemical parameters and a p-value of p > 0.05.

CONCLUSIONS: These results can indicate the potential benefit of stem cell transfusion in patients with ALS and suggest some diagnostic biomarkers. Several studies are required to approve these results.}, } @article {pmid38786016, year = {2024}, author = {Salzinger, A and Ramesh, V and Das Sharma, S and Chandran, S and Thangaraj Selvaraj, B}, title = {Neuronal Circuit Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {10}, pages = {}, pmid = {38786016}, issn = {2073-4409}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Humans ; *Motor Neurons/pathology/physiology ; Animals ; Nerve Net/physiopathology/pathology ; Neuromuscular Junction/physiopathology/pathology ; Disease Models, Animal ; Motor Cortex/physiopathology/pathology ; }, abstract = {The primary neural circuit affected in Amyotrophic Lateral Sclerosis (ALS) patients is the corticospinal motor circuit, originating in upper motor neurons (UMNs) in the cerebral motor cortex which descend to synapse with the lower motor neurons (LMNs) in the spinal cord to ultimately innervate the skeletal muscle. Perturbation of these neural circuits and consequent loss of both UMNs and LMNs, leading to muscle wastage and impaired movement, is the key pathophysiology observed. Despite decades of research, we are still lacking in ALS disease-modifying treatments. In this review, we document the current research from patient studies, rodent models, and human stem cell models in understanding the mechanisms of corticomotor circuit dysfunction and its implication in ALS. We summarize the current knowledge about cortical UMN dysfunction and degeneration, altered excitability in LMNs, neuromuscular junction degeneration, and the non-cell autonomous role of glial cells in motor circuit dysfunction in relation to ALS. We further highlight the advances in human stem cell technology to model the complex neural circuitry and how these can aid in future studies to better understand the mechanisms of neural circuit dysfunction underpinning ALS.}, } @article {pmid38787599, year = {2024}, author = {Wong, JPH and Blazev, R and Ng, YK and Goodman, CA and Montgomery, MK and Watt, KI and Carl, CS and Watt, MJ and Voldstedlund, CT and Richter, EA and Crouch, PJ and Steyn, FJ and Ngo, ST and Parker, BL}, title = {Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in amyotrophic lateral sclerosis.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {38}, number = {10}, pages = {e23647}, doi = {10.1096/fj.202400045R}, pmid = {38787599}, issn = {1530-6860}, support = {APP2009642//DHAC | National Health and Medical Research Council (NHMRC)/ ; 1185427//DHAC | National Health and Medical Research Council (NHMRC)/ ; //University of Melbourne Driving Research Momentum/ ; //Motor Neurone Disease Research Australia Charcot/ ; //Department of Anatomy and Physiology (The University of Melbourne) ECR Seeding Grant/ ; }, mesh = {*Muscle, Skeletal/metabolism/pathology ; *Arginine/metabolism/analogs & derivatives ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; Mice ; *Protein-Arginine N-Methyltransferases/metabolism/genetics ; Male ; Methylation ; Female ; Protein Processing, Post-Translational ; Mice, Inbred C57BL ; Proteome/metabolism ; }, abstract = {Arginine methylation is a protein posttranslational modification important for the development of skeletal muscle mass and function. Despite this, our understanding of the regulation of arginine methylation under settings of health and disease remains largely undefined. Here, we investigated the regulation of arginine methylation in skeletal muscles in response to exercise and hypertrophic growth, and in diseases involving metabolic dysfunction and atrophy. We report a limited regulation of arginine methylation under physiological settings that promote muscle health, such as during growth and acute exercise, nor in disease models of insulin resistance. In contrast, we saw a significant remodeling of asymmetric dimethylation in models of atrophy characterized by the loss of innervation, including in muscle biopsies from patients with myotrophic lateral sclerosis (ALS). Mass spectrometry-based quantification of the proteome and asymmetric arginine dimethylome of skeletal muscle from individuals with ALS revealed the largest compendium of protein changes with the identification of 793 regulated proteins, and novel site-specific changes in asymmetric dimethyl arginine (aDMA) of key sarcomeric and cytoskeletal proteins. Finally, we show that in vivo overexpression of PRMT1 and aDMA resulted in increased fatigue resistance and functional recovery in mice. Our study provides evidence for asymmetric dimethylation as a regulator of muscle pathophysiology and presents a valuable proteomics resource and rationale for numerous methylated and nonmethylated proteins, including PRMT1, to be pursued for therapeutic development in ALS.}, } @article {pmid38788085, year = {2024}, author = {Mohassel, P and Abdullah, M and Eichler, FS and Dunn, TM}, title = {Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {4}, pages = {735-747}, pmid = {38788085}, issn = {2214-3602}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Hereditary Sensory and Autonomic Neuropathies/genetics/metabolism/physiopathology ; *Neurodegenerative Diseases/metabolism ; *Neurodevelopmental Disorders ; *Serine C-Palmitoyltransferase/metabolism/genetics ; Spastic Paraplegia, Hereditary/genetics/metabolism ; Sphingolipids/metabolism ; }, abstract = {Motor neuron diseases and peripheral neuropathies are heterogeneous groups of neurodegenerative disorders that manifest with distinct symptoms due to progressive dysfunction or loss of specific neuronal subpopulations during different stages of development. A few monogenic, neurodegenerative diseases associated with primary metabolic disruptions of sphingolipid biosynthesis have been recently discovered. Sphingolipids are a subclass of lipids that form critical building blocks of all cellular and subcellular organelle membranes including the membrane components of the nervous system cells. They are especially abundant within the lipid portion of myelin. In this review, we will focus on our current understanding of disease phenotypes in three monogenic, neuromuscular diseases associated with pathogenic variants in components of serine palmitoyltransferase, the first step in sphingolipid biosynthesis. These include hereditary sensory and autonomic neuropathy type 1 (HSAN1), a sensory predominant peripheral neuropathy, and two neurodegenerative disorders: juvenile amyotrophic lateral sclerosis affecting the upper and lower motor neurons with sparing of sensory neurons, and a complicated form of hereditary spastic paraplegia with selective involvement of the upper motor neurons and more broad CNS neurodegeneration. We will also review our current understanding of disease pathomechanisms, therapeutic approaches, and the unanswered questions to explore in future studies.}, } @article {pmid38788288, year = {2024}, author = {van Neerven, GJL and Schelling, WJ and van den Borne, K and Bijleveld, K and Baars, A and Flink, H and Gilissen, LPL}, title = {The periprocedural respiratory safety of propofol sedation in patients with a motor neuron disease undergoing percutaneous endoscopic gastrostomy insertion.}, journal = {Journal of the neurological sciences}, volume = {461}, number = {}, pages = {123049}, doi = {10.1016/j.jns.2024.123049}, pmid = {38788288}, issn = {1878-5883}, mesh = {Humans ; Male ; Female ; Aged ; *Gastrostomy/adverse effects/methods ; *Propofol/adverse effects/administration & dosage/therapeutic use ; Retrospective Studies ; *Motor Neuron Disease ; Middle Aged ; *Hypnotics and Sedatives/adverse effects ; Pneumonia, Aspiration/etiology ; Aged, 80 and over ; Enteral Nutrition/methods/adverse effects ; }, abstract = {Motor neuron diseases (MND), such as Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS), may cause swallowing and respiratory problems, due to muscle weakness. Chronic enteral feeding via percutaneous endoscopic gastrostomy (PEG) is often indicated in these patients. PEG insertion is normally performed with sedation. Some guidelines withhold sedation in MND patients, due to the risk of respiratory complications. These guidelines seem to be defensive however and evidence is lacking. Our aim was to examine periprocedural respiratory complications occurring in MND patients undergoing PEG insertion with propofol sedation. A retrospective monocentre study was conducted in a referral hospital with an experienced PEG team. Patients with MND who underwent PEG insertion with propofol sedation between January 1. 2016 to January 1. 2023 were analysed to identify periprocedural respiratory complications. 46 patients were included. In five patients (10.9%) respiratory adverse events (AE) occurred, of which two serious (4.3%) and four AE (8.7%). Serious AE (SAE) were fatal in both cases: aspiration pneumonia (2.2%) and hypercapnia (2.2%) a few days after insertion. Sedation may have influenced the first case. Respiratory AE consisted of desaturation in two (4.3%), mild aspiration pneumonia in one (2.2%), and apnea in one patient (2.2%). Compared to previous studies respiratory complications and mortality had comparable prevalences.}, } @article {pmid38788509, year = {2024}, author = {Valeriano, MC and Neto, AM and Batista, ACF and Mamián-López, MB}, title = {Raman spectra soft modeling of the biodiesel oxidation through evolving factor analysis & multivariate curve resolution.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {318}, number = {}, pages = {124498}, doi = {10.1016/j.saa.2024.124498}, pmid = {38788509}, issn = {1873-3557}, abstract = {The oxidative stability of biodiesel is defined by its relative resistance to the action of oxygen at room temperature. Its determination is an essential reference to the quality of biofuel and a significant parameter to be determined. This parameter concerns the quality of the biodiesel to be supplied to the consumer, and its determination is fundamental to maintaining the engine's proper functioning. Raman spectroscopy allows the rapid obtaining of structural information regarding biodiesel quality and, when aided by multivariate analysis methods, allows a quantitative determination of specific properties. This work uses Raman spectroscopy, Multivariate Curve Resolution with Alternative Least Squares (MCR-ALS) method, and Evolving Factor Analysis (EFA) to study biodiesel's oxidation kinetics. Also, the vibrational modes C = C, CH2, and CH3 were identified as the main structural groups involved in this process, corroborating previous studies. The MCR-ALS & EFA combination allowed modeling of the degradation kinetics following an A → B → C mechanism, where A corresponds to the biodiesel (starting material), B is related to the hydroperoxide mixture, and C is the final product. The results also suggested that this process follows a first-order reaction, with kinetic constant values of k1 = 0.0056 min[-1] and k2 = 0.0031 min[-1].}, } @article {pmid38788796, year = {2024}, author = {Togawa, N and Ayaki, T and Yoshii, D and Maki, T and Sawamoto, N and Takahashi, R}, title = {TMEM119-positive microglia were increased in the brains of patients with amyotrophic lateral sclerosis.}, journal = {Neuroscience letters}, volume = {833}, number = {}, pages = {137829}, doi = {10.1016/j.neulet.2024.137829}, pmid = {38788796}, issn = {1872-7972}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Microglia/metabolism/pathology ; Male ; Female ; Aged ; Middle Aged ; *Membrane Proteins/metabolism ; *Brain/pathology/metabolism ; Macrophages/metabolism/pathology ; Receptors, CCR2/metabolism ; White Matter/pathology/metabolism ; Spinal Cord/metabolism/pathology ; Aged, 80 and over ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has been reported to be affected by inflammatory cells, such as microglia and macrophages, through the concept of non-cell autonomous neuronal death. Resident microglia in the human brain and monocyte-derived macrophages (MoDM) infiltrating in tissues are difficult to distinguish. Therefore, the effects of microglia and MoDMs in ALS remain poorly understood. This study aimed to investigate the role of resident microglia and MoDMs in the pathogenesis of ALS using postmortem brain and spinal cord samples. The samples used for immunohistochemical analysis included 11 cases of sporadic ALS and 11 age-matched controls. We stained the cells with TMEM119 to detect resident microglia and CCR2 to detect MoDMs. In ALS cases, TMEM119-immunopositive resident microglia were abundant in the motor cortex and subcortical white matter (SWM) of the motor area, whereas CCR2-immunopositive MoDM was similar to control cases. In addition, the mean density of CD68-immunopositive cells in the SWM significantly correlated with the mean density of pTDP-43-positive GCIs. These results suggest that resident microglial activation plays an important role in the cerebral pathogenesis of ALS and may provide novel therapeutic strategies to target excessive activation of resident microglia in ALS.}, } @article {pmid38788983, year = {2024}, author = {de Holanda Paranhos, L and Magalhães, RSS and de Araújo Brasil, A and Neto, JRM and Ribeiro, GD and Queiroz, DD and Dos Santos, VM and Eleutherio, ECA}, title = {The familial amyotrophic lateral sclerosis-associated A4V SOD1 mutant is not able to regulate aerobic glycolysis.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1868}, number = {8}, pages = {130634}, doi = {10.1016/j.bbagen.2024.130634}, pmid = {38788983}, issn = {1872-8006}, mesh = {*Glycolysis ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Superoxide Dismutase-1/genetics/metabolism ; *Saccharomyces cerevisiae/genetics/metabolism ; Glucose/metabolism ; Mutation ; }, abstract = {Under certain stress conditions, astrocytes operate in aerobic glycolysis, a process controlled by pyruvate dehydrogenase (PDH) inhibition through its E1 α subunit (Pda1) phosphorylation. This supplies lactate to neurons, which save glucose to obtain NADPH to, among other roles, counteract reactive oxygen species. A failure in this metabolic cooperation causes severe damage to neurons. In this work, using humanized Saccharomyces cerevisiae cells in which its endogenous Cu/Zn Superoxide Dismutase (SOD1) was replaced by human ortholog, we investigated the role of human SOD1 (hSOD1) in aerobic glycolysis regulation and its implications to amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. Yeast cells ferment glucose even in the presence of oxygen and switch to respiratory metabolism after glucose exhaustion. However, like cells of SOD1-knockout strain, cells expressing A4V mutant of hSOD1 growing on glucose showed a respiratory phenotype, i.e., low glucose and high oxygen consumptions and low intracellular oxidation levels in response to peroxide stress, contrary to cells expressing wild-type (WT) SOD1 (yeast or human). The A4V mutation in hSOD1 is linked to ALS. In contrast to WT SOD1 strains, PDH activity of both sod1Δ and A4V hSOD1 cells did not change in response to a metabolic shift toward oxidative metabolism, which was associated to lower Pda1 phosphorylation levels under growth on glucose. Taken together, our results suggest that A4V mutant cannot regulate aerobic glycolysis via Pda1 phosphorylation the same way WT hSOD1, which might be linked to problems observed in the motor neurons of ALS patients with the SOD1 A4V mutation.}, } @article {pmid38790450, year = {2024}, author = {Eisen, A and Pioro, EP and Goutman, SA and Kiernan, MC}, title = {Nanoplastics and Neurodegeneration in ALS.}, journal = {Brain sciences}, volume = {14}, number = {5}, pages = {}, pmid = {38790450}, issn = {2076-3425}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, abstract = {Plastic production, which exceeds one million tons per year, is of global concern. The constituent low-density polymers enable spread over large distances and micro/nano particles (MNPLs) induce organ toxicity via digestion, inhalation, and skin contact. Particles have been documented in all human tissues including breast milk. MNPLs, especially weathered particles, can breach the blood-brain barrier, inducing neurotoxicity. This has been documented in non-human species, and in human-induced pluripotent stem cell lines. Within the brain, MNPLs initiate an inflammatory response with pro-inflammatory cytokine production, oxidative stress with generation of reactive oxygen species, and mitochondrial dysfunction. Glutamate and GABA neurotransmitter dysfunction also ensues with alteration of excitatory/inhibitory balance in favor of reduced inhibition and resultant neuro-excitation. Inflammation and cortical hyperexcitability are key abnormalities involved in the pathogenic cascade of amyotrophic lateral sclerosis (ALS) and are intricately related to the mislocalization and aggregation of TDP-43, a hallmark of ALS. Water and many foods contain MNPLs and in humans, ingestion is the main form of exposure. Digestion of plastics within the gut can alter their properties, rendering them more toxic, and they cause gut microbiome dysbiosis and a dysfunctional gut-brain axis. This is recognized as a trigger and/or aggravating factor for ALS. ALS is associated with a long (years or decades) preclinical period and neonates and infants are exposed to MNPLs through breast milk, milk substitutes, and toys. This endangers a time of intense neurogenesis and establishment of neuronal circuitry, setting the stage for development of neurodegeneration in later life. MNPL neurotoxicity should be considered as a yet unrecognized risk factor for ALS and related diseases.}, } @article {pmid38790979, year = {2024}, author = {Mishra, PS and Phaneuf, D and Boutej, H and Picher-Martel, V and Dupre, N and Kriz, J and Julien, JP}, title = {Inhibition of NF-κB with an Analog of Withaferin-A Restores TDP-43 Homeostasis and Proteome Profiles in a Model of Sporadic ALS.}, journal = {Biomedicines}, volume = {12}, number = {5}, pages = {}, pmid = {38790979}, issn = {2227-9059}, support = {143275/CAPMC/CIHR/Canada ; 231575//Canada Research Chairs/ ; }, abstract = {The current knowledge on pathogenic mechanisms in amyotrophic lateral sclerosis (ALS) has widely been derived from studies with cell and animal models bearing ALS-linked genetic mutations. However, it remains unclear to what extent these disease models are of relevance to sporadic ALS. Few years ago, we reported that the cerebrospinal fluid (CSF) from sporadic ALS patients contains toxic factors for disease transmission in mice via chronic intracerebroventricular (i.c.v.) infusion. Thus a 14-day i.c.v. infusion of pooled CSF samples from ALS cases in mice provoked motor impairment as well as ALS-like pathological features. This offers a unique paradigm to test therapeutics in the context of sporadic ALS disease. Here, we tested a new Withaferin-A analog (IMS-088) inhibitor of NF-κB that was found recently to mitigate disease phenotypes in mouse models of familial disease expressing TDP-43 mutant. Our results show that oral intake of IMS-088 ameliorated motor performance of mice infused with ALS-CSF and it alleviated pathological changes including TDP-43 proteinopathy, neurofilament disorganization, and neuroinflammation. Moreover, CSF infusion experiments were carried out with transgenic mice having neuronal expression of tagged ribosomal protein (hNfL-RFP mice), which allowed immunoprecipitation of neuronal ribosomes for analysis by mass spectrometry of the translational peptide signatures. The results indicate that treatment with IMS-088 prevented many proteomic alterations associated with exposure to ALS-CSF involving pathways related to cytoskeletal changes, inflammation, metabolic dysfunction, mitochondria, UPS, and autophagy dysfunction. The effective disease-modifying effects of this drug in a mouse model based on i.c.v. infusion of ALS-CSF suggest that the NF-κB signaling pathway represents a compelling therapeutic target for sporadic ALS.}, } @article {pmid38790984, year = {2024}, author = {Zhdanov, DD and Gladilina, YA and Blinova, VG and Abramova, AA and Shishparenok, AN and Eliseeva, DD}, title = {Induction of FoxP3 Pre-mRNA Alternative Splicing to Enhance the Suppressive Activity of Regulatory T Cells from Amyotrophic Lateral Sclerosis Patients.}, journal = {Biomedicines}, volume = {12}, number = {5}, pages = {}, pmid = {38790984}, issn = {2227-9059}, support = {23-24-00326//Russian Science Foundation/ ; }, abstract = {Forkhead box protein 3 (FoxP3) is a key transcription factor responsible for the development, maturation, and function of regulatory T cells (Tregs). The FoxP3 pre-mRNA is subject to alternative splicing, resulting in the translation of multiple splice variants. We have shown that Tregs from patients with amyotrophic lateral sclerosis (ALS) have reduced expression of full-length (FL) FoxP3, while other truncated splice variants are expressed predominantly. A correlation was observed between the reduced number of Tregs in the peripheral blood of ALS patients, reduced total FoxP3 mRNA, and reduced mRNA of its FL splice variant. Induction of FL FoxP3 was achieved using splice-switching oligonucleotides capable of base pairing with FoxP3 pre-mRNA and selectively modulating the inclusion of exons 2 and 7 in the mature mRNA. Selective expression of FL FoxP3 resulted in the induction of CD127[low], CD152, and Helios-positive cells, while the cell markers CD4 and CD25 were not altered. Such Tregs had an increased proliferative activity and a higher frequency of cell divisions per day. The increased suppressive activity of Tregs with the induced FL FoxP3 splice variant was associated with the increased synthesis of the pro-apoptotic granzymes A and B, and perforin, IL-10, and IL-35, which are responsible for contact-independent suppression, and with the increased ability to suppress telomerase in target cells. The upregulation of Treg suppressive and proliferative activity using splice-switching oligonucleotides to induce the predominant expression of the FoxP3 FL variant is a promising approach for regenerative cell therapy in Treg-associated diseases.}, } @article {pmid38791099, year = {2024}, author = {Moțățăianu, A and Mănescu, IB and Șerban, G and Bărcuțean, L and Ion, V and Bălașa, R and Andone, S}, title = {Exploring the Role of Metabolic Hormones in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {10}, pages = {}, pmid = {38791099}, issn = {1422-0067}, support = {PN-III-P1-1.1-TE-2021-0960//Ministry of Research, Innovation and Digitization, CNCS - UEFISCDI, Romania/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; Male ; Female ; Middle Aged ; Aged ; *Islet Amyloid Polypeptide/metabolism/blood ; Cross-Sectional Studies ; *Biomarkers/blood ; *Insulin/metabolism/blood ; Disease Progression ; Leptin/blood/metabolism ; Glucagon-Like Peptide 1/metabolism/blood ; C-Peptide/blood/metabolism ; Ghrelin/metabolism/blood ; Glucagon/blood/metabolism ; Adult ; Hormones/metabolism/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons. Emerging evidence suggests a potential link between metabolic dysregulation and ALS pathogenesis. This study aimed to investigate the relationship between metabolic hormones and disease progression in ALS patients. A cross-sectional study was conducted involving 44 ALS patients recruited from a tertiary care center. Serum levels of insulin, total amylin, C-peptide, active ghrelin, GIP (gastric inhibitory peptide), GLP-1 active (glucagon-like peptide-1), glucagon, PYY (peptide YY), PP (pancreatic polypeptide), leptin, interleukin-6, MCP-1 (monocyte chemoattractant protein-1), and TNFα (tumor necrosis factor alpha) were measured, and correlations with ALSFRS-R, evolution scores, and biomarkers were analyzed using Spearman correlation coefficients. Subgroup analyses based on ALS subtypes, progression pattern of disease, and disease progression rate patterns were performed. Significant correlations were observed between metabolic hormones and ALS evolution scores. Insulin and amylin exhibited strong correlations with disease progression and clinical functional outcomes, with insulin showing particularly robust associations. Other hormones such as C-peptide, leptin, and GLP-1 also showed correlations with ALS progression and functional status. Subgroup analyses revealed differences in hormone levels based on sex and disease evolution patterns, with male patients showing higher amylin and glucagon levels. ALS patients with slower disease progression exhibited elevated levels of amylin and insulin. Our findings suggest a potential role for metabolic hormones in modulating ALS progression and functional outcomes. Further research is needed to elucidate the underlying mechanisms and explore the therapeutic implications of targeting metabolic pathways in ALS management.}, } @article {pmid38791160, year = {2024}, author = {Bocheva, G and Bakalov, D and Iliev, P and Tafradjiiska-Hadjiolova, R}, title = {The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging.}, journal = {International journal of molecular sciences}, volume = {25}, number = {10}, pages = {}, pmid = {38791160}, issn = {1422-0067}, mesh = {*Melatonin/metabolism/pharmacology/therapeutic use ; Humans ; *Brain/metabolism/drug effects ; *Aging/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Neuroprotection/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Kynuramine/metabolism/analogs & derivatives ; }, abstract = {While primarily produced in the pineal gland, melatonin's influence goes beyond its well-known role in regulating sleep, nighttime metabolism, and circadian rhythms, in the field of chronobiology. A plethora of new data demonstrates melatonin to be a very powerful molecule, being a potent ROS/RNS scavenger with anti-inflammatory, immunoregulatory, and oncostatic properties. Melatonin and its metabolites exert multiple beneficial effects in cutaneous and systemic aging. This review is focused on the neuroprotective role of melatonin during aging. Melatonin has an anti-aging capacity, retarding the rate of healthy brain aging and the development of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. Melatonin, as well as its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), can reduce oxidative brain damage by shielding mitochondria from dysfunction during the aging process. Melatonin could also be implicated in the treatment of neurodegenerative conditions, by modifying their characteristic low-grade neuroinflammation. It can either prevent the initiation of inflammatory responses or attenuate the ongoing inflammation. Drawing on the current knowledge, this review discusses the potential benefits of melatonin supplementation in preventing and managing cognitive impairment and neurodegenerative diseases.}, } @article {pmid38795036, year = {2024}, author = {Chen, X and Cao, Z and Wang, Y}, title = {Amyotrophic Lateral Sclerosis-Associated Mutants of SOD1 Perturb mRNA Splicing through Aberrant Interactions with SRSF2.}, journal = {Analytical chemistry}, volume = {96}, number = {23}, pages = {9713-9720}, pmid = {38795036}, issn = {1520-6882}, support = {R35 ES031707/ES/NIEHS NIH HHS/United States ; }, mesh = {*Serine-Arginine Splicing Factors/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; *RNA Splicing ; *Mutation ; RNA, Messenger/genetics/metabolism ; HEK293 Cells ; Biotinylation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that results in the degeneration of neurons in the brain and spinal cord. Although a substantial number of studies have been conducted, much remains to be learned about the cellular mechanisms underlying ALS. In this study, we employed an engineered ascorbate peroxidase (APEX)-based proximity biotinylation, together with affinity pull-down of the ensuing biotinylated peptides, to investigate the proximity proteomes of human SOD1 and its two ALS-linked mutants, G85R and G93A. We were able to identify 25 common biotinylated peptides with preferential enrichment in the proximity proteomes of SOD1[G85R] and SOD1[G93A] over wild-type SOD1. Our coimmunoprecipitation followed by Western blot analyses revealed that one of these proteins, SRSF2, binds more strongly with the two SOD1 mutants than its wild-type counterpart. We also observed aberrant splicing of mRNAs in cells with ectopic expression of the two SOD1 mutants relative to cells expressing the wild-type protein. In addition, the aberrations in splicing elicited by the SOD1 variants were markedly attenuated upon knockdown of SRSF2. Collectively, we uncovered that ALS-liked SOD1[G85R] and SOD1[G93A] mutants interact more strongly with SRSF2, where the aberrant interactions perturbed mRNA splicing. Thus, our work offered novel mechanistic insights into the contributions of the ALS-linked SOD1 mutants to disease etiology.}, } @article {pmid38795640, year = {2024}, author = {Li, Z and Zhang, Y and Ji, M and Wu, C and Zhang, Y and Ji, S}, title = {Targeting ferroptosis in neuroimmune and neurodegenerative disorders for the development of novel therapeutics.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {176}, number = {}, pages = {116777}, doi = {10.1016/j.biopha.2024.116777}, pmid = {38795640}, issn = {1950-6007}, mesh = {*Ferroptosis/drug effects/physiology ; Humans ; *Neurodegenerative Diseases/drug therapy/immunology/metabolism/pathology ; Animals ; Neuroimmunomodulation ; }, abstract = {Neuroimmune and neurodegenerative ailments impose a substantial societal burden. Neuroimmune disorders involve the intricate regulatory interactions between the immune system and the central nervous system. Prominent examples of neuroimmune disorders encompass multiple sclerosis and neuromyelitis optica. Neurodegenerative diseases result from neuronal degeneration or demyelination in the brain or spinal cord, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The precise underlying pathogenesis of these conditions remains incompletely understood. Ferroptosis, a programmed form of cell death characterised by lipid peroxidation and iron overload, plays a pivotal role in neuroimmune and neurodegenerative diseases. In this review, we provide a detailed overview of ferroptosis, its mechanisms, pathways, and regulation during the progression of neuroimmune and neurodegenerative diseases. Furthermore, we summarise the impact of ferroptosis on neuroimmune-related cells (T cells, B cells, neutrophils, and macrophages) and neural cells (glial cells and neurons). Finally, we explore the potential therapeutic implications of ferroptosis inhibitors in diverse neuroimmune and neurodegenerative diseases.}, } @article {pmid38795892, year = {2024}, author = {Ridho, MR and Lubis, MAR and Nawawi, DS and Fatriasari, W}, title = {Optimization of areca leaf sheath nanolignin synthesis by a mechanical method for in situ modification of ultra-low molar ratio urea-formaldehyde adhesives.}, journal = {International journal of biological macromolecules}, volume = {271}, number = {Pt 1}, pages = {132614}, doi = {10.1016/j.ijbiomac.2024.132614}, pmid = {38795892}, issn = {1879-0003}, mesh = {*Formaldehyde/chemistry ; *Adhesives/chemistry ; *Urea/chemistry ; Plant Leaves/chemistry ; Particle Size ; Lignin/chemistry ; }, abstract = {This study addresses the optimization of the nanolignin preparation method from the areca leaf sheath (ALS) by a mechanical process using a high shear homogenizer at 13,000-16,000 rpm for 1-4 h and its application in enhancing the performance of ultralow molar ratio urea-formaldehyde (UF) adhesive. Response surface methodology (RSM) with a central composite design (CCD) model was used to determine the optimum nanolignin preparation method. The mathematical model obtained was quadratic for the particle size response and linear for the zeta potential response. Under the optimum conditions, a speed of 16,000 rpm for 4 h resulted in a particle size of 227.7 nm and a zeta potential of -18.57 mV with a high desirability value of 0.970. FE-SEM revealed that the characteristic changes of lignin to nanolignin occur from an irregular or nonuniform shape to an oval shape with uniform particles. Nanolignin was introduced during the addition reaction of UF resin synthesis. UF modified with nanolignin (UF-NL) was analyzed for its adhesive characteristics, functional groups, crystallinity, and thermomechanical properties. The UF-NL adhesive had a slightly greater solid content (73.23 %) than the UF adhesive, a gelation time of 4.10 min, and a viscosity of 1066 mPa[.]s. The UF-NL adhesive had similar functional groups as the UF adhesive, with a lower crystallinity of 59.73 %. Compared with the control plywood which has a tensile shear strength value of 0.79 MPa, the plywood bonded with UF-NL had a greater tensile shear strength of 1.07 MPa, with a lower formaldehyde emission of 0.065 mg/L.}, } @article {pmid38795957, year = {2024}, author = {Bhushan, NL and Romano, CD and Gras-Najjar, J and Reno, J and Rockwood, N and Quattrone, W and Adams, ET and Kelly, B and McLeod, L and Bhavnani, SP and Bocell, FD and Campbell, M and Kontson, K and Reasner, D and Zhang, C and Retzky, S}, title = {Remote-Use Applications of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised Clinical Outcome Assessment Tool: A Scoping Review.}, journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research}, volume = {27}, number = {10}, pages = {1454-1465}, doi = {10.1016/j.jval.2024.05.005}, pmid = {38795957}, issn = {1524-4733}, support = {75F40120A00017/FD/FDA HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/physiopathology ; Humans ; *Outcome Assessment, Health Care/methods ; Telemedicine ; Severity of Illness Index ; Videoconferencing ; }, abstract = {OBJECTIVES: In 2021, the US Congress passed the Accelerating Access to Critical Therapies for Amyotrophic Lateral Sclerosis Act. The law encourages development of "tools, methods, and processes" to improve clinical trial efficiency for neurodegenerative diseases. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is an outcome measure administered during in-person clinic visits and used to support investigational studies for persons living with amyotrophic lateral sclerosis. Availability of a standardized, remote-use version of the ALSFRS-R may promote more inclusive, decentralized clinical trials. A scoping literature review was conducted to identify existing remote-use ALSFRS-R tools, synthesize feasibility and comparability of administration modes, and summarize barriers and facilitators to inform development of a standardized remote-use ALSFRS-R tool.

METHODS: Included studies reported comparisons between remote and in-person, clinician-reported, ALSFRS-R administration and were published in English (2002-2022). References were identified by searching peer-reviewed and gray literature. Twelve studies met the inclusion criteria and were analyzed to compare findings within and across modes of administration.

RESULTS: Remote modes of ALSFRS-R administration were categorized into 4 nonmutually exclusive categories: telephone (n = 6), videoconferencing (n = 3), computer or online platforms (n = 3), mobile applications and wearables (n = 2), and 1 unspecified telemedicine modality (n = 1). Studies comparing in-person to telephone or videoconferencing administration reported high ALSFRS-R rating correlations and nonsignificant between-mode differences.

CONCLUSIONS: There is insufficient information in the ALSFRS-R literature to support remote clinician administration for collecting high quality data. Future research should engage persons living with amyotrophic lateral sclerosis, care partners, and providers to develop a standardized remote-use ALSFRS-R version.}, } @article {pmid38796647, year = {2024}, author = {Chong, NF and Van de Wouw, AP and Idnurm, A}, title = {The ilv2 gene, encoding acetolactate synthase for branched chain amino acid biosynthesis, is required for plant pathogenicity by Leptosphaeria maculans.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {682}, pmid = {38796647}, issn = {1573-4978}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Plant Diseases/microbiology ; *Herbicides/pharmacology ; *Amino Acids, Branched-Chain/biosynthesis/metabolism ; *Leptosphaeria/genetics/pathogenicity ; Mutation/genetics ; Fungal Proteins/genetics/metabolism ; Gene Editing/methods ; Plant Leaves/microbiology ; CRISPR-Cas Systems/genetics ; Brassica/microbiology ; Ascomycota/pathogenicity/genetics ; }, abstract = {BACKGROUND: Control of blackleg disease of canola caused by the fungus Leptosphaeria maculans relies on strategies such as the inhibition of growth with fungicides. However, other chemicals are used during canola cultivation, including fertilizers and herbicides. There is widespread use of herbicides that target the acetolactate synthase (ALS) enzyme involved in branched chain amino acid synthesis and low levels of these amino acids within leaves of Brassica species. In L. maculans the ilv2 gene encodes ALS and thus ALS-inhibiting herbicides may inadvertently impact the fungus.

METHODS AND RESULTS: Here, the impact of a commercial herbicide targeting ALS and mutation of the homologous ilv2 gene in L. maculans was explored. Exposure to herbicide had limited impact on growth in vitro but reduced lesion sizes in plant disease experiments. Furthermore, the mutation of the ilv2 gene via CRISPR-Cas9 gene editing rendered the fungus non-pathogenic.

CONCLUSION: Herbicide applications can influence disease outcome, but likely to a minor extent.}, } @article {pmid38796984, year = {2024}, author = {Jiang, L and Tracey, TJ and Gill, MK and Howe, SL and Power, DT and Bharti, V and McCombe, PA and Henderson, RD and Steyn, FJ and Ngo, ST}, title = {Generation of human induced pluripotent stem cell lines from sporadic, sporadic frontotemporal dementia, familial SOD1, and familial C9orf72 amyotrophic lateral sclerosis (ALS) patients.}, journal = {Stem cell research}, volume = {78}, number = {}, pages = {103447}, doi = {10.1016/j.scr.2024.103447}, pmid = {38796984}, issn = {1876-7753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; Female ; Male ; Cell Line ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Clinical heterogeneity and complex genetics pose challenges to understanding disease mechanisms and producing effective cures. To model clinical heterogeneity, we generated human induced pluripotent stem cells (iPSCs) from two sporadic ALS patients (sporadic ALS and sporadic ALS with frontotemporal dementia), two familial ALS patients (familial SOD1 mutation positive and familial C9orf72 repeat expansion positive), and four age- and sex-matched healthy controls. These iPSCs can be used to generate 2D and 3D in vitro models of ALS to investigate mechanisms of disease and screen for therapeutics.}, } @article {pmid38798341, year = {2025}, author = {Provasek, VE and Bacolla, A and Rangaswamy, S and Kodavati, M and Mitra, J and Yusuf, IO and Malojirao, VH and Vasquez, V and Britz, GW and Li, GM and Xu, Z and Mitra, S and Garruto, RM and Tainer, JA and Hegde, ML}, title = {RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38798341}, issn = {2692-8205}, support = {R35 CA220430/CA/NCI NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; P01 CA092584/CA/NCI NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {TDP43 is an RNA/DNA binding protein increasingly recognized for its role in neurodegenerative conditions, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to the formation of detrimental cytosolic aggregates and a reduction in nuclear functionality within neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expressions. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.}, } @article {pmid38798645, year = {2024}, author = {Landry, C and Costanzo, J and Mitne-Neto, M and Zatz, M and Schaffer, A and Hatzoglou, M and Muotri, A and Miranda, HC}, title = {Mitochondrial dysfunction heightens the integrated stress response to drive ALS pathogenesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.05.13.594000}, pmid = {38798645}, issn = {2692-8205}, support = {R01 NS121374/NS/NINDS NIH HHS/United States ; R61 NS133212/NS/NINDS NIH HHS/United States ; }, abstract = {Vesicle-associated membrane protein-associated protein-B (VAPB) is an ER membrane bound protein. VAPB P56S causes a dominant, familial form of amyotrophic lateral sclerosis (ALS), however, the mechanism through which this mutation causes motor neuron (MN) disease remains unknown. Using inducible wild type (WT) and VAPB P56S expressing iPSC-derived MNs we show that VAPB P56S, but not WT, protein decreased neuronal firing and mitochondrial-ER contact (MERC) with an associated age-dependent decrease in mitochondrial membrane potential (MMP); all typical characteristics of MN-disease. We further show that VAPB P56S expressing iPSC-derived MNs have enhanced age-dependent sensitivity to ER stress. We identified elevated expression of the master regulator of the Integrated Stress Response (ISR) marker ATF4 and decreased protein synthesis in the VAPB P56S iPSC-derived MNs. Chemical inhibition of ISR with the compound, ISRIB, rescued all MN disease phenotype in VAPB P56S MNs. Thus, our results not only support ISR inhibition as a potential therapeutic target for ALS patients, but also provides evidence to pathogenesis.}, } @article {pmid38798695, year = {2024}, author = {Conforti, FL and Renton, AE and Houlden, H}, title = {Editorial: Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia volume II.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1420029}, doi = {10.3389/fgene.2024.1420029}, pmid = {38798695}, issn = {1664-8021}, } @article {pmid38799643, year = {2024}, author = {Xu, S and Ma, Q and Shen, J and Li, N and Sun, S and Wang, N and Chen, Y and Dong, C and Tam, KY and Prehn, JHM and Wang, H and Ying, Z}, title = {ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2-BECN1 interaction.}, journal = {Acta pharmaceutica Sinica. B}, volume = {14}, number = {5}, pages = {2026-2038}, pmid = {38799643}, issn = {2211-3835}, abstract = {Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative disorders. The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72 (C9orf72) is the most genetic cause of both ALS and FTD. According to the previous studies, GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation, which produces dipeptide repeat (DPR) proteins. Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD, whether these DPRs can affect autophagy remains unclear. In the present study, we find that poly-GR and poly-PR, two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies, strongly inhibit starvation-induced autophagy. Moreover, our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation, therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells. Importantly, our study not only highlights the role of C9orf72 DPR in autophagy dysfunction, but also provides novel insight that pharmacological intervention of autophagy using SW063058, a small molecule compound that can disrupt the interaction between BECN1 and BCL2, may reduce C9orf72 DPR-induced neurotoxicity.}, } @article {pmid38802173, year = {2024}, author = {Van Es, MA}, title = {Amyotrophic lateral sclerosis; clinical features, differential diagnosis and pathology.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {1-47}, doi = {10.1016/bs.irn.2024.04.011}, pmid = {38802173}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/pathology/physiopathology ; Diagnosis, Differential ; Frontotemporal Dementia/diagnosis/genetics/physiopathology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset syndrome characterized by the progressive degeneration of both upper motor neurons (UMN) and lower motor neurons (LMN). ALS forms a clinical continuum with frontotemporal dementia (FTD), in which there are progressive language deficits or behavioral changes. The genetics and pathology underlying both ALS and FTD overlap as well, with cytoplasmatic misvocalization of TDP-43 as the hallmark. ALS is diagnosed by exclusion. Over the years several diagnostic criteria have been proposed, which in essence all require a history of slowly progressive motor symptoms, with UMN and LMN signs on neurological examination, clear spread of symptoms through the body, the exclusion of other disorder that cause similar symptoms and an EMG that it is compatible with LMN loss. ALS is heterogeneous disorder that may present in multitude ways, which makes the diagnosis challenging. Therefore, a systematic approach in the diagnostic process is required in line with the most common presentations. Subsequently, assessing whether there are cognitive and/or behavioral changes within the spectrum of FTD and lastly determining the cause is genetic. This chapter, an outline on how to navigate this 3 step process.}, } @article {pmid38802174, year = {2024}, author = {Hobson, E and McDermott, C}, title = {Advances in symptom management and in monitoring disease progression in motor neuron disease.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {119-169}, doi = {10.1016/bs.irn.2024.04.004}, pmid = {38802174}, issn = {2162-5514}, mesh = {Humans ; *Motor Neuron Disease/therapy/physiopathology ; *Disease Progression ; Disease Management ; Quality of Life ; }, abstract = {The aim of supportive management of motor neuron disease is to improve survival, promote good quality of life and patient independence and autonomy whilst preparing for future progression and the end of life. Multidisciplinary specialist care aims to address the multifaceted and interacting biopsychosocial problems associated with motor neuron disease that leads to proven benefits in both survival and quality of life. This chapter will explore principles, structure and details of treatment options, and make recommendations for practice and for future research.}, } @article {pmid38802175, year = {2024}, author = {Malaspina, A}, title = {Use of biomarkers in clinical trials and future developments that will help identify novel biomarkers.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {171-207}, doi = {10.1016/bs.irn.2024.04.010}, pmid = {38802175}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/genetics/metabolism/drug therapy ; *Biomarkers ; *Clinical Trials as Topic/methods ; }, abstract = {Engineering new solutions for therapeutic benefit in Amyotrophic Lateral Sclerosis (ALS) has proved a difficult task to accomplish. This is largely the reflection of complexities at multiple levels, that require solutions to improve cost-effectiveness and outcomes. The main obstacle related to the condition's clinical heterogeneity, chiefly the broad difference in survival observed among ALS patients, imposes large populations studies and long follow-up to evaluate any efficacy. The emerging solution is composite clinical and biological parameters enabling prognostic stratification into homogeneous phenotypes for more affordable studies. From a therapeutic development perspective, the choice of a medicinal product requires the availability of treatment-specific biomarkers of target engagement to identify off-target effects based on the compound's putative modality of action. More importantly, there are no established biomarkers of treatment response that can complement clinical outcome measures and support futility and end of treatment analyses of efficacy. Ultimately the onus rests on the development of biomarkers encompassing the unmet needs of clinical trial design, from inclusion to efficacy. These readouts of the pathological process may be used in combination with clinical and paraclinical outcome measured, significantly reducing the time and financial burden of clinical studies. Progress towards a biomarker-driven clinical trial design in ALS has been possible thanks to the accurate detection of neurofilaments and of other immunological mediators in biological fluids with the disease progression, a step change enabling the testing of novel therapeutic agents in a new clinical trial setting. However, further progress remains to be made to find treatment specific target engagement biomarkers along with readouts of treatment response that can be reliably applied to all emerging therapies and clinical studies. Here we will cover the basic notions of biomarker development in ALS clinical trials, the most crucial unanswered questions and the unmet needs in the ALS biomarkers space.}, } @article {pmid38802176, year = {2024}, author = {Castelli, L and Vasta, R and Allen, SP and Waller, R and Chiò, A and Traynor, BJ and Kirby, J}, title = {From use of omics to systems biology: Identifying therapeutic targets for amyotrophic lateral sclerosis.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {209-268}, doi = {10.1016/bs.irn.2024.02.001}, pmid = {38802176}, issn = {2162-5514}, support = {ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy/therapy ; *Systems Biology/methods ; *Genomics/methods ; Proteomics/methods ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous progressive neurodegenerative disorder with available treatments such as riluzole and edaravone extending survival by an average of 3-6 months. The lack of highly effective, widely available therapies reflects the complexity of ALS. Omics technologies, including genomics, transcriptomic and proteomics have contributed to the identification of biological pathways dysregulated and targeted by therapeutic strategies in preclinical and clinical trials. Integrating clinical, environmental and neuroimaging information with omics data and applying a systems biology approach can further improve our understanding of the disease with the potential to stratify patients and provide more personalised medicine. This chapter will review the omics technologies that contribute to a systems biology approach and how these components have assisted in identifying therapeutic targets. Current strategies, including the use of genetic screening and biosampling in clinical trials, as well as the future application of additional technological advances, will also be discussed.}, } @article {pmid38802177, year = {2024}, author = {Lee, J and Pye, N and Ellis, L and Vos, K and Mortiboys, H}, title = {Evidence of mitochondrial dysfunction in ALS and methods for measuring in model systems.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {269-325}, doi = {10.1016/bs.irn.2024.04.006}, pmid = {38802177}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Mitochondria/metabolism ; Animals ; Reactive Oxygen Species/metabolism ; Disease Models, Animal ; Oxidative Stress/physiology ; }, abstract = {Metabolic dysfunction is a hallmark of multiple amyotrophic lateral sclerosis (ALS) models with a majority of ALS patients exhibiting hypermetabolism. The central sites of metabolism in the cell are mitochondria, capable of utilising a multitude of cellular substrates in an array of ATP-generating reactions. With reactive oxygen species (ROS) production occurring during some of these reactions, mitochondria can contribute considerably to oxidative stress. Mitochondria are also very dynamic organelles, interacting with other organelles, undergoing fusion/fission in response to changing metabolic states and being turned over by the cell regularly. Disruptions to many of these mitochondrial functions and processes have been reported in ALS models, largely indicating compromised mitochondrial function, increased ROS production by mitochondria, disrupted interactions with the endoplasmic reticulum and reduced turnover. This chapter summarises methods routinely used to assess mitochondria in ALS models and the alterations that have been reported in these models.}, } @article {pmid38802179, year = {2024}, author = {Pandya, VA and Patani, R}, title = {The role of glial cells in amyotrophic lateral sclerosis.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {381-450}, doi = {10.1016/bs.irn.2024.04.005}, pmid = {38802179}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology/therapy ; Humans ; *Neuroglia/physiology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has traditionally been considered a neuron-centric disease. This view is now outdated, with increasing recognition of cell autonomous and non-cell autonomous contributions of central and peripheral nervous system glia to ALS pathomechanisms. With glial research rapidly accelerating, we comprehensively interrogate the roles of astrocytes, microglia, oligodendrocytes, ependymal cells, Schwann cells and satellite glia in nervous system physiology and ALS-associated pathology. Moreover, we highlight the inter-glial, glial-neuronal and inter-system polylogue which constitutes the healthy nervous system and destabilises in disease. We also propose classification based on function for complex glial reactive phenotypes and discuss the pre-requisite for integrative modelling to advance translation. Given the paucity of life-enhancing therapies currently available for ALS patients, we discuss the promising potential of harnessing glia in driving ALS therapeutic discovery.}, } @article {pmid38802180, year = {2024}, author = {Shelkovnikova, TA and Hautbergue, GM}, title = {RNP granules in ALS and neurodegeneration: From multifunctional membraneless organelles to therapeutic opportunities.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {455-479}, doi = {10.1016/bs.irn.2024.04.009}, pmid = {38802180}, issn = {2162-5514}, support = {MR/R024162/1/MRC_/Medical Research Council/United Kingdom ; MR/W004615/1//UKRI Future Leaders Fellowship/ ; MR/R024162/1//Medical Research Council (MRC)/ ; BB/S005277/1//Biotechnology and Biological Sciences Research Council (BBSRC)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Ribonucleoproteins/metabolism ; Animals ; *Cytoplasmic Granules/metabolism ; Neurodegenerative Diseases/metabolism ; Organelles/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases are characterised by dysfunction of a host of RNA-binding proteins (RBPs) and a severely disrupted RNA metabolism. Recently, RBP-harbouring phase-separated complexes, ribonucleoprotein (RNP) granules, have come into the limelight as "crucibles" of neuronal pathology in ALS. RNP granules are indispensable for the multitude of regulatory processes underlying cellular RNA metabolism and serve as critical organisers of cellular biochemistry. Neurons, highly specialised cells, heavily rely on RNP granules for efficient trafficking, signalling and stress responses. Multiple RNP granule components, primarily RBPs such as TDP-43 and FUS, are affected by ALS mutations. However, even in the absence of mutations, RBP proteinopathies represent pathophysiological hallmarks of ALS. Given the high local concentrations of RBPs and RNAs, their weakened or enhanced interactions within RNP granules disrupt their homeostasis. Thus, the physiological process of phase separation and RNP granule formation, vital for maintaining the high-functioning state of neuronal cells, becomes their Achilles heel. Here, we will review the recent literature on the causes and consequences of abnormal RNP granule functioning in ALS and related disorders. In particular, we will summarise the evidence for the network-level dysfunction of RNP granules in these conditions and discuss considerations for therapeutic interventions to target RBPs, RNP granules and their network as a whole.}, } @article {pmid38802181, year = {2024}, author = {De Cock, L and Bercier, V and Van Den Bosch, L}, title = {New developments in pre-clinical models of ALS to guide translation.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {477-524}, doi = {10.1016/bs.irn.2024.04.008}, pmid = {38802181}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/physiopathology/therapy ; Animals ; *Disease Models, Animal ; Humans ; Translational Research, Biomedical/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder in which selective death of motor neurons leads to muscle weakness and paralysis. Most research has focused on understanding and treating monogenic familial forms, most frequently caused by mutations in SOD1, FUS, TARDBP and C9orf72, although ALS is mostly sporadic and without a clear genetic cause. Rodent models have been developed to study monogenic ALS, but despite numerous pre-clinical studies and clinical trials, few disease-modifying therapies are available. ALS is a heterogeneous disease with complex underlying mechanisms where several genes and molecular pathways appear to play a role. One reason for the high failure rate of clinical translation from the current models could be oversimplification in pre-clinical studies. Here, we review advances in pre-clinical models to better capture the heterogeneous nature of ALS and discuss the value of novel model systems to guide translation and aid in the development of precision medicine.}, } @article {pmid38802182, year = {2024}, author = {Al-Chalabi, A and Andrews, J and Farhan, S}, title = {Recent advances in the genetics of familial and sporadic ALS.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {49-74}, doi = {10.1016/bs.irn.2024.04.007}, pmid = {38802182}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genetic Predisposition to Disease/genetics ; }, abstract = {ALS shows complex genetic inheritance patterns. In about 5% to 10% of cases, there is a family history of ALS or a related condition such as frontotemporal dementia in a first or second degree relative, and for about 80% of such people a pathogenic gene variant can be identified. Such variants are also seen in people with no family history because of factor influencing the expression of genes, such as age. Genetic susceptibility factors also contribute to risk, and the heritability of ALS is between 40% and 60%. The genetic variants influencing ALS risk include single base changes, repeat expansions, copy number variants, and others. Here we review what is known of the genetic landscape and architecture of ALS.}, } @article {pmid38802183, year = {2024}, author = {Moll, T and Harvey, C and Alhathli, E and Gornall, S and O'Brien, D and Cooper-Knock, J}, title = {Non-coding genome contribution to ALS.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {75-86}, doi = {10.1016/bs.irn.2024.04.002}, pmid = {38802183}, issn = {2162-5514}, support = {216596/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Animals ; Genetic Predisposition to Disease/genetics ; }, abstract = {The majority of amyotrophic lateral sclerosis (ALS) is caused by a complex gene-environment interaction. Despite high estimates of heritability, the genetic basis of disease in the majority of ALS patients are unknown. This limits the development of targeted genetic therapies which require an understanding of patient-specific genetic drivers. There is good evidence that the majority of these missing genetic risk factors are likely to be found within the non-coding genome. However, a major challenge in the discovery of non-coding risk variants is determining which variants are functional in which specific CNS cell type. We summarise current discoveries of ALS-associated genetic drivers within the non-coding genome and we make the case that improved cell-specific annotation of genomic function is required to advance this field, particularly via single-cell epigenetic profiling and spatial transcriptomics. We highlight the example of TBK1 where an apparent paradox exists between pathogenic coding variants which cause loss of protein function, and protective non-coding variants which cause reduced gene expression; the paradox is resolved when it is understood that the non-coding variants are acting primarily via change in gene expression within microglia, and the effect of coding variants is most prominent in neurons. We propose that cell-specific functional annotation of ALS-associated genetic variants will accelerate discovery of the genetic architecture underpinning disease in the vast majority of patients.}, } @article {pmid38802184, year = {2024}, author = {Vucic, S and de Carvalho, M and Bashford, J and Alix, JJP}, title = {Contribution of neurophysiology to the diagnosis and monitoring of ALS.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {87-118}, doi = {10.1016/bs.irn.2024.04.001}, pmid = {38802184}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; *Transcranial Magnetic Stimulation/methods ; *Electromyography/methods ; *Neurophysiology/methods ; Disease Progression ; Motor Cortex/physiopathology ; }, abstract = {This chapter describes the role of neurophysiological techniques in diagnosing and monitoring amyotrophic lateral sclerosis (ALS). Despite many advances, electromyography (EMG) remains a keystone investigation from which to build support for a diagnosis of ALS, demonstrating the pathophysiological processes of motor unit hyperexcitability, denervation and reinnervation. We consider development of the different diagnostic criteria and the role of EMG therein. While not formally recognised by established diagnostic criteria, we discuss the pioneering studies that have demonstrated the diagnostic potential of transcranial magnetic stimulation (TMS) of the motor cortex and highlight the growing evidence for TMS in the diagnostic process. Finally, accurately monitoring disease progression is crucial for the successful implementation of clinical trials. Neurophysiological measures of disease state have been incorporated into clinical trials for over 20 years and we review prominent techniques for assessing disease progression.}, } @article {pmid38802492, year = {2024}, author = {Watanabe, S and Amporndanai, K and Awais, R and Latham, C and Awais, M and O'Neill, PM and Yamanaka, K and Hasnain, SS}, title = {Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {12118}, pmid = {38802492}, issn = {2045-2322}, support = {WA1198//ALS Association/ ; }, mesh = {*Superoxide Dismutase-1/genetics/metabolism ; Animals ; *Organoselenium Compounds/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Isoindoles/pharmacology ; Mice ; *Azoles/pharmacology ; Humans ; Mice, Transgenic ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) selectively affects motor neurons. SOD1 is the first causative gene to be identified for ALS and accounts for at least 20% of the familial (fALS) and up to 4% of sporadic (sALS) cases globally with some geographical variability. The destabilisation of the SOD1 dimer is a key driving force in fALS and sALS. Protein aggregation resulting from the destabilised SOD1 is arrested by the clinical drug ebselen and its analogues (MR6-8-2 and MR6-26-2) by redeeming the stability of the SOD1 dimer. The in vitro target engagement of these compounds is demonstrated using the bimolecular fluorescence complementation assay with protein-ligand binding directly visualised by co-crystallography in G93A SOD1. MR6-26-2 offers neuroprotection slowing disease onset of SOD1[G93A] mice by approximately 15 days. It also protected neuromuscular junction from muscle denervation in SOD1[G93A] mice clearly indicating functional improvement.}, } @article {pmid38802624, year = {2024}, author = {Riva, N and Domi, T and Pozzi, L and Lunetta, C and Schito, P and Spinelli, EG and Cabras, S and Matteoni, E and Consonni, M and Bella, ED and Agosta, F and Filippi, M and Calvo, A and Quattrini, A}, title = {Update on recent advances in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4693-4723}, pmid = {38802624}, issn = {1432-1459}, support = {IDEALS//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; Marazzina Project//Marazzina Foundation/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; Animals ; }, abstract = {In the last few years, our understanding of disease molecular mechanisms underpinning ALS has advanced greatly, allowing the first steps in translating into clinical practice novel research findings, including gene therapy approaches. Similarly, the recent advent of assistive technologies has greatly improved the possibility of a more personalized approach to supportive and symptomatic care, in the context of an increasingly complex multidisciplinary line of actions, which remains the cornerstone of ALS management. Against this rapidly growing background, here we provide an comprehensive update on the most recent studies that have contributed towards our understanding of ALS pathogenesis, the latest results from clinical trials as well as the future directions for improving the clinical management of ALS patients.}, } @article {pmid38805053, year = {2024}, author = {Bjelica, B and Bartels, MB and Hesebeck-Brinckmann, J and Petri, S}, title = {Non-motor symptoms in patients with amyotrophic lateral sclerosis: current state and future directions.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {3953-3977}, pmid = {38805053}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of both upper and lower motor neurons. A defining histopathological feature in approximately 97% of all ALS cases is the accumulation of phosphorylated trans-activation response (TAR) DNA-binding protein 43 protein (pTDP-43) aggregates in the cytoplasm of neurons and glial cells within the central nervous system. Traditionally, it was believed that the accumulation of TDP-43 aggregates and subsequent neurodegeneration primarily occurs in motor neurons. However, contemporary evidence suggests that as the disease progresses, other systems and brain regions are also affected. Despite this, there has been a limited number of clinical studies assessing the non-motor symptoms in ALS patients. These studies often employ various outcome measures, resulting in a wide range of reported frequencies of non-motor symptoms in ALS patients. The importance of assessing the non-motor symptoms reflects in a fact that they have a significant impact on patients' quality of life, yet they frequently go underdiagnosed and unreported during clinical evaluations. This review aims to provide an up-to-date overview of the current knowledge concerning non-motor symptoms in ALS. Furthermore, we address their diagnosis and treatment in everyday clinical practice.}, } @article {pmid38805054, year = {2024}, author = {Beswick, E and Christides, A and Symonds, A and Johnson, M and Fawcett, T and Newton, J and Lyle, D and Weaver, C and Chandran, S and Pal, S}, title = {Exploratory study to evaluate the acceptability of a wearable accelerometer to assess motor progression in motor neuron disease.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5083-5101}, pmid = {38805054}, issn = {1432-1459}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Motor Neuron Disease/physiopathology/diagnosis ; Aged ; *Wearable Electronic Devices ; *Accelerometry/instrumentation ; *Disease Progression ; Patient Acceptance of Health Care ; Surveys and Questionnaires/standards ; }, abstract = {Motor neuron disease (MND) is a rapidly progressive condition traditionally assessed using a questionnaire to evaluate physical function, the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R). Its use can be associated with poor sensitivity in detecting subtle changes over time and there is an urgent need for more sensitive and specific outcome measures. The ActiGraph GT9X is a wearable device containing multiple sensors that can be used to provide metrics that represent physical activity. The primary aim of this study was to investigate the initial suitability and acceptability of limb-worn wearable devices to group of people with MND in Scotland. A secondary aim was to explore the preliminary associations between the accelerometer sensor data within the ActiGraph GT9X and established measures of physical function. 10 participants with MND completed a 12-week schedule of assessments including fortnightly study visits, both in-person and over videoconferencing software. Participants wore the device on their right wrist and right ankle for a series of movements, during a 6-min walking test and for a period of 24-h wear, including overnight. Participants also completed an ALSFRS-R and questionnaires on their experience with the devices. 80% of the participants found wearing these devices to be a positive experience and no one reported interference with daily living or added burden. However, 30% of the participants experienced technical issues with their devices. Data from the wearable devices correlated with established measures of physical function.}, } @article {pmid38805282, year = {2024}, author = {Bell, AM and Utting, C and Dickie, AC and Kucharczyk, MW and Quillet, R and Gutierrez-Mecinas, M and Razlan, ANB and Cooper, AH and Lan, Y and Hachisuka, J and Weir, GA and Bannister, K and Watanabe, M and Kania, A and Hoon, MA and Macaulay, IC and Denk, F and Todd, AJ}, title = {Deep sequencing of Phox2a nuclei reveals five classes of anterolateral system neurons.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {23}, pages = {e2314213121}, pmid = {38805282}, issn = {1091-6490}, support = {BB/S017178/1//UKRI | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; 204820/Z/16/Z//Wellcome Trust (WT)/ ; MR/W004739/1//UKRI | Medical Research Council (MRC)/ ; BBS/E/T/000PR9816//UKRI | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; MR/V033638/1//UKRI | Medical Research Council (MRC)/ ; /WT_/Wellcome Trust/United Kingdom ; SGL025\1079//Academy of Medical Sciences (The Academy of Medical Sciences)/ ; MR/W002426/1//UKRI | Medical Research Council (MRC)/ ; MR/T01072X/1//UKRI | Medical Research Council (MRC)/ ; ZIADE000721-22//HHS | NIH | National Institute of Dental and Craniofacial Research (NIDCR)/ ; MRF-160-0015-ELP-DENK-C0844//UKRI | MRC | Medical Research Foundation/ ; 219433/Z/19/Z//Wellcome Trust (WT)/ ; MR/T01072X/1/MRC_/Medical Research Council/United Kingdom ; MR/V033638/1/MRC_/Medical Research Council/United Kingdom ; BB/CCG1720/1//UKRI | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; }, mesh = {Animals ; Mice ; *Homeodomain Proteins/genetics/metabolism ; Spinal Cord/cytology/metabolism ; Neurons/metabolism ; High-Throughput Nucleotide Sequencing ; Male ; Cell Nucleus/metabolism/genetics ; Transcription Factors/genetics/metabolism ; }, abstract = {The anterolateral system (ALS) is a major ascending pathway from the spinal cord that projects to multiple brain areas and underlies the perception of pain, itch, and skin temperature. Despite its importance, our understanding of this system has been hampered by the considerable functional and molecular diversity of its constituent cells. Here, we use fluorescence-activated cell sorting to isolate ALS neurons belonging to the Phox2a-lineage for single-nucleus RNA sequencing. We reveal five distinct clusters of ALS neurons (ALS1-5) and document their laminar distribution in the spinal cord using in situ hybridization. We identify three clusters of neurons located predominantly in laminae I-III of the dorsal horn (ALS1-3) and two clusters with cell bodies located in deeper laminae (ALS4 and ALS5). Our findings reveal the transcriptional logic that underlies ALS neuronal diversity in the adult mouse and uncover the molecular identity of two previously identified classes of projection neurons. We also show that these molecular signatures can be used to target groups of ALS neurons using retrograde viral tracing. Overall, our findings provide a valuable resource for studying somatosensory biology and targeting subclasses of ALS neurons.}, } @article {pmid38805448, year = {2024}, author = {Fernandes, APM and Holanda, LJ and Lucena, LC and Silva, KERD and Lopes, ACSM and Borges, DT and Nagem, DAP and Valentim, RAM and Bougrain, L and Rodrigues Lindquist, AR}, title = {Electromyography as a tool to motion analysis for people with Amyotrophic Lateral Sclerosis: A protocol for a systematic review.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0302479}, pmid = {38805448}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Humans ; *Electromyography/methods ; Systematic Reviews as Topic ; Muscle, Skeletal/physiopathology ; Movement/physiology ; Biomechanical Phenomena ; }, abstract = {Biomechanical analysis of human movement plays an essential role in understanding functional changes in people with Amyotrophic Lateral Sclerosis (ALS), providing information on muscle impairment. Studies suggest that surface electromyography (sEMG) may be able to quantify muscle activity, identify levels of fatigue, assess muscle strength, and monitor variation in limb movement. In this article, a systematic review protocol will analyze the psychometric properties of the sEMG regarding the clinical data on the skeletal muscles of people with ALS. This protocol uses the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodological tool. A specific field structure was defined to reach each phase. Nine scientific databases (PubMed, Web of Science, Embase, Elsevier, IEEE, Google Scholar, SciELO, PEDro, LILACS E CENTRAL) were searched. The framework developed will extract data (i.e. study information, sample information, sEMG information, intervention, and outcomes) from the selected studies using a rigorous approach. The data will be described quantitatively using frequency and trend analysis methods, and heterogeneity between the included studies will be assessed using the I2 test. The risk of bias will be summarized using the most recent prediction model risk of bias assessment tool. Be sure to include relevant statistics here, such as sample sizes, response rates, P values or Confidence Intervals. Be specific (by stating the value) rather than general (eg, "there were differences between the groups"). This protocol will map out the construction of a systematic review that will identify and synthesize the advances in movement analysis of people with ALS through sEMG, using data extracted from articles.}, } @article {pmid38806131, year = {2024}, author = {Oliveira, D and Assoni, AF and Alves, LM and Sakugawa, A and Melo, US and Teles E Silva, AL and Sertie, AL and Caires, LC and Goulart, E and Ghirotto, B and Carvalho, VM and Ferrari, MR and Zatz, M}, title = {ALS-associated VRK1 R321C mutation causes proteostatic imbalance and mitochondrial defects in iPSC-derived motor neurons.}, journal = {Neurobiology of disease}, volume = {198}, number = {}, pages = {106540}, doi = {10.1016/j.nbd.2024.106540}, pmid = {38806131}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; *Mitochondria/metabolism/genetics/pathology ; Male ; *Protein Serine-Threonine Kinases/genetics/metabolism ; Female ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Proteostasis/genetics ; Middle Aged ; Mutation, Missense ; Adult ; }, abstract = {Vaccinia-related kinase 1 (VRK1) is a gene which has been implicated in the pathological process of a broad range of neurodevelopmental disorders as well as neuropathies, such as Amyotrophic Lateral Sclerosis (ALS). Here we report a family presenting ALS in an autosomal recessive mode of inheritance, segregating with a homozygous missense mutation located in VRK1 gene (p.R321C; Arg321Cys). Proteomic analyses from iPSC-derived motor neurons identified 720 proteins eligible for subsequent investigation, and our exploration of protein profiles revealed significant enrichments in pathways such as mTOR signaling, E2F, MYC targets, DNA repair response, cell proliferation and energetic metabolism. Functional studies further validated such alterations, showing that affected motor neurons presented decreased levels of global protein output, ER stress and downregulation of mTOR signaling. Mitochondrial alterations also pointed to decreased reserve capacity and increased non-mitochondrial oxygen consumption. Taken together, our results present the main pathological alterations associated with VRK1 mutation in ALS.}, } @article {pmid38806659, year = {2024}, author = {Xie, C and Chen, G and Li, M and Huang, P and Chen, Z and Lei, K and Li, D and Wang, Y and Cleetus, A and Mohamed, MA and Sonar, P and Feng, W and Ökten, Z and Ou, G}, title = {Neurons dispose of hyperactive kinesin into glial cells for clearance.}, journal = {The EMBO journal}, volume = {43}, number = {13}, pages = {2606-2635}, pmid = {38806659}, issn = {1460-2075}, support = {31991191//MOST | National Natural Science Foundation of China (NSFC)/ ; 32200612//MOST | National Natural Science Foundation of China (NSFC)/ ; 32071191//MOST | National Natural Science Foundation of China (NSFC)/ ; 31971160//MOST | National Natural Science Foundation of China (NSFC)/ ; 2019YFA0508401//MOST | National Key Research and Development Program of China (NKPs)/ ; XDB37020302//Strategic Priority Research Program of CAS/ ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; *Kinesins/metabolism/genetics ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Neuroglia/metabolism ; *Cilia/metabolism ; Neurons/metabolism ; Mutation ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; }, abstract = {Microtubule-based kinesin motor proteins are crucial for intracellular transport, but their hyperactivation can be detrimental for cellular functions. This study investigated the impact of a constitutively active ciliary kinesin mutant, OSM-3CA, on sensory cilia in C. elegans. Surprisingly, we found that OSM-3CA was absent from cilia but underwent disposal through membrane abscission at the tips of aberrant neurites. Neighboring glial cells engulf and eliminate the released OSM-3CA, a process that depends on the engulfment receptor CED-1. Through genetic suppressor screens, we identified intragenic mutations in the OSM-3CA motor domain and mutations inhibiting the ciliary kinase DYF-5, both of which restored normal cilia in OSM-3CA-expressing animals. We showed that conformational changes in OSM-3CA prevent its entry into cilia, and OSM-3CA disposal requires its hyperactivity. Finally, we provide evidence that neurons also dispose of hyperactive kinesin-1 resulting from a clinic variant associated with amyotrophic lateral sclerosis, suggesting a widespread mechanism for regulating hyperactive kinesins.}, } @article {pmid38807021, year = {2024}, author = {Rahimian, S and Najafi, H and Webber, CA and Jalali, H}, title = {Advances in Exosome-Based Therapies for the Repair of Peripheral Nerve Injuries.}, journal = {Neurochemical research}, volume = {49}, number = {8}, pages = {1905-1925}, pmid = {38807021}, issn = {1573-6903}, mesh = {*Exosomes/metabolism/transplantation ; Humans ; *Peripheral Nerve Injuries/therapy/metabolism ; Animals ; Nerve Regeneration/physiology ; }, abstract = {Peripheral nerve injuries (PNIs) are the term used to describe injuries that occur to the nerve fibers of the peripheral nervous system (PNS). Such injuries may be caused by trauma, infection, or aberrant immunological response. Although the peripheral nervous system has a limited capacity for self-repair, in cases of severe damage, this process is either interrupted entirely or is only partially completed. The evaluation of variables that promote the repair of peripheral nerves has consistently been a focal point. Exosomes are a subtype of extracellular vesicles that originate from cellular sources and possess abundant proteins, lipids, and nucleic acids, play a critical role in facilitating intercellular communication. Due to their modifiable composition, they possess exceptional capabilities as carriers for therapeutic compounds, including but not limited to mRNAs or microRNAs. Exosome-based therapies have gained significant attention in the treatment of several nervous system diseases due to their advantageous properties, such as low toxicity, high stability, and limited immune system activation. The objective of this review article is to provide an overview of exosome-based treatments that have been developed in recent years for a range of PNIs, including nerve trauma, diabetic neuropathy, amyotrophic lateral sclerosis (ALS), glaucoma, and Guillain-Barre syndrome (GBS). It was concluded that exosomes could provide favorable results in the improvement of peripheral PNIs by facilitating the transfer of regenerative factors. The development of bioengineered exosome therapy for PNIs should be given more attention to enhance the efficacy of exosome treatment for PNIs.}, } @article {pmid38807398, year = {2024}, author = {Kekenadze, M and Kvirkvelia, N and Beridze, M and Vashadze, S}, title = {SEROTONIN AND AMYOTROPHIC LATERAL SCLEROSIS.}, journal = {Georgian medical news}, volume = {}, number = {348}, pages = {87-90}, pmid = {38807398}, issn = {1512-0112}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Serotonin/metabolism ; Middle Aged ; Female ; Male ; Adult ; Aged ; Aged, 80 and over ; Adolescent ; Motor Neurons/pathology ; Electromyography ; Magnetic Resonance Imaging ; }, abstract = {Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Does serotonin (5-HT) play a role in progression or development of disease is under the research. The topic of the present paper is pressing as there is no data available regarding the spread of amyotrophic lateral sclerosis. It is also noteworthy that previous studies have indicated that the pathogenesis of ALS is closely linked to 5-hydroxytryptamine (5-HT). The clinical research was conducted in Georgia. During the last five years, 60 patients from different parts of Georgia have been studied, searched, and examined by us. Including from Samegrolo, Kartli, Adjara, Abkhazia, Guria, Kakheti regions. The Georgian Neurologists Corps participated and helped us in finding patients. Brain MRI and electromyography were also performed. 60 patients with different forms of ALS participated in the study, including 34 (56.66%) men and 26 (43.33%) women. Their age ranges from 30 to 81 years. The study was conducted after obtaining the written consent of the patients, taking into account the ethical requirements for the study. We also compared the results of the serotonin level of patients with amyotrophic lateral sclerosis with a control group of 20 people (aged 18 to 50 years) who had no neurological disease in past medical history. Patients of the first group, with LMN damage, are observed with decreased amount of serotonin (61.3) %, compared to other pairs, followed by patients of the upper neuron and bulbar syndrome groups, the level of serotonin in the control group is quite high. Thus, the level of serotonin in the group of patients with bulbar events is higher than in the other groups. Low serotonin requires further investigation. According to our research, the longer the anamnesis of amyotrophic lateral sclerosis patients is, the lower the level of serotonin is observed. It should also be taken into account that a low level of serotonin may be due to the presence of depression, which requires additional research. We speculate that 5-HT could therefore be a potential therapeutic target for amyotrophic lateral sclerosis.}, } @article {pmid38808993, year = {2024}, author = {Solomon, B}, title = {Bone marrow-derived microglia confer neuroprotection to a mouse model of amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {12}, pages = {2586-2587}, pmid = {38808993}, issn = {1673-5374}, } @article {pmid38809094, year = {2024}, author = {Gafni, R and Nassar, JA and Matzrafi, M and Blank, L and Eizenberg, H}, title = {Unraveling the reasons for failure to control Amaranthus albus: insights into herbicide application at different growth stages, temperature effect, and herbicide resistance on a regional scale.}, journal = {Pest management science}, volume = {80}, number = {9}, pages = {4757-4769}, doi = {10.1002/ps.8192}, pmid = {38809094}, issn = {1526-4998}, support = {132187417//Chief Scientist, Israel Ministry of Agriculture and Rural Development/ ; }, mesh = {*Amaranthus/drug effects/growth & development/genetics ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Temperature ; *Acetolactate Synthase/metabolism/genetics ; Weed Control/methods ; Israel ; Triazines ; }, abstract = {BACKGROUND: This study investigates factors contributing Amaranthus albus control failure in processing tomato fields in northern Israel. The study region is characterized by a significant climate gradient from east to west, providing the opportunity to investigate the effect of critical elements of the agricultural environment, e.g., temperature. Eight populations were collected from commercial fields in this region. Post-emergence herbicide efficacy of metribuzin, a photosystem II inhibitor, and rimsulfuron, an acetolactate synthase (ALS) inhibitor, was assessed through dose-response analyses at various growth stages. Temperature effects on control efficacy and resistance mechanisms were also explored.

RESULTS: Standard metribuzin dose (X) was ineffective on A. albus plants with more than six true-leaves, whereas 2X dose proved effective. Rimsulfuron at 16X dose was ineffective on plants with more than four true-leaves. We report here the first case of target site resistance to ALS inhibitors in A. albus, due to point mutation in the ALS gene (Pro197 to Leu). Furthermore, our findings suggest potential involvement of CYT P450 enzymes in enhanced metabolizing of rimsulfuron. An overall decrease in dry weight was observed in response to both herbicides at 16/22 °C (P < 0.0001). Rimsulfuron was effective against only one population when applied at 28/34 °C. A possible fitness cost associated with target site-resistant biotypes was observed under low temperature conditions, leading to effective control.

CONCLUSION: This regional-scale study highlights the challenges faced by growers, emphasizes the need for adapting management practices to the local climatic conditions and lays the groundwork for implementing location-specific weed management strategies in commercial fields. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid38809531, year = {2024}, author = {Yang, CN and Chen, WL and Yeh, HH and Chu, HS and Wu, JH and Hsieh, YT}, title = {Convolutional Neural Network-Based Prediction of Axial Length Using Color Fundus Photography.}, journal = {Translational vision science & technology}, volume = {13}, number = {5}, pages = {23}, pmid = {38809531}, issn = {2164-2591}, mesh = {Humans ; Male ; Female ; *Neural Networks, Computer ; Middle Aged ; Adult ; *Photography/methods ; Aged ; *Axial Length, Eye/diagnostic imaging ; Fundus Oculi ; Young Adult ; Aged, 80 and over ; }, abstract = {PURPOSE: To develop convolutional neural network (CNN)-based models for predicting the axial length (AL) using color fundus photography (CFP) and explore associated clinical and structural characteristics.

METHODS: This study enrolled 1105 fundus images from 467 participants with ALs ranging from 19.91 to 32.59 mm, obtained at National Taiwan University Hospital between 2020 and 2021. The AL measurements obtained from a scanning laser interferometer served as the gold standard. The accuracy of prediction was compared among CNN-based models with different inputs, including CFP, age, and/or sex. Heatmaps were interpreted by integrated gradients.

RESULTS: Using age, sex, and CFP as input, the mean ± standard deviation absolute error (MAE) for AL prediction by the model was 0.771 ± 0.128 mm, outperforming models that used age and sex alone (1.263 ± 0.115 mm; P < 0.001) and CFP alone (0.831 ± 0.216 mm; P = 0.016) by 39.0% and 7.31%, respectively. The removal of relatively poor-quality CFPs resulted in a slight MAE reduction to 0.759 ± 0.120 mm without statistical significance (P = 0.24). The inclusion of age and CFP improved prediction accuracy by 5.59% (P = 0.043), while adding sex had no significant improvement (P = 0.41). The optic disc and temporal peripapillary area were highlighted as the focused areas on the heatmaps.

CONCLUSIONS: Deep learning-based prediction of AL using CFP was fairly accurate and enhanced by age inclusion. The optic disc and temporal peripapillary area may contain crucial structural information for AL prediction in CFP.

TRANSLATIONAL RELEVANCE: This study might aid AL assessments and the understanding of the morphologic characteristics of the fundus related to AL.}, } @article {pmid38809826, year = {2024}, author = {Krajewski, E and Lee, J and Viswanathan, N and Olmstead, A and Simmons, Z}, title = {The Effects of Interactive Context on Acoustic Characteristics of Speech in People With Dysarthria: A Preliminary Study.}, journal = {American journal of speech-language pathology}, volume = {33}, number = {4}, pages = {1952-1964}, pmid = {38809826}, issn = {1558-9110}, support = {R01 DC021714/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Dysarthria/etiology/physiopathology/diagnosis ; Male ; Female ; *Speech Acoustics ; Middle Aged ; Aged ; *Speech Production Measurement ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Phonetics ; Speech Intelligibility ; Voice Quality ; Preliminary Data ; Sound Spectrography ; Time Factors ; Aged, 80 and over ; Acoustics ; }, abstract = {PURPOSE: The current study compared temporal and spectral acoustic contrast between vowel segments produced by speakers with dysarthria across three speech tasks-interactive, solo habitual, and solo clear.

METHOD: Nine speakers with dysarthria secondary to amyotrophic lateral sclerosis participated in the study. Each speaker was paired with a typical interlocutor over videoconferencing software. The speakers produced the vowels /i, ɪ, ɛ, æ/ in /h/-vowel-/d/ words. For the solo tasks, speakers read the stimuli aloud in both their habitual and clear speaking styles. For the interactive task, speakers produced a target stimulus for their interlocutor to select among the four possibilities. We measured the duration difference between long and short vowels, as well as the F1/F2 Euclidean distance between adjacent vowels, and also determined how well the vowels could be classified based on their acoustic characteristics.

RESULTS: Temporal contrast between long and short vowels was higher in the interactive task than in both solo tasks. Spectral distance between adjacent vowel pairs was also higher for some pairs in the interactive task than the habitual speech task. Finally, vowel classification accuracy was highest in the interactive task.

CONCLUSIONS: Overall, we found evidence that individuals with dysarthria produced vowels with greater acoustic contrast in structured interactions than they did in solo tasks. Furthermore, the speech adjustments they made to the vowel segments differed from those observed in solo speech.}, } @article {pmid38811858, year = {2024}, author = {Benatar, M and Wuu, J and Huey, ED and McMillan, CT and Petersen, RC and Postuma, R and McHutchison, C and Dratch, L and Arias, JJ and Crawley, A and Houlden, H and McDermott, MP and Cai, X and Thakur, N and Boxer, A and Rosen, H and Boeve, BF and Dacks, P and Cosentino, S and Abrahams, S and Shneider, N and Lingor, P and Shefner, J and Andersen, PM and Al-Chalabi, A and Turner, MR and , }, title = {Publisher Correction: The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {6}, pages = {377}, doi = {10.1038/s41582-024-00978-4}, pmid = {38811858}, issn = {1759-4766}, support = {K01 AG057796/AG/NIA NIH HHS/United States ; R01 AG062268/AG/NIA NIH HHS/United States ; R01 MH120794/MH/NIMH NIH HHS/United States ; U01 AG079850/AG/NIA NIH HHS/United States ; }, } @article {pmid38811997, year = {2024}, author = {Huang, M and Liu, YU and Yao, X and Qin, D and Su, H}, title = {Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {28}, pmid = {38811997}, issn = {2047-9158}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/epidemiology/diagnosis ; Humans ; *Superoxide Dismutase-1/genetics ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1, the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1-associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies.}, } @article {pmid38812789, year = {2024}, author = {Sidisky, JM and Winters, A and Caratenuto, R and Babcock, DT}, title = {Synaptic defects in a drosophila model of muscular dystrophy.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1381112}, pmid = {38812789}, issn = {1662-5102}, support = {R01 NS110727/NS/NINDS NIH HHS/United States ; }, abstract = {Muscular dystrophies are a devastating class of diseases that result in a progressive loss of muscle integrity. Duchenne Muscular Dystrophy, the most prevalent form of Muscular Dystrophy, is due to the loss of functional Dystrophin. While much is known regarding destruction of muscle tissue in these diseases, much less is known regarding the synaptic defects that also occur in these diseases. Synaptic defects are also among the earliest hallmarks of neurodegenerative diseases, including the neuromuscular disease Amyotrophic Lateral Sclerosis (ALS). Our current study investigates synaptic defects within adult muscle tissues as well as presynaptic motor neurons in Drosophila dystrophin mutants. Here we demonstrate that the progressive, age-dependent loss of flight ability in dystrophin mutants is accompanied by disorganization of Neuromuscular Junctions (NMJs), including impaired localization of both presynaptic and postsynaptic markers. We show that these synaptic defects, including presynaptic defects within motor neurons, are due to the loss of Dystrophin specifically within muscles. These results should help to better understand the early synaptic defects preceding cell loss in neuromuscular disorders.}, } @article {pmid38812793, year = {2024}, author = {Jadhav, SP}, title = {MicroRNAs in microglia: deciphering their role in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1391537}, pmid = {38812793}, issn = {1662-5102}, abstract = {This review presents a comprehensive analysis of the role of microRNAs in microglia and their implications in the pathogenesis of neurodegenerative diseases. Microglia, as the resident immune cells of the central nervous system (CNS), are pivotal in maintaining neural homeostasis and responding to pathological changes. Recent studies have highlighted the significance of miRNAs, small non-coding RNA molecules, in regulating microglial functions. In neurodegenerative diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), dysregulated miRNA expression in microglia contributes to disease progression through various mechanisms such regulation of gene expression, as modulation of cytokine response and phagocytosis. This review synthesizes current knowledge on how miRNAs influence microglial activation, cytokine production, and phagocytic activity. Specific miRNAs, such as miR-155, are explored for their roles in modulating microglial responses in the context of neuroinflammation and neurodegeneration. The study also discusses the impact of miRNA dysregulation on the transition of microglia from a neuroprotective to a neurotoxic phenotype, a critical aspect in the progression of neurodegenerative diseases.}, } @article {pmid38812975, year = {2024}, author = {Fu, J and Lai, X and Wei, Q and Chen, X and Shang, H}, title = {Associations of cerebrospinal fluid profiles with severity and mortality risk of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1375892}, pmid = {38812975}, issn = {1662-4548}, abstract = {BACKGROUND: The relationship between routine cerebrospinal fluid (CSF) testing and the disease phenotype of amyotrophic lateral sclerosis (ALS) is unclear, and there are some contradictions in current studies.

METHODS: This study aimed to analyze the relationship between CSF profiles and disease phenotype in ALS patients. We collected 870 ALS patients and 96 control subjects admitted to West China Hospital of Sichuan University. CSF microprotein, albumin, IgG, index of IgG (IgGindex), albumin quotient (QALB), and serum IgG were examined.

RESULTS: In ALS patients, CSF IgG, and QALB were significantly increased, while CSF IgGindex was decreased, compared with control subjects. Approximately one-third of ALS patients had higher CSF IgG levels. The multiple linear regression analysis identified that CSF IgGindex was weakly negatively associated with ALS functional rating scale revised (ALSFRS-R) scores (β = -0.062, p = 0.041). This significance was found in male ALS but not in female ALS. The Cox survival analyses found that upregulated CSF IgG was significantly associated with the increased mortality risk in ALS [HR = 1.219 (1.010-1.470), p = 0.039].

CONCLUSION: In the current study, the higher CFS IgG was associated with increased mortality risk of ALS. CSF IgGindex may be associated with the severity of ALS. These findings may be sex-specific.}, } @article {pmid38813353, year = {2024}, author = {Firstenfeld, AJ}, title = {A positive effect of Cerebrolysin on motor functions and spasticity in ALS with limb or bulbar onset is questionable.}, journal = {Journal of medicine and life}, volume = {17}, number = {2}, pages = {243}, pmid = {38813353}, issn = {1844-3117}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Muscle Spasticity/drug therapy ; *Amino Acids/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; }, } @article {pmid38813358, year = {2024}, author = {Finsterer, J}, title = {A positive effect of Cerebrolysin on motor functions and spasticity in ALS with limb or bulbar onset is questionable.}, journal = {Journal of medicine and life}, volume = {17}, number = {2}, pages = {242}, pmid = {38813358}, issn = {1844-3117}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Muscle Spasticity/drug therapy ; *Amino Acids/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; }, } @article {pmid38813817, year = {2024}, author = {Sprunger, ML and Jackrel, ME}, title = {The role of Matrin-3 in physiology and its dysregulation in disease.}, journal = {Biochemical Society transactions}, volume = {52}, number = {3}, pages = {961-972}, pmid = {38813817}, issn = {1470-8752}, support = {F31 NS120512/NS/NINDS NIH HHS/United States ; R21 AG080393/AG/NIA NIH HHS/United States ; R35 GM128772/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *RNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Nuclear Matrix-Associated Proteins/metabolism ; *Frontotemporal Dementia/metabolism/genetics ; DNA-Binding Proteins/metabolism ; Animals ; DNA Damage ; RNA-Binding Protein FUS/metabolism/chemistry ; }, abstract = {The dysfunction of many RNA-binding proteins (RBPs) that are heavily disordered, including TDP-43 and FUS, are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). These proteins serve many important roles in the cell, and their capacity to form biomolecular condensates (BMCs) is key to their function, but also a vulnerability that can lead to misregulation and disease. Matrin-3 (MATR3) is an intrinsically disordered RBP implicated both genetically and pathologically in ALS/FTD, though it is relatively understudied as compared with TDP-43 and FUS. In addition to binding RNA, MATR3 also binds DNA and is implicated in many cellular processes including the DNA damage response, transcription, splicing, and cell differentiation. It is unclear if MATR3 localizes to BMCs under physiological conditions, which is brought further into question due to its lack of a prion-like domain. Here, we review recent studies regarding MATR3 and its roles in numerous physiological processes, as well as its implication in a range of diseases.}, } @article {pmid38814471, year = {2024}, author = {Costantino, I and Meng, A and Ravits, J}, title = {Alternatively spliced ELAVL3 cryptic exon 4a causes ELAVL3 downregulation in ALS TDP-43 proteinopathy.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {93}, pmid = {38814471}, issn = {1432-0533}, support = {T32 AG066596/AG/NIA NIH HHS/United States ; P30 NS047101/RG/CSR NIH HHS/United States ; P30 NS047101/NS/NINDS NIH HHS/United States ; R21 NS121805/NS/NINDS NIH HHS/United States ; T32 AG066596/RG/CSR NIH HHS/United States ; R21 NS121805/RG/CSR NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Alternative Splicing/genetics ; *Exons/genetics ; *Down-Regulation ; TDP-43 Proteinopathies/genetics/pathology/metabolism ; Male ; Female ; Middle Aged ; DNA-Binding Proteins ; }, } @article {pmid38814545, year = {2024}, author = {Sun, S and Chen, Y and Zhao, B and Zhu, J and Wen, T and Peng, B and Ren, Q and Sun, X and Lin, P and Zhang, D and Liu, S}, title = {Abnormal brain functional network dynamics in amyotrophic lateral sclerosis patients with depression.}, journal = {Brain imaging and behavior}, volume = {18}, number = {5}, pages = {1034-1043}, pmid = {38814545}, issn = {1931-7565}, support = {2020M672067//China postdoctoral science foundation/ ; NSFC82001354//National natural science foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology/complications/diagnostic imaging ; Female ; Male ; *Magnetic Resonance Imaging/methods ; Middle Aged ; *Brain/physiopathology/diagnostic imaging ; *Depression/physiopathology/diagnostic imaging ; *Nerve Net/physiopathology/diagnostic imaging ; Adult ; Neural Pathways/physiopathology/diagnostic imaging ; Aged ; Brain Mapping/methods ; }, abstract = {Since depression is common in amyotrophic lateral sclerosis (ALS) patients, we aimed to explore the specific brain functional network dynamics in ALS patients with depression (ALS-D) compared with healthy controls (HCs) and ALS patients without depressive symptoms (ALS-ND). According to the DSM-V, 32 ALS-D patients were selected from a large and newly diagnosed ALS cohort. Then, 32 demographic- and cognitive-matched ALS-ND patients were also selected, and 64 HCs were recruited. These participants underwent resting-state fMRI scans, and functional connectivity state analysis and dynamic graph theory were applied to evaluate brain functional network dynamics. Moreover, the Hamilton Depression Rating Scale (HDRS) was used to quantify depressive symptoms in the ALS-D patients. Four distinct states were identified in the ALS-D patients and controls. Compared with that in HCs, the fraction rate (FR) in state 2 was significantly decreased in ALS-D patients, and the FR in state 4 was significantly increased in ALS-D patients. Compared with that of HCs, the dwell time in state 4 was significantly increased in the ALS-D patients. Moreover, compared with that in the ALS-D patients, the FR in state 3 was significantly decreased in the ALS-ND patients. Among the ALS-D patients, there was the suggestion of a positive association between HDRS scores and dwell time of state 4, but this association did not reach statistical significance (r = 0.354; p = 0.055). Depression is an important feature of ALS patients, and we found a special pattern of brain functional network dynamics in ALS-D patients. Our findings may play an important role in understanding the mechanism underlying depression in ALS patients and help develop therapeutic interventions for depressed ALS patients.}, } @article {pmid38816479, year = {2024}, author = {Mathis, S and Beauvais, D and Duval, F and Solé, G and Le Masson, G}, title = {The various forms of hereditary motor neuron disorders and their historical descriptions.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {3978-3990}, pmid = {38816479}, issn = {1432-1459}, mesh = {Humans ; *Motor Neuron Disease/history/genetics ; History, 20th Century ; History, 19th Century ; Spastic Paraplegia, Hereditary/genetics/history ; }, abstract = {Motor neuron disorders comprise a clinically and pathologically heterogeneous group of neurologic diseases characterized by progressive degeneration of motor neurons (including both sporadic and hereditary diseases), affecting the upper motor neurons, lower motor neurons, or both. Hereditary motor neuron disorders themselves represent a vast and heterogeneous group, with numerous clinical and genetic overlaps that can be a source of error. This narrative review aims at providing an overview of the main types of inherited motor neuron disorders by recounting the stages in their historical descriptions. For practical purposes, this review of the literature sets out their various clinical characteristics and updates the list of all the genes involved in the various forms of inherited motor neuron disorders, including spinal muscular atrophy, familial amyotrophic lateral sclerosis, hereditary spastic paraplegia, distal hereditary motor neuropathies/neuronopathies, Kennedy's disease, riboflavin transporter deficiencies, VCPopathy and the neurogenic scapuloperoneal syndrome.}, } @article {pmid38816580, year = {2024}, author = {Wu, Y and Zheng, W and Xu, G and Zhu, L and Li, Z and Chen, J and Wang, L and Chen, S}, title = {C9orf72 controls hepatic lipid metabolism by regulating SREBP1 transport.}, journal = {Cell death and differentiation}, volume = {31}, number = {8}, pages = {1070-1084}, pmid = {38816580}, issn = {1476-5403}, mesh = {Humans ; *C9orf72 Protein/metabolism/genetics ; *Lipid Metabolism ; *Sterol Regulatory Element Binding Protein 1/metabolism/genetics ; Animals ; *Endoplasmic Reticulum/metabolism ; *Liver/metabolism ; Monomeric GTP-Binding Proteins/metabolism/genetics ; Mice ; COP-Coated Vesicles/metabolism ; Vesicular Transport Proteins/metabolism/genetics ; Lipogenesis/genetics ; }, abstract = {Sterol regulatory element binding transcription factors (SREBPs) play a crucial role in lipid homeostasis. They are processed and transported to the nucleus via COPII, where they induce the expression of lipogenic genes. COPII maintains the homeostasis of organelles and plays an essential role in the protein secretion pathways in eukaryotes. The formation of COPII begins at endoplasmic reticulum exit sites (ERES), and is regulated by SEC16A, which provides a platform for the assembly of COPII. However, there have been few studies on the changes in SEC16A protein levels. The repetitive expansion of the hexanucleotide sequence GGGGCC within the chromosome 9 open reading frame 72 (C9orf72) gene is a prevalent factor in the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we found that the absence of C9orf72 leads to a decrease in SEC16A protein levels, resulting in reduced localization of the guanine nucleotide exchange factor SEC12 at the ERES. Consequently, the small GTP binding protein SAR1 is unable to bind the endoplasmic reticulum normally, impairing the assembly of COPII. Ultimately, the disruption of SREBPs transport decreases de novo lipogenesis. These results suggest that C9orf72 acts as a novel role in regulating lipid homeostasis and may serve as a potential therapeutic target for obesity.}, } @article {pmid38816946, year = {2024}, author = {Karas, M and Olsen, J and Straczkiewicz, M and Johnson, SA and Burke, KM and Iwasaki, S and Lahav, A and Scheier, ZA and Clark, AP and Iyer, AS and Huang, E and Berry, JD and Onnela, JP}, title = {Tracking amyotrophic lateral sclerosis disease progression using passively collected smartphone sensor data.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {6}, pages = {1380-1392}, pmid = {38816946}, issn = {2328-9503}, support = {//The research reported in this paper was financially supported in part by a grant from Mitsubishi Tanabe Pharma Holdings America, Inc. (MTPHA)./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Smartphone ; Male ; Female ; Middle Aged ; *Disease Progression ; Aged ; *Accelerometry/instrumentation ; Mobile Applications ; Walking/physiology ; Exercise/physiology ; }, abstract = {BACKGROUND: Passively collected smartphone sensor data provide an opportunity to study physical activity and mobility unobtrusively over long periods of time and may enable disease monitoring in people with amyotrophic lateral sclerosis (PALS).

METHODS: We enrolled 63 PALS who used Beiwe mobile application that collected their smartphone accelerometer and GPS data and administered the self-entry ALS Functional Rating Scale-Revised (ALSFRS-RSE) survey. We identified individual steps from accelerometer data and used the Activity Index to summarize activity at the minute level. Walking, Activity Index, and GPS outcomes were then aggregated into day-level measures. We used linear mixed effect models (LMMs) to estimate baseline and monthly change for ALSFRS-RSE scores (total score, subscores Q1-3, Q4-6, Q7-9, Q10-12) and smartphone sensor data measures, as well as the associations between them.

FINDINGS: The analytic sample (N = 45) was 64.4% male with a mean age of 60.1 years. The mean observation period was 292.3 days. The ALSFRS-RSE total score baseline mean was 35.8 and had a monthly rate of decline of -0.48 (p-value <0.001). We observed statistically significant change over time and association with ALSFRS-RSE total score for four smartphone sensor data-derived measures: walking cadence from top 1 min and log-transformed step count, step count from top 1 min, and Activity Index from top 1 min.

INTERPRETATION: Smartphone sensors can unobtrusively track physical changes in PALS, potentially aiding disease monitoring and future research.}, } @article {pmid38817347, year = {2024}, author = {Du, R and Zhu, Y and Chen, P and Li, M and Zhang, Y and Huang, X}, title = {Causal association between obstructive sleep apnea and amyotrophic lateral sclerosis: a Mendelian randomization study.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1357070}, pmid = {38817347}, issn = {1663-4365}, abstract = {BACKGROUND: Obstructive sleep apnea (OSA) had a high prevalence in the population. Whether OSA increases the risk of amyotrophic lateral sclerosis (ALS) is unknown. Our aim was to clarify this issue using two-sample Mendelian randomization (MR) analysis in a large cohort.

METHODS: Two-sample MR was used to evaluate the potential causality between OSA and ALS by selecting single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) from genome-wide association studies (GWAS). The inverse-variance weighted (IVW) method was chosen as the primary method to estimate causal association. Weighted median, weighted mode and simple mode methods were used as sensitivity analyses to ensure the robustness of the results.

RESULTS: In MR analysis, IVW mode showed genetic liability to OSA was found to be significantly associated with a higher ALS risk (OR, 1.220; 95% confidence interval, 1.031-1.443; p = 0.021). No evidence of heterogeneity and horizontal pleiotropy were suggested.

CONCLUSION: We found potential evidence for a causal effect of OSA on an increased risk of ALS.}, } @article {pmid38817709, year = {2024}, author = {Ghaderi, S and Batouli, SAH and Kalra, S and Mohammadi, S and Fatehi, F}, title = {A 65-year-old woman with ALS and bilateral precentral motor band sign.}, journal = {Clinical case reports}, volume = {12}, number = {6}, pages = {e9014}, pmid = {38817709}, issn = {2050-0904}, abstract = {Advanced MRI techniques, including SWI, MinIP, and QSM, are instrumental in detecting the "motor band sign" in ALS, aiding in the early diagnosis and assessment of upper motor neuron involvement, which is critical for therapeutic interventions.}, } @article {pmid38818523, year = {2024}, author = {Shen, J and Wang, X and Wang, M and Zhang, H}, title = {Potential molecular mechanism of exercise reversing insulin resistance and improving neurodegenerative diseases.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1337442}, pmid = {38818523}, issn = {1664-042X}, abstract = {Neurodegenerative diseases are debilitating nervous system disorders attributed to various conditions such as body aging, gene mutations, genetic factors, and immune system disorders. Prominent neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Insulin resistance refers to the inability of the peripheral and central tissues of the body to respond to insulin and effectively regulate blood sugar levels. Insulin resistance has been observed in various neurodegenerative diseases and has been suggested to induce the occurrence, development, and exacerbation of neurodegenerative diseases. Furthermore, an increasing number of studies have suggested that reversing insulin resistance may be a critical intervention for the treatment of neurodegenerative diseases. Among the numerous measures available to improve insulin sensitivity, exercise is a widely accepted strategy due to its convenience, affordability, and significant impact on increasing insulin sensitivity. This review examines the association between neurodegenerative diseases and insulin resistance and highlights the molecular mechanisms by which exercise can reverse insulin resistance under these conditions. The focus was on regulating insulin resistance through exercise and providing practical ideas and suggestions for future research focused on exercise-induced insulin sensitivity in the context of neurodegenerative diseases.}, } @article {pmid38819224, year = {2024}, author = {Shen, J and Gu, X and Xiao, C and Yan, H and Feng, Y and Li, X}, title = {Genome-wide association analysis reveals potential genetic correlation and causality between circulating inflammatory proteins and amyotrophic lateral sclerosis.}, journal = {Aging}, volume = {16}, number = {11}, pages = {9470-9484}, pmid = {38819224}, issn = {1945-4589}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood ; Humans ; *Genome-Wide Association Study ; *Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Mendelian Randomization Analysis ; Genetic Pleiotropy ; Inflammation/genetics/blood ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease, continues to elude complete comprehension of its pathological underpinnings. Recent focus on inflammation in ALS pathogenesis prompts this investigation into the genetic correlation and potential causal relationships between circulating inflammatory proteins and ALS.

METHODS: Genome-wide association study (GWAS) data encompassing 91 circulating inflammatory protein measures from 14,824 individuals of European ancestry, alongside records from 27,205 ALS cases and 110,881 controls, were employed. Assessment of genetic correlation and overlap utilized LD score regression (LDSC), high-definition likelihood (HDL), and genetic analysis integrating pleiotropy and annotation (GPA) methodologies. Identification of shared genetic loci involved pleiotropy analysis, functional mapping and annotation (FUMA), and co-localization analysis. Finally, Mendelian randomization was applied to probe causal relationships between inflammatory proteins and ALS.

RESULTS: Our investigation revealed significant genetic correlation and overlap between ALS and various inflammatory proteins, including C-C motif chemokine 28, Interleukin-18, C-X-C motif chemokine 1, and Leukemia inhibitory factor receptor (LIFR). Pleiotropy analysis uncovered shared variations at specific genetic loci, some of which bore potential harm. Mendelian randomization analysis suggested that alterations in specific inflammatory protein levels, notably LIFR, could impact ALS risk.

CONCLUSIONS: Our findings uncover a genetic correlation between certain circulating inflammatory proteins and ALS, suggesting their possible causal involvement in ALS pathogenesis. Moreover, the identification of LIFR as a crucial protein may yield new insights into ALS pathomechanisms and offer a promising avenue for therapeutic interventions. These discoveries provide novel perspectives for advancing the comprehension of ALS pathophysiology and exploring potential therapeutic avenues.}, } @article {pmid38819416, year = {2024}, author = {Finsterer, J}, title = {Sleep Disorders Can Only be a Risk Factor for Breathing Disorders in Amyotrophic Lateral Sclerosis if All Other Risk Factors are Excluded.}, journal = {Annals of Indian Academy of Neurology}, volume = {27}, number = {4}, pages = {450-451}, pmid = {38819416}, issn = {0972-2327}, } @article {pmid38819491, year = {2024}, author = {Juarez, D and Handal-Silva, A and Morán-Perales, JL and Torres-Cifuentes, DM and Flores, G and Treviño, S and Moreno-Rodriguez, A and Guevara, J and Diaz, A}, title = {New insights into sodium phenylbutyrate as a pharmacotherapeutic option for neurological disorders.}, journal = {Synapse (New York, N.Y.)}, volume = {78}, number = {4}, pages = {e22301}, doi = {10.1002/syn.22301}, pmid = {38819491}, issn = {1098-2396}, support = {IN214117//PAPITT-UNAM/ ; DIFA-NAT24-G//Vicerrectoría de Investigación y Estudios de Posgrado, Benemérita Universidad Autónoma de Puebla/ ; TEMS-NAT24-G//Vicerrectoría de Investigación y Estudios de Posgrado, Benemérita Universidad Autónoma de Puebla/ ; }, mesh = {Humans ; *Phenylbutyrates/therapeutic use/pharmacology ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Neurological disorders (NDs) are diseases of the central and peripheral nervous systems that affect more than one billion people worldwide. The risk of developing an ND increases with age due to the vulnerability of the different organs and systems to genetic, environmental, and social changes that consequently cause motor and cognitive deficits that disable the person from their daily activities and individual and social productivity. Intrinsic factors (genetic factors, age, gender) and extrinsic factors (addictions, infections, or lifestyle) favor the persistence of systemic inflammatory processes that contribute to the evolution of NDs. Neuroinflammation is recognized as a common etiopathogenic factor of ND. The study of new pharmacological options for the treatment of ND should focus on improving the characteristic symptoms and attacking specific molecular targets that allow the delay of damage processes such as neuroinflammation, oxidative stress, cellular metabolic dysfunction, and deregulation of transcriptional processes. In this review, we describe the possible role of sodium phenylbutyrate (NaPB) in the pathogenesis of Alzheimer's disease, hepatic encephalopathy, aging, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis; in addition, we describe the mechanism of action of NaPB and its beneficial effects that have been shown in various in vivo and in vitro studies to delay the evolution of any ND.}, } @article {pmid38819717, year = {2024}, author = {Tappenden, P and Hardiman, O and Kwon, SH and Mon-Yee, M and Galvin, M and McDermott, C and , }, title = {A Model-Based Economic Evaluation of Hypothetical Treatments for Amyotrophic Lateral Sclerosis in the UK: Implications for Pricing of New and Emerging Health Technologies.}, journal = {PharmacoEconomics}, volume = {42}, number = {9}, pages = {1003-1016}, pmid = {38819717}, issn = {1179-2027}, support = {NIHR301648//NIHR Sheffield BRC and an NIHR Research Professorship/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy/drug therapy ; Humans ; *Cost-Benefit Analysis ; *Quality-Adjusted Life Years ; United Kingdom ; *Models, Economic ; Disease Progression ; Biomedical Technology/economics ; Technology Assessment, Biomedical ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease which leads to loss of muscle function and paralysis. Historically, clinical drug development has been unsuccessful, but promising disease-modifying therapies (DMTs) may be on the horizon.

OBJECTIVES: The aims of this study were to estimate survival, quality-adjusted life-years (QALYs) and costs under current care, and to explore the conditions under which new therapies might be considered cost effective.

METHODS: We developed a health economic model to evaluate the cost effectiveness of future ALS treatments from a UK National Health Service and Personal Social Services perspective over a lifetime horizon using data from the ALS-CarE study. Costs were valued at 2021/22 prices. Two hypothetical interventions were evaluated: a DMT which delays progression and mortality, and a symptomatic therapy which improves utility only. Sensitivity analysis was conducted to identify key drivers of cost effectiveness.

RESULTS: Starting from King's stage 2, patients receiving current care accrue an estimated 2.27 life-years, 0.75 QALYs and lifetime costs of £68,047. Assuming a 50% reduction in progression rates and a UK-converted estimate of the price of edaravone, the incremental cost-effectiveness ratio for a new DMT versus current care is likely to exceed £735,000 per QALY gained. Symptomatic therapies may be more likely to achieve acceptable levels of cost effectiveness.

CONCLUSIONS: Regardless of efficacy, DMTs may struggle to demonstrate cost effectiveness, even at a low price. The cost effectiveness of DMTs is likely to be strongly influenced by drug price, the magnitude and durability of relative treatment effects, treatment starting/stopping rules and any additional utility benefits over current care.}, } @article {pmid38820149, year = {2024}, author = {Montañana-Rosell, R and Selvan, R and Hernández-Varas, P and Kaminski, JM and Sidhu, SK and Ahlmark, DB and Kiehn, O and Allodi, I}, title = {Spinal inhibitory neurons degenerate before motor neurons and excitatory neurons in a mouse model of ALS.}, journal = {Science advances}, volume = {10}, number = {22}, pages = {eadk3229}, pmid = {38820149}, issn = {2375-2548}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Animals ; *Motor Neurons/metabolism/pathology ; *Disease Models, Animal ; Mice ; *Interneurons/metabolism/pathology ; *Spinal Cord/pathology/metabolism ; *Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Humans ; Disease Progression ; Nerve Degeneration/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons. A major focus has been directed to motor neuron intrinsic properties as a cause for degeneration, while less attention has been given to the contribution of spinal interneurons. In the present work, we applied multiplexing detection of transcripts and machine learning-based image analysis to investigate the fate of multiple spinal interneuron populations during ALS progression in the SOD1[G93A] mouse model. The analysis showed that spinal inhibitory interneurons are affected early in the disease, before motor neuron death, and are characterized by a slow progressive degeneration, while excitatory interneurons are affected later with a steep progression. Moreover, we report differential vulnerability within inhibitory and excitatory subpopulations. Our study reveals a strong interneuron involvement in ALS development with interneuron specific degeneration. These observations point to differential involvement of diverse spinal neuronal circuits that eventually may be determining motor neuron degeneration.}, } @article {pmid38820331, year = {2025}, author = {Dessie, G and Li, J and Nghiem, S and Doan, T}, title = {Prevalence and Determinants of Stunting-Anemia and Wasting-Anemia Comorbidities and Micronutrient Deficiencies in Children Under 5 in the Least-Developed Countries: A Systematic Review and Meta-analysis.}, journal = {Nutrition reviews}, volume = {83}, number = {2}, pages = {e178-e194}, pmid = {38820331}, issn = {1753-4887}, support = {//Australia National University/ ; }, mesh = {Child, Preschool ; Female ; Humans ; Infant ; *Anemia/epidemiology ; Comorbidity ; *Developing Countries/statistics & numerical data ; *Growth Disorders/epidemiology ; *Micronutrients/deficiency ; Prevalence ; *Wasting Syndrome/epidemiology ; }, abstract = {CONTEXT: Despite shifting from addressing isolated forms of malnutrition to recognizing its multifaceted nature, evidence on the prevalence and determinants of micronutrient deficiencies, and their coexistence with undernutrition in children under 5, remains insufficient, unsystematic, and incohesive.

OBJECTIVE: The aim of this systematic review and meta-analysis was to assess the prevalence and determinants of stunting-anemia and wasting-anemia comorbidities and micronutrient deficiencies in children under 5 in the least-developed countries (LDCs).

DATA SOURCES: Electronic searches took place from January 15, 2023, to February 14, 2024, across multiple databases, including PubMed, Embase, Web of Science, SCOPUS, African Index Medicus (AIM), World Health Organization's Institutional Repository for Information Sharing (IRIS), and African Journals Online. The search spanned the years 2000 to 2024, yet it yielded eligible full-text English research articles from only 2005 to 2021 conducted in LDCs. Studies lacking quantitative data on malnutrition types and their determinants were excluded.

DATA EXTRACTION: Two independent authors assessed articles for bias and quality using Hoy et al's 10-item scale and Newcastle-Ottawa Scale (NOS) criteria. Prevalence and other details were extracted using a Joanna Briggs Institute Excel template. Authors extracted adjusted odds ratios (aORs) for determinant factors such as sex and vitamin A and iron supplementation.

DATA ANALYSIS: The search yielded 6248 articles from 46 LDCs. Sixty-nine articles, with a total sample size of 181 605, met inclusion criteria for the final meta-analysis. Vitamin A deficiency affected 16.32% of children, and iodine deficiency affected 43.41% of children. The pooled prevalence of wasting-anemia and stunting-anemia comorbidity was 5.44% and 19.47%, respectively. Stunting was associated with vitamin A deficiency (aOR: 1.54; 95% CI: 1.01-2.37), and not taking vitamin A supplementation was associated with iron-deficiency anemia (aOR: 1.37; 95% CI: 1.21-1.55).

CONCLUSION: A significant proportion of children under 5 in LDCs experienced stunting-anemia and wasting-anemia comorbidities and micronutrient deficiencies. This study underscores the urgent need to address factors driving these burdens.

PROSPERO registration no. CRD42023409483.}, } @article {pmid38821351, year = {2024}, author = {Pocock, J and Vasilopoulou, F and Svensson, E and Cosker, K}, title = {Microglia and TREM2.}, journal = {Neuropharmacology}, volume = {257}, number = {}, pages = {110020}, doi = {10.1016/j.neuropharm.2024.110020}, pmid = {38821351}, issn = {1873-7064}, mesh = {Humans ; *Microglia/metabolism ; *Receptors, Immunologic/metabolism/genetics ; *Membrane Glycoproteins/metabolism/genetics ; Animals ; Neurodegenerative Diseases/metabolism/pathology/genetics ; Induced Pluripotent Stem Cells/metabolism ; Phagocytosis/physiology ; }, abstract = {TREM2 is a membrane receptor solely expressed on microglia in normal brain. In this review we outline recent advances in TREM2 biology and its implications for microglial function, with particular emphasis on findings from iPSC-derived microglia (iMG) expressing TREM2 loss-of-function mutations. Alterations in receptor proximal and distal signalling underlie TREM2 risk variants linked to neurodegenerative disease, principally NH-linked FTD, and late-onset AD, but emerging data suggest roles for TREM2 in PD, MS and ALS. TREM2 downstream functions include phagocytosis of myelin debris, amyloid beta peptides, and phosphatidylserine-expressing cells (resulting from damage or stress). Microglial survival, migration, DAMP signalling, inflammasome activation, and intercellular signalling including tau spreading via exosomes, as well as roles for sTREM2 in protection and as a biomarker are discussed. The role of TREM2 in metabolic homeostasis, and immunometabolic switching are discussed regarding microglial responses to damage and protection. The use of iPSC models to investigate the role of TREM2 in AD, PD, MS, ALS, and other neurodegenerative diseases could prove invaluable due to their ability to recapitulate human pathology, allowing a full understanding of TREM2 and microglial involvement in the underlying disease mechanisms and progression. This article is part of the Special Issue on "Microglia".}, } @article {pmid38822416, year = {2024}, author = {Yadav, S and Deepika, and Moar, K and Kumar, A and Khola, N and Pant, A and Kakde, GS and Maurya, PK}, title = {Reconsidering red blood cells as the diagnostic potential for neurodegenerative disorders.}, journal = {Biology of the cell}, volume = {116}, number = {7}, pages = {e2400019}, doi = {10.1111/boc.202400019}, pmid = {38822416}, issn = {1768-322X}, support = {//Council of Scientific and Industrial Research (CSIR), Government of India/ ; //University Grant Commission (UGC)/ ; HSCIT-3946//Haryana State Council for Science, Innovation, and Technology/ ; //Central University of Haryana, Mahendergarh/ ; //Indian Council of Medical Research (ICMR), Government of India/ ; }, mesh = {Humans ; *Erythrocytes/metabolism ; *Neurodegenerative Diseases/diagnosis/metabolism/blood ; *Biomarkers/metabolism/blood ; Oxidative Stress ; Animals ; Alzheimer Disease/diagnosis/metabolism/blood ; }, abstract = {BACKGROUND: Red blood cells (RBCs) are usually considered simple cells and transporters of gases to tissues.

HYPOTHESIS: However, recent research has suggested that RBCs may have diagnostic potential in major neurodegenerative disorders (NDDs).

RESULTS: This review summarizes the current knowledge on changes in RBC in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other NDDs. It discusses the deposition of neuronal proteins like amyloid-β, tau, and α-synuclein, polyamines, changes in the proteins of RBCs like band-3, membrane transporter proteins, heat shock proteins, oxidative stress biomarkers, and altered metabolic pathways in RBCs during neurodegeneration. It also highlights the comparison of RBC diagnostic markers to other in-market diagnoses and discusses the challenges in utilizing RBCs as diagnostic tools, such as the need for standardized protocols and further validation studies.

SIGNIFICANCE STATEMENT: The evidence suggests that RBCs have diagnostic potential in neurodegenerative disorders, and this study can pave the foundation for further research which may lead to the development of novel diagnostic approaches and treatments.}, } @article {pmid38822985, year = {2024}, author = {Faysal, M and Dehbia, Z and Zehravi, M and Sweilam, SH and Haque, MA and Kumar, KP and Chakole, RD and Shelke, SP and Sirikonda, S and Nafady, MH and Khan, SL and Nainu, F and Ahmad, I and Emran, TB}, title = {Flavonoids as Potential Therapeutics Against Neurodegenerative Disorders: Unlocking the Prospects.}, journal = {Neurochemical research}, volume = {49}, number = {8}, pages = {1926-1944}, pmid = {38822985}, issn = {1573-6903}, mesh = {*Flavonoids/therapeutic use/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Antioxidants/therapeutic use/pharmacology ; }, abstract = {Neurodegeneration, the decline of nerve cells in the brain, is a common feature of neurodegenerative disorders (NDDs). Oxidative stress, a key factor in NDDs such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease can lead to neuronal cell death, mitochondria impairment, excitotoxicity, and Ca[2+] stress. Environmental factors compromising stress response lead to cell damage, necessitating novel therapeutics for preventing or treating brain disorders in older individuals and an aging population. Synthetic medications offer symptomatic benefits but can have adverse effects. This research explores the potential of flavonoids derived from plants in treating NDDs. Flavonoids compounds, have been studied for their potential to enter the brain and treat NDDs. These compounds have diverse biological effects and are currently being explored for their potential in the treatment of central nervous system disorders. Flavonoids have various beneficial effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic, and antioxidant properties. Their potential to alleviate symptoms of NDDs is significant.}, } @article {pmid38823229, year = {2024}, author = {Roman-Pognuz, E and Rigutti, S and Colussi, G and Lena, E and Bonsano, M and Lucangelo, U}, title = {Acute esophageal necrosis following cardiac arrest: A rare and lethal syndrome with diagnostic challenges.}, journal = {International journal of surgery case reports}, volume = {120}, number = {}, pages = {109751}, pmid = {38823229}, issn = {2210-2612}, abstract = {Acute esophageal necrosis (AEN) is a condition characterized by the necrosis of the distal portion of the esophageal mucosa. Risk factors predisposing to this condition are associated to compromised vascular perfusion (e.g. diabetes mellitus, chronic kidney disease, advanced age, and hypertension, shock states). Complications of AEN can be severe including UGI stricture, perforation and overall increased mortality. The true incidence of AEN remains uncertain due to potential subclincal presentations and early resolution.

CASE PRESENTATION: The case outlined involves a 66-years-old obese male with history of alcoholism and lymph-edema of the left leg who presented to the emergency department with hematemesis, haemodynamic instability and impaired consciousness. Shortly after initial assessment, the patient went into cardiac arrest with pulse-less electrical activity (PEA). Return of spontaneous circulation (ROSC) was achieved following instigation of ALS protocol, fluid resuscitation and the administration of a total of 5 mg of adrenaline. Following stabilization, a CT scan was performed which reported a moderately enlarged esophagus with a thickened wall, liquid hypodense material within the esophagus and stomach, and liver cirrhosis. The emergent esophagogastroduodenoscopy (EGDS) revealed extensive mucosal findings indicative of diffuse necrosis with initial scarring, which was later diagnosed as AEN. The patient unfortunately deceased in ICU after developing progression of the AEN, post-cardiac arrest syndrome and liver failure.

CLINICAL DISCUSSION: The presented case highlights several crucial clinical issues and management problems related to AEN. To diagnose AEN, EGDS is still the gold-standard since it allows direct inspection of the esophageal mucosal layer. The management of AEN necessitates a multidisciplinary approach that includes aggressive resuscitation, treatment of underlying comorbidities, and supportive care (e.g. proton pump inhibitors). The mortality rate for AEN remains high despite improvements in diagnosis and treatment highlighting the need to recognize this condition early and intervene promptly in the patients affected. Moreover, long-term sequelae like stricture formation of the esophagus and impaired esophageal motility may contribute to morbidity requiring continuos monitoring. Therefore, to optimize outcomes while reducing complications among affected patients, prompt identification associated with appropriate medical measures are essential. More research needs to be done aiming to better understand the pathophysiology of AEN thereby identifying strategies for its prevention or cure.

CONCLUSIONS: AEN is a rare syndrome characterized by upper gastrointestinal bleeding and hypoxic damage of the esophageal mucosa, often associated with ischemia, gastric outlet obstruction, and compromised protective barriers. Treatment involves aggressive resuscitation, proton pump inhibitors, and monitoring for infection or perforation. However, despite intensive efforts, the mortality rate for AEN remains high at 32 %.}, } @article {pmid38823272, year = {2024}, author = {Bijl, I and Vianen, NJ and Van Lieshout, EMM and Beekers, CHJ and Van Der Waarden, NWPL and Pekbay, B and Maissan, IM and Verhofstad, MHJ and Van Vledder, MG}, title = {Emergency reflex action drill for traumatic cardiac arrest in a simulated pre-hospital setting; a one-group pre-post intervention study.}, journal = {Intensive & critical care nursing}, volume = {84}, number = {}, pages = {103731}, doi = {10.1016/j.iccn.2024.103731}, pmid = {38823272}, issn = {1532-4036}, mesh = {Humans ; Prospective Studies ; Female ; Adult ; *Emergency Medical Services/methods/standards/statistics & numerical data ; Male ; Heart Arrest/complications/therapy ; Middle Aged ; Simulation Training/methods/standards ; Patient Simulation ; }, abstract = {BACKGROUND: Emergency Reflex Action Drills (ERADs) are meant to decrease stress-associated cognitive demand in high urgency situations. The aim of this study was to develop and test an ERAD for witnessed traumatic cardiac arrest (TCA), an event in which potentially reversible causes need to be systematically addressed and treated in a short period of time. We hypothesize that this ERAD (the TCA-Drill) helps ground Emergency Medical Services (EMS) nurses in overcoming performance decline during this specific high-pressure situation.

METHODS: This was a prospective, experimental one-group pre-post intervention study. Ground EMS nurses participated in a session of four simulated scenarios, with an in-between educational session to teach the TCA-Drill. Scenarios were video recorded, after which adherence and time differences were analyzed. Self-confidence on clinical practice was measured before and after the scenarios.

RESULTS: Twelve ground EMS nurses participated in this study. Overall median time to address reversible causes of TCA decreased significantly using the TCA-Drill (132 vs. 110 s; p = 0.030) compared with the conventional ALS strategy. More specifically, participants adhering to the TCA-Drill showed a significantly lower time needed for hemorrhage control (58 vs. 37 s; p = 0.012). Eight of 12 (67 %) ground EMS nurses performed the ERAD without protocol deviations. Reported self-confidence significantly increased on 11 of the 13 surveyed items.

CONCLUSIONS: The use of an ERAD for TCA (the TCA-Drill) significantly reduces the time to address reversible causes for TCA without delaying chest compressions in a simulated environment and can be easily taught to ground EMS nurses and increases self-confidence.

The use of an ERAD for TCA (the TCA-Drill can significantly reduce the time to address reversible causes for TCA without delaying chest compression. This drill can be easily taught to ground EMS nurses and increases their self-confidence in addressing TCA-patients.}, } @article {pmid38824664, year = {2024}, author = {Ahmed, Z and Shahzadi, K and Jin, Y and Li, R and Momanyi, BM and Zulfiqar, H and Ning, L and Lin, H}, title = {[Not Available].}, journal = {Proteomics}, volume = {24}, number = {21-22}, pages = {e2400044}, doi = {10.1002/pmic.202400044}, pmid = {38824664}, issn = {1615-9861}, support = {62372088//National Natural Science Foundation of China/ ; }, mesh = {*RNA/metabolism ; Humans ; *Artificial Intelligence ; Proteins/metabolism/chemistry/analysis ; Databases, Protein ; Computational Biology/methods ; Phase Separation ; }, abstract = {RNA-dependent liquid-liquid phase separation (LLPS) proteins play critical roles in cellular processes such as stress granule formation, DNA repair, RNA metabolism, germ cell development, and protein translation regulation. The abnormal behavior of these proteins is associated with various diseases, particularly neurodegenerative disorders like amyotrophic lateral sclerosis and frontotemporal dementia, making their identification crucial. However, conventional biochemistry-based methods for identifying these proteins are time-consuming and costly. Addressing this challenge, our study developed a robust computational model for their identification. We constructed a comprehensive dataset containing 137 RNA-dependent and 606 non-RNA-dependent LLPS protein sequences, which were then encoded using amino acid composition, composition of K-spaced amino acid pairs, Geary autocorrelation, and conjoined triad methods. Through a combination of correlation analysis, mutual information scoring, and incremental feature selection, we identified an optimal feature subset. This subset was used to train a random forest model, which achieved an accuracy of 90% when tested against an independent dataset. This study demonstrates the potential of computational methods as efficient alternatives for the identification of RNA-dependent LLPS proteins. To enhance the accessibility of the model, a user-centric web server has been established and can be accessed via the link: http://rpp.lin-group.cn.}, } @article {pmid38825034, year = {2024}, author = {Fang, T and Pacut, P and Bose, A and Sun, Y and Gao, J and Sivakumar, S and Bloom, B and Nascimento Andrade, EI and Trombetta, B and Ghasemi, M}, title = {Clinical and genetic factors affecting diagnostic timeline of amyotrophic lateral sclerosis: a 15-year retrospective study.}, journal = {Neurological research}, volume = {46}, number = {9}, pages = {859-867}, doi = {10.1080/01616412.2024.2362578}, pmid = {38825034}, issn = {1743-1328}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Genetic Testing/methods ; Adult ; Delayed Diagnosis ; Time Factors ; }, abstract = {OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) diagnosis can take 10-16 months from symptom onset, leading to delays in treatment and patient counselling. We studied the impact of clinical and genetic risk factors on the diagnostic timeline of ALS.

METHODS: Baseline characteristics, family history, gene testing, onset location, time from symptom onset to diagnosis, and time from first doctor visit to suspected ALS was collected. We used multiple regression to assess the interaction of these factors on ALS diagnostic timeline. We analysed a subgroup of patients with genetic testing and compared positive or negative tests, sporadic or familial and ALS-related genes to time for diagnosis.

RESULTS: Four hundred and forty-eight patients diagnosed with ALS at the University of Massachusetts Chan Medical Center between January 2007 and December 2021 were analysed. The median time to ALS diagnosis was 12 months and remained unchanged from 2007 to 2021 (p = 0.20). Diagnosis was delayed in patients with sporadic compared with familial ALS (mean months [standard deviation], 16.5[13.5] and 11.2[8.5], p < 0.001); cognitive onset (41[21.26]) had longer time to diagnosis than bulbar (11.9[8.2]), limb (15.9[13.2]), respiratory (19.7[13.9]) and ALS with multiple onset locations (20.77[15.71], p < 0.001). One hundred and thirty-four patients had gene testing and 32 tested positive (23.8%). Gene testing (p = 0.23), a positive genetic test (p = 0.16), different ALS genes (p = 0.25) and sporadic (p = 0.92) or familial (p = 0.85) ALS testing positive for ALS genes did not influence time to diagnosis.

DISCUSSION: Time for ALS diagnosis remained unchanged from 2007 to 2021, bulbar-onset and familial ALS made for faster diagnosis.}, } @article {pmid38826044, year = {2024}, author = {Rooney, JPK and Geoghegan, G and O'Reilly, F and Heverin, M and Bose-O'Reilly, S and Casale, F and Chio, A and Günther, K and Schuster, J and Klopstock, T and Ludolph, A and Hardiman, O and Rakete, S}, title = {Serum heat shock protein concentrations are not associated with amyotrophic lateral sclerosis risk or survival in three European populations.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {751-759}, doi = {10.1080/21678421.2024.2358805}, pmid = {38826044}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality/epidemiology/diagnosis ; Female ; Male ; Middle Aged ; Aged ; *Biomarkers/blood ; Germany/epidemiology ; HSP70 Heat-Shock Proteins/blood ; Ireland/epidemiology ; Italy/epidemiology ; Heat-Shock Proteins/blood ; HSP90 Heat-Shock Proteins/blood ; Cohort Studies ; Adult ; Europe/epidemiology ; }, abstract = {Introduction: Serum heat shock protein (HSP) concentrations have been reported as potential biomarkers for amyotrophic lateral sclerosis (ALS). Here, we investigate the role of serum HSP70, HSP90, and DNAJC7 as biomarkers for ALS. Methods: Serum samples were collected from ALS patients and volunteer controls from three different clinical cohorts (in Germany, Ireland, and Italy). Serum HSP concentrations were determined using enzyme-linked immunosorbent assay. Descriptive statistics, generalized logistic regression, and Cox proportional hazards models were used to model associations between log serum HSP concentrations and ALS risk. Results: In total, 251 ALS patients and 184 healthy volunteers were included. Logistic regression models failed to find associations between ALS risk and log serum concentration of HSP70 (OR 0.43, 95% CI: 0.10-1.78, p = 0.242), HSP90 (OR 0.95, 95% CI: 0.39-2.37, p = 0.904), or DNAJC7 (OR 1.55, 95% CI: 0.90-2.68, p = 0.118). Survival of ALS patients was not associated with log serum concentration of HSP HSP70 (HR1.06, 95% CI: 0.36-3.14, p = 0.916), HSP90 (HR 1.17, 95% CI: 0.67-2.02, p = 0.584), or DNAJC7 (HR 0.83, 95% CI: 0.57-1.21, p = 0.337). Discussion: We did not replicate previous findings that serum HSP70 and HSP90 concentrations were associated with risk of ALS. DNAJC7 was not associated with ALS risk, and there were no obvious longitudinal patterns in log serum concentrations of HSP70, HSP90, or DNAJC7. In addition, serum HSP concentrations were not associated with ALS survival.}, } @article {pmid38826088, year = {2024}, author = {Mehta, P and Raymond, J and Nair, T and Han, M and Punjani, R and Larson, T and Berry, J and Mohidul, S and Horton, DK}, title = {Prevalence of ALS in all 50 states in the United States, data from the National ALS Registry, 2011-2018.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {687-693}, doi = {10.1080/21678421.2024.2358786}, pmid = {38826088}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology ; Humans ; United States/epidemiology ; *Registries ; Male ; Prevalence ; Aged ; Female ; Middle Aged ; Aged, 80 and over ; Adult ; Risk Factors ; }, abstract = {Objective: To summarize the prevalence of ALS in all 50 states and Washington, DC in the United States from 2011 to 2018 using data collected and analyzed by the National ALS Registry. In October 2010, the federal Agency for Toxic Substances and Disease Registry (ATSDR) launched the congressionally mandated Registry to determine the incidence and prevalence of ALS within the USA, characterize the demographics of persons with ALS, and identify the potential risk factors for the disease. This is the first analysis of state-level ALS prevalence estimates. Methods: ALS is not a notifiable disease in the USA, so the Registry uses a two-pronged approach to identify cases. The first approach uses existing national administrative databases (Medicare, Veterans Health Administration, and Veterans Benefits Administration). The second method uses a secure web portal to gather voluntary participant data and identify cases not included in the national administrative databases. Results: State-level age-adjusted average prevalence from 2011-2018 ranged from 2.6 per 100,000 persons (Hawaii) to 7.8 per 100,000 persons (Vermont), with an average of 4.4 per 100,000 persons in the US. New England and Midwest regions had higher prevalence rates than the national average. Conclusions: These findings summarize the prevalence of ALS for all 50 states from 2011 to 2018. This is a continuing effort to identify ALS cases on a national population basis. The establishment of the National ALS Registry has allowed for epidemiological trends of this disease and the assessment of potential risk factors that could cause ALS.}, } @article {pmid38826246, year = {2024}, author = {Martínez, P and Silva, M and Abarzúa, S and Tevy, MF and Jaimovich, E and Constantine-Paton, M and Bustos, FJ and van Zundert, B}, title = {Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.05.24.595817}, pmid = {38826246}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1 [G93A] (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2+ transients and reactive oxygen species (i.e., H 2 O 2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.}, } @article {pmid38826483, year = {2024}, author = {Provasek, VE and Kodavati, M and Kim, B and Mitra, J and Hegde, ML}, title = {TDP43 Interacts with MLH1 and MSH6 Proteins in A DNA Damage-Inducible Manner.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38826483}, issn = {2693-5015}, support = {R35 CA220430/CA/NCI NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; P01 CA092584/CA/NCI NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complimentary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 hr treatment of 10μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS affected neurons.}, } @article {pmid38826647, year = {2024}, author = {Zhao, H and Xie, J and Chen, Y and Cao, J and Liao, WH and Cao, H}, title = {Diagnosis of neurodegenerative diseases with a refined Lempel-Ziv complexity.}, journal = {Cognitive neurodynamics}, volume = {18}, number = {3}, pages = {1153-1166}, pmid = {38826647}, issn = {1871-4080}, abstract = {The investigation into the distinctive difference of gait is of significance for the clinical diagnosis of neurodegenerative diseases. However, human gait is affected by many factors like behavior, occupation and so on, and they may confuse the gait differences among Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. For the purpose of examining distinctive gait differences of neurodegenerative diseases, this study extracts various features from both vertical ground reaction force and time intervals. Moreover, refined Lempel-Ziv complexity is proposed considering the detailed distribution of signals based on the median and quartiles. Basic features (mean, coefficient of variance, and the asymmetry index), nonlinear dynamic features (Hurst exponent, correlation dimension, largest Lyapunov exponent), and refined Lempel-Ziv complexity of different neurodegenerative diseases are compared statistically by violin plot and Kruskal-Wallis test to reveal distinction and regularities. The comparative analysis results illustrate the gait differences across these neurodegenerative diseases by basic features and nonlinear dynamic features. Classification results by random forest indicate that the refined Lempel-Ziv complexity can robustly enhance the diagnosis accuracy when combined with basic features.}, } @article {pmid38827490, year = {2024}, author = {Yotsukura, E and Torii, H and Mori, K and Ogawa, M and Hanyuda, A and Negishi, K and Kurihara, T and Tsubota, K}, title = {Slowing of Greater Axial Length Elongation Stemming from the Coronavirus Disease 2019 Pandemic with Increasing Time Outdoors: The Tokyo Myopia Study.}, journal = {Ophthalmology science}, volume = {4}, number = {5}, pages = {100491}, pmid = {38827490}, issn = {2666-9145}, abstract = {PURPOSE: To investigate the changes in axial length (AL) elongation and other ocular parameters before and during the coronavirus disease 2019 pandemic.

DESIGN: A longitudinal school-based study.

PARTICIPANTS: Public elementary schoolchildren in Tokyo (grades 1-6; age, 6-12 years) participated in this study from 2018 to 2021.

METHODS: All participants underwent eye examinations and provided written consent to measurements of the noncycloplegic refraction and ocular biometry including AL, among others. The students' parents also completed a questionnaire about the students' lifestyles. We included the right eye in our analysis and compared the changes in the ocular parameters among the periods using a linear mixed-effects model for repeated measures and examined the univariate and step-wise multiple regression analyses to evaluate the associations between myopia and other covariates.

MAIN OUTCOME MEASURES: Changes in AL elongation and other ocular parameters from 2018 to 2019 (prepandemic), that of 2019 to 2020 (immediately after the pandemic onset), and that of 2020 to 2021 (during the pandemic).

RESULTS: A total of 578 students before the pandemic period, 432 immediately after the pandemic onset, and 457 during the pandemic period were evaluated. The changes in the ALs and spherical equivalents (SEs) a year before, immediately after onset, and during the pandemic were 0.31 mm/-0.20 diopter, 0.38 mm/-0.27 diopter, and 0.28 mm/-0.47 diopter, respectively (ALs, P < 0.001; SEs, P = 0.014). The results of the questionnaire showed that time spent outdoors daily had changed during the 3 years to 79, 63, and 77 minutes/day, respectively (P < 0.001). Time spent using smartphones or tablets increased year by year to 41, 52, and 62 minutes/day (P < 0.001). The greatest AL elongation occurred during the period when the shortest amount of time was spent outdoors during the 3 years.

CONCLUSIONS: These results suggested that the school closures and decreasing time spent outdoors might have caused greater AL elongation among schoolchildren in Tokyo; however, it is possible that, although the time spent in near work still increased, the return to the time spent outdoors to the prepandemic levels may have affected the slowing of AL elongation after lockdown.

FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.}, } @article {pmid38828849, year = {2024}, author = {Mamarabadi, M and Fafoutis, E and Geronimo, A and Walsh, S and Simmons, Z}, title = {Sodium phenylbutyrate-taurursodiol access, adherence and adverse event in patients with amyotrophic lateral sclerosis: Experience at one center in the United States.}, journal = {Muscle & nerve}, volume = {70}, number = {2}, pages = {204-209}, doi = {10.1002/mus.28175}, pmid = {38828849}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/economics ; Male ; Female ; Middle Aged ; Aged ; Adult ; *Medication Adherence ; United States ; Aged, 80 and over ; Phenylbutyrates/therapeutic use/economics ; Health Expenditures ; Retrospective Studies ; }, abstract = {INTRODUCTION/AIMS: Sodium phenylbutyrate-taurursodiol (PB-TURSO) was recently approved for treating amyotrophic lateral sclerosis (ALS). Third-party payors' coverage policies are evolving, and adverse events are just being fully assessed. The goals of this study were to evaluate patients' experiences in obtaining and continuing PB-TURSO and assess adverse events and medication adherence.

METHODS: Medical records of 109 ALS patients who were considered PB-TURSO candidates by the treating physician at a tertiary ALS clinic from October 2022 to May 2023 were reviewed. Data was recorded for demographics, clinical, and insurance information. A survey was e-mailed to patients asking about out-of-pocket expenses for PB-TURSO, financial assistance, medication start and (if applicable) stop dates, and reasons for discontinuation.

RESULTS: Insurance information was available for 91 patients [57 males (62%); mean age 64.8 years (range 25.7-88)]. Of 79 who applied for insurance approval, 71 (90%) were approved; however, 19 required 1-3 appeals. Among 73 patients with available data about medication status, 54 started PB-TURSO and 19 did not, most commonly due to personal choice or out-of-pocket expenses. About 44% of patients (24/54) stopped taking PB-TURSO, primarily due to adverse events. Monthly out-of-pocket expenses varied from $0 to $3500 and 36 patients qualified for financial assistance. Administrative and nursing staff devoted 7.2 hours/week to the insurance authorization process.

DISCUSSION: Most patients received insurance approval for PB-TURSO, but one-fourth required appeals. Some out-of-pocket costs were very high. Investment of staff time was substantial. These findings have implications for insurance coverage of, and adherence to, future ALS treatments.}, } @article {pmid38829007, year = {2024}, author = {Foucher, J and Bunte, TM and Bertone, V and Verschoor, RL and Couillard, M and Straub, C and Genge, A and Ingre, C and van den Berg, LH}, title = {International network for ALS research and care (INARC).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {795-796}, doi = {10.1080/21678421.2024.2362850}, pmid = {38829007}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Biomedical Research/methods/trends ; }, abstract = {The International Network for Amyotrophic Lateral Sclerosis (ALS) Research and Care (INARC) was founded in 2022. INARC's main goals are to offer a platform dedicated to staff members for ALS clinics and research teams who are not physicians. By nurturing experience and expertise exchanges to improve problem solving skills, the ultimate goal is to increase the standard ALS care and research. This brief report aims to describe the formation of INARC, the 2023 INARC meeting, as well as to report topics discussed, lessons learned and challenges raised by INARC members.}, } @article {pmid38829015, year = {2024}, author = {Negri, C and Usberti, N and Contaldo, G and Bracconi, M and Nova, I and Maestri, M and Tronconi, E}, title = {Quantitative Kinetic Insights from Operando-UV/Vis Spectroscopy: An Application to NH3-SCR of NOx on Cu-CHA Catalysts.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {41}, pages = {e202408328}, doi = {10.1002/anie.202408328}, pmid = {38829015}, issn = {1521-3773}, abstract = {We employ UV/Vis Diffuse Reflectance spectroscopy directly coupled with a packed bed flow reactor to extract quantitative kinetic information. We use as a show-case the Cu[II]/Cu[I] redox dynamics during the reduction half cycle of the NH3-Selective Catalytic Reduction (SCR) on Cu-CHA catalysts. Our measurements enable quantification of the fraction of oxidized Cu, reconstructed by Multivariate Curve Resolution (MCR) together with monitoring of the gas-phase evolution during the reaction. These data both on the dynamics of the gas-phase and of the active site oxidation state have been used to assess the reduction half cycle rate equation and estimate the rate constant. Our results in terms of reaction orders and kinetic constant are in line with previous findings in the literature. Overall, our results demonstrate that the combined analysis of the UV spectra and of the gas-phase dynamics provides converging and unparalleled kinetic insight: this approach effectively resolves ambiguities concerning RHC kinetics and mechanism. More in general, this work provides evidence that operando spectroscopy can be used to extract quantitative kinetic information on catalytic cycles.}, } @article {pmid38829431, year = {2024}, author = {Sabatelli, M and Cerri, F and Zuccarino, R and Patanella, AK and Bernardo, D and Bisogni, G and Tanel, R and Sansone, V and Filosto, M and Lattante, S and Martello, F and Doronzio, PN and Stano, S and Zanfini, BA and Coccia, M and Costantini, EM and Lizio, A and Lucioli, G and Padovani, A and Merlini, GP and Conte, A}, title = {Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5177-5186}, pmid = {38829431}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/blood ; Male ; Female ; Middle Aged ; Aged ; *Superoxide Dismutase-1/genetics ; Neurofilament Proteins/blood/cerebrospinal fluid ; Disease Progression ; Adult ; Retrospective Studies ; Treatment Outcome ; Cohort Studies ; }, abstract = {BACKGROUND: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant.

METHODS: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients.

RESULTS: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy.

CONCLUSIONS: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.}, } @article {pmid38829511, year = {2025}, author = {Jiang, S and Xu, R}, title = {The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {221-232}, pmid = {38829511}, issn = {1559-1182}, support = {30560042//National Natural Science Foundation of China/ ; 81160161//National Natural Science Foundation of China/ ; 81360198//National Natural Science Foundation of China/ ; 82160255//National Natural Science Foundation of China/ ; GJJ13198//Education Department of Jiangxi Province/ ; GJJ170021//Education Department of Jiangxi Province/ ; 20192BAB205043//Jiangxi Provincial Department of Science and Technology/ ; 20181019//Health and Family Planning Commission of Jiangxi Province/ ; 202210002//Health and Family Planning Commission of Jiangxi Province/ ; 202310119//Health and Family Planning Commission of Jiangxi Province/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/microbiology/pathology/physiopathology ; Autophagy/physiology ; Dysbiosis/complications/microbiology/physiopathology ; Extracellular Vesicles/metabolism ; Gastrointestinal Microbiome/physiology ; Mitochondria/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease mainly characterized by the accumulation of ubiquitinated proteins in the affected motor neurons. At present, the accurate pathogenesis of ALS remains unclear and there are still no effective treatment measures for ALS. The potential pathogenesis of ALS mainly includes the misfolding of some pathogenic proteins, the genetic variation, mitochondrial dysfunction, autophagy disorders, neuroinflammation, the misregulation of RNA, the altered axonal transport, and gut microbial dysbiosis. Exploring the pathogenesis of ALS is a critical step in searching for the effective therapeutic approaches. The current studies suggested that the genetic variation, gut microbial dysbiosis, the activation of glial cells, and the transportation disorder of extracellular vesicles may play some important roles in the pathogenesis of ALS. This review conducts a systematic review of these current potential promising topics closely related to the pathogenesis of ALS; it aims to provide some new evidences and clues for searching the novel treatment measures of ALS.}, } @article {pmid38829866, year = {2024}, author = {Laurido-Soto, OJ and Faust, IM and Nielsen, SS and Racette, BA}, title = {Adherence to practice parameters in Medicare beneficiaries with amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0304083}, pmid = {38829866}, issn = {1932-6203}, support = {K01 ES028295/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Medicare ; Male ; Female ; United States ; Aged ; Retrospective Studies ; Aged, 80 and over ; Guideline Adherence/statistics & numerical data ; Middle Aged ; Practice Patterns, Physicians'/statistics & numerical data ; }, abstract = {OBJECTIVE: Physician adherence to evidence-based clinical practice parameters impacts outcomes of amyotrophic lateral sclerosis (ALS) patients. We sought to investigate compliance with the 2009 practice parameters for treatment of ALS patients in the United States, and sociodemographic and provider characteristics associated with adherence.

METHODS: In this population-based, retrospective cohort study of incident ALS patients in 2009-2014, we included all Medicare beneficiaries age ≥20 with ≥1 International Classification of Diseases, Ninth Revision, Clinical Modification ALS code (335.20) in 2009 and no prior years (N = 8,575). Variables of interest included race/ethnicity, sex, age, urban residence, Area Deprivation Index (ADI), and provider specialty (neurologist vs. non-neurologist). Outcomes were use of practice parameters, which included feeding tubes, non-invasive ventilation (NIV), riluzole, and receiving care from a neurologist.

RESULTS: Overall, 42.9% of patients with ALS received neurologist care. Black beneficiaries (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.47-0.67), older beneficiaries (OR 0.964, 95% CI 0.961-0.968 per year), and those living in disadvantaged areas (OR 0.70, 95% CI 0.61-0.80) received less care from neurologists. Overall, only 26.7% of beneficiaries received a feeding tube, 19.2% NIV, and 15.3% riluzole. Neurologist-treated patients were more likely to receive interventions than other ALS patients: feeding tube (OR 2.80, 95% CI 2.52-3.11); NIV (OR 10.8, 95% CI 9.28-12.6); and riluzole (OR 7.67, 95% CI 6.13-9.58), after adjusting for sociodemographics. These associations remained marked and significant when we excluded ALS patients who subsequently received a code for other diseases that mimic ALS.

CONCLUSIONS: ALS patients treated by neurologists received care consistent with practice parameters more often than those not treated by a neurologist. Black, older, and disadvantaged beneficiaries received less care consistent with the practice parameters.}, } @article {pmid38830181, year = {2024}, author = {Weemering, DN and Beelen, A and Kliest, T and van Leeuwen, LAG and van den Berg, LH and van Eijk, RPA}, title = {Trial Participation in Neurodegenerative Diseases: Barriers and Facilitators: A Systematic Review and Meta-Analysis.}, journal = {Neurology}, volume = {103}, number = {1}, pages = {e209503}, pmid = {38830181}, issn = {1526-632X}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Clinical Trials as Topic ; *Patient Participation ; Patient Selection ; }, abstract = {BACKGROUND AND OBJECTIVES: Clinical trials in neurodegenerative diseases often encounter selective enrollment and under-representation of certain patient populations. This delays drug development and substantially limits the generalizability of clinical trial results. To inform recruitment and retention strategies, and to better understand the generalizability of clinical trial populations, we investigated which factors drive participation.

METHODS: We reviewed the literature systematically to identify barriers to and facilitators of trial participation in 4 major neurodegenerative disease areas: Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease. Inclusion criteria included original research articles published in a peer-reviewed journal and evaluating barriers to and/or facilitators of participation in a clinical trial with a drug therapy (either symptomatic or disease-modifying). The Critical Appraisal Skills Program checklist for qualitative studies was used to assess and ensure the quality of the studies. Qualitative thematic analyses were employed to identify key enablers of trial participation. Subsequently, we pooled quantitative data of each enabler using meta-analytical models.

RESULTS: Overall, we identified 36 studies, enrolling a cumulative sample size of 5,269 patients, caregivers, and health care professionals. In total, the thematic analysis resulted in 31 unique enablers of trial participation; the key factors were patient-related (own health benefit and altruism), study-related (treatment and study burden), and health care professional-related (information availability and patient-physician relationship). When meta-analyzed across studies, responders reported that the reason to participate was mainly driven by (1) the relationship with clinical staff (70% of the respondents; 95% CI 53%-83%), (2) the availability of study information (67%, 95% CI 38%-87%), and (3) the use or absence of a placebo or sham-control arm (53% 95% CI 32%-72%). There was, however, significant heterogeneity between studies (all p < 0.001).

DISCUSSION: We have provided a comprehensive list of reasons why patients participate in clinical trials for neurodegenerative diseases. These results may help to increase participation rates, better inform patients, and facilitate patient-centric approaches, thereby potentially reducing selection mechanisms and improving generalizability of trial results.}, } @article {pmid38830304, year = {2024}, author = {Chin, B and Um, J and Kim, MK and Kim, HS and Yim, HS and Cho, HJ and Lim, SY and Kim, Y and Jeon, J and Park, JS}, title = {Clinical presentation, viral shedding, and neutralizing antibody responses of mpox cases in South Korea: Single center experience.}, journal = {Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology}, volume = {173}, number = {}, pages = {105692}, doi = {10.1016/j.jcv.2024.105692}, pmid = {38830304}, issn = {1873-5967}, mesh = {Humans ; Male ; Female ; Adult ; Republic of Korea/epidemiology ; *Antibodies, Neutralizing/blood ; Middle Aged ; *Virus Shedding ; Young Adult ; *Antibodies, Viral/blood ; Disease Outbreaks ; DNA, Viral/blood ; Mpox, Monkeypox ; }, abstract = {BACKGROUND: A global mpox outbreak occurred in 2022, and a domestic outbreak started in South Korea in April 2023. This study aimed to evaluate the clinical characteristics, viral shedding, and immune response of mpox in South Korea.

METHODS: Patients hospitalized with mpox in the National Medical Center between September 2022 and June 2023 were included in this study. Oropharyngeal (OP), anogenital lesion (AL), and skin lesion (SL) swabs and blood samples were collected, and monkeypox virus (MPXV) DNA using real-time polymerase chain reaction (RT-PCR) and culture assays were performed. Neutralizing antibodies (NAbs) against MPXV A.2.1, B.1.1, and B.1.3 were detected using plaque reduction neutralization tests.

RESULTS: Eighteen patients were enrolled, of whom 17 (94.4 %) were male, with a median (IQR) age of 32.5 (24-51) years. While nine (50 %) were HIV-infected individuals, none of them revealed CD4+ counts less than 200 cells/μL. MPXV DNA was detected in 87.3 % and 82.7 % of patient's ALs and SLs, respectively, until 2 weeks after symptom onset. While MPXV was isolated for up to 15 days in all three sample types, the culture positivity decreased to 53.8 % and 42.9 % in ALs and SLs after 10 days, respectively, and 28.6 % and 22.2 %, respectively, after 2 weeks from symptom onset. The NAb titers against MPXV A.2.1 were significantly lower than those against B.1.1 and B.1.3.

CONCLUSIONS: Infectious MPXV was isolated from various anatomical sites up to 15 days after symptom onset. The MPXV NAb response was varied among different lineages, and this implies limited cross-lineage protection.}, } @article {pmid38830342, year = {2024}, author = {Li, J and Li, S and Fei, G}, title = {Potential Correlation between Tea Intake and the Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.}, journal = {Neuro-degenerative diseases}, volume = {24}, number = {2}, pages = {45-53}, doi = {10.1159/000539590}, pmid = {38830342}, issn = {1660-2862}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Tea ; *Mendelian Randomization Analysis/methods ; *Polymorphism, Single Nucleotide/genetics ; Risk Factors ; }, abstract = {INTRODUCTION: There were limited observation studies on the association between tea intake and amyotrophic lateral sclerosis (ALS) with inconsistent results. This study aimed to determine the potential relationship between tea intake and ALS by a two-sample Mendelian randomization (MR) analysis.

METHODS: We identified 41 independent SNPs strongly associated with tea intake from 448,060 participants of European ancestry in the UK Biobank. Summary statistics associated with ALS were also obtained from the UK Biobank including 20,806 cases and 59,804 controls. The study used MR analysis to assess the potential effect of tea consumption on ALS, and several methods such as sensitivity analyses and MR-pleiotropy residual sum and outlier method were performed to further test the robustness of our findings.

RESULTS: The F statistic was more than 10 in each SNP, which meets the first assumption for the MR study. Using the inverse variance weighted MR analysis as the primary method, we found that a one standard deviation increase in tea consumption was associated with a 14% lower risk of ALS (OR = 0.86, 95% CI = 0.74-0.99, p < 0.05). Sensitivity analyses detected no potential pleiotropy and directional heterogeneity.

CONCLUSION: Our MR study supported the potential relationship between tea intake and ALS risk, suggesting the potential advantages of tea intake for preventing ALS. Future clinical trials and research are needed to further validate the results and elucidate possible mechanisms.}, } @article {pmid38831349, year = {2024}, author = {López-Carbonero, JI and García-Toledo, I and Fernández-Hernández, L and Bascuñana, P and Gil-Moreno, MJ and Matías-Guiu, JA and Corrochano, S}, title = {In vivo diagnosis of TDP-43 proteinopathies: in search of biomarkers of clinical use.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {29}, pmid = {38831349}, issn = {2047-9158}, support = {2022-5A/BMD-24221//Consejería de Educación, Juventud y Deporte, Comunidad de Madrid/ ; PDI2020-1153-70RB-100/AEI/10.13039/501100011033//Ministerio de Ciencia e Innovación/ ; CM23/00094//Instituto de Salud Carlos III/ ; INT20/00079//Instituto de Salud Carlos III/ ; INT23/00017//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *TDP-43 Proteinopathies/diagnosis/metabolism/genetics ; *Biomarkers/analysis/metabolism ; *DNA-Binding Proteins/metabolism ; Brain/metabolism/pathology ; }, abstract = {TDP-43 proteinopathies are a heterogeneous group of neurodegenerative disorders that share the presence of aberrant, misfolded and mislocalized deposits of the protein TDP-43, as in the case of amyotrophic lateral sclerosis and some, but not all, pathological variants of frontotemporal dementia. In recent years, many other diseases have been reported to have primary or secondary TDP-43 proteinopathy, such as Alzheimer's disease, Huntington's disease or the recently described limbic-predominant age-related TDP-43 encephalopathy, highlighting the need for new and accurate methods for the early detection of TDP-43 proteinopathy to help on the stratification of patients with overlapping clinical diagnosis. Currently, TDP-43 proteinopathy remains a post-mortem pathologic diagnosis. Although the main aim is to determine the pathologic TDP-43 proteinopathy in the central nervous system (CNS), the ubiquitous expression of TDP-43 in biofluids and cells outside the CNS facilitates the use of other accessible target tissues that might reflect the potential TDP-43 alterations in the brain. In this review, we describe the main developments in the early detection of TDP-43 proteinopathies, and their potential implications on diagnosis and future treatments.}, } @article {pmid38832104, year = {2024}, author = {Oh, HJ and Lee, WJ and Sung, JJ and Hong, YH and , }, title = {Individualized predictions for clinical milestone in amyotrophic lateral sclerosis: A multialgorithmic approach.}, journal = {Digital health}, volume = {10}, number = {}, pages = {20552076241260120}, pmid = {38832104}, issn = {2055-2076}, abstract = {OBJECTIVE: The phenotypic heterogeneity and complex disease trajectory complicate the ability to predict specific clinical milestone for individual patients with amyotrophic lateral sclerosis (ALS). Here we developed individualized prediction models to estimate the time to the loss of autonomy in swallowing function.

METHODS: Utilizing the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we built three models of distinct time-to-event prediction algorithms: accelerated failure time (AFT), cox proportional hazard (COX) and random survival forest (RSF) for an individualized risk assessment of the swallowing milestone. The target variable was defined as the time to a decline in the ALSFRS-R swallowing item score to 1 or below, indicating a need for supplementary tube feeding.

RESULTS: Internal cross-validation revealed the median concordance index (C-index) of 0.851 (IQR, 0.842-0.859) for AFT, 0.850 (0.841-0.859) for COX and 0.846 (0.839-0.854) for RSF, and all models demonstrated good distributional calibration with predicted and observed event probabilities closely matched across different time intervals. For external validation with a registry dataset with characteristics different from PRO-ACT, the discriminative power was replicated with comparable C-indices for all models, whereas the calibration revealed a left-skewed distribution suggesting a bias towards overestimation of event probabilities in real-world data. While all models were effective at stratifying patients, the results of RSF model, unlike AFT and COX, did not match well with the KM curves of the corresponding risk groups, supporting the importance of nuanced understanding of data structure and algorithmic properties.

CONCLUSION: Our models are implemented into a web application which could be applied to individualized counselling, management and clinical trial design for gastrostomy intervention. Further studies for model optimization will advance personalized care in patients with ALS.}, } @article {pmid38832321, year = {2024}, author = {Patel, JS and McCall, NS and Thomas, M and Zhou, J and Higgins, KA and Bradley, JD and Tian, S and McDonald, MW and Kesarwala, AH and Stokes, WA}, title = {Immune System Dose With Proton Versus Photon Radiotherapy for Treatment of Locally Advanced NSCLC.}, journal = {International journal of particle therapy}, volume = {12}, number = {}, pages = {100016}, pmid = {38832321}, issn = {2331-5180}, abstract = {PURPOSE: Emerging data have illuminated the impact of effective radiation dose to immune cells (EDIC) on outcomes in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT). Hypothesizing that intensity-modulated proton therapy (IMPT) may reduce EDIC versus IMRT, we conducted a dosimetric analysis of patients treated at our institution.

MATERIALS AND METHODS: Data were retrospectively collected for 12 patients with locally advanced, unresectable NSCLC diagnosed between 2019 and 2021 who had physician-approved IMRT and IMPT plans. Data to calculate EDIC from both Jin et al (PMID: 34944813) and Ladbury et al's (PMID: 31175902) models were abstracted. Paired t tests were utilized to compare the difference in mean EDIC between IMPT and IMRT plans.

RESULTS: IMPT decreased EDIC for 11 of 12 patients (91.7%). The mean EDIC per the Jin model was significantly lower with IMPT than IMRT (3.04 GyE vs 4.99 Gy, P < .001). Similarly, the mean EDIC per the Ladbury model was significantly lower with IMPT than IMRT (4.50 GyE vs 7.60 Gy, P < .002). Modeled 2-year overall survival was significantly longer with IMPT than IMRT (median 71% vs 63%; P = .03).

CONCLUSION: IMPT offers a statistically significant reduction in EDIC compared to IMRT. Given the emergence of EDIC as a modifiable prognostic factor in treatment planning, our dosimetric study highlights a potential role for IMPT to address an unmet need in improving oncologic outcomes in patients with locoregionally advanced NSCLC.}, } @article {pmid38833116, year = {2024}, author = {Mubeen, H and Masood, A and Zafar, A and Khan, ZQ and Khan, MQ and Nisa, AU}, title = {Insights into AlphaFold's breakthrough in neurodegenerative diseases.}, journal = {Irish journal of medical science}, volume = {193}, number = {5}, pages = {2577-2588}, pmid = {38833116}, issn = {1863-4362}, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology ; Artificial Intelligence ; Deep Learning ; Parkinson Disease ; Alzheimer Disease ; Algorithms ; Frontotemporal Dementia/genetics ; }, abstract = {Neurodegenerative diseases (ND) are disorders of the central nervous system (CNS) characterized by impairment in neurons' functions, and complete loss, leading to memory loss, and difficulty in learning, language, and movement processes. The most common among these NDs are Alzheimer's disease (AD) and Parkinson's disease (PD), although several other disorders also exist. These are frontotemporal dementia (FTD), amyotrophic lateral syndrome (ALS), Huntington's disease (HD), and others; the major pathological hallmark of NDs is the proteinopathies, either of amyloid-β (Aβ), tauopathies, or synucleinopathies. Aggregation of proteins that do not undergo normal configuration, either due to mutations or through some disturbance in cellular pathway contributes to the diseases. Artificial Intelligence (AI) and deep learning (DL) have proven to be successful in the diagnosis and treatment of various congenital diseases. DL approaches like AlphaFold (AF) are a major leap towards success in CNS disorders. This 3D protein geometry modeling algorithm developed by DeepMind has the potential to revolutionize biology. AF has the potential to predict 3D-protein confirmation at an accuracy level comparable to experimentally predicted one, with the additional advantage of precisely estimating protein interactions. This breakthrough will be beneficial to identify diseases' advancement and the disturbance of signaling pathways stimulating impaired functions of proteins. Though AlphaFold has solved a major problem in structural biology, it cannot predict membrane proteins-a beneficial approach for drug designing.}, } @article {pmid38834164, year = {2024}, author = {Griñán-Ferré, C and Bellver-Sanchis, A and Guerrero, A and Pallàs, M}, title = {Advancing personalized medicine in neurodegenerative diseases: The role of epigenetics and pharmacoepigenomics in pharmacotherapy.}, journal = {Pharmacological research}, volume = {205}, number = {}, pages = {107247}, doi = {10.1016/j.phrs.2024.107247}, pmid = {38834164}, issn = {1096-1186}, mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/drug therapy/genetics ; *Pharmacogenetics/methods ; *Epigenesis, Genetic/drug effects ; Animals ; Epigenomics/methods ; }, abstract = {About 80 % of brain disorders have a genetic basis. The pathogenesis of most neurodegenerative diseases is associated with a myriad of genetic defects, epigenetic alterations (DNA methylation, histone/chromatin remodeling, miRNA dysregulation), and environmental factors. The emergence of new sequencing technologies and tools to study the epigenome has led to identifying predictive biomarkers for earlier diagnosis, opening up the possibility of prophylactical interventions. As a result, advances in pharmacogenetics and pharmacoepigenomics now allow for personalized treatments based on the profile of each patient and the specific genetic and epigenetic mechanisms involved. This Review highlights the complexity of neurodegenerative diseases and the variability in patient responses to pharmacotherapy, emphasizing the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of drugs used to treat those conditions. We specifically discuss the potential modulatory effect of several genetic polymorphisms associated with an increased risk of developing different neurodegenerative diseases. We explore genetic and genomic technologies and the potential of analyzing individual-specific drug metabolism to predict and influence drug response and associated clinical outcomes. We also provide insights into the mechanism of action of the drugs under investigation and their potential impact on disease-modifying pathways. Finally, the Review underscores the great potential of this field to enhance the effectiveness and safety of drug treatments through personalized medicine.}, } @article {pmid38835198, year = {2024}, author = {Trudel, P and Quesnel-Olivo, MH and Blais, M and Shoesmith, C and Dupré, N}, title = {ALS, MAiD and Tissue Donation: Case Reports from Six Patients' Care Journeys.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-2}, doi = {10.1017/cjn.2024.277}, pmid = {38835198}, issn = {0317-1671}, } @article {pmid38835201, year = {2024}, author = {Tsai, CC and Tao, B and Wong, M and Suntharalingam, H and Abrahao, A and Barnett-Tapia, C}, title = {Sex, racial, and ethnic disparities in motor neuron disease: clinical trial enrolment.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {694-701}, doi = {10.1080/21678421.2024.2358793}, pmid = {38835201}, issn = {2167-9223}, mesh = {Female ; Humans ; Male ; Clinical Trials as Topic ; Ethnicity ; *Healthcare Disparities/ethnology/statistics & numerical data ; *Motor Neuron Disease/ethnology ; Sex Factors ; Racial Groups ; *Patient Selection ; }, abstract = {OBJECTIVE: Motor neuron disease (MND) is a group of neurological diseases, the majority being amyotrophic lateral sclerosis (ALS), with varying clinical presentations across demographics. Clinical trial enrollment reflecting global disease burden improves understanding of diverse presentations and aids personalized therapy development. We assessed the sex, racial, and ethnic composition of MND/ALS clinical trial participants relative to global disease burdens.

METHODS: We searched 'motor neuron disease OR amyotrophic lateral sclerosis' on ClinicalTrials.gov from 02/2000-04/2024. We extracted trial (start year, study site, sponsor location, phase, masking, intervention) and demographic data (sex, race, ethnicity) from randomized interventional studies. We obtained sex-based MND/ALS disease burden estimates from the Global Burden of Disease database. For females, we calculated pooled participation-to-prevalence ratio (PPR) with 95% confidence intervals (CIs), with PPR of 0.8-1.2 indicating adequate enrollment. We used Kruskal-Wallis tests to compare demographic groups across trial characteristics.

RESULTS: Of 85 trials, females comprised 37.47% (n = 5011) of 13,372 participants; the pooled female PPR was 0.97 (95% CI: 0.77-1.16). Of 41 trials (9340 participants) reporting race, 121 (1.30%) participants were Black or African American, 16 (0.17%) American Indian or Alaskan Native, and 6 (0.06%) Native Hawaiian or Other Pacific Islander. 24 trials (595 participants) reported ethnicity, with a minority of Hispanic participants (n = 153; 2.57%).

CONCLUSIONS: MND/ALS clinical trials had adequate female enrollment relative to global disease burdens. Race and ethnicity data were underreported. However, there were enrollment disparities of racial and ethnic groups. Increased trial leadership diversity, equitable enrollment policies, and addressing barriers to participation could improve enrollment diversity.}, } @article {pmid38835240, year = {2024}, author = {McAlary, L and Nan, JR and Shyu, C and Sher, M and Plotkin, SS and Cashman, NR}, title = {Amyloidogenic regions in beta-strands II and III modulate the aggregation and toxicity of SOD1 in living cells.}, journal = {Open biology}, volume = {14}, number = {6}, pages = {230418}, pmid = {38835240}, issn = {2046-2441}, support = {//R. Howard Webster Foundation/ ; //CIHR/Canada ; //Canadian Consortium for Neurodegeneration/ ; //Brain Canada/ ; }, mesh = {*Superoxide Dismutase-1/metabolism/genetics/chemistry ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Protein Aggregates ; Protein Aggregation, Pathological/genetics/metabolism ; Mutation ; Protein Conformation, beta-Strand ; Models, Molecular ; Proline/metabolism ; Amyloid/metabolism/chemistry ; Protein Folding ; }, abstract = {Mutations in the protein superoxide dismutase-1 (SOD1) promote its misfolding and aggregation, ultimately causing familial forms of the debilitating neurodegenerative disease amyotrophic lateral sclerosis (ALS). Currently, over 220 (mostly missense) ALS-causing mutations in the SOD1 protein have been identified, indicating that common structural features are responsible for aggregation and toxicity. Using in silico tools, we predicted amyloidogenic regions in the ALS-associated SOD1-G85R mutant, finding seven regions throughout the structure. Introduction of proline residues into β-strands II (I18P) or III (I35P) reduced the aggregation propensity and toxicity of SOD1-G85R in cells, significantly more so than proline mutations in other amyloidogenic regions. The I18P and I35P mutations also reduced the capability of SOD1-G85R to template onto previously formed non-proline mutant SOD1 aggregates as measured by fluorescence recovery after photobleaching. Finally, we found that, while the I18P and I35P mutants are less structurally stable than SOD1-G85R, the proline mutants are less aggregation-prone during proteasome inhibition, and less toxic to cells overall. Our research highlights the importance of a previously underappreciated SOD1 amyloidogenic region in β-strand II ([15]QGIINF[20]) to the aggregation and toxicity of SOD1 in ALS mutants, and suggests that β-strands II and III may be good targets for the development of SOD1-associated ALS therapies.}, } @article {pmid38836001, year = {2024}, author = {Rong, P and Heidrick, L and Pattee, GL}, title = {A multimodal approach to automated hierarchical assessment of bulbar involvement in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1396002}, pmid = {38836001}, issn = {1664-2295}, abstract = {INTRODUCTION: As a hallmark feature of amyotrophic lateral sclerosis (ALS), bulbar involvement leads to progressive declines of speech and swallowing functions, significantly impacting social, emotional, and physical health, and quality of life. Standard clinical tools for bulbar assessment focus primarily on clinical symptoms and functional outcomes. However, ALS is known to have a long, clinically silent prodromal stage characterized by complex subclinical changes at various levels of the bulbar motor system. These changes accumulate over time and eventually culminate in clinical symptoms and functional declines. Detection of these subclinical changes is critical, both for mechanistic understanding of bulbar neuromuscular pathology and for optimal clinical management of bulbar dysfunction in ALS. To this end, we developed a novel multimodal measurement tool based on two clinically readily available, noninvasive instruments-facial surface electromyography (sEMG) and acoustic techniques-to hierarchically assess seven constructs of bulbar/speech motor control at the neuromuscular and acoustic levels. These constructs, including prosody, pause, functional connectivity, amplitude, rhythm, complexity, and regularity, are both mechanically and clinically relevant to bulbar involvement.

METHODS: Using a custom-developed, fully automated data analytic algorithm, a variety of features were extracted from the sEMG and acoustic recordings of a speech task performed by 13 individuals with ALS and 10 neurologically healthy controls. These features were then factorized into 10 composite outcome measures using confirmatory factor analysis. Statistical and machine learning techniques were applied to these composite outcome measures to evaluate their reliability (internal consistency), validity (concurrent and construct), and efficacy for early detection and progress monitoring of bulbar involvement in ALS.

RESULTS: The composite outcome measures were demonstrated to (1) be internally consistent and structurally valid in measuring the targeted constructs; (2) hold concurrent validity with the existing clinical and functional criteria for bulbar assessment; and (3) outperform the outcome measures obtained from each constituent modality in differentiating individuals with ALS from healthy controls. Moreover, the composite outcome measures combined demonstrated high efficacy for detecting subclinical changes in the targeted constructs, both during the prodromal stage and during the transition from prodromal to symptomatic stages.

DISCUSSION: The findings provided compelling initial evidence for the utility of the multimodal measurement tool for improving early detection and progress monitoring of bulbar involvement in ALS, which have important implications in facilitating timely access to and delivery of optimal clinical care of bulbar dysfunction.}, } @article {pmid38836336, year = {2024}, author = {Foucher, J and Öijerstedt, L and Lovik, A and Sun, J and Ismail, MA and Sennfält, S and Savitcheva, I and Estenberg, U and Pagani, M and Fang, F and Pereira, JB and Ingre, C}, title = {ECAS correlation with metabolic alterations on FDG-PET imaging in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {708-716}, doi = {10.1080/21678421.2024.2361695}, pmid = {38836336}, issn = {2167-9223}, support = {R01 TS000324/TS/ATSDR CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Male ; Female ; *Fluorodeoxyglucose F18 ; Middle Aged ; *Positron-Emission Tomography/methods ; Aged ; Brain/metabolism/diagnostic imaging ; Cognitive Dysfunction/metabolism/diagnostic imaging ; Adult ; Neuropsychological Tests ; Glucose/metabolism ; Radiopharmaceuticals ; }, abstract = {Background: Cognitive impairment is observed in up to 50% of patients with amyotrophic lateral sclerosis (ALS). The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is an ALS-specific multi-domain screening tool. Few studies have examined the relationship between ECAS scores and [[18]F]fluorodeoxyglucose positron emission tomography ([[18]F]FDG-PET) findings. Objective: To assess the relationship between ECAS scores and glucose metabolism patterns on [[18]F]FDG -PET images in ALS. Methods: We collected [[18]F]FDG-PET images from 65 patients with ALS and 39 healthy controls. ECAS scores were collected on all patients and we calculated the correlation to [[18]F]FDG-PET in order to investigate the potential links between cognition and glucose metabolism. Results: We observed hypometabolism in the frontal cortex, insula, and limbic system, together with hypermetabolism in the cerebellum in patients with ALS compared to controls. A lower ECAS total score was associated with lower glucose metabolism in the right orbitofrontal gyrus and higher glucose metabolism in lateral occipital, medial occipital, and cerebellar regions, among patients with ALS. Similar results, although less widespread, were observed in the analyses of ECAS ALS-specific scores. Conclusions: The metabolic patterns in [[18]F]FDG -PET show that changes in the glucose metabolism of corresponding areas are related to cognitive dysfunction in ALS, and can be detected using the ECAS.}, } @article {pmid38837229, year = {2024}, author = {Ó Murchú, SC and O'Halloran, KD}, title = {BREATHE DMD: boosting respiratory efficacy after therapeutic hypoxic episodes in Duchenne muscular dystrophy.}, journal = {The Journal of physiology}, volume = {602}, number = {14}, pages = {3255-3272}, doi = {10.1113/JP280280}, pmid = {38837229}, issn = {1469-7793}, support = {SFI FFP/19/6628 INSPIRE DMD/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {*Muscular Dystrophy, Duchenne/physiopathology/therapy ; Humans ; *Hypoxia/physiopathology ; Animals ; Respiration ; }, abstract = {Duchenne muscular dystrophy (DMD) is a fatal genetic neuromuscular disorder, characterised by progressive decline in skeletal muscle function due to the secondary consequences of dystrophin deficiency. Weakness extends to the respiratory musculature, and cardiorespiratory failure is the leading cause of death in men with DMD. Intermittent hypoxia has emerged as a potential therapy to counteract ventilatory insufficiency by eliciting long-term facilitation of breathing. Mechanisms of sensory and motor facilitation of breathing have been well delineated in animal models. Various paradigms of intermittent hypoxia have been designed and implemented in human trials culminating in clinical trials in people with spinal cord injury and amyotrophic lateral sclerosis. Application of therapeutic intermittent hypoxia to DMD is considered together with discussion of the potential barriers to progression owing to the complexity of this devastating disease. Notwithstanding the considerable challenges and potential pitfalls of intermittent hypoxia-based therapies for DMD, we suggest it is incumbent on the research community to explore the potential benefits in pre-clinical models. Intermittent hypoxia paradigms should be implemented to explore the proclivity to express respiratory plasticity with the longer-term aim of preserving and potentiating ventilation in pre-clinical models and people with DMD.}, } @article {pmid38837773, year = {2024}, author = {Connaghan, KP and Green, JR and Eshghi, M and Haenssler, AE and Scheier, ZA and Clark, A and Iyer, A and Richburg, BD and Rowe, HP and Okada, J and Johnson, SA and Onnela, JP and Burke, KM and Berry, JD}, title = {The relationship of rate and pause features to the communicative participation of people living with ALS.}, journal = {Muscle & nerve}, volume = {70}, number = {2}, pages = {217-225}, pmid = {38837773}, issn = {1097-4598}, support = {K23 DC019179/DC/NIDCD NIH HHS/United States ; DP2-MH103909/NH/NIH HHS/United States ; R15 DC018944/DC/NIDCD NIH HHS/United States ; 1R15DC018944/NH/NIH HHS/United States ; NIH-NIDCD K24DC016312/NH/NIH HHS/United States ; K23DC019179/NH/NIH HHS/United States ; DP2 MH103909/MH/NIMH NIH HHS/United States ; K24 DC016312/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology ; Female ; Male ; Middle Aged ; Aged ; Speech/physiology ; Adult ; Communication ; Self Report ; }, abstract = {INTRODUCTION/AIMS: Many people living with amyotrophic lateral sclerosis (PALS) report restrictions in their day-to-day communication (communicative participation). However, little is known about which speech features contribute to these restrictions. This study evaluated the effects of common speech symptoms in PALS (reduced overall speaking rate, slowed articulation rate, and increased pausing) on communicative participation restrictions.

METHODS: Participants completed surveys (the Communicative Participation Item Bank-short form; the self-entry version of the ALS Functional Rating Scale-Revised) and recorded themselves reading the Bamboo Passage aloud using a smartphone app. Rate and pause measures were extracted from the recordings. The association of various demographic, clinical, self-reported, and acoustic speech features with communicative participation was evaluated with bivariate correlations. The contribution of salient rate and pause measures to communicative participation was assessed using multiple linear regression.

RESULTS: Fifty seven people living with ALS participated in the study (mean age = 61.1 years). Acoustic and self-report measures of speech and bulbar function were moderately to highly associated with communicative participation (Spearman rho coefficients ranged from rs = 0.48 to rs = 0.77). A regression model including participant age, sex, articulation rate, and percent pause time accounted for 57% of the variance of communicative participation ratings.

DISCUSSION: Even though PALS with slowed articulation rate and increased pausing may convey their message clearly, these speech features predict communicative participation restrictions. The identification of quantitative speech features, such as articulation rate and percent pause time, is critical to facilitating early and targeted intervention and for monitoring bulbar decline in ALS.}, } @article {pmid38837845, year = {2024}, author = {Huang, Q and Zhang, Q and Cao, B}, title = {Causal relationship between PCSK9 inhibitor and common neurodegenerative diseases: A drug target Mendelian randomization study.}, journal = {Brain and behavior}, volume = {14}, number = {6}, pages = {e3543}, pmid = {38837845}, issn = {2162-3279}, support = {2022NSFSC0749 to BC//the National Natural Science Fund of Sichuan/ ; }, mesh = {Humans ; Alzheimer Disease/genetics/drug therapy ; Amyotrophic Lateral Sclerosis/genetics/drug therapy/epidemiology ; Genome-Wide Association Study ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology/adverse effects ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/drug therapy/genetics ; Parkinson Disease/genetics/drug therapy ; *PCSK9 Inhibitors ; *Polymorphism, Single Nucleotide ; Proprotein Convertase 9 ; }, abstract = {BACKGROUND: In addition to lowering cholesterol levels, the proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has a variety of effects, including anti-neuroapoptosis. However, the effects of PCSK9 inhibitors on neurodegenerative diseases are controversial. Therefore, we used drug-targeted Mendelian randomization (MR) analysis to investigate the effects of PCSK9 inhibitors on different neurodegenerative diseases.

METHODS: We collected single nucleotide polymorphisms (SNPs) of PCSK9 from published statistics of genome-wide association studies and performed drug target MR analyses to detect a causal relationship between PCSK9 inhibitors and the risk of neurodegenerative diseases. We utilized the effects of 3-Hydroxy -3- methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors (statin targets) for comparison with PCSK9 inhibitors. Coronary heart disease risk was used as a positive control, and primary outcomes included amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD).

RESULTS: PCSK9 inhibitors marginally reduced the risk of ALS (OR [95%] = 0.89 [0.77 to 1.00], p = 0.048), while they increased the risk of PD (OR [95%] = 1.417 [1.178 to 1.657], p = 0.004). However, HMGCR inhibitors increased the risk of PD (OR [95%] = 1.907 [1.502 to 2.312], p = 0.001).

CONCLUSION: PCSK9 inhibitors significantly reduce the risk of ALS but increase the risk of PD. HMGCR inhibitors may be the risk factor for PD.}, } @article {pmid38838021, year = {2024}, author = {Ho, DM and Shaban, M and Mahmood, F and Ganguly, P and Todeschini, L and Van Vactor, D and Artavanis-Tsakonas, S}, title = {cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {24}, pages = {e2400732121}, pmid = {38838021}, issn = {1091-6490}, support = {R21 NS123207/NS/NINDS NIH HHS/United States ; R21NS123207//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *Cyclic AMP/metabolism ; *Drosophila melanogaster/metabolism ; *Cyclic AMP-Dependent Protein Kinases/metabolism/genetics ; *Drosophila Proteins/metabolism/genetics ; *Signal Transduction ; *DNA-Binding Proteins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; Motor Neurons/metabolism ; }, abstract = {Cytoplasmic mislocalization and aggregation of TDP-43 protein are hallmarks of amyotrophic lateral sclerosis (ALS) and are observed in the vast majority of both familial and sporadic cases. How these two interconnected processes are regulated on a molecular level, however, remains enigmatic. Genome-wide screens for modifiers of the ALS-associated genes TDP-43 and FUS have identified the phospholipase D (Pld) pathway as a key regulator of ALS-related phenotypes in the fruit fly Drosophila melanogaster [M. W. Kankel et al., Genetics 215, 747-766 (2020)]. Here, we report the results of our search for downstream targets of the enzymatic product of Pld, phosphatidic acid. We identify two conserved negative regulators of the cAMP/PKA signaling pathway, the phosphodiesterase dunce and the inhibitory subunit PKA-R2, as modifiers of pathogenic phenotypes resulting from overexpression of the Drosophila TDP-43 ortholog TBPH. We show that knockdown of either of these genes results in a mitigation of both TBPH aggregation and mislocalization in larval motor neuron cell bodies, as well as an amelioration of adult-onset motor defects and shortened lifespan induced by TBPH. We determine that PKA kinase activity is downstream of both TBPH and Pld and that overexpression of the PKA target CrebA can rescue TBPH mislocalization. These findings suggest a model whereby increasing cAMP/PKA signaling can ameliorate the molecular and functional effects of pathological TDP-43.}, } @article {pmid38838248, year = {2024}, author = {Liss, J and Berisha, V}, title = {Operationalizing Clinical Speech Analytics: Moving From Features to Measures for Real-World Clinical Impact.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {11}, pages = {4226-4232}, pmid = {38838248}, issn = {1558-9102}, support = {R01 DC006859/DC/NIDCD NIH HHS/United States ; R13 DC003383/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Speech Production Measurement/methods ; Speech ; Reproducibility of Results ; }, abstract = {OBJECTIVE: This research note advocates for a methodological shift in clinical speech analytics, emphasizing the transition from high-dimensional speech feature representations to clinically validated speech measures designed to operationalize clinically relevant constructs of interest. The aim is to enhance model generalizability and clinical applicability in real-world settings.

METHOD: We outline the challenges of using conventional supervised machine learning models in clinical speech analytics, particularly their limited generalizability and interpretability. We propose a new framework focusing on speech measures that are closely tied to specific speech constructs and have undergone rigorous validation. This research note discusses a case study involving the development of a measure for articulatory precision in amyotrophic lateral sclerosis (ALS), detailing the process from ideation through Food and Drug Administration (FDA) breakthrough status designation.

RESULTS: The case study demonstrates how the operationalization of the articulatory precision construct into a quantifiable measure yields robust, clinically meaningful results. The measure's validation followed the V3 framework (verification, analytical validation, and clinical validation), showing high correlation with clinical status and speech intelligibility. The practical application of these measures is exemplified in a clinical trial and designation by the FDA as a breakthrough status device, underscoring their real-world impact.

CONCLUSIONS: Transitioning from speech features to speech measures offers a more targeted approach for developing speech analytics tools in clinical settings. This shift ensures that models are not only technically sound but also clinically relevant and interpretable, thereby bridging the gap between laboratory research and practical health care applications. We encourage further exploration and adoption of this approach for developing interpretable speech representations tailored to specific clinical needs.}, } @article {pmid38838600, year = {2024}, author = {Ou, H and Zhang, P and Wang, X and Lin, M and Li, Y and Wang, G}, title = {Gaining insights into the responses of individual yeast cells to ethanol fermentation using Raman tweezers and chemometrics.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {319}, number = {}, pages = {124584}, doi = {10.1016/j.saa.2024.124584}, pmid = {38838600}, issn = {1873-3557}, mesh = {*Spectrum Analysis, Raman/methods ; *Ethanol/metabolism ; *Saccharomyces cerevisiae/metabolism ; *Fermentation ; *Principal Component Analysis ; Least-Squares Analysis ; Optical Tweezers ; Single-Cell Analysis/methods ; }, abstract = {Saccharomyces cerevisiae is the most common microbe used for the industrial production of bioethanol, and it encounters various stresses that inhibit cell growth and metabolism during fermentation. However, little is currently known about the physiological changes that occur in individual yeast cells during ethanol fermentation. Therefore, in this work, Raman spectroscopy and chemometric techniques were employed to monitor the metabolic changes of individual yeast cells at distinct stages during high gravity ethanol fermentation. Raman tweezers was used to acquire the Raman spectra of individual yeast cells. Multivariate curve resolution-alternating least squares (MCR-ALS) and principal component analysis were employed to analyze the Raman spectra dataset. MCR-ALS extracted the spectra of proteins, phospholipids, and triacylglycerols and their relative contents in individual cells. Changes in intracellular biomolecules showed that yeast cells undergo three distinct physiological stages during fermentation. In addition, heterogeneity among yeast cells significantly increased in the late fermentation period, and different yeast cells may respond to ethanol stress via different mechanisms. Our findings suggest that the combination of Raman tweezers and chemometrics approaches allows for characterizing the dynamics of molecular components within individual cells. This approach can serve as a valuable tool in investigating the resistance mechanism and metabolic heterogeneity of yeast cells during ethanol fermentation.}, } @article {pmid38839275, year = {2024}, author = {Palumbo, F and Iazzolino, B and Callegaro, S and Canosa, A and Manera, U and Vasta, R and Grassano, M and Matteoni, E and Cabras, S and Pellegrino, G and Salamone, P and Peotta, L and Casale, F and Fuda, G and Moglia, C and Chio, A and Calvo, A}, title = {Disentangling the relationship between social cognition, executive functions and behaviour changes in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {8}, pages = {722-729}, doi = {10.1136/jnnp-2023-332700}, pmid = {38839275}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; *Executive Function ; Male ; Female ; *Social Cognition ; Middle Aged ; Cross-Sectional Studies ; *Theory of Mind/physiology ; Aged ; Neuropsychological Tests ; Cognitive Dysfunction/psychology/diagnosis ; Case-Control Studies ; }, abstract = {BACKGROUND: Social cognition (SC) deficits are included in the amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTDS) revised diagnostic criteria. However, the impact of SC assessment on cognitive classification and the cognitive-behavioural correlates of SC remain unclear. This cross-sectional study aimed to assess the impact of SC assessment on ALS-FTDS categorisation and explore the relationship of SC with executive functions (EF) and behaviour changes in a cohort of ALS patients.

METHODS: 121 patients and 56 healthy controls from the Turin ALS Centre underwent cognitive/behavioural testing, including the SC subdomains of facial emotion recognition, and cognitive and affective theory of mind (ToM).

RESULTS: Patients performed significantly worse than controls in all SC explored domains, and 45% of patients exhibited a deficit in at least one SC test, dissociated from the presence of EF deficits. In 13% of cases, the SC deficit was isolated and subclinical. SC assessment contributed to the attribution of cognitive impairment in 10% of patients. Through a statistical clustering approach, we found that ToM only partially overlaps with EF while behaviour changes are associated with emotional disorders (anxiety and depression).

CONCLUSIONS: SC is overall independent of EF in ALS, with ToM only partially associated with specific EF measures, and behaviour changes associated with emotional disorders. The influence of SC on cognitive categorisation and the frequent identification of a subclinical SC impairment have implications in a clinical setting, considering the substantial impact of cognitive impairment on disease burden and therapeutic choices.}, } @article {pmid38840222, year = {2024}, author = {Provasek, VE and Kodavati, M and Kim, B and Mitra, J and Hegde, ML}, title = {TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner.}, journal = {Molecular brain}, volume = {17}, number = {1}, pages = {32}, pmid = {38840222}, issn = {1756-6606}, support = {RF1 NS112719/NS/NINDS NIH HHS/United States ; RF1NS112719/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *MutL Protein Homolog 1/metabolism ; *DNA Damage ; *Protein Binding/drug effects ; Cell Line, Tumor ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Neurons/metabolism ; Middle Aged ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double-strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that the TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complementary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 h treatment of 10 μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS-affected neurons.}, } @article {pmid38841627, year = {2024}, author = {Picher-Martel, V and Babu, S and Amato, AA}, title = {TARDBP Mutations in Facial-Onset Sensory and Motor Neuronopathy.}, journal = {Neurology. Genetics}, volume = {10}, number = {3}, pages = {e200160}, pmid = {38841627}, issn = {2376-7839}, abstract = {OBJECTIVES: Facial-onset sensory and motor neuronopathy (FOSMN) is a rare neuromuscular disorder characterized by progressive facial sensory impairment followed by motor dysfunction in a rostro-caudal distribution. FOSMN is clinically and pathologically associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In contrast to ALS/FTD, the genetic profile of patients with FOSMN and the role of genetic testing are poorly defined.

METHODS: A 66-year-old woman was evaluated in our neuromuscular clinic for progressive facial pain, dysphagia, and dysarthria. Her diagnostic evaluation included brain and cervical MRI, nerve conduction studies and EMG, and an ALS/FTD next-generation sequencing panel.

RESULTS: The patient was diagnosed with FOSMN, and we identified a N390D variant in transactive response DNA-binding protein (TDP-43/TARDBP). This variant has never been reported in FOSMN but was previously reported in 2 cases of ALS, and a N390S variant was also previously reported in FOSMN. A review of the literature revealed that TARDBP mutations are overrepresented in patients with FOSMN compared with patients with ALS/FTD. By contrast, other common familial forms of ALS, including C9ORF72 or SOD1, are respectively absent or rare in FOSMN.

DISCUSSION: FOSMN is pathologically and genetically associated with TDP-43. Therefore, ALS genetic testing that includes specifically TARDBP should be considered in patients with FOSMN.}, } @article {pmid38842106, year = {2024}, author = {Neel, DV and Baselga-Garriga, C and Benson, M and Keegan, M and Chase, M and D'Agostino, D and Drake, K and Hagar, JL and Hasenoehrl, MG and Kulesa-Kelley, J and Leite, A and Mohapatra, S and Portaro, SM and Pothier, LM and Rosenthal, J and Sherman, AV and Yu, H and McCaffrey, A and Ho, D and Luppino, S and Bedlack, R and Heitzman, D and Ajroud-Driss, S and Katz, J and Felice, K and Whitaker, C and Ladha, S and Alameda, G and Locatelli, E and Qureshi, IA and Hotchkin, MT and Hayden, MR and Cudkowicz, ME and Babu, S and Berry, JD and Paganoni, S}, title = {Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {2}, pages = {232-239}, pmid = {38842106}, issn = {1097-4598}, support = {T32 GM144273/GM/NIGMS NIH HHS/United States ; //I AM ALS/ ; //Biohaven Pharmaceuticals, Inc/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; United States ; Male ; Female ; Middle Aged ; Aged ; Drugs, Investigational/therapeutic use ; United States Food and Drug Administration ; Adult ; Health Services Accessibility ; Adaptive Clinical Trials as Topic ; }, abstract = {INTRODUCTION/AIMS: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers.

METHODS: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration.

RESULTS: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing.

DISCUSSION: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.}, } @article {pmid38844339, year = {2024}, author = {Robinson, G}, title = {Neuropsychological assessment in ALS.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {8}, pages = {692}, pmid = {38844339}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis/complications ; *Neuropsychological Tests ; Cognition Disorders/diagnosis ; }, } @article {pmid38844617, year = {2024}, author = {Tyr, A and Heldring, N and Zilg, B}, title = {Examining the use of alternative light sources in medico-legal assessments of blunt-force trauma: a systematic review.}, journal = {International journal of legal medicine}, volume = {138}, number = {5}, pages = {1925-1938}, pmid = {38844617}, issn = {1437-1596}, mesh = {Humans ; *Contusions ; *Wounds, Nonpenetrating ; Light ; Forensic Medicine/methods ; }, abstract = {The ability to analyze blunt-force trauma is crucial for deciphering valuable clues concerning mechanisms of injury and as evidence for medico-legal investigations. The use of alternate light sources (ALS) has been studied over the past decade, and is proposed to outperform conventional white light (CWL) during bruise assessments. In response to the growing interest of the technology worldwide, a systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) to address the ability of ALS to detect and visualize bruising. From an initial 4055 records identified, ten studies met the eligibly criteria and were selected for this review. Evaluation also included a novel framework, referred to as SPICOT, to further systematically assess both scientific evidence and risk of bias in forensic literature. Analysis reveals that narrowband wavelengths within in the infrared or ultraviolet spectral ranges do not significantly outperform CWL in visualizing or detecting bruising. However, wavelengths within the visible spectrum, particularly 415 nm combined with longpass or bandpass yellow filters, are more effective. However, the majority of selected studies only address the sensitivity of ALS, and therefore, results may only be considered valid when the location of a bruise is known. Further investigation is required to understand the specificity of ALS, in particular how the use of topical cosmetic products, previous wounds/scar-tissue, tattoos, moles and freckles may affect detection. The ethical concern regarding the interpretation of enhanced visualized trauma should also be considered in prospect discussions prior to implementing ALS into routine practice. Nevertheless, this review finds that narrowband ALS within the visible spectrum demonstrates potential for improved injury documentation, outperforming CWL in the detection and visualization of bruising.}, } @article {pmid38845026, year = {2024}, author = {Kettunen, P and Koistinaho, J and Rolova, T}, title = {Contribution of CNS and extra-CNS infections to neurodegeneration: a narrative review.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {152}, pmid = {38845026}, issn = {1742-2094}, support = {334525//Research Council of Finland/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Central Nervous System Infections ; Animals ; }, abstract = {Central nervous system infections have been suggested as a possible cause for neurodegenerative diseases, particularly sporadic cases. They trigger neuroinflammation which is considered integrally involved in neurodegenerative processes. In this review, we will look at data linking a variety of viral, bacterial, fungal, and protozoan infections to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis and unspecified dementia. This narrative review aims to bring together a broad range of data currently supporting the involvement of central nervous system infections in the development of neurodegenerative diseases. The idea that no single pathogen or pathogen group is responsible for neurodegenerative diseases will be discussed. Instead, we suggest that a wide range of susceptibility factors may make individuals differentially vulnerable to different infectious pathogens and subsequent pathologies.}, } @article {pmid38845371, year = {2024}, author = {Rooney, J and Murray, D and Meldrum, D and Al-Chalabi, A and Bunte, T and Chiwera, T and Choudhury, M and Chio, A and Fenton, L and Fortune, J and Maidment, L and Manera, U and McDermott, CJ and Meyjes, M and Tattersall, R and Torrieri, MC and Van Damme, P and Vanderlinden, E and Wood, C and van den Berg, LH and Hardiman, O}, title = {REVEALS-a longitudinal cohort study of multifaceted respiratory assessment in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {661-671}, pmid = {38845371}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; *Disease Progression ; Respiratory Function Tests/methods ; Vital Capacity/physiology ; Cohort Studies ; Cough/physiopathology/diagnosis ; }, abstract = {OBJECTIVE: To systematically assess decline in respiratory measures in amyotrophic lateral sclerosis (ALS) and to examine the impact of sex, disease onset type and baseline morbidity on progression.

METHODS: The REVEALS study (Registry of Endpoints and Validated Experiences in ALS) was conducted between April 2018 and February 2021 in six European ALS centers. Slow and forced vital capacity (S/FVC), sniff nasal inspiratory pressure (SNIP), peak cough flow, amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R), and respiratory morbidity were collected. Data were analyzed using a Bayesian multiple outcomes random effects model.

RESULTS: Two hundred and eighty participants had a median of three assessments (IQR 2.0, 5.0) over a median of 8 months (IQR 2.3, 14.1). There were 974 data collection timepoints. Differences in respiratory measures and rates of decline between disease-onset and sex subgroups were identified. Females had lower scores in all respiratory measures and females with bulbar onset ALS had faster decline compared with other sub-groups. These differences were not detected by the ALSFRS-r respiratory subscale. Dyspnea, orthopnea, and a higher King's stage at baseline were associated with lower respiratory scores throughout follow-up, while having a regular productive cough at baseline was associated with lower peak cough flow scores.

CONCLUSION: Respiratory function declines more quickly in females with ALS compared with males when measured by FVC, SVC, SNIP, or PCF, but not the ALSFRS-R respiratory sub-score. Higher baseline King's staging and the presence of clinical respiratory symptoms at baseline were associated with worse respiratory function. The ALSFRS-R respiratory sub-score is poorly correlated with objective respiratory measurements.}, } @article {pmid38846532, year = {2024}, author = {Murage, B and Tan, H and Mashimo, T and Jackson, M and Skehel, PA}, title = {Spinal cord neurone loss and foot placement changes in a rat knock-in model of amyotrophic lateral sclerosis Type 8.}, journal = {Brain communications}, volume = {6}, number = {3}, pages = {fcae184}, pmid = {38846532}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is an age-dependent cell type-selective degenerative disease. Genetic studies indicate that amyotrophic lateral sclerosis is part of a spectrum of disorders, ranging from spinal muscular atrophy to frontotemporal dementia that share common pathological mechanisms. Amyotrophic lateral sclerosis Type 8 is a familial disease caused by mis-sense mutations in VAPB. VAPB is localized to the cytoplasmic surface of the endoplasmic reticulum, where it serves as a docking point for cytoplasmic proteins and mediates inter-organelle interactions with the endoplasmic reticulum membrane. A gene knock-in model of amyotrophic lateral sclerosis Type 8 based on the VapB[P56S] mutation and VapB gene deletion has been generated in rats. These animals display a range of age-dependent phenotypes distinct from those previously reported in mouse models of amyotrophic lateral sclerosis Type 8. A loss of motor neurones in VapB[P56S/+] and VapB[P56S/P56S] animals is indicated by a reduction in the number of large choline acetyl transferase-staining cells in the spinal cord. VapB[-/-] animals exhibit a relative increase in cytoplasmic TDP-43 levels compared with the nucleus, but no large protein aggregates. Concomitant with these spinal cord pathologies VapB[P56S/+] , VapB[P56S/P56S] and VapB[-/-] animals exhibit age-dependent changes in paw placement and exerted pressures when traversing a CatWalk apparatus, consistent with a somatosensory dysfunction. Extramotor dysfunction is reported in half the cases of motor neurone disease, and this is the first indication of an associated sensory dysfunction in a rodent model of amyotrophic lateral sclerosis. Different rodent models may offer complementary experimental platforms with which to understand the human disease.}, } @article {pmid38846716, year = {2024}, author = {Bradford, D and Rodgers, KE}, title = {Advancements and challenges in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1401706}, pmid = {38846716}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) continues to pose a significant challenge due to the disease complexity and heterogeneous manifestations. Despite recent drug approvals, there remains a critical need for the development of more effective therapies. This review explores the underlying mechanisms involved; including neuroinflammation, glutamate mediated excitotoxicity, mitochondrial dysfunction, and hypermetabolism, and how researchers are trying to develop novel drugs to target these pathways. While progress has been made, the unmet need of ALS patients highlights the urgency for continued research and resource allocation in the pursuit of effective treatments.}, } @article {pmid38847056, year = {2024}, author = {Michelotti, G and Egger-Sigg, M and Bornstein, MM}, title = {[Komplexes Odontom im Unterkieferfrontzahnbereich bei einer 16-jährigen Patientin - Diagnostik, Therapie und Nachsorge].}, journal = {Swiss dental journal}, volume = {134}, number = {3}, pages = {}, doi = {10.61872/sdj-2024-03-08}, pmid = {38847056}, issn = {2296-6498}, mesh = {Adolescent ; Humans ; Diagnosis, Differential ; Mandibular Neoplasms/surgery/pathology/diagnosis ; Maxillary Neoplasms/surgery/pathology/diagnosis ; *Odontoma/surgery/diagnosis/pathology ; }, abstract = {Odontome gelten zusammen mit den Amelo- blastomen als die häufigsten odontogenen Tumoren. Sie entstehen während der embryo- nalen Zahnkeimentwicklung durch fehlerhaft differenziertes Keimgewebe und werden daher auch als Hamartome bezeichnet. Somit sind sie also strenggenommen keine klassischen Neoplasien.}, } @article {pmid38847583, year = {2024}, author = {Zhou, M and Sheng, Z and Ji, G and Zhang, X}, title = {Aerogel-Involved Triple-State Gels Resemble Natural Living Leaves in Structure and Multi-Functions.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {36}, number = {32}, pages = {e2406007}, doi = {10.1002/adma.202406007}, pmid = {38847583}, issn = {1521-4095}, support = {52173052//National Natural Science Foundation of China/ ; SYC2022125//Suzhou Municipal Science and Technology Bureau/ ; }, mesh = {*Plant Leaves/chemistry/metabolism ; Gels/chemistry ; Silicon Dioxide/chemistry ; Hydrogels/chemistry ; Photosynthesis ; Polyvinyl Alcohol/chemistry ; Hydrophobic and Hydrophilic Interactions ; }, abstract = {Natural plant leaves with multiple functions, for example, spectral features, transpiration, photosynthesis, etc., have played a significant role in the ecosystem, and artificial synthesis of plant leaves with multiple functions of natural ones is still a great challenge. Herein, this work presents an aerogel-involved living leaf (AL), most similar to natural ones so far, by embedding super-hydrophobic SiO2 aerogel microparticles in polyvinyl alcohol hydrogel in the presence of hygroscopic salt and chlorophyllin copper sodium to form solid-liquid-vapor triple-state gel. The AL shows a high spectral similarity with all sampled 15 species of natural leaves and exhibits ≈4-7 times transpiration speed higher than natural leaves. More importantly, AL can achieve several times higher photosynthesis than natural leaves without the energy provided by the respiratory action of natural ones. This work demonstrates the feasibility of creating ALs with natural leaf-like triple-state gel structures and multiple functions, opening up new avenues for energy conversion, environmental engineering, and biomimetic applications.}, } @article {pmid38848023, year = {2024}, author = {Fabi, JP}, title = {The connection between gut microbiota and its metabolites with neurodegenerative diseases in humans.}, journal = {Metabolic brain disease}, volume = {39}, number = {5}, pages = {967-984}, doi = {10.1007/s11011-024-01369-w}, pmid = {38848023}, issn = {1573-7365}, support = {2013/07914-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 307842/2022-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/metabolism/microbiology ; *Dysbiosis/metabolism ; *Brain-Gut Axis/physiology ; Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; }, abstract = {The aging of populations is a global phenomenon that follows a possible increase in the incidence of neurodegenerative diseases. Alzheimer's, Parkinson's, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Huntington's diseases are some neurodegenerative disorders that aging could initiate or aggravate. Recent research has indicated that intestinal microbiota dysbiosis can trigger metabolism and brain functioning, contributing to the etiopathogenesis of those neurodegenerative diseases. The intestinal microbiota and its metabolites show significant functions in various aspects, such as the immune system modulation (development and maturation), the maintenance of the intestinal barrier integrity, the modulation of neuromuscular functions in the intestine, and the facilitation of essential metabolic processes for both the microbiota and humans. The primary evidence supporting the connection between intestinal microbiota and its metabolites with neurodegenerative diseases are epidemiological observations and animal models experimentation. This paper reviews up-to-date evidence on the correlation between the microbiota-gut-brain axis and neurodegenerative diseases, with a specially focus on gut metabolites. Dysbiosis can increase inflammatory cytokines and bacterial metabolites, altering intestinal and blood-brain barrier permeability and causing neuroinflammation, thus facilitating the pathogenesis of neurodegenerative diseases. Clinical data supporting this evidence still needs to be improved. Most of the works found are descriptive and associated with the presence of phyla or species of bacteria with neurodegenerative diseases. Despite the limitations of recent research, the potential for elucidating clinical questions that have thus far eluded clarification within prevailing pathophysiological frameworks of health and disease is promising through investigation of the interplay between the host and microbiota.}, } @article {pmid38848044, year = {2025}, author = {Samalia, P and Niederer, R}, title = {Letter to the Editor: Comment on Raad et al's "Adalimumab for the Treatment of Non-Infectious Uveitis: A Real Life Experience".}, journal = {Ocular immunology and inflammation}, volume = {33}, number = {3}, pages = {377}, doi = {10.1080/09273948.2024.2362879}, pmid = {38848044}, issn = {1744-5078}, } @article {pmid38848664, year = {2024}, author = {Morioka, D and Sagisaka, R and Nakagawa, K and Takahashi, H and Tanaka, H}, title = {Effect of timing of advanced life support on out-of-hospital cardiac arrests at home.}, journal = {The American journal of emergency medicine}, volume = {82}, number = {}, pages = {94-100}, doi = {10.1016/j.ajem.2024.05.021}, pmid = {38848664}, issn = {1532-8171}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; Retrospective Studies ; Aged ; *Epinephrine/administration & dosage/therapeutic use ; Japan/epidemiology ; Middle Aged ; *Emergency Medical Services ; *Advanced Cardiac Life Support/methods ; Intubation, Intratracheal/statistics & numerical data ; Time-to-Treatment/statistics & numerical data ; Aged, 80 and over ; Registries ; Time Factors ; Return of Spontaneous Circulation ; Cardiopulmonary Resuscitation/methods ; }, abstract = {AIM: In cases of out-of-hospital cardiac arrests (OHCA) occurring at home, Japanese emergency medical services personnel decide whether to provide treatment on the scene or during transport based on their judgment. This study aimed to evaluate the association between the timing of advanced life support (ALS) (i.e., endotracheal intubation [ETI] or adrenaline administration) for OHCA at home and prognosis.

METHOD: This retrospective cohort study used data from the Japan Utstein Registry and emergency transport data collected from patients who underwent pre-hospital ETI (n = 6806) and received adrenaline (n = 22,636) between 2016 and 2019. The timing of ETI or adrenaline administration was determined as "on the scene" or "in the ambulance." Multiple logistic regression analysis was used to estimate the association among the timing of ALS implementation, pre-hospital return of spontaneous circulation (ROSC), and survival at 1 month.

RESULT: ETI on the scene was significantly positively associated with pre-hospital ROSC (adjusted odds ratio [AOR], 1.81; 95% confidence interval [CI], 1.57-2.09) and survival at 1 month (AOR, 1.81; 95% CI, 1.47-2.23). Adrenaline administration on the scene was significantly positively associated with pre-hospital ROSC (AOR, 2.51; 95% CI, 2.33-2.70) and survival at 1 month (AOR, 2.13; 95% CI, 1.89-2.40).

CONCLUSION: Our analysis suggests performing ALS on the scene was associated with pre-hospital ROSC and survival at 1 month. Further efforts are needed to increase the rate of ALS implementation on the scene by emergency life-saving technicians.}, } @article {pmid38849340, year = {2024}, author = {Caldi Gomes, L and Hänzelmann, S and Hausmann, F and Khatri, R and Oller, S and Parvaz, M and Tzeplaeff, L and Pasetto, L and Gebelin, M and Ebbing, M and Holzapfel, C and Columbro, SF and Scozzari, S and Knöferle, J and Cordts, I and Demleitner, AF and Deschauer, M and Dufke, C and Sturm, M and Zhou, Q and Zelina, P and Sudria-Lopez, E and Haack, TB and Streb, S and Kuzma-Kozakiewicz, M and Edbauer, D and Pasterkamp, RJ and Laczko, E and Rehrauer, H and Schlapbach, R and Carapito, C and Bonetto, V and Bonn, S and Lingor, P}, title = {Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4893}, pmid = {38849340}, issn = {2041-1723}, support = {01GM1917A//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; SFB1192 PB8, and PC3//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism ; Humans ; Female ; Animals ; Male ; Mice ; *Mice, Transgenic ; *MAP Kinase Signaling System/drug effects ; *Disease Models, Animal ; Pyridones/pharmacology/therapeutic use ; RNA-Binding Protein FUS/metabolism/genetics ; Prefrontal Cortex/metabolism ; Transcriptome ; Superoxide Dismutase-1/genetics/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Middle Aged ; MicroRNAs/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Sex Characteristics ; Aged ; Sex Factors ; Pyrimidinones ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments.}, } @article {pmid38849367, year = {2024}, author = {Mora, S and Stuckert, A and von Huth Friis, R and Pietersz, K and Noes-Holt, G and Montañana-Rosell, R and Wang, H and Sørensen, AT and Selvan, R and Verhaagen, J and Allodi, I}, title = {Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4867}, pmid = {38849367}, issn = {2041-1723}, support = {21-2B-9477/L102 and 18-2B-3570//Aage og Johanne Louis-Hansens Fond (Aage and Johanne Louis-Hansen Foundation)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/metabolism/therapy ; *Interneurons/metabolism ; *Motor Neurons/metabolism ; *Disease Models, Animal ; Mice ; *Mice, Transgenic ; *Synapses/metabolism ; Phenotype ; Male ; Genetic Therapy/methods ; Humans ; Female ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Loss of connectivity between spinal V1 inhibitory interneurons and motor neurons is found early in disease in the SOD1[G93A] mice. Such changes in premotor inputs can contribute to homeostatic imbalance of motor neurons. Here, we show that the Extended Synaptotagmin 1 (Esyt1) presynaptic organizer is downregulated in V1 interneurons. V1 restricted overexpression of Esyt1 rescues inhibitory synapses, increases motor neuron survival, and ameliorates motor phenotypes. Two gene therapy approaches overexpressing ESYT1 were investigated; one for local intraspinal delivery, and the other for systemic administration using an AAV-PHP.eB vector delivered intravenously. Improvement of motor functions is observed in both approaches, however systemic administration appears to significantly reduce onset of motor impairment in the SOD1[G93A] mice in absence of side effects. Altogether, we show that stabilization of V1 synapses by ESYT1 overexpression has the potential to improve motor functions in ALS, demonstrating that interneurons can be a target to attenuate ALS symptoms.}, } @article {pmid38849544, year = {2024}, author = {Sun, H and Yang, B and Li, Q and Zhu, X and Song, E and Liu, C and Song, Y and Jiang, G}, title = {Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms.}, journal = {Nature nanotechnology}, volume = {19}, number = {9}, pages = {1354-1365}, pmid = {38849544}, issn = {1748-3395}, support = {22176206, 22174116 and 22241604//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {*Polystyrenes/chemistry/toxicity ; *Amyotrophic Lateral Sclerosis/metabolism/chemically induced ; *DNA-Binding Proteins/metabolism ; Humans ; *Nanoparticles/chemistry ; Animals ; Mice ; Oxidative Stress/drug effects ; Motor Neurons/metabolism/drug effects/pathology ; HSP70 Heat-Shock Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the dysfunction and progressive death of cerebral and spinal motor neurons. Preliminary epidemiological research has hinted at a relationship between environmental risks and the escalation of ALS, but the underlying reasons remain mostly mysterious. Here we show that nanosize polystyrene plastics (PS) induce ALS-like symptoms and illustrate the related molecular mechanism. When exposed to PS, cells endure internal oxidative stress, which leads to the aggregation of TAR DNA-binding protein 43 kDa (TDP-43), triggering ALS-like characteristics. In addition, the oxidized heat shock protein 70 fails to escort TDP-43 back to the nucleus. The cytoplasmic accumulation of TDP-43 facilitates the formation of a complex between PS and TDP-43, enhancing the condensation and solidification of TDP-43. These findings are corroborated through in silico and in vivo assays. Altogether, our work illustrates a unique toxicological mechanism induced by nanoparticles and provides insights into the connection between environmental pollution and neurodegenerative disorders.}, } @article {pmid38850875, year = {2024}, author = {Coen, M and Benyamine, A and Delmont, E and Kaplanski, G and Bouabdallah, R and Xerri, L and Attarian, S and Serratrice, J}, title = {Tell-tale immune-related neurological syndromes: Should we look for and underlying low-grade B-cell lymphoma? A retrospective study on 12 cases.}, journal = {Pathology, research and practice}, volume = {260}, number = {}, pages = {155377}, doi = {10.1016/j.prp.2024.155377}, pmid = {38850875}, issn = {1618-0631}, mesh = {Humans ; Retrospective Studies ; Male ; Female ; Middle Aged ; *Lymphoma, B-Cell/pathology/immunology ; Aged ; Adult ; }, abstract = {INTRODUCTION: Immune-related neurological syndromes (affecting both the central and peripheral nervous system, as well as the neuromuscular junction) can associate with low-grade B-cell lymphomas.

METHODS: We conducted a retrospective study on the records of patients with miscellaneous immune-related neuropathies followed by the "Referral Centre for Neuromuscular Diseases and ALS" in collaboration with the Services of Internal Medicine and Hematology (La Timone Hospital, and the Paoli Calmettes-Insitute, Marseille, France; Geneva University Hospitals, Geneva, Switzerland). Clinical, biological, immunological and histological work-up was carried out and data collected.

RESULTS: We identified 12 patients with neurological syndromes and atypical presentation/course. In all these patients multiple autoantibodies were found. This prompted us to perform thorough hematologic investigations, that led to the diagnosis of different type of Low-Grade B-Cell lymphomas [i.e. marginal zone lymphomas with lymphoplasmacytic differentiation (n=3), splenic marginal area lymphoma with secondary lymph node invasion (n=1), unclassified marginal area lymphomas (n=8)]. Treatment of the underling lymphoma resulted in an improvement (n=8) or stabilization (n=4) of neurological disease.

CONCLUSION: Atypical presentation of immune-related neurological syndromes, as well as the presence of antibodies with different antigenic targets should be regarded as "warning signs" and raise the suspicion of a paraneoplastic origin sustained by an underlying low-grade B-cell lymphoma that should be actively sought and treated. Close collaboration between internists, neurologists and hematologists allows for the appropriate management of each case.}, } @article {pmid38851229, year = {2024}, author = {Yu, Y and Zeng, L and Wu, M and Li, C and Qiu, Y and Liu, J and Yang, F and Xia, P}, title = {Exploring amyotrophic lateral sclerosis patients' experiences of psychological distress during the disease course in China: a qualitative study.}, journal = {BMJ open}, volume = {14}, number = {6}, pages = {e082398}, pmid = {38851229}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Female ; Male ; China ; Middle Aged ; *Qualitative Research ; *Psychological Distress ; *Quality of Life ; Adult ; Aged ; Stress, Psychological/psychology ; Interviews as Topic ; Social Stigma ; Adaptation, Psychological ; }, abstract = {OBJECTIVE: This study aims to explore the psychological distress course of Chinese amyotrophic lateral sclerosis (ALS) patients after the onset of the disease and to provide targeted nursing guidance.

DESIGN: The interview content was analysed qualitatively. We used seven steps of Colaizzi's method to analyse the participants' data.

SETTING: Wuhan, China, Traditional Chinese Medicine Hospital.

PARTICIPANTS: A semistructured face-to-face interview were performed among 22 people with ALS from the motor neuron disease rehabilitation centre of a tertiary Chinese medicine hospital in China.

RESULT: This study included a total of 22 participants, from whom three main themes regarding the psychological distress trajectory of ALS patients were extracted from the interview data: 'Time begins to run out' include tormented and restless waiting and shock and doubt in ALS disease confirmation, 'Family out of control' include the burden of stigma and function loss, the burden of missing family roles, the burden of marriage's emotional needs and the burden of offspring health, 'Way forward' include struggle between live and death and struggle between quality of life and the value of life.

CONCLUSION: This study outlines the psychologically distressing journey of ALS patients. Studies have pointed out the need for targeted care to address patients' various sources of psychological distress to improve their quality of life and coping ability, increase their psychological resilience and reconstruct their life beliefs.}, } @article {pmid38852112, year = {2024}, author = {Leighton, DJ and Ansari, M and Newton, J and Cleary, E and Stephenson, L and Beswick, E and Carod Artal, J and Davenport, R and Duncan, C and Gorrie, GH and Morrison, I and Swingler, R and Deary, IJ and Porteous, M and Chandran, S and Pal, S and , }, title = {Genotypes and phenotypes of motor neuron disease: an update of the genetic landscape in Scotland.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5256-5266}, pmid = {38852112}, issn = {1432-1459}, support = {CAF/MND/15/01//Chief Scientist Office, Scottish Government Health and Social Care Directorate/ ; CAF/MND/15/01//MND Scotland/ ; CAF/MND/15/01/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; Scotland/epidemiology ; *Motor Neuron Disease/genetics/epidemiology ; Male ; Female ; Middle Aged ; Aged ; *Phenotype ; *C9orf72 Protein/genetics ; Genotype ; Adult ; DNA Repeat Expansion/genetics ; Cohort Studies ; Aged, 80 and over ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Using the Clinical Audit Research and Evaluation of Motor Neuron Disease (CARE-MND) database and the Scottish Regenerative Neurology Tissue Bank, we aimed to outline the genetic epidemiology and phenotypes of an incident cohort of people with MND (pwMND) to gain a realistic impression of the genetic landscape and genotype-phenotype associations.

METHODS: Phenotypic markers were identified from the CARE-MND platform. Sequence analysis of 48 genes was undertaken. Variants were classified using a structured evidence-based approach. Samples were also tested for C9orf72 hexanucleotide expansions using repeat-prime PCR methodology.

RESULTS: 339 pwMND donated a DNA sample: 44 (13.0%) fulfilled criteria for having a pathogenic variant/repeat expansion, 53.5% of those with a family history of MND and 9.3% of those without. The majority (30 (8.8%)) had a pathogenic C9orf72 repeat expansion, including two with intermediate expansions. Having a C9orf72 expansion was associated with a significantly lower Edinburgh Cognitive and Behavioural ALS Screen ALS-Specific score (p = 0.0005). The known pathogenic SOD1 variant p.(Ile114Thr), frequently observed in the Scottish population, was detected in 9 (2.7%) of total cases but in 17.9% of familial cases. Rare variants were detected in FUS and NEK1. One individual carried both a C9orf72 expansion and SOD1 variant.

CONCLUSIONS: Our results provide an accurate summary of MND demographics and genetic epidemiology. We recommend early genetic testing of people with cognitive impairment to ensure that C9orf72 carriers are given the best opportunity for informed treatment planning. Scotland is enriched for the SOD1 p.(Ile114Thr) variant and this has significant implications with regards to future genetically-targeted treatments.}, } @article {pmid38852741, year = {2024}, author = {Moncayo, AK and Grossman, D and Kim, CC and Hartman, RI}, title = {Response to Bass et al's "Significant discordance in DermTech test results when paired with histopathology: Caveat emptor".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e101-e102}, doi = {10.1016/j.jaad.2024.05.079}, pmid = {38852741}, issn = {1097-6787}, support = {CSR&D CX-002531/VA/VA/United States ; W81XWH2110819//Department of Defense/ ; }, mesh = {Humans ; *Skin Neoplasms/pathology ; Dermoscopy ; Melanoma/pathology ; }, } @article {pmid38852806, year = {2024}, author = {Yazdani, S and Lovik, A and Seitz, C and Ingre, C and Fang, F and Andersson, J}, title = {T cell subset composition differs between blood and cerebrospinal fluid in amyotrophic lateral sclerosis.}, journal = {Clinical immunology (Orlando, Fla.)}, volume = {265}, number = {}, pages = {110270}, doi = {10.1016/j.clim.2024.110270}, pmid = {38852806}, issn = {1521-7035}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/immunology/blood ; Male ; Female ; Middle Aged ; *Flow Cytometry ; Aged ; *T-Lymphocyte Subsets/immunology ; Adult ; }, abstract = {Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS) and is often assessed through biological samples. Due to the easier access, peripheral blood is more commonly phenotyped instead of cerebrospinal fluid (CSF) or affected tissues in ALS. Here, using flow cytometry, we compared the composition of T cell subsets in blood and CSF in ALS patients. We found consistent but weak correlations between blood and CSF for all T cell subsets examined. This finding implies that blood and CSF offer complementary information when characterizing T cell immunity in ALS and blood may not be used as a surrogate for CSF.}, } @article {pmid38853167, year = {2024}, author = {Öijerstedt, L and Foucher, J and Lovik, A and Yazdani, S and Juto, A and Kläppe, U and Fang, F and Ingre, C}, title = {Repeated cognitive assessments show stable function over time in patients with ALS.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5267-5274}, pmid = {38853167}, issn = {1432-1459}, support = {SLS-986189//Svenska Läkaresällskapet/ ; 2023-02428//Vetenskapsrådet/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Male ; Female ; Middle Aged ; Aged ; *Cognitive Dysfunction/etiology/physiopathology/diagnosis ; Longitudinal Studies ; *Neuropsychological Tests ; Disease Progression ; Executive Function/physiology ; Sweden/epidemiology ; Follow-Up Studies ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multisystem disorder with not only motor symptoms but also extra-motor features including cognitive impairment. The most common cognitive profile observed in patients with ALS includes deficits in executive function, language, and social cognition. However, longitudinal studies on cognitive changes over time in ALS are sparse. We aimed to investigate the presence and nature of cognitive impairment at the time of ALS diagnosis and its association with survival as well as explore longitudinal cognitive change.

METHOD: Patients (n = 216) were recruited at the Karolinska University Hospital in Stockholm, Sweden. Follow-up visits (n = 307 in total) were performed every 6 months. Cognitive impairment was assessed using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and/or Montreal Cognitive Assessment (MoCA).

RESULTS: Cognitive impairment was observed in 38% of the patients at the time of ALS diagnosis, and the majority of these patients had deficits in executive function and/or language. Patients with cognitive impairment at the time of diagnosis had a more rapid decline in ALSFRS-R at 12- and 18-months follow-up, and a shorter survival. Cognitive function was stable during the first 2 years after diagnosis, and did not follow the trajectories of decline in motor functions.

CONCLUSION: Cognitive impairment in ALS was associated with a faster decline of motor functions, and shorter survival. However, cognitive function did not deteriorate over time. Cognitive assessment is essential for the patients and caregivers to understand the phenotypic expression of ALS.}, } @article {pmid38853763, year = {2024}, author = {Maranzano, A and Verde, F and Dubini, A and Torre, S and Colombo, E and Doretti, A and Gentile, F and Manini, A and Milone, I and Brusati, A and Peverelli, S and Santangelo, S and Spinelli, EG and Torresani, E and Gentilini, D and Messina, S and Morelli, C and Poletti, B and Agosta, F and Ratti, A and Filippi, M and Silani, V and Ticozzi, N}, title = {Association of APOE genotype and cerebrospinal fluid Aβ and tau biomarkers with cognitive and motor phenotype in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {9}, pages = {e16374}, pmid = {38853763}, issn = {1468-1331}, support = {RF-2021-12374238//Ministry of Health/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/genetics ; *Apolipoproteins E/genetics/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Cognition Disorders/cerebrospinal fluid/genetics/etiology ; Genotype ; Peptide Fragments/cerebrospinal fluid ; *Phenotype ; *tau Proteins/cerebrospinal fluid ; }, abstract = {OBJECTIVE: Little is known about amyotrophic lateral sclerosis (ALS)-nonspecific cognitive deficits - most notably memory disturbance - and their biological underpinnings. We investigated the associations of the Alzheimer's disease (AD) genetic risk factor APOE and cerebrospinal fluid (CSF) biomarkers Aβ and tau proteins with cognitive and motor phenotype in ALS.

METHODS: APOE haplotype was determined in 281 ALS patients; for 105 of these, CSF levels of Aβ42, Aβ40, total tau (T-tau), and phosphorylated tau (P-tau181) were quantified by chemiluminescence enzyme immunoassay (CLEIA). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was employed to evaluate the neuropsychological phenotype.

RESULTS: APOE-E4 allele was associated with worse ECAS memory score (median, 14.0 in carriers vs. 16.0 in non-carriers) and lower CSF Aβ42 (-0.8 vs. 0.1, log-transformed values) and Aβ42/40 ratio (-0.1 vs. 0.3). Some 37.1% of ALS patients showed low Aβ42 levels, possibly reflecting cerebral Aβ deposition. While lower Aβ42/40 correlated with lower memory score (β = 0.20), Aβ42 positively correlated with both ALS-specific (β = 0.24) and ALS-nonspecific (β = 0.24) scores. Although Aβ42/40 negatively correlated with T-tau (β = -0.29) and P-tau181 (β = -0.33), we found an unexpected positive association of Aβ42 and Aβ40 with both tau proteins. Regarding motor phenotype, lower levels of Aβ species were associated with lower motor neuron (LMN) signs (Aβ40: β = 0.34; Aβ42: β = 0.22).

CONCLUSIONS: APOE haplotype and CSF Aβ biomarkers are associated with cognitive deficits in ALS and particularly with memory impairment. This might partly reflect AD-like pathophysiological processes, but additional ALS-specific mechanisms could be involved.}, } @article {pmid38853922, year = {2024}, author = {Dilliott, AA and Costanzo, MC and Bandres-Ciga, S and Blauwendraat, C and Casey, B and Hoang, Q and Iwaki, H and Jang, D and Kim, JJ and Leonard, HL and Levine, KS and Makarious, M and Nguyen, TT and Rouleau, GA and Singleton, AB and Smadbeck, P and Solle, J and Vitale, D and Nalls, MA and Flannick, J and Burtt, NP and Farhan, SMK}, title = {The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38853922}, abstract = {Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.}, } @article {pmid38853969, year = {2024}, author = {Bingham, IN and Norel, R and Roitberg, EG and Peller, J and Trevisan, MA and Agurto, C and Shalom, DE and Aguirre, F and Embon, I and Taitz, A and Harris, D and Wright, A and Seaver, K and Sullivan, S and Green, JR and Ostrow, LW and Fraenkel, E and Berry, JD}, title = {Listener effort quantifies clinically meaningful progression of dysarthria in people living with amyotrophic lateral sclerosis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38853969}, support = {K24 DC016312/DC/NIDCD NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disease that causes progressive muscle weakness. Progressive bulbar dysfunction causes dysarthria and thus social isolation, reducing quality of life. The Everything ALS Speech Study obtained longitudinal clinical information and speech recordings from 292 participants. In a subset of 120 participants, we measured speaking rate (SR) and listener effort (LE), a measure of dysarthria severity rated by speech pathologists from recordings. LE intra- and inter-rater reliability was very high (ICC 0.88 to 0.92). LE correlated with other measures of dysarthria at baseline. LE changed over time in participants with ALS (slope 0.77 pts/month; p<0.001) but not controls (slope 0.005 pts/month; p=0.807). The slope of LE progression was similar in all participants with ALS who had bulbar dysfunction at baseline, regardless of ALS site of onset. LE could be a remotely collected clinically meaningful clinical outcome assessment for ALS clinical trials.}, } @article {pmid38854008, year = {2024}, author = {Rifai, OM and Waldron, FM and O'Shaughnessy, J and Read, FL and Gilodi, M and Pastore, A and Shneider, N and Tartaglia, GG and Zacco, E and Spence, H and Gregory, JM}, title = {Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38854008}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 NS127186/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Cognitive and behavioural symptoms associated with amyotrophic lateral sclerosis and frontotemporal spectrum disorders (ALSFTSD) are thought to be driven, at least in part, by the pathological accumulation of TDP-43.

METHODS: Here we examine post-mortem tissue from six brain regions associated with cognitive and behavioural symptoms in a cohort of 30 people with sporadic ALS (sALS), a proportion of which underwent standardized neuropsychological behavioural assessment as part of the Edinburgh Cognitive ALS Screen (ECAS).

RESULTS: Overall, the behavioural screen performed as part of the ECAS predicted accumulation of pathological phosphorylated TDP-43 (pTDP-43) with 100% specificity and 86% sensitivity in behaviour-associated brain regions. Notably, of these regions, pathology in the amygdala was the most predictive correlate of behavioural dysfunction in sALS. In the amygdala of sALS patients, we show variation in morphology, cell type predominance, and severity of pTDP-43 pathology. Further, we demonstrate that the presence and severity of intra-neuronal pTDP-43 pathology, but not astroglial pathology, or phosphorylated Tau pathology, is associated with behavioural dysfunction. Cases were also evaluated using a TDP-43 aptamer (TDP-43[APT]), which revealed that pathology was not only associated with behavioural symptoms, but also with ferritin levels, a measure of brain iron.

CONCLUSIONS: Intra-neuronal pTDP-43 and cytoplasmic TDP-43[APT] pathology in the amygdala is associated with behavioural symptoms in sALS. TDP-43[APT] staining intensity is also associated with increased ferritin, regardless of behavioural phenotype, suggesting that ferritin increases may occur upstream of clinical manifestation, in line with early TDP-43[APT] pathology, representing a potential region-specific imaging biomarker of early disease in ALS.}, } @article {pmid38855322, year = {2024}, author = {Tsekrekou, M and Giannakou, M and Papanikolopoulou, K and Skretas, G}, title = {Protein aggregation and therapeutic strategies in SOD1- and TDP-43- linked ALS.}, journal = {Frontiers in molecular biosciences}, volume = {11}, number = {}, pages = {1383453}, pmid = {38855322}, issn = {2296-889X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with severe socio-economic impact. A hallmark of ALS pathology is the presence of aberrant cytoplasmic inclusions composed of misfolded and aggregated proteins, including both wild-type and mutant forms. This review highlights the critical role of misfolded protein species in ALS pathogenesis, particularly focusing on Cu/Zn superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP-43), and emphasizes the urgent need for innovative therapeutic strategies targeting these misfolded proteins directly. Despite significant advancements in understanding ALS mechanisms, the disease remains incurable, with current treatments offering limited clinical benefits. Through a comprehensive analysis, the review focuses on the direct modulation of the misfolded proteins and presents recent discoveries in small molecules and peptides that inhibit SOD1 and TDP-43 aggregation, underscoring their potential as effective treatments to modify disease progression and improve clinical outcomes.}, } @article {pmid38855716, year = {2024}, author = {Morganroth, J and Bardakjian, TM and Dratch, L and Quinn, CC and Elman, LB}, title = {Enhancing Clinical Infrastructure for the Delivery of Intrathecal and Genetic Therapies: A Qalsody (Tofersen) Model for Patients With SOD1-ALS.}, journal = {Neurology. Clinical practice}, volume = {14}, number = {4}, pages = {e200303}, pmid = {38855716}, issn = {2163-0402}, abstract = {BACKGROUND: Qalsody (tofersen), an intrathecal therapy (IT) antisense oligonucleotide (ASO), was granted accelerated approval by the Food and Drug Administration for the treatment of SOD1-mediated amyotrophic lateral sclerosis (ALS) on April 25, 2023. Academic centers need to be prepared for expedited drug delivery. The purpose of this model was to predict the number of SOD1-ALS patients whom we expect to see at our center at the time of Qalsody approval and to use it to extrapolate to a model for a hypothetical sporadic IT ALS therapy.

RECENT FINDINGS: We predicted that 6 symptomatic and 14 presymptomatic SOD1 patients would come to our center, whereas a sporadic therapy would generate 108 patients, creating excess office visits, lumbar punctures, and genetic counseling visits.

IMPLICATIONS FOR PRACTICE: As new therapies for neurologic diseases come to market, preparing for increased office volume and complex drug delivery are essential for optimal care.}, } @article {pmid38856793, year = {2025}, author = {Kumari, S and Kamiya, A and Karnik, SS and Rohilla, S and Dubey, SK and Taliyan, R}, title = {Novel Gene Therapy Approaches for Targeting Neurodegenerative Disorders: Focusing on Delivering Neurotrophic Genes.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {386-411}, pmid = {38856793}, issn = {1559-1182}, mesh = {Humans ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics ; Animals ; *Nerve Growth Factors/genetics ; Gene Transfer Techniques ; Genetic Vectors ; }, abstract = {Neurodegenerative illnesses (NDDs) like Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, spinal muscular atrophy, and Huntington's disease have demonstrated considerable potential for gene therapy as a viable therapeutic intervention. NDDs are marked by the decline of neurons, resulting in changes in both behavior and pathology within the body. Strikingly, only symptomatic management is available without a cure for the NDDs. There is an unmet need for a permanent therapeutic approach. Many studies have been going on to target the newer therapeutic molecular targets for NDDs including gene-based therapy. Gene therapy has the potential to provide therapeutic benefits to a large number of patients with NDDs by offering mechanisms including neuroprotection, neuro-restoration, and rectification of pathogenic pathways. Gene therapy is a medical approach that aims to modify the biological characteristics of living cells by controlling the expression of specific genes in certain neurological disorders. Despite being the most complex and well-protected organ in the human body, there is clinical evidence to show that it is possible to specifically target the central nervous system (CNS). This provides hope for the prospective application of gene therapy in treating NDDs in the future. There are several advanced techniques available for using viral or non-viral vectors to deliver the therapeutic gene to the afflicted region. Neurotrophic factors (NTF) in the brain are crucial for the development, differentiation, and survival of neurons in the CNS, making them important in the context of various neurological illnesses. Gene delivery of NTF has the potential to be used as a therapeutic approach for the treatment of neurological problems in the brain. This review primarily focuses on the methodologies employed for delivering the genes of different NTFs to treat neurological disorders. These techniques are currently being explored as a viable therapeutic approach for neurodegenerative diseases. The article exclusively addresses gene delivery approaches and does not cover additional therapy strategies for NDDs. Gene therapy offers a promising alternative treatment for NDDs by stimulating neuronal growth instead of solely relying on symptom relief from drugs and their associated adverse effects. It can serve as a long-lasting and advantageous treatment choice for the management of NDDs. The likelihood of developing NDDs increases with age as a result of neuronal degradation in the brain. Gene therapy is an optimal approach for promoting neuronal growth through the introduction of nerve growth factor genes.}, } @article {pmid38856805, year = {2024}, author = {Zhang, Z and He, X and Cui, J and Wang, J and Shi, B}, title = {Translation and reliability and validity of the Chinese version of Amyotrophic Lateral Sclerosis-Specific Quality of Life-Short Form.}, journal = {Journal of patient-reported outcomes}, volume = {8}, number = {1}, pages = {57}, pmid = {38856805}, issn = {2509-8020}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; *Quality of Life/psychology ; Male ; Female ; Middle Aged ; Reproducibility of Results ; Cross-Sectional Studies ; China ; Surveys and Questionnaires ; Adult ; *Psychometrics/methods/instrumentation ; Translations ; Aged ; Translating ; }, abstract = {OBJECTIVE: To translate Amyotrophic Lateral Sclerosis-Specific Quality of Life-Short Form (ALSSQOL-SF) and test its reliability and validity, so that explore feasibility in Chinese mainland and make up the gap of specific tools for measuring quality of life of patients with ALS.

METHODS: This was a cross-sectional design. The Brislin translation model was used to translate ALSSQOL-SF, and the Chinese version of ALSSQOL-SF (C-ALSSQOL-SF) was revised through cultural adaptation and pre-test. The convenience sampling method was used to investigate 138 patients with ALS in Tianjin to test the reliability and validity of the C-ALSSQOL-SF.

RESULTS: The C-ALSSQOL-SF included 20 items, covering 6 dimensions: physical symptoms, bulbar function, negative emotion, interaction with people and the environment, religiosity and intimacy. The scale-level content validity index (S-CVI) of C-ALSSQOL-SF was 0.964, and the item-level content validity index (I-CVI) was between 0.857 to 1.000. The results of Confirmatory Factor Analysis (CFA) showed that CMIN/DF = 1.161, RMSEA = 0.034, GFI = 0.892, IFI = 0.976, TLI = 0.969, CFI = 0.975, and the 6-factor model fitted well. The scores of C-ALSSQOL-SF and WHOQOL-BREF were positively correlated (r = 0.745). The Cronbach's α coefficient of the scale was 0.85, the Cronbach's α coefficient of each dimension was between 0.59 to 0.86, and the split-half reliability was 0.78.

CONCLUSION: The Chinese version of ALSSQOL-SF has good reliability and validity, and can be used as a tool to evaluate the quality of life of patients with ALS in Chinese mainland.}, } @article {pmid38856890, year = {2024}, author = {Tripathi, S and Bhawana, }, title = {Epigenetic Orchestration of Neurodegenerative Disorders: A Possible Target for Curcumin as a Therapeutic.}, journal = {Neurochemical research}, volume = {49}, number = {9}, pages = {2319-2335}, pmid = {38856890}, issn = {1573-6903}, mesh = {*Curcumin/therapeutic use/pharmacology ; Humans ; *Epigenesis, Genetic/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism/genetics ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; Mitochondria/metabolism/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Epigenetic modulations play a major role in gene expression and thus are responsible for various physiological changes including age-associated neurological disorders. Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), although symptomatically different, may share common underlying mechanisms. Most neurodegenerative diseases are associated with increased oxidative stress, aggregation of certain proteins, mitochondrial dysfunction, inactivation/dysregulation of protein degradation machinery, DNA damage and cell excitotoxicity. Epigenetic modulations has been reported to play a significant role in onset and progression of neurodegenerative diseases by regulating these processes. Previous studies have highlighted the marked antioxidant and neuroprotective abilities of polyphenols such as curcumin, by increased activity of detoxification systems like superoxide dismutase (SOD), catalase or glutathione peroxidase. The role of curcumin as an epigenetic modulator in neurological disorders and neuroinflammation apart from other chronic diseases have also been reported by a few groups. Nonetheless, the evidences for the role of curcumin mediated epigenetic modulation in its neuroprotective ability are still limited. This review summarizes the current knowledge of the role of mitochondrial dysfunction, epigenetic modulations and mitoepigenetics in age-associated neurological disorders such as PD, AD, HD, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and describes the neuroprotective effects of curcumin in the treatment and/or prevention of these neurodegenerative diseases by regulation of the epigenetic machinery.}, } @article {pmid38857767, year = {2024}, author = {Bass, J and Hill, H and Jaworsky, C}, title = {Response to Hartman et al in reply to Bass et al's "Significant discordance in DermTech test results when paired with histopathology: Caveat emptor".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e103}, doi = {10.1016/j.jaad.2024.06.003}, pmid = {38857767}, issn = {1097-6787}, mesh = {Humans ; *Dermoscopy ; Skin Neoplasms/pathology ; }, } @article {pmid38859579, year = {2024}, author = {Meyer, T and Dreger, M and Grehl, T and Weyen, U and Kettemann, D and Weydt, P and Günther, R and Lingor, P and Petri, S and Koch, JC and Großkreutz, J and Rödiger, A and Baum, P and Hermann, A and Prudlo, J and Boentert, M and Weishaupt, JH and Löscher, WN and Dorst, J and Koc, Y and Bernsen, S and Cordts, I and Vidovic, M and Steinbach, R and Metelmann, M and Kleinveld, VE and Norden, J and Ludolph, A and Walter, B and Schumann, P and Münch, C and Körtvélyessy, P and Maier, A}, title = {Serum neurofilament light chain in distinct phenotypes of amyotrophic lateral sclerosis: A longitudinal, multicenter study.}, journal = {European journal of neurology}, volume = {31}, number = {9}, pages = {e16379}, pmid = {38859579}, issn = {1468-1331}, support = {//Bosis Canessa ALS Stiftung, Düsseldorf, Germany/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood ; *Neurofilament Proteins/blood ; Male ; Female ; Middle Aged ; *Phenotype ; Aged ; Longitudinal Studies ; Disease Progression ; Biomarkers/blood ; Adult ; Germany/epidemiology ; }, abstract = {OBJECTIVE: To assess the performance of serum neurofilament light chain (sNfL) in clinical phenotypes of amyotrophic lateral sclerosis (ALS).

METHODS: In 2949 ALS patients at 16 ALS centers in Germany and Austria, clinical characteristics and sNfL were assessed. Phenotypes were differentiated for two anatomical determinants: (1) upper and/or lower motor involvement (typical, typMN; upper/lower motor neuron predominant, UMNp/LMNp; primary lateral sclerosis, PLS) and (2) region of onset and propagation of motor neuron dysfunction (bulbar, limb, flail-arm, flail-leg, thoracic onset). Phenotypes were correlated to sNfL, progression, and survival.

RESULTS: Mean sNfL was - compared to typMN (75.7 pg/mL, n = 1791) - significantly lower in LMNp (45.1 pg/mL, n = 413), UMNp (58.7 pg/mL n = 206), and PLS (37.6 pg/mL, n = 84). Also, sNfL significantly differed in the bulbar (92.7 pg/mL, n = 669), limb (64.1 pg/mL, n = 1305), flail-arm (46.4 pg/mL, n = 283), flail-leg (53.6 pg/mL, n = 141), and thoracic (74.5 pg/mL, n = 96) phenotypes. Binary logistic regression analysis showed highest contribution to sNfL elevation for faster progression (odds ratio [OR] 3.24) and for the bulbar onset phenotype (OR 1.94). In contrast, PLS (OR 0.20), LMNp (OR 0.45), and thoracic onset (OR 0.43) showed reduced contributions to sNfL. Longitudinal sNfL (median 12 months, n = 2862) showed minor monthly changes (<0.2%) across all phenotypes. Correlation of sNfL with survival was confirmed (p < 0.001).

CONCLUSIONS: This study underscored the correlation of ALS phenotypes - differentiated for motor neuron involvement and region of onset/propagation - with sNfL, progression, and survival. These phenotypes demonstrated a significant effect on sNfL and should be recognized as independent confounders of sNfL analyses in ALS trials and clinical practice.}, } @article {pmid38859699, year = {2024}, author = {Finsterer, J and Strobl, W}, title = {Gastrointestinal involvement in neuromuscular disorders.}, journal = {Journal of gastroenterology and hepatology}, volume = {39}, number = {10}, pages = {1982-1993}, doi = {10.1111/jgh.16650}, pmid = {38859699}, issn = {1440-1746}, mesh = {Humans ; *Neuromuscular Diseases/complications/etiology ; *Gastrointestinal Diseases/etiology/therapy/diagnosis ; Myotonic Dystrophy/complications/diagnosis/physiopathology ; Mitochondrial Diseases/complications ; }, abstract = {Although not often discussed, many of the neuromuscular disorders (NMDs) affect the gastrointestinal tract (GIT). Depending on the type of NMD, the prevalence of GIT involvement ranges from <5% (e.g. hereditary neuropathies, myofibrillar myopathies) to 100% (e.g. MNGIE, OPMD). Particularly in NMDs with multisystem affection, involvement of the GIT can dominate the clinical presentation or at least make up a significant part of the clinical picture. The most prominent representatives of NMDs with multisystem involvement are the mitochondrial disorders (MIDs) and the myotonic dystrophies. The best known syndromic MIDs with GIT involvement are MNGIE, MELAS, Leigh, and Pearson syndromes. Among neuropathies, GIT involvement is most commonly found in ALS and GBS. GIT involvement may also be a feature of myasthenia. The clinical manifestations of GIT involvement are diverse and can affect the entire GIT, from the teeth to the rectum, including the liver and pancreas. The most well-known clinical manifestations of GIT involvement are dysphagia, nausea, vomiting, reflux, hollow organ dysmotility, hepatopathy, diabetes, diarrhea, constipation, and fecal incontinence. Even if treatment can usually only be symptomatic, the therapeutic options are diverse, are often effective, and can significantly and beneficially influence the course of the underlying NMD.}, } @article {pmid38860134, year = {2024}, author = {Levison, LS and Jepsen, P and Andersen, H}, title = {Registration of Amyotrophic Lateral Sclerosis: Validity in the Danish National Patient Registry.}, journal = {Clinical epidemiology}, volume = {16}, number = {}, pages = {409-415}, pmid = {38860134}, issn = {1179-1349}, abstract = {PURPOSE: Health care databases are a valuable source for epidemiological research on amyotrophic lateral sclerosis (ALS) if diagnosis codes are valid. We evaluated the validity of the diagnostic codes for ALS in the Danish National Patient Registry (DNPR).

PATIENTS AND METHODS: We obtained data from the DNPR for all adult (>17 years) patients registered with ALS in Denmark between 1987 and 2022 (median population of 4.2 million during the study period). We randomly selected adult patients living in the North Denmark Region and Central Denmark Region (median population 1.4 million), with a primary discharge diagnosis code of ALS, diagnosed at three departments of neurology. We retrieved and reviewed medical records and estimated the positive predictive value (PPV) of the ALS diagnosis.

RESULTS: Over 36 years, we identified 5679 patients. From the validation cohort of 300 patients, we were able to retrieve 240 (80%) medical records, and 215 ALS diagnoses were confirmed. The overall positive predictive value was 89.6% (95% confidence interval (CI): 85.1-92.8). The highest PPV was achieved for diagnoses registered for patients aged ≥70 years (93.8; 95% CI: 86.2-97.3) compared to patients <60 years (83.4; 95% CI: 73.3-90.7).

CONCLUSION: We found a high PPV of primary diagnostic codes for ALS from Danish departments of neurology, demonstrating high validity. Thus, the DNPR is a well-suited data source for large-scale epidemiological research on ALS.}, } @article {pmid38860430, year = {2024}, author = {Geng, Y and Liu, C and Xu, N and Suen, MC and Miao, H and Xie, Y and Zhang, B and Chen, X and Song, Y and Wang, Z and Cai, Q and Zhu, G}, title = {Crystal structure of a tetrameric RNA G-quadruplex formed by hexanucleotide repeat expansions of C9orf72 in ALS/FTD.}, journal = {Nucleic acids research}, volume = {52}, number = {13}, pages = {7961-7970}, pmid = {38860430}, issn = {1362-4962}, support = {32071188//National Scientific Foundation of China/ ; 16101120//Research Grants Council of the Hong Kong Special Administrative Region/ ; 3502Z20214001//Hong Kong University of Science and Technology/ ; 2021A1515220104//Guangdong Basic and Applied Basic Research Foundation/ ; }, mesh = {*C9orf72 Protein/genetics/chemistry ; *G-Quadruplexes ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; Humans ; *RNA/chemistry/genetics ; *DNA Repeat Expansion/genetics ; Crystallography, X-Ray ; Models, Molecular ; }, abstract = {The abnormal GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause the fatal neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal dementia. The transcribed RNA HREs, short for r(G4C2)n, can form toxic RNA foci which sequestrate RNA binding proteins and impair RNA processing, ultimately leading to neurodegeneration. Here, we determined the crystal structure of r(G4C2)2, which folds into a parallel tetrameric G-quadruplex composed of two four-layer dimeric G-quadruplex via 5'-to-5' stacking in coordination with a K+ ion. Notably, the two C bases locate at 3'- end stack on the outer G-tetrad with the assistance of two additional K+ ions. The high-resolution structure reported here lays a foundation in understanding the mechanism of neurological toxicity of RNA HREs. Furthermore, the atomic details provide a structural basis for the development of potential therapeutic agents against the fatal neurodegenerative diseases ALS/FTD.}, } @article {pmid38860943, year = {2024}, author = {Zhang, Y and Xia, Y and Sun, J}, title = {Probiotics and microbial metabolites maintain barrier and neuromuscular functions and clean protein aggregation to delay disease progression in TDP43 mutation mice.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2363880}, pmid = {38860943}, issn = {1949-0984}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK105118/DK/NIDDK NIH HHS/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy ; Blood-Brain Barrier/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Disease Progression ; *DNA-Binding Proteins/metabolism/genetics ; *Gastrointestinal Microbiome ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Neuroglia/metabolism ; *Probiotics/administration & dosage/pharmacology ; Spinal Cord/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. The ALS mice expressing human mutant of transactive response DNA binding protein of 43 kDa (hmTDP43) showed intestinal dysfunction before neuromuscular symptoms. We hypothesize that restoring the intestinal and microbial homeostasis with a bacterial metabolite or probiotics delays the ALS disease onset. We investigate the pathophysiological changes in the intestine and neurons, intestinal and blood-brain barriers, and inflammation during the ALS progression. We then cultured enteric glial cells (EGCs) isolated from TDP43 mice for mechanistic studies. TDP43 mice had significantly decreased intestinal mobility, increased permeability, and weakened muscle, compared with the age-matched wild-type mice. We observed increased hmTDP43 and Glial fibrillary acidic protein (GFAP), and decreased expression of α-smooth muscle actin (α-SMA), tight junction proteins (ZO-1 and Claudin-5) in the colon, spinal cord, and brain in TDP43 mice. TDP43 mice had reduced Butyryl-coenzyme A CoA transferase, decreased butyrate-producing bacteria Butyrivibrio fibrisolvens, and increased Bacteroides fragilis, compared to the WT mice. Serum inflammation cytokines (IL-6, IL-17, and IFN-γ) and LPS were elevated in TDP43 mice. EGCs from TDP43 mice showed aggregation of hmTDP43 associated with increased GFAP and ionized calcium-binding adaptor molecule (IBA1, a microglia marker). TDP43 mice treated with butyrate or probiotic VSL#3 had significantly increased rotarod time, increased intestinal mobility and decreased permeability, compared to the untreated group. Butyrate or probiotics treatment decreased the expression of GFAP, TDP43, and increased α-SMA, ZO-1, and Claudin-5 in the colon, spinal cord, and brain. Also, butyrate or probiotics treatment enhanced the Butyryl-coenzyme A CoA transferase, Butyrivibrio fibrisolvens, and reduced inflammatory cytokines in TDP43 mice. The TDP43 EGCs treated with butyrate or probiotics showed reduced GFAP, IBA1, and TDP43 aggregation. Restoring the intestinal and microbial homeostasis by beneficial bacteria and metabolites provide a potential therapeutic strategy to treat ALS.}, } @article {pmid38861034, year = {2024}, author = {Lehto, A and Schumacher, J and Kasper, E and Teipel, S and Hermann, A and Kurth, J and Krause, BJ and Prudlo, J}, title = {Cerebral glucose metabolic correlates of cognitive and behavioural impairments in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5290-5300}, pmid = {38861034}, issn = {1432-1459}, support = {13GW0482D//Bundesministerium für Bildung und Forschung/Verein Deutscher Ingenieure/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; Male ; Female ; Middle Aged ; *Positron-Emission Tomography ; *Fluorodeoxyglucose F18/metabolism ; Aged ; *Glucose/metabolism ; *Neuropsychological Tests ; Magnetic Resonance Imaging ; Cognition Disorders/diagnostic imaging/metabolism/etiology ; Mental Disorders/metabolism/diagnostic imaging ; Brain/diagnostic imaging/metabolism ; Cerebral Cortex/diagnostic imaging/metabolism ; }, abstract = {OBJECTIVE: Half of ALS patients are cognitively and/or behaviourally impaired. As cognition/behaviour and cerebral glucose metabolism can be correlated by means of [18]F-Fluorodeoxyglucose positron emission tomography (FDG-PET), we aimed to utilise FDG-PET, first, to replicate group-level differences in glucose metabolism between non-demented ALS patients separated into non-impaired (ALSni), cognitively impaired (ALSci), behaviourally impaired (ALSbi), and cognitively and behaviourally impaired (ALScbi) groups; second, to investigate glucose metabolism and performance in various cognitive domains; and third, to examine the impact of partial volume effects correction (PVEC) of the FDG-PET data on the results.

METHODS: We analysed neuropsychological, clinical, and imaging data from 67 ALS patients (30 ALSni, 21 ALSci, 5 ALSbi, and 11 ALScbi). Cognition was assessed with the Edinburgh Cognitive and Behavioural ALS Screen, and two social cognition tests. FDG-PET and structural MRI scans were acquired for each patient. Voxel-based statistical analyses were undertaken on grey matter volume (GMV) and non-corrected vs. PVE-corrected FDG-PET scans.

RESULTS: ALSci and ALScbi had lower cognitive scores than ALSni. In contrast to both ALSni and ALSci, ALScbi showed widespread hypometabolism in the superior- and middle-frontal gyri in addition to the right temporal pole. Correlations were observed between the GMV, the FDG-PET signal, and various cognitive scores. The FDG-PET results were largely unaffected by PVEC.

INTERPRETATION: Our study identified widespread differences in hypometabolism in the ALScbi-ni but not in the ALSci-ni group comparison, raising the possibility that cerebral metabolism may be more closely related to the presence of behavioural changes than to mild cognitive deficits.}, } @article {pmid38861223, year = {2024}, author = {Parakh, S and Perri, ER and Vidal, M and Takalloo, Z and Jagaraj, CJ and Mehta, P and Yang, S and Thomas, CJ and Blair, IP and Hong, Y and Atkin, JD}, title = {Protein Disulfide Isomerase Endoplasmic Reticulum Protein 57 (ERp57) is Protective Against ALS-Associated Mutant TDP-43 in Neuronal Cells.}, journal = {Neuromolecular medicine}, volume = {26}, number = {1}, pages = {23}, pmid = {38861223}, issn = {1559-1174}, mesh = {*Protein Disulfide-Isomerases/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Humans ; *Inclusion Bodies/metabolism/genetics ; Animals ; Mice ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Neurons/metabolism/drug effects ; Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease affecting motor neurons. Pathological forms of Tar-DNA binding protein-43 (TDP-43), involving its mislocalisation to the cytoplasm and the formation of misfolded inclusions, are present in almost all ALS cases (97%), and ~ 50% cases of the related condition, frontotemporal dementia (FTD), highlighting its importance in neurodegeneration. Previous studies have shown that endoplasmic reticulum protein 57 (ERp57), a member of the protein disulphide isomerase (PDI) family of redox chaperones, is protective against ALS-linked mutant superoxide dismutase (SOD1) in neuronal cells and transgenic SOD1[G93A] mouse models. However, it remains unclear whether ERp57 is protective against pathological TDP-43 in ALS. Here, we demonstrate that ERp57 is protective against key features of TDP-43 pathology in neuronal cells. ERp57 inhibited the mislocalisation of TDP-43[M337V] from the nucleus to the cytoplasm. In addition, ERp57 inhibited the number of inclusions formed by ALS-associated variant TDP-43[M337V] and reduced the size of these inclusions. ERp57 was also protective against ER stress and induction of apoptosis. Furthermore, ERp57 modulated the steady-state expression levels of TDP-43. This study therefore demonstrates a novel mechanism of action of ERp57 in ALS. It also implies that ERp57 may have potential as a novel therapeutic target to prevent the TDP-43 pathology associated with neurodegeneration.}, } @article {pmid38862967, year = {2024}, author = {Vazquez-Sanchez, S and Tilkin, B and Gasset-Rosa, F and Zhang, S and Piol, D and McAlonis-Downes, M and Artates, J and Govea-Perez, N and Verresen, Y and Guo, L and Cleveland, DW and Shorter, J and Da Cruz, S}, title = {Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {46}, pmid = {38862967}, issn = {1750-1326}, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Brain/metabolism/pathology ; Disease Models, Animal ; *Disease Progression ; *Frontotemporal Dementia/pathology/metabolism/genetics ; *Mice, Transgenic ; Protein Aggregation, Pathological/metabolism ; *RNA-Binding Protein FUS/metabolism/genetics ; }, abstract = {RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.}, } @article {pmid38863235, year = {2024}, author = {Priyanka, and Raymandal, B and Mondal, S}, title = {Native State Stabilization of Amyloidogenic Proteins by Kinetic Stabilizers: Inhibition of Protein Aggregation and Clinical Relevance.}, journal = {ChemMedChem}, volume = {19}, number = {19}, pages = {e202400244}, doi = {10.1002/cmdc.202400244}, pmid = {38863235}, issn = {1860-7187}, support = {SRG/2023/000434//Science and Engineering Research Board, India/ ; }, mesh = {Humans ; Kinetics ; *Amyloidogenic Proteins/metabolism/antagonists & inhibitors/chemistry ; Protein Aggregates/drug effects ; Superoxide Dismutase-1/metabolism/chemistry/antagonists & inhibitors ; Prealbumin/metabolism/chemistry/antagonists & inhibitors ; Amyloidosis/drug therapy/metabolism ; Clinical Relevance ; }, abstract = {Proteinopathies or amyloidoses are a group of life-threatening disorders that result from misfolding of proteins and aggregation into toxic insoluble amyloid aggregates. Amyloid aggregates have low clearance from the body due to the insoluble nature, leading to their deposition in various organs and consequent organ dysfunction. While amyloid deposition in the central nervous system leads to neurodegenerative diseases that mostly cause dementia and difficulty in movement, several other organs, including heart, liver and kidney are also affected by systemic amyloidoses. Regardless of the site of amyloid deposition, misfolding and structural alteration of the precursor proteins play the central role in amyloid formation. Kinetic stabilizers are an emerging class of drugs, which act like pharmacological chaperones to stabilize the native state structure of amyloidogenic proteins and to increase the activation energy barrier that is required for adopting a misfolded structure or conformation, ultimately leading to the inhibition of protein aggregation. In this review, we discuss the kinetic stabilizers that stabilize the native quaternary structure of transthyretin, immunoglobulin light chain and superoxide dismutase 1 that cause transthyretin amyloidoses, light chain amyloidosis and familial amyotrophic lateral sclerosis, respectively.}, } @article {pmid38864944, year = {2024}, author = {Wang, LY and Zhang, L and Bai, XY and Qiang, RR and Zhang, N and Hu, QQ and Cheng, JZ and Yang, YL and Xiang, Y}, title = {The Role of Ferroptosis in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Neurochemical research}, volume = {49}, number = {10}, pages = {2653-2667}, pmid = {38864944}, issn = {1573-6903}, mesh = {*Ferroptosis/drug effects/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; Humans ; Animals ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Iron/metabolism ; Antioxidants/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a challenging treatment landscape, due to its complex pathogenesis and limited availability of clinical drugs. Ferroptosis, an iron-dependent form of programmed cell death (PCD), stands distinct from apoptosis, necrosis, autophagy, and other cell death mechanisms. Recent studies have increasingly highlighted the role of iron deposition, reactive oxygen species (ROS) accumulation, oxidative stress, as well as systemic Xc- and glutamate accumulation in the antioxidant system in the pathogenesis of amyotrophic lateral sclerosis. Therefore, targeting ferroptosis emerges as a promising strategy for amyotrophic lateral sclerosis treatment. This review introduces the regulatory mechanism of ferroptosis, the relationship between amyotrophic lateral sclerosis and ferroptosis, and the drugs used in the clinic, then discusses the current status of amyotrophic lateral sclerosis treatment, hoping to provide new directions and targets for its treatment.}, } @article {pmid38865034, year = {2024}, author = {Rashed, HR and Staff, NP and Milone, M and Mauermann, ML and Berini, S and Cheshire, WP and Coon, EA and Fealey, RD and Sorenson, E and Cutsforth-Gregory, J and Benarroch, EE and Sandroni, P and Low, PA and Singer, W and Shouman, K}, title = {Autonomic impairment in primary lateral sclerosis.}, journal = {Clinical autonomic research : official journal of the Clinical Autonomic Research Society}, volume = {34}, number = {4}, pages = {421-425}, pmid = {38865034}, issn = {1619-1560}, mesh = {Humans ; Male ; Middle Aged ; Female ; *Autonomic Nervous System Diseases/physiopathology/diagnosis/etiology ; Adult ; Retrospective Studies ; Aged ; Sweating/physiology ; Motor Neuron Disease/physiopathology/diagnosis/complications ; Autonomic Nervous System/physiopathology ; }, abstract = {PURPOSE: Prior studies reported evidence of autonomic involvement in motor neuron disease and suggested more severe dysfunction in upper motor neuron predominant syndromes. Hence, we sought to characterize autonomic impairment in primary lateral sclerosis.

METHODS: Neurological evaluations, thermoregulatory sweat tests, and autonomic reflex screens were analyzed retrospectively in 34 primary lateral sclerosis patients (28 definite and 6 probable). Patients with other potential causes of autonomic failure and patients with autonomic testing results compromised by artifact were excluded.

RESULTS: A total of 17 patients reported autonomic symptoms. Orthostatic lightheadedness was most frequent (8 patients), followed by bladder (7), bowel (5), and erectile dysfunction (3). The autonomic reflex screens of 33 patients were reviewed; 20 patients had abnormal studies. The thermoregulatory sweat tests of 19 patients were reviewed; 11 patients had abnormal studies. Composite Autonomic Severity Score was calculated for 33 patients and found abnormal in 20/33 patients (60.6%): 15/20 patients (75%) had mild impairment, and 5/20 patients (25%) had moderate impairment. The frequencies of testing abnormalities were: sudomotor 18/20 (90%), cardiovagal 9/20 (45%), and adrenergic 6/20 (30%). Sweat loss pattern analysis showed global, regional, and mixed patterns to be more common than length-dependent and distal patterns.

CONCLUSION: We found evidence of frequent autonomic dysfunction in primary lateral sclerosis, which is generally of modest severity akin to prior reports for amyotrophic lateral sclerosis, but more commonly in a pattern consistent with preganglionic/ganglionic localization. This suggests that primary lateral sclerosis, as with amyotrophic lateral sclerosis, is a multisystem disease that affects the autonomic nervous system.}, } @article {pmid38865943, year = {2024}, author = {Ipek, L and Güneş Gencer, GY}, title = {Is caregiver burden of patients with amyotrophic lateral sclerosis related to caregivers' mindfulness, quality of life, and patients' functional level.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {126}, number = {}, pages = {95-100}, doi = {10.1016/j.jocn.2024.06.007}, pmid = {38865943}, issn = {1532-2653}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/nursing/therapy ; Female ; *Quality of Life/psychology ; Male ; Middle Aged ; *Mindfulness ; *Caregiver Burden/psychology ; Adult ; Caregivers/psychology ; Aged ; Cost of Illness ; }, abstract = {BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the caregiver burden, mindfulness, and quality of life (QoL) of caregivers of ALS patients and the patient's functional level.

METHODS: This study was conducted with 57 ALS patients and their primary caregivers. The data were collected using the Zarit Burden Interview, Mindful Attention Awareness Scale (MAAS), the Short Form-36 (SF-36), and the ALS Functional Rating Scale (ALS-FRS).

RESULTS: The mean age of the caregivers was 49.7 ± 12 years; 66 % were female, and 73.7 % were spouses of the patients. Around 65 % of caregivers experienced a moderate to severe caregiver burden. A low and negative correlation was found between the caregiver burden and mindfulness of caregivers of ALS patients. As the mindfulness levels of the caregivers increased, the caregiver burden decreased, and the physical role difficulty score, one of the sub-dimensions of the QoL, increased. Also, caregivers' QoL decreased as caregiver burden increased (except physical function QoL, p < 0.05). Moreover, there was a positive correlation between the caregiver burden and ALSFRS-R scores (bulbar, motor, respiratory, and total) of the caregivers of ALS patients (p < 0.05).

DISCUSSION: Improved technology for managing ALS disease has increased patient life expectancy. However, caregivers may experience a high burden as the patient's functional level declines. Increasing caregiver mindfulness can help reduce the burden and improve their QoL.}, } @article {pmid38866783, year = {2024}, author = {Di Timoteo, G and Giuliani, A and Setti, A and Biagi, MC and Lisi, M and Santini, T and Grandioso, A and Mariani, D and Castagnetti, F and Perego, E and Zappone, S and Lattante, S and Sabatelli, M and Rotili, D and Vicidomini, G and Bozzoni, I}, title = {M[6]A reduction relieves FUS-associated ALS granules.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5033}, pmid = {38866783}, issn = {2041-1723}, support = {ERC-2019-SyG 855923-ASTRA//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; ERC-2018-CoG 818669-BrightEyes//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; AIRC IG 2019 Id. 23053//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; PRIN 2017 2017P352Z4//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; NextGenerationEU PNRR MUR//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; "National Center for Gene Therapy and Drugbased on RNA Technology" (CN00000041)//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; "National Center for Gene Therapy and Drug based on RNA Technology" (CN00000041)//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; NextGenerationEU PNRR MUR//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; "Sapienza" Ateneo Project 2021 n. RM12117A61C811CE//Sapienza Università di Roma (Sapienza University of Rome)/ ; Regione Lazio PROGETTI DI GRUPPI DI RICERCA 2020 - A0375-2020-36597//Regione Lazio (Region of Lazio)/ ; }, mesh = {*RNA-Binding Protein FUS/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Cytoplasmic Granules/metabolism ; Fibroblasts/metabolism ; Adenosine/metabolism/analogs & derivatives ; Methyltransferases/metabolism/genetics ; Mutation ; Inclusion Bodies/metabolism ; Stress Granules/metabolism ; Transcriptome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motoneurons (MN) degeneration. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by aggregation of mutant proteins, among which the RNA binding protein FUS. Here we show that, in neuronal cells and in iPSC-derived MN expressing mutant FUS, such inclusions are significantly reduced in number and dissolve faster when the RNA m[6]A content is diminished. Interestingly, stress granules formed in ALS conditions showed a distinctive transcriptome with respect to control cells, which reverted to similar to control after m[6]A downregulation. Notably, cells expressing mutant FUS were characterized by higher m[6]A levels suggesting a possible link between m[6]A homeostasis and pathological aggregates. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, an inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS.}, } @article {pmid38867220, year = {2024}, author = {Jia, Q and Song, Y and Zhang, C and Li, M and Feng, L and Sugimoto, K and Zhang, X and Liu, J and Gao, Y}, title = {Reasons and experience for patients with amyotrophic lateral sclerosis using traditional Chinese medicine: a CARE-TCM based mixed method study.}, journal = {BMC complementary medicine and therapies}, volume = {24}, number = {1}, pages = {231}, pmid = {38867220}, issn = {2662-7671}, support = {QN2021110001L//National Foreign Expert Project/ ; 2018, 12//Chinese Medicine Inheritance and Innovation Talent Project Leading Talent Support Program of National Traditional Chinese Medicine/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Medicine, Chinese Traditional/methods ; Female ; Male ; Middle Aged ; Surveys and Questionnaires ; Aged ; China ; Adult ; Quality of Life ; Qualitative Research ; }, abstract = {BACKGROUND AND AIM: Traditional Chinese medicine (TCM) is widely used by patients with amyotrophic lateral sclerosis (ALS). However, their reasons and experience in using TCM have received insufficient attention. Therefore, we conducted a mixed method study to gain insights into this issue.

MATERIALS AND METHODS: This study was conducted on the basis of the China Amyotrophic Lateral Sclerosis Registry of Patients with Traditional Chinese Medicine (CARE-TCM). Data were collected from Dongzhimen Hospital through a mixed method approach, including a questionnaire and a semi-structured interview. Patients with ALS who were using TCM when they were initially registered with CARE-TCM and who had been followed-up for over six months were recruited. The questionnaires' outcomes were statistically outlined, and the interview transcripts were thematically analysed to identify themes and sub-themes.

RESULTS: Fifty-two and sixteen patients were included in the questionnaire and semi-structured interview groups, respectively. Patients used TCM with the hope of regulating their body holistically to improve nonmotor symptoms and quality of life (QOL). Those who recognised TCM as ineffective tended to discontinue it after a three-month trial period. Although quality was a major concern, herbal medicine (HM) was the most frequently used modality among all participants (n = 52), with the majority (n = 44, 84.6%) continuing to use it. Patients emphasised in-person consultations as a crucial part of TCM treatment. However, the disability caused by disease often made this interaction unattainable.

CONCLUSION: Nonmotor symptoms and QOL hold substantial importance for patients with ALS using TCM. HM is a more suitable modality than other TCM treatment modalities, but patients are facing challenges in seeking HM treatment. It is necessary to promote the implementation of hierarchical diagnosis and treatment, thus making TCM more accessible.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04885374 (registered on May 13, 2021).}, } @article {pmid38868068, year = {2024}, author = {Nuredini, A and Bottignole, D and Stragliati, F and Anceschi, P and Romano, S and Pollara, I and Abramo, A and Rausa, F and Parrino, L and Zinno, L and Mutti, C}, title = {Unraveling sleep respiratory dysfunction in amyotrophic lateral sclerosis: Beyond the apnea-hypopnea index and sleep-related hypoxia.}, journal = {Heliyon}, volume = {10}, number = {11}, pages = {e32250}, pmid = {38868068}, issn = {2405-8440}, abstract = {The timely introduction of non-invasive ventilation (NIV) is extremely relevant in the multidisciplinary management of patients affected by amyotrophic lateral sclerosis (ALS) and is based on the proper identification of red flags for early diaphragmatic exhaustion. Polygraphic sleep recording may provide insightful information on the ongoing respiratory impairment; in particular, atypical breathing patterns need to be recognized, as the application of current guidelines for sleep-related hypoxemia or sleep apnea may be insufficient for detecting early signs of diaphragmatic fatigue. We report the case of a 51-year-old man affected by ALS who was asymptomatic for breathing impairment, but whose nocturnal polysomnographic recording, despite not significant for obstructive sleep apnea nor for conventional hypoventilatory patterns, strongly suggested initial respiratory failure, as lately confirmed by the pulmonary follow-up. We discuss the advantages of including sleep recording in the clinical work-up of patients affected by ALS.}, } @article {pmid38869076, year = {2024}, author = {Ye, Y and Jia, P and Miao, J and Wang, Y and Li, Z and Lin, Y and He, M and Liu, S and Zheng, BR and Wu, J and Pan, J and Li, CM and Hou, P and Guo, D}, title = {CCDC50 mediates the clearance of protein aggregates to prevent cellular proteotoxicity.}, journal = {Autophagy}, volume = {20}, number = {11}, pages = {2529-2539}, pmid = {38869076}, issn = {1554-8635}, mesh = {Animals ; *Autophagy/physiology ; Humans ; Mice ; *Protein Aggregates ; Neurons/metabolism ; Cell Survival ; Brain/metabolism/pathology ; Proteostasis ; Neurodegenerative Diseases/metabolism/genetics ; Ubiquitination ; Protein Aggregation, Pathological/metabolism ; }, abstract = {Protein aggregation caused by the disruption of proteostasis will lead to cellular cytotoxicity and even cell death, which is implicated in multiple neurodegenerative diseases. The elimination of aggregated proteins is mediated by selective macroautophagy receptors, which is termed aggrephagy. However, the identity and redundancy of aggrephagy receptors in recognizing substrates remain largely unexplored. Here, we find that CCDC50, a highly expressed autophagy receptor in brain, is recruited to proteotoxic stresses-induced polyubiquitinated protein aggregates and ectopically expressed aggregation-prone proteins. CCDC50 recognizes and further clears these cytotoxic aggregates through autophagy. The ectopic expression of CCDC50 increases the tolerance to stress-induced proteotoxicity and hence improved cell survival in neuron cells, whereas CCDC50 deficiency caused accumulation of lipid deposits and polyubiquitinated protein conjugates in the brain of one-year-old mice. Our study illustrates how aggrephagy receptor CCDC50 combats proteotoxic stress for the benefit of neuronal cell survival, thus suggesting a protective role in neurotoxic proteinopathy.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; ATG5: autophagy related 5; BODIPY: boron-dipyrromethene; CASP3: caspase 3; CCDC50: coiled-coil domain containing 50; CCT2: chaperonin containing TCP1 subunit 2; CHX: cycloheximide; CQ: chloroquine; CRISPR: clustered regulatory interspaced short palindromic repeat; Cas9: CRISPR-associated system 9; DAPI: 4',6-diamidino-2-phenylindole; FK2: Anti-ubiquitinylated proteins antibody, clone FK2; FUS: FUS RNA binding protein; GFP: green fluorescent protein; HD: Huntington disease; HTT: huntingtin; KEGG: Kyoto Encyclopedia of Genes and Genomes; LDS: LIR-docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPT/tau: microtubule associated protein tau; MIU: motif interacting with ubiquitin; NBR1: NBR1, autophagy cargo receptor; OPTN: optineurin; PD: Parkinson disease; PI: propidium iodide; ROS: reactive oxygen species; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; Ub: ubiquitin; UDS: UIM-docking site; UIM: ubiquitin interacting motif; UPS: ubiquitin-proteasome system.}, } @article {pmid38869826, year = {2024}, author = {Wang, H and Zeng, R}, title = {Aberrant protein aggregation in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {4826-4851}, pmid = {38869826}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates/physiology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease. As its pathological mechanisms are not well understood, there are no efficient therapeutics for it at present. While it is highly heterogenous both etiologically and clinically, it has a common salient hallmark, i.e., aberrant protein aggregation (APA). The upstream pathogenesis and the downstream effects of APA in ALS are sophisticated and the investigation of this pathology would be of consequence for understanding ALS. In this paper, the pathomechanism of APA in ALS and the candidate treatment strategies for it are discussed.}, } @article {pmid38870470, year = {2024}, author = {McDool, E and Carlton, J and Powell, PA and Coates, E and Knox, L and Mayberry, E and Appleby, N and Griffiths, AW and Hobson, E and McDermott, CJ}, title = {Measuring Health-Related Quality of Life in Amyotrophic Lateral Sclerosis: A Systematic Review and Conceptual Framework.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209549}, pmid = {38870470}, issn = {1526-632X}, mesh = {*Amyotrophic Lateral Sclerosis/psychology/physiopathology ; Humans ; *Quality of Life/psychology ; Patient Reported Outcome Measures ; }, abstract = {BACKGROUND AND OBJECTIVES: The assessment of health-related quality of life (HRQoL) in patients with amyotrophic lateral sclerosis (ALS) is heterogeneous and inconsistent. The objectives of this study were (1) to develop a comprehensive conceptual framework of HRQoL in ALS and (2) map the content of existing patient-reported outcome measures (PROMs) used in ALS to this novel framework.

METHODS: Our model of HRQoL in ALS (Health-related Quality of life in Amyotrophic Lateral Sclerosis, QuALS) was developed from a systematic literature review and consultative input from key stakeholders (patients, carers, and health care professionals). Five electronic databases were searched in April 2022. Primary studies of any design that assessed HRQoL in ALS by using a multi-item PROM and/or qualitative methods were identified. Using an a priori framework, HRQoL themes were extracted and iteratively modified from the content of each PROM and qualitative study quotations identified in the literature. The conceptual framework was ratified by stakeholders with lived experience and clinical experts. The QuALS framework was used to map the content of identified PROMs and qualitative studies based on thematic coverage.

RESULTS: QuALS covers 3 high-level domains of HRQoL (physical, psychological, and social functioning) and consists of 7 themes (Activities; Physical Health; Autonomy; Cognition; Feelings and Emotions; Self-identity; Relationships), characterized by 42 subthemes. Of 8,220 studies identified, 274 were included in the review that informed QuALS. In these studies, 111 PROMs were used to assess at least 1 aspect of HRQoL, and 11 studies used qualitative methods. Of the 3 high-level domains, physical functioning was the most commonly assessed, particularly within ALS-specific PROMs where almost one-quarter of PROMs exclusively assessed physical functioning. None of the PROMs or qualitative studies identified assessed all aspects of HRQoL in the QuALS framework.

DISCUSSION: This study presents a new comprehensive conceptual framework of HRQoL in ALS (QuALS), informed by a robust systematic review of existing literature and stakeholder input, incorporating lived experience. QuALS provides a valuable resource for researchers and clinicians interested in taking a holistic approach to assessing and understanding the full impact of ALS on HRQoL and how this may be affected by treatments.}, } @article {pmid38870925, year = {2025}, author = {Hamdi, N and Ocab, O and Soliman, R and Ludolph, A and Anwar, W and Logroscino, G and Fahmy, N}, title = {Motor Neuron Disease Population-Based Registry in Egypt: Where Do We Stand?.}, journal = {Neuroepidemiology}, volume = {59}, number = {3}, pages = {277-289}, doi = {10.1159/000539468}, pmid = {38870925}, issn = {1423-0208}, mesh = {Humans ; Egypt/epidemiology ; *Registries ; *Motor Neuron Disease/epidemiology ; *Amyotrophic Lateral Sclerosis/epidemiology ; Prevalence ; Incidence ; }, abstract = {BACKGROUND: There is a growing body of evidence indicating that the worldwide distribution of amyotrophic lateral sclerosis (ALS) is far from uniform. This is evident through variations in the epidemiology, genetics, and phenotypical characteristics of ALS and other motor neuron diseases (MND) across different regions. However, comprehensive ALS epidemiological studies are still lacking in many parts of the world, especially in Africa. Therefore, we propose the establishment of a population-based register for ALS/MND in Egypt, an important part of Africa with a population of more than 100 millions of people.

SUMMARY: Given Egypt's distinctive social and demographic characteristics, it is highly recommended to employ specific, recently developed epidemiological techniques for assessing the prevalence and incidence of these diseases within the country. By utilizing these methods, we can gather invaluable data that will contribute to a deeper understanding of ALS and enable us to effectively address its impact on the population of Egypt.

KEY MESSAGES: Our goal with this pioneering ALS/MND population-based register in Egypt is to define the burden of ALS in this part of Africa and to increase the chances for this consanguineous population to get access to modern individualized genetic therapies. Additionally, we aspire to uncover potential environmental factors and gene-environment interactions that contribute to the development of ALS. This knowledge of MND individual and group risk in Egypt will not only open doors for interventions but also provide opportunities for future research and discovery.}, } @article {pmid38871941, year = {2025}, author = {Naik, B and Sasikumar, J and Das, SP}, title = {From Skin and Gut to the Brain: The Infectious Journey of the Human Commensal Fungus Malassezia and Its Neurological Consequences.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {533-556}, pmid = {38871941}, issn = {1559-1182}, support = {GIA/2019/000620/PRCGIA//Indian Council of Medical Research/ ; }, mesh = {Animals ; Humans ; *Brain/microbiology/pathology ; *Malassezia/genetics/isolation & purification/pathogenicity ; *Nervous System Diseases/diagnosis/microbiology/pathology ; *Skin/microbiology ; }, abstract = {The human mycobiome encompasses diverse communities of fungal organisms residing within the body and has emerged as a critical player in shaping health and disease. While extensive research has focused on the skin and gut mycobiome, recent investigations have pointed toward the potential role of fungal organisms in neurological disorders. Among those fungal organisms, the presence of the commensal fungus Malassezia in the brain has created curiosity because of its commensal nature and primary association with the human skin and gut. This budding yeast is responsible for several diseases, such as Seborrheic dermatitis, Atopic dermatitis, Pityriasis versicolor, Malassezia folliculitis, dandruff, and others. However recent findings surprisingly show the presence of Malassezia DNA in the brain and have been linked to diseases like Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis. The exact role of Malassezia in these disorders is unknown, but its ability to infect human cells, travel through the bloodstream, cross the blood-brain barrier, and reside along with the lipid-rich neuronal cells are potential mechanisms responsible for pathogenesis. This also includes the induction of pro-inflammatory cytokines, disruption of the blood-brain barrier, gut-microbe interaction, and accumulation of metabolic changes in the brain environment. In this review, we discuss these key findings from studies linking Malassezia to neurological disorders, emphasizing the complex and multifaceted nature of these cases. Furthermore, we discuss potential mechanisms through which Malassezia might contribute to the development of neurological conditions. Future investigations will open up new avenues for our understanding of the fungal gut-brain axis and how it influences human behavior. Collaborative research efforts among microbiologists, neuroscientists, immunologists, and clinicians hold promise for unraveling the enigmatic connections between human commensal Malassezia and neurological disorders.}, } @article {pmid38872258, year = {2024}, author = {Xiong, B and Yang, C and Yang, X and Luo, S and Li, S and Chen, C and He, K and Nie, L and Li, P and Li, S and Huang, H and Liu, J and Zhang, Z and Xie, Y and Zou, L and Yang, X}, title = {Arctigenin derivative A-1 ameliorates motor dysfunction and pathological manifestations in SOD1[G93A] transgenic mice via the AMPK/SIRT1/PGC-1α and AMPK/SIRT1/IL-1β/NF-κB pathways.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {6}, pages = {e14692}, pmid = {38872258}, issn = {1755-5949}, support = {SZSM201611090//Sanming Project of Medicine in Shenzhen/ ; 82171583//National Natural Science Foundation of China/ ; JCYJ20200109144418639//The Key Basic Research Program of Shenzhen Science and Technology Innovation Commission/ ; JCYJ20200109150717745//The Key Basic Research Program of Shenzhen Science and Technology Innovation Commission/ ; SZXK069//Shenzhen Key Medical Discipline Construction Fund/ ; }, mesh = {Animals ; *Mice, Transgenic ; *Sirtuin 1/metabolism ; Mice ; *NF-kappa B/metabolism ; *AMP-Activated Protein Kinases/metabolism ; *Furans/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; *Interleukin-1beta/metabolism ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Lignans/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; Male ; Motor Neurons/drug effects/pathology/metabolism ; Spinal Cord/drug effects/pathology/metabolism ; }, abstract = {AIM: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A-1, a derivative of arctigenin with AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated.

METHODS: A-1 at 33.3 mg/kg was administrated in SOD1[G93A] transgenic mice orally from the 13th week for a 6-week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit.

RESULTS: A-1 administration in SOD1[G93A] mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A-1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial-related proteins. The A-1 treatment group showed decreased levels of IL-1β, pIκBα/IκBα, and pNF-κB/NF-κB.

CONCLUSIONS: A-1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC-1α pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL-1β/NF-κB pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A-1 as a promising therapeutic approach for ALS.}, } @article {pmid38872308, year = {2024}, author = {Çelik, MH and Gagneur, J and Lim, RG and Wu, J and Thompson, LM and Xie, X}, title = {Identifying dysregulated regions in amyotrophic lateral sclerosis through chromatin accessibility outliers.}, journal = {HGG advances}, volume = {5}, number = {3}, pages = {100318}, pmid = {38872308}, issn = {2666-2477}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Chromatin/metabolism/genetics ; Promoter Regions, Genetic/genetics ; Algorithms ; Gene Expression Regulation ; Chromatin Immunoprecipitation Sequencing ; Histones/metabolism/genetics ; }, abstract = {The high heritability of amyotrophic lateral sclerosis (ALS) contrasts with its low molecular diagnosis rate post-genetic testing, pointing to potential undiscovered genetic factors. To aid the exploration of these factors, we introduced EpiOut, an algorithm to identify chromatin accessibility outliers that are regions exhibiting divergent accessibility from the population baseline in a single or few samples. Annotation of accessible regions with histone chromatin immunoprecipitation sequencing and Hi-C indicates that outliers are concentrated in functional loci, especially among promoters interacting with active enhancers. Across different omics levels, outliers are robustly replicated, and chromatin accessibility outliers are reliable predictors of gene expression outliers and aberrant protein levels. When promoter accessibility does not align with gene expression, our results indicate that molecular aberrations are more likely to be linked to post-transcriptional regulation rather than transcriptional regulation. Our findings demonstrate that the outlier detection paradigm can uncover dysregulated regions in rare diseases. EpiOut is available at github.com/uci-cbcl/EpiOut.}, } @article {pmid38873369, year = {2024}, author = {Hong, J and Kim, GC and Cha, JG and Park, J and Park, B and Park, SY and Kim, SU}, title = {Transcholecystic Duodenal Drainage as an Alternative Decompression Method for Afferent Loop Syndrome: Two Case Reports.}, journal = {Journal of the Korean Society of Radiology}, volume = {85}, number = {3}, pages = {661-667}, pmid = {38873369}, issn = {2951-0805}, abstract = {Afferent loop syndrome (ALS) is a rare complication of gastrectomies and gastrointestinal reconstruction. This can predispose patients to fatal conditions, such as cholangitis, pancreatitis, and duodenal perforation with peritonitis. Therefore, emergency decompression is necessary to prevent these complications. Herein, we report two cases in which transcholecystic duodenal drainage, an alternative decompression treatment, was performed in ALS patients without bile duct dilatation. Two patients who underwent distal gastrectomy with Billroth II anastomosis sought consultation in an emergency department for epigastric pain and vomiting. On CT, ALS with acute pancreatitis was diagnosed. However, biliary access could not be achieved because of the absence of bile duct dilatation. To overcome this problem, a duodenal drainage catheter was placed to decompress the afferent loop after traversing the cystic duct via a transcholecystic approach. The patients were discharged without additional surgical treatment 2 weeks and 1 month after drainage.}, } @article {pmid38874845, year = {2025}, author = {Birbaumer, N}, title = {"Your Thoughts are (were) Free!": Brain-Computer-Interfaces, Neurofeedback, Detection of Deception, and the Future of Mind-Reading.}, journal = {Applied psychophysiology and biofeedback}, volume = {50}, number = {4}, pages = {551-568}, pmid = {38874845}, issn = {1573-3270}, mesh = {Humans ; *Brain-Computer Interfaces ; *Neurofeedback/methods/ethics ; *Deception ; Amyotrophic Lateral Sclerosis ; }, abstract = {This review describes the historical developement and rationale of clinically relevant research on neurophysiological "mind reading" paradims: Brain- Computer-Interfaces, detection of deception, brain stimulation and neurofeedback and the clinical applications in drug resistant epilepsy, chronic stroke, and communication with paralyzed locked-in persons. The emphasis lies on completely locked-in patients with amyotrophic lateral sclerosis using non-invasive and invasive brain computer interfaces and neurofeedback to restore verbal communication with the social environment. In the second part of the article we argue that success and failure of neurophysiological "mind reading" paradigms may be explained with a motor theory of thinking and emotion in combination with learning theory. The ethical implications of brain computer interface and neurofeedback approaches, particularly for severe chronic paralysis and loss of communication diseases and decisions on hastened death and euthanasia are discussed.}, } @article {pmid38875346, year = {2024}, author = {}, title = {Erratum for the Research Article: "Sulfated disaccharide protects membrane and DNA damages from arginine-rich dipeptide repeats in ALS" by Chang et al.}, journal = {Science advances}, volume = {10}, number = {24}, pages = {eadq7259}, doi = {10.1126/sciadv.adq7259}, pmid = {38875346}, issn = {2375-2548}, } @article {pmid38875513, year = {2024}, author = {van Eijk, RPA and van den Berg, LH and Lu, Y}, title = {Cultivating Patient Preferences in ALS Clinical Trials: Reliability and Prognostic Value of the Patient-Ranked Order of Function.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209502}, pmid = {38875513}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Patient Preference ; Reproducibility of Results ; Prognosis ; Aged ; Netherlands ; Clinical Trials as Topic ; Surveys and Questionnaires ; Registries ; }, abstract = {BACKGROUND AND OBJECTIVES: The Patient-Ranked Order of Function (PROOF) is a novel approach to account for patient-reported preferences in the evaluation of treatments of amyotrophic lateral sclerosis (ALS). In this study, we assess the reliability and prognostic value of different sets of patient-reported preferences that can be used for the PROOF end point.

METHODS: Data were obtained through online surveys over the course of 12 months using the population-based registry of the Netherlands. Patients were asked to score functional domains of the ALS Functional Rating Scale (ALSFRS-R) and rank the order of importance of each domain. Two weeks after the initial invite, the questionnaire was repeated to evaluate test-retest reliability. Vital status was extracted from the municipal population register.

RESULTS: In total, 611 patients with ALS were followed up for survival and 382 patients were included in the test-retest reliability study. All versions of PROOF, using different sets of preferences, resulted in excellent reliability (intraclass correlation coefficients ranged from 0.89 [95% CI 0.87-0.91] to 0.97 [95% CI 0.97-0.98], all p < 0.001), without systematic differences between baseline and week 2 (mean rank difference range -1 to -3 [95% CI range -8 to 2], all p > 0.20). Preferences about future events were more variable than preferences about current symptoms. All versions of PROOF strongly predicted overall survival (hazard ratios per 10th rank percentile ranged from 0.80 to 0.83 [95% CI range 0.76-0.87], all p < 0.001) and had a more even separation of survival curves between rank-stratified subgroups compared with the ALSFRS-R total score.

DISCUSSION: In a large cohort of patients, we show how patient-reported preferences can be measured and integrated reliably with the ALSFRS-R without leading to systematic bias. Patient preferences may provide unique prognostic information in addition to what is already measured conventionally. This could provide a more comprehensive understanding of how medical interventions effectively address the patient's concerns and improve what matters most to them.}, } @article {pmid38875517, year = {2024}, author = {Michielsen, A and van Veenhuijzen, K and Janse van Mantgem, MR and van Es, MA and Veldink, JH and van Eijk, RPA and van den Berg, LH and Westeneng, HJ}, title = {Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209603}, pmid = {38875517}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Hypothalamus/diagnostic imaging/metabolism/pathology ; *Magnetic Resonance Imaging ; Aged ; Cross-Sectional Studies ; Longitudinal Studies ; Disease Progression ; Cognition/physiology ; Adult ; Energy Metabolism/physiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival.

METHODS: Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate.

RESULTS: Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (β = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (β = -4.79 [-8.39 to -2.49], p = 0.001, β = -10.14 [-15.88 to -4.39], p = 0.004, and β = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (β = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029).

DISCUSSION: We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.}, } @article {pmid38876108, year = {2024}, author = {Scaber, J and Thomas-Wright, I and Clark, AJ and Xu, Y and Vahsen, BF and Carcolé, M and Dafinca, R and Farrimond, L and Isaacs, AM and Bennett, DL and Talbot, K}, title = {Cellular and axonal transport phenotypes due to the C9ORF72 HRE in iPSC motor and sensory neurons.}, journal = {Stem cell reports}, volume = {19}, number = {7}, pages = {957-972}, pmid = {38876108}, issn = {2213-6711}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/T020113/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Induced Pluripotent Stem Cells/metabolism/cytology ; *C9orf72 Protein/genetics/metabolism ; Humans ; *Motor Neurons/metabolism ; *Sensory Receptor Cells/metabolism ; *Axonal Transport ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Phenotype ; *DNA Repeat Expansion/genetics ; }, abstract = {Induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) from patients with amyotrophic lateral sclerosis (ALS) and the C9ORF72 hexanucleotide repeat expansion (HRE) have multiple cellular phenotypes, but which of these accurately reflect the biology underlying the cell-specific vulnerability of ALS is uncertain. We therefore compared phenotypes due to the C9ORF72 HRE in MNs with sensory neurons (SNs), which are relatively spared in ALS. The iPSC models were able to partially reproduce the differential gene expression seen between adult SNs and MNs. We demonstrated that the typical hallmarks of C9ORF72-ALS, including RNA foci and dipeptide formation, as well as specific axonal transport defects, occurred equally in MNs and SNs, suggesting that these in vitro phenotypes are not sufficient to explain the cell-type selectivity of ALS in isolation.}, } @article {pmid38876730, year = {2024}, author = {The Lancet Neurology, }, title = {Multidisciplinary care for amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {649}, doi = {10.1016/S1474-4422(24)00227-8}, pmid = {38876730}, issn = {1474-4465}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Patient Care Team ; }, } @article {pmid38876745, year = {2024}, author = {van Selms, MKA and van der Linden, MW and van der Meijden, C and Lobbezoo, F}, title = {A call for optimal oral care in patients with ALS.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {670}, doi = {10.1016/S1474-4422(24)00226-6}, pmid = {38876745}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Oral Hygiene ; }, } @article {pmid38877004, year = {2024}, author = {Costa, RG and Conceição, A and Matos, CA and Nóbrega, C}, title = {The polyglutamine protein ATXN2: from its molecular functions to its involvement in disease.}, journal = {Cell death & disease}, volume = {15}, number = {6}, pages = {415}, pmid = {38877004}, issn = {2041-4889}, mesh = {Humans ; *Ataxin-2/metabolism/genetics ; *Peptides/metabolism/genetics ; Animals ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Spinocerebellar Ataxias/metabolism/genetics/pathology ; }, abstract = {A CAG repeat sequence in the ATXN2 gene encodes a polyglutamine (polyQ) tract within the ataxin-2 (ATXN2) protein, showcasing a complex landscape of functions that have been progressively unveiled over recent decades. Despite significant progresses in the field, a comprehensive overview of the mechanisms governed by ATXN2 remains elusive. This multifaceted protein emerges as a key player in RNA metabolism, stress granules dynamics, endocytosis, calcium signaling, and the regulation of the circadian rhythm. The CAG overexpansion within the ATXN2 gene produces a protein with an extended poly(Q) tract, inducing consequential alterations in conformational dynamics which confer a toxic gain and/or partial loss of function. Although overexpanded ATXN2 is predominantly linked to spinocerebellar ataxia type 2 (SCA2), intermediate expansions are also implicated in amyotrophic lateral sclerosis (ALS) and parkinsonism. While the molecular intricacies await full elucidation, SCA2 presents ATXN2-associated pathological features, encompassing autophagy impairment, RNA-mediated toxicity, heightened oxidative stress, and disruption of calcium homeostasis. Presently, SCA2 remains incurable, with patients reliant on symptomatic and supportive treatments. In the pursuit of therapeutic solutions, various studies have explored avenues ranging from pharmacological drugs to advanced therapies, including cell or gene-based approaches. These endeavours aim to address the root causes or counteract distinct pathological features of SCA2. This review is intended to provide an updated compendium of ATXN2 functions, delineate the associated pathological mechanisms, and present current perspectives on the development of innovative therapeutic strategies.}, } @article {pmid38878106, year = {2024}, author = {Chourpiliadis, C and Seitz, C and Lovik, A and Joyce, EE and Pan, L and Hu, Y and Kläppe, U and Samuelsson, K and Press, R and Ingre, C and Fang, F}, title = {Lifestyle and medical conditions in relation to ALS risk and progression-an introduction to the Swedish ALSrisc Study.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5447-5459}, pmid = {38878106}, issn = {1432-1459}, support = {R01TS000324-01-00//US Center for Disease Control and Prevention/ ; 2019-01088//Swedish Research Council/ ; 2023-02428//Swedish Research Council/ ; MegaALS 802091//European Research Council Starting Grant/ ; R01 TS000324/TS/ATSDR CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Male ; Sweden/epidemiology ; Female ; Middle Aged ; Aged ; *Life Style ; *Disease Progression ; *Body Mass Index ; Adult ; Risk Factors ; Smoking/epidemiology ; Diabetes Mellitus/epidemiology ; Hypertension/epidemiology ; Hypercholesterolemia/epidemiology ; }, abstract = {BACKGROUND: This study was an introduction to the Swedish ALSrisc Study and explored the association of lifestyle and medical conditions, with risk and progression of amyotrophic lateral sclerosis (ALS).

METHODS: We included 265 newly diagnosed ALS patients during 2016-2022 in Stockholm and 207 ALS-free siblings and partners of the patients as controls. Information on body mass index (BMI), smoking, and history of head injuries, diabetes mellitus, hypercholesterolemia, and hypertension was obtained through the Euro-MOTOR questionnaire at recruitment. Patients were followed from diagnosis until death, invasive ventilation, or November 30, 2022.

RESULTS: Higher BMI at recruitment was associated with lower risk for ALS (OR 0.89, 95%CI 0.83-0.95), especially among those diagnosed after 65 years. One unit increase in the average BMI during the 3 decades before diagnosis was associated with a lower risk for ALS (OR 0.94, 95%CI 0.89-0.99). Diabetes was associated with lower risk of ALS (OR 0.38, 95%CI 0.16-0.90), while hypercholesterolemia was associated with higher risk of ALS (OR 2.10, 95%CI 1.13-3.90). Higher BMI at diagnosis was associated with lower risk of death (HR 0.91, 95%CI 0.84-0.98), while the highest level of smoking exposure (in pack-years) (HR 1.90, 95%CI 1.20-3.00), hypercholesterolemia (HR 1.84, 95%CI 1.06-3.19), and hypertension (HR 1.76, 95%CI 1.03-3.01) were associated with higher risk of death, following ALS diagnosis.

CONCLUSIONS: Higher BMI and diabetes were associated with lower risk of ALS. Higher BMI was associated with lower risk of death, whereas smoking (especially in high pack-years), hypercholesterolemia, and hypertension were associated with higher risk of death after ALS diagnosis.}, } @article {pmid38878150, year = {2025}, author = {Wang, F and Wen, H and Liu, L and Aisa, HA and Xin, X}, title = {A Pair of Epimers of Lignan Alleviate Neuroinflammatory Effects by Modulating iNOS/COX-2 and MAPK/NF-κB Signaling Pathways.}, journal = {Inflammation}, volume = {48}, number = {1}, pages = {361-371}, pmid = {38878150}, issn = {1573-2576}, support = {2020YFE0205600//the National Key Research and Development Program of China/ ; U1703235//the National Natural Science Foundation of China/ ; }, mesh = {*Lignans/pharmacology/chemistry ; *Cyclooxygenase 2/metabolism ; Animals ; *Nitric Oxide Synthase Type II/metabolism/antagonists & inhibitors ; Mice ; *NF-kappa B/metabolism ; *MAP Kinase Signaling System/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Signal Transduction/drug effects ; *Anti-Inflammatory Agents/pharmacology ; Cell Line ; Lipopolysaccharides ; Microglia/drug effects ; }, abstract = {Neuroinflammation is a causative factor in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Previous studies have shown that Artemisia mongolica has anti-inflammatory properties. Aschantin (AM3) has been shown to have anti-inflammatory effects. However, the mechanism of AM3 and its epimer epi-aschantin (AM2) remains controversial. Therefore, the present study explored the mechanism of neuroinflammation by AM2 and AM3 and attempted to reveal the relationship between the structure of AM2 and AM3 and anti-neuroinflammatory activity. We isolated for the first time 12 lignans from A. mongolica that inhibited NO content at 10 μM in LPS-stimulated BV2 cells. Among them, epi-aschantin (AM2) and Aschantin (AM3) showed significant inhibition in NO screening. With further studies, we found that both AM2 and AM3 effectively inhibited the overproduction of NO, PGE2, IL-6, TNF-α and MCP-1, as well as the overexpression of COX-2 and iNOS. Mechanistic studies have shown AM2 and AM3 significantly inhibited the phosphorylation of ERK, JNK and P-38 in the MAPK signaling pathway and p-IκBα,p-p65 and blocked p65 entry into the nucleus. The results suggested that the pair of epimers (AM2 and AM3) can be used as potential therapeutic agents in the treatment of various brain disorders and that structural differences do not differ in anti-neuroinflammatory effects.}, } @article {pmid38878554, year = {2024}, author = {Mincic, AM and Antal, M and Filip, L and Miere, D}, title = {Modulation of gut microbiome in the treatment of neurodegenerative diseases: A systematic review.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {43}, number = {7}, pages = {1832-1849}, doi = {10.1016/j.clnu.2024.05.036}, pmid = {38878554}, issn = {1532-1983}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/microbiology/therapy ; *Probiotics/administration & dosage/therapeutic use ; *Prebiotics/administration & dosage ; *Dysbiosis/therapy/microbiology ; Animals ; Fecal Microbiota Transplantation ; }, abstract = {BACKGROUND AND AIMS: Microbiota plays an essential role in maintaining body health, through positive influences on metabolic, defensive, and trophic processes and on intercellular communication. Imbalance in intestinal flora, with the proliferation of harmful bacterial species (dysbiosis) is consistently reported in chronic illnesses, including neurodegenerative diseases (ND). Correcting dysbiosis can have a beneficial impact on the symptoms and evolution of ND. This review examines the effects of microbiota modulation through administration of probiotics, prebiotics, symbiotics, or prebiotics' metabolites (postbiotics) in patients with ND like multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).

METHODS: PubMed, Web of Science, Medline databases and ClinicalTrials.gov registry searches were performed using pre-/pro-/postbiotics and ND-related terms. Further references were obtained by checking relevant articles.

RESULTS: Although few compared to animal studies, the human studies generally show positive effects on disease-specific symptoms, overall health, metabolic parameters, on oxidative stress and immunological markers. Therapy with probiotics in various forms (mixtures of bacterial strains, fecal microbiota transplant, diets rich in fermented foods) exert favorable effects on patients' mental health, cognition, and quality of life, targeting pathogenetic ND mechanisms and inducing reparatory mechanisms at the cellular level. More encouraging results have been observed in prebiotic/postbiotic therapy in some ND.

CONCLUSIONS: The effects of probiotic-related interventions depend on the patients' ND stage and pre-existing allopathic medication. Further studies on larger cohorts and long term comprehensive neuropsychiatric, metabolic, biochemical testing, and neuroimaging monitoring are necessary to optimize therapeutic protocols in ND.}, } @article {pmid38878774, year = {2024}, author = {Kumbier, K and Roth, M and Li, Z and Lazzari-Dean, J and Waters, C and Hammerlindl, S and Rinaldi, C and Huang, P and Korben, VA and , and Phatnani, H and Shneider, N and Jacobson, MP and Wu, LF and Altschuler, SJ}, title = {Identifying FUS amyotrophic lateral sclerosis disease signatures in patient dermal fibroblasts.}, journal = {Developmental cell}, volume = {59}, number = {16}, pages = {2134-2142.e6}, doi = {10.1016/j.devcel.2024.05.011}, pmid = {38878774}, issn = {1878-1551}, support = {R01 NS106236/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Fibroblasts/metabolism/pathology ; *RNA-Binding Protein FUS/metabolism/genetics ; Mutation/genetics ; Male ; Female ; Skin/pathology/metabolism ; Machine Learning ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, highly heterogeneous neurodegenerative disease, underscoring the importance of obtaining information to personalize clinical decisions quickly after diagnosis. Here, we investigated whether ALS-relevant signatures can be detected directly from biopsied patient fibroblasts. We profiled familial ALS (fALS) fibroblasts, representing a range of mutations in the fused in sarcoma (FUS) gene and ages of onset. To differentiate FUS fALS and healthy control fibroblasts, machine-learning classifiers were trained separately on high-content imaging and transcriptional profiles. "Molecular ALS phenotype" scores, derived from these classifiers, captured a spectrum from disease to health. Interestingly, these scores negatively correlated with age of onset, identified several pre-symptomatic individuals and sporadic ALS (sALS) patients with FUS-like fibroblasts, and quantified "movement" of FUS fALS and "FUS-like" sALS toward health upon FUS ASO treatment. Taken together, these findings provide evidence that non-neuronal patient fibroblasts can be used for rapid, personalized assessment in ALS.}, } @article {pmid38879065, year = {2024}, author = {Ashrafzadeh-Kian, S and Figdore, D and Larson, B and Deters, R and Abou-Diwan, C and Bornhorst, J and Algeciras-Schimnich, A}, title = {Head-to-head comparison of four plasma neurofilament light chain (NfL) immunoassays.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {561}, number = {}, pages = {119817}, doi = {10.1016/j.cca.2024.119817}, pmid = {38879065}, issn = {1873-3492}, mesh = {Humans ; Immunoassay/methods ; *Neurofilament Proteins/blood ; Multiple Sclerosis/blood/diagnosis ; Biomarkers/blood ; Amyotrophic Lateral Sclerosis/blood/diagnosis ; Female ; Male ; Middle Aged ; }, abstract = {BACKGROUND: Neurofilament Light Chain (NfL) is an emerging blood biomarker of neuro-axonal injury and neurodegeneration with the potential to be used in the clinical management of various neurological conditions. Various NfL immunoassays are in development on high-throughput automated systems, but little information is available related to the comparability between assays. In this study, we performed a head-to-head comparison of four NfL immunoassays using plasma samples from individuals with various neurological conditions.

METHODS: EDTA plasma samples in which NfL was ordered clinically were stratified according to diagnosis. NfL concentrations (pg/mL) in plasma were obtained using the Quanterix Simoa®, the Roche Elecsys, the Siemens Healthineers Atellica®IM, and the Fujirebio Lumipulse® NfL assays. Passing-Bablok regression analyses were performed to assess the correlation and bias between methods. Additionally, the distribution of NfL concentrations for each assay was assessed in three disease groups: amyotrophic lateral sclerosis (ALS) upon initial diagnosis, ALS treated, and multiple sclerosis (MS).

RESULTS: The R[2] between assays were all ≥ 0.95, however, significant proportional bias was observed between some assays. In particular, the Roche Elecsys assay NfL concentrations were significantly lower (∼85 %) when compared against the other three assays. The four assays were comparable with regards to the percentage of patients that were identified as having an elevated NfL result in the various clinical groups: ALS initial diagnoses (83-94 %), ALS untreated (93-100 %), and MS (8-18 %).

CONCLUSIONS: This is the first study describing a head-to-head comparison of four automated NfL immunoassays. We demonstrate that there is a strong correlation between assays but a lack of standardization which is evident by the bias observed between some of the evaluated methods. These analytical differences will be important to consider when using NfL as a biomarker of neurodegeneration.}, } @article {pmid38879100, year = {2024}, author = {Viccaro, F and Lecci, A and Baccolini, V and Sciurti, A and Piamonti, D and Inghilleri, M and D'Antoni, L and Palange, P}, title = {Prediction of cough effectiveness in amyotrophic lateral sclerosis patients assessed by ultrasuond of the diaphragm during the cough expiration phase.}, journal = {Respiratory physiology & neurobiology}, volume = {327}, number = {}, pages = {104299}, doi = {10.1016/j.resp.2024.104299}, pmid = {38879100}, issn = {1878-1519}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnostic imaging ; *Cough/physiopathology ; Male ; *Diaphragm/physiopathology/diagnostic imaging ; Female ; Middle Aged ; Aged ; *Ultrasonography ; Exhalation/physiology ; Peak Expiratory Flow Rate/physiology ; Adult ; }, abstract = {Assessing cough effectiveness, using Cough Peak Flow, is crucial for patients with Neuromuscular Diseases, such as Amyotrophic Lateral Sclerosis. Impaired cough function can contribute to respiratory decline and failure. The goal of the study is to determine the correlation between diaphragmatic excursion and cough expiratory phase, potentially utilizing ultrasonographic indices to estimate Cough Peak Flow in these patients. Twenty-two patients were enrolled in this study. The upward displacement of the diaphragm was measured with ultrasonography during voluntary cough expiration and Cough Peak Flow was simultaneously measured. A multivariable linear regression model was built to quantify the association between Cough Peak Flow and diaphragm expiratory excursion. There is significative relationship between Cough Peak Flow and diaphragm excursion with a Pearson's r coefficient of 0.86 observed in the patients group. Multiple linear regression analysis for Cough Peak Flow (Adjusted R[2] = 0.86) revealed significant associations between Cough Peak Flow and expiratory excursion (adjusted β-coefficient: 64.78, 95 %, CI: 51.50-78.07, p<0.001) and sex (adjusted β-coefficient: -69.06; 95 % CI: -109.98 to -28.15, p=0.001). Our results predict the cough effectiveness by using M-mode diaphragmatic sonography with a potentially significant impact on therapeutic choices.}, } @article {pmid38879294, year = {2024}, author = {Xu, H and Cheng, J and Leng, Q and Liang, S and Sun, L and Su, W and Xue, F and Wu, R}, title = {Nontarget site-based resistance to nicosulfuron and identification of candidate genes in Cucumis melo L. var. agrestis Naud. via RNA-Seq transcriptome analysis.}, journal = {Pesticide biochemistry and physiology}, volume = {202}, number = {}, pages = {105912}, doi = {10.1016/j.pestbp.2024.105912}, pmid = {38879294}, issn = {1095-9939}, mesh = {*Herbicide Resistance/genetics ; *Sulfonylurea Compounds/pharmacology ; *Herbicides/pharmacology/toxicity ; *Acetolactate Synthase/genetics/metabolism ; *Cucumis melo/genetics/drug effects ; *Pyridines/pharmacology ; RNA-Seq ; Gene Expression Profiling ; Malathion/pharmacology ; Gene Expression Regulation, Plant/drug effects ; Plant Proteins/genetics/metabolism ; }, abstract = {Herbicide resistance is a worldwide concern for weed control. Cucumis melo L. var. agrestis Naud. (C. melo) is an annual trailing vine weed that is commonly controlled by nicosulfuron, acetolactate synthase (ALS)-inhibiting herbicides. However, long-term use of this herbicide has led to the emergence of resistance and several nicosulfuron resistant populations of C. melo have been found. Here we identified a resistant (R) C. melo population exhibiting 7.31-fold resistance to nicosulfuron compared with a reference sensitive (S) population. ALS gene sequencing of the target site revealed no amino acid substitution in R plants, and no difference in enzyme activity, as shown by ALS activity assays in vitro. ALS gene expression was not significantly different before and after the application of nicosulfuron. Pretreatment with the cytochrome P450 monooxygenase (P450) inhibitor malathion reduced nicosulfuron resistance in the R population. RNA-Seq transcriptome analysis was used to identify candidate genes that may confer metabolic resistance to nicosulfuron. We selected genes with annotations related to detoxification functions. A total of 20 candidate genes (7 P450 genes, 1 glutathione S-transferase (GST) gene, 2 ATP-binding cassette (ABC) transporters, and 10 glycosyltransferase (GT)) were identified; 12 of them (7 P450s, 1 GST, 2 ABC transporters, and 2 GTs) were demonstrated significantly differential expression between R and S by quantitative real-time RT-PCR (qRT-PCR). Our findings revealed that the resistance mechanism in C. melo was nontarget-site based. Our results also provide a valuable resource for studying the molecular mechanisms of weed resistance.}, } @article {pmid38879333, year = {2024}, author = {Han, Y and Gao, H and Sun, Y and Wang, Y and Yan, C and Ma, H and Liu, X and Huang, Z}, title = {Target gene overexpression and enhanced metabolism confer resistance to nicosulfuron in Eriochloa villosa (Thunb.).}, journal = {Pesticide biochemistry and physiology}, volume = {202}, number = {}, pages = {105946}, doi = {10.1016/j.pestbp.2024.105946}, pmid = {38879333}, issn = {1095-9939}, mesh = {*Sulfonylurea Compounds/pharmacology ; *Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Pyridines/pharmacology ; Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Poaceae/genetics/drug effects ; }, abstract = {Eriochloa villosa (Thunb.) Kunth is a troublesome weed widely distributed in maize (Zea mays L.) fields in Northeast China. Many populations of E. villosa have evolved resistance to nicosulfuron herbicides, which inhibit acetolactate synthase (ALS). The objectives of this research were to confirm that E. villosa is resistant to nicosulfuron and to investigate the basis of nicosulfuron resistance. Whole-plant dose-response studies revealed that the R population had not developed a high level of cross-resistance and exhibited greater resistant (25.62-fold) to nicosulfuron than that of the S population and had not yet developed a high level of cross-resistance. An in vitro ALS activity assay demonstrated that the I50 of nicosulfuron was 6.87-fold greater in the R population than the S population. However, based on ALS gene sequencing, the target ALS gene in the R population did not contain mutations. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed that ALS gene expression between the R and S populations was significantly different after nicosulfuron application, but no differences were observed in the gene copy number. After the cytochrome P450 inhibitor malathion or the GST inhibitor NBD-Cl was applied, the resistant E. villosa population exhibited increased sensitivity to nicosulfuron. Based on the activities of GSTs and P450s, the activities of the R population were greater than those of the S population after nicosulfuron application. This is the first report that the resistance of E. villosa to ALS inhibitors results from increased target gene expression and increased metabolism. These findings provide a theoretical foundation for the effective control of herbicide-resistant E. villosa.}, } @article {pmid38879469, year = {2024}, author = {Dai, Z and Zhou, X}, title = {Associations between allostatic load and hepatic steatosis and liver fibrosis: evidence from NHANES 2017-2020.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {1602}, pmid = {38879469}, issn = {1471-2458}, mesh = {Humans ; Female ; Male ; *Allostasis/physiology ; Middle Aged ; *Liver Cirrhosis ; *Nutrition Surveys ; *Fatty Liver/physiopathology ; Adult ; Aged ; Cross-Sectional Studies ; Risk Factors ; }, abstract = {BACKGROUND: Allostatic load, the cumulative strain resulting from chronic stress responses, has been linked to disease occurrence and progression, yet research quantifying this relationship is limited. This study aimed to explore the relationship between allostatic load score (ALS) levels and the degree of hepatic steatosis and fibrosis.

METHODS: Data from the National Health and Nutrition Examination Survey 2017-2020 were analyzed. The ALS was based on the statistical distribution, assigning one point for each biomarker if it was in the highest risk quartile, and then summing them to generate the ALS score (range, 0-8). The multivariate linear regression was employed to analyze the association between the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) with ALS. Additionally, multinomial logistic regression was used to investigate the association between ALS and the degree of hepatic steatosis and fibrosis.

RESULTS: Participants had a weighted mean age of 52.69 years and 56.14% were female. In the multivariate linear regression analysis, ALS showed a significant positive correlation with CAP (β = 15.56, 95% CI: 14.50-16.62) and LSM (β = 0.58, 95% CI: 0.48-0.67). Age, healthy dietary level, and PIR had significant interactions with this positive correlation. In the multinomial logistic regression analysis, ALS exhibited a significant positive correlation with different degrees of hepatic steatosis and fibrosis. Consistency of the results was observed in sensitivity analyses using clinical thresholds of ALS.

CONCLUSIONS: Comprehensive clinical assessment targeting load adaptation may enhance the effectiveness of risk assessment in patients with hepatic steatosis and fibrosis.}, } @article {pmid38879591, year = {2024}, author = {Lambert-Smith, IA and Shephard, VK and McAlary, L and Yerbury, JJ and Saunders, DN}, title = {High-content analysis of proteostasis capacity in cellular models of amyotrophic lateral sclerosis (ALS).}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {13844}, pmid = {38879591}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Proteostasis ; Humans ; *Superoxide Dismutase-1/metabolism/genetics ; *Protein Folding ; *Mutation ; Cell Line ; Mice ; Animals ; }, abstract = {Disrupted proteome homeostasis (proteostasis) in amyotrophic lateral sclerosis (ALS) has been a major focus of research in the past two decades. However, the proteostasis processes that become disturbed in ALS are not fully understood. Obtaining more detailed knowledge of proteostasis disruption in association with different ALS-causing mutations will improve our understanding of ALS pathophysiology and may identify novel therapeutic targets and strategies for ALS patients. Here we describe the development and use of a novel high-content analysis (HCA) assay to investigate proteostasis disturbances caused by the expression of several ALS-causing gene variants. This assay involves the use of conformationally-destabilised mutants of firefly luciferase (Fluc) to examine protein folding/re-folding capacity in NSC-34 cells expressing ALS-associated mutations in the genes encoding superoxide dismutase-1 (SOD1[A4V]) and cyclin F (CCNF[S621G]). We demonstrate that these Fluc isoforms can be used in high-throughput format to report on reductions in the activity of the chaperone network that result from the expression of SOD1[A4V], providing multiplexed information at single-cell resolution. In addition to SOD1[A4V] and CCNF[S621G], NSC-34 models of ALS-associated TDP-43, FUS, UBQLN2, OPTN, VCP and VAPB mutants were generated that could be screened using this assay in future work. For ALS-associated mutant proteins that do cause reductions in protein quality control capacity, such as SOD1[A4V], this assay has potential to be applied in drug screening studies to identify candidate compounds that can ameliorate this deficiency.}, } @article {pmid38879765, year = {2025}, author = {Sharma, A and Kakkar, A and Khanna, M and Devi, S}, title = {Arbutin's Potential in Neuroprotection: A Promising Role in Mitigating Neurodegenerative Diseases.}, journal = {Current drug research reviews}, volume = {17}, number = {3}, pages = {343-351}, pmid = {38879765}, issn = {2589-9783}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use/pharmacokinetics ; *Arbutin/pharmacology/therapeutic use/pharmacokinetics ; Animals ; Oxidative Stress/drug effects ; Blood-Brain Barrier/metabolism ; Neuroprotection/drug effects ; }, abstract = {Naturally occurring glycosylated hydroquinone Arbutin, has drawn interest due to its possible function in reducing the risk of neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Arbutin is well-known for its anti-inflammatory and antioxidant properties, which are essential in preventing oxidative stress and neuroinflammation. Research has shown that arbutin might alter important physiological pathways connected to protein misfolding, synapse function, and neuronal survival processes linked to the development of neurodegenerative diseases. Arbutin can also penetrate the blood- -brain barrier, which increases its therapeutic potential. Arbutin's neuroprotective properties and promise as a therapeutic agent for neurodegenerative illnesses are summarized in this review, which also emphasizes the need for further study into the molecular processes behind these effects.}, } @article {pmid38879961, year = {2024}, author = {Milella, G and Zoccolella, S and Giugno, A and Filardi, M and D'Errico, E and Piccirilli, G and Nanni, AG and Urso, D and Nigro, S and Tafuri, B and Tamburrino, L and Gnoni, V and Logroscino, G}, title = {Mapping lower-limbs muscle vulnerability in patients with ALS: The role of upper and lower motor neurons.}, journal = {Journal of the neurological sciences}, volume = {462}, number = {}, pages = {123098}, doi = {10.1016/j.jns.2024.123098}, pmid = {38879961}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Muscle, Skeletal/physiopathology ; *Motor Neurons/physiology ; Aged ; *Muscle Strength/physiology ; *Lower Extremity/physiopathology ; Muscle Weakness/physiopathology/etiology ; Adult ; Cohort Studies ; }, abstract = {BACKGROUND: Several studies have reported disproportionate wasting of the flexor muscles of the lower limbs (LL) compared to the extensors in patients with amyotrophic lateral sclerosis (ALS). However, these studies have involved small sample sizes (n 〈100), and their findings have been inconsistent. Thus, it remains uncertain whether a distinct pattern of LL muscle weakness is specific to ALS.

AIMS: To investigate the muscle weakness pattern in the LL at the knee, ankle, and toes in a large cohort of ALS patients and evaluate the relationship between the pattern of muscle strength and the extent of upper (UMN) and lower (LMN) motoneuron impairment.

MATERIAL AND METHODS: The strength of flexor and extensor muscle was evaluated in 1250 legs of newly diagnosed ALS patients at the knee, ankle, and foot toes. UMN and LMN burden were assessed using validated scores. Within-subjects ANOVA considering the type of muscle (flexor/extensor) and anatomical sites (knee/ankle/toes) and mixed-factorial ANOVA were conducted to explore the impact of UMN and LMN impairments on the muscle weakness pattern.

RESULTS: Muscle strength showed a significant decline from proximal to distal regions. Indeed both flexor and extensor muscles at the knee outperformed those at the ankle and toes. Within each site, extensor muscles exhibited less strength than flexor, except at the knee. Patients with heightened UMN impairment showed a more marked difference between flexors and extensors within each site, with extensor muscles being more compromised at the ankle and toes. Higher LMN impairment corresponded to a more pronounced weakness in flexor muscles at the ankle and toes compared to those at the knee.

CONCLUSIONS: The extensor muscle at the knee and the flexors at the foot and toes displayed relative resistance to ALS disease. UMN impairment amplified the differences between flexor and extensor muscles within each site, while LMN impairment demonstrated a clear distal-to-proximal vulnerability.}, } @article {pmid38882692, year = {2024}, author = {Yang, T and Wei, Q and Li, C and Ou, R and Lin, J and Cheng, Y and Xiao, Y and Shang, H}, title = {Peripheral immunity involvement in the cognitive impairment of sporadic amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1405275}, pmid = {38882692}, issn = {1664-2295}, abstract = {BACKGROUND: Recent research has indicated the significance of immune activation in amyotrophic lateral sclerosis (ALS). However, the impact of peripheral immunity on cognitive impairment in sporadic ALS remains poorly characterized. Therefore, we aim to assess the relationship between peripheral immune parameters and cognitive impairment in patients with sporadic ALS.

METHODS: A case-control study involving 289 patients with sporadic ALS was conducted. All participants underwent cognitive assessment and measurements of blood immune parameters. The main outcomes included adjusted odds ratios (ORs) in multivariate logistic regression analysis and adjusted coefficients in a multivariate linear regression model. Sensitivity analysis was performed with stratification by the King's clinical stage.

RESULTS: Cognitive impairment was observed in 98 (33.9%) patients. Higher counts of leukocyte (OR, 0.53; 95% CI, 0.29 to 0.95; p = 0.03), neutrophil (OR, 0.48; 95% CI, 0.26 to 0.88; p = 0.02), and monocyte (OR, 0.33; 95% CI, 0.18 to 0.60; p < 0.001) were significantly associated with better cognitive preformence in sporadic ALS, particularly among patients in King's clinical stages 1 and 2. Conversely, a higher percentage of CD4+ T cells was linked to an increased risk of cognitive impairment (OR, 2.79; 95% CI, 1.52 to 5.09; p = 0.001), particularly evident in patients in King's clinical stage 3.

CONCLUSION: These results highlight the involvement of peripheral immunity in the cognitive impairment of sporadic ALS and suggest dynamic and intricate roles that vary across disease stages. Elucidating the links between immunity and ALS sheds light on the pathophysiological mechanisms underlying this fatal neurodegenerative disorder and informs potential immunotherapeutic strategies.}, } @article {pmid38883980, year = {2024}, author = {Azam, HMH and Rößling, RI and Geithe, C and Khan, MM and Dinter, F and Hanack, K and Prüß, H and Husse, B and Roggenbuck, D and Schierack, P and Rödiger, S}, title = {MicroRNA biomarkers as next-generation diagnostic tools for neurodegenerative diseases: a comprehensive review.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1386735}, pmid = {38883980}, issn = {1662-5099}, abstract = {Neurodegenerative diseases (NDs) are characterized by abnormalities within neurons of the brain or spinal cord that gradually lose function, eventually leading to cell death. Upon examination of affected tissue, pathological changes reveal a loss of synapses, misfolded proteins, and activation of immune cells-all indicative of disease progression-before severe clinical symptoms become apparent. Early detection of NDs is crucial for potentially administering targeted medications that may delay disease advancement. Given their complex pathophysiological features and diverse clinical symptoms, there is a pressing need for sensitive and effective diagnostic methods for NDs. Biomarkers such as microRNAs (miRNAs) have been identified as potential tools for detecting these diseases. We explore the pivotal role of miRNAs in the context of NDs, focusing on Alzheimer's disease, Parkinson's disease, Multiple sclerosis, Huntington's disease, and Amyotrophic Lateral Sclerosis. The review delves into the intricate relationship between aging and NDs, highlighting structural and functional alterations in the aging brain and their implications for disease development. It elucidates how miRNAs and RNA-binding proteins are implicated in the pathogenesis of NDs and underscores the importance of investigating their expression and function in aging. Significantly, miRNAs exert substantial influence on post-translational modifications (PTMs), impacting not just the nervous system but a wide array of tissues and cell types as well. Specific miRNAs have been found to target proteins involved in ubiquitination or de-ubiquitination processes, which play a significant role in regulating protein function and stability. We discuss the link between miRNA, PTM, and NDs. Additionally, the review discusses the significance of miRNAs as biomarkers for early disease detection, offering insights into diagnostic strategies.}, } @article {pmid38884572, year = {2024}, author = {Benkirane, M and Bonhomme, M and Morsy, H and Safgren, SL and Marelli, C and Chaussenot, A and Smedley, D and Cipriani, V and de Sainte-Agathe, JM and Ding, C and Larrieu, L and Vestito, L and Margot, H and Lesca, G and Ramond, F and Castrioto, A and Baux, D and Verheijen, J and Sansa, E and Giunti, P and Haetty, A and Bergougnoux, A and Pointaux, M and Ardouin, O and Van Goethem, C and Vincent, MC and Hadjivassiliou, M and Cossée, M and Rouaud, T and Bartsch, O and Freeman, WD and Wierenga, KJ and Klee, EW and Vandrovcova, J and Houlden, H and Debant, A and Koenig, M}, title = {De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {11}, pages = {3681-3689}, doi = {10.1093/brain/awae193}, pmid = {38884572}, issn = {1460-2156}, support = {//Connaître les Syndromes Cérébelleux/ ; }, mesh = {Humans ; *Tubulin/genetics ; Male ; Female ; Middle Aged ; *Muscle Spasticity/genetics ; *Mutation, Missense/genetics ; Adult ; Aged ; Cerebellar Ataxia/genetics ; Spinocerebellar Ataxias/genetics ; Pedigree ; Cohort Studies ; France ; Intellectual Disability ; Optic Atrophy ; }, abstract = {Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis and frontotemporal dementia, based on identification of likely pathogenic variants in patients from distinct amyotrophic lateral sclerosis and frontotemporal dementia cohorts. By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in silico tools. In addition, gene burden analyses in the 100 000 Genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls [odds ratio: 57.0847 (10.2-576.7); P = 4.02 ×10-7]. Taken together, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense mutation, including five confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from three patients harbouring distinct TUBA4A missense showed significant alterations in microtubule organization and dynamics, providing insight of TUBA4A variants pathogenicity. Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes.}, } @article {pmid38884646, year = {2024}, author = {Mielke, JK and Klingeborn, M and Schultz, EP and Markham, EL and Reese, ED and Alam, P and Mackenzie, IR and Ly, CV and Caughey, B and Cashman, NR and Leavens, MJ}, title = {Seeding activity of human superoxide dismutase 1 aggregates in familial and sporadic amyotrophic lateral sclerosis postmortem neural tissues by real-time quaking-induced conversion.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {100}, pmid = {38884646}, issn = {1432-0533}, support = {5P30GM140963-03/GM/NIGMS NIH HHS/United States ; P20 GM152335/GM/NIGMS NIH HHS/United States ; Sloan Scholars Mentoring Network Seed Grant//Alfred P. Sloan Foundation/ ; R21 EY033057/EY/NEI NIH HHS/United States ; P30 GM140963/GM/NIGMS NIH HHS/United States ; R01 NS138499/NS/NINDS NIH HHS/United States ; 1P20GM152335-01/GM/NIGMS NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; C9orf72 Protein/genetics ; Motor Cortex/pathology/metabolism ; Mutation/genetics ; *Spinal Cord/pathology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Biomarkers/analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with average lifespan of 2-5 years after diagnosis. The identification of novel prognostic and pharmacodynamic biomarkers are needed to facilitate therapeutic development. Metalloprotein human superoxide dismutase 1 (SOD1) is known to accumulate and form aggregates in patient neural tissue with familial ALS linked to mutations in their SOD1 gene. Aggregates of SOD1 have also been detected in other forms of ALS, including the sporadic form and the most common familial form linked to abnormal hexanucleotide repeat expansions in the Chromosome 9 open reading frame 72 (C9ORF72) gene. Here, we report the development of a real-time quaking-induced conversion (RT-QuIC) seed amplification assay using a recombinant human SOD1 substrate to measure SOD1 seeding activity in postmortem spinal cord and motor cortex tissue from persons with different ALS etiologies. Our SOD1 RT-QuIC assay detected SOD1 seeds in motor cortex and spinal cord dilutions down to 10[-5]. Importantly, we detected SOD1 seeding activity in specimens from both sporadic and familial ALS cases, with the latter having mutations in either their SOD1 or C9ORF72 genes. Analyses of RT-QuIC parameters indicated similar lag phases in spinal cords of sporadic and familial ALS patients, but higher ThT fluorescence maxima by SOD1 familial ALS specimens and sporadic ALS thoracic cord specimens. For a subset of sporadic ALS patients, motor cortex and spinal cords were examined, with seeding activity in both anatomical regions. Our results suggest SOD1 seeds are in ALS patient neural tissues not linked to SOD1 mutation, suggesting that SOD1 seeding activity may be a promising biomarker, particularly in sporadic ALS cases for whom genetic testing is uninformative.}, } @article {pmid38885838, year = {2024}, author = {López Sanz, P and Azaña Defez, JM}, title = {Is ILVEN a misnomer? Proposal of MALID as an accurate nomenclature. Response to Polubothu et al's "ILVEN should be genotyped to direct treatment and genetic counselling".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e107-e108}, doi = {10.1016/j.jaad.2024.05.084}, pmid = {38885838}, issn = {1097-6787}, mesh = {Humans ; *Terminology as Topic ; *Genetic Counseling ; Genotype ; }, } @article {pmid38886047, year = {2024}, author = {Jiang, Q and Lin, J and Wei, Q and Yang, T and Hou, Y and Zhang, L and Ou, R and Xiao, Y and Wang, S and Zheng, X and Li, C and Shang, H}, title = {Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China.}, journal = {Journal of medical genetics}, volume = {61}, number = {9}, pages = {839-846}, doi = {10.1136/jmg-2024-109909}, pmid = {38886047}, issn = {1468-6244}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/mortality/pathology ; Male ; Female ; *C9orf72 Protein/genetics ; *Mutation ; Middle Aged ; *Phenotype ; China/epidemiology ; *Superoxide Dismutase-1/genetics ; Adult ; *Genetic Association Studies/methods ; RNA-Binding Protein FUS/genetics ; DNA-Binding Proteins/genetics ; Aged ; Genotype ; Age of Onset ; Genetic Predisposition to Disease ; Proteins/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (SOD1, TARDBP, FUS, C9orf72) and phenotype in ALS.

METHODS: Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis.

RESULTS: A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (SOD1, n=65; FUS, n=43; TARDBP, n=27; C9orf72, n=37). SOD1 mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). C9orf72 expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). SOD1 and FUS mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with SOD1 mutations, C9orf72 expansions and those carrying pathogenic FUS mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with C9orf72 expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128).

CONCLUSION: Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.}, } @article {pmid38886938, year = {2025}, author = {Helmold, BR and Ahrens, A and Fitzgerald, Z and Ozdinler, PH}, title = {Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets.}, journal = {Neural regeneration research}, volume = {20}, number = {3}, pages = {725-739}, pmid = {38886938}, issn = {1673-5374}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; }, abstract = {Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein-protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as "causative" for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration-approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.}, } @article {pmid38887187, year = {2024}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Mohammadi, S and Zemorshidi, F and Ramezani, M and Hesami, O and Pezeshgi, S and Batouli, SAH}, title = {Volume loss in the left anterior-superior subunit of the hypothalamus in amyotrophic lateral sclerosis.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {6}, pages = {e14801}, pmid = {38887187}, issn = {1755-5949}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Hypothalamus/diagnostic imaging/pathology ; Aged ; *Magnetic Resonance Imaging ; Adult ; }, abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic lateral sclerosis (ALS) causes motor neuron loss and progressive paralysis. While traditionally viewed as motor neuron disease (MND), ALS also affects non-motor regions, such as the hypothalamus. This study aimed to quantify the hypothalamic subregion volumes in patients with ALS versus healthy controls (HCs) and examine their associations with demographic and clinical features.

METHODS: Forty-eight participants (24 ALS patients and 24 HCs) underwent structural MRI. A deep convolutional neural network was used for the automated segmentation of the hypothalamic subunits, including the anterior-superior (a-sHyp), anterior-inferior (a-iHyp), superior tuberal (supTub), inferior tuberal (infTub), and posterior (posHyp). The neural network was validated using FreeSurfer v7.4.1, with individual head size variations normalized using total intracranial volume (TIV) normalization. Statistical analyses were performed for comparisons using independent sample t-tests. Correlations were calculated using Pearson's and Spearman's tests (p < 0.05). The standard mean difference (SMD) was used to compare the mean differences between parametric variables.

RESULTS: The volume of the left a-sHyp hypothalamic subunit was significantly lower in ALS patients than in HCs (p = 0.023, SMD = -0.681). No significant correlation was found between the volume of the hypothalamic subunits, body mass index (BMI), and ALSFRS-R in patients with ALS. However, right a-sHyp (r = 0.420, p = 0.041) was correlated with disease duration, whereas right supTub (r = -0.471, p = 0.020) and left postHyp (r = -0.406, p = 0.049) were negatively correlated with age. There was no significant difference in the volume of hypothalamic subunits between males and females, and no significant difference was found between patients with revised ALS Functional Rating Scale (ALSFRS-R) scores ≤41 and >41 and those with a disease duration of 9 months or less.

DISCUSSION AND CONCLUSION: The main finding suggests atrophy of the left a-sHyp hypothalamic subunit in patients with ALS, which is supported by previous research as an extra-motor neuroimaging finding for ALS.}, } @article {pmid38887384, year = {2024}, author = {Tang, X and Li, Q and Huang, G and Chen, Z and Huang, Y and Pei, X and Zhao, S and Liu, Z and Guo, T and Liang, F}, title = {Immediate Efficacy of Contralateral Acupuncture on SI3 Combined with Active Exercise for Acute Lumbar Sprains: Protocol for a Randomized Controlled Trial.}, journal = {Journal of pain research}, volume = {17}, number = {}, pages = {2099-2110}, pmid = {38887384}, issn = {1178-7090}, abstract = {PURPOSE: Acute lumbar sprain (ALS) is a common clinical disease characterized by persistent intolerable low back pain and limitation of movement, and quick pain relief and restoration of mobility in a short time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of contralateral acupuncture (CAT) on SI3 combined with active exercise in treating ALS.

METHODS AND ANALYSIS: This study is a randomized controlled trial which will recruit 118 eligible participants aged 18 to 55 years with ALS at the Second Affiliated Hospital of Yunnan University of Chinese Medicine between March 2024 and December 2026. Participants will be randomly assigned to the acupuncture group or the sham-acupuncture group in a 1:1 ratio. The acupuncture group will receive a 10-minute acupuncture treatment combined with active exercise, while the sham-acupuncture group will receive a 10-minute sham acupuncture treatment combined with active exercise. Randomization will use a computer-generated sequence with allocation concealed in opaque envelopes. The primary outcome will be the pain visual analogue scale (VAS) scores after 10 minutes of treatment. Secondary outcomes will include the pain VAS scores at other time points (2, 4, 6, and 8 minutes post-treatment), the lumbar range of motion (ROM) scores at various time points, blinded assessment, the treatment effect expectancy scale, and the rescue analgesia rate. The analysis will follow the intention-to-treat principle. The primary outcome will be analyzed using ANCOVA, and secondary outcomes with repeated measures ANOVA. The rescue analgesia rate will be assessed using either the χ[2] test or Fisher's exact test.

DISCUSSION: This study is the first randomized controlled trial to assess the immediate efficacy of CAT in combination with active exercise for ALS. This study will provide a simple, rapid, and effective treatment for the clinical management of ALS.}, } @article {pmid38887944, year = {2024}, author = {Mendes, AE and Silva, GD and Jorge, FMH and Callegaro, D}, title = {Tongue pressure is a strong predictor of recommendation for gastrostomy in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {3}, pages = {409-412}, doi = {10.1002/mus.28174}, pmid = {38887944}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/therapy ; *Gastrostomy ; Female ; Male ; Middle Aged ; Aged ; Prospective Studies ; *Tongue/physiopathology ; Pressure ; ROC Curve ; Follow-Up Studies ; }, abstract = {INTRODUCTION/AIMS: Objective and practical biomarkers to determine the need for gastrostomy in patients with amyotrophic lateral sclerosis (ALS) are lacking. Tongue pressure (TP) is a promising biomarker because it is associated with bulbar dysfunction. The aims of this study were to evaluate the association of TP with the need for gastrostomy, and to determine its optimal cut-off value.

METHODS: This prospective observational study included participants with ALS taking nutrition orally. TP was evaluated using the Iowa Oral Performance Instrument. Need for gastrostomy as determined by a multidisciplinary team during a 12-month follow up period was recorded. Associations between TP and need for gastrostomy placement were performed. ROC curve analysis determined the optimal cut-off value of TP to predict gastrostomy.

RESULTS: Of 208 screened participants, 119 were included. Gastrostomy was indicated in 45% (53), in a 12-month follow up period. TP of ≤20 kPA was a strong predictor of gastrostomy indication (OR 11.8, CI 95% [4.61, 34.7], p < .001). The association persisted even after adjustment for weight loss, pneumonia, prolonged feeding duration, Revised ALS Functional Rating Scale score, and American Speech-Language-Hearing Association scale score (OR 4.51, CI 95% [1.50, 14.9], p = .009). By receiver operating characteristic curve analysis, 20 kPA represented the optimal cut-off value (sensitivity 0.75, specificity 0.89).

DISCUSSION: TP is a strong independent predictor of gastrostomy indication in the subsequent 12 months in patients with ALS, with good sensitivity and specificity at a cutoff value of ≤20 kPA, suggesting that it may be a promising biomarker in clinical practice.}, } @article {pmid38888068, year = {2024}, author = {Shefner, JM and Cudkowicz, ME}, title = {Failures to Replicate: What Recent Negative Phase 3 Trials Have Taught Us about Amyotrophic Lateral Sclerosis Clinical Research.}, journal = {Annals of neurology}, volume = {96}, number = {2}, pages = {211-215}, doi = {10.1002/ana.26999}, pmid = {38888068}, issn = {1531-8249}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Clinical Trials, Phase III as Topic/methods ; Biomedical Research ; }, } @article {pmid38889403, year = {2024}, author = {Zhu, Y and Wang, F and Xia, Y and Wang, L and Lin, H and Zhong, T and Wang, X}, title = {Research progress on astrocyte-derived extracellular vesicles in the pathogenesis and treatment of neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {8}, pages = {855-875}, pmid = {38889403}, issn = {2191-0200}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; *Astrocytes/metabolism ; Animals ; Cell Communication/physiology ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), pose significant global health risks and represent a substantial public health concern in the contemporary era. A primary factor in the pathophysiology of these disorders is aberrant accumulation and aggregation of pathogenic proteins within the brain and spinal cord. Recent investigations have identified extracellular vesicles (EVs) in the central nervous system (CNS) as potential carriers for intercellular transport of misfolded proteins associated with neurodegenerative diseases. EVs are involved in pathological processes that contribute to various brain disorders including neurodegenerative disorders. Proteins linked to neurodegenerative disorders are secreted and distributed from cell to cell via EVs, serving as a mechanism for direct intercellular communication through the transfer of biomolecules. Astrocytes, as active participants in CNS intercellular communication, release astrocyte-derived extracellular vesicles (ADEVs) that are capable of interacting with diverse target cells. This review primarily focuses on the involvement of ADEVs in the development of neurological disorders and explores their potential dual roles - both advantageous and disadvantageous in the context of neurological disorders. Furthermore, this review examines the current studies investigating ADEVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases. The prospects and challenges associated with the application of ADEVs in clinical settings were also comprehensively reviewed.}, } @article {pmid38889523, year = {2024}, author = {Müller, HP and Abrahao, A and Beaulieu, C and Benatar, M and Dionne, A and Genge, A and Frayne, R and Graham, SJ and Gibson, S and Korngut, L and Luk, C and Welsh, RC and Zinman, L and Kassubek, J and Kalra, S}, title = {Temporal and spatial progression of microstructural cerebral degeneration in ALS: A multicentre longitudinal diffusion tensor imaging study.}, journal = {NeuroImage. Clinical}, volume = {43}, number = {}, pages = {103633}, pmid = {38889523}, issn = {2213-1582}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Disease Progression ; *Diffusion Tensor Imaging/methods ; Longitudinal Studies ; Aged ; *Pyramidal Tracts/diagnostic imaging/pathology ; Adult ; Cross-Sectional Studies ; Anisotropy ; Prospective Studies ; }, abstract = {OBJECTIVE: The corticospinal tract (CST) reveals progressive microstructural alterations in ALS measurable by DTI. The aim of this study was to evaluate fractional anisotropy (FA) along the CST as a longitudinal marker of disease progression in ALS.

METHODS: The study cohort consisted of 114 patients with ALS and 110 healthy controls from the second prospective, longitudinal, multicentre study of the Canadian ALS Neuroimaging Consortium (CALSNIC-2). DTI and clinical data from a harmonized protocol across 7 centres were collected. Thirty-nine ALS patients and 61 controls completed baseline and two follow-up visits and were included for longitudinal analyses. Whole brain-based spatial statistics and hypothesis-guided tract-of-interest analyses were performed for cross-sectional and longitudinal analyses.

RESULTS: FA was reduced at baseline and longitudinally in the CST, mid-corpus callosum (CC), frontal lobe, and other ALS-related tracts, with alterations most evident in the CST and mid-CC. CST and pontine FA correlated with functional impairment (ALSFRS-R), upper motor neuron function, and clinical disease progression rate. Reduction in FA was largely located in the upper CST; however, the longitudinal decline was greatest in the lower CST. Effect sizes were dependent on region, resulting in study group sizes between 17 and 31 per group over a 9-month interval. Cross-sectional effect sizes were maximal in the upper CST; whereas, longitudinal effect sizes were maximal in mid-callosal tracts.

CONCLUSIONS: Progressive microstructural alterations in ALS are most prominent in the CST and CC. DTI can provide a biomarker of cerebral degeneration in ALS, with longitudinal changes in white matter demonstrable over a reasonable observation period, with a feasible number of participants, and within a multicentre framework.}, } @article {pmid37720544, year = {2023}, author = {McGoldrick, P and Robertson, J}, title = {Unraveling the impact of disrupted nucleocytoplasmic transport systems in C9orf72-associated ALS.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1247297}, pmid = {37720544}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two adult-onset neurodegenerative diseases that are part of a common disease spectrum due to clinical, genetic, and pathological overlap. A prominent genetic factor contributing to both diseases is a hexanucleotide repeat expansion in a non-coding region of the C9orf72 gene. This mutation in C9orf72 leads to nuclear depletion and cytoplasmic aggregation of Tar DNA-RNA binding protein 43 (TDP-43). TDP-43 pathology is characteristic of the majority of ALS cases, irrespective of disease causation, and is present in ~50% of FTD cases. Defects in nucleocytoplasmic transport involving the nuclear pore complex, the Ran-GTPase cycle, and nuclear transport factors have been linked with the mislocalization of TDP-43. Here, we will explore and discuss the implications of these system abnormalities of nucleocytoplasmic transport in C9orf72-ALS/FTD, as well as in other forms of familial and sporadic ALS.}, } @article {pmid37720552, year = {2023}, author = {Naskar, A and Nayak, A and Salaikumaran, MR and Vishal, SS and Gopal, PP}, title = {Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1242925}, pmid = {37720552}, issn = {1662-5099}, support = {R01 NS122907/NS/NINDS NIH HHS/United States ; }, abstract = {Liquid-liquid phase separation results in the formation of dynamic biomolecular condensates, also known as membrane-less organelles, that allow for the assembly of functional compartments and higher order structures within cells. Multivalent, reversible interactions between RNA-binding proteins (RBPs), including FUS, TDP-43, and hnRNPA1, and/or RNA (e.g., RBP-RBP, RBP-RNA, RNA-RNA), result in the formation of ribonucleoprotein (RNP) condensates, which are critical for RNA processing, mRNA transport, stability, stress granule assembly, and translation. Stress granules, neuronal transport granules, and processing bodies are examples of cytoplasmic RNP condensates, while the nucleolus and Cajal bodies are representative nuclear RNP condensates. In neurons, RNP condensates promote long-range mRNA transport and local translation in the dendrites and axon, and are essential for spatiotemporal regulation of gene expression, axonal integrity and synaptic function. Mutations of RBPs and/or pathologic mislocalization and aggregation of RBPs are hallmarks of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease. ALS/FTD-linked mutations of RBPs alter the strength and reversibility of multivalent interactions with other RBPs and RNAs, resulting in aberrant phase transitions. These aberrant RNP condensates have detrimental functional consequences on mRNA stability, localization, and translation, and ultimately lead to compromised axonal integrity and synaptic function in disease. Pathogenic protein aggregation is dependent on various factors, and aberrant dynamically arrested RNP condensates may serve as an initial nucleation step for pathologic aggregate formation. Recent studies have focused on identifying mechanisms by which neurons resolve phase transitioned condensates to prevent the formation of pathogenic inclusions/aggregates. The present review focuses on the phase separation of neurodegenerative disease-linked RBPs, physiological functions of RNP condensates, and the pathologic role of aberrant phase transitions in neurodegenerative disease, particularly ALS/FTD. We also examine cellular mechanisms that contribute to the resolution of aberrant condensates in neurons, and potential therapeutic approaches to resolve aberrantly phase transitioned condensates at a molecular level.}, } @article {pmid37720931, year = {2023}, author = {Martínez-Camarena, Á and Sour, A and Faller, P}, title = {Impact of human serum albumin on Cu[II] and Zn[II] complexation by ATSM (diacetyl-bis(N4-methylthiosemicarbazone)) and a water soluble analogue.}, journal = {Dalton transactions (Cambridge, England : 2003)}, volume = {52}, number = {38}, pages = {13758-13768}, doi = {10.1039/d3dt02380j}, pmid = {37720931}, issn = {1477-9234}, mesh = {Humans ; *Coordination Complexes ; *Organometallic Compounds/chemistry ; Diacetyl ; Serum Albumin, Human ; Ligands ; Zinc ; *Thiosemicarbazones/chemistry ; Copper Radioisotopes ; Radiopharmaceuticals ; }, abstract = {The chelator diacetyl-bis(N4-methylthiosemicarbazone) (ATSM) and its complexes with Cu[II] and Zn[II] are becoming increasingly investigated for medical applications such as PET imaging for anti-tumour therapy and the treatment of amyotrophic lateral sclerosis. However, the solubility in water of both the ligand and the complexes presents certain limitations for in vitro studies. Moreover, the stability of the Cu[II] and Zn[II] complexes and their metal exchange reaction against the potential biological competitor human serum albumin (HSA) has not been studied in depth. In this work it was observed that the ATSM with an added carboxylic group into the structure increases its solubility in aqueous solutions without altering the coordination mode and the conjugated system of the ligand. The poorly water-soluble Cu[II]- and Zn[II]-ATSM complexes were prevented from precipitating due to the binding to HSA. Both HSA and ATSM show a similar thermodynamic affinity for Zn[II]. Finally, the Cu[II]-competition experiments with EDTA and the water-soluble ATSM ligands yielded an apparent log Kd at pH 7.4 of about -19. When ATSM was added to Cu[II]- and Zn[II]-loaded HSA, withdrawing of Zn[II] was kinetically favoured, but this metal is slowly substituted by the Cu[II] afterwards taken from HSA so that this protein could be considered as a source of Cu[II] for ATSM.}, } @article {pmid37721118, year = {2024}, author = {Gao, J and Jiang, M and Erricolo, D and Magin, RL and Morfini, G and Royston, T and Larson, AC and Li, W}, title = {Identifying potential imaging markers for diffusion property changes in a mouse model of amyotrophic lateral sclerosis: Application of the continuous time random walk model to ultrahigh b-value diffusion-weighted MR images of spinal cord tissue.}, journal = {NMR in biomedicine}, volume = {37}, number = {1}, pages = {e5037}, doi = {10.1002/nbm.5037}, pmid = {37721118}, issn = {1099-1492}, support = {RO1CA181658/GF/NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Superoxide Dismutase-1 ; Spinal Cord/diagnostic imaging/pathology ; Mice, Transgenic ; Diffusion Magnetic Resonance Imaging ; Disease Models, Animal ; }, abstract = {Diffusion MRI (dMRI) explores tissue microstructures by analyzing diffusion-weighted signal decay measured at different b-values. While relatively low b-values are used for most dMRI models, high b-value diffusion-weighted imaging (DWI) techniques have gained interest given that the non-Gaussian water diffusion behavior observed at high b-values can yield potentially valuable information. In this study, we investigated anomalous diffusion behaviors associated with degeneration of spinal cord tissue using a continuous time random walk (CTRW) model for DWI data acquired across an extensive range of ultrahigh b-values. The diffusion data were acquired in situ from the lumbar level of spinal cords of wild-type and age-matched transgenic SOD1[G93A] mice, a well-established animal model of amyotrophic lateral sclerosis (ALS) featuring progressive degeneration of axonal tracts in this tissue. Based on the diffusion decay behaviors at low and ultrahigh b-values, we applied the CTRW model using various combinations of b-values and compared diffusion metrics calculated from the CTRW model between the experimental groups. We found that diffusion-weighted signal decay curves measured with ultrahigh b-values (up to 858,022 s/mm[2] in this study) were well represented by the CTRW model. The anomalous diffusion coefficient obtained from lumbar spinal cords was significantly higher in SOD1[G93A] mice compared with control mice (14.7 × 10[-5] ± 5.54 × 10[-5] vs. 7.87 × 10[-5] ± 2.48 × 10[-5] mm[2] /s, p = 0.01). We believe this is the first study to illustrate the efficacy of the CTRW model for analyzing anomalous diffusion regimes at ultrahigh b-values. The CTRW modeling of ultrahigh b-value dMRI can potentially present a novel approach for noninvasively evaluating alterations in spinal cord tissue associated with ALS pathology.}, } @article {pmid37721161, year = {2024}, author = {Guo, K and Figueroa-Romero, C and Noureldein, MH and Murdock, BJ and Savelieff, MG and Hur, J and Goutman, SA and Feldman, EL}, title = {Gut microbiome correlates with plasma lipids in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {2}, pages = {665-679}, pmid = {37721161}, issn = {1460-2156}, support = {UL1TR002240/NH/NIH HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01TS000339/ACL/ACL HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; R01 TS000339/TS/ATSDR CDC HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; /CC/CDC HHS/United States ; UL1 TR000433/TR/NCATS NIH HHS/United States ; UM1 TR004404/TR/NCATS NIH HHS/United States ; R01 TS000289/TS/ATSDR CDC HHS/United States ; R01TS000289/ACL/ACL HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Gastrointestinal Microbiome/genetics ; *Neurodegenerative Diseases ; Biomarkers ; Lipids ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex, fatal neurodegenerative disease. Disease pathophysiology is incompletely understood but evidence suggests gut dysbiosis occurs in ALS, linked to impaired gastrointestinal integrity, immune system dysregulation and altered metabolism. Gut microbiome and plasma metabolome have been separately investigated in ALS, but little is known about gut microbe-plasma metabolite correlations, which could identify robust disease biomarkers and potentially shed mechanistic insight. Here, gut microbiome changes were longitudinally profiled in ALS and correlated to plasma metabolome. Gut microbial structure at the phylum level differed in ALS versus control participants, with differential abundance of several distinct genera. Unsupervised clustering of microbe and metabolite levels identified modules, which differed significantly in ALS versus control participants. Network analysis found several prominent amplicon sequence variants strongly linked to a group of metabolites, primarily lipids. Similarly, identifying the features that contributed most to case versus control separation pinpointed several bacteria correlated to metabolites, predominantly lipids. Mendelian randomization indicated possible causality from specific lipids related to fatty acid and acylcarnitine metabolism. Overall, the results suggest ALS cases and controls differ in their gut microbiome, which correlates with plasma metabolites, particularly lipids, through specific genera. These findings have the potential to identify robust disease biomarkers and shed mechanistic insight into ALS.}, } @article {pmid37721281, year = {2024}, author = {Jourdi, G and Fleury, S and Boukhatem, I and Lordkipanidzé, M}, title = {Soluble p75 neurotrophic receptor as a reliable biomarker in neurodegenerative diseases: what is the evidence?.}, journal = {Neural regeneration research}, volume = {19}, number = {3}, pages = {536-541}, pmid = {37721281}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are often misdiagnosed, especially when the diagnosis is based solely on clinical symptoms. The p75 neurotrophic receptor (p75[NTR]) has been studied as an index of sensory and motor nerve development and maturation. Its cleavable extracellular domain (ECD) is readily detectable in various biological fluids including plasma, serum and urine. There is evidence for increased p75[NTR] ECD levels in neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, age-related dementia, schizophrenia, and diabetic neuropathy. Whether p75[NTR] ECD could be used as a biomarker for diagnosis and/or prognosis in these disorders, and whether it could potentially lead to the development of targeted therapies, remains an open question. In this review, we present and discuss published studies that have evaluated the relevance of this emerging biomarker in the context of various neurodegenerative diseases. We also highlight areas that require further investigation to better understand the role of p75[NTR] ECD in the clinical diagnosis and management of neurodegenerative disorders.}, } @article {pmid37722062, year = {2023}, author = {Chi, B and Öztürk, MM and Paraggio, CL and Leonard, CE and Sanita, ME and Dastpak, M and O'Connell, JD and Coady, JA and Zhang, J and Gygi, SP and Lopez-Gonzalez, R and Yin, S and Reed, R}, title = {Causal ALS genes impact the MHC class II antigen presentation pathway.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {39}, pages = {e2305756120}, pmid = {37722062}, issn = {1091-6490}, support = {R01 GM067945/GM/NIGMS NIH HHS/United States ; R35 GM122524/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Antigen Presentation/genetics ; Genes, MHC Class II ; Major Histocompatibility Complex ; Motor Neurons ; RNA-Binding Proteins/genetics ; Nuclear Matrix-Associated Proteins ; }, abstract = {Mutations in RNA/DNA-binding proteins cause amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain unclear. Here, we report that a set of ALS-associated proteins, namely FUS, EWSR1, TAF15, and MATR3, impact the expression of genes encoding the major histocompatibility complex II (MHC II) antigen presentation pathway. Both subunits of the MHC II heterodimer, HLA-DR, are down-regulated in ALS gene knockouts/knockdown in HeLa and human microglial cells, due to loss of the MHC II transcription factor CIITA. Importantly, hematopoietic progenitor cells (HPCs) derived from human embryonic stem cells bearing the FUS[R495X] mutation and HPCs derived from C9ORF72 ALS patient induced pluripotent stem cells also exhibit disrupted MHC II expression. Given that HPCs give rise to numerous immune cells, our data raise the possibility that loss of the MHC II pathway results in global failure of the immune system to protect motor neurons from damage that leads to ALS.}, } @article {pmid37723203, year = {2023}, author = {Huang, X and Jia, H and Xu, J and Wang, Y and Wen, J and Wang, N}, title = {Transgene-free genome editing of vegetatively propagated and perennial plant species in the T0 generation via a co-editing strategy.}, journal = {Nature plants}, volume = {9}, number = {10}, pages = {1591-1597}, pmid = {37723203}, issn = {2055-0278}, support = {2022-70029-38471//US Department of Agriculture/ ; 2021-67013-34588//US Department of Agriculture/ ; 2018-70016-27412//US Department of Agriculture/ ; 2016-70016-24833//US Department of Agriculture/ ; FLA-CRC-005979//Florida Department of Agriculture and Consumer Services/ ; }, mesh = {*Gene Editing ; CRISPR-Cas Systems ; Transgenes ; Plants, Genetically Modified/genetics ; *Herbicides ; Genome, Plant ; }, abstract = {Transgene-free plant genome editing in the T0 generation is highly desirable but challenging[1,2]. Here we achieved such a goal using a co-editing strategy via Agrobacterium-mediated transient expression of cytosine base editor to edit ALS encoding acetolactate synthase to confer herbicide chlorsulfuron resistance as a selection marker, Cas12a/CRISPR RNA for editing gene(s) of interest, and green fluorescent protein for selecting transgene-free transformants. The biallelic/homozygous transgene-free mutation rates for target genes among herbicide-resistant transformants ranged from 1.9% to 42.1% in tomato, tobacco, potato and citrus. This co-editing strategy is particularly useful for transgene-free genome editing of vegetatively propagated and perennial plant species in the T0 generation.}, } @article {pmid37723585, year = {2023}, author = {Beckers, J and Tharkeshwar, AK and Fumagalli, L and Contardo, M and Van Schoor, E and Fazal, R and Thal, DR and Chandran, S and Mancuso, R and Van Den Bosch, L and Van Damme, P}, title = {A toxic gain-of-function mechanism in C9orf72 ALS impairs the autophagy-lysosome pathway in neurons.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {151}, pmid = {37723585}, issn = {2051-5960}, support = {MR/N013255/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; Gain of Function Mutation ; Lysosomes ; Motor Neurons ; Autophagy ; }, abstract = {BACKGROUND: Motor neurons (MNs), which are primarily affected in amyotrophic lateral sclerosis (ALS), are a specialized type of neurons that are long and non-dividing. Given their unique structure, these cells heavily rely on transport of organelles along their axons and the process of autophagy to maintain their cellular homeostasis. It has been shown that disruption of the autophagy pathway is sufficient to cause progressive neurodegeneration and defects in autophagy have been associated with various subtypes of ALS, including those caused by hexanucleotide repeat expansions in the C9orf72 gene. A more comprehensive understanding of the dysfunctional cellular mechanisms will help rationalize the design of potent and selective therapies for C9orf72-ALS.

METHODS: In this study, we used induced pluripotent stem cell (iPSC)-derived MNs from C9orf72-ALS patients and isogenic control lines to identify the underlying mechanisms causing dysregulations of the autophagy-lysosome pathway. Additionally, to ascertain the potential impact of C9orf72 loss-of-function on autophagic defects, we characterized the observed phenotypes in a C9orf72 knockout iPSC line (C9-KO).

RESULTS: Despite the evident presence of dysfunctions in several aspects of the autophagy-lysosome pathway, such as disrupted lysosomal homeostasis, abnormal lysosome morphology, inhibition of autophagic flux, and accumulation of p62 in C9orf72-ALS MNs, we were surprised to find that C9orf72 loss-of-function had minimal influence on these phenotypes. Instead, we primarily observed impairment in endosome maturation as a result of C9orf72 loss-of-function. Additionally, our study shed light on the pathological mechanisms underlying C9orf72-ALS, as we detected an increased TBK1 phosphorylation at S172 in MNs derived from C9orf72 ALS patients.

CONCLUSIONS: Our data provides further insight into the involvement of defects in the autophagy-lysosome pathway in C9orf72-ALS and strongly indicate that those defects are mainly due to the toxic gain-of-function mechanisms underlying C9orf72-ALS.}, } @article {pmid37725216, year = {2024}, author = {Dar, NJ and John, U and Bano, N and Khan, S and Bhat, SA}, title = {Oxytosis/Ferroptosis in Neurodegeneration: the Underlying Role of Master Regulator Glutathione Peroxidase 4 (GPX4).}, journal = {Molecular neurobiology}, volume = {61}, number = {3}, pages = {1507-1526}, pmid = {37725216}, issn = {1559-1182}, mesh = {Humans ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; *Ferroptosis ; Cell Death ; Oxidation-Reduction ; *Neurodegenerative Diseases ; Glutathione Peroxidase/metabolism ; Glutathione/metabolism ; Lipid Peroxidation ; }, abstract = {Oxytosis/ferroptosis is an iron-dependent oxidative form of cell death triggered by lethal accumulation of phospholipid hydroperoxides (PLOOHs) in membranes. Failure of the intricate PLOOH repair system is a principle cause of ferroptotic cell death. Glutathione peroxidase 4 (GPX4) is distinctly vital for converting PLOOHs in membranes to non-toxic alcohols. As such, GPX4 is known as the master regulator of oxytosis/ferroptosis. Ferroptosis has been implicated in a number of disorders such as neurodegenerative diseases (amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), etc.), ischemia/reperfusion injury, and kidney degeneration. Reduced function of GPX4 is frequently observed in degenerative disorders. In this study, we examine how diminished GPX4 function may be a critical event in triggering oxytosis/ferroptosis to perpetuate or initiate the neurodegenerative diseases and assess the possible therapeutic importance of oxytosis/ferroptosis in neurodegenerative disorders. These discoveries are important for advancing our understanding of neurodegenerative diseases because oxytosis/ferroptosis may provide a new target to slow the course of the disease.}, } @article {pmid37725878, year = {2023}, author = {Singh, N and Vishwas, S and Kaur, A and Kaur, H and Kakoty, V and Khursheed, R and Chaitanya, MVNL and Babu, MR and Awasthi, A and Corrie, L and Harish, V and Yanadaiah, P and Gupta, S and Sayed, AA and El-Sayed, A and Ali, I and Kensara, OA and Ghaboura, N and Gupta, G and Dou, AM and Algahtani, M and El-Kott, AF and Dua, K and Singh, SK and Abdel-Daim, MM}, title = {Harnessing role of sesamol and its nanoformulations against neurodegenerative diseases.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {167}, number = {}, pages = {115512}, doi = {10.1016/j.biopha.2023.115512}, pmid = {37725878}, issn = {1950-6007}, mesh = {*Benzodioxoles/administration & dosage/chemistry/therapeutic use/pharmacology/pharmacokinetics ; Animals ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Phenols/administration & dosage/chemistry/therapeutic use/pharmacology/pharmacokinetics ; *Neuroprotective Agents/administration & dosage/chemistry ; *Nanoparticles ; Drug Compounding ; }, abstract = {Sesamol is a lignan of sesame seeds and a natural phenolic molecule that has emerged as a useful medical agent. Sesamol is a non-toxic phytoconstituent, which exerts certain valuable effects in the management of cancer, diabetes, cardiovascular diseases, neurodegenerative diseases (NDs), etc. Sesamol is known to depict its neuroprotective role by various mechanisms, such as metabolic regulators, action on oxidative stress, neuroinflammation, etc. However, its poor oral bioavailability, rapid excretion (as conjugates), and susceptibility to gastric irritation/toxicity (particularly in rats' forestomach) may restrict its effectiveness. To overcome the associated limitations, novel drug delivery system-based formulations of sesamol are emerging and being researched extensively. These can conjugate with sesamol and enhance the bioavailability and solubility of free sesamol, along with delivery at the target site. In this review, we have summarized various research works highlighting the role of sesamol on various NDs, including Alzheimer's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Parkinson's disease. Moreover, the formulation strategies and neuroprotective role of sesamol-based nano-formulations have also been discussed.}, } @article {pmid37725936, year = {2024}, author = {Giannakopoulos, A and Papanastasiou, AD and Zarkadis, IK and Andrew, SF and Rosenfeld, RG and Efthymiadou, A and Chrysis, D and Hwa, V}, title = {A Novel, Heterozygous, de novo Splicing Variant Affecting the Intracellular Domain of the Growth Hormone Receptor, and Causing a Mild Short Stature.}, journal = {Hormone research in paediatrics}, volume = {97}, number = {4}, pages = {397-403}, doi = {10.1159/000534183}, pmid = {37725936}, issn = {1663-2826}, mesh = {Humans ; Male ; Adolescent ; *Receptors, Somatotropin/genetics ; Heterozygote ; RNA Splicing ; Laron Syndrome/genetics ; Protein Domains ; Dwarfism/genetics ; Mutation ; Body Height/genetics ; }, abstract = {INTRODUCTION: Although the majority of growth hormone insensitivity syndrome (GHIS) cases are classical, the spectrum of clinical phenotypes has expanded to include "atypical" GHIS subjects with milder phenotypes due to very rare heterozygous growth hormone receptor (GHR) mutations with dominant negative effects.

CASE PRESENTATION: A 13-year-old pubertal boy presented with short stature (-1.7 SDS) and delayed bone age (11.5 years). His serum IGF-1 was low (16 ng/mL; reference range: 179-540). IGFBP-3 (1.3 mg/L; 3.1-9.5) and ALS (565 mU/mL; 1,500-3,500) were also low. GH stimulation test was normal, and GHBP was markedly elevated (6,300 pmol/L; 240-3,000). Additionally, the boy had insulin resistance and liver steatosis. His final height reached -1.8 SDS, which was 3.0 SDS below his mid-parental height. GHR gene from genomic DNA and established primary fibroblast culture was analyzed and a synonymous heterozygous GHR: c.945G>A variant, in the last nucleotide of exon 9 (encoding intracellular domain of GHR) was identified. In vitro analysis of the GHR cDNA demonstrated a splicing defect, leading to the heterozygous excision of exon 9. The final predicted product was a truncated GHR protein which explained the elevated GHBP levels.

CONCLUSION: We describe the first synonymous heterozygous GHR splicing variant in the exon 9-encoding part of the intracellular domain of GHR identified in a patient with mild short stature, thus supporting the continuum of genotype-phenotype of GHIS.}, } @article {pmid37728307, year = {2024}, author = {Shefner, JM and Bunte, T and Kittle, G and Genge, A and van den Berg, LH}, title = {Harmonized standard operating procedures for administering the ALS functional rating scale-revised.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {26-33}, doi = {10.1080/21678421.2023.2260832}, pmid = {37728307}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Outcome Assessment, Health Care ; Europe ; }, abstract = {The ALS Functional Rating Scale-Revised is the most commonly used primary outcome measure in current ALS clinical trials. While rigorous training and certification is generally recognized as critical to reliable performance, differences have existed between training in the two groups responsible for most training in ALS outcome measures. We present a harmonized standard operating procedure which is intended to further reduce response variability by the use of identical training in North America and Europe.}, } @article {pmid37728482, year = {2023}, author = {Keun, CH and Choi, SJ and Kim, YJ and Kim, SM and Hong, YH and Sung, JJ}, title = {Suicide Attempts in Patients With Amyotrophic Lateral Sclerosis: An Analysis of the Korean National Health Insurance Database.}, journal = {The Journal of clinical psychiatry}, volume = {84}, number = {6}, pages = {}, doi = {10.4088/JCP.22m14754}, pmid = {37728482}, issn = {1555-2101}, mesh = {Humans ; *Suicide, Attempted ; *Amyotrophic Lateral Sclerosis/epidemiology ; Cohort Studies ; National Health Programs ; Republic of Korea/epidemiology ; }, abstract = {Objective: The knowledge of the common risk factors for suicide attempts may not be simply applicable to patients with amyotrophic lateral sclerosis (ALS). We aimed to identify risk factors associated with suicide attempts in patients with ALS and to determine the annual prevalence and periods of vulnerability associated with attempts. Methods: This nationwide cohort study was performed using the Korean National Health Insurance Database. All patients with ALS concomitantly registered for the Exempted Calculation of Health Insurance for rare, incurable diseases between 2011 and 2017 were identified. We used the Cox proportional hazards regression model and competing risk model to identify the risk factors for suicide attempts. The multivariable models were adjusted for potential risk factors from the univariate analysis. Results: Among 2,955 incident patients, 47 attempted suicide. After adjusting for sex, previous attempts, and previous psychiatric disorders, the hazard ratios for psychiatric hospitalization before ALS diagnosis were 3.17 (95% confidence interval [CI], 1.31-7.70; P = .01) and 3.02 (95% CI, 1.32-6.90; P = .01) in the Cox regression model and the competing risk model, respectively. The annual prevalence of suicide attempts was 0.29%-1.12%. Twenty (42.6%) and 9 (19.1%) attempts occurred within 3 months and 12-18 months after diagnosis, respectively. Conclusions: Psychiatric hospitalization increased the risk of suicide attempts, which clustered at the early stage or on losing autonomy. Those with a history of psychiatric hospitalization should receive an in-depth evaluation and be cautiously monitored.}, } @article {pmid37729728, year = {2023}, author = {Anzilotti, S and Valente, V and Brancaccio, P and Franco, C and Casamassa, A and Lombardi, G and Palazzi, A and Conte, A and Paladino, S and Canzoniero, LMT and Annunziato, L and Pierantoni, GM and Pignataro, G}, title = {Chronic exposure to l-BMAA cyanotoxin induces cytoplasmic TDP-43 accumulation and glial activation, reproducing an amyotrophic lateral sclerosis-like phenotype in mice.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {167}, number = {}, pages = {115503}, doi = {10.1016/j.biopha.2023.115503}, pmid = {37729728}, issn = {1950-6007}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and often fatal neurodegenerative disease characterized by the loss of Motor Neurons (MNs) in spinal cord, motor cortex and brainstem. Despite significant efforts in the field, the exact pathogenetic mechanisms underlying both familial and sporadic forms of ALS have not been fully elucidated, and the therapeutic possibilities are still very limited. Here we investigate the molecular mechanisms of neurodegeneration induced by chronic exposure to the environmental cyanotoxin L-BMAA, which causes a form of ALS/Parkinson's disease (PD) in several populations consuming food and/or water containing high amounts of this compound.

METHODS: In this effort, mice were chronically exposed to L-BMAA and analyzed at different time points to evaluate cellular and molecular alterations and behavioral deficits, performing MTT assay, immunoblot, immunofluorescence and immunohistochemistry analysis, and behavioral tests.

RESULTS: We found that cyanotoxin L-BMAA determines apoptotic cell death and a marked astrogliosis in spinal cord and motor cortex, and induces neurotoxicity by favoring TDP-43 cytoplasmic accumulation.

CONCLUSIONS: Overall, our results characterize a new versatile neurotoxic animal model of ALS that may be useful for the identification of new druggable targets to develop innovative therapeutic strategies for this disease.}, } @article {pmid37730668, year = {2023}, author = {Zhu, L and Li, S and Li, XJ and Yin, P}, title = {Pathological insights from amyotrophic lateral sclerosis animal models: comparisons, limitations, and challenges.}, journal = {Translational neurodegeneration}, volume = {12}, number = {1}, pages = {46}, pmid = {37730668}, issn = {2047-9158}, mesh = {Humans ; Animals ; Swine ; *Amyotrophic Lateral Sclerosis/genetics ; *Neurodegenerative Diseases ; Brain ; }, abstract = {In order to dissect amyotrophic lateral sclerosis (ALS), a multigenic, multifactorial, and progressive neurodegenerative disease with heterogeneous clinical presentations, researchers have generated numerous animal models to mimic the genetic defects. Concurrent and comparative analysis of these various models allows identification of the causes and mechanisms of ALS in order to finally obtain effective therapeutics. However, most genetically modified rodent models lack overt pathological features, imposing challenges and limitations in utilizing them to rigorously test the potential mechanisms. Recent studies using large animals, including pigs and non-human primates, have uncovered important events that resemble neurodegeneration in patients' brains but could not be produced in small animals. Here we describe common features as well as discrepancies among these models, highlighting new insights from these models. Furthermore, we will discuss how to make rodent models more capable of recapitulating important pathological features based on the important pathogenic insights from large animal models.}, } @article {pmid37730935, year = {2024}, author = {Ferrari, C and Ingannato, A and Matà, S and Ramat, S and Caremani, L and Bagnoli, S and Bessi, V and Sorbi, S and Nacmias, B}, title = {Parkinson-ALS with a novel MAPT variant.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {3}, pages = {1051-1055}, pmid = {37730935}, issn = {1590-3478}, mesh = {Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics/pathology ; tau Proteins/genetics ; *Parkinson Disease/genetics ; Mutation/genetics ; *Parkinsonian Disorders/genetics ; }, abstract = {The mutations on microtubule associated protein tau (MAPT) gene manifest clinically with behavioural frontotemporal dementia (FTD), parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration, and rarely with amyotrophic lateral sclerosis (ALS). FTD-parkinsonism and FTD-ALS are clinical overlaps included in the spectrum of MAPT mutation's phenotypes. The mutations on MAPT gene cause the dysfunction of tau protein determining its accumulation in neurofibrillary tangles. Recent data describe frequently the co-occurrence of the aggregation of tau protein and α-synuclein in patients with parkinsonism and Parkinson disease (PD), suggesting an interaction of the two proteins in determining neurodegenerative process. The sporadic description of PD-ALS clinical complex, known as Brait-Fahn-Schwarz disease, supports the hypothesis of common neuropathological pathways between different disorders. Here we report the case of a 54-year-old Italian woman with idiopathic PD later complicated by ALS carrying a novel MAPT variant (Pro494Leu). The variant is characterized by an amino acid substitution and is classified as damaging for MAPT functions. The case supports the hypothesis of tau dysfunction as the basis of multiple neurodegenerative disorders.}, } @article {pmid37732211, year = {2023}, author = {Guo, L and Mann, JR and Mauna, JC and Copley, KE and Wang, H and Rubien, JD and Odeh, HM and Lin, J and Lee, BL and Ganser, L and Robinson, E and Kim, KM and Murthy, AC and Paul, T and Portz, B and Gleixner, AM and Diaz, Z and Carey, JL and Smirnov, A and Padilla, G and Lavorando, E and Espy, C and Shang, Y and Huang, EJ and Chesi, A and Fawzi, NL and Myong, S and Donnelly, CJ and Shorter, J}, title = {Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.09.04.555754}, pmid = {37732211}, issn = {2692-8205}, support = {F31 NS129101/NS/NINDS NIH HHS/United States ; R01 NS121143/NS/NINDS NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; RF1 NS121143/NS/NINDS NIH HHS/United States ; }, abstract = {RNA-binding proteins with prion-like domains, such as FUS and TDP-43, condense into functional liquids, which can transform into pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs (24-48 nucleotides) that prevent FUS fibrillization by promoting liquid phases, and distinct short RNAs that prevent and, remarkably, reverse FUS condensation and fibrillization. These activities require interactions with multiple RNA-binding domains of FUS and are encoded by RNA sequence, length, and structure. Importantly, we define a short RNA that dissolves aberrant cytoplasmic FUS condensates, restores nuclear FUS, and mitigates FUS proteotoxicity in optogenetic models and human motor neurons. Another short RNA dissolves aberrant cytoplasmic TDP-43 condensates, restores nuclear TDP-43, and mitigates TDP-43 proteotoxicity. Since short RNAs can be effectively delivered to the human brain, these oligonucleotides could have therapeutic utility for ALS/FTD and related disorders.}, } @article {pmid37733208, year = {2023}, author = {Hernández, S and Salvany, S and Casanovas, A and Piedrafita, L and Soto-Bernardini, MC and Tarabal, O and Blasco, A and Gras, S and Gatius, A and Schwab, MH and Calderó, J and Esquerda, JE}, title = {Persistent NRG1 Type III Overexpression in Spinal Motor Neurons Has No Therapeutic Effect on ALS-Related Pathology in SOD1[G93A] Mice.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {20}, number = {6}, pages = {1820-1834}, pmid = {37733208}, issn = {1878-7479}, support = {PID2021-122785OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; 202005-30//Fundació la Marató de TV3/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Mice, Transgenic ; Motor Neurons/pathology ; Neuregulin-1/genetics ; *Neurodegenerative Diseases/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons (MNs). Neuregulin-1 (NRG1) is a pleiotropic growth factor that has been shown to be potentially valuable for ALS when supplemented by means of viral-mediated gene therapy. However, these results are inconsistent with other reports. An alternative approach for investigating the therapeutic impact of NRG1 on ALS is the use of transgenic mouse lines with genetically defined NRG1 overexpression. Here, we took advantage of a mouse line with NRG1 type III overexpression in spinal cord α motor neurons (MN) to determine the impact of steadily enhanced NRG1 signalling on mutant superoxide dismutase 1 (SOD1)-induced disease. The phenotype of SOD1[G93A]-NRG1 double transgenic mice was analysed in detail, including neuropathology and extensive behavioural testing. At least 3 animals per condition and sex were histopathologically assessed, and a minimum of 10 mice per condition and sex were clinically evaluated. The accumulation of misfolded SOD1 (mfSOD1), MN degeneration, and a glia-mediated neuroinflammatory response are pathological hallmarks of ALS progression in SOD1[G93A] mice. None of these aspects was significantly improved when examined in double transgenic NRG1-SOD1[G93A] mice. In addition, behavioural testing revealed that NRG1 type III overexpression did not affect the survival of SOD1[G93A] mice but accelerated disease onset and worsened the motor phenotype.}, } @article {pmid37734132, year = {2023}, author = {Cengiz, B and Koçak, ÖK and Erdoğan, T and Yanık, E and Pek, G and Savrun, Y and Evren Boran, H and Reha Kuruoğlu, H}, title = {Excitability of somatosensory cortex is increased in ALS: A SEP recovery function study.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {155}, number = {}, pages = {58-64}, doi = {10.1016/j.clinph.2023.08.013}, pmid = {37734132}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Somatosensory Cortex/physiopathology ; Male ; Female ; *Evoked Potentials, Somatosensory/physiology ; Middle Aged ; Aged ; Adult ; *Recovery of Function/physiology ; Neural Conduction/physiology ; Evoked Potentials, Motor/physiology ; Median Nerve/physiopathology ; }, abstract = {OBJECTIVE: Neuronal loss in the somatosensory, as well as the motor cortex in amyotrophic lateral sclerosis (ALS), indicative of a structural abnormality has been reported. Previously we have shown that afferent inhibition was impaired in ALS, suggestive of sensory involvement. In this study, we aimed to evaluate excitability changes in the somatosensory cortex of ALS patients.

METHODS: ALS patients underwent a paired pulse somatosensory evoked potential (SEP) paradigm at various interstimulus intervals (ISI). The amplitude ratio obtained by dividing the amplitude of paired pulse SEP stimulation S2 (paired pulse stimulation) to S1 (the single pulse stimulation) was considered the somatosensory cortex excitability parameter. Findings were compared to the results obtained from healthy controls. Resting motor threshold (RMT) was also assessed in the ALS group.

RESULTS: An increased S2/S1 ratio was found in the ALS group in every ISI examined. Additionally, the reduced inhibition correlated negatively with forced vital capacity, Medical Research Council sum score, median nerve compound muscle action potential amplitude, while there was a positive association with Penn upper motor neuron score and sural nerve conduction velocity. No correlation existed with RMT.

CONCLUSIONS: Our findings demonstrated increased somatosensory cortical excitability in ALS, which was associated with clinical parameters such as reduced pulmonary function and motor strength.

SIGNIFICANCE: Somatosensory cortical excitability is impaired in ALS. Whether this is associated with increased motor cortical excitability requires further studies.}, } @article {pmid37734449, year = {2023}, author = {Hayashi, K and Sasaki, K}, title = {Number of kinesins engaged in axonal cargo transport: A novel biomarker for neurological disorders.}, journal = {Neuroscience research}, volume = {197}, number = {}, pages = {25-30}, doi = {10.1016/j.neures.2023.09.004}, pmid = {37734449}, issn = {1872-8111}, mesh = {Humans ; *Kinesins/metabolism ; Axonal Transport/physiology ; Axons/metabolism ; Dyneins/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Kinesin motor proteins play crucial roles in anterograde transport of cargo vesicles in neurons, moving them along axons from the cell body towards the synaptic region. Not only the transport force and velocity of single motor protein, but also the number of kinesin molecules involved in transporting a specific cargo, is pivotal for synapse formation. This collective transport by multiple kinesins ensures stable and efficient cargo transport in neurons. Abnormal increases or decreases in the number of engaged kinesin molecules per cargo could potentially act as biomarkers for neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), spastic paraplegia, polydactyly syndrome, and virus transport disorders. We review here a model constructed using physical measurements to quantify the number of kinesin molecules associated with their cargo, which could shed light on the molecular mechanisms of neurodegenerative diseases related to axonal transport.}, } @article {pmid37734916, year = {2023}, author = {Kredentser, MS and Mackenzie, CS and McClement, SE and Enns, MW and Hiebert-Murphy, D and Murphy, DJ and Chochinov, HM}, title = {Neuroticism as a moderator of symptom-related distress and depression in 4 noncancer end-of-life populations.}, journal = {Palliative & supportive care}, volume = {}, number = {}, pages = {1-9}, doi = {10.1017/S147895152300127X}, pmid = {37734916}, issn = {1478-9523}, abstract = {OBJECTIVES: Neuroticism is a significant predictor of adverse psychological outcomes in patients with cancer. Less is known about how this relationship manifests in those with noncancer illness at the end-of-life (EOL). The objective of this study was to examine the impact of neuroticism as a moderator of physical symptoms and development of depression in patients with amyotrophic lateral sclerosis (ALS), chronic obstructive pulmonary disease (COPD), end-stage renal disease (ESRD), and frailty in the last 6 months of life.

METHODS: We met this objective using secondary data collected in the Dignity and Distress across End-of-Life Populations study. The data included N = 404 patients with ALS (N = 101), COPD (N = 100), ESRD (N = 101), and frailty (N = 102) in the estimated last 6 months of life, with a range of illness-related symptoms, assessed longitudinally at 2 time points. We examined neuroticism as a moderator of illness-related symptoms at Time 1 (∼6 months before death) and depression at Time 2 (∼3 months before death) using ordinary least squares regression.

RESULTS: Results revealed that neuroticism significantly moderated the relationship between the following symptoms and depression measured 3 months later: drowsiness, fatigue, shortness of breath, wellbeing (ALS); drowsiness, trouble sleeping, will to live, activity (COPD); constipation (ESRD); and weakness and will to live (frailty).

SIGNIFICANCE OF RESULTS: These findings suggest that neuroticism represents a vulnerability factor that either attenuates or amplifies the relationship of specific illness and depressive symptoms in these noncancer illness groups at the EOL. Identifying those high in neuroticism may provide insight into patient populations that require special care at the EOL.}, } @article {pmid37735015, year = {2023}, author = {Corcia, P and Vourc'h, P and Bernard, E and Cassereau, J and Codron, P and Fleury, MC and Guy, N and Mouzat, K and Pradat, PF and Soriani, MH and Couratier, P}, title = {French National Protocol for genetic of amyotrophic lateral sclerosis.}, journal = {Revue neurologique}, volume = {179}, number = {9}, pages = {1020-1029}, doi = {10.1016/j.neurol.2023.05.005}, pmid = {37735015}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; Mutation ; }, abstract = {Relationships between genes and amyotrophic lateral sclerosis (ALS) have been widely accepted since the first studies highlighting pathogenic mutations in the SOD1 gene 30years ago. Over the last three decades, scientific literature has clearly highlighted the central role played by genetic factors in the disease, in both clinics and pathophysiology, as well as in therapeutics. This implies that health professionals who care for patients with ALS are increasingly faced with patients and relatives eager to have answers to questions related to the role of genetic factors in the occurrence of the disease and the risk for their relatives to develop ALS. In order to address these public health issues, the French ALS network FILSLAN proposed to the Haute Autorité de santé (HAS) the drafting of a French National Protocol (PNDS) on ALS genetics. This PNDS was developed according to the "method for developing a national diagnosis and care protocol for rare diseases" published by the HAS in 2012 (methodological guide for PNDS available on the HAS website: http://www.has-sante.fr/). This document aims to provide the most recent data on the role of genes in ALS and to detail the implications for diagnosis and care.}, } @article {pmid37735229, year = {2023}, author = {He, X and Yang, J and Feng, J and Huang, H and Dong, X and Zhao, Q and Shen, Q and Hu, C and Xu, Y}, title = {Venous blood parameters in determination of respiratory impairment in amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {15695}, pmid = {37735229}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Respiratory Insufficiency ; Leukocyte Count ; Cholesterol, HDL ; Cholesterol, LDL ; Creatinine ; }, abstract = {This study aimed to investigate the relationship between venous blood parameters and respiratory functions in patients with amyotrophic lateral sclerosis (ALS) and develop a model to predict respiratory impairment for individual patients with ALS. A total of 416 ALS patients were included in the study, and various hematologic and biochemical laboratory parameters as well as demographic and clinical factors were collected and compared. A multivariable logistic regression model was constructed to assess the association between FVC and venous blood biomarkers and clinical factors. The results showed that along with onset age, bulbar-onset, disease duration, BMI, eosinophil count (EO#), basophil count (BASO#), creatinine (CREA), uric acid (URCI) and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL/HDL) ratio were associated with reduced FVC. The area under the ROC curve is 0.735 for the test set and 0.721 for the validation set. The study also developed a relatively acceptable model for predicting respiratory impairment in ALS patients. These findings suggest that EO#, BASO#, CREA, URIC and LDL/HDL ratio can be useful in assessing FVC in ALS and can be easily accessible, accurate, and low-cost parameters.}, } @article {pmid37735487, year = {2023}, author = {Gao, C and Jiang, J and Tan, Y and Chen, S}, title = {Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets.}, journal = {Signal transduction and targeted therapy}, volume = {8}, number = {1}, pages = {359}, pmid = {37735487}, issn = {2059-3635}, mesh = {Animals ; *Neurodegenerative Diseases/genetics ; Microglia ; Neuroinflammatory Diseases ; Protein Aggregates ; *Alzheimer Disease/genetics ; }, abstract = {Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions. Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates and play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression. Microglia also act as a mobile vehicle to propagate protein aggregates. Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration. Thus, enhancing microglial phagocytosis, reducing microglial-mediated neuroinflammation, inhibiting microglial exosome synthesis and secretion, and promoting microglial conversion into a protective phenotype are considered to be promising strategies for the therapy of neurodegenerative diseases. Here we comprehensively review the biology of microglia and the roles of microglia in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and Huntington's disease. We also summarize the possible microglia-targeted interventions and treatments against neurodegenerative diseases with preclinical and clinical evidence in cell experiments, animal studies, and clinical trials.}, } @article {pmid37735622, year = {2023}, author = {Sarkar, S and Elliott, EC and Henry, HR and Ludovico, ID and Melchior, JT and Frazer-Abel, A and Webb-Robertson, BJ and Davidson, WS and Holers, VM and Rewers, MJ and Metz, TO and Nakayasu, ES}, title = {Systematic review of type 1 diabetes biomarkers reveals regulation in circulating proteins related to complement, lipid metabolism, and immune response.}, journal = {Clinical proteomics}, volume = {20}, number = {1}, pages = {38}, pmid = {37735622}, issn = {1542-6416}, support = {P30 DK116073/DK/NIDDK NIH HHS/United States ; R01 DK032493/DK/NIDDK NIH HHS/United States ; U01 DK127505/DK/NIDDK NIH HHS/United States ; U01 DK127786/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Type 1 diabetes (T1D) results from an autoimmune attack of the pancreatic β cells that progresses to dysglycemia and symptomatic hyperglycemia. Current biomarkers to track this evolution are limited, with development of islet autoantibodies marking the onset of autoimmunity and metabolic tests used to detect dysglycemia. Therefore, additional biomarkers are needed to better track disease initiation and progression. Multiple clinical studies have used proteomics to identify biomarker candidates. However, most of the studies were limited to the initial candidate identification, which needs to be further validated and have assays developed for clinical use. Here we curate these studies to help prioritize biomarker candidates for validation studies and to obtain a broader view of processes regulated during disease development.

METHODS: This systematic review was registered with Open Science Framework (https://doi.org/10.17605/OSF.IO/N8TSA). Using PRISMA guidelines, we conducted a systematic search of proteomics studies of T1D in the PubMed to identify putative protein biomarkers of the disease. Studies that performed mass spectrometry-based untargeted/targeted proteomic analysis of human serum/plasma of control, pre-seroconversion, post-seroconversion, and/or T1D-diagnosed subjects were included. For unbiased screening, 3 reviewers screened all the articles independently using the pre-determined criteria.

RESULTS: A total of 13 studies met our inclusion criteria, resulting in the identification of 266 unique proteins, with 31 (11.6%) being identified across 3 or more studies. The circulating protein biomarkers were found to be enriched in complement, lipid metabolism, and immune response pathways, all of which are found to be dysregulated in different phases of T1D development. We found 2 subsets: 17 proteins (C3, C1R, C8G, C4B, IBP2, IBP3, ITIH1, ITIH2, BTD, APOE, TETN, C1S, C6A3, SAA4, ALS, SEPP1 and PI16) and 3 proteins (C3, CLUS and C4A) have consistent regulation in at least 2 independent studies at post-seroconversion and post-diagnosis compared to controls, respectively, making them strong candidates for clinical assay development.

CONCLUSIONS: Biomarkers analyzed in this systematic review highlight alterations in specific biological processes in T1D, including complement, lipid metabolism, and immune response pathways, and may have potential for further use in the clinic as prognostic or diagnostic assays.}, } @article {pmid37735683, year = {2023}, author = {Sołek, P and Czechowska, E and Sowa-Kućma, M and Stachowicz, K and Kaczka, P and Tabęcka-Łonczyńska, A}, title = {Elucidating the molecular mechanisms underlying the induction of autophagy by antidepressant-like substances in C57BL/6J mouse testis model upon LPS challenge.}, journal = {Cell communication and signaling : CCS}, volume = {21}, number = {1}, pages = {251}, pmid = {37735683}, issn = {1478-811X}, mesh = {Animals ; Male ; Mice ; Antidepressive Agents/pharmacology ; Autophagy ; *Lipopolysaccharides/pharmacology ; Mice, Inbred C57BL ; Testis ; }, abstract = {The treatment of depression with pharmaceuticals is associated with many adverse side effects, including male fertility problems. The precise mechanisms by which these agents affect testicular cells remain largely unknown, but they are believed to induce cellular stress, which is sensed by the endoplasmic reticulum (ER) and the Golgi apparatus. These organelles are responsible for maintaining cellular homeostasis and regulating signal pathways that lead to autophagy or apoptosis. Therefore, in this study, we aimed to investigate the autophagy, ER, and Golgi stress-related pathways in mouse testis following treatment with antidepressant-like substances (ALS) and ALS combined with lipopolysaccharide (LPS). We found that most ALS and activated proteins are associated with the induction of apoptosis. However, when imipramine (IMI) was combined with NS-398 (a cyclooxygenase-2 inhibitor) after LPS administration, we observed a marked increase in the BECLIN1, Bcl-2, ATG16L, and LC3 expression, which are marker proteins of autophagosome formation. The expression of the BECN1 and ATG16L genes was also high compared to the control, indicating the induction of autophagy processes that may potentially protect mouse testicular cells from death and regulate metabolism in the testis. Our findings may provide a better understanding of the stress-related effects of specific ALS on the testis. Video Abstract.}, } @article {pmid37735909, year = {2023}, author = {Irie, T and Sawa, M}, title = {CDC7 kinase inhibitors: a survey of recent patent literature (2017-2022).}, journal = {Expert opinion on therapeutic patents}, volume = {33}, number = {7-8}, pages = {493-501}, doi = {10.1080/13543776.2023.2262138}, pmid = {37735909}, issn = {1744-7674}, mesh = {Humans ; *Cell Cycle Proteins/metabolism ; Patents as Topic ; Protein Serine-Threonine Kinases ; DNA Replication ; *Neoplasms ; }, abstract = {INTRODUCTION: CDC7 is a serine/threonine kinase which plays an important role in DNA replication. Inhibition of CDC7 in cancer cells causes lethal S phase or M phase progression, whereas inhibition of CDC7 in normal cells does not cause cell death and only leads to cell cycle arrest at the DNA replication checkpoint. Therefore, CDC7 has been recognized as a potential target for novel therapeutic interventions in cancers.

AREAS COVERED: Patent literature claiming novel small molecule compounds inhibiting CDC7 disclosed from 2017 to 2022.

EXPERT OPINION: Despite the indisputable positive impact of CDC7 as a drug target, there have been reported only a handful of chemical scaffolds as CDC7 inhibitors. Several CDC7 inhibitors have been progressed into clinical trials for cancer treatments, but they did not result in satisfactory efficacies in those trials. One possible reason for the failure might be due to the dose-limiting toxicities, and some of the observed toxicities were thought to be not related to CDC7 inhibition, suggesting it should be important to identify novel chemical scaffolds to eliminate unwanted toxicities. Another important factor is the patient stratification that would enable greater response, and the identification of such predictive biomarkers should be the key to success for the development of CDC7 inhibitors.}, } @article {pmid37736067, year = {2023}, author = {Chambers, C and Lichten, L and Crook, A and Uhlmann, WR and Dratch, L}, title = {Incorporating Genetic Testing Into the Care of Patients With Amyotrophic Lateral Sclerosis/Frontotemporal Degeneration Spectrum Disorders.}, journal = {Neurology. Clinical practice}, volume = {13}, number = {5}, pages = {e200201}, pmid = {37736067}, issn = {2163-0402}, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorders have a strong genetic component. Genetic counselors are a limited resource, and therefore, other providers must be prepared to integrate genetic testing into their practice.

RECENT FINDINGS: Recent ALS/FTD studies have demonstrated that lack of family history does not preclude a genetic etiology. The benefits of a genetic diagnosis have expanded to include the potential to treat; thus, genetic testing is increasingly recommended to be offered to all persons with ALS/FTD.

SUMMARY: Offering genetic testing to persons with ALS/FTD spectrum disorders should be part of routine clinical neurologic care. All genetic testing should include discussion about the medical and psychosocial implications of testing for the patient and family members. Neurologists should be prepared to facilitate this process and recognize when referral to a genetic counselor is indicated.}, } @article {pmid37736625, year = {2023}, author = {Kvande, K and Garetto, B and Deplano, G and Signorile, M and Solemsli, BG and Prodinger, S and Olsbye, U and Beato, P and Bordiga, S and Svelle, S and Borfecchia, E}, title = {Understanding C-H activation in light alkanes over Cu-MOR zeolites by coupling advanced spectroscopy and temperature-programmed reduction experiments.}, journal = {Chemical science}, volume = {14}, number = {36}, pages = {9704-9723}, pmid = {37736625}, issn = {2041-6520}, abstract = {The direct activation of methane to methanol (MTM) proceeds through a chemical-looping process over Cu-oxo sites in zeolites. Herein, we extend the overall understanding of oxidation reactions over metal-oxo sites and C-H activation reactions by pinpointing the evolution of Cu species during reduction. To do so, a set of temperature-programmed reduction experiments were performed with CH4, C2H6, and CO. With a temperature ramp, the Cu reduction could be accelerated to detect changes in Cu speciation that are normally not detected due to the slow CH4 adsorption/interaction during MTM (∼200 °C). To follow the Cu-speciation with the three reductants, X-ray absorption spectroscopy (XAS), UV-vis and FT-IR spectroscopy were applied. Multivariate curve resolution alternating least-square (MCR-ALS) analysis was used to resolve the time-dependent concentration profiles of pure Cu components in the X-ray absorption near edge structure (XANES) spectra. Within the large datasets, as many as six different Cu[II] and Cu[I] components were found. Close correlations were found between the XANES-derived Cu[II] to Cu[I] reduction, CH4 consumption, and CO2 production. A reducibility-activity relationship was also observed for the Cu-MOR zeolites. Extended X-ray absorption fine structure (EXAFS) spectra for the pure Cu components were furthermore obtained with MCR-ALS analysis. With wavelet transform (WT) analysis of the EXAFS spectra, we were able to resolve the atomic speciation at different radial distances from Cu (up to about 4 Å). These results indicate that all the Cu[II] components consist of multimeric Cu[II]-oxo sites, albeit with different Cu-Cu distances.}, } @article {pmid37736756, year = {2023}, author = {Vahsen, BF and Nalluru, S and Morgan, GR and Farrimond, L and Carroll, E and Xu, Y and Cramb, KML and Amein, B and Scaber, J and Katsikoudi, A and Candalija, A and Carcolé, M and Dafinca, R and Isaacs, AM and Wade-Martins, R and Gray, E and Turner, MR and Cowley, SA and Talbot, K}, title = {C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {5898}, pmid = {37736756}, issn = {2041-1723}, support = {102176/Z/13/Z/WT_/Wellcome Trust/United Kingdom ; MR/N013468/1/MRC_/Medical Research Council/United Kingdom ; WADE-MARTINS/OCT13/867-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; 203141/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; /DH_/Department of Health/United Kingdom ; MR/M024962/1/MRC_/Medical Research Council/United Kingdom ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Matrix Metalloproteinase 9/genetics ; C9orf72 Protein/genetics ; Microglia ; Coculture Techniques ; *Induced Pluripotent Stem Cells ; Lipopolysaccharides ; *Neurodegenerative Diseases ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant is a hexanucleotide repeat expansion (HRE) mutation in C9orf72. Here, we study its consequences for microglial function using human iPSC-derived microglia. By RNA-sequencing, we identify enrichment of pathways associated with immune cell activation and cyto-/chemokines in C9orf72 HRE mutant microglia versus healthy controls, most prominently after LPS priming. Specifically, LPS-primed C9orf72 HRE mutant microglia show consistently increased expression and release of matrix metalloproteinase-9 (MMP9). LPS-primed C9orf72 HRE mutant microglia are toxic to co-cultured healthy motor neurons, which is ameliorated by concomitant application of an MMP9 inhibitor. Finally, we identify release of dipeptidyl peptidase-4 (DPP4) as a marker for MMP9-dependent microglial dysregulation in co-culture. These results demonstrate cellular dysfunction of C9orf72 HRE mutant microglia, and a non-cell-autonomous role in driving C9orf72-ALS pathophysiology in motor neurons through MMP9 signaling.}, } @article {pmid37736795, year = {2024}, author = {Liu, WS and Zhang, YR and Ge, YJ and Wang, HF and Cheng, W and Yu, JT}, title = {Inflammation and Brain Structure in Alzheimer's Disease and Other Neurodegenerative Disorders: a Mendelian Randomization Study.}, journal = {Molecular neurobiology}, volume = {61}, number = {3}, pages = {1593-1604}, pmid = {37736795}, issn = {1559-1182}, mesh = {Humans ; *Alzheimer Disease/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics ; *Parkinson Disease/genetics ; Brain/metabolism ; Inflammation/genetics ; Cytokines/genetics/metabolism ; *Encephalitis ; }, abstract = {Previous in vitro and post-mortem studies have reported the role of inflammation in neurodegenerative disorders. However, the association between inflammation and brain structure in vivo and the transcriptome-driven functional basis with relevance to neurodegenerative disorders remains elusive. The aim of the present study is to identify the association among inflammation, brain structure, and neurodegenerative disorders at genetic and transcriptomic levels. Genetic variants associated with inflammatory cytokines were selected from the latest and largest genome-wide association studies of European ancestry. Neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and dementia with Lewy bodies (DLB) and brain structure imaging measures were selected as the outcomes. Two-sample Mendelian randomization analyses were conducted to identify the causal associations. Single-nucleus transcriptome data of the occipitotemporal cortex was further analyzed to identify the differential expressed genes in AD, which were tested for biological processes and protein interaction network. MR analysis indicated that genetically predicted TREM2 and sTREM2 were significantly associated with AD (TREM2: z-score = -9.088, p-value = 1.02 × 10[-19]; sTREM2: z-score = -7.495, p-value = 6.61 × 10[-14]). The present study found no evidence to support the causal associations between other inflammatory cytokines and the risks of AD, PD, ALS, or DLB. Genetically predicted TREM2 was significantly associated with the cortical thickness of inferior temporal (z-score = -4.238, p-value = 2.26 × 10[-5]) and pole temporal (z-score = -4.549, p-value = 5.40 × 10[-6]). In the occipitotemporal cortex samples, microglia were the main source of TREM2 gene and showed increasing expression of genes associated with inflammation and immunity. The present study has leveraged genetic and transcriptomic data to identify the association among TREM2, temporal lobe, and AD and the underlying cellular and molecular basis, thus providing a new perspective on the role of TREM2 in AD and insights into the complex associations among inflammation, brain structure, and neurodegenerative disorders, particularly AD.}, } @article {pmid37737151, year = {2024}, author = {Cabona, C and Ferraro, PM and Scialò, C and Bandettini Di Poggio, M and Novi, G and Gemelli, C and Vignolo, M and Rao, F and Capovilla, M and Marogna, M and Mandich, P and Origone, P and Schenone, A and Caponnetto, C}, title = {Clinical epidemiology of amyotrophic lateral sclerosis in Liguria, Italy: a ten year follow up study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {104-111}, doi = {10.1080/21678421.2023.2260842}, pmid = {37737151}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/therapy ; Follow-Up Studies ; Prospective Studies ; Delayed Diagnosis ; Italy/epidemiology ; }, abstract = {OBJECTIVE: This article presents an updated analysis of the LIGALS register, a prospective study conducted over a ten-year period (2009-2018) in Liguria, Italy, aimed at evaluating the incidence, prevalence, clinical presentation, and management of amyotrophic lateral sclerosis (ALS).

METHODS: We calculated the mean annual crude incidence rate of ALS, assessed the point prevalence of ALS on January 1, 2018, and analyzed demographic factors, clinical characteristics, and clinical management strategies. Data analysis included Cox regression analysis to identify predictors of survival.

RESULTS: The mean annual crude incidence rate of ALS was 3.16/100,000 per year (CI 95%) while the point prevalence of ALS on January 1, 2018, was 9.31/100,000 population (CI 95%). Among the patients, 6.5% were familial ALS, while 93.5% were sporadic cases. Clinical management strategies, including percutaneous endoscopic gastrostomy (PEG) and noninvasive ventilation (NIV), were employed. The study observed a stable frequency of NIV initiation and PEG placement over time, with a growing trend toward earlier PEG positioning. The mean survival from symptom onset was 39 months, whereas from diagnosis, it was 26 months. Cox regression analysis identified several predictors of survival, including gender, age at onset and diagnosis, site of onset, diagnostic category, phenotype, and diagnostic delay.

CONCLUSIONS: This comprehensive analysis provides valuable insights into the long-term trends in ALS epidemiology and clinical management in Liguria, Italy. It underscores the importance of continued research efforts in understanding and addressing the challenges posed by ALS, particularly in terms of early diagnosis and optimizing clinical interventions to improve patient outcomes.}, } @article {pmid37738797, year = {2023}, author = {Dong, W and Peng, Q and Liu, Z and Xie, Z and Guo, X and Li, Y and Chen, C}, title = {Estrogen plays an important role by influencing the NLRP3 inflammasome.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {167}, number = {}, pages = {115554}, doi = {10.1016/j.biopha.2023.115554}, pmid = {37738797}, issn = {1950-6007}, mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Humans ; *Inflammasomes/metabolism ; *Estrogens/metabolism ; Animals ; }, abstract = {The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is an important part of the natural immune system that plays an important role in many diseases. Estrogen is a sex hormone that plays an important role in controlling reproduction and regulates many physiological and pathological processes. Recent studies have indicated that estrogen is associated with disease progression. Estrogen can ameliorate some diseases (e. g, sepsis, mood disturbances, cerebral ischemia, some hepatopathy, Parkinson's disease, amyotrophic lateral sclerosis, inflammatory bowel disease, spinal cord injury, multiple sclerosis, myocardial ischemia/reperfusion injury, osteoarthritis, and renal fibrosis) by inhibiting the NLRP3 inflammasome. Estrogen can also promote the development of diseases (e.g., ovarian endometriosis, dry eye disease, and systemic lupus erythematosus) by upregulating the NLRP3 inflammasome. In addition, estrogen has a dual effect on the development of cancers and asthma. However, the mechanism of these effects is not summarized. This article reviewed the progress in understanding the effects of estrogen on the NLRP3 inflammasome and its mechanisms in recent years to provide a theoretical basis for an in-depth study.}, } @article {pmid37739033, year = {2023}, author = {Tanaka, Y and Ito, SI and Honma, Y and Hasegawa, M and Kametani, F and Suzuki, G and Kozuma, L and Takeya, K and Eto, M}, title = {Dysregulation of the progranulin-driven autophagy-lysosomal pathway mediates secretion of the nuclear protein TDP-43.}, journal = {The Journal of biological chemistry}, volume = {299}, number = {11}, pages = {105272}, pmid = {37739033}, issn = {1083-351X}, mesh = {Humans ; *Autophagy/drug effects/genetics ; *DNA-Binding Proteins/genetics/metabolism ; HeLa Cells ; Intercellular Signaling Peptides and Proteins/genetics/metabolism ; *Lysosomes/metabolism ; *Progranulins/genetics/metabolism ; Microtubule-Associated Proteins/genetics/metabolism ; Gene Expression Regulation/drug effects ; Extracellular Vesicles/metabolism ; Enzyme Inhibitors/pharmacology ; Autophagosomes/drug effects/metabolism ; Autophagy-Related Proteins/genetics/metabolism ; Leupeptins ; Macrolides ; }, abstract = {The cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 kDa (TDP-43) has been linked to the progression of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 secreted into the extracellular space has been suggested to contribute to the cell-to-cell spread of the cytoplasmic accumulation of TDP-43 throughout the brain; however, the underlying mechanisms remain unknown. We herein demonstrated that the secretion of TDP-43 was stimulated by the inhibition of the autophagy-lysosomal pathway driven by progranulin (PGRN), a causal protein of frontotemporal lobar degeneration. Among modulators of autophagy, only vacuolar-ATPase inhibitors, such as bafilomycin A1 (Baf), increased the levels of the full-length and cleaved forms of TDP-43 and the autophagosome marker LC3-II (microtubule-associated proteins 1A/1B light chain 3B) in extracellular vesicle fractions prepared from the culture media of HeLa, SH-SY5Y, or NSC-34 cells, whereas vacuolin-1, MG132, chloroquine, rapamycin, and serum starvation did not. The C-terminal fragment of TDP-43 was required for Baf-induced TDP-43 secretion. The Baf treatment induced the translocation of the aggregate-prone GFP-tagged C-terminal fragment of TDP-43 and mCherry-tagged LC3 to the plasma membrane. The Baf-induced secretion of TDP-43 was attenuated in autophagy-deficient ATG16L1 knockout HeLa cells. The knockdown of PGRN induced the secretion of cleaved TDP-43 in an autophagy-dependent manner in HeLa cells. The KO of PGRN in mouse embryonic fibroblasts increased the secretion of the cleaved forms of TDP-43 and LC3-II. The treatment inducing TDP-43 secretion increased the nuclear translocation of GFP-tagged transcription factor EB, a master regulator of the autophagy-lysosomal pathway in SH-SY5Y cells. These results suggest that the secretion of TDP-43 is promoted by dysregulation of the PGRN-driven autophagy-lysosomal pathway.}, } @article {pmid37739207, year = {2023}, author = {Verdile, V and Palombo, R and Ferrante, G and Ferri, A and Amadio, S and Volonté, C and Paronetto, MP}, title = {Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis.}, journal = {Progress in neurobiology}, volume = {231}, number = {}, pages = {102529}, doi = {10.1016/j.pneurobio.2023.102529}, pmid = {37739207}, issn = {1873-5118}, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Alternative Splicing/genetics ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Superoxide Dismutase-1/genetics ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding proteins (RBPs) in motor neurons (MN), which leads to aberrant alternative splicing regulation. However, whether altered splicing patterns are also present in familial models of ALS without mutations in RBP-encoding genes has not been investigated yet. Herein, we found that altered splicing of synaptic genes is a common trait of familial ALS MNs. Similar deregulation was also observed in hSOD1[G93A] MN-like cells. In silico analysis identified the potential regulators of these pre-mRNAs, including the RBP Sam68. Immunofluorescence analysis and biochemical fractionation experiments revealed that Sam68 accumulates in the cytoplasmic insoluble ribonucleoprotein fraction of MN. Remarkably, the synaptic splicing events deregulated in ALS MNs were also affected in Sam68[-/-] spinal cords. Recombinant expression of Sam68 protein was sufficient to rescue these splicing changes in ALS hSOD1[G93A] MN-like cells. Hence, our study highlights an aberrant function of Sam68, which leads to splicing changes in synaptic genes and may contribute to the MN phenotype that characterizes ALS.}, } @article {pmid37739217, year = {2023}, author = {Chakraborty, J and Chakraborty, S and Chakraborty, S and Narayan, MN}, title = {Entanglement of MAPK pathways with gene expression and its omnipresence in the etiology for cancer and neurodegenerative disorders.}, journal = {Biochimica et biophysica acta. Gene regulatory mechanisms}, volume = {1866}, number = {4}, pages = {194988}, doi = {10.1016/j.bbagrm.2023.194988}, pmid = {37739217}, issn = {1876-4320}, mesh = {Humans ; Mitogen-Activated Protein Kinases ; MAP Kinase Signaling System/genetics ; *Neoplasms/genetics/drug therapy ; *Neurodegenerative Diseases/genetics ; Gene Expression ; }, abstract = {Mitogen Activated Protein Kinase (MAPK) is one of the most well characterized cellular signaling pathways that controls fundamental cellular processes including proliferation, differentiation, and apoptosis. These cellular functions are consequences of transcription of regulatory genes that are influenced and regulated by the MAP-Kinase signaling cascade. MAP kinase components such as Receptor Tyrosine Kinases (RTKs) sense external cues or ligands and transmit these signals via multiple protein complexes such as RAS-RAF, MEK, and ERKs and eventually modulate the transcription factors inside the nucleus to induce transcription and other regulatory functions. Aberrant activation, dysregulation of this signaling pathway, and genetic alterations in any of these components results in the developmental disorders, cancer, and neurodegenerative disorders. Over the years, the MAPK pathway has been a prime pharmacological target, to treat complex human disorders that are genetically linked such as cancer, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The current review re-visits the mechanism of MAPK pathways in gene expression regulation. Further, a current update on the progress of the mechanistic understanding of MAPK components is discussed from a disease perspective.}, } @article {pmid37740686, year = {2023}, author = {Vucic, S and Kiernan, MC}, title = {Nanocrystalline gold (CNM-Au8): a novel bioenergetic treatment for ALS.}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {9}, pages = {783-785}, doi = {10.1080/13543784.2023.2263368}, pmid = {37740686}, issn = {1744-7658}, } @article {pmid37741154, year = {2023}, author = {Wabwile, JM and Angeyo, HK and Massop, AD}, title = {Exploring band-free Raman microspectrometry combined with PCA and MCR-ALS for size-resolved forensic analysis of uranium in aerosols in a model nuclear atmosphere.}, journal = {Journal of environmental radioactivity}, volume = {270}, number = {}, pages = {107295}, doi = {10.1016/j.jenvrad.2023.107295}, pmid = {37741154}, issn = {1879-1700}, mesh = {*Radiation Monitoring ; *Uranium/analysis ; Least-Squares Analysis ; Principal Component Analysis ; Aerosols/analysis ; Atmosphere ; }, abstract = {Achieving non-destructive micrometer-scale molecular and structural analysis of uranic materials in atmospheric aerosols with traditional methodologies is a challenge. Spatially resolved analysis of uranium in actinide-bearing aerosols is critical for nuclear forensics. Although laser Raman microspectrometry enables this, for the normally low uranium concentrations in the aerosols the spectra are indiscernible (band-free) against pronounced background: trace analysis requires a push in analytical strategy. We combined laser Raman microspectrometry (utilizing two lasers (λ = 532 nm, λ = 785 nm)) with principal component analysis (PCA) and multivariate curve resolution-alternate least squares (MCR-ALS) to perform size-resolved analysis of uranium in aerosols. Uranium-specific Raman scatter bands corresponding to uranyl nitrate (860 cm[-1]), uranium sulphate (868 cm[-1]), uranyl chloride (816 cm[-1]) and uranium trioxide (839 cm[-1]) were detected. The 816 cm[-1], 854 cm[-1], 868 cm[-1] bands were resolved by MCR-ALS and used to identify and map uranium in PM4.5 size aerosols. Based on spectral feature selection of the signature bands, PCA identified two sources of aerosol particles in model nuclear atmosphere - Sea spray for PM4.5 and re-suspension of 'nuclear' dust from a rare earth element (REE) mine for PM2.5. The MCR-ALS-resolved uranium bands showed the potential for attributive nuclear forensic analysis.}, } @article {pmid37741265, year = {2024}, author = {Li, M and Zhang, L and Jiang, LL and Zhao, ZB and Long, YH and Chen, DM and Bin, J and Kang, C and Liu, YJ}, title = {Label-free Raman microspectroscopic imaging with chemometrics for cellular investigation of apple ring rot and nondestructive early recognition using near-infrared reflection spectroscopy with machine learning.}, journal = {Talanta}, volume = {267}, number = {}, pages = {125212}, doi = {10.1016/j.talanta.2023.125212}, pmid = {37741265}, issn = {1873-3573}, mesh = {Machine Learning ; *Malus ; Chemometrics ; Spectroscopy, Near-Infrared/methods ; Ascomycota ; Pectins ; }, abstract = {Apple ring rot caused by Botryosphaeria dothidea can cause fruit decay during the growth and storage stages of apple fruit. Understanding the infection process and cellular defense response at the cellular micro-level holds immense importance in the field of prevention and control. Consequently, there is a pressing need to develop suitable chemical imaging analysis methods. Here we proposed a label-free, high-throughput imaging method for cellular investigation of apple fruit ring rot infected by Botryosphaeria dothidea, based on confocal Raman microspectroscopic imaging technology combined with multivariate curve resolution-alternating least squares algorithm (MCR-ALS). We conducted Raman measurements on every apple fruit and obtain an image cube. This cube was then unfolded into an augmented matrix in a column-wise manner. We proceeded with simultaneous MCR-ALS analysis, resolving the single-substance spectrum and concentration profile from the mixed signals. Lastly, the accurate and pure molecular imaging of low methoxyl pectin, high methoxyl pectin, cellulose, lignin, and phenols were realized by refolding the resolved concentration data to construct the composition image. Thereafter, we realized the study of the spatial-temporal changes distribution of the above substances in the cuticle and cell wall of green and red apples at different stages of infection. The imaging method proposed in this paper is expected to provide a chemical imaging strategy for studying pathogen infection process and fruit defense response at the cellular level. In addition, by utilizing a fiber-optic probe near-infrared reflection spectrometer in conjunction with machine learning, we developed a rapid and non-destructive classification method. This method allows for the timely identification of apples exhibiting early infection by Botryosphaeria dothidea. Notably, both principal component analysis-quadratic discriminant analysis and support vector machine achieved a classification accuracy of 100%.}, } @article {pmid37741764, year = {2024}, author = {Ducharme, S and Pijnenburg, Y and Rohrer, JD and Huey, E and Finger, E and Tatton, N}, title = {Identifying and Diagnosing TDP-43 Neurodegenerative Diseases in Psychiatry.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {32}, number = {1}, pages = {98-113}, pmid = {37741764}, issn = {1545-7214}, support = {U01 AG079850/AG/NIA NIH HHS/United States ; R01 MH120794/MH/NIMH NIH HHS/United States ; R01 AG062268/AG/NIA NIH HHS/United States ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; DNA-Binding Proteins/genetics ; *Frontotemporal Dementia/diagnosis/genetics ; *Neurodegenerative Diseases/diagnosis/genetics ; *Psychiatry ; }, abstract = {Neuropsychiatric symptoms (NPS) are common manifestations of neurodegenerative disorders and are often early signs of those diseases. Among those neurodegenerative diseases, TDP-43 proteinopathies are an increasingly recognized cause of early neuropsychiatric manifestations. TDP-43-related diseases include frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE). The majority of TDP-43-related diseases are sporadic, but a significant proportion is hereditary, with progranulin (GRN) mutations and C9orf72 repeat expansions as the most common genetic etiologies. Studies reveal that NPS can be the initial manifestation of those diseases or can complicate disease course, but there is a lack of awareness among clinicians about TDP-43-related diseases, which leads to common diagnostic mistakes or delays. There is also emerging evidence that TDP-43 accumulations could play a role in late-onset primary psychiatric disorders. In the absence of robust biomarkers for TDP-43, the diagnosis remains primarily based on clinical assessment and neuroimaging. Given the association with psychiatric symptoms, clinical psychiatrists have a key role in the early identification of patients with TDP-43-related diseases. This narrative review provides a comprehensive overview of the pathobiology of TDP-43, resulting clinical presentations, and associated neuropsychiatric manifestations to help guide clinical practice.}, } @article {pmid37744877, year = {2023}, author = {Wilkins, JM and Gakh, O and Guo, Y and Popescu, B and Staff, NP and Lucchinetti, CF}, title = {Biomolecular alterations detected in multiple sclerosis skin fibroblasts using Fourier transform infrared spectroscopy.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1223912}, pmid = {37744877}, issn = {1662-5102}, abstract = {Multiple sclerosis (MS) is the leading cause of non-traumatic disability in young adults. New avenues are needed to help predict individuals at risk for developing MS and aid in diagnosis, prognosis, and outcome of therapeutic treatments. Previously, we showed that skin fibroblasts derived from patients with MS have altered signatures of cell stress and bioenergetics, which likely reflects changes in their protein, lipid, and biochemical profiles. Here, we used Fourier transform infrared (FTIR) spectroscopy to determine if the biochemical landscape of MS skin fibroblasts were altered when compared to age- and sex-matched controls (CTRL). More so, we sought to determine if FTIR spectroscopic signatures detected in MS skin fibroblasts are disease specific by comparing them to amyotrophic lateral sclerosis (ALS) skin fibroblasts. Spectral profiling of skin fibroblasts from MS individuals suggests significant alterations in lipid and protein organization and homeostasis, which may be affecting metabolic processes, cellular organization, and oxidation status. Sparse partial least squares-discriminant analysis of spectral profiles show that CTRL skin fibroblasts segregate well from diseased cells and that changes in MS and ALS may be unique. Differential changes in the spectral profile of CTRL, MS, and ALS cells support the development of FTIR spectroscopy to detect biomolecular modifications in patient-derived skin fibroblasts, which may eventually help establish novel peripheral biomarkers.}, } @article {pmid37745304, year = {2023}, author = {Yokota, M and Yoshino, Y and Hosoi, M and Hashimoto, R and Kakuta, S and Shiga, T and Ishikawa, KI and Okano, H and Hattori, N and Akamatsu, W and Koike, M}, title = {Reduced ER-mitochondrial contact sites and mitochondrial Ca[2+] flux in PRKN-mutant patient tyrosine hydroxylase reporter iPSC lines.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1171440}, pmid = {37745304}, issn = {2296-634X}, abstract = {Endoplasmic reticulum-mitochondrial contact sites (ERMCS) play an important role in mitochondrial dynamics, calcium signaling, and autophagy. Disruption of the ERMCS has been linked to several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, the etiological role of ERMCS in these diseases remains unclear. We previously established tyrosine hydroxylase reporter (TH-GFP) iPSC lines from a PD patient with a PRKN mutation to perform correlative light-electron microscopy (CLEM) analysis and live cell imaging in GFP-expressing dopaminergic neurons. Here, we analyzed ERMCS in GFP-expressing PRKN-mutant dopaminergic neurons from patients using CLEM and a proximity ligation assay (PLA). The PLA showed that the ERMCS were significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control under normal conditions. The reduction of the ERMCS in PRKN-mutant patient dopaminergic neurons was further enhanced by treatment with a mitochondrial uncoupler. In addition, mitochondrial calcium imaging showed that mitochondrial Ca[2+] flux was significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control. These results suggest a defect in calcium flux from ER to mitochondria is due to the decreased ERMCS in PRKN-mutant patient dopaminergic neurons. Our study of ERMCS using TH-GFP iPSC lines would contribute to further understanding of the mechanisms of dopaminergic neuron degeneration in patients with PRKN mutations.}, } @article {pmid37745492, year = {2024}, author = {Hwang, RD and Lu, Y and Tang, Q and Periz, G and Park, G and Li, X and Xiang, Q and Liu, Y and Zhang, T and Wang, J}, title = {DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.09.12.556394}, pmid = {37745492}, issn = {2692-8205}, abstract = {Proteotoxic stress impairs cellular homeostasis and underlies the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, the loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 in Drosophila and mammalian neurons. DBT is upregulated in the tissues from ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.}, } @article {pmid37746061, year = {2023}, author = {Bennett, SA and Cobos, SN and Son, E and Segal, R and Mathew, S and Yousuf, H and Torrente, MP}, title = {Impaired RNA Binding Does Not Prevent Histone Modification Changes in a FUS ALS/FTD Yeast Model.}, journal = {microPublication biology}, volume = {2023}, number = {}, pages = {}, pmid = {37746061}, issn = {2578-9430}, support = {R15 NS125394/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in the RNA-binding protein FUS are linked to amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). FUS mutants mislocalize and aggregate in dying neurons. We previously established that FUS proteinopathy is linked to changes in the histone modification landscape in a yeast ALS/FTD model. Here, we examine whether FUS' RNA binding is necessary for this connection. We find that overexpression of a FUS mutant unable to bind RNA is still associated with reduced levels of H3S10ph, H3K14ac and H3K56ac. Hence, FUS' ability to bind RNA is not required in the mechanism connecting FUS proteinopathy to altered histone post-translational modifications.}, } @article {pmid37746513, year = {2023}, author = {Singh, A and Arora, S and Chavan, M and Shahbaz, S and Jabeen, H}, title = {An Overview of the Neurotrophic and Neuroprotective Properties of the Psychoactive Drug Lithium as an Autophagy Modulator in Neurodegenerative Conditions.}, journal = {Cureus}, volume = {15}, number = {8}, pages = {e44051}, pmid = {37746513}, issn = {2168-8184}, abstract = {For both short-term and long-term treatment of bipolar disorder, lithium is a prototypical mood stabilizer. Lithium's neuroprotective properties were revealed by cumulative translational research, which opened the door to reforming the chemical as a treatment for neurodegenerative illnesses. The control of homeostatic systems such as oxidative stress, autophagy, apoptosis, mitochondrial function, and inflammation underlies lithium's neuroprotective characteristics. The fact that lithium inhibits the enzymes inositol monophosphatase (IMPase) and glycogen synthase kinase (GSK)-3 may be the cause of the various intracellular reactions. In this article, we review lithium's neurobiological properties, as demonstrated by its neurotrophic and neuroprotective capabilities, as well as translational studies in cells in culture and in animal models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Prion disease, amyotrophic lateral sclerosis (ALS), ischemic stroke, and neuronal ceroid lipofuscinosis (NCL), discussing the justification for the drug's use in the treatment of these neurodegenerative disorders.}, } @article {pmid37746849, year = {2023}, author = {Martino, J and Liu, Q and Vukojevic, K and Ke, J and Lim, TY and Khan, A and Gupta, Y and Perez, A and Yan, Z and Milo Rasouly, H and Vena, N and Lippa, N and Giordano, JL and Saraga, M and Saraga-Babic, M and Westland, R and Bodria, M and Piaggio, G and Bendapudi, PK and Iglesias, AD and Wapner, RJ and Tasic, V and Wang, F and Ionita-Laza, I and Ghiggeri, GM and Kiryluk, K and Sampogna, RV and Mendelsohn, CL and D'Agati, VD and Gharavi, AG and Sanna-Cherchi, S}, title = {Mouse and human studies support DSTYK loss of function as a low-penetrance and variable expressivity risk factor for congenital urinary tract anomalies.}, journal = {Genetics in medicine : official journal of the American College of Medical Genetics}, volume = {25}, number = {12}, pages = {100983}, pmid = {37746849}, issn = {1530-0366}, support = {F32 DK121454/DK/NIDDK NIH HHS/United States ; P20 DK116191/DK/NIDDK NIH HHS/United States ; K25 DK128563/DK/NIDDK NIH HHS/United States ; R01 DK103184/DK/NIDDK NIH HHS/United States ; T35 DK093430/DK/NIDDK NIH HHS/United States ; R01 DK115574/DK/NIDDK NIH HHS/United States ; U54 DK104309/DK/NIDDK NIH HHS/United States ; R01 DK080099/DK/NIDDK NIH HHS/United States ; }, mesh = {*Urogenital Abnormalities/genetics ; Vesico-Ureteral Reflux ; Mice, Inbred C3H ; Mice, Inbred C57BL ; *Urinary Tract ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Risk Factors ; Penetrance ; Humans ; Mice ; Animals ; *Epilepsy/genetics ; Kidney/abnormalities ; }, abstract = {PURPOSE: Previous work identified rare variants in DSTYK associated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse and human studies to clarify the association, penetrance, and expressivity of DSTYK variants.

METHODS: We phenotypically characterized Dstyk knockout mice of 3 separate inbred backgrounds and re-analyzed the original family segregating the DSTYK c.654+1G>A splice-site variant (referred to as "SSV" below). DSTYK loss of function (LOF) and SSVs were annotated in individuals with CAKUT, epilepsy, or amyotrophic lateral sclerosis vs controls. A phenome-wide association study analysis was also performed using United Kingdom Biobank (UKBB) data.

RESULTS: Results demonstrate ∼20% to 25% penetrance of obstructive uropathy, at least, in C57BL/6J and FVB/NJ Dstyk[-/-] mice. Phenotypic penetrance increased to ∼40% in C3H/HeJ mutants, with mild-to-moderate severity. Re-analysis of the original family segregating the rare SSV showed low penetrance (43.8%) and no alternative genetic causes for CAKUT. LOF DSTYK variants burden showed significant excess for CAKUT and epilepsy vs controls and an exploratory phenome-wide association study supported association with neurological disorders.

CONCLUSION: These data support causality for DSTYK LOF variants and highlights the need for large-scale sequencing studies (here >200,000 cases) to accurately assess causality for genes and variants to lowly penetrant traits with common population prevalence.}, } @article {pmid37747451, year = {2023}, author = {Brisley, A and Lambert, H and Rodrigues, C}, title = {Antibiotics in Catalan Primary Care: Prescription, Use and Remedies for a Crisis of Care.}, journal = {Medical anthropology}, volume = {42}, number = {7}, pages = {682-696}, pmid = {37747451}, issn = {1545-5882}, support = {/WT_/Wellcome Trust/United Kingdom ; 210359/Z/18/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Anti-Bacterial Agents/therapeutic use ; Anthropology, Medical ; *Prescriptions ; Primary Health Care ; Europe ; }, abstract = {Antimicrobial resistance is one of the twenty-first century's major health challenges. Linked to the extensive use of antibiotics and other antimicrobials, resistance occurs when microbes stop responding to medications. Rates of antibiotic consumption in Spain are among the highest in Europe. Drawing on research conducted in Catalonia, in this article we present findings from ethnographic fieldwork and semi-structured interviews with general practitioners, residents of Barcelona, and professionals who have worked in antibiotic stewardship. We argue that the circulation of antibiotics should be understood in relation to broader historical processes and the deficient systems of health and social care provision they have produced.}, } @article {pmid37747630, year = {2023}, author = {Oh, JE and Oh, JA and Demopoulos, M and Clark, KM and Phillips, MC}, title = {Impact of the metabolic syndrome on prevalence and survival in motor neuron disease: a retrospective case series.}, journal = {Metabolic brain disease}, volume = {38}, number = {8}, pages = {2583-2589}, pmid = {37747630}, issn = {1573-7365}, support = {Waikato Hospital Neurology Research Fund//Waikato Hospital Neurology Research Fund/ ; }, mesh = {Prevalence ; Retrospective Studies ; *Amyotrophic Lateral Sclerosis ; *Motor Neuron Disease/epidemiology/complications/diagnosis ; *Metabolic Syndrome/epidemiology/complications ; Humans ; Australasian People ; Maori People ; }, abstract = {Metabolic dysfunction is an important factor in the pathogenesis of motor neuron disease, but its prevalence and association with survival in this disorder is unknown. We hypothesized that patients with motor neuron disease would show a higher prevalence of metabolic syndrome compared to the general New Zealand population, and that metabolic syndrome would be associated with worsened survival. We undertook a retrospective analysis in 109 motor neuron disease patients diagnosed and treated at Waikato Hospital from 2013 to 2020. Demographic, clinical, and laboratory data were collected. Survival was defined as the date of initial symptom onset to the date of death. Of 104 eligible patients, 34 patients (33%) had metabolic syndrome (33% of Europeans, 46% of Māori). Mean survival in motor neuron disease patients with metabolic syndrome was significantly reduced compared to patients without metabolic syndrome (38 vs. 61 months, P = 0.044), with a 5-year survival rate of 21% for the former and 38% for the latter (P = 0.012). Compared with the general New Zealand population, metabolic syndrome is highly prevalent amongst motor neuron disease patients in the Waikato region and it is associated with worsened survival. Metabolic dysfunction may be a key factor underlying the pathogenesis of motor neuron disease.}, } @article {pmid37747929, year = {2023}, author = {Krupp, S and Hubbard, I and Tam, O and Hammell, GM and Dubnau, J}, title = {TDP-43 pathology in Drosophila induces glial-cell type specific toxicity that can be ameliorated by knock-down of SF2/SRSF1.}, journal = {PLoS genetics}, volume = {19}, number = {9}, pages = {e1010973}, pmid = {37747929}, issn = {1553-7404}, support = {R01 AG076493/AG/NIA NIH HHS/United States ; R01 AG078788/AG/NIA NIH HHS/United States ; RF1 AG057338/AG/NIA NIH HHS/United States ; RF1 AG076493/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Astrocytes/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Drosophila/genetics/metabolism ; *Drosophila Proteins/genetics/metabolism ; *Frontotemporal Dementia ; Neurons/metabolism ; RNA Splicing Factors/metabolism ; }, abstract = {Accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43) is seen in both neurons and glia in a range of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). Disease progression involves non-cell autonomous interactions among multiple cell types, including neurons, microglia and astrocytes. We investigated the effects in Drosophila of inducible, glial cell type-specific TDP-43 overexpression, a model that causes TDP-43 protein pathology including loss of nuclear TDP-43 and accumulation of cytoplasmic inclusions. We report that TDP-43 pathology in Drosophila is sufficient to cause progressive loss of each of the 5 glial sub-types. But the effects on organismal survival were most pronounced when TDP-43 pathology was induced in the perineural glia (PNG) or astrocytes. In the case of PNG, this effect is not attributable to loss of the glial population, because ablation of these glia by expression of pro-apoptotic reaper expression has relatively little impact on survival. To uncover underlying mechanisms, we used cell-type-specific nuclear RNA sequencing to characterize the transcriptional changes induced by pathological TDP-43 expression. We identified numerous glial cell-type specific transcriptional changes. Notably, SF2/SRSF1 levels were found to be decreased in both PNG and in astrocytes. We found that further knockdown of SF2/SRSF1 in either PNG or astrocytes lessens the detrimental effects of TDP-43 pathology on lifespan, but extends survival of the glial cells. Thus TDP-43 pathology in astrocytes or PNG causes systemic effects that shorten lifespan and SF2/SRSF1 knockdown rescues the loss of these glia, and also reduces their systemic toxicity to the organism.}, } @article {pmid37748443, year = {2024}, author = {Jütte, R}, title = {Involving Voters and Consumers in Decision-Making about the Health Care System - The Swiss Case: A Review.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {78-83}, doi = {10.1159/000534268}, pmid = {37748443}, issn = {2504-2106}, mesh = {Humans ; Switzerland ; *Voting ; *Complementary Therapies ; Evidence-Based Medicine ; }, abstract = {BACKGROUND: Behind the principle of involving users and voters directly in decision-making about the health care system are ideas relating to empowerment. This implies a challenge to the traditional view that scientific knowledge is generally believed to be of higher value than empirical knowledge, as it is the case with CAM. The objectives of this review are (a) to show that this assumption disregards the fact that CAM is as scientific as conventional medicine but has different basic assumptions what the world is being made of and consequently uses different/adapted scientific methods; (b) to demonstrate how a perspective of the history of medicine and science as well as direct democracy mechanisms such as stipulated in the Swiss constitution can be used to achieve the acceptance of CAM in a modern medical health care system. A public health care system financed by levies from the population should also reflect the widely documented desire in the population for medical pluralism (provided that therapeutical alternatives are not risky). Otherwise, the problem of social inequality arises because only people with a good financial background can afford this medicine.

SUMMARY: From the perspective of scientific theory and the history of science, the answer to the question of whether complementary medicine and conventional medical procedures must provide proof of efficacy according to a uniform scientific is quite controversial according to epistemologically oriented studies on this issue.

KEY MESSAGES: This review found strong evidence for involving voters and consumers directly in decision-making about the provision of CAM in the health care system. It also seems necessary to step back in the debate on evidence-based medicine, taking a history of medicine and science perspective, as the role which the proper method occupies and plays in medicine is defined by the scientific nature of the world view.

UNLABELLED: Hinter dem Grundsatz, Nutzer und Wähler direkt in die Entscheidungsfindung über das Gesundheitssystem einzubeziehen, stehen Vorstellungen von Empowerment. Dies impliziert eine Infragestellung der traditionellen Ansicht, dass wissenschaftliches Wissen im Allgemeinen als wertvoller angesehen wird als empirisches Wissen und erprobte Erfahrung, wie es bei der Komplementärmedizin der Fall ist. Die Ziele dieser Übersichtsarbeit sind: (a) zu zeigen, dass diese Annahme die Tatsache außer Acht lässt, dass die Komplementärmedizin ebenso wissenschaftlich ist wie die Schulmedizin, aber von anderen Grundannahmen ausgeht, wie die Welt beschaffen ist, und folglich andere/angepasste wissenschaftliche Methoden anwendet; (b) aufzuzeigen, wie eine medizin- und wissenschaftsgeschichtliche Perspektive sowie Mechanismen der direkten Demokratie, wie sie in der Schweizer Verfassung vorgesehen sind, genutzt werden können, um die Akzeptanz der Komplementärmedizin in einem modernen medizinischen Gesundheitssystem zu erreichen. Ein öffentliches, durch Abgaben der Bevölkerung finanziertes Gesundheitssystem sollte auch dem vielfach dokumentierten Wunsch der Bevölkerung nach medizinischem Pluralismus Rechnung tragen (sofern die therapeutischen Alternativen nicht riskant sind). Andernfalls stellt sich das Problem der sozialen Ungleichheit, weil sich nur Menschen mit einem guten finanziellen Hintergrund diese Medizin leisten können.}, } @article {pmid37748861, year = {2023}, author = {Soustelle, L and Aimond, F and López-Andrés, C and Brugioti, V and Raoul, C and Layalle, S}, title = {ALS-Associated KIF5A Mutation Causes Locomotor Deficits Associated with Cytoplasmic Inclusions, Alterations of Neuromuscular Junctions, and Motor Neuron Loss.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {43}, number = {47}, pages = {8058-8072}, pmid = {37748861}, issn = {1529-2401}, mesh = {Male ; Animals ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Kinesins/genetics/metabolism ; Genome-Wide Association Study ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Neuromuscular Junction/metabolism ; Mutation/genetics ; Drosophila/metabolism ; Inclusion Bodies/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Recently, genome-wide association studies identified KIF5A as a new ALS-causing gene. KIF5A encodes a protein of the kinesin-1 family, allowing the anterograde transport of cargos along the microtubule rails in neurons. In ALS patients, mutations in the KIF5A gene induce exon 27 skipping, resulting in a mutated protein with a new C-terminal region (KIF5A Δ27). To understand how KIF5A Δ27 underpins the disease, we developed an ALS-associated KIF5A Drosophila model. When selectively expressed in motor neurons, KIF5A Δ27 alters larval locomotion as well as morphology and synaptic transmission at neuromuscular junctions in both males and females. We show that the distribution of mitochondria and synaptic vesicles is profoundly disturbed by KIF5A Δ27 expression. That is consistent with the numerous KIF5A Δ27-containing inclusions observed in motor neuron soma and axons. Moreover, KIF5A Δ27 expression leads to motor neuron death and reduces life expectancy. Our in vivo model reveals that a toxic gain of function underlies the pathogenicity of ALS-linked KIF5A mutant.SIGNIFICANCE STATEMENT Understanding how a mutation identified in patients with amyotrophic lateral sclerosis (ALS) causes the disease and the loss of motor neurons is crucial to fight against this disease. To this end, we have created a Drosophila model based on the motor neuron expression of the KIF5A mutant gene, recently identified in ALS patients. KIF5A encodes a kinesin that allows the anterograde transport of cargos. This model recapitulates the main features of ALS, including alterations of locomotion, synaptic neurotransmission, and morphology at neuromuscular junctions, as well as motor neuron death. KIF5A mutant is found in cytoplasmic inclusions, and its pathogenicity is because of a toxic gain of function.}, } @article {pmid37748881, year = {2023}, author = {McFarlane, R and Peelo, C and Galvin, M and Heverin, M and Hardiman, O}, title = {Epidemiologic Trends of Amyotrophic Lateral Sclerosis in Ireland, 1996-2021.}, journal = {Neurology}, volume = {101}, number = {19}, pages = {e1905-e1912}, pmid = {37748881}, issn = {1526-632X}, mesh = {Male ; Humans ; Female ; Middle Aged ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis ; Ireland/epidemiology ; Delayed Diagnosis ; Riluzole ; Proportional Hazards Models ; }, abstract = {BACKGROUND AND OBJECTIVES: The objective of this study was to examine changes to the incidence, prevalence, age at onset, and survival of patients diagnosed with amyotrophic lateral sclerosis (ALS) in the Republic of Ireland over 25 years.

METHODS: Incident and prevalent cases of ALS were estimated using the Irish population-based ALS Register, which has been in continuous operation since 1994. Incident cases were age standardized using the direct method and applied to 3 standard populations (Irish, European, and American). Survival was determined using Kaplan-Meier curves and Cox regression models. Non-normally distributed groups were compared using the Kruskal-Wallis test with a Bonferroni correction.

RESULTS: A total of 2,771 patients with ALS were identified in the Republic of Ireland over 25 years. Incidence per 100,000 was determined for the population older than 15 years. Crude incidence increased from 2.64 to 5.46 per 100,000. Standardized incidence increased from 2.64 to 3.1 per 100,000. Prevalence increased from 5.83 to 8.10 per 100,000. The median age at onset increased from 64 to 67 years. The peak age of incidence increased from those between 70 and 74 years to those between 75 and 79 years. Overall, women had a consistently later median age at onset of 67 years compared with men at 65 years (p < 0.001). No significant difference in survival was noted between those captured across 3 different epochs (1996-2003, 2004-2012, 2013-2021). Older age at onset (hazard ratio [HR] 1.03, CI 1.02-1.04, p < 0.001) was a negative predictive factor of survival in multivariate Cox regression analysis. Riluzole use (HR 0.67, CI 0.50-0.90, p = 0.033) and diagnostic delay (HR 0.98, CI 0.98-0.99, p < 0.001) were positive predictive factors.

DISCUSSION: Within the Republic of Ireland, the age-standardized overall incidence, peak incidence, prevalence, and age at onset of ALS have all increased over 25 years. Despite the widespread use of noninvasive ventilation, aggressive secretion management, and changes in ALS care, the mean survival within the Irish population has not changed.}, } @article {pmid37749234, year = {2023}, author = {Linsenmeier, M and Faltova, L and Morelli, C and Capasso Palmiero, U and Seiffert, C and Küffner, AM and Pinotsi, D and Zhou, J and Mezzenga, R and Arosio, P}, title = {The interface of condensates of the hnRNPA1 low-complexity domain promotes formation of amyloid fibrils.}, journal = {Nature chemistry}, volume = {15}, number = {10}, pages = {1340-1349}, pmid = {37749234}, issn = {1755-4349}, support = {101002094//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; }, mesh = {*Amyloid/chemistry/metabolism ; Humans ; *Heterogeneous Nuclear Ribonucleoprotein A1/chemistry/metabolism ; Protein Domains ; }, abstract = {The maturation of liquid-like protein condensates into amyloid fibrils has been associated with several neurodegenerative diseases. However, the molecular mechanisms underlying this liquid-to-solid transition have remained largely unclear. Here we analyse the amyloid formation mediated by condensation of the low-complexity domain of hnRNPA1, a protein involved in amyotrophic lateral sclerosis. We show that phase separation and fibrillization are connected but distinct processes that are modulated by different regions of the protein sequence. By monitoring the spatial and temporal evolution of amyloid formation we demonstrate that the formation of fibrils does not occur homogeneously inside the droplets but is promoted at the interface of the condensates. We further show that coating the interface of the droplets with surfactant molecules inhibits fibril formation. Our results reveal that the interface of biomolecular condensates of hnRNPA1 promotes fibril formation, therefore suggesting interfaces as a potential novel therapeutic target against the formation of aberrant amyloids mediated by condensation.}, } @article {pmid37751804, year = {2023}, author = {Wang, Z and Zhang, C and Fan, C and Liu, Y}, title = {Post-translational modifications in stress granule and their implications in neurodegenerative diseases.}, journal = {Biochimica et biophysica acta. Gene regulatory mechanisms}, volume = {1866}, number = {4}, pages = {194989}, doi = {10.1016/j.bbagrm.2023.194989}, pmid = {37751804}, issn = {1876-4320}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Stress Granules ; Protein Processing, Post-Translational ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; RNA, Messenger/metabolism ; }, abstract = {Stress granules (SGs) arise as formations of mRNAs and proteins in response to translation initiation inhibition during stress. These dynamic compartments adopt a fluidic nature through liquid-liquid phase separation (LLPS), exhibiting a composition subject to constant change within cellular contexts. Research has unveiled an array of post-translational modifications (PTMs) occurring on SG proteins, intricately orchestrating SG dynamics. In the realm of neurodegenerative diseases, pathological mutant proteins congregate into insoluble aggregates alongside numerous SG proteins, manifesting resilience against disassembly. Specific PTMs conspicuously label these aggregates, designating them for subsequent degradation. The strategic manipulation of aberrant SGs via PTMs emerges as a promising avenue for therapeutic intervention. This review discerns recent strides in comprehending the impact of PTMs on LLPS behavior and the assembly/disassembly kinetics of SGs. By delving into the roles of PTMs in governing SG dynamics, we augment our cognizance of the molecular underpinnings of neurodegeneration. Furthermore, we offer invaluable insights into potential targets for therapeutic intervention in neurodegenerative afflictions, encompassing conditions like amyotrophic lateral sclerosis and frontotemporal dementia.}, } @article {pmid37751856, year = {2023}, author = {Martin Schaff, C and Kurent, JE and Kolodziejczak, S and Milic, M and Foster, LA and Mehta, AK}, title = {Neuroprognostication for Patients with Amyotrophic Lateral Sclerosis: An Updated, Evidence-Based Review.}, journal = {Seminars in neurology}, volume = {43}, number = {5}, pages = {776-790}, doi = {10.1055/s-0043-1775595}, pmid = {37751856}, issn = {1098-9021}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Quality of Life ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that presents and progresses in various ways, making prognostication difficult. Several paradigms exist for providers to elucidate prognosis in a way that addresses not only the amount of time a patient has to live, but also a patient's quality of their life moving forward. Prognostication, with regard to both survivability and quality of life, is impacted by several features that include, but are not limited to, patient demographics, clinical features on presentation, and over time, access to therapy, and access to multidisciplinary clinics. An understanding of the impact that these features have on the life of a patient with ALS can help providers to develop a better and more personalized approach for patients related to their clinical prognosis after a diagnosis is made. The ultimate goal of prognostication is to empower patients with ALS to take control and make decisions with their care teams to ensure that their goals are addressed and met.}, } @article {pmid37752099, year = {2024}, author = {Koreki, A and Michel, S and Lebeaux, C and Trouilh, L and Délye, C}, title = {Prevalence, spatial structure and evolution of resistance to acetolactate-synthase (ALS) inhibitors and 2,4-D in the major weed Papaver rhoeas (L.) assessed using a massive, country-wide sampling.}, journal = {Pest management science}, volume = {80}, number = {2}, pages = {637-647}, doi = {10.1002/ps.7791}, pmid = {37752099}, issn = {1526-4998}, support = {//Corteva Agriscience/ ; }, mesh = {2,4-Dichlorophenoxyacetic Acid/pharmacology ; *Acetolactate Synthase/antagonists & inhibitors/genetics ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Lactates ; Mutation ; Nucleotides ; *Papaver/drug effects/genetics ; }, abstract = {BACKGROUND: Corn poppy (Papaver rhoeas) is the most damaging broadleaf weed in France. Massively parallel amplicon sequencing was used to investigate the prevalence, mode of evolution and spread of resistance-endowing ALS alleles in 422 populations randomly sampled throughout poppy's range in France. Bioassays were used to detect resistance to the synthetic auxin 2,4-D in 43 of these populations.

RESULTS: A total of 21 100 plants were analysed and 24 mutant ALS alleles carrying an amino-acid substitution involved or potentially involved in resistance were identified. The vast majority (97.6%) of the substitutions occurred at codon Pro197, where all six possible single-nucleotide non-synonymous substitutions plus four double-nucleotide substitutions were identified. Changes observed in the enzymatic properties of the mutant ALS isoforms could not explain the differences in prevalence among the corresponding alleles. Sequence read analysis showed that mutant ALS alleles had multiple, independent evolutionary origins, and could have evolved several times independently within an area of a few kilometres. Finally, 2,4-D resistance was associated with mutant ALS alleles in individual plants in one third of the populations assayed.

CONCLUSION: The intricate geographical mosaic of mutant ALS alleles observed is the likely result of the combination of huge population sizes, multiple independent mutation events and human-mediated spread of resistance. Our work highlights the ability of poppy populations and individual plants to accumulate different ALS alleles and as yet unknown mechanisms conferring resistance to synthetic auxins. This does not bode well for the continued use of chemical herbicides to control poppy. © 2023 Society of Chemical Industry.}, } @article {pmid37752346, year = {2024}, author = {Cabrera, GT and Meijboom, KE and Abdallah, A and Tran, H and Foster, Z and Weiss, A and Wightman, N and Stock, R and Gendron, T and Gruntman, A and Giampetruzzi, A and Petrucelli, L and Brown, RH and Mueller, C}, title = {Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo.}, journal = {Gene therapy}, volume = {31}, number = {3-4}, pages = {105-118}, pmid = {37752346}, issn = {1476-5462}, support = {NS088689//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS088689/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; C9orf72 Protein/genetics/metabolism ; Dipeptides/genetics/metabolism ; DNA Repeat Expansion/genetics ; Mice, Transgenic ; *MicroRNAs/genetics ; *Neurodegenerative Diseases ; Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons, causing progressive muscle weakness and respiratory failure. The presence of an expanded hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) is the most frequent mutation causing familial ALS and frontotemporal dementia (FTD). To determine if suppressing expression of C9ORF72 gene products can reduce toxicity, we designed a set of artificial microRNAs (amiRNA) targeting the human C9ORF72 gene. Here we report that an AAV9-mediated amiRNA significantly suppresses expression of the C9ORF72 mRNA, protein, and toxic dipeptide repeat proteins generated by the expanded repeat in the brain and spinal cord of C9ORF72 transgenic mice.}, } @article {pmid37752364, year = {2023}, author = {Guan, T and Zhou, T and Zhang, X and Guo, Y and Yang, C and Lin, J and Zhang, JV and Cheng, Y and Marzban, H and Wang, YT and Kong, J}, title = {Selective removal of misfolded SOD1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {80}, number = {10}, pages = {304}, pmid = {37752364}, issn = {1420-9071}, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Disease Models, Animal ; Motor Neurons ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. There is no cure currently. The discovery that mutations in the gene SOD1 are a cause of ALS marks a breakthrough in the search for effective treatments for ALS. SOD1 is an antioxidant that is highly expressed in motor neurons. Human SOD1 is prone to aberrant modifications. Familial ALS-linked SOD1 variants are particularly susceptible to aberrant modifications. Once modified, SOD1 undergoes conformational changes and becomes misfolded. This study aims to determine the effect of selective removal of misfolded SOD1 on the pathogenesis of ALS.

METHODS: Based on the chaperone-mediated protein degradation pathway, we designed a fusion peptide named CT4 and tested its efficiency in knocking down intracellularly misfolded SOD1 and its efficacy in modifying the pathogenesis of ALS.

RESULTS: Expression of the plasmid carrying the CT4 sequence in human HEK cells resulted in robust removal of misfolded SOD1 induced by serum deprivation. Co-transfection of the CT4 and the G93A-hSOD1 plasmids at various ratios demonstrated a dose-dependent knockdown efficiency on G93A-hSOD1, which could be further increased when misfolding of SOD1 was enhanced by serum deprivation. Application of the full-length CT4 peptide to primary cultures of neurons expressing the G93A variant of human SOD1 revealed a time course of the degradation of misfolded SOD1; misfolded SOD1 started to decrease by 2 h after the application of CT4 and disappeared by 7 h. Intravenous administration of the CT4 peptide at 10 mg/kg to the G93A-hSOD1 reduced human SOD1 in spinal cord tissue by 68% in 24 h and 54% in 48 h in presymptomatic ALS mice. Intraperitoneal administration of the CT4 peptide starting from 60 days of age significantly delayed the onset of ALS and prolonged the lifespan of the G93A-hSOD1 mice.

CONCLUSIONS: The CT4 peptide directs the degradation of misfolded SOD1 in high efficiency and specificity. Selective removal of misfolded SOD1 significantly delays the onset of ALS, demonstrating that misfolded SOD1 is the toxic form of SOD1 that causes motor neuron death. The study proves that selective removal of misfolded SOD1 is a promising treatment for ALS.}, } @article {pmid37753182, year = {2023}, author = {Marciante, AB and Seven, YB and Kelly, MN and Perim, RR and Mitchell, GS}, title = {Magnitude and Mechanism of Phrenic Long-term Facilitation Shift Between Daily Rest Versus Active Phase.}, journal = {Function (Oxford, England)}, volume = {4}, number = {6}, pages = {zqad041}, pmid = {37753182}, issn = {2633-8823}, support = {R01 HL148030/HL/NHLBI NIH HHS/United States ; T32 HL134621/HL/NHLBI NIH HHS/United States ; R01 HL149800/HL/NHLBI NIH HHS/United States ; }, mesh = {Rats ; Animals ; Humans ; Rats, Sprague-Dawley ; *Serotonin ; *Hypoxia ; Signal Transduction ; Adenosine ; }, abstract = {Plasticity is a fundamental property of the neural system controlling breathing. One key example of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a persistent increase in phrenic nerve activity elicited by acute intermittent hypoxia (AIH). pLTF can arise from distinct cell signaling cascades initiated by serotonin versus adenosine receptor activation, respectively, and interact via powerful cross-talk inhibition. Here, we demonstrate that the daily rest/active phase and the duration of hypoxic episodes within an AIH protocol have profound impact on the magnitude and mechanism of pLTF due to shifts in serotonin/adenosine balance. Using the historical "standard" AIH protocol (3, 5-min moderate hypoxic episodes), we demonstrate that pLTF magnitude is unaffected by exposure in the midactive versus midrest phase, yet the mechanism driving pLTF shifts from serotonin-dominant (midrest) to adenosine-dominant (midactive). This mechanistic "flip" results from combined influences of hypoxia-evoked adenosine release and daily fluctuations in basal spinal adenosine. Since AIH evokes less adenosine with shorter (15, 1-min) hypoxic episodes, midrest pLTF is amplified due to diminished adenosine constraint on serotonin-driven plasticity; in contrast, elevated background adenosine during the midactive phase suppresses serotonin-dominant pLTF. These findings demonstrate the importance of the serotonin/adenosine balance in regulating the amplitude and mechanism of AIH-induced pLTF. Since AIH is emerging as a promising therapeutic modality to restore respiratory and nonrespiratory movements in people with spinal cord injury or ALS, knowledge of how time-of-day and hypoxic episode duration impact the serotonin/adenosine balance and the magnitude and mechanism of pLTF has profound biological, experimental, and translational implications.}, } @article {pmid37753280, year = {2023}, author = {Orr, JE and Chen, K and Vaida, F and Schmickl, CN and Laverty, CG and Ravits, J and Lesser, D and Bhattacharjee, R and Malhotra, A and Owens, RL}, title = {Effectiveness of long-term noninvasive ventilation measured by remote monitoring in neuromuscular disease.}, journal = {ERJ open research}, volume = {9}, number = {5}, pages = {}, pmid = {37753280}, issn = {2312-0541}, support = {K23 HL151880/HL/NHLBI NIH HHS/United States ; K23 HL161336/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVE: Patients with neuromuscular disease are often treated with home noninvasive ventilation (NIV) with devices capable of remote patient monitoring. We sought to determine whether long-term NIV data could provide insight into the effectiveness of ventilation over time.

METHODS: We abstracted available longitudinal data for adults with neuromuscular disease in monthly increments from first available to most recent. Generalised linear mixed-effects modelling with subject-level random effects was used to evaluate trajectories over time.

RESULTS: 1799 months of data across 85 individuals (median age 61, interquartile range (IQR) 46-71 years; 44% female; 49% amyotrophic lateral sclerosis (ALS)) were analysed, with a median (IQR) of 17 (8-35) months per individual. Over time, tidal volume increased and respiratory rate decreased. Dynamic respiratory system compliance decreased, accompanied by increased pressure support. Compared to volume-assured mode, fixed-pressure modes were associated with lower initial tidal volume, higher respiratory rate and lower pressures, which did not fully equalise with volume-assured mode over time. Compared with non-ALS patients, those with ALS had lower initial pressure support, but faster increases in pressure support over time, and ALS was associated wtih a more robust increase in respiratory rate in response to low tidal volume. Nonsurvivors did not differ from survivors in ventilatory trajectories over time, but did exhibit decreasing NIV use prior to death, in contrast with stable use in survivors.

CONCLUSION: NIV keeps breathing patterns stable over time, but support needs are dynamic and influenced by diagnosis and ventilation mode. Mortality is preceded by decreased NIV use rather than inadequate support during use.}, } @article {pmid37753578, year = {2023}, author = {Yang, X and Hayes, LR}, title = {Order from chaos: Using CSF proteomics to predict ALS progression.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {12}, pages = {2176-2178}, pmid = {37753578}, issn = {2328-9503}, support = {R03 NS127011/NS/NINDS NIH HHS/United States ; R01 NS123538/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Biomarkers ; Disease Progression ; *Proteomics ; *Cerebrospinal Fluid Proteins/analysis ; }, } @article {pmid37755677, year = {2024}, author = {Hu, C and Yan, Y and Jin, Y and Yang, J and Xi, Y and Zhong, Z}, title = {Decoding the Cellular Trafficking of Prion-like Proteins in Neurodegenerative Diseases.}, journal = {Neuroscience bulletin}, volume = {40}, number = {2}, pages = {241-254}, pmid = {37755677}, issn = {1995-8218}, mesh = {Humans ; *Prions ; *Neurodegenerative Diseases/pathology ; Amyloid beta-Peptides ; *Alzheimer Disease ; alpha-Synuclein ; tau Proteins ; *Parkinson Disease ; }, abstract = {The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.}, } @article {pmid37756598, year = {2023}, author = {Prior-González, M and Lazo-Gómez, R and Tapia, R}, title = {Sodium butyrate does not protect spinal motor neurons from AMPA-induced excitotoxic degeneration in vivo.}, journal = {Disease models & mechanisms}, volume = {16}, number = {10}, pages = {}, pmid = {37756598}, issn = {1754-8411}, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis/pathology ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism ; Butyric Acid/pharmacology/metabolism ; Motor Neurons/pathology ; Spinal Cord/pathology ; }, abstract = {Motor neuron (MN) loss is the primary pathological hallmark of amyotrophic lateral sclerosis (ALS). Histone deacetylase 4 (HDAC4) is one of several factors involved in nerve-muscle communication during MN loss, hindering muscle reinnervation, as shown in humans and in animal models of ALS, and may explain the differential progression observed in patients with ALS - rapid versus slow progression. In this work, we inhibited HDAC4 activity through the administration of a pan-histone deacetylase inhibitor, sodium butyrate, in an in vivo model of chronic spinal MN death induced by AMPA-mediated excitotoxicity. We infused AMPA into the spinal cord at low and high doses, which mimic the rapid and slow progression observed in humans, respectively. We found that muscle HDAC4 expression was increased by high-dose infusion of AMPA. Treatment of animals with sodium butyrate further decreased expression of muscle HDAC4, although non-significantly, and did not prevent the paralysis or the MN loss induced by AMPA infusion. These results inform on the role of muscle HDAC4 in MN degeneration in vivo and provide insights for the search for more suitable therapeutic strategies.}, } @article {pmid37756636, year = {2023}, author = {Wang, Y and Liu, L and Chen, H and Yang, Y and Mu, C and Ren, H and Liu, Y and Yu, L and Fang, Q and Wang, G and Hao, Z}, title = {Disrupted phase behavior of FUS underlies poly-PR-induced DNA damage in amyotrophic lateral sclerosis.}, journal = {Human molecular genetics}, volume = {33}, number = {1}, pages = {64-77}, doi = {10.1093/hmg/ddad163}, pmid = {37756636}, issn = {1460-2083}, support = {//National Natural Science Foundation of China/ ; //Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; 2020M671572//China Postdoctoral Science Foundation/ ; 21KJA180003//Key Project of Natural Science Foundation of Jiangsu Provincial Higher Education Institutions/ ; 32271039//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA Repeat Expansion ; *Frontotemporal Dementia/genetics/metabolism ; Proteins/genetics ; DNA Damage/genetics ; Arginine/genetics ; C9orf72 Protein/genetics/metabolism ; Dipeptides/genetics ; }, abstract = {GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the first intron of the chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Among the five dipeptide repeat proteins translated from G4C2 HRE, arginine-rich poly-PR (proline:arginine) is extremely toxic. However, the molecular mechanism responsible for poly-PR-induced cell toxicity remains incompletely understood. Here, we found that poly-PR overexpression triggers severe DNA damage in cultured cells, primary cortical neurons, and the motor cortex of a poly-PR transgenic mouse model. Interestingly, we identified a linkage between poly-PR and RNA-binding protein fused in sarcoma (FUS), another ALS-related gene product associated with DNA repair. Poly-PR interacts with FUS both in vitro and in vivo, phase separates with FUS in a poly-PR concentration-dependent manner, and impairs the fluidity of FUS droplets in vitro and in cells. Moreover, poly-PR impedes the recruitment of FUS and its downstream protein XRCC1 to DNA damage foci after microirradiation. Importantly, overexpression of FUS significantly decreased the level of DNA damage and dramatically reduced poly-PR-induced cell death. Our data suggest the severe DNA damage caused by poly-PR and highlight the interconnection between poly-PR and FUS, enlightening the potential therapeutic role of FUS in alleviating poly-PR-induced cell toxicity.}, } @article {pmid37758263, year = {2024}, author = {Crumbley, C and Cepni, AB and Taylor, A and Thompson, D and Moran, NE and Olvera, N and O'Connor, DP and Johnston, CA and Ledoux, TA}, title = {Exploring Factors Associated With Accelerometer Validity Among Ethnically Diverse Toddlers.}, journal = {Pediatric exercise science}, volume = {36}, number = {2}, pages = {66-74}, doi = {10.1123/pes.2022-0114}, pmid = {37758263}, issn = {1543-2920}, support = {P20 CA221697/CA/NCI NIH HHS/United States ; CRIS 3092-51000-063-01S//USDA/ ; CRIS 3092-51000-059-NEW2S//USDA/ ; }, mesh = {Humans ; Male ; Female ; Child, Preschool ; Adult ; *Exercise ; *Sedentary Behavior ; Parents ; Patient Compliance ; Accelerometry ; }, abstract = {PURPOSE: Studying physical activity in toddlers using accelerometers is challenging due to noncompliance with wear time (WT) and activity log (AL) instructions. The aims of this study are to examine relationships between WT and AL completion and (1) demographic and socioeconomic variables, (2) parenting style, and (3) whether sedentary time differs by AL completion.

METHODS: Secondary analysis was performed using baseline data from a community wellness program randomized controlled trial for parents with toddlers (12-35 mo). Parents had toddlers wear ActiGraph wGT3x accelerometers and completed ALs. Valid days included ≥600-minute WT. Analysis of variance and chi-square analyses were used.

RESULTS: The sample (n = 50) comprised racial and ethnically diverse toddlers (mean age = 27 mo, 58% male) and parents (mean age = 31.7 y, 84% female). Twenty-eight families (56%) returned valid accelerometer data with ALs. Participants in relationships were more likely to complete ALs (P < .05). Toddler sedentary time did not differ between those with ALs and those without.

CONCLUSIONS: We found varied compliance with WT instructions and AL completion. Returned AL quality was poor, presenting challenges in correctly characterizing low-activity counts to improve internal validity of WT and physical activity measures. Support from marital partners may be important for adherence to study protocols.}, } @article {pmid37758454, year = {2024}, author = {Goutman, SA and Boss, J and Jang, DG and Mukherjee, B and Richardson, RJ and Batterman, S and Feldman, EL}, title = {Environmental risk scores of persistent organic pollutants associate with higher ALS risk and shorter survival in a new Michigan case/control cohort.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {3}, pages = {241-248}, pmid = {37758454}, issn = {1468-330X}, support = {K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000289/TS/ATSDR CDC HHS/United States ; R01TS000289/ACL/ACL HHS/United States ; }, mesh = {Humans ; Persistent Organic Pollutants ; Michigan/epidemiology ; *Amyotrophic Lateral Sclerosis ; *Environmental Pollutants/adverse effects ; Risk Factors ; *Hydrocarbons, Chlorinated ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurogenerative disease caused by combined genetic susceptibilities and environmental exposures. Identifying and validating these exposures are of paramount importance to modify disease risk. We previously reported that persistent organic pollutants (POPs) associate with ALS risk and survival and aimed to replicate these findings in a new cohort.

METHOD: Participants with and without ALS recruited in Michigan provided plasma samples for POPs analysis by isotope dilution with triple quadrupole mass spectrometry. ORs for risk models and hazard ratios for survival models were calculated for individual POPs. POP mixtures were represented by environmental risk scores (ERS), a summation of total exposures, to evaluate the association with risk (ERS[risk]) and survival (ERS[survival]).

RESULTS: Samples from 164 ALS and 105 control participants were analysed. Several individual POPs significantly associated with ALS, including 8 of 22 polychlorinated biphenyls and 7 of 10 organochlorine pesticides (OCPs). ALS risk was most strongly represented by the mixture effects of OCPs alpha-hexachlorocyclohexane, hexachlorobenzene, trans-nonachlor and cis-nonachlor and an interquartile increase in ERS[risk] enhanced ALS risk 2.58 times (p<0.001). ALS survival was represented by the combined mixture of all POPs and an interquartile increase in ERS[survival] enhanced ALS mortality rate 1.65 times (p=0.008).

CONCLUSIONS: These data continue to support POPs as important factors for ALS risk and progression and replicate findings in a new cohort. The assessments of POPs in non-Michigan ALS cohorts are encouraged to better understand the global effect and the need for targeted disease risk reduction strategies.}, } @article {pmid37758732, year = {2023}, author = {Marzullo, M and Romano, G and Pellacani, C and Riccardi, F and Ciapponi, L and Feiguin, F}, title = {Su(var)3-9 mediates age-dependent increase in H3K9 methylation on TDP-43 promoter triggering neurodegeneration.}, journal = {Cell death discovery}, volume = {9}, number = {1}, pages = {357}, pmid = {37758732}, issn = {2058-7716}, abstract = {Aging progressively modifies the physiological balance of the organism increasing susceptibility to both genetic and sporadic neurodegenerative diseases. These changes include epigenetic chromatin remodeling events that may modify the transcription levels of disease-causing genes affecting neuronal survival. However, how these events interconnect is not well understood. Here, we found that Su(var)3-9 causes increased methylation of histone H3K9 in the promoter region of TDP-43, the most frequently altered factor in amyotrophic lateral sclerosis (ALS), affecting the mRNA and protein expression levels of this gene through epigenetic modifications that appear to be conserved in aged Drosophila brains, mouse, and human cells. Remarkably, augmented Su(var)3-9 activity causes a decrease in TDP-43 expression followed by early defects in locomotor activities. In contrast, decreasing Su(var)3-9 action promotes higher levels of TDP-43 expression, improving motility parameters in old flies. The data uncover a novel role of this enzyme in regulating TDP-43 expression and locomotor senescence and indicate conserved epigenetic mechanisms that may play a role in the pathogenesis of ALS.}, } @article {pmid37759084, year = {2024}, author = {Tan, EL and Tahedl, M and Lope, J and Hengeveld, JC and Doherty, MA and McLaughlin, RL and Hardiman, O and Chang, KM and Finegan, E and Bede, P}, title = {Language deficits in primary lateral sclerosis: cortical atrophy, white matter degeneration and functional disconnection between cerebral regions.}, journal = {Journal of neurology}, volume = {271}, number = {1}, pages = {431-445}, pmid = {37759084}, issn = {1432-1459}, mesh = {Humans ; *White Matter/diagnostic imaging/pathology ; Diffusion Tensor Imaging/methods ; Prospective Studies ; *Motor Neuron Disease/pathology ; Atrophy/pathology ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: Primary lateral sclerosis (PLS) is traditionally regarded as a pure upper motor neuron disorder, but recent cases series have highlighted cognitive deficits in executive and language domains.

METHODS: A single-centre, prospective neuroimaging study was conducted with comprehensive clinical and genetic profiling. The structural and functional integrity of language-associated brain regions and networks were systematically evaluated in 40 patients with PLS in comparison to 111 healthy controls. The structural integrity of the arcuate fascicle, frontal aslant tract, inferior occipito-frontal fascicle, inferior longitudinal fascicle, superior longitudinal fascicle and uncinate fascicle was evaluated. Functional connectivity between the supplementary motor region and the inferior frontal gyrus and connectivity between Wernicke's and Broca's areas was also assessed.

RESULTS: Cortical thickness reductions were observed in both Wernicke's and Broca's areas. Fractional anisotropy reduction was noted in the aslant tract and increased radical diffusivity (RD) identified in the aslant tract, arcuate fascicle and superior longitudinal fascicle in the left hemisphere. Functional connectivity was reduced along the aslant track, i.e. between the supplementary motor region and the inferior frontal gyrus, but unaffected between Wernicke's and Broca's areas. Cortical thickness alterations, structural and functional connectivity changes were also noted in the right hemisphere.

CONCLUSIONS: Disease-burden in PLS is not confined to motor regions, but there is also a marked involvement of language-associated tracts, networks and cortical regions. Given the considerably longer survival in PLS compared to ALS, the impact of language impairment on the management of PLS needs to be carefully considered.}, } @article {pmid37759179, year = {2023}, author = {Garcia-Vaquero, ML and Heim, M and Flix, B and Pereira, M and Palin, L and Marques, TM and Pinto, FR and de Las Rivas, J and Voigt, A and Besse, F and Gama-Carvalho, M}, title = {Analysis of asymptomatic Drosophila models for ALS and SMA reveals convergent impact on functional protein complexes linked to neuro-muscular degeneration.}, journal = {BMC genomics}, volume = {24}, number = {1}, pages = {576}, pmid = {37759179}, issn = {1471-2164}, mesh = {Adult ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Drosophila/genetics ; *Muscular Atrophy, Spinal ; Motor Neurons ; RNA ; DNA-Binding Proteins ; *Drosophila Proteins/genetics ; }, abstract = {BACKGROUND: Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) share phenotypic and molecular commonalities, including the fact that they can be caused by mutations in ubiquitous proteins involved in RNA metabolism, namely SMN, TDP-43 and FUS. Although this suggests the existence of common disease mechanisms, there is currently no model to explain the resulting motor neuron dysfunction. In this work we generated a parallel set of Drosophila models for adult-onset RNAi and tagged neuronal expression of the fly orthologues of the three human proteins, named Smn, TBPH and Caz, respectively. We profiled nuclear and cytoplasmic bound mRNAs using a RIP-seq approach and characterized the transcriptome of the RNAi models by RNA-seq. To unravel the mechanisms underlying the common functional impact of these proteins on neuronal cells, we devised a computational approach based on the construction of a tissue-specific library of protein functional modules, selected by an overall impact score measuring the estimated extent of perturbation caused by each gene knockdown.

RESULTS: Transcriptome analysis revealed that the three proteins do not bind to the same RNA molecules and that only a limited set of functionally unrelated transcripts is commonly affected by their knock-down. However, through our integrative approach we were able to identify a concerted effect on protein functional modules, albeit acting through distinct targets. Most strikingly, functional annotation revealed that these modules are involved in critical cellular pathways for motor neurons, including neuromuscular junction function. Furthermore, selected modules were found to be significantly enriched in orthologues of human neuronal disease genes.

CONCLUSIONS: The results presented here show that SMA and ALS disease-associated genes linked to RNA metabolism functionally converge on neuronal protein complexes, providing a new hypothesis to explain the common motor neuron phenotype. The functional modules identified represent promising biomarkers and therapeutic targets, namely given their alteration in asymptomatic settings.}, } @article {pmid37759469, year = {2023}, author = {Castillo Bautista, CM and Eismann, K and Gentzel, M and Pelucchi, S and Mertens, J and Walters, HE and Yun, MH and Sterneckert, J}, title = {Obatoclax Rescues FUS-ALS Phenotypes in iPSC-Derived Neurons by Inducing Autophagy.}, journal = {Cells}, volume = {12}, number = {18}, pages = {}, pmid = {37759469}, issn = {2073-4409}, support = {R01 AG056306/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; ERC-STG-2019-852086/ERC_/European Research Council/International ; AG056306/AG/NIA NIH HHS/United States ; RF1 AG056306/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Mutation ; Autophagy/physiology ; Phenotype ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; Indoles ; Pyrroles ; }, abstract = {Aging is associated with the disruption of protein homeostasis and causally contributes to multiple diseases, including amyotrophic lateral sclerosis (ALS). One strategy for restoring protein homeostasis and protecting neurons against age-dependent diseases such as ALS is to de-repress autophagy. BECN1 is a master regulator of autophagy; however, is repressed by BCL2 via a BH3 domain-mediated interaction. We used an induced pluripotent stem cell model of ALS caused by mutant FUS to identify a small molecule BH3 mimetic that disrupts the BECN1-BCL2 interaction. We identified obatoclax as a brain-penetrant drug candidate that rescued neurons at nanomolar concentrations by reducing cytoplasmic FUS levels, restoring protein homeostasis, and reducing degeneration. Proteomics data suggest that obatoclax protects neurons via multiple mechanisms. Thus, obatoclax is a candidate for repurposing as a possible ALS therapeutic and, potentially, for other age-associated disorders linked to defects in protein homeostasis.}, } @article {pmid37759540, year = {2023}, author = {Sanghai, N and Tranmer, GK}, title = {Biochemical and Molecular Pathways in Neurodegenerative Diseases: An Integrated View.}, journal = {Cells}, volume = {12}, number = {18}, pages = {}, pmid = {37759540}, issn = {2073-4409}, support = {//CIHR/Canada ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Oxidative Stress ; Autophagy ; Amyotrophic Lateral Sclerosis/metabolism ; *Signal Transduction ; }, abstract = {Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are defined by a myriad of complex aetiologies. Understanding the common biochemical molecular pathologies among NDDs gives an opportunity to decipher the overlapping and numerous cross-talk mechanisms of neurodegeneration. Numerous interrelated pathways lead to the progression of neurodegeneration. We present evidence from the past pieces of literature for the most usual global convergent hallmarks like ageing, oxidative stress, excitotoxicity-induced calcium butterfly effect, defective proteostasis including chaperones, autophagy, mitophagy, and proteosome networks, and neuroinflammation. Herein, we applied a holistic approach to identify and represent the shared mechanism across NDDs. Further, we believe that this approach could be helpful in identifying key modulators across NDDs, with a particular focus on AD, PD, and ALS. Moreover, these concepts could be applied to the development and diagnosis of novel strategies for diverse NDDs.}, } @article {pmid37759591, year = {2023}, author = {Wang, X and Hu, W and Li, Y and Jiang, M and Zhao, N and Cao, H and Liao, M}, title = {Cytochrome P450s-Involved Enhanced Metabolism Contributes to the High Level of Nicosulfuron Resistance in Digitaria sanguinalis from China.}, journal = {Biology}, volume = {12}, number = {9}, pages = {}, pmid = {37759591}, issn = {2079-7737}, support = {202203a06020016//the Science and Technology Major Project of Anhui Province/ ; rc342004//the Talent Research Project of Anhui Agricultural University/ ; X202310364519//the College Students' Innovation Training Project in Anhui Agricultural University/ ; }, abstract = {Large crabgrass (Digitaria sanguinalis (L.) Scop.) is one of the major malignant grass weeds in Chinese maize (Zea mays L.) fields, and it has recently developed resistance to the acetolactate synthase (ALS)-inhibiting herbicide nicosulfuron. This study focused on a suspected nicosulfuron-resistant (R) population (LJ-01) of D. sanguinalis, collected from Lujiang County in Anhui Province, China, to explore the resistance level and potential resistance mechanism. Whole-plant dose-response testing confirmed that the LJ-01 population evolved a high level of resistance to nicosulfuron (11.5-fold) compared to the susceptible (S) population, DY-02. The ALS gene sequencing and relative expression assay of the R plants indicated that target gene mutation and overexpression were not responsible for the resistance phenotype. However, pretreatment with malathion, a known cytochrome P450 monooxygenase (P450) inhibitor, alleviated the resistance of the R population to nicosulfuron by approximately 36%. High-performance liquid chromatography (HPLC) analysis revealed that the R plants metabolized nicosulfuron faster than the S plants. Moreover, cross-resistance testing suggested that the R population exhibited low levels of resistance to thifensulfuron-methyl and pyrazosulfuron-ethyl, but it remained susceptible to rimsulfuron. Multiple resistance patterns showed that the R population evolved low resistance to the photosystem inhibitors bromoxynil octanoate and atrazine and sensitivity to the acetyl-CoA carboxylase (ACCase) inhibitor cyhalofop-butyl and the 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors tembotrione, mesotrione, and topramezone. This study reports, for the first time, the simultaneous resistance to ALS and different photosystem inhibitors in D. sanguinalis. The nicosulfuron resistance observed in the R population could primarily be attributed to an enhanced metabolism involving P450 enzymes.}, } @article {pmid37759656, year = {2023}, author = {Angelopoulou, E and Pyrgelis, ES and Ahire, C and Suman, P and Mishra, A and Piperi, C}, title = {Functional Implications of Protein Arginine Methyltransferases (PRMTs) in Neurodegenerative Diseases.}, journal = {Biology}, volume = {12}, number = {9}, pages = {}, pmid = {37759656}, issn = {2079-7737}, abstract = {During the aging of the global population, the prevalence of neurodegenerative diseases will be continuously growing. Although each disorder is characterized by disease-specific protein accumulations, several common pathophysiological mechanisms encompassing both genetic and environmental factors have been detected. Among them, protein arginine methyltransferases (PRMTs), which catalyze the methylation of arginine of various substrates, have been revealed to regulate several cellular mechanisms, including neuronal cell survival and excitability, axonal transport, synaptic maturation, and myelination. Emerging evidence highlights their critical involvement in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum, Huntington's disease (HD), spinal muscular atrophy (SMA) and spinal and bulbar muscular atrophy (SBMA). Underlying mechanisms include the regulation of gene transcription and RNA splicing, as well as their implication in various signaling pathways related to oxidative stress responses, apoptosis, neuroinflammation, vacuole degeneration, abnormal protein accumulation and neurotransmission. The targeting of PRMTs is a therapeutic approach initially developed against various forms of cancer but currently presents a novel potential strategy for neurodegenerative diseases. In this review, we discuss the accumulating evidence on the role of PRMTs in the pathophysiology of neurodegenerative diseases, enlightening their pathogenesis and stimulating future research.}, } @article {pmid37759773, year = {2023}, author = {Goto, S and Zhang, Y and Vyas, SA and Zhu, Q and Wildsoet, CF}, title = {Changes in Expression in BMP2 and Two Closely Related Genes in Guinea Pig Retinal Pigment Epithelium during Induction and Recovery from Myopia.}, journal = {Biomolecules}, volume = {13}, number = {9}, pages = {}, pmid = {37759773}, issn = {2218-273X}, support = {R01 EY012392/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Guinea Pigs ; Bone Morphogenetic Protein 2/genetics ; Choroid ; *Myopia/genetics ; *Retinal Pigment Epithelium ; }, abstract = {PURPOSE: We previously reported differential gene expression of the bone morphogenetic protein 2 (Bmp2) in guinea pig retinal pigment epithelium (RPE) after 1 day of hyperopic defocus, imposed with a negative contact lens (CLs). The study reported here sought to obtain insights into the temporal profiles of gene expression changes in Bmp2, as well as those of two closely related genes, the inhibitor of DNA binding 3 (Id3) and Noggin (Nog), both during myopia induction and when the CL treatment was terminated to allow recovery from induced myopia.

METHODS: To induce myopia, 2-week-old pigmented guinea pigs (New Zealand strain, n = 8) wore monocular -10 diopter (D) rigid gas-permeable (RGP) CLs for one week, while the other eye served as a control. Ocular measurements were made at baseline, 3 days, and 7 days after the initiation of CL wear, with treatment then being terminated and additional measurements being made after a further 3 days, 1 week, and 2 weeks. Spherical equivalent refractive errors (SERs), axial length (AL), choroidal thickness (ChT), and scleral thickness (ScT) data were collected using retinoscopy, optical biometry (Lenstar), and spectral domain optical coherence tomography (SD-OCT), respectively. RPE samples were collected from both eyes of the guinea pigs after either 1 day or 1 week of CL wear or 1 day or 2 weeks after its termination, and RNA was subsequently isolated and subjected to quantitative real-time PCR (qRT-PCR) analyses, targeting the Bmp2, Id3, and Nog genes.

RESULTS: Mean interocular differences (treated-control) in AL and SER were significantly different from baseline after 3 and 7 days of CL wear, consistent with induced myopia (p < 0.001 for all cases). Termination of CL wear resulted in the normalization (i.e., recovery) of the ALs and SERs of the treated eyes within 7 days, and the earlier significant ChT thinning with CL wear (p = 0004, day 7) was replaced by rapid thickening, which remained significant on day 7 (p = 0.009) but had normalized by day 14. The ChT changes were much smaller in magnitude than the AL changes in both phases. Interocular differences in the ScT showed no significant changes. The Bmp2 and Id3 genes were both significantly downregulated with CL wear, after 1 day (p = 0.012 and 0.016) and 7 days (p = 0.002 and 0.005), while Bmp2 gene expression increased and Nog gene expression decreased after the termination of CL wear, albeit transiently, which was significant on 1 day (p = 0.004 and 0.04) but not 2 weeks later. No change in Id3 gene expression was observed over the latter period. Conclusions: The above patterns of myopia induction and recovery validate this negative RGP-CL model as an alternative to traditional spectacle lens models for guinea pigs. The defocus-driven, sign-dependent changes in the expression of the Bmp2 gene in guinea pig RPE are consistent with observations in chicks and demonstrate the important role of BMP2 in eye growth regulation.}, } @article {pmid37759926, year = {2023}, author = {Shimizu, T and Nakayama, Y and Bokuda, K and Takahashi, K}, title = {Sensory Gating during Voluntary Finger Movement in Amyotrophic Lateral Sclerosis with Sensory Cortex Hyperexcitability.}, journal = {Brain sciences}, volume = {13}, number = {9}, pages = {}, pmid = {37759926}, issn = {2076-3425}, support = {16H05583//Japan Society for the Promotion of Science/ ; 19H03939//Japan Society for the Promotion of Science/ ; 22H03398//Japan Society for the Promotion of Science/ ; }, abstract = {Cortical responses in somatosensory evoked potentials (SEP) are enhanced in patients with amyotrophic lateral sclerosis (ALS). This study investigated whether sensory gating is involved in the pathophysiology of sensory cortical hyperactivity in ALS patients. The median nerve SEP was recorded at rest and during voluntary finger movements in 14 ALS patients and 13 healthy control subjects. The parietal N20, P25, and frontal N30 were analyzed, and sensory gating was assessed by measuring the amplitude of each component during finger movement. The amplitudes of the N20 onset-peak, N20 peak-P25 peak, and N30 onset-peak were higher in ALS patients than in controls. Nonetheless, there were no significant differences in the amplitude reduction ratio of SEPs between patients and controls. There was a significant correlation between the baseline amplitudes of the N20 onset-peak or N20 peak-P25 peak and their gating ratios in patients with ALS. Our findings indicate that the excitability of the primary sensory cortex and secondary motor cortex is enhanced in ALS, while sensory gating is preserved in the early stages of ALS. This result suggests that enhanced SEP is caused by the hyperexcitability of the primary sensory and secondary motor cortices but not by the dysfunction of inhibitory mechanisms during voluntary movements.}, } @article {pmid37760050, year = {2023}, author = {Rubino, V and La Rosa, G and Pipicelli, L and Carriero, F and Damiano, S and Santillo, M and Terrazzano, G and Ruggiero, G and Mondola, P}, title = {Insights on the Multifaceted Roles of Wild-Type and Mutated Superoxide Dismutase 1 in Amyotrophic Lateral Sclerosis Pathogenesis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {9}, pages = {}, pmid = {37760050}, issn = {2076-3921}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neurodegenerative disease. Cell damage in ALS is the result of many different, largely unknown, pathogenetic mechanisms. Astrocytes and microglial cells play a critical role also for their ability to enhance a deranged inflammatory response. Excitotoxicity, due to excessive glutamate levels and increased intracellular Ca[2+] concentration, has also been proposed to play a key role in ALS pathogenesis/progression. Reactive Oxygen Species (ROS) behave as key second messengers for multiple receptor/ligand interactions. ROS-dependent regulatory networks are usually mediated by peroxides. Superoxide Dismutase 1 (SOD1) physiologically mediates intracellular peroxide generation. About 10% of ALS subjects show a familial disease associated with different gain-of-function SOD1 mutations. The occurrence of sporadic ALS, not clearly associated with SOD1 defects, has been also described. SOD1-dependent pathways have been involved in neuron functional network as well as in immune-response regulation. Both, neuron depolarization and antigen-dependent T-cell activation mediate SOD1 exocytosis, inducing increased interaction of the enzyme with a complex molecular network involved in the regulation of neuron functional activity and immune response. Here, alteration of SOD1-dependent pathways mediating increased intracellular Ca[2+] levels, altered mitochondria functions and defective inflammatory process regulation have been proposed to be relevant for ALS pathogenesis/progression.}, } @article {pmid37760880, year = {2023}, author = {Milella, G and Sciancalepore, D and Cavallaro, G and Piccirilli, G and Nanni, AG and Fraddosio, A and D'Errico, E and Paolicelli, D and Fiorella, ML and Simone, IL}, title = {Acoustic Voice Analysis as a Useful Tool to Discriminate Different ALS Phenotypes.}, journal = {Biomedicines}, volume = {11}, number = {9}, pages = {}, pmid = {37760880}, issn = {2227-9059}, abstract = {Approximately 80-96% of people with amyotrophic lateral sclerosis (ALS) become unable to speak during the disease progression. Assessing upper and lower motor neuron impairment in bulbar regions of ALS patients remains challenging, particularly in distinguishing spastic and flaccid dysarthria. This study aimed to evaluate acoustic voice parameters as useful biomarkers to discriminate ALS clinical phenotypes. Triangular vowel space area (tVSA), alternating motion rates (AMRs), and sequential motion rates (SMRs) were analyzed in 36 ALS patients and 20 sex/age-matched healthy controls (HCs). tVSA, AMR, and SMR values significantly differed between ALS and HCs, and between ALS with prevalent upper (pUMN) and lower motor neuron (pLMN) impairment. tVSA showed higher accuracy in discriminating pUMN from pLMN patients. AMR and SMR were significantly lower in patients with bulbar onset than those with spinal onset, both with and without bulbar symptoms. Furthermore, these values were also lower in patients with spinal onset associated with bulbar symptoms than in those with spinal onset alone. Additionally, AMR and SMR values correlated with the degree of dysphagia. Acoustic voice analysis may be considered a useful prognostic tool to differentiate spastic and flaccid dysarthria and to assess the degree of bulbar involvement in ALS.}, } @article {pmid37761265, year = {2023}, author = {Anghel, L and Ciubară, A and Nechita, A and Nechita, L and Manole, C and Baroiu, L and Ciubară, AB and Mușat, CL}, title = {Sleep Disorders Associated with Neurodegenerative Diseases.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {13}, number = {18}, pages = {}, pmid = {37761265}, issn = {2075-4418}, abstract = {Sleep disturbances are common in various neurological pathologies, including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), hereditary ataxias, Huntington's disease (HD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). This article reviews the prevalence and characteristics of sleep disorders in these conditions, highlighting their impact on patients' quality of life and disease progression. Sleep-related breathing disorders, insomnia, restless legs syndrome (RLS), periodic limb movement syndrome (PLMS), and rapid eye movement sleep behavior disorder (RBD) are among the common sleep disturbances reported. Both pharmacological and non-pharmacological interventions play crucial roles in managing sleep disturbances and enhancing overall patient care.}, } @article {pmid37762010, year = {2023}, author = {Tsuruta, K and Shidara, T and Miyagishi, H and Nango, H and Nakatani, Y and Suzuki, N and Amano, T and Suzuki, T and Kosuge, Y}, title = {Anti-Inflammatory Effects of Miyako Bidens pilosa in a Mouse Model of Amyotrophic Lateral Sclerosis and Lipopolysaccharide-Stimulated BV-2 Microglia.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762010}, issn = {1422-0067}, support = {22K06654 (Y.K.) and 21K06620 (H.M. and Y.K.)//JSPS KAKENHI/ ; 2211//a Nihon University Research Grant for 2022-2023/ ; 2019//Shorei Foundation for Science and Technology/ ; 2020//The Research Foundation for Pharmaceutical Sciences/ ; }, mesh = {Humans ; Animals ; Mice ; Microglia ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Bidens ; Interleukin-6 ; Lipopolysaccharides/toxicity ; Cytokines ; Disease Models, Animal ; }, abstract = {Neuroinflammation is a fundamental feature in the pathogenesis of amyotrophic lateral sclerosis (ALS) and arises from the activation of astrocytes and microglial cells. Previously, we reported that Miyako Bidens pilosa extract (MBP) inhibited microglial activation and prolonged the life span in a human ALS-linked mutant superoxide dismutase-1 (SOD1[G93A]) transgenic mouse model of ALS (G93A mice). Herein, we evaluated the effect of MBP on microglial activation in the spinal cord of G93A mice and lipopolysaccharide-stimulated BV-2 microglial cells. The administration of MBP inhibited the upregulation of the M1-microglia/macrophage marker (interferon-γ receptor (IFN-γR)) and pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6) in G93A mice. However, MBP did not affect the increase in the M2-microglia/macrophage marker (IL-13R) and anti-inflammatory cytokines (transforming growth factor (TGF)-β and IL-10) in G93A mice. BV-2 cell exposure to MBP resulted in a decrease in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) reduction activity and bromodeoxyuridine incorporation, without an increase in the number of ethidium homodimer-1-stained dead cells. Moreover, MBP suppressed the production of lipopolysaccharide-induced pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in BV-2 cells. These results suggest that the selective suppression of M1-related pro-inflammatory cytokines is involved in the therapeutic potential of MBP in ALS model mice.}, } @article {pmid37762112, year = {2023}, author = {Gimenez, J and Spalloni, A and Cappelli, S and Ciaiola, F and Orlando, V and Buratti, E and Longone, P}, title = {TDP-43 Epigenetic Facets and Their Neurodegenerative Implications.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762112}, issn = {1422-0067}, support = {PathensTDP//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; JPND2020-568-078//EU Joint Programme - Neurodegenerative Disease Research/ ; }, mesh = {Humans ; *Chromatin ; Cytoplasm ; *DNA-Binding Proteins/genetics ; Epigenesis, Genetic ; Epigenomics ; }, abstract = {Since its initial involvement in numerous neurodegenerative pathologies in 2006, either as a principal actor or as a cofactor, new pathologies implicating transactive response (TAR) DNA-binding protein 43 (TDP-43) are regularly emerging also beyond the neuronal system. This reflects the fact that TDP-43 functions are particularly complex and broad in a great variety of human cells. In neurodegenerative diseases, this protein is often pathologically delocalized to the cytoplasm, where it irreversibly aggregates and is subjected to various post-translational modifications such as phosphorylation, polyubiquitination, and cleavage. Until a few years ago, the research emphasis has been focused particularly on the impacts of this aggregation and/or on its widely described role in complex RNA splicing, whether related to loss- or gain-of-function mechanisms. Interestingly, recent studies have strengthened the knowledge of TDP-43 activity at the chromatin level and its implication in the regulation of DNA transcription and stability. These discoveries have highlighted new features regarding its own transcriptional regulation and suggested additional mechanistic and disease models for the effects of TPD-43. In this review, we aim to give a comprehensive view of the potential epigenetic (de)regulations driven by (and driving) this multitask DNA/RNA-binding protein.}, } @article {pmid37762278, year = {2023}, author = {Mastrangelo, A and Vacchiano, V and Zenesini, C and Ruggeri, E and Baiardi, S and Cherici, A and Avoni, P and Polischi, B and Santoro, F and Capellari, S and Liguori, R and Parchi, P}, title = {Amyloid-Beta Co-Pathology Is a Major Determinant of the Elevated Plasma GFAP Values in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762278}, issn = {1422-0067}, support = {Ricerca Corrente//Ministero della Salute/ ; PE0000006//#NextGenerationEU/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/pathology ; Male ; Female ; *Glial Fibrillary Acidic Protein/blood ; Middle Aged ; Biomarkers/blood/cerebrospinal fluid ; *Amyloid beta-Peptides/metabolism/blood ; Aged ; *Alzheimer Disease/blood/cerebrospinal fluid/pathology ; tau Proteins/blood/cerebrospinal fluid ; Case-Control Studies ; }, abstract = {Recent studies reported increased plasma glial acidic fibrillary protein (GFAP) levels in amyotrophic lateral sclerosis (ALS) patients compared to controls. We expanded these findings in a larger cohort, including 156 ALS patients and 48 controls, and investigated the associations of plasma GFAP with clinical variables and other biofluid biomarkers. Plasma GFAP and Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers were assessed by the single molecule array and the Lumipulse platforms, respectively. In ALS patients, plasma GFAP was higher than in controls (p < 0.001) and associated with measures of cognitive decline. Twenty ALS patients (12.8%) showed a positive amyloid status (A+), of which nine also exhibited tau pathology (A+T+, namely ALS-AD). ALS-AD patients showed higher plasma GFAP than A- ALS participants (p < 0.001) and controls (p < 0.001), whereas the comparison between A- ALS and controls missed statistical significance (p = 0.07). Plasma GFAP distinguished ALS-AD subjects more accurately (area under the curve (AUC) 0.932 ± 0.027) than plasma p-tau181 (AUC 0.692 ± 0.058, p < 0.0001) and plasma neurofilament light chain protein (AUC, 0.548 ± 0.088, p < 0.0001). Cognitive measures differed between ALS-AD and other ALS patients. AD co-pathology deeply affects plasma GFAP values in ALS patients. Plasma GFAP is an accurate biomarker for identifying AD co-pathology in ALS, which can influence the cognitive phenotype.}, } @article {pmid37762599, year = {2023}, author = {Taneva, SG and Todinova, S and Andreeva, T}, title = {Morphometric and Nanomechanical Screening of Peripheral Blood Cells with Atomic Force Microscopy for Label-Free Assessment of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762599}, issn = {1422-0067}, support = {KP-06-H31/8//Bulgarian Science Fund/ ; funding programme Open Access Publishing//Baden-Württemberg Ministry of Science, Research and Culture/ ; }, mesh = {Humans ; *Parkinson Disease/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Alzheimer Disease/diagnosis ; Microscopy, Atomic Force ; Blood Cells ; }, abstract = {Neurodegenerative disorders (NDDs) are complex, multifactorial disorders with significant social and economic impact in today's society. NDDs are predicted to become the second-most common cause of death in the next few decades due to an increase in life expectancy but also to a lack of early diagnosis and mainly symptomatic treatment. Despite recent advances in diagnostic and therapeutic methods, there are yet no reliable biomarkers identifying the complex pathways contributing to these pathologies. The development of new approaches for early diagnosis and new therapies, together with the identification of non-invasive and more cost-effective diagnostic biomarkers, is one of the main trends in NDD biomedical research. Here we summarize data on peripheral biomarkers, biofluids (cerebrospinal fluid and blood plasma), and peripheral blood cells (platelets (PLTs) and red blood cells (RBCs)), reported so far for the three most common NDDs-Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). PLTs and RBCs, beyond their primary physiological functions, are increasingly recognized as valuable sources of biomarkers for NDDs. Special attention is given to the morphological and nanomechanical signatures of PLTs and RBCs as biophysical markers for the three pathologies. Modifications of the surface nanostructure and morphometric and nanomechanical signatures of PLTs and RBCs from patients with AD, PD, and ALS have been revealed by atomic force microscopy (AFM). AFM is currently experiencing rapid and widespread adoption in biomedicine and clinical medicine, in particular for early diagnostics of various medical conditions. AFM is a unique instrument without an analog, allowing the generation of three-dimensional cell images with extremely high spatial resolution at near-atomic scale, which are complemented by insights into the mechanical properties of cells and subcellular structures. Data demonstrate that AFM can distinguish between the three pathologies and the normal, healthy state. The specific PLT and RBC signatures can serve as biomarkers in combination with the currently used diagnostic tools. We highlight the strong correlation of the morphological and nanomechanical signatures between RBCs and PLTs in PD, ALS, and AD.}, } @article {pmid37762807, year = {2023}, author = {Annunziata, A and Calabrese, C and Simioli, F and Coppola, A and Pierucci, P and Mariniello, DF and Fiorentino, G}, title = {Psychological Factors Influencing Adherence to NIV in Neuromuscular Patients Dependent on Non Invasive Mechanical Ventilation: Preliminary Results.}, journal = {Journal of clinical medicine}, volume = {12}, number = {18}, pages = {}, pmid = {37762807}, issn = {2077-0383}, abstract = {BACKGROUND: Non-invasive ventilation (NIV) is associated with improvement of both morbility and mortality in patients affected by neuromuscular diseases with chronic respiratory failure. Several studies have also shown that long-term NIV positively impacts the patient's quality of life and perception of disease status. Its effectiveness is likely related to the adherence to NIV. Several factors, patient- and not patient-related, may compromise adherence to NIV, such as physical, behavioral, familiar, and social issues. Few data are currently available on the role of psychological factors in influencing NIV adherence.

MATERIALS AND METHODS: In this pilot study, we evaluated the adherence to NIV in a group of 15 adult patients with neuromuscular diseases (Duchenne muscular dystrophy, myotonic dystrophy, and amyotrophic lateral sclerosis) in relation to their grade of depression assessed by the Beck Depression Inventory (BDI) questionnaire. Other data were collected, such as clinical features (age and sex), use of anxiolytic drugs, the presence of a family or professional caregiver, the quality of patient-physician relationship, the beginning of psychological support after BDI screening, and the family acceptance of NIV. NIV adherence was definied as the use of NIV for at least 4 h per night on 70% of nights in a month.

RESULTS: The overall rate of NIV adherence was 60%. Based on the BDI questionnaire, patients who were non-adherent to NIV had a higher rate of depression, mainly observed in the oldest patients. The acceptance of NIV by the family and positive physician-patient interaction seem to favor NIV adherence.

CONCLUSION: Depression can interfere with NIV adherence in patients with neuromuscolar diseases.}, } @article {pmid37763163, year = {2023}, author = {Kortazar-Zubizarreta, I and Manero-Azua, A and Afonso-Agüera, J and Perez de Nanclares, G}, title = {C9ORF72 Gene GGGGCC Hexanucleotide Expansion: A High Clinical Variability from Amyotrophic Lateral Sclerosis to Frontotemporal Dementia.}, journal = {Journal of personalized medicine}, volume = {13}, number = {9}, pages = {}, pmid = {37763163}, issn = {2075-4426}, abstract = {The expanded GGGGCC hexanucleotide repeat (HRE) in the non-coding region of the C9ORF72 gene (C9ORF72-HRE) is the most common genetic cause of familial forms of amyotrophic lateral sclerosis (ALS), FTD, and concurrent ALS and FTD (ALS-FTD), in addition to contributing to the sporadic forms of these diseases. Both syndromes overlap not only genetically, but also sharing similar clinical and neuropathological findings, being considered as a spectrum. In this paper we describe the clinical-genetic findings in a Basque family with different manifestations within the spectrum, our difficulties in reaching the diagnosis, and a narrative review, carried out as a consequence, of the main features associated with C9ORF72-HRE. Family members underwent a detailed clinical assessment, neurological examination, and genetic analysis by repeat-primed PCR. We studied 10 relatives of a symptomatic carrier of the C9ORF72-HRE expansion. Two of them presented the expansion in the pathological range, one of them was symptomatic whereas the other one remained asymptomatic at 72 years. Given the great intrafamilial clinical variability of C9ORF72-HRE, the characterization of patients and family members with particular clinical and genetic subgroups within ALS and FTD becomes a bottleneck for medication development, in particular for genetically focused medicines for ALS and FTD.}, } @article {pmid37766226, year = {2023}, author = {Ayers, JI and Xu, G and Lu, Q and Dillon, K and Fromholt, S and Borchelt, DR}, title = {Multiple Factors Influence the Incubation Period of ALS Prion-like Transmission in SOD1 Transgenic Mice.}, journal = {Viruses}, volume = {15}, number = {9}, pages = {}, pmid = {37766226}, issn = {1999-4915}, support = {R01 NS092788/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Young Adult ; *Amyotrophic Lateral Sclerosis/genetics ; Mice, Transgenic ; Paralysis ; *Prions ; Superoxide Dismutase-1/genetics ; }, abstract = {Mutations in superoxide dismutase 1 (SOD1) that are associated with amyotrophic lateral sclerosis (ALS) cause its misfolding and aggregation. Prior studies have demonstrated that the misfolded conformation of ALS-SOD1 can template with naïve SOD1 "host proteins" to propagate, spread, and induce paralysis in SOD1 transgenic mice. These observations have advanced the argument that SOD1 is a host protein for an ALS conformer that is prion-like and experimentally transmissible. Here, we investigated the propagation of different isolates of G93A-SOD1 ALS conformers using a paradigm involving transmission to mice expressing human G85R-SOD1 fused to yellow fluorescent protein (G85R-SOD1:YFP). In these studies, we also utilized a newly developed line of mice in which the G85R-SOD1:YFP construct was flanked by loxp sites, allowing its temporal and spatial regulation. We used methods in which the G93A ALS conformers were injected into the sciatic nerve or hindlimb muscle of adult transgenic mice. We observed that the incubation period to paralysis varied significantly depending upon the source of inoculum containing misfolded G93A SOD1. Serial passage and selection produced stable isolates of G93A ALS conformers that exhibited a defined minimum incubation period of ~2.5 months when injected into the sciatic nerve of young adult mice. As expected, neuronal excision of the transgene in loxpG85R-SOD1:YFP mice blocked induction of paralysis by transmission of G93A ALS conformers. Our findings indicate that G93A ALS conformers capable of inducing disease require neuronal expression of a receptive host SOD1 protein for propagation, with a defined incubation period to paralysis.}, } @article {pmid37766430, year = {2023}, author = {Cheng, W and Huang, J and Fu, XQ and Tian, WY and Zeng, PM and Li, Y and Luo, ZG}, title = {Intrathecal delivery of AAV-NDNF ameliorates disease progression of ALS mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {31}, number = {11}, pages = {3277-3289}, pmid = {37766430}, issn = {1525-0024}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Dependovirus/genetics ; Disease Models, Animal ; Disease Progression ; Mice, Transgenic ; Motor Neurons/metabolism ; Nerve Growth Factors/metabolism ; *Neurodegenerative Diseases/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a uniformly lethal neurodegenerative disease characterized by progressive deterioration of motor neurons and neuromuscular denervation. Adeno-associated virus (AAV)-mediated delivery of trophic factors is being considered as a potential disease-modifying therapeutic avenue. Here we show a marked effect of AAV-mediated over-expression of neuron-derived neurotrophic factor (NDNF) on SOD1[G93A] ALS model mice. First, we adopt AAV-PHP.eB capsid to enable widespread expression of target proteins in the brain and spinal cord when delivered intrathecally. Then we tested the effects of AAV-NDNF on SOD1[G93A] mice at different stages of disease. Interestingly, AAV-NDNF markedly improved motor performance and alleviated weight loss when delivered at early post-symptomatic stage. Injection in the middle post-symptomatic stages still improved the locomotion ability, although it did not alleviate the loss of body weight. Injection in the late stage also extended the life span of SOD1[G93A] mice. Furthermore, NDNF expression promoted the survival of spinal motoneurons, reduced abnormal protein aggregation, and preserved the innervated neuromuscular functions. We further analyzed the signaling pathways of NDNF expression and found that it activates cell survival and growth-associated mammalian target of rapamycin signaling pathway and downregulates apoptosis-related pathways. Thus, intrathecally AAV-NDNF delivery has provided a potential strategy for the treatment of ALS.}, } @article {pmid37766843, year = {2023}, author = {Olukoya, AO and Stires, H and Bahnassy, S and Persaud, S and Guerra, Y and Ranjit, S and Ma, S and Cruz, MI and Benitez, C and Rozeboom, AM and Ceuleers, H and Berry, DL and Jacobsen, BM and Raj, GV and Riggins, RB}, title = {Riluzole Suppresses Growth and Enhances Response to Endocrine Therapy in ER+ Breast Cancer.}, journal = {Journal of the Endocrine Society}, volume = {7}, number = {10}, pages = {bvad117}, pmid = {37766843}, issn = {2472-1972}, support = {P30 CA051008/CA/NCI NIH HHS/United States ; T32 CA009686/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, riluzole has shown antitumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. We previously reported that the acquisition of tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by riluzole.

METHODS: We tested the ability of riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent, ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI.

RESULTS: Single-agent riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell lines in vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). Riluzole induced apoptosis and ferroptosis and reduced phosphorylation of multiple prosurvival signaling molecules, including Akt/mTOR, CREB, and Fak/Src family kinases. Riluzole, in combination with either fulvestrant or 4-hydroxytamoxifen, additively suppressed ER+ breast cancer cell growth in vitro. Single-agent riluzole significantly inhibited HCI-013EI patient-derived xenograft growth in vivo, and the combination of riluzole plus fulvestrant significantly reduced proliferation in ex vivo primary breast tumor explant cultures.

CONCLUSION: Riluzole may offer therapeutic benefits in diverse ER+ breast cancers, including lobular breast cancer.}, } @article {pmid37767023, year = {2023}, author = {Ayoubi, R and Alshafie, W and Southern, K and McPherson, PS and Laflamme, C and , }, title = {The identification of high-performing antibodies for Coiled-coil-helix-coiled-coil-helix domain containing protein 10 (CHCHD10) for use in Western Blot, immunoprecipitation and immunofluorescence.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {403}, pmid = {37767023}, issn = {2046-1402}, mesh = {Humans ; *Fluorescent Antibody Technique/methods ; *Immunoprecipitation/methods ; *Mitochondrial Proteins/immunology ; *Blotting, Western ; *Antibodies/immunology ; HEK293 Cells ; }, abstract = {CHCHD10 is a mitochondrial protein, implicated in the regulation of mitochondrial morphology and cristae structure, as well as the maintenance of mitochondrial DNA integrity. Recently discovered to be associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in its mutant form, the scientific community would benefit from the availability of validated anti-CHCHD10 antibodies. In this study, we characterized four CHCHD10 commercial antibodies for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. As this study highlights high-performing antibodies for CHCHD10, we encourage readers to use it as a guide to select the most appropriate antibody for their specific needs.}, } @article {pmid37767237, year = {2023}, author = {Trofimov, A and Pavlov, D and Goswami, A and Gorlova, A and Chaprov, K and Umriukhin, A and Kalueff, A and Deykin, A and Lesch, KP and Anthony, DC and Strekalova, T}, title = {Lipopolysaccharide triggers exacerbated microglial activation, excessive cytokine release and behavioural disturbances in mice with truncated Fused-in-Sarcoma Protein (FUS).}, journal = {Brain, behavior, & immunity - health}, volume = {33}, number = {}, pages = {100686}, pmid = {37767237}, issn = {2666-3546}, abstract = {CNS inflammation, including microglial activation, in response to peripheral infections are known to contribute to the pathology of both familial and sporadic neurodegenerative disease. The relationship between Fused-in-Sarcoma Protein (FUS)-mediated disease in the transgenic FUS[1-359] animals and the systemic inflammatory response have not been explored. Here, we investigated microglial activation, inflammatory gene expression and the behavioural responses to lipopolysaccharide-induced (LPS; 0.1 mg/kg) systemic inflammation in the FUS[1-359] transgenic mice. The pathology of these mice recapitulates the key features of mutant FUS-associated familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here, pre-symptomatic 8-week-old mutant or wild type controls were challenged with LPS or with saline and sucrose intake, novel cage exploration, marble burying and swimming behaviours were analyzed. The level of pro-inflammatory gene expression was also determined, and microglial activation was evaluated. In chronic experiments, to discover whether the LPS challenge would affect the onset of ALS-like paralysis, animals were evaluated for clinical signs from 5 to 7 weeks post-injection. Compared to controls, acutely challenged FUS[1-359]-tg mice exhibited decreased sucrose intake and increased floating behaviours. The FUS[1-359]-tg mice exhibited an increase in immunoreactivity for Iba1-positive cells in the prefrontal cortex and ventral horn of the spinal cord, which was accompanied by increased expression of interleukin-1β, tumour necrosis factor, cyclooxygenase-(COX)-1 and COX-2. However, the single LPS challenge did not alter the time to development of paralysis in the FUS[1-359]-tg mice. Thus, while the acute inflammatory response was enhanced in the FUS mutant animals, it did not have a lasting impact on disease progression.}, } @article {pmid37767949, year = {2024}, author = {Liang, W and Liu, Y and Zhao, Y and Chen, Y and Yin, Y and Zhai, L and Li, Z and Gong, Z and Zhang, J and Zhang, M}, title = {Quantitative MRI Analysis of Brachial Plexus and Limb-Girdle Muscles in Upper Extremity Onset Amyotrophic Lateral Sclerosis.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {60}, number = {1}, pages = {291-301}, doi = {10.1002/jmri.29027}, pmid = {37767949}, issn = {1522-2586}, support = {82271478//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Female ; Male ; Middle Aged ; *Magnetic Resonance Imaging/methods ; *Brachial Plexus/diagnostic imaging ; *Upper Extremity/diagnostic imaging ; Retrospective Studies ; Aged ; Adult ; Muscle, Skeletal/diagnostic imaging ; }, abstract = {BACKGROUND: Recent evidence highlights the potential of axonal degeneration as a biomarker for amyotrophic lateral sclerosis (ALS) detection. However, the diagnostic potential of peripheral nerve axon changes in ALS remains unclear.

PURPOSE: To evaluate the diagnostic performance of quantitative MRI of the brachial plexus and limb-girdle muscles (LGMs) in patients with upper extremity onset of ALS.

STUDY TYPE: Retrospective.

POPULATION: 47 patients with upper extremity onset of ALS and 20 healthy volunteers.

FIELD STRENGTH/SEQUENCE: 3-T, three-dimensional sampling perfection with application-optimized contrasts using different flip angle evolutions with short-tau inversion recovery sequences, T2-weighted turbo spin-echo Dixon sequence.

ASSESSMENT: The cross-sectional area (CSA) and nerve-muscle T2 signal intensity ratio (nT2) of the bilateral brachial plexus as well as the CSA and fat fraction (FF) of the bilateral LGMs were assessed by two radiologists. Disease severity and clinical stage of ALS patients were assessed by two neurologists.

STATISTICAL TESTS: Student's t-test, Wilcoxon rank-sum test, binary logistic regression, interclass correlation coefficient, receiver operating characteristic analysis, and correlation analysis were performed for MRI quantitative metrics and clinical variables. Significance level: P < 0.05.

RESULTS: In the affected limbs of patients with ALS, the CSA of the brachial plexus roots, trunks, and cords and the nT2 values of the brachial plexus trunks were significantly smaller than in the healthy controls. In the LGMs, the affected limbs of ALS showed significantly smaller CSA and higher FF than controls. The model containing parameters such as brachial plexus trunk CSA, subscapularis CSA, infraspinatus CSA, and subscapularis FF had excellent diagnostic efficacy for ALS. Additionally, increased subscapularis FF and supraspinatus FF were correlated with disease severity, and subscapularis CSA was negatively correlated with the clinical stage.

DATA CONCLUSION: Brachial plexus thinning, LGM atrophy, and fatty infiltration might serve as MRI-derived biomarkers for ALS with upper extremity onset.

LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.}, } @article {pmid37768183, year = {2023}, author = {Trajano, GS and Orssatto, LBR and McCombe, PA and Rivlin, W and Tang, L and Henderson, RD}, title = {Longitudinal changes in intrinsic motoneuron excitability in amyotrophic lateral sclerosis are dependent on disease progression.}, journal = {The Journal of physiology}, volume = {601}, number = {21}, pages = {4723-4735}, doi = {10.1113/JP285181}, pmid = {37768183}, issn = {1469-7793}, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis ; Cross-Sectional Studies ; Superoxide Dismutase-1/genetics ; Motor Neurons/physiology ; Muscle, Skeletal ; Muscle Weakness ; Paresis ; Disease Progression ; }, abstract = {Increased amplitude of persistent inward currents (PICs) is observed in pre-symptomatic genetically modified SOD1 mice models of amyotrophic lateral sclerosis (ALS). However, at the symptomatic stage this reverses and there is a large reduction in PIC amplitude. It remains unclear whether these changes in PICs can be observed in humans, with cross-sectional studies in humans reporting contradictory findings. In people with ALS, we estimated the PIC contribution to self-sustained firing of motoneurons, using the paired-motor unit analysis to calculate the Δfrequency (ΔF), to compare the weaker and stronger muscles during the course of disease. We hypothesised that, with disease progression, ΔFs would relatively increase in the stronger muscles; and decline in the weaker muscles. Forty-three individuals with ALS were assessed in two occasions on average 17 weeks apart. Tibialis anterior high-density electromyograms were recorded during dorsiflexion (40% of maximal capacity) ramped contractions, followed by clinical tests. ∆F increased from 3.14 (2.57, 3.71) peaks per second (pps) to 3.55 (2.94, 4.17) pps on the stronger muscles (0.41 (0.041, 0.781) pps, standardised difference (d) = 0.287 (0.023, 0.552), P = 0.030). ∆F reduced from 3.38 (95% CI 2.92, 3.84) pps to 2.88 (2.40, 3.36) pps on the weaker muscles (-0.50 (-0.80, -0.21) pps, d = 0.353 (0.138, 0.567), P = 0.001). The ALSFRS-R score reduced 3.9 (2.3, 5.5) points. These data indicate that the contribution of PICs to motoneuron self-sustained firing increases over time in early stages of the disease when there is little weakness before decreasing as the disease progresses and muscle weakness exacerbates, in alignment with the findings from studies using SOD1 mice. KEY POINTS: Research on mouse model of amyotrophic lateral sclerosis (ALS) suggests that the amplitude of persistent inward currents (PICs) is increased in early stages before decreasing as the disease progresses. Cross-sectional studies in humans have reported contradictory findings with both higher and lower PIC contributions to motoneuron self-sustained firing. In this longitudinal (∼17 weeks) study we tracked changes in PIC contribution to motoneuron self-sustained firing, using the ΔF calculation (i.e. onset-offset hysteresis of motor unit pairs), in tibialis anterior muscles with normal strength and with clinical signs of weakness in people with ALS. ΔFs decreased over time in muscles with clinical signs of weakness. The PIC contribution to motoneuron self-sustained firing increases before the onset of muscle weakness, and subsequently decreases when muscle weakness progresses.}, } @article {pmid37768719, year = {2023}, author = {Aksoy, ME and Özkan, AE and Kitapcioglu, D and Usseli, T}, title = {Comparing the Outcomes of Virtual Reality-Based Serious Gaming and Lecture-Based Training for Advanced Life Support Training: Randomized Controlled Trial.}, journal = {JMIR serious games}, volume = {11}, number = {}, pages = {e46964}, pmid = {37768719}, issn = {2291-9279}, abstract = {BACKGROUND: Simulation-based Advanced Cardiac Life Support (ACLS) or Advanced Life Support (ALS) training for health care professionals is important worldwide for saving lives. Virtual reality (VR)-based serious gaming can be an alternative modality to be used as a part of simulation-based ALS training.

OBJECTIVE: The aim of this study is to investigate whether a VR-based ALS serious game module can replace classroom-based ALS lectures, the latter being part of existing conventional ALS training protocols in addition to skills training.

METHODS: Participants were students from Acibadem Mehmet Ali Aydinlar University's Vocational School for Anesthesiology (N=29) randomly divided into 2 groups with 15 (conventional training group) and 14 (VR-based training group) participants each. Participants in the conventional training group had to complete the pretest consisting of multiple-choice questions at the beginning of the study. Afterward, they took part in an interactive classroom-based ALS lecture. The next step involved skills training with task trainers to teach them compression skills. Following this, the conventional training group was divided into Code Blue teams, each consisting of 5 participants for the simulation session. Two independent instructors evaluated video recordings in terms of technical and nontechnical skills. The score acquired from the manikin-based simulation session was considered the main performance indicator in this study to measure the learning outcome. A similar workflow was used for the VR-based training group, but this group was trained with the VR-based ALS serious game module instead of the theoretical lecture. The final stage of the study involved completing the posttest consisting of multiple-choice questions. A preference survey was conducted among the study participants. Mann-Whitney U and Wilcoxon signed-rank tests were used to analyze the 2 groups' performances in this study.

RESULTS: The improvement in posttest results compared with pretest results was significant in the conventional training group (P=.002). Hands-on technical scores of the conventional training group were higher than those of the VR-based training group during manikin-based simulation, but total scores, including those for technical and crisis resource management skills, acquired from the manikin-based simulation session did not reveal any significant difference between the 2 groups. The results of the VR preference survey revealed that the majority of the participants prefer VR-based serious game-based training instead of classroom lectures.

CONCLUSIONS: Although hands-on technical scores of the conventional training group during the manikin-based simulation session were higher than those of the VR-based training group, both groups' total performance scores, including those for technical and crisis resource management skills, did not differ significantly. The preference survey reveals that the majority of the participants would prefer a VR-based ALS serious gaming module instead of lecture-based training. Further studies are required to reveal the learning outcome of VR-based ALS serious gaming.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05798910; https://clinicaltrials.gov/study/NCT05798910.}, } @article {pmid37768998, year = {2023}, author = {Abraham, A and Fainmesser, Y and Drory, VE and Bril, V}, title = {Quantitative sonographic assessment of muscle thickness and fasciculations distribution is a sensitive tool for neuromuscular disorders.}, journal = {PloS one}, volume = {18}, number = {9}, pages = {e0292123}, pmid = {37768998}, issn = {1932-6203}, mesh = {Humans ; Fasciculation/diagnostic imaging ; Muscle, Skeletal/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Electromyography ; *Neuromuscular Diseases/diagnostic imaging ; *Muscular Diseases ; Ultrasonography ; *Polyneuropathies/diagnostic imaging ; }, abstract = {INTRODUCTION: Loss of muscle thickness can be demonstrated in a wide spectrum of neuromuscular disorders, while fasciculations are more frequent in amyotrophic lateral sclerosis (ALS). In the current study, we aimed to determine the sensitivity and specificity of quantitative sonographic assessment of muscle thickness and the presence of fasciculations for diagnosing various neuromuscular disorders.

METHODS: The thickness and the presence of fasciculations in eight muscles were determined by sonography in patients with myopathy (22), polyneuropathy (36), ALS (91), and spinal muscular atrophy (SMA) (31) and compared to normative values determined in 65 heathy control subjects.

RESULTS: Reduced muscle thickness in at least one relaxed muscle showed 92-100% sensitivity for diagnosing a neuromuscular disease, with a specificity of 85% for differentiating patients from heathy controls (AUC = 0.90). Subtracting distal from proximal muscle thickness may differentiate between myopathy and polyneuropathy. Fasciculations in ≥1 proximal muscle showed good diagnostic accuracy (AUC = 0.87) for diagnosing ALS.

DISCUSSION: Sonographic assessment of muscle thickness is a sensitive tool for diagnosing a wide spectrum of neuromuscular diseases, and may facilitate diagnosis even in patients with normal strength on neurological examination, while the presence of fasciculations in proximal muscles may facilitate ALS diagnosis.}, } @article {pmid37769591, year = {2023}, author = {Pazian Martins, M and González-Salazar, C and de Lima, FD and Bernardes Leoni, T and R M Martinez, A and Nunes Gonçalves, JP and Nucci, A and Cavalcante França, M}, title = {Autonomic function in sporadic and familial ALS type 8.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {155}, number = {}, pages = {68-74}, doi = {10.1016/j.clinph.2023.08.006}, pmid = {37769591}, issn = {1872-8952}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/genetics ; Aged ; *Autonomic Nervous System/physiopathology ; Heart Rate/physiology ; *Autonomic Nervous System Diseases/physiopathology/diagnosis/etiology ; Adult ; }, abstract = {OBJECTIVE: To characterize and compare autonomic function in patients with sporadic (sALS) and familial ALS type 8 (fALS8).

METHODS: We selected 11 patients with sALS (7 men), 14 with fALS8 (8 men) and 26 controls (15 men). All groups were gender and age-matched. For each subject, Scale for Outcomes in Parkinson's Disease for Autonomic Symptoms (SCOPA-AUT) was applied and data from heart rate variability, Quantitative Sudomotor Axon Reflex Test (QSART) and skin sympathetic response (SSR) were collected. These data were compared across groups using nonparametric tests. P-values < 0.05 were considered significant.

RESULTS: SCOPA-AUT revealed predominant clinical complaints in thermoregulatory, pupillomotor and sexual domains in fALS8 relative to sALS as well as controls. Neurophysiological tests demonstrated significant differences in Valsalva ratio, Expiratory:Inspiratory index and RR minimum values in both ALS groups relative to controls. Sudomotor dysfunction was also observed in sALS and fALS8 groups, as shown by reduced medial forearm and foot QSART volumes and absence of SSR in lower limbs.

CONCLUSIONS: Dysautonomia - cardiac and sudomotor - is part of the phenotype in sALS and fALS8. The profile of autonomic symptoms, however, is different in each group.

SIGNIFICANCE: Patients with fALS8 and sALS have autonomic dysfunction involving both sympathetic and parasympathetic divisions.}, } @article {pmid37770137, year = {2023}, author = {Bivehed, E and Hellman, B and Fan, Y and Haglöf, J and Buratovic, S}, title = {DNA integrity under alkaline conditions: An investigation of factors affecting the comet assay.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {891}, number = {}, pages = {503680}, doi = {10.1016/j.mrgentox.2023.503680}, pmid = {37770137}, issn = {1879-3592}, mesh = {Humans ; *Comet Assay/methods ; DNA ; DNA Damage ; DNA Repair ; Hydrogen-Ion Concentration ; }, abstract = {The effect of pH on DNA integrity was assessed using a three-step approach. The comet assay was used on a whole genome level, with three different protocols: neutral (no alkaline unwinding), flash (pH 12.5 with 2.5 min unwinding), and the conventional alkaline protocol (pH>13 with 40 min unwinding). Real-time quantitative PCR (RT-qPCR) was then used to study the isolated DNA, revealing that gene amplification decreased with increasing pH, indicating DNA degradation. Specially designed molecular beacons were used to examine DNA at the molecular level, with or without alkali-labile site (ALS) insertions. At pH 12.5, fluorescence in the hairpins with ALS started to increase after 30 min, while at pH> 13, this increase was already observed after 5 min, indicating a significant increase in DNA strand breaks. Liquid chromatography analysis was also used, demonstrating that the hairpins remained intact up to pH 10, even after 1 h exposure, whereas, at pH 12.5, partial conversion into strand breaks occurred after 30 min. At pH> 13, the hairpins were almost completely degraded after 30 min. The flash protocol effectively detects DNA single- and double-strand breaks and identified these damages after 2.5 min of alkaline treatment at pH 12.5. When the hairpins were exposed to pH 12.5 for 60 min, ALS were converted to strand breaks, demonstrating the sensitivity of this approach to detect changes in DNA structure. These findings indicate that pH poses a substantial risk to DNA integrity, leading to significantly higher background levels of DNA damage compared to conditions closer to neutrality. Our study demonstrates the importance of understanding the influence of pH on DNA stability and provides insights into risks associated with alkaline environments, especially at pH> 13.}, } @article {pmid37770379, year = {2023}, author = {Souza, INO and Roychaudhuri, R and de Belleroche, J and Mothet, JP}, title = {d-Amino acids: new clinical pathways for brain diseases.}, journal = {Trends in molecular medicine}, volume = {29}, number = {12}, pages = {1014-1028}, doi = {10.1016/j.molmed.2023.09.001}, pmid = {37770379}, issn = {1471-499X}, mesh = {Humans ; *Amino Acids/metabolism ; Critical Pathways ; Central Nervous System/metabolism ; Brain/metabolism ; *Alzheimer Disease/metabolism ; }, abstract = {Free d-amino acids (d-AAs) are emerging as a novel and important class of signaling molecules in many organs, including the brain and endocrine systems. There has been considerable progress in our understanding of the fundamental roles of these atypical messengers, with increasingly recognized implications in a wide range of neuropathologies, including schizophrenia (SCZ), epilepsy, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), substance abuse, and chronic pain, among others. Research has enabled the discovery that d-serine, d-aspartate and more recently d-cysteine are essential for the healthy development and function of the central nervous system (CNS). We discuss recent progress that has profoundly transformed our vision of numerous physiological processes but has also shown how d-AAs are now offering therapeutic promise in clinical settings for several human diseases.}, } @article {pmid37772684, year = {2023}, author = {Ali, Z and Godoy-Corchuelo, JM and Martins-Bach, AB and Garcia-Toledo, I and Fernández-Beltrán, LC and Nair, RR and Spring, S and Nieman, BJ and Jimenez-Coca, I and Bains, RS and Forrest, H and Lerch, JP and Miller, KL and Fisher, EMC and Cunningham, TJ and Corrochano, S}, title = {Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations.}, journal = {Disease models & mechanisms}, volume = {16}, number = {10}, pages = {}, pmid = {37772684}, issn = {1754-8411}, support = {FISHER/APR14/874-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0801110/MRC_/Medical Research Council/United Kingdom ; MR/L021056/1/MRC_/Medical Research Council/United Kingdom ; MC_EX_MR/N501931/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/pathology ; Nuclear Localization Signals/genetics/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; Mutation/genetics ; Neurons/metabolism ; }, abstract = {Variants in the ubiquitously expressed DNA/RNA-binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). Most FUS mutation studies have focused on motor neuron degeneration; little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues, given the link between ALS-frontotemporal dementia and altered metabolism. Few genes were commonly altered across all tissues, and most genes and pathways affected were generally tissue specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. Magnetic resonance imaging brain scans and histological characterisation revealed that homozygous FUSDelta14 brains were smaller than heterozygous and wild-type brains and displayed significant morphological alterations, including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. These findings show that the disease aetiology of FUS variants can include both neurodevelopmental and systemic alterations.}, } @article {pmid37773166, year = {2023}, author = {Aguilar-Vázquez, CA and Gallardo-González, LI and Raymundo-Carrillo, AD and Reyes-Sosa, LC and Martínez-Romo, ES}, title = {[Parkinson-dementia and amyotrophic lateral sclerosis association (complex of Guam). Diagnostic challenge, Mexican patient].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {61}, number = {5}, pages = {677-684}, pmid = {37773166}, issn = {2448-5667}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; *Parkinson Disease/complications/pathology ; *Dementia/complications/epidemiology/pathology ; *Neurodegenerative Diseases ; Guam/epidemiology ; *Parkinsonian Disorders/etiology/complications ; }, abstract = {BACKGROUND: The Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex (ALS-PDC) was first described in the islands of Guam. This pathology presented its peak incidence in the 1950s. Due to the rarity of the association, we report a clinical case with this complex. The objective was to describe the nosological and pathogenic implications of these neurodegenerative disorder, since they are not frequent to find in our population.

CLINICAL CASE: We present a case of Latinoamerican origin who initially manifested systemic symptoms of more than 6 years of evolution, with subsequent cognitive alterations. Later, patient began with gait disturbances and motor symptoms suggestive of parkinsonism with atypical data and data of motor neurone disease (MND). More studies were carried out and confirmed findings compatible with upper and lower motor neuron involvement. A mutation in the POLG gene was observed, related to mitochondrial depletion syndrome.

CONCLUSION: Despite the knowledge of this association, it is an entity whose clinical diagnosis could be very difficult to achieve. In addition, molecular mechanisms have not been fully identified, the most common genes related to Parkinsonism and ALS have been excluded, and even attempts to locate the locus were made, without achieving accurate results. Unfortunately, being a neurodegenerative disease, the prognosis is fatal, with no disease-modifying treatment.}, } @article {pmid37773576, year = {2024}, author = {Aiello, EN and Solca, F and Torre, S and Gentile, F and Scheveger, F and Olivero, M and Colombo, E and Maranzano, A and Manzoni, M and Morelli, C and Doretti, A and Verde, F and Silani, V and Ticozzi, N and Poletti, B}, title = {Frontotemporal-spectrum disorders and functional independence in non-demented ALS patients.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {3}, pages = {1087-1095}, pmid = {37773576}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Activities of Daily Living ; Functional Status ; Neuropsychological Tests ; *Frontotemporal Dementia ; Cognition ; }, abstract = {BACKGROUND: The present study aimed at determining whether, net of motor confounders, neuropsychological features affect functional independence (FI) in activities of daily living (ADLs) in non-demented amyotrophic lateral sclerosis (ALS) patients.

METHODS: N = 88 ALS patients without frontotemporal dementia were assessed for FI-Katz's Basic ADL Scale (BADL) and Lawton-Brody's Instrumental ADL Scale (IADL)-, cognition-Edinburgh Cognitive and Behavioural ALS Screen (ECAS)-and behaviour-Beaumont Behavioural Inventory and Dimensional Apathy Scale. The association between cognitive and behavioural measures and BADL/IADL scores was assessed by covarying for demographics, anxiety and depression levels, disease duration and motor confounders-i.e. ALS Functional Rating Scale-Revised (ALSFRS-R) scores, progression rate and both King's and Milano-Torino stages.

RESULTS: Higher scores on the ECAS-Language were associated with higher IADL scores (p = 0.005), whilst higher apathetic features-as measured by the Dimensional Apathy Scale (DAS)-were inversely related to the BADL (p = 0.003). Whilst IADL scores were related to all ECAS-Language tasks, the DAS-Initiation was the only subscale associated with BADL scores. Patients with abnormal ECAS-Language (p = 0.023) and DAS (p = 0.008) scores were more functionally dependent than those without.

DISCUSSION: Among non-motor features, language changes and apathetic features detrimentally affect FI in non-demented ALS patients.}, } @article {pmid37774738, year = {2023}, author = {Stipancic, KL and Golzy, M and Zhao, Y and Pinkerton, L and Rohl, A and Kuruvilla-Dugdale, M}, title = {Improving Perceptual Speech Ratings: The Effects of Auditory Training on Judgments of Dysarthric Speech.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {66}, number = {11}, pages = {4236-4258}, pmid = {37774738}, issn = {1558-9102}, support = {R15 DC016383/DC/NIDCD NIH HHS/United States ; R21 DC019952/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; Dysarthria/therapy ; *Speech Perception ; Judgment ; Reproducibility of Results ; *Amyotrophic Lateral Sclerosis ; Speech Intelligibility ; Speech Production Measurement ; *Parkinson Disease/complications ; }, abstract = {PURPOSE: Auditory training has been shown to reduce rater variability in perceptual voice assessment. Because rater variability is also a central issue in the auditory-perceptual assessment of dysarthria, this study sought to determine if training produces a meaningful change in rater reliability, criterion validity, and scaling magnitude of four features: overall speech impairment, articulatory imprecision, monotony, and slow rate.

METHOD: Forty-four nonexperts randomized to training and nontraining listener groups completed a pretest and posttest. Only the former group underwent auditory training between pre- and posttests. For both testing and training, listeners rated samples from speakers with amyotrophic lateral sclerosis (ALS), speakers with Parkinson's disease (PD), and neurologically healthy control speakers using separate visual analog scales (VASs) for each of the four features. Intraclass correlation coefficients were used to compare inter- and intrarater reliability between pre- and posttest for both listener groups. For criterion validity, severity ratings from the two nonexpert listener groups were compared to those of two experienced listeners for all four features. To determine changes in scaling magnitude, raw VAS scores for each feature were compared from pre- to posttest within the two nonexpert listener groups. Scaling changes were also compared between the two listener groups for the pre- and posttest conditions.

RESULTS AND CONCLUSIONS: In the training group, a meaningful improvement in interrater reliability was observed for some features in all three speaker groups, but not in the nontraining group. In contrast, for intrarater reliability, in the nontraining group, a meaningful improvement was observed for many features in all three speaker groups, but only for PD monotony and slow rate in the training group. All ratings from the nonexpert listeners were valid except for monotony. Raw VAS scores did not meaningfully change from pre- to posttest for any of the features, but there was a trend toward lower scores posttraining, mainly for the ALS samples. Modifications to the auditory training paradigm to further improve reliability and validity, along with future goals for optimizing training, are discussed.}, } @article {pmid37774774, year = {2023}, author = {Gschwendtberger, T and Thau-Habermann, N and von der Ohe, J and Luo, T and Hass, R and Petri, S}, title = {Protective effects of EVs/exosomes derived from permanently growing human MSC on primary murine ALS motor neurons.}, journal = {Neuroscience letters}, volume = {816}, number = {}, pages = {137493}, doi = {10.1016/j.neulet.2023.137493}, pmid = {37774774}, issn = {1872-7972}, mesh = {Mice ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Exosomes/metabolism ; Antioxidants/pharmacology ; Motor Neurons/metabolism ; *Mesenchymal Stem Cells/metabolism ; }, abstract = {In recent years, the neuroprotective potential of mesenchymal stroma-/stem-like cells (MSC) as well as of MSC-derived extracellular vesicles (EVs) like exosomes has been intensively explored. This included preclinical evaluation regarding treatment of neurodegenerative disorders such as the fatal motor neuron disease amyotrophic Lateral Sclerosis (ALS). Several studies have reported that MSC-derived exosomes can stimulate tissue regeneration and reduce inflammation. MSC release EVs and trophic factors and thereby modify cell-to-cell communication. These cell-free products may protect degenerating motor neurons (MNs) and represent a potential therapeutic approach for ALS. In the present study we investigated the effects of exosomes derived from a permanently growing MSC line on both, wild type and ALS (SOD1[G93A] transgenic) primary motor neurons. Following application in a normal and stressed environment we could demonstrate beneficial effects of MSC exosomes on neurite growth and morphology indicating the potential for further preclinical evaluation and clinical therapeutic development. Investigation of gene expression profiles detected transcripts of several antioxidant and anti-inflammatory genes in MSC exosomes. Characterization of their microRNA (miRNA) content revealed miRNAs capable of regulating antioxidant and anti-apoptotic pathways.}, } @article {pmid37776476, year = {2023}, author = {Ocharán-Mercado, A and Loaeza-Loaeza, J and Castro-Coronel, Y and Acosta-Saavedra, LC and Hernández-Kelly, LC and Hernández-Sotelo, D and Ortega, A}, title = {RNA-Binding Proteins: A Role in Neurotoxicity?.}, journal = {Neurotoxicity research}, volume = {41}, number = {6}, pages = {681-697}, pmid = {37776476}, issn = {1476-3524}, mesh = {Humans ; Aged ; *Neurodegenerative Diseases/metabolism ; RNA-Binding Proteins/metabolism ; Neurons/metabolism ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Despite sustained efforts to treat neurodegenerative diseases, little is known at the molecular level to understand and generate novel therapeutic approaches for these malignancies. Therefore, it is not surprising that neurogenerative diseases are among the leading causes of death in the aged population. Neurons require sophisticated cellular mechanisms to maintain proper protein homeostasis. These cells are generally sensitive to loss of gene expression control at the post-transcriptional level. Post-translational control responds to signals that can arise from intracellular processes or environmental factors that can be regulated through RNA-binding proteins. These proteins recognize RNA through one or more RNA-binding domains and form ribonucleoproteins that are critically involved in the regulation of post-transcriptional processes from splicing to the regulation of association of the translation machinery allowing a relatively rapid and precise modulation of the transcriptome. Neurotoxicity is the result of the biological, chemical, or physical interaction of agents with an adverse effect on the structure and function of the central nervous system. The disruption of the proper levels or function of RBPs in neurons and glial cells triggers neurotoxic events that are linked to neurodegenerative diseases such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), fragile X syndrome (FXS), and frontotemporal dementia (FTD) among many others. The connection between RBPs and neurodegenerative diseases opens a new landscape for potentially novel therapeutic targets for the intervention of these neurodegenerative pathologies. In this contribution, a summary of the recent findings of the molecular mechanisms involved in the plausible role of RBPs in RNA processing in neurodegenerative disease is discussed.}, } @article {pmid37776851, year = {2023}, author = {Tsioras, K and Smith, KC and Edassery, SL and Garjani, M and Li, Y and Williams, C and McKenna, ED and Guo, W and Wilen, AP and Hark, TJ and Marklund, SL and Ostrow, LW and Gilthorpe, JD and Ichida, JK and Kalb, RG and Savas, JN and Kiskinis, E}, title = {Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis.}, journal = {Cell reports}, volume = {42}, number = {10}, pages = {113160}, pmid = {37776851}, issn = {2211-1247}, support = {S10 OD032464/OD/NIH HHS/United States ; R01 AG078796/AG/NIA NIH HHS/United States ; R01 NS134166/NS/NINDS NIH HHS/United States ; R21 NS107761/NS/NINDS NIH HHS/United States ; R01 NS097850/NS/NINDS NIH HHS/United States ; R01 NS124802/NS/NINDS NIH HHS/United States ; R01 NS104219/NS/NINDS NIH HHS/United States ; R01 NS122908/NS/NINDS NIH HHS/United States ; R01 NS096746/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Proteome/metabolism ; Valosin Containing Protein/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Caenorhabditis elegans/metabolism ; Motor Neurons/metabolism ; Homeostasis ; Mutation ; }, abstract = {Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS) through gain-of-function effects, yet the mechanisms by which misfolded mutant SOD1 (mutSOD1) protein impairs human motor neurons (MNs) remain unclear. Here, we use induced-pluripotent-stem-cell-derived MNs coupled to metabolic stable isotope labeling and mass spectrometry to investigate proteome-wide degradation dynamics. We find several proteins, including the ALS-causal valosin-containing protein (VCP), which predominantly acts in proteasome degradation and autophagy, that degrade slower in mutSOD1 relative to isogenic control MNs. The interactome of VCP is altered in mutSOD1 MNs in vitro, while VCP selectively accumulates in the affected motor cortex of ALS-SOD1 patients. Overexpression of VCP rescues mutSOD1 toxicity in MNs in vitro and in a C. elegans model in vivo, in part due to its ability to modulate the degradation of insoluble mutSOD1. Our results demonstrate that VCP contributes to mutSOD1-dependent degeneration, link two distinct ALS-causal genes, and highlight selective protein degradation impairment in ALS pathophysiology.}, } @article {pmid37777552, year = {2023}, author = {Ometto, JP and Gorgens, EB and de Souza Pereira, FR and Sato, L and de Assis, MLR and Cantinho, R and Longo, M and Jacon, AD and Keller, M}, title = {A biomass map of the Brazilian Amazon from multisource remote sensing.}, journal = {Scientific data}, volume = {10}, number = {1}, pages = {668}, pmid = {37777552}, issn = {2052-4463}, mesh = {*Biomass ; Brazil ; Carbon/analysis ; *Forests ; *Remote Sensing Technology/methods ; Tropical Climate ; }, abstract = {The Amazon Forest, the largest contiguous tropical forest in the world, stores a significant fraction of the carbon on land. Changes in climate and land use affect total carbon stocks, making it critical to continuously update and revise the best estimates for the region, particularly considering changes in forest dynamics. Forest inventory data cover only a tiny fraction of the Amazon region, and the coverage is not sufficient to ensure reliable data interpolation and validation. This paper presents a new forest above-ground biomass map for the Brazilian Amazon and the associated uncertainty both with a resolution of 250 meters and baseline for the satellite dataset the year of 2016 (i.e., the year of the satellite observation). A significant increase in data availability from forest inventories and remote sensing has enabled progress towards high-resolution biomass estimates. This work uses the largest airborne LiDAR database ever collected in the Amazon, mapping 360,000 km[2] through transects distributed in all vegetation categories in the region. The map uses airborne laser scanning (ALS) data calibrated by field forest inventories that are extrapolated to the region using a machine learning approach with inputs from Synthetic Aperture Radar (PALSAR), vegetation indices obtained from the Moderate-Resolution Imaging Spectroradiometer (MODIS) satellite, and precipitation information from the Tropical Rainfall Measuring Mission (TRMM). A total of 174 field inventories geolocated using a Differential Global Positioning System (DGPS) were used to validate the biomass estimations. The experimental design allowed for a comprehensive representation of several vegetation types, producing an above-ground biomass map varying from a maximum value of 518 Mg ha[-1], a mean of 174 Mg ha[-1], and a standard deviation of 102 Mg ha[-1]. This unique dataset enabled a better representation of the regional distribution of the forest biomass and structure, providing further studies and critical information for decision-making concerning forest conservation, planning, carbon emissions estimate, and mechanisms for supporting carbon emissions reductions.}, } @article {pmid37779364, year = {2024}, author = {Matveeva, A and Watters, O and Rukhadze, A and Khemka, N and Gentile, D and Perez, IF and Llorente-Folch, I and Farrell, C and Lo Cacciato, E and Jackson, J and Piazzesi, A and Wischhof, L and Woods, I and Halang, L and Hogg, M and Muñoz, AG and Dillon, ET and Matallanas, D and Arijs, I and Lambrechts, D and Bano, D and Connolly, NMC and Prehn, JHM}, title = {Integrated analysis of transcriptomic and proteomic alterations in mouse models of ALS/FTD identify early metabolic adaptions with similarities to mitochondrial dysfunction disorders.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {135-149}, doi = {10.1080/21678421.2023.2261979}, pmid = {37779364}, issn = {2167-9223}, mesh = {Mice ; Animals ; Humans ; *Frontotemporal Dementia/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Proteomics ; *Neurodegenerative Diseases ; *Pick Disease of the Brain ; Mice, Transgenic ; *Mitochondrial Diseases ; Gene Expression Profiling ; RNA, Messenger ; }, abstract = {OBJECTIVE: Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD.

METHODS: By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage.

RESULTS: In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology.

CONCLUSIONS: Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS.}, } @article {pmid37780560, year = {2023}, author = {Zwicker, J and Smith, IC and Rice, J and Murphy, R and Breiner, A and McNeely, S and Duff, M and Buenger, U and Zehrt, B and Nogo, D and Watt, CL}, title = {Palliative care at any stage of amyotrophic lateral sclerosis: a prospective feasibility study.}, journal = {Frontiers in medicine}, volume = {10}, number = {}, pages = {1204816}, pmid = {37780560}, issn = {2296-858X}, abstract = {INTRODUCTION: Many patients with amyotrophic lateral sclerosis (ALS) receive palliative care (PC) very late or not at all. The impact of PC on patients with ALS and caregivers has not been quantified. Study goals included (1) measuring the impact of early PC on quality of life and mood of patients/caregivers and (2) describing patient/caregiver satisfaction with PC.

METHODS: The study was a non-randomized, prospective feasibility study of patients with ALS being treated at The Ottawa Hospital ALS Clinic and their caregivers. Exclusion criteria were age < 18 years, inability to complete questionnaires, and prior receipt of PC. The ALS Specific Quality of Life-Revised (ALSSQOL-R) questionnaire (patients only) and Hospital Anxiety and Depression Scale (HADS) were completed at regular intervals for up to 2 years. Patients accepting a PC consultation completed a post-PC satisfaction survey. Primary outcome measures included ALSSQOL-R and HADS scores compared before and after PC consultation, and between groups receiving and not receiving a PC consultation. Secondary outcome measures included responses on the post-PC satisfaction survey (1 = strongly disagree, 5 = strongly agree).

RESULTS: 39 patients with ALS (age 66 ± 10 years, median time from diagnosis = 6 months) and 22 caregivers were enrolled. 32 patients had a PC consultation (30 were virtual). Patients and caregivers agreed with statements that the PC consult was helpful (mean ± SD = 4.54 ± 0.60, range = 3-5) and they would recommend PC to others with ALS (4.59 ± 0.59, range = 3-5). Participants disagreed with statements that the consult would have been better later in disease course (1.87 ± 0.80, range = 1-4) and that it took too much time/energy (1.44 ± 0.85, range = 1-4). Average ALSSQOL-R scores worsened significantly over time. HADS and ALSSQOL-R scores did not significantly differ between groups receiving and not receiving PC.

CONCLUSION: Patients with ALS and their caregivers found virtual PC consultations beneficial irrespective of disease duration or severity. Offering routine PC to all patients with ALS is feasible and should be considered as part of standard care.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04257760, identifier NCT04257760.}, } @article {pmid37780700, year = {2023}, author = {Li, H and Xuan, T and Xu, T and Yang, J and Cheng, J and Wang, Z}, title = {SIGMAR1 variants in ALS-PD complex cases: a case report of a novel mutation and literature review.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1242472}, pmid = {37780700}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons, with occasional involvement of the extrapyramidal system. Mutations in the sigma non-opioid intracellular receptor 1 (SIGMAR1) gene have been identified as one of the causes of ALS. Here, we present a case of a 49-year-old man diagnosed with ALS-Parkinson's disease (PD) complex. The patient exhibited bradykinesia and tremor, and whole-exome sequencing revealed homozygous mutations in the SIGMAR1 gene (c.446-2A > T). In addition, we conducted an investigation into the clinical and molecular phenotype of previously reported variants of SIGMAR1 associated with ALS. This case report aims to raise awareness among physicians regarding atypical phenotypes of amyotrophic lateral sclerosis and to encourage further research on the factors leading to SIGMAR1 mutations in patients.}, } @article {pmid37781096, year = {2023}, author = {Yu, H and Xiong, M and Zhang, Z}, title = {The role of glycogen synthase kinase 3 beta in neurodegenerative diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1209703}, pmid = {37781096}, issn = {1662-5099}, abstract = {Neurodegenerative diseases (NDDs) pose an increasingly prevalent threat to the well-being and survival of elderly individuals worldwide. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and so on. They are characterized by progressive loss or dysfunction of neurons in the central or peripheral nervous system and share several cellular and molecular mechanisms, including protein aggregation, mitochondrial dysfunction, gene mutations, and chronic neuroinflammation. Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase that is believed to play a pivotal role in the pathogenesis of NDDs. Here we summarize the structure and physiological functions of GSK3β and explore its involvement in NDDs. We also discussed its potential as a therapeutic target.}, } @article {pmid37781884, year = {2023}, author = {Erdag, E and Haskologlu, IC and Mercan, M and Abacioglu, N and Sehirli, AO}, title = {An in silico investigation: Can melatonin serve as an adjuvant in NR1D1-linked chronotherapy for amyotrophic lateral sclerosis?.}, journal = {Chronobiology international}, volume = {40}, number = {10}, pages = {1395-1403}, doi = {10.1080/07420528.2023.2265476}, pmid = {37781884}, issn = {1525-6073}, mesh = {Animals ; Humans ; *Melatonin/pharmacology ; Circadian Rhythm/physiology ; *Amyotrophic Lateral Sclerosis/drug therapy ; Molecular Docking Simulation ; Chronotherapy/methods ; Nuclear Receptor Subfamily 1, Group D, Member 1/genetics ; }, abstract = {Chronobiology, which studies biological rhythms and their impacts on health, presents a potential avenue for treating amyotrophic lateral sclerosis. Clock gene-related therapies, focusing on genes responsible for regulating biological rhythms, may hold promise in the treatment. Among these clock genes, nuclear receptor subfamily 1 Group D member 1 (NR1D1) plays a vital role in neurodegenerative diseases. In this particular study, it was aimed to investigate the potential of FDA-approved drugs commonly used in amyotrophic lateral sclerosis treatment and melatonin, a hormone known for its role in regulating sleep-wake cycles, as ligands for clock gene-related therapy. The ligands were subjected to molecular docking and molecular dynamics simulation methods against the NR1D1 clock gene. These results suggested that combining melatonin with FDA-approved medications commonly used in the treatment might yield positive outcomes. This study provides preliminary data and lays the groundwork for future investigations involving in vitro (laboratory-based) and in vivo (animal or human-based) research on chronotherapy. In summary, this research highlights the potential of clock gene-related therapy utilizing melatonin in conjunction with FDA-approved drugs for amyotrophic lateral sclerosis treatment, offering insights into novel treatment strategies. The findings underscore the need for further studies to explore the effectiveness of this hypothetical approach in experimental and clinical settings.}, } @article {pmid37782142, year = {2023}, author = {Rahman, A and Saikia, B and Baruah, A}, title = {In silico analysis of SOD1 aggregation inhibition modes of tertiary amine pyrazolone and pyrano coumarin ferulate as ALS drug candidates.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {25}, number = {39}, pages = {26833-26846}, doi = {10.1039/d3cp03978a}, pmid = {37782142}, issn = {1463-9084}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Mutation ; *Neurodegenerative Diseases ; Protein Folding ; Superoxide Dismutase-1/chemistry/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, the familial form (fALS) of which is often cognate to mutations in the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) leading to misfolding and aggregation. Two small molecules, a tertiary amine pyrazolone (TAP) and a pyrano coumarin ferulate (PCF) were suggested to be ALS drug candidates following experimental observation of their ability to inhibit SOD1 protein misfolding and aggregation. The present work aims at computational investigation of these experimentally proposed drug candidates to gain insight into their mechanism of SOD1 misfolding and aggregation inhibition. On the basis of molecular docking, molecular dynamics simulation, MM-PBSA and per-residue energy decomposition analysis, we examined the specific interactions of TAP and PCF with three probable binding sites of SOD1, namely, dimeric interface cavity, W32 and, UMP binding sites. Results suggest that the binding of TAP at W32 and at UMP sites are least probable due to absence of any favorable interaction. The binding of TAP to dimeric cavity is also unstable due to strong unfavorable interactions. In case of PCF, binding at the UMP site is least probable while binding at dimeric cavity is accompanied by unfavorable interactions. PCF, however, exhibits stable binding with the W32 binding site of SOD1 by stabilizing the solvent accessible hydrophobic residues, which otherwise would have acted as contact points for aggregation. Thus the results imply that compound PCF functions as an inhibitior of SOD1 misfolding/aggregation through direct interaction with the protein SOD1 at the W32 binding site. However, TAP is likely to act as an inhibitor through a different mechanism rather than direct interaction with the protein SOD1. These results apart from reinforcing previous experimental findings, shed light on the probable mechanism of action of the proposed drug candidates.}, } @article {pmid37782260, year = {2023}, author = {Bchara, L and Eritja, R and Gargallo, R and Benavente, F}, title = {Rapid and Highly Efficient Separation of i-Motif DNA Species by CE-UV and Multivariate Curve Resolution.}, journal = {Analytical chemistry}, volume = {95}, number = {41}, pages = {15189-15198}, pmid = {37782260}, issn = {1520-6882}, mesh = {*DNA ; Spectrophotometry ; Spectrophotometry, Ultraviolet/methods ; Temperature ; *Electrophoresis, Capillary/methods ; }, abstract = {The i-motif is a class of nonstandard DNA structure with potential biological implications. A novel capillary electrophoresis with an ultraviolet absorption spectrophotometric detection (CE-UV) method has been developed for the rapid analysis of the i-motif folding equilibrium as a function of pH and temperature. The electrophoretic analyses are performed in reverse polarity of the separation voltage with 32 cm long fused silica capillaries permanently coated with hydroxypropyl cellulose (HPC), after an appropriate conditioning procedure was used to achieve good repeatability. However, the electrophoretic separation between the folded and unfolded conformers of the studied cytosine-rich i-motif sequences (i.e., TT, Py39WT, and nmy01) is compromised, especially for Py39WT and nmy01, which result in completely overlapped peaks. Therefore, deconvolution with multivariate curve resolution-alternating least-squares (MCR-ALS) has been required for the efficient separation of the folded and unfolded species found at different concentration levels at pH 6.5 and between 12 and 40 °C, taking advantage of the small dissimilarities in the electrophoretic mobilities and UV spectra levels. MCR-ALS has also provided quantitative information that has been used to estimate melting temperatures (Tm), which are similar to those determined by UV and circular dichroism (CD) spectroscopies. The obtained results demonstrate that CE-UV assisted by MCR-ALS may become a very useful tool to get novel insight into the folding of i-motifs and other complex DNA structures.}, } @article {pmid37782409, year = {2023}, author = {Lee, SY and Cho, HY and Oh, JP and Park, J and Bae, SH and Park, H and Kim, EJ and Lee, JH}, title = {Therapeutic Effects of Combination of Nebivolol and Donepezil: Targeting Multifactorial Mechanisms in ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {20}, number = {6}, pages = {1779-1795}, pmid = {37782409}, issn = {1878-7479}, support = {S3030175//Korea Technology and Information Promotion Agency for SMEs/ ; }, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Donepezil/therapeutic use ; Nebivolol/therapeutic use/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; HeLa Cells ; Quality of Life ; Spinal Cord/metabolism ; Disease Progression ; Disease Models, Animal ; Mice, Transgenic ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in the spinal cord. Although the disease's pathophysiological mechanism remains poorly understood, multifactorial mechanisms affecting motor neuron loss converge to worsen the disease. Although two FDA-approved drugs, riluzole and edaravone, targeting excitotoxicity and oxidative stress, respectively, are available, their efficacies are limited to extending survival by only a few months. Here, we developed combinatorial drugs targeting multifactorial mechanisms underlying key components in ALS disease progression. Using data analysis based on the genetic information of patients with ALS-derived cells and pharmacogenomic data of the drugs, a combination of nebivolol and donepezil (nebivolol-donepezil) was identified for ALS therapy. Here, nebivolol-donepezil markedly reduced the levels of cytokines in the microglial cell line, inhibited nuclear factor-κB (NF-κB) nucleus translocation in the HeLa cell and substantially protected against excitotoxicity-induced neuronal loss by regulating the PI3K-Akt pathway. Nebivolol-donepezil significantly promoted the differentiation of neural progenitor cells (NPC) into motor neurons. Furthermore, we verified the low dose efficacy of nebivolol-donepezil on multiple indices corresponding to the quality of life of patients with ALS in vivo using SOD1[G93A] mice. Nebivolol-donepezil delayed motor function deterioration and halted motor neuronal loss in the spinal cord. Drug administration effectively suppressed muscle atrophy by mitigating the proportion of smaller myofibers and substantially reducing phospho-neurofilament heavy chain (pNF-H) levels in the serum, a promising ALS biomarker. High-dose nebivolol-donepezil significantly prolonged survival and delayed disease onset compared with vehicle-treated mice. These results indicate that the combination of nebivolol-donepezil efficiently prevents ALS disease progression, benefiting the patients' quality of life and life expectancy.}, } @article {pmid37782796, year = {2023}, author = {Huang, J and Fan, X and Jin, X and Teng, L and Yan, N}, title = {Dual-pocket inhibition of Nav channels by the antiepileptic drug lamotrigine.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {41}, pages = {e2309773120}, pmid = {37782796}, issn = {1091-6490}, mesh = {Humans ; Anticonvulsants/pharmacology ; Lamotrigine/pharmacology ; *Cannabidiol ; Sodium/metabolism ; *Voltage-Gated Sodium Channels/chemistry ; }, abstract = {Voltage-gated sodium (Nav) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Nav channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Nav1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Nav1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Nav channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Nav channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs.}, } @article {pmid37782813, year = {2023}, author = {Pennisi, F and Lo Presti, T and Ricciardi, GE and Dalla Valle, Z and Minerva, M and Privitera, G and Signorelli, C}, title = {Training and career opportunities for residencies in Hygiene and Preventive Medicine: results of a survey on 39 Italian schools.}, journal = {Igiene e sanita pubblica}, volume = {80}, number = {4}, pages = {94-100}, pmid = {37782813}, issn = {0019-1639}, mesh = {Humans ; *Internship and Residency ; State Medicine ; Public Health/education ; Hygiene/education ; Universities ; Preventive Medicine/education ; }, abstract = {INTRODUCTION: The Italian National Health Service (SSN) is currently grappling. with a complex situation, characterized by a persistent shortage of medical personnel and the divergent aspirations of young medical graduates. Additionally, recent regulatory developments concerning specialist training further contribute to the intricacies of the landscape, calling for a comprehensive analysis of the challenges and opportunities within the sector. This study aims to provide an updated overview of the current placement of medical graduates, residents and specialists in the specific hygiene and preventive medicine (Public Health) field.

METHODS: Data on admissions, withdrawals and resignations were obtained from the Ministries of Universities and Health and from the archives of the "Associazione Liberi Specializzandi" (ALS). Information regarding the professional prospects for specialists and residents in the field of Public Health was gathered through a tailored survey conducted by the "Consulta dei Medici in Formazione Specialistica" (Council of Medical Residents) of the Italian Society of Hygiene (SItI).

RESULTS: In 2022, a total of 483 specialization contracts were granted, indicating a decrease of 37% compared to the previous year. Notably, 85 positions (17.6%) remained unallocated or resulted in dropouts. Six months after completing their residency, 1.5% of hygiene residents were still actively seeking employment. On a positive note, 75.4% of fourth-year residents secured contracts under the "Decreto Calabria". Career opportunities within the Italian SSN have witnessed growth, with a significant proportion of placements in territorial services and hospital medical directorates.

DISCUSSION AND CONCLUSIONS: The updating of training programs provided by residency schools and the exploration of innovative approaches are of paramount importance to address the urgent need for high-quality training and to cater to the requirements of the national health system.}, } @article {pmid37783557, year = {2023}, author = {Chen, D and Huang, H and Saberi, H and Sharma, HS}, title = {Positive and negative cell therapy in randomized control trials for central nervous system diseases.}, journal = {International review of neurobiology}, volume = {171}, number = {}, pages = {241-254}, doi = {10.1016/bs.irn.2023.05.017}, pmid = {37783557}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; *Central Nervous System Diseases/therapy ; Cell- and Tissue-Based Therapy ; *Parkinson Disease/therapy ; Brain Damage, Chronic ; }, abstract = {Neurorestorative cell therapies have been tested to treat patients with nervous system diseases for over 20 years. Now it is still hard to answer which kinds of cells can really play a role on improving these patients' quality of life. Non-randomized clinical trials or studies could not provide strong evidences in answering this critical question. In this review, we summarized randomized clinical trials of cell therapies for central nervous diseases, such as stroke, spinal cord injury, cerebral palsy (CP), Parkinson's disease (PD), multiple sclerosis (MS), brain trauma, amyotrophic lateral sclerosis (ALS), etc. Most kinds of cell therapies demonstrated negative results for stoke, brain trauma and amyotrophic lateral sclerosis. A few kinds of cell therapies showed neurorestorative effects in this level of evidence-based medicine, such as olfactory ensheating cells for chronic ischemic stroke. Some kinds of cells showed positive or negative effects from different teams in the same or different diseases. We analyzed the possible failed reasons of negative results and the cellular bio-propriety basis of positive results. Based on therapeutic results of randomized control trials and reasonable analysis, we recommend: (1) to further conduct trials for successful cell therapies with positive results to increase neurorestorative effects; (2) to avoid in repeating failed cell therapies with negative results in same diseases because it is nonsense for them to be done with similar treatment methods, such as cell dosage, transplanting way, time of window, etc. Furthermore, we strongly suggest not to do non-randomized clinical trials for cells that had shown negative results in randomized clinical trials.}, } @article {pmid37786726, year = {2023}, author = {Bell, AM and Utting, C and Dickie, AC and Kucharczyk, MW and Quillet, R and Gutierrez-Mecinas, M and Razlan, ANB and Cooper, AH and Lan, Y and Hachisuka, J and Weir, GA and Bannister, K and Watanabe, M and Kania, A and Hoon, MA and Macaulay, IC and Denk, F and Todd, AJ}, title = {Deep sequencing of Phox2a nuclei reveals five classes of anterolateral system neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37786726}, issn = {2692-8205}, support = {MR/T01072X/1/MRC_/Medical Research Council/United Kingdom ; MRF-160-0015-ELP-DENK-C0844/MRF_/MRF_/United Kingdom ; MR/W004739/1/MRC_/Medical Research Council/United Kingdom ; MR/V033638/1/MRC_/Medical Research Council/United Kingdom ; 26815/CRUK_/Cancer Research UK/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, abstract = {The anterolateral system (ALS) is a major ascending pathway from the spinal cord that projects to multiple brain areas and underlies the perception of pain, itch and skin temperature. Despite its importance, our understanding of this system has been hampered by the considerable functional and molecular diversity of its constituent cells. Here we use fluorescence-activated cell sorting to isolate ALS neurons belonging to the Phox2a-lineage for single-nucleus RNA sequencing. We reveal five distinct clusters of ALS neurons (ALS1-5) and document their laminar distribution in the spinal cord using in situ hybridization. We identify 3 clusters of neurons located predominantly in laminae I-III of the dorsal horn (ALS1-3) and two clusters with cell bodies located in deeper laminae (ALS4 & ALS5). Our findings reveal the transcriptional logic that underlies ALS neuronal diversity in the adult mouse and uncover the molecular identity of two previously identified classes of projection neurons. We also show that these molecular signatures can be used to target groups of ALS neurons using retrograde viral tracing. Overall, our findings provide a valuable resource for studying somatosensory biology and targeting subclasses of ALS neurons.}, } @article {pmid37786905, year = {2021}, author = {Huang, ZQ and Ba, ZS and Huang, NQ and Li, YY and Luo, Y}, title = {Aberrant TDP-43 phosphorylation: a key wind gap from TDP-43 to TDP-43 proteinopathy.}, journal = {Ibrain}, volume = {7}, number = {2}, pages = {119-131}, pmid = {37786905}, issn = {2769-2795}, abstract = {TDP-43 proteinopathy is a kind of neurodegenerative diseases related to the TAR DNA-binding protein of 43-kDa molecular weight (TDP-43). The typical neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD) and so on. As the disease process cannot be blocked or slowed down, these patients have poor quality of life and poor prognosis, and bring a huge burden to the family and society. So far, the specific pathogenesis of TDP-43 proteinopathy is not clear, and there is no effective preventive measure and treatment program for this kind of disease. TDP-43 plays an important role in triggering or promoting the occurrence and progression of TDP-43 proteinopathy. The hyperphosphorylation of TDP-43 is undoubtedly an important factor in triggering or promoting the process of TDP-43 proteinopathy. Hyperphosphorylation of TDP-43 can inhibit the degradation of TDP-43, aggravate the aggregation of TDP-43 protein, increase the wrong localization of TDP-43 in cells, and enhance the cytotoxicity of TDP-43. More and more evidences show that the hyperphosphorylation of TDP-43 plays an important role in the pathogenesis of TDP-43 proteinopathy. Inhibition of TDP-43 hyperphosphorylation may be one of the important strategies for the treatment of TDP-43 proteinopathy. Therefore, this article reviews the role of TDP-43 phosphorylation in TDP-43 proteinopathy and the related mechanisms.}, } @article {pmid37787459, year = {2023}, author = {Wei, S and Yang, Y and Wang, Y}, title = {Proximity Proteomics Revealed Aberrant mRNA Splicing Elicited by ALS-Linked Profilin-1 Mutants.}, journal = {Analytical chemistry}, volume = {95}, number = {41}, pages = {15141-15145}, pmid = {37787459}, issn = {1520-6882}, support = {R35 ES031707/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Profilins/genetics/metabolism ; Actins/metabolism ; Proteomics ; Mutation ; Basic Helix-Loop-Helix Proteins/genetics ; }, abstract = {Profilin 1 (PFN1) is a cytoskeleton protein that modulates actin dynamics through binding to monomeric actin and polyproline-containing proteins. Mutations in PFN1 have been linked to the pathogenesis of familial amyotrophic lateral sclerosis (ALS). Here, we employed an unbiased proximity labeling strategy in combination with proteomic analysis for proteome-wide profiling of proteins that differentially interact with mutant and wild-type (WT) PFN1 proteins in human cells. We uncovered 11 mRNA splicing proteins that are preferentially enriched in the proximity proteomes of the two ALS-linked PFN1 variants, C71G and M114T, over that of wild-type PFN1. We validated the preferential interactions of the ALS-linked PFN1 variants with two mRNA splicing factors, hnRNPC and U2AF2, by immunoprecipitation, followed with immunoblotting. We also found that the two ALS-linked PFN1 variants promoted the exonization of Alu elements in the mRNAs of MTO1, TCFL5, WRN and POLE genes in human cells. Together, we showed that the two ALS-linked PFN1 variants interacted preferentially with mRNA splicing proteins, which elicited aberrant exonization of the Alu elements in mRNAs. Thus, our work provided pivotal insights into the perturbations of ALS-linked PFN1 variants in RNA biology and their potential contributions to ALS pathology.}, } @article {pmid37787812, year = {2024}, author = {Beswick, E and Johnson, M and Newton, J and Dakin, R and Stenson, A and Abrahams, S and Carson, A and Chandran, S and Pal, S}, title = {Factors impacting trial participation in people with motor neuron disease.}, journal = {Journal of neurology}, volume = {271}, number = {1}, pages = {543-552}, pmid = {37787812}, issn = {1432-1459}, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/therapy ; *Motor Neuron Disease/therapy ; Probability ; Prospective Studies ; Randomized Controlled Trials as Topic ; Adaptive Clinical Trials as Topic ; }, abstract = {Motor neuron disease (MND) is a rapidly progressive neurodegenerative disorder with limited treatment options. Historically, neurological trials have been plagued by suboptimal recruitment and high rates of attrition. The Motor Neuron Disease-Systematic Multi-Arm Randomised Adaptive Trial (MND-SMART) seeks to identify effective disease modifying drugs. This study investigates person-specific factors affecting recruitment and retention. Improved understanding of these factors may improve trial protocol design, optimise recruitment and retention. Participants with MND completed questionnaires and this was supplemented with clinical data. 12 months after completing the questionnaires we used MND-SMART recruitment data to establish if members of our cohort engaged with the trial. 120 people with MND completed questionnaires for this study. Mean age at participation was 66 (SD = 9), 14% (n = 17) were categorised as long survivors, with 68% (n = 81) of participants male and 60% (n = 73) had the ALS sub-type. Of the 120 study participants, 50% (n = 60) were randomised into MND-SMART and 78% (n = 94) expressed interest an in participating. After the 1-year follow-up period 65% (n = 39) of the 60 randomised participants remained in MND-SMART. Older age was significantly associated with reduced likelihood of participation (OR = 0.92, 95% CI = 0.88-0.96, p = 0.000488). The findings show that people with MND are highly motivated to engage in research, but older individuals remain significantly less likely to participate. We recommend the inclusion of studies to explore characteristics of prospective and current participants alongside trials.}, } @article {pmid37787835, year = {2024}, author = {Li, S and Zhao, L and Xiao, J and Guo, Y and Fu, R and Zhang, Y and Xu, S}, title = {The gut microbiome: an important role in neurodegenerative diseases and their therapeutic advances.}, journal = {Molecular and cellular biochemistry}, volume = {479}, number = {9}, pages = {2217-2243}, pmid = {37787835}, issn = {1573-4919}, support = {No. 81973626, No. 81774059//National Natural Science Foundation of China/ ; No. 21JCYBJC01620//Tianjin Municipal Science and Technology Commission of China/ ; No. 2021099//Tianjin Health Committee/ ; No. 2021KJ146//Tianjin Education Committee/ ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; *Neurodegenerative Diseases/therapy/microbiology ; *Fecal Microbiota Transplantation ; *Probiotics/therapeutic use ; Animals ; Parkinson Disease/therapy/microbiology ; Alzheimer Disease/therapy/microbiology ; }, abstract = {There are complex interactions between the gut and the brain. With increasing research on the relationship between gut microbiota and brain function, accumulated clinical and preclinical evidence suggests that gut microbiota is intimately involved in the pathogenesis of neurodegenerative diseases (NDs). Increasingly studies are beginning to focus on the association between gut microbiota and central nervous system (CNS) degenerative pathologies to find potential therapies for these refractory diseases. In this review, we summarize the changes in the gut microbiota in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis and contribute to our understanding of the function of the gut microbiota in NDs and its possible involvement in the pathogenesis. We subsequently discuss therapeutic approaches targeting gut microbial abnormalities in these diseases, including antibiotics, diet, probiotics, and fecal microbiota transplantation (FMT). Furthermore, we summarize some completed and ongoing clinical trials of interventions with gut microbes for NDs, which may provide new ideas for studying NDs.}, } @article {pmid37789557, year = {2024}, author = {Kläppe, U and Sennfält, S and Lovik, A and Finn, A and Bofaisal, U and Zetterberg, H and Blennow, K and Piehl, F and Kmezic, I and Press, R and Samuelsson, K and Månberg, A and Fang, F and Ingre, C}, title = {Neurodegenerative biomarkers outperform neuroinflammatory biomarkers in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {150-161}, doi = {10.1080/21678421.2023.2263874}, pmid = {37789557}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Neuroinflammatory Diseases ; Case-Control Studies ; Biomarkers ; Prognosis ; Neurofilament Proteins/cerebrospinal fluid ; }, abstract = {OBJECTIVE: To describe the diagnostic and prognostic performance, and longitudinal trajectories, of potential biomarkers of neuroaxonal degeneration and neuroinflammation in amyotrophic lateral sclerosis (ALS).

METHODS: This case-control study included 192 incident ALS patients, 42 ALS mimics, 114 neurological controls, and 117 healthy controls from Stockholm, Sweden. Forty-four ALS patients provided repeated measurements. We assessed biomarkers of (1)neuroaxonal degeneration: neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in cerebrospinal fluid (CSF) and NfL in serum, and (2)neuroinflammation: chitotriosidase-1 (CHIT1) and monocyte chemoattractant protein 1 (MCP-1) in CSF. To evaluate diagnostic performance, we calculated the area under the curve (AUC). To estimate prognostic performance, we applied quantile regression and Cox regression. We used linear regression models with robust standard errors to assess temporal changes over time.

RESULTS: Neurofilaments performed better at differentiating ALS patients from mimics (AUC: pNfH 0.92, CSF NfL 0.86, serum NfL 0.91) than neuroinflammatory biomarkers (AUC: CHIT1 0.71, MCP-1 0.56). Combining biomarkers did not improve diagnostic performance. Similarly, neurofilaments performed better than neuroinflammatory biomarkers at predicting functional decline and survival. The stratified analysis revealed differences according to the site of onset: in bulbar patients, neurofilaments and CHIT1 performed worse at predicting survival and correlations were lower between biomarkers. Finally, in bulbar patients, neurofilaments and CHIT1 increased longitudinally but were stable in spinal patients.

CONCLUSIONS: Biomarkers of neuroaxonal degeneration displayed better diagnostic and prognostic value compared with neuroinflammatory biomarkers. However, in contrast to spinal patients, in bulbar patients neurofilaments and CHIT1 performed worse at predicting survival and seemed to increase over time.}, } @article {pmid37789566, year = {2024}, author = {Raymond, J and Berry, J and Kasarskis, EJ and Larson, T and Horton, DK and Mehta, P}, title = {A brief report on juvenile amyotrophic lateral sclerosis cases in the United States National ALS Registry: 2010-2018.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {211-213}, pmid = {37789566}, issn = {2167-9223}, support = {CC999999/ImCDC/Intramural CDC HHS/United States ; }, mesh = {Adult ; Humans ; Male ; United States/epidemiology ; Young Adult ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Risk Factors ; Registries ; Databases, Factual ; }, abstract = {Juvenile ALS (jALS) is a rare form of ALS, defined as symptom onset before age 25. This report describes the demographic characteristics of confirmed and likely jALS cases in a large cohort of ALS patients ascertained in the National ALS Registry (Registry) from 2010 to 2018. Patients in the Registry must be at least 18 years of age. Of the 44 identified patients, 37.8% were diagnosed at age 24, were more likely to be nonwhite (54.5%), male (79.5%), and live in the Midwest or Northeast regions (54.5%) of the US. Some 68.9% of the jALS cases were received from federal administrative databases, and 16% came from the web portal only. Demographic characteristics for jALS cases in the Registry differed from previous publications examining ALS cases for all adults. More research is needed to better understand risk factors contributing to jALS, which could lead to earlier diagnosis and therapeutic interventions.}, } @article {pmid37790622, year = {2023}, author = {Renz, M and Müller, L and Herbst, M and Riedel, J and Mohnke, K and Ziebart, A and Ruemmler, R}, title = {Analysis of cerebral Interleukin-6 and tumor necrosis factor alpha patterns following different ventilation strategies during cardiac arrest in pigs.}, journal = {PeerJ}, volume = {11}, number = {}, pages = {e16062}, pmid = {37790622}, issn = {2167-8359}, mesh = {Animals ; *Cardiopulmonary Resuscitation/methods ; Cytokines ; *Heart Arrest/therapy ; Interleukin-6/genetics ; Prospective Studies ; RNA, Messenger ; Swine ; Tumor Necrosis Factor-alpha/genetics ; }, abstract = {Hypoxia-induced neuroinflammation after cardiac arrest has been shown to be mitigated by different ventilation methods. In this prospective randomized animal trial, 35 landrace pigs were randomly divided into four groups: intermittent positive pressure ventilation (IPPV), synchronized ventilation 20 mbar (SV 20 mbar), chest compression synchronized ventilation 40 mbar (CCSV 40 mbar) and a control group (Sham). After inducing ventricular fibrillation, basic life support (BLS) and advanced life support (ALS) were performed, followed by post-resuscitation monitoring. After 6 hours, the animals were euthanized, and direct postmortem brain tissue samples were taken from the hippocampus (HC) and cortex (Cor) for molecular biological investigation of cytokine mRNA levels of Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα). The data analysis showed that CCSV 40 mbar displayed low TNFα mRNA-levels, especially in the HC, while the highest TNFα mRNA-levels were detected in SV 20 mbar. The results indicate that chest compression synchronized ventilation may have a potential positive impact on the cytokine expression levels post-resuscitation. Further studies are needed to derive potential therapeutic algorithms from these findings.}, } @article {pmid37791043, year = {2023}, author = {Richter, V and Neumann, M and Green, JR and Richburg, B and Roesler, O and Kothare, H and Ramanarayanan, V}, title = {Remote Assessment for ALS using Multimodal Dialog Agents: Data Quality, Feasibility and Task Compliance.}, journal = {Interspeech}, volume = {2023}, number = {}, pages = {5441-5445}, pmid = {37791043}, issn = {2958-1796}, support = {K24 DC016312/DC/NIDCD NIH HHS/United States ; R42 DC019877/DC/NIDCD NIH HHS/United States ; }, abstract = {We investigate the feasibility, task compliance and audiovisual data quality of a multimodal dialog-based solution for remote assessment of Amyotrophic Lateral Sclerosis (ALS). 53 people with ALS and 52 healthy controls interacted with Tina, a cloud-based conversational agent, in performing speech tasks designed to probe various aspects of motor speech function while their audio and video was recorded. We rated a total of 250 recordings for audio/video quality and participant task compliance, along with the relative frequency of different issues observed. We observed excellent compliance (98%) and audio (95.2%) and visual quality rates (84.8%), resulting in an overall yield of 80.8% recordings that were both compliant and of high quality. Furthermore, recording quality and compliance were not affected by level of speech severity and did not differ significantly across end devices. These findings support the utility of dialog systems for remote monitoring of speech in ALS.}, } @article {pmid37791472, year = {2023}, author = {Zhang, Y and Nelson, SCK and Viera Ortiz, AP and Lee, EB and Fairman, R}, title = {C9orf72 proline-arginine dipeptide repeats disrupt the proteasome and perturb proteolytic activities.}, journal = {Journal of neuropathology and experimental neurology}, volume = {82}, number = {11}, pages = {901-910}, pmid = {37791472}, issn = {1554-6578}, support = {P40 OD018537/OD/NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; R01 NS095793/NS/NINDS NIH HHS/United States ; P30AG072979/NH/NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Drosophila melanogaster/genetics/metabolism ; Proteasome Endopeptidase Complex/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Arginine/genetics/metabolism ; Proteolysis ; Dipeptides/genetics/metabolism ; Proline/genetics/metabolism ; *Frontotemporal Dementia/genetics ; DNA Repeat Expansion ; }, abstract = {The hexanucleotide G4C2 repeat expansion in C9orf72 is the most frequent genetic cause of familial amyotrophic lateral sclerosis (ALS). Aberrant translation of this hexanucleotide sequence leads to production of 5 dipeptide repeats (DPRs). One of these DPRs is proline-arginine (polyPR), which is found in C9orf72-expanded ALS (C9ALS) patient brain tissue and is neurotoxic across multiple model systems. PolyPR was previously reported to bind and impair proteasomes in vitro. Nevertheless, the clinical relevance of the polyPR-proteasome interaction and its functional consequences in vivo are yet to be established. Here, we aim to confirm and functionally characterize polyPR-induced impairment of proteolysis in C9ALS patient tissue and an in vivo model system. Confocal microscopy and immunofluorescence studies on both human and Drosophila melanogaster brain tissues revealed sequestration of proteasomes by polyPR into inclusion-like bodies. Co-immunoprecipitation in D. melanogaster showed that polyPR strongly binds to the proteasome. In vivo, functional evidence for proteasome impairment is further shown by the accumulation of ubiquitinated proteins along with lysosomal accumulation and hyper-acidification, which can be rescued by a small-molecule proteasomal enhancer. Together, we provide the first clinical report of polyPR-proteasome interactions and offer in vivo evidence proposing polyPR-induced proteolytic dysfunction as a pathogenic mechanism in C9ALS.}, } @article {pmid37791757, year = {2023}, author = {Rønne, ME and Tandrup, T and Madsen, M and Hunt, CJ and Myers, PN and Moll, JM and Holck, J and Brix, S and Strube, ML and Aachmann, FL and Wilkens, C and Svensson, B}, title = {Three alginate lyases provide a new gut Bacteroides ovatus isolate with the ability to grow on alginate.}, journal = {Applied and environmental microbiology}, volume = {89}, number = {10}, pages = {e0118523}, pmid = {37791757}, issn = {1098-5336}, mesh = {Polysaccharide-Lyases/metabolism ; Bacteroides ; Oligosaccharides/metabolism ; *Bacteria/metabolism ; *Alginates/metabolism ; Humans ; Substrate Specificity ; }, abstract = {Humans consume alginate in the form of seaweed, food hydrocolloids, and encapsulations, making the digestion of this mannuronic acid (M) and guluronic acid (G) polymer of key interest for human health. To increase knowledge on alginate degradation in the gut, a gene catalog from human feces was mined for potential alginate lyases (ALs). The predicted ALs were present in nine species of the Bacteroidetes phylum, of which two required supplementation of an endo-acting AL, expected to mimic cross-feeding in the gut. However, only a new isolate grew on alginate. Whole-genome sequencing of this alginate-utilizing isolate suggested that it is a new Bacteroides ovatus strain harboring a polysaccharide utilization locus (PUL) containing three ALs of families: PL6, PL17, and PL38. The BoPL6 degraded polyG to oligosaccharides of DP 1-3, and BoPL17 released 4,5-unsaturated monouronate from polyM. BoPL38 degraded both alginates, polyM, polyG, and polyMG, in endo-mode; hence, it was assumed to deliver oligosaccharide substrates for BoPL6 and BoPL17, corresponding well with synergistic action on alginate. BoPL17 and BoPL38 crystal structures, determined at 1.61 and 2.11 Å, respectively, showed (α/α)6-barrel + anti-parallel β-sheet and (α/α)7-barrel folds, distinctive for these PL families. BoPL17 had a more open active site than the two homologous structures. BoPL38 was very similar to the structure of an uncharacterized PL38, albeit with a different triad of residues possibly interacting with substrate in the presumed active site tunnel. Altogether, the study provides unique functional and structural insights into alginate-degrading lyases of a PUL in a human gut bacterium.IMPORTANCEHuman ingestion of sustainable biopolymers calls for insight into their utilization in our gut. Seaweed is one such resource with alginate, a major cell wall component, used as a food hydrocolloid and for encapsulation of pharmaceuticals and probiotics. Knowledge is sparse on the molecular basis for alginate utilization in the gut. We identified a new Bacteroides ovatus strain from human feces that grew on alginate and encoded three alginate lyases in a gene cluster. BoPL6 and BoPL17 show complementary specificity toward guluronate (G) and mannuronate (M) residues, releasing unsaturated oligosaccharides and monouronic acids. BoPL38 produces oligosaccharides degraded by BoPL6 and BoPL17 from both alginates, G-, M-, and MG-substrates. Enzymatic and structural characterization discloses the mode of action and synergistic degradation of alginate by these alginate lyases. Other bacteria were cross-feeding on alginate oligosaccharides produced by an endo-acting alginate lyase. Hence, there is an interdependent community in our guts that can utilize alginate.}, } @article {pmid37791834, year = {2024}, author = {Hyppa-Martin, J and Lilley, J and Chen, M and Friese, J and Schmidt, C and Bunnell, HT}, title = {A large-scale comparison of two voice synthesis techniques on intelligibility, naturalness, preferences, and attitudes toward voices banked by individuals with amyotrophic lateral sclerosis.}, journal = {Augmentative and alternative communication (Baltimore, Md. : 1985)}, volume = {40}, number = {1}, pages = {31-45}, doi = {10.1080/07434618.2023.2262032}, pmid = {37791834}, issn = {1477-3848}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis ; *Communication Devices for People with Disabilities ; *Communication Disorders/complications ; *Voice ; Dysarthria ; Speech Intelligibility ; }, abstract = {Amyotrophic lateral sclerosis (ALS) commonly results in the inability to produce natural speech, making speech-generating devices (SGDs) important. Historically, synthetic voices generated by SGDs were neither unique, nor age- or dialect-appropriate, which depersonalized SGD use. Voices generated by SGDs can now be customized via voice banking and should ideally sound uniquely like the individual's natural speech, be intelligible, and elicit positive reactions from communication partners. This large-scale 2 x 2 mixed between- and within-participants design examined perceptions of 831 adult listeners regarding custom synthetic voices created for two individuals diagnosed with ALS via two synthesis systems in common clinical use (waveform concatenation and statistical parametric synthesis). The study explored relationships among synthesis system, dysarthria severity, synthetic speech intelligibility, naturalness, and preferences, and also provided a preliminary examination of attitudes regarding the custom synthetic voices. Synthetic voices generated via statistical parametric synthesis trained on deep neural networks were more intelligible, natural, and preferred than voices produced via waveform concatenation, and were associated with more positive attitudes. The custom synthetic voice created from moderately dysarthric speech was more intelligible than the voice created from mildly dysarthric speech. Clinical implications and factors that may have contributed to the relative intelligibilities are discussed.}, } @article {pmid37791873, year = {2023}, author = {Kour, S and Fortuna, T and Anderson, EN and Mawrie, D and Bilstein, J and Sivasubramanian, R and Ward, C and Roy, R and Rajasundaram, D and Sterneckert, J and Pandey, UB}, title = {Drosha-dependent microRNAs modulate FUS-mediated neurodegeneration in vivo.}, journal = {Nucleic acids research}, volume = {51}, number = {20}, pages = {11258-11276}, pmid = {37791873}, issn = {1362-4962}, support = {R01 NS081303/NS/NINDS NIH HHS/United States ; S10 OD028483/OD/NIH HHS/United States ; }, mesh = {Animals ; Amyotrophic Lateral Sclerosis/metabolism ; Drosophila/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; Mutation ; Neurons/metabolism ; RNA-Binding Proteins/genetics/metabolism ; Neurodegenerative Diseases/metabolism ; *Heterogeneous-Nuclear Ribonucleoprotein Group F-H/metabolism ; Humans ; *Ribonuclease III/metabolism ; *Drosophila Proteins/metabolism ; }, abstract = {Mutations in the Fused in Sarcoma (FUS) gene cause the familial and progressive form of amyotrophic lateral sclerosis (ALS). FUS is a nuclear RNA-binding protein involved in RNA processing and the biogenesis of a specific set of microRNAs. Here we report that Drosha and two previously uncharacterized Drosha-dependent miRNAs are strong modulators of FUS expression and prevent the cytoplasmic segregation of insoluble mutant FUS in vivo. We demonstrate that depletion of Drosha mitigates FUS-mediated degeneration, survival and motor defects in Drosophila. Mutant FUS strongly interacts with Drosha and causes its cytoplasmic mis-localization into the insoluble FUS inclusions. Reduction in Drosha levels increases the solubility of mutant FUS. Interestingly, we found two Drosha dependent microRNAs, miR-378i and miR-6832-5p, which differentially regulate the expression, solubility and cytoplasmic aggregation of mutant FUS in iPSC neurons and mammalian cells. More importantly, we report different modes of action of these miRNAs against mutant FUS. Whereas miR-378i may regulate mutant FUS inclusions by preventing G3BP-mediated stress granule formation, miR-6832-5p may affect FUS expression via other proteins or pathways. Overall, our research reveals a possible association between ALS-linked FUS mutations and the Drosha-dependent miRNA regulatory circuit, as well as a useful perspective on potential ALS treatment via microRNAs.}, } @article {pmid37793650, year = {2024}, author = {Mori, F and Yasui, H and Miki, Y and Kon, T and Arai, A and Kurotaki, H and Tomiyama, M and Wakabayashi, K}, title = {Colocalization of TDP-43 and stress granules at the early stage of TDP-43 aggregation in amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {2}, pages = {e13215}, pmid = {37793650}, issn = {1750-3639}, support = {21K07452//Japan Society for the Promotion of Science/ ; 22H02948//Japan Society for the Promotion of Science/ ; 23K06802//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Anterior Horn Cells/pathology ; Cytoplasm ; DNA-Binding Proteins ; Stress Granules ; }, abstract = {TDP-43 aggregates (skeins and round inclusions [RIs]) are frequent histopathological features of amyotrophic lateral sclerosis (ALS). We have shown that diffuse punctate cytoplasmic staining (DPCS) is the earliest pathologic manifestation of TDP-43 in ALS, corresponding to nonfibrillar TDP-43 located in the rough endoplasmic reticulum. Previous in vitro studies have suggested that TDP-43 inclusions may be derived from stress granules (SGs). Therefore, we investigated the involvement of SGs in the formation of TDP-43 inclusions. Formalin-fixed spinal cords of six ALS patients with a disease duration of less than 1 year (short duration), eight patients with a disease duration of 2-5 years (standard duration), and five normal controls were subjected to histopathological examination using antibodies against an SG marker, HuR. In normal controls, the cytoplasm of anterior horn cells was diffusely HuR-positive. In short-duration and standard-duration ALS, the number of HuR-positive anterior horn cells was significantly decreased relative to the controls. DPCS and RIs were more frequent in short-duration ALS than in standard-duration ALS. The majority of DPCS areas and a small proportion of RIs, but not skeins, were positive for HuR. Immunoelectron microscopy showed that ribosome-like granular structures in DPCS areas and RIs were labeled with anti-HuR, whereas skeins were not. These findings suggest that colocalization of TDP-43 and SGs occurs at the early stage of TDP-43 aggregation.}, } @article {pmid37794794, year = {2024}, author = {Goyal, NA and Bonar, K and Savic, N and Beau Lejdstrom, R and Wright, J and Mellor, J and McDermott, C}, title = {Misdiagnosis of amyotrophic lateral sclerosis in clinical practice in Europe and the USA: a patient chart review and physician survey.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {16-25}, doi = {10.1080/21678421.2023.2260808}, pmid = {37794794}, issn = {2167-9223}, mesh = {Humans ; Adolescent ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/therapy ; Cross-Sectional Studies ; Europe/epidemiology ; *Physicians ; Diagnostic Errors ; }, abstract = {OBJECTIVE: Delays in amyotrophic lateral sclerosis (ALS) diagnosis can result in compromised disease management and unnecessary costs. We examined the extent of ALS misdiagnosis in the US and Europe.

METHODS: Data were collected via the Adelphi ALS Disease Specific Programme™, a cross-sectional survey of physicians and a medical chart review of their consulting patients with ALS in France, Germany, Italy, Spain, the UK (EU5), and the US. Between July 2020 and March 2021, eligible physicians (primary speciality neurology, active involvement in managing patients with ALS) abstracted data from patients (≥18 years old) with confirmed ALS.

RESULTS: Overall, 138 physicians completed the survey (EU5 107, US 31), with data reviewed from 795 patient medical charts (EU5 568, US 227); 278 (35.0%) patients (EU5 183 [32.2%], US 95 [41.9%]) had received ≥1 initial misdiagnosis based on symptoms later attributed to ALS. Mean (SD) time from symptom onset to first healthcare professional consultation was 3.8 (5.2) months (EU5 4.3 [4.8] months, US 2.6 [5.8] months). Mean (SD) time from symptom onset to ALS diagnosis was 8.2 (12.5) months (EU5 9.6 [14.0] months, US 5.0 [6.8] months) and increased to 10.4 (17.9) for patients with a misdiagnosis (compared with 6.9 [7.2] for patients with no misdiagnosis). Physician-identified barriers to timely ALS diagnosis included the similarity of symptoms to other conditions and delayed referral to neurologists.

CONCLUSIONS: Misdiagnosis of ALS is frequent, with a protracted diagnostic pathway. Targeted education of patients and physicians about signs and symptoms and benefits of prompt referral to multidisciplinary care are needed.}, } @article {pmid37794802, year = {2024}, author = {Din Abdul Jabbar, MA and Guo, L and Guo, Y and Simmons, Z and Pioro, EP and Ramasamy, S and Yeo, CJJ}, title = {Describing and characterising variability in ALS disease progression.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {34-45}, doi = {10.1080/21678421.2023.2260838}, pmid = {37794802}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; }, abstract = {BACKGROUND, OBJECTIVES: Decrease in the revised ALS Functional Rating Scale (ALSFRS-R) score is currently the most widely used measure of disease progression. However, it does not sufficiently encompass the heterogeneity of ALS. We describe a measure of variability in ALSFRS-R scores and demonstrate its utility in disease characterization.

METHODS: We used 5030 ALS clinical trial patients from the Pooled Resource Open-Access ALS Clinical Trials database to calculate variability in disease progression employing a novel measure and correlated variability with disease span. We characterized the more and less variable populations and designed a machine learning model that used clinical, laboratory and demographic data to predict class of variability. The model was validated with a holdout clinical trial dataset of 84 ALS patients (NCT00818389).

RESULTS: Greater variability in disease progression was indicative of longer disease span on the patient-level. The machine learning model was able to predict class of variability with accuracy of 60.1-72.7% across different time periods and yielded a set of predictors based on clinical, laboratory and demographic data. A reduced set of 16 predictors and the holdout dataset yielded similar accuracy.

DISCUSSION: This measure of variability is a significant determinant of disease span for fast-progressing patients. The predictors identified may shed light on pathophysiology of variability, with greater variability in fast-progressing patients possibly indicative of greater compensatory reinnervation and longer disease span. Increasing variability alongside decreasing rate of disease progression could be a future aim of trials for faster-progressing patients.}, } @article {pmid37795262, year = {2023}, author = {Lin, TJ and Cheng, KC and Wu, LY and Lai, WY and Ling, TY and Kuo, YC and Huang, YH}, title = {Corrigendum: Potential of cellular therapy for ALS: current strategies and future prospects.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1292681}, doi = {10.3389/fcell.2023.1292681}, pmid = {37795262}, issn = {2296-634X}, abstract = {[This corrects the article DOI: 10.3389/fcell.2022.851613.].}, } @article {pmid37795273, year = {2023}, author = {Venediktov, AA and Bushueva, OY and Kudryavtseva, VA and Kuzmin, EA and Moiseeva, AV and Baldycheva, A and Meglinski, I and Piavchenko, GA}, title = {Closest horizons of Hsp70 engagement to manage neurodegeneration.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1230436}, pmid = {37795273}, issn = {1662-5099}, abstract = {Our review seeks to elucidate the current state-of-the-art in studies of 70-kilodalton-weighed heat shock proteins (Hsp70) in neurodegenerative diseases (NDs). The family has already been shown to play a crucial role in pathological aggregation for a wide spectrum of brain pathologies. However, a slender boundary between a big body of fundamental data and its implementation has only recently been crossed. Currently, we are witnessing an anticipated advancement in the domain with dozens of studies published every month. In this review, we briefly summarize scattered results regarding the role of Hsp70 in the most common NDs including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We also bridge translational studies and clinical trials to portray the output for medical practice. Available options to regulate Hsp70 activity in NDs are outlined, too.}, } @article {pmid37795580, year = {2024}, author = {Rodriguez, P and Blakely, RD}, title = {Sink or swim: Does a worm paralysis phenotype hold clues to neurodegenerative disease?.}, journal = {Journal of cellular physiology}, volume = {239}, number = {6}, pages = {e31125}, doi = {10.1002/jcp.31125}, pmid = {37795580}, issn = {1097-4652}, support = {22A01//Florida Department of Health Ed/ ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics ; *Neurodegenerative Diseases/genetics ; *Phenotype ; Humans ; *Disease Models, Animal ; Caenorhabditis elegans Proteins/genetics/metabolism ; Paralysis/genetics ; Swimming ; Signal Transduction/genetics ; Dopamine/metabolism ; }, abstract = {Receiving a neurodegenerative disease (NDD) diagnosis, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis, is devastating, particularly given the limited options for treatment. Advances in genetic technologies have allowed for efficient modeling of NDDs in animals and brought hope for new disease-modifying medications. The complexity of the mammalian brain and the costs and time needed to identify and develop therapeutic leads limits progress. Modeling NDDs in invertebrates, such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, offers orders of magnitude increases in speed of genetic analysis and manipulation, and can be pursued at substantially reduced cost, providing an important, platform complement and inform research with mammalian NDD models. In this review, we describe how our efforts to exploit C. elegans for the study of neural signaling and health led to the discovery of a paralytic phenotype (swimming-induced paralysis) associated with altered dopamine signaling and, surprisingly, to the discovery of a novel gene and pathway whose dysfunction in glial cells triggers neurodegeneration. Research to date on swip-10 and its putative mammalian ortholog MBLAC1, suggests that a tandem analysis will offer insights into NDD mechanisms and insights into novel, disease-modifying therapeutics.}, } @article {pmid37796077, year = {2023}, author = {Belenky, VV and Plakhotina, NA and Skoromets, AA and Dugaev, PP and Komantsev, VN and Leontiev, OV}, title = {[Diagnostic capabilities of spinal MR angiography and spinal MR tractography in a patient with motor neuron disease].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {123}, number = {9}, pages = {111-115}, doi = {10.17116/jnevro2023123091111}, pmid = {37796077}, issn = {1997-7298}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Magnetic Resonance Angiography ; *Motor Neuron Disease/diagnostic imaging ; Motor Neurons/pathology ; *Muscular Atrophy, Spinal ; Spinal Cord/diagnostic imaging ; }, abstract = {Motor neuron diseases (MND) include two main forms - amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). A certain part of these diseases is hereditary, while etiology of sporadic cases remains unknown. Both entities are known to develop because of motoneurons damage. Difference between them lies in the state of the descending pyramidal pathways. The pyramidal pathways in SMA are intact, as brain pyramidal neurons are not affected, thus pathology of SMA is restricted to anterior horns of spinal cord. Meanwhile, most forms of ALS arise due to loss of both cerebral and spinal motoneurons, which, in addition to anterior horn lesion, leads to pyramidal descending pathways damage either in brain or in spinal cord. While pathological distinction between these two entities is clear and definite, the clinical difference remains obscure. We present the case of 41-year old patient with MND, in whom spinal MR tractography has revealed lateral columns to be intact that proves the utility of spinal MR tractography in differential diagnosis between ALS and SMA. Given that ischemic diseases of the spinal cord often occur with a clinical picture of MND, we also examined this patient using spinal MRI angiography, revealing a pronounced narrowing and tortuosity of the spinal arteries, complicated by occlusion of the right twelve intercostal artery.}, } @article {pmid37796272, year = {2023}, author = {Weber, S and Corcia, P and Viader, F}, title = {[Genetics of amyotrophic lateral sclerosis].}, journal = {La Revue du praticien}, volume = {73}, number = {7}, pages = {783-787}, pmid = {37796272}, issn = {2101-017X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; }, abstract = {GENETICS OF AMYOTROPHIC LATERAL SCLEROSIS. Approximately 10 to 15% of people with amyotrophic lateral sclerosis (ALS) have a family history of the disease. In 2/3 of them, but also in 10% of subjects without any family history of ALS, a pathogenic genetic variant can be identified. Many genes are involved, the four main ones being C9orf72 (which can also be responsible for dementia), SOD1, TARDBP and FUS. ALS of genetic origin is almost always inherited in an autosomal dominant pattern. The progress made in recent years in the knowledge of the genetic forms of ALS has led to a better understanding of the pathophysiology of the disease and has opened up new therapeutic avenues, some of which are already being explored. For all these reasons, it is now recommended that all patients with ALS, whether familial or not, undergo a genetic investigation, with analyses appropriate to their age and family history. When a pathogenic variant is found, it can then be sought in at-risk relatives who so desire. These tests must follow legally mandated procedures and can only be conducted in a specialized ALS center under the supervision of a geneticist after a thorough discussion of the personal and family implications of the result and written consent from the patient.}, } @article {pmid37797620, year = {2023}, author = {Yonekura, K and Maki-Yonekura, S and Takaba, K}, title = {Applications and limitations of electron 3D crystallography.}, journal = {Structure (London, England : 1993)}, volume = {31}, number = {11}, pages = {1328-1334}, doi = {10.1016/j.str.2023.09.007}, pmid = {37797620}, issn = {1878-4186}, mesh = {Crystallography/methods ; *Electrons ; Crystallography, X-Ray ; *Proteins/chemistry ; Microscopy, Electron, Transmission ; Peptides ; }, abstract = {Three-dimensional electron diffraction (3D ED) is a measurement and analysis technique in transmission electron microscopy that is used for determining atomic structures from small crystals. Diverse targets such as proteins, polypeptides, and organic compounds, whose crystals exist in aqueous solutions and organic solvents, or as dried powders, can be studied with 3D ED. We have been involved in the development of this technique, which can now rapidly process a large number of data collected through AI control, enabling efficient structure determination. Here, we introduce this method and describe our recent results. These include the structures and pathogenic mechanisms of wild-type and mutant polypeptides associated with the debilitating disease amyotrophic lateral sclerosis (ALS), the double helical structure of nanographene promoting nanofiber formation, and the structural properties of an organic semiconductor containing disordered regions. We also discuss the limitations and prospects of 3D ED compared to microcrystallography with X-ray free electron lasers.}, } @article {pmid37797839, year = {2024}, author = {Hooper, MJ and Veon, FL and Enriquez, GL and Nguyen, M and Grimes, CB and LeWitt, TM and Pang, Y and Case, S and Choi, J and Guitart, J and Burns, MB and Zhou, XA}, title = {Reply to Wu et al's US SEER analysis of sepsis in Black patients with CTCL.}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {2}, pages = {e79}, pmid = {37797839}, issn = {1097-6787}, support = {KL2 TR001424/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Lymphoma, T-Cell, Cutaneous ; SEER Program ; Black People ; *Sepsis/diagnosis/epidemiology ; *Skin Neoplasms/epidemiology ; }, } @article {pmid37798838, year = {2024}, author = {Shojaie, A and Al Khleifat, A and Opie-Martin, S and Sarraf, P and Al-Chalabi, A}, title = {Non-motor symptoms in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {61-66}, pmid = {37798838}, issn = {2167-9223}, support = {/WT_/Wellcome Trust/United Kingdom ; P30 AG066509/AG/NIA NIH HHS/United States ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Quality of Life ; Pain/etiology ; Disease Progression ; }, abstract = {OBJECTIVE: While motor symptoms are well-known in ALS, non-motor symptoms are often under-reported and may have a significant impact on quality of life. In this study, we aimed to examine the nature and extent of non-motor symptoms in ALS.

METHODS: A 20-item questionnaire was developed covering the domains of autonomic function, sleep, pain, gastrointestinal disturbance, and emotional lability, posted online and shared on social media platforms to target people with ALS and controls.

RESULTS: A total of 1018 responses were received, of which 927 were complete from 506 people with ALS and 421 unaffected individuals. Cold limbs (p 1.66 × 10[-36)], painful limbs (p 6.14 × 10[-28]), and urinary urgency (p 4.70 × 10[-23]) were associated with ALS. People with ALS were more likely to report autonomic symptoms, pain, and psychiatric symptoms than controls (autonomic symptoms B = 0.043, p 6.10 × 10[-5], pain domain B = 0.18, p 3.72 × 10[-11] and psychiatric domain B = 0.173, p 1.32 × 10[-4]).

CONCLUSIONS: Non-motor symptoms in ALS are common. The identification and management of non-motor symptoms should be integrated into routine clinical care for people with ALS. Further research is warranted to investigate the relationship between non-motor symptoms and disease progression, as well as to develop targeted interventions to improve the quality of life for people with ALS.}, } @article {pmid37800457, year = {2023}, author = {Billings, JL and Hilton, JBW and Liddell, JR and Hare, DJ and Crouch, PJ}, title = {Fundamental Neurochemistry Review: Copper availability as a potential therapeutic target in progressive supranuclear palsy: Insight from other neurodegenerative diseases.}, journal = {Journal of neurochemistry}, volume = {167}, number = {3}, pages = {337-346}, doi = {10.1111/jnc.15978}, pmid = {37800457}, issn = {1471-4159}, mesh = {Humans ; *Supranuclear Palsy, Progressive/diagnosis/pathology ; Copper ; *Neurodegenerative Diseases/therapy ; Superoxide Dismutase-1 ; *Neurochemistry ; *Parkinson Disease/pathology ; }, abstract = {Since the first description of Parkinson's disease (PD) over two centuries ago, the recognition of rare types of atypical parkinsonism has introduced a spectrum of related PD-like diseases. Among these is progressive supranuclear palsy (PSP), a neurodegenerative condition that clinically differentiates through the presence of additional symptoms uncommon in PD. As with PD, the initial symptoms of PSP generally present in the sixth decade of life when the underpinning neurodegeneration is already significantly advanced. The causal trigger of neuronal cell loss in PSP is unknown and treatment options are consequently limited. However, converging lines of evidence from the distinct neurodegenerative conditions of PD and amyotrophic lateral sclerosis (ALS) are beginning to provide insights into potential commonalities in PSP pathology and opportunity for novel therapeutic intervention. These include accumulation of the high abundance cuproenzyme superoxide dismutase 1 (SOD1) in an aberrant copper-deficient state, associated evidence for altered availability of the essential micronutrient copper, and evidence for neuroprotection using compounds that can deliver available copper to the central nervous system. Herein, we discuss the existing evidence for SOD1 pathology and copper imbalance in PSP and speculate that treatments able to provide neuroprotection through manipulation of copper availability could be applicable to the treatment of PSP.}, } @article {pmid37800716, year = {2023}, author = {Shipley, PZ and Falkenstern, SK}, title = {Life Patterns of Family Caregivers of Patients With Amyotrophic Lateral Sclerosis.}, journal = {Nursing science quarterly}, volume = {36}, number = {4}, pages = {356-368}, doi = {10.1177/08943184231187903}, pmid = {37800716}, issn = {1552-7409}, mesh = {Humans ; Caregivers/psychology ; *Amyotrophic Lateral Sclerosis/psychology ; Adaptation, Psychological ; *Nursing Research ; Surveys and Questionnaires ; Family/psychology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a terminal disease that greatly affects patients and the family caregivers who provide most of their care. Despite the psychological, physical, and financial strain placed on ALS caregivers, few research efforts have been directed to this caregiving phenomenon. The purpose of this research study, utilizing Newman's health as expanding consciousness as the theoretical framework and research method, was to advance understanding of the experience of ALS family caregivers for the advancement of nursing science. Nine patterns of the whole across all family caregivers emerged from the data, showing important implications for nursing research and practice.}, } @article {pmid37801095, year = {2024}, author = {Gentile, F and Maranzano, A and Verde, F and Bettoni, V and Colombo, E and Doretti, A and Olivero, M and Scheveger, F and Colombrita, C and Bulgarelli, I and Spinelli, EG and Torresani, E and Messina, S and Maderna, L and Agosta, F and Morelli, C and Filippi, M and Silani, V and Ticozzi, N}, title = {The value of routine blood work-up in clinical stratification and prognosis of patients with amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {2}, pages = {794-803}, pmid = {37801095}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Creatinine ; Chlorides ; Disease Progression ; Prognosis ; Biomarkers ; }, abstract = {BACKGROUND: There is an unmet need in amyotrophic lateral sclerosis (ALS) to provide specific biomarkers for the disease. Due to their easy availability, we aimed to investigate whether routine blood parameters provide useful clues for phenotypic classification and disease prognosis.

METHODS: We analyzed a large inpatient cohort of 836 ALS patients who underwent deep phenotyping with evaluation of the clinical and neurophysiological burden of upper (UMN) and lower (LMN) motor neuron signs. Disability and progression rate were measured through the revised ALS Functional Rating Scale (ALSFRS-R) and its changes during time. Cox regression analysis was performed to assess survival associations.

RESULTS: Creatinine significantly correlated with LMN damage (r = 0.38), active (r = 0.18) and chronic (r = 0.24) denervation and baseline ALSFRS-R (r = 0.33). Creatine kinase (CK), alanine (ALT) and aspartate (AST) transaminases correlated with active (r = 0.35, r = 0.27, r = 0.24) and chronic (r = 0.37, r = 0.20, r = 0.19) denervation, while albumin and C-reactive protein significantly correlated with LMN score (r = 0.20 and r = 0.17). Disease progression rate showed correlations with chloride (r = -0.19) and potassium levels (r = -0.16). After adjustment for known prognostic factors, total protein [HR 0.70 (95% CI 0.57-0.86)], creatinine [HR 0.86 (95% CI 0.81-0.92)], chloride [HR 0.95 (95% CI 0.92-0.99)], lactate dehydrogenase [HR 0.99 (95% CI 0.99-0.99)], and AST [HR 1.02 (95% CI 1.01-1.02)] were independently associated with survival.

CONCLUSIONS: Creatinine is a reliable biomarker for ALS, associated with clinical features, disability and survival. Markers of nutrition/inflammation may offer additional prognostic information and partially correlate with clinical features. AST and chloride could further assist in predicting progression rate and survival.}, } @article {pmid37802187, year = {2024}, author = {Weiss, BD}, title = {Role of health literacy screening in clinical practice-Response to Reddy et al's JAAD paper titled "Health literacy screening tools to identify patients at risk of misunderstanding wound care instructions after dermatologic surgery".}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {1}, pages = {e39}, doi = {10.1016/j.jaad.2023.07.1046}, pmid = {37802187}, issn = {1097-6787}, mesh = {Humans ; *Health Literacy ; Dermatologic Surgical Procedures/adverse effects ; }, } @article {pmid37803257, year = {2023}, author = {Genuis, SK and Luth, W and Weber, G and Bubela, T and Johnston, WS}, title = {Asynchronous online focus groups for research with people living with amyotrophic lateral sclerosis and family caregivers: usefulness, acceptability and lessons learned.}, journal = {BMC medical research methodology}, volume = {23}, number = {1}, pages = {222}, pmid = {37803257}, issn = {1471-2288}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Caregivers ; Focus Groups ; Travel ; Travel-Related Illness ; }, abstract = {BACKGROUND: People with amyotrophic lateral sclerosis (ALS) face disability- and travel-related barriers to research participation. We investigate the usefulness and acceptability of asynchronous, online focus groups (AOFGs) for research involving people affected by ALS (patients and family caregivers) and outline lessons learned.

METHODS: The ALS Talk Project, consisting of seven AOFGs and 100 participants affected by ALS, provided context for this investigation. Hosted on the secure itracks Board™ platform, participants interacted in a threaded web forum structure. Moderators posted weekly discussion questions and facilitated discussion. Data pertaining to methodology, participant interaction and experience, and moderator technique were analyzed using itracks and NVivo 12 analytics (quantitative) and conventional content analysis and the constant-comparative approach (qualitative).

RESULTS: There was active engagement within groups, with post lengths averaging 111.48 words and a complex network of branching interactions between participants. One third of participant responses included individual reflections without further interaction. Participants affirmed their co-group members, offered practical advice, and discussed shared and differing perspectives. Moderators responded to all posts, indicating presence and probing answers. AOFGs facilitated qualitative and quantitative data-gathering and flexible response to unanticipated events. Although total participation fell below 50% after 10-12 weeks, participants valued interacting with peers in an inclusive, confidential forum. Participants used a variety of personal devices, browsers, and operating systems when interacting on the online platform.

CONCLUSIONS: This methodological examination of AOFGs for patient-centred investigations involving people affected by ALS demonstrates their usefulness and acceptability, and advances knowledge of online research methodologies. Lessons learned include: early identification of research goals and participant needs is critical to selecting an AOFG platform; although duration longer than 10-12 weeks may be burdensome in this population, participants were positive about AOFGs; AOFGs offer real world flexibility enabling response to research challenges and opportunities; and, AOGFs can effectively foster safe spaces for sharing personal perspectives and discussing sensitive topics. With moderators playing an important role in fostering engagement, AOFGs facilitated rich data gathering and promoted reciprocity by fostering the exchange of ideas and interaction between peers. Findings may have implications for research involving other neurologically impaired and/or medically vulnerable populations.}, } @article {pmid37804412, year = {2024}, author = {Kusama-Eguchi, K and Tokui, Y and Minoura, A and Yanai, Y and Hirose, D and Furukawa, M and Kosuge, Y and Miura, M and Ohkoshi, E and Makino, M and Minagawa, K and Matsuzaki, K and Ogawa, Y and Watanabe, K and Ohsaki, A}, title = {2(3H)-Dihydrofranolactone metabolites from Pleosporales sp. NUH322 as anti-amyotrophic lateral sclerosis drugs.}, journal = {Journal of natural medicines}, volume = {78}, number = {1}, pages = {146-159}, pmid = {37804412}, issn = {1861-0293}, support = {12-021//A Grant from the Ministry of Education, Culture, Sports, Science, and Technology to promote 2001-multidisciplinary research projects/ ; 13-023//A Grant from the Ministry of Education, Culture, Sports, Science, and Technology to promote 2001-multidisciplinary research projects/ ; 22590088//Grant-in-Aid for Scientific Research/ ; }, mesh = {Mice ; Male ; Female ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Motor Neurons/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; Spinal Cord/metabolism ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor disease with limited treatment options. A domestic fungal extract library was screened using three assays related to the pathophysiology of ALS with the aim of developing a novel ALS drug. 2(3H)-dihydrofuranolactones 1 and 2, and five known compounds 3-7 were isolated from Pleosporales sp. NUH322 culture media, and their protective activity against the excitotoxicity of β-N-oxalyl-L-α,β-diaminopropionic acid (ODAP), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamatergic agonist, was evaluated under low mitochondrial glutathione levels induced by ethacrynic acid (EA) and low sulfur amino acids using our developed ODAP-EA assay. Additional assays evaluated the recovery from cytotoxicity caused by transfected SOD1-G93A, an ALS-causal gene, and the inhibitory effect against reactive oxygen species (ROS) elevation. The structures of 1 and 2 were elucidated using various spectroscopic methods. We synthesized 1 from D-ribose, and confirmed the absolute structure. Isolated and synthesized 1 displayed higher ODAP-EA activities than the extract and represented its activity. Furthermore, 1 exhibited protective activity against SOD1-G93A-induced toxicity. An ALS mouse model, SOD1-G93A, of both sexes, was treated orally with 1 at pre- and post-symptomatic stages. The latter treatment significantly extended their lifespan (p = 0.03) and delayed motor deterioration (p = 0.001-0.01). Our result suggests that 1 is a promising lead compound for the development of ALS drugs with a new spectrum of action targeting both SOD1-G93A proteopathy and excitotoxicity through its action on the AMPA-type glutamatergic receptor.}, } @article {pmid37804508, year = {2023}, author = {Mamontova, EM and Clément, MJ and Sukhanova, MV and Joshi, V and Bouhss, A and Rengifo-Gonzalez, JC and Desforges, B and Hamon, L and Lavrik, OI and Pastré, D}, title = {FUS RRM regulates poly(ADP-ribose) levels after transcriptional arrest and PARP-1 activation on DNA damage.}, journal = {Cell reports}, volume = {42}, number = {10}, pages = {113199}, doi = {10.1016/j.celrep.2023.113199}, pmid = {37804508}, issn = {2211-1247}, mesh = {Humans ; *DNA Damage ; DNA Repair ; HeLa Cells ; Poly (ADP-Ribose) Polymerase-1/genetics/metabolism ; *Poly Adenosine Diphosphate Ribose/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors ; *Poly(ADP-ribose) Polymerases/genetics/metabolism ; RNA Recognition Motif ; *RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {PARP-1 activation at DNA damage sites leads to the synthesis of long poly(ADP-ribose) (PAR) chains, which serve as a signal for DNA repair. Here we show that FUS, an RNA-binding protein, is specifically directed to PAR through its RNA recognition motif (RRM) to increase PAR synthesis by PARP-1 in HeLa cells after genotoxic stress. Using a structural approach, we also identify specific residues located in the FUS RRM, which can be PARylated by PARP-1 to control the level of PAR synthesis. Based on the results of this work, we propose a model in which, following a transcriptional arrest that releases FUS from nascent mRNA, FUS can be recruited by PARP-1 activated by DNA damage to stimulate PAR synthesis. We anticipate that this model offers new perspectives to understand the role of FET proteins in cancers and in certain neurodegenerative diseases such as amyotrophic lateral sclerosis.}, } @article {pmid37806880, year = {2024}, author = {Wang, L and Cao, W and Xi, MH and Li, Y}, title = {Appendectomy and the risk of neurodegenerative diseases: A two-sample Mendelian randomization study.}, journal = {Asian journal of surgery}, volume = {47}, number = {1}, pages = {673-674}, doi = {10.1016/j.asjsur.2023.09.170}, pmid = {37806880}, issn = {0219-3108}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; Mendelian Randomization Analysis ; Appendectomy ; Genetic Predisposition to Disease ; }, } @article {pmid37807406, year = {2023}, author = {Anderson, G}, title = {Gut Microbiome and Circadian Interactions with Platelets Across Human Diseases, including Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Cancer.}, journal = {Current topics in medicinal chemistry}, volume = {23}, number = {28}, pages = {2699-2719}, doi = {10.2174/0115680266253465230920114223}, pmid = {37807406}, issn = {1873-4294}, mesh = {Humans ; *Melatonin/metabolism ; *Alzheimer Disease ; *Gastrointestinal Microbiome ; *Amyotrophic Lateral Sclerosis ; *Neoplasms ; Tumor Microenvironment ; }, abstract = {Platelets have traditionally been investigated for their role in clot formation in the course of cardiovascular diseases and strokes. However, recent work indicates platelets to be an integral aspect of wider systemic processes, with relevance to the pathophysiology of a host of diverse medical conditions, including neurodegenerative disorders and cancer. This article reviews platelet function and interactions with the gut microbiome and circadian systems, highlighting the role of the platelet mitochondrial melatonergic pathway in determining platelet activation, fluxes and plasticity. This provides a number of novel conceptualizations of platelet function and mode of interaction with other cell types, including in the pathoetiology and pathophysiology of diverse medical conditions, such as cancer, Alzheimer's disease, and amyotrophic lateral sclerosis. It is proposed that a platelet-gut axis allows platelets to contribute to many of the pathophysiological processes linked to gut dysbiosis and gut permeability. This is at least partly via platelet sphingosine- 1-phosphate release, which regulates enteric glial cells and lymphocyte chemotaxis, indicating an etiological role for platelets in a wide array of medical conditions linked to alterations in the gut microbiome. Platelets are also an important regulator of the various microenvironments that underpin most human medical conditions, including the tumor microenvironment, neurodegenerative diseases, and autoimmune disorders. Platelet serotonin release regulates the availability of the mitochondrial melatonergic pathway systemically, thereby being an important determinant of the dynamic metabolic interactions occurring across cell types that underpin the pathoetiology of many medical conditions. In addition, a number of novel and diverse future research directions and treatment implications are proposed.}, } @article {pmid37807784, year = {2023}, author = {Barba, L and Otto, M and Abu-Rumeileh, S}, title = {The Underestimated Relevance of Alzheimer's Disease Copathology in Amyotrophic Lateral Sclerosis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {95}, number = {4}, pages = {1401-1404}, doi = {10.3233/JAD-230900}, pmid = {37807784}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis ; tau Proteins/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; *Cognitive Dysfunction ; Amyloid beta-Peptides/cerebrospinal fluid ; }, abstract = {Concomitant Alzheimer's disease (AD) pathology can be observed in approximately 10-15% of cases with amyotrophic lateral sclerosis (ALS). ALS-AD patients have a higher prevalence of amnestic cognitive disturbances, which may often precede motor symptoms. Cerebrospinal fluid (CSF) AD core biomarkers usually show no or slightly significant changes in ALS, whereas blood phosphorylated tau protein might be increased independently from AD copathology. Neurofilament proteins are consistently elevated in CSF and blood of ALS, but have been poorly investigated in ALS-AD. All these issues should be taken into account when using fluid biomarkers as inclusion criteria or secondary endpoints in clinical trials.}, } @article {pmid37807839, year = {2023}, author = {Paganoni, S and Quintana, M and Sherman, AV and Vestrucci, M and Wu, Y and Timmons, J and Cudkowicz, M and , }, title = {Analysis of sodium phenylbutyrate and taurursodiol survival effect in ALS using external controls.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {12}, pages = {2297-2304}, pmid = {37807839}, issn = {2328-9503}, support = {//ALS Association/ ; //ALS Finding a Cure®/ ; //Amylyx Pharmaceuticals, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Phenylbutyrates/pharmacology/therapeutic use ; Survival Analysis ; Proportional Hazards Models ; }, abstract = {OBJECTIVE: Sodium phenylbutyrate and taurursodiol (PB and TURSO) was evaluated in amyotrophic lateral sclerosis (ALS) in the CENTAUR trial encompassing randomized placebo-controlled and open-label extension phases. On intent-to-treat (ITT) survival analysis, median overall survival (OS) was 4.8 months longer and risk of death 36% lower in those originally randomized to an initial 6-month double-blind period of PB and TURSO versus placebo. To estimate PB and TURSO treatment effect without placebo-to-active crossover, we performed a post hoc survival analysis comparing PB and TURSO-randomized participants from CENTAUR and a propensity score-matched, PB and TURSO-naïve external control cohort from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.

METHODS: Clinical trial control participants from the PRO-ACT database who met prespecified eligibility criteria were propensity score matched 1:1 with PB and TURSO-randomized CENTAUR participants using prognostically significant covariates in ALS.

RESULTS: Baseline characteristics including propensity score-matched covariates were generally well balanced between CENTAUR PB and TURSO (n = 89) and PRO-ACT external control (n = 85) groups. Estimated median (IQR) OS was 23.54 (14.56-39.32) months in the CENTAUR PB and TURSO group and 13.15 (9.83-19.20) months in the PRO-ACT external control group; hazard of death was 52% lower in the former group (hazard ratio, 0.48; 95% CI, 0.31-0.72; p = 0.00048).

INTERPRETATION: This analysis suggests potentially greater survival benefit with PB and TURSO in ALS without placebo-to-active crossover than seen on ITT analysis in CENTAUR. Analyses using well-matched external controls may provide additional context for evaluating survival effects in future ALS trials.}, } @article {pmid37807882, year = {2023}, author = {Pereira-Elizeu, AV and de Ávila-Panisset, J and Rodrigues-da Silva, ML and da Silva-Paz, LP and da Costa-Cunha, K and da Silva, ML and Monsores, N}, title = {Factors associated with the time taken for diagnosis of amyotrophic lateral sclerosis (ALS) in Brazil. An online population-based inquiry.}, journal = {Revista de neurologia}, volume = {77}, number = {8}, pages = {177-183}, pmid = {37807882}, issn = {1576-6578}, mesh = {Male ; Humans ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis ; Brazil ; }, abstract = {OBJECTIVE: This study evaluated factors associated with the time, in months, between the onset of symptoms and the diagnosis (time taken for diagnosis) of ALS for patients in Brazil, in the year 2014.

PATIENTS AND METHODS: An electronic questionnaire composed of 38 questions was developed and applied through internet-based social networks of patients. From the 210 replies, 194 were considered (86 from women, 108 from men). Most respondents were 51 to 60 years old. The Mann-Whitney test was used to compare the time taken for diagnosis between the strata of the sample.

RESULTS: The mean time taken for diagnosis was 14.21 (±16.87) months. There was a statistically significant difference only for higher education conditions (p = 0.009) and low education status (p = 0.042). There was no statistically significant difference between sexes, bulbar onset, age groups, and the presence of spouse, or 'partnership with ALS patients associations or exchange of experiences'.

CONCLUSION: These data suggest that the time taken for diagnosis of ALS is influenced by socioeconomic conditions that promote access to information and/or health services.}, } @article {pmid37808871, year = {2024}, author = {Okekenwa, S and Tsai, M and Dooley, P and Wang, B and Comassio, P and Moreira, J and Kriefall, N and Martin, S and Morfini, G and Brady, S and Song, Y}, title = {Divergent Molecular Pathways for Toxicity of Selected Mutant C9ORF72-derived Dipeptide Repeats.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.09.28.558663}, pmid = {37808871}, issn = {2692-8205}, abstract = {Expansion of a hexanucleotide repeat in a noncoding region of the C9ORF72 gene is responsible for a significant fraction of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) cases, but mechanisms linking mutant gene products to neuronal toxicity remain debatable. Pathogenesis was proposed to involve the production of toxic RNA species and/or accumulation of toxic dipeptide repeats (DPRs) but distinguishing between these mechanisms has been challenging. In this study, we first use complementary model systems for analyzing pathogenesis in adult-onset neurodegenerative diseases to characterize the pathogenicity of DPRs produced by Repeat Associated Non-ATG translation of C9ORF72 in specific cellular compartments: isolated axoplasm and giant synapse from the squid. Results showed selective axonal and presynaptic toxicity of GP-DPRs, independent of associated RNA. These effects involved a MAPK signaling pathway that affects fast axonal transport and synaptic function, a pathogenic mechanism shared with other mutant proteins associated with familial ALS, like SOD1 and FUS. In primary cultured neurons, GP but not other DPRs promote the "dying-back" axonopathy seen in ALS. Interestingly, GR- and PR-DPRs, which had no effect on axonal transport or synaptic transmission, were found to disrupt the nuclear membrane, promoting "dying-forward" neuropathy. All C9-DPR-mediated toxic effects observed in these studies are independent of whether the corresponding mRNAs contained hexanucleotide repeats or alternative codons. Finally, C9ORF72 human tissues confirmed a close association between GP and active P38 in degenerating motor neurons as well as GR-associated nuclear damage in the cortex. Collectively, our studies establish compartment-specific toxic effects of C9-DPRs associated with degeneration, suggesting that two independent pathogenic mechanisms may contribute to disease heterogeneity and/or synergize on disease progression in C9ORF72 patients with ALS and/or FTD symptoms.}, } @article {pmid37809062, year = {2023}, author = {Akhtar, M and Basher, SR and Nizam, NN and Hossain, L and Bhuiyan, TR and Qadri, F and Lundgren, A}, title = {T helper cell responses in adult diarrheal patients following natural infection with enterotoxigenic Escherichia coli are primarily of the Th17 type.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1220130}, pmid = {37809062}, issn = {1664-3224}, mesh = {Adult ; Humans ; Antibodies, Bacterial ; *Bacterial Toxins ; Diarrhea ; *Enterotoxigenic Escherichia coli ; Enterotoxins ; Immunoglobulin A ; Interleukin-17 ; Leukocytes, Mononuclear/chemistry ; Th17 Cells ; }, abstract = {BACKGROUND: Infection with enterotoxigenic Escherichia coli (ETEC) gives rise to IgA antibodies against both the heat labile toxin (LT) and colonization factors (CFs), which are considered to synergistically protect against ETEC diarrhea. Since the development of ETEC-specific long lived plasma cells and memory B cells is likely to be dependent on T helper (Th) cells, we investigated if natural ETEC diarrhea elicits ETEC-specific Th cells and their relation to IgA responses.

METHODS: Th cell subsets were analyzed in adult Bangladeshi patients hospitalized due to ETEC diarrhea by flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) isolated from blood collected day 2, 7, 30 and 90 after hospitalization as well as in healthy controls. The LT- and CF-specific Th responses were determined by analysis of IL-17A and IFN-γ in antigen stimulated PBMC cultures using ELISA. ETEC-specific IgA secreted by circulating antibody secreting cells (plasmablasts) were analyzed by using the antibodies in lymphocyte supernatants (ALS) ELISA-based method and plasma IgA was also measured by ELISA.

RESULTS: ETEC patients mounted significant ALS and plasma IgA responses against LTB and CFs on day 7 after hospitalization. ETEC patients had significantly elevated proportions of memory Th cells with a Th17 phenotype (CCR6+CXCR3-) in blood compared to controls, while frequencies of Th1 (CCR6-CXCR3+) or Th2 (CCR6-CXCR3-) cells were not increased. Antigen stimulation of PBMCs revealed IL-17A responses to LT, most clearly observed after stimulation with double mutant heat labile toxin (dmLT), but also with LT B subunit (LTB), and to CS6 in samples from patients with LT+ or CS6+ ETEC bacteria. Some individuals also mounted IFN-γ responses to dmLT and LTB. Levels of LTB specific IgA antibodies in ALS, but not plasma samples correlated with both IL-17A (r=0.5, p=0.02) and IFN-γ (r=0.6, p=0.01) responses to dmLT.

CONCLUSIONS: Our results show that ETEC diarrhea induces T cell responses, which are predominantly of the Th17 type. The correlations between IL-17A and IFN-g and intestine-derived plasmablast responses support that Th responses may contribute to the development of protective IgA responses against ETEC infection. These observations provide important insights into T cell responses that need to be considered in the evaluation of advanced ETEC vaccine candidates.}, } @article {pmid37810917, year = {2023}, author = {Carrera-Juliá, S and Estrela, JM and Zacarés, M and Navarro, MÁ and Vega-Bello, MJ and de la Rubia Ortí, JE and Moreno, ML and Drehmer, E}, title = {Effect of the Mediterranean diet supplemented with nicotinamide riboside and pterostilbene and/or coconut oil on anthropometric variables in amyotrophic lateral sclerosis. A pilot study.}, journal = {Frontiers in nutrition}, volume = {10}, number = {}, pages = {1232184}, pmid = {37810917}, issn = {2296-861X}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a chronic and progressive neurodegenerative disease that causes the death of motor neurons and alters patients' body composition. Supplementation with the antioxidants nicotinamide riboside (NR) and pterostilbene (PTER) can combat associated oxidative stress. Additionally, coconut oil is an alternative energy substrate that can address mitochondrial dysfunction. The aim of the present study is to assess the impact of a Mediterranean Diet supplemented with NR and PTER and/or with coconut oil on the anthropometric variables of patients with ALS. A prospective, mixed, randomized, analytical and experimental pilot study in humans was performed through a clinical trial (registered with ClinicalTrials.gov under number NCT03489200) with pre- and post-intervention assessments. The sample was made up of 40 subjects categorized into four study groups (Control, Antioxidants, Coconut oil, and Antioxidants + Coconut oil). Pre- and post-intervention anthropometric assessments were carried out to determine the following data: weight, percentage of fat and muscle mass, skinfolds, body perimeters, Body Mass Index (BMI), Waste-to-Hip Index (WHI) and Waist-Height Ratio (WHR). Compared to the Control group, GAx significantly increased muscle mass percentage and decreased fat mass percentage, triceps, iliac crest, and abdominal skinfolds. GCoco significantly increased muscle mass percentage and decreased fat mass percentage, subscapular skinfolds, and abdominal skinfolds. GAx + coco significantly increased muscle mass percentage and decreased abdominal skinfolds. Therefore, our results suggest that the Mediterranean Diet supplemented with NR and PTER and the Mediterranean Diet supplemented with coconut oil (ketogenic diet) are the two nutritional interventions that have reported the greatest benefits, at anthropometric level.}, } @article {pmid37811740, year = {2023}, author = {Grossschaedl, K and Vallant, C and Dernoscheg, MT and Richtig, M and Öllinger, A and Balakirski, G and Wilsmann-Theis, D and Nguyen, VA and Weinlich, G and Tsiogka, A and Koelblinger, P and Scheffel, J and Richtig, E and Richtig, G}, title = {[Verwendung und Nutzen des Internets als Informationsquelle für Erkrankungen und Therapien in der Dermatologie: Usage and benefit of the Internet as a source of information on disease and therapy in dermatology].}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {21}, number = {11}, pages = {1383-1386}, doi = {10.1111/ddg.15199_g}, pmid = {37811740}, issn = {1610-0387}, } @article {pmid37812352, year = {2023}, author = {Salemi, M and Mandarà, LGM and Salluzzo, MG and Schillaci, FA and Castiglione, R and Cordella, A and Iorio, R and Perrotta, CS and Ferri, R and Romano, C}, title = {NGS study in a sicilian case series with a genetic diagnosis for Gerstmann-Sträussler-Scheinker syndrome (PRNP, p.P102L).}, journal = {Molecular biology reports}, volume = {50}, number = {11}, pages = {9715-9720}, pmid = {37812352}, issn = {1573-4978}, support = {(RC 2773804)//Ministero della Salute/ ; }, mesh = {Animals ; Humans ; *Gerstmann-Straussler-Scheinker Disease/diagnosis/genetics/metabolism ; *Prions/genetics ; Prion Proteins/genetics ; Mutation/genetics ; High-Throughput Nucleotide Sequencing ; }, abstract = {BACKGROUND: Gerstmann Sträussler Scheinker (GSS) is an inherited, invariably fatal prion disease. Like other human prion diseases, GSS is caused by missense mutations in the prion protein (PrP) gene (PRNP), and by the formation and overtime accumulation of the misfolded, pathogenic scrapie PrP (PrPSc). The first mutation identified in the PRNP gene, and the one blamed as the main cause of the disease, is c.C305T:p.P102L.

METHODS AND RESULTS: The Sanger sequencing method was performed on the PRNP gene for the detection of c.C305T:p.P102L mutations in a cohort of 10 subjects; moreover, a study was carried out, using Next Generation Sequencing (NGS), by sequencing a group of genes related to amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), movement disorders and dementia which show a phenotypic profile similar to that of GSS. The results obtained from the study using NGS indicate the potential role of other genetic variants which could contribute to the various GSS phenotypes.

CONCLUSIONS: In conclusion, we highlight the large clinical variability in subjects presenting with GSS and p.P102L, as well as the hypothesis that the mutation in PrP codon 102 alone is not sufficient to trigger the cardinal clinical signs of the disease; furthermore, we do not exclude the possibility that further genetic variants play a decisive role in the aspects of the various phenotypes with which GSS manifests itself.}, } @article {pmid37813148, year = {2023}, author = {Heidet, M and Benjamin Leung, KH and Bougouin, W and Alam, R and Frattini, B and Liang, D and Jost, D and Canon, V and Deakin, J and Hubert, H and Christenson, J and Vivien, B and Chan, T and Cariou, A and Dumas, F and Jouven, X and Marijon, E and Bennington, S and Travers, S and Souihi, S and Mermet, E and Freyssenge, J and Arrouy, L and Lecarpentier, E and Derkenne, C and Grunau, B}, title = {Improving EMS response times for out-of-hospital cardiac arrest in urban areas using drone-like vertical take-off and landing air ambulances: An international, simulation-based cohort study.}, journal = {Resuscitation}, volume = {193}, number = {}, pages = {109995}, doi = {10.1016/j.resuscitation.2023.109995}, pmid = {37813148}, issn = {1873-1570}, mesh = {Adult ; Humans ; *Cardiopulmonary Resuscitation ; Cohort Studies ; *Air Ambulances ; *Out-of-Hospital Cardiac Arrest/therapy ; Reaction Time ; Unmanned Aerial Devices ; *Emergency Medical Services ; }, abstract = {BACKGROUND: Advances in vertical take-off and landing (VTOL) technologies may enable drone-like crewed air ambulances to rapidly respond to out-of-hospital cardiac arrest (OHCA) in urban areas. We estimated the impact of incorporating VTOL air ambulances on OHCA response intervals in two large urban centres in France and Canada.

METHODS: We included adult OHCAs occurring between Jan. 2017-Dec. 2018 within Greater Paris in France and Metro Vancouver in Canada. Both regions utilize tiered OHCA response with basic (BLS)- and advanced life support (ALS)-capable units. We simulated incorporating 1-2 ALS-capable VTOL air ambulances dedicated to OHCA response in each study region, and computed time intervals from call reception by emergency medical services (EMS) to arrival of the: (1) first ALS unit ("call-to-ALS arrival interval"); and (2) first EMS unit ("call-to-first EMS arrival interval").

RESULTS: There were 6,217 OHCAs included during the study period (3,760 in Greater Paris and 2,457 in Metro Vancouver). Historical median call-to-ALS arrival intervals were 21 min [IQR 16-29] in Greater Paris and 12 min [IQR 9-17] in Metro Vancouver, while median call-to-first EMS arrival intervals were 11 min [IQR 8-14] and 7 min [IQR 5-8] respectively. Incorporating 1-2 VTOL air ambulances improved median call-to-ALS arrival intervals to 7-9 min and call-to-first EMS arrival intervals to 6-8 min in both study regions (all P < 0.001).

CONCLUSION: VTOL air ambulances dedicated to OHCA response may improve EMS response intervals, with substantial improvements in ALS response metrics.}, } @article {pmid37813308, year = {2023}, author = {Babazadeh, A and Rayner, SL and Lee, A and Chung, RS}, title = {TDP-43 as a therapeutic target in neurodegenerative diseases: Focusing on motor neuron disease and frontotemporal dementia.}, journal = {Ageing research reviews}, volume = {92}, number = {}, pages = {102085}, doi = {10.1016/j.arr.2023.102085}, pmid = {37813308}, issn = {1872-9649}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy ; DNA-Binding Proteins/metabolism ; *Frontotemporal Dementia/therapy ; *Motor Neuron Disease/therapy/pathology ; *Neurodegenerative Diseases/therapy ; }, abstract = {A common feature of adult-onset neurodegenerative diseases is the presence of characteristic pathological accumulations of specific proteins. These pathological protein depositions can vary in their protein composition, cell-type distribution, and intracellular (or extracellular) location. For example, abnormal cytoplasmic protein deposits which consist of the TDP-43 protein are found within motor neurons in patients with amyotrophic lateral sclerosis (ALS, a common form of motor neuron disease) and frontotemporal dementia (FTD). The presence of these insoluble intracellular TDP-43 inclusions suggests that restoring TDP-43 homeostasis represents a potential therapeutical strategy, which has been demonstrated in alleviating neurodegenerative symptoms in cell and animal models of ALS/FTD. We have reviewed the mechanisms that lead to disrupted TDP-43 homeostasis and discussed how small molecule-based therapies could be applied in modulating these mechanisms. This review covers recent advancements and challenges in small molecule-based therapies that could be used to clear pathological forms of TDP-43 through various protein homeostasis mechanisms and advance the way towards finding effective therapeutical drug discoveries for neurodegenerative diseases characterized by TDP-43 proteinopathies, especially ALS and FTD. We also consider the wider insight of these therapeutic strategies for other neurodegenerative diseases.}, } @article {pmid37814465, year = {2023}, author = {Fan, J and Li, Y and Niu, JW and Hu, N and Guan, YZ and Cui, LY and Liu, MS}, title = {Differentiation Between Amyotrophic Lateral Sclerosis and Mimics Using Quantitative Analysis of Fsciculation with Muscle Ultrasound.}, journal = {Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih}, volume = {38}, number = {4}, pages = {265-272}, doi = {10.24920/004282}, pmid = {37814465}, issn = {1001-9294}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Fasciculation/diagnostic imaging ; *Radiculopathy ; Muscle, Skeletal/diagnostic imaging ; Ultrasonography/methods ; }, abstract = {Objective To determine the diagnostic accuracy of the intensity of fasciculation evaluated by muscle ultrasound in the differential diagnosis of amyotrophic lateral sclerosis (ALS). Methods We prospectively recruited patients who had ALS and neuropathy-radiculopathy attending Peking Union Medical College Hospital from 2017 to 2020. Healthy adults from a community were recruited as healthy controls. Muscle strength was assessed using the Medical Research Council (MRC) scale. At the first visit to the hospital, patients were assessed for maximal grade of fasciculations, total fasciculation score, and fasciculation grade in 16 muscle groups of bilateral upper and lower limbs using ultrasonography. The sensitivity and specificity of maximal grade of fasciculations, total fasciculation score, and fasciculation grade for the diagnosis of ALS were assessed by receiver operating characteristic analyses. Results The percentage of limb muscles with a maximal fasciculation grade higher than grade 2 in ALS patients and neuropathy-radiculopathy patients was 84.9% and 9.8%, respectively (χ[2] = 172.436, P < 0.01). Of the 16 limb muscles detected, the total fasciculation score [median (interquartile range)] was 29 (15, 41) in ALS patients and 3 (0, 8) in neuropathy-radiculopathy patients (Z = 9.642, P < 0.001). Remarkable fasciculations were seen in ALS patients whose muscles with a MRC score ranging from 2 to 4, followed by patients with MRC score 5, and then in those with MRC score 0 and 1. The sensitivity and specificity of total fasciculation score for diagnosis of ALS were 80.6% and 93.4%, respectively (cut-off value 14). In patients with ALS, for muscles with MRC score 4 and 5, the percentage of muscles with fasciculation grades ≥ 3 was 42.3% and 24.1% respectively, while in neuropathy-radiculopathy patients, the percentage for muscles with MRC score 4 and 5 was only 1.7% and 0, respectively. Conclusion A combined analysis of fasciculation intensity and MRC score of the limb muscles may be helpful for differential diagnosis of ALS.}, } @article {pmid37814618, year = {2023}, author = {Li, B and Zhang, W and Zhong, S and Pan, J and Wang, X and Zou, H and Dou, X}, title = {Short-term outcome of plasma adsorption therapy in amyotrophic lateral sclerosis.}, journal = {Journal of medical biochemistry}, volume = {42}, number = {3}, pages = {401-406}, pmid = {37814618}, issn = {1452-8258}, abstract = {BACKGROUND: To observe the short-term outcome of plasma adsorption PA therapy in amyotrophic lateral sclerosis (ALS).

METHODS: 28 cases of als patients were recruited in this study, of which 20 were male and 8 were female with a mean age of 53.21±9.07 years and the average course of 33±23.35 months. The clinical manifestations were limb weakness (N=27), muscular atrophy (N=27), muscular tremor (N=5), dysphagia (N=12) and dysarthria (N=12). The clinical data of the patients recruited were graded by Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRSR) : <10 (N=1), 11-20 (N=4), 21-30 (N=6), 31-40 (N=12), >40 (N=5). All patients received PA therapy once a week for three successive times after examining the conditions of blood coagulation and virus infection. PA therapy was supplemented with neurotrophic therapy meanwhile. All patients' clinical manifestations and scores of ALSFRSR before treatment and one week after treatment were evaluated and compared. The levels of serum superoxide dismutase (SOD), interleukin-10 (IL-10), serum creatine kinase (CK) and lactate dehydrogenase (LDH) before and after treatment were compared.

RESULTS: After PA therapy, 14 patients have improved obviously in muscle strength, 4 patients in hypermyotonia partially, 3 patients in muscular tremor, 5 patients in dysarthria, 3 patients in salivation to some extent and 2 patients in swallowing function. The score of ALSFRSR after PA treatment (31.89±10.36) was remarkably higher than that before PA treatment (30.68±10.52) (P<0.01). The levels of SOD (155.10±21.87 IU/L) and IL-10 (138.06±185.88 pg/mL) after PA treatment were significantly higher than the levels before PA treatment (143.08.3±19.16 IU/L and 46.34±75.31 pg/mL, respectively) (P<0.05). The levels of CK (168.86±113.50 IU/L) and LDH (152.07±32.65 IU/L) after PA treatment were significantly lower than the levels before PA treatment (356.68±250.30 IU/L and 181.36±33.74 IU/L respectively) (P<0.01). At the end of follow-up period (November, 2019), five patients died of respiratory failure 16-21 months after PA treatment and two patents died of respiratory infection 15-20 months after PA treatment. 7 patients were still alive. The score of ALSFRS-R of these patients who survived at the end of follow-up (13.00±13.37) were significantly lower than before PA treatment (36.71±8.56) (P<0.05) and after PA treatment (38.14±8.82) (P<0.05).

CONCLUSIONS: Plasma adsorption (PA) therapy has shortterm therapeutic effects on als. The effects might be attributed to the anti-oxygen free radical effect by increasing SOD level and the anti-inflammation effect by increasing IL-10 level. As the efficacy of PA therapy was obtained in a small sample size and short follow-up period, the longterm observation of PA efficacy in treating als should be further investigated.}, } @article {pmid37814924, year = {2023}, author = {Spiliopoulos, KC and Lykouras, D and Veltsista, D and Skaramagkas, V and Karkoulias, K and Tzouvelekis, A and Chroni, E}, title = {The utility of diaphragm ultrasound thickening indices for assessing respiratory decompensation in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {68}, number = {6}, pages = {850-856}, doi = {10.1002/mus.27980}, pmid = {37814924}, issn = {1097-4598}, mesh = {Humans ; Diaphragm/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging ; *Noninvasive Ventilation ; *Respiratory Insufficiency/diagnostic imaging/etiology ; Ultrasonography ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) leads to diaphragmatic weakness at some point during its course, which is a major cause of respiratory insufficiency. The aim of this study was to evaluate ultrasound-based measures for assessing the diaphragmatic competency and the need for ventilatory support.

METHODS: Twenty-six subjects with ALS and 12 healthy controls were enrolled. All participants underwent B-mode diaphragm ultrasound (DUS). Diaphragm thickness and thickening indices were recorded. In the subjects with ALS, further assessments included functional scales and spirometry. We investigated the diagnostic accuracy of DUS thickening indices in predicting diaphragmatic dysfunction and the correlation between clinical, spirometric, and DUS data.

RESULTS: Significant relationships were found between forced vital capacity and all diaphragmatic thickening indices. Similarly, all diaphragmatic thickening indices correlated with both Milano Torino staging and disease progression rate. Only thickening fraction (TFdi) correlated with score on the revised ALS Functional Rating Scale (r = 0.459, P = .024). TFdi had better accuracy in predicting diaphragmatic dysfunction (area under the curve [AUC] = 0.839, 95% confidence interval [CI] 0.643 to 0.953) and the need for initiation of noninvasive ventilation (NIV) (AUC = 0.989, 95% CI 0.847 to 1.000) compared with the other indices. A TFdi cut-off point of 0.50 was a sensitive threshold to consider NIV.

DISCUSSION: DUS successfully identifies diaphragmatic dysfunction in ALS, being a valuable accessory modality for investigating respiratory symptoms. TFdi was found to be the most useful DUS index, which encourages further investigation.}, } @article {pmid37815061, year = {2024}, author = {Zhang, X and Dai, L and Long, Y and Chen, X and Alhafi, MAK}, title = {Healthcare costs for patients with rare diseases: Evidence from China.}, journal = {The International journal of health planning and management}, volume = {39}, number = {1}, pages = {48-61}, doi = {10.1002/hpm.3713}, pmid = {37815061}, issn = {1099-1751}, support = {21Y012//Hubei Provincial Department of Education Project/ ; }, mesh = {Humans ; *Insurance, Health ; Rare Diseases/therapy ; *Amyotrophic Lateral Sclerosis ; Health Care Costs ; Health Expenditures ; China ; }, abstract = {OBJECTIVE: Rare diseases cause a huge financial burden to countless patients and families. It is an important public health issue that requires widespread attention. This study analyzes medical expenses composition and the change in trends of out-of-pocket (OOP) expenses for patients with Amyotrophic lateral sclerosis (ALS) and explores the factors influencing these changes.

METHODS: Data were obtained from the Chinese Medical Insurance Department database from 2018 to 2020, including 857 patients with ALS in 60 cities across 30 provinces. We used descriptive methods to analyse the baseline characteristics and medical expenses of outpatients and inpatients with ALS. And we used quantile regression to analyse the differences in patient OOP ratio and the factors influencing them.

RESULTS: In China, 80.3% of ALS patients chose tertiary hospitals, with an annual direct medical cost of 11,339.7 RMB per patient and an OOP ratio of 41.6%. The annual medical cost for outpatients was 345.1 RMB per patient, with an OOP ratio of 36.7%. The annual medical cost for inpatients was 28,139.8 RMB per patient, with an OOP ratio of 41.7%. Compared to outpatients, inpatients had higher medical costs but lower actual reimbursement rates. The OOP ratio of ALS patients decreased, then increased over time. And the OOP ratio was influenced by medical institution, medical insurance, and age (p < 0.05). Patients who chose tertiary hospitals, those who were covered by the urban resident basic medical insurance and younger patients had relatively higher OOP ratio.

CONCLUSION: In recent years, although China has begun to pay attention to the rights and interests of patients with rare diseases, the government has provided some healthcare security to patients with rare diseases. However, the level of medical insurance coverage was still low, the equity of protection was still insufficient and the financial burden on patients was high. Therefore, the government should further improve the healthcare system to provide full life-cycle and affordable healthcare services to patients with rare diseases.}, } @article {pmid37815224, year = {2024}, author = {Northall, A and Doehler, J and Weber, M and Tellez, I and Petri, S and Prudlo, J and Vielhaber, S and Schreiber, S and Kuehn, E}, title = {Multimodal layer modelling reveals in vivo pathology in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {3}, pages = {1087-1099}, pmid = {37815224}, issn = {1460-2156}, support = {2019-A03//Else Kröner Fresenius Stiftung/ ; KU 3711/2-1//Deutsche Forschungsgemeinschaft/ ; 501214112//SCHR/ ; }, mesh = {Humans ; Calcium ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Neurodegenerative Diseases ; *Dermatitis ; Iron ; *Demyelinating Diseases ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by the loss of motor control. Current understanding of ALS pathology is largely based on post-mortem investigations at advanced disease stages. A systematic in vivo description of the microstructural changes that characterize early stage ALS, and their subsequent development, is so far lacking. Recent advances in ultra-high field (7 T) MRI data modelling allow us to investigate cortical layers in vivo. Given the layer-specific and topographic signature of ALS pathology, we combined submillimetre structural 7 T MRI data (qT1, QSM), functional localizers of body parts (upper limb, lower limb, face) and layer modelling to systematically describe pathology in the primary motor cortex (M1), in 12 living ALS patients with reference to 12 matched controls. Longitudinal sampling was performed for a subset of patients. We calculated multimodal pathology maps for each layer (superficial layer, layer 5a, layer 5b, layer 6) of M1 to identify hot spots of demyelination, iron and calcium accumulation in different cortical fields. We show preserved mean cortical thickness and layer architecture of M1, despite significantly increased iron in layer 6 and significantly increased calcium in layer 5a and superficial layer, in patients compared to controls. The behaviourally first-affected cortical field shows significantly increased iron in L6 compared to other fields, while calcium accumulation is atopographic and significantly increased in the low myelin borders between cortical fields compared to the fields themselves. A subset of patients with longitudinal data shows that the low myelin borders are particularly disrupted and that calcium hot spots, but to a lesser extent iron hot spots, precede demyelination. Finally, we highlight that a very slow progressing patient (Patient P4) shows a distinct pathology profile compared to the other patients. Our data show that layer-specific markers of in vivo pathology can be identified in ALS patients with a single 7 T MRI measurement after first diagnosis, and that such data provide critical insights into the individual disease state. Our data highlight the non-topographic architecture of ALS disease spread and the role of calcium, rather than iron accumulation, in predicting future demyelination. We also highlight a potentially important role of low myelin borders, that are known to connect to multiple areas within the M1 architecture, in disease spread. Finally, the distinct pathology profile of a very-slow progressing patient (Patient P4) highlights a distinction between disease duration and progression. Our findings demonstrate the importance of in vivo histology imaging for the diagnosis and prognosis of neurodegenerative diseases such as ALS.}, } @article {pmid37815307, year = {2024}, author = {Liu, KF and Ramachandran, S and Chang, CW and Chen, RF and Huang, CH and Huang, HT and Lee, CC and Li, YT and Kuo, YR}, title = {The Synergistic Effect of Full-Spectrum Light Therapy and Transient Immunosuppressants Prolonged Allotransplant Survival.}, journal = {Plastic and reconstructive surgery}, volume = {154}, number = {4}, pages = {775-783}, doi = {10.1097/PRS.0000000000011135}, pmid = {37815307}, issn = {1529-4242}, support = {SH11003//Kaohsiung Medical University Hospital, Taiwan./ ; }, mesh = {Animals ; *Immunosuppressive Agents/therapeutic use ; *Graft Survival/drug effects/immunology ; *Rats, Inbred Lew ; Rats ; *Vascularized Composite Allotransplantation/methods ; *Hindlimb/transplantation ; Male ; Combined Modality Therapy ; Cyclosporine ; Graft Rejection/prevention & control/immunology ; Phototherapy/methods ; Rats, Inbred BN ; Antilymphocyte Serum ; }, abstract = {BACKGROUND: The lifelong administration of immunosuppressants remains the largest drawback in vascularized composite allotransplantation (VCA). Therefore, developing alternative strategies to minimize the long-term use of immunosuppressive agents is crucial. This study investigated whether full-spectrum bright light therapy (FBLT) combined with short-term immunosuppressant therapy could prolong VCA survival in a rodent hindlimb model.

METHODS: Hindlimb allotransplantation was conducted from Brown-Norway to Lewis rats, and the rats were divided into 4 groups. Group 1 did not receive treatment as a rejection control. Group 2 received FBLT alone. Group 3 was treated with short-term antilymphocyte serum (ALS) and cyclosporine A (CsA). Group 4 was administered short-term ALS/CsA combined with FBLT for 8 weeks. Peripheral blood and transplanted tissues were collected for analysis.

RESULTS: The results revealed median survival time of FBLT alone (group 2) did not increase allograft survival compared with the control (group 1). However, in group 4, FBLT combined with short-term ALS/CsA, median composite tissue allograft survival time (266 days) was significantly prolonged compared with groups 1 (11 days), 2 (10 days), and 3 (41 days) (P < 0.01). Group 4 also showed a significant increase in regulatory T cells (P = 0.04) and transforming growth factor-β1 levels (P = 0.02), and a trend toward a decrease in interleukin-1β levels (P = 0.03) at 16 weeks after transplantation as compared with control (group 1).

CONCLUSIONS: FBLT combined with short-term immunosuppressants prolonged allotransplant survival by modulating T-cell regulatory functions and antiinflammatory cytokine expression. This approach could be a potential strategy to increase VCA survival.

CLINICAL RELEVANCE STATEMENT: Full-spectrum light therapy could be a potential strategy to increase vascularized composite allotransplant survival.}, } @article {pmid37815936, year = {2023}, author = {Shammas, MK and Nie, Y and Gilsrud, A and Huang, X and Narendra, DP and Chinnery, PF}, title = {CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature.}, journal = {Human molecular genetics}, volume = {33}, number = {1}, pages = {91-101}, pmid = {37815936}, issn = {1460-2083}, support = {212219/Z/18/Z/WT_/Wellcome Trust/United Kingdom ; 224486/Z/21/Z/WT_/Wellcome Trust/United Kingdom ; MR/S005021/1/MRC_/Medical Research Council/United Kingdom ; MR/S035699/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; DNA, Mitochondrial/genetics/metabolism ; *Frontotemporal Dementia/genetics ; Mitochondria/metabolism ; *Mitochondrial Proteins/genetics/metabolism ; Mutation ; }, abstract = {Mutations affecting the mitochondrial intermembrane space protein CHCHD10 cause human disease, but it is not known why different amino acid substitutions cause markedly different clinical phenotypes, including amyotrophic lateral sclerosis-frontotemporal dementia, spinal muscular atrophy Jokela-type, isolated autosomal dominant mitochondrial myopathy and cardiomyopathy. CHCHD10 mutations have been associated with deletions of mitochondrial DNA (mtDNA deletions), raising the possibility that these explain the clinical variability. Here, we sequenced mtDNA obtained from hearts, skeletal muscle, livers and spinal cords of WT and Chchd10 G58R or S59L knockin mice to characterise the mtDNA deletion signatures of the two mutant lines. We found that the deletion levels were higher in G58R and S59L mice than in WT mice in some tissues depending on the Chchd10 genotype, and the deletion burden increased with age. Furthermore, we observed that the spinal cord was less prone to the development of mtDNA deletions than the other tissues examined. Finally, in addition to accelerating the rate of naturally occurring deletions, Chchd10 mutations also led to the accumulation of a novel set of deletions characterised by shorter direct repeats flanking the deletion breakpoints. Our results indicate that Chchd10 mutations in mice induce tissue-specific deletions which may also contribute to the clinical phenotype associated with these mutations in humans.}, } @article {pmid37816542, year = {2024}, author = {McHenry, KL}, title = {Airway Clearance Strategies and Secretion Management in Amyotrophic Lateral Sclerosis.}, journal = {Respiratory care}, volume = {69}, number = {2}, pages = {227-237}, pmid = {37816542}, issn = {1943-3654}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Respiratory Therapy/methods ; *Chest Wall Oscillation ; Bodily Secretions ; *Insufflation/methods ; Cough/etiology ; *Respiratory Insufficiency/therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative motor neuron disease that affects voluntary muscle movement. Often, difficulty in coughing, breathing, and swallowing are sequela associated with the condition, and the presence of bulbar muscle predominant weakness results in deleterious effects on airway clearance and secretion management. This narrative review will provide practical guidance for clinicians treating this population. Cough insufficiency in this population typically manifests as a prolonged, slow, weak cough effort that impedes the clearability of secretions and airway protection. Dystussia and dysphagia frequently occur simultaneously in bulbar dysfunction, subsequently impacting respiratory health. Measures of respiratory strength should be obtained and monitored every 3-6 months, preferably in a multidisciplinary clinic setting. Cough augmentation, whether manual or mechanical techniques, should be sought as early in the disease progression as possible to adequately control secretions in the proximal airways. This airway clearance strategy can aid in the prevention and treatment of respiratory tract infections (RTIs), which can pose a significant clinical hurdle to those with ALS. The use of mechanical insufflation-exsufflation may be complicated by severe bulbar dysfunction rendering this technique ineffective. Though peripheral airway clearance strategies, such as high-frequency chest-wall compression, have the advantage of being less impacted by bulbar dysfunction, it is only recommended this modality be used in conjunction with, versus in lieu of, proximal strategies. Salivary secretion management includes the use of anticholinergics, botulinum toxin, and radiation therapy depending on severity and desire for relief.}, } @article {pmid37817804, year = {2023}, author = {Cui, S and Zhang, T and Xiong, X and Zhao, J and Cao, Q and Zhou, H and Xia, XG}, title = {Detergent-insoluble PFN1 inoculation expedites disease onset and progression in PFN1 transgenic rats.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1279259}, pmid = {37817804}, issn = {1662-4548}, support = {R01 NS089701/NS/NINDS NIH HHS/United States ; R01 NS099635/NS/NINDS NIH HHS/United States ; R01 NS110455/NS/NINDS NIH HHS/United States ; RF1 AG064822/AG/NIA NIH HHS/United States ; }, abstract = {Accumulating evidence suggests a gain of elusive toxicity in pathogenically mutated PFN1. The prominence of PFN1 aggregates as a pivotal pathological hallmark in PFN1 transgenic rats underscores the crucial involvement of protein aggregation in the initiation and progression of neurodegeneration. Detergent-insoluble materials were extracted from the spinal cords of paralyzed rats afflicted with ALS and were intramuscularly administered to asymptomatic recipient rats expressing mutant PFN1, resulting in an accelerated development of PFN1 inclusions and ALS-like phenotypes. This effect diminished when the extracts derived from wildtype PFN1 transgenic rats were employed, as detergent-insoluble PFN1 was detected exclusively in mutant PFN1 transgenic rats. Consequently, the factor influencing the progression of ALS pathology in recipient rats is likely associated with the presence of detergent-insoluble PFN1 within the extracted materials. Noteworthy is the absence of disease course modification upon administering detergent-insoluble extracts to rats that already displayed PFN1 inclusions, suggesting a seeding rather than augmenting role of such extracts in initiating neuropathological changes. Remarkably, pathogenic PFN1 exhibited an enhanced affinity for the molecular chaperone DNAJB6, leading to the sequestration of DNAJB6 within protein inclusions, thereby depleting its availability for cellular functions. These findings shed light on a novel mechanism that underscores the prion-like characteristics of pathogenic PFN1 in driving neurodegeneration in the context of PFN1-related ALS.}, } @article {pmid37818590, year = {2023}, author = {Grima, N and Liu, S and Southwood, D and Henden, L and Smith, A and Lee, A and Rowe, DB and D'Silva, S and Blair, IP and Williams, KL}, title = {RNA sequencing of peripheral blood in amyotrophic lateral sclerosis reveals distinct molecular subtypes: Considerations for biomarker discovery.}, journal = {Neuropathology and applied neurobiology}, volume = {49}, number = {6}, pages = {e12943}, pmid = {37818590}, issn = {1365-2990}, support = {//Motor Neurone Disease Research Australia/ ; //National Health and Medical Research Council/ ; 2011120//NHMRC/ ; //FightMND/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Neurodegenerative Diseases ; Australia ; Biomarkers ; Sequence Analysis, RNA ; }, abstract = {AIM: Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease with limited therapeutic options. A key factor limiting the development of effective therapeutics is the lack of disease biomarkers. We sought to assess whether biomarkers for diagnosis, prognosis or cohort stratification could be identified by RNA sequencing (RNA-seq) of ALS patient peripheral blood.

METHODS: Whole blood RNA-seq data were generated for 96 Australian sporadic ALS (sALS) cases and 48 healthy controls (NCBI GEO accession GSE234297). Differences in sALS-control gene expression, transcript usage and predicted leukocyte proportions were assessed, with pathway analysis used to predict the activity state of biological processes. Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning algorithms were applied to search for diagnostic and prognostic gene expression patterns. Unsupervised clustering analysis was employed to determine whether sALS patient subgroups could be detected.

RESULTS: Two hundred and forty-five differentially expressed genes were identified in sALS patients relative to controls, with enrichment of immune, metabolic and stress-related pathways. sALS patients also demonstrated switches in transcript usage across a small set of genes. We established a classification model that distinguished sALS patients from controls with an accuracy of 78% (sensitivity: 79%, specificity: 75%) using the expression of 20 genes. Clustering analysis identified four patient subgroups with gene expression signatures and immune cell proportions reflective of distinct peripheral effects.

CONCLUSIONS: Our findings suggest that peripheral blood RNA-seq can identify diagnostic biomarkers and distinguish molecular subtypes of sALS patients however, its prognostic value requires further investigation.}, } @article {pmid37818935, year = {2024}, author = {Rehmann, R}, title = {Editorial for: "Quantitative MRI Analysis of Brachial Plexus and Limb-Girdle Muscles in Upper Extremity Onset Amyotrophic Lateral Sclerosis".}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {60}, number = {1}, pages = {302-303}, doi = {10.1002/jmri.29051}, pmid = {37818935}, issn = {1522-2586}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; *Brachial Plexus/diagnostic imaging ; *Muscle, Skeletal/diagnostic imaging ; Upper Extremity/diagnostic imaging ; }, } @article {pmid37819053, year = {2023}, author = {Necarsulmer, JC and Simon, JM and Evangelista, BA and Chen, Y and Tian, X and Nafees, S and Marquez, AB and Jiang, H and Wang, P and Ajit, D and Nikolova, VD and Harper, KM and Ezzell, JA and Lin, FC and Beltran, AS and Moy, SS and Cohen, TJ}, title = {RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {37819053}, issn = {2050-084X}, support = {F31 NS122242/NS/NINDS NIH HHS/United States ; R01 NS105981/NS/NINDS NIH HHS/United States ; P50 HD103573/HD/NICHD NIH HHS/United States ; P30NS045892/NS/NINDS NIH HHS/United States ; P30 NS045892/NS/NINDS NIH HHS/United States ; T32 GM133364/GM/NIGMS NIH HHS/United States ; F30 AG072786/AG/NIA NIH HHS/United States ; R01NS105981/NS/NINDS NIH HHS/United States ; UM1TR004406/TR/NCATS NIH HHS/United States ; T32 GM008719/GM/NIGMS NIH HHS/United States ; UM1 TR004406/TR/NCATS NIH HHS/United States ; F31NS122242/NS/NINDS NIH HHS/United States ; U54 HD079124/HD/NICHD NIH HHS/United States ; F30AG072786/AG/NIA NIH HHS/United States ; 1T32GM133364-01A1/GM/NIGMS NIH HHS/United States ; 5T32GM008719-19/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Animals ; Mice ; *TDP-43 Proteinopathies/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Lobar Degeneration/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; Disease Models, Animal ; *Cognitive Dysfunction ; RNA ; }, abstract = {TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic acid-binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed endogenous models of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43[K145Q] resulted in stress-induced nuclear TDP-43 foci and loss of TDP-43 function in primary mouse and human-induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43[K145Q] mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of human FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies.}, } @article {pmid37819399, year = {2023}, author = {Feng, CY and Han, JR and Lu, CY and Gu, L and Li, S and Lian, WH and Dong, L and Li, WJ}, title = {Telluribacter roseus sp. nov., Isolated from the Kumtag Desert Soil.}, journal = {Current microbiology}, volume = {80}, number = {12}, pages = {365}, pmid = {37819399}, issn = {1432-0991}, support = {32061143043//National Natural Science Foundation of China/ ; 32270076//National Natural Science Foundation of China/ ; 32000005//National Natural Science Foundation of China/ ; 2022xjkk1204//the Third Xinjiang Scientific Expedition Program/ ; 2023A1515012020//Guangdong Basic and Applied Basic Research Foundation, China/ ; MB2020KF05//Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases/ ; }, mesh = {*Soil ; Phylogeny ; RNA, Ribosomal, 16S/genetics ; Bacterial Typing Techniques ; DNA, Bacterial/genetics ; *Phospholipids/chemistry ; Fatty Acids/chemistry ; Sequence Analysis, DNA ; }, abstract = {A pink-pigmented bacterium, designated as strain SYSU D00476[T], was isolated from sandy soil collected from the Kumtag Desert in China. Colonies were opaque, smooth and of a slight convexity with a clearly defined border. Cells were rod-shaped, Gram-stain-negative, catalase- and oxidase-positive. Growth occurred at 4-45 ℃ (optimum at 28-30 ℃), pH 6.0-8.0 (optimum at 7.0), and with 0-3.0% NaCl (w/v, optimum at 0-2.0%). Major fatty acids (> 10%) were C16:0, summed feature 3 (C16:1 ω7c and/or C16:1 ω6c), iso-C17:0 3-OH and iso-C15:0. Polar lipids comprised of three unidentified polar aminolipids (ALs), two unidentified aminophosphoglycolipids (APLs), one unidentified glycolipid (GL) and three unidentified phospholipids (PLs). The predominant respiratory quinone was MK-7. The genomic DNA G + C content was 50.5%. The low digital DNA-DNA hybridization (dDDH, 27.4%) and average nucleotide identity (ANI, 85%) values between strain SYSU D00476[T] and Telluribacter humicola KCTC 42819[T] indicated that SYSU D00476[T] represent a distinct species. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SYSU D00476[T] belonged to the genus Telluribacter, showing 97.5% similarity with T. humicola KCTC 42819[T]. All these data support that strain SYSU D00476[T] represent a novel species of the genus Telluribacter within the family Spirosomataceae, named as Telluribacter roseus sp. nov. The type strain is SYSU D00476[T] (= KCTC 82285[T] = CGMCC 1.18647[T] = MCCC 1K04983[T]).}, } @article {pmid37819987, year = {2023}, author = {Zhang, Z and Sun, S}, title = {Linking ALS mutations to the disruption of the MHC-II pathway.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {43}, pages = {e2315240120}, pmid = {37819987}, issn = {1091-6490}, support = {R01 AG078948/AG/NIA NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; }, mesh = {*Antigen Presentation ; *Histocompatibility Antigens Class II/immunology ; Genes, MHC Class II ; Mutation ; }, } @article {pmid37821429, year = {2023}, author = {Zhang, S and Tong, M and Zheng, D and Huang, H and Li, L and Ungermann, C and Pan, Y and Luo, H and Lei, M and Tang, Z and Fu, W and Chen, S and Liu, X and Zhong, Q}, title = {C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {6360}, pmid = {37821429}, issn = {2041-1723}, mesh = {Animals ; Autophagy ; C9orf72 Protein/genetics/metabolism ; Catalysis ; Guanosine Triphosphate/metabolism ; Mammals/metabolism ; *Membrane Fusion/physiology ; Vacuoles/metabolism ; }, abstract = {The multi-subunit homotypic fusion and vacuole protein sorting (HOPS) membrane-tethering complex is required for autophagosome-lysosome fusion in mammals, yet reconstituting the mammalian HOPS complex remains a challenge. Here we propose a "hook-up" model for mammalian HOPS complex assembly, which requires two HOPS sub-complexes docking on membranes via membrane-associated Rabs. We identify Rab39A as a key small GTPase that recruits HOPS onto autophagic vesicles. Proper pairing with Rab2 and Rab39A enables HOPS complex assembly between proteoliposomes for its tethering function, facilitating efficient membrane fusion. GTP loading of Rab39A is important for the recruitment of HOPS to autophagic membranes. Activation of Rab39A is catalyzed by C9orf72, a guanine exchange factor associated with amyotrophic lateral sclerosis and familial frontotemporal dementia. Constitutive activation of Rab39A can rescue autophagy defects caused by C9orf72 depletion. These results therefore reveal a crucial role for the C9orf72-Rab39A-HOPS axis in autophagosome-lysosome fusion.}, } @article {pmid37821950, year = {2023}, author = {Košir, M and Možina, H and Podbregar, M}, title = {Skeletal muscle oxygenation during cardiopulmonary resuscitation as a predictor of return of spontaneous circulation: a pilot study.}, journal = {European journal of medical research}, volume = {28}, number = {1}, pages = {418}, pmid = {37821950}, issn = {2047-783X}, mesh = {Adult ; Humans ; Male ; Aged ; Female ; *Cardiopulmonary Resuscitation/methods ; Pilot Projects ; Return of Spontaneous Circulation ; Cerebrovascular Circulation/physiology ; *Out-of-Hospital Cardiac Arrest/therapy ; }, abstract = {BACKGROUND: Near-infrared spectroscopy (NIRS) provides regional tissue oxygenation (rSO2) even in pulseless states, such as out-of-hospital cardiac arrest (OHCA). Brain rSO2 seems to be important predictor of return of spontaneous circulation (ROSC) during cardiopulmonary resuscitation (CPR). Aim of our study was to explore feasibility for monitoring and detecting changes of skeletal muscle rSO2 during resuscitation.

METHODS: Skeletal muscle and brain rSO2 were measured by NIRS (SenSmart Model X-100, Nonin, USA) during CPR in adult patient with OHCA. Start (basal) rSO2, maximal during CPR (maximal) and difference between maximal-minimal rSO2 (delta-rSO2), were recorded. Patients were divided into ROSC and NO-ROSC group.

RESULTS: 20 patients [age: 66.0ys (60.5-79.5), 65% male] with OHCA [50% witnessed, 70% BLS, time to ALS 13.5 min (11.0-19.0)] were finally analyzed. ROSC was confirmed in 5 (25%) patients. Basal and maximal skeletal muscle rSO2 were higher in ROSC compared to NO-ROSC group [49.0% (39.7-53.7) vs. 15.0% (12.0-25.2), P =  0.006; 76.0% (52.7-80.5) vs. 34.0% (18.0-49.5), P =  0.005, respectively]. There was non-linear cubic relationship between time of collapse and basal skeletal muscle rSO2 in witnessed OHCA and without BLS (F-ratio = 9.7713, P =  0.0261). There was correlation between maximal skeletal muscle and brain rSO2 (n = 18, rho: 0.578, P =   0.0121).

CONCLUSIONS: Recording of skeletal muscle rSO2 during CPR in patients with OHCA is feasible. Basal and maximal skeletal muscle rSO2 were higher in ROSC compared to NO-ROSC group. Clinical trial registration number ClinicalTrials.gov, NCT04058925, registered on: 16th August 2019. URL of trial registry record: https://www.

CLINICALTRIALS: gov/ct2/show/NCT04058925?titles=Tissue+Oxygenation+During+Cardiopulmonary+Resuscitation+as+a+Predictor+of+Return+of+Spontaneous+Circulation&draw=2&rank=1 .}, } @article {pmid37822527, year = {2023}, author = {Colombo, E and Gentile, F and Maranzano, A and Doretti, A and Verde, F and Olivero, M and Gagliardi, D and Faré, M and Meneri, M and Poletti, B and Maderna, L and Corti, S and Corbo, M and Morelli, C and Silani, V and Ticozzi, N}, title = {The impact of upper motor neuron involvement on clinical features, disease progression and prognosis in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1249429}, pmid = {37822527}, issn = {1664-2295}, } @article {pmid37823580, year = {2023}, author = {Mehta, AK and Sarmet, M and Maiser, S and Meyer, JA and Kolodziejczak, S and Washington, K and Simmons, Z}, title = {Quality-of-life assessment instruments used across ALS clinics.}, journal = {Muscle & nerve}, volume = {68}, number = {6}, pages = {865-872}, doi = {10.1002/mus.27985}, pmid = {37823580}, issn = {1097-4598}, mesh = {Humans ; *Quality of Life ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Palliative Care ; Surveys and Questionnaires ; Ambulatory Care ; }, abstract = {INTRODUCTION/AIMS: Instruments have been developed to assess quality of life (QoL) among people with amyotrophic lateral sclerosis (ALS). It is unclear whether these are utilized regularly in the clinical setting to guide individual patient care. In this study we aimed to understand the current use of instruments and existing barriers to assessing QoL in clinical ALS care.

METHODS: An anonymous survey developed by Northeast ALS (NEALS) Consortium Palliative Committee members was distributed to all multidisciplinary NEALS members. Data were summarized via calculation of descriptive statistics. ALS Center characteristics were compared using chi-square and Fisher exact tests for categorical variables.

RESULTS: Seventy-three (6.4%) of the 1132 NEALS members responded to the survey, representing 148 clinics, 49.3% of whom reported assessing QoL during clinic visits. The most used ALS-specific instruments were the ALS Assessment Questionnaire (19.4%) and Amyotrophic Lateral Sclerosis Specific Quality of Life scale (16.6%). Barriers reported were uncertainty regarding which instrument to use and length of visits. QoL assessment was not significantly correlated with length of clinic visit but with access to specialty palliative care.

DISCUSSION: QoL assessments are performed by some, but not all, ALS centers during clinical visits. Although this study did have a low number of responding centers, the percentage, the proportion is similar to that seen in earlier studies, which limits the findings' generalizability. The value of QoL assessments' impact on outcomes should be further investigated and, if warranted, creative ways sought to increase the frequency of their use, including patient self-assessments before clinic and/or the use of teleheath to reduce the length of clinic visits.}, } @article {pmid37823684, year = {2024}, author = {Marlin, E and Valencia, M and Peregrín, N and Ferrero, R and Nicolás, MJ and Vinueza-Gavilanes, R and Pineda-Lucena, A and Artieda, J and Arrasate, M and Aragón, T}, title = {Pharmacological inhibition of the integrated stress response accelerates disease progression in an amyotrophic lateral sclerosis mouse model.}, journal = {British journal of pharmacology}, volume = {181}, number = {3}, pages = {495-508}, doi = {10.1111/bph.16260}, pmid = {37823684}, issn = {1476-5381}, support = {Predoctoral Fellowship//AC-CIMA/ ; Proyectos I+D 2017//Fundación para la Investigación Médica Aplicada/ ; 0011-0537-2018-000006 Predoctoral fellowship//Gobierno de Navarra, Departamento de Universidad, Innovación y Transformación Digital/ ; Intramural IdiSNA 2022//Instituto de Investigación Sanitaria de Navarra (IdiSNA)/ ; BFU2017-90043-P MICINN/ AEI/10.13039/501100011033//Ministerio de Ciencia e Innovación/ ; PID2020-120497RB-I00 MICINN/ AEI /10.13039/501100011//Ministerio de Ciencia e Innovación/ ; //Proyecto Intramural IdisNa 2022/ ; //Fundación para la Investigación Médica Aplicada (FIMA)/ ; 0011-0537-2018-000006//Departamento de Educación, Gobierno de Navarra/ ; //Asociación de Amigos (ADA)/ ; }, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Superoxide Dismutase-1/genetics ; Eukaryotic Initiation Factor-2B ; Superoxide Dismutase/metabolism ; Mice, Transgenic ; Disease Progression ; Disease Models, Animal ; }, abstract = {BACKGROUND AND PURPOSE: The integrated stress response (ISR) regulates translation in response to diverse stresses. ISR activation has been documented in amyotrophic lateral sclerosis (ALS) patients and ALS experimental models. In experimental models, both ISR stimulation and inhibition prevented ALS neurodegeneration; however, which mode of ISR regulation would work in patients is still debated. We previously demonstrated that the ISR modulator ISRIB (Integrated Stress Response InhiBitor, an eIF2B activator) enhances survival of neurons expressing the ALS neurotoxic allele SOD1 G93A. Here, we tested the effect of two ISRIB-like eIF2B activators (2BAct and PRXS571) in the disease progression of transgenic SOD1[G93A] mice.

EXPERIMENTAL APPROACH: After biochemical characterization in primary neurons, SOD1[G93A] mice were treated with 2BAct and PRXS571. Muscle denervation of vulnerable motor units was monitored with a longitudinal electromyographic test. We used a clinical score to document disease onset and progression; force loss was determined with the hanging wire motor test. Motor neuronal survival was assessed by immunohistochemistry.

KEY RESULTS: In primary neurons, 2BAct and PRXS571 relieve the ISR-imposed translational inhibition while maintaining high ATF4 levels. Electromyographic recordings evidenced an earlier and more dramatic muscle denervation in treated SOD1[G93A] mice that correlated with a decrease in motor neuron survival. Both compounds anticipated disease onset and shortened survival time.

CONCLUSION AND IMPLICATIONS: 2BAct and PRXS571 anticipate disease onset, aggravating muscle denervation and motor neuronal death of SOD1[G93A] mice. This study reveals that the ISR works as a neuroprotective pathway in ALS motor neurons and reveals the toxicity that eIF2B activators may display in ALS patients.}, } @article {pmid37827137, year = {2024}, author = {Heckmann, JG and Kiem, M and Immich, G}, title = {Forest Therapy as a Nature-Based Intervention: An Option for Neurological Rehabilitation?.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {56-63}, doi = {10.1159/000534533}, pmid = {37827137}, issn = {2504-2106}, mesh = {Humans ; *Medicine ; *Neurological Rehabilitation ; *Sleep Wake Disorders ; *Stroke/therapy ; *Dementia ; Observational Studies as Topic ; }, abstract = {BACKGROUND: Forest therapy demonstrates positive effects on mood, immune system, stress levels, and general well-being. Studies on depression, stress-related illnesses, sleep disorders, and arterial hypertension have provided evidence-based proof of this.

SUMMARY: The aim of this review was to examine the possible effects of forest therapy with regard to its evidence in the treatment of chronic neurological diseases such as stroke in the rehabilitation phase, Parkinson's disease, dementia, and multiple sclerosis. Therefore, the electronic databases Medline, Scopus, and Cochrane were searched for such clinical trials for the years 1970 to mid-2023 without language restriction. The literature search revealed only few studies with positive indications but too few cases to be able to make generalizable evidence-based statements. In terms of improvement in the Hamilton Depression Scale analysis of two studies in stroke patients showed slight benefits in the forest therapy group (standard mean difference -0.43; 95% CI: -0.76 to -0.10; p < 0.01). One observational study revealed a higher rate of stroke survival in patients living in marked greenness. Few nature-based interventions in dementia patients showed certain benefits in particular details.

KEY MESSAGES: There are no evidence-based results on the benefit of forest therapy for chronic neurological diseases. However, there are hints that forest therapy could have a positive benefit. Therefore, a proposal for forest therapy as a component of multimodal neurological rehabilitation is presented.

UNLABELLED: HintergrundDie Waldtherapie zeigt positive Auswirkungen auf die Stimmung, das Immunsystem, das Stressniveau und das allgemeine Wohlbefinden. Studien zu Depressionen, stressbedingten Erkrankungen, Schlafstörungen und arteriellem Bluthochdruck haben dies evidenzbasiert belegt.ZusammenfassungZiel dieser Übersichtsarbeit war es, die möglichen Wirkungen der Waldtherapie im Hinblick auf ihre Evidenz bei der Behandlung chronischer neurologischer Erkrankungen wie Schlaganfall in der Rehabilitationsphase, Morbus Parkinson, Demenz und Multiple Sklerose zu untersuchen. Dazu wurden die elektronischen Datenbanken Medline, Scopus und Cochrane für die Jahre 1970 bis Mitte 2023 ohne sprachliche Einschränkung nach solchen klinischen Studien durchsucht. Die Literaturrecherche ergab nur wenige Studien mit positiven Indikationen, aber zu wenigen Fällen, um verallgemeinerbare evidenzbasierte Aussagen machen zu können. Im Hinblick auf Verbesserung in der Hamilton Depressionsskala zeigte die Analyse von 2 Studien bei Schlaganfallpatienten leichte Vorteile der Waldtherapiegruppen (Standard Mean Difference −0.43; 95% CI: -0.76- -0,10; p < 0.01). Eine Beobachtungsstudie ergab eine höhere Schlaganfall-Überlebensrate bei Patienten, die in ausgeprägtem Grün leben. Einige naturbasierte Interventionen bei Demenzpatienten zeigten in einzelnen Parametern gewisse Vorteile.FazitEs gibt bis dato keine verallgemeinerbaren evidenzbasierten Ergebnisse zum Nutzen der Waldtherapie bei chronischen neurologischen Erkrankungen. Es gibt jedoch Hinweise, dass die Waldtherapie einen positiven Nutzen haben könnte. Es wird daher ein Vorschlag für eine Waldtherapie als Bestandteil einer multimodalen neurologischen Rehabilitation vorgestellt.}, } @article {pmid37827425, year = {2024}, author = {Jia, H and Li, Z and Guo, F and Hua, Z and Zhou, X and Li, X and Li, R and Liu, Q and Liu, Y and Dong, H}, title = {Cortical structure and the risk of amyotrophic lateral sclerosis: A bidirectional Mendelian randomization study.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {129}, number = {}, pages = {110872}, doi = {10.1016/j.pnpbp.2023.110872}, pmid = {37827425}, issn = {1878-4216}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Reproducibility of Results ; Magnetic Resonance Imaging/methods ; }, abstract = {BACKGROUND: Current observational studies indicate progressive brain atrophy is closely associated with the clinical feature of amyotrophic lateral sclerosis. However, it is unclear whether the changes in cortical structure are the cause or result of ALS. Our study aimed to investigate the causal relationship between cortical structure and ALS risk using a bidirectional two-sample MR study.

METHODS: We collected publicly available genome-wide association studies' summary statistics for cortical structure from UK Biobank and ENIGMA consortium (n = 33,992) and ALS from the Project MinE (n = 138,086). We used the inverse variance weighted method (IVW) as primary analysis in order to evaluate the causal effects. In addition, the weighted median and MR Egger methods were performed to ensure the robustness and reliability of the IVW results.

RESULTS: We found the decreased surface of the paracentral lobule and thickness of the frontal pole and middle temporal lobe were suggestively associated with an increased risk of ALS as well as the increased surface of medial orbitofrontal and middle temporal lobe. In another aspect, the causalities between the susceptibility to ALS and the volume of the transverse temporal gyrus and superior temporal gyrus were negative. Besides, the susceptibility to ALS might also contribute to an increased thickness of the postcentral gyrus and superior parietal gyrus.

CONCLUSION: In this two-sample MR analysis, we observed that multiple cortical brain regions are associated with a higher ALS risk. Further research into the underlying mechanisms is required to back up our findings.}, } @article {pmid37827570, year = {2024}, author = {McHutchison, CA and Wuu, J and McMillan, CT and Rademakers, R and Statland, J and Wu, G and Rampersaud, E and Myers, J and Hernandez, JP and Abrahams, S and Benatar, M and , }, title = {Temporal course of cognitive and behavioural changes in motor neuron diseases.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {4}, pages = {316-324}, pmid = {37827570}, issn = {1468-330X}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/diagnosis ; C9orf72 Protein/genetics ; *Motor Neuron Disease/genetics/complications ; *Cognitive Dysfunction/genetics/complications ; Cognition/physiology ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Cognitive and behavioural dysfunction may occur in people with motor neuron disease (MND), with some studies suggesting an association with the C9ORF72 repeat expansion. Their onset and progression, however, is poorly understood. We explored how cognition and behaviour change over time, and whether demographic, clinical and genetic factors impact these changes.

METHODS: Participants with MND were recruited through the Phenotype-Genotype-Biomarker study. Every 3-6 months, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was used to assess amyotrophic lateral sclerosis (ALS) specific (executive functioning, verbal fluency, language) and ALS non-specific (memory, visuospatial) functions. Informants reported on behaviour symptoms via semi-structured interview.

RESULTS: Participants with neuropsychological data at ≥3 visits were included (n=237, mean age=59, 60% male), of which 18 (8%) were C9ORF72 positive. Baseline cognitive impairment was apparent in 18 (8%), typically in ALS specific domains, and associated with lower education, but not C9ORF72 status. Cognition, on average, remained stable over time, with two exceptions: (1) C9ORF72 carriers declined in all ECAS domains, (2) 8%-9% of participants with baseline cognitive impairment further declined, primarily in the ALS non-specific domain, which was associated with less education. Behavioural symptoms were uncommon.

CONCLUSIONS: In this study, cognitive dysfunction was less common than previously reported and remained stable over time for most. However, cognition declines longitudinally in a small subset, which is not entirely related to C9ORF72 status. Our findings raise questions about the timing of cognitive impairment in MND, and whether it arises during early clinically manifest disease or even prior to motor manifestations.}, } @article {pmid37827876, year = {2023}, author = {Shimizu, T and Nakayama, Y and Hayashi, K and Mochizuki, Y and Matsuda, C and Haraguchi, M and Bokuda, K and Komori, T and Takahashi, K}, title = {Somatosensory pathway dysfunction in patients with amyotrophic lateral sclerosis in a completely locked-in state.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {156}, number = {}, pages = {253-261}, doi = {10.1016/j.clinph.2023.09.004}, pmid = {37827876}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Superoxide Dismutase-1 ; Evoked Potentials, Somatosensory/physiology ; Median Nerve ; }, abstract = {OBJECTIVE: To investigate somatosensory pathway function in patients with amyotrophic lateral sclerosis (ALS) dependent on invasive ventilation and in a completely locked-in state (CLIS).

METHODS: We examined median nerve somatosensory evoked potentials (SEPs) in 17 ALS patients in a CLIS, including 11 patients with sporadic ALS, one with familial ALS with genes not examined, four with a Cu/Zn superoxide-dismutase-1 (SOD1) gene variant (Val118Leu, Gly93Ser, Cys146Arg), and one with a fused-in-sarcoma gene variant (P525L). We evaluated N9, N13, N20 and P25, and central conduction time (CCT); the data were compared with those of 73 healthy controls.

RESULTS: N20 and N13 were abolished in 12 and 10 patients, and their latencies was prolonged in four and three patients, respectively. The CCT was prolonged in five patients with measurable N13 and N20. Two patients with SOD1 gene mutations had absent or slightly visible N9. Compared to the CCT and latencies and amplitudes of N13 and N20 in the controls, those in the patient cohort were significantly abnormal.

CONCLUSIONS: The central somatosensory pathway is severely involved in patients with ALS in a CLIS.

SIGNIFICANCE: Our findings suggest that median nerve SEP cannot be utilized for communication in patients with ALS in a CLIS.}, } @article {pmid37827904, year = {2023}, author = {Santiago, JA and Karthikeyan, M and Lackey, M and Villavicencio, D and Potashkin, JA}, title = {Diabetes: a tipping point in neurodegenerative diseases.}, journal = {Trends in molecular medicine}, volume = {29}, number = {12}, pages = {1029-1044}, pmid = {37827904}, issn = {1471-499X}, support = {R01 AG062176/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Brain/metabolism ; *Diabetes Mellitus/metabolism ; }, abstract = {Diabetes is associated with an increased risk and progression of Alzheimer's (AD) and Parkinson's (PD) diseases. Conversely, diabetes may confer neuroprotection against amyotrophic lateral sclerosis (ALS). It has been posited that perturbations in glucose and insulin regulation, cholesterol metabolism, and mitochondrial bioenergetics defects may underlie the molecular underpinnings of diabetes effects on the brain. Nevertheless, the precise molecular mechanisms remain elusive. Here, we discuss the evidence from molecular, epidemiological, and clinical studies investigating the impact of diabetes on neurodegeneration and highlight shared dysregulated pathways between these complex comorbidities. We also discuss promising antidiabetic drugs, molecular diagnostics currently in clinical trials, and outstanding questions and challenges for future pursuit.}, } @article {pmid37827930, year = {2023}, author = {Cassereau, J and Bernard, E and Genestet, S and Chebbah, M and Le Clanche, S and Verschueren, A and Couratier, P}, title = {Management of amyotrophic lateral sclerosis in clinical practice: Results of the expert consensus using the Delphi methodology.}, journal = {Revue neurologique}, volume = {179}, number = {10}, pages = {1134-1144}, doi = {10.1016/j.neurol.2023.07.011}, pmid = {37827930}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Riluzole/therapeutic use ; Motor Neurons ; Diagnosis, Differential ; Phenylbutyrates ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare disease characterized by a progressive and irreversible degeneration of upper and lower motor neurons leading to death. In France, limited data exist describing the criteria used in clinical practice for diagnosis and follow-up, and how novel therapies may fit in. The objective of this Delphi panel was to obtain an overview of current French practices in ALS diagnosis, management, and follow-up by determining the scales and criteria used in clinical practice outside of clinical trials, as well as the place of a future treatment like AMX0035, acting on endoplasmic reticulum (ER) stress and mitochondrial dysfunction, in the current therapeutic strategies. A questionnaire was administered to 24 ALS healthcare providers practicing in ALS centers in France. Two rounds of remote voting were organized, before proposition of final consensus statements. Consensus was considered reached when at least 66% of the voters agreed. Consensus were obtained to define the new Gold Coast criteria as the ones used in clinical practice to establish the diagnosis of ALS, thus replacing the revised El Escorial criteria, considered too complex and now mainly used to characterize the patient populations to be included in clinical trials. The clinical factors considered to establish ALS diagnosis are mainly the demonstration of progression of the motor deficit and elimination of differential diagnoses. The ALSFRS-R scale is used in daily clinical practice to assess patient's functional impairment in terms of number of points lost, with the bulbar, respiratory, and fine motor subscores being the most important to evaluate independently. A critical medical need was identified regarding the provision of new therapeutic alternatives in ALS. The panel members would support the earliest management of patients. In this landscape, based on data from a very encouraging phase II (Centaur trial), AMX0035 represents a new tool of choice in current treatment strategies for all patients for whom experts are confident in the diagnosis of ALS, in combination with riluzole. These results will need to be confirmed by the ongoing phase III trial (Phoenix trial).}, } @article {pmid37827960, year = {2023}, author = {Todd, TW and Shao, W and Zhang, YJ and Petrucelli, L}, title = {The endolysosomal pathway and ALS/FTD.}, journal = {Trends in neurosciences}, volume = {46}, number = {12}, pages = {1025-1041}, pmid = {37827960}, issn = {1878-108X}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; RF1 AG062171/AG/NIA NIH HHS/United States ; RF1 AG062077/AG/NIA NIH HHS/United States ; R21 NS127331/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R01 NS117461/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics ; Mutation ; Autophagy ; C9orf72 Protein/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are considered to be part of a disease spectrum that is associated with causative mutations and risk variants in a wide range of genes. Mounting evidence indicates that several of these genes are linked to the endolysosomal system, highlighting the importance of this pathway in ALS/FTD. Although many studies have focused on how disruption of this pathway impacts on autophagy, recent findings reveal that this may not be the whole picture: specifically, disrupting autophagy may not be sufficient to induce disease, whereas disrupting the endolysosomal system could represent a crucial pathogenic driver. In this review we discuss the connections between ALS/FTD and the endolysosomal system, including a breakdown of how disease-associated genes are implicated in this pathway. We also explore the potential downstream consequences of disrupting endolysosomal activity in the brain, outside of an effect on autophagy.}, } @article {pmid37828358, year = {2023}, author = {Abrahams, S}, title = {Neuropsychological impairment in amyotrophic lateral sclerosis-frontotemporal spectrum disorder.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {11}, pages = {655-667}, pmid = {37828358}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Frontotemporal Dementia/complications ; *Neurodegenerative Diseases ; *Cognitive Dysfunction ; *Cognition Disorders/diagnosis/etiology ; Neuropsychological Tests ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a rapid course, characterized by motor neuron dysfunction, leading to progressive disability and death. This Review, which is aimed at neurologists, psychologists and other health professionals who follow evidence-based practice relating to ALS and frontotemporal dementia (FTD), examines the neuropsychological evidence that has driven the reconceptualization of ALS as a spectrum disorder ranging from a pure motor phenotype to ALS-FTD. It focuses on changes in cognition and behaviour, which vary in severity across the spectrum: around 50% individuals with ALS are within the normal range, 15% meet the criteria for ALS-FTD, and the remaining 35% are in the mid-spectrum range with milder and more focal impairments. The cognitive impairments include deficits in verbal fluency, executive functions, social cognition and language, and apathy is the most prevalent behavioural change. The pattern and severity of cognitive and behavioural change predicts underlying regional cerebral dysfunction from brain imaging and post-mortem pathology. Our increased recognition of cognition and behaviour as part of the ALS phenotype has led to the development and standardization of assessment tools, which have been incorporated into research and clinical care. Measuring change over the course of the disease is vital for clinical trials, and neuropsychology is proving to be a biomarker for the earliest preclinical changes.}, } @article {pmid37828541, year = {2023}, author = {Richardson, PJ and Smith, DP and de Giorgio, A and Snetkov, X and Almond-Thynne, J and Cronin, S and Mead, RJ and McDermott, CJ and Shaw, PJ}, title = {Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {12}, number = {1}, pages = {47}, pmid = {37828541}, issn = {2047-9158}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Janus Kinase Inhibitors/therapeutic use ; *Neurodegenerative Diseases ; Central Nervous System/metabolism ; Janus Kinases/metabolism/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with other multifactorial diseases, it is likely that drugs will need to target multiple disease processes and cell types to be effective. We review here the role of Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signalling in ALS, confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph, and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons, glia, muscle fibres, and blood cells. Specifically, we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease. Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system. Therefore, we recommend that this drug be tested in appropriately designed clinical trials for ALS.}, } @article {pmid37830099, year = {2023}, author = {Berlowitz, DJ and Mathers, S and Hutchinson, K and Hogden, A and Carey, KA and Graco, M and Whelan, BM and Charania, S and Steyn, F and Allcroft, P and Crook, A and Sheers, NL}, title = {The complexity of multidisciplinary respiratory care in amyotrophic lateral sclerosis.}, journal = {Breathe (Sheffield, England)}, volume = {19}, number = {3}, pages = {220269}, pmid = {37830099}, issn = {1810-6838}, abstract = {UNLABELLED: Motor neurone disease/amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no known cure, where death is usually secondary to progressive respiratory failure. Assisting people with ALS through their disease journey is complex and supported by clinics that provide comprehensive multidisciplinary care (MDC). This review aims to apply both a respiratory and a complexity lens to the key roles and areas of practice within the MDC model in ALS. Models of noninvasive ventilation care, and considerations in the provision of palliative therapy, respiratory support, and speech and language therapy are discussed. The impact on people living with ALS of both inequitable funding models and the complexity of clinical care decisions are illustrated using case vignettes. Considerations of the impact of emerging antisense and gene modifying therapies on MDC challenges are also highlighted. The review seeks to illustrate how MDC members contribute to collective decision-making in ALS, how the sum of the parts is greater than any individual care component or health professional, and that the MDC per se adds value to the person living with ALS. Through this approach we hope to support clinicians to navigate the space between what are minimum, guideline-driven, standards of care and what excellent, person-centred ALS care that fully embraces complexity could be.

EDUCATIONAL AIMS: To highlight the complexities surrounding respiratory care in ALS.To alert clinicians to the risk that complexity of ALS care may modify the effectiveness of any specific, evidence-based therapy for ALS.To describe the importance of person-centred care and shared decision-making in optimising care in ALS.}, } @article {pmid37831200, year = {2023}, author = {Latorre-Rodríguez, AR and Huang, J and Schaheen, L and Smith, MA and Hashimi, S and Bremner, RM and Mittal, SK}, title = {Diagnosis and management of anastomotic leaks after Ivor Lewis esophagectomy: a single-center experience.}, journal = {Langenbeck's archives of surgery}, volume = {408}, number = {1}, pages = {397}, pmid = {37831200}, issn = {1435-2451}, mesh = {Humans ; *Anastomotic Leak/diagnosis/etiology/therapy ; Esophagectomy/adverse effects ; *Esophageal Neoplasms/surgery ; Endoscopy, Gastrointestinal/adverse effects ; Retrospective Studies ; Postoperative Complications/diagnosis/epidemiology/etiology ; Anastomosis, Surgical/adverse effects ; Treatment Outcome ; }, abstract = {PURPOSE: Esophageal anastomotic leaks (ALs) after esophagectomy are a common and serious complication. The incidence, diagnostic approach, and management have changed over time. We described the diagnosis and management of patients who developed an esophageal AL after an Ivor Lewis esophagectomy at our center.

METHODS: After IRB approval, we queried our prospectively maintained database for patients who developed an esophageal AL after esophagectomy from August 2016 through July 2022. Data pertaining to demographics, comorbidities, surgical and oncological characteristics, and clinical course were extracted and analyzed.

RESULTS: During the study period, 145 patients underwent an Ivor Lewis esophagectomy; 10 (6.9%) developed an AL, diagnosed a median of 7.5 days after surgery, and detected by enteric contents in wound drains (n = 3), endoscopy (n = 3), CT (n = 2), and contrast esophagogram (n = 2). Nine patients (90%) had an increasing white blood cell count and additional signs of sepsis. One asymptomatic patient was identified by contrast esophagography. All patients received enteral nutritional support, intravenous antibiotics, and antifungals. Primary treatment of ALs included endoscopic placement of a self-expanding metal stent (SEMS; n = 6), surgery (n = 2), and SEMS with endoluminal vacuum therapy (n = 2). One patient required surgery after SEMS placement. The median length of ICU and total hospital stays were 11.5 and 22.5 days, respectively. There was no 30-day mortality.

CONCLUSION: The incidence of esophageal ALs at our center is similar to that of other high-volume centers. Most ALs can be managed without surgery; however, ALs remain a significant source of postoperative morbidity despite clinical advancements that have improved mortality.}, } @article {pmid37831552, year = {2023}, author = {Trabelsi, T and Esposito, VJ and Francisco, JS}, title = {Spectroscopy and Photochemistry of Aluminum-Bearing Species in the Universe.}, journal = {Accounts of chemical research}, volume = {56}, number = {21}, pages = {3045-3052}, doi = {10.1021/acs.accounts.3c00481}, pmid = {37831552}, issn = {1520-4898}, abstract = {ConspectusMetal-bearing molecules impact the chemical and physical environment of many astronomical sources such as the circumstellar envelopes of large asymptotic giant branch and red supergiant stars, the interstellar medium, and planetary atmospheres (e.g., ablation of ∼20 tons per day into the Earth's upper atmosphere). In recent decades, the number of successfully detected metal-containing molecules has increased via rotational spectroscopic observations, which are driven by theoretical and experimental investigations. Following formation, the ultimate fate of each species (stabilization, dissociation, etc.) is determined by its electronic structure and electronic spectroscopic properties as it encounters the pervasive radiation fields in the vacuum of space. Studying these properties can evince the possibility of detection and predict the impact each molecule has on its surrounding environment. Aluminum, one of the most abundant elements and metals, is distributed throughout the universe as a constituent of gas-phase molecules (e.g., AlO, AlOH, AlCl, etc.) as well as condensed onto solid dust grains such as Al2O3. Free gas-phase aluminum-bearing molecules are synthesized by nonthermal equilibrium processes such as shocks and pulsations near the stellar photosphere or via the reaction of molecules on the surface of dust grains. Recent investigations in our research group utilizing quantum chemical methods, such as coupled cluster (CCSD(T) and CCSD(T)-F12) and multireference configuration interaction (MRCI) with large basis sets, have explored a wide breadth of spectroscopy and photochemistry of small (triatomic and tetratomic) aluminum-bearing molecules, including Al-H, Al-C, Al-N, Al-O, Al-Si, Al-P, and Al-S bonds, among others. The ground-state spectroscopy (rotational and vibrational) of various aluminum-bearing molecules is discussed in the context of experimental and observational detection potentials. These detection potentials depend on various factors, such as the magnitude of the permanent dipole moment (PDM) and the population of states yielding transition frequencies in detectable ranges. Many aluminum-bearing molecules possess large PDMs and may be prime candidates for astronomical and laboratory detection. Within this discussion, interesting aspects of the ground-state molecular orbital configuration of OAlNO are shown to lead to an uncommon triplet ground state. Additionally, the electronic absorption spectrum of the quasi-isoenergetic ground-state isomers of AlOSO is discussed as a sensitive method for detecting this species and differentiating between the two isomers. Finally, photochemical mechanisms key to the production of AlO and AlOH in low-density regions and the destruction of AlCO and AlOC are also discussed in order to understand the radiation-induced formation and destruction of these molecules.}, } @article {pmid37831677, year = {2023}, author = {Kim, JA and Jang, H and Choi, Y and Min, YG and Hong, YH and Sung, JJ and Choi, SJ}, title = {Subclinical articulatory changes of vowel parameters in Korean amyotrophic lateral sclerosis patients with perceptually normal voices.}, journal = {PloS one}, volume = {18}, number = {10}, pages = {e0292460}, pmid = {37831677}, issn = {1932-6203}, mesh = {Humans ; *Dysarthria/diagnosis/etiology ; *Amyotrophic Lateral Sclerosis ; Speech Intelligibility ; Phonetics ; Republic of Korea ; Speech Acoustics ; }, abstract = {The available quantitative methods for evaluating bulbar dysfunction in patients with amyotrophic lateral sclerosis (ALS) are limited. We aimed to characterize vowel properties in Korean ALS patients, investigate associations between vowel parameters and clinical features of ALS, and analyze subclinical articulatory changes of vowel parameters in those with perceptually normal voices. Forty-three patients with ALS (27 with dysarthria and 16 without dysarthria) and 20 healthy controls were prospectively collected in the study. Dysarthria was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R) speech subscores, with any loss of 4 points indicating the presence of dysarthria. The structured speech samples were recorded and analyzed using Praat software. For three corner vowels (/a/, /i/, and /u/), data on the vowel duration, fundamental frequency, frequencies of the first two formants (F1 and F2), harmonics-to-noise ratio, vowel space area (VSA), and vowel articulation index (VAI) were extracted from the speech samples. Corner vowel durations were significantly longer in ALS patients with dysarthria than in healthy controls. The F1 frequency of /a/, F2 frequencies of /i/ and /u/, the VSA, and the VAI showed significant differences between ALS patients with dysarthria and healthy controls. The area under the curve (AUC) was 0.912. The F1 frequency of /a/ and the VSA were the major determinants for differentiating ALS patients who had not yet developed apparent dysarthria from healthy controls (AUC 0.887). In linear regression analyses, as the ALSFRS-R speech subscore decreased, both the VSA and VAI were reduced. In contrast, vowel durations were found to be rather prolonged. The analyses of vowel parameters provided a useful metric correlated with disease severity for detecting subclinical bulbar dysfunction in ALS patients.}, } @article {pmid37832380, year = {2023}, author = {Kwon, S and Kim, B and Han, KD and Jung, W and Cho, EB and Yang, JH and Shin, DW and Min, JH}, title = {Increased risk of myocardial infarction in amyotrophic lateral sclerosis: A nationwide cohort study in South Korea.}, journal = {Journal of the neurological sciences}, volume = {454}, number = {}, pages = {120829}, doi = {10.1016/j.jns.2023.120829}, pmid = {37832380}, issn = {1878-5883}, mesh = {Humans ; Male ; Female ; Cohort Studies ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Myocardial Infarction/epidemiology ; Obesity ; Incidence ; }, abstract = {BACKGROUND: The risk of myocardial infarction (MI), the major form of CVD, in amyotrophic lateral sclerosis (ALS) is currently unknown. We investigated the risk of MI in ALS and analyzed the effect of ALS-related physical disability on the risk of MI using the Korean National Health Insurance Service database.

METHODS: A total of 659 ALS patients and 10,927 non-ALS participants were finally selected between January 1, 2011, and December 31, 2015. A Cox hazard regression model was used to examine the hazard ratios (HRs) for MI in ALS after adjustment for potential confounders.

RESULTS: The incidence rate of MI was 26.2 per 1000 person-years, and the adjusted HR (aHR) for MI in ALS patients was 10.6 (95% confidence interval [CI] 7.2-15.4) compared with the controls. ALS patients who developed physical disability had an even higher risk of MI (aHR 18.6, 95% CI 11.5-30.0) compared with those who did not develop disability (aHR 7.4, 95% CI 4.6-11.9). The increased risk of MI was more prominent in female subjects than in male subjects (aHR 17.8, 95% CI 10.8-29.4 vs. aHR 6.9, 95% CI 4.1-11.6, P for interaction 0.006) and in obese subjects than in non-obese subjects (aHR 17.8, 95% CI 10.5-30.1 vs. aHR 7.9, 95% CI 4.9-12.8, P for interaction 0.018).

CONCLUSIONS: Our findings suggest that the risk of MI is high in ALS patients compared with a control population, and the risk is more prominent in those who develop physical disability, or who are female or obese.}, } @article {pmid37832429, year = {2023}, author = {Migliorelli, L and Scoppolini Massini, L and Coccia, M and Villani, L and Frontoni, E and Squartini, S}, title = {A deep learning-based telemonitoring application to automatically assess oral diadochokinesis in patients with bulbar amyotrophic lateral sclerosis.}, journal = {Computer methods and programs in biomedicine}, volume = {242}, number = {}, pages = {107840}, doi = {10.1016/j.cmpb.2023.107840}, pmid = {37832429}, issn = {1872-7565}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Deep Learning ; Software ; }, abstract = {BACKGROUND AND OBJECTIVES: Timely identification of dysarthria progression in patients with bulbar-onset amyotrophic lateral sclerosis (ALS) is relevant to have a comprehensive assessment of the disease evolution. To this goal literature recognized the utmost importance of the assessment of the number of syllables uttered by a subject during the oral diadochokinesis (DDK) test.

METHODS: To support clinicians, this work proposes a remote deep learning-based system, which consists (i) of a web application to acquire audio tracks of bulbar-onset ALS patients and healthy control subjects while performing the oral DDK test (i.e., repeating the /pa/, /pa-ta-ka/ and /oo-ee/ syllables) and (ii) a DDK-AID network designed to process the acquired audio signals which have different duration and to output the number of per-task syllables repeated by the subject.

RESULTS: The DDK-AID network overcomes the comparative method achieving a mean Accuracy of 90.23 in counting syllables repeated by the eleven bulbar-onset ALS-patients while performing the oral DDK test.

CONCLUSIONS: The proposed remote monitoring system, in the light of the achieved performance, represents an important step towards the implementation of self-service telemedicine systems which may ensure customised care plans.}, } @article {pmid37832609, year = {2023}, author = {Rezaee, D and Saadatpour, F and Akbari, N and Zoghi, A and Najafi, S and Beyranvand, P and Zamani-Rarani, F and Rashidi, MA and Bagheri-Mohammadi, S and Bakhtiari, M}, title = {The role of microRNAs in the pathophysiology of human central nervous system: A focus on neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {92}, number = {}, pages = {102090}, doi = {10.1016/j.arr.2023.102090}, pmid = {37832609}, issn = {1872-9649}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Amyloid beta-Peptides ; *Alzheimer Disease/genetics/metabolism ; Central Nervous System/metabolism ; *Neoplasms ; }, abstract = {microRNAs (miRNAs) are suggested to play substantial roles in regulating the development and various physiologic functions of the central nervous system (CNS). These include neurogenesis, cell fate and differentiation, morphogenesis, formation of dendrites, and targeting non-neural mRNAs. Notably, deregulation of an increasing number of miRNAs is associated with several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and CNS tumors. They are particularly known to affect the amyloid β (Aβ) cleavage and accumulation, tau protein homeostasis, and expression of alpha-synuclein (α-syn), Parkin, PINK1, and brain-derived neurotrophic factor (BDNF) that play pivotal roles in the pathogenesis of neurodegenerative diseases. These include miR-16, miR-17-5p, miR-20a, miR-106a, miR-106b, miR-15a, miR-15b, miR-103, miR-107, miR-298, miR-328, miR-195, miR-485, and miR-29. In CNS tumors, several miRNAs, including miR-31, miR-16, and miR-21 have been identified to modulate tumorigenesis through impacting tumor invasion and apoptosis. In this review article, we have a look at the recent advances on our knowledge about the role of miRNAs in human brain development and functions, neurodegenerative diseases, and their clinical potentials.}, } @article {pmid37833013, year = {2023}, author = {Bryukhovetskiy, AS and Grivtsova, LY and Bogachev, SS and Ustyugov, AA and Nebogatikov, VO and Shurdov, MA}, title = {Technology of genomic balancing of chromatin of autologous hematopoietic stem cells for gene therapy of fatal immune-mediated diseases of civilization, extended life expectancy and sudden human death prevention.}, journal = {International review of neurobiology}, volume = {172}, number = {}, pages = {237-284}, doi = {10.1016/bs.irn.2023.07.005}, pmid = {37833013}, issn = {2162-5514}, mesh = {Rats ; Humans ; Animals ; Mice ; *Chromatin/metabolism ; *Quality of Life ; Rats, Wistar ; Hematopoietic Stem Cells/metabolism ; Genetic Therapy ; Life Expectancy ; Genomics ; DNA/metabolism ; Technology ; Death, Sudden ; Civilization ; }, abstract = {A biotechnology for personalized ex vivo gene therapy based on molecular genomic balancing of hematopoietic stem cell (HSC) chromatin with nucleosome monomers of human genomic DNA (hDNA[nmr]) has been developed and implemented in the clinic to change (to "correct") mutant chromosome loci genomes of dominant HSC clones that form mono- and oligoclonal hematopoiesis during aging and major (oncological, cardiovascular, neurodegenerative and autoimmune) fatal immune-mediated diseases of civilization. A fundamentally new biotechnological approach has been applied to the delivery of genetic material into eukaryotic stem and progenitor cells by establishing an artificial "recombinogenic situation" in them to induce homologous recombination (equivalent replacement) of mutant DNA regions with healthy hDNA[nmr]. In experimental preclinical trials, the effectiveness of genomic balancing technology has been proven to reduce the risk of sudden death in old animals and to increase the lifespan of outbred mice by 30% and Wistar rats by 57%. The improvement in their quality of life, compared with the control, is explained by an increase in the telomeric regions of the HSCs and HPCs chromosomes by 1.5-2 times. The potential of the technology to slow down the hereditary neurodegenerative diseases on the model of amyotrophic lateral sclerosis is shown. The effectiveness of this technology in clinical practice is presented on the example of a terminal patient with stage 4 neuroendocrine cancer. This technology used in the treatment of a number of oncological, neurodegenerative, autoimmune and hereditary diseases with clonal hematopoiesis is able to arrest the progression of the disease, prevent its recurrence, prolong the active life of a person, increase the average life expectancy and prevent sudden death.}, } @article {pmid37833071, year = {2023}, author = {}, title = {Erratum: Huh et al., "Time Course of Alterations in Adult Spinal Motoneuron Properties in the SOD1(G93A) Mouse Model of ALS".}, journal = {eNeuro}, volume = {10}, number = {10}, pages = {}, doi = {10.1523/ENEURO.0370-23.2023}, pmid = {37833071}, issn = {2373-2822}, } @article {pmid37834094, year = {2023}, author = {Jellinger, KA}, title = {The Spectrum of Cognitive Dysfunction in Amyotrophic Lateral Sclerosis: An Update.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834094}, issn = {1422-0067}, support = {000//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; Brain/pathology ; *Cognition Disorders/pathology ; *Cognitive Dysfunction/pathology ; *Neurodegenerative Diseases/pathology ; *Pick Disease of the Brain/pathology ; }, abstract = {Cognitive dysfunction is an important non-motor symptom in amyotrophic lateral sclerosis (ALS) that has a negative impact on survival and caregiver burden. It shows a wide spectrum ranging from subjective cognitive decline to frontotemporal dementia (FTD) and covers various cognitive domains, mainly executive/attention, language and verbal memory deficits. The frequency of cognitive impairment across the different ALS phenotypes ranges from 30% to 75%, with up to 45% fulfilling the criteria of FTD. Significant genetic, clinical, and pathological heterogeneity reflects deficits in various cognitive domains. Modern neuroimaging studies revealed frontotemporal degeneration and widespread involvement of limbic and white matter systems, with hypometabolism of the relevant areas. Morphological substrates are frontotemporal and hippocampal atrophy with synaptic loss, associated with TDP-43 and other co-pathologies, including tau deposition. Widespread functional disruptions of motor and extramotor networks, as well as of frontoparietal, frontostriatal and other connectivities, are markers for cognitive deficits in ALS. Cognitive reserve may moderate the effect of brain damage but is not protective against cognitive decline. The natural history of cognitive dysfunction in ALS and its relationship to FTD are not fully understood, although there is an overlap between the ALS variants and ALS-related frontotemporal syndromes, suggesting a differential vulnerability of motor and non-motor networks. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of cognitive impairment in ALS, which might even serve as novel targets for effective disease-modifying therapies.}, } @article {pmid37834128, year = {2023}, author = {Huber, K and Szerenos, E and Lewandowski, D and Toczylowski, K and Sulik, A}, title = {The Role of Adipokines in the Pathologies of the Central Nervous System.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834128}, issn = {1422-0067}, mesh = {Humans ; Adipokines/metabolism ; Central Nervous System/metabolism ; *Alzheimer Disease/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Adipose Tissue/metabolism ; }, abstract = {Adipokines are protein hormones secreted by adipose tissue in response to disruptions in physiological homeostasis within the body's systems. The regulatory functions of adipokines within the central nervous system (CNS) are multifaceted and intricate, and they have been identified in a number of pathologies. Therefore, specific adipokines have the potential to be used as biomarkers for screening purposes in neurological dysfunctions. The systematic review presented herein focuses on the analysis of the functions of various adipokines in the pathogenesis of CNS diseases. Thirteen proteins were selected for analysis through scientific databases. It was found that these proteins can be identified within the cerebrospinal fluid either by their ability to modify their molecular complex and cross the blood-brain barrier or by being endogenously produced within the CNS itself. As a result, this can correlate with their measurability during pathological processes, including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, depression, or brain tumors.}, } @article {pmid37834374, year = {2023}, author = {Oprisan, AL and Popescu, BO}, title = {Dysautonomia in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834374}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Neurodegenerative Diseases/pathology ; Motor Neurons/pathology ; *Primary Dysautonomias/etiology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized in its typical presentation by a combination of lower and upper motor neuron symptoms, with a progressive course and fatal outcome. Due to increased recognition of the non-motor symptoms, it is currently considered a multisystem disorder with great heterogeneity, regarding genetical, clinical, and neuropathological features. Often underestimated, autonomic signs and symptoms have been described in patients with ALS, and various method analyses have been used to assess autonomic nervous system involvement. The aim of this paper is to offer a narrative literature review on autonomic disturbances in ALS, based on the scarce data available to date.}, } @article {pmid37834407, year = {2023}, author = {Baj, J and Flieger, W and Barbachowska, A and Kowalska, B and Flieger, M and Forma, A and Teresiński, G and Portincasa, P and Buszewicz, G and Radzikowska-Büchner, E and Flieger, J}, title = {Consequences of Disturbing Manganese Homeostasis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834407}, issn = {1422-0067}, mesh = {Humans ; Manganese/toxicity/metabolism ; *Diabetes Mellitus, Type 2 ; *Manganese Poisoning/metabolism ; Homeostasis ; *Neurodegenerative Diseases ; }, abstract = {Manganese (Mn) is an essential trace element with unique functions in the body; it acts as a cofactor for many enzymes involved in energy metabolism, the endogenous antioxidant enzyme systems, neurotransmitter production, and the regulation of reproductive hormones. However, overexposure to Mn is toxic, particularly to the central nervous system (CNS) due to it causing the progressive destruction of nerve cells. Exposure to manganese is widespread and occurs by inhalation, ingestion, or dermal contact. Associations have been observed between Mn accumulation and neurodegenerative diseases such as manganism, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. People with genetic diseases associated with a mutation in the gene associated with impaired Mn excretion, kidney disease, iron deficiency, or a vegetarian diet are at particular risk of excessive exposure to Mn. This review has collected data on the current knowledge of the source of Mn exposure, the experimental data supporting the dispersive accumulation of Mn in the brain, the controversies surrounding the reference values of biomarkers related to Mn status in different matrices, and the competitiveness of Mn with other metals, such as iron (Fe), magnesium (Mg), zinc (Zn), copper (Cu), lead (Pb), calcium (Ca). The disturbed homeostasis of Mn in the body has been connected with susceptibility to neurodegenerative diseases, fertility, and infectious diseases. The current evidence on the involvement of Mn in metabolic diseases, such as type 2 diabetes mellitus/insulin resistance, osteoporosis, obesity, atherosclerosis, and non-alcoholic fatty liver disease, was collected and discussed.}, } @article {pmid37834458, year = {2023}, author = {Shvetcov, A and Thomson, S and Spathos, J and Cho, AN and Wilkins, HM and Andrews, SJ and Delerue, F and Couttas, TA and Issar, JK and Isik, F and Kaur, S and Drummond, E and Dobson-Stone, C and Duffy, SL and Rogers, NM and Catchpoole, D and Gold, WA and Swerdlow, RH and Brown, DA and Finney, CA}, title = {Blood-Based Transcriptomic Biomarkers Are Predictive of Neurodegeneration Rather Than Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834458}, issn = {1422-0067}, support = {P01 AG060882/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis/genetics/metabolism ; *Neurodegenerative Diseases ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Transcriptome ; *Parkinson Disease/diagnosis/genetics/metabolism ; Biomarkers/metabolism ; }, abstract = {Alzheimer's disease (AD) is a growing global health crisis affecting millions and incurring substantial economic costs. However, clinical diagnosis remains challenging, with misdiagnoses and underdiagnoses being prevalent. There is an increased focus on putative, blood-based biomarkers that may be useful for the diagnosis as well as early detection of AD. In the present study, we used an unbiased combination of machine learning and functional network analyses to identify blood gene biomarker candidates in AD. Using supervised machine learning, we also determined whether these candidates were indeed unique to AD or whether they were indicative of other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Our analyses showed that genes involved in spliceosome assembly, RNA binding, transcription, protein synthesis, mitoribosomes, and NADH dehydrogenase were the best-performing genes for identifying AD patients relative to cognitively healthy controls. This transcriptomic signature, however, was not unique to AD, and subsequent machine learning showed that this signature could also predict PD and ALS relative to controls without neurodegenerative disease. Combined, our results suggest that mRNA from whole blood can indeed be used to screen for patients with neurodegeneration but may be less effective in diagnosing the specific neurodegenerative disease.}, } @article {pmid37836771, year = {2023}, author = {Colombo, E and Olla, S and Minnelli, C and Formato, A and Veroni, C and Corbisiero, S and Pericolo, M and Siguri, C and Mobbili, G and Agresti, C and Seneci, P}, title = {Synthesis and Characterization of Edaravone Analogues as Remyelinating Agents and Putative Mechanistic Probes.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {19}, pages = {}, pmid = {37836771}, issn = {1420-3049}, support = {2017/R/2//Fondazione Italiana Sclerosi Multipla/ ; }, mesh = {Humans ; Edaravone/pharmacology/therapeutic use ; *Antioxidants/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Oxidative Stress ; Esters/pharmacology ; }, abstract = {Edaravone (EDA), an antioxidant drug approved for the treatment of ischemic stroke and amyotrophic lateral sclerosis, was recently proposed as a remyelinating candidate for the treatment of multiple sclerosis. Here, we synthesized twelve EDA analogues 2b-4c showing three substitution patterns A-C, searching for improved remyelinating agents and putative molecular targets responsible for their regenerative activity. We profiled them in three primary assays to determine their stimulation of oligodendrocyte progenitor cell metabolism (tetrazolium MTT assay), their antioxidant potential (2,2-diphenyl-1-picrylhydrazyl-DPPH assay) and to predict their bioavailability (virtual ADME profile). Active 4'-carboxylate 2b, 4'-ester 2c and N[1]-carbamate-4'-ester 4a were further characterized, justifying their in vitro effects and selecting 4a as a putative EDA 1 prodrug suitable for in vivo testing.}, } @article {pmid37837507, year = {2024}, author = {Hamad, AA and Amer, BE and Abbas, NB and Alnajjar, AZ and Meshref, M}, title = {Prevalence and correlates of fatigue in amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {2}, pages = {485-493}, pmid = {37837507}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/epidemiology ; Prevalence ; Quality of Life ; Fatigue/etiology/complications ; }, abstract = {OBJECTIVES: This systematic review and meta-analysis aimed to determine the frequency and correlates of fatigue in patients with amyotrophic lateral sclerosis (ALS).

METHODS: Three databases were searched up to 2nd May 2023 to identify studies reporting fatigue frequency in ALS. Studies included had to identify ALS patients through one of ALS diagnostic criteria and measure fatigue by a validated tool with a specific cut-off value. Meta-analysis was conducted using RStudio's "meta" package with a random-effects model. Subgroup analyses and meta-regression explored the relationship between fatigue frequency in ALS and different covariates.

RESULTS: Eleven studies, compromising 1072 patients, met the inclusion criteria and were included in our analysis. The pooled frequency of fatigue across all studies was 48% (95% CI = 40% to 57%). Our subgroup analysis based on the ALSFRS-R revealed a higher frequency of fatigue in studies with lower scores (< 30) compared to those with higher scores (≥ 30), with a pooled frequency of 62% (95% CI = 43% to 79%) and 43% (95% CI = 37% to 49%), respectively. Also, the meta-regression analysis showed a significant negative association between fatigue and ALSFRS-R mean (P = 0.02). The included studies reported an association between fatigue and lower functional status and poorer quality of life in patients with ALS.

CONCLUSION: Our findings suggest that fatigue is prevalent in almost half of ALS patients and is associated with lower functional status and poorer quality of life, highlighting the importance of assessing and managing fatigue in ALS patients.}, } @article {pmid37837871, year = {2023}, author = {Nakamori, M and Shimizu, Y and Takahashi, T and Toko, M and Yamada, H and Hayashi, Y and Ushio, K and Yoshikawa, K and Hiraoka, A and Yoshikawa, M and Nagasaki, T and Mikami, Y and Maruyama, H}, title = {Swallowing sound index analysis using electronic stethoscope and artificial intelligence for patients with Parkinson's disease.}, journal = {Journal of the neurological sciences}, volume = {454}, number = {}, pages = {120831}, doi = {10.1016/j.jns.2023.120831}, pmid = {37837871}, issn = {1878-5883}, mesh = {Humans ; Deglutition/physiology ; *Parkinson Disease/diagnosis/diagnostic imaging ; *Deglutition Disorders/diagnostic imaging/etiology ; Artificial Intelligence ; *Stethoscopes ; Electronics ; }, abstract = {BACKGROUND AND PURPOSE: Several noninvasive tools assess swallowing disorders, including electronic stethoscope artificial intelligence (AI) analysis for remote diagnosis, with the potential for telemedicine. This study investigated the swallowing sound index in patients with Parkinson's disease (PD).

METHODS: This single-arm, open-label trial assessed the impact of cervical percutaneous interferential current stimulation on swallowing in patients with PD classified as Hoehn-Yahr stages 2-4. Stimulation was conducted for 8 weeks. Baseline data were used to examine the link between the swallowing sound index and indicators such as videofluoroscopy (VF). Furthermore, we examined changes in the swallowing sound index after the intervention.

RESULTS: Twenty-five patients were included. The swallowing sound index in patients with PD was higher than that in those with amyotrophic lateral sclerosis but considerably lower than that in healthy controls. The number of patients with normal EAT-10 scores positively correlated with the swallowing sound index, whereas elevated C-reactive protein levels were negatively correlated with the swallowing sound index. However, the index displayed no correlation with other indicators, including the VF results. Despite the intervention, the index remained unchanged throughout the study.

CONCLUSION: In patients with PD, a decrease in the swallowing sound index suggests a potential association between swallowing disorders and the risk of aspiration pneumonia.

TRIAL REGISTRATION NUMBER: jRCTs062220013.}, } @article {pmid37838312, year = {2023}, author = {Kumar, R and Malik, MZ and Thanaraj, TA and Bagabir, SA and Haque, S and Tambuwala, M and Haider, S}, title = {A computational biology approach to identify potential protein biomarkers and drug targets for sporadic amyotrophic lateral sclerosis.}, journal = {Cellular signalling}, volume = {112}, number = {}, pages = {110915}, doi = {10.1016/j.cellsig.2023.110915}, pmid = {37838312}, issn = {1873-3913}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Neurodegenerative Diseases ; Molecular Docking Simulation ; Proteins ; Computational Biology ; Biomarkers ; *Cyclosporins/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the loss of upper and lower motor neurons. The sporadic ALS (sALS) is a multigenic disorder and the complex mechanisms underlying its onset are still not fully delineated. Despite the recent scientific advancements, certain aspects of ALS pathogenic targets need to be yet clarified. The aim of the presented study is to identify potential genetic biomarkers and drug targets for sALS, by analysing gene expression profiles, presented in the publicly available GSE68605 dataset, of motor neurons cells obtained from sALS patients. We used different computational approaches including differential expression analysis, protein network mapping, candidate protein biomarker (CPB) identification, elucidation of the role of functional modules, and molecular docking analysis. The resultant top ten up- and downregulated genes were further used to construct protein-protein interaction network (PPIN). The PPIN analysis resulted in identifying four CPBs (namely RIOK2, AKT1, CTNNB1, and TNF) that commonly overlapped with one another in network parameters (degree, bottleneck and maximum neighbourhood component). The RIOK2 protein emerged as a potential mediator of top five functional modules that are associated with RNA binding, lipoprotein particle receptor binding in pre-ribosome, and interferon, cytokine-mediated signaling pathway. Furthermore, molecular docking analysis revealed that cyclosporine exhibited the highest binding affinity (-8.6 kJ/mol) with RIOK2, and surpassed the FDA-approved ALS drugs, such as riluzole and edaravone. This suggested that cyclosporine may serve as a promising candidate for targeting RIOK2 downregulation observed in sALS patients. In order to validate our computational results, it is suggested that in vitro and in vivo studies may be conducted in future to provide a more detailed understanding of ALS diagnosis, prognosis, and therapeutic intervention.}, } @article {pmid37838538, year = {2024}, author = {Wang, SA and Lee, HW and Ko, YC and Sun, JT and Matsuyama, T and Lin, CH and Hsieh, MJ and Chiang, WC and Ma, MH}, title = {Effect of crew ratio of advanced life support-trained personnel on patients with out-of-hospital cardiac arrest: A systematic review and meta-analysis.}, journal = {Journal of the Formosan Medical Association = Taiwan yi zhi}, volume = {123}, number = {5}, pages = {561-570}, doi = {10.1016/j.jfma.2023.10.008}, pmid = {37838538}, issn = {0929-6646}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; *Emergency Medical Services ; *Advanced Cardiac Life Support ; Cardiopulmonary Resuscitation ; Taiwan ; Return of Spontaneous Circulation ; Japan ; }, abstract = {BACKGROUND/PURPOSE: This review aimed to investigate the effect of crew ratios of on-scene advanced life support (ALS)-trained personnel on patients with out-of-hospital cardiac arrest (OHCA).

METHODS: We systematically searched PubMed, Ovid EMBASE, and the Cochrane Central Register of Controlled Trials databases from the inception date until September 30, 2022, for eligible studies. Two reviewers independently screened the studies for relevance, extracted data, and quality. We compared the effect of the ratio of on-scene ALS-trained personnel >50 % to those with a ratio ≤50 % among prehospital personnel on the clinical outcomes of OHCA patients. The primary outcome was survival-to-discharge and secondary outcomes were any return of spontaneous circulation (ROSC), sustained ROSC (≥2 h), and favourable neurological outcome at discharge (cerebral performance category scores: 1 or 2). Pooled odds ratios (ORs) were calculated, and the certainty of evidence was assessed.

RESULTS: From 10,864 references, we identified four non-randomised studies, including 16,475 patients. Two studies were performed in Japan and two in Taiwan. There were significant differences in survival-to-discharge (OR: 1.24, 95 % confidence interval [CI]: 1.07-1.44, I[2]: 7 %), any ROSC (OR:1.22, 95 % CI: 1.04-1.43, I[2]: 74 %) and sustained ROSC (OR: 1.39, 95 % CI: 1.16-1.65, I[2]: 40 %), but insignificant differences in favourable neurological outcome at discharge. The overall certainty of evidence was rated as very low for all outcomes.

CONCLUSION: Prehospital ALS care with a ratio of on-scene ALS-trained personnel >50 % could improve OHCA patient outcomes than crew ratios ≤50 %. Further studies are required to reach a robust conclusion.}, } @article {pmid37838698, year = {2023}, author = {Zeballos C, MA and Moore, HJ and Smith, TJ and Powell, JE and Ahsan, NS and Zhang, S and Gaj, T}, title = {Mitigating a TDP-43 proteinopathy by targeting ataxin-2 using RNA-targeting CRISPR effector proteins.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {6492}, pmid = {37838698}, issn = {2041-1723}, support = {R01 GM141296/GM/NIGMS NIH HHS/United States ; T32 EB019944/EB/NIBIB NIH HHS/United States ; U01 NS122102/NS/NINDS NIH HHS/United States ; R01 NS123556/NS/NINDS NIH HHS/United States ; }, mesh = {Mice ; Animals ; Ataxin-2/genetics ; RNA/metabolism ; *TDP-43 Proteinopathies/genetics/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {The TDP-43 proteinopathies, which include amyotrophic lateral sclerosis and frontotemporal dementia, are a devastating group of neurodegenerative disorders that are characterized by the mislocalization and aggregation of TDP-43. Here we demonstrate that RNA-targeting CRISPR effector proteins, a programmable class of gene silencing agents that includes the Cas13 family of enzymes and Cas7-11, can be used to mitigate TDP-43 pathology when programmed to target ataxin-2, a modifier of TDP-43-associated toxicity. In addition to inhibiting the aggregation and transit of TDP-43 to stress granules, we find that the in vivo delivery of an ataxin-2-targeting Cas13 system to a mouse model of TDP-43 proteinopathy improved functional deficits, extended survival, and reduced the severity of neuropathological hallmarks. Further, we benchmark RNA-targeting CRISPR platforms against ataxin-2 and find that high-fidelity forms of Cas13 possess improved transcriptome-wide specificity compared to Cas7-11 and a first-generation effector. Our results demonstrate the potential of CRISPR technology for TDP-43 proteinopathies.}, } @article {pmid37838979, year = {2024}, author = {Jagadish, A and Shankaranarayana, AM and Natarajan, M and Solomon, JM}, title = {Transcranial direct current stimulation for fatigue in neurological conditions: A systematic scoping review.}, journal = {Physiotherapy research international : the journal for researchers and clinicians in physical therapy}, volume = {29}, number = {1}, pages = {e2054}, doi = {10.1002/pri.2054}, pmid = {37838979}, issn = {1471-2865}, mesh = {Humans ; *Brain Injuries, Traumatic ; Fatigue/therapy/etiology ; *Multiple Sclerosis/complications/therapy ; *Parkinson Disease ; Quality of Life ; *Stroke ; *Transcranial Direct Current Stimulation/adverse effects ; }, abstract = {BACKGROUND AND PURPOSE: Fatigue following neurological conditions negatively impacts daily activities, reducing overall quality of life. Transcranial direct current stimulation (tDCS) for fatigue management is still underexplored. This scoping review explores its use in managing fatigue among various neurological conditions.

METHODS: A thorough literature search was carried out using PubMed, Scopus, CINAHL, Web of Science, Embase, ProQuest, and the Cochrane Library. Google Scholar and clinicaltrials.gov were manually searched for gray literature and ongoing trials, respectively. Regardless of the study design, all studies utilizing tDCS for the management of fatigue in various neurological conditions were considered. Two reviewers independently screened all the studies, following which the data were retrieved.

RESULTS: Studies employing tDCS for fatigue management across neurological conditions is as follows: Multiple sclerosis (MS) (n = 28, 66%), stroke (n = 5, 12%), Parkinson's disease (PD) (n = 4, 10%), post-polio syndrome (PPS) (n = 2, 5%), traumatic brain injury (TBI) (n = 2, 5%), and amyotrophic lateral sclerosis (n = 1, 2%). All the studies used anodal stimulation, with the common stimulation site being the left dorsolateral prefrontal cortex for MS, stroke, and PD. A stimulation intensity of 1.0-4.0 mA with a duration ranging from 15 to 30 min in 1 to 24 sessions were commonly reported. The Fatigue Severity Scale (n = 21) and Modified Fatigue Impact Scale (n = 17) were frequently implemented outcome measures. Regardless of the study design, 36/42 (85.7%) studies reported an improvement in fatigue scores in the tDCS group. The common adverse events noted were tingling (n = 8, 35%), headache (n = 6, 26%), and itching (n = 6, 26%).

DISCUSSION: Application of tDCS for fatigue was explored in individuals with stroke, PD, PPS, and TBI after MS. Even though a wide range of treatment parameters and outcome measures were adopted to assess and target fatigue, tDCS proves to have a promising role in alleviating this symptom.}, } @article {pmid37839080, year = {2024}, author = {Gaynor, LS and Yadollahikhales, G and Tsoy, E and Hall, M and Boxer, AL and Miller, BL and Grinberg, LT}, title = {C9orf72 Repeat Expansion Initially Presenting as Late-Onset Bipolar Disorder With Psychosis.}, journal = {The neurologist}, volume = {29}, number = {2}, pages = {109-112}, pmid = {37839080}, issn = {2331-2637}, support = {P50 AG023501/AG/NIA NIH HHS/United States ; K24 AG045333/AG/NIA NIH HHS/United States ; K24 AG053435/AG/NIA NIH HHS/United States ; R01 AG038791/AG/NIA NIH HHS/United States ; R01 AG060477/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; U54 NS092089/NS/NINDS NIH HHS/United States ; T32 AG023481/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; }, mesh = {Female ; Humans ; Adult ; Middle Aged ; *Bipolar Disorder/diagnosis/genetics ; C9orf72 Protein/genetics ; *Frontotemporal Dementia/diagnosis/genetics ; *Psychotic Disorders/diagnosis/genetics ; *Apraxias ; }, abstract = {INTRODUCTION: C9orf72 expansion is the most common genetic abnormality in behavioral variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis. Although psychiatric prodromes are common in C9orf72 expansion carriers, there are only scattered reported cases of primary psychiatric disorders, such as bipolar disorder, diagnosed at disease onset. Moreover, C9orf72 carrier status is rarely identified in bipolar disorder genetic studies.

CASE REPORT: A 51-year-old, right-handed woman with 16 years of education presented for evaluation of long-standing cognitive and behavioral change. She initially displayed symptoms of mania and florid, multimodal psychotic symptoms at age 39. Her bipolar disorder symptoms were initially responsive to medication; however, she later developed executive dysfunction and behavioral symptoms consistent with bvFTD. She became progressively nonverbal, and her limited speech was notable for speech apraxia. At the time of presentation, she demonstrated cortical sensory deficit, ideomotor and oral-buccal apraxia, and unstable gait. Neuroimaging revealed diffuse brain atrophy. Postmortem histopathological evaluation revealed frontotemporal lobar degeneration with TDP-43 inclusions, type B, and genetic study identified C9orf72 expansion. A detailed review of family history found a strong paternal history of bipolar disorder and substance use disorder.

CONCLUSIONS: We describe a rare case of C9orf72 expansion initially characterized by late-onset bipolar disorder and florid, multimodal psychotic symptoms, followed years later by bvFTD diagnosis. This report emphasizes the importance of completing a neurological examination, obtaining a detailed family history, and pursuing genetic screening to distinguish between primary psychiatric disorder and bvFTD in individuals who meet the criteria for late-onset bipolar disorder.}, } @article {pmid37839397, year = {2023}, author = {Helwa, N and Sharma, M and Vanama, MS and Helwa, Y and El-Falou, A}, title = {Colonic Anastomotic Leak Model in Swine.}, journal = {European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes}, volume = {64}, number = {4}, pages = {406-411}, doi = {10.1159/000534580}, pmid = {37839397}, issn = {1421-9921}, mesh = {Swine ; Animals ; *Anastomotic Leak/etiology ; *Colon/surgery ; Anastomosis, Surgical/adverse effects ; Postoperative Complications/etiology ; Models, Animal ; }, abstract = {INTRODUCTION: Anastomotic leaks (ALs) are serious postoperative complications. Current experimental studies designed to investigate leaks are based on acute intraoperative dehiscence of the anastomosis. Clinically, however, AL usually happens later in the postoperative course. Presented here is a clinically relevant colonic AL model in swine.

METHODS: Seventeen Yorkshire pigs were divided into 2 groups: the control group (n = 6) and the experimental group (n = 11). An enterotomy was performed on the descending colon and an end-to-end handsewn anastomosis was created in the groups. The proximal and distal ends of the suture were exteriorized and tied to a plastic tube. Subsequently, the suture was cut and pulled to induce breakdown of the anastomosis in the experimental group 3-4 h postoperatively. Study endpoints included behavioral changes, clinical assessment, laboratory indicators, and macroscopic indicators of leakage.

RESULTS: Leaks were successfully created in 8/11 of the experimental group animals and confirmed through exploratory relaparotomy. Seven of the experimental pigs showed complete anastomotic breakdown and one showed partial rupture. Fecal peritonitis and enteric spillage were observed macroscopically within the abdomen of the experimental pigs, confirming the presence of a leak. The remaining (3/11) experimental pigs did not experience those findings due to either a tamponade/containment by the abdominal wall or surrounding organs. Statistical significance (p < 0.05) was achieved between the experimental and control cohorts for laboratory and clinical indicators including fever, leukocytosis, and decreased blood potassium.

CONCLUSION: This animal model generated postoperative induced leak in approximately three-quarters (8/11) of experimental pigs, allowing control over the time of leak onset to simulate clinical settings.}, } @article {pmid37840177, year = {2023}, author = {Li, XG and Liu, MS and Cui, LY}, title = {[Attention should be paid to the importance of genetic testing in clinical practice of amyotrophic lateral sclerosis].}, journal = {Zhonghua yi xue za zhi}, volume = {103}, number = {39}, pages = {3071-3076}, doi = {10.3760/cma.j.cn112137-20230516-00796}, pmid = {37840177}, issn = {0376-2491}, support = {81750002//National Natural Science Foundation of China/ ; 320675017092//the WJP Medical Foundation/ ; 2021I2MC&TA003//CAMS Innovation Fund for Medical Sciences (CIFMS)/ ; YJXJJZ2021001406//Beijing Yicheng Cooperative Development Foundation Research Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Neurodegenerative Diseases/genetics/pathology ; Motor Neurons/pathology ; Superoxide Dismutase-1/genetics ; Genetic Testing ; Mutation ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis(ALS) is a progressive and fatal neurodegenerative disease that mainly involves upper and lower motor neurons. It lacks clear biomarkers and can be clearly diagnosed only one and a half years after the onset. Gene test is of great significance for diagnosis, prognosis and genetic counseling. In recent years, several gene therapy studies have entered the clinical trial stage of ALS, among which the antisense oligonucleotide therapy targeting the pathogenic variation of the superoxide dismutase 1 (SOD1) gene has been launched, and it is urgent to carry out routine gene test in clinical practice. On the basis of progress of ALS gene research in recent years, family history, age of onset and typical clinical manifestations of patients are no longer considered as the basis for genetic testing. However, the target genes of clinical gene testing needs to be further clarified according to the diagnostic purpose, the testing method and scheme need to be standardized, and the genetic consultation before testing should be paid attention to, and the informed consent should be fully achieved.}, } @article {pmid37841575, year = {2023}, author = {Ayala, YM}, title = {Uncovering Critical Roles for RNA in Neurodegeneration.}, journal = {Missouri medicine}, volume = {120}, number = {5}, pages = {374-380}, pmid = {37841575}, issn = {0026-6620}, mesh = {Humans ; RNA/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; }, abstract = {RNA-binding proteins, in particular TDP-43, are key players in neurodegenerative disorders, mainly amyotrophic lateral sclerosis and frontotemporal dementia. We aim to elucidate how TDP-43 dysfunction alters cell metabolism and to identify mechanisms linked to aberrant behavior. We find that RNA binding plays a key role in maintaining TDP-43 homeostasis and in controlling cellular organization, two processes of essential importance to TDP-43 pathology. This research will provide insight into pathogenesis and help develop therapeutic interventions.}, } @article {pmid37841873, year = {2023}, author = {Crone, N and Candrea, D and Shah, S and Luo, S and Angrick, M and Rabbani, Q and Coogan, C and Milsap, G and Nathan, K and Wester, B and Anderson, W and Rosenblatt, K and Clawson, L and Maragakis, N and Vansteensel, M and Tenore, F and Ramsey, N and Fifer, M and Uchil, A}, title = {A click-based electrocorticographic brain-computer interface enables long-term high-performance switch-scan spelling.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37841873}, issn = {2693-5015}, support = {T32 HD007414/HD/NICHD NIH HHS/United States ; UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Brain-computer interfaces (BCIs) can restore communication in movement- and/or speech-impaired individuals by enabling neural control of computer typing applications. Single command "click" decoders provide a basic yet highly functional capability.

METHODS: We sought to test the performance and long-term stability of click-decoding using a chronically implanted high density electrocorticographic (ECoG) BCI with coverage of the sensorimotor cortex in a human clinical trial participant (ClinicalTrials.gov, NCT03567213) with amyotrophic lateral sclerosis (ALS). We trained the participant's click decoder using a small amount of training data (< 44 minutes across four days) collected up to 21 days prior to BCI use, and then tested it over a period of 90 days without any retraining or updating.

RESULTS: Using this click decoder to navigate a switch-scanning spelling interface, the study participant was able to maintain a median spelling rate of 10.2 characters per min. Though a transient reduction in signal power modulation interrupted testing with this fixed model, a new click decoder achieved comparable performance despite being trained with even less data (< 15 min, within one day).

CONCLUSION: These results demonstrate that a click decoder can be trained with a small ECoG dataset while retaining robust performance for extended periods, providing functional text-based communication to BCI users.}, } @article {pmid37842553, year = {2023}, author = {Zucchi, E and Musazzi, UM and Fedele, G and Martinelli, I and Gianferrari, G and Simonini, C and Fini, N and Ghezzi, A and Caputo, M and Sette, E and Vacchiano, V and Zinno, L and Anceschi, P and Canali, E and Vinceti, M and Ferro, S and Mandrioli, J and , }, title = {Effect of tauroursodeoxycholic acid on survival and safety in amyotrophic lateral sclerosis: a retrospective population-based cohort study.}, journal = {EClinicalMedicine}, volume = {65}, number = {}, pages = {102256}, pmid = {37842553}, issn = {2589-5370}, abstract = {BACKGROUND: Oral tauroursodeoxycholic acid (TUDCA) is a commercial drug currently tested in patients with amyotrophic lateral sclerosis (ALS) both singly and combined with sodium phenylbutyrate. This retrospective study aimed to investigate, in a real-world setting, whether TUDCA had an impact on the overall survival of patients with ALS who were treated with this drug compared to those patients who received standard care only.

METHODS: This propensity score-matched study was conducted in the Emilia Romagna Region (Italy), which has had an ALS regional registry since 2009. Out of 627 patients with ALS diagnosed from January 1st, 2015 to June 30th, 2021 and recorded in the registry with available information on death/tracheostomy, 86 patients took TUDCA and were matched in a 1:2 ratio with patients who received only usual care according to age at onset, sex, phenotype, diagnostic latency, ALS Functional Rating Scale-Revised (ALSFRS-R) at first visit, disease progression rate at first visit, and BMI at diagnosis. The primary outcome was survival difference (time from onset of symptoms to tracheostomy/death) between TUDCA exposed and unexposed patients.

FINDINGS: A total of 86 patients treated with TUDCA were matched to 172 patients who did not receive treatment. TUDCA-exposed patients were stratified based on dosage (less than or equal to 1000 mg/day or greater) and duration (less than or equal to 12 months or longer) of treatment. The median overall survival was 49.6 months (95% CI 41.7-93.5) among those treated with TUDCA and 36.2 months (95% CI 32.7-41.6) in the control group, with a reduced risk of death observed in patients exposed to a higher dosage (defined as ≥ 1000 mg/day) of TUDCA (HR 0.56; 95% CI 0.38-0.83; p = 0.0042) compared to both the control group and those with lower TUDCA dosages (defined as < 1000 mg/day). TUDCA was generally well-tolerated, except for a minority of patients (n = 7, 8.1%) who discontinued treatment due to side effects, primarily gastrointestinal and mild in severity; only 2 adverse events required hospital access but resolved without sequelae.

INTERPRETATION: In this population-based exploratory study, patients with ALS who were treated with TUDCA may have prolonged survival compared to patients receiving standard care only. Additional prospective randomized studies are needed to confirm the efficacy and safety of this drug.

FUNDING: Emilia-Romagna Region.}, } @article {pmid37843208, year = {2024}, author = {King, PH}, title = {Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis: a narrative review.}, journal = {Neural regeneration research}, volume = {19}, number = {4}, pages = {747-753}, pmid = {37843208}, issn = {1673-5374}, support = {I01 BX001148/BX/BLRD VA/United States ; I01 BX005899/BX/BLRD VA/United States ; R01 NS092651/NS/NINDS NIH HHS/United States ; R21 NS111275/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target. Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis, there is considerable heterogeneity, including clinical presentation, progression, and the underlying triggers for disease initiation. Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations, it has become apparent that overt disease is preceded by a prodromal phase, possibly in years, where compensatory mechanisms delay symptom onset. Since 85-90% of amyotrophic lateral sclerosis is sporadic, there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration. Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease. Skeletal muscle, including the neuromuscular junction, manifests abnormalities at the earliest stages of the disease, before motor neuron loss, making it a promising source for identifying biomarkers of the prodromal phase. The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time. The advent of "omics" technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle, ranging from coding and non-coding RNAs to proteins and metabolites. This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms. A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease. There are two major goals of this review. The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity, evidence of a similar dysregulation in the SOD1[G93A] mouse during presymptomatic stages, and evidence of progressive change during disease progression. The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression, and as such, their potential as therapeutic targets in amyotrophic lateral sclerosis.}, } @article {pmid37843214, year = {2024}, author = {Wang, X and Hu, Y and Xu, R}, title = {The pathogenic mechanism of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {4}, pages = {800-806}, pmid = {37843214}, issn = {1673-5374}, abstract = {The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex, basal ganglia, brainstem, and spinal cord, and commonly involves the muscles of the upper and/or lower extremities, and the muscles of the bulbar and/or respiratory regions. However, as the disease progresses, it affects the adjacent body regions, leading to generalized muscle weakness, occasionally along with memory, cognitive, behavioral, and language impairments; respiratory dysfunction occurs at the final stage of the disease. The disease has a complicated pathophysiology and currently, only riluzole, edaravone, and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries. The TAR DNA-binding protein 43 inclusions are observed in 97% of those diagnosed with amyotrophic lateral sclerosis. This review provides a preliminary overview of the potential effects of TAR DNA-binding protein 43 in the pathogenesis of amyotrophic lateral sclerosis, including the abnormalities in nucleoplasmic transport, RNA function, post-translational modification, liquid-liquid phase separation, stress granules, mitochondrial dysfunction, oxidative stress, axonal transport, protein quality control system, and non-cellular autonomous functions (e.g., glial cell functions and prion-like propagation).}, } @article {pmid37843219, year = {2024}, author = {Liu, X and Liu, Y and Liu, J and Zhang, H and Shan, C and Guo, Y and Gong, X and Cui, M and Li, X and Tang, M}, title = {Correlation between the gut microbiome and neurodegenerative diseases: a review of metagenomics evidence.}, journal = {Neural regeneration research}, volume = {19}, number = {4}, pages = {833-845}, pmid = {37843219}, issn = {1673-5374}, abstract = {A growing body of evidence suggests that the gut microbiota contributes to the development of neurodegenerative diseases via the microbiota-gut-brain axis. As a contributing factor, microbiota dysbiosis always occurs in pathological changes of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. High-throughput sequencing technology has helped to reveal that the bidirectional communication between the central nervous system and the enteric nervous system is facilitated by the microbiota's diverse microorganisms, and for both neuroimmune and neuroendocrine systems. Here, we summarize the bioinformatics analysis and wet-biology validation for the gut metagenomics in neurodegenerative diseases, with an emphasis on multi-omics studies and the gut virome. The pathogen-associated signaling biomarkers for identifying brain disorders and potential therapeutic targets are also elucidated. Finally, we discuss the role of diet, prebiotics, probiotics, postbiotics and exercise interventions in remodeling the microbiome and reducing the symptoms of neurodegenerative diseases.}, } @article {pmid37844376, year = {2023}, author = {Qassim, HM and Seyedalipour, B and Baziyar, P and Ahamady-Asbchin, S}, title = {Polyphenolic flavonoid compounds act as the inhibitory potential of aggregation process: Implications for the prevention and therapeutics against FALS-associated D101G SOD1 mutant.}, journal = {Computational biology and chemistry}, volume = {107}, number = {}, pages = {107967}, doi = {10.1016/j.compbiolchem.2023.107967}, pmid = {37844376}, issn = {1476-928X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Superoxide Dismutase-1/genetics/chemistry/metabolism ; *Hesperidin/pharmacology ; Superoxide Dismutase/chemistry/genetics/metabolism ; Mutation ; }, abstract = {Aggregation of proteins is a biological phenomenon caused by misfolded proteins. Human superoxide dismutase (hSOD1) misfolding and aggregation underlie the neurological illness amyotrophic lateral sclerosis (ALS). The most significant contributing factor to ALS is genetic point mutations in SOD1. particularly, D101G mutant is the most harmful because it significantly reduces the life expectancy of patients. Subsequently, the use of natural polyphenolic flavonoids is strongly recommended to reduce the amyloidogenic behavior of protopathic proteins. In this study, using computational parameters such as protein-ligand interaction and molecular dynamics (MD) simulation analyses, we are trying to identify a pharmacodynamically promising flavonoid compound that can effectively inhibit the pathogenic behavior of the D101G mutant. Epigallocatechin-gallate (EGCG), Hesperidin, Isorhamnetin, and Diosmetin were identified as potential leads in a preliminary screening of flavonoids to anti-amyloid action. The results of MD showed that the binding of flavonoids to D101G mutant caused changes in stability, hydrophobicity of protein, and flexibility, as well as significantly led to the restoration of lost hydrogen bonds. Secondary structure analysis showed that protein destabilization and the increased propensity of β-sheet caused by the mutation were restored to the wild-type state upon binding of flavonoids. Besides, to differentiate aggregation, we elucidated alterations in the free energy landscape (FEL) and dynamic cross-correlation matrix (DCCM) of WT-SOD1 and mutant (unbound /bound) states. Among flavonoids, Epigallocatechin-gallate and Hesperidin had the most therapeutic efficacy against the D101G mutant. Therefore, Epigallocatechin-gallate and Hesperidin promise considerable therapeutic potential to develop highly effective inhibitors in reducing fatal and irreversible ALS.}, } @article {pmid37844546, year = {2023}, author = {Polverino, M and Sampaolo, S and Capuozzo, A and Fasolino, M and Aliberti, M and Satta, E and Santoriello, C and Orengo, JP and Polverino, F}, title = {Respiratory Function Changes as Early Signs of Amyotrophic Lateral Sclerosis.}, journal = {Respiration; international review of thoracic diseases}, volume = {102}, number = {11}, pages = {919-923}, pmid = {37844546}, issn = {1423-0356}, support = {R01 HL149744/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Respiration ; Respiratory Function Tests ; Lung ; Exhalation ; }, abstract = {BACKGROUND: The current diagnostic criteria for amyotrophic lateral sclerosis (ALS) may remain unsatisfactory for months or years in the early disease. Pulmonary assessment has never been considered useful in the early diagnosis of ALS, and studies of pulmonary function in this patient category are lacking.

OBJECTIVES: The objective of this study was to assess the pulmonary function in subjects with unspecific symptoms of ALS in whom an ALS diagnosis cannot be reached based on the current available guidelines.

METHODS: We performed pulmonary function tests, arterial gas analysis, maximal inspiratory (MIP) and expiratory (MEP) pressure, and respiratory drive (P0.1) assessment in 35 patients with unspecific neurological symptoms at the time of the visit and those were subsequently diagnosed with ALS 2 years after the initial visit ("pre-ALS"); we compared these patients with 29 patients with established ALS and with 28 control subjects.

RESULTS: Spirometric parameters were not different between the three groups. However, MIP was significantly lower and P0.1 was significantly increased (with the ratio P0.1/MIP significantly higher) in both established and pre-ALS patients compared to controls, while both MIP and P0.1 were similar between established ALS and pre-ALS.

CONCLUSIONS: Changes in MIP, P0.1, and P0.1/MIP ratio are highly suggestive of preclinical ALS when the spirometry and neurodiagnostic tests are still inconclusive. MIP and P0.1 are noninvasive measurements that can be easily assessed in an ambulatory setting. Future studies on larger cohorts are needed to validate the use of these parameters in the preclinical diagnosis of ALS as well as in other neuromuscular diseases.}, } @article {pmid37845101, year = {2023}, author = {Ugawa, Y}, title = {Somatosensory cortex/tracts involvement in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {156}, number = {}, pages = {249-250}, doi = {10.1016/j.clinph.2023.09.009}, pmid = {37845101}, issn = {1872-8952}, } @article {pmid37845420, year = {2024}, author = {Zhang, J and Liu, Y and Xu, G and Cao, X and Wang, W and Zhang, D and Zhu, M}, title = {Causal relationship between coffee intake and neurological diseases: a Mendelian randomization study.}, journal = {European journal of clinical nutrition}, volume = {78}, number = {2}, pages = {114-119}, pmid = {37845420}, issn = {1476-5640}, support = {82260225//National Natural Science Foundation of China (National Science Foundation of China)/ ; 20202BAB216043//Natural Science Foundation of Jiangxi Province (Jiangxi Province Natural Science Foundation)/ ; }, mesh = {Humans ; Coffee/adverse effects ; Mendelian Randomization Analysis ; *Nervous System Diseases/etiology/genetics ; *Migraine Disorders/genetics ; Causality ; }, abstract = {BACKGROUND: Previous observational studies focused on the association of coffee consumption and neurological disease. However, it is not known whether these associations are causal.

METHODS: We used Mendelian randomization (MR) study to assess the causal relationship of coffee intake with the risk of neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, and migraine. Single-nucleotide polymorphisms (SNPs) which had genetic statistical significance with coffee intake were used as instrumental variable (IV). Genetic instruments were stretched from the MRC-IEU (MRC Integrative Epidemiology Unit) analysis on the UK Biobank. We performed MR analyses using the inverse variance weighted (IVW) method as the main approach. Sensitivity analyses were further performed using MR-Egger and MR-PRESSO to assess the robustness.

RESULTS: In the MR analysis, 40 SNPs were selected as IV, the F statistics for all SNPs ranged from 16 to 359. In IVW approach, our results provide genetic evidence supporting a potential causal association between coffee intake and a lower risk of migraine (OR = 0.528, 95% CI = 0.342-0.817, P = 0.004) and migraine with aura (OR = 0.374, 95% CI = 0.208-0.672, P = 0.001). However, we found no significant association between coffee intake and other neurological diseases along with their subtypes in this MR study.

CONCLUSION: Using genetic data, our MR study found significant evidence supporting a causal association between coffee intake and migraine. This suggests that coffee consumption is likely a trigger or a prevention strategy for migraine.}, } @article {pmid37845449, year = {2023}, author = {Shin, J and Kang, H and Kim, S}, title = {Primo Vessels Inside Lymphatic Vessels Are Absent in an ALS Mouse Model.}, journal = {Advances in experimental medicine and biology}, volume = {1438}, number = {}, pages = {113-117}, pmid = {37845449}, issn = {0065-2598}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; *Lymphatic Vessels ; Lymph Nodes ; Oxygen/analysis ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the central nervous system. It is also a representative rare disease among degenerative diseases of the nervous system. Although many drugs for the treatment of degenerative brain diseases are being developed, they are not delivered correctly to the target due to the blood-brain barrier. The present study aimed to analyze changes in the primo vascular system (PVS) in ALS mice with symptoms and the partial oxygen pressure (pO2) in normal mice. In normal mice, we consistently observed primo vessels in lymphatic vessels (L-PVS). However, in ALS mice with symptoms, L-PVS were mostly lost, rendering them difficult to observe. The pO2 of the L-PVS in normal mice was significantly higher than that of normal dermis and lymph nodes.In conclusion, the relatively higher oxygen levels measured in the L-PVS than in normal dermis and lymph nodes suggest a role for the PVS in oxygen transport and enable a hypothesis that the L-PVS can function as a drug delivery pathway.}, } @article {pmid37845749, year = {2023}, author = {Bennett, CL and Dastidar, S and Arnold, FJ and McKinstry, SU and Stockford, C and Freibaum, BD and Sopher, BL and Wu, M and Seidner, G and Joiner, W and Taylor, JP and West, RJH and La Spada, AR}, title = {Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {164}, pmid = {37845749}, issn = {2051-5960}, support = {R01 GM125080/GM/NIGMS NIH HHS/United States ; R35 NS122140/NS/NINDS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Dipeptides/genetics ; C9orf72 Protein/genetics/metabolism ; Arginine/genetics/metabolism ; HEK293 Cells ; Motor Neurons/metabolism ; Drosophila/metabolism ; RNA/metabolism ; *Frontotemporal Dementia/genetics ; DNA Repeat Expansion/genetics ; DNA Helicases/genetics ; RNA Helicases/genetics ; Multifunctional Enzymes/genetics ; }, abstract = {Identifying genetic modifiers of familial amyotrophic lateral sclerosis (ALS) may reveal targets for therapeutic modulation with potential application to sporadic ALS. GGGGCC (G4C2) repeat expansions in the C9orf72 gene underlie the most common form of familial ALS, and generate toxic arginine-containing dipeptide repeats (DPRs), which interfere with membraneless organelles, such as the nucleolus. Here we considered senataxin (SETX), the genetic cause of ALS4, as a modifier of C9orf72 ALS, because SETX is a nuclear helicase that may regulate RNA-protein interactions involved in ALS dysfunction. After documenting that decreased SETX expression enhances arginine-containing DPR toxicity and C9orf72 repeat expansion toxicity in HEK293 cells and primary neurons, we generated SETX fly lines and evaluated the effect of SETX in flies expressing either (G4C2)58 repeats or glycine-arginine-50 [GR(50)] DPRs. We observed dramatic suppression of disease phenotypes in (G4C2)58 and GR(50) Drosophila models, and detected a striking relocalization of GR(50) out of the nucleolus in flies co-expressing SETX. Next-generation GR(1000) fly models, that show age-related motor deficits in climbing and movement assays, were similarly rescued with SETX co-expression. We noted that the physical interaction between SETX and arginine-containing DPRs is partially RNA-dependent. Finally, we directly assessed the nucleolus in cells expressing GR-DPRs, confirmed reduced mobility of proteins trafficking to the nucleolus upon GR-DPR expression, and found that SETX dosage modulated nucleolus liquidity in GR-DPR-expressing cells and motor neurons. These findings reveal a hitherto unknown connection between SETX function and cellular processes contributing to neuron demise in the most common form of familial ALS.}, } @article {pmid37845811, year = {2024}, author = {Holt, MW and Robinson, EC and Shlobin, NA and Hanson, JT and Bozkurt, I}, title = {Intracortical brain-computer interfaces for improved motor function: a systematic review.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {2}, pages = {213-223}, pmid = {37845811}, issn = {2191-0200}, mesh = {Humans ; *Brain-Computer Interfaces ; *Motor Cortex/physiology/physiopathology ; }, abstract = {In this systematic review, we address the status of intracortical brain-computer interfaces (iBCIs) applied to the motor cortex to improve function in patients with impaired motor ability. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Guidelines for Systematic Reviews. Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) and the Effective Public Health Practice Project (EPHPP) were used to assess bias and quality. Advances in iBCIs in the last two decades demonstrated the use of iBCI to activate limbs for functional tasks, achieve neural typing for communication, and other applications. However, the inconsistency of performance metrics employed by these studies suggests the need for standardization. Each study was a pilot clinical trial consisting of 1-4, majority male (64.28 %) participants, with most trials featuring participants treated for more than 12 months (55.55 %). The systems treated patients with various conditions: amyotrophic lateral sclerosis, stroke, spinocerebellar degeneration without cerebellar involvement, and spinal cord injury. All participants presented with tetraplegia at implantation and were implanted with microelectrode arrays via pneumatic insertion, with nearly all electrode locations solely at the precentral gyrus of the motor cortex (88.88 %). The development of iBCI devices using neural signals from the motor cortex to improve motor-impaired patients has enhanced the ability of these systems to return ability to their users. However, many milestones remain before these devices can prove their feasibility for recovery. This review summarizes the achievements and shortfalls of these systems and their respective trials.}, } @article {pmid37847372, year = {2023}, author = {Sattler, R and Traynor, BJ and Robertson, J and Van Den Bosch, L and Barmada, SJ and Svendsen, CN and Disney, MD and Gendron, TF and Wong, PC and Turner, MR and Boxer, A and Babu, S and Benatar, M and Kurnellas, M and Rohrer, JD and Donnelly, CJ and Bustos, LM and Van Keuren-Jensen, K and Dacks, PA and Sabbagh, MN and , }, title = {Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.}, journal = {Neurology and therapy}, volume = {12}, number = {6}, pages = {1821-1843}, pmid = {37847372}, issn = {2193-8253}, support = {RF1 NS114128/NS/NINDS NIH HHS/United States ; ZIAAG000933-15/AG/NIA NIH HHS/United States ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; R35 NS116846/NS/NINDS NIH HHS/United States ; ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; }, abstract = {A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion in the C9ORF72 gene and its relevance in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this summit was to connect basic scientists, clinical researchers, drug developers, and individuals affected by C9ORF72-FTD/ALS to evaluate how collaborative efforts across the FTD-ALS disease spectrum might break down existing disease silos. Presentations and discussions covered recent discoveries in C9ORF72-FTD/ALS disease mechanisms, availability of disease biomarkers and recent advances in therapeutic development, and clinical trial design for prevention and treatment for individuals affected by C9ORF72-FTD/ALS and asymptomatic pathological expansion carriers. The C9ORF72-associated hexanucleotide repeat expansion is an important locus for both ALS and FTD. C9ORF72-FTD/ALS may be characterized by loss of function of the C9ORF72 protein and toxic gain of functions caused by both dipeptide repeat (DPR) proteins and hexanucleotide repeat RNA. C9ORF72-FTD/ALS therapeutic strategies discussed at the summit included the use of antisense oligonucleotides, adeno-associated virus (AAV)-mediated gene silencing and gene delivery, and engineered small molecules targeting RNA structures associated with the C9ORF72 expansion. Neurofilament light chain, DPR proteins, and transactive response (TAR) DNA-binding protein 43 (TDP-43)-associated molecular changes were presented as biomarker candidates. Similarly, brain imaging modalities (i.e., magnetic resonance imaging [MRI] and positron emission tomography [PET]) measuring structural, functional, and metabolic changes were discussed as important tools to monitor individuals affected with C9ORF72-FTD/ALS, at both pre-symptomatic and symptomatic disease stages. Finally, summit attendees evaluated current clinical trial designs available for FTD or ALS patients and concluded that therapeutics relevant to FTD/ALS patients, such as those specifically targeting C9ORF72, may need to be tested with composite endpoints covering clinical symptoms of both FTD and ALS. The latter will require novel clinical trial designs to be inclusive of all patient subgroups spanning the FTD/ALS spectrum.}, } @article {pmid37849306, year = {2024}, author = {Olsen, CG and Busk, ØL and Holla, ØL and Tveten, K and Holmøy, T and Tysnes, OB and Høyer, H}, title = {Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {177-187}, doi = {10.1080/21678421.2023.2270705}, pmid = {37849306}, issn = {2167-9223}, mesh = {Humans ; Genetic Predisposition to Disease/genetics ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Genetic Association Studies ; Family ; *Neurodegenerative Diseases/epidemiology/genetics ; ATPases Associated with Diverse Cellular Activities/genetics ; ATP-Dependent Proteases/genetics ; LDL-Receptor Related Proteins/genetics ; Membrane Transport Proteins/genetics ; Kinesins/genetics ; Cytoskeletal Proteins/genetics ; *Cell Cycle Proteins ; }, abstract = {OBJECTIVE: In Norway, 89% of patients with Amyotrophic lateral sclerosis (ALS) lacks a genetic diagnose. ALS genes and genes that cause other neuromuscular or neurodegenerative disorders extensively overlap. This population-based study examined whether patients with ALS have a family history of neurological disorders and explored the occurrence of rare genetic variants associated with other neurodegenerative or neuromuscular disorders.

METHODS: During a two-year period, blood samples and clinical data from patients with ALS were collected from all 17 neurological departments in Norway. Our genetic analysis involved exome sequencing and bioinformatics filtering of 510 genes associated with neurodegenerative and neuromuscular disorders. The variants were interpreted using genotype-phenotype correlations and bioinformatics tools.

RESULTS: A total of 279 patients from a Norwegian population-based ALS cohort participated in this study. Thirty-one percent of the patients had first- or second-degree relatives with other neurodegenerative disorders, most commonly dementia and Parkinson's disease. The genetic analysis identified 20 possible pathogenic variants, in ATL3, AFG3L2, ATP7A, BICD2, HARS1, KIF1A, LRRK2, MSTO1, NEK1, NEFH, and SORL1, in 25 patients. NEK1 risk variants were present in 2.5% of this ALS cohort. Only four of the 25 patients reported relatives with other neurodegenerative or neuromuscular disorders.

CONCLUSION: Gene variants known to cause other neurodegenerative or neuromuscular disorders, most frequently in NEK1, were identified in 9% of the patients with ALS. Most of these patients had no family history of other neurodegenerative or neuromuscular disorders. Our findings indicated that AFG3L2, ATP7A, BICD2, KIF1A, and MSTO1 should be further explored as potential ALS-causing genes.}, } @article {pmid37849367, year = {2023}, author = {Takagi, S and Daimon, S and Inoue, K and Umeda, M and Kobayashi, Z}, title = {[A Case of Amyotrophic Lateral Sclerosis with Semantic Variant Primary Progressive Aphasia: A Study of Language Symptoms and Agraphia].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {75}, number = {10}, pages = {1155-1161}, doi = {10.11477/mf.1416202493}, pmid = {37849367}, issn = {1881-6096}, mesh = {Male ; Humans ; Aged ; *Agraphia/etiology ; Semantics ; *Amyotrophic Lateral Sclerosis/complications ; Language ; Magnetic Resonance Imaging/adverse effects ; *Aphasia, Primary Progressive/diagnostic imaging/complications ; Atrophy/complications ; }, abstract = {The patient was a 66-year-old man brought to the emergency room with impaired consciousness due to hypercarbonemia, managed on a respirator, and diagnosed with amyotrophic lateral sclerosis (ALS). MRI showed atrophy of the anterior and medial surfaces of the bilateral temporal lobes that was more severe in the right side. The patient had dysgraphia in both kana and kanji. Detailed examinations of the language function revealed impaired single-word comprehension, impaired naming, and surface dysgraphia, leading to the diagnosis of semantic variant primary progressive aphasia (svPPA). ALS patients with atrophy of the anterior temporal lobe and surface dysgraphia of kanji may have svPPA as a complication. (Received April 14, 2023; Accepted June 21, 2023; Published October 1, 2023).}, } @article {pmid37849894, year = {2023}, author = {Fang, M and Deibler, SK and Nana, AL and Vatsavayai, SC and Banday, S and Zhou, Y and Almeida, S and Weiss, A and Brown, RH and Seeley, WW and Gao, FB and Green, MR}, title = {Loss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1251228}, pmid = {37849894}, issn = {1662-4548}, support = {R01 NS104437/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; R01 GM035490/GM/NIGMS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; R21 NS112766/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; }, abstract = {A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the cytoplasmic mislocalization and aggregation of the DNA/RNA-binding protein TDP-43, but how loss of nuclear TDP-43 function contributes to ALS and FTD pathogenesis remains largely unknown. Here, using large-scale RNAi screening, we identify TARDBP, which encodes TDP-43, as a gene whose loss-of-function results in elevated DNA mutation rate and genomic instability. Consistent with this finding, we observe increased DNA damage in induced pluripotent stem cells (iPSCs) and iPSC-derived post-mitotic neurons generated from ALS patients harboring TARDBP mutations. We find that the increase in DNA damage in ALS iPSC-derived neurons is due to defects in two major pathways for DNA double-strand break repair: non-homologous end joining and homologous recombination. Cells with defects in DNA repair are sensitive to DNA damaging agents and, accordingly, we find that ALS iPSC-derived neurons show a marked reduction in survival following treatment with a DNA damaging agent. Importantly, we find that increased DNA damage is also observed in neurons with nuclear TDP-43 depletion from ALS/FTD patient brain tissues. Collectively, our results demonstrate that ALS neurons with loss of nuclear TDP-43 function have elevated levels of DNA damage and contribute to the idea that genomic instability is a defining pathological feature of ALS/FTD patients with TDP-43 pathology.}, } @article {pmid37850654, year = {2024}, author = {Chen, S and Huan, X and Xu, CZ and Luo, SS and Zhao, CB and Zhong, HH and Zheng, XY and Qiao, K and Dong, Y and Wang, Y and Liu, CY and Huang, HP and Chen, Y and Zou, ZY}, title = {Eomesodermin expression in CD4[+]T-cells associated with disease progression in amyotrophic lateral sclerosis.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {4}, pages = {e14503}, pmid = {37850654}, issn = {1755-5949}, support = {81901286, 81974199, 82271458//National Natural Science Foundation of China/ ; 2018Y9026, 2021Y9065//The Joint Funds for the innovation of science and Technology, Fujian province/ ; 2018QH1032//The Startup Fund for scientific research, Fujian Medical University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/immunology ; Biomarkers ; Disease Progression ; Longitudinal Studies ; Prognosis ; T-Lymphocytes ; *T-Box Domain Proteins/metabolism ; *CD4-Positive T-Lymphocytes/immunology/metabolism ; }, abstract = {AIM: To clarify the role of Eomesodermin (EOMES) to serve as a disease-relevant biomarker and the intracellular molecules underlying the immunophenotype shifting of CD4[+]T subsets in amyotrophic lateral sclerosis (ALS).

METHODS: The derivation and validation cohorts included a total of 148 ALS patients and 101 healthy controls (HCs). Clinical data and peripheral blood were collected. T-cell subsets and the EOMES expression were quantified using multicolor flow cytometry. Serum neurofilament light chain (NFL) was measured. In 1-year longitudinal follow-ups, the ALSFRS-R scores and primary endpoint events were further recorded in the ALS patients of the validation cohort.

RESULTS: In the derivation cohort, the CD4[+]EOMES[+]T-cell subsets were significantly increased (p < 0.001). EOMES[+] subset was positively correlated with increased serum NFL levels in patients with onset longer than 12 months. In the validation cohort, the elevated CD4[+]EOMES[+]T-cell proportions and their association with NFL levels were also identified. The longitudinal study revealed that ALS patients with higher EOMES expression were associated with higher progression rates (p = .010) and worse prognosis (p = .003).

CONCLUSIONS: We demonstrated that increased CD4[+]EOMES[+]T-cell subsets in ALS were associated with disease progression and poor prognosis. Identifying these associations may contribute to a better understanding of the immunopathological mechanism of ALS.}, } @article {pmid37851042, year = {2023}, author = {Izenberg, A}, title = {Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {29}, number = {5}, pages = {1538-1563}, pmid = {37851042}, issn = {1538-6899}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Motor Neuron Disease/diagnosis/genetics/therapy ; Biomarkers ; }, abstract = {OBJECTIVE: This article reviews the clinical spectrum of amyotrophic lateral sclerosis (ALS), its variant presentations, and the approach to diagnosis and management. This review includes a detailed discussion of current and emerging disease-modifying therapies and the management of respiratory and bulbar manifestations of disease. An updated review of ALS genetics and pathophysiology is also provided. This article also touches on several other important motor neuron diseases.

LATEST DEVELOPMENTS: A new set of simplified diagnostic criteria may help identify patients at earlier stages of the disease. A coformulation of sodium phenylbutyrate and tauroursodeoxycholic acid has been shown to have a significant benefit on disease progression and survival, leading to approval by regulatory authorities in the United States and Canada. An oral formulation of edaravone and an antisense oligonucleotide to a SOD1 gene variation (tofersen) have also recently been approved by the US Food and Drug Administration (FDA). Phase 3 trials of intrathecal mesenchymal stem cells failed to meet primary end points for efficacy. Updated American Academy of Neurology quality measures for the care of patients with ALS were published in 2023.

ESSENTIAL POINTS: There has been continued progress in ALS genetics, diagnosis, and disease-modifying therapies. However, we still lack a definitive biomarker or a treatment that can halt the progression or reverse the course of disease. The evolving understanding of the genetic and pathophysiologic underpinnings of disease offers promise for more effective and clinically meaningful treatments in the future.}, } @article {pmid37851044, year = {2023}, author = {Gwathmey, K and Heiman-Patterson, TD}, title = {Multidisciplinary Clinics in Neuromuscular Medicine.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {29}, number = {5}, pages = {1585-1594}, pmid = {37851044}, issn = {1538-6899}, mesh = {Humans ; Quality of Life ; *Telemedicine ; *Amyotrophic Lateral Sclerosis/diagnosis ; Ambulatory Care ; *Neuromuscular Diseases/diagnosis/therapy ; }, abstract = {Multidisciplinary care is comprehensive, coordinated clinical care across medical disciplines and allied health professions. Neuromuscular disorders, such as amyotrophic lateral sclerosis and muscular dystrophies, are often associated with disabling weakness and extramuscular symptoms and may benefit from care in a model that consolidates numerous clinic visits into a single more efficient multidisciplinary clinic visit. The goal of the neuromuscular multidisciplinary care model is to improve patient outcomes, patient satisfaction, quality of life, access to medications and equipment, and survival. Although the costs of running a multidisciplinary clinic are high, they are likely associated with cost savings from the patient's perspective. Several barriers to acceptance of multidisciplinary clinics include the distance needed to travel to the clinic and the duration of the clinic visit. Telehealth multidisciplinary clinic visits may address some of these concerns. Further study is needed to understand the value of multidisciplinary clinics and is a necessary step toward creating a sustainable model.}, } @article {pmid37852234, year = {2023}, author = {Sueda, T and Tei, M and Mori, S and Nishida, K and Yasuyama, A and Nomura, M and Yoshikawa, Y and Tsujie, M}, title = {Clinical Impact of Transanal Drainage Tube on Anastomosis Leakage Following Minimally Invasive Resection Without Diverting Stoma in Patients With Rectal Cancer: A Propensity Score-matched Analysis.}, journal = {Surgical laparoscopy, endoscopy & percutaneous techniques}, volume = {33}, number = {6}, pages = {608-616}, doi = {10.1097/SLE.0000000000001237}, pmid = {37852234}, issn = {1534-4908}, mesh = {Humans ; *Anastomotic Leak/etiology/prevention & control/surgery ; Anastomosis, Surgical/adverse effects/methods ; Retrospective Studies ; Propensity Score ; *Rectal Neoplasms/surgery/complications ; Drainage/methods ; }, abstract = {OBJECTIVES: As one of the most serious complications of rectal cancer (RC) surgery, preventing anastomotic leakage (AL) is crucial. Several studies have suggested a positive role of the transanal drainage tube (TaDT) in AL prevention. However, whether TaDT is beneficial for AL in patients with RC remains controversial. The present study aimed to evaluate the clinical impact of TaDT on AL following minimally invasive resection without diverting stoma (DS) in patients with RC.

MATERIALS AND METHODS: We retrospectively analyzed 392 consecutive patients with RC who had undergone minimally invasive resection without DS between 2010 and 2021. Propensity score matching (PSM) was performed to reduce selection bias. AL was classified as grade A, B, or C.

RESULTS: A TaDT was used in 214 patients overall. After PSM, we enrolled 316 patients (n=158 in each group). Before PSM, significant group-dependent differences were observed in terms of age, American Society of Anesthesiologists physical status, and the use of antiplatelet/anticoagulant agents. The frequency of AL was 7.3% in the overall cohort and was significantly lower in the TaDT group (3.7%) than in the non-TaDT group (11.8%). The rate of grade B AL was significantly lower in the TaDT group than in the non-TaDT group (before PSM, P <0.01; after PSM, P =0.02). However, no significant differences between groups were found for grade C AL. Moreover, multivariate analysis identified the lack of a TaDT as an independent risk factor for AL in the overall and matched cohorts [before PSM, odds ratio, 3.64, P <0.01; after PSM, odds ratio, 2.91, P =0.02].

CONCLUSION: These results indicated that TaDT may play a beneficial role in preventing AL, particularly of grade B, for patients with RC undergoing minimally invasive resection without DS. However, further randomized controlled trials, including patient-reported outcomes, are still needed to understand better the role of TaDT in preventing ALs in patients with RC undergoing minimally invasive resection without DS.}, } @article {pmid37853696, year = {2023}, author = {Ingólfsson, HI and Rizuan, A and Liu, X and Mohanty, P and Souza, PCT and Marrink, SJ and Bowers, MT and Mittal, J and Berry, J}, title = {Multiscale simulations reveal TDP-43 molecular-level interactions driving condensation.}, journal = {Biophysical journal}, volume = {122}, number = {22}, pages = {4370-4381}, pmid = {37853696}, issn = {1542-0086}, support = {R01 NS116176/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Protein Domains ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/metabolism ; Molecular Dynamics Simulation ; Amyloid ; }, abstract = {The RNA-binding protein TDP-43 is associated with mRNA processing and transport from the nucleus to the cytoplasm. TDP-43 localizes in the nucleus as well as accumulating in cytoplasmic condensates such as stress granules. Aggregation and formation of amyloid-like fibrils of cytoplasmic TDP-43 are hallmarks of numerous neurodegenerative diseases, most strikingly present in >90% of amyotrophic lateral sclerosis (ALS) patients. If excessive accumulation of cytoplasmic TDP-43 causes, or is caused by, neurodegeneration is presently not known. In this work, we use molecular dynamics simulations at multiple resolutions to explore TDP-43 self- and cross-interaction dynamics. A full-length molecular model of TDP-43, all 414 amino acids, was constructed from select structures of the protein functional domains (N-terminal domain, and two RNA recognition motifs, RRM1 and RRM2) and modeling of disordered connecting loops and the low complexity glycine-rich C-terminus domain. All-atom CHARMM36m simulations of single TDP-43 proteins served as guides to construct a coarse-grained Martini 3 model of TDP-43. The Martini model and a coarser implicit solvent C⍺ model, optimized for disordered proteins, were subsequently used to probe TDP-43 interactions; self-interactions from single-chain full-length TDP-43 simulations, cross-interactions from simulations with two proteins and simulations with assemblies of dozens to hundreds of proteins. Our findings illustrate the utility of different modeling scales for accessing TDP-43 molecular-level interactions and suggest that TDP-43 has numerous interaction preferences or patterns, exhibiting an overall strong, but dynamic, association and driving the formation of biomolecular condensates.}, } @article {pmid37855109, year = {2024}, author = {Jia, H and Li, Z and Liu, H and Ren, M and Liu, T and Zhou, X and Li, X and Li, R and Liu, Q and Liu, Y and Dong, H}, title = {The Beaumont behavioral intervention in a Chinese amyotrophic lateral sclerosis cohort.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {88-95}, doi = {10.1080/21678421.2023.2271518}, pmid = {37855109}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/complications ; *Frontotemporal Dementia/diagnosis ; Cross-Sectional Studies ; Sensitivity and Specificity ; *Pick Disease of the Brain ; Neuropsychological Tests ; }, abstract = {OBJECTIVE: The prevalence of behavior impairment (27.38%) in the Chinese amyotrophic lateral sclerosis (ALS) cohort is lower. We hypothesize that the screening scales used among studies might not be appropriate to diagnose behavioral disorders in ALS patients. So, we urgently need to find a behavior scale with a high detection rate designed specifically for ALS. This study aims to verify the Chinese translation of the Beaumont Behavioral Inventory (BBI) as an effective assessment in a Chinese ALS cohort.

METHODS: Ninety-eighty ALS patients and ninety-three healthy controls were included in this cross-sectional study. All participants took emotional state, overall cognitive, sleep quality and gastroenteric function, and behavioral evaluation.

RESULTS: The BBI scores showed a strong association with the amyotrophic lateral sclerosis-Frontotemporal Dementia-Questionnaire (ALS-FTD-Q) (rs = 0.71, p < 0.001) as well as a moderate correlation with the Frontal Behavioral Inventory (FBI) (rs = 0.55, p < 0.001). High internal consistency was demonstrated in patients using BBI-after items (Cronbach's a = 0.89). When tested against clinical diagnoses, the optimal cutoff of total BBI score was identified at 5.5 (AUC = 0.95; SE = 0.02; 95% CI [0.91, 0.99]), the BBI reached optimal sensitivity and specificity values (91.5% and 87.2%). The BBI turned out to be more precise than the FBI (AUC = 0.76; SE = 0.05; 95% CI [0.66, 0.86]) and the ALS-FTD-Q (AUC = 0.84; SE = 0.04; 95% CI [0.77, 0.92]).

CONCLUSION: The Chinese version of BBI is a quicker and more efficient instrument for assessing behavioral impairment in the ALS population in China.}, } @article {pmid37855859, year = {2024}, author = {Vieira, TCRG and Barros, CA and Domingues, R and Outeiro, TF}, title = {PrP meets alpha-synuclein: Molecular mechanisms and implications for disease.}, journal = {Journal of neurochemistry}, volume = {168}, number = {8}, pages = {1625-1639}, doi = {10.1111/jnc.15992}, pmid = {37855859}, issn = {1471-4159}, support = {SFB1286 (B8)//Deutsche Forschungsgemeinschaft/ ; EXC 2067/1-390729940//Deutsche Forschungsgemeinschaft/ ; //Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)/ ; //Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; }, mesh = {Humans ; *alpha-Synuclein/metabolism ; Animals ; Synucleinopathies/metabolism/pathology ; Prion Proteins/metabolism ; }, abstract = {The discovery of prions has challenged dogmas and has revolutionized our understanding of protein-misfolding diseases. The concept of self-propagation via protein conformational changes, originally discovered for the prion protein (PrP), also applies to other proteins that exhibit similar behavior, such as alpha-synuclein (aSyn), a central player in Parkinson's disease and in other synucleinopathies. aSyn pathology appears to spread from one cell to another during disease progression, and involves the misfolding and aggregation of aSyn. How the transfer of aSyn between cells occurs is still being studied, but one important hypothesis involves receptor-mediated transport. Interestingly, recent studies indicate that the cellular prion protein (PrP[C]) may play a crucial role in this process. PrP[C] has been shown to act as a receptor/sensor for protein aggregates in different neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. Here, we provide a comprehensive overview of the current state of knowledge regarding the interaction between aSyn and PrP[C] and discuss its role in synucleinopathies. We examine the properties of PrP and aSyn, including their structure, function, and aggregation. Additionally, we discuss the current understanding of PrP[C]'s role as a receptor/sensor for aSyn aggregates and identify remaining unanswered questions in this area of research. Ultimately, we posit that exploring the interaction between aSyn and PrP[C] may offer potential treatment options for synucleinopathies.}, } @article {pmid37855870, year = {2024}, author = {Borghero, G and Pili, F and Muroni, A and Ercoli, T and Pateri, MI and Pilotto, S and Maccabeo, A and Defazio, G}, title = {Disease survival and progression in TARDBP ALS patients from Sardinia, Italy.}, journal = {Journal of neurology}, volume = {271}, number = {2}, pages = {929-934}, pmid = {37855870}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; C9orf72 Protein/genetics ; Delayed Diagnosis ; Disease Progression ; Italy/epidemiology ; Mutation/genetics ; Phenotype ; DNA-Binding Proteins ; }, abstract = {BACKGROUND: Common genes implicated in amyotrophic lateral sclerosis (ALS) development may also influence its progression rate. The C9orf72 mutations featured a faster progression rate while the European SOD1 mutations were associated with a slower progression. In this study, we assessed the relationship between TARDBP and ALS progression/survival.

METHODS: ALS incident patients (2010-2019) were diagnosed by El Escorial revised criteria and staged over the disease course by the King's staging system. Disease progression was analysed by Kaplan-Meier survival curves and Cox regression models, with survival measured from symptom onset to death/tracheostomy or censor date.

RESULTS: The study population included 76 patients carrying TARDBP mutations (A382T/G295S), 28 patients carrying the C9orf72 GGGGCC expansion, and 158 patients who had no evidence of causative genetic mutations (nmALS group). TARDBP patients reached death/tracheostomy later than C9orf72 and nmALS patients, independently of possible prognostic indicators (sex, age at ALS onset, diagnostic delay, phenotype at onset, and family history of ALS). On King's staging, the time elapsed between disease onset (King's stage 1) and involvement of the second body region (King's stage 2B) was similar in TARDBP and nmALS patients but longer in TARDBP than in C9orf72 patients. TARDBP patients reached King's stages 3 and 4 later than C9orf72 and nmALS patients.

CONCLUSIONS: TARDBP patients have a better survival/prognosis than C9orf72-positive and nmALS patients. King's staging also suggested that the higher survival rate and the slower progression associated with the TARDBP mutation could mainly be attributed to the longer time elapsed between King's stages 2B to 3.}, } @article {pmid37855949, year = {2023}, author = {Suh, A and Ong, J and Kamran, SA and Waisberg, E and Paladugu, P and Zaman, N and Sarker, P and Tavakkoli, A and Lee, AG}, title = {Retina Oculomics in Neurodegenerative Disease.}, journal = {Annals of biomedical engineering}, volume = {51}, number = {12}, pages = {2708-2721}, pmid = {37855949}, issn = {1573-9686}, support = {80NSSC20K183//NASA Grant/ ; }, mesh = {Humans ; *Artificial Intelligence ; *Neurodegenerative Diseases/diagnostic imaging ; Quality of Life ; Retina/diagnostic imaging ; Tomography, Optical Coherence/methods ; Biomarkers ; }, abstract = {Ophthalmic biomarkers have long played a critical role in diagnosing and managing ocular diseases. Oculomics has emerged as a field that utilizes ocular imaging biomarkers to provide insights into systemic diseases. Advances in diagnostic and imaging technologies including electroretinography, optical coherence tomography (OCT), confocal scanning laser ophthalmoscopy, fluorescence lifetime imaging ophthalmoscopy, and OCT angiography have revolutionized the ability to understand systemic diseases and even detect them earlier than clinical manifestations for earlier intervention. With the advent of increasingly large ophthalmic imaging datasets, machine learning models can be integrated into these ocular imaging biomarkers to provide further insights and prognostic predictions of neurodegenerative disease. In this manuscript, we review the use of ophthalmic imaging to provide insights into neurodegenerative diseases including Alzheimer Disease, Parkinson Disease, Amyotrophic Lateral Sclerosis, and Huntington Disease. We discuss recent advances in ophthalmic technology including eye-tracking technology and integration of artificial intelligence techniques to further provide insights into these neurodegenerative diseases. Ultimately, oculomics opens the opportunity to detect and monitor systemic diseases at a higher acuity. Thus, earlier detection of systemic diseases may allow for timely intervention for improving the quality of life in patients with neurodegenerative disease.}, } @article {pmid37856900, year = {2023}, author = {Magrì, B and D'Amico, AG and Maugeri, G and Morello, G and La Cognata, V and Saccone, S and Federico, C and Cavallaro, S and D'Agata, V}, title = {Neuroprotective effect of the PACAP-ADNP axis on SOD1G93A mutant motor neuron death induced by trophic factors deprivation.}, journal = {Neuropeptides}, volume = {102}, number = {}, pages = {102386}, doi = {10.1016/j.npep.2023.102386}, pmid = {37856900}, issn = {1532-2785}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Pituitary Adenylate Cyclase-Activating Polypeptide/pharmacology/metabolism ; *Neuroprotective Agents/pharmacology/metabolism ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; *Neurodegenerative Diseases ; Motor Neurons/metabolism/pathology ; Superoxide Dismutase/genetics/metabolism ; Nerve Degeneration/metabolism/pathology ; Mutation ; Nerve Tissue Proteins/metabolism ; Homeodomain Proteins/genetics/metabolism/pharmacology ; }, abstract = {Amyotrophic lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motor neurons in the central nervous system. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) account for approximately in 20% of familial ALS cases. The pathological mechanisms underlying the toxicity induced by mutated SOD1 are still unknown. However, it has been hypothesized that oxidative stress (OS) has a crucial role in motor neuron degeneration in ALS patients. Moreover, it has been described that SOD1 mutation interferes expression of nuclear factor erythroid 2-related factor 2 (Nrf2), a protective key modulator against OS and reactive oxygen species (ROS) formation. The protective effect of pituitary adenylate cyclase-activating peptide (PACAP) has been demonstrated in various neurological disorders, including ALS. Some of its effects are mediated by the stimulation of an intracellular factor known as activity-dependent protein (ADNP). The role of PACAP-ADNP axis on mutated SOD1 motor neuron degeneration has not been explored, yet. The present study aimed to investigate whether PACAP prevented apoptotic cell death induced by growth factor deprivation through ADNP activation and whether the peptidergic axis can counteract the OS insult. By using an in vitro model of ALS, we demonstrated that PACAP by binding to PAC1 receptor (PAC1R) prevented motor neuron death induced by serum deprivation through induction of the ADNP expression via PKC stimulation. Furthermore, we have also demonstrated that the PACAP/ADNP axis counteracted ROS formation by inducing translocation of the Nfr2 from the cytoplasm to the nucleus. In conclusion, our study provides new insights regarding the protective role of PACAP-ADNP in ALS.}, } @article {pmid37857264, year = {2024}, author = {Kiene, H and Hamre, HJ}, title = {A Fundamental Question for Complementary Medicine: Are There Other Forces in the Natural World Besides the Physical Forces?.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {71-77}, doi = {10.1159/000534592}, pmid = {37857264}, issn = {2504-2106}, mesh = {*Complementary Therapies ; *Homeopathy ; DNA ; RNA ; }, abstract = {BACKGROUND: The integration of conventional and complementary medicine reflects the pluralism in science. Still, a critical issue is the conception of the natural world. Many complementary therapy systems seem to contradict the reductionist-atomistic paradigm that all of natural reality is essentially based on the physical interactions of atoms and molecules. Thus, a fundamental question about the natural world is: Do other than the physical forces exist?

SUMMARY: The assumption that no other than physical forces exist and work in the natural world is not tenable. For example, the formation and maintenance of the functional Gestalt of organisms cannot possibly be explained by molecular processes (e.g., from DNA to RNA and further to amino acids and proteins). The processes on each structural level - from molecules, organelles, cells, organs up to the whole organism - are regulated in regard to the formation of the next higher level. Specific Gestalt-forming forces exist and can be systematically investigated. Their existence implies an extended conception of matter. The Gestalt-forming forces and the extended concept of matter may be relevant for the scientific assessment of complementary therapies.

KEY MESSAGES: (i) In the natural world, specific Gestalt-forming forces exist in addition to the physical forces, and can be systematically investigated. (ii) The existence of these forces implies an extended conception of matter. (iii) These forces and this extended concept of matter may be relevant for the scientific assessment of complementary therapies, e.g., homeopathy.

UNLABELLED: HintergrundIn der Integration von konventioneller und komplementärer Medizin spiegelt sich der Methodenpluralismus der Wissenschaft. Die Ontologien vieler komplementärmedizinisches Systeme liegen allerdings außerhalb der Erklärbarkeit durch die Kräfte der Physik. Eine zentrale Frage ist deshalb: Gibt es Kräfte in der Natur, die eine materielle Wirkung haben, deren Ursprung aber nicht in Atomen oder Molekülen und in diesem Sinne nicht in der Materie liegt?ZusammenfassungDie Annahme, dass in der Natur keine anderen als die mit Atomen und Molekülen assoziierten physikalischen Kräfte existent und wirksam seien, ist wissenschaftlich nicht begründet. Beispielsweise ist die Bildung und Erhaltung der funktionsfähigen Gestalt von Organismen nicht durch molekulare Prozesse (z.B. von der DNA zur RNA und weiter zu Aminosäuren und Proteinen) erklärbar. Die Prozesse auf jeder strukturellen Ebene – von den Molekülen, Organellen, Zellen, Organen bis hinauf zum Gesamtorganismus – sind in Hinblick auf die Bildung der funktionsfähigen Gestalt der jeweils nächsthöheren Ebene gesteuert. Für diese Gestaltbildung gibt es spezifische Kräfte, die systematisch erforscht werden können. Ihre Existenz impliziert eine erweiterte Konzeption von Materie. Diese Gestalt-bildenden Kräfte und dieses erweiterte Konzept von Materie sind relevant für die wissenschaftliche Erfassung komplementärmedizinischer Systeme.Zentrale Aussagen(i) In der Natur sind außer den physikalischen Kräften noch weitere spezifische Kräfte wirksam, beispielsweise bei der Bildung und Erhaltung der funktionsfähigen Gestalt von Organismen. Diese Kräfte können systematisch erforscht werden. (ii) Die Existenz dieser Kräfte impliziert eine erweitere Konzeption von Materie. (iii) Diese Kräfte und das erweiterte Materiekonzept sind relevant für die wissenschaftliche Erfassung komplementärmedizinischer Systeme, beispielsweise der Homöopathie.}, } @article {pmid37858176, year = {2023}, author = {Xie, M and Pallegar, PN and Parusel, S and Nguyen, AT and Wu, LJ}, title = {Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {75}, pmid = {37858176}, issn = {1750-1326}, support = {R35 NS132326/NS/NINDS NIH HHS/United States ; RF1AG082314/AG/NIA NIH HHS/United States ; RF1 AG082314/AG/NIA NIH HHS/United States ; U19AG 069701/AG/NIA NIH HHS/United States ; R01 AG082314/AG/NIA NIH HHS/United States ; R35NS132326/NS/NINDS NIH HHS/United States ; U19 AG069701/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Motor Neurons/pathology ; Neuroglia/pathology ; Microglia/pathology ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, and eventually death. Motor cortical hyperexcitability is a common phenomenon observed at the presymptomatic stage of ALS. Both cell-autonomous (the intrinsic properties of motor neurons) and non-cell-autonomous mechanisms (cells other than motor neurons) are believed to contribute to cortical hyperexcitability. Decoding the pathological relevance of these dynamic changes in motor neurons and glial cells has remained a major challenge. This review summarizes the evidence of cortical hyperexcitability from both clinical and preclinical research, as well as the underlying mechanisms. We discuss the potential role of glial cells, particularly microglia, in regulating abnormal neuronal activity during the disease progression. Identifying early changes such as neuronal hyperexcitability in the motor system may provide new insights for earlier diagnosis of ALS and reveal novel targets to halt the disease progression.}, } @article {pmid37858563, year = {2023}, author = {Ezenarro, J and García-Pizarro, Á and Busto, O and de Juan, A and Boqué, R}, title = {Analysing olive ripening with digital image RGB histograms.}, journal = {Analytica chimica acta}, volume = {1280}, number = {}, pages = {341884}, doi = {10.1016/j.aca.2023.341884}, pmid = {37858563}, issn = {1873-4324}, mesh = {*Olea/chemistry ; Olive Oil/analysis ; Fruit/chemistry ; }, abstract = {Digital images are commonly used to monitor processes that are based on colour changes due to their simplicity and easy capture. Colour information in these images can be analysed objectively and accurately using colour histograms. One such process is olive ripening, which is characterized by changes in chemical composition, sensory properties and can be followed by changes in physical appearance, mainly colour. The reference method to quantify the ripeness of olives is the Maturity Index (MI), which is determined by trained experts assigning individual olives into a colour scale through visual inspection. Instead, this study proposes a methodology based on Chemometrics Assisted Colour Histogram-based Analytical Systems (CACHAS) to automatically assess the MI of olives based on R, G, and B colour histograms derived from digital images. The methodology was shown to be easily transferable for routine analysis and capable of controlling the ripening of olives. The study also confirms the high potential of digital images to understand the ripening process of olives (and potentially other fruits) and to predict the MI with satisfactory accuracy, providing an objective and reproducible alternative to visual inspection of trained experts.}, } @article {pmid37858624, year = {2024}, author = {Lauck, KC and Malick, H and Tolkachjov, SN}, title = {Response to Joshi et al's "Considerations for perioperative antibiotic prophylaxis in Mohs micrographic surgery".}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {3}, pages = {e103-e104}, doi = {10.1016/j.jaad.2023.10.019}, pmid = {37858624}, issn = {1097-6787}, mesh = {Humans ; *Mohs Surgery/adverse effects ; Antibiotic Prophylaxis ; *Skin Neoplasms/surgery ; Surgical Wound Infection/prevention & control ; }, } @article {pmid37858681, year = {2023}, author = {Wang, Y and Liang, W and Wang, T and Zhang, C and Yang, Y and Cong, C and Wang, X and Wang, S and Wang, D and Huo, D and Wang, H and Su, X and Tan, X and Feng, H}, title = {Researches of calcium-activated chloride channel ANO1 intervening amyotrophic lateral sclerosis progression by activating EGFR and CaMKII signaling.}, journal = {Brain research bulletin}, volume = {204}, number = {}, pages = {110792}, doi = {10.1016/j.brainresbull.2023.110792}, pmid = {37858681}, issn = {1873-2747}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Anoctamin-1 ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Chloride Channels ; Disease Models, Animal ; ErbB Receptors/metabolism ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/metabolism ; }, abstract = {BACKGROUND: ANO1 is closely correlated with the activation of EGFR and CaMKII, while EGFR and CaMKII show low activation in amyotrophic lateral sclerosis (ALS) models. Therefore, we designed experiments to verify that ANO1 may play a protective role on motor neurons in ALS by activating EGFR and CaMKII.

METHODS: The expression changes of ANO1, EGFR, CaMKII, pEGFR, and pCaMKII, cell survival status, and apoptosis were studied by western blot, real-time quantitative PCR, immunofluorescence, immunohistochemistry, CCK-8, and flow cytometry. The role of ANO1 in the ALS model by activating EGFR and CaMKII was studied by applying corresponding activators, inhibitors, gene silencing, and overexpression.

RESULTS: In hSOD1[G93A] transgenic animals and cell lines, low expression of ANO1 and low activation of EGFR and CaMKII were identified. ANO1 expression decreased gradually with the progression of ALS. Overexpression of ANO1 in the hSOD1[G93A] cell line and primary neurons of hSOD1[G93A] transgenic mice increased cell viability and decreased cell apoptosis. After the application of ANO1 inhibitor CaCC-inhA01 in hSOD1[G93A] cell line and primary neurons of hSOD1[G93A] transgenic mice, EGFR activator EGF and CaMKII activator Carbachol, increased cell viability and reduced cell apoptosis. After ANO1 was overexpressed in the hSOD1[G93A] cell line and primary neurons of hSOD1[G93A] transgenic mice, EGFR inhibitor AEE788 and CaMKII inhibitor KN93 decreased cell viability and increased cell apoptosis.

CONCLUSIONS: Our results suggest that ANO1 plays an important role in the survival of ALS motor neurons. ANO1 can increase cell activity and reduce apoptosis by activating EGFR and CaMKII signals.}, } @article {pmid37859765, year = {2023}, author = {Vinceti, G and Carbone, C and Gallingani, C and Fiondella, L and Salemme, S and Zucchi, E and Martinelli, I and Gianferrari, G and Tondelli, M and Mandrioli, J and Chiari, A and Zamboni, G}, title = {The association between lifelong personality and clinical phenotype in the FTD-ALS spectrum.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1248622}, pmid = {37859765}, issn = {1662-4548}, abstract = {INTRODUCTION: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two phenotypes of the same neurodegenerative disease, the FTD-ALS spectrum. What determines the development of one rather than the other phenotype is still unknown. Based on the clinical observation that patients' personality seems to differ between the two phenotypes, i.e., ALS patients tend to display kind, prosocial behaviors whereas FTD patients tend to present anti-social behaviors, and that these traits are often reported as pre-existing the disease onset by caregivers, we set up to study experimentally patients' personality in their premorbid life.

METHODS: We first tested for differences between groups, then tested the association between premorbid personality and current functional organization of the brain. Premorbid personality of a cohort of forty patients, 27 FTD and 13 ALS, was explored through the NEO Personality Inventory 3 (NEO-PI-3), which analyses the five main personality factors, completed by the caregiver with reference to patient's personality 20 years before symptoms onset (premorbid). A subgroup of patients underwent a brain MRI including structural and resting-state functional MRI (rsfMRI).

RESULTS: A significant difference between FTD and ALS in premorbid personality emerged in the Openness (133.92 FTD vs. 149.84 ALS, p = 0.01) and Extraversion (136.55 FTD vs. 150.53 ALS, p = 0.04) factors. This suggests that ALS patients had been, in their premorbid life, more open to new experiences, more sociable and optimistic than FTD patients. They also showed greater functional connectivity than both FTD and a control group in the Salience resting state network, over and above differences in gray matter atrophy. Finally, there was a positive correlation between premorbid Openness and functional connectivity in the Salience network across all patients, suggesting a possible association between premorbid personality and current functional organization of the brain, irrespective of the degree of atrophy.

DISCUSSION: Our proof-of-concept results suggest that premorbid personality may eventually predispose to the development of one, rather than the other, phenotype in the FTD-ALS spectrum.}, } @article {pmid37860271, year = {2023}, author = {Ayoubi, R and Alshafie, W and You, Z and Southern, K and McPherson, PS and Laflamme, C}, title = {Identification of high-performing antibodies for Superoxide dismutase [Cu-Zn] 1 (SOD1) for use in Western blot, immunoprecipitation, and immunofluorescence.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {391}, pmid = {37860271}, issn = {2046-1402}, support = {FDN154305//CIHR/Canada ; }, mesh = {Humans ; *Superoxide Dismutase-1/immunology/genetics ; *Fluorescent Antibody Technique/methods ; *Immunoprecipitation/methods ; *Blotting, Western/methods ; *Antibodies/immunology ; Animals ; Mice ; }, abstract = {Superoxide dismutase [Cu-Zn] 1 (SOD1), is an antioxidant enzyme encoded by the gene SOD1, responsible for regulating oxidative stress levels by sequestering free radicals. Identified as the first gene with mutations in Amyotrophic lateral sclerosis (ALS), SOD1 is a determinant for studying diseases of aging and neurodegeneration. With guidance on well-characterized anti-SOD1 antibodies, the reproducibility of SOD1 research would be enhanced. In this study, we characterized eleven SOD1 commercial antibodies for Western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.}, } @article {pmid37860934, year = {2024}, author = {Recasens, BB and Balañá Corberó, A and Llorens, JMM and Guillen-Sola, A and Moreno, MV and Escobar, GG and Umayahara, Y and Soh, Z and Tsuji, T and Rubio, MÁ}, title = {Sound-based cough peak flow estimation in patients with neuromuscular disorders.}, journal = {Muscle & nerve}, volume = {69}, number = {2}, pages = {213-217}, doi = {10.1002/mus.27987}, pmid = {37860934}, issn = {1097-4598}, mesh = {Humans ; Reproducibility of Results ; *Neuromuscular Diseases/complications ; Peak Expiratory Flow Rate ; *Nervous System Diseases ; Cough ; }, abstract = {INTRODUCTION/AIMS: Cough impairment is common in individuals with neuromuscular disorders and is associated with respiratory infections and shorter survival. Cough strength is assessed by measuring cough peak flow (CPF) using a flow meter, but this method requires a complex device setup and trained staff. The aim of the study is to evaluate the reliability of a smartphone app to estimate CPF based on cough sounds in a cohort of individuals with neuromuscular disorders.

METHODS: Individuals with neuromuscular disorders underwent CPF measurement with a flow meter and a smartphone app. A CPF <270 L/min was considered abnormal.

RESULTS: Of the 50 patients studied, 26 had amyotrophic lateral sclerosis (52%), 15 had hereditary myopathies (30%), and 9 had myasthenia gravis (18%). The intraclass correlation coefficient (ICC) between the CPF measured with a flow meter and CPF estimated with cough sounds was 0.774 (p < .001) even if the patients had orofacial weakness (ICC = 0.806, p < .001). The smartphone app had 94.4% sensitivity and 100% specificity to detect patients with CPF of less than 270 L/min.

DISCUSSION: Our findings suggest that sounds measured with a smartphone app provide a reliable estimate of CPF in patients with neuromuscular disorders, even in the presence of with orofacial weakness. This may be a convenient way to monitor respiratory involvement in patients with neuromuscular disorders, but larger studies of more diverse patient cohorts are needed.}, } @article {pmid37861203, year = {2024}, author = {Van Wijk, IF and Van Eijk, RPA and Van Boxmeer, L and Westeneng, HJ and Van Es, MA and Van Rheenen, W and Van Den Berg, LH and Eijkemans, MJC and Veldink, JH}, title = {Assessment of risk of ALS conferred by the GGGGCC hexanucleotide repeat expansion in C9orf72 among first-degree relatives of patients with ALS carrying the repeat expansion.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {188-196}, doi = {10.1080/21678421.2023.2272187}, pmid = {37861203}, issn = {2167-9223}, mesh = {Humans ; Aged, 80 and over ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; Proteins/genetics ; }, abstract = {OBJECTIVES: We aimed to estimate the age-related risk of ALS in first-degree relatives of patients with ALS carrying the C9orf72 repeat expansion.

METHODS: We included all patients with ALS carrying a C9orf72 repeat expansion in The Netherlands. Using structured questionnaires, we determined the number of first-degree relatives, their age at death due to ALS or another cause, or age at time of questionnaire. The cumulative incidence of ALS among first-degree relatives was estimated, while accounting for death from other causes. Variability in ALS risk between families was evaluated using a random effects hazards model. We used a second, distinct approach to estimate the risk of ALS and FTD in the general population, using previously published data.

RESULTS: In total, 214 of the 2,486 (9.2%) patients with ALS carried the C9orf72 repeat expansion. The mean risk of ALS at age 80 for first-degree relatives carrying the repeat expansion was 24.1%, but ranged between individual families from 16.0 to 60.6%. Using the second approach, we found the risk of ALS and FTD combined was 28.7% (95% CI 17.8%-54.3%) for carriers in the general population.

CONCLUSIONS: On average, our estimated risk of ALS in the C9orf72 repeat expansion was lower compared to historical estimates. We showed, however, that the risk of ALS likely varies between families and one overall penetrance estimate may not be sufficient to describe ALS risk. This warrants a tailor-made, patient-specific approach in testing. Further studies are needed to assess the risk of FTD in the C9orf72 repeat expansion.}, } @article {pmid37862201, year = {2024}, author = {Yang, K and Yan, Y and Yu, A and Zhang, R and Zhang, Y and Qiu, Z and Li, Z and Zhang, Q and Wu, S and Li, F}, title = {Mitophagy in neurodegenerative disease pathogenesis.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {998-1005}, pmid = {37862201}, issn = {1673-5374}, abstract = {Mitochondria are critical cellular energy resources and are central to the life of the neuron. Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis. Mature neurons are postmitotic and consume substantial energy, thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria. Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases. However, more work is needed to study mitophagy pathway components as potential therapeutic targets. In this review, we briefly discuss the characteristics of nonselective autophagy and selective autophagy, including ERphagy, aggrephagy, and mitophagy. We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions. Next, we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy. Importantly, we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Last, we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases. Together, our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.}, } @article {pmid37862202, year = {2024}, author = {Tarot, P and Lasbleiz, C and Liévens, JC}, title = {NRF2 signaling cascade in amyotrophic lateral sclerosis: bridging the gap between promise and reality.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {1006-1012}, pmid = {37862202}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons. Symptoms include muscle weakness and atrophy, spasticity, and progressive paralysis. Currently, there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis. The only two treatments actually approved, riluzole and edaravone, have shown mitigated beneficial effects. The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis. Among mechanisms, abnormal RNA metabolism, nucleocytoplasmic transport defects, accumulation of unfolded protein, and mitochondrial dysfunction would in fine induce oxidative damage and vice versa. A potent therapeutic strategy will be to find molecules that break this vicious circle. Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense, mitochondrial functioning, and inflammation. We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.}, } @article {pmid37862205, year = {2024}, author = {Romano, R and Bucci, C}, title = {Antisense therapy: a potential breakthrough in the treatment of neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {1027-1035}, pmid = {37862205}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system. Currently, there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide. Therefore, it is necessary to find new therapeutic approaches, and antisense therapies offer this possibility, having the great advantage of not modifying cellular genome and potentially being safer. Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases. The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases, with a focus on those antisense therapies that have already received the approval of the U.S. Food and Drug Administration.}, } @article {pmid37862206, year = {2024}, author = {Hu, Y and Chen, W and Wei, C and Jiang, S and Li, S and Wang, X and Xu, R}, title = {Pathological mechanisms of amyotrophic lateral Sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {1036-1044}, pmid = {37862206}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system, the cause of which remains unexplained despite several years of research. Thus, the journey to understanding or treating amyotrophic lateral sclerosis is still a long one. According to current research, amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways. The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis. Here, we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis, as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis. In addition, we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis. Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.}, } @article {pmid37862967, year = {2023}, author = {Rabeh, N and Hajjar, B and Maraka, JO and Sammanasunathan, AF and Khan, M and Alkhaaldi, SMI and Mansour, S and Almheiri, RT and Hamdan, H and Abd-Elrahman, KS}, title = {Targeting mGluR group III for the treatment of neurodegenerative diseases.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {168}, number = {}, pages = {115733}, doi = {10.1016/j.biopha.2023.115733}, pmid = {37862967}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Signal Transduction/physiology ; Glutamic Acid ; Neurotransmitter Agents ; Neurons ; *Receptors, Metabotropic Glutamate/physiology ; }, abstract = {Glutamate, an excitatory neurotransmitter, is essential for neuronal function, and it acts on ionotropic or metabotropic glutamate receptors (mGluRs). A disturbance in glutamatergic signaling is a hallmark of many neurodegenerative diseases. Developing disease-modifying treatments for neurodegenerative diseases targeting glutamate receptors is a promising avenue. The understudied group III mGluR 4, 6-8 are commonly found in the presynaptic membrane, and their activation inhibits glutamate release. Thus, targeted mGluRs therapies could aid in treating neurodegenerative diseases. This review describes group III mGluRs and their pharmacological ligands in the context of amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's diseases. Attempts to evaluate the efficacy of these drugs in clinical trials are also discussed. Despite a growing list of group III mGluR-specific pharmacological ligands, research on the use of these drugs in neurodegenerative diseases is limited, except for Parkinson's disease. Future efforts should focus on delineating the contribution of group III mGluR to neurodegeneration and developing novel ligands with superior efficacy and a favorable side effect profile for the treatment of neurodegenerative diseases.}, } @article {pmid37863594, year = {2023}, author = {The Lancet Neurology, }, title = {Speeding up research to improve the lives of people with ALS.}, journal = {The Lancet. Neurology}, volume = {22}, number = {11}, pages = {971}, doi = {10.1016/S1474-4422(23)00380-0}, pmid = {37863594}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; }, } @article {pmid37863900, year = {2023}, author = {Hutter, N and Hendricks, S and Jutila, A and Ricker, R and von Albedyll, L and Birnbaum, G and Haas, C}, title = {Digital elevation models of the sea-ice surface from airborne laser scanning during MOSAiC.}, journal = {Scientific data}, volume = {10}, number = {1}, pages = {729}, pmid = {37863900}, issn = {2052-4463}, support = {03F0866A//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; 03F0866A//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; NA20OAR4320271 - 2023-1311//United States Department of Commerce | National Oceanic and Atmospheric Administration (NOAA)/ ; }, abstract = {Airborne laser scanners (ALS) are used to map the sea-ice surface at sub-meter resolution. We conducted 64 flights over the Arctic sea ice between September 2019 and September 2020 during the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition to measure sea-ice surface elevation. The flights ranged from repeated, local-scale 5 × 5 km[2] floe grid surveys to regional-scale transects more than 100 km long. We provide data at different processing levels: geolocated elevation point clouds and gridded segments of elevation and freeboard with a spatial resolution of 0.5 m. The latter product is corrected for atmospheric backscatter, sea-ice drift, and offset in elevation due to degraded INS/GNSS solutions > 85° N. For floe grid surveys, all data are combined to merged two-dimensional elevation maps. Other provided parameters include laser reflectance and echo width. The presented data offer a unique possibility to study the temporal evolution, spatial distribution, and variability of the snow and sea-ice surface and their properties in addition to validating satellite products.}, } @article {pmid37864255, year = {2023}, author = {Godfrey, RK and Alsop, E and Bjork, RT and Chauhan, BS and Ruvalcaba, HC and Antone, J and Gittings, LM and Michael, AF and Williams, C and Hala'ufia, G and Blythe, AD and Hall, M and Sattler, R and Van Keuren-Jensen, K and Zarnescu, DC}, title = {Modelling TDP-43 proteinopathy in Drosophila uncovers shared and neuron-specific targets across ALS and FTD relevant circuits.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {168}, pmid = {37864255}, issn = {2051-5960}, support = {R01 NS091299/NS/NINDS NIH HHS/United States ; RF1 NS091299/NS/NINDS NIH HHS/United States ; T34 GM008718/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; DNA-Binding Proteins/genetics/metabolism ; Drosophila/metabolism ; *Frontotemporal Dementia/genetics/pathology ; Motor Neurons/metabolism ; *Pick Disease of the Brain/pathology ; RNA, Messenger ; *TDP-43 Proteinopathies/pathology ; Drosophila Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy, which at the cellular level, is characterized by loss of nuclear TDP-43 and accumulation of cytoplasmic TDP-43 inclusions that ultimately cause RNA processing defects including dysregulation of splicing, mRNA transport and translation. Complementing our previous work in motor neurons, here we report a novel model of TDP-43 proteinopathy based on overexpression of TDP-43 in a subset of Drosophila Kenyon cells of the mushroom body (MB), a circuit with structural characteristics reminiscent of vertebrate cortical networks. This model recapitulates several aspects of dementia-relevant pathological features including age-dependent neuronal loss, nuclear depletion and cytoplasmic accumulation of TDP-43, and behavioral deficits in working memory and sleep that occur prior to axonal degeneration. RNA immunoprecipitations identify several candidate mRNA targets of TDP-43 in MBs, some of which are unique to the MB circuit and others that are shared with motor neurons. Among the latter is the glypican Dally-like-protein (Dlp), which exhibits significant TDP-43 associated reduction in expression during aging. Using genetic interactions we show that overexpression of Dlp in MBs mitigates TDP-43 dependent working memory deficits, conistent with Dlp acting as a mediator of TDP-43 toxicity. Substantiating our findings in the fly model, we find that the expression of GPC6 mRNA, a human ortholog of dlp, is specifically altered in neurons exhibiting the molecular signature of TDP-43 pathology in FTD patient brains. These findings suggest that circuit-specific Drosophila models provide a platform for uncovering shared or disease-specific molecular mechanisms and vulnerabilities across the spectrum of TDP-43 proteinopathies.}, } @article {pmid37864389, year = {2024}, author = {Xiao, F and He, Z and Wang, S and Li, J and Fan, X and Yan, T and Yang, M and Yang, D}, title = {Regulatory mechanism of circular RNAs in neurodegenerative diseases.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {4}, pages = {e14499}, pmid = {37864389}, issn = {1755-5949}, support = {//China Scholarship Council/ ; //National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/genetics ; RNA, Circular/metabolism ; *MicroRNAs/genetics ; *Alzheimer Disease/genetics ; *Parkinson Disease ; Biomarkers ; }, abstract = {BACKGROUND: Neurodegenerative disease is a collective term for a category of diseases that are caused by neuronal dysfunction, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Circular RNAs (circRNAs) are a class of non-coding RNAs without the 3' cap and 5' poly(A) and are linked by covalent bonds. CircRNAs are highly expressed in brain neurons and can regulate the pathological process of neurodegenerative diseases by affecting the levels of various deposition proteins.

AIMS: This review is aiming to suggest that the majority of circRNAs influence neurodegenerative pathologies mainly by affecting the abnormal deposition of proteins in neurodegenerative diseases.

METHODS: We systematically summarized the pathological features of neurodegenerative diseases and the regulatory mechanisms of circRNAs in various types of neurodegenerative diseases.

RESULTS: Neurodegenerative disease main features include intercellular ubiquitin-proteasome system abnormalities, changes in cytoskeletal proteins, and the continuous deposition of insoluble protein fragments and inclusion bodies in the cytoplasm or nucleus, resulting in impairment of the normal physiological processes of the neuronal system. CircRNAs have multiple mechanisms, such as acting as microRNA sponges, binding to proteins, and regulating transcription. CircRNAs, which are highly stable molecules, are expected to be potential biomarkers for the pathological detection of neurodegenerative diseases such as AD and PD.

CONCLUSIONS: In this review, we describe the regulatory roles and mechanisms of circRNAs in neurodegenerative diseases and aim to employ circRNAs as biomarkers for the diagnosis and treatment of neurodegenerative diseases.}, } @article {pmid37865833, year = {2023}, author = {Wu, YK and Wecht, JM and Bloom, OE and Panza, GS and Harel, NY}, title = {Remote Ischemic conditioning as an emerging tool to improve corticospinal transmission in individuals with chronic spinal cord injury.}, journal = {Current opinion in neurology}, volume = {36}, number = {6}, pages = {523-530}, doi = {10.1097/WCO.0000000000001216}, pmid = {37865833}, issn = {1473-6551}, support = {R03 HD097709/HD/NICHD NIH HHS/United States ; }, mesh = {Adult ; Humans ; *Myocardial Infarction ; *Stroke ; *Spinal Cord Injuries ; Hypoxia ; }, abstract = {PURPOSE OF REVIEW: Remote ischemic conditioning (RIC) involves transient blood flow restriction to one limb leading to systemic tissue-protective effects. RIC shares some potential underlying mechanisms with intermittent hypoxia (IH), in which brief bouts of systemic hypoxia trigger increases in growth factor expression and neural plasticity. RIC has shown promise in acute myocardial infarction and stroke but may be applicable toward chronic neuropathology as well. Consequently, this review discusses similarities and differences between RIC and IH and presents preliminary and ongoing research findings regarding RIC.

RECENT FINDINGS: Several publications demonstrated that combining RIC with motor training may enhance motor learning in adults with intact nervous systems, though the precise mechanisms were unclear. Our own preliminary data has found that RIC, in conjunction with task specific exercise, can increase corticospinal excitability in a subset of people without neurological injury and in those with chronic cervical spinal cord injury or amyotrophic lateral sclerosis.

SUMMARY: RIC is a low-cost intervention easy to deliver in a clinical or home setting. Its potential application to facilitate neural plasticity and motor learning during rehabilitation training for individuals with chronic neurological disorders is a novel concept requiring further investigation to characterize mechanisms, safety, and efficacy.}, } @article {pmid37865869, year = {2024}, author = {Vélez-GóMEZ, B and Perna, A and Vazquez, C and Ketzoian, C and Lillo, P and Godoy-Reyes, G and Sáez, D and Zaldivar Vaillant, T and Gutiérrez Gil, JV and Lara-Fernández, GE and Povedano, M and Heverin, M and McFarlane, R and Logroscino, G and Hardiman, O}, title = {LAENALS: epidemiological and clinical features of amyotrophic lateral sclerosis in Latin America.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {119-127}, doi = {10.1080/21678421.2023.2271517}, pmid = {37865869}, issn = {2167-9223}, mesh = {Male ; Humans ; Female ; Latin America/epidemiology ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Cuba/epidemiology ; Uruguay/epidemiology ; Prevalence ; }, abstract = {OBJECTIVE: The Latin American Epidemiologic study of ALS (LAENALS) aims to gather data on ALS epidemiology, phenotype, and risk factors in Cuba, Chile, and Uruguay, to understand the impact of genetic and environmental factors on ALS.

METHODS: A harmonized data collection protocol was generated, and a Latin-American Spanish language Register was constructed. Patient data were collected in Uruguay in 2018, in Chile from 2017 to 2019, and in Cuba between 2017 and 2018. Statistical analysis was performed using SPSS 25.0.0 software. Crude cumulative incidence, standardized incidence, and prevalence were calculated in the population aged 15 years and older.

RESULTS: During 2017-2019, 90 people with ALS from Uruguay (55.6% men), 219 from Chile (54.6% men), and 49 from Cuba (55.1% men) were included. The cumulative crude incidence in 2018 was 1.73/100,000 persons in Uruguay, 1.08 in Chile and 0.195 in Cuba. Crude prevalence in 2018 was 2.19 per 100,000 persons in Uruguay, 1.39 in Chile and 0.55 in Cuba. Mean age at onset was 61.8 ± 11.96 SD years in Uruguay, 61.9 ± 10.4 SD years in Chile, and 60.21 ± 12.45 SD years in Cuba (p = 0.75). Median survival from onset was 32.43 months (21.93 - 42.36) in Uruguay, 24 months (13.5 - 33.5) in Chile, and 29 months (15 - 42.5) in Cuba (p = 0.006).

CONCLUSIONS: These preliminary data from LAENALS confirm the lower incidence and prevalence of ALS in counties with admixed populations. The LAENALS database is now open to other Latin American countries for harmonized prospective data collection.}, } @article {pmid37868386, year = {2023}, author = {Hoxhaj, P and Hastings, N and Kachhadia, MP and Gupta, R and Sindhu, U and Durve, SA and Azam, A and Auz Vinueza, MJ and Bhuvan, and Win, SH and Rathod, DC and Afsar, AP}, title = {Exploring Advancements in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review of Current Modalities and Future Prospects.}, journal = {Cureus}, volume = {15}, number = {9}, pages = {e45489}, pmid = {37868386}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease requiring a multidisciplinary treatment approach and a collaborative therapeutic effort. A combination of both upper and lower motor neuron degeneration ultimately leads to respiratory failure, similar to other dementia-type neurodegenerative diseases. The aim of this paper is to pioneer current ALS research by carrying out a narrative literature review of the current treatment modalities of the disease. Through these efforts, we hope to condense the most pertinent information regarding current treatments and enhance the management of ALS patients as a whole, giving these patients a better quality of life as the search for a cure continues. We used a Pubmed search strategy and specific MeSH terms for the selection of the literature articles using the keywords "ALS," "new treatment," "treatment," and "symptomatic treatment." A combination of pharmaceutical interventions, psychological support, and physical rehabilitation has been most effective in enhancing the quality of life of patients with ALS (PALS). Among potential pharmacological therapies, only a few have been approved by the US Food and Drug Administration(FDA) to be used to treat ALS and its symptoms. Other treatment modalities being considered include gene therapy, cellular therapy, psychological therapy, physical therapy, and speech therapy, alongside robotics, alternative feeding methods, and communication devices.}, } @article {pmid37870566, year = {2023}, author = {Miller, CCJ and Gomez-Suaga, P}, title = {Poor communication between ER and mitochondria: a signature of ALS/FTD?.}, journal = {Aging}, volume = {15}, number = {20}, pages = {10814-10816}, pmid = {37870566}, issn = {1945-4589}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; DNA Repeat Expansion ; Mitochondria ; }, } @article {pmid37870677, year = {2024}, author = {Wang, S and Zheng, X and Wei, Q and Lin, J and Yang, T and Xiao, Y and Jiang, Q and Li, C and Shang, H}, title = {Rare DNAJC7 Variants May Play a Minor Role in Chinese Patients with ALS.}, journal = {Molecular neurobiology}, volume = {61}, number = {4}, pages = {2265-2269}, pmid = {37870677}, issn = {1559-1182}, support = {2022ZDZX0023//Sichuan Science and Technology Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Genetic Association Studies ; Mutation, Missense ; Gene Frequency ; China ; Heat-Shock Proteins/genetics ; Molecular Chaperones ; }, abstract = {DnaJ heat shock protein family member C7 gene (DNAJC7) has been identified as a genetic risk factor for amyotrophic lateral sclerosis (ALS). In our study, we aimed to screen for rare variants in DNAJC7 in a large cohort of Chinese ALS patients, and investigate the genotype-phenotype correlation of DNAJC7 in ALS. Four (0.19%) variants of DNAJC7 with minor allele frequency (MAF) < 0.1% among 2124 patients were identified, including 1 protein-truncating variant and 3 missense variants, all of which were predicted to be damaging. The patients carrying variants of DNAJC7 in our cohort tented to have a limb onset and a relatively slow disease progression. However, burden analysis did not show an enrichment of rare damaging variants in ALS patients compared to controls. Further analysis involving diverse regions and larger sample size is necessary to elucidate the role of DNAJC7 in the pathogenicity of ALS.}, } @article {pmid37870685, year = {2023}, author = {Zhou, L and Chen, W and Jiang, S and Xu, R}, title = {In Vitro Models of Amyotrophic Lateral Sclerosis.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {8}, pages = {3783-3799}, pmid = {37870685}, issn = {1573-6830}, support = {30560042//National Natural Science Foundation of China/ ; 81160161//National Natural Science Foundation of China/ ; 81360198//National Natural Science Foundation of China/ ; 82160255//National Natural Science Foundation of China/ ; GJJ13198//Education Department of Jiangxi Province/ ; GJJ170021//Education Department of Jiangxi Province/ ; 20192BAB205043//Jiangxi Provincial Department of Science and Technology/ ; 20181019//Health and Family Planning Commission of Jiangxi Province/ ; 202210002//Health and Family Planning Commission of Jiangxi Province/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Disease Models, Animal ; Motor Neurons/metabolism ; Mutation/genetics ; Superoxide Dismutase/metabolism ; Mice, Transgenic ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is one of the commonest neurodegenerative diseases of adult-onset, which is characterized by the progressive death of motor neurons in the cerebral cortex, brain stem and spinal cord. The dysfunction and death of motor neurons lead to the progressive muscle weakness, atrophy, fasciculations, spasticity and ultimately the whole paralysis of body. Despite the identification of several genetic mutations associated with the pathogenesis of ALS, including mutations in chromosome 9 open reading frame 72 leading to the abnormal expansion of GGGGCC repeat sequence, TAR DNA-binding protein 43, fused in sarcoma/translocated in liposarcoma, copper/zinc superoxide dismutase 1 (SOD1) and TANK-binding kinase 1, the exact mechanisms underlying the specific degeneration of motor neurons that causes ALS remain incompletely understood. At present, since the transgenic model expressed SOD1 mutants was established, multiple in vitro models of ALS have been developed for studying the pathology, pathophysiology and pathogenesis of ALS as well as searching the effective neurotherapeutics. This review reviewed the details of present established in vitro models used in studying the pathology, pathophysiology and pathogenesis of ALS. Meanwhile, we also discussed the advantages, disadvantages, cost and availability of each models.}, } @article {pmid37871782, year = {2024}, author = {Burns, B and Marschner, I and Eggins, R and Buscher, H and Morton, RL and Bendall, J and Keech, A and Dennis, M and , }, title = {A randomized trial of expedited intra-arrest transfer versus more extended on-scene resuscitation for refractory out of hospital cardiac arrest: Rationale and design of the EVIDENCE trial.}, journal = {American heart journal}, volume = {267}, number = {}, pages = {22-32}, doi = {10.1016/j.ahj.2023.10.003}, pmid = {37871782}, issn = {1097-6744}, mesh = {Adolescent ; Adult ; Aged ; Humans ; Middle Aged ; Young Adult ; *Cardiopulmonary Resuscitation ; *Emergency Medical Services ; *Out-of-Hospital Cardiac Arrest/therapy ; Prospective Studies ; Quality of Life ; *Tachycardia, Ventricular ; Clinical Trials, Phase III as Topic ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Refractory Out of Hospital Cardiac Arrest (r-OHCA) is common and the benefit versus harm of intra-arrest transport of patients to hospital is not clear.

OBJECTIVE: To assess the rate of survival to hospital discharge in adult patients with r-OHCA, initial rhythm pulseless ventricular tachycardia (VT)/ventricular fibrillation (VF) or Pulseless Electrical Activity (PEA) treated with 1 of 2 locally accepted standards of care:[1] expedited transport from scene; or[2] ongoing advanced life support (ALS) resuscitation on-scene.

HYPOTHESIS: We hypothesize that expedited transport from scene in r-OHCA improves survival with favorable neurological status/outcome.

METHODS/DESIGN: Phase III, multi-center, partially blinded, prospective, intention-to-treat, safety and efficacy clinical trial with contemporaneous registry of patient ineligible for the clinical trial. Eligible patients for inclusion are adults with witnessed r-OHCA; estimated age 18 to 70, assumed medical cause with immediate bystander cardiopulmonary resuscitation (CPR); initial rhythm of VF/pulseless VT, or PEA; no return of spontaneous circulation following 3 shocks and/or 15 minutes of professional on-scene resuscitation; with mechanical CPR available. Two hundred patients will be randomized in a 1:1 ratio to either expedited transport from scene or ongoing ALS at the scene of cardiac arrest.

SETTING: Two urban regions in NSW Australia.

OUTCOMES: Primary: survival to hospital discharge with cerebral performance category (CPC) 1 or 2. Secondary: safety, survival, prognostic factors, use of ECMO supported CPR and functional assessment at hospital discharge and 4 weeks and 6 months, quality of life, healthcare use and cost-effectiveness.

CONCLUSIONS: The EVIDENCE trial will determine the potential risks and benefits of an expedited transport from scene of cardiac arrest.}, } @article {pmid37872557, year = {2023}, author = {Li, C and Wei, Q and Hou, Y and Lin, J and Ou, R and Zhang, L and Jiang, Q and Xiao, Y and Liu, K and Chen, X and Yang, T and Song, W and Zhao, B and Wu, Y and Shang, H}, title = {Genome-wide analyses identify NEAT1 as genetic modifier of age at onset of amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {77}, pmid = {37872557}, issn = {1750-1326}, mesh = {Humans ; Age of Onset ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Asian People ; Genome-Wide Association Study/methods ; Polymorphism, Single Nucleotide ; RNA, Long Noncoding ; }, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) demonstrate great heterogeneity in the age at onset (AAO), which is closely related to the course of disease. However, most genetic studies focused on the risk of ALS, while the genetic background underlying AAO of ALS is still unknown.

METHODS: To identify genetic determinants influencing AAO of ALS, we performed genome-wide association analysis using a Cox proportional hazards model in 2,841 patients with ALS (Ndiscovery = 2,272, Nreplication = 569) in the Chinese population. We further conducted colocalization analysis using public cis-eQTL dataset, and Mendelian randomization analysis to identify risk factors for AAO of ALS. Finally, functional experiments including dual-luciferase reporter assay and RT-qPCR were performed to explore the regulatory effect of the target variant.

RESULTS: The total heritability of AAO of ALS was ~ 0.24. One novel locus rs10128627 (FRMD8) was significantly associated with earlier AAO by ~ 3.15 years (P = 1.54E-08, beta = 0.31, SE = 0.05). This locus was cis-eQTL of NEAT1 in multiple brain tissues and blood. Colocalization analysis detected association signals at this locus between AAO of ALS and expression of NEAT1. Furthermore, functional exploration supported the variant rs10128627 was associated with upregulated expression of NEAT1 in cell models and patients with ALS. Causal inference suggested higher total cholesterol, low-density lipoprotein, and eosinophil were nominally associated with earlier AAO of ALS, while monocyte might delay the AAO.

CONCLUSIONS: Collective evidence from genetic, bioinformatic, and functional results suggested NEAT1 as a key player in the disease progression of ALS. These findings improve the current understanding of the genetic role in AAO of ALS, and provide a novel target for further research on the pathogenesis and therapeutic options to delay the disease onset.}, } @article {pmid37872558, year = {2023}, author = {Schmitz, J and Liebold, F and Hinkelbein, J and Nöhl, S and Thal, SC and Sellmann, T}, title = {Cardiopulmonary resuscitation during hyperbaric oxygen therapy: a comprehensive review and recommendations for practice.}, journal = {Scandinavian journal of trauma, resuscitation and emergency medicine}, volume = {31}, number = {1}, pages = {57}, pmid = {37872558}, issn = {1757-7241}, mesh = {Humans ; *Cardiopulmonary Resuscitation ; *Heart Arrest/therapy ; Heart Massage ; *Hyperbaric Oxygenation ; Ventricular Fibrillation ; Practice Guidelines as Topic ; }, abstract = {BACKGROUND: Cardiopulmonary resuscitation (CPR) during hyperbaric oxygen therapy (HBOT) presents unique challenges due to limited access to patients in cardiac arrest (CA) and the distinct physiological conditions present during hyperbaric therapy. Despite these challenges, guidelines specifically addressing CPR during HBOT are lacking. This review aims to consolidate the available evidence and offer recommendations for clinical practice in this context.

MATERIALS AND METHODS: A comprehensive literature search was conducted in PubMed, EMBASE, Cochrane Library, and CINAHL using the search string: "(pressure chamber OR decompression OR hyperbaric) AND (cardiac arrest OR cardiopulmonary resuscitation OR advanced life support OR ALS OR life support OR chest compression OR ventricular fibrillation OR heart arrest OR heart massage OR resuscitation)". Additionally, relevant publications and book chapters not identified through this search were included.

RESULTS: The search yielded 10,223 publications, with 41 deemed relevant to the topic. Among these, 18 articles (primarily case reports) described CPR or defibrillation in 22 patients undergoing HBOT. The remaining 23 articles provided information or recommendations pertaining to CPR during HBOT. Given the unique physiological factors during HBOT, the limitations of current resuscitation guidelines are discussed.

CONCLUSIONS: CPR in the context of HBOT is a rare, yet critical event requiring special considerations. Existing guidelines should be adapted to address these unique circumstances and integrated into regular training for HBOT practitioners. This review serves as a valuable contribution to the literature on "CPR under special circumstances".}, } @article {pmid37872607, year = {2023}, author = {Falker-Gieske, C}, title = {Transcriptome driven discovery of novel candidate genes for human neurological disorders in the telomer-to-telomer genome assembly era.}, journal = {Human genomics}, volume = {17}, number = {1}, pages = {94}, pmid = {37872607}, issn = {1479-7364}, support = {R01 GM129325/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Transcriptome/genetics ; Genomics ; *Nervous System Diseases/genetics ; Sequence Analysis, RNA ; Telomere ; }, abstract = {BACKGROUND: With the first complete draft of a human genome, the Telomere-to-Telomere Consortium unlocked previously concealed genomic regions for genetic analyses. These regions harbour nearly 2000 potential novel genes with unknown function. In order to uncover candidate genes associated with human neurological pathologies, a comparative transcriptome study using the T2T-CHM13 and the GRCh38 genome assemblies was conducted on previously published datasets for eight distinct human neurological disorders.

RESULTS: The analysis of differential expression in RNA sequencing data led to the identification of 336 novel candidate genes linked to human neurological disorders. Additionally, it was revealed that, on average, 3.6% of the differentially expressed genes detected with the GRCh38 assembly may represent potential false positives. Among the noteworthy findings, two novel genes were discovered, one encoding a pore-structured protein and the other a highly ordered β-strand-rich protein. These genes exhibited upregulation in multiple epilepsy datasets and hold promise as candidate genes potentially modulating the progression of the disease. Furthermore, an analysis of RNA derived from white matter lesions in multiple sclerosis patients indicated significant upregulation of 26 rRNA encoding genes. Additionally, putative pathology related genes were identified for Alzheimer's disease, amyotrophic lateral sclerosis, glioblastoma, glioma, and conditions resulting from the m.3242 A > G mtDNA mutation.

CONCLUSION: The results presented here underline the potential of the T2T-CHM13 assembly in facilitating the discovery of candidate genes from transcriptome data in the context of human disorders. Moreover, the results demonstrate the value of remapping sequencing data to a superior genome assembly. Numerous potential pathology related genes, either as causative factors or related elements, have been unveiled, warranting further experimental validation.}, } @article {pmid37872794, year = {2023}, author = {You, FL and Xia, GF and Cai, J}, title = {Behavioural Variant Frontotemporal Dementia due to CCNF Gene Mutation: A Case Report.}, journal = {Current Alzheimer research}, volume = {20}, number = {5}, pages = {371-378}, doi = {10.2174/1567205020666230811092906}, pmid = {37872794}, issn = {1875-5828}, mesh = {Male ; Humans ; Aged ; *Frontotemporal Dementia/diagnosis/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Neurodegenerative Diseases ; Memantine/therapeutic use ; Mutation/genetics ; Neuropsychological Tests ; Sodium ; Cyclins/genetics ; }, abstract = {BACKGROUND: Frontal, temporal lobe dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative diseases. Studies have found that CCNF mutations have been found in patients with familial and sporadic ALS and FTD. Behavioural variant frontotemporal dementia (bvFTD) is a clinical syndrome characterized by progressive deterioration of personality, social behaviour, and cognitive function, which is most closely related to genetic factors. As the early symptoms of bvFTD are highly heterogeneous, the condition is often misdiagnosed as Alzheimer's disease or psychiatric disorders. In this study, a bvFTD patient had a CCNF gene mutation, which led to ubiquitinated protein accumulation and ultimately caused neurodegenerative disease. Genetic detection should be improved urgently for bvFTD patients and family members to provide a clinical reference for early diagnosis of frontotemporal dementia.

CASE PRESENTATION: In this case, the patient was 65 years old with an insidious onset, early-onset memory loss, a significant decline in the episodic memory, an early AD diagnosis, and oral treatment with donepezil hydrochloride for 3 years with poor efficacy, followed by a change to oral memantine hydrochloride tablets, which controlled the condition for several months. His medication was switched to sodium oligomannate capsules, and his condition was gradually controlled, but no significant improvement was observed. After spontaneous drug withdrawal, the patient's condition progressed rapidly; therefore, he visited our hospital and underwent neuropsychological tests for moderate to severe cognitive impairment. AD cerebrospinal fluid markers showed no significant abnormalities, and cranial MRI revealed frontotemporal lobe atrophy and decreased hippocampal volume. Genetic testing for the presence of the CCNF gene revealed a c.1532C > A (p. T511N) heterozygous variant, which might be a diagnostic criterion for bvFTD. Therefore, the patient's symptoms recurred after transient improvement with the combination of donepezil, oral memantine hydrochloride tablets, and sodium oligomannate, but his overall condition was improved compared to that before, and this treatment regimen was continued to observe changes during the follow-up.

CONCLUSION: The early clinical manifestations of bvFTD are complex and variable, and the condition is easily misdiagnosed, thus delaying treatment. Therefore, for patients with a high clinical suspicion of FTD, in addition to a detailed understanding of their medical history and family history and improvement of relevant examinations, genetic testing should be performed as early as possible to help confirm the diagnosis. For diseases closely related to genes, genetic testing of other family members should be optimised as much as possible to allow early diagnosis and intervention and guide fertility in the next generation.}, } @article {pmid37873064, year = {2023}, author = {Mann, N and Hill, J and Wang, K and Hughes, RM}, title = {OptoProfilin: A Single Component Biosensor of Applied Cellular Stress.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37873064}, issn = {2692-8205}, support = {R15 NS125564/NS/NINDS NIH HHS/United States ; }, abstract = {The actin cytoskeleton is a biosensor of cellular stress and a potential prognosticator of human disease. In particular, aberrant cytoskeletal structures such as cofilin-actin rods and stress granules formed in response to energetic and oxidative stress are closely linked to neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. Whether these cytoskeletal phenomena can be harnessed for the development of biosensors for cytoskeletal dysfunction and, by extension, neurodegenerative disease progression, remains an open question. In this work, we describe the design and development of an optogenetic iteration of profilin, an actin monomer binding protein with critical functions in cytoskeletal dynamics. We demonstrate that this optically activated profilin ('OptoProfilin') can act as an optically triggered biosensor of applied cellular stress in select immortalized cell lines. Notably, OptoProfilin is a single component biosensor, likely increasing its utility for experimentalists. While a large body of preexisting work closely links profilin activity with cellular stress and neurodegenerative disease, this, to our knowledge, is the first example of profilin as an optogenetic biosensor of stress-induced changes in the cytoskeleton.}, } @article {pmid37873158, year = {2024}, author = {Alecki, C and Rizwan, J and Le, P and Jacob-Tomas, S and Fernandez-Comaduran, M and Verbrugghe, M and Xu, JSM and Minotti, S and Lynch, J and Biswas, J and Wu, T and Durham, H and Yeo, GW and Vera, M}, title = {Localized synthesis of molecular chaperones sustains neuronal proteostasis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.10.03.560761}, pmid = {37873158}, issn = {2692-8205}, support = {RF1 MH126719/MH/NIMH NIH HHS/United States ; U41 HG009889/HG/NHGRI NIH HHS/United States ; U24 HG009889/HG/NHGRI NIH HHS/United States ; R01 HG004659/HG/NHGRI NIH HHS/United States ; R01 HG011864/HG/NHGRI NIH HHS/United States ; R01 NS103172/NS/NINDS NIH HHS/United States ; }, abstract = {Neurons are challenged to maintain proteostasis in neuronal projections, particularly with the physiological stress at synapses to support intercellular communication underlying important functions such as memory and movement control. Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. Using high-resolution fluorescent microscopy, we discovered that neurons localize a subset of chaperone mRNAs to their dendrites, particularly more proximal regions, and increase this asymmetric localization following proteotoxic stress through microtubule-based transport from the soma. The most abundant chaperone mRNA in dendrites encodes the constitutive heat shock protein 70, HSPA8. Proteotoxic stress in cultured neurons, induced by inhibiting proteasome activity or inducing oxidative stress, enhanced transport of Hspa8 mRNAs to dendrites and the percentage of mRNAs engaged in translation on mono and polyribosomes. Knocking down the ALS-related protein Fused in Sarcoma (FUS) and a dominant mutation in the heterogenous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) impaired stress-mediated localization of Hspa8 mRNA to dendrites in cultured murine motor neurons and human iPSC-derived neurons, respectively, revealing the importance of these RNA-binding proteins in maintaining proteostasis. These results reveal the increased dendritic localization and translation of the constitutive HSP70 Hspa8 mRNA as a crucial neuronal stress response to uphold proteostasis and prevent neurodegeneration.}, } @article {pmid37873269, year = {2023}, author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and , and Aitman, TJ and Santoyo-Lopez, J and , and Mitsumoto, H and , and , and , and Goldstein, DB and Harms, MB}, title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37873269}, support = {K01 MH098126/MH/NIMH NIH HHS/United States ; RC2 MH089915/MH/NIMH NIH HHS/United States ; P01 HD080642/HD/NICHD NIH HHS/United States ; R01 MH097971/MH/NIMH NIH HHS/United States ; RC2 NS070344/NS/NINDS NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; P30 AG028377/AG/NIA NIH HHS/United States ; U54 NS078059/NS/NINDS NIH HHS/United States ; P01 AG007232/AG/NIA NIH HHS/United States ; RF1 AG054023/AG/NIA NIH HHS/United States ; R01 HD048805/HD/NICHD NIH HHS/United States ; U01 HG007672/HG/NHGRI NIH HHS/United States ; U01 NS053998/NS/NINDS NIH HHS/United States ; U01 NS077303/NS/NINDS NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; R01 ES016348/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 30,000 people in the United States. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms, such as antisense oligonucleotides, continue to develop, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.

METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger cohort of 6,970 ALS patients from a large multi-ethnic cohort as well as 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.

RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR=19.18, p = 3.67 × 10[-39]; OR=4.73, p = 2 × 10[-10]; OR=2.3, p = 7.49 × 10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10[-7]), was protective for ALS in this model. An intolerant domain based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR=10.08, p = 3.62 × 10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p=8.38 × 10[-6]).

CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, rare variant burden testing validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.}, } @article {pmid37874476, year = {2024}, author = {Liu, Y and He, X and Yuan, Y and Li, B and Liu, Z and Li, W and Li, K and Tan, S and Zhu, Q and Tang, Z and Han, F and Wu, Z and Shen, L and Jiang, H and Tang, B and Qiu, J and Hu, Z and Wang, J}, title = {Association of TRMT2B gene variants with juvenile amyotrophic lateral sclerosis.}, journal = {Frontiers of medicine}, volume = {18}, number = {1}, pages = {68-80}, pmid = {37874476}, issn = {2095-0225}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Neurodegenerative Diseases ; HEK293 Cells ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons, and it demonstrates high clinical heterogeneity and complex genetic architecture. A variation within TRMT2B (c.1356G>T; p.K452N) was identified to be associated with ALS in a family comprising two patients with juvenile ALS (JALS). Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS, and three more variants were identified in a public ALS database including 3317 patients with ALS. A decreased number of mitochondria, swollen mitochondria, lower expression of ND1, decreased mitochondrial complex I activities, lower mitochondrial aerobic respiration, and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells. Further, TRMT2B variations overexpression cells also displayed decreased ND1. In conclusion, a novel JALS-associated gene called TRMT2B was identified, thus broadening the clinical and genetic spectrum of ALS.}, } @article {pmid37874905, year = {2023}, author = {Harrison, D and Billinton, A and Bock, MG and Doedens, JR and Gabel, CA and Holloway, MK and Porter, RA and Reader, V and Scanlon, J and Schooley, K and Watt, AP}, title = {Discovery of Clinical Candidate NT-0796, a Brain-Penetrant and Highly Potent NLRP3 Inflammasome Inhibitor for Neuroinflammatory Disorders.}, journal = {Journal of medicinal chemistry}, volume = {66}, number = {21}, pages = {14897-14911}, doi = {10.1021/acs.jmedchem.3c01398}, pmid = {37874905}, issn = {1520-4804}, mesh = {Humans ; *Inflammasomes/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/physiology ; Neuroinflammatory Diseases ; Brain/metabolism ; Esters ; }, abstract = {The NLRP3 inflammasome is a component of the innate immune system involved in the production of proinflammatory cytokines. Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, have been shown to have a component driven by NLRP3 inflammasome activation. Diseases such as these with large unmet medical needs have resulted in an interest in inhibiting the NLRP3 inflammasome as a potential pharmacological treatment, but to date, no marketed drugs specifically targeting NLRP3 have been approved. Furthermore, the requirement for CNS-penetrant molecules adds additional complexity to the search for NLRP3 inflammasome inhibitors suitable for clinical investigation of neuroinflammatory disorders. We designed a series of ester-substituted carbamate compounds as selective NLRP3 inflammasome inhibitors, leading to NT-0796, an isopropyl ester that undergoes intracellular conversion to NDT-19795, the carboxylic acid active species. NT-0796 was shown to be a potent and selective NLRP3 inflammasome inhibitor with demonstrated in vivo brain penetration.}, } @article {pmid37875101, year = {2024}, author = {Karacaoglu, C and Ersoy, S and Pala, E and Engin, VS}, title = {Evaluation of the Effectiveness of Wet Cupping Therapy in Fibromyalgia Patients: A Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {10-19}, doi = {10.1159/000534637}, pmid = {37875101}, issn = {2504-2106}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Cupping Therapy ; *Fibromyalgia/therapy ; Quality of Life ; Treatment Outcome ; Adolescent ; Young Adult ; Aged ; }, abstract = {INTRODUCTION: The aim of this study was to investigate the efficacy of wet cupping therapy (WCT) in patients diagnosed with fibromyalgia syndrome (FMS) as a complementary method in fibromyalgia treatment.

MATERIALS AND METHODS: A total of 120 participants between 18 and 65 years who were diagnosed with FMS were included in the study. They were randomized into two groups: 60 patients as the intervention and 60 patients as the control group. Each participant in the intervention group received 3 sessions of WCT once a month in addition to their ongoing treatment whereas the control group received only routine medical treatment. The evaluation was conducted in both groups based on the fibromyalgia impact questionnaire (FIQ), visual analog scale (VAS), and quality of life scale (QoL) parameters initially (at 0th week) and 1 week after the WCT sessions (at the 10th week). For the comparison of quantitative variables showing a normal distribution between the two groups, the Student's t test was used, while the Mann-Whitney U test was employed for variables not showing a normal distribution. The χ2 test and Continuity (Yates) Correction were used for the comparison of qualitative data. The significance level was set at p < 0.05.

RESULTS: The study included 107 female and 13 male participants, with a mean age of 45.79 ± 8.49 years. When comparing the pretreatment FIQ, VAS, and QoL scores with the scores obtained after three sessions of WCT, it was observed that in the WCT group, the FIQ and VAS values significantly decreased compared to the control group while the QoL significantly increased compared to the control group (p < 0.001 in all).

CONCLUSION: The findings obtained from this study indicate that WCT can be an effective treatment option for patients with FMS.

UNLABELLED: EinleitungMit dieser Studie soll die Wirksamkeit der blutigen Schröpftherapie (wet cupping therapy, WCT) bei Patienten mit diagnostiziertem Fibromyalgie-Syndrom (FMS) als komplementäre Methode in der Fibromyalgie-Behandlung untersucht werden.Material und MethodenInsgesamt wurden 120 Teilnehmer mit diagnostiziertem FMS zwischen 18 und 65 Jahren in die Studie aufgenommen. Diese wurden randomisiert zwei Gruppen zugeordnet: 60 Patienten wurden der Interventionsgruppe zugewiesen und 60 Patienten der Kontrollgruppe. Alle Teilnehmer der Interventionsgruppe erhielten einmal im Monat drei Sitzungen WCT zusätzlich zu ihrer laufenden Therapie, während die Kontrollgruppe lediglich die Standardbehandlung erhielt. Die Bewertung erfolgte in beiden Gruppen anhand des Fibromyalgia Impact Questionnaire (FIQ), der Visuellen Analogskala (VAS) und der Parameter der Quality of Life (QoL) Scale zu Beginn (in Woche 0) und eine Woche nach den WCT-Sitzungen (in Woche 10). Für den Vergleich von quantitativen Variablen, die eine Normalverteilung zwischen den beiden Gruppen aufwiesen, wurde der Student’s t-Test verwendet, während bei Variablen ohne Normalverteilung der Mann-Whitney-U-Test zur Anwendung kam. Qualitative Daten wurden mit dem Chi-Quadrat-Test und der Kontinuitätskorrektur (Yates) verglichen. Das Signifikanzniveau wurde auf p < 0,05 festgelegt.ErgebnisseIn die Studie wurden 107 Frauen und 13 Männer mit einem Durchschnittsalter von 45,79 ± 8,49 Jahren aufgenommen. Beim Vergleich der FIQ-, VAS- und QoL-Werte vor der Behandlung mit den nach drei WCT-Sitzungen erhobenen Werten zeigte sich in der WCT-Gruppe ein signifikanter Rückgang der FIQ- und VAS-Werte im Vergleich zur Kontrollgruppe, wohingegen bei der QoL ein signifikanter Anstieg gegenüber der Kontrollgruppe zu beobachten war (p < 0,001 in allen Fällen).SchlussfolgerungDie Ergebnisse dieser Studie deuten darauf hin, dass die WCT eine wirksame therapeutische Option für Patienten mit FMS sein kann.}, } @article {pmid37875404, year = {2023}, author = {Luo, S and Angrick, M and Coogan, C and Candrea, DN and Wyse-Sookoo, K and Shah, S and Rabbani, Q and Milsap, GW and Weiss, AR and Anderson, WS and Tippett, DC and Maragakis, NJ and Clawson, LL and Vansteensel, MJ and Wester, BA and Tenore, FV and Hermansky, H and Fifer, MS and Ramsey, NF and Crone, NE}, title = {Stable Decoding from a Speech BCI Enables Control for an Individual with ALS without Recalibration for 3 Months.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {10}, number = {35}, pages = {e2304853}, pmid = {37875404}, issn = {2198-3844}, support = {U01 DC016686/DC/NIDCD NIH HHS/United States ; UH3 NS114439/NS/NINDS NIH HHS/United States ; U01DC016686/DC/NIDCD NIH HHS/United States ; UH3NS114439/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Speech ; *Brain-Computer Interfaces ; *Amyotrophic Lateral Sclerosis/complications ; Electrocorticography ; }, abstract = {Brain-computer interfaces (BCIs) can be used to control assistive devices by patients with neurological disorders like amyotrophic lateral sclerosis (ALS) that limit speech and movement. For assistive control, it is desirable for BCI systems to be accurate and reliable, preferably with minimal setup time. In this study, a participant with severe dysarthria due to ALS operates computer applications with six intuitive speech commands via a chronic electrocorticographic (ECoG) implant over the ventral sensorimotor cortex. Speech commands are accurately detected and decoded (median accuracy: 90.59%) throughout a 3-month study period without model retraining or recalibration. Use of the BCI does not require exogenous timing cues, enabling the participant to issue self-paced commands at will. These results demonstrate that a chronically implanted ECoG-based speech BCI can reliably control assistive devices over long time periods with only initial model training and calibration, supporting the feasibility of unassisted home use.}, } @article {pmid37875807, year = {2023}, author = {Loubet, I and Meyer, L and Michel, S and Pernin, F and Carrère, S and Barrès, B and Le Corre, V and Délye, C}, title = {A high diversity of non-target site resistance mechanisms to acetolactate-synthase (ALS) inhibiting herbicides has evolved within and among field populations of common ragweed (Ambrosia artemisiifolia L.).}, journal = {BMC plant biology}, volume = {23}, number = {1}, pages = {510}, pmid = {37875807}, issn = {1471-2229}, support = {DRAGON 29001099-1944//Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement/ ; DRAGON 29001099-1944//ACTA - Les instituts techniques agricoles/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; }, mesh = {Humans ; Ambrosia/genetics ; *Herbicides/pharmacology ; *Acetolactate Synthase ; Transcriptome ; Herbicide Resistance/genetics ; Lactates ; }, abstract = {BACKGROUND: Non-target site resistance (NTSR) to herbicides is a polygenic trait that threatens the chemical control of agricultural weeds. NTSR involves differential regulation of plant secondary metabolism pathways, but its precise genetic determinisms remain fairly unclear. Full-transcriptome sequencing had previously been implemented to identify NTSR genes. However, this approach had generally been applied to a single weed population, limiting our insight into the diversity of NTSR mechanisms. Here, we sought to explore the diversity of NTSR mechanisms in common ragweed (Ambrosia artemisiifolia L.) by investigating six field populations from different French regions where NTSR to acetolactate-synthase-inhibiting herbicides had evolved.

RESULTS: A de novo transcriptome assembly (51,242 contigs, 80.2% completeness) was generated as a reference to seek genes differentially expressed between sensitive and resistant plants from the six populations. Overall, 4,609 constitutively differentially expressed genes were identified, of which none were common to all populations, and only 197 were shared by several populations. Similarly, population-specific transcriptomic response was observed when investigating early herbicide response. Gene ontology enrichment analysis highlighted the involvement of stress response and regulatory pathways, before and after treatment. The expression of 121 candidate constitutive NTSR genes including CYP71, CYP72, CYP94, oxidoreductase, ABC transporters, gluco and glycosyltransferases was measured in 220 phenotyped plants. Differential expression was validated in at least one ragweed population for 28 candidate genes. We investigated whether expression patterns at some combinations of candidate genes could predict phenotype. Within populations, prediction accuracy decreased when applied to an additional, independent plant sampling. Overall, a wide variety of genes linked to NTSR was identified within and among ragweed populations, of which only a subset was captured in our experiments.

CONCLUSION: Our results highlight the complexity and the diversity of NTSR mechanisms that can evolve in a weed species in response to herbicide selective pressure. They strongly point to a non-redundant, population-specific evolution of NTSR to ALS inhibitors in ragweed. It also alerts on the potential of common ragweed for rapid adaptation to drastic environmental or human-driven selective pressures.}, } @article {pmid37877011, year = {2023}, author = {Ghaderi, S and Batouli, SAH and Mohammadi, S and Fatehi, F}, title = {Iron quantification in basal ganglia using quantitative susceptibility mapping in a patient with ALS: a case report and literature review.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1229082}, pmid = {37877011}, issn = {1662-4548}, abstract = {BACKGROUND: Quantitative susceptibility mapping (QSM) is a magnetic resonance imaging (MRI) technique that can measure the magnetic susceptibility of tissues, which can reflect their iron content. QSM has been used to detect iron accumulation in cortical and subcortical brain regions. However, its application in subcortical regions such as the basal ganglia, particularly the putamen, is rare in patients with amyotrophic lateral sclerosis (ALS).

We present the case of a 40-year-old male patient with ALS who underwent an MRI for QSM. We compared his QSM images with those of a control subject and performed a quantitative analysis of the magnetic susceptibility values in the putamen regions. We also reviewed the literature on previous QSM studies in ALS and summarized their methods and findings. Our QSM analysis revealed increased magnetic susceptibility values in the bilateral putamen of the ALS patient compared to controls, indicating iron overload. This finding is consistent with previous studies reporting iron dysregulation in subcortical nuclei in ALS. We also discussed the QSM processing techniques used in our study and in the literature, highlighting their advantages and limitations.

CONCLUSION: This case report demonstrates the potential of QSM as a sensitive MRI biomarker for evaluating iron levels in subcortical regions of ALS patients. QSM can provide quantitative information on iron deposition patterns in both motor and extra-motor areas of ALS patients, which may help understand the pathophysiology of ALS and monitor disease progression. Further studies with larger samples are needed to validate these results and explore the clinical implications of QSM in ALS.}, } @article {pmid37877256, year = {2024}, author = {Gariscsak, PJ and Appireddy, R and Vyas, A and Ritsma, BR}, title = {Virtual Multidisciplinary ALS Clinic Care During the COVID-19 Pandemic: A Canadian Cohort.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {51}, number = {5}, pages = {719-722}, doi = {10.1017/cjn.2023.302}, pmid = {37877256}, issn = {0317-1671}, } @article {pmid37877320, year = {2024}, author = {Yom-Tov, E and Navar, I and Fraenkel, E and Berry, JD}, title = {Identifying amyotrophic lateral sclerosis through interactions with an internet search engine.}, journal = {Muscle & nerve}, volume = {69}, number = {1}, pages = {40-47}, doi = {10.1002/mus.27991}, pmid = {37877320}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Search Engine ; Delayed Diagnosis ; *Motor Neuron Disease ; *Cognitive Dysfunction ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS), a motor neuron disease, remains a clinical diagnosis with an average time from onset of symptoms to diagnosis of about 1 year. Herein we examine the possibility that interactions with an internet search engine can identify people with ALS.

METHODS: We identified 285 anonymous Bing users whose queries indicated that they had been diagnosed with ALS and matched them to: (1) 3276 control users; and (2) 1814 users whose searches indicated they had ALS disease mimics. We tested whether the ALS group could be distinguished from controls and disease mimics based on search engine query data. Finally, we conducted a prospective validation from participants who provided access to their Bing search data.

RESULTS: The model distinguished between the ALS group and controls with an area under the curve (AUC) of 0.81. Model scores for the ALS group differed from the disease mimics group (rank sum test, p < .05 with Bonferroni correction). Mild cognitive impairment could not be distinguished from ALS (p > .05). In the prospective analysis, the model reached an AUC of 0.74.

DISCUSSION: Our results suggest that interactions with search engines should be further studied to understand the potential to act as a tool to assist in screening for ALS and to reduce diagnostic delay.}, } @article {pmid37877361, year = {2023}, author = {Heyming, TW and Knudsen-Robbins, C and Shelton, SK and Pham, PK and Brukman, S and Wickens, M and Valdez, B and Bacon, K and Thorpe, J and Kwon, KT and Schultz, C}, title = {9-1-1 Activations from Ambulatory Care Centers: A Sicker Pediatric Population.}, journal = {Prehospital and disaster medicine}, volume = {38}, number = {6}, pages = {749-756}, pmid = {37877361}, issn = {1945-1938}, mesh = {Child ; Child, Preschool ; Female ; Humans ; Male ; Ambulatory Care/statistics & numerical data ; *Emergency Medical Services/statistics & numerical data ; Emergency Service, Hospital ; Retrospective Studies ; Life Support Care/statistics & numerical data ; }, abstract = {BACKGROUND: Pediatric patients transferred by Emergency Medical Services (EMS) from urgent care (UC) and office-based physician practices to the emergency department (ED) following activation of the 9-1-1 EMS system are an under-studied population with scarce literature regarding outcomes for these children. The objectives of this study were to describe this population, explore EMS level-of-care transport decisions, and examine ED outcomes.

METHODS: This was a retrospective review of patients zero to <15 years of age transported by EMS from UC and office-based physician practices to the ED of two pediatric receiving centers from January 2017 through December 2019. Variables included reason for transfer, level of transport, EMS interventions and medications, ED medications/labs/imaging ordered in the first hour, ED procedures, ED disposition, and demographics. Data were analyzed with descriptive statistics, X test, point biserial correlation, two-sample z test, Mann-Whitney U test, and 2-way ANOVA.

RESULTS: A total of 450 EMS transports were included in this study: 382 Advanced Life Support (ALS) runs and 68 Basic Life Support (BLS) runs. The median patient age was 2.66 years, 60.9% were male, and 60.7% had private insurance. Overall, 48.9% of patients were transported from an office-based physician practice and 25.1% were transported from UC. Almost one-half (48.7%) of ALS patients received an EMS intervention or medication, as did 4.41% of BLS patients. Respiratory distress was the most common reason for transport (46.9%). Supplemental oxygen was the most common EMS intervention and albuterol was the most administered EMS medication. There was no significant association between level of transport and ED disposition (P = .23). The in-patient admission rate for transported patients was significantly higher than the general ED admission rate (P <.001).

CONCLUSION: This study demonstrates that pediatric patients transferred via EMS after activation of the 9-1-1 system from UC and medical offices are more acutely ill than the general pediatric ED population and are likely sicker than the general pediatric EMS population. Paramedics appear to be making appropriate level-of-care transport decisions.}, } @article {pmid37877583, year = {2024}, author = {Haldar, S and Khan, AH and De, A and Reichmayr, F and Morag, A and Yu, M and Schneemann, A and Kaskel, S}, title = {Fluorinated Benzimidazole-Linked Highly Conjugated Polymer Enabling Covalent Polysulfide Anchoring for Stable Sulfur Batteries.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {30}, number = {2}, pages = {e202302779}, doi = {10.1002/chem.202302779}, pmid = {37877583}, issn = {1521-3765}, support = {SPP2248//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Sulfur is one of the most abundant and economical elements in the p-block family and highly redox active, potentially utilizable as a charge-storing electrode with high theoretical capacities. However, its inherent good solubility in many electrolytes inhibits its accessibility as an electrode material in typical metal-sulfur batteries. In this work, the synthetically designed fluorinated porous polymer, when treated with elemental sulfur through a well-known nucleophilic aromatic substitution mechanism (SN Ar), allows for the covalent integration of polysulfides into a highly conjugated benzimidazole polymer by replacing the fluorine atoms. Chemically robust benzimidazole linkages allow such harsh post-synthetic treatment and facilitate the electronic activation of the anchored polysulfides for redox reactions under applied potential. The electrode amalgamated with sulfurized polymer mitigates the so-called polysulfide shuttle effect in the lithium-sulfur (Li-S) battery and also enables a reversible, more environmentally friendly, and more economical aluminum-sulfur (Al-S) battery that is configured with mostly p-block elements as cathode, anode, and electrolytes. The improved cycling stabilities and reduction of the overpotential in both cases pave the way for future sustainable energy storage solutions.}, } @article {pmid37879951, year = {2023}, author = {Liu, JY and Lu, YR and Guo, J and Li, H and Wang, Y and Zhao, YQ and Li, J and Wang, Q}, title = {Effect of electroacupuncture intervention on the spinal cord PPIA/NF-κB signaling pathway in mice with amyotrophic lateral sclerosis.}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {48}, number = {10}, pages = {1009-1016}, doi = {10.13702/j.1000-0607.20230251}, pmid = {37879951}, issn = {1000-0607}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; DNA-Binding Proteins/metabolism ; *Electroacupuncture ; Motor Neurons/metabolism ; NF-kappa B/genetics/metabolism ; Riluzole ; Signal Transduction ; Spinal Cord ; Superoxide Dismutase-1/genetics/metabolism ; Peptidylprolyl Isomerase/metabolism ; }, abstract = {OBJECTIVES: To observe the effects of electroacupuncture (EA) on motor function, expression of extracellular cyclophile A(PPIA) and PPIA/nuclear factor-κB (NF-κB) signaling pathway in spinal cord of amyotrophic la-teral sclerosis (ALS) mice, so as to explore the mechanism of EA intervention in regulating extracellular PPIA on neuroinflammation in ALS mice.

METHODS: Thirty ALS-SOD1[G93A] mice with hSOD1-G93A gene were randomly divided into model, EA and Riluzole groups , with 10 mice in each group, and other 10 ALS-SOD1[G93A] negative mice were used as the blank group. EA was applied to bilateral "Yanglingquan"(GB34) and "Zusanli"(ST36) for 20 min once daily, 5 days a week for 2 weeks. In the Riluzole group, riluzole solution (30 mg·kg[-1]·d[-1]) was administrated intragastrically, and the treatment time was the same as that in the EA group.Rotating rod experiment and open field experiment were used to evaluate the changes in motor function of mice .The morphology of motor neurons in the anterior horn of spinal cord was observed by HE staining.The relative protein expression levels of PPIA, TDP-43 and NF-κB in the spinal cord were detected by Western blot.The positive expression level of TDP-43 in the spinal cord was detected by immunohistochemistry. The positive expression level of PPIA in spinal cord was marked by immunofluorescence. Serum PPIA content was determined by ELISA.

RESULTS: Compared with the blank group, the time of rod dropping and the total distance of open field movement in the model group were shortened (P<0.01), the number of motor neurons in the anterior horn of the spinal cord was reduced, the cell morphology was incomplete, the cell body was atrophied, the protein expression and positive expression of TDP-43 were increased (P<0.01), the protein expressions of PPIA and NF-κB in the spinal cord were increased(P<0.01), the serum content of PPIA and immunofluorescence expression of PPIA in spinal cord were increased (P<0.01). Compared with the model group, the time of rod dropping and the total distance of open field movement of mice in the EA group and the Riluzole group were prolonged (P<0.05, P<0.01), and the injury of motor neuron in the anterior horn of the spinal cord was decreased, the protein expression and positive expression of TDP-43 in the spinal cord were decreased (P<0.05, P<0.01)；the relative expression levels of PPIA and NF-κB proteins were decreased (P<0.05, P<0.01), and the content of PPIA in serum and the immunofluorescence expression of PPIA in the spinal cord were decreased (P<0.05, P<0.01) in the EA group；the relative protein expression of NF-κB and fluorescence expression of PPIA in spinal cord of mice in the Riluzole group were decreased (P<0.05).

CONCLUSIONS: EA intervention can improve motor function in ALS mice, and its mechanism may be related to the inhibition of PPIA/NF-κB signaling pathway by EA to alleviating neuroinflammatory response.}, } @article {pmid37880536, year = {2024}, author = {Iazzolino, B and Grassano, M and Moglia, C and Canosa, A and Manera, U and Vasta, R and Cabras, S and Callegaro, S and Matteoni, E and Di Pede, F and Palumbo, F and Mora, G and Calvo, A and Chiò, A}, title = {High serum uric acid levels are protective against cognitive impairment in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {2}, pages = {955-961}, pmid = {37880536}, issn = {1432-1459}, support = {RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Frontotemporal Dementia/complications/diagnosis ; Uric Acid ; *Cognitive Dysfunction/diagnosis ; *Cognition Disorders/complications ; }, abstract = {BACKGROUND: Uric acid (UA) has emerged as a factor that can modify cognitive function both in the general population and in people with neurodegenerative disorders. Since very few data are available concerning amyotrophic lateral sclerosis (ALS), we explored the correlation of UA levels and cognitive impairment in a large cohort of ALS patients.

METHODS: We enrolled ALS patients consecutively seen at the Turin ALS expert center in the 2007-2018 period who underwent both cognitive/behavioral and UA evaluation at diagnosis. Patients were classified in 5 categories: normal cognition (ALS-CN), isolated cognitive impairment (ALSci), isolated behavioural impairment (ALSbi), cognitive and behavioural impairment (ALScbi), frontotemporal dementia (ALS-FTD). For this study, ALSci, ALSbi and ALScbi were merged as ALS with intermediate cognitive impairment (ALS-INT).

RESULTS: Out of the 841 ALS patients, 422 had ALS-CN, 271 ALS-INT and 148 ALS-FTD. The mean values of UA were significantly different among the cognitive subgroups of patients, with the lowest values in the ALS-FTD (ALS-CN, 288.5 ± 78.0 (μmol/L; ALS-INT, 289.7 ± 75.5 μmol/L; ALS-FTD, 271.8 ± 74.9 μmol/L; p = 0.046). The frequency of ALS-FTD was significantly higher in the 1st tertile of UA. Lower UA levels were independently associated with FTD (OR 1.32, 95% c.i. 1.01-1.43; p = 0.038) in binary logistic regression.

CONCLUSIONS: We found that in ALS lower UA serum levels are correlated with reduced frequency of co-morbid FTD. Patients with intermediate cognitive impairment showed UA levels similar to ALS-CN but higher than ALS-FTD, implying that higher UA levels can prevent or delay cognitive function deterioration.}, } @article {pmid37880984, year = {2024}, author = {Menon, D and Nashi, S and Mohanty, M and Dubbal, R and Mk, F and Vengalil, S and Thomas, A and Kumar, V and Baskar, D and Arunachal, G and Nalini, A}, title = {A novel DHTKD1 gene mutation with ALS like presentation: a case report.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {413-415}, doi = {10.1080/21678421.2023.2273366}, pmid = {37880984}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Ketoglutarate Dehydrogenase Complex/genetics/metabolism ; *Ketone Oxidoreductases/genetics/metabolism ; Mitochondria ; Mutation/genetics ; Aged ; }, abstract = {DHTKD1 is a nuclear gene that encodes "dehydrogenase E1 and transketolase domain-containing 1", essential in mitochondrial metabolism. First identified in the patients of 2-amino-apidic and 2 oxoapidic aciduria, mutation in this gene has recently been implicated in CMT2Q and ALS. Here we report the case of a septuagenarian who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical exome sequencing revealed a heterozygous nonsense variant in exon 8 of the DHTKD1 gene, which was previously described in CMT2Q. This report highlights the pleotropic phenotypic presentation of DHTKD1 mutation and the need for genetic testing even in sporadic cases of ALS presenting at a later age.}, } @article {pmid37881309, year = {2023}, author = {Li, T and Ye, M and Yang, G and Diao, S and Zhou, Y and Qin, Y and Ding, D and Zhu, M and Fang, Q}, title = {Regional white matter hyperintensity volume predicts persistent cognitive impairment in acute lacunar infarct patients.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1265743}, pmid = {37881309}, issn = {1664-2295}, abstract = {BACKGROUND: White matter hyperintensity (WMH) is often described in acute lacunar stroke (ALS) patients. However, the specific relationship between regional WMH volume and persistent cognitive impairment remains unclear.

METHODS: We enrolled patients with ALS who were hospitalized at the First Affiliated Hospital of Soochow University between January 2020 and November 2022. All patients were assessed for global cognitive function using the Montreal Cognitive Assessment (MoCA) scale at 14 ± 2 days and 6 months after the onset of ALS. Manifestations of chronic cerebral small vessel disease (CSVD) were assessed via MRI scan. The distributions of regional WMH were segmented, and their relationship with cognitive impairment was evaluated.

RESULTS: A total of 129 patients were enrolled. Baseline frontal WMH volume (OR = 1.18, P = 0.04) was an independent risk factor for long-term cognitive impairment after ALS. Furthermore, the presence of WMH at the genu of the corpus callosum (GCC) at baseline (OR = 3.1, P = 0.033) was strongly associated with persistent cognitive decline. Multivariable logistic regression analysis showed that depression (OR = 6.252, P = 0.029), NIHSS score (OR = 1.24, P = 0.011), and albumin at admission (OR = 0.841, P = 0.032) were also important determinants of long-term cognitive impairment after ALS.

CONCLUSIONS: Our study found that WMH, especially frontal WMH volume and the presence of WMH at the GCC at baseline, independently contributed to long-term cognitive decline in ALS patients. This study provides new evidence of the clinical relationship between regional WMH volume and cognitive impairment in ALS patients.}, } @article {pmid37881503, year = {2023}, author = {Petrashen, AP and Lin, Y and Kun, B and Kreiling, JA}, title = {A cluster of X-linked miRNAs are de-repressed with age in mouse liver and target growth hormone signaling.}, journal = {Frontiers in aging}, volume = {4}, number = {}, pages = {1261121}, pmid = {37881503}, issn = {2673-6217}, support = {P20 GM119943/GM/NIGMS NIH HHS/United States ; T32 AG041688/AG/NIA NIH HHS/United States ; T32 GM136566/GM/NIGMS NIH HHS/United States ; }, abstract = {Growth hormone (GH) signaling influences lifespan in a wide variety of mammalian species. We previously reported that a cluster of miRNAs located on the X-chromosome are de-repressed with age in male mouse liver, and a subset, the mir-465 family, can directly attenuate expression of the growth hormone receptor (GHR) in vitro leading to a reduction in GH signaling. Here we show that this cluster of miRNAs is also upregulated in the liver with age in females, and that calorie restriction and the Ames dwarf genotype, both known to delay aging, attenuate the upregulation of the miRNA cluster. Upregulation of mir-465 in vivo leads to a reduction in GHR mRNA in the liver and an attenuation of GH signaling, indicated by a reduction in GHR, IGF-1, IGFBP3, and ALS mRNA expression. There is a corresponding reduction in IGF-1 protein levels in the liver and plasma. These results suggest that the age-associated upregulation of the X-chromosomal cluster of miRNAs could influence lifespan.}, } @article {pmid37882288, year = {2023}, author = {Barco-Antoñanzas, M and Font-Farre, M and Eceiza, MV and Gil-Monreal, M and van der Hoorn, RAL and Royuela, M and Zabalza, A}, title = {Cysteine proteases are activated in sensitive Amaranthus palmeri populations upon treatment with herbicides inhibiting amino acid biosynthesis.}, journal = {Physiologia plantarum}, volume = {175}, number = {5}, pages = {e13993}, doi = {10.1111/ppl.13993}, pmid = {37882288}, issn = {1399-3054}, support = {//Eusko Jaurlaritza/ ; 2020 117723-RB-100//Ministerio de Ciencia e Innovación/ ; AGL2016-77531-R//Ministerio de Economía y Competitividad/ ; }, mesh = {Herbicide Resistance ; *Amaranthus/metabolism ; *Herbicides/pharmacology/metabolism ; *Cysteine Proteases/metabolism/pharmacology ; }, abstract = {The herbicides glyphosate and pyrithiobac inhibit the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) in the aromatic amino acid biosynthetic pathway and acetolactate synthase (ALS) in the branched-chain amino acid biosynthetic pathway, respectively. Here we characterise the protease activity profiles of a sensitive (S), a glyphosate-resistant (GR) and a multiple-resistant (MR) population of Amaranthus palmeri in response to glyphosate and pyrithiobac. Amino acid accumulation and cysteine protease activities were induced with both herbicides in the S population and with pyrithiobac in the GR population, suggesting that the increase in cysteine proteases is responsible for the increased degradation of the available proteins and the observed increase in free amino acids. Herbicides did not induce any changes in the proteolytic activities in the populations with target-site resistance, indicating that this effect was only induced in sensitive plants.}, } @article {pmid37882537, year = {2024}, author = {Hung, C and Patani, R}, title = {Elevated 4R tau contributes to endolysosomal dysfunction and neurodegeneration in VCP-related frontotemporal dementia.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {3}, pages = {970-979}, pmid = {37882537}, issn = {1460-2156}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; /CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; *Induced Pluripotent Stem Cells ; Lysosomes ; *Valosin Containing Protein/genetics ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two incurable neurodegenerative diseases that exist on a clinical, genetic and pathological spectrum. The VCP gene is highly relevant, being directly implicated in both FTD and ALS. Here, we investigate the effects of VCP mutations on the cellular homoeostasis of human induced pluripotent stem cell-derived cortical neurons, focusing on endolysosomal biology and tau pathology. We found that VCP mutations cause abnormal accumulation of enlarged endolysosomes accompanied by impaired interaction between two nuclear RNA binding proteins: fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) in human cortical neurons. The spatial dissociation of intranuclear FUS and SFPQ correlates with alternative splicing of the MAPT pre-mRNA and increased tau phosphorylation. Importantly, we show that inducing 4R tau expression using antisense oligonucleotide technology is sufficient to drive neurodegeneration in control human neurons, which phenocopies VCP-mutant neurons. In summary, our findings demonstrate that tau hyperphosphorylation, endolysosomal dysfunction, lysosomal membrane rupture, endoplasmic reticulum stress and apoptosis are driven by a pathogenic increase in 4R tau.}, } @article {pmid37882882, year = {2023}, author = {Wang, Y and Sun, S and Zhai, J and Liu, Y and Song, C and Sun, C and Li, Q and Liu, J and Jiang, H and Liu, Y}, title = {scAAV9-VEGF alleviates symptoms of amyotrophic lateral sclerosis (ALS) mice through regulating aromatase.}, journal = {Experimental brain research}, volume = {241}, number = {11-12}, pages = {2817-2827}, pmid = {37882882}, issn = {1432-1106}, support = {ZR2020QH126//Natural Science Foundation of Shandong Province Youth Fund/ ; ZR2020QH124//Natural Science Foundation of Shandong Province Youth Fund/ ; 2019ZC010137//Zibo city key research and development plan/ ; 2021Q048//TCM science and technology Project of Shandong Province/ ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Motor Neurons/physiology ; Vascular Endothelial Growth Factor A/metabolism/pharmacology ; *Neurodegenerative Diseases/metabolism ; Aromatase/genetics/metabolism/pharmacology ; Superoxide Dismutase/genetics/metabolism/pharmacology ; Mice, Transgenic ; Disease Models, Animal ; Estrogens/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset, chronic, progressive, and fatal neurodegenerative disease that leads to progressive atrophy and weakness of the muscles throughout the body. Herein, we found that the intrathecal injection of adeno-associated virus (AAV)-delivered VEGF in SOD1-G93A transgenic mice, as well as ALS mice, could significantly delay disease onset and preserve motor functions and neurological functions, thus prolonging the survival of mice models. Moreover, we found that VEGF treatment could induce the elevated expression of aromatase, which is a key enzyme in estrogen synthesis, in neurons but not in astrocytes. On the other hand, the changes in the expression of oxidative stress-related factors HO-1 and GCLM and autophagy-related proteins p62 and LC3II upon the administration of VEGF revealed the involvement of oxidative stress and autophagy underlying the downstream of the VEGF-induced mitigation of ALS. In conclusion, this study proved the protective effects of VEGF in the onset and development of ALS and revealed the involvement of estrogen, oxidative stress and autophagy in the VEGF-induced alleviation of ALS. Our results highlighted the potential of VEGF as a promising therapeutic agent in the treatment of ALS.}, } @article {pmid37885330, year = {2023}, author = {Lunghi, G and Di Biase, E and Carsana, EV and Henriques, A and Callizot, N and Mauri, L and Ciampa, MG and Mari, L and Loberto, N and Aureli, M and Sonnino, S and Spedding, M and Chiricozzi, E and Fazzari, M}, title = {GM1 ganglioside exerts protective effects against glutamate-excitotoxicity via its oligosaccharide in wild-type and amyotrophic lateral sclerosis motor neurons.}, journal = {FEBS open bio}, volume = {13}, number = {12}, pages = {2324-2341}, pmid = {37885330}, issn = {2211-5463}, support = {//Banca d'Italia/ ; 200045//Mizutani Foundation for Glycoscience/ ; //APC central fund of the University of Milan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; G(M1) Ganglioside/pharmacology/metabolism ; Glutamic Acid ; *Neurodegenerative Diseases/metabolism ; Superoxide Dismutase/metabolism ; Motor Neurons/metabolism ; }, abstract = {Alterations in glycosphingolipid metabolism have been linked to the pathophysiological mechanisms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Accordingly, administration of GM1, a sialic acid-containing glycosphingolipid, is protective against neuronal damage and supports neuronal homeostasis, with these effects mediated by its bioactive component, the oligosaccharide head (GM1-OS). Here, we add new evidence to the therapeutic efficacy of GM1 in ALS: Its administration to WT and SOD1[G93A] motor neurons affected by glutamate-induced excitotoxicity significantly increased neuronal survival and preserved neurite networks, counteracting intracellular protein accumulation and mitochondria impairment. Importantly, the GM1-OS faithfully replicates GM1 activity, emphasizing that even in ALS the protective function of GM1 strictly depends on its pentasaccharide.}, } @article {pmid37885418, year = {2023}, author = {Biebelberg, B and Klompas, M and Rhee, C}, title = {The authors' reply to Schaffzin et al's Letter to the Editor.}, journal = {Infection control and hospital epidemiology}, volume = {44}, number = {12}, pages = {2098}, doi = {10.1017/ice.2023.222}, pmid = {37885418}, issn = {1559-6834}, } @article {pmid37885757, year = {2023}, author = {Krannich, T and Sarrias, MH and Ben Aribi, H and Shokrof, M and Iacoangeli, A and Al-Chalabi, A and Sedlazeck, FJ and Busby, B and Al Khleifat, A}, title = {VariantSurvival: a tool to identify genotype-treatment response.}, journal = {Frontiers in bioinformatics}, volume = {3}, number = {}, pages = {1277923}, pmid = {37885757}, issn = {2673-7647}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Motivation: For a number of neurological diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, and many others, certain genes are known to be involved in the disease mechanism. A common question is whether a structural variant in any such gene may be related to drug response in clinical trials and how this relationship can contribute to the lifecycle of drug development. Results: To this end, we introduce VariantSurvival, a tool that identifies changes in survival relative to structural variants within target genes. VariantSurvival matches annotated structural variants with genes that are clinically relevant to neurological diseases. A Cox regression model determines the change in survival between the placebo and clinical trial groups with respect to the number of structural variants in the drug target genes. We demonstrate the functionality of our approach with the exemplary case of the SETX gene. VariantSurvival has a user-friendly and lightweight graphical user interface built on the shiny web application package.}, } @article {pmid37886540, year = {2023}, author = {Snyder, A and Ryan, VH and Hawrot, J and Lawton, S and Ramos, DM and Qi, YA and Johnson, K and Reed, X and Johnson, NL and Kollasch, AW and Duffy, M and VandeVrede, L and Cochran, JN and Miller, BL and Toro, C and Bielekova, B and Yokoyama, JS and Marks, DS and Kwan, JY and Cookson, MR and Ward, ME}, title = {An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37886540}, issn = {2693-5015}, support = {P50 AG023501/AG/NIA NIH HHS/United States ; 75N95022C00031/DA/NIDA NIH HHS/United States ; K01 AG049152/AG/NIA NIH HHS/United States ; R01 AG062588/AG/NIA NIH HHS/United States ; FI2 GM142475/GM/NIGMS NIH HHS/United States ; U54 NS123985/NS/NINDS NIH HHS/United States ; U19 AG079774/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; ZIA AG000534/ImNIH/Intramural NIH HHS/United States ; ZIA AG000539/ImNIH/Intramural NIH HHS/United States ; R00 AG068271/AG/NIA NIH HHS/United States ; K23 AG073514/AG/NIA NIH HHS/United States ; }, abstract = {As genetic testing has become more accessible and affordable, variants of uncertain significance (VUS) are increasingly identified, and determining whether these variants play causal roles in disease is a major challenge. The known disease-associated Annexin A11 (ANXA11) mutations result in ANXA11 aggregation, alterations in lysosomal-RNA granule co-trafficking, and TDP-43 mis-localization and present as amyotrophic lateral sclerosis or frontotemporal dementia. We identified a novel VUS in ANXA11 (P93S) in a kindred with corticobasal syndrome and unique radiographic features that segregated with disease. We then queried neurodegenerative disorder clinic databases to identify the phenotypic spread of ANXA11 mutations. Multi-modal computational analysis of this variant was performed and the effect of this VUS on ANXA11 function and TDP-43 biology was characterized in iPSC-derived neurons. Single-cell sequencing and proteomic analysis of iPSC-derived neurons and microglia were used to determine the multiomic signature of this VUS. Mutations in ANXA11 were found in association with clinically diagnosed corticobasal syndrome, thereby establishing corticobasal syndrome as part of ANXA11 clinical spectrum. In iPSC-derived neurons expressing mutant ANXA11, we found decreased colocalization of lysosomes and decreased neuritic RNA as well as decreased nuclear TDP-43 and increased formation of cryptic exons compared to controls. Multiomic assessment of the P93S variant in iPSC-derived neurons and microglia indicates that the pathogenic omic signature in neurons is modest compared to microglia. Additionally, omic studies reveal that immune dysregulation and interferon signaling pathways in microglia are central to disease. Collectively, these findings identify a new pathogenic variant in ANXA11, expand the range of clinical syndromes caused by ANXA11 mutations, and implicate both neuronal and microglia dysfunction in ANXA11 pathophysiology. This work illustrates the potential for iPSC-derived cellular models to revolutionize the variant annotation process and provides a generalizable approach to determining causality of novel variants across genes.}, } @article {pmid37887017, year = {2023}, author = {You, J and Youssef, MMM and Santos, JR and Lee, J and Park, J}, title = {Microglia and Astrocytes in Amyotrophic Lateral Sclerosis: Disease-Associated States, Pathological Roles, and Therapeutic Potential.}, journal = {Biology}, volume = {12}, number = {10}, pages = {}, pmid = {37887017}, issn = {2079-7737}, abstract = {Microglial and astrocytic reactivity is a prominent feature of amyotrophic lateral sclerosis (ALS). Microglia and astrocytes have been increasingly appreciated to play pivotal roles in disease pathogenesis. These cells can adopt distinct states characterized by a specific molecular profile or function depending on the different contexts of development, health, aging, and disease. Accumulating evidence from ALS rodent and cell models has demonstrated neuroprotective and neurotoxic functions from microglia and astrocytes. In this review, we focused on the recent advancements of knowledge in microglial and astrocytic states and nomenclature, the landmark discoveries demonstrating a clear contribution of microglia and astrocytes to ALS pathogenesis, and novel therapeutic candidates leveraging these cells that are currently undergoing clinical trials.}, } @article {pmid37887305, year = {2023}, author = {Provasek, VE and Kodavati, M and Guo, W and Wang, H and Boldogh, I and Van Den Bosch, L and Britz, G and Hegde, ML}, title = {lncRNA Sequencing Reveals Neurodegeneration-Associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists in Motor Neurons.}, journal = {Cells}, volume = {12}, number = {20}, pages = {}, pmid = {37887305}, issn = {2073-4409}, support = {RF1NS112719/NS/NINDS NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; R03AG064266/NH/NIH HHS/United States ; R01NS094535/NH/NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; R01NS088645/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; Motor Neurons/metabolism ; Mutation/genetics ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Fused-in sarcoma (FUS) gene mutations have been implicated in amyotrophic lateral sclerosis (ALS). This study aimed to investigate the impact of FUS mutations (R521H and P525L) on the transcriptome of induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs). Using RNA sequencing (RNA Seq), we characterized differentially expressed genes (DEGs) and differentially expressed lncRNAs (DELs) and subsequently predicted lncRNA-mRNA target pairs (TAR pairs). Our results show that FUS mutations significantly altered the expression profiles of mRNAs and lncRNAs in iPSCs. Using this large dataset, we identified and verified six key differentially regulated TAR pairs in iPSCs that were also altered in iMNs. These target transcripts included: GPR149, NR4A, LMO3, SLC15A4, ZNF404, and CRACD. These findings indicated that selected mutant FUS-induced transcriptional alterations persist from iPSCs into differentiated iMNs. Functional enrichment analyses of DEGs indicated pathways associated with neuronal development and carcinogenesis as likely altered by these FUS mutations. Furthermore, ingenuity pathway analysis (IPA) and GO network analysis of lncRNA-targeted mRNAs indicated associations between RNA metabolism, lncRNA regulation, and DNA damage repair. Our findings provide insights into potential molecular mechanisms underlying the pathophysiology of ALS-associated FUS mutations and suggest potential therapeutic targets for the treatment of ALS.}, } @article {pmid37887320, year = {2023}, author = {Fu, RH and Chen, HJ and Hong, SY}, title = {Interaction of the C9orf72-Amyotrophic Lateral Sclerosis-Related Proline-Arginine Dipeptide Repeat Protein with the RNA-Binding Protein NOVA1 Causes Decreased Expression of UNC13A Due to Enhanced Inclusion of Cryptic Exons, Which Is Reversed by Betulin Treatment.}, journal = {Cells}, volume = {12}, number = {20}, pages = {}, pmid = {37887320}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Arginine/metabolism ; C9orf72 Protein/genetics/metabolism ; Dipeptides/metabolism ; Motor Neurons/pathology ; Neuro-Oncological Ventral Antigen ; Proline/metabolism ; RNA, Messenger/genetics/metabolism ; RNA-Binding Proteins/genetics/metabolism ; Betulinic Acid ; Nerve Tissue Proteins ; }, abstract = {C9orf72 mutations are the most common form of familial amyotrophic lateral sclerosis (C9-ALS). It causes the production of proline-arginine dipeptide repeat proteins (PR-DPRs) in motor neurons (MNs), leading to the molecular pathology characteristic of ALS. UNC13A is critical for maintaining the synaptic function of MNs. Most ALS patients have nuclear deletion of the splicing repressor TDP-43 in MNs, which causes inclusion of the cryptic exon (CE) of UNC13A mRNA, resulting in nonsense-mediated mRNA decay and reduced protein expression. Therefore, in this study, we explored the role of PR-DPR in CE inclusion of UNC13A mRNA. Our results showed that PR-DPR (PR50) induced CE inclusion and decreased the protein expression of UNC13A in human neuronal cell lines. We also identified an interaction between the RNA-binding protein NOVA1 and PR50 by yeast two-hybrid screening. NOVA1 expression is known to be reduced in patients with ALS. We found that knockdown of NOVA1 enhanced CE inclusion of UNC13A mRNA. Furthermore, the naturally occurring triterpene betulin can inhibit the interaction between NOVA1 and PR50, thus preventing CE inclusion of UNC13A mRNA and protein reduction in human neuronal cell lines. This study linked PR-DPR with CE inclusion of UNC13A mRNA and developed candidate therapeutic strategies for C9-ALS using betulin.}, } @article {pmid37887472, year = {2023}, author = {Palazzo, L and Pizzolato, L and Rigo, M and Bondì, G}, title = {Amyotrophic Lateral Sclerosis and Its Management during the COVID-19 Pandemic: A Qualitative Study with Thematic Analysis of Patients and Caregivers Who Participated in Self-Help Groups.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {13}, number = {10}, pages = {}, pmid = {37887472}, issn = {2076-328X}, abstract = {This study employs a qualitative methodology to explore the effects of the pandemic on the lives of ALS patients and their caregivers. It aims to understand whether and how online self-help groups have assisted families dealing with amyotrophic lateral sclerosis (ALS) patients. ALS is a neurodegenerative disease with both physical and psychosocial implications. Consequently, it significantly affects the lives of patients' caregivers. In 2020, the COVID-19 pandemic exacerbated this situation. The results show that the pandemic has had a negative impact on the well-being of ALS caregivers and patients. Furthermore, bereavement and death were dealt with in different ways by the families involved. The pandemic aggravated the health of ALS patients and increased the workload of their caregivers; however, online psychological support was appreciated for its role in providing emotional help and diminishing social isolation.}, } @article {pmid37889099, year = {2023}, author = {Liddell, JR and Hilton, JBW and Crouch, PJ}, title = {Cu[II](atsm) significantly decreases microglial reactivity in patients with sporadic amyotrophic lateral sclerosis.}, journal = {Neuropathology and applied neurobiology}, volume = {49}, number = {5}, pages = {e12938}, doi = {10.1111/nan.12938}, pmid = {37889099}, issn = {1365-2990}, support = {//National Health and Medical Research Council/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis ; Microglia ; Copper ; Mice, Transgenic ; }, } @article {pmid37889424, year = {2024}, author = {Yan, Z and Xu, Y and Li, K and Liu, L}, title = {Association between genetically proxied lipid-lowering drug targets, lipid traits, and amyotrophic lateral sclerosis: a mendelian randomization study.}, journal = {Acta neurologica Belgica}, volume = {124}, number = {2}, pages = {485-494}, pmid = {37889424}, issn = {2240-2993}, support = {No. 81860826//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Cholesterol, LDL/genetics ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; *Amyotrophic Lateral Sclerosis/genetics ; Mendelian Randomization Analysis ; Apolipoproteins B/genetics ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: The use of circulating lipid traits as biomarkers to predict the risk of amyotrophic lateral sclerosis (ALS) is currently controversial, and the evidence-based medical evidence for the use of lipid-lowering agents, especially statins, on ALS risk remains insufficient. Our aim was to apply a Mendelian randomization (MR) approach to assess the causal impact of lipid-lowering agents and circulating lipid traits on ALS risk.

MATERIALS AND METHODS: Our study included primary and secondary analyses, in which the risk associations of lipid-lowering gene inhibitors, lipid traits, and ALS were assessed by the inverse variance weighting method as the primary approach. The robustness of the results was assessed using LDSC assessment, conventional MR sensitivity analysis, and used Mediating MR to explore potential mechanisms of occurrence. In the secondary analysis, the association of lipid-lowering genes with ALS was validated using the Summary data-based Mendelian Randomization (SMR) method.

RESULTS: Our results showed strong evidence between genetic proxies for Apolipoprotein B (ApoB) inhibitor (OR = 0.76, 95% CI = 0.68 - 0.86; P = 5.58 × 10[-6]) and reduced risk of ALS. Additionally, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (OR = 1.06, 95% CI = 0. 85-1.33) was not found to increase ALS risk. SMR results suggested that ApoB expression was associated with increased ALS risk, and colocalization analysis did not support a significant common genetic variation between ApoB and ALS. Mediator MR analysis suggested a possible mediating role for interleukin-6 and low-density lipoprotein cholesterol (LDL-C). While elevated LDL-C was significantly associated with increased risk of ALS among lipid traits, total cholesterol (TC) and ApoB were weakly associated with ALS. LDSC results suggested a potential genetic correlation between these lipid traits and ALS.

CONCLUSIONS: Using ApoB inhibitor can lower the risk of ALS, statins do not trigger ALS, and LDL-C, TC, and ApoB levels can predict the risk of ALS.}, } @article {pmid37890889, year = {2023}, author = {Ilieva, H and Vullaganti, M and Kwan, J}, title = {Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis.}, journal = {BMJ (Clinical research ed.)}, volume = {383}, number = {}, pages = {e075037}, pmid = {37890889}, issn = {1756-1833}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Pathology, Molecular ; Disease Progression ; }, abstract = {Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.}, } @article {pmid37891396, year = {2023}, author = {Carey, LB and Bambling, M and Hodgson, TJ and Jamieson, N and Bakhurst, MG and Koenig, HG}, title = {Pastoral Narrative Disclosure: The Development and Evaluation of an Australian Chaplaincy Intervention Strategy for Addressing Moral Injury.}, journal = {Journal of religion and health}, volume = {62}, number = {6}, pages = {4032-4071}, pmid = {37891396}, issn = {1573-6571}, mesh = {Humans ; *Stress Disorders, Post-Traumatic ; Australia ; *Veterans ; Morals ; Narration ; *Pastoral Care/methods ; Clergy ; *Chaplaincy Service, Hospital ; Spirituality ; }, abstract = {This paper describes the development and initial chaplaincy user evaluation of 'Pastoral Narrative Disclosure' (PND) as a rehabilitation strategy developed for chaplains to address moral injury among veterans. PND is an empirically informed and integrated intervention comprising eight stages of pastoral counselling, guidance and education that was developed by combining two previously existing therapeutic techniques, namely Litz et al's (2017) 'Adaptive Disclosure' and 'Confessional Practice' (Joob & Kettunen, 2013). The development and results of PND can be categorized into five phases. Phase 1: PND Strategy Formation-based upon extensive international research demonstrating that MI is a complex bio-psycho-social-spiritual syndrome with symptoms sufficiently distinct from post-traumatic stress disorder. The review also provided evidence of the importance of chaplains being involved in moral injury rehabilitation. Phase II: Development and Implementation of 'Moral Injury Skills Training' (MIST)-which involved the majority of available Australian Defence Force (ADF) Chaplains (n = 242/255: 94.9%) completing a basic 'Introduction to Moral Injury' (MIST-1) as well as an 'Introduction to PND' (MIST-2). Phase III: MIST-3-PND-Pilot evaluation-involved a representative chaplaincy cohort (n = 13) undergoing the PND eight-stage strategy to ensure the integrity and quality of PND from a chaplaincy perspective prior to wider implementation. The pilot PND evaluation indicated a favourable satisfaction rating (n = 11/13: 84.6%; M = 4.73/5.0 satisfaction). Phase IV: MIST-3-PND Implementation-involved a larger cohort of ADF Chaplaincy participants (n = 210) completing a revised and finalized PND strategy which was regarded favourably by the majority of ADF Chaplains (n = 201/210: 95.7%; M = 4.73/5.0 satisfaction). Phase V: Summation. In conclusion the positive satisfaction ratings by a significant number of ADF chaplaincy personnel completing MIST-3-PND, provided evidence that chaplains evaluated PND as a suitable counselling, guidance and education strategy, which affirmed its utilisation and justifies further research for using PND to address MI among veterans, that may also prove valuable for other chaplains working in community health and first responder contexts.}, } @article {pmid37891753, year = {2023}, author = {Rostás, R and Fekete, I and Horváth, L and Fekete, K}, title = {Blink Reflex Examination in Patients with Amyotrophic Lateral Sclerosis Compared to Diseases Affecting the Peripheral Nervous System and Healthy Controls.}, journal = {Brain sciences}, volume = {13}, number = {10}, pages = {}, pmid = {37891753}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal form of neuromuscular disease. The aim of this study was to assess changes in the blink reflex (BR) parameters as a valid and easy-to-use tool in ALS patients. We assessed the BR test in patients with a definitive diagnosis of ALS, healthy volunteers, and patients with diseases affecting the peripheral nervous system. The BR was studied in 29 patients who met the Awaji criteria. Latencies were compared with our healthy controls (N = 50) and other diseases of the peripheral nervous system (N = 61). The ALS Functional Rating Scale-Revised (ALSFRS-R) was used to evaluate functional status. Significantly prolonged R2i and R2c latencies were found in the ALS group compared with the healthy control group (p < 0.001). The latencies of R1, R2i, R2c were all increased in the bulbar subtype compared to the limb-onset subtype (p < 0.05). According to our results, BR examination might be a promising tool to monitor the course of the disease or serve as a prognostic biomarker in patients with ALS, but it should be assessed in further studies. The abnormalities detected through BR might help perform earlier interventions in ALS patients and might be useful in other diseases affecting the peripheral nervous system.}, } @article {pmid37891890, year = {2023}, author = {Korczowska-Łącka, I and Słowikowski, B and Piekut, T and Hurła, M and Banaszek, N and Szymanowicz, O and Jagodziński, PP and Kozubski, W and Permoda-Pachuta, A and Dorszewska, J}, title = {Disorders of Endogenous and Exogenous Antioxidants in Neurological Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {37891890}, issn = {2076-3921}, abstract = {In diseases of the central nervous system, such as Alzheimer's disease (AD), Parkinson's disease (PD), stroke, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and even epilepsy and migraine, oxidative stress load commonly surpasses endogenous antioxidative capacity. While oxidative processes have been robustly implicated in the pathogenesis of these diseases, the significance of particular antioxidants, both endogenous and especially exogenous, in maintaining redox homeostasis requires further research. Among endogenous antioxidants, enzymes such as catalase, superoxide dismutase, and glutathione peroxidase are central to disabling free radicals, thereby preventing oxidative damage to cellular lipids, proteins, and nucleic acids. Whether supplementation with endogenously occurring antioxidant compounds such as melatonin and glutathione carries any benefit, however, remains equivocal. Similarly, while the health benefits of certain exogenous antioxidants, including ascorbic acid (vitamin C), carotenoids, polyphenols, sulforaphanes, and anthocyanins are commonly touted, their clinical efficacy and effectiveness in particular neurological disease contexts need to be more robustly defined. Here, we review the current literature on the cellular mechanisms mitigating oxidative stress and comment on the possible benefit of the most common exogenous antioxidants in diseases such as AD, PD, ALS, HD, stroke, epilepsy, and migraine. We selected common neurological diseases of a basically neurodegenerative nature.}, } @article {pmid37891966, year = {2023}, author = {Grossini, E and De Marchi, F and Venkatesan, S and Mele, A and Ferrante, D and Mazzini, L}, title = {Effects of Acetyl-L-Carnitine on Oxidative Stress in Amyotrophic Lateral Sclerosis Patients: Evaluation on Plasma Markers and Members of the Neurovascular Unit.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {37891966}, issn = {2076-3921}, abstract = {Oxidative stress, the alteration of mitochondrial function, and the neurovascular unit (NVU), play a role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. We aimed to demonstrate the changes in the plasma redox system and nitric oxide (NO) in 32 new ALS-diagnosed patients in treatment with Acetyl-L-Carnitine (ALCAR) compared to healthy controls. We also evaluated the effects of plasma on human umbilical cord-derived endothelial vascular cells (HUVEC) and astrocytes. The analyses were performed at the baseline (T0), after three months (T1), and after six months (T2). In ALS patients at T0/T1, the plasma markers of lipid peroxidation, thiobarbituric acid reactive substances (TBARS) and 4-hydroxy nonenal (4-HNE) were higher, whereas the antioxidants, glutathione (GSH) and the glutathione peroxidase (GPx) activity were lower than in healthy controls. At T2, plasma TBARS and 4-HNE decreased, whereas plasma GSH and the GPx activity increased in ALS patients. As regards NO, the plasma levels were firmly lower at T0-T2 than those of healthy controls. Cell viability, and mitochondrial membrane potential in HUVEC/astrocytes treated with the plasma of ALS patients at T0-T2 were reduced, while the oxidant release increased. Those results, which confirmed the fundamental role of oxidative stress, mitochondrial function, and of the NVU in ALS pathogenesis, can have a double meaning, acting as disease markers at baseline and potential markers of drug effects in clinical practice and during clinical trials.}, } @article {pmid37891975, year = {2023}, author = {Fu, RH and Chen, HJ and Hong, SY}, title = {Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {37891975}, issn = {2076-3921}, support = {MOST 105-2314-B-039-017-MY3//the Ministry of Science and Technology (Taiwan)/ ; DMR-111-140//China Medical University Hospital (Taiwan)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal rare disease of progressive degeneration of motor neurons. The most common genetic mutation in ALS is the hexanucleotide repeat expansion (HRE) located in the first intron of the C9orf72 gene (C9-ALS). HRE can produce dipeptide repeat proteins (DPRs) such as poly glycine-alanine (GA) in a repeat-associated non-ATG (RAN) translation. GA-DPR has been shown to be toxic to motor neurons in various biological models. However, its effects on microglia involved in C9-ALS have not been reported. Here, we show that GA-DPR (GA50) activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome in a human HMC3 microglia model. MCC950 (specific inhibitor of the NLRP3) treatment can abrogate this activity. Next, using yeast two-hybrid screening, we identified sulfide quinone oxidoreductase (SQOR) as a GA50 interacting protein. SQOR knockdown in HMC3 cells can significantly induce the activity of the NLRP3 inflammasome by upregulating the level of intracellular reactive oxygen species and the cytoplasmic escape of mitochondrial DNA. Furthermore, we obtained irisflorentin as an effective blocker of the interaction between SQOR and GA50, thus inhibiting NLRP3 inflammasome activity in GA50-expressing HMC3 cells. These results imply the association of GA-DPR, SQOR, and NLRP3 inflammasomes in microglia and establish a treatment strategy for C9-ALS with irisflorentin.}, } @article {pmid37892126, year = {2023}, author = {Ramos, V and Reis, M and Ferreira, L and Silva, AM and Ferraz, R and Vieira, M and Vasconcelos, V and Martins, R}, title = {Stalling the Course of Neurodegenerative Diseases: Could Cyanobacteria Constitute a New Approach toward Therapy?.}, journal = {Biomolecules}, volume = {13}, number = {10}, pages = {}, pmid = {37892126}, issn = {2218-273X}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress ; *Parkinson Disease/drug therapy ; Antioxidants/pharmacology ; *Cyanobacteria/metabolism ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by progressive and irreversible neuronal loss, accompanied by a range of pathological pathways, including aberrant protein aggregation, altered energy metabolism, excitotoxicity, inflammation, and oxidative stress. Some of the most common NDs include Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD). There are currently no available cures; there are only therapeutic approaches that ameliorate the progression of symptoms, which makes the search for new drugs and therapeutic targets a constant battle. Cyanobacteria are ancient prokaryotic oxygenic phototrophs whose long evolutionary history has resulted in the production of a plethora of biomedically relevant compounds with anti-inflammatory, antioxidant, immunomodulatory, and neuroprotective properties, that can be valuable in this field. This review summarizes the major NDs and their pathophysiology, with a focus on the anti-neurodegenerative properties of cyanobacterial compounds and their main effects.}, } @article {pmid37893003, year = {2023}, author = {Wu, YS and Taniar, D and Adhinugraha, K and Tsai, LK and Pai, TW}, title = {Detection of Amyotrophic Lateral Sclerosis (ALS) Comorbidity Trajectories Based on Principal Tree Model Analytics.}, journal = {Biomedicines}, volume = {11}, number = {10}, pages = {}, pmid = {37893003}, issn = {2227-9059}, support = {MOST 111-2221-E-027 -113 -MY2//National Science and Technology Council/ ; }, abstract = {The multifaceted nature and swift progression of Amyotrophic Lateral Sclerosis (ALS) pose considerable challenges to our understanding of its evolution and interplay with comorbid conditions. This study seeks to elucidate the temporal dynamics of ALS progression and its interaction with associated diseases. We employed a principal tree-based model to decipher patterns within clinical data derived from a population-based database in Taiwan. The disease progression was portrayed as branched trajectories, each path representing a series of distinct stages. Each stage embodied the cumulative occurrence of co-existing diseases, depicted as nodes on the tree, with edges symbolizing potential transitions between these linked nodes. Our model identified eight distinct ALS patient trajectories, unveiling unique patterns of disease associations at various stages of progression. These patterns may suggest underlying disease mechanisms or risk factors. This research re-conceptualizes ALS progression as a migration through diverse stages, instead of the perspective of a sequence of isolated events. This new approach illuminates patterns of disease association across different progression phases. The insights obtained from this study hold the potential to inform doctors regarding the development of personalized treatment strategies, ultimately enhancing patient prognosis and quality of life.}, } @article {pmid37893165, year = {2023}, author = {De Marchi, F and Munitic, I and Vidatic, L and Papić, E and Rački, V and Nimac, J and Jurak, I and Novotni, G and Rogelj, B and Vuletic, V and Liscic, RM and Cannon, JR and Buratti, E and Mazzini, L and Hecimovic, S}, title = {Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders.}, journal = {Biomedicines}, volume = {11}, number = {10}, pages = {}, pmid = {37893165}, issn = {2227-9059}, abstract = {Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann-Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.}, } @article {pmid37893463, year = {2023}, author = {Laucius, O and Drūteika, J and Balnytė, R and Petrikonis, K and Ališauskienė, M and Vaitkus, A}, title = {Sonographic Phrenic Nerve Changes in Amyotrophic Lateral Sclerosis.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {59}, number = {10}, pages = {}, pmid = {37893463}, issn = {1648-9144}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging ; Phrenic Nerve/physiology ; *Neurodegenerative Diseases ; Prognosis ; Muscle Weakness/complications ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects both the upper and lower motor neurons in the nervous system, causing muscle weakness and severe disability. The progressive course of the disease reduces the functional capacity of the affected patients, limits daily activities, and leads to complete dependence on caregivers, ultimately resulting in a fatal outcome. Respiratory dysfunction mostly occurs later in the disease and is associated with a worse prognosis. Forty-six participants were included in our study, with 23 patients in the ALS group and 23 individuals in the control group. The ultrasound examination of the phrenic nerve (PN) was performed by two authors using a high-resolution "Philips EPIQ 7" ultrasound machine with a linear 4-18 MHz transducer. Our study revealed that the phrenic nerve is significantly smaller on both sides in ALS patients compared to the control group (p < 0.001). Only one significant study on PN ultrasound in ALS, conducted in Japan, also showed significant results (p < 0.00001). These small studies are particularly promising, as they suggest that ultrasound findings could serve as an additional diagnostic tool for ALS.}, } @article {pmid37894774, year = {2023}, author = {Moțățăianu, A and Șerban, G and Andone, S}, title = {The Role of Short-Chain Fatty Acids in Microbiota-Gut-Brain Cross-Talk with a Focus on Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37894774}, issn = {1422-0067}, support = {PN-III-P1-1.1-TE-2021-0960//Ministry of Research, Innovation and Digitization, CNCS - UEFISCDI/ ; }, mesh = {Humans ; Aged ; *Gastrointestinal Microbiome/physiology ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Brain/metabolism ; Fatty Acids, Volatile/metabolism ; Fatty Acids/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by the gradual loss of motor neurons in the brain and spinal cord, leading to progressive motor function decline. Unfortunately, there is no effective treatment, and its increasing prevalence is linked to an aging population, improved diagnostics, heightened awareness, and changing lifestyles. In the gastrointestinal system, the gut microbiota plays a vital role in producing metabolites, neurotransmitters, and immune molecules. Short-chain fatty acids, of interest for their potential health benefits, are influenced by a fiber- and plant-based diet, promoting a diverse and balanced gut microbiome. These fatty acids impact the body by binding to receptors on enteroendocrine cells, influencing hormones like glucagon-like peptide-1 and peptide YY, which regulate appetite and insulin sensitivity. Furthermore, these fatty acids impact the blood-brain barrier, neurotransmitter levels, and neurotrophic factors, and directly stimulate vagal afferent nerves, affecting gut-brain communication. The vagus nerve is a crucial link between the gut and the brain, transmitting signals related to appetite, inflammation, and various processes. Dysregulation of this pathway can contribute to conditions like obesity and irritable bowel syndrome. Emerging evidence suggests the complex interplay among these fatty acids, the gut microbiota, and environmental factors influences neurodegenerative processes via interconnected pathways, including immune function, anti-inflammation, gut barrier, and energy metabolism. Embracing a balanced, fiber-rich diet may foster a diverse gut microbiome, potentially impacting neurodegenerative disease risk. Comprehensive understanding requires further research into interventions targeting the gut microbiome and fatty acid production and their potential therapeutic role in neurodegeneration.}, } @article {pmid37895020, year = {2023}, author = {Davis, SE and Cirincione, AB and Jimenez-Torres, AC and Zhu, J}, title = {The Impact of Neurotransmitters on the Neurobiology of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37895020}, issn = {1422-0067}, support = {R01 DA057866/DA/NIDA NIH HHS/United States ; F31 DA057163/DA/NIDA NIH HHS/United States ; R01 DA047924/DA/NIDA NIH HHS/United States ; R01 DA035714/DA/NIDA NIH HHS/United States ; DA047924/NH/NIH HHS/United States ; DA035714/NH/NIH HHS/United States ; DA057866/NH/NIH HHS/United States ; DA057163/NH/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Alzheimer Disease/pathology ; Brain/pathology ; *Huntington Disease/pathology ; *HIV Infections/pathology ; }, abstract = {Neurodegenerative diseases affect millions of people worldwide. Neurodegenerative diseases result from progressive damage to nerve cells in the brain or peripheral nervous system connections that are essential for cognition, coordination, strength, sensation, and mobility. Dysfunction of these brain and nerve functions is associated with Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and motor neuron disease. In addition to these, 50% of people living with HIV develop a spectrum of cognitive, motor, and/or mood problems collectively referred to as HIV-Associated Neurocognitive Disorders (HAND) despite the widespread use of a combination of antiretroviral therapies. Neuroinflammation and neurotransmitter systems have a pathological correlation and play a critical role in developing neurodegenerative diseases. Each of these diseases has a unique pattern of dysregulation of the neurotransmitter system, which has been attributed to different forms of cell-specific neuronal loss. In this review, we will focus on a discussion of the regulation of dopaminergic and cholinergic systems, which are more commonly disturbed in neurodegenerative disorders. Additionally, we will provide evidence for the hypothesis that disturbances in neurotransmission contribute to the neuronal loss observed in neurodegenerative disorders. Further, we will highlight the critical role of dopamine as a mediator of neuronal injury and loss in the context of NeuroHIV. This review will highlight the need to further investigate neurotransmission systems for their role in the etiology of neurodegenerative disorders.}, } @article {pmid37895110, year = {2023}, author = {Provenzano, F and Torazza, C and Bonifacino, T and Bonanno, G and Milanese, M}, title = {The Key Role of Astrocytes in Amyotrophic Lateral Sclerosis and Their Commitment to Glutamate Excitotoxicity.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37895110}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Glutamic Acid/metabolism ; Astrocytes/metabolism ; Neuroglia/metabolism ; Neurons/metabolism ; }, abstract = {In the last two decades, there has been increasing evidence supporting non-neuronal cells as active contributors to neurodegenerative disorders. Among glial cells, astrocytes play a pivotal role in driving amyotrophic lateral sclerosis (ALS) progression, leading the scientific community to focus on the "astrocytic signature" in ALS. Here, we summarized the main pathological mechanisms characterizing astrocyte contribution to MN damage and ALS progression, such as neuroinflammation, mitochondrial dysfunction, oxidative stress, energy metabolism impairment, miRNAs and extracellular vesicles contribution, autophagy dysfunction, protein misfolding, and altered neurotrophic factor release. Since glutamate excitotoxicity is one of the most relevant ALS features, we focused on the specific contribution of ALS astrocytes in this aspect, highlighting the known or potential molecular mechanisms by which astrocytes participate in increasing the extracellular glutamate level in ALS and, conversely, undergo the toxic effect of the excessive glutamate. In this scenario, astrocytes can behave as "producers" and "targets" of the high extracellular glutamate levels, going through changes that can affect themselves and, in turn, the neuronal and non-neuronal surrounding cells, thus actively impacting the ALS course. Moreover, this review aims to point out knowledge gaps that deserve further investigation.}, } @article {pmid37897436, year = {2024}, author = {Connolly, A and Bailey, S and Lamont, R and Tu, A}, title = {Factors associated with assistive technology prescription and acceptance in motor neurone disease.}, journal = {Disability and rehabilitation. Assistive technology}, volume = {19}, number = {6}, pages = {2229-2238}, doi = {10.1080/17483107.2023.2272858}, pmid = {37897436}, issn = {1748-3115}, mesh = {Humans ; *Motor Neuron Disease/rehabilitation ; *Self-Help Devices ; Male ; Female ; Middle Aged ; *Focus Groups ; *Qualitative Research ; Adult ; Quality of Life ; Aged ; Attitude of Health Personnel ; Interviews as Topic ; Patient Acceptance of Health Care ; }, abstract = {PURPOSE: The risk of delaying assistive technology (AT) prescription and implementation has significant implications on the safety and quality of life of people with Motor Neurone Disease (PwMND). This study aims to explore the barriers and enablers of AT prescription and implementation identified by PwMND and clinicians.

METHODS: A qualitative study using semi-structured focus groups with clinicians and in-depth interviews with PwMND. Sixteen clinicians and ten PwMND were recruited. Thematic analysis was completed and results were compared and discussed to reach an agreement on the final themes.

RESULTS: Three main factors were identified - PwMND, Clinician and Extrapersonal. For PwMND, personal characteristics, such as mindset, was the strongest enabler and inability to accept diagnosis and AT was the key barrier. For Clinician, communication approach was both the most identified enabler and barrier. For Extrapersonal, the availability of interactive education of AT was the strongest enabler and long wait time was a significant barrier.

CONCLUSION: Our study identified themes that clinicians could have an impact on, such as, providing interactive education, engaging PwMND and their support network, and ongoing upskilling of clinicians working in this field. Themes identified that were beyond the control of clinicians were personal characteristics, acceptance and support networks. It highlights the importance for clinicians to be flexible with their communication approach to accommodate the needs of PwMND in the acceptance of AT.}, } @article {pmid37898010, year = {2023}, author = {Halkiadakis, Y and Davidson, N and Morgan, KD}, title = {Time series modeling characterizes stride time variability to identify individuals with neurodegenerative disorders.}, journal = {Human movement science}, volume = {92}, number = {}, pages = {103152}, doi = {10.1016/j.humov.2023.103152}, pmid = {37898010}, issn = {1872-7646}, mesh = {Humans ; Time Factors ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases/diagnosis ; Gait/physiology ; Walking/physiology ; *Huntington Disease ; }, abstract = {The progressive death and dysfunction of neurons causes altered stride-to-stride variability in individuals with Amyotrophic Lateral Sclerosis (ALS) and Huntington's Disease (HD). Yet these altered gait dynamics can manifest differently in these populations based on how and where these neurodegenerative disorders attack the central nervous system. Time series analyses can quantify differences in stride time variability which can help contribute to the detection and identification of these disorders. Here, autoregressive modeling time series analysis was utilized to quantify differences in stride time variability amongst the Controls, the individuals with ALS, and the individuals with HD. For this study, fifteen Controls, 12 individuals with ALS and 15 individuals with HD walked up and down a hallway continuously for 5-min. Participants wore force sensitive resistors in their shoes to collect stride time data. A second order autoregressive (AR) model was fit to the time series created from the stride time data. The mean stride time and two AR model coefficients served as metrics to identify differences in stride time variability amongst the three groups. The individuals with HD walked with significantly greater stride time variability indicating a more chaotic gait while the individuals with ALS adopted more ordered, less variable stride time dynamics (p < 0.001). A plot of the stride time metrics illustrated how each group exhibited significantly different stride time dynamics. The stride time metrics successfully quantified differences in stride time variability amongst individuals with neurodegenerative disorders. This work provided valuable insight about how these neuromuscular disorders disrupt motor coordination leading to the adoption of new gait dynamics.}, } @article {pmid37901127, year = {2023}, author = {Aslam, A and Sarmad, E and Nawaz, A and Numan, A and Ahmad, A and Hassan, MA}, title = {Brait-Fahn-Schwartz Disease: A Unique Co-Occurrence of Parkinson's Disease and Amyotrophic Lateral Sclerosis.}, journal = {Case reports in neurology}, volume = {15}, number = {1}, pages = {207-214}, pmid = {37901127}, issn = {1662-680X}, abstract = {The Parkinson's disease-amyotrophic lateral sclerosis (ALS) complex typically manifests as levodopa-responsive parkinsonism, followed by ALS. It is extremely rare for Parkinson's disease and ALS to coexist without other neurological disorders. Named after the scientists who first described this overlap of two neurodegenerative conditions, it is referred to as Brait-Fahn-Schwartz disease. Given its variable presentation, increasing rarity, and lack of any diagnostic test, it poses a diagnostic challenge for physicians. We present a case of a 55-year-old Pakistani male experiencing progressive quadriparesis with spastic lower limbs and flaccid upper limbs, in addition to the cardinal features of idiopathic Parkinson's disease. Since there is currently no cure available for either Parkinson's disease or ALS, all available treatment focuses on improving quality of life, which we achieved in our patient. This case is unique in being the first incidence of Parkinson's disease-ALS complex in a novel geographic region such as Pakistan, where genetic testing and cost constraints limit the diagnosis of rare disorders. The coexistence of extrapyramidal symptoms and pyramidal symptoms is uncommon. In such situations, physicians may overlook one group of symptoms, potentially leading to a misdiagnosis. This case highlights the value of a thorough physical examination and electrodiagnostic studies and suggests the association between Parkinson's disease and ALS. This case demonstrates the significance of understanding when Parkinson's disease symptoms start to appear in patients with ALS and the need to start dopaminergic therapy in those who had Parkinson's disease features before ALS to alleviate the suffering of an individual and enhance quality of life.}, } @article {pmid37902807, year = {2024}, author = {Sampson, CS and Maberry, MD and Stilley, JA}, title = {Football Saturday: are collegiate football stadiums adequately prepared to handle spectator emergencies?.}, journal = {The Journal of sports medicine and physical fitness}, volume = {64}, number = {1}, pages = {73-77}, doi = {10.23736/S0022-4707.23.15428-4}, pmid = {37902807}, issn = {1827-1928}, mesh = {Humans ; Emergencies ; *Emergency Medical Services/organization & administration ; *Football ; *Sports and Recreational Facilities/organization & administration ; }, abstract = {BACKGROUND: Mass gatherings are a commonly occurring event, especially on college campuses. Any mass gathering gives rise to possible small- or large-scale emergencies. Mass gathering medicine is an integral part of emergency medical services (EMS). An assessment was performed to see if collegiate stadiums possess capabilities for advanced medical care when emergencies arise among attendees.

METHODS: A standardized survey was sent by a single researcher to all National Collegiate Athletic Association (NCAA) Division I programs regarding medical services they currently have in place at their stadiums during Saturday football games. A follow-up inquiry was made at each local community office of emergency management (OEM) to confirm responses or obtain missing data.

RESULTS: Only 21.5% (N.=17) of stadium facilities reported having physicians solely dedicated to the care of fans and other support staff. Most stadiums (N.=70, 88.6%) offered ALS services for their fans, with the remaining ALS services provided by paramedics (N.=46, 58.2%) or registered nurses (N.=7, 8.9%). The remaining stadiums only offered BLS services (N.=6, 7.6%) or basic first aid (N.=3, 3.8%). One stadium offered athletic trainer services to its fan in addition to the ALS care.

CONCLUSIONS: Given the potential for a large influx of patients at sporting events, almost all stadiums have some degree of prehospital emergency care on site. More than a 10% of stadiums lacked ALS services and very few stadiums have physicians on site. Many stadiums were unaware of the resources available during these events. The ability to have ALS services on site who can provide rapid, advanced care to spectators is important due to likely delays in 911 response. At a minimum ALS services should be available within the stadium with consideration of physician coverage as well.}, } @article {pmid37904013, year = {2024}, author = {Chen, X and Luo, J and Zheng, W and Huang, Q and Du, C and Yuan, H and Xiao, F}, title = {Hyperhidrosis as the initial symptom in FUS mutation-associated amyotrophic lateral sclerosis: a case report and comprehensive literature review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {4}, pages = {1523-1527}, pmid = {37904013}, issn = {1590-3478}, mesh = {Female ; Humans ; Young Adult ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/genetics ; *Hyperhidrosis/genetics ; Mutation ; *Neurodegenerative Diseases ; Quality of Life ; RNA-Binding Protein FUS/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is now recognized to involve autonomic dysfunction. The burden of autonomic dysfunction is an important factor in the quality of life and prognosis of ALS patients. This article presents the clinical characteristics of a young female ALS patient with a fused in sarcoma (FUS) gene mutation and notable hyperhidrosis.

METHOD: Detailed clinical characteristics of the patients were collected, and comprehensive examinations such as electrophysiological assessment, neuro-ultrasound, genetic testing, and relevant blood tests were conducted.

RESULT: A 24-year-old female experienced progressive weakness in both lower limbs for over 5 months, along with excessive sweating on both palms and feet. A positive skin iodine-starch test was observed. Electromyography revealed extensive neurogenic damage and prolonged sympathetic skin response (SSR) latency in both lower limbs. Full exon gene sequencing showed a heterozygous mutation c.1574C>T (p.Pro525Leu) in the FUS gene.

CONCLUSION: The pathogenesis of ALS remains unclear at present. This case underscores the presence of autonomic nervous symptoms in ALS associated with FUS mutation and highlights the importance of early diagnosis and timely treatment intervention to enhance patient prognosis.}, } @article {pmid37904275, year = {2024}, author = {Kacem, I and Sghaier, I and Peverelli, S and Abida, Y and Ben Brahim, H and Ratti, A and Nasri, A and Ticozzi, N and Silani, V and Gouider, R}, title = {Optineurin in patients with Amyotrophic Lateral Sclerosis associated to atypical Parkinsonism in Tunisian population.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {128-134}, doi = {10.1080/21678421.2023.2273961}, pmid = {37904275}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Family ; *Frontotemporal Dementia/genetics ; Mutation/genetics ; *Parkinson Disease ; Cell Cycle Proteins ; Membrane Transport Proteins ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous disorder and the phenotypic variability goes far beyond the used clinical stratification parameter. Evidence has emerged that ALS may coexist with distinct neurodegenerative diseases in single cases. We aim to study the clinical features of two familial cases of ALS carriers of two distinct variants harbored in the Optineurin (OPTN) gene. We included definite familial ALS followed up in the Department of Neurology of Razi University Hospital, Tunisia, and selected according to Byrne criteria. Preliminary screening for the four main ALS genes (SOD1, C9ORF72, TARDBP, FUS) was conducted. Given the negative results, we proceeded to NGS target-re-sequencing with a custom panel including genes associated with ALS-FTD, Alzheimer's, and Parkinson's diseases. Both families are carriers of two different OPTN variants and they present very different ALS clinical features. The first family comprises two siblings diagnosed with ALS and Corticobasal syndrome (ALS-CBS) at an early age of onset and carriers of OPTN p.E135X in the homozygous state. The proband for the second family was diagnosed with ALS at an early age of onset presenting as progressive muscular atrophy with rapid progression. Genetic analysis revealed the presence of the homozygous variant p.R520H. Our findings highlight the peculiarity of genetic Tunisian drift. Indeed, genes with a recessive mode of inheritance may explain part of ALS diversity in clinical features. Therefore, the screening of the OPTN gene is highly recommended among inbreeding populations such as the Tunisian one.}, } @article {pmid37905855, year = {2024}, author = {Claud, K and Sun, J}, title = {Metabolites and micronutrition in modulating amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {6}, pages = {1183-1184}, pmid = {37905855}, issn = {1673-5374}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; }, } @article {pmid37905864, year = {2024}, author = {Cauchi, RJ}, title = {SCFD1 in amyotrophic lateral sclerosis: reconciling a genetic association with in vivo functional analysis.}, journal = {Neural regeneration research}, volume = {19}, number = {6}, pages = {1201-1202}, pmid = {37905864}, issn = {1673-5374}, } @article {pmid37905867, year = {2024}, author = {Xiong, W and Lu, L and Li, J}, title = {Long non-coding RNAs with essential roles in neurodegenerative disorders.}, journal = {Neural regeneration research}, volume = {19}, number = {6}, pages = {1212-1220}, pmid = {37905867}, issn = {1673-5374}, abstract = {Recently, with the advent of high-resolution and high-throughput sequencing technologies, an increasing number of long non-coding RNAs (lncRNAs) have been found to be involved in the regulation of neuronal function in the central nervous system with specific spatiotemporal patterns, across different neurodegenerative diseases. However, the underlying mechanisms of lncRNAs during neurodegeneration remain poorly understood. This review provides an overview of the current knowledge of the biology of lncRNAs and focuses on introducing the latest identified roles, regulatory mechanisms, and research status of lncRNAs in Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Finally, this review discusses the potential values of lncRNAs as diagnostic biomarkers and therapeutic targets for neurodegenerative diseases, hoping to provide broader implications for developing effective treatments.}, } @article {pmid37905874, year = {2024}, author = {Abyadeh, M and Gupta, V and Paulo, JA and Mahmoudabad, AG and Shadfar, S and Mirshahvaladi, S and Gupta, V and Nguyen, CTO and Finkelstein, DI and You, Y and Haynes, PA and Salekdeh, GH and Graham, SL and Mirzaei, M}, title = {Amyloid-beta and tau protein beyond Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {19}, number = {6}, pages = {1262-1276}, pmid = {37905874}, issn = {1673-5374}, support = {R01 GM132129/GM/NIGMS NIH HHS/United States ; }, abstract = {The aggregation of amyloid-beta peptide and tau protein dysregulation are implicated to play key roles in Alzheimer's disease pathogenesis and are considered the main pathological hallmarks of this devastating disease. Physiologically, these two proteins are produced and expressed within the normal human body. However, under pathological conditions, abnormal expression, post-translational modifications, conformational changes, and truncation can make these proteins prone to aggregation, triggering specific disease-related cascades. Recent studies have indicated associations between aberrant behavior of amyloid-beta and tau proteins and various neurological diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as retinal neurodegenerative diseases like Glaucoma and age-related macular degeneration. Additionally, these proteins have been linked to cardiovascular disease, cancer, traumatic brain injury, and diabetes, which are all leading causes of morbidity and mortality. In this comprehensive review, we provide an overview of the connections between amyloid-beta and tau proteins and a spectrum of disorders.}, } @article {pmid37906538, year = {2023}, author = {Dong, H and Zhang, H and Jalin, J and He, Z and Wang, R and Huang, L and Liu, Z and Zhang, S and Dai, B and Li, D}, title = {Nucleocapsid proteins from human coronaviruses possess phase separation capabilities and promote FUS pathological aggregation.}, journal = {Protein science : a publication of the Protein Society}, volume = {32}, number = {12}, pages = {e4826}, pmid = {37906538}, issn = {1469-896X}, support = {32170683//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Nucleocapsid Proteins/genetics/metabolism ; Amyloid/metabolism ; Amyloidogenic Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; SARS-CoV-2/genetics/metabolism ; RNA-Binding Protein FUS/chemistry ; }, abstract = {The nucleocapsid (N) protein is an essential structural component necessary for genomic packaging and replication in various human coronaviruses (HCoVs), such as SARS-CoV-2 and MERS-CoV. Recent studies have revealed that the SARS-CoV-2 N protein exhibits a high capacity for liquid-liquid phase separation (LLPS), which plays multiple roles in viral infection and replication. In this study, we systematically investigate the LLPS capabilities of seven homologous N proteins from different HCoVs using a high-throughput protein phase separation assay. We found that LLPS is a shared intrinsic property among these N proteins. However, the phase separation profiles of the various N protein homologs differ, and they undergo phase separation under distinct in vitro conditions. Moreover, we demonstrate that N protein homologs can co-phase separate with FUS, a SG-containing protein, and accelerate its liquid-to-solid phase transition and amyloid aggregation, which is closely related to amyotrophic lateral sclerosis. Further study shows that N protein homologs can directly bind to the low complexity domain of FUS. Together, our work demonstrates that N proteins of different HCoVs possess phase separation capabilities, which may contribute to promoting pathological aggregation of host proteins and disrupting SG homeostasis during the infection and replication of various HCoVs.}, } @article {pmid37906785, year = {2022}, author = {Matamala, JM and Moreno-Roco, J and Acosta, I and Hughes, R and Lillo, P and Casar, JC and Earle, N}, title = {[Multidisciplinary care and therapeutic advances in amyotrophic lateral sclerosis].}, journal = {Revista medica de Chile}, volume = {150}, number = {12}, pages = {1633-1646}, doi = {10.4067/s0034-98872022001201633}, pmid = {37906785}, issn = {0717-6163}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/psychology ; *Neurodegenerative Diseases ; Quality of Life ; Palliative Care ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that mainly affects the motor system, resulting in progressive weakness and muscle wasting. Despite the tremendous advances in physiopathological and clinical characterization, we do not have a curative treatment yet. The progressive and fatal course of ALS makes its management particularly complex and challenging given the diversity of symptoms presenting during the disease progression. The main goal in the treatment of ALS patients is to minimize morbidity and maximize the quality of life. Currently, a series of therapeutic interventions improve the quality of life and prolong survival, including multidisciplinary care, respiratory management, and disease-modifying therapy. Within the supportive interventions, weight maintenance through nutritional and metabolic support is critical. In addition, the management of neuropsychiatric manifestations and preservation of communicative capacity before speech loss are also crucial. Lastly, early palliative care intervention is essential to optimize symptomatic management. Anticipatory guidelines to face the inevitable patient deterioration should be devised. This article updates the main therapeutic strategies used in these patients, including evolving clinical trials with promising novel therapies.}, } @article {pmid37906991, year = {2023}, author = {Prohaska, S and Matthias, K}, title = {Effectiveness of Mindfulness-Based Stress Reduction as a Nondrug Preventive Intervention in Patients with Migraine: A Systematic Review with Meta-Analyses.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {525-534}, doi = {10.1159/000534653}, pmid = {37906991}, issn = {2504-2106}, mesh = {Adult ; Humans ; *Mindfulness ; Treatment Outcome ; *Migraine Disorders/prevention & control ; Headache ; Stress, Psychological ; }, abstract = {INTRODUCTION: Migraine is a neurological disorder characterized by recurrent, severe headaches that are often accompanied by other symptoms. There are various factors that can trigger a migraine in sufferers. Stress can be such a trigger. Drug and nondrug treatments are available for the preventive treatment of migraine. According to a German guideline, mindfulness can be recommended for the prophylaxis of migraine. Therefore, the aim was to investigate the effectiveness of mindfulness-based stress reduction (MBSR) in relation to patient-relevant outcomes in adult patients with migraine. Patient-relevant outcomes in this context are migraine frequency, headache intensity during a migraine attack, depressive symptoms, and quality of life.

MATERIAL AND METHODS: The conduct of this study was guided by the PRISMA 2020 statement. A systematic literature search for randomized controlled trials (RCTs) of the effectiveness of MBSR in adult migraine patients was conducted in December 2021 in three databases: MEDLINE via PubMed, the Cochrane Library, and Web of Science. In addition, a review of reference lists and a search of study registries were performed. The last search was conducted on October 7, 2022. In a two-step process, studies were selected based on predefined inclusion and exclusion criteria. The potential for bias was assessed using the Cochrane Risk of Bias Tool 2. The results were summarized descriptively and by means of quantitative synthesis.

RESULTS: Four RCTs with a total of 275 patients and the follow-up publication of one of these studies were included. The risk of bias in one study each was judged to be low or of some concern and high in two studies. Four studies were included in the quantitative analysis. For the endpoint migraine frequency, the meta-analytic summary of three studies failed to show a statistically significant benefit for MBSR (SMD: -0.23; 95% CI: -0.79 to 0.32). For the endpoint depressive symptoms, a meta-analytic summary of three studies showed a statistically significant benefit for MBSR (SMD: -0.59; 95% CI: -0.93 to -0.25). No study had examined the severity of headaches during a migraine episode.

CONCLUSION: Some results suggest that migraine patients may benefit from MBSR. However, the evidence base is currently insufficient for recommendations on the use of MBSR as a nondrug treatment option. Further adequately powered, high-quality RCTs are needed.

UNLABELLED: EinleitungMigräne ist eine neurologische Erkrankung, die durch wiederkehrende, starke Kopfschmerzen gekennzeichnet ist, die häufig von anderen Symptomen einhergehen. Es gibt verschiedene Faktoren, die bei den Betroffenen eine Migräne auslösen können. Ein solcher Auslöser kann Stress sein. Für die präventive Behandlung der Migräne stehen medikamentöse und nichtmedikamentöse Verfahren zur Verfügung. Laut einer deutschen Leitlinie kann Achtsamkeit zur Prophylaxe von Migräne empfohlen werden. Ziel der Studie war es daher, die Wirksamkeit von achtsamkeitsbasierter Stressreduktion (MBSR) in Bezug auf patientenrelevante Outcomes bei erwachsenen Migränepatienten zu untersuchen. Patientenrelevante Outcomes in diesem Zusammenhang sind Migränehäufigkeit, Kopfschmerzintensität während einer Migräneattacke, depressive Symptome und Lebensqualität.MethodenDie Durchführung dieser Studie orientierte sich am PRISMA-Statement. Eine systematische Literatursuche nach randomisierten kontrollierten Studien zur Wirksamkeit von MBSR bei erwachsenen Migränepatienten wurde im Dezember 2021 in drei Datenbanken durchgeführt: MEDLINE über PubMed, die Cochrane Library und Web of Science. Darüber hinaus wurden Referenzlisten und Studienregister durchsucht. Die letzte Suche erfolgte am 7. Oktober 2022. In einem zweistufigen Verfahren wurden die Studien anhand von vordefinierten Ein- und Ausschlusskriterien ausgewählt. Das Verzerrungspotential der Studien wurde mit dem Cochrane Risk of Bias Tool 2 bewertet. Die Ergebnisse wurden deskriptiv und mit Hilfe einer quantitativen Synthese zusammengefasst.ErgebnisseEs wurden vier randomisiert-kontrollierte Studien mit insgesamt 275 Patienten und die Nachfolgepublikation einer dieser Studien eingeschlossen. Das Verzerrungspotential wurde bei je einer Studie als gering oder bedenklich und bei zwei Studien als hoch eingestuft. Vier Studien wurden in die quantitative Analyse einbezogen. Für den Endpunkt Migränehäufigkeit ergab die metaanalytische Zusammenfassung von drei Studien keinen statistisch signifikanten Vorteil für MBSR (SMD −0.23; 95% CI −0.79 bis 0.32). Für den Endpunkt depressive Symptome zeigte eine metaanalytische Zusammenfassung von drei Studien einen statistisch signifikanten Vorteil für MBSR (SMD −0.59; 95% CI −0.93 bis −0.25). Keine Studie hatte die Schwere der Kopfschmerzen während einer Migräneepisode untersucht.SchlussfolgerungEinige Ergebnisse deuten darauf hin, dass Migränepatienten von MBSR profitieren können. Allerdings ist die Evidenzbasis derzeit nicht ausreichend, um Empfehlungen für den Einsatz von MBSR als nichtmedikamentöse Behandlungsoption abzuleiten. Es werden daher weitere qualitativ hochwertige randomisiert-kontrollierte Studien mit ausreichender statistischer Power benötigt.}, } @article {pmid37907134, year = {2023}, author = {Birajdar, SV and Mazahir, F and Alam, MI and Kumar, A and Yadav, AK}, title = {Repurposing and clinical attributes of antidiabetic drugs for the treatment of neurodegenerative disorders.}, journal = {European journal of pharmacology}, volume = {961}, number = {}, pages = {176117}, doi = {10.1016/j.ejphar.2023.176117}, pmid = {37907134}, issn = {1879-0712}, mesh = {Humans ; Mice ; Animals ; Hypoglycemic Agents/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; *Diabetes Mellitus, Type 2/drug therapy ; Drug Repositioning ; Neuroinflammatory Diseases ; *Alzheimer Disease/drug therapy ; Insulin/metabolism ; *Metformin/pharmacology ; }, abstract = {The risk of neurodegeneration was found to be increased among people with type 2 diabetes mellitus (T2DM). Brain disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and others are considered neurodegenerative diseases and can be characterized by progressive loss of neurons. The deficiency of insulin, impaired signaling, and its resistance lead to alteration in the neuronal functioning of the brain. Insulin degrading enzyme (IDE) plays a significant role in the amyloid β metabolism, aggregation, and deposition of misfolded proteins in the brain's hippocampal and cortical neuronal regions. The insulin signaling via IP3 activation upregulates the IDE and could be a promising approach to regulate neurodegeneration. The repurposing of existing antidiabetic drugs such as Metformin, DPP-4 inhibitors, thiazolidinediones, glucagon-like peptides (GLP-1), sodium-glucose co-transport-2 (SGCT-2) inhibitors, and insulin could be an alternative and effective strategy to treat neurodegeneration via modulating insulin signaling, insulin resistance, IDE activity, oxidative stress, mitochondrial dysfunction, serum lipid profile and neuroinflammation in the brain. Antidiabetic medications reduce the risk of neuroinflammation, oxidative stress, and Aβ deposition by enhancing their clearance rate. The downregulation of IDE alters the degradation of Aβ monomers in the Tg2576 APP mice. Also, the treatment with metformin activated the AMPK pathway and suppressed mTOR and BACE-1 protein expression in the APP/PS1-induced mice model. Thus, the primary intention of this review is to explore the link between T2DM and neurodegenerative disorders, and the possible role of various antidiabetic drugs in the management of neurodegenerative disorders.}, } @article {pmid37907717, year = {2024}, author = {Yamamoto, K and Itoi, T and Matsunami, Y and Sofuni, A and Tsuchiya, T and Mukai, S and Kojima, H and Minami, H and Nakatsubo, R and Tonozuka, R}, title = {Early and late effects of endoscopic interventions in patients with malignant afferent loop syndrome: A single-center experience and literature review.}, journal = {Journal of hepato-biliary-pancreatic sciences}, volume = {31}, number = {2}, pages = {120-132}, doi = {10.1002/jhbp.1380}, pmid = {37907717}, issn = {1868-6982}, mesh = {Humans ; *Afferent Loop Syndrome/diagnostic imaging/etiology/surgery ; *Cholestasis/etiology ; Drainage ; Endoscopy ; Endosonography ; Liver/pathology ; Retrospective Studies ; Stents/adverse effects ; Treatment Outcome ; }, abstract = {BACKGROUND/PURPOSE: Afferent loop syndrome (ALS) is a rare adverse event after gastrointestinal surgery requiring appropriate early decompression treatment. Several endoscopic interventions have been attempted for treatment, including endoscopic enteral metal stent placement (EMSP), endoscopic ultrasound (EUS)-guided entero-enterostomy (EUS-EE), and EUS-guided hepaticogastrostomy (EUS-HGS). However, there are limited data on outcomes, including duration of stent patency. In this study, we evaluated the usefulness of each endoscopic intervention for malignant ALS.

METHODS: We retrospectively investigated nine patients with malignant ALS who underwent EMSP, EUS-EE, or EUS-HGS. Information on technical success, clinical efficacy, adverse events, stent dysfunction, and overall survival was collected and analyzed.

RESULTS: The most common symptoms were abdominal pain and cholangitis. ALS was treated by EMSP in three patients, EUS-EE in three patients, and EUS-HGS in three patients. Stent placement was successful and clinically effective in all patients with no adverse events. During follow-up, stent dysfunction occurred in two patients treated by EUS-HGS. Eight patients died of primary disease during a median follow-up of 157 days.

CONCLUSIONS: Each of the available endoscopic interventions for malignant ALS can be expected to produce similar outcomes, including duration of stent patency. The choice of endoscopic intervention should be made based on the characteristics of each treatment.}, } @article {pmid37908143, year = {2024}, author = {Azad, A and Gökmen, ÜR and Uysal, H and Köksoy, S and Bilge, U and Manguoğlu, AE}, title = {Autophagy dysregulation plays a crucial role in regulatory T-cell loss and neuroinflammation in amyotrophic lateral sclerosis (ALS).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {336-344}, doi = {10.1080/21678421.2023.2273365}, pmid = {37908143}, issn = {2167-9223}, mesh = {Humans ; *T-Lymphocytes, Regulatory/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Neuroinflammatory Diseases ; Autophagy ; Forkhead Transcription Factors/metabolism ; }, abstract = {OBJECTIVE: Neuroinflammation is the hallmark of amyotrophic lateral sclerosis (ALS) disease. Regulatory T cells (Tregs) are essential in immune tolerance and neuroinflammation prevention. It has been shown that a significant decrease in Treg and FoxP3 protein expression is observed in ALS patients. The main reason for the FoxP3[+] Treg loss in ALS is unknown. In this study, the role of autophagy dysregulation in FoxP3[+] Tregs in ALS was investigated.

METHODS: Twenty-three ALS patients and 24 healthy controls were recruited for the study. Mononuclear cells (MNCs) were obtained from peripheral blood, and then Tregs were isolated. Isolated Tregs were stained with FoxP3 and LC3 antibodies and analyzed in flow cytometry to determine autophagy levels in FoxP3[+] Tregs in patients and controls.

RESULTS: The mean of FoxP3[+] LC3[+] cells, were 0.47 and 0.45 in patients and controls, respectively. The mean of FoxP3[+] LC3- cells was 0.15 in patients and 0.20 in controls, p = 0.030 (p < 0.05). There is no significant correlation between ALSFRS-R decay rate and autophagy level in patients. Also, there is no significant difference between autophagy levels in FoxP3[+] Tregs in patients with rapidly progressing ALS and slow-progressing ALS.

CONCLUSION: Excessive autophagy levels in FoxP3[+] Tregs in ALS patients can potentially be an explanation for an increased cell death and result in worsened neuroinflammation and disease onset. However, the disease progress is not attributable to autophagy levels in FoxP3[+] Tregs.}, } @article {pmid37909302, year = {2024}, author = {Chen, S and Carter, D and Brockenbrough, PB and Cox, S and Gwathmey, K}, title = {Racial disparities in ALS diagnostic delay: a single center's experience and review of potential contributing factors.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {112-118}, doi = {10.1080/21678421.2023.2273361}, pmid = {37909302}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Delayed Diagnosis ; Retrospective Studies ; Vital Capacity ; }, abstract = {OBJECTIVE: Outcomes for amyotrophic lateral sclerosis (ALS) patients are improved with prompt diagnosis, earlier initiation of disease-modifying treatments, and participation in a multidisciplinary clinic. We studied diagnostic delay and disease severity at time of clinic presentation between Black and non-Hispanic Caucasian ALS patients.

METHODS: We performed a retrospective analysis of non-Hispanic Caucasian and Black ALS patients seen in the Virginia Commonwealth University Health System multidisciplinary ALS clinic between 2017 and 2023. Diagnostic delay, ALS Functional Rating Scale-Revised (ALSFRS-R) and upright forced vital capacity (FVC) scores at baseline appointment were collected. Patient's distance from clinic and affluency of residential neighborhood were evaluated.

RESULTS: We analyzed 172 non-Hispanic Caucasian and 33 Black ALS patients. Black patients had a 64% increase in diagnostic delay compared to non-Hispanic Caucasian patients. Black patients had a lower performance on ALSFRS-R (5.3 points, p < 0.001) and FVC (17.9 percentage points p < 0.001) at time of first clinic visit. Black patients lived closer to clinic, with higher proportion living in the city of Richmond, but in less affluent areas with lower median house income ($55,300 ± 22,600 vs $69,900 ± 23,700).

DISCUSSION: Our findings demonstrate a large racial difference in ALS diagnostic delay, and greater disease severity and lower respiratory function at time of diagnosis for Black ALS patients. Delay in diagnosis prolongs access to disease-modifying therapies, multidisciplinary care, durable medical equipment, and respiratory and nutritional support. Potential sources of these racial disparities include providers' implicit bias and structural racism.}, } @article {pmid37909610, year = {2023}, author = {Reis, AHO and Figalo, LB and Orsini, M and Lemos, B}, title = {The implications of DNA methylation for amyotrophic lateral sclerosis.}, journal = {Anais da Academia Brasileira de Ciencias}, volume = {95}, number = {suppl 2}, pages = {e20230277}, doi = {10.1590/0001-3765202320230277}, pmid = {37909610}, issn = {1678-2690}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA Methylation/genetics ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and serious neurodegenerative disorder that develops in consequence of the progressive loss of the upper and lower motor neurons. Cases of ALS are classified as sporadic (sALS), or familial (fALS). Over 90% of cases are sALS, while roughly 10% are related to inherited genetic mutations (fALS). Approximately 70% of the genetic mutations that contribute to fALS have been identified. On the other hand, the majority of the sALS cases have an undetermined genetic contributor and few mutations have been described, despite the advanced genetic analysis methods. Also, several factors contribute to the onset and progression of ALS. Numerous lines of evidence indicate that epigenetic changes are linked to aging, as well as neurodegenerative disorders, such as ALS. In most cases, they act as the heritable regulation of transcription by DNA methylation, histone modification and expression of noncoding RNAs. Mechanisms involving aberrant DNA methylation could be relevant to human ALS pathobiology and therapeutic targeting. Despite advances in research to find factors associated with ALS and more effective treatments, this disease remains complex and has low patient survival. Here, we provide a narrative review of the role of DNA methylation for this complex neurodegenerative disorder.}, } @article {pmid37910250, year = {2024}, author = {Khamaysa, M and Lefort, M and Pélégrini-Issac, M and Lackmy-Vallée, A and Mendili, MME and Preuilh, A and Devos, D and Bruneteau, G and Salachas, F and Lenglet, T and Amador, MM and Le Forestier, N and Hesters, A and Gonzalez, J and Rolland, AS and Desnuelle, C and Chupin, M and Querin, G and Georges, M and Morelot-Panzini, C and Marchand-Pauvert, V and Pradat, PF and , }, title = {Quantitative brainstem and spinal MRI in amyotrophic lateral sclerosis: implications for predicting noninvasive ventilation needs.}, journal = {Journal of neurology}, volume = {271}, number = {3}, pages = {1235-1246}, pmid = {37910250}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/therapy/complications ; *Noninvasive Ventilation/methods ; Disease Progression ; Magnetic Resonance Imaging/methods ; Brain Stem/diagnostic imaging ; }, abstract = {BACKGROUND: Respiratory complications resulting from motor neurons degeneration are the primary cause of death in amyotrophic lateral sclerosis (ALS). Predicting the need for non-invasive ventilation (NIV) in ALS is important for advance care planning and clinical trial design. The aim of this study was to assess the potential of quantitative MRI at the brainstem and spinal cord levels to predict the need for NIV during the first six months after diagnosis.

METHODS: Forty-one ALS patients underwent MRI and spirometry shortly after diagnosis. The need for NIV was monitored according to French health guidelines for 6 months. The performance of four regression models based on: clinical variables, brainstem structures volumes, cervical spinal measurements, and combined variables were compared to predict the need for NIV within this period.

RESULTS: Both the clinical model (R[2] = 0.28, AUC = 0.85, AICc = 42.67, BIC = 49.8) and the brainstem structures' volumes model (R[2] = 0.30, AUC = 0.85, AICc = 40.13, BIC = 46.99) demonstrated good predictive performance. In addition, cervical spinal cord measurements model similar performance (R[2] = 0.338, AUC = 0.87, AICc = 37.99, BIC = 44.49). Notably, the combined model incorporating predictors from all three models yielded the best performance (R[2] = 0.60, AUC = 0.959, AICc = 36.38, BIC = 44.8). These findings are supported by observed positive correlations between brainstem volumes, cervical (C4/C7) cross-sectional area, and spirometry-measured lung volumes.

CONCLUSIONS: Our study shows that brainstem volumes and spinal cord area are promising measures to predict respiratory intervention needs in ALS.}, } @article {pmid37910562, year = {2023}, author = {Lugg, A and Schindle, M and Sivak, A and Tankisi, H and Jones, KE}, title = {Nerve excitability measured with the TROND protocol in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurophysiology}, volume = {130}, number = {6}, pages = {1480-1491}, doi = {10.1152/jn.00174.2023}, pmid = {37910562}, issn = {1522-1598}, support = {RGPIN-2017-05624//Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; }, mesh = {Humans ; Action Potentials/physiology ; *Amyotrophic Lateral Sclerosis ; Axons/physiology ; Biomarkers ; Prospective Studies ; Clinical Protocols ; Sarcosine/analogs & derivatives ; Thiocarbamates ; }, abstract = {This meta-analysis assessed the 30+ nerve excitability indices generated by the TROND protocol to identify potential biomarkers for amyotrophic lateral sclerosis (ALS). A comprehensive search was conducted in multiple databases to identify human studies that tested median motor axons. Forest plot analyses were performed using a random-effects model to determine the pooled effect (Z-score), heterogeneity (I[2]), and Cohen's d for potential biomarker identification. Out of 2,866 studies, 23 studies met the inclusion criteria, incorporating data from 719 controls and 942 patients with ALS. Seven indices emerged as potential biomarkers: depolarizing threshold electrotonus (TEd) 90-100 ms, strength-duration time constant (SDTC), superexcitability, TEd 40-60 ms, resting I/V slope, 50% depolarizing I/V, and subexcitability (ranked by the magnitude of the difference between patients and controls from largest to smallest). In a sensitivity analysis focusing on patients with larger compound muscle action potentials (CMAPs), only four indices were potential biomarkers: TEd 10-20 ms, TEd 90-100 ms, superexcitability, and SDTC. Among the extensive range of 30+ excitability indices generated by the TROND protocol, we have identified seven indices that effectively differentiate patients with ALS from healthy controls. Furthermore, a smaller subset of four indices shows promise as potential biomarkers when the CMAP remains relatively large. However, most studies were considered to be at moderate risk of bias due to case-control designs and absence of sensitivity and specificity calculations, underscoring the need for more prospective diagnostic test-accuracy studies with appropriate disease controls.NEW & NOTEWORTHY This meta-analysis uncovers seven potential axonal excitability biomarkers for lower motor neuron pathology in ALS, shedding light on ion channel dysfunction. The identified dysfunction aligns with the primary pathology-protein homeostasis disruption. These biomarkers could fill a gap to detect presymptomatic spread of the disease in the spinal cord and monitor treatments targeting protein homeostasis and limiting spread, toward enhancing patient care.}, } @article {pmid37910649, year = {2025}, author = {Franklin, JE}, title = {Palliative hypnosis approaches in the symptomatic treatment of amyotrophic lateral sclerosis (ALS).}, journal = {The American journal of clinical hypnosis}, volume = {67}, number = {1}, pages = {54-68}, doi = {10.1080/00029157.2023.2252875}, pmid = {37910649}, issn = {2160-0562}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; *Palliative Care/methods ; *Hypnosis/methods ; Male ; Middle Aged ; Aged ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, incurable, and ultimately fatal, devastating, progressive degenerative neurologic disease. It causes upheaval in the lives of patients and family caregivers alike. Palliative care can play an important supportive role in the care of patients and families dealing with the devastation of this illness. Clinical hypnosis has demonstrated benefits in treating the symptoms associated with severe chronic illness. There are, however, few studies looking at the benefits of clinical hypnosis in treating the symptom burden of ALS. This article describes palliative care and how it can provide an additional layer of support to seriously ill patients. A brief review of previous studies of hypnosis in the supportive, symptomatic treatment of ALS is provided, followed by a description of a case series of 30 Veterans who received clinical hypnosis and self-hypnosis training as a complementary treatment for the symptoms of ALS. Details of three case histories are included to highlight and discuss specific strategies and emblematic clinical responses. There is evidence that clinical hypnosis can benefit ALS patients and family caregivers struggling with this devastating illness.}, } @article {pmid37913752, year = {2023}, author = {Chou, PY and Chen, CM and Wang, CC and Tai, CJ and Lin, YK and Tang, YJ}, title = {Characteristics and Effects of Chinese Herbal Medicine in the Management of Female Infertility: A Hospital-Based Study.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {481-491}, doi = {10.1159/000534590}, pmid = {37913752}, issn = {2504-2106}, mesh = {Humans ; Female ; Retrospective Studies ; *Drugs, Chinese Herbal/therapeutic use ; *Infertility, Female/therapy ; Treatment Outcome ; Hospitals ; }, abstract = {BACKGROUND: In Taiwan, Chinese herbal medicine (CHM) is used to treat female infertility. Evidence indicates that the absence of monotherapy efficacy assessment and comparison with mainstream interventions may lead to the improper use of CHM for female infertility.

METHODS: A retrospective cohort study enrolled female patients at a hospital undergoing CHM intervention to treat infertility from 2012 to 2020 in order to determine the outcomes of CHM monotherapy for female infertility. Kaplan-Meier analysis under strict assumptions was used to estimate the cumulative probability of pregnancy and live births after CHM. Cox hazard regression analysis was used to estimate the hazard ratios of prognostic variables, namely, the woman's age and diagnostic category.

RESULTS: 694 women met the inclusion criteria and accounted for 2,145 cycles. A total of 190 pregnancies resulted in 125 live births, all of which were singleton births of babies with 16 perinatal complications requiring hospitalization. The real cumulative pregnancy rate and cumulative live birth rate (CLBR) for the total population after 10 cycles were between 27.4% and 35.2% and between 18% and 22.1%, respectively. Compared with the live birth rate corresponding to patients aged under 35 years, that of older patients, particularly those aged 38-39 years, was significantly lower (hazard ratio: 0.19, 95% confidence interval: 0.11-0.33). Women with other diagnoses, namely, uterine problems or endometriosis, had a greater probability of a live birth than did women with tubal pathology (hazard ratio: 6.31, 95% confidence interval: 1.99-20.07).

CONCLUSION: To the best of our knowledge, this is the first retrospective study to employ life table analysis to determine the CHM treatment outcomes in terms of female infertility. The study established a basis to compare in vitro fertilization (IVF) with CHM and identified the advantages and disadvantages of CHM for treating female infertility. Although the CLBR of present study is lower than those reported in IVF studies, CHM in treating female infertility can still be beneficial to women aged younger than 38 years or with diagnoses other than tubal pathology and worth recommendation by reproductive specialists according to the promising results gained from the strict criteria. However, in order to determine the optimal timing, possible mechanism, corresponding side effects, and the efficacy of CHM combined with IVF for treating female infertility, rigorous research is required.

UNLABELLED: HintergrundIn Taiwan wird die chinesische Heilpflanzenmedizin (CHM) zur Behandlung weiblicher Infertilität angewendet. Es liegen Hinweise vor, nach denen fehlende Wirksamkeitsbeurteilungen der Monotherapien und Vergleiche mit herkömmlichen Interventionen zu einer unsachgemäßen Anwendung von CHM bei weiblicher Infertilität führen können.MethodenEine retrospektive Kohortenstudie schloss Patientinnen eines Krankenhauses ein, die von 2012 bis 2020 wegen Infertilität mit CHM behandelt wurden, um die Behandlungsergebnisse der CHM-Monotherapie bei weiblicher Infertilität zu ermitteln. Zur Schätzung der kumulativen Wahrscheinlichkeit von Schwangerschaften und Lebendgeburten nach einer CHM-Behandlung wurde die Kaplan-Meier-Analyse unter strengen Annahmen verwendet. Mit Hilfe der Cox-Hazard-Regressionsanalyse wurden die Risikoverhältnisse der prognostischen Variablen Alter der Frau und Diagnosekategorie geschätzt.Ergebnisse694 Frauen erfüllten die Einschlusskriterien und die Zahl der Zyklen betrug 2,145. Insgesamt 190 Schwangerschaften führten zu 125 Lebendgeburten, allesamt Einlingsgeburten, mit 16 perinatalen Komplikationen, die eine Hospitalisierung erforderten. Die reale kumulative Schwangerschaftsrate und die kumulative Lebendgeburtenrate (cumulative live birth rate, CLBR) für die Gesamtpopulation nach 10 Zyklen lagen zwischen 27.4% und 35.2% bzw. zwischen 18% und 22.1%. Die Lebendgeburtenrate bei älteren Patientinnen, insbesondere im Alter von 38 bis 39 Jahren, war deutlich niedriger als bei Patientinnen unter 35 Jahren (Hazard Ratio: 0.19, 95%-Konfidenzintervall: 0.11–0.33). Bei Frauen mit anderen Diagnosen wie Gebärmutterproblemen oder Endometriose war die Wahrscheinlichkeit einer Lebendgeburt höher als bei Frauen mit Eileitererkrankungen (Hazard Ratio: 6.31, 95%-Konfidenzintervall: 1.99–20.07).SchlussfolgerungUnseres Wissens ist dies die erste retrospektive Studie, in der die Ergebnisse der CHM-Behandlung bei weiblicher Infertilität mittels Sterbetafelanalyse ermittelt wurden. Die Studie bildet eine Grundlage für den Vergleich von In-vitro-Fertilisation (IVF) mit CHM und zeigt die Vor- und Nachteile der CHM zur Behandlung weiblicher Infertilität auf. Zwar fällt die kumulative Lebendgeburtenrate in der vorliegenden Studie niedriger aus als in IVF-Studien, doch kann die CHM bei der Behandlung weiblicher Infertilität für Frauen unter 38 Jahren oder Frauen, die eine andere Diagnose als eine Eileitererkrankung haben, von Nutzen sein und angesichts der vielversprechenden Ergebnisse, die aus den strengen Kriterien gewonnen wurden, ist sie eine Empfehlung durch Reproduktionsspezialisten wert. Allerdings sind rigorose Forschungsarbeiten erforderlich, um die optimale Zeitplanung, den möglichen Mechanismus, die entsprechenden Nebenwirkungen und die Wirksamkeit der CHM in Kombination mit IVF zur Behandlung der weiblichen Infertilität zu ermitteln.}, } @article {pmid37914747, year = {2023}, author = {Sung, W and Kim, JA and Kim, YS and Park, J and Oh, KW and Sung, JJ and Ki, CS and Kim, YE and Kim, SH}, title = {An analysis of variants in TARDBP in the Korean population with amyotrophic lateral sclerosis: comparison with previous data.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {18805}, pmid = {37914747}, issn = {2045-2322}, mesh = {Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/pathology ; Cohort Studies ; Genetic Testing ; Mutation ; Mutation, Missense ; Republic of Korea/epidemiology ; DNA-Binding Proteins ; }, abstract = {The TARDBP gene variant is a known major cause of amyotrophic lateral sclerosis (ALS), with limited reports of Korean patients with ALS harboring the variants in TARDBP. This large cohort study introduces four ALS patients who share the p.M337V variant of the TARDBP, allowing for an investigation of clinical characteristics and prognosis by analyzing previously reported cases with the same variant. From November 2014 to August 2022, participants were recruited from two tertiary hospitals in Seoul, Korea. Clinical characteristics of patients diagnosed with ALS carrying the variant in TARDBP were evaluated. Previous articles demonstrating subjects' characteristics were reviewed. Four patients were identified with the pathogenic missense variant (c.1009A>G; p.M337V) in the TARDBP. The mean age of onset was 55 years old, and none of the patients showed severe cognitive impairment. Sixty-three patients carrying the p.M337V variant in TARDBP from this study and previous reports delineated young age of onset (51.6 years), high frequency of bulbar onset patients (61.9%), and low comorbidity of frontotemporal dementia. This study reveals the presence of pathogenic variant of TARDBP in Korea and emphasizes the importance of genetic screening of the TARDBP gene, in diagnosing ALS and evaluating prognosis among familial and simplex ALS patients in Korea.}, } @article {pmid37915239, year = {2024}, author = {Lee, J and Yoon, D and Sung, KW and Bae, EJ and Park, DH and Suh, YH and Kwon, YT}, title = {Targeted degradation of SNCA/α-synuclein aggregates in neurodegeneration using the AUTOTAC chemical platform.}, journal = {Autophagy}, volume = {20}, number = {2}, pages = {463-465}, pmid = {37915239}, issn = {1554-8635}, mesh = {Mice ; Animals ; *alpha-Synuclein/metabolism ; Autophagy/physiology ; Ligands ; *Parkinson Disease/metabolism ; Brain/metabolism ; }, abstract = {Parkinson disease (PD) characterized by dopaminergic neuronal loss is caused by aggregation of misfolded SNCA/α-synuclein. We recently developed autophagy-targeting chimera (AUTOTAC), a targeted protein degradation (TPD) technology based on the macroautophagy/autophagy-lysosome pathway (ALP). In this study, we employed AUTOTAC to synthesize ATC161, a chimeric compound that adopts Anle138b as target-binding ligand (TBL) for SNCA aggregates. The autophagy-targeting ligand (ATL) of ATC161 was designed to allosterically activate the autophagy receptor SQSTSM1/p62 (sequestosome 1), a key step for targeting SNCA aggregates to the phagophore. The lysosomal degradation of SNCA aggregates by ATC161 acutely occurs at DC50 of 100-500 nM with no significant off-target degradation of monomeric SNCA. ATC161 protects cells from DNA and mitochondrial damage by SNCA aggregates. In PD model mice, oral administration of ATC161 decreases the level of SNCA aggregates and their propagation across brain regions, which mitigates glial inflammatory responses and improves muscle strength and locomotive activity. An Investigational New Drug (IND) was approved by the Korean Food and Drug Administration for a phase 1 clinical trial to treat PD, Alzheimer disease (AD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). We suggest that AUTOTAC provides a platform for drug discovery in proteinopathies and other diseases.}, } @article {pmid37915644, year = {2023}, author = {Kassahun Bekele, B and Kwizera, L and Abdul Razzak, R and Alfadul, ESA and Anand, A and Wojtara, M and Nazir, A and Uwishema, O}, title = {ALS in Africa: current knowledge and exciting opportunities for future study - short communication.}, journal = {Annals of medicine and surgery (2012)}, volume = {85}, number = {11}, pages = {5827-5830}, pmid = {37915644}, issn = {2049-0801}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can present with motor and extra-motor manifestations. Its global prevalence is 4.42 per 1 000 000, and it has a high mortality rate. In sub-Saharan Africa alone, 15 per 100 000 develop ALS mainly between their 40s and 60s and only one-fourth of them have access to treatment. ALS was found to be not only affected by genetic variation but also by the patient's mood and lifestyle. In Africa, males and younger people tend to be affected with ALS and rarely present with bulbar onset. ALS diagnosis is very challenging due to the lack of ALS-specific biomarkers and the sharing of some clinical features with other syndromes. ALS treatment is mainly riluzole and supportive treatment via nasogastric tube and ventilatory support. The access to treatment in Africa is very limited, thus a very bad prognosis with a median survival time of 14 months post-diagnosis. Further research is needed to assess the real situation in Africa and to try to closely monitor patients suffering from ALS.}, } @article {pmid37916886, year = {2024}, author = {Tang, L and Tang, X and Zhao, Q and Li, Y and Bu, Y and Liu, Z and Li, J and Guo, J and Shen, L and Jiang, H and Tang, B and Xu, R and Cao, W and Yuan, Y and Wang, J}, title = {Mutation and clinical analysis of the CLCC1 gene in amyotrophic lateral sclerosis patients from Central South China.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {1}, pages = {79-88}, pmid = {37916886}, issn = {2328-9503}, support = {2021YFA0805202//National Key Research and Development Program of China/ ; 81300981//National Natural Science Foundation of China/ ; 81671120//National Natural Science Foundation of China/ ; 82171431//National Natural Science Foundation of China/ ; 2020LNJJ13//the Project Program of National Clinical Research Center for Geriatric Disorders at Xiangya Hospital/ ; STI2030 Major Projects 2021ZD0201803//the Science and Technology Innovation 2030/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; Mutation, Missense ; Genetic Association Studies ; China ; Chloride Channels/genetics ; }, abstract = {INTRODUCTION: Recently, chloride channel CLIC-like 1 (CLCC1) was reported to be a novel ALS-related gene. We aimed to screen CLCC1 variants in our ALS cohort and further explore the genotype-phenotype correlation of CLCC1-related ALS.

METHODS: We screened rare damaging variants in CLCC1 from our cohorts of 1005 ALS patients and 1224 healthy controls with whole-exome sequencing in Central South China. Fisher's exact test was conducted for association analysis at the entire gene level and single variant level.

RESULTS: In total, four heterozygous missense variants in CLCC1 were identified from four unrelated sporadic ALS patients and predicted to be putative pathogenic by in silico tools and protein model prediction, accounting for 0.40% of all patients (4/1005). The four variants were c.A275C (p.Q92P), c.G1139A (p.R380K), c.C1244T (p.T415M), and c.G1328A (p.R443Q), respectively, which had not been reported in ALS patients previously. Three of four variants were located in exon 10. Patients harboring CLCC1 variants seemed to share a group of similar clinical features, including earlier age at onset, rapid progression, spinal onset, and vulnerable cognitive status. Statistically, we did not find CLCC1 to be associated with the risk of ALS at the entire gene level or single variant level.

CONCLUSION: Our findings further expanded the genetic and clinical spectrum of CLCC1-related ALS and provided more genetic evidence for anion channel involvement in the pathogenesis of ALS, but further investigations are needed to verify our findings.}, } @article {pmid37918554, year = {2023}, author = {Mishra, D and Narain, P and Dave, U and Gomes, J}, title = {Role of ALS-associated OPTN-K489E mutation in neuronal cell-death regulation.}, journal = {Molecular and cellular neurosciences}, volume = {127}, number = {}, pages = {103904}, doi = {10.1016/j.mcn.2023.103904}, pmid = {37918554}, issn = {1095-9327}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neuroblastoma ; Mutation ; Cell Death ; Apoptosis/genetics ; }, abstract = {Optineurin (OPTN) gene is a marker of amyotrophic lateral sclerosis (ALS). However, the role of optineurin protein (OPTN) in ALS pathology is unclear, even though it is known to regulate autophagy, apoptosis, and other survival-death cellular processes. Genetic analysis of Indian ALS patients by our group ascertained a novel mutation K489E in the OPTN gene. To identify the molecular mechanism associated with OPTN and its mutation, we developed an in-vitro cell model using SH-SY5Y cells harbouring OPTN and OPTN-K489E mutation along with its control vector. Since we observed a significant decrease in cell viability in the mutant, we measured the expressions of genes and proteins mediating apoptosis, necroptosis, and autophagy, to establish the role of OPTN in cell death regulation. Our results show that OPTN-K489E mutation changes the relative gene expressions of miRNA-9, REST, CoREST and BDNF, and causes apoptosis. We also observed an up-regulation in the expressions of necroptosis mediated genes RIPK1, RIPK3, and MLKL and autophagy mediated genes TBK1, P62, and LC3II. The results of FACS analyses revealed that this mutation promotes apoptotic and necroptotic processes confirming the pathogenicity of OPTN-K489E.}, } @article {pmid37919089, year = {2023}, author = {Moda, F and Ciullini, A and Dellarole, IL and Lombardo, A and Campanella, N and Bufano, G and Cazzaniga, FA and Giaccone, G}, title = {Secondary Protein Aggregates in Neurodegenerative Diseases: Almost the Rule Rather than the Exception.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {28}, number = {10}, pages = {255}, doi = {10.31083/j.fbl2810255}, pmid = {37919089}, issn = {2768-6698}, mesh = {Humans ; Aged ; *Neurodegenerative Diseases/pathology ; Protein Aggregates ; *Lewy Body Disease/metabolism/pathology ; *Synucleinopathies ; *Alzheimer Disease/metabolism ; *Parkinson Disease/metabolism ; tau Proteins/metabolism ; *Prion Diseases ; Amyloid beta-Peptides ; *Frontotemporal Lobar Degeneration ; }, abstract = {The presence of protein aggregates is a hallmark of many neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). Traditionally, each disease has been associated with the aggregation of specific proteins, which serve as disease-specific biomarkers. For example, aggregates of α-synuclein (α-syn) are found in α-synucleinopathies such as PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Similarly, AD is characterized by aggregates of amyloid-beta (Aβ) and tau proteins. However, it has been observed that these protein aggregates can also occur in other neurodegenerative diseases, contributing to disease progression. For instance, α-syn aggregates have been detected in AD, Down syndrome, Huntington's disease, prion diseases, and various forms of FTLD. Similarly, Aβ aggregates have been found in conditions like DLB and PD. Tau aggregates, in addition to being present in primary tauopathies, have been identified in prion diseases, α-synucleinopathies, and cognitively healthy aged subjects. Finally, aggregates of TDP-43, typically associated with FTLD and amyotrophic lateral sclerosis (ALS), have been observed in AD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), MSA, DLB, and other neurodegenerative diseases. These findings highlight the complexity of protein aggregation in neurodegeneration and suggest potential interactions and common mechanisms underlying different diseases. A deeper understating of this complex scenario may eventually lead to the identification of a better elucidation of the pathogenetic mechanisms of these devastating conditions and hopefully new therapeutic stragegies.}, } @article {pmid37920145, year = {2024}, author = {Stamatelatou, A and Bertinetto, CG and Jansen, JJ and Postma, G and Selnaes, KM and Bathen, TF and Heerschap, A and Scheenen, TWJ and , }, title = {A multivariate curve resolution analysis of multicenter proton spectroscopic imaging of the prostate for cancer localization and assessment of aggressiveness.}, journal = {NMR in biomedicine}, volume = {37}, number = {3}, pages = {e5062}, doi = {10.1002/nbm.5062}, pmid = {37920145}, issn = {1099-1492}, support = {813120//European Union's Horizon 2020 research and innovation program/ ; }, mesh = {Male ; Humans ; *Prostate/diagnostic imaging/pathology ; Protons ; *Prostatic Neoplasms/diagnostic imaging ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy/methods ; Least-Squares Analysis ; }, abstract = {In this study, we investigated the potential of the multivariate curve resolution alternating least squares (MCR-ALS) algorithm for analyzing three-dimensional (3D) [1] H-MRSI data of the prostate in prostate cancer (PCa) patients. MCR-ALS generates relative intensities of components representing spectral profiles derived from a large training set of patients, providing an interpretable model. Our objectives were to classify magnetic resonance (MR) spectra, differentiating tumor lesions from benign tissue, and to assess PCa aggressiveness. We included multicenter 3D [1] H-MRSI data from 106 PCa patients across eight centers. The patient cohort was divided into a training set (N = 63) and an independent test set (N = 43). Singular value decomposition determined that MR spectra were optimally represented by five components. The profiles of these components were extracted from the training set by MCR-ALS and assigned to specific tissue types. Using these components, MCR-ALS was applied to the test set for a quantitative analysis to discriminate tumor lesions from benign tissue and to assess tumor aggressiveness. Relative intensity maps of the components were reconstructed and compared with histopathology reports. The quantitative analysis demonstrated a significant separation between tumor and benign voxels (t-test, p < 0.001). This result was achieved including voxels with low-quality MR spectra. A receiver operating characteristic analysis of the relative intensity of the tumor component revealed that low- and high-risk tumor lesions could be distinguished with an area under the curve of 0.88. Maps of this component properly identified the extent of tumor lesions. Our study demonstrated that MCR-ALS analysis of [1] H-MRSI of the prostate can reliably identify tumor lesions and assess their aggressiveness. It handled multicenter data with minimal preprocessing and without using prior knowledge or quality control. These findings indicate that MCR-ALS can serve as an automated tool to assess the presence, extent, and aggressiveness of tumor lesions in the prostate, enhancing diagnostic capabilities and treatment planning of PCa patients.}, } @article {pmid37920473, year = {2023}, author = {Lemos, JP and Tenório, LPG and Mouly, V and Butler-Browne, G and Mendes-da-Cruz, DA and Savino, W and Smeriglio, P}, title = {T cell biology in neuromuscular disorders: a focus on Duchenne Muscular Dystrophy and Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1202834}, pmid = {37920473}, issn = {1664-3224}, mesh = {Humans ; *Muscular Dystrophy, Duchenne/therapy ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; *Neuromuscular Diseases ; Muscles ; Genetic Therapy/methods ; }, abstract = {Growing evidence demonstrates a continuous interaction between the immune system, the nerve and the muscle in neuromuscular disorders of different pathogenetic origins, such as Duchenne Muscular Dystrophy (DMD) and Amyotrophic Lateral Sclerosis (ALS), the focus of this review. Herein we highlight the complexity of the cellular and molecular interactions involving the immune system in neuromuscular disorders, as exemplified by DMD and ALS. We describe the distinct types of cell-mediated interactions, such as cytokine/chemokine production as well as cell-matrix and cell-cell interactions between T lymphocytes and other immune cells, which target cells of the muscular or nervous tissues. Most of these interactions occur independently of exogenous pathogens, through ligand-receptor binding and subsequent signal transduction cascades, at distinct levels of specificity. Although this issue reveals the complexity of the system, it can also be envisioned as a window of opportunity to design therapeutic strategies (including synthetic moieties, cell and gene therapy, as well as immunotherapy) by acting upon one or more targets. In this respect, we discuss ongoing clinical trials using VLA-4 inhibition in DMD, and in ALS, with a focus on regulatory T cells, both revealing promising results.}, } @article {pmid37920668, year = {2023}, author = {Ho, WY and Chak, LL and Hor, JH and Liu, F and Diaz-Garcia, S and Chang, JC and Sanford, E and Rodriguez, MJ and Alagappan, D and Lim, SM and Cho, YL and Shimizu, Y and Sun, AX and Tyan, SH and Koo, E and Kim, SH and Ravits, J and Ng, SY and Okamura, K and Ling, SC}, title = {FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons.}, journal = {iScience}, volume = {26}, number = {11}, pages = {108152}, pmid = {37920668}, issn = {2589-0042}, abstract = {MicroRNAs (miRNAs) modulate mRNA expression, and their deregulation contributes to various diseases including amyotrophic lateral sclerosis (ALS). As fused in sarcoma (FUS) is a causal gene for ALS and regulates biogenesis of miRNAs, we systematically analyzed the miRNA repertoires in spinal cords and hippocampi from ALS-FUS mice to understand how FUS-dependent miRNA deregulation contributes to ALS. miRNA profiling identified differentially expressed miRNAs between different central nervous system (CNS) regions as well as disease states. Among the up-regulated miRNAs, miR-1197 targets the pro-survival pseudokinase Trib2. A reduced TRIB2 expression was observed in iPSC-derived motor neurons from ALS patients. Pharmacological stabilization of TRIB2 protein with a clinically approved cancer drug rescues the survival of iPSC-derived human motor neurons, including those from a sporadic ALS patient. Collectively, our data indicate that miRNA profiling can be used to probe the molecular mechanisms underlying selective vulnerability, and TRIB2 is a potential therapeutic target for ALS.}, } @article {pmid37922093, year = {2024}, author = {Jellinger, KA}, title = {Understanding depression with amyotrophic lateral sclerosis: a short assessment of facts and perceptions.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {131}, number = {2}, pages = {107-115}, pmid = {37922093}, issn = {1435-1463}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/diagnosis ; Depression/complications ; Quality of Life ; Affect ; *Neurodegenerative Diseases/complications ; }, abstract = {Depression with an average prevalence of 25-40% is a serious condition in amyotrophic lateral sclerosis (ALS) that can impact quality of life and survival of patients and caregiver burden, yet the underlying neurobiology is poorly understood. Preexisting depression has been associated with a higher risk of developing ALS, while people with ALS have a significantly higher risk of developing depression that can cause multiple complications. Depression may be a prodromal or subclinical symptom prior to motor involvement, although its relations with disease progression and impairment of quality of life are under discussion. Unfortunately, there are no studies existing that explore the pathogenic mechanisms of depression associated with the basic neurodegenerative process, and no specific neuroimaging data or postmortem findings for the combination of ALS and depression are currently available. Experience from other neurodegenerative processes suggests that depressive symptoms in ALS may be the consequence of cortical thinning in prefrontal regions and other cortex areas, disruption of mood-related brain networks, dysfunction of neurotransmitter systems, changing cortisol levels and other, hitherto unknown mechanisms. Treatment of both ALS and depression is a multidisciplinary task, depression generally being treated with a combination of antidepressant medication, physiotherapy, psychological and other interventions, while electroconvulsive therapy and deep brain stimulation might not be indicated in the majority of patients in view of their poor prognosis. Since compared to depression in other neurodegenerative diseases, our knowledge of its molecular basis in ALS is missing, multidisciplinary clinicopathological studies to elucidate the pathomechanism of depression in motor system disorders including ALS are urgently warranted.}, } @article {pmid37924056, year = {2023}, author = {Sun, J and Chen, J and Xie, Q and Sun, M and Zhang, W and Wang, H and Liu, N and Wang, Q and Wang, M}, title = {Sodium butyrate alleviates R97-116 peptide-induced myasthenia gravis in mice by improving the gut microbiota and modulating immune response.}, journal = {Journal of inflammation (London, England)}, volume = {20}, number = {1}, pages = {37}, pmid = {37924056}, issn = {1476-9255}, abstract = {Fermented butyrate exhibits an anti-inflammatory response to maintain immune homeostasis within the gut. However, the effect and underlying mechanism of butyrate on myasthenia gravis (MG) remain unclear. The changes in the gut microbiota and fecal contents of SCFAs in MG patients were examined. R97-116 peptide was used to induce the experimental autoimmune myasthenia gravis (EAMG) mice and sodium butyrate (NaB) was gavaged to the EAMG mice. Gut microbiota, the frequency of Th1, Th17, Treg, Tfh, and B cells, the levels of IFN-γ, IL-17 A, IL-10, IL-21, and anti-R97-116 IgG, RNA-seq of total B cells in the spleen were explored by metagenomics, flow cytometry, ELISA, and transcriptomics. A significant reduction in SCFA-producing bacteria including Butyricimonas synergistica and functional modules including butyrate synthesis/production II was observed in MG patients and fecal SCFAs detection confirmed the increase. The EAMG mice were successfully constructed and NaB supplementation has changed the composition and function of the gut microbiota. The numbers of Th1, Th17, Tfh, and B cells were significantly increased while that of Treg cells was obviously decreased in EAMG mice compared with controls. Interestingly, NaB treatment has reduced the amounts of Th17, Tfh, and B cells but increased that of Treg cells. Accordingly, the levels of IL-17 A, IL-21, and IgG were increased while IL-10 was decreased in EAMG mice. However, NaB treatment reduced IL-17 A and IL-21 but increased that of IL-10. RNA-seq of B cells has revealed 4577 deferentially expressed genes (DEGs), in which 1218 DEGs were up-regulated while 3359 DEGs were down-regulated in NaB-treated EAMG mice. GO enrichment and KEGG pathway analysis unveiled that the function of these DEGs was mainly focused on immunoglobulin production, mitochondrial respiratory chain complex, ribosome, oxidative phosphorylation, and CNS diseases including amyotrophic lateral sclerosis. We have found that butyrate was significantly reduced in MG patients and NaB gavage could evidently improve MG symptoms in EAMG mice by changing the gut microbiota, regulating the immune response, and altering the gene expression and function of B cells, suggesting NaB might be a potential immunomodulatory supplement for MG drugs.}, } @article {pmid37926865, year = {2024}, author = {Xiao, X and Li, M and Ye, Z and He, X and Wei, J and Zha, Y}, title = {FUS gene mutation in amyotrophic lateral sclerosis: a new case report and systematic review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {1-15}, doi = {10.1080/21678421.2023.2272170}, pmid = {37926865}, issn = {2167-9223}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Mutation/genetics ; Mutation, Missense ; *Neurodegenerative Diseases ; Retrospective Studies ; RNA-Binding Protein FUS/genetics ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with upper and lower motor neuron degeneration and necrosis, characterized by progressive muscle weakness, atrophy, and paralysis. The FUS mutation-associated ALS has been classified as ALS6. We reported a case of ALS6 with de novo mutation and investigated retrospectively the characteristics of cases with FUS mutation.

METHODS: We reported a male patient with a new heterozygous variant of the FUS gene and comprehensively reviewed 173 ALS cases with FUS mutation. The literature was reviewed from the PubMed MEDLINE electronic database (https://www.ncbi.nlm.nih.gov/pubmed) using "Amyotrophic Lateral Sclerosis and Fus mutation" or "Fus mutation" as key words from 1 January 2009 to 1 January 2022.

RESULTS: We report a case of ALS6 with a new mutation point (c.1225-1227delGGA) and comprehensively review 173 ALS cases with FUS mutation. Though ALS6 is all with FUS mutation, it is still a highly heterogenous subtype. The average onset age of ALS6 is 35.2 ± 1.3 years, which is much lower than the average onset age of ALS (60 years old). Juvenile FUS mutations have an aggressive progression of disease, with an average time from onset to death or tracheostomy of 18.2 ± 0.5 months. FUS gene has the characteristics of early onset, faster progress, and shorter survival, especially in deletion mutation p.G504Wfs *12 and missense mutation of p.P525L.

CONCLUSIONS: ALS6 is a highly heterogenous subtype. Our study could allow clinicians to better understand the non-ALS typical symptoms, phenotypes, and pathophysiology of ALS6.}, } @article {pmid37928442, year = {2023}, author = {Chen, SK and Hawley, ZCE and Zavodszky, MI and Hana, S and Ferretti, D and Grubor, B and Hawes, M and Xu, S and Hamann, S and Marsh, G and Cullen, P and Challa, R and Carlile, TM and Zhang, H and Lee, WH and Peralta, A and Clarner, P and Wei, C and Koszka, K and Gao, F and Lo, SC}, title = {Efficacy and safety of a SOD1-targeting artificial miRNA delivered by AAV9 in mice are impacted by miRNA scaffold selection.}, journal = {Molecular therapy. Nucleic acids}, volume = {34}, number = {}, pages = {102057}, pmid = {37928442}, issn = {2162-2531}, abstract = {Toxic gain-of-function mutations in superoxide dismutase 1 (SOD1) contribute to approximately 2%-3% of all amyotrophic lateral sclerosis (ALS) cases. Artificial microRNAs (amiRs) delivered by adeno-associated virus (AAV) have been proposed as a potential treatment option to silence SOD1 expression and mitigate disease progression. Primary microRNA (pri-miRNA) scaffolds are used in amiRs to shuttle a hairpin RNA into the endogenous miRNA pathway, but it is unclear whether different primary miRNA (pri-miRNA) scaffolds impact the potency and safety profile of the expressed amiR in vivo. In our process to develop an AAV amiR targeting SOD1, we performed a preclinical characterization of two pri-miRNA scaffolds, miR155 and miR30a, sharing the same guide strand sequence. We report that, while the miR155-based vector, compared with the miR30a-based vector, leads to a higher level of the amiR and more robust suppression of SOD1 in vitro and in vivo, it also presents significantly greater risks for CNS-related toxicities in vivo. Despite miR30a-based vector showing relatively lower potency, it can significantly delay the development of ALS-like phenotypes in SOD1-G93A mice and increase survival in a dose-dependent manner. These data highlight the importance of scaffold selection in the pursuit of highly efficacious and safe amiRs for RNA interference gene therapy.}, } @article {pmid37928737, year = {2023}, author = {Johnson, GA and Krishnamoorthy, RR and Stankowska, DL}, title = {Modulating mitochondrial calcium channels (TRPM2/MCU/NCX) as a therapeutic strategy for neurodegenerative disorders.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1202167}, pmid = {37928737}, issn = {1662-4548}, support = {T32 AG020494/AG/NIA NIH HHS/United States ; }, abstract = {Efficient cellular communication is essential for the brain to regulate diverse functions like muscle contractions, memory formation and recall, decision-making, and task execution. This communication is facilitated by rapid signaling through electrical and chemical messengers, including voltage-gated ion channels and neurotransmitters. These messengers elicit broad responses by propagating action potentials and mediating synaptic transmission. Calcium influx and efflux are essential for releasing neurotransmitters and regulating synaptic transmission. Mitochondria, which are involved in oxidative phosphorylation, and the energy generation process, also interact with the endoplasmic reticulum to store and regulate cytoplasmic calcium levels. The number, morphology, and distribution of mitochondria in different cell types vary based on energy demands. Mitochondrial damage can cause excess reactive oxygen species (ROS) generation. Mitophagy is a selective process that targets and degrades damaged mitochondria via autophagosome-lysosome fusion. Defects in mitophagy can lead to a buildup of ROS and cell death. Numerous studies have attempted to characterize the relationship between mitochondrial dysfunction and calcium dysregulation in neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic lateral sclerosis, spinocerebellar ataxia, and aging. Interventional strategies to reduce mitochondrial damage and accumulation could serve as a therapeutic target, but further research is needed to unravel this potential. This review offers an overview of calcium signaling related to mitochondria in various neuronal cells. It critically examines recent findings, exploring the potential roles that mitochondrial dysfunction might play in multiple neurodegenerative diseases and aging. Furthermore, the review identifies existing gaps in knowledge to guide the direction of future research.}, } @article {pmid37929431, year = {2023}, author = {Nagappa, M and Sharma, S and Govindaraj, P and Chickabasaviah, YT and Siram, R and Shroti, A and Seshagiri, DV and Debnath, M and Sinha, S and Bindu, PS and Taly, AB}, title = {Characterisation of Patients with SH3TC2 Associated Neuropathy in an Indian Cohort.}, journal = {Neurology India}, volume = {71}, number = {5}, pages = {940-945}, doi = {10.4103/0028-3886.388101}, pmid = {37929431}, issn = {1998-4022}, mesh = {Humans ; Female ; Male ; *Intracellular Signaling Peptides and Proteins/genetics ; Mutation ; Phenotype ; *Charcot-Marie-Tooth Disease/genetics ; Electrophysiological Phenomena ; }, abstract = {BACKGROUND: SH3TC2 variations lead to demyelinating recessive Charcot-Marie-Tooth (CMT) disease, which is commonly associated with early-onset scoliosis and cranial neuropathy. Data from Indian ethnicity is limited.

OBJECTIVE: We aim to report the characteristics of patients with SH3TC2-associated neuropathy from an Indian cohort.

PATIENTS AND METHODS: Data of five unrelated subjects with SH3TC2 variations were analyzed.

RESULTS: Clinical features included female predominance (n = 4), early-onset neuropathy (n = 2), pes cavus and hammer toes (n = 4), kyphoscoliosis (n = 1), impaired vision and hearing (n = 1), facial muscle weakness (n = 1), impaired kinaesthetic sense (n = 3), tremor (n = 2), and ataxia (n = 1). Four patients had the "CMT" phenotype, while one patient had Roussy-Levy syndrome. All had demyelinating electrophysiology with conduction velocities being "very slow" in one, "slow" in one, "mildly slow" in two, and "intermediate" in one patient. Brain stem auditory evoked potentials were universally abnormal though only one patient had symptomatic deafness. Seven variants were identified in SH3TC2 [homozygous = 3 (c.1412del, c.69del, c.3152G>A), heterozygous = 4 (c.1105C>T, c.3511C>T, c.2028G>C, c.254A>T)]. Except for c.3511C>T variant, the rest were novel. Three patients had additional variations in genes having pathobiological relevance in other CMTs or amyotrophic lateral sclerosis.

CONCLUSION: We provide data on a cohort of patients of Indian origin with SH3TC2 variations and highlight differences from other cohorts. Though the majority were not symptomatic for hearing impairment, evoked potentials disclosed abnormalities in all. Further studies are required to establish the functional consequences of novel variants and their interacting molecular partners identified in the present study to strengthen their association with the phenotype.}, } @article {pmid37930016, year = {2023}, author = {Ahn, JJ and Miller, RH and Islam, Y}, title = {Isolation of Pure Astrocytes and Microglia from the Adult Mouse Spinal Cord For In Vitro Assays and Transcriptomic Studies.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {200}, pages = {}, doi = {10.3791/65893}, pmid = {37930016}, issn = {1940-087X}, support = {F31 NS117085/NS/NINDS NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Microglia ; Astrocytes ; Transcriptome ; Proteomics ; Spinal Cord ; *Spinal Cord Injuries/pathology ; }, abstract = {Astrocytes and microglia play pivotal roles in central nervous system development, injury responses, and neurodegenerative diseases. These highly dynamic cells exhibit rapid responses to environmental changes and display significant heterogeneity in terms of morphology, transcriptional profiles, and functions. While our understanding of the functions of glial cells in health and disease has advanced substantially, there remains a need for in vitro, cell-specific analyses conducted in the context of insults or injuries to comprehensively characterize distinct cell populations. Isolating cells from the adult mouse offers several advantages over cell lines or neonatal animals, as it allows for the analysis of cells under pathological conditions and at specific time points. Furthermore, focusing on spinal cord-specific isolation, excluding brain involvement, enables research into spinal cord pathologies, including experimental autoimmune encephalomyelitis, spinal cord injury, and amyotrophic lateral sclerosis. This protocol presents an efficient method for isolating astrocytes and microglia from the adult mouse spinal cord, facilitating immediate or future analysis with potential applications in functional, molecular, or proteomic downstream studies.}, } @article {pmid37930481, year = {2024}, author = {Domi, T and Schito, P and Sferruzza, G and Russo, T and Pozzi, L and Agosta, F and Carrera, P and Riva, N and Filippi, M and Quattrini, A and Falzone, YM}, title = {Unveiling the SOD1-mediated ALS phenotype: insights from a comprehensive meta-analysis.}, journal = {Journal of neurology}, volume = {271}, number = {3}, pages = {1342-1354}, pmid = {37930481}, issn = {1432-1459}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Phenotype ; Genetic Testing ; Mutation ; C9orf72 Protein/genetics ; RNA-Binding Protein FUS/genetics ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis associated with mutations in SOD1 (SOD1-ALS) might be susceptible to specific treatment. The aim of the study is to outline the clinical features of SOD1-ALS patients by comparing them to patients without ALS major gene variants and patients with variants in other major ALS genes. Defining SOD1-ALS phenotype may assist clinicians in identifying patients who should be prioritized for genetic testing.

METHODS: We performed an extensive literature research including original studies which reported the clinical features of SOD1-ALS and at least one of the following patient groups: C9ORF72 hexanucleotide repeat expansion (C9-ALS), TARDBP (TARDBP-ALS), FUS (FUS-ALS) or patients without a positive test for a major-ALS gene (N-ALS). A random effects meta-analytic model was applied to clinical data extracted encompassing sex, site and age of onset. To reconstruct individual patient survival data, the published Kaplan-Meier curves were digitized. Data were measured as odds ratio (OR) or standardized mean difference (SMD) as appropriate. Median survival was compared between groups.

RESULTS: Twenty studies met the inclusion criteria. We identified 721 SOD1-ALS, 470 C9-ALS, 183 TARDBP-ALS, 113 FUS-ALS and 2824 N-ALS. SOD1-ALS showed a higher rate of spinal onset compared with N-ALS and C9-ALS (OR = 4.85, 95% CI = 3.04-7.76; OR = 10.47, 95% CI = 4.32-27.87) and an earlier onset compared with N-ALS (SMD = - 0.45, 95% CI = - 0.72 to - 0.18). SOD1-ALS had a similar survival compared with N-ALS (p = 0.14), a longer survival compared with C9-ALS (p < 0.01) and FUS-ALS (p = 0.019) and a shorter survival compared with TARDBP-ALS (p < 0.01).

DISCUSSION: This study indicates the presence of a specific SOD1-ALS phenotype. Insights in SOD1-ALS clinical features are important in genetic counseling, disease prognosis and support patients' stratification in clinical trials.}, } @article {pmid37930717, year = {2023}, author = {Lam, K and Cenzer, I and Levy, CR and Matlock, DD and Smith, AK and Covinsky, KE}, title = {The Natural History of Disability and Caregiving Before and After Long-Term Care Entry.}, journal = {JAMA internal medicine}, volume = {183}, number = {12}, pages = {1295-1303}, pmid = {37930717}, issn = {2168-6114}, support = {P30 AG044281/AG/NIA NIH HHS/United States ; K24 AG068312/AG/NIA NIH HHS/United States ; R03 AG074038/AG/NIA NIH HHS/United States ; KL2 TR001870/TR/NCATS NIH HHS/United States ; }, mesh = {Aged ; Humans ; Female ; United States/epidemiology ; Aged, 80 and over ; Male ; *Long-Term Care ; *Activities of Daily Living ; Longitudinal Studies ; Medicare ; Caregivers/statistics & numerical data ; }, abstract = {IMPORTANCE: Many older persons move into long-term care facilities (LTCFs) due to disability and insufficient home caregiving options. However, the extent of disability and caregiving provided around the time of entry is unknown.

OBJECTIVE: To quantitatively describe disability and caregiving before and after LTCF entry, comparing nursing home (NH), assisted living (AL), and independent living (IL) entrants.

A longitudinal cohort study using prospectively collected annual data from the National Health and Aging Trends Study from 2011 to 2020 including participants in the continental US. Overall, 932 community-dwelling Medicare beneficiaries entering LTCF from 2011 to 2019 were included. Entry into LTCF was set as t = 0, and participant interviews from 4 years before and 2 years after were used.

MAIN OUTCOMES AND MEASURES: Prevalence of severe disability (severe difficulty or dependence in ≥3 activities of daily living), prevalence of caregivers, and median weekly caregiving hours per entrant, using weighted mixed-effects regression against time as linear spline.

RESULTS: At entry, mean (SD) age was 84 (8.4) years, 609 (64%, all percentages survey weighted) were women, 143 (6%) were Black, 29 (3%) were Hispanic, 30 (4%) were other (other race and ethnicity included American Indian, Asian, Native Hawaiian, and other), and 497 (49%) had dementia. 349 (34%) entered NH, 426 (45%) entered AL, and 157 (21%) entered IL. Overall, NH and AL entry were preceded by months of severe disability and escalating caregiving. Before entry, 49% (95% CI, 29%-68%) of NH entrants and 10% (95% CI, 3%-24%) of AL entrants had severe disability. Most (>97%) had at least a caregiver, but only one-third (NH, 33%; 95% CI, 20%-50%; AL, 33%; 95% CI, 24%-44%) had a paid caregiver. Median care was 27 hours weekly (95% CI, 18-40) in NH entrants and 18 (95% CI, 14-24) in AL entrants. On NH and AL entry, severe disability rose to 89% (95% CI, 82%-94%) and 28% (95% CI, 16%-44%) on NH and AL entry and was 66% (95% CI, 55%-75%) 2 years after entry in AL residents. Few IL entrants (<2%) had severe disability and their median care remained less than 7 hours weekly before and after entry.

CONCLUSIONS: This study found that persons often enter NHs and ALs after months of severe disability and substantial help at home, usually from unpaid caregivers. Assisted living residents move when less disabled, but approach levels of disability similar to NH entrants within 2 years. Data may help clinicians understand when home supports approach a breaking point.}, } @article {pmid37931648, year = {2024}, author = {Aust, E and Günther, R and Hermann, A and Linse, K}, title = {[Psychologically guided group meetings for family caregivers of ALS patients].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {92}, number = {3}, pages = {81-89}, doi = {10.1055/a-2156-9013}, pmid = {37931648}, issn = {1439-3522}, mesh = {Humans ; *Caregivers/psychology ; Adaptation, Psychological ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Emotions ; Palliative Care ; Quality of Life/psychology ; }, abstract = {BACKGROUND: The course of amyotrophic lateral sclerosis (ALS,) associated with progressive physical limitations, is a challenge to the patients themselves and also to their family caregivers, who have to deal with psychosocial, socio-medical and organizational issues. Caregivers are often closely involved and heavily burdened themselves, which is why specific support is recommended. The aim of this study was to investigate the feasibility and acceptance of psychologically guided supportive group meetings for family caregivers in a specialist ALS outpatient clinic.

METHODS: Over a period of two years, data were collected from a total of 26 caregivers of ALS patients in order to evaluate the relevance, usefulness and criticisms of open-topic meetings that took place every three months.

RESULTS: Topics discussed in the meetings included mainly psychosocial issues such as self-care, dealing with emotions or with conflicts with the patients and third parties, as well as practical and organizational matters. The meetings were predominantly rated as helpful, well understandable and personally relevant and the exchange in a "community of destiny" was perceived as emotionally relieving.

DISCUSSION: The ALS caregiver group meetings in the described format were easy to carry out and well accepted. Supportive interventions, such as the one reported here, might be a valuable component of ALS care, to relieve the highly burdened caregivers of ALS-patients by providing them with social, emotional and practical support. However, the quantitative verification of the intervention's effectiveness is challenging - both methodologically and due to the caregivers' complex life situation. Psychosocial support services for ALS caregivers are feasible with little effort and should be an integral part of the standard ALS care based on a multi-dimensional, palliative care concept.}, } @article {pmid37931706, year = {2024}, author = {Xuan, X and Zheng, G and Zhu, W and Sun, Q and Zeng, Y and Du, J and Huang, X}, title = {Alterations in regional homogeneity and functional connectivity in the cerebellum of patients with sporadic amyotrophic lateral sclerosis.}, journal = {Behavioural brain research}, volume = {458}, number = {}, pages = {114749}, doi = {10.1016/j.bbr.2023.114749}, pmid = {37931706}, issn = {1872-7549}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Magnetic Resonance Imaging/methods ; Brain ; Cerebellum/pathology ; }, abstract = {OBJECTIVE: The purpose of this study was to examine the cerebellum's local and global functional characteristics in individuals with sporadic amyotrophic lateral sclerosis (sALS) and their correlation with clinical data.

METHODS: Resting-state functional magnetic resonance imaging was performed on 39 patients with sALS and on 23 healthy controls. Regional homogeneity (ReHo) in the cerebellum of all participants was analyzed, and the cerebellar regions with differences in ReHo were considered regions of interest (ROIs). In addition, the functional connectivity between the ROIs and other brain regions was analyzed.

RESULTS: In patients with sALS, ReHo increased in parts of the posterior cerebellar lobe. Then, the two regions with increased ReHo of the cerebellum were used as seeds, and further analysis revealed that the connectivity of the right cerebellum to the right medial superior frontal gyrus, left lingual gyrus (calcarine sulcus), left precentral gyrus, left supplementary motor area, and right Crus II was significantly increased.

CONCLUSION: The results demonstrate that resting-state functional connectivity changes in both motor and extra-motor regions of the cerebellum in patients with sALS, and that the cerebellum plays a pathophysiological role in sALS.}, } @article {pmid37933884, year = {2024}, author = {Walter, U and Sobiella, G and Prudlo, J and Batchakaschvili, M and Böhmert, J and Storch, A and Hermann, A}, title = {Ultrasonic detection of vagus, accessory, and phrenic nerve atrophy in amyotrophic lateral sclerosis: Relation to impairment and mortality.}, journal = {European journal of neurology}, volume = {31}, number = {2}, pages = {e16127}, pmid = {37933884}, issn = {1468-1331}, support = {GHS-15-0017//European Regional Development Fund/ ; //Hermann und Lilly Schilling-Stiftung für Medizinische Forschung/ ; }, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging ; Atrophy ; Phrenic Nerve/diagnostic imaging ; Ultrasonics ; Vagus Nerve ; Male ; Female ; }, abstract = {BACKGROUND AND PURPOSE: In amyotrophic lateral sclerosis (ALS), phrenic nerve (PN) atrophy has been found, whereas there is controversy regarding vagus nerve (VN) atrophy. Here, we aimed to find out whether PN atrophy is related to respiratory function and 12-month survival. Moreover, we investigated the relevance of VN and spinal accessory nerve (AN) atrophy in ALS.

METHODS: This prospective observational monocentric study included 80 adult participants (40 ALS patients, 40 age- and sex-matched controls). The cross-sectional area (CSA) of bilateral cervical VN, AN, and PN was measured on high-resolution ultrasonography. Clinical assessments included the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), the Non-Motor Symptoms Questionnaire, and handheld spirometry of forced vital capacity (FVC). One-year survival was documented.

RESULTS: The CSA of each nerve, VN, AN, and PN, was smaller in ALS patients compared to controls. VN atrophy was unrelated to nonmotor symptom scores. PN CSA correlated with the respiratory subscore of the ALSFRS-R (Spearman test, r = 0.59, p < 0.001), the supine FVC (r = 0.71, p < 0.001), and the relative change of sitting-supine FVC (r = -0.64, p = 0.001). Respiratory impairment was predicted by bilateral mean PN CSA (p = 0.046, optimum cutoff value of ≤0.37 mm[2] , sensitivity = 92%, specificity = 56%) and by the sum of PN and AN CSA (p = 0.036). The combination of ALSFRS-R score with PN and AN CSA measures predicted 1-year survival with similar accuracy as the combination of ALSFRS-R score and FVC.

CONCLUSIONS: Ultrasonography detects degeneration of cranial nerve motor fibers. PN and AN calibers are tightly related to respiratory function and 1-year survival in ALS.}, } @article {pmid37934011, year = {2024}, author = {Palmieri, JL and Bach, JR}, title = {Pulmonary care for ALS: There is more to the story.}, journal = {Muscle & nerve}, volume = {69}, number = {1}, pages = {115-116}, doi = {10.1002/mus.27996}, pmid = {37934011}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; }, } @article {pmid37934576, year = {2023}, author = {Gao, H and Yu, J and Chen, J and Wang, H and Liang, S and Feng, Z and Gu, Y and Dong, L}, title = {Target-Site and Metabolic Resistance Mechanisms to Penoxsulam in Late Watergrass (Echinochloa phyllopogon) in China.}, journal = {Journal of agricultural and food chemistry}, volume = {71}, number = {46}, pages = {17742-17751}, doi = {10.1021/acs.jafc.3c05921}, pmid = {37934576}, issn = {1520-5118}, mesh = {*Echinochloa/genetics/metabolism ; Herbicide Resistance/genetics ; Tandem Mass Spectrometry ; *Herbicides/pharmacology/metabolism ; *Acetolactate Synthase/genetics/metabolism ; Sulfonamides ; Uridine/analogs & derivatives ; }, abstract = {Echinochloa phyllopogon, a malignant weed in Northeast China's paddy fields, is currently presenting escalating resistance concerns. Our study centered on the HJHL-715 E. phyllopogon population, which showed heightened resistance to penoxsulam, through a whole-plant bioassay. Pretreatment with a P450 inhibitor malathion significantly increased penoxsulam sensitivity in resistant plants. In order to determine the resistance mechanism of the resistant population, we purified the resistant population from individual plants and isolated target-site resistance (TSR) and nontarget-site resistance (NTSR) materials. Pro-197-Thr and Trp-574-Leu mutations in acetolactate synthase (ALS) 1 and ALS2 of the resistant population drove reduced sensitivity of penoxsulam to the target-site ALS, the primary resistance mechanisms. To fully understand the NTSR mechanism, NTSR materials were investigated by using RNA-sequencing (RNA-seq) combined with a reference genome. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis further supported the enhanced penoxsulam metabolism in NTSR materials. Gene expression data and quantitative reverse transcription polymerase chain reaction (qRT-PCR) validation confirmed 29 overexpressed genes under penoxsulam treatment, with 16 genes concurrently upregulated with quinclorac and metamifop treatment. Overall, our study confirmed coexisting TSR and NTSR mechanisms in E. phyllopogon's resistance to ALS inhibitors.}, } @article {pmid37935449, year = {2024}, author = {Darke, AC}, title = {Can I Be Honest With My Neurologist? A Problem of Health Technology Assessment in Canada.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {51}, number = {5}, pages = {603-605}, doi = {10.1017/cjn.2023.307}, pmid = {37935449}, issn = {0317-1671}, } @article {pmid37938192, year = {2023}, author = {Maharaj, D and Kaur, K and Saltese, A and Gouvea, J}, title = {Personalized Precision Immunotherapy for Amyotrophic Lateral Sclerosis (ALS).}, journal = {Critical reviews in immunology}, volume = {43}, number = {2}, pages = {1-11}, doi = {10.1615/CritRevImmunol.2023048372}, pmid = {37938192}, issn = {2162-6472}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Immunotherapy ; Brain ; Cytokines ; Inflammation ; }, abstract = {Neurological syndrome amyotrophic lateral sclerosis (ALS) affects motor neurons and is characterized by progressive motor neuron loss in the brain and spinal cord. ALS starts with mainly focal onset but when the disease progresses, it spreads to different parts of the body, with survival limits of 2-5 years after disease initiation. To date, only supportive care is provided for ALS patients, and no effective treatment or cure has been discovered. This review is focused on clinical and immunological aspects of ALS patients, based on our case studies, and we discuss the treatment we have provided to those patients based on a detailed evaluation of their peripheral blood immune cells and blood-derived serum secreted factors, cytokines, chemokines and growth factors. We show that using a personalized approach of low dose immunotherapy there is an improvement in the effects on inflammation and immunological dysfunction.}, } @article {pmid37939160, year = {2023}, author = {Gendron, TF and Petrucelli, L}, title = {Immunological drivers of amyotrophic lateral sclerosis.}, journal = {Science translational medicine}, volume = {15}, number = {721}, pages = {eadj9332}, doi = {10.1126/scitranslmed.adj9332}, pmid = {37939160}, issn = {1946-6242}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease involving complex genetic and environmental factors, is associated with neuroinflammation. Preclinical and clinical studies support immune system involvement in ALS pathogenesis, thereby spurring investigations into potential pathogenic mechanisms, immune response biomarkers, and ALS therapeutics.}, } @article {pmid37939393, year = {2023}, author = {Lualdi, M and Casale, F and Rizzone, MG and Zibetti, M and Monti, C and Colugnat, I and Calvo, A and De Marco, G and Moglia, C and Fuda, G and Comi, C and Chiò, A and Lopiano, L and Fasano, M and Alberio, T}, title = {Shared and Unique Disease Pathways in Amyotrophic Lateral Sclerosis and Parkinson's Disease Unveiled in Peripheral Blood Mononuclear Cells.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {23}, pages = {4240-4251}, pmid = {37939393}, issn = {1948-7193}, mesh = {Humans ; *Parkinson Disease/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Prospective Studies ; Leukocytes, Mononuclear/metabolism ; Proteomics ; }, abstract = {Recent evidence supports an association between amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Indeed, prospective population-based studies demonstrated that about one-third of ALS patients develop parkinsonian (PK) signs, even though different neuronal circuitries are involved. In this context, proteomics represents a valuable tool to identify unique and shared pathological pathways. Here, we used two-dimensional electrophoresis to obtain the proteomic profile of peripheral blood mononuclear cells (PBMCs) from PD and ALS patients including a small cohort of ALS patients with parkinsonian signs (ALS-PK). After the removal of protein spots correlating with confounding factors, we applied a sparse partial least square discriminant analysis followed by recursive feature elimination to obtain two protein classifiers able to discriminate (i) PD and ALS patients (30 spots) and (ii) ALS-PK patients among all ALS subjects (20 spots). Functionally, the glycolysis pathway was significantly overrepresented in the first signature, while extracellular interactions and intracellular signaling were enriched in the second signature. These results represent molecular evidence at the periphery for the classification of ALS-PK as ALS patients that manifest parkinsonian signs, rather than comorbid patients suffering from both ALS and PD. Moreover, we confirmed that low levels of fibrinogen in PBMCs is a characteristic feature of PD, also when compared with another movement disorder. Collectively, we provide evidence that peripheral protein signatures are a tool to differentially investigate neurodegenerative diseases and highlight altered biochemical pathways.}, } @article {pmid37941028, year = {2023}, author = {Huang, Y and Liu, B and Sinha, SC and Amin, S and Gan, L}, title = {Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {79}, pmid = {37941028}, issn = {1750-1326}, support = {R01AG054214/AG/NIA NIH HHS/United States ; R01AG072758/AG/NIA NIH HHS/United States ; R01 AG074541/AG/NIA NIH HHS/United States ; R01 AG072758/AG/NIA NIH HHS/United States ; R01 AG054214/AG/NIA NIH HHS/United States ; R01AG074541/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Signal Transduction/physiology ; Nucleotidyltransferases/genetics/metabolism ; DNA/metabolism ; *Interferon Type I/genetics/metabolism ; *Nervous System Diseases ; }, abstract = {DNA sensing is a pivotal component of the innate immune system that is responsible for detecting mislocalized DNA and triggering downstream inflammatory pathways. Among the DNA sensors, cyclic GMP-AMP synthase (cGAS) is a primary player in detecting cytosolic DNA, including foreign DNA from pathogens and self-DNA released during cellular damage, culminating in a type I interferon (IFN-I) response through stimulator of interferon genes (STING) activation. IFN-I cytokines are essential in mediating neuroinflammation, which is widely observed in CNS injury, neurodegeneration, and aging, suggesting an upstream role for the cGAS DNA sensing pathway. In this review, we summarize the latest developments on the cGAS-STING DNA-driven immune response in various neurological diseases and conditions. Our review covers the current understanding of the molecular mechanisms of cGAS activation and highlights cGAS-STING signaling in various cell types of central and peripheral nervous systems, such as resident brain immune cells, neurons, and glial cells. We then discuss the role of cGAS-STING signaling in different neurodegenerative conditions, including tauopathies, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as aging and senescence. Finally, we lay out the current advancements in research and development of cGAS inhibitors and assess the prospects of targeting cGAS and STING as therapeutic strategies for a wide spectrum of neurological diseases.}, } @article {pmid37941227, year = {2023}, author = {Young, H and Gerez, L and Cole, T and Inirio, B and Proietti, T and Closs, B and Paganoni, S and Walsh, C}, title = {Air Efficient Soft Wearable Robot for High-Torque Elbow Flexion Assistance.}, journal = {IEEE ... International Conference on Rehabilitation Robotics : [proceedings]}, volume = {2023}, number = {}, pages = {1-6}, doi = {10.1109/ICORR58425.2023.10304679}, pmid = {37941227}, issn = {1945-7901}, mesh = {Humans ; Elbow/physiology ; *Robotics ; *Elbow Joint ; Torque ; *Amyotrophic Lateral Sclerosis ; *Wearable Electronic Devices ; }, abstract = {Recent developments in soft wearable robots have shown promise for assistive and rehabilitative use-cases. For inflatable approaches, a major challenge in developing portable systems is finding a balance between portability, performance, and usability. In this paper, we present a textile-based robotic sleeve that can provide functional elbow flexion assistance and is compatible with a portable actuation unit (PAU). Flexion is driven by a curved textile actuator with internal pneumatic supports (IPS). We show that the addition of IPS improves torque generation and increases battery-powered actuations by 60%. We demonstrate that the device can provide enough torque throughout the ROM of the elbow joint for daily life assistance. Specifically, the device generates 13.5 Nm of torque at 90°. Experimental testing in five healthy individuals and two individuals with Amyotrophic Lateral Sclerosis (ALS) demonstrates its impact on wearer muscle activity and kinematics. The results with healthy subjects show that the device was able to reduce the bicep muscle activity by an average of 49.1±13.3% during static and dynamic exercises, 43.6±11.1% during simulated ADLs, and provided an assisted ROM of 134°±13°. Both ALS participants reported a reduced rate of perceived exertion during both static and dynamic tasks while wearing the device and had an average ROM of 115°±8°. Future work will explore other applications of the IPS and extend the approach to assisting multiple joints.}, } @article {pmid37941604, year = {2023}, author = {Dyer, MS and Odierna, GL and Clark, RM and Woodhouse, A and Blizzard, CA}, title = {Synaptic remodeling follows upper motor neuron hyperexcitability in a rodent model of TDP-43.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1274979}, pmid = {37941604}, issn = {1662-5102}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable disease characterized by relentlessly progressive degeneration of the corticomotor system. Cortical hyperexcitability has been identified as an early pre-symptomatic biomarker of ALS. This suggests that hyperexcitability occurs upstream in the ALS pathological cascade and may even be part of the mechanism that drives development of symptoms or loss of motor neurons in the spinal cord. However, many studies also indicate a loss to the synaptic machinery that mediates synaptic input which raises the question of which is the driver of disease, and which is a homeostatic response. Herein, we used an inducible mouse model of TDP-43 mediated ALS that permits for the construction of detailed phenotypic timelines. Our work comprehensively describes the relationship between intrinsic hyperexcitability and altered synaptic input onto motor cortical layer 5 pyramidal neurons over time. As a result, we have constructed the most complete timeline of electrophysiological changes following induction of TDP-43 dysfunction in the motor cortex. We report that intrinsic hyperexcitability of layer 5 pyramidal neurons precedes changes to excitatory synaptic connections, which manifest as an overall loss of inputs onto layer 5 pyramidal neurons. This finding highlights the importance of hyperexcitability as a primary mechanism of ALS and re-contextualizes synaptic changes as possibly representing secondary adaptive responses. Recognition of the relationship between intrinsic hyperexcitability and reduced excitatory synaptic input has important implications for the development of useful therapies against ALS. Novel strategies will need to be developed that target neuronal output by managing excitability against synapses separately.}, } @article {pmid37941924, year = {2023}, author = {Zaita, BM and Ghosh, A and Lee, S and Raymond, A and Agnihotri, T and Akhter, NM}, title = {Radiologically inserted gastrostomy tube in neurological disease: A retrospective study.}, journal = {Journal of clinical imaging science}, volume = {13}, number = {}, pages = {35}, pmid = {37941924}, issn = {2156-7514}, abstract = {OBJECTIVES: This study aimed to compare the safety and efficacy of balloon and non-balloon (or dilator) gastrostomy devices in radiologically inserted gastrostomy (RIG) for patients with neurological disease.

MATERIAL AND METHODS: A retrospective analysis of 152 patients was conducted at a tertiary care hospital from July 2017 to September 2020. 104 and 48 patients were included in the balloon and non-balloon groups, respectively. The frequency of complications per specific neurological indication as well as the breakdown of the different complications pertaining to each indication was recorded for analysis. The recovery time, fluoroscopy time, contrast volume, peak radiation, and pain management dosages for each procedure were all reviewed to evaluate for statistical differences between the balloon and non-balloon groups. An adjusted model odds ratio (OR) was conducted to evaluate how each of the variables (type of gastrostomy tube, body mass index [BMI], age, and gender) affected the frequency of complications within our cohort.

RESULTS: This study included 152 patients, with an average age of 65.17 years (interquartile range [IQR] = 12.66) and an average BMI of 26.97 (IQR = 7.19). The majority of patients were male (71.1%). The most common indication for the procedure was stroke (24.3%), followed by post-intubation dysphagia (16.4%) and intracranial hemorrhage (11.8%). Amyotrophic lateral sclerosis (ALS) and altered mental status had a similar prevalence at 9.9%. The overall complication rate was 33.8%, overall mortality rate 3.3%, 30-day mortality rate of 2.6%, and no other major complications according to CIRSE criteria. Notably, patients with neurodegenerative disorders exhibited comparable rates of minor complications: 33.3% in ALS (5/15 patients), 50% in myasthenia gravis (1/2 patients), and 100% in muscular dystrophy (1/1 patient). The study compared two groups: the balloon group (104 patients) and the dilator group (48 patients). The balloon group received significantly lower preoperative sedation in the form of fentanyl (Avg = 4.46 min vs. 6.54 min, P = 0.287). The balloon group had shorter fluoroscopy time, lower radiation exposure dose, and shorter operating time compared to the dilator group, though not statistically significant. In the logistic regression model, there was no statistical difference in complication rates between the dilator and balloon groups. BMI, age, and gender did not significantly affect minor complication rates.

CONCLUSION: RIG tube insertions may serve as a valuable, alternative approach in providing enteral support in patients with neurological disease.}, } @article {pmid37942130, year = {2023}, author = {Piñeros-Fernández, MC}, title = {Artificial Intelligence Applications in the Diagnosis of Neuromuscular Diseases: A Narrative Review.}, journal = {Cureus}, volume = {15}, number = {11}, pages = {e48458}, pmid = {37942130}, issn = {2168-8184}, abstract = {The accurate diagnosis of neuromuscular diseases (NMD) is in many cases difficult; the starting point is the clinical approach based on the course of the disease and a careful physical examination of the patient. Electrodiagnostic tests, imaging, muscle biopsy, and genetics are fundamental complementary studies for the diagnosis of NMD. The large volume of data obtained from such studies makes it necessary to look for efficient solutions, such as artificial intelligence (AI) applications, which can help classify, synthesize, and organize the information of patients with NMD to facilitate their accurate and timely diagnosis. The objective of this study was to describe the usefulness of AI applications in the diagnosis of patients with neuromuscular diseases. A narrative review was done, including publications on artificial intelligence applied to the diagnostic methods of NMD currently existing. Twelve studies were included. Two of the studies focused on muscle ultrasound, five of the studies on muscle MRI, two studies on electromyography, two studies on amyotrophic lateral sclerosis (ALS) biomarkers, and one study on genes related to myopathies. The accuracy of classification using different classification algorithms used in each of the studies included in this narrative review was already 90% in most studies. In conclusion, the future design of more accurate algorithms applied to NMD with greater precision will have an impact on the earlier diagnosis of this group of diseases.}, } @article {pmid37942135, year = {2023}, author = {Shi, Y and Zhu, R}, title = {Analysis of damage-associated molecular patterns in amyotrophic lateral sclerosis based on ScRNA-seq and bulk RNA-seq data.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1259742}, pmid = {37942135}, issn = {1662-4548}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons. Despite extensive research, the exact etiology of ALS remains elusive. Emerging evidence highlights the critical role of the immune system in ALS pathogenesis and progression. Damage-Associated Molecular Patterns (DAMPs) are endogenous molecules released by stressed or damaged cells, acting as danger signals and activating immune responses. However, their specific involvement in ALS remains unclear.

METHODS: We obtained single-cell RNA sequencing (scRNA-seq) data of ALS from the primary motor cortex in the Gene Expression Omnibus (GEO) database. To better understand genes associated with DAMPs, we performed analyses on cell-cell communication and trajectory. The abundance of immune-infiltrating cells was assessed using the single-sample Gene Set Enrichment Analysis (ssGSEA) method. We performed univariate Cox analysis to construct the risk model and utilized the least absolute shrinkage and selection operator (LASSO) analysis. Finally, we identified potential small molecule drugs targeting ALS by screening the Connectivity Map database (CMap) and confirmed their potential through molecular docking analysis.

RESULTS: Our study annotated 10 cell types, with the expression of genes related to DAMPs predominantly observed in microglia. Analysis of intercellular communication revealed 12 ligand-receptor pairs in the pathways associated with DAMPs, where microglial cells acted as ligands. Among these pairs, the SPP1-CD44 pair demonstrated the greatest contribution. Furthermore, trajectory analysis demonstrated distinct differentiation fates of different microglial states. Additionally, we constructed a risk model incorporating four genes (TRPM2, ROCK1, HSP90AA1, and HSPA4). The validity of the risk model was supported by multivariate analysis. Moreover, external validation from dataset GSE112681 confirmed the predictive power of the model, which yielded consistent results with datasets GSE112676 and GSE112680. Lastly, the molecular docking analysis suggested that five compounds, namely mead-acid, nifedipine, nifekalant, androstenol, and hydrastine, hold promise as potential candidates for the treatment of ALS.

CONCLUSION: Taken together, our study demonstrated that DAMP entities were predominantly observed in microglial cells within the context of ALS. The utilization of a prognostic risk model can accurately predict ALS patient survival. Additionally, genes related to DAMPs may present viable drug targets for ALS therapy.}, } @article {pmid37942236, year = {2023}, author = {Itou, J and Munakata, Y and Kuramitsu, Y and Madarame, H and Okazaki, K}, title = {Incidence and Distribution of Deep Vein Thrombosis Following Total Hip Arthroplasty Using an Anterolateral Supine Approach.}, journal = {Orthopedic research and reviews}, volume = {15}, number = {}, pages = {199-205}, pmid = {37942236}, issn = {1179-1462}, abstract = {PURPOSE: Venous thromboembolism (VTE) is a potential major complication in patients undergoing total hip arthroplasty (THA). However, the incidence of VTE following THA using anterolateral supine approach (ALS) has not been reported. The purpose of this study was to investigate the incidence of perioperative VTE and the distribution and characteristics of deep vein thrombosis (DVT) following ALS THA.

PATIENTS AND METHODS: This retrospective single-arm study analyzed the 182 consecutive hips of 164 patients who underwent primary ALS THA. Pharmacological prophylaxis consisted of enoxaparin 20 mg twice daily for approximately 6 days starting 24 h postoperatively until duplex ultrasonography was performed to determine whether postoperative DVT was present. DVT was assessed by whole-leg Doppler ultrasound, and the location and characteristics of any thrombus were recorded. If pulmonary thromboembolism was suspected, contrast-enhanced computed tomography was performed.

RESULTS: The overall incidence of VTE was 9.9% for DVT (18/182 hips) and 0.5% for pulmonary thromboembolism (1/182 hips). Most DVTs were in the soleal vein on the affected side and showed isoechoic or hypoechoic echogenicity. All thrombi were non-floating.

CONCLUSION: Following ALS THA with standard pharmacological prophylaxis and an early weight-bearing protocol, the incidence of perioperative DVT was approximately 10%, mostly occurring in the lower leg.}, } @article {pmid37942848, year = {2024}, author = {Soreq, H}, title = {Novel single-nucleus transcriptomics unravels developmental and functionally controlled principles of mammalian neuromuscular junctions.}, journal = {Journal of neurochemistry}, volume = {168}, number = {4}, pages = {339-341}, doi = {10.1111/jnc.15986}, pmid = {37942848}, issn = {1471-4159}, mesh = {Animals ; Humans ; Neuromuscular Junction/metabolism ; *Receptors, Nicotinic/genetics/metabolism ; Synaptic Transmission ; *Amyotrophic Lateral Sclerosis/metabolism ; Gene Expression Profiling ; Mammals/metabolism ; }, abstract = {Prof Ohno's team (Ohkawara et al. 2023, current issue) underscored the dynamic and functional features that co-shape the embryonic and early post-natal development of mammalian neuromuscular junctions (NMJs) using single-nucleus transcriptomics which provides specific insights into the activities of individually studied nuclei and their functional characteristics. Unlike other single-nucleus transcriptomics studies, which tend to be limited to single developmental time points, this article provides novel views of the complex developmental and regulatory dynamics and embryonic cell type origins underscoring the formation of functioning mammalian NMJs by combining this transcriptomic approach with interference tests in cultured C2C12 myotubes. This reveals intriguing novel links between the particular nicotinic acetylcholine receptor genes (nAChR) and regulator transcripts thereof and enables outlining the sequential development of functioning NMJs along embryogenesis and soon after delivery. Specifically, the timewise and cell type origins of the studied nuclei emerged as essential for NMJ neurogenesis and inter-cellular transfer of specific regulators has been indicated. Breaking the barriers between distinct research subdisciplines, this study opens new neurochemistry research directions that recombine developmental, regulatory, and functional transcriptomics in NMJ-including tissues. Moreover, these findings may facilitate tests of diverse pharmaceutical and therapeutic modulators of neuromuscular functioning in health and disease, assisting the translational research progress in treating devastating neuromuscular states such as in amyotrophic lateral sclerosis, myasthenia gravis or individuals poisoned occupationally or otherwise with anticholinesterase inhibitors.}, } @article {pmid37944503, year = {2023}, author = {Sun, HJ and Zhang, J and Lu, JP and Wu, MT}, title = {The Improvement in Function of Poststroke Spasticity by Vibrational and Heated Stone-Needle Therapy and Meridian Dredging Exercise: A Randomized, Controlled, Preliminary Trial.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {492-501}, doi = {10.1159/000534993}, pmid = {37944503}, issn = {2504-2106}, mesh = {Humans ; Animals ; Mice ; *Quality of Life ; *Meridians ; Physical Therapy Modalities ; }, abstract = {BACKGROUND: Poststroke spasticity (PSS) is a common complication of stroke. Current PSS treatments have been linked to high costs, lack of long-term effectiveness, and undesirable side effects. Vibrational and heated stone-needle therapy (VHS) has not been utilized to treat PSS, and its safety and effectiveness have yet to be proven by high-quality clinical research.

OBJECTIVE: The aim of this study was to determine the effectiveness of VHS combined with meridian dredging exercise (MDE) in patients with PSS.

METHODS: One hundred participants with stroke were included and randomly assigned to a treatment group (VHS plus MDEs) and a control group (MDEs alone). Patients in both groups were treated for 4 weeks. The primary outcome measures were the Modified Ashworth Scale (MAS) and Fugl-Meyer Assessment (FMA), while the secondary outcome measures were the Activity of Daily Living (ADL) Scale and Stroke-Specific Quality of Life Scale (SS-QOL). The evaluations were at baseline (T0) at 4 weeks of treatment (T1) and at 12 weeks of follow-up without treatment (T2).

RESULTS: At T1 and T2, there were significant differences in MAS between the two groups (p = 0.001). From the perspective of distribution, the VHS plus MDE group had significant changes, and the group-time interactions of upper and lower extremities in FMA, ADL, and SS-QOL were statistically significant (p < 0.001), indicating that patients' symptoms improved after treatment. But the overall effect size is small, especially the effect size of improvement in SS-QOL at T1.

CONCLUSION: VHS in combination with MDE can consistently alleviate PSS, enhance limb function, and improve the quality of life of patients with PSS. But we need to optimize the device further and observe the improvement of patients for a more extended period.

UNLABELLED: HintergrundSpastik nach Schlaganfall (PSS; post-stroke spasticity) ist eine häufige Komplikation des Schlaganfalls. Gegenwärtige PSS-Behandlungen sind mit hohen Kosten, mangelnder langfristiger Wirksamkeit und unerwünschten Nebenwirkungen in Verbindung gebracht worden. Vibrierende und erhitzte Steinnadeln (VHS) sind bisher nicht zur Behandlung des PSS eingesetzt worden, und der Nachweis ihrer Sicherheit und Wirksamkeit durch hochwertige klinische Forschung steht noch aus.ZielBeurteilung der Wirksamkeit von vibrierenden und erhitzten Steinnadeln (VHS) in Kombination mit Meridian-Ausbagger-Übungen (MDE) bei Patienten mit PSS.Methoden100 Patienten mit Schlaganfall wurden eingeschlossen und per Randomisierung auf eine Behandlungsgruppe (VHS plus MDEs) und eine Kontrollgruppe (nur MDE) aufgeteilt. In beiden Gruppen wurden die Patienten 4 Wochen lang behandelt. Die primären Messinstrumente waren die Modified Ashworth Scale (MAS) und das Fugl-Meyer Assessment (FMA), als sekundäre Messinstrumente wurden die Activity of Daily Living Scale (ADL) und die Stroke-Specific Quality of Life Scale (SS-QOL) erhoben. Die Beurteilungszeitpunkte waren bei Baseline (T0) nach 4 Wochen Behandlung (T1) und nach 12 Wochen Nachbeobachtung ohne Behandlung (T2).ErgebnisseBei T1 und T2 bestanden signifikante Unterschiede bei der MAS zwischen den Gruppen (p = 0.001). Aus der Perspektive der Distribution zeigte die “VHS plus MDE”-Gruppe signifikante Veränderungen, und die Gruppe*Zeit-Interaktionen der oberen and unteren Extremitäten bei FMA, ADL und SS-QOL waren statistisch signifikant (p < 0.001), was darauf hindeutet, dass die Beschwerden der Patienten sich nach der Behandlung besserten. Die Effektstärke ist allerdings gering, insbesondere die der SS-QOL-Verbesserung bei T1.SchlussfolgerungDie Anwendung von vibrierenden und erhitzten Steinnadeln in Kombination mit Meridian-Ausbagger-Übungen kann PSS durchgängig lindern, die Funktion der Extremitäten verbessern und die Lebensqualität der Patienten mit PSS erhöhen. Jedoch muss das Produkt weiter optimiert werden, und die Verbesserungen bei den Patienten müssen über einen längeren Zeitraum beobachtet werden.}, } @article {pmid37944521, year = {2024}, author = {Yang, K and Tang, Z and Xing, C and Yan, N}, title = {STING signaling in the brain: Molecular threats, signaling activities, and therapeutic challenges.}, journal = {Neuron}, volume = {112}, number = {4}, pages = {539-557}, pmid = {37944521}, issn = {1097-4199}, support = {R01 AI151708/AI/NIAID NIH HHS/United States ; R01 NS117424/NS/NINDS NIH HHS/United States ; R01 NS122825/NS/NINDS NIH HHS/United States ; R56 AI151708/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Brain/pathology ; *Nervous System Diseases ; Signal Transduction ; }, abstract = {Stimulator of interferon genes (STING) is an innate immune signaling protein critical to infections, autoimmunity, and cancer. STING signaling is also emerging as an exciting and integral part of many neurological diseases. Here, we discuss recent advances in STING signaling in the brain. We summarize how molecular threats activate STING signaling in the diseased brain and how STING signaling activities in glial and neuronal cells cause neuropathology. We also review human studies of STING neurobiology and consider therapeutic challenges in targeting STING to treat neurological diseases.}, } @article {pmid37944939, year = {2024}, author = {Kalantari, F and Rendl, G and Hecht, S and Pirich, C and Beheshti, M}, title = {[Atypisches lokales Larynxkarzinom-Rezidiv imitiert als entzündlicher thyreoidaler Uptake in der 18F-FDG PET/CT].}, journal = {RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin}, volume = {196}, number = {2}, pages = {195-196}, doi = {10.1055/a-2123-3867}, pmid = {37944939}, issn = {1438-9010}, mesh = {*Fluorodeoxyglucose F18 ; *Positron Emission Tomography Computed Tomography ; Positron-Emission Tomography ; Tomography, X-Ray Computed ; Radiopharmaceuticals ; }, } @article {pmid37945618, year = {2023}, author = {Ramon-Gonen, R and Dori, A and Shelly, S}, title = {Towards a practical use of text mining approaches in electrodiagnostic data.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19483}, pmid = {37945618}, issn = {2045-2322}, mesh = {Humans ; Male ; Female ; Retrospective Studies ; Data Mining/methods ; *Brachial Plexus Neuropathies ; *Myasthenia Gravis ; *Polyneuropathies ; }, abstract = {Healthcare professionals produce abounding textual data in their daily clinical practice. Text mining can yield valuable insights from unstructured data. Extracting insights from multiple information sources is a major challenge in computational medicine. In this study, our objective was to illustrate how combining text mining techniques with statistical methodologies can yield new insights and contribute to the development of neurological and neuromuscular-related health information. We demonstrate how to utilize and derive knowledge from medical text, identify patient groups with similar diagnostic attributes, and examine differences between groups using demographical data and past medical history (PMH). We conducted a retrospective study for all patients who underwent electrodiagnostic (EDX) evaluation in Israel's Sheba Medical Center between May 2016 and February 2022. The data extracted for each patient included demographic data, test results, and unstructured summary reports. We conducted several analyses, including topic modeling that targeted clinical impressions and topic analysis to reveal age- and sex-related differences. The use of suspected clinical condition text enriched the data and generated additional attributes used to find associations between patients' PMH and the emerging diagnosis topics. We identified 6096 abnormal EMG results, of which 58% (n = 3512) were males. Based on the latent Dirichlet allocation algorithm we identified 25 topics that represent different diagnoses. Sex-related differences emerged in 7 topics, 3 male-associated and 4 female-associated. Brachial plexopathy, myasthenia gravis, and NMJ Disorders showed statistically significant age and sex differences. We extracted keywords related to past medical history (n = 37) and tested them for association with the different topics. Several topics revealed a close association with past medical history, for example, length-dependent symmetric axonal polyneuropathy with diabetes mellitus (DM), length-dependent sensory polyneuropathy with chemotherapy treatments and DM, brachial plexopathy with motor vehicle accidents, myasthenia gravis and NMJ disorders with botulin treatments, and amyotrophic lateral sclerosis with swallowing difficulty. Summarizing visualizations were created to easily grasp the results and facilitate focusing on the main insights. In this study, we demonstrate the efficacy of utilizing advanced computational methods in a corpus of textual data to accelerate clinical research. Additionally, using these methods allows for generating clinical insights, which may aid in the development of a decision-making process in real-life clinical practice.}, } @article {pmid37945695, year = {2023}, author = {Faria Assoni, A and Giove Mitsugi, T and Wardenaar, R and Oliveira Ferreira, R and Farias Jandrey, EH and Machado Novaes, G and Fonseca de Oliveira Granha, I and Bakker, P and Kaid, C and Zatz, M and Foijer, F and Keith Okamoto, O}, title = {Neurodegeneration-associated protein VAPB regulates proliferation in medulloblastoma.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19481}, pmid = {37945695}, issn = {2045-2322}, mesh = {Child ; Humans ; *Medulloblastoma/genetics ; *Cerebellar Neoplasms/genetics ; Cell Proliferation/genetics ; Vesicular Transport Proteins ; }, abstract = {VAMP (Vesicle-associated membrane protein)-associated protein B and C (VAPB) has been widely studied in neurodegenerative diseases such as ALS, but little is known about its role in cancer. Medulloblastoma is a common brain malignancy in children and arises from undifferentiated cells during neuronal development. Therefore, medulloblastoma is an interesting model to investigate the possible relationship between VAPB and tumorigenesis. Here we demonstrate that high VAPB expression in medulloblastoma correlates with decreased overall patient survival. Consistent with this clinical correlation, we find that VAPB is required for normal proliferation rates of medulloblastoma cells in vitro and in vivo. Knockout of VAPB (VAPB[KO]) delayed cell cycle progression. Furthermore, transcript levels of WNT-related proteins were decreased in the VAPB[KO]. We conclude that VAPB is required for proliferation of medulloblastoma cells, thus revealing VAPB as a potential therapeutic target for medulloblastoma treatment.}, } @article {pmid37946655, year = {2023}, author = {Lochbaum, R and Hoffmann, TK and Greve, J and Hahn, J}, title = {[Medikamente als Auslöser Bradykinin-vermittelter Angioödeme - mehr als ACE-Hemmer].}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {21}, number = {11}, pages = {1283-1290}, doi = {10.1111/ddg.15154_g}, pmid = {37946655}, issn = {1610-0387}, } @article {pmid37946741, year = {2023}, author = {Ebrahimi, A and Kamyab, A and Hosseini, S and Ebrahimi, S and Ashkani-Esfahani, S}, title = {Involvement of Coenzyme Q10 in Various Neurodegenerative and Psychiatric Diseases.}, journal = {Biochemistry research international}, volume = {2023}, number = {}, pages = {5510874}, pmid = {37946741}, issn = {2090-2247}, abstract = {Coenzyme Q10 (CoQ10), commonly known as ubiquinone, is a vitamin-like component generated in mitochondrial inner membranes. This molecule is detected broadly in different parts of the human body in various quantities. This molecule can be absorbed by the digestive system from various nutritional sources as supplements. CoQ10 exists in three states: in a of reduced form (ubiquinol), in a semiquinone radical form, and in oxidized ubiquinone form in different organs of the body, playing a crucial role in electron transportation and contributing to energy metabolism and oxygen utilization, especially in the musculoskeletal and nervous systems. Since the early 1980s, research about CoQ10 has become the interest for two reasons. First, CoQ10 deficiency has been found to have a link with cardiovascular, neurologic, and cancer disorders. Second, this molecule has an antioxidant and free-radical scavenger nature. Since then, several investigations have indicated that the drug may benefit patients with cardiovascular, neuromuscular, and neurodegenerative illnesses. CoQ10 may protect the neurological system from degeneration and degradation due to its antioxidant and energy-regulating activity in mitochondria. This agent has shown its efficacy in preventing and treating neurological diseases such as migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and Friedreich's ataxia. This study reviews the literature to highlight this agent's potential therapeutic effects in the mentioned neurological disorders.}, } @article {pmid37946793, year = {2023}, author = {Rogers, ML and Schultz, DW and Karnaros, V and Shepheard, SR}, title = {Urinary biomarkers for amyotrophic lateral sclerosis: candidates, opportunities and considerations.}, journal = {Brain communications}, volume = {5}, number = {6}, pages = {fcad287}, pmid = {37946793}, issn = {2632-1297}, support = {U01 NS107027/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis is a relentless neurodegenerative disease that is mostly fatal within 3-5 years and is diagnosed on evidence of progressive upper and lower motor neuron degeneration. Around 15% of those with amyotrophic lateral sclerosis also have frontotemporal degeneration, and gene mutations account for ∼10%. Amyotrophic lateral sclerosis is a variable heterogeneous disease, and it is becoming increasingly clear that numerous different disease processes culminate in the final degeneration of motor neurons. There is a profound need to clearly articulate and measure pathological process that occurs. Such information is needed to tailor treatments to individuals with amyotrophic lateral sclerosis according to an individual's pathological fingerprint. For new candidate therapies, there is also a need for methods to select patients according to expected treatment outcomes and measure the success, or not, of treatments. Biomarkers are essential tools to fulfil these needs, and urine is a rich source for candidate biofluid biomarkers. This review will describe promising candidate urinary biomarkers of amyotrophic lateral sclerosis and other possible urinary candidates in future areas of investigation as well as the limitations of urinary biomarkers.}, } @article {pmid37947306, year = {2024}, author = {Ackrivo, J}, title = {Response to: "Pulmonary care for ALS: There is more to the story": We agree more than we disagree.}, journal = {Muscle & nerve}, volume = {69}, number = {1}, pages = {117-118}, pmid = {37947306}, issn = {1097-4598}, support = {K23 HL151879/HL/NHLBI NIH HHS/United States ; HL-151879/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Respiratory Insufficiency ; *Noninvasive Ventilation ; }, } @article {pmid37948306, year = {2023}, author = {Lai, Q and Mason, AH and Agarwal, A and Edenfield, WC and Zhang, X and Kobayashi, T and Kratish, Y and Marks, TJ}, title = {Rapid Polyolefin Hydrogenolysis by a Single-Site Organo-Tantalum Catalyst on a Super-Acidic Support: Structure and Mechanism.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {62}, number = {50}, pages = {e202312546}, doi = {10.1002/anie.202312546}, pmid = {37948306}, issn = {1521-3773}, support = {DE-FG02-03ER15457//Office of Science/ ; ECCS-2025633//National Science Foundation/ ; NNA04CC36G//Ames Research Center/ ; DE-SC0001329//U.S. Department of Energy/ ; DE-AC02-06CH11357//U.S. Department of Energy/ ; DE-AC02-07CH11358//U.S. Department of Energy/ ; DE-SC0014664//Oak Ridge Institute for Science and Education/ ; }, abstract = {The novel electrophilic organo-tantalum catalyst AlS/TaNpx (1) (Np=neopentyl) is prepared by chemisorption of the alkylidene Np3 Ta=CH[t] Bu onto highly Brønsted acidic sulfated alumina (AlS). The proposed catalyst structure is supported by EXAFS, XANES, ICP, DRIFTS, elemental analysis, and SSNMR measurements and is in good agreement with DFT analysis. Catalyst 1 is highly effective for the hydrogenolysis of diverse linear and branched hydrocarbons, ranging from C2 to polyolefins. To the best of our knowledge, 1 exhibits one of the highest polyolefin hydrogenolysis activities (9,800 (CH2 units) ⋅ mol(Ta)[-1] ⋅ h[-1] at 200 °C/17 atm H2) reported to date in the peer-reviewed literature. Unlike the AlS/ZrNp2 analog, the Ta catalyst is more thermally stable and offers multiple potential C-C bond activation pathways. For hydrogenolysis, AlS/TaNpx is effective for a wide variety of pre- and post-consumer polyolefin plastics and is not significantly deactivated by standard polyolefin additives at typical industrial concentrations.}, } @article {pmid37948524, year = {2023}, author = {Ortega, JA and Sasselli, IR and Boccitto, M and Fleming, AC and Fortuna, TR and Li, Y and Sato, K and Clemons, TD and Mckenna, ED and Nguyen, TP and Anderson, EN and Asin, J and Ichida, JK and Pandey, UB and Wolin, SL and Stupp, SI and Kiskinis, E}, title = {CLIP-Seq analysis enables the design of protective ribosomal RNA bait oligonucleotides against C9ORF72 ALS/FTD poly-GR pathophysiology.}, journal = {Science advances}, volume = {9}, number = {45}, pages = {eadf7997}, pmid = {37948524}, issn = {2375-2548}, support = {R01 NS097850/NS/NINDS NIH HHS/United States ; R01 NS104219/NS/NINDS NIH HHS/United States ; R01 NS131409/NS/NINDS NIH HHS/United States ; R21 NS107761/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics/metabolism ; RNA, Ribosomal/genetics ; Chromatin Immunoprecipitation Sequencing ; RNA/genetics ; Drosophila/genetics/metabolism ; DNA Repeat Expansion ; }, abstract = {Amyotrophic lateral sclerosis and frontotemporal dementia patients with a hexanucleotide repeat expansion in C9ORF72 (C9-HRE) accumulate poly-GR and poly-PR aggregates. The pathogenicity of these arginine-rich dipeptide repeats (R-DPRs) is thought to be driven by their propensity to bind low-complexity domains of multivalent proteins. However, the ability of R-DPRs to bind native RNA and the significance of this interaction remain unclear. Here, we used computational and experimental approaches to characterize the physicochemical properties of R-DPRs and their interaction with RNA. We find that poly-GR predominantly binds ribosomal RNA (rRNA) in cells and exhibits an interaction that is predicted to be energetically stronger than that for associated ribosomal proteins. Critically, modified rRNA "bait" oligonucleotides restore poly-GR-associated ribosomal deficits and ameliorate poly-GR toxicity in patient neurons and Drosophila models. Our work strengthens the hypothesis that ribosomal function is impaired by R-DPRs, highlights a role for direct rRNA binding in mediating ribosomal dysfunction, and presents a strategy for protecting against C9-HRE pathophysiological mechanisms.}, } @article {pmid37948743, year = {2024}, author = {Wang, SW and Igarashi-Yokoi, T and Mochida, S and Fujinami, K and Ohno-Matsui, K}, title = {PREVALENCE AND CLINICAL FEATURES OF RADIAL FUNDUS AUTOFLUORESCENCE IN HIGH MYOPIC WOMEN.}, journal = {Retina (Philadelphia, Pa.)}, volume = {44}, number = {3}, pages = {446-454}, doi = {10.1097/IAE.0000000000003981}, pmid = {37948743}, issn = {1539-2864}, mesh = {Humans ; Female ; Child ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Prevalence ; Fundus Oculi ; *Retinitis Pigmentosa/diagnosis ; *Myopia/diagnosis/epidemiology ; Electroretinography ; Retrospective Studies ; Fluorescein Angiography ; Tomography, Optical Coherence ; Eye Proteins ; }, abstract = {PURPOSE: To determine the prevalence and characteristics of radial fundus autofluorescence (FAF) in highly myopic women.

METHODS: This was a retrospective, observational case study to determine the prevalence of radial FAF in the ultra-widefield FAF images in women. The clinical characteristics of these patients were evaluated.

RESULTS: Fifteen of 1,935 (0.78%) highly myopic women were found to have radial FAF. Their mean age was 36.6 ± 25.6 years, and their mean best-corrected visual acuity was 0.3 ± 0.42 logMAR units. The mean axial length (AL) was 28.8 ± 2.8 mm. Among the 15 cases, eight did not have pigmentary changes and seven had pigmentary changes in the ultra-widefield FAF images. The women with the pigmentary changes were significantly older (P = 0.021), had poorer BCVA (P = 0.001), and had longer ALs (P = 0.002). The visual fields and electroretinograms were worse in the eyes with pigmentary changes.

CONCLUSION: The prevalence of radial FAF was 0.78% in women with high myopia. These patients might have mutations in the RPGR or RP2 genes and can develop high myopia and retinitis pigmentosa. Ultra-widefield FAF images should be examined in all highly myopic patients for early detection of radial FAF, and myopia prevention and genetic counseling for possible genetic therapy are recommended.}, } @article {pmid37949836, year = {2024}, author = {Yang, L and Jasiqi, Y and Zettor, A and Vadas, O and Chiaravalli, J and Agou, F and Lashuel, HA}, title = {Effective Inhibition of TDP-43 Aggregation by Native State Stabilization.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {3}, pages = {e202314587}, doi = {10.1002/anie.202314587}, pmid = {37949836}, issn = {1521-3773}, support = {1398//École Polytechnique Fédérale de Lausanne/ ; }, mesh = {Humans ; *TDP-43 Proteinopathies/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases ; DNA-Binding Proteins/chemistry ; }, abstract = {Preventing the misfolding or aggregation of transactive response DNA binding protein with 43 kDa (TDP-43) is the most actively pursued disease-modifying strategy to treat amyotrophic lateral sclerosis and other neurodegenerative diseases. In this work, we provide proof of concept that native state stabilization of TDP-43 is a viable and effective strategy for treating TDP-43 proteinopathies. Firstly, we leveraged the Cryo-EM structures of TDP-43 fibrils to design C-terminal substitutions that disrupt TDP-43 aggregation. Secondly, we showed that these substitutions (S333D/S342D) stabilize monomeric TDP-43 without altering its physiological properties. Thirdly, we demonstrated that binding native oligonucleotide ligands stabilized monomeric TDP-43 and prevented its fibrillization and phase separation in the absence of direct binding to the aggregation-prone C-terminal domain. Fourthly, we showed that the monomeric TDP-43 variant could be induced to aggregate in a controlled manner, which enabled the design and implementation of a high-throughput screening assay to identify native state stabilizers of TDP-43. Altogether, our findings demonstrate that different structural domains in TDP-43 could be exploited and targeted to develop drugs that stabilize the native state of TDP-43 and provide a platform to discover novel drugs to treat TDP-43 proteinopathies.}, } @article {pmid37949878, year = {2023}, author = {Nagel, G and Kurz, D and Peter, RS and Rosenbohm, A and Koenig, W and Dupuis, L and Bäzner, H and Börtlein, A and Dempewolf, S and Schabet, M and Hecht, M and Kohler, A and Opherk, C and Naegele, A and Sommer, N and Lindner, A and Tumani, H and Ludolph, AC and Rothenbacher, D}, title = {Cystatin C based estimation of chronic kidney disease and amyotrophic lateral sclerosis in the ALS registry Swabia: associated risk and prognostic value.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19594}, pmid = {37949878}, issn = {2045-2322}, mesh = {Male ; Humans ; Aged ; Female ; Prognosis ; *Amyotrophic Lateral Sclerosis ; Case-Control Studies ; Prospective Studies ; Cystatin C ; *Renal Insufficiency, Chronic/complications ; Glomerular Filtration Rate ; Registries ; Creatinine ; Biomarkers ; }, abstract = {Kidney function as part of metabolic changes could be associated with amyotrophic lateral-sclerosis (ALS). We investigated the associations between estimated chronic kidney disease (CKD), based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C equation, and the risk at onset and prognostic value of CKD for ALS. Between October 2010 and June 2014, 362 ALS cases (59.4% men, mean age 65.7 years) and 681 controls (59.5% men, means age 66.3 years) were included in a population-based case-control study based on the ALS registry Swabia in Southern Germany. All ALS cases were followed-up (median 89.7 months), 317 died. Serum samples were measured for cystatin C to estimate the glomerular filtration rate (eGFR) according to the CKD-EPI equation. Information on covariates were assessed by an interview-based standardized questionnaire. Conditional logistic regression models were applied to calculate odds ratios (OR) for risk of ALS associated with eGFR/CKD stages. Time-to-death associated with renal parameters at baseline was assessed in ALS cases only. ALS cases were characterized by lower body mass index, slightly lower smoking prevalence, more intense occupational work and lower education than controls. Median serum cystatin-C based eGFR concentrations were lower in ALS cases than in controls (54.0 vs. 59.5 mL/min pro 1.73 m[2]). The prevalence of CKD stage ≥ 3 was slightly higher in ALS cases than in controls (14.1 vs. 11.0%). In the adjusted models, CKD stage 2 (OR 1.82, 95% CI 1.32, 2.52) and stage 3 (OR 2.34, 95% CI 1.38, 3.96) were associated with increased ALS risk. In this cohort of ALS cases, eGFR and CKD stage ≥ 3 (HR 0.94; 95% CI 0.64, 1.38) were not associated with prognosis. In this case-control study, higher CKD stages were associated with increased ALS risk, while in the prospective cohort of ALS cases, no indication of an association of CysC-based CKD on mortality was seen. In addition, our work strengthens the importance to evaluate renal function using a marker independent of muscle mass in ALS patients.}, } @article {pmid37949994, year = {2023}, author = {McMackin, R and Bede, P and Ingre, C and Malaspina, A and Hardiman, O}, title = {Biomarkers in amyotrophic lateral sclerosis: current status and future prospects.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {12}, pages = {754-768}, pmid = {37949994}, issn = {1759-4766}, support = {MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers ; Prognosis ; Disease Progression ; Drug Development ; }, abstract = {Disease heterogeneity in amyotrophic lateral sclerosis poses a substantial challenge in drug development. Categorization based on clinical features alone can help us predict the disease course and survival, but quantitative measures are also needed that can enhance the sensitivity of the clinical categorization. In this Review, we describe the emerging landscape of diagnostic, categorical and pharmacodynamic biomarkers in amyotrophic lateral sclerosis and their place in the rapidly evolving landscape of new therapeutics. Fluid-based markers from cerebrospinal fluid, blood and urine are emerging as useful diagnostic, pharmacodynamic and predictive biomarkers. Combinations of imaging measures have the potential to provide important diagnostic and prognostic information, and neurophysiological methods, including various electromyography-based measures and quantitative EEG-magnetoencephalography-evoked responses and corticomuscular coherence, are generating useful diagnostic, categorical and prognostic markers. Although none of these biomarker technologies has been fully incorporated into clinical practice or clinical trials as a primary outcome measure, strong evidence is accumulating to support their clinical utility.}, } @article {pmid37950613, year = {2024}, author = {Gray, D and Lesley, R and Mayberry, EJ and Williams, L and McHutchison, C and Newton, J and Pal, S and Chandran, S and MacPherson, SE and Abrahams, S and , }, title = {Development, reliability, validity, and acceptability of the remote administration of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {96-103}, doi = {10.1080/21678421.2023.2278512}, pmid = {37950613}, issn = {2167-9223}, mesh = {Humans ; *Cognition Disorders/diagnosis/etiology/psychology ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Reproducibility of Results ; Pandemics ; Neuropsychological Tests ; Cognition ; }, abstract = {BACKGROUND: ALS clinical care and research has changed dramatically since the COVID-19 pandemic, accelerating the need for cognitive assessments to be adapted for remote use.

OBJECTIVES: To develop the remote administration method of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), and determine its reliability and validity. Methods: The validation process consisted of: (1) Two versions of the ECAS (A and B) were administered, one in-person and one remotely via video call in a randomized order to 27 people without ALS; (2) The ECAS was administered remotely to 24 pwALS, with a second rater independently scoring performance; and (3) Acceptability was assessed by gathering feedback from 17 pwALS and 19 clinicians and researchers about their experience of using the ECAS remotely.

RESULTS: In the group without ALS, the remote and in-person ECAS total scores were found to be equivalent, and a Bland-Altman plot showed good agreement between the two administration methods. In pwALS, there was excellent agreement between two raters (ICC = 0.99). Positive feedback was gained from pwALS, researchers and clinicians with regards to ease of process, convenience, time, and the environment.

CONCLUSIONS: These findings provide evidence of the reliability and validity of the remote administration of the ECAS for pwALS, with clinicians, researchers and pwALS viewing it as a good alternative to face-to-face administration.}, } @article {pmid37950760, year = {2024}, author = {Beloribi-Djefaflia, S and Morales, RJ and Fatehi, F and Isapof, A and Servais, L and Leonard-Louis, S and Michaud, M and Verdure, P and Gidaro, T and Pouget, J and Poinsignon, V and Bonello-Palot, N and Attarian, S}, title = {Clinical and genetic features of patients suffering from CMT4J.}, journal = {Journal of neurology}, volume = {271}, number = {3}, pages = {1355-1365}, pmid = {37950760}, issn = {1432-1459}, mesh = {Adolescent ; Humans ; *Amyotrophic Lateral Sclerosis ; *Charcot-Marie-Tooth Disease/diagnosis/genetics ; *Flavoproteins/genetics ; Heterozygote ; Mutation/genetics ; Phenotype ; *Phosphoric Monoester Hydrolases/genetics ; }, abstract = {Mutations in the FIG4 gene have been identified in various diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Charcot-Marie-Tooth 4 J (CMT4J), with a wide range of phenotypic manifestations. We present eight cases of CMT4J patients carrying the p.Ile41Thr mutation of FIG4. The patients were categorized according to their phenotype. Six patients had a pure CMT; whereas, two patients had a CMT associated with parkinsonism. Three patients had an early onset and exhibited more severe forms of the disease. Three others experienced symptoms in their teenage years and had milder forms. Two patients had a late onset in adulthood. Four patients showed electrophysiological evidence of conduction blocks, typically associated with acquired neuropathies. Consequently, two of them received intravenous immunoglobulin treatment without a significant objective response. Interestingly, two heterozygous patients with the same mutations exhibited contrasting phenotypes, one having a severe early-onset form and the other experiencing a slow disease progression starting at the age of 49. Notably, although 7 out of 8 patients in this study were compound heterozygous for the p.Ile41Thr mutation, only one individual was found to be homozygous for this genetic variant and exhibited an early-onset, severe form of the disease. Additionally, one patient who developed the disease in his youth was also diagnosed with hereditary neuropathy with pressure palsies. Our findings provide insights into the CMT4J subtype by reporting on eight heterogeneous patient cases and highlight the potential for misdiagnosis when conduction blocks or asymmetrical nerve conduction study results are observed in patients with FIG4 mutations.}, } @article {pmid37951279, year = {2024}, author = {Vu Trung, K and Heise, C and Abou-Ali, E and Auriemma, F and Karam, E and van der Wiel, SE and Bruno, MJ and Caillol, F and Giovannini, M and Masaryk, V and Will, U and Anderloni, A and Pérez-Cuadrado-Robles, E and Dugic, A and Meier, B and Paik, WH and Petrone, MC and Wichmann, D and Dinis-Ribeiro, M and Gonçalves, TC and Wedi, E and Schmidt, A and Gulla, A and Hoffmeister, A and Rosendahl, J and Ratone, JP and Saadeh, R and Repici, A and Deprez, P and Sauvanet, A and Souche, FR and Fabre, JM and Muehldorfer, S and Caca, K and Löhr, M and Michl, P and Krug, S and Regner, S and Gaujoux, S and Hollenbach, M}, title = {Endoscopic papillectomy for ampullary lesions of minor papilla.}, journal = {Gastrointestinal endoscopy}, volume = {99}, number = {4}, pages = {587-595.e1}, doi = {10.1016/j.gie.2023.10.040}, pmid = {37951279}, issn = {1097-6779}, mesh = {Humans ; Treatment Outcome ; *Ampulla of Vater/surgery/pathology ; Endoscopy, Gastrointestinal ; Pancreatic Ducts/pathology ; *Pancreatic Neoplasms/pathology ; *Duodenal Neoplasms/pathology ; *Common Bile Duct Neoplasms/surgery/pathology ; Retrospective Studies ; }, abstract = {BACKGROUND AND AIMS: Ampullary lesions (ALs) of the minor duodenal papilla are extremely rare. Endoscopic papillectomy (EP) is a routinely used treatment for AL of the major duodenal papilla, but the role of EP for minor AL has not been accurately studied.

METHODS: We identified 20 patients with ALs of minor duodenal papilla in the multicentric database from the Endoscopic Papillectomy vs Surgical Ampullectomy vs Pancreatitcoduodenectomy for Ampullary Neoplasm study, which included 1422 EPs. We used propensity score matching (nearest-neighbor method) to match these cases with ALs of the major duodenal papilla based on age, sex, histologic subtype, and size of the lesion in a 1:2 ratio. Cohorts were compared by means of chi-square or Fisher exact test as well as Mann-Whitney U test.

RESULTS: Propensity score-based matching identified a cohort of 60 (minor papilla 20, major papilla 40) patients with similar baseline characteristics. The most common histologic subtype of lesions of minor papilla was an ampullary adenoma in 12 patients (3 low-grade dysplasia and 9 high-grade dysplasia). Five patients revealed nonneoplastic lesions. Invasive cancer (T1a), adenomyoma, and neuroendocrine neoplasia were each found in 1 case. The rate of complete resection, en-bloc resection, and recurrences were similar between the groups. There were no severe adverse events after EP of lesions of minor papilla. One patient had delayed bleeding that could be treated by endoscopic hemostasis, and 2 patients showed a recurrence in surveillance endoscopy after a median follow-up of 21 months (interquartile range, 12-50 months).

CONCLUSIONS: EP is safe and effective in ALs of the minor duodenal papilla. Such lesions could be managed according to guidelines for EP of major duodenal papilla.}, } @article {pmid37952009, year = {2024}, author = {Hu, N and Zhang, L and Shen, D and Yang, X and Liu, M and Cui, L}, title = {Incidence of amyotrophic lateral sclerosis-associated genetic variants: a clinic-based study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {4}, pages = {1515-1522}, pmid = {37952009}, issn = {1590-3478}, support = {XDB39040000//The Strategic Priority Research Program (Pilot study)"Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; CIFMS 2021-I2M-1-003//CAMS Innovation Fund for Medical Sciences/ ; 2022-PUMCH-B-017//National High Level Hospital Clinical Research Funding/ ; 7202158//Natural Science Foundation of Beijing Municipality/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Incidence ; *Cerebellar Ataxia ; Mutation ; }, abstract = {OBJECTIVE: This study is to determine the incidence of genetic forms of amyotrophic lateral sclerosis (ALS) in clinic-based population.

METHODS: Next-generation sequencing (NGS) of whole exome sequencing (WES) was conducted among a total of 374 patients with definite or probable ALS to identify ALS-associated genes based on ALSoD database (https://alsod.ac.uk) [2023-07-01].

RESULTS: Variants of ALS-associated genes were detected in 54.01% (202/374) ALS patients, among which 8.29% (31/374) were pathogenic/likely pathogenic (P/LP). The detection rates of P/LP variants were significantly higher in familial ALS than sporadic ALS (42.31% vs 5.75%, p < 0.001), while VUS mutations were more commonly detected in sporadic ALS (23.07% vs 47.13%, p = 0.018). There is no significant difference in detection rate between patients with and without early onset (8.93% vs 7.77%), rapid progression (9.30% vs 8.91%), cognitive decline (15.00% vs 7.93%), and cerebellar ataxia (20.00% vs 8.15%) (p > 0.05).

CONCLUSION: Over half of our ALS patients carried variants of ALS-related genes, most of which were variants of uncertain significance (VUS). Family history of ALS could work as strong evidence for carrying P/LP variants regarding ALS. There was no additionally suggestive effect of indicators including early onset, progression rate, cognitive decline, or cerebellar ataxia on the recommendation of genetic testing in clinical practice.}, } @article {pmid37952511, year = {2023}, author = {Zhang, X and Qu, X and Zou, Y}, title = {The Effect of Astragalus on Humoral and Cellular Immune Response: A Systematic Review and Meta-Analysis of Human Studies.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {535-543}, doi = {10.1159/000534826}, pmid = {37952511}, issn = {2504-2106}, mesh = {Humans ; *Interleukin-10 ; *Interleukin-2 ; Interleukin-4 ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Biomarkers ; }, abstract = {INTRODUCTION: Astragalus is used in traditional Chinese medicine for immune system disorders. Its effect on immune system function is evaluated in multiple studies. The objective of this systematic review and meta-analysis was to evaluate the effect of Astragalus on humoral and cellular immune response in human studies.

METHODS: A comprehensive search of electronic databases was conducted to identify relevant studies published up to April 2023. Studies that assessed the impact of Astragalus on humoral and cellular immune markers were included. The data were extracted, and a random-effects meta-analysis was performed to determine the overall effect size. Subgroup analyses were conducted based on outcome measures.

RESULTS: A total of 19 studies, including 1,094 human participants, were included in the meta-analysis. The analysis of humoral immune markers revealed a significant reduction in proinflammatory cytokines, including IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ, following Astragalus intervention (SMD -2.8765, 95% CI: -3.2385 to -2.5145, p < 0.0001). In the cellular immunity domain, Astragalus was found to significantly increase CD3 levels and the CD4/CD8 ratio (SMD 2.4629, 95% CI: 1.9598; 2.9661). Subgroup analyses based on outcome measures supported these findings. However, substantial heterogeneity was observed among the included studies.

CONCLUSION: This systematic review and meta-analysis provide evidence supporting the immunomodulatory effects of Astragalus on humoral and cellular response. Astragalus demonstrated a significant reduction in proinflammatory cytokines and an enhancement of cellular immune markers, suggesting its potential as a therapeutic agent for immune-related disorders.

UNLABELLED: EinleitungAstragalus wird in der traditionellen chinesischen Medizin bei Erkrankungen des Immunsystems eingesetzt. Seine Wirkung auf das Immunsystem ist in mehreren Studien untersucht worden. Das Ziel dieser systematischen Übersichtsarbeit und Metaanalyse ist es, die Wirkung von Astragalus auf die humorale und zelluläre Immunantwort in Studien am Menschen zu untersuchen.MethodenEine umfassende Suche in elektronischen Datenbanken wurde durchgeführt, um einschlägige Studien zu finden, die bis April 2023 veröffentlicht wurden. Eingeschlossen wurden Studien, die die Auswirkung von Astragalus auf Marker der humoralen und zellulären Immunantwort untersuchten. Die Daten wurden extrahiert und eine Random-Effects-Metaanalyse durchgeführt, um die Gesamt-Effektstärke zu ermitteln. Subgruppenanalysen wurden basierend auf Zielgrößen durchgeführt.ErgebnisseInsgesamt 19 Studien mit 1’094 menschlichen Teilnehmern wurden in die Metaanalyse eingeschlossen. Die Analyse der humoralen Immunmarker ergab eine signifikante Abnahme proinflammatorischer Zytokine, darunter IL-2, IL-4, IL-6, IL-10, TNF-α und IFN-γ, nach Anwendung von Astragalus (SMD –2.8765; 95%-KI: −3.2385, −2.5145; p < 0.0001). Bei der zellulären Immunität zeigte Astralagus eine signifikante Erhöhung der CD3-Konzentration und des CD4/CD8-Quotienten (SMD 2.4629; 95%-KI: 1.9598, 2.9661). Die Subgruppenanalysen nach Zielgrößen bestätigten diese Ergebnisse. Zwischen den eingeschlossenen Studien bestand jedoch erhebliche Heterogenität.SchlussfolgerungDiese systematische Übersichtsarbeit und Metaanalyse liefert Belege für die immunmodulatorischen Effekte von Astragalus auf die humorale und zelluläre Immunantwort. Astragalus zeigte eine signifikante Abnahme proinflammatorischer Zytokine und eine Verbesserung von Markern der zellulären Immunität, was auf sein Potenzial als Therapeutikum bei immunvermittelten Störungen hindeutet.}, } @article {pmid37952517, year = {2024}, author = {Zürcher, BF}, title = {The Tibetan Formula Cong zhi 6 in the ORL (ENT) Practice: Experiences with Laryngopharyngeal Reflux.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {84-88}, doi = {10.1159/000534212}, pmid = {37952517}, issn = {2504-2106}, mesh = {Humans ; *Laryngopharyngeal Reflux/drug therapy ; Retrospective Studies ; Pepsin A ; Tibet ; Europe ; }, abstract = {BACKGROUND: Laryngopharyngeal reflux (LPR) is a frequent condition; in European countries, the prevalence can be estimated as 10-30% of the general population. Treatment includes lifestyle measures and highly dosed proton pump inhibitors (PPIs) over at least 4 weeks. However, PPIs are not unproblematic due to their potential side effects and the known phenomenon of rebound acid hypersecretion. Cong zhi 6 is a multi-herbal Tibetan formula additionally containing calcium carbonate and is available in several European countries as a food supplement Padma Aciben/Padma AciTib.

CASE REPORT: Ten patients with LPR took Cong zhi 6. The course of the complaints was documented, and the data were retrospectively analysed. Clinical symptoms as assessed with the Reflux Symptom Index (RSI) questionnaire and the findings in laryngoscopy with the Reflux Finding Score (RFS) both showed marked improvement of several symptoms. The number of patients with pathological LPR sum score was significantly reduced from 8 to 2 patients and from 10 to 1 patient in RSI and RFS, respectively. The mean sum scores were reduced from 18.1 to 8.4 (RSI) and from 12.9 to 4.4 (RFS), respectively. Also, other gastrointestinal symptoms, such as abdominal pain, bloating, feeling of fullness, and nausea, which are usually associated with functional dyspepsia and irritable bowel syndrome, were markedly improved (reduction of mean score of the 3 most frequent symptoms by 77-87%).

CONCLUSION: Standard medical treatment for LPR consists in high dosed PPI for at least 4 weeks, which is known for several side effects and does not treat reliable the nonacid component of LPR of pepsin or other gastric enzymes. Therefore, other medical treatment options are urgently needed. The promising data of this case series suggest that the Tibetan herbal formula Cong zhi 6 may be a treatment option in LPR and related gastrointestinal symptoms and warrant further research.

UNLABELLED: HintergrundDer laryngopharyngeale Reflux (LPR) ist eine häufige Erkrankung. In europäischen Ländern wird die Prävalenz in der Gesamtbevölkerung auf 10–30% geschätzt. Die Behandlung beinhaltet Ernährungs- und Verhaltensänderung sowie die Gabe hochdosierter Protonen-Pumpen-Hemmer (PPI) über mindestens 4 Wochen. PPI sind jedoch aufgrund ihrer hohen potenziellen Nebenwirkungen und des bekannten Rebound-Phänomens der sauren Magensafthypersekretion nicht unproblematisch. Cong zhi 6 ist eine tibetische Rezeptur aus einem Vielpflanzengemisch sowie zusätzlich Calciumcarbonat und ist in einigen europäischen Ländern als Nahrungsergänzungsmittel Padma Aciben/Padma AciTib erhältlich.Case ReportZehn Patienten mit laryngo-pharyngealem Reflux (LPR) nahmen Cong zhi 6 ein. Der Beschwerdeverlauf wurde dokumentiert und die Daten retrospektiv analysiert. Die klinischen Symptome, die mithilfe des Reflux Symptom Index (RSI) Fragebogens erfasst wurden und die mittels des Reflux Finding Score (RFS) beurteilten laryngoskopischen Befunde zeigten beide eine deutliche Verbesserung verschiedener Symptome. Die Zahl der Patienten mit pathologischen LPR-Summenscore reduzierte sich signifikant, im RSI von 8 auf 2 und im RFS von 10 auf 1 Patienten. Der mittlere Summenwert sank von 18.1 auf 8.4 (RSI) und von 12.9 auf 4.4 (RFS). Des Weiteren zeigte sich auch bei anderen gastrointestinalen Beschwerden, wie Bauchschmerzen, Blähungen, Völlegefühl und Übelkeit, die normalerweise mit funktioneller Dyspepsie oder Reizdarm zusammenhängen, eine deutliche Verbesserung (durchschnittliche Verringerung des Scores der drei häufigsten Symptome um 77–87%).ZusammenfassungDie medikamentöse Standardbehandlung bei LPR besteht aus der hochdosierten PPI-Gabe über mindestens 4 Wochen, die jedoch für verschiedene Nebenwirkungen bekannt ist und die nicht-saure Komponente von LPR, wie Pepsin oder andere digestive Enzyme, nicht mitbehandelt. Daher sind andere medikamentöse Behandlungsmöglichkeiten dringend erforderlich. Die vielversprechenden Daten dieser Fallserie deuten darauf hin, dass die tibetische Pflanzenrezeptur Cong zhi 6 eine Behandlungsoption bei LPR sowie deren gastrointestinalen Symptome darstellt und rechtfertigen weitere Studien.}, } @article {pmid37952981, year = {2023}, author = {Okano, H and Morimoto, S and Kato, C and Nakahara, J and Takahashi, S}, title = {Induced pluripotent stem cells-based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {167}, number = {5}, pages = {603-614}, doi = {10.1111/jnc.16005}, pmid = {37952981}, issn = {1471-4159}, support = {JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Drug Evaluation, Preclinical ; *Neurodegenerative Diseases/metabolism ; Translational Research, Biomedical ; Randomized Controlled Trials as Topic ; Carbamates ; Phenylenediamines ; }, abstract = {It has been more than 10 years since the hopes for disease modeling and drug discovery using induced pluripotent stem cell (iPSC) technology boomed. Recently, clinical trials have been conducted with drugs identified using this technology, and some promising results have been reported. For amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, several groups have identified candidate drugs, ezogabine (retigabine), bosutinib, and ropinirole, using iPSCs-based drug discovery, and clinical trials using these drugs have been conducted, yielding interesting results. In our previous study, an iPSCs-based drug repurposing approach was utilized to show the potential of ropinirole hydrochloride (ROPI) in reducing ALS-specific pathological phenotypes. Recently, a phase 1/2a trial was conducted to investigate the effects of ropinirole on ALS further. This double-blind, randomized, placebo-controlled study confirmed the safety and tolerability of and provided evidence of its ability to delay disease progression and prolong the time to respiratory failure in ALS patients. Furthermore, in the reverse translational research, in vitro characterization of patient-derived iPSCs-motor neurons (MNs) mimicked the therapeutic effects of ROPI in vivo, suggesting the potential application of this technology to the precision medicine of ALS. Interestingly, RNA-seq data showed that ROPI treatment suppressed the sterol regulatory element-binding protein 2-dependent cholesterol biosynthesis pathway. Therefore, this pathway may be involved in the therapeutic effect of ROPI on ALS. The possibility that this pathway may be involved in the therapeutic effect of ALS was demonstrated. Finally, new future strategies for ALS using iPSCs technology will be discussed in this paper.}, } @article {pmid37953075, year = {2023}, author = {Shimizu, H and Nishimura, Y and Shiide, Y and Akimoto, M and Yashiro, M and Ueda, M and Hirai, M and Yoshino, H and Mizutani, T and Kanai, K and Kano, O and Kimura, H and Sekino, H and Ito, K}, title = {Pharmacokinetics of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Clinical therapeutics}, volume = {45}, number = {12}, pages = {1251-1258}, doi = {10.1016/j.clinthera.2023.09.025}, pmid = {37953075}, issn = {1879-114X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/pharmacokinetics ; Glucuronides/therapeutic use ; *Neuroprotective Agents/pharmacokinetics ; Sulfates/therapeutic use ; }, abstract = {PURPOSE: Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration.

METHODS: Two single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated.

FINDINGS: After reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported.

IMPLICATIONS: In patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www.

CLINICALTRIALS: gov.}, } @article {pmid37953591, year = {2023}, author = {Benlefki, S and Younes, R and Challuau, D and Bernard-Marissal, N and Hilaire, C and Scamps, F and Bowerman, M and Kothary, R and Schneider, BL and Raoul, C}, title = {Differential effect of Fas activation on spinal muscular atrophy motoneuron death and induction of axonal growth.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {69}, number = {10}, pages = {1-8}, doi = {10.14715/cmb/2023.69.10.1}, pmid = {37953591}, issn = {1165-158X}, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; *Muscular Atrophy, Spinal/genetics/metabolism/pathology ; Axons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most common motoneuron diseases affecting adults and infants, respectively. ALS and SMA are both characterized by the selective degeneration of motoneurons. Although different in their genetic etiology, growing evidence indicates that they share molecular and cellular pathogenic signatures that constitute potential common therapeutic targets. We previously described a motoneuron-specific death pathway elicited by the Fas death receptor, whereby vulnerable ALS motoneurons show an exacerbated sensitivity to Fas activation. However, the mechanisms that drive the loss of SMA motoneurons remains poorly understood. Here, we describe an in vitro model of SMA-associated degeneration using primary motoneurons derived from Smn2B/- SMA mice and show that Fas activation selectively triggers death of the proximal motoneurons. Fas-induced death of SMA motoneurons has the molecular signature of the motoneuron-selective Fas death pathway that requires activation of p38 kinase, caspase-8, -9 and -3 as well as upregulation of collapsin response mediator protein 4 (CRMP4). In addition, Rho-associated Kinase (ROCK) is required for Fas recruitment. Remarkably, we found that exogenous activation of Fas also promotes axonal elongation in both wildtype and SMA motoneurons. Axon outgrowth of motoneurons promoted by Fas requires the activity of ERK, ROCK and caspases. This work defines a dual role of Fas signaling in motoneurons that can elicit distinct responses from cell death to axonal growth.}, } @article {pmid37954145, year = {2023}, author = {Kalia, M and Miotto, M and Ness, D and Opie-Martin, S and Spargo, TP and Di Rienzo, L and Biagini, T and Petrizzelli, F and Al Khleifat, A and Kabiljo, R and , and , and Mazza, T and Ruocco, G and Milanetti, E and Dobson, RJ and Al-Chalabi, A and Iacoangeli, A}, title = {Molecular dynamics analysis of superoxide dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression.}, journal = {Computational and structural biotechnology journal}, volume = {21}, number = {}, pages = {5296-5308}, pmid = {37954145}, issn = {2001-0370}, abstract = {Mutations in the superoxide dismutase 1 (SOD1) gene are the second most common known cause of ALS. SOD1 variants express high phenotypic variability and over 200 have been reported in people with ALS. It was previously proposed that variants can be broadly classified in two groups, 'wild-type like' (WTL) and 'metal binding region' (MBR) variants, based on their structural location and biophysical properties. MBR variants, but not WTL variants, were associated with a reduction of SOD1 enzymatic activity. In this study we used molecular dynamics and large clinical datasets to characterise the differences in the structural and dynamic behaviour of WTL and MBR variants with respect to the wild-type SOD1, and how such differences influence the ALS clinical phenotype. Our study identified marked structural differences, some of which are observed in both variant groups, while others are group specific. Moreover, collecting clinical data of approximately 500 SOD1 ALS patients carrying variants, we showed that the survival time of patients carrying an MBR variant is generally longer (∼6 years median difference, p < 0.001) with respect to patients with a WTL variant. In conclusion, our study highlighted key differences in the dynamic behaviour between WTL and MBR SOD1 variants, and between variants and wild-type SOD1 at an atomic and molecular level, that could be further investigated to explain the associated phenotypic variability. Our results support the hypothesis of a decoupling between mechanisms of onset and progression of SOD1 ALS, and an involvement of loss-of-function of SOD1 with the disease progression.}, } @article {pmid37954904, year = {2023}, author = {Zhao, K and Chen, P and Alexander-Bloch, A and Wei, Y and Dyrba, M and Yang, F and Kang, X and Wang, D and Fan, D and Ye, S and Tang, Y and Yao, H and Zhou, B and Lu, J and Yu, C and Wang, P and Liao, Z and Chen, Y and Huang, L and Zhang, X and Han, Y and Li, S and Liu, Y}, title = {A neuroimaging biomarker for Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN): a cross-sectional study.}, journal = {EClinicalMedicine}, volume = {65}, number = {}, pages = {102276}, pmid = {37954904}, issn = {2589-5370}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that poses a worldwide public health challenge. A neuroimaging biomarker would significantly improve early diagnosis and intervention, ultimately enhancing the quality of life for affected individuals and reducing the burden on healthcare systems.

METHODS: Cross-sectional and longitudinal data (10,099 participants with 13,380 scans) from 12 independent datasets were used in the present study (this study was performed between September 1, 2021 and February 15, 2023). The Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN) score was developed via integrated regional- and network-based measures under an ensemble machine learning model based on structural MRI data. We systematically assessed whether IBRAIN could be a neuroimaging biomarker for AD.

FINDINGS: IBRAIN accurately differentiated individuals with AD from NCs (AUC = 0.92) and other neurodegenerative diseases, including Frontotemporal dementia (FTD), Parkinson's disease (PD), Vascular dementia (VaD) and Amyotrophic Lateral Sclerosis (ALS) (AUC = 0.92). IBRAIN was significantly correlated to clinical measures and gene expression, enriched in immune process and protein metabolism. The IBRAIN score exhibited a significant ability to reveal the distinct progression of prodromal AD (i.e., Mild cognitive impairment, MCI) (Hazard Ratio (HR) = 6.52 [95% CI: 4.42∼9.62], p < 1 × 10[-16]), which offers similar powerful performance with Cerebrospinal Fluid (CSF) Aβ (HR = 3.78 [95% CI: 2.63∼5.43], p = 2.13 × 10[-14]) and CSF Tau (HR = 3.77 [95% CI: 2.64∼5.39], p = 9.53 × 10[-15]) based on the COX and Log-rank test. Notably, the IBRAIN shows comparable sensitivity (beta = -0.70, p < 1 × 10[-16]) in capturing longitudinal changes in individuals with conversion to AD than CSF Aβ (beta = -0.26, p = 4.40 × 10[-9]) and CSF Tau (beta = 0.12, p = 1.02 × 10[-5]).

INTERPRETATION: Our findings suggested that IBRAIN is a biologically relevant, specific, and sensitive neuroimaging biomarker that can serve as a clinical measure to uncover prodromal AD progression. It has strong potential for application in future clinical practice and treatment trials.

FUNDING: Science and Technology Innovation 2030 Major Projects, the National Natural Science Foundation of China, Beijing Natural Science Funds, the Fundamental Research Funds for the CentralUniversity, and the Startup Funds for Talents at Beijing Normal University.}, } @article {pmid37955056, year = {2024}, author = {Spörndly-Nees, S and Jakobsson Larsson, B and Zetterberg, L and Åkerblom, Y and Nyholm, D and Åsenlöf, P}, title = {Pain in patients with motor neuron disease: Variation of pain and association with disease severity, health-related quality of life and depression - A longitudinal study.}, journal = {Palliative & supportive care}, volume = {22}, number = {5}, pages = {1150-1157}, doi = {10.1017/S1478951523001347}, pmid = {37955056}, issn = {1478-9523}, mesh = {Humans ; Female ; Male ; *Quality of Life/psychology ; Middle Aged ; Longitudinal Studies ; *Depression/psychology/etiology/complications ; Aged ; *Motor Neuron Disease/complications/psychology ; Prospective Studies ; *Pain/psychology/etiology/complications ; Severity of Illness Index ; Surveys and Questionnaires ; Pain Measurement/methods ; Adult ; Cohort Studies ; Disease Progression ; Psychometrics/methods/instrumentation ; }, abstract = {OBJECTIVES: To describe levels of pain over time during disease progression in individual patients and for a total sample of patients with motor neuron disease (MND), respectively, and to examine associations between pain, disease severity, health-related quality of life (HRQOL), and depression.

METHODS: A prospective cohort study was conducted on 68 patients with MND, including data collected on five occasions over a period of 2 years. Pain was assessed using the Brief Pain Inventory - Short Form. Depression was assessed using the Amyotrophic Lateral Sclerosis (ALS)-Depression-Inventory (ADI-12). Disability progression was measured using the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Version (ALSFRS-R). HRQOL was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5).

RESULTS: Participants reported great individual variation over time. The median level of pain was 4 (min 0 and max 10). Higher levels of pain during the last 24 h were associated with higher depression scores (ADI-12), poorer quality of life (ALSAQ-5), and lower reporting of fine and gross motor skills (ALSFRS-R). Baseline pain levels did not predict future values of depression and function. Individuals reporting average pain >3 experienced more hopelessness toward the future and reported higher depression scores compared with participants reporting average pain <3.

SIGNIFICANCE OF RESULTS: Great within-individual variation of pain intensity was reported. Pain intensity was associated with depression, function and HRQOL cross-sectionally, but it did not have a strong prognostic value for future depression, function, or HRQOL. Patients with MND should be offered frequent assessment of pain and depressive symptoms in person-centered care, allowing for individualization of treatment.}, } @article {pmid37955299, year = {2023}, author = {Yuan, YH and Mao, ND and Duan, JL and Zhang, H and Garrido, C and Lirussi, F and Gao, Y and Xie, T and Ye, XY}, title = {Recent progress in discovery of novel AAK1 inhibitors: from pain therapy to potential anti-viral agents.}, journal = {Journal of enzyme inhibition and medicinal chemistry}, volume = {38}, number = {1}, pages = {2279906}, pmid = {37955299}, issn = {1475-6374}, mesh = {Humans ; *Protein Serine-Threonine Kinases ; *Antiviral Agents/pharmacology ; Phosphorylation ; Pain ; }, abstract = {Adaptor associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of Ser/Thr kinases, is a specific key kinase regulating Thr156 phosphorylation at the μ2 subunit of the adapter complex-2 (AP-2) protein. Due to their important biological functions, AAK1 systems have been validated in clinics for neuropathic pain therapy, and are being explored as potential therapeutic targets for diseases caused by various viruses such as Hepatitis C (HCV), Dengue, Ebola, and COVID-19 viruses and for amyotrophic lateral sclerosis (ALS). Centreing on the advances of drug discovery programs in this field up to 2023, AAK1 inhibitors are discussed from the aspects of the structure-based rational molecular design, pharmacology, toxicology and synthetic routes for the compounds of interest in this review. The aim is to provide the medicinal chemistry community with up-to-date information and to accelerate the drug discovery programs in the field of AAK1 small molecule inhibitors.}, } @article {pmid37955564, year = {2024}, author = {Pinto, S and Oliveira Santos, M and Gromicho, M and Swash, M and de Carvalho, M}, title = {Impact of diabetes mellitus on the respiratory function of amyotrophic lateral sclerosis patients.}, journal = {European journal of neurology}, volume = {31}, number = {2}, pages = {e16129}, pmid = {37955564}, issn = {1468-1331}, support = {GA101017598//European Union's Horizon 2020 research and innovation program/ ; }, mesh = {Male ; Humans ; Middle Aged ; Aged ; *Amyotrophic Lateral Sclerosis ; Retrospective Studies ; *Respiratory Insufficiency/complications ; Respiratory Function Tests/adverse effects ; *Diabetes Mellitus ; }, abstract = {BACKGROUND AND PURPOSE: Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). The impact of diabetes mellitus (DM) on respiratory function of ALS patients is uncertain.

METHODS: A retrospective cohort study was carried out. From the 1710 patients with motor neuron disease followed in our unit, ALS and progressive muscular atrophy patients were included. We recorded demographic characteristics, functional ALS rating scale (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R]) and its subscores at first visit, respiratory function tests, arterial blood gases, phrenic nerve amplitude (PhrenAmpl), and mean nocturnal oxygen saturation (SpO2 mean). We excluded patients with other relevant diseases. Two subgroups were analysed: DIAB (patients with DM) and noDIAB (patients without DM). Independent t-test, χ[2] , or Fisher exact test was applied. Binomial logistic regression analyses assessed DM effects. Kaplan-Meier analysis assessed survival. p < 0.05 was considered significant.

RESULTS: We included 1639 patients (922 men, mean onset age = 62.5 ± 12.6 years, mean disease duration = 18.1 ± 22.0 months). Mean survival was 43.3 ± 40.7 months. More men had DM (p = 0.021). Disease duration was similar between groups (p = 0.063). Time to noninvasive ventilation (NIV) was shorter in DIAB (p = 0.004); total survival was similar. No differences were seen for ALSFRS-R or its decay rate. At entry, DIAB patients were older (p < 0.001), with lower forced vital capacity (p = 0.001), arterial oxygen pressure (p = 0.01), PhrenAmpl (p < 0.001), and SpO2 mean (p = 0.014).

CONCLUSIONS: ALS patients with DM had increased risk of respiratory impairment and should be closely monitored. Early NIV allowed for similar survival rate between groups.}, } @article {pmid37955773, year = {2023}, author = {Colasuonno, F and Price, R and Moreno, S}, title = {Upper and Lower Motor Neurons and the Skeletal Muscle: Implication for Amyotrophic Lateral Sclerosis (ALS).}, journal = {Advances in anatomy, embryology, and cell biology}, volume = {236}, number = {}, pages = {111-129}, pmid = {37955773}, issn = {0301-5556}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis ; Motor Neurons ; Muscle, Skeletal ; Neurons, Efferent ; *Nerve Tissue ; }, abstract = {The relationships between motor neurons and the skeletal muscle during development and in pathologic contexts are addressed in this Chapter.We discuss the developmental interplay of muscle and nervous tissue, through neurotrophins and the activation of differentiation and survival pathways. After a brief overview on muscular regulatory factors, we focus on the contribution of muscle to early and late neurodevelopment. Such a role seems especially intriguing in relation to the epigenetic shaping of developing motor neuron fate choices. In this context, emphasis is attributed to factors regulating energy metabolism, which may concomitantly act in muscle and neural cells, being involved in common pathways.We then review the main features of motor neuron diseases, addressing the cellular processes underlying clinical symptoms. The involvement of different muscle-associated neurotrophic factors for survival of lateral motor column neurons, innervating MyoD-dependent limb muscles, and of medial motor column neurons, innervating Myf5-dependent back musculature is discussed. Among the pathogenic mechanisms, we focus on oxidative stress, that represents a common and early trait in several neurodegenerative disorders. The role of organelles primarily involved in reactive oxygen species scavenging and, more generally, in energy metabolism-namely mitochondria and peroxisomes-is discussed in the frame of motor neuron degeneration.We finally address muscular involvement in amyotrophic lateral sclerosis (ALS), a multifactorial degenerative disorder, hallmarked by severe weight loss, caused by imbalanced lipid metabolism. Even though multiple mechanisms have been recognized to play a role in the disease, current literature generally assumes that the primum movens is neuronal degeneration and that muscle atrophy is only a consequence of such pathogenic event. However, several lines of evidence point to the muscle as primarily involved in the disease, mainly through its role in energy homeostasis. Data from different ALS mouse models strongly argue for an early mitochondrial dysfunction in muscle tissue, possibly leading to motor neuron disturbances. Detailed understanding of skeletal muscle contribution to ALS pathogenesis will likely lead to the identification of novel therapeutic strategies.}, } @article {pmid37957721, year = {2023}, author = {Tan, RH and McCann, H and Shepherd, CE and Pinkerton, M and Mazumder, S and Devenney, EM and Adler, GL and Rowe, DB and Kril, J and Halliday, GM and Kiernan, MC}, title = {Heterogeneity of cortical pTDP-43 inclusion morphologies in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {180}, pmid = {37957721}, issn = {2051-5960}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Frontotemporal Dementia/pathology ; DNA-Binding Proteins/genetics ; Neurons/pathology ; Phenotype ; }, abstract = {BACKGROUND: Despite the presence of significant cortical pTDP-43 inclusions of heterogeneous morphologies in patients diagnosed with amyotrophic lateral sclerosis (ALS), pathological subclassification is routinely performed in the minority of patients with concomitant frontotemporal dementia (FTD).

OBJECTIVE: In order to improve current understanding of the presence and relevance of pathological pTDP-43 subtypes in ALS, the present study examined the pattern of cortical pTDP-43 aggregates in 61 ALS cases without FTD.

RESULTS: Based on the presence, morphology and composition of pTDP-43 pathology, three distinct ALS-TDP subtypes were delineated: (1) A predominant pattern of pTDP-43 granulofilamentous neuronal inclusions (GFNIs) and grains that were immuno-negative for p62 was identified in 18% of cases designated ALS-TDP type E; (2) neuronal cytoplasmic inclusions (NCIs) that were immuno-positive for both pTDP-43 and p62 were observed in 67% of cases assigned ALS-TDP type B; and (3) scarce cortical pTDP-43 and p62 aggregates were identified in 15% of cases coined ALS-TDP type SC (scarce cortical). Quantitative analyses revealed a significantly greater burden of pTDP-43 GFNI and grains in ALS-TDP type E. Principal component analysis demonstrated significant relationships between GFNIs, grains and ALS-TDP subtypes to support the distinction of subtypes E and B. No significant difference in age at death or disease duration was found between ALS-TDP subgroups to suggest that these subtypes represent earlier or later stages of the same disease process. Instead, a significantly higher ALS-TDP stage, indicating greater topographical spread of pTDP-43, was identified in ALS-TDP type E. Alzheimer's disease neuropathological change (ABC score ≥ intermediate) and Lewy body disease (Braak stage ≥ IV) was more prevalent in the ALS-TDP type SC cohort, which also demonstrated a significantly lower overall cognitive score.

CONCLUSION: In summary, the present study demonstrates that ALS-TDP does not represent a single homogenous neuropathology. We propose the subclassification of ALS-TDP into three distinct subtypes using standard immuno-stains for pTDP-43 and p62 in the motor cortex, which is routinely sampled and evaluated for diagnostic neuropathological characterisation of ALS. We propose that future studies specify both clinicopathological group and pTDP-43 subtype to advance current understanding of the pathogenesis of clinical phenotypes in pTDP-43 proteinopathies, which will have significant relevance to the development of targeted therapies for this heterogeneous disorder.}, } @article {pmid37958596, year = {2023}, author = {Stoka, V and Vasiljeva, O and Nakanishi, H and Turk, V}, title = {The Role of Cysteine Protease Cathepsins B, H, C, and X/Z in Neurodegenerative Diseases and Cancer.}, journal = {International journal of molecular sciences}, volume = {24}, number = {21}, pages = {}, pmid = {37958596}, issn = {1422-0067}, support = {J1-2473, P1-0140//Slovenian Research Agency/ ; }, mesh = {Humans ; *Cysteine Proteases ; *Neurodegenerative Diseases ; Cysteine/metabolism ; Cathepsin B ; *Neoplasms ; Lysosomes/metabolism ; }, abstract = {Papain-like cysteine proteases are composed of 11 human cysteine cathepsins, originally located in the lysosomes. They exhibit broad specificity and act as endopeptidases and/or exopeptidases. Among them, only cathepsins B, H, C, and X/Z exhibit exopeptidase activity. Recently, cysteine cathepsins have been found to be present outside the lysosomes and often participate in various pathological processes. Hence, they have been considered key signalling molecules. Their potentially hazardous proteolytic activities are tightly regulated. This review aims to discuss recent advances in understanding the structural aspects of these four cathepsins, mechanisms of their zymogen activation, regulation of their activities, and functional aspects of these enzymes in neurodegeneration and cancer. Neurodegenerative effects have been evaluated, particularly in Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and neuropsychiatric disorders. Cysteine cathepsins also participate in tumour progression and metastasis through the overexpression and secretion of proteases, which trigger extracellular matrix degradation. To our knowledge, this is the first review to provide an in-depth analysis regarding the roles of cysteine cathepsins B, H, C, and X in neurodegenerative diseases and cancer. Further advances in understanding the functions of cysteine cathepsins in these conditions will result in the development of novel, targeted therapeutic strategies.}, } @article {pmid37958767, year = {2023}, author = {Gonzalo-Gobernado, R and Moreno-Martínez, L and González, P and Dopazo, XM and Calvo, AC and Pidal-Ladrón de Guevara, I and Seisdedos, E and Díaz-Muñoz, R and Mellström, B and Osta, R and Naranjo, JR}, title = {Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice.}, journal = {International journal of molecular sciences}, volume = {24}, number = {21}, pages = {}, pmid = {37958767}, issn = {1422-0067}, support = {PI21/00372//Instituto de Salud Carlos III/ ; 307//Biomedical Research Networking Center on Neurodegenerative Diseases/ ; }, mesh = {Mice ; Animals ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Activating Transcription Factor 6/genetics/metabolism ; Neuroprotection ; Motor Neurons/metabolism ; Kv Channel-Interacting Proteins/metabolism ; Superoxide Dismutase/genetics/metabolism ; Disease Models, Animal ; Carbamates ; Piperidines ; }, abstract = {The interaction of the activating transcription factor 6 (ATF6), a key effector of the unfolded protein response (UPR) in the endoplasmic reticulum, with the neuronal calcium sensor Downstream Regulatory Element Antagonist Modulator (DREAM) is a potential therapeutic target in neurodegeneration. Modulation of the ATF6-DREAM interaction with repaglinide (RP) induced neuroprotection in a model of Huntington's disease. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no cure, characterized by the progressive loss of motoneurons resulting in muscle denervation, atrophy, paralysis, and death. The aim of this work was to investigate the potential therapeutic significance of DREAM as a target for intervention in ALS. We found that the expression of the DREAM protein was reduced in the spinal cord of SOD1G93A mice compared to wild-type littermates. RP treatment improved motor strength and reduced the expression of the ALS progression marker collagen type XIXα1 (Col19α1 mRNA) in the quadriceps muscle in SOD1G93A mice. Moreover, treated SOD1G93A mice showed reduced motoneuron loss and glial activation and increased ATF6 processing in the spinal cord. These results indicate that the modulation of the DREAM-ATF6 interaction ameliorates ALS symptoms in SOD1G93A mice.}, } @article {pmid37958929, year = {2023}, author = {Boylan, MA and Pincetic, A and Romano, G and Tatton, N and Kenkare-Mitra, S and Rosenthal, A}, title = {Targeting Progranulin as an Immuno-Neurology Therapeutic Approach.}, journal = {International journal of molecular sciences}, volume = {24}, number = {21}, pages = {}, pmid = {37958929}, issn = {1422-0067}, mesh = {Humans ; Progranulins/genetics ; Intercellular Signaling Peptides and Proteins/genetics ; *Frontotemporal Dementia/genetics ; Neurons/pathology ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Immuno-neurology is an emerging therapeutic strategy for dementia and neurodegeneration designed to address immune surveillance failure in the brain. Microglia, as central nervous system (CNS)-resident myeloid cells, routinely perform surveillance of the brain and support neuronal function. Loss-of-function (LOF) mutations causing decreased levels of progranulin (PGRN), an immune regulatory protein, lead to dysfunctional microglia and are associated with multiple neurodegenerative diseases, including frontotemporal dementia caused by the progranulin gene (GRN) mutation (FTD-GRN), Alzheimer's disease (AD), Parkinson's disease (PD), limbic-predominant age-related transactivation response deoxyribonucleic acid binding protein 43 (TDP-43) encephalopathy (LATE), and amyotrophic lateral sclerosis (ALS). Immuno-neurology targets immune checkpoint-like proteins, offering the potential to convert aging and dysfunctional microglia into disease-fighting cells that counteract multiple disease pathologies, clear misfolded proteins and debris, promote myelin and synapse repair, optimize neuronal function, support astrocytes and oligodendrocytes, and maintain brain vasculature. Several clinical trials are underway to elevate PGRN levels as one strategy to modulate the function of microglia and counteract neurodegenerative changes associated with various disease states. If successful, these and other immuno-neurology drugs have the potential to revolutionize the treatment of neurodegenerative disorders by harnessing the brain's immune system and shifting it from an inflammatory/pathological state to an enhanced physiological/homeostatic state.}, } @article {pmid37959385, year = {2023}, author = {Azcarate, I and Urigüen, JA and Leturiondo, M and Sandoval, CL and Redondo, K and Gutiérrez, JJ and Russell, JK and Wallmüller, P and Sterz, F and Daya, MR and Ruiz de Gauna, S}, title = {The Role of Chest Compressions on Ventilation during Advanced Cardiopulmonary Resuscitation.}, journal = {Journal of clinical medicine}, volume = {12}, number = {21}, pages = {}, pmid = {37959385}, issn = {2077-0383}, abstract = {Background: There is growing interest in the quality of manual ventilation during cardiopulmonary resuscitation (CPR), but accurate assessment of ventilation parameters remains a challenge. Waveform capnography is currently the reference for monitoring ventilation rate in intubated patients, but fails to provide information on tidal volumes and inspiration-expiration timing. Moreover, the capnogram is often distorted when chest compressions (CCs) are performed during ventilation compromising its reliability during CPR. Our main purpose was to characterize manual ventilation during CPR and to assess how CCs may impact on ventilation quality. Methods: Retrospective analysis were performed of CPR recordings fromtwo databases of adult patients in cardiac arrest including capnogram, compression depth, and airway flow, pressure and volume signals. Using automated signal processing techniques followed by manual revision, individual ventilations were identified and ventilation parameters were measured. Oscillations on the capnogram plateau during CCs were characterized, and its correlation with compression depth and airway volume was assessed. Finally, we identified events of reversed airflow caused by CCs and their effect on volume and capnogram waveform. Results: Ventilation rates were higher than the recommended 10 breaths/min in 66.7% of the cases. Variability in ventilation rates correlated with the variability in tidal volumes and other ventilatory parameters. Oscillations caused by CCs on capnograms were of high amplitude (median above 74%) and were associated with low pseudo-volumes (median 26 mL). Correlation between the amplitude of those oscillations with either the CCs depth or the generated passive volumes was low, with correlation coefficients of -0.24 and 0.40, respectively. During inspiration and expiration, reversed airflow events caused opposed movement of gases in 80% of ventilations. Conclusions: Our study confirmed lack of adherence between measured ventilation rates and the guideline recommendations, and a substantial dispersion in manual ventilation parameters during CPR. Oscillations on the capnogram plateau caused by CCs did not correlate with compression depth or associated small tidal volumes. CCs caused reversed flow during inspiration, expiration and in the interval between ventilations, sufficient to generate volume changes and causing oscillations on capnogram. Further research is warranted to assess the impact of these findings on ventilation quality during CPR.}, } @article {pmid37960284, year = {2023}, author = {Zheng, Y and Bonfili, L and Wei, T and Eleuteri, AM}, title = {Understanding the Gut-Brain Axis and Its Therapeutic Implications for Neurodegenerative Disorders.}, journal = {Nutrients}, volume = {15}, number = {21}, pages = {}, pmid = {37960284}, issn = {2072-6643}, support = {Fondi Studenti PhD//University of Camerino/ ; }, mesh = {Humans ; Brain-Gut Axis ; *Neurodegenerative Diseases/therapy ; *Gastrointestinal Microbiome ; *Alzheimer Disease/therapy ; *Parkinson Disease/therapy ; Brain ; Dysbiosis/therapy ; }, abstract = {The gut-brain axis (GBA) is a complex bidirectional communication network connecting the gut and brain. It involves neural, immune, and endocrine communication pathways between the gastrointestinal (GI) tract and the central nervous system (CNS). Perturbations of the GBA have been reported in many neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), among others, suggesting a possible role in disease pathogenesis. The gut microbiota is a pivotal component of the GBA, and alterations in its composition, known as gut dysbiosis, have been associated with GBA dysfunction and neurodegeneration. The gut microbiota might influence the homeostasis of the CNS by modulating the immune system and, more directly, regulating the production of molecules and metabolites that influence the nervous and endocrine systems, making it a potential therapeutic target. Preclinical trials manipulating microbial composition through dietary intervention, probiotic and prebiotic supplementation, and fecal microbial transplantation (FMT) have provided promising outcomes. However, its clear mechanism is not well understood, and the results are not always consistent. Here, we provide an overview of the major components and communication pathways of the GBA, as well as therapeutic approaches targeting the GBA to ameliorate NDDs.}, } @article {pmid37960542, year = {2023}, author = {Zhao, D and Ji, L and Yang, F}, title = {Land Cover Classification Based on Airborne Lidar Point Cloud with Possibility Method and Multi-Classifier.}, journal = {Sensors (Basel, Switzerland)}, volume = {23}, number = {21}, pages = {}, pmid = {37960542}, issn = {1424-8220}, support = {61972363//National Natural Science Foundation of China/ ; YDZJSX2021C008//Central Government Leading Local Science and Technology Development Fund Project/ ; 20221832//Postgraduate Science and Technology Project of North University of China/ ; }, abstract = {As important geospatial data, point cloud collected from an aerial laser scanner (ALS) provides three-dimensional (3D) information for the study of the distribution of typical urban land cover, which is critical in the construction of a "digital city". However, existing point cloud classification methods usually use a single machine learning classifier that experiences uncertainty in making decisions for fuzzy samples in confusing areas. This limits the improvement of classification accuracy. To take full advantage of different classifiers and reduce uncertainty, we propose a classification method based on possibility theory and multi-classifier fusion. Firstly, the feature importance measure was performed by the XGBoost algorithm to construct a feature space, and two commonly used support vector machines (SVMs) were the chosen base classifiers. Then, classification results from the two base classifiers were quantitatively evaluated to define the confusing areas in classification. Finally, the confidence degree of each classifier for different categories was calculated by the confusion matrix and normalized to obtain the weights. Then, we synthesize different classifiers based on possibility theory to achieve more accurate classification in the confusion areas. DALES datasets were utilized to assess the proposed method. The results reveal that the proposed method can significantly improve classification accuracy in confusing areas.}, } @article {pmid37960974, year = {2023}, author = {Li, M and Liao, Y and Luo, Z and Song, H and Yang, Z}, title = {Work-related factors and risk of amyotrophic lateral sclerosis: A multivariable Mendelian randomization study.}, journal = {Brain and behavior}, volume = {13}, number = {12}, pages = {e3317}, pmid = {37960974}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Smoking ; Tobacco Smoking ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: The causal relationship between work-related factors and amyotrophic lateral sclerosis (ALS) is unclear. We used a Mendelian randomization (MR) analysis to investigate the unconfounded association between work-related factors and ALS.

METHODS: Univariable MR analyses were conducted to evaluate the causal effects of work-related factors on ALS. Instrumental variables from the UK Biobank on work-related factors (n = 263,615) were used as proxies. The outcome dataset used ALS (n case = 20,806, n control = 59,804) summary-level data from a large-scale genome-wide association study based on European ancestry. MR analysis used inverse variance weighted (IVW), MR-Egger, and weighted median (WM) to assess causal effects and other methods of MR for sensitivity analysis. Further multivariable MR analyses were performed to explore potential mediating effects.

RESULTS: In univariable MR, IVW methods support evidence that genetically determined job involves heavy manual or physical work (OR = 2.04, 95% CI: 1.26-3.31; p = .004) was associated with an increased risk of ALS, and the WM methods also confirm this result (OR = 2.36, 95% CI: 1.30-4.28; p = .005). No evidence of heterogeneity or horizontal pleiotropy was found in the results. In multivariable MR, the association was absent after adjusting for smoking and blood pressure.

CONCLUSIONS: Our MR analysis results demonstrate the potential causal relationship between jobs that involve heavy manual or physical work and ALS, which might be mediated by smoking and high systolic blood pressure.}, } @article {pmid37961353, year = {2023}, author = {Salaikumaran, MR and Gopal, PP}, title = {Rational Design of TDP-43 Derived α-Helical Peptide Inhibitors: an In-Silico Strategy to Prevent TDP-43 Aggregation in Neurodegenerative Disorders.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.10.26.564235}, pmid = {37961353}, issn = {2692-8205}, support = {R01 NS122907/NS/NINDS NIH HHS/United States ; }, abstract = {TDP-43, an essential RNA/DNA-binding protein, is central to the pathology of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Pathological mislocalization and aggregation of TDP-43 disrupts RNA splicing, mRNA stability, and mRNA transport, thereby impairing neuronal function and survival. The formation of amyloid-like TDP-43 filaments is largely facilitated by the destabilization of an α-helical segment within the disordered C-terminal region. In this study, we hypothesized that preventing the destabilization of the α-helical domain could potentially halt the growth of these pathological filaments. To explore this, we utilized a range of in-silico techniques to design and evaluate peptide-based therapeutics. Various pathological TDP-43 amyloid-like filament crystal structures were selected for their potential to inhibit the binding of additional TDP-43 monomers to the growing filaments. Our computational approaches included biophysical and secondary structure property prediction, molecular docking, 3D structure prediction, and molecular dynamics simulations. Through these techniques, we were able to assess the structure, stability, and binding affinity of these peptides in relation to pathological TDP-43 filaments. The results of our in-silico analyses identified a selection of promising peptides, which displayed a stable α-helical structure, exhibited an increased number of intramolecular hydrogen bonds within the helical domain, and demonstrated high binding affinities for pathological TDP-43 amyloid-like filaments. Additionally, molecular dynamics simulations provided further support for the stability of these peptides, as they exhibited lower root mean square deviations in their helical propensity over 100ns. These findings establish α-helical propensity peptides as potential lead molecules for the development of novel therapeutics against TDP-43 aggregation. This structure-based computational approach for rational design of peptide inhibitors opens a new direction in the search for effective interventions for ALS, FTD, and other related neurodegenerative diseases. The peptides identified as the most promising candidates in this study are currently subject to further testing and validation through both in vitro and in vivo experiments.}, } @article {pmid37961424, year = {2023}, author = {Johnson, CN and Sojitra, KA and Sohn, EJ and Moreno-Romero, AK and Baudin, A and Xu, X and Mittal, J and Libich, DS}, title = {Insights into Molecular Diversity within the FET Family: Unraveling Phase Separation of the N-Terminal Low Complexity Domain from RNA-Binding Protein EWS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37961424}, issn = {2692-8205}, support = {R01 GM136917/GM/NIGMS NIH HHS/United States ; R01 GM140127/GM/NIGMS NIH HHS/United States ; }, abstract = {The FET family proteins, which includes FUS, EWS, and TAF15, are RNA chaperones instrumental in processes such as mRNA maturation, transcriptional regulation, and the DNA damage response. These proteins have clinical significance: chromosomal rearrangements in FET proteins are implicated in Ewing family tumors and related sarcomas. Furthermore, point mutations in FUS and TAF15 are associated with neurodegenerative conditions like amyotrophic lateral sclerosis and frontotemporal lobar dementia. The fusion protein EWS::FLI1, the causative mutation of Ewing sarcoma, arises from a genomic translocation that fuses the low-complexity domain (LCD) of EWS (EWS[LCD]) with the DNA binding domain of the ETS transcription factor FLI1. This fusion not only alters transcriptional programs but also hinders native EWS functions like splicing. However, the precise function of the intrinsically disordered EWS[LCD] is still a topic of active investigation. Due to its flexible nature, EWS[LCD] can form transient interactions with itself and other biomolecules, leading to the formation of biomolecular condensates through phase separation - a mechanism thought to be central to the oncogenicity of EWS::FLI1. In our study, we used paramagnetic relaxation enhancement NMR, analytical ultracentrifugation, light microscopy, and all-atom molecular dynamics (MD) simulations to better understand the self-association and phase separation tendencies of EWS[LCD]. Our aim was to elucidate the molecular events that underpin EWS[LCD]-mediated biomolecular condensation. Our NMR data suggest tyrosine residues primarily drive the interactions vital for EWS[LCD] phase separation. Moreover, a higher density and proximity of tyrosine residues amplify the likelihood of condensate formation. Atomistic MD simulations and hydrodynamic experiments revealed that the tyrosine-rich N and C-termini tend to populate compact conformations, establishing unique contact networks, that are connected by a predominantly extended, tyrosine-depleted, linker region. MD simulations provide critical input on the relationship between contacts formed within a single molecule (intramolecular) and inside the condensed phase (intermolecular), and changes in protein conformations upon condensation. These results offer deeper insights into the condensate-forming abilities of the FET proteins and highlights unique structural and functional nuances between EWS and its counterparts, FUS and TAF15.}, } @article {pmid37961916, year = {2023}, author = {Joilin, G and Hafezparast, M}, title = {A case for non-coding RNA as a suitable biomarker of amyotrophic lateral sclerosis.}, journal = {Expert review of molecular diagnostics}, volume = {23}, number = {12}, pages = {1049-1051}, doi = {10.1080/14737159.2023.2283522}, pmid = {37961916}, issn = {1744-8352}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Biomarkers ; RNA, Untranslated ; }, } @article {pmid37962258, year = {2024}, author = {Nowakowska-Kotas, M and Korbecki, A and Budrewicz, S and Bladowska, J}, title = {Investigation of cerebellar damage in adult amyotrophic lateral sclerosis patients using magnetic resonance imaging and diffusion tensor imaging.}, journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University}, volume = {33}, number = {9}, pages = {1023-1028}, doi = {10.17219/acem/172698}, pmid = {37962258}, issn = {1899-5276}, mesh = {Humans ; Female ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Diffusion Tensor Imaging/methods ; Retrospective Studies ; Aged ; *Cerebellum/diagnostic imaging/pathology ; Adult ; Magnetic Resonance Imaging/methods ; }, abstract = {BACKGROUND: Research on amyotrophic lateral sclerosis (ALS) reveals that the disorder is not restricted to motor neurons.

OBJECTIVES: This neuroimaging study aimed to investigate the presence of cerebellar damage in adult ALS patients.

MATERIAL AND METHODS: The study retrospectively analyzed magnetic resonance imaging (MRI) examinations performed on a 1.5T MR unit of 33 patients (17 men and 16 women with a mean age of 59.3 years) diagnosed with ALS. Cerebellar and posterior fossa dimensions were calculated using plain MR images. In addition, diffusion tensor imaging (DTI) was used to obtain white matter integrity measurements, represented as fractional anisotropy (FA) values, in the posterior limbs of internal capsules (PLIC) and middle cerebellar peduncles (MCPs). These measurements were compared to 36 healthy volunteers (11 men and 25 women with a mean age of 55.3 years). The study also assessed clinical data for correlations with cerebellar imaging findings.

RESULTS: The linear measurements of the cerebellum did not differ between groups. However, the transverse cerebellar dimension (TCD) ratio to the maximum length of the posterior fossa (0.973 compared to 0.982, t = -2.76, p < 0.01) and FA value in both MCPs (0.67 compared to 0.65 and 0.69 compared to 0.67, p < 0.05) were significantly lower in ALS patients. No significant differences were found in FA value in the PLIC, and no significant correlations were observed between patient clinical characteristics and cerebellar damage.

CONCLUSION: This study provides evidence of cerebellar damage in adult ALS patients. These findings contribute to ALS understanding and highlight the importance of considering cerebellar involvement in the disease process. The results suggest that measuring the TCD ratio and FA value in both MCPs could be potential biomarkers for cerebellar damage in ALS patients.}, } @article {pmid37964005, year = {2023}, author = {Lim, L and Kang, J and Song, J}, title = {Extreme diversity of 12 cations in folding ALS-linked hSOD1 unveils novel hSOD1-dependent mechanisms for Fe[2+]/Cu[2+]-induced cytotoxicity.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19868}, pmid = {37964005}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Cations/chemistry/metabolism ; Copper ; Disulfides/chemistry/metabolism ; *Superoxide Dismutase-1/chemistry/genetics/metabolism ; Zinc ; Protein Folding ; }, abstract = {153-Residue copper-zinc superoxide dismutase 1 (hSOD1) is the first gene whose mutation was linked to FALS. To date, > 180 ALS-causing mutations have been identified within hSOD1, yet the underlying mechanism still remains mysterious. Mature hSOD1 is exceptionally stable constrained by a disulfide bridge to adopt a Greek-key β-barrel fold that accommodates copper/zinc cofactors. Conversely, nascent hSOD1 is unfolded and susceptible to aggregation and amyloid formation, requiring Zn[2+] to initiate folding to a coexistence of folded and unfolded states. Recent studies demonstrate mutations that disrupt Zn[2+]-binding correlate with their ability to form toxic aggregates. Therefore, to decode the role of cations in hSOD1 folding provides not only mechanistic insights, but may bear therapeutic implications for hSOD1-linked ALS. Here by NMR, we visualized the effect of 12 cations: 8 essential for humans (Na[+], K[+], Ca[2+], Zn[2+], Mg[2+], Mn[2+], Cu[2+], Fe[2+]), 3 mimicking zinc (Ni[2+], Cd[2+], Co[2+]), and environmentally abundant Al[3+]. Surprisingly, most cations, including Zn[2+]-mimics, showed negligible binding or induction for folding of nascent hSOD1. Cu[2+] exhibited extensive binding to the unfolded state but led to severe aggregation. Unexpectedly, for the first time Fe[2+] was deciphered to have Zn[2+]-like folding-inducing capacity. Zn[2+] was unable to induce folding of H80S/D83S-hSOD1, while Fe[2+] could. In contrast, Zn[2+] could trigger folding of G93A-hSOD1, but Fe[2+] failed. Notably, pre-existing Fe[2+] disrupted the Zn[2+]-induced folding of G93A-hSOD1. Comparing with the ATP-induced folded state, our findings delineate that hSOD1 maturation requires: (1) intrinsic folding capacity encoded by the sequence; (2) specific Zn[2+]-coordination; (3) disulfide formation and Cu-load catalyzed by hCCS. This study unveils a previously-unknown interplay of cations in governing the initial folding of hSOD1, emphasizing the pivotal role of Zn[2+] in hSOD1-related ALS and implying new hSOD1-dependent mechanisms for Cu[2+]/Fe[2+]-induced cytotoxicity, likely relevant to aging and other diseases.}, } @article {pmid37965583, year = {2023}, author = {Oh, Y}, title = {Editorial: Cell-based neurodegenerative disease modeling.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1323954}, doi = {10.3389/fcell.2023.1323954}, pmid = {37965583}, issn = {2296-634X}, } @article {pmid37966683, year = {2024}, author = {Ansari, MA and Tripathi, T and Venkidasamy, B and Monziani, A and Rajakumar, G and Alomary, MN and Alyahya, SA and Onimus, O and D'souza, N and Barkat, MA and Al-Suhaimi, EA and Samynathan, R and Thiruvengadam, M}, title = {Multifunctional Nanocarriers for Alzheimer's Disease: Befriending the Barriers.}, journal = {Molecular neurobiology}, volume = {61}, number = {5}, pages = {3042-3089}, pmid = {37966683}, issn = {1559-1182}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Animals ; *Drug Carriers/chemistry ; Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism/drug effects ; Nanoparticles/chemistry ; Multifunctional Nanoparticles/chemistry ; }, abstract = {Neurodegenerative diseases (NDDs) have been increasing in incidence in recent years and are now widespread worldwide. Neuronal death is defined as the progressive loss of neuronal structure or function which is closely associated with NDDs and represents the intrinsic features of such disorders. Amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's, Parkinson's, and Huntington's diseases (AD, PD, and HD, respectively) are considered neurodegenerative diseases that affect a large number of people worldwide. Despite the testing of various drugs, there is currently no available therapy that can remedy or effectively slow the progression of these diseases. Nanomedicine has the potential to revolutionize drug delivery for the management of NDDs. The use of nanoparticles (NPs) has recently been developed to improve drug delivery efficiency and is currently subjected to extensive studies. Nanoengineered particles, known as nanodrugs, can cross the blood-brain barrier while also being less invasive compared to the most treatment strategies in use. Polymeric, magnetic, carbonic, and inorganic NPs are examples of NPs that have been developed to improve drug delivery efficiency. Primary research studies using NPs to cure AD are promising, but thorough research is needed to introduce these approaches to clinical use. In the present review, we discussed the role of metal-based NPs, polymeric nanogels, nanocarrier systems such as liposomes, solid lipid NPs, polymeric NPs, exosomes, quantum dots, dendrimers, polymersomes, carbon nanotubes, and nanofibers and surfactant-based systems for the therapy of neurodegenerative diseases. In addition, we highlighted nanoformulations such as N-butyl cyanoacrylate, poly(butyl cyanoacrylate), D-penicillamine, citrate-coated peptide, magnetic iron oxide, chitosan (CS), lipoprotein, ceria, silica, metallic nanoparticles, cholinesterase inhibitors, an acetylcholinesterase inhibitors, metal chelators, anti-amyloid, protein, and peptide-loaded NPs for the treatment of AD.}, } @article {pmid37966813, year = {2024}, author = {Fang, M and Liu, Y and Huang, C and Fan, S}, title = {Targeting stress granules in neurodegenerative diseases: A focus on biological function and dynamics disorders.}, journal = {BioFactors (Oxford, England)}, volume = {50}, number = {3}, pages = {422-438}, doi = {10.1002/biof.2017}, pmid = {37966813}, issn = {1872-8081}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Stress Granules/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Alzheimer Disease/metabolism/pathology/genetics ; Huntington Disease/metabolism/genetics/pathology ; Parkinson Disease/metabolism/pathology/genetics ; Animals ; Frontotemporal Dementia/metabolism/pathology/genetics ; Neurons/metabolism/pathology ; }, abstract = {Stress granules (SGs) are membraneless organelles formed by eukaryotic cells in response to stress to promote cell survival through their pleiotropic cytoprotective effects. SGs recruit a variety of components to enhance their physiological function, and play a critical role in the propagation of pathological proteins, a key factor in neurodegeneration. Recent advances indicate that SG dynamic disorders exacerbate neuronal susceptibility to stress in neurodegenerative diseases (NDs) including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD) and Parkinson's disease (PD). Here, we outline the biological functions of SGs, highlight SG dynamic disorders in NDs, and emphasize therapeutic approaches for enhancing SG dynamics to provide new insights into ND intervention.}, } @article {pmid37966863, year = {2024}, author = {Babcock, CD and Volk, VL and Zeng, W and Hamilton, LD and Shelburne, KB and Fitzpatrick, CK}, title = {Neural-driven activation of 3D muscle within a finite element framework: exploring applications in healthy and neurodegenerative simulations.}, journal = {Computer methods in biomechanics and biomedical engineering}, volume = {27}, number = {16}, pages = {2389-2399}, pmid = {37966863}, issn = {1476-8259}, support = {U01 AR072989/AR/NIAMS NIH HHS/United States ; }, mesh = {Humans ; *Finite Element Analysis ; *Amyotrophic Lateral Sclerosis/physiopathology ; Muscle, Skeletal/physiopathology/physiology ; Computer Simulation ; Models, Biological ; Motor Neurons/physiology ; }, abstract = {This paper presents a novel computational framework for neural-driven finite element muscle models, with an application to amyotrophic lateral sclerosis (ALS). The multiscale neuromusculoskeletal (NMS) model incorporates physiologically accurate motor neurons, 3D muscle geometry, and muscle fiber recruitment. It successfully predicts healthy muscle force and tendon elongation and demonstrates a progressive decline in muscle force due to ALS, dropping from 203 N (healthy) to 155 N (120 days after ALS onset). This approach represents a preliminary step towards developing integrated neural and musculoskeletal simulations to enhance our understanding of neurodegenerative and neurodevelopmental conditions through predictive NMS models.}, } @article {pmid37967220, year = {2023}, author = {Watanabe, S and Murata, Y and Oka, Y and Oiwa, K and Horiuchi, M and Iguchi, Y and Komine, O and Sobue, A and Katsuno, M and Ogi, T and Yamanaka, K}, title = {Mitochondria-associated membrane collapse impairs TBK1-mediated proteostatic stress response in ALS.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {47}, pages = {e2315347120}, pmid = {37967220}, issn = {1091-6490}, support = {17H04986 23K06826//Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 18H02740 18H04860 19KK0214 22H00467//Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; JP21ek0109426 JP23wm0425014//Japan Agency for Medical Research and Development (AMED)/ ; //Uehara Memorial Foundation (UMF)/ ; //Public Foundation of Chubu Science and Technology Center (CSTC)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Endoplasmic Reticulum/metabolism ; Protein Serine-Threonine Kinases/genetics/metabolism ; }, abstract = {The organelle contact site of the endoplasmic reticulum and mitochondria, known as the mitochondria-associated membrane (MAM), is a multifunctional microdomain in cellular homeostasis. We previously reported that MAM disruption is a common pathological feature in amyotrophic lateral sclerosis (ALS); however, the precise role of MAM in ALS was uncovered. Here, we show that the MAM is essential for TANK-binding kinase 1 (TBK1) activation under proteostatic stress conditions. A MAM-specific E3 ubiquitin ligase, autocrine motility factor receptor, ubiquitinated nascent proteins to activate TBK1 at the MAM, which results in ribosomal protein degradation. MAM or TBK1 deficiency under proteostatic stress conditions resulted in increased cellular vulnerability in vitro and motor impairment in vivo. Thus, MAM disruption exacerbates proteostatic stress via TBK1 inactivation in ALS. Our study has revealed a proteostatic mechanism mediated by the MAM-TBK1 axis, highlighting the physiological importance of the organelle contact sites.}, } @article {pmid37967511, year = {2023}, author = {Pavey, N and Hannaford, A and Higashihara, M and van den Bos, M and Kiernan, MC and Menon, P and Vucic, S}, title = {Utility of split hand index with different motor unit number estimation techniques in ALS.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {156}, number = {}, pages = {175-182}, doi = {10.1016/j.clinph.2023.09.018}, pmid = {37967511}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Muscle, Skeletal ; Hand ; Area Under Curve ; Action Potentials/physiology ; Electromyography/methods ; }, abstract = {OBJECTIVE: Utility of the split hand index (SI) in amyotrophic lateral sclerosis (ALS) has been reported when using the compound muscle action potential (CMAP) amplitude method (SICMAP amp). A motor unit number index (MUNIX) based SI method (SIMUNIX) was purported to exhibit higher sensitivity. The present study assessed the clinical utility of SI, derived by CMAP amplitude, MUNIX and MScan-MUNE (SIMScanFit-MUNE) methods, in ALS.

METHODS: Sixty-two consecutive patients with neuromuscular symptoms (36 ALS and 26 ALS-mimics) were prospectively recruited. The SI was derived by dividing the product of the CMAP amplitude, MUNIX and MScan-MUNE values recorded over first dorsal interosseous and abductor pollicis brevis by values recorded over abductor digit minimi.

RESULTS: SICMAP amp, SIMUNIX and SIMScanFit-MUNE were significantly reduced in ALS, with SICMAP amp (area under curve (AUC) = 0.801) and SIMScanFit-MUNE (AUC = 0.805) exhibiting greater diagnostic utility than SIMUNIX (AUC = 0.713). SICMAP amp and SIMScanFit-MUNE exhibited significant correlations with clinical measures of functional disability and weakness of intrinsic hand muscles.

CONCLUSIONS: SI differentiated ALS from mimic disorders, with SICMAP amp and SIMScanFit-MUNE exhibiting greater utility.

SIGNIFICANCE: The split hand index represents could serve as a potential diagnostic biomarker in ALS.}, } @article {pmid37967540, year = {2023}, author = {Jalal Jumaah, T and Faal Siahkal, S and Behboodi Moghadam, Z and Ebrahimi, E}, title = {The Effect of Yoga on Maternal Anxiety in Women with Excessive Gestational Weight Gain: A Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {517-524}, doi = {10.1159/000534776}, pmid = {37967540}, issn = {2504-2106}, mesh = {Pregnancy ; Infant, Newborn ; Humans ; Female ; *Yoga ; *Gestational Weight Gain ; Anxiety/therapy ; Iran ; }, abstract = {BACKGROUND: Excessive gestational weight gain (EGWG) and anxiety are comorbid conditions that increase the risk of adverse maternal and neonatal outcomes. This study was conducted to investigate the effect of yoga on the anxiety of women with EGWG.

MATERIALS AND METHODS: This randomized controlled trial was performed on EGWG pregnant women referring to comprehensive health centers in Qom city, Iran, between October 2021 and August 2022. Eighty-eight participants were assigned to the intervention (N = 44) and control (N = 44) groups. The experimental group participated in six sessions of 90-min yoga classes, and the control group only received routine care. Two questionnaires including a demographic information questionnaire and the State-Trait Anxiety Inventory (STAI) questionnaire were used for data collection. Data were analyzed using SPSS software version 22.

RESULTS: The results of this study showed a statistically significant difference between the two groups in terms of trait anxiety (25.84 ± 3.45 vs. 57.38 ± 8.07; p < 0.05) and state anxiety (27.93 ± 3.72 vs. 60.13 ± 8.13; p < 0.05) after intervention. On the other hand, the trait and state anxiety rates were stable in the experimental group before and after intervention, while they increased to the severe form of anxiety in the control group (effect size = -21.84 ± 10.66 vs. -19.43 ± 8.44).

CONCLUSION: The result of this study showed that yoga has a positive effect on the anxiety of pregnant women with EGWG and can be used as a preventive or complementary solution to control the anxiety of these mothers.

UNLABELLED: HintergrundExzessive Gewichtszunahme in der Schwangerschaft (EGWG) und Angst sind Komorbiditäten, die das Risiko für einen ungünstigen Verlauf für Mutter und Kind erhöhen. Diese Studie wurde durchgeführt, um die Auswirkung von Yoga auf Angst bei Frauen mit exzessiver Gewichtszunahme in der Schwangerschaft zu untersuchen.Material und MethodenDiese randomisierte, kontrollierte Studie wurde bei Schwangeren mit EGWG durchgeführt, die sich zwischen Oktober 2021 und August 2022 an Zentren für ganzheitliche Gesundheit in der Stadt Ghom im Iran vorstellten. 88 Teilnehmerinnen wurden einer Interventions- (N = 44) und einer Kontrollgruppe (N = 44) zugeteilt. Die experimentelle Gruppe nahm an einem Yogakurs von sechsmal 90 minuten Dauer teil, die Kontrollgruppe erhielt lediglich die Standardversorgung. Die Datenerhebung erfolgte mit zwei Fragebögen: einem Fragebogen zu demografischen Angaben und dem State-Trait-Angstinventar (STAI). Die Auswertung der Daten erfolgte mit SPSS-Software, Version 22.ErgebnisseDie Ergebnisse dieser Studie zeigten einen statistisch signifikanten Unterschied zwischen beiden Gruppen im Hinblick auf Eigenschaftsangst (25.84 ± 3.45 vs. 57.38 ± 8.07; p < 0.05) und Zustandsangst (27.93 ± 3.72 vs. 60.13 ± 8.13; p < 0.05) nach der Intervention. Auf der anderen Seite waren die Raten von Eigenschafts- und Zustandsangst in der experimentellen Gruppe vor und nach der Intervention stabil, während sie in der Kontrollgruppe zur schweren Form von Angst anstiegen (Effektstärke = −21.84 ± 10.66 vs. −19.43 ± 8.44).SchlussfolgerungDie Ergebnisse dieser Studie zeigen, dass Yoga sich bei Schwangeren mit EGWG positive auf Angst auswirkt und als präventive oder komplementäre Lösung zur Beherrschung von Angst bei diesen Müttern eingesetzt werden kann.}, } @article {pmid37968324, year = {2023}, author = {Beni, T and Borselli, D and Bonechi, L and Lombardi, L and Gonzi, S and Melelli, L and Turchetti, MA and Fanò, L and D'Alessandro, R and Gigli, G and Casagli, N}, title = {Laser scanner and UAV digital photogrammetry as support tools for cosmic-ray muon radiography applications: an archaeological case study from Italy.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19983}, pmid = {37968324}, issn = {2045-2322}, abstract = {The use of light detection and ranging technologies, i.e. terrestrial laser scanner (TLS), airborne laser scanner (ALS) and mobile laser scanner (MLS), together with the unmanned aerial vehicles digital photogrammetry (UAV-DP) and satellite data are proving to be fundamental tools to carry out reliable muographic measurement campaigns. The main purpose of this paper is to propose a workflow to correctly plan and exploit these types of data for muon radiography aims. To this end, a real case study is presented: searching for hidden tombs in the Etruscan necropolis of Palazzone (Umbria, Italy). A high-resolution digital elevation model (DEM) and three-dimensional models of the ground surface/sub-surface of the study area were created by merging data obtained using different survey methods to achieve the most accurate three-dimensional environment. Indeed, the simulated muon flux transmission used to infer relative transmission values, and the estimated density distribution, depends on the reliability of the three-dimensional reconstructed ground surface model. The aim of this study is to provide knowledge on the use of TLS and UAV-DP data and GPS-acquired points within the transmission-based muography process and how these data could improve or worsen the muon imaging results. Moreover, this study confirmed that muography applications require a multidisciplinary approach.}, } @article {pmid37968433, year = {2024}, author = {Quattrocchi, S and Bonan, L and Cirillo, L and Avoni, P and Di Stasi, V and Rizzo, G and Liguori, R and Vacchiano, V}, title = {Bibrachial amyotrophy as a rare manifestation of intraspinal fluid collection: a case report and systematic review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {2279-2288}, pmid = {37968433}, issn = {1590-3478}, mesh = {Humans ; Male ; Middle Aged ; *Magnetic Resonance Imaging ; Electromyography ; Motor Neuron Disease/diagnosis/complications ; }, abstract = {INTRODUCTION: Intraspinal cerebrospinal fluid (CSF) collection has been reported as a rare cause of lower motor neuron (LMN) disorder. We report a case of bibrachial diplegia associated with intraspinal CSF collection and perform a systematic literature review.

PATIENT AND METHODS: A 52-year-old man developed a bibrachial amyotrophy over 6 years, confirmed by the presence of cervical subacute neurogenic changes at electromyography (EMG). Brain magnetic resonance imaging (MRI) revealed cerebral siderosis, while spine MRI showed a ventral longitudinal intraspinal fluid collection (VLISFC) from C2 to L2. No CSF leakage was localized at myelography; a conservative treatment was chosen. We searched for all published cases until 30th April 2023 and extrapolated data of 44 patients reported in 27 publications.

RESULTS: We observed a male predominance, a younger disease onset compared to amyotrophic lateral sclerosis, and a quite long disease duration, highlighting a slow disease progression. LMN signs were more frequently bilateral, mostly involving C5-C6 myotomes. Around 61% of patients presented additional symptoms, but only three referred to a history of headache. Accordingly, CSF opening pressure was mostly normal. Spinal MRI revealed the presence of VLISFC and in some cases myelomalacia. EMG patterns displayed both chronic and subacute neurogenic change in the cervical region. The disease course mainly depended on the treatment choice, which was mostly represented by a surgical approach when a specific dural defect was detected by imaging.

CONCLUSION: Bibrachial diplegia due to VLISFC can be a treatable cause of focal amyotrophy and presents some clinical and radiological "red flags" which cannot be missed by a clinical neurologist.}, } @article {pmid37971544, year = {2024}, author = {Fergany, A and Zong, C and Ekuban, FA and Wu, B and Ueha, S and Shichino, S and Matsushima, K and Iwakura, Y and Ichihara, S and Ichihara, G}, title = {Transcriptome analysis of the cerebral cortex of acrylamide-exposed wild-type and IL-1β-knockout mice.}, journal = {Archives of toxicology}, volume = {98}, number = {1}, pages = {181-205}, pmid = {37971544}, issn = {1432-0738}, support = {17H06396//Japan Society for the Promotion of Science London/ ; 19H04279//Japan Society for the Promotion of Science London/ ; }, mesh = {Animals ; Mice ; *Acrylamide/toxicity ; Brain ; Cerebral Cortex ; Gene Expression Profiling ; Mice, Inbred C57BL ; *Neurotoxicity Syndromes/genetics ; Interleukin-1beta ; }, abstract = {Acrylamide is an environmental electrophile that has been produced in large amounts for many years. There is concern about the adverse health effects of acrylamide exposure due to its widespread industrial use and also presence in commonly consumed foods and others. IL-1β is a key cytokine that protects the brain from inflammatory insults, but its role in acrylamide-induced neurotoxicity remains unknown. We reported recently that deletion of IL-1β gene exacerbates ACR-induced neurotoxicity in mice. The aim of this study was to identify genes or signaling pathway(s) involved in enhancement of ACR-induced neurotoxicity by IL-1β gene deletion or ACR-induced neurotoxicity to generate a hypothesis mechanism explaining ACR-induced neurotoxicity. C57BL/6 J wild-type and IL-1β KO mice were exposed to ACR at 0, 12.5, 25 mg/kg by oral gavage for 7 days/week for 4 weeks, followed by extraction of mRNA from mice cerebral cortex for RNA sequence analysis. IL-1β deletion altered the expression of genes involved in extracellular region, including upregulation of PFN1 gene related to amyotrophic lateral sclerosis and increased the expression of the opposite strand of IL-1β. Acrylamide exposure enhanced mitochondria oxidative phosphorylation, synapse and ribosome pathways, and activated various pathways of different neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, Huntington disease, and prion disease. Protein network analysis suggested the involvement of different proteins in related to learning and cognitive function, such as Egr1, Egr2, Fos, Nr4a1, and Btg2. Our results identified possible pathways involved in IL-1β deletion-potentiated and ACR-induced neurotoxicity in mice.}, } @article {pmid37972860, year = {2023}, author = {Rizzuti, M and Sali, L and Melzi, V and Scarcella, S and Costamagna, G and Ottoboni, L and Quetti, L and Brambilla, L and Papadimitriou, D and Verde, F and Ratti, A and Ticozzi, N and Comi, GP and Corti, S and Gagliardi, D}, title = {Genomic and transcriptomic advances in amyotrophic lateral sclerosis.}, journal = {Ageing research reviews}, volume = {92}, number = {}, pages = {102126}, doi = {10.1016/j.arr.2023.102126}, pmid = {37972860}, issn = {1872-9649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Transcriptome/genetics ; Gene Expression Profiling/methods ; *MicroRNAs/genetics/metabolism ; Biomarkers ; Epigenomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. ALS shows substantial clinical and molecular heterogeneity. In vitro and in vivo models coupled with multiomic techniques have provided important contributions to unraveling the pathomechanisms underlying ALS. To date, despite promising results and accumulating knowledge, an effective treatment is still lacking. Here, we provide an overview of the literature on the use of genomics, epigenomics, transcriptomics and microRNAs to deeply investigate the molecular mechanisms developing and sustaining ALS. We report the most relevant genes implicated in ALS pathogenesis, discussing the use of different high-throughput sequencing techniques and the role of epigenomic modifications. Furthermore, we present transcriptomic studies discussing the most recent advances, from microarrays to bulk and single-cell RNA sequencing. Finally, we discuss the use of microRNAs as potential biomarkers and promising tools for molecular intervention. The integration of data from multiple omic approaches may provide new insights into pathogenic pathways in ALS by shedding light on diagnostic and prognostic biomarkers, helping to stratify patients into clinically relevant subgroups, revealing novel therapeutic targets and supporting the development of new effective therapies.}, } @article {pmid37972988, year = {2024}, author = {Ando, T and Riku, Y and Akagi, A and Miyahara, H and Uematsu, T and Aiba, I and Sone, J and Katsuno, M and Yoshida, M and Iwasaki, Y}, title = {Degeneration of olivospinal tract in the upper cervical spinal cord of multiple system atrophy patients: Reappraisal of Helweg's triangular tract.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {3}, pages = {e13226}, pmid = {37972988}, issn = {1750-3639}, support = {//Health, Labor, and Welfare Sciences Research Grants/ ; 30-8//Intramural Research Grant for Neurological and Psychiatric Disorders from the NCNP/ ; JP22wm0425019//Japan Agency for Medical Research and Development/ ; JP23K06935//JSPS KAKENHI/ ; //The HORI Science and Arts Foundation/ ; NFRCH 23-0002//The Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital Research Grant/ ; //The Ministry of Health, Labor, and Welfare, Japan/ ; //The Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases/ ; }, mesh = {Adult ; Humans ; *Multiple System Atrophy/metabolism ; alpha-Synuclein/metabolism ; *Cervical Cord/metabolism ; *Olivopontocerebellar Atrophies ; }, abstract = {Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder that presents with variable combinations of autonomic dysfunction, cerebellar ataxia, parkinsonism, and pyramidal signs. The inferior olivary nucleus is targeted in MSA, with a phenotype of olivopontocerebellar atrophy in particular, and involvement of the olivocerebellar tract is well known. However, degeneration of the olivospinal tract has not been studied in MSA. We examined 97 spinal cords from consecutively autopsied patients with MSA. Myelin staining revealed that 22 cords (22.7%) had small, bilateral, triangular-shaped tract degeneration in the boundary of the anterior and lateral funiculi, which appeared continuously from C1 to C5. The anatomical pathway of the degenerated tract was consistent with the description of the olivospinal tract provided by Helweg in 1888. The MSA patients showing degeneration of this tract were younger at disease onset (average: 56.4 ± 8.7 years, range: 42-74), and had longer disease duration (average: 10.1 ± 4.8 years, range: 2-25) and more severe olivopontocerebellar changes compared to other MSA patients. Quantitative analyses revealed that patients with olivospinal tract degeneration had a lower neuronal density in the inferior olivary nucleus compared to other patients. Microglial density in this tract was negatively correlated with the neuronal density in the inferior olivary nucleus. The densities of glial cytoplasmic inclusions in the inferior olivary nucleus and in the olivospinal tract were strongly correlated with each other. Neurologically healthy controls (n = 22) and disease controls with Lewy body disease (n = 30), amyotrophic lateral sclerosis (n = 30), and progressive supranuclear palsy (n = 30) did not present the olivospinal tract degeneration. Our results indicate an impairment of the neural connection between the inferior olivary nucleus and the spinal cord in MSA patients, which may develop in a descending manner.}, } @article {pmid37973064, year = {2024}, author = {Lisi, E and Abellan, JJ}, title = {Statistical analysis of actigraphy data with generalised additive models.}, journal = {Pharmaceutical statistics}, volume = {23}, number = {3}, pages = {308-324}, doi = {10.1002/pst.2350}, pmid = {37973064}, issn = {1539-1612}, support = {//GlaxoSmithKline/ ; }, mesh = {Humans ; *Actigraphy/statistics & numerical data/methods ; *Models, Statistical ; Exercise/physiology ; Data Interpretation, Statistical ; Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Pulmonary Disease, Chronic Obstructive/physiopathology/diagnosis ; Time Factors ; }, abstract = {There is a growing interest in the use of physical activity data in clinical studies, particularly in diseases that limit mobility in patients. High-frequency data collected with digital sensors are typically summarised into actigraphy features aggregated at epoch level (e.g., by minute). The statistical analysis of such volume of data is not straightforward. The general trend is to derive metrics, capturing specific aspects of physical activity, that condense (say) a week worth of data into a single numerical value. Here we propose to analyse the entire time-series data using Generalised Additive Models (GAMs). GAMs are semi-parametric models that allow inclusion of both parametric and non-parametric terms in the linear predictor. The latter are smooth terms (e.g., splines) and, in the context of actigraphy minute-by-minute data analysis, they can be used to assess daily patterns of physical activity. This in turn can be used to better understand changes over time in longitudinal studies as well as to compare treatment groups. We illustrate the application of GAMs in two clinical studies where actigraphy data was collected: a non-drug, single-arm study in patients with amyotrophic lateral sclerosis, and a physical-activity sub-study included in a phase 2b clinical trial in patients with chronic obstructive pulmonary disease.}, } @article {pmid37973672, year = {2023}, author = {Lo Giudice, M and Cocco, A and Reggiardo, G and Lalli, S and Albanese, A}, title = {Tauro-Urso-Deoxycholic Acid Trials in Amyotrophic Lateral Sclerosis: What is Achieved and What to Expect.}, journal = {Clinical drug investigation}, volume = {43}, number = {12}, pages = {893-903}, pmid = {37973672}, issn = {1179-1918}, support = {755094//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Phenylbutyrates ; Taurochenodeoxycholic Acid/adverse effects ; }, abstract = {Phase II studies on tauro-urso-deoxycholic acid (TUDCA) raised the promise of safety and efficacy in patients with amyotrophic lateral sclerosis, a currently incurable and devastating disease. We review the available evidence on the efficacy and safety of TUDCA, administered alone or in combination, by analyzing and comparing published and ongoing studies on amyotrophic lateral sclerosis. Two independent phase II studies (using TUDCA solo or combined with sodium phenylbutyrate) showed similar efficacy in slowing disease progression measured by functional scales. One open-label follow-up TUDCA+sodium phenylbutyrate study suggested a benefit on survival. Two subsequent phase III studies with TUDCA (solo or combined with sodium phenylbutyrate) have been initiated and are currently ongoing. Their completion is expected by the end of 2023 and beginning of 2024. Evidence collected by phase II studies indicates that there are no safety concerns in patients with amyotrophic lateral sclerosis. The efficacy shown in phase II studies was considered sufficient to grant approval in some countries but not in others, owing to discrepant views on the strength of evidence. It will be necessary to wait for the results of ongoing phase III studies to attain a full appreciation of these data.}, } @article {pmid37974227, year = {2023}, author = {Awuah, WA and Ahluwalia, A and Ghosh, S and Roy, S and Tan, JK and Adebusoye, FT and Ferreira, T and Bharadwaj, HR and Shet, V and Kundu, M and Yee, ALW and Abdul-Rahman, T and Atallah, O}, title = {The molecular landscape of neurological disorders: insights from single-cell RNA sequencing in neurology and neurosurgery.}, journal = {European journal of medical research}, volume = {28}, number = {1}, pages = {529}, pmid = {37974227}, issn = {2047-783X}, mesh = {Humans ; *Neurosurgery ; Neurosurgical Procedures ; *Neurology ; *Brain Neoplasms/genetics ; Sequence Analysis, RNA ; Tumor Microenvironment ; }, abstract = {Single-cell ribonucleic acid sequencing (scRNA-seq) has emerged as a transformative technology in neurological and neurosurgical research, revolutionising our comprehension of complex neurological disorders. In brain tumours, scRNA-seq has provided valuable insights into cancer heterogeneity, the tumour microenvironment, treatment resistance, and invasion patterns. It has also elucidated the brain tri-lineage cancer hierarchy and addressed limitations of current models. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis have been molecularly subtyped, dysregulated pathways have been identified, and potential therapeutic targets have been revealed using scRNA-seq. In epilepsy, scRNA-seq has explored the cellular and molecular heterogeneity underlying the condition, uncovering unique glial subpopulations and dysregulation of the immune system. ScRNA-seq has characterised distinct cellular constituents and responses to spinal cord injury in spinal cord diseases, as well as provided molecular signatures of various cell types and identified interactions involved in vascular remodelling. Furthermore, scRNA-seq has shed light on the molecular complexities of cerebrovascular diseases, such as stroke, providing insights into specific genes, cell-specific expression patterns, and potential therapeutic interventions. This review highlights the potential of scRNA-seq in guiding precision medicine approaches, identifying clinical biomarkers, and facilitating therapeutic discovery. However, challenges related to data analysis, standardisation, sample acquisition, scalability, and cost-effectiveness need to be addressed. Despite these challenges, scRNA-seq has the potential to transform clinical practice in neurological and neurosurgical research by providing personalised insights and improving patient outcomes.}, } @article {pmid37974279, year = {2023}, author = {Pelaez, MC and Desmeules, A and Gelon, PA and Glasson, B and Marcadet, L and Rodgers, A and Phaneuf, D and Pozzi, S and Dutchak, PA and Julien, JP and Sephton, CF}, title = {Neuronal dysfunction caused by FUSR521G promotes ALS-associated phenotypes that are attenuated by NF-κB inhibition.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {182}, pmid = {37974279}, issn = {2051-5960}, support = {RGPIN-2020-06376//Natural Sciences and Engineering Research Council of Canada/ ; DGECR-2020-00060//Natural Sciences and Engineering Research Council of Canada/ ; RGPIN-2018-06227//Natural Sciences and Engineering Research Council of Canada/ ; DGECR-2018-00093//Natural Sciences and Engineering Research Council of Canada/ ; Junior 1//Fonds de Recherche du Québec - Santé/ ; }, mesh = {Aged ; Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; Disease Progression ; *Frontotemporal Dementia/pathology ; Mice, Transgenic ; Motor Neurons/metabolism ; Mutation ; NF-kappa B/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative diseases that belong to a common disease spectrum based on overlapping clinical, pathological and genetic evidence. Early pathological changes to the morphology and synapses of affected neuron populations in ALS/FTD suggest a common underlying mechanism of disease that requires further investigation. Fused in sarcoma (FUS) is a DNA/RNA-binding protein with known genetic and pathological links to ALS/FTD. Expression of ALS-linked FUS mutants in mice causes cognitive and motor defects, which correlate with loss of motor neuron dendritic branching and synapses, in addition to other pathological features of ALS/FTD. The role of ALS-linked FUS mutants in causing ALS/FTD-associated disease phenotypes is well established, but there are significant gaps in our understanding of the cell-autonomous role of FUS in promoting structural changes to motor neurons, and how these changes relate to disease progression. Here we generated a neuron-specific FUS-transgenic mouse model expressing the ALS-linked human FUSR521G variant, hFUS[R521G/Syn1], to investigate the cell-autonomous role of FUSR521G in causing loss of dendritic branching and synapses of motor neurons, and to understand how these changes relate to ALS-associated phenotypes. Longitudinal analysis of mice revealed that cognitive impairments in juvenile hFUS[R521G/Syn1] mice coincide with reduced dendritic branching of cortical motor neurons in the absence of motor impairments or changes in the neuromorphology of spinal motor neurons. Motor impairments and dendritic attrition of spinal motor neurons developed later in aged hFUS[R521G/Syn1] mice, along with FUS cytoplasmic mislocalisation, mitochondrial abnormalities and glial activation. Neuroinflammation promotes neuronal dysfunction and drives disease progression in ALS/FTD. The therapeutic effects of inhibiting the pro-inflammatory nuclear factor kappa B (NF-κB) pathway with an analog of Withaferin A, IMS-088, were assessed in symptomatic hFUS[R521G/Syn1] mice and were found to improve cognitive and motor function, increase dendritic branches and synapses of motor neurons, and attenuate other ALS/FTD-associated pathological features. Treatment of primary cortical neurons expressing FUSR521G with IMS-088 promoted the restoration of dendritic mitochondrial numbers and mitochondrial activity to wild-type levels, suggesting that inhibition of NF-κB permits the restoration of mitochondrial stasis in our models. Collectively, this work demonstrates that FUSR521G has a cell-autonomous role in causing early pathological changes to dendritic and synaptic structures of motor neurons, and that these changes precede motor defects and other well-known pathological features of ALS/FTD. Finally, these findings provide further support that modulation of the NF-κB pathway in ALS/FTD is an important therapeutic approach to attenuate disease.}, } @article {pmid37974959, year = {2023}, author = {Bhargava, S and Kulkarni, R and Dewangan, B and Kulkarni, N and Jiaswar, C and Kumar, K and Kumar, A and Bodhe, PR and Kumar, H and Sahu, B}, title = {Microtubule stabilising peptides: new paradigm towards management of neuronal disorders.}, journal = {RSC medicinal chemistry}, volume = {14}, number = {11}, pages = {2192-2205}, pmid = {37974959}, issn = {2632-8682}, abstract = {Neuronal cells made of soma, axon, and dendrites are highly compartmentalized and possess a specialized transport system that can convey long-distance electrical signals for the cross-talk. The transport system is made up of microtubule (MT) polymers and MT-binding proteins. MTs play vital and diverse roles in various cellular processes. Therefore, defects and dysregulation of MTs and their binding proteins lead to many neurological disorders as exemplified by Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and many others. MT-stabilising agents (MSAs) altering the MT-associated protein connections have shown great potential for several neurodegenerative disorders. Peptides are an important class of molecules with high specificity, biocompatibility and are devoid of side effects. In the past, peptides have been explored in various neuronal disorders as therapeutics. Davunetide, a MT-stabilising octapeptide, has entered into phase II clinical trials for schizophrenia. Numerous examples of peptides emerging as MSAs reflect the emergence of a new paradigm for peptides which can be explored further as drug candidates for neuronal disorders. Although small molecule-based MSAs have been reviewed in the past, there is no systematic review in recent years focusing on peptides as MSAs apart from davunetide in 2013. Therefore, a systematic updated review on MT stabilising peptides may shed light on many hidden aspects and enable researchers to develop new therapies for diseases related to the CNS. In this review we have summarised the recent examples of peptides as MSAs.}, } @article {pmid37975189, year = {2024}, author = {Lee, I and Mitsumoto, H and Lee, S and Kasarskis, E and Rosenbaum, M and Factor-Litvak, P and Nieves, JW}, title = {Higher Glycemic Index and Glycemic Load Diet Is Associated with Slower Disease Progression in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {95}, number = {2}, pages = {217-229}, pmid = {37975189}, issn = {1531-8249}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; K23NS131586/NS/NINDS NIH HHS/United States ; R01ES016348/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Cohort Studies ; Glycemic Index ; Prospective Studies ; *Glycemic Load ; Diet ; Disease Progression ; }, abstract = {OBJECTIVE: High-caloric diets may slow the progression of amyotrophic lateral sclerosis; however, key macronutrients have not been identified. We examined whether dietary macronutrients are associated with the rate of progression and length of survival among the prospective cohort study participants.

METHODS: Participants with a confirmed diagnosis of sporadic amyotrophic lateral sclerosis enrolled in the Multicenter Cohort Study of Oxidative Stress were included (n = 304). We evaluated baseline macronutrient intake assessed by food frequency questionnaire in relation to change in revised amyotrophic lateral sclerosis functional rating scale total-score, and tracheostomy-free survival using linear regression and Cox proportional hazard models. Baseline age, sex, disease duration, diagnostic certainty, body mass index, bulbar onset, revised amyotrophic lateral sclerosis functional rating scale total-score, and forced vital capacity were included as covariates.

RESULTS: Baseline higher glycemic index and load were associated with less decline of revised amyotrophic lateral sclerosis functional rating scale total score at 3-month follow-up (β = -0.13, 95% CI -0.2, -0.01, p = 0.03) and (β = -0.01, 95% CI -0.03, -0.0007, p = 0.04), respectively. Glycemic index second-quartile, third-quartile, and fourth-quartile groups were associated with less decline at 3 months by 1.9 (95% CI -3.3, -0.5, p = 0.008), 2.0 (95% CI -3.3, -0.6, p = 0.006), and 1.6 (95% CI -3.0, -0.2, p = 0.03) points compared with the first-quartile group; the glycemic load fourth-quartile group had 1.4 points less decline compared with the first-quartile group (95% CI -2.8, 0.1, p = 0.07). Higher glycemic index was associated with a trend toward longer tracheostomy-free survival (HR 0.97, 95% CI 0.93, 1.00, p = 0.07).

INTERPRETATION: Higher dietary glycemic index and load are associated with slower disease progression in amyotrophic lateral sclerosis. ANN NEUROL 2024;95:217-229.}, } @article {pmid37975411, year = {2025}, author = {Noorbakhsh Varnosfaderani, SM and Sadat Haeri, M and Arian, AS and Yousefi Rad, A and Yazdanpour, M and Mojahedian, F and Yaghoubzad-Maleki, M and Zalpoor, H and Baziyar, P and Nabi-Afjadi, M}, title = {Fighting against amyotrophic lateral sclerosis (ALS) with flavonoids: a computational approach to inhibit superoxide dismutase (SOD1) mutant aggregation.}, journal = {Journal of biomolecular structure & dynamics}, volume = {43}, number = {1}, pages = {419-436}, doi = {10.1080/07391102.2023.2281641}, pmid = {37975411}, issn = {1538-0254}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Flavonoids/pharmacology/chemistry ; Humans ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; *Molecular Dynamics Simulation ; *Mutation ; Protein Aggregates/drug effects ; Molecular Docking Simulation ; Protein Binding ; Hydrogen Bonding ; Protein Aggregation, Pathological/drug therapy/genetics ; Hydrophobic and Hydrophilic Interactions ; Thermodynamics ; }, abstract = {Protein aggregation is a biological process that occurs when proteins misfold. Misfolding and aggregation of human superoxide dismutase (hSOD1) cause a neurodegenerative disease called amyotrophic lateral sclerosis (ALS). Among the mutations occurring, targeting the E21K mutation could be a good choice to understand the pathological mechanism of SOD1 in ALS, whereof it significantly reduces life hopefulness in patients. Naturally occurring polyphenolic flavonoids have been suggested as a way to alleviate the amyloidogenic behavior of proteins. In this study, computational tools were used to identify promising flavonoid compounds that effectively inhibit the pathogenic behavior of the E21K mutant. Initial screening identified Pelargonidin, Curcumin, and Silybin as promising leads. Molecular dynamics (MD) simulations showed that the binding of flavonoids to the mutated SOD1 caused changes in the protein stability, hydrophobicity, flexibility, and restoration of lost hydrogen bonds. Secondary structure analysis indicated that the protein destabilization and the increased propensity of β-sheet caused by the mutation were restored to the wild-type state upon binding of flavonoids. Free energy landscape (FEL) analysis was also used to differentiate aggregation, and results showed that Silybin followed by Pelargonidin had the most therapeutic efficacy against the E21K mutant SOD1. Therefore, these flavonoids hold great potential as highly effective inhibitors in mitigating ALS's fatal and insuperable effects.Communicated by Ramaswamy H. Sarma.}, } @article {pmid37975632, year = {2024}, author = {Fornage, LB and O'Neil, C and Dowker, SR and Wanta, ER and Lewis, RS and Brown, LH}, title = {Prehospital Intervention Improves Outcomes for Patients Presenting in Atrial Fibrillation with Rapid Ventricular Response.}, journal = {Prehospital emergency care}, volume = {28}, number = {7}, pages = {910-919}, doi = {10.1080/10903127.2023.2283885}, pmid = {37975632}, issn = {1545-0066}, support = {R01-HL137964/NH/NIH HHS/United States ; }, mesh = {Humans ; Retrospective Studies ; Male ; Female ; *Atrial Fibrillation/therapy/drug therapy ; Aged ; *Emergency Medical Services/methods ; Middle Aged ; Adult ; Aged, 80 and over ; Adolescent ; Cohort Studies ; Advanced Cardiac Life Support/methods ; Propensity Score ; Out-of-Hospital Cardiac Arrest/therapy/mortality ; Young Adult ; }, abstract = {OBJECTIVE: To compare outcomes of patients presenting to emergency medical services (EMS) with atrial fibrillation with rapid ventricular response (AF-RVR) who did and did not receive prehospital advanced life support (ALS) rate or rhythm control intervention(s).

METHODS: This retrospective cohort study used the 2021 ESO Data Collaborative (Austin, TX) dataset. We identified 9-1-1 scene responses for patients aged 16 to 100 years old presenting with AF and an initial heart rate ≥ 110 beats per minute (bpm). Prehospital ALS interventions for AF-RVR included medications (e.g., calcium channel blockers, beta blockers, etc.) or electrical cardioversion. Outcome measures included prehospital rate control (i.e., final prehospital heart rate < 110 bpm), emergency department (ED) discharge to home, ED and hospital length of stay, and mortality. We also evaluated prehospital adverse events-specifically bradycardia, hypotension, and cardiac arrest. We used propensity score matching to compare outcomes among treated and untreated patients with similar demographic and clinical characteristics. We determined the average treatment effect on the treated (ATET) with 95% confidence intervals (CI) and the number needed to treat (NNT).

RESULTS: After propensity score matching, prehospital outcomes were available for 4,859 treated patients matched with 4,859 similar untreated patients. Prehospital rate control was more frequent for treated than for untreated patients (41.0% vs. 18.2%, ATET +22.8%, CI: +21.1%; +24.6%, NNT = 5). Hospital outcomes were available for 1,347 treated patients matched with 1,347 similar untreated patients. Treated patients were more likely to be discharged from the ED (37.9% vs. 34.0%, ATET +3.9%, CI: +0.2%; +7.5%, NNT = 26) and less likely to die (4.3% vs. 6.7%, ATET -2.5%, CI: -4.2%; -0.8%, NNT = 40) compared to untreated patients. Hypotension occurred more often in treated patients (ATET +2.6%, CI: +1.5%; +3.7%), but resolved before ED arrival in 73% of affected patients. Otherwise, adverse event rates did not significantly differ for the two groups.

CONCLUSIONS: In this propensity score matched study of patients presenting to EMS with AF-RVR, prehospital ALS interventions were associated with more frequent prehospital rate control, more frequent discharge to home from the ED, and lower mortality.}, } @article {pmid37975796, year = {2024}, author = {Witzel, S and Statland, JM and Steinacker, P and Otto, M and Dorst, J and Schuster, J and Barohn, RJ and Ludolph, AC}, title = {Longitudinal course of neurofilament light chain levels in amyotrophic lateral sclerosis-insights from a completed randomized controlled trial with rasagiline.}, journal = {European journal of neurology}, volume = {31}, number = {3}, pages = {e16154}, pmid = {37975796}, issn = {1468-1331}, support = {R01 FD003739/FD/FDA HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Intermediate Filaments ; Biomarkers ; Neurofilament Proteins ; Disease Progression ; *Indans ; }, abstract = {BACKGROUND AND PURPOSE: Rasagiline might be disease modifying in patients with amyotrophic lateral sclerosis (ALS). The aim was to evaluate the effect of rasagiline 2 mg/day on neurofilament light chain (NfL), a prognostic biomarker in ALS.

METHODS: In 65 patients with ALS randomized in a 3:1 ratio to rasagiline 2 mg/day (n = 48) or placebo (n = 17) in a completed randomized controlled multicentre trial, NfL levels in plasma were measured at baseline, month 6 and month 12. Longitudinal changes in NfL levels were evaluated regarding treatment and clinical parameters.

RESULTS: Baseline NfL levels did not differ between the study arms and correlated with disease progression rates both pre-baseline (r = 0.64, p < 0.001) and during the study (r = 0.61, p < 0.001). NfL measured at months 6 and 12 did not change significantly from baseline in both arms, with a median individual NfL change of +1.4 pg/mL (interquartile range [IQR] -5.6, 14.2) across all follow-up time points. However, a significant difference in NfL change at month 12 was observed between patients with high and low NfL baseline levels treated with rasagiline (high [n = 13], -6.9 pg/mL, IQR -20.4, 6.0; low [n = 18], +5.9 pg/mL, IQR -1.4, 19.7; p = 0.025). Additionally, generally higher longitudinal NfL variability was observed in patients with high baseline levels, whereas disease progression rates and disease duration at baseline had no impact on the longitudinal NfL course.

CONCLUSION: Post hoc NfL measurements in completed clinical trials are helpful in interpreting NfL data from ongoing and future interventional trials and could provide hypothesis-generating complementary insights. Further studies are warranted to ultimately differentiate NfL response to treatment from other factors.}, } @article {pmid37975798, year = {2024}, author = {Saini, A and Chawla, PA}, title = {Breaking barriers with tofersen: Enhancing therapeutic opportunities in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {2}, pages = {e16140}, pmid = {37975798}, issn = {1468-1331}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Oligonucleotides/therapeutic use ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects adults, characterized by muscle weakness resulting from the specific death of motor neurons in the spinal cord and brain. The pathogenesis of ALS is associated with the accumulation of mutant superoxide dismutase 1 (SOD1) proteins and neurofilaments in motor neurons, highlighting the critical need for disease-modifying treatments. Current therapies, such as riluzole and edaravone, provide only symptomatic relief. Recently, tofersen gained approval from the US FDA under the brand name Qalsody as the first and only gene therapy for ALS, addressing a significant pathological aspect of the disease.

METHODS: We carried out a literature survey using PubMed, Scopus, National Institutes of Health, and Biogen for articles published in the English language concerned with "amyotrophic lateral sclerosis", pathophysiology, current treatment, treatment under clinical trial, and the newly approved drug "tofersen" and its detailed summary.

RESULTS: A comprehensive review of the literature on the pathophysiology, available treatment, and newly approved drug for this condition revealed convincing evidence that we are now able to better monitor and treat ALS.

CONCLUSIONS: Although treatment of ALS is difficult, the newly approved drug tofersen has emerged as a potential therapy to slow down the progression of ALS by targeting SOD1 mRNA, representing a significant advancement in the treatment of ALS.}, } @article {pmid37976792, year = {2023}, author = {Larsson, BJ and Nordin, K and Nygren, I}, title = {Symptoms of anxiety and depression in patients with amyotrophic lateral sclerosis and their relatives during the disease trajectory.}, journal = {Journal of the neurological sciences}, volume = {455}, number = {}, pages = {122780}, doi = {10.1016/j.jns.2023.122780}, pmid = {37976792}, issn = {1878-5883}, mesh = {Humans ; *Depression/epidemiology/diagnosis ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; Longitudinal Studies ; Prospective Studies ; Anxiety/epidemiology ; }, abstract = {OBJECTS: The aim of this study was to describe the presence of anxiety and depression among patients with Amyotrophic Lateral Sclerosis (ALS) and their relatives from diagnosis and during the disease progression. An additional aim was to explore if the patient's physical function correlated with the patients' or relatives' anxiety and depression.

METHODS: A prospective and longitudinal study, including 33 patients with ALS and their relatives who filled out the Hospital Anxiety and Depression Scale (HADS) at the time of diagnosis and over a period of two years. The patient's physical function was measured with the revised Amyotrophic Lateral Sclerosis Functional and Rating Scale (ALS FRS-R).

RESULTS: The results showed that many patients (45%) and relatives (58%) had symptoms of anxiety and that 13% of the patients and 29% of the relatives had symptoms of depression soon after the patient had been diagnosed with ALS. The prevalence of anxiety decreased over time in the group of patients but remained stable in the group of relatives. Relatives had more symptoms of anxiety compared to patients. There was a correlation between the patient's physical function and HADS in the group of relatives; however, no correlation was found in the group of patients.

CONCLUSION: The results showed that many patients and relatives suffered from symptoms of anxiety quite soon after their diagnosis, and that many relatives had symptoms of anxiety during the disease trajectory. This highlights the need to continuously measure patients' anxiety/depression level but also to pay attention to symptoms among relatives.}, } @article {pmid37977335, year = {2023}, author = {Benussi, A and Cantoni, V and Grassi, M and Libri, I and Cotelli, MS and Tarantino, B and Datta, A and Thomas, C and Huber, N and Kärkkäinen, S and Herukka, SK and Haapasalo, A and Filosto, M and Padovani, A and Borroni, B}, title = {Cortico-spinal tDCS in amyotrophic lateral sclerosis: A randomized, double-blind, sham-controlled trial followed by an open-label phase.}, journal = {Brain stimulation}, volume = {16}, number = {6}, pages = {1666-1676}, doi = {10.1016/j.brs.2023.11.008}, pmid = {37977335}, issn = {1876-4754}, mesh = {Humans ; *Transcranial Direct Current Stimulation ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; Transcranial Magnetic Stimulation ; Double-Blind Method ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive disease for which no curative treatment is currently available.

OBJECTIVE: This study aimed to investigate whether cortico-spinal transcranial direct current stimulation (tDCS) could mitigate symptoms in ALS patients via a randomized, double-blind, sham-controlled trial, followed by an open-label phase.

METHODS: Thirty-one participants were randomized into two groups for the initial controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS), while Group 2 received cortico-spinal stimulation (real tDCS) for five days/week for two weeks (T1), with an 8-week (T2) follow-up (randomized, double-blind, sham-controlled phase). At the 24-week follow-up (T3), all participants (Groups 1 and 2) received a second treatment of anodal bilateral motor cortex and cathodal spinal stimulation (real tDCS) for five days/week for two weeks (T4). Follow-up evaluations were performed at 32-weeks (T5) and 48-weeks (T6) (open-label phase). At each time point, clinical assessment, blood sampling, and intracortical connectivity measures using transcranial magnetic stimulation (TMS) were evaluated. Additionally, we evaluated survival rates.

RESULTS: Compared to sham stimulation, cortico-spinal tDCS significantly improved global strength, caregiver burden, and quality of life scores, which correlated with the restoration of intracortical connectivity measures. Serum neurofilament light levels decreased among patients who underwent real tDCS but not in those receiving sham tDCS. The number of completed 2-week tDCS treatments significantly influenced patient survival.

CONCLUSIONS: Cortico-spinal tDCS may represent a promising therapeutic and rehabilitative approach for patients with ALS. Further larger-scale studies are necessary to evaluate whether tDCS could potentially impact patient survival.

CLINICAL TRIAL REGISTRATION: NCT04293484.}, } @article {pmid37979250, year = {2024}, author = {Chen, K and Gao, T and Liu, Y and Zhu, K and Wang, T and Zeng, P}, title = {Identifying risk loci for FTD and shared genetic component with ALS: A large-scale multitrait association analysis.}, journal = {Neurobiology of aging}, volume = {134}, number = {}, pages = {28-39}, doi = {10.1016/j.neurobiolaging.2023.09.017}, pmid = {37979250}, issn = {1558-1497}, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Genome-Wide Association Study ; Mutation ; *Pick Disease of the Brain ; Proteins/genetics ; Nuclear Proteins/genetics ; }, abstract = {Current genome-wide association studies of frontotemporal dementia (FTD) are underpowered due to limited samples. Further, common genetic etiologies between FTD and amyotrophic lateral sclerosis (ALS) remain unknown. Using the largest summary statistics of FTD (3526 cases and 9402 controls) and ALS (27,205 cases and 110,881 controls), we found a significant genetic correlation between them (rˆg = 0.637, P = 0.032) and identified 190 FTD-related variants within 5 loci (3p22.1, 5q35.1, 9p21.2, 19p13.11, and 20q13.13). Among these, ALS and FTD had causal variants in 9p21.2 and 19p13.11. Moreover, MOBP (3p22.1), C9orf72 (9p21.2), MOB3B (9p21.2), UNC13A (19p13.11), SLC9A8 (20q13.13), SNAI1 (20q13.13), and SPATA2 (20q13.13) were discovered by both SNP- and gene-level analyses, which together discovered 15 FTD-associated genes, with 10 not detected before (IFNK, RNF114, SLC9A8, SPATA2, SNAI1, SCFD1, POLDIP2, TMEM97, G2E3, and PIGW). Functional analyses showed these genes were enriched in heart left ventricle, kidney cortex, and some brain regions. Overall, this study provides insights into genetic determinants of FTD and shared genetic etiology underlying FTD and ALS.}, } @article {pmid37980296, year = {2024}, author = {He, D and Liu, Y and Dong, S and Shen, D and Yang, X and Hao, M and Yin, X and He, X and Li, Y and Wang, Y and Liu, M and Wang, J and Chen, X and Cui, L}, title = {The prognostic value of systematic genetic screening in amyotrophic lateral sclerosis patients.}, journal = {Journal of neurology}, volume = {271}, number = {3}, pages = {1385-1396}, pmid = {37980296}, issn = {1432-1459}, support = {XDB39040000//Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Prognosis ; *Neurodegenerative Diseases/genetics ; Genetic Association Studies ; Genetic Testing ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with complex genetic architecture. Emerging evidence has indicated comorbidity between ALS and autoimmune conditions, suggesting a potential shared genetic basis. The objective of this study is to assess the prognostic value of systematic screening for rare deleterious mutations in genes associated with ALS and aberrant inflammatory responses.

METHODS: A discovery cohort of 494 patients and a validation cohort of 69 patients were analyzed in this study, with population-matched healthy subjects (n = 4961) served as controls. Whole exome sequencing (WES) was performed to identify rare deleterious variants in 50 ALS genes and 1177 genes associated with abnormal inflammatory responses. Genotype-phenotype correlation was assessed, and an integrative prognostic model incorporating genetic and clinical factors was constructed.

RESULTS: In the discovery cohort, 8.1% of patients carried confirmed ALS variants, and an additional 15.2% of patients carried novel ALS variants. Gene burden analysis revealed 303 immune-implicated genes with enriched rare variants, and 13.4% of patients harbored rare deleterious variants in these genes. Patients with ALS variants exhibited a more rapid disease progression (HR 2.87 [95% CI 2.03-4.07], p < 0.0001), while no significant effect was observed for immune-implicated variants. The nomogram model incorporating genetic and clinical information demonstrated improved accuracy in predicting disease outcomes (C-index, 0.749).

CONCLUSION: Our findings enhance the comprehension of the genetic basis of ALS within the Chinese population. It also appears that rare deleterious mutations occurring in immune-implicated genes exert minimal influence on the clinical trajectories of ALS patients.}, } @article {pmid37981175, year = {2023}, author = {Wang, C and Cui, Y and Xu, T and Zhou, Y and Yang, R and Wang, T}, title = {New insights into glycogen synthase kinase-3: A common target for neurodegenerative diseases.}, journal = {Biochemical pharmacology}, volume = {218}, number = {}, pages = {115923}, doi = {10.1016/j.bcp.2023.115923}, pmid = {37981175}, issn = {1873-2968}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Glycogen Synthase Kinase 3 ; *Parkinson Disease ; *Alzheimer Disease ; *Diabetes Mellitus/drug therapy ; Glycogen Synthase Kinase 3 beta ; }, abstract = {Glycogen synthase kinase 3 (GSK-3) is a highly conserved protein serine/threonine kinase that plays a central role in a wide variety of cellular processes to coordinate catabolic and anabolic pathways and regulate cell growth and fate. There is increasing evidence showing that abnormal glycogen synthase kinase 3 (GSK-3) is associated with the pathogenesis and progression of many disorders, such as cancer, diabetes, psychiatric diseases, and neurodegenerative diseases. In this review, we summarize recent findings about the regulatory role of GSK-3 in the occurrence and development of multiple neurodegenerative diseases, mainly focusing on Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The aim of this study is to provide new insight into the shared working mechanism of GSK-3 as a therapeutic target of multiple neurodegenerative diseases.}, } @article {pmid37981210, year = {2024}, author = {Kim, Y and Lee, Y and Choo, M and Yun, N and Cho, JW and Oh, YJ}, title = {A surge of cytosolic calcium dysregulates lysosomal function and impairs autophagy flux during cupric chloride-induced neuronal death.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {1}, pages = {105479}, pmid = {37981210}, issn = {1083-351X}, mesh = {*Autophagy/drug effects/genetics ; *Calcium/metabolism ; *Copper/pharmacology ; *Dopaminergic Neurons/cytology/drug effects/metabolism/ultrastructure ; *Lysosomes/metabolism ; Animals ; Mice ; Cell Line ; Cell Survival/drug effects ; Cytosol/metabolism ; }, abstract = {Autophagy is a degradative pathway that plays an important role in maintaining cellular homeostasis. Dysfunction of autophagy is associated with the progression of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although one of the typical features of brain aging is an accumulation of redox-active metals that eventually lead to neurodegeneration, a plausible link between trace metal-induced neurodegeneration and dysregulated autophagy has not been clearly determined. Here, we used a cupric chloride-induced neurodegeneration model in MN9D dopaminergic neuronal cells along with ultrastructural and biochemical analyses to demonstrate impaired autophagic flux with accompanying lysosomal dysfunction. We found that a surge of cytosolic calcium was involved in cupric chloride-induced dysregulated autophagy. Consequently, buffering of cytosolic calcium by calbindin-D28K overexpression or co-treatment with the calcium chelator BAPTA attenuated the cupric chloride-induced impairment in autophagic flux by ameliorating dysregulation of lysosomal function. Thus, these events allowed the rescue of cells from cupric chloride-induced neuronal death. These phenomena were largely confirmed in cupric chloride-treated primary cultures of cortical neurons. Taken together, these results suggest that abnormal accumulation of trace metal elements and a resultant surge of cytosolic calcium leads to neuronal death by impairing autophagic flux at the lysosomal level.}, } @article {pmid37981468, year = {2024}, author = {Sutter, PA and Lavoie, ER and Lombardo, ET and Pinter, MK and Crocker, SJ}, title = {Emerging Role of Astrocyte-Derived Extracellular Vesicles as Active Participants in CNS Neuroimmune Responses.}, journal = {Immunological investigations}, volume = {53}, number = {1}, pages = {26-39}, pmid = {37981468}, issn = {1532-4311}, support = {F30 NS129238/NS/NINDS NIH HHS/United States ; R01 NS131327/NS/NINDS NIH HHS/United States ; R21 NS125332/NS/NINDS NIH HHS/United States ; R56 NS099359/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Astrocytes ; *Extracellular Vesicles ; Cell Communication ; Biomarkers ; }, abstract = {Astrocyte-derived extracellular vesicles (ADEVs) have garnered attention as a fundamental mechanism of intercellular communication in health and disease. In the context of neurological diseases, for which prodromal diagnosis would be advantageous, ADEVs are also being explored for their potential utility as biomarkers. In this review, we provide the current state of data supporting our understanding on the manifold roles of ADEVs in several common neurological disorders. We also discuss these findings from a unique emerging perspective that ADEVs represent a means by which the central nervous system may broadcast influence over other systems in the body to affect neuroinflammatory processes, with both dual potential to either propagate illness or restore health and homeostasis.}, } @article {pmid37981575, year = {2024}, author = {Shojaie, A and Al Khleifat, A and Sarraf, P and Al-Chalabi, A}, title = {Analysis of non-motor symptoms in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {237-241}, pmid = {37981575}, issn = {2167-9223}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; Surveys and Questionnaires ; Pain/epidemiology/etiology ; }, abstract = {OBJECTIVE: We investigated non-motor symptoms in ALS using sequential questionnaires; here we report the findings of the second questionnaire.

METHODS: A social media platform (Twitter, now known as X) was used to publicize the questionnaires. Data were downloaded from SurveyMonkey and analyzed by descriptive statistics, comparison of means, and regression models.

RESULTS: There were 182 people with ALS and 57 controls. The most important non-motor symptoms were cold limbs (60.4% cases, 14% controls, p = 9.67 x 10[-10]) and appetite loss (29.7% cases, 5.3% controls, p = 1.6 x 10[-4]). The weaker limb was most likely to feel cold (p = 9.67 x 10[-10]), and symptoms were more apparent in the evening and night. Appetite loss was reported as due to feeling full and the time taken to eat. People with ALS experienced medium-intensity pain, more usually shock-like pain than burning or cold-like pain, although the most prevalent type of pain was non-differentiated.

CONCLUSIONS: Non-motor symptoms are an important feature of ALS. Further investigation is needed to understand their physiological basis and whether they represent phenotypic differences useful for subtyping ALS.}, } @article {pmid37982655, year = {2024}, author = {Mossa, A and Mayahara, M and Emezue, C and Paun, O}, title = {The Impact of Rapidly Progressing Neurodegenerative Disorders on Caregivers: An Integrative Literature Review.}, journal = {Journal of hospice and palliative nursing : JHPN : the official journal of the Hospice and Palliative Nurses Association}, volume = {26}, number = {2}, pages = {E62-E73}, pmid = {37982655}, issn = {1539-0705}, mesh = {Humans ; *Quality of Life ; Caregivers ; *Amyotrophic Lateral Sclerosis ; Disease Progression ; Death ; }, abstract = {Neurodegenerative disorders affect over 6 million people in the United States. A subset of these patients experiences symptoms that progress rapidly, along with a 5- to 10-year life expectancy (amyotrophic lateral sclerosis). This subgroup often becomes dependent on family caregivers. Managing care demands at the end of life that are brought on by rapid disease progression has a negative impact on caregiver quality of life. The purpose of this integrative review is to highlight the gaps in the existing body of research on the effect of neuropalliative care on quality of life of this caregiver population. A total of 13 articles met inclusion criteria and were selected for review. The most frequently occurring themes and findings in the literature shed light on neuropalliative care and provided some insight into both caregivers and patients' perspective at the end of life. What sets this population apart from caregivers and patients of other terminal diseases is the nature of disease progression and the rapid life adjustments that come along with it. Integration of neuropalliative has shown to provide additional support for caregivers and patients; however, it remains underused. To promote equitable access to these services, it is necessary to address several structural barriers.}, } @article {pmid37982993, year = {2023}, author = {Tsui, A and Kouznetsova, VL and Kesari, S and Fiala, M and Tsigelny, IF}, title = {Role of Senataxin in Amyotrophic Lateral Sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {73}, number = {11-12}, pages = {996-1009}, pmid = {37982993}, issn = {1559-1166}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/metabolism ; Gene Expression Regulation ; Mutation ; DNA Helicases/genetics ; RNA Helicases/genetics/metabolism ; Multifunctional Enzymes/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, uncurable neurodegenerative disorder characterized by the degradation of motor neurons leading to muscle impairment, failure, and death. Senataxin, encoded by the SETX gene, is a human helicase protein whose mutations have been linked with ALS onset, particularly in its juvenile ALS4 form. Using senataxin's yeast homolog Sen1 as a model for study, it is suggested that senataxin's N-terminus interacts with RNA polymerase II, whilst its C-terminus engages in helicase activity. Senataxin is heavily involved in transcription regulation, termination, and R-loop resolution, enabled by recruitment and interactions with enzymes such as ubiquitin protein ligase SAN1 and ribonuclease H (RNase H). Senataxin also engages in DNA damage response (DDR), primarily interacting with the exosome subunit Rrp45. The Sen1 mutation E1597K, alongside the L389S and R2136H gain-of-function mutations to senataxin, is shown to cause negative structural and thus functional effects to the protein, thus contributing to a disruption in WT functions, motor neuron (MN) degeneration, and the manifestation of ALS clinical symptoms. This review corroborates and summarizes published papers concerning the structure and function of senataxin as well as the effects of their mutations in ALS pathology in order to compile current knowledge and provide a reference for future research. The findings compiled in this review are indicative of the experimental and therapeutic potential of senataxin and its mutations as a target in future ALS treatment/cure discovery, with some potential therapeutic routes also being discussed in the review.}, } @article {pmid37983563, year = {2024}, author = {Wen, D and Ji, Y and Li, Y and Duan, W and Wang, Y and Li, Z and Tao, M and Liu, Y}, title = {OPTN gene therapy increases autophagy and protects mitochondria in SOD1-G93A-expressing transgenic mice and cells.}, journal = {The FEBS journal}, volume = {291}, number = {4}, pages = {795-813}, doi = {10.1111/febs.17009}, pmid = {37983563}, issn = {1742-4658}, support = {H2021206048//Hebei Natural Science Foundation/ ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; Superoxide Dismutase/genetics/metabolism ; Autophagy/genetics ; Mitochondria/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron (MN) death. Mutation of the superoxide dismutase 1 (SOD1) gene, which results in abnormal protein aggregation, is one of the causes of familial ALS. Autophagic dysfunction occurs in SOD1-G93A mutant mice as the disease progresses, but the etiology of this disease is still unclear. Optineurin (OPTN) is an adaptor that is involved in autophagy and participates in aggrephagy and mitophagy. Previous studies have established that OPTN mutations contribute to diseases such as glaucoma and ALS. However, the function of OPTN in autophagy and mitophagy has not been intensively investigated in models of ALS. In this study, we assessed the beneficial effect of OPTN on autophagy and mitochondrial function by intrathecally injecting adeno-associated virus 9 (AAV9)-OPTN into SOD1-G93A transgenic mice and by administering lentivirus (LV)-OPTN to cells expressing the SOD1-G93A mutant protein. The expression of voltage-dependent anion channel 1 (VDAC1) was increased and autophagy was elevated after OPTN gene therapy, as shown by a lower level of p62 and a higher level of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II. Moreover, using electron microscopy, we observed a hyperpolarized mitochondrial transmembrane potential and reversal of mitochondrial morphological abnormalities. Furthermore, the protein level of TANK-binding kinase 1 (TBK1) was increased, suggesting that mitophagy was increased. Our findings from both animal and cell line studies strongly suggest that OPTN gene therapy is a powerful strategy to increase autophagy and protect mitochondria to prevent the progression of ALS and could be effective in the treatment of ALS.}, } @article {pmid37983951, year = {2024}, author = {Turhan, SA and Karlsson, P and Ozun, Y and Gunes, H and Surucu, S and Toker, E and Isak, B}, title = {Identification of corneal and intra-epidermal axonal swellings in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {69}, number = {1}, pages = {78-86}, doi = {10.1002/mus.27995}, pmid = {37983951}, issn = {1097-4598}, support = {//Novo Nordisk/ ; NNF18OC0052301//PK (Pall Karlsson) is funded by a grant from the Novo Nordisk Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Axons/pathology ; Cornea/innervation ; Skin/pathology ; Nerve Fibers, Unmyelinated/pathology ; Microscopy, Confocal ; }, abstract = {INTRODUCTION/AIMS: In patients with amyotrophic lateral sclerosis (ALS), axonal spheroids in motor axons have been identified in post-mortem studies. In this study, axonal spheroids and swellings on C-fibers of ALS patients were investigated using corneal confocal microscopy (CCM) and skin biopsy, respectively.

METHODS: Thirty-one ALS patients and 20 healthy subjects were evaluated with CCM to assess corneal nerve-fiber length (CNFL), -fiber density (CNFD), -branch density (CNBD), dendritic cell (DC) density, and axonal spheroids originating from C-fibers (>100 μm[2]). In addition, intraepidermal nerve fiber density (IENFD) and axonal swellings (>1.5 μm) were assessed in skin biopsies obtained from the arms and legs of 22 patients and 17 controls.

RESULTS: In ALS patients, IENFD, CNFD, CNFL, and CNBD were not different from controls. The density of DCs and the number of patients with increased DC density were higher in ALS patients than controls (p = .0005 and p = .008). The number of patients with axonal spheroids was higher than controls (p = .03).

DISCUSSION: Evaluation of DCs and axonal bulbs in C-fibers of ALS patients could provide insights into pathophysiology or potentially serve as biomarkers in ALS.}, } @article {pmid37983967, year = {2024}, author = {Slyne, AD and Ó Murchú, SC}, title = {Persistent inward currents: PICking apart the temporal changes in intrinsic motor neuron excitability in amyotrophic lateral sclerosis.}, journal = {The Journal of physiology}, volume = {602}, number = {1}, pages = {13-14}, doi = {10.1113/JP285776}, pmid = {37983967}, issn = {1469-7793}, support = {//Lilly Research Scholarship/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Motor Neurons/physiology ; Action Potentials/physiology ; }, } @article {pmid37984338, year = {2023}, author = {Topaloğlu Ören, ED and Dorukoğlu, S and Ertem, G}, title = {The Use of Complementary and Alternative Medicine and Coping with Stress by Patients with Gynecological Cancer: A Cross-Sectional Study in Türkiye.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {502-516}, doi = {10.1159/000534707}, pmid = {37984338}, issn = {2504-2106}, mesh = {Humans ; Female ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Cross-Sectional Studies ; Turkey ; *Neoplasms ; *Complementary Therapies ; Adaptation, Psychological ; }, abstract = {INTRODUCTION: Gynecological cancers are long-term, challenging, and stressful diseases. In Türkiye, the majority of patients with gynecological cancer use complementary and alternative medicine (CAM). Considering the stress that gynecological cancer patients are exposed to, patients need to know how to cope with stress.

OBJECTIVE: This study aimed to determine the use of CAM and coping with stress by patients with gynecological cancer and the relationships between them and the factors that predict the approaches to coping with stress in women with gynecological cancer in Türkiye.

METHODS: This is a descriptive and cross-sectional study. The study was conducted with 204 patients between April and August 2022. The data of the study were collected by face-to-face interview and filled out by the patients using the Descriptive Information Form and the Stress Coping Styles Scale (SCSS). Number, percentage, mean, χ2, one-way ANOVA, t test, and the Spearman correlation analysis were used in the data analysis. To analyze the multivariate independent associations between variables, a multivariate ordinal logistic regression model was used, with the SCSS domains as dependent variables. A 95% confidence interval was calculated, and all statistical tests had an alpha level of 0.05.

RESULTS: The mean age of the patients was 58.38 ± 12.64 years (32-80). The prevalence of CAM use by patients was 39.2%, and the most common types of CAM were herbal products (43.8%) and supplication (42.5%). The reasons for using CAM were relaxation (symptomatic)-feeling healthy (63.8%) and treating cancer (36.2%). No statistically significant difference was found between the use of CAM and their approaches to coping with stress (p > 0.05). As a result of multivariate ordinal logistic regression analysis, education level under high school, having ovary, cervix, and endometrium cancer, being in the first stage of cancer, receiving chemotherapy, receiving surgical treatment, having another cancer patient in the social environment and increased interest in a partner after the diagnosis of cancer was associated with an effective coping with stress (p < 0.05, adjusted R2 = 0.27, 0.79, and 0.32, respectively). Not working, experiencing an abortion, having another cancer patient in their social environment, being in the third stage of cancer, having an extended family, and living in a rural area of residence were associated with ineffective coping with stress (p < 0.05, adjusted R2 = 0.20 and 0.24, respectively).

CONCLUSIONS: The prevalence of CAM use by patients was low. While determining the approaches of the patients to cope with stress, their education level, place of residence, family type, diagnosis of cancer, stage of cancer, treatment, partner support, and stressful life events should be considered. As nurses, we need to be more knowledgeable about the use of CAM to provide correct guidance to our patients for access to accurate and effective information. We need to determine our patients' stressors and how our patients cope with stress.

UNLABELLED: EinleitungGynäkologische Krebserkrankungen sind langfristige, herausfordernde und belastende Krankheiten. In der Türkei nehmen die meisten Patientinnen mit gynäkologischen Krebserkrankungen Komplementär- und Alternativmedizin in Anspruch. Angesichts der großen Belastungen, denen Patientinnen mit gynäkologischen Krebserkrankungen ausgesetzt sind, müssen sie wissen, wie sie mit Stress umgehen können.ZielMit dieser Studie sollen die Inanspruchnahme von Komplementär- und Alternativmedizin und die Stressbewältigung von Patientinnen mit gynäkologischer Krebserkrankung ermittelt werden und es sollen die Zusammenhänge zwischen diesen beiden Aspekten und den prädiktiven Faktoren für die Ansätze zur Stressbewältigung bei Frauen mit gynäkologischer Krebserkrankung untersucht werden.MethodenEs handelt sich um eine deskriptive Querschnittsstudie. Die Studie wurde mit 204 Patientinnen zwischen April und August 2022 durchgeführt. Die Erhebung der Studiendaten erfolgte durch persönliche Befragung und mithilfe des deskriptiven Informationsformulars sowie der Stress Coping Styles-Skala, die die Patientinnen ausfüllten. Für die Datenanalyse wurden Anzahl, Prozentanteil, Mittelwert, Chi-Quadrat-Test, einfaktorielle ANOVA, t Test und die Spearman-Korrelationsanalyse verwendet. Zur Analyse der multivariaten unabhängigen Zusammenhänge zwischen den Variablen wurde ein multivariates ordinales logistisches Regressionsmodell verwendet mit den SCSS (Stress Coping Styles-Skala)-Domänen als abhängigen Variablen. Es wurde ein 95%-Konfidenzintervall berechnet, und das Signifikanzniveau betrug für alle statistischen Tests α = 0.05.ErgebnisseDas Durchschnittsalter der Patientinnen betrug 58.38 ± 12.64 Jahre (32–80 Jahre). Die Prävalenz der Inanspruchnahme von Komplementär- und Alternativmedizin (CAM) durch die Patientinnen lag bei 39.2%, und die häufigsten CAM-Arten waren pflanzliche Produkte (43.8%) und Bittgebete (42.5%). Die Gründe für die Inanspruchnahme von Komplementär- und Alternativmedizin waren Entspannung (symptomatisch), das Gefühl von Gesundheit (63.8%) und die Behandlung der Krebserkrankung (36.2%). Es fand sich kein statistisch signifikanter Unterschied zwischen der Inanspruchnahme von Komplementär- und Alternativmedizin und ihren Ansätzen zur Stressbewältigung (p > 0.05). Die multivariate ordinale logistische Regressionsanalyse zeigte, dass ein Bildungsniveau unterhalb der Oberstufe sowie Ovarial-, Zervix- und Endometriumkarzinom, Krebs im Anfangsstadium, Chemotherapie, operative Behandlung, eine andere Krebspatientin im sozialen Umfeld und ein gesteigertes Interesse an einem Partner nach der Krebsdiagnose mit effektiver Stressbewältigung assoziiert waren (p < 0.05, adjustiertes R2 = 0.27, 0.79 bzw. 0.32). Fehlende Berufstätigkeit, Fehlgeburt/Schwangerschaftsabbruch, eine andere Krebspatientin im sozialen Umfeld, eine Krebserkrankung im dritten Stadium, eine Großfamilie zu haben und in einer ländlichen Gegend zu leben waren mit ineffektiver Stressbewältigung verbunden (p < 0.05, adjustiertes R2 = 0.20 bzw. 0.24).SchlussfolgerungenDie Prävalenz der Inanspruchnahme von Komplementär- und Alternativmedizin durch die Patientinnen war gering. Bei der Ermittlung der Ansätze der Patientinnen zur Stressbewältigung sollten ihr Bildungsniveau, ihr Wohnort, ihr Familientyp, die Krebsdiagnose, das Krebsstadium, die Behandlung, die Unterstützung durch den Partner und belastende Lebensereignisse berücksichtigt werden. Als Pflegekräfte müssen wir mehr über die Inanspruchnahme von Komplementär- und Alternativmedizin wissen, um unsere Patientinnen in Hinblick auf den Zugang zu genauen und wirksamen Informationen die richtige Orientierungshilfe zu geben. Wir müssen die Stressfaktoren unserer Patientinnen ermitteln und herausfinden, wie unsere Patientinnen mit Stress umgehen.}, } @article {pmid37986728, year = {2023}, author = {Fan, C and Hahn, N and Kamdar, F and Avansino, D and Wilson, GH and Hochberg, L and Shenoy, KV and Henderson, JM and Willett, FR}, title = {Plug-and-Play Stability for Intracortical Brain-Computer Interfaces: A One-Year Demonstration of Seamless Brain-to-Text Communication.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {37986728}, issn = {2331-8422}, abstract = {Intracortical brain-computer interfaces (iBCIs) have shown promise for restoring rapid communication to people with neurological disorders such as amyotrophic lateral sclerosis (ALS). However, to maintain high performance over time, iBCIs typically need frequent recalibration to combat changes in the neural recordings that accrue over days. This requires iBCI users to stop using the iBCI and engage in supervised data collection, making the iBCI system hard to use. In this paper, we propose a method that enables self-recalibration of communication iBCIs without interrupting the user. Our method leverages large language models (LMs) to automatically correct errors in iBCI outputs. The self-recalibration process uses these corrected outputs ("pseudo-labels") to continually update the iBCI decoder online. Over a period of more than one year (403 days), we evaluated our Continual Online Recalibration with Pseudo-labels (CORP) framework with one clinical trial participant. CORP achieved a stable decoding accuracy of 93.84% in an online handwriting iBCI task, significantly outperforming other baseline methods. Notably, this is the longest-running iBCI stability demonstration involving a human participant. Our results provide the first evidence for long-term stabilization of a plug-and-play, high-performance communication iBCI, addressing a major barrier for the clinical translation of iBCIs.}, } @article {pmid37986813, year = {2023}, author = {Glineburg, MR and Yildirim, E and Gomez, N and Li, X and Pak, J and Altheim, C and Waksmacki, J and McInerney, G and Barmada, SJ and Todd, PK}, title = {Stress granule formation helps to mitigate neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37986813}, issn = {2692-8205}, support = {R01 NS086810/NS/NINDS NIH HHS/United States ; P50 HD104463/HD/NICHD NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; }, abstract = {Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known. To address this, we took advantage of the alphavirus protein nsP3, which selectively binds dimers of the central stress granule nucleator protein G3BP (rin in Drosophila) and markedly reduces stress granule formation without directly impacting the protein translational inhibitory pathways that trigger stress granule formation. In Drosophila and rodent neurons, reducing stress granule formation with nsP3 had modest impacts on lifespan even in the setting of serial stress pathway induction. In contrast, reducing stress granule formation in models of ataxia, amyotrophic lateral sclerosis and frontotemporal dementia largely exacerbated disease phenotypes. These data support a model whereby stress granules mitigate, rather than promote, neurodegenerative cascades.}, } @article {pmid37986827, year = {2023}, author = {Simmonds, E and Levine, KS and Han, J and Iwaki, H and Koretsky, MJ and Kuznetsov, N and Faghri, F and Solsberg, CW and Schuh, A and Jones, L and Bandres-Ciga, S and Blauwendraat, C and Singleton, A and Escott-Price, V and Leonard, HL and Nalls, MA}, title = {Sleep disturbances as risk factors for neurodegeneration later in life.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37986827}, abstract = {The relationship between sleep disorders and neurodegeneration is complex and multi-faceted. Using over one million electronic health records (EHRs) from Wales, UK, and Finland, we mined biobank data to identify the relationships between sleep disorders and the subsequent manifestation of neurodegenerative diseases (NDDs) later in life. We then examined how these sleep disorders' severity impacts neurodegeneration risk. Additionally, we investigated how sleep attributed risk may compensate for the lack of genetic risk factors (i.e. a lower polygenic risk score) in NDD manifestation. We found that sleep disorders such as sleep apnea were associated with the risk of Alzheimer's disease (AD), amyotrophic lateral sclerosis, dementia, Parkinson's disease (PD), and vascular dementia in three national scale biobanks, with hazard ratios (HRs) ranging from 1.31 for PD to 5.11 for dementia. These sleep disorders imparted significant risk up to 15 years before the onset of an NDD. Cumulative number of sleep disorders in the EHRs were associated with a higher risk of neurodegeneration for dementia and vascular dementia. Sleep related risk factors were independent of genetic risk for Alzheimer's and Parkinson's, potentially compensating for low genetic risk in overall disease etiology. There is a significant multiplicative interaction regarding the combined risk of sleep disorders and Parkinson's disease. Poor sleep hygiene and sleep apnea are relatively modifiable risk factors with several treatment options, including CPAP and surgery, that could potentially reduce the risk of neurodegeneration. This is particularly interesting in how sleep related risk factors are significantly and independently enriched in manifesting NDD patients with low levels of genetic risk factors for these diseases.}, } @article {pmid37988405, year = {2024}, author = {Nusrath, S and Kalluru, P and Shukla, S and Dharanikota, A and Basude, M and Jonnada, P and Abualjadayel, M and Alabbad, S and Mir, TA and Broering, DC and Raju, K and Rao, TS and Vashist, YK}, title = {Current status of indocyanine green fluorescent angiography in assessing perfusion of gastric conduit and oesophago-gastric anastomosis.}, journal = {International journal of surgery (London, England)}, volume = {110}, number = {2}, pages = {1079-1089}, pmid = {37988405}, issn = {1743-9159}, mesh = {Humans ; *Indocyanine Green ; *Coloring Agents ; Angiography/adverse effects ; Anastomotic Leak/diagnostic imaging/etiology ; Anastomosis, Surgical/adverse effects/methods ; Esophagectomy/adverse effects/methods ; Perfusion ; }, abstract = {Anastomotic leak (AL) remains a significant complication after esophagectomy. Indocyanine green fluorescent angiography (ICG-FA) is a promising and safe technique for assessing gastric conduit (GC) perfusion intraoperatively. It provides detailed visualization of tissue perfusion and has demonstrated usefulness in oesophageal surgery. GC perfusion analysis by ICG-FA is crucial in constructing the conduit and selecting the anastomotic site and enables surgeons to make necessary adjustments during surgery to potentially reduce ALs. However, anastomotic integrity involves multiple factors, and ICG-FA must be combined with optimization of patient and procedural factors to decrease AL rates. This review summarizes ICG-FA's current applications in assessing esophago-gastric anastomosis perfusion, including qualitative and quantitative analysis and different imaging systems. It also explores how fluorescent imaging could decrease ALs and aid clinicians in utilizing ICG-FA to improve esophagectomy outcomes.}, } @article {pmid37988653, year = {2024}, author = {Teplansky, KJ and Wisler, A and Goffman, L and Wang, J}, title = {The Impact of Stimulus Length in Tongue and Lip Movement Pattern Stability in Amyotrophic Lateral Sclerosis.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {10S}, pages = {4002-4014}, pmid = {37988653}, issn = {1558-9102}, support = {R01 DC013547/DC/NIDCD NIH HHS/United States ; R01 DC016621/DC/NIDCD NIH HHS/United States ; R03 DC013990/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Lip/physiopathology/physiology ; *Tongue/physiopathology/physiology ; Male ; Female ; Middle Aged ; Aged ; *Movement/physiology ; Speech/physiology ; Adult ; Speech Production Measurement ; Biomechanical Phenomena ; Case-Control Studies ; }, abstract = {PURPOSE: This study aimed to investigate the effect of stimulus signal length on tongue and lip motion pattern stability in speakers diagnosed with amyotrophic lateral sclerosis (ALS) compared to healthy controls.

METHOD: Electromagnetic articulography was used to derive articulatory motion patterns from individuals with mild (n = 27) and severe (n = 16) ALS and healthy controls (n = 25). The spatiotemporal index (STI) was used as a measure of articulatory stability. Two experiments were conducted to evaluate signal length effects on the STI: (a) the effect of the number of syllables on STI values and (b) increasing lengths of subcomponents of a single phrase. Two-way mixed analyses of variance were conducted to assess the effects of syllable length and group on the STI for the tongue tip (TT), tongue back (TB), and lower lip (LL).

RESULTS: Experiment 1 showed a significant main effect of syllable length (TT, p < .001; TB, p < .001; and LL, p < .001) and group (TT, p = .037; TB, p = .007; and LL, p = .017). TB and LL stability was generally higher with speech stimuli that included a greater number of syllables. Articulatory variability was significantly higher in speakers diagnosed with ALS compared to healthy controls. Experiment 2 showed a significant main effect of length (TT, p < .001; TB, p = .015; and LL, p < .001), providing additional support that STI values tend to be greater when calculated on longer speech signals.

CONCLUSIONS: Articulatory stability is influenced by the length of speech signals and manifests similarly in both healthy speakers and persons with ALS. TT stability may be significantly impacted by phonemic content due to greater movement flexibility. Compared to healthy controls, there was an increase in articulatory variability in those with ALS, which likely reflects deviations in speech motor control.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24463924.}, } @article {pmid37988788, year = {2024}, author = {Basith, S and Manavalan, B and Lee, G}, title = {Unveiling local and global conformational changes and allosteric communications in SOD1 systems using molecular dynamics simulation and network analyses.}, journal = {Computers in biology and medicine}, volume = {168}, number = {}, pages = {107688}, doi = {10.1016/j.compbiomed.2023.107688}, pmid = {37988788}, issn = {1879-0534}, mesh = {Humans ; Superoxide Dismutase-1/genetics/metabolism ; *Molecular Dynamics Simulation ; Superoxide Dismutase/chemistry/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; Protein Folding ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disorder affecting nerve cells in the brain and spinal cord that is caused by mutations in the superoxide dismutase 1 (SOD1) enzyme. ALS-related mutations cause misfolding, dimerisation instability, and increased formation of aggregates. The underlying allosteric mechanisms, however, remain obscure as far as details of their fundamental atomistic structure are concerned. Hence, this gap in knowledge limits the development of novel SOD1 inhibitors and the understanding of how disease-associated mutations in distal sites affect enzyme activity.

METHODS: We combined microsecond-scale based unbiased molecular dynamics (MD) simulation with network analysis to elucidate the local and global conformational changes and allosteric communications in SOD1 Apo (unmetallated form), Holo, Apo_CallA (mutant and unmetallated form), and Holo_CallA (mutant form) systems. To identify hotspot residues involved in SOD1 signalling and allosteric communications, we performed network centrality, community network, and path analyses.

RESULTS: Structural analyses showed that unmetallated SOD1 systems and cysteine mutations displayed large structural variations in the catalytic sites, affecting structural stability. Inter- and intra H-bond analyses identified several important residues crucial for maintaining interfacial stability, structural stability, and enzyme catalysis. Dynamic motion analysis demonstrated more balanced atomic displacement and highly correlated motions in the Holo system. The rationale for structural disparity observed in the disulfide bond formation and R143 configuration in Apo and Holo systems were elucidated using distance and dihedral probability distribution analyses.

CONCLUSION: Our study highlights the efficiency of combining extensive MD simulations with network analyses to unravel the features of protein allostery.}, } @article {pmid37990637, year = {2024}, author = {Ng, SC and McCombie, A and Frizelle, F and Eglinton, T}, title = {Influence of the type of anatomic resection on anastomotic leak after surgery for colon cancer.}, journal = {ANZ journal of surgery}, volume = {94}, number = {3}, pages = {424-428}, doi = {10.1111/ans.18782}, pmid = {37990637}, issn = {1445-2197}, mesh = {Humans ; Male ; *Anastomotic Leak/epidemiology/etiology ; Retrospective Studies ; Risk Factors ; *Colonic Neoplasms/pathology ; Colectomy/adverse effects/methods ; Anastomosis, Surgical/adverse effects/methods ; }, abstract = {INTRODUCTION: Anastomotic leak (AL) after colon cancer resection is feared by surgeons because of its associated morbidity and mortality. Considerable research has been directed at predictive factors for AL, but not the anatomic type of colonic resection. Anecdotally, certain types of resection are associated with higher leak rates although there remains a paucity of data on this. This study aimed to determine the AL rate for different types of colon cancer resection to inform decisions regarding the choice of operation.

METHODOLOGY: Retrospective analysis of Bowel Cancer Outcome Registry (BCOR) for all colonic cancer resections with anastomosis between January 2007 and December 2020. Demographic, patient, tumour and outcome data were analysed. AL rates were compared among the different colonic procedures with both univariate and multivariate analysis.

RESULTS: 20 191 patients who underwent resection with anastomosis for cancer were included in this study. Of these 535 (2.6%) suffered ALs. While the univariate analysis found male sex, procedure type, symptomatic cancers, emergency surgery, unsupervised registrars, conversion to open surgery, medical complications and higher TNM staging were associated with AL, multivariate analysis, found only procedure type remained a significant predictor of AL (total colectomy (OR 4.049, P<0.001), subtotal colectomy (OR 2.477, P<0.001) and extended right hemicolectomy (OR 2.171, P < 0.001)).

CONCLUSION: AL is more common in extended colonic resections. With growing evidence of similar oncological outcomes between subtotal colectomy and left hemicolectomy for splenic flexure cancers, more limited resections should be considered. The type of colonic resection should be integrated into prediction tools for AL.}, } @article {pmid37991691, year = {2024}, author = {Yu, L and Xu, G and Zhou, Q and Ouyang, M and Gao, L and Zeng, S}, title = {Biomechanical properties of the ascending aorta in patients with arterial hypertension by velocity vector imaging.}, journal = {The international journal of cardiovascular imaging}, volume = {40}, number = {2}, pages = {397-405}, pmid = {37991691}, issn = {1875-8312}, support = {81801721//the State Natural Sciences Foundation of China/ ; 81871372//the State Natural Sciences Foundation of China/ ; 2019JJ50880//the Natural Science Foundation of Hunan Province/ ; 2019JJ40425//the Natural Science Foundation of Hunan Province/ ; }, mesh = {Humans ; Aorta, Thoracic ; Predictive Value of Tests ; *Hypertension/complications/diagnosis/epidemiology ; Aorta/diagnostic imaging ; Echocardiography/methods ; *Aortic Diseases ; *Ventricular Dysfunction, Left ; }, abstract = {Aortic stiffness is an important risk factor for cardiovascular events and morbidity. Increased aortic stiffness is associated with an increase in cardiac and vascular hypertension-related organ damage. To evaluate the biomechanical properties of the ascending aorta (AA) in patients with arterial hypertension (AH) by velocity vector imaging (VVI). Ninety-five patients with AH and 53 normal healthy control participants were prospectively enrolled. AA biomechanical properties, i.e., ascending aortic global longitudinal strain (ALS), ascending aortic global circumferential strain (ACS), and fractional area change (FAC), were evaluated by VVI. Relative wall thickness (RWT) and left ventricular mass (LVM) were calculated. Pulsed Doppler early transmitral peak flow velocity (E), early diastolic mitral annular velocity (e'), left ventricular global longitudinal strain (GLS), distensibility (D) and stiffness index (SI) of AA were also obtained. The ALS, ACS and FAC were significantly lower in the AH patients, especially in those with ascending aorta dilatation (AAD), than in the normal healthy control subjects. The patients with AAD had a higher E/e' ratio, RWT, LVM and SI and a lower GLS and D than patients without AAD and normal healthy volunteers (p < 0.05). There were significant associations between biomechanical properties and D, SI, E/e' and GLS (ALS and D: r = 0.606, ALS and SI: r = - 0.645, ALS and E/e': r = - 0.489, ALS and GLS: r = 0.466, ACS and D: r = 0.564, ACS and SI: r = - 0.567, ACS and E/e': r = - 0.313, ACS and GLS: r = 0.320, FAC and D: r = 0.649, FAC and SI: r = - 0.601, FAC and E/e': r = - 0.504, FAC and GLS: r = 0.524, respectively, p < 0.05). The biomechanical properties of AA were impaired in patients with AH, especially patients with ascending aorta dilatation. Hypertension is associated with a high prevalence of diastolic and systolic dysfunction and increased arterial stiffness. Further study is needed to evaluate the clinical application of AA biomechanical properties by VVI.}, } @article {pmid37992159, year = {2023}, author = {Shimizu, M and Shiraishi, N and Tada, S and Sasaki, T and Beck, G and Nagano, S and Kinoshita, M and Sumi, H and Sugimoto, T and Ishida, Y and Koda, T and Ishikura, T and Sugiyama, Y and Kihara, K and Kanakura, M and Nakajima, T and Takeda, S and Takahashi, MP and Yamashita, T and Okuno, T and Mochizuki, H}, title = {RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS.}, journal = {Science advances}, volume = {9}, number = {47}, pages = {eadg3193}, pmid = {37992159}, issn = {2375-2548}, mesh = {Animals ; Humans ; Mice ; Actins ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Antibodies ; Mice, Transgenic ; Motor Neurons/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics ; Nerve Tissue Proteins ; GPI-Linked Proteins ; }, abstract = {Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone-collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.}, } @article {pmid37992921, year = {2024}, author = {Li, L and Lei, T and Xing, C and Du, H}, title = {Advances in microfluidic chips targeting toxic aggregation proteins for neurodegenerative diseases.}, journal = {International journal of biological macromolecules}, volume = {256}, number = {Pt 2}, pages = {128308}, doi = {10.1016/j.ijbiomac.2023.128308}, pmid = {37992921}, issn = {1879-0003}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Microfluidics ; *Alzheimer Disease ; Amyloid beta-Peptides ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by nervous system damage, often influenced by genetic and aging factors. Pathological analysis frequently reveals the presence of aggregated toxic proteins. The intricate and poorly understood origins of these diseases have hindered progress in early diagnosis and drug development. The development of novel in-vitro and in-vivo models could enhance our comprehension of ND mechanisms and facilitate clinical treatment advancements. Microfluidic chips are employed to establish three-dimensional culture conditions, replicating the human ecological niche and creating a microenvironment conducive to neuronal cell survival. The incorporation of mechatronic controls unifies the chip, cells, and culture medium optimizing living conditions for the cells. This study provides a comprehensive overview of microfluidic chip applications in drug and biomarker screening for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Our Lab-on-a-Chip system releases toxic proteins to simulate the pathological characteristics of neurodegenerative diseases, encompassing β-amyloid, α-synuclein, huntingtin, TAR DNA-binding protein 43, and Myelin Basic Protein. Investigating molecular and cellular interactions in vitro can enhance our understanding of disease mechanisms while minimizing harmful protein levels and can aid in screening potential therapeutic agents. We anticipate that our research will promote the utilization of microfluidic chips in both fundamental research and clinical applications for neurodegenerative diseases.}, } @article {pmid37993052, year = {2024}, author = {Wu, F and Malek, AM and Buchanich, JM and Arena, VC and Rager, JR and Sharma, RK and Vena, JE and Bear, T and Talbott, EO}, title = {Exposure to ambient air toxicants and the risk of amyotrophic lateral sclerosis (ALS): A matched case control study.}, journal = {Environmental research}, volume = {242}, number = {}, pages = {117719}, doi = {10.1016/j.envres.2023.117719}, pmid = {37993052}, issn = {1096-0953}, support = {R01 TS000272/TS/ATSDR CDC HHS/United States ; }, mesh = {Humans ; United States/epidemiology ; Case-Control Studies ; *Amyotrophic Lateral Sclerosis/chemically induced/epidemiology ; *Vinyl Chloride ; Bayes Theorem ; Risk Factors ; Solvents ; Cyanides ; *Dinitrobenzenes ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with few risk factors identified and no known cure. Gene-environment interaction is hypothesized especially for sporadic ALS cases (90-95%) which are of unknown etiology. We aimed to investigate risk factors for ALS including exposure to ambient air toxics.

METHODS: This population-based case-control study included 267 ALS cases (from the United States [U.S.] Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry National ALS Registry and Biorepository) and 267 age, sex, and county-matched controls identified via a commercial database. Exposure assessment for 34 ambient air toxicants was performed by assigning census tract-level U.S. Environmental Protection Agency (EPA) 2011 National Air Toxics Assessment (NATA) data to participants' residential ZIP codes. Conditional logistic regression was used to compute adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for individual compounds, chemical classes, and overall exposure. Sensitivity analyses using both conditional logistic regression and Bayesian grouped weighted quartile sum (GWQS) models were performed to assess the integrity of findings.

RESULTS: Using the 2011 NATA, the highest exposure quartile (Q4) compared to the lowest (Q1) of vinyl chloride (aOR = 6.00, 95% CI: 1.87-19.25), 2,4-dinitrotoluene (aOR = 5.45, 95% CI: 1.53-19.36), cyanide (aOR = 4.34, 95% CI: 1.52-12.43), cadmium (aOR = 3.30, 95% CI: 1.11-9.77), and carbon disulfide (aOR = 2.98, 95% CI: 1.00-8.91) was associated with increased odds of ALS. Residential air selenium showed an inverse association with ALS (second quartile [Q2] vs. Q1: aOR = 0.38, 95% CI: 0.18-0.79). Additionally, residential exposure to organic/chlorinated solvents (Q4 vs Q1: aOR = 2.62, 95% CI: 1.003-6.85) was associated with ALS.

CONCLUSIONS: Our findings using the 2011 NATA linked by census tract to residential area provide evidence of increased ALS risk in cases compared to controls for 2,4-dinitrotoluene, vinyl chloride, cyanide, and the organic/chlorinated solvents class. This underscores the importance of ongoing surveillance of potential exposures for at-risk populations.}, } @article {pmid37993492, year = {2023}, author = {Ragagnin, AMG and Sundaramoorthy, V and Farzana, F and Gautam, S and Saravanabavan, S and Takalloo, Z and Mehta, P and Do-Ha, D and Parakh, S and Shadfar, S and Hunter, J and Vidal, M and Jagaraj, CJ and Brocardo, M and Konopka, A and Yang, S and Rayner, SL and Williams, KL and Blair, IP and Chung, RS and Lee, A and Ooi, L and Atkin, JD}, title = {ALS/FTD-associated mutation in cyclin F inhibits ER-Golgi trafficking, inducing ER stress, ERAD and Golgi fragmentation.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {20467}, pmid = {37993492}, issn = {2045-2322}, support = {10305133//National Health and Medical Research Council of Australia (NHMRC)/ ; 1086887//National Health and Medical Research Council of Australia (NHMRC)/ ; 1095215//National Health and Medical Research Council of Australia (NHMRC)/ ; 10305133//National Health and Medical Research Council of Australia (NHMRC)/ ; 1086887//National Health and Medical Research Council of Australia (NHMRC)/ ; 1095215//National Health and Medical Research Council of Australia (NHMRC)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Endoplasmic Reticulum-Associated Degradation ; Endoplasmic Reticulum/metabolism ; Golgi Apparatus/metabolism ; Mutation ; Cyclins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severely debilitating neurodegenerative condition that is part of the same disease spectrum as frontotemporal dementia (FTD). Mutations in the CCNF gene, encoding cyclin F, are present in both sporadic and familial ALS and FTD. However, the pathophysiological mechanisms underlying neurodegeneration remain unclear. Proper functioning of the endoplasmic reticulum (ER) and Golgi apparatus compartments is essential for normal physiological activities and to maintain cellular viability. Here, we demonstrate that ALS/FTD-associated variant cyclin F[S621G] inhibits secretory protein transport from the ER to Golgi apparatus, by a mechanism involving dysregulation of COPII vesicles at ER exit sites. Consistent with this finding, cyclin F[S621G] also induces fragmentation of the Golgi apparatus and activates ER stress, ER-associated degradation, and apoptosis. Induction of Golgi fragmentation and ER stress were confirmed with a second ALS/FTD variant cyclin F[S195R], and in cortical primary neurons. Hence, this study provides novel insights into pathogenic mechanisms associated with ALS/FTD-variant cyclin F, involving perturbations to both secretory protein trafficking and ER-Golgi homeostasis.}, } @article {pmid37994346, year = {2022}, author = {Yang, C and Qian, C and Singh, N and Xiao, C and Westover, MB and Solomonik, E and Sun, J}, title = {ATD: Augmenting CP Tensor Decomposition by Self Supervision.}, journal = {Advances in neural information processing systems}, volume = {35}, number = {}, pages = {32039-32052}, pmid = {37994346}, issn = {1049-5258}, support = {R01 NS102190/NS/NINDS NIH HHS/United States ; RF1 NS120947/NS/NINDS NIH HHS/United States ; R01 HL161253/HL/NHLBI NIH HHS/United States ; R01 NS126282/NS/NINDS NIH HHS/United States ; R01 NS107291/NS/NINDS NIH HHS/United States ; }, abstract = {Tensor decompositions are powerful tools for dimensionality reduction and feature interpretation of multidimensional data such as signals. Existing tensor decomposition objectives (e.g., Frobenius norm) are designed for fitting raw data under statistical assumptions, which may not align with downstream classification tasks. In practice, raw input tensor can contain irrelevant information while data augmentation techniques may be used to smooth out class-irrelevant noise in samples. This paper addresses the above challenges by proposing augmented tensor decomposition (ATD), which effectively incorporates data augmentations and self-supervised learning (SSL) to boost downstream classification. To address the non-convexity of the new augmented objective, we develop an iterative method that enables the optimization to follow an alternating least squares (ALS) fashion. We evaluate our proposed ATD on multiple datasets. It can achieve 0.8% ~ 2.5% accuracy gain over tensor-based baselines. Also, our ATD model shows comparable or better performance (e.g., up to 15% in accuracy) over self-supervised and autoencoder baselines while using less than 5% of learnable parameters of these baseline models.}, } @article {pmid37995198, year = {2023}, author = {Ayoubi, R and Ryan, J and Biddle, MS and Alshafie, W and Fotouhi, M and Bolivar, SG and Ruiz Moleon, V and Eckmann, P and Worrall, D and McDowell, I and Southern, K and Reintsch, W and Durcan, TM and Brown, C and Bandrowski, A and Virk, H and Edwards, AM and McPherson, P and Laflamme, C}, title = {Scaling of an antibody validation procedure enables quantification of antibody performance in major research applications.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {37995198}, issn = {2050-084X}, support = {U54 AG065187/AG/NIA NIH HHS/United States ; RF1AG057443/AG/NIA NIH HHS/United States ; R24 GM144308/GM/NIGMS NIH HHS/United States ; FDN154305//CIHR/Canada ; SGC/JAN18/988-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; RF1 AG057443/AG/NIA NIH HHS/United States ; U54AG065187/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Proteome ; *Antibodies/chemistry ; }, abstract = {Antibodies are critical reagents to detect and characterize proteins. It is commonly understood that many commercial antibodies do not recognize their intended targets, but information on the scope of the problem remains largely anecdotal, and as such, feasibility of the goal of at least one potent and specific antibody targeting each protein in a proteome cannot be assessed. Focusing on antibodies for human proteins, we have scaled a standardized characterization approach using parental and knockout cell lines (Laflamme et al., 2019) to assess the performance of 614 commercial antibodies for 65 neuroscience-related proteins. Side-by-side comparisons of all antibodies against each target, obtained from multiple commercial partners, have demonstrated that: (i) more than 50% of all antibodies failed in one or more applications, (ii) yet, ~50-75% of the protein set was covered by at least one high-performing antibody, depending on application, suggesting that coverage of human proteins by commercial antibodies is significant; and (iii) recombinant antibodies performed better than monoclonal or polyclonal antibodies. The hundreds of underperforming antibodies identified in this study were found to have been used in a large number of published articles, which should raise alarm. Encouragingly, more than half of the underperforming commercial antibodies were reassessed by the manufacturers, and many had alterations to their recommended usage or were removed from the market. This first study helps demonstrate the scale of the antibody specificity problem but also suggests an efficient strategy toward achieving coverage of the human proteome; mine the existing commercial antibody repertoire, and use the data to focus new renewable antibody generation efforts.}, } @article {pmid37996229, year = {2023}, author = {Del Pozo Vegas, C and Zalama-Sánchez, D and Sanz-Garcia, A and López-Izquierdo, R and Sáez-Belloso, S and Mazas Perez Oleaga, C and Domínguez Azpíroz, I and Elío Pascual, I and Martín-Rodríguez, F}, title = {Prehospital acute life-threatening cardiovascular disease in elderly: an observational, prospective, multicentre, ambulance-based cohort study.}, journal = {BMJ open}, volume = {13}, number = {11}, pages = {e078815}, pmid = {37996229}, issn = {2044-6055}, mesh = {Adult ; Aged ; Humans ; Ambulances ; *Cardiovascular Diseases/therapy ; Cohort Studies ; *Emergency Medical Services/methods ; Prospective Studies ; }, abstract = {OBJECTIVE: The aim was to explore the association of demographic and prehospital parameters with short-term and long-term mortality in acute life-threatening cardiovascular disease by using a hazard model, focusing on elderly individuals, by comparing patients under 75 years versus patients over 75 years of age.

DESIGN: Prospective, multicentre, observational study.

SETTING: Emergency medical services (EMS) delivery study gathering data from two back-to-back studies between 1 October 2019 and 30 November 2021. Six advanced life support (ALS), 43 basic life support and five hospitals in Spain were considered.

PARTICIPANTS: Adult patients suffering from acute life-threatening cardiovascular disease attended by the EMS.

The primary outcome was in-hospital mortality from any cause within the first to the 365 days following EMS attendance. The main measures included prehospital demographics, biochemical variables, prehospital ALS techniques used and syndromic suspected conditions.

RESULTS: A total of 1744 patients fulfilled the inclusion criteria. The 365-day cumulative mortality in the elderly amounted to 26.1% (229 cases) versus 11.6% (11.6%) in patients under 75 years old. Elderly patients (≥75 years) presented a twofold risk of mortality compared with patients ≤74 years. Life-threatening interventions (mechanical ventilation, cardioversion and defibrillation) were also related to a twofold increased risk of mortality. Importantly, patients suffering from acute heart failure presented a more than twofold increased risk of mortality.

CONCLUSIONS: This study revealed the prehospital variables associated with the long-term mortality of patients suffering from acute cardiovascular disease. Our results provide important insights for the development of specific codes or scores for cardiovascular diseases to facilitate the risk of mortality characterisation.}, } @article {pmid37996528, year = {2024}, author = {López-Erauskin, J and Bravo-Hernandez, M and Presa, M and Baughn, MW and Melamed, Z and Beccari, MS and Agra de Almeida Quadros, AR and Arnold-Garcia, O and Zuberi, A and Ling, K and Platoshyn, O and Niño-Jara, E and Ndayambaje, IS and McAlonis-Downes, M and Cabrera, L and Artates, JW and Ryan, J and Hermann, A and Ravits, J and Bennett, CF and Jafar-Nejad, P and Rigo, F and Marsala, M and Lutz, CM and Cleveland, DW and Lagier-Tourenne, C}, title = {Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation.}, journal = {Nature neuroscience}, volume = {27}, number = {1}, pages = {34-47}, pmid = {37996528}, issn = {1546-1726}, support = {RF1 NS124203/NS/NINDS NIH HHS/United States ; R01 NS124203/NS/NINDS NIH HHS/United States ; T32 AG066596/AG/NIA NIH HHS/United States ; P30 NS047101/NS/NINDS NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; T32 GM008666/GM/NIGMS NIH HHS/United States ; R01 NS112503/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Axons/physiology ; Denervation ; DNA-Binding Proteins/genetics ; Intermediate Filaments/metabolism/pathology ; Motor Neurons/metabolism ; Stathmin/genetics/metabolism ; Disease Models, Animal ; }, abstract = {The mRNA transcript of the human STMN2 gene, encoding for stathmin-2 protein (also called SCG10), is profoundly impacted by TAR DNA-binding protein 43 (TDP-43) loss of function. The latter is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Using a combination of approaches, including transient antisense oligonucleotide-mediated suppression, sustained shRNA-induced depletion in aging mice, and germline deletion, we show that stathmin-2 has an important role in the establishment and maintenance of neurofilament-dependent axoplasmic organization that is critical for preserving the caliber and conduction velocity of myelinated large-diameter axons. Persistent stathmin-2 loss in adult mice results in pathologies found in ALS, including reduced interneurofilament spacing, axonal caliber collapse that drives tearing within outer myelin layers, diminished conduction velocity, progressive motor and sensory deficits, and muscle denervation. These findings reinforce restoration of stathmin-2 as an attractive therapeutic approach for ALS and other TDP-43-dependent neurodegenerative diseases.}, } @article {pmid37997256, year = {2024}, author = {Barker, MS and Ceslis, A and Argall, R and McCombe, P and Henderson, RD and Robinson, GA}, title = {Verbal and nonverbal fluency in amyotrophic lateral sclerosis.}, journal = {Journal of neuropsychology}, volume = {18}, number = {2}, pages = {265-285}, doi = {10.1111/jnp.12354}, pmid = {37997256}, issn = {1748-6653}, support = {//Brazil Family Program for Neurology/ ; //Motor Neurone Disease Research Institute of Australia/ ; APP1135769//National Health and Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; Middle Aged ; Aged ; *Neuropsychological Tests ; *Gestures ; Verbal Behavior/physiology ; Apathy/physiology ; Adult ; Semantics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multi-system disorder that commonly affects cognition and behaviour. Verbal fluency impairments are consistently reported in ALS patients, and we aimed to investigate whether this deficit extends beyond the verbal domain. We further aimed to determine whether deficits are underpinned by a primary intrinsic response generation impairment (i.e., a global reduction across tasks), potentially related to apathy, or an inability to maintain responding over time (i.e., a 'drop off' pattern). Twenty-two ALS patients and 21 demographically-matched controls completed verbal and nonverbal fluency tasks (phonemic/semantic word fluency, design fluency, gesture fluency and ideational fluency), requiring the generation of responses over a specified time period. Fluency performance was analysed in terms of the overall number of novel items produced, as well as the number of items produced in the first 'initiation' and the remaining 'maintenance' time periods. ALS patients' overall performance was not globally reduced across tasks. Patients were impaired only on meaningful gesture fluency, which requires the generation of gestures that communicate meaning (e.g., waving). On phonemic fluency, ALS patients showed a 'drop off' pattern of performance, where they had difficulty maintaining responding over time, but this pattern was not evident on the other fluency tasks. Apathy did not appear to be related to fluency performance. The selective meaningful gesture fluency deficit, in the context of preserved meaningless gesture fluency, highlights that the retrieval of action knowledge may be weakened in early ALS.}, } @article {pmid37999501, year = {2023}, author = {Metcalf, JS and Banack, SA and Wyatt, PB and Nunn, PB and Cox, PA}, title = {A Direct Analysis of β-N-methylamino-l-alanine Enantiomers and Isomers and Its Application to Cyanobacteria and Marine Mollusks.}, journal = {Toxins}, volume = {15}, number = {11}, pages = {}, pmid = {37999501}, issn = {2072-6651}, mesh = {Animals ; Humans ; Chromatography, Liquid/methods ; Tandem Mass Spectrometry ; *Amino Acids, Diamino/toxicity ; Amino Acids/analysis ; *Bivalvia/chemistry ; *Cyanobacteria/metabolism ; Neurotoxins/toxicity ; Cyanobacteria Toxins ; }, abstract = {Of the wide variety of toxic compounds produced by cyanobacteria, the neurotoxic amino acid β-N-methylamino-l-alanine (BMAA) has attracted attention as a result of its association with chronic human neurodegenerative diseases such as ALS and Alzheimer's. Consequently, specific detection methods are required to assess the presence of BMAA and its isomers in environmental and clinical materials, including cyanobacteria and mollusks. Although the separation of isomers such as β-amino-N-methylalanine (BAMA), N-(2-aminoethyl)glycine (AEG) and 2,4-diaminobutyric acid (DAB) from BMAA has been demonstrated during routine analysis, a further compounding factor is the potential presence of enantiomers for some of these isomers. Current analytical methods for BMAA mostly do not discriminate between enantiomers, and the chiral configuration of BMAA in cyanobacteria is still largely unexplored. To understand the potential for the occurrence of D-BMAA in cyanobacteria, a chiral UPLC-MS/MS method was developed to separate BMAA enantiomers and isomers and to determine the enantiomeric configuration of endogenous free BMAA in a marine Lyngbya mat and two mussel reference materials. After extraction, purification and derivatization with N-(4-nitrophenoxycarbonyl)-l-phenylalanine 2-methoxyethyl ester ((S)-NIFE), both L- and D-BMAA were identified as free amino acids in cyanobacterial materials, whereas only L-BMAA was identified in mussel tissues. The finding of D-BMAA in biological environmental materials raises questions concerning the source and role of BMAA enantiomers in neurological disease.}, } @article {pmid37999510, year = {2023}, author = {Violi, JP and Pu, L and Pravadali-Cekic, S and Bishop, DP and Phillips, CR and Rodgers, KJ}, title = {Effects of the Toxic Non-Protein Amino Acid β-Methylamino-L-Alanine (BMAA) on Intracellular Amino Acid Levels in Neuroblastoma Cells.}, journal = {Toxins}, volume = {15}, number = {11}, pages = {}, pmid = {37999510}, issn = {2072-6651}, mesh = {Animals ; Humans ; Amino Acids ; *Amino Acids, Diamino/toxicity/metabolism ; Serine/pharmacology ; Neurotoxins/toxicity ; *Neuroblastoma ; Cyanobacteria Toxins ; }, abstract = {The cyanobacterial non-protein amino acid (AA) β-Methylamino-L-alanine (BMAA) is considered to be a neurotoxin. BMAA caused histopathological changes in brains and spinal cords of primates consistent with some of those seen in early motor neuron disease; however, supplementation with L-serine protected against some of those changes. We examined the impact of BMAA on AA concentrations in human neuroblastoma cells in vitro. Cells were treated with 1000 µM BMAA and intracellular free AA concentrations in treated and control cells were compared at six time-points over a 48 h culture period. BMAA had a profound effect on intracellular AA levels at specific time points but in most cases, AA homeostasis was re-established in the cell. The most heavily impacted amino acid was serine which was depleted in BMAA-treated cells from 9 h onwards. Correction of serine depletion could be a factor in the observation that supplementation with L-serine protects against BMAA toxicity in vitro and in vivo. AAs that could potentially be involved in protection against BMAA-induced oxidation such as histidine, tyrosine, and phenylalanine were depleted in cells at later time points.}, } @article {pmid37999522, year = {2023}, author = {Metcalf, JS and Banack, SA and Cox, PA}, title = {Cyanotoxin Analysis of Air Samples from the Great Salt Lake.}, journal = {Toxins}, volume = {15}, number = {11}, pages = {}, pmid = {37999522}, issn = {2072-6651}, mesh = {Humans ; *Lakes/microbiology ; *Cyanobacteria ; Water ; Utah ; Cyanobacteria Toxins ; }, abstract = {The Great Salt Lake in Utah is the largest saline lake in the Western hemisphere and one of the largest terminal lakes in the world. Situated at the eastern edge of the Great Basin, it is a remnant of the freshwater Lake Bonneville whose water level precipitously lowered about 12,000 years ago due to a natural break in Red Rock pass to the north. It contains a diverse assemblage of cyanobacteria which vary spatially dependent on salinity. In 1984, the waters of the Great Salt Lake occupied 8500 km[2]. Nearly four decades later, the waters occupy 2500 km[2]-a reduction in surface area of 71%. With predominantly westerly winds, there is a potential for the adjacent metropolitan residents to the east to be exposed to airborne cyanobacteria- and cyanotoxin-containing dust. During the summer and fall months of 2022, air and dried sediment samples were collected and assessed for the presence of BMAA which has been identified as a risk factor for ALS. Collection of air samples equivalent to a person breathing for 1 h resulted in BMAA and isomers being found in some air samples, along with their presence in exposed lakebed samples. There was no clear relationship between the presence of these toxins in airborne and adjacent lakebed samples, suggesting that airborne toxins may originate from diffuse rather than point sources. These findings confirm that continued low water levels in the Great Salt Lake may constitute an increasing health hazard for the 2.5 million inhabitants of communities along the Wasatch Front.}, } @article {pmid37999738, year = {2024}, author = {Ovsepian, SV and O'Leary, VB and Martinez, S}, title = {Selective vulnerability of motor neuron types and functional groups to degeneration in amyotrophic lateral sclerosis: review of the neurobiological mechanisms and functional correlates.}, journal = {Brain structure & function}, volume = {229}, number = {1}, pages = {1-14}, pmid = {37999738}, issn = {1863-2661}, support = {Innovation Fund Award 2022//University of Greenwich/ ; COOPERATIO-207036//VBO, Charles University/ ; SAF2017-83702-R//Una manera de hacer Europa/ ; }, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis ; Motor Neurons ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterised by a progressive loss of motor neurons controlling voluntary muscle activity. The disease manifests through a variety of motor dysfunctions related to the extent of damage and loss of neurons at different anatomical locations. Despite extensive research, it remains unclear why some motor neurons are especially susceptible to the disease, while others are affected less or even spared. In this article, we review the neurobiological mechanisms, neurochemical profiles, and morpho-functional characteristics of various motor neuron groups and types of motor units implicated in their differential exposure to degeneration. We discuss specific cell-autonomous (intrinsic) and extrinsic factors influencing the vulnerability gradient of motor units and motor neuron types to ALS, with their impact on disease manifestation, course, and prognosis, as revealed in preclinical and clinical studies. We consider the outstanding challenges and emerging opportunities for interpreting the phenotypic and mechanistic variability of the disease to identify targets for clinical interventions.}, } @article {pmid38000932, year = {2024}, author = {Abel, EJ and Master, VA and Spiess, PE and Raman, JD and Shapiro, DD and Sexton, WJ and Zemp, L and Patil, D and Lauer, K and Allen, GO and Matin, SF and Karam, JA}, title = {Reply to Eduard Roussel, Riccardo Bertolo, Chiara Ciccarese, et al's Letter to the Editor re: E. Jason Abel, Viraj A. Master, Philippe E. Spiess, et al. The Selection for Cytoreductive Nephrectomy (SCREEN) Score: Improving Surgical Risk Stratification by Integrating Common Radiographic Features. Eur Urol Oncol. 2023;6:266-274.}, journal = {European urology oncology}, volume = {7}, number = {2}, pages = {302-303}, doi = {10.1016/j.euo.2023.10.025}, pmid = {38000932}, issn = {2588-9311}, mesh = {Humans ; *Cytoreduction Surgical Procedures ; *Kidney Neoplasms/surgery ; Nephrectomy ; Risk Assessment ; }, } @article {pmid38001260, year = {2023}, author = {Kuan, LH and Parnianpour, P and Kushol, R and Kumar, N and Anand, T and Kalra, S and Greiner, R}, title = {Accurate personalized survival prediction for amyotrophic lateral sclerosis patients.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {20713}, pmid = {38001260}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Neurodegenerative Diseases ; Probability ; Brain ; Learning ; Disease Progression ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease. Accurately predicting the survival time for ALS patients can help patients and clinicians to plan for future treatment and care. We describe the application of a machine-learned tool that incorporates clinical features and cortical thickness from brain magnetic resonance (MR) images to estimate the time until a composite respiratory failure event for ALS patients, and presents the prediction as individual survival distributions (ISDs). These ISDs provide the probability of survival (none of the respiratory failures) at multiple future time points, for each individual patient. Our learner considers several survival prediction models, and selects the best model to provide predictions. We evaluate our learned model using the mean absolute error margin (MAE-margin), a modified version of mean absolute error that handles data with censored outcomes. We show that our tool can provide helpful information for patients and clinicians in planning future treatment.}, } @article {pmid38001557, year = {2024}, author = {Genge, A and Wainwright, S and Vande Velde, C}, title = {Amyotrophic lateral sclerosis: exploring pathophysiology in the context of treatment.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {225-236}, doi = {10.1080/21678421.2023.2278503}, pmid = {38001557}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex, neurodegenerative disorder in which alterations in structural, physiological, and metabolic parameters act synergistically. Over the last decade there has been a considerable focus on developing drugs to slow the progression of the disease. Despite this, only four disease-modifying therapies are approved in North America. Although additional research is required for a thorough understanding of ALS, we have accumulated a large amount of knowledge that could be better integrated into future clinical trials to accelerate drug development and provide patients with improved treatment options. It is likely that future, successful ALS treatments will take a multi-pronged therapeutic approach, targeting different pathways, akin to personalized medicine in oncology. In this review, we discuss the link between ALS pathophysiology and treatments, looking at the therapeutic failures as learning opportunities that can help us refine and optimize drug development.}, } @article {pmid38001563, year = {2023}, author = {Fröhlich, A and Pfaff, AL and Bubb, VJ and Quinn, JP and Koks, S}, title = {Transcriptomic profiling of cerebrospinal fluid identifies ALS pathway enrichment and RNA biomarkers in MND individuals.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {248}, number = {23}, pages = {2325-2331}, pmid = {38001563}, issn = {1535-3699}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications/metabolism ; *Motor Neuron Disease/cerebrospinal fluid/complications ; Gene Expression Profiling ; Biomarkers/metabolism ; RNA ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and the most common form of motor neurone disease (MND) which is characterized by the damage and death of motor neurons in the brain and spinal cord of affected individuals. Due to the heterogeneity of the disease, a better understanding of the interaction between genetics and biochemistry with the identification of biomarkers is crucial for therapy development. In this study, we used cerebrospinal fluid (CSF) RNA-sequencing data from the New York Genome Center (NYGC) ALS Consortium and analyzed differential gene expression between 47 MND individuals and 29 healthy controls. Pathway analysis showed that the affected genes are enriched in many pathways associated with ALS, including nucleocytoplasmic transport, autophagy, and apoptosis. Moreover, we assessed differential expression on both gene- and transcript-based levels and demonstrate that the expression of previously identified potential biomarkers, including CAPG, CCL3, and MAP2, was significantly higher in MND individuals. Ultimately, this study highlights the transcriptomic composition of CSF which enables insights into changes in the brain in ALS and therefore increases the confidence in the use of CSF for biomarker development.}, } @article {pmid38001860, year = {2023}, author = {Martinez, A and Lamaizon, CM and Valls, C and Llambi, F and Leal, N and Fitzgerald, P and Guy, C and Kamiński, MM and Inestrosa, NC and van Zundert, B and Cancino, GI and Dulcey, AE and Zanlungo, S and Marugan, JJ and Hetz, C and Green, DR and Alvarez, AR}, title = {c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {11}, pages = {}, pmid = {38001860}, issn = {2076-3921}, support = {R35 CA231620/CA/NCI NIH HHS/United States ; R35CA23160/BC/NCI NIH HHS/United States ; Intramural funding/TR/NCATS NIH HHS/United States ; }, abstract = {The endoplasmic reticulum is a subcellular organelle key in the control of synthesis, folding, and sorting of proteins. Under endoplasmic reticulum stress, an adaptative unfolded protein response is activated; however, if this activation is prolonged, cells can undergo cell death, in part due to oxidative stress and mitochondrial fragmentation. Here, we report that endoplasmic reticulum stress activates c-Abl tyrosine kinase, inducing its translocation to mitochondria. We found that endoplasmic reticulum stress-activated c-Abl interacts with and phosphorylates the mitochondrial fusion protein MFN2, resulting in mitochondrial fragmentation and apoptosis. Moreover, the pharmacological or genetic inhibition of c-Abl prevents MFN2 phosphorylation, mitochondrial fragmentation, and apoptosis in cells under endoplasmic reticulum stress. Finally, in the amyotrophic lateral sclerosis mouse model, where endoplasmic reticulum and oxidative stress has been linked to neuronal cell death, we demonstrated that the administration of c-Abl inhibitor neurotinib delays the onset of symptoms. Our results uncovered a function of c-Abl in the crosstalk between endoplasmic reticulum stress and mitochondrial dynamics via MFN2 phosphorylation.}, } @article {pmid38001861, year = {2023}, author = {Fu, RH}, title = {Pectolinarigenin Improves Oxidative Stress and Apoptosis in Mouse NSC-34 Motor Neuron Cell Lines Induced by C9-ALS-Associated Proline-Arginine Dipeptide Repeat Proteins by Enhancing Mitochondrial Fusion Mediated via the SIRT3/OPA1 Axis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {11}, pages = {}, pmid = {38001861}, issn = {2076-3921}, support = {MOST 105-2314-B-039-017-MY3//The Ministry of Science and Technology (Taiwan)/ ; DMR112-122//China Medical University Hospital (Taiwan)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is considered a fatal progressive degeneration of motor neurons (MN) caused by oxidative stress and mitochondrial dysfunction. There are currently no treatments available. The most common inherited form of ALS is the C9orf72 mutation (C9-ALS). The proline-arginine dipeptide repeat protein (PR-DPR) produced by C9-ALS has been confirmed to be a functionally acquired pathogenic factor that can cause increased ROS, mitochondrial defects, and apoptosis in motor neurons. Pectolinarigenin (PLG) from the traditional medicinal herb Linaria vulgaris has antioxidant and anti-apoptotic properties. I established a mouse NSC-34 motor neuron cell line model expressing PR-DPR and confirmed the neuroprotective effect of PLG. The results showed that ROS production and apoptosis caused by PR-DPR could be improved by PLG treatment. In terms of mechanism research, PR-DPR inhibited the activity of the mitochondrial fusion proteins OPA1 and mitofusin 2. Conversely, the expression of fission protein fission 1 and dynamin-related protein 1 (DRP1) increased. However, PLG treatment reversed these effects. Furthermore, I found that PLG increased the expression and deacetylation of OPA1. Deacetylation of OPA1 enhances mitochondrial fusion and resistance to apoptosis. Finally, transfection with Sirt3 small interfering RNA abolished the neuroprotective effects of PLG. In summary, the mechanism by which PLG alleviates PR-DPR toxicity is mainly achieved by activating the SIRT3/OPA1 axis to regulate the balance of mitochondrial dynamics. Taken together, the potential of PLG in preclinical studies for C9-ALS drug development deserves further evaluation.}, } @article {pmid38001926, year = {2023}, author = {Reddy, VP}, title = {Oxidative Stress in Health and Disease.}, journal = {Biomedicines}, volume = {11}, number = {11}, pages = {}, pmid = {38001926}, issn = {2227-9059}, abstract = {Oxidative stress, resulting from the excessive intracellular accumulation of reactive oxygen species (ROS), reactive nitrogen species (RNS), and other free radical species, contributes to the onset and progression of various diseases, including diabetes, obesity, diabetic nephropathy, diabetic neuropathy, and neurological diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Oxidative stress is also implicated in cardiovascular disease and cancer. Exacerbated oxidative stress leads to the accelerated formation of advanced glycation end products (AGEs), a complex mixture of crosslinked proteins and protein modifications. Relatively high levels of AGEs are generated in diabetes, obesity, AD, and other I neurological diseases. AGEs such as N[e]-carboxymethyllysine (CML) serve as markers for disease progression. AGEs, through interaction with receptors for advanced glycation end products (RAGE), initiate a cascade of deleterious signaling events to form inflammatory cytokines, and thereby further exacerbate oxidative stress in a vicious cycle. AGE inhibitors, AGE breakers, and RAGE inhibitors are therefore potential therapeutic agents for multiple diseases, including diabetes and AD. The complexity of the AGEs and the lack of well-established mechanisms for AGE formation are largely responsible for the lack of effective therapeutics targeting oxidative stress and AGE-related diseases. This review addresses the role of oxidative stress in the pathogenesis of AGE-related chronic diseases, including diabetes and neurological disorders, and recent progress in the development of therapeutics based on antioxidants, AGE breakers and RAGE inhibitors. Furthermore, this review outlines therapeutic strategies based on single-atom nanozymes that attenuate oxidative stress through the sequestering of reactive oxygen species (ROS) and reactive nitrogen species (RNS).}, } @article {pmid38001967, year = {2023}, author = {Seki, S and Kitaoka, Y and Kawata, S and Nishiura, A and Uchihashi, T and Hiraoka, SI and Yokota, Y and Isomura, ET and Kogo, M and Tanaka, S}, title = {Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy.}, journal = {Biomedicines}, volume = {11}, number = {11}, pages = {}, pmid = {38001967}, issn = {2227-9059}, support = {21K17088//JSPS KAKENHI/ ; 20H03887//JSPS KAKENHI/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by the progressive degeneration of motor neurons, resulting in muscle weakness, paralysis, and, ultimately, death. Presently, no effective treatment for ALS has been established. Although motor neuron dysfunction is a hallmark of ALS, emerging evidence suggests that sensory neurons are also involved in the disease. In clinical research, 30% of patients with ALS had sensory symptoms and abnormal sensory nerve conduction studies in the lower extremities. Peroneal nerve biopsies show histological abnormalities in 90% of the patients. Preclinical research has reported several genetic abnormalities in the sensory neurons of animal models of ALS, as well as in motor neurons. Furthermore, the aggregation of misfolded proteins like TAR DNA-binding protein 43 has been reported in sensory neurons. This review aims to provide a comprehensive description of ALS-related sensory neuron dysfunction, focusing on its clinical changes and underlying mechanisms. Sensory neuron abnormalities in ALS are not limited to somatosensory issues; proprioceptive sensory neurons, such as MesV and DRG neurons, have been reported to form networks with motor neurons and may be involved in motor control. Despite receiving limited attention, sensory neuron abnormalities in ALS hold potential for new therapies targeting proprioceptive sensory neurons.}, } @article {pmid38001994, year = {2023}, author = {Jauregui, C and Blanco-Luquin, I and Macías, M and Roldan, M and Caballero, C and Pagola, I and Mendioroz, M and Jericó, I}, title = {Exploring the Disease-Associated Microglia State in Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {11}, number = {11}, pages = {}, pmid = {38001994}, issn = {2227-9059}, abstract = {BACKGROUND: Neuroinflammation, and specifically microglia, plays an important but not-yet well-understood role in the pathophysiology of amyotrophic lateral sclerosis (ALS), constituting a potential therapeutic target for the disease. Recent studies have described the involvement of different microglial transcriptional patterns throughout neurodegenerative processes, identifying a new state of microglia: disease-associated microglia (DAM). The aim of this study is to investigate expression patterns of microglial-related genes in ALS spinal cord.

METHODS: We analyzed mRNA expression levels via RT-qPCR of several microglia-related genes in their homeostatic and DAM state in postmortem tissue (anterior horn of the spinal cord) from 20 subjects with ALS-TDP43 and 19 controls donors from the Navarrabiomed Biobank.

RESULTS: The expression levels of TREM2, MS4A, CD33, APOE and TYROBP were found to be elevated in the spinal cord from ALS subjects versus controls (p-value < 0.05). However, no statistically significant gene expression differences were observed for TMEM119, SPP1 and LPL.

CONCLUSIONS: This study suggests that a DAM-mediated inflammatory response is present in ALS, and TREM2 plays a significant role in immune function of microglia. It also supports the role of C33 and MS4A in the physiopathology of ALS.}, } @article {pmid38002264, year = {2023}, author = {Duranti, E and Villa, C}, title = {Muscle Involvement in Amyotrophic Lateral Sclerosis: Understanding the Pathogenesis and Advancing Therapeutics.}, journal = {Biomolecules}, volume = {13}, number = {11}, pages = {}, pmid = {38002264}, issn = {2218-273X}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy/pathology ; Motor Neurons/metabolism ; Muscle, Skeletal/pathology ; Muscular Atrophy/metabolism ; Paralysis/complications/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal condition characterized by the selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. Muscle involvement, muscle atrophy, and subsequent paralysis are among the main features of this disease, which is defined as a neuromuscular disorder. ALS is a persistently progressive disease, and as motor neurons continue to degenerate, individuals with ALS experience a gradual decline in their ability to perform daily activities. Ultimately, muscle function loss may result in paralysis, presenting significant challenges in mobility, communication, and self-care. While the majority of ALS research has traditionally focused on pathogenic pathways in the central nervous system, there has been a great interest in muscle research. These studies were carried out on patients and animal models in order to better understand the molecular mechanisms involved and to develop therapies aimed at improving muscle function. This review summarizes the features of ALS and discusses the role of muscle, as well as examines recent studies in the development of treatments.}, } @article {pmid38002405, year = {2023}, author = {Wu, CM and Chen, YJ and Chen, SC and Zheng, SF}, title = {Creating an AI-Enhanced Morse Code Translation System Based on Images for People with Severe Disabilities.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {10}, number = {11}, pages = {}, pmid = {38002405}, issn = {2306-5354}, support = {NSTC 111-2221-E-167-039 and MOST 111-2221-E-218-023//the National Science and Technology Council (NSTC), Taiwan/ ; }, abstract = {(1) Background: Patients with severe physical impairments (spinal cord injury, cerebral palsy, amyotrophic lateral sclerosis) often have limited mobility due to physical limitations, and may even be bedridden all day long, losing the ability to take care of themselves. In more severe cases, the ability to speak may even be lost, making even basic communication very difficult. (2) Methods: This research will design a set of image-assistive communication equipment based on artificial intelligence to solve communication problems of daily needs. Using artificial intelligence for facial positioning, and facial-motion-recognition-generated Morse code, and then translating it into readable characters or commands, it allows users to control computer software by themselves and communicate through wireless networks or a Bluetooth protocol to control environment peripherals. (3) Results: In this study, 23 human-typed data sets were subjected to recognition using fuzzy algorithms. The average recognition rates for expert-generated data and data input by individuals with disabilities were 99.83% and 98.6%, respectively. (4) Conclusions: Through this system, users can express their thoughts and needs through their facial movements, thereby improving their quality of life and having an independent living space. Moreover, the system can be used without touching external switches, greatly improving convenience and safety.}, } @article {pmid38002490, year = {2023}, author = {Yang, J and Xin, C and Huo, J and Li, X and Dong, H and Liu, Q and Li, R and Liu, Y}, title = {Rab Geranylgeranyltransferase Subunit Beta as a Potential Indicator to Assess the Progression of Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {13}, number = {11}, pages = {}, pmid = {38002490}, issn = {2076-3425}, support = {H2021206310//Natural Science Foundation of Hebei Province/ ; }, abstract = {BACKGROUND: Currently, there is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder. Many biomarkers have been proposed, but because ALS is a clinically heterogeneous disease with an unclear etiology, biomarker discovery for ALS has been challenging due to the lack of specificity of these biomarkers. In recent years, the role of autophagy in the development and treatment of ALS has become a research hotspot. In our previous studies, we found that the expression of RabGGTase (low RABGGTB expression and no change in RABGGTA) is lower in the lumbar and thoracic regions of spinal cord motoneurons in SOD1G93A mice compared with WT (wild-type) mice groups, and upregulation of RABGGTB promoted prenylation modification of Rab7, which promoted autophagy to protect neurons by degrading SOD1. Given that RabGGTase is associated with autophagy and autophagy is associated with inflammation, and based on the above findings, since peripheral blood mononuclear cells are readily available from patients with ALS, we proposed to investigate the expression of RabGGTase in peripheral inflammatory cells.

METHODS: Information and venous blood were collected from 86 patients diagnosed with ALS between January 2021 and August 2023. Flow cytometry was used to detect the expression of RABGGTB in monocytes from peripheral blood samples collected from patients with ALS and healthy controls. Extracted peripheral blood mononuclear cells (PBMCs) were differentiated in vitro into macrophages, and then the expression of RABGGTB was detected by immunofluorescence. RABGGTB levels in patients with ALS were analyzed to determine their impact on disease progression.

RESULTS: Using flow cytometry in monocytes and immunofluorescence in macrophages, we found that RABGGTB expression in the ALS group was significantly higher than in the control group. Age, sex, original location, disease course, C-reactive protein (CRP), and interleukin-6 (IL-6) did not correlate with the ALS functional rating scale-revised (ALSFRS-R), whereas the RABGGTB level was significantly correlated with the ALSFRS-R. In addition, multivariate analysis revealed a significant correlation between RABGGTB and ALSFRS-R score. Further analysis revealed a significant correlation between RABGGTB expression levels and disease progression levels (ΔFS).

CONCLUSIONS: The RABGGTB level was significantly increased in patients with ALS compared with healthy controls. An elevated RABGGTB level in patients with ALS is associated with the rate of progression in ALS, suggesting that elevated RABGGTB levels in patients with ALS may serve as an indicator for tracking ALS progression.}, } @article {pmid38002573, year = {2023}, author = {Goto, S and Maeda, N and Uehara, K and Ogawa, K and Matsumaru, M and Sugiyama, S and Ohnuma, K and Lawu, T and Noda, T}, title = {Effect of Segmented Optical Axial Length on the Performance of New-Generation Intraocular Lens Power Calculation Formulas in Extremely Long Eyes.}, journal = {Journal of clinical medicine}, volume = {12}, number = {22}, pages = {}, pmid = {38002573}, issn = {2077-0383}, abstract = {PURPOSE: To evaluate the performance of traditional vergence formulas with segmented axial length (AL) compared to traditional composite AL in extremely long eyes, and to determine whether the segmented AL can be extended to the new-generation formulas, including the Barrett Universal II, Emmetropia Verifying Optical 2.0 (EVO2), Hill-RBF 3.0 (Hill3), Kane, and Ladas Super formula (LSF) formulas in extremely long eyes.

SETTING: National Hospital. Organization, Tokyo Medical Center, Japan.

DESIGN: Retrospective case series.

METHODS: Consecutive patients who underwent uncomplicated cataract surgery implanted with a three-piece intraocular lens between December 2015 and March 2021 were retrospectively reviewed. The composite AL was measured with a swept-source optical coherence tomography (SS-OCT) biometer using a mean refractive index. The segmented AL was calculated by summing the geometric lengths of the ocular segments (cornea, aqueous, lens, and vitreous) using multiple specific refractive indices based on the data obtained by the SS-OCT-based biometer. When refraction was measured at three months postoperatively, the median absolute errors (MedAEs) were calculated with two ALs for each formula.

RESULTS: The study included 31 eyes of 22 patients. The segmented AL (30.45 ± 1.23 mm) was significantly shorter than the composite AL (30.71 ± 1.28 mm, p < 0.001). The MedAEs were significantly reduced when using segmented AL for SRK/T, Haigis, Hill3, and LSF, compared to those obtained using composite AL (0.38 vs. 0.62, 0.48 vs. 0.79, 0.50 vs. 0.90, 0.34 vs. 0.61, p < 0.001 for all formulas, respectively). On the contrary, the MedAE obtained by Kane with segmented AL was significantly worse compared to the one with composite AL (0.35 vs. 0.27, p = 0.03).

CONCLUSION: In extremely high myopic eyes, the segmented AL improves the performance of SRK/T, Haigis, Hill3, and LSF formulas compared to the composite AL, while the segmented AL worsens the prediction accuracy of the Kane formula.}, } @article {pmid38002659, year = {2023}, author = {O'Day, DH}, title = {Protein Biomarkers Shared by Multiple Neurodegenerative Diseases Are Calmodulin-Binding Proteins Offering Novel and Potentially Universal Therapeutic Targets.}, journal = {Journal of clinical medicine}, volume = {12}, number = {22}, pages = {}, pmid = {38002659}, issn = {2077-0383}, abstract = {Seven major neurodegenerative diseases and their variants share many overlapping biomarkers that are calmodulin-binding proteins: Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTD), Huntington's disease (HD), Lewy body disease (LBD), multiple sclerosis (MS), and Parkinson's disease (PD). Calcium dysregulation is an early and persistent event in each of these diseases, with calmodulin serving as an initial and primary target of increased cytosolic calcium. Considering the central role of calcium dysregulation and its downstream impact on calcium signaling, calmodulin has gained interest as a major regulator of neurodegenerative events. Here, we show that calmodulin serves a critical role in neurodegenerative diseases via binding to and regulating an abundance of biomarkers, many of which are involved in multiple neurodegenerative diseases. Of special interest are the shared functions of calmodulin in the generation of protein biomarker aggregates in AD, HD, LBD, and PD, where calmodulin not only binds to amyloid beta, pTau, alpha-synuclein, and mutant huntingtin but also, via its regulation of transglutaminase 2, converts them into toxic protein aggregates. It is suggested that several calmodulin binding proteins could immediately serve as primary drug targets, while combinations of calmodulin binding proteins could provide simultaneous insight into the onset and progression of multiple neurodegenerative diseases.}, } @article {pmid38002924, year = {2023}, author = {Genin, EC and Abou-Ali, M and Paquis-Flucklinger, V}, title = {Mitochondria, a Key Target in Amyotrophic Lateral Sclerosis Pathogenesis.}, journal = {Genes}, volume = {14}, number = {11}, pages = {}, pmid = {38002924}, issn = {2073-4425}, support = {ANR-16-CE16-0024-01//Agence Nationale de la Recherche/ ; MND202004011475//Fondation pour la Recherche Médicale/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Cell Death/genetics ; Mitochondrial Proteins/genetics/metabolism ; }, abstract = {Mitochondrial dysfunction occurs in numerous neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS), where it contributes to motor neuron (MN) death. Of all the factors involved in ALS, mitochondria have been considered as a major player, as secondary mitochondrial dysfunction has been found in various models and patients. Abnormal mitochondrial morphology, defects in mitochondrial dynamics, altered activities of respiratory chain enzymes and increased production of reactive oxygen species have been described. Moreover, the identification of CHCHD10 variants in ALS patients was the first genetic evidence that a mitochondrial defect may be a primary cause of MN damage and directly links mitochondrial dysfunction to the pathogenesis of ALS. In this review, we focus on the role of mitochondria in ALS and highlight the pathogenic variants of ALS genes associated with impaired mitochondrial functions. The multiple pathways demonstrated in ALS pathogenesis suggest that all converge to a common endpoint leading to MN loss. This may explain the disappointing results obtained with treatments targeting a single pathological process. Fighting against mitochondrial dysfunction appears to be a promising avenue for developing combined therapies in the future.}, } @article {pmid38002967, year = {2023}, author = {Tourtourikov, I and Dabchev, K and Todorov, T and Angelov, T and Chamova, T and Tournev, I and Kadiyska, T and Mitev, V and Todorova, A}, title = {Navigating the ALS Genetic Labyrinth: The Role of MAPT Haplotypes.}, journal = {Genes}, volume = {14}, number = {11}, pages = {}, pmid = {38002967}, issn = {2073-4425}, support = {D-186/ 14.06.2022//Medical University Sofia/ ; }, mesh = {Humans ; Haplotypes ; *Amyotrophic Lateral Sclerosis/genetics ; tau Proteins/genetics ; *Neurodegenerative Diseases ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by wide clinical and biological heterogeneity, with a large proportion of ALS patients also exhibiting frontotemporal dementia (FTD) spectrum symptoms. This project aimed to characterize risk subtypes of the H1 haplotype within the MAPT (microtubule-associated protein tau) gene, according to their possible effect as a risk factor and as a modifying factor in relation to the age of disease onset. One hundred patients from Bulgaria with sporadic ALS were genotyped for the variants rs1467967, rs242557, rs1800547, rs3785883, rs2471738, and rs7521. Haploview 4.2 and SHEsisPlus were used to reconstruct haplotype frequencies using genotyping data from the 1000 Genomes project as controls. Genotype-phenotype correlation was investigated in the context of age of disease onset and risk of disease development. While the individual variants of the subtypes do not influence the age of onset of the disease, a correlation was found between the specific haplotype GGAGCA (H1b) and the risk of developing sALS, with results showing that individuals harboring this haplotype have a nearly two-fold increased risk of developing sALS compared to other H1 subtypes. The results from this study suggest that fine transcriptional regulation at the MAPT locus can influence the risk of ALS.}, } @article {pmid38002982, year = {2023}, author = {Lombardi, M and Corrado, L and Piola, B and Comi, C and Cantello, R and D'Alfonso, S and Mazzini, L and De Marchi, F}, title = {Variability in Clinical Phenotype in TARDBP Mutations: Amyotrophic Lateral Sclerosis Case Description and Literature Review.}, journal = {Genes}, volume = {14}, number = {11}, pages = {}, pmid = {38002982}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Italy ; Mutation ; Phenotype ; }, abstract = {Mutations in the 43 kDa transactive-response (TAR)-DNA-binding protein (TARDBP) are associated with 2-5% of familial Amyotrophic Lateral Sclerosis (ALS) cases. TAR DNA-Binding Protein 43 (TDP-43) is an RNA/DNA-binding protein involved in several cellular mechanisms (e.g., transcription, pre-mRNA processing, and splicing). Many ALS-linked TARDBP mutations have been described in the literature, but few phenotypic data on monogenic TARDBP-mutated ALS are available. In this paper, (1) we describe the clinical features of ALS patients carrying mutations in the TARDBP gene evaluated at the Tertiary ALS Center at Maggiore della Carità University Hospital, Novara, Italy, from 2010 to 2020 and (2) present the results of our review of the literature on this topic, analyzing data obtained for 267 patients and highlighting their main clinical and demographic features.}, } @article {pmid38003212, year = {2023}, author = {Lovatto, M and Gonçalves-Vidigal, MC and Vaz Bisneta, M and Calvi, AC and Mazucheli, J and Vidigal Filho, PS and Miranda, EGR and Melotto, M}, title = {Responsiveness of Candidate Genes on CoPv01[CDRK]/PhgPv01[CD][RK] Loci in Common Bean Challenged by Anthracnose and Angular Leaf Spot Pathogens.}, journal = {International journal of molecular sciences}, volume = {24}, number = {22}, pages = {}, pmid = {38003212}, issn = {1422-0067}, support = {408472/2018-9//National Council for Scientific and Technological Development/ ; BEX 88881.170662//2018-01//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; }, mesh = {Chromosome Mapping ; *Colletotrichum/genetics ; Disease Resistance/genetics ; Genetic Linkage ; Genetic Markers ; Kidney ; *Phaseolus/genetics ; Plant Diseases/genetics ; }, abstract = {Anthracnose (ANT) and angular leaf spot (ALS) are significant diseases in common bean, leading to considerable yield losses under specific environmental conditions. The California Dark Red Kidney (CDRK) bean cultivar is known for its resistance to multiple races of both pathogens. Previous studies have identified the CoPv01[CDRK]/PhgPv01[CDRK] resistance loci on chromosome Pv01. Here, we evaluated the expression levels of ten candidate genes near the CoPv01[CDRK]/PhgPv01[CDRK] loci and plant defense genes using quantitative real-time PCR in CDRK cultivar inoculated with races 73 of Colletotrichum lindemuthianum and 63-39 of Pseudocercospora griseola. Gene expression analysis revealed that the Phvul.001G246300 gene exhibited the most elevated levels, showing remarkable 7.8-fold and 8.5-fold increases for ANT and ALS, respectively. The Phvul.001G246300 gene encodes an abscisic acid (ABA) receptor with pyrabactin resistance, PYR1-like (PYL) protein, which plays a central role in the crosstalk between ABA and jasmonic acid responses. Interestingly, our results also showed that the other defense genes were initially activated. These findings provide critical insights into the molecular mechanisms underlying plant defense against these diseases and could contribute to the development of more effective disease management strategies in the future.}, } @article {pmid38003309, year = {2023}, author = {Toader, C and Dobrin, N and Brehar, FM and Popa, C and Covache-Busuioc, RA and Glavan, LA and Costin, HP and Bratu, BG and Corlatescu, AD and Popa, AA and Ciurea, AV}, title = {From Recognition to Remedy: The Significance of Biomarkers in Neurodegenerative Disease Pathology.}, journal = {International journal of molecular sciences}, volume = {24}, number = {22}, pages = {}, pmid = {38003309}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Amyotrophic Lateral Sclerosis ; *Parkinson Disease/diagnosis/metabolism ; *Alzheimer Disease/diagnosis ; Biomarkers/metabolism ; }, abstract = {With the inexorable aging of the global populace, neurodegenerative diseases (NDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose escalating challenges, which are underscored by their socioeconomic repercussions. A pivotal aspect in addressing these challenges lies in the elucidation and application of biomarkers for timely diagnosis, vigilant monitoring, and effective treatment modalities. This review delineates the quintessence of biomarkers in the realm of NDs, elucidating various classifications and their indispensable roles. Particularly, the quest for novel biomarkers in AD, transcending traditional markers in PD, and the frontier of biomarker research in ALS are scrutinized. Emergent susceptibility and trait markers herald a new era of personalized medicine, promising enhanced treatment initiation especially in cases of SOD1-ALS. The discourse extends to diagnostic and state markers, revolutionizing early detection and monitoring, alongside progression markers that unveil the trajectory of NDs, propelling forward the potential for tailored interventions. The synergy between burgeoning technologies and innovative techniques like -omics, histologic assessments, and imaging is spotlighted, underscoring their pivotal roles in biomarker discovery. Reflecting on the progress hitherto, the review underscores the exigent need for multidisciplinary collaborations to surmount the challenges ahead, accelerate biomarker discovery, and herald a new epoch of understanding and managing NDs. Through a panoramic lens, this article endeavors to provide a comprehensive insight into the burgeoning field of biomarkers in NDs, spotlighting the promise they hold in transforming the diagnostic landscape, enhancing disease management, and illuminating the pathway toward efficacious therapeutic interventions.}, } @article {pmid38003404, year = {2023}, author = {Huang, B and Liu, X and Zhang, T and Wu, Q and Huang, C and Xia, XG and Zhou, H}, title = {Increase in hnRNPA1 Expression Suffices to Kill Motor Neurons in Transgenic Rats.}, journal = {International journal of molecular sciences}, volume = {24}, number = {22}, pages = {}, pmid = {38003404}, issn = {1422-0067}, support = {R01 NS089701/NS/NINDS NIH HHS/United States ; R01 NS095962/NS/NINDS NIH HHS/United States ; R01 NS110455/NS/NINDS NIH HHS/United States ; NS089701, NS095962, NS110455/NS/NINDS NIH HHS/United States ; }, mesh = {Rats ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Rats, Transgenic ; Motor Neurons/metabolism ; Phenotype ; Mutation ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase-1/genetics ; }, abstract = {A dominant mutation in hnRNPA1 causes amyotrophic lateral sclerosis (ALS), but it is not known whether this mutation leads to motor neuron death through increased or decreased function. To elucidate the relationship between pathogenic hnRNPA1 mutation and its native function, we created novel transgenic rats that overexpressed wildtype rat hnRNPA1 exclusively in motor neurons. This targeted expression of wildtype hnRNPA1 caused severe motor neuron loss and subsequent denervation muscle atrophy in transgenic rats that recapitulated the characteristics of ALS. These findings demonstrate that the augmentation of hnRNPA1 expression suffices to trigger motor neuron degeneration and the manifestation of ALS-like phenotypes. It is reasonable to infer that an amplification of an as-yet undetermined hnRNPA1 function plays a pivotal role in the pathogenesis of familial ALS caused by pathogenic hnRNPA1 mutation.}, } @article {pmid38004577, year = {2023}, author = {Niazi, SK}, title = {Non-Invasive Drug Delivery across the Blood-Brain Barrier: A Prospective Analysis.}, journal = {Pharmaceutics}, volume = {15}, number = {11}, pages = {}, pmid = {38004577}, issn = {1999-4923}, abstract = {Non-invasive drug delivery across the blood-brain barrier (BBB) represents a significant advancement in treating neurological diseases. The BBB is a tightly packed layer of endothelial cells that shields the brain from harmful substances in the blood, allowing necessary nutrients to pass through. It is a highly selective barrier, which poses a challenge to delivering therapeutic agents into the brain. Several non-invasive procedures and devices have been developed or are currently being investigated to enhance drug delivery across the BBB. This paper presents a review and a prospective analysis of the art and science that address pharmacology, technology, delivery systems, regulatory approval, ethical concerns, and future possibilities.}, } @article {pmid38005288, year = {2023}, author = {Lapshina, MA and Shevtsova, EF and Grigoriev, VV and Aksinenko, AY and Ustyugov, AA and Steinberg, DA and Maleev, GV and Dubrovskaya, ES and Goreva, TV and Epishina, TA and Zamoyski, VL and Makhaeva, GF and Fisenko, VP and Veselov, IM and Vinogradova, DV and Bachurin, SO}, title = {New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {22}, pages = {}, pmid = {38005288}, issn = {1420-3049}, support = {19-13-00378-P//Russian Science Foundation/ ; }, mesh = {Humans ; Edaravone/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Adamantane ; Riluzole ; Amantadine/therapeutic use ; }, abstract = {Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone-phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.}, } @article {pmid38005489, year = {2023}, author = {Li, J and Liang, W and Yin, X and Li, J and Guan, W}, title = {Multimodal Gait Abnormality Recognition Using a Convolutional Neural Network-Bidirectional Long Short-Term Memory (CNN-BiLSTM) Network Based on Multi-Sensor Data Fusion.}, journal = {Sensors (Basel, Switzerland)}, volume = {23}, number = {22}, pages = {}, pmid = {38005489}, issn = {1424-8220}, support = {No. 2021AAA007//Department of Science and Technology of Hubei Province/ ; }, mesh = {Humans ; *Parkinson Disease/diagnosis ; *Amyotrophic Lateral Sclerosis ; Neural Networks, Computer ; Gait ; *Huntington Disease ; }, abstract = {Global aging leads to a surge in neurological diseases. Quantitative gait analysis for the early detection of neurological diseases can effectively reduce the impact of the diseases. Recently, extensive research has focused on gait-abnormality-recognition algorithms using a single type of portable sensor. However, these studies are limited by the sensor's type and the task specificity, constraining the widespread application of quantitative gait recognition. In this study, we propose a multimodal gait-abnormality-recognition framework based on a Convolutional Neural Network-Bidirectional Long Short-Term Memory (CNN-BiLSTM) network. The as-established framework effectively addresses the challenges arising from smooth data interference and lengthy time series by employing an adaptive sliding window technique. Then, we convert the time series into time-frequency plots to capture the characteristic variations in different abnormality gaits and achieve a unified representation of the multiple data types. This makes our signal processing method adaptable to several types of sensors. Additionally, we use a pre-trained Deep Convolutional Neural Network (DCNN) for feature extraction, and the consequently established CNN-BiLSTM network can achieve high-accuracy recognition by fusing and classifying the multi-sensor input data. To validate the proposed method, we conducted diversified experiments to recognize the gait abnormalities caused by different neuropathic diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Huntington's disease (HD). In the PDgait dataset, the framework achieved an accuracy of 98.89% in the classification of Parkinson's disease severity, surpassing DCLSTM's 96.71%. Moreover, the recognition accuracy of ALS, PD, and HD on the PDgait dataset was 100%, 96.97%, and 95.43% respectively, surpassing the majority of previously reported methods. These experimental results strongly demonstrate the potential of the proposed multimodal framework for gait abnormality identification. Due to the advantages of the framework, such as its suitability for different types of sensors and fewer training parameters, it is more suitable for gait monitoring in daily life and the customization of medical rehabilitation schedules, which will help more patients alleviate the harm caused by their diseases.}, } @article {pmid38006254, year = {2024}, author = {Kabir, V and Ombelet, F and Hobin, F and Lamaire, N and De Vocht, J and Van Damme, P}, title = {Prognostic value of motor and extramotor involvement in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {67-74}, doi = {10.1080/21678421.2023.2284899}, pmid = {38006254}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; *Frontotemporal Dementia/complications/diagnosis/psychology ; Cohort Studies ; Prognosis ; Retrospective Studies ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder resulting in upper and lower motor neuron loss. ALS often has a focal onset of weakness, which subsequently spreads to other body regions. Survival is limited to two to five years after disease onset, often due to respiratory failure. Cognitive impairment is present in approximately 30% to 50% of patients and in 10%-15% of patients, the clinical criteria of frontotemporal dementia (FTD) are met.

METHODS: In this retrospective single-center ALS cohort study, we examined the occurrence of cognitive and behavioral impairment in relation to motor impairment at disease presentation and studied its impact on survival.

RESULTS: The degree of lower motor neuron involvement was associated with a worse survival, but there was no effect for upper motor neuron involvement. Patients who were cognitively normal had a significantly better survival compared to patients with cognitive or behavioral impairment and to patients with comorbid FTD. There was no significant difference regarding survival between patients with FTD and patients with cognitive or behavioral impairment.

CONCLUSIONS: The extent of motor and extramotor involvement in patients with ALS at disease presentation holds complementary prognostic information.}, } @article {pmid38007141, year = {2024}, author = {Wong, CH and Rahat, A and Chang, HC}, title = {Fused in sarcoma regulates glutamate signaling and oxidative stress response.}, journal = {Free radical biology & medicine}, volume = {210}, number = {}, pages = {172-182}, pmid = {38007141}, issn = {1873-4596}, support = {P40 OD010440/OD/NIH HHS/United States ; R01 GM131156/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Caenorhabditis elegans/metabolism ; Glutamates/metabolism ; Mutation ; Oxidation-Reduction ; Oxidative Stress/genetics ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics ; Disease Models, Animal ; *RNA-Binding Protein FUS/genetics/metabolism ; Caenorhabditis elegans Proteins/genetics/metabolism ; }, abstract = {Mutations in fused in sarcoma (fust-1) are linked to ALS. However, how these ALS causative mutations alter physiological processes and lead to the onset of ALS remains largely unknown. By obtaining humanized fust-1 ALS mutations via CRISPR-CAS9, we generated a C. elegans ALS model. Homozygous fust-1 ALS mutant and fust-1 deletion animals are viable in C. elegans. This allows us to better characterize the molecular mechanisms of fust-1-dependent responses. We found FUST-1 plays a role in regulating superoxide dismutase, glutamate signaling, and oxidative stress. FUST-1 suppresses SOD-1 and VGLUT/EAT-4 in the nervous system. FUST-1 also regulates synaptic AMPA-type glutamate receptor GLR-1. We found that fust-1 ALS mutations act as loss-of-function in SOD-1 and VGLUT/EAT-4 phenotypes, whereas the fust-1 ALS mutations act as gain-of-function in redox homeostasis and the microbe-induced oxidative stress response. We hypothesized that FUST-1 is a link between glutamate signaling and SOD-1. Our results may provide new insights into the human ALS alleles and their roles in pathological mechanisms that lead to ALS.}, } @article {pmid38007795, year = {2023}, author = {Feng, T}, title = {Applications of Artificial Intelligence to Diagnosis of Neurodegenerative Diseases.}, journal = {Studies in health technology and informatics}, volume = {308}, number = {}, pages = {648-655}, doi = {10.3233/SHTI230896}, pmid = {38007795}, issn = {1879-8365}, mesh = {Humans ; Artificial Intelligence ; *Neurodegenerative Diseases/diagnostic imaging ; *Alzheimer Disease/diagnostic imaging ; Machine Learning ; Natural Language Processing ; }, abstract = {Artificial Intelligence (AI) is an umbrella term that represents a new technology for simulating and expanding human intelligence by using machines and computer systems. It consists of methods such as machine learning (ML), deep learning (DL), and natural language processing (NLP). In the era of big data, AI has emerged as an essential tool for improving the detection of neurodegenerative diseases, such as Alzheimer's diseases (AD), Parkinson's diseases, amyotrophic lateral sclerosis, etc. AI with its ability to extract critical information from the mass of data has enabled scientists to deal with various types of large-volume data, including genetic data, imaging data, and clinical data, rapidly generated in the course of neurodegenerative disease research. This review provides a comprehensive overview of the literature on current AI applications in the diagnosis of neurodegenerative diseases. Firstly, bioinformatics and AI approaches to identify potential biomarkers for neurodegenerative diseases such as AD are reviewed. Secondly, the use of ML and DL methods to analyze Magnetic Resonance Imaging (MRI) data for a better understanding of disease progression and predicting patient outcomes is discussed. Finally, the use of AI methods including NLP for Electronic Health Record (EHR) data analysis to extract meaningful information and identify patterns that may contribute to early diagnosis and treatment planning are reviewed. The potential benefits of AI-based approaches in improving patient outcomes and the challenges associated with their implementations are also discussed. Overall, this paper highlights the promise of AI in transforming the diagnosis and management of neurodegenerative diseases.}, } @article {pmid38008065, year = {2024}, author = {Maier, GS and Rosar, G and Dietz, G and Hemken, N and Kafchitsas, K and Seeger, JB and Horas, K}, title = {Effectiveness of Mud-Pack Therapy and Mud-Bath Therapy in Osteoarthritis: A Systematic Review.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {30-39}, doi = {10.1159/000535437}, pmid = {38008065}, issn = {2504-2106}, mesh = {Humans ; *Mud Therapy ; *Osteoarthritis, Knee ; *Osteoarthritis, Hip ; Quality of Life ; *Low Back Pain ; }, abstract = {OBJECTIVES: Osteoarthritis has a tremendous socioeconomic impact in terms of drug spending, hospital admissions, work productivity, and temporary or permanent incapacity. Mud therapy has been discussed as potential conservative treatment options for osteoarthritis. However, findings from several trials still remain controversial. For this reason, we aimed to systematically review the highest evidence provided by published trials to estimate the clinical effect of mud-pack and mud-bath therapy for the treatment of osteoarthritis.

METHODS: We searched PubMed, PEDro, and the Cochrane CENTRAL Register for Controlled Trials for articles published between 2000 and 2020 using the terms "orthopedics," "orthopaedics," "musculoskeletal," "osteoarthritis," and "mud bath," "mud pack."

RESULTS: Of the 19 studies included, 15 examined the effects of mud-bath therapy in knee osteoarthritis treatment. One study focused on the treatment effect of mud bath on hand osteoarthritis, another study examined treatment effects in hip and knee osteoarthritis, and two studies enrolled patients with chronic low back pain caused by lumbar spine osteoarthritis. We systematically reviewed the data obtained from the literature and summarized the results on the basis of the main outcomes. The results show significant improvements in function, quality of life, and perceived pain for patients with osteoarthritis.

CONCLUSION: Results of randomized controlled trials suggest that mud therapy is part of a promising integrated and synergistic multidisciplinary approach in combination with other treatment forms like pharmacotherapy or physiotherapy.

UNLABELLED: ZieleDie sozio-ökonomischen Auswirkungen der Arthrose sind immens. Heiltorfbehandlungen sind seit einiger Zeit als mögliche Ergänzung der konservativen Therapieoptionen dieser Erkrankung Gegenstand wissenschaftlicher Untersuchungen. Ziel dieser Studie war es, die aktuellen Erkenntnisse zur Heiltorftherapie bei Arthrose zusammenzufassen.MethodenWir führten eine systematische Literaturrecherche der Datenbanken Pubmed, PEDro und Cochrane CENTRAL Register of Controlled Trials durch. Hierbei wurden Artikel, die zwischen 2000 und 2020 publiziert wurden und mit den Schlagwörtern “orthopedics”, “orthopaedics”, “musculoskeletal”, “osteoarthritis” und “mud-bath”, “mud-pack” assoziiert waren, erfasst.ErgebnisseVon den 19 näher untersuchten Studien beschäftigten sich 15 mit den Effekten der Heiltorftherapie bei Patienten mit Kniearthrose, eine Studie untersuchte Patienten mit Arthrose der Hand, eine weitere Studie untersuchte die Auswirkung der Therapie bei Arthrose der Hüfte. 2 Studien untersuchten den Effekt der Moorbäder bei Patienten mit chronischen Rückenschmerzen. Insgesamt zeigten sich signifikante Verbesserungen der Funktion, Lebensqualität und Schmerzlinderung bei den Patienten unter Heiltorftherapie.ZusammenfassungDie Ergebnisse der randomisierten, kontrollierten Studien zeigen, dass die Heiltorftherapie eine vielversprechende Ergänzung in einem multidisziplinären Ansatz der Arthrosetherapie ist.}, } @article {pmid38008074, year = {2024}, author = {Saha, S and Singh, R and Mani, I and Chakraborty, K and Sarkar, P and Saha, S and Rana, A and Chattopadhyay, R}, title = {Individualized Homeopathic Medicines in the Treatment of Post-COVID-19 Fatigue in Adults: Single-Blind, Randomized, Placebo-Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {1-9}, doi = {10.1159/000535279}, pmid = {38008074}, issn = {2504-2106}, mesh = {Adult ; Humans ; *COVID-19/therapy ; India ; *Materia Medica ; Quality of Life ; Single-Blind Method ; Sulfur ; }, abstract = {INTRODUCTION: The coronavirus disease 2019 (COVID-19) is leading to unknown and unusual health conditions that are challenging to manage. Post-COVID-19 fatigue is one of those challenges, becoming increasingly common as the pandemic evolves, as it impairs the quality of life of an individual. This trial attempts to identify the preliminary evidence of the efficacy of individualized homeopathic medicines (IHMs) against placebos in the treatment of post-COVID-19 fatigue in adults.

METHODS: A 3-month, single-blind, randomized, placebo-controlled, parallel-arm trial was conducted at the outpatient department of The Calcutta Homoeopathic Medical College and Hospital, India. Sixty participants were randomized in a 1:1 ratio to receive either IHMs (n = 30) or identical-looking placebos (n = 30). The primary and secondary outcome measures were the Fatigue Assessment Scale (FAS) and Outcome in Relation to Impact on Daily Living (ORIDL), respectively, measured every month, for up to 3 months. Comparative analysis was carried out on the intention-to-treat sample to detect group differences.

RESULTS: Group differences in both the primary (FAS total: F1, 58 = 14.356, p < 0.001) and secondary outcomes (ORIDL: F1, 58 = 210.986, p < 0.001) after 3 months favored IHMs against placebos. Lycopodium clavatum (11.7%), sulfur (11.7%), Arsenicum album (10%), and Thuja occidentalis (10%) were the most frequently indicated medicines. No harm, unintended effects, homeopathic aggravations, or any serious adverse events were reported from either of the groups.

CONCLUSION: IHMs produced significantly better effects than placebos in the treatment of post-COVID-19 fatigue in adults. Definitive robust trials may be undertaken to confirm the findings.

UNLABELLED: EinleitungDie Coronainfektion (COVID-19) zieht unbekannte und ungewöhnliche gesundheitliche Probleme nach sich, deren Management oft eine Herausforderung darstellt. Das gilt unter anderem für Ermüdung nach einer COVID-19-Erkrankung, die mit zunehmender Dauer der Pandemie immer häufiger auftritt und die Lebensqualität der Betroffenen beeinträchtigt. In dieser Studie wird versucht, vorläufige Belege für die Wirksamkeit individualisierter homöopathischer Mittel (IHM) im Vergleich zu Placebo zur Behandlung von Ermüdung nach COVID-19 bei Erwachsenen zu identifizieren.MethodenEine einfach verblindete, randomisierte, placebokontrollierte Parallelgruppenstudie von 3 Monaten Dauer wurde im ambulanten Bereich des Calcutta Homoeopathic Medical College and Hospital in Indien durchgeführt. 60 Teilnehmer erhielten nach Randomisierung im Verhältnis 1:1 entweder IHM (n = 30) oder identisch aussehendes Placebo (n = 30). Die primäre und die sekundäre Zielgröße waren die Fatigue Assessment Scale (FAS) und das Outcome in Relation to Impact on Daily Living (ORIDL) für bis zu 3 Monate, jeweils monatlich gemessen. Vergleichende Analysen wurden an der Intent-to-treat-Population durchgeführt, um Unterschiede zwischen den Gruppen zu erkennen.ErgebnisseGruppenunterschiede bei der primären (FAS gesamt: F1, 58 = 14,356; p < 0.001) sowie der sekundären Zielgröße (ORIDL: F1, 58 = 210,986; p < 0.001) nach 3 Monaten sprachen für die IHM gegenüber Placebo. Lycopodium clavatum (11.7%), sulfur (11.7%), Arsenicum album (10%) und Thuja occidentalis (10%) waren die am häufigsten indizierten Mittel. In beiden Gruppen wurden keine Schädigungen, unbeabsichtigten Wirkungen, homöopathischen Verschlechterungen oder jegliche schwerwiegenden unerwünschten Ereignisse beobachtet.SchlussfolgerungDie IHM erzielten signifikant bessere Effekte als Placebo in der Behandlung von Post-COVID-Ermüdung bei Erwachsenen. Definitive, belastbare Studien können eingeleitet werden, um diese Befunde zu bestätigen.}, } @article {pmid38008627, year = {2024}, author = {Zhang, J and Wang, C and Zhou, M and Wang, Z}, title = {Comprehensive treatment of amyotrophic lateral sclerosis combined with colon cancer: A case report.}, journal = {Asian journal of surgery}, volume = {47}, number = {2}, pages = {1274-1275}, doi = {10.1016/j.asjsur.2023.11.063}, pmid = {38008627}, issn = {0219-3108}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Colonic Neoplasms ; }, } @article {pmid38009843, year = {2024}, author = {Cykowski, MD and Arumanayagam, AS and Powell, SZ and Appel, SH}, title = {Primary visual cortex pathology in ALS patients with C9ORF72 expansion.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {5}, pages = {e13229}, pmid = {38009843}, issn = {1750-3639}, support = {R01 NS118584/NS/NINDS NIH HHS/United States ; RF1 NS118584/NS/NINDS NIH HHS/United States ; RF1NS118584/NS/NINDS NIH HHS/United States ; 19-IIA-465//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics ; Middle Aged ; Female ; Male ; DNA Repeat Expansion ; Primary Visual Cortex/pathology ; Aged ; Proteins/genetics/metabolism ; }, abstract = {Poly-GA and poly-GP immunofluorescence studies show conspicuous dipeptide repeat pathology in layers IV and II of primary visual cortex in C9ALS patients.}, } @article {pmid38010108, year = {2024}, author = {Hincelin-Mery, A and Nicolas, X and Cantalloube, C and Pomponio, R and Lewanczyk, P and Benamor, M and Ofengeim, D and Krupka, E and Hsiao-Nakamoto, J and Eastenson, A and Atassi, N}, title = {Safety, pharmacokinetics, and target engagement of a brain penetrant RIPK1 inhibitor, SAR443820 (DNL788), in healthy adult participants.}, journal = {Clinical and translational science}, volume = {17}, number = {1}, pages = {e13690}, pmid = {38010108}, issn = {1752-8062}, mesh = {Adult ; Humans ; Healthy Volunteers ; Dose-Response Relationship, Drug ; Area Under Curve ; Half-Life ; Double-Blind Method ; *Brain ; *Receptor-Interacting Protein Serine-Threonine Kinases ; }, abstract = {SAR443820 (DNL788) is a selective, orally bioavailable, brain penetrant inhibitor of receptor-interacting serine/threonine protein kinase 1 (RIPK1). This phase I first-in-human healthy participant study (NCT05795907) was comprised of three parts: randomized, double-blind, placebo-controlled single ascending dose (SAD; part 1a); 14-day multiple ascending dose (MAD; part 2) parts that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of SAR443820; and a separate open-label, single-dose part 1b (PK-cerebrospinal fluid [CSF]) to assess SAR443820 levels in CSF. SAR443820 was well-tolerated in healthy participants, and no treatment discontinuation related to an adverse event (AE) occurred. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in laboratory values, vital signs, or electrocardiogram parameters. SAR443820 had a favorable PK profile, with plasma half-lives (geometric mean) ranged between 5.7-8.0 h and 7.2-8.9 h after single and repeated doses, respectively. There were no major deviations from dose proportionality for maximum concentration and area under the curve across SAR443820 doses. Mean CSF-to-unbound plasma concentration ratio ranged from 0.8 to 1.3 over time (assessed up to 10 h postdose), indicating high brain penetrance. High levels of inhibition of activated RIPK1, as measured by decrease in pS166-RIPK1, were achieved in both SAD and MAD parts, with a maximum median inhibition from baseline close to 90% at predose (Ctrough) after multiple dosing in MAD, reflecting a marked RIPK1 target engagement at the peripheral level. These results support further development of SAR443820 in phase II trials in amyotrophic lateral sclerosis (NCT05237284) and multiple sclerosis (NCT05630547).}, } @article {pmid38010626, year = {2024}, author = {Zhong, R and Rua, MT and Wei-LaPierre, L}, title = {Targeting mitochondrial Ca[2+] uptake for the treatment of amyotrophic lateral sclerosis.}, journal = {The Journal of physiology}, volume = {602}, number = {8}, pages = {1519-1549}, pmid = {38010626}, issn = {1469-7793}, support = {R01 NS127858/NS/NINDS NIH HHS/United States ; R21 NS099545/NS/NINDS NIH HHS/United States ; R56 NS117429/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Calcium/metabolism ; *Neurodegenerative Diseases ; Motor Neurons/physiology ; Mitochondria/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare adult-onset neurodegenerative disease characterized by progressive motor neuron (MN) loss, muscle denervation and paralysis. Over the past several decades, researchers have made tremendous efforts to understand the pathogenic mechanisms underpinning ALS, with much yet to be resolved. ALS is described as a non-cell autonomous condition with pathology detected in both MNs and non-neuronal cells, such as glial cells and skeletal muscle. Studies in ALS patient and animal models reveal ubiquitous abnormalities in mitochondrial structure and function, and disturbance of intracellular calcium homeostasis in various tissue types, suggesting a pivotal role of aberrant mitochondrial calcium uptake and dysfunctional calcium signalling cascades in ALS pathogenesis. Calcium signalling and mitochondrial dysfunction are intricately related to the manifestation of cell death contributing to MN loss and skeletal muscle dysfunction. In this review, we discuss the potential contribution of intracellular calcium signalling, particularly mitochondrial calcium uptake, in ALS pathogenesis. Functional consequences of excessive mitochondrial calcium uptake and possible therapeutic strategies targeting mitochondrial calcium uptake or the mitochondrial calcium uniporter, the main channel mediating mitochondrial calcium influx, are also discussed.}, } @article {pmid38011396, year = {2020}, author = {Okhovat, AA and Fatehi, F and Rafiemehr, M and Moradi, K and Kiani-Mehr, G and Nafissi, S}, title = {Evaluation of quality of life and mood disorders in caregivers of patients with amyotrophic lateral sclerosis: A single-center cross-sectional study.}, journal = {Current journal of neurology}, volume = {19}, number = {4}, pages = {190-195}, pmid = {38011396}, issn = {2717-011X}, abstract = {Background: Caregivers of patients with amyotrophic lateral sclerosis (ALS) may suffer from anxiety, depression, and reduced quality of life (QoL). Our goal was to evaluate the QoL and mood disorders in caregivers and their correlation with the patients' demographic, physical, and mental conditions. Methods: We analyzed data from 39 patients with ALS and their caregivers. Patients completed questionnaires of anxiety assessed by Generalised Anxiety Disorder Assessment (GAD-7), depression using the Beck Depression Inventory-II (BDI-II), and QoL via 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40). Physical impairment was also measured in the patients using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Caregivers were also assessed by BDI-II, GAD-7, and 36-item Short-Form Health Survey questionnaire (SF-36). Results: The prevalence of depression and anxiety in the patients was 82.1% and 71.8%, respectively. Caregivers also had higher rates of anxiety and depression and lower levels of QoL in comparison with the general population (anxiety: 66.7%, depression: 43.6%). Depression and anxiety were considerably associated with worsened QoL in the caregivers. None of the demographic, physical, or mental characteristics of patients with ALS were related to either mood status or QoL of the caregiver population. Conclusion: Caregivers experience higher rates of anxiety and depression and lower QoL in comparison with the general population. The severity of mood disorders is inversely associated with the physical and mental domains of caregivers' QoL. Nonetheless, QoL in the caregivers is not affected by the physical or mental disability of the patients.}, } @article {pmid38011400, year = {2021}, author = {Afrakhteh, M and Esmaeili, S and Shati, M and Shojaei, SF and Bahadori, M and Zamani, B and Almasi-Doghaee, M and Haghi-Ashtiani, B}, title = {Validating the Persian version of the amyotrophic lateral sclerosis-specific quality of life-revised instrument.}, journal = {Current journal of neurology}, volume = {20}, number = {1}, pages = {37-42}, pmid = {38011400}, issn = {2717-011X}, abstract = {Background: Amyotrophic Lateral Sclerosis-Specific Quality of Life-Revised (ALSSQOL-R) encompasses 50 items which assess quality of life (QOL) in patients with amyotrophic lateral sclerosis (ALS) in six major domains. This study aims to translate the ALSSQOL-R into Persian and evaluate its reliability and validity among Iranian patients. Methods: ALSSQOL-R was translated by the standard multi-step forward-backward method. Content validity was calculated using item content validity index (I-CVI). Three items in the "intimacy" domain were deleted considering Iranian culture. Cronbach's alpha was used for all 6 dimensions to calculate the internal consistency reliability. Test-retest reliability was evaluated using intraclass correlation coefficient (ICC) with one-month interval. Concurrent validity was measured by the validated version of 36-Item Short Form Health Survey (SF-36) questionnaire. Results: Sixty-three patients with ALS were enrolled in the study. I-CVI was 70%, promoted to 85% after modifications (acceptable). Regarding internal consistency reliability, Cronbach's alpha in all six domains was 0.70 and total Cronbach's alpha was 0.89 which is assumed as good. In terms of test-retest reliability, ICC [95% confidence interval (CI)] was 0.91 (91%) and Pearson correlation coefficient (r) was 0.90 (P < 0.001), all indicating an excellent reliability. The concurrent validity was established based on a strong correlation with SF-36 (r = 0.744, P < 0.001). Conclusion: The findings show that the modified Persian version of ALSSQOL-R is a valid and reliable QOL questionnaire which can be used for Iranian patients with ALS in both clinical and research settings.}, } @article {pmid38011420, year = {2021}, author = {Eishi-Oskouei, A and Basiri, K}, title = {Safety and efficacy of edaravone in well-defined Iranian patients with amyotrophic lateral sclerosis: A parallel-group single-blind trial.}, journal = {Current journal of neurology}, volume = {20}, number = {1}, pages = {1-7}, pmid = {38011420}, issn = {2717-011X}, abstract = {Background: This parallel-group single-blind trial evaluates the safety and efficacy of Edaravone, as a free radical scavenger, in a highly selective subgroup of Iranian patients with amyotrophic lateral sclerosis (ALS). Methods: The study was registered in ClinicalTrials.gov (registration number: NCT03272802) and Iranian Registry of Clinical Trials (registration number: IRCT20190324043105N). Patients were included into the study, who were diagnosed as probable or definite ALS (according to revised El Escorial criteria), mildly to moderately affected by the disease [according to Amyotrophic Lateral Sclerosis Health State Scale (ALS/HSS)], scored ≥ 2 points on all items of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and had forced vital capacity (FVC) of at least 80%. 20 patients (10 cases, 10 controls) were observed for 12 cycles (each cycle lasted four weeks). Cases received Edaravone for the first 14 days in the first cycle and for the first 10 days in the next cycles. In addition, all patients received Riluzole. The 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40), ALSFRS-R, and Manual Muscle Testing (MMT) scores were measured every 3 cycles to evaluate the physical and functional status of the patients. Besides, injection reactions, adverse events (AEs), and serious adverse events (SAEs) were measured during the study. Results: ALSAQ-40, ALSFRS-R, and MMT scores were not significantly different between cases and controls in 5 different time points. During the study, no injection reactions were observed. AEs and SAEs were not significantly different between cases and controls. Conclusion: Our data did not demonstrate efficacy of Edaravone in ALS treatment, but showed its safety for use in patients with ALS. Further studies are necessary to investigate Edaravone efficacy in patients with ALS before prescribing this new drug outside Japan.}, } @article {pmid38011426, year = {2022}, author = {Fateh, HR and Askary-Kachoosangy, R and Shirzad, N and Akbarzadeh-Baghban, A and Fatehi, F}, title = {The effect of energy conservation strategies on fatigue, function, and quality of life in adults with motor neuron disease: Randomized controlled trial.}, journal = {Current journal of neurology}, volume = {21}, number = {2}, pages = {83-90}, pmid = {38011426}, issn = {2717-011X}, abstract = {Background: Fatigue is one of the most frequent complaints in patients with motor neuron diseases (MNDs), with a significant impact on the quality of life (QOL). There is lack of enough evidence for current pharmacological or non-pharmacological treatments of fatigue in this population to be applied in clinical setting. Energy conservation strategies are one of the key interventions for fatigue management in chronic diseases. We aimed to investigate the effect of applying these techniques in the fatigue management of patients with MND. Methods: This randomized controlled trial (RCT) study was carried out on 28 patients with MND. Participants were randomly assigned to either the intervention or control group. In addition to routine treatment, patients in the intervention group participated in 3 weekly 1-hour energy conservation programs provided by an experienced occupational therapist. The Fatigue Severity Scale (FSS) score, 36-Item Short Form Survey (SF-36), and Canadian Occupational Performance Measure (COPM) were measured at baseline, immediately after the last intervention session, and one month later. Results: FSS and COPM significantly changed after the course in the intervention group (P < 0.001 and P = 0.001, respectively). Both FSS and COPM improved significantly toward the final assessment only in the intervention group. The SF-36 changes were not significant in each of the groups. Conclusion: According to the findings of the present study, using energy conservation strategies could lead to better mid-term fatigue management and occupational performance improvement, but it did not improve QOL in patients with MND.}, } @article {pmid38011840, year = {2024}, author = {Asawadethmetakul, P and Xie, F and Xie, C and Ma, J and You, Y and Yao, F}, title = {Effect of Tuina Combined with Chinese Herbal Compress on Primary Dysmenorrhea with Cold Coagulation and Blood Stasis Syndrome: A Study Protocol for a Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {20-29}, doi = {10.1159/000534335}, pmid = {38011840}, issn = {2504-2106}, mesh = {Female ; Humans ; *Dysmenorrhea/drug therapy ; China ; *Pain Threshold ; Randomized Controlled Trials as Topic ; Observational Studies as Topic ; }, abstract = {INDRODUCTION: Primary dysmenorrhea (PD) is a very common issue in young women that reduces the quality of women's lives. Both Western medicine and traditional Chinese medicine (TCM) provide several ways to treat PD; however, TCM treatment exhibits fewer side effects for the patient. Tuina massage and Chinese herbal compresses are considered forms of external TCM therapy that have been widely used to treat PD, especially in China. Therefore, to provide the most effective and safe treatment for PD, we combined Tuina and Chinese herbal compresses together in this observational study.

METHODS: A randomized controlled trial (RCT) consisting of 114 participants from the Shanghai University of Traditional Chinese Medicine who meet inclusion criteria will be divided into two groups in a 1:1 allocation ratio. The intervention group will receive Tuina combined with Chinese herbal compress therapy, while the control group will only receive Chinese herbal compress therapy. The treatment will be given 3 days before menstruation (once per day, 3 times per menstrual cycle). The primary outcome will be measured with the Visual Analog Scale (VAS). The secondary outcomes will be measured by the Dysmenorrhea Symptom Score, the Chinese Medical Dysmenorrhea Symptom Score, the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), and the pain threshold at Guanyuan (CV4).

CONCLUSION: This study will be the first RCT that will entail the combination of Tuina and Chinese herbal compresses to treat PD in the category of cold coagulation and blood stasis syndrome. If the results demonstrate that Tuina combined with a Chinese herbal compress is effective, we posit that this study will provide evidence-based references for a potential alternative treatment to treat PD in the future.

UNLABELLED: EinleitungDie primäre Dysmenorrhoe (PD) ist ein Problem, das bei jungen Frauen sehr häufig auftritt und ihre Lebensqualität beeinträchtigt. Sowohl die westliche Medizin als auch die traditionelle chinesische Medizin (TCM) bieten verschiedene Therapiemöglichkeiten zur Behandlung der PD, allerdings ist die TCM mit weniger Nebenwirkungen für die Patientin verbunden. Tuina-Massage und chinesische Kräuterkompressen gelten als Formen der äußerlichen TCM-Therapie, die besonders in China zur Behandlung der PD weit verbreitet sind. Daher haben wir in dieser Beobachtungsstudie Tuina und chinesische Kräuterkompressen kombiniert, um eine möglichst wirksame und sichere Behandlung der PD bereitzustellen.MethodenEs handelt sich um eine randomisierte kontrollierte Studie (randomized controlled trial, RCT), bei der 114 Teilnehmerinnen der Shanghai University of Traditional Chinese Medicine, die die Einschlusskriterien erfüllen, im Verhältnis 1:1 in zwei Gruppen aufgeteilt werden. Die Interventionsgruppe erhält Tuina in Kombination mit chinesischen Kräuterkompressen, während die Kontrollgruppe nur eine Behandlung mit chinesischen Kräuterkompressen erhält. Die Behandlung erfolgt drei Tage vor der Menstruation (einmal täglich, dreimal pro Menstruationszyklus). Das primäre Zielkriterium wird anhand der visuellen Analogskala (VAS) gemessen. Die sekundären Zielkriterien werden mithilfe des Dysmenorrhoe-Symptom-Scores, des chinesischen medizinischen Dysmenorrhoe-Symptom-Scores, der Self-rating Anxiety Scale (SAS), der Self-rating Depression Scale (SDS) und der Schmerzschwelle am Guanyuan-Akupunkturpunkt (CV4) ermittelt.SchlussfolgerungDiese Studie ist die erste randomisierte kontrollierte Studie, die die Kombination von Tuina und chinesischen Kräuterkompressen zur Behandlung von PD in der Kategorie Kältekoagulation und Blutstauungssyndrom untersucht. Sollten die Ergebnisse zeigen, dass Tuina in Kombination mit chinesischen Kräuterkompressen wirksam ist, erwarten wir, dass diese Studie evidenzbasierte Belege für eine mögliche alternative Behandlung von PD in der Zukunft liefern wird.}, } @article {pmid38013317, year = {2023}, author = {Wang, Z and Yang, H and Han, Y and Teng, J and Kong, X and Qi, X}, title = {Screening and identification of key biomarkers associated with amyotrophic lateral sclerosis and depression using bioinformatics.}, journal = {Medicine}, volume = {102}, number = {47}, pages = {e36265}, pmid = {38013317}, issn = {1536-5964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Depression/diagnosis/genetics ; Gene Expression Profiling ; *MicroRNAs/genetics ; Biomarkers ; Gene Regulatory Networks ; Computational Biology/methods ; }, abstract = {This study aims to identify common molecular biomarkers between amyotrophic lateral sclerosis (ALS) and depression using bioinformatics methods, in order to provide potential targets and new ideas and methods for the diagnosis and treatment of these diseases. Microarray datasets GSE139384, GSE35978 and GSE87610 were obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) between ALS and depression were identified. After screening for overlapping DEGs, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape software, and hub genes were identified. Finally, a network between miRNAs and hub genes was constructed using the NetworkAnalyst tool, and possible key miRNAs were predicted. A total of 357 genes have been identified as common DEGs between ALS and depression. GO and KEGG enrichment analyses of the 357 DEGs showed that they were mainly involved in cytoplasmic translation. Further analysis of the PPI network using Cytoscape and MCODE plugins identified 6 hub genes, including mitochondrial ribosomal protein S12 (MRPS12), poly(rC) binding protein 1 (PARP1), SNRNP200, PCBP1, small G protein signaling modulator 1 (SGSM1), and DNA methyltransferase 1 (DNMT1). Five possible target miRNAs, including miR-221-5p, miR-21-5p, miR-100-5p, miR-30b-5p, and miR-615-3p, were predicted by constructing a miRNA-gene network. This study used bioinformatics techniques to explore the potential association between ALS and depression, and identified potential biomarkers. These biomarkers may provide new ideas and methods for the early diagnosis, treatment, and monitoring of ALS and depression.}, } @article {pmid38013452, year = {2024}, author = {Smith, EN and Lee, J and Prilutsky, D and Zicha, S and Wang, Z and Han, S and Zach, N}, title = {Plasma neurofilament light levels show elevation two years prior to diagnosis of amyotrophic lateral sclerosis in the UK Biobank.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {170-176}, doi = {10.1080/21678421.2023.2285428}, pmid = {38013452}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Cohort Studies ; Biomarkers ; Biological Specimen Banks ; Intermediate Filaments ; *Neurodegenerative Diseases ; UK Biobank ; Neurofilament Proteins ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease with profound unmet need. In patients carrying genetic mutations, elevations in neurofilament light (NfL) have been shown to precede symptom onset, however, the natural history of NfL in general ALS patients is less characterized.

METHODS: We performed a secondary analysis of the UK Biobank Pharma Proteomics Project (UKB-PPP), a subset of the UK Biobank, a population-based cohort study in the United Kingdom, to examine plasma NfL levels in 237 participants subsequently diagnosed with ALS. We applied logistic and Cox proportional hazards regression to compare cases to 42,752 population-based and 948 age and sex-matched controls. Genetic information was obtained from exome and genotype array data.Results and Conclusions: We observed that NfL was 1.42-fold higher in cases vs population-based controls. At two to three years pre-diagnosis, NfL levels in patients exceeded the 95[th] percentile of age and sex-matched controls. A time-to-diagnosis analysis showed that a 2-fold increase in NfL levels was associated with a 3.4-fold risk of diagnosis per year, with NfL being most predictive of case status at two years (AUC = 0.96). Participants with genetic variation that might put them at risk for familial disease (N = 46) did not show a different pattern of association than those without (N = 191).

DISCUSSION: Our findings show that NfL is elevated and discriminative of future ALS diagnosis up to two years prior to diagnosis in patients with and without genetic risk variants.}, } @article {pmid38014069, year = {2023}, author = {Yang, S and Wijegunawardana, D and Sheth, U and Veire, AM and Salgado, JMS and Agrawal, M and Zhou, J and Pereira, JD and Gendron, TF and Guo, JU}, title = {Aberrant splicing exonizes C9ORF72 repeat expansion in ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38014069}, issn = {2692-8205}, support = {DP2 GM132930/GM/NIGMS NIH HHS/United States ; R35 GM152208/GM/NIGMS NIH HHS/United States ; }, abstract = {A nucleotide repeat expansion (NRE) in the first annotated intron of the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While C9 NRE-containing RNAs can be translated into several toxic dipeptide repeat proteins, how an intronic NRE can assess the translation machinery in the cytoplasm remains unclear. By capturing and sequencing NRE-containing RNAs from patient-derived cells, we found that C9 NRE was exonized by the usage of downstream 5' splice sites and exported from the nucleus in a variety of spliced mRNA isoforms. C9ORF72 aberrant splicing was substantially elevated in both C9 NRE[+] motor neurons and human brain tissues. Furthermore, NREs above the pathological threshold were sufficient to activate cryptic splice sites in reporter mRNAs. In summary, our results revealed a crucial and potentially widespread role of repeat-induced aberrant splicing in the biogenesis, localization, and translation of NRE-containing RNAs.}, } @article {pmid38014203, year = {2023}, author = {Wilkins, OG and Chien, MZYJ and Wlaschin, JJ and Pisliakova, M and Thompson, D and Digby, H and Simkin, RL and Diaz, JA and Mehta, PR and Keuss, MJ and Zanovello, M and Brown, AL and Harley, P and Darbey, A and Karda, R and Fisher, EMC and Cunningham, TJ and Le Pichon, CE and Ule, J and Fratta, P}, title = {Creation of de novo cryptic splicing for ALS/FTD precision medicine.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38014203}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; ZIA HD008966/ImNIH/Intramural NIH HHS/United States ; }, abstract = {A system enabling the expression of therapeutic proteins specifically in diseased cells would be transformative, providing greatly increased safety and the possibility of pre-emptive treatment. Here we describe "TDP-REG", a precision medicine approach primarily for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which exploits the cryptic splicing events that occur in cells with TDP-43 loss-of-function (TDP-LOF) in order to drive expression specifically in diseased cells. In addition to modifying existing cryptic exons for this purpose, we develop a deep-learning-powered algorithm for generating customisable cryptic splicing events, which can be embedded within virtually any coding sequence. By placing part of a coding sequence within a novel cryptic exon, we tightly couple protein expression to TDP-LOF. Protein expression is activated by TDP-LOF in vitro and in vivo, including TDP-LOF induced by cytoplasmic TDP-43 aggregation. In addition to generating a variety of fluorescent and luminescent reporters, we use this system to perform TDP-LOF-dependent genomic prime editing to ablate the UNC13A cryptic donor splice site. Furthermore, we design a panel of tightly gated, autoregulating vectors encoding a TDP-43/Raver1 fusion protein, which rescue key pathological cryptic splicing events. In summary, we combine deep-learning and rational design to create sophisticated splicing sensors, resulting in a platform that provides far safer therapeutics for neurodegeneration, potentially even enabling preemptive treatment of at-risk individuals.}, } @article {pmid38014237, year = {2023}, author = {Alvarado, CX and Weller, CA and Johnson, N and Leonard, HL and Singleton, AB and Reed, X and Blauewendraat, C and Nalls, MA}, title = {Human brain single nucleus cell type enrichments in neurodegenerative diseases.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38014237}, issn = {2693-5015}, support = {Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; ZIA AG000534/ImNIH/Intramural NIH HHS/United States ; ZIA NS003154/ImNIH/Intramural NIH HHS/United States ; }, abstract = {BACKGROUND: Single-cell RNA sequencing has opened a window into clarifying the complex underpinnings of disease, particularly in quantifying the relevance of tissue- and cell-type-specific gene expression.

METHODS: To identify the cell types and genes important to therapeutic target development across the neurodegenerative disease spectrum, we leveraged genome-wide association studies, recent single-cell sequencing data, and bulk expression studies in a diverse series of brain region tissues.

RESULTS: We were able to identify significant immune-related cell types in the brain across three major neurodegenerative diseases: Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Subsequently, putative roles of 30 fine-mapped loci implicating seven genes in multiple neurodegenerative diseases and their pathogenesis were identified.

CONCLUSIONS: We have helped refine the genetic regions and cell types effected across multiple neurodegenerative diseases, helping focus future translational research efforts.}, } @article {pmid38014545, year = {2023}, author = {Pestelacci, S and Hofer-Inteeworn, N and Dennler, M and Glaus, T}, title = {Balloon dilation and transient stenting of unilateral membranous choanal atresia in a British Shorthair cat with chronic purulent rhinitis and ascending meningoencephalitis.}, journal = {Schweizer Archiv fur Tierheilkunde}, volume = {165}, number = {12}, pages = {793-800}, doi = {10.17236/sat00414}, pmid = {38014545}, issn = {1664-2848}, mesh = {Humans ; Animals ; Cats ; *Rhinitis/surgery/veterinary ; *Choanal Atresia/surgery/veterinary ; Constriction, Pathologic/surgery/veterinary ; Dilatation/veterinary ; *Cat Diseases/surgery ; }, abstract = {Choanal atresia is a rare congenital anomaly in humans and animals, characterized by the absence of communication of one or both nasal cavities with the nasopharynx. The severity of clinical signs depends on the presence of unilateral versus bilateral stenosis as well as comorbidities. With bilateral atresia, respiration may be severely compromised particularly during sleep, as airflow can only occur when breathing through the open mouth. Various therapeutic modalities have been described in people and adopted for animals. All treatments may be associated with complications, the most important being post-therapeutic scar formation with re-stenosis. This report describes a 10-month-old British Shorthair cat with chronic unilateral serosal nasal discharge that changed to mucopurulent discharge. When acute neurological signs developed, the cat was presented to the veterinary hospital. A diagnosis of primary, membranous right sided choanal atresia was achieved via computed tomography (CT) and nasopharyngeal (posterior) rhinoscopy. Secondary changes included destructive rhinitis with progression to the CNS with a subdural empyema and meningoencephalitis. Retinal changes and aspiration bronchopneumonia were suspected additional complications. After recovery from the secondary infections, the membranous obstruction was perforated and dilated using a valvuloplasty balloon by an orthograde transnasal approach under endoscopic guidance from a retroflexed nasopharyngeal view. To prevent re-stenosis, a foley catheter was placed as a transient stent for 6 days. The cat recovered uneventfully and was asymptomatic after the stent removal. Endoscopic re-examination after 5 months confirmed a persistent opening and patency of the generated right choanal passage. The cat remains asymptomatic 10 months after the procedure. Transnasal endoscopic balloon dilation and transient stenting of choanal atresia is a minimally invasive and relatively simple procedure with potentially sustained success.}, } @article {pmid38014622, year = {2023}, author = {Yamashita, T and Nakano, Y and Sasaki, R and Tadokoro, K and Omote, Y and Yunoki, T and Kawahara, Y and Matsumoto, N and Taira, Y and Matsuoka, C and Morihara, R and Abe, K}, title = {Safety and Clinical Effects of a Muse Cell-Based Product in Patients With Amyotrophic Lateral Sclerosis: Results of a Phase 2 Clinical Trial.}, journal = {Cell transplantation}, volume = {32}, number = {}, pages = {9636897231214370}, pmid = {38014622}, issn = {1555-3892}, mesh = {Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Alprostadil/therapeutic use ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons. Multilineage-differentiating stress-enduring (Muse) cells are unique endogenous stem cells that show therapeutic effects on motor function in ALS mouse models. We conducted a single-center open phase II clinical trial to evaluate the safety and clinical effects of repeated intravenous injections of an allogenic Muse cell-based product, CL2020, in patients with ALS. Five patients with ALS received CL2020 intravenously once a month for a total of six doses. The primary endpoints were safety and tolerability, and the secondary endpoint was the rate of change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score. In addition, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), sphingosine-1-phosphate (S1P), cerebrospinal fluid chitotriosidase-1 (CHIT-1), and neurofilament light chain (NfL) levels were evaluated. The CL2020 treatment was highly tolerated without serious side effects. The ALSFRS-R score change trended upward at 12 months post-CL2020 treatment compared with that at 3 months pre-administration, but the difference was not statistically significant. Among five patients diagnosed with ALS, three exhibited a decrease in the rate of ALSFRS-R score change, one demonstrated an increase, and another showed no change. In addition, the patients' serum IL-6 and TNF-α levels and cerebrospinal fluid CHIT-1 and NfL levels increased for up to 6 months post-treatment; however, their serum S1P levels continuously decreased over 12 months. These findings indicate a favorable safety profile of CL2020 therapy. In the near future, a double-blind study of a larger number of ALS patients should be conducted to confirm the efficacy of ALS treatment with CL2020.}, } @article {pmid38014869, year = {2024}, author = {Li, X and Pura, J and Allen, A and Owzar, K and Lu, J and Harms, M and Xie, J}, title = {DYNATE: Localizing rare-variant association regions via multiple testing embedded in an aggregation tree.}, journal = {Genetic epidemiology}, volume = {48}, number = {1}, pages = {42-55}, pmid = {38014869}, issn = {1098-2272}, support = {R01 HG012555/HG/NHGRI NIH HHS/United States ; 1R01HG012555-01/GF/NIH HHS/United States ; }, mesh = {Humans ; *Genetic Variation ; *Trees ; Models, Genetic ; Genetic Association Studies ; Mutation ; Genome-Wide Association Study/methods ; Autophagy-Related Proteins ; Vesicular Transport Proteins ; }, abstract = {Rare-variants (RVs) genetic association studies enable researchers to uncover the variation in phenotypic traits left unexplained by common variation. Traditional single-variant analysis lacks power; thus, researchers have developed various methods to aggregate the effects of RVs across genomic regions to study their collective impact. Some existing methods utilize a static delineation of genomic regions, often resulting in suboptimal effect aggregation, as neutral subregions within the test region will result in an attenuation of signal. Other methods use varying windows to search for signals but often result in long regions containing many neutral RVs. To pinpoint short genomic regions enriched for disease-associated RVs, we developed a novel method, DYNamic Aggregation TEsting (DYNATE). DYNATE dynamically and hierarchically aggregates smaller genomic regions into larger ones and performs multiple testing for disease associations with a controlled weighted false discovery rate. DYNATE's main advantage lies in its strong ability to identify short genomic regions highly enriched for disease-associated RVs. Extensive numerical simulations demonstrate the superior performance of DYNATE under various scenarios compared with existing methods. We applied DYNATE to an amyotrophic lateral sclerosis study and identified a new gene, EPG5, harboring possibly pathogenic mutations.}, } @article {pmid38014926, year = {2024}, author = {Giometto, S and Finocchietti, M and Paoletti, O and Lombardi, N and Celani, MG and Sciancalepore, F and Lucenteforte, E and Kirchmayer, U and , }, title = {Adherence to riluzole therapy in patients with amyotrophic lateral sclerosis in three Italian regions-The CAESAR study.}, journal = {Pharmacoepidemiology and drug safety}, volume = {33}, number = {1}, pages = {e5736}, doi = {10.1002/pds.5736}, pmid = {38014926}, issn = {1099-1557}, support = {//Agenzia Italiana del Farmaco, Ministero della Salute/ ; }, mesh = {Male ; Humans ; Aged ; Riluzole/adverse effects ; *Amyotrophic Lateral Sclerosis/drug therapy/epidemiology/chemically induced ; Retrospective Studies ; *Neurodegenerative Diseases/chemically induced/drug therapy ; *Neuroprotective Agents/therapeutic use ; Italy/epidemiology ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease. Riluzole may increase survival and delay the need for mechanical ventilation. The CAESAR project ('Comparative evaluation of the efficacy and safety of drugs used in rare neuromuscular and neurodegenerative diseases', FV AIFA project 2012-2013-2014) involves evaluating prescribing patterns, and analysing effectiveness and comparative safety of drugs, in patients with neurodegenerative diseases. The aim of this study is to evaluate adherence to riluzole in patients with ALS during the first year of use, identifying adherence clusters.

METHODS: A retrospective cohort study was conducted using administrative data from Latium, Tuscany, and Umbria. We identified subjects with a new diagnosis of ALS between 2014 and 2019, with the first dispensation of riluzole within 180 days of diagnosis. We considered a two-year look-back period for the characterization of patients, and we followed them from the date of first dispensing of riluzole for 1 year. We calculated 12 monthly adherence measures, through a modified version of the Medication Possession Ratio, estimating drug coverage with Defined Daily Dose. Adherence trajectories were identified using a three-step method: (1) calculation of statistical measures; (2) principal component analysis; (3) cluster analysis. Patient characteristics at baseline and during follow-up were described and compared between adherence groups identified.

RESULTS: We included 264 ALS patients as new users of riluzole in Latium, 344 in Tuscany, and 63 in Umbria. We observed a higher frequency of males (56.2%) and a mean age of 67.4 (standard deviation, SD, 10.4) in the overall population. We identified two clusters in all regions: one more numerous, including adherent patients (60%, 74%, 88%, respectively), and another one including patients who discontinued therapy (40%, 26%, 12%, respectively). In Tuscany patients discontinuing riluzole more frequently died (28.6% vs. 15.4%, p-value <0.01). Additionally, low-adherers had a higher frequency of central nervous system disorders (69.0% vs. 52.5%, p-value 0.01), and a greater use of non-pharmacological treatments (p-values ≤0.01 for invasive ventilation and tracheostomy). We did not observe any differences in Lazio, whereas in Umbria we observed a higher use of drugs for dementia-related psychiatric problems among low-adherers (57.1% vs. 7.8%, respectively, p-value <0.01), although with small numbers.

CONCLUSION: Most ALS patients who start riluzole adhere to therapy during the first year. Patients who discontinue therapy early show greater fragility and mortality.}, } @article {pmid38015828, year = {2023}, author = {Iyer, AK and Schoch, KM and Verbeck, A and Galasso, G and Chen, H and Smith, S and Oldenborg, A and Miller, TM and Karch, CM and Bonni, A}, title = {Targeted ASO-mediated Atp1a2 knockdown in astrocytes reduces SOD1 aggregation and accelerates disease onset in mutant SOD1 mice.}, journal = {PloS one}, volume = {18}, number = {11}, pages = {e0294731}, pmid = {38015828}, issn = {1932-6203}, support = {R01 NS078398/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; Astrocytes/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Motor Neurons/metabolism ; Sodium-Potassium-Exchanging ATPase/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Astrocyte-specific ion pump α2-Na+/K+-ATPase plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we test the effect of Atp1a2 mRNA-specific antisense oligonucleotides (ASOs) to induce α2-Na+/K+-ATPase knockdown in the widely used ALS animal model, SOD1*G93A mice. Two ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo. Although Atp1a2 ASO-treated mice displayed no off-target or systemic toxicity, the ASO-treated mice exhibited an accelerated disease onset and shorter lifespan than control mice. Transcriptomics studies reveal downregulation of genes involved in oxidative response, metabolic pathways, trans-synaptic signaling, and upregulation of genes involved in glutamate receptor signaling and complement activation, suggesting a potential role for these molecular pathways in de-coupling SOD1 aggregation from survival in Atp1a2 ASO-treated mice. Together, these results reveal a role for α2-Na+/K+-ATPase in SOD1 aggregation and highlight the critical effect of temporal modulation of genetically validated therapeutic targets in neurodegenerative diseases.}, } @article {pmid38017952, year = {2023}, author = {Li, Y and Chen, M and Qi, J and Deng, C and Du, L and Bo, Z and Han, C and Mao, Z and He, Y and Shao, X and Han, S}, title = {Underwater ghost imaging with detection distance up to 9.3 attenuation lengths.}, journal = {Optics express}, volume = {31}, number = {23}, pages = {38457-38474}, doi = {10.1364/OE.499186}, pmid = {38017952}, issn = {1094-4087}, abstract = {Underwater ghost imaging LiDAR is an effective method of underwater detection. In this research, theoretical and experimental investigations were conducted on underwater ghost imaging, combining the underwater optical field transmission model with the inherent optical parameters of a water body. In addition, the Wells model and the approximate Sahu-Shanmugam scattering phase function were used to create a model for underwater optical transmission. The second-order Glauber function of the optical field was then employed to analyze the scattering field degradation during the transmission process. The simulation and experimental results verified that the proposed underwater model could better reveal the degrading effect of a water body on ghost imaging. A further series of experiments comparing underwater ghost imaging at different detection distances was also conducted. In the experimental system, gated photomultiplier tube (PMT) was used to filter out the peak of backscattering, allowing a larger gain to be set for longer-range detection of the target. The laser with a central wavelength of 532 nm was operated at a frequency of 2 KHz, with a single pulse energy of 2 mJ, a pulse width of 10 ns. High-reflective targets were imaged up to 65.2 m (9.3 attenuation lengths (ALs), attenuation coefficient c = 0.1426 m[-1], and scattering coefficient b = 0.052 m[-1]) and diffuse-reflection targets up to 41.2 m (6.4 ALs, c = 0.1569 m[-1], and b = 0.081 m[-1]). For the Jerlov-I (c = 0.048 m[-1] and b = 0.002 m[-1]) water body, the experimentally obtained maximum detection distance of 9.3 ALs can be equivalent to 193.7 m under the same optical system conditions.}, } @article {pmid38018119, year = {2024}, author = {Brown, A and Armon, C and Barkhaus, P and Beauchamp, M and Bertorini, T and Bromberg, M and Cadavid, JM and Carter, GT and Crayle, J and Feldman, EL and Heiman-Patterson, T and Jhooty, S and Linares, A and Li, X and Mallon, E and Mcdermott, C and Mushannen, T and Nathaniel, G and Pattee, G and Pierce, K and Ratner, D and Slactova, L and Wicks, P and Bedlack, R}, title = {ALSUntangled #72: Insulin.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {416-419}, doi = {10.1080/21678421.2023.2288110}, pmid = {38018119}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Insulin/adverse effects ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review insulin, which has at least one plausible mechanism for slowing ALS progression. However, pre-clinical studies are limited and there have been no trials in PALS yet. Insulin use in patients without a metabolic need may cause very serious and potentially lethal side effects. While further studies to evaluate potential benefits may be warranted, at this time we cannot endorse insulin treatment to slow ALS progression.}, } @article {pmid38018200, year = {2024}, author = {Monteiro, KLC and de Aquino, TM and da Silva-Júnior, EF}, title = {Natural Compounds as Inhibitors of Aβ Peptide and Tau Aggregation.}, journal = {CNS & neurological disorders drug targets}, volume = {23}, number = {10}, pages = {1234-1250}, pmid = {38018200}, issn = {1996-3181}, mesh = {Humans ; *tau Proteins/metabolism/antagonists & inhibitors ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Biological Products/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Plaque, Amyloid/drug therapy/metabolism ; Protein Aggregation, Pathological/drug therapy ; Neurofibrillary Tangles/drug effects/metabolism ; }, abstract = {Neurodegenerative conditions like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) encompass disorders characterized by the degeneration of neurons in specific circumstances. The quest for novel agents to influence these diseases, particularly AD, has unearthed various natural compounds displaying multifaceted activities and diverse pharmacological mechanisms. Given the ongoing extensive study of pathways associated with the accumulation of neurofibrillary aggregates and amyloid plaques, this paper aims to comprehensively review around 130 studies exploring natural products. These studies focus on inhibiting the formation of amyloid plaques and tau protein tangles, with the objective of potentially alleviating or delaying AD.}, } @article {pmid38018433, year = {2023}, author = {Naylor, K and Chrzanowska-Wąsik, M and Okońska, P and Kucmin, T and Al-Wathinani, AM and Goniewicz, K}, title = {Adapting to a Pandemic: Web-Based Residency Training and Script Concordance Testing in Emergency Medicine During COVID-19.}, journal = {Disaster medicine and public health preparedness}, volume = {17}, number = {}, pages = {e541}, doi = {10.1017/dmp.2023.195}, pmid = {38018433}, issn = {1938-744X}, mesh = {Humans ; Child ; *Internship and Residency ; Educational Measurement/methods ; Pandemics ; *COVID-19/epidemiology ; Education, Medical, Continuing/methods ; *Emergency Medicine/education ; Clinical Competence ; Internet ; }, abstract = {OBJECTIVE: The coronavirus disease (COVID-19) pandemic necessitated alternative methods to ensure the continuity of medical education. Our study explores the efficacy and acceptability of a digital continuous medical education initiative for medical residents during this challenging period.

METHODS: From September to December 2020, 47 out of 60 enrolled trainee doctors participated in this innovative digital Continuous Medical Education (CME) approach. We utilized the Script Concordance Test to bolster clinical reasoning skills. Three simulation scenarios, namely Advanced Trauma Life Support (ATLS), Advanced Life Support (ALS), and European Paediatric Life Support (EPLS), were transformed into interactive online sessions via Zoom™. Participant feedback was also collected through a survey.

RESULTS: Consistent Script Concordance Testing (SCT) scores among participants indicated the effectiveness of the online training module. Feedback suggested a broad acceptance of this novel training approach. However, discrepancies observed between formative SCT scores, and summative Multiple-Choice Questions (MCQ) assessments highlighted areas for potential refinement.

CONCLUSIONS: Our findings showcase the resilience and adaptability of medical education amidst challenges like the global pandemic. The success of methodologies such as SCT, endorsed by prestigious bodies like the European Resuscitation Council and the American Heart Association, suggests their potential in preparing health care professionals for emergent situations. This research offers valuable insights for shaping future online CME strategies.}, } @article {pmid38019311, year = {2023}, author = {Rothstein, JD and Baskerville, V and Rapuri, S and Mehlhop, E and Jafar-Nejad, P and Rigo, F and Bennett, F and Mizielinska, S and Isaacs, A and Coyne, AN}, title = {G2C4 targeting antisense oligonucleotides potently mitigate TDP-43 dysfunction in human C9orf72 ALS/FTD induced pluripotent stem cell derived neurons.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {1}, pmid = {38019311}, issn = {1432-0533}, support = {R00 NS123242/NS/NINDS NIH HHS/United States ; R01 NS132836/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Oligonucleotides, Antisense/pharmacology ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; *Induced Pluripotent Stem Cells ; DNA-Binding Proteins/genetics ; RNA, Antisense ; Dipeptides ; Neurons ; }, abstract = {The G4C2 repeat expansion in the C9orf72 gene is the most common genetic cause of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Many studies suggest that dipeptide repeat proteins produced from this repeat are toxic, yet, the contribution of repeat RNA toxicity is under investigated and even less is known regarding the pathogenicity of antisense repeat RNA. Recently, two clinical trials targeting G4C2 (sense) repeat RNA via antisense oligonucleotide failed despite a robust decrease in sense-encoded dipeptide repeat proteins demonstrating target engagement. Here, in this brief report, we show that G2C4 antisense, but not G4C2 sense, repeat RNA is sufficient to induce TDP-43 dysfunction in induced pluripotent stem cell (iPSC) derived neurons (iPSNs). Unexpectedly, only G2C4, but not G4C2 sense strand targeting, ASOs mitigate deficits in TDP-43 function in authentic C9orf72 ALS/FTD patient iPSNs. Collectively, our data suggest that the G2C4 antisense repeat RNA may be an important therapeutic target and provide insights into a possible explanation for the recent G4C2 ASO clinical trial failure.}, } @article {pmid38019415, year = {2024}, author = {Zhu, Y and Li, M and Wang, H and Yang, F and Du, R and Pang, X and Bai, J and Huang, X}, title = {Mendelian Randomization Identifies Genetically Supported Drug Targets for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Molecular neurobiology}, volume = {61}, number = {7}, pages = {3809-3818}, pmid = {38019415}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Frontotemporal Dementia/genetics/drug therapy ; Humans ; *Mendelian Randomization Analysis/methods ; Genome-Wide Association Study ; Quantitative Trait Loci ; Drug Repositioning/methods ; }, abstract = {Currently, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have no effective treatments. Drug repurposing offers a rapid method to meet therapeutic need for ALS and FTD. To identify therapeutic targets associated with ALS and FTD, Mendelian randomization (MR) analysis and colocalization were performed. Genetic instruments were based on transcriptomic and proteomic data for 422 actionable proteins targeted by approved drugs or clinical drug candidates. The publicly available ALS GWAS summary data (including a total of 20,806 ALS cases and 59,804 controls) and FTD GWAS summary data (including a total of 2154 patients with FTD and 4308 controls) were used. Using cis-expression quantitative trait loci and cis-protein quantitative trait loci genetic instruments, we identified several drug targets for repurposing (ALS: MARK3, false-discovery rate (FDR) = 0.043; LTBR, FDR = 0.068) (FTD: HLA-DRB1, FDR = 0.083; ADH5, FDR = 0.056). Our MR study analyzed the actionable druggable proteins and provided potential therapeutic targets for ALS and FTD. Future studies should further elucidate the underlying mechanism of corresponding drug targets in the pathogenesis of ALS and FTD.}, } @article {pmid38019651, year = {2023}, author = {Harley, P and Kerins, C and Gatt, A and Neves, G and Riccio, F and Machado, CB and Cheesbrough, A and R'Bibo, L and Burrone, J and Lieberam, I}, title = {Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons.}, journal = {Cell reports}, volume = {42}, number = {12}, pages = {113509}, pmid = {38019651}, issn = {2211-1247}, support = {215508/WT_/Wellcome Trust/United Kingdom ; MR/N025865/1/MRC_/Medical Research Council/United Kingdom ; MR/N026063/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Axon Initial Segment/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; Action Potentials/physiology ; }, abstract = {Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment (AIS), the site of action potential generation, could impact neuronal excitability in ALS human induced pluripotent stem cell (hiPSC) motor neurons. We find that early TDP-43 and C9orf72 hiPSC motor neurons show an increase in the length of the AIS and impaired activity-dependent AIS plasticity that is linked to abnormal homeostatic regulation of neuronal activity and intrinsic hyperexcitability. In turn, these hyperactive neurons drive increased spontaneous myofiber contractions of in vitro hiPSC motor units. In contrast, late hiPSC and postmortem ALS motor neurons show AIS shortening, and hiPSC motor neurons progress to hypoexcitability. At a molecular level, aberrant expression of the AIS master scaffolding protein ankyrin-G and AIS-specific voltage-gated sodium channels mirror these dynamic changes in AIS function and excitability. Our results point toward the AIS as an important site of dysfunction in ALS motor neurons.}, } @article {pmid38020004, year = {2023}, author = {Du, W and Yan, M and Yin, C and Zhang, Z}, title = {A novel modified nano-alumina composite sol for potential application in forest firefighting.}, journal = {RSC advances}, volume = {13}, number = {48}, pages = {33820-33825}, pmid = {38020004}, issn = {2046-2069}, abstract = {Herein, modified ammonium polyphosphate wrapped nano-alumina (mAPP@Als) was first synthesized and then dispersed in traditional fire extinguishing solution (FES) to fabricate a FES-mAPP@Als composite sol. It was found that the phosphorus-silica containing units were attached onto the nano-alumina surface, and the mAPP@Als particles showed excellent dispersion level in FES with a single-domain particle size distribution range. Due to the synergistic effects of the phosphorus-nitrogen and silica-alumina flame retardant components, FES-mAPP@Als (5% concentration) coated wood exhibited improved limiting oxygen index (33.2%) and carbonization ability, and depressed heat release (41.9%) and smoke production (10.7%), as compared to the pristine wood. In addition, the FES-mAPP@Als composite sol showed enhanced fire-extinguishing and anti-reignition capacities compared to the FES. This research offers a novel composite sol fire extinguishing agent for fighting forest fires.}, } @article {pmid38020546, year = {2023}, author = {de Brito Siqueira, ALG and Cremasco, PVV and Bahú, JO and Pioli da Silva, A and Melo de Andrade, LR and González, PGA and Crivellin, S and Cárdenas Concha, VO and Krambeck, K and Lodi, L and Severino, P and Souto, EB}, title = {Phytocannabinoids: Pharmacological effects, biomedical applications, and worldwide prospection.}, journal = {Journal of traditional and complementary medicine}, volume = {13}, number = {6}, pages = {575-587}, pmid = {38020546}, issn = {2225-4110}, abstract = {Scientific evidence exists about the association between neurological diseases (i.e., Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, depression, and memory loss) and oxidative damage. The increasing worldwide incidence of such diseases is attracting the attention of researchers to find palliative medications to reduce the symptoms and promote quality of life, in particular, in developing countries, e.g., South America and Africa. Among potential alternatives, extracts of Cannabis Sativa L. are suitable for people who have neurological disorders, spasticity, and pain, nausea, resulting from diseases such as cancer and arthritis. In this review, we discuss the latest developments in the use of Cannabis, its subtypes and constituents, extraction methods, and relevant pharmacological effects. Biomedical applications, marketed products, and prospects for the worldwide use of Cannabis Sativa L. extracts are also discussed, providing the bibliometric maps of scientific literature published in representative countries from South America (i.e., Brazil) and Africa (i.e., South Africa). A lack of evidence on the effectiveness and safety of Cannabis, besides the concerns about addiction and other adverse events, has led many countries to act with caution before changing Cannabis-related regulations. Recent findings are expected to increase the social acceptance of Cannabis, while new technologies seem to boost the global cannabis market because the benefits of (-)-trans-delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) use have been proven in several studies in addition to the potential to general new employment.}, } @article {pmid38020597, year = {2023}, author = {Nakamura, R and Kurihara, M and Kobashi, S and Tamaki, Y and Ogawa, N and Kitamura, A and Yamakawa, I and Bamba, S and Terashima, T and Urushitani, M}, title = {Ideal body weight-based determination of minimum oral calories beneficial to function and survival in ALS.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1286153}, pmid = {38020597}, issn = {1664-2295}, abstract = {INTRODUCTION: This study sought to identify the optimal caloric intake to improve function and survival in ALS patients by comparing oral intake per ideal body weight (IBW) and its discrepancy with total energy expenditure (TEE) using the Shimizu formula.

METHODS: A retrospective analysis of 104 ALS patients was conducted, categorizing them based on their average intake during the first week after admission using two primary intake cutoffs: 25 kcal/kgIBW and 30 kcal/kgIBW. The variance between oral intake and TEE was also evaluated using -300 kcal and 0 kcal as reference points.

RESULTS: Oral caloric intake per IBW and functional decline rate (rs = -0.35, p < 0.001), but the variance from TEE was not significantly correlated (-0.11, p = 0.27). Survival data showed that patients consuming less than 25 kcal/kgIBW had a median survival of 24 months, increasing to 38 months for those consuming between 25-30 kcal/kgIBW and 63 months for those consuming 30 kcal/kgIBW or more. Deviations from the TEE did not significantly affect survival (p = 0.36). Among patients consuming less than their TEE, those consuming less than 25 kcal/kgIBW had a shorter median survival (24 months) compared to their counterparts (46 months) (p = 0.022). Consumption of less than 25 kcal/kgBW emerged as a significant negative predictor of patient outcome, independent of factors such as age, gender or disease progression.

DISCUSSION: Intakes of 25 kcal/kgIBW or more are correlated with improved ALS outcomes, and larger, multi-regional studies are recommended for deeper insights.}, } @article {pmid38020614, year = {2023}, author = {Xu, D and Chu, M and Chen, Y and Fang, Y and Wang, J and Zhang, X and Xu, F}, title = {Identification and verification of ferroptosis-related genes in the pathology of epilepsy: insights from CIBERSORT algorithm analysis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1275606}, pmid = {38020614}, issn = {1664-2295}, abstract = {BACKGROUND: Epilepsy is a neurological disorder characterized by recurrent seizures. A mechanism of cell death regulation, known as ferroptosis, which involves iron-dependent lipid peroxidation, has been implicated in various diseases, including epilepsy.

OBJECTIVE: This study aimed to provide a comprehensive understanding of the relationship between ferroptosis and epilepsy through bioinformatics analysis. By identifying key genes, pathways, and potential therapeutic targets, we aimed to shed light on the underlying mechanisms involved in the pathogenesis of epilepsy.

MATERIALS AND METHODS: We conducted a comprehensive analysis by screening gene expression data from the Gene Expression Omnibus (GEO) database and identified the differentially expressed genes (DEGs) related to ferroptosis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to gain insights into the biological processes and pathways involved. Moreover, we constructed a protein-protein interaction (PPI) network to identify hub genes, which was further validated using the receiver operating characteristic (ROC) curve analysis. To explore the relationship between immune infiltration and genes, we employed the CIBERSORT algorithm. Furthermore, we visualized four distinct interaction networks-mRNA-miRNA, mRNA-transcription factor, mRNA-drug, and mRNA-compound-to investigate potential regulatory mechanisms.

RESULTS: In this study, we identified a total of 33 differentially expressed genes (FDEGs) associated with epilepsy and presented them using a Venn diagram. Enrichment analysis revealed significant enrichment in the pathways related to reactive oxygen species, secondary lysosomes, and ubiquitin protein ligase binding. Furthermore, GSVA enrichment analysis highlighted significant differences between epilepsy and control groups in terms of the generation of precursor metabolites and energy, chaperone complex, and antioxidant activity in Gene Ontology (GO) analysis. Furthermore, during the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we observed differential expression in pathways associated with amyotrophic lateral sclerosis (ALS) and acute myeloid leukemia (AML) between the two groups. To identify hub genes, we constructed a protein-protein interaction (PPI) network using 30 FDEGs and utilized algorithms. This analysis led to the identification of three hub genes, namely, HIF1A, TLR4, and CASP8. The application of the CIBERSORT algorithm allowed us to explore the immune infiltration patterns between epilepsy and control groups. We found that CD4-naïve T cells, gamma delta T cells, M1 macrophages, and neutrophils exhibited higher expression in the control group than in the epilepsy group.

CONCLUSION: This study identified three FDEGs and analyzed the immune cells in epilepsy. These findings pave the way for future research and the development of innovative therapeutic strategies for epilepsy.}, } @article {pmid38021968, year = {2023}, author = {Munoz, NR and Agwuegbo, CC and Ghorbani, A and Vincent Coralde, JM and Abdelmalik, R}, title = {Takotsubo Cardiomyopathy Induced by Stress From Amyotrophic Lateral Sclerosis and a Mechanical Fall.}, journal = {Cureus}, volume = {15}, number = {10}, pages = {e47068}, pmid = {38021968}, issn = {2168-8184}, abstract = {Named after the Japanese octopus trap, Takotsubo cardiomyopathy is an acute myocardial condition characterized by a reversible ventricular dysfunction with ballooning of the left ventricle (LV) during systole. A catecholamine surge is likely the primary mechanism responsible for myocardial damage in this condition. The association between amyotrophic lateral sclerosis (ALS) and Takotsubo cardiomyopathy has not been well established. We present a unique case of Takotsubo cardiomyopathy diagnosed in a patient with ALS who presented after a fall with shortness of breath, generalized weakness, and hypotension. She was found to have troponinemia, elevated brain natriuretic peptide, and Osborn waves without ST-segment changes noted on electrocardiography (EKG). The diagnosis of Takotsubo cardiomyopathy was confirmed via transthoracic echocardiography (TTE), which revealed reduced left ventricular ejection fraction, apical ballooning of the LV, akinesis of the ventricular apex, and hyperkinesis of the base of the heart. Coronary angiography revealed no coronary artery disease. She was managed medically and was hemodynamically stable at the time of discharge.}, } @article {pmid38022117, year = {2023}, author = {Jain, A and Madkan, S and Patil, P}, title = {The Role of Gut Microbiota in Neurodegenerative Diseases: Current Insights and Therapeutic Implications.}, journal = {Cureus}, volume = {15}, number = {10}, pages = {e47861}, pmid = {38022117}, issn = {2168-8184}, abstract = {Small microscopic entities known as microbes, having a population of hundreds of billions or perhaps even in trillions, reside in our gastrointestinal tract. A healthy immune system, digestion, and creation of vitamins and enzymes are all thanks to these microbes. However, new research has shown a hitherto unrecognized connection between the microbiota of the intestines and the genesis of neurodegenerative diseases. Neurons in the CNS gradually deteriorate in neurodegenerative illnesses like multiple sclerosis and Parkinson's disease (PD). This deterioration impairs cognitive and physical function. Amyotrophic lateral sclerosis (ALS), PD, and Alzheimer's disease (AD) are just a few examples of neurodegenerative illnesses that pose a serious threat to world health and have few effective treatments. Recent research suggests that the gut microbiota, a diverse microbial population found in the gastrointestinal system, may substantially impact the cause and development of various diseases. The discovery of altered gut microbiota composition in people with these illnesses is one of the most critical lines of evidence connecting gut microbiota dysbiosis to neurodegenerative diseases. AD patients have a distinct characteristic of having a particular microbiota profile. In addition, an excess population of a specific microbe data profile is seen as compared to a healthy individual. Similar changes in the gut microbiota composition have been noted in people with multiple sclerosis and PD. The latest study indicates the potential that dysbiosis, a condition characterized by alteration in the intestinal microbiota's makeup and functioning, may have an effect on the onset and progression of neurodegenerative diseases, including PD and multiple sclerosis. In order to emphasize any potential underlying mechanisms and examine potential treatment repercussions, the review article's goal is to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders. The review article aims to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders, highlighting potential underlying mechanisms and examining potential treatment repercussions.}, } @article {pmid38022431, year = {2023}, author = {Hiew, FL}, title = {Sleep and Survival in Amyotrophic Lateral Sclerosis (ALS): The Parallelism in Motor and Non-Motor Progression.}, journal = {Annals of Indian Academy of Neurology}, volume = {26}, number = {5}, pages = {628}, pmid = {38022431}, issn = {0972-2327}, } @article {pmid38022476, year = {2023}, author = {Chawla, T and Goyal, V}, title = {Tofersen: Silver Lining or Hyperbole??.}, journal = {Annals of Indian Academy of Neurology}, volume = {26}, number = {5}, pages = {638-640}, pmid = {38022476}, issn = {0972-2327}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of anterior horn cells with a dismal prognosis. Over a century since its description, we still do not have a cure for this disorder. Edaravone, Riluzole, and combination of phenylbutyrate and taurursodiol are a handful of FDA-approved drugs that only delay the progression of the disease by a few months. Tofersen, an antisense oligonucleotide, in SOD1 related ALS, has joined the bandwagon of FDA-approved drugs for ALS recently. It is a gene therapy that has been found to lower SOD1 concentrations and neurofilament light chain concentrations in blood and CSF, a known biomarker of ALS, leading to the accelerated approval of the drug. Although it did not show any statistically significant clinical improvement. In this article, we discuss the development and approval process of the first gene-based therapy, Tofersen, for ALS.}, } @article {pmid38022487, year = {2023}, author = {Li, X and Liu, Q and Niu, T and Jia, H and Liu, T and Xin, Z and Li, Z and Zhou, X and Li, R and Liu, Y and Dong, H}, title = {Sleep Disturbances as a Potential Risk Factor for Deterioration of Respiratory Function in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Annals of Indian Academy of Neurology}, volume = {26}, number = {5}, pages = {754-760}, pmid = {38022487}, issn = {0972-2327}, abstract = {OBJECTIVES: Sleep disturbances are common in amyotrophic lateral sclerosis (ALS). However, previous studies have explored sleep quality at the cross-sectional level and the longitudinal variability characteristics are currently unknown. Our study aimed to longitudinally explore the effect of sleep quality on disease progression in patients with ALS.

METHODS: All enrolled patients with ALS were first diagnosed and completed the 6- and 12-month follow-ups. Subjective sleep disturbance was assessed using the Pittsburgh Sleep Quality Index (PSQI). Based on the PSQI score at baseline, patients with ALS were classified as poor sleepers (PSQI >5) and good sleepers (PSQI ≤5). Disease progression was assessed using the rate of disease progression, the absolute change from baseline forced vital capacity (ΔFVC) and the percentage change from baseline FVC (ΔFVC%) over the follow-up period.

RESULTS: Sixty-three patients were included in the study, 24 (38.1%) were poor sleepers and 39 were good sleepers. The percentage of patients with poor sleep quality was 38.1% at baseline, increasing to 60.3% and 74.6% at 6- and 12-month, respectively. Compared to good sleepers, ΔFVC and ΔFVC% values were greater in poor sleepers (P < 0.001 and P = 0.001, respectively). Poor sleep quality at diagnosis is associated with rapid deterioration of respiratory function during disease progression.

CONCLUSIONS: Sleep disturbances maybe a potential risk factor for deterioration of respiratory function in patients with ALS. The role of sleep disturbances in disease progression deserves attention, and early assessment and intervention may slow disease progression and improve life quality of patients with ALS.}, } @article {pmid38022694, year = {2023}, author = {Maselli, F and D'Antona, S and Utichi, M and Arnaudi, M and Castiglioni, I and Porro, D and Papaleo, E and Gandellini, P and Cava, C}, title = {Computational analysis of five neurodegenerative diseases reveals shared and specific genetic loci.}, journal = {Computational and structural biotechnology journal}, volume = {21}, number = {}, pages = {5395-5407}, pmid = {38022694}, issn = {2001-0370}, abstract = {Neurodegenerative diseases (ND) are heterogeneous disorders of the central nervous system that share a chronic and selective process of neuronal cell death. A computational approach to investigate shared genetic and specific loci was applied to 5 different ND: Amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and Lewy body dementia (LBD). The datasets were analyzed separately, and then we compared the obtained results. For this purpose, we applied a genetic correlation analysis to genome-wide association datasets and revealed different genetic correlations with several human traits and diseases. In addition, a clumping analysis was carried out to identify SNPs genetically associated with each disease. We found 27 SNPs in AD, 6 SNPs in ALS, 10 SNPs in PD, 17 SNPs in MS, and 3 SNPs in LBD. Most of them are located in non-coding regions, with the exception of 5 SNPs on which a protein structure and stability prediction was performed to verify their impact on disease. Furthermore, an analysis of the differentially expressed miRNAs of the 5 examined pathologies was performed to reveal regulatory mechanisms that could involve genes associated with selected SNPs. In conclusion, the results obtained constitute an important step toward the discovery of diagnostic biomarkers and a better understanding of the diseases.}, } @article {pmid38025276, year = {2023}, author = {Audrain, M and Egesipe, AL and Tentillier, N and Font, L and Ratnam, M and Mottier, L and Clavel, M and Le Roux-Bourdieu, M and Fenyi, A and Ollier, R and Chevalier, E and Guilhot, F and Fuchs, A and Piorkowska, K and Carlyle, B and Arnold, SE and Berry, JD and Luthi-Carter, R and Adolfsson, O and Pfeifer, A and Kosco-Vilbois, M and Seredenina, T and Afroz, T}, title = {Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF.}, journal = {Brain communications}, volume = {5}, number = {6}, pages = {fcad306}, pmid = {38025276}, issn = {2632-1297}, abstract = {In amyotrophic lateral sclerosis, a disease driven by abnormal transactive response DNA-binding protein of 43 kDa aggregation, CSF may contain pathological species of transactive response DNA-binding protein of 43 kDa contributing to the propagation of pathology and neuronal toxicity. These species, released in part by degenerating neurons, would act as a template for the aggregation of physiological protein contributing to the spread of pathology in the brain and spinal cord. In this study, a robust seed amplification assay was established to assess the presence of seeding-competent transactive response DNA-binding protein of 43 kDa species in CSF of apparently sporadic amyotrophic lateral sclerosis patients. These samples resulted in a significant acceleration of substrate aggregation differentiating the kinetics from healthy controls. In parallel, a second assay was developed to determine the level of target engagement that would be necessary to neutralize such species in human CSF by a therapeutic monoclonal antibody targeting transactive response DNA-binding protein of 43 kDa. For this, evaluation of the pharmacokinetic/pharmacodynamic effect for the monoclonal antibody, ACI-5891.9, in vivo and in vitro confirmed that a CSF concentration of ≍1100 ng/mL would be sufficient for sustained target saturation. Using this concentration in the seed amplification assay, ACI-5891.9 was able to neutralize the transactive response DNA-binding protein of 43 kDa pathogenic seeds derived from amyotrophic lateral sclerosis patient CSF. This translational work adds to the evidence of transmission of transactive response DNA-binding protein of 43 kDa pathology via CSF that could contribute to the non-contiguous pattern of clinical manifestations observed in amyotrophic lateral sclerosis and demonstrates the ability of a therapeutic monoclonal antibody to neutralize the toxic, extracellular seeding-competent transactive response DNA-binding protein of 43 kDa species in the CSF of apparently sporadic amyotrophic lateral sclerosis patients.}, } @article {pmid38025370, year = {2023}, author = {Narayan, MS and Sameer, M and Viburajah, V}, title = {Hip Fracture in a Patient with Overlap Syndrome - Conundrums Involved in the Management - A Case Report.}, journal = {Journal of orthopaedic case reports}, volume = {13}, number = {11}, pages = {106-111}, pmid = {38025370}, issn = {2250-0685}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition producing symptoms of varying severity depending on the extent and progression of the disease pathology most importantly respiratory insufficiency and pulmonary complications. Myasthenia gravis (MG) on the other hand is an autoimmune condition due to the pathology involving failure of neuromuscular transmission causing muscle weakness exacerbated by activity and involvement of the respiratory muscles leading to respiratory failure. Overlap syndrome is a condition wherein both motor neuron disease (MND) and MG are present in the same patient. The safety of using muscle-relaxing agents in patients with MG undergoing major surgical procedures has so far been assessed as insufficient. There have been many concerns regarding anesthetic management in relation to complications with respiratory function in patients with ALS, with regional anesthesia being considered slightly safer.

CASE REPORT: An 81-year-old female presented with a closed injury to her left hip, and she was diagnosed to have a left neck of femur fracture. She was also a known case of bulbar MND with an overlap syndrome of MG. She was hypertensive and controlled with regular medication. She was planned for a left hip bipolar arthroplasty. Anesthetic requirements and management of these patients require a high degree of expertise and anesthesia in patients undergoing surgery is prone to more complications and mortality. In addition, as the patient had an overlap of both MG and MND, more meticulous assessment and management strategies were necessary.

CONCLUSION: The importance and purpose of this study are to highlight a case of overlap syndrome of MND and MG patients who sustained a left neck femur fracture and underwent bipolar arthroplasty highlighting the anesthetic considerations in the patient for the procedure. We concluded that the choice of mode of anesthesia needs to be individualized based on each patient's requirements after careful analysis of the risk-benefit ratio of general versus regional. Regional anesthesia was successfully administered for this patient.}, } @article {pmid38026695, year = {2023}, author = {Donison, N and Hintermayer, M and Subramaniam, M and Santandrea, E and Volkening, K and Strong, MJ}, title = {Upregulation of LRRK2 following traumatic brain injury does not directly phosphorylate Thr[175] tau.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1272899}, pmid = {38026695}, issn = {1662-5102}, abstract = {Phosphorylated microtubule-associated protein tau (tau) aggregates are a pathological hallmark of various neurodegenerative diseases, including chronic traumatic encephalopathy and amyotrophic lateral sclerosis with cognitive impairment. While there are many residues phosphorylated on tau, phosphorylation of threonine 175 (pThr[175] tau) has been shown to initiate fibril formation in vitro and is present in pathological tau aggregates in vivo. Given this, preventing Thr[175] tau phosphorylation presents a potential approach to reduce fibril formation; however, the kinase(s) acting on Thr[175] are not yet fully defined. Using a single controlled cortical impact rodent model of traumatic brain injury (TBI), which rapidly induces Thr[175] tau phosphorylation, we observed an upregulation and alteration in subcellular localization of leucine-rich repeat kinase 2 (LRRK2), a kinase that has been implicated in tau phosphorylation. LRRK2 upregulation was evident by one-day post-injury and persisted to day 10. The most notable changes were observed in microglia at the site of injury in the cortex. To determine if the appearance of pThr[175] tau was causally related to the upregulation of LRRK2 expression, we examined the ability of LRRK2 to phosphorylate Thr[175]in vitro by co-transfecting 2N4R human WT-tau with either LRRK2-WT, constitutively-active LRRK2-G2019S or inactive LRRK2-3XKD. We found no significant difference in the level of pThr[175] tau between the overexpression of LRRK2-WT, -G2019S or -3XKD, suggesting LRRK2 does not phosphorylate tau at Thr[175]. Further, downstream events known to follow Thr[175] phosphorylation and known to be associated with pathological tau fibril formation (pSer[9]-GSK3β and pThr[231] tau induction) also remained unchanged. We conclude that while LRRK2 expression is altered in TBI, it does not contribute directly to pThr[175] tau generation.}, } @article {pmid38026702, year = {2023}, author = {Pisciottani, A and Croci, L and Lauria, F and Marullo, C and Savino, E and Ambrosi, A and Podini, P and Marchioretto, M and Casoni, F and Cremona, O and Taverna, S and Quattrini, A and Cioni, JM and Viero, G and Codazzi, F and Consalez, GG}, title = {Neuronal models of TDP-43 proteinopathy display reduced axonal translation, increased oxidative stress, and defective exocytosis.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1253543}, pmid = {38026702}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neurodegenerative disease mostly affecting people around 50-60 years of age. TDP-43, an RNA-binding protein involved in pre-mRNA splicing and controlling mRNA stability and translation, forms neuronal cytoplasmic inclusions in an overwhelming majority of ALS patients, a phenomenon referred to as TDP-43 proteinopathy. These cytoplasmic aggregates disrupt mRNA transport and localization. The axon, like dendrites, is a site of mRNA translation, permitting the local synthesis of selected proteins. This is especially relevant in upper and lower motor neurons, whose axon spans long distances, likely accentuating their susceptibility to ALS-related noxae. In this work we have generated and characterized two cellular models, consisting of virtually pure populations of primary mouse cortical neurons expressing a human TDP-43 fusion protein, wt or carrying an ALS mutation. Both forms facilitate cytoplasmic aggregate formation, unlike the corresponding native proteins, giving rise to bona fide primary culture models of TDP-43 proteinopathy. Neurons expressing TDP-43 fusion proteins exhibit a global impairment in axonal protein synthesis, an increase in oxidative stress, and defects in presynaptic function and electrical activity. These changes correlate with deregulation of axonal levels of polysome-engaged mRNAs playing relevant roles in the same processes. Our data support the emerging notion that deregulation of mRNA metabolism and of axonal mRNA transport may trigger the dying-back neuropathy that initiates motor neuron degeneration in ALS.}, } @article {pmid38028604, year = {2023}, author = {Kumar, R and Madhavan, T and Ponnusamy, K and Sohn, H and Haider, S}, title = {Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators.}, journal = {Frontiers in genetics}, volume = {14}, number = {}, pages = {1282234}, pmid = {38028604}, issn = {1664-8021}, abstract = {Introduction: Kinesin family member 5A (KIF5A) is a motor neuron protein expressed in neurons and involved in anterograde transportation of organelles, proteins, and RNA. Variations in the KIF5A gene that interfere with axonal transport have emerged as a distinguishing feature in several neurodegenerative disorders, including hereditary spastic paraplegia (HSP10), Charcot-Marie-Tooth disease type 2 (CMT2), and Amyotrophic Lateral Sclerosis (ALS). Methods: In this study, we implemented a computational structural and systems biology approach to uncover the role of KIF5A in ALS. Using the computational structural biology method, we explored the role of non-synonymous Single Nucleotide Polymorphism (nsSNPs) in KIF5A. Further, to identify the potential inhibitory molecule against the highly destabilizing structure variant, we docked 24 plant-derived phytochemicals involved in ALS. Results: We found KIF5A[S291F] variant showed the most structure destabilizing behavior and the phytocompound "epigallocatechin gallate" showed the highest binding affinity (-9.0 Kcal/mol) as compared to wild KIF5A (-8.4 Kcal/mol). Further, with the systems biology approach, we constructed the KIF5A protein-protein interaction (PPI) network to identify the associated Kinesin Families (KIFs) proteins, modules, and their function. We also constructed a transcriptional and post-transcriptional regulatory network of KIF5A. With the network topological parameters of PPIN (Degree, Bottleneck, Closeness, and MNC) using CytoHubba and computational knock-out experiment using Network Analyzer, we found KIF1A, 5B, and 5C were the significant proteins. The functional modules were highly enriched with microtubule motor activity, chemical synaptic transmission in neurons, GTP binding, and GABA receptor activity. In regulatory network analysis, we found KIF5A post-transcriptionally down-regulated by miR-107 which is further transcriptionally up-regulated by four TFs (HIF1A, PPARA, SREBF1, and TP53) and down-regulated by three TFs (ZEB1, ZEB2, and LIN28A). Discussion: We concluded our study by finding a crucial variant of KIF5A and its potential therapeutic target (epigallocatechin gallate) and KIF5A associated significant genes with important regulators which could decrypt the novel therapeutics in ALS and other neurodegenerative diseases.}, } @article {pmid38029395, year = {2024}, author = {Song, J}, title = {Molecular Mechanisms of Phase Separation and Amyloidosis of ALS/FTD-linked FUS and TDP-43.}, journal = {Aging and disease}, volume = {15}, number = {5}, pages = {2084-2112}, pmid = {38029395}, issn = {2152-5250}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *RNA-Binding Protein FUS/metabolism/chemistry/genetics ; *DNA-Binding Proteins/metabolism/chemistry/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Amyloidosis/metabolism/pathology/genetics ; Phase Separation ; }, abstract = {FUS and TDP-43, two RNA-binding proteins from the heterogeneous nuclear ribonucleoprotein family, have gained significant attention in the field of neurodegenerative diseases due to their association with amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). They possess folded domains for binding ATP and various nucleic acids including DNA and RNA, as well as substantial intrinsically disordered regions (IDRs) including prion-like domains (PLDs) and RG-/RGG-rich regions. They play vital roles in various cellular processes, including transcription, splicing, microRNA maturation, RNA stability and transport and DNA repair. In particular, they are key components for forming ribonucleoprotein granules and stress granules (SGs) through homotypic or heterotypic liquid-liquid phase separation (LLPS). Strikingly, liquid-like droplets formed by FUS and TDP-43 may undergo aging to transform into less dynamic assemblies such as hydrogels, inclusions, and amyloid fibrils, which are the pathological hallmarks of ALS and FTD. This review aims to synthesize and consolidate the biophysical knowledge of the sequences, structures, stability, dynamics, and inter-domain interactions of FUS and TDP-43 domains, so as to shed light on the molecular mechanisms underlying their liquid-liquid phase separation (LLPS) and amyloidosis. The review further delves into the mechanisms through which ALS-causing mutants of the well-folded hPFN1 disrupt the dynamics of LLPS of FUS prion-like domain, providing key insights into a potential mechanism for misfolding/aggregation-prone proteins to cause neurodegenerative diseases and aging by gain of functions. With better understanding of different biophysical aspects of FUS and TDP-43, the ultimate goal is to develop drugs targeting LLPS and amyloidosis, which could mediate protein homeostasis within cells and lead to new treatments for currently intractable diseases, particularly neurodegenerative diseases such as ALS, FTD and aging. However, the study of membrane-less organelles and condensates is still in its infancy and therefore the review also highlights key questions that require future investigation.}, } @article {pmid38030509, year = {2024}, author = {Jacobs, MT and San Gil, R and Walker, AK}, title = {UndERACting ion channels in neurodegeneration.}, journal = {Trends in neurosciences}, volume = {47}, number = {2}, pages = {87-89}, doi = {10.1016/j.tins.2023.11.002}, pmid = {38030509}, issn = {1878-108X}, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Endoplasmic Reticulum ; Ion Channels/genetics/metabolism ; Chloride Channels/metabolism ; }, abstract = {In a recent study, Guo and colleagues characterised the function of an elusive endoplasmic reticulum (ER) anion channel protein, Chloride Channel CLiC Like 1 (CLCC1), and identified rare CLCC1 variants in people with amyotrophic lateral sclerosis (ALS). CLCC1 mutants disrupted ER function in vitro and promoted ALS-like pathology and neurodegeneration in mice. This work reveals a previously uncharacterised pathway involved in ER calcium release and highlights new pathogenic mechanisms underlying neurodegeneration.}, } @article {pmid38030693, year = {2023}, author = {Vanbilsen, N and Kotz, SA and Rosso, M and Leman, M and Triccas, LT and Feys, P and Moumdjian, L}, title = {Auditory attention measured by EEG in neurological populations: systematic review of literature and meta-analysis.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {21064}, pmid = {38030693}, issn = {2045-2322}, support = {G082021N//Fonds Wetenschappelijk Onderzoek/ ; 1295923N//Fonds Wetenschappelijk Onderzoek/ ; }, mesh = {Humans ; Cross-Sectional Studies ; *Attention ; *Parkinson Disease ; Gait ; Electroencephalography ; }, abstract = {Sensorimotor synchronization strategies have been frequently used for gait rehabilitation in different neurological populations. Despite these positive effects on gait, attentional processes required to dynamically attend to the auditory stimuli needs elaboration. Here, we investigate auditory attention in neurological populations compared to healthy controls quantified by EEG recordings. Literature was systematically searched in databases PubMed and Web of Science. Inclusion criteria were investigation of auditory attention quantified by EEG recordings in neurological populations in cross-sectional studies. In total, 35 studies were included, including participants with Parkinson's disease (PD), stroke, Traumatic Brain Injury (TBI), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS). A meta-analysis was performed on P3 amplitude and latency separately to look at the differences between neurological populations and healthy controls in terms of P3 amplitude and latency. Overall, neurological populations showed impairments in auditory processing in terms of magnitude and delay compared to healthy controls. Consideration of individual auditory processes and thereafter selecting and/or designing the auditory structure during sensorimotor synchronization paradigms in neurological physical rehabilitation is recommended.}, } @article {pmid38031465, year = {2024}, author = {Ghasemi, A and Sadedel, M and Moghaddam, MM}, title = {A wearable system to assist impaired-neck patients: Design and evaluation.}, journal = {Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine}, volume = {238}, number = {1}, pages = {63-77}, doi = {10.1177/09544119231211362}, pmid = {38031465}, issn = {2041-3033}, mesh = {Humans ; *Robotics ; Electromyography/methods ; *Stroke ; Movement ; *Wearable Electronic Devices ; }, abstract = {Patients with neurological disorders, such as amyotrophic lateral sclerosis, Parkinson's disease, and cerebral palsy, often face challenges due to head-neck immobility. The conventional treatment approach involves using a neck collar to maintain an upright head position, but this can be cumbersome and restricts head-neck movements over prolonged periods. This study introduces a wearable robot capable of providing three anatomical head motions for training and assistance. The primary contributions of this research include the design of an optimized structure and the incorporation of human-robot interaction. Based on human head motion data, our primary focus centered on developing a robot capable of accommodating a significant range of neutral head movements. To ensure safety, impedance control was employed to facilitate human-robot interaction. A human study was conducted involving 10 healthy subjects who participated in an experiment to assess the robot's assistance capabilities. Passive and active modes were used to evaluate the robot's effectiveness, taking into account head-neck movement error and muscle activity levels. Surface electromyography signals (sEMG) were collected from the splenius capitis muscles during the experiment. The results demonstrated that the robot covered nearly 85% of the overall range of head rotations. Importantly, using the robot during rehabilitation led to reduced muscle activation, highlighting its potential for assisting individuals with post-stroke movement impairments.}, } @article {pmid38033614, year = {2023}, author = {Nakken, O and Vaage, AM and Stigum, H and Heldal, E and Meyer, HE and Holmøy, T}, title = {Tuberculin responses after BCG vaccination predict amyotrophic lateral sclerosis risk.}, journal = {Brain, behavior, & immunity - health}, volume = {34}, number = {}, pages = {100704}, pmid = {38033614}, issn = {2666-3546}, abstract = {BACKGROUND: T cell infiltration around dying motor neurons is a hallmark of amyotrophic lateral sclerosis (ALS). It is not known if this immune response represents a cause or a consequence of the disease. We aimed to establish whether individual variation in regulation of a T cell driven immune response is associated with long-term ALS risk.

METHODS: Tuberculin skin test (TST) following BCG vaccination represents a standardized measure of a secondary T cell driven immune response. During a Norwegian tuberculosis screening program (1963-1975) Norwegian citizens born from 1910 to 1955 underwent TST. In those previously BCG vaccinated (median 7 years prior to TST), we related tuberculin skin tests to later ALS disease identified through validated Norwegian health registers. We fitted Cox proportional hazard models to investigate the association between tuberculin reactivity and ALS risk.

RESULTS: Among 324,629 participants (52 % women) with median age 22 (IQR 10) years at tuberculosis screening, 496 (50 % women) later developed ALS. Hazard ratio for ALS was 0.74 (95% CI 0.57-0.95) for those who remained TST negative compared to those who mounted a positive TST. The association was strongest when time between BCG immunization and TST was short. The associations observed persisted for more than four decades after TST measurement.

CONCLUSIONS: Negative TST responses after BCG vaccination is associated with decreased long-term risk for ALS development, supporting a primary role for adaptive immunity in ALS development.}, } @article {pmid38033869, year = {2023}, author = {Vukolova, MN and Yen, LY and Khmyz, MI and Sobolevsky, AI and Yelshanskaya, MV}, title = {Parkinson's disease, epilepsy, and amyotrophic lateral sclerosis-emerging role of AMPA and kainate subtypes of ionotropic glutamate receptors.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1252953}, pmid = {38033869}, issn = {2296-634X}, support = {R37 NS083660/NS/NINDS NIH HHS/United States ; R01 NS107253/NS/NINDS NIH HHS/United States ; R01 NS083660/NS/NINDS NIH HHS/United States ; R01 AR078814/AR/NIAMS NIH HHS/United States ; R01 CA206573/CA/NCI NIH HHS/United States ; }, abstract = {Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission and are implicated in various neurological disorders. In this review, we discuss the role of the two fastest iGluRs subtypes, namely, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, in the pathogenesis and treatment of Parkinson's disease, epilepsy, and amyotrophic lateral sclerosis. Although both AMPA and kainate receptors represent promising therapeutic targets for the treatment of these diseases, many of their antagonists show adverse side effects. Further studies of factors affecting the selective subunit expression and trafficking of AMPA and kainate receptors, and a reasonable approach to their regulation by the recently identified novel compounds remain promising directions for pharmacological research.}, } @article {pmid38035964, year = {2024}, author = {Khan, S and Upadhyay, S and Dave, U and Kumar, A and Gomes, J}, title = {Structural and mechanistic insights into ALS patient derived mutations in D-amino acid oxidase.}, journal = {International journal of biological macromolecules}, volume = {256}, number = {Pt 2}, pages = {128403}, doi = {10.1016/j.ijbiomac.2023.128403}, pmid = {38035964}, issn = {1879-0003}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Kinetics ; Mutation ; Serine/genetics ; }, abstract = {The D-amino acid oxidase protein modulates neurotransmission by controlling the levels of D-serine, a co-agonist of N-methyl-D-aspartate receptors. Mutations in the DAO gene have been associated with ALS, with some studies reporting pathogenic mechanisms of the R199W mutation. We have characterized two novel mutations R38H and Q201R found in ALS patients and report certain novel findings related to the R199W mutation. We report the first instance of crystal structure analysis of a patient-derived mutant of DAO, R38H, solved at 2.10 Å. The structure revealed significant perturbations and altered binding with the cofactor (FAD) and the inhibitor benzoate, supported by biochemical assays. Q201R-DAO also exhibited significantly lower ligand binding efficiency. Furthermore, kinetic analysis across all variants revealed reduced oxidase activity and substrate binding. Notably, R38H-DAO exhibited near-WT activity only at high substrate concentrations, while R199W-DAO and Q201R-DAO displayed drastic activity reduction. Additionally, structural perturbations were inferred for R199W-DAO and Q201R-DAO, evident by the higher oligomeric state in the holoenzyme form. We also observed thermal instability in case of R199W-DAO mutant. We hypothesize that the mutant enzymes may be rendered non-functional in a cellular context, potentially leading to NMDAR-associated excitotoxicity. The study provides novel insights into structural and functional aspects of DAO mutations in ALS.}, } @article {pmid38036035, year = {2024}, author = {Wang, X and Zhu, Z and Sun, J and Jia, L and Cai, L and Chen, Q and Yang, W and Wang, Y and Zhang, Y and Guo, S and Liu, W and Yang, Z and Zhao, P and Wang, Z and Lv, H}, title = {Changes in iron load in specific brain areas lead to neurodegenerative diseases of the central nervous system.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {129}, number = {}, pages = {110903}, doi = {10.1016/j.pnpbp.2023.110903}, pmid = {38036035}, issn = {1878-4216}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/pathology ; Iron ; Genome-Wide Association Study ; Magnetic Resonance Imaging/methods ; Brain/diagnostic imaging/pathology ; *Alzheimer Disease/pathology ; *Parkinson Disease ; *Multiple Sclerosis ; }, abstract = {The causes of neurodegenerative diseases remain largely elusive, increasing their personal and societal impacts. To reveal the causal effects of iron load on Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis and multiple sclerosis, we used Mendelian randomisation and brain imaging data from a UK Biobank genome-wide association study of 39,691 brain imaging samples (predominantly of European origin). Using susceptibility-weighted images, which reflect iron load, we analysed genetically significant brain regions. Inverse variance weighting was used as the main estimate, while MR Egger and weighted median were used to detect heterogeneity and pleiotropy. Nine clear associations were obtained. For AD and PD, an increased iron load was causative: the right pallidum for AD and the right caudate, left caudate and right accumbens for PD. However, a reduced iron load was identified in the right and left caudate for multiple sclerosis, the bilateral hippocampus for mixed vascular dementia and the left thalamus and bilateral accumbens for subcortical vascular dementia. Thus, changes in iron load in different brain regions have causal effects on neurodegenerative diseases. Our results are crucial for understanding the pathogenesis and investigating the treatment of these diseases.}, } @article {pmid38036140, year = {2024}, author = {Karaśkiewicz, J and Wójcik, R}, title = {Modelling optimal water retention in hydrogenic habitats using LIDAR laser data.}, journal = {The Science of the total environment}, volume = {912}, number = {}, pages = {168983}, doi = {10.1016/j.scitotenv.2023.168983}, pmid = {38036140}, issn = {1879-1026}, abstract = {Degradation of hydrogenic habitats in climate change increased rapidly. It is important that we take actions to stop this process. Solution is to increase efficiency of water usage by ecosystems - especially water based ones. Building devices for delaying surface water runoff - like locks and dams - should improve hydrogenic habitats conditions and allow surrounding ecosystems use rainwater more efficient. Modelling of small retention in forests is an important aspect in decision making schema. Aim of this paper is to point optimal solutions for height and placement of devices which delay surface water runoff to set necessary water table level for renaturalization and maintenance of degrading natural habitats. Data used for analyses were acquired in the Polanów Forest Inspectorate in West Pomeranian voivodeship because of the topography diversification and the drainage infrastructure presence. There were three research plots selected based on decreased stability of habitats and historic data stated that there were natural water reservoirs, which were drained in past. Based on 2012 LiDAR (Light Detection and Ranging) point cloud the digital terrain model (DTM) was built. Water outflow points - melioration canals - were identified and analysed for optimal device localization. In following part of research specific data for each hydrogenic habitat were used to model height of devices which delay surface water runoff. Optimal level of device and area covered by water were set for each site separately. The results were handed over to the investor for implementation, then the compliance of the assumptions of the simulation of raising the water table with the as-built field measurements was checked. Study shows that it is possible to use laser technology to optimize location and height of devices which delay surface water runoff what allows to restore degraded hydrogenic habitats. Presented method supports small local retention what increases limited water resources in this region, decreases rapid runoff of surface water which causes frequent floods. Proposed method of modelling the location and height of the dams or locks is universal. Even though results are unique for each object the method is possible to be applied to every other situation.}, } @article {pmid38037913, year = {2024}, author = {Zhong, G and Wang, X and Li, J and Xie, Z and Wu, Q and Chen, J and Wang, Y and Chen, Z and Cao, X and Li, T and Liu, J and Wang, Q}, title = {Insights Into the Role of Copper in Neurodegenerative Diseases and the Therapeutic Potential of Natural Compounds.}, journal = {Current neuropharmacology}, volume = {22}, number = {10}, pages = {1650-1671}, pmid = {38037913}, issn = {1875-6190}, support = {81973918, 82274616//National Natural Science Foundation of China/ ; 2019KSYS005//Key laboratory project of colleges and universities in Guangdong Province/ ; 2020A0505100052//Guangdong province science and technology plan international cooperation project/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Copper/metabolism ; Animals ; Biological Products/therapeutic use/pharmacology ; Homeostasis/drug effects ; Chelating Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases encompass a collection of neurological disorders originating from the progressive degeneration of neurons, resulting in the dysfunction of neurons. Unfortunately, effective therapeutic interventions for these diseases are presently lacking. Copper (Cu), a crucial trace element within the human body, assumes a pivotal role in various biological metabolic processes, including energy metabolism, antioxidant defense, and neurotransmission. These processes are vital for the sustenance, growth, and development of organisms. Mounting evidence suggests that disrupted copper homeostasis contributes to numerous age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), Menkes disease (MD), prion diseases, and multiple sclerosis (MS). This comprehensive review investigates the connection between the imbalance of copper homeostasis and neurodegenerative diseases, summarizing pertinent drugs and therapies that ameliorate neuropathological changes, motor deficits, and cognitive impairments in these conditions through the modulation of copper metabolism. These interventions include Metal-Protein Attenuating Compounds (MPACs), copper chelators, copper supplements, and zinc salts. Moreover, this review highlights the potential of active compounds derived from natural plant medicines to enhance neurodegenerative disease outcomes by regulating copper homeostasis. Among these compounds, polyphenols are particularly abundant. Consequently, this review holds significant implications for the future development of innovative drugs targeting the treatment of neurodegenerative diseases.}, } @article {pmid38038225, year = {2024}, author = {Sanghani, N and Claytor, B and Li, Y}, title = {Electrodiagnostic findings in amyotrophic lateral sclerosis: Variation with region of onset and utility of thoracic paraspinal muscle examination.}, journal = {Muscle & nerve}, volume = {69}, number = {2}, pages = {172-178}, doi = {10.1002/mus.28012}, pmid = {38038225}, issn = {1097-4598}, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis ; Retrospective Studies ; Paraspinal Muscles ; Electromyography ; Electrodiagnosis ; }, abstract = {INTRODUCTION/AIMS: Limited data exist regarding variation of electrodiagnostic (EDX) findings in amyotrophic lateral sclerosis (ALS) patients with different onset regions and specificity of thoracic paraspinal muscle (TPSP) examination for confirming a diagnosis of ALS. We aimed to demonstrate the variation of EDX features and characterize the utility of TPSP muscle examination in the electrodiagnosis of ALS.

METHODS: This is a retrospective study of a large cohort of ALS patients who had a comprehensive EDX evaluation.

RESULTS: The study included 448 patients; all fulfilled the Gold Coast criteria for ALS. The average age at the time of EDX study was 64 years, and 41.1% were women. The onset region was identified as follows: bulbar (N = 149), cervical (N = 127), lumbosacral (N = 162), and other (N = 10). In contrast to limb onset, bulbar-onset patients more frequently demonstrated a pattern of normal or near normal needle electromyography (EMG) (p < .0001) and less frequently had abnormalities on EMG of TPSP (p = .002). Clinical or EDX diagnosis of sensory polyneuropathy was present in 12.6% patients, more frequently in the lumbosacral onset subgroup (p < .03). EMG showed active denervation in 9.6% and chronic denervation in 59% of craniobulbar muscles examined, without observed difference among different onset regions. TPSP showed higher frequencies of active and chronic denervation in ALS than a group of patients with non-ALS neuromuscular disorders.

DISCUSSION: EDX features may differ among ALS patients of different onset regions. TPSP EMG is highly useful in differentiating ALS from non-ALS neuromuscular disorders while the yield of craniobulbar muscles, especially for active denervation, is low.}, } @article {pmid38041659, year = {2024}, author = {Kiernan, MC and Farrar, MA}, title = {Emerging role for sphingolipids in the genetics of amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {2}, pages = {101-102}, doi = {10.1136/jnnp-2023-332719}, pmid = {38041659}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Sphingolipids ; *Motor Neuron Disease ; }, } @article {pmid38041662, year = {2024}, author = {Shy, ME}, title = {Genetics, cell biology and a novel mechanism for ALS.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {3}, pages = {199-200}, doi = {10.1136/jnnp-2023-332720}, pmid = {38041662}, issn = {1468-330X}, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Motor Neurons ; Disease Models, Animal ; *Motor Neuron Disease ; }, } @article {pmid38041669, year = {2024}, author = {Guissart, C and De la Cruz, E and Flabeau, O and Grapperon, AM and Corazza, G and Junilhon, L and Delmas, JC and Millecamps, S and Polge, A and Amador, MDM and Salachas, F and Rochat, J and Goizet, C and Juntas Morales, R and Lumbroso, S and Philibert, P and Cheillan, D and Mouzat, K}, title = {Heterozygous SPTLC1 p.Leu39del is a major cause of slow-progressing juvenile ALS.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {3}, pages = {288-290}, doi = {10.1136/jnnp-2023-331753}, pmid = {38041669}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; *Serine C-Palmitoyltransferase/genetics ; }, } @article {pmid38041679, year = {2024}, author = {Syeda, SB and Lone, MA and Mohassel, P and Donkervoort, S and Munot, P and França, MC and Galarza-Brito, JE and Eckenweiler, M and Asamoah, A and Gable, K and Majumdar, A and Schumann, A and Gupta, SD and Lakhotia, A and Shieh, PB and Foley, AR and Jackson, KE and Chao, KR and Winder, TL and Catapano, F and Feng, L and Kirschner, J and Muntoni, F and Dunn, TM and Hornemann, T and Bönnemann, CG}, title = {Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {2}, pages = {103-113}, pmid = {38041679}, issn = {1468-330X}, support = {R01 HG009141/HG/NHGRI NIH HHS/United States ; UM1 HG008900/HG/NHGRI NIH HHS/United States ; }, mesh = {Child ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Neurodegenerative Diseases ; Sphingolipids ; Serine C-Palmitoyltransferase/genetics/metabolism ; *Hereditary Sensory and Autonomic Neuropathies/genetics ; Serine ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific SPTLC1 variants resulting in sphingolipid overproduction as a cause for juvenile ALS. Here, we report six patients from six independent families with a recurrent, de novo, heterozygous variant in SPTLC2 c.778G>A [p.Glu260Lys] manifesting with juvenile ALS.

METHODS: Clinical examination of the patients along with ancillary and genetic testing, followed by biochemical investigation of patients' blood and fibroblasts, was performed.

RESULTS: All patients presented with early-childhood-onset progressive weakness, with signs and symptoms of upper and lower motor neuron degeneration in multiple myotomes, without sensory neuropathy. These findings were supported on ancillary testing including nerve conduction studies and electromyography, muscle biopsies and muscle ultrasound studies. Biochemical investigations in plasma and fibroblasts showed elevated levels of ceramides and unrestrained de novo sphingolipid synthesis. Our studies indicate that SPTLC2 variant [c.778G>A, p.Glu260Lys] acts distinctly from hereditary sensory and autonomic neuropathy (HSAN)-causing SPTLC2 variants by causing excess canonical sphingolipid biosynthesis, similar to the recently reported SPTLC1 ALS associated pathogenic variants. Our studies also indicate that serine supplementation, which is a therapeutic in SPTLC1 and SPTCL2-associated HSAN, is expected to exacerbate the excess sphingolipid synthesis in serine palmitoyltransferase (SPT)-associated ALS.

CONCLUSIONS: SPTLC2 is the second SPT-associated gene that underlies monogenic, juvenile ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Our findings also have important therapeutic implications: serine supplementation must be avoided in SPT-associated ALS, as it is expected to drive pathogenesis further.}, } @article {pmid38041684, year = {2024}, author = {Dohrn, MF and Beijer, D and Lone, MA and Bayraktar, E and Oflazer, P and Orbach, R and Donkervoort, S and Foley, AR and Rose, A and Lyons, M and Louie, RJ and Gable, K and Dunn, T and Chen, S and Danzi, MC and Synofzik, M and Bönnemann, CG and Nazlı Başak, A and Hornemann, T and Zuchner, S}, title = {Recurrent de-novo gain-of-function mutation in SPTLC2 confirms dysregulated sphingolipid production to cause juvenile amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {3}, pages = {201-205}, pmid = {38041684}, issn = {1468-330X}, support = {R01 NS072248/NS/NINDS NIH HHS/United States ; R01 NS105755/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Ceramides ; Gain of Function Mutation ; Mutation/genetics ; *Serine C-Palmitoyltransferase/genetics/chemistry ; Sphingolipids ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) leads to paralysis and death by progressive degeneration of motor neurons. Recently, specific gain-of-function mutations in SPTLC1 were identified in patients with juvenile form of ALS. SPTLC2 encodes the second catalytic subunit of the serine-palmitoyltransferase (SPT) complex.

METHODS: We used the GENESIS platform to screen 700 ALS whole-genome and whole-exome data sets for variants in SPTLC2. The de-novo status was confirmed by Sanger sequencing. Sphingolipidomics was performed using liquid chromatography and high-resolution mass spectrometry.

RESULTS: Two unrelated patients presented with early-onset progressive proximal and distal muscle weakness, oral fasciculations, and pyramidal signs. Both patients carried the novel de-novo SPTLC2 mutation, c.203T>G, p.Met68Arg. This variant lies within a single short transmembrane domain of SPTLC2, suggesting that the mutation renders the SPT complex irresponsive to regulation through ORMDL3. Confirming this hypothesis, ceramide and complex sphingolipid levels were significantly increased in patient plasma. Accordingly, excessive sphingolipid production was shown in mutant-expressing human embryonic kindney (HEK) cells.

CONCLUSIONS: Specific gain-of-function mutations in both core subunits affect the homoeostatic control of SPT. SPTLC2 represents a new Mendelian ALS gene, highlighting a key role of dysregulated sphingolipid synthesis in the pathogenesis of juvenile ALS. Given the direct interaction of SPTLC1 and SPTLC2, this knowledge might open new therapeutic avenues for motor neuron diseases.}, } @article {pmid38042502, year = {2024}, author = {Ma, H and Huo, J and Xin, C and Yang, J and Liu, Q and Dong, H and Li, R and Liu, Y}, title = {RABGGTB plays a critical role in ALS pathogenesis.}, journal = {Brain research bulletin}, volume = {206}, number = {}, pages = {110833}, doi = {10.1016/j.brainresbull.2023.110833}, pmid = {38042502}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Spinal Cord/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with unknown causes, which mainly affects motor neurons in the anterior horn of the spinal cord, brain stem, and cerebral cortex, also known as motor neuron disease. An important pathological feature of ALS is the formation of aggregates of mutant SOD1 protein, CTF25 of TDP-43, or other abnormal proteins in motor neurons, which require autophagy for degradation. Protein prenylation is known to participate in membrane association and proper localization of proteins. RABGGTB is the β subunit of GGTase II (one of the prenyltransferases) that can regulate autophagy via Rab7 geranylgeranylation. In this study, we overexpressed RABGGTB via lentiviral transfection in NSC34-hSOD1G93A and TDP-43 cells. Overexpression of RABGGTB improved ALS cell proliferation by facilitating autophagosome-lysosome fusion. Furthermore, the abnormal aggregation of SOD1 protein was reduced. This indicates that protein prenylation is important for the proliferation and autophagy of cells autophagy. Enhanced autophagy has been observed in two of the most widely used ALS cell models. These findings indicate the widespread applicability of prenylation in ALS. In summary, overexpression of RABGGTB improved the geranylgeranylation of the Rab7 protein and had a positive effect on cells. These findings provide insights into the development of a novel therapeutic strategy for ALS.}, } @article {pmid38043051, year = {2024}, author = {Graber, DJ and Cook, WJ and Sentman, ML and Murad-Mabaera, JM and Sentman, CL}, title = {Human CD4+CD25+ T cells expressing a chimeric antigen receptor against aberrant superoxide dismutase 1 trigger antigen-specific immunomodulation.}, journal = {Cytotherapy}, volume = {26}, number = {2}, pages = {126-135}, pmid = {38043051}, issn = {1477-2566}, support = {P30 CA023108/CA/NCI NIH HHS/United States ; R21 NS102556/NS/NINDS NIH HHS/United States ; R21 NS117895/NS/NINDS NIH HHS/United States ; }, mesh = {Mice ; Animals ; Humans ; Superoxide Dismutase-1/genetics/metabolism/therapeutic use ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Receptors, Chimeric Antigen/therapeutic use ; Interleukin-10/genetics ; Superoxide Dismutase/metabolism ; Mice, Transgenic ; CD4-Positive T-Lymphocytes/metabolism ; Immunomodulation ; Disease Models, Animal ; }, abstract = {BACKGROUND AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal disease associated with motor neuron degeneration, accumulation of aggregated misfolded proteins and neuroinflammation in motor regions of the central nervous system (CNS). Clinical trials using regulatory T cells (Tregs) are ongoing because of Tregs' immunomodulatory function, ability to traffic to the CNS, high numbers correlating with slower disease in ALS and disease-modifying activity in ALS mouse models. In the current study, a chimeric antigen receptor (CAR) was developed and characterized in human Tregs to enhance their immunomodulatory activity when in contact with an ALS protein aggregate.

METHODS: A CAR (DG05-28-3z) consisting of a human superoxide dismutase 1 (hSOD1)-binding single-chain variable fragment, CD28 hinge, transmembrane and co-stimulatory domain and CD3ζ signaling domain was created and expressed in human Tregs. Human Tregs were isolated by either magnetic enrichment for CD4+CD25[hi] cells (Enr-Tregs) or cell sorting for CD4+CD25[hi]CD127[lo] cells (FP-Tregs), transduced and expanded for 17 days.

RESULTS: The CAR bound preferentially to the ALS mutant G93A-hSOD1 protein relative to the wild-type hSOD1 protein. The CAR Tregs produced IL-10 when cultured with aggregated G93A-hSOD1 proteins or spinal cord explants from G93A-hSOD1 transgenic mice. Co-culturing DG05-28-3z CAR Tregs with human monocytes/macrophages inhibited production of tumor necrosis factor alpha and reactive oxygen species. Expanded FP-Tregs resulted in more robust Tregs compared with Enr-Tregs. FP-Tregs produced similar IL-10 and less interferon gamma, had lower Treg-specific demethylated region methylation and expressed higher FoxP3 and CD39.

CONCLUSIONS: Taken together, this study demonstrates that gene-modified Tregs can be developed to target an aggregated ALS-relevant protein to elicit CAR-mediated Treg effector functions and provides an approach for generating Treg therapies for ALS with the goal of enhanced disease site-specific immunomodulation.}, } @article {pmid38043854, year = {2024}, author = {Pourzand, P and Moore, J and Metzger, A and Salverda, B and Suresh, M and Arango, S and Rosenhagen, H and Kaizer, A and Duval, S and Debaty, G and Lurie, K}, title = {Hemodynamics, survival and neurological function with early versus delayed automated head-up CPR in a porcine model of prolonged cardiac arrest.}, journal = {Resuscitation}, volume = {194}, number = {}, pages = {110067}, doi = {10.1016/j.resuscitation.2023.110067}, pmid = {38043854}, issn = {1873-1570}, support = {R43HL158361/NH/NIH HHS/United States ; }, mesh = {Animals ; *Cardiopulmonary Resuscitation/methods ; Disease Models, Animal ; Epinephrine ; *Heart Arrest ; Hemodynamics ; Swine ; }, abstract = {AIM: To determine if controlled head and thorax elevation, active compression-decompression cardiopulmonary resuscitation (CPR), and an impedance threshold device combined, termed automated head-up positioning CPR (AHUP-CPR), should be initiated early, as a basic (BLS) intervention, or later, as an advanced (ALS) intervention, in a severe porcine model of cardiac arrest.

METHODS: Yorkshire pigs (n = 22) weighing ∼40 kg were anesthetized and ventilated. After 15 minutes of untreated ventricular fibrillation, pigs were randomized to AHUP-CPR for 25 minutes (BLS group) or conventional CPR for 10 minutes, followed by 15 minutes of AHUP-CPR (ALS group). Thereafter, epinephrine, amiodarone, and defibrillation were administered. Neurologic function, the primary endpoint, was assessed 24-hours later with a Neurological Deficit Score (NDS, 0 = normal and 260 = worst deficit score or death). Secondary outcomes included return of spontaneous circulation (ROSC), cumulative survival, hemodynamics and epinephrine responsivity. Data, expressed as mean ± standard deviation, were compared using Fisher's Exact, log-rank, Mann-Whitney U and unpaired t-tests.

RESULTS: ROSC was achieved in 10/11 pigs with early AHUP-CPR versus 6/11 with delayed AHUP-CPR (p = 0.14), and cumulative 24-hour survival was 45.5% versus 9.1%, respectively (p < 0.02). The NDS was 203 ± 80 with early AHUP-CPR versus 259 ± 3 with delayed AHUP-CPR (p = 0.035). ETCO2, rSO2, and responsiveness to epinephrine were significantly higher in the early versus delayed AHUP-CPR.

CONCLUSION: When delivered early rather than late, AHUP-CPR resulted in significantly increased hemodynamics, 24-hour survival, and improved neurological function in pigs after prolonged cardiac arrest. Based on these findings, AHUP-CPR should be considered a BLS intervention.}, } @article {pmid38045991, year = {2023}, author = {Barberio, J and Lally, C and Kupelian, V and Hardiman, O and Flanders, WD}, title = {Estimated Familial Amyotrophic Lateral Sclerosis Proportion: A Literature Review and Meta-analysis.}, journal = {Neurology. Genetics}, volume = {9}, number = {6}, pages = {e200109}, pmid = {38045991}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder. Familial (fALS) cases are usually reported to constitute 5%-10% of all ALS cases; however, no recent literature review or meta-analysis of this proportion (referred to throughout as "proportion fALS") has been conducted. Our objective was to estimate the proportion fALS by geographic region and to assess the effect of study characteristics on the estimates.

METHODS: A comprehensive literature review was performed to identify all original studies reporting the number of fALS cases in an ALS cohort. The results were stratified by geographic region, study design (case series or population-based), and decade of study publication. Subgroup analyses were conducted according to family history criteria used to define fALS. We report pooled estimates of the proportion fALS from random-effects meta-analyses when >2 studies are available and I[2] is < 90%; weighted averages and ranges are otherwise presented.

RESULTS: The overall pooled proportion fALS based on a total 165 studies was 8% (0%, 71%). The proportion fALS was 9% (0%, 71%) among 107 case series and 5% (4%, 6%) among 58 population-based studies. Among population-based studies, proportion fALS by geographic region was 6% (5%, 7%; N = 37) for Europe, 5% (3%, 7%; N = 5) for Latin America, and 5% (4%, 7%; N = 12) for North America. Criteria used to define fALS were reported by 21 population-based studies (36%), and proportion fALS was 5% (4%, 5%; N = 9) for first-degree relative, 7% (4%, 11%; N = 4) for first or second-degree relative, and 11% (N = 1) for more distant ALS family history. Population-based studies published in the 2000s or earlier generated a lower pooled proportion fALS than studies published in the 2010s or later.

DISCUSSION: The results suggest that variability in the reported proportion fALS in the literature may be, in part, due to the differences in geography, study design, fALS definition, and decade of case ascertainment. Few studies outside of European ancestral populations were available. The proportion fALS was marginally higher among case series compared with population-based studies, likely because of referral bias. Criteria used to define fALS were largely unreported. Consensus criteria for fALS and additional population-based studies in non-European ancestral populations are needed.}, } @article {pmid38046408, year = {2023}, author = {Liu, J and Li, H and Zhou, Y and Zhang, Y and Song, S and Gu, X and Xu, J and Yu, X}, title = {Deep learning-based estimation of axial length using macular optical coherence tomography images.}, journal = {Frontiers in medicine}, volume = {10}, number = {}, pages = {1308923}, pmid = {38046408}, issn = {2296-858X}, abstract = {BACKGROUND: This study aimed to develop deep learning models using macular optical coherence tomography (OCT) images to estimate axial lengths (ALs) in eyes without maculopathy.

METHODS: A total of 2,664 macular OCT images from 444 patients' eyes without maculopathy, who visited Beijing Hospital between March 2019 and October 2021, were included. The dataset was divided into training, validation, and testing sets with a ratio of 6:2:2. Three pre-trained models (ResNet 18, ResNet 50, and ViT) were developed for binary classification (AL ≥ 26 mm) and regression task. Ten-fold cross-validation was performed, and Grad-CAM analysis was employed to visualize AL-related macular features. Additionally, retinal thickness measurements were used to predict AL by linear and logistic regression models.

RESULTS: ResNet 50 achieved an accuracy of 0.872 (95% Confidence Interval [CI], 0.840-0.899), with high sensitivity of 0.804 (95% CI, 0.728-0.867) and specificity of 0.895 (95% CI, 0.861-0.923). The mean absolute error for AL prediction was 0.83 mm (95% CI, 0.72-0.95 mm). The best AUC, and accuracy of AL estimation using macular OCT images (0.929, 87.2%) was superior to using retinal thickness measurements alone (0.747, 77.8%). AL-related macular features were on the fovea and adjacent regions.

CONCLUSION: OCT images can be effectively utilized for estimating AL with good performance via deep learning. The AL-related macular features exhibit a localized pattern in the macula, rather than continuous alterations throughout the entire region. These findings can lay the foundation for future research in the pathogenesis of AL-related maculopathy.}, } @article {pmid38046601, year = {2023}, author = {Quan, W and Chan, Z and Wei, P and Mao, Y and Bartels, D and Liu, X}, title = {PHD finger proteins function in plant development and abiotic stress responses: an overview.}, journal = {Frontiers in plant science}, volume = {14}, number = {}, pages = {1297607}, pmid = {38046601}, issn = {1664-462X}, abstract = {The plant homeodomain (PHD) finger with a conserved Cys4-His-Cys3 motif is a common zinc-binding domain, which is widely present in all eukaryotic genomes. The PHD finger is the "reader" domain of methylation marks in histone H3 and plays a role in the regulation of gene expression patterns. Numerous proteins containing the PHD finger have been found in plants. In this review, we summarize the functional studies on PHD finger proteins in plant growth and development and responses to abiotic stresses in recent years. Some PHD finger proteins, such as VIN3, VILs, and Ehd3, are involved in the regulation of flowering time, while some PHD finger proteins participate in the pollen development, for example, MS, TIP3, and MMD1. Furthermore, other PHD finger proteins regulate the plant tolerance to abiotic stresses, including Alfin1, ALs, and AtSIZ1. Research suggests that PHD finger proteins, as an essential transcription regulator family, play critical roles in various plant biological processes, which is helpful in understanding the molecular mechanisms of novel PHD finger proteins to perform specific function.}, } @article {pmid38046608, year = {2023}, author = {Wang, R and Sun, Y and Lan, Y and Wei, S and Huang, H and Li, X and Huang, Z}, title = {ALS gene overexpression and enhanced metabolism conferring Digitaria sanguinalis resistance to nicosulfuron in China.}, journal = {Frontiers in plant science}, volume = {14}, number = {}, pages = {1290600}, pmid = {38046608}, issn = {1664-462X}, abstract = {Crabgrass (Digitaria sanguinalis) is a common malignant weed in corn fields in China. Recently, the acetolactate synthase (ALS) inhibitor, nicosulfuron, has shown decreasing efficacy against crabgrass. In order to elucidate the molecular basis of resistance to nicosulfuron in crabgrass, we conducted bioassays, combined with gene sequence analysis, relative expression and relative copy number analysis, to characterize resistance in crabgrass populations collected from Beijing, Heilongjiang, Jilin and Anhui provinces. Whole-plant dose-response results indicated that only population collected in Heilongjiang province (HLJ) had developed low level of resistance to nicosulfuron compared with the sensitive population (SD22). No known resistant mutation of ALS gene was found in HLJ population. The real-time fluorescence quantitative PCR results showed that the ALS gene copy number did not differ significantly between the HLJ and SD22 populations. However, the ALS gene expression in the HLJ was 2.07-fold higher than that of the SD22 population at 24 h after treatment with nicosulfuron. Pretreatment with the cytochrome P450 (CYP450) inhibitor malathion, piperonyl butoxide (PBO), and the glutathione S-transferase (GST) inhibitor 4-Chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) all partially reversed HLJ resistance. Among them, the synergistic effect of PBO and nicosulfuron is the most significant. This is the first report of resistance to nicosulfuron in crabgrass through ALS gene overexpression and possible metabolic resistance.}, } @article {pmid38049068, year = {2024}, author = {Wang, B and Huang, Y and Li, J}, title = {Response to John et al's comments of "paroxetine is an effective treatment for refractory erythema of rosacea: Primary results from the prospective rosacea refractory erythema randomized clinical trial".}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {4}, pages = {e143-e144}, doi = {10.1016/j.jaad.2023.11.050}, pmid = {38049068}, issn = {1097-6787}, mesh = {Humans ; *Paroxetine/therapeutic use ; Prospective Studies ; *Rosacea/drug therapy ; Erythema/drug therapy/etiology ; Treatment Outcome ; }, } @article {pmid38049069, year = {2024}, author = {Navarro-Fernandez, I}, title = {Tracing the origins of setons in hidradenitis suppurativa: A commentary to Vilarrasa et al's "Drainage setons for the management of sinus tracts in hidradenitis suppurativa".}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {4}, pages = {e139}, doi = {10.1016/j.jaad.2023.10.068}, pmid = {38049069}, issn = {1097-6787}, mesh = {Humans ; *Hidradenitis Suppurativa ; Inflammation ; }, } @article {pmid38049418, year = {2023}, author = {Megat, S and Mora, N and Sanogo, J and Roman, O and Catanese, A and Alami, NO and Freischmidt, A and Mingaj, X and De Calbiac, H and Muratet, F and Dirrig-Grosch, S and Dieterle, S and Van Bakel, N and Müller, K and Sieverding, K and Weishaupt, J and Andersen, PM and Weber, M and Neuwirth, C and Margelisch, M and Sommacal, A and Van Eijk, KR and Veldink, JH and , and Lautrette, G and Couratier, P and Camuzat, A and Le Ber, I and Grassano, M and Chio, A and Boeckers, T and Ludolph, AC and Roselli, F and Yilmazer-Hanke, D and Millecamps, S and Kabashi, E and Storkebaum, E and Sellier, C and Dupuis, L}, title = {Author Correction: Integrative genetic analysis illuminates ALS heritability and identifies risk genes.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {8026}, doi = {10.1038/s41467-023-43710-4}, pmid = {38049418}, issn = {2041-1723}, } @article {pmid38049549, year = {2024}, author = {Wu, T and Li, H}, title = {A case of Mills' syndrome: initially characterized by one cerebral hemisphere atrophy and decreased brain metabolism then evolving into amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {3}, pages = {1311-1313}, pmid = {38049549}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/pathology ; *Motor Neuron Disease ; Brain/diagnostic imaging/pathology ; Chronic Disease ; Atrophy/pathology ; Muscular Atrophy ; *Cerebrum ; }, abstract = {This article reports a case of Mills' syndrome that initially manifested as atrophy of one cerebral hemisphere and decreased brain metabolism, which developed into amyotrophic lateral sclerosis in the fourth year of the disease. Mills' syndrome is a rare type of motor neuron disease, with only over 20 cases reported since 1990, but most lack imaging such as PET and DTI. This article provides a complete report of the 18F-FDG-PET and DTI images consistent with the characteristics of Mills' syndrome. In addition, we have discovered some new phenomena, which have certain clinical and teaching values. Firstly, the frontal, parietal and temporal lobes on the side of the lesion in the pyramidal tract of this patient were significantly atrophic, indicating that unilateral brain lobe atrophy may be a new feature of Mills' syndrome. Secondly, although there were no abnormalities in three EMG tests taken during the 4 years prior to the onset of the disease, amyotrophy and ALS-like EMG features appeared in the fourth year, suggesting that some Mills' syndrome may progress more rapidly to ALS. This highlights the importance of regular follow-up electromyography in Mills' syndrome patients.}, } @article {pmid38049641, year = {2024}, author = {Kiani, L}, title = {ALS pathogenesis linked to actin barrier collapse.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {1}, pages = {1}, pmid = {38049641}, issn = {1759-4766}, mesh = {Humans ; *Actins ; *Amyotrophic Lateral Sclerosis/etiology ; }, } @article {pmid38049694, year = {2024}, author = {Sequeira, M and Godinho, F and Lourenço, J}, title = {Amyotrophic Lateral Sclerosis with SOD1 Mutation Presenting with Progressive Cerebellar Ataxia.}, journal = {Cerebellum (London, England)}, volume = {23}, number = {4}, pages = {1702-1704}, pmid = {38049694}, issn = {1473-4230}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Superoxide Dismutase-1/genetics ; *Cerebellar Ataxia/genetics/diagnostic imaging ; *Mutation ; *Superoxide Dismutase/genetics ; Male ; Middle Aged ; Female ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder that affects upper and lower motor neurons. SOD1 mutations are the second most commonly found in familial and sporadic cases. We describe a patient with a homozygous pathogenic mutation in SOD1 gene that presented with a progressive cerebellar ataxia and ultimately developed a complex phenotype of cerebellar ataxia and motor neuron disease. The linkage between the cerebellum and ALS is shortly discussed.}, } @article {pmid38050066, year = {2024}, author = {Bowser, R and An, J and Mehta, L and Chen, J and Timmons, J and Cudkowicz, M and Paganoni, S}, title = {Effect of sodium phenylbutyrate and taurursodiol on plasma concentrations of neuroinflammatory biomarkers in amyotrophic lateral sclerosis: results from the CENTAUR trial.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {7}, pages = {605-608}, pmid = {38050066}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/drug therapy ; *Biomarkers/blood ; *Chitinase-3-Like Protein 1/blood ; *C-Reactive Protein/analysis ; *Phenylbutyrates/therapeutic use ; Female ; Male ; Middle Aged ; Hexosaminidases/blood ; Aged ; Double-Blind Method ; Chitinases/blood ; }, abstract = {BACKGROUND: An oral sodium phenylbutyrate and taurursodiol combination (PB and TURSO) significantly reduced functional decline in people living with amyotrophic lateral sclerosis (ALS) in the CENTAUR trial. Biomarkers linking clinical therapeutic effect with biological changes are of high interest in ALS. We performed analyses of neuroinflammatory biomarkers associated with ALS in the literature, including YKL-40 (also known as chitinase-3-like protein 1), chitinase 1 (CHIT1) and C reactive protein (CRP), in plasma samples collected in CENTAUR.

METHODS: Log10-transformed plasma biomarker measurements were analysed using a linear mixed-effects model. Correlation between paired biomarker concentrations and ALS Functional Rating Scale-Revised (ALSFRS-R) total scores was assessed via Pearson correlation coefficients.

RESULTS: By week 24, geometric least squares mean YKL-40 plasma concentration decreased by approximately 20% (p=0.008) and CRP by 30% (p=0.048) in the PB and TURSO versus placebo group. YKL-40 (r of -0.21; p<0.0001) and CRP (r of -0.19; p=0.0002) concentration correlated with ALSFRS-R total score. CHIT1 levels were not significantly different between groups.

CONCLUSIONS: YKL-40 and CRP plasma levels were significantly reduced in participants with ALS receiving PB and TURSO in CENTAUR and correlated with disease progression. These findings suggest YKL-40 and CRP could be treatment-sensitive biomarkers in ALS, pending further confirmatory studies.

TRIAL REGISTRATION NUMBER: https://clinicaltrials.gov/study/NCT03127514.}, } @article {pmid38050140, year = {2024}, author = {Thompson, AG and Taschler, B and Smith, SM and Turner, MR}, title = {Premorbid brain structure influences risk of amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {4}, pages = {360-365}, pmid = {38050140}, issn = {1468-330X}, support = {/WT_/Wellcome Trust/United Kingdom ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; Brain/diagnostic imaging ; Gray Matter/diagnostic imaging ; Magnetic Resonance Imaging ; *White Matter/diagnostic imaging ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease of the motor network associated with brain structure and functional connectivity alterations that are implicated in disease progression. Whether such changes have a causal role in ALS, fitting with a postulated influence of premorbid cerebral architecture on the phenotypes associated with neurodegenerative disorders is not known.

METHODS: This study considered causal effects and shared genetic risk of 2240 structural and functional MRI brain scan imaging-derived phenotypes (IDPs) on ALS using two sample Mendelian randomisation, with putative associations further examined with extensive sensitivity analysis. Shared genetic predisposition between IDPs and ALS was explored using genetic correlation analysis.

RESULTS: Increased white matter volume in the cerebral hemispheres was causally associated with ALS. Weaker causal associations were observed for brain stem grey matter volume, parieto-occipital white matter surface and volume of the left thalamic ventral anterior nucleus. Genetic correlation was observed between ALS and intracellular volume fraction and isotropic free water volume fraction within the posterior limb of the internal capsule.

CONCLUSIONS: This study provides evidence that premorbid brain structure, in particular white matter volume, contributes to the risk of ALS.}, } @article {pmid38050178, year = {2024}, author = {Megens, M and de Souza, A}, title = {Amyotrophic lateral sclerosis with demyelinating neurophysiology and a motor band sign.}, journal = {Practical neurology}, volume = {24}, number = {3}, pages = {219-222}, doi = {10.1136/pn-2023-003963}, pmid = {38050178}, issn = {1474-7766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Aged ; Neural Conduction/physiology ; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/physiopathology/diagnosis/diagnostic imaging ; Magnetic Resonance Imaging/methods ; Demyelinating Diseases/diagnostic imaging/physiopathology ; }, abstract = {We describe an unusual case of clinical amyotrophic lateral sclerosis (ALS) with initial neurophysiological studies suggesting demyelination, along with neuroimaging findings that helped to support the eventual diagnosis. An otherwise well 68-year-old man had 8 weeks of left upper limb weakness. On examination, there were widespread lower and upper motor neurone findings suggesting ALS. However, nerve conduction studies identified sensorimotor demyelinating changes suggesting chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a diagnosis further supported by cerebrospinal fluid analysis. MR scan of the brain revealed a 'motor band', a feature seen commonly in ALS. His condition was refractory to immunotherapy with clinical progression in-keeping with ALS, establishing the diagnosis. ALS is rarely associated with demyelinating neurophysiological changes resembling CIDP. The clinical phenotype is crucial to support the correct diagnosis and imaging findings may help.}, } @article {pmid38050862, year = {2023}, author = {Liu, X and Duan, S and Jin, Y and Walker, E and Tsao, M and Jang, JH and Chen, Z and Singh, AK and Cantrell, KL and Ingolfsson, HI and Buratto, SK and Bowers, MT}, title = {Computationally Designed Molecules Modulate ALS-Related Amyloidogenic TDP-43307-319 Aggregation.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {24}, pages = {4395-4408}, doi = {10.1021/acschemneuro.3c00582}, pmid = {38050862}, issn = {1948-7193}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Frontotemporal Dementia ; *Frontotemporal Lobar Degeneration ; *Alzheimer Disease ; DNA-Binding Proteins/metabolism ; }, abstract = {Abnormal cytosolic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is observed in multiple diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease. Previous studies have shown that TDP-43307-319 located at the C-terminal of TDP-43 can form higher-order oligomers and fibrils. Of particular interest are the hexamers that adopt a cylindrin structure that has been strongly correlated to neurotoxicity. In this study, we use the joint pharmacophore space (JPS) model to identify and generate potential TDP-43 inhibitors. Five JPS-designed molecules are evaluated using both experimental and computational methods: ion mobility mass spectrometry, thioflavin T fluorescence assay, circular dichroism spectroscopy, atomic force microscopy, and molecular dynamics simulations. We found that all five molecules can prevent the amyloid fibril formation of TDP-43307-319, but their efficacy varies significantly. Furthermore, among the five molecules, [AC0101] is the most efficient in preventing the formation of higher-order oligomers and dissociating preformed higher-order oligomers. Molecular dynamics simulations show that [AC0101] both is the most flexible and forms the most hydrogen bonds with the TDP-43307-319 monomer. The JPS-designed molecules can insert themselves between the β-strands in the hexameric cylindrin structure of TDP-43307-319 and can open its structure. Possible mechanisms for JPS-designed molecules to inhibit and dissociate TDP-43307-319 oligomers on an atomistic scale are proposed.}, } @article {pmid38050971, year = {2024}, author = {Shellikeri, S and Cho, S and Ash, S and Gonzalez-Recober, C and Mcmillan, CT and Elman, L and Quinn, C and Amado, DA and Baer, M and Irwin, DJ and Massimo, L and Olm, CA and Liberman, MY and Grossman, M and Nevler, N}, title = {Digital markers of motor speech impairments in spontaneous speech of patients with ALS-FTD spectrum disorders.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {317-325}, pmid = {38050971}, issn = {2167-9223}, support = {K99 AG073510/AG/NIA NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; R01 NS109260/NS/NINDS NIH HHS/United States ; K08 NS114106/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG054519/AG/NIA NIH HHS/United States ; W81XWH-20-1-0531//Department of Defense/ ; }, mesh = {Humans ; *Frontotemporal Dementia/diagnosis/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Speech ; Magnetic Resonance Imaging ; *Dystonic Disorders ; }, abstract = {OBJECTIVE: To evaluate automated digital speech measures, derived from spontaneous speech (picture descriptions), in assessing bulbar motor impairments in patients with ALS-FTD spectrum disorders (ALS-FTSD).

METHODS: Automated vowel algorithms were employed to extract two vowel acoustic measures: vowel space area (VSA), and mean second formant slope (F2 slope). Vowel measures were compared between ALS with and without clinical bulbar symptoms (ALS + bulbar (n = 49, ALSFRS-r bulbar subscore: x¯ = 9.8 (SD = 1.7)) vs. ALS-nonbulbar (n = 23), behavioral variant frontotemporal dementia (bvFTD, n = 25) without a motor syndrome, and healthy controls (HC, n = 32). Correlations with bulbar motor clinical scales, perceived listener effort, and MRI cortical thickness of the orobuccal primary motor cortex (oral PMC) were examined. We compared vowel measures to speaking rate, a conventional metric for assessing bulbar dysfunction.

RESULTS: ALS + bulbar had significantly reduced VSA and F2 slope than ALS-nonbulbar (|d|=0.94 and |d|=1.04, respectively), bvFTD (|d|=0.89 and |d|=1.47), and HC (|d|=0.73 and |d|=0.99). These reductions correlated with worse bulbar clinical scores (VSA: R = 0.33, p = 0.043; F2 slope: R = 0.38, p = 0.011), greater listener effort (VSA: R=-0.43, p = 0.041; F2 slope: p > 0.05), and cortical thinning in oral PMC (F2 slope: β = 0.0026, p = 0.017). Vowel measures demonstrated greater sensitivity and specificity for bulbar impairment than speaking rate, while showing independence from cognitive and respiratory impairments.

CONCLUSION: Automatic vowel measures are easily derived from a brief spontaneous speech sample, are sensitive to mild-moderate stage of bulbar disease in ALS-FTSD, and may present better sensitivity to bulbar impairment compared to traditional assessments such as speaking rate.}, } @article {pmid38051870, year = {2024}, author = {Hartopp, N and Markovinovic, A and Miller, CC and Gomez-Suaga, P}, title = {Insight into endoplasmic reticulum-mitochondria contacts in human amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {7}, pages = {1407-1408}, pmid = {38051870}, issn = {1673-5374}, support = {MR/R022666/1/MRC_/Medical Research Council/United Kingdom ; }, } @article {pmid38051885, year = {2024}, author = {Helgudóttir, SS and Mørkholt, AS and Lichota, J and Bruun-Nyzell, P and Andersen, MC and Kristensen, NMJ and Johansen, AK and Zinn, MR and Jensdóttir, HM and Nieland, JDV}, title = {Rethinking neurodegenerative diseases: neurometabolic concept linking lipid oxidation to diseases in the central nervous system.}, journal = {Neural regeneration research}, volume = {19}, number = {7}, pages = {1437-1445}, pmid = {38051885}, issn = {1673-5374}, abstract = {Currently, there is a lack of effective medicines capable of halting or reversing the progression of neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, or Alzheimer's disease. Given the unmet medical need, it is necessary to reevaluate the existing paradigms of how to target these diseases. When considering neurodegenerative diseases from a systemic neurometabolic perspective, it becomes possible to explain the shared pathological features. This innovative approach presented in this paper draws upon extensive research conducted by the authors and researchers worldwide. In this review, we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative diseases. We provide an overview of the risk factors associated with developing neurodegenerative disorders, including genetic, epigenetic, and environmental factors. Additionally, we examine pathological mechanisms implicated in these diseases such as oxidative stress, accumulation of misfolded proteins, inflammation, demyelination, death of neurons, insulin resistance, dysbiosis, and neurotransmitter disturbances. Finally, we outline a proposal for the restoration of mitochondrial metabolism, a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.}, } @article {pmid38051886, year = {2024}, author = {Liang, S and Zhou, J and Yu, X and Lu, S and Liu, R}, title = {Neuronal conversion from glia to replenish the lost neurons.}, journal = {Neural regeneration research}, volume = {19}, number = {7}, pages = {1446-1453}, pmid = {38051886}, issn = {1673-5374}, abstract = {Neuronal injury, aging, and cerebrovascular and neurodegenerative diseases such as cerebral infarction, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Huntington's disease are characterized by significant neuronal loss. Unfortunately, the neurons of most mammals including humans do not possess the ability to self-regenerate. Replenishment of lost neurons becomes an appealing therapeutic strategy to reverse the disease phenotype. Transplantation of pluripotent neural stem cells can supplement the missing neurons in the brain, but it carries the risk of causing gene mutation, tumorigenesis, severe inflammation, and obstructive hydrocephalus induced by brain edema. Conversion of neural or non-neural lineage cells into functional neurons is a promising strategy for the diseases involving neuron loss, which may overcome the above-mentioned disadvantages of neural stem cell therapy. Thus far, many strategies to transform astrocytes, fibroblasts, microglia, Müller glia, NG2 cells, and other glial cells to mature and functional neurons, or for the conversion between neuronal subtypes have been developed through the regulation of transcription factors, polypyrimidine tract binding protein 1 (PTBP1), and small chemical molecules or are based on a combination of several factors and the location in the central nervous system. However, some recent papers did not obtain expected results, and discrepancies exist. Therefore, in this review, we discuss the history of neuronal transdifferentiation, summarize the strategies for neuronal replenishment and conversion from glia, especially astrocytes, and point out that biosafety, new strategies, and the accurate origin of the truly converted neurons in vivo should be focused upon in future studies. It also arises the attention of replenishing the lost neurons from glia by gene therapies such as up-regulation of some transcription factors or down-regulation of PTBP1 or drug interference therapies.}, } @article {pmid38052188, year = {2024}, author = {Crowe, AL and Kerr, K and McAneney, H and McMullan, J and Duffy, G and McKnight, AJ}, title = {Stakeholder Perceptions of Complementary and Integrative Medicines from People Living with Rare Diseases in Northern Ireland: A Mixed Methods Study.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {107-115}, pmid = {38052188}, issn = {2504-2106}, mesh = {Humans ; Northern Ireland ; *Complementary Therapies/statistics & numerical data/psychology ; *Rare Diseases/therapy ; *Integrative Medicine ; Female ; Surveys and Questionnaires ; Male ; Adult ; Middle Aged ; Health Personnel/psychology ; *Stakeholder Participation ; }, abstract = {INTRODUCTION: Only 5% of rare diseases have an approved treatment available, therefore patients often utilise complementary and integrative medicines (CIMs) to help manage their condition. Limited high-quality evidence-based studies are available which support the effectiveness of CIM, as it is difficult to show that an outcome is a direct result of the CIM intervention and not due to bias. Patients and healthcare professionals must weigh up the evidence quality, safety, efficacy, practical logistics, and financial implications of utilising CIM for rare diseases. This study aimed to elucidate perspectives of stakeholders (individuals with rare diseases, carers, family members, CIM practitioners and healthcare professionals), on the usage of CIM for rare diseases across Northern Ireland.

METHODS: This was a mixed methods study. An online survey was open from January to February 2019 (n = 29 responses). Themes identified from the survey were then discussed with stakeholders in a semi-structured discussion workshop in March 2019.

RESULTS: A limited number of participants responded to the survey (n = 29). Some individuals with rare diseases reported CIM as effective in the management of their condition, in particular acupuncture, dietary supplements, herbal medicines, homoeopathy, hydrotherapy, kinesiology, mindfulness, pilates, reflexology, tai chi, and yoga. However, a number of respondents (n = 7) experienced a negative side effect from CIM. Workshop participants raised concerns over the lack of information available about CIM and rare disease. Both the survey and workshop identified inequality of access with participants reporting CIM to be expensive.

CONCLUSIONS: More information, high-quality research, and education about CIM are required for patients and healthcare professionals to help make informed decisions about the usage of CIM for rare diseases. Improved communication, information, and health and social care in general would help individuals be more confident and knowledgeable about therapeutic options in relation to their rare disease(s).

UNLABELLED: EinleitungNur für fünf Prozent der seltenen Erkrankungen existiert eine zugelassene Behandlung, weshalb Patienten häufig komplementäre und integrative Medizin (CIM) nutzen, um ihre Krankheit zu behandeln. Es liegen nur wenige qualitativ hochwertige evidenzbasierte Studien vor, die die Wirksamkeit von CIM stützen, da sich schwer nachweisen lässt, dass ein Behandlungsergebnis direkt durch die CIM-Intervention bedingt und nicht Folge einer Verzerrung ist. Patienten und Angehörige der Gesundheitsberufe müssen die Qualität der Evidenz, die Sicherheit und Wirksamkeit sowie praktische logistische Aspekte und die finanziellen Folgen der Anwendung von CIM bei seltenen Erkrankungen abwägen. Mit der vorliegenden Studie sollte die Perspektive der Betroffenen (Menschen mit seltenen Erkrankungen, Betreuungspersonen, Familienangehörige, CIM-Praktiker und Angehörige der Gesundheitsberufe) in Bezug auf die Anwendung von CIM bei seltenen Erkrankungen in Nordirland untersucht werden.MethodenEs handelte sich um eine Studie mit gemischten Methoden. Eine Online-Umfrage war von Januar bis Februar 2019 geöffnet (n = 29 Antworten). Die in der Umfrage ermittelten Themen wurden anschließend im März 2019 im Rahmen eines halbstrukturierten Diskussionsworkshops mit den Betroffenen erörtert.ErgebnisseEine begrenzte Anzahl von Teilnehmern antwortete auf die Umfrage (n = 29). Einige Personen mit seltenen Erkrankungen gaben an, dass CIM bei der Behandlung ihrer Erkrankung wirksam war, insbesondere Akupunktur, Nahrungsergänzungsmittel, pflanzliche Arzneimittel, Homöopathie, Hydrotherapie, Kinesiologie, Achtsamkeit, Pilates, Reflexologie, Tai Chi und Yoga. Einige Befragte (n = 7) berichteten jedoch über negative Nebenwirkungen der CIM. Die Workshop-Teilnehmer äußerten Bedenken in Bezug auf den Mangel an Informationen über CIM und seltene Erkrankungen. Sowohl in der Umfrage als auch im Workshop zeigte sich eine Ungleichheit beim Zugang zu CIM und die Teilnehmer berichteten, dass CIM teuer sei.SchlussfolgerungenPatienten und Angehörige der Gesundheitsberufe benötigen mehr Informationen, qualitativ hochwertige Forschung und Aufklärung über CIM, um fundierte Entscheidungen über die Anwendung von CIM bei seltenen Erkrankungen treffen zu können. Eine bessere Kommunikation, Information sowie gesundheitliche und soziale Versorgung im Allgemeinen würden zu mehr Selbstvertrauen und Wissen der Betroffenen über die therapeutischen Möglichkeiten im Zusammenhang mit ihrer seltenen Erkrankung beitragen.}, } @article {pmid38052485, year = {2024}, author = {Din Abdul Jabbar, MA and Guo, L and Nag, S and Guo, Y and Simmons, Z and Pioro, EP and Ramasamy, S and Yeo, CJJ}, title = {Predicting amyotrophic lateral sclerosis (ALS) progression with machine learning.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {242-255}, doi = {10.1080/21678421.2023.2285443}, pmid = {38052485}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Bayes Theorem ; Disease Progression ; Machine Learning ; Databases, Factual ; }, abstract = {OBJECTIVE: To predict ALS progression with varying observation and prediction window lengths, using machine learning (ML).

METHODS: We used demographic, clinical, and laboratory parameters from 5030 patients in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database to model ALS disease progression as fast (at least 1.5 points decline in ALS Functional Rating Scale-Revised (ALSFRS-R) per month) or non-fast, using Extreme Gradient Boosting (XGBoost) and Bayesian Long Short Term Memory (BLSTM). XGBoost identified predictors of progression while BLSTM provided a confidence level for each prediction.

RESULTS: ML models achieved area under receiver-operating-characteristics curve (AUROC) of 0.570-0.748 and were non-inferior to clinician assessments. Performance was similar with observation lengths of a single visit, 3, 6, or 12 months and on a holdout validation dataset, but was better for longer prediction lengths. 21 important predictors were identified, with the top 3 being days since disease onset, past ALSFRS-R and forced vital capacity. Nonstandard predictors included phosphorus, chloride and albumin. BLSTM demonstrated higher performance for the samples about which it was most confident. Patient screening by models may reduce hypothetical Phase II/III clinical trial sizes by 18.3%.

CONCLUSION: Similar accuracies across ML models using different observation lengths suggest that a clinical trial observation period could be shortened to a single visit and clinical trial sizes reduced. Confidence levels provided by BLSTM gave additional information on the trustworthiness of predictions, which could aid decision-making. The identified predictors of ALS progression are potential biomarkers and therapeutic targets for further research.}, } @article {pmid38052682, year = {2024}, author = {Festa, LK and Grinspan, JB and Jordan-Sciutto, KL}, title = {White matter injury across neurodegenerative disease.}, journal = {Trends in neurosciences}, volume = {47}, number = {1}, pages = {47-57}, pmid = {38052682}, issn = {1878-108X}, support = {R01 MH098742/MH/NIMH NIH HHS/United States ; R01 MH126773/MH/NIMH NIH HHS/United States ; R21 MH118121/MH/NIMH NIH HHS/United States ; T32 AI007632/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *White Matter/metabolism ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Oligodendrocytes (OLs), the myelin-generating cells of the central nervous system (CNS), are active players in shaping neuronal circuitry and function. It has become increasingly apparent that injury to cells within the OL lineage plays a central role in neurodegeneration. In this review, we focus primarily on three degenerative disorders in which white matter loss is well documented: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We discuss clinical data implicating white matter injury as a key feature of these disorders, as well as shared and divergent phenotypes between them. We examine the cellular and molecular mechanisms underlying the alterations to OLs, including chronic neuroinflammation, aggregation of proteins, lipid dysregulation, and organellar stress. Last, we highlight prospects for therapeutic intervention targeting the OL lineage to restore function.}, } @article {pmid38053196, year = {2023}, author = {Lombardo, FL and Spila Alegiani, S and Mayer, F and Cipriani, M and Lo Giudice, M and Ludolph, AC and McDermott, CJ and Corcia, P and Van Damme, P and Van den Berg, LH and Hardiman, O and Nicolini, G and Vanacore, N and Dickie, B and Albanese, A and Puopolo, M and , }, title = {A randomized double-blind clinical trial on safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS): the statistical analysis plan of TUDCA-ALS trial.}, journal = {Trials}, volume = {24}, number = {1}, pages = {792}, pmid = {38053196}, issn = {1745-6215}, support = {755094//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Riluzole ; *Neuroprotective Agents/adverse effects ; Reproducibility of Results ; Double-Blind Method ; Treatment Outcome ; Disease Progression ; Taurochenodeoxycholic Acid ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities.

METHODS: The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18 months) compared to the lead-in period (3 months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023.

DISCUSSION: This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03800524 . Registered on January 11, 2019.}, } @article {pmid38056214, year = {2024}, author = {Jia, F and Zhang, B and Yu, W and Chen, Z and Xu, W and Zhao, W and Wang, Z}, title = {Exploring the cuproptosis-related molecular clusters in the peripheral blood of patients with amyotrophic lateral sclerosis.}, journal = {Computers in biology and medicine}, volume = {168}, number = {}, pages = {107776}, doi = {10.1016/j.compbiomed.2023.107776}, pmid = {38056214}, issn = {1879-0534}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Neurodegenerative Diseases ; Algorithms ; Calibration ; Cluster Analysis ; Apoptosis ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and lethal neurodegenerative disease. Several studies have suggested the involvement of cuproptosis in its pathogenesis. In this research, we intend to explore the cuproptosis-related molecular clusters in ALS and develop a novel cuproptosis-related genes prediction model.

METHODS: The peripheral blood gene expression data was downloaded from the Gene Expression Omnibus (GEO) online database. Based on the GSE112681 dataset, we investigated the critical cuproptosis-related genes (CuRGs) and pathological clustering of ALS. The immune microenvironment features of the peripheral blood in ALS patients were also examined using the CIBERSORT algorithm. Cluster-specific hub genes were determined by the WGCNA. The most accurate prediction model was selected by comparing the performance of four machine learning techniques. ROC curves and two independent datasets were applied to validate the prediction accuracy. The available compounds targeting these hub genes were filtered to investigate their efficacy in treating ALS.

RESULTS: We successfully determined four critical cuproptosis-related genes and two pathological clusters with various immune profiles and biological characteristics in ALS. Functional analysis showed that genes in Cluster1 were primarily enriched in pathways closely associated with immunity. The Support Vector Machine (SVM) model exhibited the best discrimination properties with a large area under the curve (AUC = 0.862). Five hub prediction genes (BAP1, SMG1, BCLAF1, DHX15, EIF4G2) were selected to establish a nomogram model, suggesting significant risk prediction potential for ALS. The accuracy of this model in predicting ALS incidence was also demonstrated through calibration curves, nomograms, and decision curve analysis. Finally, three drugs targeting BAP1 were determined through drug-gene interactions.

CONCLUSION: This study elucidated the complex associations between cuproptosis and ALS and constructed a satisfactory predictive model to explore the pathological characteristics of different clusters in ALS patients.}, } @article {pmid38056247, year = {2024}, author = {Jiang, H and Zhang, Y and Hu, J and Wang, Z and Li, G and Lu, Y}, title = {An alternative spliced UPF2 transcript in pancreatic inflammatory myofibroblastic tumors.}, journal = {Biochemical and biophysical research communications}, volume = {691}, number = {}, pages = {149306}, doi = {10.1016/j.bbrc.2023.149306}, pmid = {38056247}, issn = {1090-2104}, mesh = {Humans ; *Neoplasms ; Nonsense Mediated mRNA Decay ; RNA, Messenger/genetics/metabolism ; RNA-Binding Proteins/metabolism ; }, abstract = {BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are characterized by myofibroblast proliferation and an inflammatory cell infiltrate. Our previous study on IMTs reveals that disrupt NMD pathway causes to lower the threshold for triggering the immune cell infiltration, thereby resulting in inappropriate immune activation. However, myofibroblast differentiation and proliferation is not yet known.

METHODS: RT-PCR, RT-qPCR, DNA sequence, western bolt, 5'race analysis and site-specific mutagenesis were used in this study.

RESULTS: Here, an alternative spliced (ALS) UPF2 mRNA skipping exon 2 and 3 and corresponding to the truncated UPF2 protein were found in 2 pancreatic IMTs. We showed that the uORF present in the 5'UTR of UPF2 mRNA is responsible for the translation inhibition, whiles ALS UPF2 is more facilitated to be translated into the truncated UPF2 protein. Several mRNA targets of the NMD were upregulated in IMT samples, indicating that the truncated UPF2 function is strongly perturbed, resulted in disrupted NMD pathway in IMTs. These upregulated NMD targets included cdkn1a expression and the generation of high levels of p21 (waf1/cip1), which may contribute to triggering IMTs.

CONCLUSION: The disrupt UPFs/NMD pathway may link to molecular alteration associated with differentiation and proliferation for IMTs.}, } @article {pmid38056310, year = {2024}, author = {Guo, Y and Guan, T and Yu, Q and Sanghai, N and Shafiq, K and Li, M and Jiao, X and Na, D and Zhang, G and Kong, J}, title = {ALS-linked SOD1 mutations impair mitochondrial-derived vesicle formation and accelerate aging.}, journal = {Redox biology}, volume = {69}, number = {}, pages = {102972}, pmid = {38056310}, issn = {2213-2317}, mesh = {Animals ; Humans ; Infant ; Mice ; Middle Aged ; Aging/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Motor Neurons ; Mutation ; *Sirtuins/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Oxidative stress (OS) is regarded as the dominant theory for aging. While compelling correlative data have been generated to support the OS theory, a direct cause-and-effect relationship between the accumulation of oxidation-mediated damage and aging has not been firmly established. Superoxide dismutase 1 (SOD1) is a primary antioxidant in all cells. It is, however, susceptible to oxidation due to OS and gains toxic properties to cells. This study investigates the role of oxidized SOD1 derived from amyotrophic lateral sclerosis (ALS) linked SOD1 mutations in cell senescence and aging. Herein, we have shown that the cell line NSC34 expressing the G93A mutation of human SOD1 (hSOD1[G93A]) entered premature senescence as evidenced by a decreased number of the 5-ethynyl-2'-deoxyuridine (EdU)-positive cells. There was an upregulation of cellular senescence markers compared to cells expressing the wild-type human SOD1 (hSOD1[WT]). Transgenic mice carrying the hSOD1[G93A] gene showed aging phenotypes at an early age (135 days) with high levels of P53 and P16 but low levels of SIRT1 and SIRT6 compared with age-matched hSOD1[WT] transgenic mice. Notably, the levels of oxidized SOD1 were significantly elevated in both the senescent NSC34 cells and 135-day hSOD1[G93A] mice. Selective removal of oxidized SOD1 by our CT4-directed autophagy significantly decelerated aging, indicating that oxidized SOD1 is a causal factor of aging. Intriguingly, mitochondria malfunctioned in both senescent NSC34 cells and middle-aged hSOD[G93A] transgenic mice. They exhibited increased production of mitochondrial-derived vesicles (MDVs) in response to mild OS in mutant humanSOD1 (hSOD1) transgenic mice at a younger age; however, the mitochondrial response gradually declined with aging. In conclusion, our data show that oxidized SOD1 derived from ALS-linked SOD1 mutants is a causal factor for cellular senescence and aging. Compromised mitochondrial responsiveness to OS may serve as an indicator of premature aging.}, } @article {pmid38056528, year = {2024}, author = {Camiña-Conforto, G and Vilarrasa, E and Cabo, F and Fernández-Vela, J and Pousa, M and Romaní, J}, title = {Response letter to "Tracing the origins of setons in hidradenitis suppurativa: A commentary to Vilarrasa et al's 'Drainage setons for the management of sinus tracts in hidradenitis suppurativa'".}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {4}, pages = {e141-e142}, doi = {10.1016/j.jaad.2023.11.049}, pmid = {38056528}, issn = {1097-6787}, mesh = {Humans ; *Hidradenitis Suppurativa ; Inflammation ; }, } @article {pmid38057503, year = {2023}, author = {Vernikouskaya, I and Müller, HP and Roselli, F and Ludolph, AC and Kassubek, J and Rasche, V}, title = {AI-assisted quantification of hypothalamic atrophy in amyotrophic lateral sclerosis by convolutional neural network-based automatic segmentation.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {21505}, pmid = {38057503}, issn = {2045-2322}, support = {LU 336/15-1//Deutsche Forschungsgemeinschaft/ ; 01GM1103A//German Network for Motor Neuron Diseases/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Neural Networks, Computer ; Magnetic Resonance Imaging/methods ; Neuroimaging/methods ; Atrophy ; Image Processing, Computer-Assisted/methods ; }, abstract = {The hypothalamus is a small structure of the brain with an essential role in metabolic homeostasis, sleep regulation, and body temperature control. Some neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and dementia syndromes are reported to be related to hypothalamic volume alterations. Despite its crucial role in human body regulation, neuroimaging studies of this structure are rather scarce due to work-intensive operator-dependent manual delineations from MRI and lack of automated segmentation tools. In this study we present a fully automatic approach based on deep convolutional neural networks (CNN) for hypothalamic segmentation and volume quantification. We applied CNN of U-Net architecture with EfficientNetB0 backbone to allow for accurate automatic hypothalamic segmentation in seconds on a GPU. We further applied our approach for the quantification of the normalized hypothalamic volumes to a large neuroimaging dataset of 432 ALS patients and 112 healthy controls (without the ground truth labels). Using the automated volumetric analysis, we could reproduce hypothalamic atrophy findings associated with ALS by detecting significant volume differences between ALS patients and controls at the group level. In conclusion, a fast and unbiased AI-assisted hypothalamic quantification method is introduced in this study (whose acceptance rate based on the outlier removal strategy was estimated to be above 95%) and made publicly available for researchers interested in the conduction of hypothalamus studies at a large scale.}, } @article {pmid38059522, year = {2024}, author = {Xu, R and Wang, X and Zhu, S and Jiang, B and Wan, J and Ma, J and Yu, Y and Yu, L and Fang, Q and Hu, C and Zhu, M}, title = {Assessment of Cerebral White Matter Involvement in Amyotrophic Lateral Sclerosis Patients With Disease Progression and Cognitive Impairment by Fixel-Based Analysis and Neurite Orientation Dispersion and Density Imaging.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {60}, number = {3}, pages = {900-908}, doi = {10.1002/jmri.29171}, pmid = {38059522}, issn = {1522-2586}, support = {LK2021017//Application Fundamental Research Program of the Jiangsu Provincial Health Commission's Elderly Health Project/ ; UTPIE2023006//the Undergraduate Training Program for Innovation and Entrepreneurship, Soochow University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Female ; Male ; Middle Aged ; *Disease Progression ; *White Matter/diagnostic imaging/pathology ; *Neurites/pathology ; *Cognitive Dysfunction/diagnostic imaging ; Aged ; Prospective Studies ; Image Processing, Computer-Assisted/methods ; Brain/diagnostic imaging/pathology ; Magnetic Resonance Imaging/methods ; Diffusion Tensor Imaging/methods ; Diffusion Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: Previous studies using emerging diffusion MRI techniques have revealed damage to the white matter (WM) microstructure in amyotrophic lateral sclerosis (ALS), particularly the influence of crossed fibers, but there is a lack of subgroup analyses.

PURPOSE: To detect WM microstructural changes in ALS patients using fixel-based analysis (FBA) and neurite orientation dispersion and density imaging (NODDI) MRI.

STUDY TYPE: Prospective.

POPULATION: Thirty-six ALS patients (aged 60.50 ± 9.5 years) and 25 healthy controls (HCs) (aged 58.90 ± 8.1 years).

FIELD STRENGTH/SEQUENCE: 3 T; NODDI and FBA (b-values = 0, 1000, and 2500 seconds/mm[2]).

ASSESSMENT: Subgroups were performed according to progression rate and cognition, including fast and slow progression (FP/SP), ALS with and without cognitive impairment (ALS-ci/ALS-nci). Fiber density (FD), fiber-bundle cross-section (FC), combined fiber density and cross-section (FDC), neurite density index (NDI), orientation dispersion index (ODI), isotropic volume fraction (ISO), and fractional anisotropy (FA) were calculated and their correlation with clinical variables examined.

STATISTICAL TESTING: Chi-square test, Mann-Whitney U test, two-sample t test, partial correlation analysis, and false discovery rate (FDR) corrected. A P-value <0.05 was considered significant.

RESULTS: ALS patients had lower FD and FDC values predominantly in the corticospinal tract (CST) and corpus callosum (CC) regions, as well as lower NDI value in the CC, radial crown, and internal capsule compared to HCs. Subgroup analysis based on progression rate and cognitive function showed significant differences in FBA results. The FC in the right CST region was significantly lower in the FP than SP, and the FD in the CC region was significantly lower in the ALS-ci than ALS-nci. Furthermore, a negative correlation was found between the mean FC value and the rate of progression in ALS patients (r = -0.408).

DATA CONCLUSION: FBA is a powerful tool for detecting complex cerebral WM microstructural damage for evaluating ALS cognition and disease progression.}, } @article {pmid38061331, year = {2023}, author = {Yadav, A and Matson, KJE and Lee, D and Alkaslasi, MR and Roome, RB and Ward, ME and Phatnani, H and Le Pichon, CE and Menon, V and Levine, AJ}, title = {A reproducible signature of cytoskeletal and ALS-related genes in human motoneurons.}, journal = {Neuron}, volume = {111}, number = {23}, pages = {3742-3744}, pmid = {38061331}, issn = {1097-4199}, support = {R01 AG066831/AG/NIA NIH HHS/United States ; U54 AG076040/AG/NIA NIH HHS/United States ; ZIA HD008966/ImNIH/Intramural NIH HHS/United States ; ZIA NS003153/ImNIH/Intramural NIH HHS/United States ; }, } @article {pmid38061694, year = {2024}, author = {Ai, Y and Li, F and Hou, Y and Li, X and Li, W and Qin, K and Suo, X and Lei, D and Shang, H and Gong, Q}, title = {Differential cortical gray matter changes in early- and late-onset patients with amyotrophic lateral sclerosis.}, journal = {Cerebral cortex (New York, N.Y. : 1991)}, volume = {34}, number = {1}, pages = {}, doi = {10.1093/cercor/bhad426}, pmid = {38061694}, issn = {1460-2199}, support = {2022YFC2009900//National Key Research and Development Program of China/ ; 81621003//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Gray Matter/diagnostic imaging/pathology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Brain/pathology ; *Motor Cortex/pathology ; }, abstract = {Age at onset may be an important feature associated with distinct subtypes of amyotrophic lateral sclerosis (ALS). Little is known about the neuropathological mechanism of early-onset ALS (EO-ALS) and late-onset ALS (LO-ALS). Ninety ALS patients were divided into EO-ALS and LO-ALS group, and 128 healthy controls were matched into young controls(YCs) and old controls (OCs). A voxel-based morphometry approach was employed to investigate differences in gray matter volume (GMV). Significant age at onset-by-diagnosis interactions were found in the left parietal operculum, left precentral gyrus, bilateral postcentral gyrus, right occipital gyrus, and right orbitofrontal cortex. Post hoc analysis revealed a significant decrease in GMV in all affected regions of EO-ALS patients compared with YCs, with increased GMV in 5 of the 6 brain regions, except for the right orbitofrontal cortex, in LO-ALS patients compared with OCs. LO-ALS patients had a significantly increased GMV than EO-ALS patients after removing the aging effect. Correspondingly, GMV of the left postcentral gyrus correlated with disease severity in the 2 ALS groups. Our findings suggested that the pathological mechanisms in ALS patients with different ages at onset might differ. These findings provide unique insight into the clinical and biological heterogeneity of the 2 ALS subtypes.}, } @article {pmid38062079, year = {2023}, author = {Bowden, M and Beswick, E and Tam, J and Perry, D and Smith, A and Newton, J and Chandran, S and Watts, O and Pal, S}, title = {A systematic review and narrative analysis of digital speech biomarkers in Motor Neuron Disease.}, journal = {NPJ digital medicine}, volume = {6}, number = {1}, pages = {228}, pmid = {38062079}, issn = {2398-6352}, abstract = {Motor Neuron Disease (MND) is a progressive and largely fatal neurodegeneritve disorder with a lifetime risk of approximately 1 in 300. At diagnosis, up to 25% of people with MND (pwMND) exhibit bulbar dysfunction. Currently, pwMND are assessed using clinical examination and diagnostic tools including the ALS Functional Rating Scale Revised (ALS-FRS(R)), a clinician-administered questionnaire with a single item on speech intelligibility. Here we report on the use of digital technologies to assess speech features as a marker of disease diagnosis and progression in pwMND. Google Scholar, PubMed, Medline and EMBASE were systematically searched. 40 studies were evaluated including 3670 participants; 1878 with a diagnosis of MND. 24 studies used microphones, 5 used smartphones, 6 used apps, 2 used tape recorders and 1 used the Multi-Dimensional Voice Programme (MDVP) to record speech samples. Data extraction and analysis methods varied but included traditional statistical analysis, CSpeech, MATLAB and machine learning (ML) algorithms. Speech features assessed also varied and included jitter, shimmer, fundamental frequency, intelligible speaking rate, pause duration and syllable repetition. Findings from this systematic review indicate that digital speech biomarkers can distinguish pwMND from healthy controls and can help identify bulbar involvement in pwMND. Preliminary evidence suggests digitally assessed acoustic features can identify more nuanced changes in those affected by voice dysfunction. No one digital speech biomarker alone is consistently able to diagnose or prognosticate MND. Further longitudinal studies involving larger samples are required to validate the use of these technologies as diagnostic tools or prognostic biomarkers.}, } @article {pmid38062485, year = {2023}, author = {Shen, T and Vogel, JW and Duda, J and Phillips, JS and Cook, PA and Gee, J and Elman, L and Quinn, C and Amado, DA and Baer, M and Massimo, L and Grossman, M and Irwin, DJ and McMillan, CT}, title = {Novel data-driven subtypes and stages of brain atrophy in the ALS-FTD spectrum.}, journal = {Translational neurodegeneration}, volume = {12}, number = {1}, pages = {57}, pmid = {38062485}, issn = {2047-9158}, support = {K08 NS114106/NS/NINDS NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 NS109260/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; *Frontotemporal Dementia/diagnostic imaging/genetics ; *Neurodegenerative Diseases/pathology ; Brain/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Atrophy/genetics/complications/pathology ; }, abstract = {BACKGROUND: TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum.

METHODS: We used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS-FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS-FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease.

RESULTS: SuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 types B, E and C. In contrast, the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS-FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King's stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology.

CONCLUSIONS: Our findings suggest distinct neurodegenerative subtypes of disease along the ALS-FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.}, } @article {pmid38062520, year = {2023}, author = {Rahman, MAA and Elghobashy, MR and Zaazaa, HE and El-Mosallamy, SS}, title = {Novel analytical method based on chemometric models applied to UV-Vis spectrophotometric data for simultaneous determination of Etoricoxib and Paracetamol in presence of Paracetamol impurities.}, journal = {BMC chemistry}, volume = {17}, number = {1}, pages = {176}, pmid = {38062520}, issn = {2661-801X}, abstract = {The multivariate models that are used for spectral data analysis have many beneficial applications, and one of the important applications is the analysis of drugs and their impurities. Three Chemometrically-assisted spectrophotometric models have been proposed and validated. The proposed models are Partial Least Squares (PLS), Artificial Neural Networks (ANN), and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). The advanced chemometric models were applied to resolve the significantly overlapping spectra of Etoricoxib (ETO) and Paracetamol (PCM), along with impurities of PCM namely; P-aminophenol (PAP) and P-hydroxy acetophenone (PHA). The proposed models succeeded in simultaneously analyzing the mixture of ETO and PCM along with the impurities of PCM. So, the proposed techniques can be used without requiring a separation step in the analysis of pharmaceutical formulation. Moreover, no significant differences were found when the results of the suggested and published chemometric models were compared statistically with the reported HPLC method.}, } @article {pmid38063178, year = {2023}, author = {Xu, C and Zarrabeitia, M and Li, Y and Biskupek, J and Kaiser, U and Liu, X and Passerini, S}, title = {Three-Dimensional Nitrogen-Doped Carbonaceous Networks Anchored with Cobalt as Separator Modification Layers for Low-Polarization and Long-Lifespan Aluminum-Sulfur Batteries.}, journal = {ACS nano}, volume = {17}, number = {24}, pages = {25234-25242}, doi = {10.1021/acsnano.3c08476}, pmid = {38063178}, issn = {1936-086X}, abstract = {Aluminum-sulfur (Al-S) batteries have attracted extensive interest due to their high theoretical energy density, inherent safety, and low cost. However, severe polarization and poor cycling performance significantly limit the development of Al-S batteries. Herein, three-dimensional (3D) nitrogen-doped carbonaceous networks anchored with cobalt (Co@CMel-ZIF) is proposed as a separator modification layer to mitigate these issues, prepared via carbonizations of a mixture of ZIF-7, melamine, and CoCl2. It exhibits a 3D network structure with a moderate surface area and high average pore diameter, which is demonstrated to be effective in adsorbing the aluminum polysulfides and hindering the mobility of polysulfides across the separator for enhanced cyclic stability of Al-S batteries. Meanwhile, Co@CMel-ZIF are characterized by abundant catalytic pyridinic-N and Co-Nx active sites that effectively eliminate the barrier of sulfides' conversion and thereby facilitate the polarization reduction. As a result, Al-S cells based on the separator modified with Co@CMel-ZIF exhibit a low voltage polarization of 0.47 V under the current density of 50 mA g[-1] at 20 °C and a high discharge specific capacity of 503 mAh g[-1] after 150 cycles. In contrast, the cell employing a bare separator exhibits a polarization of 1.01 V and a discharge capacity of 300 mAh g[-1] after 70 cycles under the same conditions. This work demonstrates that modifying the separators is a promising strategy to mitigate the high polarization and poor cyclability of Al-S batteries.}, } @article {pmid38063868, year = {2024}, author = {Luib, E and Demleitner, AF and Cordts, I and Westenberg, E and Rau, P and Pürner, D and Haller, B and Lingor, P}, title = {Reduced tear fluid production in neurological diseases: a cohort study in 708 patients.}, journal = {Journal of neurology}, volume = {271}, number = {4}, pages = {1824-1836}, pmid = {38063868}, issn = {1432-1459}, mesh = {Humans ; Cohort Studies ; *Nervous System Diseases ; *Motor Neuron Disease ; *Amyotrophic Lateral Sclerosis/pathology ; Brain/pathology ; *Parkinson Disease ; }, abstract = {BACKGROUND: Tear fluid (TF) production is an important component of normal ocular function. It is regulated by parasympathetic and sympathetic innervation. Because parasympathetic nerve fibers originate in the brainstem, pathology in this brain region may affect TF production. For example, a reduction in TF production has been described in patients with Parkinson's disease (PD).

METHODS: TF was collected at one center from 772 individuals, 708 of which were patients with different neurological diseases, and 64 healthy controls. Wetting lengths (WL) were recorded using Schirmer test strips with a collection time of 10 min.

RESULTS: WL correlated negatively with age and was significantly reduced in subgroups of patients with neurodegenerative diseases (NDDs) (PD, Amyotrophic lateral sclerosis (ALS), other motor neuron diseases (MNDs)), as well as inflammatory/autoimmune/infectious central nervous system (CNS) diseases and vascular CNS diseases (VCDs), even if corrected for age or sex. While temperature had a significant negative effect on TF production, other environmental factors, such as hours of sunlight and humidity, did not.

CONCLUSION: WL was altered in many neurological diseases compared to healthy controls. Most importantly, we observed a reduction of WL in NDDs, independent of age or sex. This study highlights the potential of WL as an easily obtainable parameter and suggests functional alterations in the autonomic innervation in various neurological disorders.}, } @article {pmid38064278, year = {2024}, author = {Mao, Y and Li, Y and McGarry, B and Wang, J and Temkin-Greener, H}, title = {Home time and state regulations among Medicare beneficiaries in assisted living communities.}, journal = {Journal of the American Geriatrics Society}, volume = {72}, number = {3}, pages = {742-752}, pmid = {38064278}, issn = {1532-5415}, support = {R01 HS026893/HS/AHRQ HHS/United States ; }, mesh = {Aged ; Humans ; United States ; *Medicare ; *Quality of Life ; Nursing Homes ; Medicaid ; Chronic Disease ; }, abstract = {BACKGROUND: Home time is an important patient-centric quality metric, which has been largely unexamined among assisted living (AL) residents. Our objectives were to assess variation in home time among AL residents in the year following admission and to examine the associations with state regulations for direct care workers (DCW) training and staffing and for licensed nurse staffing.

METHODS: Medicare beneficiaries who entered AL communities in 2018 were identified, and their home time in the year following admission was measured. Home time was calculated as the percentage of time spent at home per day being alive. Resident characteristics and state regulations in DCW staffing, DCW training, and licensed staffing were measured. We used a multivariate linear regression model with AL-level fixed effects to estimate the relationship between person-level characteristics and home time. Linear regression models adjusting for resident characteristics were used to estimate the association between state regulations and residents' home time.

RESULTS: The study sample included 59,831 new Medicare beneficiary residents in 12,143 ALs. In the year following AL admission, residents spent 94% (standard deviation = 14.6) of their time at home. Several resident characteristics were associated with lower home time: Medicare-Medicaid dual eligibility, having more chronic conditions, and specific chronic conditions, for example, dementia. In states with greater regulatory specificity for DCW training and staffing, and lower specificity for licensed staffing, residents had longer adjusted home time.

CONCLUSION/IMPLICATIONS: Home time varied substantially among AL residents depending on resident characteristics and state-level regulatory specificity. AL residents eligible for Medicare and Medicaid had substantially shorter home time than the Medicare-only residents, largely due to longer time spent in nursing homes. State AL regulatory specificity for DCWs and licensed staff also impacted AL residents' home time. These findings may guide AL operators and state legislators in efforts to improve this important quality of life metric.}, } @article {pmid38064514, year = {2023}, author = {Tang, D and Zheng, K and Zhu, J and Jin, X and Bao, H and Jiang, L and Li, H and Wang, Y and Lu, Y and Liu, J and Liu, H and Tang, C and Feng, S and Dong, X and Xu, L and Yin, Y and Dang, S and Wei, X and Ren, H and Dong, B and Dai, L and Cheng, W and Wan, M and Li, Z and Chen, J and Li, H and Kong, E and Wang, K and Lu, K and Qi, S}, title = {ALS-linked C9orf72-SMCR8 complex is a negative regulator of primary ciliogenesis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {50}, pages = {e2220496120}, pmid = {38064514}, issn = {1091-6490}, support = {32071214//MOST | National Natural Science Foundation of China (NSFC)/ ; 32022020//MOST | National Natural Science Foundation of China (NSFC)/ ; 31970693//MOST | National Natural Science Foundation of China (NSFC)/ ; ZYYC20016//the 135 Project for Disciplines of Excellence, West China Hospital, Sichuan University/ ; ZYYC20015//the 135 Project for Disciplines of Excellence, West China Hospital, Sichuan University/ ; ZYJC18015//the 135 Project for Disciplines of Excellence, West China Hospital, Sichuan University/ ; 2022SCU12041//the Fundamental Research Funds for the Central Universities/ ; 2022NSFSC0049//the Natural Science Foundation of Sichuan, China/ ; 32201025//MOST | National Natural Science Foundation of China (NSFC)/ ; ZYGD18011//the 135 Project for Disciplines of Excellence, West China Hospital, Sichuan University/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Cilia/metabolism ; DNA Repeat Expansion ; *Frontotemporal Dementia/metabolism ; GTPase-Activating Proteins/metabolism ; Humans ; HEK293 Cells ; Carrier Proteins ; }, abstract = {Massive GGGGCC (G4C2) repeat expansion in C9orf72 and the resulting loss of C9orf72 function are the key features of ~50% of inherited amyotrophic lateral sclerosis and frontotemporal dementia cases. However, the biological function of C9orf72 remains unclear. We previously found that C9orf72 can form a stable GTPase activating protein (GAP) complex with SMCR8 (Smith-Magenis chromosome region 8). Herein, we report that the C9orf72-SMCR8 complex is a major negative regulator of primary ciliogenesis, abnormalities in which lead to ciliopathies. Mechanistically, the C9orf72-SMCR8 complex suppresses the primary cilium as a RAB8A GAP. Moreover, based on biochemical analysis, we found that C9orf72 is the RAB8A binding subunit and that SMCR8 is the GAP subunit in the complex. We further found that the C9orf72-SMCR8 complex suppressed the primary cilium in multiple tissues from mice, including but not limited to the brain, kidney, and spleen. Importantly, cells with C9orf72 or SMCR8 knocked out were more sensitive to hedgehog signaling. These results reveal the unexpected impact of C9orf72 on primary ciliogenesis and elucidate the pathogenesis of diseases caused by the loss of C9orf72 function.}, } @article {pmid38064644, year = {2024}, author = {Rong, P and Rasmussen, L}, title = {A Fine-Grained Temporal Analysis of Multimodal Oral Diadochokinetic Performance to Assess Speech Impairment in Amyotrophic Lateral Sclerosis.}, journal = {American journal of speech-language pathology}, volume = {33}, number = {1}, pages = {307-332}, doi = {10.1044/2023_AJSLP-23-00177}, pmid = {38064644}, issn = {1558-9110}, mesh = {Humans ; *Speech/physiology ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Jaw ; Speech Disorders/complications ; Speech Production Measurement ; }, abstract = {PURPOSE: This study used a semiautomated fine-grained temporal analysis to extract features of temporal oral diadochokinetic (DDK) performance across multiple modalities and tasks, from neurologically healthy and impaired individuals secondary to amyotrophic lateral sclerosis (ALS). The aims were to (a) delineate temporal oral DDK deficits relating to the neuromotor pathology of ALS and (b) identify the optimal task-feature combinations to detect speech impairment in ALS.

METHOD: Mandibular myoelectric, kinematic, and acoustic data were acquired from 13 individuals with ALS and 10 healthy controls producing three alternating motion rate tasks and one sequential motion rate task. Twenty-seven features were extracted from the multimodal data, characterizing three temporal constructs: duration/rate, variability, and coordination. The disease impacts on these features were assessed across tasks, and the task eliciting the greatest disease-related change was identified for each feature. Such "optimal" task-feature combinations were fed into logistic regression to differentiate individuals with ALS from healthy controls.

RESULTS: Temporal deficits in ALS were characterized by (a) increased duration and variability and reduced coordination of jaw muscle activities, (b) increased duration and variability and altered temporal symmetry of jaw velocity profile, (c) increased muscle-burst-to-peak-velocity duration, and (d) increased motion-to-voice onset duration. These temporal features were differentially affected across tasks. The optimal task-feature combinations, which were further clustered into three composite factors reflecting temporal variability, coarser-grained duration, and finer-grained duration, differentiated ALS from controls with an F1 score of 0.86 (precision = 1.00, recall = 0.75).

CONCLUSIONS: Temporal oral DDK deficits are likely attributed to a hierarchy of interrelated neurophysiological and biomechanical factors associated with the neuromotor pathology of ALS. These deficits, as assessed crossmodally, provide previously unavailable insights into the multifaceted timing impairment of oromotor performance in ALS. The optimal task-feature combinations targeting these deficits show promise as quantitative markers for (early) detection of speech impairment in ALS.}, } @article {pmid38065418, year = {2024}, author = {Yuan, Y and Bailey, JM and Rivera-Lopez, GM and Atchison, WD}, title = {Preferential potentiation of AMPA-mediated currents in brainstem hypoglossal motoneurons by subchronic exposure of mice expressing the human superoxide dismutase 1 G93A gene mutation to neurotoxicant methylmercury in vivo.}, journal = {Neurotoxicology}, volume = {100}, number = {}, pages = {72-84}, pmid = {38065418}, issn = {1872-9711}, support = {R01 ES024064/ES/NIEHS NIH HHS/United States ; }, mesh = {Mice ; Humans ; Animals ; Superoxide Dismutase-1 ; *Amyotrophic Lateral Sclerosis/chemically induced/genetics ; *Methylmercury Compounds/toxicity ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology ; Superoxide Dismutase/metabolism ; Mice, Transgenic ; Motor Neurons/metabolism ; Brain Stem/metabolism ; Mutation ; Disease Models, Animal ; Spinal Cord/metabolism ; }, abstract = {The exact causes of Amyotrophic lateral sclerosis (ALS), a progressive and fatal neurological disorder due to loss of upper and/or lower motoneurons, remain elusive. Gene-environment interactions are believed to be an important factor in the development of ALS. We previously showed that in vivo exposure of mice overexpressing the human superoxide dismutase 1 (hSOD1) gene mutation (hSOD1G93A; G93A), a mouse model for ALS, to environmental neurotoxicant methylmercury (MeHg) accelerated the onset of ALS-like phenotype. Here we examined the time-course of effects of MeHg on AMPA receptor (AMPAR)-mediated currents in hypoglossal motoneurons in brainstem slices prepared from G93A, hSOD1wild-type (hWT) and non-carrier WT mice following in vivo exposure to MeHg. Mice were exposed daily to 3 ppm (approximately 0.7 mg/kg/day) MeHg via drinking water beginning at postnatal day 28 (P28) and continued until P47, 64 or 84, then acute brainstem slices were prepared, and spontaneous excitatory postsynaptic currents (sEPSCs) or AMPA-evoked currents were examined using whole cell patch-clamp recording technique. Brainstem slices of untreated littermates were prepared at the same time points to serve as control. MeHg exposure had no significant effect on either sEPSCs or AMPA-evoked currents in slices from hWT or WT mice during any of those exposure time periods under our experimental conditions. MeHg also did not cause any significant effect on sEPSCs or AMPA-currents in G93A hypoglossal motoneurons at P47 and P64. However, at P84, MeHg significantly increased amplitudes of both sEPSCs and AMPA-evoked currents in hypoglossal motineurons from G93A mice (p < 0.05), but not the sEPSC frequency, suggesting a postsynaptic action on AMPARs. MeHg exposure did not cause any significant effect on GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs). Therefore, MeHg exposure in vivo caused differential effects on AMPARs in hypoglossal motoneurons from mice with different genetic backgrounds. MeHg appears to preferentially stimulate the AMPAR-mediated currents in G93A hypoglossal motoneurons in an exposure time-dependent manner, which may contribute to the AMPAR-mediated motoneuron excitotoxicity, thereby facilitating development of ALS-like phenotype.}, } @article {pmid38066205, year = {2024}, author = {Reilich, P and Schöberl, F and Hiebeler, M and Tonon, M and Ludolph, AC and Senel, M}, title = {Myelitis as a side effect of tofersen therapy in SOD1-associated ALS.}, journal = {Journal of neurology}, volume = {271}, number = {4}, pages = {2114-2118}, pmid = {38066205}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Mutation ; *Myelitis/genetics ; Oligonucleotides/adverse effects ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/antagonists & inhibitors/genetics ; }, } @article {pmid38066647, year = {2024}, author = {Barrios, V and Martín-Rivada, Á and Guerra-Cantera, S and Campillo-Calatayud, A and Camarneiro, RA and Graell, M and Chowen, JA and Argente, J}, title = {Reduction in Pappalysin-2 Levels and Lower IGF-I Bioavailability in Female Adolescents With Anorexia Nervosa.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {109}, number = {3}, pages = {e920-e931}, doi = {10.1210/clinem/dgad713}, pmid = {38066647}, issn = {1945-7197}, support = {FIS-PI19/00166//Ministerio de Ciencia e Innovación/ ; //European Union/ ; //Centro de Investigación Biomédica en Red Fisiopatología de Obesidad y Nutrición/ ; CD19/00008//Instituto de Salud Carlos III/ ; //Comunidad Autónoma de Madrid/ ; }, mesh = {Humans ; Female ; Adolescent ; Insulin-Like Growth Factor I/metabolism ; Insulin-Like Growth Factor Binding Protein 4 ; Insulin-Like Growth Factor Binding Protein 3 ; Insulin-Like Growth Factor Binding Protein 2 ; *Anorexia Nervosa ; Biological Availability ; Amenorrhea ; Insulin-Like Growth Factor Binding Proteins ; *Peptide Hormones ; Pregnancy-Associated Plasma Protein-A/metabolism ; }, abstract = {CONTEXT: Anorexia nervosa (AN) can cause severe undernutrition associated with alterations in the IGF axis. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) modulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implications in AN are unknown.

OBJECTIVE: We determined serum levels of PAPP-As and STCs in relationship with classical IGF axis parameters in female adolescents with AN and their association with nutritional status and secondary amenorrhea.

METHODS: Parameters of the IGF axis were determined in fasting serum samples of 68 female adolescents with AN at diagnosis and 62 sex- and age-matched controls. Standardized body mass index (BMI) and bone mineral density (BMD) were calculated.

RESULTS: Patients with AN had lower concentrations of total and free IGF-I, total IGFBP-3, acid-labile subunit (ALS), insulin, PAPP-A2, STC-1, and STC-2 and higher levels of IGF-II and IGFBP-2. Their free/total IGF-I ratio was decreased and the intact/total IGFBP-3 and -4 ratios increased. BMI was directly related to total IGF-I and intact IGFBP-3 and inversely with IGFBP-2 and intact IGFBP-4. Weight loss was directly correlated with intact IGFBP-4 and negatively with intact IGFBP-3, ALS, STC-2, and PAPP-A2 concentrations. BMD was directly related to intact IGFBP-3 and inversely with intact IGFBP-4 and PAPP-A2 levels. Patients with amenorrhea had lower levels of total IGF-I and IGFBP-3 than those with menses.

CONCLUSION: The reduction of PAPP-A2 in patients with AN may be involved in a decline in IGFBP cleavage, which could underlie the decrease in IGF-I bioavailability that is influenced by nutritional status and amenorrhea.}, } @article {pmid38067180, year = {2023}, author = {Stella, R and Bonadio, RS and Cagnin, S and Andreotti, R and Massimino, ML and Bertoli, A and Peggion, C}, title = {Secreted Metabolome of ALS-Related hSOD1(G93A) Primary Cultures of Myocytes and Implications for Myogenesis.}, journal = {Cells}, volume = {12}, number = {23}, pages = {}, pmid = {38067180}, issn = {2073-4409}, support = {BIRD 202151/20//University of Padova/ ; DOR2331994/2//University of Padova/ ; 2016-1006//The Cariplo Foundation/ ; }, mesh = {Mice ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/pathology ; Mice, Transgenic ; Superoxide Dismutase-1/metabolism ; *Motor Neuron Disease/metabolism ; Muscle Cells/metabolism ; Metabolome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron (MN) disease associated with progressive muscle atrophy, paralysis, and eventually death. Growing evidence demonstrates that the pathological process leading to ALS is the result of multiple altered mechanisms occurring not only in MNs but also in other cell types inside and outside the central nervous system. In this context, the involvement of skeletal muscle has been the subject of a few studies on patients and ALS animal models. In this work, by using primary myocytes derived from the ALS transgenic hSOD1(G93A) mouse model, we observed that the myogenic capability of such cells was defective compared to cells derived from control mice expressing the nonpathogenic hSOD1(WT) isoform. The correct in vitro myogenesis of hSOD1(G93A) primary skeletal muscle cells was rescued by the addition of a conditioned medium from healthy hSOD1(WT) myocytes, suggesting the existence of an in trans activity of secreted factors. To define a dataset of molecules participating in such safeguard action, we conducted comparative metabolomic profiling of a culture medium collected from hSOD1(G93A) and hSOD1(WT) primary myocytes and report here an altered secretion of amino acids and lipid-based signaling molecules. These findings support the urgency of better understanding the role of the skeletal muscle secretome in the regulation of the myogenic program and mechanisms of ALS pathogenesis and progression.}, } @article {pmid38068637, year = {2023}, author = {Roth, IS and Singer, A and Yadid, I and Sibony, M and Peleg, Z and Rubin, B}, title = {Do Traits Travel? Multiple-Herbicide-Resistant A. tuberculatus, an Alien Weed Species in Israel.}, journal = {Plants (Basel, Switzerland)}, volume = {12}, number = {23}, pages = {}, pmid = {38068637}, issn = {2223-7747}, support = {3011002657//Israel Cotton Board/ ; 811-0210-98//The Chief Scientist Fund, Ministry of Agriculture, Israel/ ; }, abstract = {Amaranthus tuberculatus is the most common weed in soybean and corn in the USA and Canada. In Israel, it has been a minor riverbank weed. However, in recent years, growing densities of this plant have been observed in field crops, orchards, and roadsides. Between 2017 and 2022, we surveyed the distribution of A. tuberculatus and collected seeds for further study. We identified three main distribution zones in Israel: the Jezreel Valley, Hula Valley, and Coastal Plain. Most of the populations were found near water sources, fishponds, barns, dairies, or bird-feeding sites, suggesting the involvement of imported grain in introducing A. tuberculatus to Israel. Populations were screened for their responses to various post-emergence herbicides (i.e., ALS, EPSPS, PPO, HPPD, and PSII inhibitors). Several populations from the Jezreel Valley were found to be putatively resistant to ALS, EPSPS, and PPO inhibitors. The responses of those populations to trifloxysulfuron, glyphosate, and carfentrazone-ethyl were also studied. A single ALS-, EPSPS- and PPO-resistant plant was vegetatively propagated to create a clonal population, which was treated with foramsulfuron, glyphosate, and carfentrazone-ethyl. No resistance to PSII or HPPD inhibitors was observed, but resistance to herbicides that inhibit ALS, EPSPS, and PPO was observed. A clonal propagation assay revealed the existence of a population that was resistant to ALS, EPSPS, and PPO inhibitors. Since the local A. tuberculatus populations have not been exposed to herbicide selection pressure, these traits probably reached Israel through seed-mediated gene flow via imported grain.}, } @article {pmid38068696, year = {2023}, author = {Sun, J and Yu, X and Xu, H and Yang, Y and Liu, M and Zhang, Y and Lu, Y and Tang, W}, title = {Post-Emergence Water-Dispersal Application Provides Equal Herbicidal Activity against Echinochloa crus-galli and Rice Safety as Foliar Spraying of Penoxsulam.}, journal = {Plants (Basel, Switzerland)}, volume = {12}, number = {23}, pages = {}, pmid = {38068696}, issn = {2223-7747}, support = {LGN21C140003//Zhejiang Provincial Natural Science Foundation/ ; 32071508//National Natural Science Foundation of China/ ; CARS-01//the China Agriculture Research System/ ; }, abstract = {Penoxsulam is an acetolactate synthase (ALS)-inhibiting herbicide usually applied by post-emergence foliar spraying (PFS) for the control of Echinochloa crus-galli and numerous annual weeds in paddy fields. Herbicides applied by foliar spraying can have negative impacts on the environment, ecosystems, and human health. In this study, the response of E. crus-galli and rice to the PFS and post-emergence water-dispersal (PWD) applications of penoxsulam, and the differences in the detoxification displayed by them between the two treatment methods were compared. The results showed that the PWD application of penoxsulam provides a similar control efficacy against E. crus-galli as PFS at the 1-, 3-, and 5-leaf stages. Meanwhile, the PWD application had a higher safety for the rice. After being treated with 30 g a.i. ha[-1] penoxsulam, residues were not detected in the rice treated by the PWD application method, whereas, with the PFS treatment, there was 59.0 µg/kg penoxsulam remaining. With the PFS application, there were many more residues of penoxsulam in the E. crus-galli than with the PWD method; the amount of residues was 32-fold higher 12 h after treatment. The in vitro enzyme activity assays revealed that the activities of ALS, glutathione-S-transferase (GST), and cytochrome P450 monooxygenases (P450) were increased in the PWD treatments, and were 1.5-, 1.3-, and 2.3-fold higher than with PFS 72 h after treatment. The real-time quantitative PCR (qRT-PCR) revealed that the GST1 and P450 genes, CYP81A14, CYP81A12, CYP81A18, and CYP81A21 were upregulated with the PWD application versus PFS in the E. crus-galli. In summary, these results demonstrate that the herbicidal activity was not affected by the upregulation of target and metabolic enzyme activities with the PWD application of penoxsulam. This research could contribute to application strategies reducing the risk of rice injury and environmental impacts by using water-dispersal formulations of penoxsulam.}, } @article {pmid38069154, year = {2023}, author = {Belosludtseva, NV and Matveeva, LA and Belosludtsev, KN}, title = {Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {23}, pages = {}, pmid = {38069154}, issn = {1422-0067}, support = {23-25-00286//Russian Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Energy Metabolism ; Disease Progression ; Superoxide Dismutase-1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multisystem disease characterized by progressive death of motor neurons, loss of muscle mass, and impaired energy metabolism. More than 40 genes are now known to be associated with ALS, which together account for the majority of familial forms of ALS and only 10% of sporadic ALS cases. To date, there is no consensus on the pathogenesis of ALS, which makes it difficult to develop effective therapy. Accumulating evidence indicates that mitochondria, which play an important role in cellular homeostasis, are the earliest targets in ALS, and abnormalities in their structure and functions contribute to the development of bioenergetic stress and disease progression. Mitochondria are known to be highly dynamic organelles, and their stability is maintained through a number of key regulatory pathways. Mitochondrial homeostasis is dynamically regulated via mitochondrial biogenesis, clearance, fission/fusion, and trafficking; however, the processes providing "quality control" and distribution of the organelles are prone to dysregulation in ALS. Here, we systematically summarized changes in mitochondrial turnover, dynamics, calcium homeostasis, and alterations in mitochondrial transport and functions to provide in-depth insights into disease progression pathways, which may have a significant impact on current symptomatic therapies and personalized treatment programs for patients with ALS.}, } @article {pmid38069329, year = {2023}, author = {Kim, H and Kim, GS and Hyun, SH and Kim, E}, title = {Advancements in 2D and 3D In Vitro Models for Studying Neuromuscular Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {23}, pages = {}, pmid = {38069329}, issn = {1422-0067}, support = {NRF-2021R1C1C2007132//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neuromuscular Diseases ; Muscle, Skeletal ; Neuromuscular Junction ; Motor Neurons ; Organoids ; }, abstract = {Neuromuscular diseases (NMDs) are a genetically or clinically heterogeneous group of diseases that involve injury or dysfunction of neuromuscular tissue components, including peripheral motor neurons, skeletal muscles, and neuromuscular junctions. To study NMDs and develop potential therapies, remarkable progress has been made in generating in vitro neuromuscular models using engineering approaches to recapitulate the complex physical and biochemical microenvironments of 3D human neuromuscular tissues. In this review, we discuss recent studies focusing on the development of in vitro co-culture models of human motor neurons and skeletal muscles, with the pros and cons of each approach. Furthermore, we explain how neuromuscular in vitro models recapitulate certain aspects of specific NMDs, including amyotrophic lateral sclerosis and muscular dystrophy. Research on neuromuscular organoids (NMO) will continue to co-develop to better mimic tissues in vivo and will provide a better understanding of the development of the neuromuscular tissue, mechanisms of NMD action, and tools applicable to preclinical studies, including drug screening and toxicity tests.}, } @article {pmid38069599, year = {2024}, author = {Hansen, G and Burton-MacLeod, S and Schellenberg, KL}, title = {ALS Health care provider wellness.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {299-307}, doi = {10.1080/21678421.2023.2291710}, pmid = {38069599}, issn = {2167-9223}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/epidemiology ; Pandemics ; Canada/epidemiology ; Health Personnel/psychology ; *Physicians/psychology ; *Burnout, Professional/epidemiology/psychology ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Interest in health care provider (HCP) wellness and burnout is increasing; however, minimal literature explores HCP wellness in the context of Amyotrophic Lateral Sclerosis (ALS) care.

OBJECTIVES: We sought to determine rates of burnout and resiliency, as well as challenges and rewards in the provision of ALS care.

METHODS: A survey link was sent to physicians at all Canadian ALS centers for distribution to ALS HCPs in their network. The survey included demographics questions, and validated measures for resiliency and burnout; the Brief Resilient Coping Scale (BRCS) and the Single Item Burnout Score (SIBS). Participants were asked to describe challenges and rewards of ALS care, impact of COVID-19 pandemic, and how their workplace could better support them.

RESULTS: There were 85 respondents across multiple disciplines. The rate of burnout was 47%. Burnout for female respondents was significantly higher (p = 0.007), but not for age, role, or years in ALS clinic. Most participants were medium resilient copers n = 48 (56.5%), but resiliency was not related to burnout. Challenges included feeling helpless while patients relentlessly progressed to death, and emotionally charged interactions. Participants found fulfillment in providing care, and through relationships with patients and colleagues. There was a strongly expressed desire for increased resources, team building/debriefing, and formal training in emotional exhaustion and burnout.

CONCLUSIONS: The high rate of burnout and challenges of ALS care highlight the need for additional resources, team-building, and formal education around wellness.}, } @article {pmid38069659, year = {2024}, author = {Sommers-Spijkerman, M and Stukker, A and Kavanaugh, MS and Ketelaar, M and Visser-Meily, JMA and Beelen, A}, title = {What, how and when do families communicate about ALS? A qualitative exploration of parents' and children's perceptions.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {256-263}, doi = {10.1080/21678421.2023.2290738}, pmid = {38069659}, issn = {2167-9223}, mesh = {Child ; Humans ; Adolescent ; Young Adult ; Adult ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Parents ; Communication ; Qualitative Research ; }, abstract = {Objectives: In families with a parent diagnosed with amyotrophic lateral sclerosis (ALS), children's adaptation depends among others on how their parents communicate with them about the disease and its trajectory. The aim of this study was to explore parents' and children's perceptions of ALS-related family communication. Methods: A qualitative analysis using a conventional content analysis approach was applied to interview data previously collected from 21 parents (8 with ALS) and 15 children (age 13-23 years) about their experiences living with ALS. Results: Three themes emerged from the interviews: communication topics, styles and timing. Communication topics include facts about disease and prognosis, feelings, care and equipment, and the end. Although most parents perceived the familial communication style concerning ALS as open, the interviews revealed that both parents and children sometimes avoid interactions about ALS, because they do not know what to say or how to open the dialogue, are afraid to burden other family members, or are unwilling to discuss. Communication timing is directed by changes in the disease trajectory and/or questions of children. A family-level analysis showed that ALS-related family communication is sometimes perceived differently by parents and children. Conclusions: The study provides a better understanding of what, how and when parents and children in families living with ALS communicate about the disease. Most families opened the dialogue about ALS yet encountered challenges which may hamper good familial communication. Through addressing those challenges, healthcare professionals may facilitate better communication and adaptation in families with a parent with ALS.}, } @article {pmid38070417, year = {2024}, author = {Ur Rahman, S and Han, JC and Ahmad, M and Ashraf, MN and Khaliq, MA and Yousaf, M and Wang, Y and Yasin, G and Nawaz, MF and Khan, KA and Du, Z}, title = {Aluminum phytotoxicity in acidic environments: A comprehensive review of plant tolerance and adaptation strategies.}, journal = {Ecotoxicology and environmental safety}, volume = {269}, number = {}, pages = {115791}, doi = {10.1016/j.ecoenv.2023.115791}, pmid = {38070417}, issn = {1090-2414}, mesh = {*Aluminum/toxicity/metabolism ; Malates/metabolism ; Plant Breeding ; Plants/metabolism ; *Alkaloids/pharmacology ; Organic Chemicals/metabolism ; Soil/chemistry ; Plant Roots/metabolism ; Gene Expression Regulation, Plant ; }, abstract = {Aluminum (Al), a non-essential metal for plant growth, exerts significant phytotoxic effects, particularly on root growth. Anthropogenic activities would intensify Al's toxic effects by releasing Al[3+] into the soil solution, especially in acidic soils with a pH lower than 5.5 and rich mineral content. The severity of Al-induced phytotoxicity varies based on factors such as Al concentration, ionic form, plant species, and growth stages. Al toxicity leads to inhibited root and shoot growth, reduced plant biomass, disrupted water uptake causing nutritional imbalance, and adverse alterations in physiological, biochemical, and molecular processes. These effects collectively lead to diminished plant yield and quality, along with reduced soil fertility. Plants employ various mechanisms to counter Al toxicity under stress conditions, including sequestering Al in vacuoles, exuding organic acids (OAs) like citrate, oxalate, and malate from root tip cells to form Al-complexes, activating antioxidative enzymes, and overexpressing Al-stress regulatory genes. Recent advancements focus on enhancing the exudation of OAs to prevent Al from entering the plant, and developing Al-tolerant varieties. Gene transporter families, such as ATP-Binding Cassette (ABC), Aluminum-activated Malate Transporter (ALMT), Natural resistance-associated macrophage protein (Nramp), Multidrug and Toxic compounds Extrusion (MATE), and aquaporin, play a crucial role in regulating Al toxicity. This comprehensive review examined recent progress in understanding the cytotoxic impact of Al on plants at the cellular and molecular levels. Diverse strategies developed by both plants and scientists to mitigate Al-induced phytotoxicity were discussed. Furthermore, the review explored recent genomic developments, identifying candidate genes responsible for OAs exudation, and delved into genome-mediated breeding initiatives, isolating transgenic and advanced breeding lines to cultivate Al-tolerant plants.}, } @article {pmid38070961, year = {2023}, author = {Krall, JTW and Chakravartty, A and Caress, JB and Files, DC}, title = {Identification and Management of Acute Neuromuscular Respiratory Failure in the ICU.}, journal = {Chest}, volume = {164}, number = {6}, pages = {1454-1461}, doi = {10.1016/j.chest.2023.09.009}, pmid = {38070961}, issn = {1931-3543}, mesh = {Humans ; *Neuromuscular Diseases/complications/diagnosis/therapy ; *Respiratory Insufficiency/diagnosis/etiology/therapy ; Prognosis ; Intensive Care Units ; }, abstract = {Respiratory failure is a common and potentially life-threatening complication of neuromuscular diseases. Prompt recognition and accurate diagnosis of new or worsening chronic neuromuscular disease have important clinical management and prognostic implications. In this article, we present an approach to the acute presentation of undifferentiated neuromuscular respiratory failure in the ICU and guidance for determination and respiratory management of the underlying disorder.}, } @article {pmid38071852, year = {2024}, author = {Musso, G and Blasi, L and Mion, MM and Fortuna, A and Sabbatini, D and Zaninotto, M and Bello, L and Pegoraro, E and Basso, D and Plebani, M and Sorarù, G}, title = {Troponin T in spinal and bulbar muscular atrophy (SBMA).}, journal = {Journal of the neurological sciences}, volume = {456}, number = {}, pages = {122816}, doi = {10.1016/j.jns.2023.122816}, pmid = {38071852}, issn = {1878-5883}, mesh = {Adult ; Humans ; Troponin T ; *Bulbo-Spinal Atrophy, X-Linked ; *Muscular Atrophy, Spinal/diagnosis ; Biomarkers ; *Neuromuscular Diseases ; *Amyotrophic Lateral Sclerosis ; *Spinal Muscular Atrophies of Childhood ; }, abstract = {Serum biomarkers that might detect clinical progression are currently lacking for Spinal and bulbar muscular atrophy (SBMA), thus limiting the effectiveness of possible future pharmacological trials. Elevation of cardiac troponin T (cTnT) unrelated to myocardial damage in a motor neuron (MN) disease as amyotrophic lateral sclerosis (ALS) was associated to disease severity. We enrolled 47 SBMA patients and 5 Spinal muscular atrophy (SMA) type 3 adult patients as control group; each SBMA patient was evaluated at baseline and at one-year follow-up visit. Demographic and clinical data including functional scores (SBMAFRS) were collected; serum was collected as standard of care and tested for cardiac troponins. Levels of cTnT but not cTnI were increased in SBMA with respect to reference values; unlike other neuromuscular diseases, SMA patients had overall normal cTnT values. Median cTnT concentrations did not change after one year and values were correlated to motor function, particularly with lower limb subdomain, at baseline only. Variations of cTnT and of SBMAFRS were unrelated. The cautiously promising results of cTnT as potential biomarker should undergo a more extensive clinical validation, including studies with longer follow-up period. When evaluating SBMA patients for a potential cardiac damage cTnI testing should be coupled or preferred to cTnT.}, } @article {pmid38072051, year = {2024}, author = {Lu, J and Ge, P and Sawaya, MR and Hughes, MP and Boyer, DR and Cao, Q and Abskharon, R and Cascio, D and Tayeb-Fligelman, E and Eisenberg, DS}, title = {Cryo-EM structures of the D290V mutant of the hnRNPA2 low-complexity domain suggests how D290V affects phase separation and aggregation.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {2}, pages = {105531}, pmid = {38072051}, issn = {1083-351X}, support = {R01 AG048120/AG/NIA NIH HHS/United States ; R01 AG070895/AG/NIA NIH HHS/United States ; RF1 AG065407/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Cryoelectron Microscopy ; Phase Separation ; Protein Domains ; Mutation ; Hydrogen-Ion Concentration ; *Models, Molecular ; Protein Stability ; Protein Structure, Tertiary ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/chemistry/metabolism ; }, abstract = {Heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) is a human ribonucleoprotein that transports RNA to designated locations for translation via its ability to phase separate. Its mutated form, D290V, is implicated in multisystem proteinopathy known to afflict two families, mainly with myopathy and Paget's disease of bone. Here, we investigate this mutant form of hnRNPA2 by determining cryo-EM structures of the recombinant D290V low complexity domain. We find that the mutant form of hnRNPA2 differs from the WT fibrils in four ways. In contrast to the WT fibrils, the PY-nuclear localization signals in the fibril cores of all three mutant polymorphs are less accessible to chaperones. Also, the mutant fibrils are more stable than WT fibrils as judged by phase separation, thermal stability, and energetic calculations. Similar to other pathogenic amyloids, the mutant fibrils are polymorphic. Thus, these structures offer evidence to explain how a D-to-V missense mutation diverts the assembly of reversible, functional amyloid-like fibrils into the assembly of pathogenic amyloid, and may shed light on analogous conversions occurring in other ribonucleoproteins that lead to neurological diseases such as amyotrophic lateral sclerosis and frontotemporal dementia.}, } @article {pmid38072117, year = {2024}, author = {Alaoui Mansouri, M and Kharbach, M and Bouklouze, A}, title = {Current Applications of Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) in Pharmaceutical Analysis: Review.}, journal = {Journal of pharmaceutical sciences}, volume = {113}, number = {4}, pages = {856-865}, doi = {10.1016/j.xphs.2023.12.004}, pmid = {38072117}, issn = {1520-6017}, mesh = {Least-Squares Analysis ; *Biopharmaceutics ; Pharmaceutical Preparations ; Multivariate Analysis ; }, abstract = {The present review encompasses various applications of multivariate curve resolution- alternating least squares (MCR-ALS) as a promising data handling, which is issued by analytical techniques in pharmaceutics. It involves different sections starting from a concise theory of MCR-ALS and four detailed applications in drugs analysis. Dissolution, stability, polymorphism, and quantification are the main four detailed applications. The data generated by analytical techniques associated with MCR-ALS deals accurately with different challenges compared to other chemometric tools. For each reviewed purpose, it was explained how MCR-ALS was applied and detailed information was given. Different approaches were introduced to overcome challenges that limit the use of MCR-ALS efficiently in pharmaceutical mixture were also discussed.}, } @article {pmid38072442, year = {2024}, author = {Matsushita, M and Nakamura, Y and Hosokawa, T and Takahashi, Y and Mizusawa, H and Arawaka, S}, title = {[Spinocerebellar ataxia 2 develop lower motor neuron involvement as an initial symptom: a case report].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {64}, number = {1}, pages = {28-32}, doi = {10.5692/clinicalneurol.cn-001910}, pmid = {38072442}, issn = {1882-0654}, mesh = {Male ; Humans ; Adult ; *Trinucleotide Repeat Expansion ; *Spinocerebellar Ataxias/diagnosis/genetics ; Ataxia ; Motor Neurons ; Atrophy ; }, abstract = {A 36-year-old man has developed weakness of left thumb and atrophy of left thenar muscle and left first dorsal interosseous muscle without sensory disturbance for a year. A nerve conduction study revealed decreases in the amplitude of compound muscle action potentials and occurrence of F-waves on left medial nerve. Needle electromyography examination revealed positive sharp waves and later recruited motor units on left abductor pollicis brevis muscle. Brain MRI showed atrophy of bilateral cerebellar hemisphere. His grandmother and his two uncles have been diagnosed as spinocerebellar degeneration. After discharge, he developed bilateral lower limb ataxia. Genetic analysis showed heterozygous CAG repeat expansion (19/39) in ATXN2 gene, being diagnosed as spinocerebellar ataxia 2 (SCA2). A previous report has shown that motor neuron involvement is recognized as part of SCA2 in the same pedigree with full CAG repeat expansions in ATXN2 gene. We here report the patient with lower motor neuron involvement as an initial symptom of SCA2.}, } @article {pmid38072525, year = {2023}, author = {Han, Y and Sun, Y and Ma, H and Wang, R and Lan, Y and Gao, H and Huang, Z}, title = {Target-site and non-target-site based resistance to clodinafop-propargyl in wild oats (Avena fatua L.).}, journal = {Pesticide biochemistry and physiology}, volume = {197}, number = {}, pages = {105650}, doi = {10.1016/j.pestbp.2023.105650}, pmid = {38072525}, issn = {1095-9939}, mesh = {*Avena/genetics ; Poaceae/genetics ; Plant Proteins/genetics/metabolism ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Acetyl-CoA Carboxylase/genetics/metabolism ; Mutation ; Propionates ; Pyridines ; Oxazoles ; }, abstract = {Wild oat (Avena fatua L.) is a common and problematic weed in wheat fields in China. In recent years, farmers found it increasingly difficult to control A. fatua using acetyl-CoA carboxylase (ACCase)-inhibiting herbicides. The purpose of this study was to identify the molecular basis of clodinafop-propargyl resistance in A. fatua. In comparison to the S1496 population, whole dose response studies revealed that the R1623 and R1625 populations were 71.71- and 67.76-fold resistant to clodinafop-propargyl, respectively. The two resistant A. fatua populations displayed high resistance to fenoxaprop-p-ethyl (APP) and low resistance to clethodim (CHD) and pinoxaden (PPZ), but they were still sensitive to the ALS inhibitors mesosulfuron-methyl and pyroxsulam. An Ile-2041-Asn mutation was identified in both resistant individual plants. The copy number and relative expression of the ACCase gene in the resistant population were not significantly different from those in the S1496 population. Under the application of 2160 g ai ha [-1] of clodinafop-propargyl, the fresh weight of the R1623 population was reduced to 74.9%; however, pretreatment with the application of the cytochrome P450 inhibitor malathion and the GST inhibitor NBD-Cl reduced the fresh weight to 50.91% and 47.16%, respectively, which proved the presence of metabolic resistance. This is the first report of an Ile-2041-Asn mutation and probable metabolic resistance in A. fatua, resulting in resistance to clodinafop-propargyl.}, } @article {pmid38072540, year = {2023}, author = {Yu, H and Guo, X and Peng, L and Li, X and Chen, J and Cui, H}, title = {Target gene mutations endowed cross-resistance to acetolactate synthase-inhibiting herbicides in wild Brassica juncea.}, journal = {Pesticide biochemistry and physiology}, volume = {197}, number = {}, pages = {105683}, doi = {10.1016/j.pestbp.2023.105683}, pmid = {38072540}, issn = {1095-9939}, mesh = {Amino Acids ; Mustard Plant/genetics/metabolism ; *Herbicides/pharmacology ; *Acetolactate Synthase/metabolism ; Herbicide Resistance/genetics ; Sodium ; Mutation ; Pyrimidines ; Sulfonamides ; Arylsulfonates ; Amyotrophic Lateral Sclerosis ; }, abstract = {Wild Brassica juncea is a troublesome weed that infests wheat fields in China. Two suspected wild B. juncea populations (19-5 and 19-6) resistant to acetolactate synthase (ALS) inhibitors were collected from wheat fields in China. To clarify their resistance profiles and resistance mechanism, the resistance levels of populations 19-5 and 19-6 to ALS-inhibiting herbicides and their underlying target-site resistance mechanism were investigated. The results showed that the 19-5 population exhibited resistance to tribenuron-methyl, pyrithiobac‑sodium and florasulam, while the 19-6 population was resistant to tribenuron-methyl, pyrithiobac‑sodium, imazethapyr and florasulam. Using the homologous cloning method, two ALS genes were identified in wild B. juncea, with one gene (ALS1) encoding 652 amino acids and the other (ALS2) encoding 655 amino acids. Pro-197-Arg mutation on ALS2 and Trp-574-Leu mutation on ALS1, together with the combination of these two mutations in a single plant, were observed in both 19-5 and 19-6 populations. ALS2 enzymes carrying the Pro-197-Arg mutation were cross-resistant to tribenuron-methyl, pyrithiobac‑sodium, imazerthapyr and florasulam, with resistance index (RI) values of 6.23, 32.81, 7.97 and 1162.50, respectively. Similarly, ALS1 enzymes with Trp-574-leu substitutions also displayed high resistance to these four herbicides (RI values ranging from 132.61 to 3375.00). In addition, the combination of Pro-197-Arg (ALS2) and Trp-574-Leu (ALS1) mutations increased the resistance level of the ALS enzyme to ALS inhibitors, with its RI values 3.83-214.19, 6.88-37.34, 1.91-31.82 and 2.03-5.90-fold higher than a single mutation for tribenuron-methyl, pyrithiobac‑sodium, imazerthapyr and florasulam, respectively. Collectively, Pro-197-Arg mutation on ALS2, Trp-574-Leu mutation on ALS1 and the combination of Pro-197-Arg (ALS2) and Trp-574-Leu (ALS1) mutations in wild B. juncea could endow broad-spectrum resistance to ALS inhibitors, which might provide guides for establishing effective strategies to prevent or delay such resistance evolution in this weed.}, } @article {pmid38073637, year = {2023}, author = {Mitsi, E and Christodoulou, CC and Nicolaou, P and Christodoulou, K and Zamba-Papanicolaou, E}, title = {The influence of environmental risk factors in the development of ALS in the Mediterranean Island of Cyprus.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1264743}, pmid = {38073637}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disease of motor neurons, presenting with relentlessly progressive muscle atrophy and weakness. The etiology of ALS remains unexplained for over 85% of all cases, suggesting that besides the genetic basis of the disease, various environmental factors are implicated in the pathogenesis of ALS. This study aimed to investigate the contribution of known environmental risk factors of ALS in the Cypriot population.

METHODS: We conducted a case-control study with a total of 56 ALS cases and 56 healthy gender/age-matched controls of Cypriot nationality. Demographic, lifestyle characteristics, medical conditions, and environmental exposures were collected through the use of a detailed questionnaire. Statistical analyses using the R programming language examined the association between the above environmental factors and ALS.

RESULTS: A chi-square test analysis revealed a statistically significant (p = 0.000461) difference in smoking status between the two groups. In addition, univariate logistic regression analysis showed a statistically significant association between ALS cases for head trauma/injury (p = 0.0398) and exposure to chemicals (p = 0.00128), compared to controls.

CONCLUSION: This case-control investigation has shed some light on the epidemiological data of ALS in Cyprus, by identifying environmental determinants of ALS, such as smoking, head trauma, and chemical exposure, in the Cypriot population.}, } @article {pmid38076820, year = {2024}, author = {Worthy, AE and Anderson, JT and Lane, AR and Gomez-Perez, L and Wang, AA and Griffith, RW and Rivard, AF and Bikoff, JB and Alvarez, FJ}, title = {Spinal V1 inhibitory interneuron clades differ in birthdate, projections to motoneurons, and heterogeneity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.11.29.569270}, pmid = {38076820}, issn = {2692-8205}, support = {R01 NS047357/NS/NINDS NIH HHS/United States ; }, abstract = {UNLABELLED: Spinal cord interneurons play critical roles shaping motor output, but their precise identity and connectivity remain unclear. Focusing on the V1 interneuron cardinal class we defined four major V1 subsets according to neurogenesis timing, genetic lineage-tracing, synaptic output to motoneurons, and synaptic inputs from muscle afferents. Birthdate delineates two early born (Renshaw and Pou6f2) and two late born (Foxp2 and Sp8) V1 clades, showing that sequential neurogenesis produces different V1 subsets. Early born Renshaw cells and late born Foxp2-V1 interneurons are tightly coupled to motoneurons, while early born Pou6f2-V1 and late born Sp8-V1 interneurons are not, indicating that timing of neurogenesis does not correlate with motoneuron targeting. V1 clades also differ in cell numbers and diversity. Lineage labeling shows that the Foxp2-V1 clade contains over half of all V1 interneurons, provides the largest inhibitory input to motoneuron cell bodies and includes subgroups that differ in birthdate, location, and proprioceptive input. Notably, one Foxp2-V1 subgroup, defined by postnatal Otp expression is positioned near the lateral motor column and receives substantial input from proprioceptors, consistent with an involvement in reciprocal inhibitory pathways. Combined tracing of ankle flexor sensory afferents and interneurons monosynaptically connected to ankle extensors confirmed placement of Foxp2-V1 interneurons in reciprocal inhibitory pathways. Our results validate previously proposed V1 clades as unique functional subtypes that differ in circuit placement, with Foxp2-V1 cells forming the most heterogeneous subgroup. We discuss how V1 organizational diversity enables understanding of their roles in motor control, with implications for their diverse ontogenetic and phylogenetic origins.

SIGNIFICANCE STATEMENT: The complexity of spinal interneuron diversity and circuit organization represents a challenge to understand neural control of movement in normal adults as well as during motor development and in disease. Inhibitory interneurons are a core element of these spinal circuits. V1 interneurons comprise the largest group of inhibitory interneurons in the ventral horn, and their organization remains unclear. Here we present a comprehensive examination of V1 subtypes according to neurogenesis, placement in spinal motor circuits, and motoneuron synaptic targeting. V1 diversity increases during evolution from axial-swimming fishes to limb-based mammalian terrestrial locomotion. This increased diversity is reflected in the size and heterogeneity of the Foxp2-V1 clade, a group closely associated with limb motor pools. We show that Foxp2-V1 interneurons establish the densest direct inhibitory input to motoneurons, especially on cell bodies. These findings are particularly significant because recent studies have shown that motor neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) affect inhibitory V1 synapses on motoneuron cell bodies and Foxp2-V1 interneurons themselves in the earliest stages of pathology.}, } @article {pmid38077003, year = {2023}, author = {Zhou, Z and Kim, J and Huang, AY and Nolan, M and Park, J and Doan, R and Shin, T and Miller, MB and Chhouk, B and Morillo, K and Yeh, RC and Kenny, C and Neil, JE and Lee, CZ and Ohkubo, T and Ravits, J and Ansorge, O and Ostrow, LW and Lagier-Tourenne, C and Lee, EA and Walsh, CA}, title = {Somatic Mosaicism in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Reveals Widespread Degeneration from Focal Mutations.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38077003}, issn = {2692-8205}, support = {R56 AG079857/AG/NIA NIH HHS/United States ; DP2 AG072437/AG/NIA NIH HHS/United States ; K01 AG051791/AG/NIA NIH HHS/United States ; R01 AG070921/AG/NIA NIH HHS/United States ; R01 NS032457/NS/NINDS NIH HHS/United States ; DP2 AG086138/AG/NIA NIH HHS/United States ; R01 AG082346/AG/NIA NIH HHS/United States ; K08 AG065502/AG/NIA NIH HHS/United States ; }, abstract = {Although mutations in dozens of genes have been implicated in familial forms of amyotrophic lateral sclerosis (fALS) and frontotemporal degeneration (fFTD), most cases of these conditions are sporadic (sALS and sFTD), with no family history, and their etiology remains obscure. We tested the hypothesis that somatic mosaic mutations, present in some but not all cells, might contribute in these cases, by performing ultra-deep, targeted sequencing of 88 genes associated with neurodegenerative diseases in postmortem brain and spinal cord samples from 404 individuals with sALS or sFTD and 144 controls. Known pathogenic germline mutations were found in 20.6% of ALS, and 26.5% of FTD cases. Predicted pathogenic somatic mutations in ALS/FTD genes were observed in 2.7% of sALS and sFTD cases that did not carry known pathogenic or novel germline mutations. Somatic mutations showed low variant allele fraction (typically <2%) and were often restricted to the region of initial discovery, preventing detection through genetic screening in peripheral tissues. Damaging somatic mutations were preferentially enriched in primary motor cortex of sALS and prefrontal cortex of sFTD, mirroring regions most severely affected in each disease. Somatic mutation analysis of bulk RNA-seq data from brain and spinal cord from an additional 143 sALS cases and 23 controls confirmed an overall enrichment of somatic mutations in sALS. Two adult sALS cases were identified bearing pathogenic somatic mutations in DYNC1H1 and LMNA, two genes associated with pediatric motor neuron degeneration. Our study suggests that somatic mutations in fALS/fFTD genes, and in genes associated with more severe diseases in the germline state, contribute to sALS and sFTD, and that mosaic mutations in a small fraction of cells in focal regions of the nervous system can ultimately result in widespread degeneration.}, } @article {pmid38077837, year = {2023}, author = {Bekdik, P and Baslo, MB}, title = {Investigation of Ongoing Denervation and Reinnervation in Amyotrophic Lateral Sclerosis by Using Concentric Needle Electrode with Single Fiber Electromyography Method.}, journal = {Noro psikiyatri arsivi}, volume = {60}, number = {4}, pages = {298-303}, pmid = {38077837}, issn = {1300-0667}, abstract = {INTRODUCTION: The aim of this study is to demonstrate the conduction disturbance at the neuromuscular junction in a cranial muscle by measuring jitter with a concentric needle (CN) electrode in the diagnosis of Amyotrophic Lateral Sclerosis (ALS) and to investigate the utility of evaluating the peak number as an ongoing reinnervation marker.

METHOD: Twelve patients diagnosed with ALS were included in this study. Single fiber electromyography (SFEMG) was performed using a CN electrode during the voluntary contraction of the right extensor digitorum communis (EDC) and left frontalis muscles.

RESULTS: In SFEMG from the right EDC muscle, the mean jitter value was high in all of them. The average jitter calculated in EDC muscles was 57.76±24.17 μs. The mean jitter value in the frontal muscles was 28.91±10.21 μs. In all patients, the number of CN electrode peaks was more than 4 in the EDC muscle and above 4 in 91.67% of the frontal muscle.

CONCLUSION: Detection of high jitter in SFEMG examination indicates that the examined muscle undergoes a denervation-reinnervation process in the case of increased peak number values. When such a determination is made in the extremity muscles, it becomes important for the diagnosis of ALS.}, } @article {pmid38077871, year = {2023}, author = {Methods In Medicine, CAM}, title = {Retracted: Study on the Diagnostic Value of Neuroelectrophysiological Examination in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Computational and mathematical methods in medicine}, volume = {2023}, number = {}, pages = {9858143}, pmid = {38077871}, issn = {1748-6718}, abstract = {[This retracts the article DOI: 10.1155/2022/3907751.].}, } @article {pmid38077951, year = {2023}, author = {Adachi, K and Miyata, K and Chida, Y and Hirose, M and Morisaki, Y and Yamanaka, K and Misawa, H}, title = {Depletion of perivascular macrophages delays ALS disease progression by ameliorating blood-spinal cord barrier impairment in SOD1[G93A] mice.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1291673}, pmid = {38077951}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease in which non-cell-autonomous processes have been proposed as its cause. Non-neuronal cells that constitute the environment around motor neurons are known to mediate the pathogenesis of ALS. Perivascular macrophages (PVM) are immune cells that reside between the blood vessels of the central nervous system and the brain parenchyma; PVM are components of the neurovascular unit and regulate the integrity of the blood-spinal cord barrier (BSCB). However, it is not known whether regulation of BSCB function by PVM is involved in the pathogenesis of ALS. Here, we used SOD1[G93A] mice to investigate whether PVM is involved in the pathogenesis of ALS. Immunostaining revealed that the number of PVM was increased during the disease progression of ALS in the spinal cord. We also found that both anti-inflammatory Lyve1[+] PVM and pro-inflammatory MHCII[+] PVM subtypes were increased in SOD1[G93A] mice, and that subtype heterogeneity was shifted toward MHCII[+] PVM compared to wild-type (WT) mice. Then we depleted PVM selectively and continuously in SOD1[G93A] mice by repeated injection of clodronate liposomes into the cerebrospinal fluid and assessed motor neuron number, neurological score, and survival. Results showed that PVM depletion prevented the loss of motoneurons, slowed disease progression, and prolonged survival. Further histological analysis showed that PVM depletion prevents BSCB collapse by ameliorating the reduction of extracellular matrix proteins necessary for the maintenance of barrier function. These results indicate that PVM are involved in the pathogenesis of ALS, as PVM degrades the extracellular matrix and reduces BSCB function, which may affect motor neuron loss and disease progression. Targeting PVM interventions may represent a novel ALS therapeutic strategy.}, } @article {pmid38078079, year = {2023}, author = {Shi, J and Yu, H and Fu, Y and Wang, T and Zhang, Y and Huang, J and Li, S and Zheng, T and Ni, X and Zhao, J}, title = {Development and validation of functional kompetitive allele-specific PCR markers for herbicide resistance in Brassica napus.}, journal = {Frontiers in plant science}, volume = {14}, number = {}, pages = {1213476}, pmid = {38078079}, issn = {1664-462X}, abstract = {Effective weed control in the field is essential for maintaining favorable growing conditions and rapeseed yields. Sulfonylurea herbicides are one kind of most widely used herbicides worldwide, which control weeds by inhibiting acetolactate synthase (ALS). Molecular markers have been designed from polymorphic sites within the sequences of ALS genes, aiding marker-assisted selection in breeding herbicide-resistant rapeseed cultivars. However, most of them are not breeder friendly and have relatively limited application due to higher costs and lower throughput in the breeding projects. The aims of this study were to develop high throughput kompetitive allele-specific PCR (KASP) assays for herbicide resistance. We first cloned and sequenced BnALS1 and BnALS3 genes from susceptible cultivars and resistant 5N (als1als1/als3als3 double mutant). Sequence alignments of BnALS1 and BnALS3 genes for cultivars and 5N showed single nucleotide polymorphisms (SNPs) at positions 1676 and 1667 respectively. These two SNPs for BnALS1 and BnALS3 resulted in amino acid substitutions and were used to develop a KASP assay. These functional markers were validated in three distinct BC1F2 populations. The KASP assay developed in this study will be valuable for the high-throughput selection of elite materials with high herbicide resistance in rapeseed breeding programs.}, } @article {pmid38078426, year = {2023}, author = {Handberg, C and Werlauff, U}, title = {People with neuromuscular diseases and their relatives' perspectives on challenges in everyday life and healthcare.}, journal = {Neurodegenerative disease management}, volume = {13}, number = {5}, pages = {289-302}, doi = {10.2217/nmt-2023-0008}, pmid = {38078426}, issn = {1758-2032}, mesh = {Humans ; *Delivery of Health Care ; *Neuromuscular Diseases ; }, abstract = {Objective: People with a neuromuscular disease (NMD) often experience challenges in everyday life and healthcare. Aim: To investigate experiences of and perspectives on challenges in everyday life and healthcare of people with NMDs and their relatives to gain new insights into how life-long rehabilitation can be tailored. Patients & methods: The design was qualitative using the interpretive description methodology and the Sense of Coherence theory. An ethnographic fieldwork was conducted where 45 persons with NMD and their relatives were included for interviews and participant observations. Results & conclusion: People with NMDs continually adapt to a changing functioning and balance their need for knowledge with their dependency on help when navigating the healthcare system. Structured, professionally facilitated peer support is needed.}, } @article {pmid38078970, year = {2024}, author = {Sun, Z and Zhang, B and Peng, Y}, title = {Development of novel treatments for amyotrophic lateral sclerosis.}, journal = {Metabolic brain disease}, volume = {39}, number = {3}, pages = {467-482}, pmid = {38078970}, issn = {1573-7365}, support = {No. 82073835, and 81872855//National Natural Sciences Foundation of China/ ; No. 2021-I2M-1-054//CAMS Innovation Fund for Medical Sciences/ ; 201920200802//Disciplines construction project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; *Neurodegenerative Diseases ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes paralysis whose etiology and pathogenesis have not been fully elucidated. Presently it is incurable and rapidly progressive with a survival of 2-5 years from onset, and no treatments could cure it. Therefore, it is urgent to identify which therapeutic target(s) are more promising to develop treatments that could effectively treat ALS. So far, more than 90 novel treatments for ALS patients have been registered on ClinicalTrials.gov, of which 23 are in clinical trials, 12 have been terminated and the rest suspended. This review will systematically summarize the possible targets of these novel treatments under development or failing based on published literature and information released by sponsors, so as to provide basis and support for subsequent drug research and development.}, } @article {pmid38079474, year = {2024}, author = {Zibold, J and Lessard, LER and Picard, F and da Silva, LG and Zadorozhna, Y and Streichenberger, N and Belotti, E and Osseni, A and Emerit, A and Errazuriz-Cerda, E and Michel-Calemard, L and Menassa, R and Coudert, L and Wiessner, M and Stucka, R and Klopstock, T and Simonetti, F and Hutten, S and Nonaka, T and Hasegawa, M and Strom, TM and Bernard, E and Ollagnon, E and Urtizberea, A and Dormann, D and Petiot, P and Schaeffer, L and Senderek, J and Leblanc, P}, title = {The new missense G376V-TDP-43 variant induces late-onset distal myopathy but not amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {5}, pages = {1768-1783}, pmid = {38079474}, issn = {1460-2156}, support = {//CNRS/ ; //Fondation pour la Recherche Médicale/ ; //Federal Ministry of Education and Research/ ; //German Research Foundation/ ; //Core/ ; //CLSM/ ; }, mesh = {Humans ; *Mutation, Missense/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Male ; *Distal Myopathies/genetics/pathology ; *DNA-Binding Proteins/genetics ; Female ; Middle Aged ; Aged ; Pedigree ; Muscle, Skeletal/pathology/metabolism ; }, abstract = {TAR DNA binding protein of 43 kDa (TDP-43)-positive inclusions in neurons are a hallmark of several neurodegenerative diseases including familial amyotrophic lateral sclerosis (fALS) caused by pathogenic TARDBP variants as well as more common non-Mendelian sporadic ALS (sALS). Here we report a G376V-TDP-43 missense variant in the C-terminal prion-like domain of the protein in two French families affected by an autosomal dominant myopathy but not fulfilling diagnostic criteria for ALS. Patients from both families presented with progressive weakness and atrophy of distal muscles, starting in their fifth to seventh decade. Muscle biopsies revealed a degenerative myopathy characterized by accumulation of rimmed (autophagic) vacuoles, disruption of sarcomere integrity and severe myofibrillar disorganization. The G376V variant altered a highly conserved amino acid residue and was absent in databases on human genome variation. Variant pathogenicity was supported by in silico analyses and functional studies. The G376V mutant increased the formation of cytoplasmic TDP-43 condensates in cell culture models, promoted assembly into high molecular weight oligomers and aggregates in vitro, and altered morphology of TDP-43 condensates arising from phase separation. Moreover, the variant led to the formation of cytoplasmic TDP-43 condensates in patient-derived myoblasts and induced abnormal mRNA splicing in patient muscle tissue. The identification of individuals with TDP-43-related myopathy, but not ALS, implies that TARDBP missense variants may have more pleiotropic effects than previously anticipated and support a primary role for TDP-43 in skeletal muscle pathophysiology. We propose to include TARDBP screening in the genetic work-up of patients with late-onset distal myopathy. Further research is warranted to examine the precise pathogenic mechanisms of TARDBP variants causing either a neurodegenerative or myopathic phenotype.}, } @article {pmid38081672, year = {2023}, author = {Xiong, S and Klesges, L and Doering, M and Pratt, RJ}, title = {Applications of implementation science frameworks, models and theories in disparities-focused cancer screening interventions: a scoping review protocol.}, journal = {BMJ open}, volume = {13}, number = {12}, pages = {e078212}, pmid = {38081672}, issn = {2044-6055}, support = {T32 CA190194/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Early Detection of Cancer ; Implementation Science ; *Neoplasms/diagnosis/prevention & control ; Research Design ; Scoping Reviews as Topic ; }, abstract = {BACKGROUND: Implementation science (IS) frameworks, models and theories (FMTs) have gained popularity in guiding the implementation and evaluation of evidence-based interventions (EBIs) for cancer screening. However, there are significant research gaps in understanding their applications in cancer health disparities contexts. This paper outlines a scoping review protocol designed to explore the utilisation of IS FMTs in cancer screening EBIs to inform intervention designs and adaptations.

METHODS AND ANALYSIS: This scoping review protocol adheres to Arksey and O'Malley's five-step methodological framework for conducting scoping studies. Search strategies were conducted in five bibliographic databases: Ovid MEDLINE, PubMed, Scopus, Web of Science and EMBASE. The search was run on 22 June 2023 with an English language filter and a date limit of 2001-current. Two reviewers will independently screen studies for inclusion and exclusion criteria. A third reviewer will be consulted, where appropriate at any of the review stages, to achieve consensus or resolve conflicts. Data will be collected, managed and analysed using Covidence. A narrative synthesis, based on Popay et al's methodology, will guide reporting and summarisation of results. The review will adhere to the PRISMA Extension for Scoping Reviews guidelines.

ETHICS AND DISSEMINATION: This scoping review is a novel approach for examining a growing corpus of research literature on IS FMT applications used in cancer screening EBIs. As a secondary analysis, this scoping review does not require approval from an institutional review board. We anticipate the review will produce insightful information (eg, challenges, key areas for future directions) on the applications of IS TMFs in designing, deploying and testing EBIs for populations experiencing cancer screening disparities. We will disseminate the results through journals and conferences targeting IS and cancer prevention researchers and practitioners.}, } @article {pmid38082513, year = {2023}, author = {Lluch-Galcerá, JJ and Alcoverro, C and Prat, E and Martinez-Molina, M and Bielsa, I and Quer, A and Bassas, J}, title = {[Refraktärer IgA-Pemphigus erfolgreich mit Adalimumab als Monotherapie behandelt].}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {21}, number = {12}, pages = {1560-1562}, doi = {10.1111/ddg.15232_g}, pmid = {38082513}, issn = {1610-0387}, } @article {pmid38082598, year = {2023}, author = {Zhang, C and Deng, F and Li, Y and Hall, T and Goldys, E}, title = {Paper-based lateral flow assay for the point-of-care detection of neurofilament light chain.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2023}, number = {}, pages = {1-4}, doi = {10.1109/EMBC40787.2023.10340109}, pmid = {38082598}, issn = {2694-0604}, mesh = {Humans ; *Point-of-Care Systems ; Intermediate Filaments/metabolism ; Reproducibility of Results ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Biomarkers ; }, abstract = {Neurofilament light chain (NF-L) is a protein found in neurons of the nervous system and is widely used as a biomarker for neurological disorders. However, the current methods for detecting NF-L levels are complicated, expensive, and require specialized equipment, making it challenging to implement in a point-of-care (POC) setting. In this study, we developed a gold nanoshell (AuNS)-assisted lateral flow assay (LFA) based test strip for the POC detection of NF-L at a low ng/mL level (8 ng/mL = 117.65 pM). The test strip is a simple, rapid, and cost-effective method for detecting NF-L, making it suitable for use in a POC setting for the diagnosis and treatment of various neurological disorders. With its ease of use and reliability, the paper-based LFA is a valuable tool for the diagnosis and management of neurological conditions.Clinical Relevance- The AuNS-assisted LFA test strip developed in this study offers a rapid, cost-effective, and simple method for detecting NF-L levels, making it of great interest to practicing clinicians for the diagnosis of various neurological diseases such as HIV-associated dementia (HID), Amyotrophic Lateral Sclerosis (ALS), and Creutzfeldt-Jakob disease (CJD).}, } @article {pmid38082727, year = {2023}, author = {Khan, SU and Majid, M and Linguraru, MG and Muhammad Anwar, S}, title = {Upper Limb Movement Execution Classification using Electroencephalography for Brain Computer Interface.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2023}, number = {}, pages = {1-4}, doi = {10.1109/EMBC40787.2023.10341008}, pmid = {38082727}, issn = {2694-0604}, mesh = {Humans ; *Brain-Computer Interfaces ; Upper Extremity ; Electroencephalography/methods ; Movement ; Motion ; }, abstract = {An accurate classification of upper limb movements using electroencephalogram (EEG) signals is gaining significant importance in recent years due to the prevalence of brain-computer interfaces. The upper limbs in the human body are crucial since different skeletal segments combine to make a range of motions that helps us in our trivial daily tasks. Decoding EEG-based upper limb movements can be of great help to people with spinal cord injury (SCI) or other neuro-muscular diseases such as amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and periodic paralysis. This can manifest in a loss of sensory and motor function, which could make a person reliant on others to provide care in day-to-day activities. We can detect and classify upper limb movement activities, whether they be executed or imagined using an EEG-based brain-computer interface (BCI). Toward this goal, we focus our attention on decoding movement execution (ME) of the upper limb in this study. For this purpose, we utilize a publicly available EEG dataset that contains EEG signal recordings from fifteen subjects acquired using a 61-channel EEG device. We propose a method to classify four ME classes for different subjects using spectrograms of the EEG data through pre-trained deep learning (DL) models. Our proposed method of using EEG spectrograms for the classification of ME has shown significant results, where the highest average classification accuracy (for four ME classes) obtained is 87.36%, with one subject achieving the best classification accuracy of 97.03%.Clinical relevance- This research shows that movement execution of upper limbs is classified with significant accuracy by employing a spectrogram of the EEG signals and a pre-trained deep learning model which is fine-tuned for the downstream task.}, } @article {pmid38083694, year = {2023}, author = {Migliorelli, L and Moccia, S and Berardini, D and Frontoni, E and Coccia, M and Villani, L and Bandini, A}, title = {A preliminary study on self-care telemonitoring of dysarthria in spinal muscular atrophy.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2023}, number = {}, pages = {1-4}, doi = {10.1109/EMBC40787.2023.10340908}, pmid = {38083694}, issn = {2694-0604}, mesh = {Humans ; Dysarthria/diagnosis/etiology ; Self Care ; *Muscular Atrophy, Spinal/complications/diagnosis ; *Amyotrophic Lateral Sclerosis/complications ; Rare Diseases ; }, abstract = {Spinal muscular atrophy (SMA) is a rare neuromuscular disease which may cause impairments in oro-facial musculature. Most of the individuals with SMA present bulbar signs such as flaccid dysarthria which mines their abilities to speak and, as consequence, their psychic balance. To support clinicians, recent work has demonstrated the feasibility of video-based techniques for assessing the oro-facial functions in patients with neurological disorders such as amyotrophic lateral sclerosis. However, no work has so far focused on automatic and quantitative monitoring of dysarthria in SMA. To overcome limitations this work's aim is to propose a cloud-based store-and-forward telemonitoring system for automatic and quantitative evaluation of oro-facial muscles in individuals with SMA. The system integrates a convolutional neural network (CNN) aimed at identifying the position of facial landmarks from video recordings acquired via a web application by an SMA patient.Clinical relevance- The proposed work is in the preliminary stage, but it represents the first step towards a better understanding of the bulbar-functions' evolution in patients with SMA.}, } @article {pmid38083843, year = {2024}, author = {Zhang, S and Li, L and Liu, X and Zhong, Q}, title = {The hookup model of the HOPS complex in autophagosome-lysosome fusion.}, journal = {Autophagy}, volume = {20}, number = {3}, pages = {714-715}, pmid = {38083843}, issn = {1554-8635}, mesh = {*Macroautophagy ; C9orf72 Protein/metabolism ; *Autophagy ; Autophagosomes/metabolism ; Membrane Fusion/physiology ; SNARE Proteins/metabolism ; Lysosomes/metabolism ; }, abstract = {Macroautophagy/autophagy is a highly conserved process that involves the degradation of proteins, damaged organelles, and other cytoplasmic macromolecules. Autophagosome-lysosome fusion is critical for successful substrate degradation and is mediated by SNARE proteins. The fusion process requires additional vesicle docking and tethering-regulating factors. Our recent work has uncovered a functional model of autophagosome-lysosome fusion. We demonstrated that the six-subunit homotypic fusion and vacuole protein sorting (HOPS) complex can be assembled by two subcomplexes, the VPS39-VPS11 subcomplex (HOPS-2) and the VPS41-VPS16-VPS18-VPS33A subcomplex (HOPS-4). VPS39 binds with RAB2 on the autophagosome and VPS41 binds with RAB39A on the lysosome, which then promotes membrane tethering and autophagic SNARE-mediated membrane fusion. Moreover, we have revealed that ALS- and FTD-related C9orf72 is a guanine exchange factor (GEF) for RAB39A. In this punctum, we discuss how the C9orf72-RAB39A-HOPS axis function regulates autophagosome-lysosome fusion.}, } @article {pmid38084253, year = {2023}, author = {Minić, R and Arsić, A and Kojadinović, M and Palibrk, A and Đorđević, B and Stević, Z}, title = {Erythrocyte fatty acid aberrations in Amyotrophic Lateral Sclerosis: Correlation with disease duration.}, journal = {Journal of medical biochemistry}, volume = {42}, number = {4}, pages = {621-629}, pmid = {38084253}, issn = {1452-8258}, abstract = {BACKGROUND: Recent literature data highlights metabolic changes in amyotrophic lateral sclerosis (ALS). To explore possible early metabolic changes, we aimed to analyse the fatty acids (FA) composition of erythrocytes in newly diagnosed als patients and to see whether fatty acid levels correlate with the ALSFRS-R score or disease duration.

METHODS: The severity of motor function involvement was assessed by the ALSFRS-R scale at the initial evaluation. The fatty acid profile of erythrocyte membranes was analysed by gas-liquid chromatography. The study comprised 26 clinically diagnosed als patients, with mean ALSFRS-R 38±8. The control group included 26 healthy volunteers.}, } @article {pmid38084484, year = {2023}, author = {Reniers, PWA and Leontjevas, R and Declercq, IJN and Molog, M and Enders-Slegers, MJ and Gerritsen, DL and Hediger, K}, title = {[Not Available].}, journal = {Tijdschrift voor gerontologie en geriatrie}, volume = {}, number = {4}, pages = {}, doi = {10.54195/tgg.18095}, pmid = {38084484}, issn = {0167-9228}, abstract = {Achtergrond: Huisdieren zijn belangrijk in het leven van thuiswonende ouderen en van degenen die langdurige thuiszorg (LTZ) ontvangen. Het doel van dit project was om de betekenis van huisdieren voor thuiswonende ouderen te verkennen en te onderzoeken of deze ook van toepassing zijn op LTZ-cliënten. Daarnaast exploreerden we mogelijke huisdiergerelateerde uitdagingen en de invloed van huisdierbezit op zorgrelaties in de LTZ. Methoden: Het project startte met een systematische kwalitatieve literatuur review gevolgd door een studie met de Consensual Qualitative Research (CQR) methode en een onlinevragenlijst om de resultaten van de review in de LTZ te toetsen. LTZ-cliënten, mantelzorgers en professionele zorgverleners namen deel aan de CQR-studie en vragenlijst. De vragenlijst bevatte daarnaast open vragen over mogelijke huisdiergerelateerde uitdagingen en hun invloed op zorgrelaties in de LTZ. Resultaten: De review bevatte vijftien artikelen die achtentwintig rollen gerelateerd aan de betekenis van huisdieren beschreven, onderverdeeld in zeven categorieën. De uitkomsten van de CQR-studie en vragenlijst toonden dat huisdieren een vergelijkbare betekenis hebben voor thuiswonende ouderen en LTZ-cliënten. Deelnemers rapporteerden mogelijke uitdagingen en zowel positieve als negatieve effecten van huisdieren op zorgrelaties. Conclusies: Huisdieren hebben een vergelijkbare betekenis voor thuiswonende ouderen en LTZ-cliënten. Bovendien ervaren LTZ-cliënten mogelijke specifieke huisdiergerelateerde uitdagingen en kunnen huisdieren zorgrelaties beïnvloeden. Daarom is het noodzakelijk om rekening te houden met huisdieren in de LTZ.}, } @article {pmid38086800, year = {2023}, author = {Wei, J and Li, M and Ye, Z and Hu, X and He, X and Wang, J and Chen, G and Zou, C and Xu, D and Zhang, H and Yuan, J and Zha, Y}, title = {Elevated peripheral levels of receptor-interacting protein kinase 1 (RIPK1) and IL-8 as biomarkers of human amyotrophic lateral sclerosis.}, journal = {Signal transduction and targeted therapy}, volume = {8}, number = {1}, pages = {451}, pmid = {38086800}, issn = {2059-3635}, support = {WJ2021M257//Health and Family Planning Commission of Hubei Province (Hubei Provincial Health Department)/ ; 2019SHZDZX02//Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)/ ; 32070737//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82188101, 91849204, 21837004, 92049303 and 32170755//National Natural Science Foundation of China (National Science Foundation of China)/ ; 20JC1411600//Shanghai Science and Technology Development Foundation (Shanghai Science and Technology Development Fund)/ ; 20QA1411500//Shanghai Science and Technology Development Foundation (Shanghai Science and Technology Development Fund)/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Biomarkers ; Interleukin-8/genetics ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; *Neurodegenerative Diseases/metabolism ; Primidone/metabolism/pharmacology/therapeutic use ; Protein Kinases/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/metabolism/pharmacology ; Superoxide Dismutase/metabolism/pharmacology/therapeutic use ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to mediate pathogenesis of ALS. Primidone has been identified as an old drug that can also inhibit RIPK1 kinase. We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1[G93A] mice and ALS patients. SOD1[G93A] mice treated with primidone showed significant delay of symptomatic onset and improved motor performance. One-hundred-sixty-two ALS participants dosed daily with primidone (62.5 mg) completed 24-week follow-up. A significant reduction was showed in serum levels of RIPK1 and IL-8, which were significantly higher in ALS patients than that of healthy controls (P < 0.0001). Serum RIPK1 levels were correlated positively with the severity of bulbar symptoms (P < 0.05). Our study suggests that serum levels of RIPK1 and IL-8 in peripheral can be used as clinical biomarkers for the activation of RIPK1 in central nervous system in human ALS patients. Repurposing primidone may provide a promising therapeutic strategy for ALS. The effect of primidone for the treatment of other inflammatory diseases may also be considered, since the activation of RIPK1 has been implicated in mediating a variety of inflammatory diseases including COVID-19-associated cytokine release syndrome (CRS). (ChiCTR2200060149).}, } @article {pmid38086894, year = {2024}, author = {Kraft, S and Mease, C and Jillapalli, D and Fermaglich, LJ and Miller, KL}, title = {Trends in drug development for amyotrophic lateral sclerosis.}, journal = {Nature reviews. Drug discovery}, volume = {23}, number = {2}, pages = {99-100}, doi = {10.1038/d41573-023-00199-2}, pmid = {38086894}, issn = {1474-1784}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Drug Development ; }, } @article {pmid38087359, year = {2023}, author = {Nayab, DE and Din, FU and Ali, H and Kausar, WA and Urooj, S and Zafar, M and Khan, I and Shabbir, K and Khan, GM}, title = {Nano biomaterials based strategies for enhanced brain targeting in the treatment of neurodegenerative diseases: an up-to-date perspective.}, journal = {Journal of nanobiotechnology}, volume = {21}, number = {1}, pages = {477}, pmid = {38087359}, issn = {1477-3155}, support = {20-14604/NRPU/R&D/HEC/2021//Higher Education Commision, Pakistan/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Brain ; Blood-Brain Barrier ; Drug Delivery Systems/methods ; Nanotechnology ; }, abstract = {Neurons and their connecting axons gradually degenerate in neurodegenerative diseases (NDs), leading to dysfunctionality of the neuronal cells and eventually their death. Drug delivery for the treatment of effected nervous system is notoriously complicated because of the presence of natural barriers, i.e., the blood-brain barrier and the blood cerebrospinal fluid barrier. Palliative care is currently the standard care for many diseases. Therefore, treatment programs that target the disease's origin rather than its symptoms are recommended. Nanotechnology-based drug delivery platforms offer an innovative way to circumvent these obstacles and deliver medications directly to the central nervous system, thereby enabling treatment of several common neurological problems, i.e., Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. Interestingly, the combination of nanomedicine and gene therapy enables targeting of selective mutant genes responsible for the progression of NDs, which may provide a much-needed boost in the struggle against these diseases. Herein, we discussed various central nervous system delivery obstacles, followed by a detailed insight into the recently developed techniques to restore neurological function via the differentiation of neural stem cells. Moreover, a comprehensive background on the role of nanomedicine in controlling neurogenesis via differentiation of neural stem cells is explained. Additionally, numerous phytoconstituents with their neuroprotective properties and molecular targets in the identification and management of NDs are also deliberated. Furthermore, a detailed insight of the ongoing clinical trials and currently marketed products for the treatment of NDs is provided in this manuscript.}, } @article {pmid38087504, year = {2024}, author = {Dellar, ER and Vendrell, I and Talbot, K and Kessler, BM and Fischer, R and Turner, MR and Thompson, AG}, title = {Data-independent acquisition proteomics of cerebrospinal fluid implicates endoplasmic reticulum and inflammatory mechanisms in amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {168}, number = {2}, pages = {115-127}, pmid = {38087504}, issn = {1471-4159}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0701923/MRC_/Medical Research Council/United Kingdom ; MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; Thompson/Jan20/952-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Proteomics/methods ; Biomarkers/cerebrospinal fluid ; Prognosis ; Mass Spectrometry ; }, abstract = {While unbiased proteomics of human cerebrospinal fluid (CSF) has been used successfully to identify biomarkers of amyotrophic lateral sclerosis (ALS), high-abundance proteins mask the presence of lower abundance proteins that may have diagnostic and prognostic value. However, developments in mass spectrometry (MS) proteomic data acquisition methods offer improved protein depth. In this study, MS with library-free data-independent acquisition (DIA) was used to compare the CSF proteome of people with ALS (n = 40), healthy (n = 15) and disease (n = 8) controls. Quantified protein groups were subsequently correlated with clinical variables. Univariate analysis identified 7 proteins, all significantly upregulated in ALS versus healthy controls, and 9 with altered abundance in ALS versus disease controls (FDR < 0.1). Elevated chitotriosidase-1 (CHIT1) was common to both comparisons and was proportional to ALS disability progression rate (Pearson r = 0.41, FDR-adjusted p = 0.035) but not overall survival. Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1; upregulated in ALS versus healthy controls) was proportional to disability progression rate (Pearson r = 0.53, FDR-adjusted p = 0.003) and survival (Kaplan Meier log-rank p = 0.013) but not independently in multivariate proportional hazards models. Weighted correlation network analysis was used to identify functionally relevant modules of proteins. One module, enriched for inflammatory functions, was associated with age at symptom onset (Pearson r = 0.58, FDR-adjusted p = 0.005) and survival (Hazard Ratio = 1.78, FDR = 0.065), and a second module, enriched for endoplasmic reticulum proteins, was negatively correlated with disability progression rate (r = -0.42, FDR-adjusted p = 0.109). DIA acquisition methodology therefore strengthened the biomarker candidacy of CHIT1 and UCHL1 in ALS, while additionally highlighted inflammatory and endoplasmic reticulum proteins as novel sources of prognostic biomarkers.}, } @article {pmid38087950, year = {2024}, author = {Metzger, M and Dukic, S and McMackin, R and Giglia, E and Mitchell, M and Bista, S and Costello, E and Peelo, C and Tadjine, Y and Sirenko, V and Plaitano, S and Coffey, A and McManus, L and Farnell Sharp, A and Mehra, P and Heverin, M and Bede, P and Muthuraman, M and Pender, N and Hardiman, O and Nasseroleslami, B}, title = {Functional network dynamics revealed by EEG microstates reflect cognitive decline in amyotrophic lateral sclerosis.}, journal = {Human brain mapping}, volume = {45}, number = {1}, pages = {e26536}, pmid = {38087950}, issn = {1097-0193}, support = {/WT_/Wellcome Trust/United Kingdom ; 16/ERCD/3854/SFI_/Science Foundation Ireland/Ireland ; URF\R1\221917/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Electroencephalography ; Retrospective Studies ; Brain ; Brain Mapping ; *Cognitive Dysfunction/etiology ; }, abstract = {Recent electroencephalography (EEG) studies have shown that patterns of brain activity can be used to differentiate amyotrophic lateral sclerosis (ALS) and control groups. These differences can be interrogated by examining EEG microstates, which are distinct, reoccurring topographies of the scalp's electrical potentials. Quantifying the temporal properties of the four canonical microstates can elucidate how the dynamics of functional brain networks are altered in neurological conditions. Here we have analysed the properties of microstates to detect and quantify signal-based abnormality in ALS. High-density resting-state EEG data from 129 people with ALS and 78 HC were recorded longitudinally over a 24-month period. EEG topographies were extracted at instances of peak global field power to identify four microstate classes (labelled A-D) using K-means clustering. Each EEG topography was retrospectively associated with a microstate class based on global map dissimilarity. Changes in microstate properties over the course of the disease were assessed in people with ALS and compared with changes in clinical scores. The topographies of microstate classes remained consistent across participants and conditions. Differences were observed in coverage, occurrence, duration, and transition probabilities between ALS and control groups. The duration of microstate class B and coverage of microstate class C correlated with lower limb functional decline. The transition probabilities A to D, C to B and C to B also correlated with cognitive decline (total ECAS) in those with cognitive and behavioural impairments. Microstate characteristics also significantly changed over the course of the disease. Examining the temporal dependencies in the sequences of microstates revealed that the symmetry and stationarity of transition matrices were increased in people with late-stage ALS. These alterations in the properties of EEG microstates in ALS may reflect abnormalities within the sensory network and higher-order networks. Microstate properties could also prospectively predict symptom progression in those with cognitive impairments.}, } @article {pmid38088823, year = {2023}, author = {Hannan, AJ}, title = {Expanding horizons of tandem repeats in biology and medicine: Why 'genomic dark matter' matters.}, journal = {Emerging topics in life sciences}, volume = {7}, number = {3}, pages = {239-247}, pmid = {38088823}, issn = {2397-8554}, abstract = {Approximately half of the human genome includes repetitive sequences, and these DNA sequences (as well as their transcribed repetitive RNA and translated amino-acid repeat sequences) are known as the repeatome. Within this repeatome there are a couple of million tandem repeats, dispersed throughout the genome. These tandem repeats have been estimated to constitute ∼8% of the entire human genome. These tandem repeats can be located throughout exons, introns and intergenic regions, thus potentially affecting the structure and function of tandemly repetitive DNA, RNA and protein sequences. Over more than three decades, more than 60 monogenic human disorders have been found to be caused by tandem-repeat mutations. These monogenic tandem-repeat disorders include Huntington's disease, a variety of ataxias, amyotrophic lateral sclerosis and frontotemporal dementia, as well as many other neurodegenerative diseases. Furthermore, tandem-repeat disorders can include fragile X syndrome, related fragile X disorders, as well as other neurological and psychiatric disorders. However, these monogenic tandem-repeat disorders, which were discovered via their dominant or recessive modes of inheritance, may represent the 'tip of the iceberg' with respect to tandem-repeat contributions to human disorders. A previous proposal that tandem repeats may contribute to the 'missing heritability' of various common polygenic human disorders has recently been supported by a variety of new evidence. This includes genome-wide studies that associate tandem-repeat mutations with autism, schizophrenia, Parkinson's disease and various types of cancers. In this article, I will discuss how tandem-repeat mutations and polymorphisms could contribute to a wide range of common disorders, along with some of the many major challenges of tandem-repeat biology and medicine. Finally, I will discuss the potential of tandem repeats to be therapeutically targeted, so as to prevent and treat an expanding range of human disorders.}, } @article {pmid38090276, year = {2023}, author = {}, title = {Correction to: Urinary biomarkers for amyotrophic lateral sclerosis: candidates, opportunities and considerations.}, journal = {Brain communications}, volume = {5}, number = {6}, pages = {fcad334}, doi = {10.1093/braincomms/fcad334}, pmid = {38090276}, issn = {2632-1297}, abstract = {[This corrects the article DOI: 10.1093/braincomms/fcad287.].}, } @article {pmid38090405, year = {2023}, author = {Gupta, D and Vagha, S and Dhingra, H and Shirsath, H}, title = {Advances in Understanding and Treating Amyotrophic Lateral Sclerosis (ALS): A Comprehensive Review.}, journal = {Cureus}, volume = {15}, number = {11}, pages = {e48691}, pmid = {38090405}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a deadly CNS neurodegenerative disease. The way ALS is now managed, from diagnosis to prognosis, is still not ideal despite many studies. Early diagnosis can help ALS patients live longer since prompt treatment can halt the disease's development. Two medications, riluzole and edaravone, have recently been licensed for use in therapy, and they very slightly increase life expectancy. Still, a lot of cutting-edge experimental medications are being developed. In the following article, we give a synopsis of the innovative medications and genetic remodeling that have emerged recently and help to halt the course of the illness. Studies have also been conducted on a few symptomatic and rehabilitative therapies that enhance the quality of life for ALS patients.}, } @article {pmid38090719, year = {2023}, author = {Brusati, A and Peverelli, S and Calzari, L and Tiloca, C and Casiraghi, V and Sorce, MN and Invernizzi, S and Carbone, E and Cavagnola, R and Verde, F and Silani, V and Ticozzi, N and Ratti, A and Gentilini, D}, title = {Exploring epigenetic drift and rare epivariations in amyotrophic lateral sclerosis by epigenome-wide association study.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1272135}, pmid = {38090719}, issn = {1663-4365}, abstract = {During the last decades, our knowledge about the genetic architecture of sporadic amyotrophic lateral sclerosis (sALS) has significantly increased. However, besides the recognized genetic risk factors, also the environment is supposed to have a role in disease pathogenesis. Epigenetic modifications reflect the results of the interaction between environmental factors and genes and may play a role in the development and progression of ALS. A recent epigenome-wide association study (EWAS) in blood identified differentially methylated positions mapping to 42 genes involved in cholesterol biosynthesis and immune-related pathways. Here we performed a genome-wide DNA methylation analysis in the blood of an Italian cohort of 61 sALS patients and 61 healthy controls. Initially, a conventional genome-wide association analysis was performed, and results were subsequently integrated with the findings from the previous EWAS using a meta-analytical approach. To delve deeper into the significant outcomes, over-representation analysis (ORA) was employed. Moreover, the epigenetic signature obtained from the meta-analysis was examined to determine potential associations with chemical compounds, utilizing the Toxicogenomic Database. Expanding the scope of the epigenetic analysis, we explored both epigenetic drift and rare epivariations. Notably, we observed an elevated epigenetic drift in sALS patients compared to controls, both at a global and single gene level. Interestingly, epigenetic drift at a single gene level revealed an enrichment of genes related to the neurotrophin signaling pathway. Moreover, for the first time, we identified rare epivariations exclusively enriched in sALS cases associated with 153 genes, 88 of whom with a strong expression in cerebral areas. Overall, our study reinforces the evidence that epigenetics may contribute to the pathogenesis of ALS and that epigenetic drift may be a useful diagnostic marker. Moreover, this study suggests the potential role of epivariations in ALS.}, } @article {pmid38092270, year = {2024}, author = {Deng, C and Chen, H}, title = {Brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling in spinal muscular atrophy and amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {190}, number = {}, pages = {106377}, doi = {10.1016/j.nbd.2023.106377}, pmid = {38092270}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Brain-Derived Neurotrophic Factor ; Motor Neurons/physiology ; Tropomyosin ; *Muscular Atrophy, Spinal ; Receptor, trkB ; }, abstract = {Tropomyosin receptor kinase B (TrkB) and its primary ligand brain-derived neurotrophic factor (BDNF) are expressed in the neuromuscular system, where they affect neuronal survival, differentiation, and functions. Changes in BDNF levels and full-length TrkB (TrkB-FL) signaling have been revealed in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), two common forms of motor neuron diseases that are characterized by defective neuromuscular junctions in early disease stages and subsequently progressive muscle weakness. This review summarizes the current understanding of BDNF/TrkB-FL-related research in SMA and ALS, with an emphasis on their alterations in the neuromuscular system and possible BDNF/TrkB-FL-targeting therapeutic strategies. The limitations of current studies and future directions are also discussed, giving the hope of discovering novel and effective treatments.}, } @article {pmid38092667, year = {2024}, author = {Canosa, A and Cabras, S and Di Pede, F and Manera, U and Vasta, R and Moglia, C and Calvo, A and Gallone, S and Chiò, A}, title = {A mother and her daughter carrying a pathogenic expansion of the HTT gene with a phenotype encompassing motor neuron disease and Huntington's disease.}, journal = {Clinical genetics}, volume = {105}, number = {4}, pages = {430-433}, doi = {10.1111/cge.14472}, pmid = {38092667}, issn = {1399-0004}, support = {PRIN-2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; RF-2016-02362405//Ministero della Salute/ ; }, mesh = {Female ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Huntington Disease/genetics/pathology ; Mothers ; Nuclear Family ; *Frontotemporal Dementia ; *Motor Neuron Disease/genetics ; Phenotype ; Huntingtin Protein/genetics ; }, abstract = {Recently, pathogenic expansions (range 40-64 CAG repeats) in the HTT gene have been found in patients diagnosed with pure frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). We report a mother with Huntington's disease (HD) associated with motor neuron disease (MND) signs and her daughter suffering from ALS with subtle signs of HD, both carrying a pathogenic allele of the HTT gene (i.e., >39 repeats). The co-occurrence of MND and chorea has been reported in previous cases. Subjects showing both ALS and HD signs and carrying HTT pathogenic expansions in two generations of the same kindred have never been reported so far. The study of the overlap of disease mechanisms at the cellular level between TDP-43 and Huntingtin is relevant in an era offering promising strategies of targeted treatments in neurodegenerative disorders.}, } @article {pmid38092738, year = {2023}, author = {Raguseo, F and Wang, Y and Li, J and Petrić Howe, M and Balendra, R and Huyghebaert, A and Vadukul, DM and Tanase, DA and Maher, TE and Malouf, L and Rubio-Sánchez, R and Aprile, FA and Elani, Y and Patani, R and Di Michele, L and Di Antonio, M}, title = {The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {8272}, pmid = {38092738}, issn = {2041-1723}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; MR/S033947/1/MRC_/Medical Research Council/United Kingdom ; SGL027\1022/AMS_/Academy of Medical Sciences/United Kingdom ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; RNA/genetics/chemistry ; *G-Quadruplexes ; C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC)n in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC)n, which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions leads to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validate the biological relevance of our findings by detecting an increased prevalence of G4-structures in C9orf72 mutant human motor neurons when compared to healthy motor neurons by staining with a G4-selective fluorescent probe, revealing signal in putative condensates. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation-related ALS/FTD.}, } @article {pmid38092849, year = {2023}, author = {Ou, Y and Zhao, Y}, title = {On enhancing the noise-reduction performance of the acoustic lined duct utilizing the phase-modulating metasurface.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {22184}, pmid = {38092849}, issn = {2045-2322}, abstract = {This work proposes a noise-reduction structure that integrates phase-modulating metasurface (PMM) with acoustic liners (ALs) to enhance the narrow band absorption performance of a duct with relatively small length-diameter ratio. The PMM manipulates the wavefront by introducing different transmission phase shifts based on an array of Helmholtz resonators, so that the spinning wave within the duct can be generated. Compared with the plane wave, the generated spinning wave has a lower group velocity, which results in a greater traveling distance over the ALs in the duct. The optimization design is performed to determine the final structural parameters of the PMM, which is based on the predictions of the amplitude and phase shift of the acoustic wave at the outlet of the PMM using the theory of passive phased array. With the manipulation of the PMM, the incident plane wave is modulated into a spinning wave, and then enters into the acoustic liner duct (ALD), whose structural parameters are optimized by maximizing the transmission loss using the mode-matching technique. Finally, the noise-reduction performance of this combined structure is evaluated by numerical simulations in the presence of grazing flow. The results demonstrate that, compared with the traditional ALD, the proposed structure exhibits a significant increase in transmission loss within the considered frequency band, especially near the peak frequency of the narrow band noise.}, } @article {pmid38093132, year = {2023}, author = {Grigoriev, VV and Shevtsova, EF and Aksinenko, AY and Veselov, IM and Goreva, TV and Gabrelyan, AV and Bachurin, SO}, title = {New Hybrid Structures Based on Memanthine and Edaravone Molecules.}, journal = {Doklady. Biochemistry and biophysics}, volume = {512}, number = {1}, pages = {284-287}, pmid = {38093132}, issn = {1608-3091}, mesh = {*Memantine/pharmacology/chemistry ; Edaravone ; Receptors, N-Methyl-D-Aspartate ; *Adamantane/pharmacology ; }, abstract = {New hybrid structures based on memantine and edaravone molecules, in which the pyrazolone ring and adamantane fragments are linked by an alkyl linker, were synthesized. It was found that, in addition to the ability to block the intrachannel site of NMDA receptors, the new hybrid compounds exhibit the property of blockers of the allosteric site of NMDA receptors, which is not inherent in memantine and edaravone preparations. The most active hit compound was determined, which, along with the properties of a two-site blocker of the NMDA receptor, exhibits a pronounced activity as an inhibitor of lipid peroxidation, similarly to the drug edaravone.}, } @article {pmid38093670, year = {2024}, author = {Oliveira Santos, M and Swash, M and de Carvalho, M}, title = {Current challenges in primary lateral sclerosis diagnosis.}, journal = {Expert review of neurotherapeutics}, volume = {24}, number = {1}, pages = {45-53}, doi = {10.1080/14737175.2023.2295010}, pmid = {38093670}, issn = {1744-8360}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis ; *Motor Neuron Disease/diagnosis ; Neuroimaging ; Diagnosis, Differential ; Biomarkers ; Multicenter Studies as Topic ; }, abstract = {INTRODUCTION: Primary lateral sclerosis (PLS) is a rare, adult-onset and slowly progressive motor neuron disorder whose clinical core is characterized by upper motor neuron (UMN) dysfunction. Its formal diagnosis is clinically based and disease duration-dependent. Differentiating PLS from other disorders involving UMN can be challenging, particularly in the early stages.

AREAS COVERED: Our review covers and discusses different aspects of the PLS field, including the diagnostic criteria and its limitations, its differential diagnosis and their major pitfalls, and the actual role of neurophysiology, neuroimaging, genetics, and molecular biomarkers. Symptomatic treatment of the different manifestations is also addressed. The authors searched MEDLINE and Scopus. They also searched the reference lists of articles identified by our search strategy and reviewed and selected those deemed relevant. They selected papers and studies based on the quality of the report, significance of the findings, and on the author's critical appraise and expertise.

EXPERT OPINION: It is important to investigate novel molecular biomarkers and plan multicenter clinical trials for PLS. However, this will require a large international project to recruit enough patients, particularly given the diagnostic uncertainty of the current clinical criteria. A better understanding of PLS pathophysiology is crucial for designing disease-targeted therapies.}, } @article {pmid38094423, year = {2023}, author = {Methods In Medicine, CAM}, title = {Retracted: Amyotrophic Lateral Sclerosis Symptom Score in Integrative Treatments (ALS-SSIT) for Evaluating Therapeutic Effect of Traditional Chinese Medicine: A Prospective Study.}, journal = {Computational and mathematical methods in medicine}, volume = {2023}, number = {}, pages = {9763080}, pmid = {38094423}, issn = {1748-6718}, abstract = {[This retracts the article DOI: 10.1155/2022/7594481.].}, } @article {pmid38096601, year = {2024}, author = {Chiba, K and Niwa, S}, title = {Autoinhibition and activation of kinesin-1 and their involvement in amyotrophic lateral sclerosis.}, journal = {Current opinion in cell biology}, volume = {86}, number = {}, pages = {102301}, doi = {10.1016/j.ceb.2023.102301}, pmid = {38096601}, issn = {1879-0410}, mesh = {Humans ; *Kinesins/metabolism ; *Amyotrophic Lateral Sclerosis ; Neurons/metabolism ; Biological Transport ; }, abstract = {Kinesin-1, composed of kinesin heavy chain and kinesin light chain, is a founding member of kinesin superfamily and transports various neuronal cargos. Kinesin-1 is one of the most abundant ATPases in the cell and thus need to be tightly regulated to avoid wastage of energy. It has been well established that kinesin-1 is regulated by the autoinhibition mechanism. This review focuses on the recent researches that have contributed to the understanding of mechanisms for the autoinhibition of kinesin-1 and its unlocking. Recent electron microscopic studies have shown an unanticipated structure of autoinhibited kinesin-1. Biochemical reconstitution have revealed detailed molecular mechanisms how the autoinhibition is unlocked. Importantly, misregulation of kinesin-1 is emerging as one of the major causes of amyotrophic lateral sclerosis.}, } @article {pmid38096766, year = {2024}, author = {Arslan, BT and Görkem Özyurt, M and İşak, B and Cecen, S and Türker, KS}, title = {Single motor unit estimation of the cutaneous silent period in ALS.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {157}, number = {}, pages = {110-119}, doi = {10.1016/j.clinph.2023.11.013}, pmid = {38096766}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Motor Neurons/physiology ; Electromyography/methods ; Spine ; }, abstract = {OBJECTIVE: Recent evidence indicated that amyotrophic lateral sclerosis (ALS) also impairs spinal circuits, including those mediating cutaneous silent period (CSP). However, most studies utilised surface electromyography (sEMG), which needs more resolution to pinpoint changes at the single motoneuron level. We aimed to investigate CSP properties using single motor unit discharges in ALS.

METHODS: In mild and severe ALS patients and controls, CSP was recorded in the first dorsal interosseus and analysed using the discharge rate method, which accurately shows the inhibitory postsynaptic potentials (IPSPs) profile.

RESULTS: Our findings confirmed that the CSP latency was prolonged only in severe ALS patients. Moreover, the CSP duration was similar in each group, but late-stage ALS patients tend to have a longer CSP duration. The discharge rate method revealed a significantly longer duration (up to 150 ms) than the duration detected using sEMG. Strikingly, the motoneuron discharge rate - IPSP duration inverse relationship is lost in ALS patients, indicating a possible impairment in the motoneuron integrative properties.

CONCLUSIONS: Our data support previous findings of prolonged latency, presented input-output modifications of motoneurons, and revealed the entire course of the CSP, representing a much stronger inhibitory event than previously thought.

SIGNIFICANCE: Motoneuron integrative property modification assessed by CSP could be a new biomarker for ALS.}, } @article {pmid38097227, year = {2023}, author = {Ebihara, S and Katsumata, T and Park, U}, title = {[Rehabilitation for Amyotrophic Lateral Sclerosis and ALS clinic].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {75}, number = {12}, pages = {1349-1353}, doi = {10.11477/mf.1416202539}, pmid = {38097227}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Exercise Therapy ; *Medicine ; }, abstract = {The dysfunctions of amyotrophic lateral sclerosis (ALS) are highly variable. Rehabilitation medicine for movement disorders differs in accordance with the degree of severity. Exercise therapy should be performed while the disease is mild, with compensatory training increasing as the severity increases. Exercise therapy with a Hybrid Assistive Limb®(HAL®) is generally thought to preserve lower extremity function compared to those without HAL®. The mechanism may be effective on disused muscle fibers. ALS clinic may improve the prognosis of ALS patients.}, } @article {pmid38097540, year = {2023}, author = {Ikeda, T and Takahashi, K and Higashi, M and Komiya, H and Asano, T and Ogasawara, A and Kubota, S and Hashiguchi, S and Kunii, M and Tanaka, K and Tada, M and Doi, H and Takeuchi, H and Takei, K and Tanaka, F}, title = {Lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor antagonist, ameliorates disease progression in amyotrophic lateral sclerosis model mice.}, journal = {Cell death discovery}, volume = {9}, number = {1}, pages = {454}, pmid = {38097540}, issn = {2058-7716}, support = {17H03561//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 18K07532//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 20H03342//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 20K07761//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; }, abstract = {Nogo-Nogo receptor 1 (NgR1) signaling is significantly implicated in neurodegeneration in amyotrophic lateral sclerosis (ALS). We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of NgR1 that prevents all myelin-associated inhibitors (MAIs), including Nogo, from binding to NgR1. Here we investigated the role of LOTUS in ALS pathogenesis by analyzing G93A-mutated human superoxide dismutase 1 (SOD1) transgenic (Tg) mice, as an ALS model, as well as newly generated LOTUS-overexpressing SOD1 Tg mice. We examined expression profiles of LOTUS and MAIs and compared motor functions and survival periods in these mice. We also investigated motor neuron survival, glial proliferation in the lumbar spinal cord, and neuromuscular junction (NMJ) morphology. We analyzed downstream molecules of NgR1 signaling such as ROCK2, LIMK1, cofilin, and ataxin-2, and also neurotrophins. In addition, we investigated LOTUS protein levels in the ventral horn of ALS patients. We found significantly decreased LOTUS expression in both SOD1 Tg mice and ALS patients. LOTUS overexpression in SOD1 Tg mice increased lifespan and improved motor function, in association with prevention of motor neuron loss, reduced gliosis, increased NMJ innervation, maintenance of cofilin phosphorylation dynamics, decreased levels of ataxin-2, and increased levels of brain-derived neurotrophic factor (BDNF). Reduced LOTUS expression may enhance neurodegeneration in SOD1 Tg mice and ALS patients by activating NgR1 signaling, and in this study LOTUS overexpression significantly ameliorated ALS pathogenesis. LOTUS might serve as a promising therapeutic target for ALS.}, } @article {pmid38097873, year = {2024}, author = {Seo, J and Saurkar, S and Fernandez, GS and Das, A and Goutman, SA and Heidenreich, S}, title = {Preferences of Patients with Amyotrophic Lateral Sclerosis for Intrathecal Drug Delivery: Choosing between an Implanted Drug-Delivery Device and Therapeutic Lumbar Puncture.}, journal = {The patient}, volume = {17}, number = {2}, pages = {161-177}, pmid = {38097873}, issn = {1178-1661}, mesh = {Humans ; Middle Aged ; *Choice Behavior ; *Amyotrophic Lateral Sclerosis/drug therapy ; Spinal Puncture/adverse effects ; Patient Preference ; Europe ; }, abstract = {BACKGROUND: Novel intrathecal treatments for amyotrophic lateral sclerosis (ALS) may require delivery using lumbar puncture (LP). Implanted drug-delivery devices (IDDDs) could be an alternative but little is known about patients' preferences for intrathecal drug-delivery methods.

OBJECTIVE: We aimed to elicit preferences of patients with ALS for routine LP and IDDD use.

METHODS: A discrete choice experiment (DCE) and a threshold technique (TT) exercise were conducted online among patients with ALS in the US and Europe. In the DCE, patients made trade-offs between administration attributes. Attributes were identified from qualitative interviews. The TT elicited maximum acceptable risks (MARs) of complications from device implantation surgery. DCE data were analyzed using mixed logit to quantify relative attribute importance (RAI) as the maximum contribution of each attribute to a preference, and to estimate MARs of device failure. TT data were analyzed using interval regression. Four scenarios of LP and IDDD were compared.

RESULTS: Participants (N = 295) had a mean age of 57.7 years; most (74.2%) were diagnosed < 3 years ago. Preferences were affected by device failure risk (RAI 28.6%), administration frequency (26.4%), administration risk (19.7%), overall duration (17.8%), and appointment location (7.5%). Patients accepted a 5.6% device failure risk to reduce overall duration from 2 h to 30 min and a 3.6% risk for administration in a local clinic instead of a hospital. The average MAR of complications from implantation surgery was 29%. Patients preferred IDDD over LP in three of four scenarios.

CONCLUSION: Patients considered an IDDD as a valuable alternative to LP in multiple clinical settings.}, } @article {pmid38099605, year = {2024}, author = {Peverelli, S and Brusati, A and Casiraghi, V and Sorce, MN and Invernizzi, S and Santangelo, S and Morelli, C and Verde, F and Silani, V and Ticozzi, N and Ratti, A}, title = {Analysis of normal C9orf72 repeat length as possible disease modifier in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {207-210}, doi = {10.1080/21678421.2023.2273965}, pmid = {38099605}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; DNA Repeat Expansion/genetics ; C9orf72 Protein/genetics ; Mutation/genetics ; Genotype ; }, abstract = {The C9orf72 hexanucleotide repeat (HR) expansion is the main genetic cause of amyotrophic lateral sclerosis (ALS), with expansion size from 30 to >4000 units. Normal C9orf72 HR length is polymorphic (2-23 repeats) with alleles >8 units showing a low frequency in the general population. This study aimed to investigate if the normal C9orf72 HR length influences C9orf72 gene expression and acts as disease modifier in ALS patients negative for C9orf72 mutation (ALS-C9Neg). We found that the distribution of HR alleles was similar in 325 ALS-C9Neg and 303 healthy controls. Gene expression analysis in blood revealed a significant increase of total C9orf72 and V3 mRNA levels in ALS-C9Neg carrying two long alleles (L/L; ≥8 units) compared to patients homozygous for the 2-unit short allele (S/S). However, HR allele genotypes (L/L, S/L, S/S) correlated with no clinical parameters. Our data suggest that normal C9orf72 HR length does not act as disease modifier in ALS-C9Neg despite increasing gene expression.}, } @article {pmid38099851, year = {2024}, author = {Rong, P and Heidrick, L}, title = {Hierarchical Temporal Structuring of Speech: A Multiscale, Multimodal Framework to Inform the Assessment and Management of Neuromotor Speech Disorder.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {1}, pages = {92-115}, doi = {10.1044/2023_JSLHR-23-00219}, pmid = {38099851}, issn = {1558-9102}, mesh = {Humans ; *Speech ; Speech Intelligibility ; *Amyotrophic Lateral Sclerosis/complications ; Jaw ; Speech Disorders ; Speech Production Measurement ; Tongue ; Speech Acoustics ; }, abstract = {PURPOSE: Hierarchical temporal structuring of speech is the key to multiscale linguistic information transfer toward effective communication. This study investigated and linked the hierarchical temporal cues of the kinematic and acoustic modalities of natural, unscripted speech in neurologically healthy and impaired speakers.

METHOD: Thirteen individuals with amyotrophic lateral sclerosis (ALS) and 10 age-matched healthy controls performed a story-telling task. The hierarchical temporal structure of the speech stimulus was measured by (a) 26 articulatory-kinematic features characterizing the depth, phase synchronization, and coherence of temporal modulation of the tongue tip, tongue body, lower lip, and jaw, at three hierarchically nested timescales corresponding to prosodic stress, syllables, and onset-rime/phonemes, and (b) 25 acoustic features characterizing the parallel aspects of temporal modulation of five critical-spectral-band envelopes. All features were compared between groups. For each aspect of temporal modulation, the contributions of all articulatory features to the parallel acoustic features were evaluated by group.

RESULTS: Generally consistent disease impacts were identified on the articulatory and acoustic features, manifested by reduced modulation depths of most articulators and critical-spectral-band envelopes, primarily at the timescales of syllables and onset-rime/phonemes. For healthy speakers, the strongest articulatory-acoustic relationships were found for (a) jaw and lip, in modulating stress timing, and (b) tongue tip, in modulating the timing relation between onset-rime/phonemes and syllables. For speakers with ALS, the tongue body, tongue tip, and jaw all showed the greatest contributions to modulating syllable timing.

CONCLUSIONS: The observed disease impacts likely reflect reduced entrainment of speech motor activities to finer-grained linguistic events, presumably due to the dynamic constraints of the neuromuscular system. To accommodate these restrictions, speakers with ALS appear to use their residual articulatory motor capacities to accentuate and convey the perceptually most salient temporal cues underpinned by the syllable-centric parsing mechanism. This adaptive strategy has potential implications in managing neuromotor speech disorders.}, } @article {pmid38100267, year = {2024}, author = {Qi, S and Peng, Y and Wang, G and Zhang, X and Liu, M and He, L}, title = {A tale of dual functions of SERF family proteins in regulating amyloid formation.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {25}, number = {5}, pages = {e202300727}, doi = {10.1002/cbic.202300727}, pmid = {38100267}, issn = {1439-7633}, support = {2018YFE0202301//National Key R&D Program of China/ ; 2018YFE0202300//National Key R&D Program of China/ ; 22174151//National Natural Sciences Foundation of China/ ; 21991080//National Natural Sciences Foundation of China/ ; XDB0540000//Strategic Priority Research Program of the Chinese Academy of Sciences/ ; 2023AFA041//Hubei Provincial Natural Science Foundation of China/ ; }, mesh = {Animals ; Caenorhabditis elegans ; *Neurodegenerative Diseases ; Amyloidogenic Proteins ; Amyloid beta-Peptides ; *Alzheimer Disease ; *Caenorhabditis elegans Proteins ; }, abstract = {The abnormal aggregation of proteins is a significant pathological hallmark of diseases, such as the amyloid formation associated with fused in sarcoma protein (FUS) in frontotemporal lobar degeneration and amyotrophic lateral sclerosis diseases. Understanding which cellular components and how these components regulate the process of abnormal protein aggregation in living organisms is crucial for the prevention and treatment of neurodegenerative diseases. MOAG-4/SERF is a conserved family of proteins with rich positive charged residues, which was initially identified as an enhancer for the formation of amyloids in C. elegans. Knocking out SERF impedes the amyloid formation of various proteins, including α-synuclein and β-amyloid, which are linked to Parkinson's and Alzheimer's diseases, respectively. However, recent studies revealed SERF exhibited dual functions, as it could both promote and inhibit the fibril formation of the neurodegenerative disease-related amyloidogenic proteins. The connection between functions and structure basis of SERF in regulating the amyloid formation is still unclear. This review will outline the hallmark proteins in neurodegenerative diseases, summarize the contradictory role of the SERF protein family in promoting and inhibiting the aggregation of neurodegenerative proteins, and finally explore the potential structural basis and functional selectivity of the SERF protein.}, } @article {pmid38100415, year = {2023}, author = {Qi, C and Verheijen, BM and Kokubo, Y and Shi, Y and Tetter, S and Murzin, AG and Nakahara, A and Morimoto, S and Vermulst, M and Sasaki, R and Aronica, E and Hirokawa, Y and Oyanagi, K and Kakita, A and Ryskeldi-Falcon, B and Yoshida, M and Hasegawa, M and Scheres, SHW and Goedert, M}, title = {Tau filaments from amyotrophic lateral sclerosis/parkinsonism-dementia complex adopt the CTE fold.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {51}, pages = {e2306767120}, pmid = {38100415}, issn = {1091-6490}, support = {MC_UP_1201/25/MRC_/Medical Research Council/United Kingdom ; MC_U105184291/MRC_/Medical Research Council/United Kingdom ; R01 AG054641/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; MC_UP_A025_1013/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Dementia/etiology ; *Chronic Traumatic Encephalopathy ; *Neurodegenerative Diseases ; *Parkinsonian Disorders/complications ; *Tauopathies ; Japan ; tau Proteins ; }, abstract = {The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterized by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here, we used electron cryo-microscopy to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in three Kii cases and tau filaments with the corticobasal degeneration fold in one Kii case. We identified a new Type III CTE tau filament, where protofilaments pack against each other in an antiparallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.}, } @article {pmid38101818, year = {2024}, author = {Ryan, L and Rubinsztein, DC}, title = {The autophagy of stress granules.}, journal = {FEBS letters}, volume = {598}, number = {1}, pages = {59-72}, doi = {10.1002/1873-3468.14787}, pmid = {38101818}, issn = {1873-3468}, support = {//Raymond and Beverly Sackler Fund/ ; NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; //UK Dementia Research Institute/ ; }, mesh = {Humans ; *Stress Granules ; Proteins ; Autophagy ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Our understanding of stress granule (SG) biology has deepened considerably in recent years, and with this, increased understanding of links has been made between SGs and numerous neurodegenerative diseases. One of the proposed mechanisms by which SGs and any associated protein aggregates may become pathological is based upon defects in their autophagic clearance, and so the precise processes governing the degradation of SGs are important to understand. Mutations and disease-associated variants implicated in amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and frontotemporal lobar dementia compromise autophagy, whilst autophagy-inhibiting drugs or knockdown of essential autophagy proteins result in the persistence of SGs. In this review, we will consider the current knowledge regarding the autophagy of SG.}, } @article {pmid38102515, year = {2024}, author = {Shen, D and Ji, Y and Qiu, C and Wang, K and Gao, Z and Liu, B and Shen, Y and Gong, L and Yang, X and Chen, X and Sun, H and Yao, X}, title = {Single-Cell RNA Sequencing Analysis of Microglia Dissected the Energy Metabolism and Revealed Potential Biomarkers in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {61}, number = {7}, pages = {4473-4487}, pmid = {38102515}, issn = {1559-1182}, support = {92068112//National Natural Science Foundation of China/ ; 82072160//National Natural Science Foundation of China/ ; 32130060//National Natural Science Foundation of China/ ; 81901933//National Natural Science Foundation of China/ ; 20KJA310012//Major Natural Science Research Projects in Universities of Jiangsu Province/ ; BK20202013//Natural Science Foundation of Jiangsu Province/ ; BK20201209//Natural Science Foundation of Jiangsu Province/ ; JC22022037//Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; MS22022010//Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Microglia/metabolism/pathology ; Animals ; *Energy Metabolism/genetics ; Humans ; *Biomarkers/metabolism ; *Single-Cell Analysis ; Sequence Analysis, RNA/methods ; Mice ; Mice, Transgenic ; Male ; Superoxide Dismutase-1/genetics/metabolism ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease, accompanied by the gradual loss of motor neuron, even life-threatening. However, the pathogenesis, early diagnosis, and effective strategies of ALS are not yet completely understood. In this study, the function of differentially expressed genes (DEGs) in non-neuronal cells of the primary motor cortex of ALS patients (DATA1), the brainstem of SOD1 mutant ALS mice (DATA2), and the whole blood tissue of ALS patients (DATA3) were explored. The results showed that the functions of DEGs in non-neuronal cells were mainly related to energy metabolism (such as oxidative phosphorylation) and protein synthesis. In non-neuronal cells, six upregulated DEGs (HSPA8, SOD1, CALM1, CALM2, NEFL, COX6C) and three downregulated DEGs (SNRNP70, HSPA1A, HSPA1B) might be key factors in regulating ALS. Microglia played a key role in the development of ALS. The expression of SOD1 and TUBA4A in microglia in DATA1 was significantly increased. The integration analysis of DEGs in DATA1 and DATA2 showed that SOD1 and CALM1 might be potential biomarkers. The integration analysis of DEGs in DATA1 and DATA3 showed that CALM2 and HSPA1A might be potential biomarkers. Cell interaction showed that the interaction between microglia and other cells was reduced in high oxidative phosphorylation states, which might be a risk factor in ALS. Our research provided evidence for the pathogenesis, early diagnosis, and potential targeted therapy for ALS.}, } @article {pmid38102715, year = {2023}, author = {Stringer, RN and Weiss, N}, title = {Pathophysiology of ion channels in amyotrophic lateral sclerosis.}, journal = {Molecular brain}, volume = {16}, number = {1}, pages = {82}, pmid = {38102715}, issn = {1756-6606}, support = {#22-23242S//Grantová Agentura České Republiky/ ; VEGA #2/0073/22//Agentúra Ministerstva Školstva, Vedy, Výskumu a Športu SR/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Motor Neurons ; Ion Channels ; Muscle Weakness ; }, abstract = {Amyotrophic lateral sclerosis (ALS) stands as the most prevalent and severe form of motor neuron disease, affecting an estimated 2 in 100,000 individuals worldwide. It is characterized by the progressive loss of cortical, brainstem, and spinal motor neurons, ultimately resulting in muscle weakness and death. Although the etiology of ALS remains poorly understood in most cases, the remodelling of ion channels and alteration in neuronal excitability represent a hallmark of the disease, manifesting not only during the symptomatic period but also in the early pre-symptomatic stages. In this review, we delve into these alterations observed in ALS patients and preclinical disease models, and explore their consequences on neuronal activities. Furthermore, we discuss the potential of ion channels as therapeutic targets in the context of ALS.}, } @article {pmid38103074, year = {2023}, author = {Villavicencio-Tejo, F and Olesen, MA and Navarro, L and Calisto, N and Iribarren, C and García, K and Corsini, G and Quintanilla, RA}, title = {Gut-Brain Axis Deregulation and Its Possible Contribution to Neurodegenerative Disorders.}, journal = {Neurotoxicity research}, volume = {42}, number = {1}, pages = {4}, pmid = {38103074}, issn = {1476-3524}, support = {1200178//Agencia Nacional de Investigación y Desarrollo/ ; }, mesh = {Animals ; Humans ; Brain-Gut Axis ; *Amyotrophic Lateral Sclerosis ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/pathology ; Central Nervous System ; *Parkinson Disease/pathology ; *Huntington Disease/pathology ; *Alzheimer Disease ; }, abstract = {The gut-brain axis is an essential communication pathway between the central nervous system (CNS) and the gastrointestinal tract. The human microbiota is composed of a diverse and abundant microbial community that compasses more than 100 trillion microorganisms that participate in relevant physiological functions such as host nutrient metabolism, structural integrity, maintenance of the gut mucosal barrier, and immunomodulation. Recent evidence in animal models has been instrumental in demonstrating the possible role of the microbiota in neurodevelopment, neuroinflammation, and behavior. Furthermore, clinical studies suggested that adverse changes in the microbiota can be considered a susceptibility factor for neurological disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). In this review, we will discuss evidence describing the role of gut microbes in health and disease as a relevant risk factor in the pathogenesis of neurodegenerative disorders, including AD, PD, HD, and ALS.}, } @article {pmid38103219, year = {2024}, author = {Ma, S and Zhang, CL}, title = {MAP4K inhibition as a potential therapy for amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {8}, pages = {1639-1640}, pmid = {38103219}, issn = {1673-5374}, support = {R01 NS092616/NS/NINDS NIH HHS/United States ; R01 NS111776/NS/NINDS NIH HHS/United States ; R01 NS117065/NS/NINDS NIH HHS/United States ; R01 NS127375/NS/NINDS NIH HHS/United States ; }, } @article {pmid38103252, year = {2024}, author = {He, L and Zhou, Q and Xiu, C and Shao, Y and Shen, D and Meng, H and Le, W and Chen, S}, title = {Circulating proteomic biomarkers for diagnosing sporadic amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {Neural regeneration research}, volume = {19}, number = {8}, pages = {1842-1848}, pmid = {38103252}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202408000-00039/figure1/v/2023-12-16T180322Z/r/image-tiff Biomarkers are required for the early detection, prognosis prediction, and monitoring of amyotrophic lateral sclerosis, a progressive disease. Proteomics is an unbiased and quantitative method that can be used to detect neurochemical signatures to aid in the identification of candidate biomarkers. In this study, we used a label-free quantitative proteomics approach to screen for substantially differentially regulated proteins in ten patients with sporadic amyotrophic lateral sclerosis compared with five healthy controls. Substantial upregulation of serum proteins related to multiple functional clusters was observed in patients with sporadic amyotrophic lateral sclerosis. Potential biomarkers were selected based on functionality and expression specificity. To validate the proteomics profiles, blood samples from an additional cohort comprising 100 patients with sporadic amyotrophic lateral sclerosis and 100 healthy controls were subjected to enzyme-linked immunosorbent assay. Eight substantially upregulated serum proteins in patients with sporadic amyotrophic lateral sclerosis were selected, of which the cathelicidin-related antimicrobial peptide demonstrated the best discriminative ability between patients with sporadic amyotrophic lateral sclerosis and healthy controls (area under the curve [AUC] = 0.713, P < 0.0001). To further enhance diagnostic accuracy, a multi-protein combined discriminant algorithm was developed incorporating five proteins (hemoglobin beta, cathelicidin-related antimicrobial peptide, talin-1, zyxin, and translationally-controlled tumor protein). The algorithm achieved an AUC of 0.811 and a P-value of < 0.0001, resulting in 79% sensitivity and 71% specificity for the diagnosis of sporadic amyotrophic lateral sclerosis. Subsequently, the ability of candidate biomarkers to discriminate between early-stage amyotrophic lateral sclerosis patients and controls, as well as patients with different disease severities, was examined. A two-protein panel comprising talin-1 and translationally-controlled tumor protein effectively distinguished early-stage amyotrophic lateral sclerosis patients from controls (AUC = 0.766, P < 0.0001). Moreover, the expression of three proteins (FK506 binding protein 1A, cathelicidin-related antimicrobial peptide, and hemoglobin beta-1) was found to increase with disease progression. The proteomic signatures developed in this study may help facilitate early diagnosis and monitor the progression of sporadic amyotrophic lateral sclerosis when used in combination with current clinical-based parameters.}, } @article {pmid38105306, year = {2024}, author = {Katerelos, A and Alexopoulos, P and Economou, P and Polychronopoulos, P and Chroni, E}, title = {Cognitive function in amyotrophic lateral sclerosis: a cross-sectional and prospective pragmatic clinical study with review of the literature.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {2075-2085}, pmid = {38105306}, issn = {1590-3478}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Cognition Disorders/etiology/complications ; Neuropsychological Tests ; Prospective Studies ; Quality of Life ; Cross-Sectional Studies ; Cognition/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) can present with either bulbar or spinal symptoms, and in some cases, both types of symptoms may be present. In addition, cognitive impairment has been observed in ALS. The study aimed to evaluate the frontal and general cognitive performance in ALS not only cross-sectionally but also longitudinally.

METHODS AND MATERIALS: The Frontal Assessment Battery (FAB) and the Montreal Cognitive Assessment (MoCA) were employed to assess cognitive function in 52 adults with ALS and 52 cognitively healthy individuals. The statistical analyses encompassed the Pearson Chi square test, the Skillings-Mack test, the Spearman's rank correlation coefficient, and the Proportional Odds Logistic Regression Model (POLR).

RESULTS: Cross-sectionally, lower cognitive performance was associated with ALS diagnosis, older age, and motor functional decline. The cognitive impairment of individuals with bulbar and spinal-bulbar symptoms showed faster deterioration compared to those with spinal symptoms. The spinal subgroup consistently performed worst in delayed recall and attention, while the spinal-bulbar and bulbar subgroups exhibited inferior scores in delayed recall, attention, visuospatial skills, orientation, and verbal fluency.

CONCLUSION: The incorporation of cognitive screening in the diagnostic workup of ALS may be beneficial, as early detection can enhance symptom management and improve the quality of life for both individuals with ALS and their care partners.}, } @article {pmid38105307, year = {2024}, author = {Hamad, AA and Amer, BE and Hawas, Y and Mabrouk, MA and Meshref, M}, title = {Masitinib as a neuroprotective agent: a scoping review of preclinical and clinical evidence.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {1861-1873}, pmid = {38105307}, issn = {1590-3478}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Benzamides/pharmacology/therapeutic use ; *Thiazoles/pharmacology/therapeutic use ; *Piperidines/pharmacology/therapeutic use ; *Pyridines/pharmacology/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; }, abstract = {OBJECTIVES: Masitinib, originally developed as a tyrosine kinase inhibitor for cancer treatment, has shown potential neuroprotective effects in various neurological disorders by modulating key pathways implicated in neurodegeneration. This scoping review aimed to summarize the current evidence of masitinib's neuroprotective activities from preclinical to clinical studies.

METHODS: This scoping review was conducted following the guidelines described by Arksey and O'Malley and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The inclusion criteria covered all original studies reporting on the neuroprotective effects of masitinib, including clinical studies, animal studies, and in vitro studies.

RESULTS: A total of 16 studies met the inclusion criteria and were included in the review. These comprised five randomized controlled trials (RCTs), one post-hoc analysis study, one case report, and nine animal studies. The RCTs focused on Alzheimer's disease (two studies), multiple sclerosis (two studies), and amyotrophic lateral sclerosis (one study). Across all included studies, masitinib consistently demonstrated neuroprotective properties. However, the majority of RCTs reported concerns regarding the safety profile of masitinib. Preclinical studies revealed the neuroprotective mechanisms of masitinib, which include inhibition of certain kinases interfering with cell proliferation and survival, reduction of neuroinflammation, and exhibition of antioxidant activity.

CONCLUSION: The current evidence suggests a promising therapeutic benefit of masitinib in neurodegenerative diseases. However, further research is necessary to validate and expand upon these findings, particularly regarding the precise mechanisms through which masitinib exerts its therapeutic effects. Future studies should also focus on addressing the safety concerns associated with masitinib use.}, } @article {pmid38105925, year = {2023}, author = {Mimic, S and Aru, B and Pehlivanoğlu, C and Sleiman, H and Andjus, PR and Yanıkkaya Demirel, G}, title = {Immunology of amyotrophic lateral sclerosis - role of the innate and adaptive immunity.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1277399}, pmid = {38105925}, issn = {1662-4548}, abstract = {This review aims to summarize the latest evidence about the role of innate and adaptive immunity in Amyotrophic Lateral Sclerosis (ALS). ALS is a devastating neurodegenerative disease affecting upper and lower motor neurons, which involves essential cells of the immune system that play a basic role in innate or adaptive immunity, that can be neurotoxic or neuroprotective for neurons. However, distinguishing between the sole neurotoxic or neuroprotective function of certain cells such as astrocytes can be challenging due to intricate nature of these cells, the complexity of the microenvironment and the contextual factors. In this review, in regard to innate immunity we focus on the involvement of monocytes/macrophages, microglia, the complement, NK cells, neutrophils, mast cells, and astrocytes, while regarding adaptive immunity, in addition to humoral immunity the most important features and roles of T and B cells are highlighted, specifically different subsets of CD4[+] as well as CD8[+] T cells. The role of autoantibodies and cytokines is also discussed in distinct sections of this review.}, } @article {pmid38106242, year = {2023}, author = {Wang, S and Man, X and Chen, Y and Gong, T and Gao, F and Chen, W and Wang, G and Zhao, B and Chhabra, A}, title = {Three-dimensional magnetic resonance neurography aids in detection of brachial plexus nerve root signal and size alterations in patients with amyotrophic lateral sclerosis: a case-control study.}, journal = {Quantitative imaging in medicine and surgery}, volume = {13}, number = {12}, pages = {8694-8703}, pmid = {38106242}, issn = {2223-4292}, abstract = {BACKGROUND: Since previous histopathological studies have shown a distal to proximal gradient of axonal damage in peripheral nerves of patients with amyotrophic lateral sclerosis (ALS), it would be worthwhile to evaluate consequence of such changes on magnetic resonance imaging (MRI). The aim of this study was to assess proximal-distal longitudinal signal and size alterations of brachial plexus nerve roots in ALS patients using 3-dimensional (3D) magnetic resonance neurography (MRN).

METHODS: A total of 21 ALS patients and 19 controls were evaluated. The diameters and signal-to-noise (SNR) ratio values of C5-C8 roots were measured at five points from proximal to distal sites. Student's t-test was performed to compare the differences at each point between two groups. Linear regression was performed for each nerve root, and the differences in linear regression slopes between two groups were analyzed. Receiver operating characteristic (ROC) analysis was performed for the diameter and SNR value ratio of the distal to the proximal points.

RESULTS: Interobserver agreement was excellent [intraclass correlation coefficient (ICC): 0.802-0.913]. The diameters and SNR values of C5-C8 roots showed a significant decrease (P<0.05) from proximal to distal except SNR value of C5 root in controls. The slope values of diameters in ALS were -0.01924 for C5, -0.04404 for C6, -0.06228 for C7, and -0.06464 for C8. The slope values of SNR values in ALS were -10.14 for C5, -12.86 for C6, -15.99 for C7, and -19.06 for C8. The slope of nerve diameters and SNR values for ALS patients were more negatively sloped than controls (P<0.05) except SNR values of C5 and C7 roots. The ROC analysis confirmed that the diameter and SNR value ratio could differentiate ALS patients from controls with high accuracy. The cutoff values of diameter ratio were 0.7418 for C5, 0.6952 for C6, 0.6431 for C7, and 0.7147 for C8. The cutoff values of SNR value ratio were 0.5989 for C5, 0.6516 for C6, 0.6065 for C7, and 0.6758 for C8.

CONCLUSIONS: Proximal-distal longitudinal diameters and SNR values decreased significantly for brachial plexus nerve roots in ALS patients with larger differences in slopes compared to controls. These results reflect pathophysiological changes of ALS and may be helpful in improving the diagnosis of ALS.}, } @article {pmid38108666, year = {2024}, author = {Clemente-Gutierrez, U and Pieterman, CRC and Lui, MS and Yamashita, TS and Tame-Elorduy, A and Huang, BL and Shirali, AS and Erstad, DJ and Lee, JE and Fisher, SB and Graham, PH and Grubbs, EG and Waguespack, SG and Ng, CS and Perrier, N}, title = {Beyond the three P's: adrenal involvement in MEN1.}, journal = {Endocrine-related cancer}, volume = {31}, number = {2}, pages = {}, pmid = {38108666}, issn = {1479-6821}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Adult ; Middle Aged ; *Multiple Endocrine Neoplasia Type 1/pathology ; Retrospective Studies ; *Adrenal Gland Neoplasms/epidemiology ; *Adrenocortical Carcinoma ; *Adrenal Cortex Neoplasms ; }, abstract = {Adrenal lesions (ALs) are often detected in patients with multiple endocrine neoplasia type 1 (MEN1). However, they are not well described in MEN1, making their clinical management unclear. This study examined the prevalence and outcomes of ALs found in MEN1. We performed a retrospective chart review of patients diagnosed with MEN1 from 1990 to 2021. ALs were diagnosed using abdominal or thoracic imaging and classified as being unilateral or bilateral, having single or multiple nodules, and as having diffuse enlargement or not. Measurable nodular lesions were analyzed for their size and growth over time. Patients' clinical and radiographic characteristics were collected. We identified 382 patients with MEN1, 89 (23.3%) of whom had ALs. The mean age at detection was 47 ± 11.9 years. We documented 101 measurable nodular lesions (mean size, 17.5 mm; range, 3-123 mm). Twenty-seven nodules (26.7%) were smaller than 1 cm. Watchful waiting was indicated in 79 (78.2%) patients, of whom 28 (35.4%) had growing lesions. Functional lesions were diagnosed in 6 (15.8%) of 38 that had functional work-up (diagnoses: pheochromocytoma (n = 2), adrenocorticotropic hormone-dependent hypercortisolism (n = 2), hyperandrogenism (n = 1), hyperaldosteronism (n = 1)); surgery was indicated for 5 (83.3%; n = 12 nodules), 2 of whom had bilateral, diffuse adrenal enlargement. Two patients were diagnosed with adrenocortical carcinoma and two with neoplasms of uncertain malignant potential. Radiographic or clinical progression of ALs is uncommon. Malignancy should be suspected on the basis of a lesion's growth rate and size. A baseline hormonal work-up is recommended, and no further biochemical work-up is suggested when the initial assessment shows nonfunctioning lesions.}, } @article {pmid38108952, year = {2024}, author = {Xiao, X and Rui, Y and Jin, Y and Chen, M}, title = {Relationship of Sleep Disorder with Neurodegenerative and Psychiatric Diseases: An Updated Review.}, journal = {Neurochemical research}, volume = {49}, number = {3}, pages = {568-582}, pmid = {38108952}, issn = {1573-6903}, support = {82371541//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Alzheimer Disease/metabolism ; Brain/metabolism ; *Huntington Disease/metabolism ; *Sleep Wake Disorders/metabolism ; }, abstract = {Sleep disorders affect many people worldwide and can accompany neurodegenerative and psychiatric diseases. Sleep may be altered before the clinical manifestations of some of these diseases appear. Moreover, some sleep disorders affect the physiological organization and function of the brain by influencing gene expression, accelerating the accumulation of abnormal proteins, interfering with the clearance of abnormal proteins, or altering the levels of related hormones and neurotransmitters, which can cause or may be associated with the development of neurodegenerative and psychiatric diseases. However, the detailed mechanisms of these effects are unclear. This review mainly focuses on the relationship between and mechanisms of action of sleep in Alzheimer's disease, depression, and anxiety, as well as the relationships between sleep and Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This summary of current research hotspots may provide researchers with better clues and ideas to develop treatment solutions for neurodegenerative and psychiatric diseases associated with sleep disorders.}, } @article {pmid38109186, year = {2023}, author = {Nimma, S and Gans, A and Wardhan, R and Allen, W}, title = {Remimazolam Sedation and Neuraxial Anesthesia in a Patient with Amyotrophic Lateral Sclerosis Undergoing an Open Colectomy: A Case Report.}, journal = {A&A practice}, volume = {17}, number = {12}, pages = {e01733}, doi = {10.1213/XAA.0000000000001733}, pmid = {38109186}, issn = {2575-3126}, mesh = {Male ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/surgery ; *Neurodegenerative Diseases ; Benzodiazepines ; *Anesthesia, Conduction ; Colectomy ; *Respiratory Insufficiency ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving the upper and lower motor neurons. Perioperative management of patients with ALS can be challenging due to the risk of hemodynamic instability, aspiration, and ventilatory failure. We discuss a 58-year-old male patient with ALS who underwent open abdominal surgery under regional anesthesia utilizing a remimazolam infusion for sedation. While various sedation agents have been used successfully in patients with ALS, remimazolam, a new short-acting benzodiazepine with unique pharmacologic properties and reversible anxiolysis, provides amnesia while avoiding ventilatory depression.}, } @article {pmid38109536, year = {2023}, author = {Qin, F and Cai, B and Cao, R and Bai, X and Yuan, J and Zhang, Y and Liu, Y and Chen, T and Liu, F and Sun, W and Zheng, Y and Qi, X and Zhao, W and Liu, B and Gao, C}, title = {Listerin promotes cGAS protein degradation through the ESCRT pathway to negatively regulate cGAS-mediated immune response.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {52}, pages = {e2308853120}, pmid = {38109536}, issn = {1091-6490}, support = {32230033//MOST | National Natural Science Foundation of China (NSFC)/ ; 81930039//MOST | National Natural Science Foundation of China (NSFC)/ ; 82222027//MOST | National Natural Science Foundation of China (NSFC)/ ; 32270918//MOST | National Natural Science Foundation of China (NSFC)/ ; 31900680//MOST | National Natural Science Foundation of China (NSFC)/ ; 2021YFC2300603//MOST | National Key Research and Development Program of China (NKPs)/ ; ZR201911140289//| Natural Science Foundation of Shandong Province ()/ ; ZR2021YQ48//| Natural Science Foundation of Shandong Province ()/ ; ZR2018BC021//| Natural Science Foundation of Shandong Province ()/ ; ZR2021ZD08//| Natural Science Foundation of Shandong Province ()/ ; 82321002//MOST | National Natural Science Foundation of China (NSFC)/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology ; Endosomal Sorting Complexes Required for Transport/metabolism ; Immunity, Innate/genetics ; Nucleotidyltransferases/metabolism ; Proteolysis ; Signal Transduction/physiology ; Disease Models, Animal ; *Ubiquitin-Protein Ligases/antagonists & inhibitors/immunology/metabolism ; }, abstract = {The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.}, } @article {pmid38110144, year = {2024}, author = {Hafner, C and Manschein, V and Klaus, DA and Schaubmayr, W and Tiboldi, A and Scharner, V and Gleiss, A and Thal, B and Krammel, M and Hamp, T and Willschke, H and Hermann, M}, title = {Live stream of prehospital point-of-care ultrasound during cardiopulmonary resuscitation - A feasibility trial.}, journal = {Resuscitation}, volume = {194}, number = {}, pages = {110089}, doi = {10.1016/j.resuscitation.2023.110089}, pmid = {38110144}, issn = {1873-1570}, support = {21044//Medical Scientific Fund of the Mayor of the City of Vienna/ ; }, mesh = {Humans ; *Cardiopulmonary Resuscitation/methods ; *Emergency Medical Services/methods ; Feasibility Studies ; *Out-of-Hospital Cardiac Arrest/diagnostic imaging/therapy ; Point-of-Care Systems ; }, abstract = {BACKGROUND: Current resuscitation guidelines recommend that skilled persons could use ultrasound to detect reversible causes during cardiopulmonary resuscitation (CPR) where the examination can be safely integrated into the Advanced Life Support (ALS) algorithm. However, in a prehospital setting performing and rapidly interpreting ultrasound can be challenging for physicians. Implementing remote, expert-guided, and real-time transmissions of ultrasound examinations offers the opportunity for tele-support, even during an out-of-hospital cardiac arrest (OHCA). The aim of this feasibility study was to evaluate the impact of tele-supported ultrasound in ALS on hands-off time during an OHCA.

METHODS: In an urban setting, physicians performed point-of-care ultrasound (POCUS) on patients during OHCA using a portable device, either with tele-support (n = 30) or without tele-support (n = 12). Where tele-support was used, the ultrasound image was transmitted via a remote real-time connection to an on-call specialist in anaesthesia and intensive care medicine with an advanced level of critical care ultrasound expertise. The primary safety endpoint of this study was to evaluate whether POCUS can be safely integrated into the algorithm, and to provide an analysis of hands-off time before, during, and after POCUS during OHCA.

RESULTS: In all 42 cases it was possible to perform POCUS during regular rhythm analyses, and no additional hands-off time was required. In 40 of these 42 cases, the physicians were able to perform POCUS during a single regular rhythm analysis, with two periods required only in two cases. The median hands-off time during these rhythm analyses for POCUS with tele-support was 10 (8-13) seconds, and 11 (9-14) seconds for POCUS without tele-support. Furthermore, as a result of POCUS, in a quarter of all cases the physician on scene altered their diagnosis of the primary suspected cause of cardiac arrest, leading to a change in treatment strategy.

CONCLUSIONS: This feasibility study demonstrated that POCUS with tele-support can be safely performed during OHCA in an urban environment. Trial Registration (before patient enrolment): ClinicalTrials.gov, NCT04817475.}, } @article {pmid38110419, year = {2023}, author = {Chen, ZS and Ou, M and Taylor, S and Dafinca, R and Peng, SI and Talbot, K and Chan, HYE}, title = {Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {8420}, pmid = {38110419}, issn = {2041-1723}, mesh = {Humans ; *Frontotemporal Dementia/genetics ; RNA ; beta Catenin/genetics/metabolism ; C9orf72 Protein/genetics ; DNA Repeat Expansion ; *Amyotrophic Lateral Sclerosis/genetics ; YY1 Transcription Factor/genetics/metabolism ; }, abstract = {The GGGGCC hexanucleotide repeat expansion mutation in the chromosome 9 open reading frame 72 (C9orf72) gene is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). In this study, we demonstrate that the zinc finger (ZF) transcriptional regulator Yin Yang 1 (YY1) binds to the promoter region of the planar cell polarity gene Fuzzy to regulate its transcription. We show that YY1 interacts with GGGGCC repeat RNA via its ZF and that this interaction compromises the binding of YY1 to the Fuzzy[YY1] promoter sites, resulting in the downregulation of Fuzzy transcription. The decrease in Fuzzy protein expression in turn activates the canonical Wnt/β-catenin pathway and induces synaptic deficits in C9ALS/FTD neurons. Our findings demonstrate a C9orf72 GGGGCC RNA-initiated perturbation of YY1-Fuzzy transcriptional control that implicates aberrant Wnt/β-catenin signalling in C9ALS/FTD-associated neurodegeneration. This pathogenic cascade provides a potential new target for disease-modifying therapy.}, } @article {pmid38110502, year = {2023}, author = {Ludolph, AC and Grandjean, H and Reviers, E and De Micheli, V and Bianchi, C and Cardosi, L and Russ, H and Silani, V}, title = {The preferences of people with amyotrophic lateral sclerosis on riluzole treatment in Europe.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {22497}, pmid = {38110502}, issn = {2045-2322}, mesh = {Humans ; Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Suspensions ; Europe ; *Airway Obstruction ; Tablets ; *Neuroprotective Agents ; }, abstract = {The Patient Preference Survey aims to understand unmet needs related to riluzole management in people with Amyotrophic Lateral Sclerosis (ALS) and to identify which characteristics of a new formulation could better match their preferences. The survey involved 117 people with ALS (PALS) treated with riluzole in four European countries. The dysphagic PALS were least satisfied with the riluzole tablet and oral suspension and with ease in self-administration; up to 68% of respondents postponed or missed the treatment due to swallowing difficulties and need of caregiver assistance. Overall, 51% of tablet and 53% of oral suspension users regularly crushed or mixed riluzole with beverages, respectively; PALS who always manipulated riluzole showed low satisfaction with the formulation and considered the risk of choking and pneumonia the most worrisome event. The survey evaluated the driving factors in choosing/switching the therapy: 67% of PALS declared a low risk of choking. The research finally evaluated which attributes of a new formulation would be preferred: the most relevant were ease of use (4.3/5), convenient/portable packaging (4.0/5) and oral-dissolving properties without tongue motility (3.9/5). The Patient Preference Survey suggests that patients have several unmet needs and preferences that could be addressed by a different formulation, e.g. using oral film technologies.}, } @article {pmid38110839, year = {2024}, author = {Benatar, M and Ostrow, LW and Lewcock, JW and Bennett, F and Shefner, J and Bowser, R and Larkin, P and Bruijn, L and Wuu, J}, title = {Biomarker Qualification for Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: Theory and Practice.}, journal = {Annals of neurology}, volume = {95}, number = {2}, pages = {211-216}, pmid = {38110839}, issn = {1531-8249}, support = {U01 NS107027/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; U01 NS107027/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Superoxide Dismutase-1 ; Intermediate Filaments ; Biomarkers ; Prognosis ; Neurofilament Proteins ; }, abstract = {OBJECTIVE: To explore whether the utility of neurofilament light chain (NfL), as a biomarker to aid amyotrophic lateral sclerosis (ALS) therapy development, would be enhanced by obtaining formal qualification from the US Food and Drug Administration for a defined context-of-use.

METHODS: Consensus discussion among academic, industry, and patient advocacy group representatives.

RESULTS: A wealth of scientific evidence supports the use of NfL as a prognostic, response, and potential safety biomarker in the broad ALS population, and as a risk/susceptibility biomarker among the subset of SOD1 pathogenic variant carriers. Although NfL has not yet been formally qualified for any of these contexts-of-use, the US Food and Drug Administration has provided accelerated approval for an SOD1-lowering antisense oligonucleotide, based partially on the recognition that a reduction in NfL is reasonably likely to predict a clinical benefit.

INTERPRETATION: The increasing incorporation of NfL into ALS therapy development plans provides evidence that its utility-as a prognostic, response, risk/susceptibility, and/or safety biomarker-is already widely accepted by the community. The willingness of the US Food and Drug Administration to base regulatory decisions on rigorous peer-reviewed data-absent formal qualification, leads us to conclude that formal qualification, despite some benefits, is not essential for ongoing and future use of NfL as a tool to aid ALS therapy development. Although the balance of considerations for and against seeking NfL biomarker qualification will undoubtedly vary across different diseases and contexts-of-use, the robustness of the published data and careful deliberations of the ALS community may offer valuable insights for other disease communities grappling with the same issues. ANN NEUROL 2024;95:211-216.}, } @article {pmid38111057, year = {2023}, author = {Zhao, B and Cowan, CM and Coutts, JA and Christy, DD and Saraph, A and Hsueh, SCC and Plotkin, SS and Mackenzie, IR and Kaplan, JM and Cashman, NR}, title = {Targeting RACK1 to alleviate TDP-43 and FUS proteinopathy-mediated suppression of protein translation and neurodegeneration.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {200}, pmid = {38111057}, issn = {2051-5960}, support = {SRA F16-05805//ProMIS Neurosciences/ ; PJT-159546//Canadian Institute of Health Research/ ; CCNA-20R04367//Canadian Institute of Health Research/ ; 20R74974//Fondation Brain Canada/ ; F20-04056//Fondation Brain Canada/ ; F17-00928//William A. Lambert donation/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Drosophila melanogaster/genetics/metabolism ; HEK293 Cells ; Motor Neurons/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/pathology ; *Frontotemporal Lobar Degeneration/pathology ; Protein Biosynthesis ; *Sarcoma/metabolism/pathology ; RNA-Binding Protein FUS/genetics/metabolism ; Receptors for Activated C Kinase/genetics/metabolism ; Neoplasm Proteins/genetics ; Drosophila Proteins ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) and Fused in Sarcoma/Translocated in Sarcoma (FUS) are ribonucleoproteins associated with pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under physiological conditions, TDP-43 and FUS are predominantly localized in the nucleus, where they participate in transcriptional regulation, RNA splicing and metabolism. In disease, however, they are typically mislocalized to the cytoplasm where they form aggregated inclusions. A number of shared cellular pathways have been identified that contribute to TDP-43 and FUS toxicity in neurodegeneration. In the present study, we report a novel pathogenic mechanism shared by these two proteins. We found that pathological FUS co-aggregates with a ribosomal protein, the Receptor for Activated C-Kinase 1 (RACK1), in the cytoplasm of spinal cord motor neurons of ALS, as previously reported for pathological TDP-43. In HEK293T cells transiently transfected with TDP-43 or FUS mutant lacking a functional nuclear localization signal (NLS; TDP-43[ΔNLS] and FUS[ΔNLS]), cytoplasmic TDP-43 and FUS induced co-aggregation with endogenous RACK1. These co-aggregates sequestered the translational machinery through interaction with the polyribosome, accompanied by a significant reduction of global protein translation. RACK1 knockdown decreased cytoplasmic aggregation of TDP-43[ΔNLS] or FUS[ΔNLS] and alleviated associated global translational suppression. Surprisingly, RACK1 knockdown also led to partial nuclear localization of TDP-43[ΔNLS] and FUS[ΔNLS] in some transfected cells, despite the absence of NLS. In vivo, RACK1 knockdown alleviated retinal neuronal degeneration in transgenic Drosophila melanogaster expressing hTDP-43[WT] or hTDP-43[Q331K] and improved motor function of hTDP-43[WT] flies, with no observed adverse effects on neuronal health in control knockdown flies. In conclusion, our results revealed a novel shared mechanism of pathogenesis for misfolded aggregates of TDP-43 and FUS mediated by interference with protein translation in a RACK1-dependent manner. We provide proof-of-concept evidence for targeting RACK1 as a potential therapeutic approach for TDP-43 or FUS proteinopathy associated with ALS and FTLD.}, } @article {pmid38111121, year = {2024}, author = {}, title = {Erratum to "Suicide among veterans with amyotrophic lateral sclerosis".}, journal = {Muscle & nerve}, volume = {69}, number = {2}, pages = {246-247}, doi = {10.1002/mus.28011}, pmid = {38111121}, issn = {1097-4598}, } @article {pmid38111871, year = {2023}, author = {Poletti, B and Aiello, EN and Tagini, S and Solca, F and Torre, S and Colombo, E and Maranzano, A and Bonetti, R and Schevegher, F and Morelli, C and Doretti, A and Verde, F and Barbieri, S and Mameli, F and Priori, A and Ferrucci, R and Silani, V and Cherubini, P and Pravettoni, G and Ticozzi, N}, title = {An exploratory study on counterfactual thinking in amyotrophic lateral sclerosis.}, journal = {Frontiers in psychology}, volume = {14}, number = {}, pages = {1281976}, pmid = {38111871}, issn = {1664-1078}, abstract = {OBJECTIVES: This study aimed at exploring (1) the motor and non-motor correlates of counterfactual thinking (CFT) abilities in non-demented amyotrophic lateral sclerosis (ALS) patients and (2) the ability of CFT measures to discriminate these patients from healthy controls (HCs) and patients with and without cognitive impairment.

METHODS: N = 110 ALS patients and N = 51 HCs were administered two CFT tasks, whose sum, resulting in a CFT Index (CFTI), was addressed as the outcome. Patients further underwent an in-depth cognitive, behavioral, and motor-functional evaluation. Correlational analyses were run to explore the correlates of the CFTI in patients. Logistic regressions were performed to test whether the CFTI could discriminate patients from HCs.

RESULTS: The CFTI was selectively associated (p ≤ 0.005) with fluency and memory subscales of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), but not with other variables. CFTI scores discriminated patients from HCs (p < 0.001) with high accuracy (82%), but not patients with a normal vs. defective performance on the ECAS-Total.

CONCLUSION: CFT measures in non-demented ALS patients were associated with verbal fluency and memory functions, and they were also able to discriminate them from HCs.}, } @article {pmid38112253, year = {2023}, author = {Juranek, J and Osowski, A and Wojtkiewicz, J and Banach, M}, title = {Plasma levels of soluble RAGE, AGEs and AOPPs at the early stage of amyotrophic lateral sclerosis: A preliminary study.}, journal = {Polimery w medycynie}, volume = {53}, number = {2}, pages = {105-110}, doi = {10.17219/pim/175544}, pmid = {38112253}, issn = {0370-0747}, mesh = {Humans ; Receptor for Advanced Glycation End Products/metabolism ; *Advanced Oxidation Protein Products/metabolism ; *Amyotrophic Lateral Sclerosis ; Longitudinal Studies ; Oxidative Stress ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with largely unknown pathogenesis and no effective cure. It is believed that several, not mutually exclusive mechanisms contribute to the pathogenesis and progression of this disease, including, among others, elevated oxidative stress, excitotoxicity, increased neuroinflammation, and protein aggregation. Receptor for advanced glycation end products (RAGE) is a part of immunoglobulin superfamily; it is believed to participate in ALS pathogenesis.

OBJECTIVES: Our previous studies on ALS demonstrated that RAGE is likely one of the key players in ALS, acting on its own and in tandem with its oxidative stress and pro-inflammatory ligands, such as advanced glycation end products (AGEs) or advanced oxidation protein products (AOPPs). In this study, based on our previous results, we aimed to establish blood levels of soluble RAGE, AGE and AOPP in ALS patients.

MATERIAL AND METHODS: Forty-six coded and anonymized surplus plasma samples from ALS patients and non-neurological control were used in the study. The plasma levels of RAGE, AGE and AOPP were measured using enzyme-linked immunosorbent assay (ELISA) commercially available kits. Statistical evaluation of data was performed using one-way non-parametric analysis of variance (ANOVA) with Kruskal-Wallis post hoc test.

RESULTS: Our results revealed a decline in soluble RAGE level, concurrent with an increase in the levels of AGEs and AOPPs in blood samples from ALS patients, signifying a loss of neuroprotective form of RAGE and a simultaneous increase in AGE and AOPP production and uptake at the early stage of the disease.

CONCLUSIONS: The results obtained from our study indicate that further longitudinal study of RAGE, AGE and AOPP levels would be beneficial, outlining the dynamics between RAGE and its ligand levels as the disease progresses, and making them valuable diagnostic tools and potential therapeutic targets.}, } @article {pmid38112345, year = {2024}, author = {Battaglini, M and Marino, A and Montorsi, M and Carmignani, A and Ceccarelli, MC and Ciofani, G}, title = {Nanomaterials as Microglia Modulators in the Treatment of Central Nervous System Disorders.}, journal = {Advanced healthcare materials}, volume = {13}, number = {12}, pages = {e2304180}, doi = {10.1002/adhm.202304180}, pmid = {38112345}, issn = {2192-2659}, mesh = {*Microglia/drug effects/metabolism ; Humans ; *Nanostructures/chemistry ; Animals ; *Central Nervous System Diseases/drug therapy/metabolism ; Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Microglia play a pivotal role in the central nervous system (CNS) homeostasis, acting as housekeepers and defenders of the surrounding environment. These cells can elicit their functions by shifting into two main phenotypes: pro-inflammatory classical phenotype, M1, and anti-inflammatory alternative phenotype, M2. Despite their pivotal role in CNS homeostasis, microglia phenotypes can influence the development and progression of several CNS disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, ischemic stroke, traumatic brain injuries, and even brain cancer. It is thus clear that the possibility of modulating microglia activation has gained attention as a therapeutic tool against many CNS pathologies. Nanomaterials are an unprecedented tool for manipulating microglia responses, in particular, to specifically target microglia and elicit an in situ immunomodulation activity. This review focuses the discussion on two main aspects: analyzing the possibility of using nanomaterials to stimulate a pro-inflammatory response of microglia against brain cancer and introducing nanostructures able to foster an anti-inflammatory response for treating neurodegenerative disorders. The final aim is to stimulate the analysis of the development of new microglia nano-immunomodulators, paving the way for innovative and effective therapeutic approaches for the treatment of CNS disorders.}, } @article {pmid38112636, year = {2024}, author = {Wang, Y and Shen, O and Xu, Q and Sun, L and Jia, Y and Liu, Y and He, Y and Chang, X and Guo, D and Shi, M and Chen, GC and Zheng, J and Zhu, Z}, title = {Genetic analyses identify brain imaging-derived phenotypes associated with the risk of amyotrophic lateral sclerosis.}, journal = {Cerebral cortex (New York, N.Y. : 1991)}, volume = {34}, number = {1}, pages = {}, doi = {10.1093/cercor/bhad496}, pmid = {38112636}, issn = {1460-2199}, support = {82103917//National Natural Science Foundation of China/ ; 21KJB330006//Natural Science Research Project of Jiangsu Provincial Higher Education/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; Brain/diagnostic imaging ; Genome-Wide Association Study ; Neuroimaging ; Phenotype ; Polymorphism, Single Nucleotide ; Mendelian Randomization Analysis ; }, abstract = {Brain imaging-derived phenotypes have been suggested to be associated with amyotrophic lateral sclerosis in observational studies, but whether these associations are causal remains unclear. We aimed to assess the potential bidirectional causal associations between imaging-derived phenotypes and amyotrophic lateral sclerosis using bidirectional 2-sample Mendelian randomization analyses. Summary statistics for 469 imaging-derived phenotypes (33,224 individuals) and amyotrophic lateral sclerosis (20,806 cases and 59,804 controls) were obtained from 2 large-scale genome-wide association studies of European ancestry. We used the inverse-variance weighted Mendelian randomization method in the main analysis to assess the bidirectional associations between imaging-derived phenotypes and amyotrophic lateral sclerosis, followed by several sensitivity analyses for robustness validation. In the forward Mendelian randomization analyses, we found that genetically determined high orientation dispersion index in the right cerebral peduncle was associated with the increased risk of amyotrophic lateral sclerosis (odds ratio = 1.30, 95% confidence interval = 1.16-1.45, P = 2.26 × 10-6). In addition, the reverse Mendelian randomization analysis indicated that amyotrophic lateral sclerosis had no effect on 469 imaging-derived phenotypes. Mendelian randomization-Egger regression analysis showed no directional pleiotropy for the association between high orientation dispersion index in the right cerebral peduncle and amyotrophic lateral sclerosis, and sensitivity analyses with different Mendelian randomization models further confirmed these findings. The present systematic bidirectional Mendelian randomization analysis showed that high orientation dispersion index in the right cerebral peduncle might be the potential causal mediator of amyotrophic lateral sclerosis, which may provide predictive guidance for the prevention of amyotrophic lateral sclerosis. Further studies are warranted to replicate our findings and clarify the underlying mechanisms.}, } @article {pmid38112783, year = {2024}, author = {Libonati, L and Cambieri, C and Colavito, D and Moret, F and D'Andrea, E and Del Giudice, E and Leon, A and Inghilleri, M and Ceccanti, M}, title = {Genetics screening in an Italian cohort of patients with Amyotrophic Lateral Sclerosis: the importance of early testing and its implication.}, journal = {Journal of neurology}, volume = {271}, number = {4}, pages = {1921-1936}, pmid = {38112783}, issn = {1432-1459}, mesh = {Humans ; Mutation ; *Amyotrophic Lateral Sclerosis/epidemiology ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; *Neurodegenerative Diseases ; Italy ; Heat-Shock Proteins/genetics ; Molecular Chaperones/genetics ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with an elusive etiology. While environmental factors have been considered, familial ALS cases have raised the possibility of genetic involvement. This genetic connection is increasingly evident, even in patients with sporadic ALS. We allowed access to the genetic test to all patients attending our clinic to identify the prevalence and the role of genetic variants in the development of the disease and to identify patients with potentially treatable forms of the disease.

MATERIALS AND METHODS: 194 patients with probable or definite ALS, were enrolled. A comprehensive genetic testing was performed, including sequencing all exons of the SOD1 gene and testing for hexanucleotide intronic repeat expansions (G4C2) in the C9orf72 gene using fluorescent repeat-primed PCR (RP-PCR). Whole Exome NGS Sequencing (WES) was performed, followed by an in silico multigene panel targeting neuromuscular diseases, spastic paraplegia, and motor distal neuropathies. We conducted statistical analyses to compare different patient groups.

RESULTS: Clinically significant pathogenetic variants were detected in 14.43% of cases. The highest prevalence of pathogenetic variants was observed in fALS patients, but a substantial proportion of sALS patients also displayed at least one variant, either pathogenetic or of uncertain significance (VUS). The most observed pathogenetic variant was the expansion of the C9orf72 gene, which was associated with a shorter survival. SOD1 variants were found in 1.6% of fALS and 2.5% of sALS patients.

DISCUSSION: The study reveals a significant number of ALS patients carrying pathogenic or likely pathogenic variants, with a higher prevalence in familial ALS cases. The expansion of the C9orf72 gene emerges as the most common genetic cause of ALS, affecting familial and sporadic cases. Additionally, SOD1 variants are detected at an unexpectedly higher rate, even in patients without a familial history of ALS, underscoring the crucial role of genetic testing in treatment decisions and potential participation in clinical trials. We also investigated variants in genes such as TARDBP, FUS, NEK1, TBK1, and DNAJC7, shedding light on their potential involvement in ALS. These findings underscore the complexity of interpreting variants of uncertain significance (VUS) and their ethical implications in patient communication and genetic counseling for patients' relatives.

CONCLUSION: This study emphasizes the diverse genetic basis of ALS and advocates for integrating comprehensive genetic testing into diagnostic protocols. The evolving landscape of genetic therapies requires identifying all eligible patients transcending traditional familial boundaries. The presence of VUS highlights the multifaceted nature of ALS genetics, prompting further exploration of complex interactions among genetic variants, environmental factors, and disease development.}, } @article {pmid38115557, year = {2024}, author = {Nementzik, LR and Thumbadoo, KM and Murray, HC and Gordon, D and Yang, S and Blair, IP and Turner, C and Faull, RLM and Curtis, MA and McLean, C and Nicholson, GA and Swanson, MEV and Scotter, EL}, title = {Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS in UBQLN2 p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {3}, pages = {e13230}, pmid = {38115557}, issn = {1750-3639}, support = {//Amelia Pais-Rodriguez and Marcus Gerbich/ ; //Freemasons Foundation of New Zealand/ ; //Health Education Trust/ ; 15-UOA-157//Marsden Fund/ ; //Matteo de Nora/ ; //Motor Neuron Disease NZ/ ; //PaR NZ Golfing/ ; 15-UOA-003//Royal Society Te Apārangi/ ; }, mesh = {Humans ; Adaptor Proteins, Signal Transducing/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Autophagy-Related Proteins/metabolism ; DNA-Binding Proteins/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Mutation ; Transcription Factors/metabolism ; }, abstract = {Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2-linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the transactive response DNA-binding protein of 43 kDa (TDP-43). ALS and FTD without UBQLN2 mutations are also characterised by TDP-43 aggregates, that may or may not colocalise with wildtype ubiquilin 2. Despite this, the relative contributions of TDP-43 and ubiquilin 2 to disease pathogenesis remain largely under-characterised, as does their relative deposition as aggregates across the central nervous system (CNS). Here we conducted multiplex immunohistochemistry of three UBQLN2 p.T487I-linked ALS/FTD cases, three non-UBQLN2-linked (sporadic) ALS cases, and 8 non-neurodegenerative disease controls, covering 40 CNS regions. We then quantified ubiquilin 2 aggregates, TDP-43 aggregates and aggregates containing both proteins in regions of interest to determine how UBQLN2-linked and non-UBQLN2-linked proteinopathy differ. We find that ubiquilin 2 aggregates that are negative for TDP-43 are predominantly small and punctate and are abundant in the hippocampal formation, spinal cord, all tested regions of neocortex, medulla and substantia nigra in UBQLN2-linked ALS/FTD but not sporadic ALS. Curiously, the striatum harboured small punctate ubiquilin 2 aggregates in all cases examined, while large diffuse striatal ubiquilin 2 aggregates were specific to UBQLN2-linked ALS/FTD. Overall, ubiquilin 2 is mainly deposited in clinically unaffected regions throughout the CNS such that symptomology in UBQLN2-linked cases maps best to the aggregation of TDP-43.}, } @article {pmid38116771, year = {2023}, author = {Máčová, L and Kancheva, R and Bičíková, M}, title = {Molecular Regulation of the CNS by Vitamin D.}, journal = {Physiological research}, volume = {72}, number = {S4}, pages = {S339-S356}, doi = {10.33549/physiolres.935248}, pmid = {38116771}, issn = {1802-9973}, mesh = {Humans ; Vitamin D/therapeutic use ; Vitamins ; *Alzheimer Disease ; *Nervous System Diseases ; *Parkinson Disease ; }, abstract = {Vitamin D is a lipid-soluble vitamin that can be found in some foods. It is also produced endogenously (in the presence of ultraviolet light), transported through the blood to the targets organs and this is the reason to consider vitamin D as a hormone. It is known that vitamin D has genomic and non-genomic effects. This review is focused mainly on the vitamin D receptors, the importance of vitamin D as a neuromodulator, the role of vitamin D in the pathophysiology of devastating neurological disorders such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and the benefit of vitamin D and its derivates in alleviating these disorders.}, } @article {pmid38117120, year = {2024}, author = {Vaage, AM and Benth, JŠ and Meyer, HE and Holmøy, T and Nakken, O}, title = {Premorbid lipid levels and long-term risk of ALS-a population-based cohort study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {358-366}, doi = {10.1080/21678421.2023.2295455}, pmid = {38117120}, issn = {2167-9223}, mesh = {Female ; Humans ; Male ; Cholesterol, LDL ; Cohort Studies ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Triglycerides ; Cholesterol, HDL ; Risk Factors ; }, abstract = {OBJECTIVE: To assess the temporal relationship between premorbid lipid levels and long-term amyotrophic lateral sclerosis (ALS) risk.

METHODS: From Norwegian cardiovascular health surveys (1974-2003), we collected information on total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucose, and other cardiovascular risk factors. ALS incidence and mortality were identified through validated Norwegian health registries. The relation between premorbid lipid levels and ALS risk was assessed by Cox regression models.

RESULTS: Out of 640,066 study participants (51.5% females), 974 individuals (43.5% females) developed ALS. Mean follow-up time was 23.7 (SD 7.1) years among ALS cases. One mmol/l increase in LDL-C was associated with 6% increase in risk for ALS (hazard ratio 1.06 [95% CI: 1.01-1.09]). Higher levels of TC and TG were also associated with increased ALS risk, but only within the last 6-7 years prior to ALS diagnosis or death. No association between HDL-C and ALS risk was found. Adjusting for body mass index, birth cohort, smoking, and physical activity did not alter the results.

CONCLUSIONS: Higher levels of LDL-C are associated with increased ALS risk over 40 years later, compatible with a causal relationship. The temporal relationship between TG, TC, and ALS risk suggests that increased levels of these lipid biomarkers represent consequences of ALS.}, } @article {pmid38123099, year = {2024}, author = {Stackhouse, LA and Coops, NC and Kuiper, SD and Hinch, SG and White, JC and Tompalski, P and Nonis, A and Gergel, SE}, title = {Modeling instream temperature from solar insolation under varying timber harvesting intensities using RPAS laser scanning.}, journal = {The Science of the total environment}, volume = {912}, number = {}, pages = {169459}, doi = {10.1016/j.scitotenv.2023.169459}, pmid = {38123099}, issn = {1879-1026}, abstract = {Stream temperatures are influenced by the amount of solar insolation they receive. Increasing stream temperatures associated with climate warming pose detrimental health risks to freshwater ecosystems. In British Columbia (BC), Canada, timber harvesting along forested streams is managed using riparian buffer zones of varying widths and designations. Within buffer zones, depending on distance from the stream, selective thinning may be permitted or harvest may be forbidden. In this study, we used airborne laser scanning (ALS) point cloud data acquired via a remotely piloted aircraft system (RPAS) to derive forest canopy characteristics that were then used to estimate daily incoming summer and fall solar insolation for five stream reaches in coastal conifer-dominated temperate forests in Vancouver Island, BC, Canada. We then examined empirical relationships between estimated insolation and actual instream temperature measurements. Based on these empirical relationships, the potential effects of timber harvest on instream temperatures were simulated by comparing scenarios of different riparian forest harvest intensities. Our results indicated that modeled solar insolation explained 43-90 % of the variation in observed stream reach temperatures, and furthermore, when a single cold-water stream reach was excluded explained an overall 81 % of variation. Simulated harvesting scenarios generally projected increases in maximum stream reach temperatures 1-2 °C in summer and early fall months. However, in a full clearcut scenario (i.e. where all trees were removed), maximum stream reach temperatures increased as much as 5.8 °C. Our results emphasize the importance of retaining riparian vegetation for the maintenance of habitable temperatures for freshwater-reliant fish with thermal restrictions. In addition, we demonstrate the feasibility of RPAS-based monitoring of stream reach shading and canopy cover, enabling detailed assessment of environmental stressors faced by fish populations under climate warming.}, } @article {pmid38123494, year = {2024}, author = {Nolano, M and Provitera, V and Caporaso, G and Fasolino, I and Borreca, I and Stancanelli, A and Iuzzolino, VV and Senerchia, G and Vitale, F and Tozza, S and Ruggiero, L and Iodice, R and Ferrari, S and Santoro, L and Manganelli, F and Dubbioso, R}, title = {Skin innervation across amyotrophic lateral sclerosis clinical stages: new prognostic biomarkers.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {5}, pages = {1740-1750}, doi = {10.1093/brain/awad426}, pmid = {38123494}, issn = {1460-2156}, support = {//Istituti Clinici Scientifici Maugeri IRCCS/ ; //Italian Ministry of Health/ ; //Ministry of University and Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Male ; Female ; Middle Aged ; *Skin/innervation/pathology ; Aged ; Prognosis ; Biomarkers/blood ; Neural Conduction/physiology ; Adult ; Disease Progression ; Neurofilament Proteins/blood/metabolism ; Longitudinal Studies ; }, abstract = {Over recent decades, peripheral sensory abnormalities, including the evidence of cutaneous denervation, have been reported among the non-motor manifestations in amyotrophic lateral sclerosis (ALS). However, a correlation between cutaneous innervation and clinical features has not been found. The aims of this study were to assess sensory involvement by applying a morpho-functional approach to a large population of ALS patients stratified according to King's stages and correlate these findings with the severity and prognosis of the disease. We recruited 149 ALS patients and 41 healthy controls. Patients undertook clinical questionnaires for small fibre neuropathy symptoms (Small Fiber Neuropathy Symptoms Inventory Questionnaire) and underwent nerve conductions studies (NCS) and 3-mm punch skin biopsies from leg, thigh and fingertip. We assessed intraepidermal nerve fibre (IENF) and Meissner corpuscle (MC) density by applying an indirect immunofluorescence technique. Moreover, a subset of 65 ALS patients underwent a longitudinal study with repeat biopsies from the thigh at 6- and 12-month follow-ups. Serum NfL levels were measured in 40 patients. Sensory symptoms and sensory NCS abnormalities were present in 32.2% and 24% of patients, respectively, and increased across clinical stages. Analogously, we observed a progressive reduction in amplitude of the sensory and motor ulnar nerve potential from stage 1 to stage 4. Skin biopsy showed a significant loss of IENFs and MCs in ALS compared with healthy controls (all P < 0.001). Across the clinical stages, we found a progressive reduction in MCs (P = 0.004) and an increase in IENFs (all P < 0.027). The increase in IENFs was confirmed by the longitudinal study. Interestingly, the MC density inversely correlated with NfL level (r = -0.424, P = 0.012), and survival analysis revealed that low MC density, higher NfL levels and increasing IENF density over time were associated with a poorer prognosis (all P < 0.024). To summarize, in patients with ALS, peripheral sensory involvement worsens in parallel with motor disability. Furthermore, the correlation between skin innervation and disease activity may suggest the use of skin innervation as a putative prognostic biomarker.}, } @article {pmid38123999, year = {2024}, author = {Douglas, AGL and Baralle, D}, title = {Reduced penetrance of gene variants causing amyotrophic lateral sclerosis.}, journal = {Journal of medical genetics}, volume = {61}, number = {3}, pages = {294-297}, doi = {10.1136/jmg-2023-109580}, pmid = {38123999}, issn = {1468-6244}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/pathology ; *Frontotemporal Dementia/epidemiology/genetics ; C9orf72 Protein/genetics ; Penetrance ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most commonly implicated genes are C9orf72, SOD1, TARDBP and FUS. Penetrance of disease-causing variants in these genes is known to be incomplete, but has not been well studied at population level.

OBJECTIVE: We sought to determine the population-level penetrance of pathogenic and likely pathogenic variants in genes commonly causing amyotrophic lateral sclerosis.

METHODS: Published epidemiological data for amyotrophic lateral sclerosis and frontotemporal dementia were used to calculate expected frequencies of disease-causing variants per gene at population level. Variant data from gnomAD and ClinVar databases were used to ascertain observed numbers of disease-causing variants and to estimate population-level penetrance per gene. Data for C9orf72 were obtained from the published literature.

RESULTS: Maximum population penetrance for either amyotrophic lateral sclerosis or frontotemporal dementia was found to be 33% for C9orf72 (95% CI (20.9 to 53.2)), 54% for SOD1 (95% CI (32.7 to 88.6)), 38% for TARDBP (95% CI (21.1 to 69.8)) and 19% for FUS (95% CI (13.0 to 28.4)).

CONCLUSION: Population-level penetrance of amyotrophic lateral sclerosis disease genes is reduced. This finding has implications for the genetic testing and counselling of affected individuals and their unaffected relatives.}, } @article {pmid38124685, year = {2024}, author = {Strunge, K and Bostock, H and Howells, J and Cengiz, B and Samusyte, G and Koltzenburg, M and Tankisi, H}, title = {Caffeine and cortical excitability, as measured with paired-pulse transcranial magnetic stimulation.}, journal = {Muscle & nerve}, volume = {69}, number = {2}, pages = {206-212}, doi = {10.1002/mus.28027}, pmid = {38124685}, issn = {1097-4598}, support = {//Lundbeck Foundation/ ; //Grosserer L. F. Foghts Fond/ ; //Aase og Ejnar Danielsens Fond/ ; //Dagmar Marshalls Fond/ ; }, mesh = {Female ; Humans ; Male ; Caffeine/pharmacology ; Chewing Gum ; *Cortical Excitability ; Evoked Potentials, Motor/physiology ; *Motor Cortex/physiology ; Neural Inhibition/physiology ; Transcranial Magnetic Stimulation/methods ; Young Adult ; Adult ; }, abstract = {INTRODUCTION/AIMS: The transcranial magnetic stimulation tests of short-interval intracortical inhibition (SICI) by both conventional amplitude measurements (A-SICI) and threshold-tracking (T-SICI) are important methods to investigate intracortical inhibitory circuits, and T-SICI has been proposed to aid the diagnosis of amyotrophic lateral sclerosis. Beverages containing caffeine are widely consumed, and caffeine has been reported to affect cortical excitability. The aim of this study was to determine whether these SICI tests are affected by caffeine.

METHODS: Twenty-four healthy subjects (13 females, 11 males, aged from 19 to 31, mean: 26.2 ± 2.4 years) were studied in a single fixed-dose randomized double-blind placebo-controlled cross-over trial of 200 mg caffeine or placebo ingested as chewing gum. A-SICI and T-SICI, using parallel tracking (T-SICIp), were performed before and after chewing gum.

RESULTS: There was no significant change in SICI parameters after placebo in A-SICI (p > .10) or T-SICIp (p > .30), and no significant effect of caffeine was found on A-SICI (p > .10) or T-SICIp (p > .50) for any of the interstimulus intervals.

DISCUSSION: There is no need for caffeine abstention before measurements of SICI by either the T-SICI or A-SICI measurements.}, } @article {pmid38126188, year = {2025}, author = {Alamri, SH and Haque, S and Alghamdi, BS and Tayeb, HO and Azhari, S and Farsi, RM and Elmokadem, A and Alamri, TA and Harakeh, S and Prakash, A and Kumar, V}, title = {Comprehensive mapping of mutations in TDP-43 and α-Synuclein that affect stability and binding.}, journal = {Journal of biomolecular structure & dynamics}, volume = {43}, number = {4}, pages = {1818-1830}, doi = {10.1080/07391102.2023.2293258}, pmid = {38126188}, issn = {1538-0254}, mesh = {*alpha-Synuclein/genetics/chemistry/metabolism ; *DNA-Binding Proteins/genetics/chemistry/metabolism ; Protein Binding ; Humans ; Protein Stability ; Molecular Dynamics Simulation ; *Mutation ; Mutation, Missense ; Binding Sites ; Thermodynamics ; }, abstract = {Abnormal aggregation and amyloid inclusions of TAR DNA-binding protein 43 (TDP-43) and α-Synuclein (α-Syn) are frequently co-observed in amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Several reports showed TDP-43 C-terminal domain (CTD) and α-Syn interact with each other and the aggregates of these two proteins colocalized together in different cellular and animal models. Molecular dynamics simulation was conducted to elucidate the stability of the TDP-43 and Syn complex structure. The interfacial mutations in protein complexes changes the stability and binding affinity of the protein that may cause diseases. Here, we have utilized the computational saturation mutagenesis approach including structure-based stability and binding energy calculations to compute the systemic effects of missense mutations of TDP-43 CTD and α-Syn on protein stability and binding affinity. Most of the interfacial mutations of CTD and α-Syn were found to destabilize the protein and reduced the protein binding affinity. The results thus shed light on the functional consequences of missense mutations observed in TDP-43 associated proteinopathies and may provide the mechanisms of co-morbidities involving these two proteins.Communicated by Ramaswamy H. Sarma.}, } @article {pmid38127186, year = {2024}, author = {Guo, R and Chen, Y and Zhang, J and Zhou, Z and Feng, B and Du, X and Liu, X and Ma, J and Cui, H}, title = {Neural Differentiation and spinal cord organoid generation from induced pluripotent stem cells (iPSCs) for ALS modelling and inflammatory screening.}, journal = {Molecular neurobiology}, volume = {61}, number = {7}, pages = {4732-4749}, pmid = {38127186}, issn = {1559-1182}, support = {81801278//Natural Science Foundation of China/ ; 201608130015//China National Textile and Apparel Council/ ; H2019206637//Natural Science Foundation of Hebei Province/ ; H2015206409//Natural Science Foundation of Hebei Province/ ; H2020206557//Key Natural Science Foundation of Hebei Province/ ; C20190509//Overseas researcher Program in Hebei Provincial Department of human resources and social security/ ; }, mesh = {*Induced Pluripotent Stem Cells/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *Organoids/metabolism/pathology ; *Cell Differentiation ; *Spinal Cord/pathology ; *Motor Neurons/pathology/metabolism ; Astrocytes/metabolism/pathology ; Inflammation/pathology ; C9orf72 Protein/genetics/metabolism ; Models, Biological ; Neurons/metabolism/pathology ; }, abstract = {C9orf72 genetic mutation is the most common genetic cause of ALS/FTD accompanied by abnormal protein insufficiency. Induced pluripotent stem cell (iPSC)-derived two-dimensional (2D) and three-dimensional (3D) cultures are providing new approaches. Therefore, this study established neuronal cell types and generated spinal cord organoids (SCOs) derived from C9orf72 knockdown human iPSCs to model ALS disease and screen the unrevealed phenotype. Wild-type (WT) iPSC lines from three healthy donor fibroblasts were established, and pluripotency and differentiation ability were identified by RT-PCR, immunofluorescence and flow cytometry. After infection by the lentivirus with C9orf72-targeting shRNA, stable C9-knockdown iPSC colonies were selected and differentiated into astrocytes, motor neurons and SCOs. Finally, we analyzed the extracted RNA-seq data of human C9 mutant/knockout iPSC-derived motor neurons and astrocytes from the GEO database and the inflammatory regulation-related genes in function and pathways. The expression of inflammatory factors was measured by qRT-PCR. The results showed that both WT-iPSCs and edited C9-iPSCs maintained a similar ability to differentiate into the three germ layers, astrocytes and motor neurons, forming SCOs in a 3D culture system. The constructed C9-SCOs have features of spinal cord development and multiple neuronal cell types, including sensory neurons, motor neurons, and other neurons. Based on the bioinformatics analysis, proinflammatory factors were confirmed to be upregulated in C9-iPSC-derived 2D cells and 3D cultured SCOs. The above differentiated models exhibited low C9orf72 expression and the pathological characteristics of ALS, especially neuroinflammation.}, } @article {pmid38127305, year = {2023}, author = {Lester, EG and Vitolo, OV and Flaherty, A and Beaussant, Y and Cramer, M and Harley, R and Cohen, JN}, title = {"When Will All of This End?": A 65-Year-Old Man With Amyotrophic Lateral Sclerosis and Psychiatric Distress.}, journal = {The Journal of clinical psychiatry}, volume = {85}, number = {1}, pages = {}, doi = {10.4088/JCP.23ct15038}, pmid = {38127305}, issn = {1555-2101}, mesh = {Aged ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/therapy ; *Cognitive Behavioral Therapy ; Psychotherapy ; *Psychological Distress ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) are impacted both physically and psychiatrically during their illness. Emotional distress (ie, anxiety, depression, stress) is common in patients diagnosed with ALS, as prognosis is poor and there are very few effective treatments. The progression of symptoms is unpredictable, and all cases are terminal. Neuropsychiatric symptoms are also increasingly recognized as part of ALS symptomatology. There are currently no empirically supported interventions or best practices for adjustment to ALS. This case presents both the psychological and pharmacologic aspects of caring for a patient with ALS. Psychotherapy utilized a cognitive behavioral therapy-informed approach, and pharmacotherapy was tailored to the specific needs of the patient. We explore how these approaches impacted our patient, as well as how ALS-specific challenges presented throughout the course of treatment.}, } @article {pmid38127306, year = {2023}, author = {Ho, DT and Berry, JD}, title = {The Intense Psychological Burden of ALS, the Enduring Strength of People Living With ALS, and the Tools We Can Use to Help.}, journal = {The Journal of clinical psychiatry}, volume = {85}, number = {1}, pages = {}, doi = {10.4088/JCP.23com15173}, pmid = {38127306}, issn = {1555-2101}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; }, } @article {pmid38128171, year = {2024}, author = {Manrique Rabelo, CM}, title = {[Resistance to the use of a wheelchair and gait aids by patients with amyotrophic ALS: Learned beliefs and attitudes].}, journal = {Rehabilitacion}, volume = {58}, number = {1}, pages = {100830}, doi = {10.1016/j.rh.2023.100830}, pmid = {38128171}, issn = {1578-3278}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Gait ; *Wheelchairs ; Muscular Atrophy ; }, } @article {pmid38128275, year = {2024}, author = {Alcaraz, MR and Espinosa-Mansilla, A and Durán-Merás, I and Muñoz de la Peña, A}, title = {An optimized methodology for the determination of multiclass organic ultraviolet sunscreens and metabolites in human milk through chromatographic and chemometric resolution.}, journal = {Talanta}, volume = {270}, number = {}, pages = {125560}, doi = {10.1016/j.talanta.2023.125560}, pmid = {38128275}, issn = {1873-3573}, mesh = {Humans ; *Milk, Human ; Sunscreening Agents ; Chemometrics ; Ecosystem ; Chromatography, Reverse-Phase ; *Liquid Phase Microextraction/methods ; Chromatography, High Pressure Liquid/methods ; }, abstract = {Organic UV filters (UVFS) are used to mitigate the dermal effects associated with health risks from UV radiation, making them essential in personal care products. UVFS are frequently identified in environmental samples due to their high lipophilicity and persistence, underscoring the urgency of comprehensive assessments and regulatory measures aimed at safeguarding ecosystems and human health. The present study reports a multiclass analytical method for determining 16 UV sunscreens and metabolites in breast milk based on an ultrasound-assisted-dispersive liquid-liquid micro-extraction (UA-DLLME) with further chromatographic and chemometric resolution. The experimental conditions of the UA-DLLME were optimized through the implementation of the Design of Experiment tools. To model the responses, least-squares and artificial neural network methodologies were implemented. The optimal conditions were found by employing the desirability function. The samples were analyzed through reverse-phase liquid chromatographic separation, UV diode array, and fast-scanning fluorescence detection. The chromatographic analysis enabled the resolution of 16 analytes in a total time of 13.0 min. Multivariate curve resolution-alternating least-square (MCR-ALS) modelling was implemented to resolve analytes that were not fully resolved and to determine analytes that coeluted with endogenous components of the breast milk samples. An enrichment factor of 5-fold concentration was obtained with this methodology, reaching recoveries between 65 % and 105 % for 13 multiclass UV sunscreens and metabolites in breast milk samples with RSD % and REP % lower than 12 %.}, } @article {pmid38129120, year = {2024}, author = {Allison, RL and Ebert, AD}, title = {ALS iPSC-derived microglia and motor neurons respond to astrocyte-targeted IL-10 and CCL2 modulation.}, journal = {Human molecular genetics}, volume = {33}, number = {6}, pages = {530-542}, doi = {10.1093/hmg/ddad209}, pmid = {38129120}, issn = {1460-2083}, support = {//Medical College of Wisconsin Center for Immunology/ ; //Neuroscience Research Center/ ; }, mesh = {Humans ; Interleukin-10/genetics ; Astrocytes ; C9orf72 Protein ; Microglia ; *Amyotrophic Lateral Sclerosis/genetics ; *Induced Pluripotent Stem Cells ; *Neurodegenerative Diseases ; Superoxide Dismutase-1/genetics ; Motor Neurons ; Chemokine CCL2/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs). The loss of MNs in ALS leads to muscle weakness and wasting, respiratory failure, and death often within two years of diagnosis. Glial cells in ALS show aberrant expression of pro-inflammatory and neurotoxic proteins associated with activation and have been proposed as ideal therapeutic targets. In this study, we examined astrocyte-targeted treatments to reduce glial activation and neuron pathology using cells differentiated from ALS patient-derived iPSC carrying SOD1 and C9ORF72 mutations. Specifically, we tested the ability of increasing interleukin 10 (IL-10) and reducing C-C motif chemokine ligand 2 (CCL2/MCP-1) signaling targeted to astrocytes to reduce activation phenotypes in both astrocytes and microglia. Overall, we found IL10/CCL2NAb treated astrocytes to support anti-inflammatory phenotypes and reduce neurotoxicity, through different mechanisms in SOD1 and C9ORF72 cultures. We also found altered responses of microglia and motor neurons to astrocytic influences when cells were cultured together rather than in isolation. Together these data support IL-10 and CCL2 as non-mutation-specific therapeutic targets for ALS and highlight the role of glial-mediated pathology in this disease.}, } @article {pmid38129650, year = {2023}, author = {Ito, H and Machida, K and Hasumi, M and Ueyama, M and Nagai, Y and Imataka, H and Taguchi, H}, title = {Reconstitution of C9orf72 GGGGCC repeat-associated non-AUG translation with purified human translation factors.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {22826}, pmid = {38129650}, issn = {2045-2322}, support = {JPMJFS2112//Japan Science and Technology Agency/ ; JP26116002//Ministry of Education, Culture, Sports, Science and Technology/ ; JP18H03984//Ministry of Education, Culture, Sports, Science and Technology/ ; JP21H04763//Ministry of Education, Culture, Sports, Science and Technology/ ; JP20H05925//Ministry of Education, Culture, Sports, Science and Technology/ ; 2019-25//Mitsubishi Foundation/ ; 2019//Uehara Memorial Foundation/ ; }, mesh = {Peptide Chain Elongation, Translational ; Peptide Elongation Factors/metabolism ; Humans ; *C9orf72 Protein/genetics ; Frameshifting, Ribosomal ; Peptide Chain Initiation, Translational ; In Vitro Techniques ; HeLa Cells ; *Protein Biosynthesis ; Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics ; }, abstract = {Nucleotide repeat expansion of GGGGCC (G4C2) in the non-coding region of C9orf72 is the most common genetic cause underlying amyotrophic lateral sclerosis and frontotemporal dementia. Transcripts harboring this repeat expansion undergo the translation of dipeptide repeats via a non-canonical process known as repeat-associated non-AUG (RAN) translation. In order to ascertain the essential components required for RAN translation, we successfully recapitulated G4C2-RAN translation using an in vitro reconstituted translation system comprising human factors, namely the human PURE system. Our findings conclusively demonstrate that the presence of fundamental translation factors is sufficient to mediate the elongation from the G4C2 repeat. Furthermore, the initiation mechanism proceeded in a 5' cap-dependent manner, independent of eIF2A or eIF2D. In contrast to cell lysate-mediated RAN translation, where longer G4C2 repeats enhanced translation, we discovered that the expansion of the G4C2 repeats inhibited translation elongation using the human PURE system. These results suggest that the repeat RNA itself functions as a repressor of RAN translation. Taken together, our utilization of a reconstituted RAN translation system employing minimal factors represents a distinctive and potent approach for elucidating the intricacies underlying RAN translation mechanism.}, } @article {pmid38129934, year = {2023}, author = {Marriott, H and Kabiljo, R and Hunt, GP and Khleifat, AA and Jones, A and Troakes, C and , and , and Pfaff, AL and Quinn, JP and Koks, S and Dobson, RJ and Schwab, P and Al-Chalabi, A and Iacoangeli, A}, title = {Unsupervised machine learning identifies distinct ALS molecular subtypes in post-mortem motor cortex and blood expression data.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {208}, pmid = {38129934}, issn = {2051-5960}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; Motor Neurone Disease Association/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Unsupervised Machine Learning ; *Motor Cortex/metabolism ; Brain/pathology ; Autopsy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) displays considerable clinical and genetic heterogeneity. Machine learning approaches have previously been utilised for patient stratification in ALS as they can disentangle complex disease landscapes. However, lack of independent validation in different populations and tissue samples have greatly limited their use in clinical and research settings. We overcame these issues by performing hierarchical clustering on the 5000 most variably expressed autosomal genes from motor cortex expression data of people with sporadic ALS from the KCL BrainBank (N = 112). Three molecular phenotypes linked to ALS pathogenesis were identified: synaptic and neuropeptide signalling, oxidative stress and apoptosis, and neuroinflammation. Cluster validation was achieved by applying linear discriminant analysis models to cases from TargetALS US motor cortex (N = 93), as well as Italian (N = 15) and Dutch (N = 397) blood expression datasets, for which there was a high assignment probability (80-90%) for each molecular subtype. The ALS and motor cortex specificity of the expression signatures were tested by mapping KCL BrainBank controls (N = 59), and occipital cortex (N = 45) and cerebellum (N = 123) samples from TargetALS to each cluster, before constructing case-control and motor cortex-region logistic regression classifiers. We found that the signatures were not only able to distinguish people with ALS from controls (AUC 0.88 ± 0.10), but also reflect the motor cortex-based disease process, as there was perfect discrimination between motor cortex and the other brain regions. Cell types known to be involved in the biological processes of each molecular phenotype were found in higher proportions, reinforcing their biological interpretation. Phenotype analysis revealed distinct cluster-related outcomes in both motor cortex datasets, relating to disease onset and progression-related measures. Our results support the hypothesis that different mechanisms underpin ALS pathogenesis in subgroups of patients and demonstrate potential for the development of personalised treatment approaches. Our method is available for the scientific and clinical community at https://alsgeclustering.er.kcl.ac.uk .}, } @article {pmid38131496, year = {2023}, author = {Lynch, HF}, title = {Big Mistake: Knowing and Doing Better in Patient Engagement.}, journal = {The Hastings Center report}, volume = {53}, number = {6}, pages = {2}, doi = {10.1002/hast.1537}, pmid = {38131496}, issn = {1552-146X}, mesh = {Humans ; Female ; Patient Participation ; *Bioethics ; Ethicists ; Dissent and Disputes ; *Amyotrophic Lateral Sclerosis/therapy ; }, abstract = {Pushing back on policies favored by dying patients is a challenging endeavor, requiring tact, engagement, openness to bidirectional learning, and willingness to offer alternative solutions. It's easy to make missteps, especially in the age of social media. Holly Fernandez Lynch shares her experience learning with and from the amyotrophic lateral sclerosis (ALS) community, first as a caricature of an ivory tower bioethicist and more recently as a trusted advisor, at least for some. Patient-engaged bioethics doesn't mean taking the view that patients are always right, but even when disagreement continues, progress is possible if academics and patients recognize the unique expertise each has to offer.}, } @article {pmid38131803, year = {2023}, author = {Miteva, D and Vasilev, GV and Velikova, T}, title = {Role of Specific Autoantibodies in Neurodegenerative Diseases: Pathogenic Antibodies or Promising Biomarkers for Diagnosis.}, journal = {Antibodies (Basel, Switzerland)}, volume = {12}, number = {4}, pages = {}, pmid = {38131803}, issn = {2073-4468}, support = {BG-RRP-2.004-0008//the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria/ ; }, abstract = {Neurodegenerative diseases (NDDs) affect millions of people worldwide. They develop due to the pathological accumulation and aggregation of various misfolded proteins, axonal and synaptic loss and dysfunction, inflammation, cytoskeletal abnormalities, defects in DNA and RNA, and neuronal death. This leads to the activation of immune responses and the release of the antibodies against them. Recently, it has become clear that autoantibodies (Aabs) can contribute to demyelination, axonal loss, and brain and cognitive dysfunction. This has significantly changed the understanding of the participation of humoral autoimmunity in neurodegenerative disorders. It is crucial to understand how neuroinflammation is involved in neurodegeneration, to aid in improving the diagnostic and therapeutic value of Aabs in the future. This review aims to provide data on the immune system's role in NDDs, the pathogenic role of some specific Aabs against molecules associated with the most common NDDs, and their potential role as biomarkers for monitoring and diagnosing NDDs. It is suggested that the autoimmune aspects of NDDs will facilitate early diagnosis and help to elucidate previously unknown aspects of the pathobiology of these diseases.}, } @article {pmid38132101, year = {2023}, author = {Liu, T and Wetzel, L and Zhu, Z and Kumaraguru, P and Gorthi, V and Yan, Y and Bukhari, MZ and Ermekbaeva, A and Jeon, H and Kee, TR and Woo, JA and Kang, DE}, title = {Disruption of Mitophagy Flux through the PARL-PINK1 Pathway by CHCHD10 Mutations or CHCHD10 Depletion.}, journal = {Cells}, volume = {12}, number = {24}, pages = {}, pmid = {38132101}, issn = {2073-4409}, support = {I01 BX004680/BX/BLRD VA/United States ; R21 AG070299/AG/NIA NIH HHS/United States ; R01 AG080924/AG/NIA NIH HHS/United States ; R01AG080924/NH/NIH HHS/United States ; R01NS122350/NH/NIH HHS/United States ; R21AG070299/NH/NIH HHS/United States ; R01 AG059721/AG/NIA NIH HHS/United States ; R01AG059721/NH/NIH HHS/United States ; R01 NS122350/NS/NINDS NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; RF1AG053060/NH/NIH HHS/United States ; RF1 AG053060/AG/NIA NIH HHS/United States ; R01AG067741/NH/NIH HHS/United States ; RF1 NS122218/NS/NINDS NIH HHS/United States ; R01 AG067741/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/genetics/pathology ; Mitophagy/genetics ; Mitochondrial Proteins/genetics/metabolism ; Mutation/genetics ; DNA-Binding Proteins/genetics/metabolism ; Protein Kinases/genetics ; Mammals/metabolism ; Metalloproteases/genetics ; }, abstract = {Coiled-coil-helix-coiled-coil-helix domain-containing 10 (CHCHD10) is a nuclear-encoded mitochondrial protein which is primarily mutated in the spectrum of familial and sporadic amyotrophic lateral sclerosis (ALS)-frontotemporal dementia (FTD). Endogenous CHCHD10 levels decline in the brains of ALS-FTD patients, and the CHCHD10[S59L] mutation in Drosophila induces dominant toxicity together with PTEN-induced kinase 1 (PINK1), a protein critical for the induction of mitophagy. However, whether and how CHCHD10 variants regulate mitophagy flux in the mammalian brain is unknown. Here, we demonstrate through in vivo and in vitro models, as well as human FTD brain tissue, that ALS/FTD-linked CHCHD10 mutations (R15L and S59L) impair mitophagy flux and mitochondrial Parkin recruitment, whereas wild-type CHCHD10 (CHCHD10[WT]) normally enhances these measures. Specifically, we show that CHCHD10[R15L] and CHCHD10[S59L] mutations reduce PINK1 levels by increasing PARL activity, whereas CHCHD10[WT] produces the opposite results through its stronger interaction with PARL, suppressing its activity. Importantly, we also demonstrate that FTD brains with TAR DNA-binding protein-43 (TDP-43) pathology demonstrate disruption of the PARL-PINK1 pathway and that experimentally impairing mitophagy promotes TDP-43 aggregation. Thus, we provide herein new insights into the regulation of mitophagy and TDP-43 aggregation in the mammalian brain through the CHCHD10-PARL-PINK1 pathway.}, } @article {pmid38132330, year = {2023}, author = {Spisni, E and Valerii, MC and Massimino, ML}, title = {Essential Oil Molecules Can Break the Loop of Oxidative Stress in Neurodegenerative Diseases.}, journal = {Biology}, volume = {12}, number = {12}, pages = {}, pmid = {38132330}, issn = {2079-7737}, support = {0000//Xeda international (1397 Route Nationale 7, Zac la Crau, 13670 Saint Andiol, France)./ ; }, abstract = {Essential oils (EOs) are mixtures of volatile compounds, extracted from aromatic plants, with multiple activities including antioxidant and anti-inflammatory ones. EOs are complex mixtures easy to find on the market and with low costs. In this mini narrative review, we have collected the results of in vitro and in vivo studies, which tested these EOs on validated models of neurodegeneration and in particular of the two main neurodegenerative diseases (NDs) that afflict humans: Alzheimer's and Parkinson's. Since EO compositions can vary greatly, depending on the environmental conditions, plant cultivar, and extraction methods, we focused our attention to studies involving single EO molecules, and in particular those that have demonstrated the ability to cross the blood-brain barrier. These single EO molecules, alone or in defined mixtures, could be interesting new therapies to prevent or slow down oxidative and inflammatory processes which are common mechanisms that contribute to neuronal death in all NDs.}, } @article {pmid38134563, year = {2024}, author = {Dave, U and Narain, P and Mishra, D and Gomes, J}, title = {Aggregation of E121K mutant D-amino acid oxidase and ubiquitination-mediated autophagy mechanisms leading to amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {456}, number = {}, pages = {122845}, doi = {10.1016/j.jns.2023.122845}, pmid = {38134563}, issn = {1878-5883}, mesh = {Adult ; Humans ; Amino Acids ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Autophagy/genetics ; Mutation/genetics ; *Neuroblastoma ; Oxidoreductases ; Protein Aggregates ; Ubiquitin/metabolism ; Ubiquitination ; D-Amino-Acid Oxidase ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a terminal adult-onset neuromuscular disorder. Our group has been studying this illness and previously reported novel mutations and rare mutations in a study using next-generation sequencing of DNA samples from Indian ALS patients. In this paper, we focus on the E121K mutation in the DAO gene to understand how it leads to ALS. Our experiments in SH-SY5Y cells indicate that the E121K mutation results in the accumulation of mutant protein aggregates, a change in cell morphology, and the death of neuronal cells. These protein aggregates get ubiquitinated and cause an imbalance in autophagy regulation. We observed an increase in the cellular concentrations of p62, OPTN, and LC3II. Through confocal microscopy studies, we show that the binding of p62 with ubiquitinated aggregates and its recruitment to LC3II mediates autophagosome generation. These relative changes in the key partners in autophagy increase cell death in cells harboring the E121K mutation and is a probable mechanism leading to ALS.}, } @article {pmid38134913, year = {2024}, author = {Wicke, F and Lorenz, E and Pokora, RM}, title = {[Schätzung der Wirksamkeit der Grippeimpfung anhand von Sekundärdaten: Eine Kohortenstudie und Propensity-Score-Matching-Analyse von Leistungsdaten aus Baden-Württemberg].}, journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))}, volume = {86}, number = {S 03}, pages = {S205-S211}, doi = {10.1055/a-2173-8160}, pmid = {38134913}, issn = {1439-4421}, mesh = {Humans ; Germany/epidemiology ; *Influenza, Human/prevention & control/epidemiology ; *Influenza Vaccines/administration & dosage ; Male ; *Propensity Score ; Female ; Middle Aged ; Adult ; Aged ; Adolescent ; Young Adult ; Cohort Studies ; Aged, 80 and over ; Hospitalization/statistics & numerical data ; Vaccine Efficacy/statistics & numerical data ; Treatment Outcome ; Age Distribution ; Sex Distribution ; Reproducibility of Results ; }, abstract = {Ziel war es die Wirksamkeit der Influenza-Impfung (VE) für die Grippesaison 2014/2015 auf Grundlage von Routinedaten aus Krankenkassendatensatz zu schätzen und zu replizieren. Zusätzlich sollten methodische Aspekte untersucht werden. Es wurden Abrechnungsdaten von 2,64 Millionen Versicherten der AOK Baden-Württemberg mit dortigem Wohnsitz ab 15 Jahren analysiert. Basierend auf Abrechnungsdaten für die Influenza-Impfung 2014, wurden die Teilnehmer als ungeimpft oder geimpft klassifiziert. Kovariablen, die den Zusammenhang zwischen Impfung und Influenzainfektion beeinträchtigen könnten, wurden berücksichtigt. Hierzu gehörten Alter, Geschlecht, Wohnort sowie Kovariablen, die auf den Gesundheitszustand und die Inanspruchnahme von Gesundheitsdienstleistungen hinweisen. Der primäre Endpunkt war ein Krankenhausaufenthalt wegen Influenza während der Grippesaison 2015. Zu den sekundären Endpunkten gehörten unter anderem Krankenhausaufenthalte wegen Lungenentzündung und die Gesamtmortalität. Um eine vergleichbare Gruppe von geimpften und ungeimpften Teilnehmern zu ermitteln, wurde ein Propensity-Score-Matching (PSM) durchgeführt. Es wurde eine Bias-Analyse durchgeführt, bei der die VE vor und nach der Grippesaison geschätzt wurde, also zu Zeitpunkten, in denen angenommen wurde, dass die Influenza nicht in der Bevölkerung zirkulierte und die Impfung nicht wirken konnte. Insgesamt konnten 839.706 Teilnehmer 1:1 gematcht werden. Die geschätzte VE (basierend auf Influenza bedingten Krankenhausaufenthalten) betrug 27% [95%Konfidenzintervall (KI): 17%; 36%], was der Schätzung des RKI für dieselbe Saison (27% [95%KI: -1%; 47%]) entspricht. Die Bias-Analyse zeigte, dass das Ergebnis teilweise durch residuale Konfundierung erklärt werden kann, was zu einer potenziellen Überschätzung des zugrunde liegenden Effekts führt. Die Ergebnisse der sekundären Endpunkte zeigten ähnliche Ergebnisse, obwohl sie wahrscheinlich in höherem Maße durch residuale Konfundierung bedingt sind. Zusammenfassend zeigt sich, dass (1) sekundäre Daten der deutschen Krankenkassen verwendet werden können, um plausible VE-Schätzungen abzuleiten, und dass (2) das PSM eine nützliche und transparente Methode zur Ableitung dieser Schätzungen ist. Darüber hinaus ist (3) residuale Konfundierung ein relevantes Problem in Beobachtungsstudien zu VE und (4) Bias-Analysen vor- und nach der Grippesaison sind eine wesentliche Ergänzung für die Interpretation der Ergebnisse.}, } @article {pmid38135852, year = {2024}, author = {Huang, J and Yu, Y and Pang, D and Li, C and Wei, Q and Cheng, Y and Cui, Y and Ou, R and Shang, H}, title = {Lnc-HIBADH-4 Regulates Autophagy-Lysosome Pathway in Amyotrophic Lateral Sclerosis by Targeting Cathepsin D.}, journal = {Molecular neurobiology}, volume = {61}, number = {7}, pages = {4768-4782}, pmid = {38135852}, issn = {1559-1182}, support = {81871000//National Natural Science Foundation of China/ ; 82101485//National Natural Science Foundation of China/ ; 2022ZYD0051//Sichuan Province Science and Technology Support Program/ ; No.2022NSFSC0750//Sichuan Province Science and Technology Support Program/ ; }, mesh = {Humans ; *Autophagy/physiology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; *Lysosomes/metabolism ; *Cathepsin D/metabolism/genetics ; Male ; Female ; Signal Transduction ; MicroRNAs/genetics/metabolism ; Apoptosis/genetics ; Middle Aged ; Cell Proliferation ; Down-Regulation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most prevalent and lethal class of severe motor neuron diseases (MND) with no efficacious treatment. The pathogenic mechanisms underlying ALS remain unclear. Nearly 90% of patients exhibit sporadic onset (sALS). Therefore, elucidating the pathophysiology of ALS is imperative. Long non-coding RNA (lncRNA) is a large class of non-coding RNAs that regulate transcription, translation, and post-translational processes. LncRNAs contribute to the pathogenesis of diverse neurodegenerative disorders and hold promise as targets for interference in the realm of neurodegeneration. However, the mechanisms of which lncRNAs are involved in ALS have not been thoroughly investigated. We identified and validated a downregulated lncRNA, lnc-HIBADH-4, in ALS which correlated with disease severity and overall survival. Lnc-HIBADH-4 acted as a "molecular sponge" regulating lysosomal function through the lnc-HIBADH-4/miR-326/CTSD pathway, thereby impacting autophagy-lysosome dynamics and the levels of cell proliferation and apoptosis. Therefore, this study discovered and revealed the role of lnc-HIBADH-4 in the pathogenesis of ALS. With further research, lnc-HIBADH-4 is expected to provide a new biomarker in the diagnosis and treatment of ALS.}, } @article {pmid38136561, year = {2023}, author = {Cotet, C and Alarcan, H and Hérault, O and Corcia, P and Vourc'h, P and Andres, CR and Blasco, H and Veyrat-Durebex, C}, title = {Neutrophil to Lymphocyte Ratio as a Prognostic Marker in Amyotrophic Lateral Sclerosis.}, journal = {Biomolecules}, volume = {13}, number = {12}, pages = {}, pmid = {38136561}, issn = {2218-273X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Neutrophils ; Retrospective Studies ; Prognosis ; Disease Progression ; Lymphocytes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative motor neuron disease and remains misunderstood with a difficult diagnosis and prognosis. The implication of the immune system is recognized in ALS pathophysiology, hence the interest in leucocyte count as lymphocytes and neutrophils. The neutrophil-to-lymphocyte ratio (NLR) has recently been used as a prognosis factor to assess the progression of ALS. Thus, the aim of this study was to analyze the evolution of the NLR during disease evolution in a French cohort of ALS patients and its relation with survival. In this monocentric retrospective study, clinical parameters and NLR were collected in ALS patients followed at the University Hospital of Tours (France). ALS patients were subdivided into three groups regarding their NLR value at inclusion: group 1 (NLR < 2); group 2 (NLR: 2-3); group 3 (NLR > 3). A comparison of qualitative and quantitative clinical and biological variables between NLR groups was performed. Then, Cox regressions were carried out to determine the association of NLR with survival. We observed a significant correlation of NLR with ALSFRS-r score (p < 0.0001) and with vital forced capacity (p = 0.0004) at inclusion. We observed that increased NLR at diagnosis is associated with decreased ALS patients' survival.}, } @article {pmid38136659, year = {2023}, author = {Cilleros-Holgado, P and Gómez-Fernández, D and Piñero-Pérez, R and Romero-Domínguez, JM and Reche-López, D and López-Cabrera, A and Álvarez-Córdoba, M and Munuera-Cabeza, M and Talaverón-Rey, M and Suárez-Carrillo, A and Romero-González, A and Sánchez-Alcázar, JA}, title = {Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {13}, number = {12}, pages = {}, pmid = {38136659}, issn = {2218-273X}, support = {FIS PI19/00377 and PI22/00142 grants//Instituto de Salud Carlos III/ ; CTS-5725, PY18-850, and UPO-FEDER 2018 (UPO-1380614)//Regional Government of Andalusia/ ; }, mesh = {Animals ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; *Mitochondrial Diseases ; Aging ; Unfolded Protein Response ; }, abstract = {Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.}, } @article {pmid38136980, year = {2023}, author = {Bouike, Y and Sakima, M and Taninishi, Y and Matsutani, T and Noguchi, Y and Bo, R and Awano, H and Nishio, H}, title = {Real-Time PCR-Based Screening for Homozygous SMN2 Deletion Using Residual Dried Blood Spots.}, journal = {Genes}, volume = {14}, number = {12}, pages = {}, pmid = {38136980}, issn = {2073-4425}, support = {23K07279//the Ministry of Education, Culture, Sports, Science, and Technology, Japan/ ; }, mesh = {Infant ; Infant, Newborn ; Humans ; Real-Time Polymerase Chain Reaction/methods ; Retrospective Studies ; Prospective Studies ; Gene Deletion ; *Muscular Atrophy, Spinal/diagnosis/genetics ; Motor Neurons ; Neonatal Screening/methods ; Survival of Motor Neuron 2 Protein/genetics ; }, abstract = {The survival motor neuron 2 (SMN2) gene is a recognized modifier gene of spinal muscular atrophy (SMA). However, our knowledge about the role of SMN2-other than its modification of SMA phenotypes-is very limited. Discussions regarding the relationship between homozygous SMN2 deletion and motor neuron diseases, including amyotrophic lateral sclerosis, have been mainly based on retrospective epidemiological studies of the diseases, and the precise relationship remains inconclusive. In the present study, we first estimated that the frequency of homozygous SMN2 deletion was ~1 in 20 in Japan. We then established a real-time polymerase chain reaction (PCR)-based screening method using residual dried blood spots to identify infants with homozygous SMN2 deletion. This method can be applied to a future prospective cohort study to clarify the relationship between homozygous SMN2 deletion and motor neuron diseases. In our real-time PCR experiment, both PCR (low annealing temperatures) and blood (high hematocrit values and low white blood cell counts) conditions were associated with incorrect results (i.e., false negatives and positives). Together, our findings not only help to elucidate the role of SMN2, but also aid in our understanding of the pitfalls of current SMA newborn screening programs for detecting homozygous SMN1 deletions.}, } @article {pmid38139294, year = {2023}, author = {Peggion, C and Massimino, ML and Pereira, D and Granuzzo, S and Righetto, F and Bortolotto, R and Agostini, J and Sartori, G and Bertoli, A and Lopreiato, R}, title = {Structural Integrity of Nucleolin Is Required to Suppress TDP-43-Mediated Cytotoxicity in Yeast and Human Cell Models.}, journal = {International journal of molecular sciences}, volume = {24}, number = {24}, pages = {}, pmid = {38139294}, issn = {1422-0067}, support = {DOR2395544/23; BIRD202151/20; DOR2331994/23//University of Padova/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA ; *DNA-Binding Proteins/metabolism ; *Frontotemporal Lobar Degeneration/genetics/metabolism ; *Nucleolin/metabolism ; RNA ; Saccharomyces cerevisiae/genetics/metabolism ; }, abstract = {The Transactivating response (TAR) element DNA-binding of 43 kDa (TDP-43) is mainly implicated in the regulation of gene expression, playing multiple roles in RNA metabolism. Pathologically, it is implicated in amyotrophic lateral sclerosis and in a class of neurodegenerative diseases broadly going under the name of frontotemporal lobar degeneration (FTLD). A common hallmark of most forms of such diseases is the presence of TDP-43 insoluble inclusions in the cell cytosol. The molecular mechanisms of TDP-43-related cell toxicity are still unclear, and the contribution to cell damage from either loss of normal TDP-43 function or acquired toxic properties of protein aggregates is yet to be established. Here, we investigate the effects on cell viability of FTLD-related TDP-43 mutations in both yeast and mammalian cell models. Moreover, we focus on nucleolin (NCL) gene, recently identified as a genetic suppressor of TDP-43 toxicity, through a thorough structure/function characterization aimed at understanding the role of NCL domains in rescuing TDP-43-induced cytotoxicity. Using functional and biochemical assays, our data demonstrate that the N-terminus of NCL is necessary, but not sufficient, to exert its antagonizing effects on TDP-43, and further support the relevance of the DNA/RNA binding central region of the protein. Concurrently, data suggest the importance of the NCL nuclear localization for TDP-43 trafficking, possibly related to both TDP-43 physiology and toxicity.}, } @article {pmid38140224, year = {2023}, author = {Park, JS and Ahmad, R and Choe, K and Kang, MH and Park, TJ and Kim, MO}, title = {Immunization Effects of a Novel α-Synuclein-Based Peptide Epitope Vaccine in Parkinson's Disease-Associated Pathology.}, journal = {Vaccines}, volume = {11}, number = {12}, pages = {}, pmid = {38140224}, issn = {2076-393X}, support = {2020M3E5D9080660//National Research Foundation of Korea/ ; }, abstract = {Parkinson's disease (PD) is a chronic neurodegenerative disease that affects the central nervous system, specifically the motor system. It is mainly caused by the loss of dopamine due to the accumulation of α-synuclein (α-syn) protein in the striatum and substantia nigra pars compacta (SNpc). Previous studies have reported that immunization may be a potential preventive strategy for neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Therefore, the aim of the study was to design an α-syn specific epitope vaccine and investigate its effect in PD-related pathophysiology using an α-syn-induced mouse model. We used an in silico model to identify and design a non-toxic α-syn-based peptide epitope vaccine and, to overcome poor immunogenicity, the vaccine was coupled with immunogenic carrier proteins, i.e., ovalbumin (OVA) and keyhole limpet haemocyanin (KLH). Our results showed that vaccinated PD mouse models, especially with vaccines with carrier proteins, improved in motor functions compared with the non-vaccinated PD model. Additionally, the vaccinated groups showed increased immunoglobulin G (IgG) levels in the spleen and plasma as well as decreased interleukin-10 (IL-10) levels in the plasma. Furthermore, vaccinated groups, especially OVA and KLH groups, showed decrease in α-syn levels and increased dopamine-related markers, i.e., tyrosine hydroxylase (TH), vesicle monoamine transporter 2 (VMAT2), and dopamine transporter (DAT), and autophagy activities in the striatum and SNpc. Lastly, our data showed decreased neuroinflammation by reducing the activation of microglia and astrocytes and pro-inflammatory cytokines in the immunized groups, especially with OVA and KLH carrier proteins. Overall, these results suggest that vaccination, especially with immunogenic carrier proteins, is effective in reducing the accumulation of α-syn aggregates in the brain and ameliorate PD-related pathophysiology. Hence, further development of this approach might have a potential role in preventing the development of PD.}, } @article {pmid38141002, year = {2024}, author = {Muhanna, M and Lund, I and Bromberg, M and Wicks, P and Benatar, M and Barnes, B and Pierce, K and Ratner, D and Brown, A and Bertorini, T and Barkhaus, P and Carter, G and Mascias Cadavid, J and McDermott, C and Glass, JD and Pattee, G and Armon, C and Bedlack, R and Li, X}, title = {ALSUntangled #73: Lion's Mane.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {420-423}, doi = {10.1080/21678421.2023.2296557}, pmid = {38141002}, issn = {2167-9223}, mesh = {Animals ; Humans ; *Agaricales ; *Amyotrophic Lateral Sclerosis ; Europe ; *Neurodegenerative Diseases ; }, abstract = {Lion's Mane (Hericium erinaceus) has historically been used as traditional medicine in Asia and Europe for its potential benefits in fighting infection and cancer. It has gained interest in the neurodegenerative disease field because of its mechanisms of action; these include anti-inflammation, neuroprotection, and promoting neurite growth demonstrated in various cell and animal models. A very small, double-blind, placebo-controlled trial in patients with mild cognitive impairment showed a temporary improvement in cognitive function; this finding has yet to be replicated. However, there have been no studies in ALS cell or animal models or in humans with ALS. Lion's Mane appears safe and inexpensive when consumed in powder or capsule, but one anaphylactic case was reported after a patient consumed fresh Lion's Mane mushroom. Currently, we do not have enough information to support the use of Lion's Mane for treating ALS. We support further research in ALS disease models and clinical trials to study its efficacy.}, } @article {pmid38141272, year = {2024}, author = {Sancho-Cantus, D and Cubero-Plazas, L and Privado, J and García-Iturrospe, EJA and Cañabate Ros, M and Navarro-Illana, E and Ortí, JER}, title = {Spanish adaptation and validation of the ALS Depression Inventory-12 (ADI-12) in patients with Amyotrophic Lateral Sclerosis.}, journal = {Archives of medical research}, volume = {55}, number = {1}, pages = {102936}, doi = {10.1016/j.arcmed.2023.102936}, pmid = {38141272}, issn = {1873-5487}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; Depression/diagnosis/etiology/epidemiology ; Surveys and Questionnaires ; Mood Disorders ; Reproducibility of Results ; }, abstract = {BACKGROUND: Patients with Amyotrophic Lateral Sclerosis (ALS) have a higher prevalence of mood disorders, including depression, than the general population. Non-specific measurement instruments have been used to evaluate depression in these patients, which complicates accurate diagnosis. The ALS Depression Inventory (ADI-12) exclusively assesses depressive symptoms in patients with ALS.

AIM: To adapt and validate the ADI-12 in a Spanish sample.

METHODS: A selective design was used with 74 patients with ALS, using the ADI-12 questionnaire. The original instrument was translated and back-translated into Spanish. The internal structure, temporal stability, convergent, and discriminant validity of the instrument were analyzed.

RESULTS: Two confirmatory models showed internal validity (p = 0.502 for the one-factor model, p = 0.507 for the two-factor model). The Cronbach's alpha (0.900 in the first measurement and 0.889 in the second one) indicated a high internal consistency of the test. The Pearson correlation (0.90) indicated high temporal stability. In terms of convergent validity, the ADI-12 showed moderate correlations with the Beck Anxiety Inventory (BAI) (0.51-0.58), and low correlations with time since ALS diagnosis (-0.26 to -0.27).

LIMITATIONS: The main limitation of the present study was the small sample size.

CONCLUSIONS: The ADI-12 is fitted to a single general factor of depression, and the scale shows high internal consistency and high temporal stability, therefore, its use is recommended for the diagnosis of depression in patients with ALS.}, } @article {pmid38141357, year = {2024}, author = {Tang, M and Xiong, M and Zhou, W and Lei, J and Huang, M and Huang, C and Wang, F and Liu, J and Li, J and Xu, X}, title = {Generation of a human induced pluripotent stem cell line (SMUSHi002-A) from an ALS patient carrying a heterozygous mutation c.1562G > A in the FUS gene.}, journal = {Stem cell research}, volume = {74}, number = {}, pages = {103286}, doi = {10.1016/j.scr.2023.103286}, pmid = {38141357}, issn = {1876-7753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Mutation/genetics ; RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Affected patients experience gradual loss of their spinal cord and cortical motor neurons with consequent muscle weakness and emaciation, and eventual respiratory failure. The pathogenesis of ALS remains largely unknown although the FUS (sarcoma fusion gene) gene is known to be one of the major pathogenic genes. We have generated an induced pluripotent stem cell line SMUSHi002-A from an ALS patient who carries a heterozygous mutation c.1562G > A in FUS. This cell line will serve as a useful model to investigate disease pathogenesis and develop potential therapeutic approaches for ALS.}, } @article {pmid38142663, year = {2024}, author = {Castro, J and Pedrosa, T and Alves, I and Simão, S and Swash, M and de Carvalho, M}, title = {A neurophysiological approach to mirror movements in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {158}, number = {}, pages = {27-34}, doi = {10.1016/j.clinph.2023.12.002}, pmid = {38142663}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Muscle, Skeletal ; *Movement Disorders ; Neurophysiology ; Transcranial Magnetic Stimulation/methods ; }, abstract = {OBJECTIVE: To investigate mirror activity in amyotrophic lateral sclerosis (ALS) patients, using a simple paradigm of signal quantification.

METHODS: Patients were asked to perform a brief isometric maximum contraction of the abductor digiti minimi (ADM) or tibialis anterior (TA) on one side, while relaxing the contralateral side of the body. Both sides were investigated. Signals were stored and analyzed offline, for quantification of electromyographic signal. Clinical signs of upper motor neuron (UMN) dysfunction, transcranial magnetic stimulation (TMS) for the upper (UL) and lower limbs (LL), the ADM ipsilateral cortical silent period (iSP) and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) cognitive scale were also investigated.

RESULTS: 42 ALS patients were included. In the 4 investigated muscles the amount of mirror activity was significantly higher than in the matched healthy group. The amount of mirror activity was similar between sides, but significantly higher in UL and LL with abnormal TMS results for ADM (p = 0.005) and TA (p = 0.002), as well as in UL with abnormal iSP values (p = 0.009). No association was found between mirror activity and clinical signs of UMN involvement.

CONCLUSIONS: Mirror activity is a common phenomenon in ALS. Mirror activity intensity corresponds to the severity of UMN dysfunction, as measured by TMS, and probably derives from the abnormal transcallosal inhibition as mirrored by iSP abnormality.

SIGNIFICANCE: Mirror activity is increased in ALS and is associated with abnormal transcallosal inhibition and UMN dysfunction.}, } @article {pmid38143357, year = {2024}, author = {de Boer, SCM and Riedl, L and Fenoglio, C and Rue, I and Landin-Romero, R and Matis, S and Chatterton, Z and Galimberti, D and Halliday, G and Diehl-Schmid, J and Piguet, O and Pijnenburg, YAL and Ducharme, S}, title = {Rationale and Design of the "DIagnostic and Prognostic Precision Algorithm for behavioral variant Frontotemporal Dementia" (DIPPA-FTD) Study: A Study Aiming to Distinguish Early Stage Sporadic FTD from Late-Onset Primary Psychiatric Disorders.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {97}, number = {2}, pages = {963-973}, pmid = {38143357}, issn = {1875-8908}, mesh = {Humans ; *Frontotemporal Dementia/genetics ; Prospective Studies ; Prognosis ; Neuropsychological Tests ; Biomarkers ; *Acetamides ; *Isothiocyanates ; }, abstract = {BACKGROUND: The behavioral variant of frontotemporal dementia (bvFTD) is very heterogeneous in pathology, genetics, and disease course. Unlike Alzheimer's disease, reliable biomarkers are lacking and sporadic bvFTD is often misdiagnosed as a primary psychiatric disorder (PPD) due to overlapping clinical features. Current efforts to characterize and improve diagnostics are centered on the minority of genetic cases.

OBJECTIVE: The multi-center study DIPPA-FTD aims to develop diagnostic and prognostic algorithms to help distinguish sporadic bvFTD from late-onset PPD in its earliest stages.

METHODS: The prospective DIPPA-FTD study recruits participants with late-life behavioral changes, suspect for bvFTD or late-onset PPD diagnosis with a negative family history for FTD and/or amyotrophic lateral sclerosis. Subjects are invited to participate after diagnostic screening at participating memory clinics or recruited by referrals from psychiatric departments. At baseline visit, participants undergo neurological and psychiatric examination, questionnaires, neuropsychological tests, and brain imaging. Blood is obtained to investigate biomarkers. Patients are informed about brain donation programs. Follow-up takes place 10-14 months after baseline visit where all examinations are repeated. Results from the DIPPA-FTD study will be integrated in a data-driven approach to develop diagnostic and prognostic models.

CONCLUSIONS: DIPPA-FTD will make an important contribution to early sporadic bvFTD identification. By recruiting subjects with ambiguous or prodromal diagnoses, our research strategy will allow the characterization of early disease stages that are not covered in current sporadic FTD research. Results will hopefully increase the ability to diagnose sporadic bvFTD in the early stage and predict progression rate, which is pivotal for patient stratification and trial design.}, } @article {pmid38143367, year = {2024}, author = {Gao, J and Leinonen, H and Wang, EJ and Ding, M and Perry, G and Palczewski, K and Wang, X}, title = {Sex-Specific Early Retinal Dysfunction in Mutant TDP-43 Transgenic Mice.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {97}, number = {2}, pages = {927-937}, pmid = {38143367}, issn = {1875-8908}, support = {RF1 AG056320/AG/NIA NIH HHS/United States ; R01 AG066578/AG/NIA NIH HHS/United States ; RF1 AG065342/AG/NIA NIH HHS/United States ; P30 EY034070/EY/NEI NIH HHS/United States ; R01 EY009339/EY/NEI NIH HHS/United States ; }, mesh = {Mice ; Humans ; Male ; Female ; Animals ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia ; *Neurodegenerative Diseases ; DNA-Binding Proteins/genetics/metabolism ; Retina/pathology ; }, abstract = {BACKGROUND: Increasing evidence has highlighted retinal impairments in neurodegenerative diseases. Dominant mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the accumulation of TDP-43 in the cytoplasm is a pathological hallmark of ALS, frontotemporal dementia (FTD), and many other neurodegenerative diseases.

OBJECTIVE: While homozygous transgenic mice expressing the disease-causing human TDP-43 M337V mutant (TDP-43M337V mice) experience premature death, hemizygous TDP-43M337V mice do not suffer sudden death, but they exhibit age-dependent motor-coordinative and cognitive deficits. This study aims to leverage the hemizygous TDP-43M337V mice as a valuable ALS/FTD disease model for the assessment also of retinal changes during the disease progression.

METHODS: We evaluated the retinal function of young TDP-43M337V mice by full field electroretinogram (ERG) recordings.

RESULTS: At 3-4 months of age, well before the onset of brain dysfunction at 8 months, the ERG responses were notably impaired in the retinas of young female TDP-43M337V mice in contrast to their male counterparts and age-matched non-transgenic mice. Mitochondria have been implicated as critical targets of TDP-43. Further investigation revealed that significant changes in the key regulators of mitochondrial dynamics and bioenergetics were only observed in the retinas of young female TDP-43M337V mice, while these alterations were not present in the brains of either gender.

CONCLUSIONS: Together our findings suggest a sex-specific vulnerability within the retina in the early disease stage, and highlight the importance of retinal changes and mitochondrial markers as potential early diagnostic indicators for ALS, FTD, and other TDP-43 related neurodegenerative conditions.}, } @article {pmid38143551, year = {2023}, author = {Kasindi, A and Carstarphen, KJ}, title = {Bulbar Onset Amyotrophic Lateral Sclerosis in an African American Older Adult.}, journal = {Ochsner journal}, volume = {23}, number = {4}, pages = {353-356}, pmid = {38143551}, issn = {1524-5012}, abstract = {Background: Amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease, affects the motor tracts and anterior horn cells of the spinal cord, causing both upper and lower motor neuron dysfunction. ALS typically involves progressive peripheral weakness and mobility issues. Case Report: An African American male in his early 70s presented to his primary care provider (PCP) with bulbar weakness and urinary tract symptoms. At presentation, and even later in the disease course, he ambulated well and did not report any limb issues. After some months of worsening symptoms of dyspnea, dysarthria, dysphagia, and urinary incontinence, a diagnosis of ALS was made via collaborative work between the PCP, a medical student, and various medical specialists including a neurosurgeon and neurologist. Because of the absence of limb abnormalities, the patient had difficulty accepting a diagnosis of ALS, thus delaying treatment onset. Conclusion: Clinicians must consider the patient's presentation holistically so that they do not miss insidious, complex, or unique presentations. ALS can present with bulbar symptoms early in the disease course with no upper motor neuron/lower motor neuron involvement. Older adult African American males can present with ALS. Mistrust of health care systems and resistance to science based on religious beliefs can impact patient acceptance of diagnoses and engagement in treatments. Having a long-term relationship with a PCP who also represents the patient's community can influence patient willingness to accept diagnoses, especially those that are life-limiting.}, } @article {pmid38143564, year = {2023}, author = {Quillet, R and Gutierrez-Mecinas, M and Polgár, E and Dickie, AC and Boyle, KA and Watanabe, M and Todd, AJ}, title = {Synaptic circuits involving gastrin-releasing peptide receptor-expressing neurons in the dorsal horn of the mouse spinal cord.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1294994}, pmid = {38143564}, issn = {1662-5099}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/V033638/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {The superficial dorsal horn (SDH) of the spinal cord contains a diverse array of neurons. The vast majority of these are interneurons, most of which are glutamatergic. These can be assigned to several populations, one of which is defined by expression of gastrin-releasing peptide receptor (GRPR). The GRPR cells are thought to be "tertiary pruritoceptors," conveying itch information to lamina I projection neurons of the anterolateral system (ALS). Surprisingly, we recently found that GRPR-expressing neurons belong to a morphological class known as vertical cells, which are believed to transmit nociceptive information to lamina I ALS cells. Little is currently known about synaptic circuits engaged by the GRPR cells. Here we combine viral-mediated expression of PSD95-tagRFP fusion protein with super-resolution microscopy to reveal sources of excitatory input to GRPR cells. We find that they receive a relatively sparse input from peptidergic and non-peptidergic nociceptors in SDH, and a limited input from A- and C-low threshold mechanoreceptors on their ventral dendrites. They receive synapses from several excitatory interneuron populations, including those defined by expression of substance P, neuropeptide FF, cholecystokinin, neurokinin B, and neurotensin. We investigated downstream targets of GRPR cells by chemogenetically exciting them and identifying Fos-positive (activated) cells. In addition to lamina I projection neurons, many ALS cells in lateral lamina V and the lateral spinal nucleus were Fos-positive, suggesting that GRPR-expressing cells target a broader population of projection neurons than was previously recognised. Our findings indicate that GRPR cells receive a diverse synaptic input from various types of primary afferent and excitatory interneuron, and that they can activate ALS cells in both superficial and deep regions of the dorsal horn.}, } @article {pmid38144173, year = {2023}, author = {Simmatis, LE and Robin, J and Pommée, T and McKinlay, S and Sran, R and Taati, N and Truong, J and Koyani, B and Yunusova, Y}, title = {Validation of automated pipeline for the assessment of a motor speech disorder in amyotrophic lateral sclerosis (ALS).}, journal = {Digital health}, volume = {9}, number = {}, pages = {20552076231219102}, pmid = {38144173}, issn = {2055-2076}, support = {R01 DC013547/DC/NIDCD NIH HHS/United States ; R01 DC017291/DC/NIDCD NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic lateral sclerosis (ALS) frequently causes speech impairments, which can be valuable early indicators of decline. Automated acoustic assessment of speech in ALS is attractive, and there is a pressing need to validate such tools in line with best practices, including analytical and clinical validation. We hypothesized that data analysis using a novel speech assessment pipeline would correspond strongly to analyses performed using lab-standard practices and that acoustic features from the novel pipeline would correspond to clinical outcomes of interest in ALS.

METHODS: We analyzed data from three standard speech assessment tasks (i.e., vowel phonation, passage reading, and diadochokinesis) in 122 ALS patients. Data were analyzed automatically using a pipeline developed by Winterlight Labs, which yielded 53 acoustic features. First, for analytical validation, data were analyzed using a lab-standard analysis pipeline for comparison. This was followed by univariate analysis (Spearman correlations between individual features in Winterlight and in-lab datasets) and multivariate analysis (sparse canonical correlation analysis (SCCA)). Subsequently, clinical validation was performed. This included univariate analysis (Spearman correlation between automated acoustic features and clinical measures) and multivariate analysis (interpretable autoencoder-based dimensionality reduction).

RESULTS: Analytical validity was demonstrated by substantial univariate correlations (Spearman's ρ > 0.70) between corresponding pairs of features from automated and lab-based datasets, as well as interpretable SCCA feature groups. Clinical validity was supported by strong univariate correlations between automated features and clinical measures (Spearman's ρ > 0.70), as well as associations between multivariate outputs and clinical measures.

CONCLUSION: This novel, automated speech assessment feature set demonstrates substantial promise as a valid tool for analyzing impaired speech in ALS patients and for the further development of these technologies.}, } @article {pmid38147116, year = {2024}, author = {Louro, H and Vettorazzi, A and López de Cerain, A and Spyropoulou, A and Solhaug, A and Straumfors, A and Behr, AC and Mertens, B and Žegura, B and Fæste, CK and Ndiaye, D and Spilioti, E and Varga, E and Dubreil, E and Borsos, E and Crudo, F and Eriksen, GS and Snapkow, I and Henri, J and Sanders, J and Machera, K and Gaté, L and Le Hegarat, L and Novak, M and Smith, NM and Krapf, S and Hager, S and Fessard, V and Kohl, Y and Silva, MJ and Dirven, H and Dietrich, J and Marko, D}, title = {Hazard characterization of Alternaria toxins to identify data gaps and improve risk assessment for human health.}, journal = {Archives of toxicology}, volume = {98}, number = {2}, pages = {425-469}, pmid = {38147116}, issn = {1432-0738}, support = {101057014//European Commission/ ; }, mesh = {Humans ; *Perylene/analogs & derivatives ; Alternaria/metabolism ; *Mycotoxins/toxicity/analysis ; Mutagens/toxicity/metabolism ; Lactones/toxicity/metabolism ; Risk Assessment ; Food Contamination/analysis ; }, abstract = {Fungi of the genus Alternaria are ubiquitous plant pathogens and saprophytes which are able to grow under varying temperature and moisture conditions as well as on a large range of substrates. A spectrum of structurally diverse secondary metabolites with toxic potential has been identified, but occurrence and relative proportion of the different metabolites in complex mixtures depend on strain, substrate, and growth conditions. This review compiles the available knowledge on hazard identification and characterization of Alternaria toxins. Alternariol (AOH), its monomethylether AME and the perylene quinones altertoxin I (ATX-I), ATX-II, ATX-III, alterperylenol (ALP), and stemphyltoxin III (STTX-III) showed in vitro genotoxic and mutagenic properties. Of all identified Alternaria toxins, the epoxide-bearing analogs ATX-II, ATX-III, and STTX-III show the highest cytotoxic, genotoxic, and mutagenic potential in vitro. Under hormone-sensitive conditions, AOH and AME act as moderate xenoestrogens, but in silico modeling predicts further Alternaria toxins as potential estrogenic factors. Recent studies indicate also an immunosuppressive role of AOH and ATX-II; however, no data are available for the majority of Alternaria toxins. Overall, hazard characterization of Alternaria toxins focused, so far, primarily on the commercially available dibenzo-α-pyrones AOH and AME and tenuazonic acid (TeA). Limited data sets are available for altersetin (ALS), altenuene (ALT), and tentoxin (TEN). The occurrence and toxicological relevance of perylene quinone-based Alternaria toxins still remain to be fully elucidated. We identified data gaps on hazard identification and characterization crucial to improve risk assessment of Alternaria mycotoxins for consumers and occupationally exposed workers.}, } @article {pmid38148559, year = {2024}, author = {Gautam, S and Latif, S and Kang, YS}, title = {Effect of Various Pathological Conditions on Nitric Oxide Level and L-Citrulline Uptake in Motor Neuron-Like (NSC-34) Cell Lines.}, journal = {Biomolecules & therapeutics}, volume = {32}, number = {1}, pages = {154-161}, pmid = {38148559}, issn = {1976-9148}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder that causes progressive paralysis. L-Citrulline is a non-essential neutral amino acid produced by L-arginine via nitric oxide synthase (NOS). According to previous studies, the pathogenesis of ALS entails glutamate toxicity, oxidative stress, protein misfolding, and neurofilament disruption. In addition, L-citrulline prevents neuronal cell death in brain ischemia; therefore, we investigated the change in the transport of L-citrulline under various pathological conditions in a cell line model of ALS. We examined the uptake of [[14]C]L-citrulline in wild-type (hSOD1wt/WT) and mutant NSC-34/ SOD1[G93A] (MT) cell lines. The cell viability was determined via MTT assay. A transport study was performed to determine the uptake of [[14]C]L-citrulline. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to determine the expression levels of rat large neutral amino acid transported 1 (rLAT1) in ALS cell lines. Nitric oxide (NO) assay was performed using Griess reagent. L-Citrulline had a restorative effect on glutamate induced cell death, and increased [[14]C]L-citrulline uptake and mRNA levels of the large neutral amino acid transporter (LAT1) in the glutamate-treated ALS disease model (MT). NO levels increased significantly when MT cells were pretreated with glutamate for 24 h and restored by co-treatment with L-citrulline. Co-treatment of MT cells with L-arginine, an NO donor, increased NO levels. NSC-34 cells exposed to high glucose conditions showed a significant increase in [[14]C]L-citrulline uptake and LAT1 mRNA expression levels, which were restored to normal levels upon co-treatment with unlabeled L-citrulline. In contrast, exposure of the MT cell line to tumor necrosis factor alpha, lipopolysaccharides, and hypertonic condition decreased the uptake significantly which was restored to the normal level by co-treating with unlabeled L-citrulline. L-Citrulline can restore NO levels and cellular uptake in ALS-affected cells with glutamate cytotoxicity, pro-inflammatory cytokines, or other pathological states, suggesting that L-citrulline supplementation in ALS may play a key role in providing neuroprotection.}, } @article {pmid38148722, year = {2023}, author = {Kiernan, MC and Halliday, GM and Rowe, DB and Tan, RH}, title = {The importance of patient-centred drug development for amyotrophic lateral sclerosis.}, journal = {Neuropathology and applied neurobiology}, volume = {49}, number = {6}, pages = {e12944}, doi = {10.1111/nan.12944}, pmid = {38148722}, issn = {1365-2990}, support = {//FightMND/ ; //National Health and Medical Research Council./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Drug Development ; }, } @article {pmid38149039, year = {2024}, author = {Ryan, M and Doherty, MA and Al Khleifat, A and Costello, E and Hengeveld, JC and Heverin, M and Al-Chalabi, A and Mclaughlin, RL and Hardiman, O}, title = {C9orf72 Repeat Expansion Discordance in 6 Multigenerational Kindreds.}, journal = {Neurology. Genetics}, volume = {10}, number = {1}, pages = {e200112}, pmid = {38149039}, issn = {2376-7839}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {BACKGROUND AND OBJECTIVES: A hexanucleotide repeat expansion in the noncoding region of the C9orf72 gene is the most common genetically identifiable cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in populations of European ancestry. Pedigrees associated with this expansion exhibit phenotypic heterogeneity and incomplete disease penetrance, the basis of which is poorly understood. Relatives of those carrying the C9orf72 repeat expansion exhibit a characteristic cognitive endophenotype independent of carrier status. To examine whether additional shared genetic or environmental risks within kindreds could compel this observation, we have conducted a detailed cross-sectional study of the inheritance within multigenerational Irish kindreds carrying the C9orf72 repeat expansion.

METHODS: One hundred thirty-one familial ALS pedigrees, 59 of which carried the C9orf72 repeat expansion (45.0% [95% CI 36.7-53.5]), were identified through the Irish population-based ALS register. C9orf72 genotyping was performed using repeat-primed PCR with amplicon fragment length analysis. Pedigrees were further investigated using SNP, targeted sequencing data, whole-exome sequencing, and whole-genome sequencing.

RESULTS: We identified 21 kindreds where at least 1 family member with ALS carried the C9orf72 repeat expansion and from whom DNA was available from multiple affected family members. Of these, 6 kindreds (28.6% [95% CI 11.8-48.3]) exhibited discordant segregation. The C9orf72 haplotype was studied in 2 families and was found to segregate with the C9orf72-positive affected relative but not the C9orf72-negative affected relative. No other ALS pathogenic variants were identified within these discordant kindreds.

DISCUSSION: Family members of kindreds associated with the C9orf72 repeat expansion may carry an increased risk of developing ALS independent of their observed carrier status. This has implications for assessment and counseling of asymptomatic individuals regarding their genetic risk.}, } @article {pmid38149648, year = {2024}, author = {Nicholas, R and Magliozzi, R and Marastoni, D and Howell, O and Roncaroli, F and Muraro, P and Reynolds, R and Friede, T}, title = {High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study.}, journal = {Annals of neurology}, volume = {95}, number = {4}, pages = {706-719}, doi = {10.1002/ana.26870}, pmid = {38149648}, issn = {1531-8249}, mesh = {Humans ; *Multiple Sclerosis/pathology ; Cohort Studies ; Retrospective Studies ; Inflammation/complications ; Brain/pathology ; *Multiple Sclerosis, Chronic Progressive/pathology ; }, abstract = {OBJECTIVE: Analysis of postmortem multiple sclerosis (MS) tissues combined with in vivo disease milestones suggests that whereas perivascular white matter infiltrates are associated with demyelinating activity in the initial stages, leptomeningeal immune cell infiltration, enriched in B cells, and associated cortical lesions contribute to disease progression. We systematically examine the association of inflammatory features and white matter demyelination at postmortem with clinical milestones.

METHODS: In 269 MS brains, 20 sites were examined using immunohistochemistry for active lesions (ALs) and perivenular inflammation (PVI). In a subset of 22, a detailed count of CD20+ B cells and CD3+ T cells in PVIs was performed.

RESULTS: ALs were detected in 22%, whereas high levels of PVI were detected in 52% of cases. ALs were present in 35% of cases with high levels of PVI. Shorter time from onset of progression to death was associated with increased prevalence and higher levels of PVI (both p < 0.0001). Shorter time from onset of progression to wheelchair use was associated with higher prevalence of ALs (odds ratio [OR] = 0.921, 95% confidence interval [CI] = 0.858-0.989, p = 0.0230) and higher level of PVI (OR = 0.932, 95% CI = 0.886-0.981, p = 0.0071). High levels of PVI were associated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocytes within the PVI.

INTERPRETATION: ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. These features link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supporting the hypothesis that chronic inflammation drives progression in MS. ANN NEUROL 2024;95:706-719.}, } @article {pmid38149762, year = {2024}, author = {Lopes, CS and Pronto-Laborinho, AC and Conceição, VA and Freitas, T and Matias, GL and Gromicho, M and Santos, NC and de Carvalho, M and Carvalho, FA}, title = {Erythrocytes' surface properties and stiffness predict survival and functional decline in ALS patients.}, journal = {BioFactors (Oxford, England)}, volume = {50}, number = {3}, pages = {558-571}, doi = {10.1002/biof.2030}, pmid = {38149762}, issn = {1872-8081}, support = {COVID/BD/151823/2021//Fundação para a Ciência e a Tecnologia/ ; PD/BD/135045/2017//Fundação para a Ciência e a Tecnologia/ ; PTDC/EMD-TLM/7289/2020//Fundação para a Ciência e a Tecnologia/ ; UID/BIM/50005/2019//Fundação para a Ciência e a Tecnologia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology/mortality/blood ; Female ; Middle Aged ; Male ; *Erythrocytes/metabolism/pathology ; *Microscopy, Atomic Force ; Aged ; Surface Properties ; Erythrocyte Membrane/metabolism ; Adult ; Vital Capacity ; Disease Progression ; }, abstract = {Erythrocytes play a fundamental role in oxygen delivery to tissues and binding to inflammatory mediators. Evidences suggest that dysregulated erythrocyte function could contribute to the pathophysiology of several neurodegenerative diseases. We aimed to evaluate changes in morphological, biomechanical, and biophysical properties of erythrocytes from amyotrophic lateral sclerosis (ALS) patients, as new areas of study in this disease. Blood samples were collected from ALS patients, comparing with healthy volunteers. Erythrocytes were assessed using atomic force microscopy (AFM) and zeta potential analysis. The patients' motor and respiratory functions were evaluated using the revised ALS Functional Rating Scale (ALSFRS-R) and percentage of forced vital capacity (%FVC). Patient survival was also assessed. Erythrocyte surface roughness was significantly smoother in ALS patients, and this parameter was a predictor of faster decline in ALSFRS-R scores. ALS patients exhibited higher erythrocyte stiffness, as indicated by reduced AFM tip penetration depth, which predicted a faster ALSFRS-R score and respiratory subscore decay. A lower negative charge on the erythrocyte membrane was predictor of a faster ALSFRS-R and FVC decline. Additionally, a larger erythrocyte surface area was an independent predictor of lower survival. These changes in morphological and biophysical membrane properties of ALS patients' erythrocytes, lead to increased cell stiffness and morphological variations. We speculate that these changes might precipitate motoneurons dysfunction and accelerate disease progression. Further studies should explore the molecular alterations related to these observations. Our findings may contribute to dissect the complex interplay between respiratory function, tissue hypoxia, progression rate, and survival in ALS.}, } @article {pmid38151482, year = {2024}, author = {Taha, MA and Morren, JA}, title = {The role of artificial intelligence in electrodiagnostic and neuromuscular medicine: Current state and future directions.}, journal = {Muscle & nerve}, volume = {69}, number = {3}, pages = {260-272}, doi = {10.1002/mus.28023}, pmid = {38151482}, issn = {1097-4598}, mesh = {Humans ; *Artificial Intelligence ; Machine Learning ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Brain ; Electromyography ; }, abstract = {The rapid advancements in artificial intelligence (AI), including machine learning (ML), and deep learning (DL) have ushered in a new era of technological breakthroughs in healthcare. These technologies are revolutionizing the way we utilize medical data, enabling improved disease classification, more precise diagnoses, better treatment selection, therapeutic monitoring, and highly accurate prognostication. Different ML and DL models have been used to distinguish between electromyography signals in normal individuals and those with amyotrophic lateral sclerosis and myopathy, with accuracy ranging from 67% to 99.5%. DL models have also been successfully applied in neuromuscular ultrasound, with the use of segmentation techniques achieving diagnostic accuracy of at least 90% for nerve entrapment disorders, and 87% for inflammatory myopathies. Other successful AI applications include prediction of treatment response, and prognostication including prediction of intensive care unit admissions for patients with myasthenia gravis. Despite these remarkable strides, significant knowledge, attitude, and practice gaps persist, including within the field of electrodiagnostic and neuromuscular medicine. In this narrative review, we highlight the fundamental principles of AI and draw parallels with the intricacies of human brain networks. Specifically, we explore the immense potential that AI holds for applications in electrodiagnostic studies, neuromuscular ultrasound, and other aspects of neuromuscular medicine. While there are exciting possibilities for the future, it is essential to acknowledge and understand the limitations of AI and take proactive steps to mitigate these challenges. This collective endeavor holds immense potential for the advancement of healthcare through the strategic and responsible integration of AI technologies.}, } @article {pmid38151605, year = {2024}, author = {Molin, J and Hartmann, J and Pærregaard, MM and Thygesen, CB and Sillesen, AS and Raja, AA and Vøgg, ROB and Iversen, KK and Bundgaard, H and Christensen, AH}, title = {The Neonatal QRS Complex and Its Association with Left Ventricular Mass.}, journal = {Pediatric cardiology}, volume = {45}, number = {2}, pages = {248-256}, pmid = {38151605}, issn = {1432-1971}, support = {NNF20OC0065799//The Novo Nordisk Foundation/ ; Grant 0134-00363B//The Independent Research Fund Denmark/ ; }, mesh = {Male ; Infant, Newborn ; Humans ; Female ; *Hypertrophy, Left Ventricular/diagnosis ; Prospective Studies ; *Electrocardiography/methods ; Heart ; Echocardiography ; }, abstract = {To evaluate QRS complex features during the first month of life and the association with echocardiographic measurements of left ventricular mass in neonates. Prospective cohort study of neonates with electrocardiography (ECG) and echocardiography performed during the first month of life. Left ventricular mass index (LVMI) was determined by echocardiography and the correlation with electrocardiographic markers of LVMI outliers (≥ 98th percentile) were analyzed. We included 17,450 neonates (52% boys; median age at examination 11 days) and found an increase in median QRS duration and LVMI during the first month of life (54 vs. 56 ms and 24.7 vs. 28.6 g/m[2] at days 0-4 and 25-30, respectively; both p < 0.001). All investigated ECG features (QRS duration, QRS area in V1/V6, maximum amplitudes of S-V1/R-V6, and the Sokolow-Lyon voltage product) showed no to low correlation with LVMI, resulting in low sensitivities (0-9.0%), but high specificities (97.2-98.1%), and area under the curve values close to the identity line (0.49-0.61) for identifying LVMI outliers. Adjustment of outlier definition for LVMI and threshold for QRS features had no significant effect on sensitivity. We present reference values for QRS complex features and their association with LVMI in neonates from a large, unselected, population-based cohort. The QRS complex gradually evolved during the first month of life but had a low correlation with LVMI. Our results indicate a poor diagnostic value of using ECG features to identify LVMI outliers in neonates.Trial Registry Copenhagen Baby Heart, NCT02753348, https://clinicaltri-als.gov/ct2/show/NCT02753348?cond=Copenhagen+Baby+Heart&draw=2&rank=1 , deidentified individual participant data will not be made available.}, } @article {pmid38151890, year = {2024}, author = {Talebi, S and Khodagholi, F and Bahaeddin, Z and Ansari Dezfouli, M and Zeinaddini-Meymand, A and Berchi Kankam, S and Foolad, F and Alijaniha, F and Fayazi Piranghar, F}, title = {Does hazelnut consumption affect brain health and function against neurodegenerative diseases?.}, journal = {Nutritional neuroscience}, volume = {27}, number = {9}, pages = {1008-1024}, doi = {10.1080/1028415X.2023.2296164}, pmid = {38151890}, issn = {1476-8305}, mesh = {*Corylus ; Humans ; *Neurodegenerative Diseases/prevention & control ; *Brain ; Nuts ; Antioxidants/administration & dosage ; Neuroprotective Agents/administration & dosage ; Animals ; Diet ; Nutritive Value ; }, abstract = {INTRODUCTION: A healthy daily diet and consuming certain nutrients, such as polyphenols, vitamins, and unsaturated fatty acids, may help neuronal health maintenance. Polyphenolic chemicals, which have antioxidant and anti-inflammatory properties, are involved in the neuroprotective pathway. Because of their nutritional value, nuts have been shown in recent research to be helpful in neuroprotection.

OBJECTIVE: Hazelnut is often consumed worldwide in various items, including processed foods, particularly in bakery, chocolate, and confectionery products. This nut is an excellent source of vitamins, amino acids, tocopherols, phytosterols, polyphenols, minerals, and unsaturated fatty acids. Consuming hazelnut may attenuate the risk of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease due to its anti-inflammatory and anti-oxidant qualities.

RESULTS: Many documents introduce hazelnut as an excellent choice to provide neuroprotection against neurodegenerative disorders and there is some direct proof of its neuroprotective effects.

DISCUSSION: So hazelnut consumption in daily diet may reduce neurodegenerative disease risk and be advantageous in reducing the imposed costs of dealing with neurodegenerative diseases.}, } @article {pmid38152548, year = {2023}, author = {Neurology, B}, title = {Retracted: Classification of Myopathy and Amyotrophic Lateral Sclerosis Electromyograms Using Bat Algorithm and Deep Neural Networks.}, journal = {Behavioural neurology}, volume = {2023}, number = {}, pages = {9769130}, pmid = {38152548}, issn = {1875-8584}, abstract = {[This retracts the article DOI: 10.1155/2022/3517872.].}, } @article {pmid38152653, year = {2023}, author = {Vacchiano, V and Palombo, F and Ormanbekova, D and Fiorini, C and Fiorentino, A and Caporali, L and Mastrangelo, A and Valentino, ML and Capellari, S and Liguori, R and Carelli, V}, title = {The genetic puzzle of a SOD1-patient with ocular ptosis and a motor neuron disease: a case report.}, journal = {Frontiers in genetics}, volume = {14}, number = {}, pages = {1322067}, pmid = {38152653}, issn = {1664-8021}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex genetic architecture, showing monogenic, oligogenic, and polygenic inheritance. In this study, we describe the case of a 71 years-old man diagnosed with ALS with atypical clinical features consisting in progressive ocular ptosis and sensorineural deafness. Genetic analyses revealed two heterozygous variants, in the SOD1 (OMIM*147450) and the TBK1 (OMIM*604834) genes respectively, and furthermore mitochondrial DNA (mtDNA) sequencing identified the homoplasmic m.14484T>C variant usually associated with Leber's Hereditary Optic Neuropathy (LHON). We discuss how all these variants may synergically impinge on mitochondrial function, possibly contributing to the pathogenic mechanisms which might ultimately lead to the neurodegenerative process, shaping the clinical ALS phenotype enriched by adjunctive clinical features.}, } @article {pmid38154301, year = {2024}, author = {Li, X and Gao, X and Fu, B and Lu, C and Han, H and Zhou, Q and Xu, H}, title = {Study on the toxicity prediction model ofacetolactate synthase inhibitor herbicides based on human serum albumin and superoxide dismutase binding information.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {309}, number = {}, pages = {123789}, doi = {10.1016/j.saa.2023.123789}, pmid = {38154301}, issn = {1873-3557}, mesh = {Animals ; Humans ; *Herbicides/toxicity/metabolism ; Serum Albumin, Human/metabolism ; Molecular Docking Simulation ; *Pesticides ; Protein Binding ; Enzyme Inhibitors/toxicity ; Carrier Proteins ; Superoxide Dismutase/metabolism ; Spectrometry, Fluorescence ; }, abstract = {Toxicity significantly influences the successful development of drugs. Based on the toxicity prediction method (carrier protein binding information-toxicity relationship) previously established by the our group, this paper introduces information on the interaction between pesticides and environmental markers (SOD) into the model for the first time, so that the toxicity prediction model can not only predict the toxicity of pesticides to humans and animals, but also predict the toxicity of pesticides to the environment. Firstly, the interaction of acetolactate synthase inhibitor herbicides (ALS inhibitor herbicides) with human serum albumin (HSA) and superoxide dismutase (SOD) was investigated systematically from theory combined with experiments by spectroscopy methods and molecular docking, and important fluorescence parameters were obtained. Then, the fluorescence parameters, pesticides acute toxicity LD50 and structural splitting information were used to construct predictive modeling of ALS inhibitor herbicides based on the carrier protein binding information (R[2] = 0.977) and the predictive modeling of drug acute toxicity based on carrier protein binding information and conformational relationship (R[2] = 0.991), which had effectively predicted pesticides toxicity in humans and animals. To predict potential environmental toxicity, the predictive modeling of drug acute toxicity based on superoxide dismutase binding information was established (R[2] = 0.883) by ALS inhibitor herbicides-SOD binding information, which has a good predictive ability in the potential toxicity of pesticides to the environment. This study lays the foundation for developing low toxicity pesticides.}, } @article {pmid38156274, year = {2023}, author = {Zheng, Q and Wang, D and Lin, R and Chen, Y and Huang, H and Xu, Z and Zheng, C and Xu, W}, title = {Mendelian randomization analysis suggests no associations of human herpes viruses with amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1299122}, pmid = {38156274}, issn = {1662-4548}, abstract = {BACKGROUND: The causal associations between infections with human herpes viruses (HHVs) and amyotrophic lateral sclerosis (ALS) has been disputed. This study investigated the causal associations between herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6, and HHV-7 infections and ALS through a bidirectional Mendelian randomization (MR) method.

METHODS: The genome-wide association studies (GWAS) database were analyzed by inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. MR-Egger intercept test, MR-PRESSO test, Cochran's Q test, funnel plots, and leaveone-out analysis were used to verify the validity and robustness of the MR results.

RESULTS: In the forward MR analysis of the IVW, genetically predicted HSV infections [odds ratio (OR) = 0.9917; 95% confidence interval (CI): 0.9685-1.0154; p = 0.4886], HSV keratitis and keratoconjunctivitis (OR = 0.9897; 95% CI: 0.9739-1.0059; p = 0.2107), anogenital HSV infection (OR = 1.0062; 95% CI: 0.9826-1.0304; p = 0.6081), VZV IgG (OR = 1.0003; 95% CI: 0.9849-1.0160; p = 0.9659), EBV IgG (OR = 0.9509; 95% CI: 0.8879-1.0183; p = 0.1497), CMV (OR = 0.9481; 95% CI: 0.8680-1.0357; p = 0.2374), HHV-6 IgG (OR = 0.9884; 95% CI: 0.9486-1.0298; p = 0.5765) and HHV-7 IgG (OR = 0.9991; 95% CI: 0.9693-1.0299; p = 0.9557) were not causally associated with ALS. The reverse MR analysis of the IVW revealed comparable findings, indicating no link between HHVs infections and ALS. The reliability and validity of the findings were verified by the sensitivity analysis.

CONCLUSION: According to the MR study, there is no evidence of causal associations between genetically predicted HHVs (HSV, VZV, EBV, CMV, HHV-6, and HHV-7) and ALS.}, } @article {pmid38156828, year = {2024}, author = {Gebrehiwet, P and Brekke, J and Rudnicki, SA and Mellor, J and Wright, J and Earl, L and Ball, N and Iqbal, H and Thomas, O and Castellano, G}, title = {Time from amyotrophic lateral sclerosis symptom onset to key disease milestones: analysis of data from a multinational cross-sectional survey.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {345-357}, doi = {10.1080/21678421.2023.2297795}, pmid = {38156828}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Disease Progression ; Cross-Sectional Studies ; Body Mass Index ; Time Factors ; }, abstract = {OBJECTIVE: To determine the average time from Amyotrophic Lateral Sclerosis (ALS) symptom onset to 11 pre-defined milestones, overall and according to ALS progression rate and geographic location.

METHODS: Data were drawn from the Adelphi Real World ALS Disease-Specific Programme[TM], a point-in-time survey of neurologists caring for people living with ALS (pALS) conducted in France, Germany, Italy, Spain, the United Kingdom and the United States from 2020-2021. ALS progression rate was calculated using time since symptom onset and ALS Functional Rating Scale Revised score.

RESULTS: Survey results were available for N = 1003 pALS (progression rate for N = 867). Mean time from symptom onset was 3.8 months to first consultation, 8.0 months to diagnosis, 16.2 months to employment change (part-time/sick leave/retirement/unemployment), 17.5 months to use of a walking aid, 18.5 months to first occurrence of caregiver support, 22.8 months to use of a wheelchair, 24.6 months to use of a communication aid, 27.3 months to use of a respiratory aid, 28.6 months to use of gastrostomy feeding, 29.7 months to use of eye gaze technology and 30.3 months to entering a care facility. Multivariate analysis indicated significant effects of fast (versus slow) progression rate on time to reach all 11 milestones, as well as US (versus European) location, age, body mass index and bulbar onset (versus other) on time to reach milestones.

CONCLUSIONS: pALS rapidly reached clinical and disease-related milestones within 30 months from symptom onset. Milestones were reached significantly faster by pALS with fast versus slow progression. Geographic differences were observed.}, } @article {pmid38157256, year = {2023}, author = {Kang, Q and Jiang, S and Min, J and Hu, F and Xu, R}, title = {Parvalbumin interneurons dysfunction is potentially associated with FαMNs decrease and NRG1-ErbB4 signaling inhibition in spinal cord in amyotrophic lateral sclerosis.}, journal = {Aging}, volume = {15}, number = {24}, pages = {15324-15339}, pmid = {38157256}, issn = {1945-4589}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; *Interneurons/metabolism ; Matrix Metalloproteinase 9/metabolism ; Mice, Transgenic ; Parvalbumins/metabolism ; Receptor, ErbB-4/genetics/metabolism ; Neuregulin-1/genetics/metabolism ; }, abstract = {OBJECTIVE: To investigate the alteration of PV interneurons in ALS mainly focusing its dynamic changes and its relationship with motor neurons and ErbB4 signaling.

METHODS: SOD1G93A mice were used as ALS model. ALS animals were divided into different groups according to birth age: symptomatic prophase (50~60 days), symptomatic phase (90~100 days), and symptomatic progression (130~140 days). Immunofluorescence was performed for measurement of PV-positive interneurons, MMP-9, ChAT, NeuN and ErbB4. RT-qPCR and western blot were used to determine the expression of PV and MMP-9.

RESULTS: PV expression was remarkably higher in the anterior horn of gray matter compared with posterior horn and area in the middle of gray matter in control mice. In ALS mice, PV, MMP-9 and ErbB4 levels were gradually decreased along with onset. PV, MMP-9 and ErbB4 levels in ALS mice were significantly down-regulated than control mice after onset, indicating the alteration of PV interneurons, FαMNs and ErbB4. SαMNs levels only decreased remarkably at symptomatic progression in ALS mice compared with control mice, while γMNs levels showed no significant change during whole period in all mice. MMP-9 and ErbB4 were positively correlated with PV. NRG1 treatment significantly enhanced the expression of ErBb4, PV and MMP-9 in ALS mice.

CONCLUSION: PV interneurons decrease is along with FαMNs and ErbB4 decrease in ALS mice.}, } @article {pmid38157654, year = {2024}, author = {Halseth, M and Mahoney, R and Hsiou, J and Jones, HN and Kimonis, V}, title = {Remote respiratory resistance exercise training improves respiratory function in individuals with VCP multisystem proteinopathy.}, journal = {Neuromuscular disorders : NMD}, volume = {34}, number = {}, pages = {68-74}, doi = {10.1016/j.nmd.2023.12.001}, pmid = {38157654}, issn = {1873-2364}, mesh = {Adult ; Humans ; Valosin Containing Protein/genetics ; *Resistance Training ; *Muscular Diseases ; Respiration ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis ; Mutation ; Cell Cycle Proteins/genetics ; }, abstract = {Valosin-containing protein (VCP) disease is an autosomal dominant multisystem proteinopathy associated with hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Myopathy frequently results in respiratory muscle weakness, leading to early mortality due to respiratory failure. We investigated the effects of a remotely administered inspiratory muscle training program in individuals with VCP disease. Nine adults with VCP mutation-positive familial myopathy without evidence of dementia were recruited for a 40-week remotely administered study. Baseline performance was established during the first 8 weeks, followed by 32 weeks of inspiratory muscle training. The primary outcome was maximum inspiratory pressure (MIP). The secondary and exploratory endpoints included spirometry, grip strength, Inclusion Body Myopathy Functional Rating Scale (IBMFRS), Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS), timed up and go, and six-minute walk test (6MWT). During the treatment phase, MIP increased significantly by a weekly mean of 0.392cm. H2O (p=0.023). In contrast, grip strength and ALSFRS significantly decreased by 0.088 lbs. (p=0.031) and 0.043 points (p=0.004) per week, respectively, as expected from the natural progression of this disease. A remotely administered inspiratory muscle training program is therefore feasible, safe, and well-tolerated in individuals with VCP disease and results in improved inspiratory muscle strength.}, } @article {pmid38158673, year = {2023}, author = {Luo, S and Yang, L and Ma, B and Wang, X and Lu, Y and Ma, S and Wang, D and Qu, H and Zou, L}, title = {Explore the pharmacological basis of ShengJiYiSui decoction in the treatment of amyotrophic lateral sclerosis based on network pharmacology and molecular docking technology.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {69}, number = {13}, pages = {156-161}, doi = {10.14715/cmb/2023.69.13.24}, pmid = {38158673}, issn = {1165-158X}, mesh = {Humans ; Network Pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Molecular Docking Simulation ; Phosphatidylinositol 3-Kinases/genetics ; Proto-Oncogene Proteins c-akt ; Medicine, Chinese Traditional ; Technology ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative illnesses have long been handled clinically by traditional Chinese medicine. This study is the first time to explore the pharmacological basis of application in amyotrophic lateral sclerosis (ALS) through network pharmacology and molecular docking techniques. In the present investigation, the TCMSP database and HIT2 database were examined for 9 TCM constituents of Sheng Ji Yu Sui Decoction (SJYSD), and the desired sites for the components were searched in the Drugbank database. and the Sjysd-target network was constructed. Associated targets for Amyotrophic lateral sclerosis (ALS) were then retrieved and collected in the OMIM, TTD, Genecards and DisGeNET databases. Protein-protein interaction and enrichment analysis were performed for the common targets of drugs and diseases, and molecular anchoring for the chosen core targets and related molecules was carried out. The results showed that SJYSD had 100 active compounds corresponding to 598 targets. ALS has a total of 5,325 genes. SJYSD and ALS share 163 genes, and these targets involve PI3K-AKT signaling, p53 signaling and IL-17 signaling, etc. The core components of luteolin and quercetin were discovered and may be used to treat ALS by regulating PI3K-AKT signaling pathway by HSP90AB1 protein.}, } @article {pmid38158701, year = {2024}, author = {Izumi, R and Ikeda, K and Niihori, T and Suzuki, N and Shirota, M and Funayama, R and Nakayama, K and Warita, H and Tateyama, M and Aoki, Y and Aoki, M}, title = {Nuclear pore pathology underlying multisystem proteinopathy type 3-related inclusion body myopathy.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {3}, pages = {577-592}, pmid = {38158701}, issn = {2328-9503}, support = {KAKENHI (20K16571)//Grant-in-Aid for Early-Career Scientists from Japan Society for the Promotion of Science (JSPS)/ ; KAKENHI (20H03586)//Grant-in-Aid for Scientific Research (B) from Japan Society for the Promotion of Science (JSPS)/ ; KAKENHI (23H02821)//Grant-in-Aid for Scientific Research (B) from Japan Society for the Promotion of Science (JSPS)/ ; KAKENHI (20K07897)//Grant-in-Aid for Scientific Research (C) from Japan Society for the Promotion of Science (JSPS)/ ; 23FC1008//Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, the Ministry of Health, Labour and Welfare, Japan/ ; 23FC1010//Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, the Ministry of Health, Labour and Welfare, Japan/ ; 20FC1036//Grants-in-Aid for Research on Rare and Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan/ ; 23FC1014//Grants-in-Aid for Research on Rare and Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan/ ; //Haruki ALS Research Foundation/ ; 2-5//Intramural Research Grant for Neurological and Psychiatric Disorders Provided from National Center of Neurology and Psychiatry of Japan/ ; 5-6//Intramural Research Grant for Neurological and Psychiatric Disorders Provided from National Center of Neurology and Psychiatry of Japan/ ; }, mesh = {Humans ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Nuclear Pore/metabolism/pathology ; Muscle, Skeletal/metabolism ; Inclusion Bodies/metabolism/pathology ; *Muscular Diseases/metabolism ; Nuclear Pore Complex Proteins/genetics/metabolism ; }, abstract = {OBJECTIVE: Multisystem proteinopathy type 3 (MSP3) is an inherited, pleiotropic degenerative disorder caused by a mutation in heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which can affect the muscle, bone, and/or nervous system. This study aimed to determine detailed histopathological features and transcriptomic profile of HNRNPA1-mutated skeletal muscles to reveal the core pathomechanism of hereditary inclusion body myopathy (hIBM), a predominant phenotype of MSP3.

METHODS: Histopathological analyses and RNA sequencing of HNRNPA1-mutated skeletal muscles harboring a c.940G > A (p.D314N) mutation (NM_031157) were performed, and the results were compared with those of HNRNPA1-unlinked hIBM and control muscle tissues.

RESULTS: RNA sequencing revealed aberrant alternative splicing events that predominantly occurred in myofibril components and mitochondrial respiratory complex. Enrichment analyses identified the nuclear pore complex (NPC) and nucleocytoplasmic transport as suppressed pathways. These two pathways were linked by the hub genes NUP50, NUP98, NUP153, NUP205, and RanBP2. In immunohistochemistry, these nucleoporin proteins (NUPs) were mislocalized to the cytoplasm and aggregated mostly with TAR DNA-binding protein 43 kDa and, to a lesser extent, with hnRNPA1. Based on ultrastructural observation, irregularly shaped myonuclei with deep invaginations were frequently observed in atrophic fibers, consistent with the disorganization of NPCs. Additionally, regarding the expression profiles of overall NUPs, reduced expression of NUP98, NUP153, and RanBP2 was shared with HNRNPA1-unlinked hIBMs.

INTERPRETATION: The shared subset of altered NUPs in amyotrophic lateral sclerosis (ALS), as demonstrated in prior research, HNRNPA1-mutated, and HNRNPA1-unlinked hIBM muscle tissues may provide evidence regarding the underlying common nuclear pore pathology of hIBM, ALS, and MSP.}, } @article {pmid38159307, year = {2024}, author = {Lalechère, E and Monnet, JM and Breen, J and Fuhr, M}, title = {Assessing the potential of remote sensing-based models to predict old-growth forests on large spatiotemporal scales.}, journal = {Journal of environmental management}, volume = {351}, number = {}, pages = {119865}, doi = {10.1016/j.jenvman.2023.119865}, pmid = {38159307}, issn = {1095-8630}, mesh = {*Ecosystem ; Remote Sensing Technology ; Retrospective Studies ; *Biological Phenomena ; }, abstract = {Old-growth forests provide a broad range of ecosystem services. However, due to poor knowledge of their spatiotemporal distribution, implementing conservation and restoration strategies is challenging. The goal of this study is to compare the predictive ability of socioecological factors and different sources of remotely sensed data that determine the spatiotemporal scales at which forest maturity attributes can be predicted. We evaluated various remotely sensed data that cover a broad range of spatial (from local to global) and temporal (from current to decades) extents, from Airborne Laser Scanning (ALS), aerial multispectral and stereo-imagery, Sentinel-1, Sentinel-2 and Landsat data. Using random forests, remotely sensed data were related to a forest maturity index available in 688 forest plots across four ranges of the French Alps. Each model also includes socioecological predictors related to topography, socioeconomy, pedology and climatology. We found that the different remotely sensed data provide information on the main forest structural characteristics as defined by ALS, except for Landsat, which has a too coarse resolution, and Sentinel-1, which responds differently to vegetation structure. The predictions were quite similar considering aerial remotely sensed data, on the one hand, and satellite remotely sensed data, on the other hand. Socioecological variables are the most important predictors compared to the remote sensing metrics. In conclusion, our results indicate that a wide range of remotely sensed data can be used to study old-growth forests beyond the use of ALS and despite different abilities to predict forest structure. Accounting for socioecological predictors is indispensable to avoid a significant loss of predictive accuracy. Remotely sensed data can allow for predictions to be made at different spatiotemporal resolutions and extents. This study paves the way to large-scale monitoring of forest maturity, as well as for retrospective analyses which will show to what extent predicted maturity change at different dates.}, } @article {pmid38159460, year = {2024}, author = {Soontrapa, P and Seven, NA and Liewluck, T and Cui, G and Mer, G and Milone, M}, title = {Adolescent-onset multisystem proteinopathy due to a novel VCP variant.}, journal = {Neuromuscular disorders : NMD}, volume = {34}, number = {}, pages = {89-94}, doi = {10.1016/j.nmd.2023.11.014}, pmid = {38159460}, issn = {1873-2364}, mesh = {Adolescent ; Adult ; Child ; Humans ; Cell Cycle Proteins/genetics ; *Muscular Diseases ; Mutation/genetics ; *Myositis, Inclusion Body/diagnosis/genetics/pathology ; *Osteitis Deformans/diagnosis/genetics/pathology ; *Proteostasis Deficiencies ; Valosin Containing Protein/genetics ; }, abstract = {Valosin-containing protein (VCP) pathogenic variants are the most common cause of multisystem proteinopathy presenting with inclusion body myopathy, amyotrophic lateral sclerosis/frontotemporal dementia, and Paget disease of bone in isolation or in combination. We report a patient manifesting with adolescent-onset myopathy caused by a novel heterozygous VCP variant (c.467G > T, p.Gly156Val). The myopathy manifested asymmetrically in lower limbs and extended to proximal, axial, and upper limb muscles, with loss of ambulation at age 35. Creatine kinase value was normal. Alkaline phosphatase was elevated. Electromyography detected mixed low amplitude, short duration and high amplitude, long duration motor unit potentials. Muscle biopsy showed features of inclusion body myopathy, which in combination with newly diagnosed Paget disease of bone, supported the VCP variant pathogenicity. In conclusion, VCP-multisystem proteinopathy is not only a disease of adulthood but can have a pediatric onset and should be considered in differential diagnosis of neuromuscular weakness in the pediatric population.}, } @article {pmid38160320, year = {2024}, author = {Mohanty, P and Rizuan, A and Kim, YC and Fawzi, NL and Mittal, J}, title = {A complex network of interdomain interactions underlies the conformational ensemble of monomeric TDP-43 and modulates its phase behavior.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {2}, pages = {e4891}, pmid = {38160320}, issn = {1469-896X}, support = {R01 NS116176/NS/NINDS NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Protein Domains ; *Frontotemporal Dementia ; DNA-Binding Proteins/chemistry ; RNA/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a multidomain protein involved in the regulation of RNA metabolism, and its aggregates have been observed in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Numerous studies indicate TDP-43 can undergo liquid-liquid phase separation (LLPS) in vitro and is a component of biological condensates. Homo-oligomerization via the folded N-terminal domain (aa:1-77) and the conserved helical region (aa:319-341) of the disordered, C-terminal domain is found to be an important driver of TDP-43 phase separation. However, a comprehensive molecular view of TDP-43 phase separation, particularly regarding the nature of heterodomain interactions, is lacking due to the challenges associated with its stability and purification. Here, we utilize all-atom and coarse-grained (CG) molecular dynamics (MD) simulations to uncover the network of interdomain interactions implicated in TDP-43 phase separation. All-atom simulations uncovered the presence of transient, interdomain interactions involving flexible linkers, RNA-recognition motif (RRM) domains and a charged segment of disordered C-terminal domain (CTD). CG simulations indicate these inter-domain interactions which affect the conformational landscape of TDP-43 in the dilute phase are also prevalent in the condensed phase. Finally, sequence and surface charge distribution analysis coupled with all-atom simulations (at high salt) confirmed that the transient interdomain contacts are predominantly electrostatic in nature. Overall, our findings from multiscale simulations lead to a greater appreciation of the complex interaction network underlying the structural landscape and phase separation of TDP-43.}, } @article {pmid38161591, year = {2023}, author = {Li, J and Ma, C and Huang, H and Liao, H}, title = {Amyotrophic lateral sclerosis and osteoporosis: a two-sample Mendelian randomization study.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1305040}, pmid = {38161591}, issn = {1663-4365}, abstract = {BACKGROUND: A few observational studies revealed that amyotrophic lateral sclerosis (ALS) was tightly connected with osteoporosis. However, the results of previous studies were inconsistent, and the causal effect of ALS on osteoporosis has not been investigated. To do so, the two-sample Mendelian randomization (MR) method was employed to estimate the causality.

METHODS: The instrumental variables (IVs) for ALS were selected from one GWAS summary dataset (27,205 ALS cases and 110,881 controls), and bone mineral density (BMD) in the femoral neck (FN), lumbar spine (LS), and forearm, extracted from another large-scale GWAS summary database (53,236 cases), were used as phenotypes for osteoporosis. Random-effects inverse variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode were conducted to evaluate the causality. Sensitivity analyses were further performed to explore heterogeneity and pleiotropy.

RESULTS: A total of 10 qualified SNPs were finally selected as proxies for ALS. The results of random effects from IVW revealed that ALS has no causal effect on FN-BMD (beta: -0.038, 95% CI: -0.090 to 0.015, SE: 0.027, p = 0.158), LS-BMD (beta: -0.015, 95% CI: -0.076 to 0.046, SE: 0.031, p = 0.629), and forearm BMD (beta: 0.044, 95% CI: -0.063 to 0.152, SE: 0.055, p = 0.418). These results were confirmed using the MR-Egger, weighted median, simple model, and weighted model. No heterogeneity or pleiotropy was detected (p > 0.05 for all).

CONCLUSION: Contrary to previous observational studies, our study figured out that no causal effect existed between ALS and osteoporosis. The disparity in results is probably attributed to secondary effects such as physical inactivity and muscle atrophy caused by ALS.}, } @article {pmid38162899, year = {2024}, author = {Waller, R and Bury, JJ and Appleby-Mallinder, C and Wyles, M and Loxley, G and Babel, A and Shekari, S and Kazoka, M and Wollff, H and Al-Chalabi, A and Heath, PR and Shaw, PJ and Kirby, J}, title = {Establishing mRNA and microRNA interactions driving disease heterogeneity in amyotrophic lateral sclerosis patient survival.}, journal = {Brain communications}, volume = {6}, number = {1}, pages = {fcad331}, pmid = {38162899}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease, associated with the degeneration of both upper and lower motor neurons of the motor cortex, brainstem and spinal cord. Death in most patients results from respiratory failure within 3-4 years from symptom onset. However, due to disease heterogeneity some individuals survive only months from symptom onset while others live for several years. Identifying specific biomarkers that aid in establishing disease prognosis, particularly in terms of predicting disease progression, will help our understanding of amyotrophic lateral sclerosis pathophysiology and could be used to monitor a patient's response to drugs and therapeutic agents. Transcriptomic profiling technologies are continually evolving, enabling us to identify key gene changes in biological processes associated with disease. MicroRNAs are small non-coding RNAs typically associated with regulating gene expression, by degrading mRNA or reducing levels of gene expression. Being able to associate gene expression changes with corresponding microRNA changes would help to distinguish a more complex biomarker signature enabling us to address key challenges associated with complex diseases such as amyotrophic lateral sclerosis. The present study aimed to investigate the transcriptomic profile (mRNA and microRNA) of lymphoblastoid cell lines from amyotrophic lateral sclerosis patients to identify key signatures that are distinguishable in those patients who suffered a short disease duration (<12 months) (n = 22) compared with those that had a longer disease duration (>6 years) (n = 20). Transcriptional profiling of microRNA-mRNA interactions from lymphoblastoid cell lines in amyotrophic lateral sclerosis patients revealed differential expression of genes involved in cell cycle, DNA damage and RNA processing in patients with longer survival from disease onset compared with those with short survival. Understanding these particular microRNA-mRNA interactions and the pathways in which they are involved may help to distinguish potential therapeutic targets that could exert neuroprotective effects to prolong the life expectancy of amyotrophic lateral sclerosis patients.}, } @article {pmid38162906, year = {2024}, author = {Beswick, E and Forbes, D and Johnson, M and Newton, J and Dakin, R and Glasmcher, S and Abrahams, S and Carson, A and Chandran, S and Pal, S}, title = {Non-motor symptoms in motor neuron disease: prevalence, assessment and impact.}, journal = {Brain communications}, volume = {6}, number = {1}, pages = {fcad336}, pmid = {38162906}, issn = {2632-1297}, abstract = {People with motor neuron disease often experience non-motor symptoms that may occur secondary to, or distinct from, motor degeneration and that may significantly reduce quality of life, despite being under-recognized and evaluated in clinical practice. Non-motor symptoms explored in this population-based study include pain, fatigue, gastrointestinal issues, poor sleep, low mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction. People registered on the Clinical Audit Research and Evaluation of motor neuron disease platform, the Scottish Motor Neuron Disease Register, were invited to complete a questionnaire on non-motor symptoms and a self-reported Amyotrophic Lateral Sclerosis Functional Rating Scale. The questionnaire comprised a pre-defined list of 11 potential non-motor symptoms, with the opportunity to list additional symptoms. A total of 120 individuals participated in this cross-sectional study, a 39% response rate of those sent questionnaires (n = 311); 99% of participants recruited (n = 120) experienced at least one non-motor symptom, with 72% (n = 120) reporting five or more. The symptoms most often reported were pain and fatigue (reported by 76% of participants, respectively). The symptoms reported to be most impactful were gastrointestinal issues (reported as 'severe' by 54% of participants who experienced them), followed by pain and problematic saliva (51%, respectively). Lower Amyotrophic Lateral Sclerosis Functional Rating Scale scores, indicating more advanced disease and being a long survivor [diagnosed over 8 years ago; Black et al. (Genetic epidemiology of motor neuron disease-associated variants in the Scottish population. Neurobiol Aging. 2017;51:178.e11-178.e20.)], were significantly associated with reporting more symptoms; 73% of respondents were satisfied with the frequency that non-motor symptoms were discussed in clinical care; 80% of participants indicated they believe evaluation of non-motor symptom is important to include as outcomes in trials, independent of their personal experience of these symptoms. The preferred method of assessment was completing questionnaires, at home. The overwhelming majority of people with motor neuron disease report non-motor symptoms and these frequently co-occur. Pain, fatigue, gastrointestinal issues, sleep, mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction are prevalent. People with motor neuron disease who had worse physical function and those who were long survivors were more likely to report more symptoms. Where reported, these symptoms are frequent, impactful and a priority for people with motor neuron disease in clinical care and trial design.}, } @article {pmid38165188, year = {2023}, author = {Altuwaijri, F}, title = {Simulation-based Comparison of British and Australian Advanced Life Support Guidelines.}, journal = {The western journal of emergency medicine}, volume = {24}, number = {6}, pages = {1064-1068}, pmid = {38165188}, issn = {1936-9018}, mesh = {Humans ; Australia ; *Cardiopulmonary Resuscitation/methods ; *Emergency Medical Services ; *Heart Arrest/therapy ; }, abstract = {INTRODUCTION: Cardiac arrest is a major health concern that has been linked to poor disease outcomes. Cardiopulmonary resuscitation (CPR) is a critical protocol for restoring spontaneous circulation. The guidelines used by medical staff differ across different countries. A comparison of these guidelines can help in designing more efficient Advanced Life Support (ALS) protocols. The goal in this study was to compare the guidelines for interruption of compression during CPR (hands-off time) for ALS protocols provided by Australian and United Kingdom (UK) resuscitation councils.

METHODS: The author designed a simulation-based study using a mannequin and a defibrillator, and then recruited six participants. Three participants were certified ALS practitioners who followed UK guidelines, and three were certified ALS practitioners who followed Australian guidelines. Each participant received a random task assignment for each scenario, as a team leader, performer of cardiopulmonary resuscitation, or assistant. The team leader and the chest compressor were unaware of the shockability of each case's rhythm. Eight minutes total were spent on 10 CPR trials, each lasting four cycles. A video of the simulation was recorded for automated timekeeping. An independent sample t-test was used to compare the amount of hands-off time (seconds) throughout each cycle between two procedures. For purposes of calculating statistical significance, a 0.05 P-value was employed.

RESULTS: The mean duration of second cycle hands-off time (seconds) in the UK ALS protocol was statistically significantly longer than the Australian ALS (t = -2.100; P = 0.05). For shockable rhythms, the hands-off time of the UK ALS protocol was significantly longer than Australian ALS protocol, as reflected in the second cycle (t = -0.621; P < 0.001), third cycle (t = -8.083; P < 0.001), and fourth cycle (t = -5.814; p < 0.001), while the difference in the first cycle between groups was not statistically significant. (t = -0.258; P = 0.803).

CONCLUSION: This simulation-based study demonstrated that the UK ALS guidelines led to an increased duration of hands-off time during the second cycle. The hands-off time in the shockable rhythms was also higher during the second, third, and fourth cycles in the UK ALS protocol compared to the Australian ALS protocol. These points must be focused on in future revisions of the UK ALS guidelines. For better results, it is critical to limit hands-off time between chest compression cycles.}, } @article {pmid38165299, year = {2024}, author = {Nelke, C}, title = {Right Brain: The Strangeness of a Good Diagnosis.}, journal = {Neurology}, volume = {102}, number = {3}, pages = {e208103}, doi = {10.1212/WNL.0000000000208103}, pmid = {38165299}, issn = {1526-632X}, mesh = {Humans ; Female ; Male ; *Cerebral Cortex ; *Amyotrophic Lateral Sclerosis ; Emotions ; Face ; Fasciculation ; }, abstract = {Coffee, black with a spritz of milk. I enjoyed routine, and today was no different. We were on the 12th floor of the "tower", as our hospital is lovingly called. It was my second year of residency, and I was charged with admissions to our neurological ward. Sighing with the expectation of a long day, I walked over to our patients. The first was a woman in her sixties. She complained of trouble swallowing for the past 2 months that was getting worse. She was otherwise healthy. Asked about her social background, she looked over to her husband with an impish grin and replied: "happily married for almost thirty years." Physical examination was next. There was no apparent muscle weakness, but, strangely enough, the Babinski sign was clearly positive. Looking at her tongue, I noticed a single, delicate strain of muscle twitching. It was subtle, but impossible to miss. The twitching was adamant. It was not rhythmic, but it was unrelenting. I could not help but stare, and eventually, the patient closed her mouth, looking at me puzzled. I did not make the connection at first. But, walking back to our room, I realized that the concert of neurological dysfunction was spelling out the diagnosis. I caught myself feeling excited despite my knowledge of the potential outcome. Reporting my findings to my consultant, I remember him saying: "Sure sounds like amyotrophic lateral sclerosis, but we still have to complete our work-up." And so we did, dutifully.}, } @article {pmid38165325, year = {2024}, author = {Spinelli, EG and Ghirelli, A and Basaia, S and Canu, E and Castelnovo, V and Cividini, C and Russo, T and Schito, P and Falzone, YM and Riva, N and Filippi, M and Agosta, F}, title = {Structural and Functional Brain Network Connectivity at Different King's Stages in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {102}, number = {2}, pages = {e207946}, pmid = {38165325}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Basal Ganglia ; Brain/diagnostic imaging ; Diffusion ; Motor Neurons ; Male ; Female ; }, abstract = {BACKGROUND AND OBJECTIVES: There is currently no validated disease-stage biomarker for amyotrophic lateral sclerosis (ALS). The identification of quantitative and reproducible markers of disease stratification in ALS is fundamental for study design definition and inclusion of homogenous patient cohorts into clinical trials. Our aim was to assess the rearrangements of structural and functional brain connectivity underlying the clinical stages of ALS, to suggest objective, reproducible measures provided by MRI connectomics mirroring disease staging.

METHODS: In this observational study, patients with ALS and healthy controls (HCs) underwent clinical evaluation and brain MRI on a 3T scanner. Patients were classified into 4 groups, according to the King's staging system. Structural and functional brain connectivity matrices were obtained using diffusion tensor and resting-state fMRI data, respectively. Whole-brain network-based statistics (NBS) analysis and comparisons of intraregional and inter-regional connectivity values using analysis of covariance models were performed between groups. Correlations between MRI and clinical/cognitive measures were tested using Pearson coefficient.

RESULTS: One hundred four patients with ALS and 61 age-matched and sex-matched HCs were included. NBS and regional connectivity analyses demonstrated a progressive decrease of intranetwork and internetwork structural connectivity of sensorimotor regions at increasing ALS stages in our cohort, compared with HCs. By contrast, functional connectivity showed divergent patterns between King's stages 3 (increase in basal ganglia and temporal circuits [p = 0.04 and p = 0.05, respectively]) and 4 (frontotemporal decrease [p = 0.03]), suggesting a complex interplay between opposite phenomena in late stages of the disease. Intraregional sensorimotor structural connectivity was correlated with ALS Functional Rating Scale-revised (ALSFRS-r) score (r = 0.31, p < 0.001) and upper motor neuron burden (r = -0.25, p = 0.01). Inter-regional frontal-sensorimotor structural connectivity was also correlated with ALSFRS-r (r = 0.24, p = 0.02). No correlations with cognitive measures were found.

DISCUSSION: MRI of the brain allows to demonstrate and quantify increasing disruption of structural connectivity involving the sensorimotor networks in ALS, mirroring disease stages. Frontotemporal functional disconnection seems to characterize only advanced disease phases. Our findings support the utility of MRI connectomics to stratify patients and stage brain pathology in ALS in a reproducible way, which may mirror clinical progression.}, } @article {pmid38165347, year = {2024}, author = {}, title = {Observing Patterns in MRI With QSM in Patients With SOD1 Genetic ALS (5047).}, journal = {Neurology}, volume = {102}, number = {2}, pages = {e208121}, doi = {10.1212/WNL.0000000000208121}, pmid = {38165347}, issn = {1526-632X}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; Magnetic Resonance Imaging ; Patients ; }, } @article {pmid38166850, year = {2024}, author = {Yu, W and Yu, F and Li, M and Yang, F and Wang, H and Song, H and Huang, X}, title = {Quantitative association between lead exposure and amyotrophic lateral sclerosis: a Bayesian network-based predictive study.}, journal = {Environmental health : a global access science source}, volume = {23}, number = {1}, pages = {2}, pmid = {38166850}, issn = {1476-069X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Bayes Theorem ; Lead ; Retrospective Studies ; Risk Factors ; }, abstract = {BACKGROUND: Environmental lead (Pb) exposure have been suggested as a causative factor for amyotrophic lateral sclerosis (ALS). However, the role of Pb content of human body in ALS outcomes has not been quantified clearly. The purpose of this study was to apply Bayesian networks to forecast the risk of Pb exposure on the disease occurrence.

METHODS: We retrospectively collected medical records of ALS inpatients who underwent blood Pb testing, while matched controlled inpatients on age, gender, hospital ward and admission time according to the radio of 1:9. Tree Augmented Naïve Bayes (TAN), a semi-naïve Bayes classifier, was established to predict probability of ALS or controls with risk factors.

RESULTS: A total of 140 inpatients were included in this study. The whole blood Pb levels of ALS patients (57.00 μg/L) were more than twice as high as the controls (27.71 μg/L). Using the blood Pb concentrations to calculate probability of ALS, TAN produced the total coincidence rate of 90.00%. The specificity, sensitivity of Pb for ALS prediction was 0.79, or 0.74, respectively.

CONCLUSION: Therefore, these results provided quantitative evidence that Pb exposure may contribute to the development of ALS. Bayesian networks may be used to predict the ALS early onset with blood Pb levels.}, } @article {pmid38167886, year = {2024}, author = {Le, MUT and Park, JH and Son, JG and Shon, HK and Joh, S and Chung, CG and Cho, JH and Pirkl, A and Lee, SB and Lee, TG}, title = {Monitoring lipid alterations in Drosophila heads in an amyotrophic lateral sclerosis model with time-of-flight secondary ion mass spectrometry.}, journal = {The Analyst}, volume = {149}, number = {3}, pages = {846-858}, doi = {10.1039/d3an01670f}, pmid = {38167886}, issn = {1364-5528}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Drosophila ; Spectrometry, Mass, Secondary Ion ; Lipids ; }, abstract = {Lipid alterations in the brain are well-documented in disease and aging, but our understanding of their pathogenic implications remains incomplete. Recent technological advances in assessing lipid profiles have enabled us to intricately examine the spatiotemporal variations in lipid compositions within the complex brain characterized by diverse cell types and intricate neural networks. In this study, we coupled time-of-flight secondary ion mass spectrometry (ToF-SIMS) to an amyotrophic lateral sclerosis (ALS) Drosophila model, for the first time, to elucidate changes in the lipid landscape and investigate their potential role in the disease process, serving as a methodological and analytical complement to our prior approach that utilized matrix-assisted laser desorption/ionization mass spectrometry. The expansion of G4C2 repeats in the C9orf72 gene is the most prevalent genetic factor in ALS. Our findings indicate that expressing these repeats in fly brains elevates the levels of fatty acids, diacylglycerols, and ceramides during the early stages (day 5) of disease progression, preceding motor dysfunction. Using RNAi-based genetic screening targeting lipid regulators, we found that reducing fatty acid transport protein 1 (FATP1) and Acyl-CoA-binding protein (ACBP) alleviates the retinal degeneration caused by G4C2 repeat expression and also markedly restores the G4C2-dependent alterations in lipid profiles. Significantly, the expression of FATP1 and ACBP is upregulated in G4C2-expressing flies, suggesting their contribution to lipid dysregulation. Collectively, our novel use of ToF-SIMS with the ALS Drosophila model, alongside methodological and analytical improvements, successfully identifies crucial lipids and related genetic factors in ALS pathogenesis.}, } @article {pmid38168171, year = {2023}, author = {Maltby, CJ and Krans, A and Grudzien, SJ and Palacios, Y and Muiños, J and Suárez, A and Asher, M and Khurana, V and Barmada, SJ and Dijkstra, AA and Todd, PK}, title = {AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS Neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38168171}, issn = {2692-8205}, support = {R01 NS086810/NS/NINDS NIH HHS/United States ; P50 HD104463/HD/NICHD NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R21 NS129096/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; }, abstract = {Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late onset, recessively inherited neurodegenerative disorder caused by biallelic, non-reference pentameric AAGGG(CCCTT) repeat expansions within the second intron of replication factor complex subunit 1 (RFC1). To investigate how these repeats cause disease, we generated CANVAS patient induced pluripotent stem cell (iPSC) derived neurons (iNeurons) and utilized calcium imaging and transcriptomic analysis to define repeat-elicited gain-of-function and loss-of-function contributions to neuronal toxicity. AAGGG repeat expansions do not alter neuronal RFC1 splicing, expression, or DNA repair pathway functions. In reporter assays, AAGGG repeats are translated into pentapeptide repeat proteins that selectively accumulate in CANVAS patient brains. However, neither these proteins nor repeat RNA foci were detected in iNeurons, and overexpression of these repeats in isolation did not induce neuronal toxicity. CANVAS iNeurons exhibit defects in neuronal development and diminished synaptic connectivity that is rescued by CRISPR deletion of a single expanded allele. These phenotypic deficits were not replicated by knockdown of RFC1 in control neurons and were not rescued by ectopic expression of RFC1. These findings support a repeat-dependent but RFC1-independent cause of neuronal dysfunction in CANVAS, with important implications for therapeutic development in this currently untreatable condition.}, } @article {pmid38168276, year = {2023}, author = {Omar, OMF and Kimble, AL and Cheemala, A and Tyburski, JD and Pandey, S and Wu, Q and Reese, B and Jellison, ER and Li, Y and Hao, B and Yan, R and Murphy, PA}, title = {Targeted inCITE-Seq Analysis Identifies the Loss of Nuclear TDP-43 in Endothelium as a Mediator of Blood Brain Barrier Signaling Pathway Dysfunction in Neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38168276}, issn = {2692-8205}, support = {K99 HL125727/HL/NHLBI NIH HHS/United States ; R00 HL125727/HL/NHLBI NIH HHS/United States ; R01 GM135592/GM/NIGMS NIH HHS/United States ; RF1 NS117449/NS/NINDS NIH HHS/United States ; }, abstract = {Despite the importance of the endothelium in the regulation of the blood brain barrier (BBB) in aging and neurodegenerative disease, difficulties in extracting endothelial cell (EC) nuclei have limited analysis of these cells. In addition, nearly all Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Degeneration (FTD), and a large portion of Alzheimer's Disease (AD) exhibit neuronal TDP-43 aggregation, leading to loss of nuclear function, but whether TDP-43 is similarly altered in human BBB ECs is unknown. Here we utilize a novel technique for the enrichment of endothelial and microglial nuclei from human cortical brain tissues, combined with inCITE-seq, to analyze nuclear proteins and RNA transcripts in a large cohort of healthy and diseased donors. Our findings reveal a unique transcriptional signature in nearly half of the capillary endothelial cells across neurodegenerative states, characterized by reduced levels of nuclear β-Catenin and canonical downstream genes, and an increase in TNF/NF-kB target genes. We demonstrate that this does not correlate with increased nuclear p65/NF-kB, but rather a specific loss of nuclear TDP-43 in these disease associated ECs. Comparative analysis in animal models with targeted disruption of TDP-43 shows that this is sufficient to drive these transcriptional alterations. This work reveals that TDP-43 is a critical governor of the transcriptional output from nuclear p65/NF-kB, which has paradoxical roles in barrier maintenance and also barrier compromising inflammatory responses, and suggests that disease specific loss in ECs contributes to BBB defects observed in the progression of AD, ALS and FTD.}, } @article {pmid38168312, year = {2023}, author = {Rothstein, JD and Warlick, C and Coyne, AN}, title = {Highly variable molecular signatures of TDP-43 loss of function are associated with nuclear pore complex injury in a population study of sporadic ALS patient iPSNs.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38168312}, issn = {2692-8205}, support = {RF1 AG062171/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; R01 NS122236/NS/NINDS NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; R00 NS123242/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 NS132836/NS/NINDS NIH HHS/United States ; }, abstract = {The nuclear depletion and cytoplasmic aggregation of the RNA binding protein TDP-43 is widely considered a pathological hallmark of Amyotrophic Lateral Sclerosis (ALS) and related neurodegenerative diseases. Recent studies have artificially reduced TDP-43 in wildtype human neurons to replicate loss of function associated events. Although this prior work has defined a number of gene expression and mRNA splicing changes that occur in a TDP-43 dependent manner, it is unclear how these alterations relate to authentic ALS where TDP-43 is not depleted from the cell but miscompartmentalized to variable extents. Here, in this population study, we generate ~30,000 qRT-PCR data points spanning 20 genes in induced pluripotent stem cell (iPSC) derived neurons (iPSNs) from >150 control, C9orf72 ALS/FTD, and sALS patients to examine molecular signatures of TDP-43 dysfunction. This data set defines a time dependent and variable profile of individual molecular hallmarks of TDP-43 loss of function within and amongst individual patient lines. Importantly, nearly identical changes are observed in postmortem CNS tissues obtained from a subset of patients whose iPSNs were examined. Notably, these studies provide evidence that induction of nuclear pore complex (NPC) injury via reduction of the transmembrane Nup POM121 in wildtype iPSNs is sufficient to phenocopy disease associated signatured of TDP-43 loss of function thereby directly linking NPC integrity to TDP-43 loss of function. Therapeutically, we demonstrate that the expression of all mRNA species associated with TDP-43 loss of function can be restored in sALS iPSNs via two independent methods to repair NPC injury. Collectively, this data 1) represents a substantial resource for the community to examine TDP-43 loss of function events in authentic sALS patient iPSNs, 2) demonstrates that patient derived iPSNs can accurately reflect actual TDP-43 associated alterations in patient brain, and 3) that targeting NPC injury events can be preclinically and reliably accomplished in an iPSN based platform of a sporadic disease.}, } @article {pmid38168370, year = {2023}, author = {McCallister, TX and Lim, CKW and Terpstra, WM and Alejandra Zeballos C, M and Zhang, S and Powell, JE and Gaj, T}, title = {A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38168370}, issn = {2692-8205}, support = {R01 GM141296/GM/NIGMS NIH HHS/United States ; R01 NS123556/NS/NINDS NIH HHS/United States ; T32 EB019944/EB/NIBIB NIH HHS/United States ; U01 NS122102/NS/NINDS NIH HHS/United States ; }, abstract = {An abnormal expansion of a GGGGCC hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we developed a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform effectively curbed the expression of the GGGGCC repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci and reversed transcriptional deficits. This high-fidelity Cas13 variant possessed improved transcriptome-wide specificity compared to its native form and mediated efficient targeting in motor neuron-like cells derived from a patient with ALS. Our results lay the foundation for the implementation of RNA-targeting CRISPR technologies for C9ORF72-linked ALS/FTD.}, } @article {pmid38168388, year = {2023}, author = {Cheemala, A and Kimble, AL and Tyburski, JD and Leclair, NK and Zuberi, AR and Murphy, M and Jellison, ER and Reese, B and Hu, X and Lutz, CM and Yan, R and Murphy, PA}, title = {Loss of Endothelial TDP-43 Leads to Blood Brain Barrier Defects in Mouse Models of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38168388}, issn = {2692-8205}, support = {R00 HL125727/HL/NHLBI NIH HHS/United States ; K99 HL125727/HL/NHLBI NIH HHS/United States ; U54 OD020351/OD/NIH HHS/United States ; P30 CA034196/CA/NCI NIH HHS/United States ; RF1 NS117449/NS/NINDS NIH HHS/United States ; }, abstract = {Loss of nuclear TDP-43 occurs in a wide range of neurodegenerative diseases, and specific mutations in the TARDBP gene that encodes the protein are linked to familial Frontal Temporal Lobar Dementia (FTD), and Amyotrophic Lateral Sclerosis (ALS). Although the focus has been on neuronal cell dysfunction caused by TDP-43 variants, TARDBP mRNA transcripts are expressed at similar levels in brain endothelial cells (ECs). Since increased permeability across the blood brain barrier (BBB) precedes cognitive decline, we postulated that altered functions of TDP-43 in ECs contributes to BBB dysfunction in neurodegenerative disease. To test this hypothesis, we examined EC function and BBB properties in mice with either knock-in mutations found in ALS/FTLD patients (TARDBP [G348C] and GRN [R493X]) or EC-specific deletion of TDP-43 throughout the endothelium (Cdh5(PAC)CreERT2; Tardbp [ff]) or restricted to brain endothelium (Slco1c1(BAC)CreERT2; Tardbp [ff]). We found that TARDBP [G348C] mice exhibited increased permeability to 3kDa Texas Red dextran and NHS-biotin, relative to their littermate controls, which could be recapitulated in cultured brain ECs from these mice. Nuclear levels of TDP-43 were reduced in vitro and in vivo in ECs from TARDBP [G348C] mice. This coincided with a reduction in junctional proteins VE-cadherin, claudin-5 and ZO-1 in isolated ECs, supporting a cell autonomous effect on barrier function through a loss of nuclear TDP-43. We further examined two models of Tardbp deletion in ECs, and found that the loss of TDP-43 throughout the endothelium led to systemic endothelial activation and permeability. Deletion specifically within the brain endothelium acutely increased BBB permeability, and eventually led to hallmarks of FTD, including fibrin deposition, microglial and astrocyte activation, and behavioral defects. Together, these data show that TDP-43 dysfunction specifically within brain ECs would contribute to the BBB defects observed early in the progression of ALS/FTLD.}, } @article {pmid38168426, year = {2023}, author = {Talaia, G and Bentley-DeSousa, A and Ferguson, SM}, title = {Lysosomal TBK1 Responds to Amino Acid Availability to Relieve Rab7-Dependent mTORC1 Inhibition.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38168426}, issn = {2692-8205}, support = {R01 GM105718/GM/NIGMS NIH HHS/United States ; }, abstract = {Lysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. At lysosomes, this TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD.}, } @article {pmid38168440, year = {2023}, author = {Ugalde, MV and Alecki, C and Rizwan, J and Le, P and Jacob-Tomas, S and Xu, JM and Minotti, S and Wu, T and Durham, H and Yeo, G}, title = {Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38168440}, issn = {2693-5015}, support = {RF1 MH126719/MH/NIMH NIH HHS/United States ; U41 HG009889/HG/NHGRI NIH HHS/United States ; U24 HG009889/HG/NHGRI NIH HHS/United States ; R01 HG004659/HG/NHGRI NIH HHS/United States ; R01 HG011864/HG/NHGRI NIH HHS/United States ; R01 NS103172/NS/NINDS NIH HHS/United States ; }, abstract = {Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discovered that neurons localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress. The most abundant dendritic chaperone mRNA encodes a constitutive heat shock protein 70 family member (HSPA8). Proteotoxic stress also enhanced HSPA8 mRNA translation efficiency in dendrites. Stress-mediated HSPA8 mRNA localization to the dendrites was impaired by depleting fused in sarcoma-an amyotrophic lateral sclerosis-related protein-in cultured mouse motor neurons and expressing a pathogenic variant of heterogenous nuclear ribonucleoprotein A2/B1 in neurons derived from human induced pluripotent stem cells. These results reveal a crucial and unexpected neuronal stress response in which RNA-binding proteins increase the dendritic localization of HSPA8 mRNA to maintain proteostasis and prevent neurodegeneration.}, } @article {pmid38169680, year = {2023}, author = {Zhang, Z and Liu, N and Pan, X and Zhang, C and Yang, Y and Li, X and Shao, Y}, title = {Assessing causal associations between neurodegenerative diseases and neurological tumors with biological aging: a bidirectional Mendelian randomization study.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1321246}, pmid = {38169680}, issn = {1662-4548}, abstract = {BACKGROUND: Aging is a significant risk factor for many neurodegenerative diseases and neurological tumors. Previous studies indicate that the frailty index, facial aging, telomere length (TL), and epigenetic aging clock acceleration are commonly used biological aging proxy indicators. This study aims to comprehensively explore potential relationships between biological aging and neurodegenerative diseases and neurological tumors by integrating various biological aging proxy indicators, employing Mendelian randomization (MR) analysis.

METHODS: Two-sample bidirectional MR analyses were conducted using genome-wide association study (GWAS) data. Summary statistics for various neurodegenerative diseases and neurological tumors, along with biological aging proxy indicators, were obtained from extensive meta-analyses of GWAS. Genetic single-nucleotide polymorphisms (SNPs) associated with the exposures were used as instrumental variables, assessing causal relationships between three neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), two benign neurological tumors (vestibular schwannoma and meningioma), one malignant neurological tumor (glioma), and four biological aging indicators (frailty index, facial aging, TL, and epigenetic aging clock acceleration). Sensitivity analyses were also performed.

RESULTS: Our analysis revealed that genetically predicted longer TL reduces the risk of Alzheimer's disease but increases the risk of vestibular schwannoma and glioma (All Glioma, GBM, non-GBM). In addition, there is a suggestive causal relationship between some diseases (PD and GBM) and DNA methylation GrimAge acceleration. Causal relationships between biological aging proxy indicators and other neurodegenerative diseases and neurological tumors were not observed.

CONCLUSION: Building upon prior investigations into the causal relationships between telomeres and neurodegenerative diseases and neurological tumors, our study validates these findings using larger GWAS data and demonstrates, for the first time, that Parkinson's disease and GBM may promote epigenetic age acceleration. Our research provides new insights and evidence into the causal relationships between biological aging and the risk of neurodegenerative diseases and neurological tumors.}, } @article {pmid38170217, year = {2024}, author = {Zhu, Y and Burg, T and Neyrinck, K and Vervliet, T and Nami, F and Vervoort, E and Ahuja, K and Sassano, ML and Chai, YC and Tharkeshwar, AK and De Smedt, J and Hu, H and Bultynck, G and Agostinis, P and Swinnen, JV and Van Den Bosch, L and da Costa, RFM and Verfaillie, C}, title = {Disruption of MAM integrity in mutant FUS oligodendroglial progenitors from hiPSCs.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {6}, pmid = {38170217}, issn = {1432-0533}, support = {12ZG121N//Fonds Wetenschappelijk Onderzoek/ ; SBO-S001221N//Fonds Wetenschappelijk Onderzoek/ ; 12AIK24N//Fonds Wetenschappelijk Onderzoek/ ; W001422N//Fonds Wetenschappelijk Onderzoek/ ; W001422N//Fonds Wetenschappelijk Onderzoek/ ; 201908440360//China Scholarship Council/ ; C14-17-107//Universitaire Ziekenhuizen Leuven, KU Leuven/ ; C14/22/132//Universitaire Ziekenhuizen Leuven, KU Leuven/ ; ALS-OL//Fondation Thierry Latran/ ; C14/19/099//Research Council of the KU Leuven/ ; AKUL/19/34//Research Council of the KU Leuven/ ; iBOF/23/02//the ALS Liga ('A Cure for ALS')/ ; IDN/22/012//Generet Award for Rare Diseases/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; Mutation ; Oligodendroglia/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; DNA-Binding Proteins ; Transcription Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder, characterized by selective loss of motor neurons (MNs). A number of causative genetic mutations underlie the disease, including mutations in the fused in sarcoma (FUS) gene, which can lead to both juvenile and late-onset ALS. Although ALS results from MN death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a R521H or a P525L mutation in FUS and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette. Mutant and control iPSCs differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Lipidomic studies demonstrated defects in myelin-related lipids, with a reduction of glycerophospholipids in mutant OPCs. Interestingly, FUS[R521H] OPCs displayed a decrease in the phosphatidylcholine/phosphatidylethanolamine ratio, known to be associated with maintaining membrane integrity. A proximity ligation assay further indicated that mitochondria-associated endoplasmic reticulum membranes (MAM) were diminished in both mutant FUS OPCs. Moreover, both mutant FUS OPCs displayed increased susceptibility to ER stress when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca[2+] signaling from ER Ca[2+] stores. Taken together, these results demonstrate a pathological role of mutant FUS in OPCs, causing defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and with suppressed physiological Ca[2+] signaling. As such, further exploration of the role of oligodendrocyte dysfunction in the demise of MNs is crucial and will provide new insights into the complex cellular mechanisms underlying ALS.}, } @article {pmid38170440, year = {2024}, author = {Kumar, S and Mehan, S and Khan, Z and Das Gupta, G and Narula, AS}, title = {Guggulsterone Selectively Modulates STAT-3, mTOR, and PPAR-Gamma Signaling in a Methylmercury-Exposed Experimental Neurotoxicity: Evidence from CSF, Blood Plasma, and Brain Samples.}, journal = {Molecular neurobiology}, volume = {61}, number = {8}, pages = {5161-5193}, pmid = {38170440}, issn = {1559-1182}, support = {DST-SERB//DST-SERB, Govt. of India; Core Research Grant/ ; Govt. of India; Core Research Grant - CRG/2021/001009//DST-SERB, Govt. of India; Core Research Grant/ ; }, mesh = {Animals ; *TOR Serine-Threonine Kinases/metabolism ; *PPAR gamma/metabolism ; *STAT3 Transcription Factor/metabolism ; *Methylmercury Compounds/toxicity ; Male ; *Brain/drug effects/pathology/metabolism ; *Signal Transduction/drug effects ; Rats ; *Pregnenediones/pharmacology ; Rats, Wistar ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a paralytic disease that damages the brain and spinal cord motor neurons. Several clinical and preclinical studies have found that methylmercury (MeHg[+]) causes ALS. In ALS, MeHg[+]-induced neurotoxicity manifests as oligodendrocyte destruction; myelin basic protein (MBP) deficiency leads to axonal death. ALS development has been connected to an increase in signal transducer and activator of transcription-3 (STAT-3), a mammalian target of rapamycin (mTOR), and a decrease in peroxisome proliferator-activated receptor (PPAR)-gamma. Guggulsterone (GST), a plant-derived chemical produced from Commiphorawhighitii resin, has been found to protect against ALS by modulating these signaling pathways. Vitamin D3 (VitD3) deficiency has been related to oligodendrocyte precursor cells (OPC) damage, demyelination, and white matter deterioration, which results in motor neuron death. As a result, the primary goal of this work was to investigate the therapeutic potential of GST by altering STAT-3, mTOR, and PPAR-gamma levels in a MeHg[+]-exposed experimental model of ALS in adult rats. The GST30 and 60 mg/kg oral treatments significantly improved the behavioral, motor, and cognitive dysfunctions and increased remyelination, as proven by the Luxol Fast Blue stain (LFB), and reduced neuroinflammation as measured by histological examinations. Furthermore, the co-administration of VitD3 exhibits moderate efficacy when administered in combination with GST60. Our results show that GST protects neurons by decreasing STAT-3 and mTOR levels while increasing PPAR-gamma protein levels in ALS rats.}, } @article {pmid38170745, year = {2024}, author = {Aubrey, LD and Ninkina, N and Ulamec, SM and Abramycheva, NY and Vasili, E and Devine, OM and Wilkinson, M and Mackinnon, E and Limorenko, G and Walko, M and Muwanga, S and Amadio, L and Peters, OM and Illarioshkin, SN and Outeiro, TF and Ranson, NA and Brockwell, DJ and Buchman, VL and Radford, SE}, title = {Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {2}, pages = {e2309700120}, pmid = {38170745}, issn = {1091-6490}, support = {MC_PC_16030/2/MRC_/Medical Research Council/United Kingdom ; P40 OD018537/OD/NIH HHS/United States ; 221524/WT_/Wellcome Trust/United Kingdom ; MR/T011149/1/MRC_/Medical Research Council/United Kingdom ; 204963/WT_/Wellcome Trust/United Kingdom ; 204963/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Humans ; Amyloid/chemistry ; *Amyotrophic Lateral Sclerosis/genetics ; gamma-Synuclein/genetics ; alpha-Synuclein/metabolism ; *Parkinson Disease/metabolism ; Amyloidogenic Proteins ; }, abstract = {α-, β-, and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson's disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member.}, } @article {pmid38171451, year = {2024}, author = {Halon-Golabek, M and Flis, DJ and Zischka, H and Akdogan, B and Wieckowski, MR and Antosiewicz, J and Ziolkowski, W}, title = {Amyotrophic lateral sclerosis associated disturbance of iron metabolism is blunted by swim training-role of AKT signaling pathway.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1870}, number = {3}, pages = {167014}, doi = {10.1016/j.bbadis.2023.167014}, pmid = {38171451}, issn = {1879-260X}, mesh = {Mice ; Animals ; Humans ; Proto-Oncogene Proteins c-akt/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Superoxide Dismutase-1/metabolism ; *Neuroblastoma ; Signal Transduction ; Iron/metabolism ; Disease Models, Animal ; Ferritins/metabolism ; RNA-Binding Proteins/metabolism ; }, abstract = {Swim training has increased the life span of the transgenic animal model of amyotrophic lateral sclerosis (ALS). Conversely, the progress of the disease is associated with the impairment of iron metabolism and insulin signaling. We used transgenic hmSOD1 G93A (ALS model) and non-transgenic mice in the present study. The study was performed on the muscles taken from trained (ONSET and TERMINAL) and untrained animals at three stages of the disease: BEFORE, ONSET, and TERMINAL. In order to study the molecular mechanism of changes in iron metabolism, we used SH-SY5Y and C2C12 cell lines expression vector pcDNA3.1 and transiently transfected with specific siRNAs. The progress of ALS resulted in decreased P-Akt/Akt ratio, which is associated with increased proteins responsible for iron storage ferritin L, ferritin H, PCBP1, and skeletal muscle iron at ONSET. Conversely, proteins responsible for iron export- TAU significantly decrease. The training partially reverses changes in proteins responsible for iron metabolism. AKT silencing in the SH-SY5Y cell line decreased PCBP2 and ferroportin and increased ferritin L, H, PCBP1, TAU, transferrin receptor 1, and APP. Moreover, silencing APP led to an increase in ferritin L and H. Our data suggest that swim training in the mice ALS model is associated with significant changes in iron metabolism related to AKT activity. Down-regulation of AKT mainly upregulates proteins involved in iron import and storage but decreases proteins involved in iron export.}, } @article {pmid38174271, year = {2024}, author = {Aguila-Rosas, J and García-Martínez, BA and Ríos, C and Diaz-Ruiz, A and Obeso, JL and Quirino-Barreda, CT and Ibarra, IA and Guzmán-Vargas, A and Lima, E}, title = {Copper release by MOF-74(Cu): a novel pharmacological alternative to diseases with deficiency of a vital oligoelement.}, journal = {RSC advances}, volume = {14}, number = {2}, pages = {855-862}, pmid = {38174271}, issn = {2046-2069}, abstract = {Copper deficiency can trigger various diseases such as Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD) and even compromise the development of living beings, as manifested in Menkes disease (MS). Thus, the regulated administration (controlled release) of copper represents an alternative to reduce neuronal deterioration and prevent disease progression. Therefore, we present, to the best of our knowledge, the first experimental in vitro investigation for the kinetics of copper release from MOF-74(Cu) and its distribution in vivo after oral administration in male Wistar rats. Taking advantage of the abundance and high periodicity of copper within the crystalline-nanostructured metal-organic framework material (MOF-74(Cu)), it was possible to control the release of copper due to the partial degradation of the material. Thus, we simultaneously corroborated a low accumulation of copper in the liver (the main detoxification organ) and a slight increase of copper in the brain (striatum and midbrain), demonstrating that MOF-74(Cu) is a promising pharmacological alternative (controlled copper source) to these diseases.}, } @article {pmid38174587, year = {2024}, author = {Hung, C and Patani, R}, title = {4R tau drives endolysosomal and autophagy dysfunction in frontotemporal dementia.}, journal = {Autophagy}, volume = {20}, number = {5}, pages = {1201-1202}, pmid = {38174587}, issn = {1554-8635}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Frontotemporal Dementia/metabolism/genetics/pathology ; *Autophagy/physiology ; *tau Proteins/metabolism ; *Lysosomes/metabolism ; Endosomes/metabolism ; Neurons/metabolism ; Mutation/genetics ; Valosin Containing Protein/metabolism/genetics ; }, abstract = {Dysfunction of the neuronal endolysosome and macroautophagy/autophagy pathway is emerging as an important pathogenic mechanism in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The VCP (valosin-containing protein) gene is of significant relevance, directly implicated in both FTD and ALS. In our recent study, we used patient-derived stem cells to study the effects of VCP mutations on the endolysosome and autophagy system in human cortical excitatory neurons. We found that VCP mutations cause an abnormal accumulation of enlarged endosomes and lysosomes, accompanied by reduced autophagy flux. VCP mutations also lead to the spatial dissociation of intra-nuclear RNA-binding proteins, FUS and SFPQ, which correlates with alternative splicing of the MAPT pre-mRNA and increased tau phosphorylation. Importantly, we found that an increase in the 4R-tau isoform is sufficient to drive toxic changes in healthy human cortical excitatory neurons, including tau hyperphosphorylation, endolysosomal dysfunction, lysosomal membrane rupture, endoplasmic reticulum stress, and apoptosis. Together, our data suggest that endolysosomal and autophagy dysfunction could represent a convergent pathogenic "design principle" shared by both FTD and ALS.}, } @article {pmid38174670, year = {2023}, author = {Maksymowicz-Śliwińska, A and Lulé, D and Nieporęcki, K and Ciećwierska, K and Ludolph, AC and Kuźma-Kozakiewicz, M}, title = {Attitudes of caregivers towards prolonging and shortening life in advanced stages of amyotrophic lateral sclerosis.}, journal = {Folia neuropathologica}, volume = {61}, number = {4}, pages = {349-359}, doi = {10.5114/fn.2023.130444}, pmid = {38174670}, issn = {1509-572X}, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; Caregivers ; Death ; Disease Progression ; }, abstract = {INTRODUCTION: Inevitable disease progression in amyotrophic lateral sclerosis (ALS) forces patients and their caregivers (CGs) to reflect on end-of-life treatment. The CGs are often heavily burdened with their role of surrogate decision-makers. The aim of the study was to analyze attitudes of CGs and presumable attitudes of ALS patients from the CGs' perspective towards palliative care in advanced disease stages.

MATERIAL AND METHODS: One hundred and sixty four CGs from Germany and Poland were interviewed regarding their own preferences and patients' ideational attitudes towards life-prolonging (invasive and non-invasive ventilation, tube feeding) and life-shortening methods (termination of measures, active measures if permitted by law). The data were correlated with patient- and CG-related factors: demographic and clinical data, care commitment, depression and quality of life (QoL).

RESULTS: The CGs were mostly female spouses of ALS patients, with secondary/higher education. Nearly 70% (81% in Poland, 57% in Germany; p = 0.0001) reported positive attitudes towards life-prolonging methods, which positively correlated with religiousness and negatively with patients' age. Approximately 40% of CGs (25% and 51% respectively; p = 0.001) reported positive attitudes towards life-shortening methods. It positively correlated with time since diagnosis and negatively with the CG's QoL, religiosity and religious/spiritual faith as factors that significantly influenced end-of-life decisions. There was a strongly positive correlation between CGs' positive attitudes towards life-shortening methods and presumed positive patients' attitudes assessed by their CGs (p < 0.000001).

CONCLUSIONS: Although attitudes towards treatment differed between countries, the CGs of ALS patients were generally positive towards life-prolonging treatment. A greater acceptance of life-shortening methods in the case of longer disease duration and poorer QoL may indicate worse coping with disease progression and weaker adaptation mechanisms in CGs compared to those previously reported in ALS patients. A close resemblance of the CGs' answers to probable patients' attitudes reported by the CGs indicates that many GCs might actually express their own culturally shaped attitudes towards end-of-life methods. In light of earlier-reported discrepancies between presumed opinions of the CGs and of patients themselves, a greater focus should be placed on thorough discussions on future treatment options with ALS patients in the presence of their CGs, to stay in line with the patient's authentic will.}, } @article {pmid38175192, year = {2024}, author = {Wu, Z and Li, H and Zhang, Z and Su, X and Shi, H and Huang, YN}, title = {Design of Deep-Ultraviolet Zero-Order Waveplate Materials by Rational Assembly of [AlO2F4] and [SO4] Groups.}, journal = {Inorganic chemistry}, volume = {63}, number = {3}, pages = {1674-1681}, doi = {10.1021/acs.inorgchem.3c03904}, pmid = {38175192}, issn = {1520-510X}, abstract = {Zero-order waveplates are widely used in the manufacture of laser polarizer waves, which are important in polarimetry and the laser industry. However, there are still challenges in designing deep-ultraviolet (DUV) waveplate materials that satisfy large band gaps and small optical anisotropy simultaneously. Herein, three cases of aluminum sulfate fluorides: Na2AlSO4F3, Li4NH4Al(SO4)2F4, and Li6K3Al(SO4)4F4, with novel [AlSO4F3] layers or isolated [AlS2O8F4] trimers were designed and synthesized by the rational assembly of [AlO2F4] and [SO4] groups through a hydrothermal method. Experiments and theoretical calculations imply that these three possess short cutoff edges (λ < 200 nm) and small birefringence (0.0014-0.0076 @ 1064 nm), which fulfils the prerequisite for potential DUV zero-order waveplate materials. This work extends the exploration of DUV zero-order waveplate materials to the aluminum sulfate fluoride systems.}, } @article {pmid38175301, year = {2024}, author = {Agra Almeida Quadros, AR and Li, Z and Wang, X and Ndayambaje, IS and Aryal, S and Ramesh, N and Nolan, M and Jayakumar, R and Han, Y and Stillman, H and Aguilar, C and Wheeler, HJ and Connors, T and Lopez-Erauskin, J and Baughn, MW and Melamed, Z and Beccari, MS and Olmedo Martínez, L and Canori, M and Lee, CZ and Moran, L and Draper, I and Kopin, AS and Oakley, DH and Dickson, DW and Cleveland, DW and Hyman, BT and Das, S and Ertekin-Taner, N and Lagier-Tourenne, C}, title = {Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer's disease.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {9}, pmid = {38175301}, issn = {1432-0533}, support = {P50 AG025711/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; R01 AG061796/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; R01 NS112503/NS/NINDS NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; C06 RR016574/RR/NCRR NIH HHS/United States ; T32 AG066592/AG/NIA NIH HHS/United States ; R01 AG018023/AG/NIA NIH HHS/United States ; R38 AG065762/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; T32 AG066596/AG/NIA NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; T32 GM008666/GM/NIGMS NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics ; *Amyotrophic Lateral Sclerosis ; DNA-Binding Proteins/genetics ; *Frontotemporal Dementia ; *Pick Disease of the Brain ; RNA Splicing ; RNA, Messenger/genetics ; Stathmin/genetics ; Nerve Tissue Proteins ; }, abstract = {Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) and up to 50% of patients with frontotemporal dementia (FTD) and Alzheimer's disease. In Alzheimer's disease, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. Disruption of nuclear TDP-43 function leads to abnormal RNA splicing and incorporation of erroneous cryptic exons in numerous transcripts including Stathmin-2 (STMN2, also known as SCG10) and UNC13A, recently reported in tissues from patients with ALS and FTD. Here, we identify both STMN2 and UNC13A cryptic exons in Alzheimer's disease patients, that correlate with TDP-43 pathology burden, but not with amyloid-β or tau deposits. We also demonstrate that processing of the STMN2 pre-mRNA is more sensitive to TDP-43 loss of function than UNC13A. In addition, full-length RNAs encoding STMN2 and UNC13A are suppressed in large RNA-seq datasets generated from Alzheimer's disease post-mortem brain tissue. Collectively, these results open exciting new avenues to use STMN2 and UNC13A as potential therapeutic targets in a broad range of neurodegenerative conditions with TDP-43 proteinopathy including Alzheimer's disease.}, } @article {pmid38176936, year = {2023}, author = {Windhorst, U and Dibaj, P}, title = {Plastic Spinal Motor Circuits in Health and Disease.}, journal = {Journal of integrative neuroscience}, volume = {22}, number = {6}, pages = {167}, doi = {10.31083/j.jin2206167}, pmid = {38176936}, issn = {0219-6352}, mesh = {Animals ; Humans ; Spinal Cord ; *Amyotrophic Lateral Sclerosis ; *Muscular Atrophy, Spinal/pathology ; *Spinal Cord Injuries/pathology ; Disease Models, Animal ; *Stroke/pathology ; }, abstract = {In the past, the spinal cord was considered a hard-wired network responsible for spinal reflexes and a conduit for long-range connections. This view has changed dramatically over the past few decades. It is now recognized as a plastic structure that has the potential to adapt to changing environments. While such changes occur under physiological conditions, the most dramatic alterations take place in response to pathological events. Many of the changes that occur following such pathological events are maladaptive, but some appear to help adapt to the new conditions. Although a number of studies have been devoted to elucidating the underlying mechanisms, in humans and animal models, the etiology and pathophysiology of various diseases impacting the spinal cord are still not well understood. In this review, we summarize current understanding and outstanding challenges for a number of diseases, including spinal muscular atrophy (SMA), amyotrophic laterals sclerosis (ALS), and spinal cord injury (SCI), with occasional relations to stroke. In particular, we focus on changes resulting from SCI (and stroke), and various influencing factors such as cause, site and extent of the afflicted damage.}, } @article {pmid38177100, year = {2024}, author = {Liu, ML and Ma, S and Tai, W and Zhong, X and Ni, H and Zou, Y and Wang, J and Zhang, CL}, title = {Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease.}, journal = {Cell death & disease}, volume = {15}, number = {1}, pages = {4}, pmid = {38177100}, issn = {2041-4889}, support = {R01 NS092616/NS/NINDS NIH HHS/United States ; R01 NS111776/NS/NINDS NIH HHS/United States ; R01 NS117065/NS/NINDS NIH HHS/United States ; R01 NS127375/NS/NINDS NIH HHS/United States ; }, mesh = {Mice ; Animals ; Adult ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Aging ; Disease Models, Animal ; Mice, Transgenic ; }, abstract = {Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.}, } @article {pmid38177103, year = {2024}, author = {Bapat, O and Purimetla, T and Kruessel, S and Shah, M and Fan, R and Thum, C and Rupprecht, F and Langer, JD and Rangaraju, V}, title = {VAP spatially stabilizes dendritic mitochondria to locally support synaptic plasticity.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {205}, pmid = {38177103}, issn = {2041-1723}, mesh = {*Actins/metabolism ; *Dendritic Spines/metabolism ; Neuronal Plasticity ; Synapses/metabolism ; Mitochondria/metabolism ; }, abstract = {Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses are energy consumption hotspots susceptible to dysfunction when their energy supplies are perturbed. Mitochondria are stabilized near synapses via the cytoskeleton and provide the local energy required for synaptic plasticity. However, the mechanisms that tether and stabilize mitochondria to support synaptic plasticity are unknown. We identified proteins exclusively tethering mitochondria to actin near postsynaptic spines. We find that VAP, the vesicle-associated membrane protein-associated protein implicated in amyotrophic lateral sclerosis, stabilizes mitochondria via actin near the spines. To test if the VAP-dependent stable mitochondrial compartments can locally support synaptic plasticity, we used two-photon glutamate uncaging for spine plasticity induction and investigated the induced and adjacent uninduced spines. We find VAP functions as a spatial stabilizer of mitochondrial compartments for up to ~60 min and as a spatial ruler determining the ~30 μm dendritic segment supported during synaptic plasticity.}, } @article {pmid38177242, year = {2024}, author = {Shi, Y and Huang, L and Dong, H and Yang, M and Ding, W and Zhou, X and Lu, T and Liu, Z and Zhou, X and Wang, M and Zeng, B and Sun, Y and Zhong, S and Wang, B and Wang, W and Yin, C and Wang, X and Wu, Q}, title = {Decoding the spatiotemporal regulation of transcription factors during human spinal cord development.}, journal = {Cell research}, volume = {34}, number = {3}, pages = {193-213}, pmid = {38177242}, issn = {1748-7838}, support = {81891001//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32122037//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; Humans ; *Transcription Factors/genetics ; *Amyotrophic Lateral Sclerosis ; Neurogenesis ; Central Nervous System ; }, abstract = {The spinal cord is a crucial component of the central nervous system that facilitates sensory processing and motor performance. Despite its importance, the spatiotemporal codes underlying human spinal cord development have remained elusive. In this study, we have introduced an image-based single-cell transcription factor (TF) expression decoding spatial transcriptome method (TF-seqFISH) to investigate the spatial expression and regulation of TFs during human spinal cord development. By combining spatial transcriptomic data from TF-seqFISH and single-cell RNA-sequencing data, we uncovered the spatial distribution of neural progenitor cells characterized by combinatorial TFs along the dorsoventral axis, as well as the molecular and spatial features governing neuronal generation, migration, and differentiation along the mediolateral axis. Notably, we observed a sandwich-like organization of excitatory and inhibitory interneurons transiently appearing in the dorsal horns of the developing human spinal cord. In addition, we integrated data from 10× Visium to identify early and late waves of neurogenesis in the dorsal horn, revealing the formation of laminas in the dorsal horns. Our study also illuminated the spatial differences and molecular cues underlying motor neuron (MN) diversification, and the enrichment of Amyotrophic Lateral Sclerosis (ALS) risk genes in MNs and microglia. Interestingly, we detected disease-associated microglia (DAM)-like microglia groups in the developing human spinal cord, which are predicted to be vulnerable to ALS and engaged in the TYROBP causal network and response to unfolded proteins. These findings provide spatiotemporal transcriptomic resources on the developing human spinal cord and potential strategies for spinal cord injury repair and ALS treatment.}, } @article {pmid38177466, year = {2022}, author = {Ramamoorthy, D and Severson, K and Ghosh, S and Sachs, K and , and Glass, JD and Fournier, CN and , and , and Herrington, TM and Berry, JD and Ng, K and Fraenkel, E}, title = {Identifying patterns in amyotrophic lateral sclerosis progression from sparse longitudinal data.}, journal = {Nature computational science}, volume = {2}, number = {9}, pages = {605-616}, pmid = {38177466}, issn = {2662-8457}, support = {IK2 CX001595/CX/CSRD VA/United States ; K23 NS099380/NS/NINDS NIH HHS/United States ; U54 NS091046/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; *Neurodegenerative Diseases ; *Parkinson Disease/diagnosis ; }, abstract = {The clinical presentation of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, varies widely across patients, making it challenging to determine if potential therapeutics slow progression. We sought to determine whether there were common patterns of disease progression that could aid in the design and analysis of clinical trials. We developed an approach based on a mixture of Gaussian processes to identify clusters of patients sharing similar disease progression patterns, modeling their average trajectories and the variability in each cluster. We show that ALS progression is frequently nonlinear, with periods of stable disease preceded or followed by rapid decline. We also show that our approach can be extended to Alzheimer's and Parkinson's diseases. Our results advance the characterization of disease progression of ALS and provide a flexible modeling approach that can be applied to other progressive diseases.}, } @article {pmid38178044, year = {2024}, author = {Peng, Q and Zhu, T and Huang, J and Liu, Y and Huang, J and Zhang, W}, title = {Factors and a model to predict three-month mortality in patients with acute fatty liver of pregnancy from two medical centers.}, journal = {BMC pregnancy and childbirth}, volume = {24}, number = {1}, pages = {27}, pmid = {38178044}, issn = {1471-2393}, support = {2023JJ40980//Natural Science Foundation of Hunan Province/ ; 2022JJ40789//Natural Science Foundation of Hunan Province/ ; 82301927//National Natural Science Foundation of China/ ; 82371700//National Natural Science Foundation of China/ ; }, mesh = {Female ; Humans ; Pregnancy ; *Fatty Liver/diagnosis/mortality ; Prognosis ; Retrospective Studies ; ROC Curve ; Severity of Illness Index ; *Pregnancy Complications/diagnosis/mortality ; Models, Biological ; }, abstract = {BACKGROUND: Acute fatty liver of pregnancy (AFLP) is an uncommon but potentially life-threatening complication. Lacking of prognostic factors and models renders prediction of outcomes difficult. This study aims to explore factors and develop a prognostic model to predict three-month mortality of AFLP.

METHODS: This retrospective study included 78 consecutive patients fulfilling both clinical and laboratory criteria and Swansea criteria for diagnosis of AFLP. Univariate and multivariate cox regression analyses were used to identify predictive factors of mortality. Predictive efficacy of prognostic index for AFLP (PI-AFLP) was compared with the other four liver disease models using receiver operating characteristic (ROC) curve.

RESULTS: AFLP-related three-month mortality of two medical centers was 14.10% (11/78). International normalised ratio (INR, hazard ratio [HR] = 3.446; 95% confidence interval [CI], 1.324-8.970), total bilirubin (TBIL, HR = 1.005; 95% CI, 1.000-1.010), creatine (Scr, HR = 1.007; 95% CI, 1.001-1.013), low platelet (PLT, HR = 0.964; 95% CI, 0.931-0.997) at 72 h postpartum were confirmed as significant predictors of mortality. Artificial liver support (ALS, HR = 0.123; 95% CI, 0.012-1.254) was confirmed as an effective measure to improve severe patients' prognosis. Predictive accuracy of PI-AFLP was 0.874. Area under the receiver operating characteristic curves (AUCs) of liver disease models for end-stage liver disease (MELD), MELD-Na, integrated MELD (iMELD) and pregnancy-specific liver disease (PSLD) were 0.781, 0.774, 0.744 and 0.643, respectively.

CONCLUSION: TBIL, INR, Scr and PLT at 72 h postpartum are significant predictors of three-month mortality in AFLP patients. ALS is an effective measure to improve severe patients' prognosis. PI-AFLP calculated by TBIL, INR, Scr, PLT and ALS was a sensitive and specific model to predict mortality of AFLP.}, } @article {pmid38178278, year = {2024}, author = {Meira, MDV and Silva, RSD and Chochinov, HM and Medeiros, MOSF and Ferreira, MMM and de Góes Salvetti, M}, title = {Effects of Dignity Therapy on individuals with amyotrophic lateral sclerosis: Case studies.}, journal = {Palliative & supportive care}, volume = {22}, number = {3}, pages = {517-525}, doi = {10.1017/S1478951523001888}, pmid = {38178278}, issn = {1478-9523}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/therapy ; Female ; Male ; Middle Aged ; Aged ; Qualitative Research ; Respect ; Personhood ; Surveys and Questionnaires ; Quality of Life/psychology ; Dignity Therapy ; }, abstract = {OBJECTIVES: To analyze the effects of Dignity Therapy (DT) on the physical, existential, and psychosocial symptoms of individuals with amyotrophic lateral sclerosis (ALS).

METHODS: This is a mixed-methods case study research that used the concurrent triangulation strategy to analyze the effects of DT on 3 individuals with ALS. Data collection included 3 instances of administering validated scales to assess multiple physical symptoms, anxiety, depression, spiritual well-being, and the Patient Dignity Inventory (PDI), followed by the implementation of DT and a semi-structured interview.

RESULTS: The scale results indicate that DT led to an improvement in the assessment of physical, social, emotional, spiritual, and existential symptoms according to the score results. It is worth noting that the patient with a recent diagnosis showed higher scores for anxiety and depression after DT. Regarding the PDI, the scores indicate improvements in the sense of dignity in all 3 cases, which aligns with the positive verbal reports after the implementation of DT.

SIGNIFICANCE OF RESULTS: This study allowed us to analyze the effects of DT on the physical, existential, and psychosocial symptoms of individuals with ALS, suggesting the potential benefits of this approach for this group of patients. Participants reported positive effects regarding pain and fatigue, could reflect on their life trajectories, and regained their value and meaning.}, } @article {pmid38178578, year = {2024}, author = {Haider, R and Penumutchu, S and Boyko, S and Surewicz, WK}, title = {Phosphomimetic substitutions in TDP-43's transiently α-helical region suppress phase separation.}, journal = {Biophysical journal}, volume = {123}, number = {3}, pages = {361-373}, pmid = {38178578}, issn = {1542-0086}, support = {S10 OD024996/OD/NIH HHS/United States ; F30 AG071339/AG/NIA NIH HHS/United States ; T32 NS077888/NS/NINDS NIH HHS/United States ; RF1 AG061797/AG/NIA NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA-Binding Proteins/metabolism ; *Frontotemporal Lobar Degeneration/metabolism ; Phase Separation ; Phosphorylation ; }, abstract = {Phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) is present within the aggregates of several age-related neurodegenerative disorders, such as amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimer's disease, to the point that the presence of phosphorylated TDP-43 is considered a hallmark of some of these diseases. The majority of known TDP-43 phosphorylation sites detected in amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients is located in the low-complexity domain (LCD), the same domain that has been shown to be critical for TDP-43 liquid-liquid phase separation (LLPS). However, the effect of these LCD phosphorylation sites on TDP-43 LLPS has been largely unexplored, and any work that has been done has mainly focused on sites near the C-terminal end of the LCD. Here, we used a phosphomimetic approach to explore the impact of phosphorylation at residues S332 and S333, sites located within the transiently α-helical region of TDP-43 that have been observed to be phosphorylated in disease, on protein LLPS. Our turbidimetry and fluorescence microscopy data demonstrate that these phosphomimetic substitutions greatly suppress LLPS, and solution NMR data strongly suggest that this effect is at least in part due to the loss of α-helical propensity of the phosphomimetic protein variant. We also show that the S332D and S333D substitutions slow TDP-43 LCD droplet aging and fibrillation of the protein. Overall, these findings provide a biophysical basis for understanding the effect of phosphorylation within the transiently α-helical region of TDP-43 LCD on protein LLPS and fibrillation, suggesting that phosphorylation at residues 332 and 333 is not necessarily directly related to the pathogenic process.}, } @article {pmid38178788, year = {2024}, author = {Noda, I}, title = {Two-Dimensional Correlation Spectroscopy (2D-COS) Analysis of Evolving Hyperspectral Images.}, journal = {Applied spectroscopy}, volume = {}, number = {}, pages = {37028231222011}, doi = {10.1177/00037028231222011}, pmid = {38178788}, issn = {1943-3530}, abstract = {The evolutionary behavior is examined for heterogeneously distributed hyperspectral images of a simulated biological tissue sample comprising lipid-like and protein-like components during the aging process. Taking a simple planar average of a spectral image loses useful information about the spatially resolved nature of the data. In contrast, multivariate curve resolution (MCR) analysis of a spectral image at a given stage of aging produces a set of loadings of major component groups. Each loading represents the combined spectral contributions of a mixture of similar but not identical constituents (i.e., lipid-like and protein-like components). Temporal analysis of individual component groups using two-dimensional correlation spectroscopy (2D-COS) and MCR provides much-streamlined results without interferences from the overlapped contributions. Grouping of data into separate components also allows for the effective comparison of the parallel processes of lipid oxidation and protein denaturation involving a number of constituents using the heterocomponent 2D-COS analysis. The complex interplays of lipid constituents and protein secondary structures during the tissue aging process are unambiguously highlighted. The possibility of extending this approach to a much more general form of applications using a moving window analysis is also discussed.}, } @article {pmid38178841, year = {2023}, author = {Zhao, S and Chen, R and Gao, Y and Lu, Y and Bai, X and Zhang, J}, title = {Fundamental roles of the Optineurin gene in the molecular pathology of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1319706}, pmid = {38178841}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons (MNs) in the brain and spinal cord. It is caused by multiple factors, including mutations in any one of several specific genes. Optineurin (OPTN) mutation is an essential cause of some familial and sporadic ALS. Besides, as a multifunctional protein, OPTN is highly expressed and conserved in the central nervous system. OPTN exerts its functions by interacting with various proteins, often acting as an adaptor to provide a link between two or more core proteins related to autophagy and inflammation, etc. OPTN mutation mainly results in its function deficiency, which alters these interactions, leading to functional impairment in many processes. Meanwhile, OPTN immunopositive inclusions are also confirmed in the cases of ALS due to C9ORF72, FUS, TARDBP, and SOD1 mutations. Therefore, OPTN gene may play fundamental roles in the molecular pathology of ALS in addition to OPTN mutation. In this review, we summarize the recent advances in the ALS pathology of OPTN defect, such as mitophagy disorder, neuroinflammation, neuronal axonal degeneration, vesicular transport dysfunction, etc., which will provide a reference for research on the pathogenesis and treatment of ALS.}, } @article {pmid38179225, year = {2023}, author = {Ji, X and Walczak, P and Boltze, J}, title = {Exploring novel experimental treatments for major neurodegenerative disorders.}, journal = {Neuroprotection (Chichester, England)}, volume = {1}, number = {2}, pages = {81-83}, pmid = {38179225}, issn = {2770-730X}, support = {R01 DA056739/DA/NIDA NIH HHS/United States ; }, } @article {pmid38179454, year = {2023}, author = {Li, H and Liu, S and Zhang, K and Zhu, X and Dai, J and Lu, Y}, title = {Gut microbiome and plasma metabolome alterations in myopic mice.}, journal = {Frontiers in microbiology}, volume = {14}, number = {}, pages = {1251243}, pmid = {38179454}, issn = {1664-302X}, abstract = {BACKGROUND: Myopia is one of the most common eye diseases leading to blurred distance vision. Inflammatory diseases could trigger or exacerbate myopic changes. Although gut microbiota bacteria are associated with various inflammatory diseases, little is known about its role in myopia.

MATERIALS AND METHODS: The mice were randomly divided into control and model groups, with the model group being attached-30D lens onto the eyes for 3 weeks. Then, mouse cecal contents and plasma were collected to analyze their intestinal microbiota and plasma metabolome.

RESULTS: We identified that the microbial composition differed considerably between the myopic and non-myopic mice, with the relative abundance of Firmicutes phylum decreased obviously while that of Actinobacteria phylum was increased in myopia. Furthermore, Actinobacteria and Bifidobacterium were positively correlated with axial lengths (ALs) of eyeballs while negatively correlated with refractive diopters. Untargeted metabolomic analysis identified 141 differentially expressed metabolites, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed considerable enrichment mainly in amino acid metabolism pathways. Notably, pathways involved glutamate metabolism including "Glutamine and D-glutamate metabolism" and "Alanine, aspartate and glutamate metabolism" was changed dramatically, which presented as the concentrations of L-Glutamate and L-Glutamine decreased obviously in myopia. Interestingly, microbiome dysbiosis and metabolites alternations in myopia have a disrupting gut barrier feature. We further demonstrated that the gut barrier function was impaired in myopic mice manifesting in decreased expression of Occludin, ZO-1 and increased permeation of FITC-dextran.

DISCUSSION: Myopic mice had obviously altered gut microbiome and metabolites profiles compared to non-myopic mice. The dysbiosis and plasma metabolomics shift in myopia had an interrupting gut barrier feature. Our study provides new insights into the possible role of the gut microbiota in myopia and reinforces the potential feasibility of microbiome-based therapies in myopia.}, } @article {pmid38179776, year = {2023}, author = {Yang, EJ and Lee, SH}, title = {Anti-Inflammatory Effects of Chaenomeles sinensis Extract in an ALS Animal Model.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {28}, number = {12}, pages = {326}, doi = {10.31083/j.fbl2812326}, pmid = {38179776}, issn = {2768-6698}, support = {NRF-2020R1A2C2006703//National Research Foundation of Korea, South Korea/ ; KSN2212010//KIOM, South Korea/ ; C18040//KIOM, South Korea/ ; }, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Mice, Transgenic ; Disease Models, Animal ; Spinal Cord ; *Rosaceae/chemistry ; Antioxidants/pharmacology/therapeutic use ; Plant Extracts/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a systemic disease with multiple pathological effects, including neuroinflammation, oxidative stress, autophagy, mitochondrial dysfunction, and endoplasmic reticulum stress. Despite many studies seeking to identify and develop effective therapies, effective ALS treatment has yet to be approved. Hence, patients with ALS ultimately experience muscle atrophy and loss of motor neurons. Herbal medicines have been used to treat numerous diseases by modulating multiple biological processes and exerting pharmacological effects, including anti-inflammatory and antioxidant properties. In particular, Chaenomeles sinensis Koehne (CS) exhibits anti-hyperuricemic and nephroprotective effects and is used to treat anaphylaxis, viral infections, and neurodegenerative diseases, such as Alzheimer's disease. This study monitored the effects of CS supplementation on muscle function and motor neurons in hSOD1G93A mice, an established ALS animal model.

METHODS: Body weight measurements and behavioral tests were performed; additionally, western blotting and immunohistochemistry analyses were conducted using the mice gastrocnemius, tibialis anterior, and spinal cord.

RESULTS: CS augmented anti-inflammatory and antioxidant effects in the muscle and spinal cord of hSOD1G93A mice. Furthermore, CS improved motor function and regulated autophagy in the muscles of the hSOD1G93A mice.

CONCLUSIONS: CS might represent a promising supplement for improving motor function and delaying ALS progression. However, its development for clinical use warrants further investigation.}, } @article {pmid38180358, year = {2024}, author = {Ferguson, R and van Es, MA and van den Berg, LH and Subramanian, V}, title = {Neural stem cell homeostasis is affected in cortical organoids carrying a mutation in Angiogenin.}, journal = {The Journal of pathology}, volume = {262}, number = {4}, pages = {410-426}, doi = {10.1002/path.6244}, pmid = {38180358}, issn = {1096-9896}, support = {084562/Z/07/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics/pathology ; *Neural Stem Cells/metabolism ; Mutation ; Homeostasis ; *Ribonuclease, Pancreatic ; }, abstract = {Mutations in Angiogenin (ANG) and TARDBP encoding the 43 kDa transactive response DNA binding protein (TDP-43) are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). ANG is neuroprotective and plays a role in stem cell dynamics in the haematopoietic system. We obtained skin fibroblasts from members of an ALS-FTD family, one with mutation in ANG, one with mutation in both TARDBP and ANG, and one with neither mutation. We reprogrammed these fibroblasts to induced pluripotent stem cells (iPSCs) and generated cortical organoids as well as induced stage-wise differentiation of the iPSCs to neurons. Using these two approaches we investigated the effects of FTD-associated mutations in ANG and TARDBP on neural precursor cells, neural differentiation, and response to stress. We observed striking neurodevelopmental defects such as abnormal and persistent rosettes in the organoids accompanied by increased self-renewal of neural precursor cells. There was also a propensity for differentiation to later-born neurons. In addition, cortical neurons showed increased susceptibility to stress, which is exacerbated in neurons carrying mutations in both ANG and TARDBP. The cortical organoids and neurons generated from patient-derived iPSCs carrying ANG and TARDBP gene variants recapitulate dysfunctions characteristic of frontotemporal lobar degeneration observed in FTD patients. These dysfunctions were ameliorated upon treatment with wild type ANG. In addition to its well-established role during the stress response of mature neurons, ANG also appears to play a role in neural progenitor dynamics. This has implications for neurogenesis and may indicate that subtle developmental defects play a role in disease susceptibility or onset. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.}, } @article {pmid38180612, year = {2024}, author = {Lin, CY and Wu, HE and Weng, EF and Wu, HC and Su, TP and Wang, SM}, title = {Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB.}, journal = {Molecular neurobiology}, volume = {61}, number = {8}, pages = {5282-5294}, pmid = {38180612}, issn = {1559-1182}, mesh = {*Sigma-1 Receptor ; *Fluvoxamine/pharmacology ; *Receptors, sigma/metabolism ; *Autophagy/drug effects ; *Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Humans ; *Active Transport, Cell Nucleus/drug effects ; Animals ; Mice ; Cell Nucleus/metabolism/drug effects ; C9orf72 Protein/metabolism/genetics ; Cell Line ; }, abstract = {Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer's disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G4C2)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G4C2)31-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In C9orf72-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G4C2)31-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with C9orf72-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G4C2)31-RNA-expressing NSC34 cells.}, } @article {pmid38181637, year = {2024}, author = {Wen, S and Fu, S and Gao, C and Lei, K and Liu, X}, title = {Generation of two induced pluripotent stem cell lines from two sporadic amyotrophic lateral sclerosis patients.}, journal = {Stem cell research}, volume = {74}, number = {}, pages = {103288}, doi = {10.1016/j.scr.2023.103288}, pmid = {38181637}, issn = {1876-7753}, mesh = {Male ; Female ; Humans ; Middle Aged ; *Induced Pluripotent Stem Cells/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Leukocytes, Mononuclear/metabolism ; Kruppel-Like Factor 4 ; Cell Differentiation ; }, abstract = {Peripheral blood mononuclear cells were obtained from two patients diagnosed with amyotrophic lateral sclerosis (ALS), a 47-year-old female and a 45-year-old male. Induced pluripotent stem cells (iPSCs) were generated using a non-integrating SeV-based method, delivering the transcription factors OCT4, SOX2, c-MYC, and KLF4. These transgene-free iPSC lines exhibited typical pluripotent cell morphology, expressed pluripotency-associated markers, and had tri-lineage differentiation potential. Both iPSC lines were free of mycoplasma contamination and displayed normal karyotypes. The availability of these two cell lines provides a promising opportunity to use sporadic ALS models for investigating the intricate pathological mechanisms of ALS.}, } @article {pmid38181731, year = {2024}, author = {Alvarado, CX and Makarious, MB and Weller, CA and Vitale, D and Koretsky, MJ and Bandres-Ciga, S and Iwaki, H and Levine, K and Singleton, A and Faghri, F and Nalls, MA and Leonard, HL}, title = {omicSynth: An open multi-omic community resource for identifying druggable targets across neurodegenerative diseases.}, journal = {American journal of human genetics}, volume = {111}, number = {1}, pages = {150-164}, pmid = {38181731}, issn = {1537-6605}, support = {Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; ZIA AG000534/ImNIH/Intramural NIH HHS/United States ; ZIA NS003154/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics ; Community Resources ; Multiomics ; *Neurodegenerative Diseases/drug therapy/genetics ; *Parkinson Disease ; Mendelian Randomization Analysis ; }, abstract = {Treatments for neurodegenerative disorders remain rare, but recent FDA approvals, such as lecanemab and aducanumab for Alzheimer disease (MIM: 607822), highlight the importance of the underlying biological mechanisms in driving discovery and creating disease modifying therapies. The global population is aging, driving an urgent need for therapeutics that stop disease progression and eliminate symptoms. In this study, we create an open framework and resource for evidence-based identification of therapeutic targets for neurodegenerative disease. We use summary-data-based Mendelian randomization to identify genetic targets for drug discovery and repurposing. In parallel, we provide mechanistic insights into disease processes and potential network-level consequences of gene-based therapeutics. We identify 116 Alzheimer disease, 3 amyotrophic lateral sclerosis (MIM: 105400), 5 Lewy body dementia (MIM: 127750), 46 Parkinson disease (MIM: 605909), and 9 progressive supranuclear palsy (MIM: 601104) target genes passing multiple test corrections (pSMR_multi < 2.95 × 10[-6] and pHEIDI > 0.01). We created a therapeutic scheme to classify our identified target genes into strata based on druggability and approved therapeutics, classifying 41 novel targets, 3 known targets, and 115 difficult targets (of these, 69.8% are expressed in the disease-relevant cell type from single-nucleus experiments). Our novel class of genes provides a springboard for new opportunities in drug discovery, development, and repurposing in the pre-competitive space. In addition, looking at drug-gene interaction networks, we identify previous trials that may require further follow-up such as riluzole in Alzheimer disease. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community.}, } @article {pmid38182429, year = {2024}, author = {Lee, YJ and Rio, DC}, title = {A mutation in the low-complexity domain of splicing factor hnRNPA1 linked to amyotrophic lateral sclerosis disrupts distinct neuronal RNA splicing networks.}, journal = {Genes & development}, volume = {38}, number = {1-2}, pages = {11-30}, pmid = {38182429}, issn = {1549-5477}, support = {S10 RR026866/RR/NCRR NIH HHS/United States ; R35 GM118121/GM/NIGMS NIH HHS/United States ; S10 RR029668/RR/NCRR NIH HHS/United States ; S10 RR025622/RR/NCRR NIH HHS/United States ; R01 GM097352/GM/NIGMS NIH HHS/United States ; S10 RR027303/RR/NCRR NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism ; Mutation ; *Neurodegenerative Diseases ; RNA Splicing/genetics ; RNA Splicing Factors/genetics ; Heterogeneous Nuclear Ribonucleoprotein A1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by loss of motor neurons. Human genetic studies have linked mutations in RNA-binding proteins as causative for this disease. The hnRNPA1 protein, a known pre-mRNA splicing factor, is mutated in some ALS patients. Here, two human cell models were generated to investigate how a mutation in the C-terminal low-complexity domain (LCD) of hnRNPA1 can cause splicing changes of thousands of transcripts that collectively are linked to the DNA damage response, cilium organization, and translation. We show that the hnRNPA1 D262V mutant protein binds to new binding sites on differentially spliced transcripts from genes that are linked to ALS. We demonstrate that this ALS-linked hnRNPA1 mutation alters normal RNA-dependent protein-protein interactions. Furthermore, cells expressing this hnRNPA1 mutant exhibit a cell aggregation phenotype, markedly reduced growth rates, changes in stress granule kinetics, and aberrant growth of neuronal processes. This study provides insight into how a single amino acid mutation in a splicing factor can alter RNA splicing networks of genes linked to ALS.}, } @article {pmid38182485, year = {2024}, author = {Mainous, RO and Dunlap, JJ and Brewer, TL}, title = {Author Response to Kesten et al's Letter to the Editor.}, journal = {Nursing outlook}, volume = {72}, number = {2}, pages = {102106}, doi = {10.1016/j.outlook.2023.102106}, pmid = {38182485}, issn = {1528-3968}, } @article {pmid38183365, year = {2024}, author = {Barć, K and Finsel, J and Helczyk, O and Baader, S and Aho-Özhan, H and Ludolph, AC and Lulé, D and Kuźma-Kozakiewicz, M}, title = {One third of physicians discuss exit strategies with patients with amyotrophic lateral sclerosis: Results from nationwide surveys among German and Polish neurologists.}, journal = {Brain and behavior}, volume = {14}, number = {2}, pages = {e3243}, pmid = {38183365}, issn = {2162-3279}, support = {NEEDSinALS 01ED1405//EU Joint Programme-Neurodegenerative Disease Research/ ; FTLDc O1GI1007A//Bundesministerium für Bildung und Forschung/ ; MND-Net 01GM1103A//Bundesministerium für Bildung und Forschung/ ; PaCeMed 01DS18031//Bundesministerium für Bildung und Forschung/ ; K.N.K.B.008.04//Kompetenznetzwerk Präventivmedizin Baden-Württemberg/ ; //Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)/ ; }, abstract = {OBJECTIVE: This paper examines neurologists' approaches to exit strategies (ESs), such as euthanasia and physician-assisted suicide, in patients with amyotrophic lateral sclerosis (PALS) in two European countries.

METHODS: In a nationwide anonymous survey, we collected responses from 237 Polish and 228 German neurologists, focusing on their practices and beliefs about ESs, as well as their viewpoints on life-sustaining measures (LSMs) (percutaneous endoscopic gastrostomy, non-invasive, and invasive ventilation). To analyze the data, we employed statistical methods, including Mann-Whitney U, Kruskal-Wallis, chi-square tests, Spearman's rank correlation, and multiple regression analysis.

RESULTS: One third of the neurologists initiated the discussion about ESs with PALS. Half were ready to have this conversation upon patient's request. Age, gender, religiousness, and nationality were closely associated with this approach. One in 9 neurologists received a request to terminate an LSM, whereas 1 in 10 to implement an ES. German neurologists and palliative care trainees acquired both demands more commonly. Neurologists quoted a low quality of life, decreased mood, and being a burden to the family/closest ones as primary reasons for a wish to hasten death among PALS. Although the majority expressed a willingness to terminate an LSM at a request of the patient, most opposed the legalization of euthanasia. Younger and less religious individuals were more likely to favor accepting euthanasia.

CONCLUSION: Neurologists vary significantly in their approaches to terminal care. Complex relationships exist among personal indices, shared beliefs, and current practices.}, } @article {pmid38183652, year = {2024}, author = {Guise, AJ and Misal, SA and Carson, R and Chu, JH and Boekweg, H and Van Der Watt, D and Welsh, NC and Truong, T and Liang, Y and Xu, S and Benedetto, G and Gagnon, J and Payne, SH and Plowey, ED and Kelly, RT}, title = {TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis.}, journal = {Cell reports}, volume = {43}, number = {1}, pages = {113636}, pmid = {38183652}, issn = {2211-1247}, support = {R01 GM138931/GM/NIGMS NIH HHS/United States ; R33 CA225248/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; DNA-Binding Proteins/metabolism ; Motor Neurons/metabolism ; Proteome/metabolism ; Proteomics ; }, abstract = {A limitation of conventional bulk-tissue proteome studies in amyotrophic lateral sclerosis (ALS) is the confounding of motor neuron (MN) signals by admixed non-MN proteins. Here, we leverage laser capture microdissection and nanoPOTS single-cell mass spectrometry-based proteomics to query changes in protein expression in single MNs from postmortem ALS and control tissues. In a follow-up analysis, we examine the impact of stratification of MNs based on cytoplasmic transactive response DNA-binding protein 43 (TDP-43)+ inclusion pathology on the profiles of 2,238 proteins. We report extensive overlap in differentially abundant proteins identified in ALS MNs with or without overt TDP-43 pathology, suggesting early and sustained dysregulation of cellular respiration, mRNA splicing, translation, and vesicular transport in ALS. Together, these data provide insights into proteome-level changes associated with TDP-43 proteinopathy and begin to demonstrate the utility of pathology-stratified trace sample proteomics for understanding single-cell protein dynamics in human neurologic diseases.}, } @article {pmid38184629, year = {2024}, author = {Klíčová, K and Mareš, J and Menšíková, K and Kaiserová, M and Friedecký, D and Kaňovský, P and Strnad, M and Matěj, R}, title = {Utilizing neurodegenerative markers for the diagnostic evaluation of amyotrophic lateral sclerosis.}, journal = {European journal of medical research}, volume = {29}, number = {1}, pages = {31}, pmid = {38184629}, issn = {2047-783X}, support = {CZ.02.1.01 / 0.0 / 0.0 / 16_019 / 0000868//European Regional Development Fund - ENOCH project/ ; NV19-04-00090//Grant Agency of the Ministry of Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Clusterin ; Delayed Diagnosis ; tau Proteins ; Biomarkers ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive deterioration of upper and lower motor neurons. A definitive diagnostic test or biomarker for ALS is currently unavailable, leading to a diagnostic delay following the onset of initial symptoms. Our study focused on cerebrospinal fluid (CSF) concentrations of clusterin, tau protein, phosphorylated tau protein, and beta-amyloid1-42 in ALS patients and a control group.

METHODS: Our study involved 54 ALS patients and 58 control subjects. Among the ALS patients, 14 presented with bulbar-onset ALS, and 40 with limb-onset ALS. We quantified biomarker levels using enzyme-linked immunosorbent assay (ELISA) and compared the results using the Mann-Whitney U-test.

RESULTS: Significant elevations in neurodegenerative markers, including tau protein (p < 0.0001), phosphorylated tau protein (p < 0.0001), and clusterin (p = 0.038), were observed in ALS patients compared to controls. Elevated levels of tau protein and phosphorylated tau protein were also noted in both bulbar and limb-onset ALS patients. However, no significant difference was observed for beta-amyloid1-42. ROC analysis identified tau protein (AUC = 0.767) and p-tau protein (AUC = 0.719) as statistically significant predictors for ALS.

CONCLUSION: Our study demonstrates that neurodegenerative marker levels indicate an ongoing neurodegenerative process in ALS. Nonetheless, the progression of ALS cannot be predicted solely based on these markers. The discovery of a specific biomarker could potentially complement existing diagnostic criteria for ALS.}, } @article {pmid38185101, year = {2024}, author = {Huber, T and Krüerke, D and Simões-Wüst, AP}, title = {How Physicians and Nursing Staff Perceive Effectiveness and Tolerability of Bryophyllum Preparations: An Online Survey in an Anthroposophic Hospital.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {116-123}, pmid = {38185101}, issn = {2504-2106}, mesh = {Humans ; Male ; Surveys and Questionnaires ; Female ; Adult ; Switzerland ; *Kalanchoe ; Anthroposophy ; Middle Aged ; *Attitude of Health Personnel ; *Nursing Staff, Hospital/psychology/statistics & numerical data ; *Physicians/psychology ; *Phytotherapy ; *Plant Extracts/therapeutic use ; *Medical Staff, Hospital/psychology ; }, abstract = {BACKGROUND: Bryophyllum preparations are widely used in anthroposophic medicine, most often for mental and behavioural disorders. Three prospective studies have revealed positive effects of Bryophyllum pinnatum on sleep quality, and various trials have shown very good tolerability. Results from animal models have indicated CNS depressant and anxiolytic effects. This survey was conducted at the hospital "Klinik Arlesheim" in Switzerland to find out how the physicians and the nursing staff perceive the effectiveness and the tolerability of the Bryophyllum preparations they most frequently use.

DESIGN: Internal, anonymous online survey of healthcare professionals (April 8-May 31, 2022). The questionnaire comprised 105 multiple-choice questions. Answering the questions was taken as consent to participate in the survey.

PARTICIPANTS AND METHODS: All physicians and nursing staff with a valid email address at the hospital "Klinik Arlesheim AG" were invited via email to participate in this REDCap survey. The data were analysed descriptively.

RESULTS: Out of 266 invited participants, 48 answered some and 36 answered all questions (response rate between 18.0% and 13.5%). The participants had long experience with Bryophyllum preparations and were comprised approximately equal numbers of physicians and nursing staff. Various Bryophyllum preparations from the hospital's own production and Wala Heilmittel GmbH (in both cases produced from the species B. daigremontianum) and from Weleda AG (species B. pinnatum) were used. The indications for which most participants had prescribed or administered Bryophyllum preparations "very frequently" were anxiety, sleep disorders, crisis situations in oncology, posttraumatic stress disorder, benzodiazepine dependence/withdrawal, and depression. Improvements such as relief from restlessness, decreased anxiety, balance, easier falling asleep, better sleeping through, increased resilience, mood elevation, and less urge to move one's legs were reported "frequently" or "very frequently." Almost all participants agreed that Bryophyllum can be used to reduce the intake of synthetic sedatives or psychotropic drugs, but only approximately half believed that it could replace them. The majority of participants mentioned good tolerability of the various products, but a few reported occasional stomach or intestinal irritation, daytime fatigue, drowsiness, diarrhoea, and nausea.

CONCLUSION: Bryophyllum preparations are perceived as helpful in the treatment of various mental disorders, particularly anxiety, and are generally well tolerated. Most of these preparations are used for indications that have not yet been clinically investigated.

UNLABELLED: HintergrundBryophyllum-Präparate werden in der Anthroposophischen Medizin sehr häufig zur Behandlung von psychischen und Verhaltensstörungen eingesetzt. Drei prospektive Studien zeigten zudem positive Wirkungen von Bryophyllum pinnatum (BP) auf die Schlafqualität. Auch die Verträglichkeit wurde in allen bisherigen Studien als sehr gut bewertet. In Tiermodellen wurden ZNS-depressive und anxiolytische Effekte von BP festgestellt. Die hier durchgeführte Umfrage fand an der Klinik Arlesheim (Schweiz) statt. Sie diente dazu herauszufinden, wie Ärztinnen und Ärzte sowie das Pflegepersonal die Wirksamkeit und Verträglichkeit der von ihnen am häufigsten verwendeten Bryophyllum-Präparate wahrnehmen.DesignInterne, anonyme, Online-Befragung unter ärztlichen und pflegerischen Fachkräften (8. April–31. Mai 2022). Der Fragebogen umfasste 105 Multiple-Choice-Fragen. Die Beantwortung der Fragen wurde als Zustimmung zur Teilnahme an der Umfrage interpretiert.Teilnehmende und MethodenAlle Ärztinnen, Ärzte und Pflegefachpersonen mit einer gültigen E-Mail-Adresse der “Klinik Arlesheim AG” wurden per E-Mail eingeladen, an dieser REDCap-Umfrage teilzunehmen. Die Daten wurden deskriptiv ausgewertet.ErgebnisseVon den 266 eingeladenen Teilnehmenden beantworteten 48 einige und 36 alle Fragen (Antwortquote zwischen 18.0% und 13.5%). Die Teilnehmenden hatten langjährige Erfahrung mit Bryophyllum-Präparaten und setzten sich etwa zu gleichen Teilen aus ärztlichen und pflegerischen Fachkräften zusammen. Die Resultate zeigen, dass verschiedenste Bryophyllum-Präparate aus klinikeigener Herstellung, von der Wala Heilmittel GmbH (Art B. daigremontianum) und von der Weleda AG (Art B. pinnatum) verwendet werden. Zu den Indikationen, bei denen die meisten Teilnehmenden Bryophyllum-Präparate “sehr häufig” verordnet oder angewendet haben, gehören Angstzustände, Schlafstörungen, Krisensituationen in der Onkologie, Posttraumatische Belastungsstörung, Benzodiazepin-Abhängigkeit/Entzug und Depressionen. Gesundheitsverbesserungen wie Linderung von Unruhe, verminderte Angst, Ausgeglichenheit, leichteres Einschlafen, besseres Durchschlafen, erhöhte Belastbarkeit, Stimmungsaufhellung und weniger Drang, die Beine zu bewegen, wurden als “häufig” oder “sehr häufig” angegeben. Fast alle Teilnehmenden waren sich einig, dass Bryophyllum verwendet werden kann, um die Einnahme von synthetischen Beruhigungsmitteln oder Psychopharmaka zu reduzieren, aber nur etwa die Hälfte gab an, dass es diese ersetzen kann. Die Mehrheit der Teilnehmenden spricht von einer guten Verträglichkeit der verschiedenen Produkte. Einige wenige berichteten von gelegentlicher Magen- oder Darmreizung, Tagesmüdigkeit, Schläfrigkeit, Durchfall und Übelkeit.SchlussfolgerungBryophyllum-Präparate werden als hilfreich bei der Behandlung verschiedener psychischen Störungen, insbesondere bei Angstzuständen, angesehen und im Allgemeinen gut vertragen. Die meisten der angegebenen Präparate werden für Indikationen verwendet, die noch nicht klinisch untersucht worden sind.}, } @article {pmid38185916, year = {2024}, author = {Barber, S and Gomez-Godinez, V and Young, J and Wei, A and Chen, S and Snissarenko, A and Chan, SS and Wu, C and Shi, L}, title = {Impacts of H2O2, SARM1 inhibition, and high NAm concentrations on Huntington's disease laser-induced degeneration.}, journal = {Journal of biophotonics}, volume = {17}, number = {3}, pages = {e202300370}, doi = {10.1002/jbio.202300370}, pmid = {38185916}, issn = {1864-0648}, support = {//Beckman Laser Inc/ ; }, mesh = {Animals ; Mice ; Humans ; *Hydrogen Peroxide ; Niacinamide ; *Huntington Disease ; Mice, Knockout ; Neurons/metabolism ; Cytoskeletal Proteins/metabolism ; Armadillo Domain Proteins/genetics/metabolism ; }, abstract = {Axonal degeneration is a key component of neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease, and amyotrophic lateral sclerosis. Nicotinamide, an NAD+ precursor, has long since been implicated in axonal protection and reduction of degeneration. However, studies on nicotinamide (NAm) supplementation in humans indicate that NAm has no protective effect. Sterile alpha and toll/interleukin receptor motif-containing protein 1 (SARM1) regulates several cell responses to axonal damage and has been implicated in promoting neuronal degeneration. SARM1 inhibition seems to result in protection from neuronal degeneration while hydrogen peroxide has been implicated in oxidative stress and axonal degeneration. The effects of laser-induced axonal damage in wild-type and HD dorsal root ganglion cells treated with NAm, hydrogen peroxide (H2O2), and SARM1 inhibitor DSRM-3716 were investigated and the cell body width, axon width, axonal strength, and axon shrinkage post laser-induced injury were measured.}, } @article {pmid38185999, year = {2024}, author = {Liu, Z and Qiang, Y and Shan, S and Wang, S and Song, F}, title = {Carbon disulfide induces accumulation of TDP-43 in the cytoplasm and mitochondrial dysfunction in rat spinal cords.}, journal = {Cerebral cortex (New York, N.Y. : 1991)}, volume = {34}, number = {2}, pages = {}, doi = {10.1093/cercor/bhad526}, pmid = {38185999}, issn = {1460-2199}, support = {82173552//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Rats ; Animals ; *Carbon Disulfide/metabolism ; *Neuroblastoma/metabolism/pathology ; Cytoplasm/metabolism ; DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/chemically induced/pathology ; Spinal Cord/pathology ; *Neurodegenerative Diseases/metabolism ; *Mitochondrial Diseases/metabolism/pathology ; }, abstract = {The relationship between environmental neurotoxicant exposure and neurodegenerative diseases is being extensively investigated. Carbon disulfide, a classic neurotoxicant and prototype of dithiocarbamates fungicides and anti-inflammatory agents, has been detected in urban adults, raising questions about whether exposure to carbon disulfide is associated with a high incidence of neurodegenerative diseases. Here, using rat models and SH-SY5Y cells, we investigated the possible mechanistic linkages between carbon disulfide neurotoxicity and the expression of TDP-43 protein, a marker of amyotrophic lateral sclerosis/frontotemporal lobar degeneration. Our results showed that rats exhibited severe dyskinesia and increased TDP-43 expression in the spinal cord following carbon disulfide exposure. Moreover, carbon disulfide exposure induced abnormal cytoplasmic localization and phosphorylation of TDP-43 in motor neurons. Importantly, carbon disulfide treatment led to the accumulation of TDP-43 in the mitochondria of motor neurons and resulted in subsequent mitochondrial damage, including mitochondrial structural disruption, mitochondrial respiratory chain complex I inhibition, and impaired VCP/p97-dependent mitophagy. In summary, our study provides support for carbon disulfide exposure-mediated TDP-43 mislocalization and mitochondrial dysfunction, contributes to understanding the pathogenesis of environmental neurotoxin-induced neurodegeneration, and provides inspiration for potential therapeutic strategies.}, } @article {pmid38187117, year = {2023}, author = {Dorça, A and Vergara, J and Skoretz, SA and Brenner, MJ and Diniz, DS and Zeredo, JL and Sarmet, M}, title = {Respiratory support effect on pharyngeal area in patients with amyotrophic lateral sclerosis: A fluoroscopic comparison of NIV, helmet/CPAP, and high-flow nasal cannula.}, journal = {Respiratory medicine case reports}, volume = {46}, number = {}, pages = {101958}, pmid = {38187117}, issn = {2213-0071}, abstract = {The global use of noninvasive respiratory support provided by different supportive ventilation delivery methods (SVDMs) has increased, but the impact of these devices on the upper airway structures of patients with amyotrophic lateral sclerosis (ALS) is not known. We aimed to compare the pharyngeal cross-sectional area during spontaneous breathing with four different SVDMs: intranasal masks, oronasal masks, high-flow nasal cannula (HFNC), and helmet in patients with ALS. We compared measures of the pharyngeal area during spontaneous breathing and SVDM use. The greatest increase was observed with intranasal mask use, followed by HFNC, oronasal mask, and helmet respectively. In conclusion, upper airway opening in patients with ALS is enhanced by positive pressure with intranasal masks and HFNC, showing promise for increasing pharyngeal patency. Future studies should explore its applicability and effectiveness in maintaining long-term pharyngeal patency, especially in this population with bulbar weakness.}, } @article {pmid38187158, year = {2023}, author = {Yang, J and Liu, T and Zhang, L and Li, X and Du, FP and Liu, Q and Dong, H and Liu, Y}, title = {Eosinophils at diagnosis are elevated in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1289467}, pmid = {38187158}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare, devastating neurodegenerative disease that affects upper and lower motor neurons. To date, no effective treatment or reliable biomarker for ALS has been developed. In recent years, many factors have been proposed as possible biomarkers of ALS; however, no consensus has been reached. Therefore, a reliable biomarker is urgently needed. Eosinophils may play a crucial role in healthy humans and diseases, and serve as a biomarker for many chronic diseases.

METHODS: Routine blood test results were collected from 66 healthy controls and 59 patients with ALS. The percentages and total numbers of each cell population were analyzed, and the correlation between these indicators and patient ALS functional rating scale-revised (ALSFRS-R) score or disease progression rate (ΔFS score) was analyzed.

RESULTS: Compared to healthy controls, the number of blood leukocytes, neutrophils, monocytes, and basophils was significantly decreased in patients with ALS (p = 0.002, p = 0.001, p = 0.049, and p < 0.0001, respectively). There was an increase in the number of eosinophils (p < 0.0001), but no difference in the number of lymphocytes between patients with ALS and healthy controls was found (p = 0.563). Compared to healthy controls, the percentage of neutrophils was decreased and the percentage of lymphocytes and eosinophils was increased in patients with ALS (p = 0.01, p = 0.012, and p = 0.001, respectively). There was no difference between patients with ALS and healthy controls in the percentage of monocytes and basophils (p = 0.622 and p = 0.09, respectively). However, only the percentage and number of eosinophils had a correlation with the ΔFS score. Further multivariate analysis revealed a significant correlation between the disease duration, eosinophil count and percentage, and the disease progression rate (p < 0.0001, p = 0.048, and p = 0.023, respectively). The neutrophil-to-eosinophil ratio (NER), lymphocyte-to-eosinophil ratio (LER), and monocyte-to-eosinophil ratio (MER) were significantly lower in patients with ALS than in healthy controls. However, only the LER was significantly correlated with the ΔFS score.

CONCLUSION: These observations implicate neutrophils, lymphocytes, and eosinophils as important factors, and increasing eosinophil counts were negatively correlated with the ΔFS score in patients with ALS.}, } @article {pmid38187588, year = {2024}, author = {McKeever, PM and Sababi, AM and Sharma, R and Xu, Z and Xiao, S and McGoldrick, P and Ketela, T and Sato, C and Moreno, D and Visanji, N and Kovacs, GG and Keith, J and Zinman, L and Rogaeva, E and Goodarzi, H and Bader, GD and Robertson, J}, title = {Single-nucleus transcriptome atlas of orbitofrontal cortex in amyotrophic lateral sclerosis with a deep learning-based decoding of alternative polyadenylation mechanisms.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.12.22.573083}, pmid = {38187588}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two age-related and fatal neurodegenerative disorders that lie on a shared disease spectrum. While both disorders involve complex interactions between neuronal and glial cells, the specific cell-type alterations and their contributions to disease pathophysiology remain incompletely understood. Here, we applied single-nucleus RNA sequencing of the orbitofrontal cortex, a region affected in ALS-FTLD, to map cell-type specific transcriptional signatures in C9orf72-related ALS (with and without FTLD) and sporadic ALS cases. Our findings reveal disease- and cell-type-specific transcriptional changes, with neurons exhibiting the most pronounced alterations, primarily affecting mitochondrial function, protein homeostasis, and chromatin remodeling. A comparison with independent datasets from different cortical regions of C9orf72 and sporadic ALS cases showed concordance in several pathways, with neuronal STMN2 and NEFL showing consistent up-regulation between brain regions and disease subtypes. We also interrogated alternative polyadenylation (APA) as an additional layer of transcriptional regulation, demonstrating that APA events are not correlated with identified gene expression changes. To interpret these events, we developed APA-Net, a deep learning model that integrates transcript sequences with RNA-binding protein expression profiles, revealing cell type-specific patterns of APA regulation. Our atlas illuminates cell type-specific pathomechanisms of ALS/FTLD, providing a valuable resource for further investigation.}, } @article {pmid38188002, year = {2023}, author = {Ansari, U and Wen, J and Taguinod, I and Nadora, D and Nadora, D and Lui, F}, title = {Exploring dietary approaches in the prevention and management of Amyotrophic Lateral Sclerosis: A literature review.}, journal = {AIMS neuroscience}, volume = {10}, number = {4}, pages = {376-387}, pmid = {38188002}, issn = {2373-7972}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and complex neurodegenerative disease of upper and lower motor neurons of the central nervous system. The pathogenesis of this multifaceted disease is unknown. However, diet has emerged as a modifiable risk factor that has neuroprotective effects towards other neurological disorders such as Alzheimer's, Parkinson's and dementia. Thus, this review aims to explore how diet can potentially influence ALS onset and/or progression. In this review, five popular diets (Mediterranean, Vegan, Carnivore, Paleolithic and Ketogenic) and their distinct macromolecule composition, nutritional profile, biochemical pathways and their potential therapeutic effects for ALS are thoroughly examined. However, the composition of these diets varies, and the data is controversial, with conflicting studies on the effectiveness of nutrient intake of several of these diets. Although these five diets show that a higher intake of foods containing anti-inflammatory and antioxidant compounds have a positive correlation towards reducing the oxidative stress of ALS, further research is needed to directly compare the effects of these diets and the mechanisms leading to ALS and its progression.}, } @article {pmid38188011, year = {2023}, author = {Ansari, U and Chen, V and Sedighi, R and Syed, B and Muttalib, Z and Ansari, K and Ansari, F and Nadora, D and Razick, D and Lui, F}, title = {Role of the UNC13 family in human diseases: A literature review.}, journal = {AIMS neuroscience}, volume = {10}, number = {4}, pages = {388-400}, pmid = {38188011}, issn = {2373-7972}, abstract = {This literature review explores the pivotal roles of the Uncoordinated-13 (UNC13) protein family, encompassing UNC13A, UNC13B, UNC13C, and UNC13D, in the pathogenesis of various human diseases. These proteins, which are evolutionarily conserved and crucial for synaptic vesicle priming and exocytosis, have been implicated in a range of disorders, spanning from neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) to immune-related conditions such as familial hemophagocytic lymphohistiocytosis (FHL). The involvement of UNC13A in neurotransmitter release and synaptic plasticity is linked to ALS and FTD, with genetic variations affecting disease progression. UNC13B, which is closely related to UNC13A, plays a role in autism spectrum disorders (ASD), epilepsy, and schizophrenia. UNC13C is implicated in oral squamous cell carcinoma (OSCC) and hepatocellular carcinoma (HCC), and has a neuroprotective role in Alzheimer's disease (AD). UNC13D has an essential role in immune cell function, making it a key player in FHL. This review highlights the distinct molecular functions of each UNC13 family member and their implications in disease contexts, shedding light on potential therapeutic strategies and avenues for future research. Understanding these proteins' roles offers new insights into the management and treatment of neurological and immunological disorders.}, } @article {pmid38188028, year = {2023}, author = {Hu, Z and Zuo, C and Mao, C and Shi, C and Xu, Y}, title = {Peripheral immune markers and amyotrophic lateral sclerosis: a Mendelian randomization study.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1269354}, pmid = {38188028}, issn = {1662-4548}, abstract = {INTRODUCTION: The peripheral immune system changes in amyotrophic lateral sclerosis (ALS), but the causal relationship between the two is still controversial.

METHODS: In this study, we aimed to estimate the causal relationship between peripheral immune markers and ALS using a two-sample Mendelian randomization method. Genome-wide association study (GWAS) data on peripheral blood immune traits from European populations were used for exposure, and ALS summary statistics were used as the outcome. The causal relationship was evaluated by inverse variance weighting, MR-Egger, and weighted median methods and verified by multiple sensitivity analysis.

RESULTS: We found that the increase of one standard deviation of lymphocyte count is related to reducing ALS risk. CD3 on effector memory CD4[+] T cell, HLA DR[+] CD4[+] T cell, effector memory CD8[+] T cell, terminally differentiated CD8[+] T cell and CD28- CD8[+] T cell is also a protective factor for ALS. Among the circulating immune protein, the increase of one standard deviation of α-2-macroglobulin receptor-associated protein (α-2-MRAP) and C4b showed associated with low risk of ALS, while Interleukin-21 (IL-21) increases the risk of ALS.

DISCUSSION: Our study further reveals the important role of peripheral immune activity in ALS.}, } @article {pmid38188146, year = {2024}, author = {Shao, BZ and Jiang, JJ and Zhao, YC and Zheng, XR and Xi, N and Zhao, GR and Huang, XW and Wang, SL}, title = {Neutrophil extracellular traps in central nervous system (CNS) diseases.}, journal = {PeerJ}, volume = {12}, number = {}, pages = {e16465}, pmid = {38188146}, issn = {2167-8359}, mesh = {Humans ; *Extracellular Traps ; *Central Nervous System Diseases ; *Multiple Sclerosis ; Central Nervous System ; Neutrophils ; }, abstract = {Excessive induction of inflammatory and immune responses is widely considered as one of vital factors contributing to the pathogenesis and progression of central nervous system (CNS) diseases. Neutrophils are well-studied members of inflammatory and immune cell family, contributing to the innate and adaptive immunity. Neutrophil-released neutrophil extracellular traps (NETs) play an important role in the regulation of various kinds of diseases, including CNS diseases. In this review, current knowledge on the biological features of NETs will be introduced. In addition, the role of NETs in several popular and well-studied CNS diseases including cerebral stroke, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and neurological cancers will be described and discussed through the reviewing of previous related studies.}, } @article {pmid38188233, year = {2023}, author = {Lockard, G and Gordon, J and Schimmel, S and Sayed, BE and Monsour, M and Garbuzova-Davis, S and Borlongan, CV}, title = {Attenuation of amyotrophic lateral sclerosis via stem cell and extracellular vesicle therapy: An updated review.}, journal = {Neuroprotection (Chichester, England)}, volume = {1}, number = {2}, pages = {130-138}, pmid = {38188233}, issn = {2770-730X}, support = {R21 NS132576/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly fatal neurological disease characterized by upper and lower motor neuron degeneration. Though typically idiopathic, familial forms of ALS are commonly comprised of a superoxide dismutase 1 (SOD1) mutation. Basic science frequently utilizes SOD1 models in vitro and in vivo to replicate ALS conditions. Therapies are sparse; those that exist on the market extend life minimally, thus driving the demand for research to identify novel therapeutics. Transplantation of stem cells is a promising approach for many diseases and has shown efficacy in SOD1 models and clinical trials. The underlying mechanism for stem cell therapy presents an exciting venue for research investigations. Most notably, the paracrine actions of stem cell-derived extracellular vesicles (EVs) have been suggested as a potent mitigating factor. This literature review focuses on the most recent preclinical research investigating cell-free methods for treating ALS. Various avenues are being explored, differing on the EV contents (protein, microRNA, etc.) and on the cell target (astrocyte, endothelial cell, motor neuron-like cells, etc.), and both molecular and behavioral outcomes are being examined. Unfortunately, EVs may also play a role in propagating ALS pathology. Nonetheless, the overarching goal remains clear; to identify efficient cell-free techniques to attenuate the deadly consequences of ALS.}, } @article {pmid38188422, year = {2023}, author = {Doyle, JJ and Parker, JA}, title = {Genetic Interactions of Progranulin Across the ALS-FTD Spectrum and Beyond.}, journal = {microPublication biology}, volume = {2023}, number = {}, pages = {}, pmid = {38188422}, issn = {2578-9430}, support = {P40 OD010440/OD/NIH HHS/United States ; }, abstract = {Progranulin (PGRN) is a growth factor in which mutations are one of the leading causes of frontotemporal dementia (FTD), and has been implicated in an assortment of neurodegenerative diseases. Conversely, higher levels of the protein have shown potential as a general neuronal protective factor. While examining its neuroprotective applications on a broader scale would be unfeasible in mammalian models, we turned to the nematode C. elegans to map the interactions of PGRN across multiple genetic models of neurodegenerative diseases. Our results indicate that while the overexpression of PGRN appears to be protective across all models tested, the loss of PGRN exacerbated the disease phenotypes of all but three of the models tested. Given the ease of genetic analysis in nematodes, we propose this model organism as an efficient tool to build a comprehensive map of PGRN's genetic interactions.}, } @article {pmid38189033, year = {2023}, author = {Moreno-Roco, J and Del Valle, L and Jiménez, D and Acosta, I and Castillo, JL and Dharmadasa, T and Kiernan, MC and Matamala, JM}, title = {Diagnostic utility of transcranial magnetic stimulation for neurodegenerative disease: a critical review.}, journal = {Dementia & neuropsychologia}, volume = {17}, number = {}, pages = {e20230048}, pmid = {38189033}, issn = {1980-5764}, abstract = {Neurodegenerative diseases pose significant challenges due to their impact on brain structure, function, and cognition. As life expectancy rises, the prevalence of these disorders is rapidly increasing, resulting in substantial personal, familial, and societal burdens. Efforts have been made to optimize the diagnostic and therapeutic processes, primarily focusing on clinical, cognitive, and imaging characterization. However, the emergence of non-invasive brain stimulation techniques, specifically transcranial magnetic stimulation (TMS), offers unique functional insights and diagnostic potential. TMS allows direct evaluation of brain function, providing valuable information inaccessible through other methods. This review aims to summarize the current and potential diagnostic utility of TMS in investigating neurodegenerative diseases, highlighting its relevance to the field of cognitive neuroscience. The findings presented herein contribute to the growing body of research focused on improving our understanding and management of these debilitating conditions, particularly in regions with limited resources and a pressing need for innovative approaches.}, } @article {pmid38189364, year = {2025}, author = {Lim, SJ and Muhd Noor, ND and Sabri, S and Mohamad Ali, MS and Salleh, AB and Oslan, SN}, title = {Features of the rare pathogen Meyerozyma guilliermondii strain SO and comprehensive in silico analyses of its adherence-contributing virulence factor agglutinin-like sequences.}, journal = {Journal of biomolecular structure & dynamics}, volume = {43}, number = {7}, pages = {3728-3748}, doi = {10.1080/07391102.2023.2300757}, pmid = {38189364}, issn = {1538-0254}, mesh = {*Virulence Factors/chemistry/metabolism/genetics ; Biofilms/growth & development ; Fungal Proteins/chemistry/metabolism/genetics ; Animals ; Virulence ; Amino Acid Sequence ; Zebrafish ; *Saccharomycetales/pathogenicity/metabolism ; Computer Simulation ; Molecular Docking Simulation ; }, abstract = {Meyerozyma guilliermondii is a rare yeast pathogen contributing to the deadly invasive candidiasis. M. guilliermondii strain SO, as a promising protein expression host, showed 99% proteome similarity with the clinically isolated ATCC 6260 (type strain) in a recent comparative genomic analysis. However, their in vitro virulence features and in vivo pathogenicity were uncharacterized. This study aimed to characterize the in vitro and in vivo pathogenicity of M. guilliermondii strain SO and analyze its Als proteins (MgAls) via comprehensive bioinformatics approaches. M. guilliermondii strain SO showed lower and higher sensitivity towards β-mercaptoethanol and lithium, respectively than the avirulent S. cerevisiae but exhibited the same tolerance towards cell wall-perturbing Congo Red with C. albicans. With 7.5× higher biofilm mass, M. guilliermondii strain SO also demonstrated 75% higher mortality rate in the zebrafish embryos with a thicker biofilm layer on the chorion compared to the avirulent S. cerevisiae. Being one of the most important Candida adhesins, sequence and structural analyses of four statistically identified MgAls showed that MgAls1056 was predicted to exhibit the most conserved amyloid-forming regions, tandem repeat domain and peptide binding cavity (PBC) compared to C. albicans Als3. Favoured from the predicted largest ligand binding site and druggable pockets, it showed the highest affinity towards hepta-threonine. Non-PBC druggable pockets in the most potent virulence contributing MgAls1056 provide new insights into developing antifungal drugs targeting non-albicans Candida spp. Virtual screening of available synthetic or natural bioactive compounds and MgAls1056 deletion from the fungal genome should be further performed and validated experimentally.}, } @article {pmid38189756, year = {2024}, author = {Zeng, Y and Cao, S and Pang, K and Tang, J and Lin, G}, title = {Causal Association Between Sepsis and Neurodegenerative Diseases: A Bidirectional Two-Sample Mendelian Randomization Study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {97}, number = {1}, pages = {229-237}, doi = {10.3233/JAD-230954}, pmid = {38189756}, issn = {1875-8908}, mesh = {Humans ; *Neurodegenerative Diseases/complications/epidemiology/genetics ; *Alzheimer Disease/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Reproducibility of Results ; *Sepsis/complications/genetics ; }, abstract = {BACKGROUND: Previous observational studies suggested an association between sepsis and neurodegenerative diseases, but causality remains unclear.

OBJECTIVE: Determining the causal association between sepsis and four neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Lewy body dementia) through bidirectional two-sample Mendelian randomization (MR) analysis.

METHODS: Genome-wide association study summary statistics for all traits were obtained from publicly available databases. Inverse variance weighted (IVW) was the primary method for evaluating causal associations. In addition, three additional MR methods (MR-Egger, weighted median, and maximum likelihood method) were employed to supplement IVW. Furthermore, various sensitivity tests were conducted to assess the reliability: 1) Cochrane's Q test for assessing heterogeneity; 2) MR-Egger intercept test and MR-PRESSO global test for evaluating horizontal pleiotropy; 3) leave-one-out sensitivity test for determining the stability.

RESULTS: The results of IVW indicated that sepsis significantly increased the risk of Alzheimer's disease (OR = 1.11, 95% CI: 1.01-1.21, p = 0.025). In addition, three additional MR methods suggested parallel results. However, no causal effect of sepsis on the three other neurodegenerative diseases was identified. Subsequently, reverse MR analysis indicated that the four neurodegenerative diseases do not causally affect sepsis. Furthermore, sensitivity tests demonstrated the reliability of the MR analyses, suggesting no heterogeneity or horizontal pleiotropy.

CONCLUSIONS: The present study contributes to a deeper comprehension of the intricate interplay between sepsis and neurodegenerative disorders, thereby offering potential avenues for the development of therapeutic agents that can effectively mitigate the multifarious complications associated with sepsis.}, } @article {pmid38191789, year = {2024}, author = {Salomonsson, SE and Maltos, AM and Gill, K and Aladesuyi Arogundade, O and Brown, KA and Sachdev, A and Sckaff, M and Lam, KJK and Fisher, IJ and Chouhan, RS and Van Laar, VS and Marley, CB and McLaughlin, I and Bankiewicz, KS and Tsai, YC and Conklin, BR and Clelland, CD}, title = {Validated assays for the quantification of C9orf72 human pathology.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {828}, pmid = {38191789}, issn = {2045-2322}, support = {P01 HL146366/HL/NHLBI NIH HHS/United States ; K08 NS112330/NS/NINDS NIH HHS/United States ; U19 NS132303/NS/NINDS NIH HHS/United States ; TL1 TR001871/TR/NCATS NIH HHS/United States ; R01 HL130533/HL/NHLBI NIH HHS/United States ; AACSF-17-531484/ALZ/Alzheimer's Association/United States ; RF1 AG072052/AG/NIA NIH HHS/United States ; R01 AG072052/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; *Frontotemporal Dementia ; Antibodies ; *Craniocerebral Trauma ; Mice, Transgenic ; DNA ; RNA ; }, abstract = {A repeat expansion mutation in the C9orf72 gene is the leading known genetic cause of FTD and ALS. The C9orf72-ALS/FTD field has been plagued by a lack of reliable tools to monitor this genomic locus and its RNA and protein products. We have validated assays that quantify C9orf72 pathobiology at the DNA, RNA and protein levels using knock-out human iPSC lines as controls. Here we show that single-molecule sequencing can accurately measure the repeat expansion and faithfully report on changes to the C9orf72 locus in what has been a traditionally hard to sequence genomic region. This is of particular value to sizing and phasing the repeat expansion and determining changes to the gene locus after gene editing. We developed ddPCR assays to quantify two major C9orf72 transcript variants, which we validated by selective excision of their distinct transcriptional start sites. Using validated knock-out human iPSC lines, we validated 4 commercially available antibodies (of 9 tested) that were specific for C9orf72 protein quantification by Western blot, but none were specific for immunocytochemistry. We tested 15 combinations of antibodies against dipeptide repeat proteins (DPRs) across 66 concentrations using MSD immunoassay, and found two (against poly-GA and poly-GP) that yielded a 1.5-fold or greater signal increase in patient iPSC-motor neurons compared to knock-out control, and validated them in human postmortem and transgenic mouse brain tissue. Our validated DNA, RNA and protein assays are applicable to discovery research as well as clinical trials.}, } @article {pmid38191942, year = {2024}, author = {Hernandez-Candia, CN and Brady, BR and Harrison, E and Tucker, CL}, title = {A platform to induce and mature biomolecular condensates using chemicals and light.}, journal = {Nature chemical biology}, volume = {20}, number = {4}, pages = {452-462}, pmid = {38191942}, issn = {1552-4469}, support = {R21 MH134019/MH/NIMH NIH HHS/United States ; R35 GM136367/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Biomolecular Condensates ; *Huntington Disease/genetics ; Optogenetics ; Proteostasis ; }, abstract = {Biomolecular condensates are membraneless compartments that impart spatial and temporal organization to cells. Condensates can undergo maturation, transitioning from dynamic liquid-like states into solid-like states associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington's disease. Despite their important roles, many aspects of condensate biology remain incompletely understood, requiring tools for acutely manipulating condensate-relevant processes within cells. Here we used the BCL6 BTB domain and its ligands BI-3802 and BI-3812 to create a chemical genetic platform, BTBolig, allowing inducible condensate formation and dissolution. We also developed optogenetic and chemical methods for controlled induction of condensate maturation, where we surprisingly observed recruitment of chaperones into the condensate core and formation of dynamic biphasic condensates. Our work provides insights into the interaction of condensates with proteostasis pathways and introduces a suite of chemical-genetic approaches to probe the role of biomolecular condensates in health and disease.}, } @article {pmid38193356, year = {2024}, author = {Tsuji, K and Nakayama, Y and Taruya, J and Ito, H}, title = {Persistence of Kii amyotrophic lateral sclerosis after the 2000s and its characteristic aging-related tau astrogliopathy.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {2}, pages = {79-93}, doi = {10.1093/jnen/nlad113}, pmid = {38193356}, issn = {1554-6578}, support = {18H02743//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Brain/pathology ; *Dementia/pathology ; Japan/epidemiology ; *Parkinsonian Disorders ; Tauopathies/pathology ; TDP-43 Proteinopathies/pathology ; }, abstract = {Kii amyotrophic lateral sclerosis (ALS) is a unique disease that occurs in the southern portion of the Kii Peninsula and exhibits a dual pathology of TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy and tauopathy. The incidence of ALS in this region was very high in the 1960s, briefly decreased through the 1980s, but began increasing again after 2000 with a change of high-concentration geographic foci. It is unclear, however, whether the unique pathological features have changed along with the incidence changes. This study analyzed postmortem specimens from neuropathologically confirmed Kii ALS cases from the 1970s (n = 4) and those after 1999 (n = 12) from the southern Kii Peninsula or outside of the area. Our results confirm the continued occurrence of Kii ALS after 2000 in the southern Kii Peninsula and the preservation of disease-specific neuronal tau pathology, including the widespread occurrence throughout the brain and spinal cord, sparse neuropil threads, and predominance in superficial layers. Furthermore, we assessed the glial tau pathology of Kii and non-Kii ALS in accordance with the aging-related tau astrogliopathy classification method for the first time and detected a unique brainstem predominant appearance of gray matter aging-related tau astrogliopathy in Kii ALS cases, which may provide clues to pathogenetic mechanisms.}, } @article {pmid38193795, year = {2024}, author = {Corrales-Guerrero, L and Díaz-Moreno, I}, title = {Deciphering the role of Zn[2+]-binding histidines from TIA-1 on the assembly and dynamics of stress granules.}, journal = {BioFactors (Oxford, England)}, volume = {50}, number = {4}, pages = {750-755}, doi = {10.1002/biof.2037}, pmid = {38193795}, issn = {1872-8081}, support = {DOC_00796//Agencia de Innovación y Desarrollo de Andalucía/ ; P18-FR-3487//Agencia de Innovación y Desarrollo de Andalucía/ ; PID2021-126663NB-I00//Ministerio de Ciencia e Innovación/ ; }, mesh = {*T-Cell Intracellular Antigen-1/metabolism/genetics ; *Zinc/metabolism ; *Histidine/metabolism/genetics/chemistry ; *Stress Granules/metabolism/genetics ; Humans ; Protein Binding ; Binding Sites ; Cytoplasmic Granules/metabolism/genetics ; }, abstract = {T-cell intracellular antigen-1 (TIA-1) is a key RNA-binding protein that participates in translation regulation and RNA splicing. TIA-1 undergoes liquid-liquid phase separation as a fundamental mechanism that enables the condensation of RNA and proteins into membraneless organelles called stress granules (SGs). However, this dynamic behavior can lead to aberrant fibril formation, implicated in neurodegenerative disorders, and must be tightly regulated. In this study, we investigated the role in the cell of histidine residues His94 and His96, responsible for Zn[2+] binding. Using fluorescence microscopy, we found that the specific binding site formed by these residues is critical for SG assembly. Furthermore, it also plays a role maintaining the dynamic behavior of SG-assembled TIA-1. Collectively, our findings confirm the physiological relevance of TIA-1 His94 and His96 in the Zn[2+]-mediated regulatory mechanism for protection against fibril formation in SGs.}, } @article {pmid38194085, year = {2024}, author = {Zhu, L and Deng, F and Bai, D and Hou, J and Jia, Q and Zhang, C and Ou, K and Li, S and Li, XJ and Yin, P}, title = {Loss of TDP-43 mediates severe neurotoxicity by suppressing PJA1 gene transcription in the monkey brain.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {16}, pmid = {38194085}, issn = {1420-9071}, support = {32270564//National Natural Science Foundation of China/ ; 81830032//National Natural Science Foundation of China/ ; 82071421//National Natural Science Foundation of China/ ; 2023A1515010811//Guangdong Basic and Applied Basic Research/ ; 2022A1515011205//Guangdong Basic and Applied Basic Research/ ; 2021ZT09Y007//Department of Science and Technology of Guangdong Province/ ; 2018B030337001//Department of Science and Technology of Guangdong Province/ ; 202007030008//Guangzhou Key Research Program on Brain Science/ ; 21622113//Fundamental Research Funds for the Central Universities/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; *Brain ; *DNA-Binding Proteins/genetics ; Haplorhini ; Transcription, Genetic ; *Ubiquitin-Protein Ligases/genetics ; Disease Models, Animal ; }, abstract = {The nuclear loss and cytoplasmic accumulation of TDP-43 (TAR DNA/RNA binding protein 43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previously, we reported that the primate-specific cleavage of TDP-43 accounts for its cytoplasmic mislocalization in patients' brains. This prompted us to investigate further whether and how the loss of nuclear TDP-43 mediates neuropathology in primate brain. In this study, we report that TDP-43 knockdown at the similar effectiveness, induces more damage to neuronal cells in the monkey brain than rodent mouse. Importantly, the loss of TDP-43 suppresses the E3 ubiquitin ligase PJA1 expression in the monkey brain at transcriptional level, but yields an opposite upregulation of PJA1 in the mouse brain. This distinct effect is due to the species-dependent binding of nuclear TDP-43 to the unique promoter sequences of the PJA1 genes. Further analyses reveal that the reduction of PJA1 accelerates neurotoxicity, whereas overexpressing PJA1 diminishes neuronal cell death by the TDP-43 knockdown in vivo. Our findings not only uncover a novel primate-specific neurotoxic contribution to the loss of function theory of TDP-43 proteinopathy, but also underscore a potential therapeutic approach of PJA1 to the loss of nuclear TDP-43.}, } @article {pmid38194198, year = {2024}, author = {Xu, A and Luo, Y and Tang, Y and Yang, F and Gao, X and Qiao, G and Zhu, X and Zhou, J}, title = {Chitinases as a potential diagnostic and prognostic biomarker for amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {6}, pages = {2489-2503}, pmid = {38194198}, issn = {1590-3478}, support = {2023AFD128//Hubei Provincial Natural Science Foundation and the Innovation and Development of Traditional Chinese Medicine of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/blood ; Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Chitinases/cerebrospinal fluid/blood ; Prognosis ; Hexosaminidases/cerebrospinal fluid/blood ; Chitinase-3-Like Protein 1/cerebrospinal fluid/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons, and there is currently a lack of reliable diagnostic biomarkers. This meta-analysis aimed to evaluate CHIT1, CHI3L1, and CHI3L2 levels in the cerebrospinal fluid (CSF) or blood and their diagnostic potential in ALS patients. A systematic, comprehensive search was performed of peer-reviewed English-language articles published before April 1, 2023, in PubMed, Scopus, Embase, Cochrane Library, and Web of Science. After a thorough screening, 13 primary articles were included, and their chitinases-related data were extracted for systematic review and meta-analysis. In ALS patients, the CSF CHIT1 levels were significantly elevated compared to controls with healthy control (HC) (SMD, 1.92; 95% CI, 0.78 - 3.06; P < 0.001). CHIT1 levels were elevated in the CSF of ALS patients compared to other neurodegenerative diseases (ONDS) control (SMD, 0.74; 95% CI, 0.22 - 1.27; P < 0.001) and exhibited an even more substantial increase when compared to ALS-mimicking diseases (AMDS) (SMD, 1.15; 95% CI, 0.35 - 1.94, P < 0.001). Similarly, the CSF CHI3L1 levels were significantly higher in ALS patients compared to HC (SMD, 3.16; 95% CI, 1.26 - 5.06, P < 0.001). CHI3L1 levels were elevated in the CSF of ALS patients compared to ONDS (SMD, 0.75; 95% CI, 0.32 - 1.19; P = 0.017) and exhibited a more pronounced increase when compared to AMDS (SMD, 1.92; 95% CI, 0.41 - 3.42; P < 0.001). The levels of CSF chitinases in the ALS patients showed a significant increase, supporting the role of CSF chitinases as diagnostic biomarkers for ALS.}, } @article {pmid38194904, year = {2024}, author = {Nassar, J and Rizk, C and Fares, G and Tohme, C and Braidy, C and Farah, J}, title = {Clinical image quality assessment and mean glandular dose for full field digital mammography.}, journal = {Journal of radiological protection : official journal of the Society for Radiological Protection}, volume = {44}, number = {1}, pages = {}, doi = {10.1088/1361-6498/ad1cd4}, pmid = {38194904}, issn = {1361-6498}, mesh = {Humans ; Female ; Radiation Dosage ; Retrospective Studies ; Mammography ; *Radiation Exposure ; Diagnostic Reference Levels ; *Breast Neoplasms/diagnostic imaging ; Radiographic Image Enhancement/methods ; }, abstract = {This study aims to assess the image quality (IQ) of 12 mammographic units and to identify units with potential optimisation needs. Data for 350 mammography examinations meeting inclusion criteria were collected retrospectively from April 2021 to April 2022. They were categorised based on the medical reports into 10 normal cases, 10 cases displaying calcifications and 10 cases presenting lesions. Two radiologists assessed the IQ of 1400 mammograms, evaluating system performance per Boitaet al's study and positioning performance following European guidelines. To measure agreement between the two radiologists, the Cohen's Kappa coefficient (κ) was computed, quantifying the excess of agreement beyond chance. The visual grading analysis score (VGAS) was computed to compare system and positioning performance assessments across different categories and facilities. Median average glandular dose (AGD) values for cranio caudal and medio lateral oblique views were calculated for each category and facility and compared to the national diagnostic reference levels. The health facilities were categorised by considering both IQ VGAS and AGD levels. Inter-rater agreement between radiologists ranged from poor (κ< 0.20) to moderate (0.41 <κ< 0.60), likely influenced by inherent biases and distinct IQ expectations. 50% of the facilities were classified as needing corrective actions for their system performance as they had IQ or high AGD that could increase recall rate and radiation risk and 50% of the health facilities exhibited insufficient positioning performance that could mask tumour masses and microcalcifications. The study's findings emphasise the importance of implementing quality assurance programs to ensure optimal IQ for accurate diagnoses while adhering to radiation exposure guidelines. Additionally, comprehensive training for technologists is essential to address positioning challenges. These initiatives collectively aim to enhance the overall quality of breast imaging services, contributing to improved patient care.}, } @article {pmid38195712, year = {2024}, author = {Ravichandran, KA and Heneka, MT}, title = {Inflammasomes in neurological disorders - mechanisms and therapeutic potential.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {2}, pages = {67-83}, pmid = {38195712}, issn = {1759-4766}, mesh = {Humans ; Inflammasomes/metabolism ; *Nervous System Diseases/drug therapy ; *Stroke ; *Multiple Sclerosis ; Brain/metabolism ; }, abstract = {Inflammasomes are molecular scaffolds that are activated by damage-associated and pathogen-associated molecular patterns and form a key element of innate immune responses. Consequently, the involvement of inflammasomes in several diseases that are characterized by inflammatory processes, such as multiple sclerosis, is widely appreciated. However, many other neurological conditions, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, stroke, epilepsy, traumatic brain injury, sepsis-associated encephalopathy and neurological sequelae of COVID-19, all involve persistent inflammation in the brain, and increasing evidence suggests that inflammasome activation contributes to disease progression in these conditions. Understanding the biology and mechanisms of inflammasome activation is, therefore, crucial for the development of inflammasome-targeted therapies for neurological conditions. In this Review, we present the current evidence for and understanding of inflammasome activation in neurological diseases and discuss current and potential interventional strategies that target inflammasome activation to mitigate its pathological consequences.}, } @article {pmid38196030, year = {2024}, author = {Mohammadi, S and Seyedalipour, B and Hashemi, SZ and Hosseinkhani, S and Mohseni, M}, title = {Implications of ALS-Associated Mutations on Biochemical and Biophysical Features of hSOD1 and Aggregation Formation.}, journal = {Biochemical genetics}, volume = {62}, number = {5}, pages = {3658-3680}, pmid = {38196030}, issn = {1573-4927}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Mutation ; Amyloid/metabolism ; Protein Aggregates ; Protein Aggregation, Pathological/genetics ; }, abstract = {One of the recognized motor neuron degenerative disorders is amyotrophic lateral sclerosis (ALS). By now, several mutations have been reported and linked to ALS patients, some of which are induced by mutations in the human superoxide dismutase (hSOD1) gene. The ALS-provoking mutations are located throughout the structure of hSOD1 and promote the propensity to aggregate. Despite numerous investigations, the underlying mechanism related to the toxicity of mutant hSOD1 through the gain of a toxic function is still vague. We surveyed two mutant forms of hSOD1 by removing and adding cysteine at positions 146 and 72, respectively, to investigate the biochemical characterization and amyloid formation. Our findings predicted the harmful and destabilizing impact of two SOD1 mutants using multiple programs. The specific activity of the wild-type form was about 1.42- and 1.92-fold higher than that of C146R and G72C mutants, respectively. Comparative structural studies using CD spectropolarimetry, and intrinsic and ANS fluorescence showed alterations in secondary structure content, exposure of hydrophobic patches, and structural compactness of WT-hSOD1 vs. mutants. We demonstrated that two mutants were able to promote amyloid-like aggregates under amyloid induction circumstances (50-mM Tris-HCl pH 7.4, 0.2-M KSCN, 50-mM DTT, 37 °C, 190 rpm). Monitoring aggregates were done using an enhancement in thioflavin T fluorescence and alterations in Congo red absorption. The mutants accelerated fibrillation with subsequently greater fluorescence amplitude and a shorter lag time compared to WT-SOD1. These findings support the aggregation of ALS-associated SOD1 mutants as an integral part of ALS pathology.}, } @article {pmid38196621, year = {2023}, author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and , and Aitman, TJ and Santoyo-Lopez, J and , and Mitsumoto, H and , and Goldstein, DB and Harms, MB}, title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38196621}, issn = {2693-5015}, support = {K01 MH098126/MH/NIMH NIH HHS/United States ; MC_PC_15080/MRC_/Medical Research Council/United Kingdom ; RC2 MH089915/MH/NIMH NIH HHS/United States ; P01 HD080642/HD/NICHD NIH HHS/United States ; R01 MH097971/MH/NIMH NIH HHS/United States ; RC2 NS070344/NS/NINDS NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; P30 AG028377/AG/NIA NIH HHS/United States ; U54 NS078059/NS/NINDS NIH HHS/United States ; P01 AG007232/AG/NIA NIH HHS/United States ; RF1 AG054023/AG/NIA NIH HHS/United States ; R01 HD048805/HD/NICHD NIH HHS/United States ; U01 HG007672/HG/NHGRI NIH HHS/United States ; U01 NS053998/NS/NINDS NIH HHS/United States ; U01 NS077303/NS/NINDS NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; R01 ES016348/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 30,000 people in the United States. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms, such as antisense oligonucleotides, continue to develop, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.

METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger cohort of 6,970 ALS patients from a large multi-ethnic cohort as well as 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.

RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR=19.18, p = 3.67 × 10[-39]; OR=4.73, p = 2 × 10[-10]; OR=2.3, p = 7.49 × 10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10[-7]), was protective for ALS in this model. An intolerant domain based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR=10.08, p = 3.62 × 10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p=8.38 × 10[-6]).

CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, rare variant burden testing validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.}, } @article {pmid38197897, year = {2024}, author = {Iguchi, Y and Takahashi, Y and Li, J and Araki, K and Amakusa, Y and Kawakami, Y and Kobayashi, K and Yokoi, S and Katsuno, M}, title = {IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation.}, journal = {The Journal of cell biology}, volume = {223}, number = {2}, pages = {}, pmid = {38197897}, issn = {1540-8140}, support = {JP20H03589//Japan Society for the Promotion of Science/ ; JP21wm0425013//Japan Agency for Medical Research and Development/ ; //SERIKA/ ; //Japan ALS Association/ ; //Takeda Science Foundation/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; Disease Models, Animal ; *DNA-Binding Proteins/genetics ; *Frontotemporal Dementia ; *Frontotemporal Lobar Degeneration ; *I-kappa B Kinase/genetics ; Proteasome Endopeptidase Complex ; Humans ; }, abstract = {Cytoplasmic aggregation of TDP-43 in neurons is a pathological feature common to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We demonstrate that the IκB kinase (IKK) complex promotes the degradation of cytoplasmic TDP-43 through proteasomes. While IKKβ is a major factor in TDP-43 degradation, IKKα acts as a cofactor, and NEMO functions as a scaffold for the recruitment of TDP-43 to the IKK complex. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK. TDP-43 phosphorylation at Ser92 was detected in a pattern different from that of C-terminal phosphorylation in the pathological inclusion of ALS. IKKβ was also found to significantly reduce the expression level and toxicity of the disease-causing TDP-43 mutation. Finally, the favorable effect of IKKβ on TDP-43 aggregation was confirmed in the hippocampus of mice. IKK and the N-terminal phosphorylation of TDP-43 are potential therapeutic targets for ALS and FTLD.}, } @article {pmid38197966, year = {2024}, author = {Dzik, KP and Flis, DJ and Kaczor-Keller, KB and Bytowska, ZK and Karnia, MJ and Ziółkowski, W and Kaczor, JJ}, title = {Spinal cord abnormal autophagy and mitochondria energy metabolism are modified by swim training in SOD1-G93A mice.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {102}, number = {3}, pages = {379-390}, pmid = {38197966}, issn = {1432-1440}, support = {(2018/29/N/NZ7/01627)//Narodowe Centrum Nauki/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Autophagy ; Disease Models, Animal ; Energy Metabolism ; Insulin-Like Growth Factor I ; Mice, Transgenic ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) may result from the dysfunctions of various mechanisms such as protein accumulation, mitophagy, and biogenesis of mitochondria. The purpose of the study was to evaluate the molecular mechanisms in ALS development and the impact of swim training on these processes. In the present study, an animal model of ALS, SOD1-G93A mice, was used with the wild-type mice as controls. Mice swam five times per week for 30 min. Mice were analyzed before ALS onset (70 days old), at ALS 1 disease onset (116 days old), and at the terminal stage of the disease ALS (130 days old), and compared with the corresponding ALS untrained groups and normalized to the wild-type group. Enzyme activity and protein content were analyzed in the spinal cord homogenates. The results show autophagy disruptions causing accumulation of p62 accompanied by low PGC-1α and IGF-1 content in the spinal cord of SOD1-G93A mice. Swim training triggered a neuroprotective effect, attenuation of NF-l degradation, less accumulated p62, and lower autophagy initiation. The IGF-1 pathway induces pathophysiological adaptation to maintain energy demands through anaerobic metabolism and mitochondrial protection. KEY MESSAGES: The increased protein content of p62 in the spinal cord of SOD1-G93A mice suggests that autophagic clearance and transportation are disrupted. Swim training attenuates neurofilament light destruction in the spinal cord of SOD1-G93A mice. Swim training reducing OGDH provokes suppression of ATP-consuming anabolic pathways. Swim training induces energy metabolic changes and mitochondria protection through the IGF-1 signaling pathway.}, } @article {pmid38198547, year = {2024}, author = {Perlegos, AE and Durkin, J and Belfer, SJ and Rodriguez, A and Shcherbakova, O and Park, K and Luong, J and Bonini, NM and Kayser, MS}, title = {TDP-43 impairs sleep in Drosophila through Ataxin-2-dependent metabolic disturbance.}, journal = {Science advances}, volume = {10}, number = {2}, pages = {eadj4457}, pmid = {38198547}, issn = {2375-2548}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; T32 HL007953/HL/NHLBI NIH HHS/United States ; P40 OD018537/OD/NIH HHS/United States ; F31 AG063470/AG/NIA NIH HHS/United States ; T32 MH014654/MH/NIMH NIH HHS/United States ; R01 AG071777/AG/NIA NIH HHS/United States ; R56 AG071777/AG/NIA NIH HHS/United States ; R01 GM084947/GM/NIGMS NIH HHS/United States ; F30 AG058409/AG/NIA NIH HHS/United States ; P40 OD010949/OD/NIH HHS/United States ; F32 NS117785/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis ; Ataxin-2 ; DNA-Binding Proteins/genetics ; Drosophila ; *Neurodegenerative Diseases ; Drosophila Proteins ; }, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia are associated with substantial sleep disruption, which may accelerate cognitive decline and brain degeneration. Here, we define a role for trans-activation response element (TAR) DNA binding protein 43 (TDP-43), a protein associated with human neurodegenerative disease, in regulating sleep using Drosophila. Expression of TDP-43 severely disrupts sleep, and the sleep deficit is rescued by Atx2 knockdown. Brain RNA sequencing revealed that Atx2 RNA interference regulates transcripts enriched for small-molecule metabolic signaling in TDP-43 brains. Focusing on these Atx2-regulated genes, we identified suppressors of the TDP-43 sleep phenotype enriched for metabolism pathways. Knockdown of Atx2 or treatment with rapamycin attenuated the sleep phenotype and mitigated the disruption of small-molecule glycogen metabolism caused by TDP-43. Our findings provide a connection between toxicity of TDP-43 and sleep disturbances and highlight key aspects of metabolism that interplay with TDP-43 toxicity upon Atx2 rescue.}, } @article {pmid38200398, year = {2024}, author = {Stenson, K and Fecteau, TE and O'Callaghan, L and Bryden, P and Mellor, J and Wright, J and Earl, L and Thomas, O and Iqbal, H and Barlow, S and Parvanta, S}, title = {Health-related quality of life across disease stages in patients with amyotrophic lateral sclerosis: results from a real-world survey.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2390-2404}, pmid = {38200398}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology/complications ; *Quality of Life ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; *Disease Progression ; Aged ; Adult ; Severity of Illness Index ; Surveys and Questionnaires ; Caregivers/psychology ; Neurologists ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by a rapid disease course, with disease severity being associated with declining health-related quality of life (HRQoL) in persons living with ALS (pALS). The main objective of this study was to assess the impact of disease progression on HRQoL across King's, Milano-Torino Staging (MiToS), and physician-judgement clinical staging. Additionally, we evaluated the impact of the disease on the HRQoL of care partners (cALS).

METHODS: Data were sourced from the Adelphi ALS Disease Specific Programme (DSP)™, a cross-sectional survey of neurologists, pALS and cALS presenting in a real-world clinical setting between July 2020 and March 2021 in Europe and the United States.

RESULTS: Neurologists (n = 142) provided data for 880 pALS. There were significant negative correlations between all three clinical staging systems and EuroQol (European Quality of Life) Five Dimension Five Level Scale (EQ-5D-5L) utility scores and visual analogue scale (VAS) ratings. Although not all differences were significant, 5-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) scores showed a stepwise increase in HRQoL impairment at each stage of the disease regardless of the staging system. At later stages, high levels of fatigue and substantial activity impairment were reported. As pALS disease states progressed, cALS also experienced a decline in HRQoL and increased burden.

CONCLUSIONS: Across outcomes, pALS and cALS generally reported worse outcomes at later stages of the disease, highlighting an unmet need in this population for strategies to maximise QoL despite disease progression. Recognition and treatment of symptoms such as pain and fatigue may lead to improved outcomes for pALS and cALS.}, } @article {pmid38200884, year = {2024}, author = {Fürmann, A and Syring, C and Becker, J and Sarbach, A and Weber, J and Welham Ruiters, M and Steiner, A}, title = {Prevalence of Painful Lesions of the Digits and Risk Factors Associated with Digital Dermatitis, Ulcers and White Line Disease on Swiss Cattle Farms.}, journal = {Animals : an open access journal from MDPI}, volume = {14}, number = {1}, pages = {}, pmid = {38200884}, issn = {2076-2615}, abstract = {The first aim of this study was to calculate the prevalence of painful lesions of the digits ("alarm" lesions; ALs) in Swiss dairy herds and cow-calf operations over a three-year study period. The following ALs were included in the calculation: the M2 stage of digital dermatitis (DD M2), ulcers (U), white line fissures (WLF) of moderate and high severity, white line abscesses (WLA), interdigital phlegmon (IP) and swelling of the coronet and/or bulb (SW). Between February 2020 and February 2023, digit disorders were electronically recorded during routine trimmings by 40 specially trained hoof trimmers on Swiss cattle farms participating in the national claw health programme. The data set used consisted of over 35,000 observations from almost 25,000 cows from 702 herds. While at the herd-level, the predominant AL documented in 2022 was U with 50.3% followed by WLF with 38.1%, at the cow-level, in 2022, it was DD M2 with 5.4% followed by U with 3.7%. During the study period, within-herd prevalences of ALs ranged from 0.0% to a maximum of 66.1% in 2020. The second aim of this study was to determine herd- and cow-level risk factors associated with digital dermatitis (DD), U and white line disease (WL) in dairy cows using data from 2022. While for DD, analysed herd-level factors appeared to have a greater effect on the probability of its occurrence, the presence of U and WL was mainly associated with the analysed cow-level factors. The risk for DD increased with a higher herd trimming frequency. Herds kept in tie stalls had a lower risk for DD and WL and a higher risk for U compared to herds kept in loose housing systems. Herds with predominantly Holstein Friesian cows as well as Holstein Friesian cows had a higher risk for the occurrence of DD compared to herds and cows of other breeds. With increasing parity, cows had a higher risk of developing U and WL, whereas for DD, parity was negatively associated with prevalence. Cows trimmed during the grazing period had a higher risk of U and WL than cows trimmed during the housing period. These findings may contribute to improve management measures affecting the health of the digits in farms with structures similar to those evaluated in the current study, such as small herds with frequent access to pasture. Further research is warranted to demonstrate how measures addressing the current results combined with those of individual herd risk assessments might contribute to an improvement in the health of the digits in the respective dairy herds.}, } @article {pmid38201303, year = {2024}, author = {Chen, L and Zhang, S and Liu, S and Gao, S}, title = {Amyotrophic Lateral Sclerosis Mechanism: Insights from the Caenorhabditis elegans Models.}, journal = {Cells}, volume = {13}, number = {1}, pages = {}, pmid = {38201303}, issn = {2073-4409}, support = {32020103007//Major International (Regional) Joint Research Project/ ; 2022YFA1206001//National Key Research and Development Program of China/ ; 32371189, 32300984//the National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Caenorhabditis elegans ; Motor Neurons ; Protein Aggregates ; Signal Transduction ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a debilitating neurodegenerative condition characterized by the progressive degeneration of motor neurons. Despite extensive research in various model animals, the cellular signal mechanisms of ALS remain elusive, impeding the development of efficacious treatments. Among these models, a well-characterized and diminutive organism, Caenorhabditis elegans (C. elegans), has emerged as a potent tool for investigating the molecular and cellular dimensions of ALS pathogenesis. This review summarizes the contributions of C. elegans models to our comprehension of ALS, emphasizing pivotal findings pertaining to genetics, protein aggregation, cellular pathways, and potential therapeutic strategies. We analyze both the merits and constraints of the C. elegans system in the realm of ALS research and point towards future investigations that could bridge the chasm between C. elegans foundational discoveries and clinical applications.}, } @article {pmid38201932, year = {2023}, author = {Sharma, H and Sharma, N and An, SSA}, title = {Unique Bioactives from Zombie Fungus (Cordyceps) as Promising Multitargeted Neuroprotective Agents.}, journal = {Nutrients}, volume = {16}, number = {1}, pages = {}, pmid = {38201932}, issn = {2072-6643}, support = {RS-2023-00251396 and 2021R1A6A1A03038996//National Research Foundation of Korea/ ; }, mesh = {*Neuroprotective Agents/pharmacology ; *Cordyceps ; *Agaricales ; Neuroprotection ; Adenosine ; }, abstract = {Cordyceps, also known as "zombie fungus", is a non-poisonous mushroom that parasitizes insects for growth and development by manipulating the host system in a way that makes the victim behave like a "zombie". These species produce promising bioactive metabolites, like adenosine, β-glucans, cordycepin, and ergosterol. Cordyceps has been used in traditional medicine due to its immense health benefits, as it boosts stamina, appetite, immunity, longevity, libido, memory, and sleep. Neuronal loss is the typical feature of neurodegenerative diseases (NDs) (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS)) and neurotrauma. Both these conditions share common pathophysiological features, like oxidative stress, neuroinflammation, and glutamatergic excitotoxicity. Cordyceps bioactives (adenosine, N[6]-(2-hydroxyethyl)-adenosine, ergosta-7, 9 (11), 22-trien-3β-ol, active peptides, and polysaccharides) exert potential antioxidant, anti-inflammatory, and anti-apoptotic activities and display beneficial effects in the management and/or treatment of neurodegenerative disorders in vitro and in vivo. Although a considerable list of compounds is available from Cordyceps, only a few have been evaluated for their neuroprotective potential and still lack information for clinical trials. In this review, the neuroprotective mechanisms and safety profile of Cordyceps extracts/bioactives have been discussed, which might be helpful in the identification of novel potential therapeutic entities in the future.}, } @article {pmid38202163, year = {2023}, author = {Ueha, R and Cotaoco, C and Kondo, K and Yamasoba, T}, title = {Management and Treatment for Dysphagia in Neurodegenerative Disorders.}, journal = {Journal of clinical medicine}, volume = {13}, number = {1}, pages = {}, pmid = {38202163}, issn = {2077-0383}, abstract = {Patients with neurodegenerative disorders (NDDs) often experience functional dysphagia, which may involve dysfunction in a specific phase of swallowing or in the entire process. This review outlines the approach to dysphagia in the setting of NDDs. Distinguishing the etiology of dysphagia can be difficult, and it is important to always look out for signs pointing to NDD as the cause. Thorough diagnostic work-up is essential, and it includes a comprehensive history and physical examination, alongside swallowing function tests, such as fiberoptic endoscopic evaluation of swallowing, videofluoroscopic swallowing study, and high-resolution manometry. Management requires a multidisciplinary approach with a treatment plan tailored to each patient. This involves dietary guidance, swallowing rehabilitation, and surgery in cases in which improvement with rehabilitation is inadequate. Surgery may involve altering certain pharyngolaryngeal structures to facilitate swallowing and reduce the risk of aspiration (swallowing improvement surgery) or separating the airway and digestive tract while sacrificing laryngeal function, with the main goal of preventing aspiration (aspiration prevention surgery). Proper management stems from recognizing the impact of these disorders on swallowing and consistently finding ways to improve the quality of life of patients.}, } @article {pmid38202942, year = {2023}, author = {Kosmyna, N and Hauptmann, E and Hmaidan, Y}, title = {A Brain-Controlled Quadruped Robot: A Proof-of-Concept Demonstration.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {1}, pages = {}, pmid = {38202942}, issn = {1424-8220}, mesh = {Humans ; Animals ; Dogs ; *Robotics ; Brainwashing ; Proof of Concept Study ; *Amyotrophic Lateral Sclerosis ; Brain ; }, abstract = {Coupling brain-computer interfaces (BCIs) and robotic systems in the future can enable seamless personal assistant systems in everyday life, with the requests that can be performed in a discrete manner, using one's brain activity only. These types of systems might be of a particular interest for people with locked-in syndrome (LIS) or amyotrophic lateral sclerosis (ALS) because they can benefit from communicating with robotic assistants using brain sensing interfaces. In this proof-of-concept work, we explored how a wireless and wearable BCI device can control a quadruped robot-Boston Dynamics' Spot. The device measures the user's electroencephalography (EEG) and electrooculography (EOG) activity of the user from the electrodes embedded in the glasses' frame. The user responds to a series of questions with YES/NO answers by performing a brain-teaser activity of mental calculus. Each question-answer pair has a pre-configured set of actions for Spot. For instance, Spot was prompted to walk across a room, pick up an object, and retrieve it for the user (i.e., bring a bottle of water) when a sequence resolved to a YES response. Our system achieved at a success rate of 83.4%. To the best of our knowledge, this is the first integration of wireless, non-visual-based BCI systems with Spot in the context of personal assistant use cases. While this BCI quadruped robot system is an early prototype, future iterations may embody friendly and intuitive cues similar to regular service dogs. As such, this project aims to pave a path towards future developments in modern day personal assistant robots powered by wireless and wearable BCI systems in everyday living conditions.}, } @article {pmid38203300, year = {2023}, author = {Wei, J and Wong, LC and Boland, S}, title = {Lipids as Emerging Biomarkers in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {1}, pages = {}, pmid = {38203300}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; *Alzheimer Disease/diagnosis ; *Parkinson Disease ; Biomarkers ; Monoglycerides ; }, abstract = {Biomarkers are molecules that can be used to observe changes in an individual's biochemical or medical status and provide information to aid diagnosis or treatment decisions. Dysregulation in lipid metabolism in the brain is a major risk factor for many neurodegenerative disorders, including frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Thus, there is a growing interest in using lipids as biomarkers in neurodegenerative diseases, with the anionic phospholipid bis(monoacylglycerol)phosphate and (glyco-)sphingolipids being the most promising lipid classes thus far. In this review, we provide a general overview of lipid biology, provide examples of abnormal lysosomal lipid metabolism in neurodegenerative diseases, and discuss how these insights might offer novel and promising opportunities in biomarker development and therapeutic discovery. Finally, we discuss the challenges and opportunities of lipid biomarkers and biomarker panels in diagnosis, prognosis, and/or treatment response in the clinic.}, } @article {pmid38203614, year = {2023}, author = {Wu, Y and Chen, Y and Yu, X and Zhang, M and Li, Z}, title = {Towards Understanding Neurodegenerative Diseases: Insights from Caenorhabditis elegans.}, journal = {International journal of molecular sciences}, volume = {25}, number = {1}, pages = {}, pmid = {38203614}, issn = {1422-0067}, support = {2002472//National Health and Medical Research Council/ ; }, mesh = {Animals ; Caenorhabditis elegans/genetics ; *Neurodegenerative Diseases/genetics ; *Alzheimer Disease ; *Huntington Disease ; *Parkinson Disease ; Mammals ; }, abstract = {The elevated occurrence of debilitating neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD) and Machado-Joseph disease (MJD), demands urgent disease-modifying therapeutics. Owing to the evolutionarily conserved molecular signalling pathways with mammalian species and facile genetic manipulation, the nematode Caenorhabditis elegans (C. elegans) emerges as a powerful and manipulative model system for mechanistic insights into neurodegenerative diseases. Herein, we review several representative C. elegans models established for five common neurodegenerative diseases, which closely simulate disease phenotypes specifically in the gain-of-function aspect. We exemplify applications of high-throughput genetic and drug screenings to illustrate the potential of C. elegans to probe novel therapeutic targets. This review highlights the utility of C. elegans as a comprehensive and versatile platform for the dissection of neurodegenerative diseases at the molecular level.}, } @article {pmid38205130, year = {2024}, author = {Izquierdo-Condoy, JS and Naranjo-Lara, P and Arias Rodríguez, FD and Puglla-Mendoza, AG and Jima-Sanmartín, J and Andrade Casanova, D and Duque-Sánchez, EP and Alegría N, N and Rojas Cadena, MG and Ortiz-Prado, E}, title = {Assessing the Proficiency in Basic and Advanced Life Support Among Physicians in Ecuador: A Cross-Sectional Study.}, journal = {Advances in medical education and practice}, volume = {15}, number = {}, pages = {25-35}, pmid = {38205130}, issn = {1179-7258}, abstract = {PURPOSE: Cardiorespiratory arrest's unpredictability poses a global health challenge, with gaps in physicians' life support knowledge potentially leading to poor patient outcomes, a factor yet unstudied among Ecuadorian physicians. This study aims to elucidate the state of physicians' theoretical knowledge in Ecuador based on Basic Life Support (BLS) and Advanced Life Support (ALS) guidelines.

PATIENTS AND METHODS: A national cross-sectional online 35-questions survey was conducted between February and March 2023 using a self-administered, expert-validated questionnaire. Participants' responses were obtained through official social media groups (WhatsApp and Facebook). The survey evaluated the theoretical knowledge of BLS and ALS, with scores based on the number of correct answers out of a maximum of 10.0 points. For descriptive analysis, frequencies, percentages, means, and standard deviations (SD) were used. The T-test and one-way ANOVA were utilized to analyze the associations between knowledge levels and demographic and academic training variables of Ecuadorian doctors. Values of p < 0.05 were considered statistically significant for all analyses.

RESULTS: The survey garnered responses from 385 physicians, with a majority being female (56.6%) and possessing less than 3 years of work experience (75.1%). Of these, 71.7% and 51.9% held BLS and ALS certifications, respectively. Knowledge scores for BLS (5.8/10 ± 1.6) surpassed those for ALS (4.7/10 ± 1.8) (p < 0.001). Physicians with less than 3 years of work experience exhibited higher knowledge scores in both BLS and ALS tests (p < 0.05).

CONCLUSION: This study revealed a notable deficiency in the theoretical knowledge of BLS and ALS among surveyed Ecuadorian physicians. Factors such as prior certification and years of work experience appeared to influence knowledge levels. Continual training and updates in life support protocols at universities and healthcare institutions are key to enhancing physicians' skills and patient outcomes.}, } @article {pmid38206346, year = {2024}, author = {Vosough, M and Salemi, A and Rockel, S and Schmidt, TC}, title = {Enhanced efficiency of MS/MS all-ion fragmentation for non-targeted analysis of trace contaminants in surface water using multivariate curve resolution and data fusion.}, journal = {Analytical and bioanalytical chemistry}, volume = {416}, number = {5}, pages = {1165-1177}, pmid = {38206346}, issn = {1618-2650}, support = {520243139//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Data-independent acquisition-all-ion fragmentation (DIA-AIF) mode of mass spectrometry can facilitate wide-scope non-target analysis of contaminants in surface water due to comprehensive spectral identification. However, because of the complexity of the resulting MS[2] AIF spectra, identifying unknown pollutants remains a significant challenge, with a significant bottleneck in translating non-targeted chemical signatures into environmental impacts. The present study proposes to process fused MS[1] and MS[2] data sets obtained from LC-HRMS/MS measurements in non-targeted AIF workflows on surface water samples using multivariate curve resolution-alternating least squares (MCR-ALS). This enables straightforward assignment between precursor ions obtained from resolved MS[1] spectra and their corresponding MS[2] spectra. The method was evaluated for two sets of tap water and surface water contaminated with 14 target chemicals as a proof of concept. The data set of surface water samples consisting of 3506 MS[1] and 2170 MS[2] AIF mass spectral features was reduced to 81 components via a fused MS[1]-MS[2] MCR model that describes at least 98.8% of the data. Each component summarizes the distinct chromatographic elution of components together with their corresponding MS[1] and MS[2] spectra. MS[2] spectral similarity of more than 82% was obtained for most target chemicals. This highlights the potential of this method for unraveling the composition of MS/MS complex data in a water environment. Ultimately, the developed approach was applied to the retrospective non-target analysis of an independent set of surface water samples.}, } @article {pmid38212334, year = {2024}, author = {Sharma, K and Stockert, F and Shenoy, J and Berbon, M and Abdul-Shukkoor, MB and Habenstein, B and Loquet, A and Schmidt, M and Fändrich, M}, title = {Cryo-EM observation of the amyloid key structure of polymorphic TDP-43 amyloid fibrils.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {486}, pmid = {38212334}, issn = {2041-1723}, mesh = {Humans ; Amyloid/metabolism ; Cryoelectron Microscopy ; Amyloidogenic Proteins ; *Frontotemporal Lobar Degeneration/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {The transactive response DNA-binding protein-43 (TDP-43) is a multi-facet protein involved in phase separation, RNA-binding, and alternative splicing. In the context of neurodegenerative diseases, abnormal aggregation of TDP-43 has been linked to amyotrophic lateral sclerosis and frontotemporal lobar degeneration through the aggregation of its C-terminal domain. Here, we report a cryo-electron microscopy (cryo-EM)-based structural characterization of TDP-43 fibrils obtained from the full-length protein. We find that the fibrils are polymorphic and contain three different amyloid structures. The structures differ in the number and relative orientation of the protofilaments, although they share a similar fold containing an amyloid key motif. The observed fibril structures differ from previously described conformations of TDP-43 fibrils and help to better understand the structural landscape of the amyloid fibril structures derived from this protein.}, } @article {pmid38212665, year = {2024}, author = {Jang, MS and Yoo, SH and Kim, MS and Cho, B and Kim, KH and Shin, J and Hwang, I and Choi, SJ and Sung, JJ and Lee, SY}, title = {Healthcare Utilization and Supportive Care Timing in South Korean People Living With Amyotrophic Lateral Sclerosis: A Single-Center Retrospective Study.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {20}, number = {2}, pages = {166-174}, pmid = {38212665}, issn = {1738-6586}, support = {27302C0115/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND AND PURPOSE: Despite the growing demands and challenges faced by patients with amyotrophic lateral sclerosis (ALS) in accessing healthcare services, our understanding of this access remains poor. This study aimed to investigate the healthcare utilization patterns and timing of nutritional and respiration support in patients with ALS in South Korea.

METHODS: A retrospective cohort study was conducted on patients diagnosed with ALS at a single tertiary hospital between 2016 and 2019 and followed up for 2 years. We evaluated patient characteristics, healthcare utilization (hospital admissions, outpatient visits, and emergency department [ED] visits), and the timing of nutritional and respiration support (noninvasive positive pressure ventilation [NIPPV], tracheostomy, gastrostomy, and nasogastric tube) at 6-month intervals from the first outpatient visit.

RESULTS: Among the 143 included patients, 73.4% were admitted at least once, 18.9% experienced unplanned admissions, and 30.1% visited the ED at least once during the study period. The most-common reason for ED visits was neurological symptoms during the first 6 months (59.1%), followed by respiratory symptoms. One fifth of patients who visited the ED underwent tracheostomy (20.9%) or NIPPV (20.9%). Two years after the first visit, 32.2% used a ventilator, and 13.3%, 26.6%, and 6.3% had undergone tracheostomy, gastrostomy, and nasogastric tube insertion, respectively.

CONCLUSIONS: During the 2 years following their first outpatient visit, 20% of patients with ALS experienced unplanned admissions and 30% visited the ED. An active and prompt supportive-care program should be implemented to ensure timely functional support in order to reduce these risks of unplanned admissions.}, } @article {pmid38212835, year = {2024}, author = {Zaccai, S and Nemirovsky, A and Lerner, L and Alfahel, L and Eremenko, E and Israelson, A and Monsonego, A}, title = {CD4 T-cell aging exacerbates neuroinflammation in a late-onset mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {17}, pmid = {38212835}, issn = {1742-2094}, support = {3-16148//Ministry of Science, Technology and Space/ ; 284/19//Israel Science Foundation grant/ ; }, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; CD4-Positive T-Lymphocytes/metabolism ; Mice, Transgenic ; Neuroinflammatory Diseases ; T-Cell Senescence ; Superoxide Dismutase/genetics/metabolism ; Spinal Cord/metabolism ; Disease Progression ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons in the brain and spinal cord. Accumulating evidence suggests that ALS is not solely a neuronal cell- or brain tissue-autonomous disease and that neuroinflammation plays a key role in disease progression. Furthermore, whereas both CD4 and CD8 T cells were observed in spinal cords of ALS patients and in mouse models of the disease, their role in the neuroinflammatory process, especially considering their functional changes with age, is not fully explored. In this study, we revealed the structure of the CD4 T-cell compartment during disease progression of early-onset SOD1[G93A] and late-onset SOD1[G37R] mouse models of ALS. We show age-related changes in the CD4 T-cell subset organization between these mutant SOD1 mouse models towards increased frequency of effector T cells in spleens of SOD1[G37R] mice and robust infiltration of CD4 T cells expressing activation markers and the checkpoint molecule PD1 into the spinal cord. The frequency of infiltrating CD4 T cells correlated with the frequency of infiltrating CD8 T cells which displayed a more exhausted phenotype. Moreover, RNA-Seq and immunohistochemistry analyses of spinal cords from SOD1[G37R] mice with early clinical symptoms demonstrated immunological trajectories reminiscent of a neurotoxic inflammatory response which involved proinflammatory T cells and antigen presentation related pathways. Overall, our findings suggest that age-related changes of the CD4 T cell landscape is indicative of a chronic inflammatory response, which aggravates the disease process and can be therapeutically targeted.}, } @article {pmid38213020, year = {2024}, author = {Chen, M and Guo, X and Guo, J and Shi, C and Wu, Y and Chen, L and Mao, R and Fan, Y}, title = {Cytoplasmic Accumulation of Histones Induced by BET Inhibition Protects Cells from C9orf72 Poly(PR)-Induced Cell Death.}, journal = {Advanced biology}, volume = {8}, number = {3}, pages = {e2300334}, doi = {10.1002/adbi.202300334}, pmid = {38213020}, issn = {2701-0198}, support = {31970616//National Natural Science Foundation of China/ ; 81873531//National Natural Science Foundation of China/ ; BK20211330//Jiangsu Provincial Natural Science Foundation/ ; KYCX20_2796//Graduate Research and Innovation Projects of Jiangsu Province/ ; KYCX22_3362//Graduate Research and Innovation Projects of Jiangsu Province/ ; }, mesh = {*Histones/genetics/metabolism/pharmacology ; C9orf72 Protein/genetics/metabolism/pharmacology ; *Nuclear Proteins/genetics/metabolism/pharmacology ; DNA Repeat Expansion ; Transcription Factors/genetics/metabolism/pharmacology ; Dipeptides/genetics/metabolism/pharmacology ; Cell Death/genetics ; }, abstract = {Repeat dipeptides such as poly(proline-arginine) (polyPR) are generated from the hexanucleotide GGGGCC repeat expansions in the C9orf72 gene. These dipeptides are often considered as the genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In the study, fluorescein isothiocyanate (FITC) labeled PR20 is used to investigate PR20-induced cell death. The findings reveal that the cell death induced by PR20 is dependent on its nuclear distribution and can be blocked by a nuclear import inhibitor called importazole. Further investigation reveals that BRD4 inhibitors, such as JQ-1 and I-BET762, restrict cytoplasmic localization of PR20, thereby reducing its cytotoxic effect. Mechanistically, the inhibition of BRD4 leads to an increase in the expression of numerous histones, resulting in the accumulation of histones in the cytoplasm. These cytoplasmic histones associate with PR20 and limit its distribution within the nucleus. Notably, the ectopic expression of histones alone is enough to confer protection to cells treated with PR20. In addition, phenylephrine (PE) induces cellular hypertrophy and cytoplasmic distribution of histone, which also helps protect cells from PR20-induced cell death. The research suggests that temporarily inducing the presence of cytoplasmic histones may alleviate the neurotoxic effects of dipeptide repeat proteins.}, } @article {pmid38213309, year = {2024}, author = {Eisen, A and Vucic, S and Mitsumoto, H}, title = {History of ALS and the competing theories on pathogenesis: IFCN handbook chapter.}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {1-12}, pmid = {38213309}, issn = {2467-981X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the human motor system, first described in the 19th Century. The etiology of ALS appears to be multifactorial, with a complex interaction of genetic, epigenetic, and environmental factors underlying the onset of disease. Importantly, there are no known naturally occurring animal models, and transgenic mouse models fail to faithfully reproduce ALS as it manifests in patients. Debate as to the site of onset of ALS remain, with three competing theories proposed, including (i) the dying-forward hypothesis, whereby motor neuron degeneration is mediated by hyperexcitable corticomotoneurons via an anterograde transsynaptic excitotoxic mechanism, (ii) dying-back hypothesis, proposing the ALS begins in the peripheral nervous system with a toxic factor(s) retrogradely transported into the central nervous system and mediating upper motor neuron dysfunction, and (iii) independent hypothesis, suggesting that upper and lower motor neuron degenerated independently. Transcranial magnetic stimulation studies, along with pathological and genetic findings have supported the dying forward hypothesis theory, although the science is yet to be settled. The review provides a historical overview of ALS, discusses phenotypes and likely pathogenic mechanisms.}, } @article {pmid38213752, year = {2024}, author = {}, title = {Erratum: Estimated Familial Amyotrophic Lateral Sclerosis Proportion: A Literature Review and Meta-Analysis.}, journal = {Neurology. Genetics}, volume = {10}, number = {1}, pages = {e200131}, pmid = {38213752}, issn = {2376-7839}, abstract = {[This corrects the article DOI: 10.1212/NXG.0000000000200109.].}, } @article {pmid38214845, year = {2024}, author = {Fang, A and Zhao, Y and Yang, P and Zhang, X and Giovannucci, EL}, title = {Vitamin D and human health: evidence from Mendelian randomization studies.}, journal = {European journal of epidemiology}, volume = {39}, number = {5}, pages = {467-490}, pmid = {38214845}, issn = {1573-7284}, support = {81803219//National Natural Science Foundation of China/ ; 2018A030310335//Natural Science Foundation of Guangdong Province/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Vitamin D/blood/analogs & derivatives ; Vitamin D Deficiency/epidemiology/complications/genetics ; }, abstract = {We summarized the current evidence on vitamin D and major health outcomes from Mendelian randomization (MR) studies. PubMed and Embase were searched for original MR studies on vitamin D in relation to any health outcome from inception to September 1, 2022. Nonlinear MR findings were excluded due to concerns about the validity of the statistical methods used. A meta-analysis was preformed to synthesize study-specific estimates after excluding overlapping samples, where applicable. The methodological quality of the included studies was evaluated according to the STROBE-MR checklist. A total of 133 MR publications were eligible for inclusion in the analyses. The causal association between vitamin D status and 275 individual outcomes was examined. Linear MR analyses showed genetically high 25-hydroxyvitamin D (25(OH)D) concentrations were associated with reduced risk of multiple sclerosis incidence and relapse, non-infectious uveitis and scleritis, psoriasis, femur fracture, leg fracture, amyotrophic lateral sclerosis, anorexia nervosa, delirium, heart failure, ovarian cancer, non-alcoholic fatty liver disease, dyslipidemia, and bacterial pneumonia, but increased risk of Behçet's disease, Graves' disease, kidney stone disease, fracture of radium/ulna, basal cell carcinoma, and overall cataracts. Stratified analyses showed that the inverse association between genetically predisposed 25(OH)D concentrations and multiple sclerosis risk was significant and consistent regardless of the genetic instruments GIs selected. However, the associations with most of the other outcomes were only pronounced when using genetic variants not limited to those in the vitamin D pathway as GIs. The methodological quality of the included MR studies was substantially heterogeneous. Current evidence from linear MR studies strongly supports a causal role of vitamin D in the development of multiple sclerosis. Suggestive support for a number of other health conditions could help prioritize conditions where vitamin D may be beneficial or harmful.}, } @article {pmid38216448, year = {2024}, author = {Van Daele, SH and Masrori, P and Van Damme, P and Van Den Bosch, L}, title = {The sense of antisense therapies in ALS.}, journal = {Trends in molecular medicine}, volume = {30}, number = {3}, pages = {252-262}, doi = {10.1016/j.molmed.2023.12.003}, pmid = {38216448}, issn = {1471-499X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; Oligonucleotides, Antisense/therapeutic use ; RNA Splicing ; }, abstract = {Treatment of patients with amyotrophic lateral sclerosis (ALS) has entered a new era now that encouraging results about antisense oligonucleotides (ASOs) are becoming available and a first ASO therapy for ALS has been approved by the FDA. Moreover, there is hope not only that ALS can be stopped but also that symptoms can be reversed. Until now, degrading ASOs seemed to be successful mostly for rarer forms of familial ALS. However, the first attempts to correct mis-splicing events in sporadic ALS are underway, as well as a clinical trial examining interference with a genetic modifier. In this review, we discuss the current status of using ASOs in ALS and the possibilities and pitfalls of this therapeutic strategy.}, } @article {pmid38217066, year = {2024}, author = {Tsagakis, I and Yamanaka, K}, title = {An open chat with… Koji Yamanaka.}, journal = {FEBS open bio}, volume = {14}, number = {2}, pages = {162-164}, pmid = {38217066}, issn = {2211-5463}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Koji Yamanaka is a Professor at the Research Institute of Environmental Medicine at Nagoya University of Japan. His research interests lie in understanding the mechanism of onset and progression of motor neuron disease as well as the role of glial cells in Alzheimer's disease neuroinflammation. Koji has been serving on the FEBS Open Bio Editorial Board since 2013. In this interview, he explains the implications of recent findings in neurobiology for amyotrophic lateral sclerosis, provides updates on the research environment in Japan and discusses how editors might use their position to positively influence academic culture.}, } @article {pmid38217607, year = {2024}, author = {Mázala, DAG and Chen, D and Chin, ER}, title = {SERCA1 Overexpression in Skeletal Muscle Attenuates Muscle Atrophy and Improves Motor Function in a Mouse Model of ALS.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {2}, pages = {315-326}, pmid = {38217607}, issn = {2214-3602}, support = {T32 AG000268/AG/NIA NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis ; Endoplasmic Reticulum Chaperone BiP ; Calcium/metabolism ; Fura-2/metabolism ; Muscle, Skeletal ; Mice, Transgenic ; Muscular Atrophy/metabolism ; Calcium-Transporting ATPases/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of muscle mass and muscle function. Previous work from our lab demonstrated that skeletal muscles from a mouse model of ALS show elevated intracellular calcium (Ca2+) levels and heightened endoplasmic reticulum (ER) stress.

OBJECTIVE: To investigate whether overexpression of sarcoplasmic reticulum (SR) Ca2+ ATPase 1 (SERCA1) in skeletal muscle would improve intracellular Ca2+ handling, attenuate ER stress, and improve motor function ALS transgenic mice.

METHODS: B6SJL-Tg (SOD1*G93A)1Gur/J (ALS-Tg) mice were bred with skeletal muscle α-actinin SERCA1 overexpressing mice to generate wild type (WT), SERCA1 overexpression (WT/+SERCA1), ALS-Tg, and SERCA1 overexpressing ALS-Tg (ALS-Tg/+SERCA1) mice. Motor function (grip test) was assessed weekly and skeletal muscles were harvested at 16 weeks of age to evaluate muscle mass, SR-Ca2+ ATPase activity, levels of SERCA1 and ER stress proteins - protein disulfide isomerase (PDI), Grp78/BiP, and C/EBP homologous protein (CHOP). Single muscle fibers were also isolated from the flexor digitorum brevis muscle to assess changes in resting and peak Fura-2 ratios.

RESULTS: ALS-Tg/+SERCA1 mice showed improved motor function, delayed onset of disease, and improved muscle mass compared to ALS-Tg. Further, ALS-Tg/+SERCA1 mice returned levels of SERCA1 protein and SR-Ca2+ ATPase activity back to levels in WT mice. Unexpectedly, SERCA-1 overexpression increased levels of the ER stress maker Grp78/BiP in both WT and ALS-Tg mice, while not altering protein levels of PDI or CHOP. Lastly, single muscle fibers from ALS-Tg/+SERCA1 had similar resting but lower peak Fura-2 levels (at 30 Hz and 100 Hz) compared to ALS-Tg mice.

CONCLUSIONS: These data indicate that SERCA1 overexpression attenuates the progressive loss of muscle mass and maintains motor function in ALS-Tg mice while not lowering resting Ca2+ levels or ER stress.}, } @article {pmid38218077, year = {2024}, author = {Di Lazzaro, V and Ranieri, F and Bączyk, M and de Carvalho, M and Dileone, M and Dubbioso, R and Fernandes, S and Kozak, G and Motolese, F and Ziemann, U}, title = {Novel approaches to motoneuron disease/ALS treatment using non-invasive brain and spinal stimulation: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {158}, number = {}, pages = {114-136}, doi = {10.1016/j.clinph.2023.12.012}, pmid = {38218077}, issn = {1872-8952}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; *Transcranial Direct Current Stimulation ; *Motor Neuron Disease/diagnosis/therapy ; Motor Neurons/physiology ; Brain ; Transcranial Magnetic Stimulation/methods ; }, abstract = {Non-invasive brain stimulation techniques have been exploited in motor neuron disease (MND) with multifold objectives: to support the diagnosis, to get insights in the pathophysiology of these disorders and, more recently, to slow down disease progression. In this review, we consider how neuromodulation can now be employed to treat MND, with specific attention to amyotrophic lateral sclerosis (ALS), the most common form with upper motoneuron (UMN) involvement, taking into account electrophysiological abnormalities revealed by human and animal studies that can be targeted by neuromodulation techniques. This review article encompasses repetitive transcranial magnetic stimulation methods (including low-frequency, high-frequency, and pattern stimulation paradigms), transcranial direct current stimulation as well as experimental findings with the newer approach of trans-spinal direct current stimulation. We also survey and discuss the trials that have been performed, and future perspectives.}, } @article {pmid38218579, year = {2024}, author = {Huo, D and Liang, W and Wang, D and Liu, Q and Wang, H and Wang, Y and Zhang, C and Cong, C and Su, X and Tan, X and Zhang, W and Han, L and Zhang, D and Wang, M and Feng, H}, title = {Roflupram alleviates autophagy defects and reduces mutant hSOD1-induced motor neuron damage in cell and mouse models of amyotrophic lateral sclerosis.}, journal = {Neuropharmacology}, volume = {247}, number = {}, pages = {109812}, doi = {10.1016/j.neuropharm.2023.109812}, pmid = {38218579}, issn = {1873-7064}, mesh = {Mice ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; AMP-Activated Protein Kinases/metabolism ; Superoxide Dismutase/genetics/metabolism ; Motor Neurons ; Spinal Cord/metabolism ; Mice, Transgenic ; Autophagy ; Disease Models, Animal ; *Benzene Derivatives ; *Furans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease involving motor neuron (MN) degeneration and is characterized by ongoing myasthenia and amyotrophia in adults. Most ALS patients die of respiratory muscle paralysis after an average of 3-5 years. Defective autophagy in MNs is considered an important trigger of ALS pathogenesis. Roflupram (ROF) was demonstrated to activate autophagy in microglial cells and exert protective effects against Parkinson's disease (PD) and Alzheimer's disease (AD). Therefore, our research aimed to investigate the efficacy and mechanism of ROF in treating ALS both in vivo and in vitro. We found that ROF could delay disease onset and prolong the survival of hSOD1-G93A transgenic mice. Moreover, ROF protected MNs in the anterior horn of the spinal cord, activated the AMPK/ULK1 signaling pathway, increased autophagic flow, and reduced SOD1 aggregation. In an NSC34 cell line stably transfected with hSOD1-G93A, ROF protected against cellular damage caused by hSOD1-G93A. Moreover, we have demonstrated that ROF inhibited gliosis in ALS model mice. Collectively, our study suggested that ROF is neuroprotective in ALS models and the AMPK/ULK1 signaling pathway is a potential therapeutic target in ALS, which increases autophagic flow and reduces SOD1 aggregation.}, } @article {pmid38218903, year = {2024}, author = {Lee, MH and Kang, S and Um, KH and Lee, SW and Hwang, H and Baek, K and Choi, JW}, title = {Brain-targeted delivery of neuroprotective survival gene minimizing hematopoietic cell contamination: implications for Parkinson's disease treatment.}, journal = {Journal of translational medicine}, volume = {22}, number = {1}, pages = {53}, pmid = {38218903}, issn = {1479-5876}, support = {NRF-2017R1A5A2014768//Ministry of Science and ICT, South Korea/ ; NRF-2022R1A2C2009281//Ministry of Science and ICT, South Korea/ ; NRF-2019R1A2C1006752//Ministry of Science and ICT, South Korea/ ; 21153MFDS601//Ministry of Food and Drug Safety/ ; }, mesh = {Animals ; *Parkinson Disease/genetics/therapy ; Leukocytes, Mononuclear ; Brain/metabolism ; Genetic Therapy/methods ; Transgenes ; Genetic Vectors ; Dependovirus/genetics ; }, abstract = {BACKGROUND: Neurodegenerative diseases, including Parkinson's disease, Amyotropic Lateral Sclerosis (ALS) and Alzheimer's disease, present significant challenges for therapeutic development due to drug delivery restrictions and toxicity concerns. Prevailing strategies often employ adeno-associated viral (AAV) vectors to deliver neuroprotective survival genes directly into the central nervous system (CNS). However, these methods have been limited by triggering immunogenic responses and risk of tumorigenicity, resulting from overexpression of survival genes in peripheral blood mononuclear cells (PBMC), thereby increasing the risk of tumorigenicity in specific immune cells. Thus, by coding selectively suppressive microRNA (miRNA) target sequences in AAV genome, we designed CNS-targeted neuroprotective gene expression vector system without leakage to blood cells.

METHODS: To minimize the potential for transgene contamination in the blood, we designed a CNS-specific AAV system. Our system utilized a self-complementary AAV (scAAV), encoding a quadruple repeated target sequence of the hematopoietic cell-specific miR142-3p at the 3' untranslated region (UTR). As a representative therapeutic survival gene for Parkinson's disease treatment, we integrated DX2, an antagonistic splice variant of the apoptotic gene AIMP2, known to be implicated in Parkinson's disease, into the vector.

RESULTS: This configuration ensured that transgene expression was stringently localized to the CNS, even if the vector found its way into the blood cells. A single injection of scAAV-DX2 demonstrated marked improvement in behavior and motor activity in animal models of Parkinson's disease induced by either Rotenone or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Importantly, comprehensive preclinical data adhering to Good Laboratory Practice (GLP) standards revealed no adverse effects in the treated animals.

CONCLUSIONS: Our CNS-specific vector system, which encodes a survival transgene DX2, signifies a promising avenue for safe gene therapy, avoiding unintended expression of survival gene in blood cells, applicable to various neurodegenerative diseases.}, } @article {pmid38220221, year = {2024}, author = {Castro, J and Oliveira Santos, M and Swash, M and de Carvalho, M}, title = {Segmental motor neuron dysfunction in amyotrophic lateral sclerosis: Insights from H reflex paradigms.}, journal = {Muscle & nerve}, volume = {69}, number = {3}, pages = {303-312}, doi = {10.1002/mus.28035}, pmid = {38220221}, issn = {1097-4598}, support = {//Biogen/ ; }, mesh = {Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis ; H-Reflex/physiology ; Motor Neurons/physiology ; Muscle, Skeletal ; Spine ; }, abstract = {INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS), the role of spinal interneurons in ALS is underrecognized. We aimed to investigate pre- and post-synaptic modulation of spinal motor neuron excitability by studying the H reflex, to understand spinal interneuron function in ALS.

METHODS: We evaluated the soleus H reflex, and three different modulation paradigms, to study segmental spinal inhibitory mechanisms. Homonymous recurrent inhibition (H'RI) was assessed using the paired H reflex technique. Presynaptic inhibition of Ia afferents (H'Pre) was evaluated using D1 inhibition after stimulation of the common peroneal nerve. We also studied inhibition of the H reflex after cutaneous stimulation of the sural nerve (H'Pos).

RESULTS: Fifteen ALS patients (median age 57.0 years), with minimal signs of lower motor neuron involvement and good functional status, and a control group of 10 healthy people (median age 57.0 years) were studied. ALS patients showed reduced inhibition, compared to controls, in all paradigms (H'RI 0.35 vs. 0.11, p = .036; H'Pre 1.0 vs. 5.0, p = .001; H'Pos 0.0 vs. 2.5, p = .031). The clinical UMN score was a significant predictor of the amount of recurrent and presynaptic inhibition.

DISCUSSION: Spinal inhibitory mechanisms are impaired in ALS. We argue that hyperreflexia could be associated with dysfunction of spinal inhibitory interneurons. In this case, an interneuronopathy could be deemed a major feature of ALS.}, } @article {pmid38220307, year = {2024}, author = {Carabajal, MD and Bortolato, SA and Lisandrini, FT and Olivieri, AC}, title = {An exhaustive analysis of the use of image moments for second-order calibration. A comparison with multivariate curve resolution-alternating least-squares.}, journal = {Analytica chimica acta}, volume = {1288}, number = {}, pages = {342177}, doi = {10.1016/j.aca.2023.342177}, pmid = {38220307}, issn = {1873-4324}, abstract = {BACKGROUND: the chemometric processing of second-order chromatographic-spectral data is usually carried out with the aid of multivariate curve resolution-alternating least-squares (MCR-ALS). Recently, an alternative procedure was described based on the estimation of image moments for each data matrix and subsequent application of multiple linear regression after suitable variable selection.

RESULTS: The analysis of both simulated and experimental data leads to the conclusion that the image moment method, although can cope with chromatographic lack of reproducibility across injections, it only performs well in the absence of uncalibrated interferents. MCR-ALS, on the other hand, provides good analytical results in all studied situations, whether the test samples contain uncalibrated interferents or not.

SIGNIFICANCE: The results are useful to assess the real usefulness of newly proposed methodologies for second-order calibration in the case of chromatographic-spectral data sets, especially when samples contain unexpected chemical constituents.}, } @article {pmid38220456, year = {2024}, author = {Li, Y and Guo, Y and Xia, CX and Meng, XY and Wang, X and Xu, T and Zhong, Y and Wang, F}, title = {[Echocardiographic two-dimensional strain evaluation of right ventricular function in healthy adults].}, journal = {Zhonghua xin xue guan bing za zhi}, volume = {52}, number = {1}, pages = {58-63}, doi = {10.3760/cma.j.cn112148-20231019-00348}, pmid = {38220456}, issn = {0253-3758}, support = {2020YFC2002700//National Key R & D Program/ ; BJ-2019-133//Scientific Research Project of Beijing Hospital/ ; }, mesh = {Adult ; Female ; Humans ; Male ; Cross-Sectional Studies ; *Echocardiography/methods ; Heart Ventricles/diagnostic imaging ; *Ventricular Dysfunction, Right/diagnosis ; Ventricular Function, Right ; Feasibility Studies ; }, abstract = {Objective: To explore the feasibility of using two-dimensional speckle tracking echocardiography for measuring right ventricular strain and function in healthy adults, and to analyze the impact of age and gender. Methods: This study is a cross-sectional study. Healthy adults who underwent physical examination in the Physical Examination Center of Beijing Hospital from January 1, 2020 to January 1, 2021 were included. Two researchers independently measured various right ventricular longitudinal strain indices using the Echopac software, including (global longitudinal strain (GLS), apical longitudinal strain (ALS), midventricle longitudinal strain (MLS), basal longitudinal strain (BLS), free wall GLS (FWGLS), free wall ALS (FWALS), free wall MLS (FWMLS) and free wall BLS (FWBLS)) as well as tricuspid annular plane systolic excursion (TAPSE) and right ventricle-fraction of area change (RVFAC). The above indicators were taken as the average of two physicians. The consistency of the measurements by two physicians was evaluated by the within-group correlation coefficient (ICC). Results: A total of 233 subjects were included, including 137 males, aged (58.5±14.2) years. ICC values was all above 0.8 with excellent agreement. The values of FWGLS and GLS in healthy adults were -26.63% and -21.89%, respectively. There was no statistically significant difference in TAPSE ((2.06±0.41)cm vs. (2.10±0.39)cm, P=0.510) and RVFAC ((51.17±9.91)% vs. (50.89±8.65)%, P=0.826) between males and females. The values of various right ventricular long axis strain indicators (GLS, ALS, MLS, BLS, FWGLS, FWMLS, FWMLS, FWBLS) in females aged 18 to 40 and 41 to 65 years were higher than those in males of the same age (all P<0.05), while there was no statistically significant difference in the values of various right ventricular long axis strain indicators between the sexes in subjects aged 65 years and above (all P>0.05). In females, the right ventricular GLS, ALS, MLS, FWGLS, FWALS, FWMLS, and FWBLS values in the groups aged 18 to 40 and 41 to 65 years were significantly higher than those in the group aged 65 years and above (all P<0.05). In contrast, no significant differences were found in these indices among different age groups in males (all P>0.05). Conclusions: Using two-dimensional speckle tracking technology in echocardiography to measure right ventricular strain indicators is feasible and highly reproducible. Gender and age have an impact on right ventricular strain indicators.}, } @article {pmid38220602, year = {2023}, author = {Seow-Choen, F and Ng, PKL}, title = {On the correct lectotype for Marmessoidea unicolor Redtenbacher, 1908 (Insecta: Phasmatodea).}, journal = {Zootaxa}, volume = {5360}, number = {3}, pages = {448-450}, doi = {10.11646/zootaxa.5360.3.8}, pmid = {38220602}, issn = {1175-5334}, mesh = {Animals ; *Insecta ; *Neoptera ; }, abstract = {Hennemann, F.H., Conle, O.V. & Brock, P.D. (2023) The types of Phasmatodea (= Phasmida) deposited in the Eidgenssisches Technisches Hochschulzentrum, Zrich, Switzerland (ETHZ). Zootaxa, 5278 (1), 176188. https://doi.org/10.11646/zootaxa.5278.1.10 Hovinga, H. (2010) The Sumatra Railroad: Final destination Pakan Baroe, 19431945. Brill, Leiden, 391 pp. https://doi.org/10.1163/9789004253711 ICZN [International Commission on Zoological Nomenclature] (1999) International Code of Zoological Nomenclature. International Commission of Zoological Nomenclature. 4th Edition. Adopted by the XXI General Assembly of the International Union of Biological Sciences. International Trust for Zoological Nomenclature, in association with the British Museum (Natural History), London, 338 pp. Redtenbacher, J. (1908) Die Insektenfamilie der Phasmiden. III. Phasmidae Anareolatae (Phibalosomini, Acrophyllini, Necrosciini). Wilhelm Engelmann, Leipzig, pp. 341589, pls. 1627. Seow-Choen, F. (2021) A Taxonomic Guide to Stick Insects of Peninsular Malaysia. Vol. 1. Natural History Publications, Borneo, Kota Kinabalu, 944 pp. Weidmann, W. (1936) Der Schweizer als Pionier und Kolonist in Sumatra. In: Der Schweizer Verein Deli-Sumatra (Ed.), Der Schweizer Verein Deli-Sumatra: Zum fnfzigjhrigen Bestehen, 18861936. Buchdruckerei der Neuen Zrcher Zeitung, Zrich, pp. 3348.}, } @article {pmid38222431, year = {2023}, author = {Turabieh, H and Afshar, AS and Statland, J and Song, X and , }, title = {Towards a Machine Learning Empowered Prognostic Model for Predicting Disease Progression for Amyotrophic Lateral Sclerosis.}, journal = {AMIA ... Annual Symposium proceedings. AMIA Symposium}, volume = {2023}, number = {}, pages = {718-725}, pmid = {38222431}, issn = {1942-597X}, mesh = {Humans ; Prognosis ; *Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; Algorithms ; Machine Learning ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disorder that is highly heterogeneous and invariably fatal. Due to the unpredictable nature of its progression, accurate tools and algorithms are needed to predict disease progression and improve patient care. To address this need, we developed and compared an extensive set of screener-learner machine learning models to accurately predict the ALS Function-Rating-Scale (ALSFRS) score reduction between 3 and 12 months, by paring 5 state-of-arts feature selection algorithms with 17 predictive models and 4 ensemble models using the publicly available Pooled Open Access Clinical Trials Database (PRO-ACT). Our experiment showed promising results with the blender-type ensemble model achieving the best prediction accuracy and highest prognostic potential.}, } @article {pmid38223824, year = {2024}, author = {Lee, MY and Kim, M}, title = {Effects of Red ginseng on neuroinflammation in neurodegenerative diseases.}, journal = {Journal of ginseng research}, volume = {48}, number = {1}, pages = {20-30}, pmid = {38223824}, issn = {1226-8453}, abstract = {Red ginseng (RG) is widely used as a herbal medicine. As the human lifespan has increased, numerous diseases have developed, and RG has also been used to treat various diseases. Neurodegenerative diseases are major problems that modern people face through their lives. Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are featured by progressive nerve system damage. Recently, neuroinflammation has emerged as a degenerative factor and is an immune response in which cytokines with nerve cells that constitute the nervous system. RG, a natural herbal medicine with fewer side effects than chemically synthesized drugs, is currently in the spotlight. Therefore, we reviewed studies reporting the roles of RG in treating neuroinflammation and neurodegenerative diseases and found that RG might help alleviate neurodegenerative diseases by regulating neuroinflammation.}, } @article {pmid38224498, year = {2024}, author = {Urban, MW and Charsar, BA and Heinsinger, NM and Markandaiah, SS and Sprimont, L and Zhou, W and Brown, EV and Henderson, NT and Thomas, SJ and Ghosh, B and Cain, RE and Trotti, D and Pasinelli, P and Wright, MC and Dalva, MB and Lepore, AC}, title = {EphrinB2 knockdown in cervical spinal cord preserves diaphragm innervation in a mutant SOD1 mouse model of ALS.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38224498}, issn = {2050-084X}, support = {R01 NS079702/NS/NINDS NIH HHS/United States ; R01 NS110385/NS/NINDS NIH HHS/United States ; R01NS109150/NS/NINDS NIH HHS/United States ; R21 NS090912/NS/NINDS NIH HHS/United States ; T32 GM144302/GM/NIGMS NIH HHS/United States ; R01 NS109150/NS/NINDS NIH HHS/United States ; R01NS110385/NS/NINDS NIH HHS/United States ; R01NS079702/NS/NINDS NIH HHS/United States ; RF1AG057882/NS/NINDS NIH HHS/United States ; R21NS090912/NS/NINDS NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; Astrocytes/metabolism ; *Cervical Cord/metabolism/pathology ; Diaphragm/innervation ; Disease Models, Animal ; *Ephrin-B2/genetics ; Mice, Transgenic ; *Neurodegenerative Diseases/pathology ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss. Importantly, non-neuronal cell types such as astrocytes also play significant roles in disease pathogenesis. However, mechanisms of astrocyte contribution to ALS remain incompletely understood. Astrocyte involvement suggests that transcellular signaling may play a role in disease. We examined contribution of transmembrane signaling molecule ephrinB2 to ALS pathogenesis, in particular its role in driving motor neuron damage by spinal cord astrocytes. In symptomatic SOD1[G93A] mice (a well-established ALS model), ephrinB2 expression was dramatically increased in ventral horn astrocytes. Reducing ephrinB2 in the cervical spinal cord ventral horn via viral-mediated shRNA delivery reduced motor neuron loss and preserved respiratory function by maintaining phrenic motor neuron innervation of diaphragm. EphrinB2 expression was also elevated in human ALS spinal cord. These findings implicate ephrinB2 upregulation as both a transcellular signaling mechanism in mutant SOD1-associated ALS and a promising therapeutic target.}, } @article {pmid38225062, year = {2024}, author = {Xu, X and Zhao, B and Li, B and Shen, B and Qi, Z and Wang, J and Cui, H and Chen, S and Wang, G and Liu, X}, title = {Trp-574-Leu mutation and metabolic resistance by cytochrome P450 gene conferred high resistance to ALS-inhibiting herbicides in Descurainia sophia.}, journal = {Pesticide biochemistry and physiology}, volume = {198}, number = {}, pages = {105708}, doi = {10.1016/j.pestbp.2023.105708}, pmid = {38225062}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/antagonists & inhibitors/metabolism ; *Arylsulfonates ; *Brassicaceae/drug effects/genetics ; Cytochrome P-450 Enzyme System/genetics ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Mutation ; }, abstract = {Descurainia sophia (flixweed) is a troublesome weed in winter wheat fields in North China. Resistant D. sophia populations with different acetolactate synthetase (ALS) mutations have been reported in recent years. In addition, metabolic resistance to ALS-inhibiting herbicides has also been identified. In this study, we collected and purified two resistant D. sophia populations (R1 and R2), which were collected from winter wheat fields where tribenuron-methyl provided no control of D. sophia at 30 g a.i. ha[-1]. Whole plant bioassay and ALS activity assay results showed the R1 and R2 populations had evolved high-level resistance to tribenuron-methyl and florasulam and cross-resistance to imazethapyr and pyrithiobac‑sodium. The two ALS genes were cloned from the leaves of R1 and R2 populations, ALS1 (2004 bp) and ALS2 (1998 bp). A mutation of Trp 574 to Leu in ALS1 was present in both R1 and R2. ALS1 and ALS2 were cloned from R1 and R2 populations respectively and transferred into Arabidopsis thaliana. Homozygous T3 transgenic seedlings with ALS1 of R1 or R2 were resistant to ALS-inhibiting herbicides and the resistant levels were the same. Transgenic seedlings with ALS2 from R1 or R2 were susceptible to ALS-inhibiting herbicides. Treatment with cytochrome P450 inhibitor malathion decreased the resistant levels to tribenuron-methyl in R1 and R2. RNA-Seq was used to identify target cytochrome P450 genes possibly involved in resistance to ALS-inhibiting herbicides. There were five up-regulated differentially expressed cytochrome P450 genes: CYP72A15, CYP83B1, CYP81D8, CYP72A13 and CYP71A12. Among of them, CYP72A15 had the highest expression level in R1 and R2 populations. The R1 and R2 populations of D. sophia have evolved resistance to ALS-inhibiting herbicides due to Trp 574 Leu mutation in ALS1 and possibly other mechanisms. The resistant function of CYP72A15 needs further research.}, } @article {pmid38225088, year = {2024}, author = {Ohta, K and Sada, Y}, title = {Inheritance and stacking effect of mutant ALS genes in Schoenoplectiella juncoides (Roxb.) Lye (Cyperaceae).}, journal = {Pesticide biochemistry and physiology}, volume = {198}, number = {}, pages = {105745}, doi = {10.1016/j.pestbp.2023.105745}, pmid = {38225088}, issn = {1095-9939}, mesh = {*Lye/pharmacology ; *Cyperaceae/genetics ; *Herbicides/pharmacology ; Mutation ; Alleles ; Herbicide Resistance/genetics ; *Acetolactate Synthase/genetics ; }, abstract = {Schoenoplectiella juncoides, a noxious sedge weed in Japanese rice paddy, has two ALS genes, and ALS-inhibitor-resistant plants have a mutation in one of the ALS genes. The authors aimed (a) to quantitate the effect of the number of mutant alleles of ALS genes on whole-plant resistance of S. juncoides and (b) to clarify a mode of inheritance of the resistance by investigating resistance levels of the progenies of a hybrid between two S. juncoides plants with Trp574Leu substitution in different ALS. A dose-response analysis on the parental lines and the F1 population suggested that the two ALS genes contribute equally to whole-plant resistant levels. A dose-response study on the F2 population indicated that it could be classified into five groups based on the sensitivities to metsulfuron-methyl. The five groups (in ascending order of resistance levels) were considered to have zero, one, two, three, and four mutant alleles. The stacking effect of mutant alleles on resistance enhancement was more significant when the number of mutant alleles was low than when it was high; in other words, each additional mutant allele stacking increases plant resistance, but the effect saturates as the number of mutant alleles increases. A chi-square test supported that the segregation ratio of the five groups corresponds to 1:4:6:4:1 of Mendelian independence for the two ALS loci.}, } @article {pmid38225089, year = {2024}, author = {Unan, R and Azapoglu, O and Deligoz, İ and Mennan, H and Al-Khatib, K}, title = {Gene flow and spontaneous mutations are responsible for imidazolinone herbicide-resistant weedy rice (Oryza sativa L.).}, journal = {Pesticide biochemistry and physiology}, volume = {198}, number = {}, pages = {105746}, doi = {10.1016/j.pestbp.2023.105746}, pmid = {38225089}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology ; *Oryza/genetics ; Gene Flow ; Plant Weeds/genetics ; Herbicide Resistance/genetics ; Mutation ; }, abstract = {For more than two decades, weedy rice (Oryza sativa L.) has been controlled in rice fields by using imidazolinone (IMI) herbicide-resistant rice technology (Clearfield®). Outcrossing in weedy rice populations and spontaneous mutations are potential problems with herbicide-resistant crop management technologies, such as the IMI-resistant rice. The aim of this study was to characterize the mechanism of IMI herbicide resistance in weedy rice through dose-response bioassay study and evaluating amino acid substitutions in acetolactate synthase (ALS) protein. A total of 118 suspected IMI-resistant weedy rice samples, which survived in the field after an IMI herbicide application, were collected at harvest time from Türkiye in 2020 and 2021. Single-dose imazamox application experiment revealed that 38 plants survived herbicide treatment. The imazamox resistance of the surviving plants was confirmed by dose-response experiment. ALS gene region underwent a sanger DNA partial sequencing. No substitution was found in 10 samples, however, amino acid substitutions were found in 26 samples with S563N, one sample with S653T, and one sample with E630D. The S653N point is the same substitution point that serves as the origin of resistance for the Clearfield® rice varieties that are commonly cultivated in the region. It has been hypothesized that the gene flow from IMI-resistant rice may be the cause of resistance in the IMI resistant weedy rice samples with S653N. The other substitution, S653T, were considered spontaneous mutation to IMI resistance. Interestingly, the S653T mutation was detected for the first time in weedy rice. The mechanism of resistance of 10 resistant weedy rice was not confirmed in this study, however, it may be a non-target resistance or another mutation point in target site, but evidently, they did not acquire resistance by gene flow from IMI-resistant rice. It has been concluded that the effectiveness of IMI-resistant rice technology in controlling weedy rice has drastically decreased due to possible gene flow, spontaneous mutation and non-target resistance. In addition to cultural controls like clean seed, clean machinery and crop rotation, other herbicide-tolerant rice systems such as Provisia® and Roxy-RPS® rice are needed to create a diverse weedy rice management ensemble available for rice production and move towards sustainable rice farming.}, } @article {pmid38226024, year = {2024}, author = {de Jongh, CA and Bikker, FJ and de Vries, TJ and Werner, A and Gibbs, S and Krom, BP}, title = {Porphyromonas gingivalis interaction with Candida albicans allows for aerobic escape, virulence and adherence.}, journal = {Biofilm}, volume = {7}, number = {}, pages = {100172}, pmid = {38226024}, issn = {2590-2075}, abstract = {In the oral cavity Candida albicans interacts with many oral bacteria, including Porphyromonas gingivalis, both physically and metabolically. The aim of this in vitro study was to characterize these interactions and study their effects on the survival of P. gingivalis. First, metabolic interactions were evaluated by counting the colony forming units (CFU) after co-culturing. The results indicated that the anaerobic bacterium P. gingivalis survives under aerobic conditions when co-cultured with C. albicans. This is due to the oxygen consumption by C. albicans as determined by a reduction in survival upon the addition of Antimycin A. By measuring the protease activity, it was found that the presence of C. albicans induced gingipain activity by P. gingivalis, which is an important virulence factor. Adherence of P. gingivalis to hyphae of C. albicans was observed with a dynamic flow system. Using various C. albicans mutants, it was shown that the mechanism of adhesion was mediated by the cell wall adhesins, members of the agglutinin-like sequence (Als) family: Als3 and Als1. Furthermore, the two microorganisms could be co-cultured into forming a biofilm in which P. gingivalis can survive under aerobic culturing conditions, which was imaged using scanning electron microscopy. This study has further elucidated mechanisms of interaction, virulence acquisition and survival of P. gingivalis when co-cultured with C. albicans. Such survival could be essential for the pathogenicity of P. gingivalis in the oxygen-rich niches of the oral cavity. This study has emphasized the importance of interaction between different microbes in promoting survival, virulence and attachment of pathogens, which could be essential in facilitating penetration into the environment of the host.}, } @article {pmid38226086, year = {2023}, author = {AlMadan, N and AlMajed, A and AlAbbad, M and AlNashmi, F and Aleissa, A}, title = {Dental Management of Patients With Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e50602}, pmid = {38226086}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons with upper and lower motor neuron manifestations. It is divided into two variants: a spinal onset and a bulbar onset. The first starts as focal muscle weakness and wasting that spreads with disease progression, while the second phenotype presents with dysarthria, dysphonia, and dysphagia. Moreover, an extra-motor manifestation could be reported with the most commonly reported symptoms being the change in cognition and sleep disorder. Oral manifestations include increased salivation, limited mouth opening, and dysphagia. Patients with ALS have difficulty maintaining oral hygiene, and it is important for the practitioner and the caregiver to take care of this group of population. We herein provide a short review of the disease with a focus on the oral manifestations and dental considerations for management for this group.}, } @article {pmid38226245, year = {2024}, author = {Sharma, S and Mehan, S and Khan, Z and Gupta, GD and Narula, AS}, title = {Icariin prevents methylmercury-induced experimental neurotoxicity: Evidence from cerebrospinal fluid, blood plasma, brain samples, and in-silico investigations.}, journal = {Heliyon}, volume = {10}, number = {1}, pages = {e24050}, pmid = {38226245}, issn = {2405-8440}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that causes significant neurodegeneration. Methylmercury (MeHg+) is a neurotoxin that induces axonal neurodegeneration and motor nerve degeneration by destroying oligodendrocytes, degenerating white matter, inducing apoptosis, excitotoxicity, and reducing myelin basic protein (MBP). This study examines the inhibition of SIRT-1 (silence information regulator 1), Nrf-2 (nuclear factor E2-related factor 2), HO-1 (heme oxygenase 1), and TDP-43 (TAR-DNA-binding protein 43) accumulation in the context of ALS, as well as the modulation of these proteins by icariin (15 and 30 mg/kg, orally), a glycoside flavonoid with neuroprotective properties. Neuroprotective icariin activates SIRT-1, Nrf-2, and HO-1, mitigating inflammation and neuronal injury in neurodegenerative disorders. In-vivo and in-silico testing of experimental ALS models confirmed icariin efficacy in modulating these cellular targets. The addition of sirtinol 10 mg/kg, an inhibitor of SIRT-1, helps determine the effectiveness of icariin. In this study, we also examined neurobehavioral, neurochemical, histopathological, and LFB (Luxol fast blue) markers in various biological samples, including Cerebrospinal fluid (CSF), blood plasma, and brain homogenates (Cerebral Cortex, Hippocampus, Striatum, mid-brain, and Cerebellum). These results demonstrate that the administration of icariin ameliorates experimental ALS and that the mechanism underlying these benefits is likely related to regulating the SIRT-1, Nrf-2, and HO-1 signaling pathways.}, } @article {pmid38226616, year = {2024}, author = {Otani, R and Shibuya, K and Shimizu, T and Kitaoji, T and Noto, YI and Bokuda, K and Kimura, H and Suichi, T and Nakamura, K and Kano, H and Morooka, M and Aotsuka, Y and Ogushi, M and Misawa, S and Kuwabara, S}, title = {Diagnostic utility of Gold Coast criteria for amyotrophic lateral sclerosis in Asia.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {264-270}, doi = {10.1080/21678421.2024.2303062}, pmid = {38226616}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Asia ; Electromyography ; Sensitivity and Specificity ; }, abstract = {Objective: This study aimed to reveal the diagnostic utility of Gold Coast (GC) criteria in Japanese patients with amyotrophic lateral sclerosis (ALS) by comparing the sensitivity/specificity with revised El Escorial (R-EE) and Awaji criteria, because its utility has not been studied in Asian ALS. Methods: Consecutive 639 patients (529 with ALS and 110 with ALS mimics), who were suspected of ALS and referred to three Japanese ALS centers, were enrolled. Diagnostic accuracy and characteristics of false positive and negative in GC criteria were compared with those of the Awaji and R-EE criteria. Patients were categorized as definite, probable or possible ALS according to each criterion. Results: The sensitivity of GC criteria (96.8%, 95% confidence interval [CI]: 95.3-98.3%) was higher than that of Awaji (89.6%, 95% CI: 87.0-92.2%) and R-EEC (89.2, 95% CI: 86.6-91.8%) criteria (both, p < 0.001). The specificity was also higher with GC criteria (77.3%, 95% CI: 69.5-85.1%) than Awaji (65.5%, 95% CI: 56.6-74.4%) and R-EEC (66.4, 95% CI: 57.6-75.2%) criteria (both, p < 0.01). Using GC criteria, patients with cervical spondylosis and Parkinson's syndrome tended to be diagnosed with ALS (i.e. "false positive"). Additionally, ALS patients diagnosed only by GC criteria less frequently had upper motor neuron (UMN) signs, compared with the other two criteria. Conclusion: Gold Coast criteria improve diagnostic accuracy for ALS in an Asian population, especially in patients with subtle UMN signs.}, } @article {pmid38227505, year = {2024}, author = {Goswami, A and Carra, S}, title = {PML nuclear bodies: new players in familial amyotrophic lateral sclerosis-frontotemporal dementia?.}, journal = {Neural regeneration research}, volume = {19}, number = {9}, pages = {1875-1876}, pmid = {38227505}, issn = {1673-5374}, } @article {pmid38227807, year = {2024}, author = {Carbayo, Á and Borrego-Écija, S and Turon-Sans, J and Cortés-Vicente, E and Molina-Porcel, L and Gascón-Bayarri, J and Rubio, MÁ and Povedano, M and Gámez, J and Sotoca, J and Juntas-Morales, R and Almendrote, M and Marquié, M and Sánchez-Valle, R and Illán-Gala, I and Dols-Icardo, O and Rubio-Guerra, S and Bernal, S and Caballero-Ávila, M and Vesperinas, A and Gelpi, E and Rojas-García, R}, title = {Clinicopathological correlates in the frontotemporal lobar degeneration-motor neuron disease spectrum.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {7}, pages = {2357-2367}, pmid = {38227807}, issn = {1460-2156}, support = {CM21/00057//Río Hortega Contract/ ; //Instituto de Salud Carlos III/ ; //Atlantic Fellow for Equity in Brain Health/ ; //Global Brain Health Institute/ ; /ALZ/Alzheimer's Association/United States ; ALZ UK-21-720973/ALZS_/Alzheimer's Society/United Kingdom ; JR20/0018//Juan Rodés Contract/ ; JR19/00037//Juan Rodés Contract/ ; }, mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; *Frontotemporal Lobar Degeneration/pathology/genetics ; Retrospective Studies ; *Motor Neuron Disease/pathology/genetics ; Amyotrophic Lateral Sclerosis/pathology/genetics ; Frontotemporal Dementia/pathology/genetics ; Brain/pathology ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10%-15% of cases. In the absence of a precise biomarker, neuropathology is still a valuable tool to understand disease nosology, reach a definite diagnostic confirmation and help define specific subgroups of patients with common phenotypic, genetic and biomarker profiles. However, few neuropathological series have been published, and the frequency of frontotemporal lobar degeneration (FTLD) in MND is difficult to estimate. In this work we describe a large clinicopathological series of MND patients, analysing the frequency of concurrent FTLD changes and trying to define specific subgroups of patients based on their clinical, genetic and pathological characteristics. We performed an observational, retrospective, multicentre case study. We included all cases meeting neuropathological criteria for MND from the Neurological Tissue Bank of the FRCB-IDIBAPS-Hospital Clínic Barcelona Biobank between 1994 and 2022, regardless of their last clinical diagnosis. While brain donation is encouraged in all patients, it is performed in very few, and representativeness of the cohort might not be precise for all patients with MND. We retrospectively reviewed clinical and neuropathological data and describe the main clinical, genetic and pathogenic features, comparing neuropathologic groups between MND with and without FTLD changes and aiming to define specific subgroups. We included brain samples from 124 patients, 44 of whom (35.5%) had FTLD neuropathologic features (i.e. FTLD-MND). Pathologic TDP-43 aggregates were present in 93.6% of the cohort and were more extensive (higher Brettschneider stage) in those with concurrent FTLD (P < 0.001). Motor symptom onset was more frequent in the bulbar region in FTLD-MND cases than in those with isolated MND (P = 0.023), with no differences in survival. We observed a better clinicopathological correlation in the MND group than in the FTLD-MND group (93.8% versus 61.4%; P < 0.001). Pathogenic genetic variants were more common in the FTLD-MND group, especially C9orf72. We describe a frequency of FTLD of 35.5% in our series of neuropathologically confirmed cases of MND. The FTLD-MND spectrum is highly heterogeneous in all aspects, especially in patients with FTLD, in whom it is particularly difficult to define specific subgroups. In the absence of definite biomarkers, neuropathology remains a valuable tool for a definite diagnosis, increasing our knowledge in disease nosology.}, } @article {pmid38229194, year = {2024}, author = {Jadhav, PA and Hole, A and Ingle, A and Govekar, R and Noothalapati, H and Krishna, CM}, title = {Serum Raman spectroscopy: Evaluation of tumour load variations in experimental carcinogenesis.}, journal = {Journal of biophotonics}, volume = {17}, number = {4}, pages = {e202300424}, doi = {10.1002/jbio.202300424}, pmid = {38229194}, issn = {1864-0648}, mesh = {Animals ; Cricetinae ; Humans ; *Spectrum Analysis, Raman/methods ; Tumor Burden ; Multivariate Analysis ; Discriminant Analysis ; *Cell Transformation, Neoplastic ; Least-Squares Analysis ; }, abstract = {Several serum Raman spectroscopy (RS) studies have demonstrated its potential as an oral cancer screening tool. This study investigates influence of low tumour load (LTL) and high tumour load (HTL) on serum RS using hamster buccal pouch model of experimental oral carcinogenesis. Sera of untreated control, LTL, and HTL groups at week intervals during malignant transformation were employed. Serum Raman spectra were subjected to multivariate analyses-principal component analysis, principal component-based linear discriminant analysis (for stratification of study groups), and multivariate curve resolution-alternating least squares (MCR-ALS) (to comprehend biomolecular differences). Multivariate analysis revealed misclassifications between LTL and HTL at all week intervals. MCR-ALS components showed statistically significant abundances between control versus LTL and control versus HTL, but could not discern LTL and HTL. MCR-ALS components exhibited spectral mixtures of proteins, lipids, heme and nucleic acids. Thus, these findings support use of serum RS as a screening tool as varying tumour load is not a confounding factor influencing the technique.}, } @article {pmid38229533, year = {2024}, author = {Feng, Y and Xu, Z and Jin, H and Chen, Y and Fu, C and Zhang, Y and Yin, Y and Wang, H and Cheng, W}, title = {Metformin ameliorates mitochondrial damage induced by C9orf72 poly(GR) via upregulating AKT phosphorylation.}, journal = {Journal of cellular biochemistry}, volume = {125}, number = {3}, pages = {e30526}, doi = {10.1002/jcb.30526}, pmid = {38229533}, issn = {1097-4644}, support = {23ZR1441200//Natural Science Foundation of Shanghai/ ; 20QA1406300//Shanghai Rising-Star Program/ ; 81901162//National Natural Science Foundation of China/ ; 81974270//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Frontotemporal Dementia/drug therapy/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Phosphorylation ; Dipeptides ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with no effective cure. GGGGCC repeat expansion in C9orf72 is the most common genetic cause of both ALS and FTD. A key pathological feature of C9orf72 related ALS/FTD is the presence of abnormal dipeptide repeat proteins translated from GGGGCC repeat expansion, including poly Glycine-Arginine (GR). In this study, we observed that (GR)50 conferred significant mitochondria damage and cytotoxicity. Metformin, the most widely used clinical drug, successfully relieved (GR)50 induced mitochondrial damage and inhibited (GR)50 related cytotoxicity. Further research revealed metformin effectively restored mitochondrial function by upregulating AKT phosphorylation in (GR)50 expressed cells. Taken together, our results indicated restoring mitochondrial function with metformin may be a rational therapeutic strategy to reduce poly(GR) toxicity in C9orf72 ALS/FTD patients.}, } @article {pmid38229740, year = {2024}, author = {Rosse, G}, title = {Novel Pyrazolopyridine Inhibitors of Monoacylglycerol Lipase for the Treatment of Neurodegenerative Diseases and Neuroinflammation.}, journal = {ACS medicinal chemistry letters}, volume = {15}, number = {1}, pages = {19-20}, pmid = {38229740}, issn = {1948-5875}, abstract = {This work highlights the use of bicyclic heterocyclic compounds as monoacylglycerol lipase inhibitors potentially in the treatment of Alzheimer's disease, Parkinson's disease, ALS, traumatic brain injury, and multiple sclerosis.}, } @article {pmid38233111, year = {2025}, author = {Kunji Koya, R and Branston, JR and Gallagher, AWA and Bui, WKT and Ross, H and Mohamed Nor, N}, title = {Improving estimates of the illicit cigarette trade through collaboration: lessons from two studies of Malaysia.}, journal = {Tobacco control}, volume = {34}, number = {2}, pages = {242-247}, pmid = {38233111}, issn = {1468-3318}, mesh = {Malaysia ; *Tobacco Products/economics/statistics & numerical data ; Humans ; *Commerce/statistics & numerical data/economics ; *Taxes/statistics & numerical data ; *Crime/statistics & numerical data ; Cooperative Behavior ; }, abstract = {This paper critically analyses contrasting estimates of Malaysia's illicit cigarette trade in 2011, 2015 and 2019 by Bui et al and Koya et al who previously produced independent estimates at about the same time using tax gap analysis. Collaboration between the two authors' teams emerged due to the discrepancies in their results, generating this paper to explore the methodological issues identified and hence produce revised estimates of the rate of illicit. Key issues identified were: Bui et al's assessment of legally imported cigarettes impacting all years; their exclusion of ad valorem duty affecting the 2011 and 2015 estimates; Koya et al overlooked the value of cigarettes for export market in their ad valorem calculation and used the sales value of imported tobacco/tobacco products, not just cigarettes, both of which impact estimates for 2011 and 2015. Recalculations using Koya et al's consumption data reveal that in 2019, illicit cigarettes accounted for about 70% of the market, which is higher than Bui et al's estimate (38%) but slightly lower than Koya et al's (72%). For 2011 and 2015 where ad valorem applied, the corrected estimates show a share of the illicit cigarette market of approximately 41.1% and 52.7%, respectively, differing from Bui et al's 0% in 2011 and 29.6% in 2015, and Koya et al's 51% in 2011 and 55% in 2015. This paper provides essential lessons for addressing methodological issues between authors' teams and updated estimates of Malaysia's illicit cigarette trade, verifying that Malaysia faces a substantial illicit cigarette trade problem.}, } @article {pmid38234062, year = {2024}, author = {Stanziano, M and Fedeli, D and Manera, U and Ferraro, S and Medina Carrion, JP and Palermo, S and Sciortino, P and Cogoni, M and Agosta, F and Basaia, S and Filippi, M and Grisoli, M and Valentini, MC and De Mattei, F and Canosa, A and Calvo, A and Bruzzone, MG and Chiò, A and Nigri, A and Moglia, C}, title = {Resting-state fMRI functional connectome of C9orf72 mutation status.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {3}, pages = {686-697}, pmid = {38234062}, issn = {2328-9503}, support = {GR-2019-12371291//Italian Ministry of Health/ ; RF-2016-02362405//Italian Ministry of Health/ ; RRC//Italian Ministry of Health/ ; //Ministero della Salute/ ; //Ricerca Sanitaria Finalizzata/ ; //Giovani ricercatori/ ; 259867//European Commission's Health Seventh Framework Programme/ ; //Italian Ministry of Education, University and Research/ ; 2017SNW5MB//Progetti di Ricerca di Rilevante Interesse Nazionale, PRIN/ ; //Joint Programme - Neurodegenerative Disease Research/ ; //Department of Excellence/ ; //'Rita Levi Montalcini' Department of Neuroscience/ ; //University of Torino, Italy/ ; }, mesh = {Humans ; Magnetic Resonance Imaging ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics/pathology ; C9orf72 Protein/genetics ; *Connectome ; DNA Repeat Expansion/genetics ; Proteins/genetics ; Mutation ; }, abstract = {OBJECTIVE: The resting-state functional connectome has not been extensively investigated in amyotrophic lateral sclerosis (ALS) spectrum disease, in particular in relationship with patients' genetic status.

METHODS: Here we studied the network-to-network connectivity of 19 ALS patients carrying the C9orf72 hexanucleotide repeat expansion (C9orf72+), 19 ALS patients not affected by C9orf72 mutation (C9orf72-), and 19 ALS-mimic patients (ALSm) well-matched for demographic and clinical variables.

RESULTS: When compared with ALSm, we observed greater connectivity of the default mode and frontoparietal networks with the visual network for C9orf72+ patients (P = 0.001). Moreover, the whole-connectome showed greater node degree (P < 0.001), while sensorimotor cortices resulted isolated in C9orf72+.

INTERPRETATION: Our results suggest a crucial involvement of extra-motor functions in ALS spectrum disease. In particular, alterations of the visual cortex may have a pathogenic role in C9orf72-related ALS. The prominent feature of these patients would be increased visual system connectivity with the networks responsible of the functional balance between internal and external attention.}, } @article {pmid38235589, year = {2024}, author = {Gebrehiwet, P and Aggarwal, S and Topaloglu, O and Chiò, A}, title = {Feasibility assessment of using the MiToS staging system for conducting economic evaluation in amyotrophic lateral sclerosis.}, journal = {Expert review of pharmacoeconomics & outcomes research}, volume = {24}, number = {3}, pages = {447-458}, doi = {10.1080/14737167.2024.2306819}, pmid = {38235589}, issn = {1744-8379}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Cost-Benefit Analysis ; Feasibility Studies ; Mitochondria Associated Membranes ; Disease Progression ; Quality-Adjusted Life Years ; }, abstract = {OBJECTIVES: This study assessed the feasibility of using the Milano-Torino staging (MiToS) system for conducting economic evaluation to measure health outcomes in amyotrophic lateral sclerosis (ALS).

METHODS: A Markov model was developed using the MiToS system and evaluated with a hypothetical treatment versus standard of care. Health utilities and transition probabilities were derived from the literature. Four-time horizons (1, 5, 10, and 20 years) were examined. Treatment effects of 20-35% relative risk reduction (RRR) of progressing to the next MiToS stage were assessed. Three patient distribution scenarios were tested: (1) all patients began in stage 0; (2) patient distribution based on real-world TONiC study; (3) distribution based on the PRO-ACT database. Health outcomes (quality-adjusted life-years [QALYs], life-years [LYs]) were reported with a 3% discount rate.

RESULTS: A time horizon of 10 years fully captured treatment benefits: incremental QALYs were 0.28-0.60, 0.21-0.45, and 0.26-0.55 for scenarios 1-3, respectively; incremental LYs were 0.56-1.17, 0.46-0.97, and 0.53-1.11, respectively.

CONCLUSION: MiToS-based staging can be used for conducting economic analyses in ALS. Estimated incremental QALY and LY gains were meaningful within the context of ALS, for hypothetical treatments with RRR of 20-35%.}, } @article {pmid38235844, year = {2024}, author = {Zhang, L and Li, Y and Niu, J and Hu, N and Ding, J and Cui, L and Liu, M}, title = {Neuromuscular ultrasound in combination with nerve conduction studies helps identify inflammatory motor neuropathies from lower motor neuron syndromes.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16202}, pmid = {38235844}, issn = {1468-1331}, support = {CIFMS 2021-I2M-1-003//CAMS Innovation Fund for Medical Sciences/ ; 2022-PUMCH-B-017//National High Level Hospital Clinical Research Funding/ ; 2016YFC0905103//National Key Research and Development Program of China/ ; grant XDB39040000//the Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/therapy ; Nerve Conduction Studies ; Neural Conduction/physiology ; Motor Neurons ; *Polyneuropathies ; *Motor Neuron Disease ; }, abstract = {BACKGROUND AND PURPOSE: Identifying patients with inflammatory motor neuropathies (IMNs) is warranted since effective treatments are available and the prognosis of these patients differs from that of amyotrophic lateral sclerosis patients.

METHODS: Between January 2019 and May 2022, 102 consecutive treatment-naïve lower motor neuron syndrome (LMNS) patients were recruited; these patients were suspected of having multifocal motor neuropathy, pure motor chronic inflammatory demyelinating polyneuropathy or amyotrophic lateral sclerosis with initial lower motor neuron presentation. Neuromuscular ultrasound (US) and nerve conduction studies (NCSs) were conducted at baseline. Relevant diagnostic investigations were performed if clinically warranted. The proposed US evidence of IMN was as follows: (i) nerve enlargement at ≥1 of the predetermined sites or (ii) absence of high intensity fasciculations in predefined muscle groups. Final diagnoses were made by experienced physicians after a prolonged follow-up period (≥12 months). IMN patients were defined as LMNS patients who experienced convincing improvements in response to immunotherapies. IMN patients without electrodiagnostic demyelinating features were diagnosed with treatment-responsive LMNS (TR-LMNS).

RESULTS: In total, 16 patients were classified as IMN, including nine chronic inflammatory demyelinating polyneuropathy/multifocal motor neuropathy patients and seven TR-LMNS patients. Six TR-LMNS patients were identified by neuromuscular US. The sensitivity and specificity of NCSs, nerve US and muscle US were 56.3% and 100%, 43.8% and 90.7% and 68.8% and 97.7%, respectively. When these three modalities were combined, the sensitivity and specificity were 93.8% and 88.4%, respectively.

CONCLUSION: Neuromuscular US studies are supplementary modalities to NCSs, and the combined use of these techniques might improve the identification of IMNs in LMNS patients.}, } @article {pmid38235854, year = {2024}, author = {Dukic, S and Fasano, A and Coffey, A and Buxó, T and McMackin, R and Chipika, R and Heverin, M and Bede, P and Muthuraman, M and Lowery, M and Carson, RG and Hardiman, O and Nasseroleslami, B}, title = {Electroencephalographic β-band oscillations in the sensorimotor network reflect motor symptom severity in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16201}, pmid = {38235854}, issn = {1468-1331}, support = {/WT_/Wellcome Trust/United Kingdom ; 16/ERCD/3854/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Electroencephalography ; Motor Neurons ; Brain ; Brain Mapping ; }, abstract = {BACKGROUND AND PURPOSE: Resting-state electroencephalography (EEG) holds promise for assessing brain networks in amyotrophic lateral sclerosis (ALS). We investigated whether neural β-band oscillations in the sensorimotor network could serve as an objective quantitative measure of progressive motor impairment and functional disability in ALS patients.

METHODS: Resting-state EEG was recorded in 18 people with ALS and 38 age- and gender-matched healthy controls. We estimated source-localized β-band spectral power in the sensorimotor cortex. Clinical evaluation included lower (LMN) and upper motor neuron scores, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, fine motor function (FMF) subscore, and progression rate. Correlations between clinical scores and β-band power were analysed and corrected using a false discovery rate of q = 0.05.

RESULTS: β-Band power was significantly lower in people with ALS than controls (p = 0.004), and correlated with LMN score (R = -0.65, p = 0.013), FMF subscore (R = -0.53, p = 0.036), and FMF progression rate (R = 0.52, p = 0.036).

CONCLUSIONS: β-Band spectral power in the sensorimotor cortex reflects clinically evaluated motor impairment in ALS. This technology merits further investigation as a biomarker of progressive functional disability.}, } @article {pmid38236205, year = {2024}, author = {Bryson, JB and Kourgiantaki, A and Jiang, D and Demosthenous, A and Greensmith, L}, title = {An optogenetic cell therapy to restore control of target muscles in an aggressive mouse model of amyotrophic lateral sclerosis.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38236205}, issn = {2050-084X}, support = {Bryson 965-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R011648/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Optogenetics ; Muscle, Skeletal ; Paralysis ; Cell- and Tissue-Based Therapy ; Disease Models, Animal ; }, abstract = {Breakdown of neuromuscular junctions (NMJs) is an early pathological hallmark of amyotrophic lateral sclerosis (ALS) that blocks neuromuscular transmission, leading to muscle weakness, paralysis and, ultimately, premature death. Currently, no therapies exist that can prevent progressive motor neuron degeneration, muscle denervation, or paralysis in ALS. Here, we report important advances in the development of an optogenetic, neural replacement strategy that can effectively restore innervation of severely affected skeletal muscles in the aggressive SOD1[G93A] mouse model of ALS, thus providing an interface to selectively control the function of targeted muscles using optical stimulation. We also identify a specific approach to confer complete survival of allogeneic replacement motor neurons. Furthermore, we demonstrate that an optical stimulation training paradigm can prevent atrophy of reinnervated muscle fibers and results in a tenfold increase in optically evoked contractile force. Together, these advances pave the way for an assistive therapy that could benefit all ALS patients.}, } @article {pmid38237070, year = {2024}, author = {Goto, S and Maeda, N and Ohnuma, K and Lawu, T and Ogawa, K and Sugiyama, S and Matsumaru, M and Noda, T}, title = {Impact of segmented optical axial length on the performance of intraocular lens power calculation formulas.}, journal = {Journal of cataract and refractive surgery}, volume = {50}, number = {5}, pages = {492-497}, doi = {10.1097/j.jcrs.0000000000001397}, pmid = {38237070}, issn = {1873-4502}, mesh = {Humans ; *Axial Length, Eye/pathology/diagnostic imaging ; *Lenses, Intraocular ; Retrospective Studies ; *Biometry/methods ; *Optics and Photonics ; Male ; Female ; *Tomography, Optical Coherence/methods ; *Phacoemulsification ; *Refraction, Ocular/physiology ; Lens Implantation, Intraocular ; Aged ; Middle Aged ; Aged, 80 and over ; Visual Acuity/physiology ; Pseudophakia/physiopathology ; }, abstract = {PURPOSE: To investigate the difference between the segmented axial length (AL) and the composite AL on a swept-source optical coherence tomography biometer and to evaluate the subsequent effects on artificial intelligence intraocular lens (IOL) power calculations: the Kane and Hill-RBF 3.0 formulas compared with established vergence formulas.

SETTING: National Hospital Organization, Tokyo Medical Center, Japan.

DESIGN: Retrospective case series.

METHODS: Consecutive patients undergoing cataract surgery with a single-piece IOL were reviewed. The prediction accuracy of the Barrett Universal II, Haigis, Hill-RBF 3.0, Hoffer Q, Holladay 1, Kane, and SRK/T formulas based on 2 ALs were compared for each formula. The heteroscedastic test was used with the SD of prediction errors as the endpoint for formula performance.

RESULTS: The study included 145 eyes of 145 patients. The segmented AL (24.83 ± 1.89) was significantly shorter than the composite AL (24.88 ± 1.96, P < .001). Bland-Altman analysis revealed a negative proportional bias for the differences between the segmented AL and the composite AL. The SD values obtained by Hoffer Q, Holladay 1, and SRK/T formulas based on the segmented AL (0.52 diopters [D], 0.54 D, and 0.50 D, respectively) were significantly lower than those based on the composite AL (0.57 D, 0.60 D, and 0.52 D, respectively, P < .01).

CONCLUSIONS: The segmented ALs were longer in short eyes and shorter in long eyes than the composite ALs. The refractive accuracy can be improved in the Hoffer Q, Holladay 1, and SRK/T formulas by changing the composite ALs to the segmented ALs.}, } @article {pmid38238759, year = {2024}, author = {Séguin, P and Maby, E and Fouillen, M and Otman, A and Luauté, J and Giraux, P and Morlet, D and Mattout, J}, title = {The challenge of controlling an auditory BCI in the case of severe motor disability.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {9}, pmid = {38238759}, issn = {1743-0003}, support = {DEA20140629858//Fondation pour la Recherche Médicale/ ; ING20121226307//Fondation pour la Recherche Médicale/ ; ANR-17-CE40-0005//Agence Nationale de la Recherche/ ; Labex Cortex (ANR-11-LABX-0042)//Agence Nationale de la Recherche/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Brain-Computer Interfaces ; *Persons with Disabilities ; Electroencephalography ; *Locked-In Syndrome ; *Motor Disorders ; }, abstract = {BACKGROUND: The locked-in syndrome (LIS), due to a lesion in the pons, impedes communication. This situation can also be met after some severe brain injury or in advanced Amyotrophic Lateral Sclerosis (ALS). In the most severe condition, the persons cannot communicate at all because of a complete oculomotor paralysis (Complete LIS or CLIS). This even prevents the detection of consciousness. Some studies suggest that auditory brain-computer interface (BCI) could restore a communication through a « yes-no» code.

METHODS: We developed an auditory EEG-based interface which makes use of voluntary modulations of attention, to restore a yes-no communication code in non-responding persons. This binary BCI uses repeated speech sounds (alternating "yes" on the right ear and "no" on the left ear) corresponding to either frequent (short) or rare (long) stimuli. Users are instructed to pay attention to the relevant stimuli only. We tested this BCI with 18 healthy subjects, and 7 people with severe motor disability (3 "classical" persons with locked-in syndrome and 4 persons with ALS).

RESULTS: We report online BCI performance and offline event-related potential analysis. On average in healthy subjects, online BCI accuracy reached 86% based on 50 questions. Only one out of 18 subjects could not perform above chance level. Ten subjects had an accuracy above 90%. However, most patients could not produce online performance above chance level, except for two people with ALS who obtained 100% accuracy. We report individual event-related potentials and their modulation by attention. In addition to the classical P3b, we observed a signature of sustained attention on responses to frequent sounds, but in healthy subjects and patients with good BCI control only.

CONCLUSIONS: Auditory BCI can be very well controlled by healthy subjects, but it is not a guarantee that it can be readily used by the target population of persons in LIS or CLIS. A conclusion that is supported by a few previous findings in BCI and should now trigger research to assess the reasons of such a gap in order to propose new and efficient solutions.

CLINICAL TRIAL REGISTRATIONS: No. NCT02567201 (2015) and NCT03233282 (2013).}, } @article {pmid38239147, year = {2024}, author = {Lin, J and Wang, J and Wang, C and Shan, Y and Jing, W and Fei, Z and Pan, W}, title = {Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 1: Biogenic components and identification of targets and signaling pathways in amyotrophic lateral sclerosis patients.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {62}, number = {4}, pages = {155-161}, doi = {10.5414/CP204501}, pmid = {38239147}, issn = {0946-1965}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Medicine, Chinese Traditional ; Network Pharmacology ; Treatment Outcome ; Busulfan ; Signal Transduction ; Molecular Docking Simulation ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: There is evidence that Bu-Shen-Jian-Pi (BSJP), a traditional Chinese medicine, has curative effects in patients suffering from amyotrophic lateral sclerosis (ALS), a progressive and potentially fatal hypoxic condition.

OBJECTIVE: To identify biogenic components in BSJP extracts having potential pharmacological efficacy in ALS.

MATERIALS AND METHODS: Biogenic components in BSJP and their potential pharmacological targets and signaling pathways in ALS were identified and assessed using network pharmacology/hub node analysis.

RESULTS: Network pharmacology analysis identified icariin, naringenin, kaempferol, quercetin, and formononetin as core components in BSJP with potential activity involving mitochondrial protection in patients with ALS.

CONCLUSION: Network pharmacology analysis proved to be a successful screening tool for obtaining information from scientific databases on the pharmacology of biogenic components in BSJP showing potential therapeutic activity in ALS.}, } @article {pmid38239315, year = {2024}, author = {Kim, K and Ko, DS and Kim, JW and Lee, D and Son, E and Kim, HW and Song, TJ and Kim, YH}, title = {Association of smoking with amyotrophic lateral sclerosis: A systematic review, meta-analysis, and dose-response analysis.}, journal = {Tobacco induced diseases}, volume = {22}, number = {}, pages = {}, pmid = {38239315}, issn = {1617-9625}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder primarily affecting the voluntary motor nervous system. Several observational studies have provided conflicting results regarding the association between smoking and ALS. Therefore, our objective was to investigate this association through a systematic review, meta-analysis, and dose-response analysis.

METHODS: On 16 January 2023, we initially extracted records from medical databases, which included Medline, Embase, Web of Science, Scopus, and ScienceDirect. We included case-control and cohort studies as eligible studies. Subgroup analyses were performed based on sex, study design, and current smoking. Restricted cubic-spline analysis was utilized to assess the dose-response relationship between smoking (pack-years) and ALS.

RESULTS: Twenty-eight case-control and four cohort studies met the inclusion criteria. The unadjusted OR for the overall association between smoking and ALS was 1.14 (95% CI: 1.06-1.22, I[2]=44%, p<0.001), and the adjusted OR (AOR) was 1.12 (95% CI: 1.03-1.21, I[2]=49%, p=0.009). Subgroup analysis revealed a more pronounced association among current smokers, with an AOR of 1.28 (95% CI: 1.10-1.49, I[2]=66%, p<0.001) and AOR of 1.28 (95% CI: 1.10-1.48, I[2]=58%, p=0.001). In the dose-response analysis, the non-linear model revealed an inverted U-shaped curve.

CONCLUSIONS: Our study provides evidence of a positive relationship between smoking and the risk of ALS. To mitigate the risk of developing ALS, discontinuing smoking, which is a modifiable risk factor, may be crucial.TRIAL REGISTRATION: The study was registered in PROSPERO.IDENTIFIER: CRD42023388822.}, } @article {pmid38239560, year = {2023}, author = {Wang, G and Jin, S and Liu, J and Li, X and Dai, P and Wang, Y and Hou, SX}, title = {A neuron-immune circuit regulates neurodegeneration in the hindbrain and spinal cord of Arf1-ablated mice.}, journal = {National science review}, volume = {10}, number = {12}, pages = {nwad222}, pmid = {38239560}, issn = {2053-714X}, abstract = {Neuroimmune connections have been revealed to play a central role in neurodegenerative diseases (NDs). However, the mechanisms that link the central nervous system (CNS) and peripheral immune cells are still mostly unknown. We recently found that specific ablation of the Arf1 gene in hindbrain and spinal cord neurons promoted NDs through activating the NLRP3 inflammasome in microglia via peroxided lipids and adenosine triphosphate (ATP) releasing. Here, we demonstrate that IL-1β with elevated chemokines in the neuronal Arf1-ablated mouse hindbrain and spinal cord recruited and activated γδ T cells in meninges. The activated γδ T cells then secreted IFN-γ that entered into parenchyma to activate the microglia-A1 astrocyte-C3-neuronal C3aR neurotoxic pathway. Remarkably, the neurodegenerative phenotypes of the neuronal Arf1-ablated mice were strongly ameliorated by IFN-γ or C3 knockout. Finally, we show that the Arf1-reduction-induced neuroimmune-IFN-γ-gliosis pathway exists in human NDs, particularly in amyotrophic lateral sclerosis and multiple sclerosis. Together, our results uncover a previously unknown mechanism that links the CNS and peripheral immune cells to promote neurodegeneration.}, } @article {pmid38239833, year = {2023}, author = {Eck, RJ and Stair, JG and Kraemer, BC and Liachko, NF}, title = {Simple models to understand complex disease: 10 years of progress from Caenorhabditis elegans models of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1300705}, pmid = {38239833}, issn = {1662-4548}, support = {RF1 AG078374/AG/NIA NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; F31 AG082391/AG/NIA NIH HHS/United States ; I01 BX005762/BX/BLRD VA/United States ; I01 BX004044/BX/BLRD VA/United States ; RF1 AG055474/AG/NIA NIH HHS/United States ; T32 GM136534/GM/NIGMS NIH HHS/United States ; I01 BX002619/BX/BLRD VA/United States ; R01 AG066729/AG/NIA NIH HHS/United States ; IK6 BX006467/BX/BLRD VA/United States ; R01 NS064131/NS/NINDS NIH HHS/United States ; }, abstract = {The nematode Caenorhabditis elegans are a powerful model system to study human disease, with numerous experimental advantages including significant genetic and cellular homology to vertebrate animals, a short lifespan, and tractable behavioral, molecular biology and imaging assays. Beginning with the identification of SOD1 as a genetic cause of amyotrophic lateral sclerosis (ALS), C. elegans have contributed to a deeper understanding of the mechanistic underpinnings of this devastating neurodegenerative disease. More recently this work has expanded to encompass models of other types of ALS and the related disease frontotemporal lobar degeneration (FTLD-TDP), including those characterized by mutation or accumulation of the proteins TDP-43, C9orf72, FUS, HnRNPA2B1, ALS2, DCTN1, CHCHD10, ELP3, TUBA4A, CAV1, UBQLN2, ATXN3, TIA1, KIF5A, VAPB, GRN, and RAB38. In this review we summarize these models and the progress and insights from the last ten years of using C. elegans to study the neurodegenerative diseases ALS and FTLD-TDP.}, } @article {pmid38240367, year = {2024}, author = {Hobin, F and De Vocht, J and Lamaire, N and Beyens, H and Ombelet, F and Van Damme, P}, title = {Specialized multidisciplinary care improves ALS survival in Belgium: a population-based retrospective study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {282-289}, doi = {10.1080/21678421.2024.2304058}, pmid = {38240367}, issn = {2167-9223}, mesh = {Humans ; Retrospective Studies ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/therapy ; Belgium/epidemiology ; *Neurodegenerative Diseases ; Prognosis ; }, abstract = {ALS is a neurodegenerative disease characterized by loss of motor neurons, resulting in progressive weakness and wasting of muscles. The average survival time is 2-5 years, mostly due to respiratory failure. Since current therapies can prolong survival time by only a few months, multidisciplinary care remains the cornerstone of the management of ALS. At the ALS Expert Centre of University Hospitals Leuven, a large proportion of Belgian ALS patients are seen for diagnosis and a significant number is also in follow-up with the multidisciplinary team. In this retrospective study, we compared the outcome of incident patients who were in follow-up at our site with patients who were not in follow-up. We included 659 patients of which 557 (84.5%) received specialized care at the ALS Expert Centre. After adjusting for clinically relevant prognostic parameters, multidisciplinary follow-up significantly prolonged survival (p = 0.004; HR = 0.683; CI 95% [0.528 - 0.884]). This increase in survival is mainly driven by patients with spinal onset (p = 0.035; HR = 0.746; CI 95% [0.568 - 0.980]), since no significant increased survival time was observed in patients with bulbar onset (p = 0.28; HR = 0.778; CI 95% [0.495 - 1.223]). These data confirm that multidisciplinary follow-up contributes to a better outcome of patients, emphasizing the importance of multidisciplinary specialized care in ALS.}, } @article {pmid38240416, year = {2024}, author = {Schuster, J and Dreyhaupt, J and Mönkemöller, K and Dupuis, L and Dieterlé, S and Weishaupt, JH and Kassubek, J and Petri, S and Meyer, T and Grosskreutz, J and Schrank, B and Boentert, M and Emmer, A and Hermann, A and Zeller, D and Prudlo, J and Winkler, AS and Grehl, T and Heneka, MT and Johannesen, S and Göricke, B and Witzel, S and Dorst, J and Ludolph, AC and , }, title = {In-depth analysis of data from the RAS-ALS study reveals new insights in rasagiline treatment for amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16204}, pmid = {38240416}, issn = {1468-1331}, support = {//Teva Pharmaceutical Industries/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Indans/therapeutic use ; Disease Progression ; }, abstract = {BACKGROUND AND PURPOSE: In 2016, we concluded a randomized controlled trial testing 1 mg rasagiline per day add-on to standard therapy in 252 amyotrophic lateral sclerosis (ALS) patients. This article aims at better characterizing ALS patients who could possibly benefit from rasagiline by reporting new subgroup analysis and genetic data.

METHODS: We performed further exploratory in-depth analyses of the study population and investigated the relevance of single nucleotide polymorphisms (SNPs) related to the dopaminergic system.

RESULTS: Placebo-treated patients with very slow disease progression (loss of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R] per month before randomization of ≤0.328 points) showed a per se survival probability after 24 months of 0.85 (95% confidence interval = 0.65-0.94). The large group of intermediate to fast progressing ALS patients showed a prolonged survival in the rasagiline group compared to placebo after 6 and 12 months (p = 0.02, p = 0.04), and a reduced decline of ALSFRS-R after 18 months (p = 0.049). SNP genotypes in the MAOB gene and DRD2 gene did not show clear associations with rasagiline treatment effects.

CONCLUSIONS: These results underline the need to consider individual disease progression at baseline in future ALS studies. Very slow disease progressors compromise the statistical power of studies with treatment durations of 12-18 months using clinical endpoints. Analysis of MAOB and DRD2 SNPs revealed no clear relationship to any outcome parameter. More insights are expected from future studies elucidating whether patients with DRD2CC genotype (Rs2283265) show a pronounced benefit from treatment with rasagiline, pointing to the opportunities precision medicine could open up for ALS patients in the future.}, } @article {pmid38241160, year = {2024}, author = {López-Blanch, R and Salvador-Palmer, R and Oriol-Caballo, M and Moreno-Murciano, P and Dellinger, RW and Estrela, JM and Obrador, E}, title = {Nicotinamide riboside, pterostilbene and ibudilast protect motor neurons and extend survival in ALS mice.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {1}, pages = {e00301}, pmid = {38241160}, issn = {1878-7479}, mesh = {Mice ; Animals ; Humans ; Superoxide Dismutase-1 ; *Amyotrophic Lateral Sclerosis/drug therapy ; Neuroinflammatory Diseases ; Tumor Necrosis Factor-alpha ; Endothelial Cells ; Hydrogen Peroxide ; Pilot Projects ; Motor Neurons ; Niacinamide/pharmacology/therapeutic use/*analogs & derivatives ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase ; Spinal Cord ; *Indolizines ; *Pyrazoles ; *Pyridinium Compounds ; }, abstract = {Oxidative stress and neuroinflammation are major contributors to the pathophysiology of ALS. Nicotinamide riboside (a NAD[+] precursor) and pterostilbene (a natural antioxidant) were efficacious in a human pilot study of ALS patients and in ALS SOD1[G93A] transgenic mice. Ibudilast targets different phosphodiesterases and the macrophage migration inhibitory factor, reduces neuroinflammation, and in early-phase studies improved survival and slowed progression in ALS patients. Using two ALS murine models (SOD1[G93A], FUS[R521C]) the effects of nicotinamide riboside, pterostilbene, and ibudilast on disease onset, progression and survival were studied. In both models ibudilast enhanced the effects of nicotinamide riboside and pterostilbene on survival and neuromotor functions. The triple combination reduced microgliosis and astrogliosis, and the levels of different proinflammatory cytokines in the CSF. TNFα, IFNγ and IL1β increased H2O2 and NO generation by motor neurons, astrocytes, microglia and endothelial cells isolated from ALS mice. Nicotinamide riboside and pterostilbene decreased H2O2 and NO generation in all these cells. Ibudilast specifically decreased TNFα levels and H2O2 generation by microglia and endothelial cells. Unexpectedly, pathophysiological concentrations of H2O2 or NO caused minimal motor neuron cytotoxicity. H2O2-induced cytotoxicity was increased by NO via a trace metal-dependent formation of potent oxidants (i.e. OH and [-]OONO radicals). In conclusion, our results show that the combination of nicotinamide riboside, pterostilbene and ibudilast improve neuromotor functions and survival in ALS murine models. Studies on the underlying mechanisms show that motor neuron protection involves the decrease of oxidative and nitrosative stress, the combination of which is highly damaging to motor neurons.}, } @article {pmid38241161, year = {2024}, author = {Klemmensen, MM and Borrowman, SH and Pearce, C and Pyles, B and Chandra, B}, title = {Mitochondrial dysfunction in neurodegenerative disorders.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {1}, pages = {e00292}, pmid = {38241161}, issn = {1878-7479}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/drug therapy ; Mitochondria ; Reactive Oxygen Species/therapeutic use ; *Alzheimer Disease/pathology ; *Mitochondrial Diseases/genetics/therapy ; }, abstract = {Recent advances in understanding the role of mitochondrial dysfunction in neurodegenerative diseases have expanded the opportunities for neurotherapeutics targeting mitochondria to alleviate symptoms and slow disease progression. In this review, we offer a historical account of advances in mitochondrial biology and neurodegenerative disease. Additionally, we summarize current knowledge of the normal physiology of mitochondria and the pathogenesis of mitochondrial dysfunction, the role of mitochondrial dysfunction in neurodegenerative disease, current therapeutics and recent therapeutic advances, as well as future directions for neurotherapeutics targeting mitochondrial function. A focus is placed on reactive oxygen species and their role in the disruption of telomeres and their effects on the epigenome. The effects of mitochondrial dysfunction in the etiology and progression of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease are discussed in depth. Current clinical trials for mitochondria-targeting neurotherapeutics are discussed.}, } @article {pmid38241787, year = {2025}, author = {Hromas, G and Jackson, CE and Cooper, DB and Sullivan, AC}, title = {Primary progressive aphasia and amyotrophic lateral sclerosis (PPA-ALS): A longitudinal case study.}, journal = {Applied neuropsychology. Adult}, volume = {32}, number = {6}, pages = {1819-1822}, doi = {10.1080/23279095.2024.2302833}, pmid = {38241787}, issn = {2327-9109}, mesh = {Aged ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology ; *Aphasia, Primary Progressive/diagnosis/complications/physiopathology ; Longitudinal Studies ; Neuropsychological Tests ; }, abstract = {OBJECTIVE: Approximately 50% of patients with amyotrophic lateral sclerosis (ALS) experience cognitive decline, with frontotemporal dementia (FTD) accounting for up to 15% of these cases. Despite this, there is considerable delay in diagnosis, which affects patient care.

METHODS: We report longitudinal results of neuropsychological evaluations in a patient diagnosed with non-fluent/agrammatic primary progressive aphasia (nfvPPA) and amyotrophic lateral sclerosis (ALS). The patient, Ms. X, presented with progressive speech difficulties starting in her late-60's. Initial diagnosis was nfvPPA. After 4-5 years of progressive swallowing difficulties, as well as facial weakness, her diagnosis was modified to PPA-ALS.

RESULTS: Ms. X underwent neuropsychological evaluations three times over a period of five years. Results of evaluations were intact and stable over time, except for progressive loss of speech impacting her performance on a sentence repetition task.

CONCLUSION: This case study provides valuable insight into the overlap between PPA-ALS from a neuropsychological standpoint. The results reflect preserved cognitive skills in the context of loss of speech and motor abilities. This case study also shows the length of time between onset of symptoms and clear diagnosis, which often requires an immense amount of health literacy and personal advocacy on the part of the patient.}, } @article {pmid38242117, year = {2024}, author = {Rautila, OS and Kaivola, K and Rautila, H and Hokkanen, L and Launes, J and Strandberg, TE and Laaksovirta, H and Palmio, J and Tienari, PJ}, title = {The shared ancestry between the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles using haplotype sharing trees and HAPTK.}, journal = {American journal of human genetics}, volume = {111}, number = {2}, pages = {383-392}, pmid = {38242117}, issn = {1537-6605}, mesh = {Humans ; Alleles ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; Haplotypes/genetics ; Receptor Protein-Tyrosine Kinases/genetics ; *Trees/genetics ; }, abstract = {The C9orf72 hexanucleotide repeat expansion (HRE) is a common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The inheritance is autosomal dominant, but a high proportion of subjects with the mutation are simplex cases. One possible explanation is de novo expansions of unstable intermediate-length alleles (IAs). Using haplotype sharing trees (HSTs) with the haplotype analysis tool kit (HAPTK), we derived majority-based ancestral haplotypes of HRE samples and discovered that IAs containing ≥18-20 repeats share large haplotypes in common with the HRE. Using HSTs of HRE and IA samples, we demonstrate that the longer IA haplotypes are largely indistinguishable from HRE haplotypes and that several ≥18-20 IA haplotypes share over 5 Mb (>600 markers) haplotypes in common with the HRE haplotypes. These analysis tools allow physical understanding of the haplotype blocks shared with the majority-based ancestral haplotype. Our results demonstrate that the haplotypes with longer IAs belong to the same pool of haplotypes as the HRE and suggest that longer IAs represent potential premutation alleles.}, } @article {pmid38242131, year = {2024}, author = {Shum, C and Hedges, EC and Allison, J and Lee, YB and Arias, N and Cocks, G and Chandran, S and Ruepp, MD and Shaw, CE and Nishimura, AL}, title = {Mutations in FUS lead to synaptic dysregulation in ALS-iPSC derived neurons.}, journal = {Stem cell reports}, volume = {19}, number = {2}, pages = {187-195}, pmid = {38242131}, issn = {2213-6711}, support = {MR/N013255/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; Mutation ; Glutamates/metabolism ; RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disorder characterized by progressive muscular weakness due to the selective loss of motor neurons. Mutations in the gene Fused in Sarcoma (FUS) were identified as one cause of ALS. Here, we report that mutations in FUS lead to upregulation of synaptic proteins, increasing synaptic activity and abnormal release of vesicles at the synaptic cleft. Consequently, FUS-ALS neurons showed greater vulnerability to glutamate excitotoxicity, which raised neuronal swellings (varicose neurites) and led to neuronal death. Fragile X mental retardation protein (FMRP) is an RNA-binding protein known to regulate synaptic protein translation, and its expression is reduced in the FUS-ALS lines. Collectively, our data suggest that a reduction of FMRP levels alters the synaptic protein dynamics, leading to synaptic dysfunction and glutamate excitotoxicity. Here, we present a mechanistic hypothesis linking dysregulation of peripheral translation with synaptic vulnerability in the pathogenesis of FUS-ALS.}, } @article {pmid38243956, year = {2024}, author = {Singh, S and Ahuja, A and Pathak, S}, title = {Potential Role of Oxidative Stress in the Pathophysiology of Neurodegenerative Disorders.}, journal = {Combinatorial chemistry & high throughput screening}, volume = {27}, number = {14}, pages = {2043-2061}, pmid = {38243956}, issn = {1875-5402}, mesh = {Humans ; *Oxidative Stress/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Antioxidants/pharmacology ; Reactive Oxygen Species/metabolism ; Animals ; Neuroprotective Agents/pharmacology/chemistry ; }, abstract = {Neurodegeneration causes premature death in the peripheral and central nervous system. Neurodegeneration leads to the accumulation of oxidative stress, inflammatory responses, and the generation of free radicals responsible for nervous disorders like amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disorders. Therefore, focus must be diverted towards treating and managing these disorders, as it is very challenging. Furthermore, effective therapies are also lacking, so the growing interest of the global market must be inclined towards developing newer therapeutic approaches that can intercept the progression of neurodegeneration. Emerging evidences of research findings suggest that antioxidant therapy has significant potential in modulating disease phenotypes. This makes them promising candidates for further investigation. This review focuses on the role of oxidative stress and reactive oxygen species in the pathological mechanisms of various neurodegenerative diseases, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disorders and their neuroprotection. Additionally, it highlights the potential of antioxidant-based therapeutics in mitigating disease severity in humans and improving patient compliance. Ongoing extensive global research further sheds light on exploring new therapeutic targets for a deeper understanding of disease mechanisms in the field of medicine and biology targeting neurogenerative disorders.}, } @article {pmid38244210, year = {2024}, author = {Xu, C and Diemant, T and Mariani, A and Di Pietro, ME and Mele, A and Liu, X and Passerini, S}, title = {Locally Concentrated Ionic Liquid Electrolytes for Wide-Temperature-Range Aluminum-Sulfur Batteries.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {10}, pages = {e202318204}, doi = {10.1002/anie.202318204}, pmid = {38244210}, issn = {1521-3773}, support = {//China Sponsorship Council/ ; //Helmholtz Association/ ; MSCA EF Master Class 2018//Politecnico di Milano/ ; }, abstract = {Aluminum-sulfur (Al-S) batteries are promising energy storage devices due to their high theoretical capacity, low cost, and high safety. However, the high viscosity and inferior ion transport of conventionally used ionic liquid electrolytes (ILEs) limit the kinetics of Al-S batteries, especially at sub-zero temperatures. Herein, locally concentrated ionic liquid electrolytes (LCILE) formed via diluting the ILEs with non-solvating 1,2-difluorobenzene (dFBn) co-solvent are proposed for wide-temperature-range Al-S batteries. The addition of dFBn effectively promotes the fluidity and ionic conductivity without affecting the AlCl4 [-] /Al2 Cl7 [-] equilibrium, which preserves the reversible stripping/plating of aluminum and further promotes the overall kinetics of Al-S batteries. As a result, Al-S cells employing the LCILE exhibit higher specific capacity, better cyclability, and lower polarization with respect to the neat ILE in a wide temperature range from -20 to 40 °C. For instance, Al-S batteries employing the LCILE sustain a remarkable capacity of 507 mAh g[-1] after 300 cycles at 20 °C, while only 229 mAh g[-1] is delivered with the dFBn-free electrolyte under the same condition. This work demonstrates the favorable use of LCILEs for wide-temperature Al-S batteries.}, } @article {pmid38244235, year = {2024}, author = {Kim, SH and Oh, KW and Noh, MY and Kwon, MS}, title = {Optimal Therapeutic Strategy of Bone Marrow-Originated Autologous Mesenchymal Stromal/Stem Cells for ALS.}, journal = {Stem cells translational medicine}, volume = {13}, number = {4}, pages = {309-316}, pmid = {38244235}, issn = {2157-6580}, support = {NRF//National Research Foundation/ ; MSIT; RS-2023-00265515//Korean government/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Bone Marrow ; Biomarkers ; *Mesenchymal Stem Cells ; *Mesenchymal Stem Cell Transplantation/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by selective and progressive neurodegenerative changes in motor neural networks. Given the system complexity, including anatomically distributed sites of degeneration from the motor cortex to the spinal cord and chronic pro-inflammatory conditions, a cell-based therapeutic strategy could be an alternative approach to treating ALS. Lessons from previous mesenchymal stromal/stem cell (MSC) trials in ALS realized the importance of 3 aspects in current and future MSC therapy, including the preparation of MSCs, administration routes and methods, and recipient-related factors. This review briefly describes the current status and future prerequisites for an optimal strategy using bone-marrow-originated MSCs to treat ALS. We suggest mandatory factors in the optimized therapeutic strategy focused on advanced therapy medicinal products produced according to Good Manufacturing Practice, an optimal administration method, the selection of proper patients, and the importance of biomarkers.}, } @article {pmid38244886, year = {2024}, author = {DSouza, AA and Kulkarni, P and Ferris, CF and Amiji, MM and Bleier, BS}, title = {Mild repetitive TBI reduces brain-derived neurotrophic factor (BDNF) in the substantia nigra and hippocampus: A preclinical model for testing BDNF-targeted therapeutics.}, journal = {Experimental neurology}, volume = {374}, number = {}, pages = {114696}, pmid = {38244886}, issn = {1090-2430}, support = {P30 EY003790/EY/NEI NIH HHS/United States ; R01 NS108968/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Female ; Male ; Rats ; *Brain Concussion/complications ; *Brain Injuries, Traumatic/drug therapy/complications ; Brain-Derived Neurotrophic Factor/metabolism ; Hippocampus/metabolism ; Substantia Nigra/metabolism ; }, abstract = {Clinical studies have consistently shown that neurodegenerative diseases (NDs) such as Parkinson's disease, Alzheimer's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease show absent or low levels of brain-derived neurotrophic factor (BDNF). Despite this relationship between BDNF and ND, only a few ND animal models have been able to recapitulate the low BDNF state, thereby hindering research into the therapeutic targeting of this important neurotrophic factor. In order to address this unmet need, we sought to develop a reproducible model of BDNF reduction by inducing traumatic brain injury (TBI) using a closed head momentum exchange injury model in mature 9-month-old male and female rats. Head impacts were repetitive and varied in intensity from mild to severe. BDNF levels, as assessed by ELISA, were significantly reduced in the hippocampus of both males and females as well as in the substantia nigra of males 12 days after mild TBI. However, we observed significant sexual dimorphism in multiple sequelae, including magnetic resonance imaging-determined vasogenic edema, astrogliosis (GFAP-activation), and microgliosis (Iba1 activation). This study provides an opportunity to investigate the mechanism of BDNF reduction in rodent models and provides a reliable paradigm to test BDNF-targeted therapeutics for the treatment of ND.}, } @article {pmid38245992, year = {2024}, author = {Robertson, DJ and Jeziorczak, PM and Aprahamian, CJ}, title = {Diaphragmatic pacing for respiratory failure in children.}, journal = {Seminars in pediatric surgery}, volume = {33}, number = {1}, pages = {151386}, doi = {10.1016/j.sempedsurg.2024.151386}, pmid = {38245992}, issn = {1532-9453}, mesh = {Child ; Humans ; *Amyotrophic Lateral Sclerosis/complications ; Diaphragm ; Phrenic Nerve/surgery ; *Respiratory Insufficiency/etiology/therapy ; }, abstract = {Diaphragm pacing is a ventilation strategy in respiratory failure. Most of the literature on pacing involves adults with common indications being spinal cord injury and amyotrophic lateral sclerosis (ALS). Previous reports in pediatric patients consist of case reports or small series; most describe direct phrenic nerve stimulation for central hypoventilation syndrome. This differs from adult reports that focus most commonly on spinal cord injuries and the rehabilitative nature of diaphragm pacing. This review describes the current state of diaphragm pacing in pediatric patients. Indications, current available technologies, surgical techniques, advantages, and pitfalls/problems are discussed.}, } @article {pmid38246117, year = {2024}, author = {de Jonge, S and Potters, WV and Verhamme, C}, title = {Artificial intelligence for automatic classification of needle EMG signals: A scoping review.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {159}, number = {}, pages = {41-55}, doi = {10.1016/j.clinph.2023.12.134}, pmid = {38246117}, issn = {1872-8952}, mesh = {Humans ; *Artificial Intelligence ; *Amyotrophic Lateral Sclerosis ; Electromyography ; Needles ; }, abstract = {OBJECTIVE: This scoping review provides an overview of artificial intelligence (AI), including machine and deep learning techniques, in the interpretation of clinical needle electromyography (nEMG) signals.

METHODS: A comprehensive search of Medline, Embase and Web of Science was conducted to find peer-reviewed journal articles. All papers published after 2010 were included. The methodological quality of the included studies was assessed with CLAIM (checklist for artificial intelligence in medical imaging).

RESULTS: 51 studies were identified that fulfilled the inclusion criteria. 61% used open-source EMGlab data set to develop models to classify nEMG signal in healthy, amyotrophic lateral sclerosis (ALS) and myopathy (25 subjects). Only two articles developed models to classify signals recorded at rest. Most articles reported high performance accuracies, but many were subject to bias and overtraining.

CONCLUSIONS: Current AI-models of nEMG signals are not sufficient for clinical implementation. Suggestions for future research include emphasizing the need for an optimal training and validation approach using large datasets of clinical nEMG data from a diverse patient population.

SIGNIFICANCE: The outcomes of this study and the suggestions made aim to contribute to developing AI-models that can effectively handle signal quality variability and are suitable for daily clinical practice in interpreting nEMG signals.}, } @article {pmid38247869, year = {2024}, author = {Smeele, PH and Cesare, G and Vaccari, T}, title = {ALS' Perfect Storm: C9orf72-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis.}, journal = {Cells}, volume = {13}, number = {2}, pages = {}, pmid = {38247869}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; Dipeptides ; *Frontotemporal Dementia/genetics ; *Proteostasis ; }, abstract = {Protein homeostasis is essential for neuron longevity, requiring a balanced regulation between protein synthesis and degradation. The clearance of misfolded and aggregated proteins, mediated by autophagy and the ubiquitin-proteasome systems, maintains protein homeostasis in neurons, which are post-mitotic and thus cannot use cell division to diminish the burden of misfolded proteins. When protein clearance pathways are overwhelmed or otherwise disrupted, the accumulation of misfolded or aggregated proteins can lead to the activation of ER stress and the formation of stress granules, which predominantly attempt to restore the homeostasis by suppressing global protein translation. Alterations in these processes have been widely reported among studies investigating the toxic function of dipeptide repeats (DPRs) produced by G4C2 expansion in the C9orf72 gene of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this review, we outline the modalities of DPR-induced disruptions in protein homeostasis observed in a wide range of models of C9orf72-linked ALS/FTD. We also discuss the relative importance of each DPR for toxicity, possible synergies between DPRs, and discuss the possible functional relevance of DPR aggregation to disease pathogenesis. Finally, we highlight the interdependencies of the observed effects and reflect on the importance of feedback and feedforward mechanisms in their contribution to disease progression. A better understanding of DPR-associated disease pathogenesis discussed in this review might shed light on disease vulnerabilities that may be amenable with therapeutic interventions.}, } @article {pmid38247879, year = {2024}, author = {Shehjar, F and Almarghalani, DA and Mahajan, R and Hasan, SA and Shah, ZA}, title = {The Multifaceted Role of Cofilin in Neurodegeneration and Stroke: Insights into Pathogenesis and Targeting as a Therapy.}, journal = {Cells}, volume = {13}, number = {2}, pages = {}, pmid = {38247879}, issn = {2073-4409}, support = {R01 NS112642/NS/NINDS NIH HHS/United States ; R01NS112642/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Actin Depolymerizing Factors ; alpha-Synuclein ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Parkinson Disease ; *Stroke/metabolism ; }, abstract = {This comprehensive review explores the complex role of cofilin, an actin-binding protein, across various neurodegenerative diseases (Alzheimer's, Parkinson's, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's) and stroke. Cofilin is an essential protein in cytoskeletal dynamics, and any dysregulation could lead to potentially serious complications. Cofilin's involvement is underscored by its impact on pathological hallmarks like Aβ plaques and α-synuclein aggregates, triggering synaptic dysfunction, dendritic spine loss, and impaired neuronal plasticity, leading to cognitive decline. In Parkinson's disease, cofilin collaborates with α-synuclein, exacerbating neurotoxicity and impairing mitochondrial and axonal function. ALS and frontotemporal dementia showcase cofilin's association with genetic factors like C9ORF72, affecting actin dynamics and contributing to neurotoxicity. Huntington's disease brings cofilin into focus by impairing microglial migration and influencing synaptic plasticity through AMPA receptor regulation. Alzheimer's, Parkinson's, and schizophrenia exhibit 14-3-3 proteins in cofilin dysregulation as a shared pathological mechanism. In the case of stroke, cofilin takes center stage, mediating neurotoxicity and neuronal cell death. Notably, there is a potential overlap in the pathologies and involvement of cofilin in various diseases. In this context, referencing cofilin dysfunction could provide valuable insights into the common pathologies associated with the aforementioned conditions. Moreover, this review explores promising therapeutic interventions, including cofilin inhibitors and gene therapy, demonstrating efficacy in preclinical models. Challenges in inhibitor development, brain delivery, tissue/cell specificity, and long-term safety are acknowledged, emphasizing the need for precision drug therapy. The call to action involves collaborative research, biomarker identification, and advancing translational efforts. Cofilin emerges as a pivotal player, offering potential as a therapeutic target. However, unraveling its complexities requires concerted multidisciplinary efforts for nuanced and effective interventions across the intricate landscape of neurodegenerative diseases and stroke, presenting a hopeful avenue for improved patient care.}, } @article {pmid38249102, year = {2024}, author = {Bakaeva, M and Chetverikov, S and Starikov, S and Kendjieva, A and Khudaygulov, G and Chetverikova, D}, title = {Effect of Plant Growth-Promoting Bacteria on Antioxidant Status, Acetolactate Synthase Activity, and Growth of Common Wheat and Canola Exposed to Metsulfuron-Methyl.}, journal = {Journal of xenobiotics}, volume = {14}, number = {1}, pages = {79-95}, pmid = {38249102}, issn = {2039-4713}, support = {23-26-00097//Russian Science Foundation/ ; }, abstract = {Metsulfuron-methyl, a widely used herbicide, could cause damage to the sensitive plants in crop-rotation systems at extremely low levels in the soil. The potential of plant growth-promoting bacteria (PGPB) for enhancing the resistance of plants against herbicide stress has been discovered recently. Therefore, it is poorly understood how physiological processes occur in plants, while PGPB reduce the phytotoxicity of herbicides for agricultural crops. In greenhouse studies, the effect of strains Pseudomonas protegens DA1.2 and Pseudomonas chlororaphis 4CH on oxidative damage, acetolactate synthase (ALS), enzymatic and non-enzymatic antioxidants in canola (Brassica napus L.), and wheat (Triticum aestivum L.) were investigated under two levels (0.05 and 0.25 mg∙kg[-1]) of metsulfuron-methyl using spectrophotometric assays. The inoculation of herbicide-exposed wheat with bacteria significantly increased the shoots fresh weight (24-28%), amount of glutathione GSH (60-73%), and flavonoids (5-14%), as well as activity of ascorbate peroxidase (129-140%), superoxide dismutase SOD (35-49%), and ALS (50-57%). Bacterial treatment stimulated the activity of SOD (37-94%), ALS (65-73%), glutathione reductase (19-20%), and the accumulation of GSH (61-261%), flavonoids (17-22%), and shoots weight (27-33%) in herbicide-exposed canola. Simultaneous inoculation prevented lipid peroxidation induced by metsulfuron-methyl in sensitive plants. Based on the findings, it is possible that the protective role of bacterial strains against metsulfuron-metil is linked to antioxidant system activation.}, } @article {pmid38249293, year = {2023}, author = {Krishnamurthy, K and Pradhan, RK}, title = {Emerging perspectives of synaptic biomarkers in ALS and FTD.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1279999}, pmid = {38249293}, issn = {1662-5099}, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are debilitating neurodegenerative diseases with shared pathological features like transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions and genetic mutations. Both diseases involve synaptic dysfunction, contributing to their clinical features. Synaptic biomarkers, representing proteins associated with synaptic function or structure, offer insights into disease mechanisms, progression, and treatment responses. These biomarkers can detect disease early, track its progression, and evaluate therapeutic efficacy. ALS is characterized by elevated neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) and blood, correlating with disease progression. TDP-43 is another key ALS biomarker, its mislocalization linked to synaptic dysfunction. In FTD, TDP-43 and tau proteins are studied as biomarkers. Synaptic biomarkers like neuronal pentraxins (NPs), including neuronal pentraxin 2 (NPTX2), and neuronal pentraxin receptor (NPTXR), offer insights into FTD pathology and cognitive decline. Advanced technologies, like machine learning (ML) and artificial intelligence (AI), aid biomarker discovery and drug development. Challenges in this research include technological limitations in detection, variability across patients, and translating findings from animal models. ML/AI can accelerate discovery by analyzing complex data and predicting disease outcomes. Synaptic biomarkers offer early disease detection, personalized treatment strategies, and insights into disease mechanisms. While challenges persist, technological advancements and interdisciplinary efforts promise to revolutionize the understanding and management of ALS and FTD. This review will explore the present comprehension of synaptic biomarkers in ALS and FTD and discuss their significance and emphasize the prospects and obstacles.}, } @article {pmid38249592, year = {2023}, author = {Jiang, Q and Guo, Y and Yang, T and Li, S and Hou, Y and Lin, J and Xiao, Y and Ou, R and Wei, Q and Shang, H}, title = {Cystatin C is associated with poor survival in amyotrophic lateral sclerosis patients.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1309568}, pmid = {38249592}, issn = {1662-4548}, abstract = {BACKGROUND: Cystatin C (CysC) levels in amyotrophic lateral sclerosis (ALS) have been found changes, however, the associations between serum CysC levels and the progression and survival of ALS remain largely unknown.

METHODS: A total of 1,086 ALS patients and 1,026 sex-age matched healthy controls (HCs) were enrolled in this study. Serum CysC, other renal function, and metabolic parameters were measured. Correlation analysis and binary logistic regression were used to explore the factors related to serum CysC. Kaplan-Meier curve and Cox regression model were used for survival analysis.

RESULTS: CysC levels were significantly higher in ALS patients compared to HCs (0.94 vs. 0.85 mg/L, p < 0.001). Compared with ALS patients with lower CysC levels, those with higher CysC levels had an older age of onset, significantly lower ALSFRS-R scores (40.1 vs. 41.3, p < 0.001), a faster disease progression rate (0.75 vs. 0.67, p = 0.011), and lower frontal lobe function scores (15.8 vs. 16.1, p = 0.020). In the correlation analysis, CysC levels were significantly negatively correlated with ALSFRS-R scores (r = -0.16, p < 0.001). Additionally, ALS patients with higher CysC levels had significantly shorter survival time (40.0 vs. 51.8, p < 0.001) compared to patients with lower CysC levels. Higher CysC levels were associated with a higher risk of death in Cox analysis (HR: 1.204, 95% CI: 1.012-1.433). However, when treatment was included in the model, the result was no longer significant.

CONCLUSION: CysC levels in ALS patients were higher compared to HCs. Higher CysC levels were associated with greater disease severity, faster progression rate and shorter survival, needing early intervention.}, } @article {pmid38249738, year = {2023}, author = {Croucher, KM and Fleming, SM}, title = {ATP13A2 (PARK9) and basal ganglia function.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1252400}, pmid = {38249738}, issn = {1664-2295}, support = {R01 ES031124/ES/NIEHS NIH HHS/United States ; }, abstract = {ATP13A2 is a lysosomal protein involved in polyamine transport with loss of function mutations associated with multiple neurodegenerative conditions. These include early onset Parkinson's disease, Kufor-Rakeb Syndrome, neuronal ceroid lipofuscinosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. While ATP13A2 mutations may result in clinical heterogeneity, the basal ganglia appear to be impacted in the majority of cases. The basal ganglia is particularly vulnerable to environmental exposures such as heavy metals, pesticides, and industrial agents which are also established risk factors for many neurodegenerative conditions. Not surprisingly then, impaired function of ATP13A2 has been linked to heavy metal toxicity including manganese, iron, and zinc. This review discusses the role of ATP13A2 in basal ganglia function and dysfunction, potential common pathological mechanisms in ATP13A2-related disorders, and how gene x environment interactions may contribute to basal ganglia dysfunction.}, } @article {pmid38249779, year = {2024}, author = {de Carvalho, M and Swash, M}, title = {[Not Available].}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {27-38}, pmid = {38249779}, issn = {2467-981X}, abstract = {Accurate and rapid diagnosis of amyotrophic lateral sclerosis (ALS) is essential in order to provide accurate information for patient and family, to avoid time-consuming investigations and to permit an appropriate management plan. ALS is variable regarding presentation, disease progression, genetic profile and patient reaction to the diagnosis. It is obviously important to exclude treatable conditions but, in most patients, for experienced neurologists the diagnosis is clear-cut, depending on the presence of progressive upper and lower motor neuron signs. Patients with signs of restricted lower motor neuron (LMN) or upper motor neuron (UMN) dysfunction may present diagnostic difficulty, but electromyography (EMG) is often a determinant diagnostic test since it may exclude other disorders. Transcranial magnetic stimulation may aid detection of UMN dysfunction, and brain and spinal cord MRI, ultrasound and blood neurofilament measurements, have begun to have clinical impact, although none are themselves diagnostic tests. Several sets of diagnostic criteria have been proposed in the past; all rely on clinical LMN and UMN signs in different anatomic territories, EMG changes, exclusion of other disorders, and disease progression, in particular evidence of spreading to other anatomic territories. Fasciculations are a characteristic clinical feature and increased importance is now attached to fasciculation potentials detected by EMG, when associated with classical signs of denervation and reinnervation. The Gold Coast diagnostic criteria rely on the presence of UMN and LMN signs in one (or more) anatomic territory, or LMN signs in two (or more) anatomic territories, recognizing the fundamental clinical requirements of disease progression and exclusion of other diseases. Recent studies confirm a high sensitivity without loss of specificity using these Gold Coast criteria. In considering the diagnosis of ALS a critical question for future understanding is whether ALS should be considered a syndrome or a specific clinico-pathologic entity; this can only be addressed in the light of more complete knowledge.}, } @article {pmid38250183, year = {2024}, author = {Xia, J and Guo, S and Hu, F and Fan, L and Yu, L and Ye, J}, title = {Changes in Corneal Higher-Order Aberrations and Ocular Biometric Measurements after Phacoemulsification Combined with Goniosynechialysis in Primary Angle Closure/Glaucoma Patients.}, journal = {Journal of ophthalmology}, volume = {2024}, number = {}, pages = {5833543}, pmid = {38250183}, issn = {2090-004X}, abstract = {PURPOSE: To compare corneal higher-order aberrations (HOAs), refractive error, and ocular biological parameters before and after phacoemulsification combined with goniosynechialysis (Phaco-GSL) in primary angle closure/glaucoma (PAC/PACG) patients with different axial lengths (ALs).

METHODS: In this prospective study, cataract patients diagnosed with PAC/PACG were categorized into two groups based on their ALs: the short AL group (AL ≤ 22.5 mm) and the normal AL group (22.5 < AL ≤ 24.5 mm). The pre- and postsurgery measurements of intraocular pressure (IOP) and best-corrected visual acuity (BCVA) were conducted at 1 day, 1 week, 1 month, 3 months, 6 months, and 12 months. Additionally, the assessments included corneal HOAs, the number of antiglaucoma medications, visual field parameters, manifest refraction, and other ocular biological parameters before surgery and at the final follow-up.

RESULTS: Prior to surgery, the two groups exhibited no significant differences, except for AL, curvature value, and Z (4, 0) of the posterior corneal surface (all P < 0.01). Following surgery, BCVA improved, and IOP decreased significantly in both groups (P < 0.01). Both anterior and total corneal HOAs, along with Z (3, -3), increased in the two groups (all P < 0.05), with the normal AL group exhibiting a significantly greater increase in total cornea Z (3, -3) than the short AL group (P=0.047). The normal AL group also exhibited a slight tendency towards hyperopia (P < 0.01). Significant changes were observed in the visual field index and mean deviation in both groups (P < 0.05).

CONCLUSIONS: Phaco-GSL resulted in an increased corneal HOAs, particularly trefoil, with variations based on the patient's AL. Patients with normal ALs tended to shift towards hyperopia after surgery.}, } @article {pmid38250776, year = {2024}, author = {Du, P and Zhang, X and Lian, X and Hölscher, C and Xue, G}, title = {O-GlcNAcylation and Its Roles in Neurodegenerative Diseases.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {97}, number = {3}, pages = {1051-1068}, doi = {10.3233/JAD-230955}, pmid = {38250776}, issn = {1875-8908}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Protein Processing, Post-Translational ; Proteins/metabolism ; *Alzheimer Disease/pathology ; Acetylglucosamine/metabolism ; Disease Progression ; N-Acetylglucosaminyltransferases/metabolism ; }, abstract = {As a non-classical post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is widely found in human organ systems, particularly in our brains, and is indispensable for healthy cell biology. With the increasing age of the global population, the incidence of neurodegenerative diseases is increasing, too. The common characteristic of these disorders is the aggregation of abnormal proteins in the brain. Current research has found that O-GlcNAcylation dysregulation is involved in misfolding or aggregation of these abnormal proteins to mediate disease progression, but the specific mechanism has not been defined. This paper reviews recent studies on O-GlcNAcylation's roles in several neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, Machado-Joseph's disease, and giant axonal neuropathy, and shows that O-GlcNAcylation, as glucose metabolism sensor, mediating synaptic function, participating in oxidative stress response and signaling pathway conduction, directly or indirectly regulates characteristic pathological protein toxicity and affects disease progression. The existing results suggest that targeting O-GlcNAcylation will provide new ideas for clinical diagnosis, prevention, and treatment of neurodegenerative diseases.}, } @article {pmid38251257, year = {2024}, author = {Garamszegi, SP and Brzostowicki, DJ and Coyne, TM and Vontell, RT and Davis, DA}, title = {TDP-43 and Alzheimer's Disease Pathology in the Brain of a Harbor Porpoise Exposed to the Cyanobacterial Toxin BMAA.}, journal = {Toxins}, volume = {16}, number = {1}, pages = {}, pmid = {38251257}, issn = {2072-6651}, support = {GR012556 DAVIS//Herbert W. Hoover Foundation/ ; }, mesh = {Animals ; *Phocoena ; *Alzheimer Disease/chemically induced ; *Neurodegenerative Diseases ; Brain ; DNA-Binding Proteins ; }, abstract = {Cetaceans are well-regarded as sentinels for toxin exposure. Emerging studies suggest that cetaceans can also develop neuropathological changes associated with neurodegenerative disease. The occurrence of neuropathology makes cetaceans an ideal species for examining the impact of marine toxins on the brain across the lifespan. Here, we describe TAR DNA-binding protein 43 (TDP-43) proteinopathy and Alzheimer's disease (AD) neuropathological changes in a beached harbor porpoise (Phocoena phocoena) that was exposed to a toxin produced by cyanobacteria called β-N-methylamino-L-alanine (BMAA). We found pathogenic TDP-43 cytoplasmic inclusions in neurons throughout the cerebral cortex, midbrain and brainstem. P62/sequestosome-1, responsible for the autophagy of misfolded proteins, was observed in the amygdala, hippocampus and frontal cortex. Genes implicated in AD and TDP-43 neuropathology such as APP and TARDBP were expressed in the brain. AD neuropathological changes such as amyloid-β plaques, neurofibrillary tangles, granulovacuolar degeneration and Hirano bodies were present in the hippocampus. These findings further support the development of progressive neurodegenerative disease in cetaceans and a potential causative link to cyanobacterial toxins. Climate change, nutrient pollution and industrial waste are increasing the frequency of harmful cyanobacterial blooms. Cyanotoxins like BMAA that are associated with neurodegenerative disease pose an increasing public health risk.}, } @article {pmid38252383, year = {2024}, author = {Vassileff, N and Spiers, JG and Lee, JD and Woodruff, TM and Ebrahimie, E and Mohammadi Dehcheshmeh, M and Hill, AF and Cheng, L}, title = {A Panel of miRNA Biomarkers Common to Serum and Brain-Derived Extracellular Vesicles Identified in Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {61}, number = {8}, pages = {5901-5915}, pmid = {38252383}, issn = {1559-1182}, support = {GNT1041413//National Health and Medical Research Council/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/blood/genetics/pathology/metabolism ; *Extracellular Vesicles/metabolism ; *MicroRNAs/genetics/metabolism/blood ; *Disease Models, Animal ; *Biomarkers/blood/metabolism ; *Brain/metabolism/pathology ; Mice ; Mice, Transgenic ; DNA-Binding Proteins/metabolism/genetics ; Male ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease characterised by the deposition of aggregated proteins including TAR DNA-binding protein 43 (TDP-43) in vulnerable motor neurons and the brain. Extracellular vesicles (EVs) facilitate the spread of neurodegenerative diseases and can be easily accessed in the bloodstream. This study aimed to identify a panel of EV miRNAs that can capture the pathology occurring in the brain and peripheral circulation. EVs were isolated from the cortex (BDEVs) and serum (serum EVs) of 3 month-old and 6-month-old TDP-43*Q331K and TDP-43*WT mice. Following characterisation and miRNA isolation, the EVs underwent next-generation sequencing where 24 differentially packaged miRNAs were identified in the TDP-43*Q331K BDEVs and 7 in the TDP-43*Q331K serum EVs. Several miRNAs, including miR-183-5p, were linked to ALS. Additionally, miR-122-5p and miR-486b-5p were identified in both panels, demonstrating the ability of the serum EVs to capture the dysregulation occurring in the brain. This is the first study to identify miRNAs common to both the serum EVs and BDEVs in a mouse model of ALS.}, } @article {pmid38253209, year = {2024}, author = {Yusuf, IO and Parsi, S and Ostrow, LW and Brown, RH and Thompson, PR and Xu, Z}, title = {PAD2 dysregulation and aberrant protein citrullination feature prominently in reactive astrogliosis and myelin protein aggregation in sporadic ALS.}, journal = {Neurobiology of disease}, volume = {192}, number = {}, pages = {106414}, pmid = {38253209}, issn = {1095-953X}, support = {R01 NS118145/NS/NINDS NIH HHS/United States ; R35 GM118112/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; *Citrullination ; Gliosis/metabolism ; Hydrolases/genetics/metabolism ; Myelin Proteins/metabolism ; Myelin Sheath/pathology ; Protein Aggregates ; Protein-Arginine Deiminase Type 2/metabolism ; Protein-Arginine Deiminases/metabolism ; Proteins/metabolism ; Spinal Cord/pathology ; }, abstract = {Alteration in protein citrullination (PC), a common posttranslational modification (PTM), contributes to pathogenesis in various inflammatory disorders. We previously reported that PC and protein arginine deiminase 2 (PAD2), the predominant enzyme isoform that catalyzes this PTM in the central nervous system (CNS), are altered in mouse models of amyotrophic lateral sclerosis (ALS). We now demonstrate that PAD2 expression and PC are altered in human postmortem ALS spinal cord and motor cortex compared to controls, increasing in astrocytes while trending lower in neurons. Furthermore, PC is enriched in protein aggregates that contain the myelin proteins PLP and MBP in ALS. These results confirm our findings in ALS mouse models and suggest that altered PAD2 and PC contribute to neurodegeneration in ALS.}, } @article {pmid38253550, year = {2024}, author = {Voorhees, J and Bailey, S and Waterman, H and Checkland, K}, title = {A paradox of problems in accessing general practice: a qualitative participatory case study.}, journal = {The British journal of general practice : the journal of the Royal College of General Practitioners}, volume = {74}, number = {739}, pages = {e104-e112}, pmid = {38253550}, issn = {1478-5242}, mesh = {Humans ; *General Practice ; Qualitative Research ; Family Practice ; Focus Groups ; England ; }, abstract = {BACKGROUND: Despite longstanding problems of access to general practice, attempts to understand and address the issues do not adequately include perspectives of the people providing or using care, nor do they use established theories of access to understand complexity.

AIM: To understand problems of access to general practice from the multiple perspectives of service users and staff using an applied theory of access.

DESIGN AND SETTING: A qualitative participatory case study in an area of northwest England.

METHOD: A community-based participatory approach was used with qualitative interviews, focus groups, and observation to understand perspectives about accessing general practice. Data were collected between October 2015 and October 2016. Inductive and abductive analysis, informed by Levesque et al's theory of access, allowed the team to identify complexities and relationships between interrelated problems.

RESULTS: This study presents a paradox of problems in accessing general practice, in which the demand on general practice both creates and hides unmet need in the population. Data show how reactive rules to control demand have undermined important aspects of care, such as continuity. The layers of rules and decreased continuity create extra work for practice staff, clinicians, and patients. Complicated rules, combined with a lack of capacity to reach out or be flexible, leave many patients, including those with complex and/or unrecognised health needs, unable to navigate the system to access care. This relationship between demand and unmet need exacerbates existing health inequities.

CONCLUSION: Understanding the paradox of access problems allows for different targets for change and different solutions to free up capacity in general practice to address the unmet need in the population.}, } @article {pmid38253707, year = {2024}, author = {El-Malla, SF and Hamza, AA and Elagamy, SH}, title = {Simultaneous determination of meloxicam and bupivacaine via a novel modified dual wavelength method and an advanced chemometric approach.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {1893}, pmid = {38253707}, issn = {2045-2322}, mesh = {Meloxicam ; *Chemometrics ; *Bupivacaine ; Chromatography, High Pressure Liquid ; Spectrophotometry ; }, abstract = {This study presents two spectrophotometric methods; a novel dual wavelength-derivative spectrophotometry and multivariate curve resolution-alternating least squares (MCR-ALS) for the simultaneous determination of a fixed dose combination of bupivacaine (BUP) and meloxicam (MEL) in a ratio of 30:1. The extended UV spectrum of MEL enables its direct determination at λmax 360 nm with no interference from BUP. The determination of BUP was unfeasible directly because the UV spectra of both drugs are moderately overlapped over the wavelength range of 250-450 nm, thus new chemometric based spectrophotometric methods should be developed for its determination. Dual wavelength-derivative method was employed based on using first derivative spectra. The selected dual wavelengths for determination BUP were 274.6 nm and 374.6 nm where the dA/dλ amplitudes differences for MET are equal to zero. MCR-ALS is advanced chemometric tool that enables analysis of multicomponent samples in complex matrices with high resolution based on the decomposition of signal/spectral data into the pure spectra and corresponding concentration profile. The figures of merits for MCR model show that there is a good agreement between the actual and predicted concentrations for MEL and BUP. The methods were validated and statistically compared with a reported HPLC method.}, } @article {pmid38254109, year = {2024}, author = {Nagy, ZF and Pál, M and Engelhardt, JI and Molnár, MJ and Klivényi, P and Széll, M}, title = {Beyond C9orf72: repeat expansions and copy number variations as risk factors of amyotrophic lateral sclerosis across various populations.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {30}, pmid = {38254109}, issn = {1755-8794}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; DNA Copy Number Variations ; Genes, Regulator ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another. The most frequent genetic cause of ALS is the repeat expansion of the C9orf72 gene. With the emergence of next-generation sequencing techniques and copy number alteration calling tools the focus in ALS genetics has shifted from disease causing genes and mutations towards genetic susceptibility and risk factors.In this review we aimed to summarize the most widely recognized and studied ALS linked repeat expansions and copy number variations other than the hexanucleotide repeat expansion in the C9orf72 gene. We compare and contrast their involvement and phenotype modifying roles in ALS among different populations.}, } @article {pmid38254150, year = {2024}, author = {Khalil, B and Linsenmeier, M and Smith, CL and Shorter, J and Rossoll, W}, title = {Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {8}, pmid = {38254150}, issn = {1750-1326}, support = {R33NS110960/NS/NINDS NIH HHS/United States ; R21AG061784/AG/NIA NIH HHS/United States ; RF1AG076122/AG/NIA NIH HHS/United States ; R01 AG068581/AG/NIA NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; R21 AG061784/AG/NIA NIH HHS/United States ; R33 NS110960/NS/NINDS NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; R21 AG079609/AG/NIA NIH HHS/United States ; R21AG065854/AG/NIA NIH HHS/United States ; W81XWH-20–1-0242//Department of Defense/ ; RF1 AG068581/AG/NIA NIH HHS/United States ; RF1 AG076122/AG/NIA NIH HHS/United States ; R21 AG085314/AG/NIA NIH HHS/United States ; R01 AG077771/AG/NIA NIH HHS/United States ; RF1AG068581/AG/NIA NIH HHS/United States ; R01GM099836/GM/NIGMS NIH HHS/United States ; R01 AG076122/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis ; Active Transport, Cell Nucleus ; DNA-Binding Proteins ; *Prions ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function. Here, we showcase the NIR family and how they recognize cargo, drive nuclear import, and chaperone prion-like RBPs linked to ALS/FTD. We also discuss the promise of enhancing NIR levels and developing potentiated NIR variants as therapeutic strategies for ALS/FTD and related neurodegenerative proteinopathies.}, } @article {pmid38254647, year = {2023}, author = {Lauria, G and Curcio, R and Tucci, P}, title = {A Machine Learning Approach for Highlighting microRNAs as Biomarkers Linked to Amyotrophic Lateral Sclerosis Diagnosis and Progression.}, journal = {Biomolecules}, volume = {14}, number = {1}, pages = {}, pmid = {38254647}, issn = {2218-273X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Biomarkers ; Machine Learning ; *MicroRNAs/genetics ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord. The early diagnosis of ALS can be challenging, as it usually depends on clinical examination and the exclusion of other possible causes. In this regard, the analysis of miRNA expression profiles in biofluids makes miRNAs promising non-invasive clinical biomarkers. Due to the increasing amount of scientific literature that often provides controversial results, this work aims to deepen the understanding of the current state of the art on this topic using a machine-learning-based approach. A systematic literature search was conducted to analyze a set of 308 scientific articles using the MySLR digital platform and the Latent Dirichlet Allocation (LDA) algorithm. Two relevant topics were identified, and the articles clustered in each of them were analyzed and discussed in terms of biomolecular mechanisms, as well as in translational and clinical settings. Several miRNAs detected in the tissues and biofluids of ALS patients, including blood and cerebrospinal fluid (CSF), have been linked to ALS diagnosis and progression. Some of them may represent promising non-invasive clinical biomarkers. In this context, future scientific priorities and goals have been proposed.}, } @article {pmid38256050, year = {2024}, author = {Bruno, A and Milillo, C and Anaclerio, F and Buccolini, C and Dell'Elice, A and Angilletta, I and Gatta, M and Ballerini, P and Antonucci, I}, title = {Perinatal Tissue-Derived Stem Cells: An Emerging Therapeutic Strategy for Challenging Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {2}, pages = {}, pmid = {38256050}, issn = {1422-0067}, mesh = {Female ; Pregnancy ; Humans ; *Neurodegenerative Diseases/therapy ; *Alzheimer Disease ; *Huntington Disease/therapy ; *Parkinson Disease/therapy ; Stem Cells ; }, abstract = {Over the past 20 years, stem cell therapy has been considered a promising option for treating numerous disorders, in particular, neurodegenerative disorders. Stem cells exert neuroprotective and neurodegenerative benefits through different mechanisms, such as the secretion of neurotrophic factors, cell replacement, the activation of endogenous stem cells, and decreased neuroinflammation. Several sources of stem cells have been proposed for transplantation and the restoration of damaged tissue. Over recent decades, intensive research has focused on gestational stem cells considered a novel resource for cell transplantation therapy. The present review provides an update on the recent preclinical/clinical applications of gestational stem cells for the treatment of protein-misfolding diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). However, further studies should be encouraged to translate this promising therapeutic approach into the clinical setting.}, } @article {pmid38256091, year = {2024}, author = {Iskusnykh, IY and Zakharova, AA and Kryl'skii, ED and Popova, TN}, title = {Aging, Neurodegenerative Disorders, and Cerebellum.}, journal = {International journal of molecular sciences}, volume = {25}, number = {2}, pages = {}, pmid = {38256091}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases ; Cerebellum ; *Alzheimer Disease ; *Huntington Disease ; Aging ; }, abstract = {An important part of the central nervous system (CNS), the cerebellum is involved in motor control, learning, reflex adaptation, and cognition. Diminished cerebellar function results in the motor and cognitive impairment observed in patients with neurodegenerative disorders such as Alzheimer's disease (AD), vascular dementia (VD), Parkinson's disease (PD), Huntington's disease (HD), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Friedreich's ataxia (FRDA), and multiple sclerosis (MS), and even during the normal aging process. In most neurodegenerative disorders, impairment mainly occurs as a result of morphological changes over time, although during the early stages of some disorders such as AD, the cerebellum also serves a compensatory function. Biological aging is accompanied by changes in cerebellar circuits, which are predominantly involved in motor control. Despite decades of research, the functional contributions of the cerebellum and the underlying molecular mechanisms in aging and neurodegenerative disorders remain largely unknown. Therefore, this review will highlight the molecular and cellular events in the cerebellum that are disrupted during the process of aging and the development of neurodegenerative disorders. We believe that deeper insights into the pathophysiological mechanisms of the cerebellum during aging and the development of neurodegenerative disorders will be essential for the design of new effective strategies for neuroprotection and the alleviation of some neurodegenerative disorders.}, } @article {pmid38259504, year = {2023}, author = {Rashid, S and Dimitriadi, M}, title = {Autophagy in spinal muscular atrophy: from pathogenic mechanisms to therapeutic approaches.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1307636}, pmid = {38259504}, issn = {1662-5102}, abstract = {Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by the depletion of the ubiquitously expressed survival motor neuron (SMN) protein. While the genetic cause of SMA has been well documented, the exact mechanism(s) by which SMN depletion results in disease progression remain elusive. A wide body of evidence has highlighted the involvement and dysregulation of autophagy in SMA. Autophagy is a highly conserved lysosomal degradation process which is necessary for cellular homeostasis; defects in the autophagic machinery have been linked with a wide range of neurodegenerative disorders, including amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. The pathway is particularly known to prevent neurodegeneration and has been suggested to act as a neuroprotective factor, thus presenting an attractive target for novel therapies for SMA patients. In this review, (a) we provide for the first time a comprehensive summary of the perturbations in the autophagic networks that characterize SMA development, (b) highlight the autophagic regulators which may play a key role in SMA pathogenesis and (c) propose decreased autophagic flux as the causative agent underlying the autophagic dysregulation observed in these patients.}, } @article {pmid38259506, year = {2023}, author = {Gallo, JM and Nishimura, A and Haapasalo, A}, title = {Editorial: Molecular mechanisms underlying C9orf72 neurodegeneration, volume II.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1357319}, pmid = {38259506}, issn = {1662-5102}, } @article {pmid38260082, year = {2023}, author = {Norgren, J and Kåreholt, I and Sindi, S}, title = {Is there evidence of a ketogenic effect of coconut oil? Commentary: Effect of the Mediterranean diet supplemented with nicotinamide riboside and pterostilbene and/or coconut oil on anthropometric variables in amyotrophic lateral sclerosis. A pilot study.}, journal = {Frontiers in nutrition}, volume = {10}, number = {}, pages = {1333933}, pmid = {38260082}, issn = {2296-861X}, } @article {pmid38260379, year = {2025}, author = {Zhu, Y and Cho, K and Lacin, H and Zhu, Y and DiPaola, JT and Wilson, BA and Patti, GJ and Skeath, JB}, title = {Loss of dihydroceramide desaturase drives neurodegeneration by disrupting endoplasmic reticulum and lipid droplet homeostasis in glial cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38260379}, issn = {2692-8205}, support = {P30 CA091842/CA/NCI NIH HHS/United States ; P30 DK020579/DK/NIDDK NIH HHS/United States ; R01 NS036570/NS/NINDS NIH HHS/United States ; R01 NS122903/NS/NINDS NIH HHS/United States ; }, abstract = {Dihydroceramide desaturases convert dihydroceramides to ceramides, the precursors of all complex sphingolipids. Reduction of DEGS1 dihydroceramide desaturase function causes pediatric neurodegenerative disorder hypomyelinating leukodystrophy-18 (HLD-18). We discovered that infertile crescent (ifc), the Drosophila DEGS1 homolog, is expressed primarily in glial cells to promote CNS development by guarding against neurodegeneration. Loss of ifc causes massive dihydroceramide accumulation and severe morphological defects in cortex glia, including endoplasmic reticulum (ER) expansion, failure of neuronal ensheathment, and lipid droplet depletion. RNAi knockdown of the upstream ceramide synthase schlank in glia of ifc mutants rescues ER expansion, suggesting dihydroceramide accumulation in the ER drives this phenotype. RNAi knockdown of ifc in glia but not neurons drives neuronal cell death, suggesting that ifc function in glia promotes neuronal survival. Our work identifies glia as the primary site of disease progression in HLD-18 and may inform on juvenile forms of ALS, which also feature elevated dihydroceramide levels.}, } @article {pmid38260395, year = {2024}, author = {Evangelista, BA and Ragusa, JV and Pellegrino, K and Wu, Y and Quiroga-Barber, IY and Cahalan, SR and Arooji, OK and Madren, JA and Schroeter, S and Cozzarin, J and Xie, L and Chen, X and White, KK and Ezzell, JA and Iannone, MA and Cohen, S and Traub, RE and Li, X and Bedlack, R and Phanstiel, DH and Meeker, R and Stanley, N and Cohen, TJ}, title = {TDP-43 pathology links innate and adaptive immunity in amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.07.574541}, pmid = {38260395}, issn = {2692-8205}, support = {R21 AG071229/AG/NIA NIH HHS/United States ; T35 AG038047/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis is the most common fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 pathology elicits disease-modifying immune responses in ALS remains underexplored. In this study, we demonstrate that TDP-43 pathology is internalized by antigen presenting cells, causes vesicle rupture, and leads to innate and adaptive immune cell activation. Using a multiplex imaging platform, we observed interactions between innate and adaptive immune cells near TDP-43 pathological lesions in ALS brain. We used a mass cytometry-based whole-blood stimulation assay to provide evidence that ALS patient peripheral immune cells exhibit responses to TDP-43 aggregates. Taken together, this study provides a novel link between TDP-43 pathology and ALS immune dysfunction, and further highlights the translational and diagnostic implications of monitoring and manipulating the ALS immune response.}, } @article {pmid38260601, year = {2024}, author = {Bosco, DB and Kremen, V and Haruwaka, K and Zhao, S and Wang, L and Ebner, BA and Zheng, J and Dheer, A and Perry, JF and Xie, M and Nguyen, AT and Worrell, GA and Wu, LJ}, title = {Impaired microglial phagocytosis promotes seizure development.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38260601}, issn = {2692-8205}, support = {R01 NS088627/NS/NINDS NIH HHS/United States ; R01 NS112144/NS/NINDS NIH HHS/United States ; R35 NS132326/NS/NINDS NIH HHS/United States ; }, abstract = {In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. TREM2 plays an important role in neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis. However, little is known about the role TREM2 plays in epileptogenesis. To investigate this, we utilized TREM2 knockout (KO) mice within the murine intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both acute status epilepticus and spontaneous recurrent seizures characteristic of chronic focal epilepsy. Mechanistically, phagocytic clearance of damaged neurons by microglia was impaired in TREM2 KO mice and the reduced phagocytic capacity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between microglial phagocytic activity and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity may be important to epileptogenesis and the progression of focal temporal lobe epilepsy.}, } @article {pmid38260655, year = {2024}, author = {Chen, D and Philippidou, P and Brenha, BF and Schaffer, AE and Miranda, HC}, title = {Scalable, optically-responsive human neuromuscular junction model reveals convergent mechanisms of synaptic dysfunction in familial ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.11.575304}, pmid = {38260655}, issn = {2692-8205}, support = {K01 NS116119/NS/NINDS NIH HHS/United States ; R01 NS114510/NS/NINDS NIH HHS/United States ; R01 NS121374/NS/NINDS NIH HHS/United States ; }, abstract = {Neuromuscular junctions (NMJs) are specialized synapses that mediate communication between motor neurons and skeletal muscles and are essential for movement. The degeneration of this system can lead to symptoms observed in neuromuscular and motor neuron diseases. Studying these synapses and their degeneration has proven challenging. Prior NMJ studies heavily relied upon the use of mouse, chick, or isolated primary human cells, which have demonstrated limited fidelity for disease modeling. To enable the study of NMJ dysfunction and model genetic diseases, we, and others, have developed methods to generate human NMJs from pluripotent stem cells (PSCs), embryonic stem cells, and induced pluripotent stem cells. However, published studies have highlighted technical limitations associated with these complex in vitro NMJ models. In this study, we developed a robust PSC-derived motor neuron and skeletal muscle co-culture method, and demonstrated its sensitivity in modeling motor neuron disease. Our method spontaneously and reproducibly forms human NMJs. We developed multiwell-multielectrode array (MEA) parameters to quantify the activity of PSC-derived skeletal muscles, as well as measured the electrophysiological activity of functional human PSC-derived NMJs. We further leveraged our method to morphologically and functionally assess NMJs from the familial amyotrophic lateral sclerosis (fALS) PSCs, C9orf72 hexanucleotide (G4C2)n repeat expansion (HRE), SOD1 [A5V] , and TDP43 [G298S] to define the reproducibility and sensitivity of our system. We observed a significant decrease in the numbers and activity of PSC-derived NMJs developed from the different ALS lines compared to their respective controls. Furthermore, we evaluated a therapeutic candidate undergoing clinical trials and observed a variant-dependent rescue of functionality of NMJs. Our newly developed method provides a platform for the systematic investigation of genetic causes of NMJ neurodegeneration and highlights the need for therapeutic avenues to consider patient genotype.}, } @article {pmid38260713, year = {2023}, author = {Geraci, J and Bhargava, R and Qorri, B and Leonchyk, P and Cook, D and Cook, M and Sie, F and Pani, L}, title = {Machine learning hypothesis-generation for patient stratification and target discovery in rare disease: our experience with Open Science in ALS.}, journal = {Frontiers in computational neuroscience}, volume = {17}, number = {}, pages = {1199736}, pmid = {38260713}, issn = {1662-5188}, abstract = {INTRODUCTION: Advances in machine learning (ML) methodologies, combined with multidisciplinary collaborations across biological and physical sciences, has the potential to propel drug discovery and development. Open Science fosters this collaboration by releasing datasets and methods into the public space; however, further education and widespread acceptance and adoption of Open Science approaches are necessary to tackle the plethora of known disease states.

MOTIVATION: In addition to providing much needed insights into potential therapeutic protein targets, we also aim to demonstrate that small patient datasets have the potential to provide insights that usually require many samples (>5,000). There are many such datasets available and novel advancements in ML can provide valuable insights from these patient datasets.

PROBLEM STATEMENT: Using a public dataset made available by patient advocacy group AnswerALS and a multidisciplinary Open Science approach with a systems biology augmented ML technology, we aim to validate previously reported drug targets in ALS and provide novel insights about ALS subpopulations and potential drug targets using a unique combination of ML methods and graph theory.

METHODOLOGY: We use NetraAI to generate hypotheses about specific patient subpopulations, which were then refined and validated through a combination of ML techniques, systems biology methods, and expert input.

RESULTS: We extracted 8 target classes, each comprising of several genes that shed light into ALS pathophysiology and represent new avenues for treatment. These target classes are broadly categorized as inflammation, epigenetic, heat shock, neuromuscular junction, autophagy, apoptosis, axonal transport, and excitotoxicity. These findings are not mutually exclusive, and instead represent a systematic view of ALS pathophysiology. Based on these findings, we suggest that simultaneous targeting of ALS has the potential to mitigate ALS progression, with the plausibility of maintaining and sustaining an improved quality of life (QoL) for ALS patients. Even further, we identified subpopulations based on disease onset.

CONCLUSION: In the spirit of Open Science, this work aims to bridge the knowledge gap in ALS pathophysiology to aid in diagnostic, prognostic, and therapeutic strategies and pave the way for the development of personalized treatments tailored to the individual's needs.}, } @article {pmid38261020, year = {2024}, author = {Ricci, V and Mezian, K and Chang, KV and Onishi, K and Kara, M and Naňka, O and Özçakar, L}, title = {Ultrasound-guided injection of the ankle joint: cadaveric investigation of the anterolateral approach.}, journal = {Surgical and radiologic anatomy : SRA}, volume = {46}, number = {2}, pages = {241-248}, pmid = {38261020}, issn = {1279-8517}, mesh = {Humans ; *Ankle Joint/diagnostic imaging ; Cadaver ; Injections, Intra-Articular/methods ; Ultrasonography, Interventional/methods ; }, abstract = {OBJECTIVE: Injection of the tibiotalar (TT) joint is commonly performed in clinical practice under ultrasound (US) guidance using an anteromedial approach. However, in some patients, this approach may be technically challenging due to post-traumatic and/or degenerative bony changes. Therefore, the aim of this cadaveric investigation was to demonstrate the feasibility of the ultrasound-guided (USG) injection of the ankle joint via the anterolateral sulcus (ALS) by confirming the dye placement/distribution inside the articular space. Likewise, the safety of the procedure has also been evaluated by measuring the distance between the needle and the intermediate dorsal cutaneous nerve of the foot.

DESIGN: A descriptive laboratory study with eight embalmed cadaveric ankles using the Fix for Life (F4L) method was performed at the setting of an academic institution. The interventional technique and the related anatomical findings were illustrated. During the injection, the needle was advanced into the TT joint through the ALS under US guidance, i.e., in-plane anterior-to-posterior approach. With the objective to confirm its correct placement, the needle was kept in situ and-to demonstrate the location of the dye inside the articular space-all eight ankles were injected with 3 mL of green color dye. Thereafter, a layer-by-layer anatomical dissection was performed on all four cadavers.

RESULTS: The position of the needle's tip within the ALS was confirmed in all specimens. Accurate placement of the dye inside the articular space of the ankle was confirmed in seven of the eight cadaveric ankles, with 87.5% of accuracy. Herewith, unintentional spilling of the dye within the superficial soft tissues was reported in two of the eight ankles (25.0%). The mean distance between the needle and the intermediate dorsal cutaneous nerve of the foot, measured in all eight procedures, was 3 cm.

CONCLUSION: USG injection of the ALS using the in-plane, anterior-to-posterior approach can accurately place the injectate inside the articular space.

CLINICAL RELEVANCE: This cadaveric investigation described the accuracy and potential pitfalls of USG injection of the ankle via the anterolateral approach which represents an alternative technique in patients with reduced accessibility of the anteromedial recess due to degenerative and/or post-traumatic bony changes.}, } @article {pmid38261034, year = {2024}, author = {Sian-Hulsmann, J and Riederer, P}, title = {Virus-induced brain pathology and the neuroinflammation-inflammation continuum: the neurochemists view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {131}, number = {12}, pages = {1429-1453}, pmid = {38261034}, issn = {1435-1463}, mesh = {Humans ; *Neuroinflammatory Diseases/pathology/immunology/metabolism ; Animals ; Neurodegenerative Diseases/pathology/metabolism/immunology ; Brain/pathology/metabolism/immunology ; Inflammation/pathology/metabolism/immunology ; }, abstract = {Fascinatingly, an abundance of recent studies has subscribed to the importance of cytotoxic immune mechanisms that appear to increase the risk/trigger for many progressive neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis, and multiple sclerosis. Events associated with the neuroinflammatory cascades, such as ageing, immunologic dysfunction, and eventually disruption of the blood-brain barrier and the "cytokine storm", appear to be orchestrated mainly through the activation of microglial cells and communication with the neurons. The inflammatory processes prompt cellular protein dyshomeostasis. Parkinson's and Alzheimer's disease share a common feature marked by characteristic pathological hallmarks of abnormal neuronal protein accumulation. These Lewy bodies contain misfolded α-synuclein aggregates in PD or in the case of AD, they are Aβ deposits and tau-containing neurofibrillary tangles. Subsequently, these abnormal protein aggregates further elicit neurotoxic processes and events which contribute to the onset of neurodegeneration and to its progression including aggravation of neuroinflammation. However, there is a caveat for exclusively linking neuroinflammation with neurodegeneration, since it's highly unlikely that immune dysregulation is the only factor that contributes to the manifestation of many of these neurodegenerative disorders. It is unquestionably a complex interaction with other factors such as genetics, age, and environment. This endorses the "multiple hit hypothesis". Consequently, if the host has a genetic susceptibility coupled to an age-related weakened immune system, this makes them more susceptible to the virus/bacteria-related infection. This may trigger the onset of chronic cytotoxic neuroinflammatory processes leading to protein dyshomeostasis and accumulation, and finally, these events lead to neuronal destruction. Here, we differentiate "neuroinflammation" and "inflammation" with regard to the involvement of the blood-brain barrier, which seems to be intact in the case of neuroinflammation but defect in the case of inflammation. There is a neuroinflammation-inflammation continuum with regard to virus-induced brain affection. Therefore, we propose a staging of this process, which might be further developed by adding blood- and CSF parameters, their stage-dependent composition and stage-dependent severeness grade. If so, this might be suitable to optimise therapeutic strategies to fight brain neuroinflammation in its beginning and avoid inflammation at all.}, } @article {pmid38261256, year = {2024}, author = {Ouyang, J and Peng, S and Wu, G and Liu, R}, title = {Association Between Neurodegenerative Diseases and an Increased Risk of Epilepsy Based on Single Nucleotide Polymorphisms: A Mendelian Randomization Study.}, journal = {Molecular neurobiology}, volume = {61}, number = {8}, pages = {5950-5957}, pmid = {38261256}, issn = {1559-1182}, mesh = {Humans ; *Polymorphism, Single Nucleotide/genetics ; *Mendelian Randomization Analysis ; *Epilepsy/genetics ; *Genetic Predisposition to Disease ; *Neurodegenerative Diseases/genetics/epidemiology ; Genome-Wide Association Study ; Risk Factors ; }, abstract = {Epilepsy is a common neurological disorder characterized by transient brain dysfunction, attributed to a multitude of factors. The purpose of this study is to explore whether neurodegenerative diseases, specifically Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), have a causal effect on epilepsy. Mendelian randomization (MR) methods were used to analyze the causal association between neurodegenerative diseases (AD, PD, ALS, and MS) and epilepsy based on single nucleotide polymorphisms from genome-wide association studies, including inverse-variance weighted, weighted median, MR-Egger, and weighted mode methods. The reliability and stability of the MR analysis results were assessed by the MR-Egger intercept, MR-PRESSO, and heterogeneity tests. Forty-three SNPs were selected for the MR analysis of MS and epilepsy. The inverse-variance weighted method showed a significant causal association between MS and increased risk of epilepsy (odds ratio 1.046; 95% confidence interval 1.001-1.093; P = 0.043). However, AD (P = 0.986), PD (P = 0.894), and ALS (P = 0.533) were not causally associated with epilepsy. Sensitivity analysis showed that the results were robust. The MR study confirmed the causal relationship between genetically predicted MS and epilepsy but did not support the causal relationship between genetically predicted AD, PD, and ALS on epilepsy.}, } @article {pmid38261295, year = {2024}, author = {Khabibrakhmanov, AN and Zueva, IV and Petrov, KA and Bogdanov, EI and Mukhamedyarov, MA}, title = {[Plasma and salivary acetylcholinesterase activity in amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {1}, pages = {128-134}, doi = {10.17116/jnevro2024124011128}, pmid = {38261295}, issn = {1997-7298}, mesh = {Animals ; Humans ; Mice ; Middle Aged ; *Acetylcholinesterase ; *Amyotrophic Lateral Sclerosis/diagnosis ; Mice, Transgenic ; Saliva ; }, abstract = {OBJECTIVE: Assessment of plasma and salivary acetylcholinesterase (AChE) activity in patients with amyotrophic lateral sclerosis (ALS) and in an animal model of the disease.

MATERIAL AND METHODS: We studied 41 participants, aged 31 to 71 years, including 17 patients with diagnosed ALS (ALS group, average age 62.3±2.2), 9 patients with ALS mimics (disease control, average age 58.1±2.9), and 15 healthy people (normal control, average age 57.7±2.3). Plasma and salivary AChE activity was measured by using the Ellman colorimetric method. ALS severity was assessed using the ALSFRS-R scale. The King's College staging system and the Milano-Torino Scale (MiToS) were used to determine the stage of the disease. Transgenic FUS-mice were used as ALS model.

RESULTS: Plasma AChE activity in the ALS group did not significantly differ from the control groups. There was also no significant correlation between plasma AChE activity and disease parameters such as the stage, duration, rate of progression, and severity. In transgenic FUS-mice plasma AChE activity also did not differ from wild-type mice. However, it has been shown that patients with ALS have significantly higher saliva AChE activity compared to normal controls. However, patients with the bulbar form of ALS had significantly higher values of salivary AChE activity compared to healthy controls.

CONCLUSION: In patients with the bulbar form of ALS, an increase in salivary AChE activity was noted, which can be used for diagnostic and prognostic purposes. There is no significant change in plasma AChE activity in ALS patients.}, } @article {pmid38261358, year = {2024}, author = {}, title = {Correction to: Persistence of Kii amyotrophic lateral sclerosis after the 2000s and its characteristic aging-related tau astrogliopathy.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {9}, pages = {795}, doi = {10.1093/jnen/nlae006}, pmid = {38261358}, issn = {1554-6578}, } @article {pmid38261942, year = {2024}, author = {Sumera, K and Ilczak, T and Bakkerud, M and Lane, JD and Pallas, J and Martorell, SO and Sumera, A and Webster, CA and Quinn, T and Sandars, J and Niroshan Siriwardena, A}, title = {CPR Quality Officer role to improve CPR quality: A multi-centred international simulation randomised control trial.}, journal = {Resuscitation plus}, volume = {17}, number = {}, pages = {100537}, pmid = {38261942}, issn = {2666-5204}, abstract = {BACKGROUND: An out-of-hospital cardiac arrest requires early recognition, prompt and quality clinical interventions, and coordination between different clinicians to improve outcomes. Clinical team leaders and clinical teams have high levels of cognitive burden. We aimed to investigate the effect of a dedicated Cardio-Pulmonary Resuscitation (CPR) Quality Officer role on team performance.

METHODS: This multi-centre randomised control trial used simulation in universities from the UK, Poland, and Norway. Student Paramedics participated in out-of-hospital cardiac arrest scenarios before randomisation to either traditional roles or assigning one member as the CPR Quality Officer. The quality of CPR was measured using QCPR® and Advanced Life Support (ALS) elements were evaluated.

RESULTS: In total, 36 teams (108 individuals) participated. CPR quality from the first attempt (72.45%, 95% confidence interval [CI] 64.94 to 79.97) significantly increased after addition of the CPR Quality role (81.14%, 95% CI 74.20 to 88.07, p = 0.045). Improvement was not seen in the control group. The time to first defibrillation had no significant difference in the intervention group between the first attempt (53.77, 95% CI 36.57-70.98) and the second attempt (48.68, 95% CI 31.31-66.05, p = 0.84). The time to manage an obstructive airway in the intervention group showed significant difference (p = 0.006) in the first attempt (168.95, 95% CI 110.54-227.37) compared with the second attempt (136.95, 95% CI 87.03-186.88, p = 0.1).

CONCLUSION: A dedicated CPR Quality Officer in simulated scenarios improved the quality of CPR compressions without a negative impact on time to first defibrillation, managing the airway, or adherence to local ALS protocols.}, } @article {pmid38261982, year = {2024}, author = {Moglia, C and Calvo, A and Canosa, A and Manera, U and Vasta, R and Di Pede, F and Daviddi, M and Matteoni, E and Brunetti, M and Sbaiz, L and Cabras, S and Gallone, S and Grassano, M and Peotta, L and Palumbo, F and Mora, G and Iazzolino, B and Chio, A}, title = {Cognitive and Behavioral Features of Patients With Amyotrophic Lateral Sclerosis Who Are Carriers of the TARDBP Pathogenic Variant.}, journal = {Neurology}, volume = {102}, number = {4}, pages = {e208082}, pmid = {38261982}, issn = {1526-632X}, mesh = {Aged ; Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis ; *Apathy ; Cognition ; *Frontotemporal Dementia ; Memory, Short-Term ; Male ; DNA-Binding Proteins ; }, abstract = {BACKGROUND AND OBJECTIVES: TARDBP patients are considered particularly prone to cognitive involvement, but no systematic studies of cognitive impairment in TARDBP patients are available. The aim of this article was to depict in depth the cognitive-behavioral characteristics of a cohort of patients with amyotrophic lateral sclerosis (ALS) carrying TARDBP pathogenetic variants followed by an ALS referral center.

METHODS: We enrolled all patients with ALS seen at the Turin ALS expert center in the 2009-2021 period who underwent extensive genetic testing and a neuropsychological battery encompassing executive function, verbal memory, language, visual memory, visuoconstructive abilities, attention/working memory, psychomotor speed, nonverbal intelligence, cognitive flexibility, social cognition, and behavior. Tests were compared with the Mann-Whitney U test on age-corrected, sex-corrected, and education-corrected scores. Cognition was classified as normal (ALS-CN); isolated cognitive impairment (ALSci), that is, evidence of executive and/or language dysfunction; isolated behavioral impairment (ALSbi), that is, identification of apathy; cognitive and behavioral impairment (ALScbi), that is, evidence meeting the criteria for both ALSci and ALSbi; and frontotemporal dementia (ALS-FTD).

RESULTS: This study includes 33 patients with TARDBP pathogenetic variants (TARDBP-ALS) (median age 61 years [interquartile range (IQR) 53-67], 8 female [24.2%]) and 928 patients with ALS not carrying the pathogenic variant (WT-ALS) (median age 67 years [IQR 59-74], 386 female [41.6%]). TARDBP-ALS cases were also compared with 129 matched controls (median age 66 years [IQR 57.5-71.5], 55 female [42.6%]). TARDBP-ALS and WT-ALS patients were cognitively classified as ALS-CN (54% vs 58.8%, respectively), ALSci (21.2% vs 18.3%), ALSci (9.1% vs 9.5%), ALScbi (6.1% vs 6.0%), and ALS-FTD (9.1 vs 6.7%), with no significant difference (p = 0.623). Compared with controls, TARDBP-ALS had a worse performance in executive functions, visual memory, visuoconstructive abilities, verbal fluency, and the apathy behavioral component of FrSBe. The scores of performed tests, including all Edinburgh Cognitive and Behavioral ALS Screen subdomains, were similar in TARDBP-ALS and WT-ALS.

DISCUSSION: TARDBP-ALS patients were significantly more impaired than controls in most examined domains but do not show any specific pattern of cognitive impairment compared with WT-ALS. Our findings are relevant both clinically, considering the effect of cognitive impairment on patients' decision-making and caregivers' burden, and in designing clinical trials for the treatment of patients carrying TARDBP pathogenetic variants.}, } @article {pmid38262101, year = {2024}, author = {Masegosa, VM and Navarro, X and Herrando-Grabulosa, M}, title = {ICA-27243 improves neuromuscular function and preserves motoneurons in the transgenic SOD1[G93A] mice.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {2}, pages = {e00319}, pmid = {38262101}, issn = {1878-7479}, mesh = {Mice ; Animals ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Motor Neurons ; Spinal Cord ; Disease Models, Animal ; Superoxide Dismutase ; *Benzamides ; *Pyridines ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the death of upper and lower motor neurons (MNs). Excessive neuronal excitability has been implicated in MN degeneration; thus, modulation of hyperexcitability appears as a promising therapeutic strategy. Potassium channels are attractive targets since they can be activated at subthreshold voltages and can regulate neuronal excitability. In this study, we assayed the effects of N-(6-Chloro-pyridin-3-yl)-3,4-difluorobenzamide compound, known as ICA-27243, as a potential treatment for ALS. ICA-27243 is a highly selective Kv7.2/7.3 opener used mainly in epilepsy models. In the in vitro model of spinal cord organotypic cultures (SCOCs) exposed to acute excitotoxicity, ICA-27243 prevented MN degeneration at a dose-of 10 μM. Administration of ICA-27243 to transgenic SOD1[G93A] ALS mice improved the decline of neuromuscular function, maintained locomotion and coordination in the rotarod, decreased spinal MN death and attenuated glial reactivity. In conclusion, we report here for the first time that ICA-27243 is an effective treatment for ALS, emphasizing the potential of targeting Kv channels to reduce neuronal hyperexcitability.}, } @article {pmid38262892, year = {2024}, author = {Adams-Mitchell, CJ and Smith, WR and Wilkie, DJ}, title = {Dysphagia in patients with sickle cell disease: An understudied problem.}, journal = {Journal of the National Medical Association}, volume = {116}, number = {2 Pt 1}, pages = {126-130}, doi = {10.1016/j.jnma.2023.11.005}, pmid = {38262892}, issn = {1943-4693}, mesh = {Humans ; *Deglutition Disorders/complications/diagnosis ; *Anemia, Sickle Cell/complications ; *Stroke/complications ; *Nervous System Diseases/complications ; *Parkinson Disease ; }, abstract = {Dysphagia which is defined as disordered swallowing is well known as one of the most common and dangerous symptoms of many diseases, including neurological disorders such as Parkinson's disease, amyotrophic lateral sclerosis, myasthenia gravis, and most commonly, stroke. Strokes are a potentially devastating complication of sickle cell disease (SCD), the most common genetic hemoglobinopathy worldwide, yet little is known about dysphagia as it relates to SCD. Thus, the purposes of this article are to review briefly the primary causes and health consequences of dysphagia, to highlight the relevance of dysphagia to SCD, to review what little is known about dysphagia in SCD, to recommend, based on our consensus and the available literature, when to screen, evaluate, and monitor dysphagia in patients with SCD, and to outline unanswered questions where research on dysphagia in SCD might improve health outcomes.}, } @article {pmid38263228, year = {2024}, author = {Ayyappan, MV and Kishore, P and Panda, SK and Kumar, A and Uchoi, D and Nadella, RK and Priyadarshi, H and Obaiah, MC and George, D and Hamza, M and Ramannathan, SK and Ravishankar, CN}, title = {Emergence of multidrug resistant, ctx negative seventh pandemic Vibrio cholerae O1 El Tor sequence type (ST) 69 in coastal water of Kerala, India.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {2031}, pmid = {38263228}, issn = {2045-2322}, mesh = {Animals ; *Vibrio cholerae O1 ; Ecosystem ; Pandemics ; Phylogeny ; *Cholera ; India ; *Lepidoptera ; Water ; }, abstract = {Seventh pandemic Vibrio choleare O1 El Tor strain is responsible for the on-going pandemic outbreak of cholera globally. This strain evolved from non-pathogenic V. cholerae by acquiring seventh pandemic gene (VC 2346), pandemic Islands (VSP1 and VSP2), pathogenicity islands (VP1 and VP2) and CTX prophage region. The cholera toxin production is mainly attributed to the presence of ctx gene in these strains. However, several variants of this strain emerged as hybrid strains or atypical strains. The present study aimed to assess the aquatic environment of Cochin, India, over a period of 5 years for the emergence of multidrug resistant V. cholerae and its similarity with seventh pandemic strain. The continuous surveillance and monitoring resulted in the isolation of ctx negative, O1 positive V. cholerae isolate (VC6) from coastal water, Cochin, Kerala. The isolate possessed the biotype specific O1 El Tor tcpA gene and lacked other biotype specific ctx, zot, ace and rst genes. Whole genome analysis revealed the isolate belongs to pandemic sequence type (ST) 69 with the possession of pandemic VC2346 gene, pathogenic island VPI1, VPI2, and pandemic island VSP1 and VSP2. The isolate possessed several insertion sequences and the SXT/R391 family related Integrative Conjugative Elements (ICEs). In addition to this, the isolate genome carried virulence genes such as VgrG, mshA, ompT, toxR, ompU, rtxA, als, VasX, makA, and hlyA and antimicrobial resistance genes such as gyrA, dfrA1, strB, parE, sul2, parC, strA, VC1786ICE9-floR, and catB9. Moreover, the phylogenetic analysis suggests that the isolate genome is more closely related to seventh pandemic V. cholerae O1 N16961 strain. This study reports the first incidence of environmental ctx negative seventh pandemic V. choleare O1 El Tor isolate, globally and its presence in the aquatic system likely to induce toxicity in terms of public health point of view. The presence of this isolate in the aquatic environment warns the strict implementation of the epidemiological surveillance on the occurrence of emerging strains and the execution of flagship program for the judicious use of antibiotics in the aquatic ecosystem.}, } @article {pmid38264389, year = {2023}, author = {Gouveia, C and Araújo, L and Freitas, S and Correia, J and Passos, V and Camacho, G and Gomes, L and Fragoeiro, H and Camacho, C and Chambino, B}, title = {A Palliative Care Approach to Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e51048}, pmid = {38264389}, issn = {2168-8184}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a degenerative disease characterized by motor dysfunction. Currently, treatment options are limited and management is based mostly on symptom control and quality of life optimization, so palliative care plays a fundamental role. Our objective was to characterize the ALS population in Madeira Island that was referenced and/or followed by a palliative care unit over a five-year period.

METHODS: Longitudinal, retrospective, descriptive, and observational study to analyze patients with ALS who were referred and/or followed by a palliative care unit during a five-year period, between 2017 and 2021. Patient's medical electronic and physical records were analyzed to gather data. Descriptive and inferential statistical analysis was done using Microsoft Excel and Statistical Package for the Social Sciences (version 28.0.1).

RESULTS: During this five-year period, a total of 38 patients were diagnosed with ALS in Madeira Island and 23 (60.53%) were referred to palliative care. Three patients died before assessment, so 20 (50.63%) were followed by the palliative care team. They had a median life expectancy of 425 days and the median time spent in palliative care was 137 days. Of this population, 56.52% (n=13) was male with an average age of 64 years. The median period from diagnosis to referral was 167 days, with most referrals being made by family medicine (39.13%; n=9) motivated by uncontrolled symptoms (95.65%; n=22). The median period from referral to first assessment by a palliative care physician was 19 days. The Palliative Performance Scale (PPS) and Confusion Assessment Method (CAM) applied on the first visit had a median score of 40% in the former and was negative in 95.00% (n=19) of patients in the latter. Advanced care directives were present in 55.00% (n=11) of patients and all provided care was in accordance with the patient's wishes. The most common symptoms were dysphagia, dyspnea, pain, anxiety, and sialorrhea. The most used drugs were morphine, riluzole, butylscopolamine, bisacodyl, and midazolam. As for other interventions, 55.00% (n=11) of patients underwent noninvasive ventilation (NIV), 15.00% (n=3) were submitted to percutaneous endoscopic gastrostomy (PEG), and one patient (5.00%) was nasogastrically intubated. The death rate was 95.00% (n=19) with 73.68% (n=14) of deaths occurring in the palliative care unit.

CONCLUSION: Literature has shown that there are many advantages to the early inclusion of palliative care in ALS management, achieving effective symptom control and greater quality of life, but also reducing caregiver burden. However, in this study, we found that referrals to palliative care were late and included mostly cases of advanced disease with uncontrolled symptoms.}, } @article {pmid38265475, year = {2024}, author = {Xiang, Y and Song, X and Long, D}, title = {Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases.}, journal = {Archives of toxicology}, volume = {98}, number = {3}, pages = {579-615}, pmid = {38265475}, issn = {1432-0738}, support = {81673227//National Natural Science Foundation of China/ ; 2020JJ4080//Natural Science Foundation of Hunan Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; NF-E2-Related Factor 2/metabolism ; *Ferroptosis ; Oxidative Stress/physiology ; Antioxidants/metabolism ; }, abstract = {This article provides an overview of the background knowledge of ferroptosis in the nervous system, as well as the key role of nuclear factor E2-related factor 2 (Nrf2) in regulating ferroptosis. The article takes Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as the starting point to explore the close association between Nrf2 and ferroptosis, which is of clear and significant importance for understanding the mechanism of neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links ferroptosis to the pathogenesis of NDs. As the disease progresses, damage to the antioxidant system, excessive OS, and altered Nrf2 expression levels, especially the inhibition of ferroptosis by lipid peroxidation inhibitors and adaptive enhancement of Nrf2 signaling, demonstrate the potential clinical significance of Nrf2 in detecting and identifying ferroptosis, as well as targeted therapy for neuronal loss and mitochondrial dysfunction. These findings provide new insights and possibilities for the treatment and prevention of NDs.}, } @article {pmid38266701, year = {2024}, author = {Eisen, A and Nedergaard, M and Gray, E and Kiernan, MC}, title = {The glymphatic system and Amyotrophic lateral sclerosis.}, journal = {Progress in neurobiology}, volume = {234}, number = {}, pages = {102571}, doi = {10.1016/j.pneurobio.2024.102571}, pmid = {38266701}, issn = {1873-5118}, mesh = {Humans ; *Glymphatic System/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/metabolism ; Brain/metabolism ; *Alzheimer Disease/metabolism ; Sleep ; }, abstract = {The glymphatic system and the meningeal lymphatic vessels provide a pathway for transport of solutes and clearance of toxic material from the brain. Of specific relevance to ALS, this is applicable for TDP-43 and glutamate, both major elements in disease pathogenesis. Flow is propelled by arterial pulsation, respiration, posture, as well as the positioning and proportion of aquaporin-4 channels (AQP4). Non-REM slow wave sleep is the is key to glymphatic drainage which discontinues during wakefulness. In Parkinson's disease and Alzheimer's disease, sleep impairment is known to predate the development of characteristic clinical features by several years and is associated with progressive accumulation of toxic proteinaceous products. While sleep issues are well described in ALS, consideration of preclinical sleep impairment or the potential of a failing glymphatic system in ALS has rarely been considered. Here we review how the glymphatic system may impact ALS. Preclinical sleep impairment as an unrecognized major risk factor for ALS is considered, while potential therapeutic options to improve glymphatic flow are explored.}, } @article {pmid38266764, year = {2024}, author = {Lundt, S and Zhang, N and Polo-Parada, L and Wang, X and Ding, S}, title = {Dietary NMN supplementation enhances motor and NMJ function in ALS.}, journal = {Experimental neurology}, volume = {374}, number = {}, pages = {114698}, pmid = {38266764}, issn = {1090-2430}, support = {R01 NS069726/NS/NINDS NIH HHS/United States ; R01 NS094539/NS/NINDS NIH HHS/United States ; R01 NS123023/NS/NINDS NIH HHS/United States ; R21 AG080715/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; NAD/metabolism ; Neuromuscular Junction/metabolism ; Dietary Supplements ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that causes the degeneration of motor neurons in the motor cortex and spinal cord. Patients with ALS experience muscle weakness and atrophy in the limbs which eventually leads to paralysis and death. NAD[+] is critical for energy metabolism, such as glycolysis and oxidative phosphorylation, but is also involved in non-metabolic cellular reactions. In the current study, we determined whether the supplementation of nicotinamide mononucleotide (NMN), an NAD[+] precursor, in the diet had beneficial impacts on disease progression using a SOD1[G93A] mouse model of ALS. We found that the ALS mice fed with an NMN-supplemented diet (ALS[+NMN] mice) had modestly extended lifespan and exhibited delayed motor dysfunction. Using electrophysiology, we studied the effect of NMN on synaptic transmission at neuromuscular junctions (NMJs) in symptomatic of ALS mice (18 weeks old). ALS[+NMN] mice had larger end-plate potential (EPP) amplitudes and maintained better responses than ALS mice, and also had restored EPP facilitation. While quantal content was not affected by NMN, miniature EPP (mEPP) amplitude and frequency were elevated in ALS[+NMN] mice. NMN supplementation in diet also improved NMJ morphology, innervation, mitochondrial structure, and reduced reactive astrogliosis in the ventral horn of the lumbar spinal cord. Overall, our results indicate that dietary consumption of NMN can slow motor impairment, enhance NMJ function and improve healthspan of ALS mice.}, } @article {pmid38267040, year = {2024}, author = {Fukui, Y and Shirakawa, H and Kaneko, S and Nagayasu, K}, title = {Wild-Type DCTN1 Suppresses the Aggregation of DCTN1 Mutants Associated with Perry Disease.}, journal = {Biological & pharmaceutical bulletin}, volume = {47}, number = {1}, pages = {253-258}, doi = {10.1248/bpb.b23-00828}, pmid = {38267040}, issn = {1347-5215}, mesh = {Humans ; Dynactin Complex/genetics ; HEK293 Cells ; Cytosol ; Mutation ; *Motor Neuron Disease ; }, abstract = {Perry disease, a rare autosomal dominant neurodegenerative disorder, is characterized by parkinsonism, depression or apathy, unexpected weight loss, and central hypoventilation. Genetic analyses have revealed a strong association between point mutations in the dynactin I gene (DCTN1) coding p150[glued] and Perry disease. Although previous reports have suggested a critical role of p150[glued] aggregation in Perry disease pathology, whether and how p150[glued] mutations affect protein aggregation is not fully understood. In this study, we comprehensively investigated the intracellular distribution of the p150[glued] mutants in HEK293T cells. We further assessed the effect of co-overexpression of the wild-type p150[glued] protein with mutants on the formation of mutant aggregates. Notably, overexpression of p150[glued] mutants identified in healthy controls, which is also associated with amyotrophic lateral sclerosis, showed a thread-like cytoplasmic distribution, similar to the wild-type p150[glued]. In contrast, p150[glued] mutants in Perry disease and motor neuron disease caused aggregation. In addition, the co-overexpression of the wild-type protein with p150[glued] mutants in Perry disease suppressed aggregate formation. In contrast, the p150[glued] aggregation of motor neuron disease mutants was less affected by the wild-type p150[glued]. Further investigation of the mechanism of aggregate formation, contents of the aggregates, and biological mechanisms of Perry disease could help develop novel therapeutics.}, } @article {pmid38267282, year = {2024}, author = {Tortorella, MEC and Alves, I and Gromicho, M and Santos, MO and de Carvalho, M}, title = {Proton pump inhibitors and amyotrophic lateral sclerosis: A case-control study.}, journal = {Journal of the neurological sciences}, volume = {457}, number = {}, pages = {122895}, doi = {10.1016/j.jns.2024.122895}, pmid = {38267282}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Case-Control Studies ; Proton Pump Inhibitors/adverse effects ; Disease Progression ; }, } @article {pmid38267456, year = {2024}, author = {Feró, O and Varga, D and Nagy, É and Karányi, Z and Sipos, É and Engelhardt, J and Török, N and Balogh, I and Vető, B and Likó, I and Fóthi, Á and Szabó, Z and Halmos, G and Vécsei, L and Arányi, T and Székvölgyi, L}, title = {DNA methylome, R-loop and clinical exome profiling of patients with sporadic amyotrophic lateral sclerosis.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {123}, pmid = {38267456}, issn = {2052-4463}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; DNA ; Epigenome ; Exome ; R-Loop Structures ; *DNA Methylation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the death of motor neurons, the aetiology of which is essentially unknown. Here, we present an integrative epigenomic study in blood samples from seven clinically characterised sporadic ALS patients to elucidate molecular factors associated with the disease. We used clinical exome sequencing (CES) to study DNA variants, DNA-RNA hybrid immunoprecipitation sequencing (DRIP-seq) to assess R-loop distribution, and reduced representation bisulfite sequencing (RRBS) to examine DNA methylation changes. The above datasets were combined to create a comprehensive repository of genetic and epigenetic changes associated with the ALS cases studied. This repository is well-suited to unveil new correlations within individual patients and across the entire patient cohort. The molecular attributes described here are expected to guide further mechanistic studies on ALS, shedding light on the underlying genetic causes and facilitating the development of new epigenetic therapies to combat this life-threatening disease.}, } @article {pmid38267577, year = {2024}, author = {Obara, CJ and Nixon-Abell, J and Moore, AS and Riccio, F and Hoffman, DP and Shtengel, G and Xu, CS and Schaefer, K and Pasolli, HA and Masson, JB and Hess, HF and Calderon, CP and Blackstone, C and Lippincott-Schwartz, J}, title = {Motion of VAPB molecules reveals ER-mitochondria contact site subdomains.}, journal = {Nature}, volume = {626}, number = {7997}, pages = {169-176}, pmid = {38267577}, issn = {1476-4687}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/genetics ; *Endoplasmic Reticulum/chemistry/metabolism/ultrastructure ; *Mitochondria/chemistry/metabolism/ultrastructure ; *Mitochondrial Membranes/chemistry/metabolism/ultrastructure ; Signal Transduction ; *Vesicular Transport Proteins/genetics/metabolism/ultrastructure ; Microscopy, Electron ; Imaging, Three-Dimensional ; Binding Sites ; Diffusion ; Time Factors ; Mutation ; Homeostasis ; *Movement ; }, abstract = {To coordinate cellular physiology, eukaryotic cells rely on the rapid exchange of molecules at specialized organelle-organelle contact sites[1,2]. Endoplasmic reticulum-mitochondrial contact sites (ERMCSs) are particularly vital communication hubs, playing key roles in the exchange of signalling molecules, lipids and metabolites[3,4]. ERMCSs are maintained by interactions between complementary tethering molecules on the surface of each organelle[5,6]. However, due to the extreme sensitivity of these membrane interfaces to experimental perturbation[7,8], a clear understanding of their nanoscale organization and regulation is still lacking. Here we combine three-dimensional electron microscopy with high-speed molecular tracking of a model organelle tether, Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), to map the structure and diffusion landscape of ERMCSs. We uncovered dynamic subdomains within VAPB contact sites that correlate with ER membrane curvature and undergo rapid remodelling. We show that VAPB molecules enter and leave ERMCSs within seconds, despite the contact site itself remaining stable over much longer time scales. This metastability allows ERMCSs to remodel with changes in the physiological environment to accommodate metabolic needs of the cell. An amyotrophic lateral sclerosis-associated mutation in VAPB perturbs these subdomains, likely impairing their remodelling capacity and resulting in impaired interorganelle communication. These results establish high-speed single-molecule imaging as a new tool for mapping the structure of contact site interfaces and reveal that the diffusion landscape of VAPB at contact sites is a crucial component of ERMCS homeostasis.}, } @article {pmid38267984, year = {2024}, author = {Irwin, KE and Sheth, U and Wong, PC and Gendron, TF}, title = {Fluid biomarkers for amyotrophic lateral sclerosis: a review.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {9}, pmid = {38267984}, issn = {1750-1326}, support = {R01 NS095969/NS/NINDS NIH HHS/United States ; T32 GM136577/GM/NIGMS NIH HHS/United States ; P01NS084974/NH/NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; U19AG063911/NH/NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; RF1 NS095969/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Neurodegenerative Diseases ; Biomarkers ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients with ALS and to expedite ALS treatment development. Here, we provide a review of the efforts made towards identifying diagnostic, prognostic, susceptibility/risk, and response fluid biomarkers with the intent to facilitate a more rapid and accurate ALS diagnosis, to better predict prognosis, to improve clinical trial design, and to inform interpretation of clinical trial results. Over the course of 20 + years, several promising fluid biomarker candidates for ALS have emerged. These will be discussed, as will the exciting new strategies being explored for ALS biomarker discovery and development.}, } @article {pmid38268041, year = {2024}, author = {Cascella, M and Monaco, F and Vittori, A and Elshazly, M and Carlucci, A and Piazza, O}, title = {Bridging knowledge gaps: a bibliometric analysis of non-invasive ventilation in palliative care studies.}, journal = {Journal of anesthesia, analgesia and critical care}, volume = {4}, number = {1}, pages = {5}, pmid = {38268041}, issn = {2731-3786}, abstract = {BACKGROUND: Despite being a useful strategy for providing respiratory support to patients with advanced or terminal illnesses, non-invasive ventilation (NIV) requires in-depth investigation in several key aspects.

OBJECTIVES: This bibliometric analysis seeks to comprehensively examine the existing research on the subject. Its goal is to uncover valuable insights that can inform the prediction trajectory of studies, guide the implementation of corrective measures, and contribute to the improvement of research networks.

METHODS: A comprehensive review of literature on NIV in the context of palliative care was conducted using the Web of Science core collection online database. The search utilized the key terms "non-invasive ventilation" and "palliative care" to identify the most relevant articles. All data were gathered on November 7, 2023. Relevant information from documents meeting the specified criteria was extracted, and Journal Citation Reports™ 2022 (Clarivate Analytics) served as the data source. The analysis employed literature analysis and knowledge visualization tools, specifically CiteScope (version 6.2.R4) and VOSviewer (version 1.6.20).

RESULTS: A dataset with bibliometric findings from 192 items was analyzed. We found a consistent upward of the scientific output trend over time. Guidelines on amyotrophic lateral sclerosis management received the highest number of citations. Most documents were published in top-ranked journals. Less than one-third of the documents pertain to clinical studies, especially retrospective analyses (25%). Key topics such as "decision making", and "communication" were less addressed.

CONCLUSIONS: Given the substantial clinical implications, further high-quality studies on this subject are recommended. Encouraging international collaborations is needed. Despite the growing volume of documents in the field, this bibliometric analysis indicates a decline in collaborative networks.}, } @article {pmid38270154, year = {2024}, author = {Jiang, Q and Wei, Q and Zhang, L and Yang, T and Lin, J and Xiao, Y and Li, C and Hou, Y and Ou, R and Liu, K and Zhao, B and Wu, Y and Lai, X and Shang, H}, title = {Peripheral immunity relate to disease progression and prognosis in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {465-474}, doi = {10.1080/21678421.2024.2306969}, pmid = {38270154}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/blood/mortality ; Male ; Female ; Middle Aged ; *Disease Progression ; Aged ; Prognosis ; Adult ; CD4-Positive T-Lymphocytes/immunology ; Immunoglobulin G/blood ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Abnormalities in the peripheral immune system in ALS have been paid attention; however, the results of changes in peripheral immune parameters were inconsistent.

METHODS: A total of 1109 ALS patients were enrolled in the study. All patients received clinical evaluation and peripheral immune parameters measurement. The outcomes were analyzed by correlation analysis, multiple linear regression and cox survival analysis.

RESULTS: We found that ALS patients had significantly higher percentage of CD4[+] T cells (39.3 vs. 37.1%, p < 0.001) and CD4[+]/CD8[+] ratio (1.88 vs. 1.72, p = 0.011), significantly lower IgG (11.73 vs.12.82, p < 0.001) and IgA (2130.70 vs. 2284.8, p = 0.013) compared with the health controls. In the multivariate linear model, we found that each increase of 1.262, 0.278, and 4.44E-4 in ALSFRS-R scores were significantly associated with each increment of lymphocyte count, IgG, and IgA, respectively. However, each decrease of 0.341, 0.068, and 0.682 in ALSFRS-R score was associated with each increment in neutrophils, CD4[+] T cells, and CD4[+]/CD8[+] ratio, respectively. Cox survival regression analysis showed that the death risk of ALS patients was related to the levels of C3 (HR 0.592, 95% CI 0.361-0.973).

CONCLUSION: We found that there were differences in peripheral immune parameters of ALS patients with the severity of the disease, especially neutrophil, lymphocyte, CD4[+] T, and IgG; C3 is an independent predictor of survival in ALS patients. More studies are needed to elucidate the mechanisms associated with altered immune parameters in ALS.}, } @article {pmid38270442, year = {2024}, author = {Smith, R and Hovren, H and Bowser, R and Bakkar, N and Garruto, R and Ludolph, A and Ravits, J and Gaertner, L and Murphy, D and Lebovitz, R}, title = {Misfolded alpha-synuclein in amyotrophic lateral sclerosis: Implications for diagnosis and treatment.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16206}, pmid = {38270442}, issn = {1468-1331}, mesh = {Humans ; *alpha-Synuclein/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Lewy Bodies/metabolism/pathology ; Superoxide Dismutase-1 ; }, abstract = {BACKGROUND: Alpha-synuclein (α-Syn) oligomers and fibrils have been shown to augment the aggregation of TAR DNA-binding Protein 43 (TDP-43) monomers in vitro, supporting the idea that TDP-43 proteinopathies such as ALS may be modulated by the presence of toxic forms of α-Syn. Recently, parkinsonian features were reported in a study of European patients and Lewy bodies have been demonstrated pathologically in a similar series of patients. Based on these and other considerations, we sought to determine whether seed-competent α-Syn can be identified in spinal fluid of patients with ALS including familial, sporadic, and Guamanian forms of the disease.

METHODS: Based on the finding that α-Syn has been found to be a prion-like protein, we have utilized a validated α-Synuclein seed amplification assay to determine if seed-competent α-Syn could be detected in the spinal fluid of patients with ALS.

RESULTS: Toxic species of α-Syn were detected in CSF in 18 of 127 ALS patients, 5 of whom were from Guam. Two out of twenty six samples from patients with C9orf72 variant ALS had positive seed-amplification assays (SAAs). No positive tests were noted in superoxide dismutase type 1 ALS subjects (n = 14). The SAA was negative in 31 control subjects.

CONCLUSIONS: Our findings suggest that a sub-group of ALS occurs in which self-replicating α-Syn is detectable and likely contributes to its pathogenesis. This finding may have implications for the diagnosis and treatment of this disorder.}, } @article {pmid38270730, year = {2024}, author = {Abbasi, A and Fryk, H and Rudnik, J and White, R and Vanderkelen, M and Scowcroft, A and Bonar, K}, title = {Using an expanded algorithm to estimate prevalence of amyotrophic lateral sclerosis in U.S. and UK.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {2321-2324}, pmid = {38270730}, issn = {1590-3478}, mesh = {Humans ; Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/diagnosis ; Prevalence ; *Motor Neuron Disease ; Algorithms ; United Kingdom/epidemiology ; }, abstract = {BACKGROUND: There is an increasing need to better understand the burden of amyotrophic lateral sclerosis (ALS) using real-world data (RWD). However, identifying ALS cases using RWD presents several challenges due to the rarity of ALS and the differences in database coding systems.

METHODS: MarketScan claims, and the UK Clinical Practice Research Datalink (CPRD) databases were searched for diagnosis codes of ALS or MND, the only drugs approved for treating ALS (riluzole and edaravone) and clinical visits with 12-month enrolment prior to 1 January 2011. The main algorithm required ≥ 1 ALS diagnosis code together with prescriptions or clinical visits. We expanded the existing algorithm to identify unspecific (possible) ALS group that had codes for motor neuron disease (MND) and the ALS drugs. The study period was from 1 January 2011 until 31 December 2020.

RESULTS: We identified 16,246 patients with ≥ 1 ALS code in Marketscan (denominator n = 85,279,619), yet only 184 were found in the UK CPRD (denominator n = 21,318,589). Using the main algorithm 9,433 ALS patients were included in MarketScan, with a prevalence ranged between 4.5 per 100,000 in 2019 and 6.2 in 2015. In MarketScan, 3,658 (4.3 per 100,000) had ≥ 1 MND code and the ALS drug codes (possible cases). In CPRD, 47.9% of 2,785 patients with ≥ 1 MND code had a prescription for riluzole (6.3 per 100,000), regarded as possible ALS cases.

CONCLUSIONS: The expanded algorithm enabled the identification of a large population with ALS, or possible ALS, and the estimation of ALS prevalence in MarketScan and CPRD.}, } @article {pmid38270797, year = {2024}, author = {Singh, S and Borkar, MR and Bhatt, LK}, title = {Transposable Elements: Emerging Therapeutic Targets in Neurodegenerative Diseases.}, journal = {Neurotoxicity research}, volume = {42}, number = {1}, pages = {9}, pmid = {38270797}, issn = {1476-3524}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; DNA Transposable Elements/genetics ; *Amyotrophic Lateral Sclerosis ; *Alzheimer Disease ; *Parkinson Disease ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by the progressive loss of neuronal function and structure. While several genetic and environmental factors have been implicated in the pathogenesis of these disorders, emerging evidence suggests that transposable elements (TEs), once considered "junk DNA," play a significant role in their development and progression. TEs are mobile genetic elements capable of moving within the genome, and their dysregulation has been associated with genomic instability, altered gene expression, and neuroinflammation. This review provides an overview of TEs, including long interspersed nuclear elements (LINEs), short interspersed nuclear elements (SINEs), and endogenous retroviruses (ERVs), mechanisms of repression and derepression, and their potential impact on neurodegeneration. The evidence linking TEs to AD, PD, and ALS by shedding light on the complex interactions between TEs and neurodegeneration has been discussed. Furthermore, the therapeutic potential of targeting TEs in neurodegenerative diseases has been explored. Understanding the role of TEs in neurodegeneration holds promise for developing novel therapeutic strategies aimed at mitigating disease progression and preserving neuronal health.}, } @article {pmid38271732, year = {2024}, author = {Sample, C and Rahmim, A and Benard, F and Wu, J and Clark, H}, title = {PSMA PET/CT as a predictive tool for subregional importance estimates in the parotid gland.}, journal = {Biomedical physics & engineering express}, volume = {10}, number = {2}, pages = {}, doi = {10.1088/2057-1976/ad229c}, pmid = {38271732}, issn = {2057-1976}, mesh = {Humans ; Head ; *Parotid Gland/diagnostic imaging ; *Positron Emission Tomography Computed Tomography ; Positron-Emission Tomography ; }, abstract = {Objective. Xerostomia and radiation-induced salivary gland dysfunction remain a common side effect for head-and-neck radiotherapy patients, and attempts have been made to quantify the heterogeneity of the dose response within parotid glands. Prostate Specific Membrane Antigen (PSMA) ligands have demonstrated high uptake in salivary glands, which has been shown to correlate with gland functionality. Here we compare several models of parotid gland subregional relative importance with PSMA positron emission tomography (PET) uptake. We then develop a predictive model for Clarket al's relative importance estimates using PSMA PET and CT radiomic features, and demonstrate a methodology for predicting patient-specific importance deviations from the population.Approach. Intra-parotid gland uptake was compared with four regional importance models using 30 [18F]DCFPyL PSMA PET images. The correlation of uptake and importance was ascertained when numerous non-overlapping subregions were defined, while a paired t-test was used to compare binary region pairs. A radiomics-based predictive model of population importance was developed using a double cross-validation methodology. A model was then devised for supplementing population-level subregional importance estimates for each patient using patient-specific radiomic features.Main Results. Anticorrelative relationships were found to exist between PSMA PET uptake and four independent models of subregional parotid gland importance from the literature. Kernel Ridge Regression with principal component analysis feature selection performed best over test sets (Mean Absolute Error = 0.08), with gray level co-occurrence matrix (GLCM) features being particularly important. Deblurring PSMA PET images with neural blind deconvolution strengthened correlations and improved model performance.Significance. This study suggests that regions of relatively low PSMA PET uptake in parotid glands may exhibit relatively high dose-sensitivity. We've demonstrated the utility of PSMA PET radiomic features for predicting relative importance within subregions of parotid glands. PSMA PET appears to be a promising quantitative imaging modality for analyzing salivary gland functionality.}, } @article {pmid38274887, year = {2023}, author = {Ito, M and Fujii, N and Kohara, S and Tanaka, M and Takao, M and Mihara, B and Saito, Y and Mizuma, A and Nakayama, T and Netsu, S and Suzuki, N and Kakita, A and Nagata, E}, title = {Elevation of inositol pyrophosphate IP7 in the mammalian spinal cord of amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1334004}, pmid = {38274887}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive impairment of spinal motor neurons. Continuous research endeavor is underway to fully understand the molecular mechanisms associating with this disorder. Although several studies have implied the involvement of inositol pyrophosphate IP7 in ALS, there is no direct experimental evidence proving this notion. In this study, we analyzed inositol pyrophosphate IP7 and its precursor IP6 in the mouse and human ALS biological samples to directly assess whether IP7 level and/or its metabolism are altered in ALS disease state.

METHODS: We used a liquid chromatography-mass spectrometry (LC-MS) protocol originally-designed for mammalian IP6 and IP7 analysis. We measured the abundance of these molecules in the central nervous system (CNS) of ALS mouse model SOD1(G93A) transgenic (TG) mice as well as postmortem spinal cord of ALS patients. Cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) from ALS patients were also analyzed to assess if IP7 status in these biofluids is associated with ALS disease state.

RESULTS: SOD1(G93A) TG mice showed significant increase of IP7 level in the spinal cord compared with control mice at the late stage of disease progression, while its level in cerebrum and cerebellum remains constant. We also observed significantly elevated IP7 level and its product-to-precursor ratio (IP7/IP6) in the postmortem spinal cord of ALS patients, suggesting enhanced enzymatic activity of IP7-synthesizing kinases in the human ALS spinal cord. In contrast, human CSF did not contain detectable level of IP6 and IP7, and neither the IP7 level nor the IP7/IP6 ratio in human PBMCs differentiated ALS patients from age-matched healthy individuals.

CONCLUSION: By directly analyzing IP7 in the CNS of ALS mice and humans, the findings of this study provide direct evidence that IP7 level and/or the enzymatic activity of IP7-generating kinases IP6Ks are elevated in ALS spinal cord. On the other hand, this study also showed that IP7 is not suitable for biofluid-based ALS diagnosis. Further investigation is required to elucidate a role of IP7 in ALS pathology and utilize IP7 metabolism on the diagnostic application of ALS.}, } @article {pmid38276084, year = {2024}, author = {Vacchiano, V and Bonan, L and Liguori, R and Rizzo, G}, title = {Primary Lateral Sclerosis: An Overview.}, journal = {Journal of clinical medicine}, volume = {13}, number = {2}, pages = {}, pmid = {38276084}, issn = {2077-0383}, abstract = {Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder which causes the selective deterioration of the upper motor neurons (UMNs), sparing the lower motor neuron (LMN) system. The clinical course is defined by a progressive motor disability due to muscle spasticity which typically involves lower extremities and bulbar muscles. Although classically considered a sporadic disease, some familiar cases and possible causative genes have been reported. Despite it having been recognized as a rare but distinct entity, whether it actually represents an extreme end of the motor neuron diseases continuum is still an open issue. The main knowledge gap is the lack of specific biomarkers to improve the clinical diagnostic accuracy. Indeed, the diagnostic imprecision, together with some uncertainty about overlap with UMN-predominant ALS and Hereditary Spastic Paraplegia (HSP), has become an obstacle to the development of specific therapeutic trials. In this study, we provided a comprehensive analysis of the existing literature, including neuropathological, clinical, neuroimaging, and neurophysiological features of the disease, and highlighting the controversies still unsolved in the differential diagnoses and the current diagnostic criteria. We also discussed the current knowledge gaps still present in both diagnostic and therapeutic fields when approaching this rare condition.}, } @article {pmid38277467, year = {2024}, author = {Seddighi, S and Qi, YA and Brown, AL and Wilkins, OG and Bereda, C and Belair, C and Zhang, YJ and Prudencio, M and Keuss, MJ and Khandeshi, A and Pickles, S and Kargbo-Hill, SE and Hawrot, J and Ramos, DM and Yuan, H and Roberts, J and Sacramento, EK and Shah, SI and Nalls, MA and Colón-Mercado, JM and Reyes, JF and Ryan, VH and Nelson, MP and Cook, CN and Li, Z and Screven, L and Kwan, JY and Mehta, PR and Zanovello, M and Hallegger, M and Shantaraman, A and Ping, L and Koike, Y and Oskarsson, B and Staff, NP and Duong, DM and Ahmed, A and Secrier, M and Ule, J and Jacobson, S and Reich, DS and Rohrer, JD and Malaspina, A and Dickson, DW and Glass, JD and Ori, A and Seyfried, NT and Maragkakis, M and Petrucelli, L and Fratta, P and Ward, ME}, title = {Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.}, journal = {Science translational medicine}, volume = {16}, number = {734}, pages = {eadg7162}, pmid = {38277467}, issn = {1946-6242}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; RF1 AG062171/AG/NIA NIH HHS/United States ; T32 GM136577/GM/NIGMS NIH HHS/United States ; MC_PC_MR/S022708/1/MRC_/Medical Research Council/United Kingdom ; U19 AG063911/AG/NIA NIH HHS/United States ; CC0102/WT_/Wellcome Trust/United Kingdom ; MR/J009482/1/MRC_/Medical Research Council/United Kingdom ; P30 AG062677/AG/NIA NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; ZIA NS003155/ImNIH/Intramural NIH HHS/United States ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MR/W005190/1/MRC_/Medical Research Council/United Kingdom ; FI2 GM142475/GM/NIGMS NIH HHS/United States ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; HALLEGGER/OCT15/959-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; RF1 AG062077/AG/NIA NIH HHS/United States ; MR/M023664/1/MRC_/Medical Research Council/United Kingdom ; P01 NS084974/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics ; Peptides ; Proteomics ; }, abstract = {Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.}, } @article {pmid38277781, year = {2024}, author = {Hirsch, E and Bornemissza, Z and Nagy, ZK and Marosi, GJ and Farkas, A}, title = {Quantitative and qualitative analysis of cell culture media powders for mammalian cells by Raman microscopy.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {310}, number = {}, pages = {123906}, doi = {10.1016/j.saa.2024.123906}, pmid = {38277781}, issn = {1873-3557}, mesh = {Animals ; Powders ; *Microscopy ; *Cell Culture Techniques/methods ; Recombinant Proteins ; Least-Squares Analysis ; Spectrum Analysis, Raman/methods ; Culture Media/chemistry ; Multivariate Analysis ; Mammals ; }, abstract = {Cell culture media are essential for large-scale recombinant protein production using mammalian cell cultures. The composition and quality of media significantly impact cell growth and product formation. Analyzing media poses challenges due to complex compositions and undisclosed exact compositions. Traditional methods like NMR and chromatography offer sensitivity but require time-consuming sample preparation and lack spatial information. Raman chemical mapping characterizes solids, but its use in cell culture media analysis is limited so far. We present a chemometric evaluation for Raman maps to qualify and quantify media components, evaluate powder homogeneity, and perform lot-to-lot comparisons. Three lots of a marketed cell culture media powder were measured with Raman mapping technique. Chemometrics techniques have outlined a strategy to extract information from complex data. First, a spectral library has been structured. In addition to the 23 spectra for presumed ingredients, we obtained another 9 pure components with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). Then the Spectral Angle Mapper-Orthogonal Projection (SAM-OP) algorithm revealed whether references actually occur in the mapped media powders. Finally, a quantification was provided by Classical Least Squares (CLS) modelling. Quantities of 18 significant amino acids mostly correlated with the reference method. The proposed method can be generally applied even for such complicated samples. Leveraging Raman mapping and innovative chemometric methods enhance recombinant protein production by improving the understanding of the spatial distribution and composition of cell culture media in mammalian cell cultivations.}, } @article {pmid38278093, year = {2024}, author = {Goutman, SA and Boss, J and Jang, DG and Piecuch, C and Farid, H and Batra, M and Mukherjee, B and Feldman, EL and Batterman, SA}, title = {Avocational exposure associations with ALS risk, survival, and phenotype: A Michigan-based case-control study.}, journal = {Journal of the neurological sciences}, volume = {457}, number = {}, pages = {122899}, pmid = {38278093}, issn = {1878-5883}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; R01TS000344/ACL/ACL HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, mesh = {Humans ; Middle Aged ; Case-Control Studies ; Michigan/epidemiology ; Risk Factors ; *Environmental Exposure ; Phenotype ; *Amyotrophic Lateral Sclerosis/epidemiology ; }, abstract = {INTRODUCTION: Environmental exposures strongly influence ALS risk and identification is needed to reduce ALS burden. Participation in hobbies and exercise may alter ALS risk and phenotype, warranting an assessment to understand their contribution to the ALS exposome.

METHODS: Participants with ALS and healthy controls were recruited from University of Michigan and self-completed a survey to ascertain hobbies, exercise, and avocational exposures. Exposure variables were associated with ALS risk, survival, onset segment, and onset age.

RESULTS: ALS (n = 400) and control (n = 287) participants self-reported avocational activities. Cases were slightly older (median age 63.0 vs. 61.1 years, p = 0.019) and had a lower educational attainment (p < 0.001) compared to controls; otherwise, demographics were well balanced. Risks associating with ALS after multiple comparison correction included golfing (odds ratio (OR) 3.48, padjusted = 0.004), recreational dancing (OR 2.00, padjusted = 0.040), performing gardening or yard work (OR 1.71, padjusted = 0.040) five years prior to ALS and personal (OR 1.76, padjusted = 0.047) or family (OR 2.21, padjusted = 0.040) participation in woodworking, and personal participation in hunting and shooting (OR 1.89, padjusted = 0.040). No exposures associated with ALS survival and onset. Those reporting swimming (3.86 years, padjusted = 0.016) and weightlifting (3.83 years, padjusted = 0.020) exercise 5 years prior to ALS onset had an earlier onset age.

DISCUSSION: The identified exposures in this study may represent important modifiable ALS factors that influence ALS phenotype. Thus, exposures related to hobbies and exercise should be captured in studies examining the ALS exposome.}, } @article {pmid38278691, year = {2024}, author = {Kwon, Y and Kang, M and Jeon, YM and Lee, S and Lee, HW and Park, JS and Kim, HJ}, title = {Identification and characterization of novel ERBB4 variant associated with sporadic amyotrophic lateral sclerosis (ALS).}, journal = {Journal of the neurological sciences}, volume = {457}, number = {}, pages = {122885}, doi = {10.1016/j.jns.2024.122885}, pmid = {38278691}, issn = {1878-5883}, mesh = {Male ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/metabolism ; Mutation/genetics ; Receptor, ErbB-4/genetics/metabolism ; Tyrosine ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common type of motor neuron disease characterized by progressive motor neuron degeneration in brain and spinal cord. Most cases are sporadic in ALS and 5-10% of cases are familiar. >50 genes are known to be associated with ALS and one of them is ERBB4. In this paper, we report the case of a 53-year-old ALS patient with progressive muscle weakness and fasciculation, but he had no cognitive decline. We performed the next generation sequencing (NGS) and in silico analysis, it predicted a highly pathogenic variant, c.2116 A > G, p.Asn706Asp (N706D) in the ERBB4 gene. The amino acid residue is highly conserved among species. ERBB4 is a member of the ERBB family of receptor tyrosine kinases. ERBB4 has multiple tyrosine phosphorylation sites, including an autophosphorylation site at tyrosine 1284 residue. Autophosphorylation of ERBB4 promotes biological activity and it associated with NRG-1/ERBB4 pathway. It is already known that tyrosine 128 phosphorylation of ERBB4 is decreased in patients who have ALS-associated ERBB4 mutations. We generated ERBB4 N706D construct using site-directed mutagenesis and checked the phosphorylation level of ERBB4 N706D in NSC-34 cells. We found that the phosphorylation of ERBB4 N706D was decreased compared to ERBB4 wild-type, indicating a loss of function mutation in ERBB4. We report a novel variant in ERBB4 gene leading to ALS through dysfunction of ERBB4.}, } @article {pmid38278991, year = {2024}, author = {Irwin, KE and Jasin, P and Braunstein, KE and Sinha, IR and Garret, MA and Bowden, KD and Chang, K and Troncoso, JC and Moghekar, A and Oh, ES and Raitcheva, D and Bartlett, D and Miller, T and Berry, JD and Traynor, BJ and Ling, JP and Wong, PC}, title = {A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD.}, journal = {Nature medicine}, volume = {30}, number = {2}, pages = {382-393}, pmid = {38278991}, issn = {1546-170X}, support = {T32 GM136577/GM/NIGMS NIH HHS/United States ; R33 NS115161/NS/NINDS NIH HHS/United States ; ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; RF1 NS095969/NS/NINDS NIH HHS/United States ; R01 NS095969/NS/NINDS NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; U01 FD008129/FD/FDA HHS/United States ; UH3 NS115608/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics/metabolism ; Biomarkers/cerebrospinal fluid ; }, abstract = {Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in ALS-FTD, including in presymptomatic C9orf72 mutation carriers. Cryptic hepatoma-derived growth factor-like protein 2 (HDGFL2) accumulates in CSF at significantly higher levels in familial ALS-FTD and sporadic ALS compared with controls and is elevated earlier than neurofilament light and phosphorylated neurofilament heavy chain protein levels in familial disease. Cryptic HDGFL2 can also be detected in blood of individuals with ALS-FTD, including in presymptomatic C9orf72 mutation carriers, and accumulates at levels highly correlated with those in CSF. Our findings indicate that loss of TDP-43 cryptic splicing repression occurs early in disease progression, even presymptomatically, and that detection of the HDGFL2 cryptic neoepitope serves as a potential diagnostic biomarker for ALS, which should facilitate patient recruitment and measurement of target engagement in clinical trials.}, } @article {pmid38279584, year = {2024}, author = {Lai, C and Chuang, LH and Lai, CC and Liu, CF and Yang, JW and Chen, HSL}, title = {Longitudinal changes in optical coherence tomography angiography characteristics in normal-tension glaucoma with or without high myopia.}, journal = {Acta ophthalmologica}, volume = {102}, number = {5}, pages = {e762-e773}, doi = {10.1111/aos.16644}, pmid = {38279584}, issn = {1755-3768}, mesh = {Humans ; *Tomography, Optical Coherence/methods ; *Low Tension Glaucoma/physiopathology/diagnosis ; Male ; Female ; *Visual Fields/physiology ; Middle Aged ; *Fluorescein Angiography/methods ; *Retinal Ganglion Cells/pathology ; *Nerve Fibers/pathology ; *Intraocular Pressure/physiology ; *Optic Disk/blood supply ; Retinal Vessels/diagnostic imaging/pathology ; Aged ; Follow-Up Studies ; Disease Progression ; Myopia, Degenerative/physiopathology/diagnosis/complications ; Retrospective Studies ; Fundus Oculi ; }, abstract = {PURPOSE: To evaluate the structural, microvascular, and functional progression of normal tension glaucoma (NTG) with or without high myopia by examining longitudinal changes in optical coherence tomography angiography (OCTA) and visual field (VF) parameters.

METHODS: We evaluated 61 NTG eyes and classified 25 of the eyes with axial lengths (ALs) of ≥26 mm as highly myopic. We assessed the rate of change in OCTA parameters, namely radial peripapillary capillary (RPC) vessel density (VD), parafovea VD, deep parafovea VD, retinal nerve fibre layer (RNFL) thickness, and ganglion cell complex thickness. We evaluated the correlation of the rate of change in OCTA parameters with VF loss and AL.

RESULTS: Among the 61 NTG eyes, rates of loss of RPC VD, parafovea VD, deep parafovea VD, and RNFL thickness were significantly different from zero despite the nonsignificant rate of change in VF mean deviation (MD). Changes in these OCTA parameters did not differ significantly in highly myopic NTG eyes. The rate of change in VF MD was significantly correlated with the rate of change in parafovea VD in highly myopic and non-highly myopic NTG eyes. In highly myopic NTG eyes, AL was negatively correlated with the rates of loss of RNFL thickness, VF MD, and VF PSD.

CONCLUSION: NTG eyes with a relatively stable VF exhibited loss of VD and RNFL thickness. VF progression in NTG was correlated with decreasing parafovea VD, indicating a structure-function correlation. Greater AL may indicate faster VF loss and RNFL thinning in highly myopic NTG eyes.}, } @article {pmid38280780, year = {2024}, author = {Karimvand, SK and Pahlevan, A and Zade, SV and Jafari, JM and Abdollahi, H}, title = {Multivariate curve resolution-soft independent modelling of class analogy (MCR-SIMCA).}, journal = {Analytica chimica acta}, volume = {1291}, number = {}, pages = {342205}, doi = {10.1016/j.aca.2024.342205}, pmid = {38280780}, issn = {1873-4324}, abstract = {BACKGROUND: Various classification, class modeling, and clustering techniques operate within abstract spaces, utilizing Principal Components (e.g., Linear Discriminant Analysis (LDA), Principal Component Analysis (PCA)) or latent variable spaces (e.g., Partial Least Squares Discriminant Analysis (PLS-DA)). It's important to note that PCA, despite being a mathematical tool, defines its Principal Components under certain mathematical constraints, it has a wide range of applications in the analysis of real-world systems. In this research, we assess the viability of employing the Multivariate Curve Resolution (MCR) subspace within class modeling techniques, as an alternative to the PC subspace. (92).

RESULTS: This study evaluates the use of the MCR subspace in class modeling methods, specifically in tandem with soft independent modeling of class analogy (SIMCA), to investigate the advantages of employing the meaningful physico-chemical subspace of MCR over the mathematical subspace of PCA. In the MCR-SIMCA strategy, the model is constructed by applying MCR to training samples from a target class. The MCR model effectively partitions the data into two smaller sub-matrices: the contribution matrix and the corresponding response matrix. In the next step, the contribution matrix resulting from the decomposition of the training set develops a distance plot (DP). First, the theory of the MCR-SIMCA model is discussed in detail. Next, two real experimental datasets were analyzed, and their performance was compared with the DD-SIMCA model. In most cases, the results were as good as or even more satisfactory than those obtained with the DD-SIMCA model. (146).

SIGNIFICANCE: The suggested class modeling method presents a promising avenue for the analysis of real-world natural systems. The study's results emphasize the practical utility of the MCR approach, underscoring the significance of the MCR subspace advantages over the PCA subspace. (39).}, } @article {pmid38281010, year = {2024}, author = {Fouda, AES and Etaiw, SEH and Abd El-Aziz, DM and El-Hossiany, AA and Elbaz, UA}, title = {Experimental and theoretical studies of the efficiency of metal-organic frameworks (MOFs) in preventing aluminum corrosion in hydrochloric acid solution.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {21}, pmid = {38281010}, issn = {2661-801X}, abstract = {Aluminum corrosion inhibitors "{[CuI (CN)2(phen) CuII (CN)2(phen)]5H2O}, (MOF1) and {[CuI(CN)2(phen)CuII(CN)2(phen)]5H2O} @TiO2 (MOF1@TiO2) were studied in one molar HCl solution". The ML results for three different temperatures (25-45 °C) were compared with the results of PDP and EIS analyses. The adsorption of inhibitors on Al surfaces has been calculated and discussed by a Langmuir isotherm. The inhibitors that were created showed great effectiveness, with a noticeable increase in their inhibitory efficiency as the dosage was raised and the temperature was lowered. Inhibition efficiency each amounted to 88.6%, 84.5% at 400 ppm and 25 °C for MOF1@TiO2 and MOF1, respectively. Analyzing the polarization curves of synthesized inhibitors revealed that they were mixed-type inhibitors. Al was found to be surface inhibited when coated with a thin film of inhibitors, and "Al's surface morphology was assessed by different techniques such as scanning electron microscopy (SEM), energy dispersive X-ray (EDX) and atomic force microscope (AFM)". "Theoretical models like quantum chemical and molecular dynamics simulation authenticated the experimental observation". The MOFs exhibit exceptional corrosion resistance against Al when exposed to acidic environments, according to several tests.}, } @article {pmid38282082, year = {2024}, author = {Parnianpour, P and Benatar, M and Briemberg, H and Dey, A and Dionne, A and Dupré, N and Evans, KC and Frayne, R and Genge, A and Graham, SJ and Korngut, L and McLaren, DG and Seres, P and Welsh, RC and Wilman, A and Zinman, L and Kalra, S}, title = {Mismatch between clinically defined classification of ALS stage and the burden of cerebral pathology.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2547-2559}, pmid = {38282082}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Disease Progression ; Aged ; *Magnetic Resonance Imaging ; Adult ; Brain/diagnostic imaging/pathology ; Severity of Illness Index ; Longitudinal Studies ; Cerebral Cortex/diagnostic imaging/pathology ; }, abstract = {This study aimed to investigate the clinical stratification of amyotrophic lateral sclerosis (ALS) patients in relation to in vivo cerebral degeneration. One hundred forty-nine ALS patients and one hundred forty-four healthy controls (HCs) were recruited from the Canadian ALS Neuroimaging Consortium (CALSNIC). Texture analysis was performed on T1-weighted scans to extract the texture feature "autocorrelation" (autoc), an imaging biomarker of cerebral degeneration. Patients were stratified at baseline into early and advanced disease stages based on criteria adapted from ALS clinical trials and the King's College staging system, as well as into slow and fast progressors (disease progression rates, DPR). Patients had increased autoc in the internal capsule. These changes extended beyond the internal capsule in early-stage patients (clinical trial-based criteria), fast progressors, and in advanced-stage patients (King's staging criteria). Longitudinal increases in autoc were observed in the postcentral gyrus, corticospinal tract, posterior cingulate cortex, and putamen; whereas decreases were observed in corpus callosum, caudate, central opercular cortex, and frontotemporal areas. Both longitudinal increases and decreases of autoc were observed in non-overlapping regions within insula and precentral gyrus. Within-criteria comparisons of autoc revealed more pronounced changes at baseline and longitudinally in early- (clinical trial-based criteria) and advanced-stage (King's staging criteria) patients and fast progressors. In summary, comparative patterns of baseline and longitudinal progression in cerebral degeneration are dependent on sub-group selection criteria, with clinical trial-based stratification insufficiently characterizing disease stage based on pathological cerebral burden.}, } @article {pmid38283093, year = {2023}, author = {Calderón-Garcidueñas, L and Stommel, EW and Torres-Jardón, R and Hernández-Luna, J and Aiello-Mora, M and González-Maciel, A and Reynoso-Robles, R and Pérez-Guillé, B and Silva-Pereyra, HG and Tehuacanero-Cuapa, S and Rodríguez-Gómez, A and Lachmann, I and Galaz-Montoya, C and Doty, RL and Roy, A and Mukherjee, PS}, title = {Alzheimer and Parkinson diseases, frontotemporal lobar degeneration and amyotrophic lateral sclerosis overlapping neuropathology start in the first two decades of life in pollution exposed urbanites and brain ultrafine particulate matter and industrial nanoparticles, including Fe, Ti, Al, V, Ni, Hg, Co, Cu, Zn, Ag, Pt, Ce, La, Pr and W are key players. Metropolitan Mexico City health crisis is in progress.}, journal = {Frontiers in human neuroscience}, volume = {17}, number = {}, pages = {1297467}, pmid = {38283093}, issn = {1662-5161}, abstract = {The neuropathological hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) are present in urban children exposed to fine particulate matter (PM2.5), combustion and friction ultrafine PM (UFPM), and industrial nanoparticles (NPs). Metropolitan Mexico City (MMC) forensic autopsies strongly suggest that anthropogenic UFPM and industrial NPs reach the brain through the nasal/olfactory, lung, gastrointestinal tract, skin, and placental barriers. Diesel-heavy unregulated vehicles are a key UFPM source for 21.8 million MMC residents. We found that hyperphosphorylated tau, beta amyloid1-42, α-synuclein, and TAR DNA-binding protein-43 were associated with NPs in 186 forensic autopsies (mean age 27.45 ± 11.89 years). The neurovascular unit is an early NPs anatomical target, and the first two decades of life are critical: 100% of 57 children aged 14.8 ± 5.2 years had AD pathology; 25 (43.9%) AD+TDP-43; 11 (19.3%) AD + PD + TDP-43; and 2 (3.56%) AD +PD. Fe, Ti, Hg, Ni, Co, Cu, Zn, Cd, Al, Mg, Ag, Ce, La, Pr, W, Ca, Cl, K, Si, S, Na, and C NPs are seen in frontal and temporal lobes, olfactory bulb, caudate, substantia nigra, locus coeruleus, medulla, cerebellum, and/or motor cortical and spinal regions. Endothelial, neuronal, and glial damages are extensive, with NPs in mitochondria, rough endoplasmic reticulum, the Golgi apparatus, and lysosomes. Autophagy, cell and nuclear membrane damage, disruption of nuclear pores and heterochromatin, and cell death are present. Metals associated with abrasion and deterioration of automobile catalysts and electronic waste and rare earth elements, i.e., lanthanum, cerium, and praseodymium, are entering young brains. Exposure to environmental UFPM and industrial NPs in the first two decades of life are prime candidates for initiating the early stages of fatal neurodegenerative diseases. MMC children and young adults-surrogates for children in polluted areas around the world-exhibit early AD, PD, FTLD, and ALS neuropathological hallmarks forecasting serious health, social, economic, academic, and judicial societal detrimental impact. Neurodegeneration prevention should be a public health priority as the problem of human exposure to particle pollution is solvable. We are knowledgeable of the main emission sources and the technological options to control them. What are we waiting for?}, } @article {pmid38283317, year = {2022}, author = {Cheung, K and Mitsumoto, H}, title = {Evaluating Personalized (N-of-1) Trials in Rare Diseases: How Much Experimentation Is Enough?.}, journal = {Harvard data science review}, volume = {2022}, number = {Spec Iss 3}, pages = {}, pmid = {38283317}, issn = {2644-2353}, support = {P30 AG063786/AG/NIA NIH HHS/United States ; R01 LM012836/LM/NLM NIH HHS/United States ; R01 MH109496/MH/NIMH NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; }, abstract = {For rare diseases, conducting large, randomized trials of new treatments can be infeasible due to limited sample size, and it may answer the wrong scientific questions due to heterogeneity of treatment effects. Personalized (N-of-1) trials are multi-period crossover studies that aim to estimate individual treatment effects, thereby identifying the optimal treatments for individuals. This article examines the statistical design issues of evaluating a personalized (N-of-1) treatment program in people with amyotrophic lateral sclerosis (ALS). We propose an evaluation framework based on an analytical model for longitudinal data observed in a personalized trial. Under this framework, we address two design parameters: length of experimentation in each trial and number of trials needed. For the former, we consider patient-centric design criteria that aim to maximize the benefits of enrolled patients. Using theoretical investigation and numerical studies, we demonstrate that, from a patient's perspective, the duration of an experimentation period should be no longer than one-third of the entire follow-up period of the trial. For the latter, we provide analytical formulae to calculate the power for testing quality improvement due to personalized trials in a randomized evaluation program and hence determine the required number of trials needed for the program. We apply our theoretical results to design an evaluation program for ALS treatments informed by pilot data and show that the length of experimentation has a small impact on power relative to other factors such as the degree of heterogeneity of treatment effects.}, } @article {pmid38284068, year = {2024}, author = {Sunildutt, N and Ahmed, F and Chethikkattuveli Salih, AR and Lim, JH and Choi, KH}, title = {Integrating Transcriptomic and Structural Insights: Revealing Drug Repurposing Opportunities for Sporadic ALS.}, journal = {ACS omega}, volume = {9}, number = {3}, pages = {3793-3806}, pmid = {38284068}, issn = {2470-1343}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disorder characterized by the loss of upper and lower motor neurons, resulting in debilitating muscle weakness and atrophy. Currently, there are no effective treatments available for ALS, posing significant challenges in managing the disease that affects approximately two individuals per 100,000 people annually. To address the urgent need for effective ALS treatments, we conducted a drug repurposing study using a combination of bioinformatics tools and molecular docking techniques. We analyzed sporadic ALS-related genes from the GEO database and identified key signaling pathways involved in sporadic ALS pathogenesis through pathway analysis using DAVID. Subsequently, we utilized the Clue Connectivity Map to identify potential drug candidates and performed molecular docking using AutoDock Vina to evaluate the binding affinity of short-listed drugs to key sporadic ALS-related genes. Our study identified Cefaclor, Diphenidol, Flubendazole, Fluticasone, Lestaurtinib, Nadolol, Phenamil, Temozolomide, and Tolterodine as potential drug candidates for repurposing in sporadic ALS treatment. Notably, Lestaurtinib demonstrated high binding affinity toward multiple proteins, suggesting its potential as a broad-spectrum therapeutic agent for sporadic ALS. Additionally, docking analysis revealed NOS3 as the gene that interacts with all the short-listed drugs, suggesting its possible involvement in the mechanisms underlying the therapeutic potential of these drugs in sporadic ALS. Overall, our study provides a systematic framework for identifying potential drug candidates for sporadic ALS therapy and highlights the potential of drug repurposing as a promising strategy for discovering new therapies for neurodegenerative diseases.}, } @article {pmid38284771, year = {2024}, author = {Grassano, M and Koumantakis, E and Manera, U and Canosa, A and Vasta, R and Palumbo, F and Fuda, G and Salamone, P and Marchese, G and Casale, F and Charrier, L and Mora, G and Moglia, C and Calvo, A and Chiò, A}, title = {Giving Breath to Motor Neurons: Noninvasive Mechanical Ventilation Slows Disease Progression in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {95}, number = {4}, pages = {817-822}, doi = {10.1002/ana.26875}, pmid = {38284771}, issn = {1531-8249}, support = {2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; RF-2016-02362405//Ministero della Salute/ ; //EU Joint Programme - Neurodegenerative Disease Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Respiration, Artificial ; Disease Progression ; Quality of Life ; Motor Neurons ; }, abstract = {OBJECTIVE: Noninvasive mechanical ventilation (NIMV) improves amyotrophic lateral sclerosis (ALS) quality of life and survival. However, data about its effect on disease progression are still lacking. Here, we test whether NIMV use changed the rate of functional decline among ALS patients.

METHODS: In this retrospective observational study, we included 448 ALS patients followed up at the ALS Center in Turin, Italy, who underwent NIMV during the disease course. The primary outcome was the change in functional decline after NIMV initiation adjusting for covariates. Functional decline was based on the nonrespiratory items of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R).

RESULTS: NIMV initiation resulted in a slower functional decline (mean improvement = 0.16 points per month, 95% confidence interval = 0.12-0.19, p < 0.001), with consistent effects observed across various demographic factors, including sex, age at diagnosis, and disease duration before NIMV initiation. This finding was replicated using the PRO-ACT (Pooled Resource Open-Access ALS Clinical Trials) dataset. The favorable impact of NIMV on ALSFRS-R progression was evident independently of disease stages. Notably, NIMV benefits were not dose-dependent but were particularly prominent for nighttime respiratory support.

INTERPRETATION: NIMV significantly influences the rate of motor progression in ALS, and this effect is not determined by the nonlinearity of ALSFRS-R trajectory. The functional decline slowed following NIMV initiation, independently of the site of disease onset or disease severity at the time of NIMV initiation. Our findings underscore the importance of timely NIMV initiation for all ALS patients and highlight the need to consider NIMV-induced slowing of disease progression when evaluating clinical trial outcomes. ANN NEUROL 2024;95:817-822.}, } @article {pmid38285093, year = {2024}, author = {Díaz, M and Fabelo, N and Martín, MV and Santos, G and Ferrer, I}, title = {Evidence for alterations in lipid profiles and biophysical properties of lipid rafts from spinal cord in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {102}, number = {3}, pages = {391-402}, pmid = {38285093}, issn = {1432-1440}, support = {SAF2014-52582-R//Ministerio de Ciencia e Innovación/ ; SAF2017-84454-R//Ministerio de Ciencia e Innovación/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Neurodegenerative Diseases/metabolism ; Lipids ; Membrane Microdomains/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an age-dependent neurodegenerative disease affecting motor neurons in the spinal cord and brainstem whose etiopathogenesis remains unclear. Recent studies have linked major neurodegenerative diseases with altered function of multimolecular lipid-protein complexes named lipid rafts. In the present study, we have isolated lipid rafts from the anterior horn of the spinal cords of controls and ALS individuals and analysed their lipid composition. We found that ALS affects levels of different fatty acids, lipid classes and related ratios and indexes. The most significant changes affected the contents of n-9/n-7 monounsaturated fatty acids and arachidonic acid, the main n-6 long-chain polyunsaturated fatty acid (LCPUFA), which were higher in ALS lipid rafts. Paralleling these findings, ALS lipid rafts lower saturates-to-unsaturates ratio compared to controls. Further, levels of cholesteryl ester (SE) and anionic-to-zwitterionic phospholipids ratio were augmented in ALS lipid rafts, while sulfatide contents were reduced. Further, regression analyses revealed augmented SE esterification to (mono)unsaturated fatty acids in ALS, but to saturates in controls. Overall, these changes indicate that lipid rafts from ALS spinal cord undergo destabilization of the lipid structure, which might impact their biophysical properties, likely leading to more fluid membranes. Indeed, estimations of membrane microviscosity confirmed less viscous membranes in ALS, as well as more mobile yet smaller lipid rafts compared to surrounding membranes. Overall, these results demonstrate that the changes in ALS lipid rafts are unrelated to oxidative stress, but to anomalies in lipid metabolism and/or lipid raft membrane biogenesis in motor neurons. KEY MESSAGES: The lipid matrix of multimolecular membrane complexes named lipid rafts are altered in human spinal cord in sporadic amyotrophic lateral sclerosis (ALS). Lipid rafts from ALS spinal cord contain higher levels of n-6 LCPUFA (but not n-3 LCPUFA), n-7/n-9 monounsaturates and lower saturates-to-unsaturates ratio. ALS lipid rafts display increased contents of cholesteryl esters, anomalous anionic-to-zwitterionic phospholipids and phospholipid remodelling and reduced sulphated and total sphingolipid levels, compared to control lipid rafts. Destabilization of the lipid structure of lipid raft affects their biophysical properties and leads to more fluid, less viscous membrane microdomains. The changes in ALS lipid rafts are unlikely related to increased oxidative stress, but to anomalies in lipid metabolism and/or raft membrane biogenesis in motor neurons.}, } @article {pmid38286111, year = {2024}, author = {Wang, M and Wang, T and Gu, F}, title = {Efficacy of Huanglian Jiedu Decoction for Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {187-200}, doi = {10.1159/000536453}, pmid = {38286111}, issn = {2504-2106}, mesh = {*Diabetes Mellitus, Type 2/drug therapy ; Humans ; *Drugs, Chinese Herbal/therapeutic use ; Blood Glucose/drug effects ; Glycated Hemoglobin ; Randomized Controlled Trials as Topic ; *Hypoglycemic Agents/therapeutic use ; }, abstract = {OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder, and there is an increasing interest in the potential benefits of traditional Chinese medicine, such as Huanglian Jiedu decoction (HJD), for its management. This meta-analysis aimed to determine the efficacy and safety of HJD in the treatment of T2DM.

METHODS: A systematic review was conducted across six databases including PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang, from their inception to August 24, 2023. We focused on randomized controlled trials (RCTs) that evaluated HJD as both a monotherapy and in combination treatments for T2DM patients. Data analysis was performed using RevMan 5.3 and Stata 17.0, with evaluations for heterogeneity and publication bias. Additionally, subgroup analyses were stratified based on the duration of treatment.

RESULTS: A total of 40 studies involving 3,934 participants were included in the meta-analysis. Both HJD monotherapy and combined with other therapies significantly reduced hemoglobin A1C (HbA1c) fasting blood glucose (FBG) and 2-h postprandial glucose (2hPG) levels, as well as improved insulin resistance. Furthermore, combination therapy enhanced the efficacy rate and favorably altered lipid profiles, including increasing HDL-C and decreasing LDL-C, TC, and TG levels. It was worth noting that the results of the subgroup analysis indicated that, in terms of reducing HbA1c and 2hPG, the efficacy of HJD alone for a duration of less than 3 months was found to be potentially superior to that observed in treatments exceeding 3 months. Adverse event assessment suggested that HJD did not increase the incidence of side effects, including diarrhea, affirming its safety.

CONCLUSION: HJD appears to be an effective and safe alternative or adjunctive therapy for T2DM, showing significant improvements in glycemic control and lipid profiles without increasing adverse events. Further rigorous, multicenter RCTs outside China are warranted to validate these findings.

UNLABELLED: ZielDiabetes mellitus Typ 2 (DMT2) ist eine weit verbreitete Stoffwechselerkrankung, und es besteht ein steigendes Interesse an den potenziellen Vorteilen der traditionellen chinesischen Medizin, wie beispielsweise Huanglian Jiedu-Dekokt (HJD), zu seiner Behandlung. Mit dieser Metaanalyse sollten die Wirksamkeit und Sicherheit von HJD zur Behandlung von DMT2 ermittelt werden.MethodenEs wurde eine systematische Recherche in sechs Datenbanken durchgeführt, darunter PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure (CNKI) und Wanfang, für die Zeit vom Beginn der Datenbank bis zum 24. August 2023. Dabei lag unser Hauptaugenmerk auf randomisierten kontrollierten Studien (RCTs), die HJD sowohl als Monotherapie als auch in Kombinationstherapien bei Patienten mit DMT2 untersuchten. Die Datenanalyse erfolgte mithilfe von RevMan 5.3 und Stata 17.0 mit Untersuchungen auf Heterogenität und Publikationsverzerrungen. Darüber hinaus wurden Subgruppenanalysen stratifiziert nach Behandlungsdauer durchgeführt.ErgebnisseInsgesamt wurden 40 Studien mit 3.934 Teilnehmern in die Metaanalyse eingeschlossen. HJD führte sowohl als Monotherapie als auch in Kombination mit anderen Therapien zu einer signifikanten Senkung des HbA1c-Nüchternblutzuckerspiegels (fasting blood glucose, FBG) und der postprandialen Blutzuckerwerte 2 Stunden nach dem Essen (2-h postprandial glucose, 2hPG) sowie zu einer Verbesserung der Insulinresistenz. Darüber hinaus verbesserte die Kombinationstherapie die Wirksamkeitsrate und führte zu einer positiven Veränderung der Lipidprofile, die eine Erhöhung der HDL-Cholesterinwerte und eine Senkung der LDL-, Gesamtcholesterin- und Trigylceridwerte einschloss. Erwähnenswert ist, dass nach den Ergebnissen der Subgruppenanalyse die Wirksamkeit von HJD als Monotherapie in Hinblick auf die Senkung der HbA1c- und 2hPG-Werte bei einer Behandlungsdauer von weniger als drei Monaten gegenüber derjenigen von Behandlungen, die länger als drei Monate dauerten, potenziell überlegen war. Die Bewertung der unerwünschten Ereignisse zeigte, dass HJD nicht zu einem Anstieg der Nebenwirkungen wie Durchfall führte, was seine Sicherheit bestätigte.SchlussfolgerungHJD scheint eine wirksame und sichere Alternative oder Zusatztherapie bei DMT2 zu sein, die signifikante Verbesserungen der Blutzuckerkontrolle und der Lipidprofile ohne Zunahme der unerwünschten Ereignisse bewirkt. Weitere rigorose, multizentrische RCTs außerhalb Chinas sind erforderlich, um diese Ergebnisse zu validieren.}, } @article {pmid38286113, year = {2024}, author = {Dutta, A and Manna, A and Ghosh, S and Mundle, M and Saha, M and Gourav, K and Maiti, S and Chattopadhyay, B}, title = {Prespecified Homeopathic Medicines in the Prevention of Confirmed and Suspected Cases of COVID-19: A Community-Based, Double-Blind, Randomized, Placebo-Controlled Prophylaxis Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {140-148}, doi = {10.1159/000536395}, pmid = {38286113}, issn = {2504-2106}, mesh = {Humans ; Double-Blind Method ; *COVID-19/prevention & control ; Male ; Female ; Adult ; *Homeopathy/methods ; Middle Aged ; India/epidemiology ; *Materia Medica/therapeutic use ; SARS-CoV-2 ; *COVID-19 Drug Treatment ; }, abstract = {INTRODUCTION: Homeopathic medicines have been used for decades in the prevention and treatment of infectious diseases. However, the preventive efficacy of specific homeopathic medicines in COVID-19 is not well characterized. This study aimed to evaluate the comparative efficacy of prespecified homeopathic medicines in preventing COVID-19.

METHODS: A community-based, double-blind, randomized, placebo-controlled trial was conducted on 4,034 participants residing in Ward No. 27 of the Howrah Municipal Corporation in India. Participants were randomized to receive one of three prespecified homeopathic medicines [Influenzinum 30C, Arsenicum album 30C, Anas barbariae hepatis et cordis extractum 200K (Oscillococcinum®)], or placebo. The outcomes were the incidence of laboratory-confirmed and suspected cases of COVID-19 during a follow-up period of 1 month.

RESULTS: During the follow-up period, a total of 13 new laboratory-confirmed COVID-19 cases were reported in the study population. Among these, 5 cases in Influenzinum group, 2 cases in Arsenicum album group, 1 case in Oscillococcinum® group, and 5 cases in Placebo group were reported. On the other hand, number of suspected COVID-19 cases was significantly less in all the three homeopathic medicine groups compared to placebo. The least number of suspected cases reported in the Oscillococcinum® group (aOR: 0.058; 95% confidence interval [CI]: 0.029, 0.114), followed by the Arsenicum album (aOR: 0.337; 95% CI: 0.238, 0.475) and Influenzinum (aOR: 0.539; 95% CI: 0.401, 0.726) groups.

CONCLUSION: Prespecified homeopathic medicines, particularly Oscillococcinum® and Arsenicum album 30C, may have a role in preventing COVID-19, especially in reducing the incidence of suspected or COVID-19-like respiratory illnesses. However, the result failed to demonstrate a statistically significant difference in the occurrence of confirmed cases of COVID-19 between the study groups. Further research is needed to evaluate the efficacy of these medicines in different populations and settings.

UNLABELLED: EinleitungHomöopathische Arzneimittel werden seit Jahrzehnten zur Prävention und Behandlung von Infektionskrankheiten eingesetzt. Die Wirksamkeit spezifischer homöopathischer Arzneimittel zur Prophylaxe von COVID-19 ist jedoch nicht gut untersucht. Mit dieser Studie sollte die vergleichende Wirksamkeit spezifischer homöopathischer Arzneimittel bei der Prävention von COVID-19 untersucht werden.MethodenEs handelte sich um eine gemeindebasierte, doppelblinde, randomisierte, placebokontrollierte Studie mit 4.034 Teilnehmern, die im Bezirk Nr. 27 der Howrah Municipal Corporation in Indien lebten. Die Teilnehmer erhielten randomisiert eines von drei zuvor festgelegten homöopathischen Arzneimitteln [Influenzinum 30C, Arsenicum album 30C, Anas barbariae hepatis et cordis extractum 200K (Oscillococcinum®)] oder Placebo. Zielkriterien waren die Inzidenz von laborchemisch bestätigten und vermuteten COVID-19-Fällen während des Follow-up-Zeitraums von einem Monat.ErgebnisseWährend des Follow-up-Zeitraums wurden insgesamt 13 neue, laborchemisch bestätigte COVID-19-Fälle in der Studienpopulation berichtet, davon 5 Fälle in der Influenzinum-Gruppe, 2 Fälle in der Arsenicum album-Gruppe, 1 Fall in der Oscillococcinum®-Gruppe und 5 Fälle in der Placebo-Gruppe. Demgegenüber fiel Zahl der COVID-19-Verdachtsfälle in allen drei homöopathischen Arzneimittelgruppen signifikant geringer aus als in der Placebogruppe. Die wenigsten Verdachtsfälle wurden in der Oscillococcinum®-Gruppe berichtet (aOR: 0.058; 95%-KI: 0.029, 0.114), gefolgt von der Arsenicum album- (aOR: 0.337; 95%-KI: 0.238, 0.475) und der Influenzinum- (aOR: 0.539; 95%-KI: 0.401, 0.726) Gruppe.SchlussfolgerungSpezifische homöopathische Arzneimittel, insbesondere Oscillococcinum® und Arsenicum album 30C, könnten bei der Prävention von COVID-19 eine Rolle spielen, vor allem bei der Senkung der Inzidenz von COVID-19-Verdachtsfällen oder COVID-19-ähnlichen Atemwegserkrankungen. Allerdings war kein statistisch signifikanter Unterschied im Auftreten von bestätigten COVID-19-Fällen zwischen den Studiengruppen nachweisbar. Weitere Untersuchungen sind erforderlich, um die Wirksamkeit dieser Arzneimittel in verschiedenen Populationen und Umgebungen zu bewerten.}, } @article {pmid38286389, year = {2024}, author = {Rayner, SL and Hogan, A and Davidson, JM and Chapman, T and Cheng, F and Luu, L and Wu, S and Zhang, S and Yang, S and Blair, I and Morsch, M and Chung, R and Lee, A}, title = {Cyclin F can alter the turnover of TDP-43.}, journal = {Neurobiology of disease}, volume = {192}, number = {}, pages = {106421}, doi = {10.1016/j.nbd.2024.106421}, pmid = {38286389}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Zebrafish ; DNA-Binding Proteins/metabolism ; Ubiquitination ; Cyclins/genetics/metabolism ; }, abstract = {Previously, we demonstrated that the SCF[cyclin F] complex directly mediates the poly-ubiquitylation of TDP-43, raising the question of whether cyclin F can be used to enhance the turnover of TDP-43. A hurdle to the use of cyclin F, however, is that the overexpression of cyclin F can lead to the initiation of cell death pathways. Accordingly, the aim of this study was to identify and evaluate a less toxic variant of cyclin F. To do so, we first confirmed and validated our previous findings that cyclin F binds to TDP-43 in an atypical manner. Additionally, we demonstrated that mutating the canonical substrate region in cyclin F (to generate cyclin F[MRL/AAA]) led to reduced binding affinity to known canonical substrates without impacting the interaction between cyclin F and TDP-43. Notably, both wild-type and cyclin F[MRL/AAA] effectively reduced the abundance of TDP-43 in cultured cells whilst cyclin F[MRL/AAA] also demonstrated reduced cell death compared to the wild-type control. The decrease in toxicity also led to a reduction in morphological defects in zebrafish embryos. These results suggest that cyclin F can be modified to enhance its targeting of TDP-43, which in turn reduces the toxicity associated with the overexpression of cyclin F. This study provides greater insights into the interaction that occurs between cyclin F and TDP-43 in cells and in vivo.}, } @article {pmid38286832, year = {2024}, author = {Lu, J and He, AX and Jin, ZY and Zhang, M and Li, ZX and Zhou, F and Ma, L and Jin, HM and Wang, JY and Shen, X}, title = {Desloratadine alleviates ALS-like pathology in hSOD1[G93A] mice via targeting 5HTR2A on activated spinal astrocytes.}, journal = {Acta pharmacologica Sinica}, volume = {45}, number = {5}, pages = {926-944}, pmid = {38286832}, issn = {1745-7254}, mesh = {Animals ; Humans ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Astrocytes/drug effects/metabolism/pathology ; Disease Models, Animal ; *Loratadine/analogs & derivatives/pharmacology/therapeutic use ; Mice, Inbred C57BL ; *Mice, Transgenic ; Receptor, Serotonin, 5-HT2A/genetics/metabolism ; Serotonin 5-HT2 Receptor Antagonists/pharmacology/therapeutic use ; *Spinal Cord/drug effects/pathology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive loss of motor neurons in the spinal cord, cerebral cortex and brain stem. ALS is characterized by gradual muscle atrophy and dyskinesia. The limited knowledge on the pathology of ALS has impeded the development of therapeutics for the disease. Previous studies have shown that autophagy and astrocyte-mediated neuroinflammation are involved in the pathogenesis of ALS, while 5HTR2A participates in the early stage of astrocyte activation, and 5HTR2A antagonism may suppress astrocyte activation. In this study, we evaluated the therapeutic effects of desloratadine (DLT), a selective 5HTR2A antagonist, in human SOD1[G93A] (hSOD1[G93A]) ALS model mice, and elucidated the underlying mechanisms. HSOD1[G93A] mice were administered DLT (20 mg·kg[-1]·d[-1], i.g.) from the age of 8 weeks for 10 weeks or until death. ALS onset time and lifespan were determined using rotarod and righting reflex tests, respectively. We found that astrocyte activation accompanying with serotonin receptor 2 A (5HTR2A) upregulation in the spinal cord was tightly associated with ALS-like pathology, which was effectively attenuated by DLT administration. We showed that DLT administration significantly delayed ALS symptom onset time, prolonged lifespan and ameliorated movement disorders, gastrocnemius injury and spinal motor neuronal loss in hSOD1[G93A] mice. Spinal cord-specific knockdown of 5HTR2A by intrathecal injection of adeno-associated virus9 (AAV9)-si-5Htr2a also ameliorated ALS pathology in hSOD1[G93A] mice, and occluded the therapeutic effects of DLT administration. Furthermore, we demonstrated that DLT administration promoted autophagy to reduce mutant hSOD1 levels through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocyte neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1[G93A] mice. In summary, 5HTR2A antagonism shows promise as a therapeutic strategy for ALS, highlighting the potential of DLT in the treatment of the disease. DLT as a 5HTR2A antagonist effectively promoted autophagy to reduce mutant hSOD1 level through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocytic neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1[G93A] mice.}, } @article {pmid38287112, year = {2024}, author = {Wang, J and Wang, Y and Zhang, Q and Li, SZ and He, MG and Wang, N and Zhang, Y}, title = {Quantitative analysis of dynamic iris changes in primary angle-closure disease with long axial lengths: the Handan Eye Study.}, journal = {Eye (London, England)}, volume = {38}, number = {7}, pages = {1362-1367}, pmid = {38287112}, issn = {1476-5454}, mesh = {Humans ; *Glaucoma, Angle-Closure/physiopathology/diagnosis ; Cross-Sectional Studies ; Female ; Male ; *Tomography, Optical Coherence/methods ; Middle Aged ; *Axial Length, Eye/pathology/diagnostic imaging ; *Iris/pathology/diagnostic imaging ; Aged ; Adult ; Intraocular Pressure/physiology ; Gonioscopy ; Anterior Chamber/pathology/diagnostic imaging ; }, abstract = {OBJECTIVE: To investigate dynamic iris changes in patients with primary angle-closure disease (PACD) with long axial length (AL) compared to those with short and medium AL.

METHODS: This observational cross-sectional study enrolled participants aged 35 years or older from the Handan Eye Study follow-up examination who were diagnosed with PACD and underwent Visante anterior segment optical coherence tomography (ASOCT) imaging under light and dark conditions. The right eye of each participant was included in the analysis. AL was categorized as short (<22.0 mm), medium (≥22.0 to ≤23.5 mm), or long (>23.5 mm). Anterior segment parameters, including iris dynamic changes, were compared among the three groups with different ALs.

RESULTS: Data from 448 patients with PACD were analyzed. We found that 10.9% of included eyes had a long AL with a flatter cornea; larger central anterior chamber depth, angle opening distance, anterior chamber width, anterior chamber area, and volume; and smaller lens thickness and lens vault (LV) (P < 0.05) than those with short AL. No significant difference existed between the three groups in iris thickness, iris cross-sectional area (IA), iris curvature, or pupil diameter (PD) change between light and dark (P > 0.05). The significant associated factors for IA changes were area recess area (ARA) in the dark, LV in the dark, and PD change from light to dark (P < 0.05).

CONCLUSIONS: Dynamic and static iris parameters were consistent across patients with PACD with short, medium, or long AL and may contribute to the pathogenesis of angle closure in atypical PACD.}, } @article {pmid38287331, year = {2024}, author = {Oh, J and An, J and Park, K and Park, Y}, title = {Psychosocial interventions for people with amyotrophic lateral sclerosis and motor neuron disease and their caregivers: a scoping review.}, journal = {BMC nursing}, volume = {23}, number = {1}, pages = {75}, pmid = {38287331}, issn = {1472-6955}, support = {2022R1F1A1064038//National Research Foundation of Korea grant funded by the Korea government/ ; }, abstract = {BACKGROUND: As amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) is a fatal progressive neurodegenerative disorder, patients experience severe impairments, with patients and family caregivers facing emotional distress and exhaustion. Several psychosocial interventions are aimed at providing tailored support for ALS/MND patients and caregivers. The aim of this study was to conduct a scoping review and present a comprehensive overview of psychosocial interventions designed for individuals and families affected by ALS/MND, while also pinpointing research gaps.

METHODS: This scoping review utilized Arksey and O'Malley's methodological framework to investigate psychosocial interventions designed for individuals with ALS/MND and their families. The study adhered to the PRISMA-ScR checklist for reporting.

RESULTS: A total of 27 articles describing 25 interventions met the inclusion criteria. The predominant interventions observed in the research encompassed education-related strategies, closely followed by behavior therapy, counseling, social support interventions, and psychotherapy interventions. Across the majority of the studies, findings indicated promising feasibility and acceptability of these interventions. Notably, a significant proportion of quantitative investigations yielded one or more statistically significant effects, while qualitative studies consistently reported favorable outcomes, including enhancements in well-being and heightened awareness of individual circumstances.

CONCLUSIONS: Given the progressive and debilitating nature of this condition, coupled with the absence of a cure, the adoption of a psychosocial approach can prove beneficial for both ALS/MND patients and their families. However, high-quality RCTs with a large sample size are recommended to examine and confirm the effectiveness.}, } @article {pmid38287907, year = {2024}, author = {Pan, MT and Zhang, H and Li, XJ and Guo, XY}, title = {Genetically modified non-human primate models for research on neurodegenerative diseases.}, journal = {Zoological research}, volume = {45}, number = {2}, pages = {263-274}, pmid = {38287907}, issn = {2095-8137}, mesh = {Humans ; Animals ; Chlorocebus aethiops ; *Neurodegenerative Diseases/genetics/therapy/veterinary ; Animals, Genetically Modified ; Disease Models, Animal ; *Parkinson Disease/pathology/veterinary ; Macaca mulatta ; }, abstract = {Neurodegenerative diseases (NDs) are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Currently, there are no therapies available that can delay, stop, or reverse the pathological progression of NDs in clinical settings. As the population ages, NDs are imposing a huge burden on public health systems and affected families. Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments. While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms, the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap. Old World non-human primates (NHPs), such as rhesus, cynomolgus, and vervet monkeys, are phylogenetically, physiologically, biochemically, and behaviorally most relevant to humans. This is particularly evident in the similarity of the structure and function of their central nervous systems, rendering such species uniquely valuable for neuroscience research. Recently, the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms. This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained, as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.}, } @article {pmid38288290, year = {2023}, author = {Aussenac, R and Monnet, JM and Klopčič, M and Hawryło, P and Socha, J and Mahnken, M and Gutsch, M and Cordonnier, T and Vallet, P}, title = {Diameter, height and species of 42 million trees in three European landscapes generated from field data and airborne laser scanning data.}, journal = {Open research Europe}, volume = {3}, number = {}, pages = {32}, pmid = {38288290}, issn = {2732-5121}, abstract = {Ecology and forestry sciences are using an increasing amount of data to address a wide variety of technical and research questions at the local, continental and global scales. However, one type of data remains rare: fine-grain descriptions of large landscapes. Yet, this type of data could help address the scaling issues in ecology and could prove useful for testing forest management strategies and accurately predicting the dynamics of ecosystem services. Here we present three datasets describing three large European landscapes in France, Poland and Slovenia down to the tree level. Tree diameter, height and species data were generated combining field data, vegetation maps and airborne laser scanning (ALS) data following an area-based approach. Together, these landscapes cover more than 100 000 ha and consist of more than 42 million trees of 51 different species. Alongside the data, we provide here a simple method to produce high-resolution descriptions of large landscapes using increasingly available data: inventory and ALS data. We carried out an in-depth evaluation of our workflow including, among other analyses, a leave-one-out cross validation. Overall, the landscapes we generated are in good agreement with the landscapes they aim to reproduce. In the most favourable conditions, the root mean square error (RMSE) of stand basal area (BA) and mean quadratic diameter (Dg) predictions were respectively 5.4 m [2].ha [-1] and 3.9 cm, and the generated main species corresponded to the observed main species in 76.2% of cases.}, } @article {pmid38288843, year = {2024}, author = {Fatima, J and Siddique, YH}, title = {Application of Nanocomposites and Nanoparticles in Treating Neurodegenerative Disorders.}, journal = {CNS & neurological disorders drug targets}, volume = {23}, number = {10}, pages = {1217-1233}, pmid = {38288843}, issn = {1996-3181}, support = {211610179057//University Grants Commission/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Nanoparticles/therapeutic use ; *Nanocomposites/therapeutic use ; Animals ; Drug Delivery Systems/methods ; Blood-Brain Barrier/drug effects/metabolism ; Neuroprotective Agents/therapeutic use ; }, abstract = {Neurodegenerative diseases represent a formidable global health challenge, affecting millions and imposing substantial burdens on healthcare systems worldwide. Conditions, like Alzheimer's, Parkinson's, and Huntington's diseases, among others, share common characteristics, such as neuronal loss, misfolded protein aggregation, and nervous system dysfunction. One of the major obstacles in treating these diseases is the presence of the blood-brain barrier, limiting the delivery of therapeutic agents to the central nervous system. Nanotechnology offers promising solutions to overcome these challenges. In Alzheimer's disease, NPs loaded with various compounds have shown remarkable promise in preventing amyloid-beta (Aβ) aggregation and reducing neurotoxicity. Parkinson's disease benefits from improved dopamine delivery and neuroprotection. Huntington's disease poses its own set of challenges, but nanotechnology continues to offer innovative solutions. The promising developments in nanoparticle-based interventions for neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), have offered new avenues for effective treatment. Nanotechnology represents a promising frontier in biomedical research, offering tailored solutions to the complex challenges posed by neurodegenerative diseases. While much progress has been made, ongoing research is essential to optimize nanomaterial designs, improve targeting, and ensure biocompatibility and safety. Nanomaterials possess unique properties that make them excellent candidates for targeted drug delivery and neuroprotection. They can effectively bypass the blood-brain barrier, opening doors to precise drug delivery strategies. This review explores the extensive research on nanoparticles (NPs) and nanocomposites in diagnosing and treating neurodegenerative disorders. These nanomaterials exhibit exceptional abilities to target neurodegenerative processes and halt disease progression.}, } @article {pmid38288970, year = {2024}, author = {Lini, RS and Scanferla, DTP and de Oliveira, NG and Aguera, RG and Santos, TDS and Teixeira, JJV and Kaneshima, AMS and Mossini, SAG}, title = {Fungicides as a risk factor for the development of neurological diseases and disorders in humans: a systematic review.}, journal = {Critical reviews in toxicology}, volume = {54}, number = {1}, pages = {35-54}, doi = {10.1080/10408444.2024.2303481}, pmid = {38288970}, issn = {1547-6898}, mesh = {Humans ; *Fungicides, Industrial/toxicity ; *Nervous System Diseases/chemically induced ; Risk Factors ; Brazil ; }, abstract = {Although studies show that pesticides, especially insecticides, may be toxic to humans, publications on the neurological effects of fungicides are scarce. As fungicides are used widely in Brazil, it is necessary to gather evidence to support actions aimed at safely using of these chemicals. We investigated through a systematic review of publications on the use of fungicides and consequences of exposure related to nervous system diseases or neurological disorders in humans. The protocol review was registered on PROSPERO and followed the guidelines of the PRISMA-Statement. As far as it is known, there is no apparent systematic review in the literature on this topic. The search was comprised of the following databases: PubMed; Web of Science; Scopus and EMBASE, using groups of Mesh terms and strategies specific to each database. Thirteen articles were selected for this review. Regarding the substances analyzed in the studies, some reported the use of fungicides in general, without separating them by type, while others summarized the categories of all pesticides by their function (insecticides, herbicides, fungicides, etc.) or chemical class (dithiocarbamate, dicarboximide, inorganic, etc.). However, most of the articles referred to fungicides that contain the metal manganese (Mn) in their composition. As for neurological disorders, articles addressed Parkinson's disease (PD), neurodevelopmental outcomes, extrapyramidal syndrome resembling PD, cognitive disorders, depression, neural tube defects, motor neurone disease, and amyotrophic lateral sclerosis. Most investigations pointed to exposure to fungicides, mainly maneb and mancozeb, leading to the development of at least one neurological disease, which suggests the need for further multicentric clinical trials and prospective studies for greater clarity of the research problem.}, } @article {pmid38289193, year = {2024}, author = {Nolan, M and Scott, C and Hof, PR and Ansorge, O}, title = {Betz cells of the primary motor cortex.}, journal = {The Journal of comparative neurology}, volume = {532}, number = {1}, pages = {e25567}, pmid = {38289193}, issn = {1096-9861}, support = {ANSORGE/OCT14/877-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L022656/1/MRC_/Medical Research Council/United Kingdom ; 14/877-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Adult ; Humans ; Animals ; *Motor Cortex ; *Amyotrophic Lateral Sclerosis ; Pyramidal Cells ; Motor Neurons ; Primates ; Mammals ; }, abstract = {Betz cells, named in honor of Volodymyr Betz (1834-1894), who described them as "giant pyramids" in the primary motor cortex of primates and other mammalian species, are layer V extratelencephalic projection (ETP) neurons that directly innervate α-motoneurons of the brainstem and spinal cord. Despite their large volume and circumferential dendritic architecture, to date, no single molecular criterion has been established that unequivocally distinguishes adult Betz cells from other layer V ETP neurons. In primates, transcriptional signatures suggest the presence of at least two ETP neuron clusters that contain mature Betz cells; these are characterized by an abundance of axon guidance and oxidative phosphorylation transcripts. How neurodevelopmental programs drive the distinct positional and morphological features of Betz cells in humans remains unknown. Betz cells display a distinct biphasic firing pattern involving early cessation of firing followed by delayed sustained acceleration in spike frequency and magnitude. Few cell type-specific transcripts and electrophysiological characteristics are conserved between rodent layer V ETP neurons of the motor cortex and primate Betz cells. This has implications for the modeling of disorders that affect the motor cortex in humans, such as amyotrophic lateral sclerosis (ALS). Perhaps vulnerability to ALS is linked to the evolution of neural networks for fine motor control reflected in the distinct morphomolecular architecture of the human motor cortex, including Betz cells. Here, we discuss histological, molecular, and functional data concerning the position of Betz cells in the emerging taxonomy of neurons across diverse species and their role in neurological disorders.}, } @article {pmid38289969, year = {2024}, author = {Hossain, MA and Sarin, R and Donnelly, DP and Miller, BC and Weiss, A and McAlary, L and Antonyuk, SV and Salisbury, JP and Amin, J and Conway, JB and Watson, SS and Winters, JN and Xu, Y and Alam, N and Brahme, RR and Shahbazian, H and Sivasankar, D and Padmakumar, S and Sattarova, A and Ponmudiyan, AC and Gawde, T and Verrill, DE and Yang, W and Kannapadi, S and Plant, LD and Auclair, JR and Makowski, L and Petsko, GA and Ringe, D and Agar, NYR and Greenblatt, DJ and Ondrechen, MJ and Chen, Y and Yerbury, JJ and Manetsch, R and Hasnain, SS and Brown, RH and Agar, JN}, title = {Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS.}, journal = {PLoS biology}, volume = {22}, number = {1}, pages = {e3002462}, pmid = {38289969}, issn = {1545-7885}, support = {P30 GM124166/GM/NIGMS NIH HHS/United States ; R01 NS065263/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Cysteine/genetics ; Mutation ; Superoxide Dismutase/genetics/chemistry/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, "S-XL6," was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A's in vivo half-life; and that S-XL6 crosses the blood-brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS.}, } @article {pmid38290242, year = {2024}, author = {Shadish, JA and Lee, JC}, title = {Genetically encoded lysine photocage for spatiotemporal control of TDP-43 nuclear import.}, journal = {Biophysical chemistry}, volume = {307}, number = {}, pages = {107191}, pmid = {38290242}, issn = {1873-4200}, support = {ZIA HL001055/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; Active Transport, Cell Nucleus ; *Amyotrophic Lateral Sclerosis/genetics ; DNA-Binding Proteins/chemistry ; HEK293 Cells ; *Lysine/metabolism ; }, abstract = {Intracellular aggregation of transactive response DNA binding protein of 43 kDa (TDP-43) is a hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis. While primarily a nuclear protein, TDP-43 translocates to the cytosol during cellular stress. Consequences of cytosolic accumulation of TDP-43 is difficult to evaluate in the absence of exogenous toxins. Here, we demonstrate spatiotemporal control over the nuclear import of TDP-43 by installing a photocage (ortho-nitrobenzyl ester) on a single lysine residue (K84) through amber codon suppression in HEK293T cells. Translocation of this cytosolic construct is photo-triggerable in a dose-dependent manner with 355 nm light. Interestingly, both fluid- and solid-like puncta were found based on fluorescence recovery after photobleaching experiments, similar to what is expected of stress granules and intracellular aggregates, respectively. This optogenetic method is advantageous as it is minimally perturbative and broadly applicable to other studies of protein translocation between cellular compartments.}, } @article {pmid38290377, year = {2024}, author = {Takeda, T and Koreki, A and Kokubun, S and Saito, Y and Ishikawa, A and Isose, S and Ito, K and Arai, K and Kitagawa, K and Kuwabara, S and Honda, K}, title = {Deep vein thrombosis and its risk factors in neurodegenerative diseases: A markedly higher incidence in Parkinson's disease.}, journal = {Journal of the neurological sciences}, volume = {457}, number = {}, pages = {122896}, doi = {10.1016/j.jns.2024.122896}, pmid = {38290377}, issn = {1878-5883}, mesh = {Humans ; Female ; *Parkinson Disease/complications/diagnostic imaging/epidemiology ; *Amyotrophic Lateral Sclerosis ; Incidence ; *Supranuclear Palsy, Progressive ; *Multiple System Atrophy ; Risk Factors ; *Venous Thrombosis/diagnostic imaging/epidemiology ; }, abstract = {BACKGROUND: Information on the incidence and risk factors of deep vein thrombosis (DVT) in neurodegenerative diseases is limited. We aimed to determine the incidence of DVT among neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Parkinson's disease [PD], multiple system atrophy [MSA], and progressive supranuclear palsy [PSP]-corticobasal syndrome [CBS]) and the risk factors for the development of DVT.

METHODS: Overall, 229 hospitalized patients with neurodegenerative diseases (65 patients with ALS, 61 with PD, 53 with MSA, and 50 with PSP-CBS) were included in this study. D-dimer value and ultrasonography of the leg vein were assessed to determine the presence or absence of leg DVT. We compared the DVT incidence among each disease group. To identify the risk factors for DVT, a multivariate analysis was performed.

RESULTS: Of 229 patients, 34 had leg DVT; the incidence was significantly higher in patients with PD (38%) than in those with ALS (2%), MSA (5%), or PSP-CBS (4%). Patients with DVT were older, had a smaller waist circumference, had a longer disease duration, and had a high blood pressure (BP) variability. Multivariate analysis revealed that a PD diagnosis and female sex, with a high BP variability were predictive of leg DVT.

CONCLUSIONS: Among the neurodegenerative diseases, the DVT incidence was markedly higher in PD than in ALS, MSA, and PSP-CBS. Several risk factors have been identified in patients with leg DVT. Recognition of these risk factors will improve patient care and guide the appropriate use of anticoagulants.}, } @article {pmid38290651, year = {2024}, author = {Lõhelaid, H and Saarma, M and Airavaara, M}, title = {CDNF and ER stress: Pharmacology and therapeutic possibilities.}, journal = {Pharmacology & therapeutics}, volume = {254}, number = {}, pages = {108594}, doi = {10.1016/j.pharmthera.2024.108594}, pmid = {38290651}, issn = {1879-016X}, mesh = {Animals ; Humans ; *Parkinson Disease/drug therapy ; Nerve Growth Factors/therapeutic use/metabolism ; Recombinant Proteins/therapeutic use ; }, abstract = {Cerebral dopamine neurotrophic factor (CDNF) is an endogenous protein in humans and other vertebrates, and it has been shown to have protective and restorative effects on cells in various disease models. Although it is named as a neurotrophic factor, its actions are drastically different from classical neurotrophic factors such as neurotrophins or the glial cell line-derived neurotrophic family of proteins. Like all secreted proteins, CDNF has a signal sequence at the N-terminus, but unlike common growth factors it has a KDEL-receptor retrieval sequence at the C-terminus. Thus, CDNF is mainly located in the ER. In response to adverse effects, such as ER stress, the expression of CDNF is upregulated and can alleviate ER stress. Also different from other neurotrophic factors, CDNF reduces protein aggregation and inflammation in disease models. Although it is an ER luminal protein, it can surprisingly directly interact with alpha-synuclein, a protein involved in the pathogenesis of synucleinopathies e.g., Parkinson's disease. Pleiotropic CDNF has therapeutic potential and has been tested as a recombinant human protein and gene therapy. The neuroprotective and neurorestorative effects have been described in a number of preclinical studies of Parkinson's disease, stroke and amyotrophic lateral sclerosis. Currently, it was successfully evaluated for safety in a phase 1/2 clinical trial for Parkinson's disease. Collectively, based on recent findings on the mode of action and therapeutic potential of CDNF, its use as a drug could be expanded to other ER stress-related diseases.}, } @article {pmid38291418, year = {2024}, author = {Cai, Y and Peng, Z and He, Q and Sun, P}, title = {Behavioral variant frontotemporal dementia associated with GRN and ErbB4 gene mutations: a case report and literature review.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {43}, pmid = {38291418}, issn = {1755-8794}, mesh = {Male ; Humans ; Middle Aged ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Positron Emission Tomography Computed Tomography ; Progranulins/genetics ; Mutation ; }, abstract = {OBJECTIVE: To report the clinical manifestation and genetic characteristics of a patient having frontotemporal dementia (FTD) with abnormal behavior and unstable walking.

METHODS: The clinical and imaging features of a patient who was eventually diagnosed with FTD were analyzed. The patient's neuropsychological, PET-CT, electromyography, and genetic data were collected. Furthermore, the patient's blood samples were examined for FTD-related genes.

RESULTS: The patient was a 52-year-old man with hidden onset. The symptoms progressed gradually, presenting with abnormal behaviors, including repeated shopping, taking away other people's things, constantly eating snacks, and frequently calling friends at night. The patient also exhibited executive dysfunction, such as the inability to cook and multiple driving problems, e.g., constantly deviates from his lane while driving. In addition, the patient showed personality changes such as irritability, indifference, and withdrawal, as well as motor symptoms, including unstable walking and frequent falls when walking. Brain magnetic resonance imaging revealed hippocampal sclerosis along with widening and deepening of the bilateral temporal lobe sulcus. Brain metabolic imaging via PET-CT demonstrated decreased metabolism in the bilateral prefrontal lobe, with the abnormal energy metabolism indicating FTD. Lastly, blood sample analysis detected mutations in the amyotrophic lateral sclerosis (ALS)-related GRN gene c.1352C > T (p.P451L) and ErbB4 gene c.256 T > C (p.Y86H).

CONCLUSION: This is the first case of heterozygous mutations in the GRN and ErbB4 genes in FTD alone. The GRN and ErbB4 genes are likely to be important in the pathogenesis of FTD, expanding the common genetic profile of ALS and FTD.}, } @article {pmid38292023, year = {2023}, author = {Ratano, P and Cocozza, G and Pinchera, C and Busdraghi, LM and Cantando, I and Martinello, K and Scioli, M and Rosito, M and Bezzi, P and Fucile, S and Wulff, H and Limatola, C and D'Alessandro, G}, title = {Reduction of inflammation and mitochondrial degeneration in mutant SOD1 mice through inhibition of voltage-gated potassium channel Kv1.3.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1333745}, pmid = {38292023}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective therapy, causing progressive loss of motor neurons in the spinal cord, brainstem, and motor cortex. Regardless of its genetic or sporadic origin, there is currently no cure for ALS or therapy that can reverse or control its progression. In the present study, taking advantage of a human superoxide dismutase-1 mutant (hSOD1-G93A) mouse that recapitulates key pathological features of human ALS, we investigated the possible role of voltage-gated potassium channel Kv1.3 in disease progression. We found that chronic administration of the brain-penetrant Kv1.3 inhibitor, PAP-1 (40 mg/Kg), in early symptomatic mice (i) improves motor deficits and prolongs survival of diseased mice (ii) reduces astrocyte reactivity, microglial Kv1.3 expression, and serum pro-inflammatory soluble factors (iii) improves structural mitochondrial deficits in motor neuron mitochondria (iv) restores mitochondrial respiratory dysfunction. Taken together, these findings underscore the potential significance of Kv1.3 activity as a contributing factor to the metabolic disturbances observed in ALS. Consequently, targeting Kv1.3 presents a promising avenue for modulating disease progression, shedding new light on potential therapeutic strategies for ALS.}, } @article {pmid38292603, year = {2024}, author = {Weerawarna, PM and Schiefer, IT and Soares, P and Fox, S and Morimoto, RI and Melani, RD and Kelleher, NL and Luan, CH and Silverman, RB}, title = {Target Identification of a Class of Pyrazolone Protein Aggregation Inhibitor Therapeutics for Amyotrophic Lateral Sclerosis.}, journal = {ACS central science}, volume = {10}, number = {1}, pages = {87-103}, pmid = {38292603}, issn = {2374-7943}, support = {P41 GM108569/GM/NIGMS NIH HHS/United States ; R01 AG061708/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure, and current treatment options are very limited. Previously, we performed a high-throughput screen to identify small molecules that inhibit protein aggregation caused by a mutation in the gene that encodes superoxide dismutase 1 (SOD1), which is responsible for about 25% of familial ALS. This resulted in three hit series of compounds that were optimized over several years to give three compounds that were highly active in a mutant SOD1 ALS model. Here we identify the target of two of the active compounds (6 and 7) with the use of photoaffinity labeling, chemical biology reporters, affinity purification, proteomic analysis, and fluorescent/cellular thermal shift assays. Evidence is provided to demonstrate that these two pyrazolone compounds directly interact with 14-3-3-E and 14-3-3-Q isoforms, which have chaperone activity and are known to interact with mutant SOD1[G93A] aggregates and become insoluble in the subcellular JUNQ compartment, leading to apoptosis. Because protein aggregation is the hallmark of all neurodegenerative diseases, knowledge of the target compounds that inhibit protein aggregation allows for the design of more effective molecules for the treatment of ALS and possibly other neurodegenerative diseases.}, } @article {pmid38293619, year = {2023}, author = {Lu, B and Meng, R and Wang, Y and Xiong, W and Ma, Y and Gao, P and Ren, J and Zhang, L and Zhao, Z and Fan, G and Wen, Y and Yuan, X}, title = {Distinctive physiological and molecular responses of foxtail millet and maize to nicosulfuron.}, journal = {Frontiers in plant science}, volume = {14}, number = {}, pages = {1308584}, pmid = {38293619}, issn = {1664-462X}, abstract = {INTRODUCTION: Nicosulfuron is the leading acetolactate synthase inhibitor herbicide product, and widely used to control gramineous weeds. Here, we investigated the metabolic process of nicosulfuron into foxtail millet and maize, in order to clarify the mechanism of the difference in sensitivity of foxtail millet and maize to nicosulfuron from the perspective of physiological metabolism and provide a theoretical basis for the breeding of nicosulfuron-resistant foxtail millet varieties.

METHODS: We treated foxtail millet (Zhangzagu 10, Jingu 21) and maize (Nongda 108, Ditian 8) with various doses of nicosulfuron in both pot and field experiments. The malonaldehyde (MDA) content, target enzymes, detoxification enzymes, and antioxidant enzymes, as well as related gene expression levels in the leaf tissues of foxtail millet and maize were measured, and the yield was determined after maturity.

RESULTS: The results showed that the recommended dose of nicosulfuron caused Zhangzagu 10 and Jingu 21 to fail to harvest; the yield of the sensitive maize variety (Ditian 8) decreased by 37.09%, whereas that of the resistant maize variety (Nongda 108) did not decrease. Nicosulfuron stress increased the CYP450 enzyme activity, MDA content, and antioxidant enzyme activity of foxtail millet and maize, reduced the acetolactate synthase (ALS) activity and ALS gene expression of foxtail millet and Ditian 8, and reduced the glutathione S-transferase (GST) activity and GST gene expression of foxtail millet. In conclusion, target enzymes, detoxification enzymes, and antioxidant enzymes were involved in the detoxification metabolism of nicosulfuron in plants. ALS and GST are the main factors responsible for the metabolic differences among foxtail millet, sensitive maize varieties, and resistant maize varieties.

DISCUSSION: These findings offer valuable insights for exploring the target resistance (TSR) and non-target resistance (NTSR) mechanisms in foxtail millet under herbicide stress and provides theoretical basis for future research of develop foxtail millet germplasm with diverse herbicide resistance traits.}, } @article {pmid38293807, year = {2024}, author = {Tang, D and Bao, H and Qi, S}, title = {The C9orf72-SMCR8 complex suppresses primary ciliogenesis as a RAB8A GAP.}, journal = {Autophagy}, volume = {20}, number = {5}, pages = {1205-1207}, pmid = {38293807}, issn = {1554-8635}, mesh = {*rab GTP-Binding Proteins/metabolism/genetics ; *Cilia/metabolism ; Humans ; *C9orf72 Protein/genetics/metabolism ; *Autophagy/genetics ; Animals ; Signal Transduction ; Hedgehog Proteins/metabolism ; HEK293 Cells ; GTPase-Activating Proteins/metabolism/genetics ; Protein Binding ; Mice ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Carrier Proteins ; }, abstract = {Approximately half of the familial cases of amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD) are attributed to the abnormal GGGGCC repeat expansion within the first intron of C9orf72, potentializing C9orf72 and its product as the most promising target for ALS therapeutics. Nevertheless, the biological function of C9orf72 remains unclear. Previously, we reported that C9orf72 and its binding partner, SMCR8, form a GTPase-activating protein (GAP) complex, which is proposed to regulate membrane trafficking and autophagy. Hereby, we found that the C9orf72-SMCR8 complex negatively regulates primary ciliogenesis and hedgehog (HH) signaling. Furthermore, the biochemical analysis and cell biology experiments identified C9orf72 as the RAB8A binding subunit and SMCR8 as the GAP subunit within the complex. Further, we discussed the relationship among the C9orf72-SMCR8 complex, primary ciliogenesis, and autophagy.}, } @article {pmid38294285, year = {2024}, author = {Castro-Rodriguez, E and Azagra-Ledesma, R and Gómez-Batiste, X and Aguyé-Batista, A and Clemente-Azagra, C and Díaz-Herrera, MA}, title = {Complexity of needs in amyotrophic lateral sclerosis (ALS) patients using the ENP-E scale in the north-eastern region of Spain.}, journal = {Palliative & supportive care}, volume = {22}, number = {3}, pages = {460-469}, doi = {10.1017/S1478951523001773}, pmid = {38294285}, issn = {1478-9523}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/complications ; Male ; Spain ; Female ; Aged ; Middle Aged ; Longitudinal Studies ; Palliative Care/methods/statistics & numerical data/standards/psychology ; Needs Assessment/statistics & numerical data ; Aged, 80 and over ; Surveys and Questionnaires ; Terminal Care/methods/psychology/statistics & numerical data/standards ; }, abstract = {OBJECTIVES: This study aimed to explore the clinical characteristics of amyotrophic lateral sclerosis (ALS) patients in Spain's north-eastern region, their inclusion in chronic care programmes, and their psychosocial and spiritual needs (PSNs).

METHODS: A longitudinal descriptive study in adult patients with ALS. We analyzed clinical variables and participation in chronicity and PSNs assessment using the tool Psychosocial and Spiritual Needs Evaluation scale in end-of-life patients (ENP-E scale).

RESULTS: 81 patients (average age 65.6 ± 11.7) were studied. At the study's outset, 29.7% employed non-invasive ventilation (NIV), increasing to 51.9% by its conclusion. Initial percutaneous endoscopic gastrostomy (PEG) utilization was 14.8%, rising to 35.85%. Chronic care programme participation was as follows: home care (24.7% initially, 50.6% end), palliative care (16% initially, 40.7% end), case management (13.6% initially, 50.6% end), and advance care planning registration (6.2% initially, 35.8% end). At study start, 47.8% of patients (n = 46) showed moderate-to-severe complexity in PSNs assessment using the ENP-E scale, without showing differences in age, sex, and time of evolution; whereas, on the evolutionary analysis, it was 75% (n = 24). A higher evolutionary complexity was observed in males <60 and >70 years, with no PEG and evolution of ALS of <2 and ≥5 years, and not included in chronicity programmes. When assessing concerns, physical pain and family aspects stand out in all measurements. Forty-eight percent of patients at study start and 71% at end of study showed external signs of emotional distress.

SIGNIFICANCE OF RESULTS: Most ALS patients showed a high degree of complexity and were not integrated in chronicity programmes. A "care path" is proposed to integrate ALS patients in these programmes and systematically assess their needs.}, } @article {pmid38295187, year = {2024}, author = {Limone, F and Couto, A and Wang, JY and Zhang, Y and McCourt, B and Huang, C and Minkin, A and Jani, M and McNeer, S and Keaney, J and Gillet, G and Gonzalez, RL and Goodman, WA and Kadiu, I and Eggan, K and Burberry, A}, title = {Myeloid and lymphoid expression of C9orf72 regulates IL-17A signaling in mice.}, journal = {Science translational medicine}, volume = {16}, number = {732}, pages = {eadg7895}, pmid = {38295187}, issn = {1946-6242}, support = {R01 NS089742/NS/NINDS NIH HHS/United States ; R01 DK128143/DK/NIDDK NIH HHS/United States ; S10 OD021559/OD/NIH HHS/United States ; R01 AG085316/AG/NIA NIH HHS/United States ; T32 AI089474/AI/NIAID NIH HHS/United States ; R00 AG057808/AG/NIA NIH HHS/United States ; R35 NS097303/NS/NINDS NIH HHS/United States ; T32 AG071474/AG/NIA NIH HHS/United States ; K99 AG057808/AG/NIA NIH HHS/United States ; R03 AG080175/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *C9orf72 Protein/genetics ; Endothelial Cells/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Interleukin-17 ; Neuroinflammatory Diseases ; }, abstract = {A mutation in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Patients with ALS or FTD often develop autoimmunity and inflammation that precedes or coincides with the onset of neurological symptoms, but the underlying mechanisms are poorly understood. Here, we knocked out murine C9orf72 in seven hematopoietic progenitor compartments by conditional mutagenesis and found that myeloid lineage C9orf72 prevents splenomegaly, loss of tolerance, and premature mortality. Furthermore, we demonstrated that C9orf72 plays a role in lymphoid cells to prevent interleukin-17A (IL-17A) production and neutrophilia. Mass cytometry identified early and sustained elevation of the costimulatory molecule CD80 expressed on C9orf72-deficient mouse macrophages, monocytes, and microglia. Enrichment of CD80 was similarly observed in human spinal cord microglia from patients with C9ORF72-mediated ALS compared with non-ALS controls. Single-cell RNA sequencing of murine spinal cord, brain cortex, and spleen demonstrated coordinated induction of gene modules related to antigen processing and presentation and antiviral immunity in C9orf72-deficient endothelial cells, microglia, and macrophages. Mechanistically, C9ORF72 repressed the trafficking of CD80 to the cell surface in response to Toll-like receptor agonists, interferon-γ, and IL-17A. Deletion of Il17a in C9orf72-deficient mice prevented CD80 enrichment in the spinal cord, reduced neutrophilia, and reduced gut T helper type 17 cells. Last, systemic delivery of an IL-17A neutralizing antibody augmented motor performance and suppressed neuroinflammation in C9orf72-deficient mice. Altogether, we show that C9orf72 orchestrates myeloid costimulatory potency and provide support for IL-17A as a therapeutic target for neuroinflammation associated with ALS or FTD.}, } @article {pmid38295729, year = {2024}, author = {Bhatt, N and Puangmalai, N and Sengupta, U and Jerez, C and Kidd, M and Gandhi, S and Kayed, R}, title = {C9orf72-associated dipeptide protein repeats form A11-positive oligomers in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {2}, pages = {105628}, pmid = {38295729}, issn = {1083-351X}, support = {R01 AG054025/AG/NIA NIH HHS/United States ; R01 NS094557/NS/NINDS NIH HHS/United States ; R01 AG060718/AG/NIA NIH HHS/United States ; RF1 AG055771/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; DNA Repeat Expansion ; Dipeptides/chemistry ; Arginine ; Amyloidogenic Proteins ; Glycine ; }, abstract = {Hexanucleotide repeat expansion in C9orf72 is one of the most common causes of amyotrophic lateral sclerosis and frontotemporal dementia. The hexanucleotide expansion, formed by GGGGCC (G4C2) repeats, leads to the production of five dipeptide protein repeats (DPRs) via repeat-associated non-AUG translation. Among the five dipeptide repeats, Gly-Arg, Pro-Arg, and Gly-Ala form neuronal inclusions that contain aggregates of the peptides. Several studies have attempted to model DPR-associated toxicity using various repeat lengths, which suggests a unique conformation that is cytotoxic and is independent of the repeat length. However, the structural characteristics of DPR aggregates have yet to be determined. Increasing evidence suggests that soluble species, such as oligomers, are the main cause of toxicity in proteinopathies, such as Alzheimer's and Parkinson's disease. To investigate the ability of DPRs to aggregate and form toxic oligomers, we adopted a reductionist approach using small dipeptide repeats of 3, 6, and 12. This study shows that DPRs, particularly glycine-arginine and proline-arginine, form oligomers that exhibit distinct dye-binding properties and morphologies. Importantly, we also identified toxic DPR oligomers in amyotrophic lateral sclerosis and frontotemporal dementia postmortem brains that are morphologically similar to those generated recombinantly. This study demonstrates that, similar to soluble oligomers formed by various amyloid proteins, DPR oligomers are toxic, independent of their repeat length.}, } @article {pmid38296522, year = {2025}, author = {Kamiya, K and Hanashiro, S and Kano, O and Uchida, W and Kamagata, K and Aoki, S and Hori, M}, title = {Surface-based Analyses of Diffusional Kurtosis Imaging in Amyotrophic Lateral Sclerosis: Relationship with Onset Subtypes.}, journal = {Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine}, volume = {24}, number = {1}, pages = {122-132}, pmid = {38296522}, issn = {1880-2206}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; Aged ; *Diffusion Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/pathology ; Anisotropy ; Adult ; Image Processing, Computer-Assisted/methods ; Diffusion Tensor Imaging/methods ; }, abstract = {PURPOSE: Here, we aimed to characterize the cortical and subcortical microstructural alterations in the brains of patients with amyotrophic lateral sclerosis (ALS). In particular, we compared these features between bulbar-onset ALS (b-ALS) and limb-onset ALS (l-ALS).

METHODS: Diffusion MRI data (b = 0, 700, 2000 ms/mm[2], 1.7-mm isotropic voxel) from 28 patients with ALS (9 b-ALS and 19 l-ALS) and 17 healthy control subjects (HCs) were analyzed. Diffusional kurtosis imaging (DKI) metrics were sampled at the mid-cortical and subcortical surfaces. We used permutation testing with a nonparametric combination of mean diffusivity (MD), fractional anisotropy (FA), and mean kurtosis (MK) to assess intergroup differences over the cerebrum. We also carried out an atlas-based analysis focusing on Brodmann Area 4 and 6 (primary motor and premotor areas) and investigated the correlation between MRI metrics and clinical parameters.

RESULTS: At both the mid-cortical and subcortical surfaces, b-ALS was associated with significantly greater MD, smaller FA, and smaller MK in the motor and premotor areas than HC. In contrast, the patients with l-ALS showed relatively moderate differences relative to HCs. The ALS Functional Rating Scale-Revised bulbar subscore was significantly correlated with the diffusion metrics in Brodmann Area 4.

CONCLUSION: The distribution of abnormalities over the cerebral hemispheres and the more severe microstructural alteration in b-ALS compared to l-ALS were in good agreement with findings from postmortem histology. Our results suggest the feasibility of surface-based DKI analyses for exploring brain microstructural pathologies in ALS. The observed differences between b-ALS and l-ALS and their correlations with functional bulbar impairment support the clinical relevance of DKI measurement in the cortical and juxtacortical regions of patients with ALS.}, } @article {pmid38297144, year = {2024}, author = {Sun, K and Ray, S and Gupta, N and Aldworth, Z and Stopfer, M}, title = {Olfactory system structure and function in newly hatched and adult locusts.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {2608}, pmid = {38297144}, issn = {2045-2322}, support = {Intramural Grant//National Institute of Child Health and Human Development/ ; }, mesh = {Animals ; *Grasshoppers ; Odorants ; Olfactory Pathways/physiology ; *Olfactory Receptor Neurons/physiology ; Interneurons ; Smell/physiology ; }, abstract = {An important question in neuroscience is how sensory systems change as animals grow and interact with the environment. Exploring sensory systems in animals as they develop can reveal how networks of neurons process information as the neurons themselves grow and the needs of the animal change. Here we compared the structure and function of peripheral parts of the olfactory pathway in newly hatched and adult locusts. We found that populations of olfactory sensory neurons (OSNs) in hatchlings and adults responded with similar tunings to a panel of odors. The morphologies of local neurons (LNs) and projection neurons (PNs) in the antennal lobes (ALs) were very similar in both age groups, though they were smaller in hatchlings, they were proportional to overall brain size. The odor evoked responses of LNs and PNs were also very similar in both age groups, characterized by complex patterns of activity including oscillatory synchronization. Notably, in hatchlings, spontaneous and odor-evoked firing rates of PNs were lower, and LFP oscillations were lower in frequency, than in the adult. Hatchlings have smaller antennae with fewer OSNs; removing antennal segments from adults also reduced LFP oscillation frequency. Thus, consistent with earlier computational models, the developmental increase in frequency is due to increasing intensity of input to the oscillation circuitry. Overall, our results show that locusts hatch with a fully formed olfactory system that structurally and functionally matches that of the adult, despite its small size and lack of prior experience with olfactory stimuli.}, } @article {pmid38297405, year = {2024}, author = {Larson, KC and Martens, LH and Marconi, M and Dejesus, C and Bruhn, S and Miller, TA and Tate, B and Levenson, JM}, title = {Preclinical translational platform of neuroinflammatory disease biology relevant to neurodegenerative disease.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {37}, pmid = {38297405}, issn = {1742-2094}, mesh = {Humans ; Mice ; Animals ; *Neurodegenerative Diseases/metabolism ; Neuroinflammatory Diseases ; Microglia/metabolism ; Inflammasomes/metabolism ; Biology ; }, abstract = {Neuroinflammation is a key driver of neurodegenerative disease, however the tools available to model this disease biology at the systems level are lacking. We describe a translational drug discovery platform based on organotypic culture of murine cortical brain slices that recapitulate disease-relevant neuroinflammatory biology. After an acute injury response, the brain slices assume a chronic neuroinflammatory state marked by transcriptomic profiles indicative of activation of microglia and astrocytes and loss of neuronal function. Microglia are necessary for manifestation of this neuroinflammation, as depletion of microglia prior to isolation of the brain slices prevents both activation of astrocytes and robust loss of synaptic function genes. The transcriptomic pattern of neuroinflammation in the mouse platform is present in published datasets derived from patients with amyotrophic lateral sclerosis, Huntington's disease, and frontotemporal dementia. Pharmacological utility of the platform was validated by demonstrating reversal of microglial activation and the overall transcriptomic signature with transforming growth factor-β. Additional anti-inflammatory targets were screened and inhibitors of glucocorticoid receptors, COX-2, dihydrofolate reductase, and NLRP3 inflammasome all failed to reverse the neuroinflammatory signature. Bioinformatics analysis of the neuroinflammatory signature identified protein tyrosine phosphatase non-receptor type 11 (PTPN11/SHP2) as a potential target. Three structurally distinct inhibitors of PTPN11 (RMC-4550, TN0155, IACS-13909) reversed the neuroinflammatory disease signature. Collectively, these results highlight the utility of this novel neuroinflammatory platform for facilitating identification and validation of targets for neuroinflammatory neurodegenerative disease drug discovery.}, } @article {pmid38299458, year = {2024}, author = {Villarruel, FD and Denofrio, MP and de León, TS and Erra-Balsells, R and Wolcan, E and García Einschlag, FS and Cabrerizo, FM}, title = {Exploring potooxidative degradation pathways of harmol and harmalol alkaloids in water: effects of pH, excitation sources and atmospheric conditions.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {26}, number = {7}, pages = {6068-6079}, doi = {10.1039/d3cp05223k}, pmid = {38299458}, issn = {1463-9084}, mesh = {*Water ; *Alkaloids ; Indoles ; Hydrogen-Ion Concentration ; Harmaline/*analogs & derivatives ; Harmine/*analogs & derivatives ; }, abstract = {This work explores the photochemical degradation of cationic species of 7-hydroxy-1-methyl-2H-pyrido[3,4-b]indole or harmol (1C) and the corresponding partially hydrogenated derivative 7-hydroxy-1-methyl-3,4-dihydro-2H-pyrido[3,4-b]indole or harmalol (2C) in aqueous solution. UV-visible absorption and fluorescence emission spectroscopy coupled with multivariate data analysis (MCR-ALS and PARAFAC), HPLC and HRESI-MS techniques were used for both quantitative and qualitative analysis. The formation of hydrogen peroxide reactive oxygen species (ROS) was quantified, and the influence of pH, oxygen partial pressure and photoexcitation source on the photochemical degradation of both compounds was assessed. The potential implications on the biosynthesis of βCs and their biological role in living systems are discussed.}, } @article {pmid38300375, year = {2024}, author = {Sarkar, S and Patranabis, S}, title = {Emerging Role of Extracellular Vesicles in Intercellular Communication in the Brain: Implications for Neurodegenerative Diseases and Therapeutics.}, journal = {Cell biochemistry and biophysics}, volume = {82}, number = {2}, pages = {379-398}, pmid = {38300375}, issn = {1559-0283}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; *Cell Communication ; *Brain/metabolism/pathology ; Animals ; }, abstract = {Extracellular vesicles (EVs) are minute lipid-bilayer sacs discharged by cells, encompassing a diverse array of proteins, nucleic acids, and lipids. The identification of EVs as pivotal agents in intercellular communication has sparked compelling research pathways in the realms of cell biology and neurodegenerative diseases. Utilizing EVs for medicinal reasons has garnered interest due to the adaptability of EV-mediated communication. EVs can be classified based on their physical characteristics, biochemical composition, or cell of origin following purification. This review delves into the primary sub-types of EVs, providing an overview of the biogenesis of each type. Additionally, it explores the diverse environmental conditions triggering EV release and the originating cells, including stem cells and those from the Central Nervous System. Within the brain, EVs play a pivotal role as essential mediators of intercellular communication, significantly impacting synaptic plasticity, brain development, and the etiology of neurological diseases. Their potential diagnostic and therapeutic applications in various brain-related conditions are underscored, given their ability to carry specific cargo. Specially engineered EVs hold promise for treating diverse diseases, including neurodegenerative disorders. This study primarily emphasizes the diagnostic and potential therapeutic uses of EVs in neurological disorders such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Prions disease. It also summarizes innovative techniques for detecting EVs in the brain, suggesting that EVs could serve as non-invasive biomarkers for early detection, disease monitoring, and prognosis in neurological disorders.}, } @article {pmid38301596, year = {2024}, author = {Wang, H and Liu, YT and Ren, YL and Guo, XY and Wang, Y}, title = {Association of peripheral immune activation with amyotrophic lateral sclerosis and Parkinson's disease: A systematic review and meta-analysis.}, journal = {Journal of neuroimmunology}, volume = {388}, number = {}, pages = {578290}, doi = {10.1016/j.jneuroim.2024.578290}, pmid = {38301596}, issn = {1872-8421}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology ; Biomarkers ; *Neurodegenerative Diseases/immunology ; *Parkinson Disease/immunology ; }, abstract = {BACKGROUND: Recent studies have revealed the link between immune activation and neurodegenerative diseases.

METHODS: By employing meta-analysis, we estimated the standardized mean difference (SMD) and their corresponding 95% confidence intervals (CIs) between the groups.

RESULTS: According to the pre-set criteria, a total of 21 published articles including 2377 ALS patients and 1244 HCs, as well as 60 articles including 5111 PD patients and 4237 HCs, were identified. This study provided evidence of peripheral immune activation in the pathogenesis of ALS and PD.

CONCLUSION: Our results suggested monitoring changes in peripheral blood immune cell populations, particularly lymphocyte subsets, will benefit understanding the developments and exploring reliable and specific biomarkers of these two diseases.}, } @article {pmid38301895, year = {2024}, author = {Gotoh, S and Mori, K and Fujino, Y and Kawabe, Y and Yamashita, T and Omi, T and Nagata, K and Tagami, S and Nagai, Y and Ikeda, M}, title = {eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {3}, pages = {105703}, pmid = {38301895}, issn = {1083-351X}, support = {P40 OD018537/OD/NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; *C9orf72 Protein/genetics ; Dipeptides/genetics ; *DNA Repeat Expansion/genetics ; Drosophila/genetics/metabolism ; *Eukaryotic Initiation Factor-5/genetics/metabolism ; *Frontotemporal Lobar Degeneration/genetics/physiopathology ; HeLa Cells ; Humans ; Disease Models, Animal ; }, abstract = {Tandem GGGGCC repeat expansion in C9orf72 is a genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeats are translated into dipeptide repeat proteins via repeat-associated non-AUG (RAN) translation. However, the regulatory mechanism of RAN translation remains unclear. Here, we reveal a GTPase-activating protein, eukaryotic initiation factor 5 (eIF5), which allosterically facilitates the conversion of eIF2-bound GTP into GDP upon start codon recognition, as a novel modifier of C9orf72 RAN translation. Compared to global translation, eIF5, but not its inactive mutants, preferentially stimulates poly-GA RAN translation. RAN translation is increased during integrated stress response, but the stimulatory effect of eIF5 on poly-GA RAN translation was additive to the increase of RAN translation during integrated stress response, with no further increase in phosphorylated eIF2α. Moreover, an alteration of the CUG near cognate codon to CCG or AUG in the poly-GA reading frame abolished the stimulatory effects, indicating that eIF5 primarily acts through the CUG-dependent initiation. Lastly, in a Drosophila model of C9orf72 FTLD/ALS that expresses GGGGCC repeats in the eye, knockdown of endogenous eIF5 by two independent RNAi strains significantly reduced poly-GA expressions, confirming in vivo effect of eIF5 on poly-GA RAN translation. Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS.}, } @article {pmid38302116, year = {2024}, author = {Ikeda, T and Yamazaki, K and Okumura, F and Kamura, T and Nakatsukasa, K}, title = {Role of the San1 ubiquitin ligase in the heat stress-induced degradation of nonnative Nup1 in the nuclear pore complex.}, journal = {Genetics}, volume = {226}, number = {4}, pages = {}, doi = {10.1093/genetics/iyae017}, pmid = {38302116}, issn = {1943-2631}, support = {//Toray Science Foundation/ ; //Toyoaki Scholarship Foundation/ ; 15K18503//JSPS KAKENHI/ ; //Institute for Fermentation, Osaka/ ; //Hori Science and Arts Foundation/ ; }, mesh = {Nuclear Pore/genetics/chemistry/metabolism ; Nuclear Pore Complex Proteins/genetics/metabolism ; *Proteasome Endopeptidase Complex/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Ubiquitin/analysis/genetics/metabolism ; Ubiquitin-Protein Ligases/genetics/metabolism ; }, abstract = {The nuclear pore complex (NPC) mediates the selective exchange of macromolecules between the nucleus and the cytoplasm. Neurodegenerative diseases such as amyotrophic lateral sclerosis are characterized by mislocalization of nucleoporins (Nups), transport receptors, and Ras-related nuclear proteins into nucleoplasmic or cytosolic aggregates, underscoring the importance of precise assembly of the NPC. The assembly state of large protein complexes is strictly monitored by the protein quality control system. The ubiquitin-proteasome system may eliminate aberrant, misfolded, and/or orphan components; however, the involvement of the ubiquitin-proteasome system in the degradation of nonnative Nups in the NPC remains unclear. Here, we show that in Saccharomyces cerevisiae, although Nup1 (the FG-Nup component of the central core of the NPC) was stable, C-terminally green fluorescent protein-tagged Nup1, which had been incorporated into the NPC, was degraded by the proteasome especially under heat stress conditions. The degradation was dependent on the San1 ubiquitin ligase and Cdc48/p97, as well as its cofactor Doa1. We also demonstrate that San1 weakly but certainly contributes to the degradation of nontagged endogenous Nup1 in cells defective in NPC biogenesis by the deletion of NUP120. In addition, the overexpression of SAN1 exacerbated the growth defect phenotype of nup120Δ cells, which may be caused by excess degradation of defective Nups due to the deletion of NUP120. These biochemical and genetic data suggest that San1 is involved in the degradation of nonnative Nups generated by genetic mutation or when NPC biogenesis is impaired.}, } @article {pmid38302474, year = {2024}, author = {Fernández-Beltrán, LC and Ali, Z and Larrad-Sanz, A and Lopez-Carbonero, JI and Godoy-Corchuelo, JM and Jimenez-Coca, I and Garcia-Toledo, I and Bentley, L and Gomez-Pinedo, U and Matias-Guiu, JA and Gil-Moreno, MJ and Matias-Guiu, J and Corrochano, S}, title = {Leptin haploinsufficiency exerts sex-dependent partial protection in SOD1[G93A] mice by reducing inflammatory pathways in the adipose tissue.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {2671}, pmid = {38302474}, issn = {2045-2322}, support = {2018-T1/BMD-10731//Consejeria de Educacion, Ciencia y Universidades de la Comunidad de Madrid/ ; 2018-T1/BMD-10731//Consejeria de Educacion, Ciencia y Universidades de la Comunidad de Madrid/ ; INT20/00079//European Regional Development/ ; }, mesh = {Animals ; Female ; Humans ; Male ; Mice ; Adipose Tissue/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Disease Models, Animal ; Haploinsufficiency ; Leptin/metabolism ; Mice, Transgenic ; Spinal Cord/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by significant metabolic disruptions, including weight loss and hypermetabolism in both patients and animal models. Leptin, an adipose-derived hormone, displays altered levels in ALS. Genetically reducing leptin levels (Lepob/+) to maintain body weight improved motor performance and extended survival in female SOD1G93A mice, although the exact molecular mechanisms behind these effects remain elusive. Here, we corroborated the sexual dimorphism in circulating leptin levels in ALS patients and in SOD1G93A mice. We reproduced a previous strategy to generate a genetically deficient leptin SOD1G93A mice (SOD1G93ALepob/+) and studied the transcriptomic profile in the subcutaneous adipose tissue and the spinal cord. We found that leptin deficiency reduced the inflammation pathways activated by the SOD1G93A mutation in the adipose tissue, but not in the spinal cord. These findings emphasize the importance of considering sex-specific approaches in metabolic therapies and highlight the role of leptin in the systemic modulation of ALS by regulating immune responses outside the central nervous system.}, } @article {pmid38302810, year = {2024}, author = {Teixeira, LCR and Mamede, I and Luizon, MR and Gomes, KB}, title = {Role of long non-coding RNAs in the pathophysiology of Alzheimer's disease and other dementias.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {270}, pmid = {38302810}, issn = {1573-4978}, mesh = {Humans ; *Alzheimer Disease/genetics ; *RNA, Long Noncoding/genetics ; Amyloid beta-Peptides ; *Frontotemporal Dementia ; }, abstract = {Dementia is the term used to describe a group of cognitive disorders characterized by a decline in memory, thinking, and reasoning abilities that interfere with daily life activities. Examples of dementia include Alzheimer's Disease (AD), Frontotemporal dementia (FTD), Amyotrophic lateral sclerosis (ALS), Vascular dementia (VaD) and Progressive supranuclear palsy (PSP). AD is the most common form of dementia. The hallmark pathology of AD includes formation of β-amyloid (Aβ) oligomers and tau hyperphosphorylation in the brain, which induces neuroinflammation, oxidative stress, synaptic dysfunction, and neuronal apoptosis. Emerging studies have associated long non-coding RNAs (lncRNAs) with the pathogenesis and progression of the neurodegenerative diseases. LncRNAs are defined as RNAs longer than 200 nucleotides that lack the ability to encode functional proteins. LncRNAs play crucial roles in numerous biological functions for their ability to interact with different molecules, such as proteins and microRNAs, and subsequently regulate the expression of their target genes at transcriptional and post-transcriptional levels. In this narrative review, we report the function and mechanisms of action of lncRNAs found to be deregulated in different types of dementia, with the focus on AD. Finally, we discuss the emerging role of lncRNAs as biomarkers of dementias.}, } @article {pmid38304180, year = {2024}, author = {Kreiml, V and Sauter, A and Abu-Omar, K and Eickmann, S and Herrmann-Johns, A}, title = {"That's like therapy"-A qualitative study on socially disadvantaged women's views on the effects of a community-based participatory research project on their health and health behavior.}, journal = {Frontiers in public health}, volume = {12}, number = {}, pages = {1339556}, pmid = {38304180}, issn = {2296-2565}, mesh = {Humans ; Female ; *Community-Based Participatory Research ; *Health Behavior ; Health Promotion/methods ; Exercise ; Social Support ; }, abstract = {BACKGROUND: Regular physical activity has positive effects on both physical and mental health. Nevertheless, socially disadvantaged women are often insufficiently physically active. Through needs-based physical activity offers, community-based participatory research (CBPR) projects have the potential to reach these women and increase the effectiveness of physical activity interventions by supporting women's empowerment, health, and health behaviors. This study aimed to examine socially disadvantaged women's views on the effects of long-term participation in Bewegung als Investition in Gesundheit (BIG, i.e., movement as an investment in health), a long-standing German CBPR project, on their health and health behavior.

METHODS: Semi-structured qualitative interviews were conducted with 30 participating women at five BIG sites across Germany between April and August 2022. The interviews were recorded, transcribed verbatim, and analyzed using framework analysis.

RESULTS: Women reported that participation in BIG classes contributed to their physical, mental, and social health. For many women, the positive effects on their mental and social wellbeing were most important. In addition to increased fitness and improved physical endurance, many participating women were able to expand their social networks, thus receiving further social support, and improve their self-esteem, self-confidence, and self-efficacy. Furthermore, participation in BIG physical activity classes positively influenced the health awareness of many women helping them to improve their activity level and diet over time.

CONCLUSION: Our results suggest that CBPR projects, such as the BIG project, can increase physical activity among socially disadvantaged groups and contribute to their overall health and wellbeing. CBPR projects could thus be considered a key element of health promotion for this target group. Future interventional research is required to confirm and further explore the effects of CBPR interventions and to examine whether the effects can be replicated in other settings.}, } @article {pmid38304328, year = {2023}, author = {Phillips, MCL and Johnston, SE and Simpson, P and Chang, DK and Mather, D and Dick, RJ}, title = {Time-restricted ketogenic diet in amyotrophic lateral sclerosis: a case study.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1329541}, pmid = {38304328}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder. The most devastating variant is bulbar-onset ALS, which portends a median survival of 24 months from the onset of symptoms. Abundant evidence indicates that neuron metabolism and mitochondrial function are impaired in ALS. Metabolic strategies, particularly fasting and ketogenic diet protocols, alter neuron metabolism and mitochondria function in a manner that may mitigate the symptoms of this disorder. We report the case of a 64-year-old man with a 21-month history of progressive, deteriorating bulbar-onset ALS, with an associated pseudobulbar affect, who implemented a time-restricted ketogenic diet (TRKD) for 18 months. During this time, he improved in ALS-related function (7% improvement from baseline), forced expiratory volume (17% improvement), forced vital capacity (13% improvement), depression (normalized), stress levels (normalized), and quality of life (19% improvement), particularly fatigue (23% improvement). His swallowing impairment and neurocognitive status remained stable. Declines were measured in physical function, maximal inspiratory pressure, and maximal expiratory pressure. Weight loss was attenuated and no significant adverse effects occurred. This case study represents the first documented occurrence of a patient with ALS managed with either a fasting or ketogenic diet protocol, co-administered as a TRKD. We measured improved or stabilized ALS-related function, forced expiratory volume, forced vital capacity, swallowing, neurocognitive status, mood, and quality of life. Measurable declines were restricted to physical function, maximal inspiratory pressure, and maximal expiratory pressure. Now over 45 months since symptom onset, our patient remains functionally independent and dedicated to his TRKD.}, } @article {pmid38304795, year = {2024}, author = {Matsuura, S and Tatebe, H and Higuchi, M and Tokuda, T}, title = {Validation of a newly developed immunoassay for TDP-43 in human plasma.}, journal = {Heliyon}, volume = {10}, number = {2}, pages = {e24672}, pmid = {38304795}, issn = {2405-8440}, abstract = {The level of TAR DNA-binding protein 43 (TDP-43) in human blood was reported to have potential for use as a specific fluid biomarker, which represents disease-specific pathologies, for TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), which involves the aggregation and deposition of TDP-43 in the nervous system. However, at present, no reliable immunoassay can precisely quantify TDP-43 in human plasma and detect the difference in plasma TDP-43 levels between patients with ALS and controls. We recently developed a novel ultrasensitive immunoassay to quantify TDP-43 in human plasma, and in this study, we analytically validated this assay for application as a diagnostic biomarker for TDP-43 proteinopathies. The novel TDP-43 assay was assessed for the limit of detection, lower limit of quantification, intra- and interassay variation, linearity, parallelism, and analytical spike recoveries. Additionally, 17 pilot plasma samples obtained from patients with ALS and age-matched controls were analyzed using the assay. Our novel TDP-43 assay showed sufficient analytical performance to quantify TDP-43 in human plasma, with high sensitivity (LOD and LLOQ of 0.109 and 0.759 pg/mL, respectively) and high intra- and interassay precision (%CV) below 15 %. The experimental results for spike recovery, parallelism, and dilution linearity were also acceptable. In addition, despite a small sample size, significant differences in the plasma levels of TDP-43 were found between patients with ALS and controls (ALS, 66.63 ± 20.52 pg/mL; control, 42.70 ± 23.06 pg/mL, p = 0.0330). These results support that our novel TDP-43 assay is a reliable and innovative method for the quantification of TDP-43 in human plasma and can be a potential blood-based biomarker for the diagnosis of TDP-43 proteinopathies. Further large-scale studies are warranted to validate its usefulness.}, } @article {pmid38305586, year = {2024}, author = {Raghav, Y and Dilliott, AA and Petrozziello, T and Kim, SE and Berry, JD and Cudkowicz, ME and Vakili, K and , and Fraenkel, E and Farhan, SMK and Sadri-Vakili, G}, title = {Identification of gene fusions associated with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {69}, number = {4}, pages = {477-489}, doi = {10.1002/mus.28043}, pmid = {38305586}, issn = {1097-4598}, support = {//ALS Finding a Cure/ ; //Active Against ALS/ ; //Answer ALS Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Neurodegenerative Diseases ; Motor Neurons/pathology ; Gene Fusion ; }, abstract = {INTRODUCTION/AIMS: Genetics is an important risk factor for amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Recent findings demonstrate that in addition to specific genetic mutations, structural variants caused by genetic instability can also play a causative role in ALS. Genomic instability can lead to deletions, duplications, insertions, inversions, and translocations in the genome, and these changes can sometimes lead to fusion of distinct genes into a single transcript. Gene fusion events have been studied extensively in cancer; however, they have not been thoroughly investigated in ALS. The aim of this study was to determine whether gene fusions are present in ALS.

METHODS: Gene fusions were identified using STAR Fusion v1.10.0 software in bulk RNA-Seq data from human postmortem samples from publicly available data sets from Target ALS and the New York Genome Center ALS Consortium.

RESULTS: We report the presence of gene fusion events in several brain regions as well as in spinal cord samples in ALS. Although most gene fusions were intra-chromosomal events between neighboring genes and present in both ALS and control samples, there was a significantly greater number of unique gene fusions in ALS compared to controls. Lastly, we identified specific gene fusions with a significant burden in ALS, that were absent from both control samples and known cancer gene fusion databases.

DISCUSSION: Collectively, our findings reveal an enrichment of gene fusions in ALS and suggest that these events may be an additional genetic cause linked to ALS pathogenesis.}, } @article {pmid38306019, year = {2024}, author = {Kasper, E and Temp, AGM and Köckritz, V and Meier, L and Machts, J and Vielhaber, S and Hermann, A and Prudlo, J}, title = {Verbal expressive language minimally affected in non-demented people living with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {308-316}, doi = {10.1080/21678421.2024.2307512}, pmid = {38306019}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Bayes Theorem ; Dysarthria/etiology ; Language ; *Language Disorders ; *Communication Disorders ; Neuropsychological Tests ; }, abstract = {Objective: Language dysfunction is one of the most common cognitive impairments in amyotrophic lateral sclerosis (ALS). Although discourse capacities are essential for daily functioning, verbal expressive language has not been widely investigated in ALS. The existing research available suggests that discourse impairments are prevalent. This study investigates verbal expressive language in people living with ALS (plwALS) in contrast to healthy controls (HC).Methods: 64 plwALS and 49 age, gender and education-matched healthy controls were ask to describe the Cookie Theft Picture Task. The recordings were analyzed for discourse productivity, discourse content, syntactic complexity, speech fluency and verb processing. We applied the Bayesian hypothesis-testing framework, incorporating the effects of dysarthria, cognitive impairment status (CIS), and premorbid crystalline verbal IQ.Results: Compared to HC, plwALS only showed a single impairment: speech dysfluency. Discourse productivity, discourse content, syntactic complexity and verb processing were not impaired. Cognition and dysarthria exceeded the influence of verbal IQ for total words spoken and content density. Cognition alone seemed to explain dysfluency. Body-agent verbs were produced at even higher rates than other verb types. For the remaining outcomes, verbal IQ was the most decisive factor.Conclusions: In contrast to existing research, our data demonstrates no discernible impairment in verbal expressive language in ALS. What our findings show to be decisive is accounting for the influence of dysarthria, cognitive impairment status, and verbal IQ as variables on spontaneous verbal expressive language. Minor impairments in verbal expressive language appear to be influenced to a greater degree by executive dysfunctioning and dysarthria than by language impairment.}, } @article {pmid38308282, year = {2024}, author = {Cai, R and Yang, J and Wu, L and Liu, Y and Wang, X and Zheng, Q and Li, L}, title = {Accelerating drug development for amyotrophic lateral sclerosis: construction and application of a disease course model using historical placebo group data.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {40}, pmid = {38308282}, issn = {1750-1172}, support = {82174229//the National Natural Science Funds of China/ ; 2022YFC3502000//China national key research and development program/ ; ZY [2021-2023]-0401//Shanghai 3-year Action Plan for Inheritance, Innovation, and Development of traditional Chinese Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Drug Development ; *Riluzole/therapeutic use ; Male ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an irreversible degenerative disease. Placebo-controlled randomized trials are currently the main trial design to assess the clinical efficacy of drugs for ALS treatment. The aim of this study was to establish models to quantitatively describe the course of ALS, explore influencing factors, and provide the necessary information for ALS drug development.

METHODS: We conducted a comprehensive search of PubMed and the Cochrane Library Central Register for placebo-controlled trials that evaluated treatments for ALS. From these trials, we extracted the clinical and demographic characteristics of participants in the placebo group, as well as outcome data, which encompassed overall survival (OS) and Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores, at various time points.

RESULTS: In total, 47 studies involving 6118 participants were included. Disease duration and the proportion of patients receiving riluzole were identified as significant factors influencing OS in the placebo group. Specifically, the median OS was 35.5 months for a disease duration of 9 months, whereas it was 20.0 months for a disease duration of 36 months. Furthermore, for every 10% increase in the proportion of patients treated with riluzole (100 mg daily), there was an association with a median OS extension of approximately 0.4 months. The estimated time for the ALSFRS-R score in the placebo group to decrease to 50% of its maximum effect from baseline level was approximately 17.5 months, and the time to reach a plateau was about 40 months.

CONCLUSIONS: The established disease course model of the historical placebo group is valuable in the decision-making process for the clinical development of ALS drugs. It serves not only as an external control to evaluate the efficacy of the tested drug in single-arm trials but also as prior information that aids in accurately estimating the posterior distribution of the disease course in the placebo group during small-sample clinical trials.}, } @article {pmid38308916, year = {2024}, author = {Pietrobon, D and Conti, F}, title = {Astrocytic Na[+], K[+] ATPases in physiology and pathophysiology.}, journal = {Cell calcium}, volume = {118}, number = {}, pages = {102851}, doi = {10.1016/j.ceca.2024.102851}, pmid = {38308916}, issn = {1532-1991}, mesh = {Humans ; Mice ; Animals ; Sodium-Potassium-Exchanging ATPase/genetics/metabolism ; *Migraine with Aura/genetics/metabolism ; Astrocytes/metabolism ; *Alzheimer Disease/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; }, abstract = {The Na[+], K[+] ATPases play a fundamental role in the homeostatic functions of astrocytes. After a brief historic prologue and discussion of the subunit composition and localization of the astrocytic Na[+], K[+] ATPases, the review focuses on the role of the astrocytic Na[+], K[+] pumps in extracellular K[+] and glutamate homeostasis, intracellular Na[+] and Ca[2+] homeostasis and signaling, regulation of synaptic transmission and neurometabolic coupling between astrocytes and neurons. Loss-of-function mutations in the gene encoding the astrocytic α2 Na[+], K[+] ATPase cause a rare monogenic form of migraine with aura (familial hemiplegic migraine type 2). On the other hand, the α2 Na[+], K[+] ATPase is upregulated in spinal cord and brain samples from amyotrophic lateral sclerosis and Alzheimer disease patients, respectively. In the last part, the review focuses on i) the migraine relevant phenotypes shown by familial hemiplegic migraine type 2 knock-in mice with 50 % reduced expression of the astrocytic α2 Na[+], K[+] ATPase and the insights into the pathophysiology of migraine obtained from these genetic mouse models, and ii) the evidence that upregulation of the astrocytic α2 Na[+], K[+] ATPase in mouse models of amyotrophic lateral sclerosis and Alzheimer disease promotes neuroinflammation and contributes to progressive neurodegeneration.}, } @article {pmid38309276, year = {2024}, author = {Ku, J and Lee, K and Ku, D and Kim, S and Lee, J and Bang, H and Kim, N and Do, H and Lee, H and Lim, C and Han, J and Lee, YS and Kim, Y}, title = {Alternative polyadenylation determines the functional landscape of inverted Alu repeats.}, journal = {Molecular cell}, volume = {84}, number = {6}, pages = {1062-1077.e9}, doi = {10.1016/j.molcel.2024.01.008}, pmid = {38309276}, issn = {1097-4164}, mesh = {Humans ; Mice ; Animals ; *Tumor Suppressor Protein p53/genetics ; *Polyadenylation ; 3' Untranslated Regions/genetics ; Gene Expression Regulation ; Introns ; }, abstract = {Inverted Alu repeats (IRAlus) are abundantly found in the transcriptome, especially in introns and 3' untranslated regions (UTRs). Yet, the biological significance of IRAlus embedded in 3' UTRs remains largely unknown. Here, we find that 3' UTR IRAlus silences genes involved in essential signaling pathways. We utilize J2 antibody to directly capture and map the double-stranded RNA structure of 3' UTR IRAlus in the transcriptome. Bioinformatic analysis reveals alternative polyadenylation as a major axis of IRAlus-mediated gene regulation. Notably, the expression of mouse double minute 2 (MDM2), an inhibitor of p53, is upregulated by the exclusion of IRAlus during UTR shortening, which is exploited to silence p53 during tumorigenesis. Moreover, the transcriptome-wide UTR lengthening in neural progenitor cells results in the global downregulation of genes associated with neurodegenerative diseases, including amyotrophic lateral sclerosis, via IRAlus inclusion. Our study establishes the functional landscape of 3' UTR IRAlus and its role in human pathophysiology.}, } @article {pmid38311174, year = {2024}, author = {Demongin, C and Tranier, S and Joshi, V and Ceschi, L and Desforges, B and Pastré, D and Hamon, L}, title = {RNA and the RNA-binding protein FUS act in concert to prevent TDP-43 spatial segregation.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {3}, pages = {105716}, pmid = {38311174}, issn = {1083-351X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Peptide Fragments/metabolism ; *RNA/metabolism ; RNA, Messenger/genetics/metabolism ; *RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {FUS and TDP-43 are two self-adhesive aggregation-prone mRNA-binding proteins whose pathological mutations have been linked to neurodegeneration. While TDP-43 and FUS form reversible mRNA-rich compartments in the nucleus, pathological mutations promote their respective cytoplasmic aggregation in neurons with no apparent link between the two proteins except their intertwined function in mRNA processing. By combining analyses in cellular context and at high resolution in vitro, we unraveled that TDP-43 is specifically recruited in FUS assemblies to form TDP-43-rich subcompartments but without reciprocity. The presence of mRNA provides an additional scaffold to promote the mixing between TDP-43 and FUS. Accordingly, we also found that the pathological truncated form of TDP-43, TDP-25, which has an impaired RNA-binding ability, no longer mixes with FUS. Together, these results suggest that the binding of FUS along nascent mRNAs enables TDP-43, which is highly aggregation-prone, to mix with FUS phase to form mRNA-rich subcompartments. A functional link between FUS and TDP-43 may explain their common implication in amyotrophic lateral sclerosis.}, } @article {pmid38311731, year = {2024}, author = {Simmatis, LER and Robin, J and Spilka, MJ and Yunusova, Y}, title = {Detecting bulbar amyotrophic lateral sclerosis (ALS) using automatic acoustic analysis.}, journal = {Biomedical engineering online}, volume = {23}, number = {1}, pages = {15}, pmid = {38311731}, issn = {1475-925X}, support = {R01 DC013547/DC/NIDCD NIH HHS/United States ; R01 DC017291/DC/NIDCD NIH HHS/United States ; R01DC013547/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Bayes Theorem ; Speech ; Speech Disorders/diagnosis ; ROC Curve ; }, abstract = {Automatic speech assessments have the potential to dramatically improve ALS clinical practice and facilitate patient stratification for ALS clinical trials. Acoustic speech analysis has demonstrated the ability to capture a variety of relevant speech motor impairments, but implementation has been hindered by both the nature of lab-based assessments (requiring travel and time for patients) and also by the opacity of some acoustic feature analysis methods. These challenges and others have obscured the ability to distinguish different ALS disease stages/severities. Validation of automated acoustic analysis tools could enable detection of early signs of ALS, and these tools could be deployed to screen and monitor patients without requiring clinic visits. Here, we sought to determine whether acoustic features gathered using an automated assessment app could detect ALS as well as different levels of speech impairment severity resulting from ALS. Speech samples (readings of a standardized, 99-word passage) from 119 ALS patients with varying degrees of disease severity as well as 22 neurologically healthy participants were analyzed, and 53 acoustic features were extracted. Patients were stratified into early and late stages of disease (ALS-early/ALS-E and ALS-late/ALS-L) based on the ALS Functional Ratings Scale-Revised bulbar score (FRS-bulb) (median [interquartile range] of FRS-bulbar scores: 11[3]). The data were analyzed using a sparse Bayesian logistic regression classifier. It was determined that the current relatively small set of acoustic features could distinguish between ALS and controls well (area under receiver-operating characteristic curve/AUROC = 0.85), that the ALS-E patients could be separated well from control participants (AUROC = 0.78), and that ALS-E and ALS-L patients could be reasonably separated (AUROC = 0.70). These results highlight the potential for automated acoustic analyses to detect and stratify ALS.}, } @article {pmid38311779, year = {2024}, author = {Ueda, T and Takeuchi, T and Fujikake, N and Suzuki, M and Minakawa, EN and Ueyama, M and Fujino, Y and Kimura, N and Nagano, S and Yokoseki, A and Onodera, O and Mochizuki, H and Mizuno, T and Wada, K and Nagai, Y}, title = {Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {20}, pmid = {38311779}, issn = {2051-5960}, support = {21H02840//Japan Society for the Promotion of Science/ ; 22H02792//Japan Society for the Promotion of Science/ ; 24659438//Japan Society for the Promotion of Science/ ; 17H05699//Japan Society for the Promotion of Science/ ; 20H05927//Japan Society for the Promotion of Science/ ; 11013026//Japan Society for the Promotion of Science/ ; JP15dm0107026//Japan Agency for Medical Research and Development/ ; JP20dm0107061//Japan Agency for Medical Research and Development/ ; JP16ek0109018//Japan Agency for Medical Research and Development/ ; JP19ek0109222//Japan Agency for Medical Research and Development/ ; JP20ek0109316//Japan Agency for Medical Research and Development/ ; JPMJPR17H8//Precursory Research for Embryonic Science and Technology/ ; RGY0066/2017//Human Frontier Science Program/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *DNA-Binding Proteins/genetics/metabolism ; Drosophila/metabolism ; *Dynactin Complex/genetics ; *Frontotemporal Dementia/pathology ; Stress Granules ; *Drosophila Proteins/genetics ; }, abstract = {The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is aberrantly accumulated in the neurons of most patients with sporadic ALS/FTD and other TDP-43 proteinopathies, how TDP-43 forms cytoplasmic aggregates remains unknown. In this study, we show that a deficiency in DCTN1, a subunit of the microtubule-associated motor protein complex dynactin, perturbs the dynamics of stress granules and drives the formation of TDP-43 cytoplasmic aggregation in cultured cells, leading to the exacerbation of TDP-43 pathology and neurodegeneration in vivo. We demonstrated using a Drosophila model of ALS/FTD that genetic knockdown of DCTN1 accelerates the formation of ubiquitin-positive cytoplasmic inclusions of TDP-43. Knockdown of components of other microtubule-associated motor protein complexes, including dynein and kinesin, also increased the formation of TDP-43 inclusions, indicating that intracellular transport along microtubules plays a key role in TDP-43 pathology. Notably, DCTN1 knockdown delayed the disassembly of stress granules in stressed cells, leading to an increase in the formation of pathological cytoplasmic inclusions of TDP-43. Our results indicate that a deficiency in DCTN1, as well as disruption of intracellular transport along microtubules, is a modifier that drives the formation of TDP-43 pathology through the dysregulation of stress granule dynamics.}, } @article {pmid38312023, year = {2024}, author = {Stoccoro, A and Smith, AR and Mosca, L and Marocchi, A and Gerardi, F and Lunetta, C and Lunnon, K and Migliore, L and Coppedè, F}, title = {Mitochondrial D-loop methylation levels inversely correlate with disease duration in amyotrophic lateral sclerosis.}, journal = {Epigenomics}, volume = {16}, number = {4}, pages = {203-214}, doi = {10.2217/epi-2023-0265}, pmid = {38312023}, issn = {1750-192X}, support = {Researcher's intramural funds (ATENEO Funds, Uni)//Università di Pisa/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; DNA Methylation ; DNA, Mitochondrial/genetics ; Mitochondria/genetics ; }, abstract = {Aim: To correlate mitochondrial D-loop region methylation levels and mtDNA copy number with disease duration in familial amyotrophic lateral sclerosis (ALS) patients. Patients & methods: The study population included 12 ALS patients with a mutation in SOD1 and 13 ALS patients with the C9orf72 hexanucleotide repeat expansion. Methylation levels of the D-loop region and mtDNA copy number were quantified using pyrosequencing and quantitative PCR, respectively. Results: We observed that D-loop methylation levels inversely correlated while mtDNA copy number positively correlated with disease duration. Conclusion: Considering the central role played by mitochondria in ALS, this preliminary study provides new knowledge for future studies aimed at identifying biomarkers of disease progression and new targets for therapeutic interventions.}, } @article {pmid38313254, year = {2024}, author = {Bryce-Smith, S and Brown, AL and Mehta, PR and Mattedi, F and Mikheenko, A and Barattucci, S and Zanovello, M and Dattilo, D and Yome, M and Hill, SE and Qi, YA and Wilkins, OG and Sun, K and Ryadnov, E and Wan, Y and , and Vargas, JNS and Birsa, N and Raj, T and Humphrey, J and Keuss, M and Ward, M and Secrier, M and Fratta, P}, title = {TDP-43 loss induces extensive cryptic polyadenylation in ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38313254}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; MC_PC_MR/S022708/1/MRC_/Medical Research Council/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, abstract = {Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 is the hallmark of ALS, occurring in over 97% of cases. A key consequence of TDP-43 nuclear loss is the de-repression of cryptic exons. Whilst TDP-43 regulated cryptic splicing is increasingly well catalogued, cryptic alternative polyadenylation (APA) events, which define the 3' end of last exons, have been largely overlooked, especially when not associated with novel upstream splice junctions. We developed a novel bioinformatic approach to reliably identify distinct APA event types: alternative last exons (ALE), 3'UTR extensions (3'Ext) and intronic polyadenylation (IPA) events. We identified novel neuronal cryptic APA sites induced by TDP-43 loss of function by systematically applying our pipeline to a compendium of publicly available and in house datasets. We find that TDP-43 binding sites and target motifs are enriched at these cryptic events and that TDP-43 can have both repressive and enhancing action on APA. Importantly, all categories of cryptic APA can also be identified in ALS and FTD post mortem brain regions with TDP-43 proteinopathy underlining their potential disease relevance. RNA-seq and Ribo-seq analyses indicate that distinct cryptic APA categories have different downstream effects on transcript and translation. Intriguingly, cryptic 3'Exts occur in multiple transcription factors, such as ELK1, SIX3, and TLX1, and lead to an increase in wild-type protein levels and function. Finally, we show that an increase in RNA stability leading to a higher cytoplasmic localisation underlies these observations. In summary, we demonstrate that TDP-43 nuclear depletion induces a novel category of cryptic RNA processing events and we expand the palette of TDP-43 loss consequences by showing this can also lead to an increase in normal protein translation.}, } @article {pmid38313408, year = {2023}, author = {Monov, D and Molodozhnikova, N}, title = {Biochemical parameters as a tool to assess the nutritional status of patients with amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1258224}, pmid = {38313408}, issn = {1664-2295}, abstract = {BACKGROUND: The research aimed to analyze blood biochemical parameters in patients with amyotrophic lateral sclerosis and to determine whether they can be used to assess their nutritional status.

METHODS: The study included 45 patients diagnosed with amyotrophic lateral sclerosis (ALS): 28 (62.2%) were men and 17 (37.8%) were women. The mean age of the study participants was 50.69 ± 7.24 years. The control group consisted of 30 practically healthy individuals.

RESULTS: Compared with practically healthy individuals, patients with ALS had significantly lower blood parameters, including total lymphocyte count (1.49 ± 0.11 vs. 2.86 ± 0.25, p < 0.05), total protein (60.55 ± 2.38 vs. 77.80 ± 4.41, p < 0.05), albumin (33.70 ± 2.03 vs. 46.49 ± 3.22, p < 0.05), urea (3.09 ± 0.36 vs. 5.37 ± 0.50, p < 0.05), creatinine (51.28 ± 4.42 vs. 70.91 ± 5.13, p < 0.05), and transferrin (1.84 ± 0.12 vs. 2.32 ± 0.10, p < 0.05). These parameters correspond to first-degree malnutrition. There were direct correlations between anthropometric and biochemical parameters in the ALS group. BMI correlated with the blood levels of total protein (r = 0.22, p < 0.05), albumin (r = 0.27, p < 0.05), urea (r = 0.33, p < 0.05), creatinine (r = 0.30, p < 0.05), transferrin (r = 0.18, p < 0.05), and total lymphocyte count (r = 0.20, p < 0.05). PNI correlated with the blood levels of total protein (r = 0.53, p < 0.05), albumin (r = 0.87, p < 0.05), total cholesterol (r = 0.34, p < 0.05), transferrin (r = 0.40, p < 0.05), total lymphocyte count (r = 0.79, p < 0.05), urea (r = 0, 37, p < 0.05), and creatinine (r = 0.32, p < 0.05).

CONCLUSION: The study presents compelling evidence supporting the utilization of biochemical parameters, including total protein, albumin, urea, creatinine, transferrin, and total lymphocyte count, for potentially evaluating the nutritional status of individuals diagnosed with ALS.}, } @article {pmid38313873, year = {2024}, author = {Hill, J and Sanghani, N and Li, Y}, title = {Features Suggestive of Coexisting Amyotrophic Lateral Sclerosis in Patients With Spinal Stenosis and Influence of Spinal Decompression.}, journal = {Cureus}, volume = {16}, number = {1}, pages = {e51587}, pmid = {38313873}, issn = {2168-8184}, abstract = {BACKGROUND: Spinal stenosis and amyotrophic lateral sclerosis (ALS) can co-occur and both manifest as signs of dysfunction of lower and/or upper motor neurons. Few studies have identified factors that alert the diagnosis of ALS in patients with spinal stenosis, and the influence of spinal decompression surgery on ALS progression remains unclear.

OBJECTIVE: The objective of this study is to describe factors that are suggestive of an ALS diagnosis in patients with spinal stenosis and influence of spinal decompression surgery on the progression of ALS  Materials and methods: A retrospective review of the institutional ALS database and electronic medical records was performed to identify patients with coexisting diagnoses of ALS and moderate to severe cervical and/or lumbosacral spine stenosis. Identified patients were divided into two subgroups: those with spinal decompression surgery and those without. Comparisons of clinical features and progression of ALS were made between subgroups.

RESULTS:  A total of 77 patients with ALS and coexisting moderate to severe cervical or lumbosacral spine stenosis were included. Among them, 50 patients underwent spinal decompression surgery and 27 did not. In comparison to patients with spinal decompression, patients without spinal decompression surgery were seen more frequently by neurologists (74% versus 26%), had less prominent radicular pain (19% versus 50%), demonstrated more frequent bulbar signs (30% versus 8%), experienced more likely weight loss (41% versus 4%), and disclosed more noticeable axonal loss changes on electromyography. Spinal decompression surgery did not modify the progression of ALS based on ALSFRS-R score change and analysis of survival duration.

CONCLUSION: Our study identified a number of useful features that are suggestive of an ALS diagnosis when evaluating patients with spinal stenosis and may support the performance of spinal decompression surgery in a subset of selected ALS patients with symptomatic spinal stenosis.}, } @article {pmid38314277, year = {2024}, author = {Mohan, S and Alhazmi, HA and Hassani, R and Khuwaja, G and Maheshkumar, VP and Aldahish, A and Chidambaram, K}, title = {Role of ferroptosis pathways in neuroinflammation and neurological disorders: From pathogenesis to treatment.}, journal = {Heliyon}, volume = {10}, number = {3}, pages = {e24786}, pmid = {38314277}, issn = {2405-8440}, abstract = {Ferroptosis is a newly discovered non-apoptotic and iron-dependent type of cell death. Ferroptosis mainly takes place owing to the imbalance of anti-oxidation and oxidation in the body. It is regulated via a number of factors and pathways both inside and outside the cell. Ferroptosis is closely linked with brain and various neurological disorders (NDs). In the human body, the brain contains the highest levels of polyunsaturated fatty acids, which are known as lipid peroxide precursors. In addition, there is also a connection of glutathione depletion and lipid peroxidation with NDs. There is growing evidence regarding the possible link between neuroinflammation and multiple NDs, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and stroke. Recent studies have demonstrated that disruptions of lipid reactive oxygen species (ROS), glutamate excitatory toxicity, iron homeostasis, and various other manifestations linked with ferroptosis can be identified in various neuroinflammation-mediated NDs. It has also been reported that damage-associated molecular pattern molecules including ROS are generated during the events of ferroptosis and can cause glial activation via activating neuroimmune pathways, which subsequently leads to the generation of various inflammatory factors that play a role in various NDs. This review summarizes the regulation pathways of ferroptosis, the link between ferroptosis as well as inflammation in NDs, and the potential of a range of therapeutic agents that can be used to target ferroptosis and inflammation in the treatment of neurological disorders.}, } @article {pmid38314348, year = {2023}, author = {Watts, ME and Giadone, RM and Ordureau, A and Holton, KM and Harper, JW and Rubin, LL}, title = {Analyzing the ER stress response in ALS patient derived motor neurons identifies druggable neuroprotective targets.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1327361}, pmid = {38314348}, issn = {1662-5102}, support = {F32 AG079593/AG/NIA NIH HHS/United States ; R01 NS083524/NS/NINDS NIH HHS/United States ; R01 NS110395/NS/NINDS NIH HHS/United States ; R37 NS083524/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron (MN) disease with severely limited treatment options. Identification of effective treatments has been limited in part by the lack of predictive animal models for complex human disorders. Here, we utilized pharmacologic ER stressors to exacerbate underlying sensitivities conferred by ALS patient genetics in induced pluripotent stem cell (iPSC)-derived motor neurons (MNs). In doing so, we found that thapsigargin and tunicamycin exposure recapitulated ALS-associated degeneration, and that we could rescue this degeneration via MAP4K4 inhibition (MAP4K4i). We subsequently identified mechanisms underlying MAP4K4i-mediated protection by performing phosphoproteomics on iPSC-derived MNs treated with ER stressors ±MAP4K4i. Through these analyses, we found JNK, PKC, and BRAF to be differentially modulated in MAP4K4i-protected MNs, and that inhibitors to these proteins could also rescue MN toxicity. Collectively, this study highlights the value of utilizing ER stressors in ALS patient MNs to identify novel druggable targets.}, } @article {pmid38316400, year = {2024}, author = {Taule, T and Tysnes, OB and Aßmus, J and Rekand, T}, title = {A prospective study for using cognitive decline as a predictor for survival and use of feeding/respiratory support for patients with motor neuron disease in Norway.}, journal = {Annals of palliative medicine}, volume = {13}, number = {1}, pages = {86-92}, doi = {10.21037/apm-23-386}, pmid = {38316400}, issn = {2224-5839}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Prospective Studies ; *Motor Neuron Disease/complications/therapy ; *Cognitive Dysfunction ; Enteral Nutrition ; }, abstract = {BACKGROUND: There is a need for knowledge regarding the medical management of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) with and without cognitive decline. It has scarcely been studied whether cognitive decline will influence the course of disease or interfere with the use of life-prolonging aids for respiration and nutrition. Cognitive decline may impact the length of illness.

METHODS: Patients were prospectively recruited from an ALS outpatient clinic at Haukeland University Hospital. Participants underwent the standardized cognitive test Edinburgh Cognitive and Behavioral ALS Screen Norwegian version (ECAS-N), clinical examination, and were functionally assessed by the ALS Functioning Rating Scale-revised version (ALS-FRS-R). The time and indication for installation of a feeding tube [percutaneous endoscopic gastrostomy (PEG)] and/or respiratory aid [bilevel positive airway pressure device (BiPAP)] or invasive respirator were retrieved from the medical records. Kaplan-Meier tests were used to study the risk of death and the probability for implementing PEG and/or BiPAP in relation to time from diagnosis. The individual assessment was used for analyzing the establishment of aids in relation to point of death.

RESULTS: A total of 40 patients were evaluated for the study, 31 of whom were finally included. None of the included patients did not use an invasive respirator. The patients were divided into two subgroups (normal cognition or cognitive decline, cut-off 92 points) according to their performance in the ECAS-N. The course of the disease, shown as a risk of death, was higher among the ALS/MND patients with cognitive decline compared to those with cognitive intact function throughout the study period. The cognitive status did not influence the fitting of aids. Use of aids did not influence the survival in subgroups significantly.

CONCLUSIONS: The study demonstrated shorter survival for the patients with ALS/MND with cognitive decline compared to those without cognitive decline. The practice and implementation of both BiPAP and PEG did not differ among the ALS/MND patients with and without cognitive decline in Norway.}, } @article {pmid37125006, year = {2023}, author = {Patocka, C and Lockey, A and Lauridsen, KG and Greif, R}, title = {Impact of accredited advanced life support course participation on in-hospital cardiac arrest patient outcomes: A systematic review.}, journal = {Resuscitation plus}, volume = {14}, number = {}, pages = {100389}, pmid = {37125006}, issn = {2666-5204}, abstract = {AIM: Advanced life support courses have a clear educational impact; however, it is important to determine whether participation of one or more members of the resuscitation team in an accredited advanced life support course improves in-hospital cardiac arrest patient survival outcomes.

METHODS: We searched EMBASE.com, Medline, Cochrane and CINAHL from inception to 1 November 2022. Included studies were randomised or non-randomised interventional studies assessing the impact of attendance at accredited life support courses on patient outcomes. Accredited life support courses were classified into 3 contexts: Advanced Life Support (ALS), Neonatal Resuscitation Training (NRT), and Helping Babies Breathe (HBB). Existing systematic reviews were identified for each of the contexts and an adolopment process was pursued. Appropriate risk of bias assessment tools were used across all outcomes. When meta-analysis was appropriate a random-effects model was used to produce a summary of effect sizes for each outcome.

RESULTS: Of 2714 citations screened, 19 studies (1 ALS; 7 NRT; 11 HBB) were eligible for inclusion. Three systematic reviews which satisfied AMSTAR-2 criteria for methodological quality, included 16 of the studies we identified in our search. Among adult patients all outcomes including return of spontaneous circulation, survival to discharge and survival to 30 days were consistently better with accredited ALS training. Among neonatal patients there were reductions in stillbirths and early neonatal mortality.

CONCLUSION: These results support the recommendation that accredited advanced life support courses, specifically Advanced Life Support, Neonatal Resuscitation Training, and Helping Babies Breathe improve patient outcomes.}, } @article {pmid37125971, year = {2023}, author = {Mitchnik, IY and Talmy, T and Feldman, B and Almog, O and Fogel, I}, title = {Exploring the characteristics of successful prehospital trauma care teams: Insights from military trauma care simulations.}, journal = {The journal of trauma and acute care surgery}, volume = {95}, number = {2S Suppl 1}, pages = {S106-S112}, pmid = {37125971}, issn = {2163-0763}, mesh = {Humans ; *Emergency Medical Services/methods ; *Military Personnel ; Retrospective Studies ; *Emergency Medical Technicians ; Israel ; }, abstract = {BACKGROUND: Trauma care teams play a crucial role in determining the outcomes of trauma victims. The composition and training of these teams can vary. Our study seeks to examine the characteristics of successful military Advanced Life Support (ALS) teams and the factors that affect them.

METHODS: A retrospective study was conducted at the Israel Defense Force (IDF) Military Medical Academy throughout 2021, where prehospital medical teams were observed in trauma care simulations. Teams were led by ALS providers (military physicians or paramedics) trained in IDF Military Trauma Life Support. Demographic and training data were collected. Teams were categorized into high or subpar performance groups based on simulation scores. Specific skills were assessed by trauma instructors using a points system. Scores were compared between the groups and analyzed for correlations with demographic and training data.

RESULTS: Overall, 63 team simulations were analyzed, with teams led by a military paramedic in 78% of simulations. The mean overall simulation performance was 81% ±6.2, and there were no differences in scores of single or multicasualty simulations. A total 3% of the teams achieved successful results and were more likely to have a paramedic as the ALS provider (p = 0.028). A sensitivity analysis excluding physicians was conducted and showed that high-performance teams had significantly higher skill assessments for primary survey (p = 0.004), injury recognition (p = 0.002), exposure (p = 0.006), adherence to clinical practice guidelines (p = 0.032), and medical device use (p = 0.002).

CONCLUSION: Our study found that ALS provider is associated with overall simulation performance in prehospital ALS teams, with military paramedics more likely to be successful. These findings have implications for the training and staffing of prehospital ALS teams, suggesting that teams should be composed accordingly and that training should focus on skills affected by the ALS provider type.

LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.}, } @article {pmid37126792, year = {2023}, author = {Del Furia, MJ and Battel, I}, title = {What Are the Effects of Treatments for Sialorrhea in People With Motor Neuron Disease/Amyotrophic Lateral Sclerosis?: A Cochrane Review Summary With Commentary.}, journal = {American journal of physical medicine & rehabilitation}, volume = {102}, number = {10}, pages = {926-928}, doi = {10.1097/PHM.0000000000002272}, pmid = {37126792}, issn = {1537-7385}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Sialorrhea/drug therapy/etiology ; *Motor Neuron Disease/complications ; }, } @article {pmid37127082, year = {2023}, author = {Nicoletti, A and Baschi, R and Cicero, CE and Iacono, S and Re, VL and Luca, A and Schirò, G and Monastero, R and , }, title = {Sex and gender differences in Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis: A narrative review.}, journal = {Mechanisms of ageing and development}, volume = {212}, number = {}, pages = {111821}, doi = {10.1016/j.mad.2023.111821}, pmid = {37127082}, issn = {1872-6216}, mesh = {Male ; Female ; Humans ; *Alzheimer Disease/diagnosis/epidemiology ; *Parkinson Disease/diagnosis/epidemiology/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; Sex Factors ; Biomarkers ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), exhibit high phenotypic variability and they are very common in the general population. These diseases are associated with poor prognosis and a significant burden on patients and their caregivers. Although increasing evidence suggests that biological sex is an important factor for the development and phenotypical expression of some NDs, the role of sex and gender in the diagnosis and prognosis of NDs has been poorly explored. Current knowledge relating to sex- and gender-related differences in the epidemiology, clinical features, biomarkers, and treatment of AD, PD, and ALS will be summarized in this narrative review. The cumulative evidence hitherto collected suggests that sex and gender are factors to be considered in explaining the heterogeneity of these NDs. Clarifying the role of sex and gender in AD, PD, and ALS is a key topic in precision medicine, which will facilitate sex-specific prevention and treatment strategies to be implemented in the near future.}, } @article {pmid37128837, year = {2024}, author = {Phillips, J and Dixon, S and Koehler, T and Kluger, B}, title = {Advance Care Planning Among Patients With Amyotrophic Lateral Sclerosis: Patient Perspectives on Goals of Care Conversations.}, journal = {The American journal of hospice & palliative care}, volume = {41}, number = {3}, pages = {295-301}, doi = {10.1177/10499091231172901}, pmid = {37128837}, issn = {1938-2715}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Terminal Care ; *Advance Care Planning ; Advance Directives ; Living Wills ; Death ; }, abstract = {INTRODUCTION: Little is known regarding circumstances surrounding advanced care planning (ACP) for patients with amyotrophic lateral sclerosis (ALS). We aim to describe preferences, and perspectives surrounding ACP in patients with ALS.

METHODS: We conducted a survey of patients with ALS. Survey questions were related to advance directive completion and ACP discussions regarding end-of-life (EoL) choices.

RESULTS: 49 surveys were included. Patients have given thought to advance directives, goals of care, and EoL treatments within months of diagnosis (Median: 1 month; IQR: .6 - 3 months). Twenty-seven opened dialogue with spouses, 24 with family members, 19 with health professionals and 16 with their lawyer. Eighty percent were comfortable discussing advance directives and power of attorney while fewer (70%) are less comfortable regarding specific aspects of care such as CPR or invasive ventilation. Only one barrier to discussion was identified with one patient reporting they did not wish to talk about the topic. There was no significant correlation between timing of diagnosis and whether an EoL discussion had occurred (τb = .23, P = .14: n = 42). Level of feeling informed was significantly associated with making EoL decisions for CPR, legal arrangements for a decision maker and completion of living will or AD.

CONCLUSION: In this small cohort, a substantial proportion of ALS patients initiated EoL conversations early. When feeling informed, patients were more likely to make specific EoL choices. Findings suggest an opportunity for providers to help facilitate conversations, ensuring patient wishes.}, } @article {pmid37130044, year = {2023}, author = {Chow, DS and Nguyen, A and Park, J and Wu, L and Toups, EG and Harrop, JS and Guest, JD and Schmitt, KM and Aarabi, B and Fehlings, MG and Boakye, M and Grossman, RG}, title = {Riluzole in Spinal Cord Injury Study (RISCIS)-Pharmacokinetic (PK) Sub-Study: An Analysis of Pharmacokinetics, Pharmacodynamics, and Impact on Axonal Degradation of Riluzole in Patients With Traumatic Cervical Spinal Cord Injury Enrolled in the RISCIS Phase III Randomized Controlled Trial.}, journal = {Journal of neurotrauma}, volume = {40}, number = {17-18}, pages = {1889-1906}, doi = {10.1089/neu.2022.0499}, pmid = {37130044}, issn = {1557-9042}, mesh = {Male ; Middle Aged ; Humans ; Riluzole/adverse effects ; *Neuroprotective Agents/adverse effects/pharmacokinetics ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Cervical Cord ; *Spinal Cord Injuries/drug therapy ; *Neck Injuries/drug therapy ; }, abstract = {To date, no drug therapy has shown significant efficacy in improving functional outcomes in patients with acute spinal cord injury (SCI). Riluzole is an approved benzothiazole sodium channel blocker to attenuate neurodegeneration in amyotrophic lateral sclerosis (ALS) and is of interest for neuroprotection in SCI. In a Phase I clinical trial (ClinicalTrials.gov Identifier: NCT00876889), riluzole was well tolerated with a 2-week treatment at the dose level approved for ALS and exhibited potential efficacy in patients with SCI. The acute and progressive nature of traumatic SCI and the complexity of secondary injury processes alter the pharmacokinetics (PK) of therapeutics. In the PK sub-study of the multi-center, randomized, placebo-controlled, double-blinded Riluzole in Spinal Cord Injury Study (RISCIS) Phase II/III trial (ClinicalTrials.gov Identifier: NCT01597518), a total of 32 SCI patients were enrolled, and most of our patients were middle-age Caucasian males with head and neck injuries. We studied the PK and pharmacodynamics (PD) of riluzole on motor recovery, measured by International Standards for Neurological Classification of SCI (ISNCSCI) Motor Score at injury and at 3-month and 6-month follow-ups, along with levels of the axonal injury biomarker phosphorylated neurofilament heavy chain (pNF-H), during the 2-week treatment. PK modeling, PK/PD correlations were developed to identify the potential effective exposure of riluzole for intended PD outcomes. The longitudinal impacts of SCI on the PK of riluzole are characterized. A time-varying population PK model of riluzole is established, incorporating time-varying clearance and volume of distribution from combined data of Phase I and Phase II/III trials. With the developed model, a rational, optimal dosing scheme can be designed with time-dependent modification to preserve the required therapeutic exposure of riluzole. The PD of riluzole and the relationship between PK and neurological outcomes of the treatment were established. The time course of efficacy in total motor score improvement (ΔTMS) and pNF-H were monitored. A three-dimensional (3D) PK/PD correlation was established for ΔTMS at 6 months with overall riluzole exposure area under the curve for Day 0-Day14 (AUCD0-D14) and baseline TMS for individual patients. Patients with baseline TMS between 1 and 36 benefited from the optimal exposure range of 16-48 mg*h/mL. The PD models of pNF-H revealed the riluzole efficacy, as treated subjects exhibited a diminished increase in progression of pNF-H, indicative of reduced axonal breakdown. The independent parameter of area between effective curves (ABEC) between the time profiles of pNF-H in placebo and treatment groups was statistically identified as a significant predictor for the treatment effect on the biomarker. A mechanistic clinical outcomes (CO)/PD (pNF-H) model was established, and the proposed structure demonstrated the feasibility of PK/PD/CO correlation model. No appreciable hepatic toxicity was observed with the current riluzole treatment regimen. The development of effective treatment for SCI is challenging. However, the future model-informed and PK-guided drug development and regimen modification can be rationally executed with the optimal dosing regimen design based on the developed 3D PK/PD model. The PK/PD/CO model can serve as a rational guide for future drug development, PKPD model refinement, and extension to other studies in SCI settings.}, } @article {pmid37130459, year = {2023}, author = {Kang, J and Lim, L and Song, J}, title = {ALS-causing hPFN1 mutants differentially disrupt LLPS of FUS prion-like domain.}, journal = {Biochemical and biophysical research communications}, volume = {664}, number = {}, pages = {35-42}, doi = {10.1016/j.bbrc.2023.04.101}, pmid = {37130459}, issn = {1090-2104}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Mutation ; Magnetic Resonance Spectroscopy ; Magnetic Resonance Imaging ; *Prions/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {hPFN1 mutations including C71G cause ALS by gain of toxicity but the mechanism still remains unknown. Stress granules (SGs) are formed by phase separation of the prion-like domain (PLD) of RNA-binding proteins including FUS, whose inclusion was also associated with ALS. C71G-hPFN1 triggers seed-dependent co-aggregation with FUS/TDP-43 to manifest the prion-like propagandation but its biophysical basis remains unexplored. Here by DIC imaging we first showed that three hPFN1 mutants have differential capacity in disrupting the dynamics of liquid droplets formed by phase separation of FUS prion-like domain (PLD). C71G-hPFN1 co-exists with the folded and unfolded states, thus allowing to simultaneously characterize conformations, hydrodynamics and dynamics of the interactions of both states with the phase separated FUS PLD by NMR. The results reveal that the folded state is not significantly affected while by contrast, the unfolded state has extensive interactions with FUS PLD. As a consequence, the dynamics of FUS liquid droplets become significantly reduced. Such interactions might act to recruit C71G-hPFN1 into the droplets, thus leading to the increase of the local concentrations and subsequent co-aggregation of C71G-hPFN1 with FUS. Our study sheds the first light on the biophysical basis by which hPFN1 mutants gain toxicity to cause ALS. As other aggregation-prone proteins have no fundamental difference from hPFN1 mutants, aggregation-prone proteins might share a common capacity in disrupting phase separation responsible for organizing various membrane-less organelles. As such, the mechanism for C71G-hPFN1 might also be utilized by other aggregation-prone proteins for gain of toxicity to trigger diseases and aging.}, } @article {pmid37131843, year = {2023}, author = {Taylor, M and Marx, O and Norris, A}, title = {TDP-1 and FUST-1 co-inhibit exon inclusion and control fertility together with transcriptional regulation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37131843}, issn = {2692-8205}, support = {R01 NS111055/NS/NINDS NIH HHS/United States ; R35 GM133461/GM/NIGMS NIH HHS/United States ; }, abstract = {Gene expression is a multistep, carefully controlled process, and crosstalk between regulatory layers plays an important role in coordinating gene expression. To identify functionally relevant coordination between transcriptional and post-transcriptional gene regulation, we performed a systematic reverse-genetic interaction screen in C. elegans . We combined RNA binding protein (RBP) and transcription factor (TF) mutants, creating over 100 RBP; TF double mutants. This screen identified a variety of unexpected double mutant phenotypes, including two strong genetic interactions between the ALS-related RBPs, fust-1 and tdp-1 , and the homeodomain TF ceh-14 . Losing any one of these genes alone has no significant effect on the health of the organism. However, fust-1; ceh-14 and tdp-1; ceh-14 double mutants both exhibit strong temperature-sensitive fertility defects. Both double mutants exhibit defects in gonad morphology, sperm function, and oocyte function. RNA-seq analysis of double mutants identifies ceh-14 as the main controller of transcript levels, while fust-1 and tdp-1 control splicing through a shared role in exon inhibition. We identify a cassette exon in the polyglutamine-repeat protein pqn-41 which tdp-1 inhibits. Loss of tdp-1 causes the pqn-41 exon to be aberrantly included, and forced skipping of this exon in tdp-1; ceh-14 double mutants rescues fertility. Together our findings identify a novel shared physiological role for fust-1 and tdp-1 in promoting C. elegans fertility in a ceh-14 mutant background and reveal a shared molecular function of fust-1 and tdp-1 in exon inhibition.}, } @article {pmid37132107, year = {2023}, author = {Alameri, AA and Ghanni, MU and Ali, A and Singh, M and Al-Gazally, ME and Almulla, AF and Alexis Ramírez-Coronel, A and Mustafa, YF and Gupta, R and Obaid, RF and Gabr, GA and Farhood, B}, title = {The Effects of Curcumin on Astrocytes in Common Neurodegenerative Conditions.}, journal = {Mini reviews in medicinal chemistry}, volume = {23}, number = {22}, pages = {2117-2129}, doi = {10.2174/1389557523666230502143131}, pmid = {37132107}, issn = {1875-5607}, mesh = {*Curcumin/pharmacology/chemistry/therapeutic use ; Humans ; *Astrocytes/drug effects/metabolism/pathology ; *Neurodegenerative Diseases/drug therapy/pathology/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/chemistry ; }, abstract = {Neurodegenerative diseases are age-related, multifactorial, and complicated conditions that affect the nervous system. In most cases, these diseases may begin with an accumulation of misfolded proteins rather than decay before they develop clinical symptoms. The progression of these diseases can be influenced by a number of internal and external factors, including oxidative damage, neuro-inflammation, and the accumulation of misfolded amyloid proteins. Astrocytes, with the highest abundance among the cells of the mammalian central nervous system, perform several important activities, such as maintaining brain homeostasis and playing a role in the neurodegenerative condition onset and progress. Therefore, these cells have been considered to be potential targets for managing neurodegeneration. Curcumin, with multiple special properties, has been effectively prescribed to manage various diseases. It has hepato-protective, anti-carcinogenic, cardio-protective, thrombo-suppressive, anti-inflammatory, chemo-therapeutic, anti-arthritic, chemo-preventive, and anti-oxidant activities. In the current review, the effects of curcumin on astrocytes in common neurodegenerative conditions, such as Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, and Parkinson's disease, are discussed. Hence, it can be concluded that astrocytes play a critical role in neurodegenerative diseases, and curcumin is able to directly modulate astrocyte activity in neurodegenerative diseases.}, } @article {pmid37133535, year = {2023}, author = {de Boer, EMJ and de Vries, BS and Pennings, M and Kamsteeg, EJ and Veldink, JH and van den Berg, LH and van Es, MA}, title = {Genetic characterization of primary lateral sclerosis.}, journal = {Journal of neurology}, volume = {270}, number = {8}, pages = {3970-3980}, pmid = {37133535}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; C9orf72 Protein/genetics ; *Frontotemporal Dementia/complications ; *Motor Neuron Disease/diagnosis ; Motor Neurons/pathology ; Spastin ; Proteins ; Flavoproteins ; Phosphoric Monoester Hydrolases ; }, abstract = {BACKGROUND AND OBJECTIVES: Primary lateral sclerosis (PLS) is a motor neuron disease characterised by loss of the upper motor neurons. Most patients present with slowly progressive spasticity of the legs, which may also spread to the arms or bulbar regions. It is challenging to distinguish between PLS, early-stage amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). The current diagnostic criteria advise against extensive genetic testing. This recommendation is, however, based on limited data.

METHODS: We aim to genetically characterize a PLS cohort using whole exome sequencing (WES) for genes associated with ALS, HSP, ataxia and movement disorders (364 genes) and C9orf72 repeat expansions. Patients fulfilling the definite PLS criteria by Turner et al. and with available DNA samples of sufficient quality were recruited from an on-going, population-based epidemiological study. Genetic variants were classified according to the ACMG criteria and assigned to groups based on disease association.

RESULTS: WES was performed in 139 patients and the presence of repeat expansions in C9orf72 was analysed separately in 129 patients. This resulted in 31 variants of which 11 were (likely) pathogenic. (Likely) pathogenic variants resulted in 3 groups based on disease association: ALS-FTD (C9orf72, TBK1), pure HSP (SPAST, SPG7), "ALS-HSP-CMT overlap" (FIG4, NEFL, SPG11).

DISCUSSION: In a cohort of 139 PLS patients, genetic analyses resulted in 31 variants (22%) of which 10 (7%) (likely) pathogenic associated with different diseases (predominantly ALS and HSP). Based on these results and the literature, we advise to consider genetic analyses in the diagnostic work-up for PLS.}, } @article {pmid37133944, year = {2023}, author = {Hübers, A}, title = {[Similarities between amyotrophic lateral sclerosis and frontotemporal dementia].}, journal = {Revue medicale suisse}, volume = {19}, number = {824}, pages = {820-821}, doi = {10.53738/REVMED.2023.19.824.820}, pmid = {37133944}, issn = {1660-9379}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Frontotemporal Dementia/diagnosis ; *Neurodegenerative Diseases ; }, abstract = {Frontotemporal dementia (FTD) is characterized by degeneration of the frontal and temporal lobes. Classic symptoms include behavioural alterations and executive dysfunction. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of the first and second motoneurones, as well as of cortical neurons, presenting with weakness and wasting of the limb, respiratory and bulbar muscles. Accumulation of a mis-localized protein in the neuronal cytoplasma is the main neuropathological marker of ALS but has also been described in certain FTD-variants. Molecules interfering specifically on this level of mis-localization and toxic aggregation may thus represent a very interesting therapeutic approach in both, ALS and FTD.}, } @article {pmid37134270, year = {2023}, author = {Sarthak, K and Winogradoff, D and Ge, Y and Myong, S and Aksimentiev, A}, title = {Benchmarking Molecular Dynamics Force Fields for All-Atom Simulations of Biological Condensates.}, journal = {Journal of chemical theory and computation}, volume = {19}, number = {12}, pages = {3721-3740}, pmid = {37134270}, issn = {1549-9626}, support = {RF1 AG071326/AG/NIA NIH HHS/United States ; RF1 NS113636/NS/NINDS NIH HHS/United States ; R01 GM116961/GM/NIGMS NIH HHS/United States ; R21 HG011741/HG/NHGRI NIH HHS/United States ; R01 GM137015/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Infant, Newborn ; *Molecular Dynamics Simulation ; *Benchmarking ; Proteins ; Molecular Conformation ; RNA/chemistry ; Protein Conformation ; }, abstract = {Proteins containing intrinsically disordered regions are integral parts of the cellular signaling pathways and common components of biological condensates. Point mutations in the protein sequence, genetic at birth or acquired through aging, can alter the properties of the condensates, marking the onset of neurodegenerative diseases such as ALS and dementia. While the all-atom molecular dynamics method can, in principle, elucidate the conformational changes that arise from point mutations, the applications of this method to protein condensate systems is conditioned upon the availability of molecular force fields that can accurately describe both structured and disordered regions of such proteins. Using the special-purpose Anton 2 supercomputer, we benchmarked the efficacy of nine presently available molecular force fields in describing the structure and dynamics of a Fused in sarcoma (FUS) protein. Five-microsecond simulations of the full-length FUS protein characterized the effect of the force field on the global conformation of the protein, self-interactions among its side chains, solvent accessible surface area, and the diffusion constant. Using the results of dynamic light scattering as a benchmark for the FUS radius of gyration, we identified several force fields that produced FUS conformations within the experimental range. Next, we used these force fields to perform ten-microsecond simulations of two structured RNA binding domains of FUS bound to their respective RNA targets, finding the choice of the force field to affect stability of the RNA-FUS complex. Taken together, our data suggest that a combination of protein and RNA force fields sharing a common four-point water model provides an optimal description of proteins containing both disordered and structured regions and RNA-protein interactions. To make simulations of such systems available beyond the Anton 2 machines, we describe and validate implementation of the best performing force fields in a publicly available molecular dynamics program NAMD. Our NAMD implementation enables simulations of large (tens of millions of atoms) biological condensate systems and makes such simulations accessible to a broader scientific community.}, } @article {pmid37137507, year = {2023}, author = {D'Cruz, RF and Kaltsakas, G and Suh, ES and Hart, N}, title = {Quality of life in patients with chronic respiratory failure on home mechanical ventilation.}, journal = {European respiratory review : an official journal of the European Respiratory Society}, volume = {32}, number = {168}, pages = {}, pmid = {37137507}, issn = {1600-0617}, mesh = {Humans ; Respiration, Artificial/adverse effects ; Quality of Life ; *Respiratory Insufficiency/diagnosis/etiology/therapy ; *Neuromuscular Diseases/complications/diagnosis/therapy ; *Pulmonary Disease, Chronic Obstructive/diagnosis/therapy ; *Home Care Services ; }, abstract = {Home mechanical ventilation (HMV) is a treatment for chronic respiratory failure that has shown clinical and cost effectiveness in patients with underlying COPD, obesity-related respiratory failure and neuromuscular disease (NMD). By treating chronic respiratory failure with adequate adherence to HMV, improvement in patient-reported outcomes including health-related quality of life (HRQoL) have been evaluated using general and disease-specific quantitative, semi-qualitative and qualitative methods. However, the treatment response in terms of trajectory of change in HRQoL is not uniform across the restrictive and obstructive disease groups. In this review, the effect of HMV on HRQoL across the domains of symptom perception, physical wellbeing, mental wellbeing, anxiety, depression, self-efficacy and sleep quality in stable and post-acute COPD, rapidly progressive NMD (such as amyotrophic lateral sclerosis), inherited NMD (including Duchenne muscular dystrophy) and obesity-related respiratory failure will be discussed.}, } @article {pmid37137694, year = {2023}, author = {Hosaka, T and Tsuji, H and Terada, M and Tomidokoro, Y and Ishii, A and Nakamagoe, K and Ishii, K and Terashi, H and Aizawa, H and Tamaoka, A and Kwak, S}, title = {Glutamine/arginine site-unedited GluA2 mRNA in cerebrospinal fluid as a biomarker for amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {94}, number = {10}, pages = {876-878}, doi = {10.1136/jnnp-2023-331164}, pmid = {37137694}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/cerebrospinal fluid ; Glutamine ; Case-Control Studies ; Biomarkers/cerebrospinal fluid ; }, } @article {pmid37137711, year = {2023}, author = {Jimenez, JV and Ackrivo, J and Hsu, JY and Wilson, MW and Labaki, WW and Hansen-Flaschen, J and Hyzy, RC and Choi, PJ}, title = {Lowering PCO2 With Noninvasive Ventilation Is Associated With Improved Survival in Chronic Hypercapnic Respiratory Failure.}, journal = {Respiratory care}, volume = {68}, number = {12}, pages = {1613-1622}, pmid = {37137711}, issn = {1943-3654}, mesh = {Humans ; Female ; Adult ; Middle Aged ; Aged ; Male ; *Noninvasive Ventilation/adverse effects ; Hypercapnia/therapy/complications ; Carbon Dioxide ; *Pulmonary Disease, Chronic Obstructive/therapy ; Cohort Studies ; Prospective Studies ; *Respiratory Insufficiency/etiology/therapy/diagnosis ; }, abstract = {BACKGROUND: Chronic hypercapnic respiratory failure is associated with high mortality. Although previous work has demonstrated a mortality improvement with high-intensity noninvasive ventilation in COPD, it is unclear whether a PCO2 reduction strategy is associated with improved outcomes in other populations of chronic hypercapnia.

METHODS: The objective of this study was to investigate the association between PCO2 reduction (by using transcutaneous PCO2 as an estimate for PaCO2 and survival in a broad population of individuals treated with noninvasive ventilation for chronic hypercapnia. We hypothesized that reductions in PCO2 would be associated with improved survival. Therefore, we performed a cohort study of all the subjects evaluated from February 2012 to January 2021 for noninvasive ventilation initiation and/or optimization due to chronic hypercapnia at a home ventilation clinic in an academic center. We used multivariable Cox proportional hazard models with time-varying coefficients and PCO2 as a time-varying covariate to test the association between PCO2 and all-cause mortality and when adjusting for known cofounders.

RESULTS: The mean ± SD age of 337 subjects was 57 ± 16 years, 37% women, and 85% white. In a univariate analysis, survival probability increased with reductions in PCO2 to < 50 mm Hg after 90 d, and these remained significant after adjusting for age, sex, race, body mass index, diagnosis, Charlson comorbidity index, and baseline PCO2 . In the multivariable analysis, the subjects who had a PaCO2 < 50 mm Hg had a reduced mortality risk of 94% between 90 and 179 d (hazard ratio [HR] 0.06, 95% CI 0.01-0.50), 69% between 180 and 364 d (HR 0.31, 95% CI 0.12-0.79), and 73% for 365-730 d (HR 0.27, 95% CI 0.13-0.56).

CONCLUSIONS: Reduction in PCO2 from baseline for subjects with chronic hypercapnia treated with noninvasive ventilation was associated with improved survival. Management strategies should target the greatest attainable reductions in PCO2 .}, } @article {pmid37138438, year = {2024}, author = {Barbero Mazzucca, C and Cappellano, G and Chiocchetti, A}, title = {Nutrition, Immunity and Aging: Current Scenario and Future Perspectives in Neurodegenerative Diseases.}, journal = {CNS & neurological disorders drug targets}, volume = {23}, number = {5}, pages = {573-587}, pmid = {37138438}, issn = {1996-3181}, support = {//Fondazione Cariplo/ ; }, mesh = {Humans ; *Aging/immunology/physiology ; *Neurodegenerative Diseases/immunology ; Inflammation ; Alzheimer Disease/immunology ; Nutritional Status ; Amyotrophic Lateral Sclerosis/immunology ; Parkinson Disease/immunology ; Animals ; Immunity/physiology ; }, abstract = {Aging is a gradual decline of physiological function and tissue homeostasis and, in many instances, is related to increased (neuro)-degeneration, together with inflammation, becoming one of the most important risks for developing neurodegenerative diseases. Certain individual nutrients or foods in combination may counteract aging and associated neurodegenerative diseases by promoting a balance between the pro- and anti-inflammatory responses. Thus, nutrition could represent a powerful modulator of this fine balance, other than a modifiable risk factor to contrast inflammaging. This narrative review explores from a broad perspective the impact of nutrition on the hallmarks of aging and inflammation in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis Syndrome (ALS), starting from nutrients up to single foods and complex dietary patterns.}, } @article {pmid37138765, year = {2023}, author = {Lopez-Herdoiza, MB and Bauché, S and Wilmet, B and Le Duigou, C and Roussel, D and Frah, M and Béal, J and Devely, G and Boluda, S and Frick, P and Bouteiller, D and Dussaud, S and Guillabert, P and Dalle, C and Dumont, M and Camuzat, A and Saracino, D and Barbier, M and Bruneteau, G and Ravassard, P and Neumann, M and Nicole, S and Le Ber, I and Brice, A and Latouche, M}, title = {C9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1155929}, pmid = {37138765}, issn = {1662-5102}, abstract = {The GGGGCC intronic repeat expansion within C9ORF72 is the most common genetic cause of ALS and FTD. This mutation results in toxic gain of function through accumulation of expanded RNA foci and aggregation of abnormally translated dipeptide repeat proteins, as well as loss of function due to impaired transcription of C9ORF72. A number of in vivo and in vitro models of gain and loss of function effects have suggested that both mechanisms synergize to cause the disease. However, the contribution of the loss of function mechanism remains poorly understood. We have generated C9ORF72 knockdown mice to mimic C9-FTD/ALS patients haploinsufficiency and investigate the role of this loss of function in the pathogenesis. We found that decreasing C9ORF72 leads to anomalies of the autophagy/lysosomal pathway, cytoplasmic accumulation of TDP-43 and decreased synaptic density in the cortex. Knockdown mice also developed FTD-like behavioral deficits and mild motor phenotypes at a later stage. These findings show that C9ORF72 partial loss of function contributes to the damaging events leading to C9-FTD/ALS.}, } @article {pmid37138766, year = {2023}, author = {Dane, TL and Gill, AL and Vieira, FG and Denton, KR}, title = {Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1134090}, pmid = {37138766}, issn = {1662-5102}, abstract = {INTRODUCTION: Intronic repeat expansions in the C9orf72 gene are the most frequent known single genetic causes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These repeat expansions are believed to result in both loss-of-function and toxic gain-of-function. Gain-of-function results in the production of toxic arginine-rich dipeptide repeat proteins (DPRs), namely polyGR and polyPR. Small-molecule inhibition of Type I protein arginine methyltransferases (PRMTs) has been shown to protect against toxicity resulting from polyGR and polyPR challenge in NSC-34 cells and primary mouse-derived spinal neurons, but the effect in human motor neurons (MNs) has not yet been explored.

METHODS: To study this, we generated a panel of C9orf72 homozygous and hemizygous knockout iPSCs to examine the contribution of C9orf72 loss-of-function toward disease pathogenesis. We differentiated these iPSCs into spinal motor neurons (sMNs).

RESULTS: We found that reduced levels of C9orf72 exacerbate polyGR15 toxicity in a dose-dependent manner. Type I PRMT inhibition was able to partially rescue polyGR15 toxicity in both wild-type and C9orf72-expanded sMNs.

DISCUSSION: This study explores the interplay of loss-of-function and gain-of-function toxicity in C9orf72 ALS. It also implicates type I PRMT inhibitors as a possible modulator of polyGR toxicity.}, } @article {pmid37141321, year = {2023}, author = {Taule, T and Eide, IS and Fjær, L and Myrberget, MA and Oseland, MS and Renså, MA and Revheim, T and Tysnes, OB and Aßmus, J and Rekand, T}, title = {Norwegian version of the Edinburgh cognitive and behavioural ALS screen: Construct validity, internal consistency, inter-rater, and test-retest reliability.}, journal = {PloS one}, volume = {18}, number = {5}, pages = {e0285307}, pmid = {37141321}, issn = {1932-6203}, mesh = {Humans ; *Cognition Disorders/diagnosis/psychology ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Reproducibility of Results ; Neuropsychological Tests ; Language ; *Alzheimer Disease/diagnosis ; Cognition ; }, abstract = {BACKGROUND: Research collaboration highlight a need for validated tests in other languages than English. Translation and culture adjustments may threaten essential features of the original instrument.

OBJECTIVE: To assess the internal consistency, inter-rater and test-retest reliability, and construct validity of the Norwegian version of the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis (ALS) Screen (ECAS-N).

METHODS: Performance of 71 subjects with ALS, 85 healthy controls (HC) and 6 controls with Alzheimer's disease (AD) were assessed with the ECAS-N. Test-retest interval was four months. Internal consistency was evaluated using Cronbach's alpha; reliability was assessed using intraclass correlation coefficient (ICC), Cohen's kappa, and Bland Altman plot. Five hypothesis, including the Montreal Cognitive Assessment (MoCA) screen, was evaluated for construct validity.

RESULTS: ECAS-N total score produced a Cronbach's alpha of 0.65, had excellent inter-rater reliability (ICC = 0.99) and acceptable test-retest reliability (ICC = 0.73). Construct validity analysis suggested valid use of the ECAS-N to distinguish people with ALS-specific cognitive impairment from HC (p = 0.001) and those with AD (p = 0.002). The MoCA and ECAS-N were moderately correlated (r = 0.53).

CONCLUSION: The ECAS-N has potential to be used by different testers in clinical practice and research to screen patients with ALS who speak Norwegian and for documenting cognitive impairment over time.}, } @article {pmid37142397, year = {2023}, author = {Nakamura, R and Tohnai, G and Nakatochi, M and Atsuta, N and Watanabe, H and Ito, D and Katsuno, M and Hirakawa, A and Izumi, Y and Morita, M and Hirayama, T and Kano, O and Kanai, K and Hattori, N and Taniguchi, A and Suzuki, N and Aoki, M and Iwata, I and Yabe, I and Shibuya, K and Kuwabara, S and Oda, M and Hashimoto, R and Aiba, I and Ishihara, T and Onodera, O and Yamashita, T and Abe, K and Mizoguchi, K and Shimizu, T and Ikeda, Y and Yokota, T and Hasegawa, K and Tanaka, F and Nakashima, K and Kaji, R and Niwa, JI and Doyu, M and Terao, C and Ikegawa, S and Fujimori, K and Nakamura, S and Ozawa, F and Morimoto, S and Onodera, K and Ito, T and Okada, Y and Okano, H and Sobue, G and , }, title = {Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {94}, number = {10}, pages = {816-824}, doi = {10.1136/jnnp-2022-330851}, pmid = {37142397}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Genome-Wide Association Study ; East Asian People ; Fibroblast Growth Factor 1/genetics/metabolism ; Motor Neurons/pathology ; }, abstract = {BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS.

METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS.

RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10[-9]), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10[-8]) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10[-8]). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression.

CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.}, } @article {pmid37142673, year = {2023}, author = {Guo, L and Mao, Q and He, J and Liu, X and Piao, X and Luo, L and Hao, X and Yu, H and Song, Q and Xiao, B and Fan, D and Gao, Z and Jia, Y}, title = {Disruption of ER ion homeostasis maintained by an ER anion channel CLCC1 contributes to ALS-like pathologies.}, journal = {Cell research}, volume = {33}, number = {7}, pages = {497-515}, pmid = {37142673}, issn = {1748-7838}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Biological Transport ; Chloride Channels/genetics/metabolism ; Endoplasmic Reticulum/metabolism ; Homeostasis ; Mitochondrial Proteins/metabolism ; Mutation/genetics ; Disease Models, Animal ; }, abstract = {Although anion channel activities have been demonstrated in sarcoplasmic reticulum/endoplasmic reticulum (SR/ER), their molecular identities and functions remain unclear. Here, we link rare variants of Chloride Channel CLIC Like 1 (CLCC1) to amyotrophic lateral sclerosis (ALS)-like pathologies. We demonstrate that CLCC1 is a pore-forming component of an ER anion channel and that ALS-associated mutations impair channel conductance. CLCC1 forms homomultimers and its channel activity is inhibited by luminal Ca[2+] but facilitated by phosphatidylinositol 4,5-bisphosphate (PIP2). We identified conserved residues D25 and D181 in CLCC1 N-terminus responsible for Ca[2+] binding and luminal Ca[2+]-mediated inhibition on channel open probability and K298 in CLCC1 intraluminal loop as the critical PIP2-sensing residue. CLCC1 maintains steady-state [Cl[-]]ER and [K[+]]ER and ER morphology and regulates ER Ca[2+] homeostasis, including internal Ca[2+] release and steady-state [Ca[2+]]ER. ALS-associated mutant forms of CLCC1 increase steady-state [Cl[-]]ER and impair ER Ca[2+] homeostasis, and animals with the ALS-associated mutations are sensitized to stress challenge-induced protein misfolding. Phenotypic comparisons of multiple Clcc1 loss-of-function alleles, including ALS-associated mutations, reveal a CLCC1 dosage dependence in the severity of disease phenotypes in vivo. Similar to CLCC1 rare variations dominant in ALS, 10% of K298A heterozygous mice developed ALS-like symptoms, pointing to a mechanism of channelopathy dominant-negatively induced by a loss-of-function mutation. Conditional knockout of Clcc1 cell-autonomously causes motor neuron loss and ER stress, misfolded protein accumulation, and characteristic ALS pathologies in the spinal cord. Thus, our findings support that disruption of ER ion homeostasis maintained by CLCC1 contributes to ALS-like pathologies.}, } @article {pmid37143081, year = {2023}, author = {Fisher, EMC and Greensmith, L and Malaspina, A and Fratta, P and Hanna, MG and Schiavo, G and Isaacs, AM and Orrell, RW and Cunningham, TJ and Arozena, AA}, title = {Opinion: more mouse models and more translation needed for ALS.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {30}, pmid = {37143081}, issn = {1750-1326}, support = {223022/Z/21//WT_/Wellcome Trust/United Kingdom ; FISHER/OCT14/876-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; MC_EX_MR/N501931/1/MRC_/Medical Research Council/United Kingdom ; MR/S005021/1/MRC_/Medical Research Council/United Kingdom ; MR/R005184/1/MRC_/Medical Research Council/United Kingdom ; 107116/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; MR/L021056/1/MRC_/Medical Research Council/United Kingdom ; FISHER/APR14/874-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/K018523/1/MRC_/Medical Research Council/United Kingdom ; MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0801110/MRC_/Medical Research Council/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Disease Models, Animal ; Mutation ; Phenotype ; }, abstract = {Amyotrophic lateral sclerosis is a complex disorder most of which is 'sporadic' of unknown origin but approximately 10% is familial, arising from single mutations in any of more than 30 genes. Thus, there are more than 30 familial ALS subtypes, with different, often unknown, molecular pathologies leading to a complex constellation of clinical phenotypes. We have mouse models for many genetic forms of the disorder, but these do not, on their own, necessarily show us the key pathological pathways at work in human patients. To date, we have no models for the 90% of ALS that is 'sporadic'. Potential therapies have been developed mainly using a limited set of mouse models, and through lack of alternatives, in the past these have been tested on patients regardless of aetiology. Cancer researchers have undertaken therapy development with similar challenges; they have responded by producing complex mouse models that have transformed understanding of pathological processes, and they have implemented patient stratification in multi-centre trials, leading to the effective translation of basic research findings to the clinic. ALS researchers have successfully adopted this combined approach, and now to increase our understanding of key disease pathologies, and our rate of progress for moving from mouse models to mechanism to ALS therapies we need more, innovative, complex mouse models to address specific questions.}, } @article {pmid37143267, year = {2024}, author = {Forouzanfar, F and Pourbagher-Shahri, AM and Vafaee, F and Sathyapalan, T and Sahebkar, A}, title = {Phytochemicals as Substances that Affect Astrogliosis and their Implications for the Management of Neurodegenerative Diseases.}, journal = {Current medicinal chemistry}, volume = {31}, number = {34}, pages = {5550-5566}, pmid = {37143267}, issn = {1875-533X}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/pathology ; *Phytochemicals/pharmacology/chemistry/therapeutic use ; *Astrocytes/drug effects/pathology/metabolism ; Animals ; Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Gliosis/drug therapy/pathology ; }, abstract = {Astrocytes are a multifunctional subset of glial cells that are important in maintaining the health and function of the central nervous system (CNS). Reactive astrocytes may release inflammatory mediators, chemokines, and cytokines, as well as neurotrophic factors. There may be neuroprotective (e.g., cytokines, like IL-6 and TGF-b) and neurotoxic effects (e.g., IL-1β and TNF-a) associated with these molecules. In response to CNS pathologies, astrocytes go to a state called astrogliosis which produces diverse and heterogenic functions specific to the pathology. Astrogliosis has been linked to the progression of many neurodegenerative disorders. Phytochemicals are a large group of compounds derived from natural herbs with health benefits. This review will summarize how several phytochemicals affect neurodegenerative diseases (e.g., Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and Parkinson's disease) in basic medical and clinical studies and how they might affect astrogliosis in the process.}, } @article {pmid37146135, year = {2023}, author = {Henden, L and Fearnley, LG and Grima, N and McCann, EP and Dobson-Stone, C and Fitzpatrick, L and Friend, K and Hobson, L and Chan Moi Fat, S and Rowe, DB and D'Silva, S and Kwok, JB and Halliday, GM and Kiernan, MC and Mazumder, S and Timmins, HC and Zoing, M and Pamphlett, R and Adams, L and Bahlo, M and Blair, IP and Williams, KL}, title = {Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Science advances}, volume = {9}, number = {18}, pages = {eade2044}, pmid = {37146135}, issn = {2375-2548}, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; *Spinocerebellar Ataxias/genetics ; Fragile X Messenger Ribonucleoprotein 1/genetics ; }, abstract = {Pathogenic short tandem repeat (STR) expansions cause over 20 neurodegenerative diseases. To determine the contribution of STRs in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we used ExpansionHunter, REviewer, and polymerase chain reaction validation to assess 21 neurodegenerative disease-associated STRs in whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4703 matched controls. We also propose a data-derived outlier detection method for defining allele thresholds in rare STRs. Excluding C9orf72 repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded STR allele reported to be pathogenic or intermediate for another neurodegenerative disease. We identified and validated 162 disease-relevant STR expansions in C9orf72 (ALS/FTD), ATXN1 [spinal cerebellar ataxia type 1 (SCA1)], ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington's disease), DMPK [myotonic dystrophy type 1 (DM1)], CNBP (DM2), and FMR1 (fragile-X disorders). Our findings suggest clinical and pathological pleiotropy of neurodegenerative disease genes and highlight their importance in ALS and FTD.}, } @article {pmid37146595, year = {2023}, author = {Spencer, BL and Shaikh, N and Gudex, L and Dann, T and Langley, M and Matich, H and Bartlett, RH and Rojas-Peña, A and Potkay, JA}, title = {In Vivo Testing of an Ambient Air Based, Portable, and Automated CO 2 Removal Controller for Artificial Lungs.}, journal = {ASAIO journal (American Society for Artificial Internal Organs : 1992)}, volume = {69}, number = {7}, pages = {e301-e307}, pmid = {37146595}, issn = {1538-943X}, support = {I01 RX003114/RX/RRD VA/United States ; R21 HL140995/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Sheep ; *Hemodynamics ; Carbon Dioxide ; *Extracorporeal Membrane Oxygenation ; Hypercapnia ; Lung/metabolism ; }, abstract = {Portable artificial lung (AL) systems are under development, but there are few technologies available that adjust the carbon dioxide (CO 2) removal in response to changes in patient metabolic needs. Our work describes the second generation of a CO 2 -based portable servoregulation system that automatically adjusts CO 2 removal in ALs. Four adult sheep (68 ± 14.3 kg) were used to test the servoregulator. The servoregulator controlled air sweep flow through the lung to meet a target exhaust gas CO 2 (tEGCO 2) level in normocapnic and hypercapnic (arterial partial pressure of CO 2 [PaCO 2 ] >60 mm Hg) conditions at varying flow rates (0.5-1.5 L/min) and at tEGCO 2 levels of 10, 20, and 40 mm Hg. In hypercapnic sheep, average post-AL blood partial pressure of CO 2 (pCO 2) values were 22.4 ± 3.6 mm Hg for tEGCO 2 of 10 mm Hg, 28.0 ± 4.1 mm Hg for tEGCO 2 of 20 mm Hg and 40.6 ± 4.8 mm Hg for tEGCO 2 of 40 mm Hg. The controller successfully and automatically adjusted the sweep gas flow to rapidly (<10 minutes) meet the tEGCO 2 level when challenged with changes in inlet blood flow or target EGCO 2 levels for all animals. These in vivo data demonstrate an important step toward portable ALs that can automatically modulate CO 2 removal and allow for substantial changes in patient activity or disease status in ambulatory applications.}, } @article {pmid37147380, year = {2023}, author = {Kiani, L}, title = {Hypothalamic hormone linked to weight loss in ALS.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {6}, pages = {325}, pmid = {37147380}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Weight Loss ; *Hypothalamic Hormones ; }, } @article {pmid37147520, year = {2023}, author = {Aiello, EN and Solca, F and Greco, LC and Torre, S and Carelli, L and Morelli, C and Doretti, A and Colombo, E and Messina, S and Pain, D and Radici, A and Lizio, A and Casiraghi, J and Cerri, F and Woolley, S and Murphy, J and Tremolizzo, L and Appollonio, I and Verde, F and Sansone, VA and Lunetta, C and Silani, V and Ticozzi, N and Poletti, B}, title = {Equating norms between the ALS Cognitive Behavioral Screen (ALS-CBS™) and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) in non-demented ALS patients.}, journal = {Journal of neurology}, volume = {270}, number = {8}, pages = {4090-4095}, pmid = {37147520}, issn = {1432-1459}, mesh = {Humans ; *Cognition Disorders/psychology ; Retrospective Studies ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/genetics ; Cross-Sectional Studies ; Neuropsychological Tests ; Cognition ; }, abstract = {BACKGROUND: The present study aimed at deriving equating norms to estimate scores on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) based on those on the ALS Cognitive Behavioral Screen (ALS-CBS™) in an Italian cohort of non-demented ALS patients.

METHODS: ALS-CBS™ and ECAS scores of 293 ALS patients without frontotemporal dementia were retrospectively retrieved. Concurrent validity of the ALS-CBS™ towards the ECAS was tested by covarying for demographics, disease duration and severity, presence of C9orf72 hexanucleotide repeat expansion and behavioural features. A linear-smoothing equipercentile equating (LSEE) model was employed to derive ALS-CBS™-to-ECAS cross-walks. Gaps in LSEE-based estimation were managed via a linear regression-based equating approach. Equivalence between empirical and derived ECAS scores was tested via a two-one-sided test (TOST) procedure for the dependent sample.

RESULTS: The ALS-CBS™ predicted the ECAS (β = 0.75), accounting for the vast majority of its variance (60% out of an R[2] = 0.71). Consistently, a strong, one-to-one linear association between ALS-CBS™ and ECAS scores was detected (r = 0.84; R[2] = 0.73). The LSEE was able to estimate conversions for the full range of the ALS-CBS™, except for raw scores equal to 1 and 6 - for whom a linear equating-based equation was derived. Empirical ECAS scores were equivalent to those derived with both methods.

DISCUSSION: Italian practitioners and researchers have been herewith provided with valid, straightforward cross-walks to estimate the ECAS based on ALS-CBS™ scores in non-demented ALS patients. Conversions herewith provided will help avoid cross-sectional/longitudinal inconsistencies in test adoption within research, and possibly clinical, settings.}, } @article {pmid37147573, year = {2023}, author = {Fang, X and Wu, F and Jiang, C}, title = {A novel gene, TARDBP, and the protein it encodes can predict glioma patient prognosis and establish a prediction model.}, journal = {BMC neurology}, volume = {23}, number = {1}, pages = {182}, pmid = {37147573}, issn = {1471-2377}, mesh = {Humans ; *Brain Neoplasms/genetics ; *DNA-Binding Proteins/genetics ; *Glioma/genetics ; Mutation ; Prognosis ; }, abstract = {BACKGROUND: TDP-43 (43-kD transactive response DNA-binding protein) is a DNA-/RNA-binding protein that plays an important role in several nervous system diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Whether it plays an important role in glioma patients is unknown.

METHODS: Datasets were downloaded from the Chinese Glioma Genome Atlas (CGGA) website (http://www.cgga.org.cn/). Cox survival analysis was performed to determine the relationship between TARDBP gene expression and the overall survival of glioma patients. GO analyses were performed to determine the biological functions of the TARDBP gene. Finally, we used PRS type, age, grade, IDH mutation status, 1p/19q codeletion status, and expression value of the TARDBP gene to construct a prediction model. With this model, we can predict patients' 1-, 2-, 3-, 5-, and 10-year survival rates.

RESULTS: The TARDBP gene plays an important role in glioma patients. The expression of the TARDBP gene has a significant correlation with glioma patient survival. We also constructed an ideal prediction model.

CONCLUSION: Our findings suggest that the TARDBP gene and the protein it encodes play important roles in glioma patients. The expression of the TARDBP gene has a significant correlation with the overall survival of glioma patients.}, } @article {pmid37147936, year = {2023}, author = {Dutt, M and Hartel, G and Richards, RS and Shah, AK and Mohamed, A and Apostolidou, S and Gentry-Maharaj, A and , and Hooper, JD and Perrin, LC and Menon, U and Hill, MM}, title = {Discovery and validation of serum glycoprotein biomarkers for high grade serous ovarian cancer.}, journal = {Proteomics. Clinical applications}, volume = {17}, number = {4}, pages = {e2200114}, pmid = {37147936}, issn = {1862-8354}, support = {G9901012/MRC_/Medical Research Council/United Kingdom ; G0801228/MRC_/Medical Research Council/United Kingdom ; MC_UU_00004/01/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; C1479/A2884/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Humans ; Female ; Biomarkers, Tumor/metabolism ; Tandem Mass Spectrometry/methods ; Glycoproteins ; Lectins ; *Ovarian Neoplasms/diagnosis ; *Cystadenocarcinoma, Serous ; Aryldialkylphosphatase ; }, abstract = {PURPOSE: This study aimed to identify serum glycoprotein biomarkers for early detection of high-grade serous ovarian cancer (HGSOC), the most common and aggressive histotype of ovarian cancer.

EXPERIMENTAL DESIGN: The glycoproteomics pipeline lectin magnetic bead array (LeMBA)-mass spectrometry (MS) was used in age-matched case-control serum samples. Clinical samples collected at diagnosis were divided into discovery (n = 30) and validation (n = 98) sets. We also analysed a set of preclinical sera (n = 30) collected prior to HGSOC diagnosis in the UK Collaborative Trial of Ovarian Cancer Screening.

RESULTS: A 7-lectin LeMBA-MS/MS discovery screen shortlisted 59 candidate proteins and three lectins. Validation analysis using 3-lectin LeMBA-multiple reaction monitoring (MRM) confirmed elevated A1AT, AACT, CO9, HPT and ITIH3 and reduced A2MG, ALS, IBP3 and PON1 glycoforms in HGSOC. The best performing multimarker signature had 87.7% area under the receiver operating curve, 90.7% specificity and 70.4% sensitivity for distinguishing HGSOC from benign and healthy groups. In the preclinical set, CO9, ITIH3 and A2MG glycoforms were altered in samples collected 11.1 ± 5.1 months prior to HGSOC diagnosis, suggesting potential for early detection.

Our findings provide evidence of candidate early HGSOC serum glycoprotein biomarkers, laying the foundation for further study in larger cohorts.}, } @article {pmid37148340, year = {2023}, author = {Gu, XJ and Su, WM and Dou, M and Jiang, Z and Duan, QQ and Wang, H and Ren, YL and Cao, B and Wang, Y and Chen, YP}, title = {Identifying novel genes for amyotrophic lateral sclerosis by integrating human brain proteomes with genome-wide association data.}, journal = {Journal of neurology}, volume = {270}, number = {8}, pages = {4013-4023}, pmid = {37148340}, issn = {1432-1459}, support = {No. 81971188//the National Natural Science Fund of China/ ; No. 2022NSFSC0749//the National Natural Science Fund of Sichuan/ ; No. 2021YFS0051//the Science and Technology Bureau Fund of Sichuan Province/ ; No. 2019YFS0216//the Science and Technology Bureau Fund of Sichuan Province/ ; No. 2019HXFH046//the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Genome-Wide Association Study ; Proteome/genetics ; Bayes Theorem ; Brain ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Genome-Wide Association Studies (GWAS) have identified numerous risk genes for Amyotrophic Lateral Sclerosis (ALS); however, the mechanisms by which these loci confer ALS risk are uncertain. This study aims to identify novel causal proteins in the brains of patients with ALS using an integrative analytical pipeline.

METHODS: Using the datasets of Protein Quantitative Trait Loci (pQTL) (NpQTL1 = 376, NpQTL2 = 152), expression QTL (eQTL) (N = 452), and the largest ALS GWAS (NALS=27,205, NControls = 110,881), we performed a systematic analytical pipeline including Proteome-Wide Association Study (PWAS), Mendelian Randomization (MR), Bayesian colocalization, and Transcriptome-Wide Association Study (TWAS) to identify novel causal proteins for ALS in the brain.

RESULTS: Using PWAS, we found that the altered protein abundance of 12 genes in the brain was associated with ALS. Three genes (SCFD1, SARM1 and CAMLG) were identified as lead causal genes for ALS with solid evidence (False discovery rate < 0.05, in MR analysis; PPH4 > 80% for Bayesian colocalization). Specifically, an increased abundance of SCFD1 and CAMLG led to an increased risk of ALS, whereas a higher abundance of SARM1 led to a decreased risk of developing ALS. TWAS showed that SCFD1 and CAMLG were related to ALS at the transcriptional level.

CONCLUSIONS: SCFD1, CAMLG, and SARM1 exhibited robust associations and causality with ALS. The study findings provide novel clues for identifying potential therapeutic targets in ALS. Further studies are required to explore the mechanisms underlying the identified genes.}, } @article {pmid37149731, year = {2023}, author = {Zhang, Z and Wang, W and Zhu, Y and Guo, J}, title = {Global Research Hotspots and Trends of Physical Activity in Knee Osteoarthritis: A Bibliometric Analysis.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {29}, number = {}, pages = {e938919}, pmid = {37149731}, issn = {1643-3750}, mesh = {Humans ; Aged ; *Osteoarthritis, Knee ; Exercise ; Knee Joint ; Bibliometrics ; Pain ; }, abstract = {BACKGROUND Knee osteoarthritis (OA) is a chronic joint disease characterized by pain, swelling, and limited knee activity. Numerous studies have reported the efficacy and mechanism of physical activity in patients with knee OA. However, bibliometric analyses of physical activity and knee OA are rare. This study aimed to discuss the hotspots, frontiers, and trends in physical activity and knee OA research using bibliometric methods to provide valuable information for future research. MATERIAL AND METHODS Relevant literature was obtained from the Web of Science Core Collection database from 2000 to 2021. English-language articles and reviews were selected. CiteSpace (6.1.R2), a bibliometric analytical tool, was used to analyze the countries, institutions, journals, authors, keywords, and references. RESULTS A total of 860 papers were obtained. Publications and citations have increased over the years. The most productive country, institution, author, and journal were USA, the University of Melbourne, Bennell KL, and Osteoarthritis and Cartilage. The author and journal with the most citations were Fransen M and Osteoarthritis and Cartilage. McAlindon TE et al's paper had the most citations and the strongest burst. Two references for the latest bursts were published by Fransen M et al. and Bartholdy C et al. The top 4 keywords were "hip," "knee osteoarthritis," "pain," and "older adult." The keywords for the latest burst were "guideline" and "risk." CONCLUSIONS Over the past 2 decades, research on physical activity in knee OA has received increasing attention. This study identified research hotspots and development trends, providing meaningful information for researchers.}, } @article {pmid37150307, year = {2023}, author = {Westi, EW and Andersen, JV and Aldana, BI}, title = {Using stable isotope tracing to unravel the metabolic components of neurodegeneration: Focus on neuron-glia metabolic interactions.}, journal = {Neurobiology of disease}, volume = {182}, number = {}, pages = {106145}, doi = {10.1016/j.nbd.2023.106145}, pmid = {37150307}, issn = {1095-953X}, mesh = {*Neuroglia ; *Neurons/metabolism ; Astrocytes/metabolism ; Synaptic Transmission ; Isotopes/metabolism ; }, abstract = {Disrupted brain metabolism is a critical component of several neurodegenerative diseases. Energy metabolism of both neurons and astrocytes is closely connected to neurotransmitter recycling via the glutamate/GABA-glutamine cycle. Neurons and astrocytes hereby work in close metabolic collaboration which is essential to sustain neurotransmission. Elucidating the mechanistic involvement of altered brain metabolism in disease progression has been aided by the advance of techniques to monitor cellular metabolism, in particular by mapping metabolism of substrates containing stable isotopes, a technique known as isotope tracing. Here we review key aspects of isotope tracing including advantages, drawbacks and applications to different cerebral preparations. In addition, we narrate how isotope tracing has facilitated the discovery of central metabolic features in neurodegeneration with a focus on the metabolic cooperation between neurons and astrocytes.}, } @article {pmid37150879, year = {2023}, author = {Young, AL and Vogel, JW and Robinson, JL and McMillan, CT and Ossenkoppele, R and Wolk, DA and Irwin, DJ and Elman, L and Grossman, M and Lee, VMY and Lee, EB and Hansson, O}, title = {Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {7}, pages = {2975-2988}, pmid = {37150879}, issn = {1460-2156}, support = {T32 MH019112/MH/NIMH NIH HHS/United States ; MR/T027800/1/MRC_/Medical Research Council/United Kingdom ; P01 AG066597/AG/NIA NIH HHS/United States ; U19 AG062418/AG/NIA NIH HHS/United States ; R01 NS109260/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; }, mesh = {*Frontotemporal Dementia/pathology ; *TDP-43 Proteinopathies/pathology ; *Alzheimer Disease/pathology ; *Amyotrophic Lateral Sclerosis/genetics ; Dementia ; *Frontotemporal Lobar Degeneration/pathology ; Humans ; DNA-Binding Proteins/genetics ; }, abstract = {TAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterize TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and assume each syndrome is homogeneous. Here, we use data-driven disease progression modelling to derive a fine-grained empirical staging system for the classification and differentiation of frontotemporal lobar degeneration due to TDP-43 (FTLD-TDP, n = 126), amyotrophic lateral sclerosis (ALS, n = 141) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) with and without Alzheimer's disease (n = 304). The data-driven staging of ALS and FTLD-TDP complement and extend previously described human-defined staging schema for ALS and behavioural variant frontotemporal dementia. In LATE-NC individuals, progression along data-driven stages was positively associated with age, but negatively associated with age in individuals with FTLD-TDP. Using only regional TDP-43 severity, our data driven model distinguished individuals diagnosed with ALS, FTLD-TDP or LATE-NC with a cross-validated accuracy of 85.9%, with misclassifications associated with mixed pathological diagnosis, age and genetic mutations. Adding age and SuStaIn stage to this model increased accuracy to 92.3%. Our model differentiates LATE-NC from FTLD-TDP, though some overlap was observed between late-stage LATE-NC and early-stage FTLD-TDP. We further tested for the presence of subtypes with distinct regional TDP-43 progression patterns within each diagnostic group, identifying two distinct cortical-predominant and brainstem-predominant subtypes within FTLD-TDP and a further two subcortical-predominant and corticolimbic-predominant subtypes within ALS. The FTLD-TDP subtypes exhibited differing proportions of TDP-43 type, while there was a trend for age differing between ALS subtypes. Interestingly, a negative relationship between age and SuStaIn stage was seen in the brainstem/subcortical-predominant subtype of each proteinopathy. No subtypes were observed for the LATE-NC group, despite aggregating individuals with and without Alzheimer's disease and a larger sample size for this group. Overall, we provide an empirical pathological TDP-43 staging system for ALS, FTLD-TDP and LATE-NC, which yielded accurate classification. We further demonstrate that there is substantial heterogeneity amongst ALS and FTLD-TDP progression patterns that warrants further investigation in larger cross-cohort studies.}, } @article {pmid37150967, year = {2023}, author = {Shamim, EA and Kong, MW and Lim, IY and McCarthy, RJ and Grant, SN and Nagi, HK}, title = {Anti-PL12 Anti-Synthetase Syndrome and Amyotrophic Lateral Sclerosis: A Case Report of a Rare Comorbidity.}, journal = {The American journal of case reports}, volume = {24}, number = {}, pages = {e939035}, pmid = {37150967}, issn = {1941-5923}, mesh = {Male ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; Comorbidity ; Syndrome ; Muscle Weakness ; }, abstract = {BACKGROUND Anti-PL-12 syndrome is a rare form of myositis. Amyotrophic lateral sclerosis (ALS) is the commonest of the motor neuron disorders. However, the 2 conditions have not been reported to occur together in a single individual. This case report describes a patient who was diagnosed with anti-PL-12 anti-synthetase syndrome and then subsequently was diagnosed with ALS. CASE REPORT A 55-year-old male patient had anti-PL-12 syndrome and ALS occurring together. The patient initially presented with musculoskeletal complaints and was diagnosed with anti-PL-12 syndrome. He later went on to develop shortness of breath. Neurophysiological testing subsequently confirmed ALS as the patient experienced worsening muscle weakness over a 2-year period. A muscle biopsy performed showed neurogenic and myopathic process. The patient eventually lost the ability to ambulate without mobility assistance and suffered cardiac arrest due to complications from ALS, specifically diaphragmatic dysfunction. CONCLUSIONS This case report represents the first documented case of a patient having both anit-PL-12 syndrome and ALS together. It has been suggested that having an autoimmune disease (AID) may increase the subsequent risk of developing ALS. Previous studies did not conduct evaluation to ascertain serological markers for AS antibodies. Lab tests were rechecked and revalidated multiple times in separate facilities for confirmation of results in case of initial lab error. This may suggest a common etiology for both anti-PL-12 syndrome and ALS.}, } @article {pmid37151215, year = {2023}, author = {Koopman, M and Güngördü, L and Seinstra, RI and Nollen, EAA}, title = {Neuronal overexpression of hTDP-43 in Caenorhabditis elegans impairs different neuronally controlled behaviors and decreases fecundity.}, journal = {microPublication biology}, volume = {2023}, number = {}, pages = {}, pmid = {37151215}, issn = {2578-9430}, abstract = {Cytoplasmic inclusions consisting of transactive response DNA-binding protein 43 (TDP-43) are a key hallmark of TDP-43 proteinopathies like amyotrophic lateral sclerosis (ALS). Caenorhabditis elegans is considered a useful model for studying the molecular mechanisms underlying TDP-43 toxicity in vivo . Here, we assessed different neuronal systems through established behavioral assays and extended the phenotypic characterisation of a C. elegans model expressing wildtype human TDP-43 (hTDP-43) pan-neuronally. Our data show that neuronal expression of hTDP-43 in C. elegans disrupts chemotaxis and decreases fecundity. The basal slowing response, on the other hand, appears to be preserved in the presence of hTDP-43.}, } @article {pmid37151782, year = {2023}, author = {Daneau, S and Bourbonnais, A and Allard, É and Asri, M and Ummel, D and Bolduc, E}, title = {'Intensive palliative care': a qualitative study of issues related to nurses' care of people with amyotrophic lateral sclerosis at end-of-life.}, journal = {Palliative care and social practice}, volume = {17}, number = {}, pages = {26323524231170881}, pmid = {37151782}, issn = {2632-3524}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is currently an incurable and fatal disease, which often comes with a high symptom burden at the end-of-life stage. Little is known about nurses' experiences in this context.

OBJECTIVE: To explore the experience of nurses caring for people with ALS at end-of-life.

DESIGN: A qualitative multiple-case study design.

METHOD: Individual semi-structured interviews were conducted between February and August 2022 with nurses from Quebec, Canada, who had provided care to at least one person living with ALS at the end-of-life in the past 12 months. The content analysis method was used for data analysis and within-case and cross-case analyses were conducted, as well as comparative analyses according to the type of position held by the participants that determined the cases: (1) home care, (2) hospital and (3) palliative care home.

RESULTS: Participating in the study were 24 nurses: 9 were from home care, 8 from hospitals and 7 from palliative care homes. Five main themes were identified: (1) identifying the end-of-life period, (2) communication issues, (3) supporting the need for control, (4) accompanying in the fight culture and (5) the extent of the need for care. A sixth theme was also added in order to report the need expressed by nurses to improve their care of patients living with ALS at end-of-life.

CONCLUSIONS: Although nurses' experiences varied among the different settings, the study identifies the pressing need for better education and, above all, more resources when caring for a person living with ALS at end-of-life. Future research should explore the experiences of other members of the healthcare team and test interventions designed to improve the quality of life and end-of-life of people living with ALS.}, } @article {pmid37152446, year = {2023}, author = {Schuermans, N and Verdin, H and Ghijsels, J and Hellemans, M and Debackere, E and Bogaert, E and Symoens, S and Naesens, L and Lecomte, E and Crosiers, D and Bergmans, B and Verhoeven, K and Poppe, B and Laureys, G and Herdewyn, S and Van Langenhove, T and Santens, P and De Bleecker, JL and Hemelsoet, D and Dermaut, B and , }, title = {Exome Sequencing and Multigene Panel Testing in 1,411 Patients With Adult-Onset Neurologic Disorders.}, journal = {Neurology. Genetics}, volume = {9}, number = {3}, pages = {e200071}, pmid = {37152446}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Owing to their extensive clinical and molecular heterogeneity, hereditary neurologic diseases in adults are difficult to diagnose. The current knowledge about the diagnostic yield and clinical utility of exome sequencing (ES) for neurologic diseases in adults is limited. This observational study assesses the diagnostic value of ES and multigene panel analysis in adult-onset neurologic disorders.

METHODS: From January 2019 through April 2022, ES-based multigene panel testing was conducted in 1,411 patients with molecularly unexplained neurologic phenotypes at the Ghent University Hospital. Gene panels were developed for ataxia and spasticity, leukoencephalopathy, movement disorders, paroxysmal episodic disorders, neurodegeneration with brain iron accumulation, progressive myoclonic epilepsy, and amyotrophic lateral sclerosis. Single nucleotide variants, small indels, and copy number variants were analyzed. Across all panels, our analysis covered a total of 725 genes associated with Mendelian inheritance.

RESULTS: A molecular diagnosis was established in 10% of the cases (144 of 1,411) representing 71 different monogenic disorders. The diagnostic yield depended significantly on the presenting phenotype with the highest yield seen in patients with ataxia or spastic paraparesis (19%). Most of the established diagnoses comprised disorders with an autosomal dominant inheritance (62%), and the most frequently mutated genes were NOTCH3 (13 patients), SPG7 (11 patients), and RFC1 (8 patients). 34% of the disease-causing variants were novel, including a unique likely pathogenic variant in APP (Ghent mutation, p.[Asn698Asp]) in a family presenting with stroke and severe cerebral white matter disease. 7% of the pathogenic variants comprised copy number variants detected in the ES data and confirmed by an independent technique.

DISCUSSION: ES and multigene panel testing is a powerful and efficient tool to diagnose patients with unexplained, adult-onset neurologic disorders.}, } @article {pmid37152709, year = {2023}, author = {Yazar, V and Ruf, WP and Knehr, A and Günther, K and Ammerpohl, O and Danzer, KM and Ludolph, AC}, title = {DNA Methylation Analysis in Monozygotic Twins Discordant for ALS in Blood Cells.}, journal = {Epigenetics insights}, volume = {16}, number = {}, pages = {25168657231172159}, pmid = {37152709}, issn = {2516-8657}, abstract = {ALS is a fatal motor neuron disease that displays a broad variety of phenotypes ranging from early fatal courses to slowly progressing and rather benign courses. Such divergence can also be seen in genetic ALS cases with varying phenotypes bearing specific mutations, suggesting epigenetic mechanisms like DNA methylation act as disease modifiers. However, the epigenotype dictated by, in addition to other mechanisms, DNA methylation is also strongly influenced by the individual's genotype. Hence, we performed a DNA methylation study using EPIC arrays on 7 monozygotic (MZ) twin pairs discordant for ALS in whole blood, which serves as an ideal model for eliminating the effects of the genetic-epigenetic interplay to a large extent. We found one CpG site showing intra-pair hypermethylation in the affected co-twins, which maps to the Glutamate Ionotropic Receptor Kainate Type Subunit 1 gene (GRIK1). Additionally, we found 4 DMPs which were subsequently confirmed using 2 different statistical approaches. Differentially methylated regions or blocks could not be detected within the scope of this work. In conclusion, we revealed that despite a low sample size, monozygotic twin studies discordant for the disease can bring new insights into epigenetic processes in ALS, pointing to new target loci for further investigations.}, } @article {pmid37153665, year = {2023}, author = {Hong, D and Zhang, C and Wu, W and Lu, X and Zhang, L}, title = {Modulation of the gut-brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1133546}, pmid = {37153665}, issn = {1664-2295}, abstract = {There are trillions of different microorganisms in the human digestive system. These gut microbes are involved in the digestion of food and its conversion into the nutrients required by the body. In addition, the gut microbiota communicates with other parts of the body to maintain overall health. The connection between the gut microbiota and the brain is known as the gut-brain axis (GBA), and involves connections via the central nervous system (CNS), the enteric nervous system (ENS), and endocrine and immune pathways. The gut microbiota regulates the central nervous system bottom-up through the GBA, which has prompted researchers to pay considerable attention to the potential pathways by which the gut microbiota might play a role in the prevention and treatment of amyotrophic lateral sclerosis (ALS). Studies with animal models of ALS have shown that dysregulation of the gut ecology leads to dysregulation of brain-gut signaling. This, in turn, induces changes in the intestinal barrier, endotoxemia, and systemic inflammation, which contribute to the development of ALS. Through the use of antibiotics, probiotic supplementation, phage therapy, and other methods of inducing changes in the intestinal microbiota that can inhibit inflammation and delay neuronal degeneration, the clinical symptoms of ALS can be alleviated, and the progression of the disease can be delayed. Therefore, the gut microbiota may be a key target for effective management and treatment of ALS.}, } @article {pmid37153676, year = {2023}, author = {Reggiardo, G and Lo Giudice, M and Lalli, S and Rinaldi, G and Albanese, A}, title = {Cox regression and survival analysis from the tauro-urso-deoxycholic trial in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1163855}, pmid = {37153676}, issn = {1664-2295}, abstract = {Recent phase II pilot clinical trials suggested that tauro-urso-deoxycholic acid (TUDCA) might slow functional decline and increase survival in patients with amyotrophic lateral sclerosis (ALS). We performed a multivariate analysis of the original TUDCA cohort to better define the treatment effect and allow comparability with other trials. Linear regression slope analysis showed statistical differences in the decline rate, favoring the active treatment arm (p-value < 0.01; -0.262 for the TUDCA group and -0.388 for the placebo group). Mean survival time, estimated by the Kaplan-Meier analysis, showed a 1-month difference, favoring active treatment (log-rank test p-value = 0.092). Cox regression analysis demonstrated that placebo treatment was associated with a higher risk of death (p-value = 0.055). These data further support the disease-modifying effect of TUDCA monotherapy and raise the question of what could be the additional effect of combining TUDCA with sodium phenylbutyrate.}, } @article {pmid37153900, year = {2023}, author = {Ren, B and Geng, Y and Chen, S and Gao, Z and Zheng, K and Yang, Y and Luo, Q and Feng, J and Luo, Z and Ju, Y and Huang, Z}, title = {Alisertib exerts KRAS allele‑specific anticancer effects on colorectal cancer cell lines.}, journal = {Experimental and therapeutic medicine}, volume = {25}, number = {6}, pages = {243}, pmid = {37153900}, issn = {1792-1015}, abstract = {The aim of the present study was to examine the effects of alisertib (ALS) on RAS signaling pathways against a panel of colorectal cancer (CRC) cell lines and engineered Flp-In stable cell lines expressing different Kirsten rat sarcoma virus (KRAS) mutants. The viability of Caco-2KRAS wild-type, Colo-678KRAS G12D, SK-CO-1KRAS G12V, HCT116KRAS G13D, CCCL-18KRAS A146T and HT29BRAF V600E cells was examined by Cell Titer-Glo assay, and that of stable cell lines was monitored by IncuCyte. The expression levels of phosphorylated (p-)Akt and p-Erk as RAS signal outputs were measured by western blotting. The results suggested that ALS exhibited different inhibitory effects on cell viability and different regulatory effects on guanosine triphosphate (GTP)-bound RAS in CRC cell lines. ALS also exhibited various regulatory effects on the PI3K/Akt and mitogen-activated protein kinase (MAPK) pathways, the two dominant RAS signaling pathways, and induced apoptosis and autophagy in a RAS allele-specific manner. Combined treatment with ALS and selumetinib enhanced the regulatory effects of ALS on apoptosis and autophagy in CRC cell lines in a RAS allele-specific manner. Notably, combined treatment exhibited a synergistic inhibitory effect on cell proliferation in Flp-In stable cell lines. The results of the present study suggested that ALS differentially regulates RAS signaling pathways. The combined approach of ALS and a MEK inhibitor may represent a new therapeutic strategy for precision therapy for CRC in a KRAS allele-specific manner; however, this effect requires further study in vivo.}, } @article {pmid37154159, year = {2023}, author = {Castro, RW and Lopes, MC and Settlage, RE and Valdez, G}, title = {Aging alters mechanisms underlying voluntary movements in spinal motor neurons of mice, primates, and humans.}, journal = {JCI insight}, volume = {8}, number = {9}, pages = {}, pmid = {37154159}, issn = {2379-3708}, support = {F99 AG068442/AG/NIA NIH HHS/United States ; R01 AG055545/AG/NIA NIH HHS/United States ; R21 NS106313/NS/NINDS NIH HHS/United States ; R56 AG051501/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Mice ; Male ; Female ; Animals ; Aged ; *Motor Neurons/metabolism ; Aging/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Synapses/metabolism ; Primates ; }, abstract = {Spinal motor neurons have been implicated in the loss of motor function that occurs with advancing age. However, the cellular and molecular mechanisms that impair the function of these neurons during aging remain unknown. Here, we show that motor neurons do not die in old female and male mice, rhesus monkeys, and humans. Instead, these neurons selectively and progressively shed excitatory synaptic inputs throughout the soma and dendritic arbor during aging. Thus, aged motor neurons contain a motor circuitry with a reduced ratio of excitatory to inhibitory synapses that may be responsible for the diminished ability to activate motor neurons to commence movements. An examination of the motor neuron translatome (ribosomal transcripts) in male and female mice reveals genes and molecular pathways with roles in glia-mediated synaptic pruning, inflammation, axonal regeneration, and oxidative stress that are upregulated in aged motor neurons. Some of these genes and pathways are also found altered in motor neurons affected with amyotrophic lateral sclerosis (ALS) and responding to axotomy, demonstrating that aged motor neurons are under significant stress. Our findings show mechanisms altered in aged motor neurons that could serve as therapeutic targets to preserve motor function during aging.}, } @article {pmid37154887, year = {2023}, author = {Noh, MY and Kwon, MS and Oh, KW and Nahm, M and Park, J and Kim, YE and Ki, CS and Jin, HK and Bae, JS and Kim, SH}, title = {Role of NCKAP1 in the Defective Phagocytic Function of Microglia-Like Cells Derived from Rapidly Progressing Sporadic ALS.}, journal = {Molecular neurobiology}, volume = {60}, number = {8}, pages = {4761-4777}, pmid = {37154887}, issn = {1559-1182}, support = {2018M3C7A1056512//National Research Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Microglia/metabolism ; Phagocytosis/genetics ; Monocytes/metabolism ; Adaptor Proteins, Signal Transducing/metabolism ; }, abstract = {Microglia plays a key role in determining the progression of amyotrophic lateral sclerosis (ALS), yet their precise role in ALS has not been identified in humans. This study aimed to identify a key factor related to the functional characteristics of microglia in rapidly progressing sporadic ALS patients using the induced microglia model, although it is not identical to brain resident microglia. After confirming that microglia-like cells (iMGs) induced by human monocytes could recapitulate the main signatures of brain microglia, step-by-step comparative studies were conducted to delineate functional differences using iMGs from patients with slowly progressive ALS [ALS(S), n = 14] versus rapidly progressive ALS [ALS(R), n = 15]. Despite an absence of significant differences in the expression of microglial homeostatic genes, ALS(R)-iMGs preferentially showed defective phagocytosis and an exaggerated pro-inflammatory response to LPS stimuli compared to ALS(S)-iMGs. Transcriptome analysis revealed that the perturbed phagocytosis seen in ALS(R)-iMGs was closely associated with decreased NCKAP1 (NCK-associated protein 1)-mediated abnormal actin polymerization. NCKAP1 overexpression was sufficient to rescue impaired phagocytosis in ALS(R)-iMGs. Post-hoc analysis indicated that decreased NCKAP1 expression in iMGs was correlated with the progression of ALS. Our data suggest that microglial NCKAP1 may be an alternative therapeutic target in rapidly progressive sporadic ALS.}, } @article {pmid37154895, year = {2023}, author = {Maier, PM and Iggena, D and Meyer, T and Finke, C and Ploner, CJ}, title = {Memory-guided navigation in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {270}, number = {8}, pages = {4031-4040}, pmid = {37154895}, issn = {1432-1459}, support = {327654276 - SFB 1315//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Prospective Studies ; Cognition ; Neuropsychological Tests ; Mental Recall ; }, abstract = {BACKGROUND: Previous studies have yielded inconsistent results about hippocampal involvement in non-demented patients with amyotrophic lateral sclerosis (ALS). We hypothesized that testing of memory-guided spatial navigation i.e., a highly hippocampus-dependent behaviour, might reveal behavioural correlates of hippocampal dysfunction in non-demented ALS patients.

METHODS: We conducted a prospective study of spatial cognition in 43 non-demented ALS outpatients (11f, 32 m, mean age 60.0 years, mean disease duration 27.0 months, mean ALSFRS-R score 40.0) and 43 healthy controls (14f, 29 m, mean age 57.0 years). Participants were tested with a virtual memory-guided navigation task derived from animal research ("starmaze") that has previously been used in studies of hippocampal function. Participants were further tested with neuropsychological tests of visuospatial memory (SPART, 10/36 Spatial Recall Test), fluency (5PT, five-point test) and orientation (PTSOT, Perspective Taking/Spatial Orientation Test).

RESULTS: Patients successfully learned and navigated the starmaze from memory, both in conditions that forced memory of landmarks (success: patients 50.7%, controls 47.7%, p = 0.786) and memory of path sequences (success: patients 96.5%, controls 94.0%, p = 0.937). Measures of navigational efficacy (latency, path error and navigational uncertainty) did not differ between groups (p ≥ 0.546). Likewise, SPART, 5PT and PTSOT scores did not differ between groups (p ≥ 0.238).

CONCLUSIONS: This study found no behavioural correlate for hippocampal dysfunction in non-demented ALS patients. These findings support the view that the individual cognitive phenotype of ALS may relate to distinct disease subtypes rather than being a variable expression of the same underlying condition.}, } @article {pmid37155370, year = {2023}, author = {Fukuta, T and Ikeda-Imafuku, M and Iwao, Y}, title = {Development of Edaravone Ionic Liquids and Their Application for the Treatment of Cerebral Ischemia/Reperfusion Injury.}, journal = {Molecular pharmaceutics}, volume = {20}, number = {6}, pages = {3115-3126}, pmid = {37155370}, issn = {1543-8392}, mesh = {Rats ; Animals ; Edaravone ; *Ionic Liquids ; Antipyrine/pharmacology/therapeutic use ; Free Radical Scavengers/therapeutic use ; Tissue Distribution ; *Reperfusion Injury/drug therapy ; *Brain Ischemia/drug therapy ; *Ischemic Stroke/complications/drug therapy ; }, abstract = {Preparation of the ionic liquid (IL) form of active pharmaceutical ingredients (APIs), termed API-IL, has attracted attention because it can improve upon certain disadvantages of APIs, such as poor water solubility and low stability. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a clinically approved cerebroprotective agent against ischemic stroke and amyotrophic lateral sclerosis, while new formulations that enable improvement of its physicochemical properties and biodistribution are desired. Herein, we report a newly developed API-IL of edaravone (edaravone-IL), in which edaravone is used as an anionic molecule. We investigated the physicochemical properties of edaravone-IL and its therapeutic effect against cerebral ischemia/reperfusion (I/R) injury, a secondary injury after an ischemic stroke. Among the cationic molecules used for edaravone-IL preparation, the IL prepared with tetrabutylphosphonium cation existed as a liquid at room temperature, and significantly increased the water solubility of edaravone without decreasing its antioxidative activity. Importantly, edaravone-IL formed negatively charged nanoparticles upon suspension in water. Intravenous administration of edaravone-IL showed significantly higher blood circulation time and lower distribution in the kidney compared with edaravone solution. Moreover, edaravone-IL significantly suppressed brain cell damage and motor functional deficits in model rats of cerebral I/R injury and showed comparable cerebroprotective effect to edaravone. Taken together, these results suggest that edaravone-IL could be a new form of edaravone with superior physicochemical properties and could be useful for the treatment of cerebral I/R injury.}, } @article {pmid37156398, year = {2023}, author = {Hashimoto, K and Watanabe, S and Akutsu, M and Muraki, N and Kamishina, H and Furukawa, Y and Yamanaka, K}, title = {Intrinsic structural vulnerability in the hydrophobic core induces species-specific aggregation of canine SOD1 with degenerative myelopathy-linked E40K mutation.}, journal = {The Journal of biological chemistry}, volume = {299}, number = {6}, pages = {104798}, pmid = {37156398}, issn = {1083-351X}, mesh = {Animals ; Dogs ; Humans ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Mutation ; *Neurodegenerative Diseases/genetics/metabolism/veterinary ; *Superoxide Dismutase-1/genetics/metabolism ; *Dog Diseases/genetics/metabolism ; Species Specificity ; }, abstract = {Canine degenerative myelopathy (DM), a fatal neurodegenerative disease in dogs, shares clinical and genetic features with amyotrophic lateral sclerosis, a human motor neuron disease. Mutations in the SOD1 gene encoding Cu/Zn superoxide dismutase (SOD1) cause canine DM and a subset of inherited human amyotrophic lateral sclerosis. The most frequent DM causative mutation is homozygous E40K mutation, which induces the aggregation of canine SOD1 but not of human SOD1. However, the mechanism through which canine E40K mutation induces species-specific aggregation of SOD1 remains unknown. By screening human/canine chimeric SOD1s, we identified that the humanized mutation of the 117th residue (M117L), encoded by exon 4, significantly reduced aggregation propensity of canine SOD1[E40K]. Conversely, introducing a mutation of leucine 117 to methionine, a residue homologous to canine, promoted E40K-dependent aggregation in human SOD1. M117L mutation improved protein stability and reduced cytotoxicity of canine SOD1[E40K]. Furthermore, crystal structural analysis of canine SOD1 proteins revealed that M117L increased the packing within the hydrophobic core of the β-barrel structure, contributing to the increased protein stability. Our findings indicate that the structural vulnerability derived intrinsically from Met 117 in the hydrophobic core of the β-barrel structure induces E40K-dependent species-specific aggregation in canine SOD1.}, } @article {pmid37157097, year = {2023}, author = {Liang, X and Wei, F and Yang, H and Fan, L and Cai, X and Ma, Y and Shi, J and Xing, K and Qiu, L and Li, X and Lu, L and Ji, J and Wen, Y and Feng, J}, title = {Flagella-Driven Motility Is Critical to the Virulence of Xanthomonas fragariae in Strawberry.}, journal = {Plant disease}, volume = {107}, number = {11}, pages = {3506-3516}, doi = {10.1094/PDIS-03-23-0409-RE}, pmid = {37157097}, issn = {0191-2917}, mesh = {*Fragaria/microbiology ; Multilocus Sequence Typing ; Phylogeny ; Virulence ; *Xanthomonas/pathogenicity ; }, abstract = {Xanthomonas fragariae (X. fragariae) is the causal agent of angular leaf spots (ALS) in strawberry plants. Recently, a study in China isolated X. fragariae strain YL19, which was observed to cause both typical ALS symptoms and dry cavity rot in strawberry crown tissue; this was the first X. fragariae strain to have both these effects in strawberry. In this study, from 2020 to 2022, we isolated 39 X. fragariae strains from diseased strawberries in different production areas in China. Multilocus sequence typing (MLST) and phylogenetic analysis showed that X. fragariae strain YLX21 was genetically different from YL19 and other strains. Tests indicated that YLX21 and YL19 had different pathogenicities toward strawberry leaves and stem crowns. YLX21 did not cause ALS symptoms, rarely caused dry cavity rot in strawberry crown after wound inoculation, and never caused dry cavity rot after spray inoculation, but it did cause severe ALS symptoms after spray inoculation. However, YL19 caused more severe symptoms in strawberry crowns under both conditions. Moreover, YL19 had a single polar flagellum, while YLX21 had no flagellum. Motility and chemotaxis assays showed that YLX21 had weaker motility than YL19, which may explain why YLX21 tended to multiply in situ within the strawberry leaf rather than migrate to other tissues, causing more severe ALS symptoms and mild crown rot symptoms. Taken together, the new strain YLX21 helped us reveal critical factors underlying the pathogenicity of X. fragariae and the mechanism by which dry cavity rot in strawberry crowns forms.}, } @article {pmid37158444, year = {2023}, author = {Al Burshaid, D and Corda, M and Aho-Glele, S and Guigou, C and Al Shehabi, M and Folia, M}, title = {The French way of voice rehabilitation post total laryngectomy: current clinical practices and tendencies.}, journal = {Acta oto-laryngologica}, volume = {143}, number = {5}, pages = {440-445}, doi = {10.1080/00016489.2023.2206873}, pmid = {37158444}, issn = {1651-2251}, mesh = {Humans ; Laryngectomy/rehabilitation ; *Larynx, Artificial ; *Voice ; Speech, Esophageal ; Surveys and Questionnaires ; *Laryngeal Neoplasms/surgery ; }, abstract = {BACKGROUND: Vocal rehabilitation post total laryngectomy (TL) lacks clinical guidelines, especially with the presence of multiple modalities.

OBJECTIVES: To describe the tendencies of vocal rehabilitation post TL in France and compare it with other countries. We try to identify the most practiced modalities and recognize statistically significant influencing factors.

MATERIALS AND METHODS: An electronic anonymous survey was answered by 75 ENT surgeons from France. The survey outlined the common practiced vocal rehabilitation modalities and had two versions depending on if the participant practices the tracheoesophageal speech (TES) or not.

RESULTS: 96% use TES in their practice. Single modality TES and double modality TES with esophageal speech (ES) are the two most practiced modalities. 99% agreed that there is no age limit for the TES. Single modality ES was offered 92% more when more than 10 TL were performed per year (p < .05). No influencing factors found for single modality TES or double modality TES with ES (p > .05).Conclusion: In line with tendencies from other countries, the TES is the most practiced modality of vocal rehabilitation coupled or not with the ES. TES has no age limit as per our participants. The least practiced modality is the singe modality ALS.}, } @article {pmid37158592, year = {2023}, author = {Shi, WP and Lin, WJ and Ge, WY and Chen, LL and Zhang, TD and Guo, WH and Liu, JL and Yin, DC}, title = {Curcumin inhibits liquid-liquid phase separation of fused in sarcoma and attenuates the sequestration of pyruvate kinase to restore cellular metabolism.}, journal = {Food & function}, volume = {14}, number = {10}, pages = {4621-4631}, doi = {10.1039/d2fo03224d}, pmid = {37158592}, issn = {2042-650X}, mesh = {Humans ; Pyruvate Kinase/genetics/metabolism ; *Curcumin/pharmacology ; *Frontotemporal Dementia/metabolism ; Adenosine Triphosphate ; *Sarcoma ; Mutation ; RNA-Binding Protein FUS/chemistry/genetics/metabolism ; }, abstract = {The abnormal accumulation of fused in sarcoma (FUS) is a pathological hallmark in a proportion of patients with frontotemporal dementia and amyotrophic lateral sclerosis. Therefore, the clearance of FUS aggregates is a possible therapeutic strategy for FUS-associated neurodegenerative diseases. This study reports that curcumin can strongly suppress FUS droplet formation and stress granule aggregation of FUS. Fluorescence spectra and isothermal titration calorimetry showed that curcumin can bind FUS through hydrophobic interactions, thereby reducing the β-sheet content of FUS. Aggregated FUS sequesters pyruvate kinase, leading to reduced ATP levels. However, results from a metabolomics study revealed that curcumin changed the metabolism pattern and differentially expressed metabolites were enriched in glycolysis. Curcumin attenuated FUS aggregation-mediated sequestration of pyruvate kinase and restored cellular metabolism, consequently increasing ATP levels. These results indicate that curcumin is a potent inhibitor of FUS liquid-liquid phase separation and provide novel insights into the effect of curcumin in ameliorating abnormal metabolism.}, } @article {pmid37159497, year = {2023}, author = {Scaber, J and Thompson, AG and Farrimond, L and Feneberg, E and Proudfoot, M and Ossher, L and Turner, MR and Talbot, K}, title = {Advantages of routine next-generation sequencing over standard genetic testing in the amyotrophic lateral sclerosis clinic.}, journal = {European journal of neurology}, volume = {30}, number = {8}, pages = {2240-2249}, pmid = {37159497}, issn = {1468-1331}, support = {TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; BRC127/NS/NW/5992/DH_/Department of Health/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; Genetic Testing ; High-Throughput Nucleotide Sequencing/methods ; Mutation ; Kinesins/genetics ; }, abstract = {BACKGROUND: Next-generation sequencing has enhanced our understanding of amyotrophic lateral sclerosis (ALS) and its genetic epidemiology. Outside the research setting, testing is often restricted to those who report a family history. The aim of this study was to explore the added benefit of offering routine genetic testing to all patients in a regional ALS centre.

METHODS: C9ORF72 expansion testing and exome sequencing was offered to consecutive patients (150 with ALS and 12 with primary lateral sclerosis [PLS]) attending the Oxford Motor Neuron Disease Clinic within a defined time period.

RESULTS: A total of 17 (11.3%) highly penetrant pathogenic variants in C9ORF72, SOD1, TARDBP, FUS and TBK1 were detected, of which 10 were also found through standard clinical genetic testing pathways. The systematic approach resulted in five additional diagnoses of a C9ORF72 expansion (number needed to test [NNT] = 28), and two further missense variants in TARDBP and SOD1 (NNT = 69). Additionally, 3 patients were found to carry pathogenic risk variants in NEK1, and 13 patients harboured common missense variants in CFAP410 and KIF5A, also associated with an increased risk of ALS. We report two novel non-coding loss-of-function splice variants in TBK1 and OPTN. No relevant variants were found in the PLS patients. Patients were offered double-blinded participation, but >80% requested disclosure of the results.

CONCLUSIONS: This study provides evidence that expanding genetic testing to all patients with a clinical diagnosis of ALS enhances the potential for recruitment to clinical trials, but will have direct resource implications for genetic counselling.}, } @article {pmid37159575, year = {2023}, author = {Koopman, M and Güngördü, L and Seinstra, RI and Hogewerf, W and Nollen, EAA}, title = {Neuronal overexpression of hTDP-43 in Caenorhabditis elegans mimics the cellular pathology commonly observed in TDP-43 proteinopathies.}, journal = {microPublication biology}, volume = {2023}, number = {}, pages = {}, pmid = {37159575}, issn = {2578-9430}, abstract = {Inclusions consisting of transactive response DNA-binding protein 43 (TDP-43) are a characteristic feature of amyotrophic lateral sclerosis (ALS). Caenorhabditis elegans has been instrumental in studying the underlying mechanisms of TDP-43 pathology. Here, we extend the possibilities of previous studies by examining a C. elegans model expressing human wild-type TDP-43 (hTDP-43) pan-neuronally. We show that disease-related (hyper)phosphorylation and cytosolic localisation of hTDP-43 are present in hTDP-43 worms and that these features can be enhanced by adjusting the environmental temperature.}, } @article {pmid37159576, year = {2023}, author = {Koopman, M and Güngördü, L and Seinstra, RI and Nollen, EAA}, title = {Neuronal overexpression of hTDP-43 in Caenorhabditis elegans impairs motor function.}, journal = {microPublication biology}, volume = {2023}, number = {}, pages = {}, pmid = {37159576}, issn = {2578-9430}, abstract = {Transactive response DNA binding-protein 43 (TDP-43) is a conserved RNA/DNA-binding protein with a role in RNA metabolism and homeostasis. Aberrant TDP-43 functioning has been considered a major culprit in amyotrophic lateral sclerosis (ALS). Caenorhabditis elegans can be used to phenocopy ALS in vivo . Since disrupted locomotion is a strong readout of toxicity, we examined multiple motor phenotypes of a C. elegans model expressing human wild-type TDP-43 (hTDP-43) pan-neuronally. Our data reveal that impaired locomotion includes more than the common deficits in crawling capacity and the presence of early-onset paralysis. We show that reduced thrashing, abnormal coiling, and decreased pharyngeal pumping are also observed, in a temperature-dependent fashion.}, } @article {pmid37160538, year = {2023}, author = {Prasanna Venkatesh, N and Pradeep Kumar, R and Chakravarthy Neelapu, B and Pal, K and Sivaraman, J}, title = {CatBoost-based improved detection of P-wave changes in sinus rhythm and tachycardia conditions: a lead selection study.}, journal = {Physical and engineering sciences in medicine}, volume = {46}, number = {2}, pages = {925-944}, pmid = {37160538}, issn = {2662-4737}, support = {EEQ/2019/000148//SERB/ ; }, mesh = {Humans ; Female ; Young Adult ; Adult ; Male ; *Atrial Fibrillation/diagnosis ; Tachycardia ; Heart Rate ; Heart Atria ; Electrocardiography/methods ; }, abstract = {Examining P-wave morphological changes in Electrocardiogram (ECG) is essential for characterizing atrial arrhythmias. However, standard 12-lead ECGsuffer from diagnostic redundancy due to low signal-to-noise ratio of P-waves. To address this issue, various optimal leads have been proposed for improved atrial activity recording, but the right selection among these leads is crucial for enhancing diagnostic efficacy. This study proposes an automated lead selection technique using the CatBoost machine learning (ML) model to improve the detection of P-wave changes among optimal bipolar leads under different heart rates. ECGs were obtained from healthy participants with a mean age of 25 ± 3.81 years (34% women), including 114 in sinus rhythm (SR) and 38 in sinus tachycardia (ST). The recordings were made using a newly designed atrial lead system (ALS), standard limb lead (SLL), modified limb lead (MLL), modified Lewis lead (LLM) and P-lead. P-wave features and Atrioventricular (AV) ratio were extracted for statistical analysis and ML classification. The optimum ML model was chosen to identify the best-performing optimal lead, which was selected based on the SLL metrics among different ML classifiers. CatBoost was found to outperform the other ML models in SLL-II with the highest accuracy and sensitivity of 0.82 and 0.90, respectively. The CatBoost model, amid other optimal leads, gave the best results for AL-I and AL-II (0.86 and 0.83 in accuracy and 0.91 and 0.93 in sensitivity). The developed CatBoost model selected AL-I and AL-II as the top two best-performing optimal leads for the enhanced acquisition of P-wave changes, which may be useful for diagnosing atrial arrhythmias.}, } @article {pmid37162554, year = {2023}, author = {Smida, T and Price, BS and Scheidler, J and Crowe, R and Wilson, A and Bardes, J}, title = {Stay and play or load and go? The association of on-scene advanced life support interventions with return of spontaneous circulation following traumatic cardiac arrest.}, journal = {European journal of trauma and emergency surgery : official publication of the European Trauma Society}, volume = {49}, number = {5}, pages = {2165-2172}, pmid = {37162554}, issn = {1863-9941}, support = {U54 GM104942/GM/NIGMS NIH HHS/United States ; 5U54GM104942-05/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Cardiopulmonary Resuscitation/methods ; *Emergency Medical Services/methods ; *Out-of-Hospital Cardiac Arrest/therapy ; Return of Spontaneous Circulation ; *Life Support Care ; }, abstract = {INTRODUCTION: Traumatic out-of-hospital cardiac arrest (tOHCA) has a mortality rate over 95%. Many current protocols dictate rapid intra-arrest transport of these patients. We hypothesized that on-scene advanced life support (ALS) would increase the odds of arriving at the emergency department with ROSC (ROSC at ED) in comparison to performance of no ALS or ALS en route.

METHODS: We utilized the 2018-2021 ESO Research Collaborative public use datasets for this study, which contain patient care records from ~2000 EMS agencies across the US. All OHCA patients with an etiology of "trauma" or "exsanguination" were screened (n=15,691). The time of advanced airway management, vascular access, and chest decompression was determined for each patient. Logistic regression modeling was used to evaluate the association of ALS intervention timing with ROSC at ED.

RESULTS: 4942 patients met inclusion criteria. 14.6% of patients had ROSC at ED. In comparison to no vascular access, on-scene (aOR: 2.14 [1.31, 3.49]) but not en route vascular access was associated with increased odds of having ROSC at ED arrival. In comparison to no chest decompression, neither en route nor on-scene chest decompression were associated with ROSC at ED arrival. Similarly, in comparison to no advanced airway management, neither en route nor on-scene advanced airway management were associated with ROSC at ED arrival. The odds of ROSC at ED decreased by 3% (aOR: 0.97 [0.94, 0.99]) for every 1-minute increase in time to vascular access and decreased by 5% (aOR: 0.95 [0.94, 0.99]) for every 1-minute increase in time to epinephrine.

CONCLUSION: On-scene ALS interventions were associated with increased ROSC at ED in our study. These data suggest that initiating ALS prior to rapid transport to definitive care in the setting of tOHCA may increase the number of patients with a palpable pulse at ED arrival.}, } @article {pmid37162686, year = {2023}, author = {Mangrulkar, SV and Wankhede, NL and Kale, MB and Upaganlawar, AB and Taksande, BG and Umekar, MJ and Anwer, MK and Dailah, HG and Mohan, S and Behl, T}, title = {Mitochondrial Dysfunction as a Signaling Target for Therapeutic Intervention in Major Neurodegenerative Disease.}, journal = {Neurotoxicity research}, volume = {41}, number = {6}, pages = {708-729}, pmid = {37162686}, issn = {1476-3524}, mesh = {Humans ; Aged ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; DNA, Mitochondrial/genetics/metabolism/therapeutic use ; Oxidative Stress ; Aging ; }, abstract = {Neurodegenerative diseases (NDD) are incurable and the most prevalent cognitive and motor disorders of elderly. Mitochondria are essential for a wide range of cellular processes playing a pivotal role in a number of cellular functions like metabolism, intracellular signaling, apoptosis, and immunity. A plethora of evidence indicates the central role of mitochondrial functions in pathogenesis of many aging related NDD. Considering how mitochondria function in neurodegenerative diseases, oxidative stress, and mutations in mtDNA both contribute to aging. Many substantial reports suggested the involvement of numerous contributing factors including, mitochondrial dysfunction, oxidative stress, mitophagy, accumulation of somatic mtDNA mutations, compromised mitochondrial dynamics, and transport within axons in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. Therapies therefore target fundamental mitochondrial processes such as energy metabolism, free-radical generation, mitochondrial biogenesis, mitochondrial redox state, mitochondrial dynamics, mitochondrial protein synthesis, mitochondrial quality control, and metabolism hold great promise to develop pharmacological based therapies in NDD. By emphasizing the most efficient pharmacological strategies to target dysfunction of mitochondria in the treatment of neurodegenerative diseases, this review serves the scientific community engaged in translational medical science by focusing on the establishment of novel, mitochondria-targeted treatment strategies.}, } @article {pmid37162924, year = {2023}, author = {Qi, C and Verheijen, BM and Kokubo, Y and Shi, Y and Tetter, S and Murzin, AG and Nakahara, A and Morimoto, S and Vermulst, M and Sasaki, R and Aronica, E and Hirokawa, Y and Oyanagi, K and Kakita, A and Ryskeldi-Falcon, B and Yoshida, M and Hasegawa, M and Scheres, SHW and Goedert, M}, title = {Tau Filaments from Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC) adopt the CTE Fold.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37162924}, issn = {2692-8205}, support = {MC_UP_1201/25/MRC_/Medical Research Council/United Kingdom ; R01 AG054641/AG/NIA NIH HHS/United States ; }, abstract = {The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterised by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in two Kii cases. We also identified a novel Type III CTE tau filament, where protofilaments pack against each other in an anti-parallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.}, } @article {pmid37162962, year = {2023}, author = {Liu, ML and Ma, S and Tai, W and Zhong, X and Ni, H and Zou, Y and Wang, J and Zhang, CL}, title = {Chemical screens in aging-relevant human motor neurons identify MAP4Ks as therapeutic targets for amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37162962}, issn = {2692-8205}, support = {R01 NS092616/NS/NINDS NIH HHS/United States ; R01 NS111776/NS/NINDS NIH HHS/United States ; R01 NS117065/NS/NINDS NIH HHS/United States ; R01 NS127375/NS/NINDS NIH HHS/United States ; }, abstract = {Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.}, } @article {pmid37163281, year = {2023}, author = {Sumińska, S and Kapica, Ł and Szczepański, G and Stachura-Krzyształowicz, A}, title = {[Abilitest battery - psychometric properties: a preliminary study].}, journal = {Medycyna pracy}, volume = {74}, number = {2}, pages = {103-118}, doi = {10.13075/mp.5893.01338}, pmid = {37163281}, issn = {2353-1339}, mesh = {Humans ; Psychometrics ; Reproducibility of Results ; *Memory, Short-Term ; Reaction Time ; }, abstract = {BACKGROUND: Cognitive efficiency is crucial for many areas of human activity. It affects the employees' efficiency and safety at the workplace. An important element of the prevention of accidents at work is the appropriate professional selection, which consists in checking the characteristics of candidates needed for a given position, and for this purpose, a psychological diagnosis is carried out. The aim of the study was to develop tools for cognitive diagnosis that are characterized by good psychometric properties.

MATERIAL AND METHODS: Tools for the diagnosis of simple reaction time (Abili-time), choice reaction time (Abili-select), prolonged attention (Abili-space, Abili-digit), and working memory (Abili-langmem, Abili-mathmem) were developed. Validation studies were conducted with 221 individuals aged 20-60 to assess relevance and reliability (internal consistency and temporal stability), and with the participation of 61 in a retest 3 months after the first measurement. Paper tests (CTT, TUS, Digit Span from WAIS-R(PL)) and tests from the Vienna test system (RT, SIGNAL, CORSI, ALS) were used to assess validity.

RESULTS: The analysis showed that the Abili-time and Abili-select tests have satisfactory internal consistency. Analysis of temporal stability showed significant test-retest correlations for Abili-select, Abili-space, Abili-digit and Abili-langmem. Abili-time had slightly lower temporal stability. The temporal stability of Abili-mathmem was not confirmed. Significant correlations were obtained between the results of the developed tools with measures measuring similar constructs.

CONCLUSIONS: The conducted research confirms the validity and reliability of Abili-time, Abili-select and Abili-space. Further work is needed on working memory tests, which are noteworthy due to the lack of other tools available on the market to test these functions. Further research should involve more people as well as carrying out standardization work. Med Pr. 2023;74(2):103-18.}, } @article {pmid37163440, year = {2023}, author = {Zeng, R and Wang, J and Jiang, R and Yang, J and Zheng, C and Wu, H and Zhuo, Z and Yang, Q and Li, J and Leung, FW and Sha, W and Chen, H}, title = {Investigating Causality and Shared Genetic Architecture between Neurodegenerative Disorders and Inflammatory Bowel Disease.}, journal = {Aging and disease}, volume = {14}, number = {4}, pages = {1349-1359}, pmid = {37163440}, issn = {2152-5250}, abstract = {Published observational studies have revealed the connection between neurodegenerative disorders and inflammatory bowel disease (IBD), whereas the causal association remains largely unclear. Our study aims to assess the causality and identify the shared genetic architecture between neurodegenerative disorders and IBD. Two-sample Mendelian randomization analyses were performed to assess the causality between IBD and neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], Parkinson's disease [PD], and multiple sclerosis [MS]). Shared genetic loci, functional interpretation, and transcriptomic profiles were further investigated in ALS and IBD. We identified that genetic predisposition to IBD was suggestively associated with lower odds of ALS (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.94 to 0.99). In contrast, IBD was not genetically associated with an increased risk of AD, PD, or MS (and vice versa). Two shared genetic loci (rs6571361 and rs7154847) were derived, and SCFD1, G2E3, and HEATR5A were further identified as novel risk genes with enriched functions related to membrane trafficking. G2E3 was differentially expressed and significantly correlated with SCFD1 in patients with ALS or IBD. Our study reveals the suggestively protective role of IBD on ALS, and does not support the causality of AD, PD, or MS on IBD (and vice versa). Our findings indicate possible shared genetic architecture and pathways between ALS and IBD. These results provide insights into the pathogenesis and therapeutics of IBD and neurodegenerative disorders.}, } @article {pmid37163838, year = {2023}, author = {Zhang, Y and Ren, R and Yang, L and Nie, Y and Zhang, H and Shi, Y and Sanford, LD and Vitiello, MV and Tang, X}, title = {Sleep in amyotrophic lateral sclerosis: A systematic review and meta-analysis of polysomnographic findings.}, journal = {Sleep medicine}, volume = {107}, number = {}, pages = {116-125}, doi = {10.1016/j.sleep.2023.04.014}, pmid = {37163838}, issn = {1878-5506}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Polysomnography ; Sleep ; Sleep, REM ; Sleep Latency ; }, abstract = {BACKGROUND: This study explores the polysomnographic differences between amyotrophic lateral sclerosis (ALS) patients and healthy controls.

METHODS: An electronic literature search was conducted in MEDLINE, EMBASE, All EBM databases, Web of Science, and CNKI from inception to Oct 2022.

RESULTS: Meta-analyses revealed significant reductions in sleep efficiency, total sleep time, N2%, slow wave sleep percentage, minimum SpO2, and mean SpO2, and increases in wake time after sleep onset and N1%, sleep latency, rapid eye movement sleep latency, time spent with SpO2 < 90%, oxygen desaturation index, and apnea hypopnea index in ALS patients compared with controls. Sensitivity analyses showed that some heterogeneity was explained by excluding patients taking medications impacting sleep, whether studies employed an adaptation night, and the use of different PSG scoring rules.

CONCLUSIONS: Significant polysomnographic abnormalities are present in ALS. Our findings underscore the need for a comprehensive PSG assessment of sleep changes in ALS patients. When performing PSG examinations in ALS, whether the patients are taking medication impacting sleep and the scoring system used should be considered.}, } @article {pmid37164288, year = {2023}, author = {Rich, KA and Pino, MG and Yalvac, ME and Fox, A and Harris, H and Balch, MHH and Arnold, WD and Kolb, SJ}, title = {Impaired motor unit recovery and maintenance in a knock-in mouse model of ALS-associated Kif5a variant.}, journal = {Neurobiology of disease}, volume = {182}, number = {}, pages = {106148}, pmid = {37164288}, issn = {1095-953X}, support = {R03 NS116303/NS/NINDS NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Kinesins/genetics/metabolism ; *Neurodegenerative Diseases ; Mice, Inbred C57BL ; Microtubule-Associated Proteins ; Disease Models, Animal ; *Peripheral Nervous System Diseases ; Mutant Proteins ; }, abstract = {Kinesin family member 5A (KIF5A) is an essential, neuron-specific microtubule-associated motor protein responsible for the anterograde axonal transport of various cellular cargos. Loss of function variants in the N-terminal, microtubule-binding domain are associated with hereditary spastic paraplegia and hereditary motor neuropathy. These variants result in a loss of the ability of the mutant protein to process along microtubules. Contrastingly, gain of function splice-site variants in the C-terminal, cargo-binding domain of KIF5A are associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disease involving death of upper and lower motor neurons, ultimately leading to degradation of the motor unit (MU; an alpha motor neuron and all the myofibers it innervates) and death. These ALS-associated variants result in loss of autoinhibition, increased procession of the mutant protein along microtubules, and altered cargo binding. To study the molecular and cellular consequences of ALS-associated variants in vivo, we introduced the murine homolog of an ALS-associated KIF5A variant into C57BL/6 mice using CRISPR-Cas9 gene editing which produced mutant Kif5a mRNA and protein in neuronal tissues of heterozygous (Kif5a[+/c.3005+1G>A]; HET) and homozygous (Kif5a[c.3005+1G>A/c.3005+1G>A]; HOM) mice. HET and HOM mice appeared normal in behavioral and electrophysiological (compound muscle action potential [CMAP] and MU number estimation [MUNE]) outcome measures at one year of age. When subjected to sciatic nerve injury, HET and HOM mice have delayed and incomplete recovery of the MUNE compared to wildtype (WT) mice suggesting an impairment in MU repair. Moreover, aged mutant Kif5a mice (aged two years) had reduced MUNE independent of injury, and exacerbation of the delayed and incomplete recovery after injury compared to aged WT mice. These data suggest that ALS-associated variants may result in an impairment of the MU to respond to biological challenges such as injury and aging, leading to a failure of MU repair and maintenance. In this report, we present the behavioral, electrophysiological and pathological characterization of mice harboring an ALS-associated Kif5a variant to understand the functional consequences of KIF5A C-terminal variants in vivo.}, } @article {pmid37165712, year = {2023}, author = {Kiernan, MC and Park, SB}, title = {Hyperexcitability, neurodegeneration, and disease progression in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {68}, number = {2}, pages = {103-105}, doi = {10.1002/mus.27843}, pmid = {37165712}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Motor Neurons ; Electromyography ; Disease Progression ; }, } @article {pmid37166702, year = {2023}, author = {Malar, DS and Thitilertdecha, P and Ruckvongacheep, KS and Brimson, S and Tencomnao, T and Brimson, JM}, title = {Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders.}, journal = {CNS drugs}, volume = {37}, number = {5}, pages = {399-440}, pmid = {37166702}, issn = {1179-1934}, mesh = {Humans ; *Receptors, sigma/metabolism/therapeutic use ; *Amyotrophic Lateral Sclerosis ; Neurons/metabolism ; *Huntington Disease ; *Neurodevelopmental Disorders/drug therapy/metabolism ; }, abstract = {The sigma-1 receptor is a 223 amino acid-long protein with a recently identified structure. The sigma-2 receptor is a genetically unrelated protein with a similarly shaped binding pocket and acts to influence cellular activities similar to the sigma-1 receptor. Both proteins are highly expressed in neuronal tissues. As such, they have become targets for treating neurological diseases, including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), multiple sclerosis (MS), Rett syndrome (RS), developmental and epileptic encephalopathies (DEE), and motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). In recent years, there have been many pre-clinical and clinical studies of sigma receptor (1 and 2) ligands for treating neurological disease. Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. Furthermore, several sigma-2 receptor ligands are under investigation, including CT1812, rivastigmine and SAS0132. This review aims to provide a current and up-to-date analysis of the current clinical and pre-clinical data of drugs with sigma receptor activities for treating neurological disease.}, } @article {pmid37166887, year = {2023}, author = {Kekenadze, M and Nebadze, E and Kvirkvelia, N and Keratishvili, D and Vashadze, S and Kvaratskhelia, E and Beridze, M}, title = {RISK FACTORS OF AMYOTROPHIC LATERAL SCLEROSIS IN GEORGIA.}, journal = {Georgian medical news}, volume = {}, number = {336}, pages = {91-94}, pmid = {37166887}, issn = {1512-0112}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/etiology/diagnosis ; Georgia (Republic)/epidemiology ; Risk Factors ; Environmental Exposure/adverse effects ; *Craniocerebral Trauma/complications ; }, abstract = {Objective - to identify risk factors in patients diagnosed with Amyotrophic Lateral Sclerosis in Georgia directed to The First University Clinic of TSMU and P. Sarajishvili Institute of Neurology. Totally 53 patients, aged 24 to 82 years, were investigated with Amyotrophic Lateral Sclerosis (ALS), defined by "Gold Coast " criteria. We have used the Questionnaire for Environmental Exposures, Toxins, and Neurological diseases developed by Dartmouth-Hitchcock Medical center to identify risk factors, and categorized patients according to the place of settlement and environmental hazards. The control consisted of age and sex matched 50 healthy individuals. The brain was visualized by MRI (1.5T), and Electromyography (EMG) was performed on all patients. ALS risk was higher among those ever holding a job in mechanics, painting, or construction (p<0.05), head trauma or concussion that caused a "blackout" or loss of consciousness was associated with a higher risk of ALS (p<0.01). Demographically more ALS cases were found in Tbilisi and Imereti, compared to other regions (p<0.05). According to our research on Georgian ALS cases, several occupational jobs, Head trauma is associated with developing ALS in Georgia, Research is needed to identify environmental risk factors attributing to higher rates of ALS in Tbilisi and Imereti.}, } @article {pmid37167080, year = {2023}, author = {Gold, ND and Mallard, AJ and Hermann, JC and Zeifman, RJ and Pagni, BA and Bogenschutz, MP and Ross, S}, title = {Exploring the Potential Utility of Psychedelic Therapy for Patients With Amyotrophic Lateral Sclerosis.}, journal = {Journal of palliative medicine}, volume = {26}, number = {10}, pages = {1408-1418}, doi = {10.1089/jpm.2022.0604}, pmid = {37167080}, issn = {1557-7740}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Hallucinogens/therapeutic use ; *Neurodegenerative Diseases ; *Motor Neuron Disease ; *Ketamine ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is an aggressive, terminal neurodegenerative disease that causes death of motor neurons and has an average survival time of 3-4 years. ALS is the most common motor neuron degenerative disease and is increasing in prevalence. There is a pressing need for more effective ALS treatments as available pharmacotherapies do not reverse disease progression or provide substantial clinical benefit. Furthermore, despite psychological distress being highly prevalent in ALS patients, psychological treatments remain understudied. Psychedelics (i.e., serotonergic psychedelics and related compounds like ketamine) have seen a resurgence of research into therapeutic applications for treating a multitude of neuropsychiatric conditions, including psychiatric and existential distress in life-threatening illnesses. Methods: We conducted a narrative review to examine the potential of psychedelic assisted-psychotherapy (PAP) to alleviate psychiatric and psychospiritual distress in ALS. We also discussed the safety of using psychedelics in this population and proposed putative neurobiological mechanisms that may therapeutically intervene on ALS neuropathology. Results: PAP has the potential to treat psychological dimensions and may also intervene on neuropathological dimensions of ALS. Robust improvements in psychiatric and psychospiritual distress from PAP in other populations provide a strong rationale for utilizing this therapy to treat ALS-related psychiatric and existential distress. Furthermore, relevant neuroprotective properties of psychedelics warrant future preclinical trials to investigate this area in ALS models. Conclusion: PAP has the potential to serve as an effective treatment in ALS. Given the lack of effective treatment options, researchers should rigorously explore this therapy for ALS in future trials.}, } @article {pmid37168679, year = {2023}, author = {Yang, X and Ma, Z and Lian, P and Xu, Y and Cao, X}, title = {Common mechanisms underlying axonal transport deficits in neurodegenerative diseases: a mini review.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1172197}, pmid = {37168679}, issn = {1662-5099}, abstract = {Many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are characterized by the accumulation of pathogenic proteins and abnormal localization of organelles. These pathological features may be related to axonal transport deficits in neurons, which lead to failures in pathological protein targeting to specific sites for degradation and organelle transportation to designated areas needed for normal physiological functioning. Axonal transport deficits are most likely early pathological events in such diseases and gradually lead to the loss of axonal integrity and other degenerative changes. In this review, we investigated reports of mechanisms underlying the development of axonal transport deficits in a variety of common neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease to provide new ideas for therapeutic targets that may be used early in the disease process. The mechanisms can be summarized as follows: (1) motor protein changes including expression levels and post-translational modification alteration; (2) changes in microtubules including reducing stability and disrupting tracks; (3) changes in cargoes including diminished binding to motor proteins. Future studies should determine which axonal transport defects are disease-specific and whether they are suitable therapeutic targets in neurodegenerative diseases.}, } @article {pmid37168926, year = {2023}, author = {Duan, QQ and Jiang, Z and Su, WM and Gu, XJ and Wang, H and Cheng, YF and Cao, B and Gao, X and Wang, Y and Chen, YP}, title = {Risk factors of amyotrophic lateral sclerosis: a global meta-summary.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1177431}, pmid = {37168926}, issn = {1662-4548}, abstract = {BACKGROUND: The etiology of amyotrophic lateral sclerosis (ALS) remains largely unknown. This study aimed to summarize the relationship between ALS and its genetic and non-genetic risk factors.

METHOD: A search of relevant literature from PubMed, Embase, and Cochrane Database from inception to December 2022 was performed. Random-effects or fixed-effects models were performed by Stata MP 15.0 to pool multivariate or adjusted ratios (OR). PROSPERO registration number: CRD42022301549.

RESULTS: 230 eligible studies were included, of which 67 involved 22 non-genetic factors, and 163 involved genetic factors. Four aspects of non-genetic factors, including lifestyle, environmental and occupational exposures, pre-existing diseases/comorbidity and medical exposures, and others, were analyzed. Exposure to heavy metals (OR = 1.79), pesticides (OR = 1.46), solvents (OR = 1.37), previous head trauma (OR = 1.37), military service (OR = 1.29), stroke (OR = 1.26), magnetic field (OR = 1.22) and hypertension (OR = 1.04) are significant risk factors, but use of antidiabetics (OR = 0.52), high BMI (OR = 0.60 for obese and overweight vs. normal and underweight), living in urban (OR = 0.70), diabetes mellitus (OR = 0.83), and kidney disease (OR = 0.84) decrease the risk for ALS. In addition, eight common ALS-related genes were evaluated, the mutation frequencies of these genes were ranked from highest to lowest as SOD1 (2.2%), C9orf72 (2.1%), ATXN2 (1.7%), FUS (1.7%), TARDBP (0.8%), VCP (0.6%), UBQLN2(0.6%) and SQSTM1 (0.6%) in all the ALS patients.

CONCLUSIONS: Our findings suggested that effective intervention for risk exposure and timely modification of lifestyle might prevent the occurrence of ALS. Genetic mutations are important risk factors for ALS and it is essential to detect genetic mutations correctly and scientifically.

https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=301549, identifier: CRD42022301549.}, } @article {pmid37170789, year = {2023}, author = {Kim, YS and Park, DG and Kim, MS and Yoon, JH}, title = {Deep brain stimulation in Parkinson disease with valosin-containing protein gene mutation.}, journal = {European journal of neurology}, volume = {30}, number = {8}, pages = {2583-2586}, doi = {10.1111/ene.15824}, pmid = {37170789}, issn = {1468-1331}, mesh = {Humans ; Valosin Containing Protein/genetics ; *Parkinson Disease/genetics/therapy ; *Deep Brain Stimulation ; Mutation ; *Frontotemporal Dementia/genetics/therapy ; *Muscular Diseases ; Cell Cycle Proteins/genetics ; *Osteitis Deformans/genetics ; }, abstract = {BACKGROUND AND PURPOSE: Mutations in the gene encoding valosin-containing protein (VCP) are related to myriad medical conditions, including familial amyotrophic lateral sclerosis, inclusion body myopathy, and frontotemporal dementia. There are several reports of a link between these mutations and early onset Parkinson disease (PD).

CASE DESCRIPTION: We report a 53-year-old PD patient with VCP mutation who later developed motor complications, thus receiving subthalamic nucleus deep brain stimulation (DBS) at the age of 56 years. However, myopathy emerged 1.5 years after surgery.

CONCLUSIONS: With the phenotype variability of VCP, DBS should be carefully evaluated, considering the possible unfavorable long-term outcomes due to other symptoms of this mutation.}, } @article {pmid37170865, year = {2023}, author = {Baugh, SD and Morrice, JR and Reitz, AB and Shaw, CA and Gregory-Evans, CY}, title = {Levamisole derivatives as immune modulators for the treatment of amyotrophic lateral sclerosis (ALS).}, journal = {Future medicinal chemistry}, volume = {15}, number = {8}, pages = {651-659}, doi = {10.4155/fmc-2023-0028}, pmid = {37170865}, issn = {1756-8927}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Levamisole/pharmacology/therapeutic use ; Cytokines/metabolism ; Tetramisole/therapeutic use ; }, abstract = {Aim: To discover derivatives of the anthelmintic drug levamisole, which has been reported to possess immune-modulatory properties, as treatments for amyotrophic lateral sclerosis (ALS), which has been suggested to be in part an autoimmune disease. Results: We have synthesized ten analogs of the racemic version of levamisole, tetramisole, as well as eleven analogs on a related system. All of the analogs have been tested for their ability to affect the response of five ALS-relevant cytokines. Conclusion: We have discovered a number of interesting derivatives that have encouraging cytokine response data and good metabolic stability, with the potential to have a positive impact on ALS either as single agents, or in combination.}, } @article {pmid37171577, year = {2023}, author = {Zhao, B and Jiang, Q and Lin, J and Wei, Q and Li, C and Hou, Y and Cao, B and Zhang, L and Ou, R and Liu, K and Yang, T and Xiao, Y and Huang, R and Shang, H}, title = {Genetic and Phenotypic Spectrum of Amyotrophic Lateral Sclerosis Patients with CCNF Variants from a Large Chinese Cohort.}, journal = {Molecular neurobiology}, volume = {60}, number = {7}, pages = {4150-4160}, pmid = {37171577}, issn = {1559-1182}, support = {2020YJ0457//Sichuan Science and Technology Program/ ; 2022ZDZX0023//Sichuan Science and Technology Program/ ; 82101485//National Natural Science Foundation of China/ ; 2021-YF05-00242-SN//Science and Technology commission foundation of Chengdu City/ ; }, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/genetics ; East Asian People ; *Frontotemporal Dementia/genetics ; Genetic Association Studies ; Mutation, Missense/genetics ; Mutation ; Cyclins ; }, abstract = {Cyclin F (CCNF) variants have been found to be associated with amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). However, the genetic and clinical characteristics of ALS patients who carry CCNF variants are largely unknown. Genetic analysis was performed for 1587 Chinese ALS patients, and missense variants were predicted by software analyses. Additionally, we searched PubMed, Embase, and Web of Science for relevant literature and conducted a meta-analysis of the frequency of variants. In our ALS cohort, we identified 29 nonsynonymous variants in 41 ALS patients. Among these ALS patients, 18 (1.1%) were carriers of 15 rare missense variants that were considered probably pathogenic variants, and 11 of 15 variants were novel. Seven relevant studies were identified, and a total of 43 CCNF variants in 59 ALS patients with a frequency of 0.8% were reported. The ratio of males to females in our cohort (10/8) was similar to that in Caucasian populations (4/7) and significantly higher than that in Asian populations (10/1). The proportion of bulbar onset in Caucasian CCNF carriers was similar to our cohort (25.0 vs. 27.8%); however, bulbar onset had never been reported in previous Asian studies (0/11). FTD was not found in CCNF carriers in previous Asian studies and our cohort, but it has been reported in a FALS cohort (1/75) of Caucasian individuals. There were some differences in the clinical characteristics among different ethnic ALS populations. More basic scientific studies are needed to elucidate the pathogenic mechanisms and genotype-phenotype associations of CCNF variants.}, } @article {pmid37173134, year = {2023}, author = {White, LM and Boardman, J and Lilleker, J and Chaouch, A and Kargwell, H and Ealing, J and Hamdalla, H}, title = {Phenotypical differences of C9ORF72 gene-positive and negative amyotrophic lateral sclerosis: a comparative case series.}, journal = {Journal of medical genetics}, volume = {60}, number = {10}, pages = {1016-1020}, doi = {10.1136/jmg-2022-109016}, pmid = {37173134}, issn = {1468-6244}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; C9orf72 Protein/genetics ; *Cognitive Dysfunction ; Precision Medicine ; Retrospective Studies ; }, abstract = {BACKGROUND: Hexanucleotide repeat expansions of C9ORF72 account for a significant proportion of autosomal dominant neurodegenerative diseases in the amyotrophic lateral sclerosis (ALS)-frontotemporal dementia spectrum. In the absence of a family history, clinical identification of such patients remains difficult. We aimed to identify differences in demographics and clinical presentation between patients with C9ORF72 gene-positive ALS (C9pALS) versus C9ORF72 gene-negative ALS (C9nALS), to aid identification of these patients in the clinic and examine differences in outcomes including survival.

METHODS: We retrospectively reviewed the clinical presentations of 32 patients with C9pALS and compared their characteristics with a cohort of 46 patients with C9nALS from the same tertiary neurosciences centre.

RESULTS: Patients with C9pALS more commonly presented with mixed upper and lower motor signs (C9pALS 87.5%, C9nALS 65.2%; p=0.0352), but less frequently presented with purely upper motor neuron signs (C9pALS 3.1%, C9nALS 21.7%; p=0.0226). The C9pALS cohort had a higher frequency of cognitive impairment (C9pALS 31.3%, C9nALS 10.9%; p=0.0394) and bulbar disease (C9pALS 56.3%, C9nALS 28.3%; p=0.0186). There were no differences between cohorts in age at diagnosis, gender, limb weakness, respiratory symptoms, presentation with predominantly lower motor neuron signs or overall survival.

DISCUSSION: Analysis of this ALS clinic cohort at a UK tertiary neurosciences centre adds to the small but growing understanding of the unique clinical features of patients with C9pALS. In the age of precision medicine with expanding opportunities to manage genetic diseases with disease-modifying therapies, clinical identification of such patients is increasingly important as focused therapeutic strategies become available.}, } @article {pmid37174628, year = {2023}, author = {Rajaratnam, S and Soman, AP and Phalguna, KS and Pradhan, SS and Manjunath, M and Rao, RK and Dandamudi, RB and Bhagavatham, SKS and Pulukool, SK and Rathnakumar, S and Kocherlakota, S and Pargaonkar, A and Veeranna, RP and Arumugam, N and Almansour, AI and Choudhary, B and Sivaramakrishnan, V}, title = {Integrated Omic Analysis Delineates Pathways Modulating Toxic TDP-43 Protein Aggregates in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {9}, pages = {}, pmid = {37174628}, issn = {2073-4409}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Protein Aggregates ; Saccharomyces cerevisiae/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Fatty Acids ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multi-systemic, incurable, amyloid disease affecting the motor neurons, resulting in the death of patients. The disease is either sporadic or familial with SOD1, C9orf72, FUS, and TDP-43 constituting the majority of familial ALS. Multi-omics studies on patients and model systems like mice and yeast have helped in understanding the association of various signaling and metabolic pathways with the disease. The yeast model system has played a pivotal role in elucidating the gene amyloid interactions. We carried out an integrated transcriptomic and metabolomic analysis of the TDP-43 expressing yeast model to elucidate deregulated pathways associated with the disease. The analysis shows the deregulation of the TCA cycle, single carbon metabolism, glutathione metabolism, and fatty acid metabolism. Transcriptomic analysis of GEO datasets of TDP-43 expressing motor neurons from mice models of ALS and ALS patients shows considerable overlap with experimental results. Furthermore, a yeast model was used to validate the obtained results using metabolite addition and gene knock-out experiments. Taken together, our result shows a potential role for the TCA cycle, cellular redox pathway, NAD metabolism, and fatty acid metabolism in disease. Supplementation of reduced glutathione, nicotinate, and the keto diet might help to manage the disease.}, } @article {pmid37174703, year = {2023}, author = {Kinger, S and Dubey, AR and Kumar, P and Jagtap, YA and Choudhary, A and Kumar, A and Prajapati, VK and Dhiman, R and Mishra, A}, title = {Molecular Chaperones' Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {9}, pages = {}, pmid = {37174703}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Proteostasis ; Molecular Chaperones/metabolism ; HSP40 Heat-Shock Proteins ; Mutant Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuronal degenerative condition identified via a build-up of mutant aberrantly folded proteins. The native folding of polypeptides is mediated by molecular chaperones, preventing their pathogenic aggregation. The mutant protein expression in ALS is linked with the entrapment and depletion of chaperone capacity. The lack of a thorough understanding of chaperones' involvement in ALS pathogenesis presents a significant challenge in its treatment. Here, we review how the accumulation of the ALS-linked mutant FUS, TDP-43, SOD1, and C9orf72 proteins damage cellular homeostasis mechanisms leading to neuronal loss. Further, we discuss how the HSP70 and DNAJ family co-chaperones can act as potential targets for reducing misfolded protein accumulation in ALS. Moreover, small HSPB1 and HSPB8 chaperones can facilitate neuroprotection and prevent stress-associated misfolded protein apoptosis. Designing therapeutic strategies by pharmacologically enhancing cellular chaperone capacity to reduce mutant protein proteotoxic effects on ALS pathomechanisms can be a considerable advancement. Chaperones, apart from directly interacting with misfolded proteins for protein quality control, can also filter their toxicity by initiating strong stress-response pathways, modulating transcriptional expression profiles, and promoting anti-apoptotic functions. Overall, these properties of chaperones make them an attractive target for gaining fundamental insights into misfolded protein disorders and designing more effective therapies against ALS.}, } @article {pmid37174914, year = {2023}, author = {Rajagopalan, V and Chaitanya, KG and Pioro, EP}, title = {Quantitative Brain MRI Metrics Distinguish Four Different ALS Phenotypes: A Machine Learning Based Study.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {37174914}, issn = {2075-4418}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease whose diagnosis depends on the presence of combined lower motor neuron (LMN) and upper motor neuron (UMN) degeneration. LMN degeneration assessment is aided by electromyography, whereas no equivalent exists to assess UMN dysfunction. Magnetic resonance imaging (MRI) is primarily used to exclude conditions that mimic ALS. We have identified four different clinical/radiological phenotypes of ALS patients. We hypothesize that these ALS phenotypes arise from distinct pathologic processes that result in unique MRI signatures. To our knowledge, no machine learning (ML)-based data analyses have been performed to stratify different ALS phenotypes using MRI measures. During routine clinical evaluation, we obtained T1-, T2-, PD-weighted, diffusion tensor (DT) brain MRI of 15 neurological controls and 91 ALS patients (UMN-predominant ALS with corticospinal tract CST) hyperintensity, n = 21; UMN-predominant ALS without CST hyperintensity, n = 26; classic ALS, n = 23; and ALS patients with frontotemporal dementia, n = 21). From these images, we obtained 101 white matter (WM) attributes (including DT measures, graph theory measures from DT and fractal dimension (FD) measures using T1-weighted), 10 grey matter (GM) attributes (including FD based measures from T1-weighted), and 10 non-imaging attributes (2 demographic and 8 clinical measures of ALS). We employed classification and regression tree, Random Forest (RF) and also artificial neural network for the classifications. RF algorithm provided the best accuracy (70-94%) in classifying four different phenotypes of ALS patients. WM metrics played a dominant role in classifying different phenotypes when compared to GM or clinical measures. Although WM measures from both right and left hemispheres need to be considered to identify ALS phenotypes, they appear to be differentially affected by the degenerative process. Longitudinal studies can confirm and extend our findings.}, } @article {pmid37175665, year = {2023}, author = {Khan, AW and Farooq, M and Hwang, MJ and Haseeb, M and Choi, S}, title = {Autoimmune Neuroinflammatory Diseases: Role of Interleukins.}, journal = {International journal of molecular sciences}, volume = {24}, number = {9}, pages = {}, pmid = {37175665}, issn = {1422-0067}, support = {HN21C1058//Korea Drug Development Fund funded by the Ministry of Science and ICT; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare/ ; 2022M3A9G1014520, 2023R1A2C2003034, 2019M3D1A1078940, and 2019R1A6A1A11051471//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neuroinflammatory Diseases ; Interleukin-17 ; Interleukin-6 ; Interleukins ; Inflammation/drug therapy ; Cytokines ; Th17 Cells ; Interleukin-1/therapeutic use ; *Autoimmune Diseases ; }, abstract = {Autoimmune neuroinflammatory diseases are a group of disorders resulting from abnormal immune responses in the nervous system, causing inflammation and tissue damage. The interleukin (IL) family of cytokines, especially IL-1, IL-6, and IL-17, plays a critical role in the pathogenesis of these diseases. IL-1 is involved in the activation of immune cells, production of pro-inflammatory cytokines, and promotion of blood-brain barrier breakdown. IL-6 is essential for the differentiation of T cells into Th17 cells and has been implicated in the initiation and progression of neuroinflammation. IL-17 is a potent pro-inflammatory cytokine produced by Th17 cells that plays a crucial role in recruiting immune cells to sites of inflammation. This review summarizes the current understanding of the roles of different interleukins in autoimmune neuroinflammatory diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, neuromyelitis optica, and autoimmune encephalitis, and discusses the potential of targeting ILs as a therapeutic strategy against these diseases. We also highlight the need for further research to better understand the roles of ILs in autoimmune neuroinflammatory diseases and to identify new targets for treating these debilitating diseases.}, } @article {pmid37175765, year = {2023}, author = {Llorente, X and Esteruelas, G and Bonilla, L and Agudelo, MG and Filgaira, I and Lopez-Ramajo, D and Gong, RC and Soler, C and Espina, M and García, ML and Manils, J and Pujol, M and Sánchez-López, E}, title = {Riluzole-Loaded Nanostructured Lipid Carriers for Hyperproliferative Skin Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {9}, pages = {}, pmid = {37175765}, issn = {1422-0067}, support = {PID2021-122187NB-C32//Spanish Ministry of Science and Innovation/ ; PID2020-114477RB-I00//Spanish Ministry of Science and Innovation/ ; PID2021-126249OA-I00//Spanish Ministry of Science and Innovation/ ; }, mesh = {Humans ; Riluzole/pharmacology ; Drug Carriers ; *Nanostructures ; *Skin Diseases/metabolism ; Drug Liberation ; Lipids/pharmacology ; Particle Size ; *Nanoparticles ; Skin/metabolism ; }, abstract = {Nanocarriers, and especially nanostructured lipid carriers (NLC), represent one of the most effective systems for topical drug administration. NLCs are biodegradable, biocompatible and provide a prolonged drug release. The glutamate release inhibitor Riluzole (RLZ) is a drug currently used for amyotrophic lateral sclerosis (ALS), with anti-proliferative effects potentially beneficial for diseases with excessive cell turnover. However, RLZ possesses low water solubility and high light-sensibility. We present here optimized NLCs loaded with RLZ (RLZ-NLCs) as a potential topical treatment. RLZ-NLCs were prepared by the hot-pressure homogenization method using active essential oils as liquid lipids, and optimized using the design of experiments approach. RLZ-NLCs were developed obtaining optimal properties for dermal application (mean size below 200 nm, negative surface charge and high RLZ entrapment efficacy). In vitro release study demonstrates that RLZ-NLCs allow the successful delivery of RLZ in a sustained manner. Moreover, RLZ-NLCs are not angiogenic and are able to inhibit keratinocyte cell proliferation. Hence, a NLCs delivery system loading RLZ in combination with natural essential oils constitutes a promising strategy against keratinocyte hyperproliferative conditions.}, } @article {pmid37176144, year = {2023}, author = {Valles, SL and Singh, SK and Campos-Campos, J and Colmena, C and Campo-Palacio, I and Alvarez-Gamez, K and Caballero, O and Jorda, A}, title = {Functions of Astrocytes under Normal Conditions and after a Brain Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {9}, pages = {}, pmid = {37176144}, issn = {1422-0067}, mesh = {Humans ; Rats ; Animals ; *Astrocytes/pathology ; Neuroglia/pathology ; Neurons/pathology ; Microglia/physiology ; *Alzheimer Disease/pathology ; }, abstract = {In the central nervous system (CNS) there are a greater number of glial cells than neurons (between five and ten times more). Furthermore, they have a greater number of functions (more than eight functions). Glia comprises different types of cells, those of neural origin (astrocytes, radial glia, and oligodendroglia) and differentiated blood monocytes (microglia). During ontogeny, neurons develop earlier (at fetal day 15 in the rat) and astrocytes develop later (at fetal day 21 in the rat), which could indicate their important and crucial role in the CNS. Analysis of the phylogeny reveals that reptiles have a lower number of astrocytes compared to neurons and in humans this is reversed, as there have a greater number of astrocytes compared to neurons. These data perhaps imply that astrocytes are important and special cells, involved in many vital functions, including memory, and learning processes. In addition, astrocytes are involved in different mechanisms that protect the CNS through the production of antioxidant and anti-inflammatory proteins and they clean the extracellular environment and help neurons to communicate correctly with each other. The production of inflammatory mediators is important to prevent changes in brain homeostasis. On the contrary, excessive, or continued production appears as a characteristic element in many diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and in neurodevelopmental diseases, such as bipolar disorder, schizophrenia, and autism. Furthermore, different drugs and techniques have been developed to reverse oxidative stress and/or excess of inflammation that occurs in many CNS diseases, but much remains to be investigated. This review attempts to highlight the functional relevance of astrocytes in normal and neuropathological conditions by showing the molecular and cellular mechanisms of their role in the CNS.}, } @article {pmid37177801, year = {2023}, author = {Miura, M and Sakaue, F and Matsuno, H and Morita, K and Yoshida, A and Hara, RI and Nishimura, R and Nishida, Y and Yokogawa, M and Osawa, M and Yokota, T}, title = {TDP-43 N-terminal domain dimerisation or spatial separation by RNA binding decreases its propensity to aggregate.}, journal = {FEBS letters}, volume = {597}, number = {12}, pages = {1667-1676}, doi = {10.1002/1873-3468.14635}, pmid = {37177801}, issn = {1873-3468}, mesh = {Humans ; DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Lobar Degeneration/metabolism ; Inclusion Bodies/metabolism ; RNA/genetics/metabolism ; }, abstract = {Aggregation of the 43 kDa TAR DNA-binding protein (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RNA binding and TDP-43 N-terminal domain dimerisation has been suggested to ameliorate TDP-43 aggregation. However, the relationship between these factors and the solubility of TDP-43 is largely unknown. Therefore, we developed new oligonucleotides that can recruit two TDP-43 molecules and interfere with their intermolecular interactions via spatial separation. Using these oligonucleotides and TDP-43-preferable UG-repeats, we uncovered two distinct mechanisms for modulating TDP-43 solubility by RNA binding: One is N-terminal domain dimerisation, and the other is the spatial separation of two TDP-43 molecules. This study provides new molecular insights into the regulation of TDP-43 solubility.}, } @article {pmid37178170, year = {2023}, author = {Bede, P and Lulé, D and Müller, HP and Tan, EL and Dorst, J and Ludolph, AC and Kassubek, J}, title = {Presymptomatic grey matter alterations in ALS kindreds: a computational neuroimaging study of asymptomatic C9orf72 and SOD1 mutation carriers.}, journal = {Journal of neurology}, volume = {270}, number = {9}, pages = {4235-4247}, pmid = {37178170}, issn = {1432-1459}, support = {HRB EIA-2017-019/HRBI_/Health Research Board/Ireland ; JPND-Cofund-2-2019-1/HRBI_/Health Research Board/Ireland ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; Bayes Theorem ; C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics ; Gray Matter/diagnostic imaging ; Magnetic Resonance Imaging ; Mutation ; Neuroimaging ; Prospective Studies ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: The characterisation of presymptomatic disease-burden patterns in asymptomatic mutation carriers has a dual academic and clinical relevance. The understanding of disease propagation mechanisms is of considerable conceptual interests, and defining the optimal time of pharmacological intervention is essential for improved clinical trial outcomes.

METHODS: In a prospective, multimodal neuroimaging study, 22 asymptomatic C9orf72 GGGGCC hexanucleotide repeat carriers, 13 asymptomatic subjects with SOD1, and 54 "gene-negative" ALS kindreds were enrolled. Cortical and subcortical grey matter alterations were systematically appraised using volumetric, morphometric, vertex, and cortical thickness analyses. Using a Bayesian approach, the thalamus and amygdala were further parcellated into specific nuclei and the hippocampus was segmented into anatomically defined subfields.

RESULTS: Asymptomatic GGGGCC hexanucleotide repeat carriers in C9orf72 exhibited early subcortical changes with the preferential involvement of the pulvinar and mediodorsal regions of the thalamus, as well as the lateral aspect of the hippocampus. Volumetric approaches, morphometric methods, and vertex analyses were anatomically consistent in capturing focal subcortical changes in asymptomatic C9orf72 hexanucleotide repeat expansion carriers. SOD1 mutation carriers did not exhibit significant subcortical grey matter alterations. In our study, none of the two asymptomatic cohorts exhibited cortical grey matter alterations on either cortical thickness or morphometric analyses.

DISCUSSION: The presymptomatic radiological signature of C9orf72 is associated with selective thalamic and focal hippocampal degeneration which may be readily detectable before cortical grey matter changes ensue. Our findings confirm selective subcortical grey matter involvement early in the course of C9orf72-associated neurodegeneration.}, } @article {pmid37179431, year = {2023}, author = {Bertrand, E and Demongin, C and Dobra, I and Rengifo-Gonzalez, JC and Singatulina, AS and Sukhanova, MV and Lavrik, OI and Pastré, D and Hamon, L}, title = {FUS fibrillation occurs through a nucleation-based process below the critical concentration required for liquid-liquid phase separation.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {7772}, pmid = {37179431}, issn = {2045-2322}, mesh = {Humans ; RNA, Messenger/metabolism ; *Prions/metabolism ; *Neurodegenerative Diseases/metabolism ; Cytoplasm/metabolism ; Phosphorylation ; RNA-Binding Protein FUS/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {FUS is an RNA-binding protein involved in familiar forms of ALS and FTLD that also assembles into fibrillar cytoplasmic aggregates in some neurodegenerative diseases without genetic causes. The self-adhesive prion-like domain in FUS generates reversible condensates via the liquid-liquid phase separation process (LLPS) whose maturation can lead to the formation of insoluble fibrillar aggregates in vitro, consistent with the appearance of cytoplasmic inclusions in ageing neurons. Using a single-molecule imaging approach, we reveal that FUS can assemble into nanofibrils at concentrations in the nanomolar range. These results suggest that the formation of fibrillar aggregates of FUS could occur in the cytoplasm at low concentrations of FUS, below the critical ones required to trigger the liquid-like condensate formation. Such nanofibrils may serve as seeds for the formation of pathological inclusions. Interestingly, the fibrillation of FUS at low concentrations is inhibited by its binding to mRNA or after the phosphorylation of its prion-like domain, in agreement with previous models.}, } @article {pmid37179826, year = {2023}, author = {Casanova, A and Wevers, A and Navarro-Ledesma, S and Pruimboom, L}, title = {Mitochondria: It is all about energy.}, journal = {Frontiers in physiology}, volume = {14}, number = {}, pages = {1114231}, pmid = {37179826}, issn = {1664-042X}, abstract = {Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron and calcium homeostasis to the production of hormones and neurotransmitters, such as melatonin. They enable and influence communication at all physical levels through interaction with other organelles, the nucleus, and the outside environment. The literature suggests crosstalk mechanisms between mitochondria and circadian clocks, the gut microbiota, and the immune system. They might even be the hub supporting and integrating activity across all these domains. Hence, they might be the (missing) link in both health and disease. Mitochondrial dysfunction is related to metabolic syndrome, neuronal diseases, cancer, cardiovascular and infectious diseases, and inflammatory disorders. In this regard, diseases such as cancer, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and chronic pain are discussed. This review focuses on understanding the mitochondrial mechanisms of action that allow for the maintenance of mitochondrial health and the pathways toward dysregulated mechanisms. Although mitochondria have allowed us to adapt to changes over the course of evolution, in turn, evolution has shaped mitochondria. Each evolution-based intervention influences mitochondria in its own way. The use of physiological stress triggers tolerance to the stressor, achieving adaptability and resistance. This review describes strategies that could recover mitochondrial functioning in multiple diseases, providing a comprehensive, root-cause-focused, integrative approach to recovering health and treating people suffering from chronic diseases.}, } @article {pmid37182016, year = {2023}, author = {Navarro-Esteva, J and Evora-Garcia, M and Perez-Mendoza, G}, title = {Large Pneumoperitoneum After Gastrostomy Placement in a Patient With Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {15}, number = {4}, pages = {e37298}, pmid = {37182016}, issn = {2168-8184}, abstract = {We present a 67-year-old male with amyotrophic lateral sclerosis (ALS) who developed left lower lobe atelectasis and respiratory failure caused by a large pneumoperitoneum after gastrostomy placement. The patient was successfully managed with paracentesis, postural measures, and continued application of noninvasive positive pressure ventilation (NIPPV). There is no clear evidence that links the use of NIPPV with an increased risk of pneumoperitoneum. The evacuation of air from the peritoneal cavity may help improve the respiratory mechanics in patients with diaphragmatic weakness such as the one presented.}, } @article {pmid37182071, year = {2023}, author = {Samworth, AG and Miller, K and Haswah, M and Tureanu, L and Weeks, J}, title = {Neuraxial and Regional Anesthesia in a Patient With Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Cureus}, volume = {15}, number = {4}, pages = {e37364}, pmid = {37182071}, issn = {2168-8184}, abstract = {Patients with amyotrophic lateral sclerosis (ALS) who undergo lower extremity joint arthroplasty are rarely encountered. Patients with ALS are at an increased risk for perioperative anesthetic complications. Anesthetic techniques, regional or general, present different risks to patients with ALS. The historical concern of worsening pre-existing neurologic symptoms with regional anesthesia is being re-examined in light of emerging evidence supporting its use in patients with ALS. Here, we present the successful perioperative management of a patient with severe bulbar ALS undergoing total knee arthroplasty. Despite his advanced bulbar symptoms, he was independently ambulatory with severe knee pain related to osteoarthritis. During multidisciplinary planning with the patient and his wife, it became clear that his primary perioperative concern was avoiding intubation, prolonged ventilation, and tracheostomy placement. With this in mind, we planned for a neuraxial anesthetic without intraoperative sedation, a postoperative adductor canal peripheral nerve block, and multimodal non-opioid analgesia. There were no perioperative complications. At the six-week follow-up, he experienced improved ambulation and showed no signs of worsened ALS symptoms.}, } @article {pmid37182104, year = {2023}, author = {Evangelista, BA and Cahalan, SR and Ragusa, JV and Mordant, A and Necarsulmer, JC and Perna, RJ and Ajit, T and White, K and Barker, NK and Tian, X and Cohen, S and Meeker, R and Herring, LE and Cohen, TJ}, title = {Tandem detergent-extraction and immunoprecipitation of proteinopathy: Scalable enrichment of ALS-associated TDP-43 aggregates.}, journal = {iScience}, volume = {26}, number = {5}, pages = {106645}, pmid = {37182104}, issn = {2589-0042}, support = {R01 NS108808/NS/NINDS NIH HHS/United States ; F31 NS122242/NS/NINDS NIH HHS/United States ; R01 NS105981/NS/NINDS NIH HHS/United States ; P30 CA016086/CA/NCI NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; T32 GM133364/GM/NIGMS NIH HHS/United States ; R35 GM133460/GM/NIGMS NIH HHS/United States ; R21 AG058080/AG/NIA NIH HHS/United States ; T35 AG038047/AG/NIA NIH HHS/United States ; R01 AG061188/AG/NIA NIH HHS/United States ; F30 AG072786/AG/NIA NIH HHS/United States ; }, abstract = {Transactive response DNA-binding protein of 43 kDa (TDP-43) is a highly conserved, ubiquitously expressed nucleic acid-binding protein that regulates DNA/RNA metabolism. Genetics and neuropathology studies have linked TDP-43 to several neuromuscular and neurological disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under pathological conditions, TDP-43 mislocalizes to the cytoplasm where it forms insoluble, hyper-phosphorylated aggregates during disease progression. Here, we optimized a scalable in vitro immuno-purification strategy referred to as tandem detergent-extraction and immunoprecipitation of proteinopathy (TDiP) to isolate TDP-43 aggregates that recapitulate those identified in postmortem ALS tissue. Moreover, we demonstrate that these purified aggregates can be utilized in biochemical, proteomics, and live-cell assays. This platform offers a rapid, accessible, and streamlined approach to study ALS disease mechanisms, while overcoming many limitations that have hampered TDP-43 disease modeling and therapeutic drug discovery efforts.}, } @article {pmid37182284, year = {2023}, author = {Hosomi, A and Okachi, C and Fujiwara, Y}, title = {Human SOD1 is secreted via a conventional secretion pathway in Saccharomyces cerevisiae.}, journal = {Biochemical and biophysical research communications}, volume = {666}, number = {}, pages = {101-106}, doi = {10.1016/j.bbrc.2023.05.022}, pmid = {37182284}, issn = {1090-2104}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Secretory Pathway ; Superoxide Dismutase/genetics/metabolism ; Protein Sorting Signals/genetics ; Mutation ; }, abstract = {Soluble proteins sorted through the secretory pathway contain an N-terminal signal peptide that induces their translocation into the endoplasmic reticulum (ER) from the cytosol. However, a few proteins that lack a signal peptide are still translocated into the ER, such as SOD1. SOD1 is a causative gene of amyotrophic lateral sclerosis (ALS). A relationship has been suggested between the secretion of SOD1 and the pathogenesis of ALS; however, the transport mechanism of SOD1 remains unclear. We herein report that SOD1 was translocated into the ER lumen through the translocon Sec61 and was then secreted extracellularly. The present results indicate the potential of suppressing the secretion of SOD1 as a therapeutic target for ALS.}, } @article {pmid37182892, year = {2023}, author = {Lim, WF and Rinaldi, C}, title = {RNA Transcript Diversity in Neuromuscular Research.}, journal = {Journal of neuromuscular diseases}, volume = {10}, number = {4}, pages = {473-482}, pmid = {37182892}, issn = {2214-3602}, mesh = {Humans ; *RNA Splice Sites ; *Alternative Splicing ; RNA Splicing/genetics ; Exons ; Introns ; }, abstract = {Three decades since the Human Genome Project began, scientists have now identified more then 25,000 protein coding genes in the human genome. The vast majority of the protein coding genes (> 90%) are multi-exonic, with the coding DNA being interrupted by intronic sequences, which are removed from the pre-mRNA transcripts before being translated into proteins, a process called splicing maturation. Variations in this process, i.e. by exon skipping, intron retention, alternative 5' splice site (5'ss), 3' splice site (3'ss), or polyadenylation usage, lead to remarkable transcriptome and proteome diversity in human tissues. Given its critical biological importance, alternative splicing is tightly regulated in a tissue- and developmental stage-specific manner. The central nervous system and skeletal muscle are amongst the tissues with the highest number of differentially expressed alternative exons, revealing a remarkable degree of transcriptome complexity. It is therefore not surprising that splicing mis-regulation is causally associated with a myriad of neuromuscular diseases, including but not limited to amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD), and myotonic dystrophy type 1 and 2 (DM1, DM2). A gene's transcript diversity has since become an integral and an important consideration for drug design, development and therapy. In this review, we will discuss transcript diversity in the context of neuromuscular diseases and current approaches to address splicing mis-regulation.}, } @article {pmid37183728, year = {2024}, author = {Hu, N and Li, Y and Liu, J and Cui, L and Liu, M}, title = {Split Phenomenon of Fasciculation between Antagonistic Muscles in Amyotrophic Lateral Sclerosis: An Ultrasound Study.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {51}, number = {2}, pages = {187-195}, doi = {10.1017/cjn.2023.62}, pmid = {37183728}, issn = {0317-1671}, mesh = {Humans ; *Fasciculation/diagnostic imaging/etiology ; Muscle, Skeletal/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging ; Electromyography ; Ultrasonography ; }, abstract = {OBJECTIVE: Paresis of muscle groups in patients with amyotrophic lateral sclerosis (ALS) tends to present split phenomena. We explored the split phenomenon of fasciculation in multiple antagonistic muscle groups in ALS patients.

METHODS: One hundred and forty ALS patients and 66 non-ALS patients were included from a single ALS center. Muscle ultrasonography (MUS) was performed to detect fasciculation in elbow flexor-extensor, wrist flexor-extensor, knee flexor-extensor, and ankle flexor-extensor. Split phenomena of fasciculation between different antagonistic muscle groups were summarized, and the possible influence factors were analyzed through stratified analysis.

RESULTS: The frequency of split phenomenon of fasciculation intensity was significantly higher than those of muscle strength (26.1% vs. 7.1% for elbow flexor-extensor, 38.3% vs. 5.7% for wrist flexor-extensor, 37.9% vs. 3.0% for knee extensor-flexor, and 33.6% vs. 14.4% for ankle flexor-extensor) (P < 0.01). For muscles with 0-1 level of muscle strength (the Medical Research Council, MRC, score), significance difference in mean fasciculation intensity was observed only in ankle flexor-extensor. For muscles with 2-5 level of muscle strength, significant dissociation of fasciculation grade was common, especially among patients with slow rapid progression rate and both upper and lower motor neuron (UMN and LMN) involvement. As for non-ALS patients, no significant difference was observed in fasciculation intensity between antagonistic muscles.

CONCLUSION: Split phenomenon of fasciculation between antagonistic muscles was common and relatively specific in ALS patients. Muscle strength, progression rate, and UMN involvement were influence factors of the split phenomenon of fasciculation intensity.}, } @article {pmid37184603, year = {2023}, author = {Lefebvre-Omar, C and Liu, E and Dalle, C and d'Incamps, BL and Bigou, S and Daube, C and Karpf, L and Davenne, M and Robil, N and Jost Mousseau, C and Blanchard, S and Tournaire, G and Nicaise, C and Salachas, F and Lacomblez, L and Seilhean, D and Lobsiger, CS and Millecamps, S and Boillée, S and Bohl, D}, title = {Neurofilament accumulations in amyotrophic lateral sclerosis patients' motor neurons impair axonal initial segment integrity.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {80}, number = {6}, pages = {150}, pmid = {37184603}, issn = {1420-9071}, support = {16465//AFM-Téléthon/ ; EQU202103012581//FRM/ ; ANR-10-LABX-73//Labex Revive/ ; ALS-iPSC/AAP10//Fondation Thierry Latran/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Intermediate Filaments ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; Motor Neurons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease in adults with no curative treatment. Neurofilament (NF) level in patient' fluids have recently emerged as the prime biomarker of ALS disease progression, while NF accumulation in MNs of patients is the oldest and one of the best pathological hallmarks. However, the way NF accumulations could lead to MN degeneration remains unknown. To assess NF accumulations and study the impact on MNs, we compared MNs derived from induced pluripotent stem cells (iPSC) of patients carrying mutations in C9orf72, SOD1 and TARDBP genes, the three main ALS genetic causes. We show that in all mutant MNs, light NF (NF-L) chains rapidly accumulate in MN soma, while the phosphorylated heavy/medium NF (pNF-M/H) chains pile up in axonal proximal regions of only C9orf72 and SOD1 MNs. Excitability abnormalities were also only observed in these latter MNs. We demonstrate that the integrity of the MN axonal initial segment (AIS), the region of action potential initiation and responsible for maintaining axonal integrity, is impaired in the presence of pNF-M/H accumulations in C9orf72 and SOD1 MNs. We establish a strong correlation between these pNF-M/H accumulations, an AIS distal shift, increased axonal calibers and modified repartition of sodium channels. The results expand our understanding of how NF accumulation could dysregulate components of the axonal cytoskeleton and disrupt MN homeostasis. With recent cumulative evidence that AIS alterations are implicated in different brain diseases, preserving AIS integrity could have important therapeutic implications for ALS.}, } @article {pmid37184766, year = {2023}, author = {Ramya, V and Sarkar, N and Bhagat, S and Pradhan, RK and Varghese, AM and Nalini, A and Sathyaprabha, TN and Raju, TR and Vijayalakshmi, K}, title = {Oligodendroglia Confer Neuroprotection to NSC-34 Motor Neuronal Cells Against the Toxic Insults of Cerebrospinal Fluid from Sporadic Amyotrophic Lateral Sclerosis Patients.}, journal = {Molecular neurobiology}, volume = {60}, number = {9}, pages = {4855-4871}, pmid = {37184766}, issn = {1559-1182}, mesh = {Humans ; Animals ; Rats ; *Amyotrophic Lateral Sclerosis/metabolism ; Neuroprotection ; Cells, Cultured ; Motor Neurons/metabolism ; Spinal Cord/metabolism ; Oligodendroglia/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder with multifactorial pathomechanisms affecting not only motor neurons but also glia. Both astrocytes and microglia get activated and contribute significantly to neurodegeneration. The role of oligodendroglia in such a situation remains obscure, especially in the sporadic form of ALS (SALS), which contributes to 90% of cases. Here, we have investigated the role of oligodendroglia in SALS pathophysiology using a human oligodendroglial cell line, MO3.13, by exposing the cells to cerebrospinal fluid from SALS patients (ALS-CSF; 10% v/v for 48 h). ALS-CSF significantly reduced the viability of MO3.13 cells and down-regulated the expression of oligodendroglia-specific proteins, namely, CNPase and Olig2. Furthermore, to investigate the effect of the observed oligodendroglial changes on motor neurons, NSC-34 motor neuronal cells were co-cultured/supplemented with conditioned/spent medium of MO3.13 cells upon exposure to ALS-CSF. Live cell imaging experiments revealed protection to NSC-34 cells against ALS-CSF toxicity upon co-culture with MO3.13 cells. This was evidenced by the absence of neuronal cytoplasmic vacuolation and beading of neurites, which instead resulted in better neuronal differentiation. Enhanced lactate levels and increased expression of its transporter, MCT-1, with sustained expression of trophic factors, namely, GDNF and BDNF, by MO3.13 cells hint towards metabolic and trophic support provided by the surviving oligodendroglia. Similar metabolic changes were seen in the lumbar spinal cord oligodendroglia of rat neonates intrathecally injected with ALS-CSF. The findings indicate that oligodendroglia are indeed rescuer to the degenerating motor neurons when the astrocytes and microglia turn topsy-turvy.}, } @article {pmid37185741, year = {2023}, author = {López-Pingarrón, L and Almeida, H and Soria-Aznar, M and Reyes-Gonzales, MC and Terrón, MP and García, JJ}, title = {Role of Oxidative Stress on the Etiology and Pathophysiology of Amyotrophic Lateral Sclerosis (ALS) and Its Relation with the Enteric Nervous System.}, journal = {Current issues in molecular biology}, volume = {45}, number = {4}, pages = {3315-3332}, pmid = {37185741}, issn = {1467-3045}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons in the spinal cord, cerebral cortex, and medulla oblongata. Most patients present a clinical phenotype of classic ALS-with predominant atrophy, muscle weakness, and fasciculations-and survival of 3 to 5 years following diagnosis. In the present review, we performed a literature search to provide an update on the etiology and pathophysiological mechanisms involved in ALS. There are two types of ALS: the familial form with genetic involvement, and the sporadic form with a multifactorial origin. ALS pathophysiology is characterized by involvement of multiple processes, including oxidative stress, glutamate excitotoxicity, and neuroinflammation. Moreover, it is proposed that conditioning risk factors affect ALS development, such as susceptibility to neurodegeneration in motor neurons, the intensity of performed physical activity, and intestinal dysbiosis with involvement of the enteric nervous system, which supports the existing theories of disease generation. To improve patients' prognosis and survival, it is necessary to further deepen our understanding of the etiopathogenesis of ALS.}, } @article {pmid37186563, year = {2023}, author = {Saba, PS and Canonico, ME and Gambaro, A and Gazale, G and Piga, S and Santomauro, M and Roscio, G and , }, title = {Systematic basic and advanced resuscitation training in medical students and fellows: a proposal from the Working Group on Cardiovascular Urgences and Emergencies of the Italian Society of Cardiology.}, journal = {Journal of cardiovascular medicine (Hagerstown, Md.)}, volume = {24}, number = {Suppl 2}, pages = {e128-e133}, doi = {10.2459/JCM.0000000000001421}, pmid = {37186563}, issn = {1558-2035}, mesh = {Humans ; *Cardiology/education ; *Cardiopulmonary Resuscitation/education ; Emergencies ; *Heart Arrest/therapy ; Italy ; *Students, Medical ; }, abstract = {Sudden cardiac arrest is a leading cause of death in Europe. High-quality cardiopulmonary resuscitation (CPR) and guidelines compliance of rescuers have been associated with better outcomes after cardiac arrest. However, wide variability in attempting bystander CPR manoeuvres has been reported. Educational programmes for teaching CPR to medical students and fellows are highly advisable in this context. However, there is no homogeneity regarding the CPR education offered by academic institutions. We surveyed 208 Italian medical students and 162 fellows in cardiology regarding the educational offer and needs in CPR. Among the 11 medical schools surveyed, 8 (73%) offer basic (BLS) courses but only 3 (38%) with formal certification of 'BLS provider', while none offers advanced (ACLS/ALS) courses. Among the 30 specialization schools in cardiology surveyed, 10 (33%) offer a BLS course (6 with formal certification of 'BLS provider'), and 8 (27%) offer an ACLS/ALS course (5 with formal certification). Only a minority of students and fellows perceive themselves as highly proficient either in BLS or ACLS/ALS, although most of the fellows were involved at least once in rescuing a cardiac arrest. The present position paper analyses and suggests the strategies that should be adopted by Italian medical and specialization schools to spread the CPR culture and increase the long-standing retention of CPR-related technical and nontechnical skills.}, } @article {pmid37186678, year = {2024}, author = {Samanta, S and Chakraborty, S and Bagchi, D}, title = {Pathogenesis of Neurodegenerative Diseases and the Protective Role of Natural Bioactive Components.}, journal = {Journal of the American Nutrition Association}, volume = {43}, number = {1}, pages = {20-32}, doi = {10.1080/27697061.2023.2203235}, pmid = {37186678}, issn = {2769-707X}, mesh = {Humans ; *Neurodegenerative Diseases/prevention & control ; Antioxidants/therapeutic use ; Reactive Oxygen Species/metabolism ; Neuroinflammatory Diseases ; Vitamins ; Flavonoids/pharmacology ; }, abstract = {Neurodegenerative diseases are a serious problem throughout the world. There are several causes of neurodegenerative diseases; these include genetic predisposition, accumulation of misfolded proteins, oxidative stress, neuroinflammation, and excitotoxicity. Oxidative stress increases the production of reactive oxygen species (ROS) that advance lipid peroxidation, DNA damage, and neuroinflammation. The cellular antioxidant system (superoxide dismutase, catalase, peroxidase, and reduced glutathione) plays a crucial role in scavenging free radicals. An imbalance in the defensive actions of antioxidants and overproduction of ROS intensify neurodegeneration. The formation of misfolded proteins, glutamate toxicity, oxidative stress, and cytokine imbalance promote the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Antioxidants are now attractive molecules to fight against neurodegeneration. Certain vitamins (A, E, C) and polyphenolic compounds (flavonoids) show excellent antioxidant properties. Diet is the major source of antioxidants. However, diet medicinal herbs are also rich sources of numerous flavonoids. Antioxidants prevent ROS-mediated neuronal degeneration in post-oxidative stress conditions. The present review is focused on the pathogenesis of neurodegenerative diseases and the protective role of antioxidants. KEY TEACHING POINTSThis review shows that multiple factors are directly or indirectly associated with the pathogenesis of neurodegenerative diseases.Failure to cellular antioxidant capacity increases oxidative stress that intensifies neuroinflammation and disease progression.Different vitamins, carotenoids, and flavonoids, having antioxidant capacity, can be considered protective agents.}, } @article {pmid37188479, year = {2023}, author = {Gregorczyk, M and Pastore, G and Muñoz, I and Carroll, T and Streubel, J and Munro, M and Lis, P and Lange, S and Lamoliatte, F and Macartney, T and Toth, R and Brown, F and Hastie, J and Pereira, G and Durocher, D and Rouse, J}, title = {Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.}, journal = {Life science alliance}, volume = {6}, number = {7}, pages = {}, pmid = {37188479}, issn = {2575-1077}, support = {MC_UU_00018/5/MRC_/Medical Research Council/United Kingdom ; MC_UU_12016/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *DNA Repair ; Mutation/genetics ; NIMA-Related Kinase 1/genetics ; *Osteochondrodysplasias/genetics ; Phosphorylation ; Cytoskeletal Proteins ; }, abstract = {The NEK1 kinase controls ciliogenesis, mitosis, and DNA repair, and NEK1 mutations cause human diseases including axial spondylometaphyseal dysplasia and amyotrophic lateral sclerosis. C21ORF2 mutations cause a similar pattern of human diseases, suggesting close functional links with NEK1 Here, we report that endogenous NEK1 and C21ORF2 form a tight complex in human cells. A C21ORF2 interaction domain "CID" at the C-terminus of NEK1 is necessary for its association with C21ORF2 in cells, and pathogenic mutations in this region disrupt the complex. AlphaFold modelling predicts an extended binding interface between a leucine-rich repeat domain in C21ORF2 and the NEK1-CID, and our model may explain why pathogenic mutations perturb the complex. We show that NEK1 mutations that inhibit kinase activity or weaken its association with C21ORF2 severely compromise ciliogenesis, and that C21ORF2, like NEK1 is required for homologous recombination. These data enhance our understanding of how the NEK1 kinase is regulated, and they shed light on NEK1-C21ORF2-associated diseases.}, } @article {pmid37189452, year = {2023}, author = {Ruffo, P and Catalano, S and La Bella, V and Conforti, FL}, title = {Deregulation of Plasma microRNA Expression in a TARDBP-ALS Family.}, journal = {Biomolecules}, volume = {13}, number = {4}, pages = {}, pmid = {37189452}, issn = {2218-273X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *MicroRNAs/metabolism ; Mutation ; Biomarkers ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {TDP-43 intracellular aggregates are a pathogenic sign of most amyotrophic lateral sclerosis (ALS) cases. Familial ALS, brought on by TARDBP gene mutations, emphasizes the relevance of this altered protein in pathophysiology. Growing evidence suggests a role for dysregulated microRNA (miRNA) in ALS disease. Furthermore, several studies showed that miRNAs are highly stable in various biological fluids (CSF, blood, plasma, and serum), and they are expressed differentially by comparing ALS patients and controls. In 2011, our research group discovered a rare mutation in a TARDBP gene (G376D) in a large ALS Apulian family with affected members exhibiting a rapidly progressing disease. To identify potential non-invasive biomarkers of preclinical and clinical progression in the TARDBP-ALS family, we assessed the expression levels of plasma microRNAs in affected patients (n = 7) and asymptomatic mutation carriers (n = 7) compared with healthy controls (n = 13). Applying qPCR, we investigate 10 miRNAs that bind TDP-43 in vitro during their biogenesis or in their mature form, and the other nine are known to be deregulated in the disease. We highlight the potential of miR-132-5p, miR-132-3p, miR-124-3p, and miR-133a-3p expression levels in plasma as biomarkers of preclinical progression for G376D-TARDBP-associated ALS. Our research strongly supports the potential of plasma miRNAs as biomarkers for performing predictive diagnostics and identifying new therapeutic targets.}, } @article {pmid37189613, year = {2023}, author = {Wintz, K and Post, J and Langen, KJ and Willbold, D and Willuweit, A and Kutzsche, J}, title = {Oral Treatment with d-RD2RD2 Impedes Early Disease Mechanisms in SOD1*G93A Transgenic Mice but Does Not Prolong Survival.}, journal = {Biomedicines}, volume = {11}, number = {4}, pages = {}, pmid = {37189613}, issn = {2227-9059}, support = {HVF0079//Helmholtz Association/ ; INST 208 /616-1 FUGG, INST 208/794-1 FUGG//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, thus, progressing to complete muscle loss until the patient dies from respiratory arrest. The disease is not curable, and patients die approximately 2-5 years after diagnosis. Studying the underlying disease mechanisms to get access to new treatment options is, therefore, essential for patients' benefit. However, so far, only three drugs that alleviate the symptoms have been approved by the U.S. Food and Drug Administration (FDA). A new drug candidate for the treatment of ALS is the all-d-enantiomeric peptide RD2RD2. In this study, we investigated the therapeutic effect of RD2RD2 in two setups. First, we analyzed disease progression and survival in 7 week-old B6.Cg-Tg(SOD1*G93A)1Gur/J mice. Second, we confirmed the result of the survival analysis in the B6SJL-Tg(SOD1*G93A)1Gur/J mouse line. Shortly before disease onset, the mice were treated daily with an oral dose of 50 mg/kg body weight. Treatment with RD2RD2 led to a delayed disease onset and reduced motor phenotype as shown using the SHIRPA test, the splay reflex test, and the pole test, but did not affect survival. In conclusion, RD2RD2 has the ability to delay the onset of symptoms.}, } @article {pmid37189617, year = {2023}, author = {Chiarini, A and Gui, L and Viviani, C and Armato, U and Dal Prà, I}, title = {NLRP3 Inflammasome's Activation in Acute and Chronic Brain Diseases-An Update on Pathogenetic Mechanisms and Therapeutic Perspectives with Respect to Other Inflammasomes.}, journal = {Biomedicines}, volume = {11}, number = {4}, pages = {}, pmid = {37189617}, issn = {2227-9059}, support = {FUR 2020//Italian Ministry of University & Research/ ; }, abstract = {Increasingly prevalent acute and chronic human brain diseases are scourges for the elderly. Besides the lack of therapies, these ailments share a neuroinflammation that is triggered/sustained by different innate immunity-related protein oligomers called inflammasomes. Relevant neuroinflammation players such as microglia/monocytes typically exhibit a strong NLRP3 inflammasome activation. Hence the idea that NLRP3 suppression might solve neurodegenerative ailments. Here we review the recent Literature about this topic. First, we update conditions and mechanisms, including RNAs, extracellular vesicles/exosomes, endogenous compounds, and ethnic/pharmacological agents/extracts regulating NLRP3 function. Second, we pinpoint NLRP3-activating mechanisms and known NLRP3 inhibition effects in acute (ischemia, stroke, hemorrhage), chronic (Alzheimer's disease, Parkinson's disease, Huntington's disease, MS, ALS), and virus-induced (Zika, SARS-CoV-2, and others) human brain diseases. The available data show that (i) disease-specific divergent mechanisms activate the (mainly animal) brains NLRP3; (ii) no evidence proves that NLRP3 inhibition modifies human brain diseases (yet ad hoc trials are ongoing); and (iii) no findings exclude that concurrently activated other-than-NLRP3 inflammasomes might functionally replace the inhibited NLRP3. Finally, we highlight that among the causes of the persistent lack of therapies are the species difference problem in disease models and a preference for symptomatic over etiologic therapeutic approaches. Therefore, we posit that human neural cell-based disease models could drive etiological, pathogenetic, and therapeutic advances, including NLRP3's and other inflammasomes' regulation, while minimizing failure risks in candidate drug trials.}, } @article {pmid37189749, year = {2023}, author = {Reddy, VP and Aryal, P and Soni, P}, title = {RAGE Inhibitors in Neurodegenerative Diseases.}, journal = {Biomedicines}, volume = {11}, number = {4}, pages = {}, pmid = {37189749}, issn = {2227-9059}, abstract = {Nonenzymatic reactions of reducing sugars with primary amino groups of amino acids, proteins, and nucleic acids, followed by oxidative degradations would lead to the formation of advanced glycation endproducts (AGEs). The AGEs exert multifactorial effects on cell damage leading to the onset of neurological disorders. The interaction of AGEs with the receptors for advanced glycation endproducts (RAGE) contribute to the activation of intracellular signaling and the expression of the pro-inflammatory transcription factors and various inflammatory cytokines. This inflammatory signaling cascade is associated with various neurological diseases, including Alzheimer's disease (AD), secondary effects of traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and diabetic neuropathy, and other AGE-related diseases, including diabetes and atherosclerosis. Furthermore, the imbalance of gut microbiota and intestinal inflammation are also associated with endothelial dysfunction, disrupted blood-brain barrier (BBB) and thereby the onset and progression of AD and other neurological diseases. AGEs and RAGE play an important role in altering the gut microbiota composition and thereby increase the gut permeability and affect the modulation of the immune-related cytokines. The inhibition of the AGE-RAGE interactions, through small molecule-based therapeutics, prevents the inflammatory cascade of events associated with AGE-RAGE interactions, and thereby attenuates the disease progression. Some of the RAGE antagonists, such as Azeliragon, are currently in clinical development for treating neurological diseases, including AD, although currently there have been no FDA-approved therapeutics based on the RAGE antagonists. This review outlines the AGE-RAGE interactions as a leading cause of the onset of neurological diseases and the current efforts on developing therapeutics for neurological diseases based on the RAGE antagonists.}, } @article {pmid37189768, year = {2023}, author = {Vorobyov, V and Deev, A and Chaprov, K and Ustyugov, AA and Lysikova, E}, title = {Age-Related Modifications of Electroencephalogram Coherence in Mice Models of Alzheimer's Disease and Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {11}, number = {4}, pages = {}, pmid = {37189768}, issn = {2227-9059}, abstract = {UNLABELLED: Evident similarities in pathological features in aging and Alzheimer's disease (AD) raise the question of a role for natural age-related adaptive mechanisms in the prevention/elimination of disturbances in interrelations between different brain areas. In our previous electroencephalogram (EEG) studies on 5xFAD- and FUS-transgenic mice, as models of AD and amyotrophic lateral sclerosis (ALS), this suggestion was indirectly confirmed. In the current study, age-related changes in direct EEG synchrony/coherence between the brain structures were evaluated.

METHODS: In 5xFAD mice of 6-, 9-, 12-, and 18-month ages and their wild-type (WT5xFAD) littermates, we analyzed baseline EEG coherence between the cortex, hippocampus/putamen, ventral tegmental area, and substantia nigra. Additionally, EEG coherence between the cortex and putamen was analyzed in 2- and 5-month-old FUS mice.

RESULTS: In the 5xFAD mice, suppressed levels of inter-structural coherence vs. those in WT5xFAD littermates were observed at ages of 6, 9, and 12 months. In 18-month-old 5xFAD mice, only the hippocampus ventral tegmental area coherence was significantly reduced. In 2-month-old FUS vs. WTFUS mice, the cortex-putamen coherence suppression, dominated in the right hemisphere, was observed. In 5-month-old mice, EEG coherence was maximal in both groups.

CONCLUSION: Neurodegenerative pathologies are accompanied by the significant attenuation of intracerebral EEG coherence. Our data are supportive for the involvement of age-related adaptive mechanisms in intracerebral disturbances produced by neurodegeneration.}, } @article {pmid37189772, year = {2023}, author = {Barker, S and Paul, BD and Pieper, AA}, title = {Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury.}, journal = {Biomedicines}, volume = {11}, number = {4}, pages = {}, pmid = {37189772}, issn = {2227-9059}, support = {P30 AG062428/AG/NIA NIH HHS/United States ; R01 AG071512/AG/NIA NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; R01 AG065240/AG/NIA NIH HHS/United States ; T32 AG071474/AG/NIA NIH HHS/United States ; P50 DA044123/DA/NIDA NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; R21 AG073684/AG/NIA NIH HHS/United States ; RF1 AG074346/AG/NIA NIH HHS/United States ; RM1 GM142002/GM/NIGMS NIH HHS/United States ; I01 BX005976/BX/BLRD VA/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; }, abstract = {Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number of TBI survivors, the impact and awareness of this problem are growing. The mechanisms by which TBI increases the risk of developing aging-related neurodegenerative disease, however, are not completely understood. As a result, there are no protective treatments for patients. Here, we review the current literature surrounding the epidemiology and potential mechanistic relationships between brain injury and aging-related neurodegenerative disease. In addition to increasing the risk for developing all forms of dementia, the most prominent aging-related neurodegenerative conditions that are accelerated by TBI are amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease (PD), and Alzheimer's disease (AD), with ALS and FTD being the least well-established. Mechanistic links between TBI and all forms of dementia that are reviewed include oxidative stress, dysregulated proteostasis, and neuroinflammation. Disease-specific mechanistic links with TBI that are reviewed include TAR DNA binding protein 43 and motor cortex lesions in ALS and FTD; alpha-synuclein, dopaminergic cell death, and synergistic toxin exposure in PD; and brain insulin resistance, amyloid beta pathology, and tau pathology in AD. While compelling mechanistic links have been identified, significantly expanded investigation in the field is needed to develop therapies to protect TBI survivors from the increased risk of aging-related neurodegenerative disease.}, } @article {pmid37190090, year = {2023}, author = {Sanchez-Tejerina, D and Llaurado, A and Sotoca, J and Lopez-Diego, V and Vidal Taboada, JM and Salvado, M and Juntas-Morales, R}, title = {Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications.}, journal = {Cells}, volume = {12}, number = {8}, pages = {}, pmid = {37190090}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Neurodegenerative Diseases ; Prospective Studies ; Biomarkers/metabolism ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the most explored areas of research in ALS is the discovery and validation of biomarkers that can be applied to clinical practice and incorporated into the development of innovative therapies. The study of biomarkers requires an adequate theoretical and operational framework, highlighting the "fit-for-purpose" concept and distinguishing different types of biomarkers based on common terminology. In this review, we aim to discuss the current status of fluid-based prognostic and predictive biomarkers in ALS, with particular emphasis on those that are the most promising ones for clinical trial design and routine clinical practice. Neurofilaments in cerebrospinal fluid and blood are the main prognostic and pharmacodynamic biomarkers. Furthermore, several candidates exist covering various pathological aspects of the disease, such as immune, metabolic and muscle damage markers. Urine has been studied less often and should be explored for its possible advantages. New advances in the knowledge of cryptic exons introduce the possibility of discovering new biomarkers. Collaborative efforts, prospective studies and standardized procedures are needed to validate candidate biomarkers. A combined biomarkers panel can provide a more detailed disease status.}, } @article {pmid37190097, year = {2023}, author = {Dorn, GW}, title = {Reversing Dysdynamism to Interrupt Mitochondrial Degeneration in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {8}, pages = {}, pmid = {37190097}, issn = {2073-4409}, support = {R35 HL135736/HL/NHLBI NIH HHS/United States ; R35 HL135736/NH/NIH HHS/United States ; R42 NS115184/NH/NIH HHS/United States ; R42 NS113642/NH/NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Apoptosis ; Mitochondria/metabolism ; Mitochondrial Dynamics/physiology ; *Neurodegenerative Diseases/metabolism ; Humans ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis is one of several chronic neurodegenerative conditions in which mitochondrial abnormalities are posited to contribute to disease progression. Therapeutic options targeting mitochondria include enhancing metabolism, suppressing reactive oxygen production and disrupting mitochondria-mediated programmed cell death pathways. Herein is reviewed mechanistic evidence supporting a meaningful pathophysiological role for the constellation of abnormal mitochondrial fusion, fission and transport, collectively designated mitochondrial dysdynamism, in ALS. Following this is a discussion on preclinical studies in ALS mice that seemingly validate the idea that normalizing mitochondrial dynamism can delay ALS by interrupting a vicious cycle of mitochondrial degeneration, leading to neuronal die-back and death. Finally, the relative benefits of suppressing mitochondrial fusion vs. enhancing mitochondrial fusion in ALS are speculated upon, and the paper concludes with the prediction that the two approaches could be additive or synergistic, although a side-by-side comparative trial may be challenging to perform.}, } @article {pmid37190538, year = {2023}, author = {Liu, P and Xue, X and Zhang, C and Zhou, H and Ding, Z and Wang, L and Jiang, Y and Shen, W and Yang, S and Wang, F}, title = {Transcriptional Profile Changes after Noise-Induced Tinnitus in Rats.}, journal = {Brain sciences}, volume = {13}, number = {4}, pages = {}, pmid = {37190538}, issn = {2076-3425}, abstract = {Tinnitus is an unpleasant symptom characterized by detective hearing without the actual sound input. Despite numerous studies elucidating a variety of pathomechanisms inducing tinnitus, the pathophysiology of tinnitus is not fully understood. The genes that are closely associated with this subtype of the auditory hallucination that could be utilized as potential treatment targets are still unknown. In this study, we explored the transcriptional profile changes of the auditory cortex after noise-induced tinnitus in rats using high throughput sequencing and verification of the detected genes using quantitative PCR (qPCR). Tinnitus models were established by analyzing startle behaviors through gap pre-pulse inhibition (PPI) of the acoustic startle. Two hundred and fifty-nine differential genes were identified, of which 162 genes were up-regulated and 97 genes were down-regulated. Analysis of the pathway enrichment indicated that the tinnitus group exhibited increased gene expression related to neurodegenerative disorders such as Huntington's disease and Amyotrophic lateral sclerosis. Based on the identified genes, networks of protein-protein interaction were established and five hub genes were identified through degree rank, including Fos, Nr4a1, Nr4a3, Egr2, and Egr3. Therein, the Fos gene ranked first with the highest degree after noise exposure, and may be a potential target for the modulation of noise-induced tinnitus.}, } @article {pmid37190795, year = {2023}, author = {Varma, A and Weinstein, J and Seabury, J and Rosero, S and Zizzi, C and Alexandrou, D and Wagner, E and Dilek, N and Heatwole, J and Wuu, J and Caress, J and Bedlack, R and Granit, V and Statland, J and Mehta, P and Benatar, M and Kaat, A and Heatwole, C}, title = {The amyotrophic lateral sclerosis-health index (ALS-HI): development and evaluation of a novel outcome measure.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {514-522}, doi = {10.1080/21678421.2023.2204871}, pmid = {37190795}, issn = {2167-9223}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/therapy ; Reproducibility of Results ; Cross-Sectional Studies ; Disease Progression ; Outcome Assessment, Health Care ; }, abstract = {Objective: The identification of effective therapeutics for ALS necessitates valid and responsive outcome measures to track disease progression and therapeutic gain in clinical trial settings. The Amyotrophic Lateral Sclerosis-Health Index (ALS-HI) is a multifaceted, disease-specific patient-reported outcome measure (PRO) designed to measure ALS symptomatic disease burden in adults with ALS. Methods: Through a national cross-sectional study of individuals with ALS, we identified the most important symptoms in ALS. These symptoms were incorporated into the ALS-HI, a measure that quantifies the multifaceted disease burden in ALS. We performed factor analysis, qualitative patient interviews, test-retest reliability assessment, and known groups analysis to evaluate and validate the ALS-HI. Results: The cross-sectional study included 497 participants with ALS who identified the most important symptoms to include in the ALS-HI. Fifteen participants beta tested the ALS-HI and found it to be clear, easy to use, and relevant. Twenty-one participants engaged in a test-retest reliability study, which indicated the reliability of the instrument (intraclass correlation coefficient = 0.952 for full instrument). The final ALS-HI and its subscales demonstrated a high internal consistency (Cronbach's α = 0.981 for full instrument) and an ability to differentiate between groups with dissimilar disease severity. Conclusions: This research supports use of the ALS-HI as a valid, sensitive, reliable, and relevant PRO to assess the multifactorial disease burden faced by adults with ALS. The ALS-HI has potential as a mechanism to track disease progression and treatment efficacy during therapeutic trials.}, } @article {pmid37191232, year = {2023}, author = {Ding, Y and Zhao, DM and Kang, T and Shi, J and Ye, F and Fu, Y}, title = {Design, Synthesis, and Structure-Activity Relationship of Novel Aryl-Substituted Formyl Oxazolidine Derivatives as Herbicide Safeners.}, journal = {Journal of agricultural and food chemistry}, volume = {71}, number = {20}, pages = {7654-7668}, doi = {10.1021/acs.jafc.3c00467}, pmid = {37191232}, issn = {1520-5118}, mesh = {*Herbicides/chemistry ; Molecular Docking Simulation ; *Acetolactate Synthase/metabolism ; Structure-Activity Relationship ; Zea mays/chemistry ; Oxazoles ; Pyridines ; Sulfonylurea Compounds ; }, abstract = {Nicosulfuron is the leading herbicide in the global sulfonylurea (SU) herbicide market; it was jointly developed by DuPont and Ishihara. Recently, the widespread use of nicosulfuron has led to increasingly prominent agricultural production hazards, such as environmental harm and influence on subsequent crops. The use of herbicide safeners can significantly alleviate herbicide injury to protect crop plants and expand the application scope of existing herbicides. A series of novel aryl-substituted formyl oxazolidine derivatives were designed using the active group combination method. Title compounds were synthesized using an efficient one-pot method and characterized by infrared (IR) spectrometry, [1]H and [13]C nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HRMS). The chemical structure of compound V-25 was further identified by X-ray single crystallography. The bioactivity assay and structure-activity relationship proved that nicosulfuron phytotoxicity to maize could be reduced by most title compounds. The glutathione S-transferase (GST) activity and acetolactate synthase (ALS) in vivo were determined, and compound V-12 showed inspiring activity comparable to that of the commercial safener isoxadifen-ethyl. The molecular docking model indicated that compound V-12 competed with nicosulfuron for the acetolactate synthase active site and that this is the protective mechanism of safeners. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions demonstrated that compound V-12 exhibited superior pharmacokinetic properties to the commercialized safener isoxadifen-ethyl. The target compound V-12 shows strong herbicide safener activity in maize; thus, it may be a potential candidate compound that can help further protect maize from herbicide damage.}, } @article {pmid37191427, year = {2023}, author = {Huang, Y and Zhao, M and Chen, X and Zhang, R and Le, A and Hong, M and Zhang, Y and Jia, L and Zang, W and Jiang, C and Wang, J and Fan, X and Wang, J}, title = {Tryptophan Metabolism in Central Nervous System Diseases: Pathophysiology and Potential Therapeutic Strategies.}, journal = {Aging and disease}, volume = {14}, number = {3}, pages = {858-878}, pmid = {37191427}, issn = {2152-5250}, abstract = {The metabolism of L-tryptophan (TRP) regulates homeostasis, immunity, and neuronal function. Altered TRP metabolism has been implicated in the pathophysiology of various diseases of the central nervous system. TRP is metabolized through two main pathways, the kynurenine pathway and the methoxyindole pathway. First, TRP is metabolized to kynurenine, then kynurenic acid, quinolinic acid, anthranilic acid, 3-hydroxykynurenine, and finally 3-hydroxyanthranilic acid along the kynurenine pathway. Second, TRP is metabolized to serotonin and melatonin along the methoxyindole pathway. In this review, we summarize the biological properties of key metabolites and their pathogenic functions in 12 disorders of the central nervous system: schizophrenia, bipolar disorder, major depressive disorder, spinal cord injury, traumatic brain injury, ischemic stroke, intracerebral hemorrhage, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Furthermore, we summarize preclinical and clinical studies, mainly since 2015, that investigated the metabolic pathway of TRP, focusing on changes in biomarkers of these neurologic disorders, their pathogenic implications, and potential therapeutic strategies targeting this metabolic pathway. This critical, comprehensive, and up-to-date review helps identify promising directions for future preclinical, clinical, and translational research on neuropsychiatric disorders.}, } @article {pmid37191604, year = {2023}, author = {Thomson, CG and Hutchinson, PR and Stern, PJ}, title = {Misdiagnosis in Amyotrophic Lateral Sclerosis.}, journal = {The Journal of hand surgery}, volume = {48}, number = {8}, pages = {822-826}, doi = {10.1016/j.jhsa.2023.03.023}, pmid = {37191604}, issn = {1531-6564}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/surgery ; Referral and Consultation ; *Cubital Tunnel Syndrome ; Diagnostic Errors ; Neurosurgical Procedures ; }, abstract = {The symptoms of amyotrophic lateral sclerosis (ALS) can mimic those of compressive neuropathies, such as carpal and cubital tunnel syndromes, especially early in a patient's clinical course. We surveyed members of the American Society for Surgery of the Hand and found that 11% of active and retired members have performed nerve decompression surgeries on patients later diagnosed with ALS. Hand surgeons are commonly the first providers to evaluate patients with undiagnosed ALS. As such, it is important to be aware of the history, signs, and symptoms of ALS to provide an accurate diagnosis and prevent unnecessary morbidities, such as nerve decompression surgery, which invariably results in poor outcomes. The major "red flag" symptoms warranting further work-up include weakness without sensory symptoms, profound weakness and atrophy in multiple nerve distributions, progressively bilateral and global symptoms, presence of bulbar symptoms (such as tongue fasciculations and speech/swallowing difficulties), and, if surgery is performed, failure to improve. If any of these red flags are present, we recommend neurodiagnostic testing and prompt referral to a neurologist for further work-up and treatment.}, } @article {pmid37192343, year = {2023}, author = {Koretsky, MJ and Alvarado, C and Makarious, MB and Vitale, D and Levine, K and Bandres-Ciga, S and Dadu, A and Scholz, SW and Sargent, L and Faghri, F and Iwaki, H and Blauwendraat, C and Singleton, A and Nalls, M and Leonard, H}, title = {Genetic risk factor clustering within and across neurodegenerative diseases.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {11}, pages = {4486-4494}, pmid = {37192343}, issn = {1460-2156}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; RF1 AG057440/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; R01 AG018023/AG/NIA NIH HHS/United States ; U01 AG046170/AG/NIA NIH HHS/United States ; U24 AG061340/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P50 AG025711/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; R01 AG036836/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; ZIA NS003154/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; Genome-Wide Association Study ; *Parkinson Disease/genetics ; *Lewy Body Disease/genetics ; *Alzheimer Disease/genetics ; Risk Factors ; }, abstract = {Overlapping symptoms and co-pathologies are common in closely related neurodegenerative diseases (NDDs). Investigating genetic risk variants across these NDDs can give further insight into disease manifestations. In this study we have leveraged genome-wide single nucleotide polymorphisms and genome-wide association study summary statistics to cluster patients based on their genetic status across identified risk variants for five NDDs (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Lewy body dementia and frontotemporal dementia). The multi-disease and disease-specific clustering results presented here provide evidence that NDDs have more overlapping genetic aetiology than previously expected and how neurodegeneration should be viewed as a spectrum of symptomology. These clustering analyses also show potential subsets of patients with these diseases that are significantly depleted for any known common genetic risk factors suggesting environmental or other factors at work. Establishing that NDDs with overlapping pathologies share genetic risk loci, future research into how these variants might have different effects on downstream protein expression, pathology and NDD manifestation in general is important for refining and treating NDDs.}, } @article {pmid37194211, year = {2023}, author = {Wang, DJ and Shi, JC and Fan, L and Wang, RJ and Wei, F and Ma, YY and Cai, XL and Fan, SH and Liang, X and Yang, HL and Xing, K and Qiu, LJ and Lu, LJ and Li, XX and Wen, YQ and Feng, JY}, title = {Systemic Colonization of Xanthomonas fragariae Strain YL19 Causing Dry Cavity Rot of Strawberry Crown Tissue in China.}, journal = {Plant disease}, volume = {107}, number = {11}, pages = {3542-3552}, doi = {10.1094/PDIS-04-22-0783-RE}, pmid = {37194211}, issn = {0191-2917}, mesh = {*Fragaria/microbiology ; *Xanthomonas ; China ; }, abstract = {Xanthomonas fragariae usually causes angular leaf spot (ALS) of strawberry, a serious bacterial disease in many strawberry-producing regions worldwide. Recently, a new strain of X. fragariae (YL19) was isolated from strawberry in China and has been shown to cause dry cavity rot in strawberry crown. In this study, we constructed a green fluorescent protein (GFP)-labeled Xf YL19 (YL19-GFP) to visualize the infection process and pathogen colonization in strawberries. Foliar inoculation of YL19-GFP resulted in the pathogen migrating from the leaves to the crown, whereas dip inoculation of wounded crowns or roots resulted in the migration of bacteria from the crowns or roots to the leaves. These two invasion types both resulted in the systematic spread of YL19-GFP, but inoculation of a wounded crown was more harmful to the strawberry plant than foliar inoculation. Results increased our understanding of the systemic invasion of X. fragariae, and the resultant crown cavity caused by Xf YL19.}, } @article {pmid37194327, year = {2023}, author = {Gallagher, ER and Holzbaur, ELF}, title = {SQSTM1/P62 promotes lysophagy via formation of liquid-like condensates maintained by HSP27.}, journal = {Autophagy}, volume = {19}, number = {11}, pages = {3029-3030}, pmid = {37194327}, issn = {1554-8635}, support = {F31 NS125954/NS/NINDS NIH HHS/United States ; R01 NS060698/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Sequestosome-1 Protein/metabolism ; *HSP27 Heat-Shock Proteins/metabolism ; Macroautophagy ; Autophagy ; *Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {SQSTM1/p62: Sequestosome-1; HSP27: Heat shock protein 27; LLPS: liquid-liquid phase separation; iPSC: induced pluripotent stem cell; PB1: Phox and Bem1p; FRAP: fluorescence recovery after photo-bleaching; ATG: autophagy-related; ALS: amyotrophic lateral sclerosis.}, } @article {pmid37194520, year = {2023}, author = {Ogino, M}, title = {[Drugs for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {75}, number = {5}, pages = {503-506}, doi = {10.11477/mf.1416202367}, pmid = {37194520}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/therapeutic use ; *Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Japan ; }, abstract = {Riluzole and edaravone for the treatment of amyotrophic lateral sclerosis (ALS) are currently covered by insurance in Japan. Both have been shown to prolong survival and/or inhibit progression, but neither is a cure-all treatment, and the effects are difficult to realize. The data presented in clinical trials are not applicable to all patients with ALS; the risks and benefits should be explained carefully before use. So far, edaravone has been administered intravenously, but an oral form became available in Japan on April 17, 2023. For symptomatic treatment, morphine hydrochloride and morphine sulfate are insurance-covered alternatives.}, } @article {pmid37194953, year = {2023}, author = {Tejedor, AR and Collepardo-Guevara, R and Ramírez, J and Espinosa, JR}, title = {Time-Dependent Material Properties of Aging Biomolecular Condensates from Different Viscoelasticity Measurements in Molecular Dynamics Simulations.}, journal = {The journal of physical chemistry. B}, volume = {127}, number = {20}, pages = {4441-4459}, pmid = {37194953}, issn = {1520-5207}, mesh = {*Biomolecular Condensates ; *Molecular Dynamics Simulation ; Viscosity ; Amino Acid Sequence ; }, abstract = {Biomolecular condensates are important contributors to the internal organization of the cell material. While initially described as liquid-like droplets, the term biomolecular condensates is now used to describe a diversity of condensed phase assemblies with material properties extending from low to high viscous liquids, gels, and even glasses. Because the material properties of condensates are determined by the intrinsic behavior of their molecules, characterizing such properties is integral to rationalizing the molecular mechanisms that dictate their functions and roles in health and disease. Here, we apply and compare three distinct computational methods to measure the viscoelasticity of biomolecular condensates in molecular simulations. These methods are the Green-Kubo (GK) relation, the oscillatory shear (OS) technique, and the bead tracking (BT) method. We find that, although all of these methods provide consistent results for the viscosity of the condensates, the GK and OS techniques outperform the BT method in terms of computational efficiency and statistical uncertainty. We thus apply the GK and OS techniques for a set of 12 different protein/RNA systems using a sequence-dependent coarse-grained model. Our results reveal a strong correlation between condensate viscosity and density, as well as with protein/RNA length and the number of stickers vs spacers in the amino acid protein sequence. Moreover, we couple the GK and the OS technique to nonequilibrium molecular dynamics simulations that mimic the progressive liquid-to-gel transition of protein condensates due to the accumulation of interprotein β-sheets. We compare the behavior of three different protein condensates, i.e., those formed by either hnRNPA1, FUS, or TDP-43 proteins, whose liquid-to-gel transitions are associated with the onset of amyotrophic lateral sclerosis and frontotemporal dementia. We find that both the GK and OS techniques successfully predict the transition from functional liquid-like behavior to kinetically arrested states once the network of interprotein β-sheets has percolated through the condensates. Overall, our work provides a comparison of different modeling rheological techniques to assess the viscosity of biomolecular condensates, a critical magnitude that provides information on the behavior of biomolecules inside condensates.}, } @article {pmid37195983, year = {2023}, author = {Song, Y and Racette, BA and Camacho-Soto, A and Searles Nielsen, S}, title = {Biologic targets of prescription medications and risk of neurodegenerative disease in United States Medicare beneficiaries.}, journal = {PloS one}, volume = {18}, number = {5}, pages = {e0285011}, pmid = {37195983}, issn = {1932-6203}, support = {K01 ES028295/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; Aged ; United States/epidemiology ; Allopurinol/therapeutic use ; Cohort Studies ; Medicare ; *Neurodegenerative Diseases/drug therapy/epidemiology ; Case-Control Studies ; Xanthine Dehydrogenase ; *Prescription Drugs ; Prescriptions ; *Biological Products ; Retrospective Studies ; }, abstract = {OBJECTIVE: To identify prescription medications associated with a lower risk of three neurodegenerative diseases: Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis.

METHODS: We conducted a population-based, case-control study of U.S. Medicare beneficiaries in 2009 (42,885 incident neurodegenerative disease cases, 334,387 randomly selected controls). Using medication data from 2006-2007, we categorized all filled medications according to their biological targets and mechanisms of action on those targets. We used multinomial logistic regression models, while accounting for demographics, indicators of smoking, and health care utilization, to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 141 target-action pairs and each neurodegenerative disease. For target-action pairs inversely associated with all three diseases, we attempted replication in a cohort study that included an active comparator group. We constructed the cohort by following controls forward for incident neurodegenerative disease from the beginning of 2010 until death or end of 2014, i.e., up to five years after the two-year exposure lag. We used Cox proportional hazards regression while accounting for the same covariates.

RESULTS: The most consistent inverse association across both studies and all three neurodegenerative diseases was for xanthine dehydrogenase/oxidase blockers, represented by the gout medication, allopurinol. Allopurinol was associated with a 13-34% lower risk for each neurodegenerative disease group in multinomial regression, and a mean reduction of 23% overall, as compared to individuals who did not use allopurinol. In the replication cohort we observed a significant 23% reduction for neurodegenerative disease in the fifth year of follow-up, when comparing allopurinol users to non-users, and more marked associations with an active comparator group. We observed parallel associations for a related target-action pair unique to carvedilol.

DISCUSSION/CONCLUSION: Xanthine dehydrogenase/oxidase blockade might reduce risk of neurodegenerative disease. However, further research will be necessary to confirm that the associations related to this pathway are causal or to examine whether this mechanism slows progression.}, } @article {pmid37196683, year = {2023}, author = {Prasad Panda, S and Kesharwani, A and Prasanna Mallick, S and Prasanth, D and Kumar Pasala, P and Bharadwaj Tatipamula, V}, title = {Viral-induced neuronal necroptosis: Detrimental to brain function and regulation by necroptosis inhibitors.}, journal = {Biochemical pharmacology}, volume = {213}, number = {}, pages = {115591}, doi = {10.1016/j.bcp.2023.115591}, pmid = {37196683}, issn = {1873-2968}, mesh = {Humans ; *Protein Kinases/metabolism ; Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Necroptosis ; Neuroinflammatory Diseases ; Apoptosis ; Necrosis ; Caspase 1/metabolism ; Receptors, Death Domain/metabolism ; Interleukin-1/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/metabolism ; *MicroRNAs ; }, abstract = {Neuronal necroptosis (programmed necrosis) in the CNS naturally occurs through a caspase-independent way and, especially in neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parknson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and viral infections. Understanding necroptosis pathways (death receptor-dependent and independent), and its connections with other cell death pathways could lead to new insights into treatment. Receptor-interacting protein kinase (RIPK) mediates necroptosis via mixed-lineage kinase-like (MLKL) proteins. RIPK/MLKL necrosome contains FADD, procaspase-8-cellular FLICE-inhibitory proteins (cFLIPs), RIPK1/RIPK3, and MLKL. The necrotic stimuli cause phosphorylation of MLKL and translocate to the plasma membrane, causing an influx of Ca[2+] and Na[+] ions and, the immediate opening of mitochondrial permeability transition pore (mPTP) with the release of inflammatory cell damage-associated molecular patterns (DAMPs) like mitochondrial DNA (mtDNA), high-mobility group box1 (HMGB1), and interleukin1 (IL-1). The MLKL translocates to the nucleus to induce transcription of the NLRP3 inflammasome complex elements. MLKL-induced NLRP3 activity causes caspase-1 cleavage and, IL-1 activation which promotes neuroinflammation. RIPK1-dependent transcription increases illness-associated microglial and lysosomal abnormalities to facilitate amyloid plaque (Aβ) aggregation in AD. Recent research has linked neuroinflammation and mitochondrial fission with necroptosis. MicroRNAs (miRs) such as miR512-3p, miR874, miR499, miR155, and miR128a regulate neuronal necroptosis by targeting key components of necroptotic pathways. Necroptosis inhibitors act by inhibiting the membrane translocation of MLKL and RIPK1 activity. This review insights into the RIPK/MLKL necrosome-NLRP3 inflammasome interactions during death receptor-dependent and independent neuronal necroptosis, and clinical intervention by miRs to protect the brain from NDDs.}, } @article {pmid37197644, year = {2023}, author = {Dong, S and Yin, X and Wang, K and Yang, W and Li, J and Wang, Y and Zhou, Y and Liu, X and Wang, J and Chen, X}, title = {Presence of Rare Variants is Associated with Poorer Survival in Chinese Patients with Amyotrophic Lateral Sclerosis.}, journal = {Phenomics (Cham, Switzerland)}, volume = {3}, number = {2}, pages = {167-181}, pmid = {37197644}, issn = {2730-5848}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with phenotypic and genetic heterogeneity. Recent studies have suggested an oligogenic basis of ALS, in which the co-occurrence of two or more genetic variants has additive or synergistic deleterious effects. To assess the contribution of possible oligogenic inheritance, we profiled a panel of 43 relevant genes in 57 sporadic ALS (sALS) patients and eight familial ALS (fALS) patients from five pedigrees in east China. We filtered rare variants using the combination of the Exome Aggregation Consortium, the 1000 Genomes and the HuaBiao Project. We analyzed patients with multiple rare variants in 43 known ALS causative genes and the genotype-phenotype correlation. Overall, we detected 30 rare variants in 16 different genes and found that 16 of the sALS patients and all the fALS patients examined harbored at least one variant in the investigated genes, among which two sALS and four fALS patients harbored two or more variants. Of note, the sALS patients with one or more variants in ALS genes had worse survival than the patients with no variants. Typically, in one fALS pedigree with three variants, the family member with three variants (Superoxide dismutase 1 (SOD1) p.V48A, Optineurin (OPTN) p.A433V and TANK binding kinase 1 (TBK1) p.R573H) exhibited much more severe disease phenotype than the member carrying one variant (TBK1 p.R573H). Our findings suggest that rare variants could exert a negative prognostic effect, thereby supporting the oligogenic inheritance of ALS.}, } @article {pmid37200015, year = {2023}, author = {Du, EY and Jiang, K and Carlson, MC and Reed, NS and Deal, JA}, title = {Hearing Impairment and Allostatic Load in Older Adults.}, journal = {JAMA otolaryngology-- head & neck surgery}, volume = {149}, number = {7}, pages = {597-606}, pmid = {37200015}, issn = {2168-619X}, support = {K01 AG054693/AG/NIA NIH HHS/United States ; K23 AG065443/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Allostasis ; Audiometry, Pure-Tone ; Cross-Sectional Studies ; *Deafness ; *Hearing Loss/diagnosis ; Nutrition Surveys ; }, abstract = {IMPORTANCE: Allostatic load, the cumulative strain that results from the chronic stress response, is associated with poor health outcomes. Increased cognitive load and impaired communication associated with hearing loss could potentially be associated with higher allostatic load, but few studies to date have quantified this association.

OBJECTIVE: To investigate if audiometric hearing loss is associated with allostatic load and evaluate if the association varies by demographic factors.

DESIGN, SETTING, PARTICIPANTS: This cross-sectional survey used nationally representative data from the National Health and Nutrition Examination Survey. Audiometric testing was conducted from 2003 to 2004 (ages 20-69 years) and 2009 to 2010 (70 years or older). The study was restricted to participants aged 50 years or older, and the analysis was stratified based on cycle. The data were analyzed between October 2021 and October 2022.

EXPOSURE: A 4-frequency (0.5-4.0 kHz) pure tone average was calculated in the better-hearing ear and modeled continuously and categorically (<25 dB hearing level [dB HL], no hearing loss; 26-40 dB HL, mild hearing loss; ≥41 dB HL, moderate or greater hearing loss).

MAIN OUTCOME AND MEASURES: Allostatic load score (ALS) was defined using laboratory measurements of 8 biomarkers (systolic/diastolic blood pressure, body mass index [calculated as weight in kilograms divided by height in meters squared], and total serum and high-density lipoprotein cholesterol, glycohemoglobin, albumin, and C-reactive protein levels). Each biomarker was assigned a point if it was in the highest risk quartile based on statistical distribution and then summed to yield the ALS (range, 0-8). Linear regression models adjusted for demographic and clinical covariates. Sensitivity analysis included using clinical cut points for ALS and subgroup stratification.

RESULTS: In 1412 participants (mean [SD] age, 59.7 [5.9] years; 293 women [51.9%]; 130 [23.0%] Hispanic, 89 [15.8%] non-Hispanic Black, and 318 [55.3%] non-Hispanic White individuals), a modest association was suggested between hearing loss and ALS (ages 50-69 years: β = 0.19 [95% CI, 0.02-0.36] per 10 dB HL; 70 years or older: β = 0.10 [95% CI, 0.02-0.18] per 10 dB HL) among non-hearing aid users. Results were not clearly reflected in the sensitivity analysis with clinical cut points for ALS or modeling hearing loss categorically. Sex-based stratifications identified a stronger association among male individuals (men 70 years or older: β = 0.22 [95% CI, 0.12-0.32] per 10 dB HL; women: β = 0.08 [95% CI, -0.04 to 0.20] per 10 dB HL).

CONCLUSION AND RELEVANCE: The study findings did not clearly support an association between hearing loss and ALS. While hearing loss has been shown to be associated with increased risk for numerous health comorbidities, its association with the chronic stress response and allostasis may be less than that of other health conditions.}, } @article {pmid37200039, year = {2023}, author = {Behzadi, A and Tjust, AE and Liu, JX and Andersen, PM and Brännström, T and Pedrosa Domellöf, F}, title = {Myofiber Type Shift in Extraocular Muscles in Amyotrophic Lateral Sclerosis.}, journal = {Investigative ophthalmology & visual science}, volume = {64}, number = {5}, pages = {15}, pmid = {37200039}, issn = {1552-5783}, mesh = {Humans ; *Oculomotor Muscles/pathology ; *Amyotrophic Lateral Sclerosis ; Synaptophysin ; Myosin Heavy Chains ; Protein Isoforms ; }, abstract = {PURPOSE: To investigate changes in myofiber composition in the global layer (GL) and orbital layer (OL) of extraocular muscles (EOMs) from terminal amyotrophic lateral sclerosis (ALS) donors.

METHODS: Medial recti muscles collected postmortem from spinal-onset ALS, bulbar-onset ALS, and healthy control donors were processed for immunofluorescence with antibodies against myosin heavy chain (MyHC) IIa, MyHCI, MyHCeom, laminin, neurofilaments, synaptophysin, acetylcholine receptor γ-subunit, and α-bungarotoxin.

RESULTS: The proportion of myofibers containing MyHCIIa was significantly smaller and MyHCeom was significantly larger in the GL of spinal-onset ALS and bulbar-onset ALS donors compared to control donors. Changes in the GL were more prominent in the bulbar-onset ALS donors, with a significantly larger proportion of myofibers containing MyHCeom being present compared to spinal-onset ALS donors. There were no significant differences in the myofiber composition in the OL. In the spinal-onset ALS donors, the proportions of myofibers containing MyHCIIa in the GL and MyHCeom in the OL were significantly correlated with the disease duration. Neurofilament and synaptophysin were present at motor endplates of myofibers containing MyHCeom in ALS donors.

CONCLUSIONS: The EOMs of terminal ALS donors displayed changes in the fast-type myofiber composition in the GL, with a more pronounced alteration in bulbar-onset ALS donors. Our results align with the worse prognosis and subclinical changes in eye movement function previously observed in bulbar-onset ALS patients and suggest that the myofibers in the OL might be more resistant to the pathological process in ALS.}, } @article {pmid37200320, year = {2023}, author = {Keighley, R and Sanders, T}, title = {Prevention of modern slavery within sex work: Study protocol of a mixed methods project looking at the role of adult services websites.}, journal = {PloS one}, volume = {18}, number = {5}, pages = {e0285829}, pmid = {37200320}, issn = {1932-6203}, mesh = {Adult ; Humans ; *Enslavement/prevention & control ; *Sex Work ; Internet ; *Human Trafficking/prevention & control ; }, abstract = {BACKGROUND: The core challenge this study addressed is that Adult Services Websites (ASWs) are an extensive and pervasive feature of the digital world that facilitate the advertising, negotiation and purchase of sexual services yet are also considered to be harbourers of sexual exploitation, modern slavery and human trafficking (MSHT) Giommoni L. et al. 2021, Milivojevic S. et al. 2020, Sanders, T., et al. 2018. Whilst awareness of cases of internet facilitated MSHT has entered the public and policy domain, little is known about the role and responsibilities of ASWs in this domain. Collaboratively with our partners, the findings from this study will first contribute to understanding how ASWs facilitate exploitation and second how they can become part of the prevention mechanisms and reporters of crimes.

METHODS: We present the design of our mixed methods study, underpinned by a peer Action Learning Set (ALS) approach. By working closely with ten survivors of sexual exploitation from 7 countries, the peer group have informed the study through participation in the advisory group, instrument design, implementation, analysis and dissemination. A training and support needs analysis prior to engagement in the research project ascertained what skills people would bring, what they would need for further personal and career development and if there were any additional requirements to enable participation. We provided capacity building through a bespoke training package over the project's lifetime.

DISCUSSION: Conducting a peer-researcher ALS project informs the research topic by both empowering survivors of sexual exploitation, whilst engaging with their expertise and lived experience to shape the methods and focus. The summative evaluation of our methods informs wider peer research methodologies, little utilised in the field of MSHT research. Thus, this research produces evidence which acknowledges survivors as experts with value towards social science research.}, } @article {pmid37200613, year = {2023}, author = {Xu, R and Zhu, H and Zhang, H and Ju, J and Li, Q and Fu, S}, title = {Six Sets of Aromatic Polyketides Differing in Size and Shape Derive from a Single Biosynthetic Gene Cluster.}, journal = {Journal of natural products}, volume = {86}, number = {6}, pages = {1512-1519}, doi = {10.1021/acs.jnatprod.3c00202}, pmid = {37200613}, issn = {1520-6025}, mesh = {*Carbon ; Gene Silencing ; Multigene Family ; Polyketide Synthases/genetics ; *Polyketides ; Skeleton ; Anthracenes ; Carboxylic Acids ; }, abstract = {One new aromatic polyketide, prealnumycin B (1), and four known aromatic polyketides, K1115A (2), 1,6-dihydroxy-8-propylanthraquinone (DHPA, 3), phaeochromycin B (4), and (R)-7-acetyl-3,6-dihydroxy-8-propyl-3,4dihydronaphthalen-1(2H)-one (5), were isolated from the marine-derived Streptomyces sundarbansensis SCSIO NS01; these compounds represent four sets of aromatic polyketides differing in size and shape. A type II polyketide synthase (PKS) cluster, als, was identified by complete genome sequencing and was shown, by in vivo gene inactivation experiments in the wild-type (WT) NS01 strain and heterologous expression experiments, to encode the biosynthesis of compounds 1-5. Moreover, heterologous expression of the als cluster afforded three additional aromatic polyketides representing two different carbon skeletons, the new phaeochromycin L (6) and two known aromatic polyketides, phaeochromycins D (7) and E (8). These findings expand our knowledge of type II PKS machineries and their versatility in generating structurally diverse aromatic polyketides and highlight the power of type II PKSs in accessing new polyketides via ectopic expression in heterologous hosts.}, } @article {pmid37200846, year = {2023}, author = {Sheng, L and Madika, A and Lau, MSH and Zhang, Y and Minton, NP}, title = {Metabolic engineering for the production of acetoin and 2,3-butanediol at elevated temperature in Parageobacillus thermoglucosidasius NCIMB 11955.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {11}, number = {}, pages = {1191079}, pmid = {37200846}, issn = {2296-4185}, abstract = {The current climate crisis has emphasised the need to achieve global net-zero by 2050, with countries being urged to set considerable emission reduction targets by 2030. Exploitation of a fermentative process that uses a thermophilic chassis can represent a way to manufacture chemicals and fuels through more environmentally friendly routes with a net reduction in greenhouse gas emissions. In this study, the industrially relevant thermophile Parageobacillus thermoglucosidasius NCIMB 11955 was engineered to produce 3-hydroxybutanone (acetoin) and 2,3-butanediol (2,3-BDO), organic compounds with commercial applications. Using heterologous acetolactate synthase (ALS) and acetolactate decarboxylase (ALD) enzymes, a functional 2,3-BDO biosynthetic pathway was constructed. The formation of by-products was minimized by the deletion of competing pathways surrounding the pyruvate node. Redox imbalance was addressed through autonomous overexpression of the butanediol dehydrogenase and by investigating appropriate aeration levels. Through this, we were able to produce 2,3-BDO as the predominant fermentation metabolite, with up to 6.6 g/L 2,3-BDO (0.33 g/g glucose) representing 66% of the theoretical maximum at 50°C. In addition, the identification and subsequent deletion of a previously unreported thermophilic acetoin degradation gene (acoB1) resulted in enhanced acetoin production under aerobic conditions, producing 7.6 g/L (0.38 g/g glucose) representing 78% of the theoretical maximum. Furthermore, through the generation of a ΔacoB1 mutant and by testing the effect of glucose concentration on 2,3-BDO production, we were able to produce 15.6 g/L of 2,3-BDO in media supplemented with 5% glucose, the highest titre of 2,3-BDO produced in Parageobacillus and Geobacillus species to date.}, } @article {pmid37201334, year = {2023}, author = {Diaz-Torres, S and He, W and Thorp, J and Seddighi, S and Mullany, S and , and Hammond, CJ and Hysi, PG and Pasquale, LR and Khawaja, AP and Hewitt, AW and Craig, JE and Mackey, DA and Wiggs, JL and van Duijn, C and Lupton, MK and Ong, JS and MacGregor, S and Gharahkhani, P}, title = {Disentangling the genetic overlap and causal relationships between primary open-angle glaucoma, brain morphology and four major neurodegenerative disorders.}, journal = {EBioMedicine}, volume = {92}, number = {}, pages = {104615}, pmid = {37201334}, issn = {2352-3964}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/T040912/1/MRC_/Medical Research Council/United Kingdom ; T32 GM136577/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Glaucoma, Open-Angle/genetics/pathology ; Genome-Wide Association Study ; *Parkinson Disease/pathology ; *Alzheimer Disease/genetics/pathology ; *Neurodegenerative Diseases/genetics/pathology ; *Glaucoma/genetics ; Brain/diagnostic imaging/pathology ; Nerve Degeneration/genetics/pathology ; }, abstract = {BACKGROUND: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by progressive degeneration of the optic nerve that leads to irreversible visual impairment. Multiple epidemiological studies suggest an association between POAG and major neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease). However, the nature of the overlap between neurodegenerative disorders, brain morphology and glaucoma remains inconclusive.

METHOD: In this study, we performed a comprehensive assessment of the genetic and causal relationship between POAG and neurodegenerative disorders, leveraging genome-wide association data from studies of magnetic resonance imaging of the brain, POAG, and four major neurodegenerative disorders.

FINDINGS: This study found a genetic overlap and causal relationship between POAG and its related phenotypes (i.e., intraocular pressure and optic nerve morphology traits) and brain morphology in 19 regions. We also identified 11 loci with a significant local genetic correlation and a high probability of sharing the same causal variant between neurodegenerative disorders and POAG or its related phenotypes. Of interest, a region on chromosome 17 corresponding to MAPT, a well-known risk locus for Alzheimer's and Parkinson's disease, was shared between POAG, optic nerve degeneration traits, and Alzheimer's and Parkinson's diseases. Despite these local genetic overlaps, we did not identify strong evidence of a causal association between these neurodegenerative disorders and glaucoma.

INTERPRETATION: Our findings indicate a distinctive and likely independent neurodegenerative process for POAG involving several brain regions although several POAG or optic nerve degeneration risk loci are shared with neurodegenerative disorders, consistent with a pleiotropic effect rather than a causal relationship between these traits.

FUNDING: PG was supported by an NHMRC Investigator Grant (#1173390), SM by an NHMRC Senior Research Fellowship and an NHMRC Program Grant (APP1150144), DM by an NHMRC Fellowship, LP is funded by the NEIEY015473 and EY032559 grants, SS is supported by an NIH-Oxford Cambridge Fellowship and NIH T32 grant (GM136577), APK is supported by a UK Research and Innovation Future Leaders Fellowship, an Alcon Research Institute Young Investigator Award and a Lister Institute for Preventive Medicine Award.}, } @article {pmid37202167, year = {2023}, author = {Chiò, A and Moglia, C and Canosa, A and Manera, U and Grassano, M and Vasta, R and Palumbo, F and Gallone, S and Brunetti, M and Barberis, M and De Marchi, F and Dalgard, C and Chia, R and Mora, G and Iazzolino, B and Peotta, L and Traynor, BJ and Corrado, L and D'Alfonso, S and Mazzini, L and Calvo, A}, title = {Association of Copresence of Pathogenic Variants Related to Amyotrophic Lateral Sclerosis and Prognosis.}, journal = {Neurology}, volume = {101}, number = {1}, pages = {e83-e93}, pmid = {37202167}, issn = {1526-632X}, support = {Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; C9orf72 Protein/genetics ; Alleles ; Phenotype ; Prognosis ; }, abstract = {BACKGROUND AND OBJECTIVES: Despite recent advances, it is not clear whether the various genes/genetic variants related to amyotrophic lateral sclerosis (ALS) interact in modifying patients' phenotype. The aim of this study was to determine whether the copresence of genetic variants related to ALS has interactive effects on the course of the disease.

METHODS: The study population includes 1,245 patients with ALS identified through the Piemonte Register for ALS between 2007 and 2016 and not carrying superoxide dismutase type 1, TAR DNA binding protein, and fused in sarcoma pathogenic variants. Controls were 766 Italian participants age-matched, sex-matched, and geographically matched to cases. We considered Unc-13 homolog A (UNC13A) (rs12608932), calmodulin binding transcription activator 1 (CAMTA1) (rs2412208), solute carrier family 11 member 2 (SLC11A2) (rs407135), and zinc finger protein 512B (ZNF512B) (rs2275294) variants, as well as ataxin-2 (ATXN2) polyQ intermediate repeats (≥31) and chromosome 9 open reading frame 72 (C9orf72) GGGGCC intronic expansions (≥30).

RESULTS: The median survival time of the whole cohort was 2.67 years (interquartile range [IQR] 1.67-5.25). In univariate analysis, only C9orf72 (2.51 years, IQR 1.74-3.82; p = 0.016), ATXN2 (1.82 years, IQR 1.08-2.33; p < 0.001), and UNC13A [C/C] (2.3 years, IQR 1.3-3.9; p < 0.001) significantly reduced survival. In Cox multivariable analysis, CAMTA1 also emerged to be independently related to survival (hazard ratio 1.13, 95% CI 1.001-1.30, p = 0.048). The copresence of 2 detrimental alleles/expansions was correlated with shorter survival. In particular, the median survival of patients with CAMTA1 [G/G+G/T] and UNC13A [C/C] alleles was 1.67 years (1.16-3.08) compared with 2.75 years (1.67-5.26) of the patients not carrying these variants (p < 0.001); the survival of patients with CAMTA1 [G/G+G/T] alleles and ATXN2 [≥31] intermediate polyQ repeats was 1.75 years (0.84-2.18) (p < 0.001); the survival of patients with ATXN2 [≥31] polyQ repeats and UNC13A [C/C] allele was 1.33 years (0.84-1.75) (p < 0.001); the survival of patients with C9ORF72 [≥30] and UNC13A [C/C] allele was 1.66 years (1.41-2.16). Each pair of detrimental alleles/expansions was associated to specific clinical phenotypes.

DISCUSSION: We showed that gene variants acting as modifiers of ALS survival or phenotype can act on their own or in unison. Overall, 54% of patients carried at least 1 detrimental common variant or repeat expansion, emphasizing the clinical impact of our findings. In addition, the identification of the interactive effects of modifier genes represents a crucial clue for explaining ALS clinical heterogeneity and should be considered when designing and interpreting clinical trials results.}, } @article {pmid37203062, year = {2023}, author = {Chen, J and Zhang, Y and Huang, Y and Ng, TK and Huang, C}, title = {Relatively anterior lens position in primary angle-closure glaucoma eyes with long axial length.}, journal = {Indian journal of ophthalmology}, volume = {71}, number = {5}, pages = {1941-1947}, pmid = {37203062}, issn = {1998-3689}, mesh = {Humans ; *Hyperopia/diagnosis ; *Glaucoma, Angle-Closure/diagnosis ; Refraction, Ocular ; *Lens, Crystalline ; *Myopia/complications/diagnosis ; Cornea ; Biometry ; Anterior Chamber/diagnostic imaging ; }, abstract = {PURPOSE: To evaluate the refractive status and ocular biometric parameters in primary angle-closure glaucoma (PACG) eyes with different axial lengths (ALs).

METHODS: In total, 742 Chinese PACG subjects with complete ophthalmic examinations were enrolled. The refractive status was categorized as myopia (spherical equivalent [SE] ≤-0.5 D), emmetropia (-0.5 D < SE < +0.5 D), and hyperopia (SE ≥+0.5 D), whereas the AL was divided into short (AL <22.5 mm), regular (22.5 ≤ AL <23.5 mm), and long (AL ≥23.5 mm). The refractive status and ocular biometric parameters were compared among different AL groups.

RESULTS: The mean AL of the PACG eyes was 22.53 ± 0.84 mm (range: 19.68-25.57 mm). The refractive status was significantly different among different AL groups (P < 0.001). Also, 92.6% of hyperopic PACG eyes showed AL <23.5 mm, and 19.0% of myopic PACG eyes showed AL ≥23.5 mm. The SE showed significant differences among different AL groups only in the hyperopic subjects (P = 0.012). The AL was significantly longer in myopic eyes (P < 0.001). The PACG eyes with longer AL exhibited lower keratometry, longer central anterior chamber depth and corneal diameter, and lens position and relative lens position closer to the anterior (P < 0.001).

CONCLUSION: Axial hyperopia was common in PACG eyes, and axial myopia was not uncommon. Relatively anterior lens position could explain the occurrence of PACG in the eyes with long AL.}, } @article {pmid37203321, year = {2023}, author = {Martin, M and Wongwattanakul, M and Khemtonglang, N and Kiatchoosakun, P and Heraud, P and Jearanaikoon, P and Wood, BR}, title = {Identification of Glucose-6 Phosphate Dehydrogenase Deficient Patients Using Attenuated Total Reflection Fourier Transform Infrared Spectroscopy Using Partial Least Squares Discriminant Analysis in Aqueous Blood Samples.}, journal = {Applied spectroscopy}, volume = {77}, number = {5}, pages = {513-520}, doi = {10.1177/00037028231170851}, pmid = {37203321}, issn = {1943-3530}, mesh = {Humans ; Discriminant Analysis ; *Glucosephosphate Dehydrogenase Deficiency/diagnosis ; Least-Squares Analysis ; *Malaria/diagnosis ; Phosphates ; Spectroscopy, Fourier Transform Infrared/methods ; Thailand ; }, abstract = {Glucose-6 phosphate dehydrogenase (G6PD) deficiency is an X-linked blood disease that affects 400 million people globally and is especially prevalent in malaria-endemic regions. A significant portion of carriers are asymptomatic and undiagnosed posing complications in the eradication of malaria as it restricts the types of drugs used for malaria treatment. A simple and accurate diagnosis of the deficiency is vital in the eradication of malaria. In this study, we investigate the potential of attenuated total reflection Fourier transform infrared spectroscopy (ATR FT-IR) as a diagnostic technique for G6PD deficiency. Venous blood samples were collected in lithium heparin anticoagulant tubes from G6PD partial and fully deficient volunteers, n = 17, and normal volunteers, n = 59, in Khon Kaen, Thailand. Spectra of aqueous and dry samples were acquired of whole blood, plasma, and red blood cells, and modeled using partial least squares discriminant analysis (PLS-DA). PLS-DA modeling resulted in a sensitivity of 0.800 and specificity of 0.800 correctly classifying fully deficient participants as well as a majority of partially deficient females who are often misdiagnosed as normal by current screening methods. The viability of utilizing aqueous samples has always been hindered by the variability of hydration in the sample, but by employing multicurve curve resolution-alternating least squares to subtract water from each sample we are able to produce high-quality spectra with minimized water contributions. The approach shows proof of principle that ATR FT-IR combined with multivariate data analysis could become a frontline screening tool for G6PD deficiency by improving tailored drug treatments and ultimately saving lives.}, } @article {pmid37203937, year = {2023}, author = {Rai, K and Rai, N and Chhantel Thapa, MK and Shrestha, R and Singh, S and Thapa, M}, title = {Bulbar Onset Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {JNMA; journal of the Nepal Medical Association}, volume = {61}, number = {259}, pages = {271-273}, pmid = {37203937}, issn = {1815-672X}, mesh = {Male ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/therapy ; Edaravone ; *Respiratory Insufficiency/etiology ; Prognosis ; Tracheostomy/adverse effects ; }, abstract = {UNLABELLED: Amyotrophic lateral sclerosis is a rare, progressive, incurable neurodegenerative disorder that affects motor neurons leading to progressive muscle weakness, disability, and eventually death. A 45-year-old male, initially presented with hoarseness, flickering of tongue, and intermittent aspirations. In course of three years, patient developed motor aphasia, frequent aspirations and an inability to hold his neck. Patient was diagnosed with a bulbar onset type of amyotrophic lateral sclerosis on the basis of neurodegenerative features with normal radiographic imaging. For the prevention of recurrent aspiration pneumonia, he was managed with a percutaneous endoscopic gastrostomy tube. As he started developing respiratory failure tracheostomy was performed and kept on a continuous bi-level positive airway pressure ventilator, in the meantime, two courses of injection Edaravone were given. Early evaluation, diagnosis and management of the condition is a cornerstone for better prognosis of disease and survival.

KEYWORDS: amyotrophic lateral sclerosis; aspiration pneumonia; case reports; edaravone.}, } @article {pmid37204564, year = {2023}, author = {Chang, C and Zhao, Q and Liu, P and Yuan, Y and Liu, Z and Hu, Y and Li, W and Hou, X and Tang, X and Jiao, B and Guo, J and Shen, L and Jiang, H and Tang, B and Zhang, X and Wang, J}, title = {ALS-plus related clinical and genetic study from China.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {10}, pages = {3557-3566}, pmid = {37204564}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/diagnosis ; Syndrome ; Delayed Diagnosis ; *Cognitive Dysfunction/epidemiology/genetics ; *Cognition Disorders/diagnosis ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. An increasing number of researchers have found extra motor features in ALS, which are also called ALS-plus syndromes. Besides, a great majority of ALS patients also have cognitive impairment. However, clinical surveys of the frequency and genetic background of ALS-plus syndromes are rare, especially in China.

METHODS: We investigated a large cohort of 1015 patients with ALS, classifying them into six groups according to different extramotor symptoms and documenting their clinical manifestations. Meanwhile, based on their cognitive function, we divided these patients into two groups and compared demographic characteristics. Genetic screening for rare damage variants (RDVs) was also performed on 847 patients.

RESULTS: As a result, 16.75% of patients were identified with ALS-plus syndrome, and 49.5% of patients suffered cognitive impairment. ALS-plus group had lower ALSFRS-R scores, longer diagnostic delay time, and longer survival times, compared to ALS pure group. RDVs occurred less frequently in ALS-plus patients than in ALS-pure patients (P = 0.042) but showed no difference between ALS-cognitive impairment patients and ALS-cognitive normal patients. Besides, ALS-cognitive impairment group tends to harbour more ALS-plus symptoms than ALS-cognitive normal group (P = 0.001).

CONCLUSION: In summary, ALS-plus patients in China are not rare and show multiple differences from ALS-pure patients in clinical and genetic features. Besides, ALS-cognitive impairment group tends to harbour more ALS-plus syndrome than ALS-cognitive normal group. Our observations correspond with the theory that ALS involves several diseases with different mechanisms and provide clinical validation.}, } @article {pmid37204819, year = {2023}, author = {Aouti, S and Padavattan, S and Padmanabhan, B}, title = {Structure-based discovery of an antipsychotic drug, paliperidone, as a modulator of human superoxide dismutase 1: a potential therapeutic target in amyotrophic lateral sclerosis.}, journal = {Acta crystallographica. Section D, Structural biology}, volume = {79}, number = {Pt 6}, pages = {531-544}, doi = {10.1107/S2059798323003649}, pmid = {37204819}, issn = {2059-7983}, support = {ICMR/001/101/2015/00787//Indian Council of Medical Research/ ; SR/FST/LS-I/2017(C)//Department of Science and Technology, Ministry of Science and Technology, India/ ; }, mesh = {Humans ; Superoxide Dismutase-1/chemistry/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Paliperidone Palmitate/therapeutic use ; *Antipsychotic Agents/therapeutic use ; Ligands ; Mutation ; }, abstract = {Aggregates of the antioxidant superoxide dismutase 1 (SOD1) are one of the major contributors to the pathogenesis of amyotrophic lateral sclerosis (ALS). Mutations in SOD1 lead to an unstable structure and aggregation that perturbs the balance of reactive oxygen species in cells. Oxidation damage to the solvent-exposed Trp32 also causes aggregation of SOD1. Here, the FDA-approved antipsychotic drug paliperidone is identified to interact with Trp32 of SOD1 by structure-based pharmacophore mapping and crystallographic studies. Paliperidone is used for the treatment of schizophrenia. The crystal structure of the complex with SOD1, refined to 2.1 Å resolution, revealed that the ligand binds to the SOD1 β-barrel in the β-strand 2 and 3 regions, which are known to scaffold SOD1 fibrillation. The drug also makes substantial π-π interaction with Trp32. Microscale thermophoresis studies confirm significant binding affinity of the compound, suggesting that the ligand can inhibit or prevent tryptophan oxidation. Thus, the antipsychotic drug paliperidone or a derivative may avert SOD1 aggregation and can be used as a lead for ALS drug development.}, } @article {pmid37205225, year = {2023}, author = {Cannon, AE and Zürrer, WE and Zejlon, C and Kulcsar, Z and Lewandowski, S and Piehl, F and Granberg, T and Ineichen, BV}, title = {Neuroimaging findings in preclinical amyotrophic lateral sclerosis models-How well do they mimic the clinical phenotype? A systematic review.}, journal = {Frontiers in veterinary science}, volume = {10}, number = {}, pages = {1135282}, pmid = {37205225}, issn = {2297-1769}, abstract = {BACKGROUND AND OBJECTIVES: Animal models for motor neuron diseases (MND) such as amyotrophic lateral sclerosis (ALS) are commonly used in preclinical research. However, it is insufficiently understood how much findings from these model systems can be translated to humans. Thus, we aimed at systematically assessing the translational value of MND animal models to probe their external validity with regards to magnetic resonance imaging (MRI) features.

METHODS: In a comprehensive literature search in PubMed and Embase, we retrieved 201 unique publications of which 34 were deemed eligible for qualitative synthesis including risk of bias assessment.

RESULTS: ALS animal models can indeed present with human ALS neuroimaging features: Similar to the human paradigm, (regional) brain and spinal cord atrophy as well as signal changes in motor systems are commonly observed in ALS animal models. Blood-brain barrier breakdown seems to be more specific to ALS models, at least in the imaging domain. It is noteworthy that the G93A-SOD1 model, mimicking a rare clinical genotype, was the most frequently used ALS proxy.

CONCLUSIONS: Our systematic review provides high-grade evidence that preclinical ALS models indeed show imaging features highly reminiscent of human ALS assigning them a high external validity in this domain. This opposes the high attrition of drugs during bench-to-bedside translation and thus raises concerns that phenotypic reproducibility does not necessarily render an animal model appropriate for drug development. These findings emphasize a careful application of these model systems for ALS therapy development thereby benefiting refinement of animal experiments.

https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022373146.}, } @article {pmid37205335, year = {2023}, author = {Dominov, JA and Madigan, LA and Whitt, JP and Rademacher, KL and Webster, KM and Zhang, H and Banno, H and Tang, S and Zhang, Y and Wightman, N and Shychuck, EM and Page, J and Weiss, A and Kelly, K and Kucukural, A and Brodsky, MH and Jaworski, A and Fallon, JR and Lipscombe, D and Brown, RH}, title = {Up-regulation of cholesterol synthesis pathways and limited neurodegeneration in a knock-in Sod1 mutant mouse model of ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.05.05.539444}, pmid = {37205335}, issn = {2692-8205}, support = {UL1 TR001453/TR/NCATS NIH HHS/United States ; }, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder affecting brain and spinal cord motor neurons. Mutations in the copper/zinc superoxide dismutase gene (SOD1) are associated with ∼20% of inherited and 1-2% of sporadic ALS cases. Much has been learned from mice expressing transgenic copies of mutant SOD1, which typically involve high-level transgene expression, thereby differing from ALS patients expressing one mutant gene copy. To generate a model that more closely represents patient gene expression, we created a knock-in point mutation (G85R, a human ALS-causing mutation) in the endogenous mouse Sod1 gene, leading to mutant SOD1 [G85R] protein expression. Heterozygous Sod1 [G85R] mutant mice resemble wild type, whereas homozygous mutants have reduced body weight and lifespan, a mild neurodegenerative phenotype, and express very low mutant SOD1 protein levels with no detectable SOD1 activity. Homozygous mutants exhibit partial neuromuscular junction denervation at 3-4 months of age. Spinal cord motor neuron transcriptome analyses of homozygous Sod1 [G85R] mice revealed up-regulation of cholesterol synthesis pathway genes compared to wild type. Transcriptome and phenotypic features of these mice are similar to Sod1 knock-out mice, suggesting the Sod1 [G85R] phenotype is largely driven by loss of SOD1 function. By contrast, cholesterol synthesis genes are down-regulated in severely affected human TgSOD1 [G93A] transgenic mice at 4 months. Our analyses implicate dysregulation of cholesterol or related lipid pathway genes in ALS pathogenesis. The Sod1 [G85R] knock-in mouse is a useful ALS model to examine the importance of SOD1 activity in control of cholesterol homeostasis and motor neuron survival.

SIGNIFICANCE STATEMENT: Amyotrophic lateral sclerosis is a devastating disease involving the progressive loss of motor neurons and motor function for which there is currently no cure. Understanding biological mechanisms leading to motor neuron death is critical for developing new treatments. Using a new knock-in mutant mouse model carrying a Sod1 mutation that causes ALS in patients, and in the mouse, causes a limited neurodegenerative phenotype similar to Sod1 loss-of-function, we show that cholesterol synthesis pathway genes are up-regulated in mutant motor neurons, whereas the same genes are down-regulated in transgenic SOD1 mice with a severe phenotype. Our data implicate dysregulation of cholesterol or other related lipid genes in ALS pathogenesis and provide new insights that could contribute to strategies for disease intervention.}, } @article {pmid37205372, year = {2023}, author = {Krupp, S and Tam, O and Hammell, MG and Dubnau, J}, title = {TDP-43 pathology in Drosophila induces glial-cell type specific toxicity that can be ameliorated by knock-down of SF2/SRSF1.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37205372}, issn = {2692-8205}, support = {R01 AG078788/AG/NIA NIH HHS/United States ; RF1 AG057338/AG/NIA NIH HHS/United States ; RF1 AG076493/AG/NIA NIH HHS/United States ; }, abstract = {Accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43) is seen in both neurons and glia in a range of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). Disease progression involves non-cell autonomous interactions among multiple cell types, including neurons, microglia and astrocytes. We investigated the effects in Drosophila of inducible, glial cell type-specific TDP-43 overexpression, a model that causes TDP-43 protein pathology including loss of nuclear TDP-43 and accumulation of cytoplasmic inclusions. We report that TDP-43 pathology in Drosophila is sufficient to cause progressive loss of each of the 5 glial sub-types. But the effects on organismal survival were most pronounced when TDP-43 pathology was induced in the perineural glia (PNG) or astrocytes. In the case of PNG, this effect is not attributable to loss of the glial population, because ablation of these glia by expression of pro-apoptotic reaper expression has relatively little impact on survival. To uncover underlying mechanisms, we used cell-type-specific nuclear RNA sequencing to characterize the transcriptional changes induced by pathological TDP-43 expression. We identified numerous glial cell-type specific transcriptional changes. Notably, SF2/SRSF1 levels were found to be decreased in both PNG and in astrocytes. We found that further knockdown of SF2/SRSF1 in either PNG or astrocytes lessens the detrimental effects of TDP-43 pathology on lifespan, but extends survival of the glial cells. Thus TDP-43 pathology in astrocytes or PNG causes systemic effects that shorten lifespan and SF2/SRSF1 knockdown rescues the loss of these glia, and also reduces their systemic toxicity to the organism.}, } @article {pmid37205390, year = {2023}, author = {Shellikeri, S and Cho, S and Ash, S and Gonzalez-Recober, C and McMillan, CT and Elman, L and Quinn, C and Amado, DA and Baer, M and Irwin, DJ and Massimo, L and Olm, C and Liberman, M and Grossman, M and Nevler, N}, title = {Digital markers of motor speech impairments in natural speech of patients with ALS-FTD spectrum disorders.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.04.29.23289308}, pmid = {37205390}, support = {K08 NS114106/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Patients with ALS-FTD spectrum disorders (ALS-FTSD) have mixed motor and cognitive impairments and require valid and quantitative assessment tools to support diagnosis and tracking of bulbar motor disease. This study aimed to validate a novel automated digital speech tool that analyzes vowel acoustics from natural, connected speech as a marker for impaired articulation due to bulbar motor disease in ALS-FTSD.

METHODS: We used an automatic algorithm called Forced Alignment Vowel Extraction (FAVE) to detect spoken vowels and extract vowel acoustics from 1 minute audio-recorded picture descriptions. Using automated acoustic analysis scripts, we derived two articulatory-acoustic measures: vowel space area (VSA, in Bark [2]) which represents tongue range-of-motion (size), and average second formant slope of vowel trajectories (F2 slope) which represents tongue movement speed. We compared vowel measures between ALS with and without clinically-evident bulbar motor disease (ALS+bulbar vs. ALS-bulbar), behavioral variant frontotemporal dementia (bvFTD) without a motor syndrome, and healthy controls (HC). We correlated impaired vowel measures with bulbar disease severity, estimated by clinical bulbar scores and perceived listener effort, and with MRI cortical thickness of the orobuccal part of the primary motor cortex innervating the tongue (oralPMC). We also tested correlations with respiratory capacity and cognitive impairment.

RESULTS: Participants were 45 ALS+bulbar (30 males, mean age=61±11), 22 ALS-nonbulbar (11 males, age=62±10), 22 bvFTD (13 males, age=63±7), and 34 HC (14 males, age=69±8). ALS+bulbar had smaller VSA and shallower average F2 slopes than ALS-bulbar (VSA: | d |=0.86, p =0.0088; F2 slope: | d |=0.98, p =0.0054), bvFTD (VSA: | d |=0.67, p =0.043; F2 slope: | d |=1.4, p <0.001), and HC (VSA: | d |=0.73, p =0.024; F2 slope: | d |=1.0, p <0.001). Vowel measures declined with worsening bulbar clinical scores (VSA: R=0.33, p =0.033; F2 slope: R=0.25, p =0.048), and smaller VSA was associated with greater listener effort (R=-0.43, p =0.041). Shallower F2 slopes were related to cortical thinning in oralPMC (R=0.50, p =0.03). Neither vowel measure was associated with respiratory nor cognitive test scores.

CONCLUSIONS: Vowel measures extracted with automatic processing from natural speech are sensitive to bulbar motor disease in ALS-FTD and are robust to cognitive impairment.}, } @article {pmid37207075, year = {2023}, author = {Sato, K and Takayama, KI and Inoue, S}, title = {Role of piRNA biogenesis and its neuronal function in the development of neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1157818}, pmid = {37207075}, issn = {1663-4365}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are caused by neuronal loss and dysfunction. Despite remarkable improvements in our understanding of these pathogeneses, serious worldwide problems with significant public health burdens are remained. Therefore, new efficient diagnostic and therapeutic strategies are urgently required. PIWI-interacting RNAs (piRNAs) are a major class of small non-coding RNAs that silence gene expression through transcriptional and post-transcriptional processes. Recent studies have demonstrated that piRNAs, originally found in the germ line, are also produced in non-gonadal somatic cells, including neurons, and further revealed the emerging roles of piRNAs, including their roles in neurodevelopment, aging, and neurodegenerative diseases. In this review, we aimed to summarize the current knowledge regarding the piRNA roles in the pathophysiology of neurodegenerative diseases. In this context, we first reviewed on recent updates on neuronal piRNA functions, including biogenesis, axon regeneration, behavior, and memory formation, in humans and mice. We also discuss the aberrant expression and dysregulation of neuronal piRNAs in neurodegenerative diseases, such as AD, PD, and ALS. Moreover, we review pioneering preclinical studies on piRNAs as biomarkers and therapeutic targets. Elucidation of the mechanisms underlying piRNA biogenesis and their functions in the brain would provide new perspectives for the clinical diagnosis and treatment of AD and various neurodegenerative diseases.}, } @article {pmid37207434, year = {2023}, author = {Hirai, S and Sakuma, A and Kunii, Y and Shimbo, H and Hino, M and Izumi, R and Nagaoka, A and Yabe, H and Kojima, R and Seki, E and Arai, N and Komori, T and Okado, H}, title = {Disease specific brain capillary angiopathy in schizophrenia, bipolar disorder, and Alzheimer's disease.}, journal = {Journal of psychiatric research}, volume = {163}, number = {}, pages = {74-79}, doi = {10.1016/j.jpsychires.2023.04.011}, pmid = {37207434}, issn = {1879-1379}, mesh = {Humans ; *Bipolar Disorder/complications ; *Schizophrenia/complications ; *Alzheimer Disease/complications ; Capillaries ; *Amyotrophic Lateral Sclerosis ; Endothelial Cells ; Brain ; *Brain Injuries, Traumatic ; }, abstract = {Schizophrenia (SZ) and bipolar disorder (BD), which are both psychiatric disorders, share some common clinical evidence. We recently discovered that brain capillary angiopathy is another common feature of these psychiatric disorders using fibrin accumulation in vascular endothelial cells as an indicator. This study aimed to characterize the similarities and differences in cerebral capillary injuries in various brain diseases to provide new diagnostic methods for SZ and BD and to develop new therapeutic strategies. We evaluated whether discrepancies exist in the degree of vascular damage among SZ and BD and other brain disorders (amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD)) using postmortem brains. Our results demonstrate that fibrin was strongly accumulated in the capillaries of the grey matter (GM) of brains of patients with SZ and AD and in the capillaries of the white matter (WM) in those of patients with SZ, BD, and AD when compared with control subjects without any psychiatric or neurological disease history. However, ALS and PD brains did not present a significant increase in the amount of accumulated fibrin, either in the capillaries of WM or GM. Furthermore, significant leakage of fibrin into the brain parenchyma, indicating a vascular physical disruption, was observed in the brains of patients with AD but not in the brains of other patients compared with control subjects. In conclusion, our work reveals that Fibrin-accumulation in the brain capillaries are observed in psychiatric disorders, such as SZ, BD, and AD. Furthermore, fibrin-accumulating, nonbreaking type angiopathy is characteristic of SZ and BD, even though there are regional differences between these diseases.}, } @article {pmid37208601, year = {2023}, author = {Hatano, Y and Ishihara, T and Onodera, O}, title = {Accuracy of a machine learning method based on structural and locational information from AlphaFold2 for predicting the pathogenicity of TARDBP and FUS gene variants in ALS.}, journal = {BMC bioinformatics}, volume = {24}, number = {1}, pages = {206}, pmid = {37208601}, issn = {1471-2105}, support = {21K07272//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Superoxide Dismutase-1/genetics ; Virulence ; Mutation ; Mutation, Missense ; Autophagy-Related Proteins/genetics ; Adaptor Proteins, Signal Transducing/genetics ; DNA Helicases/genetics ; RNA Helicases ; Multifunctional Enzymes/genetics ; RNA-Binding Protein FUS/genetics ; }, abstract = {BACKGROUND: In the sporadic form of amyotrophic lateral sclerosis (ALS), the pathogenicity of rare variants in the causative genes characterizing the familial form remains largely unknown. To predict the pathogenicity of such variants, in silico analysis is commonly used. In some ALS causative genes, the pathogenic variants are concentrated in specific regions, and the resulting alterations in protein structure are thought to significantly affect pathogenicity. However, existing methods have not taken this issue into account. To address this, we have developed a technique termed MOVA (method for evaluating the pathogenicity of missense variants using AlphaFold2), which applies positional information for structural variants predicted by AlphaFold2. Here we examined the utility of MOVA for analysis of several causative genes of ALS.

METHODS: We analyzed variants of 12 ALS-related genes (TARDBP, FUS, SETX, TBK1, OPTN, SOD1, VCP, SQSTM1, ANG, UBQLN2, DCTN1, and CCNF) and classified them as pathogenic or neutral. For each gene, the features of the variants, consisting of their positions in the 3D structure predicted by AlphaFold2, pLDDT score, and BLOSUM62 were trained into a random forest and evaluated by the stratified fivefold cross validation method. We compared how accurately MOVA predicted mutant pathogenicity with other in silico prediction methods and evaluated the prediction accuracy at TARDBP and FUS hotspots. We also examined which of the MOVA features had the greatest impact on pathogenicity discrimination.

RESULTS: MOVA yielded useful results (AUC ≥ 0.70) for TARDBP, FUS, SOD1, VCP, and UBQLN2 of 12 ALS causative genes. In addition, when comparing the prediction accuracy with other in silico prediction methods, MOVA obtained the best results among those compared for TARDBP, VCP, UBQLN2, and CCNF. MOVA demonstrated superior predictive accuracy for the pathogenicity of mutations at hotspots of TARDBP and FUS. Moreover, higher accuracy was achieved by combining MOVA with REVEL or CADD. Among the features of MOVA, the x, y, and z coordinates performed the best and were highly correlated with MOVA.

CONCLUSIONS: MOVA is useful for predicting the virulence of rare variants in which they are concentrated at specific structural sites, and for use in combination with other prediction methods.}, } @article {pmid37208745, year = {2023}, author = {Zhao, MH and Song, Y and Liu, JL and Li, J and Wang, Y and Hua, YJ and Wu, Q}, title = {Investigation of ocular biometry in 4- to 9-year-old Chinese children.}, journal = {BMC ophthalmology}, volume = {23}, number = {1}, pages = {225}, pmid = {37208745}, issn = {1471-2415}, mesh = {Child ; Humans ; Female ; Male ; Child, Preschool ; Cross-Sectional Studies ; *East Asian People ; *Cornea/anatomy & histology ; Biometry/methods ; Refraction, Ocular ; Anterior Chamber/anatomy & histology ; Axial Length, Eye ; }, abstract = {PURPOSE: To investigate the distribution and changes in ocular biometry in 4-to to 9-year-old Chinese children and to compare the differences between age and genders in these parameters.

METHODS: This was a school-based cross-sectional study. A total of 1,528 Chinese children, aged 4-9 years, from one primary school and 12 kindergartens, were included in the study. Axial length, corneal curvature, anterior chamber depth, and corneal diameter were measured for each child.

RESULTS: AL and anterior chamber depth gradually increased with age in both genders. No significant changes in corneal curvature or corneal diameter were detected at different ages in either genders group. The mean ALs of males and females were 22.94 ± 0.80 mm and 22.38 ± 0.79 mm, respectively. The mean corneal curvatures of males and females were 43.05 ± 1.37 D and 43.75 ± 1.48 D, respectively. The mean anterior chamber depth of males and females were 3.47 ± 0.24 mm and 3.38 ± 0.25 mm, respectively. The mean corneal diameter of males and females were 12.08 ± 0.43 mm and 11.94 ± 0.44 mm, respectively. Females had consistently shorter ALs, shorter anterior chamber depth, smaller corneal diameter, and steeper corneal curvatures than males at any age.

CONCLUSIONS: Boys had larger dimensions than girls for all ocular parameters except corneal curvature (flatter). Boys and girls showed similar trends for all parameters. Axial length and anterior chamber depth increased from 4 to 9 years of age, whereas corneal diameter and curvature did not change with age in either genders.}, } @article {pmid37208847, year = {2023}, author = {Milella, G and Zoccolella, S and Urso, D and Nigro, S and Tamburrino, L and Gnoni, V and Filardi, M and Logroscino, G}, title = {Different patterns of spreading direction and motor neurons involvement in a cohort of limb-onset amyotrophic lateral sclerosis patients from Southern Italy: Potential implication on disease course or progression?.}, journal = {Brain and behavior}, volume = {13}, number = {6}, pages = {e2899}, pmid = {37208847}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Motor Neurons ; Upper Extremity ; Lower Extremity ; Italy/epidemiology ; Disease Progression ; }, abstract = {BACKGROUND: Currently, there is a lack of knowledge concerning where the pathological process starts and how the neurodegeneration spreads during the course of amyotrophic lateral sclerosis (ALS).

AIMS: This study aims to evaluate the spreading direction of the disease and the corresponding clinical characteristics in a cohort of patients with limb-onset ALS.

PATIENTS AND METHODS: Consecutive incident ALS patients referring to an ALS tertiary center from Southern Italy, between 2015 and 2021, were recruited in the study. According to the initial directions of spread, patients were dichotomized into horizontal spreading pattern (HSP) or vertical spreading pattern (VSP) groups.

RESULTS: Among 137 newly diagnosed ALS, 87 presented a spinal onset. Ten patients with pure LMN were not included in the study. All cases reported a clear spread direction. The frequency of HSP and VSP spreading was similar overall (47 vs. 30). The prevalence of HSP was higher (74% vs. 50%) in patients with upper limb-onset (UL-ALS), compared to patients with lower limb-onset (LL-ALS; p < .05). Conversely, the occurrence of VSP spread was threefold higher in patients with LL-ALS, compared to UL-ALS (p < .05). Patients with VSP showed a wider upper motor neuron impairment, whereas the involvement of LMN resulted greater in patients with HSP. Patients with HSP exhibited a greater drop of ALSFRS-r sub-score in the region of onset, while VSP showed a slighter but more diffuse reduction of ASLFRS-r subscore in more body districts beyond the site of onset. Patients with VSP were also characterized by a higher median progression rate and an earlier median bulbar involvement, compared to HSP.

CONCLUSIONS: Our findings suggested investigating the spreading direction of ALS among patients with spinal onset, to better delineate the clinical profiles of patients with ALS, and predict an earlier impairment of bulbar muscle and a more rapid progression of the disease.}, } @article {pmid37208946, year = {2023}, author = {Huang, NX and Qin, W and Lin, JH and Dong, QY and Chen, HJ}, title = {Corticospinal fibers with different origins impair in amyotrophic lateral sclerosis: A neurite orientation dispersion and density imaging study.}, journal = {CNS neuroscience & therapeutics}, volume = {29}, number = {11}, pages = {3406-3415}, pmid = {37208946}, issn = {1755-5949}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Neurites ; Diffusion Tensor Imaging/methods ; Diffusion Magnetic Resonance Imaging ; *Motor Cortex/diagnostic imaging ; *White Matter ; }, abstract = {AIMS: To investigate microstructural impairments of corticospinal tracts (CSTs) with different origins in amyotrophic lateral sclerosis (ALS) using neurite orientation dispersion and density imaging (NODDI).

METHODS: Diffusion-weighted imaging data acquired from 39 patients with ALS and 50 controls were used to estimate NODDI and diffusion tensor imaging (DTI) models. Fine maps of CST subfibers originating from the primary motor area (M1), premotor cortex, primary sensory area, and supplementary motor area (SMA) were segmented. NODDI metrics (neurite density index [NDI] and orientation dispersion index [ODI]) and DTI metrics (fractional anisotropy [FA] and mean/axial/radial diffusivity [MD/AD/RD]) were computed.

RESULTS: The patients with ALS showed microstructural impairments (reflected by NDI, ODI, and FA reductions and MD, AD, and RD increases) in CST subfibers, especially in M1 fibers, which correlated with disease severity. Compared with other diffusion metrics, NDI yielded a higher effect size and detected the greatest extent of CST subfibers damage. Logistic regression analyses based on NDI in M1 subfiber yielded the best diagnostic performance compared with other subfibers and the whole CST.

CONCLUSIONS: Microstructural impairment of CST subfibers (especially those originating from M1) is the key feature of ALS. The combination of NODDI and CST subfibers analysis may improve diagnosing performance for ALS.}, } @article {pmid37209312, year = {2023}, author = {Strîmbu, VF and Næsset, E and Ørka, HO and Liski, J and Petersson, H and Gobakken, T}, title = {Estimating biomass and soil carbon change at the level of forest stands using repeated forest surveys assisted by airborne laser scanner data.}, journal = {Carbon balance and management}, volume = {18}, number = {1}, pages = {10}, pmid = {37209312}, issn = {1750-0680}, support = {276388//Norges Forskningsråd/ ; }, abstract = {BACKGROUND: Under the growing pressure to implement mitigation actions, the focus of forest management is shifting from a traditional resource centric view to incorporate more forest ecosystem services objectives such as carbon sequestration. Estimating the above-ground biomass in forests using airborne laser scanning (ALS) is now an operational practice in Northern Europe and is being adopted in many parts of the world. In the boreal forests, however, most of the carbon (85%) is stored in the soil organic (SO) matter. While this very important carbon pool is "invisible" to ALS, it is closely connected and feeds from the growing forest stocks. We propose an integrated methodology to estimate the changes in forest carbon pools at the level of forest stands by combining field measurements and ALS data.

RESULTS: ALS-based models of dominant height, mean diameter, and biomass were fitted using the field observations and were used to predict mean tree biophysical properties across the entire study area (50 km[2]) which was in turn used to estimate the biomass carbon stocks and the litter production that feeds into the soil. For the soil carbon pool estimation, we used the Yasso15 model. The methodology was based on (1) approximating the initial soil carbon stocks using simulations; (2) predicting the annual litter input based on the predicted growing stocks in each cell; (3) predicting the soil carbon dynamics of the annual litter using the Yasso15 soil carbon model. The estimated total carbon change (standard errors in parenthesis) for the entire area was 0.741 (0.14) Mg ha[-1] yr[-1]. The biomass carbon change was 0.405 (0.13) Mg ha[-1] yr[-1], the litter carbon change (e.g., deadwood and leaves) was 0.346 (0.027) Mg ha[-1] yr[-1], and the change in SO carbon was - 0.01 (0.003) Mg ha[-1] yr[-1].

CONCLUSIONS: Our results show that ALS data can be used indirectly through a chain of models to estimate soil carbon changes in addition to changes in biomass at the primary level of forest management, namely the forest stands. Having control of the errors contributed by each model, the stand-level uncertainty can be estimated under a model-based inferential approach.}, } @article {pmid37209406, year = {2023}, author = {Gwathmey, KG and Corcia, P and McDermott, CJ and Genge, A and Sennfält, S and de Carvalho, M and Ingre, C}, title = {Diagnostic delay in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {30}, number = {9}, pages = {2595-2601}, doi = {10.1111/ene.15874}, pmid = {37209406}, issn = {1468-1331}, support = {/DH_/Department of Health/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Delayed Diagnosis ; *Neurodegenerative Diseases ; Retrospective Studies ; *General Practitioners ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease, and the time from symptom onset to diagnosis remains long. With the advent of disease-modifying treatments, the need to identify and diagnose ALS in a timely fashion has never been greater.

METHODS: We reviewed the literature to define the severity of ALS diagnostic delay, the various factors that contribute to this delay (including patient and physician factors), and the role that site of symptom onset plays in a patient's diagnostic journey.

RESULTS: Diagnostic delay is influenced by general practitioners' lack of recognition of ALS due to disease rarity and heterogenous presentations. As a result, patients are referred to non-neurologists, have unnecessary diagnostic testing, and may ultimately be misdiagnosed. Patient factors include their illness behavior-which impacts diagnostic delay-and their site of symptom onset. Limb-onset patients have the greatest diagnostic delay because they are frequently misdiagnosed with degenerative spine disease or peripheral neuropathy.

CONCLUSION: Prompt ALS diagnosis results in more effective clinical management, with earlier access to disease-modifying therapies, multidisciplinary care, and, if desired, clinical trial involvement. Due to lack of commercially available ALS biomarkers, alternative strategies to identify and triage patients who likely have ALS must be employed. Several diagnostic tools have been developed to encourage general practitioners to consider ALS and make an urgent referral to ALS specialists, bypassing unnecessary referrals to non-neurologists and unnecessary diagnostic workup.}, } @article {pmid37210484, year = {2023}, author = {Jandhyala, R}, title = {Neutral theory: applicability and neutrality of clinical study endpoints where a disease-specific instrument is available.}, journal = {BMC medical research methodology}, volume = {23}, number = {1}, pages = {121}, pmid = {37210484}, issn = {1471-2288}, mesh = {Humans ; *Rare Diseases/diagnosis/epidemiology ; *Endpoint Determination ; Clinical Studies as Topic ; }, abstract = {BACKGROUND: There is a pressing need to improve the accuracy of rare disease clinical study endpoints. Neutral theory, first described here, can be used to assess the accuracy of endpoints and improve their selection in rare disease clinical studies, reducing the risk of patient misclassification.

METHODS: Neutral theory was used to assess the accuracy of rare disease clinical study endpoints and the resulting probability of false positive and false negative classifications at different disease prevalence rates. Search strings were extracted from the Orphanet Register of Rare Diseases using a proprietary algorithm to conduct a systematic review of studies published until January 2021. Overall, 11 rare diseases with one disease-specific disease severity scale (133 studies) and 12 rare diseases with more than one disease-specific disease severity scale (483 studies) were included. All indicators from clinical studies were extracted, and Neutral theory was used to calculate their match to disease-specific disease severity scales, which were used as surrogates for the disease phenotype. For those with more than one disease-severity scale, endpoints were compared with the first disease-specific disease severity scale and a composite of all later scales. A Neutrality score of > 1.50 was considered acceptable.

RESULTS: Around half the clinical studies for half the rare diseases with one disease-specific disease severity score (palmoplantar psoriasis, achalasia, systemic lupus erythematosus, systemic sclerosis and Fournier's gangrene) met the threshold for an acceptable match to the disease phenotype, one rare disease (Guillain-Barré syndrome) had one study with an acceptable match, and four diseases (Behcet's syndrome, Creutzfeldt-Jakob disease, atypical hemolytic uremic syndrome and Prader-Willi syndrome) had no studies. Clinical study endpoints in almost half the rare diseases with more than one disease-specific DSS (acromegaly, amyotrophic lateral sclerosis, cystic fibrosis, Fabry disease and juvenile rheumatoid arthritis) were a better match to the composite, while endpoints in the remaining rare diseases (Charcot Marie Tooth disease, Gaucher disease Type I, Huntington's disease, Sjogren's syndrome and Tourette syndrome) were a worse match. Misclassifications varied with increasing disease prevalence.

CONCLUSIONS: Neutral theory confirmed that disease-severity measurement needs improvement in rare disease clinical studies, especially for some diseases, and suggested that the potential for accuracy increases as the body of knowledge on a disease increases. Using Neutral theory to benchmark disease-severity measurement in rare disease clinical studies may reduce the risk of misclassification, ensuring that recruitment and treatment effect assessment optimise medicine adoption and benefit patients.}, } @article {pmid37210918, year = {2023}, author = {Perumal, AB and Nambiar, RB and Luo, X and Su, Z and Li, X and He, Y}, title = {Exploring dynamic changes of fungal cellular components during nanoemulsion treatment by multivariate microRaman imaging.}, journal = {Talanta}, volume = {261}, number = {}, pages = {124666}, doi = {10.1016/j.talanta.2023.124666}, pmid = {37210918}, issn = {1873-3573}, mesh = {*Antifungal Agents/pharmacology/chemistry ; *Oils, Volatile/chemistry ; Diagnostic Imaging ; Tea ; Least-Squares Analysis ; }, abstract = {Recently, essential oils (EO) have gained a lot of interest for use as antifungal agent in food and agricultural industry and extensive research is ongoing to understand their mode of action. However, the exact mechanism is not yet elucidated. Here, we integrated spectral unmixing and Raman microspectroscopy imaging to unveil the antifungal mechanism of green tea EO based nanoemulsion (NE) against Magnaporthe oryzae. The dramatic change in protein, lipid, adenine, and guanine bands indicate that NE has a significant impact on the protein, lipid and metabolic processes of purine. The results also demonstrated that the NE treatment caused damage to fungal hyphae by inducing a physical injury leading to cell wall damage and loss of integrity. Our study shows that MCR-ALS (Multivariate Curve Resolution-Alternating Least Squares) and N-FINDR (N-finder algorithm) Raman imaging could serve as a suitable complementary package to the traditional methods, for revealing the antifungal mechanism of action of EO/NE.}, } @article {pmid37212068, year = {2023}, author = {Sarasate, M and González, N and Córdoba-Izquierdo, A and Prats, E and Gonzalez-Moro, JMR and Martí, S and Lujan, M and Calle, M and Antón, A and Povedano, M and Farrero, E}, title = {Impact of Early Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis: A multicenter Randomized Controlled Trial.}, journal = {Journal of neuromuscular diseases}, volume = {10}, number = {4}, pages = {627-637}, pmid = {37212068}, issn = {2214-3602}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Noninvasive Ventilation/methods ; Respiration, Artificial ; Vital Capacity ; Patient Compliance ; }, abstract = {BACKGROUND AND OBJECTIVE: Forced vital capacity (FVC) less than 50% of predicted is one of the main parameters used for Non-Invasive Ventilation (NIV) initiation in Amyotrophic Lateral Sclerosis (ALS). Recent studies suggest that higher values of FVC could be considered as a threshold. The aim of this study is to evaluate whether early use of NIV improves the prognosis of ALS patients compared with standard initiation.

METHODS: This is a randomized, parallel, multicenter, open-label, controlled clinical trial, with recruitment at the ALS outpatient multidisciplinary units of six Spanish hospitals. Patients were included when their FVC reached the 75% threshold and were randomized by computer, stratifying by center in an allocation ratio of 1:1 to Early NIV (FVC below 75%) or Standard NIV (FVC below 50%) initiation. The primary outcome was time to death or tracheostomy.Trial registration number ClinicalTrials.gov: NCT01641965.

RESULTS: Between May 2012 and June 2014, 42 patients were randomized to two groups, 20 to Early NIV and 22 to Standard NIV initiation. We found differences in survival in favor of the intervention group: an incidence of mortality (2.68 [1.87-5.50] vs. 3.33 [1.34-4.80] person-months) and a median survival (25.2 vs. 19.4 months), although without reaching statistical significance (p = 0.267).

CONCLUSIONS: This trial did not reach the primary endpoint of survival; nevertheless, it is the first Randomized Controlled Trial (RCT) to demonstrate the benefits of early NIV in slowing the decline of respiratory muscle strength and reducing adverse events. Although not all the results reached statistical significance, all the analyzed data favor early NIV. In addition, this study demonstrates good tolerance and compliance with early NIV without quality of sleep impairment. These data reinforce the early respiratory evaluation of ALS patients and NIV initiation with an FVC of around 75%.}, } @article {pmid37213040, year = {2023}, author = {Pereira, Â and Tkachenko, N and Fortuna, AM and Alonso, I and Cardoso, M and Da Silva, JD}, title = {An SPG7 mutation as a novel cause of monogenic progressive muscular atrophy.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {9}, pages = {3303-3305}, pmid = {37213040}, issn = {1590-3478}, mesh = {Female ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Muscular Atrophy, Spinal/genetics ; Mutation/genetics ; Genetic Testing ; *Spastic Paraplegia, Hereditary/genetics ; ATPases Associated with Diverse Cellular Activities/genetics ; Metalloendopeptidases/genetics ; }, abstract = {BACKGROUND: Progressive muscular atrophy (PMA) is a rare adult-onset neurological disease that is characterized by isolated lower motor neuron degeneration. While it is still disputable whether PMA is a subtype of amyotrophic lateral sclerosis (ALS) or an isolated disorder, it is well-established as a clinically defined entity. About 5% of PMA cases are monogenic, and the implicated genes largely overlap with those causing monogenic ALS.

CASE DESCRIPTION: Here we describe a 68-year-old female patient with progressive and asymmetric upper-limb weakness throughout an 18-month period, with muscle atrophy, dysphagia and slurring of speech. The lower limbs were unaffected, and there was no sign of upper motor neuron dysfunction. Comprehensive genetic testing for single nucleotide and copy-number variants revealed a pathogenic monoallelic variant c.1529C>T, p.(Ala510Val) in the SPG7 gene.

DISCUSSION: Pathogenic biallelic SPG7 variants have been originally associated with hereditary spastic paraplegia, but other phenotypes are nowadays known to be linked to these variants, such as ALS. However, there is no report of this (or any) other SPG7 variant in association with PMA, whether it progressed to ALS or not. In conclusion, we present the first known case of PMA associated with a monoallelic SPG7 mutation.}, } @article {pmid37213901, year = {2023}, author = {Klose, V and Jesse, S and Lewerenz, J and Kassubek, J and Dorst, J and Tumani, H and Ludolph, AC and Roselli, F}, title = {CSF oligoclonal IgG bands are not associated with ALS progression and prognosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1170360}, pmid = {37213901}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is characterized by progressive motoneuron degeneration through cell autonomous and non-cell autonomous mechanisms; and the involvement of the innate and adaptive immune system has been hypothesized based on human and murine model data. We have explored if B-cell activation and IgG responses, as detected by IgG Oligoclonal bands (OCB) in serum and cerebrospinal fluid, were associated with ALS or with a subgroup of patients with distinct clinical features.

METHODS: IgG OCB were determined in patients affected by ALS (n=457), Alzheimer Disease (n=516), Mild Cognitive Impairment (n=91), Tension-type Headache (n=152) and idiopathic Facial Palsy (n=94). For ALS patients, clinico-demographic and survival data were prospectively collected in the Register Schabia.

RESULTS: The prevalence of IgG OCB is comparable in ALS and the four neurological cohorts. When the OCB pattern was considered (highlighting either intrathecal or systemic B-cells activation), no effect of OCB pattern on clinic-demographic parameters and overall. ALS patients with intrathecal IgG synthesis (type 2 and 3) were more likely to display infectious, inflammatory or systemic autoimmune conditions.

DISCUSSION: These data suggest that OCB are not related to ALS pathophysiology but rather are a finding possibly indicative a coincidental infectious or inflammatory comorbidity that merits further investigation.}, } @article {pmid37214058, year = {2023}, author = {Abu-Abaa, M and Mousa, A and Chadalawada, S and Abdulsahib, A}, title = {Bulbar Onset Amyotrophic Lateral Sclerosis in a COVID-19 Patient: A Case Report.}, journal = {Cureus}, volume = {15}, number = {4}, pages = {e37814}, pmid = {37214058}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with a largely unknown etiology. In this case, we are presenting an 84-year-old male patient who was admitted for acute hypoxemic respiratory failure secondary to coronavirus disease 2019 (COVID-19) infection. He was neurologically intact. His infection improved and oxygen requirement was gradually weaned off allowing for discharge. However, he was admitted again a month later with progressive dysphagia and aspiration that were confirmed on videofluoroscopic study. He was also found to have mild dysarthria, bulbar muscle weakness, bilateral lower motor neuron facial nerve palsy, diffuse hyporeflexia on four extremities with intact sensory function. Diagnosis of ALS was suspected after extensive workup was pursued and ruled out nutritional, structural, autoimmune, infectious and inflammatory disorders. This case is only the third reported case in medical literature to suggest COVID-19 infection as a triggering/accelerating factor of ALS progression.}, } @article {pmid37214502, year = {2023}, author = {Dratch, L and Mu, W and Wood, EM and Morgan, B and Massimo, L and Clyburn, C and Bardakjian, T and Grossman, M and Irwin, DJ and Cousins, KAQ}, title = {Evaluation of an educational conference for persons affected by hereditary frontotemporal degeneration and amyotrophic lateral sclerosis.}, journal = {PEC innovation}, volume = {2}, number = {}, pages = {100108}, pmid = {37214502}, issn = {2772-6282}, abstract = {OBJECTIVE: There are limited studies exploring the support and education needs of individuals at-risk for or diagnosed with hereditary frontotemporal degeneration (FTD) and/or amyotrophic lateral sclerosis (ALS). This study evaluated a novel conference for this population to assess conference efficacy, probe how participants assessed relevant resources, and identify outstanding needs of persons at-risk/diagnosed.

METHODS: We implemented a post-conference electronic survey that probed participants' satisfaction, prior experience with resources, and unmet needs. Along with multiple-choice, free-text items were included to gather qualitative context.

RESULTS: Survey completion rate was 31% (115/376 attendees who were emailed the survey). There was positive interest in pursuing genetic counseling among eligible responders: 61% indicated they planned to seek genetic counseling because of the conference, which was significantly more than those who were undecided (21%) or did not plan to seek genetic counseling (18%). Qualitative data demonstrated need for additional education, support, and research opportunities.

CONCLUSION: Conference reactions indicate this is a valued resource. Results indicated the importance of raising awareness about existing resources, and the need for further resource development, especially for at-risk communities.

INNOVATION: While most resources are developed for caregivers' needs, this unique program targets at-risk individuals and unites ALS and FTD communities.}, } @article {pmid37214833, year = {2024}, author = {Stains, EL and Kennalley, AL and Tian, M and Boehnke, KF and Kraus, CK and Piper, BJ}, title = {United States' qualifying conditions compared to evidence of the 2017 National Academy of Sciences Report.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.05.01.23289286}, pmid = {37214833}, abstract = {OBJECTIVE: To compare the 2017 National Academies of Sciences, Engineering, and Medicine (NAS) report to state medical cannabis (MC) laws defining approved qualifying conditions (QC) from 2017 to 2024 and to determine if there exist gaps in evidence-based decision making.

METHODS: The 2017 NAS report assessed therapeutic evidence for over twenty medical conditions treated with MC. We identified the QCs of 38 states (including Washington, D.C.) where MC was legal in 2024. We also identified the QCs that these states used in 2017. QCs were then categorized based on NAS-established level of evidence: substantial/conclusive evidence of effectiveness, moderate evidence of effectiveness, limited evidence of effectiveness, limited evidence of ineffectiveness, and no/insufficient evidence to support or refute effectiveness. This study was completed between January 31, 2023 through May 20, 2024.

RESULTS: Most states listed at least one QC with substantial evidence-80.0% of states in 2017 and 97.0% in 2024. However, in 2024 only 8.3% of the QCs on states' QC lists met the standard of substantial evidence. Of the 20 most popular QCs in the country in 2017 and 2024, one only (chronic pain) was categorized by the NAS as having substantial evidence for effectiveness. However, seven (ALS, Alzheimer's disease, epilepsy, glaucoma, Huntington's disease, Parkinson's disease, spastic spinal cord damage) were rated as either ineffective or insufficient evidence.

CONCLUSION: Most QCs lack evidence for use based on the 2017 NAS report. Many states recommend QCs with little evidence, such as amyotrophic lateral sclerosis (ALS), or even those for which MC is ineffective, like depression. There have been insufficient updates to QCs since the NAS report. These findings highlight a disparity between state-level MC recommendations and the evidence to support them.}, } @article {pmid37215009, year = {2023}, author = {Urban, MW and Charsar, BA and Heinsinger, NM and Markandaiah, SS and Sprimont, L and Zhou, W and Brown, EV and Henderson, NT and Thomas, SJ and Ghosh, B and Cain, RE and Trotti, D and Pasinelli, P and Wright, MC and Dalva, MB and Lepore, AC}, title = {EphrinB2 knockdown in cervical spinal cord preserves diaphragm innervation in a mutant SOD1 mouse model of ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.05.10.538887}, pmid = {37215009}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss. Importantly, non-neuronal cell types such as astrocytes also play significant roles in disease pathogenesis. However, mechanisms of astrocyte contribution to ALS remain incompletely understood. Astrocyte involvement suggests that transcellular signaling may play a role in disease. We examined contribution of transmembrane signaling molecule ephrinB2 to ALS pathogenesis, in particular its role in driving motor neuron damage by spinal cord astrocytes. In symptomatic SOD1-G93A mice (a well-established ALS model), ephrinB2 expression was dramatically increased in ventral horn astrocytes. Reducing ephrinB2 in the cervical spinal cord ventral horn via viral-mediated shRNA delivery reduced motor neuron loss and preserved respiratory function by maintaining phrenic motor neuron innervation of diaphragm. EphrinB2 expression was also elevated in human ALS spinal cord. These findings implicate ephrinB2 upregulation as both a transcellular signaling mechanism in mutant SOD1-associated ALS and a promising therapeutic target.}, } @article {pmid37216594, year = {2023}, author = {Taghavi, A and Baisden, JT and Childs-Disney, JL and Yildirim, I and Disney, MD}, title = {Conformational dynamics of RNA G4C2 and G2C4 repeat expansions causing ALS/FTD using NMR and molecular dynamics studies.}, journal = {Nucleic acids research}, volume = {51}, number = {11}, pages = {5325-5340}, pmid = {37216594}, issn = {1362-4962}, support = {R15 GM146199/GM/NIGMS NIH HHS/United States ; R35 NS116846/NS/NINDS NIH HHS/United States ; S10 OD021550/OD/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; DNA Repeat Expansion ; *Frontotemporal Dementia/genetics ; Magnetic Resonance Spectroscopy ; Molecular Dynamics Simulation ; RNA ; }, abstract = {G4C2 and G2C4 repeat expansions in chromosome 9 open reading frame 72 (C9orf72) are the most common cause of genetically defined amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), or c9ALS/FTD. The gene is bidirectionally transcribed, producing G4C2 repeats [r(G4C2)exp] and G2C4 repeats [r(G2C4)exp]. The c9ALS/FTD repeat expansions are highly structured, and structural studies showed that r(G4C2)exp predominantly folds into a hairpin with a periodic array of 1 × 1 G/G internal loops and a G-quadruplex. A small molecule probe revealed that r(G4C2)exp also adopts a hairpin structure with 2 × 2 GG/GG internal loops. We studied the conformational dynamics adopted by 2 × 2 GG/GG loops using temperature replica exchange molecular dynamics (T-REMD) and further characterized the structure and underlying dynamics using traditional 2D NMR techniques. These studies showed that the loop's closing base pairs influence both structure and dynamics, particularly the configuration adopted around the glycosidic bond. Interestingly, r(G2C4) repeats, which fold into an array of 2 × 2 CC/CC internal loops, are not as dynamic. Collectively, these studies emphasize the unique sensitivity of r(G4C2)exp to small changes in stacking interactions, which is not observed in r(G2C4)exp, providing important considerations for further principles in structure-based drug design.}, } @article {pmid37217723, year = {2023}, author = {Nguyen, TT and Nguyen-Thi, PT and Nguyen, THA and Ho, TT and Tran, NM and Van Vo, T and Van Vo, G}, title = {Recent Advancements in Nanomaterials: A Promising Way to Manage Neurodegenerative Disorders.}, journal = {Molecular diagnosis & therapy}, volume = {27}, number = {4}, pages = {457-473}, pmid = {37217723}, issn = {1179-2000}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/drug therapy ; *Alzheimer Disease/diagnosis/drug therapy ; Brain/metabolism ; Blood-Brain Barrier/metabolism ; *Nanoparticles/therapeutic use/chemistry ; }, abstract = {Neurodegenerative diseases (NDs) such as dementia, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis are some of the most prevalent disorders currently afflicting healthcare systems. Many of these diseases share similar pathological hallmarks, including elevated oxidative stress, mitochondrial dysfunction, protein misfolding, excitotoxicity, and neuroinflammation, all of which contribute to the deterioration of the nervous system's structure and function. The development of diagnostic and therapeutic materials in the monitoring and treatment of these diseases remains challenging. One of the biggest challenges facing therapeutic and diagnostic materials is the blood-brain barrier (BBB). The BBB is a multifunctional membrane possessing a plethora of biochemical, cellular, and immunological features that ensure brain homeostasis by preventing the entry and accumulation of unwanted compounds. With regards to neurodegenerative diseases, the recent application of tailored nanomaterials (nanocarriers and nanoparticles) has led to advances in diagnostics and therapeutics. In this review, we provide an overview of commonly used nanoparticles and their applications in NDs, which may offer new therapeutic strategies for the prevention and treatment of neurodegenerative diseases.}, } @article {pmid37218694, year = {2023}, author = {Li, F and Chen, Y and Tang, Y and Liu, X and Wei, G}, title = {Dissecting the Effect of ALS Mutation G335D on the Early Aggregation of the TDP-43 Amyloidogenic Core Peptide: Helix-to-β-Sheet Transition and Conformational Shift.}, journal = {Journal of chemical information and modeling}, volume = {63}, number = {11}, pages = {3579-3590}, doi = {10.1021/acs.jcim.3c00513}, pmid = {37218694}, issn = {1549-960X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA-Binding Proteins/chemistry ; Mutation ; Peptides/genetics ; Protein Conformation, beta-Strand ; }, abstract = {The aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) into fibrillary deposits is associated with amyotrophic lateral sclerosis (ALS). The 311-360 fragment of TDP-43 (TDP-43311-360), the amyloidogenic core region, can spontaneously aggregate into fibrils, and the ALS-associated mutation G335D has an enhanced effect on TDP-43311-360 fibrillization. However, the molecular mechanism underlying G335D-enhanced aggregation at atomic level remains largely unknown. By utilizing all-atom molecular dynamics (MD) and replica exchange with solute tempering 2 (REST2) simulations, we investigated influences of G335D on the dimerization (the first step of aggregation) and conformational ensemble of the TDP-43311-360 peptide. Our simulations show that G335D mutation increases inter-peptide interactions, especially inter-peptide hydrogen-bonding interactions in which the mutant site has a relatively large contribution, and enhances the dimerization of TDP-43311-360 peptides. The α-helix regions in the NMR-resolved conformation of the TDP-43311-360 monomer (321-330 and 335-343) play an essential role in the formation of the dimer. G335D mutation induces helix unfolding and promotes α-to-β conversion. G335D mutation alters the conformational distribution of TDP-43311-360 dimers and causes population shift from helix-rich to β-sheet-rich conformations, which facilitates the fibrillization of the TDP-43311-360 peptide. Our MD and REST2 simulation results suggest that the 321-330 region is of paramount importance to α-to-β transition and could be the initiation site for TDP-43311-360 fibrillization. Our work reveals the mechanism underlying the enhanced aggregation propensity of the G335D TDP-43311-360 peptide, which provides atomistic insights into the G335D mutation-caused pathogenicity of TDP-43 protein.}, } @article {pmid37219417, year = {2023}, author = {Sales de Campos, P and Olsen, WL and Wymer, JP and Smith, BK}, title = {Respiratory therapies for Amyotrophic Lateral Sclerosis: A state of the art review.}, journal = {Chronic respiratory disease}, volume = {20}, number = {}, pages = {14799731231175915}, pmid = {37219417}, issn = {1479-9731}, support = {T32 HL134621/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Respiration, Artificial ; Cough ; Hypoxia ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition noteworthy for upper and lower motor neuron death. Involvement of respiratory motor neuron pools leads to progressive pathology. These impairments include decreases in neural activation and muscle coordination, progressive airway obstruction, weakened airway defenses, restrictive lung disease, increased risk of pulmonary infections, and weakness and atrophy of respiratory muscles. These neural, airway, pulmonary, and neuromuscular changes deteriorate integrated respiratory-related functions including sleep, cough, swallowing, and breathing. Ultimately, respiratory complications account for a large portion of morbidity and mortality in ALS. This state-of-the-art review highlights applications of respiratory therapies for ALS, including lung volume recruitment, mechanical insufflation-exsufflation, non-invasive ventilation, and respiratory strength training. Therapeutic acute intermittent hypoxia, an emerging therapeutic tool for inducing respiratory plasticity will also be introduced. A focus on emerging evidence and future work underscores the common goal to continue to improve survival for patients living with ALS.}, } @article {pmid37219864, year = {2023}, author = {Grogan, J and Walsh, S and Haulman, A and Yazgi, H and Geronimo, A and Mamarabadi, M and Simmons, Z}, title = {Rapid Conversion to a Completely Virtual Multidisciplinary ALS Clinic in Response to the COVID-19 Pandemic: Implications for Future Care Delivery.}, journal = {Journal of clinical neuromuscular disease}, volume = {24}, number = {4}, pages = {207-213}, pmid = {37219864}, issn = {1537-1611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *COVID-19 ; Pandemics ; }, abstract = {OBJECTIVES: The goals of this study were to assess the feasibility of maintaining multidisciplinary remote care, patient preferences, and outcomes of this transition because of COVID-19.

METHODS: From March 18, 2020 to June 3, 2020, 127 patients with amyotrophic lateral sclerosis (ALS) who were scheduled to be seen in our ALS clinic were contacted and scheduled according their preference for a telemedicine visit, telephone visit, or postponement until the next available in-person visit. Age, time from disease onset, ALS Functional Rating Scale-Revised, patient choices, and outcomes were recorded.

RESULTS: Patient visit preferences were 69% telemedicine, 21% telephone, and 10% postpone for a later in-clinic visit. Patients with higher ALS Functional Rating Scale-Revised were more likely to choose the next in-person opening (P = 0.04). Age and time from disease onset were not related to visit type preference. There were 118 virtual encounters, of which 91 (77%) began as telemedicine and 27 (23%) as telephone visits. Most telemedicine visits were conducted successfully, but 10 were converted to a telephone visit. The clinic maintained 88.6% of patient volume compared with the prior year, during which most visits were in-person.

CONCLUSIONS: Telemedicine care using synchronous videoconferencing is preferable and feasible for most patients on short notice, with telephone as back-up. Clinic volumes can be maintained. These findings support the conversion of a multidisciplinary ALS clinic to 1 with exclusively virtual visits when future events again disrupt in-person care.}, } @article {pmid37219865, year = {2023}, author = {Li, X and Koeberl, DD and Lutz, MW and Bedlack, R}, title = {Clenbuterol Treatment Is Safe and Associated With Slowed Disease Progression in a Small Open-Label Trial in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical neuromuscular disease}, volume = {24}, number = {4}, pages = {214-221}, doi = {10.1097/CND.0000000000000438}, pmid = {37219865}, issn = {1537-1611}, mesh = {Humans ; Female ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis ; *Clenbuterol ; Hand Strength ; Riluzole ; Disease Progression ; }, abstract = {OBJECTIVE: Clenbuterol, a beta-agonist, has plausible mechanisms for treating amyotrophic lateral sclerosis (ALS). In this highly inclusive open-label trial (NCT04245709), we aimed to study the safety and efficacy of clenbuterol in patients with ALS.

METHODS: All participants received clenbuterol starting at 40 μg daily and increased to 80 μg twice daily. Outcomes included safety, tolerability, ALS Functional Rating Score (ALSFRS-R) progression, forced vital capacity (FVC) progression, and myometry. ALSFRS-R and FVC slopes measured during treatment were compared with slopes before treatment (calculated by assuming ALSFRS-R was 48 and FVC was 100% at ALS onset).

RESULTS: The 25 participants had a mean age of 59, mean disease duration of 43 months, ALSFRS-R score at enrollment 34, and FVC at enrollment 77%. Forty-eight percent were female, 68% were taking riluzole, and none were taking edaravone. Two participants experienced severe adverse events, neither related to the study. Twenty-four participants experienced adverse events, most commonly tremors/jitters, cramps/spasms, insomnia, and stiffness/spasticity. Fourteen participants withdrew early from the trial, 13 due to adverse events. Patients who withdrew early were significantly older and more likely to be male. Per-protocol and intention-to-treat analyses showed meaningfully slower ALSFRS-R and FVC progression during treatment. Hand grip dynamometry and myometry changes were highly variable between participants; most declined slowly, but some showed improvements.

CONCLUSIONS: Clenbuterol was safe but less tolerable at the doses we selected compared with an earlier Italian case series. Consistent with that series, our study suggested benefits on ALS progression. However, the latter result should be interpreted with caution as our study is limited by small sample size, large drop out, lack of randomization, and blinding and placebo controls. A larger, more traditional trial now seems warranted.}, } @article {pmid37219985, year = {2023}, author = {Lavender, V and Duarte, J and Lusted, C}, title = {Comprehensive evaluation of a cutaneous T-cell lymphoma education webinar.}, journal = {British journal of nursing (Mark Allen Publishing)}, volume = {32}, number = {10}, pages = {S10-S16}, doi = {10.12968/bjon.2023.32.10.S10}, pmid = {37219985}, issn = {2052-2819}, mesh = {Humans ; Learning ; Knowledge ; *Lymphoma, T-Cell, Cutaneous ; Referral and Consultation ; *Skin Neoplasms ; }, abstract = {BACKGROUND: Effective and timely referral, treatment and care of people with cutaneous T-cell lymphoma (CTCL) depend on clinical staff possessing highly specialised knowledge and skills. Because of the fragmented nature of the CTCL workforce, specialist education was delivered via a webinar.

AIM: The study aimed to comprehensively evaluate the webinar and test the validity of using an evaluation model for a one-off education event.

METHODS: The webinar was evaluated using Moore et al's conceptual model for evaluation of education. Data were collected using polling questions and post-webinar questionnaires and analysed using descriptive summaries and content analysis.

FINDINGS: Respondents agreed or strongly agreed that the webinar was an effective way to learn, enjoyable, relevant to their role and interesting. Learners also reported improvements in awareness, knowledge and understanding of CTCL, its referral and treatment.

CONCLUSION: Evaluating one-off education events using a conceptual model of evaluation for continuous medical education is recommended, with some adaptations to overcome limitations.}, } @article {pmid37220877, year = {2023}, author = {Farrawell, NE and Bax, M and McAlary, L and McKenna, J and Maksour, S and Do-Ha, D and Rayner, SL and Blair, IP and Chung, RS and Yerbury, JJ and Ooi, L and Saunders, DN}, title = {ALS-linked CCNF variant disrupts motor neuron ubiquitin homeostasis.}, journal = {Human molecular genetics}, volume = {32}, number = {14}, pages = {2386-2398}, pmid = {37220877}, issn = {1460-2083}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Cyclins/genetics ; Motor Neurons/metabolism ; Ubiquitin/genetics/metabolism ; Proteasome Endopeptidase Complex/genetics ; Ubiquitin-Protein Ligases/genetics/metabolism ; *Pick Disease of the Brain/metabolism ; Homeostasis/genetics ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that share pathological features, including the aberrant accumulation of ubiquitinated protein inclusions within motor neurons. Previously, we have shown that the sequestration of ubiquitin (Ub) into inclusions disrupts Ub homeostasis in cells expressing ALS-associated variants superoxide dismutase 1 (SOD1), fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43). Here, we investigated whether an ALS/FTD-linked pathogenic variant in the CCNF gene, encoding the E3 Ub ligase Cyclin F (CCNF), also perturbs Ub homeostasis. The presence of a pathogenic CCNF variant was shown to cause ubiquitin-proteasome system (UPS) dysfunction in induced pluripotent stem cell-derived motor neurons harboring the CCNF S621G mutation. The expression of the CCNFS621G variant was associated with an increased abundance of ubiquitinated proteins and significant changes in the ubiquitination of key UPS components. To further investigate the mechanisms responsible for this UPS dysfunction, we overexpressed CCNF in NSC-34 cells and found that the overexpression of both wild-type (WT) and the pathogenic variant of CCNF (CCNFS621G) altered free Ub levels. Furthermore, double mutants designed to decrease the ability of CCNF to form an active E3 Ub ligase complex significantly improved UPS function in cells expressing both CCNFWT and the CCNFS621G variant and were associated with increased levels of free monomeric Ub. Collectively, these results suggest that alterations to the ligase activity of the CCNF complex and the subsequent disruption to Ub homeostasis play an important role in the pathogenesis of CCNF-associated ALS/FTD.}, } @article {pmid37221648, year = {2023}, author = {McFarlane, R and Galvin, M and Heverin, M and Mac Domhnaill, É and Murray, D and Meldrum, D and Bede, P and Bolger, A and Hederman, L and Impey, S and Stephens, G and O'Meara, C and Wade, V and Al-Chalabi, A and Chiò, A and Corcia, P and van Damme, P and Ingre, C and McDermott, C and Povedanos, M and van den Berg, L and Hardiman, O}, title = {PRECISION ALS-an integrated pan European patient data platform for ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {389-393}, doi = {10.1080/21678421.2023.2215838}, pmid = {37221648}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; Artificial Intelligence ; Biomarkers ; Machine Learning ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative condition. Despite significant advances in pre-clinical models that enhance understanding of disease pathobiology, translation of candidate drugs to effective human therapies has been disappointing. There is increasing recognition of the need for a precision medicine approach toward drug development, as many failures in translation can be attributed in part to disease heterogeneity in humans. PRECISION-ALS is an academic industry collaboration between clinicians, Computer Scientists, Information engineers, technologists, data scientists and industry partners that will address the key clinical, computational, data science and technology associated research questions to generate a sustainable precision medicine based approach toward new drug development. Using extant and prospectively collected population based clinical data across nine European sites, PRECISION-ALS provides a General Data Protection Regulation (GDPR) compliant framework that seamlessly collects, processes and analyses research-quality multimodal and multi-sourced clinical, patient and caregiver journey, digitally acquired data through remote monitoring, imaging, neuro-electric-signaling, genomic and biomarker datasets using machine learning and artificial intelligence. PRECISION-ALS represents a first-in-kind modular transferable pan-European ICT framework for ALS that can be easily adapted to other regions that face similar precision medicine related challenges in multimodal data collection and analysis.}, }